00001|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/Aspirin|
00001|002|T|(Greater Than 100 mg); Salicylates|
00001|003|B||
00001|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00001|005|L|of severe adverse interaction.|
00001|006|B||
00001|007|A|MECHANISM OF ACTION:  Multiple processes are involved:  1) Salicylate doses|
00001|008|A|greater than 3 gm daily decrease plasma prothrombin levels. 2) Salicylates|
00001|009|A|may also displace anticoagulants from plasma protein binding sites. 3)|
00001|010|A|Aspirin is an irreversible platelet inhibitor. Salicylates impair platelet|
00001|011|A|function, resulting in prolonged bleeding time. 4) Salicylates may cause|
00001|012|A|gastrointestinal(GI) bleeding due to irritation.|
00001|013|B||
00001|014|E|CLINICAL EFFECTS:  The concurrent use of anticoagulants and salicylates|
00001|015|E|leads to blockade of two distinct coagulation pathways and may increase the|
00001|016|E|risk for bleeding.|
00001|017|B||
00001|018|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00001|019|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00001|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
00001|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00001|022|P|risk for bleeding (e.g. NSAIDs).|
00001|023|B||
00001|024|M|PATIENT MANAGEMENT:  Avoid concomitant administration of these drugs.  When|
00001|025|M|aspirin is required for cardioprotection, a low dose (less than 100 mg|
00001|026|M|daily) is recommended to decrease the risk for aspirin-induced GI bleeding.|
00001|027|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00001|028|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00001|029|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00001|030|M|patients with any symptoms.|
00001|031|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00001|032|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00001|033|M|anticoagulation in patients with active pathologic bleeding.|
00001|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00001|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00001|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00001|037|M|and/or swelling.|
00001|038|B||
00001|039|D|DISCUSSION:  This interaction has been reported between aspirin and warfarin|
00001|040|D|and between aspirin and dicumarol.  Diflunisal, sodium salicylate, and|
00001|041|D|topical methyl salicylate have been shown to interact with anticoagulants as|
00001|042|D|well.  Based on the proposed mechanisms, other salicylates would be expected|
00001|043|D|to interact with anticoagulants as well.|
00001|044|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
00001|045|D|pairs were reviewed and found 14% of drug pairs were associated with a|
00001|046|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
00001|047|D|of warfarin and diflunisal resulted in a ratio of rate ratios (RR) (95% CI)|
00001|048|D|of 3.85 (1.34-11.03); warfarin and aspirin ratio of RR 2.13 (1.72-2.64);|
00001|049|D|warfarin and dipyridamole ratio of RR 2.07 (1.65-2.6); and warfarin and|
00001|050|D|clopidogrel ratio of RR 1.69 (1.56-1.84).|
00001|051|D|   A large systematic review was performed on 72 warfarin drug-drug|
00001|052|D|interactions studies that reported on bleeding, thromboembolic events, or|
00001|053|D|death. Most studies were retrospective cohorts.  A meta-analysis of 38 of|
00001|054|D|those studies found a higher rate of clinically significant bleeding in|
00001|055|D|patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94).|
00001|056|D|Increased bleeding risk was also seen in subgroup analyses with aspirin|
00001|057|D|(OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and|
00001|058|D|aspirin plus clopidogrel or ticlopidine  (OR=2.07, 95% CI 1.33-3.21).(17)|
00001|059|B||
00001|060|R|REFERENCES:|
00001|061|B||
00001|062|R|1.Quick AJ, Clesceri L. Influence of acetylsalicylic acid and salicylamide|2
00001|063|R|  on the coagulation of blood. J Pharmacol Exp Ther 1960;128:95-8.|2
00001|064|R|2.Watson RM, Pierson RN Jr. Effect of anticoagulant therapy upon|2
00001|065|R|  aspirin-induced gastrointestinal bleeding. Circulation 1961 Sep;24:613-6.|2
00001|066|R|3.Barrow MV, Quick DT, Cunningham RW. Salicylate hypoprothrombinemia in|3
00001|067|R|  rheumatoid arthritis with liver disease. Report of two cases. Arch Intern|3
00001|068|R|  Med 1967 Nov;120(5):620-4.|3
00001|069|R|4.Weiss HJ, Aledort LM, Kochwa S. The effect of salicylates on the|2
00001|070|R|  hemostatic properties of platelets in man. J Clin Invest 1968 Sep;|2
00001|071|R|  47(9):2169-80.|2
00001|072|R|5.Udall JA. Drug interference with warfarin therapy. Clin Med 1970 Aug;|2
00001|073|R|  77:20-5.|2
00001|074|R|6.Fausa O. Salicylate-induced hypoprothrombinemia. A report of four cases.|3
00001|075|R|  Acta Med Scand 1970 Nov;188(5):403-8.|3
00001|076|R|7.Zucker MB, Peterson J. Effect of acetylsalicylic acid, other nonsteroidal|5
00001|077|R|  anti-inflammatory agents, and dipyridamole on human blood platelets. J Lab|5
00001|078|R|  Clin Med 1970 Jul;76(1):66-75.|5
00001|079|R|8.O'Reilly RA, Sahud MA, Aggeler PM. Impact of aspirin and chlorthalidone on|2
00001|080|R|  the pharmacodynamics of oral anticoagulant drugs in man. Ann N Y Acad Sci|2
00001|081|R|  1971 Jul 6;179:173-86.|2
00001|082|R|9.Dale J, Myhre E, Loew D. Bleeding during acetylsalicylic acid and|2
00001|083|R|  anticoagulant therapy in patients with reduced platelet reactivity after|2
00001|084|R|  aortic valve replacement. Am Heart J 1980 Jun;99(6):746-52.|2
00001|085|R|10.Donaldson DR, Sreeharan N, Crow MJ, Rajah SM. Assessment of the|2
00001|086|R|   interaction of warfarin with aspirin and dipyridamole. Thromb Haemost|2
00001|087|R|   1982 Feb 26;47(1):77.|2
00001|088|R|11.Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, Wallace|2
00001|089|R|   RB, Danielson GK, Orszulak TA, Piehler JM, Schaff HV. Trial of combined|2
00001|090|R|   warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve|2
00001|091|R|   replacement: danger of aspirin compared with dipyridamole. Am J Cardiol|2
00001|092|R|   1983 May 15;51(9):1537-41.|2
00001|093|R|12.Chow WH, Cheung KL, Ling HM, See T. Potentiation of warfarin|3
00001|094|R|   anticoagulation by topical methylsalicylate ointment. J R Soc Med 1989|3
00001|095|R|   Aug;82(8):501-2.|3
00001|096|R|13.Meade TW, Roderick PJ, Brennan PJ, Wilkes HC, Kelleher CC. Extra-cranial|2
00001|097|R|   bleeding and other symptoms due to low dose aspirin and low intensity|2
00001|098|R|   oral anticoagulation. Thromb Haemost 1992 Jul 6;68(1):1-6.|2
00001|099|R|14.Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral|6
00001|100|R|   anticoagulant therapy compared with oral anticoagulant therapy alone|6
00001|101|R|   among patients at risk for cardiovascular disease: a meta-analysis of|6
00001|102|R|   randomized trials. Arch Intern Med 2007 Jan 22;167(2):117-24.|6
00001|103|R|15.Grosser T Smyth E FitzGerald GA. Anti-Inflammatory, Antipyretic and|6
00001|104|R|   Analgesic Agents; Pharmacotherapy of Gout. In Bruton L, Chabner B,|6
00001|105|R|   Knollman B eds. Goodman & Gilman's The Pharmacological Basis of|6
00001|106|R|   Therapeutics. 12th ed. 2011.|6
00001|107|R|16.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
00001|108|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
00001|109|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
00001|110|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
00001|111|R|17.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00001|112|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00001|113|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
00001|114|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00002|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Selected|
00002|002|T|Anabolic Steroids|
00002|003|B||
00002|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00002|005|L|of severe adverse interaction.|
00002|006|B||
00002|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  It has been|
00002|008|A|hypothesized that the C-17 alkylated androgens may increase turnover of|
00002|009|A|clotting factors and decrease their synthesis.  Increased affinity for the|
00002|010|A|anticoagulant receptor site has also been hypothesized.  The C-17 alkylated|
00002|011|A|androgens have not been shown to alter the metabolism of anticoagulants.|
00002|012|B||
00002|013|E|CLINICAL EFFECTS:  The concurrent use of anticoagulants and anabolic|
00002|014|E|steroids may result in an increased risk for bleeding.|
00002|015|B||
00002|016|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00002|017|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00002|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
00002|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00002|020|P|risk for bleeding (e.g. NSAIDs).|
00002|021|B||
00002|022|M|PATIENT MANAGEMENT:  Patients should be closely monitored for increased|
00002|023|M|anticoagulant activity.  The dose of the anticoagulant may need to be|
00002|024|M|adjusted.|
00002|025|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00002|026|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00002|027|M|initiating, altering the dose or discontinuing either drug.|
00002|028|M|   When concurrent therapy is warranted, also monitor patients receiving|
00002|029|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
00002|030|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
00002|031|M|evaluate patients with any symptoms.  Discontinue anticoagulation in|
00002|032|M|patients with active pathologic bleeding.|
00002|033|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00002|034|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00002|035|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00002|036|M|and/or swelling.|
00002|037|B||
00002|038|D|DISCUSSION:  Danazol, methandrostenolone, methyltestosterone, oxymetholone,|
00002|039|D|and stanozolol have been shown to increase the hypoprothrombinemic actions|
00002|040|D|of warfarin.  Methyltestosterone has also been shown to increase the effects|
00002|041|D|of dicumarol.  Oxymetholone and ethylestrenol have been shown to increase|
00002|042|D|the effects of phenindione.  Limited data suggest that the|
00002|043|D|non-C-17-alkylated androgens do not affect anticoagulants.|
00002|044|B||
00002|045|R|REFERENCES:|
00002|046|B||
00002|047|R|1.Schrogie JJ, Solomon HM. The anticoagulant response to bishydroxycoumarin.|2
00002|048|R|  II. The effect of D- thyroxine, clofibrate, and norethandrolone. Clin|2
00002|049|R|  Pharmacol Ther 1967 Jan-Feb;8(1):70-7.|2
00002|050|R|2.Koch-Weser J, Sellers EM. Drug interactions with coumarin anticoagulants|6
00002|051|R|  (First of two parts). N Engl J Med 1971 Aug 26;285(9):487-98.|6
00002|052|R|3.Husted S, Andreasen F, Foged L. Increased sensitivity to phenprocoumon|3
00002|053|R|  during methyltestosterone therapy. Eur J Clin Pharmacol 1976;10:209-16.|3
00002|054|R|4.Pyorala K, Kekki M. Decreased anticoagulant tolerance during|2
00002|055|R|  methandrostenolone therapy. Scand J Clin Lab Invest 1963;15:367-74.|2
00002|056|R|5.Pyorala K, Kekki M. Anabolic steroids and anticoagulant requirements.|3
00002|057|R|  Lancet 1963 Aug 17;10:360-1.|3
00002|058|R|6.Murakami M, Odake K, Matsuda T, Onchi K, Umeda T, Nishino T. Effects of|2
00002|059|R|  anabolic steroids on anticoagulants requirements. Jpn Circ J 1965 Mar;|2
00002|060|R|  29:243-50.|2
00002|061|R|7.Pyorala K, Myllyla G, Kekki M. Metabolism of warfarin during|2
00002|062|R|  methandrostenolone treatment. Ann Med Exp Fenn 1965;43:95-7.|2
00002|063|R|8.Dresdale FC, Hayes JC. Potential dangers in the combined use of|3
00002|064|R|  methandrostenolone and sodium warfarin. J Med Soc N J 1967 Nov;|3
00002|065|R|  64(11):609-12.|3
00002|066|R|9.Vere DW, Fearnley GR. Suspected interaction between phenindione and|3
00002|067|R|  ethyloestrenol. Lancet 1968 Aug 3;2(7562):281.|3
00002|068|R|10.Edwards MS, Curtis JR. Decreased anticoagulant tolerance with|3
00002|069|R|   oxymetholone. Lancet 1971 Jul 24;2(7717):221.|3
00002|070|R|11.Robinson BH, Hawkins JB, Ellis JE, Moore-Robinson M. Decreased|2
00002|071|R|   anticoagulant tolerance with oxymetholone. Lancet 1971 Jun 26;|2
00002|072|R|   1(7713):1356.|2
00002|073|R|12.De Oya JC, Del Rio A, Noya M, Villanueva A. Decreased anticoagulant|3
00002|074|R|   tolerance with oxymetholone in paroxysmal nocturnal haemoglobinuria.|3
00002|075|R|   Lancet 1971 Jul 31;2(7718):259.|3
00002|076|R|13.Ekert H, Muntz RH, Colebatch JH. Decreased anticoagulant tolerance with|3
00002|077|R|   oxymetholone. Lancet 1971 Sep 11;2(7724):609-10.|3
00002|078|R|14.Longridge RG, Gillam PM, Barton GM. Decreased anticoagulant tolerance|2
00002|079|R|   with oxymetholone. Lancet 1971 Jul 10;2(7715):90.|2
00002|080|R|15.Goulbourne IA, Macleod DA. An interaction between danazol and warfarin.|3
00002|081|R|   Case report. Br J Obstet Gynaecol 1981 Sep;88(9):950-1.|3
00002|082|R|16.Small M, Peterkin M, Lowe GD, McCune G, Thomson JA. Danazol and oral|3
00002|083|R|   anticoagulants. Scott Med J 1982 Oct;27(4):331-2.|3
00002|084|R|17.Acomb C, Shaw PW. A significant interaction between warfarin and|3
00002|085|R|   stanozolol. Pharm J 1985 Jan 19;234(1):73-4.|3
00002|086|R|18.Lorentz SM, Weibert RT. Potentiation of warfarin anticoagulation by|3
00002|087|R|   topical testosterone ointment. Clin Pharm 1985 May-Jun;4(3):332-4.|3
00002|088|R|19.Meeks ML, Mahaffey KW, Katz MD. Danazol increases the anticoagulant|3
00002|089|R|   effect of warfarin. Ann Pharmacother 1992 May;26(5):641-2.|3
00002|090|R|20.Manoharan A, Hewitt B. Danazol therapy in familial antithrombin III|3
00002|091|R|   deficiency. Clin Lab Haematol 1990;12(3):357-9.|3
00002|092|R|21.Shaw PW, Smith AM. Possible interaction of warfarin and stanozolol. Clin|3
00002|093|R|   Pharm 1987 Jun;6(6):500-2.|3
00002|094|R|22.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
00002|095|R|   Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE,|6
00002|096|R|   Altman RB. Clinical Pharmacogenetics Implementation Consortium Guidelines|6
00002|097|R|   for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther|6
00002|098|R|   2011 Oct;90(4):625-9.|6
00003|001|T|MONOGRAPH TITLE:  Chlorpropamide; Tolbutamide/Acenocoumarol; Dicumarol|
00003|002|B||
00003|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00003|004|L|of severe adverse interaction.|
00003|005|B||
00003|006|A|MECHANISM OF ACTION:  The metabolism of chlorpropamide(1) and|
00003|007|A|tolbutamide(2-4) may be inhibited by dicumarol.  Dicumarol may displace|
00003|008|A|sulfonylureas from their plasma protein binding sites.(5)|
00003|009|B||
00003|010|E|CLINICAL EFFECTS:  Concurrent use may result in an enhanced hypoglycemic|
00003|011|E|effect.(1-3,6)|
00003|012|B||
00003|013|P|PREDISPOSING FACTORS:  None determined.|
00003|014|B||
00003|015|M|PATIENT MANAGEMENT:  If both drugs are administered, monitor blood glucose|
00003|016|M|levels and adjust the oral antidiabetic dose as needed.  The patient should|
00003|017|M|be watched for hypoglycemic symptoms.  This is especially important during|
00003|018|M|initiation or discontinuation of the anticoagulant.|
00003|019|M|   Warfarin, phenprocoumon, and the indanedione derivatives anisindione and|
00003|020|M|phenindione may be alternatives to acenocoumarol, coumarin, and dicumarol in|
00003|021|M|patients receiving chlorpropamide or tolbutamide therapy.|
00003|022|B||
00003|023|D|DISCUSSION:  Dicumarol has been shown to increase the half-life of|
00003|024|D|chlorpropamide(1) and tolbutamide.(2,3,6)  The effect is seen within four|
00003|025|D|days of the addition of dicumarol.(2,6)  Several studies have shown no|
00003|026|D|effect on the pharmacokinetics or pharmacodynamics of anticoagulants by|
00003|027|D|sulfonylureas.(7-9)|
00003|028|D|   The other coumarin anticoagulants (phenprocoumon, warfarin) and the|
00003|029|D|indanedione derivatives (anisindione and phenindione) have been shown not to|
00003|030|D|interact with tolbutamide.(8,10-12)  An in vitro study found minimal effects|
00003|031|D|on glyburide protein binding by warfarin.(12)  Glyburide has been shown to|
00003|032|D|have no significant effect on phenprocoumon.(13)|
00003|033|B||
00003|034|R|REFERENCES:|
00003|035|B||
00003|036|R|1.Kristensen M, Hansen JM. Accumulation of chlorpropamide caused by|2
00003|037|R|  dicoumarol. Acta Med Scand 1968 Jan-Feb;183(1-2):83-6.|2
00003|038|R|2.Solomon HM, Schrogie JJ. Effect of phenyramidol and bishydroxycoumarin on|2
00003|039|R|  the metabolism of tolbutamide in human subjects. Metabolism 1967 Nov;|2
00003|040|R|  16(11):1029-33.|2
00003|041|R|3.Skovsted L, Kristensen M, Hansen M, Siersbaek-Nielsen K. The effect of|2
00003|042|R|  different oral anticoagulants on diphenylhydantoin (DPH) and tolbutamide|2
00003|043|R|  metabolism. Acta Med Scand 1976;199(6):513-5.|2
00003|044|R|4.Spruny OM, Wolf JW, Devins GS. Protracted tolbutamide-induced|3
00003|045|R|  hypoglycemia. Arch Intern Med 1965 Jan;115:53-6.|3
00003|046|R|5.Judis J. Displacement of sulfonylureas from human serum proteins by|5
00003|047|R|  coumarin derivatives and cortical steroids. J Pharm Sci 1973 Feb;|5
00003|048|R|  62(2):232-7.|5
00003|049|R|6.Kristensen M, Hansen JM. Potentiation of the tolbutamide effect by|2
00003|050|R|  dicoumarol. Diabetes 1967 Apr;16(4):211-4.|2
00003|051|R|7.Chaplin H Jr, Cassell M. Studies on the possible relationship of|5
00003|052|R|  tolbutamide to dicumarol in anticoagulant therapy. Am J Med Sci 1958 Jun;|5
00003|053|R|  235:706-15.|5
00003|054|R|8.Poucher RL, Vecchio TJ. Absence of tolbutamide effect on anticoagulant|2
00003|055|R|  therapy. JAMA 1966 Sep 26;197(13):1069-70.|2
00003|056|R|9.Jahnchen E, Meinertz T, Gilfrich HJ, Groth U. Pharmacokinetic analysis of|2
00003|057|R|  the interaction between dicoumarol and tolbutamide in man. Eur J Clin|2
00003|058|R|  Pharmacol 1976 Sep 30;10(5):349-56.|2
00003|059|R|10.Petitpierre B, Perrin L, Rudhardt M, Herrera A, Fabre J. Behaviour of|2
00003|060|R|   chlorpropamide in renal insufficiency and under the effect of associated|2
00003|061|R|   drug therapy. Int J Clin Pharmacol 1972 Jun;6(2):120-4.|2
00003|062|R|11.Kolenda KD, Grille W, Johnsen K. Drug interaction during therapy with|2
00003|063|R|   tolbutamide. The influence of some commonly used drugs on plasma level|2
00003|064|R|   and half life in diabetic out- patients (author's transl). Med Klin 1979|2
00003|065|R|   Dec 14;74(50):1914-22.|2
00003|066|R|12.Heine P, Kewitz H, Wiegboldt KA. The influence of hypoglycaemic|2
00003|067|R|   sulphonylureas on elimination and efficacy of phenprocoumon following a|2
00003|068|R|   single oral dose in diabetic patients. Eur J Clin Pharmacol 1976;10:31-6.|2
00003|069|R|13.Brown KF, Crooks MJ. Displacement of tolbutamide, glibencalmide and|5
00003|070|R|   chlorpropamide from serum albumin by anionic drugs. Biochem Pharmacol|5
00003|071|R|   1976 May 15;25(10):1175-8.|5
00004|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Barbiturates|
00004|002|B||
00004|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00004|004|L|of severe adverse interaction.|
00004|005|B||
00004|006|A|MECHANISM OF ACTION:  It is speculated that induction of hepatic microsomal|
00004|007|A|enzymes results in increased metabolism of anticoagulants,(1) resulting in|
00004|008|A|decreased anticoagulant response.(2,3)  Phenobarbital and secobarbital are|
00004|009|A|inducers of CYP2C9 and may result in decreased levels of anticoagulants.(4)|
00004|010|A|Barbiturates may also increase the synthesis of clotting factors by the|
00004|011|A|liver.(5)  The absorption of dicumarol, but not warfarin, from the|
00004|012|A|gastrointestinal may be decreased by barbiturates.(6)|
00004|013|B||
00004|014|E|CLINICAL EFFECTS:  Concurrent use may result in decreased anticoagulant|
00004|015|E|effects.  Increased anticoagulant effects may occur if the barbiturate is|
00004|016|E|withdrawn.  The effect may be dose-related and may continue beyond the|
00004|017|E|discontinuation of the barbiturate.|
00004|018|B||
00004|019|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00004|020|P|of the inducer for longer than 1-2 weeks.|
00004|021|B||
00004|022|M|PATIENT MANAGEMENT:  If possible, avoid the concurrent use of these agents.|
00004|023|M|If a barbiturate is initiated or discontinued in a patient maintained on|
00004|024|M|anticoagulant therapy, monitor prothrombin times and adjust the dose of the|
00004|025|M|anticoagulant as needed.|
00004|026|M|   For hypnotic indications, benzodiazepines and diphenhydramine may be|
00004|027|M|alternatives to barbiturates in patients stabilized on anticoagulant|
00004|028|M|therapy.|
00004|029|B||
00004|030|D|DISCUSSION:  Amobarbital,(7) aprobarbital,(8) barbital,(9) butabarbital,(10)|
00004|031|D|pentobarbital,(5) phenobarbital,(1) and secobarbital(7) have been shown to|
00004|032|D|interact with coumarin anticoagulants.  Dicumarol,(6) warfarin(1), and|
00004|033|D|phenprocoumon(4) have been reported to interact with the barbiturates.|
00004|034|D|   It would be prudent to assume that all barbiturates and the indanedione|
00004|035|D|derivatives would interact in a similar fashion.  Primidone is metabolized|
00004|036|D|to phenobarbital.|
00004|037|D|   The time of highest risk for a coumarin-type drug interaction is when the|
00004|038|D|precipitant drug is initiated, altered, or discontinued.|
00004|039|B||
00004|040|R|REFERENCES:|
00004|041|B||
00004|042|R|1.Levy G, O'Reilly RA, Aggeler PM, Keech GM. Pharmacokinetic analysis of the|2
00004|043|R|  effect of barbiturate on the anticoagulant action of warfarin in man. Clin|2
00004|044|R|  Pharmacol Ther 1970 May-Jun;11(3):372-7.|2
00004|045|R|2.Goss JE, Dickhaus DW. Increased bishydroxycoumarin requirements in|2
00004|046|R|  patients receiving phenobarbital. N Engl J Med 1965 Nov 11;273(20):1094-5.|2
00004|047|R|3.MacDonald MG, Robinson DS. Clinical observations of possible barbiturate|6
00004|048|R|  interference with anticoagulation. JAMA 1968 Apr 8;204(2):97-100.|6
00004|049|R|4.This information is based on an extract from the Certara Drug Interaction|6
00004|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00004|051|R|5.Lucas ON. Study of the interaction of barbiturates and dicumarol and their|5
00004|052|R|  effect on prothrombin activity, hemorrhage, and sleeping time in rats. Can|5
00004|053|R|  J Physiol Pharmacol 1967 Sep;45(5):905-13.|5
00004|054|R|6.Aggeler PM, O'Reilly RA. Effect of heptabarbital on the response to|2
00004|055|R|  bishydroxycoumarin in man. J Lab Clin Med 1969 Aug;74(2):229-38.|2
00004|056|R|7.Breckenridge A, Orme M. Clinical implications of enzyme induction. Ann N Y|5
00004|057|R|  Acad Sci 1971 Jul 6;179:421-31.|5
00004|058|R|8.Johansson SA. Apparent resistance to oral anticoagulant therapy and|2
00004|059|R|  influence of hypnotics on some coagulation factors. Acta Med Scand 1968|2
00004|060|R|  Oct;184(4):297-300.|2
00004|061|R|9.Welch RM, Harrison YE, Conney AH, Burns JJ. An experimental model in dogs|5
00004|062|R|  for studying interactions of drugs with bishydroxycoumarin. Clin Pharmacol|5
00004|063|R|  Ther 1969 Nov-Dec;10(6):817-25.|5
00004|064|R|10.Antlitz AM, Tolentino M, Kosai MF. Effect of butabarbital on orally|2
00004|065|R|   administered anticoagulants. Curr Ther Res Clin Exp 1968 Feb;10(2):70-3.|2
00005|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Fibrates|
00005|002|B||
00005|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00005|004|L|of severe adverse interaction.|
00005|005|B||
00005|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Fibric acid|
00005|007|A|derivatives may displace anticoagulants from their plasma protein binding|
00005|008|A|sites or may affect anticoagulant receptor sites.  It has also been|
00005|009|A|suggested that the effect may be related to the hypolipidemic action of the|
00005|010|A|fibric acid derivatives.|
00005|011|B||
00005|012|E|CLINICAL EFFECTS:  Concurrent use of selected anticoagulants and fibric acid|
00005|013|E|derivatives may increase the risk for bleeding.|
00005|014|B||
00005|015|P|PREDISPOSING FACTORS:  Severe hyperlipidemia, larger doses of the fibric|
00005|016|P|acid derivative, and older age may predispose patients to this interaction.|
00005|017|P|   The risk for bleeding episodes may also be greater in patients with|
00005|018|P|disease-associated factors (e.g. thrombocytopenia).|
00005|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
00005|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00005|021|P|risk for bleeding (e.g. NSAIDs).|
00005|022|B||
00005|023|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with selected|
00005|024|M|anticoagulants and a fibric acid derivative should be closely monitored for|
00005|025|M|excessive anticoagulant effects.  The dose of the anticoagulant may need to|
00005|026|M|be adjusted if the fibric acid derivative is added to or discontinued from|
00005|027|M|stabilized anticoagulant therapy.  The time of highest risk for an|
00005|028|M|anticoagulant drug interaction is when the precipitant drug is initiated or|
00005|029|M|discontinued.|
00005|030|M|   When concurrent therapy is warranted, monitor patients receiving|
00005|031|M|concurrent therapy for signs of blood loss, including decreased hemoglobin|
00005|032|M|and/or hematocrit, fecal occult blood, and/or decreased blood pressure and|
00005|033|M|promptly evaluate patients with any symptoms.  Discontinue anticoagulation|
00005|034|M|in patients with active pathologic bleeding.|
00005|035|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00005|036|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00005|037|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00005|038|M|and/or swelling.|
00005|039|M|   Contact the prescriber before initiating, altering the dose or|
00005|040|M|discontinuing either drug.|
00005|041|B||
00005|042|D|DISCUSSION:  There have been case reports of bezafibrate,(1) clofibrate,|
00005|043|D|(2-5) fenofibrate,(6-8) and gemfibrozil(9-11) interacting with warfarin. The|
00005|044|D|interactions between clofibrate(12-14) and and warfarin and gemfibrozil(15)|
00005|045|D|and warfarin have also been documented in clinical trials.  There are also|
00005|046|D|case reports of bezafibrate(16) and clofibrate(17) interacting with|
00005|047|D|dicumarol.  A study showed that bezafibrate increased the effects of|
00005|048|D|phenprocoumon.(18)|
00005|049|B||
00005|050|R|REFERENCES:|
00005|051|B||
00005|052|R|1.Beringer TR. Warfarin potentiation with bezafibrate. Postgrad Med J 1997|3
00005|053|R|  Oct;73(864):657-8.|3
00005|054|R|2.Bjornsson TD, Meffin PJ, Blaschke TF. Interaction of clofibrate with|3
00005|055|R|  warfarin. I. Effect of clofibrate on the disposition of the optical|3
00005|056|R|  enantiomorphs of warfarin. J Pharmacokinet Biopharm 1977 Oct;5(5):495-505.|3
00005|057|R|3.Eastham RD. Warfarin dosage influenced by clofibrate plus age. Lancet 1973|3
00005|058|R|  Jun 23;1(7817):1450.|3
00005|059|R|4.Eastham RD. Warfarin dosage, clofibrate, and age of patient. Br Med J 1973|3
00005|060|R|  Jun 2;2(5865):554.|3
00005|061|R|5.Solomon RB, Rosner F. Massive hemorrhage and death during treatment with|3
00005|062|R|  clofibrate and warfarin. N Y State J Med 1973 Aug 1;73(15):2002-3.|3
00005|063|R|6.Ascah KJ, Rock GA, Wells PS. Interaction between fenofibrate and warfarin.|3
00005|064|R|  Ann Pharmacother 1998 Jul-Aug;32(7-8):765-8.|3
00005|065|R|7.Aldridge MA, Ito MK. Fenofibrate and warfarin interaction. Pharmacotherapy|3
00005|066|R|  2001 Jul;21(7):886-9.|3
00005|067|R|8.Kim KY, Mancano MA. Fenofibrate potentiates warfarin effects. Ann|3
00005|068|R|  Pharmacother 2003 Feb;37(2):212-5.|3
00005|069|R|9.Rindone JP, Keng HC. Gemfibrozil-warfarin drug interaction resulting in|3
00005|070|R|  profound hypoprothrombinemia. Chest 1998 Aug;114(2):641-2.|3
00005|071|R|10.Ahmad S. Gemfibrozil interaction with warfarin sodium (coumadin). Chest|3
00005|072|R|   1990 Oct;98(4):1041-2.|3
00005|073|R|11.Dixon DL, Williams VG. Interaction between gemfibrozil and warfarin: case|3
00005|074|R|   report and review of the literature. Pharmacotherapy 2009 Jun;|3
00005|075|R|   29(6):744-8.|3
00005|076|R|12.Bjornsson TD, Meffin PJ, Swezey SE, Blaschke TF. Effects of clofibrate|2
00005|077|R|   and warfarin alone and in combination on the disposition of vitamin K1. J|2
00005|078|R|   Pharmacol Exp Ther 1979 Sep;210(3):322-6.|2
00005|079|R|13.Pond SM, Graham GG, Wade DN, Sudlow G. The effects of allopurinol and|2
00005|080|R|   clofibrate on the elimination of coumarin anticoagulants in man. Aust N Z|2
00005|081|R|   J Med 1975 Aug;5(4):324-8.|2
00005|082|R|14.O'Reilly RA, Sahud MA, Robinson AJ. Studies on the interaction of|2
00005|083|R|   warfarin and clofibrate in man. Thromb Diath Haemorrh 1972 Apr 30;|2
00005|084|R|   27(2):309-18.|2
00005|085|R|15.Lilja JJ, Backman JT, Neuvonen PJ. Effect of gemfibrozil on the|2
00005|086|R|   pharmacokinetics and pharmacodynamics of racemic warfarin in healthy|2
00005|087|R|   subjects. Br J Clin Pharmacol 2005 Apr;59(4):433-9.|2
00005|088|R|16.Blum A, Seligmann H, Livneh A, Ezra D. Severe gastrointestinal bleeding|3
00005|089|R|   induced by a probable hydroxycoumarin- bezafibrate interaction. Isr J Med|3
00005|090|R|   Sci 1992 Jan;28(1):47-9.|3
00005|091|R|17.Schrogie JJ, Solomon HM. The anticoagulant response to|2
00005|092|R|   bishydroxycoumarin. II. The effect of D- thyroxine, clofibrate, and|2
00005|093|R|   norethandrolone. Clin Pharmacol Ther 1967 Jan-Feb;8(1):70-7.|2
00005|094|R|18.Zimmermann R, Ehlers W, Walter E, Hoffrichter A, Lang PD, Andrassy K,|2
00005|095|R|   Schlierf G. The effect of bezafibrate on the fibrinolytic enzyme system|2
00005|096|R|   and the drug interaction with racemic phenprocoumon. Atherosclerosis 1978|2
00005|097|R|   Apr;29(4):477-85.|2
00006|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K|
00006|002|T|antagonists)/Oxyphenbutazone; Phenylbutazone|
00006|003|B||
00006|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00006|005|L|of severe adverse interaction.|
00006|006|B||
00006|007|A|MECHANISM OF ACTION:  Concurrent oxyphenbutazone or phenylbutazone may|
00006|008|A|displace the anticoagulant from its plasma protein binding site and inhibit|
00006|009|A|anticoagulant metabolism.|
00006|010|B||
00006|011|E|CLINICAL EFFECTS:  Concurrent oxyphenbutazone or phenylbutazone may result|
00006|012|E|in increased bleeding.|
00006|013|B||
00006|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00006|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00006|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
00006|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00006|018|P|risk for bleeding (e.g. NSAIDs).|
00006|019|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
00006|020|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
00006|021|P|are expected to be more susceptible to this interaction.|
00006|022|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00006|023|P|are expected to be less susceptible to effects from this drug combination,|
00006|024|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00006|025|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
00006|026|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
00006|027|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
00006|028|P|and safe anticoagulation than patients without these CYP2C9 variants.|
00006|029|B||
00006|030|M|PATIENT MANAGEMENT:  Avoid concomitant administration of these drugs.|
00006|031|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00006|032|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00006|033|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00006|034|M|patients with any symptoms.|
00006|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00006|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00006|037|M|anticoagulation in patients with active pathologic bleeding.|
00006|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00006|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00006|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00006|041|M|and/or swelling.|
00006|042|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00006|043|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00006|044|M|initiating, altering the dose or discontinuing either drug.|
00006|045|B||
00006|046|D|DISCUSSION:  In a study of four subjects, increased prothrombin times and|
00006|047|D|decreased total plasma warfarin levels were found after receiving ten days|
00006|048|D|of phenylbutazone, then a single dose of warfarin (1.5 mg/kg), followed by|
00006|049|D|ten more days of phenylbutazone.  The study was repeated in another six|
00006|050|D|subjects who were assessed with fluorometric assay.  An 86% increase in|
00006|051|D|prothrombin time and a 30% decrease in total plasma warfarin based on a|
00006|052|D|logarithmic scale were found.(2)|
00006|053|B||
00006|054|R|REFERENCES:|
00006|055|B||
00006|056|R|1.Udall JA. Drug interference with warfarin therapy. Clin Med 1970 Aug;|2
00006|057|R|  77:20-5.|2
00006|058|R|2.O'Reilly RA. The binding of sodium warfarin to plasma albumin and its|5
00006|059|R|  displacement by phenylbutazone. Ann N Y Acad Sci 1973 Nov 26;226:293-308.|5
00007|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Cimetidine|
00007|002|B||
00007|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00007|004|L|of severe adverse interaction.|
00007|005|B||
00007|006|A|MECHANISM OF ACTION:  Cimetidine is a weak inhibitor of CYP1A2, CYP2C9, and|
00007|007|A|CYP3A4.  The more potent S-warfarin isomer is metabolized by CYP2C9 where as|
00007|008|A|the weaker warfarin R-enantiomer is metabolized by CYP1A2 and CYP3A4.  The|
00007|009|A|cimetidine inhibitory effect appears to be greater on the less active|
00007|010|A|R-warfarin isomer.|
00007|011|B||
00007|012|E|CLINICAL EFFECTS:  The pharmacologic effects of warfarin may be increased|
00007|013|E|resulting in a higher risk for bleeding.|
00007|014|B||
00007|015|P|PREDISPOSING FACTORS:  Interaction magnitude is expected to be greater with|
00007|016|P|use of prescription doses of cimetidine, e.g. 800 mg to 1,600 mg daily.|
00007|017|P|   The risk for bleeding episodes may be greater in patients with|
00007|018|P|disease-associated factors (e.g. thrombocytopenia).|
00007|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
00007|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00007|021|P|risk for bleeding (e.g. NSAIDs).|
00007|022|P|   Pharmacogenomic information: warfarin patients with a CYP2C9 intermediate|
00007|023|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
00007|024|P|are expected to be more susceptible to this interaction.|
00007|025|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00007|026|P|are expected to be less susceptible to effects from this drug combination,|
00007|027|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00007|028|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
00007|029|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
00007|030|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
00007|031|P|and safe anticoagulation than patients without these CYP2C9 variants.|
00007|032|B||
00007|033|M|PATIENT MANAGEMENT:  Given the availability of alternatives,|
00007|034|M|coadministration of cimetidine and warfarin should be avoided, particularly|
00007|035|M|if high doses of cimetidine are prescribed.  Consider use of H-2 antagonists|
00007|036|M|famotidine or nizatidine which are unlikely to interact with warfarin.|
00007|037|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00007|038|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00007|039|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00007|040|M|patients with any symptoms.|
00007|041|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00007|042|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00007|043|M|anticoagulation in patients with active pathologic bleeding.|
00007|044|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00007|045|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00007|046|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00007|047|M|and/or swelling.|
00007|048|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00007|049|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00007|050|M|initiating, altering the dose or discontinuing either drug.|
00007|051|B||
00007|052|D|DISCUSSION:  The majority of drug interaction reports involving H-2|
00007|053|D|antagonists and warfarin have occurred with cimetidine. Reports of a|
00007|054|D|possibly significant interaction between ranitidine and warfarin have been|
00007|055|D|equivocal. Famotidine and nizatidine do not appear to affect prothrombin|
00007|056|D|time.|
00007|057|D|   A study of 6 healthy subjects receiving cimetidine and warfarin|
00007|058|D|concomitant therapy had no significant effect on the S-warfarin however|
00007|059|D|increased R-warfarin trough concentrations 28% (p<0.05) and decreased|
00007|060|D|R-warfarin clearance by 23% (p<0.05).|
00007|061|B||
00007|062|R|REFERENCES:|
00007|063|B||
00007|064|R|1.Silver BA, Bell WR. Cimetidine potentiation of the hypoprothrombinemic|3
00007|065|R|  effect of warfarin. Ann Intern Med 1979 Mar;90(3):348-9.|3
00007|066|R|2.Wallin BA, Jacknowitz A, Raich PC. Cimetidine and effect of warfarin. Ann|3
00007|067|R|  Intern Med 1979 Jun;90(6):993.|3
00007|068|R|3.Serlin MJ, Sibeon RG, Breckenridge AM. Lack of effect of ranitidine on|2
00007|069|R|  warfarin action. Br J Clin Pharmacol 1981 Dec;12(6):791-4.|2
00007|070|R|4.Kerley B, Ali M. Cimetidine potentiation of warfarin action. Can Med Assoc|3
00007|071|R|  J 1982 Jan 15;126(2):116.|3
00007|072|R|5.Desmond PV, Mashford ML, Harman PJ, Morphett BJ, Breen KJ, Wang YM.|2
00007|073|R|  Decreased oral warfarin clearance after ranitidine and cimetidine. Clin|2
00007|074|R|  Pharmacol Ther 1984 Mar;35(3):338-41.|2
00007|075|R|6.Toon S, Hopkins KJ, Garstang FM, Rowland M. Comparative effects of|2
00007|076|R|  ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of|2
00007|077|R|  warfarin in man. Eur J Clin Pharmacol 1987;32(2):165-72.|2
00007|078|R|7.Cournot A, Berlin I, Sallord JC, Singlas E. Lack of interaction between|2
00007|079|R|  nizatidine and warfarin during chronic administration. J Clin Pharmacol|2
00007|080|R|  1988 Dec;28(12):1120-2.|2
00007|081|R|8.Hussey EK, Dukes GE. Do all histamine2-antagonists cause a warfarin drug|6
00007|082|R|  interaction?. DICP 1989 Sep;23(9):675-9.|6
00007|083|R|9.Hunt BA, Sax MJ, Chretien SD, Gray DR, Frank WO, Lalonde RL.|4
00007|084|R|  Stereoselective alterations in the pharmacokinetics of warfarin|4
00007|085|R|  enantiomers with two cimetidine dose regimens. Pharmacotherapy 1989;|4
00007|086|R|  9(3):184.|4
00007|087|R|10.Baciewicz AM, Morgan PJ. Ranitidine-warfarin interaction. Ann Intern Med|3
00007|088|R|   1990 Jan 1;112(1):76-7.|3
00007|089|R|11.Niopas I, Toon S, Aarons L, Rowland M. The effect of cimetidine on the|2
00007|090|R|   steady-state pharmacokinetics and pharmacodynamics of warfarin in humans.|2
00007|091|R|   Eur J Clin Pharmacol 1999 Jul;55(5):399-404.|2
00007|092|R|12.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
00007|093|R|   Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE,|6
00007|094|R|   Altman RB. Clinical Pharmacogenetics Implementation Consortium Guidelines|6
00007|095|R|   for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther|6
00007|096|R|   2011 Oct;90(4):625-9.|6
00007|097|R|13.This information is based on an extract from the Certara Drug Interaction|6
00007|098|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00008|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Quinidine|
00008|002|B||
00008|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00008|004|L|take action as needed.|
00008|005|B||
00008|006|A|MECHANISM OF ACTION:  The mechanism is unknown but may be due to synergistic|
00008|007|A|effects on vitamin K clotting factors in the liver.|
00008|008|B||
00008|009|E|CLINICAL EFFECTS:  May observe reduced prothrombin activity or increased|
00008|010|E|bleeding.|
00008|011|B||
00008|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00008|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00008|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
00008|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00008|016|P|risk for bleeding (e.g. NSAIDs).|
00008|017|B||
00008|018|M|PATIENT MANAGEMENT:  Excessive hypoprothrombinemia and hemorrhage has been|
00008|019|M|reported in patients receiving warfarin 6 to 10 days after starting|
00008|020|M|quinidine.   Monitor INR and adjust anticoagulant dose to assure efficacy|
00008|021|M|and safety of anticoagulation.|
00008|022|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
00008|023|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
00008|024|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
00008|025|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
00008|026|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00008|027|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00008|028|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00008|029|M|and/or swelling.|
00008|030|B||
00008|031|D|DISCUSSION:  Excessive hypoprothrombinemia and hemorrhage has been reported|
00008|032|D|in patients receiving warfarin 6 to 10 days after starting quinidine.|
00008|033|D|Anticipate a similar time period to be needed for the effects of quinidine|
00008|034|D|to dissipate after stopping quinidine therapy.|
00008|035|B||
00008|036|R|REFERENCES:|
00008|037|B||
00008|038|R|1.Koch-Weser J. Quinidine-induced hypoprothrombinemic hemorrhage in patients|3
00008|039|R|  on chronic warfarin therapy. Ann Intern Med 1968 Mar;68(3):511-7.|3
00008|040|R|2.Jones FL Jr. More on quinidine-induced hypoprothrombinemia. Ann Intern Med|3
00008|041|R|  1968 Nov;69(5):1074.|3
00008|042|R|3.Gazzaniga AB, Stewart DR. Possible quinidine-induced hemorrhage in a|3
00008|043|R|  patient on warfarin sodium. N Engl J Med 1969 Mar 27;280(13):711-2.|3
00008|044|R|4.Udall JA. Drug interference with warfarin therapy. Clin Med 1970 Aug;|2
00008|045|R|  77:20-5.|2
00008|046|R|5.Sylven C, Anderson P. Evidence that disopyramide does not interact with|2
00008|047|R|  warfarin. Br Med J (Clin Res Ed) 1983 Apr 9;286(6372):1181.|2
00009|001|T|MONOGRAPH TITLE:  Selected Anticoagulants/Thyroid (mono deleted 02/23/2022)|
00009|002|B||
00009|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00009|004|L|take action as needed.|
00009|005|B||
00009|006|A|MECHANISM OF ACTION:  Unknown. However, thyroid hormones may influence|
00009|007|A|concentrations of vitamin K-dependent clotting factors.|
00009|008|B||
00009|009|E|CLINICAL EFFECTS:  Concurrent use of vitamin K antagonists and thyroid|
00009|010|E|hormones may increase the risk for bleeding.  Hypothyroidism may increase|
00009|011|E|the oral anticoagulant requirements.  Administration of thyroid hormones or|
00009|012|E|hyperthyroidism may decrease oral anticoagulant requirements.|
00009|013|B||
00009|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00009|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00009|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
00009|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00009|018|P|risk for bleeding (e.g. NSAIDs).|
00009|019|B||
00009|020|M|PATIENT MANAGEMENT:  Monitor prothrombin activity and adjust the|
00009|021|M|anticoagulant dosage accordingly during initiation of warfarin therapy in|
00009|022|M|patients receiving thyroid replacement therapy, during the initiation or|
00009|023|M|titration of thyroid replacement therapy in patients receiving warfarin, or|
00009|024|M|if any changes in thyroid function occur.|
00009|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00009|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00009|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00009|028|M|patients with any symptoms.|
00009|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00009|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00009|031|M|anticoagulation in patients with active pathologic bleeding.|
00009|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00009|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00009|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00009|035|M|and/or swelling.|
00009|036|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00009|037|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00009|038|M|initiating, altering the dose or discontinuing either drug.|
00009|039|B||
00009|040|D|DISCUSSION:  Any change in thyroid status in patients stabilized on warfarin|
00009|041|D|may necessitate a change in warfarin dosage requirements.  Initiation of|
00009|042|D|thyroid replacement therapy in patients stabilized on warfarin may result in|
00009|043|D|increases in the effects of warfarin.  A decrease in the dose of warfarin|
00009|044|D|usually becomes necessary within one to four weeks after starting therapy|
00009|045|D|with thyroid compounds.  Warfarin therapy should be initiated in low doses|
00009|046|D|in patients who are hyperthyroid.|
00009|047|D|   In a 16 year population based nested matched case control study, 10,532|
00009|048|D|hospitalizations for hemorrhage were evaluated and matched to 40,595|
00009|049|D|controls.  The primary analysis showed no increase in risk of hemorrhage in|
00009|050|D|older patients on warfarin initiated on levothyroxine in previous 30 days|
00009|051|D|(OR 1.11, 95% CI 0.67-1.86).  When patients were matched up to 90 days prior|
00009|052|D|to the hemorrhage event, there was no significant association with|
00009|053|D|levothyroxine 31-60 days prior to index date (OR 0.75 95% CI 0.26-2.25) or|
00009|054|D|61-90 days prior to index date (OR 0.67 95% CI 0.15-3.01).|
00009|055|D|   A retrospective, self-controlled study of 102 patients on chronic|
00009|056|D|warfarin therapy were included if the patient had INR results 90 days before|
00009|057|D|and after starting levothyroxine.  The mean warfarin dose/INR ratio in the|
00009|058|D|pre-period and post-period had no significant change (p=0.825).  In patients|
00009|059|D|who achieved euthyroid during post-period, warfarin dose/INR ratio was|
00009|060|D|numerically lower in the post-period but not statistically significant|
00009|061|D|(13.42 versus 12.7, respectively; p=0.338).  In patients initiated on|
00009|062|D|levothyroxine doses greater than 50 mcg, pre-period and post-period warfarin|
00009|063|D|dose/INR ratio also had no significant difference (p>0.2).|
00009|064|B||
00009|065|R|REFERENCES:|
00009|066|B||
00009|067|R|1.Walters MB. The relationship between thyroid function and anticoagulant|3
00009|068|R|  therapy. Am J Cardiol 1963 Jan;11:112-4.|3
00009|069|R|2.Schrogie JJ, Solomon HM. The anticoagulant response to bishydroxycoumarin.|2
00009|070|R|  II. The effect of D- thyroxine, clofibrate, and norethandrolone. Clin|2
00009|071|R|  Pharmacol Ther 1967 Jan-Feb;8(1):70-7.|2
00009|072|R|3.Kimberg DV. The liver. In:  Werner SC, Ingbar SH, ed. Werner and Ingbar's|6
00009|073|R|  The thyroid. New York: Harper & Row; 1971: 569..|6
00009|074|R|4.Feely J, Stevenson IH, Crooks J. Altered plasma protein binding of drugs|5
00009|075|R|  in thyroid disease. Clin Pharmacokinet 1981 Jul-Aug;6(4):298-305.|5
00009|076|R|5.Weintraub M, Breckenridge RT, Griner PF. The effects of dextrothyroxine on|5
00009|077|R|  the kinetics of prothrombin activity: proposed mechanism of the|5
00009|078|R|  potentiation of warfarin by D-thyroxine. J Lab Clin Med 1973 Feb;|5
00009|079|R|  81(2):273-9.|5
00009|080|R|6.Owens JC, Neely WB, Owen WR. Effect of sodium dextrothyroxine in patients|2
00009|081|R|  receiving anticoagulants. N Engl J Med 1962 Jan 11;266(2):76-9.|2
00009|082|R|7.Self T, Weisburst M, Wooten E, Straughn A, Oliver J. Warfarin-induced|3
00009|083|R|  hypoprothrombinemia. Potentiation by hyperthyroidism. JAMA 1975 Mar 17;|3
00009|084|R|  231(11):1165-6.|3
00009|085|R|8.Rice AJ, McIntosh TJ, Fouts JR, Brunk SF, Wilson WR. Decreased sensitivity|2
00009|086|R|  to warfarin in patients with myxedema. Am J Med Sci 1971 Oct;262(4):211-5.|2
00009|087|R|9.Vagenakis AG, Cote R, Miller ME, Braverman LE, Stohlman F Jr. Enhancement|3
00009|088|R|  of warfarin-induced hypoprothrombinemia by thyrotoxicosis. Johns Hopkins|3
00009|089|R|  Med J 1972 Jul;131(1):69-73.|3
00009|090|R|10.Gotta AW, Sullivan CA, Seaman J, Jean-Gilles B. Prolonged intraoperative|3
00009|091|R|   bleeding caused by propylthiouracil-induced hypoprothrombinemia.|3
00009|092|R|   Anesthesiology 1972 Nov;37(5):562-3.|3
00009|093|R|11.Costigan DC, Freedman MH, Ehrlich RM. Potentiation of oral anticoagulant|3
00009|094|R|   effect by L-thyroxine. Clin Pediatr (Phila) 1984 Mar;23(3):172-4.|3
00009|095|R|12.Wood MD, Delate T, Clark M, Clark N, Horn JR, Witt DM. An evaluation of|2
00009|096|R|   the potential drug interaction between warfarin and levothyroxine. J|2
00009|097|R|   Thromb Haemost 2014 Aug;12(8):1313-9.|2
00009|098|R|13.Pincus D, Gomes T, Hellings C, Zheng H, Paterson JM, Mamdani MM, Juurlink|2
00009|099|R|   DN. A population-based assessment of the drug interaction between|2
00009|100|R|   levothyroxine and warfarin. Clin Pharmacol Ther 2012 Dec;92(6):766-70.|2
00010|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K|
00010|002|T|antagonists)/Cholestyramine; Colesevelam|
00010|003|B||
00010|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00010|005|L|take action as needed.|
00010|006|B||
00010|007|A|MECHANISM OF ACTION:  Cholestyramine and colesevelam may bind to|
00010|008|A|anticoagulants, which may lead to reduced GI absorption and impaired|
00010|009|A|enterohepatic circulation.  Decreased absorption of vitamin K may also|
00010|010|A|occur.|
00010|011|B||
00010|012|E|CLINICAL EFFECTS:  Concurrent use of cholestyramine or colesevelam may|
00010|013|E|result in decreased effectiveness of anticoagulants.|
00010|014|B||
00010|015|P|PREDISPOSING FACTORS:  None determined.|
00010|016|B||
00010|017|M|PATIENT MANAGEMENT:  Changes in therapy may not be required.  However, INR|
00010|018|M|levels should be monitored and anticoagulant dose adjusted as necessary|
00010|019|M|during initiation and discontinuation of cholestyramine or colesevelam|
00010|020|M|therapy.  Staggering doses of these two drugs may reduce problems, but may|
00010|021|M|be unreliable because of the possibility of altering vitamin K absorption.|
00010|022|M|   Colestipol may be an alternative to cholestyramine or colesevelam in|
00010|023|M|patients maintained on warfarin therapy who require treatment with a bile|
00010|024|M|acid sequestrant.|
00010|025|B||
00010|026|D|DISCUSSION:  In healthy volunteers, oral administration of cholestyramine|
00010|027|D|decreased the anticoagulant effect of intravenously administered warfarin by|
00010|028|D|25% suggesting that cholestyramine interferes with the enterohepatic|
00010|029|D|recirculation of warfarin.|
00010|030|D|   Cholestyramine has been used to treat anticoagulant overdoses.|
00010|031|D|   In healthy volunteers absorption of warfarin was 95% complete when|
00010|032|D|administered with colestipol compared to 68% absorption when warfarin was|
00010|033|D|given with cholestyramine.|
00010|034|D|   Although an in vivo study found no effect from colesevelam on warfarin|
00010|035|D|levels, INR values were not assessed and there are post-marketing reports of|
00010|036|D|decreased INR levels during concurrent therapy.|
00010|037|D|   If patient is receiving treatment with cholestyramine and an|
00010|038|D|anticoagulant and the cholestyramine is stopped, serum anticoagulant|
00010|039|D|concentrations may increase, increasing the hypoprothrombinemic effect of|
00010|040|D|the anticoagulant.|
00010|041|B||
00010|042|R|REFERENCES:|
00010|043|B||
00010|044|R|1.Meinertz T, Gilfrich HJ, Groth U, Jonen HG, Jahnchen E. Interruption of|2
00010|045|R|  the enterohepatic circulation of phenprocoumon by cholestyramine. Clin|2
00010|046|R|  Pharmacol Ther 1977 Jun;21(6):731-5.|2
00010|047|R|2.Robinson DS, Benjamin DM, McCormack JJ. Interaction of warfarin and|2
00010|048|R|  nonsystemic gastrointestinal drugs. Clin Pharmacol Ther 1971 May-Jun;|2
00010|049|R|  12(3):491-5.|2
00010|050|R|3.Gallo DG, Bailey KR, Sheffner AL. The interaction between cholestyramine|5
00010|051|R|  and drugs. Proc Soc Exp Biol Med 1965 Oct;120(1):60-5.|5
00010|052|R|4.Keuntzel WP, Brunk SF. Cholestyramine-warfarin interaction in man. Clin|4
00010|053|R|  Res 1970;18(3):594.|4
00010|054|R|5.Hahn KJ, Eiden W, Schettle M, Hahn M, Walter E, Weber E. Effect of|5
00010|055|R|  cholestyramine on the gastrointestinal absorption of phenprocoumon and|5
00010|056|R|  acetylosalicylic acid in man. Eur J Clin Pharmacol 1972 Jun;4(3):142-5.|5
00010|057|R|6.Harvengt C, Desager JP. Effect of colestipol, a new bile acid sequestrant,|2
00010|058|R|  on the absorption of phenprocoumon in man. Eur J Clin Pharmacol 1973 Jun;|2
00010|059|R|  6(1):19-21.|2
00010|060|R|7.Meinertz T, Gilfrich MJ, Bork R, Jahnchen E. Treatment of phenprocoumon|3
00010|061|R|  intoxication with cholestyramine. Br Med J 1977 Aug 13;2(6084):439.|3
00010|062|R|8.Hunninghake DB, Pollack E. Effect of bile acid sequestering agents on the|4
00010|063|R|  absorption of aspirin, tolbutamine, and warfarin. Fed Proc 1977;36(3):996.|4
00010|064|R|9.Jahnchen E, Meinertz T, Gilfrich HJ, Kersting F, Groth U. Enhanced|2
00010|065|R|  elimination of warfarin during treatment with cholestyramine. Br J Clin|2
00010|066|R|  Pharmacol 1978 May;5(5):437-40.|2
00010|067|R|10.Welchol (colesevelam hydrochloride) US prescribing information. Daiichi|1
00010|068|R|   Sankyo, Inc. October, 2021.|1
00011|001|T|MONOGRAPH TITLE:  Cholinergics/Quinidine|
00011|002|B||
00011|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00011|004|L|take action as needed.|
00011|005|B||
00011|006|A|MECHANISM OF ACTION:  The anticholinergic properties of quinidine may oppose|
00011|007|A|cholinergic drug effects.|
00011|008|B||
00011|009|E|CLINICAL EFFECTS:  Quinidine may antagonize the effects of cholinergic drugs|
00011|010|E|in the treatment of myasthenia gravis. Cardiac slowing secondary to|
00011|011|E|cholinergic drugs would tend to be prevented by quinidine.|
00011|012|B||
00011|013|P|PREDISPOSING FACTORS:  None determined.|
00011|014|B||
00011|015|M|PATIENT MANAGEMENT:  If both drugs are administered, observe the myasthenic|
00011|016|M|patient for signs and symptoms of the disease.|
00011|017|B||
00011|018|D|DISCUSSION:  Caution is warranted in co-administration of these drugs due to|
00011|019|D|their opposing pharmacologic properties.|
00011|020|B||
00011|021|R|REFERENCES:|
00011|022|B||
00011|023|R|1.Flacke W. Treatment of myasthenia gravis. N Engl J Med 1973 Jan 4;|6
00011|024|R|  288(1):27-31.|6
00011|025|R|2.Kornfeld P, Horowitz SH, Genkins G, Papatestas AE. Myasthenia gravis|3
00011|026|R|  unmasked by antiarrhythmic agents. Mt Sinai J Med 1976 Jan-Feb;43(1):10-4.|3
00012|001|T|MONOGRAPH TITLE:  Selected Beta-Blockers/Theophyllines|
00012|002|B||
00012|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00012|004|L|take action as needed.|
00012|005|B||
00012|006|A|MECHANISM OF ACTION:  Certain beta-blockers may inhibit theophylline|
00012|007|A|metabolism. In addition, beta-blockers, especially non-selective agents, can|
00012|008|A|antagonize the pharmacologic effects of theophylline.|
00012|009|B||
00012|010|E|CLINICAL EFFECTS:  Even though theophylline concentrations may increase|
00012|011|E|leading to increased possibility of theophylline toxicity, beta-blockers|
00012|012|E|decrease theophylline's therapeutic effects.|
00012|013|B||
00012|014|P|PREDISPOSING FACTORS:  Cigarette smoking may exacerbate this interaction.|
00012|015|B||
00012|016|M|PATIENT MANAGEMENT:  Avoid the use of non-selective beta-blockers with|
00012|017|M|theophylline. If a beta-blocker must be used, a cardioselective agent that|
00012|018|M|does not decrease the clearance of theophylline (e.g., atenolol) should be|
00012|019|M|considered. However, since cardioselectivity is not absolute and is less|
00012|020|M|selective at higher doses, cardioselective beta-blockers should be used with|
00012|021|M|caution in patients with bronchospastic disease.|
00012|022|B||
00012|023|D|DISCUSSION:  Inhibition of theophylline metabolism is greatest with|
00012|024|D|lipophilic beta-blockers undergoing hepatic metabolism (e.g., propranolol).|
00012|025|D|Additionally, the decrease in theophylline clearance appears to be dose|
00012|026|D|dependent as the higher the beta-blocker dose, the greater the decrease in|
00012|027|D|theophylline clearance.|
00012|028|D|   If the patient is on both drugs and the beta-blocker is discontinued,|
00012|029|D|serum theophylline concentrations may decrease. In these cases, monitor for|
00012|030|D|a decrease in theophylline therapeutic effect and adjust the dose as needed.|
00012|031|B||
00012|032|R|REFERENCES:|
00012|033|B||
00012|034|R|1.Horvath JS, Woolcock AJ, Tiller DJ, Donnelly P, Armstrong J, Caterson R. A|2
00012|035|R|  comparison of metoprolol and propranolol on blood pressure and respiratory|2
00012|036|R|  function in patients with hypertension. Aust N Z J Med 1978 Feb;8(1):1-6.|2
00012|037|R|2.Mue S, Sasaki T, Shibahara S, Takahashi M, Ohmi T, Yamauchi K, Suzuki S,|2
00012|038|R|  Hida W, Takishima T. Influence of metoprolol on hemodynamics and|2
00012|039|R|  respiratory function in asthmatic patients. Int J Clin Pharmacol Biopharm|2
00012|040|R|  1979 Aug;17(8):346-50.|2
00012|041|R|3.Conrad KA, Nyman DW. Effects of metoprolol and propranolol on theophylline|2
00012|042|R|  elimination. Clin Pharmacol Ther 1980 Oct;28(4):463-7.|2
00012|043|R|4.Kearney TE, Manoguerra AS, Curtis GP, Ziegler MG. Theophylline toxicity|5
00012|044|R|  and the beta-adrenergic system. Ann Intern Med 1985 Jun;102(6):766-9.|5
00012|045|R|5.Miners JO, Wing LM, Lillywhite KJ, Robson RA. Selectivity and|2
00012|046|R|  dose-dependency of the inhibitory effect of propranolol on theophylline|2
00012|047|R|  metabolism in man. Br J Clin Pharmacol 1985 Sep;20(3):219-23.|2
00012|048|R|6.Farrar KT, Dunn AM. Beta-blockers in treatment of theophylline overdose.|6
00012|049|R|  Lancet 1985 Apr 27;1(8435):983.|6
00012|050|R|7.Amin DN, Henry JA. Propranolol administration in theophylline overdose.|3
00012|051|R|  Lancet 1985 Mar 2;1(8427):520-1.|3
00012|052|R|8.Lombardi TP, Bertino JS Jr, Goldberg A, Middleton E Jr, Slaughter RL. The|2
00012|053|R|  effects of a beta-2 selective adrenergic agonist and a beta- nonselective|2
00012|054|R|  antagonist on theophylline clearance. J Clin Pharmacol 1987 Jul;|2
00012|055|R|  27(7):523-9.|2
00012|056|R|9.Cerasa LA, Bertino JS Jr, Ludwig EA, Savliwala M, Middleton E Jr,|2
00012|057|R|  Slaughter RL. Lack of effect of atenolol on the pharmacokinetics of|2
00012|058|R|  theophylline. Br J Clin Pharmacol 1988 Dec;26(6):800-2.|2
00012|059|R|10.Corsi CM, Nafziger AN, Pieper JA, Bertino JS Jr. Lack of effect of|2
00012|060|R|   atenolol and nadolol on the metabolism of theophylline. Br J Clin|2
00012|061|R|   Pharmacol 1990 Feb;29(2):265-8.|2
00013|001|T|MONOGRAPH TITLE:  Sulfonylureas/Systemic Non-Cardioselective Beta-Blockers|
00013|002|B||
00013|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00013|004|L|take action as needed.|
00013|005|B||
00013|006|A|MECHANISM OF ACTION:  Not fully established.  Probably blockade of a variety|
00013|007|A|of beta-adrenergic responses to hypoglycemia.|
00013|008|B||
00013|009|E|CLINICAL EFFECTS:  Diminished response to sulfonylureas and insulin may|
00013|010|E|occur.  Frequency and severity of hypoglycemic episodes may be increased,|
00013|011|E|while warning symptoms of low blood sugar may be masked.|
00013|012|B||
00013|013|P|PREDISPOSING FACTORS:  None determined.|
00013|014|B||
00013|015|M|PATIENT MANAGEMENT:  Try to avoid beta-blocker therapy, particularly in|
00013|016|M|diabetics prone to hypoglycemic attacks.  One of the cardioselective agents|
00013|017|M|may decrease risk of hypertensive attacks and allow more rapid glucose|
00013|018|M|recovery from hypoglycemia.|
00013|019|M|   Patients should be counseled not to rely on tachycardia to diagnose|
00013|020|M|hypoglycemia, since it is masked by beta-blocker therapy.  Diaphoresis is|
00013|021|M|unaffected by beta-blockade and can be used by the diabetic to recognize|
00013|022|M|hypoglycemia.|
00013|023|B||
00013|024|D|DISCUSSION:  A class effect of diminished glucose-lowering effects is|
00013|025|D|expected with concurrent use of beta-blockers and sulfonylureas. It is|
00013|026|D|prudent to monitor serum glucose closely in patients receiving beta-blocker|
00013|027|D|therapy because symptoms of hypoglycemia may be masked.|
00013|028|D|   A double blind, randomized, 12 month study of 39 patients tested the|
00013|029|D|metabolic effects of pindolol (5 mg BID) compared to control group on|
00013|030|D|insulin sensitivity.  The patient's insulin sensitivity index decreased 17%|
00013|031|D|when on pindolol treatment compared to placebo (p<0.01).  Insulin mediated|
00013|032|D|glucose uptake was significantly lower (p<0.05) with propranolol treatment|
00013|033|D|than with placebo.(1)|
00013|034|D|   A study of 26 patients with chronic heart failure showed that carvedilol|
00013|035|D|(average daily dose 27.5 mg/d) caused a significant decrease in fasting|
00013|036|D|insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment|
00013|037|D|levels.  This trial also showed that patients on carvedilol had|
00013|038|D|significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml)|
00013|039|D|compared to the fasting insulin levels (20.72 microU/ml) of patients on|
00013|040|D|bisoprolol treatment (5.9mg/d).(2)|
00013|041|B||
00013|042|R|REFERENCES:|
00013|043|B||
00013|044|R|1.Lithell H, Pollare T, Vessby B. Metabolic effects of pindolol and|2
00013|045|R|  propranolol in a double-blind cross-over study in hypertensive patients.|2
00013|046|R|  Blood Press 1992 Aug;1(2):92-101.|2
00013|047|R|2.Kovacic D, Marinsek M, Gobec L, Lainscak M, Podbregar M. Effect of|2
00013|048|R|  selective and non-selective beta-blockers on body weight, insulin|2
00013|049|R|  resistance and leptin concentration in chronic heart failure. Clin Res|2
00013|050|R|  Cardiol 2008 Jan;97(1):24-31.|2
00013|051|R|3.Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic|2
00013|052|R|  mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic|2
00013|053|R|  hyperglycemia in insulin- dependent diabetes mellitus. J Clin Invest 1982|2
00013|054|R|  Feb;69(2):315-26.|2
00013|055|R|4.Hansten PD. Drug interactions update. Beta-blocking agents and|6
00013|056|R|  antidiabetic drugs. Drug Intell Clin Pharm 1980 Jan;14:46-50.|6
00014|001|T|MONOGRAPH TITLE:  Selected Beta-Blockers/Barbiturates|
00014|002|B||
00014|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00014|004|L|take action as needed.|
00014|005|B||
00014|006|A|MECHANISM OF ACTION:  Induction of hepatic microsomal enzymes by|
00014|007|A|barbiturates decreases bioavailability of oral beta-blockers which are|
00014|008|A|extensively metabolized (e.g., propranolol, metoprolol).|
00014|009|A|   Primidone is metabolized to phenobarbital.|
00014|010|B||
00014|011|E|CLINICAL EFFECTS:  May observe reduced therapeutic response to those|
00014|012|E|beta-blockers metabolized by the liver (e.g., increased pulse rate and|
00014|013|E|increase in systolic and diastolic blood pressures).|
00014|014|B||
00014|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00014|016|P|of the inducer for longer than 1-2 weeks.|
00014|017|B||
00014|018|M|PATIENT MANAGEMENT:  Caution when barbiturates are started or stopped.|
00014|019|M|Adjust dosage of beta-blocker if necessary. This interaction may be avoided|
00014|020|M|by using beta-blockers primarily excreted unchanged by the kidneys (e.g.,|
00014|021|M|atenolol, nadolol).|
00014|022|B||
00014|023|D|DISCUSSION:  The effect of this interaction may be seen in 4 to 5 days after|
00014|024|D|starting barbiturate therapy. If the barbiturate is given for less than 3|
00014|025|D|days a clinically important interaction is unlikely. Serum concentration of|
00014|026|D|the beta-blocker may increase when the barbiturate is discontinued.|
00014|027|D|Additional documentation is necessary to confirm this potential interaction|
00014|028|D|for individual beta-blockers.|
00014|029|B||
00014|030|R|REFERENCES:|
00014|031|B||
00014|032|R|1.Alvan G, Piafsky K, Lind M, von Bahr C. Effect of pentobarbital on the|2
00014|033|R|  disposition of alprenolol. Clin Pharmacol Ther 1977 Sep;22(3):316-21.|2
00014|034|R|2.Alvan G, Lind M, Mellstrom B, von Bahr C. Importance of "first-pass|2
00014|035|R|  elimination" for interindividual differences in steady-state|2
00014|036|R|  concentrations of the adrenergic beta-receptor antagonist alprenolol. J|2
00014|037|R|  Pharmacokinet Biopharm 1977 Jun;5(3):193-205.|2
00014|038|R|3.Collste P, Seideman P, Borg KO, Haglund K, von Bahr C. Influence of|2
00014|039|R|  pentobarbital on effect and plasma levels of alprenolol and|2
00014|040|R|  4-hydroxy-alprenolol. Clin Pharmacol Ther 1979 Apr;25(4):423-7.|2
00014|041|R|4.Sotaniemi EA, Anttila M, Pelkonen RO, Jarvensivu P, Sundquist H. Plasma|2
00014|042|R|  clearance of propranolol and sotalol and hepatic drug- metabolizing enzyme|2
00014|043|R|  activity. Clin Pharmacol Ther 1979 Aug;26(2):153-61.|2
00014|044|R|5.Haglund K, Seideman P, Collste P, Borg KO, von Bahr C. Influence of|2
00014|045|R|  pentobarbital on metoprolol plasma levels. Clin Pharmacol Ther 1979 Sep;|2
00014|046|R|  26(3):326-9.|2
00014|047|R|6.Mantyla R, Mannisto P, Nykanen S, Koponen A, Lamminsivu U. Pharmacokinetic|2
00014|048|R|  interactions of timolol with vasodilating drugs, food and phenobarbitone|2
00014|049|R|  in healthy human volunteers. Eur J Clin Pharmacol 1983;24(2):227-30.|2
00014|050|R|7.Branch RA, Herman RJ. Enzyme induction and beta-adrenergic receptor|6
00014|051|R|  blocking drugs. Br J Clin Pharmacol 1984;17 Suppl 1:77S-84S.|6
00014|052|R|8.Seideman P, Borg KO, Haglund K, Von Bahr C. Decreased plasma|2
00014|053|R|  concentrations and clinical effects of alprenolol during combined|2
00014|054|R|  treatment with pentobarbitone in hypertension. Br J Clin Pharmacol 1987|2
00014|055|R|  Mar;23(3):267-71.|2
00015|001|T|MONOGRAPH TITLE:  Selected Anticoagulants/Antithyroid Drugs (mono deleted|
00015|002|T|02/23/2022)|
00015|003|B||
00015|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00015|005|L|take action as needed.|
00015|006|B||
00015|007|A|MECHANISM OF ACTION:  Antithyroid drugs may decrease breakdown of vitamin-K|
00015|008|A|dependent clotting factors, thus increasing the amount of clotting factors|
00015|009|A|available for use.|
00015|010|B||
00015|011|E|CLINICAL EFFECTS:  Decreased clearance of vitamin K dependent clotting|
00015|012|E|factors by antithyroid drugs may result in decreased therapeutic effects of|
00015|013|E|anticoagulants.  However, if thioamide-induced hypothrombinemia occurs, the|
00015|014|E|activity of the anticoagulant may be increased.|
00015|015|B||
00015|016|P|PREDISPOSING FACTORS:  None determined.|
00015|017|B||
00015|018|M|PATIENT MANAGEMENT:  If antithyroid treatment is started or discontinued in|
00015|019|M|patients stabilized on anticoagulant therapy, INRs should be closely|
00015|020|M|monitored and the anticoagulant dose should be adjusted as needed.  Some|
00015|021|M|patients may require alternative hyperthyroid medication in order to achieve|
00015|022|M|therapeutic anticoagulation.|
00015|023|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00015|024|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00015|025|M|initiating, altering the dose or discontinuing either drug.|
00015|026|B||
00015|027|D|DISCUSSION:  Caution should be used when this drug combination if given. In|
00015|028|D|the clinically hyperthyroid patient, the breakdown of the vitamin|
00015|029|D|k-dependent clotting factors is increased resulting in quicker and greater|
00015|030|D|response to the anticoagulant. When antithyroid drugs are administered to|
00015|031|D|correct this, the response to the anticoagulant may decrease. An increase in|
00015|032|D|the anticoagulant dosage may be required.|
00015|033|D|   There are several reports of decreased anticoagulant effects in patients|
00015|034|D|receiving antithyroid agents.  There has been one case reported where the|
00015|035|D|patient experienced an increased response to warfarin when propylthiouracil|
00015|036|D|was added to the patient's drug regimen.|
00015|037|B||
00015|038|R|REFERENCES:|
00015|039|B||
00015|040|R|1.Greenstein RH. Hypoprothrombinemia due to propylthiouracil therapy. JAMA|3
00015|041|R|  1960 Jul 2;173(9):1014-5.|3
00015|042|R|2.Naeye RL, Terrien CM. Hemorrhagic state after therapy with|3
00015|043|R|  propylthiouracil. Am J Clin Pathol 1960 Sep;34(3):254-7.|3
00015|044|R|3.Walters MB. The relationship between thyroid function and anticoagulant|3
00015|045|R|  therapy. Am J Cardiol 1963 Jan;11:112-4.|3
00015|046|R|4.Loeliger EA, van der Esch B, Mattern MJ, Hemker HC. The biological|2
00015|047|R|  disappearance rate of prothrombin, factors VII, IX and X from plasma in|2
00015|048|R|  hypothyoidism, hyperthyroidism, and during fever. Thrombos Diathes|2
00015|049|R|  Haemorrh 1963;10:267-77.|2
00015|050|R|5.Gilbert DK. Hypoprothrombinemia as a complication of propylthiouracil.|3
00015|051|R|  JAMA 1964 Sep;189(11):855.|3
00015|052|R|6.Rice AJ, McIntosh TJ, Fouts JR, Brunk SF, Wilson WR. Decreased sensitivity|2
00015|053|R|  to warfarin in patients with myxedema. Am J Med Sci 1971 Oct;262(4):211-5.|2
00015|054|R|7.Gotta AW, Sullivan CA, Seaman J, Jean-Gilles B. Prolonged intraoperative|3
00015|055|R|  bleeding caused by propylthiouracil-induced hypoprothrombinemia.|3
00015|056|R|  Anesthesiology 1972 Nov;37(5):562-3.|3
00015|057|R|8.Vagenakis AG, Cote R, Miller ME, Braverman LE, Stohlman F Jr. Enhancement|3
00015|058|R|  of warfarin-induced hypoprothrombinemia by thyrotoxicosis. Johns Hopkins|3
00015|059|R|  Med J 1972 Jul;131(1):69-73.|3
00015|060|R|9.Self T, Weisburst M, Wooten E, Straughn A, Oliver J. Warfarin-induced|3
00015|061|R|  hypoprothrombinemia. Potentiation by hyperthyroidism. JAMA 1975 Mar 17;|3
00015|062|R|  231(11):1165-6.|3
00015|063|R|10.Hansten PD. Drug interactions update. Oral anticoagulants and drugs which|6
00015|064|R|   alter thyroid function. Drug Intell Clin Pharm 1980 May;14(5):331-4.|6
00015|065|R|11.Costigan DC, Freedman MH, Ehrlich RM. Potentiation of oral anticoagulant|3
00015|066|R|   effect by L-thyroxine. Clin Pediatr (Phila) 1984 Mar;23(3):172-4.|3
00015|067|R|12.Akin F, Yaylali GF, Bastemir M, Yapar B. Effect of methimazole on|3
00015|068|R|   warfarin anticoagulation in a case of Graves' disease. Blood Coagul|3
00015|069|R|   Fibrinolysis 2008 Jan;19(1):89-91.|3
00015|070|R|13.Squizzato A, Vitale J, Gerdes VE, Romualdi E, Buller HR, Ageno W.|3
00015|071|R|   Recurrent deep venous thrombosis during optimal anticoagulation and overt|3
00015|072|R|   hyperthyroidism: a case report. Blood Coagul Fibrinolysis 2007 Dec;|3
00015|073|R|   18(8):801-3.|3
00015|074|R|14.Busenbark LA, Cushnie SA. Effect of Graves' disease and methimazole on|3
00015|075|R|   warfarin anticoagulation. Ann Pharmacother 2006 Jun;40(6):1200-3.|3
00016|001|T|MONOGRAPH TITLE:  Epinephrine/Non-Cardioselective Beta-Blockers|
00016|002|B||
00016|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00016|004|L|of severe adverse interaction.|
00016|005|B||
00016|006|A|MECHANISM OF ACTION:  Concurrent use of beta-blockers also block the beta|
00016|007|A|effects of epinephrine, which results in predomination of alpha effects.|
00016|008|A|The plasma clearance of epinephrine is decreased.|
00016|009|B||
00016|010|E|CLINICAL EFFECTS:  Concurrent use of epinephrine with beta-blockers may|
00016|011|E|result in hypertension with reflex bradycardia.  Epinephrine resistance in|
00016|012|E|patients with anaphylaxis has been reported.|
00016|013|B||
00016|014|P|PREDISPOSING FACTORS:  None determined.|
00016|015|B||
00016|016|M|PATIENT MANAGEMENT:  Avoid concomitant administration of epinephrine and|
00016|017|M|beta-blockers if possible.  If both drugs are administered, monitor blood|
00016|018|M|pressure carefully.  Hypertension and bradycardia are less likely to occur|
00016|019|M|with cardioselective beta-blockers.  Use caution when treating anaphylaxis|
00016|020|M|with epinephrine since response may be poor.|
00016|021|B||
00016|022|D|DISCUSSION:  In a study of 6 subjects, an increase in mean arterial pressure|
00016|023|D|(MAP) of 15.1% (p < 0.05) was observed after an infusion of epinephrine (10|
00016|024|D|ng/kg/min) followed by an intravenous injection of propranolol (40 mcg/kg).|
00016|025|D|In addition, plasma clearance of epinephrine decreased to 54.7% of the|
00016|026|D|control value after the dose of propranolol.(1)|
00016|027|D|   In another study of 6 subjects, patients were intravenously administered|
00016|028|D|15 mcg epinephrine, followed by propranolol 0.04 mg/kg, and then another|
00016|029|D|dose of epinephrine.  A mean decrease in heart rate of 37% (p < 0.001) was|
00016|030|D|observed following the second dose of epinephrine.(2)|
00016|031|D|   In a study in 10 healthy subjects, an increase in MAP was observed after|
00016|032|D|infusion of epinephrine (5 mcg/min) followed by infusion of propranolol (10|
00016|033|D|mg).(5)|
00016|034|D|   In a study in 1 healthy subject, marked bradycardia and atrioventricular|
00016|035|D|block occurred after administration of propranolol (40 mg orally) with|
00016|036|D|epinephrine (17 mcg/min intravenously).(6)|
00016|037|D|   In a study in 7 healthy subjects, and increase in MAP (8% increase in|
00016|038|D|systolic blood pressure, 10% increase in diastolic blood pressure) was|
00016|039|D|observed after injection of epinephrine (45 mcg in lidocaine) in to the|
00016|040|D|maxilla after pretreatment with pindolol (5 mg).(7)|
00016|041|D|   A retrospective analysis of sinus surgery patients found that 9.1% had|
00016|042|D|exaggerated intraoperative hypertensive events during the first surgical|
00016|043|D|hour (defined as relative increase greater than 20% of systolic blood|
00016|044|D|pressure or single systolic blood pressure value above 200 mmHg). Subjects|
00016|045|D|with established beta blockade were found to be three times as likely to|
00016|046|D|experience an exaggerated hypertensive event during the first intraoperative|
00016|047|D|hour.(8)|
00016|048|D|   In a study, intraoral injection with 2% lidocaine containing epinephrine|
00016|049|D|(45 mcg) after pretreatment with pindolol (5 mg) resulted reduced stroke|
00016|050|D|volume, increase in afterload, decreased myocardial contractility, decreased|
00016|051|D|heart rate, and an increase in blood pressure.(9)|
00016|052|D|   In a study in 8 subjects, a comparison of propranolol (80 mg three times|
00016|053|D|daily) or metoprolol (100 mg three times daily) with epinephrine (8 mcg/min|
00016|054|D|for 6 minutes) showed that propranolol significantly increases MAP while|
00016|055|D|metoprolol, a beta1-selective beta-blocker, does not.(10)|
00016|056|D|   There are several case reports of significant hypertension with reflex|
00016|057|D|bradycardia.(9-12) In some of these case reports patients had strokes.(12)|
00016|058|B||
00016|059|R|REFERENCES:|
00016|060|B||
00016|061|R|1.Ichinohe T, Igarashi O, Kaneko Y. The influence of propranolol on the|2
00016|062|R|  cardiovascular effects and plasma clearance of epinephrine. Anesth Prog|2
00016|063|R|  1991 Nov-Dec;38(6):217-20.|2
00016|064|R|2.Mackie K, Lam A. Epinephrine-containing test dose during beta-blockade. J|2
00016|065|R|  Clin Monit 1991 Jul;7(3):213-6.|2
00016|066|R|3.Houben H, Thien T, De Boo T, Lemmens W, Van Herwaarden CL, Fennis JF, Van|2
00016|067|R|  't Laar A. Influence of selective and non-selective beta-adrenoreceptor|2
00016|068|R|  blockade on the haemodynamic effect of adrenaline during combined|2
00016|069|R|  antihypertensive drug therapy. Clin Sci (Lond) 1979 Dec;57 Suppl|2
00016|070|R|  5:397s-399s.|2
00016|071|R|4.Newman BR, Schultz LK. Epinephrine-resistant anaphylaxis in a patient|3
00016|072|R|  taking propranolol hydrochloride. Ann Allergy 1981 Jul;47(1):35-7.|3
00016|073|R|5.Harris WS, Schoenfeld CD, Brooks RH, Weissler AM. Effect of beta|2
00016|074|R|  adrenergic blockade on the hemodynamic responses to epinephrine in man. Am|2
00016|075|R|  J Cardiol 1966 Apr;17(4):484-92.|2
00016|076|R|6.Kram J, Bourne HR, Melmon KL, Maibach H. Letter: Propranolol. Ann Intern|2
00016|077|R|  Med 1974 Feb;80(2):282.|2
00016|078|R|7.Niwa H, Shibutani T, Hori T, Kim Y, Akita M, Matsuura H. The interaction|2
00016|079|R|  between pindolol and epinephrine contained in local anesthetic solution to|2
00016|080|R|  the left ventricular diastolic filling velocity in normal subjects. Anesth|2
00016|081|R|  Prog 1996 Summer;43(3):78-84.|2
00016|082|R|8.Schechtman SA, Wertz AP, Shanks A, Thompson A, Tremper K, Pynnonen MA,|2
00016|083|R|  Healy DW. Preoperative beta-blockade and hypertension in the first hour of|2
00016|084|R|  functional endoscopic sinus surgery. Laryngoscope 2017 Jul;|2
00016|085|R|  127(7):1496-1505.|2
00016|086|R|9.Sugimura M, Hirota Y, Shibutani T, Niwa H, Hori T, Kim Y, Matsuura H. An|2
00016|087|R|  echocardiographic study of interactions between pindolol and epinephrine|2
00016|088|R|  contained in a local anesthetic solution. Anesth Prog 1995;42(2):29-35.|2
00016|089|R|10.van Herwaarden CLA, Binkhorst RA, Fennis JFM, Van't Laar A. Effects of|2
00016|090|R|   adrenaline during treatment with propranolol and metoprolol. Br Med J|2
00016|091|R|   1977 Apr;1(6067):1029.|2
00016|092|R|11.Foster CA, Aston SJ. Propranolol-epinephrine interaction: a potential|3
00016|093|R|   disaster. Plast Reconstr Surg 1983 Jul;72(1):74-8.|3
00016|094|R|12.Hansbrough JF, Near A. Propranolol-Epinephrine antagonism with|3
00016|095|R|   hypertension and stroke. Ann Intern Med 1980;92(5):717.|3
00016|096|R|13.Gandy W. Severe epinephrine-propranolol interaction. Ann Emerg Med 1989|3
00016|097|R|   Jan;18(1):98-9.|3
00016|098|R|14.Whelan TV. Propranolol, epinephrine, and accelerated hypertension during|3
00016|099|R|   hemodialysis. Ann Intern Med 1987 Feb;106(2):327.|3
00017|001|T|MONOGRAPH TITLE:  Diazoxide/Thiazide Diuretics (mono deleted 04/03/2025)|
00017|002|B||
00017|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00017|004|L|take action as needed.|
00017|005|B||
00017|006|A|MECHANISM OF ACTION:  Diazoxide may displace thiazide diuretics from protein|
00017|007|A|binding sites. The hyperglycemic effects may be additive or potentiated by|
00017|008|A|concurrent administration.|
00017|009|B||
00017|010|E|CLINICAL EFFECTS:  Increased hyperglycemic activity.|
00017|011|B||
00017|012|P|PREDISPOSING FACTORS:  None determined.|
00017|013|B||
00017|014|M|PATIENT MANAGEMENT:  If possible, select an alternative diuretic. Otherwise,|
00017|015|M|administer cautiously, monitor the patient closely and adjust the dose of|
00017|016|M|either or both agents as indicated.|
00017|017|B||
00017|018|D|DISCUSSION:  Exercise caution, especially when treating diazoxide-induced|
00017|019|D|sodium retention with thiazides. In patients with renal impairment, a|
00017|020|D|thiazide diuretic may be ineffective or aggravate the condition. In this|
00017|021|D|situation, a loop diuretic may be more effective.|
00017|022|B||
00017|023|R|REFERENCES:|
00017|024|B||
00017|025|R|1.Dollery CT, Pentecost BL, Samaan NA. Drug-induced diabetes. Lancet 1962|3
00017|026|R|  Oct 13;2:735-7.|3
00017|027|R|2.Okun R. Use of diazoxide with trichlormethiazide for hypertension. Arch|2
00017|028|R|  Int Med 1963 Dec;112(6):882-8.|2
00017|029|R|3.Ernesti M, Mitchell ML, Raben MS, Gilboa Y. Control of hypoglycaemia with|3
00017|030|R|  diazoxide and human growth hormone. Lancet 1960 Mar 20;1:628-30.|3
00017|031|R|4.Seltzer HS, Allen EW. Hyperglycemia and inhibition of insulin secretion|2
00017|032|R|  during administration of diazoxide and trichlormethiazide in man. Diabetes|2
00017|033|R|  1969 Jan;18(1):19-28.|2
00017|034|R|5.Sellers EM, Koch-Weser J. Protein binding and vascular activity of|5
00017|035|R|  diazoxide. N Engl J Med 1969 Nov 20;281(21):1141-5.|5
00017|036|R|6.Hypotensive Agents (diazoxide) 24:08. In AHFS Drug Information. Bethesda|6
00017|037|R|  MD: American Society of Health-System Pharmacists, Inc. 1994.|6
00018|001|T|MONOGRAPH TITLE:  Hydantoins/Selected Anticoagulants (Vitamin K antagonists)|
00018|002|B||
00018|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00018|004|L|of severe adverse interaction.|
00018|005|B||
00018|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Possible mechanisms|
00018|007|A|include alteration of hepatic metabolism of both agents and alteration in|
00018|008|A|levels of vitamin-K dependent clotting factors by hydantoins.|
00018|009|B||
00018|010|E|CLINICAL EFFECTS:  Multiple effects may be seen including an increase or|
00018|011|E|decrease in INR.  Anticoagulant effects have been found to increase|
00018|012|E|initially when hydantoins are initiated and then to decrease thereafter in|
00018|013|E|some patients.|
00018|014|E|   In patients receiving acenocoumarol or dicoumarol, elevation of hydantoin|
00018|015|E|plasma levels has been described.  Phenytoin has a narrow therapeutic range.|
00018|016|E|Early symptoms of hydantoin toxicity may include nystagmus, ataxia,|
00018|017|E|dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision,|
00018|018|E|nausea, and vomiting.  Severe toxicity may produce organ dysfunction (e.g.|
00018|019|E|coma, irreversible cerebellar dysfunction and atrophy, hypotension,|
00018|020|E|bradycardia, seizures, and cardiac arrest) and may be fatal.(10)|
00018|021|E|   Concurrent use of hydantoins and anticoagulants may increase the risk for|
00018|022|E|bleeding.|
00018|023|B||
00018|024|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00018|025|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00018|026|P|   Drug associated risk factors include concurrent use of multiple drugs|
00018|027|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00018|028|P|risk for bleeding (e.g. NSAIDs).|
00018|029|P|   Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2|
00018|030|P|copies of a reduced function VKORC1 gene are expected to be more susceptible|
00018|031|P|to this interaction.|
00018|032|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00018|033|P|are expected to be less susceptible to effects from this drug combination,|
00018|034|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00018|035|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
00018|036|P|warfarin-associated bleeding.  CYP2C9 poor metabolizers generally require|
00018|037|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
00018|038|P|and safe anticoagulation than patients without these CYP2C9 variants.|
00018|039|P|   Risk factors for hydantoin toxicity include renal impairment, hepatic|
00018|040|P|impairment, or hypoalbuminemia.|
00018|041|B||
00018|042|M|PATIENT MANAGEMENT:  The time of highest risk for a coumarin-type drug|
00018|043|M|interaction is when the precipitant drug is initiated or discontinued.  Use|
00018|044|M|caution when initiating, altering the dose or discontinuing either drug.|
00018|045|M|Monitor INR and adjust the anticoagulant dose accordingly.  Extended|
00018|046|M|monitoring may be needed as an initial increase in the INR may be followed|
00018|047|M|by a fall in the INR due to phenytoin induction of warfarin metabolism.|
00018|048|M|Monitor patients receiving concurrent therapy for signs of blood loss,|
00018|049|M|including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
00018|050|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
00018|051|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
00018|052|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00018|053|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00018|054|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00018|055|M|and/or swelling.|
00018|056|M|   Patients receiving acenocoumarol or dicoumarol and a hydantoin should|
00018|057|M|also have hydantoin levels monitored and adjusted when anticoagulant therapy|
00018|058|M|is initiated.  Monitor the patient for signs of hydantoin toxicity (e.g.|
00018|059|M|nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred|
00018|060|M|speech, blurred vision, nausea, and vomiting).|
00018|061|B||
00018|062|D|DISCUSSION:  In one case report, a patient had been stabilized on warfarin|
00018|063|D|2.5 mg 5 days of the week and 5 mg 2 days of the week with a maximum|
00018|064|D|prothrombin time of 21 seconds.  When phenytoin (300 mg daily) was|
00018|065|D|initiated, the patient's warfarin dose was decreased to 2.5 mg daily, but|
00018|066|D|the patient's prothrombin time increased to 32 seconds over the course of|
00018|067|D|one month (5).|
00018|068|D|   In another case report, a patient had been stabilized on warfarin (5 mg|
00018|069|D|daily) for 43 days at which time the patient experienced a seizure during|
00018|070|D|hospitalization.  Phenytoin (250 mg every 8 hours for four doses followed by|
00018|071|D|200 mg daily) was initiated along with a dose reduction in warfarin.  The|
00018|072|D|anticoagulant effect increased over the following six days and then|
00018|073|D|decreased to an anticoagulant response lower than the response prior to|
00018|074|D|initiation of phenytoin (3).|
00018|075|D|   In another report, a patient developed a retroperitoneal hemorrhage 7|
00018|076|D|days after the addition of phenytoin (300 mg daily) to his warfarin regimen.|
00018|077|D|His INR at the time was 10.41.  He died 3 days later of cardiac arrest.(4)|
00018|078|D|   Another article describes 2 case reports of elevated PTTs following the|
00018|079|D|addition of phenytoin (300 mg daily) to previously stable warfarin|
00018|080|D|regimens.(5)|
00018|081|D|   In contrast to these reports, a patient experienced elevated INR levels|
00018|082|D|following the discontinuation of phenytoin.(6)|
00018|083|D|   In a population pharmacokinetic study of patients receiving warfarin,|
00018|084|D|phenytoin use was associated with a 30% increase in warfarin clearance.(7)|
00018|085|D|   In a small study of six subjects, diphenylhydantoin (300 mg daily) was|
00018|086|D|administered until a stable concentration was achieved.  Then, dicoumarol|
00018|087|D|was administered for one week to give a prothrombin value of about 30% and|
00018|088|D|the effects on serum diphenylhydantoin concentrations were evaluated.  An|
00018|089|D|increase ranging from 38-250% was found in all six subjects.(8).|
00018|090|D|   In a case report, a patient previously stabilized on acenocoumarol|
00018|091|D|developed elevated INR levels following the addition of phenytoin (100 mg 3|
00018|092|D|times daily) to her regimen.  She also had unexpectedly high phenytoin|
00018|093|D|levels and experienced phenytoin toxicity.  She was found to have a mutation|
00018|094|D|in CYP2C9, resulting in slowed metabolism of both agents.(9)|
00018|095|B||
00018|096|R|REFERENCES:|
00018|097|B||
00018|098|R|1.Skovsted L, Kristensen M, Hansen M, Siersbaek-Nielsen K. The effect of|2
00018|099|R|  different oral anticoagulants on diphenylhydantoin (DPH) and tolbutamide|2
00018|100|R|  metabolism. Acta Med Scand 1976;199(6):513-5.|2
00018|101|R|2.Taylor JW, Alexander B, Lyon LW. A comparative evaluation of oral|6
00018|102|R|  anticoagulant-phenytoin interactions. Drug Intell Clin Pharm 1980 Oct;|6
00018|103|R|  14(10):669-73.|6
00018|104|R|3.Levine M, Sheppard I. Biphasic interaction of phenytoin with warfarin.|3
00018|105|R|  Clin Pharm 1984 Mar-Apr;3(2):200-3.|3
00018|106|R|4.Panegyres PK, Rischbieth RH. Fatal phenytoin warfarin interaction.|3
00018|107|R|  Postgrad Med J 1991 Jan;67(783):98.|3
00018|108|R|5.Nappi JM. Warfarin and phenytoin interaction. Ann Intern Med 1979 May;|3
00018|109|R|  90(5):852.|3
00018|110|R|6.Hassan Y, Awaisu A, Aziz NA, Ismail O. The complexity of achieving|3
00018|111|R|  anticoagulation control in the face of warfarin-phenytoin interaction: an|3
00018|112|R|  Asian case report. Pharm World Sci 2005 Feb;27(1):16-9.|3
00018|113|R|7.Mungall DR, Ludden TM, Marshall J, Hawkins DW, Talbert RL, Crawford MH.|2
00018|114|R|  Population pharmacokinetics of racemic warfarin in adult patients. J|2
00018|115|R|  Pharmacokinet Biopharm 1985 Jun;13(3):213-27.|2
00018|116|R|8.Hansen JM, Kristensen M, Skovsted L, Christensen LK. Dicoumarol-induced|2
00018|117|R|  diphenylhydantoin intoxication. Lancet 1966 Jul 30;2(7457):265-6.|2
00018|118|R|9.Jose L, Binila C, Chandy SJ, Mathews JE, Mathews KP. Acenocoumarol and|3
00018|119|R|  phenytoin toxicity in the presence of CYP2C9 mutation. J Assoc Physicians|3
00018|120|R|  India 2008 Apr;56:250-2.|3
00018|121|R|10.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00018|122|R|   March, 2022.|1
00019|001|T|MONOGRAPH TITLE:  Quinidine/Hydantoins (mono deleted 08/08/2013)|
00019|002|B||
00019|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00019|004|L|take action as needed.|
00019|005|B||
00019|006|A|MECHANISM OF ACTION:  It is speculated that induction of hepatic microsomal|
00019|007|A|enzymes result in increased quinidine metabolism.|
00019|008|B||
00019|009|E|CLINICAL EFFECTS:  Quinidine activity may be decreased.|
00019|010|B||
00019|011|P|PREDISPOSING FACTORS:  None determined.|
00019|012|B||
00019|013|M|PATIENT MANAGEMENT:  Caution when starting or stopping hydantoins. Adjust|
00019|014|M|quinidine dose as needed based on serum levels and clinical response.|
00019|015|B||
00019|016|D|DISCUSSION:  The interaction is likely to occur, but clinical documentation|
00019|017|D|is limited. It is noteworthy that this interaction may persist for several|
00019|018|D|days after the hydantoin is discontinued.|
00019|019|B||
00019|020|R|REFERENCE:|
00019|021|B||
00019|022|R|1.Data JL, Wilkinson GR, Nies AS. Interaction of quinidine with|3
00019|023|R|  anticonvulsant drugs. N Engl J Med 1976 Mar 25;294(13):699-702.|3
00020|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Quinidine|
00020|002|B||
00020|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00020|004|L|of severe adverse interaction.|
00020|005|B||
00020|006|A|MECHANISM OF ACTION:  Quinidine may inhibit the transport of digoxin by|
00020|007|A|P-glycoprotein (P-gp).|
00020|008|B||
00020|009|E|CLINICAL EFFECTS:  Concurrent quinidine may result in digoxin toxicity.|
00020|010|E|Symptoms of digoxin toxicity can include anorexia, nausea, vomiting,|
00020|011|E|headache, fatigue, malaise, drowsiness, generalized muscle weakness,|
00020|012|E|disorientation, hallucinations, visual disturbances, and arrhythmias.|
00020|013|B||
00020|014|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
00020|015|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00020|016|P|risk of digoxin toxicity.|
00020|017|B||
00020|018|M|PATIENT MANAGEMENT:  In patients receiving concurrent quinidine, monitor|
00020|019|M|serum digoxin levels and for signs and symptoms of digoxin toxicity.  The|
00020|020|M|dosage of digoxin may need to be adjusted by 30% to 50% or its frequency of|
00020|021|M|administration adjusted if quinidine is initiated or discontinued.  Consider|
00020|022|M|therapy with an agent which has not been shown to interact with digoxin.|
00020|023|B||
00020|024|D|DISCUSSION:  In a study of six subjects, quinidine sulfate (300 mg every 6|
00020|025|D|hours) was given orally for 3 days prior to an injection of digoxin (1 mg)|
00020|026|D|and then continued for 5 more days.  Systemic clearance of digoxin was|
00020|027|D|reduced by 45%, the renal clearance reduced by 33%, and the nonrenal|
00020|028|D|clearance reduced by 60% with all values being statistically significant.|
00020|029|D|   In another study of 101 subjects receiving digoxin alone and 20 subjects|
00020|030|D|receiving digoxin and quinidine together, the addition of quinidine was|
00020|031|D|found to decrease digoxin clearance by 26%.  In addition, 10 of the 20|
00020|032|D|subjects (50%) receiving digoxin and quinidine together were confirmed to|
00020|033|D|have digitalis toxicity, whereas only 5 of the 101 subjects (4.9%) receiving|
00020|034|D|digoxin alone were confirmed to have digitalis toxicity. The authors|
00020|035|D|concluded that quinidine caused an increase in digoxin toxicity even in the|
00020|036|D|therapeutic serum digoxin levels(2).|
00020|037|D|   In a clinical pharmacokinetic in vitro study, a portion of the jejunum|
00020|038|D|was taken from seven healthy subjects with a multilumen perfusion catheter.|
00020|039|D|A portion of the jejunal segment was added with digoxin alone while another|
00020|040|D|portion had administered digoxin with quinidine. The results indicated that|
00020|041|D|when digoxin was added alone 22.3%(+/-8.9%) was absorbed; the addition of|
00020|042|D|quinidine to the jejunal segment caused an increase in the fraction of|
00020|043|D|absorbed digoxin by 55.8%(+/-21.2%)(p<0.05). Also, the Cmax for digoxin|
00020|044|D|alone was 1.0ng/ml/mg(+/-0.4) while digoxin administered with quinidine|
00020|045|D|caused a Cmax increase to 3.8ng/ml/mg(+/-1.2) (P<0.001)(3).|
00020|046|D|   Concomitant administration of quinidine and digoxin increased the digoxin|
00020|047|D|serum concentration 100%. (17)|
00020|048|B||
00020|049|R|REFERENCES:|
00020|050|B||
00020|051|R|1.Wandell M, Powell JR, Hager WD, Fenster PE, Graves PE, Conrad KA, Goldman|2
00020|052|R|  S. Effect of quinine on digoxin kinetics. Clin Pharmacol Ther 1980 Oct;|2
00020|053|R|  28(4):425-30.|2
00020|054|R|2.Mordel A, Halkin H, Zulty L, Almog S, Ezra D. Quinidine enhances digitalis|2
00020|055|R|  toxicity at therapeutic serum digoxin levels. Clin Pharmacol Ther 1993|2
00020|056|R|  Apr;53(4):457-62.|2
00020|057|R|3.Igel S, Drescher S, Murdter T, Hofmann U, Heinkele G, Tegude H, Glaeser H,|5
00020|058|R|  Brenner SS, Somogyi AA, Omari T, Schafer C, Eichelbaum M, Fromm MF.|5
00020|059|R|  Increased absorption of digoxin from the human jejunum due to inhibition|5
00020|060|R|  of intestinal transporter-mediated efflux. Clin Pharmacokinet 2007;|5
00020|061|R|  46(9):777-85.|5
00020|062|R|4.Aronson JK, Carver JG. Interaction of digoxin with quinine. Lancet 1981|2
00020|063|R|  Jun 27;1(8235):1418.|2
00020|064|R|5.Schenck-Gustafsson K, Jogestrand T, Brodin LA, Nordlander R, Dahlqvist R.|2
00020|065|R|  Cardiac effects of treatment with quinidine and digoxin, alone and in|2
00020|066|R|  combination. Am J Cardiol 1983 Mar 1;51(5):777-82.|2
00020|067|R|6.Doering W. Effect of coadministration of verapamil and quinidine on serum|2
00020|068|R|  digoxin concentration. Eur J Clin Pharmacol 1983;25(4):517-21.|2
00020|069|R|7.Bussey HI. Update on the influence of quinidine and other agents on|6
00020|070|R|  digitalis glycosides. Am Heart J 1984 Jan;107(1):143-6.|6
00020|071|R|8.Jogestrand T, Schenck-Gustafsson K, Nordlander R, Dahlqvist R.|2
00020|072|R|  Quinidine-induced changes in serum and skeletal muscle digoxin|2
00020|073|R|  concentration; evidence of saturable binding of digoxin to skeletal|2
00020|074|R|  muscle. Eur J Clin Pharmacol 1984;27(5):571-5.|2
00020|075|R|9.Das G, Barr CE, Carlson J. Reduction of digoxin effect during the|2
00020|076|R|  digoxin-quinidine interaction. Clin Pharmacol Ther 1984 Mar;35(3):317-21.|2
00020|077|R|10.Fenster PE, Hager WD, Goodman MM. Digoxin-quinidine-spironolactone|2
00020|078|R|   interaction. Clin Pharmacol Ther 1984 Jul;36(1):70-3.|2
00020|079|R|11.Pedersen KE, Lysgaard Madsen J, Klitgaard NA, Kjaer K, Hvidt S. Effect of|2
00020|080|R|   quinine on plasma digoxin concentration and renal digoxin clearance. Acta|2
00020|081|R|   Med Scand 1985;218(2):229-32.|2
00020|082|R|12.Angelin B, Arvidsson A, Dahlqvist R, Hedman A, Schenck-Gustafsson K.|2
00020|083|R|   Quinidine reduces biliary clearance of digoxin in man. Eur J Clin Invest|2
00020|084|R|   1987 Jun;17(3):262-5.|2
00020|085|R|13.Hedman A, Angelin B, Arvidsson A, Dahlqvist R, Nilsson B. Interactions in|2
00020|086|R|   the renal and biliary elimination of digoxin: stereoselective difference|2
00020|087|R|   between quinine and quinidine. Clin Pharmacol Ther 1990 Jan;47(1):20-6.|2
00020|088|R|14.Hedman A. Inhibition by basic drugs of digoxin secretion into human bile.|5
00020|089|R|   Eur J Clin Pharmacol 1992;42(4):457-9.|5
00020|090|R|15.Williams PJ, Lane J, Murray W, Mergener MA, Kamigaki M. Pharmacokinetics|2
00020|091|R|   of the digoxin-quinidine interaction via mixed-effect modelling. Clin|2
00020|092|R|   Pharmacokinet 1992 Jan;22(1):66-74.|2
00020|093|R|16.US Food and Drug Administration (FDA). Drug Development and Drug|1
00020|094|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
00020|095|R|   at:|1
00020|096|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
00020|097|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
00020|098|R|   11/14/2017.|1
00020|099|R|17.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00020|100|R|   Pharmaceuticals, Inc. August, 2018.|1
00021|001|T|MONOGRAPH TITLE:  Corticosteroids/Hormonal Contraceptives; Estrogens|
00021|002|B||
00021|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00021|004|L|take action as needed.|
00021|005|B||
00021|006|A|MECHANISM OF ACTION:  It is speculated that hormonal contraceptives and|
00021|007|A|estrogens inhibit hepatic metabolism of some corticosteroids as well as|
00021|008|A|endogenous cortisol.  Competitive protein binding may also contribute to|
00021|009|A|elevations in serum corticosteroids.|
00021|010|B||
00021|011|E|CLINICAL EFFECTS:  Concurrent use of hormonal contraceptives or estrogens|
00021|012|E|may result in an increase in the therapeutic and toxic effects of|
00021|013|E|corticosteroids.|
00021|014|B||
00021|015|P|PREDISPOSING FACTORS:  None determined.|
00021|016|B||
00021|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent hormonal contraceptives|
00021|018|M|or estrogen should be observed for symptoms of corticosteroid toxicity. A|
00021|019|M|lower corticosteroid dose may be required.|
00021|020|B||
00021|021|D|DISCUSSION:  In a study in 6 healthy females controlled on long-term oral|
00021|022|D|contraceptives, subjects received either a placebo or high and low-dose|
00021|023|D|prednisolone (0.53 and 0.14 mg/Kg iv).  Both dosages of prednisolone|
00021|024|D|decreased the total clearance, unbound clearance, and volume of distribution|
00021|025|D|(Vd) at maximum concentration (Cmax) of total drug.  Significant increases|
00021|026|D|in half-life for free and unbound prednisolone and hydrocortisone|
00021|027|D|concentrations were also observed in comparison to the placebo group.|
00021|028|D|   In a study in 8 females controlled on oral contraceptive therapy, 8|
00021|029|D|females not receiving contraceptive therapy, and 8 males, each subject|
00021|030|D|received prednisolone 40 mg iv.  The plasma clearance of total prednisolone|
00021|031|D|in females on OC was 96 ml/min, which was significantly lower than those in|
00021|032|D|both the male and female (205 and 187 ml/min, respectively) control groups.|
00021|033|D|Prednisolone half-life and mean residence times were increased.  The oral|
00021|034|D|contraceptive group had a significantly higher (2-fold) concentration of|
00021|035|D|transcortin, resulting in lower clearance, decreased Vd, and a 2-fold|
00021|036|D|increase in the area-under-curve (AUC) for prednisolone.|
00021|037|D|   A clinical trial demonstrated the interaction between prednisolone (20|
00021|038|D|mg) and oral contraceptives containing ethinyl estradiol (30 mcg).  The oral|
00021|039|D|contraceptive users had an average plasma concentration of prednisolone 131%|
00021|040|D|higher compared to the control group, and plasma cortisol levels were|
00021|041|D|suppressed by approximately 90%.  No differences were reported for ethinyl|
00021|042|D|estradiol levels.|
00021|043|D|   In a study in 8 females taking oral contraceptives and 8 females who were|
00021|044|D|were not, subjects received IV doses of prednisolone at 0.1 mg/Kg and 1.0|
00021|045|D|mg/Kg.  Free prednisolone clearance was reduced by approximately 30% in the|
00021|046|D|contraceptive receiving subjects compared to the control group, and plasma|
00021|047|D|cortisol concentrations were reduced 2-fold compared to the control group.|
00021|048|D|   One or more of the drug pairs linked to this monograph have been included|
00021|049|D|in a list of interactions that could be considered for classification as|
00021|050|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
00021|051|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
00021|052|D|Health Information Technology.|
00021|053|B||
00021|054|R|REFERENCES:|
00021|055|B||
00021|056|R|1.Legler UF, Benet LZ. Marked alterations in dose-dependent prednisolone|2
00021|057|R|  kinetics in women taking oral contraceptives. Clin Pharmacol Ther 1986|2
00021|058|R|  Apr;39(4):425-9.|2
00021|059|R|2.Boekenoogen SJ, Szefler SJ, Jusko WJ. Prednisolone disposition and protein|2
00021|060|R|  binding in oral contraceptive users. J Clin Endocrinol Metab 1983 Apr;|2
00021|061|R|  56(4):702-9.|2
00021|062|R|3.Seidegard J, Simonsson M, Edsbacker S. Effect of an oral contraceptive on|2
00021|063|R|  the plasma levels of budesonide and prednisolone and the influence on|2
00021|064|R|  plasma cortisol. Clin Pharmacol Ther 2000 Apr;67(4):373-81.|2
00021|065|R|4.Meffin PJ, Wing LM, Sallustio BC, Brooks PM. Alterations in prednisolone|2
00021|066|R|  disposition as a result of oral contraceptive use and dose. Br J Clin|2
00021|067|R|  Pharmacol 1984 Jun;17(6):655-64.|2
00021|068|R|5.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
00021|069|R|  Middleton B, Bates DW. Drug-drug interactions that should be|6
00021|070|R|  non-interruptive in order to reduce alert fatigue in electronic health|6
00021|071|R|  records. J Am Med Inform Assoc 2012 Sep 25.|6
00022|001|T|MONOGRAPH TITLE:  Cimetidine/Procainamide|
00022|002|B||
00022|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00022|004|L|take action as needed.|
00022|005|B||
00022|006|A|MECHANISM OF ACTION:  Renal clearance of procainamide and|
00022|007|A|N-acetylprocainamide are reduced by cimetidine.|
00022|008|B||
00022|009|E|CLINICAL EFFECTS:  Enhanced procainamide and N-acetylprocainamide response|
00022|010|E|may occur in the presence of cimetidine therapy. Toxic levels may occur.|
00022|011|B||
00022|012|P|PREDISPOSING FACTORS:  Renal impairment and older age.|
00022|013|B||
00022|014|M|PATIENT MANAGEMENT:  Monitor patient for signs and symptoms of procainamide|
00022|015|M|toxicity. Procainamide and NAPA levels should be checked. Lower the dosage|
00022|016|M|of procainamide as needed. Elderly patients and those with impaired renal|
00022|017|M|function are especially at risk. Since other H-2 antagonists (e.g.,|
00022|018|M|ranitidine, famotidine) do not appear to interact, substituting cimetidine|
00022|019|M|with one of these agents may be desirable. However, if a patient is already|
00022|020|M|receiving this combination and is not experiencing adverse effects,|
00022|021|M|substitution is probably not necessary.|
00022|022|B||
00022|023|D|DISCUSSION:  Available data are limited but indicate that increases in|
00022|024|D|procainamide serum concentrations are lower with ranitidine than with|
00022|025|D|cimetidine. Famotidine does not appear to change procainamide|
00022|026|D|concentrations. Caution is warranted due to procainamide's narrow|
00022|027|D|therapeutic margin of safety.|
00022|028|D|   Signs and symptoms of procainamide toxicity include widening of the QRS|
00022|029|D|complex, tachycardia, intraventricular conduction delay, hypotension,|
00022|030|D|oliguria, lethargy, confusion, nausea and vomiting.|
00022|031|B||
00022|032|R|REFERENCES:|
00022|033|B||
00022|034|R|1.Drayer DE, Lowenthal DT, Woosley RL, Nies AS, Schwartz A, Reidenberg MM.|3
00022|035|R|  Cumulation of N-acetylprocainamide, an active metabolite of procainamide,|3
00022|036|R|  in patients with impaired renal function. Clin Pharmacol Ther 1977 Jul;|3
00022|037|R|  22(1):63-9.|3
00022|038|R|2.Somogyi A, Heinzow B. Cimetidine reduces procainamide elimination. N Engl|3
00022|039|R|  J Med 1982 Oct 21;307(17):1080.|3
00022|040|R|3.Somogyi A, McLean A, Heinzow B. Cimetidine-procainamide pharmacokinetic|2
00022|041|R|  interaction in man: evidence of competition for tubular secretion of basic|2
00022|042|R|  drugs. Eur J Clin Pharmacol 1983;25(3):339-45.|2
00022|043|R|4.Higbee MD, Wood JS, Mead RA. Procainamide-cimetidine interaction: a|3
00022|044|R|  potential toxic interaction in the elderly. J Am Geriatr Soc 1984 Feb;|3
00022|045|R|  32(2):162-4.|3
00022|046|R|5.Christian CD Jr, Meredith CG, Speeg KV Jr. Cimetidine inhibits renal|2
00022|047|R|  procainamide clearance. Clin Pharmacol Ther 1984 Aug;36(2):221-7.|2
00022|048|R|6.Somogyi A, Bochner F. Dose and concentration dependent effect of|2
00022|049|R|  ranitidine on procainamide disposition and renal clearance in man. Br J|2
00022|050|R|  Clin Pharmacol 1984 Aug;18(2):175-81.|2
00022|051|R|7.Klotz U, Arvela P, Rosenkranz B. Interaction study of diazepam (D) and|4
00022|052|R|  procainamide (PA) with the new H2-receptor antagonist famotidine (F). Clin|4
00022|053|R|  Pharmacol Ther 1985;37(2):205.|4
00022|054|R|8.Somogyi A, Bochner F. Ranitidine and procainamide absorption. Br J Clin|6
00022|055|R|  Pharmacol 1985 Aug;20(2):182-3.|6
00022|056|R|9.Rodvold KA, Paloucek FP, Jung D, Gallastegui J. Interaction of|2
00022|057|R|  steady-state procainamide with H2-receptor antagonists cimetidine and|2
00022|058|R|  ranitidine. Ther Drug Monit 1987 Dec;9(4):378-83.|2
00022|059|R|10.Lai MY, Jiang FM, Chung CH, Chen HC, Chao PD. Dose dependent effect of|2
00022|060|R|   cimetidine on procainamide disposition in man. Int J Clin Pharmacol Ther|2
00022|061|R|   Toxicol 1988 Mar;26(3):118-21.|2
00022|062|R|11.Rocci ML Jr, Kosoglou T, Ferguson RK, Vlasses PH. Ranitidine-induced|2
00022|063|R|   changes in the renal and hepatic clearances of procainamide are|2
00022|064|R|   correlated. J Pharmacol Exp Ther 1989 Mar;248(3):923-8.|2
00022|065|R|12.Bauer LA, Black D, Gensler A. Procainamide-cimetidine drug interaction in|2
00022|066|R|   elderly male patients. J Am Geriatr Soc 1990 Apr;38(4):467-9.|2
00023|001|T|MONOGRAPH TITLE:  Corticosteroids/Selected Strong CYP3A4 Inducers|
00023|002|B||
00023|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00023|004|L|take action as needed.|
00023|005|B||
00023|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
00023|007|A|corticosteroids.  Corticosteroids may affect the metabolism of phenytoin.|
00023|008|B||
00023|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
00023|010|E|result in decreased levels and effectiveness of corticosteroids.|
00023|011|E|Dexamethasone has been shown to increase and decrease phenytoin levels.|
00023|012|B||
00023|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00023|014|P|of the inducer for longer than 1-2 weeks.|
00023|015|B||
00023|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with a strong|
00023|017|M|CYP3A4 inducer should be monitored for decreased effectiveness of their|
00023|018|M|corticosteroid.  Increased dosage of corticosteroid may be required during|
00023|019|M|concurrent therapy and for several weeks after completing concurrent|
00023|020|M|therapy.  If concurrent therapy is discontinued, the dosage of the|
00023|021|M|corticosteroid may need to be adjusted.|
00023|022|M|  Phenytoin levels should be closely monitored in patients receiving|
00023|023|M|corticosteroids.  The dosage of phenytoin may need to be adjusted if|
00023|024|M|corticosteroids are initiated or discontinued.|
00023|025|B||
00023|026|D|DISCUSSION:  Carbamazepine has been shown to increase the metabolism of|
00023|027|D|methylprednisolone, prednisolone, and prednisone, resulting in decreased|
00023|028|D|levels and effectiveness of these agents.|
00023|029|D|   Phenobarbital has been shown to increase the metabolism of dexamethasone,|
00023|030|D|methylprednisolone, and prednisolone.  Primidone is metabolized to|
00023|031|D|phenobarbital.|
00023|032|D|   Phenytoin has been shown to increase the metabolism of dexamethasone,|
00023|033|D|hydrocortisone, methylprednisolone, prednisolone, and prednisone, resulting|
00023|034|D|in decreased levels and effectiveness of these agents|
00023|035|D|   Rifampin has been shown to increase the metabolism of cortisol,|
00023|036|D|dexamethasone, methylprednisolone, prednisolone, and prednisone.|
00023|037|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
00023|038|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
00023|039|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
00023|040|D|rifabutin, rifapentine, rifampin, and St. John's wort.|
00023|041|B||
00023|042|R|REFERENCES:|
00023|043|B||
00023|044|R|1.Werk EE Jr, Choi Y, Sholiton L, Olinger C, Haque N. Interference in the|2
00023|045|R|  effect of dexamethasone by diphenylhydantoin. N Engl J Med 1969 Jul 3;|2
00023|046|R|  281(1):32-4.|2
00023|047|R|2.Jubiz W, Meikle AW, Levinson RA, Mizutani S, West CD, Tyler FH. Effect of|2
00023|048|R|  diphenylhydantoin on the metabolism of dexamethasone. N Engl J Med 1970|2
00023|049|R|  Jul 2;283(1):11-4.|2
00023|050|R|3.Haque N, Thrasher K, Werk EE Jr, Knowles HC Jr, Sholiton LJ. Studies on|2
00023|051|R|  dexamethasone metabolism in man: effect of diphenylhydantoin. J Clin|2
00023|052|R|  Endocrinol Metab 1972 Jan;34(1):44-50.|2
00023|053|R|4.Stjernholm MR, Katz FH. Effects of diphenylhydantoin, phenobarbital, and|2
00023|054|R|  diazepam on the metabolism of methylprednisolone and its sodium succinate.|2
00023|055|R|  J Clin Endocrinol Metab 1975 Nov;41(5):887-93.|2
00023|056|R|5.Boylan JJ, Owen DS, Chin JB. Letter: Phenytoin interference with|3
00023|057|R|  dexamethasone. JAMA 1976 Feb 23;235(8):803-4.|3
00023|058|R|6.Wassner SJ, Malekzadeh MH, Pennisi AJ, Ettenger RB, Uittenbogaart CH, Fine|2
00023|059|R|  RN. Allograft survival in patients receiving anticonvulsant medications.|2
00023|060|R|  Clin Nephrol 1977 Jul;8(1):293-7.|2
00023|061|R|7.McLelland J, Jack W. Phenytoin/dexamethasone interaction: A clinical|3
00023|062|R|  problem. Lancet 1978 May 20;1(8073):1096-7.|3
00023|063|R|8.Lawson LA, Blouin RA, Smith RB, Rapp RP, Young AB. Phenytoin-dexamethasone|2
00023|064|R|  interaction: a previously unreported observation. Surg Neurol 1981 Jul;|2
00023|065|R|  16(1):23-4.|2
00023|066|R|9.Frey FJ, Frey BM. Urinary 6 beta-hydroxyprednisolone excretion indicates|2
00023|067|R|  enhanced prednisolone catabolism. J Lab Clin Med 1983 Apr;101(4):593-604.|2
00023|068|R|10.Frey BM, Frey FJ. Phenytoin modulates the pharmacokinetics of|2
00023|069|R|   prednisolone and the pharmacodynamics of prednisolone as assessed by the|2
00023|070|R|   inhibition of the mixed lymphocyte reaction in humans. Eur J Clin Invest|2
00023|071|R|   1984 Feb;14(1):1-6.|2
00023|072|R|11.Wong DD, Longenecker RG, Liepman M, Baker S, LaVergne M.|3
00023|073|R|   Phenytoin-dexamethasone: a possible drug-drug interaction. JAMA 1985 Oct|3
00023|074|R|   18;254(15):2062-3.|3
00023|075|R|12.Keilholz U, Guthrie GP Jr. Adverse effect of phenytoin on|3
00023|076|R|   mineralocorticoid replacement with fludrocortisone in adrenal|3
00023|077|R|   insufficiency. Am J Med Sci 1986 Apr;291(4):280-3.|3
00023|078|R|13.Lackner TE. Interaction of dexamethasone with phenytoin. Pharmacotherapy|3
00023|079|R|   1991;11(4):344-7.|3
00023|080|R|14.Sato A, Katada S, Sato M, Kobayashi H. A case of polymyalgia rheumatica|3
00023|081|R|   with improved steroid-responsibility after discontinuing carbamazepine.|3
00023|082|R|   No To Shinkei 2004 Jan;56(1):61-3.|3
00023|083|R|15.Bartoszek M, Brenner AM, Szefler SJ. Prednisolone and methylprednisolone|2
00023|084|R|   kinetics in children receiving anticonvulsant therapy. Clin Pharmacol|2
00023|085|R|   Ther 1987 Oct;42(4):424-32.|2
00023|086|R|16.Olivesi A. Modified elimination of prednisolone in epileptic patients on|2
00023|087|R|   carbamazepine monotherapy, and in women using low-dose oral|2
00023|088|R|   contraceptives. Biomed Pharmacother 1986;40(8):301-8.|2
00023|089|R|17.Buffington GA, Dominguez JH, Piering WF, Hebert LA, Kauffman HM Jr,|3
00023|090|R|   Lemann J Jr. Interaction of rifampin and glucocorticoids. Adverse effect|3
00023|091|R|   on renal allograft function. JAMA 1976 Oct 25;236(17):1958-60.|3
00023|092|R|18.Hendrickse W, McKiernan J, Pickup M, Lowe J. Rifampicin-induced|3
00023|093|R|   non-responsiveness to corticosteroid treatment in nephrotic syndrome. Br|3
00023|094|R|   Med J 1979 Feb 3;1(6159):306.|3
00023|095|R|19.Kawai S. A comparative study of the accelerated metabolism of cortisol,|2
00023|096|R|   prednisolone and dexamethasone in patients under rifampicin therapy.|2
00023|097|R|   Nippon Naibunpi Gakkai Zasshi 1985 Mar 20;61(3):145-61.|2
00023|098|R|20.Edwards OM, Courtenay-Evans RJ, Galley JM, Hunter J, Tait AD. Changes in|3
00023|099|R|   cortisol metabolism following rifampicin therapy. Lancet 1974 Sep 7;|3
00023|100|R|   2(7880):548-51.|3
00023|101|R|21.Gabrielsen J, Bendtsen A, Eriksen H, Andersen S. Methylprednisolone|2
00023|102|R|   half-life during simultaneous barbiturate treatment and mechanical|2
00023|103|R|   hyperventilation of neurosurgical patients. J Neurosurg 1985 Feb;|2
00023|104|R|   62(2):182-5.|2
00023|105|R|22.Kuntzman R, Jacobson M, Levin W, Conney AH. Stimulatory effect of|5
00023|106|R|   N-phenylbarbital (phetharbital) on cortisol hydroxylation in man. Biochem|5
00023|107|R|   Pharmacol 1968 Apr;17(4):565-71.|5
00023|108|R|23.Brooks SM, Werk EE, Ackerman SJ, Sullivan I, Thrasher K. Adverse effects|2
00023|109|R|   of phenobarbital on corticosteroid metabolism in patients with bronchial|2
00023|110|R|   asthma. N Engl J Med 1972 May 25;286(21):1125-8.|2
00023|111|R|24.Brooks PM, Buchanan WW, Grove M, Downie WW. Effects of enzyme induction|2
00023|112|R|   on metabolism of prednisolone. Clinical and laboratory study. Ann Rheum|2
00023|113|R|   Dis 1976 AUG;35(4):339-43.|2
00023|114|R|25.Gambertoglio J, Kapusnik J, Holford J, Nishikawa R, Hau T, Birnbaum J,|4
00023|115|R|   Amend W Jr. Enhancement of prednisolone elimination by anticonvulsants in|4
00023|116|R|   renal transplant recipients. Clin Pharmacol Ther 1982 Feb;31(2):228.|4
00023|117|R|26.Gambertoglio JG, Holford NH, Kapusnik JE, Nishikawa R, Saltiel M,|2
00023|118|R|   Stanik-Lizak P, Birnbaum JL, Hau T, Amend WJ Jr. Disposition of total and|2
00023|119|R|   unbound prednisolone in renal transplant patients receiving|2
00023|120|R|   anticonvulsants. Kidney Int 1984 Jan;25(1):119-23.|2
00023|121|R|27.Hancock KW, Levell MJ. Primidone/dexamethasone interaction. Lancet 1978|3
00023|122|R|   Jul 8;2(8080):97-8.|3
00023|123|R|28.Young MC, Hughes IA. Loss of therapeutic control in congenital adrenal|3
00023|124|R|   hyperplasia due to interaction between dexamethasone and primidone. Acta|3
00023|125|R|   Paediatr Scand 1991 Jan;80(1):120-4.|3
00023|126|R|29.This information is based on an extract from the Certara Drug Interaction|6
00023|127|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00024|001|T|MONOGRAPH TITLE:  Hydantoins/Isoniazid|
00024|002|B||
00024|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00024|004|L|take action as needed.|
00024|005|B||
00024|006|A|MECHANISM OF ACTION:  Isoniazid may inhibit the CYP2C9 and CYP2C19 mediated|
00024|007|A|metabolism of phenytoin and other hydantoins.|
00024|008|B||
00024|009|E|CLINICAL EFFECTS:  Increased hydantoin pharmacologic effects including|
00024|010|E|toxicity may be observed. Phenytoin has a narrow therapeutic range. Early|
00024|011|E|symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria,|
00024|012|E|tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and|
00024|013|E|vomiting. Severe toxicity may produce organ dysfunction (e.g. coma,|
00024|014|E|irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia,|
00024|015|E|seizures, and cardiac arrest) and may be fatal.(1)|
00024|016|B||
00024|017|P|PREDISPOSING FACTORS:  N-acetyltransferase 2 (NAT2) slow acetylators may|
00024|018|P|have higher concentrations of isoniazid and increased inhibition of|
00024|019|P|phenytoin metabolism.|
00024|020|P|   Renal impairment, hepatic impairment, or hypoalbuminemia.|
00024|021|B||
00024|022|M|PATIENT MANAGEMENT:  Adjust the hydantoin dose as needed based on hydantoin|
00024|023|M|plasma levels and clinical symptoms.|
00024|024|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
00024|025|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
00024|026|M|vision, nausea, and vomiting).|
00024|027|B||
00024|028|D|DISCUSSION:  Of the 22,294 patients included in the Boston Collaborative|
00024|029|D|Drug Surveillance Program, 22 patients received phenytoin with isoniazid and|
00024|030|D|6 patients (27%) experienced toxic CNS effects such as disorientation,|
00024|031|D|ataxia, nystagmus, and dysarthria. Some patients presented with psychotic|
00024|032|D|behavior, convulsions, and coma. This is compared to 3% of patients who|
00024|033|D|developed similar symptoms on phenytoin without isoniazid.(2)|
00024|034|D|   A study of 60 patients on concomitant isoniazid (300 mg daily) with|
00024|035|D|phenytoin (300 mg daily) showed that slow acetylators (23 patients) had|
00024|036|D|significantly higher plasma phenytoin levels compared to rapid|
00024|037|D|acetylators.(3,4) Slow acetylators exhibited symptoms of phenytoin toxicity;|
00024|038|D|such as, lethargy, disorientation, nystagmus, ataxia, dysarthria, and coma.|
00024|039|D|   Isoniazid has been shown to inhibit oxidation of phenytoin in an isolated|
00024|040|D|rat hepatocyte system.(5)|
00024|041|D|   A 30-year old patient developed clouded consciousness, ataxia, slurred|
00024|042|D|speech, hypertension, and hyperglycemia after concomitant administration of|
00024|043|D|phenytoin (300 mg daily) and isoniazid (300 mg daily).(6)|
00024|044|D|   A 47-year old patient developed choreiform movements and later died after|
00024|045|D|concomitant administration of phenytoin and isoniazid.(7)|
00024|046|D|   A 47-year old patient developed ataxia, difficulty standing and walking,|
00024|047|D|and nystagmus after concomitant administration of phenytoin (300 mg daily)|
00024|048|D|and isoniazid (600 mg daily).(8)|
00024|049|D|   A 28 year-old patient developed ataxia and phenytoin blood levels were|
00024|050|D|found to be twice the upper limit of therapeutic range while on concurrent|
00024|051|D|isoniazid and phenytoin therapy.(9)|
00024|052|D|   A 51-year old patient developed convulsions, restlessness, confusion|
00024|053|D|while on concurrent phenytoin (300 mg daily) and isoniazid (300 mg daily).|
00024|054|D|Phenytoin levels were found to be greatly increased.(10)|
00024|055|D|   Excessive sedation and incoordination was seen in 11% of 637 patients on|
00024|056|D|concurrent phenytoin and isoniazid compared to 2.7% of 845 patients only|
00024|057|D|taking phenytoin.(12)|
00024|058|D|   This interaction is subject to large individual variability.|
00024|059|B||
00024|060|R|REFERENCES:|
00024|061|B||
00024|062|R|1.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00024|063|R|  March, 2022.|1
00024|064|R|2.Miller RR, Porter J, Greenblatt DJ. Clinical importance of the interaction|3
00024|065|R|  of phenytoin and isoniazid: a report from the Boston Collaborative Drug|3
00024|066|R|  Surveillance Program. Chest 1979 Mar;75(3):356-8.|3
00024|067|R|3.Adole PS, Kharbanda PS, Sharma S. N-acetyltransferase 2 (NAT2) gene|2
00024|068|R|  polymorphism as a predisposing factor for phenytoin intoxication in|2
00024|069|R|  tuberculous meningitis or tuberculoma patients having seizures - A pilot|2
00024|070|R|  study. Indian J Med Res 2016 May;143(5):581-90.|2
00024|071|R|4.Adole PS, Singh A, Kharbanda PS, Sharma S. Phenotypic interaction of|2
00024|072|R|  simultaneously administered isoniazid and phenytoin in  patients with|2
00024|073|R|  tuberculous meningitis or tuberculoma having seizures. Eur J Pharmacol|2
00024|074|R|  2013 Aug 15;714(1-3):157-62.|2
00024|075|R|5.Noda H, Eto S, Minemoto M, Noda A, Ohno K. Effects of isoniazid and its|5
00024|076|R|  metabolites on phenytoin biotransformation in isolated rat hepatocytes.|5
00024|077|R|  Chem Pharm Bull (Tokyo) 1987 Jan;35(1):277-81.|5
00024|078|R|6.Johnson J. Letter: Epanutin and isoniazid interaction. Br Med J 1975 Jan|3
00024|079|R|  18;1(5950):152.|3
00024|080|R|7.Johnson J, Freeman HL. Death due to isoniazid (INH) and phenytoin. Br J|3
00024|081|R|  Psychiatry 1976 Nov;129:511.|3
00024|082|R|8.Witmer DR, Ritschel WA. Phenytoin-isoniazid interaction: a kinetic|3
00024|083|R|  approach to management. Drug Intell Clin Pharm 1984 Jun;18(6):483-6.|3
00024|084|R|9.Yew WW, Lau KS, Ling MH. Phenytoin toxicity in a patient with|3
00024|085|R|  isoniazid-induced hepatitis. Tubercle 1991 Dec;72(4):309-10.|3
00024|086|R|10.Walubo A, Aboo A. Phenytoin toxicity due to concomitant antituberculosis|3
00024|087|R|   therapy. S Afr Med J 1995 Nov;85(11):1175-6.|3
00024|088|R|11.Buttar HS, Wong LT, Moffatt JH. Effect of isoniazid on the metabolism of|5
00024|089|R|   14C-diphenylhydantoin in rats. Arch Int Pharmacodyn Ther 1978 Sep;|5
00024|090|R|   235(1):9-18.|5
00024|091|R|12.MURRAY FJ. Outbreak of unexpected reactions among epileptics taking|2
00024|092|R|   isoniazid. Am Rev Respir Dis 1962 Nov;86:729-32.|2
00025|001|T|MONOGRAPH TITLE:  Hydantoins/Folic Acid; Pyrimethamine|
00025|002|B||
00025|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00025|004|L|take action as needed.|
00025|005|B||
00025|006|A|MECHANISM OF ACTION:  Unknown, but probably involves altered metabolism of|
00025|007|A|the hydantoin.|
00025|008|B||
00025|009|E|CLINICAL EFFECTS:  May observe decreased effectiveness of hydantoin,|
00025|010|E|resulting in loss of seizure control.|
00025|011|B||
00025|012|P|PREDISPOSING FACTORS:  None determined.|
00025|013|B||
00025|014|M|PATIENT MANAGEMENT:  If both drugs are administered, monitor both the|
00025|015|M|hydantoin plasma levels as well as the seizure control of the patient.|
00025|016|M|Adjust the dose of hydantoin accordingly.|
00025|017|B||
00025|018|D|DISCUSSION:  The effects of an interaction are not expected to occur in the|
00025|019|D|majority of patients. Discontinuation of folic acid has caused phenytoin|
00025|020|D|levels to increase in patients who experienced a decrease in phenytoin|
00025|021|D|levels when folic acid was started. Monitor these patients for hydantoin|
00025|022|D|toxicity. Signs and symptoms of hydantoin toxicity include ataxia, nystagmus|
00025|023|D|and involuntary movements.|
00025|024|B||
00025|025|R|REFERENCES:|
00025|026|B||
00025|027|R|1.Kutt H, Winters W, McDowell FH. Depression of prahydroxylation of|2
00025|028|R|  diphenylhydantoin by antituberculosis chemotherapy. Neurology 1966 Jun;|2
00025|029|R|  16(6):594-602.|2
00025|030|R|2.Reynolds EH. Effects of folic acid on the mental state and fit-frequency|2
00025|031|R|  of drug- treated epileptic patients. Lancet 1967 May 20;1(7499):1086-8.|2
00025|032|R|3.Olesen OV, Jensen ON. The influence of folic acid on phenytoin (DPH)|2
00025|033|R|  metabolism and the 24- hours fluctuation in urinary output of|2
00025|034|R|  5-(p-hydroxyphenyl)-5 phenyl- hydantoin (HPPH). Acta Pharmacol Toxicol|2
00025|035|R|  (Copenh) 1970;28(4):265-9.|2
00025|036|R|4.Jensen ON, Olesen OV. Subnormal serum folate due to anticonvulsive|2
00025|037|R|  therapy. A double-blind study of the effect of folic acid treatment in|2
00025|038|R|  patients with drug- induced subnormal serum folates. Arch Neurol 1970 Feb;|2
00025|039|R|  22(2):181-2.|2
00025|040|R|5.Baylis EM, Crowley JM, Preece JM, Sylvester PE, Marks V. Influence of|2
00025|041|R|  folic acid on blood-phenytoin levels. Lancet 1971 Jan 9;1(7689):62-4.|2
00025|042|R|6.Mattson RH, Gallagher BB, Reynolds EH, Glass D. Folate therapy in|2
00025|043|R|  epilepsy. A controlled study. Arch Neurol 1973 Aug;29(2):78-81.|2
00025|044|R|7.Furlanut M, Benetello P, Avogaro A, Dainese R. Effects of folic acid on|2
00025|045|R|  phenytoin kinetics in healthy subjects. Clin Pharmacol Ther 1978 Sep;|2
00025|046|R|  24(3):294-7.|2
00025|047|R|8.Gibberd FB, Nicholls A, Wright MG. The influence of folic acid on the|2
00025|048|R|  frequency of epileptic attacks. Eur J Clin Pharmacol 1981 Jan;19(1):57-60.|2
00025|049|R|9.Inoue F. Clinical implications of anticonvulsant-induced folate|2
00025|050|R|  deficiency. Clin Pharm 1982 Jul-Aug;1(4):372-3.|2
00025|051|R|10.MacCosbe PE, Toomey K. Interaction of phenytoin and folic acid. Clin|3
00025|052|R|   Pharm 1983 Jul-Aug;2(4):362-9.|3
00025|053|R|11.Berg MJ, Fischer LJ, Rivey MP, Vern BA, Lantz RK, Schottelius DD.|2
00025|054|R|   Phenytoin and folic acid interaction: a preliminary report. Ther Drug|2
00025|055|R|   Monit 1983;5(4):389-94.|2
00025|056|R|12.Berg MJ, Rivey MP, Vern BA, Fischer LJ, Schottelius DD. Phenytoin and|3
00025|057|R|   folic acid: individualized drug-drug interaction. Ther Drug Monit 1983;|3
00025|058|R|   5(4):395-9.|3
00025|059|R|13.Yuen GJ. Interaction of phenytoin and folic acid: an alternative|6
00025|060|R|   explanation. Clin Pharm 1984 Mar-Apr;3(2):116, 119.|6
00025|061|R|14.Rivey MP, Schottelius DD, Berg MJ. Phenytoin-folic acid: a review. Drug|6
00025|062|R|   Intell Clin Pharm 1984 Apr;18(4):292-301.|6
00025|063|R|15.Berg MJ, Fincham RW, Ebert BE, Schottelius DD. Phenytoin|2
00025|064|R|   pharmacokinetics: before and after folic acid administration. Epilepsia|2
00025|065|R|   1992 Jul-Aug;33(4):712-20.|2
00026|001|T|MONOGRAPH TITLE:  Hydantoins/Sulfonamides (mono deleted 06/26/2014)|
00026|002|B||
00026|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00026|004|L|take action as needed.|
00026|005|B||
00026|006|A|MECHANISM OF ACTION:  Sulfonamides may inhibit the hepatic metabolism of|
00026|007|A|hydantoins by a CYP2C9 mediated interaction.|
00026|008|B||
00026|009|E|CLINICAL EFFECTS:  Concurrent use of a sulfonamide may result in increased|
00026|010|E|hydantoin levels and toxicity.|
00026|011|B||
00026|012|P|PREDISPOSING FACTORS:  None determined.|
00026|013|B||
00026|014|M|PATIENT MANAGEMENT:  Adjust the hydantoin dose as needed based on plasma|
00026|015|M|hydantoin levels and clinical symptoms.|
00026|016|B||
00026|017|D|DISCUSSION:  The severity of this interaction appears to vary with the|
00026|018|D|different sulfonamides and is subject to large individual variability.|
00026|019|D|   In a case-control cohort study, elderly patients hospitalized due to|
00026|020|D|phenytoin toxicity were more than twice as likely to have had concurrent use|
00026|021|D|of trimethoprim-sulfamethoxazole in the previous 30 days (729 subjects) as|
00026|022|D|compared to concurrent use of amoxicillin in the previous 30 days (3148|
00026|023|D|subjects). The adjusted odds ratio was 2.11 with a 95% CI of 1.24, 3.60. (3)|
00026|024|B||
00026|025|R|REFERENCES:|
00026|026|B||
00026|027|R|1.Lumholtz B, Siersbaek-Nielsen K, Skovsted L, Kampmann J, Hansen JM.|2
00026|028|R|  Sulfamethizole-induced inhibition of diphenlhydantoin, tolbutamide, and|2
00026|029|R|  warfarin metabolism. Clin Pharmacol Ther 1975 Jun;17(6):731-4.|2
00026|030|R|2.Hansen JM, Kampmann JP, Siersbaek-Nielsen K, Lumholtz IB, Arroe M,|5
00026|031|R|  Abildgaard U, Skovsted L. The effect of different sulfonamides on|5
00026|032|R|  phenytoin metabolism in man. Acta Med Scand Suppl 1979;624:106-10.|5
00026|033|R|3.Antoniou T, Gomes T, Mamdani MM, Juurlink DN.|2
00026|034|R|  Trimethoprim/sulfamethoxazole-induced phenytoin toxicity in the elderly: a|2
00026|035|R|  population-based study. Br J Clin Pharmacol 2011 Apr;71(4):544-9.|2
00027|001|T|MONOGRAPH TITLE:  Amiodarone/Coumarin Anticoagulants|
00027|002|B||
00027|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00027|004|L|of severe adverse interaction.|
00027|005|B||
00027|006|A|MECHANISM OF ACTION:  Amiodarone inhibits the CYP2C9 mediated metabolism of|
00027|007|A|the S-enantiomer, and the CYP3A4 mediated metabolism of the R-enantiomer of|
00027|008|A|warfarin in vivo.(1-5)  Amiodarone may also inhibit the metabolism of|
00027|009|A|acenocoumarol(6) and other coumarin anticoagulants.|
00027|010|B||
00027|011|E|CLINICAL EFFECTS:  The concurrent administration of amiodarone and a|
00027|012|E|coumarin anticoagulant may result in an increase in the clinical effects of|
00027|013|E|the anticoagulant and an increased risk of bleeding.(1-23)  It may take|
00027|014|E|several weeks of concurrent therapy before the full effects of this|
00027|015|E|interaction are noted.  The effect of amiodarone on anticoagulant levels may|
00027|016|E|continue for several months after amiodarone is discontinued.|
00027|017|B||
00027|018|P|PREDISPOSING FACTORS:  Amiodarone-induced thyrotoxicosis may increase the|
00027|019|P|metabolic clearance of some vitamin K-dependent clotting factors, decreasing|
00027|020|P|anticoagulant requirements.(8)|
00027|021|P|   In patients with the CYP2C9 intermediate and extensive metabolizer|
00027|022|P|genotypes, long-acting amiodarone inhibition of CYP2C9 may increase the risk|
00027|023|P|of phenoconversion to the poor metabolizer phenotype.(24)|
00027|024|P|   Patients with CYP2C9 intermediate metabolizer genotype are expected to be|
00027|025|P|the most susceptible to this interaction and conversion to the poor|
00027|026|P|metabolizer phenotype.|
00027|027|P|   Patients with a pre-existing CYP2C9 poor metabolizer genotype would be|
00027|028|P|less susceptible to this interaction.  However, these patients with reduced|
00027|029|P|function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) have an|
00027|030|P|inherently higher risk for bleeding at usual anticoagulant doses and thus|
00027|031|P|generally require lower doses to achieve effective and safe anticoagulation.|
00027|032|P|In addition, CYP2C9 poor metabolizers require more a prolonged time (>2 to|
00027|033|P|4 weeks) to achieve maximum INR effect for a given dosage regimen than|
00027|034|P|patients without these CYP2C9 variants.|
00027|035|B||
00027|036|M|PATIENT MANAGEMENT:  The US manufacturer of amiodarone states that|
00027|037|M|amiodarone will almost always potentiate the anticoagulant response in|
00027|038|M|patients receiving coumarin anticoagulants.  They recommend decreasing the|
00027|039|M|anticoagulant dosage by 1/3 to 1/2 when amiodarone therapy is initiated.|
00027|040|M|Although amiodarone has a long half-life, significant increases in the|
00027|041|M|INR/prothrombin time may start in 3 to 4 days.  Monitor INR closely and|
00027|042|M|adjust anticoagulant dose until stabile.(23)|
00027|043|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00027|044|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00027|045|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00027|046|M|patients with any symptoms.|
00027|047|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00027|048|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00027|049|M|anticoagulation in patients with active pathologic bleeding.|
00027|050|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00027|051|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00027|052|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00027|053|M|and/or swelling.|
00027|054|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00027|055|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00027|056|M|initiating, altering the dose or discontinuing either drug.|
00027|057|B||
00027|058|D|DISCUSSION:  Several studies and case reports have documented the potential|
00027|059|D|interaction between warfarin and amiodarone.  In several studies, the dosage|
00027|060|D|of warfarin had to be decreased between 32.9% and 70% to maintain|
00027|061|D|satisfactory prothrombin activity.(1-5,7-12)|
00027|062|D|   Several case reports and retrospective chart reviews have also documented|
00027|063|D|the potential interaction between amiodarone and acenocoumarol.  The dosage|
00027|064|D|reduction of acenocoumarol required to maintain satisfactory prothrombin|
00027|065|D|activity ranged from 20% to 60%.(13-19)|
00027|066|D|   A case report describes a 66-year-old male with a history of recurrent|
00027|067|D|atrial fibrillation.  While taking both amiodarone and a low-dose warfarin|
00027|068|D|therapy, prothrombin times were prolonged, INR values were increased and|
00027|069|D|bleeding occurred.  Both drugs were withheld, and the effect of the|
00027|070|D|interaction continued for an extended period of time.(20)|
00027|071|D|   One study evaluated the role desethylamiodarone, the active metabolite of|
00027|072|D|amiodarone, played on concurrent warfarin therapy.  After analyzing 25|
00027|073|D|patients with structural heart disease and arrhythmias, it was found that|
00027|074|D|the concentration of desethylamiodarone played a larger role in augmenting|
00027|075|D|the INR, than the concentration of amiodarone alone.  Additional examination|
00027|076|D|revealed that amiodarone primarily inhibits CYP1A2 and CYP3A4, whereas|
00027|077|D|desethylamiodarone primarily inhibits CYP2C9, the isozyme responsible for|
00027|078|D|the metabolism of S-warfarin.(21)|
00027|079|D|   An observational, cohort study reviewed the interaction of amiodarone|
00027|080|D|with warfarin for a period of at least one year, while evaluating the|
00027|081|D|adjustments needed to achieve an INR ratio between 2 and 3.  After analyzing|
00027|082|D|43 patients, baseline warfarin therapy required a mean 44% reduction in dose|
00027|083|D|after seven weeks of coadministration with amiodarone.  Five subjects|
00027|084|D|experienced minor bleeding.  For patients receiving amiodarone maintenance,|
00027|085|D|warfarin dose reductions were as follows: 400 mg/d, reduce warfarin dose|
00027|086|D|40%; 300 mg/d, reduce warfarin dose 35%; 200/d, reduce warfarin dose 30%;|
00027|087|D|and 100 mg/d, reduce warfarin dose by 25%.  All warfarin dose reductions are|
00027|088|D|approximations and must be based on aggressive INR monitoring.(22)|
00027|089|B||
00027|090|R|REFERENCES:|
00027|091|B||
00027|092|R|1.Almog S, Shafran N, Halkin H, Weiss P, Farfel Z, Martinowitz U, Bank H.|2
00027|093|R|  Mechanism of warfarin potentiation by amiodarone: dose--and|2
00027|094|R|  concentration--dependent inhibition of warfarin elimination. Eur J Clin|2
00027|095|R|  Pharmacol 1985;28(3):257-61.|2
00027|096|R|2.Rees A, Dalal JJ, Reid PG, Henderson AH, Lewis MJ. Dangers of amiodarone|3
00027|097|R|  and anticoagulant treatment. Br Med J (Clin Res Ed) 1981 May 30;|3
00027|098|R|  282(6278):1756-7.|3
00027|099|R|3.O'Reilly RA, Trager WF, Rettie AE, Goulart DA. Interaction of amiodarone|2
00027|100|R|  with racemic warfarin and its separated enantiomorphs in humans. Clin|2
00027|101|R|  Pharmacol Ther 1987 Sep;42(3):290-4.|2
00027|102|R|4.Heimark LD, Wienkers L, Kunze K, Gibaldi M, Eddy AC, Trager WF, O'Reilly|2
00027|103|R|  RA, Goulart DA. The mechanism of the interaction between amiodarone and|2
00027|104|R|  warfarin in humans. Clin Pharmacol Ther 1992 Apr;51(4):398-407.|2
00027|105|R|5.This information is based on an extract from the Certara Drug Interaction|6
00027|106|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00027|107|R|6.Richard C, Riou B, Berdeaux A, Fournier C, Khayat D, Rimailho A,|2
00027|108|R|  Giudicelli JF, Auzepy P. Prospective study of the potentiation of|2
00027|109|R|  acenocoumarol by amiodarone. Eur J Clin Pharmacol 1985;28(6):625-9.|2
00027|110|R|7.Woeber KA, Warner I. Potentiation of warfarin sodium by amiodarone-induced|3
00027|111|R|  thyrotoxicosis. West J Med 1999 Jan;170(1):49-51.|3
00027|112|R|8.Watt AH, Stephens MR, Buss DC, Routledge PA. Amiodarone reduces plasma|2
00027|113|R|  warfarin clearance in man. Br J Clin Pharmacol 1985 Dec;20(6):707-9.|2
00027|114|R|9.Hamer A, Peter T, Mandel WJ, Scheinman MM, Weiss D. The potentiation of|3
00027|115|R|  warfarin anticoagulation by amiodarone. Circulation 1982 May;65(5):1025-9.|3
00027|116|R|10.Martinowitz U, Rabinovich J, Goldfarb D, Many A, Bank H. Interaction|3
00027|117|R|   between warfarin sodium and amiodarone. N Engl J Med 1981 Mar 12;|3
00027|118|R|   304(11):671-2.|3
00027|119|R|11.Serlin MJ, Sibeon RG, Green GJ. Dangers of amiodarone and anticoagulant|3
00027|120|R|   treatment. Br Med J (Clin Res Ed) 1981 Jul 4;283(6283):58.|3
00027|121|R|12.Kerin NZ, Blevins RD, Goldman L, Faitel K, Rubenfire M. The incidence,|2
00027|122|R|   magnitude, and time course of the amiodarone-warfarin interaction. Arch|2
00027|123|R|   Intern Med 1988 Aug;148(8):1779-81.|2
00027|124|R|13.Arboix M, Frati ME, Laporte JR. The potentiation of acenocoumarol|2
00027|125|R|   anticoagulant effect by amiodarone. Br J Clin Pharmacol 1984 Sep;|2
00027|126|R|   18(3):355-60.|2
00027|127|R|14.Cheung B, Lam FM, Kumana CR. Insidiously evolving, occult drug|3
00027|128|R|   interaction involving warfarin and amiodarone. BMJ 1996 Jan 13;|3
00027|129|R|   312(7023):107-8.|3
00027|130|R|15.El Allaf D, Sprynger M, Carlier J. Potentiation of the action of oral|3
00027|131|R|   anticoagulants by amiodarone. Acta Clin Belg 1984;39(5):306-8.|3
00027|132|R|16.Fondevila C, Meschengieser S, Lazzari MA. Amiodarone potentiates|2
00027|133|R|   acenocoumarin. Thromb Res 1989 Jan 15;53(2):203-8.|2
00027|134|R|17.Caraco Y, Raveh D, Flugelman M, Raz I. Enhanced anticoagulant effect of|3
00027|135|R|   acenocoumarol induced by amiodarone coadministration. Isr J Med Sci 1988|3
00027|136|R|   Nov;24(11):688-9.|3
00027|137|R|18.Pini M, Manotti C, Quintavalla R. Interaction between amiodarone and|2
00027|138|R|   acenocoumarin. Thromb Haemost 1985 Aug 30;54(2):549.|2
00027|139|R|19.Caraco Y, Chajek-Shaul T. The incidence and clinical significance of|2
00027|140|R|   amiodarone and acenocoumarol interaction. Thromb Haemost 1989 Nov 24;|2
00027|141|R|   62(3):906-8.|2
00027|142|R|20.Hirmerova J, Suchy D, Madr T. Long-term drug interaction of warfarin with|3
00027|143|R|   amiodarone. Cas Lek Cesk 2003 Jan 20;142(1):39-42.|3
00027|144|R|21.Naganuma M, Shiga T, Nishikata K, Tsuchiya T, Kasanuki H, Fujii E. Role|2
00027|145|R|   of desethylamiodarone in the anticoagulant effect of concurrent|2
00027|146|R|   amiodarone and warfarin therapy. J Cardiovasc Pharmacol Ther 2001 Oct;|2
00027|147|R|   6(4):363-7.|2
00027|148|R|22.Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin|2
00027|149|R|   interaction: dosing relationships with long-term therapy. Chest 2002 Jan;|2
00027|150|R|   121(1):19-23.|2
00027|151|R|23.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
00027|152|R|   Pharmaceuticals October, 2018.|1
00027|153|R|24.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
00027|154|R|   Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE,|6
00027|155|R|   Altman RB. Clinical Pharmacogenetics Implementation Consortium Guidelines|6
00027|156|R|   for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther|6
00027|157|R|   2011 Oct;90(4):625-9.|6
00028|001|T|MONOGRAPH TITLE:  Antidiabetics/Epinephrine|
00028|002|B||
00028|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00028|004|L|take action as needed.|
00028|005|B||
00028|006|A|MECHANISM OF ACTION:  Gluconeogenesis, glycogenolysis, and lipolysis are|
00028|007|A|increased by epinephrine. Also, insulin secretion and glucose uptake by|
00028|008|A|peripheral tissues are decreased by epinephrine.|
00028|009|B||
00028|010|E|CLINICAL EFFECTS:  Increased blood glucose resulting in decreased|
00028|011|E|effectiveness of the antidiabetic agent.|
00028|012|B||
00028|013|P|PREDISPOSING FACTORS:  None determined.|
00028|014|B||
00028|015|M|PATIENT MANAGEMENT:  Caution when starting or stopping epinephrine in|
00028|016|M|diabetic patients. Adjust the antidiabetic dose as needed based on blood|
00028|017|M|glucose levels.|
00028|018|B||
00028|019|D|DISCUSSION:  This interaction is likely to occur based upon well documented|
00028|020|D|properties of the interacting drugs. However, there is individual|
00028|021|D|variability in its occurrence.|
00028|022|B||
00028|023|R|REFERENCES:|
00028|024|B||
00028|025|R|1.Mayer SE. Neurohumoral transmission and the autonomic nervous system. In|6
00028|026|R|  Gilman AG, Goodman LS, eds. Goodman and Gilman's The Pharmacological Basis|6
00028|027|R|  of Therapeutics. 6th ed. New York: MacMillan Publishing Company. 1980.|6
00028|028|R|2.Middleton E Jr, Finke SR. Metabolic response to epinephrine in bronchial|2
00028|029|R|  asthma. J Allergy 1968 Nov;42(5):288-99.|2
00029|001|T|MONOGRAPH TITLE:  Methotrexate (low strength inj, oral)/OAT3 Inhibitors|
00029|002|B||
00029|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00029|004|L|take action as needed.|
00029|005|B||
00029|006|A|MECHANISM OF ACTION:  Inhibitors of organic anion transporter 3 (OAT3) may|
00029|007|A|inhibit the renal elimination of methotrexate.|
00029|008|B||
00029|009|E|CLINICAL EFFECTS:  Concurrent use of organic anion transporter 3 (OAT3)|
00029|010|E|inhibitors may result in an increase in both the therapeutic and toxic|
00029|011|E|effects of methotrexate, leading to increased risk of severe neurotoxicity,|
00029|012|E|stomatitis, and myelosuppression, including neutropenia.|
00029|013|B||
00029|014|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
00029|015|P|- High-dose oncology regimens|
00029|016|P|- Impaired renal function, ascites, or pleural effusions|
00029|017|B||
00029|018|M|PATIENT MANAGEMENT:  If concurrent use cannot be avoided, monitor|
00029|019|M|methotrexate blood levels closely and adjust the dose accordingly.|
00029|020|B||
00029|021|D|DISCUSSION:  Concomitant administration of methotrexate and probenecid has|
00029|022|D|been shown to increase methotrexate plasma levels two to four times higher|
00029|023|D|than when methotrexate is administered alone.|
00029|024|D|   OAT3 inhibitors linked to this monograph include:  cabotegravir,|
00029|025|D|nitisinone, probenecid and vadadustat.(7)|
00029|026|B||
00029|027|R|REFERENCES:|
00029|028|B||
00029|029|R|1.Rheumatrex (methotrexate, oral) US prescribing information. Dava|1
00029|030|R|  Pharmaceuticals, Inc. February, 2013.|1
00029|031|R|2.Israili ZH, Soliman AM, Cunningham RF, Plowden JF, Keller JW. The|4
00029|032|R|  interaction of methotrexate and probenecid in man and dog. Proc Am Assoc|4
00029|033|R|  Cancer Res 1978;19:194.|4
00029|034|R|3.Aherne GW, Piall E, Marks V, Mould G, White WF. Prolongation and|2
00029|035|R|  enhancement of serum methotrexate concentrations by probenecid. Br Med J|2
00029|036|R|  1978 Apr 29;1(6120):1097-9.|2
00029|037|R|4.Howell SB, Olshen RA, Rice JA. Effect of probenecid on cerebrospinal fluid|2
00029|038|R|  methotrexate kinetics. Clin Pharmacol Ther 1979 Nov;26(5):641-6.|2
00029|039|R|5.Lilly MB, Omura GA. Clinical pharmacology of oral intermediate-dose|2
00029|040|R|  methotrexate with or without probenecid. Cancer Chemother Pharmacol 1985;|2
00029|041|R|  15(3):220-2.|2
00029|042|R|6.Basin KS, Escalante A, Beardmore TD. Severe pancytopenia in a patient|3
00029|043|R|  taking low dose methotrexate and probenecid. J Rheumatol 1991 Apr;|3
00029|044|R|  18(4):609-10.|3
00029|045|R|7.This information is based on an extract from the Certara Drug Interaction|6
00029|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00030|001|T|MONOGRAPH TITLE:  Selected Antidiabetics/MAOIs|
00030|002|B||
00030|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00030|004|L|take action as needed.|
00030|005|B||
00030|006|A|MECHANISM OF ACTION:  The exact mechanism by which MAO inhibitors affect|
00030|007|A|carbohydrate metabolism and subsequent enhancement of the hypoglycemic|
00030|008|A|action of insulin is not clear.  The adrenergic response to hypoglycemia may|
00030|009|A|be blocked by insulin release caused by MAOI's.  In vitro studies have shown|
00030|010|A|that MAO inhibitors are capable of both potentiating and inhibiting insulin|
00030|011|A|release, depending on their concentrations.  Stimulation of glucose-mediated|
00030|012|A|insulin secretion is believed to be related to the MAO inhibitory effects of|
00030|013|A|the drugs.|
00030|014|B||
00030|015|E|CLINICAL EFFECTS:  The hypoglycemic response to both insulin and glucose|
00030|016|E|lowering agents including alpha glucosidase inhibitors, meglitinides, and|
00030|017|E|sulfonylurea may be increased.|
00030|018|B||
00030|019|P|PREDISPOSING FACTORS:  None determined.|
00030|020|B||
00030|021|M|PATIENT MANAGEMENT:  Concurrent MAO inhibitor therapy for depression in a|
00030|022|M|diabetic patient will often require reduction in dosage of the hypoglycemic|
00030|023|M|agent because of enhanced hypoglycemic effects.  Since the extent of the|
00030|024|M|reaction is highly unpredictable, any diabetic patients receiving MAO|
00030|025|M|inhibitors should be monitored for possible excessive hypoglycemia.|
00030|026|B||
00030|027|D|DISCUSSION:  This interaction is likely to occur.  The interaction between|
00030|028|D|MAOIs and insulin is well documented.  Additional documentation is necessary|
00030|029|D|to confirm the potential interaction of MAOI's with other glucose lowering|
00030|030|D|agents including alpha glucosidase inhibitors, meglitinides, and|
00030|031|D|sulfonylureas but is expected to occur based on pharmacologic similarity.|
00030|032|D|   It may take several weeks for the full hypoglycemic effect of the MAOI to|
00030|033|D|occur.  Conversely, it may take several weeks for the effect to dissipate|
00030|034|D|after stopping the MAOI.|
00030|035|D|   Furazolidone is known to be a monoamine oxidase inhibitor.|
00030|036|D|   Methylene blue, when administered intravenously, has been shown to reach|
00030|037|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
00030|038|D|   Metaxalone is a weak inhibitor of MAO.|
00030|039|B||
00030|040|R|REFERENCES:|
00030|041|B||
00030|042|R|1.Cooper AJ, Keddie KMG. Hypotensive collapse and hypoglycaemia after|3
00030|043|R|  mebanazine -- a monoamine-oxidase inhibitor. Lancet 1964 May 23;1:1133-5.|3
00030|044|R|2.Cooper AJ, Ashcroft G. Potentiation of insulin hypoglycaemia by M.A.O.I.|5
00030|045|R|  antidepressant drugs. Lancet 1966 Feb 19;1(7434):407-9.|5
00030|046|R|3.Cooper AJ. The action of mebanazine, a mono amine oxidase inhibitor|3
00030|047|R|  antidepressant drug in diabetes. II. Int J Neuropsychiatry 1966 Aug;|3
00030|048|R|  2(4):342-5.|3
00030|049|R|4.Cooper AJ, Ashcroft G. Modification of insulin and sulfonylurea|6
00030|050|R|  hypoglycemia by monoamine- oxidase inhibitor drugs. Diabetes 1967 Apr;|6
00030|051|R|  16(4):272-4.|6
00030|052|R|5.Adnitt PI. Hypoglycemic action of monoamineoxidase inhibitors (MAOI'S).|2
00030|053|R|  Diabetes 1968 Oct;17(10):628-33.|2
00030|054|R|6.Absher JR, Black DW. Tranylcypromine withdrawal delirium. J Clin|3
00030|055|R|  Psychopharmacol 1988 Oct;8(5):379-80.|3
00030|056|R|7.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00030|057|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00030|058|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00030|059|R|8.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00030|060|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00030|061|R|  2000 Jun;56(3):247-50.|2
00030|062|R|9.Aleyassine H, Gardiner RJ. Dual action of antidepressant drugs (MAO|2
00030|063|R|  inhibitors) on insulin release. Endocrinology 1975 Mar;96(3):702-10.|2
00030|064|R|10.Aleyassine H, Lee SH. Inhibition of insulin release by substrates and|2
00030|065|R|   inhibitors of monoamine oxidase. Am J Physiol 1972 Mar;222(3):565-9.|2
00030|066|R|11.Aleyassine H, Lee SH. Inhibition by hydrazine, phenelzine and pargyline|5
00030|067|R|   of insulin release from rat pancreas. Endocrinology 1971 Jul;89(1):125-9.|5
00030|068|R|12.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00030|069|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00030|070|R|   Feb;34(2):346.e5-6.|3
00030|071|R|13.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00030|072|R|   Pfizer Inc. January, 2024.|1
00031|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/Selected|
00031|002|T|Cephalosporins|
00031|003|B||
00031|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00031|005|L|of severe adverse interaction.|
00031|006|B||
00031|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve a|
00031|008|A|combination of the cephalosporin's N-methylthiotetrazole (NMTT) side chain|
00031|009|A|antagonizing vitamin K, cephalosporin induced platelet inhibition, and|
00031|010|A|alteration of gut flora.|
00031|011|B||
00031|012|E|CLINICAL EFFECTS:  Concurrent use of some cephalosporins may increase the|
00031|013|E|hypoprothrombinemic effect of the anticoagulant with possible bleeding.|
00031|014|B||
00031|015|P|PREDISPOSING FACTORS:  High doses, hepatic and/or renal impairment, and poor|
00031|016|P|nutrition may increase the risk of bleeding.|
00031|017|P|   The risk for bleeding episodes may be greater in patients with|
00031|018|P|disease-associated factors (e.g. thrombocytopenia).|
00031|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
00031|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00031|021|P|risk for bleeding (e.g. NSAIDs).|
00031|022|B||
00031|023|M|PATIENT MANAGEMENT:  Monitor prothrombin activity (INR) and adjust the|
00031|024|M|anticoagulant dosage accordingly.  Consider using an alternative antibiotic.|
00031|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00031|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00031|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00031|028|M|patients with any symptoms.  Discontinue anticoagulation in patients with|
00031|029|M|active pathologic bleeding.|
00031|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00031|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00031|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00031|033|M|and/or swelling.|
00031|034|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00031|035|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00031|036|M|initiating, altering the dose or discontinuing either drug.|
00031|037|B||
00031|038|D|DISCUSSION:  Cephalosporins with a NMTT side chain have been reported to|
00031|039|D|significantly prolong bleeding time and cause hypoprothrombinemia;|
00031|040|D|therefore, the risk of serious bleeding may be increased in patients taking|
00031|041|D|concurrent anticoagulants.|
00031|042|D|   A large systematic review was performed on 72 warfarin drug-drug|
00031|043|D|interactions studies that reported on bleeding, thromboembolic events, or|
00031|044|D|death. Most studies were retrospective cohorts.  A meta-analysis of 11 of|
00031|045|D|those studies found a higher rate of clinically significant bleeding in|
00031|046|D|patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83).|
00031|047|D|Increased bleeding risk was also seen in subgroup analyses with|
00031|048|D|cephalosporins (OR=1.50; 95% CI 1.21-1.86).|
00031|049|B||
00031|050|R|REFERENCES:|
00031|051|B||
00031|052|R|1.Custer GM, Briggs BR, Smith RE. Effect of cefamandole nafate on blood|5
00031|053|R|  coagulation and platelet function. Antimicrob Agents Chemother 1979 Dec;|5
00031|054|R|  16(6):869-72.|5
00031|055|R|2.Rymer W, Greenlaw CL. Hypoprothrombinemia associated with cefamandole.|3
00031|056|R|  Drug Intell Clin Pharm 1980 Nov;14:780-3.|3
00031|057|R|3.Fainstein V, Bodey GP, McCredie KB, Keating MJ, Estey EH, Bolivar R,|2
00031|058|R|  Elting L. Coagulation abnormalities induced by beta-lactam antibiotics in|2
00031|059|R|  cancer patients. J Infect Dis 1983 Oct;148(4):745-50.|2
00031|060|R|4.Weitekamp MR, Aber RC. Prolonged bleeding times and bleeding diathesis|3
00031|061|R|  associated with moxalactam administration. JAMA 1983 Jan 7;249(1):69-71.|3
00031|062|R|5.Parker SW, Baxter J, Beam TR Jr. Cefoperazone-induced coagulopathy. Lancet|3
00031|063|R|  1984 May 5;1(8384):1016.|3
00031|064|R|6.Cristiano P. Hypoprothrombinemia associated with cefoperazone treatment.|3
00031|065|R|  Drug Intell Clin Pharm 1984 Apr;18(4):314-6.|3
00031|066|R|7.Angaran DM, Dias VC, Arom KV, Northrup WF, Kersten TE, Lindsay WG,|2
00031|067|R|  Nicoloff DM. The influence of prophylactic antibiotics on the warfarin|2
00031|068|R|  anticoagulation response in the postoperative prosthetic cardiac valve|2
00031|069|R|  patient. Cefamandole versus vancomycin. Ann Surg 1984 Jan;199(1):107-11.|2
00031|070|R|8.Angaran DM, Dias VC, Arom KV, Northrup WF, Kersten TG, Lindsay WG,|2
00031|071|R|  Nicoloff DM. The comparative influence of prophylactic antibiotics on the|2
00031|072|R|  prothrombin response to warfarin in the postoperative prosthetic cardiac|2
00031|073|R|  valve patient. Cefamandole, cefazolin, vancomycin. Ann Surg 1987 Aug;|2
00031|074|R|  206(2):155-61.|2
00031|075|R|9.Reddy J, Bailey RR. Vitamin K deficiency developing in patients with renal|3
00031|076|R|  failure treated with cephalosporin antibiotics. N Z Med J 1980 Nov 26;|3
00031|077|R|  92(672):378-9.|3
00031|078|R|10.Bang NU, Tessler SS, Heidenreich RO, Marks CA, Mattler LE. Effects of|2
00031|079|R|   moxalactam on blood coagulation and platelet function. Rev Infect Dis|2
00031|080|R|   1982 Nov-Dec;4 Suppl:S546-54.|2
00031|081|R|11.Joehl RJ, Rasbach DA, Ballard JO, Weitekamp MR, Sattler FR. Moxalactam.|3
00031|082|R|   Evaluation of clinical bleeding in patients with abdominal infection.|3
00031|083|R|   Arch Surg 1983 Nov;118(11):1259-61.|3
00031|084|R|12.Lipsky JJ. N-methyl-thio-tetrazole inhibition of the gamma carboxylation|5
00031|085|R|   of glutamic acid: possible mechanism for antibiotic-associated|5
00031|086|R|   hypoprothrombinaemia. Lancet 1983 Jul 23;2(8343):192-3.|5
00031|087|R|13.Meisel S. Severe bleeding diathesis associated with moxalactam|3
00031|088|R|   administration. Drug Intell Clin Pharm 1984 Sep;18(9):721-2.|3
00031|089|R|14.Osborne JC. Hypoprothrombinemia and bleeding due to cefoperazone. Ann|3
00031|090|R|   Intern Med 1985 May;102(5):721-2.|3
00031|091|R|15.Shearer MJ, Bechtold H, Andrassy K, Koderisch J, McCarthy PT, Trenk D,|2
00031|092|R|   Jahnchen E, Ritz E. Mechanism of cephalosporin-induced|2
00031|093|R|   hypoprothrombinemia: relation to cephalosporin side chain, vitamin K|2
00031|094|R|   metabolism, and vitamin K status. J Clin Pharmacol 1988 Jan;28(1):88-95.|2
00031|095|R|16.Decroix MO, Zini R, Chaumeil JC, Tillement JP. Cefazolin serum protein|5
00031|096|R|   binding and its inhibition by bilirubin, fatty acids and other drugs.|5
00031|097|R|   Biochem Pharmacol 1988 Jul 15;37(14):2807-14.|5
00031|098|R|17.Bechtold H, Lorenz J, Weilemann LS, Meinertz T, Trenk D, Andrassy K,|3
00031|099|R|   Jahnchen E. Possible coumarin-like mechanism of action for|3
00031|100|R|   cephalosporins. Klin Wochenschr 1984 Sep 17;62(18):885-6.|3
00031|101|R|18.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00031|102|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00031|103|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
00031|104|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00032|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Selected|
00032|002|T|Macrolide Antibiotics|
00032|003|B||
00032|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00032|005|L|of severe adverse interaction.|
00032|006|B||
00032|007|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
00032|008|A|anticoagulants.|
00032|009|B||
00032|010|E|CLINICAL EFFECTS:  Concurrent use of a macrolide antibiotic may result in|
00032|011|E|increased effects of the anticoagulant with possible elevated INR and/or|
00032|012|E|bleeding.|
00032|013|B||
00032|014|P|PREDISPOSING FACTORS:  Poor nutrition, fever, larger macrolide doses, and|
00032|015|P|older age.|
00032|016|P|   The risk for bleeding episodes may be greater in patients with|
00032|017|P|disease-associated factors (e.g. thrombocytopenia).|
00032|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
00032|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00032|020|P|risk for bleeding (e.g. NSAIDs).|
00032|021|B||
00032|022|M|PATIENT MANAGEMENT:  Closely monitor INR values in patients maintained on|
00032|023|M|anticoagulants in whom macrolide antibiotics are initiated or discontinued.|
00032|024|M|The dose of the anticoagulant may need to be adjusted.|
00032|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00032|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00032|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00032|028|M|patients with any symptoms.|
00032|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00032|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00032|031|M|anticoagulation in patients with active pathologic bleeding.|
00032|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00032|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00032|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00032|035|M|and/or swelling.|
00032|036|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00032|037|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00032|038|M|initiating, altering the dose, or discontinuing either drug.|
00032|039|B||
00032|040|D|DISCUSSION:  In a retrospective review comparing patients who received|
00032|041|D|concurrent warfarin and azithromycin to matched controls who received only|
00032|042|D|warfarin, azithromycin had no significant effects on INR values.(1)  Another|
00032|043|D|retrospective review compared patients who received concurrent warfarin and|
00032|044|D|azithromycin to matched controls who received concurrent warfarin and|
00032|045|D|felodipine.  Azithromycin had no significant effects on INR values.(2)  In|
00032|046|D|contrast, there are several case reports of increased warfarin effects 4 to|
00032|047|D|8 days after the addition of azithromycin.(3-7)|
00032|048|D|   There is a case report of a patient with an INR of 8.2 after adding|
00032|049|D|azithromycin to concurrent warfarin therapy.  During this time, she also|
00032|050|D|decreased her smoking from (1 pack/day to 2 packs/3 days).(5)|
00032|051|D|   There are several case reports of increased INRs after the addition of|
00032|052|D|clarithromycin to warfarin therapy.(8-11)|
00032|053|D|   In a study in 8 patients, the addition of erythromycin base (333 mg 3|
00032|054|D|times daily for 7 days) to warfarin therapy resulted in a 9.9% increase in|
00032|055|D|prothrombin time ratio from baseline (from 1.61 to 1.77).  However, values|
00032|056|D|were still within therapeutic range and no patient experienced adverse|
00032|057|D|effects.(12)  In another study in 12 healthy subjects, erythromycin (250 mg|
00032|058|D|4 times daily for 8 days) increased the clearance of a single dose of|
00032|059|D|warfarin (1 mg/kg) by 14%.(13)  There are several published case reports of|
00032|060|D|interactions between erythromycin and warfarin(14-19) and acenocoumarol.(20)|
00032|061|D|   In a study in 21 healthy subjects, roxithromycin (150 mg twice daily) had|
00032|062|D|no effect on warfarin pharmacokinetics or pharmacodynamics.(21)  However,|
00032|063|D|there has been one case report of a parietal abdominal hematoma following|
00032|064|D|concurrent roxithromycin and acenocoumarol.(22)|
00032|065|D|   There have been several case reports of increased warfarin effects|
00032|066|D|following the addition of telithromycin to therapy.(23,24)|
00032|067|B||
00032|068|R|REFERENCES:|
00032|069|B||
00032|070|R|1.Beckey NP, Parra D, Colon A. Retrospective evaluation of a potential|2
00032|071|R|  interaction between azithromycine and warfarin in patients stabilized on|2
00032|072|R|  warfarin. Pharmacotherapy 2000 Sep;20(9):1055-9.|2
00032|073|R|2.McCall KL, Anderson HG Jr, Jones AD. Determination of the lack of a drug|2
00032|074|R|  interaction between azithromycin and warfarin. Pharmacotherapy 2004 Feb;|2
00032|075|R|  24(2):188-94.|2
00032|076|R|3.Rao KB, Pallaki M, Tolbert SR, Hornick TR. Enhanced hypoprothrombinemia|3
00032|077|R|  with warfarin due to azithromycin. Ann Pharmacother 2004 Jun;38(6):982-5.|3
00032|078|R|4.Foster DR, Milan NL. Potential interaction between azithromycin and|3
00032|079|R|  warfarin. Pharmacotherapy 1999 Jul;19(7):902-8.|3
00032|080|R|5.Shrader SP, Fermo JD, Dzikowski AL. Azithromycin and warfarin interaction.|3
00032|081|R|  Pharmacotherapy 2004 Jul;24(7):945-9.|3
00032|082|R|6.Woldtvedt BR, Cahoon CL, Bradley LA, Miller SJ. Possible increased|3
00032|083|R|  anticoagulation effect of warfarin induced by azithromycin. Ann|3
00032|084|R|  Pharmacother 1998 Feb;32(2):269-70.|3
00032|085|R|7.Lane G. Increased hypoprothrombinemic effect of warfarin possibly induced|3
00032|086|R|  by azithromycin. Ann Pharmacother 1996 Jul-Aug;30(7-8):884-5.|3
00032|087|R|8.Grau E, Real E, Pastor E. Interaction between clarithromycin and oral|3
00032|088|R|  anticoagulants. Ann Pharmacother 1996 Dec;30(12):1495-6.|3
00032|089|R|9.Recker MW, Kier KL. Potential interaction between clarithromycin and|3
00032|090|R|  warfarin. Ann Pharmacother 1997 Sep;31(9):996-8.|3
00032|091|R|10.Oberg KC. Delayed elevation of international normalized ratio with|3
00032|092|R|   concurrent clarithromycin and warfarin therapy. Pharmacotherapy 1998|3
00032|093|R|   Mar-Apr;18(2):386-91.|3
00032|094|R|11.Gooderham MJ, Bolli P, Fernandez PG. Concomitant digoxin toxicity and|3
00032|095|R|   warfarin interaction in a patient receiving clarithromycin. Ann|3
00032|096|R|   Pharmacother 1999 Jul-Aug;33(7-8):796-9.|3
00032|097|R|12.Weibert RT, Lorentz SM, Townsend RJ, Cook CE, Klauber MR, Jagger PI.|2
00032|098|R|   Effect of erythromycin in patients receiving long-term warfarin therapy.|2
00032|099|R|   Clin Pharm 1989 Mar;8(3):210-4.|2
00032|100|R|13.Bachmann K, Schwartz JI, Forney R Jr, Frogameni A, Jauregui LE. The|2
00032|101|R|   effect of erythromycin on the disposition kinetics of warfarin.|2
00032|102|R|   Pharmacology 1984;28(3):171-6.|2
00032|103|R|14.Bussey HI, Knodel LC, Boyle DA. Warfarin-erythromycin interaction. Arch|3
00032|104|R|   Intern Med 1985 Sep;145(9):1736-7.|3
00032|105|R|15.Schwartz J, Bachmann K, Perrigo E. Interaction between warfarin and|3
00032|106|R|   erythromycin. South Med J 1983 Jan;76(1):91-3.|3
00032|107|R|16.Hassell D, Utt JK. Suspected interaction: warfarin and erythromycin.|3
00032|108|R|   South Med J 1985 Aug;78(8):1015-6.|3
00032|109|R|17.Sato RI, Gray DR, Brown SE. Warfarin interaction with erythromycin. Arch|3
00032|110|R|   Intern Med 1984 Dec;144(12):2413-4.|3
00032|111|R|18.Husserl FE. Erythromycin-warfarin interaction. Arch Intern Med 1983 Sep;|3
00032|112|R|   143(9):1831, 1836.|3
00032|113|R|19.Bartle WR. Possible warfarin-erythromycin interaction. Arch Intern Med|3
00032|114|R|   1980 Jul;140(7):985-7.|3
00032|115|R|20.Grau E, Fontcuberta J, Felez J. Erythromycin-oral anticoagulants|3
00032|116|R|   interaction. Arch Intern Med 1986 Aug;146(8):1639.|3
00032|117|R|21.Paulsen O, Nilsson LG, Saint-Salvi B, Manuel C, Lunell E. No effect of|2
00032|118|R|   roxithromycin on pharmacokinetic or pharmacodynamic properties of|2
00032|119|R|   warfarin and its enantiomers. Pharmacol Toxicol 1988 Oct;63(4):215-20.|2
00032|120|R|22.Chassany O, Logeart I, Choulika S, Caulin C. Parietal abdominal hematoma|3
00032|121|R|   after combined acenocoumarol and roxithromycin treatment. Presse Med 1998|3
00032|122|R|   Jun 20;27(22):1103.|3
00032|123|R|23.Kolilekas L, Anagnostopoulos GK, Lampaditis I, Eleftheriadis I. Potential|3
00032|124|R|   interaction between telithromycin and warfarin. Ann Pharmacother 2004|3
00032|125|R|   Sep;38(9):1424-7.|3
00032|126|R|24.Djelouah I. Telithromycin (ketek) and warfarin:  suspected interaction.|3
00032|127|R|   Canadian Adverse Reaction Newsletter 2005 Jan;15(1):1-2.|3
00034|001|T|MONOGRAPH TITLE:  Guanethidine; Guanadrel/Tricyclic Compounds|
00034|002|B||
00034|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00034|004|L|of severe adverse interaction.|
00034|005|B||
00034|006|A|MECHANISM OF ACTION:  Uptake of guanethidine is blocked by tricyclic|
00034|007|A|antidepressants at the adrenergic neuron.|
00034|008|B||
00034|009|E|CLINICAL EFFECTS:  Concurrent use of tricyclic antidepressants may result in|
00034|010|E|decreased guanethidine or guanadrel effectiveness.  The effects may be seen|
00034|011|E|for several days after discontinuation of the tricyclic antidepressant.|
00034|012|B||
00034|013|P|PREDISPOSING FACTORS:  Possibly concurrent administration of drugs that|
00034|014|P|inhibit hepatic enzymes.|
00034|015|B||
00034|016|M|PATIENT MANAGEMENT:  Avoid concomitant administration of these drugs. If|
00034|017|M|both drugs are administered, adjust the guanethidine dose as needed based on|
00034|018|M|blood pressure.|
00034|019|B||
00034|020|D|DISCUSSION:  This interaction is well documented. Similarity between|
00034|021|D|cyclobenzaprine and TCA's warrants consideration of TCA interactions for|
00034|022|D|cyclobenzaprine.|
00034|023|B||
00034|024|R|REFERENCES:|
00034|025|B||
00034|026|R|1.Leishman AWD, Matthews HL, Smith AJ. Antagonism of guanethidine by|3
00034|027|R|  imipramine. Lancet 1963 Jan 12;1:112.|3
00034|028|R|2.Mitchell JR, Arias L, Oates JA. Antagonism of the antihypertensive action|2
00034|029|R|  of guanethidine sulfate by desipramine hydrochloride. JAMA 1967 Dec 4;|2
00034|030|R|  202(10):973-6.|2
00035|001|T|MONOGRAPH TITLE:  Guanethidine; Guanadrel/Phenothiazines|
00035|002|B||
00035|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00035|004|L|take action as needed.|
00035|005|B||
00035|006|A|MECHANISM OF ACTION:  Phenothiazines may inhibit uptake of guanethidine at|
00035|007|A|the adrenergic neuron.|
00035|008|B||
00035|009|E|CLINICAL EFFECTS:  Decreased antihypertensive effectiveness. Effects may be|
00035|010|E|seen for several days after discontinuation of the phenothiazine.|
00035|011|B||
00035|012|P|PREDISPOSING FACTORS:  None determined.|
00035|013|B||
00035|014|M|PATIENT MANAGEMENT:  Avoid concomitant administration of these drugs. If|
00035|015|M|both drugs are administered, adjust the guanethidine dose as needed based on|
00035|016|M|blood pressure. Consider giving molindone in place of the phenothiazine.|
00035|017|M|Available data indicate that hydralazine or minoxidil do not interact with|
00035|018|M|phenothiazines. Severe hypertension was reported in one patient during|
00035|019|M|concurrent use of methyldopa and the phenothiazine trifluoperazine. However,|
00035|020|M|this interaction was not substantiated in animals.|
00035|021|B||
00035|022|D|DISCUSSION:  Documentation supports routine monitoring of this interaction.|
00035|023|D|The antihypertensive effect of guanethidine/guanadrel usually reverses over|
00035|024|D|several days to more than one week after starting concurrent phenothiazine|
00035|025|D|and guanethidine therapy. When the phenothiazine is stopped, an initial|
00035|026|D|rebound increase in blood pressure may occur.|
00035|027|B||
00035|028|R|REFERENCES:|
00035|029|B||
00035|030|R|1.Ober KF, Wang RI. Drug interactions with guanethidine. Clin Pharmacol Ther|2
00035|031|R|  1973 Mar-Apr;14(2):190-5.|2
00035|032|R|2.Janowsky DS, el-Yousef MK, Davis JM, Fann WE. Antagonism of guanethidine|2
00035|033|R|  by chlorpromazine. Am J Psychiatry 1973 Jul;130(7):808-12.|2
00035|034|R|3.Stone CA, Porter CC, Stavroski JM, Ludden CT, Totaro JA. Antagonism of|5
00035|035|R|  certain effects of catecholamine-depleting agents by antidepressant and|5
00035|036|R|  related drugs. J Pharmacol Exp Ther 1964;144:196-204.|5
00035|037|R|4.Fann WE, Janowsky DS, Davis JM, Oates JA. Chlorpromazine reversal of the|3
00035|038|R|  antihypertensive action of guanethidine. Lancet 1971 Aug 21;2(7721):436-7.|3
00035|039|R|5.Tuck D, Hamberger B, Sjokvist F. Drug interactions: effect of|6
00035|040|R|  chlorpromazine on the uptake of monoamines into adrenergic neurons in man.|6
00035|041|R|  Lancet 1972 Sep 2;2(7775):492.|6
00035|042|R|6.Gilder DA, Fain W, Simpson LL. A comparison of the abilities of|5
00035|043|R|  chlorpromazine and molindone to interact adversely with guanethidine. J|5
00035|044|R|  Pharmacol Exp Ther 1976 Aug;198(2):255-63.|5
00035|045|R|7.Simpson LL. Combined use of molindone and guanethidine in patients with|2
00035|046|R|  schizophrenia and hypertension. Am J Psychiatry 1979 Nov;136(11):1410-4.|2
00035|047|R|8.Poe TE, Edwards JL, Taylor RB. Hypertensive crisis possibly due to drug|3
00035|048|R|  interaction. Postgrad Med 1979 Nov;66(5):235-7.|3
00035|049|R|9.Rankin GO, Watkins BE, Sawutz DG. Chlorpromazine interactions with|5
00035|050|R|  guanethidine and alpha-methyldopa: effects on arterial pressure control|5
00035|051|R|  and heart rate in renovascular hypertensive rats. Arch Int Pharmacodyn|5
00035|052|R|  Ther 1982 Nov;260(1):130-40.|5
00036|001|T|MONOGRAPH TITLE:  Clonidine/Tricyclic Compounds; Mirtazapine|
00036|002|B||
00036|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00036|004|L|take action as needed.|
00036|005|B||
00036|006|A|MECHANISM OF ACTION:  Clonidine decreases blood pressure via alpha-2|
00036|007|A|agonism.(1) Tricyclic compounds(2) and mirtazapine(3) antagonize alpha-2,|
00036|008|A|which may result in a loss of effect of clonidine.|
00036|009|B||
00036|010|E|CLINICAL EFFECTS:  The concurrent use of clonidine and tricyclic|
00036|011|E|compounds(1,3,4-16) and mirtazapine(3,17) may result in decreased|
00036|012|E|effectiveness of clonidine and hypertensive crisis.|
00036|013|B||
00036|014|P|PREDISPOSING FACTORS:  None determined.|
00036|015|B||
00036|016|M|PATIENT MANAGEMENT:  If possible, avoid concurrent use of clonidine with|
00036|017|M|tricyclic compounds or mirtazapine. Consider using an alternative agent in|
00036|018|M|patients maintained on clonidine. If concurrent administration is warranted,|
00036|019|M|blood pressure should be carefully monitored, particularly in the first two|
00036|020|M|weeks of therapy, when this interaction is most likely to occur. The dosage|
00036|021|M|of clonidine may need to be adjusted or the tricyclic compound or|
00036|022|M|mirtazapine may need to be discontinued.|
00036|023|B||
00036|024|D|DISCUSSION:  This interaction has been reported in patients receiving|
00036|025|D|amitriptyline,(6) clomipramine,(7,8) desipramine,(2,9-11) imipramine(12-16),|
00036|026|D|and protriptyline.(11) In one patient, a hypertensive crisis resulted. Other|
00036|027|D|patients experienced a decrease in blood pressure control. A controlled|
00036|028|D|trial demonstrated a decrease in anti-hypertensive effect when desipramine|
00036|029|D|was added to a clonidine regimen. This decrease in hypertensive-control may|
00036|030|D|be overcome by increasing the dose of clonidine and monitoring blood|
00036|031|D|pressure closely.|
00036|032|D|   Cyclobenzaprine is structurally related to the tricyclic antidepressants|
00036|033|D|and, especially at higher dosages, has similar effects.(18) Therefore, it is|
00036|034|D|prudent to consider cyclobenzaprine in this interaction.|
00036|035|D|   Hypertensive crisis has been reported during concurrent clonidine and|
00036|036|D|mirtazapine therapy.(3,17)|
00036|037|D|   Mianserin(19,20) and maprotiline,(21) tetracyclic antidepressants, have|
00036|038|D|been shown not to affect the antihypertensive effects of clonidine.|
00036|039|B||
00036|040|R|REFERENCES:|
00036|041|B||
00036|042|R|1.Blaschke TP, Melmon KL. Antihypertensive agents and the drug therapy of|2
00036|043|R|  hypertension. In Gilman, A.G., Goodman, L.S., and Gilman,A., editors: The|2
00036|044|R|  Pharmacological Basis of Therapeutics, New York, 1980, Macmillan|2
00036|045|R|  Publishing..|2
00036|046|R|2.Checkley SA, Slade AP, Shur E, Dawling S. A pilot study of the mechanism|2
00036|047|R|  of action of desipramine. Br J Psychiatry 1981 Mar;138:248-51.|2
00036|048|R|3.Troncoso AL, Gill T. Hypertensive urgency with clonidine and mirtazepine.|3
00036|049|R|  Psychosomatics 2004 Sep-Oct;45(5):449-50.|3
00036|050|R|4.van Spanning HW, van Zwieten PA. The interference of tricyclic|5
00036|051|R|  antidepressants with the central hypotensive effect of clonidine. Eur J|5
00036|052|R|  Pharmacol 1973 Dec;24(3):402-4.|5
00036|053|R|5.van Zwieten PA. Interaction between centrally acting hypotensive drugs and|5
00036|054|R|  tricyclic antidepressants. Arch Int Pharmacodyn Ther 1975 Mar;|5
00036|055|R|  214(1):12-30.|5
00036|056|R|6.Stiff JL, Harris DB. Clonidine withdrawal complicated by amitriptyline|3
00036|057|R|  therapy. Anesthesiology 1983 Jul;59(1):73-4.|3
00036|058|R|7.Lacomblez L, Warot D, Bouche P, Derouesne C. Suppression of the|3
00036|059|R|  antihypertensive effect of clonidine by clomipramine. Rev Med Interne 1988|3
00036|060|R|  May-Jun;9(3):291-3.|3
00036|061|R|8.Andrejak M, Fournier A, Hardin JM, Coevoet B, Lambrey G, De Fremont JF,|3
00036|062|R|  Quichaud J. Suppression of the antihypertensive effect of clonidine by the|3
00036|063|R|  simultaneous intake of a tricyclic antidepressive agent. Practical problem|3
00036|064|R|  in the treatment of a depressed hypertensive patient. Nouv Presse Med 1977|3
00036|065|R|  Sep 10;6(29):2603.|3
00036|066|R|9.Briant RH, Reid JL, Dollery CT. Interaction between clonidine and|2
00036|067|R|  desipramine in man. Br Med J 1973 Mar 3;1(5852):522-3.|2
00036|068|R|10.Briant RH, Reid JL. Desmethylimipramine and the hypotensive action of|5
00036|069|R|   clonidine in the rabbit. Br J Pharmacol 1972 Nov;46(3):563P-564P.|5
00036|070|R|11.Zwieten PA. The reversal of clonidine-induced hypotension by|5
00036|071|R|   protriptyline and desipramine. Pharmacology 1976;14(3):227-31.|5
00036|072|R|12.Hui KK. Hypertensive crisis induced by interaction of clonidine with|3
00036|073|R|   imipramine. J Am Geriatr Soc 1983 Mar;31(3):164-5.|3
00036|074|R|13.Conolly ME. In:  Conolly ME., editor: Catapres in Hypertension, London,|2
00036|075|R|   1969, Butterwoth's Publishing..|2
00036|076|R|14.Coffier DE, et al. Antipsychotic drug interaction. Drug Intell Clin Pharm|3
00036|077|R|   1976;10:114.|3
00036|078|R|15.Siever LJ, Cohen RM, Murphy DL. Antidepressants and alpha 2-adrenergic|3
00036|079|R|   autoreceptor desensitization. Am J Psychiatry 1981 May;138(5):681-2.|3
00036|080|R|16.Cubeddu LX, Cloutier G, Gross K, Grippo R, Tanner L, Lerea L, Shakarjian|5
00036|081|R|   M, Knowlton G, Stat M, Harden TK, et al. Bupropion does not antagonize|5
00036|082|R|   cardiovascular actions of clonidine in normal subjects and spontaneously|5
00036|083|R|   hypertensive rats. Clin Pharmacol Ther 1984 May;35(5):576-84.|5
00036|084|R|17.Abo-Zena RA, Bobek MB, Dweik RA. Hypertensive urgency induced by an|3
00036|085|R|   interaction of mirtazapine and clonidine. Pharmacotherapy 2000 Apr;|3
00036|086|R|   20(4):476-8.|3
00036|087|R|18.Flexeril (cyclobenzaprine hydrochloride) US prescribing information.|1
00036|088|R|   Merck & Co., Inc. 1985.|1
00036|089|R|19.Elliott HL, Whiting B, Reid JL. Assessment of the interaction between|2
00036|090|R|   mianserin and centrally-acting antihypertensive drugs. Br J Clin|2
00036|091|R|   Pharmacol 1983;15 Suppl 2:323S-328S.|2
00036|092|R|20.Elliott HL, McLean K, Sumner DJ, Reid JL. Absence of an effect of|2
00036|093|R|   mianserin on the actions of clonidine or methyldopa in hypertensive|2
00036|094|R|   patients. Eur J Clin Pharmacol 1983;24(1):15-9.|2
00036|095|R|21.Gundert-Remy U, Amann E, Hildebrandt R, Weber E. Lack of interaction|2
00036|096|R|   between the tetracyclic antidepressant maprotiline and the centrally|2
00036|097|R|   acting antihypertensive drug clonidine. Eur J Clin Pharmacol 1983;|2
00036|098|R|   25(5):595-9.|2
00038|001|T|MONOGRAPH TITLE:  Narcotics/Phenothiazines (mono deleted 04/20/2017)|
00038|002|B||
00038|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00038|004|L|take action as needed.|
00038|005|B||
00038|006|A|MECHANISM OF ACTION:  The concurrent administration of phenothiazines and|
00038|007|A|narcotics may result in additive CNS depressant effects.|
00038|008|A|   Chlorpromazine increases the amount of normeperidine, a potentially toxic|
00038|009|A|metabolite of meperidine.  Chlorpromazine also seems to increase the|
00038|010|A|activity of meperidine N-demethylase, the enzyme necessary for formation of|
00038|011|A|normeperidine.|
00038|012|B||
00038|013|E|CLINICAL EFFECTS:  Concurrent use of narcotics and phenothiazines without|
00038|014|E|narcotic dose adjustment may result in potentiation of CNS depression, which|
00038|015|E|may result in hypotension, increased sedation, and decreased respiration.|
00038|016|B||
00038|017|P|PREDISPOSING FACTORS:  None determined.|
00038|018|B||
00038|019|M|PATIENT MANAGEMENT:  Respiration and blood pressure should be closely|
00038|020|M|monitored in patients receiving concurrent narcotic and phenothiazine|
00038|021|M|therapy.  The dosage of the narcotic may need to be adjusted.|
00038|022|M|   In patients receiving concurrent phenothiazines with meperidine, the dose|
00038|023|M|of meperidine should be decreased by 25% to 50%.|
00038|024|B||
00038|025|D|DISCUSSION:  This combination is commonly given, particularly in pediatrics.|
00038|026|D|Phenothiazines have been shown to potentiate the action of narcotics, thus|
00038|027|D|allowing for a dosage reduction of narcotics.  Phenothiazines also possess|
00038|028|D|anti-emetic properties which help alleviate nausea and vomiting often|
00038|029|D|associated with narcotics.  The efficacy of this combination is|
00038|030|D|controversial, and not without some risks.  Chlorpromazine has been shown to|
00038|031|D|increase recovery time from meperidine and does require more monitoring than|
00038|032|D|when meperidine is used alone.|
00038|033|D|   Prochlorperazine, promethazine, and propiomazine have all been reported|
00038|034|D|to interact with meperidine.  Other narcotics that have been reported to|
00038|035|D|interact with phenothiazines include fentanyl, hydromorphone, morphine, and|
00038|036|D|oxymorphone.|
00038|037|B||
00038|038|R|REFERENCES:|
00038|039|B||
00038|040|R|1.Swett C Jr, Cole JO, Hartz SC, Shapiro S, Slone D. Hypotension due to|2
00038|041|R|  chlorpromazine. Relation to cigarette smoking, blood pressure, and dosage.|2
00038|042|R|  Arch Gen Psychiatry 1977 Jun;34(6):661-3.|2
00038|043|R|2.Stambaugh JE Jr, Wainer IW. Drug interaction: meperidine and|2
00038|044|R|  chlorpromazine, a toxic combination. J Clin Pharmacol 1981 Apr;|2
00038|045|R|  21(4):140-6.|2
00038|046|R|3.Sadove MS, Levin MJ, Rose RF, Schwartz L. Chlorpromazine and narcotics in|2
00038|047|R|  the management of pain of malignant lesions. J Am Med Assoc 1954 Jun 12;|2
00038|048|R|  155(7):626-8.|2
00038|049|R|4.Jackson GL, Smith DA. Analgesic properties of mixtures of chlorpromazine|2
00038|050|R|  with morphine and meperidine. Ann Intern Med 1956 Oct;45(4):640-51.|2
00038|051|R|5.Dundee JW. Chlorpromazine as an adjuvant in the relief of chronic pain. Br|2
00038|052|R|  J Anaesth 1957;19:28-34.|2
00038|053|R|6.Lambertsen CJ, Wendel H, Longenhagen JB. The separate and combined|2
00038|054|R|  respiratory effects of chlorpromazine and meperidine in normal men|2
00038|055|R|  controlled at 46 MM Hg alveolar PCO2. J Pharmacol Exp Ther 1961;|2
00038|056|R|  131:281-93.|2
00038|057|R|7.Hoffman JC, Smith TC. The respiratory effects of meperidine and|2
00038|058|R|  propiomazine in man. Anesthesiology 1970 Apr;32(4):325-31.|2
00038|059|R|8.Steen SN, Yates M. The effects of benzquinamide and prochlorperazine,|2
00038|060|R|  separately and combined, on the human respiratory center. Anesthesiology|2
00038|061|R|  1972 May;36(5):519-20.|2
00038|062|R|9.Keeri-Szanto M. The mode of action of promethazine in potentiating|2
00038|063|R|  narcotic drugs. Br J Anaesth 1974 Dec;46(12):918-24.|2
00038|064|R|10.Reier CE, Johnstone RE. Respiratory depression: narcotic versus|2
00038|065|R|   narcotic-tranquilizer combinations. Anesth Analg 1970 Jan-Feb;|2
00038|066|R|   49(1):119-24.|2
00038|067|R|11.McGee JL, Alexander MR. Phenothiazine analgesia--fact or fantasy?. Am J|2
00038|068|R|   Hosp Pharm 1979 May;36(5):633-40.|2
00040|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
00040|002|T|antagonists)/Griseofulvin|
00040|003|B||
00040|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00040|005|L|take action as needed.|
00040|006|B||
00040|007|A|MECHANISM OF ACTION:  Griseofulvin may induce the metabolism of Vitamin K|
00040|008|A|antagonists, such as warfarin.|
00040|009|B||
00040|010|E|CLINICAL EFFECTS:  Concurrent or recent use of griseofulvin may result in|
00040|011|E|decreased anticoagulant response, which can increase the risk of thrombosis.|
00040|012|B||
00040|013|P|PREDISPOSING FACTORS:  None determined.|
00040|014|B||
00040|015|M|PATIENT MANAGEMENT:  Use caution when griseofulvin is started or stopped in|
00040|016|M|patients on anticoagulant therapy.  Monitor INR closely and adjust the|
00040|017|M|anticoagulant dose as necessary.|
00040|018|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00040|019|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00040|020|M|initiating, altering the dose or discontinuing either drug.|
00040|021|B||
00040|022|D|DISCUSSION:  Several case reports have shown that the administration of|
00040|023|D|griseofulvin (500mg/day to 1000mg/day) to patients maintained on warfarin|
00040|024|D|resulted in a decreased prothrombin time, requiring an increase in the dose|
00040|025|D|of warfarin.(1,2)  This interaction usually occurs after several weeks of|
00040|026|D|concurrent therapy.|
00040|027|D|   In one patient, an overall increase of 41% in warfarin dosage (from|
00040|028|D|8.5mg/day to 12mg/day) was needed to maintain the therapeutic effect of|
00040|029|D|warfarin after 12 weeks of co-administration.  Nine weeks after the|
00040|030|D|griseofulvin dosage was reduced (from 500mg/day to 250mg/day), the|
00040|031|D|prothrombin time increased to 2.3 times control. A reduction in the dose of|
00040|032|D|warfarin to 10mg/day maintained the prothrombin time between 1.6 and 1.8|
00040|033|D|times control for the next seven weeks.(1)|
00040|034|D|    In a small study in which patients served as their own controls, 4 of 10|
00040|035|D|subjects experienced a decrease in prothrombin times following two weeks of|
00040|036|D|griseofulvin therapy.(3)|
00040|037|B||
00040|038|R|REFERENCES:|
00040|039|B||
00040|040|R|1.Cullen SI, Catalano PM. Griseofulvin-warfarin antagonism. JAMA 1967 Feb|3
00040|041|R|  20;199(8):582-3.|3
00040|042|R|2.Okino K, Weibert RT. Warfarin-griseofulvin interaction. Drug Intell Clin|3
00040|043|R|  Pharm 1986 Apr;20(4):291-3.|3
00040|044|R|3.Udall JA. Drug interference with warfarin therapy. Clin Med 1970 Aug;|2
00040|045|R|  77:20-5.|2
00042|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Ethchlorvynol|
00042|002|B||
00042|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00042|004|L|take action as needed.|
00042|005|B||
00042|006|A|MECHANISM OF ACTION:  Not defined. It has been proposed that hepatic enzyme|
00042|007|A|induction enhances metabolism of anticoagulants.|
00042|008|B||
00042|009|E|CLINICAL EFFECTS:  Ethchlorvynol decreases prothrombin time with diminished|
00042|010|E|anticoagulant response.|
00042|011|B||
00042|012|P|PREDISPOSING FACTORS:  None determined.|
00042|013|B||
00042|014|M|PATIENT MANAGEMENT:  Avoid use of ethchlorvynol. If both drugs are used,|
00042|015|M|adjust the anticoagulant dose as needed based on prothrombin activity and|
00042|016|M|patient response. Consider substituting a benzodiazepine in place of|
00042|017|M|ethchlorvynol.|
00042|018|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00042|019|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00042|020|M|initiating, altering the dose or discontinuing either drug.|
00042|021|B||
00042|022|D|DISCUSSION:  The benzodiazepines chlordiazepoxide, diazepam and nitrazepam|
00042|023|D|have not been found to interact with warfarin. This is probably the case|
00042|024|D|with other benzodiazepines so these drugs should be considered as a|
00042|025|D|substitute for ethchlorvynol.|
00042|026|B||
00042|027|R|REFERENCES:|
00042|028|B||
00042|029|R|1.Cullen SI, Catalano PM. Griseofulvin-warfarin antagonism. JAMA 1967 Feb|3
00042|030|R|  20;199(8):582-3.|3
00042|031|R|2.Johansson SA. Apparent resistance to oral anticoagulant therapy and|2
00042|032|R|  influence of hypnotics on some coagulation factors. Acta Med Scand 1968|2
00042|033|R|  Oct;184(4):297-300.|2
00042|034|R|3.Orme M, Breckenridge A, Brooks RV. Interactions of benzodiazepines with|2
00042|035|R|  warfarin. Br Med J 1972 Sep 9;3(827):611-4.|2
00043|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Glucagon, Dasiglucagon|
00043|002|B||
00043|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00043|004|L|take action as needed.|
00043|005|B||
00043|006|A|MECHANISM OF ACTION:  Not defined.|
00043|007|B||
00043|008|E|CLINICAL EFFECTS:  Excess hypoprothrombinemia and possible bleeding|
00043|009|E|complications.|
00043|010|B||
00043|011|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00043|012|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00043|013|P|   Drug associated risk factors include concurrent use of multiple drugs|
00043|014|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00043|015|P|risk for bleeding (e.g. NSAIDs).|
00043|016|B||
00043|017|M|PATIENT MANAGEMENT:  If the duration of glucagon/dasiglucagon therapy is one|
00043|018|M|day, a clinically important interaction is unlikely.|
00043|019|M|   Avoid using multiple doses of glucagon/dasiglucagon in anticoagulated|
00043|020|M|patients. If this combination is necessary, decrease the warfarin dose prior|
00043|021|M|to glucagon/dasiglucagon dosing.  Monitor patients receiving concurrent|
00043|022|M|therapy for signs of blood loss, including decreased hemoglobin  and/or|
00043|023|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
00043|024|M|evaluate patients with any symptoms.|
00043|025|M|   When applicable, perform INR to monitor efficacy and safety of|
00043|026|M|anticoagulation.  Discontinue anticoagulation in patients with active|
00043|027|M|pathologic bleeding.|
00043|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00043|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00043|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00043|031|M|and/or swelling.|
00043|032|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00043|033|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00043|034|M|initiating, altering the dose or discontinuing either drug.|
00043|035|B||
00043|036|D|DISCUSSION:  If the duration of glucagon/dasiglucagon therapy is one day, a|
00043|037|D|clinically important interaction is unlikely. However, the potentiation|
00043|038|D|effects of glucagon/dasiglucagon on the anticoagulant effect of warfarin|
00043|039|D|seems to occur rapidly and can reverse within one day of stopping glucagon.|
00043|040|B||
00043|041|R|REFERENCES:|
00043|042|B||
00043|043|R|1.Koch-Weser J. Potentiation by glucagon of the hypoprothrombinemic action|3
00043|044|R|  of warfarin. Ann Intern Med 1970 Mar;72(3):331-5.|3
00043|045|R|2.Weiner M, Moses D. The effect of glucagon and insulin on the prothrombin|5
00043|046|R|  response to coumarin anticoagulants. Proc Soc Exp Biol Med 1968 Mar;|5
00043|047|R|  127(3):761-3.|5
00043|048|R|3.Zegalogue (Dasiglucagon) US Prescribing Information. Zealand Pharma A/S|1
00043|049|R|  March 2021.|1
00044|001|T|MONOGRAPH TITLE:  Aminoglycosides/Select Cephalosporins|
00044|002|B||
00044|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00044|004|L|take action as needed.|
00044|005|B||
00044|006|A|MECHANISM OF ACTION:  Unknown.|
00044|007|B||
00044|008|E|CLINICAL EFFECTS:  Nephrotoxicity may occur.|
00044|009|B||
00044|010|P|PREDISPOSING FACTORS:  Preexisting renal impairment, older age, and large|
00044|011|P|doses of either drug.|
00044|012|B||
00044|013|M|PATIENT MANAGEMENT:  Try to avoid this combination in patients at risk of|
00044|014|M|developing nephrotoxicity. Elderly patients, patients receiving large doses|
00044|015|M|of either drug, and renal patients should be considered at risk. Monitor|
00044|016|M|renal function if this combination is used.|
00044|017|B||
00044|018|D|DISCUSSION:  This interaction is likely to occur in some patients, but|
00044|019|D|clinical documentation is limited. This interaction is usually not a problem|
00044|020|D|in patients with normal renal function.|
00044|021|B||
00044|022|R|REFERENCES:|
00044|023|B||
00044|024|R|1.Bobrow SN, Jaffe E, Young RC. Anuria and acute tubular necrosis associated|3
00044|025|R|  with gentamicin and cephalothin. JAMA 1972 Dec 18;222(12):1546-7.|3
00044|026|R|2.Cabanillas F, Burgos RC, Rodriguez C, Baldizon C. Nephrotoxicity of|3
00044|027|R|  combined cephalothin-gentamicin regimen. Arch Intern Med 1975 Jun;|3
00044|028|R|  135(6):850-2.|3
00044|029|R|3.Fillastre JP, Laumonier R, Humbert G, Dubois D, Metayer J, Delpech A,|3
00044|030|R|  Leroy J, Robert M. Acute renal failure associated with combined gentamicin|3
00044|031|R|  and cephalothin therapy. Br Med J 1973 May 19;2(5863):396-7.|3
00044|032|R|4.Klastersky J, Henri A, Hensgens C, Daneau D. Gram-negative infections in|2
00044|033|R|  cancer. Study of empiric therapy comparing carbenicillin-cephalothin with|2
00044|034|R|  and without gentamicin. JAMA 1974 Jan 7;227(1):45-8.|2
00044|035|R|5.Bloomfield CD, Kennedy BJ. Cephalothin, carbenicillin, and gentamicin|2
00044|036|R|  combination therapy for febrile patients with acute non-lymphocytic|2
00044|037|R|  leukemia. Cancer 1974 Aug;34(2):431-7.|2
00044|038|R|6.Harrison WO, Silverblatt FJ, Turck M. Gentamicin nephrotoxicity: failure|5
00044|039|R|  of three cephalosporins to potentiate injury in rats. Antimicrob Agents|5
00044|040|R|  Chemother 1975 Aug;8(2):209-15.|5
00044|041|R|7.Klastersky J, Hensgens C, Debusscher L. Empiric therapy for cancer|2
00044|042|R|  patients: comparative study of ticarcillin- tobramycin,|2
00044|043|R|  ticarcillin-cephalothin, and cephalothin-tobramycin. Antimicrob Agents|2
00044|044|R|  Chemother 1975 May;7(5):640-5.|2
00044|045|R|8.Fanning WL, Gump D, Jick H. Gentamicin- and cephalothin-associated rises|2
00044|046|R|  in blood urea nitrogen. Antimicrob Agents Chemother 1976 Jul;10(1):80-2.|2
00044|047|R|9.Plager JE. Association of renal injury with combined|2
00044|048|R|  cephalothin-gentamicin therapy among patients severely ill with malignant|2
00044|049|R|  disease. Cancer 1976 Apr;37(4):1937-43.|2
00044|050|R|10.Hansen MM, Kaaber K. Nephrotoxicity in combined cephalothin and|3
00044|051|R|   gentamicin therapy. Acta Med Scand 1977;201(5):463-7.|3
00044|052|R|11.Wade JC, Smith CR, Petty BG, Lipsky JJ, Conrad G, Ellner J, Lietman PS.|2
00044|053|R|   Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin|2
00044|054|R|   plus an aminoglycoside. Lancet 1978 Sep 16;2(8090):604-6.|2
00044|055|R|12.Schimpff SC, Gaya H, Klastersky J, Tattersall MH, Zinner SH. Three|2
00044|056|R|   antibiotic regimens in the treatment of infection in febrile|2
00044|057|R|   granulocytopenic patients with cancer. The EORTC international|2
00044|058|R|   antimicrobial therapy project group. J Infect Dis 1978 Jan;137(1):14-29.|2
00044|059|R|13.Brown AE, Quesada O, Armstrong D. Minimal nephrotoxicity with|2
00044|060|R|   cephalosporin-aminoglycoside combinations in patients with neoplastic|2
00044|061|R|   disease. Antimicrob Agents Chemother 1982 Apr;21(4):592-4.|2
00044|062|R|14.Kuhlmann J, Seidel G, Grotsch H. Tobramycin nephrotoxicity: failure of|2
00044|063|R|   cefotaxime to potentiate renal toxicity. Infection 1982;10(4):233-9.|2
00044|064|R|15.Mondorf AW, Heynold FT, Scherberich JE, Hess H, Schoeppe W. Assessment of|2
00044|065|R|   the nephrotoxic potential of ceftazidime and a ceftazidime/tobramycin|2
00044|066|R|   combination in volunteers. Infection 1983;11 Suppl 1:S57-62.|2
00044|067|R|16.Van der Auwera P, Klastersky J, Lagast H, Husson M. Serum bactericidal|5
00044|068|R|   activity and killing rate for volunteers receiving imipenem, imipenem|5
00044|069|R|   plus amikacin, and ceftazidime plus amikacin against Pseudomonas|5
00044|070|R|   aeruginosa. Antimicrob Agents Chemother 1986 Jul;30(1):122-6.|5
00044|071|R|17.Braveny I, Machka K, Milatovic D. Evaluation of novel antipseudomonal|5
00044|072|R|   drugs using the serum bactericidal activity test. Eur J Clin Microbiol|5
00044|073|R|   1986 Feb;5(1):119-23.|5
00044|074|R|18.Wagenvoort JH, Brus-Weijer L, Michel MF. Bactericidal effect of|5
00044|075|R|   combinations of cephalosporins with tobramycin on clinical isolates of|5
00044|076|R|   Escherichia coli, Klebsiella and Staphylococcus aureus.|5
00044|077|R|   Arzneimittelforschung 1986 Sep;36(9):1301-2.|5
00044|078|R|19.Giamarellou H. Aminoglycosides plus beta-lactams against gram-negative|5
00044|079|R|   organisms. Evaluation of in vitro synergy and chemical interactions. Am J|5
00044|080|R|   Med 1986 Jun 30;80(6B):126-37.|5
00044|081|R|20.Bergeron MG, LeBel M, Charest A, Forcier JF, Morin J, Vallee F.|5
00044|082|R|   Comparative study of serum bactericidal activity of cefotaxime alone or|5
00044|083|R|   in combination with tobramycin. Antimicrob Agents Chemother 1986 Feb;|5
00044|084|R|   29(2):379-81.|5
00044|085|R|21.Pascual-Lopez A, Lagast H, Klastersky J. Serum bactericidal activity|5
00044|086|R|   against Klebsiella pneumoniae in volunteers receiving increasing doses of|5
00044|087|R|   tobramycin with or without cefamandole. Int J Clin Pharmacol Res 1987;|5
00044|088|R|   7(1):45-9.|5
00044|089|R|22.Bingen E, Lambert-Zechovsky N, Aujard Y, Mariani P, Lemer G, Sauzeau C,|5
00044|090|R|   Mathieu H. Early synergistic killing activity at concentrations|5
00044|091|R|   attainable in CSF of amoxicillin or cefotaxime and aminoglycosides|5
00044|092|R|   against Haemophilus influenzae. Infection 1988 Mar-Apr;16(2):121-5.|5
00045|001|T|MONOGRAPH TITLE:  Aminoglycosides/Penicillins (mono deleted 02/04/2022)|
00045|002|B||
00045|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00045|004|L|take action as needed.|
00045|005|B||
00045|006|A|MECHANISM OF ACTION:  Penicillin-induced inactivation of aminoglycoside. The|
00045|007|A|loss of aminoglycoside effect may be due to conversion of the aminoglycoside|
00045|008|A|to the microbiologically inert amide metabolite.|
00045|009|B||
00045|010|E|CLINICAL EFFECTS:  Decreased aminoglycoside antimicrobial activity.|
00045|011|B||
00045|012|P|PREDISPOSING FACTORS:  Patient with renal dysfunction and end-stage renal|
00045|013|P|disease.|
00045|014|B||
00045|015|M|PATIENT MANAGEMENT:  Do not combine these antibiotics in the same IV|
00045|016|M|solution. In patients with decreased renal function, monitor aminoglycoside|
00045|017|M|serum levels and adjust the dose of the drug accordingly.|
00045|018|B||
00045|019|D|DISCUSSION:  Numerous studies have found coadministration of aminoglycosides|
00045|020|D|and penicillins to be clinically useful. However, in patients with severe|
00045|021|D|renal impairment parenteral penicillins can produce inactivation of the|
00045|022|D|aminoglycoside.|
00045|023|B||
00045|024|R|REFERENCES:|
00045|025|B||
00045|026|R|1.Davies M, Morgan JR, Anand C. Interactions of carbenicillin and|2
00045|027|R|  ticarcillin with gentamicin. Antimicrob Agents Chemother 1975 Apr;|2
00045|028|R|  7(4):431-4.|2
00045|029|R|2.Riff LJ, Jackson GG. Laboratory and clinical conditions for gentamicin|5
00045|030|R|  inactivation by carbenicillin. Arch Intern Med 1972 Dec;130(6):887-91.|5
00045|031|R|3.Thompson MI, Russo ME, Saxon BJ, Atkin-Thor E, Matsen JM. Gentamicin|2
00045|032|R|  inactivation by piperacillin or carbenicillin in patients with end-stage|2
00045|033|R|  renal disease. Antimicrob Agents Chemother 1982 Feb;21(2):268-73.|2
00045|034|R|4.Matzke GR, Halstenson CE, Heim KL, Abraham PA, Keane WF. Netilmicin|4
00045|035|R|  disposition is not altered by concommitant piperacillin administration.|4
00045|036|R|  Clin Pharmacol Ther 1985 Feb;37(2):210.|4
00045|037|R|5.Viollier AF, Standiford HC, Drusano GL, Tatem BA, Moody MR, Schimpff SC.|2
00045|038|R|  Comparative pharmacokinetics and serum bactericidal activity of|2
00045|039|R|  mezlocillin, ticarcillin and piperacillin, with and without gentamicin. J|2
00045|040|R|  Antimicrob Chemother 1985 May;15(5):597-606.|2
00045|041|R|6.Fuursted K. Comparison of the post-antibiotic effect of Streptococcus|5
00045|042|R|  faecalis and Streptococcus faecium with ampicillin alone or combined with|5
00045|043|R|  streptomycin: studies on a novel type of antimicrobial interaction. Acta|5
00045|044|R|  Pathol Microbiol Immunol Scand B 1987 Dec;95(6):351-4.|5
00045|045|R|7.Lorian V, Ernst J. Activity of amikacin and ampicillin in succession and|5
00045|046|R|  in combination. Diagn Microbiol Infect Dis 1988 Nov;11(3):163-9.|5
00045|047|R|8.Bingen E, Lambert-Zechovsky N, Aujard Y, Mariani P, Lemer G, Sauzeau C,|5
00045|048|R|  Mathieu H. Early synergistic killing activity at concentrations attainable|5
00045|049|R|  in CSF of amoxicillin or cefotaxime and aminoglycosides against|5
00045|050|R|  Haemophilus influenzae. Infection 1988 Mar-Apr;16(2):121-5.|5
00045|051|R|9.Halstenson CE, Hirata CA, Heim-Duthoy KL, Abraham PA, Matzke GR. Effect of|2
00045|052|R|  concomitant administration of piperacillin on the dispositions of|2
00045|053|R|  netilmicin and tobramycin in patients with end-stage renal disease.|2
00045|054|R|  Antimicrob Agents Chemother 1990 Jan;34(1):128-33.|2
00045|055|R|10.Uber WE, Brundage RC, White RL, Brundage DM, Bromley HR. In vivo|3
00045|056|R|   inactivation of tobramycin by piperacillin. DICP 1991 Apr;25(4):357-9.|3
00045|057|R|11.Roberts GW, Nation RL, Jarvinen AO, Martin AJ. An in vivo assessment of|2
00045|058|R|   the tobramycin/ticarcillin interaction in cystic fibrosis patients. Br J|2
00045|059|R|   Clin Pharmacol 1993;36:372-5.|2
00046|001|T|MONOGRAPH TITLE:  Digoxin, Oral/Aminoglycosides, Oral|
00046|002|B||
00046|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00046|004|L|take action as needed.|
00046|005|B||
00046|006|A|MECHANISM OF ACTION:  Aminoglycosides appears to inhibit gastrointestinal|
00046|007|A|absorption of digoxin but the precise mechanism is unknown.|
00046|008|B||
00046|009|E|CLINICAL EFFECTS:  Therapeutic effects of digoxin may be decreased. However,|
00046|010|E|in a minority of patients (10%) gut flora inactivates digoxin. In these|
00046|011|E|patients, due to an aminoglycoside-induced reduction in GI bacteria, serum|
00046|012|E|digoxin concentrations may be increased. Symptoms of digoxin toxicity can|
00046|013|E|include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
00046|014|E|generalized muscle weakness, disorientation, hallucinations, visual|
00046|015|E|disturbances, and arrhythmias.|
00046|016|B||
00046|017|P|PREDISPOSING FACTORS:  None Determined.|
00046|018|B||
00046|019|M|PATIENT MANAGEMENT:  If both drugs are administered, monitor serum digoxin|
00046|020|M|levels when initiating, discontinuing or changing the dose of the|
00046|021|M|aminoglycoside.|
00046|022|M|   Measure serum digoxin concentrations before initiating gentamicin. Reduce|
00046|023|M|digoxin concentrations by decreasing dose by approximately 30-50% or by|
00046|024|M|modifying the dosing frequency and continue monitoring. (3)|
00046|025|B||
00046|026|D|DISCUSSION:  Separating the administration times of digoxin and the|
00046|027|D|aminoglycoside is not likely to prevent this interaction. Digoxin levels|
00046|028|D|were found to be decreased when neomycin was taken 3 or 6 hours before|
00046|029|D|digoxin. Additionally, serum digoxin concentrations may increase when the|
00046|030|D|aminoglycoside is stopped.|
00046|031|D|   Concomitant administration of gentamicin and digoxin caused an increase|
00046|032|D|in digoxin serum concentration of 129-212%. (3)|
00046|033|B||
00046|034|R|REFERENCES:|
00046|035|B||
00046|036|R|1.Lindenbaum J, Maulitz RM, Butler VP Jr. Inhibition of digoxin absorption|2
00046|037|R|  by neomycin. Gastroenterology 1976 Sep;71(3):399-404.|2
00046|038|R|2.Lindenbaum J, Tse-Eng D, Butler VP Jr, Rund DG. Urinary excretion of|2
00046|039|R|  reduced metabolites of digoxin. Am J Med 1981 Jul;71(1):67-74.|2
00046|040|R|3.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00046|041|R|  Pharmaceuticals, Inc. August, 2018.|1
00047|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Selected Azole Antifungal|
00047|002|T|Agents|
00047|003|B||
00047|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00047|005|L|of severe adverse interaction.|
00047|006|B||
00047|007|A|MECHANISM OF ACTION:  The metabolism of cyclosporine, sirolimus, and|
00047|008|A|temsirolimus by CYP3A4 may be inhibited by clotrimazole, isavuconazonium,|
00047|009|A|itraconazole, and ketoconazole.|
00047|010|B||
00047|011|E|CLINICAL EFFECTS:  Concurrent administration of an azole antifungal may|
00047|012|E|result in elevated levels of and toxicity from cyclosporine, sirolimus, or|
00047|013|E|temsirolimus.|
00047|014|B||
00047|015|P|PREDISPOSING FACTORS:  None determined.|
00047|016|B||
00047|017|M|PATIENT MANAGEMENT:  Cyclosporine, sirolimus, or temsirolimus levels and|
00047|018|M|renal function should be monitored if an azole antifungal is initiated or|
00047|019|M|discontinued from concurrent therapy.  The dosage of cyclosporine,|
00047|020|M|sirolimus, or temsirolimus may need to be adjusted.|
00047|021|M|   Guidelines from the American Society of Transplantation recommend|
00047|022|M|avoiding concurrent use of cyclosporine with itraconazole or ketoconazole.|
00047|023|M|If the combination must be used, lower the dose of the immunosuppressant by|
00047|024|M|at least 50 % and monitor levels closely.(42)|
00047|025|M|   The American Society of Transplantation guidelines state that concurrent|
00047|026|M|use of sirolimus is contraindicated with ketoconazole and is not recommended|
00047|027|M|with itraconazole.(42)  The manufacturer of sirolimus states that the|
00047|028|M|concurrent use of itraconazole or ketoconazole is not recommended and should|
00047|029|M|be avoided,(25) while the US manufacturer of itraconazole states that|
00047|030|M|concurrent therapy with sirolimus or temsirolimus (IV) is not recommended|
00047|031|M|during and two weeks after itraconazole treatment.(41)|
00047|032|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
00047|033|M|with strong CYP3A4 inhibitors such as itraconazole or ketoconazole be|
00047|034|M|avoided.  If concurrent use is warranted, a dosage reduction to 12.5 mg/week|
00047|035|M|of temsirolimus should be considered.  If the azole is discontinued, a|
00047|036|M|washout period of 1 week should be allowed before adjusting the dosage of|
00047|037|M|temsirolimus to previous levels.(27)|
00047|038|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
00047|039|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
00047|040|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
00047|041|M|inhibitors should be avoided.(44)|
00047|042|B||
00047|043|D|DISCUSSION:  Clotrimazole, fluconazole, itraconazole and ketoconazole have|
00047|044|D|been reported to increase cyclosporine concentrations although the|
00047|045|D|documentation is most supportive of the interaction with ketoconazole.|
00047|046|D|Exercise caution when stopping the antifungal agent as cyclosporine|
00047|047|D|concentration may decrease.|
00047|048|D|   Concurrent isavuconazonium increased the area-under-curve (AUC) of|
00047|049|D|cyclosporine (300 mg) by approximately 1.3-fold.|
00047|050|D|   There have been several case reports of increased sirolimus levels with|
00047|051|D|concurrent fluconazole and itraconazole therapy and decreased levels of|
00047|052|D|sirolimus after discontinuation of itraconazole.|
00047|053|D|   Concurrent isavuconazonium increased the maximum concentration (Cmax) and|
00047|054|D|AUC of sirolimus (2 mg) by approximately 1.6-fold and 1.8-fold,|
00047|055|D|respectively.|
00047|056|D|   In a multiple-dose study, concomitant administration of ketoconazole with|
00047|057|D|sirolimus oral solution increased the sirolimus Cmax, time to Cmax (Tmax),|
00047|058|D|and AUC by 4.3-fold, 38%, and 10.9-fold, respectively.  Single-dose|
00047|059|D|sirolimus did not affect steady-state 12-hour plasma ketoconazole|
00047|060|D|concentrations.|
00047|061|D|   In a study in 6 patients, ketoconazole was successfully used to augment|
00047|062|D|sirolimus levels.  Patients were able to receive one-eight to one-fourth|
00047|063|D|(0.25 - 0.50 mg daily) of the usual sirolimus dose while taking 100 to 200|
00047|064|D|mg of ketoconazole daily.|
00047|065|D|   Concurrent administration of ketoconazole had no effects on temsirolimus|
00047|066|D|AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and|
00047|067|D|2.2-fold, respectively.  Dosage adjustment of temsirolimus to 12.5 mg/week|
00047|068|D|in the presence of strong CYP3A4 inhibitors is expected to adjust levels to|
00047|069|D|the range observed without inhibitors; however, there are no data available|
00047|070|D|with this dose adjustment.|
00047|071|B||
00047|072|R|REFERENCES:|
00047|073|B||
00047|074|R|1.Ferguson RM, Sutherland DE, Simmons RL, Najarian JS. Ketoconazole,|3
00047|075|R|  cyclosporin metabolism, and renal transplantation. Lancet 1982 Oct 16;|3
00047|076|R|  2(8303):882-3.|3
00047|077|R|2.Daneshmend TK. Ketoconazole-cyclosporin interaction. Lancet 1982 Dec 11;|3
00047|078|R|  2(8311):1342-3.|3
00047|079|R|3.Smith JM, Hows JM, Gordon-Smith EC, Baughan A, Goldman JM. Interaction of|4
00047|080|R|  CyA and ketoconazole. Clin Sci 1983;64(2):67P.|4
00047|081|R|4.Shepard JH, Canafax DM, Simmons RL, Najarian JS.|3
00047|082|R|  Cyclosporine-ketoconazole: a potentially dangerous drug-drug interaction.|3
00047|083|R|  Clin Pharm 1986 Jun;5(6):468.|3
00047|084|R|5.Kwan JT, Foxall PJ, Davidson DG, Bending MR, Eisinger AJ. Interaction of|3
00047|085|R|  cyclosporin and itraconazole. Lancet 1987 Aug 1;2(8553):282.|3
00047|086|R|6.Novakova I, Donnelly P, de Witte T, de Pauw B, Boezeman J, Veltman G.|3
00047|087|R|  Itraconazole and cyclosporin nephrotoxicity. Lancet 1987 Oct 17;|3
00047|088|R|  2(8564):920-1.|3
00047|089|R|7.Trenk D, Brett W, Jahnchen E, Birnbaum D. Time course of|3
00047|090|R|  cyclosporin/itraconazole interaction. Lancet 1987 Dec 5;2(8571):1335-6.|3
00047|091|R|8.Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin|6
00047|092|R|  Pharmacokinet 1988 Jan;14(1):13-34.|6
00047|093|R|9.Sugar AM, Saunders C, Idelson BA, Bernard DB. Interaction of fluconazole|3
00047|094|R|  and cyclosporine. Ann Intern Med 1989 May 15;110(10):844.|3
00047|095|R|10.Collignon P, Hurley B, Mitchell D. Interaction of fluconazole with|3
00047|096|R|   cyclosporin. Lancet 1989 Jun 3;1(8649):1262.|3
00047|097|R|11.Charles BG, Ravenscroft PJ, Rigby RJ. The ketoconazole-cyclosporin|3
00047|098|R|   interaction in an elderly renal transplant patient. Aust N Z J Med 1989|3
00047|099|R|   Jun;19(3):292-3.|3
00047|100|R|12.Baciewicz AM, Baciewicz FA Jr. Cyclosporine pharmacokinetic drug|6
00047|101|R|   interactions. Am J Surg 1989 Feb;157(2):264-71.|6
00047|102|R|13.First MR, Schroeder TJ, Weiskittel P, Myre SA, Alexander JW, Pesce AJ.|2
00047|103|R|   Concomitant administration of cyclosporin and ketoconazole in renal|2
00047|104|R|   transplant recipients. Lancet 1989 Nov 18;2(8673):1198-201.|2
00047|105|R|14.Frey FJ. Concomitant cyclosporin and ketoconazole. Lancet 1990 Jan 13;|6
00047|106|R|   335(8681):109-10.|6
00047|107|R|15.Ah-Sing E, Poole TW, Ioannides C, King LJ. Mechanism of the|5
00047|108|R|   ketoconazole-cyclosporin interaction. Arch Toxicol 1990;64(6):511-3.|5
00047|109|R|16.Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis|6
00047|110|R|   1990 Mar-Apr;12 Suppl 3:S327-33.|6
00047|111|R|17.Katzir D, Balschke TF. The cyclosporine-ketoconazole interaction. Hosp|3
00047|112|R|   Ther 1990 Jan;15:99-112.|3
00047|113|R|18.First MR, Schroeder TJ, Alexander JW, Stephens GW, Weiskittel P, Myre SA,|2
00047|114|R|   Pesce AJ. Cyclosporine dose reduction by ketoconazole administration in|2
00047|115|R|   renal transplant recipients. Transplantation 1991 Feb;51(2):365-70.|2
00047|116|R|19.Canafax DM, Graves NM, Hilligoss DM, Carleton BC, Gardner MJ, Matas AJ.|2
00047|117|R|   Increased cyclosporine levels as a result of simultaneous fluconazole and|2
00047|118|R|   cyclosporine therapy in renal transplant recipients: a double- blind,|2
00047|119|R|   randomized pharmacokinetic and safety study. Transplant Proc 1991 Feb;|2
00047|120|R|   23(1 Pt 2):1041-2.|2
00047|121|R|20.Albengres E, Tillement JP. Cyclosporin and ketoconazole, drug interaction|6
00047|122|R|   or therapeutic association?. Int J Clin Pharmacol Ther Toxicol 1992 Dec;|6
00047|123|R|   30(12):555-70.|6
00047|124|R|21.Lopez-Gil JA. Fluconazole-cyclosporine interaction: a dose-dependent|3
00047|125|R|   effect?. Ann Pharmacother 1993 Apr;27(4):427-30.|3
00047|126|R|22.First MR, Schroeder TJ, Michael A, Hariharan S, Weiskittel P, Alexander|2
00047|127|R|   JW. Cyclosporine-ketoconazole interaction. Long-term follow-up and|2
00047|128|R|   preliminary results of a randomized trial. Transplantation 1993 May;|2
00047|129|R|   55(5):1000-4.|2
00047|130|R|23.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
00047|131|R|   Aug, 2022.|1
00047|132|R|24.Sadaba B, Campanero MA, Quetglas EG, Azanza JR. Clinical relevance of|3
00047|133|R|   sirolimus drug interactions in transplant patients. Transplant Proc 2004|3
00047|134|R|   Dec;36(10):3226-8.|3
00047|135|R|25.Said A, Garnick JJ, Dieterle N, Peres E, Abidi MH, Ibrahim RB.|3
00047|136|R|   Sirolimus-itraconazole interaction in a hematopoietic stem cell|3
00047|137|R|   transplant recipient. Pharmacotherapy 2006 Feb;26(2):289-95.|3
00047|138|R|26.Thomas PP, Manivannan J, John GT, Jacob CK. Sirolimus and ketoconazole|2
00047|139|R|   co-prescription in renal transplant recipients. Transplantation 2004 Feb|2
00047|140|R|   15;77(3):474-5.|2
00047|141|R|27.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
00047|142|R|   Inc. March, 2018.|1
00047|143|R|28.Manez R, Martin M, Raman D, Silverman D, Jain A, Warty V, Gonzalez-Pinto|2
00047|144|R|   I, Kusne S, Starzl TE. Fluconazole therapy in transplant recipients|2
00047|145|R|   receiving FK506. Transplantation 1994 May 27;57(10):1521-3.|2
00047|146|R|29.Osowski CL, Dix SP, Lin LS, Mullins RE, Geller RB, Wingard JR. Evaluation|2
00047|147|R|   of the drug interaction between intravenous high-dose fluconazole and|2
00047|148|R|   cyclosporine or tacrolimus in bone marrow transplant patients.|2
00047|149|R|   Transplantation 1996 Apr 27;61(8):1268-72.|2
00047|150|R|30.Capone D, Gentile A, Imperatore P, Palmiero G, Basile V. Effects of|3
00047|151|R|   itraconazole on tacrolimus blood concentrations in a renal transplant|3
00047|152|R|   recipient. Ann Pharmacother 1999 Oct;33(10):1124-5.|3
00047|153|R|31.Billaud EM, Guillemain R, Tacco F, Chevalier P. Evidence for a|3
00047|154|R|   pharmacokinetic interaction between itraconazole and tacrolimus in organ|3
00047|155|R|   transplant patients. Br J Clin Pharmacol 1998 Sep;46(3):271-2.|3
00047|156|R|32.Furlan V, Parquin F, Penaud JF, Cerrina J, Ladurie FL, Dartevelle P,|3
00047|157|R|   Taburet AM. Interaction between tacrolimus and itraconazole in a|3
00047|158|R|   heart-lung transplant recipient. Transplant Proc 1998 Feb;30(1):187-8.|3
00047|159|R|33.Kramer MR, Merin G, Rudis E, Bar I, Nesher T, Bublil M, Milgalter E. Dose|3
00047|160|R|   adjustment and cost of itraconazole prophylaxis in lung transplant|3
00047|161|R|   recipients receiving cyclosporine and tacrolimus (FK 506). Transplant|3
00047|162|R|   Proc 1997 Sep;29(6):2657-9.|3
00047|163|R|34.Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C,|3
00047|164|R|   Gritsch A, McCauley J, Starzl T, Demetris AJ, Randhawa PS. Clinical|3
00047|165|R|   features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney|3
00047|166|R|   transplant recipients. Clin Transplant 1997 Jun;11(3):237-42.|3
00047|167|R|35.Floren LC, Bekersky I, Benet LZ, Mekki Q, Dressler D, Lee JW, Roberts JP,|2
00047|168|R|   Hebert MF. Tacrolimus oral bioavailability doubles with coadministration|2
00047|169|R|   of ketoconazole. Clin Pharmacol Ther 1997 Jul;62(1):41-9.|2
00047|170|R|36.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
00047|171|R|   August, 2023.|1
00047|172|R|37.Assan R, Fredj G, Larger E, Feutren G, Bismuth H. FK 506/fluconazole|3
00047|173|R|   interaction enhances FK 506 nephrotoxicity. Diabete Metab 1994 Jan-Feb;|3
00047|174|R|   20(1):49-52.|3
00047|175|R|38.Mieles L, Venkataramanan R, Yokoyama I, Warty VJ, Starzl TE. Interaction|3
00047|176|R|   between FK506 and clotrimazole in a liver transplant recipient.|3
00047|177|R|   Transplantation 1991 Dec;52(6):1086-7.|3
00047|178|R|39.Cresemba (isavuconazonium sulfate) US prescribing information. Astellas|1
00047|179|R|   Pharma US, Inc. May, 2021.|1
00047|180|R|40.Viesselmann CW, Descourouez JL, Jorgenson MR, Radke NA, Odorico JS.|2
00047|181|R|   Clinically Significant Drug Interaction Between Clotrimazole and|2
00047|182|R|   Tacrolimus in Pancreas Transplant Recipients and Associated Risk of|2
00047|183|R|   Allograft Rejection. Pharmacotherapy 2016 Mar;36(3):335-41.|2
00047|184|R|41.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
00047|185|R|   Products, L.P. February, 2024.|1
00047|186|R|42.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
00047|187|R|   immunosuppressants-Guidelines from the American Society of|6
00047|188|R|   Transplantation Infectious Diseases Community of Practice. Clin|6
00047|189|R|   Transplant 2019 Feb 28;e13510.|6
00047|190|R|43.He J, Yu Y, Yin C, Liu H, Zou H, Ma J, Yang W, Liu Y, Zhong L, Chen X.|3
00047|191|R|   Clinically significant drug-drug interaction between tacrolimus and|3
00047|192|R|   fluconazole in stable renal transplant recipient and literature review. J|3
00047|193|R|   Clin Pharm Ther 2020 Apr;45(2):264-269.|3
00047|194|R|44.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
00047|195|R|   prescribing information. Aadi Bioscience, Inc. November, 2021.|1
00048|001|T|MONOGRAPH TITLE:  Aminoglycosides/Loop Diuretics|
00048|002|B||
00048|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00048|004|L|take action as needed.|
00048|005|B||
00048|006|A|MECHANISM OF ACTION:  The coadministration of aminoglycosides and loop|
00048|007|A|diuretics may result in additive or synergistic ototoxicity and/or|
00048|008|A|nephrotoxicity.|
00048|009|B||
00048|010|E|CLINICAL EFFECTS:  The combination of an aminoglycoside and a loop diuretic|
00048|011|E|may increase risk for serious nephrotoxicity or ototoxicity.(1,2) Vestibular|
00048|012|E|or auditory ototoxicity may be permanent.(1,3)|
00048|013|B||
00048|014|P|PREDISPOSING FACTORS:  Preexisting renal impairment, extended duration of|
00048|015|P|aminoglycoside therapy, greater than one aminoglycoside dose per day, rapid|
00048|016|P|injection or high doses of loop diuretics, concomitant use of additional|
00048|017|P|nephrotoxic agents such as iodinated contrast media or vancomycin, or sepsis|
00048|018|P|appear to increase the risk for nephrotoxicity and ototoxicity.(1-6).|
00048|019|P|   Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G,|
00048|020|P|m.1095T>C, and m.1494C>T) are at increased risk of developing ototoxicity.|
00048|021|P|An additional risk factor includes patients with a maternal relative known|
00048|022|P|to have a clinically relevant MT-RNR1 variant.  The risk of ototoxicity can|
00048|023|P|occur at standard recommended doses of aminoglycosides.(7)|
00048|024|B||
00048|025|M|PATIENT MANAGEMENT:  Administer aminoglycoside dosage every 24 to > 48 hours|
00048|026|M|based upon renal function and continue therapy for less than 4 to 7 days,|
00048|027|M|whenever possible.(4,5)  The recommended maximal infusion rate for high dose|
00048|028|M|furosemide therapy is 4 mg/minute.(2)|
00048|029|M|   When concurrent therapy is necessary monitor renal, hearing, and|
00048|030|M|vestibular function.  Signs of vestibular dysfunction include loss of|
00048|031|M|balance and/or the visual sensation that stationary objects are moving|
00048|032|M|(oscillopsia).  In hospitalized or bedbound patients these symptoms may not|
00048|033|M|be noticed or may be ascribed to other etiologies.(3)|
00048|034|B||
00048|035|D|DISCUSSION:  Several studies and case reports have documented altered|
00048|036|D|aminoglycoside levels, nephrotoxicity, and ototoxicity with concurrent|
00048|037|D|therapy.(8-14)|
00048|038|D|   Otic aminoglycosides are included in this interaction because high|
00048|039|D|aminoglycoside concentrations in the ear have been associated with an|
00048|040|D|increased risk for hearing loss.|
00048|041|B||
00048|042|R|REFERENCES:|
00048|043|B||
00048|044|R|1.Gentamicin Sulfate in 0.9% Sodium Chloride Injection. Baxter Healthcare|1
00048|045|R|  Corporation June 2011.|1
00048|046|R|2.Lasix (furosemide) US prescribing information. Sanofi-Aventis U.S. LLC|1
00048|047|R|  March, 2016.|1
00048|048|R|3.Ahmed RM, Hannigan IP, Macdougall HG, Chan RC, Halmagyi GM. Gentamicin|2
00048|049|R|  ototoxicity: a 23-year selected case series of 103 patients. Med J Aust|2
00048|050|R|  2012 Apr 2;196(10):.|2
00048|051|R|4.Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani|2
00048|052|R|  R. Experience with a once-daily aminoglycoside program administered to|2
00048|053|R|  2,184 adult patients. Antimicrob Agents Chemother 1995 Mar;39(3):650-5.|2
00048|054|R|5.Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL.|2
00048|055|R|  Prospective evaluation of the effect of an aminoglycoside dosing regimen|2
00048|056|R|  on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents|2
00048|057|R|  Chemother 1999 Jul;43(7):1549-55.|2
00048|058|R|6.Gerlach AT, Stawicki SP, Cook CH, Murphy C. Risk factors for|2
00048|059|R|  aminoglycoside-associated nephrotoxicity in surgical intensive care unit|2
00048|060|R|  patients. Int J Crit Illn Inj Sci 2011 Jan;1(1):17-21.|2
00048|061|R|7.McDermott JH, Wolf J, Hoshitsuki K, Huddart R, Caudle KE, Whirl-Carrillo|6
00048|062|R|  M, Steyger PS, Smith RJH, Cody N, Rodriguez-Antona C, Klein TE, Newman WG.|6
00048|063|R|  Clinical Pharmacogenetics Implementation Consortium Guideline for the use|6
00048|064|R|  of aminoglycosides based on MT-RNR1 genotype. Clin Pharmacol Ther May,|6
00048|065|R|  2021.|6
00048|066|R|8.Mathog RH, Klein WJ Jr. Ototoxicity of ethacrynic acid and aminoglycoside|3
00048|067|R|  antibiotics in uremia. N Engl J Med 1969 May 29;280(22):1223-4.|3
00048|068|R|9.Tobramycin US prescribing information. X-GEN Pharmaceuticals, Inc.|1
00048|069|R|  September, 2011.|1
00048|070|R|10.Meriwether WD, Mangi RJ, Serpick AA. Deafness following standard|3
00048|071|R|   intravenous dose of ethacrynic acid. JAMA 1971 May 3;216(5):795-8.|3
00048|072|R|11.Bates DE, Beaumont SJ, Baylis BW. Ototoxicity induced by gentamicin and|3
00048|073|R|   furosemide. Ann Pharmacother 2002 Mar;36(3):446-51.|3
00048|074|R|12.Kaka JS, Lyman C, Kilarski DJ. Tobramycin-furosemide interaction. Drug|3
00048|075|R|   Intell Clin Pharm 1984 Mar;18(3):235-8.|3
00048|076|R|13.Noel P, Levy VG. Renal toxicity of the association:|3
00048|077|R|   gentamicin/furosemide. One case (author's transl). Nouv Presse Med 1978|3
00048|078|R|   Feb 4;7(5):351-3.|3
00048|079|R|14.Lawson DH, Tilstone WJ, Gray JM, Srivastava PK. Effect of furosemide on|2
00048|080|R|   the pharmacokinetics of gentamicin in patients. J Clin Pharmacol 1982|2
00048|081|R|   May-Jun;22(5-6):254-8.|2
00048|082|R|15.Bendush CL. Chapter 19 Ototoxicity: Clinical Considerations and|6
00048|083|R|   Comparative Information. The Aminoglycosides: Microbiology, Clinical Use,|6
00048|084|R|   and Toxicology 1982;453-486.|6
00049|001|T|MONOGRAPH TITLE:  Thioridazine/Pindolol; Propranolol|
00049|002|B||
00049|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00049|004|L|is contraindicated and generally should not be dispensed or administered to|
00049|005|L|the same patient.|
00049|006|B||
00049|007|A|MECHANISM OF ACTION:  Pindolol and propranolol may inhibit the metabolism of|
00049|008|A|thioridazine at CYP3A4.(1)|
00049|009|B||
00049|010|E|CLINICAL EFFECTS:  Concurrent use of pindolol or propranolol with|
00049|011|E|thioridazine may result in elevated levels of thioridazine and prolongation|
00049|012|E|of the QTc interval, which may result in potentially life-threatening|
00049|013|E|arrhythmias,(1) and elevated levels of the beta blocker.|
00049|014|B||
00049|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00049|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
00049|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00049|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00049|019|P|female gender, or advanced age.(4)|
00049|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00049|021|P|higher systemic concentration of either QT prolonging drug are additional|
00049|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00049|023|P|drug concentrations include rapid infusion of an intravenous dose or|
00049|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00049|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00049|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
00049|027|B||
00049|028|M|PATIENT MANAGEMENT:  The manufacturer of thioridazine states that concurrent|
00049|029|M|use with pindolol or propranolol is contraindicated.(1)|
00049|030|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00049|031|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00049|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00049|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00049|034|B||
00049|035|D|DISCUSSION:  In one study, two patients receiving thioridazine (600 mg/day|
00049|036|D|to 800 mg/day) developed thioridazine levels that were in the potentially|
00049|037|D|toxic range following the administration of propranolol.  In one patient,|
00049|038|D|thioridazine levels increased 433% over 40 days of concurrent therapy.  The|
00049|039|D|other patient's level increased 275% after 26 days of concurrent therapy.|
00049|040|D|Neither patient exhibited any signs or symptoms of thioridazine toxicity.(2)|
00049|041|D|   In another study, administration of pindolol (40 mg/day) to eight|
00049|042|D|patients receiving thioridazine (150 mg/day) resulted in an increase in|
00049|043|D|thioridazine levels by 36%, as well as increases in the levels of the|
00049|044|D|thioridazine metabolites.  In addition, in seven patients, pindolol levels|
00049|045|D|were found to be increased when administered with thioridazine.(3)|
00049|046|B||
00049|047|R|REFERENCES:|
00049|048|B||
00049|049|R|1.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
00049|050|R|  September, 2014.|1
00049|051|R|2.Silver JM, Yudofsky SC, Kogan M, Katz BL. Elevation of thioridazine plasma|2
00049|052|R|  levels by propranolol. Am J Psychiatry 1986 Oct;143(10):1290-2.|2
00049|053|R|3.Greendyke RM, Gulya A. Effect of pindolol administration on serum levels|2
00049|054|R|  of thioridazine, haloperidol, phenytoin, and phenobarbital. J Clin|2
00049|055|R|  Psychiatry 1988 Mar;49(3):105-7.|2
00049|056|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00049|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00049|058|R|  settings: a scientific statement from the American Heart Association and|6
00049|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00049|060|R|  2;55(9):934-47.|6
00049|061|R|5.Wojcikowski J, Maurel P, Daniel WA. Characterization of human cytochrome|5
00049|062|R|  p450 enzymes involved in the metabolism of the piperidine-type|5
00049|063|R|  phenothiazine neuroleptic thioridazine. Drug Metab Dispos 2006 Mar;|5
00049|064|R|  34(3):471-6.|5
00051|001|T|MONOGRAPH TITLE:  Lidocaine/Cimetidine|
00051|002|B||
00051|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00051|004|L|take action as needed.|
00051|005|B||
00051|006|A|MECHANISM OF ACTION:  Cimetidine reduces the hepatic clearance of lidocaine.|
00051|007|A|Changes in hepatic blood flow may contribute.|
00051|008|B||
00051|009|E|CLINICAL EFFECTS:  Increased serum lidocaine levels with enhanced|
00051|010|E|therapeutic and toxic response.|
00051|011|B||
00051|012|P|PREDISPOSING FACTORS:  None determined.|
00051|013|B||
00051|014|M|PATIENT MANAGEMENT:  Patients receiving this combination should be monitored|
00051|015|M|for signs of lidocaine toxicity. The dosage of lidocaine should be adjusted|
00051|016|M|based on serum lidocaine levels and patient response. Since other H-2|
00051|017|M|antagonists (e.g., ranitidine, famotidine) do not appear to interact,|
00051|018|M|substituting cimetidine with one of these agents may be desirable. However,|
00051|019|M|if a patient is already receiving this combination and is not experiencing|
00051|020|M|adverse effects, substitution is probably not necessary.|
00051|021|B||
00051|022|D|DISCUSSION:  This interaction is likely to occur.|
00051|023|B||
00051|024|R|REFERENCES:|
00051|025|B||
00051|026|R|1.Feely J, Wilkinson GR, Wood AJ. Reduction of liver blood flow and|2
00051|027|R|  propranolol metabolism by cimetidine. N Engl J Med 1981 Mar 19;|2
00051|028|R|  304(12):692-5.|2
00051|029|R|2.Knapp AB, Maguire W, Keren G, Karmen A, Levitt B, Miura DS, Somberg JC.|2
00051|030|R|  The cimetidine-lidocaine interaction. Ann Intern Med 1983 Feb;98(2):174-7.|2
00051|031|R|3.Patterson JH, Foster J, Powell JR, Cross R, Wargin W, Clark JL. Influence|2
00051|032|R|  of a continuous cimetidine infusion on lidocaine plasma concentrations in|2
00051|033|R|  patients. J Clin Pharmacol 1985 Nov-Dec;25(8):607-9.|2
00051|034|R|4.Feely J, Guy E. Lack of effect of ranitidine on the disposition of|2
00051|035|R|  lignocaine. Br J Clin Pharmacol 1983 Mar;15(3):378-9.|2
00051|036|R|5.Robson RA, Wing LM, Miners JO, Lillywhite KJ, Birkett DJ. The effect of|2
00051|037|R|  ranitidine on the disposition of lignocaine. Br J Clin Pharmacol 1985 Aug;|2
00051|038|R|  20(2):170-3.|2
00051|039|R|6.Jackson JE, Bentley JB, Glass SJ, Fukui T, Gandolfi AJ, Plachetka JR.|2
00051|040|R|  Effects of histamine-2 receptor blockade on lidocaine kinetics. Clin|2
00051|041|R|  Pharmacol Ther 1985 May;37(5):544-8.|2
00051|042|R|7.Abernethy DR, Schwartz JB, Todd EL. Lack of interaction between verapamil|2
00051|043|R|  and cimetidine. Clin Pharmacol Ther 1985 Sep;38(3):342-9.|2
00051|044|R|8.Kishikawa K, Namiki A, Miyashita K, Saitoh K. Effects of famotidine and|2
00051|045|R|  cimetidine on plasma levels of epidurally administered lignocaine.|2
00051|046|R|  Anaesthesia 1990 Sep;45(9):719-21.|2
00052|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Amphotericin B|
00052|002|B||
00052|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00052|004|L|of severe adverse interaction.|
00052|005|B||
00052|006|A|MECHANISM OF ACTION:  Amphotericin B may cause hypokalemia which can|
00052|007|A|predispose patients to digitalis toxicity.|
00052|008|B||
00052|009|E|CLINICAL EFFECTS:  Possible potentiation of digitalis effects. Symptoms of|
00052|010|E|digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue,|
00052|011|E|malaise, drowsiness, generalized muscle weakness, disorientation,|
00052|012|E|hallucinations, visual disturbances, and arrhythmias.|
00052|013|B||
00052|014|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
00052|015|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00052|016|P|risk of digoxin toxicity.|
00052|017|B||
00052|018|M|PATIENT MANAGEMENT:  Monitor potassium levels carefully in patients using|
00052|019|M|these agents concomitantly. Correct potassium deficits promptly.|
00052|020|B||
00052|021|D|DISCUSSION:  Amphotericin B induced hypokalemia is a well known drug side|
00052|022|D|effect.|
00052|023|B||
00052|024|R|REFERENCES:|
00052|025|B||
00052|026|R|1.Miller RP, Bates JH. Amphotericin B toxicity. A follow-up report of 53|2
00052|027|R|  patients. Ann Intern Med 1969 Dec;71(6):1089-95.|2
00052|028|R|2.Cushard WG Jr, Kohanim M, Lantis LR. Blastomycosis of bone. Treatment with|3
00052|029|R|  intramedullary amphotericin-B. J Bone Joint Surg Am 1969 Jun;51(4):704-12.|3
00056|001|T|MONOGRAPH TITLE:  Cyclosporine/Rifamycins (mono deleted 11/01/2012)|
00056|002|B||
00056|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00056|004|L|of severe adverse interaction.|
00056|005|B||
00056|006|A|MECHANISM OF ACTION:  The rifamycins appear to increase hepatic and|
00056|007|A|intestinal enzymes increasing the clearance of cyclosporine and reducing its|
00056|008|A|bioavailability.|
00056|009|B||
00056|010|E|CLINICAL EFFECTS:  May see a decrease in the immunosuppressive effect of|
00056|011|E|cyclosporine due to reduced serum levels.|
00056|012|B||
00056|013|P|PREDISPOSING FACTORS:  None determined.|
00056|014|B||
00056|015|M|PATIENT MANAGEMENT:  If possible, consider using an alternative|
00056|016|M|antitubercular agent in patients receiving cyclosporine. Monitor|
00056|017|M|cyclosporine serum levels and observe the patient for decreased cyclosporine|
00056|018|M|activity (eg, graft rejection). Adjust the dosage accordingly. In addition|
00056|019|M|to increasing the dose of cyclosporine, it may be necessary to increase the|
00056|020|M|frequency of cyclosporine administration.|
00056|021|B||
00056|022|D|DISCUSSION:  Concurrent administration of cyclosporine and rifampin have|
00056|023|D|been associated with lowering of cyclosporine to undetectable serum levels.|
00056|024|D|Decreases in cyclosporine levels have been observed within 2 days of|
00056|025|D|concomitant therapy but will probably not be maximal for 1 week. The effects|
00056|026|D|of the interaction may persist for up to 3 weeks after rifampin is stopped.|
00056|027|D|Cyclosporine dose may need to be readjusted at this time.|
00056|028|D|   Rifabutin is chemically related to rifampin and may be expected to|
00056|029|D|interact with cyclosporine in a similar manner although it may be to a|
00056|030|D|lesser degree.|
00056|031|B||
00056|032|R|REFERENCES:|
00056|033|B||
00056|034|R|1.Langhoff E, Madsen S. Rapid metabolism of cyclosporin and prednisone in|3
00056|035|R|  kidney transplant patient receiving tuberculostatic treatment. Lancet 1983|3
00056|036|R|  Oct 29;2(8357):1031.|3
00056|037|R|2.Van Buren D, Wideman CA, Ried M, Gibbons S, Van Buren CT, Jarowenko M,|3
00056|038|R|  Flechner SM, Frazier OH, Cooley DA, Kahan BD. The antagonistic effect of|3
00056|039|R|  rifampin upon cyclosporine bioavailability. Transplant Proc 1984 Dec;|3
00056|040|R|  16(6):1642-5.|3
00056|041|R|3.Daniels NJ, Dover JS, Schachter RK. Interaction between cyclosporin and|3
00056|042|R|  rifampicin. Lancet 1984 Sep 15;2(8403):639.|3
00056|043|R|4.Allen RD, Hunnisett AG, Morris PJ. Cyclosporin and rifampicin in renal|3
00056|044|R|  transplantation. Lancet 1985 Apr 27;1(8435):980.|3
00056|045|R|5.Howard P, Bixler TJ, Gill B. Cyclosporine-rifampin drug interaction. Drug|3
00056|046|R|  Intell Clin Pharm 1985 Oct;19(10):763-4.|3
00056|047|R|6.Anonymous. Cyclosporin and antituberculous therapy. Lancet 1985 Jun 8;|3
00056|048|R|  1(8441):1342-3.|3
00056|049|R|7.Cassidy MJ, Van Zyl-Smit R, Pascoe MD, Swanepoel CR, Jacobson JE. Effect|3
00056|050|R|  of rifampicin on cyclosporin A blood levels in a renal transplant|3
00056|051|R|  recipient. Nephron 1985;41(2):207-8.|3
00056|052|R|8.Offermann G, Keller F, Molzahn M. Low cyclosporin A blood levels and acute|3
00056|053|R|  graft rejection in a renal transplant recipient during rifampin treatment.|3
00056|054|R|  Am J Nephrol 1985;5(5):385-7.|3
00056|055|R|9.al-Sulaiman MH, Dhar JM, al-Khader AA. Successful use of rifampicin in the|2
00056|056|R|  treatment of tuberculosis in renal transplant patients immunosuppressed|2
00056|057|R|  with cyclosporine. Transplantation 1990 Oct;50(4):597-8.|2
00056|058|R|10.Vandevelde C, Chang A, Andrews D, Riggs W, Jewesson P. Rifampin and|3
00056|059|R|   ansamycin interactions with cyclosporine after renal transplantation.|3
00056|060|R|   Pharmacotherapy 1991;11(1):88-9.|3
00056|061|R|11.Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of|2
00056|062|R|   cyclosporine with concomitant rifampin administration is markedly less|2
00056|063|R|   than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992 Nov;|2
00056|064|R|   52(5):453-7.|2
00057|001|T|MONOGRAPH TITLE:  Sympathomimetics/Urinary Alkalinizers|
00057|002|B||
00057|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00057|004|L|take action as needed.|
00057|005|B||
00057|006|A|MECHANISM OF ACTION:  Unionized sympathomimetic amines will be reabsorbed|
00057|007|A|into systemic circulation from the distal tubules of the kidneys.|
00057|008|B||
00057|009|E|CLINICAL EFFECTS:  Enhanced sympathomimetic activity and increased risk of|
00057|010|E|sympathomimetic toxicity.|
00057|011|B||
00057|012|P|PREDISPOSING FACTORS:  None determined.|
00057|013|B||
00057|014|M|PATIENT MANAGEMENT:  Watch patient for enhanced sympathomimetic side effects|
00057|015|M|when urinary alkalinizers are concomitantly used. A lower dose of certain|
00057|016|M|sympathomimetics may be required.|
00057|017|B||
00057|018|D|DISCUSSION:  Signs and symptoms of sympathomimetic toxicity include|
00057|019|D|euphoria, confusion, delirium, hallucinations and nervousness.|
00057|020|B||
00057|021|R|REFERENCES:|
00057|022|B||
00057|023|R|1.Wilkinson GR, Beckett AH. Absorption metabolism and excretion of the|2
00057|024|R|  ephedrines in man. I. The influence of urinary pH and urine volume output.|2
00057|025|R|  J Pharmacol Exp Ther 1968 Jul;162(1):139-47.|2
00057|026|R|2.Rowland M. Amphetamine blood and urine levels in man. J Pharm Sci 1969|2
00057|027|R|  Apr;58(4):508-9.|2
00057|028|R|3.Kuntzman RG, Tsai I, Brand L, Mark LC. The influence of urinary pH on the|5
00057|029|R|  plasma half-life of pseudoephedrine in man and dog and a sensitive assay|5
00057|030|R|  for its determination in human plasma. Clin Pharmacol Ther 1971 Jan-Feb;|5
00057|031|R|  12(1):62-7.|5
00057|032|R|4.Anggard E, Jonsson LE, Hogmark AL, Gunne LM. Amphetamine metabolism in|2
00057|033|R|  amphetamine psychosis. Clin Pharmacol Ther 1973 Sep-Oct;14(5):870-80.|2
00057|034|R|5.Brater DC, Kaojarern S, Benet LZ, Lin ET, Lockwood T, Morris RC, McSherry|2
00057|035|R|  EJ, Melmon KL. Renal excretion of pseudoephedrine. Clin Pharmacol Ther|2
00057|036|R|  1980 Nov;28(5):690-4.|2
00058|001|T|MONOGRAPH TITLE:  Cyclosporine/Macrolide Antibiotics (mono deleted|
00058|002|T|12/19/2013)|
00058|003|B||
00058|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00058|005|L|of severe adverse interaction.|
00058|006|B||
00058|007|A|MECHANISM OF ACTION:  Macrolides may decrease the clearance of cyclosporine.|
00058|008|B||
00058|009|E|CLINICAL EFFECTS:  Increased levels of cyclosporine, which may result in|
00058|010|E|cyclosporine toxicity.|
00058|011|B||
00058|012|P|PREDISPOSING FACTORS:  Progressively decreasing renal/hepatic function.|
00058|013|B||
00058|014|M|PATIENT MANAGEMENT:  Concurrent administration of cyclosporine and|
00058|015|M|erythromycin should be avoided if possible. If concurrent administration is|
00058|016|M|required, monitor cyclosporine levels and renal function closely. The dosage|
00058|017|M|of cyclosporine may need to be adjusted or the macrolide may need to be|
00058|018|M|discontinued.|
00058|019|B||
00058|020|D|DISCUSSION:  Concomitant administration of cyclosporine and erythromycin has|
00058|021|D|been shown to increase cyclosporine trough serum levels and clinical|
00058|022|D|symptoms of drug toxicity. Maximum effect may be seen one week after|
00058|023|D|concurrent administration. These effects reverse when erythromycin is|
00058|024|D|discontinued. The interaction probably occurs with troleandomycin also. Case|
00058|025|D|reports have documented increased cyclosporine and creatinine levels during|
00058|026|D|concurrent administration with clarithromycin. Several studies have shown|
00058|027|D|that spiramycin does not affect cyclosporine pharmacokinetics. Because|
00058|028|D|studies in rats have shown that azithromycin does not affect CYP P-450, it|
00058|029|D|would not be expected to interact with cyclosporine.  One case report exists|
00058|030|D|which describes a potential interaction between cyclosporine and|
00058|031|D|azithromycin; however, the time course of the events suggest that other|
00058|032|D|factors, such as the patient's failing renal graft, may have led to the|
00058|033|D|increased cyclosporine levels in this patient.|
00058|034|B||
00058|035|R|REFERENCES:|
00058|036|B||
00058|037|R|1.Danan G, Descatoire V, Pessayre D. Self-induction by erythromycin of its|5
00058|038|R|  own transformation into a metabolite forming an inactive complex with|5
00058|039|R|  reduced cytochrome P-450. J Pharmacol Exp Ther 1981 Aug;218(2):509-14.|5
00058|040|R|2.Ptachcinski RJ, Carpenter BJ, Burckart GJ, Venkataramanan R, Rosenthal JT.|3
00058|041|R|  Effect of erythromycin on cyclosporine levels. N Engl J Med 1985 Nov 28;|3
00058|042|R|  313(22):1416-7.|3
00058|043|R|3.Kohan DE. Possible interaction between cyclosporine and erythromycin. N|3
00058|044|R|  Engl J Med 1986 Feb 13;314(7):448.|3
00058|045|R|4.Martell R, Heinrichs D, Stiller CR, Jenner M, Keown PA, Dupre J. The|3
00058|046|R|  effects of erythromycin in patients treated with cyclosporine. Ann Intern|3
00058|047|R|  Med 1986 May;104(5):660-1.|3
00058|048|R|5.Grino JM, Sabate J, Castelao AM, Guardia M, Seron D, Alsina J.|3
00058|049|R|  Erythromycin and cyclosporine. Ann Intern Med 1986 Sep;105(3):467-8.|3
00058|050|R|6.Godin JR, Sketris IS, Belitsky P. Erythromycin-cyclosporin interaction.|3
00058|051|R|  Drug Intell Clin Pharm 1986 Jun;20(6):504-5.|3
00058|052|R|7.Kessler M, Louis J, Renoult E, Vigneron B, Netter P. Interaction between|3
00058|053|R|  cyclosporin and erythromycin in a kidney transplant patient. Eur J Clin|3
00058|054|R|  Pharmacol 1986;30(5):633-4.|3
00058|055|R|8.Gonwa TA, Nghiem DD, Schulak JA, Corry RJ. Erythromycin and cyclosporine.|3
00058|056|R|  Transplantation 1986 Jun;41(6):797-9.|3
00058|057|R|9.Freeman DJ, Martell R, Carruthers SG, Heinrichs D, Keown PA, Stiller CR.|2
00058|058|R|  Cyclosporin-erythromycin interaction in normal subjects. Br J Clin|2
00058|059|R|  Pharmacol 1987 Jun;23(6):776-8.|2
00058|060|R|10.Aoki FY,  Yatscoff R, Jeffery J, Rush D, Sitar D. Effects of erythromycin|4
00058|061|R|   on cyclosporine A kinetics in renal transplant patients. Clin Pharmacol|4
00058|062|R|   Ther 1987 Feb;41(2):221.|4
00058|063|R|11.Wadhwa NK, Schroeder TJ, O'Flaherty E, Pesce AJ, Myre SA, Munda R, First|3
00058|064|R|   MR. Interaction between erythromycin and cyclosporine in a kidney and|3
00058|065|R|   pancreas allograft recipient. Ther Drug Monit 1987;9(1):123-5.|3
00058|066|R|12.Vereerstraeten P, Thiry P, Kinnaert P, Toussaint C. Influence of|2
00058|067|R|   erythromycin on cyclosporine pharmacokinetics. Transplantation 1987 Jul;|2
00058|068|R|   44(1):155-6.|2
00058|069|R|13.Harnett JD, Parfrey PS, Paul MD, Gault MH. Erythromycin-cyclosporine|3
00058|070|R|   interaction in renal transplant recipients. Transplantation 1987 Feb;|3
00058|071|R|   43(2):316-8.|3
00058|072|R|14.Jensen CW, Flechner SM, Van Buren CT, Frazier OH, Cooley DA, Lorber MI,|3
00058|073|R|   Kahan BD. Exacerbation of cyclosporine toxicity by concomitant|3
00058|074|R|   administration of erythromycin. Transplantation 1987 Feb;43(2):263-70.|3
00058|075|R|15.Murray BM, Edwards L, Morse GD, Kohli RR, Venuto RC. Clinically important|3
00058|076|R|   interaction of cyclosporine and erythromycin. Transplantation 1987 Apr;|3
00058|077|R|   43(4):602-4.|3
00058|078|R|16.Gupta SK, Bakran A, Johnson RW, Rowland M. Erythromycin enhances the|2
00058|079|R|   absorption of cyclosporin. Br J Clin Pharmacol 1988 Mar;25(3):401-2.|2
00058|080|R|17.Ben-Ari J, Eisenstein B, Davidovits M, Shmueli D, Shapira Z, Stark H.|3
00058|081|R|   Effect of erythromycin on blood cyclosporine concentrations in kidney|3
00058|082|R|   transplant patients. J Pediatr 1988 Jun;112(6):992-3.|3
00058|083|R|18.Lysz K, Rosenberg JC, Kaplan MP, Migdal S, Sillix D. Interaction of|3
00058|084|R|   erythromycin with cyclosporine. Transplant Proc 1988 Apr;20(2 Suppl|3
00058|085|R|   2):543-8.|3
00058|086|R|19.Guillemain R, Billaud E, Dreyfus G, Amrein C, Kitzis M, Jebara VA,|2
00058|087|R|   Kreft-Jais C. The effects of spiramycin on plasma cyclosporin A|2
00058|088|R|   concentrations in heart transplant patients. Eur J Clin Pharmacol 1989;|2
00058|089|R|   36(1):97-8.|2
00058|090|R|20.Gupta SK, Bakran A, Johnson RW, Rowland M. Cyclosporin-erythromycin|2
00058|091|R|   interaction in renal transplant patients. Br J Clin Pharmacol 1989 Apr;|2
00058|092|R|   27(4):475-81.|2
00058|093|R|21.Vernillet L, Bertault-Peres P, Berland Y, Barradas J, Durand A, Olmer M.|2
00058|094|R|   Lack of effect of spiramycin on cyclosporin pharmacokinetics. Br J Clin|2
00058|095|R|   Pharmacol 1989 Jun;27(6):789-94.|2
00058|096|R|22.Marre F, de Sousa G, Orloff AM, Rahmani R. In vitro interaction between|2
00058|097|R|   cyclosporin A and macrolide antibiotics. Br J Clin Pharmacol 1993 Apr;|2
00058|098|R|   35(4):447-8.|2
00058|099|R|23.Moral A, Navasa M, Rimola A, Garcia-Valdecasas JC, Grande L, Visa J,|3
00058|100|R|   Rodes J. Erythromycin ototoxicity in liver transplant patients. Transpl|3
00058|101|R|   Int 1994;7(1):62-4.|3
00058|102|R|24.Koselj M, Bren A, Kandus A, Kovac D. Drug interactions between|2
00058|103|R|   cyclosporine and rifampicin, erythromycin, and azoles in kidney|2
00058|104|R|   recipients with opportunistic infections. Transplant Proc 1994 Oct;|2
00058|105|R|   26(5):2823-4.|2
00058|106|R|25.Zylber-Katz E. Multiple drug interactions with cyclosporine in a heart|3
00058|107|R|   transplant patient. Ann Pharmacother 1995 Feb;29(2):127-31.|3
00058|108|R|26.Kessler M, Netter P, Zerrouki M, Renoult E, Trechot P, Dousset B, Jonon|3
00058|109|R|   B, Mur JM. Spiramycin does not increase plasma cyclosporin concentrations|3
00058|110|R|   in renal transplant patients. Eur J Clin Pharmacol 1988;35(3):331-2.|3
00058|111|R|27.Kessler M, Netter P, Renoul HE, Trechot P, Dousset B, Bannwarth B. Lack|6
00058|112|R|   of effect of spiramycin on cyclosporin pharmacokinetics. Br J Clin|6
00058|113|R|   Pharmacol 1990 Mar;29(3):370-1.|6
00058|114|R|28.Birmele B, Lebranchu Y, Beliveau F, Rateau H, Furet Y, Nivet H, Bagros P.|3
00058|115|R|   Absence of interaction between cyclosporine and spiramycin.|3
00058|116|R|   Transplantation 1989 May;47(5):927-8.|3
00058|117|R|29.Gersema LM, Porter CB, Russell EH. Suspected drug interaction between|3
00058|118|R|   cyclosporine and clarithromycin. J Heart Lung Transplant 1994 Mar-Apr;|3
00058|119|R|   13(2):343-5.|3
00058|120|R|30.Ferrari SL, Goffin E, Mourad M, Wallemacq P, Squifflet JP, Pirson Y. The|3
00058|121|R|   interaction between clarithromycin and cyclosporine in kidney transplant|3
00058|122|R|   recipients. Transplantation 1994 Sep 27;58(6):725-7.|3
00058|123|R|31.Ljutic D, Rumboldt Z. Possible interaction between azithromycin and|3
00058|124|R|   cyclosporin: a case report. Nephron 1995;70(1):130.|3
00059|001|T|MONOGRAPH TITLE:  Carmustine/Cimetidine|
00059|002|B||
00059|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00059|004|L|of severe adverse interaction.|
00059|005|B||
00059|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Both carmustine and|
00059|007|A|cimetidine have bone marrow suppression properties, which may be additive|
00059|008|A|during concurrent therapy.  It has also been suggested that cimetidine may|
00059|009|A|inhibit the metabolism of carmustine.(1)|
00059|010|B||
00059|011|E|CLINICAL EFFECTS:  Cimetidine may enhance carmustine-induced bone marrow|
00059|012|E|suppression, including leukopenia and neutropenia.|
00059|013|B||
00059|014|P|PREDISPOSING FACTORS:  None determined.|
00059|015|B||
00059|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of these medications.  If the|
00059|017|M|drugs are used together, monitor for excessive bone marrow toxicity.  Since|
00059|018|M|other H-2 antagonists (e.g., ranitidine, famotidine) do not appear to|
00059|019|M|interact, substituting cimetidine with one of these agents may be desirable.|
00059|020|M|However, if a patient is already receiving this combination and is not|
00059|021|M|experiencing adverse effects, substitution is probably not necessary.|
00059|022|B||
00059|023|D|DISCUSSION:  Additive bone marrow depression was seen in patients receiving|
00059|024|D|concurrent therapy with carmustine and cimetidine when compared to control|
00059|025|D|patients not receiving cimetidine.(2,3)|
00059|026|D|   In an animal study, rats were given a single injection of cimetidine at|
00059|027|D|various times up to 30 minutes before or up to 60 minutes after a carmustine|
00059|028|D|injection. Enhanced carmustine bone marrow toxicity was seen with concurrent|
00059|029|D|administration of cimetidine.(4)|
00059|030|B||
00059|031|R|REFERENCES:|
00059|032|B||
00059|033|R|1.Anonymous. Alternative mechanisms for severe neutropenia. Arch Intern Med|6
00059|034|R|  1982 Oct;142(10):1971.|6
00059|035|R|2.Selker RG, Moore P, Lodolce D. Bone-marrow depression with cimetidine plus|3
00059|036|R|  carmustine. N Engl J Med 1978 Oct 12;299(15):834.|3
00059|037|R|3.Volkin RL, Shadduck RK, Winkelstein A, Zeigler ZR, Selker RG. Potentiation|2
00059|038|R|  of carmustine-cranial irradiation-induced myelosuppression by cimetidine.|2
00059|039|R|  Arch Intern Med 1982 Feb;142(2):243-5.|2
00059|040|R|4.Dorr RT, Soble MJ. H2-antagonists and carmustine. J Cancer Res Clin Oncol|5
00059|041|R|  1989;115(1):41-6.|5
00062|001|T|MONOGRAPH TITLE:  Theophylline Derivatives/Cimetidine|
00062|002|B||
00062|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00062|004|L|of severe adverse interaction.|
00062|005|B||
00062|006|A|MECHANISM OF ACTION:  Cimetidine inhibits the metabolism of theophylline by|
00062|007|A|CYP1A2.(1-10)  The duration of cimetidine's inhibitory action is uncertain.|
00062|008|A|Short-term cimetidine therapy appears to reverse rapidly(2) but may persist|
00062|009|A|in prolonged therapy.  Increased  pentoxifylline serum levels may be the|
00062|010|A|result of an increase in the oral bioavailability of pentoxifylline.(11)|
00062|011|B||
00062|012|E|CLINICAL EFFECTS:  Concurrent cimetidine and theophylline derivative therapy|
00062|013|E|may result in elevated theophylline derivative concentration levels,|
00062|014|E|prolonged elimination half-life, and decreased clearance.|
00062|015|B||
00062|016|P|PREDISPOSING FACTORS:  None determined.|
00062|017|B||
00062|018|M|PATIENT MANAGEMENT:  Theophylline derivative blood levels should be very|
00062|019|M|closely monitored if cimetidine therapy is to be initiated, changed, or|
00062|020|M|discontinued.  Theophylline has a narrow therapeutic range; therefore,|
00062|021|M|dosage reductions up to 30-50%(4) should be considered to prevent|
00062|022|M|intoxication when cimetidine therapy is started.  Antacids, famotidine, or|
00062|023|M|possibly ranitidine might be more judicious choices than cimetidine in|
00062|024|M|patients receiving theophylline derivatives.|
00062|025|B||
00062|026|D|DISCUSSION:  It is well documented that cimetidine impairs the elimination|
00062|027|D|of theophylline when the two agents are co-administered to patients.(1-10,|
00062|028|D|12-22)  This interaction has been noted by a variety of routes including|
00062|029|D|continuous intravenous infusion.(22)  Reports indicate that with concurrent|
00062|030|D|cimetidine, theophylline plasma concentrations increase, theophylline|
00062|031|D|half-life is prolonged from 29% to 73%(1-3;9,12-14) and theophylline|
00062|032|D|clearance is decreased by 18.5% to 46%.(1-3,9,13,23)  Age and smoking do not|
00062|033|D|appear to affect the magnitude of the interaction.(17,18,20)  Significant|
00062|034|D|changes can be seen within 24 hours(3,5) and may progress as co-therapy|
00062|035|D|continues.(3)|
00062|036|D|   A study involving ten healthy patients demonstrated that concomitant|
00062|037|D|administration of cimetidine significantly decreased the plasma clearance of|
00062|038|D|oxtriphylline.(24)|
00062|039|D|   Aminophylline is involved in a similar interaction as theophylline as|
00062|040|D|seen in one case report.(25)|
00062|041|D|   In one report cimetidine also decreased the clearance and prolonged the|
00062|042|D|half-life of caffeine.(26,27)|
00062|043|D|   A study demonstrated that cimetidine caused a significant increase in|
00062|044|D|plasma levels of pentoxifylline.(11)|
00062|045|D|   Information on ranitidine is conflicting. Several studies have shown that|
00062|046|D|ranitidine does not influence theophylline.(9,15,16,19,28,29)  One case|
00062|047|D|report noted toxic theophylline levels after ranitidine;(30) however, this|
00062|048|D|case report has been challenged.(31)  In another case report, theophylline|
00062|049|D|levels rose from 16.6 mcg/ml to 39.7 mcg/ml(32) when the patient was given|
00062|050|D|ranitidine.  Other reports have also noted a reduction in theophylline|
00062|051|D|elimination by ranitidine.(33,34)|
00062|052|D|   Famotidine has shown to have no effect on theophylline metabolism in a|
00062|053|D|clinical trial;(35) however, there is one case report of decreased|
00062|054|D|theophylline clearance during famotidine therapy.(36)|
00062|055|D|   Dyphylline, a theophylline derivative that is not converted to|
00062|056|D|theophylline in vivo, is not to be expected to interact with cimetidine.|
00062|057|D|   A study showed that cimetidine increased the average steady state plasma|
00062|058|D|concentration of pentoxifylline and its metabolite by 25% and 30%,|
00062|059|D|respectively.(37)|
00062|060|B||
00062|061|R|REFERENCES:|
00062|062|B||
00062|063|R|1.Roberts RK, Grice J, Wood L, Petroff V, McGuffie C. Cimetidine impairs the|2
00062|064|R|  elimination of theophylline and antipyrine. Gastroenterology 1981 Jul;|2
00062|065|R|  81(1):19-21.|2
00062|066|R|2.Campbell MA, Plachetka JR, Jackson JE, Moon JF, Finley PR. Cimetidine|3
00062|067|R|  decreases theophylline clearance. Ann Intern Med 1981 Jul;95(1):68-9.|3
00062|068|R|3.Reitberg DP, Bernhard H, Schentag JJ. Alteration of theophylline clearance|2
00062|069|R|  and half-life by cimetidine in normal volunteers. Ann Intern Med 1981 Nov;|2
00062|070|R|  95(5):582-5.|2
00062|071|R|4.Bauman JH, Kimelblatt BJ, Caraccio TR, Silverman HM, Simon GI, Beck GJ.|3
00062|072|R|  Cimetidine-theophylline interaction: report of four patients. Ann Allergy|3
00062|073|R|  1982 Feb;48(2):100-2.|3
00062|074|R|5.Cluxton RJ Jr, Rivera JO, Ritschel WA, Pesce AJ, Hanenson IB.|3
00062|075|R|  Cimetidine-theophylline interaction. Ann Intern Med 1982 May;96(5):684.|3
00062|076|R|6.Fenje PC, Isles AF, Baltodano A, MacLeod SM, Soldin S. Interaction of|3
00062|077|R|  cimetidine and theophylline in two infants. Can Med Assoc J 1982 May 15;|3
00062|078|R|  126(10):1178.|3
00062|079|R|7.Jackson JE, Powell JR, Wandell M, Bentley J, Dorr R. Cimetidine decreases|2
00062|080|R|  theophylline clearance. Am Rev Respir Dis 1981 Jun;123(6):615-7.|2
00062|081|R|8.Lalonde RL, Koob RA, McLean WM, Balsys AJ. The effects of cimetidine on|2
00062|082|R|  theophylline pharmacokinetics at steady state. Chest 1983 Feb;83(2):221-4.|2
00062|083|R|9.Powell JR, Rogers JF, Wargin WA, Eshelman FN. The influence of cimetidine|2
00062|084|R|  vs ranitidine on theophylline pharmacokinetics. Clin Pharmacol Ther 1982|2
00062|085|R|  Feb;31(2):261.|2
00062|086|R|10.Schwartz JI, Bachmann KA, Bond LW, Mahajan VK. Impact of cimetidine on|2
00062|087|R|   the pharmacokinetics of theophylline. Clin Pharm 1982 Nov-Dec;1(6):534-8.|2
00062|088|R|11.Mauro VF, Mauro LS, Hageman JH. Alteration of pentoxifylline|2
00062|089|R|   pharmacokinetics by cimetidine. J Clin Pharmacol 1988 Jul;28(7):649-54.|2
00062|090|R|12.Weinberger MM, Smith G, Milavetz G, Hendeles L. Decreased clearance of|3
00062|091|R|   theophylline due to cimetidine. N Engl J Med 1981 Mar 12;304(11):672.|3
00062|092|R|13.Wood L, Grice J, Petroff V, McGuffie C, Roberts RK. Effect of cimetidine|2
00062|093|R|   on the disposition of theophylline. Aust N Z J Med 1981 Oct;10(5):586.|2
00062|094|R|14.Roberts RK, Grice J, McGuffie C. Cimetidine-theophylline interaction in|2
00062|095|R|   patients with chronic obstructive airways disease. Med J Aust 1984 Mar 3;|2
00062|096|R|   140(5):279-80.|2
00062|097|R|15.Powell JR, Rogers JF, Wargin WA, Cross RE, Eshelman FN. Inhibition of|2
00062|098|R|   theophylline clearance by cimetidine but not ranitidine. Arch Intern Med|2
00062|099|R|   1984 Mar;144(3):484-6.|2
00062|100|R|16.Dal Negro R, Pomari C, Zoccatelli O, Trevisan F, Carloni C, Turco P.|2
00062|101|R|   Pharmacokinetics of theophylline and the H2-antagonist drugs cimetidine|2
00062|102|R|   and ranitidine. Int J Clin Pharmacol Ther Toxicol 1984 Apr;22(4):221-6.|2
00062|103|R|17.Gugler R, Wolf M, Hansen HH, Jensen JC. The inhibition of drug metabolism|2
00062|104|R|   by cimetidine in patients with liver cirrhosis. Klin Wochenschr 1984 Dec|2
00062|105|R|   3;62(23):1126-31.|2
00062|106|R|18.Cusack BJ, Dawson GW, Mercer GD, Vestal RE. Cigarette smoking and|2
00062|107|R|   theophylline metabolism: effects of cimetidine. Clin Pharmacol Ther 1985|2
00062|108|R|   Mar;37(3):330-6.|2
00062|109|R|19.Dal Negro R, Turco P, Zoccatelli O, Trevisan F, Pomart C. H2-antagonist|2
00062|110|R|   derangement of the kinetics of sustained-release oral theophylline. Int J|2
00062|111|R|   Clin Pharmacol Ther Toxicol 1985 Jun;23(6):329-32.|2
00062|112|R|20.Cohen IA, Johnson CE, Berardi RR, Hyneck ML, Achem SR.|2
00062|113|R|   Cimetidine-theophylline interaction: effects of age and cimetidine dose.|2
00062|114|R|   Ther Drug Monit 1985;7(4):426-34.|2
00062|115|R|21.Chremos AM, Lin JH, Yeh KC, Chiou R, Bayne WF, Lipschutz K, Williams RL.|2
00062|116|R|   Famotidine (F) does not interfere with the disposition of theophylline|2
00062|117|R|   (T) in man .  Comparision to cimetidine. Clin Pharmacol Ther 1986 Feb;|2
00062|118|R|   39(2):187.|2
00062|119|R|22.Krstenansky PM, Javaheri S, Thomas JP, Thomas RL. Effect of continuous|2
00062|120|R|   cimetidine infusion on steady-state theophylline concentration. Clin|2
00062|121|R|   Pharm 1989 Mar;8(3):206-9.|2
00062|122|R|23.Lalonde RL, Koob RA, McLean WM, Balsys AJ. Influence of cimetidine on|2
00062|123|R|   theophylline pharmacokinetics at steady state. Clin Pharmacol Ther 1982|2
00062|124|R|   Feb;31(2):241-42.|2
00062|125|R|24.DeAngelis C, Walker SE, Bartle WR. Effect of low-dose cimetidine on|2
00062|126|R|   theophylline metabolism. Clin Pharm 1983 Nov-Dec;2(6):563-7.|2
00062|127|R|25.Green AW, Ebling WF, Gardner MJ, Jusko WJ.|3
00062|128|R|   Cimetidine-methylprednisolone-theophylline metabolic interaction. Am J|3
00062|129|R|   Med 1984 Dec;77(6):1115-8.|3
00062|130|R|26.Broughton LJ, Rogers HJ. Decreased systemic clearance of caffeine due to|3
00062|131|R|   cimetidine. Br J Clin Pharmacol 1981 Aug;12(2):155-9.|3
00062|132|R|27.May DC, Jarboe CH, VanBakel AB, Williams WM. Effects of cimetidine on|2
00062|133|R|   caffeine disposition in smokers and nonsmokers. Clin Pharmacol Ther 1982|2
00062|134|R|   May;31(5):656-61.|2
00062|135|R|28.Breen KJ, Bury R, Desmond PV, Mashford ML, Morphett B, Westwood B, Shaw|2
00062|136|R|   RG. Effects of cimetidine and ranitidine on hepatic drug metabolism. Clin|2
00062|137|R|   Pharmacol Ther 1982 Mar;31(3):297-300.|2
00062|138|R|29.Kelly HW, Powell JR, Donohue JF. Ranitidine at very large doses does not|3
00062|139|R|   inhibit theophylline elimination. Clin Pharmacol Ther 1986 May;|3
00062|140|R|   39(5):577-81.|3
00062|141|R|30.Fernandes E, Melewicz FM. Ranitidine and theophylline. Ann Intern Med|3
00062|142|R|   1984 Mar;100(3):459.|3
00062|143|R|31.Dobbs JH, Smith RN. Ranitidine and theophylline. Ann Intern Med 1984 May;|3
00062|144|R|   100(5):769.|3
00062|145|R|32.Gardner ME, Sikorski GW. Ranitidine and theophylline. Ann Intern Med 1985|3
00062|146|R|   Apr;102(4):559.|3
00062|147|R|33.Skinner MH, Lenert L, Blaschke TF. Theophylline toxicity subsequent to|3
00062|148|R|   ranitidine administration: a possible drug-drug interaction. Am J Med|3
00062|149|R|   1989 Jan;86(1):129-32.|3
00062|150|R|34.Roy AK, Cuda MP, Levine RA. Induction of theophylline toxicity and|2
00062|151|R|   inhibition of clearance rates by ranitidine. Am J Med 1988 Oct;|2
00062|152|R|   85(4):525-7.|2
00062|153|R|35.Verdiani P, Di Carlo S, Baronti A. Famotidine effects on theophylline|2
00062|154|R|   pharmacokinetics in subjects affected by COPD. Comparison with cimetidine|2
00062|155|R|   and placebo. Chest 1988 Oct;94(4):807-10.|2
00062|156|R|36.Dal Negro R, Pomari C, Turco P. Famotidine and theophylline|2
00062|157|R|   pharmacokinetics. An unexpected cimetidine- like interaction in patients|2
00062|158|R|   with chronic obstructive pulmonary disease. Clin Pharmacokinet 1993 Mar;|2
00062|159|R|   24(3):255-8.|2
00062|160|R|37.Trental (pentoxifylline) US prescribing information. Aventis|1
00062|161|R|   Pharmaceuticals, Inc. January, 2016.|1
00063|001|T|MONOGRAPH TITLE:  Methenamine/Sulfonamides|
00063|002|B||
00063|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00063|004|L|is contraindicated and generally should not be dispensed or administered to|
00063|005|L|the same patient.|
00063|006|B||
00063|007|A|MECHANISM OF ACTION:  Methenamine is hydrolyzed to formaldehyde in acidic|
00063|008|A|urine. Sulfonamides may form an insoluble precipitate with formaldehyde in|
00063|009|A|the urine.(1,2)|
00063|010|B||
00063|011|E|CLINICAL EFFECTS:  The concurrent administration of methenamine and|
00063|012|E|sulfamethizole or sulfathiazole is likely to form a precipitate in the|
00063|013|E|urine.(1-3)|
00063|014|B||
00063|015|P|PREDISPOSING FACTORS:  None determined.|
00063|016|B||
00063|017|M|PATIENT MANAGEMENT:  Methenamine should not be administered to patients|
00063|018|M|receiving sulfonamides.(1-3)|
00063|019|B||
00063|020|D|DISCUSSION:  Methenamine is hydrolyzed to formaldehyde in acidic urine.|
00063|021|D|   An in vitro study showed that addition of methenamine and mandelic acid|
00063|022|D|to saturated solutions of sulfamethizole at pH 5.0 and 6.0 produced a|
00063|023|D|precipitate in one hour.(4)|
00063|024|B||
00063|025|R|REFERENCES:|
00063|026|B||
00063|027|R|1.Hiprex (methenamine hippurate) US prescribing information. Aventis|1
00063|028|R|  Pharmaceuticals, Inc. December, 2017.|1
00063|029|R|2.Mandelamine (methenamine mandelate) US prescribing information. . Warner|1
00063|030|R|  Chilcott, Inc. September, 2007.|1
00063|031|R|3.Urex (methenamine hippurate) Canadian prescribing information. Draxis|1
00063|032|R|  Pharmaceuticals, Inc December, 2006.|1
00063|033|R|4.DICARLO FJ, MALAMENT SG, PHILLIPS GE. Formation of an insoluble|5
00063|034|R|  condensation product from sulfamethizole and formaldehyde. J Pharm Sci|5
00063|035|R|  1963 Jan;52:104.|5
00064|001|T|MONOGRAPH TITLE:  Estrogens/Xanthine Derivatives|
00064|002|B||
00064|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00064|004|L|take action as needed.|
00064|005|B||
00064|006|A|MECHANISM OF ACTION:  Estrogens may inhibit the hepatic microsomal enzymes|
00064|007|A|responsible for the metabolism of the theophyllines.|
00064|008|B||
00064|009|E|CLINICAL EFFECTS:  Concurrent use of estrogens may result in an increase in|
00064|010|E|the pharmacologic effects of xanthine derivatives as a result of elevated|
00064|011|E|serum levels.  Signs and symptoms of theophylline toxicity including|
00064|012|E|anorexia, nausea, vomiting, nervousness, agitation, headache, tachycardia,|
00064|013|E|arrhythmias, and convulsions.|
00064|014|B||
00064|015|P|PREDISPOSING FACTORS:  Smoking.|
00064|016|B||
00064|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent estrogens should be|
00064|018|M|monitored for elevated xanthine levels and signs of toxicity.  Adjust|
00064|019|M|dosages accordingly.|
00064|020|B||
00064|021|D|DISCUSSION:  Although there are no reports of toxicity due to concurrent|
00064|022|D|administration of oral contraceptives and theophylline, use of this|
00064|023|D|combination has been associated with a decrease in the plasma clearance and|
00064|024|D|an increase in the elimination half-life of theophylline.|
00064|025|D|   One study involving a small number of patients found that low dose oral|
00064|026|D|contraceptive administration (i.e., 35 mcg) for up to 9 months, did not|
00064|027|D|alter the pharmacokinetics of theophylline.|
00064|028|D|   Other studies demonstrate the effect of caffeine, a xanthine alkaloid|
00064|029|D|chemically similar to theophylline, when administered to patients taking|
00064|030|D|oral contraceptives or hormone replacement.  Concomitant administration|
00064|031|D|resulted in decreased caffeine metabolism by ethinyl estradiol's metabolic|
00064|032|D|inhibition.  A study of 20 healthy women evaluated the effect of caffeine|
00064|033|D|elimination prior to and during one cycle of oral contraception. Compared to|
00064|034|D|pretreatment values, it was determined that clearance of caffeine was|
00064|035|D|reduced by approximately 55%.|
00064|036|D|   Another study evaluated the pharmacokinetics of caffeine in seven women|
00064|037|D|receiving an oral depot contraceptive containing ethinyl estradiol.  After|
00064|038|D|six months, the oral contraceptive was found to significantly decrease the|
00064|039|D|elimination half-life of caffeine: half-life prior to therapy was 4.9h, and|
00064|040|D|after oral contraceptive therapy, the half-life of caffeine increased to|
00064|041|D|8.0h.|
00064|042|B||
00064|043|R|REFERENCES:|
00064|044|B||
00064|045|R|1.Tornatore KM, Kanarkowski R, McCarthy TL, Gardner MJ, Yurchak AM, Jusko|2
00064|046|R|  WJ. Effect of chronic oral contraceptive steroids on theophylline|2
00064|047|R|  disposition. Eur J Clin Pharmacol 1982;23(2):129-34.|2
00064|048|R|2.Roberts RK, Grice J, McGuffie C, Heilbronn L. Oral contraceptive steroids|2
00064|049|R|  impair the elimination of theophylline. J Lab Clin Med 1983 Jun;|2
00064|050|R|  101(6):821-5.|2
00064|051|R|3.Gardner MJ, Tornatore KM, Jusko WJ, Kanarkowski R. Effects of tobacco|2
00064|052|R|  smoking and oral contraceptive use on theophylline disposition. Br J Clin|2
00064|053|R|  Pharmacol 1983 Sep;16(3):271-80.|2
00064|054|R|4.Jusko WJ, Gardner MJ, Mangione A, Schentag JJ, Koup JR, Vance JW. Factors|2
00064|055|R|  affecting theophylline clearances: age, tobacco, marijuana, cirrhosis,|2
00064|056|R|  congestive heart failure, obesity, oral contraceptives, benzodiazepines,|2
00064|057|R|  barbiturates, and ethanol. J Pharm Sci 1979 Nov;68(11):1358-66.|2
00064|058|R|5.Koren G, Chin TF, Correia J, Tesoro A, MacLeod SM. Theophylline|2
00064|059|R|  pharmacokinetics in adolescent females following coadministration of oral|2
00064|060|R|  contraceptives. Clin Invest Med 1985;8(3):222-6.|2
00064|061|R|6.Pollock BG, Wylie M, Stack JA, Sorisio DA, Thompson DS, Kirshner MA, Folan|2
00064|062|R|  MM, Condifer KA. Inhibition of caffeine metabolism by estrogen replacement|2
00064|063|R|  therapy in postmenopausal women. J Clin Pharmacol 1999 Sep;39(9):936-40.|2
00064|064|R|7.Balogh A, Klinger G, Henschel L, Borner A, Vollanth R, Kuhnz W. Influence|2
00064|065|R|  of ethinylestradiol-containing combination oral contraceptives with|2
00064|066|R|  gestodene or levonorgestrel on caffeine elimination. Eur J Clin Pharmacol|2
00064|067|R|  1995;48(2):161-6.|2
00064|068|R|8.Meyer FP, Canzler E, Giers H, Walther H. Time course of inhibition of|2
00064|069|R|  caffeine elimination in response to the oral depot contraceptive agent|2
00064|070|R|  Deposiston. Hormonal contraceptives and caffeine elimination. Zentralbl|2
00064|071|R|  Gynakol 1991;113(6):297-302.|2
00065|001|T|MONOGRAPH TITLE:  Corticosteroids/Rifamycins (mono deleted 02/02/2012)|
00065|002|B||
00065|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00065|004|L|take action as needed.|
00065|005|B||
00065|006|A|MECHANISM OF ACTION:  Hepatic metabolism is increased by rifampin.|
00065|007|B||
00065|008|E|CLINICAL EFFECTS:  Corticosteroids, which are metabolized by the liver, may|
00065|009|E|exhibit reduced pharmacologic effects. Effects may be seen for several days|
00065|010|E|after rifampin is stopped.|
00065|011|B||
00065|012|P|PREDISPOSING FACTORS:  None determined.|
00065|013|B||
00065|014|M|PATIENT MANAGEMENT:  If both drugs are administered, adjust the dose of|
00065|015|M|corticosteroids as needed based on patient response.|
00065|016|B||
00065|017|D|DISCUSSION:  This interaction is well documented.|
00065|018|B||
00065|019|R|REFERENCE:|
00065|020|B||
00065|021|R|1.Edwards OM, Courtenay-Evans RJ, Galley JM, Hunter J, Tait AD. Changes in|3
00065|022|R|  cortisol metabolism following rifampicin therapy. Lancet 1974 Sep 7;|3
00065|023|R|  2(7880):548-51.|3
00066|001|T|MONOGRAPH TITLE:  Sulfonamide Antibacterials/Paba|
00066|002|B||
00066|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00066|004|L|take action as needed.|
00066|005|B||
00066|006|A|MECHANISM OF ACTION:  Sulfonamide antibacterials are structurally similar to|
00066|007|A|PABA (p-aminobenzoic acid). PABA is an essential precursor for synthesis of|
00066|008|A|tetrahydrofolate. Sulfonamides competitively inhibit utilization of PABA and|
00066|009|A|therefore disrupt tetrahydrofolate biosynthesis. Supplementation with PABA|
00066|010|A|antagonizes sulfonamide antibacterials.|
00066|011|B||
00066|012|E|CLINICAL EFFECTS:  Reduced antibacterial effectiveness of sulfonamides with|
00066|013|E|concomitant use.|
00066|014|B||
00066|015|P|PREDISPOSING FACTORS:  None determined.|
00066|016|B||
00066|017|M|PATIENT MANAGEMENT:  Avoid concomitant administration of these drugs.|
00066|018|B||
00066|019|D|DISCUSSION:  This interaction is well documented.|
00066|020|B||
00066|021|R|REFERENCE:|
00066|022|B||
00066|023|R|1.Mandel GL, Sande MA. Antimicrobial agents. Sulfonamides, trimethoprim|6
00066|024|R|  -sulfamethoxazole, quinolones, and agents for urinary tract infections. In|6
00066|025|R|  Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's The|6
00066|026|R|  Pharmacological Basis of Therapeuctics. 8th ed. 1990.|6
00068|001|T|MONOGRAPH TITLE:  Quinidine/Cimetidine|
00068|002|B||
00068|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00068|004|L|take action as needed.|
00068|005|B||
00068|006|A|MECHANISM OF ACTION:  Cimetidine, a CYP3A4 inhibitor, may inhibit the|
00068|007|A|metabolism of quinidine.|
00068|008|B||
00068|009|E|CLINICAL EFFECTS:  Potentiation of quinidine effects by cimetidine with|
00068|010|E|possible quinidine toxicity, including QT prolongation and potentially|
00068|011|E|life-threatening cardiac arrhythmias, including torsades de pointes.|
00068|012|B||
00068|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00068|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00068|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00068|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00068|017|P|female gender, or advanced age.(7)|
00068|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00068|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00068|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00068|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00068|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00068|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00068|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)|
00068|025|B||
00068|026|M|PATIENT MANAGEMENT:  If both drugs are administered, adjust the quinidine|
00068|027|M|dose as needed based on serum quinidine levels, cardiac function, and|
00068|028|M|patient response. Since other H-2 antagonists (e.g., ranitidine, famotidine)|
00068|029|M|do not appear to interact, substituting cimetidine with one of these agents|
00068|030|M|may be desirable. Ventricular arrhythmia has been reported during concurrent|
00068|031|M|use of ranitidine and quinidine. However, if a patient is already receiving|
00068|032|M|this combination and is not experiencing adverse effects, substitution is|
00068|033|M|probably not necessary.|
00068|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00068|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00068|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00068|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00068|038|B||
00068|039|D|DISCUSSION:  The onset and reversal of the interaction may occur within 48|
00068|040|D|hours of starting or stopping cimetidine in a patient receiving quinidine.|
00068|041|D|Signs and symptoms of quinidine toxicity include nausea, vomiting and|
00068|042|D|diarrhea, headache, tinnitus, vertigo and confusion. Electrocardiogram|
00068|043|D|changes, including prolongation of the QT and QRS intervals may also occur.|
00068|044|B||
00068|045|R|REFERENCES:|
00068|046|B||
00068|047|R|1.Polish LB, Branch RA, Fitzgerald GA. Digitoxin-quinidine interaction:|3
00068|048|R|  potentiation during administration of cimetidine. South Med J 1981 May;|3
00068|049|R|  74(5):633-4.|3
00068|050|R|2.Hardy BG, Zador IT, Golden L, Lalka D, Schentag JJ. Effect of cimetidine|2
00068|051|R|  on the pharmacokinetics and pharmacodynamics of quinidine. Am J Cardiol|2
00068|052|R|  1983 Jul;52(1):172-5.|2
00068|053|R|3.Farringer JA, McWay-Hess K, Clementi WA. Cimetidine--quinidine|3
00068|054|R|  interaction. Clin Pharm 1984 Jan-Feb;3(1):81-3.|3
00068|055|R|4.Kolb KW, Garnett WR, Small RE, Vetrovec GW, Kline BJ, Fox T. Effect of|2
00068|056|R|  cimetidine on quinidine clearance. Ther Drug Monit 1984;6(3):306-12.|2
00068|057|R|5.Iliopoulou A, Kontogiannis D, Tsoutsos D, Moulopoulos S.|3
00068|058|R|  Quinidine-ranitidine adverse reaction. Eur Heart J 1986 Apr;7(4):360.|3
00068|059|R|6.Hardy BG, Schentag JJ. Lack of effect of cimetidine on the metabolism of|2
00068|060|R|  quinidine: effect on renal clearance. Int J Clin Pharmacol Ther Toxicol|2
00068|061|R|  1988 Aug;26(8):388-91.|2
00068|062|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00068|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00068|064|R|  settings: a scientific statement from the American Heart Association and|6
00068|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00068|066|R|  2;55(9):934-47.|6
00069|001|T|MONOGRAPH TITLE:  Tetracyclines/Divalent & Trivalent Cations|
00069|002|B||
00069|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00069|004|L|take action as needed.|
00069|005|B||
00069|006|A|MECHANISM OF ACTION:  Di- and trivalent cations may form chelation complexes|
00069|007|A|with tetracyclines, preventing their absorption.(1,2)|
00069|008|B||
00069|009|E|CLINICAL EFFECTS:  Simultaneous administration of di- or trivalent cations|
00069|010|E|may result in decreased levels of and therapeutics effects from|
00069|011|E|tetracyclines.|
00069|012|B||
00069|013|P|PREDISPOSING FACTORS:  None determined.|
00069|014|B||
00069|015|M|PATIENT MANAGEMENT:  Administer tetracyclines at least two hours before or|
00069|016|M|after the di- or trivalent cations.|
00069|017|M|   When used for the treatment of H. pylori infection, tetracyclines and|
00069|018|M|bismuth should be given simultaneously.|
00069|019|M|   The US manufacturer of omadacycline states to fast for at least four|
00069|020|M|hours, administer omadacycline, and then wait four hours before taking di-|
00069|021|M|or trivalent cations.(21)|
00069|022|B||
00069|023|D|DISCUSSION:  Concurrent administration of aluminum hydroxide or divalent|
00069|024|D|cations (such as calcium, magnesium, or zinc) has been shown to|
00069|025|D|significantly decrease the gastrointestinal absorption of tetracycline.(3-5)|
00069|026|D|Concurrent administration of tetracycline and magnesium-aluminum hydroxide|
00069|027|D|gel has been shown to decrease the tetracycline area-under-curve (AUC) by|
00069|028|D|90%.(6)  Magnesium-aluminum silicate has been shown to decrease the AUC of|
00069|029|D|tetracycline by 27%.(7)|
00069|030|D|   Demeclocycline(8,9) methacycline,(10) chlortetracycline,(11) and|
00069|031|D|oxytetracycline(10,12) have been shown to interact with aluminum hydroxide|
00069|032|D|and/or dairy products.  Doxycycline has been reported to interact with|
00069|033|D|aluminum hydroxide gel.(13)  Aluminum magnesium hydroxide has been shown to|
00069|034|D|decrease doxycycline absorption by 84%.(14)|
00069|035|D|   Minocycline absorption has been shown to be impaired by aluminum,|
00069|036|D|calcium, and magnesium.(15)|
00069|037|D|   Bismuth subsalicylate has been shown to decrease absorption of|
00069|038|D|doxycycline and tetracycline by 37%(16) and 34%,(17) respectively.|
00069|039|D|   Since sucralfate is an aluminum salt of a sulfated disaccharide, it may|
00069|040|D|also prevent absorption of tetracyclines.  This complex has been used to|
00069|041|D|provide site-specific delivery of tetracycline to gastric ulcers in the|
00069|042|D|treatment of Helicobacter pylori gastric ulcer disease and may be useful in|
00069|043|D|some indications.(18)|
00069|044|D|  Quinapril tablets contain a high percentage of magnesium and have been|
00069|045|D|shown to decrease the absorption of tetracycline by 28-37%.(19)|
00069|046|D|  Lanthanum is expected to interact with tetracyclines as well.(20)|
00069|047|B||
00069|048|R|REFERENCES:|
00069|049|B||
00069|050|R|1.Albert A, Rees CW. Avidity of the tetracyclines for the cations of metal.|5
00069|051|R|  Nature 1956 Mar 3;177(4505):433-4.|5
00069|052|R|2.Chin TF, Lach JL. Drug diffusion and bioavailability: tetracycline|5
00069|053|R|  metallic chelation. Am J Hosp Pharm 1975 Jun;32(6):625-9.|5
00069|054|R|3.Penttila O, Hurme H, Neuvonen PJ. Effect of zinc sulphate on the|2
00069|055|R|  absorption of tetracycline and doxycycline in man. Eur J Clin Pharmacol|2
00069|056|R|  1975 Dec 19;9(2-3):131-4.|2
00069|057|R|4.Khalil SA, Daabis NA, Naggar VF, Wafik M. Effect of magnesium trisilicate|2
00069|058|R|  and citric acid on the biovailability of tetracycline in man. Pharmazie|2
00069|059|R|  1977 Aug-Sep;32(8-9):519-22.|2
00069|060|R|5.Mapp RK, McCarthy TJ. The effect of zinc sulphate and of bicitropeptide on|2
00069|061|R|  tetracycline absorption. S Afr Med J 1976 Oct 12;50(45):1829-30.|2
00069|062|R|6.Garty M, Hurwitz A. Effect of cimetidine and antacids on gastrointestinal|2
00069|063|R|  absorption of tetracycline. Clin Pharmacol Ther 1980 Aug;28(2):203-7.|2
00069|064|R|7.Healy DP, Dansereau RJ, Dunn AB, Clendening CE, Mounts AW, Deepe GS Jr.|2
00069|065|R|  Reduced tetracycline bioavailability caused by magnesium aluminum silicate|2
00069|066|R|  in liquid formulations of bismuth subsalicylate. Ann Pharmacother 1997|2
00069|067|R|  Dec;31(12):1460-4.|2
00069|068|R|8.Scheiner J, Altemeier WA. Experimental study of factors inhibiting|2
00069|069|R|  absorption and effective therapeutic levels of declomycin. Surg Gynecol|2
00069|070|R|  Obstet 1962 Jan;114:9-14.|2
00069|071|R|9.Rosenblatt JE, Barrett JE, Brodie JL, Kirby WM. Comparison of in vitro|5
00069|072|R|  activity and clinical pharmacology of doxycycline with other|5
00069|073|R|  tetracyclines. Antimicrobial Agents Chemother 1966;6:134-41.|5
00069|074|R|10.Mattila MJ, Neuvonen PJ, Gothoni G, Hackman CR. Interference of iron|2
00069|075|R|   preparations and milk with the absorption of tetracyclines. Excerpta|2
00069|076|R|   Medica Int Cong Ser 1972;254:128-33.|2
00069|077|R|11.Waisbren BA, Hueckel JS. Reduced absorption of aureomycin caused by|2
00069|078|R|   aluminum hydroxide gel (Amphojel). Proc Soc Exp Biol Med 1950;73:73-4.|2
00069|079|R|12.Boger WP, Gavin JJ. An evaluation of tetracycline preparations. N Engl J|2
00069|080|R|   Med 1959 Oct 22;261(17):827-32.|2
00069|081|R|13.Nguyen VX, Nix DE, Gillikin S, Schentag JJ. Effect of oral antacid|2
00069|082|R|   administration on the pharmacokinetics of intravenous doxycycline.|2
00069|083|R|   Antimicrob Agents Chemother 1989 Apr;33(4):434-6.|2
00069|084|R|14.Deppermann KM, Lode H, Hoffken G, Tschink G, Kalz C, Koeppe P. Influence|2
00069|085|R|   of ranitidine, pirenzepine, and aluminum magnesium hydroxide on the|2
00069|086|R|   bioavailability of various antibiotics, including amoxicillin,|2
00069|087|R|   cephalexin, doxycycline, and amoxicillin-clavulanic acid. Antimicrob|2
00069|088|R|   Agents Chemother 1989 Nov;33(11):1901-7.|2
00069|089|R|15.Minocin (minocycline hydrochloride oral suspension) US prescribing|1
00069|090|R|   information. Triax Pharmaceuticals November, 2018.|1
00069|091|R|16.Ericsson CD, Feldman S, Pickering LK, Cleary TG. Influence of|2
00069|092|R|   subsalicylate bismuth on absorption of doxycycline. JAMA 1982 Apr 23;|2
00069|093|R|   247(16):2266-7.|2
00069|094|R|17.Albert KS, Welch RD, DeSante KA, DiSanto AR. Decreased tetracycline|2
00069|095|R|   bioavailability caused by a bismuth subsalicylate antidiarrheal mixture.|2
00069|096|R|   J Pharm Sci 1979 May;68(5):586-8.|2
00069|097|R|18.Yokel RA, Dickey KM, Goldberg AH. Selective adherence of a|5
00069|098|R|   sucralfate-tetracycline complex to gastric ulcers: implications for the|5
00069|099|R|   treatment of Helicobacter pylori. Biopharm Drug Dispos 1995 Aug;|5
00069|100|R|   16(6):475-9.|5
00069|101|R|19.Accupril (quinapril) US prescribing information. Pfizer April, 2017.|1
00069|102|R|20.Fosrenol (lanthanum carbonate) Canadian prescribing information. Shire|1
00069|103|R|   BioChem February 19, 2007.|1
00069|104|R|21.Nuzyra (omadacycline) US Prescribing Information. Paratek|1
00069|105|R|   Pharmaceuticals, Inc. October, 2018.|1
00070|001|T|MONOGRAPH TITLE:  Doxycycline/Strong CYP3A4 Inducers|
00070|002|B||
00070|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00070|004|L|take action as needed.|
00070|005|B||
00070|006|A|MECHANISM OF ACTION:  CYP3A4 inducers may induce the metabolism of|
00070|007|A|doxycyline.|
00070|008|B||
00070|009|E|CLINICAL EFFECTS:  Concurrent or recent use of an inducer of CYP3A4 may|
00070|010|E|result in decreased antimicrobial activity of doxycycline.|
00070|011|B||
00070|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00070|013|P|of the inducer for longer than 1-2 weeks.|
00070|014|B||
00070|015|M|PATIENT MANAGEMENT:  If both drugs are administered, monitor the response to|
00070|016|M|doxycycline.  Adjust the dose of the drug or consider administration of a|
00070|017|M|non-interacting tetracycline analogue (e.g. tetracycline) if necessary.|
00070|018|B||
00070|019|D|DISCUSSION:  The effects of the interaction develop over approximately one|
00070|020|D|to two weeks after starting the inducer and reverse over a period of several|
00070|021|D|weeks after stopping the inducer.  The elimination of demeclocycline,|
00070|022|D|methacycline, oxytetracycline and tetracycline are not expected to be|
00070|023|D|altered by CYP3A4 inducers as these tetracyclines are primarily excreted by|
00070|024|D|the kidneys.  Serum doxycycline concentrations may increase when the inducer|
00070|025|D|is stopped.|
00070|026|D|   In a study, the half-life of doxycycline in 7 patients on long-term|
00070|027|D|phenytoin therapy, 5 patients on long-term carbamazepine therapy, 4 patients|
00070|028|D|on long-term combination phenytoin and carbamazepine therapy, and 9 control|
00070|029|D|subjects was 7.2 hours, 8.4 hours, 7.4 hours, and 15.1 hours,|
00070|030|D|respectively.(1)|
00070|031|D|   In a study, the half-life of doxycycline was significantly reduced in|
00070|032|D|patients receiving barbiturate therapy.(2)|
00070|033|D|   In a study that compared healthy-controls with patients on long-term|
00070|034|D|antiepileptic therapy, the half-life of doxycyline was significantly|
00070|035|D|decreased in patients receiving barbiturates, phenytoin, or carbamazepine.|
00070|036|D|The half-lives of chlortetracycline, demethylchlortetracycline,|
00070|037|D|methacycline, oxytetracycline, and tetracycline were unaffected.(3)|
00070|038|D|   In a study in 7 patients, the half-life of doxycycline (200 mg/day)|
00070|039|D|decreased from 17.9 hours to 9.2 hours following the addition of rifampin|
00070|040|D|(10 mg/kg/day) to therapy.(4)|
00070|041|D|   CYP3A4 inducers linked to this monograph include: apalutamide,|
00070|042|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
00070|043|D|ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifamycins, and St.|
00070|044|D|John's Wort.|
00070|045|B||
00070|046|R|REFERENCES:|
00070|047|B||
00070|048|R|1.Penttila O, Neuvonen PJ, Aho K, Lehtovaara R. Interaction between|2
00070|049|R|  doxycycline and some antiepileptic drugs. Br Med J 1974 Jun 1;|2
00070|050|R|  2(917):470-2.|2
00070|051|R|2.Neuvonen PJ, Penttila O. Interaction between doxycycline and barbiturates.|2
00070|052|R|  Br Med J 1974 Mar 23;1(907):535-6.|2
00070|053|R|3.Neuvonen PJ, Penttila O, Lehtovaara R, Aho K. Effect of antiepileptic|2
00070|054|R|  drugs on the elimination of various tetracycline derivatives. Eur J Clin|2
00070|055|R|  Pharmacol 1975 Dec 19;9(2-3):147-54.|2
00070|056|R|4.Garraffo R, Dellamonica P, Fournier JP, Lapalus P, Bernard E, Beziau H,|2
00070|057|R|  Chichmanian RM. Effects of rifampicin on the pharmacodynamics of|2
00070|058|R|  doxycycline. Pathol Biol (Paris) 1987 Jun;35(5 Pt 2):746-9.|2
00071|001|T|MONOGRAPH TITLE:  Selected Xanthine Derivatives/Selected Macrolide|
00071|002|T|Antibiotics|
00071|003|B||
00071|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00071|005|L|take action as needed.|
00071|006|B||
00071|007|A|MECHANISM OF ACTION:  The macrolides may inhibit the metabolism of the|
00071|008|A|xanthine derivatives at CYP3A4.  Theophylline decreases the bioavailability|
00071|009|A|and increases the renal clearance of erythromycin by unknown mechanisms.|
00071|010|B||
00071|011|E|CLINICAL EFFECTS:  The concurrent administration of xanthine derivatives and|
00071|012|E|some macrolides may result in elevated levels and increased clinical and|
00071|013|E|adverse effects of the xanthine derivatives.  The serum levels of|
00071|014|E|erythromycin may be decreased.|
00071|015|B||
00071|016|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
00071|017|P|have decreased xanthine clearance rates secondary to CHF, viral URI's,|
00071|018|P|hepatic impairment, acute pulmonary edema, or cor pulmonale.  Large xanthine|
00071|019|P|doses may also pre-dispose patients to the clinical effects of the|
00071|020|P|interaction.|
00071|021|B||
00071|022|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with these agents|
00071|023|M|should be monitored for signs of xanthine toxicity (e.g. nausea, seizures,|
00071|024|M|nervousness, etc.).  Theophylline levels should be monitored during and|
00071|025|M|following concurrent macrolide therapy.  The dosage of the xanthine|
00071|026|M|derivative may need to be adjusted.|
00071|027|B||
00071|028|D|DISCUSSION:  Several controlled studies have demonstrated that concurrent|
00071|029|D|administration of erythromycin and aminophylline,(1-5) oxtriphylline,(6) and|
00071|030|D|theophylline(7-17) may reduce theophylline clearance and increase|
00071|031|D|theophylline serum levels and half-life.  Theophylline toxicity has been|
00071|032|D|reported with concomitant administration of these drugs, usually after|
00071|033|D|concurrent therapy exceeds five days.  In contrast to these reports, other|
00071|034|D|studies found that concurrent erythromycin and aminophylline(18-20) or|
00071|035|D|theophylline(21-24) had no effects on theophylline levels.|
00071|036|D|   Studies have shown that aminophylline(3) and theophylline(7-8,25) can|
00071|037|D|increase the clearance of erythromycin, resulting in lower erythromycin|
00071|038|D|levels.|
00071|039|D|   Elevated theophylline levels have also been reported during concurrent|
00071|040|D|administration of theophylline with clarithromycin.(26)|
00071|041|D|   Elevated theophylline levels have also been reported during concurrent|
00071|042|D|administration of theophylline with troleandomycin.(27-28)|
00071|043|D|   Azithromycin,(29) dirithromycin,(30-32) miocamycin,(33-34) ponsinomycin,|
00071|044|D|(35) roxithromycin,(36-38) and spiramycin(39) have been shown to not have|
00071|045|D|clinically significant effects on theophylline levels.|
00071|046|B||
00071|047|R|REFERENCES:|
00071|048|B||
00071|049|R|1.Prince RA, Wing DS, Weinberger MM, Hendeles LS, Riegelman S. Effect of|2
00071|050|R|  erythromycin on theophylline kinetics. J Allergy Clin Immunol 1981 Dec;|2
00071|051|R|  68(6):427-31.|2
00071|052|R|2.Pfeifer HJ, Greenblatt DJ, Friedman P. Effect of antibiotics on|2
00071|053|R|  theophylline kinetics in humans. Clin Pharmacol Ther 1978 Jan;23(1):124-5.|2
00071|054|R|3.Paulsen O, Hoglund P, Nilsson LG, Bengtsson HI. The interaction of|2
00071|055|R|  erythromycin with theophylline. Eur J Clin Pharmacol 1987;32(5):493-8.|2
00071|056|R|4.Reisz G, Pingleton SK, Melethil S, Ryan PB. The effect of erythromycin on|2
00071|057|R|  theophylline pharmacokinetics in chronic bronchitis. Am Rev Respir Dis|2
00071|058|R|  1983 May;127(5):581-4.|2
00071|059|R|5.Cummins LH, Kozak PP Jr, Gilllman SA. Erythromycin's effect on|2
00071|060|R|  theophylline blood level. Pediatrics 1977;59(1):144-45.|2
00071|061|R|6.Renton KW, Gray JD, Hung OR. Depression of theophylline elimination by|2
00071|062|R|  erythromycin. Clin Pharmacol Ther 1981 Sep;30(3):422-6.|2
00071|063|R|7.Zarowitz BJ, Szefler SJ, Lasezkay GM. Effect of erythromycin base on|2
00071|064|R|  theophylline kinetics. Clin Pharmacol Ther 1981 May;29(5):601-5.|2
00071|065|R|8.Iliopoulou A, Aldhous ME, Johnston A, Turner P. Pharmacokinetic|2
00071|066|R|  interaction between theophylline and erythromycin. Br J Clin Pharmacol|2
00071|067|R|  1982 Oct;14(4):495-9.|2
00071|068|R|9.LaForce CF, Miller MF, Chai H. Effect of erythromycin on theophylline|2
00071|069|R|  clearance in asthmatic children. J Pediatr 1981 Jul;99(1):153-6.|2
00071|070|R|10.May DC, Jarboe CH, Ellenburg DT, Roe EJ, Karibo J. The effects of|2
00071|071|R|   erythromycin on theophylline elimination in normal males. J Clin|2
00071|072|R|   Pharmacol 1982 Feb-Mar;22(2-3):125-30.|2
00071|073|R|11.Adebayo GI, Adewumi MO, Mabadeje AF. Time-dependent inhibition of|2
00071|074|R|   theophylline elimination by erythromycin stearate. Biopharm Drug Dispos|2
00071|075|R|   1986 Sep-Oct;7(5):479-85.|2
00071|076|R|12.Branigan TA, Robbins RA, Cady WJ, Nickols JG, Ueda CT. The effects of|2
00071|077|R|   erythromycin on the absorption and disposition of kinetics of|2
00071|078|R|   theophylline. Eur J Clin Pharmacol 1981;21(2):115-20.|2
00071|079|R|13.Richer C, Mathieu M, Bah H, Thuillez C, Duroux P, Giudicelli JF.|2
00071|080|R|   Theophylline kinetics and ventilatory flow in bronchial asthma and|2
00071|081|R|   chronic airflow obstruction: influence of erythromycin. Clin Pharmacol|2
00071|082|R|   Ther 1982 May;31(5):579-86.|2
00071|083|R|14.Kozak PP, Cummins LH, Gillman SH. Administration of erythromycin to|2
00071|084|R|   patients on theophylline. J Allergy Clin Immunol 1977 Aug;60(2):149-51.|2
00071|085|R|15.Stults BM, Felice-Johnson J, Higbee MD, Hardigan K. Effect of|2
00071|086|R|   erythromycin stearate on serum theophylline concentration in patients|2
00071|087|R|   with chronic obstructive lung disease. South Med J 1983 Jun;76(6):714-8.|2
00071|088|R|16.Bartolucci L, Gradoli C, Vincenzi V, Iapadre M, Valori C. Macrolide|2
00071|089|R|   antibiotics and serum theophylline levels in relation to the severity of|2
00071|090|R|   respiratory impairment: a comparison between the effects of erythromycin|2
00071|091|R|   and josamycin. Chemioterapia 1984 Oct;3(5):286-90.|2
00071|092|R|17.Pasic J, Jackson SH, Johnston A, Peverel-Cooper CA, Turner P, Downey K,|2
00071|093|R|   Chaput de Saintonge DM. The interaction between chronic oral slow-release|2
00071|094|R|   theophylline and single-dose intravenous erythromycin. Xenobiotica 1987|2
00071|095|R|   Apr;17(4):493-7.|2
00071|096|R|18.Pfeifer HJ, Greenblatt DJ, Friedman P. Effects of three antibiotics on|2
00071|097|R|   theophylline kinetics. Clin Pharmacol Ther 1979 Jul;26(1):36-40.|2
00071|098|R|19.Kimelblatt BJ, Slaughter RL. Lack of effect of intravenous erythromycin|2
00071|099|R|   lactobionate on theophylline clearance. J Allergy Clin Immunol 1980 Apr;|2
00071|100|R|   65(4):313-4.|2
00071|101|R|20.Vercelloni M, Cogo R, Albertini A, Granata M, Rosaschino F. Aminophylline|2
00071|102|R|   blood levels with concomitant erythromycin therapy in relapsed chronic|2
00071|103|R|   obstructive lung disease. J Int Med Res 1986;14(3):131-6.|2
00071|104|R|21.Hildebrandt R, Gundert-Remy U, Moller H, Weber E. Lack of clinically|2
00071|105|R|   important interaction between erythromycin and theophylline. Eur J Clin|2
00071|106|R|   Pharmacol 1984;26(4):485-9.|2
00071|107|R|22.Pingleton SK, Kelly SJ, Ryan PB. Lack of effect of erythromycin on|2
00071|108|R|   theophylline serum levels. Chest 1980 Aug;78(2):352.|2
00071|109|R|23.Maddux MS, Leeds NH, Organek HW, Hasegawa GR, Bauman JL. The effect of|2
00071|110|R|   erythromycin on theophylline pharmacokinetics at steady state. Chest 1982|2
00071|111|R|   May;81(5):563-5.|2
00071|112|R|24.Melethil S, Dutta A, Ryan PB, Pingleton SK, Kelly SJ. Steady state|2
00071|113|R|   urinary excretion of theophylline and its metabolites in the presence of|2
00071|114|R|   erythromycin. Res Commun Chem Pathol Pharmacol 1982 Feb;35(2):341-4.|2
00071|115|R|25.Hildebrandt R, Moller H, Gundert-Remy U. Influence of theophylline on the|2
00071|116|R|   renal clearance of erythromycin. Int J Clin Pharmacol Ther Toxicol 1987|2
00071|117|R|   Nov;25(11):601-4.|2
00071|118|R|26.Wood MJ. The tolerance and toxicity of clarithromycin. J Hosp Infect 1991|2
00071|119|R|   Sep;19 Suppl A:39-46.|2
00071|120|R|27.Weinberger M, Hudgel D, Spector S, Chidsey C. Inhibition of theophylline|2
00071|121|R|   clearance by troleandomycin. J Allergy Clin Immunol 1977 Mar;|2
00071|122|R|   59(3):228-31.|2
00071|123|R|28.Kamada AK, Hill MR, Brenner AM, Szefler SJ. Effect of low-dose|2
00071|124|R|   troleandomycin on theophylline clearance: implications for therapeutic|2
00071|125|R|   drug monitoring. Pharmacotherapy 1992;12(2):98-102.|2
00071|126|R|29.Hopkins S. Clinical toleration and safety of azithromycin. Am J Med 1991|2
00071|127|R|   Sep 12;91(3A):40S-45S.|2
00071|128|R|30.McConnell SA, Nafziger AN, Amsden GW. Lack of effect of dirithromycin on|2
00071|129|R|   theophylline pharmacokinetics in healthy volunteers. J Antimicrob|2
00071|130|R|   Chemother 1999 May;43(5):733-6.|2
00071|131|R|31.Bachmann K, Jauregui L, Sides G, Sullivan TJ. Steady-state|2
00071|132|R|   pharmacokinetics of theophylline in COPD patients treated with|2
00071|133|R|   dirithromycin. J Clin Pharmacol 1993 Sep;33(9):861-5.|2
00071|134|R|32.Bachmann K, Nunlee M, Martin M, Sullivan T, Jauregui L, DeSante K, Sides|2
00071|135|R|   GD. Changes in the steady-state pharmacokinetics of theophylline during|2
00071|136|R|   treatment with dirithromycin. J Clin Pharmacol 1990 Nov;30(11):1001-5.|2
00071|137|R|33.Dal Negro R, Turco P, Pomari C, de Conti F. Miocamycin doesn't affect|2
00071|138|R|   theophylline serum levels in COPD patients. Int J Clin Pharmacol Ther|2
00071|139|R|   Toxicol 1988 Jan;26(1):27-9.|2
00071|140|R|34.Principi N, Onorato J, Giuliani MG, Vigano A. Effect of miocamycin on|2
00071|141|R|   theophylline kinetics in children. Eur J Clin Pharmacol 1987;31(6):701-4.|2
00071|142|R|35.Couet W, Ingrand I, Reigner B, Girault J, Bizouard J, Fourtillan JB. Lack|2
00071|143|R|   of effect of ponsinomycin on the plasma pharmacokinetics of theophylline.|2
00071|144|R|   Eur J Clin Pharmacol 1989;37(1):101-4.|2
00071|145|R|36.Shimizu T, Kato M, Mochizuki H, Takei K, Maeda S, Tokuyama K, Morikawa A.|2
00071|146|R|   Roxithromycin attenuates acid-induced cough and water-induced|2
00071|147|R|   bronchoconstriction in children with asthma. J Asthma 1997;34(3):211-7.|2
00071|148|R|37.Bandera M, Fioretti M, Rimoldi R, Lazzarini A, Anelli M. Roxithromycin|2
00071|149|R|   and controlled release theophylline, an interaction study. Chemioterapia|2
00071|150|R|   1988 Oct;7(5):313-6.|2
00071|151|R|38.Saint-Salvi B, Tremblay D, Surjus A, Lefebvre MA. A study of the|2
00071|152|R|   interaction of roxithromycin with theophylline and carbamazepine. J|2
00071|153|R|   Antimicrob Chemother 1987 Nov;20 Suppl B:121-9.|2
00071|154|R|39.Debruyne D, Jehan A, Bigot MC, Lechevalier B, Prevost JN, Moulin M.|2
00071|155|R|   Spiramycin has no effect on serum theophylline in asthmatic patients. Eur|2
00071|156|R|   J Clin Pharmacol 1986;30(4):505-7.|2
00072|001|T|MONOGRAPH TITLE:  Thiopurines/Allopurinol; Oxypurinol|
00072|002|B||
00072|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00072|004|L|of severe adverse interaction.|
00072|005|B||
00072|006|A|MECHANISM OF ACTION:  Inhibition of xanthine oxidase leads to decreased|
00072|007|A|thiopurine metabolism.|
00072|008|B||
00072|009|E|CLINICAL EFFECTS:  Potentiation of thiopurine effects, with increased bone|
00072|010|E|marrow suppression.  Fatalities have been reported.|
00072|011|B||
00072|012|P|PREDISPOSING FACTORS:  Higher doses of the thiopurine would increase the|
00072|013|P|risk for severe toxicity.|
00072|014|P|   Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or|
00072|015|P|nucleotide diphosphatase (NUDT15) activity are at higher risk of|
00072|016|P|accumulating thiopurine metabolites and severe myelosuppression, since two|
00072|017|P|thiopurine metabolism pathways would be blocked.  Approximately 0.3 % of|
00072|018|P|patients of European, Latino, or African descent have mutations of the TPMT|
00072|019|P|gene resulting in little to no TPMT activity (homozygous deficiency), and|
00072|020|P|approximately 10 % have intermediate TPMT activity (heterozygous|
00072|021|P|deficiency).  NUDT15 deficiency is not seen in patients of African descent|
00072|022|P|and is seen in less than 1 % of patients of European descent.  Approximately|
00072|023|P|1 % of patients of East Asian descent, 0.5 % of patients of central/south|
00072|024|P|Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15|
00072|025|P|deficiency.  About 17 % of patients of East Asian descent, 13 % of patients|
00072|026|P|of central/south Asian descent, and 8 % of patients of Latino descent have|
00072|027|P|heterozygous NUDT15 deficiency.|
00072|028|B||
00072|029|M|PATIENT MANAGEMENT:  Due to the magnitude and severity of this interaction,|
00072|030|M|avoid the concurrent use of allopurinol and thiopurines without a dosage|
00072|031|M|adjustment of the thiopurine, especially in patients with thiopurine|
00072|032|M|S-methyltransferase (TPMT) deficiency.  Consult the thiopurine prescriber|
00072|033|M|prior to initiation of a xanthine oxidase inhibitor.|
00072|034|M|   Reduce the dose of azathioprine or mercaptopurine to one third to one|
00072|035|M|quarter of the usual dose (a 66% to 75% reduction) in patients receiving|
00072|036|M|allopurinol to decrease the risk for toxicity.  A further dose reduction or|
00072|037|M|alternative therapy is recommended in patients with low or absent TPMT|
00072|038|M|activity.  It would be prudent to reduce the dose of other thiopurines in|
00072|039|M|patients receiving allopurinol, as well as decreasing the dose of these|
00072|040|M|agents in patients taking oxypurinol.  Patients should be closely monitored|
00072|041|M|during concurrent therapy.|
00072|042|B||
00072|043|D|DISCUSSION:  The concurrent administration of either mercaptopurine or|
00072|044|D|azathioprine with allopurinol has been shown to result in increases in the|
00072|045|D|pharmacologic and toxic effects of the thiopurines.  In one study in five|
00072|046|D|patients, pretreatment with allopurinol increased the peak plasma|
00072|047|D|concentration of mercaptopurine by 500%.|
00072|048|D|   The combination of dose-adjusted thiopurines and allopurinol has been|
00072|049|D|used effectively in the treatment of auto-immune diseases such as|
00072|050|D|inflammatory bowel disease.|
00072|051|D|   Oxypurinol is the major metabolite of allopurinol and is a|
00072|052|D|non-competitive inhibitor of xanthine oxidase.|
00072|053|B||
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00072|106|R|   Improves the Outcome of Azathioprine Treatment in Chronic Eczema. Acta|2
00072|107|R|   Derm Venereol 2017 Nov 14.|2
00072|108|R|20.Moreau B, Clement P, Theoret Y, Seidman EG. Allopurinol in combination|6
00072|109|R|   with thiopurine induces mucosal healing and improves clinical and|6
00072|110|R|   metabolic outcomes in IBD. Therap Adv Gastroenterol 2017 Nov;|6
00072|111|R|   10(11):819-827.|6
00072|112|R|21.Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM,|6
00072|113|R|   Moyer AM, Evans WE, Klein TE, Antillon-Klussmann FG, Caudle KE, Kato M,|6
00072|114|R|   Yeoh AEJ, Schmiegelow K, Yang JJ. Clinical Pharmacogenetics|6
00072|115|R|   Implementation Consortium Guideline for Thiopurine Dosing  Based on TPMT|6
00072|116|R|   and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther 2019 May;|6
00072|117|R|   105(5):1095-1105.|6
00074|001|T|MONOGRAPH TITLE:  Methotrexate (low strength injection, oral)/Select|
00074|002|T|Salicylates|
00074|003|B||
00074|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00074|005|L|of severe adverse interaction.|
00074|006|B||
00074|007|A|MECHANISM OF ACTION:  Salicylates may inhibit the renal tubular excretion of|
00074|008|A|methotrexate.|
00074|009|B||
00074|010|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and salicylates may|
00074|011|E|result in an increase in the therapeutic and toxic effects of methotrexate,|
00074|012|E|leading to increased risk of severe neurotoxicity, stomatitis, and|
00074|013|E|myelosuppression, including neutropenia.|
00074|014|B||
00074|015|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
00074|016|P|- High-dose oncology regimens|
00074|017|P|- Anti-inflammatory doses of aspirin/salicylates|
00074|018|P|- impaired renal function, ascites, or pleural effusions|
00074|019|B||
00074|020|M|PATIENT MANAGEMENT:  US manufacturer prescribing information for|
00074|021|M|methotrexate states nonsteroidal anti-inflammatory drugs, including|
00074|022|M|salicylates should not be administered prior to or concomitantly with high|
00074|023|M|doses of methotrexate. If concurrent therapy is warranted, methotrexate|
00074|024|M|plasma levels should be monitored and patients should be observed for|
00074|025|M|methotrexate toxicity.  The dosage of methotrexate may need to be adjusted.|
00074|026|M|   Use caution when administering salicylates and low dose methotrexate.|
00074|027|M|Salicylate doses > or = 2 grams per day have been associated with hepatic|
00074|028|M|impairment or impaired renal elimination of methotrexate.  It would be|
00074|029|M|prudent to avoid high-dose aspirin, especially in patients with renal|
00074|030|M|impairment or near the time of methotrexate dosage (in patients receiving|
00074|031|M|weekly therapy).|
00074|032|M|   The Australian prescribing information for aspirin DL-lysine states|
00074|033|M|coadministration with methotrexate at doses of 15 mg/week or greater is|
00074|034|M|contraindicated.|
00074|035|B||
00074|036|D|DISCUSSION:  Several studies and case reports have reported increased and|
00074|037|D|prolonged methotrexate levels in patients receiving concurrent aspirin. One|
00074|038|D|study noted an effect with average weekly doses of methotrexate of 16.6 mg,|
00074|039|D|but not weekly doses of 7.5 mg. Decreased renal function has also been|
00074|040|D|reported with the combination.|
00074|041|D|   Single ingredient aspirin or buffered aspirin products with strengths <|
00074|042|D|or = to 325 mg or formulations which are associated with once daily use for|
00074|043|D|cardiovascular protection are not linked to this interaction.  Other|
00074|044|D|lower-strength aspirin formulations (e.g. headache, cough & cold, opioid|
00074|045|D|combinations) which could be consumed multiple times a day remain linked to|
00074|046|D|this interaction.|
00074|047|B||
00074|048|R|REFERENCES:|
00074|049|B||
00074|050|R|1.Liegler DG, Henderson ES, Hahn MA, Oliverio VT. The effect of organic|2
00074|051|R|  acids on renal clearance of methotrexate in man. Clin Pharmacol Ther 1969|2
00074|052|R|  Nov-Dec;10(6):849-57.|2
00074|053|R|2.Baker H. Intermittent high dose oral methotrexate therapy in psoriasis. Br|3
00074|054|R|  J Dermatol 1970 Jan;82(1):65-9.|3
00074|055|R|3.Mandel MA. The synergistic effect of salicylates on methotrexate toxicity.|2
00074|056|R|  Plast Reconstr Surg 1976 Jun;57(6):733-7.|2
00074|057|R|4.Taylor JR, Halprin KM. Effect of sodium salicylate and indomethacin on|5
00074|058|R|  methotrexate-serum albumin binding. Arch Dermatol 1977 May;113(5):588-91.|5
00074|059|R|5.Tracy TS, Krohn K, Jones DR, Bradley JD, Hall SD, Brater DC. The effects|2
00074|060|R|  of a salicylate, ibuprofen, and naproxen on the disposition of|2
00074|061|R|  methotrexate in patients with rheumatoid arthritis. Eur J Clin Pharmacol|2
00074|062|R|  1992;42(2):121-5.|2
00074|063|R|6.Harrison PV. Methotrexate-induced epidermal necrosis. Br J Dermatol 1987|3
00074|064|R|  Jun;116(6):867-9.|3
00074|065|R|7.Fries JF, Singh G, Lenert L, Furst DE. Aspirin, hydroxychloroquine, and|2
00074|066|R|  hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis.|2
00074|067|R|  Arthritis Rheum 1990 Nov;33(11):1611-9.|2
00074|068|R|8.Furst DE, Herman RA, Koehnke R, Ericksen N, Hash L, Riggs CE, Porras A,|2
00074|069|R|  Veng-Pedersen P. Effect of aspirin and sulindac on methotrexate clearance.|2
00074|070|R|  J Pharm Sci 1990 Sep;79(9):782-6.|2
00074|071|R|9.Stewart CF, Fleming RA, Germain BF, Seleznick MJ, Evans WE. Aspirin alters|2
00074|072|R|  methotrexate disposition in rheumatoid arthritis patients. Arthritis Rheum|2
00074|073|R|  1991 Dec;34(12):1514-20.|2
00074|074|R|10.Seideman P, Muller-Suur R. Renal effects of aspirin and low dose|2
00074|075|R|   methotrexate in rheumatoid arthritis. Ann Rheum Dis 1993 Aug;52(8):613-5.|2
00074|076|R|11.Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory|2
00074|077|R|   drugs on methotrexate (MTX) pharmacokinetics: impairment of renal|2
00074|078|R|   clearance of MTX at weekly maintenance doses but not at 7.5 mg. J|2
00074|079|R|   Rheumatol 1995 Nov;22(11):2072-7.|2
00074|080|R|12.Rheumatrex (methotrexate, oral) US prescribing information. Dava|1
00074|081|R|   Pharmaceuticals, Inc. February, 2013.|1
00074|082|R|13.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
00074|083|R|   Inc. March, 2018.|1
00074|084|R|14.Aspirin IV German Prescribing Information. Bayer Vital GmbH July 2019.|1
00075|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Kaluretics|
00075|002|B||
00075|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00075|004|L|take action as needed.|
00075|005|B||
00075|006|A|MECHANISM OF ACTION:  Potassium-losing diuretics may result in potassium|
00075|007|A|depletion which can predispose patients to digitalis toxicity.|
00075|008|B||
00075|009|E|CLINICAL EFFECTS:  May observe increased arrhythmias, resulting from an|
00075|010|E|increase in the cardiac response to digitalis. Symptoms of digoxin toxicity|
00075|011|E|can include anorexia, nausea, vomiting, headache, fatigue, malaise,|
00075|012|E|drowsiness, generalized muscle weakness, disorientation, hallucinations,|
00075|013|E|visual disturbances, and arrhythmias.|
00075|014|B||
00075|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
00075|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00075|017|P|risk of digoxin toxicity.|
00075|018|B||
00075|019|M|PATIENT MANAGEMENT:  Monitor serum potassium status and give potassium|
00075|020|M|replacements as needed.|
00075|021|B||
00075|022|D|DISCUSSION:  This interaction is well documented. Most patients taking|
00075|023|D|diuretics do not develop significant potassium depletion if they are on low|
00075|024|D|doses of diuretics and have adequate potassium intake.|
00075|025|B||
00075|026|R|REFERENCES:|
00075|027|B||
00075|028|R|1.Steiness E, Olesen KH. Cardiac arrhythmias induced by hypokalaemia and|2
00075|029|R|  potassium loss during maintenance digoxin therapy. Br Heart J 1976 Feb;|2
00075|030|R|  38(2):167-72.|2
00075|031|R|2.Jelliffe RW. Effect of serum potassium level upon risk of digitalis|4
00075|032|R|  toxicity. Ann Intern Med 1973;78(5):821.|4
00076|001|T|MONOGRAPH TITLE:  Digitalis Glycosides, Oral/Cholestyramine; Colestipol|
00076|002|B||
00076|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00076|004|L|take action as needed.|
00076|005|B||
00076|006|A|MECHANISM OF ACTION:  Digitalis glycosides bind to cholestyramine and|
00076|007|A|colestipol in the gastrointestinal tract reducing digitalis absorption and|
00076|008|A|enterohepatic recirculation.|
00076|009|B||
00076|010|E|CLINICAL EFFECTS:  Reduced therapeutic response to digitalis.|
00076|011|B||
00076|012|P|PREDISPOSING FACTORS:  None determined.|
00076|013|B||
00076|014|M|PATIENT MANAGEMENT:  Separate the administration times of the two drugs by|
00076|015|M|at least two hours, or more if possible.  Adjust the digitalis dose as|
00076|016|M|needed based on serum drug levels and patient response. The dosage of|
00076|017|M|digoxin may need to be increased by 20% to 40%.|
00076|018|B||
00076|019|D|DISCUSSION:  Documentation supports routine monitoring of this interaction.|
00076|020|D|Serum concentrations may increase when the cholesterol lowering resin is|
00076|021|D|discontinued. Because of the longer half-life of digitoxin over that of|
00076|022|D|digoxin, the extent of the interaction may be more profound in digitoxin.|
00076|023|B||
00076|024|R|REFERENCES:|
00076|025|B||
00076|026|R|1.Bazzano G, Bazzano GS. Digitalis intoxication. Treatment with a new|5
00076|027|R|  steroid-binding resin. JAMA 1972 May 8;220(6):828-30.|5
00076|028|R|2.Brown DD, Juhl RP, Warner SL. Decreased bioavailability of digoxin|4
00076|029|R|  produced by dietary fiber and cholestyramine. Am J Cardiol 1977 Feb;|4
00076|030|R|  39(2):297.|4
00076|031|R|3.Klotz U, Antonin KH. Biliary excretion studies with digoxin in man. Int J|2
00076|032|R|  Clin Pharmacol Biopharm 1977 Jul;15(7):332-4.|2
00076|033|R|4.Brown DD, Juhl RP, Warner SL. Decreased bioavailability of digoxin due to|2
00076|034|R|  hypocholesterolemic interventions. Circulation 1978 Jul;58(1):164-72.|2
00076|035|R|5.Cady WJ, Rehder TL, Campbell J. Use of cholestyramine resin in the|3
00076|036|R|  treatment of digitoxin toxicity. Am J Hosp Pharm 1979 Jan;36(1):92-4.|3
00076|037|R|6.Carruthers SG, Dujovne CA. Cholestyramine and spironolactone and their|2
00076|038|R|  combination in digitoxin elimination. Clin Pharmacol Ther 1980 Feb;|2
00076|039|R|  27(2):184-7.|2
00076|040|R|7.Pieroni RE, Fisher JG. Use of cholestyramine resin in digitoxin toxicity.|3
00076|041|R|  JAMA 1981 May 15;245(19):1939-40.|3
00076|042|R|8.Payne VW, Secter RA, Noback RK. Use of colestipol in a patient with|3
00076|043|R|  digoxin intoxication. Drug Intell Clin Pharm 1981 Nov;15(11):902-3.|3
00076|044|R|9.Kilgore TL, Lehmann CR. Treatment of Digoxin intoxication with colestipol.|3
00076|045|R|  South Med J 1982 Oct;75(10):1259-60.|3
00076|046|R|10.Baciewicz AM, Isaacson ML, Lipscomb GL. Cholestyramine resin in the|3
00076|047|R|   treatment of digitoxin toxicity. Drug Intell Clin Pharm 1983 Jan;|3
00076|048|R|   17(1):57-9.|3
00076|049|R|11.Kuhlmann J. Use of cholestyramine in three patients with|3
00076|050|R|   beta-acetyldigoxin, beta- methyldigoxin and digitoxin intoxication. Int J|3
00076|051|R|   Clin Pharmacol Ther Toxicol 1984 Oct;22(10):543-8.|3
00076|052|R|12.Brown DD, Schmid J, Long RA, Hull JH. A steady-state evaluation of the|2
00076|053|R|   effects of propantheline bromide and cholestyramine on the|2
00076|054|R|   bioavailability of digoxin when administered as tablets or capsules. J|2
00076|055|R|   Clin Pharmacol 1985 Jul-Aug;25(5):360-4.|2
00076|056|R|13.Henderson RP, Solomon CP. Use of cholestyramine in the treatment of|3
00076|057|R|   digoxin intoxication. Arch Intern Med 1988 Mar;148(3):745-6.|3
00076|058|R|14.Neuvonen PJ, Kivisto K, Hirvisalo EL. Effects of resins and activated|2
00076|059|R|   charcoal on the absorption of digoxin, carbamazepine and frusemide. Br J|2
00076|060|R|   Clin Pharmacol 1988 Feb;25(2):229-33.|2
00076|061|R|15.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00076|062|R|   Pharmaceuticals, Inc. August, 2018.|1
00077|001|T|MONOGRAPH TITLE:  Lithium/Thiazide Diuretics|
00077|002|B||
00077|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00077|004|L|of severe adverse interaction.|
00077|005|B||
00077|006|A|MECHANISM OF ACTION:  Lithium is eliminated unchanged by the kidney;|
00077|007|A|thiazide induced sodium elimination may lead to decreased renal clearance of|
00077|008|A|lithium.|
00077|009|B||
00077|010|E|CLINICAL EFFECTS:  Lithium has a narrow therapeutic range; even modest,|
00077|011|E|unintended increases in lithium concentration may result in lithium|
00077|012|E|toxicity.  Early symptoms of lithium toxicity may include: lethargy, muscle|
00077|013|E|weakness or stiffness, new onset or coarsening of hand tremor, vomiting,|
00077|014|E|diarrhea, confusion, ataxia, blurred vision, tinnitus and nystagmus.  Severe|
00077|015|E|toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal|
00077|016|E|failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.|
00077|017|B||
00077|018|P|PREDISPOSING FACTORS:  Risk factors for lithium toxicity include: renal|
00077|019|P|impairment or worsening of existing renal disease, dehydration, low sodium|
00077|020|P|diet, and concomitant use of multiple medications which may impair renal|
00077|021|P|elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics).|
00077|022|P|Patients who require higher therapeutic lithium levels to maintain symptom|
00077|023|P|control are particularly susceptible to these factors.|
00077|024|B||
00077|025|M|PATIENT MANAGEMENT:  If concurrent therapy cannot be avoided, monitor|
00077|026|M|closely to decrease the risk for lithium toxicity.  Evaluate renal function|
00077|027|M|and most recent lithium levels.  If renal function is not stable, it would|
00077|028|M|be prudent to withhold combination therapy until renal function is stable.|
00077|029|M|   If a thiazide diuretic is started, or if the dose is increased in a|
00077|030|M|patient stabilized on lithium therapy, consider empirically lowering the|
00077|031|M|lithium dose, and recheck lithium levels 5 to 7 days after diuretic|
00077|032|M|initiation. Adjust lithium or thiazide dose as required and continue|
00077|033|M|frequent (e.g. weekly) monitoring of lithium until levels have stabilized.|
00077|034|M|   If lithium is to be started in a patient stabilized on a thiazide|
00077|035|M|diuretic, consider starting with a lower lithium dose and titrate slowly as|
00077|036|M|half-life may be prolonged.  Monitor lithium concentrations until stabilized|
00077|037|M|on the combination.|
00077|038|M|    Counsel patient to assure they know signs and symptoms of lithium|
00077|039|M|toxicity and understand the importance of follow-up laboratory testing.|
00077|040|B||
00077|041|D|DISCUSSION:  This interaction is well documented.(1-15)|
00077|042|B||
00077|043|R|REFERENCES:|
00077|044|B||
00077|045|R|1.Thomsen K, Schou M. Renal lithium excretion in man. Am J Physiol 1968 Oct;|2
00077|046|R|  215(4):823-7.|2
00077|047|R|2.Petersen V, Hvidt S, Thomsen K, Schou M. Effect of prolonged thiazide|2
00077|048|R|  treatment on renal lithium clearance. Br Med J 1974 Jul 20;3(924):143-5.|2
00077|049|R|3.Levy ST, Forrest JN Jr, Heninger GR. Lithium-induced diabetes insipidus:|3
00077|050|R|  manic symptoms, brain and electrolyte correlates, and chlorothiazide|3
00077|051|R|  treatment. Am J Psychiatry 1973 Sep;130(9):1014-8.|3
00077|052|R|4.MacNeil S, Hanson-Nortey E, Paschalis C, Eastwood PR, Jenner FA. Letter:|6
00077|053|R|  Diuretics during lithium therapy. Lancet 1975 Jun 7;1(7919):1295-6.|6
00077|054|R|5.Himmelhoch JM, Forrest J, Neil JF, Detre TP. Thiazide-lithium synergy in|3
00077|055|R|  refractory mood swings. Am J Psychiatry 1977 Feb;134(2):149-52.|3
00077|056|R|6.Himmelhoch JM, Poust RI, Mallinger AG, Hanin I, Neil JF. Adjustment of|3
00077|057|R|  lithium dose during lithium-chlorothiazide therapy. Clin Pharmacol Ther|3
00077|058|R|  1977 Aug;22(2):225-7.|3
00077|059|R|7.Solomon K. Combined use of lithium and diuretics. South Med J 1978 Sep;|3
00077|060|R|  71(9):1098-9, 1104.|3
00077|061|R|8.Jefferson JW, Kalin NH. Serum lithium levels and long-term diuretic use.|2
00077|062|R|  JAMA 1979 Mar 16;241(11):1134-6.|2
00077|063|R|9.Maletzky BM. Enhancing the efficacy of lithium treatment by combined use|2
00077|064|R|  with diuretics and low sodium diets: a preliminary report. J Clin|2
00077|065|R|  Psychiatry 1979 Jul;40(7):317-22.|2
00077|066|R|10.Solomon JG. Lithium toxicity precipitated by a diuretic. Psychosomatics|3
00077|067|R|   1980 May;21(5):425, 429.|3
00077|068|R|11.Mehta BR, Robinson BH. Lithium toxicity induced by|3
00077|069|R|   triamterene-hydrochlorothiazide. Postgrad Med J 1980 Nov;56(661):783-4.|3
00077|070|R|12.Constandis DD, Schriever HG. Severe lithium-induced diabetes insipidus in|3
00077|071|R|   a surgical patient treated with hydrochlorothiazide. Am J Surg 1981 Jun;|3
00077|072|R|   141(6):741-3.|3
00077|073|R|13.Nurnberger JI Jr. Diuretic-induced lithium toxicity presenting as mania.|3
00077|074|R|   J Nerv Ment Dis 1985 May;173(5):316-8.|3
00077|075|R|14.Dorevitch A, Baruch E. Lithium toxicity induced by combined amiloride|3
00077|076|R|   HCl-hydrochlorothiazide administration. Am J Psychiatry 1986 Feb;|3
00077|077|R|   143(2):257-8.|3
00077|078|R|15.Hanna ME, Lobao CB, Stewart JT. Severe lithium toxicity associated with|3
00077|079|R|   indapamide therapy. J Clin Psychopharmacol 1990 Oct;10(5):379-80.|3
00077|080|R|16.Lithobid (lithium carbonate) US prescribing information. ANI|1
00077|081|R|   Pharmaceuticals, Inc. May, 2018.|1
00080|001|T|MONOGRAPH TITLE:  Potassium Supplements/Potassium Sparing Diuretics|
00080|002|B||
00080|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00080|004|L|of severe adverse interaction.|
00080|005|B||
00080|006|A|MECHANISM OF ACTION:  Decreased renal excretion of potassium, resulting from|
00080|007|A|administration of a potassium sparing diuretic.|
00080|008|B||
00080|009|E|CLINICAL EFFECTS:  May observe hyperkalemia which may be severe or even|
00080|010|E|fatal.|
00080|011|B||
00080|012|P|PREDISPOSING FACTORS:  Renal function impairment.|
00080|013|B||
00080|014|M|PATIENT MANAGEMENT:  If both drugs are administered, monitor potassium|
00080|015|M|levels. Adjust the dose of the drugs accordingly. This combination should|
00080|016|M|probably be avoided if possible.|
00080|017|B||
00080|018|D|DISCUSSION:  The interaction is well documented. Patients with decreased|
00080|019|D|renal function are especially at risk of developing hyperkalemia from this|
00080|020|D|drug combination. A commonly held belief is that a potassium sparing|
00080|021|D|diuretic formulated in combination with a thiazide diuretic, such as|
00080|022|D|Dyazide, will not exhibit this interaction. Although the likelihood of|
00080|023|D|hyperkalemia occurring may be reduced somewhat, a danger still exists.|
00080|024|B||
00080|025|R|REFERENCES:|
00080|026|B||
00080|027|R|1.Shapiro S, Slone D, Lewis GP, Jick H. Fatal drug reactions among medical|3
00080|028|R|  inpatients. JAMA 1971 Apr 19;216(3):467-72.|3
00080|029|R|2.Simborg DW. Medication prescribing on a university medical service-the|3
00080|030|R|  incidence of drug combinations with potential adverse interactions. Johns|3
00080|031|R|  Hopkins Med J 1976 Jul;139(1):23-6.|3
00081|001|T|MONOGRAPH TITLE:  Thiazide & Related Diuretics/Cholestyramine; Colestipol|
00081|002|B||
00081|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00081|004|L|take action as needed.|
00081|005|B||
00081|006|A|MECHANISM OF ACTION:  Cholestyramine and colestipol, anionic exchange|
00081|007|A|resins, bind thiazides and furosemide, preventing their absorption.|
00081|008|B||
00081|009|E|CLINICAL EFFECTS:  Concurrent administration may result in decreased|
00081|010|E|absorption of the diuretic, as well as decreased clinical effects. Decreased|
00081|011|E|absorption of furosemide by 80-90% has been reported.|
00081|012|B||
00081|013|P|PREDISPOSING FACTORS:  None determined.|
00081|014|B||
00081|015|M|PATIENT MANAGEMENT:  Available data suggest that colestipol may be|
00081|016|M|preferable to cholestyramine. Separating administration times lessens the|
00081|017|M|the extent of this interaction but still remains significant. Separate the|
00081|018|M|administration of cholestyramine and the thiazide by at least four hours and|
00081|019|M|that of colestipol by at least two hours. Separate the administration of|
00081|020|M|furosemide and cholestyramine or colestipol by two to three hours.|
00081|021|B||
00081|022|D|DISCUSSION:  Administration of cholestyramine or colestipol decreased total|
00081|023|D|urinary excretion of hydrochlorothiazide by 85% and 43% respectively.  These|
00081|024|D|studies indicate that no dosing schedule will eliminate this interaction.|
00081|025|D|Even four hours of separation reduces the absorption of hydrochlorothiazide|
00081|026|D|by 35%. Similar reductions occurred to serum hydrochlorothiazide|
00081|027|D|concentrations. In a study in six subjects, the concurrent administration of|
00081|028|D|cholestyramine and furosemide resulted in a decrease in furosemide|
00081|029|D|area-under-curve (AUC) by 90% and a decrease in furosemide's diuretic|
00081|030|D|effects.  Concurrent administration of furosemide and colestipol resulted in|
00081|031|D|a decrease in furosemide AUC by 80% and a decrease in furosemide's diuretic|
00081|032|D|effects.|
00081|033|B||
00081|034|R|REFERENCES:|
00081|035|B||
00081|036|R|1.Kauffman RE, Azarnoff DL. Effect of colestipol on gastrointestinal|2
00081|037|R|  absorption of chlorothiazide in man. Clin Pharmacol Ther 1973 Sep-Oct;|2
00081|038|R|  14(5):886-90.|2
00081|039|R|2.Hunninghake DB, King S. Effect of cholestyramine and colestipol on the|4
00081|040|R|  absorption of methyldopa and hydrochlorothiazide. Pharmacologist 1978;|4
00081|041|R|  20:220.|4
00081|042|R|3.LaCroix K, King S, Hunninghake DB. Effect of dosing schedules of|4
00081|043|R|  cholestyramine on the absorption of hydrochlorothiazide. Pharmacologist|4
00081|044|R|  1979;21:263.|4
00081|045|R|4.Hunninghake DB, King S, LaCroix K. The effect of cholestyramine and|2
00081|046|R|  colestipol on the absorption of hydrochlorothiazide. Int J Clin Pharmacol|2
00081|047|R|  Ther Toxicol 1982 Apr;20(4):151-4.|2
00081|048|R|5.Hunninghake DB, Hibbard DM. Influence of time intervals for cholestyramine|2
00081|049|R|  dosing on the absorption of hydrochlorothiazide. Clin Pharmacol Ther 1986|2
00081|050|R|  Mar;39(3):329-34.|2
00081|051|R|6.Neuvonen PJ, Kivisto K, Hirvisalo EL. Effects of resins and activated|2
00081|052|R|  charcoal on the absorption of digoxin, carbamazepine and frusemide. Br J|2
00081|053|R|  Clin Pharmacol 1988 Feb;25(2):229-33.|2
00083|001|T|MONOGRAPH TITLE:  Penicillamine, Oral/Polyvalent Cations|
00083|002|B||
00083|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00083|004|L|take action as needed.|
00083|005|B||
00083|006|A|MECHANISM OF ACTION:  Penicillamine chelates with polyvalent cations such as|
00083|007|A|aluminum, calcium, iron, magnesium, and zinc in the GI tract reducing the|
00083|008|A|absorption of the penicillamine.|
00083|009|B||
00083|010|E|CLINICAL EFFECTS:  Reduced (to 30% of fasting) bioavailability of|
00083|011|E|penicillamine with decreased pharmacologic response.|
00083|012|B||
00083|013|P|PREDISPOSING FACTORS:  None determined.|
00083|014|B||
00083|015|M|PATIENT MANAGEMENT:  In order to assure systemic absorption and maximal|
00083|016|M|effectiveness from penicillamine, counsel patient to separate penicillamine|
00083|017|M|by at least 1 hour before or 1 hours after any medications or products|
00083|018|M|containing polyvalent cations such as antacids or mineral supplements.|
00083|019|M|   Monitor clinical status for decreased effectiveness and adjust the|
00083|020|M|penicillamine dose if necessary.|
00083|021|B||
00083|022|D|DISCUSSION:  Clinical studies with polyvalent cations have not been|
00083|023|D|conducted.|
00083|024|D|   Multivitamins with low doses of cations including iron and zinc may|
00083|025|D|decrease penicillamine absorption so insure patient is aware of the risks.|
00083|026|B||
00083|027|R|REFERENCES:|
00083|028|B||
00083|029|R|1.Cuprimine (penicillamine) US prescribing information. Bausch Health US,|1
00083|030|R|  LLC October, 2020.|1
00083|031|R|2.Cuprimine (penicillamine) US prescribing information. Merck & Co., Inc.|1
00083|032|R|  March, 2004.|1
00083|033|R|3.Lyle WH. Penicillamine and iron. Lancet 1976 Aug 21;2(7982):420.|3
00083|034|R|4.Osman MA, Patel RB, Schuna A, Sundstrom WR, Welling PG. Reduction in oral|2
00083|035|R|  penicillamine absorption by food, antacid, and ferrous sulfate. Clin|2
00083|036|R|  Pharmacol Ther 1983 Apr;33(4):465-70.|2
00083|037|R|5.Muijsers AO, van de Stadt RJ, Henrichs AM, Ament HJ, van der Korst JK.|2
00083|038|R|  D-penicillamine in patients with rheumatoid arthritis. Serum levels,|2
00083|039|R|  pharmacokinetic aspects, and correlation with clinical course and side|2
00083|040|R|  effects. Arthritis Rheum 1984 Dec;27(12):1362-9.|2
00084|001|T|MONOGRAPH TITLE:  Cyclosporine/Hydantoins (mono deleted 11/01/2012)|
00084|002|B||
00084|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00084|004|L|of severe adverse interaction.|
00084|005|B||
00084|006|A|MECHANISM OF ACTION:  Hydantoins accelerate cyclosporine metabolism. It is|
00084|007|A|conceivable that bioavailability is also decreased due to enhanced first|
00084|008|A|pass metabolism.|
00084|009|B||
00084|010|E|CLINICAL EFFECTS:  A substantial (50%) reduction in average cyclosporine|
00084|011|E|blood levels occurs. This could lead to therapeutic failure (ie. graft|
00084|012|E|rejection).|
00084|013|B||
00084|014|P|PREDISPOSING FACTORS:  None determined.|
00084|015|B||
00084|016|M|PATIENT MANAGEMENT:  Increase the cyclosporine dose if necessary. Monitor|
00084|017|M|blood levels if available.|
00084|018|B||
00084|019|D|DISCUSSION:  This interaction is likely to occur. Trough cyclosporine|
00084|020|D|concentrations have been found to decrease within 48 hours after starting|
00084|021|D|phenytoin even when the dose of cyclosporine is increased. Conversely,|
00084|022|D|cyclosporine concentrations may increase when the hydantoin is discontinued.|
00084|023|D|The effect of the hydantoin on cyclosporine may reverse over a period of one|
00084|024|D|to three weeks after stopping the hydantoin. Monitor these patients for|
00084|025|D|cyclosporine excess and adjust the dose as needed.|
00084|026|B||
00084|027|R|REFERENCES:|
00084|028|B||
00084|029|R|1.Keown PA, Stiller CR, Laupacis AL, Howson W, Coles R, Stawecki M, Koegler|2
00084|030|R|  J, Carruthers G, McKenzie N, Sinclair NR. The effects and side effects of|2
00084|031|R|  cyclosporine: relationship to drug pharmacokinetics. Transplant Proc 1982|2
00084|032|R|  Dec;14(4):659-61.|2
00084|033|R|2.Freeman DJ, Laupacis A, Keown PA, Stiller CR, Carruthers SG. Evaluation of|2
00084|034|R|  cyclosporin-phenytoin interaction with observations on cyclosporin|2
00084|035|R|  metabolites. Br J Clin Pharmacol 1984 Dec;18(6):887-93.|2
00084|036|R|3.Keown PA, Laupacis A, Carruthers G, Stawecki M, Koegler J, McKenzie FN,|2
00084|037|R|  Wall W, Stiller CR. Interaction between phenytoin and cyclosporine|2
00084|038|R|  following organ transplantation. Transplantation 1984 Sep;38(3):304-6.|2
00084|039|R|4.Rowland M, Gupta SK. Cyclosporin-phenytoin interaction: re-evaluation|2
00084|040|R|  using metabolite data. Br J Clin Pharmacol 1987 Sep;24(3):329-34.|2
00085|001|T|MONOGRAPH TITLE:  NSAIDs/Corticosteroids|
00085|002|B||
00085|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00085|004|L|take action as needed.|
00085|005|B||
00085|006|A|MECHANISM OF ACTION:  Concurrent use of NSAIDs and corticosteroids result in|
00085|007|A|additive risk of GI ulceration.|
00085|008|B||
00085|009|E|CLINICAL EFFECTS:  Concurrent use of NSAIDs and corticosteroids may increase|
00085|010|E|the incidence and/or severity of GI irritation or ulceration, including|
00085|011|E|increasing the risk for bleeding.|
00085|012|B||
00085|013|P|PREDISPOSING FACTORS:  Risk of GI bleed may be increased in patients who are|
00085|014|P|of older age, in poor health status, or who use alcohol or smoke.  Risk may|
00085|015|P|also be increased by concurrent use of anticoagulants, antiplatelets,|
00085|016|P|selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine|
00085|017|P|reuptake inhibitors (SNRIs); with longer duration of NSAID use; and with|
00085|018|P|prior history of peptic ulcer disease and/or GI bleeding.|
00085|019|P|   The risk for bleeding episodes may be greater in patients with|
00085|020|P|disease-associated factors (e.g. thrombocytopenia, advanced liver disease).|
00085|021|B||
00085|022|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy carefully|
00085|023|M|for signs of gastrointestinal ulceration.   Use the lowest effective NSAID|
00085|024|M|dose for the shortest duration possible.|
00085|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00085|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00085|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00085|028|M|patients with any symptoms.|
00085|029|M|   Instruct patients to report signs of GI bleeding such as black, tarry|
00085|030|M|stools; "coffee ground" vomit; nausea; or stomach/abdominal pain.|
00085|031|B||
00085|032|D|DISCUSSION:  Concurrent use of NSAIDs and corticosteroids increase the risk|
00085|033|D|of GI bleeding.|
00085|034|B||
00085|035|R|REFERENCES:|
00085|036|B||
00085|037|R|1.Emmanuel JH, Montgomery RD. Gastric ulcer and the anti-arthritic drugs.|3
00085|038|R|  Postgrad Med J 1971 Apr;47(546):227-32.|3
00085|039|R|2.Indocin (indomethacin) US prescribing information. Merck & Co., Inc.|1
00085|040|R|  March, 2019.|1
00085|041|R|3.Celebrex (celecoxib) US prescribing information. Pfizer Inc. May, 2019.|1
00085|042|R|4.Feldene (piroxicam) US prescribing information. Pfizer Inc. May, 2019.|1
00086|001|T|MONOGRAPH TITLE:  Salicylates/Corticosteroids (mono deleted 04/15/2025)|
00086|002|B||
00086|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00086|004|L|take action as needed.|
00086|005|B||
00086|006|A|MECHANISM OF ACTION:  Unknown. However, it is speculated that renal and|
00086|007|A|hepatic elimination of salicylates may be increased by corticosteroids.|
00086|008|B||
00086|009|E|CLINICAL EFFECTS:  Decreased serum salicylate levels with reduced|
00086|010|E|therapeutic response. Salicylate intoxication may occur when corticosteroid|
00086|011|E|dosage is decreased in patients taking large doses of salicylates.|
00086|012|E|Gastrointestinal ulceration may be increased as well.|
00086|013|B||
00086|014|P|PREDISPOSING FACTORS:  None determined.|
00086|015|B||
00086|016|M|PATIENT MANAGEMENT:  Adjust the salicylate dose as needed based on|
00086|017|M|salicylate levels and patient response. Caution when discontinuing|
00086|018|M|corticosteroids, as a decrease in salicylate dose may be needed to avoid|
00086|019|M|salicylate toxicity.|
00086|020|B||
00086|021|D|DISCUSSION:  Additional documentation is necessary to confirm this potential|
00086|022|D|interaction.|
00086|023|B||
00086|024|R|REFERENCES:|
00086|025|B||
00086|026|R|1.Klinenberg JR, Miller F. Effect of corticosteroids on blood salicylate|3
00086|027|R|  concentration. JAMA 1965 Nov 8;194(6):601-4.|3
00086|028|R|2.Elliott HC. Reduced adrenocortical steroid excretion rates in man|2
00086|029|R|  following aspirin administration. Metabolism 1962 Sep;11(9):1015-8.|2
00086|030|R|3.Baer PA, Shore A, Ikeman RL. Transient fall in serum salicylate levels|2
00086|031|R|  following intraarticular injection of steroid in patients with rheumatoid|2
00086|032|R|  arthritis. Arthritis Rheum 1987 Mar;30(3):345-7.|2
00086|033|R|4.Edelman J, Potter JM, Hackett LP. The effect of intra-articular steroids|2
00086|034|R|  on plasma salicylate concentrations. Br J Clin Pharmacol 1986 Mar;|2
00086|035|R|  21(3):301-7.|2
00086|036|R|5.Lazor JM, Paton TW, Walker SE, Manuel MA. The effect of corticosteroids on|4
00086|037|R|  salicylic acid disposition. Clin Pharmacol Ther 1987 Feb;39(2):205.|4
00086|038|R|6.Koren G, Roifman C, Gelfand E, Lavi S, Suria D, Stein L.|3
00086|039|R|  Corticosteroids-salicylate interaction in a case of juvenile rheumatoid|3
00086|040|R|  arthritis. Ther Drug Monit 1987 Jun;9(2):177-9.|3
00087|001|T|MONOGRAPH TITLE:  Mixed & Indirect Sympathomimetics; Oral|
00087|002|T|Phenylephrine/MAOIs|
00087|003|B||
00087|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00087|005|L|is contraindicated and generally should not be dispensed or administered to|
00087|006|L|the same patient.|
00087|007|B||
00087|008|A|MECHANISM OF ACTION:  Catecholamine stores increased by MAOIs can be|
00087|009|A|released by indirect acting sympathomimetics such as ephedrine and|
00087|010|A|amphetamine. MAO inhibitors also interfere with gut and liver metabolism of|
00087|011|A|direct acting sympathomimetics (e.g oral phenylephrine).|
00087|012|B||
00087|013|E|CLINICAL EFFECTS:  Concurrent use of MAOIs may result in potentiation of|
00087|014|E|sympathomimetic effects, which may result in headaches, hypertensive crisis,|
00087|015|E|toxic neurological effects, and malignant hyperpyrexia.  Fatalities have|
00087|016|E|occurred.|
00087|017|B||
00087|018|P|PREDISPOSING FACTORS:  None determined.|
00087|019|B||
00087|020|M|PATIENT MANAGEMENT:  Concurrent use of monoamine oxidase inhibitors and|
00087|021|M|sympathomimetics is contraindicated.  The manufacturers of sympathomimetic|
00087|022|M|agents recommend waiting 14 days after discontinuation of MAO inhibitors|
00087|023|M|before initiating the sympathomimetic.|
00087|024|B||
00087|025|D|DISCUSSION:  Indirect acting sympathomimetic amines may cause abrupt|
00087|026|D|elevation of blood pressure when administered to patients taking monoamine|
00087|027|D|oxidase inhibitors, resulting in a potentially fatal hypertensive crisis.|
00087|028|D|   Mixed (direct and indirect) acting sympathomimetics have also been shown|
00087|029|D|to interact with monoamine oxidase inhibitors depending on their degree of|
00087|030|D|indirect action.  The direct-acting sympathomimetics have not been reported|
00087|031|D|to interact.  Dopamine is metabolized by monoamine oxidase, and its pressor|
00087|032|D|effect is enhanced by monoamine oxidase inhibitors.|
00087|033|D|   Since procarbazine, an antineoplastic agent, is a weak monoamine oxidase|
00087|034|D|inhibitor, hypertensive reactions may result from its concurrent use with|
00087|035|D|indirect and mixed acting sympathomimetics.|
00087|036|D|   Furazolidone, an antibacterial with monoamine oxidase inhibitor action,|
00087|037|D|has also been shown to interact with indirect acting sympathomimetics.|
00087|038|D|   Linezolid is another antibacterial with monoamine oxidase inhibitor|
00087|039|D|properties.|
00087|040|D|   Metaxalone is a weak inhibitor of MAO.|
00087|041|D|   Foods containing large amounts of tyramine have also been implicated in|
00087|042|D|this interaction.|
00087|043|D|   Methylene blue, when administered intravenously, has been shown to reach|
00087|044|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
00087|045|D|   At recommended dosages, rasagiline, oral selegiline, and transdermal|
00087|046|D|selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages|
00087|047|D|they have been shown to lose their selectivity.|
00087|048|D|   One or more of the drug pairs linked to this monograph have been included|
00087|049|D|in a list of interactions that should be considered "high-priority" for|
00087|050|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00087|051|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00087|052|D|Coordinator (ONC) for Health Information Technology.|
00087|053|B||
00087|054|R|REFERENCES:|
00087|055|B||
00087|056|R|1.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
00087|057|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
00087|058|R|2.Pettinger WA, Soyangco FG, Oates JA. Inhibition of monoamine oxidase in|2
00087|059|R|  man by furazolidone. Clin Pharmacol Ther 1968 Jul-Aug;9(4):442-7.|2
00087|060|R|3.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
00087|061|R|  2007.|1
00087|062|R|4.Adderall XR (amphetamine) US prescribing information. Shire US Inc. April,|1
00087|063|R|  2015.|1
00087|064|R|5.Marplan (isocarboxazid) US prescribing information. Validus|1
00087|065|R|  Pharmaceuticals August, 2007.|1
00087|066|R|6.Ritalin LA (methylphenidate hydrochloride) US prescribing information.|1
00087|067|R|  Novartis Pharmaceuticals Corporation June, 2021.|1
00087|068|R|7.Focalin (dexmethylphenidate hydrochloride) US prescribing information.|1
00087|069|R|  Novartis Pharmaceuticals Corporation June, 2021.|1
00087|070|R|8.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00087|071|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00087|072|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00087|073|R|9.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00087|074|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00087|075|R|  2000 Jun;56(3):247-50.|2
00087|076|R|10.Parnate (tranylcypromine sulfate) US prescribing information.|1
00087|077|R|   GlaxoSmithKline January 4, 2018.|1
00087|078|R|11.Cuthbert MF, Greenberg MP, Morley SW. Cough and cold remedies: a|2
00087|079|R|   potential danger to patients on monoamine oxidase inhibitors. Br Med J|2
00087|080|R|   1969 Feb 15;1(5641):404-6.|2
00087|081|R|12.Smookler S, Bermudez AJ. Hypertensive crisis resulting from an MAO|3
00087|082|R|   inhibitor and an over-the-counter appetite suppressant. Ann Emerg Med|3
00087|083|R|   1982 Sep;11(9):482-4U.|3
00087|084|R|13.Mason AM, Buckle RM. "Cold" cures and monoamine-oxidase inhibitors. Br|3
00087|085|R|   Med J 1969 Mar 29;1(5647):845-6.|3
00087|086|R|14.LLOYD JT, WALKER DR. DEATH AFTER COMBINED DEXAMPHETAMINE AND PHENELZINE.|3
00087|087|R|   Br Med J 1965 Jul 17;2(5454):168-9.|3
00087|088|R|15.Krisko I, Lewis E, Johnson JE 3rd. Severe hyperpyrexia due to|3
00087|089|R|   tranylcypromine-amphetamine toxicity. Ann Intern Med 1969 Mar;|3
00087|090|R|   70(3):559-64.|3
00087|091|R|16.Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN.|2
00087|092|R|   Interactions between sympathomimetic amines and antidepressant agents in|2
00087|093|R|   man. Br Med J 1973 Feb 10;1(5849):311-5.|2
00087|094|R|17.Elis J, Laurence DR, Mattie H, Prichard BN. Modification by monoamine|2
00087|095|R|   oxidase inhibitors of the effect of some sympathomimetics on blood|2
00087|096|R|   pressure. Br Med J 1967 Apr 8;2(5544):75-8.|2
00087|097|R|18.HORWITZ D, GOLDBERG LI, SJOERDSMA A. Increased blood pressure responses|2
00087|098|R|   to dopamine and norepinephrine produced by monoamine oxidase inhibitors|2
00087|099|R|   in man. J Lab Clin Med 1960 Nov;56:747-53.|2
00087|100|R|19.Cuthbert MF, Vere DW. Potentiation of the cardiovascular effects of some|2
00087|101|R|   catecholamines by a monoamine oxidase inhibitor. Br J Pharmacol 1971 Oct;|2
00087|102|R|   43(2):471P-472P.|2
00087|103|R|20.Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function.|5
00087|104|R|   Pharmacol Rev 1966 Jun;18(2):925-64.|5
00087|105|R|21.GOLDBERG LI. MONOAMINE OXIDASE INHIBITORS. ADVERSE REACTIONS AND POSSIBLE|6
00087|106|R|   MECHANISMS. JAMA 1964 Nov 2;190:456-62.|6
00087|107|R|22.Kopin IJ. Biochemical aspects of release of norepinephrine and other|5
00087|108|R|   amines from sympathetic nerve endings. Pharmacol Rev 1966 Mar;|5
00087|109|R|   18(1):513-23.|5
00087|110|R|23.BETHUNE HC, BURRELL RH, CULPAN RH, OGG GJ. VASCULAR CRISES ASSOCIATED|6
00087|111|R|   WITH MONOAMINE-OXIDASE INHIBITORS. Am J Psychiatry 1964 Sep;121:245-8.|6
00087|112|R|24.O'Dea K, Rand MJ. Interaction between amphetamine and monoamine oxidase|5
00087|113|R|   inhibitors. Eur J Pharmacol 1969 May;6(2):115-20.|5
00087|114|R|25.Eldepryl (selegiline) US prescribing information. Somerset|1
00087|115|R|   Pharmaceuticals February, 1997.|1
00087|116|R|26.Emsam (selegline) US prescribing information. Somerset July, 2017.|1
00087|117|R|27.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
00087|118|R|   June, 2020.|1
00087|119|R|28.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00087|120|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00087|121|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00087|122|R|   19(5):735-43.|6
00087|123|R|29.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00087|124|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00087|125|R|   Feb;34(2):346.e5-6.|3
00087|126|R|30.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00087|127|R|   Pfizer Inc. January, 2024.|1
00088|001|T|MONOGRAPH TITLE:  Tricyclic; Tetracyclic Compounds/MAOIs|
00088|002|B||
00088|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00088|004|L|is contraindicated and generally should not be dispensed or administered to|
00088|005|L|the same patient.|
00088|006|B||
00088|007|A|MECHANISM OF ACTION:  Some MAO inhibitors may enhance the effects of|
00088|008|A|tricyclic and tetracyclic compounds indirectly through inhibition of|
00088|009|A|microsomal enzymes.(1)  Tricyclic and tetracyclic compounds may sensitize|
00088|010|A|post-synaptic receptors to amines that are accumulating extraneuronally as a|
00088|011|A|result of MAO inhibition.(2)|
00088|012|A|   Similarity between cyclobenzaprine and TCAs warrants consideration of TCA|
00088|013|A|interactions for cyclobenzaprine.(6)  Mirtazapine, a tetracyclic|
00088|014|A|antidepressant, should also be considered for this interaction.(7)|
00088|015|A|   Furazolidone is known to inhibit MAO.|
00088|016|B||
00088|017|E|CLINICAL EFFECTS:  Concurrent use may result in a severe reaction including|
00088|018|E|hyperpyrexia, convulsions, excitability, fluctuations in blood pressure,|
00088|019|E|convulsions, grand mal seizures, serotonin syndrome, coma, and|
00088|020|E|death.(1,3-10)|
00088|021|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
00088|022|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
00088|023|E|rigidity.(11)|
00088|024|B||
00088|025|P|PREDISPOSING FACTORS:  High doses of tricyclics or tetracyclics, or|
00088|026|P|concurrent use of multiple drugs which increase CNS serotonin levels may|
00088|027|P|increase risk for serotonin syndrome.|
00088|028|B||
00088|029|M|PATIENT MANAGEMENT:  The concurrent use of tricyclic antidepressants,|
00088|030|M|cyclobenzaprine or mirtazapine and MAO inhibitors is contraindicated by the|
00088|031|M|manufacturers of tricyclic antidepressants, cyclobenzaprine, mirtazapine,|
00088|032|M|and tranylcypromine.(1,3-10)|
00088|033|M|   The manufacturers of tricyclic antidepressants, cyclobenzaprine and|
00088|034|M|mirtazapine recommend at least 14 days between switching therapies.(1,3-9)|
00088|035|M|The manufacturer of tranylcypromine recommends a medication-free interval of|
00088|036|M|at least a week when initiating tranylcypromine in patients who have|
00088|037|M|previously received a tricyclic antidepressant, then initiating|
00088|038|M|tranylcypromine at a reduced dosage of 50% for one week.(10)|
00088|039|M|   The US manufacturer of phenelzine states that at least 14 days should|
00088|040|M|elapse between the discontinuation of phenelzine and the initiation of|
00088|041|M|another antidepressant.  If phenelzine is used concurrently with or within|
00088|042|M|10 days of another antidepressant, the patient should be cautioned regarding|
00088|043|M|the possibility of an adverse drug interaction.(8)|
00088|044|M|   The US manufacturer of selegiline states that at least 14 days should|
00088|045|M|elapse between the discontinuation of selegiline and the initiation of a|
00088|046|M|tricyclic antidepressant.(9)|
00088|047|M|   In emergency situations in patients maintained on tricyclics or|
00088|048|M|tetracyclics, weigh the availability and safety of alternatives to methylene|
00088|049|M|blue against the risk of serotonin syndrome.  If methylene blue therapy is|
00088|050|M|required, the patient's tricyclic, cyclobenzaprine or tetracyclic should be|
00088|051|M|immediately discontinued.  Patients should be monitored for serotonin|
00088|052|M|syndrome for 2 weeks or until 24 hours after the last dose of methylene|
00088|053|M|blue, whichever comes first.(12)|
00088|054|M|   In non-emergency situations in patients maintained on tricyclics,|
00088|055|M|cyclobenzaprine or tetracyclics when methylene blue therapy is planned,|
00088|056|M|discontinue the patient's tricyclic or tetracyclic at least 2 weeks in|
00088|057|M|advance of methylene blue therapy.  The patient's tricyclic or tetracyclic|
00088|058|M|therapy may be resumed 24 hours after the last dose of linezolid or|
00088|059|M|methylene blue.(12)|
00088|060|M|   Do not initiate tricyclic, cyclobenzaprine or tetracyclic therapy in|
00088|061|M|patients receiving methylene blue until 24 hours after the last dose of|
00088|062|M|these agents.(12)|
00088|063|M|   If concurrent therapy is warranted, patients should be monitored for|
00088|064|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00088|065|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00088|066|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00088|067|M|coordination, or severe diarrhea.|
00088|068|B||
00088|069|D|DISCUSSION:  It should be noted that if this interaction occurs, the|
00088|070|D|consequences will be immediate and severe.  Effects may continue to be seen|
00088|071|D|for several days after discontinuing the MAOI.|
00088|072|D|   The interaction has been reported with tricyclic antidepressants and|
00088|073|D|selegiline.(9)|
00088|074|D|   Methylene blue, when administered intravenously, has been shown to reach|
00088|075|D|sufficient concentrations to be a potent inhibitor of MAO-A.(14,15)|
00088|076|D|   Metaxalone is a weak inhibitor of MAO.(34,35)|
00088|077|D|   The FDA AERS contains reports of serotonin syndrome with concurrent|
00088|078|D|injectable methylene blue and citalopram, clomipramine, escitalopram,|
00088|079|D|desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine,|
00088|080|D|paroxetine, sertraline, and venlafaxine.  The risk of serotonin syndrome|
00088|081|D|with other psychiatric drugs is unclear.(13)|
00088|082|D|   One or more of the drug pairs linked to this monograph have been included|
00088|083|D|in a list of interactions that should be considered "high-priority" for|
00088|084|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00088|085|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00088|086|D|Coordinator (ONC) for Health Information Technology.|
00088|087|B||
00088|088|R|REFERENCES:|
00088|089|B||
00088|090|R|1.Manerix (moclobemide) Canadian prescribing information. Hoffmann-La Roche|1
00088|091|R|  Limited May 9, 1995.|1
00088|092|R|2.Blier P, de Montigny C, Chaput Y. A role for the serotonin system in the|6
00088|093|R|  mechanism of action of antidepressant  treatments: preclinical evidence. J|6
00088|094|R|  Clin Psychiatry 1990 Apr;51 Suppl:14-20; discussion 21.|6
00088|095|R|3.Amitriptyline hydrochloride, US prescribing information. Sandoz Inc.|1
00088|096|R|  January, 2010.|1
00088|097|R|4.Anafranil (clompiramine hydrochloride) US prescribing information.|1
00088|098|R|  Mallinckrodt Inc. May 10, 2019.|1
00088|099|R|5.Pamelor (nortriptyline hydrochloride) US prescribing information.|1
00088|100|R|  Mallinckrodt Inc. October, 2012.|1
00088|101|R|6.Amrix (cyclobenzaprine extended release) US prescribing information. Teva|1
00088|102|R|  Pharmaceuticals Ltd. May, 2016.|1
00088|103|R|7.Remeron (mirtazapine) US prescribing information. Organon Inc. November,|1
00088|104|R|  2021.|1
00088|105|R|8.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
00088|106|R|  2007.|1
00088|107|R|9.Zelapar (selegiline hydrochloride) US prescribing information. Valeant|1
00088|108|R|  Pharmaceuticals June, 2021.|1
00088|109|R|10.Parnate (tranylcypromine sulfate) US prescribing information.|1
00088|110|R|   GlaxoSmithKline January 4, 2018.|1
00088|111|R|11.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00088|112|R|   352(11):1112-20.|6
00088|113|R|12.USFood and Drug Administration. FDA Drug Safety Communication: Serious|1
00088|114|R|   CNS reactions possible when methylene blue is given to patients taking|1
00088|115|R|   certain psychiatric medications. available at:|1
00088|116|R|   http://wayback.archive-it.org/7993/20170722185916/https://www.fda.gov/Dru|1
00088|117|R|   gs/DrugSafety/ucm263190.htm July 26, 2011.|1
00088|118|R|13.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
00088|119|R|   information about the drug interaction between methylene blue|1
00088|120|R|   (methylthioninium chloride) and serotonergic psychiatric medications.|1
00088|121|R|   available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
00088|122|R|   21, 2011.|1
00088|123|R|14.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00088|124|R|   inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00088|125|R|   prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00088|126|R|15.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00088|127|R|   distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00088|128|R|   2000 Jun;56(3):247-50.|2
00088|129|R|16.Brachfeld J, Wirtshafter A, Wolfe S. Imipramine-tranylcypromine|3
00088|130|R|   incompatibility. Near-fatal toxic reaction. JAMA 1963 Dec 28;|3
00088|131|R|   186(13):1172-3.|3
00088|132|R|17.Young JP, Lader MH, Hughes WC. Controlled trial of trimipramine,|2
00088|133|R|   monoamine oxidase inhibitors, and combined treatment in depressed|2
00088|134|R|   outpatients. Br Med J 1979 Nov 24;2(6201):1315-7.|2
00088|135|R|18.Pentel P, Olson KR, Becker CE, Benowitz N. Late complications of|3
00088|136|R|   tricyclic antidepressant overdose. West J Med 1983 Mar;138(3):423-4.|3
00088|137|R|19.de la Fuente JR, Berlanga C, Leon-Andrade C. Mania induced by|3
00088|138|R|   tricyclic-MAOI combination therapy in bipolar treatment-resistant|3
00088|139|R|   disorder: case reports. J Clin Psychiatry 1986 Jan;47(1):40-1.|3
00088|140|R|20.Pascual J, Combarros O, Berciano J. Partial status epilepticus following|3
00088|141|R|   single low dose of chlorimipramine in a patient on MAO-inhibitor|3
00088|142|R|   treatment. Clin Neuropharmacol 1987 Dec;10(6):565-7.|3
00088|143|R|21.Richards GA, Fritz VU, Pincus P, Reyneke J. Unusual drug interactions|3
00088|144|R|   between monoamine oxidase inhibitors and tricyclic antidepressants. J|3
00088|145|R|   Neurol Neurosurg Psychiatry 1987 Sep;50(9):1240-1.|3
00088|146|R|22.Tackley RM, Tregaskis B. Fatal disseminated intravascular coagulation|3
00088|147|R|   following a monoamine oxidase inhibitor/tricyclic interaction.|3
00088|148|R|   Anaesthesia 1987 Jul;42(7):760-3.|3
00088|149|R|23.O'Brien S, McKeon P, O'Regan M, O'Flaherty A, Patel R. Blood pressure|2
00088|150|R|   effects of tranylcypromine when prescribed singly and in combination with|2
00088|151|R|   amitriptyline. J Clin Psychopharmacol 1992 Apr;12(2):104-9.|2
00088|152|R|24.Schuckit M, Robins E, Feighner J. Tricyclic antidepressants and monoamine|6
00088|153|R|   oxidase inhibitors. Arch Gen Psychiatry 1971 Jun;24(6):509-14.|6
00088|154|R|25.Graham PM, Potter JM, Paterson J. Combination monoamine oxidase|3
00088|155|R|   inhibitor/tricyclic antidepressants interaction. Lancet 1982 Aug 21;|3
00088|156|R|   2(8295):440.|3
00088|157|R|26.White K, Simpson G. The combined use of MAOIs and tricyclics. J Clin|3
00088|158|R|   Psychiatry 1984 Jul;45(7 Pt 2):67-9.|3
00088|159|R|27.Ponto LB, Perry PJ, Liskow BI, Seaba HH. Drug therapy reviews: tricyclic|6
00088|160|R|   antidepressant and monoamine oxidase inhibitor combination therapy. Am J|6
00088|161|R|   Hosp Pharm 1977 Sep;34(9):954-61.|6
00088|162|R|28.Manshadi MS, Lippmann SB. Combined treatment of refractory depression|3
00088|163|R|   with an MAO inhibitor and a tricyclic. Psychosomatics 1984 Dec;|3
00088|164|R|   25(12):929-31.|3
00088|165|R|29.Spigset O, Mjorndal T, Lovheim O. Serotonin syndrome caused by a|3
00088|166|R|   moclobemide-clomipramine interaction. BMJ 1993 Jan 23;306(6872):248.|3
00088|167|R|30.Neuvonen PJ, Pohjola-Sintonen S, Tacke U, Vuori E. Five fatal cases of|3
00088|168|R|   serotonin syndrome after moclobemide-citalopram or|3
00088|169|R|   moclobemide-clomipramine overdoses. Lancet 1993 Dec 4;342(8884):1419.|3
00088|170|R|31.Sjoqvist F. Psychotropic drugs (2). Interaction between monoamine oxidase|6
00088|171|R|   (MAO) inhibitors and other substances. Proc R Soc Med 1965 Nov;58(11 Part|6
00088|172|R|   2):967-78.|6
00088|173|R|32.Stern SL, Mendels J. Drug combinations in the treatment of refractory|6
00088|174|R|   depression: a review. J Clin Psychiatry 1981 Oct;42(10):368-73.|6
00088|175|R|33.White K, Simpson G. Combined MAOI-tricyclic antidepressant treatment: a|6
00088|176|R|   reevaluation. J Clin Psychopharmacol 1981 Sep;1(5):264-82.|6
00088|177|R|34.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00088|178|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00088|179|R|   Feb;34(2):346.e5-6.|3
00088|180|R|35.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00088|181|R|   Pfizer Inc. January, 2024.|1
00088|182|R|36.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00088|183|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00088|184|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00088|185|R|   19(5):735-43.|6
00088|186|R|37.Pizotifen UK summary of product characteristics. Sovereign Medical March,|1
00088|187|R|   2025.|1
00091|001|T|MONOGRAPH TITLE:  Heparin/Selected Salicylates|
00091|002|B||
00091|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00091|004|L|take action as needed.|
00091|005|B||
00091|006|A|MECHANISM OF ACTION:  Additive prolongation of bleeding time.|
00091|007|B||
00091|008|E|CLINICAL EFFECTS:  Increased risk of bleeding which may extend for several|
00091|009|E|days beyond discontinuation of salicylates.|
00091|010|B||
00091|011|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00091|012|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00091|013|P|   Drug associated risk factors include concurrent use of multiple drugs|
00091|014|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00091|015|P|risk for bleeding (e.g. NSAIDs).|
00091|016|B||
00091|017|M|PATIENT MANAGEMENT:  Avoid concomitant administration of these drugs. If|
00091|018|M|this combination is used, monitor patients for signs of blood loss,|
00091|019|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
00091|020|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
00091|021|M|A non-acetylated salicylate may be used to avoid antiplatelet activity.|
00091|022|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00091|023|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00091|024|M|anticoagulation in patients with active pathologic bleeding.|
00091|025|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00091|026|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00091|027|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00091|028|M|and/or swelling.|
00091|029|M|   Single ingredient aspirin or buffered aspirin products with strengths <|
00091|030|M|or = 325 mg and combination aspirin products which are used to treat|
00091|031|M|cardiovascular disease (e.g. aspirin+statins, aspirin+dipyridamole) are not|
00091|032|M|included in this interaction.|
00091|033|B||
00091|034|D|DISCUSSION:  This interaction is likely to occur.|
00091|035|B||
00091|036|R|REFERENCES:|
00091|037|B||
00091|038|R|1.Weiss HJ, Aledort LM, Kochwa S. The effect of salicylates on the|2
00091|039|R|  hemostatic properties of platelets in man. J Clin Invest 1968 Sep;|2
00091|040|R|  47(9):2169-80.|2
00091|041|R|2.Zucker MB, Peterson J. Effect of acetylsalicylic acid, other nonsteroidal|5
00091|042|R|  anti-inflammatory agents, and dipyridamole on human blood platelets. J Lab|5
00091|043|R|  Clin Med 1970 Jul;76(1):66-75.|5
00091|044|R|3.Niklasson PM, Blomback M, Lundbergh P, Strandell T. Thrombocytopenia and|2
00091|045|R|  bleeding complications in severe cases of meningococcal infection treated|2
00091|046|R|  with heparin, dextran 70 and chlorpromazine. Scand J Infect Dis 1972;|2
00091|047|R|  4(3):183-91.|2
00091|048|R|4.Schondorf TH, Hey D. Combined administration of low dose heparin and|2
00091|049|R|  aspirin as prophylaxis of deep vein thrombosis after hip joint surgery.|2
00091|050|R|  Haemostasis 1976;5(4):250-7.|2
00091|051|R|5.Rubenstein JJ. Letter: Aspirin, heparin and hemorrhage. N Engl J Med 1976|6
00091|052|R|  May 13;294(20):1122-3.|6
00091|053|R|6.Yett HS, Skillman JJ, Salzman EW. The hazards of aspirin plus heparin. N|3
00091|054|R|  Engl J Med 1978 May 11;298(19):1092.|3
00091|055|R|7.Jick H, Porter J. Drug-induced gastrointestinal bleeding. Report from the|2
00091|056|R|  Boston Collaborative Drug Surveillance Program, Boston University Medical|2
00091|057|R|  Center. Lancet 1978 Jul 8;2(8080):87-9.|2
00091|058|R|8.Walker AM, Jick H. Predictors of bleeding during heparin therapy. JAMA|2
00091|059|R|  1980 Sep 12;244(11):1209-12.|2
00091|060|R|9.Heiden D, Rodvien R, Mielke CH. Heparin bleeding, platelet dysfunction,|6
00091|061|R|  and aspirin. JAMA 1981 Jul 24-31;246(4):330-1.|6
00091|062|R|10.Theroux P, Ouimet H, McCans J, Latour JG, Joly P, Levy G, Pelletier E,|2
00091|063|R|   Juneau M, Stasiak J, deGuise P, et al. Aspirin, heparin, or both to treat|2
00091|064|R|   acute unstable angina. N Engl J Med 1988 Oct 27;319(17):1105-11.|2
00092|001|T|MONOGRAPH TITLE:  Uricosurics/Aspirin (Greater Than 100 mg); Salicylates|
00092|002|B||
00092|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00092|004|L|take action as needed.|
00092|005|B||
00092|006|A|MECHANISM OF ACTION:  Not clearly established. Protein binding displacement|
00092|007|A|is a possibility.|
00092|008|B||
00092|009|E|CLINICAL EFFECTS:  May observe hyperuricemia and gout resulting from reduced|
00092|010|E|uricosuric response.|
00092|011|B||
00092|012|P|PREDISPOSING FACTORS:  None determined.|
00092|013|B||
00092|014|M|PATIENT MANAGEMENT:  Avoid chronic, moderate to high doses of salicylates.|
00092|015|B||
00092|016|D|DISCUSSION:  This interaction is well documented. Occasional small doses of|
00092|017|D|salicylates do not appear to inhibit the action of uricosurics.|
00092|018|B||
00092|019|R|REFERENCES:|
00092|020|B||
00092|021|R|1.Brooks CD, Ulrich JE. Effect of ibuprofen or aspirin on probenecid-induced|2
00092|022|R|  uricosuria. J Int Med Res 1980;8(4):283-5.|2
00092|023|R|2.Pascale LR, Dubin A, Bronsky D, Hoffman WS. Inhibition of the uricosuric|2
00092|024|R|  action of benemid by salicylate. J Lab Clin Med 1955 May;45(5):771-7.|2
00093|001|T|MONOGRAPH TITLE:  Select Indirect-Acting Sympathomimetics/Tricyclic|
00093|002|T|Compounds|
00093|003|B||
00093|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00093|005|L|of severe adverse interaction.|
00093|006|B||
00093|007|A|MECHANISM OF ACTION:  Unknown. However, it is speculated that|
00093|008|A|indirect-acting sympathomimetics would have decreased activity due to|
00093|009|A|tricyclic blockage of their uptake into the adrenergic neuron.|
00093|010|B||
00093|011|E|CLINICAL EFFECTS:  Decreased effect of indirect acting sympathomimetics.|
00093|012|B||
00093|013|P|PREDISPOSING FACTORS:  None determined.|
00093|014|B||
00093|015|M|PATIENT MANAGEMENT:  Use of tricyclic compounds and indirect-acting|
00093|016|M|sympathomimetics should be approached with caution.  Monitor patients|
00093|017|M|receiving concurrent therapy for decreased sympathomimetic efficacy.|
00093|018|B||
00093|019|D|DISCUSSION:  The pressor effects of the indirect-acting sympathomimetic|
00093|020|D|amines (e.g., amphetamines, ephedrine, and methylphenidate) are antagonized|
00093|021|D|by tricyclic antidepressants.|
00093|022|B||
00093|023|R|REFERENCES:|
00093|024|B||
00093|025|R|1.Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN.|2
00093|026|R|  Interactions between sympathomimetic amines and antidepressant agents in|2
00093|027|R|  man. Br Med J 1973 Feb 10;1(5849):311-5.|2
00093|028|R|2.Ghose K. Sympathomimetic amines and tricyclic antidepressant drugs.|2
00093|029|R|  Neuropharmacology 1980 Dec;19(12):1251-4.|2
00093|030|R|3.Svedmyr N. The influence of a tricyclic antidepressive agent|2
00093|031|R|  (protriptyline) on some of the circulatory effects of noradrenaline and|2
00093|032|R|  adrenaline in man. Life Sci 1968 Jan 1;7(1):77-84.|2
00093|033|R|4.Bonaccorsi A, Garattini S. Effect of desipramine on directly or indirectly|5
00093|034|R|  elicited catecholamine pressor responses in rats. J Pharm Pharmacol 1966|5
00093|035|R|  Jul;18(7):443-8.|5
00093|036|R|5.Cairncross KD. On the peripheral pharmacology of amitriptyline. Arch Int|5
00093|037|R|  Pharmacodyn Ther 1965 Apr;154(2):438-48.|5
00093|038|R|6.Ghose K, Gifford LA, Turner P, Leighton M. Studies of the interaction of|2
00093|039|R|  desmethylimipramine with tyramine in man after a single oral dose, and its|2
00093|040|R|  correlation with plasma concentration. Br J Clin Pharmacol 1976 Apr;|2
00093|041|R|  3(2):334-7.|2
00093|042|R|7.Jefferson JW. A review of the cardiovascular effects and toxicity of|6
00093|043|R|  tricyclic antidepressants. Psychosom Med 1975 Mar-Apr;37(2):160-79.|6
00093|044|R|8.Ragheb M. Drug interactions in psychiatric practice. Int|6
00093|045|R|  Pharmacopsychiatry 1981;16(2):92-118.|6
00093|046|R|9.Risch SC, Groom GP, Janowsky DS. Interfaces of psychopharmacology and|6
00093|047|R|  cardiology--part one. J Clin Psychiatry 1981 Jan;42(1):23-34.|6
00093|048|R|10.Maxwell RA, Keenan PD, Chaplin E, Roth B, Eckhardt SB. Molecular features|5
00093|049|R|   affecting the potency of tricyclic antidepressants and structurally|5
00093|050|R|   related compounds as inhibitors of the uptake of tritiated norepinephrine|5
00093|051|R|   by rabbit aortic strips. J Pharmacol Exp Ther 1969 Apr;166(2):320-9.|5
00094|001|T|MONOGRAPH TITLE:  Iron Salts, Oral/Magnesium Trisilicate (mono deleted|
00094|002|T|08/21/2014)|
00094|003|B||
00094|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00094|005|L|take action as needed.|
00094|006|B||
00094|007|A|MECHANISM OF ACTION:  Unknown. However, magnesium trisilicate appears to|
00094|008|A|decrease the gastrointestinal absorption of iron possibly by forming|
00094|009|A|insoluble iron compounds.|
00094|010|B||
00094|011|E|CLINICAL EFFECTS:  May observe a decrease in the hematologic response to|
00094|012|E|iron.|
00094|013|B||
00094|014|P|PREDISPOSING FACTORS:  None determined.|
00094|015|B||
00094|016|M|PATIENT MANAGEMENT:  If both drugs are administered, the iron and magnesium|
00094|017|M|doses should be separated by as much as possible. Consider giving the iron|
00094|018|M|salt parenterally as an important interaction will not occur.|
00094|019|B||
00094|020|D|DISCUSSION:  This potential interaction appears to be pH dependent.|
00094|021|D|Therefore, the effect varies with the solubility of different iron salts.|
00094|022|D|Additionally, other antacids may decrease the absorption of iron salts.|
00094|023|B||
00094|024|R|REFERENCE:|
00094|025|B||
00094|026|R|1.Hall GJ, Davis AE. Inhibition of iron absorption by magnesium trisilicate.|2
00094|027|R|  Med J Aust 1969 Jul 12;2(2):95-6.|2
00095|001|T|MONOGRAPH TITLE:  Slt Cation-Donating Antacids/Polystyrene Sulfonate|
00095|002|B||
00095|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00095|004|L|take action as needed.|
00095|005|B||
00095|006|A|MECHANISM OF ACTION:  Polystyrene sulfonate may bind the cation from the|
00095|007|A|antacid, resulting in increased intestinal absorption of non-neutralized|
00095|008|A|bicarbonate, which may result in systemic alkalosis and decreased potassium|
00095|009|A|binding by polystyrene sulfonate.  Intestinal obstruction has occurred with|
00095|010|A|aluminum hydroxide because of concretion.|
00095|011|B||
00095|012|E|CLINICAL EFFECTS:  Simultaneous oral use may result in metabolic alkalosis|
00095|013|E|and a decrease in the potassium lowering effect of polystyrene sulfonate.|
00095|014|E|Intestinal obstruction has been reported with aluminum hydroxide.|
00095|015|B||
00095|016|P|PREDISPOSING FACTORS:  Patients with renal failure may be at a higher risk|
00095|017|P|of systemic alkalosis.|
00095|018|B||
00095|019|M|PATIENT MANAGEMENT:  Consider the use of alternative agents to|
00095|020|M|cation-donating antacids in patients receiving oral polystyrene sulfonate|
00095|021|M|when possible.  If concurrent use is required, separate the dosing by|
00095|022|M|several hours.(1)|
00095|023|M|   Some vitamin preparations may contain sufficient quantities of calcium|
00095|024|M|and/or magnesium salts with antacid properties to interact as well.|
00095|025|B||
00095|026|D|DISCUSSION:  In a study in 11 patients with decreased renal function, the|
00095|027|D|administration of magnesium hydroxide and sodium polystyrene sulfonate|
00095|028|D|produced moderate to moderately severe metabolic alkalosis.(2)  There are|
00095|029|D|case reports documenting this affect as well.(3-7)  Intestinal obstruction|
00095|030|D|has been reported with aluminum hydroxide and sodium polystyrene|
00095|031|D|sulfonate.(8)|
00095|032|D|   If the polystyrene sulfonate is administered rectally, a clinically|
00095|033|D|significant interaction is not likely to occur.|
00095|034|B||
00095|035|R|REFERENCES:|
00095|036|B||
00095|037|R|1.Kayexalate (sodium polystyrene sulfonate) US prescribing information.|1
00095|038|R|  Concordia Pharmaceuticals Inc. July 31, 2017.|1
00095|039|R|2.Schroeder ET. Alkalosis resulting from combined administration of a|2
00095|040|R|  "nonsystemic" antacid and a cation-exchange resin. Gastroenterology 1969|2
00095|041|R|  May;56(5):868-74.|2
00095|042|R|3.Nassif F, Sinnassamy P, Bensman A. A cause of alkalosis in children under|3
00095|043|R|  hemodialysis: combined administration of  magnesium hydroxide and|3
00095|044|R|  polystyrene sodium sulfonate. Presse Med 1987 May 30;16(20):1003.|3
00095|045|R|4.Madias NE, Levey AS. Metabolic alkalosis due to absorption of|3
00095|046|R|  "nonabsorbable" antacids. Am J Med 1983 Jan;74(1):155-8.|3
00095|047|R|5.Ziessman HA. Alkalosis and seizure due to a cation-exchange resin and|3
00095|048|R|  magnesium hydroxide. South Med J 1976 Apr;69(4):497-9.|3
00095|049|R|6.Fernandez PC, Kovnat PJ. Metabolic acidosis reversed by the combination of|3
00095|050|R|  magnesium hydroxide and a cation-exchange resin. N Engl J Med 1972 Jan 6;|3
00095|051|R|  286(1):23-4.|3
00095|052|R|7.Baluarte HJ, Prebis J, Goldberg M, Gruskin AB. Metabolic alkalosis in an|3
00095|053|R|  anephric child caused by the combined use of Kayexalate and Basaljel. J|3
00095|054|R|  Pediatr 1978 Feb;92(2):237-9.|3
00095|055|R|8.Foresti V. Intestinal obstruction due to kayexalate in a patient|3
00095|056|R|  concurrently treated with aluminum hydroxide and morphine sulfate. Clin|3
00095|057|R|  Nephrol 1994 Apr;41(4):252.|3
00097|001|T|MONOGRAPH TITLE:  Hydantoins/Cimetidine; Ranitidine|
00097|002|B||
00097|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00097|004|L|take action as needed.|
00097|005|B||
00097|006|A|MECHANISM OF ACTION:  The predominant mechanism appears to be inhibition of|
00097|007|A|hepatic microsomal enzymes resulting in impaired hydantoin metabolism.|
00097|008|A|Cimetidine may inhibit the CYP2C9 and CYP2C19 mediated metabolism of|
00097|009|A|phenytoin and other hydantoins.|
00097|010|B||
00097|011|E|CLINICAL EFFECTS:  Concurrent use of cimetidine or ranitidine may result in|
00097|012|E|elevated levels of and toxicity from the hydantoin.|
00097|013|E|   Neutropenia and thrombocytopenia have been reported with concurrent|
00097|014|E|cimetidine and phenytoin.|
00097|015|E|   Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin|
00097|016|E|toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia,|
00097|017|E|lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe|
00097|018|E|toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar|
00097|019|E|dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac|
00097|020|E|arrest) and may be fatal.(21)|
00097|021|B||
00097|022|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
00097|023|P|hypoalbuminemia.|
00097|024|B||
00097|025|M|PATIENT MANAGEMENT:  Patient receiving concurrent therapy should be|
00097|026|M|monitored for increased hydantoin levels and effects.  A dosage adjustment|
00097|027|M|may be required after initiating or discontinuing cimetidine or ranitidine.|
00097|028|M|Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus, ataxia,|
00097|029|M|dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision,|
00097|030|M|nausea, and vomiting).|
00097|031|M|  Substituting famotidine or nizatidine may be considered in patients|
00097|032|M|experiencing adverse effects from the combination or to avoid the|
00097|033|M|interaction.|
00097|034|B||
00097|035|D|DISCUSSION:  There are several case reports and studies documenting|
00097|036|D|increases in phenytoin levels (50% or greater) during concurrent use of|
00097|037|D|cimetidine (400 mg/day to 2400 mg/day).(1-11)  Phenytoin toxicity occurred|
00097|038|D|in some patients.  The interaction often occurred in two to ten days after|
00097|039|D|concurrent therapy was initiated.  Neutropenia and thrombocytopenia have|
00097|040|D|also been reported during concurrent phenytoin and cimetidine.(12-15)|
00097|041|D|   There are three case reports of elevated phenytoin levels during|
00097|042|D|concurrent ranitidine therapy.(16-18)  However, in a study, no alterations|
00097|043|D|in phenytoin levels were seen,(19) suggesting the interaction may not occur|
00097|044|D|in all patients.|
00097|045|D|   Studies have shown that famotidine(1) and nizatidine(20) do not interact|
00097|046|D|with phenytoin.|
00097|047|B||
00097|048|R|REFERENCES:|
00097|049|B||
00097|050|R|1.Sambol NC, Upton RA, Chremos AN, Lin ET, Williams RL. A comparison of the|2
00097|051|R|  influence of famotidine and cimetidine on phenytoin elimination and|2
00097|052|R|  hepatic blood flow. Br J Clin Pharmacol 1989 Jan;27(1):83-7.|2
00097|053|R|2.Levine M, Jones MW, Sheppard I. Differential effect of cimetidine on serum|2
00097|054|R|  concentrations of carbamazepine and phenytoin. Neurology 1985 Apr;|2
00097|055|R|  35(4):562-5.|2
00097|056|R|3.Phillips P, Hansky J. Phenytoin toxicity secondary to cimetidine|3
00097|057|R|  administration. Med J Aust 1984 Oct 27;141(9):602.|3
00097|058|R|4.Iteogu MO, Murphy JE, Shleifer N, Davis R. Effect of cimetidine on|3
00097|059|R|  single-dose phenytoin kinetics. Clin Pharm 1983 Jul-Aug;2(4):302, 304.|3
00097|060|R|5.Salem RB, Breland BD, Mishra SK, Jordan JE. Effect of cimetidine on|2
00097|061|R|  phenytoin serum levels. Epilepsia 1983 Jun;24(3):284-8.|2
00097|062|R|6.Bartle WR, Walker SE, Shapero T. Dose-dependent effect of cimetidine on|2
00097|063|R|  phenytoin kinetics. Clin Pharmacol Ther 1983 May;33(5):649-55.|2
00097|064|R|7.Algozzine GJ, Stewart RB, Springer PK. Decreased clearance of phenytoin|3
00097|065|R|  with cimetidine. Ann Intern Med 1981 Aug;95(2):244-5.|3
00097|066|R|8.Hetzel DJ, Bochner F, Hallpike JF, Shearman DJ, Hann CS. Cimetidine|3
00097|067|R|  interaction with phenytoin. Br Med J (Clin Res Ed) 1981 May 9;|3
00097|068|R|  282(6275):1512.|3
00097|069|R|9.Neuvonen PJ, Tokola RA, Kaste M. Cimetidine-phenytoin interaction: effect|2
00097|070|R|  on serum phenytoin concentration and antipyrine test. Eur J Clin Pharmacol|2
00097|071|R|  1981;21(3):215-20.|2
00097|072|R|10.Frigo GM, Lecchini S, Caravaggi M, Gatti G, Tonini M, D'Angelo L, Perucca|2
00097|073|R|   E, Crema A. Reduction of phenytoin clearance caused by cimetidine. Eur J|2
00097|074|R|   Clin Pharmacol 1983;25(1):135-7.|2
00097|075|R|11.Griffin JW Jr, May JR, DiPiro JT. Drug interactions: theory versus|3
00097|076|R|   practice. Am J Med 1984 Nov 19;77(5B):85-9.|3
00097|077|R|12.Sazie E, Jaffe JP. Severe granulocytopenia with cimetidine and phenytoin.|3
00097|078|R|   Ann Intern Med 1980 Jul;93(1):151-2.|3
00097|079|R|13.Arbiser JL, Goldstein AM, Gordon D. Thrombocytopenia following|3
00097|080|R|   administration of phenytoin, dexamethasone and cimetidine: a case report|3
00097|081|R|   and a potential mechanism. J Intern Med 1993 Jul;234(1):91-4.|3
00097|082|R|14.Yue CP, Mann KS, Chan KH. Severe thrombocytopenia due to combined|3
00097|083|R|   cimetidine and phenytoin therapy. Neurosurgery 1987 Jun;20(6):963-5.|3
00097|084|R|15.Wong YY, Lichtor T, Brown FD. Severe thrombocytopenia associated with|3
00097|085|R|   phenytoin and cimetidine therapy. Surg Neurol 1985 Feb;23(2):169-72.|3
00097|086|R|16.Tse CS, Akinwande KI, Biallowons K. Phenytoin concentration elevation|3
00097|087|R|   subsequent to ranitidine administration. Ann Pharmacother 1993 Dec;|3
00097|088|R|   27(12):1448-51.|3
00097|089|R|17.Tse CS, Iagmin P. Phenytoin and ranitidine interaction. Ann Intern Med|3
00097|090|R|   1994 May 15;120(10):892-3.|3
00097|091|R|18.Bramhall D, Levine M. Possible interaction of ranitidine with phenytoin.|3
00097|092|R|   Drug Intell Clin Pharm 1988 Dec;22(12):979-80.|3
00097|093|R|19.Watts RW, Hetzel DJ, Bochner F, Hallpike JF, Hann CS, Shearman DJ. Lack|2
00097|094|R|   of interaction between ranitidine and phenytoin. Br J Clin Pharmacol 1983|2
00097|095|R|   Apr;15(4):499-500.|2
00097|096|R|20.Bachmann KA, Sullivan TJ, Jauregui L, Reese JH, Miller K, Levine L.|2
00097|097|R|   Absence of an inhibitory effect of omeprazole and nizatidine on phenytoin|2
00097|098|R|   disposition, a marker of CYP2C activity. Br J Clin Pharmacol 1993 Oct;|2
00097|099|R|   36(4):380-2.|2
00097|100|R|21.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00097|101|R|   March, 2022.|1
00101|001|T|MONOGRAPH TITLE:  Succinylcholine/Echothiophate Iodide|
00101|002|B||
00101|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00101|004|L|of severe adverse interaction.|
00101|005|B||
00101|006|A|MECHANISM OF ACTION:  Decreased pseudocholinesterase activity.|
00101|007|B||
00101|008|E|CLINICAL EFFECTS:  Succinylcholine administered to patients receiving|
00101|009|E|echothiophate are at risk of developing respiratory depression and prolonged|
00101|010|E|periods of apnea, with death a possibility. Effects may be seen for several|
00101|011|E|weeks after stopping the echothiophate.|
00101|012|B||
00101|013|P|PREDISPOSING FACTORS:  None determined.|
00101|014|B||
00101|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of these agents or use with|
00101|016|M|caution. It is recommended that plasma pseudocholinesterase measurements be|
00101|017|M|taken before succinylcholine is given.|
00101|018|B||
00101|019|D|DISCUSSION:  This interaction is well documented.|
00101|020|B||
00101|021|R|REFERENCES:|
00101|022|B||
00101|023|R|1.Leopold IH, Krishna N, Lehman RA. The effects of anticholinesterase agents|2
00101|024|R|  on the blood cholinesterases levels of normal and glaucoma subjects. Trans|2
00101|025|R|  Am Ophthalmol Soc 1959;57:63-86.|2
00101|026|R|2.De Roetth A Jr, Dettbarn WD, Rosenberg P, Wilensky JG, Wong A. Effect of|2
00101|027|R|  phospholine iodide on blood cholinesterase levels of normal and glaucoma|2
00101|028|R|  subjects. Am J Ophthalmol 1965;59:586-92.|2
00101|029|R|3.Pantuck EJ. Ecothiopate iodide eye drops and prolonged response to|3
00101|030|R|  suxamethonium. Br J Anaesth 1966 May;38(5):406-7.|3
00101|031|R|4.Gesztes T. Prolonged apnoea after suxamethonium injection associated with|3
00101|032|R|  eye drops containing an anticholinesterase agent. Br J Anaesth 1966 May;|3
00101|033|R|  38(5):408-9.|3
00101|034|R|5.Mone JG, Mathie WE. Qualitative defects of pseudocholinesterase activity.|2
00101|035|R|  Anaesthesia 1967 Jan;22(1):55-68.|2
00101|036|R|6.Eilderton TE, Farmati O, Zsigmond EK. Reduction in plasma cholinesterase|2
00101|037|R|  levels after prolonged administration of echothiophate iodide eyedrops.|2
00101|038|R|  Can Anaesth Soc J 1968 May;15(3):291-6.|2
00101|039|R|7.Cavallaro RJ, Krumperman LW, Kugler F. Effect of echothiophate therapy on|2
00101|040|R|  the metabolism of succinylcholine in man. Anesth Analg 1968 Sep-Oct;|2
00101|041|R|  47(5):570-4.|2
00101|042|R|8.Cohen PJ, Reynolds RC, Naidl J. A simple test for abnormal|3
00101|043|R|  pseudocholinesterase. Anesthesiology 1970 Mar;32(3):281-2.|3
00101|044|R|9.Donati F, Bevan DR. Controlled succinylcholine infusion in a patient|3
00101|045|R|  receiving echothiophate eye drops. Can Anaesth Soc J 1981 Sep;|3
00101|046|R|  28(5):488-90.|3
00103|001|T|MONOGRAPH TITLE:  NSAIDs; Salicylates/Loop Diuretics|
00103|002|B||
00103|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00103|004|L|take action as needed.|
00103|005|B||
00103|006|A|MECHANISM OF ACTION:  During concurrent administration of a loop diuretic|
00103|007|A|and a nonsteroidal anti-inflammatory drug (NSAID), patients may retain|
00103|008|A|sodium as a result of NSAID-induced prostaglandin inhibition.|
00103|009|B||
00103|010|E|CLINICAL EFFECTS:  The pharmacological effects of loop diuretics may be|
00103|011|E|decreased due to reduced antihypertensive and diuretic actions.|
00103|012|E|   Concurrent use of NSAIDs with loop diuretics and renin-angiotensin system|
00103|013|E|(RAS) inhibitors may result in increased risk of acute kidney injury (AKI).|
00103|014|B||
00103|015|P|PREDISPOSING FACTORS:  Low water intake/dehydration, drug sensitivity,|
00103|016|P|greater than 75 years of age, and renal impairment may increase an|
00103|017|P|individuals susceptibility to AKI.|
00103|018|B||
00103|019|M|PATIENT MANAGEMENT:  Monitor patients for a decrease in the effects of the|
00103|020|M|loop diuretic. It may be necessary to administer a higher dose of the|
00103|021|M|diuretic or an alternative anti-inflammatory agent.|
00103|022|M|    Concurrent use of NSAIDs with loop diuretics and RAS inhibitors should|
00103|023|M|be used with caution and monitored closely for signs of AKI.|
00103|024|B||
00103|025|D|DISCUSSION:  In a computational study, the risk of AKI using triple therapy|
00103|026|D|with a diuretic, RAS inhibitor, and NSAID was assessed.  The study found the|
00103|027|D|following factors may increase an individual's susceptibility to AKI: low|
00103|028|D|water intake, drug sensitivity, greater than 75 years of age, and renal|
00103|029|D|impairment.(19,20)|
00103|030|D|    In an observational study, current use of a triple therapy with a|
00103|031|D|diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of|
00103|032|D|acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI)|
00103|033|D|1.12-1.53). The highest risk of AKI associated with triple therapy were|
00103|034|D|observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (21)|
00103|035|D|    Administration of indomethacin alone has been reported to decrease|
00103|036|D|sodium excretion and increase blood pressure. In patients receiving a loop|
00103|037|D|diuretic (e.g., bumetanide, furosemide), these effects interfere with|
00103|038|D|clinical management. Several NSAIDs have been shown to interact with loop|
00103|039|D|diuretics interfering with the pharmacological effects of the diuretic. In|
00103|040|D|volunteers on sodium restricted diets, ibuprofen and indomethacin inhibited|
00103|041|D|furosemide diuresis.|
00103|042|B||
00103|043|R|REFERENCES:|
00103|044|B||
00103|045|R|1.Patak RV, Mookerjee BK, Bentzel CJ, Hysert PE, Babej M, Lee JB. Antagonism|2
00103|046|R|  of the effects of furosemide by indomethacin in normal and hypertensive|2
00103|047|R|  man. Prostaglandins 1975 Oct;10(4):649-59.|2
00103|048|R|2.Donker AJ, Arisz L, Brentjens JR, van der Hem GK, Hollemans HJ. The effect|2
00103|049|R|  of indomethacin on kidney function and plasma renin activity in man.|2
00103|050|R|  Nephron 1976;17(4):288-96.|2
00103|051|R|3.Brater DC. Analysis of the effect of indomethacin on the response to|2
00103|052|R|  furosemide in man: effect of dose of furosemide. J Pharmacol Exp Ther 1979|2
00103|053|R|  Sep;210(3):386-90.|2
00103|054|R|4.Smith DE, Brater DC, Lin ET, Benet LZ. Attenuation of furosemide's|2
00103|055|R|  diuretic effect by indomethacin: pharmacokinetic evaluation. J|2
00103|056|R|  Pharmacokinet Biopharm 1979 Jun;7(3):265-74.|2
00103|057|R|5.Brater DC. Effect of indomethacin on salt and water homeostasis. Clin|2
00103|058|R|  Pharmacol Ther 1979 Mar;25(3):322-30.|2
00103|059|R|6.Brater C, Chennavasin P. Indomethacin and the response to bumetanide. Clin|2
00103|060|R|  Pharmacol Ther 1980 Mar;27(3):421-5.|2
00103|061|R|7.Pedrinelli R, Magagna A, Arzilli F, Sassano P, Salvetti A. Influence of|2
00103|062|R|  indomethacin on the natriuretic and renin-stimulating effect of bumetanide|2
00103|063|R|  in essential hypertension. Clin Pharmacol Ther 1980 Dec;28(6):722-31.|2
00103|064|R|8.Allan SG, Knox J, Kerr F. Interaction between diuretics and indomethacin.|3
00103|065|R|  Br Med J (Clin Res Ed) 1981 Dec 12;283(6306):1611.|3
00103|066|R|9.Kaufman J, Hamburger R, Matheson J, Flamenbaum W. Bumetanide-induced|2
00103|067|R|  diuresis and natriuresis: effect of prostaglandin synthetase inhibition. J|2
00103|068|R|  Clin Pharmacol 1981 Nov-Dec;21(11-12 Pt 2):663-7.|2
00103|069|R|10.Brater DC, Fox WR, Chennavasin P. Interaction studies with bumetanide and|2
00103|070|R|   furosemide. Effects of probenecid and of indomethacin on response to|2
00103|071|R|   bumetanide in man. J Clin Pharmacol 1981 Nov-Dec;21(11-12 Pt 2):647-53.|2
00103|072|R|11.Bunning RD, Barth WF. Sulindac. A potentially renal-sparing nonsteroidal|3
00103|073|R|   anti-inflammatory drug. JAMA 1982 Dec 3;248(21):2864-7.|3
00103|074|R|12.Rawles JM. Antagonism between non-steroidal anti-inflammatory drugs and|2
00103|075|R|   diuretics. Scott Med J 1982 Jan;27(1):37-40.|2
00103|076|R|13.Poe TE, Scott RB, Keith JF Jr. Interaction of indomethacin with|3
00103|077|R|   furosemide. J Fam Pract 1983 Mar;16(3):610, 614-6.|3
00103|078|R|14.Wong DG, Spence JD, McDonald JWD, Lamki LM. Non-steroidal|4
00103|079|R|   antiinflammatory drugs (NSAID) vs placebo in hypertension treated with|4
00103|080|R|   diuretic and beta-blocker. Clin Pharmacol Ther 1984 Feb;35(2):284.|4
00103|081|R|15.Radack KL, Deck CC, Bloomfield SS. Ibuprofen interferes with the efficacy|2
00103|082|R|   of antihypertensive drugs. A randomized, double-blind, placebo-controlled|2
00103|083|R|   trial of ibuprofen compared with acetaminophen. Ann Intern Med 1987 Nov;|2
00103|084|R|   107(5):628-35.|2
00103|085|R|16.Skinner MH, Mutterperl R, Zeitz HJ. Sulindac inhibits bumetanide-induced|2
00103|086|R|   sodium and water excretion. Clin Pharmacol Ther 1987 Nov;42(5):542-6.|2
00103|087|R|17.Herchuelz A, Derenne F, Deger F, Juvent M, Van Ganse E, Staroukine M,|2
00103|088|R|   Verniory A, Boeynaems JM, Douchamps J. Interaction between nonsteroidal|2
00103|089|R|   anti-inflammatory drugs and loop diuretics: modulation by sodium balance.|2
00103|090|R|   J Pharmacol Exp Ther 1989 Mar;248(3):1175-81.|2
00103|091|R|18.Passmore AP, Copeland S, Johnston GD. The effects of ibuprofen and|2
00103|092|R|   indomethacin on renal function in the presence and absence of frusemide|2
00103|093|R|   in healthy volunteers on a restricted sodium diet. Br J Clin Pharmacol|2
00103|094|R|   1990 Mar;29(3):311-9.|2
00103|095|R|19.Leete J,  Wang C,  Lopez-Hernandez FJ,  Layton AT. Determining risk|6
00103|096|R|   factors for triple whammy acute kidney injury. Math Biosci 2022 Apr 4.|6
00103|097|R|20.Dreischulte T,  Morales DR,  Bell S,  Guthrie B. Combined use of|2
00103|098|R|   nonsteroidal anti-inflammatory drugs with diuretics and/or|2
00103|099|R|   renin-angiotensin system inhibitors in the community increases the risk|2
00103|100|R|   of acute kidney injury. Kidney Int 2015 Aug;88(2):396-403.|2
00103|101|R|21.Lapi F,  Azoulay L,  Yin H,  Nessim SJ,  Suissa S. Concurrent use of|2
00103|102|R|   diuretics, angiotensin converting enzyme inhibitors, and angiotensin|2
00103|103|R|   receptor blockers with non-steroidal anti-inflammatory drugs and risk of|2
00103|104|R|   acute kidney injury: nested case-control study. BMJ 2013 Jan;8(346):.|2
00103|105|R|22.Juhlin T,  Bjorkman S,  Hoglund P. Cyclooxygenase inhibition causes|2
00103|106|R|   marked impairment of renal function in elderly subjects treated with|2
00103|107|R|   diuretics and ACE-inhibitors. Eur J Heart Fail 2005 Oct;7(6):1049-56.|2
00104|001|T|MONOGRAPH TITLE:  Thyroid Preps/Bile Acid Sequestrants; Lanthanum; Sevelamer|
00104|002|B||
00104|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00104|004|L|take action as needed.|
00104|005|B||
00104|006|A|MECHANISM OF ACTION:  Bile acid sequestrants, lanthanum and sevelamer may|
00104|007|A|decrease the gastrointestinal absorption of thyroid drugs.(1)|
00104|008|B||
00104|009|E|CLINICAL EFFECTS:  Simultaneous administration of a bile acid sequestrant,|
00104|010|E|lanthanum or sevelamer may result in decreased absorption and effectiveness|
00104|011|E|of thyroid drugs.(1)|
00104|012|B||
00104|013|P|PREDISPOSING FACTORS:  None determined.|
00104|014|B||
00104|015|M|PATIENT MANAGEMENT:  For maximal bioavailability, thyroid preparations|
00104|016|M|should be taken on an empty stomach at least 4 hours apart from bile acid|
00104|017|M|sequestrants and sevelamer.(1-3)  Thyroid preparations should be taken at|
00104|018|M|least 2 hours apart from lanthanum.(4)|
00104|019|B||
00104|020|D|DISCUSSION:  The effect of cholestyramine on the absorption of thyroid drugs|
00104|021|D|appears to be clinically significant, resulting in approximately a 50%|
00104|022|D|decrease in thyroid absorption.  Cholestyramine has been used to treat|
00104|023|D|thyroid overdoses.|
00104|024|D|   When administered with colesevelam (3.75 g), the area-under-curve (AUC)|
00104|025|D|and maximum concentration (Cmax) of levothyroxine (600 mcg) decreased by 22%|
00104|026|D|and by 33%, respectively.  When administered 1 hour prior to colesevelam,|
00104|027|D|the AUC of levothyroxine increased by 6% and the Cmax of levothyroxine|
00104|028|D|decreased by 2%, respectively.  When administered 4 hours prior to|
00104|029|D|colesevelam, the AUC and Cmax of levothyroxine increased by 1% and 8%,|
00104|030|D|respectively.|
00104|031|D|   Although used for hyperphosphatemia, sevelamer is linked to this|
00104|032|D|monograph due to its structural and pharmacologic similarities to|
00104|033|D|colesevelam. Both agents are non-absorbed cross linked polymers with a high|
00104|034|D|affinity for bile acids.(2,3)|
00104|035|D|   An in vivo study in healthy subjects evaluated the bioavailability of|
00104|036|D|levothyroxine 1 mg when given with or without sevelamer 800 mg. Concomitant|
00104|037|D|administration of sevelamer decreased levothyroxine AUC by 46%.(13)|
00104|038|D|   One case report described a newly diagnosed hypothyroid patient with a|
00104|039|D|TSH of 297 mU/L (reference 0.03 - 4.20 mU/L).  She took her daily|
00104|040|D|levothyroxine with her morning blood pressure medications, acetaminophen,|
00104|041|D|B-vitamins and sevelamer 3200 mg. Over 3 months of treatment her|
00104|042|D|levothyroxine dose was increased to 150 mcg daily but the TSH remained high|
00104|043|D|at 196 mU/L. Her levothyroxine dose was changed to an evening dose taken at|
00104|044|D|least 4 hours after medications. Three weeks later she was symptomatically|
00104|045|D|improved and TSH had decreased to 19 mU/L. She was inadvertently|
00104|046|D|rechallenged on the morning levothyroxine and sevelamer regimen due to a|
00104|047|D|hospitalization. After the hospital stay her TSH risen to 76 mU/L; on return|
00104|048|D|to her evening regimen her TSH again normalized.(14)|
00104|049|B||
00104|050|R|REFERENCES:|
00104|051|B||
00104|052|R|1.Synthroid (levothyroxine sodium) US prescribing information. Abbott|1
00104|053|R|  Laboratories February, 2024.|1
00104|054|R|2.Welchol (colesevelam hydrochloride) US prescribing information. Daiichi|1
00104|055|R|  Sankyo, Inc. October, 2021.|1
00104|056|R|3.Renagel (sevelamer hydrochloride) US prescribing information. Genzyme|1
00104|057|R|  Corporation March 9, 2016.|1
00104|058|R|4.Fosrenol (lanthanum carbonate) US prescribing information. Shire US Inc.|1
00104|059|R|  May, 2020.|1
00104|060|R|5.Bergman F, Heedman PA, van der Linden W. Influence of cholestyramine on|5
00104|061|R|  absorption and excretion of thyroxine in Syrian hamster. Acta Endocrinol|5
00104|062|R|  (Copenh) 1966 Oct;53(2):256-63.|5
00104|063|R|6.Northcutt RC, Stiel JN, Hollifield JW, Stant EG Jr. The influence of|5
00104|064|R|  cholestyramine on thyroxine absorption. JAMA 1969 Jun 9;208(10):1857-61.|5
00104|065|R|7.Harmon SM, Seifert CF. Levothyroxine-cholestyramine interaction|3
00104|066|R|  reemphasized. Ann Intern Med 1991 Oct 15;115(8):658-9.|3
00104|067|R|8.Lehrner LM, Weir MR. Acute ingestions of thyroid hormones. Pediatrics 1984|3
00104|068|R|  Mar;73(3):313-7.|3
00104|069|R|9.Rosenberg R. Malabsorption of thyroid hormone with cholestyramine|3
00104|070|R|  administration. Conn Med 1994 Feb;58(2):109.|3
00104|071|R|10.Shakir KM, Michaels RD, Hays JH, Potter BB. The use of bile acid|3
00104|072|R|   sequestrants to lower serum thyroid hormones in iatrogenic|3
00104|073|R|   hyperthyroidism. Ann Intern Med 1993 Jan 15;118(2):112-3.|3
00104|074|R|11.McLean M, Kirkwood I, Epstein M, Jones B, Hall C. Cation-exchange resin|6
00104|075|R|   and inhibition of intestinal absorption of thyroxine. Lancet 1993 May 15;|6
00104|076|R|   341(8855):1286.|6
00104|077|R|12.Brown KS, Armstrong IC, Wang A, Walker JR, Noveck RJ, Swearingen D,|2
00104|078|R|   Allison M, Kissling JC, Kisicki J, Salazar DE. Effect of the bile acid|2
00104|079|R|   sequestrant colesevelam on the pharmacokinetics of pioglitazone,|2
00104|080|R|   repaglinide, estrogen estradiol, norethindrone, levothyroxine, and|2
00104|081|R|   glyburide. J Clin Pharmacol 2010 May;50(5):554-65.|2
00104|082|R|13.John-Kalarickal J, Pearlman G, Carlson HE. New medications which decrease|2
00104|083|R|   levothyroxine absorption. Thyroid 2007 Aug;17(8):763-5.|2
00104|084|R|14.Arnadottir M, Johannesson AJ. Phosphate binders and timing of|3
00104|085|R|   levothyroxine administration. Nephrol Dial Transplant 2008 Jan;23(1):420.|3
00105|001|T|MONOGRAPH TITLE:  Selected Nitroimidazole Antimicrobials/Disulfiram|
00105|002|B||
00105|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00105|004|L|is contraindicated and generally should not be dispensed or administered to|
00105|005|L|the same patient.|
00105|006|B||
00105|007|A|MECHANISM OF ACTION:  Since disulfiram has been associated with psychotic|
00105|008|A|behavior in some patients, this interaction has been attributed to a|
00105|009|A|combined toxicity with metronidazole or benznidazole.(1)|
00105|010|B||
00105|011|E|CLINICAL EFFECTS:  May observe psychotic reactions of confusional states.|
00105|012|B||
00105|013|P|PREDISPOSING FACTORS:  None determined.|
00105|014|B||
00105|015|M|PATIENT MANAGEMENT:  The manufacturers of benznidazole,(2) fexinidazole,(3)|
00105|016|M|metronidazole,(4) and tinidazole(5) state that these agents should not be|
00105|017|M|administered to patients who have received disulfiram in the previous two|
00105|018|M|weeks.|
00105|019|B||
00105|020|D|DISCUSSION:  In a study in hospitalized alcoholics, six of 29 patients|
00105|021|D|receiving concurrent disulfiram and metronidazole developed acute psychosis|
00105|022|D|or confusion.  Of these six, five had paranoid delusions and three|
00105|023|D|experienced visual and auditory hallucinations.  These reactions were not|
00105|024|D|reported in any of the 29 patients who received placebo with|
00105|025|D|disulfiram.(6,7)|
00105|026|D|   An increased central effect of ethyl alcohol was observed in a single|
00105|027|D|patient during concurrent disulfiram and metronidazole.(8)  Psychotic|
00105|028|D|symptoms were reported during concurrent use in another case report.(9)|
00105|029|B||
00105|030|R|REFERENCES:|
00105|031|B||
00105|032|R|1.Goodhue WW Jr. Disulfiram-metronidazole (well identified) toxicity. N Engl|6
00105|033|R|  J Med 1969 Jun 26;280(26):1482-3.|6
00105|034|R|2.Benznidazole. US Prescribing Information. Exeltis USA, Inc. November,|1
00105|035|R|  2019.|1
00105|036|R|3.Fexinidazole US prescribing information. Sanofi-Aventis U.S. LLC July,|1
00105|037|R|  2021.|1
00105|038|R|4.Metronidazole US prescribing information. Baxter Healthcare Corporation|1
00105|039|R|  June, 2009.|1
00105|040|R|5.Tinidazole US prescribing information. Rising Pharmaceuticals, Inc..|1
00105|041|R|  October 12, 2017.|1
00105|042|R|6.Rothstein E, Clancy DD. Toxicity of disulfiram combined with|2
00105|043|R|  metronidazole. N Engl J Med 1969 May 1;280(18):1006-7.|2
00105|044|R|7.Rothstein E, Clancy DD. Combined use of disulfiram and metronidazole in|2
00105|045|R|  treatment of alcoholism. Q J Stud Alcohol 1970 Jun;31(2):446-7.|2
00105|046|R|8.Czarnecka E. Pharmacological evaluation of the central effect of ethyl|3
00105|047|R|  alcohol after administration with disulfiram and metronidazole. Pol Tyg|3
00105|048|R|  Lek 1981 May 25;36(21):779-80.|3
00105|049|R|9.Luykx JJ, Vis R, Tijdink JK, Dirckx M, Van Hecke J, Vinkers CH. Psychotic|3
00105|050|R|  symptoms after combined metronidazole-disulfiram use. J Clin|3
00105|051|R|  Psychopharmacol 2013 Feb;33(1):136-7.|3
00107|001|T|MONOGRAPH TITLE:  Selected Antidiabetics/Rifamycins (mono deleted|
00107|002|T|07/08/2024)|
00107|003|B||
00107|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00107|005|L|take action as needed.|
00107|006|B||
00107|007|A|MECHANISM OF ACTION:  Rifamycins may induce the metabolism of pioglitazone,|
00107|008|A|repaglinide, rosiglitazone, and sulfonylureas.(1-14)|
00107|009|B||
00107|010|E|CLINICAL EFFECTS:  Concurrent or recent use of a rifamycin may result in|
00107|011|E|decreased hypoglycemic effects.|
00107|012|B||
00107|013|P|PREDISPOSING FACTORS:  None determined.|
00107|014|B||
00107|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with a rifamycin|
00107|016|M|should be monitored for decreased antidiabetic effects during and for two|
00107|017|M|weeks after discontinuation of rifamycin therapy.  Monitor blood glucose and|
00107|018|M|adjust the antidiabetic dose accordingly following the addition or|
00107|019|M|discontinuation of the rifamycin.  The maximum recommended dose of 45 mg|
00107|020|M|daily of pioglitazone should not be exceeded.(12)|
00107|021|B||
00107|022|D|DISCUSSION:  In a study in 9 healthy subjects, rifampin (600 mg daily)|
00107|023|D|decreased the area-under-curve (AUC) and half-life of gliclazide (80 mg|
00107|024|D|single dose) by 70% and 65%, respectively.  There was also a decrease in|
00107|025|D|blood glucose response during rifampin therapy.(1)|
00107|026|D|   In a study in 9 healthy subjects, multiple doses of oral rifampin|
00107|027|D|decreased the AUC and maximum concentration (Cmax) of glyburide  by 63% and|
00107|028|D|48%, respectively.(2)|
00107|029|D|   In a study in 10 healthy subjects, rifampin (600 mg daily) decreased the|
00107|030|D|AUC and Cmax of glyburide (1.75 mg single dose) by 39% and 22%,|
00107|031|D|respectively.  The blood glucose response to glyburide was also|
00107|032|D|decreased.(3)|
00107|033|D|   In a study in 29 well-controlled diabetics taking glyburide, the addition|
00107|034|D|of rifampin (450 mg to 600 mg daily) resulted in increases in fasting and|
00107|035|D|post-prandial blood sugar levels.  Dosage adjustment of glyburide was|
00107|036|D|required in 15 of the 17 subjects whose diabetes became uncontrolled.  Blood|
00107|037|D|glucose levels returned to baseline within 6 days of stopping rifampin in|
00107|038|D|all subjects.(4)|
00107|039|D|   In a study in 5 healthy subjects, rifampin (1.2 grams daily) increased|
00107|040|D|the clearance of tolbutamide by 2-fold.(5)|
00107|041|D|   There are case reports of hyperglycemia following the addition of|
00107|042|D|rifampin to chlorpropamide,(6) gliclazide,(7) and glyburide(8) therapy.|
00107|043|D|   Studies have shown that while rifampin decreases levels of glipizide(3)|
00107|044|D|and glimepiride,(9) there were no significant changes in blood glucose|
00107|045|D|response.|
00107|046|D|   A study in 9 healthy subjects examined the effects of rifampin (600 mg|
00107|047|D|daily for five days) on a single dose of repaglinide (0.5 mg). Pretreatment|
00107|048|D|with rifampin decreased the repaglinide area-under-curve (AUC), maximum|
00107|049|D|concentration (Cmax), and half-life (T1/2) by 57%, 41%, and 40%,|
00107|050|D|respectively.  The maximum decrease in blood glucose was reduced from 1.6|
00107|051|D|mmol/L to 1.0 mmol/L.(10)|
00107|052|D|  In a randomized cross-over study in 10 healthy subjects, pretreatment with|
00107|053|D|rifampin (600 mg daily for 6 days) decreased the the area-under-curve (AUC)|
00107|054|D|and half-life (T1/2) of a single dose of pioglitazone (30 mg) by 54% and by|
00107|055|D|53%, respectively.  There were no significant effects on pioglitazone|
00107|056|D|maximum concentration (Cmax) or time to Cmax (Tmax).  The AUC of the M-III|
00107|057|D|and M-IV active metabolites of pioglitazone increased by 34% and by 39%,|
00107|058|D|respectively.(11,12)|
00107|059|D|   In a randomized crossover study in 10 subjects, pretreatment with|
00107|060|D|rifampin (600 mg daily for 6 days) decreased the AUC, Cmax, and T1/2 of a|
00107|061|D|single dose of rosiglitazone (4 mg) by 54%, 28%, and 50%, respectively.  The|
00107|062|D|formation of N-desmethylrosiglitazone was increased.(13)|
00107|063|D|   In a randomized, open-label, cross-over study in 10 healthy Korean|
00107|064|D|subjects, pretreatment with rifampin (600 mg daily for 7 days) decreased the|
00107|065|D|AUC, Cmax, and T1/2 of a single dose of rosiglitazone (8 mg) by 65%, 32.6%,|
00107|066|D|and 69%, respectively.  The apparent oral clearance of rosiglitazone|
00107|067|D|increased by about 3-fold.(14)|
00107|068|B||
00107|069|R|REFERENCES:|
00107|070|B||
00107|071|R|1.Park JY, Kim KA, Park PW, Park CW, Shin JG. Effect of rifampin on the|2
00107|072|R|  pharmacokinetics and pharmacodynamics of gliclazide. Clin Pharmacol Ther|2
00107|073|R|  2003 Oct;74(4):334-40.|2
00107|074|R|2.Zheng HX, Huang Y, Frassetto LA, Benet LZ. Elucidating rifampin's inducing|2
00107|075|R|  and inhibiting effects on glyburide pharmacokinetics and blood glucose in|2
00107|076|R|  healthy volunteers: unmasking the differential effects of enzyme induction|2
00107|077|R|  and transporter inhibition for a drug and its primary metabolite. Clin|2
00107|078|R|  Pharmacol Ther 2009 Jan;85(1):78-85.|2
00107|079|R|3.Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivisto KT. Effects of|2
00107|080|R|  rifampin on the pharmacokinetics and pharmacodynamics of glyburide and|2
00107|081|R|  glipizide. Clin Pharmacol Ther 2001 Jun;69(6):400-6.|2
00107|082|R|4.Surekha V, Peter JV, Jeyaseelan L, Cherian AM. Drug interaction:|2
00107|083|R|  rifampicin and glibenclamide. Natl Med J India 1997 Jan-Feb;10(1):11-2.|2
00107|084|R|5.Zilly W, Breimer DD, Richter E. Induction of drug metabolism in man after|2
00107|085|R|  rifampicin treatment measured by increased hexobarbital and tolbutamide|2
00107|086|R|  clearance. Eur J Clin Pharmacol 1975 Dec 19;9(2-3):219-27.|2
00107|087|R|6.Self TH, Morris T. Interaction of rifampin and chlorpropamide. Chest 1980|3
00107|088|R|  Jun;77(6):800-1.|3
00107|089|R|7.Kihara Y, Otsuki M. Interaction of gliclazide and rifampicin. Diabetes|3
00107|090|R|  Care 2000 Aug;23(8):1204-5.|3
00107|091|R|8.Self TH, Tsiu SJ, Fowler JW Jr. Interaction of rifampin and glyburide.|3
00107|092|R|  Chest 1989 Dec;96(6):1443-4.|3
00107|093|R|9.Niemi M, Kivisto KT, Backman JT, Neuvonen PJ. Effect of rifampicin on the|2
00107|094|R|  pharmacokinetics and pharmacodynamics of glimepiride. Br J Clin Pharmacol|2
00107|095|R|  2000 Dec;50(6):591-5.|2
00107|096|R|10.Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivisto KT. Rifampin|2
00107|097|R|   decreases the plasma concentrations and effects of repaglinide. Clin|2
00107|098|R|   Pharmacol Ther 2000 Nov;68(5):495-500.|2
00107|099|R|11.Jaakkola T, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ. Effect of|2
00107|100|R|   rifampicin on the pharmacokinetics of pioglitazone. Br J Clin Pharmacol|2
00107|101|R|   2006 Jan;61(1):70-8.|2
00107|102|R|12.Actos (pioglitazone hydrochloride) US prescribing information. Takeda|1
00107|103|R|   Pharmaceuticals Inc. November, 2013.|1
00107|104|R|13.Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampin on|2
00107|105|R|   the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone.|2
00107|106|R|   Clin Pharmacol Ther 2004 Sep;76(3):239-49.|2
00107|107|R|14.Park JY, Kim KA, Kang MH, Kim SL, Shin JG. Effect of rifampin on the|2
00107|108|R|   pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol|2
00107|109|R|   Ther 2004 Mar;75(3):157-62.|2
00108|001|T|MONOGRAPH TITLE:  Antidiabetics, Oral/Oxy-Phenylbutazone|
00108|002|B||
00108|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00108|004|L|take action as needed.|
00108|005|B||
00108|006|A|MECHANISM OF ACTION:  Phenylbutazone may displace antidiabetics from plasma|
00108|007|A|protein binding sites. Renal elimination of the active metabolite of|
00108|008|A|acetohexamide may be reduced. Finally, tolbutamide metabolism may be|
00108|009|A|decreased.|
00108|010|B||
00108|011|E|CLINICAL EFFECTS:  Potentiation of antidiabetic effects.|
00108|012|B||
00108|013|P|PREDISPOSING FACTORS:  None determined.|
00108|014|B||
00108|015|M|PATIENT MANAGEMENT:  Hypoglycemic signs and blood glucose levels should be|
00108|016|M|monitored. Adjust the antidiabetic dose as needed.|
00108|017|B||
00108|018|D|DISCUSSION:  This interaction is well documented.|
00108|019|B||
00108|020|R|REFERENCES:|
00108|021|B||
00108|022|R|1.Field JB, Ohta M, Boyle C, Remer A. Potentiation of acetohexamide|2
00108|023|R|  hypoglycemia by phenylbutazone. N Engl J Med 1967 Oct 26;277(17):889-94.|2
00108|024|R|2.Tannenbaum H, Anderson LG, Soeldner JS. Letter: Phenylbutazone-tolbutamide|3
00108|025|R|  drug interaction. N Engl J Med 1974 Feb 7;290(6):344.|3
00110|001|T|MONOGRAPH TITLE:  Antidiabetics, Oral/Sulfonamide Antibacterials|
00110|002|B||
00110|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00110|004|L|take action as needed.|
00110|005|B||
00110|006|A|MECHANISM OF ACTION:  Not fully established. However, it is speculated that|
00110|007|A|sulfonamides may inhibit hepatic metabolism and/or displace oral|
00110|008|A|antidiabetics from plasma protein binding sites.|
00110|009|B||
00110|010|E|CLINICAL EFFECTS:  Increased serum levels of antidiabetics with potentiation|
00110|011|E|of hypoglycemic effects.|
00110|012|B||
00110|013|P|PREDISPOSING FACTORS:  None determined.|
00110|014|B||
00110|015|M|PATIENT MANAGEMENT:  Hypoglycemic signs and blood glucose levels should be|
00110|016|M|monitored. Adjust the antidiabetic dose as needed.|
00110|017|B||
00110|018|D|DISCUSSION:  Additional documentation is necessary to confirm this|
00110|019|D|interaction.|
00110|020|B||
00110|021|R|REFERENCES:|
00110|022|B||
00110|023|R|1.Christensen LK, Hansen JM, Kristensen M. Sulphaphenazole-induced|3
00110|024|R|  hypoglycaemic attackes in tolbutamide-treated diabetes. Lancet 1963 Dec|3
00110|025|R|  21;2:1298-301.|3
00110|026|R|2.Soeldner JS, Steinke J. Hypoglycemia in tolbutamide-treated diabetes. JAMA|3
00110|027|R|  1965 Aug 2;193(5):398-9.|3
00111|001|T|MONOGRAPH TITLE:  Antidiabetics, Oral/Clofibrate|
00111|002|B||
00111|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00111|004|L|take action as needed.|
00111|005|B||
00111|006|A|MECHANISM OF ACTION:  Not defined.|
00111|007|B||
00111|008|E|CLINICAL EFFECTS:  May observe enhanced hypoglycemic effects.|
00111|009|B||
00111|010|P|PREDISPOSING FACTORS:  Hypoalbuminemia.|
00111|011|B||
00111|012|M|PATIENT MANAGEMENT:  Monitor blood glucose and watch for signs of|
00111|013|M|hypoglycemia. This is particularly important when clofibrate is started or|
00111|014|M|stopped.|
00111|015|B||
00111|016|D|DISCUSSION:  Additional documentation is necessary to confirm this potential|
00111|017|D|interaction.|
00111|018|B||
00111|019|R|REFERENCES:|
00111|020|B||
00111|021|R|1.Daubresse JC, Luyckx AS, Lefebvre PJ. Letter: Potentiation of hypoglycemic|3
00111|022|R|  effect of sulfonylureas by clofibrate. N Engl J Med 1976 Mar 11;|3
00111|023|R|  294(11):613.|3
00111|024|R|2.Ferrari C, Frezzati S, Testori GP, Bertazzoni A. Potentiation of|3
00111|025|R|  hypoglycemic response to intravenous tolbutamide by clofibrate. N Engl J|3
00111|026|R|  Med 1976 May 20;294(21):1184.|3
00112|001|T|MONOGRAPH TITLE:  Antidiabetics, Oral/Aspirin (Greater Than 100 mg);|
00112|002|T|Salicylates|
00112|003|B||
00112|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00112|005|L|take action as needed.|
00112|006|B||
00112|007|A|MECHANISM OF ACTION:  Complex. Salicylates appear to have intrinsic glucose|
00112|008|A|lowering properties via several proposed mechanisms. Also, salicylates may|
00112|009|A|cause protein binding displacement of antidiabetics. Decreased renal|
00112|010|A|clearance may also occur.|
00112|011|B||
00112|012|E|CLINICAL EFFECTS:  Potentiation of hypoglycemic effects may be observed.|
00112|013|B||
00112|014|P|PREDISPOSING FACTORS:  None determined.|
00112|015|B||
00112|016|M|PATIENT MANAGEMENT:  Hypoglycemic signs and blood glucose levels should be|
00112|017|M|monitored. Adjust the antidiabetic dose as needed. Particular caution should|
00112|018|M|be taken when salicylates are started or stopped in patients previously|
00112|019|M|stabilized on antidiabetics.|
00112|020|B||
00112|021|D|DISCUSSION:  Additional documentation is necessary to confirm this potential|
00112|022|D|interaction.|
00112|023|B||
00112|024|R|REFERENCES:|
00112|025|B||
00112|026|R|1.Cherner R, Groppe CW, Rupp JJ. Prolonged tolbutamide-induced hypoglycemia.|3
00112|027|R|  JAMA 1963 Sep 14;185(11):883-4.|3
00112|028|R|2.Anonymous. Drug interaction. Br Med J 1971 Feb 13;1(745):389-91.|3
00113|001|T|MONOGRAPH TITLE:  Quinidine/Urinary Alkalinizers|
00113|002|B||
00113|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00113|004|L|take action as needed.|
00113|005|B||
00113|006|A|MECHANISM OF ACTION:  Quinidine elimination is impaired by urinary|
00113|007|A|alkalinization.|
00113|008|B||
00113|009|E|CLINICAL EFFECTS:  Potentiation of quinidine effects may be observed.|
00113|010|B||
00113|011|P|PREDISPOSING FACTORS:  None determined.|
00113|012|B||
00113|013|M|PATIENT MANAGEMENT:  Monitoring quinidine levels and cardiac function may be|
00113|014|M|indicated. The quinidine dose may need to be adjusted when a urinary|
00113|015|M|alkalinizer is started or stopped.|
00113|016|B||
00113|017|D|DISCUSSION:  Additional documentation is necessary to confirm this potential|
00113|018|D|interaction.|
00113|019|B||
00113|020|R|REFERENCES:|
00113|021|B||
00113|022|R|1.Gerhardt RE, Knouss RF, Thyrum PT, Luchi RJ, Morris JJ Jr. Quinidine|2
00113|023|R|  excretion in aciduria and alkaluria. Ann Intern Med 1969 Nov;71(5):927-33.|2
00113|024|R|2.Knouss RF, Gebhardt RE, Thyrum PT, Luchi RJ, Morris JJ. Variation in|4
00113|025|R|  quinidine excretion with changing urine pH. Ann Intern Med 1968 May;|4
00113|026|R|  68(5):1968 May.|4
00114|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Sulfinpyrazone|
00114|002|B||
00114|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00114|004|L|of severe adverse interaction.|
00114|005|B||
00114|006|A|MECHANISM OF ACTION:  Multiple processes may be involved: 1) Sulfinpyrazone|
00114|007|A|inhibits CYP2C9 hepatic metabolism of acenocoumarol and S-warfarin, the most|
00114|008|A|active warfarin enantiomer. 2) Sulfinpyrazone inhibits platelet activation.|
00114|009|B||
00114|010|E|CLINICAL EFFECTS:  Concurrent use of sulfinpyrazone with acenocoumarol or|
00114|011|E|warfarin may increase anticoagulant exposure (AUC, area-under-curve) and the|
00114|012|E|risk of bleeding.|
00114|013|B||
00114|014|P|PREDISPOSING FACTORS:  Patients with a CYP2C9 intermediate metabolizer|
00114|015|P|genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected|
00114|016|P|to be more susceptible to this interaction.|
00114|017|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00114|018|P|are expected to be less susceptible to effects from this drug combination,|
00114|019|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00114|020|P|*3/*3) result in an inherently higher warfarin or acenocoumarol half-life|
00114|021|P|and risk for anticoagulant-associated bleeding. CYP2C9 poor metabolizers|
00114|022|P|generally require lower anticoagulant doses and more time (>2 to 4 weeks) to|
00114|023|P|achieve effective and safe anticoagulation than patients without these|
00114|024|P|CYP2C9 variants.|
00114|025|B||
00114|026|M|PATIENT MANAGEMENT:  If both drugs are administered, monitor prothrombin|
00114|027|M|activity and adjust the acenocoumarol or warfarin dosage accordingly.|
00114|028|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00114|029|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00114|030|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00114|031|M|patients with any symptoms.|
00114|032|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00114|033|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00114|034|M|anticoagulation in patients with active pathologic bleeding.|
00114|035|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00114|036|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00114|037|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00114|038|M|and/or swelling.|
00114|039|M|   The time of highest risk for a warfarin drug interaction is when the|
00114|040|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00114|041|M|initiating, altering the dose or discontinuing either drug.|
00114|042|B||
00114|043|D|DISCUSSION:  In an interaction study performed in healthy males,|
00114|044|D|sulfinpyrazone 200 mg twice daily for 4 days, followed by a single dose of|
00114|045|D|warfarin 1.5 mg/kg, resulted in a 1.9-fold increase in S-warfarin exposure|
00114|046|D|(AUC).|
00114|047|B||
00114|048|R|REFERENCES:|
00114|049|B||
00114|050|R|1.Davis JW, Johns LE Jr. Possible interaction of sulfinpyrazone with|3
00114|051|R|  coumarins. N Engl J Med 1978 Oct 26;299(17):955.|3
00114|052|R|2.Girolami A, Fabris F, Casonato A, Randi ML. Potentiation of anticoagulant|2
00114|053|R|  response to warfarin by sulphinpyrazone: a double-blind study in patients|2
00114|054|R|  with prosthetic heart valves. Clin Lab Haematol 1982;4(1):23-6.|2
00114|055|R|3.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
00114|056|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
00114|057|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
00114|058|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
00114|059|R|  Oct;90(4):625-9.|6
00114|060|R|4.O'Reilly RA. Stereoselective interaction of sulfinpyrazone with racemic|2
00114|061|R|  warfarin and its separated enantiomorphs in man. Circulation 1982 Jan;|2
00114|062|R|  65(1):202-7.|2
00114|063|R|5.This information is based on an extract from the Certara Drug Interaction|6
00114|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00115|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Rifamycins|
00115|002|B||
00115|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00115|004|L|of severe adverse interaction.|
00115|005|B||
00115|006|A|MECHANISM OF ACTION:  Rifamycins (rifampin, rifabutin and rifapentine)|
00115|007|A|induce the CYP3A4 mediated metabolism of both estrogen and progestin|
00115|008|A|components of hormonal contraceptives.|
00115|009|B||
00115|010|E|CLINICAL EFFECTS:  Concurrent use of rifampin, rifabutin, or rifapentine may|
00115|011|E|result in reduced levels and clinical effectiveness of hormone containing|
00115|012|E|contraceptives.  Breakthrough bleeding and contraceptive failure/pregnancy|
00115|013|E|may result.  Effects may be seen for several weeks after discontinuation of|
00115|014|E|the rifamycin.|
00115|015|B||
00115|016|P|PREDISPOSING FACTORS:  None determined.|
00115|017|B||
00115|018|M|PATIENT MANAGEMENT:  Patients receiving rifamycins should be alerted to the|
00115|019|M|risk for decreased effectiveness(e.g. contraceptive failure) of their|
00115|020|M|hormonal contraceptive therapy.|
00115|021|M|   It is recommended that alternative or additional contraceptive methods be|
00115|022|M|used during and for several weeks after rifamycin therapy.  If a combined|
00115|023|M|oral contraceptive is used, the preparation should contain at least 30 mcg|
00115|024|M|of ethinyl estradiol should be used.  The patient should be asked to report|
00115|025|M|any spotting or bleeding.|
00115|026|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
00115|027|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
00115|028|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
00115|029|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
00115|030|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
00115|031|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
00115|032|M|and to seek medical advice if they do become pregnant.|
00115|033|B||
00115|034|D|DISCUSSION:  In an open-label, randomized crossover study, 22 healthy|
00115|035|D|females received oral contraceptives for 21 days, then were randomized to|
00115|036|D|receive rifampin or rifabutin (300 mg/d for 10 days).  Rifampin and|
00115|037|D|rifabutin decreased the area-under-curve (AUC) of ethinyl estradiol by 64%|
00115|038|D|and 35%, respectively, and maximum concentration (Cmax) by 42% and 20%,|
00115|039|D|respectively.  Rifampin and rifabutin decreased the AUC of norethindrone by|
00115|040|D|60% and 20%, respectively.  Incidences of spotting were much greater in the|
00115|041|D|rifampin co-administration group.|
00115|042|D|   In a study, a single dose of oral contraceptive (ethinyl estradiol 50 mcg|
00115|043|D|and norethindrone acetate 1 mg) was administered to 7 female patients with|
00115|044|D|tuberculosis, both during TB treatment and one month after stopping rifampin|
00115|045|D|(450-600 mg/d).  Upon cessation of rifampin therapy, the AUC for ethinyl|
00115|046|D|estradiol significantly increased by 70%, and terminal plasma half-life more|
00115|047|D|than doubled.|
00115|048|D|   A similar study design analyzed the pharmacokinetics of norethisterone (1|
00115|049|D|mg) in 8 women receiving rifampin (450-600 mg/d).  Upon termination of TB|
00115|050|D|treatment, it was found that rifampin reduced the AUC of a single dose of|
00115|051|D|norethisterone (1 mg) by approximately 40%, with a half-life reduction of|
00115|052|D|50%.|
00115|053|D|   In a study, male volunteers received 50 mcg iv of ethinyl estradiol,|
00115|054|D|followed by rifampin (600 mg for 6 days).  Ethinyl estradiol half-life|
00115|055|D|decreased by approximately 55%.  The upward titration of ethinyl estradiol|
00115|056|D|to 100 mcg resulted in a more than 2-fold increase in ethinyl estradiol|
00115|057|D|metabolism caused by rifampicin treatment.|
00115|058|D|   An analytical trial evaluated liver biopsies from four patients treated|
00115|059|D|with rifampin 600 mg for a period of 6-10 days.  Hepatic microsomes from the|
00115|060|D|biopsies were incubated with hormone substrates, including oestradiol and|
00115|061|D|ethinyl estradiol.  Rifampin resulted in a fourfold increase in|
00115|062|D|hydroxylation.  Not only did rifampin increase the rate of hydroxylation|
00115|063|D|through enzyme induction, it also caused an increase in cytochrome P-450.|
00115|064|D|   There are reports of breakthrough bleeding and unintended pregnancy|
00115|065|D|during concurrent use.|
00115|066|D|   A study of 118 HIV-positive females compared levonorgestrel|
00115|067|D|pharmacokinetics and safety between the following groups: 1. levonorgestrel|
00115|068|D|1.5 mg with dolutegravir-based antiretrovirals (ART)(control group), 2.|
00115|069|D|levonorgestrel 1.5 mg with efavirenz-based ART, 3. levonorgestrel 3 mg with|
00115|070|D|efavirenz-based ART, and 4. levonorgestrel 3 mg with rifampin.  While both|
00115|071|D|levonorgestrel 3 mg groups had Cmax and AUC(0-8h) similar to the control|
00115|072|D|group, the half life of levonorgestrel was shorter, resulting in an AUC(inf)|
00115|073|D|that was 53% lower in the efavirenz group and 37% lower in the rifampin|
00115|074|D|group than the control group.  Tolerability was similar between groups.  No|
00115|075|D|pregnancies were reported but it is unknown whether the correction of|
00115|076|D|levonorgestrel levels early in the dosing period is sufficient to maintain|
00115|077|D|overall emergency contraceptive effectiveness.(25)|
00115|078|B||
00115|079|R|REFERENCES:|
00115|080|B||
00115|081|R|1.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
00115|082|R|  Criteria for Contraceptive Use, 2016. MMWR Recomm Rep.  Available at:|6
00115|083|R|  https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf July 29, 2016;|6
00115|084|R|  65(3):.|6
00115|085|R|2.Altschuler SL, Valenteen JW. Amenorrhea following rifampin administration|3
00115|086|R|  during oral contraceptive use. Obstet Gynecol 1974 Nov;44(5):771-2.|3
00115|087|R|3.Skolnick JL, Stoler BS, Katz DB, Anderson WH. Rifampin, oral|3
00115|088|R|  contraceptives, and pregnancy. JAMA 1976 Sep 20;236(12):1382.|3
00115|089|R|4.Back DJ, Breckenridge AM, Crawford F, MacIver M, Orme ML, Park BK, Rowe|2
00115|090|R|  PH, Smith E. The effect of rifampicin on norethisterone pharmacokinetics.|2
00115|091|R|  Eur J Clin Pharmacol 1979 Apr 17;15(3):193-7.|2
00115|092|R|5.Joshi JV, Joshi UM, Sankolli GM, Gupta K, Rao AP, Hazari K, Sheth UK,|2
00115|093|R|  Saxena BN. A study of interaction of a low-dose combination oral|2
00115|094|R|  contraceptive with anti-tubercular drugs. Contraception 1980 Jun;|2
00115|095|R|  21(6):617-29.|2
00115|096|R|6.Back DJ, Breckenridge AM, Crawford FE, Hall JM, MacIver M, Orme ML, Rowe|2
00115|097|R|  PH, Smith E, Watts MJ. The effect of rifampicin on the pharmacokinetics of|2
00115|098|R|  ethynylestradiol in women. Contraception 1980 Feb;21(2):135-43.|2
00115|099|R|7.Gupta KC, Ali MY. Failure of oral contraceptive with rifampicin. Med J|3
00115|100|R|  Zambia 1980 Dec-1981 Jan;15(1):23.|3
00115|101|R|8.Baciewicz AM, Self TH. Rifampin drug interactions. Arch Intern Med 1984|6
00115|102|R|  Aug;144(8):1667-71.|6
00115|103|R|9.Barnett ML. Inhibition of oral contraceptive effectiveness by concurrent|6
00115|104|R|  antibiotic administration. A review. J Periodontol 1985 Jan;56(1):18-20.|6
00115|105|R|10.Baciewicz AM. Oral contraceptive drug interactions. Ther Drug Monit 1985;|6
00115|106|R|   7(1):26-35.|6
00115|107|R|11.Szoka PR, Edgren RA. Drug interactions with oral contraceptives:|6
00115|108|R|   compilation and analysis of an adverse experience report database. Fertil|6
00115|109|R|   Steril 1988 May;49(5 Suppl 2):31S-38S.|6
00115|110|R|12.Nor-Q-D (norethindrone) US prescribing information. WatsonPharma March,|1
00115|111|R|   2005.|1
00115|112|R|13.Barditch-Crovo P, Trapnell CB, Ette E, Zacur HA, Coresh J, Rocco LE,|2
00115|113|R|   Hendrix CW, Flexner C. The effects of rifampin and rifabutin on the|2
00115|114|R|   pharmacokinetics and pharmacodynamics of a combination oral|2
00115|115|R|   contraceptive. Clin Pharmacol Ther 1999 Apr;65(4):428-38.|2
00115|116|R|14.LeBel M, Masson E, Guilbert E, Colborn D, Paquet F, Allard S, Vallee F,|2
00115|117|R|   Narang PK. Effects of rifabutin and rifampicin on the pharmacokinetics of|2
00115|118|R|   ethinylestradiol and norethindrone. J Clin Pharmacol 1998 Nov;|2
00115|119|R|   38(11):1042-50.|2
00115|120|R|15.Buss WC. Induction of hepatic drug metabolizing enzymes and pregnancy|3
00115|121|R|   while taking oral contraceptives. J Antimicrob Chemother 1979 Jan;|3
00115|122|R|   5(1):4-5.|3
00115|123|R|16.Gelbke HP, Gethmann U, Knuppen R. Influence of rifampicin treatment on|2
00115|124|R|   the metabolic fate of. Horm Metab Res 1977 Sep;9(5):415-9.|2
00115|125|R|17.Bolt HM, Bolt M, Kappus H. Interaction of rifampicin treatment with|2
00115|126|R|   pharmacokinetics and metabolism of ethinyloestradiol in man. Acta|2
00115|127|R|   Endocrinol (Copenh) 1977 May;85(1):189-197.|2
00115|128|R|18.Bessot JC, Vandevenne A, Petitjean R, Burghard G. Antagonistic action of|2
00115|129|R|   rifampicin and isoniazid on the metabolism of oral contraceptives. Nouv|2
00115|130|R|   Presse Med 1977 Apr 30;6(18):1568.|2
00115|131|R|19.Dommisse J. Letter: Oral contraceptive failure due to drug interaction. S|3
00115|132|R|   Afr Med J 1976 May 15;50(21):796.|3
00115|133|R|20.Bolt HM, Kappus H, Bolt M. Effect of rifampicin treatment on the|5
00115|134|R|   metabolism of oestradiol and 17alpha-ethinyloestradiol by human liver|5
00115|135|R|   microsomes. Eur J Clin Pharmacol 1975 Jun 13;8(5):301-7.|5
00115|136|R|21.Priftin (rifapentine) US prescribing information. Sanofi-Aventis U.S. LLC|1
00115|137|R|   July, 2010.|1
00115|138|R|22.This information is based on an extract from the Certara Drug Interaction|6
00115|139|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00115|140|R|23.Medicines and Healthcare products Regulatory Agency.|1
00115|141|R|   Levonorgestrel-containing emergency hormonal contraception: advice on|1
00115|142|R|   interactions with hepatic enzyme inducers and contraceptive efficacy.|1
00115|143|R|   available at:|1
00115|144|R|   https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency|1
00115|145|R|   -hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-induce|1
00115|146|R|   rs-and-contraceptive-efficacy September 15, 2016..|1
00115|147|R|24.Simmons KB, Haddad LB, Nanda K, Curtis KM. Drug interactions between|6
00115|148|R|   rifamycin antibiotics and hormonal contraception: a systematic review.|6
00115|149|R|   BJOG 2018 Jun;125(7):804-811.|6
00115|150|R|25.Scarsi KK, Smeaton LM, Podany AT, Olefsky M, Woolley E, Barr E, Pham M,|2
00115|151|R|   Mawlana S, Supparatpinyo K, Gatechompol S, Jalil EM, Gadama L,|2
00115|152|R|   Badal-Faesen S, Belaunzaran-Zamudio PF, Godfrey C, etal. Pharmacokinetics|2
00115|153|R|   of dose-adjusted levonorgestrel emergency contraception combined  with|2
00115|154|R|   efavirenz-based antiretroviral therapy or rifampicin-containing|2
00115|155|R|   tuberculosis  regimens. Contraception 2023 Jan 12;109951.|2
00116|001|T|MONOGRAPH TITLE:  Carbamazepine/Hydantoins; Anticonvulsant Barbiturates|
00116|002|B||
00116|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00116|004|L|take action as needed.|
00116|005|B||
00116|006|A|MECHANISM OF ACTION:  Phenobarbital, phenytoin, primidone, and perhaps other|
00116|007|A|barbiturates and hydantoins, induce CYP3A4, which metabolizes carbamazepine.|
00116|008|A|   Carbamazepine may induce the CYP2C19 mediated metabolism of phenytoin.|
00116|009|A|The mechanism behind carbamazepine-induced increases in phenytoin levels is|
00116|010|A|unknown.|
00116|011|B||
00116|012|E|CLINICAL EFFECTS:  Concurrent use of barbiturates, phenytoin, and primidone|
00116|013|E|may result in decreased carbamazepine levels.  Concurrent use of|
00116|014|E|carbamazepine may result in increased or decreased phenytoin levels.|
00116|015|B||
00116|016|P|PREDISPOSING FACTORS:  None determined.|
00116|017|B||
00116|018|M|PATIENT MANAGEMENT:  These medications are commonly used concurrently.  The|
00116|019|M|greatest risk for a clinically significant interaction occurs when therapy|
00116|020|M|is modified.|
00116|021|M|   If carbamazepine is added to or discontinued from a regimen including|
00116|022|M|phenytoin, phenytoin levels may be altered, with some patients experiencing|
00116|023|M|increased levels and some decreased levels.  Monitor phenytoin serum levels|
00116|024|M|and adjust accordingly.  Monitor patients for both decreased efficacy (e.g.|
00116|025|M|seizures) and phenytoin toxicity.|
00116|026|M|   Patients taking phenytoin or barbiturates may require higher than|
00116|027|M|expected dosages of carbamazepine to achieve therapeutic levels.  Monitor|
00116|028|M|patients closely.|
00116|029|M|   If barbiturates, phenytoin, or primidone are added to a regimen including|
00116|030|M|carbamazepine, monitor carbamazepine levels and adjust dosages accordingly.|
00116|031|M|Monitor patients for decreased carbamazepine efficacy (e.g. seizures).  If|
00116|032|M|barbiturates, phenytoin, or primidone are discontinued, monitor patients for|
00116|033|M|carbamazepine toxicity and adjust carbamazepine dosages accordingly.|
00116|034|B||
00116|035|D|DISCUSSION:  In several studies, phenytoin's half-life and/or serum|
00116|036|D|concentrations were found to decrease when carbamazepine therapy was|
00116|037|D|instituted.  In one study, the half-life of phenytoin decreased from 10.6|
00116|038|D|hours to 6.4 hours (39.6%) after at least nine days of concomitant therapy|
00116|039|D|and the phenytoin levels decreased up to 50% in three of seven patients.|
00116|040|D|However, other studies have shown that phenytoin plasma levels increase when|
00116|041|D|carbamazepine is administered concomitantly.    In one study involving 24|
00116|042|D|patients maintained on phenytoin, the initiation of carbamazepine therapy|
00116|043|D|resulted in an 81.3% increase in phenytoin concentrations and an 82.9%|
00116|044|D|increase in the phenytoin concentration/dose ratio in 12 of the patients.|
00116|045|D|Five of the patients developed symptoms of acute phenytoin toxicity.  The|
00116|046|D|other 12 patients did not experience any change in phenytoin levels. In|
00116|047|D|another study involving 32 patients, the mean phenytoin plasma concentration|
00116|048|D|became significantly higher (36.9%) secondary to increased doses of|
00116|049|D|carbamazepine.  The phenytoin concentration/dose ratio also significantly|
00116|050|D|increased (39.3%).|
00116|051|D|   Several studies have shown decreased carbamazepine serum concentrations|
00116|052|D|when phenytoin was administered concurrently.  In one study involving 22|
00116|053|D|patients, the carbamazepine serum concentration was shown to increase by 28%|
00116|054|D|when the phenytoin dosage was reduced, indicating that phenytoin initially|
00116|055|D|reduced carbamazepine levels.|
00116|056|D|   Phenobarbital has been shown to decrease serum carbamazepine half-life|
00116|057|D|and plasma concentration levels when given in combination.  Significant|
00116|058|D|changes in carbamazepine serum concentrations were seen within five days|
00116|059|D|after the addition of phenobarbital to the therapeutic regimen.  Conversely,|
00116|060|D|carbamazepine appears to have no effect on serum phenobarbital levels.|
00116|061|D|   Another study involving children with seizure disorders evaluated the|
00116|062|D|effect of phenobarbital co-medication on carbamazepine serum levels.|
00116|063|D|Patients had been maintained on either carbamazepine alone or concurrent|
00116|064|D|carbamazepine and phenobarbital for at least one month.  There were no|
00116|065|D|significant differences in carbamazepine levels between patients receiving|
00116|066|D|carbamazepine alone or with concurrent phenobarbital.  However, the ratio of|
00116|067|D|carbamazepine level to dose was significantly decreased in patients|
00116|068|D|receiving concurrent phenobarbital (0.570?0.470 versus 0.627?0.353).  The|
00116|069|D|carbamazepine concentration ratios of two carbamazepine metabolites (the|
00116|070|D|10,11-epoxide metabolite and the 10,11-dihydroxy metabolite) were increased|
00116|071|D|in patients receiving concurrent carbamazepine and phenobarbital compared to|
00116|072|D|those receiving carbamazepine alone.|
00116|073|B||
00116|074|R|REFERENCES:|
00116|075|B||
00116|076|R|1.Lakehal F, Wurden CJ, Kalhorn TF, Levy RH. Carbamazepine and oxcarbazepine|5
00116|077|R|  decrease phenytoin metabolism through inhibition of CYP2C19. Epilepsy Res|5
00116|078|R|  2002 Dec;52(2):79-83.|5
00116|079|R|2.McKee PJ, Blacklaw J, Forrest G, Gillham RA, Walker SM, Connelly D, Brodie|2
00116|080|R|  MJ. A double-blind, placebo-controlled interaction study between|2
00116|081|R|  oxcarbazepine and carbamazepine, sodium valproate and phenytoin in|2
00116|082|R|  epileptic patients. Br J Clin Pharmacol 1994 Jan;37(1):27-32.|2
00116|083|R|3.Hansen JM, Siersboek-Nielsen K, Skovsted L. Carbamazepine-induced|2
00116|084|R|  acceleration of diphenylhydantoin and warfarin metabolism in man. Clin|2
00116|085|R|  Pharmacol Ther 1971 May-Jun;12(3):539-43.|2
00116|086|R|4.Windorfer A Jr, Sauer W. Drug interactions during anticonvulsant therapy|5
00116|087|R|  in childhood: diphenylhydantoin,  primidone, phenobarbitone, clonazepam,|5
00116|088|R|  nitrazepam, carbamazepin and dipropylacetate. Neuropadiatrie 1977 Feb;|5
00116|089|R|  8(1):29-41.|5
00116|090|R|5.Zielinski JJ, Haidukewych D, Leheta BJ. Carbamazepine-phenytoin|2
00116|091|R|  interaction: elevation of plasma phenytoin concentrations due to|2
00116|092|R|  carbamazepine comedication. Ther Drug Monit 1985;7(1):51-3.|2
00116|093|R|6.Zielinski JJ, Haidukewych D. Dual effects of carbamazepine-phenytoin|2
00116|094|R|  interaction. Ther Drug Monit 1987;9(1):21-3.|2
00116|095|R|7.Perucca E, Richens A. Reversal by phenytoin of carbamazepine-induced water|2
00116|096|R|  intoxication: a pharmacokinetic interaction. J Neurol Neurosurg Psychiatry|2
00116|097|R|  1980 Jun;43(6):540-5.|2
00116|098|R|8.Christiansen J, Dam M. Influence of phenobarbital and diphenylhydantoin on|2
00116|099|R|  plasma carbamazepine levels in patients with epilepsy. Acta Neurol Scand|2
00116|100|R|  1973;49(4):543-6.|2
00116|101|R|9.Lander CM, Eadie MJ, Tyrer JH. Interactions between anticonvulsants. Proc|2
00116|102|R|  Aust Assoc Neurol 1975;12:111-6.|2
00116|103|R|10.Lander CM, Eadie MJ, Tyrer JH. Factors influencing plasma carbamazepine|2
00116|104|R|   concentrations. Clin Exp Neurol 1977;14:184-93.|2
00116|105|R|11.Cereghino JJ, Brock JT, Van Meter JC, Penry JK, Smith LD, White BG. The|2
00116|106|R|   efficacy of carbamazepine combinations in epilepsy. Clin Pharmacol Ther|2
00116|107|R|   1975 Dec;18(6):733-41.|2
00116|108|R|12.McKauge L, Tyrer JH, Eadie MJ. Factors influencing simultaneous|2
00116|109|R|   concentrations of carbamazepine and its epoxide  in plasma. Ther Drug|2
00116|110|R|   Monit 1981;3(1):63-70.|2
00116|111|R|13.Dam M, Jensen A, Christiansen J. Plasma level and effect of carbamazepine|2
00116|112|R|   in grand mal and psychomotor epilepsy. Acta Neurol Scand Suppl 1975;|2
00116|113|R|   60:33-8.|2
00116|114|R|14.Rane A, Hojer B, Wilson JT. Kinetics of carbamazepine and its|2
00116|115|R|   10,11-epoxide metabolite in children. Clin Pharmacol Ther 1976 Mar;|2
00116|116|R|   19(3):276-83.|2
00116|117|R|15.Liu H, Delgado MR. Interactions of phenobarbital and phenytoin with|2
00116|118|R|   carbamazepine and its metabolites' concentrations, concentration ratios,|2
00116|119|R|   and level/dose ratios in epileptic children. Epilepsia 1995 Mar;|2
00116|120|R|   36(3):249-54.|2
00116|121|R|16.Venci JV, Rowcliffe MM, Wollenberg L, Rainka MM, Gengo FM.|3
00116|122|R|   Pharmacokinetic simulation of fatal carbamazepine intoxication in|3
00116|123|R|   23-month old child following phenytoin discontinuation. Forensic Sci Med|3
00116|124|R|   Pathol 2013 Mar;9(1):73-6.|3
00116|125|R|17.Fukuoka N, Tsukamoto T, Uno J, Kimura M, Morita S. Effects of concomitant|2
00116|126|R|   antiepileptic drugs on serum carbamazepine concentration in epileptic|2
00116|127|R|   patients: quantitative analysis based on extracellular water volume  as a|2
00116|128|R|   transforming factor. Yakugaku Zasshi 2003 Jan;123(1):35-42.|2
00116|129|R|18.Sennoune S, Iliadis A, Bonneton J, Barra Y, Genton P, Mesdjian E. Steady|2
00116|130|R|   state pharmacokinetics of carbamazepine-phenobarbital interaction in|2
00116|131|R|   patients with epilepsy. Biopharm Drug Dispos 1996 Mar;17(2):155-64.|2
00116|132|R|19.Chapron DJ, LaPierre BA, Abou-Elkair M. Unmasking the significant|2
00116|133|R|   enzyme-inducing effects of phenytoin on serum carbamazepine|2
00116|134|R|   concentrations during phenytoin withdrawal. Ann Pharmacother 1993 Jun;|2
00116|135|R|   27(6):708-11.|2
00116|136|R|20.Spina E, Martines C, Fazio A, Trio R, Pisani F, Tomson T. Effect of|2
00116|137|R|   phenobarbital on the pharmacokinetics of carbamazepine-10,11-epoxide, an|2
00116|138|R|   active metabolite of carbamazepine. Ther Drug Monit 1991 Mar;|2
00116|139|R|   13(2):109-12.|2
00116|140|R|21.Ichikou N, Ieiri I, Higuchi S, Hirata K, Yamada H, Aoyama T. Analysis of|2
00116|141|R|   the factors influencing anti-epileptic drug|2
00116|142|R|   concentrations--carbamazepine. J Clin Pharm Ther 1990 Oct;15(5):337-49.|2
00116|143|R|22.Benetello P, Furlanut M. Primidone-carbamazepine interaction: clinical|3
00116|144|R|   consequences. Int J Clin Pharmacol Res 1987;7(2):165-8.|3
00117|001|T|MONOGRAPH TITLE:  Metoprolol; Propranolol/Cimetidine|
00117|002|B||
00117|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00117|004|L|take action as needed.|
00117|005|B||
00117|006|A|MECHANISM OF ACTION:  Cimetidine inhibition of CYP2D6 may reduce the|
00117|007|A|metabolism of metoprolol and propranolol.|
00117|008|B||
00117|009|E|CLINICAL EFFECTS:  Concurrent use of cimetidine may result in increased|
00117|010|E|pharmacologic and toxic side effects of metoprolol and propranolol.|
00117|011|B||
00117|012|P|PREDISPOSING FACTORS:  None determined.|
00117|013|B||
00117|014|M|PATIENT MANAGEMENT:  Lower dosages of metoprolol and propranolol may be|
00117|015|M|required in patients receiving cimetidine.  When initiating cimetidine in a|
00117|016|M|patient maintained on metoprolol or propranolol, observe the patient for|
00117|017|M|increased beta-blocker effects such as lower heart rate and blood pressure.|
00117|018|M|Consider lower starting doses of metoprolol or propranolol in patients|
00117|019|M|receiving cimetidine.|
00117|020|M|   A dosage adjustment of the beta-blocker may be necessary when initiating|
00117|021|M|or discontinuing cimetidine.|
00117|022|M|   Since other H-2 antagonists (e.g., ranitidine, famotidine) do not appear|
00117|023|M|to interact, substituting cimetidine with one of these agents may be|
00117|024|M|desirable.  However, if a patient is already receiving this combination and|
00117|025|M|is not experiencing adverse effects, substitution is probably not necessary.|
00117|026|B||
00117|027|D|DISCUSSION:  Concurrent administration of cimetidine (1G/day to 1.2G/day)|
00117|028|D|and propranolol has resulted in approximately a two-fold increase in|
00117|029|D|propranolol plasma concentrations as well as an increase in its|
00117|030|D|area-under-curve (AUC) and half-life after single (80mg) or multiple|
00117|031|D|(160mg/day) doses. The alterations in propranolol levels were seen within 24|
00117|032|D|to 48 hours.(1-12)|
00117|033|D|   Concurrent administration of cimetidine increased the AUC of metoprolol|
00117|034|D|by 60% to 70%.(11-17)|
00117|035|B||
00117|036|R|REFERENCES:|
00117|037|B||
00117|038|R|1.Feely J, Wilkinson GR, Wood AJ. Reduction of liver blood flow and|2
00117|039|R|  propranolol metabolism by cimetidine. N Engl J Med 1981 Mar 19;|2
00117|040|R|  304(12):692-5.|2
00117|041|R|2.Donovan MA, Heagerty AM, Patel L, Castleden M, Pohl JE. Cimetidine and|2
00117|042|R|  bioavailability of propranolol. Lancet 1981 Jan 17;1(8212):164.|2
00117|043|R|3.Heagerty AM, Donovan MA, Castleden CM, Pohl JF, Patel L, Hedges A.|2
00117|044|R|  Influence of cimetidine on pharmacokinetics of propranolol. Br Med J (Clin|2
00117|045|R|  Res Ed) 1981 Jun 13;282(6280):1917-9.|2
00117|046|R|4.Duchin KL, Stern MA, Willard DA, McKinstry DN. Kinetic interactions of|2
00117|047|R|  nadolol and propranolol with cimetidine. Br J Clin Pharmacol 1984 Apr;|2
00117|048|R|  17(4):486-7.|2
00117|049|R|5.Duchin KL, Stern MA, Willard DA, McKinstry DN. Comparison of kinetic|2
00117|050|R|  interactions of nadolol and propranolol with cimetidine. Am Heart J 1984|2
00117|051|R|  Oct;108(4 Pt 2):1084-6.|2
00117|052|R|6.Reimann IW, Klotz U, Siems B, Frolich J. Cimetidine increases steady state|2
00117|053|R|  plasma levels of propranolol. Br J Clin Pharmacol 1981 Dec;12(6):785-90.|2
00117|054|R|7.Reimann IW, Klotz U, Frolich JC. Effects of cimetidine and ranitidine on|2
00117|055|R|  steady-state propranolol kinetics and dynamics. Clin Pharmacol Ther 1982|2
00117|056|R|  Dec;32(6):749-57.|2
00117|057|R|8.Donn KH, Powell JR, Rogers JF, Eshelman FN. The influence of H2-receptor|2
00117|058|R|  antagonists on steady-state concentrations of propranolol and|2
00117|059|R|  4-hydroxypropranolol. J Clin Pharmacol 1984 Nov-Dec;24(11-12):500-8.|2
00117|060|R|9.Kirch W, Spahn H, Kohler H, Ohnhaus EE, Mutschler E. Interaction of|2
00117|061|R|  metoprolol, propranolol and atenolol with concurrent administration of|2
00117|062|R|  cimetidine. Klin Wochenschr 1982 Nov 15;60(22):1401-7.|2
00117|063|R|10.Kirch W, Spahn H, Kohler H, Mutschler E. Accumulation and adverse effects|2
00117|064|R|   of metoprolol and propranolol after concurrent administration of|2
00117|065|R|   cimetidine. Arch Toxicol Suppl 1983;6:379-83.|2
00117|066|R|11.Mutschler E, Spahn H, Kirch W. The interaction between H2-receptor|2
00117|067|R|   antagonists and beta-adrenoceptor blockers. Br J Clin Pharmacol 1984;17|2
00117|068|R|   Suppl 1:51S-57S.|2
00117|069|R|12.Spahn H, Kirch W, Mutschler E. The interaction of cimetidine with|2
00117|070|R|   metoprolol, atenolol, propranolol, pindolol and penbutolol. Br J Clin|2
00117|071|R|   Pharmacol 1983 Apr;15(4):500-1.|2
00117|072|R|13.Kirch W, Kohler H, Spahn H, Mutschler E. Interaction of cimetidine with|2
00117|073|R|   metoprolol, propranolol, or atenolol. Lancet 1981 Sep 05;2(8245):531-2.|2
00117|074|R|14.Houtzagers JJ, Streurman O, Regardh CG. The effect of pretreatment with|2
00117|075|R|   cimetidine on the bioavailability and disposition of atenolol and|2
00117|076|R|   metoprolol. Br J Clin Pharmacol 1982 Jul;14(1):67-72.|2
00117|077|R|15.Kirch W, Ramsch K, Janisch HD, Ohnhaus EE. The influence of two histamine|2
00117|078|R|   H2-receptor antagonists, cimetidine and ranitidine, on the plasma levels|2
00117|079|R|   and clinical effect of nifedipine and metoprolol. Arch Toxicol Suppl|2
00117|080|R|   1984;7:256-9.|2
00117|081|R|16.Toon S, Davidson EM, Garstang FM, Batra H, Bowes RJ, Rowland M. The|2
00117|082|R|   racemic metoprolol H2-antagonist interaction. Clin Pharmacol Ther 1988|2
00117|083|R|   Mar;43(3):283-9.|2
00117|084|R|17.Heagerty AM, Castleden CM, Patel L. Failure of ranitidine to interact|2
00117|085|R|   with propranolol. Br Med J (Clin Res Ed) 1982 May 1;284(6325):1304.|2
00117|086|R|18.Spahn H, Mutschler E, Kirch W, Ohnhaus EE, Janisch HD. Influence of|2
00117|087|R|   ranitidine on plasma metoprolol and atenolol concentrations. Br Med J|2
00117|088|R|   (Clin Res Ed) 1983 May 14;286(6377):1546-7.|2
00117|089|R|19.Kelly JG, Salem SA, Kinney CD, Shanks RG, McDevitt DG. Effects of|2
00117|090|R|   ranitidine on the disposition of metoprolol. Br J Clin Pharmacol 1985|2
00117|091|R|   Feb;19(2):219-24.|2
00118|001|T|MONOGRAPH TITLE:  Propoxyphene/Carbamazepine|
00118|002|B||
00118|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00118|004|L|of severe adverse interaction.|
00118|005|B||
00118|006|A|MECHANISM OF ACTION:  Propoxyphene may inhibit carbamazepine metabolism.|
00118|007|B||
00118|008|E|CLINICAL EFFECTS:  Concurrent use of propoxyphene may result in elevated|
00118|009|E|levels of and toxicity from carbamazepine.|
00118|010|B||
00118|011|P|PREDISPOSING FACTORS:  None determined.|
00118|012|B||
00118|013|M|PATIENT MANAGEMENT:  If both drugs are administered, monitor plasma|
00118|014|M|carbamazepine levels and observe the patient for signs and symptoms of|
00118|015|M|carbamazepine toxicity.  Adjust the dose of the drug accordingly.|
00118|016|B||
00118|017|D|DISCUSSION:  In a study, carbamazepine levels increased 66% after 6 days of|
00118|018|D|dextropropoxyphene.  Additional increases were seen in 3 subjects after an|
00118|019|D|additional 7 days of dextropropoxyphene.(1)|
00118|020|D|   In a study in 7 patients maintained on carbamazepine, the addition of|
00118|021|D|propoxyphene increased carbamazepine levels by 45%-77%.  Two patients|
00118|022|D|discontinued propoxyphene after 2 days because of side effects.  Three other|
00118|023|D|patients had drug intoxication symptoms.(2)|
00118|024|D|   In a retrospective review, carbamazepine doses were lower but|
00118|025|D|carbamazepine levels were higher in patients receiving concurrent|
00118|026|D|propoxyphene.(3)|
00118|027|D|   There are several case reports of carbamazepine toxicity during|
00118|028|D|concurrent propoxyphene.(4-8)|
00118|029|B||
00118|030|R|REFERENCES:|
00118|031|B||
00118|032|R|1.Hansen BS, Dam M, Brandt J, Hvidberg EF, Angelo H, Christensen JM, Lous P.|2
00118|033|R|  Influence of dextropropoxyphene on steady state serum levels and protein|2
00118|034|R|  binding of three anti-epileptic drugs in man. Acta Neurol Scand 1980 Jun;|2
00118|035|R|  61(6):357-67.|2
00118|036|R|2.Dam M, Kristensen CB, Hansen BS, Christiansen J. Interaction between|2
00118|037|R|  carbamazepine and propoxyphene in man. Acta Neurol Scand 1977 Dec;|2
00118|038|R|  56(6):603-7.|2
00118|039|R|3.Bergendal L, Friberg A, Schaffrath AM, Holmdahl M, Landahl S. The clinical|2
00118|040|R|  relevance of the interaction between carbamazepine and dextropropoxyphene|2
00118|041|R|  in elderly patients in Gothenburg, Sweden. Eur J Clin Pharmacol 1997;|2
00118|042|R|  53(3-4):203-6.|2
00118|043|R|4.Yu YL, Huang CY, Chin D, Woo E, Chang CM. Interaction between|3
00118|044|R|  carbamazepine and dextropropoxyphene. Postgrad Med J 1986 Mar;|3
00118|045|R|  62(725):231-3.|3
00118|046|R|5.Kubacka RT, Ferrante JA. Carbamazepine-propoxyphene interaction. Clin|3
00118|047|R|  Pharm 1983 Mar-Apr;2(2):104.|3
00118|048|R|6.Oles KS, Mirza W, Penry JK. Catastrophic neurologic signs due to drug|3
00118|049|R|  interaction: Tegretol and Darvon. Surg Neurol 1989 Aug;32(2):144-51.|3
00118|050|R|7.Allen S. Cerebellar dysfunction following dextropropoxyphene-induced|3
00118|051|R|  carbamazepine toxicity. Postgrad Med J 1994 Oct;70(828):764.|3
00118|052|R|8.Bertholon P, Convers P, Lachheb N, Guy C, Martin C, Ollagnier M, Michel D.|3
00118|053|R|  Predominant central vestibular symptomatology caused by carbamazepine and|3
00118|054|R|  dextropropoxyphene interaction. Presse Med 1997 Nov 15;26(35):1675.|3
00119|001|T|MONOGRAPH TITLE:  NSAIDs; Salicylates/Lithium|
00119|002|B||
00119|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00119|004|L|take action as needed.|
00119|005|B||
00119|006|A|MECHANISM OF ACTION:  Decreased renal excretion of lithium, possibly|
00119|007|A|resulting from NSAID-induced prostaglandin inhibition.|
00119|008|B||
00119|009|E|CLINICAL EFFECTS:  May observe increased lithium toxicity.|
00119|010|B||
00119|011|P|PREDISPOSING FACTORS:  Risk factors for lithium toxicity include: renal|
00119|012|P|impairment or worsening of existing renal disease, dehydration, low sodium|
00119|013|P|diet, and concomitant use of multiple medications which may impair renal|
00119|014|P|elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics).|
00119|015|P|Patients who require higher therapeutic lithium levels to maintain symptom|
00119|016|P|control are particularly susceptible to these factors.|
00119|017|B||
00119|018|M|PATIENT MANAGEMENT:  The magnitude of this interaction is highly variable.|
00119|019|M|Patients with predisposing factors, e.g. dehydration, renal impairment, or|
00119|020|M|concurrent use of other agents which may impair lithium elimination, are|
00119|021|M|expected to have a higher risk for lithium toxicity.|
00119|022|M|   If both drugs are administered, monitor plasma lithium levels and observe|
00119|023|M|the patient for signs and symptoms of lithium toxicity or changes in renal|
00119|024|M|function.  Full effects of the addition or an increase in NSAID dose may not|
00119|025|M|be seen for one to two weeks.  Adjust the dose of lithium accordingly.|
00119|026|M|   If lithium is to be started in a patient stabilized on chronic NSAID|
00119|027|M|therapy, consider starting with a lower lithium dose and titrate slowly as|
00119|028|M|half-life may be prolonged.  Monitor lithium concentrations until stabilized|
00119|029|M|on the combination.|
00119|030|M|   Counsel the patient to contact their prescriber before starting an OTC|
00119|031|M|NSAID. Assure that patients are familiar with signs and symptoms of lithium|
00119|032|M|toxicity (e.g. new or worsening tremor, nausea/vomiting, diarrhea, ataxia,|
00119|033|M|or altered mental status) and to report signs and symptoms of toxicity.|
00119|034|B||
00119|035|D|DISCUSSION:  Numerous studies and case reports have been documented that|
00119|036|D|administration of a NSAID to a patient stabilized on lithium therapy may|
00119|037|D|result in increased serum lithium levels and possible toxicity. Full effects|
00119|038|D|may take 1 to 2 weeks to develop and may persist for a week after the NSAID|
00119|039|D|is discontinued.|
00119|040|B||
00119|041|R|REFERENCES:|
00119|042|B||
00119|043|R|1.Frolich JC, Leftwich R, Ragheb M, Oates JA, Reimann I, Buchanan D.|2
00119|044|R|  Indomethacin increases plasma lithium. Br Med J 1979 Apr 28;|2
00119|045|R|  1(6171):1115-6.|2
00119|046|R|2.Ragheb M, Ban TA, Buchanan D, Frolich JC. Interaction of indomethacin and|2
00119|047|R|  ibuprofen with lithium in manic patients under a steady-state lithium|2
00119|048|R|  level. J Clin Psychiatry 1980 Nov;41(11):397-8.|2
00119|049|R|3.Reimann IW, Frolich JC. Effects of diclofenac on lithium kinetics. Clin|2
00119|050|R|  Pharmacol Ther 1981 Sep;30(3):348-52.|2
00119|051|R|4.Herschberg SN, Sierles FS. Indomethacin-induced lithium toxicity. Am Fam|3
00119|052|R|  Physician 1983 Aug;28(2):155-7.|3
00119|053|R|5.Reimann IW, Diener U, Frolich JC. Indomethacin but not aspirin increases|2
00119|054|R|  plasma lithium ion levels. Arch Gen Psychiatry 1983 Mar;40(3):283-6.|2
00119|055|R|6.Kerry RJ, Owen G, Michaelson S. Possible toxic interaction between lithium|3
00119|056|R|  and piroxicam. Lancet 1983 Feb 19;1(8321):418-9.|3
00119|057|R|7.Nadarajah J, Stein GS. Piroxicam induced lithium toxicity. Ann Rheum Dis|3
00119|058|R|  1985 Jul;44(7):502.|3
00119|059|R|8.Walbridge DG, Bazire SR. An interaction between lithium carbonate and|3
00119|060|R|  piroxicam presenting as lithium toxicity. Br J Psychiatry 1985 Aug;|3
00119|061|R|  147:206-7.|3
00119|062|R|9.Ragheb M, Powell AL. Lithium interaction with sulindac and naproxen. J|2
00119|063|R|  Clin Psychopharmacol 1986 Jun;6(3):150-4.|2
00119|064|R|10.Harrison TM, Davies DW, Norris CM. Lithium carbonate and piroxicam. Br J|3
00119|065|R|   Psychiatry 1986 Jul;149:124-5.|3
00119|066|R|11.Kristoff CA, Hayes PE, Barr WH, Small RE, Townsend RJ, Ettigi PG. Effect|2
00119|067|R|   of ibuprofen on lithium plasma and red blood cell concentrations. Clin|2
00119|068|R|   Pharm 1986 Jan;5(1):51-5.|2
00119|069|R|12.Ragheb M. Ibuprofen can increase serum lithium level in lithium-treated|2
00119|070|R|   patients. J Clin Psychiatry 1987 Apr;48(4):161-3.|2
00119|071|R|13.Stein G, Robertson M, Nadarajah J. Toxic interactions between lithium and|6
00119|072|R|   non-steroidal anti-inflammatory drugs. Psychol Med 1988 Aug;18(3):535-43.|6
00119|073|R|14.Bailey CE, Stewart JT, McElroy RA. Ibuprofen-induced lithium toxicity.|3
00119|074|R|   South Med J 1989 Sep;82(9):1197.|3
00119|075|R|15.Ragheb M. The clinical significance of lithium-nonsteroidal|2
00119|076|R|   anti-inflammatory drug interactions. J Clin Psychopharmacol 1990 Oct;|2
00119|077|R|   10(5):350-4.|2
00119|078|R|16.Khan IH. Lithium and non-steroidal anti-inflammatory drugs. BMJ 1991 Jun|3
00119|079|R|   22;302(6791):1537-8.|3
00119|080|R|17.Langlois R, Paquette D. Increased serum lithium levels due to ketorolac|3
00119|081|R|   therapy. CMAJ 1994 May 1;150(9):1455-6.|3
00119|082|R|18.Iyer V. Ketorolac (Toradol) induced lithium toxicity. Headache 1994|3
00119|083|R|   Jul-Aug;34(7):442-4.|3
00119|084|R|19.Bravo AE, Egger SS, Crespo S, Probst WL, Krahenbuhl S. Lithium|3
00119|085|R|   intoxication as a result of an interaction with rofecoxib. Ann|3
00119|086|R|   Pharmacother 2004 Jul-Aug;38(7-8):1189-93.|3
00119|087|R|20.Lithobid (lithium carbonate) US prescribing information. ANI|1
00119|088|R|   Pharmaceuticals, Inc. May, 2018.|1
00120|001|T|MONOGRAPH TITLE:  Selected Anticonvulsants; Barbiturates/Contraceptives|
00120|002|B||
00120|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00120|004|L|of severe adverse interaction.|
00120|005|B||
00120|006|A|MECHANISM OF ACTION:  Barbiturates, hydantoins, and primidone may increase|
00120|007|A|the metabolism of the contraceptives via CYP3A4 induction.|
00120|008|B||
00120|009|E|CLINICAL EFFECTS:  May observe reduced contraceptive effects such as|
00120|010|E|breakthrough bleeding, spotting, or pregnancy.  Effects may be seen several|
00120|011|E|days after discontinuation of the anticonvulsant or barbiturate.|
00120|012|E|   In addition, topiramate has been associated with an increased risk of|
00120|013|E|birth defects, including cleft palate.|
00120|014|B||
00120|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00120|016|P|of the inducer for longer than 1-2 weeks.|
00120|017|B||
00120|018|M|PATIENT MANAGEMENT:  To avoid pregnancy, additional or alternative means of|
00120|019|M|non-hormonal contraception should be utilized.  Depo medroxyprogesterone may|
00120|020|M|be an alternative, since its effectiveness is not decreased by|
00120|021|M|anticonvulsants.|
00120|022|M|   Patients receiving perampanel at doses of 12 mg/day should use|
00120|023|M|alternative contraception methods, such as an intra-uterine device or|
00120|024|M|condom.|
00120|025|M|   Patients receiving topiramate may observe decreased contraceptive|
00120|026|M|efficacy and increased breakthrough bleeding, especially at doses greater|
00120|027|M|than 200 mg per day.  Patients taking topiramate and estrogen containing or|
00120|028|M|progestin-only contraceptives should be asked to report any change in their|
00120|029|M|bleeding patterns.(20)|
00120|030|M|   Patients taking the combination of phentermine/topiramate for weight loss|
00120|031|M|should be counseled that break-through bleeding may occur but is not|
00120|032|M|expected to increase the risk of pregnancy.  Instruct patients to report|
00120|033|M|changes in bleeding patterns to their physician and to continue to take|
00120|034|M|their hormonal contraceptive.  Patients should not rely on hormonal|
00120|035|M|contraceptives (other than implants or IUD) alone, but may use them in|
00120|036|M|combination with a barrier contraceptive. It is necessary to use effective|
00120|037|M|contraception with phentermine/topiramate, because the topiramate content of|
00120|038|M|the product can cause birth defects.|
00120|039|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
00120|040|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
00120|041|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
00120|042|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
00120|043|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
00120|044|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
00120|045|M|and to seek medical advice if they do become pregnant.|
00120|046|B||
00120|047|D|DISCUSSION:  Decreased effectiveness of oral contraceptives, characterized|
00120|048|D|by breakthrough bleeding and amenorrhea have been documented.  Through|
00120|049|D|August, 2010, Australia's Therapeutic Goods Association had received 32|
00120|050|D|reports of contraceptive failure leading to pregnancy as a result of a|
00120|051|D|suspected interaction between etonogestrel implants and carbamazepine.|
00120|052|D|   In a randomized, open-label study in healthy women, concurrent topiramate|
00120|053|D|(50 mg daily to 200 mg daily) and Ortho Novum 1/35 (ethinyl estradiol and|
00120|054|D|norethindrone) resulted in no changes in levels of ethinyl estradiol or|
00120|055|D|norethindrone.  However, in another study, concurrent topiramate at doses of|
00120|056|D|200 mg daily, 400 mg daily, and 800 mg daily with valproic acid decreased|
00120|057|D|the area-under-curve (AUC) of ethinyl estradiol by 18%, 21%, and 30%,|
00120|058|D|respectively.  There were no changes in norethindrone levels.  The US|
00120|059|D|manufacturer of topiramate states that the possibility of decreased|
00120|060|D|contraceptive effectiveness should be considered.|
00120|061|D|   At doses of 12 mg/day, perampanel decreased the maximum concentration|
00120|062|D|(Cmax) and AUC of levonorgestrel by 40% each.  The Cmax of ethinyl estradiol|
00120|063|D|was decreased by 18%.  There were no effects on ethinyl estradiol AUC.|
00120|064|D|Doses of perampanel of 4 mg/day and 8 mg/day had no effect on contraceptive|
00120|065|D|levels.|
00120|066|D|   The combination of phentermine/topiramate (15 mg/92 mg for 15 days)|
00120|067|D|increased the Cmax and AUC of norethindrone by 22% and 16%, respectively.|
00120|068|D|The Cmax and AUC of ethinyl estradiol decreased 8% and 16%, respectively.|
00120|069|D|Because contraceptive efficacy is primarily determined by the progestin|
00120|070|D|component, no effect on contraceptive efficacy is expected, although|
00120|071|D|breakthrough bleeding may occur.|
00120|072|D|   The effectiveness of depo medroxyprogesterone is not decreased by|
00120|073|D|anticonvulsants or barbiturates.|
00120|074|B||
00120|075|R|REFERENCES:|
00120|076|B||
00120|077|R|1.Copeman H. Oral contraceptives. Med J Aust 1963 Dec 7;2:969.|3
00120|078|R|2.McArthur J. Oral contraceptives and epilepsy. Br Med J 1967 Jul 15;3:162.|3
00120|079|R|3.Kutt H, McDowell F. Management of epilepsy with diphenylhydantoin sodium.|6
00120|080|R|  Dosage regulation for problem patients. JAMA 1968 Mar 11;203(11):969-72.|6
00120|081|R|4.Espir M, Walker ME, Lawson JP. Epilepsy and oral contraception. Br Med J|2
00120|082|R|  1969 Feb 1;1(639):294-5.|2
00120|083|R|5.Kenyon IE. Unplanned pregnancy in an epileptic. Br Med J 1972 Mar 11;|3
00120|084|R|  1(801):686-7.|3
00120|085|R|6.Janz D, Schmidt D. Letter: Anti-epileptic drugs and failure of oral|3
00120|086|R|  contraceptives. Lancet 1974 Jun 1;1(7866):1113.|3
00120|087|R|7.Laengner H, Detering K. Letter: Anti-epileptic drugs and failure of oral|3
00120|088|R|  contraceptives. Lancet 1974 Sep 7;2(7880):600.|3
00120|089|R|8.Roberton YR, Johnson ES. Interactions between oral contraceptives and|6
00120|090|R|  other drugs: a review. Curr Med Res Opin 1976;3(9):647-61.|6
00120|091|R|9.Coulam CB, Annegers JF. Do anticonvulsants reduce the efficacy of oral|3
00120|092|R|  contraceptives?. Epilepsia 1979 Oct;20(5):519-25.|3
00120|093|R|10.De Leacy EA, McLeay CD, Eadie MJ, Tyrer JH. Effects of subjects' sex, and|2
00120|094|R|   intake of tobacco, alcohol and oral contraceptives on plasma phenytoin|2
00120|095|R|   levels. Br J Clin Pharmacol 1979 Jul;8(1):33-6.|2
00120|096|R|11.Back DJ, Bates M, Bowden A, Breckenridge AM, Hall MJ, Jones H, MacIver M,|2
00120|097|R|   Orme M, Perucca E, Richens A, Rowe PH, Smith E. The interaction of|2
00120|098|R|   phenobarbital and other anticonvulsants with oral contraceptive steroid|2
00120|099|R|   therapy. Contraception 1980 Nov;22(5):495-503.|2
00120|100|R|12.Notelovitz M, Tjapkes J, Ware M. Interaction between estrogen and|3
00120|101|R|   dilantin in a menopausal woman. N Engl J Med 1981 Mar 26;304(13):788-9.|3
00120|102|R|13.Dada OA, Martins OO. Drug effects on the intestinal absorption of|6
00120|103|R|   estrogens. J Steroid Biochem 1983 Jul;19(1C):821-5.|6
00120|104|R|14.Odlind V, Olsson SE. Enhanced metabolism of levonorgestrel during|3
00120|105|R|   phenytoin treatment in a woman with Norplant implants. Contraception 1986|3
00120|106|R|   Mar;33(3):257-61.|3
00120|107|R|15.Haukkamaa M. Contraception by Norplant subdermal capsules is not reliable|2
00120|108|R|   in epileptic patients on anticonvulsant treatment. Contraception 1986|2
00120|109|R|   Jun;33(6):559-65.|2
00120|110|R|16.Mattson RH, Cramer JA, Darney PD, Naftolin F. Use of oral contraceptives|6
00120|111|R|   by women with epilepsy. JAMA 1986 Jul 11;256(2):238-40.|6
00120|112|R|17.Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M. The|2
00120|113|R|   interaction of phenytoin and carbamazepine with combined oral|2
00120|114|R|   contraceptive steroids. Br J Clin Pharmacol 1990 Dec;30(6):892-6.|2
00120|115|R|18.Nor-Q-D (norethindrone) US prescribing information. WatsonPharma March,|1
00120|116|R|   2005.|1
00120|117|R|19.Doose DR, Wang SS, Padmanabhan M, Schwabe S, Jacobs D, Bialer M. Effect|2
00120|118|R|   of topiramate or carbamazepine on the pharmacokinetics of an oral|2
00120|119|R|   contraceptive containing norethindrone and ethinyl estradiol in healthy|2
00120|120|R|   obese and nonobese female subjects. Epilepsia 2003 Apr;44(4):540-9.|2
00120|121|R|20.Topamax (topiramate) US prescribing information. Janssen Pharmaceuticals,|1
00120|122|R|   Inc. May, 2023.|1
00120|123|R|21.Therapeutic Goods Administration. Medicines Safety Update - Unintended|3
00120|124|R|   pregnancy due to interaction between etonogestrel implant (Implanon) and|3
00120|125|R|   carbamazepine. Australian Prescriber December, 2010;33(6):182-5.|3
00120|126|R|22.Fycompa (perampanel) UK summary of product characteristics. Eisai Ltd|1
00120|127|R|   August, 2021.|1
00120|128|R|23.Qsymia (phentermine and topiramate extended-release) US prescribing|1
00120|129|R|   information. Vivus, Inc. June, 2022.|1
00120|130|R|24.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
00120|131|R|   Criteria for Contraceptive Use, 2016. MMWR Recomm Rep.  Available at:|6
00120|132|R|   https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf July 29, 2016;|6
00120|133|R|   65(3):.|6
00120|134|R|25.Department of Reproductive Health World Health Organization. Medical|6
00120|135|R|   eligibility criteria for contraceptive use. Fourth Edition 2010.|6
00120|136|R|26.Medicines and Healthcare products Regulatory Agency.|1
00120|137|R|   Levonorgestrel-containing emergency hormonal contraception: advice on|1
00120|138|R|   interactions with hepatic enzyme inducers and contraceptive efficacy.|1
00120|139|R|   available at:|1
00120|140|R|   https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency|1
00120|141|R|   -hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-induce|1
00120|142|R|   rs-and-contraceptive-efficacy September 15, 2016..|1
00121|001|T|MONOGRAPH TITLE:  Corticosteroids/Selected Macrolide Antibiotics|
00121|002|B||
00121|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00121|004|L|take action as needed.|
00121|005|B||
00121|006|A|MECHANISM OF ACTION:  Some macrolide antibiotics may inhibit the metabolism|
00121|007|A|of corticosteroids.|
00121|008|B||
00121|009|E|CLINICAL EFFECTS:  Concurrent use of some macrolide antibiotics may result|
00121|010|E|in elevated levels and clinical effects of corticosteroids.|
00121|011|E|Immunosuppression and Cushing's syndrome have been reported during|
00121|012|E|concurrent therapy, including therapy with inhaled corticosteroids.|
00121|013|B||
00121|014|P|PREDISPOSING FACTORS:  Concurrent administration of enzyme inducing drugs.|
00121|015|B||
00121|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with|
00121|017|M|corticosteroids and macrolide antibiotics should be monitored for increased|
00121|018|M|corticosteroid affects.  The dosage of the corticosteroid may need to be|
00121|019|M|adjusted or the macrolide antibiotic may need to be discontinued.|
00121|020|M|   One US manufacturer of inhaled fluticasone states that the concurrent use|
00121|021|M|of macrolide antibiotics is not recommended.(1)|
00121|022|B||
00121|023|D|DISCUSSION:  In a study in 10 steroid-dependent asthmatics, concurrent|
00121|024|D|troleandomycin (1 gram/day) decreased methylprednisolone clearance by 60%.|
00121|025|D|All subjects developed adverse effects typical of excessive corticosteroid|
00121|026|D|use such as weight gain, fluid retention, and cushingoid features.(2)  Other|
00121|027|D|studies and reports have shown increased methylprednisolone levels with|
00121|028|D|concurrent troleandomycin,(3-10) in some of these reports, the interaction|
00121|029|D|was used to lower steroid dosages.(6-10)  There is one report of fatal|
00121|030|D|varicella infection in a patient receiving concurrent therapy with|
00121|031|D|methylprednisolone and troleandomycin.(11)|
00121|032|D|   Cushing's syndrome has been reported with concurrent inhaled budesonide|
00121|033|D|and clarithromycin.(12)  Psychosis(13) and mania(14) have been reported with|
00121|034|D|concurrent prednisone and clarithromycin.|
00121|035|D|   Erythromycin(3-9) and troleandomycin(9) have also been reported to|
00121|036|D|interact with methylprednisolone.|
00121|037|B||
00121|038|R|REFERENCES:|
00121|039|B||
00121|040|R|1.Flovent Diskus (fluticasone propionate) US prescribing information.|1
00121|041|R|  GlaxoSmithKline January, 2019.|1
00121|042|R|2.Szefler SJ, Rose JQ, Ellis EF, Spector SL, Green AW, Jusko WJ. The effect|2
00121|043|R|  of troleandomycin on methylprednisolone elimination. J Allergy Clin|2
00121|044|R|  Immunol 1980 Dec;66(6):447-51.|2
00121|045|R|3.LaForce CF, Szefler SJ, Miller MF, Ebling W, Brenner M. Inhibition of|2
00121|046|R|  methylprednisolone elimination in the presence of erythromycin therapy. J|2
00121|047|R|  Allergy Clin Immunol 1983 Jul;72(1):34-9.|2
00121|048|R|4.Szefler SJ, Brenner M, Jusko WJ, Spector SL, Flesher KA, Ellis EF. Dose-|2
00121|049|R|  and time-related effect of troleandomycin on methylprednisolone|2
00121|050|R|  elimination. Clin Pharmacol Ther 1982 Aug;32(2):166-71.|2
00121|051|R|5.Szefler SJ, Ellis EF, Brenner M, Rose JQ, Spector SL, Yurchak AM, Andrews|2
00121|052|R|  F, Jusko WJ. Steroid-specific and anticonvulsant interaction aspects of|2
00121|053|R|  troleandomycin-steroid therapy. J Allergy Clin Immunol 1982 May;|2
00121|054|R|  69(5):455-60.|2
00121|055|R|6.Spector SL, Katz FH, Farr RS. Troleandomycin: effectiveness in|3
00121|056|R|  steroid-dependent asthma and bronchitis. J Allergy Clin Immunol 1974 Dec;|3
00121|057|R|  54(6):367-79.|3
00121|058|R|7.Schatz M, Sperling W, Zeiger RS. Use of troleandomycin (TAO) in|3
00121|059|R|  outpatients with severe corticosteroid (CS)-dependent asthma. Am Rev|3
00121|060|R|  Respir Dis 1979 Feb;119(2):167.|3
00121|061|R|8.Zeiger RS, Schatz M, Sperling W, Simon RA, Stevenson DD. Efficacy of|2
00121|062|R|  troleandomycin in outpatients with severe, corticosteroid- dependent|2
00121|063|R|  asthma. J Allergy Clin Immunol 1980 Dec;66(6):438-46.|2
00121|064|R|9.Itkin IH, Menzel ML. The use of macrolide antibiotic substances in the|3
00121|065|R|  treatment of asthma. J Allergy 1970 Mar;45(3):146-62.|3
00121|066|R|10.Edwards D, Wald JA, Dobozin BS, Kirkpatrick CH. Troleandomycin and|2
00121|067|R|   methylprednisolone for treatment of the hypereosinophilic syndrome. N|2
00121|068|R|   Engl J Med 1987 Aug 27;317(9):573-4.|2
00121|069|R|11.Lantner R, Rockoff JB, DeMasi J, Boran-Ragotzy R, Middleton E Jr. Fatal|3
00121|070|R|   varicella in a corticosteroid-dependent asthmatic receiving|3
00121|071|R|   troleandomycin. Allergy Proc 1990 Mar-Apr;11(2):83-7.|3
00121|072|R|12.De Wachter E, Malfroot A, De Schutter I, Vanbesien J, De Schepper J.|3
00121|073|R|   Inhaled budesonide induced Cushing's syndrome in cystic fibrosis|3
00121|074|R|   patients, due to drug inhibition of cytochrome P450. J Cyst Fibros 2003|3
00121|075|R|   Jun;2(2):72-5.|3
00121|076|R|13.Finkenbine RD, Frye MD. Case of psychosis due to|3
00121|077|R|   prednisone-clarithromycin interaction. Gen Hosp Psychiatry 1998 Sep;|3
00121|078|R|   20(5):325-6.|3
00121|079|R|14.Finkenbine R, Gill HS. Case of mania due to prednisone-clarithromycin|3
00121|080|R|   interaction. Can J Psychiatry 1997 Sep;42(7):778.|3
00122|001|T|MONOGRAPH TITLE:  Lidocaine/Beta-Blockers|
00122|002|B||
00122|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00122|004|L|take action as needed.|
00122|005|B||
00122|006|A|MECHANISM OF ACTION:  Decreased cardiac output and hepatic blood flow due to|
00122|007|A|beta-blockers may result in reduced elimination of lidocaine. Inhibition of|
00122|008|A|hepatic microsomal enzymes may also contribute to decreased lidocaine|
00122|009|A|clearance.|
00122|010|B||
00122|011|E|CLINICAL EFFECTS:  Lidocaine toxicity is more likely to occur when these|
00122|012|E|drugs are used in combination.|
00122|013|B||
00122|014|P|PREDISPOSING FACTORS:  None determined.|
00122|015|B||
00122|016|M|PATIENT MANAGEMENT:  The lidocaine dose may need to be adjusted when a|
00122|017|M|beta-blocker is added or discontinued. Clinical signs of lidocaine toxicity|
00122|018|M|and lidocaine plasma levels should be monitored.|
00122|019|B||
00122|020|D|DISCUSSION:  The effect seems to be more pronounced in the lipid soluble|
00122|021|D|beta-blockers (eg. propranolol, metoprolol).|
00122|022|B||
00122|023|R|REFERENCES:|
00122|024|B||
00122|025|R|1.Ochs HR, Carstens G, Greenblatt DJ. Reduction in lidocaine clearance|2
00122|026|R|  during continuous infusion and by coadministration of propranolol. N Engl|2
00122|027|R|  J Med 1980 Aug 14;303(7):373-7.|2
00122|028|R|2.Graham CF, Turner WM, Jones JK. Lidocaine-propranolol interactions. N Engl|3
00122|029|R|  J Med 1981 May 21;304(21):1301.|3
00122|030|R|3.Conrad KA, Byers JM, Finley PR, Burnham L. Metoprolol reduces lidocaine|4
00122|031|R|  elimination. Clin Pharm Ther 1982 Feb;31(2):212.|4
00122|032|R|4.Schneck DW, Luderer JR, Davis D, Vary J. Effects of nadolol and|2
00122|033|R|  propranolol on plasma lidocaine clearance. Clin Pharmacol Ther 1984 Nov;|2
00122|034|R|  36(5):584-7.|2
00125|001|T|MONOGRAPH TITLE:  Theophyllines/Hydantoins (mono deleted 03/26/2014)|
00125|002|B||
00125|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00125|004|L|take action as needed.|
00125|005|B||
00125|006|A|MECHANISM OF ACTION:  Increased hepatic metabolism of theophylline by|
00125|007|A|hydantoins. Theophylline may also increase the hepatic metabolism of|
00125|008|A|hydantoins.|
00125|009|B||
00125|010|E|CLINICAL EFFECTS:  Possible decreased effectiveness of both drugs.|
00125|011|B||
00125|012|P|PREDISPOSING FACTORS:  None determined.|
00125|013|B||
00125|014|M|PATIENT MANAGEMENT:  The theophylline dose may need to be adjusted when a|
00125|015|M|hydantoin is added or discontinued. Clinical signs and plasma levels should|
00125|016|M|be monitored.|
00125|017|B||
00125|018|D|DISCUSSION:  This interaction is likely to occur but clinical documentation|
00125|019|D|is limited.|
00125|020|B||
00125|021|R|REFERENCES:|
00125|022|B||
00125|023|R|1.Taylor JW, Hendeles LWeinberger M, Lyon LW, Wyatt R, Riegelman S. The|4
00125|024|R|  interaction of phenytoin and theophylline. Drug Intell Clin Pharm 1980;|4
00125|025|R|  14(9):638.|4
00125|026|R|2.Marquis JF, Carruthers SG, Spence JD, Brownstone YS, Toogood JH.|3
00125|027|R|  Phenytoin-theophylline interaction. N Engl J Med 1982 Nov 4;|3
00125|028|R|  307(19):1189-90.|3
00125|029|R|3.Anonymous. Phenytoin-theophylline-quinidine interactions. N Engl J Med|3
00125|030|R|  1983 Mar 24;308(12):724-5.|3
00125|031|R|4.Miller M, Cosgriff J, Kwong T, Morken DA. Influence of phenytoin on|2
00125|032|R|  theophylline clearance. Clin Pharmacol Ther 1984 May;35(5):666-9.|2
00125|033|R|5.Sklar SJ, Wagner JC. Enhanced theophylline clearance secondary to|3
00125|034|R|  phenytoin therapy. Drug Intell Clin Pharm 1985 Jan;19(1):34-6.|3
00125|035|R|6.Crowley JJ, Cusack BJ, Jue SG, Koup JR, Park BK, Vestal RE. Aging and drug|2
00125|036|R|  interactions. II. Effect of phenytoin and smoking on the oxidation of|2
00125|037|R|  theophylline and cortisol in healthy men. J Pharmacol Exp Ther 1988 May;|2
00125|038|R|  245(2):513-23.|2
00125|039|R|7.Adebayo GI. Interaction between phenytoin and theophylline in healthy|2
00125|040|R|  volunteers. Clin Exp Pharmacol Physiol 1988 Nov;15(11):883-7.|2
00125|041|R|8.Landsberg K, Shalansky S. Interaction between phenytoin and theophylline.|3
00125|042|R|  Can J Hosp Pharm 1988 Feb;41(1):31-2.|3
00125|043|R|9.Nicholson JP, Basile SA, Cury JD. Massive theophylline dosing in a heavy|3
00125|044|R|  smoker receiving both phenytoin and phenobarbital. Ann Pharmacother 1992|3
00125|045|R|  Mar;26(3):334-6.|3
00126|001|T|MONOGRAPH TITLE:  Dyphylline/Probenecid|
00126|002|B||
00126|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00126|004|L|take action as needed.|
00126|005|B||
00126|006|A|MECHANISM OF ACTION:  It appears that probenecid reduces the renal excretion|
00126|007|A|rate of dyphylline.|
00126|008|B||
00126|009|E|CLINICAL EFFECTS:  Increased serum levels of dyphylline.|
00126|010|B||
00126|011|P|PREDISPOSING FACTORS:  None determined.|
00126|012|B||
00126|013|M|PATIENT MANAGEMENT:  If both drugs are given, adjust the dyphylline dose as|
00126|014|M|needed based on serum dyphylline levels and patient response.|
00126|015|B||
00126|016|D|DISCUSSION:  Additional documentation is necessary to confirm this potential|
00126|017|D|interaction. Since theophylline is eliminated by hepatic metabolism rather|
00126|018|D|than renal excretion, it is recommended as an alternative to dyphylline when|
00126|019|D|probenecid is given concurrently. However, the benefits of using this|
00126|020|D|combination may outweigh the risks, especially in cases of theophylline|
00126|021|D|intolerance. Professional judgement should be exercised.|
00126|022|B||
00126|023|R|REFERENCES:|
00126|024|B||
00126|025|R|1.May DC, Jarboe CH. Effect of probenecid on dyphylline elimination. Clin|2
00126|026|R|  Pharmacol Ther 1983 Jun;33(6):822-5.|2
00126|027|R|2.Chen TW, Patton TF. Effect of probenecid on the pharmacokinetics of|2
00126|028|R|  aminophylline. Drug Intell Clin Pharm 1983 Jun;17(6):465-6.|2
00127|001|T|MONOGRAPH TITLE:  Disopyramide; Mexiletine; Propafenone/Rifamycins|
00127|002|B||
00127|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00127|004|L|take action as needed.|
00127|005|B||
00127|006|A|MECHANISM OF ACTION:  Rifampin and other rifamycins may increase the hepatic|
00127|007|A|metabolism of disopyramide,(1-2) mexiletine(3) and propafenone(4-6).|
00127|008|B||
00127|009|E|CLINICAL EFFECTS:  Concurrent use of rifampin may result in decreased levels|
00127|010|E|and effectiveness of disopyramide,(2) mexiletine(3) and propafenone(4-6).|
00127|011|B||
00127|012|P|PREDISPOSING FACTORS:  None determined.|
00127|013|B||
00127|014|M|PATIENT MANAGEMENT:  Monitor patient's cardiac function and serum|
00127|015|M|disopyramide, mexiletine or propafenone levels. Adjust the dosage|
00127|016|M|accordingly.|
00127|017|B||
00127|018|D|DISCUSSION:  Coadministration of mexiletine and rifampin have been reported|
00127|019|D|to decrease the elimination half-life and increase the nonrenal clearance of|
00127|020|D|mexiletine.(3)|
00127|021|D|   In a study in six elderly subjects, pretreatment with rifampin (600 mg|
00127|022|D|daily for 9 days) decreased the bioavailability of a single dose of oral|
00127|023|D|propafenone (300 mg) by 86%.  Maximum QRS prolongation after oral|
00127|024|D|propafenone was decreased by 50%.  There were no significant effects on|
00127|025|D|intravenous propafenone.(5)|
00127|026|D|   In a study in six extensive CYP2D6 metabolizers and six poor CYP2D6|
00127|027|D|metabolizers, pretreatment with rifampin (600 mg daily for 9 days) decreased|
00127|028|D|the bioavailability of a single dose of oral propafenone by 67% and by 41%|
00127|029|D|in extensive and poor metabolizers, respectively.  Maximum QRS prolongation|
00127|030|D|after oral propafenone decreased by 38% and by 40% in extensive and poor|
00127|031|D|metabolizers, respectively.  There were no effects on intravenous|
00127|032|D|propafenone.(6)|
00127|033|D|   During concomitant administration of disopyramide and rifampin to|
00127|034|D|patients with tuberculosis, serum disopyramide concentrations decreased by|
00127|035|D|approximately 50% while the concentration of an active metabolite of|
00127|036|D|disopyramide increased.(1) Concurrent administration of disopyramide and|
00127|037|D|rifampin to a 62-year-old patient produced subtherapeutic disopyramide|
00127|038|D|levels and a failure in correcting the patient's arrhythmia. Five days after|
00127|039|D|stopping rifampin, disopyramide levels increased and the arrhythmia was|
00127|040|D|abolished.(2)|
00127|041|D|   Rifamycins linked to this monograph are rifabutin, rifampin and|
00127|042|D|rifapentine.|
00127|043|B||
00127|044|R|REFERENCES:|
00127|045|B||
00127|046|R|1.Aitio ML, Mansury L, Tala E, Haataja M, Aitio A. The effect of enzyme|2
00127|047|R|  induction on the metabolism of disopyramide in man. Br J Clin Pharmacol|2
00127|048|R|  1981 Mar;11(3):279-85.|2
00127|049|R|2.Staum JM. Enzyme induction: rifampin-disopyramide interaction. DICP 1990|3
00127|050|R|  Jul-Aug;24(7-8):701-3.|3
00127|051|R|3.Pentikainen PJ, Koivula IH, Hiltunen HA. Effect of rifampicin treatment on|2
00127|052|R|  the kinetics of mexiletine. Eur J Clin Pharmacol 1982;23(3):261-6.|2
00127|053|R|4.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
00127|054|R|  Laboratories March, 2013.|1
00127|055|R|5.Dilger K, Hofmann U, Klotz U. Enzyme induction in the elderly: effect of|2
00127|056|R|  rifampin on the pharmacokinetics and pharmacodynamics of propafenone. Clin|2
00127|057|R|  Pharmacol Ther 2000 May;67(5):512-20.|2
00127|058|R|6.Dilger K, Greiner B, Fromm MF, Hofmann U, Kroemer HK, Eichelbaum M.|2
00127|059|R|  Consequences of rifampicin treatment on propafenone disposition in|2
00127|060|R|  extensive and poor metabolizers of CYP2D6. Pharmacogenetics 1999 Oct;|2
00127|061|R|  9(5):551-9.|2
00128|001|T|MONOGRAPH TITLE:  Selected Antiarrhythmics/Quinidine|
00128|002|B||
00128|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00128|004|L|is contraindicated and generally should not be dispensed or administered to|
00128|005|L|the same patient.|
00128|006|B||
00128|007|A|MECHANISM OF ACTION:  Amiodarone inhibits quinidine metabolism via CYP3A4,|
00128|008|A|leading to increased serum levels of quinidine.(2)  In addition to additive|
00128|009|A|or synergistic effects on the QTc interval, quinidine may inhibit|
00128|010|A|CYP2D6-mediated hydroxylation of propafenone, which results in decreased|
00128|011|A|propafenone clearance.(16,17)|
00128|012|A|   Concurrent use may result in additive or synergistic effects on the QT|
00128|013|A|interval.|
00128|014|B||
00128|015|E|CLINICAL EFFECTS:  Concurrent amiodarone may result in an increase in the|
00128|016|E|pharmacologic effects of quinidine due to elevated serum levels.  The QTc|
00128|017|E|interval may be prolonged and result in life-threatening arrhythmias,|
00128|018|E|including torsades de pointes.|
00128|019|E|   Concurrent quinidine may result in elevated levels and effects of|
00128|020|E|propafenone.(16,17)|
00128|021|E|   Concurrent use of quinidine and other antiarrhythmics may result in|
00128|022|E|unpredictable and/or additive effects, including QT prolongation and|
00128|023|E|torsades de pointes.|
00128|024|B||
00128|025|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00128|026|P|may be increased in patients with cardiovascular disease (e.g. heart|
00128|027|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00128|028|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00128|029|P|female gender, or advanced age.(10)|
00128|030|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00128|031|P|higher systemic concentrations of either QT prolonging drug are additional|
00128|032|P|risk factors for torsades de pointes.  Factors which may increased systemic|
00128|033|P|drug concentrations include rapid infusion of an intravenous dose or|
00128|034|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00128|035|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00128|036|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(10)|
00128|037|P|   The effects of quinidine on propafenone levels may not be clinically|
00128|038|P|significant in poor metabolizers(17) because poor metabolizers have a|
00128|039|P|genetically-determined lack of the isoenzyme inhibited by quinidine.(18)|
00128|040|B||
00128|041|M|PATIENT MANAGEMENT:  The Australian manufacturer of amiodarone states that|
00128|042|M|concurrent use of agents known to cause torsades de pointes, such as|
00128|043|M|quinidine, is contraindicated.(3)  The US manufacturer of amiodarone states|
00128|044|M|that the concurrent use of QT prolonging drugs should be avoided.(4)  If|
00128|045|M|concurrent therapy is warranted, patients should be monitored for increased|
00128|046|M|quinidine levels and signs of quinidine toxicity.  Cardiac function should|
00128|047|M|also be monitored.  The dosage of quinidine may need to be adjusted.  The US|
00128|048|M|manufacturer of amiodarone recommends that the dosage of quinidine be|
00128|049|M|reduced by one-third during concurrent amiodarone.(4)  One study recommends|
00128|050|M|that the dosage of quinidine be reduced by 30-50% when amiodarone is added|
00128|051|M|to therapy.(2)|
00128|052|M|   The Australian manufacturer of disopyramide states that the concurrent|
00128|053|M|use of other antiarrhythmics, such as Class I, II, III, or IV is|
00128|054|M|contraindicated.(11)|
00128|055|M|   The manufacturer of dofetilide states that Class I or Class III|
00128|056|M|antiarrhythmic agents should be withheld for at least three half-lives prior|
00128|057|M|to initiating dofetilide.  Dofetilide has been administered to patients|
00128|058|M|previously treated with amiodarone when amiodarone levels were below 0.3|
00128|059|M|mg/L or amiodarone had been withdrawn for at least 3 months.(12)|
00128|060|M|   The manufacturer of ibutilide states that Class IA or III antiarrhythmics|
00128|061|M|should not be used concomitantly with ibutilide or within 4 hours|
00128|062|M|post-infusion.(13)|
00128|063|M|   The manufacturer of propafenone states that concurrent use of Class IA|
00128|064|M|and III Antiarrhythmics is not recommended and these agents should be|
00128|065|M|withheld for at least 5 half-lives prior to dosing with propafenone.(16)|
00128|066|M|   If alternatives are not available and concurrent therapy is deemed|
00128|067|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
00128|068|M|and monitor ECG at baseline and at regular intervals.  Correct any|
00128|069|M|electrolyte abnormalities.  Instruct patients to report any irregular|
00128|070|M|heartbeat, dizziness, or fainting.|
00128|071|B||
00128|072|D|DISCUSSION:  In patients receiving concurrent amiodarone and quinidine,|
00128|073|D|elevated serum levels and prolonged QT interval have been reported.(1,5-9)|
00128|074|D|In a study in 11 patients, the addition of amiodarone to quinidine therapy|
00128|075|D|resulted in an increase in quinidine levels by 32% and quinidine toxicity in|
00128|076|D|seven patients.  The increase in quinidine levels was seen as early as 24|
00128|077|D|hours after the addition of amiodarone.(2)|
00128|078|D|   Because combinations of antiarrhythmics are not well researched and|
00128|079|D|concurrent use may result in unpredictable effects, the Australian|
00128|080|D|manufacturer of disopyramide states that the concurrent use of other|
00128|081|D|antiarrhythmics, such as quinidine, is contraindicated.(11)|
00128|082|D|   Because of the risk of adverse effects, the manufacturer of dofetilide|
00128|083|D|states that Class I or Class III antiarrhythmic agents should be withheld|
00128|084|D|for at least three half-lives prior to initiating dofetilide.(12)|
00128|085|D|   In clinical trials, Class IA and III antiarrhythmics were withheld for 5|
00128|086|D|half-lives prior to the administration of ibutilide and for 4 hours|
00128|087|D|after.(13)|
00128|088|D|   In separate clinical trials, concomitant use of ibutilide with amiodarone|
00128|089|D|resulted in significantly prolonged QTc intervals.(14,15)|
00128|090|D|   In a study in 11 patients with frequent ventricular arrhythmias who had|
00128|091|D|not responded to treatment with quinidine sulfate alone, the addition of|
00128|092|D|propafenone resulted in a significantly greater mean suppression suppression|
00128|093|D|of baseline premature ventricular contractions (PVCs) than quinidine alone.|
00128|094|D|Patients on propafenone alone required a higher dose to achieve significant|
00128|095|D|suppression of PVCs when compared to concurrent quinidine and propafenone.|
00128|096|D|It was not determined if this suppression was a result of changes in the|
00128|097|D|propafenone plasma concentration or a synergistic effect of the two|
00128|098|D|antiarrhythmics.(19)|
00128|099|D|   In another study in seven extensive metabolizer prototypes, the addition|
00128|100|D|quinidine to propafenone resulted in a more than 2-fold increase in the|
00128|101|D|steady-state propafenone plasma concentration, a decrease in the|
00128|102|D|5-hydroxypropafenone concentration and a reduction in the oral clearance of|
00128|103|D|propafenone.  In the same study, two patients who were found to be poor|
00128|104|D|metabolizer phenotypes showed no change in the plasma concentrations of|
00128|105|D|propafenone or its active metabolite with concomitant quinidine|
00128|106|D|administration.(17)|
00128|107|D|   Quinidine, at a low dose, may improve efficacy of propafenone by|
00128|108|D|inhibition of CYP P-450-2D6 isozyme.  Propafenone 300 mg to 450 mg/day was|
00128|109|D|administered to 60 patients with history of paroxysmal atrial fibrillation|
00128|110|D|for a period of eight weeks resulting in 62% symptomatically controlled.|
00128|111|D|Nineteen refractory patients were randomized in a double-blind fashion to|
00128|112|D|receive either a higher dose of propafenone (450 to 675 mg/d) or standard|
00128|113|D|propafenone dose plus low-dose quinidine (150 mg/d).  After the eight week|
00128|114|D|study period, serum levels recorded propafenone levels at 259 and 336 mg/d,|
00128|115|D|respectively, not found to be significantly different.  However, the higher|
00128|116|D|dose of propafenone resulted in greater gastrointestinal side effects|
00128|117|D|compared to the addition of low-dose quinidine combination.(20)|
00128|118|D|   One or more of the drug pairs linked to this monograph have been included|
00128|119|D|in a list of interactions that should be considered "high-priority" for|
00128|120|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00128|121|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00128|122|D|Coordinator (ONC) for Health Information Technology.|
00128|123|B||
00128|124|R|REFERENCES:|
00128|125|B||
00128|126|R|1.Tartini R, Kappenberger L, Steinbrunn W, Meyer UA. Dangerous interaction|3
00128|127|R|  between amiodarone and quinidine. Lancet 1982 Jun 12;1(8285):1327-9.|3
00128|128|R|2.Saal AK, Werner JA, Greene HL, Sears GK, Graham EL. Effect of amiodarone|2
00128|129|R|  on serum quinidine and procainamide levels. Am J Cardiol 1984 May 1;|2
00128|130|R|  53(9):1264-7.|2
00128|131|R|3.Cordarone X (amiodarone hydrochloride) Australian prescribing information.|1
00128|132|R|  Sanofi-Synthelabo Australia Pty Limited Augsut 15, 2007.|1
00128|133|R|4.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
00128|134|R|  Pharmaceuticals October, 2018.|1
00128|135|R|5.Tartini R, Kappenberger L, Steinbrunn W. Harmful interactions of|3
00128|136|R|  amiodarone and class I anti-arrhythmia agents. Schweiz Med Wochenschr 1982|3
00128|137|R|  Nov 6;112(45):1585-7.|3
00128|138|R|6.Kerin NZ, Ansari-Leesar M, Faitel K, Narala C, Frumin H, Cohen A. The|2
00128|139|R|  effectiveness and safety of the simultaneous administration of quinidine|2
00128|140|R|  and amiodarone in the conversion of chronic atrial fibrillation. Am Heart|2
00128|141|R|  J 1993 Apr;125(4):1017-21.|2
00128|142|R|7.Tran HT, Chow MS, Kluger J. Amiodarone induced torsades de pointes with|3
00128|143|R|  excessive QT dispersion following quinidine induced polymorphic|3
00128|144|R|  ventricular tachycardia. Pacing Clin Electrophysiol 1997 Sep;20(9 Pt|3
00128|145|R|  1):2275-8.|3
00128|146|R|8.Genth S, Darius H, Zotz R, Treese N, Himmrich E, Meyer J. Torsade de|3
00128|147|R|  pointes during quinidine and amiodarone therapy. Med Klin (Munich) 1996|3
00128|148|R|  Mar 15;91(3):171-3.|3
00128|149|R|9.Reingardene DI. Ventricular fibrillation caused by the combined|3
00128|150|R|  administration of amiodarone and quinidine. Kardiologiia 1989 Jul;|3
00128|151|R|  29(7):121-4.|3
00128|152|R|10.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
00128|153|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
00128|154|R|   hospital settings: a scientific statement from the American Heart|6
00128|155|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
00128|156|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
00128|157|R|11.Rythmodan (disopyramide) Australian prescribing information. Aventis|1
00128|158|R|   Pharma Pty Ltd. September 22, 2000.|1
00128|159|R|12.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
00128|160|R|   2013.|1
00128|161|R|13.Corvert (ibutilide fumarate) US prescribing information. Pharmacia &|1
00128|162|R|   Upjohn Company July, 2002.|1
00128|163|R|14.Fragakis N, Papadopoulos N, Papanastasiou S, Kozirakis M, Maligkos G,|2
00128|164|R|   Tsaritsaniotis E, Katsaris G. Efficacy and safety of ibutilide for|2
00128|165|R|   cardioversion of atrial flutter and fibrillation in patients receiving|2
00128|166|R|   amiodarone or propafenone. Pacing Clin Electrophysiol 2005 Sep;|2
00128|167|R|   28(9):954-61.|2
00128|168|R|15.Glatter K, Yang Y, Chatterjee K, Modin G, Cheng J, Kayser S, Scheinman|2
00128|169|R|   MM. Chemical cardioversion of atrial fibrillation or flutter with|2
00128|170|R|   ibutilide in patients receiving amiodarone therapy. Circulation 2001 Jan|2
00128|171|R|   16;103(2):253-7.|2
00128|172|R|16.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
00128|173|R|   Laboratories March, 2013.|1
00128|174|R|17.Funck-Brentano C, Kroemer HK, Pavlou H, Woosley RL, Roden DM.|2
00128|175|R|   Genetically-determined interaction between propafenone and low dose|2
00128|176|R|   quinidine: role of active metabolites in modulating net drug effect. Br J|2
00128|177|R|   Clin Pharmacol 1989 Apr;27(4):435-44.|2
00128|178|R|18.Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, Nebert DW, Gelboin|5
00128|179|R|   HV, Hardwick JP, Meyer UA. Characterization of the common genetic defect|5
00128|180|R|   in humans deficient in debrisoquine metabolism. Nature 1988 Feb 4;|5
00128|181|R|   331(6155):442-6.|5
00128|182|R|19.Klein RC, Huang SK, Marcus FI, Horwitz L, Fenster PE, Rushforth N,|2
00128|183|R|   Kirsten EB. Enhanced antiarrhythmic efficacy of propafenone when used in|2
00128|184|R|   combination with procainamide or quinidine. Am Heart J 1987 Sep;|2
00128|185|R|   114(3):551-8.|2
00128|186|R|20.Lau CP, Chow MS, Tse HF, Tang MO, Fan C. Control of paroxysmal atrial|2
00128|187|R|   fibrillation recurrence using combined administration of propafenone and|2
00128|188|R|   quinidine. Am J Cardiol 2000 Dec 15;86(12):1327-32.|2
00128|189|R|21.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00128|190|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00128|191|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00128|192|R|   19(5):735-43.|6
00129|001|T|MONOGRAPH TITLE:  Amiodarone; Dronedarone/Digitalis Glycosides|
00129|002|B||
00129|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00129|004|L|of severe adverse interaction.|
00129|005|B||
00129|006|A|MECHANISM OF ACTION:  Multiple mechanisms appear to be involved in the|
00129|007|A|interaction between amiodarone and digitalis glycosides.  Amiodarone|
00129|008|A|decreases renal and nonrenal clearance of the digitalis glycosides, reduces|
00129|009|A|digitalis glycoside volume of distribution, and increases digitalis|
00129|010|A|glycoside bioavailability.  In addition, digitalis glycosides depress the|
00129|011|A|sinus node, producing bradycardia.|
00129|012|A|   Dronedarone increases digoxin levels by inhibiting the P-glycoprotein|
00129|013|A|transporter.  Digoxin also potentiates the electrophysiologic effects of|
00129|014|A|dronedarone.|
00129|015|B||
00129|016|E|CLINICAL EFFECTS:  Concurrent amiodarone or dronedarone may result in|
00129|017|E|elevated levels of and effects from digitalis glycosides.  The magnitude of|
00129|018|E|the interaction between amiodarone and digitalis glycosides is dependent on|
00129|019|E|the route of administration of the digitalis glycoside and proportional to|
00129|020|E|the amiodarone dose and serum level.|
00129|021|E|   Concurrent use of dronedarone and digoxin may increase the risk of|
00129|022|E|arrhythmic or sudden death.|
00129|023|E|   Symptoms of digoxin toxicity can include anorexia, nausea, vomiting,|
00129|024|E|headache, fatigue, malaise, drowsiness, generalized muscle weakness,|
00129|025|E|hallucinations, visual disturbances, and arrhythmias.|
00129|026|B||
00129|027|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
00129|028|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00129|029|P|risk of digoxin toxicity.|
00129|030|B||
00129|031|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor serum|
00129|032|M|digitalis glycoside levels and observe the patient for symptoms of digitalis|
00129|033|M|toxicity.|
00129|034|M|   Upon adding amiodarone or dronedarone, digitalis dosages should first be|
00129|035|M|decreased in anticipation of an interaction, then adjusted accordingly.  The|
00129|036|M|dosage of oral digitalis glycoside may need to be decreased by 30-50%, or|
00129|037|M|the frequency of administration may be reduced.|
00129|038|M|   For IV or IM digitalis glycoside, the dosage may need to be decreased by|
00129|039|M|15-30%, or the dosing frequency may be reduced.|
00129|040|B||
00129|041|D|DISCUSSION:  Plasma digitalis glycoside concentrations may increase several|
00129|042|D|fold after adding amiodarone to the treatment regimen.  The effect appears|
00129|043|D|related to the dose of amiodarone, with higher doses of amiodarone being|
00129|044|D|associated with the greatest increases.|
00129|045|D|   A study in 12 patients controlled on digitalis found that the addition of|
00129|046|D|amiodarone for arrhythmias resulted in a 75.42% increase in digitalis plasma|
00129|047|D|levels at initiation of amiodarone.  At the mid-point of combination|
00129|048|D|therapy, digitalis serum levels were elevated by 52.1%.  Three patients|
00129|049|D|experienced digitalis-related toxicity.|
00129|050|D|   In a study in 6 healthy volunteers, a 7-day course of amiodarone|
00129|051|D|increased the maximum concentration (Cmax) of a single dose of digoxin (0.50|
00129|052|D|mg) from 2.92 ng/ml to 5.87 ng/ml.  Digoxin area-under-curve (AUC) increased|
00129|053|D|from 30.71 ng x h/mL to 40.63 ng x h/ml.  Four out of the 6 subjects showed|
00129|054|D|a decrease in the time to Cmax (Tmax) of digoxin.|
00129|055|D|   Concurrent use of amiodarone with IV or IM digoxin increased the digoxin|
00129|056|D|AUC by 40%.(28)|
00129|057|D|   Increased serum digitalis glycoside levels with accompanying toxicity|
00129|058|D|have been reported during concomitant administration of amiodarone and|
00129|059|D|digoxin, digitalis, and digitoxin.  Torsades de pointes has been reported.|
00129|060|D|The subjects suffered torsades de pointes within 48 hours of amiodarone|
00129|061|D|loading.|
00129|062|D|   Concurrent dronedarone and digoxin (dosages not stated) increased digoxin|
00129|063|D|exposure 2.5-fold.|
00129|064|D|   In the ANDROMEDA and PALLAS trials, baseline use of digoxin was|
00129|065|D|associated with an increased risk of arrhythmic or sudden death in|
00129|066|D|dronedarone-treated patients when compared to the use of digoxin plus|
00129|067|D|placebo.  In patients not taking digoxin, there was no difference in sudden|
00129|068|D|risk of death between dronedarone and placebo.  In the ANDROMEDA trial,|
00129|069|D|baseline digoxin use was reported in 6 of 16 dronedarone patients versus 1|
00129|070|D|of 16 placebo patients who died of arrhythmia.  In the PALLAS trial,|
00129|071|D|baseline digoxin therapy was reported in 11 of 13 patients who died of|
00129|072|D|arrhythmia, versus none of the 4 patients in the placebo group who died of|
00129|073|D|arrhythmia.|
00129|074|D|   Concomitant administration of dronedarone and oral digoxin increased the|
00129|075|D|digoxin AUC by 150%.(29)|
00129|076|B||
00129|077|R|REFERENCES:|
00129|078|B||
00129|079|R|1.Moysey JO, Jaggarao NS, Grundy EN, Chamberlain DA. Amiodarone increases|2
00129|080|R|  plasma digoxin concentrations. Br Med J (Clin Res Ed) 1981 Jan 24;|2
00129|081|R|  282(6260):272.|2
00129|082|R|2.Achilli A, Serra N. Amiodarone increases plasma digoxin concentrations. Br|3
00129|083|R|  Med J (Clin Res Ed) 1981 May 16;282(6276):1630.|3
00129|084|R|3.Douste-Blazy P, Montastruc JL, Bonnet B, Auriol P, Conte D, Bernadet P.|2
00129|085|R|  Influence of amiodarone on plasma and urine digoxin concentrations. Lancet|2
00129|086|R|  1984 Apr 21;1(8382):905.|2
00129|087|R|4.Mingardi G. Amiodarone and plasma digoxin levels. Lancet 1984 Jun 2;|3
00129|088|R|  1(8388):1238.|3
00129|089|R|5.Nademanee K, Kannan R, Hendrickson J, Ookhtens M, Kay I, Singh BN.|6
00129|090|R|  Amiodarone-digoxin interaction: clinical significance, time course of|6
00129|091|R|  development, potential pharmacokinetic mechanisms and therapeutic|6
00129|092|R|  implications. J Am Coll Cardiol 1984 Jul;4(1):111-6.|6
00129|093|R|6.Oetgen WJ, Sobol SM, Tri TB, Heydorn WH, Rakita L. Amiodarone-digoxin|2
00129|094|R|  interaction. Clinical and experimental observations. Chest 1984 Jul;|2
00129|095|R|  86(1):75-9.|2
00129|096|R|7.Koren G, Hesslein PS, MacLeod SM. Digoxin toxicity associated with|3
00129|097|R|  amiodarone therapy in children. J Pediatr 1984 Mar;104(3):467-70.|3
00129|098|R|8.Ben-Chetrit E, Ackerman Z, Eliakim M. Amiodarone-associated|3
00129|099|R|  hypothyroidism--a possible cause of digoxin intoxication. Am J Med Sci|3
00129|100|R|  1985 Mar;289(3):114-6.|3
00129|101|R|9.Fenster PE, White NW Jr, Hanson CD. Pharmacokinetic evaluation of the|2
00129|102|R|  digoxin-amiodarone interaction. J Am Coll Cardiol 1985 Jan;5(1):108-12.|2
00129|103|R|10.Klein HO, Beker B, DiSegni E, Kaplinsky E. Asystole produced by the|3
00129|104|R|   combination of amiodarone and digoxin. Am Heart J 1987 Feb;113(2 Pt|3
00129|105|R|   1):399-400.|3
00129|106|R|11.Santostasi G, Fantin M, Maragno I, Gaion RM, Basadonna O, Dalla-Volta S.|2
00129|107|R|   Effects of amiodarone on oral and intravenous digoxin kinetics in healthy|2
00129|108|R|   subjects. J Cardiovasc Pharmacol 1987 Apr;9(4):385-90.|2
00129|109|R|12.Johnston A, Walker S, Robinson KC, McKenna WJ, Holt DW. The|4
00129|110|R|   digoxin-amiodarone interaction. Br J Clin Pharmacol 1987;24:253P.|4
00129|111|R|13.Robinson K, Johnston A, Walker S, Mulrow JP, McKenna WJ, Holt DW. The|2
00129|112|R|   digoxin-amiodarone interaction. Cardiovasc Drugs Ther 1989 Mar;3(1):25-8.|2
00129|113|R|14.Laer S, Scholz H, Buschmann I, Thoenes M, Meinertz T. Digitoxin|3
00129|114|R|   intoxication during concomitant use of amiodarone. Eur J Clin Pharmacol|3
00129|115|R|   1998 Mar;54(1):95-6.|3
00129|116|R|15.Giordano G, Franciosini MF, Zuanetti G, Latini R. Digitalis intoxication|3
00129|117|R|   in the presence of amiodarone-induced acute hepatitis. G Ital Cardiol|3
00129|118|R|   1988 Oct;18(10):862-4.|3
00129|119|R|16.DeVore KJ, Hobbs RA. Plasma digoxin concentration fluctuations associated|3
00129|120|R|   with timing of plasma sampling and amiodarone administration.|3
00129|121|R|   Pharmacotherapy 2007 Mar;27(3):472-5.|3
00129|122|R|17.Smellie WS, Coleman JJ. Pitfalls of testing and summary of guidance on|6
00129|123|R|   safety monitoring with amiodarone and digoxin. BMJ 2007 Feb 10;|6
00129|124|R|   334(7588):312-5.|6
00129|125|R|18.Schrickel JW, Schwab JO, Yang A, Bitzen A, Luderitz B, Lewalter T.|3
00129|126|R|   "Torsade de pointes" in patients with structural heart disease and atrial|3
00129|127|R|   fibrillation treated with amiodarone, beta-blockers, and digitalis.|3
00129|128|R|   Pacing Clin Electrophysiol 2006 Apr;29(4):363-6.|3
00129|129|R|19.Lien WC, Huang CH, Chen WJ. Bidirectional ventricular tachycardia|3
00129|130|R|   resulting from digoxin and amiodarone treatment of rapid atrial|3
00129|131|R|   fibrillation. Am J Emerg Med 2004 May;22(3):235-6.|3
00129|132|R|20.Kakumoto M, Takara K, Sakaeda T, Tanigawara Y, Kita T, Okumura K.|5
00129|133|R|   MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal|5
00129|134|R|   drugs. Biol Pharm Bull 2002 Dec;25(12):1604-7.|5
00129|135|R|21.Chauvin M, Brechenmacher C. Simultaneous prescription of digoxin and an|6
00129|136|R|   anti-arrhythmia agent, is it dangerous?. Ann Cardiol Angeiol (Paris) 1993|6
00129|137|R|   Jan;42(1):39-44.|6
00129|138|R|22.Bajaj BP, Baig MW, Perrins EJ. Amiodarone-induced torsades de pointes:|3
00129|139|R|   the possible facilitatory role of digoxin. Int J Cardiol 1991 Nov;|3
00129|140|R|   33(2):335-7.|3
00129|141|R|23.Strocchi E, Malini PL, Graziani A, Ambrosioni E, Magnani B.|2
00129|142|R|   Digoxin-amiodarone interaction. G Ital Cardiol 1984 Jan;14(1):12-5.|2
00129|143|R|24.Maragno I, Santostasi G, Gaion RM, Paleari C. Influence of amiodarone on|2
00129|144|R|   oral digoxin bioavailability in healthy volunteers. Int J Clin Pharmacol|2
00129|145|R|   Res 1984;4(2):149-53.|2
00129|146|R|25.Nager G, Nager F. Interaction of amiodarone and digoxin. Schweiz Med|2
00129|147|R|   Wochenschr 1983 Nov 19;113(46):1727-30.|2
00129|148|R|26.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
00129|149|R|   Pharmaceuticals October, 2018.|1
00129|150|R|27.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
00129|151|R|   November, 2020.|1
00129|152|R|28.Lanoxin Injection (digoxin) US prescribing information. Covis Pharma|1
00129|153|R|   October, 2019.|1
00129|154|R|29.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00129|155|R|   Pharmaceuticals, Inc. August, 2018.|1
00130|001|T|MONOGRAPH TITLE:  Selected Opioids/MAOIs|
00130|002|B||
00130|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00130|004|L|of severe adverse interaction.|
00130|005|B||
00130|006|A|MECHANISM OF ACTION:  Selected opioids inhibit neuronal reuptake of|
00130|007|A|serotonin.  Non-selective MAOIs increase neuronal serotonin concentration|
00130|008|A|via inhibition of MAO-A.|
00130|009|B||
00130|010|E|CLINICAL EFFECTS:  The concurrent use of some opioids with MAOIs has|
00130|011|E|resulted in serotonin syndrome.  Symptoms of serotonin syndrome may include|
00130|012|E|tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
00130|013|E|hyperthermia, and muscle rigidity.(1)|
00130|014|B||
00130|015|P|PREDISPOSING FACTORS:  Treatment with multiple medications which increase|
00130|016|P|serotonin levels or inhibit the metabolism of serotonin are risk factors for|
00130|017|P|serotonin syndrome.|
00130|018|P|   Higher opioid concentrations, as may occur due to inhibition of opioid|
00130|019|P|clearance, patient specific genomic factors (e.g. poor metabolizer status|
00130|020|P|for a P450 enzyme), or high opioid dosage may increase the risk for an|
00130|021|P|interaction.|
00130|022|B||
00130|023|M|PATIENT MANAGEMENT:  Use an alternative analgesic when possible.|
00130|024|M|   If concurrent therapy is warranted, patients should be monitored for|
00130|025|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00130|026|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00130|027|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00130|028|M|coordination, or severe diarrhea.|
00130|029|B||
00130|030|D|DISCUSSION:  Although documentation is lacking for some opioids, the FDA|
00130|031|D|recommends health professionals monitor and advise patients to report|
00130|032|D|symptoms of serotonin syndrome in patients receiving analgesic opioids and|
00130|033|D|serotonergic agents.(2)|
00130|034|D|   The interaction between meperidine and MAOIs has been well documented.|
00130|035|D|There are two reports of potential interactions between MAOIs and|
00130|036|D|dextromethorphan.(3,4) In another case report, the concurrent use of|
00130|037|D|propoxyphene and phenylzine resulted in sedation and somnolence. The patient|
00130|038|D|had previously taken both agents alone with no adverse effects.(5)|
00130|039|D|   Although some studies have shown that morphine does not interact with|
00130|040|D|MAOIs,(6,7) other data indicates that MAOIs markedly potentiate the effect|
00130|041|D|of morphine.(8)|
00130|042|D|   One study indicates that methadone does not interact with MAOIs;(7)|
00130|043|D|however, the UK manufacturer of methadone states that concurrent use is|
00130|044|D|contraindicated.(9)  US manufacturers recommend sensitivity tests with|
00130|045|D|small, incremental doses of methadone in patients maintained on MAOIs with|
00130|046|D|careful observation of vital signs.(11)|
00130|047|D|   Selected opioids linked to this monograph include: alfentanil,|
00130|048|D|anileridine (not available in US/CA), diphenoxin, meptazinol (not available|
00130|049|D|in US/CA), pentazocine, phenoperidine (not available in US/CA), propoxyphene|
00130|050|D|(not available in US/CA), remifentanil, and sufentanil.|
00130|051|D|   Furazolidone and linezolid are known to be monoamine oxidase inhibitors.|
00130|052|D|   Methylene blue, when administered intravenously, has been shown to reach|
00130|053|D|sufficient concentrations to be a potent inhibitor of MAO-A.(12,13)|
00130|054|B||
00130|055|R|REFERENCES:|
00130|056|B||
00130|057|R|1.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00130|058|R|  352(11):1112-20.|6
00130|059|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
00130|060|R|  warns about several safety issues with opioid pain medicines; requires|1
00130|061|R|  label changes. available at:|1
00130|062|R|  http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
00130|063|R|3.Rivers N, Horner B. Possible lethal reaction between Nardil and|3
00130|064|R|  dextromethorphan. Can Med Assoc J 1970 Jul;103:85.|3
00130|065|R|4.Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine|3
00130|066|R|  oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988 Dec 22;|3
00130|067|R|  319(25):1671.|3
00130|068|R|5.Garbutt JC. Potentiation of propoxyphene by phenelzine. Am J Psychiatry|3
00130|069|R|  1987 Feb;144(2):251-2.|3
00130|070|R|6.Evans-Prosser CD. The use of pethidine and morphine in the presence of|2
00130|071|R|  monoamine oxidase inhibitors. Br J Anaesth 1968 Apr;40(4):279-82.|2
00130|072|R|7.Carlsson A, Lindqvist M. Central and peripheral monoaminergic|2
00130|073|R|  membrane-pump blockade by some addictive analgesics and antihistamines. J|2
00130|074|R|  Pharm Pharmacol 1969 Jul;21(7):460-4.|2
00130|075|R|8.Avinza (morphine extended-release capsules) US prescribing information.|1
00130|076|R|  Ligand Pharmaceuticals Incorporated April, 2014.|1
00130|077|R|9.Metharose (methadone hydrochloride) UK summary of product characteristics.|1
00130|078|R|  Rosemone Pharmaceuticals Limited January 9, 2008.|1
00130|079|R|10.Darvon (propoxyphene hydrochloride) US prescribing information. Xanodyne|1
00130|080|R|   Pharmaceuticals, Inc. September, 2009.|1
00130|081|R|11.Diskets Dispersible (methadone hydrochloride) US prescribing information.|1
00130|082|R|   Cebert Pharmaceuticals, Inc. August, 2007.|1
00130|083|R|12.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00130|084|R|   inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00130|085|R|   prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00130|086|R|13.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00130|087|R|   distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00130|088|R|   2000 Jun;56(3):247-50.|2
00131|001|T|MONOGRAPH TITLE:  Barbiturates/Corticosteroids (mono deleted 02/02/2012)|
00131|002|B||
00131|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00131|004|L|take action as needed.|
00131|005|B||
00131|006|A|MECHANISM OF ACTION:  Barbiturates increase the metabolism of|
00131|007|A|corticosteroids by the induction of hepatic microsomal enzymes.|
00131|008|B||
00131|009|E|CLINICAL EFFECTS:  May see a decrease in the pharmacologic effect of the|
00131|010|E|corticosteroid.|
00131|011|B||
00131|012|P|PREDISPOSING FACTORS:  None determined.|
00131|013|B||
00131|014|M|PATIENT MANAGEMENT:  Since there may be a decrease in the response to the|
00131|015|M|corticosteroid, it may be necessary to increase the dose. Monitor the|
00131|016|M|patient and adjust the dosage accordingly.|
00131|017|B||
00131|018|D|DISCUSSION:  This interaction is well documented. It is noteworthy that this|
00131|019|D|interaction may persist for several days after the barbiturate is|
00131|020|D|discontinued.|
00131|021|B||
00131|022|R|REFERENCES:|
00131|023|B||
00131|024|R|1.Kuntzman R, Jacobson M, Levin W, Conney AH. Stimulatory effect of|5
00131|025|R|  N-phenylbarbital (phetharbital) on cortisol hydroxylation in man. Biochem|5
00131|026|R|  Pharmacol 1968 Apr;17(4):565-71.|5
00131|027|R|2.Brooks SM, Werk EE, Ackerman SJ, Sullivan I, Thrasher K. Adverse effects|2
00131|028|R|  of phenobarbital on corticosteroid metabolism in patients with bronchial|2
00131|029|R|  asthma. N Engl J Med 1972 May 25;286(21):1125-8.|2
00131|030|R|3.Stjernholm MR, Katz FH. Effects of diphenylhydantoin, phenobarbital, and|2
00131|031|R|  diazepam on the metabolism of methylprednisolone and its sodium succinate.|2
00131|032|R|  J Clin Endocrinol Metab 1975 Nov;41(5):887-93.|2
00131|033|R|4.Brooks PM, Buchanan WW, Grove M, Downie WW. Effects of enzyme induction on|2
00131|034|R|  metabolism of prednisolone. Clinical and laboratory study. Ann Rheum Dis|2
00131|035|R|  1976 AUG;35(4):339-43.|2
00131|036|R|5.Gambertoglio J, Kapusnik J, Holford J, Nishikawa R, Hau T, Birnbaum J,|4
00131|037|R|  Amend W Jr. Enhancement of prednisolone elimination by anticonvulsants in|4
00131|038|R|  renal transplant recipients. Clin Pharmacol Ther 1982 Feb;31(2):228.|4
00131|039|R|6.Gabrielsen J, Bendtsen A, Eriksen H, Andersen S. Methylprednisolone|2
00131|040|R|  half-life during simultaneous barbiturate treatment and mechanical|2
00131|041|R|  hyperventilation of neurosurgical patients. J Neurosurg 1985 Feb;|2
00131|042|R|  62(2):182-5.|2
00131|043|R|7.Gambertoglio JG, Holford NH, Kapusnik JE, Nishikawa R, Saltiel M,|2
00131|044|R|  Stanik-Lizak P, Birnbaum JL, Hau T, Amend WJ Jr. Disposition of total and|2
00131|045|R|  unbound prednisolone in renal transplant patients receiving|2
00131|046|R|  anticonvulsants. Kidney Int 1984 Jan;25(1):119-23.|2
00131|047|R|8.Hancock KW, Levell MJ. Primidone/dexamethasone interaction. Lancet 1978|3
00131|048|R|  Jul 8;2(8080):97-8.|3
00131|049|R|9.Young MC, Hughes IA. Loss of therapeutic control in congenital adrenal|3
00131|050|R|  hyperplasia due to interaction between dexamethasone and primidone. Acta|3
00131|051|R|  Paediatr Scand 1991 Jan;80(1):120-4.|3
00132|001|T|MONOGRAPH TITLE:  Selected Beta-blockers/Selected Calcium Channel Blockers|
00132|002|B||
00132|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00132|004|L|take action as needed.|
00132|005|B||
00132|006|A|MECHANISM OF ACTION:  Synergistic pharmacologic activity.|
00132|007|B||
00132|008|E|CLINICAL EFFECTS:  May see an increase in the therapeutic and toxic effects|
00132|009|E|of both drugs.  Concurrent use in patients with low heart rates may unmask|
00132|010|E|sick sinus syndrome.|
00132|011|B||
00132|012|P|PREDISPOSING FACTORS:  Preexisting left ventricular dysfunction and high|
00132|013|P|doses of the beta-blocking agent may predispose patients to adverse|
00132|014|P|responses to this drug combination. Other possible factors include|
00132|015|P|parenteral administration and concurrent administration of other|
00132|016|P|cardio-depressant drugs such as antiarrhythmics.|
00132|017|B||
00132|018|M|PATIENT MANAGEMENT:  Monitor the patient for signs of increased|
00132|019|M|cardio-depressant effects and hypotension. Adjust the dose accordingly.|
00132|020|B||
00132|021|D|DISCUSSION:  Coadministration of these classes of drugs may be effective in|
00132|022|D|the treatment of angina pectoris and hypertension. Patients should be|
00132|023|D|screened in order to determine who should receive this combination of|
00132|024|D|agents.  The concurrent use of mibefradil and beta-blockers in patients with|
00132|025|D|low heart rates may unmask underlying sick sinus syndrome.|
00132|026|D|   One or more of the drug pairs linked to this monograph have been included|
00132|027|D|in a list of interactions that could be considered for classification as|
00132|028|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
00132|029|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
00132|030|D|Health Information Technology.|
00132|031|B||
00132|032|R|REFERENCES:|
00132|033|B||
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00132|044|R|  beta-blockade. Br Med J 1981 Jan 17;282:225.|3
00132|045|R|5.Joshi PI, Dalal JJ, Ruttley MS, Sheridan DJ, Henderson AH. Nifedipine and|2
00132|046|R|  left ventricular function in beta-blocked patients. Br Heart J 1981 Apr;|2
00132|047|R|  45(4):457-9.|2
00132|048|R|6.Winniford MD, Markham RV Jr, Firth BG, Nicod P, Hillis LD. Hemodynamic and|2
00132|049|R|  electrophysiologic effects of verapamil and nifedipine in patients on|2
00132|050|R|  propranolol. Am J Cardiol 1982 Oct;50(4):704-710.|2
00132|051|R|7.Packer M, Meller J, Medina N, Yushak M, Smith H, Holt J, Guererro J, Todd|2
00132|052|R|  GD, McAllister RG Jr, Gorlin R. Hemodynamic consequences of combined|2
00132|053|R|  beta-adrenergic and slow calcium channel blockade in man. Circulation 1982|2
00132|054|R|  Apr;65(4):660-8.|2
00132|055|R|8.Robson RH, Vishwanath MC. Nifedipine and beta-blockade as a cause of|3
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00132|057|R|9.Anastassiades C. Nifedipine and beta-blockade as a cause of cardiac|3
00132|058|R|  failure. Br Med J (Clin Res Ed) 1982 Feb 13;284(6314):506.|3
00132|059|R|10.Vanhaleweyk GL, Serruys PW, Hugenholtz PG. Anti-anginal,|6
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00132|062|R|   D:117-28.|6
00132|063|R|11.Sinclair NI, Benzie JL. Timolol eye drops and verapamil--a dangerous|3
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00132|065|R|12.Eisenberg JN, Oakley GD. Probable adverse interaction between oral|3
00132|066|R|   metoprolol and verapamil. Postgrad Med J 1984 Oct;60(708):705-6.|3
00132|067|R|13.Findlay IN, McInnes GT, Dargie HJ. Beta blockers and verapamil: a|3
00132|068|R|   cautionary tale. Br Med J (Clin Res Ed) 1984 Oct 20;289(6451):1074.|3
00132|069|R|14.Zatuchni J. Bradycardia and hypotension after propranolol HCl and|3
00132|070|R|   verapamil. Heart Lung 1985 Jan;14(1):94-5.|3
00132|071|R|15.Winniford MD, Fulton KL, Hillis LD. Symptomatic sinus bradycardia during|2
00132|072|R|   concomitant propranolol-verapamil administration. Am Heart J 1985 Aug;|2
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00132|084|R|   blockers metoprolol and atenolol. Br J Clin Pharmacol 1984 Sep;|2
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00132|086|R|20.Leon MB, Rosing DR, Bonow RO, Epstein SE. Combination therapy with|6
00132|087|R|   calcium-channel blockers and beta blockers for chronic stable angina|6
00132|088|R|   pectoris. Am J Cardiol 1985 Jan 25;55(3):69B-80B.|6
00132|089|R|21.Vetrovec GW, Parker VE. Acute electrophysiologic, hemodynamic and left|2
00132|090|R|   ventricular effects of nifedipine and beta-blocker interactions.|2
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00132|100|R|24.Nayler WG. The potential for added benefits with beta-blockers and|6
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00132|102|R|   Suppl 4:1-8.|6
00132|103|R|25.Anonymous. Nifedipine and atenolol singly and combined for treatment of|2
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00132|105|R|   in the United Kingdom. Nifedipine-Atenolol Study Review Committee. Br Med|2
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00132|107|R|26.Maclean D, Mitchell ET, Coulson RR, Fitzsimons TJ, McDevitt DG.|2
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00132|112|R|   tolerability of atenolol, nifedipine, and their combination in the|2
00132|113|R|   management of hypertension. Eur J Clin Pharmacol 1988;34(6):543-8.|2
00132|114|R|28.McCourty JC, Silas JH, Tucker GT, Lennard MS. The effect of combined|2
00132|115|R|   therapy on the pharmacokinetics and pharmacodynamics of verapamil and|2
00132|116|R|   propranolol in patients with angina pectoris. Br J Clin Pharmacol 1988|2
00132|117|R|   Mar;25(3):349-57.|2
00132|118|R|29.Keech AC, Harper RW, Harrison PM, Pitt A, McLean AJ. Extent and|2
00132|119|R|   pharmacokinetic mechanisms of oral atenolol-verapamil interaction in man.|2
00132|120|R|   Eur J Clin Pharmacol 1988;35(4):363-6.|2
00132|121|R|30.Carruthers SG, Freeman DJ, Bailey DG. Pharmacodynamic interaction between|4
00132|122|R|   beta-blockers and verapamil: possible relevance of ancillary properties.|4
00132|123|R|   Clin Pharmacol Ther 1989 Feb;45(2):170.|4
00132|124|R|31.Murdoch D, McInnes GI, Thomson GD, Murray GD, Brodie MJ. Pharmacodynamics|4
00132|125|R|   and pharmacokinetics of verapamil and propranolol after single and|4
00132|126|R|   repeated administration. Br J Clin Pharmacol 1989;28:233P-4P.|4
00132|127|R|32.Hunt BA, Bottorff MB, Herring VL, Self TH, Lalonde RL. Effects of calcium|2
00132|128|R|   channel blockers on the pharmacokinetics of propranolol stereoisomers.|2
00132|129|R|   Clin Pharmacol Ther 1990 May;47(5):584-91.|2
00132|130|R|33.Murdoch DL, Thomson GD, Thompson GG, Murray GD, Brodie MJ, McInnes GT.|2
00132|131|R|   Evaluation of potential pharmacodynamic and pharmacokinetic interactions|2
00132|132|R|   between verapamil and propranolol in normal subjects. Br J Clin Pharmacol|2
00132|133|R|   1991 Mar;31(3):323-32.|2
00132|134|R|34.Bailey DG, Carruthers SG. Interaction between oral verapamil and|2
00132|135|R|   beta-blockers during submaximal exercise: relevance of ancillary|2
00132|136|R|   properties. Clin Pharmacol Ther 1991 Apr;49(4):370-6.|2
00132|137|R|35.Posicor (mibefradil) US prescribing information. Roche Pharmaceuticals|1
00132|138|R|   December, 1997.|1
00132|139|R|36.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
00132|140|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
00132|141|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
00132|142|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
00133|001|T|MONOGRAPH TITLE:  Carbamazepine/Macrolide Antibiotics|
00133|002|B||
00133|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00133|004|L|of severe adverse interaction.|
00133|005|B||
00133|006|A|MECHANISM OF ACTION:  Troleandomycin inhibits the hepatic metabolism of|
00133|007|A|carbamazepine by CYP3A4. Erythromycin has a similar but lesser effect (1,2).|
00133|008|B||
00133|009|E|CLINICAL EFFECTS:  Increased serum carbamazepine levels with subsequent|
00133|010|E|increases in the pharmacological and toxic effects of carbamazepine.|
00133|011|B||
00133|012|P|PREDISPOSING FACTORS:  Simultaneous use of other drugs, i.e. other|
00133|013|P|anticonvulsants, or carbamazepine blood levels already near the toxic range|
00133|014|P|before macrolide administration probably increase the risk of a severe|
00133|015|P|interaction.|
00133|016|B||
00133|017|M|PATIENT MANAGEMENT:  Avoid coadministration of these drugs. If given|
00133|018|M|together, monitor carbamazepine serum concentration and observe patient for|
00133|019|M|signs of toxicity (dizziness, ataxia, blurred vision, SIADH). Consider|
00133|020|M|discontinuing either drug or decreasing the dose of carbamazepine.|
00133|021|B||
00133|022|D|DISCUSSION:  There are numerous reports of elevated carbamazepine serum|
00133|023|D|levels in patients receiving erythromycin concurrently. Frequently, symptoms|
00133|024|D|of carbamazepine toxicity have accompanied these increased levels. The|
00133|025|D|effects of this interaction may occur rapidly (i.e., in less than 24 hours).|
00133|026|B||
00133|027|R|REFERENCES:|
00133|028|B||
00133|029|R|1.Dravet C, Mesdjian E, Cenraud B, Roger J. Interaction between|3
00133|030|R|  carbamazepine and triacetyloleandomycin. Lancet 1977 Apr 9;1(8015):810-1.|3
00133|031|R|2.Mesdjian E, Dravet C, Cenraud B, Roger J. Carbamazepine intoxication due|2
00133|032|R|  to triacetyloleandomycin administration in epileptic patients. Epilepsia|2
00133|033|R|  1980 Oct;21(5):489-96.|2
00133|034|R|3.Straughan J. Erythromycin-carbamazepine interaction?. S Afr Med J 1982 Mar|3
00133|035|R|  20;61(12):420-1.|3
00133|036|R|4.Larrey D, Funck-Brentano C, Breil P, Vitaux J, Theodore C, Babany G,|5
00133|037|R|  Pessayre D. Effects of erythromycin on hepatic drug-metabolizing enzymes|5
00133|038|R|  in humans. Biochem Pharmacol 1983 Mar 15;32(6):1063-8.|5
00133|039|R|5.Wong YY, Ludden TM, Bell RD. Effect of erythromycin on carbamazepine|2
00133|040|R|  kinetics. Clin Pharmacol Ther 1983 Apr;33(4):460-4.|2
00133|041|R|6.Hedrick R, Williams F, Morin R, Lamb WA, Cate JC 4th.|3
00133|042|R|  Carbamazepine--erythromycin interaction leading to carbamazepine toxicity|3
00133|043|R|  in four epileptic children. Ther Drug Monit 1983;5(4):405-7.|3
00133|044|R|7.Vajda FJ, Bladin PF. Carbamazepine--erythromycin-base interaction. Med J|3
00133|045|R|  Aust 1984 Jan 21;140(2):81.|3
00133|046|R|8.Carranco E, Kareus J, Co S, Peak V, Al-Rajeh S. Carbamazepine toxicity|3
00133|047|R|  induced by concurrent erythromycin therapy. Arch Neurol 1985 Feb;|3
00133|048|R|  42(2):187-8.|3
00133|049|R|9.Kessler JM. Erythromycin-carbamazepine interaction. S Afr Med J 1985 Jun|3
00133|050|R|  29;67(26):1038.|3
00133|051|R|10.Wroblewski BA, Singer WD, Whyte J. Carbamazepine-erythromycin|3
00133|052|R|   interaction. Case studies and clinical significance. JAMA 1986 Mar 7;|3
00133|053|R|   255(9):1165-7.|3
00133|054|R|11.Jaster PJ, Abbas D. Erythromycin-carbamazepine interaction. Neurology|3
00133|055|R|   1986 Apr;36(4):594-5.|3
00133|056|R|12.Berrettini WH. A case of erythromycin-induced carbamazepine toxicity. J|3
00133|057|R|   Clin Psychiatry 1986 Mar;47(3):147.|3
00133|058|R|13.Goulden KJ, Camfield P, Dooley JM, Fraser A, Meek DC, Renton KW, Tibbles|2
00133|059|R|   JA. Severe carbamazepine intoxication after coadministration of|2
00133|060|R|   erythromycin. J Pediatr 1986 Jul;109(1):135-8.|2
00133|061|R|14.Zitelli BJ, Howrie DL, Altman H, Maroon TJ. Erythromycin-induced drug|3
00133|062|R|   interactions. An illustrative case and review of the literature. Clin|3
00133|063|R|   Pediatr (Phila) 1987 Mar;26(3):117-9.|3
00133|064|R|15.Woody RC, Kearns GL, Bolyard KJ. Carbamazepine intoxication following the|3
00133|065|R|   use of erythromycin in children. Pediatr Infect Dis J 1987 Jun;|3
00133|066|R|   6(6):578-9.|3
00133|067|R|16.Macnab AJ, Robinson JL, Adderly RJ, D'Orsogna L. Heart block secondary to|3
00133|068|R|   erythromycin-induced carbamazepine toxicity. Pediatrics 1987 Dec;|3
00133|069|R|   80(6):951-3.|3
00133|070|R|17.Barzaghi N, Gatti G, Crema F, Monteleone M, Amione C, Leone L, Perucca E.|2
00133|071|R|   Inhibition by erythromycin of the conversion of carbamazepine to its|2
00133|072|R|   active 10,11-epoxide metabolite. Br J Clin Pharmacol 1987 Dec;|2
00133|073|R|   24(6):836-8.|2
00133|074|R|18.Miles MV, Tennison MB. Erythromycin effects on multiple-dose|2
00133|075|R|   carbamazepine kinetics. Ther Drug Monit 1989;11(1):47-52.|2
00134|001|T|MONOGRAPH TITLE:  Angiotensin II Receptor Blocker (ARB)/NSAIDs; Salicylates|
00134|002|B||
00134|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00134|004|L|take action as needed.|
00134|005|B||
00134|006|A|MECHANISM OF ACTION:  Angiotensin II receptor blockers (ARBs) can cause|
00134|007|A|vasodilation of the efferent renal arteriole which may result in decreased|
00134|008|A|glomerular filtration rate.  NSAIDs inhibit prostaglandin synthesis which|
00134|009|A|can lead to afferent arteriolar vasoconstriction and may negate any decrease|
00134|010|A|in blood pressure.|
00134|011|B||
00134|012|E|CLINICAL EFFECTS:  Concurrent use of ARBs with NSAIDs may result in|
00134|013|E|decreased antihypertensive effects.  In patients with existing renal|
00134|014|E|impairment, the use of these agents together may also result in further|
00134|015|E|deterioration of renal clearance caused by renal hypoperfusion.|
00134|016|E|   Concurrent use of ARBs with NSAIDs and diuretics may result in increased|
00134|017|E|risk of acute kidney injury (AKI).|
00134|018|B||
00134|019|P|PREDISPOSING FACTORS:  Low water intake/dehydration, drug sensitivity,|
00134|020|P|greater than 75 years of age, and use of diuretics can lead to hypovolemia|
00134|021|P|and increased risk of AKI.|
00134|022|B||
00134|023|M|PATIENT MANAGEMENT:  Patients maintained on ARBs should be monitored for a|
00134|024|M|loss of blood pressure control and a change in renal function if an NSAID is|
00134|025|M|added to their regimen.  Patients receiving concurrent therapy may require|
00134|026|M|higher doses of ARBs.  If blood pressure control cannot be achieved or if|
00134|027|M|the patient's renal function deteriorates, the NSAID may need to be|
00134|028|M|discontinued.  Patients should be monitored for hypotension if NSAIDs are|
00134|029|M|withdrawn from concurrent ARB therapy.|
00134|030|M|   Concurrent use of ARBs with NSAIDs and diuretics should be used with|
00134|031|M|caution and monitored for signs of AKI.|
00134|032|B||
00134|033|D|DISCUSSION:  In a computational study, the risk of AKI using triple therapy|
00134|034|D|with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was|
00134|035|D|assessed.  The study found the following factors may increase an|
00134|036|D|individual's susceptibility to AKI: low water intake, drug sensitivity,|
00134|037|D|greater than 75 years of age, and renal impairment.(22,23)|
00134|038|D|    In an observational study, current use of a triple therapy combination|
00134|039|D|was associated with an increased rate of acute kidney injury (rate ratio|
00134|040|D|(RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI|
00134|041|D|associated with triple therapy were observed in the first 30 days of use (RR|
00134|042|D|1.82, CI 1.35-2.46).(24)|
00134|043|D|   In a population based cohort study, the concurrent use of NSAIDs with|
00134|044|D|renin-angiotensin system (RAS) inhibitors in 5,710 hypertensive patients|
00134|045|D|stabilized on antihypertensive therapy required hypertension treatment|
00134|046|D|intensification.  Adjusted hazard ratios (HR) for hypertension treatment|
00134|047|D|intensification were 1.34 [95% CI 1.05-1.71] for NSAIDs in general, 1.79|
00134|048|D|(95% CI 1.15-2.78) for diclofenac and 2.02 (95% CI 1.09-3.77) for piroxicam.|
00134|049|D|There were significant interactions between NSAIDs and angiotensin|
00134|050|D|converting enzyme inhibitors (ACE inhibitors; HR 4.09, 95% CI 2.02-8.27) or|
00134|051|D|angiotensin receptor blockers (ARBs; HR 3.62, 95% CI 1.80-7.31), but not|
00134|052|D|with other antihypertensive drugs.|
00134|053|B||
00134|054|R|REFERENCES:|
00134|055|B||
00134|056|R|1.Swartz SL, Williams GH. Angiotensin-converting enzyme inhibition and|2
00134|057|R|  prostaglandins. Am J Cardiol 1982 Apr 21;49(6):1405-9.|2
00134|058|R|2.Abe K, Ito T, Sato M, Haruyama T, Sato K, Omata K, Hiwatari M, Sakurai Y,|2
00134|059|R|  Imai Y, Yoshinaga K. Role of prostaglandin in the antihypertensive|2
00134|060|R|  mechanism of captopril in low renin hypertension. Clin Sci (Lond) 1980|2
00134|061|R|  Dec;59 Suppl 6:141s-144s.|2
00134|062|R|3.Abe K, Itoh T, Imai Y, Sato M, Goto T, Otsuka Y, Yoshinaga K. Indomethacin|2
00134|063|R|  inhibits the antihypertensive effect of captopril, SQ 14225, in low renin|2
00134|064|R|  hypertension. Tohoku J Exp Med 1980 Sep;132(1):117-8.|2
00134|065|R|4.Moore TJ, Crantz FR, Hollenberg NK, Koletsky RJ, Leboff MS, Swartz SL,|2
00134|066|R|  Levine L, Podolsky S, Dluhy RG, Williams GH. Contribution of|2
00134|067|R|  prostaglandins to the antihypertensive action of captopril in essential|2
00134|068|R|  hypertension. Hypertension 1981 Mar-Apr;3(2):168-73.|2
00134|069|R|5.Fujita T, Yamashita N, Yamashita K. Effect of indomethacin on|2
00134|070|R|  antihypertensive action of captopril in hypertensive patients. Clin Exp|2
00134|071|R|  Hypertens 1981;3(5):939-52.|2
00134|072|R|6.Silberbauer K, Stanek B, Templ H. Acute hypotensive effect of captopril in|2
00134|073|R|  man modified by prostaglandin synthesis inhibition. Br J Clin Pharmacol|2
00134|074|R|  1982;14 Suppl 2:87S-93S.|2
00134|075|R|7.Salvetti A, Pedrinelli R, Magagna A, Ugenti P. Differential effects of|2
00134|076|R|  selective and non-selective prostaglandin-synthesis inhibition on the|2
00134|077|R|  pharmacological responses to captopril in patients with essential|2
00134|078|R|  hypertension. Clin Sci 1982;63(Suppl 8):261s-3s.|2
00134|079|R|8.Gilchrist NL, Richards AM, March R, Nicholls MG. Effect of sulindac on|2
00134|080|R|  angiotensin converting enzyme inhibitor-induced cough: randomised|2
00134|081|R|  placebo-controlled double-blind cross-over study. J Hum Hypertens 1989|2
00134|082|R|  Dec;3(6):451-5.|2
00134|083|R|9.Ohya Y, Kumamoto K, Fujishima M. Effects of crossover application of|3
00134|084|R|  sulindac and azelastine on enalapril-induced cough. J Hum Hypertens 1992|3
00134|085|R|  Feb;6(1):81-2.|3
00134|086|R|10.Allon M, Pasque CB, Rodriguez M. Interaction of captopril and ibuprofen|2
00134|087|R|   on glomerular and tubular function in humans. Am J Physiol 1990 Aug;259(2|2
00134|088|R|   Pt 2):F233-8.|2
00134|089|R|11.Allon M, Pasque CB, Rodriguez M. Acute effects of captopril and ibuprofen|2
00134|090|R|   on proteinuria in patients with nephrosis. J Lab Clin Med 1990 Oct;|2
00134|091|R|   116(4):462-8.|2
00134|092|R|12.Minuz P, Lechi A, Arosio E, Degan M, Capuzzo MG, Lechi C, Corsato M,|2
00134|093|R|   Dalla Riva A, Velo GP. Antihypertensive activity of enalapril. Effect of|2
00134|094|R|   ibuprofen and different salt intakes. J Clin Hypertens 1987 Dec;|2
00134|095|R|   3(4):645-53.|2
00134|096|R|13.Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood|2
00134|097|R|   pressure in elderly people with essential hypertension well controlled on|2
00134|098|R|   amlodipine or enalapril. Am J Hypertens 2000 Nov;13(11):1161-7.|2
00134|099|R|14.Conlin PR, Moore TJ, Swartz SL, Barr E, Gazdick L, Fletcher C, DeLucca P,|2
00134|100|R|   Demopoulos L. Effect of indomethacin on blood pressure lowering by|2
00134|101|R|   captopril and losartan in hypertensive patients. Hypertension 2000 Sep;|2
00134|102|R|   36(3):461-5.|2
00134|103|R|15.Fricker AF, Nussberger J, Meilenbrock S, Brunner HR, Burnier M. Effect of|2
00134|104|R|   indomethacin on the renal response to angiotensin II receptor blockade in|2
00134|105|R|   healthy subjects. Kidney Int 1998 Dec;54(6):2089-97.|2
00134|106|R|16.Morgan T, Anderson A. Interaction of indomethacin with felodipine and|2
00134|107|R|   enalapril. J Hypertens Suppl 1993 Dec;11 Suppl 5:S338-9.|2
00134|108|R|17.Halawa B. Effect of indomethacin and ibuprofen on blood pressure of|2
00134|109|R|   patients treated with nifedipine or captopril. Pol Tyg Lek 1993 Apr 5-12;|2
00134|110|R|   48(14-15):313-5.|2
00134|111|R|18.Espino DV, Lancaster MC. Neutralization of the effects of captopril by|3
00134|112|R|   the use of ibuprofen in an elderly woman. J Am Board Fam Pract 1992|3
00134|113|R|   May-Jun;5(3):319-21.|3
00134|114|R|19.Abdel-Haq B, Magagna A, Favilla S, Salvetti A. Hemodynamic and humoral|2
00134|115|R|   interactions between perindopril and indomethacin in essential|2
00134|116|R|   hypertensive subjects. J Cardiovasc Pharmacol 1991;18 Suppl 7:S33-6.|2
00134|117|R|20.Kirch W, Stroemer K, Hoogkamer JF, Kleinbloesem CH. The influence of|2
00134|118|R|   prostaglandin inhibition by indomethacin on blood pressure and renal|2
00134|119|R|   function in hypertensive patients treated with cilazapril. Br J Clin|2
00134|120|R|   Pharmacol 1989;27 Suppl 2:297S-301S.|2
00134|121|R|21.Fogari R, Zoppi A, Carretta R, Veglio F, Salvetti A. Effect of|2
00134|122|R|   indomethacin on the antihypertensive efficacy of valsartan and|2
00134|123|R|   lisinopril: a multicentre study. J Hypertens 2002 May;20(5):1007-14.|2
00134|124|R|22.Leete J,  Wang C,  Lopez-Hernandez FJ,  Layton AT. Determining risk|6
00134|125|R|   factors for triple whammy acute kidney injury. Math Biosci 2022 Apr 4.|6
00134|126|R|23.Dreischulte T,  Morales DR,  Bell S,  Guthrie B. Combined use of|2
00134|127|R|   nonsteroidal anti-inflammatory drugs with diuretics and/or|2
00134|128|R|   renin-angiotensin system inhibitors in the community increases the risk|2
00134|129|R|   of acute kidney injury. Kidney Int 2015 Aug;88(2):396-403.|2
00134|130|R|24.Lapi F,  Azoulay L,  Yin H,  Nessim SJ,  Suissa S. Concurrent use of|2
00134|131|R|   diuretics, angiotensin converting enzyme inhibitors, and angiotensin|2
00134|132|R|   receptor blockers with non-steroidal anti-inflammatory drugs and risk of|2
00134|133|R|   acute kidney injury: nested case-control study. BMJ 2013 Jan;8(346):.|2
00134|134|R|25.Juhlin T,  Bjorkman S,  Hoglund P. Cyclooxygenase inhibition causes|2
00134|135|R|   marked impairment of renal function in elderly subjects treated with|2
00134|136|R|   diuretics and ACE-inhibitors. Eur J Heart Fail 2005 Oct;7(6):1049-56.|2
00135|001|T|MONOGRAPH TITLE:  Angiotensin II Receptor Blocker (ARB)/K+ Sparing Diuretics|
00135|002|B||
00135|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00135|004|L|take action as needed.|
00135|005|B||
00135|006|A|MECHANISM OF ACTION:  Angiotensin II receptor blockers (ARBs) may decrease|
00135|007|A|the renal excretion of potassium.|
00135|008|B||
00135|009|E|CLINICAL EFFECTS:  Concurrent use of potassium sparing diuretics with an ARB|
00135|010|E|may result in hyperkalemia.|
00135|011|B||
00135|012|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
00135|013|B||
00135|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
00135|015|M|accordingly in patients receiving concurrent therapy with a potassium|
00135|016|M|sparing diuretic and an ARB.|
00135|017|M|   In all patients taking eplerenone who start taking an an ARB, check serum|
00135|018|M|potassium and creatinine levels after 3-7 days of concurrent therapy.|
00135|019|B||
00135|020|D|DISCUSSION:  In a nested case-control study of heart failure patients|
00135|021|D|receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of|
00135|022|D|hyperkalemia was significantly associated with spironolactone use (odds|
00135|023|D|ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20)|
00135|024|D|   In a systemic literature review and meta-analysis of 20 randomized|
00135|025|D|controlled studies, it was found that treatment with spironolactone and|
00135|026|D|ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased|
00135|027|D|the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26|
00135|028|D|mEq/L).(21)|
00135|029|D|   A retrospective cohort study in patients with hypertension, diabetes, and|
00135|030|D|albuminuria between 2008 and 2018 examined the efficacy and safety of|
00135|031|D|mineralocorticoid receptor antagonists eplerenone and spironolactone in|
00135|032|D|combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more|
00135|033|D|frequent in combination therapy patients (n=1,282) versus monotherapy|
00135|034|D|(n=5,484) (22.3 vs 10.9 per 100 person-years for combination and|
00135|035|D|monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22)|
00135|036|D|   Several studies have indicated that serum potassium levels increase when|
00135|037|D|ACE inhibitors and ARB therapy is initiated and decrease when the drug is|
00135|038|D|lowered.  There are case reports of hyperkalemia during concurrent therapy|
00135|039|D|with ARBs and spironolactone and with aliskiren and spironolactone.|
00135|040|D|   Based on this data, serum potassium levels should be monitored in|
00135|041|D|patients receiving concomitant ARBs with potassium sparing diuretics.|
00135|042|B||
00135|043|R|REFERENCES:|
00135|044|B||
00135|045|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
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00135|052|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
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00135|055|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
00135|056|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
00135|057|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
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00135|061|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
00135|062|R|  sustained reduction in aldosterone secretion, potassium retention and|2
00135|063|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
00135|064|R|8.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
00135|065|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
00135|066|R|9.Radley AS, Fitzpatrick RW. An evaluation of the potential interaction|2
00135|067|R|  between enalapril and amiloride. J Clin Pharm Ther 1987 Oct;12(5):319-23.|2
00135|068|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
00135|069|R|   October, 2021.|1
00135|070|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
00135|071|R|   Corporation June, 2019.|1
00135|072|R|12.Saito M, Takada M, Hirooka K, Isobe F, Yasumura Y. Serum concentration of|2
00135|073|R|   potassium in chronic heart failure patients administered spironolactone|2
00135|074|R|   plus furosemide and either enalapril maleate, losartan potassium or|2
00135|075|R|   candesartan cilexetil. J Clin Pharm Ther 2005 Dec;30(6):603-10.|2
00135|076|R|13.Fujii H, Nakahama H, Yoshihara F, Nakamura S, Inenaga T, Kawano Y.|3
00135|077|R|   Life-threatening Hyperkalemia during a Combined Therapy with the|3
00135|078|R|   Angiotensin Receptor Blocker Candesartan and Spironolactone. Kobe J Med|3
00135|079|R|   Sci 2005;51(1):1-6.|3
00135|080|R|14.Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or|2
00135|081|R|   angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney|2
00135|082|R|   Dis 2004 Oct;44(4):738-46.|2
00135|083|R|15.Kauffmann Q R, Orozco B R, Venegas G JC. Severe hyperkalemia associated|3
00135|084|R|   to the use of losartan and spironolactone: Case report. Rev Med Chil 2005|3
00135|085|R|   Aug;133(8):947-52.|3
00135|086|R|16.Venzin RM, Cohen CD, Maggiorini M, Wuthrich RP. Aliskiren-associated|3
00135|087|R|   acute renal failure with hyperkalemia. Clin Nephrol 2009 Mar;71(3):326-8.|3
00135|088|R|17.Yamauchi J, Shibagaki Y, Uehara K, Yasuda T, Kimura K.|3
00135|089|R|   Aliskiren-associated acute kidney injury in a patient with pre-existing|3
00135|090|R|   chronic kidney disease and dilated cardiomyopathy. Clin Exp Nephrol 2012|3
00135|091|R|   Apr;16(2):333-6.|3
00135|092|R|18.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
00135|093|R|   Corporation November, 2017.|1
00135|094|R|19.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
00135|095|R|20.Abbas S,  Ihle P,  Harder S,  Schubert I. Risk of hyperkalemia and|2
00135|096|R|   combined use of spironolactone and long-term ACE inhibitor/angiotensin|2
00135|097|R|   receptor blocker therapy in heart failure using real-life data: a|2
00135|098|R|   population- and insurance-based cohort. Pharmacoepidemiol and Drug Saf 12|2
00135|099|R|   Feb 2015;24:406-413.|2
00135|100|R|21.Villa-Zapata L,  Carhart BS,  Horn JR,  Hansten PD,  Subbian V,  Gephart|6
00135|101|R|   S,  Tan M,  Romero A,  Malone DC. Serum potassium changes due to|6
00135|102|R|   concomitant ACEI/ARB and spironolactone therapy: a systemic review and|6
00135|103|R|   meta-analysis. Am J Health-Syst Pharm 15 December 2021;78(24):2245-2255.|6
00135|104|R|22.An J,  Niu F,  Sim JJ. Cardiovascular and kidney outcomes of|6
00135|105|R|   spironolactone or eplerenone in combination with ACEI/ARBs in patients|6
00135|106|R|   with diabetic kidney disease. Pharmacotherapy October 2021;41:998-1008.|6
00136|001|T|MONOGRAPH TITLE:  Angiotensin II Receptor Blocker (ARB)/Potassium|
00136|002|T|Supplements|
00136|003|B||
00136|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00136|005|L|take action as needed.|
00136|006|B||
00136|007|A|MECHANISM OF ACTION:  Angiotensin II receptor blockers (ARBs) may decrease|
00136|008|A|the renal excretion of potassium.|
00136|009|B||
00136|010|E|CLINICAL EFFECTS:  Concurrent use of potassium supplements with ARBs may|
00136|011|E|result in hyperkalemia.|
00136|012|B||
00136|013|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
00136|014|B||
00136|015|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
00136|016|M|accordingly in patients receiving concurrent therapy with potassium|
00136|017|M|supplements and ARBs.|
00136|018|B||
00136|019|D|DISCUSSION:  Several studies have indicated that serum potassium levels|
00136|020|D|increase when ARB therapy is initiated and decrease when the drug is|
00136|021|D|lowered.|
00136|022|D|   Based on this data, serum potassium levels should be monitored in|
00136|023|D|patients receiving potassium supplements with ARBs.|
00136|024|B||
00136|025|R|REFERENCES:|
00136|026|B||
00136|027|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
00136|028|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
00136|029|R|2.Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal|3
00136|030|R|  failure with severe hyperkalaemia. Lancet 1980 Mar 29;1(8170):712.|3
00136|031|R|3.Warren SE, O'Connor DT. Hyperkalemia resulting from captopril|3
00136|032|R|  administration. JAMA 1980 Dec 5;244(22):2551-2.|3
00136|033|R|4.Maslowski AH, Ikram H, Nicholls MG, Espiner EA. Haemodynamic, hormonal,|2
00136|034|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
00136|035|R|  1981 Jan 10;1(8211):71-4.|2
00136|036|R|5.Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic|2
00136|037|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
00136|038|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
00136|039|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
00136|040|R|  supplementation. A potential for hyperkalemia. Arch Intern Med 1984 Dec;|3
00136|041|R|  144(12):2371-2.|3
00136|042|R|7.Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN. Interruption of the|2
00136|043|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
00136|044|R|  sustained reduction in aldosterone secretion, potassium retention and|2
00136|045|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
00136|046|R|8.Papadimitriou M, Zamboulis C, Alexopoulos E, Liamos H, Sakellariou G,|2
00136|047|R|  Memmos D, Metaxas P, Thessaloniki G. Alarming hyperkalemia during|2
00136|048|R|  captopril administration in patients on regular hemodialysis. Dialysis|2
00136|049|R|  Transplant 1985 Aug;14:473-5.|2
00136|050|R|9.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
00136|051|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
00136|052|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
00136|053|R|   October, 2021.|1
00136|054|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
00136|055|R|   Corporation June, 2019.|1
00136|056|R|12.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
00136|057|R|   Corporation November, 2017.|1
00137|001|T|MONOGRAPH TITLE:  Diazoxide/Hydantoins (mono deleted 02/01/2022)|
00137|002|B||
00137|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00137|004|L|take action as needed.|
00137|005|B||
00137|006|A|MECHANISM OF ACTION:  Diazoxide appears to increase the hepatic metabolism|
00137|007|A|of hydantoins.|
00137|008|B||
00137|009|E|CLINICAL EFFECTS:  May see a decrease in the pharmacologic effects of|
00137|010|E|hydantoins due to reduced serum levels.|
00137|011|B||
00137|012|P|PREDISPOSING FACTORS:  None determined.|
00137|013|B||
00137|014|M|PATIENT MANAGEMENT:  Monitor both serum hydantoin levels and seizure|
00137|015|M|frequency. Adjust the dosage accordingly.|
00137|016|B||
00137|017|D|DISCUSSION:  Low serum phenytoin levels have been reported in children|
00137|018|D|receiving diazoxide and phenytoin concurrently. Additional studies are|
00137|019|D|needed to assess the clinical significance of this interaction.|
00137|020|B||
00137|021|R|REFERENCES:|
00137|022|B||
00137|023|R|1.Roe TF, Podosin RL, Blaskovics ME. Drug interaction: diazoxide and|3
00137|024|R|  diphenylhydantoin. J Pediatr 1975 Sep;87(3):480-4.|3
00137|025|R|2.Petro DJ, Vannucci RC, Kulin HE. Letter: Diazoxide-diphenylhydantoin|3
00137|026|R|  interaction. J Pediatr 1976 Aug;89(2):331-2.|3
00138|001|T|MONOGRAPH TITLE:  Hydantoins/Rifamycins|
00138|002|B||
00138|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00138|004|L|of severe adverse interaction.|
00138|005|B||
00138|006|A|MECHANISM OF ACTION:  Phenytoin is primarily metabolized by CYP2C9, and|
00138|007|A|secondarily metabolized by CYP2C19.  Rifapentine induces CYP2C9.  Rifampin|
00138|008|A|induces CYP2C9 and CYP2C19.|
00138|009|B||
00138|010|E|CLINICAL EFFECTS:  Phenytoin concentrations may be substantially decreased,|
00138|011|E|increasing the risk for seizures.|
00138|012|B||
00138|013|P|PREDISPOSING FACTORS:  None determined.|
00138|014|B||
00138|015|M|PATIENT MANAGEMENT:  The magnitude of induction may gradually increase over|
00138|016|M|1-2 weeks.  Monitor phenytoin levels and adjust phenytoin dose until patient|
00138|017|M|is stabilized on concurrent therapy.|
00138|018|M|   When the rifamycin is subsequently discontinued, induction will gradually|
00138|019|M|wane.  Monitor and adjust the phenytoin dose to maintain therapeutic|
00138|020|M|concentration and prevent phenytoin toxicity.|
00138|021|B||
00138|022|D|DISCUSSION:  Rifampin administration to patients receiving phenytoin has|
00138|023|D|been reported to increase clearance and decrease the elimination half-life|
00138|024|D|of the anticonvulsant.|
00138|025|B||
00138|026|R|REFERENCES:|
00138|027|B||
00138|028|R|1.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
00138|029|R|  Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
00138|030|R|2.Kay L, Kampmann JP, Svendsen TL, Vergman B, Hansen JE, Skovsted L,|2
00138|031|R|  Kristensen M. Influence of rifampicin and isoniazid on the kinetics of|2
00138|032|R|  phenytoin. Br J Clin Pharmacol 1985 Oct;20(4):323-6.|2
00138|033|R|3.Abajo FJ. Phenytoin interaction with rifampicin. BMJ 1988 Oct 22;|3
00138|034|R|  297(6655):1048.|3
00138|035|R|4.Priftin (rifapentine) US prescribing information. Sanofi-Aventis U.S. LLC|1
00138|036|R|  July, 2010.|1
00139|001|T|MONOGRAPH TITLE:  Selected Antimalarials/Strong CYP3A4 Inducers; Selected|
00139|002|T|Barbiturates, Hydantoin|
00139|003|B||
00139|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00139|005|L|of severe adverse interaction.|
00139|006|B||
00139|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
00139|008|A|mefloquine, quinidine, and quinine.|
00139|009|B||
00139|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
00139|011|E|decreased levels and effectiveness of mefloquine, quinidine, or quinine.|
00139|012|B||
00139|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00139|014|P|of the inducer for longer than 1-2 weeks.|
00139|015|B||
00139|016|M|PATIENT MANAGEMENT:  In patients receiving concurrent strong CYP3A4|
00139|017|M|inducers, monitor mefloquine, quinidine, or quinine serum levels and observe|
00139|018|M|the patient for symptoms of reduced efficacy.  Adjust the dosage|
00139|019|M|accordingly.|
00139|020|M|   The US manufacturer of quinine recommends avoiding the concurrent use of|
00139|021|M|rifampin, a strong CYP3A4 inducer, because of the increased risk of malaria|
00139|022|M|treatment failure.|
00139|023|B||
00139|024|D|DISCUSSION:  Several studies document the reduction in quinidine response in|
00139|025|D|patients receiving concurrent rifampin.  Decreased elimination half-life,|
00139|026|D|reduced area-under-curve (AUC), and low serum quinidine level were observed.|
00139|027|D|   In healthy volunteers, quinine AUC and maximum concentration (Cmax) were|
00139|028|D|reduced 85% and 55%, respectively, after a single dose of rifampin was added|
00139|029|D|after two weeks of quinine therapy.(6)|
00139|030|D|  In a randomized control trial of 59 male patients with Plasmodium|
00139|031|D|falciparum malaria, treatment with concomitant quinine and rifampin was|
00139|032|D|associated with a cure rate of only 35% compared to 88% in those treated|
00139|033|D|with quinine monotherapy.  The AUC of quinine during treatment days 3|
00139|034|D|through 7 was significantly reduced in the quinine plus rifampin group|
00139|035|D|compared to those treated with quinine alone (11.7 vs. 47.5 mcg/ml/day; p <|
00139|036|D|0.004).(7)|
00139|037|D|   In an open-label, cross-over study in 7 healthy subjects, concurrent|
00139|038|D|rifampin (600 mg daily) decreased the AUC and Cmax of a single dose of|
00139|039|D|mefloquine (500 mg) by 68% and 19%, respectively.(8,9)|
00139|040|D|   Agents linked to this monograph include: apalutamide, barbiturates,|
00139|041|D|carbamazepine, enzalutamide, ethotoin, fosphenytoin, lumacaftor, mitotane,|
00139|042|D|natisedine, phenobarbital, phenytoin, primidone, rifabutin, rifampin,|
00139|043|D|rifapentine, and St. John's wort.(10)|
00139|044|B||
00139|045|R|REFERENCES:|
00139|046|B||
00139|047|R|1.Ahmad D, Mathur P, Ahuja S, Henderson R, Carruthers G.|3
00139|048|R|  Rifampicin-quinidine interaction. Br J Dis Chest 1979 Oct;73(4):409-11.|3
00139|049|R|2.Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction. N Engl J Med|2
00139|050|R|  1981 Jun 11;304(24):1466-9.|2
00139|051|R|3.Bussey HI, Merritt GJ, Hill EG. The influence of rifampin on quinidine and|3
00139|052|R|  digoxin. Arch Intern Med 1984 May;144(5):1021-3.|3
00139|053|R|4.Schwartz A, Brown JR. Quinidine-rifampin interaction. Am Heart J 1984 Apr;|3
00139|054|R|  107(4):789-90.|3
00139|055|R|5.Bussey HI, Farringer J, Merritt GJ. Influence of rifampin (R) on quinidine|4
00139|056|R|  (Q) and digoxin (D). Drug Intell Clin Pharm 1983;17(6):436.|4
00139|057|R|6.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
00139|058|R|  Industries, Inc. August, 2019.|1
00139|059|R|7.Pukrittayakamee S, Prakongpan S, Wanwimolruk S, Clemens R, Looareesuwan S,|2
00139|060|R|  White NJ. Adverse effect of rifampin on quinine efficacy in uncomplicated|2
00139|061|R|  falciparum malaria. Antimicrob Agents Chemother 2003 May;47(5):1509-13.|2
00139|062|R|8.Ridtitid W, Wongnawa M, Mahatthanatrakul W, Chaipol P, Sunbhanich M.|2
00139|063|R|  Effect of rifampin on plasma concentrations of mefloquine in healthy|2
00139|064|R|  volunteers. J Pharm Pharmacol 2000 Oct;52(10):1265-9.|2
00139|065|R|9.Lariam (mefloquine hydrochloride) US prescribing information. Roche|1
00139|066|R|  Pharmaceuticals August, 2009.|1
00139|067|R|10.This information is based on an extract from the Certara Drug Interaction|6
00139|068|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00140|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Quinine|
00140|002|B||
00140|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00140|004|L|of severe adverse interaction.|
00140|005|B||
00140|006|A|MECHANISM OF ACTION:  Quinine may have the potential to depress hepatic|
00140|007|A|enzyme synthesis of vitamin K-dependent clotting factors.(1)|
00140|008|B||
00140|009|E|CLINICAL EFFECTS:  Concurrent use of selected anticoagulants (vitamin K|
00140|010|E|antagonists) and quinine may increase the risk for bleeding.|
00140|011|B||
00140|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00140|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00140|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
00140|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00140|016|P|risk for bleeding (e.g. NSAIDs).|
00140|017|B||
00140|018|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
00140|019|M|receiving concurrent therapy for signs of blood loss, including decreased|
00140|020|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
00140|021|M|and promptly evaluate patients with any symptoms.|
00140|022|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00140|023|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00140|024|M|anticoagulation in patients with active pathologic bleeding.|
00140|025|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00140|026|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00140|027|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00140|028|M|and/or swelling.|
00140|029|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00140|030|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00140|031|M|initiating, altering the dose or discontinuing either drug.|
00140|032|B||
00140|033|D|DISCUSSION:  This interaction has not been reported with quinine, only with|
00140|034|D|quinidine; however, if an interaction occurs, the consequences could be|
00140|035|D|severe.|
00140|036|B||
00140|037|R|REFERENCES:|
00140|038|B||
00140|039|R|1.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
00140|040|R|  Industries, Inc. August, 2019.|1
00140|041|R|2.Koch-Weser J. Quinidine-induced hypoprothrombinemic hemorrhage in patients|3
00140|042|R|  on chronic warfarin therapy. Ann Intern Med 1968 Mar;68(3):511-7.|3
00141|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
00141|002|T|antagonists)/Allopurinol|
00141|003|B||
00141|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00141|005|L|of severe adverse interaction.|
00141|006|B||
00141|007|A|MECHANISM OF ACTION:  Possible inhibition of anticoagulant metabolism by|
00141|008|A|allopurinol.|
00141|009|B||
00141|010|E|CLINICAL EFFECTS:  Concurrent use of anticoagulants and allopurinol may|
00141|011|E|increase the risk for bleeding.|
00141|012|B||
00141|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00141|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00141|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
00141|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00141|017|P|risk for bleeding (e.g. NSAIDs).|
00141|018|B||
00141|019|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
00141|020|M|receiving concurrent therapy for signs of blood loss, including decreased|
00141|021|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
00141|022|M|and promptly evaluate patients with any symptoms.|
00141|023|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00141|024|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00141|025|M|anticoagulation in patients with active pathologic bleeding.|
00141|026|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00141|027|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00141|028|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00141|029|M|and/or swelling.|
00141|030|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00141|031|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00141|032|M|initiating, altering the dose or discontinuing either drug.|
00141|033|B||
00141|034|D|DISCUSSION:  Documentation is lacking; however, if an interaction occurs,|
00141|035|D|the consequences could be severe.|
00141|036|B||
00141|037|R|REFERENCE:|
00141|038|B||
00141|039|R|1.Vesell ES, Passananti GT, Greene FE. Impairment of drug metabolism in man|2
00141|040|R|  by allopurinol and nortriptyline. N Engl J Med 1970 Dec 31;283(27):1484-8.|2
00142|001|T|MONOGRAPH TITLE:  Selected Opioids; Dextromethorphan/Selected MAOIs|
00142|002|B||
00142|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00142|004|L|is contraindicated and generally should not be dispensed or administered to|
00142|005|L|the same patient.|
00142|006|B||
00142|007|A|MECHANISM OF ACTION:  Selected opioids inhibit neural reuptake of serotonin.|
00142|008|A|MAOIs may increase neuronal serotonin concentrations via inhibition of|
00142|009|A|MAO-A.(26)|
00142|010|B||
00142|011|E|CLINICAL EFFECTS:  The concurrent use of selected opioids with MAOIs has|
00142|012|E|resulted in hypotension, hyperpyrexia, sedation, somnolence, and death.|
00142|013|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
00142|014|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
00142|015|E|rigidity.(26)|
00142|016|B||
00142|017|P|PREDISPOSING FACTORS:  Higher opioid concentrations as may occur due to|
00142|018|P|inhibition of opioid  clearance, patient specific genomic factors (e.g. poor|
00142|019|P|metabolizer status for a P450 enzyme), or high opioid dosage may increase|
00142|020|P|the risk for a severe interaction.|
00142|021|B||
00142|022|M|PATIENT MANAGEMENT:  Dextromethorphan, diamorphine, meperidine, and|
00142|023|M|tapentadol should not be used in patients taking MAOIs.  Use alternative|
00142|024|M|agents for cough or pain.|
00142|025|M|   The US manufacturer of Nuedexta(dextromethorphan-quinidine) states|
00142|026|M|Nuedexta is contraindicated within 14 days of MAOI administration.(28)|
00142|027|M|Quinidine increases systemic dextromethorphan concentrations 10 to 20-fold.|
00142|028|M|Other strong CYP2D6 inhibitors such as bupropion, fluoxetine and paroxetine|
00142|029|M|could similarly increase dextromethorphan levels.|
00142|030|M|   The US manufacturer of selegiline states that concurrent use with|
00142|031|M|dextromethorphan or meperidine is contraindicated.|
00142|032|M|   The US manufacturers of meperidine and tapentadol and the UK manufacturer|
00142|033|M|of diamorphine state that they should not be used concurrently with or|
00142|034|M|within 14 days of taking an MAOI.|
00142|035|B||
00142|036|D|DISCUSSION:  The interaction between meperidine and MAOIs has been well|
00142|037|D|documented.|
00142|038|D|   There are at least two reports of potential interactions between MAOIs|
00142|039|D|and dextromethorphan.  Concomitant use of quinidine, a strong CYP2D6|
00142|040|D|inhibitor, increases systemic dextromethorphan concentrations 10 to 20-fold.|
00142|041|D|Other strong CYP2D6 inhibitors such as bupropion, fluoxetine and paroxetine|
00142|042|D|could similarly increase dextromethorphan levels and risk for serotonin|
00142|043|D|toxicity in patients also receiving MAOIs.|
00142|044|D|   Furazolidone is known to be a monoamine oxidase inhibitor.|
00142|045|D|   Methylene blue, when administered intravenously, has been shown to reach|
00142|046|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
00142|047|D|   One or more of the drug pairs linked to this monograph have been included|
00142|048|D|in a list of interactions that should be considered "high-priority" for|
00142|049|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00142|050|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00142|051|D|Coordinator (ONC) for Health Information Technology.|
00142|052|B||
00142|053|R|REFERENCES:|
00142|054|B||
00142|055|R|1.Mitchell RS. Fatal toxic encephalitis occurring during iproniazid therapy|2
00142|056|R|  in pulmonary tuberculosis. Ann Intern Med 1955;42:417-24.|2
00142|057|R|2.Papp C, Benaim S. Toxic effects of iproniazid in a patient with angina. Br|3
00142|058|R|  Med J 1958 Nov 1;2:1070-2.|3
00142|059|R|3.Palmer H. Potentiation of pethidine. Br Med J 1960 Sep 24;2:944.|3
00142|060|R|4.Shee JC. Dangerous potentiation of pethidine by iproniazid, and its|3
00142|061|R|  treatment. Br Med J 1960 Aug 13;2:507-9.|3
00142|062|R|5.London DR, Milne MD. Dangers of monoamine oxidase inhibitors. Br Med J|6
00142|063|R|  1962 Dec 29;2:1752.|6
00142|064|R|6.Brownlee G, Williams GW. Potentiation of amphetamine and pethidine by|5
00142|065|R|  monoamieoxidase inhibitors. Lancet 1963 Mar 23;1:669.|5
00142|066|R|7.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
00142|067|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
00142|068|R|8.VigramnIM. Dangerous potentiation of meperidine hydrochloride by pargyline|3
00142|069|R|  hydrochloride. JAMA 1964 Mar 21;187(12):953-4.|3
00142|070|R|9.Anonymous. Analgesics and monoamine-oxidase inhibitors. Br Med J 1967 Nov|6
00142|071|R|  4;4(574):284.|6
00142|072|R|10.Evans-Prosser CD. The use of pethidine and morphine in the presence of|2
00142|073|R|   monoamine oxidase inhibitors. Br J Anaesth 1968 Apr;40(4):279-82.|2
00142|074|R|11.Jounela AJ, Kivimaki T. Possible sensitivity to meperidine in|3
00142|075|R|   phenylketonuria. N Engl J Med 1973 Jun 28;288(26):1411.|3
00142|076|R|12.Barry BJ. Adverse effects of MAO inhibitors with narcotics reversed with|3
00142|077|R|   naloxone. Anaesth Intensive Care 1979 May;7(2):194.|3
00142|078|R|13.Browne B, Linter S. Monoamine oxidase inhibitors and narcotic analgesics.|6
00142|079|R|   A critical review of the implications for treatment. Br J Psychiatry 1987|6
00142|080|R|   Aug;151:210-2.|6
00142|081|R|14.Zornberg GL, Bodkin JA, Cohen BM. Severe adverse interaction between|3
00142|082|R|   pethidine and selegiline. Lancet 1991 Jan 26;337(8735):246.|3
00142|083|R|15.Rossiter A, Souney PF. Interaction between MAOIs and opioids:|6
00142|084|R|   pharmacologic and clinical considerations. Hosp Formul 1993 Aug;28:692-8.|6
00142|085|R|16.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
00142|086|R|   2007.|1
00142|087|R|17.Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine|3
00142|088|R|   oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988 Dec 22;|3
00142|089|R|   319(25):1671.|3
00142|090|R|18.Rivers N, Horner B. Possible lethal reaction between Nardil and|3
00142|091|R|   dextromethorphan. Can Med Assoc J 1970 Jul;103:85.|3
00142|092|R|19.Metharose (methadone hydrochloride) UK summary of product|1
00142|093|R|   characteristics. Rosemone Pharmaceuticals Limited January 9, 2008.|1
00142|094|R|20.Diskets Dispersible (methadone hydrochloride) US prescribing information.|1
00142|095|R|   Cebert Pharmaceuticals, Inc. August, 2007.|1
00142|096|R|21.Diamorphine hydrochloride Australian prescribing information. Auralis|1
00142|097|R|   March 13, 2008.|1
00142|098|R|22.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00142|099|R|   inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00142|100|R|   prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00142|101|R|23.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00142|102|R|   distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00142|103|R|   2000 Jun;56(3):247-50.|2
00142|104|R|24.Nucynta ER (tapentadol) US prescribing information. Janssen|1
00142|105|R|   Pharmaceuticals December, 2023.|1
00142|106|R|25.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00142|107|R|   352(11):1112-20.|6
00142|108|R|26.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
00142|109|R|   prescribing information. Avanir  Pharmaceuticals June, 2019.|1
00142|110|R|27.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
00142|111|R|   Pharmaceuticals LLC. December, 2023.|1
00142|112|R|28.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00142|113|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00142|114|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00142|115|R|   19(5):735-43.|6
00144|001|T|MONOGRAPH TITLE:  Foslevodopa; Levodopa/MAOIs|
00144|002|B||
00144|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00144|004|L|is contraindicated and generally should not be dispensed or administered to|
00144|005|L|the same patient.|
00144|006|B||
00144|007|A|MECHANISM OF ACTION:  MAOIs inhibit the enzyme responsible for degradation|
00144|008|A|of dopamine and norepinephrine which are formed by levodopa. Also, storage|
00144|009|A|and release of dopamine and norepinephrine is increased.|
00144|010|A|   Foslevodopa is a prodrug of levodopa.|
00144|011|B||
00144|012|E|CLINICAL EFFECTS:  Concurrent use of MAOIs may result in increased effects|
00144|013|E|of levodopa, including tremor, hypertensive crisis, and postural|
00144|014|E|hypotension.|
00144|015|B||
00144|016|P|PREDISPOSING FACTORS:  None determined.|
00144|017|B||
00144|018|M|PATIENT MANAGEMENT:  The US manufacturer of carbidopa/levodopa states that|
00144|019|M|the concurrent use of nonselective MAO inhibitors is contraindicated.|
00144|020|M|Carbidopa/Levodopa may be administered with recommended dosages of selective|
00144|021|M|MAO-B inhibitors.|
00144|022|M|   The Canadian manufacturer of foslevodopa/foscarbidopa states that|
00144|023|M|concurrent use of nonselective MAO inhibitors and selective MAO type A|
00144|024|M|inhibitors is contraindicated.  MAO inhibitors should be stopped at least 2|
00144|025|M|weeks prior to initiation of foslevodopa/foscarbidopa therapy.|
00144|026|M|Foslevodopa/foscarbidopa may be administered with recommended dosages of|
00144|027|M|selective MAO-B inhibitors.|
00144|028|M|   The addition of a decarboxylase inhibitor to the combination of a|
00144|029|M|non-selective MAO inhibitor and levodopa may minimize risk of adverse|
00144|030|M|effects.  Phentolamine has been effective in treating hypertension caused by|
00144|031|M|this interaction.|
00144|032|B||
00144|033|D|DISCUSSION:  Hypertensive reactions, flushing, and palpitations have been|
00144|034|D|reported as a result of this interaction.  This interaction may be possible|
00144|035|D|for several weeks after the discontinuation of a MAO inhibitor.|
00144|036|D|   At the recommended dosage of 10 mg/day, oral selegiline is presumed to be|
00144|037|D|a selective MAO B inhibitor and would thus not be expected to interact with|
00144|038|D|levodopa.  Oral selegiline is indicated as an adjunct agent with levodopa in|
00144|039|D|the management of Parkinsonian patients.  However, selegiline administered|
00144|040|D|transdermally for the treatment of depression is not selective for MAO-B.|
00144|041|D|   Furazolidone has been shown to inhibit MAO.|
00144|042|D|   Methylene blue, when administered intravenously, has been shown to reach|
00144|043|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
00144|044|D|   Metaxalone is a weak inhibitor of MAO.|
00144|045|B||
00144|046|R|REFERENCES:|
00144|047|B||
00144|048|R|1.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
00144|049|R|  February, 2011.|1
00144|050|R|2.Vyalev (foslevodopa/foscarbidopa) Canadian product monograph. AbbVie|1
00144|051|R|  Corporation May, 2023.|1
00144|052|R|3.Eldepryl (selegiline) US prescribing information. Somerset Pharmaceuticals|1
00144|053|R|  May, 1996.|1
00144|054|R|4.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
00144|055|R|  June, 2020.|1
00144|056|R|5.Emsam (selegiline) US prescribing information. Somerset August, 2007.|1
00144|057|R|6.Horwitz D, Goldberg LI, Sjoerdsma A. Increased blood pressure responses to|2
00144|058|R|  dopamine and norephinephrine produced by monoamine oxidase inhibitors in|2
00144|059|R|  man. J Lab Clin Med 1960 Nov;56(3):747-53.|2
00144|060|R|7.Schildkraut JJ, Klerman GL, Friend DG, Greenblatt M. Biochemical and|2
00144|061|R|  pressor effects of oral D,L-dihydroxyphenyalanine in patients pretreated|2
00144|062|R|  with antidepressant drugs. 1963;107:1005-15.|2
00144|063|R|8.Friend DG, Bell WR, Kline NS. The action of L-dihydroxyphenylalanine in|2
00144|064|R|  patients receiving nialamide. Clin Pharmacol Ther 1965;6(3):362-6.|2
00144|065|R|9.Hunter KR, Boakes AJ, Laurence DR, Stern GM. Monoamine oxidase inhibitors|3
00144|066|R|  and L-dopa. Br Med J 1970 Aug 15;3(719):388.|3
00144|067|R|10.Teychenne PF, Calne DB, Lewis PJ, Findley LJ. Interactions of levodopa|2
00144|068|R|   with inhibitors of monoamine oxidase and L- aromatic amino acid|2
00144|069|R|   decarboxylase. Clin Pharmacol Ther 1975 Sep;18(3):273-7.|2
00144|070|R|11.Birkmayer W, Riederer P, Ambrozi L, Youdim MB. Implications of combined|2
00144|071|R|   treatment with 'Madopar' and L-deprenil in Parkinson's disease. A|2
00144|072|R|   long-term study. Lancet 1977 Feb 26;1(8009):439-43.|2
00144|073|R|12.Sharpe J, Marquez-Julio A, Ashby P. Idiopathic orthostatic hypotension|3
00144|074|R|   treated with levodopa and MAO inhibitor: a preliminary report. Can Med|3
00144|075|R|   Assoc J 1972 Aug 19;107(4):296-300.|3
00144|076|R|13.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00144|077|R|   inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00144|078|R|   prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00144|079|R|14.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00144|080|R|   distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00144|081|R|   2000 Jun;56(3):247-50.|2
00144|082|R|15.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00144|083|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00144|084|R|   Feb;34(2):346.e5-6.|3
00144|085|R|16.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00144|086|R|   Pfizer Inc. January, 2024.|1
00145|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Sulfonamide|
00145|002|T|Antibacterials|
00145|003|B||
00145|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00145|005|L|of severe adverse interaction.|
00145|006|B||
00145|007|A|MECHANISM OF ACTION:  The mechanism may involve several processes.  Some|
00145|008|A|sulfonamides, e.g. cotrimoxazole, sulfamethizole, sulfaphenazole, inhibit|
00145|009|A|the CYP2C9 mediated metabolism of warfarin.  Sulfonamides have also been|
00145|010|A|shown to displace plasma protein bound warfarin.  The use of sulfonamides|
00145|011|A|may decrease vitamin-K producing bacteria in the gastrointestinal tract.|
00145|012|A|Disease related factors such as fever, decreased oral intake and acute|
00145|013|A|illness may also  play a role in bleeding risk.|
00145|014|B||
00145|015|E|CLINICAL EFFECTS:  Concurrent use of anticoagulants and sulfonamides may|
00145|016|E|increase the risk for bleeding.|
00145|017|B||
00145|018|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00145|019|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00145|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
00145|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00145|022|P|risk for bleeding (e.g. NSAIDs).|
00145|023|P|   Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2|
00145|024|P|copies of a reduced function VKORC1 gene are expected to be more susceptible|
00145|025|P|to this interaction.|
00145|026|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00145|027|P|are expected to be less susceptible to effects from this drug combination,|
00145|028|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00145|029|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
00145|030|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
00145|031|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
00145|032|P|and safe anticoagulation than patients without these CYP2C9 variants.|
00145|033|B||
00145|034|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
00145|035|M|receiving concurrent therapy for signs of blood loss, including decreased|
00145|036|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
00145|037|M|and promptly evaluate patients with any symptoms.|
00145|038|M|   Perform agent-specific laboratory test (e.g. INR) to monitor efficacy and|
00145|039|M|safety of anticoagulation.  Discontinue anticoagulation in patients with|
00145|040|M|active pathologic bleeding.|
00145|041|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00145|042|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00145|043|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00145|044|M|and/or swelling.|
00145|045|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00145|046|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
00145|047|M|before initiating, altering the dose or discontinuing either drug.|
00145|048|B||
00145|049|D|DISCUSSION:  Numerous studies and case reports have documented an|
00145|050|D|interaction between warfarin and sulfamethoxazole/trimethoprim.  The effects|
00145|051|D|are generally seen within two to six days and may or may not be accompanied|
00145|052|D|by increased warfarin concentrations.  Case reports also document an|
00145|053|D|interaction between warfarin and sulfisoxazole and sulfamethizole resulting|
00145|054|D|in increased bleeding, warfarin half-life and decreased warfarin clearance|
00145|055|D|rates.  Because of the proposed mechanism, it is prudent to expect similar|
00145|056|D|results during the concurrent administration of warfarin and other|
00145|057|D|sulfonamides.|
00145|058|D|   A large systematic review was performed on 72 warfarin drug-drug|
00145|059|D|interactions studies that reported on bleeding, thromboembolic events, or|
00145|060|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 11 of|
00145|061|D|those studies found a higher rate of clinically significant bleeding in|
00145|062|D|patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83).|
00145|063|D|Increased bleeding risk was also seen in subgroup analyses with sulfonamides|
00145|064|D|(OR=2.41; 95% CI 1.42-4.10).|
00145|065|B||
00145|066|R|REFERENCES:|
00145|067|B||
00145|068|R|1.Barnett DB, Hancock BW. Anticoagulant resistance: an unusual case. Br Med|3
00145|069|R|  J 1975 Mar 15;1(5958):608-9.|3
00145|070|R|2.Hassall C, Feetam CL, Leach RH, Meynell MJ. Letter: Potentiation of|3
00145|071|R|  warfarin by co-trimoxazole. Lancet 1975 Dec 6;2(7945):1155-6.|3
00145|072|R|3.Lumholtz B, Siersbaek-Nielsen K, Skovsted L, Kampmann J, Hansen JM.|2
00145|073|R|  Sulfamethizole-induced inhibition of diphenlhydantoin, tolbutamide, and|2
00145|074|R|  warfarin metabolism. Clin Pharmacol Ther 1975 Jun;17(6):731-4.|2
00145|075|R|4.Self TH, Evans W, Ferguson T. Letter: Interaction of sulfisoxazole and|3
00145|076|R|  warfarin. Circulation 1975 Sep;52(3):528.|3
00145|077|R|5.Tilstone WJ, Gray JM, Nimmo-Smith RH, Lawson DH. Interaction between|3
00145|078|R|  warfarin and sulphamethoxazole. Postgrad Med J 1977 Jul;53(621):388-90.|3
00145|079|R|6.Errick JK, Keys PW. Co-trimoxazole and warfarin: case report of an|3
00145|080|R|  interaction. Am J Hosp Pharm 1978 Nov;35(11):1399-401.|3
00145|081|R|7.O'Reilly RA, Motley CH. Racemic warfarin and trimethoprim-sulfamethoxazole|2
00145|082|R|  interaction in humans. Ann Intern Med 1979 Jul;91(1):34-6.|2
00145|083|R|8.O'Reilly RA. Stereoselective interaction of trimethoprim-sulfamethoxazole|2
00145|084|R|  with the separated enantiomorphs of racemic warfarin in man. N Engl J Med|2
00145|085|R|  1980 Jan 3;302(1):33-5.|2
00145|086|R|9.Kaufman JM, Fauver HE Jr. Potentiation of warfarin by|3
00145|087|R|  trimethoprim-sulfamethoxazole. Urology 1980 Dec;16(6):601-3.|3
00145|088|R|10.Sioris LJ, Weibert RT, Pentel PR. Potentiation of warfarin|3
00145|089|R|   anticoagulation by sulfisoxazole. Arch Intern Med 1980 Apr;140(4):546-7.|3
00145|090|R|11.Greenlaw CW. Drug interaction between co-trimoxazole and warfarin. Am J|3
00145|091|R|   Hosp Pharm 1979 Sep;36(9):1155-6.|3
00145|092|R|12.Perkash A. Experience with the management of deep vein thrombosis in|3
00145|093|R|   patients with spinal cord injury. Part II: a critical evaluation of the|3
00145|094|R|   anticoagulant therapy. Paraplegia 1980  Feb;18(1):2-14.|3
00145|095|R|13.Brooks BJ Jr, Mocklin KE. Retropharyngeal hematoma as a complication of|3
00145|096|R|   warfarin therapy. J La State Med Soc 1981 Oct;133(10):156-7.|3
00145|097|R|14.Anonymous. Letter: Potentiations of warfarin by co-trimoxazole. Br Med J|3
00145|098|R|   1975 Jun 21;2(5972):684.|3
00145|099|R|15.Serlin MJ. Antimicrobial drug interactions with oral anticoagulants. J|6
00145|100|R|   Antimicrob Chemother 1979 Nov;5(6):628-30.|6
00145|101|R|16.De Swiet J. Letter: Potentiation of warfarin by co-trimoxazole. Br Med J|6
00145|102|R|   1975 Aug 23;3(5981):491.|6
00145|103|R|17.Anonymous. Warfarin potentiated by proguanil. BMJ 1991 Sep 28;|3
00145|104|R|   303(6805):789.|3
00145|105|R|18.Koch-Weser J, Sellers EM. Drug interactions with coumarin anticoagulants|6
00145|106|R|   (First of two parts). N Engl J Med 1971 Aug 26;285(9):487-98.|6
00145|107|R|19.Weser JK, Sellers E. Drug interactions with coumarin anticoagulants. 2. N|6
00145|108|R|   Engl J Med 1971 Sep 2;285(10):547-58.|6
00145|109|R|20.Serlin MJ, Breckenridge AM. Drug interactions with warfarin. Drugs 1983|6
00145|110|R|   Jun;25(6):610-20.|6
00145|111|R|21.Fischer HD, Juurlink DN, Mamdani MM, Kopp A, Laupacis A. Hemorrhage|2
00145|112|R|   during warfarin therapy associated with cotrimoxazole and other urinary|2
00145|113|R|   tract anti-infective agents: a population-based study. Arch Intern Med|2
00145|114|R|   2010 Apr 12;170(7):617-21.|2
00145|115|R|22.Komatsu K, Ito K, Nakajima Y, Kanamitsu Si, Imaoka S, Funae Y, Green CE,|5
00145|116|R|   Tyson CA, Shimada N, Sugiyama Y. Prediction of in vivo drug-drug|5
00145|117|R|   interactions between tolbutamide and various sulfonamides in humans based|5
00145|118|R|   on in vitro experiments. Drug Metab Dispos 2000 Apr;28(4):475-81.|5
00145|119|R|23.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00145|120|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00145|121|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
00145|122|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00145|123|R|24.This information is based on an extract from the Certara Drug Interaction|6
00145|124|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00146|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Metronidazole;|
00146|002|T|Tinidazole|
00146|003|B||
00146|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00146|005|L|of severe adverse interaction.|
00146|006|B||
00146|007|A|MECHANISM OF ACTION:  Possible inhibition of anticoagulant metabolism by|
00146|008|A|metronidazole or tinidazole.|
00146|009|A|   Metronidazole is a weak CYP2C9 inhibitor and may inhibit the metabolism|
00146|010|A|of the more potent warfarin isomer, S-warfarin.(1)|
00146|011|B||
00146|012|E|CLINICAL EFFECTS:  Concurrent use of anticoagulants with metronidazole or|
00146|013|E|tinidazole may increase the risk for bleeding.|
00146|014|B||
00146|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00146|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00146|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
00146|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00146|019|P|risk for bleeding (e.g. NSAIDs).|
00146|020|P|   Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2|
00146|021|P|copies of a reduced function VKORC1 gene are expected to be most susceptible|
00146|022|P|to this interaction.|
00146|023|P|   Patients with a pre-existing CYP2C9 poor metabolizer genotype would be|
00146|024|P|less susceptible to this interaction.  However, patients with reduced|
00146|025|P|function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) have an|
00146|026|P|inherently higher risk for bleeding at usual anticoagulant doses and thus|
00146|027|P|generally require lower doses to achieve effective and safe anticoagulation.|
00146|028|P|In addition, CYP2C9 poor metabolizers may require more time (>2 to 4 weeks)|
00146|029|P|to achieve maximum INR effect for a given dosage regimen than patients|
00146|030|P|without these CYP2C9 variants.|
00146|031|B||
00146|032|M|PATIENT MANAGEMENT:  INR values should be closely monitored during and for|
00146|033|M|several days after the conclusion of concurrent metronidazole or tinidazole.|
00146|034|M|Anticoagulant dosage may need to be adjusted up to 10 days after concurrent|
00146|035|M|therapy ends.|
00146|036|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00146|037|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00146|038|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00146|039|M|patients with any symptoms.|
00146|040|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00146|041|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00146|042|M|anticoagulation in patients with active pathologic bleeding.|
00146|043|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00146|044|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00146|045|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00146|046|M|and/or swelling.|
00146|047|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00146|048|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00146|049|M|initiating, altering the dose or discontinuing either drug.|
00146|050|B||
00146|051|D|DISCUSSION:  In two studies, metronidazole significantly enhanced the|
00146|052|D|hypoprothrombinemic effect of warfarin.(2,3)  The onset of the interaction|
00146|053|D|occurred within four(2) to ten days(3) and appeared as excessive bruising of|
00146|054|D|the legs.|
00146|055|D|   In eight normal subjects, metronidazole significantly increased the|
00146|056|D|half-life of racemic warfarin and the S-enantiomer of warfarin.  The|
00146|057|D|R-enantiomer of warfarin, which is metabolized primarily by the reduction of|
00146|058|D|side chains, was unaffected by metronidazole.(4)|
00146|059|D|   In an animal study, metronidazole preferentially inhibited the|
00146|060|D|S-enantiomer of warfarin.(5)|
00146|061|D|   This interaction should also be considered during concurrent|
00146|062|D|administration and for eight days after concurrent anticoagulants and|
00146|063|D|tinidazole.(6)|
00146|064|B||
00146|065|R|REFERENCES:|
00146|066|B||
00146|067|R|1.This information is based on an extract from the Certara Drug Interaction|6
00146|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00146|069|R|2.Dean RP, Talbert RL. Bleeding associated with concurrent warfarin and|3
00146|070|R|  metronidazole therapy. Drug Intell Clin Pharm 1980 Dec;14:864-6.|3
00146|071|R|3.Kazmier FJ. A significant interaction between metronidazole and warfarin.|3
00146|072|R|  Mayo Clin Proc 1976 Dec;51(12):782-4.|3
00146|073|R|4.O'Reilly RA. The stereoselective interaction of warfarin and metronidazole|2
00146|074|R|  in man. N Engl J Med 1976 Aug 12;295(7):354-7.|2
00146|075|R|5.Yacobi A, Lai CM, Levy G. Pharmacokinetic and pharmacodynamic studies of|5
00146|076|R|  acute interaction between warfarin enantiomers and metronidazole in rats.|5
00146|077|R|  J Pharmacol Exp Ther 1984 Oct;231(1):72-9.|5
00146|078|R|6.Tinidazole US prescribing information. Rising Pharmaceuticals, Inc..|1
00146|079|R|  October 12, 2017.|1
00146|080|R|7.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
00146|081|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
00146|082|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
00146|083|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
00146|084|R|  Oct;90(4):625-9.|6
00147|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Chloral|
00147|002|T|Hydrate; Triclofos|
00147|003|B||
00147|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00147|005|L|of severe adverse interaction.|
00147|006|B||
00147|007|A|MECHANISM OF ACTION:  Chloral hydrate may cause protein binding displacement|
00147|008|A|of anticoagulants.|
00147|009|B||
00147|010|E|CLINICAL EFFECTS:  Concurrent use of anticoagulants and chloral hydrate or|
00147|011|E|triclofos may increase the risk for bleeding.|
00147|012|B||
00147|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00147|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00147|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
00147|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00147|017|P|risk for bleeding (e.g. NSAIDs).|
00147|018|B||
00147|019|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
00147|020|M|receiving concurrent therapy for signs of blood loss, including decreased|
00147|021|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
00147|022|M|and promptly evaluate patients with any symptoms.|
00147|023|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00147|024|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00147|025|M|anticoagulation in patients with active pathologic bleeding.|
00147|026|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00147|027|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00147|028|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00147|029|M|and/or swelling.|
00147|030|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00147|031|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00147|032|M|initiating, altering the dose or discontinuing either drug.|
00147|033|B||
00147|034|D|DISCUSSION:  This interaction is well documented.|
00147|035|B||
00147|036|R|REFERENCES:|
00147|037|B||
00147|038|R|1.Cucinell SA, Odessky L, Weiss M, Dayton PG. The effect of chloral hydrate|3
00147|039|R|  on bishydroxycoumarin metabolism; a fatal outcome. JAMA 1966 Aug 1;|3
00147|040|R|  197(5):366-8.|3
00147|041|R|2.MacDonald MG, Robinson DS, Sylwester D, Jaffe JJ. The effects of|2
00147|042|R|  phenobarbital, chloral betaine, and glutethimide administration on|2
00147|043|R|  warfarin plasma levels and hypoprothrombinemic responese in man. Clin|2
00147|044|R|  Pharmacol Ther 1969 Jan-Feb;10(1):80-4.|2
00147|045|R|3.Udall JA. Drug interference with warfarin therapy. Clin Med 1970 Aug;|2
00147|046|R|  77:20-5.|2
00147|047|R|4.Sellers EM, Koch-Weser J. Potentiation of warfarin-induced|2
00147|048|R|  hypoprothrombinemia by chloral hydrate. N Engl J Med 1970 Oct 15;|2
00147|049|R|  283(16):827-31.|2
00147|050|R|5.Koch-Weser J, Sellers EM, Udall JA, Griner PF, Rickles FR. Chloral hydrate|6
00147|051|R|  and warfarin therapy. Ann Intern Med 1971 Jul;75(1):141-2.|6
00147|052|R|6.Griner PF, Raisz LG, Rickles FR, Wiesner PJ, Odoroff CL. Chloral hydrate|2
00147|053|R|  and warfarin interaction: clinical significance. Ann Intern Med 1971 Apr;|2
00147|054|R|  74(4):540-3.|2
00147|055|R|7.Breckenridge A, Orme ML, Thorgeirsson S, Davies DS, Brooks RV. Drug|2
00147|056|R|  interactions with warfarin: studies with dichloralphenazone, chloral|2
00147|057|R|  hydrate and phenazone (antipyrine). Clin Sci 1971 Apr;40(4):351-64.|2
00147|058|R|8.Sellers EM, Koch-Weser J. Kinetics and clinical importance of displacement|6
00147|059|R|  of warfarin from albumin by acidic drugs. Ann N Y Acad Sci 1971 Jul 6;|6
00147|060|R|  179:213-25.|6
00147|061|R|9.Sellers EM, Lang M, Koch-Weser J, Colman RW. Enhancement of|2
00147|062|R|  warfarin-induced hypoprothrombinemia by triclofos. Clin Pharmacol Ther|2
00147|063|R|  1972 Nov-Dec;13(6):911-5.|2
00147|064|R|10.Orme M, Breckenridge A, Brooks RV. Interactions of benzodiazepines with|2
00147|065|R|   warfarin. Br Med J 1972 Sep 9;3(827):611-4.|2
00147|066|R|11.Anonymous. Chloral hydrate and oral anticoagulants. Lancet 1972 Mar 4;|6
00147|067|R|   1(7749):524.|6
00147|068|R|12.Anonymous. Interaction between chloral hydrate and warfarin. A report|2
00147|069|R|   from the Boston Collaborative Drug Surveillance Program, Boston|2
00147|070|R|   Universtiy Medical Center. N Engl J Med 1972 Jan 13;286(2):53-5.|2
00147|071|R|13.Beliles RP, Foster GV Jr. Interaction of bishydroxycoumarin with chloral|5
00147|072|R|   hydrate and trichloroethyl phosphate. Toxicol Appl Pharmacol 1974 Feb;|5
00147|073|R|   27(2):225-9.|5
00147|074|R|14.Udall JA. Warfarin-chloral hydrate interaction. Pharmacological activity|2
00147|075|R|   and clinical significance. Ann Intern Med 1974 Sep;81(3):341-4.|2
00147|076|R|15.Udall JA. Clinical implications of warfarin interactions with five|2
00147|077|R|   sedatives. Am J Cardiol 1975 Jan;35(1):67-71.|2
00149|001|T|MONOGRAPH TITLE:  Doxycycline/Hydantoins (mono deleted 08/29/2012)|
00149|002|B||
00149|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00149|004|L|take action as needed.|
00149|005|B||
00149|006|A|MECHANISM OF ACTION:  Primary mechanism appears to be hydantoin induction of|
00149|007|A|microsomal enzymes resulting in increased hepatic metabolism of doxycycline.|
00149|008|B||
00149|009|E|CLINICAL EFFECTS:  Decreased pharmacologic effectiveness of doxycycline.|
00149|010|B||
00149|011|P|PREDISPOSING FACTORS:  None determined.|
00149|012|B||
00149|013|M|PATIENT MANAGEMENT:  Monitor therapeutic response. Increased dosage of|
00149|014|M|doxycycline may be required.|
00149|015|B||
00149|016|D|DISCUSSION:  This interaction is well documented.|
00149|017|B||
00149|018|R|REFERENCE:|
00149|019|B||
00149|020|R|1.Neuvonen PJ, Penttila O, Lehtovaara R, Aho K. Effect of antiepileptic|2
00149|021|R|  drugs on the elimination of various tetracycline derivatives. Eur J Clin|2
00149|022|R|  Pharmacol 1975 Dec 19;9(2-3):147-54.|2
00150|001|T|MONOGRAPH TITLE:  Selected Barbiturates; Selected Hydantoins/Quinidine (mono|
00150|002|T|deleted 06/11/2020)|
00150|003|B||
00150|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00150|005|L|take action as needed.|
00150|006|B||
00150|007|A|MECHANISM OF ACTION:  Barbiturates and hydantoins are strong inducers of|
00150|008|A|CYP3A4(1), the enzyme which metabolizes quinidine.|
00150|009|B||
00150|010|E|CLINICAL EFFECTS:  Concurrent or recent use of barbiturates or hydantoins|
00150|011|E|may reduce the efficacy of quinidine.(2)|
00150|012|B||
00150|013|P|PREDISPOSING FACTORS:  None determined.|
00150|014|B||
00150|015|M|PATIENT MANAGEMENT:  Initiation of barbiturates or hydantoins will lead to a|
00150|016|M|gradual reduction in quinidine concentrations over approximately 1-3 weeks.|
00150|017|M|Adjust quinidine dose as needed based on serum levels, ECG and clinical|
00150|018|M|response.|
00150|019|M|   If the inducing agent is subsequently discontinued, quinidine|
00150|020|M|concentrations will increase over 1-4 weeks depending upon the agent|
00150|021|M|involved. Decrease quinidine dose to as needed maintain therapeutic efficacy|
00150|022|M|and safety.|
00150|023|B||
00150|024|D|DISCUSSION:  Four weeks of concurrent phenytoin therapy decreased the|
00150|025|D|half-life of quinidine an average of 50% and resulted in a 60% decrease in|
00150|026|D|the quinidine area-under-curve(AUC).(3)  Similar changes were seen within|
00150|027|D|three weeks of initiating co-therapy in another patient.  Quinidine|
00150|028|D|disposition returned to pre-phenytoin controls within two to three weeks|
00150|029|D|after phenytoin was discontinued.  In a case report involving a child, the|
00150|030|D|dose of quinidine had to be increased (from 60mg every six hours to 300mg|
00150|031|D|every four hours) to reach therapeutic levels in the presence of phenytoin.|
00150|032|B||
00150|033|R|REFERENCES:|
00150|034|B||
00150|035|R|1.This information is based on an extract from the Certara Drug Interaction|6
00150|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00150|037|R|2.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00150|038|R|  March, 2022.|1
00150|039|R|3.Data JL, Wilkinson GR, Nies AS. Interaction of quinidine with|3
00150|040|R|  anticonvulsant drugs. N Engl J Med 1976 Mar 25;294(13):699-702.|3
00151|001|T|MONOGRAPH TITLE:  Rifamycins/Selected Anticoagulants (Vitamin K antagonists)|
00151|002|B||
00151|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00151|004|L|of severe adverse interaction.|
00151|005|B||
00151|006|A|MECHANISM OF ACTION:  Rifamycins may induce the hepatic metabolism of the|
00151|007|A|anticoagulants.|
00151|008|B||
00151|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a rifamycin may result in|
00151|010|E|decreased levels of and clinical effects from anticoagulants.   If the|
00151|011|E|rifamycin is withdrawn, levels and effects of the anticoagulant may|
00151|012|E|increase, increasing the risk of hemorrhage. This effect may be dose-related|
00151|013|E|and continue beyond discontinuation of the rifamycin.|
00151|014|B||
00151|015|P|PREDISPOSING FACTORS:  None determined.|
00151|016|B||
00151|017|M|PATIENT MANAGEMENT:  If concurrent use of rifamycins and warfarin is|
00151|018|M|warranted, use caution during concurrent use and monitor patients closely.|
00151|019|M|The dose of the anticoagulant will need to be adjusted when the rifamycin is|
00151|020|M|initiated or discontinued.|
00151|021|M|   If concurrent use of rifampin and warfarin is warranted, monitor INR|
00151|022|M|closely to maintain target INR.  The dose of warfarin may need to be|
00151|023|M|increased 3-5 times higher than a stable baseline dose.  Goal INR may be|
00151|024|M|delayed and labile for months after starting rifampin.  After|
00151|025|M|discontinuation of rifampin, INR requires close monitoring to de-escalate|
00151|026|M|warfarin dose as induction effects fade.  Evaluate patients closely for|
00151|027|M|benefits of bridging with LMWH with risks of additional bleeding.(2)|
00151|028|M|   The time of highest risk for an anticoagulant drug interaction is when|
00151|029|M|the precipitant drug is initiated or discontinued. Contact the prescriber|
00151|030|M|before initiating, altering the dose, or discontinuing either drug.|
00151|031|B||
00151|032|D|DISCUSSION:  In a study in 4 healthy subjects, concurrent rifampin (300 mg|
00151|033|D|twice daily) decreased warfarin (0.75 mg/kg) area-under-curve (AUC) by|
00151|034|D|70%.(1)|
00151|035|D|   In a study in 10 healthy males, concurrent rifampin (600 mg daily)|
00151|036|D|decreased oral warfarin (1.5 mg/kg) AUC by 57%.  Prothrombin time decreased|
00151|037|D|by 52%.  Intravenous warfarin AUC decreased by 58%.  Prothrombin time|
00151|038|D|decreased by 56%.(3)|
00151|039|D|   In a study in 8 healthy subjects, concurrent rifampin (600 mg daily)|
00151|040|D|decreased warfarin (dosed to therapeutic effect) plasma levels by 85%.  On|
00151|041|D|warfarin alone, subjects averaged 25% of normal prothrombin activity.  On|
00151|042|D|concurrent rifampin, subjects averaged 85% of normal prothrombin|
00151|043|D|activity.(4)|
00151|044|D|   There are several case reports of decreased warfarin(5-8) and|
00151|045|D|phenprocoumon(9) effects during concurrent rifampin therapy.|
00151|046|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
00151|047|D|pairs were reviewed and found 14% of drug pairs were associated with a|
00151|048|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
00151|049|D|of warfarin and rifampin resulted in a ratio of rate ratios (RR) (95% CI) of|
00151|050|D|2.25 (1.1-4.61).(10)|
00151|051|B||
00151|052|R|REFERENCES:|
00151|053|B||
00151|054|R|1.Heimark LD, Gibaldi M, Trager WF, O'Reilly RA, Goulart DA. The mechanism|2
00151|055|R|  of the warfarin-rifampin drug interaction in humans. Clin Pharmacol Ther|2
00151|056|R|  1987 Oct;42(4):388-94.|2
00151|057|R|2.MacDougall C, Canonica T, Keh C, P Phan BA, Louie J. Systematic review of|6
00151|058|R|  drug-drug interactions between rifamycins and anticoagulant  and|6
00151|059|R|  antiplatelet agents and considerations for management. Pharmacotherapy|6
00151|060|R|  2022 Apr;42(4):343-361.|6
00151|061|R|3.O'Reilly RA. Interaction of sodium warfarin and rifampin. Studies in man.|2
00151|062|R|  Ann Intern Med 1974 Sep;81(3):337-40.|2
00151|063|R|4.O'Reilly RA. Interaction of chronic daily warfarin therapy and rifampin.|2
00151|064|R|  Ann Intern Med 1975 Oct;83(4):506-8.|2
00151|065|R|5.Lee CR, Thrasher KA. Difficulties in anticoagulation management during|3
00151|066|R|  coadministration of warfarin and rifampin. Pharmacotherapy 2001 Oct;|3
00151|067|R|  21(10):1240-6.|3
00151|068|R|6.Fox P. Warfarin-rifampicin interaction. Med J Aust 1982 Jan 23;1(2):60.|3
00151|069|R|7.Self TH, Mann RB. Interaction of rifampin and warfarin. Chest 1975 Apr;|3
00151|070|R|  67(4):490-1.|3
00151|071|R|8.Romankiewicz JA, Ehrman M. Rifampin and warfarin: a drug interaction. Ann|3
00151|072|R|  Intern Med 1975 Feb;82(2):224-5.|3
00151|073|R|9.Held H. Interaction of rifampicin with phenprocoumon (author's transl).|3
00151|074|R|  Dtsch Med Wochenschr 1979 Sep 14;104(37):1311-4.|3
00151|075|R|10.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
00151|076|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
00151|077|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
00151|078|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
00152|001|T|MONOGRAPH TITLE:  Glutethimide/Selected Anticoagulants (Vitamin K|
00152|002|T|antagonists)|
00152|003|B||
00152|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00152|005|L|take action as needed.|
00152|006|B||
00152|007|A|MECHANISM OF ACTION:  It is speculated that induction of hepatic microsomal|
00152|008|A|enzymes results in increased metabolism of anticoagulants.|
00152|009|B||
00152|010|E|CLINICAL EFFECTS:  May observe decreased anticoagulant effects. Increased|
00152|011|E|risk of hemorrhage when glutethimide is withdrawn. Effect may be|
00152|012|E|dose-related and continue beyond discontinuation of glutethimide.|
00152|013|B||
00152|014|P|PREDISPOSING FACTORS:  None determined.|
00152|015|B||
00152|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of these drugs. If both drugs are|
00152|017|M|administered, adjust the anticoagulant dose as needed based on prothrombin|
00152|018|M|activity. Caution when glutethimide is started or stopped. Benzodiazepines|
00152|019|M|and diphenhydramine do not react significantly with anticoagulants and|
00152|020|M|should be considered as alternative hypnotics.|
00152|021|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00152|022|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00152|023|M|initiating, altering the dose or discontinuing either drug.|
00152|024|B||
00152|025|D|DISCUSSION:  This interaction is well documented.|
00152|026|B||
00152|027|R|REFERENCE:|
00152|028|B||
00152|029|R|1.Udall JA. Clinical implications of warfarin interactions with five|2
00152|030|R|  sedatives. Am J Cardiol 1975 Jan;35(1):67-71.|2
00153|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Rifamycins|
00153|002|B||
00153|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00153|004|L|take action as needed.|
00153|005|B||
00153|006|A|MECHANISM OF ACTION:  Rifamycins may inhibit the absorption of digitalis|
00153|007|A|glycosides by inducing P-glycoprotein.(1-2)|
00153|008|B||
00153|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifamycins may result in|
00153|010|E|decreased levels and effectiveness of digitalis glycosides.|
00153|011|B||
00153|012|P|PREDISPOSING FACTORS:  None determined.|
00153|013|B||
00153|014|M|PATIENT MANAGEMENT:  Monitor digoxin levels if a rifamycin is initiated or|
00153|015|M|discontinued.  The dosage of digoxin may need to be increased by 20% to|
00153|016|M|40%.(2)|
00153|017|B||
00153|018|D|DISCUSSION:  In a study in 18 healthy volunteers, rifampin (300 mg BID for 7|
00153|019|D|days) decreased the maximum concentration (Cmax), 3-hour area-under-curve|
00153|020|D|(AUC), and 24-hour AUC by 38.5%, 30.4%, and 24.6%, respectively.(1)|
00153|021|D|   Case reports also document decreased digoxin(3-5) and digitoxin(6-7)|
00153|022|D|levels with rifampin.|
00153|023|B||
00153|024|R|REFERENCES:|
00153|025|B||
00153|026|R|1.Gurley BJ, Swain A, Williams DK, Barone G, Battu SK. Gauging the clinical|2
00153|027|R|  significance of P-glycoprotein-mediated herb-drug interactions:|2
00153|028|R|  comparative effects of St. John's wort, Echinacea, clarithromycin,  and|2
00153|029|R|  rifampin on digoxin pharmacokinetics. Mol Nutr Food Res 2008 Jul;|2
00153|030|R|  52(7):772-9.|2
00153|031|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00153|032|R|  Pharmaceuticals, Inc. August, 2018.|1
00153|033|R|3.Novi C, Bissoli F, Simonati V, Volpini T, Baroli A, Vignati G. Rifampin|3
00153|034|R|  and digoxin: possible drug interaction in a dialysis patient. JAMA 1980|3
00153|035|R|  Dec 5;244(22):2521-2.|3
00153|036|R|4.Gault H, Longerich L, Dawe M, Fine A. Digoxin-rifampin interaction. Clin|3
00153|037|R|  Pharmacol Ther 1984 Jun;35(6):750-4.|3
00153|038|R|5.Bussey HI, Merritt GJ, Hill EG. The influence of rifampin on quinidine and|3
00153|039|R|  digoxin. Arch Intern Med 1984 May;144(5):1021-3.|3
00153|040|R|6.Boman G, Eliasson K, Odar-Cederlof I. Acute cardiac failure during|3
00153|041|R|  treatment with digitoxin--an interaction with rifampicin. Br J Clin|3
00153|042|R|  Pharmacol 1980 Jul;10(1):89-90.|3
00153|043|R|7.Poor DM, Self TH, Davis HL. Interaction of rifampin and digitoxin. Arch|3
00153|044|R|  Intern Med 1983 Mar;143(3):599.|3
00155|001|T|MONOGRAPH TITLE:  Disulfiram/Hydantoins|
00155|002|B||
00155|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00155|004|L|of severe adverse interaction.|
00155|005|B||
00155|006|A|MECHANISM OF ACTION:  Disulfiram may inhibit the CYP2C9 mediated metabolism|
00155|007|A|of phenytoin and other hydantoins.|
00155|008|B||
00155|009|E|CLINICAL EFFECTS:  Hydantoin concentrations may increase producing toxicity.|
00155|010|E|Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin|
00155|011|E|toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia,|
00155|012|E|lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe|
00155|013|E|toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar|
00155|014|E|dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac|
00155|015|E|arrest) and may be fatal.|
00155|016|B||
00155|017|P|PREDISPOSING FACTORS:  Risk factors for phenytoin toxicity include renal|
00155|018|P|impairment, hepatic impairment, or hypoalbuminemia.|
00155|019|B||
00155|020|M|PATIENT MANAGEMENT:  Monitor closely to decrease the risk of hydantoin|
00155|021|M|toxicity. Adjust the hydantoin dose as needed based on hydantoin plasma|
00155|022|M|levels and clinical symptoms.|
00155|023|M|   Counsel patient to assure they know signs and symptoms of hydantoin|
00155|024|M|toxicity and understand the importance of follow-up laboratory testing.|
00155|025|M|Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus, ataxia,|
00155|026|M|dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision,|
00155|027|M|nausea, and vomiting).|
00155|028|B||
00155|029|D|DISCUSSION:  There are multiple case reports of increased half-life,|
00155|030|D|decreased phenytoin clearance, and significantly increased phenytoin|
00155|031|D|concentrations with concurrent administration of phenytoin and|
00155|032|D|disulfiram.(3,7) Patients showed symptoms of acute phenytoin toxicity; such|
00155|033|D|as, nystagmus, delirium, ataxia, and dizziness.|
00155|034|D|   A study in six patients showed a 40% and 55% increase in phenytoin|
00155|035|D|concentrations with concomitant administration of phenytoin and disulfiram|
00155|036|D|(400 mg daily).(4) One patient showed signs of phenytoin toxicity including|
00155|037|D|ataxia.|
00155|038|D|   One study in 10 healthy patients showed a 73% increase in phenytoin|
00155|039|D|half-life and a 34% decrease in phenytoin clearance with concomitant|
00155|040|D|administration of phenytoin (100 mg intravenously) with disulfiram (1st day|
00155|041|D|400 mg three times a day, 2nd day 400 mg, 3rd and 4th day 200 mg).(2)|
00155|042|D|   A study in 4 patients showed a 100-500% increase in phenytoin|
00155|043|D|concentrations with concomitant disulfiram (400 mg daily) and phenytoin|
00155|044|D|administration.(5)|
00155|045|B||
00155|046|R|REFERENCES:|
00155|047|B||
00155|048|R|1.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00155|049|R|  March, 2022.|1
00155|050|R|2.Svendsen TL, Kristensen MB, Hansen JM, Skovsted L. The influence of|2
00155|051|R|  disulfiram on the half life and metabolic clearance rate of|2
00155|052|R|  diphenylhydantoin and tolbtamide in man. Eur J Clin Pharmacol 1976 Mar 22;|2
00155|053|R|  09(5-6):439-41.|2
00155|054|R|3.Brown CG, Kaminsky MJ, Feroli ER Jr, Gurley HT. Delirium with phenytoin|3
00155|055|R|  and disulfiram administration. Ann Emerg Med 1983 May;12(5):310-3.|3
00155|056|R|4.Olesen OV. The influence of disulfiram and calcium carbimide on the serum|2
00155|057|R|  diphenylhydantoin. Excretion of HPPH in the urine. Arch Neurol 1967 Jun;|2
00155|058|R|  16(6):642-4.|2
00155|059|R|5.Olesen OV. Disulfiramum (antabuse) as inhibitor of phenytoin metabolism.|2
00155|060|R|  Acta Pharmacol Toxicol (Copenh) 1966;24(4):317-22.|2
00155|061|R|6.Taylor JW, Alexander B, Kathol RG, Alexander MR, Ebert BE, Rivery MP.|2
00155|062|R|  Pharmacoketinetic analysis of the phenytoin-disulfiram interaction. Drug|2
00155|063|R|  Intell Clin Pharm 1984;18:499.|2
00155|064|R|7.Kiorboe E. Phenytoin intoxication during treatment with antabuse|3
00155|065|R|  (Disulfiram). Epilepsia 1966 Sep;7(3):246-9.|3
00156|001|T|MONOGRAPH TITLE:  Sulfinpyrazone/Hydantoins|
00156|002|B||
00156|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00156|004|L|take action as needed.|
00156|005|B||
00156|006|A|MECHANISM OF ACTION:  Sulfinpyrazone may inhibit the CYP2C9 mediated|
00156|007|A|metabolism of hydantoins and may displace hydantoins from plasma protein|
00156|008|A|binding sites, resulting in increased free hydantoin concentrations.(1-6)|
00156|009|B||
00156|010|E|CLINICAL EFFECTS:  Concurrent use of these medications may result in|
00156|011|E|elevated hydantoin concentrations and toxicity. Phenytoin has a narrow|
00156|012|E|therapeutic range. Early symptoms of phenytoin toxicity mas=y include|
00156|013|E|nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred|
00156|014|E|speech, blurred vision, nausea, and vomiting. Severe toxicity may produce|
00156|015|E|organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and|
00156|016|E|atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be|
00156|017|E|fatal.(9)|
00156|018|B||
00156|019|P|PREDISPOSING FACTORS:  Concurrent use of additional CYP2C9 inhibitors,|
00156|020|P|concurrent use of CYP2C19 inhibitors (secondary phenytoin pathway,|
00156|021|P|especially when CYP2C9 saturated), CYP2C9 intermediate metabolizers.|
00156|022|P|   Renal impairment, hepatic impairment, or hypoalbuminemia.|
00156|023|B||
00156|024|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with a hydantoin|
00156|025|M|and sulfinpyrazone should be carefully monitored for hydantoin toxicity.|
00156|026|M|The dose of the hydantoin may need to be adjusted.|
00156|027|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
00156|028|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
00156|029|M|vision, nausea, and vomiting).|
00156|030|B||
00156|031|D|DISCUSSION:  Sulfinpyrazone(5) has been shown to increase phenytoin levels.|
00156|032|D|There is a high degree of interpatient variability with this interaction.|
00156|033|B||
00156|034|R|REFERENCES:|
00156|035|B||
00156|036|R|1.This information is based on an extract from the Certara Drug Interaction|6
00156|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00156|038|R|2.Glazko AJ. Antiepileptic drugs: biotransformation, metabolism, and serum|6
00156|039|R|  half-life. Epilepsia 1975 Jun;16(2):367-91.|6
00156|040|R|3.Kurata D, Wilkinson GR. Erythrocyte uptake and plasma binding of|2
00156|041|R|  diphenylhydantoin. Clin Pharmacol Ther 1974 Aug;16(2):355-62.|2
00156|042|R|4.Lunde PK, Rane A, Yaffe SJ, Lund L, Sjoqvist F. Plasma protein binding of|2
00156|043|R|  diphenylhydantoin in man. Interaction with other drugs and the effect of|2
00156|044|R|  temperature and plasma dilution. Clin Pharmacol Ther 1970 Nov-Dec;|2
00156|045|R|  11(6):846-55.|2
00156|046|R|5.Neuvonen PJ, Lehtovaara R, Bardy A, Elomaa E. Antipyretic analgesics in|2
00156|047|R|  patients on antiepileptic drug therapy. Eur J Clin Pharmacol 1979 May 21;|2
00156|048|R|  15(4):263-8.|2
00156|049|R|6.Pedersen AK, Jakobsen P, Kampmann JP, Hansen JM. Clinical pharmacokinetics|2
00156|050|R|  and potentially important drug interactions of sulphinpyrazone. Clin|2
00156|051|R|  Pharmacokinet 1982 Jan-Feb;7(1):42-56.|2
00156|052|R|7.Lucas BG. "Dilantin" overdosage. Med J Aust 1968 Oct 12;2(15):639-40.|3
00156|053|R|8.Soda DM, Levy G. Inhibition of drug metabolism by hydroxylated|5
00156|054|R|  metabolites: cross- inhibition and specificity. J Pharm Sci 1975 Dec;|5
00156|055|R|  64(12):1928-31.|5
00156|056|R|9.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00156|057|R|  March, 2022.|1
00157|001|T|MONOGRAPH TITLE:  Chloramphenicol/Hydantoins|
00157|002|B||
00157|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00157|004|L|of severe adverse interaction.|
00157|005|B||
00157|006|A|MECHANISM OF ACTION:  Chloramphenicol may inhibit the CYP2C19 metabolism|
00157|007|A|resulting in decreased hepatic metabolism of hydantoins.|
00157|008|B||
00157|009|E|CLINICAL EFFECTS:  Increased hydantoin pharmacologic effects including|
00157|010|E|toxicity may be observed. Phenytoin has a narrow therapeutic range. Early|
00157|011|E|symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria,|
00157|012|E|tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and|
00157|013|E|vomiting. Severe toxicity may produce organ dysfunction (e.g. coma,|
00157|014|E|irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia,|
00157|015|E|seizures, and cardiac arrest) and may be fatal.(3)|
00157|016|B||
00157|017|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
00157|018|P|hypoalbuminemia.|
00157|019|B||
00157|020|M|PATIENT MANAGEMENT:  Avoid concurrent administration. If both drugs are|
00157|021|M|given, adjust the hydantoin dose as needed based on hydantoin plasma levels|
00157|022|M|and clinical symptoms.|
00157|023|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
00157|024|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
00157|025|M|vision, nausea, and vomiting).|
00157|026|B||
00157|027|D|DISCUSSION:  A retrospective study compared patients on concurrent phenytoin|
00157|028|D|and chloramphenicol with patients on concurrent phenytoin and tetracycline|
00157|029|D|or chloramphenicol alone. 45% of patients on concurrent phenytoin and|
00157|030|D|chloramphenicol developed symptoms of phenytoin toxicity including ataxia,|
00157|031|D|nystagmus, dysarthria, tremor, dilated pupils, loss of visual acuity,|
00157|032|D|anxiety and/or hallucinations. This is compared to none on concurrent|
00157|033|D|phenytoin and tetracycline and 9% on chloramphenicol only.(2)|
00157|034|D|   Two patients receiving concurrent phenytoin (250 mg daily) and|
00157|035|D|chloramphenicol (2 gm daily) showed a 93-164% increase in chloramphenicol|
00157|036|D|half-life. Serum phenytoin concentration for one of the patients increased|
00157|037|D|450%.(3)|
00157|038|D|   A 58 year-old patient on concurrent phenytoin (400 mg day) and|
00157|039|D|chloramphenicol (2 gm every 6 hours) developed nystagmus. The phenytoin|
00157|040|D|concentration was found to have increased 244%.(4)|
00157|041|D|   A 64 year-old patient on concurrent phenytoin (300 mg) and|
00157|042|D|chloramphenicol (1 g every 6 hours) became stuporous, lethargic, and|
00157|043|D|responded poorly to painful stimuli.(5) The patient was found to have a|
00157|044|D|4-fold increase in phenytoin concentration.|
00157|045|D|   A 30 year-old female on concurrent phenytoin (300 mg) and chloramphenicol|
00157|046|D|(1 gm every 4 hours) developed nausea, vomiting, nystagmus, and ataxia.(6)|
00157|047|D|The patient's phenytoin level was found to have increased 142%.|
00157|048|D|   An in vitro study showed that chloramphenicol inhibits CYP2C19-mediated|
00157|049|D|metabolism of phenytoin.(7)|
00157|050|D|   An open-label parallel design study in 15 children with malaria showed a|
00157|051|D|significant increase in phenytoin half-life with concurrent administration|
00157|052|D|of intravenous chloramphenicol (25 mg/kg every 6 hours for 72h) and a single|
00157|053|D|intramuscular dose of fosphenytoin (18 mg/kg).(8)|
00157|054|B||
00157|055|R|REFERENCES:|
00157|056|B||
00157|057|R|1.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00157|058|R|  March, 2022.|1
00157|059|R|2.Harper JM, Yost RL, Stewart RB, Ciezkowski J. Phenytoin-chloramphenicol|2
00157|060|R|  interaction: a retrospective study. Drug Intell Clin Pharm 1979 Jul-Aug;|2
00157|061|R|  13:425-9.|2
00157|062|R|3.Christensen LK, Skovsted L. Inhibition of drug metabolism by|3
00157|063|R|  chloramphenicol. Lancet 1969 Dec 27;2(7635):1397-9.|3
00157|064|R|4.Ballek RE, Reidenberg MM, Orr L. Inhibition of diphenylhydantoin|3
00157|065|R|  metabolism by chloramphenicol. Lancet 1973 Jan;1(7795):150.|3
00157|066|R|5.Rose JQ, Choi HK, Schentag JJ, Kinkel WR, Jusko WJ. Intoxication caused by|3
00157|067|R|  interaction of chloramphenicol and phenytoin. JAMA 1977 Jun 13;|3
00157|068|R|  237(24):2630-1.|3
00157|069|R|6.Vincent FM, Mills L, Sullivan JK. Chloramphenicol-induced phenytoin|3
00157|070|R|  intoxication. Ann Neurol 1978 May;3(5):469.|3
00157|071|R|7.Park JY, Kim KA, Kim SL. Chloramphenicol is a potent inhibitor of|5
00157|072|R|  cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes.|5
00157|073|R|  Antimicrob Agents Chemother 2003 Nov;47(11):3464-9.|5
00157|074|R|8.Ogutu BR, Newton CR, Muchohi SN, Otieno GO, Kokwaro GO. Phenytoin|2
00157|075|R|  pharmacokinetics and clinical effects in African children following|2
00157|076|R|  fosphenytoin and chloramphenicol coadministration. Br J Clin Pharmacol|2
00157|077|R|  2002 Dec;54(6):635-42.|2
00158|001|T|MONOGRAPH TITLE:  Sympathomimetics (Direct, Mixed-Acting)/Guanethidine|
00158|002|B||
00158|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00158|004|L|take action as needed.|
00158|005|B||
00158|006|A|MECHANISM OF ACTION:  Direct or mixed-acting sympathomimetics may inhibit|
00158|007|A|uptake of guanethidine at the adrenergic neuron.|
00158|008|B||
00158|009|E|CLINICAL EFFECTS:  Decreased antihypertensive effectiveness. Effects may be|
00158|010|E|seen for several days after discontinuation of the direct or mixed-acting|
00158|011|E|sympathomimetic.|
00158|012|B||
00158|013|P|PREDISPOSING FACTORS:  None determined.|
00158|014|B||
00158|015|M|PATIENT MANAGEMENT:  Avoid concomitant administration of these drugs.  If|
00158|016|M|both drugs are administered, adjust the guanethidine dose as needed based on|
00158|017|M|blood pressure.|
00158|018|B||
00158|019|D|DISCUSSION:  Documentation supports routine monitoring of this interaction.|
00158|020|D|It should be noted that this interaction can occur quickly.|
00158|021|B||
00158|022|R|REFERENCES:|
00158|023|B||
00158|024|R|1.Laurence DR, Nagle RE. The effects of bretylium and guanethidine on the|2
00158|025|R|  pressor responses to noradrenaline and angiotensin. Br J Pharmacol 1963;|2
00158|026|R|  21:403-13.|2
00158|027|R|2.Muelheims GH, Entrup RW, Paiewonsky D, Mierzwiak DS. Increased sensitivity|2
00158|028|R|  of the heart to catecholamine-induced arrhythmias following guanethidine.|2
00158|029|R|  Clin Pharmacol Ther 1965 Nov-Dec;6(6):757-62.|2
00158|030|R|3.Gulati OD, Dave BT, Gokhale SD, Shah KM. Antagonism of adrenergic neuron|2
00158|031|R|  blockade in hypertensive subjects. Clin Pharmacol Ther 1966 Jul-Aug;|2
00158|032|R|  7(4):510-4.|2
00158|033|R|4.Sneddon JM, Turner P. The interactions of local guanethidine and|2
00158|034|R|  sympathomimetic amines in the human eye. Arch Ophthalmol 1969 May;|2
00158|035|R|  81(5):622-7.|2
00158|036|R|5.Spiers AS, Calne DB. Action of dopamine on the human iris. Br Med J 1969|2
00158|037|R|  Nov;4(679):333-5.|2
00158|038|R|6.Misage JR, McDonald RH Jr. Antagonism of hypotensive action of bethanidine|3
00158|039|R|  by "common cold" remedy. Br Med J 1970 Nov 7;4(731):347.|3
00158|040|R|7.Ober KF, Wang RI. Drug interactions with guanethidine. Clin Pharmacol Ther|2
00158|041|R|  1973 Mar-Apr;14(2):190-5.|2
00158|042|R|8.Cooper B. "Neo-synephrine" (10%) eye drops. Med J Aust 1968 Aug 31;|3
00158|043|R|  55(2):420.|3
00160|001|T|MONOGRAPH TITLE:  Corticosteroids/Antidiabetics (mono deleted 08/29/1996)|
00160|002|B||
00160|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00160|004|L|take action as needed.|
00160|005|B||
00160|006|A|MECHANISM OF ACTION:  Corticosteroids antagonize hypoglycemic effects of|
00160|007|A|antidiabetics due to their intrinsic hyperglycemic activity.|
00160|008|B||
00160|009|E|CLINICAL EFFECTS:  Impaired glucose tolerance and diminished hypoglycemic|
00160|010|E|effects of antidiabetics may occur.|
00160|011|B||
00160|012|P|PREDISPOSING FACTORS:  None determined.|
00160|013|B||
00160|014|M|PATIENT MANAGEMENT:  Caution when starting, altering, or stopping|
00160|015|M|corticosteroids in diabetic patients. Adjust the antidiabetic dose as needed|
00160|016|M|based on blood glucose levels.|
00160|017|B||
00160|018|D|DISCUSSION:  This interaction is likely to occur based upon well documented|
00160|019|D|properties of the interacting drugs. However, there is individual|
00160|020|D|variability in its occurrence.|
00160|021|B||
00160|022|R|REFERENCE:|
00160|023|B||
00160|024|R|1.Beaudry C, Laplate L. Treatment of renal failure from diabetic nephropathy|3
00160|025|R|  with cadaveric homograft. Can Med Assoc J 1973 Apr 7;108(7):887-8 passim.|3
00161|001|T|MONOGRAPH TITLE:  Thiazides/Antidiabetics|
00161|002|B||
00161|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00161|004|L|take action as needed.|
00161|005|B||
00161|006|A|MECHANISM OF ACTION:  Thiazides antagonize hypoglycemic effects of|
00161|007|A|antidiabetics due to intrinsic hyperglycemic activity.|
00161|008|B||
00161|009|E|CLINICAL EFFECTS:  Impaired glucose tolerance and diminished hypoglycemic|
00161|010|E|effects of antidiabetics may occur.|
00161|011|B||
00161|012|P|PREDISPOSING FACTORS:  None determined.|
00161|013|B||
00161|014|M|PATIENT MANAGEMENT:  Caution when starting or stopping thiazides in diabetic|
00161|015|M|patients. Adjust the antidiabetic dose as needed based on blood glucose|
00161|016|M|levels.|
00161|017|B||
00161|018|D|DISCUSSION:  This interaction is likely to occur based upon well documented|
00161|019|D|properties of the interacting drugs. However, there is individual|
00161|020|D|variability in its occurrence.|
00161|021|D|   A cross-sectional study of 425 outpatients found 46 patients with 86|
00161|022|D|suspected drug interactions resulting in uncontrolled glycemia. Recorded|
00161|023|D|drug interactions included hydrochlorothiazide-gliclazide (22.1%),|
00161|024|D|hydrochlorothiazide-insulins (2.3%), and chlorothiazide-gliclazide (1.2%).|
00161|025|D|Using the drug interaction probability scale (DIPS), these drug interactions|
00161|026|D|were categorized as possible.(2)|
00161|027|B||
00161|028|R|REFERENCES:|
00161|029|B||
00161|030|R|1.Kohner EM, Dollery CT, Lowy C, Schumer B. Effect of diuretic therapy on|2
00161|031|R|  glucose tolerance in hypertensive patients. Lancet 1971 May 15;|2
00161|032|R|  1(7707):986-90.|2
00161|033|R|2.Hammad MA, Tangiisuran B, Kharshid AM, Abdul-Aziz N, Hassan Y, Aziz NA,|6
00161|034|R|  Elsayed TM. Drug-drug Interaction-related Uncontrolled Glycemia. J Pharm|6
00161|035|R|  Bioallied Sci 2017 Oct-Dec;9(4):221-228.|6
00162|001|T|MONOGRAPH TITLE:  NSAIDs; Aspirin (Non-Cardioprotective)/Beta-Blockers|
00162|002|B||
00162|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00162|004|L|take action as needed.|
00162|005|B||
00162|006|A|MECHANISM OF ACTION:  Unknown; however, possibly related to inhibition of|
00162|007|A|prostaglandin by NSAIDs.|
00162|008|B||
00162|009|E|CLINICAL EFFECTS:  The antihypertensive action of beta-blockers may be|
00162|010|E|decreased.|
00162|011|B||
00162|012|P|PREDISPOSING FACTORS:  None determined.|
00162|013|B||
00162|014|M|PATIENT MANAGEMENT:  Monitor patient's blood pressure and adjust the dose of|
00162|015|M|the beta-blocker as needed.|
00162|016|B||
00162|017|D|DISCUSSION:  Concurrent administration of beta-blockers and NSAIDs has been|
00162|018|D|associated with a clinically significant loss in antihypertensive response.|
00162|019|D|The magnitude of the effect of NSAIDs on control of blood pressure by|
00162|020|D|beta-blockers needs to be determined for each anti-inflammatory agent.|
00162|021|D|   One or more of the drug pairs linked to this monograph have been included|
00162|022|D|in a list of interactions that could be considered for classification as|
00162|023|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
00162|024|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
00162|025|D|Health Information Technology.|
00162|026|B||
00162|027|R|REFERENCES:|
00162|028|B||
00162|029|R|1.Durao V, Prata MM, Goncalves LM. Modification of antihypertensive effect|2
00162|030|R|  of beta-adrenoceptor-blocking agents by inhibition of endogenous|2
00162|031|R|  prostaglandin synthesis. Lancet 1977 Nov 12;2(8046):1005-7.|2
00162|032|R|2.Lopez-Ovejero JA, Weber MA, Drayer JIM, Sealey JE, Laragh JH. Effects of|2
00162|033|R|  indomethacin alone and during diuretic or B-adrenoreceptor-blockade|2
00162|034|R|  therapy on blood pressure and the renin system in essential hypertension.|2
00162|035|R|  Clin Sci Mol Med 1978;55:203s-5s.|2
00162|036|R|3.Watkins J, Abbott EC, Hensby CN, Webster J, Dollery CT. Attenuation of|2
00162|037|R|  hypotensive effect of propranolol and thiazide diuretics by indomethacin.|2
00162|038|R|  Br Med J 1980 Sep 13;281(6242):702-5.|2
00162|039|R|4.Salvetti A, Arzilli F, Pedrinelli R, Beggi P, Motolese M. Interaction|2
00162|040|R|  between oxprenolol and indomethacin on blood pressure in essential|2
00162|041|R|  hypertensive patients. Eur J Clin Pharmacol 1982;22(3):197-201.|2
00162|042|R|5.Salvetti A, Pedrinelli R, Alberici P, Magagna A, Abdel-Haq B. The|2
00162|043|R|  influence of indomethacin and sulindac on some pharmacological actions of|2
00162|044|R|  atenolol in hypertensive patients. Br J Clin Pharmacol 1984;17 Suppl|2
00162|045|R|  1:108S-111S.|2
00162|046|R|6.Rodriquez Alvarez C, Baez MA, Weidler DJ. Effect of sulindac and piroxicam|4
00162|047|R|  administration on the antihypertensive effect of propranolol. J Clin|4
00162|048|R|  Pharmacol 1986;26:544.|4
00162|049|R|7.Radack KL, Deck CC, Bloomfield SS. Ibuprofen interferes with the efficacy|2
00162|050|R|  of antihypertensive drugs. A randomized, double-blind, placebo-controlled|2
00162|051|R|  trial of ibuprofen compared with acetaminophen. Ann Intern Med 1987 Nov;|2
00162|052|R|  107(5):628-35.|2
00162|053|R|8.Schoenfeld A, Freedman S, Hod M, Ovadia Y. Antagonism of antihypertensive|3
00162|054|R|  drug therapy in pregnancy by indomethacin?. Am J Obstet Gynecol 1989 Nov;|3
00162|055|R|  161(5):1204-5.|3
00162|056|R|9.Abate MA, Layne RD, Neely JL, D'Alessandri R. Effect of naproxen and|2
00162|057|R|  sulindac on blood pressure response to atenolol. DICP 1990 Sep;|2
00162|058|R|  24(9):810-3.|2
00162|059|R|10.Abate MA, Neely JL, Layne RD, D'Alessandri R. Interaction of indomethacin|2
00162|060|R|   and sulindac with labetalol. Br J Clin Pharmacol 1991 Mar;31(3):363-6.|2
00162|061|R|11.Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of|6
00162|062|R|   nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med|6
00162|063|R|   1993 Feb 22;153(4):477-84.|6
00162|064|R|12.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
00162|065|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
00162|066|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
00162|067|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
00163|001|T|MONOGRAPH TITLE:  Isoniazid/Rifampin (mono deleted 10/24/2024)|
00163|002|B||
00163|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00163|004|L|take action as needed.|
00163|005|B||
00163|006|A|MECHANISM OF ACTION:  Unknown. However, rifampin may induce the microsomal|
00163|007|A|enzymes in the liver that convert isoniazid to hepatotoxic metabolites.|
00163|008|B||
00163|009|E|CLINICAL EFFECTS:  May observe an increased incidence of hepatotoxicity.|
00163|010|B||
00163|011|P|PREDISPOSING FACTORS:  Preexisting hepatic impairment and "slow|
00163|012|P|acetylators".|
00163|013|B||
00163|014|M|PATIENT MANAGEMENT:  Monitor the patient for hepatotoxicity. If a reaction|
00163|015|M|occurs, it may be necessary to discontinue one or both drugs.|
00163|016|B||
00163|017|D|DISCUSSION:  Documentation is lacking: however, if an interaction occurs,|
00163|018|D|the consequences could be severe.|
00163|019|B||
00163|020|R|REFERENCES:|
00163|021|B||
00163|022|R|1.Venho VM, Koskinen R. The effect of pyrazinamide, rifampicin and|2
00163|023|R|  cycloserine on the blood levels and urinary excretion of isoniazid. Ann|2
00163|024|R|  Clin Res 1971 Oct;3(5):277-80.|2
00163|025|R|2.Llorens J, Serrano RJ, Sanchez R. Pharmacodynamic interference between|2
00163|026|R|  rifampicin and isoniazid. Chemotherapy 1978;24(2):97-103.|2
00164|001|T|MONOGRAPH TITLE:  Methotrexate; Pralatrexate/NSAIDs|
00164|002|B||
00164|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00164|004|L|of severe adverse interaction.|
00164|005|B||
00164|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  NSAID-induced|
00164|007|A|inhibition of prostaglandin synthesis may decrease renal perfusion rate and|
00164|008|A|therefore inhibit methotrexate and pralatrexate clearance.  NSAIDs may also|
00164|009|A|compete for renal secretion with methotrexate and pralatrexate.  Since|
00164|010|A|methotrexate is not extensively protein bound, displacement of methotrexate|
00164|011|A|by NSAIDs is unlikely to have altered methotrexate kinetics.|
00164|012|B||
00164|013|E|CLINICAL EFFECTS:  Increased levels of methotrexate and pralatrexate, with|
00164|014|E|increased effects, leading to increased risk of severe neurotoxicity,|
00164|015|E|stomatitis, and myelosuppression, including neutropenia.|
00164|016|B||
00164|017|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
00164|018|P|- High-dose oncology regimens|
00164|019|P|- Impaired renal function, ascites, or pleural effusions|
00164|020|B||
00164|021|M|PATIENT MANAGEMENT:  Avoid the use of NSAIDs with high dose methotrexate|
00164|022|M|therapy.(1)  If both drugs must be given, monitor methotrexate levels and|
00164|023|M|patient response carefully.  Consider extending leucovorin rescue duration.|
00164|024|M|   Use caution when administering NSAIDs with low dose methotrexate therapy.|
00164|025|M|(1)|
00164|026|M|   Administration of NSAIDs with pralatrexate requires close monitoring for|
00164|027|M|toxicity.(2)|
00164|028|B||
00164|029|D|DISCUSSION:     A retrospective review documented four cases of methotrexate|
00164|030|D|toxicity during concurrent administration of ketoprofen and methotrexate in|
00164|031|D|36 patients. Three cases were fatalities.(3)  In contrast, a four-way|
00164|032|D|cross-over study in ten subjects found no effect on methotrexate oral or|
00164|033|D|renal clearance by ketoprofen, piroxicam, or flurbiprofen.(4)  In a study in|
00164|034|D|19 subjects, the concurrent administration of methotrexate and piroxicam|
00164|035|D|resulted in a decrease in methotrexate maximum concentration (Cmax) but no|
00164|036|D|other changes in methotrexate kinetics.(5)  Another three-way cross-over|
00164|037|D|study in six patients showed no effect by flurbiprofen or ibuprofen on|
00164|038|D|methotrexate kinetics.(6)  In contrast, administration of ibuprofen to nine|
00164|039|D|patients resulted in a 39% decrease in methotrexate total clearance and a|
00164|040|D|40% decrease in methotrexate renal clearance.(7)  Information on naproxen is|
00164|041|D|also conflicting.  In another arm of the earlier study (7), the|
00164|042|D|administration of naproxen in nine patients decreased methotrexate total|
00164|043|D|clearance by 22%, but had no significant effects on methotrexate renal|
00164|044|D|clearance.  In another study in nine subjects, methotrexate altered naproxen|
00164|045|D|kinetics by greater than 30% in six subjects, although these changes were|
00164|046|D|not statistically significant.  Naproxen altered methotrexate kinetics by|
00164|047|D|greater than 30% in four subjects, although these changes were also not|
00164|048|D|statistically significant.(8)  In contrast, the administration of naproxen|
00164|049|D|with methotrexate in 15 subjects showed no significant effects on|
00164|050|D|methotrexate oral or renal clearance.(9)  A study in 19 subjects found that|
00164|051|D|the concurrent administration of etodolac and methotrexate decreased|
00164|052|D|methotrexate Cmax and increased methotrexate mean residence time.  There|
00164|053|D|were no changes in methotrexate clearance or area-under-curve (AUC) and no|
00164|054|D|toxicity was observed.(10)  A study in 12 patients showed no significant|
00164|055|D|effects of sulindac on methotrexate kinetics unless one patient who had low|
00164|056|D|baseline clearance of methotrexate was excluded from analysis.(11)  A study|
00164|057|D|in seven children examined the effects of the children's usual NSAID on|
00164|058|D|methotrexate kinetics.  NSAIDs were naproxen, tolmetin, and indomethacin.|
00164|059|D|Methotrexate half-life increased during NSAID administration.  There were no|
00164|060|D|significant changes in methotrexate clearance, AUC or volume of|
00164|061|D|distribution.  There was inter-subject variably in response.  In six of|
00164|062|D|seven patients, NSAID administration increased methotrexate AUC 19-140%.(12)|
00164|063|D|   Case reports have documented an interaction between methotrexate and|
00164|064|D|phenylbutazone (13), indomethacin (14), flurbiprofen (15), and naproxen|
00164|065|D|(16,17); however, one naproxen report (16) is complicated by the fact that|
00164|066|D|the patient took 27.5 mg methotrexate in one week instead of 2.5 mg three|
00164|067|D|times weekly.|
00164|068|D|   Because of the conflicting data and wide patient variability, caution is|
00164|069|D|warranted during concurrent administration of methotrexate and any NSAID.|
00164|070|B||
00164|071|R|REFERENCES:|
00164|072|B||
00164|073|R|1.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
00164|074|R|  Inc. March, 2018.|1
00164|075|R|2.Folotyn (pralatrexate) US prescribing information. Allos Therapeutics,|1
00164|076|R|  Inc. May, 2016.|1
00164|077|R|3.Thyss A, Milano G, Kubar J, Namer M, Schneider M. Clinical and|3
00164|078|R|  pharmacokinetic evidence of a life-threatening interaction between|3
00164|079|R|  methotrexate and ketoprofen. Lancet 1986 Feb 1;1(8475):256-8.|3
00164|080|R|4.Tracy TS, Worster T, Bradley JD, Greene PK, Brater DC. Methotrexate|2
00164|081|R|  disposition following concomitant administration of ketoprofen, piroxicam|2
00164|082|R|  and flurbiprofen in patients with rheumatoid arthritis. Br J Clin|2
00164|083|R|  Pharmacol 1994 May;37(5):453-6.|2
00164|084|R|5.Combe B, Edno L, Lafforgue P, Bologna C, Bernard JC, Acquaviva P, Sany J,|2
00164|085|R|  Bressolle F. Total and free methotrexate pharmacokinetics, with and|2
00164|086|R|  without piroxicam, in rheumatoid arthritis patients. Br J Rheumatol 1995|2
00164|087|R|  May;34(5):421-8.|2
00164|088|R|6.Skeith KJ, Russell AS, Jamali F, Coates J, Friedman H. Lack of significant|2
00164|089|R|  interaction between low dose methotrexate and ibuprofen or flurbiprofen in|2
00164|090|R|  patients with arthritis. J Rheumatol 1990 Aug;17(8):1008-10.|2
00164|091|R|7.Tracy TS, Krohn K, Jones DR, Bradley JD, Hall SD, Brater DC. The effects|2
00164|092|R|  of a salicylate, ibuprofen, and naproxen on the disposition of|2
00164|093|R|  methotrexate in patients with rheumatoid arthritis. Eur J Clin Pharmacol|2
00164|094|R|  1992;42(2):121-5.|2
00164|095|R|8.Wallace CA, Smith AL, Sherry DD. Pilot investigation of|2
00164|096|R|  naproxen/methotrexate interaction in patients with juvenile rheumatoid|2
00164|097|R|  arthritis. J Rheumatol 1993 Oct;20(10):1764-8.|2
00164|098|R|9.Stewart CF, Fleming RA, Arkin CR, Evans WE. Coadministration of naproxen|2
00164|099|R|  and low-dose methotrexate in patients with rheumatoid arthritis. Clin|2
00164|100|R|  Pharmacol Ther 1990 Apr;47(4):540-6.|2
00164|101|R|10.Anaya JM, Fabre D, Bressolle F, Bologna C, Alric R, Cocciglio M, Dropsy|2
00164|102|R|   R, Sany J. Effect of etodolac on methotrexate pharmacokinetics in|2
00164|103|R|   patients with rheumatoid arthritis. J Rheumatol 1994 Feb;21(2):203-8.|2
00164|104|R|11.Furst DE, Herman RA, Koehnke R, Ericksen N, Hash L, Riggs CE, Porras A,|2
00164|105|R|   Veng-Pedersen P. Effect of aspirin and sulindac on methotrexate|2
00164|106|R|   clearance. J Pharm Sci 1990 Sep;79(9):782-6.|2
00164|107|R|12.Dupuis LL, Koren G, Shore A, Silverman ED, Laxer RM.|2
00164|108|R|   Methotrexate-nonsteroidal antiinflammatory drug interaction in children|2
00164|109|R|   with arthritis. J Rheumatol 1990 Nov;17(11):1469-73.|2
00164|110|R|13.Adams JD, Hunter GA. Drug interaction in psoriasis. Australas J Dermatol|3
00164|111|R|   1976 Aug;17(2):39-40.|3
00164|112|R|14.Maiche AG. Acute renal failure due to concomitant action of methotrexate|3
00164|113|R|   and indomethacin. Lancet 1986 Jun 14;1(8494):1390.|3
00164|114|R|15.Frenia ML, Long KS. Methotrexate and nonsteroidal antiinflammatory drug|3
00164|115|R|   interactions. Ann Pharmacother 1992 Feb;26(2):234-7.|3
00164|116|R|16.Singh RR, Malaviya AN, Pandey JN, Guleria JS. Fatal interaction between|3
00164|117|R|   methotrexate and naproxen. Lancet 1986 Jun 14;1(8494):1390.|3
00164|118|R|17.Ng HW, Macfarlane AW, Graham RM, Verbov JL. Near fatal drug interactions|3
00164|119|R|   with methotrexate given for psoriasis. Br Med J (Clin Res Ed) 1987 Sep|3
00164|120|R|   26;295(6601):752-3.|3
00165|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Sympathomimetics|
00165|002|B||
00165|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00165|004|L|of severe adverse interaction.|
00165|005|B||
00165|006|A|MECHANISM OF ACTION:  Concurrent use of ergot alkaloids and sympathomimetics|
00165|007|A|may result in additive or synergistic effect on peripheral blood vessels.|
00165|008|B||
00165|009|E|CLINICAL EFFECTS:  Concurrent use of ergot alkaloids and sympathomimetics|
00165|010|E|may result in increased blood pressure due to peripheral vasoconstriction.|
00165|011|B||
00165|012|P|PREDISPOSING FACTORS:  None determined.|
00165|013|B||
00165|014|M|PATIENT MANAGEMENT:  When possible, avoid the concurrent use of ergot|
00165|015|M|alkaloids and sympathomimetics.  If concurrent use is warranted, monitor|
00165|016|M|blood pressure and for signs of vasoconstriction.  Decreasing the dose of|
00165|017|M|one or both drugs may be necessary.|
00165|018|B||
00165|019|D|DISCUSSION:  There have been reports of severe vasoconstriction resulting in|
00165|020|D|gangrene in patients receiving intravenous ergonovine with dopamine or|
00165|021|D|norepinephrine.|
00165|022|B||
00165|023|R|REFERENCES:|
00165|024|B||
00165|025|R|1.Buchanan N, Cane RD, Miller M. Symmetrical gangrene of the extremities|3
00165|026|R|  associated with the use of dopamine subsequent to ergometrine|3
00165|027|R|  administration. Intensive Care Med 1977 Aug;3(2):55-6.|3
00165|028|R|2.Barthel W, Glusa E, Koth W. Interactions of dihydroergotamine with|3
00165|029|R|  etilefrine in human leg veins in vitro and in situ. Int J Clin Pharmacol|3
00165|030|R|  Ther Toxicol 1987 Feb;25(2):63-9.|3
00165|031|R|3.Chuang SS. Finger ischemia secondary to the synergistic agonist effect of|3
00165|032|R|  norepinephrine and ergonovine and in a burn patient. Burns 2003 Feb;|3
00165|033|R|  29(1):92-4.|3
00165|034|R|4.D. H. E. 45 (dihydroergotamine mesylate) US prescribing information.|1
00165|035|R|  Valeant Pharmaceuticals North America November 6, 2017.|1
00165|036|R|5.Cafergot (ergotamine tartrate and caffeine) tablets US prescribing|1
00165|037|R|  information. Sandoz Inc May 14, 2012.|1
00166|001|T|MONOGRAPH TITLE:  Cyclosporine/Amphotericin B|
00166|002|B||
00166|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00166|004|L|of severe adverse interaction.|
00166|005|B||
00166|006|A|MECHANISM OF ACTION:  Additive nephrotoxicity is most likely mechanism.|
00166|007|B||
00166|008|E|CLINICAL EFFECTS:  May observe enhanced nephrotoxicity of one or both drugs.|
00166|009|B||
00166|010|P|PREDISPOSING FACTORS:  None determined.|
00166|011|B||
00166|012|M|PATIENT MANAGEMENT:  Administer this combination cautiously. Monitoring of|
00166|013|M|renal function is indicated. A decrease in cyclosporine dose will result in|
00166|014|M|rapid reversal of cyclosporine-induced increases in creatinine. Holding the|
00166|015|M|cyclosporine dose until serum levels are less than 150 ng/ml may reduce the|
00166|016|M|likelihood of renal toxicity.|
00166|017|B||
00166|018|D|DISCUSSION:  Documentation is lacking; however, if an interaction occurs,|
00166|019|D|the consequences could be severe.|
00166|020|B||
00166|021|R|REFERENCES:|
00166|022|B||
00166|023|R|1.Kennedy MS, Deeg HJ, Storb R. Cyclosporin A: clinical pharmacologic|4
00166|024|R|  aspects of a novel immunosuppressant. Clin Res 1981;29(2):273a.|4
00166|025|R|2.Kennedy MS, Deeg HJ, Siegel M, Crowley JJ, Storb R, Thomas ED. Acute renal|2
00166|026|R|  toxicity with combined use of amphotericin B and cyclosporine after marrow|2
00166|027|R|  transplantation. Transplantation 1983 Mar;35(3):211-5.|2
00167|001|T|MONOGRAPH TITLE:  Buspirone/MAOIs|
00167|002|B||
00167|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00167|004|L|is contraindicated and generally should not be dispensed or administered to|
00167|005|L|the same patient.|
00167|006|B||
00167|007|A|MECHANISM OF ACTION:  Combination of MAOIs, which decrease the breakdown of|
00167|008|A|serotonin, and buspirone, a 5-HT1A and moderate D2 agonist, may cause an|
00167|009|A|increase in endogenous serotonin and dopamine, which in addition to|
00167|010|A|buspirone's agonist effect, could lead to hypertensive crisis.(1-3)|
00167|011|B||
00167|012|E|CLINICAL EFFECTS:  Concurrent use of buspirone and a MAOI may result in|
00167|013|E|hypertensive crisis.(2,3)|
00167|014|B||
00167|015|P|PREDISPOSING FACTORS:  None determined.|
00167|016|B||
00167|017|M|PATIENT MANAGEMENT:  The US manufacturer of buspirone recommends that these|
00167|018|M|drugs not be administered concomitantly.  Use of MAOIs to treat depression|
00167|019|M|with buspirone or within 14 days of stopping buspirone is contraindicated.|
00167|020|M|Use of buspirone within 14 days of stopping an MAOI to treat depression is|
00167|021|M|also contraindicated.(2)|
00167|022|M|   The US manufacturer of phenelzine states that concurrent use of buspirone|
00167|023|M|is contraindicated.  At least 14 days should elapse between the|
00167|024|M|discontinuation of phenelzine and the initiation of buspirone.(3)|
00167|025|M|   In emergency situations in patients maintained on buspirone, weigh the|
00167|026|M|availability and safety of alternatives to methylene blue against the risk|
00167|027|M|of hypertensive crisis.  If methylene blue therapy is required, the|
00167|028|M|patient's buspirone should be immediately discontinued.  Patients should be|
00167|029|M|monitored for hypertensive crisis for 2 weeks or until 24 hours after the|
00167|030|M|last dose of methylene blue, whichever comes first.(4)|
00167|031|M|   In non-emergency situations in patients maintained on buspirone when|
00167|032|M|methylene blue therapy is planned, discontinue the patient's buspirone at|
00167|033|M|least 2 weeks in advance of methylene blue therapy.  The patient's buspirone|
00167|034|M|therapy may be resumed 24 hours after the last dose of methylene blue.(4)|
00167|035|M|   Do not initiate buspirone therapy in patients receiving methylene blue|
00167|036|M|until 24 hours after the last dose of these agents.(4)|
00167|037|B||
00167|038|D|DISCUSSION:  Several cases of elevated blood pressure have been reported in|
00167|039|D|patients receiving MAOIs who were given buspirone.(2)  No adverse sequelae|
00167|040|D|have been reported in these patients.|
00167|041|D|   Furazolidone is known to inhibit monoamine oxidase.|
00167|042|D|   Methylene blue, when administered intravenously, has been shown to reach|
00167|043|D|sufficient concentrations to be a potent inhibitor of MAO-A.(5,6)|
00167|044|D|   Metaxalone is a weak inhibitor of MAO.(7,8)|
00167|045|B||
00167|046|R|REFERENCES:|
00167|047|B||
00167|048|R|1.Loane C, Politis M. Buspirone: what is it all about?. Brain Res 2012 Jun|6
00167|049|R|  21;1461:111-8.|6
00167|050|R|2.BuSpar (buspirone hydrochloride) US prescribing information. Bristol Myers|1
00167|051|R|  Squibb Company September, 2007.|1
00167|052|R|3.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
00167|053|R|  2007.|1
00167|054|R|4.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
00167|055|R|  information about the drug interaction between methylene blue|1
00167|056|R|  (methylthioninium chloride) and serotonergic psychiatric medications.|1
00167|057|R|  available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
00167|058|R|  21, 2011.|1
00167|059|R|5.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00167|060|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00167|061|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00167|062|R|6.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00167|063|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00167|064|R|  2000 Jun;56(3):247-50.|2
00167|065|R|7.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00167|066|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00167|067|R|  Feb;34(2):346.e5-6.|3
00167|068|R|8.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00167|069|R|  Pfizer Inc. January, 2024.|1
00168|001|T|MONOGRAPH TITLE:  Misc Antibiotics/Neuromuscular Blocking Agents|
00168|002|B||
00168|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00168|004|L|of severe adverse interaction.|
00168|005|B||
00168|006|A|MECHANISM OF ACTION:  Aminoglycosides, bacitracin, clindamycin, lincomycin,|
00168|007|A|and polymyxins may enhance the pharmacologic effects of neuromuscular|
00168|008|A|blocking agents.|
00168|009|B||
00168|010|E|CLINICAL EFFECTS:  May see an increase in the pharmacologic effects of|
00168|011|E|neuromuscular blocking agents, including prolonged respiratory depression|
00168|012|E|and apnea.|
00168|013|B||
00168|014|P|PREDISPOSING FACTORS:  None determined.|
00168|015|B||
00168|016|M|PATIENT MANAGEMENT:  If it is necessary to administer these drugs|
00168|017|M|concurrently, do so with extreme caution. Monitor neuromuscular function and|
00168|018|M|adjust the dose of the neuromuscular blocking agent accordingly.|
00168|019|B||
00168|020|D|DISCUSSION:  Concomitant administration of aminoglycosides, bacitracin,|
00168|021|D|clindamycin, lincomycin, and polymixins with neuromuscular blocking agents|
00168|022|D|has been shown to produce synergism of the effects on skeletal muscles.|
00168|023|D|Concurrent administration of these drugs has been associated with prolonged|
00168|024|D|respiratory depression, respiratory paralysis, and fatal apnea.|
00168|025|D|  The interaction usually occurs when the antibiotic is given prior to or|
00168|026|D|concurrently with the neuromuscular blocking drug, but it may also occur|
00168|027|D|when given after administration.  Any antibiotic dosage or route of|
00168|028|D|administration may produce respiratory depression.|
00168|029|B||
00168|030|R|REFERENCES:|
00168|031|B||
00168|032|R|1.Bodley PO, Brett JE. Post-operative respiratory inadequacy and the part|3
00168|033|R|  played by antibiotics. Anaesthesia 1962 Oct;17(4):438-443.|3
00168|034|R|2.Emery ERJ. Neuromuscular blocking properties of antibiotics as a cause of|3
00168|035|R|  post-operative apnoea. Anaesthesia 1963 Jan;18(1):57-65.|3
00168|036|R|3.Foldes FF, Lunn JN, Benz HG. Prolonged respiratory depression caused by|3
00168|037|R|  drug combinations. Muscle relaxants and intraperitoneal antibiotics as|3
00168|038|R|  etiologic agents. J Am Med Assoc 1963 Feb 23;183(8):672-3.|3
00168|039|R|4.Pinkerton HH, Munro JR. Respiratory insufficiency associated with the use|3
00168|040|R|  of streptomycin. Scott Med J 1964;9:256-8.|3
00168|041|R|5.Viljoen JF. Parenteral neomycin and muscle relaxants. Two case reports of|3
00168|042|R|  interest. S Afr Med J 1966 Oct 29;40(39):963-4.|3
00168|043|R|6.Warner WA, Sanders E. Neuromuscular blockade associated with gentamicin|3
00168|044|R|  therapy. JAMA 1971 Feb 15;215(7):1153-4.|3
00168|045|R|7.Levanen J, Nordman R. Complete respiratory paralysis caused by a large|3
00168|046|R|  dose of streptomycin and its treatment with calcium chloride. Ann Clin Res|3
00168|047|R|  1975 Feb;7(1):47-9.|3
00168|048|R|8.Geha DG, Blitt CD, Moon BJ. Prolonged neuromuscular blockade with|3
00168|049|R|  pancuronium in the presence of acute renal failure: a case report. Anesth|3
00168|050|R|  Analg 1976 May-Jun;55(3):343-5.|3
00168|051|R|9.Waterman PM, Smith RB. Tobramycin-curare interaction. Anesth Analg 1977|3
00168|052|R|  Jul-Aug;56(4):587-8.|3
00168|053|R|10.Sinha SK, Levene MI. Pancuronium bromide induced joint contractures in|3
00168|054|R|   the newborn. Arch Dis Child 1984 Jan;59(1):73-5.|3
00168|055|R|11.Burkett L, Bikhazi GB, Thomas KC Jr, Rosenthal DA, Wirta MG, Foldes FF.|5
00168|056|R|   Mutual potentiation of the neuromuscular effects of antibiotics and|5
00168|057|R|   relaxants. Anesth Analg 1979 Mar-Apr;58(2):107-15.|5
00168|058|R|12.Pittinger C, Adamson R. Antibiotic blockade of neuromuscular function.|6
00168|059|R|   Annu Rev Pharmacol 1972;12:169-84.|6
00168|060|R|13.Fogdall RP, Miller RD. Prolongation of a pancuronium-induced|3
00168|061|R|   neuromuscular blockade by clindamycin. Anesthesiology 1974 Oct;|3
00168|062|R|   41(4):407-8.|3
00169|001|T|MONOGRAPH TITLE:  General Anesthetics (Inhl)/Neuromuscular Blocking Agents|
00169|002|B||
00169|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00169|004|L|of severe adverse interaction.|
00169|005|B||
00169|006|A|MECHANISM OF ACTION:  General anesthetics enhance the pharmacologic effects|
00169|007|A|of nondepolarizing muscle relaxants.|
00169|008|B||
00169|009|E|CLINICAL EFFECTS:  May see an increase in the neuromuscular blocking effects|
00169|010|E|of the nondepolarizing muscle relaxant including respiratory depression,|
00169|011|E|bradycardia, hypotension, flushing, or muscle weakness.|
00169|012|B||
00169|013|P|PREDISPOSING FACTORS:  None determined.|
00169|014|B||
00169|015|M|PATIENT MANAGEMENT:  It may be necessary to decrease the dose of the|
00169|016|M|nondepolarizing muscle relaxant. Monitor neuromuscular function and adjust|
00169|017|M|the dose of the nondepolarizing muscle relaxant accordingly.|
00169|018|B||
00169|019|D|DISCUSSION:  Concomitant administration of general anesthetics and|
00169|020|D|nondepolarizing muscle relaxants has been shown to produce synergistic|
00169|021|D|neuromuscular blocking effects of nondepolarizing muscle relaxants.|
00169|022|B||
00169|023|R|REFERENCES:|
00169|024|B||
00169|025|R|1.Miller RD, Eger EI 2nd, Way WL, Stevens WC, Dolan WM. Comparative|2
00169|026|R|  neuromuscular effects of Forane and halothane alone and in combination|2
00169|027|R|  with d-tubocurarine in man. Anesthesiology 1971 Jul;35(1):38-42.|2
00169|028|R|2.Miller RD, Way WL, Dolan WM, Stevens WC, Eger EI 2nd. Comparative|2
00169|029|R|  neuromuscular effects of pancuronium, gallamine, and succinylcholine|2
00169|030|R|  during forane and halothane anesthesia in man. Anesthesiology 1971 Nov;|2
00169|031|R|  35(5):509-14.|2
00169|032|R|3.Miller RD, Way WL, Dolan WM, Stevens WC, Eger EI 2nd. The dependence of|2
00169|033|R|  pancuronium- and d-tubocurarine-induced neuromuscular blockades on|2
00169|034|R|  alveolar concentrations of halothane and forane. Anesthesiology 1972 Dec;|2
00169|035|R|  37(6):573-81.|2
00169|036|R|4.Fogdall RP, Miller RD. Neuromuscular effects of enflurane, alone and|2
00169|037|R|  combined with d- Tubocurarine, pancuronium, and succinylcholine, in man.|2
00169|038|R|  Anesthesiology 1975 Feb;42(2):173-8.|2
00169|039|R|5.Vitez TS. Potency of metocurine during halothane-N2O and N2O-narcotic|2
00169|040|R|  anesthesia. Anesth Analg 1978 Jan-Feb;57(1):116-7.|2
00169|041|R|6.Sebel PS, Bovill JG, Wauquier A, Rog P. Effects of high-dose fentanyl|2
00169|042|R|  anesthesia on the electroencephalogram. Anesthesiology 1981 Sep;|2
00169|043|R|  55(3):203-11.|2
00169|044|R|7.Artru AA, Nugent M, Michenfelder JD. Enflurane causes a prolonged and|5
00169|045|R|  reversible increase in the rate of CSF production in the dog.|5
00169|046|R|  Anesthesiology 1982 Oct;57(4):255-60.|5
00169|047|R|8.Stirt JA, Katz RL, Murray AL, Schehl DL, Lee C. Modification of atracurium|6
00169|048|R|  blockade by halothane and by suxamethonium. A review of clinical|6
00169|049|R|  experience. Br J Anaesth 1983;55 Suppl 1:71S-75S.|6
00169|050|R|9.Brandom BW, Cook DR, Woelfel SK, Rudd GD, Fehr B, Lineberry CG. Atracurium|2
00169|051|R|  infusion requirements in children during halothane, isoflurane, and|2
00169|052|R|  narcotic anesthesia. Anesth Analg 1985 May;64(5):471-6.|2
00169|053|R|10.Rupp SM, Miller RD, Gencarelli PJ. Vecuronium-induced neuromuscular|2
00169|054|R|   blockade during enflurane, isoflurane, and halothane anesthesia in|2
00169|055|R|   humans. Anesthesiology 1984 Feb;60(2):102-5.|2
00169|056|R|11.Ostergaard D, Engbaek J, Viby-Mogensen J. Adverse reactions and|6
00169|057|R|   interactions of the neuromuscular blocking drugs. Med Toxicol Adverse|6
00169|058|R|   Drug Exp 1989 Sep-Oct;4(5):351-68.|6
00169|059|R|12.Swen J, Rashkovsky OM, Ket JM, Koot HW, Hermans J, Agoston S. Interaction|2
00169|060|R|   between nondepolarizing neuromuscular blocking agents and inhalational|2
00169|061|R|   anesthetics. Anesth Analg 1989 Dec;69(6):752-5.|2
00169|062|R|13.Withington DE, Donati F, Bevan DR, Varin F. Potentiation of atracurium|2
00169|063|R|   neuromuscular blockade by enflurane: time- course of effect. Anesth Analg|2
00169|064|R|   1991 Apr;72(4):469-73.|2
00170|001|T|MONOGRAPH TITLE:  Neuromuscular Blocking Agents/Quinine Derivatives|
00170|002|B||
00170|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00170|004|L|of severe adverse interaction.|
00170|005|B||
00170|006|A|MECHANISM OF ACTION:  Synergistic or additive pharmacologic activity.|
00170|007|B||
00170|008|E|CLINICAL EFFECTS:  May see an increase in the neuromuscular blocking|
00170|009|E|effects, including profound sedation, respiratory depression, coma, and/or|
00170|010|E|death.|
00170|011|B||
00170|012|P|PREDISPOSING FACTORS:  None determined.|
00170|013|B||
00170|014|M|PATIENT MANAGEMENT:  Avoid concurrent administration of neuromuscular|
00170|015|M|blocking agents and quinine derivatives during the first several hours of|
00170|016|M|postoperative period. If administered, respiratory support may be needed.|
00170|017|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00170|018|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00170|019|M|unresponsiveness.|
00170|020|B||
00170|021|D|DISCUSSION:  Administration of quinidine during the immediate postoperative|
00170|022|D|period has been associated with respiratory paralysis and apnea.|
00170|023|B||
00170|024|R|REFERENCES:|
00170|025|B||
00170|026|R|1.Grogono AW. Anaesthesia for a atrial defibrillation. Effect of quinidine|3
00170|027|R|  on muscular relaxation. Lancet 1963 Nov 16;2:1039-40.|3
00170|028|R|2.Schmidt JL, Vick NA, Sadove MS. The effect of quinidine on the action of|3
00170|029|R|  muscle relaxants. JAMA 1963 Feb 23;183(8):669-71.|3
00170|030|R|3.Cuthbert MF. The effect of quinidine and procainamide on the neuromuscular|5
00170|031|R|  blocking action of suxamethonium. Br J Anaesth 1966 Oct;38(10):775-9.|5
00170|032|R|4.Kambam JR, Franks JJ, Naukam R, Sastry BV. Effect of quinidine on plasma|3
00170|033|R|  cholinesterase activity and succinylcholine neuromuscular blockade.|3
00170|034|R|  Anesthesiology 1987 Nov;67(5):858-60.|3
00171|001|T|MONOGRAPH TITLE:  Succinylcholine/Trimethaphan|
00171|002|B||
00171|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00171|004|L|of severe adverse interaction.|
00171|005|B||
00171|006|A|MECHANISM OF ACTION:  Unknown. Trimethaphan is believed to inhibit plasma|
00171|007|A|cholinesterase.|
00171|008|B||
00171|009|E|CLINICAL EFFECTS:  May see an increase in the neuromuscular blocking effects|
00171|010|E|of succinylcholine, producing prolonged respiratory depression and apnea.|
00171|011|B||
00171|012|P|PREDISPOSING FACTORS:  None determined.|
00171|013|B||
00171|014|M|PATIENT MANAGEMENT:  Avoid concurrent administration of succinylcholine and|
00171|015|M|trimethaphan. If both agents are given concomitantly, prior measurement of|
00171|016|M|plasma cholinesterase activity is advisable.|
00171|017|B||
00171|018|D|DISCUSSION:  Concurrent administration of succinylcholine and trimethaphan|
00171|019|D|has been reported to produce prolonged apnea. In addition, trimethaphan has|
00171|020|D|been reported to produce nondepolarizing neuromuscular blockade and increase|
00171|021|D|the activity of both depolarizing and nondepolarizing muscle relaxants.|
00171|022|B||
00171|023|R|REFERENCES:|
00171|024|B||
00171|025|R|1.Tewfik GI. Trimetaphan. Its effect on the pseudo-cholinesterase level of|2
00171|026|R|  man. Anaesthesia 1957 Jul;12(3):326-9.|2
00171|027|R|2.Dale RC, Schroeder ET. Respiratory paralysis during treatment of|3
00171|028|R|  hypertension with trimethaphan camsylate. Arch Intern Med 1976 Jul;|3
00171|029|R|  136(7):816-8.|3
00171|030|R|3.Wilson SL, Miller RN, Wright C, Hasse D. Prolonged neuromuscular blockade|3
00171|031|R|  associated with trimethaphan: a case report. Anesth Analg 1976 May-Jun;|3
00171|032|R|  55(3):353-6.|3
00171|033|R|4.Sklar GS, Lanks KW. Effects of trimethaphan and sodium nitroprusside on|5
00171|034|R|  hydrolysis of succinylcholine in vitro. Anesthesiology 1977 Jul;|5
00171|035|R|  47(1):31-33.|5
00171|036|R|5.Poulton TJ, James FM 3rd, Lockridge O. Prolonged apnea following|3
00171|037|R|  trimethaphan and succinylcholine. Anesthesiology 1979 Jan;50(1):54-6.|3
00172|001|T|MONOGRAPH TITLE:  Antidiabetic, Oral/Chloramphenicol|
00172|002|B||
00172|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00172|004|L|take action as needed.|
00172|005|B||
00172|006|A|MECHANISM OF ACTION:  Chloramphenicol-induced inhibition of hepatic|
00172|007|A|microsomal enzyme activity, resulting in decreased oral antidiabetic agent|
00172|008|A|metabolism.|
00172|009|B||
00172|010|E|CLINICAL EFFECTS:  May see an increase in the hypoglycemic effect of certain|
00172|011|E|oral antidiabetic agents.|
00172|012|B||
00172|013|P|PREDISPOSING FACTORS:  None determined.|
00172|014|B||
00172|015|M|PATIENT MANAGEMENT:  It may be necessary to lower the dose of certain oral|
00172|016|M|antidiabetic agents during concurrent administration of chloramphenicol.|
00172|017|M|Monitor blood glucose levels and monitor the patient for symptoms of|
00172|018|M|hypoglycemia. Adjust the dose accordingly.|
00172|019|B||
00172|020|D|DISCUSSION:  Concomitant administration of chloramphenicol and tolbutamide|
00172|021|D|has been reported to increase the half-life of the oral antidiabetic agent|
00172|022|D|producing severe hypoglycemia.|
00172|023|B||
00172|024|R|REFERENCES:|
00172|025|B||
00172|026|R|1.Hansen JM, Kristensen M. Tolbutamde in the treatment of Parkinson's|2
00172|027|R|  disease--a double blind trial. Dan Med Bull 1965 Dec;12(7):181-4.|2
00172|028|R|2.Christensen LK, Skovsted L. Inhibition of drug metabolism by|3
00172|029|R|  chloramphenicol. Lancet 1969 Dec 27;2(7635):1397-9.|3
00173|001|T|MONOGRAPH TITLE:  Selected Beta-Blockers/Selected Alpha-Blockers|
00173|002|B||
00173|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00173|004|L|take action as needed.|
00173|005|B||
00173|006|A|MECHANISM OF ACTION:  Alpha-blockers may cause syncope with sudden loss of|
00173|007|A|consciousness secondary to excessive postural hypotension.  Following the|
00173|008|A|first dose of an alpha-blocker, compensatory tachycardia helps to prevent or|
00173|009|A|limit syncope.  Beta-blockers may inhibit this tachycardia, thereby|
00173|010|A|worsening alpha-blocker induced hypotension.|
00173|011|B||
00173|012|E|CLINICAL EFFECTS:  The hypotensive effects of an alpha-blocker may be|
00173|013|E|increased in patients on concurrent beta-blocker therapy.|
00173|014|B||
00173|015|P|PREDISPOSING FACTORS:  Patients may be at increased risk of postural|
00173|016|P|hypotension with concurrent diuretic therapy and those on low-sodium diets.|
00173|017|B||
00173|018|M|PATIENT MANAGEMENT:  When starting alpha-blocker therapy in patients|
00173|019|M|receiving beta-blockers, consider initiating treatment with a reduced dose|
00173|020|M|of the alpha-blocker.|
00173|021|M|   If syncope occurs, provide supportive treatment as necessary.|
00173|022|M|   The adverse effect is self limiting and in most cases does not recur|
00173|023|M|after the initial period of therapy or during subsequent dose titration with|
00173|024|M|the alpha-blocker.|
00173|025|B||
00173|026|D|DISCUSSION:  Beta-blockers increase the acute postural hypotension that|
00173|027|D|frequently follows the first dose of an alpha-blocker.  Initiation of|
00173|028|D|beta-blocker therapy in patients that have started taking an alpha-blocker|
00173|029|D|would not be expected to produce acute postural hypotension.|
00173|030|D|   Alpha-blockers linked to this interaction include alfuzosin, doxazosin,|
00173|031|D|prazosin, and terazosin.|
00173|032|D|   Beta-blockers linked to this interaction include acebutolol, atenolol,|
00173|033|D|betaxolol, bevantolol, levobunolol, metoprolol, nadolol, pindolol,|
00173|034|D|pronethalol, propranolol, and timolol.|
00173|035|B||
00173|036|R|REFERENCES:|
00173|037|B||
00173|038|R|1.Elliott HL, McLean K, Sumner DJ, Meredith PA, Reid JL. Immediate|2
00173|039|R|  cardiovascular responses to oral prazosin--effects of concurrent|2
00173|040|R|  beta-blockers. Clin Pharmacol Ther 1981 Mar;29(3):303-9.|2
00173|041|R|2.Graham RM, Thornell IR, Gain JM, Bagnoli C, Oates HF, Stokes GS. Prazosin:|2
00173|042|R|  the first-dose phenomenon. Br Med J 1976 Nov 27;2(6047):1293-4.|2
00173|043|R|3.Rubin P, Jackson G, Blaschke T. Studies on the clinical pharmacology of|2
00173|044|R|  prazosin. II: The influence of indomethacin and of propranolol on the|2
00173|045|R|  action and disposition of prazosin. Br J Clin Pharmacol 1980 Jul;|2
00173|046|R|  10(1):33-9.|2
00173|047|R|4.Seideman P, Grahnen A, Haglund K, Lindstrom B, Von Bahr C. Prazosin first|2
00173|048|R|  dose phenomenon during combined treatment with a beta- adrenoceptor|2
00173|049|R|  blocker in hypertensive patients. Br J Clin Pharmacol 1982 Jun;|2
00173|050|R|  13(6):865-70.|2
00173|051|R|5.Minipress (prazosin hydrochloride) US prescribing information. Pfizer Inc.|1
00173|052|R|  February, 2015.|1
00173|053|R|6.Hytrin (terazosin hydrochloride) US prescribing information. Abbott|1
00173|054|R|  Laboratories July, 2009.|1
00173|055|R|7.Cardura (doxazosin hydrochloride) US prescribing information. Pfizer, Inc.|1
00173|056|R|  June, 2016.|1
00173|057|R|8.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
00173|058|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
00174|001|T|MONOGRAPH TITLE:  Carbamazepine/Danazol|
00174|002|B||
00174|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00174|004|L|take action as needed.|
00174|005|B||
00174|006|A|MECHANISM OF ACTION:  Danazol-induced inhibition of CYP3A4, resulting in a|
00174|007|A|decrease in carbamazepine metabolism.|
00174|008|B||
00174|009|E|CLINICAL EFFECTS:  May see an increase in the pharmacologic activity of|
00174|010|E|carbamazepine, including carbamazepine toxicity.|
00174|011|B||
00174|012|P|PREDISPOSING FACTORS:  None determined.|
00174|013|B||
00174|014|M|PATIENT MANAGEMENT:  It may be necessary to reduce the dose of carbamazepine|
00174|015|M|during concurrent administration of danazol. Monitor serum carbamazepine|
00174|016|M|levels and monitor the patient for symptoms of carbamazepine toxicity.|
00174|017|M|Adjust the dose accordingly.|
00174|018|B||
00174|019|D|DISCUSSION:  In six patients with epilepsy and fibrocystic breast disease|
00174|020|D|the concentration in serum of antiepileptic drugs was obtained before,|
00174|021|D|during, and after danazol therapy. (1) Carbamazepine serum level increased|
00174|022|D|almost twofold in the presence of danazol. Danazol led to a pronounced|
00174|023|D|inhibition of CBZ metabolism in an epileptic patient. (2) During danazol|
00174|024|D|coadministration, CBZ elimination half-life increased from a pretreatment|
00174|025|D|value of 11 to 24.3 h. Carbamazepine plasma clearance decreased from 57.7 to|
00174|026|D|23.2 ml/h/kg. Observations in five other female patients confirm that the|
00174|027|D|steady-state plasma concentrations of CBZ increase between 50 and 100%|
00174|028|D|during coadministration of danazol.|
00174|029|B||
00174|030|R|REFERENCES:|
00174|031|B||
00174|032|R|1.Kramer G, Theisohn M, von Unruh GE, Eichelbaum M. Carbamazepine-danazol|3
00174|033|R|  drug interaction: its mechanism examined by a stable isotope technique.|3
00174|034|R|  Ther Drug Monit 1986;8(4):387-92.|3
00174|035|R|2.Zielinski JJ, Lichten EM, Haidukewych D. Clinically significant|2
00174|036|R|  danazol-carbamazepine interaction. Ther Drug Monit 1987;9(1):24-7.|2
00174|037|R|3.Anonymous. Danazol-carbamazepine interaction. Int Pharm J 1988;2(1):4-5.|3
00174|038|R|4.Hayden M, Buchanan N. Danazol-carbamazepine interaction. Med J Aust 1991|3
00174|039|R|  Dec 2-16;155(11-12):851.|3
00175|001|T|MONOGRAPH TITLE:  Acetazolamide; Methazolamide/Aspirin (Greater Than 100|
00175|002|T|mg); Salicylates|
00175|003|B||
00175|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00175|005|L|take action as needed.|
00175|006|B||
00175|007|A|MECHANISM OF ACTION:  Acetazolamide and methazolamide may reduce blood pH,|
00175|008|A|causing a shift of salicylates from plasma into tissues (eg, central nervous|
00175|009|A|system). Alternatively, toxicity may be due to salicylate-induced|
00175|010|A|displacement of the carbonic anhydrase inhibitor from its protein binding|
00175|011|A|sites and inhibition of renal tubular secretion.|
00175|012|B||
00175|013|E|CLINICAL EFFECTS:  An increase in the pharmacologic effects of salicylates|
00175|014|E|with possible toxicity may occur.|
00175|015|B||
00175|016|P|PREDISPOSING FACTORS:  High doses of salicylates, low body weight.|
00175|017|B||
00175|018|M|PATIENT MANAGEMENT:  Avoid the combination if possible. If it is necessary|
00175|019|M|to administer these drugs concurrently, monitor salicylate levels and|
00175|020|M|monitor the patient for symptoms of toxicity. Adjust the dose as needed.|
00175|021|B||
00175|022|D|DISCUSSION:  Two young patients with unimpaired renal and hepatic function|
00175|023|D|were found to have developed metabolic acidosis after treatment for glaucoma|
00175|024|D|and joint pain with a combination of salicylates and carbonic anhydrase|
00175|025|D|inhibitors in normal doses.(1)|
00175|026|D|   A 67-year old woman and a 75-year old woman taking carbonic anhydrase|
00175|027|D|inhibitors for therapy of glaucoma and high doses of aspirin for arthritis|
00175|028|D|developed severe acid-base imbalance and salicylate intoxication.(2)|
00175|029|D|Neither patient exhibited ill effects when taking high aspirin doses without|
00175|030|D|a carbonic anhydrase inhibitor.  Carbonic anhydrase inhibitor-induced|
00175|031|D|acidemia increases the risk of developing salicylate intoxication in|
00175|032|D|patients receiving high aspirin doses.|
00175|033|D|   Two elderly patients, who were chronically receiving aspirin developed|
00175|034|D|lethargy, incontinence, and confusion after dosing with acetazolamide.(3)|
00175|035|D|These effects could have been due to either drug (see mechanism).|
00175|036|B||
00175|037|R|REFERENCES:|
00175|038|B||
00175|039|R|1.Cowan RA, Hartnell GG, Lowdell CP, Baird IM, Leak AM. Metabolic acidosis|3
00175|040|R|  induced by carbonic anhydrase inhibitors and salicylates in patients with|3
00175|041|R|  normal renal function. Br Med J (Clin Res Ed) 1984 Aug 11;289(6441):347-8.|3
00175|042|R|2.Anderson CJ, Kaufman PL, Sturm RJ. Toxicity of combined therapy with|3
00175|043|R|  carbonic anhydrase inhibitors and aspirin. Am J Ophthalmol 1978 Oct;|3
00175|044|R|  86(4):516-9.|3
00175|045|R|3.Sweeney KR, Chapron DJ, Brandt JL, Gomolin IH, Feig PU, Kramer PA. Toxic|3
00175|046|R|  interaction between acetazolamide and salicylate: case reports and a|3
00175|047|R|  pharmacokinetic explanation. Clin Pharmacol Ther 1986 Nov;40(5):518-24.|3
00176|001|T|MONOGRAPH TITLE:  Penicillins/Tetracyclines (mono deleted 02/24/2022)|
00176|002|B||
00176|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00176|004|L|take action as needed.|
00176|005|B||
00176|006|A|MECHANISM OF ACTION:  Tetracycline may interfere with the antibacterial|
00176|007|A|action of penicillin.|
00176|008|B||
00176|009|E|CLINICAL EFFECTS:  May see a decrease in the bactericidal activity of|
00176|010|E|penicillin.|
00176|011|B||
00176|012|P|PREDISPOSING FACTORS:  Doses of either drug at the low end of the|
00176|013|P|therapeutic range.|
00176|014|B||
00176|015|M|PATIENT MANAGEMENT:  Avoid concurrent administration of penicillin and|
00176|016|M|tetracycline. If it is essential that this drug combination be administered,|
00176|017|M|separate the dosing of each agent by as long an interval as possible.|
00176|018|B||
00176|019|D|DISCUSSION:  Coadministration of penicillin and tetracycline have been|
00176|020|D|reported to increase morbidity and mortality in patients with pneumococcal|
00176|021|D|meningitis or scarlatina. Additional documentation is needed to fully assess|
00176|022|D|the clinical significance of this interaction.|
00176|023|B||
00176|024|R|REFERENCES:|
00176|025|B||
00176|026|R|1.Lepper MH, Dowling HF. Treatment of pneumococcic meningitis with|2
00176|027|R|  penicillin compared with penicillin plus aureomycin. Am Med Assoc Arch|2
00176|028|R|  Intern Med 1951;88:489-94.|2
00176|029|R|2.Olsson RA, Kirby JC, Romansky MJ. Pneumococcal meningitis in the adult.|6
00176|030|R|  Clinical, therapeutic, and prognostic aspects in forty-three patients. Ann|6
00176|031|R|  Intern Med 1961 Oct;55(4):545-9.|6
00177|001|T|MONOGRAPH TITLE:  Oral Contraceptives/Penicillins|
00177|002|B||
00177|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00177|004|L|take action as needed.|
00177|005|B||
00177|006|A|MECHANISM OF ACTION:  Estrogens and progesterones are extensively excreted|
00177|007|A|in bile, principally as glycuronide conjugates.  Subsequently, they undergo|
00177|008|A|enterohepatic circulation where bacterial hydrolysis occurs, allowing for|
00177|009|A|reabsorption of the oral contraceptives through the bowel wall and eventual|
00177|010|A|urinary excretion.  Treatment with antibiotics destroys the gut flora and|
00177|011|A|prevents steroid reabsorption, resulting in lower than normal concentrations|
00177|012|A|of the contraceptive and excretion via the feces rather than the urine.|
00177|013|B||
00177|014|E|CLINICAL EFFECTS:  May observe reduced pharmacologic effects of oral|
00177|015|E|contraceptives with resultant breakthrough bleeding and pregnancy.  Reduced|
00177|016|E|effects may be seen for several days after discontinuation of antibiotic|
00177|017|E|therapy.|
00177|018|B||
00177|019|P|PREDISPOSING FACTORS:  None determined.|
00177|020|B||
00177|021|M|PATIENT MANAGEMENT:  Current guidelines suggest that additional precautions|
00177|022|M|are not necessary when non-enzyme inducing antibiotics are used concurrently|
00177|023|M|with hormonal contraceptives; however, some patients may still prefer to use|
00177|024|M|an additional method of contraception.|
00177|025|B||
00177|026|D|DISCUSSION:  Evidence for this interaction is limited and conflicting;|
00177|027|D|however, the CDC and the Faculty of Sexual and Reproductive Healthcare|
00177|028|D|Clinical Effectiveness Unit no longer recommend use of a backup|
00177|029|D|contraceptive method during use of a non-enzyme inducing antibiotic.|
00177|030|D|   Reports of breakthrough bleeding and loss of contraceptive protection|
00177|031|D|leading to unwanted pregnancies have occurred in women taking oral|
00177|032|D|contraceptive agents who received concurrent ampicillin, amoxicillin,|
00177|033|D|penicillin G, or oxacillin.  Several studies have shown that the|
00177|034|D|administration of ampicillin or penicillin to pregnant and nonpregnant women|
00177|035|D|resulted in lowered urinary estrogen excretion, in some women as soon as|
00177|036|D|three days after ampicillin therapy began.  However in one small prospective|
00177|037|D|study, plasma ethinyl estradiol concentrations showed a tendency to decrease|
00177|038|D|during ampicillin administration on the third, fourth, and fifth morning of|
00177|039|D|ampicillin administration, but were never lower than pretreatment values. In|
00177|040|D|another small prospective study of women taking low dose combination|
00177|041|D|contraceptives, concurrent ampicillin therapy neither altered the plasma|
00177|042|D|levels nor the AUC of norethisterone and ethinyl estradiol.  In addition,|
00177|043|D|progesterone levels were in an anovulatory range.  In another prospective|
00177|044|D|study of 13 women taking long term oral contraceptive steroids, concurrent|
00177|045|D|ampicillin was not associated with any significant changes in plasma|
00177|046|D|concentrations of ethinyl estradiol, levonorgestrel, follicle stimulating|
00177|047|D|hormone or progesterone, although lower concentrations of ethinyl estradiol|
00177|048|D|were noted in two women.|
00177|049|B||
00177|050|R|REFERENCES:|
00177|051|B||
00177|052|R|1.Friedman CI, Huneke AL, Kim MH, Powell J. The effect of ampicillin on oral|2
00177|053|R|  contraceptive effectiveness. Obstet Gynecol 1980 Jan;55(1):33-7.|2
00177|054|R|2.Back DJ, Breckenridge AM, Crawford FE, MacIver M, Orme ML, Rowe PH.|6
00177|055|R|  Interindividual variation and drug interactions with hormonal steroid|6
00177|056|R|  contraceptives. Drugs 1981 Jan;21(1):46-61.|6
00177|057|R|3.DeSano EA Jr, Hurley SC. Possible interactions of antihistamines and|6
00177|058|R|  antibiotics with oral contraceptive effectiveness. Fertil Steril 1982 Jun;|6
00177|059|R|  37(6):853-4.|6
00177|060|R|4.Bainton R. Interaction between antibiotic therapy and contraceptive|3
00177|061|R|  medication. Oral Surg Oral Med Oral Pathol 1986 May;61(5):453-5.|3
00177|062|R|5.Silber TJ. Apparent oral contraceptive failure associated with antibiotic|3
00177|063|R|  administration. J Adolesc Health Care 1983 Dec;4(4):287-9.|3
00177|064|R|6.True RJ. Interactions between antibiotics and oral contraceptives. JAMA|6
00177|065|R|  1982 Mar 12;247(10):1408.|6
00177|066|R|7.Rubin DF. Antibiotics and oral contraceptives. Arch Dermatol 1981 Apr;|6
00177|067|R|  117(4):189.|6
00177|068|R|8.Trybuchowski H. Effect of ampicillin on the urinary output of steroidal|2
00177|069|R|  hormones in pregnant and non-pregnant women. Clin Chim Acta 1973 Apr 19;|2
00177|070|R|  45(1):9-18.|2
00177|071|R|9.Willman K, Pulkkinen MO. Reduced maternal plasma and urinary estriol|2
00177|072|R|  during ampicillin treatment. Am J Obstet Gynecol 1971 Mar 15;109(6):893-6.|2
00177|073|R|10.Sybulski S, Maughan GB. Effect of ampicillin administration on estradiol,|2
00177|074|R|   estriol, and cortisol levels in meternal plasma and on estriol levels in|2
00177|075|R|   urine. Am J Obstet Gynecol 1976 Feb 15;124(4):379-81.|2
00177|076|R|11.Boehm FH, DiPietro DL, Goss DA. The effect of ampicillin administration|2
00177|077|R|   on urinary estriol and serum estradiol in the normal pregnant patient. Am|2
00177|078|R|   J Obstet Gynecol 1974 May 1;119(1):98-103.|2
00177|079|R|12.Tikkanen MJ, Adlercreutz H, Pulkkinen MO. Effects of antibiotics on|2
00177|080|R|   oestrogen metabolism. Br Med J 1973 May 12;2(5862):369.|2
00177|081|R|13.Back DJ, Breckenridge AM, MacIver M, Orme M, Rowe PH, Staiger C, Thomas|2
00177|082|R|   E, Tjia J. The effects of ampicillin oral contraceptive steroids in|2
00177|083|R|   women. Br J Clin Pharmacol 1982 Jul;14(1):43-8.|2
00177|084|R|14.Joshi JV, Joshi UM, Sankholi GM, Krishna U, Mandlekar A, Chowdhury V,|2
00177|085|R|   Hazari K, Gupta K, Sheth UK, Saxena BN. A study of interaction of|2
00177|086|R|   low-dose combination oral contraceptive with Ampicillin and|2
00177|087|R|   Metronidazole. Contraception 1980 Dec;22(6):643-52.|2
00177|088|R|15.Adlercreutz H, Pulkkinen MO, Hamalainen EK, Korpela JT. Studies on the|2
00177|089|R|   role of intestinal bacteria in metabolism of synthetic and natural|2
00177|090|R|   steroid hormones. J Steroid Biochem 1984 Jan;20(1):217-29.|2
00177|091|R|16.Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness|6
00177|092|R|   Unit. Clinical guidance drug interactions with hormonal contraception.|6
00177|093|R|   January, 2011.|6
00177|094|R|17.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
00177|095|R|   Criteria for Contraceptive Use, 2010. MMWR Early Release 2010;59:1-86.|6
00178|001|T|MONOGRAPH TITLE:  Contraceptives/Tetracyclines; Tigecycline|
00178|002|B||
00178|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00178|004|L|take action as needed.|
00178|005|B||
00178|006|A|MECHANISM OF ACTION:  Not established.|
00178|007|B||
00178|008|E|CLINICAL EFFECTS:  Reduced pharmacologic effects of oral contraceptives with|
00178|009|E|resultant breakthrough bleeding and pregnancy may occur.|
00178|010|B||
00178|011|P|PREDISPOSING FACTORS:  None determined.|
00178|012|B||
00178|013|M|PATIENT MANAGEMENT:  Current guidelines suggest that additional precautions|
00178|014|M|are not necessary when non-enzyme inducing antibiotics are used concurrently|
00178|015|M|with hormonal contraceptives; however, some patients may still prefer to use|
00178|016|M|an additional method of contraception.|
00178|017|B||
00178|018|D|DISCUSSION:  Evidence for this interaction is limited and conflicting;|
00178|019|D|however, the CDC and the Faculty of Sexual and Reproductive Healthcare|
00178|020|D|Clinical Effectiveness Unit no longer recommend use of a backup|
00178|021|D|contraceptive method during use of a non-enzyme inducing antibiotic.|
00178|022|D|   Pregnancy has been reported following the addition of tetracycline to|
00178|023|D|oral contraceptive therapy.(1)|
00178|024|D|   In contrast, a study in 7 healthy women found no effect of tetracycline|
00178|025|D|on ethinyl estradiol or norethindrone levels.(2)|
00178|026|D|   A study in 24 healthy women found no significant effects of doxycycline|
00178|027|D|on ethinyl estradiol, norethindrone, or progesterone levels.  However, the|
00178|028|D|authors noted that there large inter-patient and inter-patient variability|
00178|029|D|in these levels and that the interaction may just manifest itself in a small|
00178|030|D|proportion of women.(3)|
00178|031|B||
00178|032|R|REFERENCES:|
00178|033|B||
00178|034|R|1.Bacon JF, Shenfield GM. Pregnancy attributable to interaction between|3
00178|035|R|  tetracycline and oral contraceptives. Br Med J 1980 Feb 2;280(6210):293.|3
00178|036|R|2.Murphy AA, Zacur HA, Charache P, Burkman RT. The effect of tetracycline on|2
00178|037|R|  levels of oral contraceptives. Am J Obstet Gynecol 1991 Jan;164(1 Pt|2
00178|038|R|  1):28-33.|2
00178|039|R|3.Neely JL, Abate M, Swinker M, D'Angio R. The effect of doxycycline on|2
00178|040|R|  serum levels of ethinyl estradiol, norethindrone, and endogenous|2
00178|041|R|  progesterone. Obstet Gynecol 1991 Mar;77(3):416-20.|2
00178|042|R|4.Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit.|6
00178|043|R|  Clinical guidance drug interactions with hormonal contraception. January,|6
00178|044|R|  2011.|6
00178|045|R|5.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
00178|046|R|  Criteria for Contraceptive Use, 2010. MMWR Early Release 2010;59:1-86.|6
00179|001|T|MONOGRAPH TITLE:  Halothane/Ketamine|
00179|002|B||
00179|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00179|004|L|take action as needed.|
00179|005|B||
00179|006|A|MECHANISM OF ACTION:  Halothane blocks the cardiovascular stimulating|
00179|007|A|effects of ketamine.|
00179|008|B||
00179|009|E|CLINICAL EFFECTS:  May see a decrease in cardiac output, pulse rate, and|
00179|010|E|blood pressure.|
00179|011|B||
00179|012|P|PREDISPOSING FACTORS:  None determined.|
00179|013|B||
00179|014|M|PATIENT MANAGEMENT:  During concurrent administration of these agents,|
00179|015|M|monitor blood pressure and cardiac function.|
00179|016|B||
00179|017|D|DISCUSSION:  Concomitant administration of ketamine and halothane|
00179|018|D|significantly alters the cardiovascular response to ketamine, resulting in|
00179|019|D|cardiac depression and hypotension. Administration of pressor agents may be|
00179|020|D|necessary.|
00179|021|B||
00179|022|R|REFERENCES:|
00179|023|B||
00179|024|R|1.Stanley TH. Blood-pressure and pulse-rate responses to ketamine during|2
00179|025|R|  general anesthesia. Anesthesiology 1973 Dec;39(6):648-9.|2
00179|026|R|2.Johnston RR, Miller RD, Way WL. The interaction of ketamine with|2
00179|027|R|  d-tubocurarine, pancuronium, and succinylcholine in man. Anesth Analg 1974|2
00179|028|R|  Jul-Aug;53(4):496-501.|2
00179|029|R|3.Bidwai AV, Stanley HT, Graves CL, Kawamura R, Sentker CR. The effects of|2
00179|030|R|  ketamine on cardiovascular dynamics during halothane and enflurane|2
00179|031|R|  anesthesia. Anesth Analg 1975 Sep-Oct;54(5):588-92.|2
00180|001|T|MONOGRAPH TITLE:  Ketamine/Tubocurarine|
00180|002|B||
00180|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00180|004|L|take action as needed.|
00180|005|B||
00180|006|A|MECHANISM OF ACTION:  Unknown.|
00180|007|B||
00180|008|E|CLINICAL EFFECTS:  May see an increase in the neuromuscular blocking effects|
00180|009|E|of tubocurarine, including profound sedation, respiratory depression, coma,|
00180|010|E|and/or death.|
00180|011|B||
00180|012|P|PREDISPOSING FACTORS:  None determined.|
00180|013|B||
00180|014|M|PATIENT MANAGEMENT:  If it is necessary to administer these drugs|
00180|015|M|concurrently, monitor respiratory function and adjust the dose of|
00180|016|M|tubocurarine accordingly.|
00180|017|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00180|018|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00180|019|M|unresponsiveness.|
00180|020|B||
00180|021|D|DISCUSSION:  Concomitant administration of ketamine and tubocurarine has|
00180|022|D|been shown to increase the neuromuscular blocking effects of tubocurarine.|
00180|023|D|Documentation from human studies is limited.|
00180|024|B||
00180|025|R|REFERENCES:|
00180|026|B||
00180|027|R|1.Johnston RR, Miller RD, Way WL. The interaction of ketamine with|2
00180|028|R|  d-tubocurarine, pancuronium, and succinylcholine in man. Anesth Analg 1974|2
00180|029|R|  Jul-Aug;53(4):496-501.|2
00180|030|R|2.Aronstam RS, Narayanan L, Wenger DA. Ketamine inhibition of ligand binding|5
00180|031|R|  to cholinergic receptors and ion channels. Eur J Pharmacol 1982 Mar 12;|5
00180|032|R|  78(3):367-70.|5
00181|001|T|MONOGRAPH TITLE:  Neuromuscular Blocking Agents/Polypeptide Antibiotics|
00181|002|B||
00181|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00181|004|L|take action as needed.|
00181|005|B||
00181|006|A|MECHANISM OF ACTION:  Synergistic pharmacologic activity. Polymyxin B|
00181|007|A|affects neuromuscular transmission by blocking acetylcholine receptors. Its|
00181|008|A|action is thus post-synaptic and the neuromuscular block has no antagonists.|
00181|009|A|Polymyxin B causes neostigmine resistance to d-tubocurarine blockade and|
00181|010|A|calcium resistance to the blockade evoked by aminoglycoside antibiotics|
00181|011|A|(1,2,3,4). A pre-synaptic mechanism may also be involved with decreased|
00181|012|A|release of acetylcholine.|
00181|013|B||
00181|014|E|CLINICAL EFFECTS:  May see an increase in the neuromuscular blocking|
00181|015|E|effects, including profound sedation, respiratory depression, coma, and/or|
00181|016|E|death.|
00181|017|B||
00181|018|P|PREDISPOSING FACTORS:  None determined.|
00181|019|B||
00181|020|M|PATIENT MANAGEMENT:  If it is necessary to administer these drugs|
00181|021|M|concurrently, do so with extreme caution. Monitor neuromuscular function and|
00181|022|M|adjust the dose of the neuromuscular blocking agent accordingly.|
00181|023|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00181|024|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00181|025|M|unresponsiveness.|
00181|026|B||
00181|027|D|DISCUSSION:  Concomitant administration of polypeptide antibiotics and|
00181|028|D|neuromuscular blocking agents has been shown to produce synergism of the|
00181|029|D|effects on skeletal muscles. Concurrent administration of these drugs has|
00181|030|D|been associated with prolonged respiratory depression, respiratory|
00181|031|D|paralysis, and apnea.  This interaction has been documented with|
00181|032|D|colistimethate, polymyxin B, bacitracin, and vancomycin.|
00181|033|B||
00181|034|R|REFERENCES:|
00181|035|B||
00181|036|R|1.Sobek V. Arrest of respiration induced by polypeptide antibiotics.|5
00181|037|R|  Arzneimittelforschung 1982;32(3):235-7.|5
00181|038|R|2.Durant NN, Lambert JJ. The action of polymyxin B at the frog neuromuscular|5
00181|039|R|  junction. Br J Pharmacol 1981 Jan;72(1):41-7.|5
00181|040|R|3.Fogdall RP, Miller RD. Prolongation of a pancuronium-induced|3
00181|041|R|  neuronmuscular blockade by polymyxin B. Anesthesiology 1974 Jan;|3
00181|042|R|  40(1):84-7.|3
00181|043|R|4.Fiekers JF. Neuromuscular block produced by polymyxin B: interaction with|5
00181|044|R|  end-plate channels. Eur J Pharmacol 1981 Mar 5;70(1):77-81.|5
00181|045|R|5.Timmerman JC, Long JP, Pittinger CB. Neuromuscular blocking properties of|5
00181|046|R|  various antibiotic agents. Tox Appl Pharmacol 1959;1:299-304.|5
00181|047|R|6.Zauder HL, Barton N, Bennett EJ, Lore J. Colistimethate as a cause of|3
00181|048|R|  postoperative apnoea. Can Anaesth Soc J 1966 Nov;13(6):607-10.|3
00181|049|R|7.Lindesmith LA, Baines RD Jr, Bigelow DB, Petty TL. Reversible respiratory|3
00181|050|R|  paralysis associated with polymyxin therapy. Ann Intern Med 1968 Feb;|3
00181|051|R|  68(2):318-27.|3
00181|052|R|8.Gebbie D. Colistimethate and curare: a case report. Anesth Analg 1971|3
00181|053|R|  Jan-Feb;50(1):109-11.|3
00181|054|R|9.Van Nyhuis LS, Miller RD, Fogdall RP. The interaction between|5
00181|055|R|  d-tubocurarine, pancuronium, polymyxin B, and neostigmine on neuromuscular|5
00181|056|R|  function. Anesth Analg 1976 Mar-Apr;55(2):224-8.|5
00181|057|R|10.Burkett L, Bikhazi GB, Thomas KC Jr, Rosenthal DA, Wirta MG, Foldes FF.|5
00181|058|R|   Mutual potentiation of the neuromuscular effects of antibiotics and|5
00181|059|R|   relaxants. Anesth Analg 1979 Mar-Apr;58(2):107-15.|5
00181|060|R|11.Chapple DJ, Clark JS, Hughes R. Interaction between atracurium and drugs|5
00181|061|R|   used in anaesthesia. Br J Anaesth 1983;55 Suppl 1:17S-22S.|5
00181|062|R|12.Kronenfeld MA, Thomas SJ, Turndorf H. Recurrence of neuromuscular|3
00181|063|R|   blockade after reversal of vecuronium in a patient receiving|3
00181|064|R|   polymyxin/amikacin sternal irrigation. Anesthesiology 1986 Jul;|3
00181|065|R|   65(1):93-4.|3
00181|066|R|13.Huang KC, Heise A, Shrader AK, Tsueda K. Vancomycin enhances the|3
00181|067|R|   neuromuscular blockade of vecuronium. Anesth Analg 1990 Aug;71(2):194-6.|3
00182|001|T|MONOGRAPH TITLE:  Anticholinesterases/Succinylcholine|
00182|002|B||
00182|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00182|004|L|take action as needed.|
00182|005|B||
00182|006|A|MECHANISM OF ACTION:  Anticholinesterases inhibit plasma cholinesterases,|
00182|007|A|delaying succinylcholine hydrolysis and prolonging its duration of action.|
00182|008|B||
00182|009|E|CLINICAL EFFECTS:  May see an increase in the neuromuscular blocking effects|
00182|010|E|of succinylcholine, producing profound sedation, respiratory depression,|
00182|011|E|coma, and/or death.|
00182|012|B||
00182|013|P|PREDISPOSING FACTORS:  None determined.|
00182|014|B||
00182|015|M|PATIENT MANAGEMENT:  Avoid concurrent administration of anticholinesterases|
00182|016|M|and succinylcholine in patients with depolarizing type (phase I)|
00182|017|M|neuromuscular blockade. In addition, use with caution in the presence of a|
00182|018|M|nondepolarizing type (phase II) blockade.|
00182|019|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00182|020|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00182|021|M|unresponsiveness.|
00182|022|B||
00182|023|D|DISCUSSION:  Concomitant administration of anticholinesterases and|
00182|024|D|succinylcholine has been associated with prolonged respiratory depression|
00182|025|D|and apnea.|
00182|026|B||
00182|027|R|REFERENCES:|
00182|028|B||
00182|029|R|1.Vickers MDA. The mismanagement of suxamethonium apnoea. Br J Anaesth 1963;|3
00182|030|R|  35(4):260-8.|3
00182|031|R|2.Gissen AJ, Katz RL, Karis JH, Papper EM. Neuromuscular block in man during|2
00182|032|R|  prolonged arterial infusion with succinylcholine. Anesthesiology 1966|2
00182|033|R|  May-Jun;27(3):242-9.|2
00182|034|R|3.Miller RD, Stevens WC. Antagonism of succinylcholine paralysis in a|3
00182|035|R|  patient with atypical pseudocholinesterase. Anesthesiology 1972 May;|3
00182|036|R|  36(5):511-3.|3
00182|037|R|4.Baraka A. Potentiation of suxamethonium blockade by neostigmine in|3
00182|038|R|  patients with atypical cholinesterase. Br J Anaesth 1975 Mar;47(3):416-8.|3
00182|039|R|5.Bentz EW, Stoelting RK. Prolonged response to succinylcholine following|3
00182|040|R|  pancuronium reversal with pyridostigmine. Anesthesiology 1976 Mar;|3
00182|041|R|  44(3):258-60.|3
00182|042|R|6.Baraka A. Suxamethonium-neostigmine interaction in patients with normal or|2
00182|043|R|  atypical cholinesterase. Br J Anaesth 1977 May;49(5):479-84.|2
00182|044|R|7.Kopman AF, Strachovsky G, Lichtenstein L. Prolonged response to|3
00182|045|R|  succinylcholine following physostigmine. Anesthesiology 1978 Aug;|3
00182|046|R|  49(2):142-3.|3
00183|001|T|MONOGRAPH TITLE:  Ketoconazole/Corticosteroids (mono deleted 05/01/2008)|
00183|002|B||
00183|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00183|004|L|take action as needed.|
00183|005|B||
00183|006|A|MECHANISM OF ACTION:  Unknown. However, it is suspected that the mechanism|
00183|007|A|involves impairment of methylprednisolone metabolism and supression of|
00183|008|A|endogenous cortisol output by ketoconazole.|
00183|009|B||
00183|010|E|CLINICAL EFFECTS:  May see an increase in the pharmacologic effects of|
00183|011|E|methylprednisolone with a possible increase in side effects.|
00183|012|B||
00183|013|P|PREDISPOSING FACTORS:  None determined.|
00183|014|B||
00183|015|M|PATIENT MANAGEMENT:  If both drugs are administered concurrently, it may be|
00183|016|M|necessary to reduce the dosage of methylprednisolone.|
00183|017|B||
00183|018|D|DISCUSSION:  In a study of six healthy males, oral administration of|
00183|019|D|ketoconazole, 200 mg daily, significantly increased the area under the|
00183|020|D|concentration-time curve and mean residence time of methylprednisolone, 20|
00183|021|D|mg IV. Methylprednisolone clearance decreased by an average of 57% while the|
00183|022|D|volume of distribution and terminal slope decreased by 23% and 37%|
00183|023|D|respectively. Prednisolone, unlike methylprednisolone, may not be affected|
00183|024|D|by ketoconazole.|
00183|025|B||
00183|026|R|REFERENCES:|
00183|027|B||
00183|028|R|1.Glynn AM, Slaughter RL, Brass C, D'Ambrosio R, Jusko WJ. Effects of|2
00183|029|R|  ketoconazole on methylprednisolone pharmacokinetics and cortisol|2
00183|030|R|  secretion. Clin Pharmacol Ther 1986 Jun;39(6):654-9.|2
00183|031|R|2.Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ. Ketoconazole effects on|2
00183|032|R|  methylprednisolone disposition and their joint suppression of endogenous|2
00183|033|R|  cortisol. Clin Pharmacol Ther 1987 Oct;42(4):465-70.|2
00183|034|R|3.Zurcher RM, Frey BM, Frey FJ. Impact of ketoconazole on the metabolism of|2
00183|035|R|  prednisolone. Clin Pharmacol Ther 1989 Apr;45(4):366-72.|2
00183|036|R|4.Jasko WJ. Ketoconazole effects on corticosteroid disposition. Clin|6
00183|037|R|  Pharmacol Ther 1990 Mar;47(3):418-21.|6
00183|038|R|5.Zurcher RM, Frey BM, Frey FJ. Ketoconazole effects on corticosteroid|6
00183|039|R|  disposition (reply). Clin Pharmacol Ther 1990 Mar;47(3):419-21.|6
00183|040|R|6.Yamashita SK, Ludwig EA, Middleton E Jr, Jusko WJ. Lack of pharmacokinetic|2
00183|041|R|  and pharmacodynamic interactions between ketoconazole and prednisolone.|2
00183|042|R|  Clin Pharmacol Ther 1991 May;49(5):558-70.|2
00184|001|T|MONOGRAPH TITLE:  Beta-Blockers, Oral/Rifamycins|
00184|002|B||
00184|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00184|004|L|take action as needed.|
00184|005|B||
00184|006|A|MECHANISM OF ACTION:  Rifampin is a well recognized enzyme inducer that|
00184|007|A|increases the clearance of many drugs that are metabolized.(1) Beta-blockers|
00184|008|A|that are extensively metabolized may be affected by rifampin.|
00184|009|B||
00184|010|E|CLINICAL EFFECTS:  Decreased pharmacologic effects of certain beta-blockers.|
00184|011|B||
00184|012|P|PREDISPOSING FACTORS:  Dose ranging of rifampin did not suggest a dose|
00184|013|P|proportional interaction.(2)|
00184|014|B||
00184|015|M|PATIENT MANAGEMENT:  Monitor the patient's response to beta-blocker therapy|
00184|016|M|when starting or stopping treatment with rifampin and adjust the dose|
00184|017|M|accordingly.|
00184|018|B||
00184|019|D|DISCUSSION:  Controlled studies involving healthy volunteers have|
00184|020|D|demonstrated rifampin to increase the clearance of metoprolol and|
00184|021|D|propranolol by more than two fold.(2),(3),(4) Steady state plasma|
00184|022|D|concentrations of propranolol were also reduced. The elimination half-life|
00184|023|D|and protein binding of propranolol were not altered by rifampin.|
00184|024|D|   In a study in eight subjects, the concurrent administration of rifampin|
00184|025|D|and carvedilol decreased carvedilol concentrations by 70%.(5)|
00184|026|B||
00184|027|R|REFERENCES:|
00184|028|B||
00184|029|R|1.Branch RA, Herman RJ. Enzyme induction and beta-adrenergic receptor|6
00184|030|R|  blocking drugs. Br J Clin Pharmacol 1984;17 Suppl 1:77S-84S.|6
00184|031|R|2.Herman RJ, Nakamura K, Wilkinson GR, Wood AJ. Induction of propranolol|2
00184|032|R|  metabolism by rifampicin. Br J Clin Pharmacol 1983 Nov;16(5):565-9.|2
00184|033|R|3.Bennett PN, John VA, Whitmarsh VB. Effect of rifampicin on metoprolol and|2
00184|034|R|  antipyrine kinetics. Br J Clin Pharmacol 1982 Mar;13(3):387-91.|2
00184|035|R|4.Shaheen O, Biollaz J, Koshakji RP, Wilkinson GR, Wood AJ. Influence of|4
00184|036|R|  debrisoquin phenotype on the inducibility of propranolol metabolism. Clin|4
00184|037|R|  Pharmacol Ther 1989 Apr;45(4):439-43.|4
00184|038|R|5.Coreg (carvedilol) US prescribing information. GlaxoSmithKline July, 2011.|1
00186|001|T|MONOGRAPH TITLE:  Digoxin, Oral/Macrolide Antibiotics|
00186|002|B||
00186|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00186|004|L|of severe adverse interaction.|
00186|005|B||
00186|006|A|MECHANISM OF ACTION:  Macrolides may alter the bacterial flora in the GI|
00186|007|A|tract, increasing the bioavailability of digoxin.  Some macrolides may|
00186|008|A|inhibit the transport of digoxin by p-glycoprotein in the intestines and|
00186|009|A|kidneys.|
00186|010|B||
00186|011|E|CLINICAL EFFECTS:  Digoxin serum levels may be elevated (up to 2-fold),|
00186|012|E|producing increased therapeutic and adverse effects.   Symptoms of digoxin|
00186|013|E|toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise,|
00186|014|E|drowsiness, generalized muscle weakness, disorientation, hallucinations,|
00186|015|E|visual disturbances, and arrhythmias. The effects of macrolides on the GI|
00186|016|E|flora may persist for several months.|
00186|017|B||
00186|018|P|PREDISPOSING FACTORS:  The increase in serum levels is greatest with those|
00186|019|P|digoxin products with the lowest bioavailability and may not be clinically|
00186|020|P|significant in patients taking digoxin elixir.  Low body weight, advanced|
00186|021|P|age, impaired renal function, hypokalemia, hypercalcemia, and/or|
00186|022|P|hypomagnesemia may increase the risk of digoxin toxicity.|
00186|023|B||
00186|024|M|PATIENT MANAGEMENT:  Monitor digoxin serum levels during concurrent|
00186|025|M|macrolide therapy and adjust the dose as needed.  The dosage of digitalis|
00186|026|M|glycoside may need to be decreased by 30-50% or the frequency of|
00186|027|M|administration may be reduced.|
00186|028|B||
00186|029|D|DISCUSSION:  In a retrospective review, azithromycin, clarithromycin, and|
00186|030|D|erythromycin use were associated with a 3.7-fold, 7.9-fold, and 3.7-fold|
00186|031|D|increased risk of digoxin toxicity.(1)|
00186|032|D|   In a retrospective review, clarithromycin prescription at 7, 14, and 30|
00186|033|D|days prior was associated with a 4.36-fold, 5.07-fold, and 2.98-fold|
00186|034|D|increase in risk of hospitalization for digoxin toxicity.(2)|
00186|035|D|   In a clinical trial in 12 healthy males, clarithromycin (250 mg twice|
00186|036|D|daily for 3 days) increased the area-under-curve (AUC) of a single oral dose|
00186|037|D|of digoxin by 1.7-fold.  Clarithromycin increased the AUC of intravenous|
00186|038|D|digoxin by 1.2-fold.(3)|
00186|039|D|   In a study in 7 patients with congestive heart failure, clarithromycin|
00186|040|D|therapy increased digoxin levels by 70%.(4)|
00186|041|D|   In a study in elderly patients taking digoxin, clarithromycin decreased|
00186|042|D|digoxin renal clearance by 56-60%.(5)|
00186|043|D|   In a study in 9 healthy males, clarithromycin and erythromycin had no|
00186|044|D|effect on levels of intravenous digoxin.(6)|
00186|045|D|   In a study in 3 subjects, erythromycin increased serum digoxin|
00186|046|D|concentrations 2-fold.(7)|
00186|047|D|   Telithromycin has been shown to increase digoxin maximum concentration|
00186|048|D|(Cmax) and trough levels (Cmin) by 73% and 21%, respectively.(8)|
00186|049|D|   Elevated digoxin levels and toxicity have been reported during concurrent|
00186|050|D|therapy with azithromycin,(9) clarithromycin,(10-25) erythromycin,(26-30)|
00186|051|D|josamycin,(31) roxithromycin,(32) and telithromycin.(33)|
00186|052|D|   Approximately 10% of the patients receiving digoxin excrete significant|
00186|053|D|amounts of inactive digoxin metabolites.(7)  Since bacterial flora in the GI|
00186|054|D|tract are involved with the conversion of cardioactive digoxin to the|
00186|055|D|inactive metabolite, administration of macrolides as well as other|
00186|056|D|antibiotics may alter the bacterial flora, interfering with the conversion|
00186|057|D|process.  These 10% of the patients are at additional risk of elevated|
00186|058|D|digoxin levels due to the drug interaction.|
00186|059|D|   Concomitant administration of erythromycin and digoxin caused digoxin|
00186|060|D|serum concentration to increase 100%. (34)|
00186|061|B||
00186|062|R|REFERENCES:|
00186|063|B||
00186|064|R|1.Gomes T, Mamdani MM, Juurlink DN. Macrolide-induced digoxin toxicity: a|2
00186|065|R|  population-based study. Clin Pharmacol Ther 2009 Oct;86(4):383-6.|2
00186|066|R|2.Chan AL, Wang MT, Su CY, Tsai FH. Risk of digoxin intoxication caused by|2
00186|067|R|  clarithromycin-digoxin interactions in heart failure patients: a|2
00186|068|R|  population-based study. Eur J Clin Pharmacol 2009 Dec;65(12):1237-43.|2
00186|069|R|3.Rengelshausen J, Goggelmann C, Burhenne J, Riedel KD, Ludwig J, Weiss J,|2
00186|070|R|  Mikus G, Walter-Sack I, Haefeli WE. Contribution of increased oral|2
00186|071|R|  bioavailability and reduced nonglomerular renal clearance of digoxin to|2
00186|072|R|  the digoxin-clarithromycin interaction. Br J Clin Pharmacol 2003 Jul;|2
00186|073|R|  56(1):32-8.|2
00186|074|R|4.Tanaka H, Matsumoto K, Ueno K, Kodama M, Yoneda K, Katayama Y, Miyatake K.|2
00186|075|R|  Effect of clarithromycin on steady-state digoxin concentrations. Ann|2
00186|076|R|  Pharmacother 2003 Feb;37(2):178-81.|2
00186|077|R|5.Zapater P, Reus S, Tello A, Torrus D, Perez-Mateo M, Horga JF. A|2
00186|078|R|  prospective study of the clarithromycin-digoxin interaction in elderly|2
00186|079|R|  patients. J Antimicrob Chemother 2002 Oct;50(4):601-6.|2
00186|080|R|6.Tsutsumi K, Kotegawa T, Kuranari M, Otani Y, Morimoto T, Matsuki S, Nakano|2
00186|081|R|  S. The effect of erythromycin and clarithromycin on the pharmacokinetics|2
00186|082|R|  of intravenous digoxin in healthy volunteers. J Clin Pharmacol 2002 Oct;|2
00186|083|R|  42(10):1159-64.|2
00186|084|R|7.Lindenbaum J, Rund DG, Butler VP Jr, Tse-Eng D, Saha JR. Inactivation of|2
00186|085|R|  digoxin by the gut flora: reversal by antibiotic therapy. N Engl J Med|2
00186|086|R|  1981 Oct 1;305(14):789-94.|2
00186|087|R|8.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
00186|088|R|  November, 2015.|1
00186|089|R|9.Thalhammer F, Hollenstein UM, Locker GJ, Janata K, Sunder-Plassmann G,|3
00186|090|R|  Frass M, Burgmann H. Azithromycin-related toxic effects of digitoxin. Br J|3
00186|091|R|  Clin Pharmacol 1998 Jan;45(1):91-2.|3
00186|092|R|10.Hirata S, Izumi S, Furukubo T, Ota M, Fujita M, Yamakawa T, Hasegawa I,|3
00186|093|R|   Ohtani H, Sawada Y. Interactions between clarithromycin and digoxin in|3
00186|094|R|   patients with end-stage renal disease. Int J Clin Pharmacol Ther 2005|3
00186|095|R|   Jan;43(1):30-6.|3
00186|096|R|11.Vergara-Lopez S, Garcia-Garcia JA, Merchante N, Mira JA. Digoxin toxicity|3
00186|097|R|   secondary to inhibition of digoxin intestinal metabolism in a patient|3
00186|098|R|   receiving clarithromycin. Med Clin (Barc) 2004 Nov 6;123(16):639.|3
00186|099|R|12.Kiran N, Azam S, Dhakam S. Clarithromycin induced digoxin toxicity: case|3
00186|100|R|   report and review. J Pak Med Assoc 2004 Aug;54(8):440-1.|3
00186|101|R|13.Xu H, Rashkow A. Clarithromycin-induced digoxin toxicity: a case report|3
00186|102|R|   and a review of the literature. Conn Med 2001 Sep;65(9):527-9.|3
00186|103|R|14.Gooderham MJ, Bolli P, Fernandez PG. Concomitant digoxin toxicity and|3
00186|104|R|   warfarin interaction in a patient receiving clarithromycin. Ann|3
00186|105|R|   Pharmacother 1999 Jul-Aug;33(7-8):796-9.|3
00186|106|R|15.Wakasugi H, Yano I, Ito T, Hashida T, Futami T, Nohara R, Sasayama S,|3
00186|107|R|   Inui K. Effect of clarithromycin on renal excretion of digoxin:|3
00186|108|R|   interaction with P-glycoprotein. Clin Pharmacol Ther 1998 Jul;|3
00186|109|R|   64(1):123-8.|3
00186|110|R|16.Nordt SP, Williams SR, Manoguerra AS, Clark RF. Clarithromycin induced|3
00186|111|R|   digoxin toxicity. J Accid Emerg Med 1998 May;15(3):194-5.|3
00186|112|R|17.Trivedi S, Hyman J, Lichstein E. Clarithromycin and digoxin toxicity. Ann|3
00186|113|R|   Intern Med 1998 Apr 1;128(7):604.|3
00186|114|R|18.Guerriero SE, Ehrenpreis E, Gallagher KL. Two cases of|3
00186|115|R|   clarithromycin-induced digoxin toxicity. Pharmacotherapy 1997 Sep-Oct;|3
00186|116|R|   17(5):1035-7.|3
00186|117|R|19.Laberge P, Martineau P. Clarithromycin-induced digoxin intoxication. Ann|3
00186|118|R|   Pharmacother 1997 Sep;31(9):999-1002.|3
00186|119|R|20.Nawarskas JJ, McCarthy DM, Spinler SA. Digoxin toxicity secondary to|3
00186|120|R|   clarithromycin therapy. Ann Pharmacother 1997 Jul-Aug;31(7-8):864-6.|3
00186|121|R|21.Guillemet C, Alt M, Arpin-Bott MP, Imler M. Clarithromycin-digoxin: an|3
00186|122|R|   unrecognized interaction in some patients. Presse Med 1997 Apr 5;|3
00186|123|R|   26(11):512.|3
00186|124|R|22.Brown BA, Wallace RJ Jr, Griffith DE, Warden R. Clarithromycin-associated|3
00186|125|R|   digoxin toxicity in the elderly. Clin Infect Dis 1997 Jan;24(1):92-3.|3
00186|126|R|23.Midoneck SR, Etingin OR. Clarithromycin-related toxic effects of digoxin.|3
00186|127|R|   N Engl J Med 1995 Nov 30;333(22):1505.|3
00186|128|R|24.Ford A, Smith LC, Baltch AL, Smith RP. Clarithromycin-induced digoxin|3
00186|129|R|   toxicity in a patient with AIDS. Clin Infect Dis 1995 Oct;21(4):1051-2.|3
00186|130|R|25.Bonilla Porras M, Lucena Campillo MA, Delgado Silveira E, Ramallal|3
00186|131|R|   Jimenez Del Llano MC, Garcia Diaz B. Digitalis intoxication secondary to|3
00186|132|R|   treatment with clarithromycin. Farm Hosp 2005 May-Jun;29(3):209-13.|3
00186|133|R|26.Maxwell DL, Gilmour-White SK, Hall MR. Digoxin toxicity due to|3
00186|134|R|   interaction of digoxin with erythromycin. BMJ 1989 Mar 4;298(6673):572.|3
00186|135|R|27.Zitelli BJ, Howrie DL, Altman H, Maroon TJ. Erythromycin-induced drug|3
00186|136|R|   interactions. An illustrative case and review of the literature. Clin|3
00186|137|R|   Pediatr (Phila) 1987 Mar;26(3):117-9.|3
00186|138|R|28.Norregaard-Hansen K, Klitgaard NA, Pedersen KE. The significance of the|3
00186|139|R|   enterohepatic circulation on the metabolism of digoxin in patients with|3
00186|140|R|   the ability of intestinal conversion of the drug. Acta Med Scand 1986;|3
00186|141|R|   220(1):89-92.|3
00186|142|R|29.Friedman HS, Bonventre MV. Erythromycin-induced digoxin toxicity. Chest|3
00186|143|R|   1982 Aug;82(2):202.|3
00186|144|R|30.Morton MR, Cooper JW. Erythromycin-induced digoxin toxicity. DICP 1989|3
00186|145|R|   Sep;23(9):668-70.|3
00186|146|R|31.Cambonie G, Sabatier E, Guillaumont S, Masson F, Charbit J, Pidoux O,|3
00186|147|R|   Hillaire-Buys D, Picaud JC. Digoxin-Josamycin: a dangerous drug|3
00186|148|R|   interaction in children. Arch Pediatr 2006 Aug;13(8):1118-20.|3
00186|149|R|32.Corallo CE, Rogers IR. Roxithromycin-induced digoxin toxicity. Med J Aust|3
00186|150|R|   1996 Oct 21;165(8):433-4.|3
00186|151|R|33.Nenciu LM, Laberge P, Thirion DJ. Telithromycin-induced digoxin toxicity|3
00186|152|R|   and electrocardiographic changes. Pharmacotherapy 2006 Jun;26(6):872-6.|3
00186|153|R|34.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00186|154|R|   Pharmaceuticals, Inc. August, 2018.|1
00187|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Thyroid; Dextrothyroxine (mono|
00187|002|T|deleted 02/23/2022)|
00187|003|B||
00187|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00187|005|L|take action as needed.|
00187|006|B||
00187|007|A|MECHANISM OF ACTION:  Unknown.|
00187|008|B||
00187|009|E|CLINICAL EFFECTS:  Decreased effectiveness of digitalis glycosides.|
00187|010|B||
00187|011|P|PREDISPOSING FACTORS:  None determined.|
00187|012|B||
00187|013|M|PATIENT MANAGEMENT:  May need higher doses of digitalis glycosides when|
00187|014|M|converting a hypothyroid patient to a euthyroid state.|
00187|015|B||
00187|016|D|DISCUSSION:  Several studies have indicated that larger doses of digitalis|
00187|017|D|glycosides may be required when converting a hypothyroid patient to a|
00187|018|D|euthyroid state. This effect may persist for several days after|
00187|019|D|discontinuing thyroid.|
00187|020|B||
00187|021|R|REFERENCES:|
00187|022|B||
00187|023|R|1.Frye RL, Braunwald E. Studies on digitalis. III. The influence of|2
00187|024|R|  triiodothyronine on digitalis requirements. Circulation 1961 Mar;|2
00187|025|R|  23:376-82.|2
00187|026|R|2.Doherty JE, Perkins WH. Digoxin metabolism in hypo- and hyperthyroidism.|3
00187|027|R|  Studies with tritiated digoxin in thyroid disease. Ann Intern Med 1966|3
00187|028|R|  Mar;64(3):489-507.|3
00187|029|R|3.Croxson MS, Ibbertson HK. Serum digoxin in patients with thyroid disease.|2
00187|030|R|  Br Med J 1975 Sep 6;3(5983):566-8.|2
00187|031|R|4.Lawrence JR, Sumner DJ, Kalk WJ, Ratcliffe WA, Whiting B, Gray K, Lindsay|2
00187|032|R|  M. Digoxin kinetics in patients with thyroid dysfunction. Clin Pharmacol|2
00187|033|R|  Ther 1977 Jul;22(1):7-13.|2
00187|034|R|5.Huffman DH, Klaassen CD, Hartman CR. Digoxin in hyperthyroidism. Clin|5
00187|035|R|  Pharmacol Ther 1977 Nov;22(5 Pt 1):533-8.|5
00187|036|R|6.Shenfield GM, Thompson J, Horn DB. Plasma and urinary digoxin in thyroid|2
00187|037|R|  dysfunction. Eur J Clin Pharmacol 1977 Dec 28;12(6):437-43.|2
00187|038|R|7.Bonelli J, Haydl H, Hruby K, Kaik G. The pharmacokinetics of digoxin in|2
00187|039|R|  patients with manifest hyperthyroidism and after normalization of thyroid|2
00187|040|R|  function. Int J Clin Pharmacol Biopharm 1978 Jul;16(7):302-6.|2
00188|001|T|MONOGRAPH TITLE:  Hydantoins/Selected Sulfonamide Antibacterials;|
00188|002|T|Trimethoprim|
00188|003|B||
00188|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00188|005|L|take action as needed.|
00188|006|B||
00188|007|A|MECHANISM OF ACTION:  Trimethoprim and selected sulfonamides may inhibit the|
00188|008|A|CYP2C9 mediated metabolism of phenytoin and possibly other hydantoins.|
00188|009|B||
00188|010|E|CLINICAL EFFECTS:  Concurrent use of trimethoprim or selected sulfonamides|
00188|011|E|may result in elevated levels of and toxicity from the hydantoin.|
00188|012|E|   Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin|
00188|013|E|toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia,|
00188|014|E|lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe|
00188|015|E|toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar|
00188|016|E|dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac|
00188|017|E|arrest) and may be fatal.|
00188|018|B||
00188|019|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
00188|020|P|hypoalbuminemia.|
00188|021|B||
00188|022|M|PATIENT MANAGEMENT:  Monitor the patient for signs of hydantoin toxicity|
00188|023|M|(e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy,|
00188|024|M|slurred speech, blurred vision, nausea, and vomiting). If available, monitor|
00188|025|M|hydantoin serum levels. Adjust the dose of hydantoins if needed.|
00188|026|B||
00188|027|D|DISCUSSION:  In a case-control cohort study, elderly patients hospitalized|
00188|028|D|due to phenytoin toxicity were more than twice as likely to have had|
00188|029|D|concurrent use of trimethoprim-sulfamethoxazole in the previous 30 days (729|
00188|030|D|subjects) as compared to concurrent use of amoxicillin in the previous 30|
00188|031|D|days (3148 subjects). The adjusted odds ratio was 2.11 with a 95% CI of|
00188|032|D|1.24, 3.60.|
00188|033|D|   In another study, concurrent administration of phenytoin and trimethoprim|
00188|034|D|as well as phenytoin and trimethoprim-sulfamethoxazole have been reported to|
00188|035|D|increase the half-life of phenytoin by 50% and 39%, respectively.|
00188|036|D|Concomitant administration of phenytoin with sulfamethoxazole alone produced|
00188|037|D|small increases in the half-life of phenytoin.|
00188|038|D|   The severity of this interaction appears to vary with the different|
00188|039|D|sulfonamides and is subject to large individual variability.|
00188|040|B||
00188|041|R|REFERENCES:|
00188|042|B||
00188|043|R|1.Hansen JM, Kampmann JP, Siersbaek-Nielsen K, Lumholtz IB, Arroe M,|5
00188|044|R|  Abildgaard U, Skovsted L. The effect of different sulfonamides on|5
00188|045|R|  phenytoin metabolism in man. Acta Med Scand Suppl 1979;624:106-10.|5
00188|046|R|2.Gillman MA, Sandyk R. Phenytoin toxicity and co-trimoxazole. Ann Intern|3
00188|047|R|  Med 1985 Apr;102(4):559.|3
00188|048|R|3.Antoniou T, Gomes T, Mamdani MM, Juurlink DN.|2
00188|049|R|  Trimethoprim/sulfamethoxazole-induced phenytoin toxicity in the elderly: a|2
00188|050|R|  population-based study. Br J Clin Pharmacol 2011 Apr;71(4):544-9.|2
00188|051|R|4.Lumholtz B, Siersbaek-Nielsen K, Skovsted L, Kampmann J, Hansen JM.|2
00188|052|R|  Sulfamethizole-induced inhibition of diphenlhydantoin, tolbutamide, and|2
00188|053|R|  warfarin metabolism. Clin Pharmacol Ther 1975 Jun;17(6):731-4.|2
00188|054|R|5.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00188|055|R|  March, 2022.|1
00189|001|T|MONOGRAPH TITLE:  Neuromuscular Blocking Agents/Trimethaphan|
00189|002|B||
00189|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00189|004|L|take action as needed.|
00189|005|B||
00189|006|A|MECHANISM OF ACTION:  Additive pharmacologic effects.|
00189|007|B||
00189|008|E|CLINICAL EFFECTS:  May see an increase in the neuromuscular blocking|
00189|009|E|effects, including profound sedation, respiratory depression, coma, and/or|
00189|010|E|death.|
00189|011|B||
00189|012|P|PREDISPOSING FACTORS:  None determined.|
00189|013|B||
00189|014|M|PATIENT MANAGEMENT:  If it is necessary to administer these drugs|
00189|015|M|concurrently, do so with extreme caution. Monitor neuromuscular function and|
00189|016|M|adjust the dose of the neuromuscular blocking agent accordingly.|
00189|017|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00189|018|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00189|019|M|unresponsiveness.|
00189|020|B||
00189|021|D|DISCUSSION:  Available data indicate that the neuromuscular blocking effects|
00189|022|D|of tubocurarine and trimethaphan may be additive.|
00189|023|B||
00189|024|R|REFERENCES:|
00189|025|B||
00189|026|R|1.Deacock AR, Davies TDW. The influence of certain ganglionic blocking|5
00189|027|R|  agents on neuromuscular transmission. Br J Anaesth 1958;30:217-25.|5
00189|028|R|2.Wilson SL, Miller RN, Wright C, Hasse D. Prolonged neuromuscular blockade|3
00189|029|R|  associated with trimethaphan: a case report. Anesth Analg 1976 May-Jun;|3
00189|030|R|  55(3):353-6.|3
00189|031|R|3.Nakamura K, Koide M, Imanaga T, Ogasawara H, Takahashi M, Yoshikawa M.|3
00189|032|R|  Prolonged neuromuscular blockade following trimetaphan infusion. A case|3
00189|033|R|  report and in vitro study of cholinesterase inhibition. Anaesthesia 1980|3
00189|034|R|  Dec;35(12):1202-7.|3
00190|001|T|MONOGRAPH TITLE:  Succinylcholine/Lidocaine (mono deleted 09/19/2008)|
00190|002|B||
00190|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00190|004|L|take action as needed.|
00190|005|B||
00190|006|A|MECHANISM OF ACTION:  Unknown.|
00190|007|B||
00190|008|E|CLINICAL EFFECTS:  The neuromuscular blocking activity of succinylcholine|
00190|009|E|may be increased, producing prolonged respiratory depression and apnea.|
00190|010|B||
00190|011|P|PREDISPOSING FACTORS:  None determined.|
00190|012|B||
00190|013|M|PATIENT MANAGEMENT:  If it is necessary to administer these drugs|
00190|014|M|concurrently, do so with extreme caution. Monitor neuromuscular function and|
00190|015|M|adjust the dose of the neuromuscular blocking agent accordingly.|
00190|016|B||
00190|017|D|DISCUSSION:  Available data indicate that bolus administration of high doses|
00190|018|D|of lidocaine prolong the neuromuscular activity of succinylcholine.|
00190|019|B||
00190|020|R|REFERENCE:|
00190|021|B||
00190|022|R|1.Usubiaga JE, Wikinski JA, Morales RL, Usubiaga LE. Interaction of|2
00190|023|R|  intravenously administered procaine, lidocaine and succinylcholine in|2
00190|024|R|  anesthetized subjects. Anesth Analg 1967 Jan-Feb;46(1):39-45.|2
00191|001|T|MONOGRAPH TITLE:  Theophyllines/Selected Quinolones|
00191|002|B||
00191|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00191|004|L|of severe adverse interaction.|
00191|005|B||
00191|006|A|MECHANISM OF ACTION:  Quinolones may inhibit the hepatic microsomal enzymes|
00191|007|A|responsible for the metabolism of theophyllines.|
00191|008|B||
00191|009|E|CLINICAL EFFECTS:  May see an increase in the pharmacologic and toxic|
00191|010|E|effects of theophylline due to elevated serum levels.  Fatalities have been|
00191|011|E|reported.|
00191|012|B||
00191|013|P|PREDISPOSING FACTORS:  Older age.|
00191|014|B||
00191|015|M|PATIENT MANAGEMENT:  Monitor theophylline serum levels and observe the|
00191|016|M|patient for symptoms of theophylline toxicity (e.g, nausea, seizure). Adjust|
00191|017|M|the dose of theophylline as needed.|
00191|018|B||
00191|019|D|DISCUSSION:  Several studies have demonstrated that quinolones (e.g.,|
00191|020|D|ciprofloxacin, enoxacin, norfloxacin) may increase serum theophylline levels|
00191|021|D|and decrease theophylline clearance. In addition, ciprofloxacin has been|
00191|022|D|reported to increase the half-life and volume of distribution of|
00191|023|D|theophylline. Theophylline toxicity has been associated with concurrent|
00191|024|D|administration of quinolone antibiotics. Some studies indicate that|
00191|025|D|norfloxacin does not interact with theophyllines.|
00191|026|B||
00191|027|R|REFERENCES:|
00191|028|B||
00191|029|R|1.Wijnands WJ, Vree TB, van Herwaarden CL. The influence of quinolone|2
00191|030|R|  derivatives on theophylline clearance. Br J Clin Pharmacol 1986 Dec;|2
00191|031|R|  22(6):677-83.|2
00191|032|R|2.Nix DE, DeVito JM, Whitbread MA, Schentag JJ. Effect of multiple dose oral|2
00191|033|R|  ciprofloxacin on the pharmacokinetics of theophylline and indocyanine|2
00191|034|R|  green. J Antimicrob Chemother 1987 Feb;19(2):263-9.|2
00191|035|R|3.Raoof S, Wollschlager C, Khan FA. Ciprofloxacin increases serum levels of|2
00191|036|R|  theophylline. Am J Med 1987 Apr 27;82(4A):115-8.|2
00191|037|R|4.Rybak MJ, Bowles SK, Chandrasekar PH, Edwards DJ. Increased theophylline|3
00191|038|R|  concentrations secondary to ciprofloxacin. Drug Intell Clin Pharm 1987|3
00191|039|R|  Nov;21(11):879-81.|3
00191|040|R|5.Thomson AH, Thomson GD, Hepburn M, Whiting B. A clinically significant|3
00191|041|R|  interaction between ciprofloxacin and theophylline. Eur J Clin Pharmacol|3
00191|042|R|  1987;33(4):435-6.|3
00191|043|R|6.Niki Y, Soejima R, Kawane H, Sumi M, Umeki S. New synthetic quinolone|2
00191|044|R|  antibacterial agents and serum concentration of theophylline. Chest 1987|2
00191|045|R|  Oct;92(4):663-9.|2
00191|046|R|7.Sano M, Yamamoto I, Ueda J, Yoshikawa E, Yamashina H, Goto M. Comparative|2
00191|047|R|  pharmacokinetics of theophylline following two fluoroquinolones|2
00191|048|R|  co-administration. Eur J Clin Pharmacol 1987;32(4):431-2.|2
00191|049|R|8.Sano M, Kawakatsu K, Ohkita C, Yamamoto I, Takeyama M, Yamashina H, Goto|2
00191|050|R|  M. Effects of enoxacin, ofloxacin and norfloxacin on theophylline|2
00191|051|R|  disposition in humans. Eur J Clin Pharmacol 1988;35(2):161-5.|2
00191|052|R|9.Holden R. Probable fatal interaction between ciprofloxacin and|3
00191|053|R|  theophylline. BMJ 1988 Nov 19;297(6659):1339.|3
00191|054|R|10.Bachmann KA, Schwartz JI, Jauregui L. Predicting the|2
00191|055|R|   ciprofloxacin-theophylline interaction from single plasma theophylline|2
00191|056|R|   measurements. Br J Clin Pharmacol 1988 Aug;26(2):191-4.|2
00191|057|R|11.Davis RL, Kelly HW, Quenzer RW, Standefer J, Steinberg B, Gallegos J.|2
00191|058|R|   Effect of norfloxacin on theophylline metabolism. Antimicrob Agents|2
00191|059|R|   Chemother 1989 Feb;33(2):212-4.|2
00191|060|R|12.Robson RA, Begg EJ, Atkinson HC, Saunders DA, Frampton CM. Comparative|2
00191|061|R|   effects of ciprofloxacin and lomefloxacin on the oxidative metabolism of|2
00191|062|R|   theophylline. Br J Clin Pharmacol 1990 Apr;29(4):491-3.|2
00191|063|R|13.Semel JD, Allen N. Seizures in patients simultaneously receiving|3
00191|064|R|   theophylline and imipenem or ciprofloxacin or metronidazole. South Med J|3
00191|065|R|   1991 Apr;84(4):465-8.|3
00191|066|R|14.Davis RL, Quenzer RW, Kelly HW, Powell JR. Effect of the addition of|2
00191|067|R|   ciprofloxacin on theophylline pharmacokinetics in subjects inhibited by|2
00191|068|R|   cimetidine. Ann Pharmacother 1992 Jan;26(1):11-3.|2
00191|069|R|15.Grasela TH Jr, Dreis MW. An evaluation of the quinolone-theophylline|6
00191|070|R|   interaction using the Food and Drug Administration spontaneous reporting|6
00191|071|R|   system. Arch Intern Med 1992 Mar;152(3):617-21.|6
00191|072|R|16.Van Slooten A, Forrest A, Collins D, Schentag JJ. Use of|4
00191|073|R|   pharmacostatistical analysis to test for a lomefloxacin-theophylline|4
00191|074|R|   interaction. Clin Pharmacol Ther 1992, feb;51(2):160.|4
00191|075|R|17.Loi CM, Parker BM, Cusack BJ, Vestal R. Individual and combined effects|2
00191|076|R|   of cimetidine and ciprofloxacin on theophylline metabolism in male|2
00191|077|R|   nonsmokers. Br J Clin Pharmacol 1993 Sep;36(3):195-200.|2
00191|078|R|18.O'Mahony MS, FitzGerald MX. Cystic fibrosis and seizures. Lancet 1991 Jul|3
00191|079|R|   27;338(8761):259.|3
00191|080|R|19.Bader MB. Role of ciprofloxacin in fatal seizures. Chest 1992 Mar;|3
00191|081|R|   101(3):883-4.|3
00191|082|R|20.Spivey JM, Laughlin PH, Goss TF, Nix DE. Theophylline toxicity secondary|3
00191|083|R|   to ciprofloxacin administration. Ann Emerg Med 1991 Oct;20(10):1131-4.|3
00191|084|R|21.Rockwood RP, Embardo LS. Theophylline, ciprofloxacin, erythromycin: a|3
00191|085|R|   potentially harmful regimen. Ann Pharmacother 1993 May;27(5):651-2.|3
00191|086|R|22.Schwartz J, Jauregui L, Lettieri J, Bachmann K. Impact of ciprofloxacin|2
00191|087|R|   on theophylline clearance and steady-state concentrations in serum.|2
00191|088|R|   Antimicrob Agents Chemother 1988 Jan;32(1):75-7.|2
00191|089|R|23.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
00191|090|R|   Corporation March, 2022.|1
00192|001|T|MONOGRAPH TITLE:  Succinylcholine/Lidocaine; Procaine|
00192|002|B||
00192|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00192|004|L|take action as needed.|
00192|005|B||
00192|006|A|MECHANISM OF ACTION:  Since both succinylcholine and procaine are|
00192|007|A|metabolized by plasma pseudocholinesterase, competitive inhibition of|
00192|008|A|succinylcholine metabolism by procaine is believed to be responsible. The|
00192|009|A|mechanism between succinylcholine and lidocaine is not well understood.|
00192|010|B||
00192|011|E|CLINICAL EFFECTS:  The neuromuscular blocking activity of succinylcholine|
00192|012|E|may be increased, producing profound sedation, respiratory depression, coma,|
00192|013|E|and/or death.|
00192|014|B||
00192|015|P|PREDISPOSING FACTORS:  None determined.|
00192|016|B||
00192|017|M|PATIENT MANAGEMENT:  If it is necessary to administer these drugs|
00192|018|M|concurrently, do so with extreme caution. Monitor neuromuscular function and|
00192|019|M|adjust the dose of the neuromuscular blocking agent accordingly.|
00192|020|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00192|021|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00192|022|M|unresponsiveness.|
00192|023|B||
00192|024|D|DISCUSSION:  Available data indicate that intravenous administration of high|
00192|025|D|doses of procaine prolonged the neuromuscular activity of succinylcholine.|
00192|026|B||
00192|027|R|REFERENCES:|
00192|028|B||
00192|029|R|1.Stilmann Salgado A. Potentiation of succinylcholine by procaine.|2
00192|030|R|  Anesthesiology 1961 Nov-Dec;22(6):897-9.|2
00192|031|R|2.Usubiaga JE, Wikinski JA, Morales RL, Usubiaga LE. Interaction of|2
00192|032|R|  intravenously administered procaine, lidocaine and succinylcholine in|2
00192|033|R|  anesthetized subjects. Anesth Analg 1967 Jan-Feb;46(1):39-45.|2
00193|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K|
00193|002|T|antagonists)/Chloramphenicol|
00193|003|B||
00193|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00193|005|L|of severe adverse interaction.|
00193|006|B||
00193|007|A|MECHANISM OF ACTION:  The mechanism has not been clearly established, but|
00193|008|A|may involve deficiency of Vitamin K. Normally, the chief source of Vitamin K|
00193|009|A|is the diet (2). If this source is absent, synthesis of vitamin K by gut|
00193|010|A|bacteria becomes important, and antibiotics, by decreasing the intestinal|
00193|011|A|flora, can produce Vitamin K deficiency (3). This situation increases the|
00193|012|A|effect of a given dose of anticoagulant.|
00193|013|B||
00193|014|E|CLINICAL EFFECTS:  Increased hypoprothrombinemic effect of the anticoagulant|
00193|015|E|with possible bleeding.|
00193|016|B||
00193|017|P|PREDISPOSING FACTORS:  Low or absent dietary Vitamin K intake is a crucial|
00193|018|P|predisposing factor, unless supplemental Vitamin K is administered. The|
00193|019|P|combination of chloramphenicol with poor nutrition, infection and diarrhea|
00193|020|P|caused marked Vitamin K deficiency and bleeding in two infants even in the|
00193|021|P|absence of any anticoagulant (5).|
00193|022|P|   The risk for bleeding episodes may be greater in patients with|
00193|023|P|disease-associated factors (e.g. thrombocytopenia).|
00193|024|P|   Drug associated risk factors include concurrent use of multiple drugs|
00193|025|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00193|026|P|risk for bleeding (e.g. NSAIDs).|
00193|027|B||
00193|028|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
00193|029|M|receiving concurrent therapy for signs of blood loss, including decreased|
00193|030|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
00193|031|M|and promptly evaluate patients with any symptoms.  If chloramphenicol is|
00193|032|M|given simultaneously, and nutritional status is acutely or chronically poor,|
00193|033|M|very close monitoring is required.|
00193|034|M|   When applicable, perform agent-specific laboratory test (e.g. INR) to|
00193|035|M|monitor efficacy and safety of anticoagulation.  Discontinue anticoagulation|
00193|036|M|in patients with active pathologic bleeding.|
00193|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00193|038|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00193|039|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00193|040|M|and/or swelling.|
00193|041|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00193|042|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00193|043|M|initiating, altering the dose or discontinuing either drug.|
00193|044|B||
00193|045|D|DISCUSSION:  Chloramphenicol has been reported to produce a two- to four|
00193|046|D|fold increase in the half-life of dicumarol. Although this interaction is|
00193|047|D|potentially very dangerous, there are few if any convincing clinical reports|
00193|048|D|of its actual occurrence. Well controlled studies are needed.|
00193|049|B||
00193|050|R|REFERENCES:|
00193|051|B||
00193|052|R|1.Magid E. Tolerance to anticoagulants during antibiotic therapy. Scand J|2
00193|053|R|  Clin Lab Invest 1962;14:565-6.|2
00193|054|R|2.Udall JA. Human sources and absorption of vitamin K in relation to|2
00193|055|R|  anticoagulation stability. JAMA 1965 Oct 11;194(2):127-9.|2
00193|056|R|3.Frick PG, Riedler G, Brogli H. Dose response and minimal daily requirement|2
00193|057|R|  for vitamin K in man. J Appl Physiol 1967 Sep;23(3):387-9.|2
00193|058|R|4.Christensen LK, Skovsted L. Inhibition of drug metabolism by|3
00193|059|R|  chloramphenicol. Lancet 1969 Dec 27;2(7635):1397-9.|3
00193|060|R|5.Matsaniotis N, Messaritakis J, Vlachou C. Hypoprothrombinaemic bleeding in|3
00193|061|R|  infants associated with diarrhea and antibiotics. Report of two cases.|3
00193|062|R|  Arch Dis Child 1970 Aug;45(242):586-7.|3
00193|063|R|6.Yacobi A, Lai CM, Levy G. Pharmacokinetic and pharmacodynamic studies of|5
00193|064|R|  acute interaction between warfarin enantiomers and chloramphenicol in|5
00193|065|R|  rats. J Pharmacol Exp Ther 1984 Oct;231(1):80-4.|5
00194|001|T|MONOGRAPH TITLE:  Serotonin Reuptake Inhibitors; SNRIs/Selected MAOIs|
00194|002|B||
00194|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00194|004|L|is contraindicated and generally should not be dispensed or administered to|
00194|005|L|the same patient.|
00194|006|B||
00194|007|A|MECHANISM OF ACTION:  Serotonin reuptake inhibitors and MAOIs may act|
00194|008|A|synergistically to increase blood pressure and evoke behavioral excitation.|
00194|009|B||
00194|010|E|CLINICAL EFFECTS:  Concurrent use or switching between agents without a|
00194|011|E|sufficient washout period may result in serotonin syndrome.  Symptoms of|
00194|012|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
00194|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
00194|014|B||
00194|015|P|PREDISPOSING FACTORS:  None determined.|
00194|016|B||
00194|017|M|PATIENT MANAGEMENT:  The manufacturers of the selective serotonin reuptake|
00194|018|M|inhibitors, the selective serotonin and norepinephrine reuptake inhibitors,|
00194|019|M|nefazodone, and venlafaxine state that concurrent use with MAOIs is|
00194|020|M|contraindicated.|
00194|021|M|   A minimum 5 week washout period should separate the switch of fluoxetine|
00194|022|M|to a MAOI.|
00194|023|M|   A washout period of at least 21 days is recommended for the switch from|
00194|024|M|vortioxetine to a MAOI.|
00194|025|M|   A washout period of at least 2 weeks is recommended for the switch of|
00194|026|M|citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, or vilazodone|
00194|027|M|to a MAOI.|
00194|028|M|   A washout period of 7 days is recommended for the switch of dapoxetine,|
00194|029|M|levomilnacipran, nefazodone, desvenlafaxine, and venlafaxine to a MAOI.|
00194|030|M|   A washout period of 5 days is recommended for the switch of duloxetine or|
00194|031|M|milnacipran to a MAOI.|
00194|032|M|   Prior to starting any selective serotonin reuptake inhibitor,|
00194|033|M|non-selective serotonin reuptake inhibitor, or duloxetine, allow a 2 week|
00194|034|M|washout period after stopping MAOI therapy.|
00194|035|M|   These washout recommendations apply to the selective MAO-B inhibitors|
00194|036|M|rasagiline and selegiline as well.|
00194|037|M|   If rasagiline is used in combination with fluvoxamine, patients should|
00194|038|M|receive no more than 0.5mg of rasagiline daily.|
00194|039|M|   In emergency situations in patients maintained on SSRIs or SNRIs, weigh|
00194|040|M|the availability and safety of alternatives to linezolid and methylene blue|
00194|041|M|against the risk of serotonin syndrome.  If linezolid or methylene blue|
00194|042|M|therapy is required, the patient's SSRI or SNRI should be immediately|
00194|043|M|discontinued.  Patients should be monitored for serotonin syndrome for 2|
00194|044|M|weeks (5 weeks in the case of fluoxetine, 21 days in the case of|
00194|045|M|vortioxetine, and 5 days in the case of duloxetine and milnacipran) or until|
00194|046|M|24 hours after the last dose of linezolid or methylene blue, whichever comes|
00194|047|M|first.|
00194|048|M|   In non-emergency situations in patients maintained on SSRIs or SNRIs when|
00194|049|M|linezolid or methylene blue therapy is planned, discontinue the patient's|
00194|050|M|SSRI or SNRI at least 2 weeks (5 weeks in the case of fluoxetine, 21 days in|
00194|051|M|the case of vortioxetine, and 5 days in the case of duloxetine and|
00194|052|M|milnacipran) in advance of linezolid or methylene blue therapy.  The|
00194|053|M|patient's SSRI or SNRI therapy may be resumed 24 hours after the last dose|
00194|054|M|of linezolid or methylene blue.|
00194|055|M|   Do not initiate SSRI or SNRI therapy in patients receiving linezolid or|
00194|056|M|methylene blue until 24 hours after the last dose of these agents.|
00194|057|B||
00194|058|D|DISCUSSION:  This serious interaction (serotonin syndrome) has been reported|
00194|059|D|with fluoxetine, sertraline, and venlafaxine. Although this has been not|
00194|060|D|been reported with the fluvoxamine, nefazodone, or paroxetine, current|
00194|061|D|recommendations by their manufacturers indicate that the potential for this|
00194|062|D|interaction should be assumed. Manufacturer's product information for|
00194|063|D|fluoxetine, paroxetine, and venlafaxine state that concurrent administration|
00194|064|D|of these agents with a MAOI is contraindicated. The other selective|
00194|065|D|serotonin reuptake inhibitors and non-selective serotonin reuptake|
00194|066|D|inhibitors have shorter half-lives than fluoxetine.  Therefore, the time|
00194|067|D|frame during which the interaction would be expected to occur with agents|
00194|068|D|and MAOIs would not be expected to be as prolonged as with fluoxetine.|
00194|069|D|Furazolidone is also known to be a monoamine oxidase inhibitor.|
00194|070|D|   In a case report, a patient had stopped taking paroxetine 10 days prior|
00194|071|D|to initiating St. John's wort. The evening after initiating St. John's wort,|
00194|072|D|the patient took a paroxetine.  At noon the next day, the patient was able|
00194|073|D|to be awakened, but was incoherent, groggy, slow-moving, and almost unable|
00194|074|D|to get up.  Two hours later during an examination, she was groggy and|
00194|075|D|lethargic, but able to respond appropriately. She complained of nausea,|
00194|076|D|weakness, and fatigue.  Her vital signs and physical exam were normal,|
00194|077|D|except for a slow response time and limp muscle tone.  She did not take any|
00194|078|D|additional paroxetine and was normal the next day.|
00194|079|D|   The metabolism of rasagiline has been shown to be inhibited by CYP|
00194|080|D|P-450-1A2 inhibitors such as fluvoxamine.|
00194|081|D|   Methylene blue, when administered intravenously, has been shown to reach|
00194|082|D|sufficient concentrations to be a potent inhibitor of MAO-A.  Serotonin|
00194|083|D|syndrome has been reported following administration of methylene blue in|
00194|084|D|patients receiving selective serotonin reuptake inhibitors (SSRIs).|
00194|085|D|   Metaxalone is a weak inhibitor of MAO.|
00194|086|D|   The FDA AERS contains reports of serotonin syndrome with the concurrent|
00194|087|D|use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram,|
00194|088|D|fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine as well as|
00194|089|D|reports of serotonin syndrome with concurrent injectable methylene blue and|
00194|090|D|citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine,|
00194|091|D|escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and|
00194|092|D|venlafaxine.|
00194|093|D|   One or more of the drug pairs linked to this monograph have been included|
00194|094|D|in a list of interactions that should be considered "high-priority" for|
00194|095|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00194|096|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00194|097|D|Coordinator (ONC) for Health Information Technology.|
00194|098|B||
00194|099|R|REFERENCES:|
00194|100|B||
00194|101|R|1.Sternbach H. Danger of MAOI therapy after fluoxetine withdrawal. Lancet|3
00194|102|R|  1988 Oct 8;2(8615):850-1.|3
00194|103|R|2.Kline SS, Mauro LS, Scala-Barnett DM, Zick D. Serotonin syndrome versus|3
00194|104|R|  neuroleptic malignant syndrome as a cause of death. Clin Pharm 1989 Jul;|3
00194|105|R|  8(7):510-4.|3
00194|106|R|3.Feighner JP, Boyer WF, Tyler DL, Neborsky RJ. Adverse consequences of|3
00194|107|R|  fluoxetine-MAOI combination therapy. J Clin Psychiatry 1990 Jun;|3
00194|108|R|  51(6):222-5.|3
00194|109|R|4.Suchowersky O, deVries JD. Interaction of fluoxetine and selegiline. Can J|3
00194|110|R|  Psychiatry 1990 Aug;35(6):571-2.|3
00194|111|R|5.Ciraulo DA, Shader RI. Fluoxetine drug-drug interactions: I.|6
00194|112|R|  Antidepressants and antipsychotics. J Clin Psychopharmacol 1990 Feb;|6
00194|113|R|  10(1):48-50.|6
00194|114|R|6.Peterson GN. Strategies for fluoxetine-MAOI combination therapy. J Clin|3
00194|115|R|  Psychiatry 1991 Feb;52(2):87-8.|3
00194|116|R|7.Grimsley SR, Jann MW. Paroxetine, sertraline, and fluvoxamine: new|6
00194|117|R|  selective serotonin reuptake inhibitors. Clin Pharm 1992 Nov;|6
00194|118|R|  11(11):930-57.|6
00194|119|R|8.Ooi TK. The serotonin syndrome. Anaesthesia 1991 Jun;46(6):507-8.|3
00194|120|R|9.Bhatara VS, Bandettini FC. Possible interaction between sertraline and|3
00194|121|R|  tranylcypromine. Clin Pharm 1993 Mar;12(3):222-5.|3
00194|122|R|10.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
00194|123|R|   and Company August, 2023.|1
00194|124|R|11.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
00194|125|R|12.Effexor XR (venlafaxine hydrochloride) US prescribing information.|1
00194|126|R|   Viatris August, 2023.|1
00194|127|R|13.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
00194|128|R|   Pharmaceuticals, Inc. August, 2023.|1
00194|129|R|14.Serzone (nefazodone hydrochloride) US prescribing information.|1
00194|130|R|   Bristol-Myers Squibb Company January, 2005.|1
00194|131|R|15.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
00194|132|R|   Technologies January, 2017.|1
00194|133|R|16.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
00194|134|R|   Therapeutics, LLC September, 2021.|1
00194|135|R|17.Brannan SK, Talley BJ, Bowden CL. Sertraline and isocarboxazid cause a|3
00194|136|R|   serotonin syndrome. J Clin Psychopharmacol 1994 Apr;14(2):144-5.|3
00194|137|R|18.Jermain DM, Hughes PL, Follender AB. Potential fluoxetine-selegiline|3
00194|138|R|   interaction. Ann Pharmacother 1992 Oct;26(10):1300.|3
00194|139|R|19.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
00194|140|R|   Pharmaceuticals Inc. May, 2023.|1
00194|141|R|20.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
00194|142|R|   Laboratories Inc. August, 2023.|1
00194|143|R|21.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
00194|144|R|   and Company September, 2021.|1
00194|145|R|22.Gordon JB. SSRIs and St.John's Wort: possible toxicity?. Am Fam Physician|3
00194|146|R|   1998 Mar 1;57(5):950,953.|3
00194|147|R|23.Muller WE, Rolli M, Schafer C, Hafner U. Effects of hypericum extract (LI|5
00194|148|R|   160) in biochemical models of antidepressant activity. Pharmacopsychiatry|5
00194|149|R|   1997 Sep;30 Suppl 2:102-7.|5
00194|150|R|24.Cott JM. In vitro receptor binding and enzyme inhibition by Hypericum|5
00194|151|R|   perforatum extract. Pharmacopsychiatry 1997 Sep;30 Suppl 2:108-12.|5
00194|152|R|25.Perovic S, Muller WE. Pharmacological profile of hypericum extract.|5
00194|153|R|   Effect on serotonin uptake by postsynaptic receptors.|5
00194|154|R|   Arzneimittelforschung 1995 Nov;45(11):1145-8.|5
00194|155|R|26.Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and|5
00194|156|R|   hypericin. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S54-6.|5
00194|157|R|27.Anonymous. St. John's wort. Med Lett Drugs Ther 1997 Nov 21;|6
00194|158|R|   39(1014):107-8.|6
00194|159|R|28.Zonneveld AM, Hagenaars M, Voermans NC, Gelissen HP, Claassen JA.|3
00194|160|R|   Life-threatening serotonin syndrome following a single dose of a|3
00194|161|R|   serotonin reuptake inhibitor during maintenance therapy with a monoamine|3
00194|162|R|   oxidase inhibitor. Ned Tijdschr Geneeskd 2006 May 13;150(19):1081-4.|3
00194|163|R|29.Zelapar (selegiline hydrochloride) US prescribing information. Valeant|1
00194|164|R|   Pharmaceuticals June, 2021.|1
00194|165|R|30.Savella (milnacipran hydrochloride) US prescribing information. Forest|1
00194|166|R|   Pharmaceuticals, Inc. September, 2021.|1
00194|167|R|31.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00194|168|R|   inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00194|169|R|   prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00194|170|R|32.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00194|171|R|   distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00194|172|R|   2000 Jun;56(3):247-50.|2
00194|173|R|33.Schwiebert C, Irving C, Gillman PK. Small doses of methylene blue,|3
00194|174|R|   previously considered safe, can precipitate serotonin toxicity.|3
00194|175|R|   Anaesthesia 2009 Aug;64(8):924.|3
00194|176|R|34.Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin toxicity|3
00194|177|R|   following co-administration of methylene blue and serotonin reuptake|3
00194|178|R|   inhibitors: an update on a case report of post-operative delirium. J|3
00194|179|R|   Psychopharmacol 2009 May 21.|3
00194|180|R|35.Rowley M, Riutort K, Shapiro D, Casler J, Festic E, Freeman WD. Methylene|3
00194|181|R|   blue-associated serotonin syndrome: a 'green' encephalopathy after|3
00194|182|R|   parathyroidectomy. Neurocrit Care 2009;11(1):88-93.|3
00194|183|R|36.Khavandi A, Whitaker J, Gonna H. Serotonin toxicity precipitated by|3
00194|184|R|   concomitant use of citalopram and methylene blue. Med J Aust 2008 Nov 3;|3
00194|185|R|   189(9):534-5.|3
00194|186|R|37.Ng BK, Cameron AJ, Liang R, Rahman H. Serotonin syndrome following|3
00194|187|R|   methylene blue infusion during parathyroidectomy: a case report and|3
00194|188|R|   literature review. Can J Anaesth 2008 Jan;55(1):36-41.|3
00194|189|R|38.Gillman PK. Methylene blue implicated in potentially fatal serotonin|3
00194|190|R|   toxicity. Anaesthesia 2006 Oct;61(10):1013-4.|3
00194|191|R|39.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
00194|192|R|   June, 2020.|1
00194|193|R|40.Eldepryl (selegiline) US prescribing information. Somerset|1
00194|194|R|   Pharmaceuticals February, 1997.|1
00194|195|R|41.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
00194|196|R|   Pharmaceuticals, Inc. August, 2023.|1
00194|197|R|42.Viibryd (vilazodone hydrochloride) US prescribing information. Forest|1
00194|198|R|   Laboratories Inc. October, 2023.|1
00194|199|R|43.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00194|200|R|   352(11):1112-20.|6
00194|201|R|44.USFood and Drug Administration. FDA Drug Safety Communication: Serious|1
00194|202|R|   CNS reactions possible when linezolid (Zyvox) is given to patients taking|1
00194|203|R|   certain psychiatric medications. available at:|1
00194|204|R|   http://wayback.archive-it.org/7993/20170722185915/https://www.fda.gov/Dru|1
00194|205|R|   gs/DrugSafety/ucm265305.htm July 26, 2011.|1
00194|206|R|45.USFood and Drug Administration. FDA Drug Safety Communication: Serious|1
00194|207|R|   CNS reactions possible when methylene blue is given to patients taking|1
00194|208|R|   certain psychiatric medications. available at:|1
00194|209|R|   http://wayback.archive-it.org/7993/20170722185916/https://www.fda.gov/Dru|1
00194|210|R|   gs/DrugSafety/ucm263190.htm July 26, 2011.|1
00194|211|R|46.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
00194|212|R|   information about the drug interaction between linezolid (Zyvox) and|1
00194|213|R|   serotonergic psychiatric medications. available at:|1
00194|214|R|   http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm October 21, 2011.|1
00194|215|R|47.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
00194|216|R|   information about the drug interaction between methylene blue|1
00194|217|R|   (methylthioninium chloride) and serotonergic psychiatric medications.|1
00194|218|R|   available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
00194|219|R|   21, 2011.|1
00194|220|R|48.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00194|221|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00194|222|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00194|223|R|   19(5):735-43.|6
00194|224|R|49.Priligy (dapoxetine hydrochloride) Australian prescribing information.|1
00194|225|R|   Ortho-McNeil Pharmaceutical March 19, 2013.|1
00194|226|R|50.Trintellix (vortioxetine) US prescribing information. Takeda|1
00194|227|R|   Pharmaceuticals America, Inc. November, 2020.|1
00194|228|R|51.Fetzima (levomilnacipran) US prescribing information. Forest|1
00194|229|R|   Pharmaceuticals, Inc. October, 2023.|1
00195|001|T|MONOGRAPH TITLE:  Theophyllines/Halothane|
00195|002|B||
00195|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00195|004|L|of severe adverse interaction.|
00195|005|B||
00195|006|A|MECHANISM OF ACTION:  Halothane is known to sensitize the heart to the|
00195|007|A|effects of adrenergic agonists.(1) It is probable that halothane similarly|
00195|008|A|sensitizes the heart to theophylline's arrhythmogenic effect, but the exact|
00195|009|A|mechanism is uncertain.|
00195|010|B||
00195|011|E|CLINICAL EFFECTS:  In several patients receiving chronic aminophylline|
00195|012|E|therapy, onset of serious arrhythmias within a few minutes after initiation|
00195|013|E|of halothane anesthesia has been reported.(2-4)|
00195|014|B||
00195|015|P|PREDISPOSING FACTORS:  Animal studies indicate an increased likelihood of|
00195|016|P|arrhythmias when aminophylline administration precedes halothane|
00195|017|P|anesthesia.(5,6)|
00195|018|B||
00195|019|M|PATIENT MANAGEMENT:  Avoid coadministration of these drugs; enflurane and|
00195|020|M|isoflurane appear less likely to interact with theophylline than halothane.|
00195|021|B||
00195|022|D|DISCUSSION:  Ventricular arrhythmias have been reported in patients during|
00195|023|D|concomitant administration of theophylline and halothane. Based upon the|
00195|024|D|limited documentation available in humans, this interaction appears to be|
00195|025|D|pharmacodynamic.|
00195|026|B||
00195|027|R|REFERENCES:|
00195|028|B||
00195|029|R|1.Munson ES, Tucker WK. Doses of epinephrine causing arrhythmia during|5
00195|030|R|  enflurane, methoxyflurane and halothane anaesthesia in dogs. Can Anaesth|5
00195|031|R|  Soc J 1975 Jul;22(4):495-501.|5
00195|032|R|2.Richards W, Thompson J, Lewis G, Levy DS, Church JA. Cardiac arrest|3
00195|033|R|  associated with halothane anesthesia in a patient receiving theophylline.|3
00195|034|R|  Ann Allergy 1988 Aug;61(2):83-4.|3
00195|035|R|3.Bedger RC Jr, Chang JL, Larson CE, Bleyaert AL. Case report: increased|3
00195|036|R|  myocardial irritability with halothane and aminophylline. Anesth Prog 1980|3
00195|037|R|  Jan-Feb;27(1):34-6.|3
00195|038|R|4.Roizen MF, Stevens WC. Multiform ventricular tachycardia due to the|3
00195|039|R|  interaction of aminophylline and halothane. Anesth Analg 1978 Nov-Dec;|3
00195|040|R|  57(6):738-41.|3
00195|041|R|5.Stirt JA, Berger JM, Ricker SM, Sullivan SF. Arrhythmogenic effects of|5
00195|042|R|  aminophylline during halothane anesthesia in experimental animals. Anesth|5
00195|043|R|  Analg 1980 Jun;59(6):410-6.|5
00195|044|R|6.Stirt JA, Berger JM, Roe SD, Ricker SM, Sullivan SF. Halothane-induced|5
00195|045|R|  cardiac arrhythmias following administration of aminophylline in|5
00195|046|R|  experimental animals. Anesth Analg 1981 Jul;60(7):517-20.|5
00195|047|R|7.Nakatsu K, Loomis CW. Postanesthetic theophylline elimination. Anesth|5
00195|048|R|  Analg 1986 Apr;65(4):423.|5
00195|049|R|8.Nicholls EA, Louie GL, Prokocimer PG, Maze M. Halothane anesthetic|5
00195|050|R|  requirements are not affected by aminophylline treatment in rats and dogs.|5
00195|051|R|  Anesthesiology 1986 Dec;65(6):637-41.|5
00195|052|R|9.Zimmerman BL. Arrhythmogenicity of theophylline and halothane used in|6
00195|053|R|  combination. Anesth Analg 1979 May-Jun;58(3):259-60.|6
00196|001|T|MONOGRAPH TITLE:  Digoxin/Propafenone;Flecainide|
00196|002|B||
00196|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00196|004|L|of severe adverse interaction.|
00196|005|B||
00196|006|A|MECHANISM OF ACTION:  Uncertain, but decreases in volume of distribution as|
00196|007|A|well as renal and metabolic clearance of digoxin have been observed.|
00196|008|B||
00196|009|E|CLINICAL EFFECTS:  Digoxin plasma concentrations may increase, producing|
00196|010|E|toxicity. Signs of digitalis toxicity include nausea, vomiting and ECG|
00196|011|E|changes like bradycardia, ventricular ectopy and shortening of the QT|
00196|012|E|interval. Propafenone use may have resulted in a digoxin-induced fatal|
00196|013|E|ventricular fibrillation (1).|
00196|014|B||
00196|015|P|PREDISPOSING FACTORS:  Propafenone should be used with caution in patients|
00196|016|P|with serious structural heart disease as it may cause or aggravate|
00196|017|P|life-threatening arrhythmias.  Low body weight, advanced age, impaired renal|
00196|018|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00196|019|P|risk of digoxin toxicity.|
00196|020|B||
00196|021|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor serum|
00196|022|M|digoxin glycoside levels and observe the patient for symptoms of digitalis|
00196|023|M|toxicity.|
00196|024|M|   Upon adding propafenone or flecainide, digoxin dosages should first be|
00196|025|M|decreased in anticipation of an interaction, then adjusted accordingly.  The|
00196|026|M|dosage of oral digoxin may need to be decreased by 30-50%, or the frequency|
00196|027|M|of administration may be reduced.|
00196|028|M|   For IV or IM digoxin, the dosage may need to be decreased by 15-30%, or|
00196|029|M|the dosing frequency may be reduced.|
00196|030|B||
00196|031|D|DISCUSSION:  Clinical studies have shown that coadministration of|
00196|032|D|propafenone and digoxin may result in an increase in serum digoxin levels of|
00196|033|D|30-60%. Symptoms of digitalis toxicity have been reported. An interaction|
00196|034|D|has been demonstrated in both adult and pediatric patients.|
00196|035|D|   Concurrent administration of flecainide and digoxin resulted in a small|
00196|036|D|but significant increase of 13% in plasma digoxin concentration. A|
00196|037|D|significant prolongation of the PR interval in six of 15 subjects was noted.|
00196|038|D|   Two studies have documented that encainide therapy does not affect|
00196|039|D|digoxin pharmacokinetics.|
00196|040|D|   Concomitant administration of propafenone and oral digoxin increased the|
00196|041|D|digoxin area-under-the-curve (AUC) 60-270%.(14)  Concurrent use of|
00196|042|D|propafenone with IV or IM digoxin increased the digoxin AUC by 29%.(15)|
00196|043|B||
00196|044|R|REFERENCES:|
00196|045|B||
00196|046|R|1.Cardaioli P, Compostella L, De Domenico R, Papalia D, Zeppellini R,|2
00196|047|R|  Libardoni M, Pulido E, Cucchini F. Effect of propafenone on the|2
00196|048|R|  pharmacokinetics of digoxin administered orally: a study in healthy|2
00196|049|R|  volunteers. G Ital Cardiol 1986 Mar;16(3):237-40.|2
00196|050|R|2.Belz GG, Doering W, Munkes R, Matthews J. Interaction between digoxin and|2
00196|051|R|  calcium antagonists and antiarrhythmic drugs. Clin Pharmacol Ther 1983|2
00196|052|R|  Apr;33(4):410-7.|2
00196|053|R|3.Salerno DM, Granrud G, Sharkey P, Asinger R, Hodges M. A controlled trial|2
00196|054|R|  of propafenone for treatment of frequent and repetitive ventricular|2
00196|055|R|  premature complexes. Am J Cardiol 1984 Jan 1;53(1):77-83.|2
00196|056|R|4.Calvo MV, Martin Suarez A, Avila MC, Martin Luengo C. Digoxin-propafenone|3
00196|057|R|  interaction. Med Clin (Barc) 1987 Jun 20;89(4):171-2.|3
00196|058|R|5.Nolan PE Jr, Marcus FI, Erstad BL, Hoyer GL, Furman C, Kirsten EB. Effects|2
00196|059|R|  of coadministration of propafenone on the pharmacokinetics of digoxin in|2
00196|060|R|  healthy volunteer subjects. J Clin Pharmacol 1989 Jan;29(1):46-52.|2
00196|061|R|6.Calvo MV, Martin-Suarez A, Martin Luengo C, Avila C, Cascon M,|2
00196|062|R|  Dominguez-Gil Hurle A. Interaction between digoxin and propafenone. Ther|2
00196|063|R|  Drug Monit 1989;11(1):10-5.|2
00196|064|R|7.Zalzstein E, Koren G, Bryson SM, Freedom RM. Interaction between digoxin|3
00196|065|R|  and propafenone in children. J Pediatr 1990 Feb;116(2):310-2.|3
00196|066|R|8.Bigot MC, Debruyne D, Bonnefoy L, Grollier G, Moulin M, Potier JC. Serum|2
00196|067|R|  digoxin levels related to plasma propafenone levels during concomitant|2
00196|068|R|  treatment. J Clin Pharmacol 1991 Jun;31(6):521-6.|2
00196|069|R|9.Hii JT, Duff HJ, Burgess ED. Clinical pharmacokinetics of propafenone.|6
00196|070|R|  Clin Pharmacokinet 1991 Jul;21(1):1-10.|6
00196|071|R|10.Lewis GP, Holtzman JL. Interaction of flecainide with digoxin and|2
00196|072|R|   propranolol. Am J Cardiol 1984 Feb 27;53(5):52B-57B.|2
00196|073|R|11.Weeks CE, Conard GJ, Kvam DC, Fox JM, Chang SF, Paone RP, Lewis GP. The|2
00196|074|R|   effect of flecainide acetate, a new antiarrhythmic, on plasma digoxin|2
00196|075|R|   levels. J Clin Pharmacol 1986 Jan;26(1):27-31.|2
00196|076|R|12.Quart BD, Gallo DG, Sami MH, Wood AJ. Drug interaction studies and|6
00196|077|R|   encainide use in renal and hepatic impairment. Am J Cardiol 1986 Aug 29;|6
00196|078|R|   58(5):104C-113C.|6
00196|079|R|13.Sami MH, Derbekyan VA, Lisbona R. Hemodynamic effects of encainide in|2
00196|080|R|   patients with ventricular arrhythmia and poor ventricular function. Am J|2
00196|081|R|   Cardiol 1983 Sep 1;52(5):507-11.|2
00196|082|R|14.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00196|083|R|   Pharmaceuticals, Inc. August, 2018.|1
00196|084|R|15.Lanoxin Injection (digoxin) US prescribing information. Covis Pharma|1
00196|085|R|   October, 2019.|1
00197|001|T|MONOGRAPH TITLE:  Cyclosporine/Sulfonamides (mono deleted 02/14/2022)|
00197|002|B||
00197|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00197|004|L|of severe adverse interaction.|
00197|005|B||
00197|006|A|MECHANISM OF ACTION:  Unknown; however, sulfonamides may increase the|
00197|007|A|metabolism of cyclosporine, decreasing serum levels.|
00197|008|B||
00197|009|E|CLINICAL EFFECTS:  The immunosuppressive effect of cyclosporine may be|
00197|010|E|decreased. In addition, coadministration of sulfonamides and cyclosporine|
00197|011|E|may produce additive nephrotoxicity.|
00197|012|B||
00197|013|P|PREDISPOSING FACTORS:  None determined.|
00197|014|B||
00197|015|M|PATIENT MANAGEMENT:  Monitor serum cyclosporine levels and renal function|
00197|016|M|during concurrent administration of sulfonamides.|
00197|017|B||
00197|018|D|DISCUSSION:  Dramatic reductions in cyclosporine levels have been observed|
00197|019|D|in patients receiving cyclosporine concomitantly with sulfonamides or with|
00197|020|D|sulfamethoxazole/trimethoprim. In some patients, therapeutic levels of|
00197|021|D|cyclosporine could not be achieved until the sulfonamide was discontinued.|
00197|022|D|This interaction was observed when the sulfonamide was given parenterally,|
00197|023|D|but not when the antiinfective was administered orally.|
00197|024|B||
00197|025|R|REFERENCES:|
00197|026|B||
00197|027|R|1.Thompson JF, Chalmers DH, Hunnisett AG, Wood RF, Morris PJ. Nephrotoxicity|3
00197|028|R|  of trimethoprim and cotrimoxazole in renal allograft recipients treated|3
00197|029|R|  with cyclosporine. Transplantation 1983 Aug;36(2):204-6.|3
00197|030|R|2.Wallwork J, McGregor CG, Wells FC, Cory-Pearce R, English TA. Cyclosporin|3
00197|031|R|  and intravenous sulphadimidine and trimethoprim therapy. Lancet 1983 Feb|3
00197|032|R|  12;1(8320):366-7.|3
00197|033|R|3.Ringden O, Myrenfors P, Klintmalm G, Tyden G, Ost L. Nephrotoxicity by|2
00197|034|R|  co-trimoxazole and cyclosporin in transplanted patients. Lancet 1984 May|2
00197|035|R|  5;1(8384):1016-7.|2
00197|036|R|4.Jones DK, Hakim M, Wallwork J, Higenbottam TW, White DJ. Serious|3
00197|037|R|  interaction between cyclosporin A and sulphadimidine. Br Med J (Clin Res|3
00197|038|R|  Ed) 1986 Mar 15;292(6522):728-9.|3
00198|001|T|MONOGRAPH TITLE:  Selected Anticholinesterase/Corticosteroids|
00198|002|B||
00198|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00198|004|L|of severe adverse interaction.|
00198|005|B||
00198|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.|
00198|007|B||
00198|008|E|CLINICAL EFFECTS:  Concurrent use of these agents may contribute to|
00198|009|E|increased muscle weakness and decreased response to anticholinesterases|
00198|010|E|shortly after onset of corticosteroid therapy in the treatment of myasthenia|
00198|011|E|gravis.  Deterioration in muscle strength, including severe muscular|
00198|012|E|depression, has been documented in patients with myasthenia gravis while|
00198|013|E|receiving corticosteroids and anticholinesterases.|
00198|014|B||
00198|015|P|PREDISPOSING FACTORS:  None determined.|
00198|016|B||
00198|017|M|PATIENT MANAGEMENT:  If possible, hold anticholinesterase agents at least 24|
00198|018|M|hours before initiating corticosteroid therapy.  If concurrent use is|
00198|019|M|necessary, close observation of the patient is indicated and life support|
00198|020|M|systems should be available.|
00198|021|B||
00198|022|D|DISCUSSION:  Decreased effectiveness of anticholinesterases during the|
00198|023|D|period of corticosteroid-induced increased weakness probably reflects a|
00198|024|D|temporary increase in the severity of the disease process itself rather than|
00198|025|D|a specific, direct interaction between the two drugs. Despite the initial|
00198|026|D|adverse effect, glucocorticoid (or ACTH) therapy subsequently produces|
00198|027|D|improvement, beyond pre-therapy muscle strength, in most myasthenia gravis|
00198|028|D|patients.|
00198|029|D|   In an uncontrolled study involving nine patients receiving therapeutic|
00198|030|D|doses of pyridostigmine, the concurrent administration of methylprednisolone|
00198|031|D|resulted in a decrease in muscle strength in 71% of treatment courses.|
00198|032|D|During 57% of treatment courses, severe muscle weakness occurred,|
00198|033|D|necessitating mechanical ventilation.  Improvement in muscle strength and|
00198|034|D|response to pyridostigmine above baseline levels occurred after|
00198|035|D|methylprednisolone was discontinued.|
00198|036|D|   Other clinical observations have indicated that the concomitant use of|
00198|037|D|these agents can affect muscle strength, although each agent alone has been|
00198|038|D|used successfully in treating myasthenia gravis.|
00198|039|B||
00198|040|R|REFERENCES:|
00198|041|B||
00198|042|R|1.Millikan CH, Eaton LE. Clinical evaluation of ACTH and cortisone in|3
00198|043|R|  myasthenia gravis. Neurology 1951;1:145-52.|3
00198|044|R|2.Grob D, McGehee Harvey A. Effect of adrenocorticotropic hormone (ACTH) and|2
00198|045|R|  cortisone administration in patients with myasthenia gravis and report of|2
00198|046|R|  onset of myasthenia gravis during prolonged cortisone administration.|2
00198|047|R|  Johns Hopkins Med J 1952;91:124-36.|2
00198|048|R|3.Warmolts JR, Engel WK, Whitaker JN. Alternate-dy prednisone in a patient|3
00198|049|R|  with myasthenia gravis. Lancet 1970 Dec 5;2(7684):1198-9.|3
00198|050|R|4.Namba T. Corticotropin therapy in patients with myasthenia gravis.|5
00198|051|R|  Electrophysiologic, pharmacologic studies. Arch Neurol 1972 Feb;|5
00198|052|R|  26(2):144-50.|5
00198|053|R|5.Brunner NG, Namba T, Grob D. Corticosteroids in management of severe,|2
00198|054|R|  generalized myasthenia gravis. Effectiveness and comparison with|2
00198|055|R|  corticotropin therapy. Neurology 1972 Jun;22(6):603-10.|2
00198|056|R|6.Arsura E, Brunner NG, Namba T, Grob D. High-dose intravenous|2
00198|057|R|  methylprednisolone in myasthenia gravis. Arch Neurol 1985 Dec;|2
00198|058|R|  42(12):1149-53.|2
00198|059|R|7.Johns TR. Long-term corticosteroid treatment of myasthenia gravis. Ann N Y|2
00198|060|R|  Acad Sci 1987;505:568-83.|2
00198|061|R|8.Drachman DB. Present and future treatment of myasthenia gravis. N Engl J|6
00198|062|R|  Med 1987 Mar 19;316(12):743-5.|6
00198|063|R|9.Cornelio F, Peluchetti D, Mantegazza R, Sghirlanzoni A, Collarile C. The|2
00198|064|R|  course of myasthenia gravis in patients treated with corticosteroids,|2
00198|065|R|  azathioprine, and plasmapheresis. Ann N Y Acad Sci 1987;505:517-25.|2
00199|001|T|MONOGRAPH TITLE:  Duloxetine; Fluvoxamine/Selected Tricyclic Compounds|
00199|002|B||
00199|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00199|004|L|take action as needed.|
00199|005|B||
00199|006|A|MECHANISM OF ACTION:  Duloxetine or fluvoxamine may impair the oxidative|
00199|007|A|hepatic metabolism of tricyclic compounds.|
00199|008|B||
00199|009|E|CLINICAL EFFECTS:  Concurrent administration of duloxetine or fluvoxamine|
00199|010|E|with a tricyclic compound may result in an increase in serum levels,|
00199|011|E|toxicities (e.g. torsades de pointes), and/or clinical effects of the|
00199|012|E|tricyclic compound.|
00199|013|B||
00199|014|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
00199|015|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
00199|016|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
00199|017|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
00199|018|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
00199|019|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
00199|020|P|systemic steroids).|
00199|021|P|   The risk of anticholinergic toxicities including cognitive decline,|
00199|022|P|delirium, falls and fractures is increased in geriatric patients using more|
00199|023|P|than one medicine with anticholinergic properties.(9)|
00199|024|B||
00199|025|M|PATIENT MANAGEMENT:  Patients should be observed for increased adverse|
00199|026|M|effects and clinical effects of tricyclic compounds at the initiation of|
00199|027|M|concurrent therapy with duloxetine or fluvoxamine.  Plasma concentrations of|
00199|028|M|the tricyclic compound should be monitored and the dosage adjusted|
00199|029|M|accordingly.|
00199|030|M|   If duloxetine or fluvoxamine is discontinued in a patient receiving a|
00199|031|M|tricyclic compound, the dosage of the tricyclic compound may need to be|
00199|032|M|adjusted.|
00199|033|B||
00199|034|D|DISCUSSION:  In a study, pretreatment with duloxetine (60 mg twice daily)|
00199|035|D|increased the area-under-curve (AUC) of a single dose of desipramine (50 mg)|
00199|036|D|by 3-fold.|
00199|037|D|   Fluvoxamine has been shown in an in vitro study to inhibit the metabolism|
00199|038|D|of imipramine. Three case reports have shown increased serum levels of|
00199|039|D|imipramine (32%, 198%, and 470% increases) and an increase in adverse|
00199|040|D|effects (anticholinergic effects, confusion, and sedation) during concurrent|
00199|041|D|administration with fluvoxamine.   Two case reports of adverse effects|
00199|042|D|(tonic-clonic seizure, tremors, dizziness, and confusion) and increased|
00199|043|D|plasma desipramine levels (79% and 54% increases) with concurrent|
00199|044|D|administration of fluvoxamine exist.|
00199|045|D|   Increased plasma levels of clomipramine (586%) and amitriptyline|
00199|046|D|(100-150%) without signs of clinical toxicity were seen following the|
00199|047|D|addition of fluvoxamine to a tricyclic compound therapy.|
00199|048|D|   The affinity of the different SSRIs, SNRIs, and tricyclics for CYP450 may|
00199|049|D|vary.|
00199|050|B||
00199|051|R|REFERENCES:|
00199|052|B||
00199|053|R|1.Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of|3
00199|054|R|  combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990|3
00199|055|R|  Apr;147(4):532.|3
00199|056|R|2.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
00199|057|R|  fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
00199|058|R|  1992 Mar;51(3):239-48.|2
00199|059|R|3.Maskall DD, Lam RW. Increased plasma concentration of imipramine following|3
00199|060|R|  augmentation with fluvoxamine. Am J Psychiatry 1993 Oct;150(10):1566.|3
00199|061|R|4.Spino E, Campo GM, Avenoso A, Pollicino MA, Caputi AP. Interaction between|3
00199|062|R|  fluvoxamine and imipramine/desipramine in four patients. Ther Drug Monit|3
00199|063|R|  1992 Jun;14(3):194-6.|3
00199|064|R|5.Bertschy G, Vandel S, Vandel B, Allers G, Volmat R. Fluvoxamine-tricyclic|3
00199|065|R|  antidepressant interaction. An accidental finding. Eur J Clin Pharmacol|3
00199|066|R|  1991;40(1):119-20.|3
00199|067|R|6.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
00199|068|R|  and Company September, 2021.|1
00199|069|R|7.Seifritz E, Holsboer-Trachsler E, Hemmeter U, Eap CB, Baumann P. Increased|3
00199|070|R|  trimipramine plasma levels during fluvoxamine comedication. Eur|3
00199|071|R|  Neuropsychopharmacol 1994 Mar;4(1):15-20.|3
00199|072|R|8.Skjelbo E, Brosen K. Inhibitors of imipramine metabolism by human liver|5
00199|073|R|  microsomes. Br J Clin Pharmacol 1992 Sep;34(3):256-61.|5
00199|074|R|9.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
00199|075|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
00199|076|R|  Soc 2023 Jul;71(7):2052-2081.|6
00200|001|T|MONOGRAPH TITLE:  Calcium Channel Blockers/Quinidine|
00200|002|B||
00200|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00200|004|L|take action as needed.|
00200|005|B||
00200|006|A|MECHANISM OF ACTION:  Diltiazem, a moderate CYP3A4 inhibitor, may inhibit|
00200|007|A|the metabolism of quinidine.  Verapamil, a moderate CYP3A4 inhibitor and|
00200|008|A|P-gp inhibitor, may inhibit the metabolism of quinidine.  Verapamil and|
00200|009|A|quinidine may slow A-V conduction and prolong the refractory period.|
00200|010|B||
00200|011|E|CLINICAL EFFECTS:  Concurrent administration of diltiazem may result in|
00200|012|E|elevated levels of and effects from quinidine, including the risk of QT|
00200|013|E|prolongation.|
00200|014|E|   Concurrent administration of quinidine and verapamil may result in result|
00200|015|E|in hypotension and elevated levels of quinidine.|
00200|016|B||
00200|017|P|PREDISPOSING FACTORS:  None determined.|
00200|018|B||
00200|019|M|PATIENT MANAGEMENT:  Patients receiving concurrent diltiazem or verapamil|
00200|020|M|should be monitored for increased effects of quinidine.|
00200|021|B||
00200|022|D|DISCUSSION:  Concurrent diltiazem has been shown to increase the|
00200|023|D|area-under-curve (AUC) and half-life (T1/2) of quinidine by 51% and 36%,|
00200|024|D|respectively. Quinidine clearance decreased by 33%.  No significant|
00200|025|D|pharmacodynamic effects were noted.|
00200|026|D|   There are several case reports documenting hypotension during concurrent|
00200|027|D|quinidine and verapamil.  In a study in 6 subjects, concurrent verapamil|
00200|028|D|decreased quinidine clearance by 35.2%.|
00200|029|B||
00200|030|R|REFERENCES:|
00200|031|B||
00200|032|R|1.Epstein SE, Rosing DR. Verapamil: its potential for causing serious|6
00200|033|R|  complications in patients with hypertrophic cardiomyopathy. Circulation|6
00200|034|R|  1981 Sep;64(3):437-41.|6
00200|035|R|2.Mitchell LB, Schroeder JS, Mason JW. Comparative clinical|6
00200|036|R|  electrophysiologic effects of diltiazem, verapamil and nifedipine: a|6
00200|037|R|  review. Am J Cardiol 1982 Feb 18;49(3):629-35.|6
00200|038|R|3.Maisel AS, Motulsky HJ, Insel PA. Hypotension after quinidine plus|3
00200|039|R|  verapamil. Possible additive competition at alpha-adrenergic receptors. N|3
00200|040|R|  Engl J Med 1985 Jan 17;312(3):167-70.|3
00200|041|R|4.Ochs HR, Anda L, Eichelbaum M, Greenblatt DJ. Diltiazem, verapamil, and|2
00200|042|R|  quinidine in patients with chronic atrial fibrillation. J Clin Pharmacol|2
00200|043|R|  1985 Apr;25(3):204-9.|2
00200|044|R|5.Edwards DJ, Lavoie R, Beckman H, Blevins R, Rubenfire M. The effect of|2
00200|045|R|  coadministration of verapamil on the pharmacokinetics and metabolism of|2
00200|046|R|  quinidine. Clin Pharmacol Ther 1987 Jan;41(1):68-73.|2
00200|047|R|6.Bigger JT, Hoffman BF. Antiarrhythmic drugs. In Gilman AG, Goodman LS,|6
00200|048|R|  Rall TW, Murad F, eds. Goodman and Gilman's The Pharmacological Basis of|6
00200|049|R|  Therapeutics. 7th ed. New York: MacMillan Publishing Company. 1985.|6
00200|050|R|7.Lavoie R, Blevins RD, Rubenfire M, Edwards DJ. The effect of verapamil on|4
00200|051|R|  quinidine pharmacokinetics in man. Clin Pharmacol Ther 1986 Jun;20:457.|4
00200|052|R|8.Trohman RG, Estes DM, Castellanos A, Palomo AR, Myerburg RJ, Kessler KM.|3
00200|053|R|  Increased quinidine plasma concentrations during administration of|3
00200|054|R|  verapamil: a new quinidine-verapamil interaction. Am J Cardiol 1986 Mar 1;|3
00200|055|R|  57(8):706-7.|3
00200|056|R|9.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
00200|057|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
00200|058|R|10.Karch M, Schmitt C, Plewan A, Schmidt G, Schomig A. Torsade de pointes|3
00200|059|R|   tachycardia during administration of quinidine and verapamil in atrial|3
00200|060|R|   fibrillation. Herz 1997 Feb;22(1):51-6.|3
00200|061|R|11.Laganiere S, Davies RF, Carignan G, Foris K, Goernert L, Carrier K,|2
00200|062|R|   Pereira C, McGilveray I. Pharmacokinetic and pharmacodynamic interactions|2
00200|063|R|   between diltiazem and quinidine. Clin Pharmacol Ther 1996 Sep;|2
00200|064|R|   60(3):255-64.|2
00201|001|T|MONOGRAPH TITLE:  Dopamine/Hydantoins (mono deleted 02/01/2022)|
00201|002|B||
00201|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00201|004|L|of severe adverse interaction.|
00201|005|B||
00201|006|A|MECHANISM OF ACTION:  Unknown.|
00201|007|B||
00201|008|E|CLINICAL EFFECTS:  Severe hypotension has been reported during|
00201|009|E|administration of IV dopamine and phenytoin.|
00201|010|B||
00201|011|P|PREDISPOSING FACTORS:  None determined.|
00201|012|B||
00201|013|M|PATIENT MANAGEMENT:  When possible, avoid coadministration of these drugs.|
00201|014|M|In patients receiving IV phenytoin and dopamine concurrently, monitor|
00201|015|M|cardiovascular status and discontinue phenytoin if hypotension occurs.|
00201|016|B||
00201|017|D|DISCUSSION:  Severe hypotension occurred in three patients and in two|
00201|018|D|patients cardiac arrest resulting in death was reported during|
00201|019|D|coadministration of dopamine and hydantoin infusions. Hypotension reversed|
00201|020|D|when phenytoin was discontinued.|
00201|021|B||
00201|022|R|REFERENCE:|
00201|023|B||
00201|024|R|1.Bivins BA, Rapp RP, Griffen WO Jr, Blouin R, Bustrack J.|3
00201|025|R|  Dopamine-phenytoin interaction. A cause of hypotension in the critically|3
00201|026|R|  ill. Arch Surg 1978 Mar;113(3):245-9.|3
00202|001|T|MONOGRAPH TITLE:  Digoxin/Cyclosporine|
00202|002|B||
00202|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00202|004|L|of severe adverse interaction.|
00202|005|B||
00202|006|A|MECHANISM OF ACTION:  Cyclosporine may increase the absorption of digoxin by|
00202|007|A|inhibiting P-glycoprotein (P-gp).|
00202|008|B||
00202|009|E|CLINICAL EFFECTS:  The pharmacological effects of digoxin may be increased|
00202|010|E|resulting in toxicity. Symptoms of digoxin toxicity can include anorexia,|
00202|011|E|nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle|
00202|012|E|weakness, disorientation, hallucinations, visual disturbances, and|
00202|013|E|arrhythmias.|
00202|014|B||
00202|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
00202|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00202|017|P|risk of digoxin toxicity.|
00202|018|B||
00202|019|M|PATIENT MANAGEMENT:  In patients receiving digoxin, monitor serum digoxin|
00202|020|M|level when treatment with cyclosporine is instituted, increased, decreased|
00202|021|M|or discontinued. Adjust the dose of digoxin accordingly.|
00202|022|B||
00202|023|D|DISCUSSION:  Digoxin toxicity has been reported in two patients following|
00202|024|D|the addition of cyclosporine to their treatment schedule. In two additional|
00202|025|D|patients, the apparent volume of distribution and the plasma clearance of|
00202|026|D|digoxin decreased by 71% and 53% respectively during concurrent|
00202|027|D|administration of cyclosporine.|
00202|028|B||
00202|029|R|REFERENCES:|
00202|030|B||
00202|031|R|1.Dorian P, Strauss M, Cardella C, David T, East S, Ogilvie R.|3
00202|032|R|  Digoxin-cyclosporine interaction: severe digitalis toxicity after|3
00202|033|R|  cyclosporine treatment. Clin Invest Med 1988 Apr;11(2):108-12.|3
00202|034|R|2.Robieux I, Dorian P, Klein J, Chung D, Zborowska-Sluis D, Ogilvie R, Koren|5
00202|035|R|  G. The effects of cardiac transplantation and cyclosporine therapy on|5
00202|036|R|  digoxin pharmacokinetics. J Clin Pharmacol 1992 Apr;32(4):338-43.|5
00203|001|T|MONOGRAPH TITLE:  Clonidine/Beta-Blockers|
00203|002|B||
00203|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00203|004|L|take action as needed.|
00203|005|B||
00203|006|A|MECHANISM OF ACTION:  Withdrawal of clonidine triggers increased|
00203|007|A|catecholamine release.  Beta-blockers inhibit the vasodilation mediated by|
00203|008|A|the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2|
00203|009|A|receptor unopposed.|
00203|010|A|   In addition, concurrent use is expected to produce additive effects on|
00203|011|A|blood pressure and heart rate requiring standard monitoring precautions.|
00203|012|B||
00203|013|E|CLINICAL EFFECTS:  Severe hypertension may occur upon abrupt discontinuation|
00203|014|E|of clonidine in patients receiving both clonidine and beta-blockers.|
00203|015|E|   In addition, concurrent use is expected to produce additive effects on|
00203|016|E|blood pressure and heart rate requiring standard monitoring precautions.|
00203|017|B||
00203|018|P|PREDISPOSING FACTORS:  None determined.|
00203|019|B||
00203|020|M|PATIENT MANAGEMENT:  In a patient receiving both drugs, discontinuation of|
00203|021|M|the beta-blocker prior to clonidine may decrease the occurrence of rebound|
00203|022|M|hypertension. If clonidine is discontinued first, rebound hypertension can|
00203|023|M|be treated by restarting the clonidine or by the IV administration of|
00203|024|M|phentolamine, phenoxybenzamine or prazosin. When adding either of these|
00203|025|M|agents to the drug regimen of the patient, monitor blood pressure. Since|
00203|026|M|labetalol has both alpha and beta activity, administration of labetalol may|
00203|027|M|prevent rebound hypertension in patients undergoing clonidine withdrawal,|
00203|028|M|although conflicting reports exist.|
00203|029|M|   In addition, concurrent use is expected to produce additive effects on|
00203|030|M|blood pressure and heart rate requiring standard monitoring precautions.|
00203|031|B||
00203|032|D|DISCUSSION:  Increased blood pressure has been observed in patients|
00203|033|D|following: 1) the discontinuation of clonidine in patients receiving|
00203|034|D|beta-blockers, 2) the replacement of clonidine therapy with beta-blockers,|
00203|035|D|3) the simultaneous discontinuation of both drugs. Conflicting reports exist|
00203|036|D|on the development of increased blood pressure after clonidine withdrawal in|
00203|037|D|patients receiving labetalol. Patients receiving labetalol who are being|
00203|038|D|withdrawn from clonidine should still be closely monitored.|
00203|039|B||
00203|040|R|REFERENCES:|
00203|041|B||
00203|042|R|1.Bailey RR, Neale TJ. Rapid clonidine withdrawal with blood pressure|3
00203|043|R|  overshoot exaggerated by beta-blockade. Br Med J 1976 Apr 17;|3
00203|044|R|  1(6015):942-3.|3
00203|045|R|2.Strauss FG, Franklin SS, Lewin AJ, Maxwell MH. Withdrawal of|3
00203|046|R|  antihypertensive therapy. Hypertensive crisis in renovascular|3
00203|047|R|  hypertension. JAMA 1977 Oct 17;238(16):1734-6.|3
00203|048|R|3.Vernon C, Sakula A. Fatal rebound hypertension after abrupt withdrawal of|3
00203|049|R|  clonidine and propranolol. Br J Clin Pract 1979 Apr;33(4):112, 121.|3
00203|050|R|4.Bruce DL, Croley TF, Lee JS. Preoperative clonidine withdrawal syndrome.|3
00203|051|R|  Anesthesiology 1979 Jul;51(1):90-2.|3
00203|052|R|5.Warren SE, Ebert E, Swerdlin AH, Steinberg SM, Stone R. Clonidine and|3
00203|053|R|  propranolol paradoxical hypertension. Arch Intern Med 1979 Feb;139(2):253.|3
00203|054|R|6.Lilja M, Jounela AJ, Juustila H, Mattila MJ. Interaction of clonidine and|2
00203|055|R|  beta-blockers. Acta Med Scand 1980;207(3):173-6.|2
00203|056|R|7.Garvey HL, Woodhouse BL. Reversal of clonidine-induced hypotension by|5
00203|057|R|  beta-adrenoceptor blocking drugs. Eur J Pharmacol 1980 Jul 11;65(1):55-62.|5
00203|058|R|8.Rosenthal T, Rabinowitz B, Boichis H, Elazar E, Brauner A, Neufeld HN. Use|3
00203|059|R|  of labetalol in hypertensive patients during discontinuation of clonidine|3
00203|060|R|  therapy. Eur J Clin Pharmacol 1981;20(4):237-40.|3
00203|061|R|9.Cummings DM, Vlasses PH. Antihypertensive drug withdrawal syndrome. Drug|6
00203|062|R|  Intell Clin Pharm 1982 Nov;16(11):817-22.|6
00203|063|R|10.Lilja M. Interaction of clonidine and labetalol in hypertension. Acta Med|2
00203|064|R|   Scand 1983;214(2):119-24.|2
00203|065|R|11.Jounela AJ, Lilja M. Interactions between beta-blockers and clonidine.|6
00203|066|R|   Ann Clin Res 1984;16(4):181-2.|6
00204|001|T|MONOGRAPH TITLE:  Metyrapone/Hydantoins|
00204|002|B||
00204|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00204|004|L|of severe adverse interaction.|
00204|005|B||
00204|006|A|MECHANISM OF ACTION:  Hydantoin increases the first pass metabolism of|
00204|007|A|metyrapone.|
00204|008|B||
00204|009|E|CLINICAL EFFECTS:  The effect of the metyrapone test may be invalidated.|
00204|010|B||
00204|011|P|PREDISPOSING FACTORS:  None determined.|
00204|012|B||
00204|013|M|PATIENT MANAGEMENT:  Discontinue or avoid phenytoin administration prior to|
00204|014|M|metyrapone administration for pituitary-adrenal axis assessment.  It may be|
00204|015|M|necessary to administer metyrapone intravenously or to double its dose in|
00204|016|M|patients receiving phenytoin.|
00204|017|B||
00204|018|D|DISCUSSION:  Invalid results to the metyrapone test have been obtained in|
00204|019|D|patients receiving standard dose of metyrapone and chronic phenytoin|
00204|020|D|treatment. Doubling the dose of metyrapone or administering metyrapone|
00204|021|D|intravenously have produced valid results.|
00204|022|B||
00204|023|R|REFERENCES:|
00204|024|B||
00204|025|R|1.Krieger DT. Effect of diphenylhydantoin on pituitary-adrenal|2
00204|026|R|  interrelations. J Clin Endocrinol Metab 1962 May;22(5):490-3.|2
00204|027|R|2.Werk EE Jr, Thrasher K, Choi Y, Sholiton LJ. Failure of metyrapone to|3
00204|028|R|  inhibit 11-hydroxylation of 11-deoxycortisol during drug therapy. J Clin|3
00204|029|R|  Endocrinol Metab 1967 Sep;27(9):1358-60.|3
00204|030|R|3.Meikle AW, Jubiz W, Matsukura S, West CD, Tyler FH. Effect of|2
00204|031|R|  diphenylhydantoin on the metabolism of metyrapone and release of ACTH in|2
00204|032|R|  man. J Clin Endocrinol Metab 1969 Dec;29(12):1553-8.|2
00204|033|R|4.Jubiz W, Levinson RA, Meikle AW, West CD, Tyler FH. Absorption and|5
00204|034|R|  conjugation of metyrapone during diphenylhydantoin therapy: mechanism of|5
00204|035|R|  the abnormal response to oral metyrapone. Endocrinology 1970 Feb;|5
00204|036|R|  86(2):328-31.|5
00205|001|T|MONOGRAPH TITLE:  Methoxyflurane/Tetracyclines|
00205|002|B||
00205|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00205|004|L|of severe adverse interaction.|
00205|005|B||
00205|006|A|MECHANISM OF ACTION:  Unknown. However, combined renal toxicity appears to|
00205|007|A|be a factor.|
00205|008|B||
00205|009|E|CLINICAL EFFECTS:  Nephrotoxicity may occur.|
00205|010|B||
00205|011|P|PREDISPOSING FACTORS:  None determined.|
00205|012|B||
00205|013|M|PATIENT MANAGEMENT:  When possible use alternative therapy.|
00205|014|B||
00205|015|D|DISCUSSION:  Renal toxicity and death have been reported in patients|
00205|016|D|receiving methoxyflurane and tetracycline. Since both drugs have been|
00205|017|D|associated with nephrotoxicity, it is difficult to determine whether the|
00205|018|D|effects are due to the drug combination or either drug alone. Additional|
00205|019|D|studies are needed to clarify this potential interaction.|
00205|020|B||
00205|021|R|REFERENCES:|
00205|022|B||
00205|023|R|1.Kuzucu EY. Methoxyflurane, tetracycline, and renal failure. JAMA 1970 Feb|3
00205|024|R|  16;211(7):1162-4.|3
00205|025|R|2.Proctor EA, Barton FL. Polyuric acute renal failure after methoxyflurane|3
00205|026|R|  and tetracycline. Br Med J 1971 Dec 11;4(788):661-2.|3
00205|027|R|3.Albers DD, Leverett CL, Sandin JH. Renal failure following|3
00205|028|R|  prostatovesiculectomy related to methoxyflurane anesthesia and|3
00205|029|R|  tetracycline--complicated by Candida infection. J Urol 1971 Sep;|3
00205|030|R|  106(3):348-50.|3
00205|031|R|4.Cousins MJ, Mazze RI. Tetracycline, methoxyflurane anaesthesia, and renal|6
00205|032|R|  dysfunction. Lancet 1972 Apr 1;1(7753):751-2.|6
00205|033|R|5.Stoelting RK, Gibbs PS. Effect of tetracycline therapy on renal function|5
00205|034|R|  after methoxyflurane anesthesia. Anesth Analg 1973 May-Jun;52(3):431-6.|5
00205|035|R|6.Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. A study of dose|3
00205|036|R|  response in man. JAMA 1973 Sep 24;225(13):1611-6.|3
00205|037|R|7.Churchill D, Knaack J, Chirito E, Barre P, Cole C, Muehrcke R, Gault MH.|3
00205|038|R|  Persisting renal insufficiency after methoxyflurane anesthesia. Report of|3
00205|039|R|  two cases and review of literature. Am J Med 1974 Apr;56(4):575-82.|3
00205|040|R|8.Rosenberg PH, Wahlstrom T. Renal and hepatic toxicity of methoxyflurane in|5
00205|041|R|  combination with tetracycline or oxytetracycline treatment in rats. Acta|5
00205|042|R|  Pharmacol Toxicol (Copenh) 1974 Jan;34(1):46-57.|5
00206|001|T|MONOGRAPH TITLE:  Digoxin, Oral/Tetracyclines (mono deleted 06/26/2025)|
00206|002|B||
00206|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00206|004|L|take action as needed.|
00206|005|B||
00206|006|A|MECHANISM OF ACTION:  In approximately 10% of patients receiving digoxin, a|
00206|007|A|considerable amount of an administered dose of the drug is metabolized by GI|
00206|008|A|bacteria to inactive digoxin reduction products (DRPs). Concomitant|
00206|009|A|administration of tetracycline may alter the GI flora, enabling an increased|
00206|010|A|amount of digoxin to be absorbed.|
00206|011|B||
00206|012|E|CLINICAL EFFECTS:  Increased serum digoxin levels with possible toxicity may|
00206|013|E|occur. This effect may persist for several months after tetracycline is|
00206|014|E|discontinued. Symptoms of digoxin toxicity can include anorexia, nausea,|
00206|015|E|vomiting, headache, fatigue, malaise, drowsiness, generalized muscle|
00206|016|E|weakness, disorientation, hallucinations, visual disturbances, and|
00206|017|E|arrhythmias.|
00206|018|B||
00206|019|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
00206|020|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00206|021|P|risk of digoxin toxicity.|
00206|022|B||
00206|023|M|PATIENT MANAGEMENT:  Monitor serum digoxin levels and observe the patient|
00206|024|M|for toxicity.  The dosage of digoxin may need to be decreased by 30-50% or|
00206|025|M|the frequency of administration may be reduced.(3)|
00206|026|B||
00206|027|D|DISCUSSION:  Approximately 10% of the patients receiving digoxin metabolize|
00206|028|D|30% or more of an ingested dose of digoxin to inactive DRPs. Concurrent|
00206|029|D|current administration of tetracycline may alter the GI flora, decreasing|
00206|030|D|the conversion of digoxin to DRPs. In these patients this could produce an|
00206|031|D|increase in plasma digoxin concentration. The effect of tetracycline on the|
00206|032|D|metabolism of digoxin to DRPs may persist for several months after the|
00206|033|D|antibiotic is discontinued.|
00206|034|D|   Concomitant administration of tetracycline and digoxin increased the|
00206|035|D|digoxin serum concentration 100%. (3)|
00206|036|B||
00206|037|R|REFERENCES:|
00206|038|B||
00206|039|R|1.Lindenbaum J, Tse-Eng D, Butler VP Jr, Rund DG. Urinary excretion of|2
00206|040|R|  reduced metabolites of digoxin. Am J Med 1981 Jul;71(1):67-74.|2
00206|041|R|2.Lindenbaum J, Rund DG, Butler VP Jr, Tse-Eng D, Saha JR. Inactivation of|2
00206|042|R|  digoxin by the gut flora: reversal by antibiotic therapy. N Engl J Med|2
00206|043|R|  1981 Oct 1;305(14):789-94.|2
00206|044|R|3.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00206|045|R|  Pharmaceuticals, Inc. August, 2018.|1
00207|001|T|MONOGRAPH TITLE:  Atorvastatin/Gemfibrozil|
00207|002|B||
00207|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00207|004|L|is contraindicated and generally should not be dispensed or administered to|
00207|005|L|the same patient.|
00207|006|B||
00207|007|A|MECHANISM OF ACTION:  Unknown.|
00207|008|B||
00207|009|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
00207|010|E|and fibric acid derivatives has been associated with severe myopathy,|
00207|011|E|rhabdomyolysis and acute renal failure.|
00207|012|B||
00207|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
00207|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
00207|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
00207|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
00207|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
00207|018|P|transporter OATP1B1 may have increased statin concentrations and be|
00207|019|P|predisposed to myopathy or rhabdomyolysis.|
00207|020|B||
00207|021|M|PATIENT MANAGEMENT:  According to 2018 ACC/AHA Blood Cholesterol Guidelines,|
00207|022|M|gemfibrozil is contraindicated in patients on statin therapy.|
00207|023|M|   According to the 2016 AHA Scientific Statement Recommendations for|
00207|024|M|Management of Clinically Significant Drug-Drug Interactions with Statins and|
00207|025|M|Select Agents Used in Patients with Cardiovascular Disease, atorvastatin|
00207|026|M|dose should be initiated at 10 mg daily and should not exceed 20 mg daily|
00207|027|M|when used concurrently with gemfibrozil.|
00207|028|M|   According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil|
00207|029|M|should not be initiated in patients on statin therapy.  Fenofibrate may be|
00207|030|M|considered with low or moderate intensity statin therapy only if benefits|
00207|031|M|outweigh the risks.|
00207|032|M|   The US, Australian, Canadian, and UK manufacturers of gemfibrozil state|
00207|033|M|that use with HMG CO-A reductase inhibitors does not outweigh the risks of|
00207|034|M|severe myopathy, rhabdomyolysis, and acute renal failure.  The Canadian|
00207|035|M|manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should|
00207|036|M|not be used concurrently.|
00207|037|M|   The US, Canadian, and UK manufacturers of atorvastatin state that|
00207|038|M|concurrent use of gemfibrozil should be avoided.|
00207|039|M|   Instruct patients receiving concurrent therapy to report any unexplained|
00207|040|M|muscle pain, tenderness or weakness.  If muscular symptoms develop, monitor|
00207|041|M|serum creatine kinase levels and renal function.  One or both agents may|
00207|042|M|need to be discontinued.|
00207|043|B||
00207|044|D|DISCUSSION:  Gemfibrozil has been shown to increase levels of cerivastatin,|
00207|045|D|lovastatin, pravastatin, rosuvastatin, and simvastatin.  Administration of|
00207|046|D|gemfibrozil with cerivastatin, lovastatin, and simvastatin has been|
00207|047|D|associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and|
00207|048|D|weakness).  Although the reaction has been reported with the statins alone,|
00207|049|D|the incidence increases dramatically with concurrent administration of|
00207|050|D|gemfibrozil.|
00207|051|D|   Concurrent fenofibrate (145 mg) with atorvastatin (20 mg) decreased the|
00207|052|D|atorvastatin area-under-curve (AUC) by 17% (range from 67% decrease to 44%|
00207|053|D|increase).  Atorvastatin maximum concentration (Cmax) and the kinetics of|
00207|054|D|fenofibrate were not significantly affected.|
00207|055|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
00207|056|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
00207|057|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
00207|058|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
00207|059|D|Veteran's Administration over a 2 year period, there were 149 reports of|
00207|060|D|rhabdomyolysis in 93,677 (0.16%) patients receiving concurrent gemfibrozil|
00207|061|D|and statin therapy compared with no reports in 1,830 patients receiving|
00207|062|D|concurrent fenofibrate and statin therapy.|
00207|063|D|   In a retrospective cohort study of 252,460 patients, concurrent use of|
00207|064|D|statins and fibrates increased the risk of rhabdomyolysis, especially in|
00207|065|D|patients with diabetes mellitus.  The risk of hospitalization for patients|
00207|066|D|aged 65 or older with diabetes mellitus, treated with a statin and fibrate,|
00207|067|D|increased 48-fold compared to statin monotherapy.|
00207|068|D|   In a retrospective study, of 468 patients with a diagnosis of myopathy,|
00207|069|D|61 received a statin prior to their diagnosis. Forty-one of these patients|
00207|070|D|developed confirmed myopathy, creatinine kinase more than or equal to 1000|
00207|071|D|IU/L.|
00207|072|B||
00207|073|R|REFERENCES:|
00207|074|B||
00207|075|R|1.Stone NJ, Robinson JG, Lichtenstein AH, Goff DC Jr, Lloyd-Jones DM, Smith|6
00207|076|R|  SC Jr, Blum C, Schwartz JS. Treatment of blood cholesterol to reduce|6
00207|077|R|  atherosclerotic cardiovascular disease risk in adults: synopsis of the|6
00207|078|R|  2013 American College of Cardiology/American Heart Association cholesterol|6
00207|079|R|  guideline. Ann Intern Med 2014 Mar 4;160(5):339-43.|6
00207|080|R|2.Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis JB, Lanfear|6
00207|081|R|  D, Virani S, Morris PB. Recommendations for Management of Clinically|6
00207|082|R|  Significant Drug-Drug Interactions With Statins and Select Agents Used in|6
00207|083|R|  Patients With Cardiovascular Disease: A Scientific Statement From the|6
00207|084|R|  American Heart Association. Circulation 2016 Nov 22;134(21):e468-e495.|6
00207|085|R|3.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
00207|086|R|  Ltd. December, 2020.|1
00207|087|R|4.Lipazil (gemfibrozil) Australian product information. Ascent Pharma Pty|1
00207|088|R|  Ltd December 5, 2011.|1
00207|089|R|5.Teva-Gemfibrozil (gemfibrozil) Canadian product monograph. Teva Canada|1
00207|090|R|  Limited June 29, 2015.|1
00207|091|R|6.Lopid (gemfibrozil) UK summary of product characteristics. Pfizer Limited|1
00207|092|R|  May, 2016.|1
00207|093|R|7.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
00207|094|R|  2020.|1
00207|095|R|8.Lipitor (atorvastatin) Canadian product information. Pfizer Canada Inc.|1
00207|096|R|  May 31, 2019.|1
00207|097|R|9.Lipitor (atorvastatin calcium trihydrate) UK summary of product|1
00207|098|R|  characteristics. Pfizer Limited April 1, 2019.|1
00207|099|R|10.Thompson GR, Ford J, Jenkinson M, Trayner I. Efficacy of mevinolin as|2
00207|100|R|   adjuvant therapy for refractory familial hypercholesterolaemia. Q J Med|2
00207|101|R|   1986 Aug;60(232):803-11.|2
00207|102|R|11.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
00207|103|R|   cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
00207|104|R|   polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
00207|105|R|12.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of|3
00207|106|R|   a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
00207|107|R|   2002;101(7):53-6.|3
00207|108|R|13.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
00207|109|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
00207|110|R|   at:|3
00207|111|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
00207|112|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
00207|113|R|14.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
00207|114|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
00207|115|R|   95(1):120-2.|2
00207|116|R|15.Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, Liu L, Lin|5
00207|117|R|   JH, Pearson PG, Baillie TA. Mechanistic studies on metabolic interactions|5
00207|118|R|   between gemfibrozil and statins. J Pharmacol Exp Ther 2002 Jun;|5
00207|119|R|   301(3):1042-51.|5
00207|120|R|16.Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly|2
00207|121|R|   decreases and gemfibrozil increases the plasma concentrations of|2
00207|122|R|   atorvastatin and its metabolites. Clin Pharmacol Ther 2005 Aug;|2
00207|123|R|   78(2):154-67.|2
00207|124|R|17.Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J.|5
00207|125|R|   Interaction between fibrates and statins--metabolic interactions with|5
00207|126|R|   gemfibrozil. Drug Metabol Drug Interact 2003;19(3):161-76.|5
00207|127|R|18.Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking|3
00207|128|R|   atorvastatin with gemfibrozil. Am J Cardiol 1998 Feb 1;81(3):368-9.|3
00207|129|R|19.Shanahan RL, Kerzee JA, Sandhoff BG, Carroll NM, Merenich JA. Low|2
00207|130|R|   myopathy rates associated with statins as monotherapy or combination|2
00207|131|R|   therapy with interacting drugs in a group model health maintenance|2
00207|132|R|   organization. Pharmacotherapy 2005 Mar;25(3):345-51.|2
00207|133|R|20.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
00207|134|R|   Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized|2
00207|135|R|   rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004|2
00207|136|R|   Dec 1;292(21):2585-90.|2
00207|137|R|21.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
00207|138|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
00207|139|R|22.Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and|3
00207|140|R|   acute renal failure after changing statin-fibrate combinations.|3
00207|141|R|   Cardiology 2000;94(2):127-8.|3
00207|142|R|23.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun|6
00207|143|R|   LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,|6
00207|144|R|   Heidenreich PA. 2018|6
00207|145|R|   AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the|6
00207|146|R|   Management of Blood Cholesterol: A Report of the American College of|6
00207|147|R|   Cardiology/American Heart Association Task Force on Clinical Practice|6
00207|148|R|   Guidelines. J Am Coll Cardiol 2019 Jun 25;73(24):e285-e350.|6
00208|001|T|MONOGRAPH TITLE:  Levodopa/Pyridoxine|
00208|002|B||
00208|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00208|004|L|take action as needed.|
00208|005|B||
00208|006|A|MECHANISM OF ACTION:  Pyridoxine increases levodopa metabolism, decreasing|
00208|007|A|the amount of levodopa available to the central nervous system.|
00208|008|B||
00208|009|E|CLINICAL EFFECTS:  The pharmacologic effects of levodopa may be decreased.|
00208|010|B||
00208|011|P|PREDISPOSING FACTORS:  None determined.|
00208|012|B||
00208|013|M|PATIENT MANAGEMENT:  Avoid pyridoxine in patients receiving levodopa alone;|
00208|014|M|however, the interaction can be minimized by giving levodopa with a|
00208|015|M|peripheral decarboxylase inhibitor (e.g. carbidopa, benserazide).|
00208|016|B||
00208|017|D|DISCUSSION:  In patients with Parkinson's disease, as little as 10 mg of|
00208|018|D|pyridoxine may reverse the clinical benefits as well as the adverse effects|
00208|019|D|of levodopa. Coadministration of levodopa with either carbidopa or|
00208|020|D|benserazide has minimized the effects of this interaction.|
00208|021|B||
00208|022|R|REFERENCES:|
00208|023|B||
00208|024|R|1.Jameson HD. Pyridoxine for levodopa-induced dystonia. JAMA 1970 Mar 9;|3
00208|025|R|  211(10):1700.|3
00208|026|R|2.Cotzias GC, Papavasiliou PS. Blocking the negative effects of pyridoxine|3
00208|027|R|  on patients receiving levodopa. JAMA 1971 Mar 1;215(9):1504-5.|3
00208|028|R|3.Yahr MD, Duvoisin RC. Pyridoxine, levodopa, and L-alpha-methyldopa|3
00208|029|R|  hydrazine regimen in parkinsonism. JAMA 1971 Jun 28;216(13):2141.|3
00208|030|R|4.Leon AS, Spiegel HE, Thomas G, Abrams WB. Pyridoxine antagonism of|3
00208|031|R|  levodopa in parkinsonism. JAMA 1971 Dec 27;218(13):1924-7.|3
00208|032|R|5.Papavasiliou PS, Cotzias GC, Duby SE, Steck AJ, Fehling C, Bell MA.|2
00208|033|R|  Levodopa in Parkinsonism: potentiation of central effects with a|2
00208|034|R|  peripheral inhibitor. N Engl J Med 1972 Jan 6;286(1):8-14.|2
00208|035|R|6.Yahr MD, Duvoisin RC. Pyridoxine and levodopa in the treatment of|6
00208|036|R|  Parkinsonism. JAMA 1972 May 8;220(6):861.|6
00208|037|R|7.Mars H. Levodopa, carbidopa, and pyridoxine in Parkinson disease.|2
00208|038|R|  Metabolic interactions. Arch Neurol 1974 Jun;30(6):444-7.|2
00208|039|R|8.Prolopa (levodopa, benserazide) CA prescribing information. Hoffmann-La|1
00208|040|R|  Roche Limited June 12, 2009.|1
00209|001|T|MONOGRAPH TITLE:  Insulin/Fenfluramine;Dexfenfluramine|
00209|002|B||
00209|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00209|004|L|take action as needed.|
00209|005|B||
00209|006|A|MECHANISM OF ACTION:  Fenfluramine increases glucose uptake at the receptor|
00209|007|A|site (ie, skeletal muscle).|
00209|008|B||
00209|009|E|CLINICAL EFFECTS:  The hypoglycemic effect of insulin is increased.|
00209|010|B||
00209|011|P|PREDISPOSING FACTORS:  Diabetes.|
00209|012|B||
00209|013|M|PATIENT MANAGEMENT:  In diabetic patients receiving insulin, monitor blood|
00209|014|M|glucose levels and observe the patient for signs of hypoglycemia when|
00209|015|M|initiating therapy with fenfluramine and for symptoms of hyperglycemia when|
00209|016|M|fenfluramine is discontinued.|
00209|017|B||
00209|018|D|DISCUSSION:  When administered before meals or to fasting patients,|
00209|019|D|fenfluramine has been found to have hypoglycemic action. Numerous reports|
00209|020|D|have demonstrated fenfluramine to potentiate the hypoglycemic effect of|
00209|021|D|insulin in diabetic patients.|
00209|022|B||
00209|023|R|REFERENCES:|
00209|024|B||
00209|025|R|1.Turtle JR, Burgess JA. Hypoglycemic action of fenfluramine in diabetes|2
00209|026|R|  mellitus. Diabetes 1973 Nov;22(11):858-67.|2
00209|027|R|2.Harrison LC, King-Roach A, Martin FI, Melick RA. The effect of|5
00209|028|R|  fenfluramine on insulin binding and on basal and insulin- stimulated|5
00209|029|R|  oxidation of 1-14C-glucose by human adipose tissue. Postgrad Med J 1975;51|5
00209|030|R|  Suppl 1:110-4.|5
00209|031|R|3.Salmela PI, Sotaniemi EA, Viikari J, Solakivi-Jaakkola T, Jarvensivu P.|2
00209|032|R|  Fenfluramine therapy in non-insulin-dependent diabetic patients: effects|2
00209|033|R|  on body weight, glucose homeostasis, serum lipoproteins, and antipyrine|2
00209|034|R|  metabolism. Diabetes Care 1981 Sep-Oct;4(5):535-40.|2
00209|035|R|4.Barseghian G, Lev-Ran A, Hwang D, Josefsberg Z, Tomkinson C. Fenfluramine|5
00209|036|R|  inhibits insulin secretion and potentiates glucagon release by the|5
00209|037|R|  perfused rat pancreas. Eur J Pharmacol 1983 Dec 9;96(1-2):53-9.|5
00209|038|R|5.Pestell RG, Crock PA, Ward GM, Alford FP, Best JD. Fenfluramine increases|2
00209|039|R|  insulin action in patients with NIDDM. Diabetes Care 1989 Apr;12(4):252-8.|2
00209|040|R|6.Storlien LH, Thorburn AW, Smythe GA, Jenkins AB, Chisholm DJ, Kraegen EW.|5
00209|041|R|  Effect of d-fenfluramine on basal glucose turnover and fat-feeding-|5
00209|042|R|  induced insulin resistance in rats. Diabetes 1989 Apr;38(4):499-503.|5
00210|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Thioamines (mono deleted 02/23/2022)|
00210|002|B||
00210|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00210|004|L|take action as needed.|
00210|005|B||
00210|006|A|MECHANISM OF ACTION:  Unknown.|
00210|007|B||
00210|008|E|CLINICAL EFFECTS:  The therapeutic and toxic effects of digitalis glycosides|
00210|009|E|may be increased. Symptoms of digoxin toxicity can include anorexia, nausea,|
00210|010|E|vomiting, headache, fatigue, malaise, drowsiness, generalized muscle|
00210|011|E|weakness, disorientation, hallucinations, visual disturbances, and|
00210|012|E|arrhythmias.|
00210|013|B||
00210|014|P|PREDISPOSING FACTORS:  Hypothyroid patients appear to be sensitive to|
00210|015|P|digitalis therapy while thyrotoxic patients appear to be resistant.|
00210|016|B||
00210|017|M|PATIENT MANAGEMENT:  Observe hyperthyroid patients for signs of toxicity and|
00210|018|M|reduce the dose of digitalis glycoside if indicated.|
00210|019|B||
00210|020|D|DISCUSSION:  Plasma levels of digoxin and digitoxin are increased in|
00210|021|D|hypothyroid patients while hyperthyroid patients have lower levels compared|
00210|022|D|to patients with normal thyroid function. Other studies have demonstrated|
00210|023|D|thyrotoxic patients to be resistant to digitalis preparations and|
00210|024|D|hypothyroid patients to be sensitive.|
00210|025|B||
00210|026|R|REFERENCES:|
00210|027|B||
00210|028|R|1.Frye RL, Braunwald E. Studies on digitalis. III. The influence of|2
00210|029|R|  triiodothyronine on digitalis requirements. Circulation 1961 Mar;|2
00210|030|R|  23:376-82.|2
00210|031|R|2.Doherty JE, Perkins WH. Digoxin metabolism in hypo- and hyperthyroidism.|3
00210|032|R|  Studies with tritiated digoxin in thyroid disease. Ann Intern Med 1966|3
00210|033|R|  Mar;64(3):489-507.|3
00210|034|R|3.Croxson MS, Ibbertson HK. Serum digoxin in patients with thyroid disease.|2
00210|035|R|  Br Med J 1975 Sep 6;3(5983):566-8.|2
00210|036|R|4.Huffman DH, Klaassen CD, Hartman CR. Digoxin in hyperthyroidism. Clin|3
00210|037|R|  Pharmacol Ther 1977 Nov;22(5 Pt 1):533-8.|3
00210|038|R|5.Shenfield GM, Thompson J, Horn DB. Plasma and urinary digoxin in thyroid|2
00210|039|R|  dysfunction. Eur J Clin Pharmacol 1977 Dec 28;12(6):437-43.|2
00210|040|R|6.Bonelli J, Haydl H, Hruby K, Kaik G. The pharmacokinetics of digoxin in|2
00210|041|R|  patients with manifest hyperthyroidism and after normalization of thyroid|2
00210|042|R|  function. Int J Clin Pharmacol Biopharm 1978 Jul;16(7):302-6.|2
00211|001|T|MONOGRAPH TITLE:  Digoxin/Quinine|
00211|002|B||
00211|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00211|004|L|take action as needed.|
00211|005|B||
00211|006|A|MECHANISM OF ACTION:  Reduced clearance of digoxin and possible displacement|
00211|007|A|of digoxin from its tissue binding sites.|
00211|008|B||
00211|009|E|CLINICAL EFFECTS:  May observe increased digoxin toxicity. Symptoms of|
00211|010|E|digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue,|
00211|011|E|malaise, drowsiness, generalized muscle weakness, disorientation,|
00211|012|E|hallucinations, visual disturbances, and arrhythmias.|
00211|013|B||
00211|014|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal and/or|
00211|015|P|hepatic function, hypokalemia, hypercalcemia, and/or hypomagnesemia may|
00211|016|P|increase the risk of digoxin toxicity.|
00211|017|B||
00211|018|M|PATIENT MANAGEMENT:  Monitor serum digoxin levels and observe the patient|
00211|019|M|for signs and symptoms of digoxin toxicity.  The dosage of digoxin may need|
00211|020|M|to be decreased by 15-30% or the frequency of administration may be|
00211|021|M|reduced.(6)  Consider therapy with an agent which has not been shown to|
00211|022|M|interact with digoxin.|
00211|023|B||
00211|024|D|DISCUSSION:  This interaction is well documented.|
00211|025|D|   Concomitant administration of digoxin and quinine resulted in a 33%|
00211|026|D|increase in digoxin area-under-the-curve (AUC).(6)|
00211|027|B||
00211|028|R|REFERENCES:|
00211|029|B||
00211|030|R|1.Wandell M, Powell JR, Hager WD, Fenster PE, Graves PE, Conrad KA, Goldman|2
00211|031|R|  S. Effect of quinine on digoxin kinetics. Clin Pharmacol Ther 1980 Oct;|2
00211|032|R|  28(4):425-30.|2
00211|033|R|2.Aronson JK, Carver JG. Interaction of digoxin with quinine. Lancet 1981|2
00211|034|R|  Jun 27;1(8235):1418.|2
00211|035|R|3.Pedersen KE, Lysgaard Madsen J, Klitgaard NA, Kjaer K, Hvidt S. Effect of|2
00211|036|R|  quinine on plasma digoxin concentration and renal digoxin clearance. Acta|2
00211|037|R|  Med Scand 1985;218(2):229-32.|2
00211|038|R|4.Hedman A, Angelin B, Arvidsson A, Dahlqvist R, Nilsson B. Interactions in|2
00211|039|R|  the renal and biliary elimination of digoxin: stereoselective difference|2
00211|040|R|  between quinine and quinidine. Clin Pharmacol Ther 1990 Jan;47(1):20-6.|2
00211|041|R|5.Hedman A. Inhibition by basic drugs of digoxin secretion into human bile.|5
00211|042|R|  Eur J Clin Pharmacol 1992;42(4):457-9.|5
00211|043|R|6.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00211|044|R|  Pharmaceuticals, Inc. August, 2018.|1
00212|001|T|MONOGRAPH TITLE:  Digoxin/Verapamil; Mibefradil|
00212|002|B||
00212|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00212|004|L|of severe adverse interaction.|
00212|005|B||
00212|006|A|MECHANISM OF ACTION:  Verapamil may reduce the clearance of digoxin and may|
00212|007|A|displace digoxin from its tissue binding sites.|
00212|008|B||
00212|009|E|CLINICAL EFFECTS:  May observe increased digoxin toxicity.  Symptoms of|
00212|010|E|digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue,|
00212|011|E|malaise, drowsiness, generalized muscle weakness, disorientation,|
00212|012|E|hallucinations, visual disturbances, and arrhythmias.|
00212|013|B||
00212|014|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal or|
00212|015|P|hepatic function, low heart rate, hypokalemia, hypercalcemia, and/or|
00212|016|P|hypomagnesemia may increase the risk of digoxin toxicity.|
00212|017|B||
00212|018|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor serum|
00212|019|M|digoxin levels and observe the patient for symptoms of digitalis toxicity.|
00212|020|M|   Upon adding verapamil, digoxin dosages should first be decreased in|
00212|021|M|anticipation of an interaction, then adjusted accordingly.  The dosage of|
00212|022|M|oral digoxin may need to be decreased by 30-50%, or the frequency of|
00212|023|M|administration may be reduced.|
00212|024|M|   For IV or IM digoxin, the dosage may need to be decreased by 15-30%, or|
00212|025|M|the dosing frequency may be reduced.|
00212|026|M|   Concurrent therapy in patients with low heart rates may unmask sick sinus|
00212|027|M|syndrome.  Consider therapy with an agent which has not been shown to|
00212|028|M|interact with digoxin.|
00212|029|B||
00212|030|D|DISCUSSION:  Serum digoxin concentrations are increased 50% to 70% during|
00212|031|D|concurrent therapy of oral digoxin and verapamil.  The increased|
00212|032|D|concentrations occur within seven days of initiation of verapamil.  The|
00212|033|D|clinical and toxic effects of digoxin have been increased.|
00212|034|D|   The manufacturer of mibefradil states that concurrent use of mibefradil|
00212|035|D|and digoxin in patients with low heart rates may result in the unmasking of|
00212|036|D|sick sinus syndrome.|
00212|037|D|   Concomitant administration of verapamil and oral digoxin increased the|
00212|038|D|digoxin serum concentration by 50-75%.(15)  Concurrent use of verapamil with|
00212|039|D|IV or IM digoxin increased digoxin area-under-curve (AUC) by 24%.(16)|
00212|040|B||
00212|041|R|REFERENCES:|
00212|042|B||
00212|043|R|1.Belz GG, Aust PE, Munkes R. Digoxin plasma concentrations and nifedipine.|2
00212|044|R|  Lancet 1981 Apr 11;1(8224):844-5.|2
00212|045|R|2.Pedersen KE, Dorph-Pedersen A, Hvidt S, Klitgaard NA, Nielsen-Kudsk F.|2
00212|046|R|  Digoxin-verapamil interaction. Clin Pharmacol Ther 1981 Sep;30(3):311-6.|2
00212|047|R|3.Klein HO, Lang R, Weiss E, Di Segni E, Libhaber C, Guerrero J, Kaplinsky|2
00212|048|R|  E. The influence of verapamil on serum digoxin concentration. Circulation|2
00212|049|R|  1982 May;65(5):998-1003.|2
00212|050|R|4.Klein HO, Kaplinsky E. Verapamil and digoxin: their respective effects on|6
00212|051|R|  atrial fibrillation and their interaction. Am J Cardiol 1982 Oct;|6
00212|052|R|  50(4):894-902.|6
00212|053|R|5.Belz GG, Doering W, Munkes R, Matthews J. Interaction between digoxin and|2
00212|054|R|  calcium antagonists and antiarrhythmic drugs. Clin Pharmacol Ther 1983|2
00212|055|R|  Apr;33(4):410-7.|2
00212|056|R|6.Zatuchni J. Verapamil-digoxin interaction. Am Heart J 1984 Aug;|3
00212|057|R|  108(2):412-3.|3
00212|058|R|7.Rameis H, Magometschnigg D, Ganzinger U. The diltiazem-digoxin|2
00212|059|R|  interaction. Clin Pharmacol Ther 1984 Aug;36(2):183-9.|2
00212|060|R|8.Elkayam U, Parikh K, Torkan B, Weber L, Cohen JL, Rahimtoola SH. Effect of|2
00212|061|R|  diltiazem on renal clearance and serum concentration of digoxin in|2
00212|062|R|  patients with cardiac disease. Am J Cardiol 1985 May 1;55(11):1393-5.|2
00212|063|R|9.Kuhlmann J. Effects of verapamil, diltiazem, and nifedipine on plasma|2
00212|064|R|  levels and renal excretion of digitoxin. Clin Pharmacol Ther 1985 Dec;|2
00212|065|R|  38(6):667-73.|2
00212|066|R|10.Johnson BF, Wilson J, Marwaha R, Hoch K, Johnson J. The comparative|2
00212|067|R|   effects of verapamil and a new dihydropyridine calcium channel blocker on|2
00212|068|R|   digoxin pharmacokinetics. Clin Pharmacol Ther 1987 Jul;42(1):66-71.|2
00212|069|R|11.Rodin SM, Johnson BF, Wilson J, Ritchie P, Johnson J. Comparative effects|2
00212|070|R|   of verapamil and isradipine on steady-state digoxin kinetics. Clin|2
00212|071|R|   Pharmacol Ther 1988 Jun;43(6):668-72.|2
00212|072|R|12.Rendtorff C, Johannessen AC, Halck S, Klitgaard NA. Verapamil-digoxin|2
00212|073|R|   interaction in chronic hemodialysis patients. Scand J Urol Nephrol 1990;|2
00212|074|R|   24(2):137-9.|2
00212|075|R|13.Hedman A, Angelin B, Arvidsson A, Beck O, Dahlqvist R, Nilsson B, Olsson|2
00212|076|R|   M, Schenck-Gustafsson K. Digoxin-verapamil interaction: reduction of|2
00212|077|R|   biliary but not renal digoxin clearance in humans. Clin Pharmacol Ther|2
00212|078|R|   1991 Mar;49(3):256-62.|2
00212|079|R|14.Posicor (mibefradil) US prescribing information. Roche Pharmaceuticals|1
00212|080|R|   December, 1997.|1
00212|081|R|15.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00212|082|R|   Pharmaceuticals, Inc. August, 2018.|1
00212|083|R|16.Lanoxin Injection (digoxin) US prescribing information. Covis Pharma|1
00212|084|R|   October, 2019.|1
00213|001|T|MONOGRAPH TITLE:  Digoxin/Selected Calcium Channel Blockers|
00213|002|B||
00213|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00213|004|L|take action as needed.|
00213|005|B||
00213|006|A|MECHANISM OF ACTION:  Calcium channel blockers may inhibit the renal|
00213|007|A|clearance of digoxin through an unknown mechanism.|
00213|008|B||
00213|009|E|CLINICAL EFFECTS:  Plasma digoxin concentrations may be elevated. In|
00213|010|E|addition, the negative chronotropic effects of digoxin and bepridil are|
00213|011|E|additive, resulting in a cumulative decrease in heart rate.|
00213|012|E|   Symptoms of digoxin toxicity can include anorexia, nausea, vomiting,|
00213|013|E|headache, fatigue, malaise, drowsiness, generalized muscle weakness,|
00213|014|E|disorientation, hallucinations, visual disturbances, and arrhythmias.|
00213|015|B||
00213|016|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
00213|017|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00213|018|P|risk of digoxin toxicity.|
00213|019|B||
00213|020|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor serum|
00213|021|M|digoxin levels and observe the patient for symptoms of digoxin toxicity.|
00213|022|M|Upon adding a calcium channel blocker, digoxin should first be decreased in|
00213|023|M|anticipation of interaction, then adjust the dosage accordingly.  The dosage|
00213|024|M|of digoxin may need to be decreased by 15-50% or the frequency of|
00213|025|M|administration may be reduced.|
00213|026|B||
00213|027|D|DISCUSSION:  The effect of bepridil on steady-state serum digoxin levels was|
00213|028|D|studied in a randomized, double-blind investigation.  Concurrent|
00213|029|D|administration of bepridil and digoxin produced a 34% increase in serum|
00213|030|D|digoxin levels compared to administration of digoxin alone.  Concomitant|
00213|031|D|administration of both drugs was associated with additive negative|
00213|032|D|chronotropic effects.|
00213|033|D|   Information on the effects of diltiazem on digoxin concentrations are|
00213|034|D|conflicting.  Several studies have reported that concurrent use of digoxin|
00213|035|D|and diltiazem led to an increased steady state digoxin level as well as an|
00213|036|D|increased digoxin area-under-curve (AUC) and decreased renal clearance, and|
00213|037|D|reduced volume of distribution.  However, one of these studies reported no|
00213|038|D|significant change in digoxin half-life, peak concentration (Cmax), time to|
00213|039|D|Cmax (Tmax), or volume of distribution, and seven other studies reported no|
00213|040|D|effect of diltiazem on serum digoxin concentrations or renal digoxin|
00213|041|D|clearance.|
00213|042|D|   Concomitant isradipine administration significantly decreased (by 9%) the|
00213|043|D|the digoxin volume of distribution and increased (by 25%) digoxin Cmax;|
00213|044|D|however, the digoxin steady state serum concentration, AUC, and renal|
00213|045|D|clearance were not affected.|
00213|046|D|   In patients with congestive heart failure on digoxin therapy, the|
00213|047|D|addition of felodipine resulted in a significant increase in digoxin Cmax|
00213|048|D|attained following oral administration. This increase was most notable in|
00213|049|D|patients with high felodipine serum concentrations.  Digoxin trough levels|
00213|050|D|and six hour post-dose levels were unaffected; as were digoxin AUC|
00213|051|D|measurements.|
00213|052|D|   There is one case report of an interaction between nifedipine and|
00213|053|D|digoxin; however, a study in 28 patients found no effect of nifedipine on|
00213|054|D|digoxin.|
00213|055|D|   A study in ten subjects showed that nisoldipine increased digoxin levels|
00213|056|D|by 15%.|
00213|057|D|   Information on the effects of nicardipine on digoxin kinetics is|
00213|058|D|conflicting.  One study in twenty patients showed no effect of nicardipine|
00213|059|D|on digoxin.  One study in ten subjects showed a significant increase in|
00213|060|D|digoxin levels: however, this was seen in only one subject.|
00213|061|D|   Concurrent nitrendipine has been shown to increase digoxin serum levels|
00213|062|D|by 57% and digoxin AUC by 15%.|
00213|063|D|   Concurrent diltiazem has been shown to increase digoxin serum|
00213|064|D|concentration by 20%. Concurrent nifedipine has been shown to increase|
00213|065|D|digoxin serum concentration by 45%.|
00213|066|B||
00213|067|R|REFERENCES:|
00213|068|B||
00213|069|R|1.Belz GG, Wistuba S, Matthews JH. Digoxin and bepridil: pharmacokinetic and|2
00213|070|R|  pharmacodynamic interactions. Clin Pharmacol Ther 1986 Jan;39(1):65-71.|2
00213|071|R|2.Kuhlmann J. Effects of nifedipine and diltiazem on plasma levels and renal|2
00213|072|R|  excretion of beta-acetyldigoxin. Clin Pharmacol Ther 1985 Feb;37(2):150-6.|2
00213|073|R|3.Oyama Y, Fujii S, Kanda K, Akino E, Kawasaki H, Nagata M, Goto K.|2
00213|074|R|  Digoxin-diltiazem interaction. Am J Cardiol 1984 May 15;53(10):1480-1.|2
00213|075|R|4.Rameis H, Magometschnigg D, Ganzinger U. The diltiazem-digoxin|2
00213|076|R|  interaction. Clin Pharmacol Ther 1984 Aug;36(2):183-9.|2
00213|077|R|5.Andrejak M, Hary L, Andrejak MT, Lesbre JP. Diltiazem increases steady|2
00213|078|R|  state digoxin serum levels in patients with cardiac disease. J Clin|2
00213|079|R|  Pharmacol 1987 Dec;27(12):967-70.|2
00213|080|R|6.North DS, Mattern AL, Hiser WW. The influence of diltiazem hydrochloride|2
00213|081|R|  on trough serum digoxin concentrations. Drug Intell Clin Pharm 1986 Jun;|2
00213|082|R|  20(6):500-3.|2
00213|083|R|7.Beltrami TR, May JJ, Bertino JS Jr. Lack of effects of diltiazem on|2
00213|084|R|  digoxin pharmacokinetics. J Clin Pharmacol 1985 Jul-Aug;25(5):390-2.|2
00213|085|R|8.Elkayam U, Parikh K, Torkan B, Weber L, Cohen JL, Rahimtoola SH. Effect of|2
00213|086|R|  diltiazem on renal clearance and serum concentration of digoxin in|2
00213|087|R|  patients with cardiac disease. Am J Cardiol 1985 May 1;55(11):1393-5.|2
00213|088|R|9.Young PM, Boden WE, More G. Lack of effect of high dose diltiazem on serum|4
00213|089|R|  digoxin levels. Clin Pharmacol Ther 1985;37(2):239.|4
00213|090|R|10.Schrager BR, Pina I, Frangi M, Applewhite S, Sequeira R, Chahine RA.|4
00213|091|R|   Diltiazem, digoxin interaction?. Circulation 1983 Oct;68(Suppl|4
00213|092|R|   III):III-368.|4
00213|093|R|11.Jones WN, Kern KB, Rindone JP, Mayersohn M, Bliss M, Goldman S.|2
00213|094|R|   Digoxin-diltiazem interaction: a pharmacokinetic evaluation. Eur J Clin|2
00213|095|R|   Pharmacol 1986;31(3):351-3.|2
00213|096|R|12.Boden WE, More G, Sharma S, Bough EW, Korr KS, Young PM, Shulman RS. No|2
00213|097|R|   increase in serum digoxin concentration with high-dose diltiazem. Am J|2
00213|098|R|   Med 1986 Sep;81(3):425-8.|2
00213|099|R|13.Johnson BF, Wilson J, Marwaha R, Hoch K, Johnson J. The comparative|2
00213|100|R|   effects of verapamil and a new dihydropyridine calcium channel blocker on|2
00213|101|R|   digoxin pharmacokinetics. Clin Pharmacol Ther 1987 Jul;42(1):66-71.|2
00213|102|R|14.Rodin SM, Johnson BF, Wilson J, Ritchie P, Johnson J. Comparative effects|2
00213|103|R|   of verapamil and isradipine on steady-state digoxin kinetics. Clin|2
00213|104|R|   Pharmacol Ther 1988 Jun;43(6):668-72.|2
00213|105|R|15.Rehnqvist N, Billing E, Moberg L, Lundman T, Olsson G. Pharmacokinetics|2
00213|106|R|   of felodipine and effect on digoxin plasma levels in patients with heart|2
00213|107|R|   failure. Drugs 1987;34 Suppl 3:33-42.|2
00213|108|R|16.Dunselman PH, Scaf AH, Kuntze CE, Lie KI, Wesseling H. Digoxin-felodipine|2
00213|109|R|   interaction in patients with congestive heart failure. Eur J Clin|2
00213|110|R|   Pharmacol 1988;35(5):461-5.|2
00213|111|R|17.Debruyne D, Commeau P, Grollier G, Huret B, Scanu P, Moulin M.|2
00213|112|R|   Nicardipine does not significantly affect serum digoxin concentrations at|2
00213|113|R|   the steady state of patients with congestive heart failure. Int J Clin|2
00213|114|R|   Pharmacol Res 1989;9(1):15-9.|2
00213|115|R|18.Lessem J, Bellinetto A. Interaction between digoxin and the calcium|2
00213|116|R|   antagonists nicardipine and tiapamil. Clin Ther 1983;5(6):595-602.|2
00213|117|R|19.Kirch W, Stenzel J, Dylewicz P, Hutt HJ, Santos SR, Ohnhaus EE. Influence|2
00213|118|R|   of nisoldipine on haemodynamic effects and plasma levels of digoxin. Br J|2
00213|119|R|   Clin Pharmacol 1986 Aug;22(2):155-9.|2
00213|120|R|20.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00213|121|R|   Pharmaceuticals, Inc. August, 2018.|1
00214|001|T|MONOGRAPH TITLE:  Misc Antifungal Agents/Astemizole; Terfenadine|
00214|002|B||
00214|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00214|004|L|is contraindicated and generally should not be dispensed or administered to|
00214|005|L|the same patient.|
00214|006|B||
00214|007|A|MECHANISM OF ACTION:  Fluconazole, itraconazole, ketoconazole, posaconazole,|
00214|008|A|and voriconazole inhibit the metabolism of astemizole, mizolastine, and|
00214|009|A|terfenadine.|
00214|010|B||
00214|011|E|CLINICAL EFFECTS:  Increased serum levels of astemizole, mizolastine, and|
00214|012|E|terfenadine with possibly increased side effects including life-threatening|
00214|013|E|cardiac arrhythmias such as QT prolongation or torsades de pointes.|
00214|014|E|   Fatalities have been reported from the combination of azole antifungals|
00214|015|E|with astemizole and terfenadine.|
00214|016|B||
00214|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00214|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
00214|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00214|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00214|021|P|female gender, or advanced age.(23)|
00214|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00214|023|P|higher systemic concentrations of either QT prolonging drug are additional|
00214|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00214|025|P|drug concentrations include rapid infusion of an intravenous dose or|
00214|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00214|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00214|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(22)|
00214|029|B||
00214|030|M|PATIENT MANAGEMENT:  Until further clinical data are available, because of|
00214|031|M|the potential seriousness of this possible interaction, avoid concomitant|
00214|032|M|administration of these drugs. The concurrent use of terfenadine or|
00214|033|M|astemizole and ketoconazole or itraconazole is contraindicated according to|
00214|034|M|package labeling.   The concurrent use of fluconazole at doses of 400 mg per|
00214|035|M|day or greater with terfenadine is contraindicated.  Concurrent therapy with|
00214|036|M|fluconazole doses of less than 400 mg per day with terfenadine should be|
00214|037|M|carefully monitored.  The concurrent use of mizolastine and azole|
00214|038|M|antifungals is contraindicated.  The manufacturer of voriconazole states|
00214|039|M|that concurrent administration with astemizole or terfenadine is|
00214|040|M|contraindicated.  The concurrent use of posaconazole and either astemizole|
00214|041|M|or terfenadine is contraindicated.|
00214|042|M|   Fexofenadine, desloratadine, and loratadine, nonsedating antihistamines|
00214|043|M|which have been shown to have no effects on cardiac function, may be|
00214|044|M|alternative in patients receiving azole antifungals.|
00214|045|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00214|046|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00214|047|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00214|048|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00214|049|B||
00214|050|D|DISCUSSION:  Cardiac toxicity (torsades de pointes, a form of polymorphic|
00214|051|D|ventricular tachycardia associated with prolongation of the QT interval) was|
00214|052|D|reported in a 39-year old woman taking terfenadine and ketoconazole|
00214|053|D|concomitantly.(1) Plasma terfenadine levels were higher than expected for a|
00214|054|D|patient receiving 60 mg twice daily. When electrocardiograms from patients|
00214|055|D|receiving terfenadine and ketoconazole concurrently were compared with|
00214|056|D|electrocardiograms from patients receiving only ketoconazole, a 10 to 20|
00214|057|D|millisecond prolongation in the corrected QT interval was found at times of|
00214|058|D|high, unchanged terfenadine levels and lower than normal levels of the acid|
00214|059|D|metabolite.(3)  One study of concurrent therapy with fluconazole 200 mg|
00214|060|D|daily did not show a prolongation of the QTc interval, while another study|
00214|061|D|with fluconazole dosages of 400 mg and 800 mg daily showed significant|
00214|062|D|increases in plasma levels of terfenadine.(13)|
00214|063|D|   In a study in 24 healthy subjects, concurrent ketoconazole (400 mg daily)|
00214|064|D|and fexofenadine (120 mg twice daily) increased the fexofenadine maximum|
00214|065|D|concentration (Cmax) and area-under-curve (AUC) by 135% and 164%,|
00214|066|D|respectively.  However, there were no changes in adverse effects or QTc|
00214|067|D|interval.(14)|
00214|068|B||
00214|069|R|REFERENCES:|
00214|070|B||
00214|071|R|1.Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR Jr.|3
00214|072|R|  Torsades de pointes occurring in association with terfenadine use. JAMA|3
00214|073|R|  1990 Dec 5;264(21):2788-90.|3
00214|074|R|2.Eller MG, Okerholm RA. Pharmacokinetic interaction between terfenadine and|4
00214|075|R|  ketoconazole. Clin Pharmacol Ther 1991 Feb;49:130.|4
00214|076|R|3.Mathews DR, McNutt B, Okerholm R, Flicker M, McBride G. Torsades de|2
00214|077|R|  pointes occurring in association with terfenadine use. JAMA 1991 Nov 6;|2
00214|078|R|  266(17):2375-6.|2
00214|079|R|4.Data on file. Janssen Pharmaceutica Products, L.P. July 31, 1992.|1
00214|080|R|5.Pohjola-Sintonen S, Viitasalo M, Toivonene L, Neuvonen P. Torsades de|3
00214|081|R|  pointes after terfenadine-itraconazole interaction. BMJ 1993 Jan 16;|3
00214|082|R|  306(6871):186.|3
00214|083|R|6.Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR.|2
00214|084|R|  Terfenadine-ketoconazole interaction. Pharmacokinetic and|2
00214|085|R|  electrocardiographic consequences. JAMA 1993 Mar 24-31;269(12):1513-8.|2
00214|086|R|7.Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic|3
00214|087|R|  actions of terfenadine. JAMA 1993 Mar 24-31;269(12):1532-6.|3
00214|088|R|8.Peck CC, Temple R, Collins JM. Understanding consequences of concurrent|6
00214|089|R|  therapies. JAMA 1993 Mar 24-31;269(12):1550-2.|6
00214|090|R|9.Claritin (loratadine) US prescribing information. Schering-Plough|1
00214|091|R|  Corporation January, 1997.|1
00214|092|R|10.Zimmermann M, Duruz H, Guinand O, Broccard O, Levy P, Lacatis D, Bloch A.|3
00214|093|R|   Torsades de Pointes after treatment with terfenadine and ketoconazole.|3
00214|094|R|   Eur Heart J 1992 Jul;13(7):1002-3.|3
00214|095|R|11.Affrime MB, Lorber R, Danzig M, Cuss F, Brannan MD. Three month|4
00214|096|R|   evaluation of electrocardiographic effects of loratatdine in humans. J|4
00214|097|R|   Allergy Clin Immunol 1993;91(1):259.|4
00214|098|R|12.Crane JK, Shih HT. Syncope and cardiac arrhythmia due to an interaction|3
00214|099|R|   between itraconazole and terfenadine. Am J Med 1993 Oct;95(4):445-6.|3
00214|100|R|13.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
00214|101|R|   2024.|1
00214|102|R|14.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00214|103|R|   September, 1997.|1
00214|104|R|15.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
00214|105|R|   Products, L.P. March, 1994.|1
00214|106|R|16.Hismanal (astemizole) US prescribing information. Janssen Pharmaceutica|1
00214|107|R|   Products, L.P. February, 1998.|1
00214|108|R|17.Allegra (fexofenadine hydrochloride) US prescribing information.|1
00214|109|R|   Sanofi-Aventis U.S. LLC October, 2006.|1
00214|110|R|18.Mizollen (mizolastine) US prescribing information. Lorex Synthelab|1
00214|111|R|   September 29, 1997.|1
00214|112|R|19.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
00214|113|R|20.Noxafil (posaconazole) UK summary of product characteristics.|1
00214|114|R|   Schering-Plough Ltd. January, 2022.|1
00214|115|R|21.Noxafil (posaconazole) US prescribing information. Schering Corporation|1
00214|116|R|   March, 2019.|1
00214|117|R|22.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
00214|118|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
00214|119|R|   hospital settings: a scientific statement from the American Heart|6
00214|120|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
00214|121|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
00215|001|T|MONOGRAPH TITLE:  Oral Quinolones/Aluminum; Lanthanum; Magnesium (mono|
00215|002|T|deleted 12/01/2011)|
00215|003|B||
00215|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00215|005|L|of severe adverse interaction.|
00215|006|B||
00215|007|A|MECHANISM OF ACTION:  Aluminum, lanthanum, and magnesium may form chelation|
00215|008|A|compounds with the quinolones.(1-36)|
00215|009|B||
00215|010|E|CLINICAL EFFECTS:  Simultaneous administration or administration of|
00215|011|E|aluminum, lanthanum, or magnesium products close to the administration time|
00215|012|E|of an oral quinolone may result in decreased absorption and clinical|
00215|013|E|effectiveness of the quinolone.|
00215|014|B||
00215|015|P|PREDISPOSING FACTORS:  None determined.|
00215|016|B||
00215|017|M|PATIENT MANAGEMENT:  If possible, avoid concomitant use of an oral quinolone|
00215|018|M|antibiotic and an aluminum- or magnesium-containing antacid or Videx|
00215|019|M|(didanosine) chewable/dispersible tablets, which contain magnesium hydroxide|
00215|020|M|and magnesium stearate.  If it is necessary to administer these agents|
00215|021|M|concurrently, follow the manufacturers' recommendations regarding timing of|
00215|022|M|administration of the quinolone and the antacid or Videx chewable/|
00215|023|M|dispersible tablets.|
00215|024|M|   The US manufacturer of lanthanum recommends that quinolones not be|
00215|025|M|administered within 1 hour before or 4 hours after lanthanum.  For short|
00215|026|M|courses of quinolones, consider eliminating doses of lanthanum that would be|
00215|027|M|administered near the time of quinolone administration.(1)  It would be|
00215|028|M|prudent to follow the quinolone manufacturers' recommendations regarding|
00215|029|M|concurrent administration of antacids for those quinolones that recommend a|
00215|030|M|longer separation of administration times.|
00215|031|M|   Manufacturer recommendations regarding the separation of administration|
00215|032|M|times of quinolones and aluminum- or magnesium-containing antacids or Videx|
00215|033|M|chewable/dispersible tablets vary. Do NOT give antacids or Videx|
00215|034|M|chewable/dispersible tablets:|
00215|035|M|--for 6 hours before or 2 hours after ciprofloxacin(2)|
00215|036|M|--for 8 hours before or 2 hours after enoxacin(3)|
00215|037|M|--until 4 hours after gatifloxacin(4)|
00215|038|M|--for 3 hours before or 2 hours after gemifloxacin(5)|
00215|039|M|--for 2 hours before or 2 hours after levofloxacin(6)|
00215|040|M|--for 4 hours before or 2 hours after lomefloxacin(7)|
00215|041|M|--for 8 hours before or 4 hours after moxifloxacin(8)|
00215|042|M|--for 2 hours before or after nalidixic acid(9)|
00215|043|M|--for 2 hours before or 2 hours after norfloxacin(10)|
00215|044|M|--for 2 hours before or 2 hours after ofloxacin(11)|
00215|045|M|--until 4 hours after sparfloxacin(12)|
00215|046|M|--for 2 hours before or 2 hours after trovafloxacin.(13)|
00215|047|B||
00215|048|D|DISCUSSION:  Magnesium and aluminum compounds have been shown to form|
00215|049|D|chelation compounds with quinolone antibiotics, resulting in decreased|
00215|050|D|absorption of the quinolone.(2-36)|
00215|051|D|   Concurrent administration of an antacid with ciprofloxacin has been shown|
00215|052|D|to reduce the bioavailability of ciprofloxacin by as much as 90% and|
00215|053|D|administration of an antacid 2 hours prior to ciprofloxacin has been shown|
00215|054|D|to decrease ciprofloxacin concentrations by 20-50%.|
00215|055|D|   In a randomized, two-way crossover study in healthy subjects, lanthanum|
00215|056|D|carbonate (1 g three times daily) decreased the maximum concentration (Cmax)|
00215|057|D|and area-under-curve (AUC) of a single dose of ciprofloxacin (750 mg) by 56%|
00215|058|D|and 54%, respectively.(1)|
00215|059|D|   The chewable/dispersible formulation of Videx (didanosine) contains|
00215|060|D|magnesium hydroxide and magnesium stearate.  The administration of|
00215|061|D|ciprofloxacin 2 hours prior to Videx chewable/dispersible tablets decreased|
00215|062|D|ciprofloxacin concentrations by 26%.(30)|
00215|063|D|   Magnesium- and aluminum-containing antacids have been shown to decrease|
00215|064|D|the bioavailability of lomefloxacin by 48%.|
00215|065|D|   Administration of moxifloxacin 2 hours before, simultaneously, or 4 hours|
00215|066|D|after a magnesium- and aluminum-containing antacid decreased moxifloxacin|
00215|067|D|AUC by 26%, 60%, and 23%, respectively.(8,31)|
00215|068|D|   Simultaneous aluminum phosphate was found to decrease the rate, but not|
00215|069|D|the extent, of absorption of ofloxacin.(32)|
00215|070|D|   The administration of an antacid containing aluminum hydroxide and|
00215|071|D|magnesium hydroxide 5 minutes before rufloxacin decreased rufloxacin levels|
00215|072|D|by 36%.  Administration of the antacid 4 hours after rufloxacin decreased|
00215|073|D|rufloxacin levels by 13%.(33)|
00215|074|D|   The administration of an antacid containing aluminum hydroxide and|
00215|075|D|magnesium hydroxide 2 hours before, 2 hours after, and 4 hours after|
00215|076|D|sparfloxacin decreased sparfloxacin levels by 23%, 17%, and 5%,|
00215|077|D|respectively.(34)|
00215|078|D|   Magnesium- and aluminum-containing antacids have been shown to decrease|
00215|079|D|the bioavailability of temafloxacin by 40%.(35)|
00215|080|D|   Administration of an antacid containing aluminum hydroxide and magnesium|
00215|081|D|hydroxide 30 minutes before trovafloxacin decreased trovafloxacin levels by|
00215|082|D|66%.(36)|
00215|083|D|   Treatment failures during concurrent use of antacids and ciprofloxacin,|
00215|084|D|(37) gatifloxacin,(38) norfloxacin,(39) and pefloxacin(40) have been|
00215|085|D|reported.|
00215|086|B||
00215|087|R|REFERENCES:|
00215|088|B||
00215|089|R|1.Fosrenol (lanthanum carbonate) US prescribing information. Shire US Inc.|1
00215|090|R|  September, 2011.|1
00215|091|R|2.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
00215|092|R|  Corporation February, 2011.|1
00215|093|R|3.Penetrex (enoxacin) US prescribing information. Aventis Pharmaceuticals,|1
00215|094|R|  Inc. July, 1998.|1
00215|095|R|4.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
00215|096|R|  Company January, 2006.|1
00215|097|R|5.Factive (gemifloxacin mesylate) US prescribing information. Oscient|1
00215|098|R|  Pharmaceuticals February, 2011.|1
00215|099|R|6.Levaquin (levofloxacin) US prescribing information. Ortho-McNeil|1
00215|100|R|  Pharmaceutical, Inc. February, 2011.|1
00215|101|R|7.Maxaquin (lomefloxacin hydrochloride) US prescribing information. Pfizer|1
00215|102|R|  Inc. January, 2005.|1
00215|103|R|8.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
00215|104|R|  Pharmaceuticals Corporation February, 2011.|1
00215|105|R|9.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
00215|106|R|  Inc. November, 2012.|1
00215|107|R|10.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc.|1
00215|108|R|   September, 2011.|1
00215|109|R|11.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
00215|110|R|   Pharmaceutical, Inc. February, 2011.|1
00215|111|R|12.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
00215|112|R|   Inc. February, 2003.|1
00215|113|R|13.Trovan (trovafloxacin mesylate) US prescribing information. Roerig April,|1
00215|114|R|   2000.|1
00215|115|R|14.Hoffken G, Borner K, Glatzel PD, Koeppe P, Lode H. Reduced enteral|2
00215|116|R|   absorption of ciprofloxacin in the presence of antacids. Eur J Clin|2
00215|117|R|   Microbiol 1985 Jun;4(3):345.|2
00215|118|R|15.Golper TA, Hartstein AI, Morthland VH, Christensen JM. Effects of|2
00215|119|R|   antacids and dialysate dwell times on multiple-dose pharmacokinetics of|2
00215|120|R|   oral ciprofloxacin in patients on continuous ambulatory peritoneal|2
00215|121|R|   dialysis. Antimicrob Agents Chemother 1987 Nov;31(11):1787-90.|2
00215|122|R|16.Maesen FP, Davies BI, Geraedts WH, Sumajow CA. Ofloxacin and antacids. J|2
00215|123|R|   Antimicrob Chemother 1987 Jun;19(6):848-50.|2
00215|124|R|17.Nix DE, Watson WA, Lener ME, Frost RW, Krol G, Goldstein H, Lettieri J,|2
00215|125|R|   Schentag JJ. Effects of aluminum and magnesium antacids and ranitidine on|2
00215|126|R|   the absorption of ciprofloxacin. Clin Pharmacol Ther 1989 Dec;|2
00215|127|R|   46(6):700-5.|2
00215|128|R|18.Grasela TH Jr, Schentag JJ, Sedman AJ, Wilton JH, Thomas DJ, Schultz RW,|2
00215|129|R|   Lebsack ME, Kinkel AW. Inhibition of enoxacin absorption by antacids or|2
00215|130|R|   ranitidine. Antimicrob Agents Chemother 1989 May;33(5):615-7.|2
00215|131|R|19.Nix DE, Wilton JH, Ronald B, Distlerath L, Williams VC, Norman A.|2
00215|132|R|   Inhibition of norfloxacin absorption by antacids. Antimicrob Agents|2
00215|133|R|   Chemother 1990 Mar;34(3):432-5.|2
00215|134|R|20.Flor S, Guay DR, Opsahl JA, Tack K, Matzke GR. Effects of|2
00215|135|R|   magnesium-aluminum hydroxide and calcium carbonate antacids on|2
00215|136|R|   bioavailability of ofloxacin. Antimicrob Agents Chemother 1990 Dec;|2
00215|137|R|   34(12):2436-8.|2
00215|138|R|21.Martinez Cabarga M, Sanchez Navarro A, Colino Gandarillas CI,|2
00215|139|R|   Dominguez-Gil A. Effects of two cations on gastrointestinal absorption of|2
00215|140|R|   ofloxacin. Antimicrob Agents Chemother 1991 Oct;35(10):2102-5.|2
00215|141|R|22.Akerele JO, Okhamafe AO. Influence of oral co-administered metallic drugs|2
00215|142|R|   on ofloxacin pharmacokinetics. J Antimicrob Chemother 1991 Jul;|2
00215|143|R|   28(1):87-94.|2
00215|144|R|23.Frost RW, Lasseter KC, Noe AJ, Shamblen EC, Lettieri JT. Effects of|2
00215|145|R|   aluminum hydroxide and calcium carbonate antacids on the bioavailability|2
00215|146|R|   of ciprofloxacin. Antimicrob Agents Chemother 1992 Apr;36(4):830-2.|2
00215|147|R|24.Campbell NR, Kara M, Hasinoff BB, Haddara WM, McKay DW. Norfloxacin|2
00215|148|R|   interaction with antacids and minerals. Br J Clin Pharmacol 1992 Jan;|2
00215|149|R|   33(1):115-6.|2
00215|150|R|25.Shimada J, Shiba K, Oguma T, Miwa H, Yoshimura Y, Nishikawa T, Okabayashi|2
00215|151|R|   Y, Kitagawa T, Yamamoto S. Effect of antacid on absorption of the|2
00215|152|R|   quinolone lomefloxacin. Antimicrob Agents Chemother 1992 Jun;|2
00215|153|R|   36(6):1219-24.|2
00215|154|R|26.Nix DE, Lebsack ME, Chapelsky M, Sedman AJ, Busch J, Norman A. Effect of|2
00215|155|R|   oral antacids on disposition of intravenous enoxacin. Antimicrob Agents|2
00215|156|R|   Chemother 1993 Apr;37(4):775-7.|2
00215|157|R|27.Sahai J, Gallicano K, Oliveras L, Khaliq S, Hawley-Foss N, Garber G.|2
00215|158|R|   Cations in the didanosine tablet reduce ciprofloxacin bioavailability.|2
00215|159|R|   Clin Pharmacol Ther 1993 Mar;53(3):292-7.|2
00215|160|R|28.Lehto P, Kivisto KT. Different effects of products containing metal ions|2
00215|161|R|   on the absorption of lomefloxacin. Clin Pharmacol Ther 1994 Nov;|2
00215|162|R|   56(5):477-82.|2
00215|163|R|29.Allen A, Vousden M, Porter A, Lewis A. Effect of Maalox on the|2
00215|164|R|   bioavailability of oral gemifloxacin in healthy volunteers. Chemotherapy|2
00215|165|R|   1999 Nov-Dec;45(6):504-11.|2
00215|166|R|30.Videx (didanosine) US prescribing information. Bristol-Myers Squibb|1
00215|167|R|   Company November, 2011.|1
00215|168|R|31.Stass H, Bottcher MF, Ochmann K. Evaluation of the influence of antacids|2
00215|169|R|   and H2 antagonists on the absorption of moxifloxacin after oral|2
00215|170|R|   administration of a 400mg dose to healthy volunteers. Clin Pharmacokinet|2
00215|171|R|   2001;40 Suppl 1:39-48.|2
00215|172|R|32.Sanchez Navarro A, Martinez Cabarga M, Dominguez-Gil Hurle A. Oral|2
00215|173|R|   absorption of ofloxacin administered together with aluminum. Antimicrob|2
00215|174|R|   Agents Chemother 1994 Oct;38(10):2510-2.|2
00215|175|R|33.Lazzaroni M, Imbimbo BP, Bargiggia S, Sangaletti O, Dal Bo L, Broccali G,|2
00215|176|R|   Porro GB. Effects of magnesium-aluminum hydroxide antacid on absorption|2
00215|177|R|   of rufloxacin. Antimicrob Agents Chemother 1993 Oct;37(10):2212-6.|2
00215|178|R|34.Johnson RD, Dorr MB, Talbot GH, Caille G. Effect of Maalox on the oral|2
00215|179|R|   absorption of sparfloxacin. Clin Ther 1998 Nov-Dec;20(6):1149-58.|2
00215|180|R|35.Granneman GR, Stephan U, Birner B, Sorgel F, Mukherjee D. Effect of|2
00215|181|R|   antacid medication on the pharmacokinetics of temafloxacin. Clin|2
00215|182|R|   Pharmacokinet 1992;22 Suppl 1:83-9.|2
00215|183|R|36.Teng R, Dogolo LC, Willavize SA, Friedman HL, Vincent J. Effect of Maalox|2
00215|184|R|   and omeprazole on the bioavailability of trovafloxacin. J Antimicrob|2
00215|185|R|   Chemother 1997 Jun;39 Suppl B:93-7.|2
00215|186|R|37.Spivey JM, Cummings DM, Pierson NR. Failure of prostatitis treatment|3
00215|187|R|   secondary to probable ciprofloxacin-sucralfate drug interaction.|3
00215|188|R|   Pharmacotherapy 1996 Mar-Apr;16(2):314-6.|3
00215|189|R|38.Mallet L, Huang A. Coadministration of gatifloxacin and multivitamin|3
00215|190|R|   preparation containing minerals: potential treatment failure in an|3
00215|191|R|   elderly patient. Ann Pharmacother 2005 Jan;39(1):150-2.|3
00215|192|R|39.Noyes M, Polk RE. Norfloxacin and absorption of magnesium-aluminum. Ann|3
00215|193|R|   Intern Med 1988 Jul 15;109(2):168-9.|3
00215|194|R|40.Vinceneux P, Weber P, Gaudin H, Boussougant Y. Decreased absorption of|3
00215|195|R|   pefloxacin by gastric antacids. Preliminary study. Presse Med 1986 Oct|3
00215|196|R|   18;15(36):1826.|3
00216|001|T|MONOGRAPH TITLE:  Labetalol/Inhalation Anesthetics|
00216|002|B||
00216|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00216|004|L|of severe adverse interaction.|
00216|005|B||
00216|006|A|MECHANISM OF ACTION:  The myocardial depressant effects of labetalol and|
00216|007|A|inhalation anesthetics appear to be synergistic.|
00216|008|B||
00216|009|E|CLINICAL EFFECTS:  Patients may experience excessive hypotension.|
00216|010|B||
00216|011|P|PREDISPOSING FACTORS:  None determined.|
00216|012|B||
00216|013|M|PATIENT MANAGEMENT:  Monitor blood pressure throughout surgical procedures|
00216|014|M|in which labetalol and inhalation anesthetics are being given concurrently.|
00216|015|B||
00216|016|D|DISCUSSION:  The combination of labetalol and inhalation anesthetics may be|
00216|017|D|used to induce hypotension in selected types of surgery. Concurrent|
00216|018|D|administration of labetalol and halothane may produce excessive reductions|
00216|019|D|in cardiac output and blood pressure. The magnitude of the interaction is|
00216|020|D|dependent on the dose of halothane.|
00216|021|B||
00216|022|R|REFERENCES:|
00216|023|B||
00216|024|R|1.Scott DB, Buckley FP, Drummond GB, Littlewoods DG, Macrae WR.|2
00216|025|R|  Cardiovascular effects of labetalol during halothane anaesthesia. Br J|2
00216|026|R|  Clin Pharmacol 1976 Aug;3(4 Suppl 3):817-21.|2
00216|027|R|2.Scott DB, Buckley FP, Littlewood DG, Macrae WR, Arthur GR, Drummond GB.|2
00216|028|R|  Circulatory effects of labetalol during halothane anaesthesia. Anaesthesia|2
00216|029|R|  1978 Feb;33(2):145-56.|2
00216|030|R|3.Hunter JM. Synergism between halothane and labetalol. Anaesthesia 1979|3
00216|031|R|  Mar;34(3):257-9.|3
00216|032|R|4.Toivonen J, Virtanen H, Kaukinen S. Deliberate hypotension induced by|2
00216|033|R|  labetalol with halothane, enflurane or isoflurane for middle-ear surgery.|2
00216|034|R|  Acta Anaesthesiol Scand 1989 May;33(4):283-9.|2
00217|001|T|MONOGRAPH TITLE:  Zidovudine/Probenecid|
00217|002|B||
00217|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00217|004|L|take action as needed.|
00217|005|B||
00217|006|A|MECHANISM OF ACTION:  Inhibition of zidovudine metabolism by probenecid.|
00217|007|B||
00217|008|E|CLINICAL EFFECTS:  Increased serum zidovudine levels and cutaneous reactions|
00217|009|E|with systemic symptoms (eg, fever, malaise, myalgia,) have been reported.|
00217|010|B||
00217|011|P|PREDISPOSING FACTORS:  There may be an increased tendency of patients with|
00217|012|P|disorders of the immune system to develop adverse reaction to these drugs.|
00217|013|B||
00217|014|M|PATIENT MANAGEMENT:  Observe patient for unexpected cutaneous reactions. It|
00217|015|M|may be necessary to reduce the dosing frequency of zidovudine if probenecid|
00217|016|M|is administered concurrently.|
00217|017|B||
00217|018|D|DISCUSSION:  Concomitant administration of zidovudine and probenecid may be|
00217|019|D|therapeutically beneficial in reducing the daily dose of zidovudine.|
00217|020|D|However, because of the narrow therapeutic index of zidovudine, the frequent|
00217|021|D|need to treat patients with immune system disorders with various additional|
00217|022|D|drugs, and the known ability of probenecid to inhibit metabolism or renal|
00217|023|D|excretion of many drugs, would make combined zidovudine/probenecid treatment|
00217|024|D|difficult to manage in many of these type of patients. Cutaneous reactions|
00217|025|D|have been reported in many patients receiving zidovudine and probenecid|
00217|026|D|concurrently.|
00217|027|B||
00217|028|R|REFERENCES:|
00217|029|B||
00217|030|R|1.Kornhauser DM, Petty BG, Hendrix CW, Woods AS, Nerhood LJ, Bartlett JG,|2
00217|031|R|  Lietman PS. Probenecid and zidovudine metabolism. Lancet 1989 Aug 26;|2
00217|032|R|  2(8661):473-5.|2
00217|033|R|2.de Miranda P, Good SS, Yarchoan R, Thomas RV, Blum MR, Myers CE, Broder S.|2
00217|034|R|  Alteration of zidovudine pharmacokinetics by probenecid in patients with|2
00217|035|R|  AIDS or AIDS-related complex. Clin Pharmacol Ther 1989 Nov;46(5):494-500.|2
00217|036|R|3.Hedaya MA, Elmquist WF, Sawchuk RJ. Mechanism of zidovudine (AZT)|4
00217|037|R|  dose-sparing by probenecid in humans. Pharm Res 1989;6(9):S-218.|4
00217|038|R|4.Petty BG, Kornhauser DM, Lietman PS. Zidovudine with probenecid: a|3
00217|039|R|  warning. Lancet 1990 Apr 28;335(8696):1044-5.|3
00217|040|R|5.Haumont M, Magdalou J, Lafaurie C, Ziegler JM, Siest G, Colin JN.|5
00217|041|R|  Phenobarbital inducible UDP-glucuronosyltransferase is responsible for|5
00217|042|R|  glucuronidation of 3'-azido-3'-deoxythymidine: characterization of the|5
00217|043|R|  enzyme in human and rat liver microsomes. Arch Biochem Biophys 1990 Sep;|5
00217|044|R|  281(2):264-70.|5
00217|045|R|6.Hedaya MA, Elmquist WF, Sawchuk RJ. Probenecid inhibits the metabolic and|2
00217|046|R|  renal clearances of zidovudine (AZT) in human volunteers. Pharm Res 1990|2
00217|047|R|  Apr;7(4):411-7.|2
00217|048|R|7.Duckworth AS, Duckworth GW, Henderson G, Contreras G. Zidovudine with|3
00217|049|R|  probenecid. Lancet 1990 Aug 18;336(8712):441.|3
00217|050|R|8.Sim SM, Back DJ, Breckenridge AM. The effect of various drugs on the|5
00217|051|R|  glucuronidation of zidovudine (azidothymidine; AZT) by human liver|5
00217|052|R|  microsomes. Br J Clin Pharmacol 1991 Jul;32(1):17-21.|5
00217|053|R|9.Cretton EM, Schinazi RF, McClure HM, Anderson DC, Sommadossi JP.|5
00217|054|R|  Pharmacokinetics of 3'-azido-3'-deoxythymidine and its catabolites and|5
00217|055|R|  interactions with probenecid in rhesus monkeys. Antimicrob Agents|5
00217|056|R|  Chemother 1991 May;35(5):801-7.|5
00218|001|T|MONOGRAPH TITLE:  Theophyllines/Mexiletine (mono deleted 09/17/2014)|
00218|002|B||
00218|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00218|004|L|take action as needed.|
00218|005|B||
00218|006|A|MECHANISM OF ACTION:  Unknown.|
00218|007|B||
00218|008|E|CLINICAL EFFECTS:  Increased pharmacologic and toxic effects of|
00218|009|E|theophyllines.|
00218|010|B||
00218|011|P|PREDISPOSING FACTORS:  None determined.|
00218|012|B||
00218|013|M|PATIENT MANAGEMENT:  Monitor serum theophylline levels and observe patients|
00218|014|M|for signs of theophylline toxicity if mexiletine is added to the treatment|
00218|015|M|schedule.|
00218|016|B||
00218|017|D|DISCUSSION:  Increased serum theophylline levels with signs and symptoms of|
00218|018|D|theophylline toxicity have been reported in patients following the addition|
00218|019|D|of mexiletine to their treatment.|
00218|020|B||
00218|021|R|REFERENCES:|
00218|022|B||
00218|023|R|1.Katz A, Buskila D, Sukenik S. Oral mexiletine-theophylline interaction.|3
00218|024|R|  Int J Cardiol 1987 Nov;17(2):227-8.|3
00218|025|R|2.Stanley R, Comer T, Taylor JL, Saliba D. Mexiletine-theophylline|3
00218|026|R|  interaction. Am J Med 1989 Jun;86(6 Pt 1):733-4.|3
00218|027|R|3.Kessler KM, Interian A Jr, Cox M, Topaz O, De Marchena EJ, Myerburg RJ.|3
00218|028|R|  Proarrhythmia related to a kinetic and dynamic interaction of mexiletine|3
00218|029|R|  and theophylline. Am Heart J 1989 Apr;117(4):964-6.|3
00218|030|R|4.Loi CM, Vestal RE. Effect of mexiletine on theophylline metabolism. Clin|4
00218|031|R|  Pharmacol Ther 1990 Feb;47(2):130.|4
00218|032|R|5.Ueno K, Miyai K, Seki T, Kawaguchi Y. Interaction between theophylline and|3
00218|033|R|  mexiletine. DICP 1990 May;24(5):471-2.|3
00218|034|R|6.Stoysich AM, Mohiuddin SM, Destache CJ, Nipper HC, Hilleman DE. Influence|2
00218|035|R|  of mexiletine on the pharmacokinetics of theophylline in healthy|2
00218|036|R|  volunteers. J Clin Pharmacol 1991 Apr;31(4):354-7.|2
00218|037|R|7.Loi CM, Wei XX, Vestal RE. Inhibition of theophylline metabolism by|2
00218|038|R|  mexiletine in young male and female nonsmokers. Clin Pharmacol Ther 1991|2
00218|039|R|  May;49(5):571-80.|2
00218|040|R|8.Hurwitz A, Vacek JL, Botteron GW, Sztern MI, Hughes EM, Jayaraj A.|2
00218|041|R|  Mexiletine effects on theophylline disposition. Clin Pharmacol Ther 1991|2
00218|042|R|  Sep;50(3):299-307.|2
00218|043|R|9.Ueno K, Miyai K, Kato M, Kawaguchi Y, Suzuki T. Mechanism of interaction|2
00218|044|R|  between theophylline and mexiletine. DICP 1991 Jul-Aug;25(7-8):727-30.|2
00219|001|T|MONOGRAPH TITLE:  Quinolones, Oral/Sucralfate|
00219|002|B||
00219|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00219|004|L|take action as needed.|
00219|005|B||
00219|006|A|MECHANISM OF ACTION:  Sucralfate decreases the absorption of certain|
00219|007|A|quinolones.  The probable mechanism is quinolone chelation with the aluminum|
00219|008|A|contained in sucralfate.|
00219|009|B||
00219|010|E|CLINICAL EFFECTS:  The pharmacologic effects of certain quinolones may be|
00219|011|E|decreased.|
00219|012|B||
00219|013|P|PREDISPOSING FACTORS:  None determined.|
00219|014|B||
00219|015|M|PATIENT MANAGEMENT:  Avoid the concomitant administration of sucralfate and|
00219|016|M|an oral quinolone.  If an oral quinolone is administered during sucralfate|
00219|017|M|therapy, the antibiotic should be administered at least two hours before|
00219|018|M|sucralfate.  Differences in gastric emptying time may impact the the|
00219|019|M|effectiveness of spacing the administration times in some patients.|
00219|020|B||
00219|021|D|DISCUSSION:  Sucralfate has been shown to extensively decrease the|
00219|022|D|bioavailability of ciprofloxacin (87.5-95.7% decrease in area-under-curve,|
00219|023|D|AUC), lomefloxacin (51% decrease in AUC), norfloxacin (91% decrease in AUC),|
00219|024|D|and ofloxacin (61% decrease in AUC), as well as the urinary concentration of|
00219|025|D|norfloxacin when the agents were administered at the same time.|
00219|026|B||
00219|027|R|REFERENCES:|
00219|028|B||
00219|029|R|1.Hoffken G, Lode H, Wiley R, Glatzel TD, Sievers D, Olschewski T, Borner K,|4
00219|030|R|  Koeppe T. Pharmacokinetics and bioavailability of ciprofloxacin and|4
00219|031|R|  ofloxacin: effect of food and antacid intake. Rev Infect Dis 1988;10(Supp|4
00219|032|R|  1):S138-9.|4
00219|033|R|2.Parpia SH, Nix DE, Hejmanowski LG, Goldstein HR, Wilton JH, Schentag JJ.|2
00219|034|R|  Sucralfate reduces the gastrointestinal absorption of norfloxacin.|2
00219|035|R|  Antimicrob Agents Chemother 1989 Jan;33(1):99-102.|2
00219|036|R|3.Grasela TH Jr, Schentag JJ, Sedman AJ, Wilton JH, Thomas DJ, Schultz RW,|2
00219|037|R|  Lebsack ME, Kinkel AW. Inhibition of enoxacin absorption by antacids or|2
00219|038|R|  ranitidine. Antimicrob Agents Chemother 1989 May;33(5):615-7.|2
00219|039|R|4.Nix DE, Watson WA, Handy L, Frost RW, Rescott DL, Goldstein HR. The effect|2
00219|040|R|  of sucralfate pretreatment on the pharmacokinetics of ciprofloxacin.|2
00219|041|R|  Pharmacotherapy 1989;9(6):377-80.|2
00219|042|R|5.Yuk JH, Nightingale CN, Quintiliani R. Ciprofloxacin levels when receiving|3
00219|043|R|  sucralfate. JAMA 1989 Aug 18;262(7):901.|3
00219|044|R|6.Brouwers JRBJ, Van der Kam HJ, Sijtsma J, Proost JH. Important reduction|2
00219|045|R|  of ciprofloxacin absorption by sucralfate and magnesium citrate solution.|2
00219|046|R|  Drug Invest 1990;2(3):197-9.|2
00219|047|R|7.Garrelts JC, Godley PJ, Peterie JD, Gerlach EH, Yakshe CC. Sucralfate|2
00219|048|R|  significantly reduces ciprofloxacin concentrations in serum. Antimicrob|2
00219|049|R|  Agents Chemother 1990 May;34(5):931-3.|2
00219|050|R|8.Van Slooten AD, Nix DE, Wilton JH, Love JH, Spivey JM, Goldstein HR.|2
00219|051|R|  Combined use of ciprofloxacin and sucralfate. DICP 1991 Jun;25(6):578-82.|2
00219|052|R|9.Yuk JH, Williams TW Jr. Drug interaction with quinolone antibiotics in|6
00219|053|R|  intensive care unit patients. Arch Intern Med 1991 Mar;151(3):619.|6
00219|054|R|10.Lomaestro BM, Bailie GR. Quinolone-cation interactions: a review. DICP|6
00219|055|R|   1991 Nov;25(11):1249-58.|6
00219|056|R|11.Kawakami J, Matsuse T, Kotaki H, Seino T, Fukuchi Y, Orimo H, Sawada Y,|2
00219|057|R|   Iga T. The effect of food on the interaction of ofloxacin with sucralfate|2
00219|058|R|   in healthy volunteers. Eur J Clin Pharmacol 1994;47(1):67-9.|2
00219|059|R|12.Lehto P, Kivisto KT. Different effects of products containing metal ions|2
00219|060|R|   on the absorption of lomefloxacin. Clin Pharmacol Ther 1994 Nov;|2
00219|061|R|   56(5):477-82.|2
00219|062|R|13.Lehto P, Kivisto KT. Effect of sucralfate on absorption of norfloxacin|2
00219|063|R|   and ofloxacin. Antimicrob Agents Chemother 1994 Feb;38(2):248-51.|2
00219|064|R|14.Factive (gemifloxacin mesylate) US prescribing information. Merus Labs|1
00219|065|R|   International, Inc. October, 2018.|1
00219|066|R|15.Allen A, Bygate E, Faessel H, Isaac L, Lewis A. The effect of ferrous|2
00219|067|R|   sulphate and sucralfate on the bioavailability of oral gemifloxacin in|2
00219|068|R|   healthy volunteers. Int J Antimicrob Agents 2000 Aug;15(4):283-9.|2
00220|001|T|MONOGRAPH TITLE:  Succinylcholine/Metoclopramide|
00220|002|B||
00220|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00220|004|L|take action as needed.|
00220|005|B||
00220|006|A|MECHANISM OF ACTION:  Metoclopramide inhibits plasma cholinesterase,|
00220|007|A|decreasing the inactivation of succinylcholine.|
00220|008|B||
00220|009|E|CLINICAL EFFECTS:  The pharmacologic effects of succinylcholine may be|
00220|010|E|increased, resulting in profound sedation, respiratory depression, coma,|
00220|011|E|and/or death.|
00220|012|B||
00220|013|P|PREDISPOSING FACTORS:  None determined.|
00220|014|B||
00220|015|M|PATIENT MANAGEMENT:  Monitor neuromuscular function and supply mechanical|
00220|016|M|respiratory support if prolonged respiratory depression occurs.|
00220|017|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00220|018|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00220|019|M|unresponsiveness.|
00220|020|B||
00220|021|D|DISCUSSION:  In controlled studies, administration of metoclopramide to|
00220|022|D|patients receiving intubating doses of succinylcholine prolonged the|
00220|023|D|neuromuscular blockade produced by succinylcholine by 23% to 228%.|
00220|024|B||
00220|025|R|REFERENCES:|
00220|026|B||
00220|027|R|1.Turner DR, Kao YJ, Bivona C. Neuromuscular block by suxamethonium|2
00220|028|R|  following treatment with histamine type 2 antagonists or metoclopramide.|2
00220|029|R|  Br J Anaesth 1989 Sep;63(3):348-50.|2
00220|030|R|2.Kao YJ, Turner DR. Prolongation of succinylcholine block by|2
00220|031|R|  metoclopramide. Anesthesiology 1989 Jun;70(6):905-8.|2
00221|001|T|MONOGRAPH TITLE:  Ethotoin/Amiodarone|
00221|002|B||
00221|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00221|004|L|take action as needed.|
00221|005|B||
00221|006|A|MECHANISM OF ACTION:  Inhibition of ethotoin metabolism by amiodarone and|
00221|007|A|increased metabolism of amiodarone by ethotoin.|
00221|008|B||
00221|009|E|CLINICAL EFFECTS:  Serum ethotoin levels may be increased while plasma|
00221|010|E|amiodarone concentrations may be decreased. The effects of this interaction|
00221|011|E|may not be apparent for several weeks.|
00221|012|B||
00221|013|P|PREDISPOSING FACTORS:  None determined.|
00221|014|B||
00221|015|M|PATIENT MANAGEMENT:  Monitor drug levels. Observe the patient for ethotoin|
00221|016|M|toxicity or a loss in therapeutic effect if amiodarone treatment is|
00221|017|M|initiated or discontinued. Monitor patients receiving amiodarone for a|
00221|018|M|decrease in antiarrhythmic activity if ethotoin therapy is started.|
00221|019|B||
00221|020|D|DISCUSSION:  Ethotoin is a CYP3A4 substrate and inducer.|
00221|021|D|   Concurrent administration of amiodarone (a CYP3A4 substrate and|
00221|022|D|inhibitor) and phenytoin (a CYP3A4 substrate and inducer) has been reported|
00221|023|D|to increase serum phenytoin levels by increasing the half life and|
00221|024|D|decreasing the clearance of phenytoin. In addition, concomitant|
00221|025|D|administration of phenytoin to healthy volunteers receiving amiodarone|
00221|026|D|produced a decrease in observed amiodarone concentrations compared to|
00221|027|D|predicted levels.|
00221|028|B||
00221|029|R|REFERENCES:|
00221|030|B||
00221|031|R|1.Gore JM, Haffajee CI, Alpert JS. Interaction of amiodarone and|3
00221|032|R|  diphenylhydantoin. Am J Cardiol 1984 Nov 1;54(8):1145.|3
00221|033|R|2.Lalloz MR, Byfield PG, Greenwood RM, Himsworth RL. Binding of amiodarone|5
00221|034|R|  by serum proteins and the effects of drugs, hormones and other interacting|5
00221|035|R|  ligands. J Pharm Pharmacol 1984 Jun;36(6):366-72.|5
00221|036|R|3.McGovern B, Geer VR, LaRaia PJ, Garan H, Ruskin JN. Possible interaction|3
00221|037|R|  between amiodarone and phenytoin. Ann Intern Med 1984 Nov;101(5):650-1.|3
00221|038|R|4.Shackleford EJ, Watson FT. Amiodarone--phenytoin interaction. Drug Intell|3
00221|039|R|  Clin Pharm 1987 Nov;21(11):921.|3
00221|040|R|5.Nolan PE Jr, Marcus FI, Hoyer GL, Bliss M, Gear K. Pharmacokinetic|2
00221|041|R|  interaction between intravenous phenytoin and amiodarone in healthy|2
00221|042|R|  volunteers. Clin Pharmacol Ther 1989 Jul;46(1):43-50.|2
00221|043|R|6.Nolan PE Jr, Erstad BL, Hoyer GL, Bliss M, Gear K, Marcus FI. Steady-state|2
00221|044|R|  interaction between amiodarone and phenytoin in normal subjects. Am J|2
00221|045|R|  Cardiol 1990 May 15;65(18):1252-7.|2
00221|046|R|7.Nolan PE Jr, Marcus FI, Karol MD, Hoyer GL, Gear K. Effect of phenytoin on|2
00221|047|R|  the clinical pharmacokinetics of amiodarone. J Clin Pharmacol 1990 Dec;|2
00221|048|R|  30(12):1112-9.|2
00221|049|R|8.Ahmad S. Amiodarone and phenytoin: interaction. J Am Geriatr Soc 1995 Dec;|3
00221|050|R|  43(12):1449-50.|3
00221|051|R|9.Preganone (ethotoin) US prescribing information. Recordate Rare June,|1
00221|052|R|  2010.|1
00222|001|T|MONOGRAPH TITLE:  Disopyramide/Rifamycins (mono deleted 04/16/2014)|
00222|002|B||
00222|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00222|004|L|take action as needed.|
00222|005|B||
00222|006|A|MECHANISM OF ACTION:  Increased hepatic metabolism of disopyramide.|
00222|007|B||
00222|008|E|CLINICAL EFFECTS:  Serum disopyramide levels may be reduced, decreasing the|
00222|009|E|therapeutic effects of disopyramide.|
00222|010|B||
00222|011|P|PREDISPOSING FACTORS:  None determined.|
00222|012|B||
00222|013|M|PATIENT MANAGEMENT:  Monitor patient's response during concurrent|
00222|014|M|administration of disopyramide and rifampin. Adjust the dose of disopyramide|
00222|015|M|accordingly.|
00222|016|B||
00222|017|D|DISCUSSION:  During concomitant administration of disopyramide and rifampin|
00222|018|D|to patients with tuberculosis, serum disopyramide concentrations decreased|
00222|019|D|by approximately 50% while the concentration of an active metabolite of|
00222|020|D|disopyramide increased. Concurrent administration of disopyramide and|
00222|021|D|rifampin to a 62-year-old patient produced subtherapeutic disopyramide|
00222|022|D|levels and a failure in correcting the patient's arrhythmia. Five days after|
00222|023|D|stopping rifampin, disopyramide levels increased and the arrhythmia was|
00222|024|D|abolished.|
00222|025|B||
00222|026|R|REFERENCES:|
00222|027|B||
00222|028|R|1.Aitio ML, Mansury L, Tala E, Haataja M, Aitio A. The effect of enzyme|2
00222|029|R|  induction on the metabolism of disopyramide in man. Br J Clin Pharmacol|2
00222|030|R|  1981 Mar;11(3):279-85.|2
00222|031|R|2.Staum JM. Enzyme induction: rifampin-disopyramide interaction. DICP 1990|3
00222|032|R|  Jul-Aug;24(7-8):701-3.|3
00223|001|T|MONOGRAPH TITLE:  Lithium/Carbamazepine|
00223|002|B||
00223|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00223|004|L|take action as needed.|
00223|005|B||
00223|006|A|MECHANISM OF ACTION:  The exact mechanism of the interaction is unknown.|
00223|007|A|Neurotoxicity symptoms (confusion, delirium, seizures, encephalopathy, and|
00223|008|A|EKG changes) may be due to potentiation or an additive effect of the|
00223|009|A|antipsychotic agent and the lithium.|
00223|010|B||
00223|011|E|CLINICAL EFFECTS:  Neurotoxicity with therapeutic serum lithium levels has|
00223|012|E|been reported.|
00223|013|B||
00223|014|P|PREDISPOSING FACTORS:  Large doses of lithium, central nervous system|
00223|015|P|disease and a history of lithium neurotoxicity may predispose this|
00223|016|P|interaction.|
00223|017|B||
00223|018|M|PATIENT MANAGEMENT:  Monitor patients for lithium toxicity during|
00223|019|M|concomitant administration of carbamazepine. Adjust therapy accordingly.|
00223|020|B||
00223|021|D|DISCUSSION:  Although lithium and carbamazepine have been given concurrently|
00223|022|D|to successfully treat manic episodes and rapid-cycling bipolar affective|
00223|023|D|disorder, other investigators have reported central nervous system toxicity,|
00223|024|D|including ataxia, hyperreflexia, lethargy, muscular weakness and tremor.|
00223|025|B||
00223|026|R|REFERENCES:|
00223|027|B||
00223|028|R|1.Ghose K. Interaction between lithium and carbamazepine. Br Med J 1980 Apr|3
00223|029|R|  26;280(6222):1122.|3
00223|030|R|2.Lipinski JF, Pope HG Jr. Possible synergistic action between carbamazepine|3
00223|031|R|  and lithium carbonate in the treatment of three acutely manic patients. Am|3
00223|032|R|  J Psychiatry 1982 Jul;139(7):948-9.|3
00223|033|R|3.Keisling R. Carbamazepine and lithium carbonate in the treatment of|3
00223|034|R|  refractory affective disorders. Arch Gen Psychiatry 1983 Feb;40(2):223.|3
00223|035|R|4.Moss GR, James CR. Carbamazepine and lithium carbonate synergism in mania.|3
00223|036|R|  Arch Gen Psychiatry 1983 May;40(5):588-9.|3
00223|037|R|5.Chaudhry RP, Waters BG. Lithium and carbamazepine interaction: possible|3
00223|038|R|  neurotoxicity. J Clin Psychiatry 1983 Jan;44(1):30-1.|3
00223|039|R|6.Post RM, Uhde TW. Carbamazepine and lithium carbonate synergism in mania.|6
00223|040|R|  Arch Gen Psychiatry 1984 Feb;41(2):210.|6
00223|041|R|7.Andrus PF. Lithium and carbamazepine. J Clin Psychiatry 1984 Dec;|3
00223|042|R|  45(12):525.|3
00223|043|R|8.Shukla S, Godwin CD, Long LE, Miller MG. Lithium-carbamazepine|3
00223|044|R|  neurotoxicity and risk factors. Am J Psychiatry 1984 Dec;141(12):1604-6.|3
00223|045|R|9.Laird LK, Knox EP. The use of carbamazepine and lithium in controlling a|3
00223|046|R|  case of chronic rapid cycling. Pharmacotherapy 1987;7(4):130-2.|3
00224|001|T|MONOGRAPH TITLE:  Haloperidol/CYP 3A4 Inducers (mono deleted 12/26/2013)|
00224|002|B||
00224|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00224|004|L|take action as needed.|
00224|005|B||
00224|006|A|MECHANISM OF ACTION:  Carbamazepine, phenytoin, rifampin, and St. John's|
00224|007|A|wort may induce hepatic metabolism of haloperidol by CYP3A4.(1)|
00224|008|B||
00224|009|E|CLINICAL EFFECTS:  Concurrent or recent use of carbamazepine, phenytoin,|
00224|010|E|rifampin, or St. John's wort may decrease haloperidol levels and|
00224|011|E|effectiveness.  Some patients may experience worsened clinical effects.  The|
00224|012|E|combination of carbamazepine and haloperidol may improve symptoms in some|
00224|013|E|patients.|
00224|014|B||
00224|015|P|PREDISPOSING FACTORS:  None determined.|
00224|016|B||
00224|017|M|PATIENT MANAGEMENT:  Carefully monitor clinical response in patients|
00224|018|M|maintained on haloperidol when initiating or discontinuing an inducer of|
00224|019|M|CYP3A4, such as carbamazepine, phenytoin, rifampin, or St. John's wort.  The|
00224|020|M|dosage of haloperidol may need to be adjusted.(1)|
00224|021|B||
00224|022|D|DISCUSSION:  In a study in 11 schizophrenic patients, the addition of|
00224|023|D|carbamazepine resulted in a dose related decrease in haloperidol levels.|
00224|024|D|Haloperidol levels were decreased by 2%, 61%, and 85%, respectively, from|
00224|025|D|baseline  following the addition and increase of carbamazepine at 100|
00224|026|D|mg/day, 300 mg/day, and 600 mg/day.(1,2)|
00224|027|D|   In a study in 27 patients with schizophrenia or schizoaffective disorder,|
00224|028|D|the use of haloperidol with carbamazepine was associated with lower|
00224|029|D|haloperidol levels and worse clinical outcomes than the use of haloperidol|
00224|030|D|alone.(3)|
00224|031|D|   In a study in schizophrenic patients, haloperidol levels were|
00224|032|D|significantly decreased in patients receiving concurrent carbamazepine.(4)|
00224|033|D|   In a study in 7 patients, haloperidol levels fell 60% following the|
00224|034|D|addition of carbamazepine to therapy.  Haloperidol levels were undetectable|
00224|035|D|in 2 subjects, whose symptoms worsened.(5)|
00224|036|D|   In a study in 23 patients, the addition of carbamazepine to haloperidol|
00224|037|D|resulted in improvement in symptoms.(6)|
00224|038|D|   In a retrospective review of 231 schizophrenic patients, patients|
00224|039|D|receiving concurrent carbamazepine or phenobarbital had haloperidol levels|
00224|040|D|that were 37% and 22% lower, respectively, than patients taking haloperidol|
00224|041|D|without these agents.(7)|
00224|042|D|   In a study in 6 schizophrenic patients, switching carbamazepine to|
00224|043|D|oxcarbazepine resulted in increased haloperidol levels by 50% to 200% after|
00224|044|D|2-4 weeks of therapy.(8)|
00224|045|D|   In a study in schizophrenic patients, carbamazepine decreased haloperidol|
00224|046|D|levels by 50%.  One subject developed worsening of symptoms, while two|
00224|047|D|improved.(9)|
00224|048|D|   There are also case reports documenting decreased haloperidol levels and|
00224|049|D|effectiveness with concurrent carbamazepine.(10-14)|
00224|050|D|   In a study in schizophrenic patients, the addition of rifampin in 12|
00224|051|D|patients resulted in decreases in haloperidol levels by 37%, 58.7%, and 70%|
00224|052|D|by Day 3, Day 7, and Day 28, respectively, of concurrent therapy.  Mean|
00224|053|D|scores on the Brief Psychiatric Rating Scale decreased from baseline.|
00224|054|D|Discontinuation of rifampin from concurrent therapy in 5 patients increased|
00224|055|D|haloperidol levels by 140.7%, 228.7%, and 329% of baseline by Day 3, Day 7,|
00224|056|D|and Day 28, respectively, after rifampin discontinuation.(1,15)|
00224|057|D|   In a study in 7 schizophrenic patients, rifampin decreased the half-life|
00224|058|D|of haloperidol by 48%.(16)|
00224|059|D|   Carbamazepine, phenytoin, rifampin, and St. John's wort are inducers of|
00224|060|D|CYP3A4.(17)|
00224|061|B||
00224|062|R|REFERENCES:|
00224|063|B||
00224|064|R|1.Haldol (haloperidol) US prescribing information. Ortho-McNeil-Janssen|1
00224|065|R|  Pharmaceuticals, Inc. August, 2011.|1
00224|066|R|2.Yasui-Furukori N, Kondo T, Mihara K, Suzuki A, Inoue Y, Kaneko S.|2
00224|067|R|  Significant dose effect of carbamazepine on reduction of steady-state|2
00224|068|R|  plasma concentration of haloperidol in schizophrenic patients. J Clin|2
00224|069|R|  Psychopharmacol 2003 Oct;23(5):435-40.|2
00224|070|R|3.Hesslinger B, Normann C, Langosch JM, Klose P, Berger M, Walden J. Effects|2
00224|071|R|  of carbamazepine and valproate on haloperidol plasma levels and on|2
00224|072|R|  psychopathologic outcome in schizophrenic patients. J Clin Psychopharmacol|2
00224|073|R|  1999 Aug;19(4):310-5.|2
00224|074|R|4.Iwahashi K, Miyatake R, Suwaki H, Hosokawa K, Ichikawa Y. The drug-drug|2
00224|075|R|  interaction effects of haloperidol on plasma carbamazepine levels. Clin|2
00224|076|R|  Neuropharmacol 1995 Jun;18(3):233-6.|2
00224|077|R|5.Arana GW, Goff DC, Friedman H, Ornsteen M, Greenblatt DJ, Black B, Shader|2
00224|078|R|  RI. Does carbamazepine-induced reduction of plasma haloperidol levels|2
00224|079|R|  worsen psychotic symptoms?. Am J Psychiatry 1986 May;143(5):650-1.|2
00224|080|R|6.Klein E, Bental E, Lerer B, Belmaker RH. Carbamazepine and haloperidol v|2
00224|081|R|  placebo and haloperidol in excited psychoses. A controlled study. Arch Gen|2
00224|082|R|  Psychiatry 1984 Feb;41(2):165-70.|2
00224|083|R|7.Hirokane G, Someya T, Takahashi S, Morita S, Shimoda K. Interindividual|2
00224|084|R|  variation of plasma haloperidol concentrations and the impact of|2
00224|085|R|  concomitant medications: the analysis of therapeutic drug monitoring data.|2
00224|086|R|  Ther Drug Monit 1999 Feb;21(1):82-6.|2
00224|087|R|8.Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching carbamazepine|3
00224|088|R|  to oxcarbazepine on the plasma levels of neuroleptics. A case report.|3
00224|089|R|  Psychopharmacology (Berl) 1994 Sep;116(1):115-6.|3
00224|090|R|9.Kahn EM, Schulz SC, Perel JM, Alexander JE. Change in haloperidol level|2
00224|091|R|  due to carbamazepine--a complicating factor in combined medication for|2
00224|092|R|  schizophrenia. J Clin Psychopharmacol 1990 Feb;10(1):54-7.|2
00224|093|R|10.Fast DK, Jones BD, Kusalic M, Erickson M. Effect of carbamazepine on|3
00224|094|R|   neuroleptic plasma levels and efficacy. Am J Psychiatry 1986 Jan;|3
00224|095|R|   143(1):117-8.|3
00224|096|R|11.Jann MW, Ereshefsky L, Saklad SR, Seidel DR, Davis CM, Burch NR, Bowden|3
00224|097|R|   CL. Effects of carbamazepine on plasma haloperidol levels. J Clin|3
00224|098|R|   Psychopharmacol 1985 Apr;5(2):106-9.|3
00224|099|R|12.Cohen D, Diemont WL. Deterioration of schizoaffective disorder due to an|3
00224|100|R|   interaction between haloperidol and carbamazepine. Ned Tijdschr Geneeskd|3
00224|101|R|   2002 Oct 12;146(41):1942-4.|3
00224|102|R|13.Kanter GL, Yerevanian BI, Ciccone JR. Case report of a possible|3
00224|103|R|   interaction between neuroleptics and carbamazepine. Am J Psychiatry 1984|3
00224|104|R|   Sep;141(9):1101-2.|3
00224|105|R|14.Brayley J, Yellowlees P. An interaction between haloperidol and|3
00224|106|R|   carbamazepine in a patient with cerebral palsy. Aust N Z J Psychiatry|3
00224|107|R|   1987 Dec;21(4):605-7.|3
00224|108|R|15.Kim YH, Cha IJ, Shim JC, Shin JG, Yoon YR, Kim YK, Kim JI, Park GH, Jang|2
00224|109|R|   IJ, Woo JI, Shin SG. Effect of rifampin on the plasma concentration and|2
00224|110|R|   the clinical effect of haloperidol concomitantly administered to|2
00224|111|R|   schizophrenic patients. J Clin Psychopharmacol 1996 Jun;16(3):247-52.|2
00224|112|R|16.Takeda M, Nishinuma K, Yamashita S, Matsubayashi T, Tanino S, Nishimura|2
00224|113|R|   T. Serum haloperidol levels of schizophrenics receiving treatment for|2
00224|114|R|   tuberculosis. Clin Neuropharmacol 1986;9(4):386-97.|2
00224|115|R|17.US Food and Drug Administration (FDA). Drug Development and Drug|1
00224|116|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
00224|117|R|   at:|1
00224|118|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
00224|119|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
00224|120|R|   11/14/2017.|1
00225|001|T|MONOGRAPH TITLE:  Lithium/Iodide Salts|
00225|002|B||
00225|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00225|004|L|take action as needed.|
00225|005|B||
00225|006|A|MECHANISM OF ACTION:  Unknown.|
00225|007|B||
00225|008|E|CLINICAL EFFECTS:  Concurrent administration of lithium and iodide salts may|
00225|009|E|produce hypothyroidism.|
00225|010|B||
00225|011|P|PREDISPOSING FACTORS:  None determined.|
00225|012|B||
00225|013|M|PATIENT MANAGEMENT:  If both drugs are given, monitor patient for signs and|
00225|014|M|symptoms of hypothyroidism. If hypothyroidism develops, thyroid hormone may|
00225|015|M|be used to treat symptoms.|
00225|016|B||
00225|017|D|DISCUSSION:  Hypothyroidism is a side effect that may occur with long-term|
00225|018|D|lithium treatment. Thyroid gland enlargement and increased thyroid|
00225|019|D|stimulating hormone may also be present. Iodide administration to patients|
00225|020|D|receiving lithium may increase the risk of patients developing|
00225|021|D|hypothyroidism.|
00225|022|B||
00225|023|R|REFERENCES:|
00225|024|B||
00225|025|R|1.Wiener JD. Lithium carbonate-induced myxedema. JAMA 1972 Apr 24;|6
00225|026|R|  220(4):587.|6
00225|027|R|2.Jorgensen JV, Brandrup F, Schroll M. Possible synergism between iodine and|6
00225|028|R|  lithium carbonate. JAMA 1973 Jan 8;223(2):192-3.|6
00225|029|R|3.Lithobid (lithium carbonate) US prescribing information. ANI|1
00225|030|R|  Pharmaceuticals, Inc. May, 2018.|1
00226|001|T|MONOGRAPH TITLE:  Mefloquine; Quinidine/Beta-Blockers|
00226|002|B||
00226|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00226|004|L|take action as needed.|
00226|005|B||
00226|006|A|MECHANISM OF ACTION:  Quinidine may inhibit the oxidative metabolism of|
00226|007|A|beta-blockers. In addition, beta-blockers and quinidine exert a negative|
00226|008|A|inotropic action on the heart.  Mefloquine is a chemical analogue of quinine|
00226|009|A|which possess 20% of the antifibrillatory action of quinidine.  Alterations|
00226|010|A|in electrocardiograms have been observed during mefloquine therapy.|
00226|011|B||
00226|012|E|CLINICAL EFFECTS:  The pharmacologic effects of certain beta-blockers may be|
00226|013|E|increased during concurrent therapy with quinidine.  During concurrent|
00226|014|E|therapy with mefloquine, electrocardiographic abnormalities or cardiac|
00226|015|E|arrest may occur.|
00226|016|B||
00226|017|P|PREDISPOSING FACTORS:  Cardiac disease.|
00226|018|B||
00226|019|M|PATIENT MANAGEMENT:  Monitor the response of the patient and adjust the dose|
00226|020|M|of the beta-blocker as needed.  The benefits of mefloquine therapy in|
00226|021|M|patients with preexisting cardiac disease should be weighed carefully.|
00226|022|B||
00226|023|D|DISCUSSION:  Quinidine and beta-blockers have been used therapeutically to|
00226|024|D|treat cardiac arrhythmias; however, they should be used cautiously since|
00226|025|D|quinidine and beta-blockers exert a negative inotropic action on the heart.|
00226|026|D|Quinidine has been associated with an increase in serum metoprolol levels. A|
00226|027|D|reduction in propranolol clearance has been demonstrated in one study,|
00226|028|D|although others have failed to show an interaction between propranolol and|
00226|029|D|quinidine. A patient using timolol eyedrops developed bradycardia following|
00226|030|D|administration of quinidine.|
00226|031|D|   There is one report of cardiac arrest, which was successfully treated, in|
00226|032|D|a patient receiving concurrent mefloquine and propranolol.  The manufacturer|
00226|033|D|of mefloquine states that concurrent use may produce electrocardiographic|
00226|034|D|abnormalities and cardiac arrest.  The manufacturer also recommends weighing|
00226|035|D|the benefits of mefloquine therapy against the risk of adverse effects in|
00226|036|D|patients with cardiac disease.|
00226|037|B||
00226|038|R|REFERENCES:|
00226|039|B||
00226|040|R|1.Fors WJ Jr, Vanderark CR, Reynolds EW Jr. Evaluation of propranolol and|2
00226|041|R|  quinidine in the treatment of quinidine- resistant arrhythmias. Am J|2
00226|042|R|  Cardiol 1971 Feb;27(2):190-4.|2
00226|043|R|2.Kessler KM, Humphries WC Jr, Black M, Spann JF. Quinidine pharmacokinetics|2
00226|044|R|  in patients with cirrhosis or receiving propranolol. Am Heart J 1978 Nov;|2
00226|045|R|  96(5):627-35.|2
00226|046|R|3.Kates RE, Blanford MF. Disposition kinetics of oral quinidine when|2
00226|047|R|  administered concurrently with propranolol. J Clin Pharmacol 1979 Jul;|2
00226|048|R|  19(7):378-83.|2
00226|049|R|4.Fenster P, Perrier D, Mayersohn M, Marcus FI. Kinetic evaluation of the|2
00226|050|R|  propranolol-quinidine combination. Clin Pharmacol Ther 1980 Apr;|2
00226|051|R|  27(4):450-3.|2
00226|052|R|5.Dinai Y, Sharir M, Naveh N, Halkin H. Bradycardia induced by interaction|3
00226|053|R|  between quinidine and ophthalmic timolol. Ann Intern Med 1985 Dec;103(6 (|3
00226|054|R|  Pt 1)):890-1.|3
00226|055|R|6.Leemann T, Dayer P, Meyer UA. Single-dose quinidine treatment inhibits|2
00226|056|R|  metoprolol oxidation in extensive metabolizers. Eur J Clin Pharmacol 1986;|2
00226|057|R|  29(6):739-41.|2
00226|058|R|7.Zhou HH, Anthony LB, Roden DM, Wood AJ. Quinidine reduces clearance of|2
00226|059|R|  (+)-propranolol more than (-)- propranolol through marked reduction in|2
00226|060|R|  4-hydroxylation. Clin Pharmacol Ther 1990 Jun;47(6):686-93.|2
00226|061|R|8.Lariam (mefloquine hydrochloride) US prescribing information. Roche|1
00226|062|R|  Pharmaceuticals August, 2009.|1
00227|001|T|MONOGRAPH TITLE:  Carbamazepine/Selected Calcium Channel Blockers|
00227|002|B||
00227|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00227|004|L|of severe adverse interaction.|
00227|005|B||
00227|006|A|MECHANISM OF ACTION:  Diltiazem and verapamil may inhibit the metabolism of|
00227|007|A|carbamazepine.  Carbamazepine may induce the metabolism of calcium channel|
00227|008|A|blockers.|
00227|009|B||
00227|010|E|CLINICAL EFFECTS:  Concurrent diltiazem or verapamil may result in elevated|
00227|011|E|levels of and toxicity from carbamazepine.|
00227|012|E|   Concurrent carbamazepine may reduce the levels and effectiveness of|
00227|013|E|calcium channel blockers.|
00227|014|B||
00227|015|P|PREDISPOSING FACTORS:  None determined.|
00227|016|B||
00227|017|M|PATIENT MANAGEMENT:  Monitor serum carbamazepine levels when starting,|
00227|018|M|stopping, or altering the dose of diltiazem or verapamil.  Adjust the dose|
00227|019|M|of carbamazepine accordingly.|
00227|020|M|   Monitor the effectiveness of calcium channel blockers in patients|
00227|021|M|maintained on carbamazepine.  An alternative antihypertensive agent may be|
00227|022|M|needed.|
00227|023|M|   The manufacturer of diltiazem states that coadministration with CYP3A4|
00227|024|M|inducers should be avoided when possible.|
00227|025|B||
00227|026|D|DISCUSSION:  Neurotoxicity has been reported during concurrent use of|
00227|027|D|carbamazepine and diltiazem or verapamil.  Diltiazem has been shown to|
00227|028|D|increase carbamazepine levels by 40% to 72%.  Verapamil has been shown to|
00227|029|D|increase carbamazepine levels by 46%.|
00227|030|D|   Diltiazem levels have been shown to become undetectable when|
00227|031|D|coadministered with rifampin, a strong CYP3A4 inducer.|
00227|032|B||
00227|033|R|REFERENCES:|
00227|034|B||
00227|035|R|1.Macphee GJ, McInnes GT, Thompson GG, Brodie MJ. Verapamil potentiates|2
00227|036|R|  carbamazepine neurotoxicity: a clinically important inhibitory|2
00227|037|R|  interaction. Lancet 1986 Mar 29;1(8483):700-3.|2
00227|038|R|2.Brodie MJ, MacPhee GJ. Carbamazepine neurotoxicity precipitated by|3
00227|039|R|  diltiazem. Br Med J (Clin Res Ed) 1986 May 3;292(6529):1170-1.|3
00227|040|R|3.Eimer M, Carter BL. Elevated serum carbamazepine concentrations following|3
00227|041|R|  diltiazem initiation. Drug Intell Clin Pharm 1987 Apr;21(4):340-2.|3
00227|042|R|4.Price WA, DiMarzio LR. Verapamil-carbamazepine neurotoxicity. J Clin|3
00227|043|R|  Psychiatry 1988 Feb;49(2):80.|3
00227|044|R|5.Beattie B, Biller J, Mehlhaus B, Murray M. Verapamil-induced carbamazepine|3
00227|045|R|  neurotoxicity. A report of two cases. Eur Neurol 1988;28(2):104-5.|3
00227|046|R|6.Gadde K, Calabrese JR. Diltiazem effect on carbamazepine levels in manic|3
00227|047|R|  depression. J Clin Psychopharmacol 1990 Oct;10(5):378-9.|3
00227|048|R|7.Ahmad S. Diltiazem-carbamazepine interaction. Am Heart J 1990 Dec;120(6 Pt|3
00227|049|R|  1):1485-6.|3
00227|050|R|8.Bahls FH, Ozuna J, Ritchie DE. Interactions between calcium channel|3
00227|051|R|  blockers and the anticonvulsants carbamazepine and phenytoin. Neurology|3
00227|052|R|  1991 May;41(5):740-2.|3
00227|053|R|9.Maoz E, Grossman E, Thaler M, Rosenthal T. Carbamazepine neurotoxic|3
00227|054|R|  reaction after administration of diltiazem. Arch Intern Med 1992 Dec;|3
00227|055|R|  152(12):2503-4.|3
00227|056|R|10.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
00227|057|R|   information. Abbott Pharmaceuticals, Inc. November, 2016.|1
00227|058|R|11.Wijdicks EF, Arendt C, Bazzell MC. Postoperative ophthalmoplegia and|3
00227|059|R|   ataxia due to carbamazepine toxicity facilitated by diltiazem. J|3
00227|060|R|   Neuroophthalmol 2004 Mar;24(1):95.|3
00227|061|R|12.Shaughnessy AF, Mosley MR. Elevated carbamazepine levels associated with|3
00227|062|R|   diltiazem use. Neurology 1992 Apr;42(4):937-8.|3
00228|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/Macrolide Antibiotics|
00228|002|B||
00228|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00228|004|L|is contraindicated and generally should not be dispensed or administered to|
00228|005|L|the same patient.|
00228|006|B||
00228|007|A|MECHANISM OF ACTION:  Inhibition of the metabolism of astemizole,|
00228|008|A|mizolastine, and terfenadine by the macrolide antibiotics.|
00228|009|B||
00228|010|E|CLINICAL EFFECTS:  Possible increased serum astemizole, mizolastine, or|
00228|011|E|terfenadine with increased side effects such as life-threatening cardiac|
00228|012|E|arrhythmias including QT prolongation or torsades de pointes.|
00228|013|B||
00228|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00228|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00228|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00228|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00228|018|P|female gender, or advanced age.(30)|
00228|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00228|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00228|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00228|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00228|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00228|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00228|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(30)|
00228|026|B||
00228|027|M|PATIENT MANAGEMENT:  The concurrent administration of astemizole,|
00228|028|M|mizolastine, or terfenadine with clarithromycin, erythromycin, or|
00228|029|M|troleandomycin is contraindicated.  Loratadine or fexofenadine may be|
00228|030|M|alternatives to astemizole, mizolastine, or terfenadine in patients|
00228|031|M|receiving clarithromycin, erythromycin, or troleandomycin.|
00228|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00228|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00228|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00228|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00228|036|B||
00228|037|D|DISCUSSION:  Inhibition of the terfenadine and astemizole metabolism to|
00228|038|D|their active metabolites by the macrolide antibiotics may result in|
00228|039|D|increased levels of their parent compounds, which is believed to produce|
00228|040|D|cardiotoxicity.  (Unmetabolized terfenadine is normally undetectable and|
00228|041|D|concentrations of unmetabolized astemizole are normally lower than the|
00228|042|D|metabolized form.)|
00228|043|D|   Several studies and case reports have documented serious cardiac events|
00228|044|D|(prolongation of the QTc interval and/or ventricular tachycardia) during|
00228|045|D|concomitant therapy with erythromycin and either terfenadine or astemizole|
00228|046|D|and with clarithromycin, troleandomycin, or josamycin and terfenadine.|
00228|047|D|   Concurrent use of clarithromycin and terfenadine has been shown to|
00228|048|D|increase the plasma concentration of the active acid metabolite of|
00228|049|D|terfenadine by 3-fold.|
00228|050|D|   A study showed that erythromycin increased fexofenadine levels; however,|
00228|051|D|there was no difference in adverse effects or QTc interval.  Studies have|
00228|052|D|have shown increased levels of loratadine during concurrent administration|
00228|053|D|of erythromycin; however, increased levels of loratadine have been shown to|
00228|054|D|produce no cardiac changes.  Fexofenadine or loratadine may be alternatives|
00228|055|D|to astemizole or terfenadine in patients receiving macrolides.|
00228|056|D|   The manufacturer of terfenadine does not recommend concurrent use of|
00228|057|D|terfenadine and azithromycin; however, two small studies in humans have|
00228|058|D|shown that concurrent use of azithromycin and terfenadine does not increase|
00228|059|D|terfenadine levels.  In addition, a study in rats indicates that|
00228|060|D|azithromycin does not inhibit CYP P-450.|
00228|061|D|   One or more of the drug pairs linked to this monograph have been included|
00228|062|D|in a list of interactions that should be considered "high-priority" for|
00228|063|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00228|064|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00228|065|D|Coordinator (ONC) for Health Information Technology.|
00228|066|B||
00228|067|R|REFERENCES:|
00228|068|B||
00228|069|R|1.Mathews DR, McNutt B, Okerholm R, Flicker M, McBride G. Torsades de|2
00228|070|R|  pointes occurring in association with terfenadine use. JAMA 1991 Nov 6;|2
00228|071|R|  266(17):2375-6.|2
00228|072|R|2.Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic|3
00228|073|R|  actions of terfenadine. JAMA 1993 Mar 24-31;269(12):1532-6.|3
00228|074|R|3.Cortese LM, Bjornson DC. Comment: the new macrolide antibiotics and|3
00228|075|R|  terfenadine. Ann Pharmacother 1992 Jul-Aug;26(7-8):1019.|3
00228|076|R|4.Peck CC, Temple R, Collins JM. Understanding consequences of concurrent|6
00228|077|R|  therapies. JAMA 1993 Mar 24-31;269(12):1550-2.|6
00228|078|R|5.Peters DH, Friedel HA, McTavish D. Azithromycin. A review of its|6
00228|079|R|  antimicrobial activity, pharmacokinetic properties and clinical efficacy.|6
00228|080|R|  Drugs 1992 Nov;44(5):750-99.|6
00228|081|R|6.Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr. Changes in the|2
00228|082|R|  pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine|2
00228|083|R|  with concomitant administration of erythromycin. Clin Pharmacol Ther 1992|2
00228|084|R|  Sep;52(3):231-8.|2
00228|085|R|7.Ballow CH, Amsden GW. Azithromycin: the first azalide antibiotic. Ann|6
00228|086|R|  Pharmacother 1992 Oct;26(10):1253-61.|6
00228|087|R|8.Snook J, Boothman-Burrell D, Watkins J, Colin-Jones D. Torsade de pointes|3
00228|088|R|  ventricular tachycardia associated with astemizole overdose. Br J Clin|3
00228|089|R|  Pract 1988 Jun;42(6):257-9.|3
00228|090|R|9.Sakemi H, VanNatta B. Torsade de pointes induced by astemizole in a|3
00228|091|R|  patient with prolongation of the QT interval. Am Heart J 1993 May;125(5 Pt|3
00228|092|R|  1):1436-8.|3
00228|093|R|10.Eller M, Russell T, Ruberg S, Okerholm R, McNutt B. Effect of|4
00228|094|R|   erythromycin on terfenadine metabolite pharmacokinetics. Clin Pharmacol|4
00228|095|R|   Ther 1993;53(2):161.|4
00228|096|R|11.Harris S, Morse I, Hilligoss DM, Colangelo PM, Eller M, Okerholm R.|4
00228|097|R|   Azithromycin and terfenadine: lack of drug interaction, a double-blind,|4
00228|098|R|   placebo-controlled study. 33rd Interscience Conference on Antimicrobial|4
00228|099|R|   Agents and Chemotherapy (ICAAC) 1993 Oct 17.|4
00228|100|R|12.Biglin KE, Faraon MS, Constance TD, Lieh-Lai M. Drug-induced torsades de|3
00228|101|R|   pointes: a possible interaction of terfenadine and erythromycin. Ann|3
00228|102|R|   Pharmacother 1994 Feb;28(2):282.|3
00228|103|R|13.Garteiz DA, Hook RH, Walker BJ, Okerholm RA. Pharmacokinetics and|2
00228|104|R|   biotransformation studies of terfenadine in man. Arzneimittelforschung|2
00228|105|R|   1982;32(9a):1185-90.|2
00228|106|R|14.Personal communication. Marion Merrell Dow 1991.|1
00228|107|R|15.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00228|108|R|   September, 1997.|1
00228|109|R|16.Data on file. Marion Merrell Dow 1991.|1
00228|110|R|17.Honig PK, Wortham DC, Zamani K, Cantilena LR. Comparison of the effect of|2
00228|111|R|   the macrolide antibiotics erythromycin, clarithromycin and azithromycin|2
00228|112|R|   on terfenadine steady-state pharmacokinetics and electrocardiographi|2
00228|113|R|   parameters. Drug Invest 1994;7(3):148-56.|2
00228|114|R|18.Goss JE, Ramo BW, Blake K. Torsades de pointes associated with astemizole|3
00228|115|R|   (Hismanal) therapy. Arch Intern Med 1993 Dec 13;153(23):2705.|3
00228|116|R|19.Brannan MD/Reidenberg P, Radwanski E, Shneyer MA, Lin C, Affrime MB.|4
00228|117|R|   Evaluation of pharmacokinetic and electrocardiographic parameters|4
00228|118|R|   following 10 days of concomitant loratadine and erythromycin|4
00228|119|R|   administration. Presented at the annual meeting of the American College|4
00228|120|R|   of Clinical Pharmacy 1994 Jun.|4
00228|121|R|20.Affrime MB, Lorber R, Danzig M, Cuss F, Brannan MD. Three month|4
00228|122|R|   evaluation of electrocardiographic effects of loratatdine in humans. J|4
00228|123|R|   Allergy Clin Immunol 1993;91(1):259.|4
00228|124|R|21.Data on file. Janssen Pharmaceutica Products, L.P. 1991.|1
00228|125|R|22.Yumibe N, Huie K, Chen KJ, Clement RP, Cayen MN. Identification of human|4
00228|126|R|   liver cytochrome P450s involved in the microsomal metabolism of the|4
00228|127|R|   antihistaminic drug loratadine. J Allergy Clin Immunol 1994 Jan;93(Part|4
00228|128|R|   2):234.|4
00228|129|R|23.Chen Y, Gillis RA, Woosley RL. Block of delayed rectifier potassium|4
00228|130|R|   current, IK, by terfenadine in cat ventricular myocytes. J Am Coll|4
00228|131|R|   Cardiol 1991 Feb;17(2):140A.|4
00228|132|R|24.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
00228|133|R|   September, 2019.|1
00228|134|R|25.Hismanal (astemizole) US prescribing information. Janssen Pharmaceutica|1
00228|135|R|   Products, L.P. February, 1996.|1
00228|136|R|26.Claritin (loratadine) US prescribing information. Schering-Plough|1
00228|137|R|   Corporation January, 1997.|1
00228|138|R|27.Allegra (fexofenadine hydrochloride) US prescribing information.|1
00228|139|R|   Sanofi-Aventis U.S. LLC October, 2006.|1
00228|140|R|28.Dear Doctor Letter. Janssen Pharmaceutica Products, L.P. February 1998.|1
00228|141|R|29.Mizollen (mizolastine) US prescribing information. Lorex Synthelab|1
00228|142|R|   September 29, 1997.|1
00228|143|R|30.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
00228|144|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
00228|145|R|   hospital settings: a scientific statement from the American Heart|6
00228|146|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
00228|147|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
00228|148|R|31.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00228|149|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00228|150|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00228|151|R|   19(5):735-43.|6
00229|001|T|MONOGRAPH TITLE:  Beta-Blockers/Thioamines (mono deleted 02/25/2022)|
00229|002|B||
00229|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00229|004|L|take action as needed.|
00229|005|B||
00229|006|A|MECHANISM OF ACTION:  Hyperthyroidism causes an increased clearance of|
00229|007|A|beta-blockers with a high extraction ratio (eg., metoprolol and|
00229|008|A|propranolol). Converting patients to a euthyroid state may decrease the|
00229|009|A|clearance of these beta-blockers.|
00229|010|B||
00229|011|E|CLINICAL EFFECTS:  Increased pharmacological effect of certain|
00229|012|E|beta-blockers.|
00229|013|B||
00229|014|P|PREDISPOSING FACTORS:  None determined.|
00229|015|B||
00229|016|M|PATIENT MANAGEMENT:  Monitor the response of hyperthyroid patients who|
00229|017|M|become euthyroid. Adjust the dose of the beta-blocker as needed.|
00229|018|B||
00229|019|D|DISCUSSION:  Oral clearance of metoprolol, practolol and propranolol was|
00229|020|D|found to be as much as 45% higher in hyperthyroid patients compared to|
00229|021|D|euthyroid patients. In a study involving 30 patients, the area under the|
00229|022|D|propranolol concentration-time curve increased by more than 90% after|
00229|023|D|treatment of hyperthyroidism. Following therapeutically-induced|
00229|024|D|euthyroidism, a 2 to 3 fold increase in serum propranolol concentrations has|
00229|025|D|been reported.|
00229|026|B||
00229|027|R|REFERENCES:|
00229|028|B||
00229|029|R|1.Bell JM, Russell CJ, Nelson JK, Kelly JG, McDevitt DG. Studies of the|2
00229|030|R|  effect of thyroid dysfunction on the elimination of beta- adrenoreceptor|2
00229|031|R|  blocking drugs. Br J Clin Pharmacol 1977 Feb;4(1):79-82.|2
00229|032|R|2.Feely J, Stevenson IH, Crooks J. Increased clearance of propranolol in|2
00229|033|R|  thyrotoxicosis. Ann Intern Med 1981 Apr;94(4 pt 1):472-4.|2
00229|034|R|3.Feely J, Crooks J, Stevenson IH. Plasma propranolol steady state|2
00229|035|R|  concentrations in thyroid disorders. Eur J Clin Pharmacol 1981;|2
00229|036|R|  19(5):329-33.|2
00229|037|R|4.Feely J, Crooks J, Stevenson IH. The influence of age, smoking and|2
00229|038|R|  hyperthyroidism on plasma propranolol steady state concentration. Br J|2
00229|039|R|  Clin Pharmacol 1981 Jul;12(1):73-8.|2
00229|040|R|5.Wells PG, Feely J, Nadeau J, Wilkinson GR, Wood AJJ. Propranolol|4
00229|041|R|  disposition in thyrotoxicosis. Clin Res 1981;29(2):279A.|4
00229|042|R|6.Aro A, Anttila M, Korhonen T, Sundquist H. Pharmacokinetics of propranolol|2
00229|043|R|  and sotalol in hyperthyroidism. Eur J Clin Pharmacol 1982;21(5):373-7.|2
00229|044|R|7.Hallengren B, Nilsson OR, Karlberg BE, Melander A, Tegler L, Wahlin-Boll|2
00229|045|R|  E. Influence of hyperthyroidism on the kinetics of methimazole,|2
00229|046|R|  propranolol, metoprolol and atenolol. Eur J Clin Pharmacol 1982;|2
00229|047|R|  21(5):379-84.|2
00229|048|R|8.Wells PG, Feely J, Wilkinson GR, Wood AJ. Effect of thyrotoxicosis on|2
00229|049|R|  liver blood flow and propranolol disposition after long-term dosing. Clin|2
00229|050|R|  Pharmacol Ther 1983 May;33(5):603-8.|2
00230|001|T|MONOGRAPH TITLE:  Lincosamides/Kaolin|
00230|002|B||
00230|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00230|004|L|take action as needed.|
00230|005|B||
00230|006|A|MECHANISM OF ACTION:  Adsorption of antibiotic to kaolin-pectin.|
00230|007|B||
00230|008|E|CLINICAL EFFECTS:  Decreased or delayed pharmacological effect of the|
00230|009|E|antibiotic.|
00230|010|B||
00230|011|P|PREDISPOSING FACTORS:  None determined.|
00230|012|B||
00230|013|M|PATIENT MANAGEMENT:  Administer the antibiotic two hours after|
00230|014|M|kaolin-pectin.|
00230|015|B||
00230|016|D|DISCUSSION:  When kaolin-pectin suspension was coadministered with|
00230|017|D|lincomycin only 9% of the antibiotic was absorbed. Coadministration of|
00230|018|D|kaolin-pectin and clindamycin decreased the peak clindamycin concentration|
00230|019|D|by 61% and delayed the time to reach peak serum concentration by 1.5 hours.|
00230|020|B||
00230|021|R|REFERENCE:|
00230|022|B||
00230|023|R|1.Albert KS, DeSante KA, Welch RD, DiSanto AR. Pharmacokinetic evaluation of|2
00230|024|R|  a drug interaction between kaolin--pectin and clindamycin. J Pharm Sci|2
00230|025|R|  1978 Nov;67(11):1579-82.|2
00231|001|T|MONOGRAPH TITLE:  Contraceptives/Troleandomycin|
00231|002|B||
00231|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00231|004|L|of severe adverse interaction.|
00231|005|B||
00231|006|A|MECHANISM OF ACTION:  Troleandomycin is a strong CYP3A4 inhibitor and may|
00231|007|A|decrease metabolism of oral contraceptives.(1,2)  Increased exposure to|
00231|008|A|estrogens may result in decreased bile acid secretion and toxic accumulation|
00231|009|A|of bile acids.|
00231|010|B||
00231|011|E|CLINICAL EFFECTS:  The concurrent use of troleandomycin with contraceptive|
00231|012|E|agents may result in intrahepatic cholestasis.|
00231|013|B||
00231|014|P|PREDISPOSING FACTORS:  None determined.|
00231|015|B||
00231|016|M|PATIENT MANAGEMENT:  Avoid concurrent administration of these drugs.|
00231|017|B||
00231|018|D|DISCUSSION:  Numerous case reports and one study document the occurrence of|
00231|019|D|intrahepatic cholestasis in patients receiving oral contraceptives and|
00231|020|D|troleandomycin concomitantly. This reaction appears to be reversible if the|
00231|021|D|drugs are discontinued.|
00231|022|B||
00231|023|R|REFERENCES:|
00231|024|B||
00231|025|R|1.Marvelon (desogestrel-ethinyl estradiol) Canadian prescribing information.|1
00231|026|R|  Organon 2008.|1
00231|027|R|2.This information is based on an extract from the Certara Drug Interaction|6
00231|028|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00231|029|R|3.Miguet JP, Vuitton D, Allemand H, Pessayre D, Monange C, Hirsch JP,|3
00231|030|R|  Metreau JM, Poupon R, Capron JP, Blanc F. Jaundice in women taking both|3
00231|031|R|  troleandomycin and oral contraceptives, an outbreak in France (author's|3
00231|032|R|  transl). Gastroenterol Clin Biol 1980 Jun-Jul;4(6-7):420-4.|3
00231|033|R|4.Fevery J, Van Steenbergen W, Desmet V, Deruyttere M, De Groote J. Severe|2
00231|034|R|  intrahepatic cholestasis due to the combined intake of oral contraceptives|2
00231|035|R|  and triacetyloleandomycin. Acta Clin Belg 1983;38(4):242-5.|2
00231|036|R|5.Ludden TM. Pharmacokinetic interactions of the macrolide antibiotics. Clin|6
00231|037|R|  Pharmacokinet 1985 Jan-Feb;10(1):63-79.|6
00231|038|R|6.Schmider J, Greenblatt DJ, von Moltke LL, Karsov D, Vena R, Friedman HL,|5
00231|039|R|  Shader RI. Biotransformation of mestranol to ethinyl estradiol in vitro:|5
00231|040|R|  the role of cytochrome P-450 2C9 and metabolic inhibitors. J Clin|5
00231|041|R|  Pharmacol 1997 Mar;37(3):193-200.|5
00231|042|R|7.von Rosensteil NA, Adam D. Macrolide antibacterials. Drug interactions of|6
00231|043|R|  clinical significance. Drug Saf 1995 Aug;13(2):105-22.|6
00232|001|T|MONOGRAPH TITLE:  Dapsone/Didanosine|
00232|002|B||
00232|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00232|004|L|of severe adverse interaction.|
00232|005|B||
00232|006|A|MECHANISM OF ACTION:  Unknown. Suspected to be due to decreased dissolution|
00232|007|A|of dapsone in the gastrointestinal tract, reducing the bioavailability of|
00232|008|A|dapsone.|
00232|009|B||
00232|010|E|CLINICAL EFFECTS:  Decreased pharmacological effect of dapsone.|
00232|011|B||
00232|012|P|PREDISPOSING FACTORS:  None determined.|
00232|013|B||
00232|014|M|PATIENT MANAGEMENT:  Separate the administration times of didanosine packets|
00232|015|M|and dapsone by at least two hours. Didanosine chewable tablets did not|
00232|016|M|significantly affect dapsone plasma concentrations.|
00232|017|B||
00232|018|D|DISCUSSION:  Eleven of 28 patients receiving dapsone for the prophylaxis of|
00232|019|D|pneumocystis carinii pneumonia (PCP) developed PCP when didanosine packets|
00232|020|D|(contains sodium citrate buffer) was administered concurrently.(1) In an|
00232|021|D|earlier unpublished study, 2 of 162 patients treated with dapsone and|
00232|022|D|zidovudine developed PCP.(2) The difference in the treatment groups was|
00232|023|D|attributed to poor dissolution of dapsone resulting from the effects of the|
00232|024|D|citrate-phosphate buffer contained in the packets of didanosine.|
00232|025|D|  In two separate studies, didanosine chewable tablets that do not contain|
00232|026|D|sodium citrate buffer did not significantly affect the plasma concentration|
00232|027|D|of dapsone. Two separate randomized, two-period, two treatment, crossover|
00232|028|D|studies with a 21 day washout between treatment groups showed that|
00232|029|D|didanosine, antacids, and other excipients used in didanosine chewable|
00232|030|D|tablets did not significantly affect dapsone plasma concentrations.(3)|
00232|031|B||
00232|032|R|REFERENCES:|
00232|033|B||
00232|034|R|1.Metroka CE, McMechan MF, Andrada R, Laubenstein LJ, Jacobus DP. Failure of|2
00232|035|R|  prophylaxis with dapsone in patients taking dideoxyinosine. N Engl J Med|2
00232|036|R|  1991 Sep 5;325(10):737.|2
00232|037|R|2.Knupp CA, Brater DC, Relue J, Dunkle LM, Barbhaiya RH. A pharmacokinetic|4
00232|038|R|  interaction study between didanosine (DDI) and ketoconazole (KET) in HIV|4
00232|039|R|  patients. Clin Pharmacol Ther 1992 Feb;51(2):155.|4
00232|040|R|3.Sahai J, Garber G, Gallicano K, Oliveras L, Cameron DW. Effects of the|6
00232|041|R|  antacids in didanosine tablets on dapsone pharmacokinetics. Ann Intern Med|6
00232|042|R|  1995 Oct 15;123(8):584-7.|6
00233|001|T|MONOGRAPH TITLE:  Metrizamide/Phenothiazines|
00233|002|B||
00233|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00233|004|L|is contraindicated and generally should not be dispensed or administered to|
00233|005|L|the same patient.|
00233|006|B||
00233|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
00233|008|A|additive effects on seizure threshold levels.|
00233|009|B||
00233|010|E|CLINICAL EFFECTS:  Concomitant use of phenothiazines with metrizamide may|
00233|011|E|precipitate a seizure.|
00233|012|B||
00233|013|P|PREDISPOSING FACTORS:  None determined.|
00233|014|B||
00233|015|M|PATIENT MANAGEMENT:  Phenothiazines and their derivatives should not be used|
00233|016|M|with metrizamide.  In addition, phenothiazines and their derivatives should|
00233|017|M|not be used for the control of nausea or vomiting either prior to or|
00233|018|M|post-procedure with metrizamide.  Discontinue phenothiazines at least 48|
00233|019|M|hours prior to administering metrizamide and do not resume phenothiazine use|
00233|020|M|for at least 24 hours post-procedure.|
00233|021|B||
00233|022|D|DISCUSSION:  Seizure activity has been reported in one patient and epileptic|
00233|023|D|patterns have been reported in a second patient undergoing myelography with|
00233|024|D|metrizamide.  Both patients were receiving maintenance therapy with|
00233|025|D|phenothiazines.  Animal data support these results and indicate that|
00233|026|D|phenothiazines should be discontinued 48 hours prior to the administration|
00233|027|D|of metrizamide.  In another study, the investigators did not report an|
00233|028|D|increase in seizure activity in patients receiving metrizamide for seizure|
00233|029|D|even though patients continued to receive phenothiazines (e.g.,|
00233|030|D|methotrimeprazine).|
00233|031|B||
00233|032|R|REFERENCES:|
00233|033|B||
00233|034|R|1.Hindmarsh T, Grepe A, Widen L. Metrizamide-phenothiazine interaction.|3
00233|035|R|  Report of a case with seizures following myelography. Acta Radiol Diagn|3
00233|036|R|  (Stockh) 1975 Mar;16(2):129-34.|3
00233|037|R|2.Hindmarsh T. Lumbar myelography with meglumine iocarmate and metrizamide.|3
00233|038|R|  Acta Radiol Diagn (Stockh) 1975 May;16(3):209-22.|3
00233|039|R|3.Gonsette RE, Brucher JM. Potentiation of Amipaque epileptogenic activity|5
00233|040|R|  by neuroleptics. Neuroradiology 1977 Aug 25;14(1):27-30.|5
00233|041|R|4.Hauge O, Falkenberg H. Neuropsychologic reactions and other side effects|2
00233|042|R|  after metrizamide myelography. AJR Am J Roentgenol 1982 Aug;139(2):357-60.|2
00233|043|R|5.Maly P, Olivecrona H, Almen T, Golman K. Interaction between|5
00233|044|R|  chlorpromazine and intrathecally injected non-ionic contrast media in|5
00233|045|R|  non-anaesthetized rabbits. Neuroradiology 1984;26(3):235-40.|5
00233|046|R|6.Thorazine (chlorpromazine) US prescribing information. GlaxoSmithKline|1
00233|047|R|  April, 2002.|1
00233|048|R|7.Hanus PM. Metrizamide: a review with emphasis on drug interactions. Am J|6
00233|049|R|  Hosp Pharm 1980 Apr;37(4):510-3.|6
00233|050|R|8.Chlorpromazine hydrochloride US prescribing information. Sandoz, Inc.|1
00233|051|R|  March, 2011.|1
00234|001|T|MONOGRAPH TITLE:  Metyrapone/Cyproheptadine|
00234|002|B||
00234|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00234|004|L|of severe adverse interaction.|
00234|005|B||
00234|006|A|MECHANISM OF ACTION:  Cyproheptadine-induced decrease in ACTH response to|
00234|007|A|metyrapone.|
00234|008|B||
00234|009|E|CLINICAL EFFECTS:  Decreased pituitary-adrenal response to metyrapone.|
00234|010|B||
00234|011|P|PREDISPOSING FACTORS:  None determined.|
00234|012|B||
00234|013|M|PATIENT MANAGEMENT:  Discontinue or avoid cyproheptadine administration|
00234|014|M|prior to metyrapone administration for pituitary-adrenal axis assessment.|
00234|015|B||
00234|016|D|DISCUSSION:  Decreased pituitary-adrenal response to metyrapone occurred|
00234|017|D|during concomitant administration of cyproheptadine.|
00234|018|B||
00234|019|R|REFERENCES:|
00234|020|B||
00234|021|R|1.Plank J, Feldman JM. Adrenal function in the carcinoid syndrome: effects|3
00234|022|R|  of the serotonin antagonist cyproheptadine. Metabolism 1975 Sep;|3
00234|023|R|  24(9):1035-46.|3
00234|024|R|2.Plonk J, Feldman J. Modification of adrenal function by the anti-serotonin|2
00234|025|R|  agent cyproheptadine. J Clin Endocrinol Metab 1976 Feb;42(2):291-5.|2
00235|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 10 mg);|
00235|002|T|Lovastatin/Cyclosporine|
00235|003|B||
00235|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00235|005|L|of severe adverse interaction.|
00235|006|B||
00235|007|A|MECHANISM OF ACTION:  Unknown.|
00235|008|B||
00235|009|E|CLINICAL EFFECTS:  Myopathy and muscle aches, tenderness and weakness|
00235|010|E|(rhabdomyolysis) may occur with concurrent administration of HMG-CoA|
00235|011|E|reductase inhibitors and cyclosporine.|
00235|012|B||
00235|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
00235|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
00235|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
00235|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
00235|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
00235|018|P|transporter OATP1B1 may have increased statin concentrations and be|
00235|019|P|predisposed to myopathy or rhabdomyolysis.|
00235|020|B||
00235|021|M|PATIENT MANAGEMENT:  Avoid the concurrent use of atorvastatin(1) or|
00235|022|M|lovastatin(2) with cyclosporine.  If concurrent use is necessary, the dose|
00235|023|M|of atorvastatin should be limited to 10 mg or less.(3)|
00235|024|M|   When possible use alternative therapy, such as fluvastatin at dosages of|
00235|025|M|20 mg BID or less,(4) pravastatin at dosages of 20 mg daily or less,(5) or|
00235|026|M|rosuvastatin at dosages of 5 mg daily or less.(6)|
00235|027|M|   Patients receiving concurrent therapy should be instructed to report|
00235|028|M|symptoms of muscle pain, tenderness, or weakness.|
00235|029|B||
00235|030|D|DISCUSSION:  Since this reaction may occur with HMG-CoA-reductase inhibitors|
00235|031|D|alone, a causal relationship is difficult to establish.  However, the|
00235|032|D|incidence of myopathy and rhabdomyolysis appears to increase with concurrent|
00235|033|D|administration of cyclosporine.|
00235|034|D|   In a study in 18 renal transplant patients, atorvastatin had no effect on|
00235|035|D|the pharmacokinetics of cyclosporine.(7)  In a study in six liver transplant|
00235|036|D|patients, atorvastatin increased the area-under-curve (AUC) of cyclosporine|
00235|037|D|by 10%, which was not considered clinically significant.(8)|
00235|038|D|   In a study in 21 renal transplant patients, cyclosporine increased|
00235|039|D|atorvastatin levels by 6.4-fold when compared to historical controls.  The|
00235|040|D|AUC of cyclosporine decreased by 9.5%.(9)|
00235|041|D|   Concurrent administration of atorvastatin (10 mg) and cyclosporine (5.2|
00235|042|D|mg/kg/day) increased atorvastatin AUC and Cmax by 8.7-fold and 10.7-fold,|
00235|043|D|respectively.(1)|
00235|044|D|   In a study in 33 renal patients, subjects were randomized to receive|
00235|045|D|either atorvastatin or cerivastatin.  In the cerivastatin group, there were|
00235|046|D|no significant effects on cyclosporine levels.  In the atorvastatin group, 4|
00235|047|D|of 10 subjects had changes in cyclosporine trough levels of 25% or more.(10)|
00235|048|D|   In a study, administration of cerivastatin (0.2 mg) in 12 renal|
00235|049|D|transplant patients receiving cyclosporine was compared to 12 healthy|
00235|050|D|control subjects not receiving cyclosporine.  Plasma concentration of|
00235|051|D|cerivastatin and its metabolites increased 3-fold to 5-fold.(11)|
00235|052|D|   In a study, administration of pravastatin in 11 heart transplant patients|
00235|053|D|receiving cyclosporine was compared to 8 control subjects not receiving|
00235|054|D|cyclosporine.  Pravastatin AUC and Cmax were 7-8-fold and 12-fold higher,|
00235|055|D|respectively, in subjects taking cyclosporine.(12)|
00235|056|D|   In a double-blind, randomized, cross-over study in 44 renal transplant|
00235|057|D|patients, neither lovastatin nor pravastatin affected cyclosporine levels.|
00235|058|D|Pravastatin levels after 1 day and after 28 days of concurrent therapy were|
00235|059|D|5-fold higher than historical controls.  Lovastatin levels accumulated over|
00235|060|D|the course of the study and by Day 28 were 20-fold higher than historical|
00235|061|D|controls.(13)|
00235|062|D|   In a study in 31 renal transplant patients, neither pravastatin nor|
00235|063|D|simvastatin affected cyclosporine levels.(14)  In contrast, in a study in 44|
00235|064|D|heart transplant subjects, cyclosporine clearance was increased following|
00235|065|D|the addition of simvastatin.(15)|
00235|066|D|   Several studies have found no effect from fluvastatin on cyclosporine|
00235|067|D|pharmacokinetics.(16-20)  One of these also noted no affects of cyclosporine|
00235|068|D|on fluvastatin levels.(15)  In contrast, a study that compared the|
00235|069|D|administration of fluvastatin in 10 heart transplant to 10 healthy control|
00235|070|D|subjects found that fluvastatin AUC and Cmax were 2.55-fold and 3.10-fold|
00235|071|D|higher than in control subjects.(21)|
00235|072|D|   In an open-label study in 10 heart transplant patients, concurrent|
00235|073|D|cyclosporine increased rosuvastatin AUC and Cmax by 7.1-fold and 10.6-fold,|
00235|074|D|respectively, when compared to historical controls.  There were no effects|
00235|075|D|on cyclosporine levels.(22)|
00235|076|D|   Rhabdomyolysis has been reported with concurrent cyclosporine and|
00235|077|D|atorvastatin,(23,24) cerivastatin,(25) and lovastatin.(26-30)|
00235|078|D|   In a PKPB model, concurrent use of atorvastatin (10 mg daily) with|
00235|079|D|cyclosporine (125 mg daily for 2 months) increased the simulated Cmax ratio|
00235|080|D|and AUC ratio of atorvastatin by 6.85 and 3.92, respectively.(31)|
00235|081|B||
00235|082|R|REFERENCES:|
00235|083|B||
00235|084|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
00235|085|R|  2020.|1
00235|086|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
00235|087|R|  February, 2014.|1
00235|088|R|3.Lipitor (atorvastatin calcium trihydrate) UK summary of product|1
00235|089|R|  characteristics. Pfizer Limited April 1, 2019.|1
00235|090|R|4.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
00235|091|R|  Pharmaceuticals Corporation August, 2017.|1
00235|092|R|5.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
00235|093|R|  Squibb Company May, 2022.|1
00235|094|R|6.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
00235|095|R|  Pharmaceuticals LP July, 2024.|1
00235|096|R|7.Hermann M, Asberg A, Christensen H, Reubsaet JL, Holdaas H, Hartmann A.|2
00235|097|R|  Atorvastatin does not affect the pharmacokinetics of cyclosporine in renal|2
00235|098|R|  transplant recipients. Eur J Clin Pharmacol 2005 Mar;61(1):59-62.|2
00235|099|R|8.Taylor PJ, Kubler PA, Lynch SV, Allen J, Butler M, Pillans PI. Effect of|2
00235|100|R|  atorvastatin on cyclosporine pharmacokinetics in liver transplant|2
00235|101|R|  recipients. Ann Pharmacother 2004 Feb;38(2):205-8.|2
00235|102|R|9.Asberg A, Hartmann A, Fjeldsa E, Bergan S, Holdaas H. Bilateral|2
00235|103|R|  pharmacokinetic interaction between cyclosporine A and atorvastatin in|2
00235|104|R|  renal transplant recipients. Am J Transplant 2001 Nov;1(4):382-6.|2
00235|105|R|10.Renders L, Mayer-Kadner I, Koch C, Scharffe S, Burkhardt K, Veelken R,|2
00235|106|R|   Schmieder RE, Hauser IA. Efficacy and drug interactions of the new|2
00235|107|R|   HMG-CoA reductase inhibitors cerivastatin and atorvastatin in CsA-treated|2
00235|108|R|   renal transplant recipients. Nephrol Dial Transplant 2001 Jan;|2
00235|109|R|   16(1):141-6.|2
00235|110|R|11.Muck W, Mai I, Fritsche L, Ochmann K, Rohde G, Unger S, Johne A, Bauer S,|2
00235|111|R|   Budde K, Roots I, Neumayer HH, Kuhlmann J. Increase in cerivastatin|2
00235|112|R|   systemic exposure after single and multiple dosing in|2
00235|113|R|   cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther|2
00235|114|R|   1999 Mar;65(3):251-61.|2
00235|115|R|12.Park JW, Siekmeier R, Merz M, Krell B, Harder S, Marz W, Seidel D,|2
00235|116|R|   Schuler S, Gross W. Pharmacokinetics of pravastatin in heart-transplant|2
00235|117|R|   patients taking cyclosporin A. Int J Clin Pharmacol Ther 2002 Oct;|2
00235|118|R|   40(10):439-50.|2
00235|119|R|13.Olbricht C, Wanner C, Eisenhauer T, Kliem V, Doll R, Boddaert M, O'Grady|2
00235|120|R|   P, Krekler M, Mangold B, Christians U. Accumulation of lovastatin, but|2
00235|121|R|   not pravastatin, in the blood of cyclosporine-treated kidney graft|2
00235|122|R|   patients after multiple doses. Clin Pharmacol Ther 1997 Sep;62(3):311-21.|2
00235|123|R|14.Capone D, Stanziale P, Gentile A, Imperatore P, Pellegrino T, Basile V.|2
00235|124|R|   Effects of simvastatin and pravastatin on hyperlipidemia and cyclosporin|2
00235|125|R|   blood levels in renal transplant recipients. Am J Nephrol 1999;|2
00235|126|R|   19(3):411-5.|2
00235|127|R|15.Akhlaghi F, McLachlan AJ, Keogh AM, Brown KF. Effect of simvastatin on|2
00235|128|R|   cyclosporine unbound fraction and apparent blood clearance in heart|2
00235|129|R|   transplant recipients. Br J Clin Pharmacol 1997 Dec;44(6):537-42.|2
00235|130|R|16.Holdaas H, Hagen E, Asberg A, Lund K, Hartman A, Vaidyanathan S, Prasad|2
00235|131|R|   P, He YL, Yeh CM, Bigler H, Rouilly M, Denouel J. Evaluation of the|2
00235|132|R|   pharmacokinetic interaction between fluvastatin XL and cyclosporine in|2
00235|133|R|   renal transplant recipients. Int J Clin Pharmacol Ther 2006 Apr;|2
00235|134|R|   44(4):163-71.|2
00235|135|R|17.Locsey L, Asztalos L, Kincses Z, Balazs G. Fluvastatin (Lescol) treatment|2
00235|136|R|   of hyperlipidaemia in patients with renal transplants. Int Urol Nephrol|2
00235|137|R|   1997;29(1):95-106.|2
00235|138|R|18.Li PK, Mak TW, Chan TH, Wang A, Lam CW, Lai KN. Effect of fluvastatin on|2
00235|139|R|   lipoprotein profiles in treating renal transplant recipients with|2
00235|140|R|   dyslipoproteinemia. Transplantation 1995 Oct 15;60(7):652-6.|2
00235|141|R|19.Holdaas H, Hartmann A, Stenstrom J, Dahl KJ, Borge M, Pfister P. Effect|2
00235|142|R|   of fluvastatin for safely lowering atherogenic lipids in renal transplant|2
00235|143|R|   patients receiving cyclosporine. Am J Cardiol 1995 Jul 13;|2
00235|144|R|   76(2):102A-106A.|2
00235|145|R|20.Li PK, Mak TW, Wang AY, Lee YT, Leung CB, Lui SF, Lam CW, Lai KN. The|2
00235|146|R|   interaction of fluvastatin and cyclosporin A in renal transplant|2
00235|147|R|   patients. Int J Clin Pharmacol Ther 1995 Apr;33(4):246-8.|2
00235|148|R|21.Park JW, Siekmeier R, Lattke P, Merz M, Mix C, Schuler S, Jaross W.|2
00235|149|R|   Pharmacokinetics and pharmacodynamics of fluvastatin in heart transplant|2
00235|150|R|   recipients taking cyclosporine A. J Cardiovasc Pharmacol Ther 2001 Oct;|2
00235|151|R|   6(4):351-61.|2
00235|152|R|22.Simonson SG, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CD, Windass|2
00235|153|R|   AS, Schneck DW. Rosuvastatin pharmacokinetics in heart transplant|2
00235|154|R|   recipients administered an antirejection regimen including cyclosporine.|2
00235|155|R|   Clin Pharmacol Ther 2004 Aug;76(2):167-77.|2
00235|156|R|23.Maltz HC, Balog DL, Cheigh JS. Rhabdomyolysis associated with concomitant|3
00235|157|R|   use of atorvastatin and cyclosporine. Ann Pharmacother 1999 Nov;|3
00235|158|R|   33(11):1176-9.|3
00235|159|R|24.Wong WM, Wai-Hung Shek T, Chan KH, Chau E, Lai KC. Rhabdomyolysis|3
00235|160|R|   triggered by cytomegalovirus infection in a heart transplant patient on|3
00235|161|R|   concomitant cyclosporine and atorvastatin therapy. J Gastroenterol|3
00235|162|R|   Hepatol 2004 Aug;19(8):952-3.|3
00235|163|R|25.Rodriguez ML, Mora C, Navarro JF. Cerivastatin-induced rhabdomyolysis.|3
00235|164|R|   Ann Intern Med 2000 Apr 4;132(7):598.|3
00235|165|R|26.Alejandro DS, Petersen J. Myoglobinuric acute renal failure in a cardiac|3
00235|166|R|   transplant patient taking lovastatin and cyclosporine. J Am Soc Nephrol|3
00235|167|R|   1994 Aug;5(2):153-60.|3
00235|168|R|27.Norman DJ, Illingworth DR, Munson J, Hosenpud J. Myolysis and acute renal|3
00235|169|R|   failure in a heart-transplant recipient receiving lovastatin. N Engl J|3
00235|170|R|   Med 1988 Jan 7;318(1):46-7.|3
00235|171|R|28.East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA. Rhabdomyolysis in|3
00235|172|R|   patients receiving lovastatin after cardiac transplantation. N Engl J Med|3
00235|173|R|   1988 Jan 7;318(1):47-8.|3
00235|174|R|29.Tobert JA. Rhabdomyolysis in patients receiving lovastatin after cardiac|3
00235|175|R|   transplantation (reply). N Engl J Med 1988 Jan 7;318(1):48.|3
00235|176|R|30.Corpier CL, Jones PH, Suki WN, Lederer ED, Quinones MA, Schmidt SW, Young|3
00235|177|R|   JB. Rhabdomyolysis and renal injury with lovastatin use. Report of two|3
00235|178|R|   cases in cardiac transplant recipients. JAMA 1988 Jul 8;260(2):239-41.|3
00235|179|R|31.Li S, Yu Y, Jin Z, Dai Y, Lin H, Jiao Z, Ma G, Cai W, Han B, Xiang X.|2
00235|180|R|   Prediction of pharmacokinetic drug-drug interactions causing|2
00235|181|R|   atorvastatin-induced rhabdomyolysis using physiologically based|2
00235|182|R|   pharmacokinetic modelling. Biomed Pharmacother 2019 Sep 10;119:109416.|2
00236|001|T|MONOGRAPH TITLE:  Contraceptives/Griseofulvin|
00236|002|B||
00236|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00236|004|L|of severe adverse interaction.|
00236|005|B||
00236|006|A|MECHANISM OF ACTION:  Unknown. However, possibly due to increased metabolism|
00236|007|A|of oral contraceptives.|
00236|008|B||
00236|009|E|CLINICAL EFFECTS:  Decreased effectiveness of oral contraceptives, producing|
00236|010|E|breakthrough bleeding, amenorrhea and unintended pregnancy.|
00236|011|B||
00236|012|P|PREDISPOSING FACTORS:  None determined.|
00236|013|B||
00236|014|M|PATIENT MANAGEMENT:  The patient should use an alternative method of|
00236|015|M|contraception during and for one month after receiving griseofulvin.|
00236|016|M|Increasing the dose of estrogen may be necessary in patients on low-dose|
00236|017|M|estrogen.|
00236|018|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
00236|019|M|Regulatory Agency (MHRA) recommends that women who have used an inducer in|
00236|020|M|the previous 4 weeks should consider a non-hormonal emergency contraceptive|
00236|021|M|(ie a copper IUD).  If a non-hormonal emergency contraceptive is not an|
00236|022|M|option, double the usual dose of levonorgestrel from 1.5 to 3 mg.  Advise|
00236|023|M|the patient to have a pregnancy test to exclude pregnancy after use and to|
00236|024|M|seek medical advice if they do become pregnant.|
00236|025|B||
00236|026|D|DISCUSSION:  Loss of oral contraceptive efficacy has been reported following|
00236|027|D|the addition of griseofulvin to the patient's drug therapy. Loss of efficacy|
00236|028|D|was indicated by breakthrough bleeding, amenorrhea and unintended pregnancy.|
00236|029|B||
00236|030|R|REFERENCES:|
00236|031|B||
00236|032|R|1.van Dijke CP, Weber JC. Interaction between oral contraceptives and|3
00236|033|R|  griseofulvin. Br Med J (Clin Res Ed) 1984 Apr 14;288(6424):1125-6.|3
00236|034|R|2.McDaniel PA, Caldroney RD. Oral contraceptives and griseofulvin|3
00236|035|R|  interactions. Drug Intell Clin Pharm 1986 May;20(5):384.|3
00236|036|R|3.Cote J. Interaction of griseofulvin and oral contraceptives. J Am Acad|3
00236|037|R|  Dermatol 1990 Jan;22(1):124-5.|3
00236|038|R|4.Nor-Q-D (norethindrone) US prescribing information. WatsonPharma March,|1
00236|039|R|  2005.|1
00236|040|R|5.Medicines and Healthcare products Regulatory Agency.|1
00236|041|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
00236|042|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
00236|043|R|  available at:|1
00236|044|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
00236|045|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
00236|046|R|  -and-contraceptive-efficacy September 15, 2016..|1
00237|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Nitrates|
00237|002|B||
00237|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00237|004|L|of severe adverse interaction.|
00237|005|B||
00237|006|A|MECHANISM OF ACTION:  Decreased first-pass metabolism of ergot alkaloids.|
00237|007|A|Ergot alkaloids may precipitate angina pectoris.|
00237|008|B||
00237|009|E|CLINICAL EFFECTS:  Increased standing systolic blood pressure and angina|
00237|010|E|attacks may occur.|
00237|011|B||
00237|012|P|PREDISPOSING FACTORS:  None determined.|
00237|013|B||
00237|014|M|PATIENT MANAGEMENT:  Avoid administration of ergot alkaloids to patients|
00237|015|M|receiving nitroglycerin for angina. When it is necessary to give this|
00237|016|M|combination, monitor the patient for increased effects of the ergot|
00237|017|M|alkaloid. Reduce the dose of ergot alkaloid as necessary.|
00237|018|B||
00237|019|D|DISCUSSION:  Dihydroergotamine has been reported to precipitate angina|
00237|020|D|pectoris. Nitroglycerin administration to patients receiving|
00237|021|D|dihydroergotamine increased the plasma dihydroergotamine level and area|
00237|022|D|under the plasma concentration-time curve. An increase in the mean standing|
00237|023|D|systolic blood pressure was measured.|
00237|024|B||
00237|025|R|REFERENCES:|
00237|026|B||
00237|027|R|1.Raberger G, Schutz W, Zimpfer M, Kraupp O. The influence of|5
00237|028|R|  dihydroergotamine on adenosine-induced and reactive coronary vasodilation.|5
00237|029|R|  Interaction of dihydroergotamine and coronary vasodilation. Basic Res|5
00237|030|R|  Cardiol 1976 Nov-Dec;71(6):645-51.|5
00237|031|R|2.Bobik A, Jennings G, Skews H, Esler M, McLean A. Low oral bioavailability|2
00237|032|R|  of dihydroergotamine and first-pass extraction in patients with|2
00237|033|R|  orthostatic hypotension. Clin Pharmacol Ther 1981 Nov;30(5):673-9.|2
00238|001|T|MONOGRAPH TITLE:  Zidovudine/Ganciclovir, Valganciclovir|
00238|002|B||
00238|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00238|004|L|of severe adverse interaction.|
00238|005|B||
00238|006|A|MECHANISM OF ACTION:  The magnitude of the toxic effects of both drugs are|
00238|007|A|increased.|
00238|008|B||
00238|009|E|CLINICAL EFFECTS:  Increased side effects, including hematologic and|
00238|010|E|gastrointestinal toxicity.|
00238|011|B||
00238|012|P|PREDISPOSING FACTORS:  None determined.|
00238|013|B||
00238|014|M|PATIENT MANAGEMENT:  When possible, avoid this combination.|
00238|015|M|Coadministration should be considered only if the potential benefits are|
00238|016|M|judged to outweigh the risks.  Dose reduction or interruption may be needed.|
00238|017|M|Monitor with frequent complete blood counts with differential and platelet|
00238|018|M|counts.|
00238|019|B||
00238|020|D|DISCUSSION:  Patients receiving zidovudine and ganciclovir concurrently|
00238|021|D|developed hematologic toxicity, including neutropenia and anemia, and|
00238|022|D|gastrointestinal toxicity.|
00238|023|D|   Both ganciclovir and zidovudine have box warnings regarding hematologic|
00238|024|D|toxicity. Granulocytopenia (neutropenia), anemia, thrombocytopenia, and|
00238|025|D|pancytopenia have been reported.|
00238|026|D|   In a study in 12 patients, an oral dose of ganciclovir (1000 mg every 8|
00238|027|D|hours) administered concurrently with zidovudine (100 mg every 4 hours)|
00238|028|D|decreased the mean steady state area-under-the-curve (AUC) of ganciclovir|
00238|029|D|17% and increased the zidovudine AUC 19%.|
00238|030|B||
00238|031|R|REFERENCES:|
00238|032|B||
00238|033|R|1.Hochster H, Dieterich D, Bozzette S, Reichman RC, Connor JD, Liebes L,|2
00238|034|R|  Sonke RL, Spector SA, Valentine F, Pettinelli C, et al. Toxicity of|2
00238|035|R|  combined ganciclovir and zidovudine for cytomegalovirus disease associated|2
00238|036|R|  with AIDS. An AIDS Clinical Trials Group Study. Ann Intern Med 1990 Jul|2
00238|037|R|  15;113(2):111-7.|2
00238|038|R|2.Teich SA, Cheung TW, Friedman AH. Systemic antiviral drugs used in|6
00238|039|R|  ophthalmology. Surv Ophthalmol 1992 Jul-Aug;37(1):19-53.|6
00238|040|R|3.Cytovene IV (ganciclovir) US prescribing information. Genentech Inc.|1
00238|041|R|  August, 2018.|1
00238|042|R|4.Retrovir (zidovudine) US prescribing information. GlaxoSmithKline|1
00238|043|R|  September, 2018.|1
00238|044|R|5.Valcyte (valganciclovir) US prescribing information. Genentech June, 2017.|1
00239|001|T|MONOGRAPH TITLE:  Itraconazole; Ketoconazole/Agents Affecting Gastric pH|
00239|002|B||
00239|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00239|004|L|take action as needed.|
00239|005|B||
00239|006|A|MECHANISM OF ACTION:  Antacids, buffers in didanosine products, H2|
00239|007|A|antagonists, and proton-pump inhibitors increase the stomach pH.  Quinapril|
00239|008|A|tablets may contain a high percentage of magnesium.  Since some orally|
00239|009|A|administered azole antifungal agents require an acidic medium for optimal|
00239|010|A|absorption, agents may decrease the absorption of azole antifungal agents.|
00239|011|B||
00239|012|E|CLINICAL EFFECTS:  Simultaneous administration of an antacid, buffered|
00239|013|E|didanosine, a H2 antagonist, or a proton-pump inhibitor may result in|
00239|014|E|decreased therapeutic effects of the azole antifungal.|
00239|015|B||
00239|016|P|PREDISPOSING FACTORS:  None determined.|
00239|017|B||
00239|018|M|PATIENT MANAGEMENT:  If the concurrent administration of these two agents|
00239|019|M|cannot be avoided, consider administering two capsules of glutamic acid|
00239|020|M|hydrochloride 15 minutes before administering the antifungal and separate|
00239|021|M|the administration times of the antifungal and the agent affecting gastric|
00239|022|M|pH by at least two hours.|
00239|023|B||
00239|024|D|DISCUSSION:  Itraconazole, ketoconazole, and posaconazole require an acidic|
00239|025|D|medium for predictable dissolution and absorption decreases as pH increases|
00239|026|D|and proton pump inhibitors are expected to decrease their absorption.(1-4)|
00239|027|D|   In a study in 11 healthy subjects, omeprazole (40 mg daily) decreased the|
00239|028|D|maximum concentration (Cmax) and area-under-curve (AUC) of itraconazole (200|
00239|029|D|mg single dose) by 66% and 64%, respectively.(5)  In a study in 15 healthy|
00239|030|D|subjects, omeprazole (40 mg daily) had no effect on the pharmacokinetics of|
00239|031|D|itraconazole solution.(6)|
00239|032|D|   In a study in 9 healthy subjects, omeprazole (60 mg) decreased the AUC of|
00239|033|D|ketoconazole (200 mg single dose) by 83.4% compared to control (ketoconazole|
00239|034|D|alone).  Administration of Coca-Cola (240 ml) with ketoconazole and|
00239|035|D|omeprazole raised ketoconazole AUC to 65% of control values.(7)|
00239|036|D|   Omeprazole has been shown to have no significant effect on the absorption|
00239|037|D|of fluconazole(8) or voriconazole.(9)|
00239|038|D|   Case reports and in-vivo studies have documented significant decreases in|
00239|039|D|ketoconazole levels during concurrent therapy with H-2 antagonists,|
00239|040|D|including cimetidine and ranitidine.  Concurrent administration of|
00239|041|D|itraconazole and famotidine resulted in a significant decrease in|
00239|042|D|itraconazole levels, but no significant changes in famotidine levels. An|
00239|043|D|interaction should be expected to occur between both ketoconazole or|
00239|044|D|itraconazole and the other H-2 antagonists.(10-14)|
00239|045|D|   In randomized, open-labeled, cross-over study in 12 healthy subjects,|
00239|046|D|simultaneous administration of an antacid decreased the area-under-curve|
00239|047|D|(AUC) and maximum concentration (Cmax) of a single dose of itraconazole (200|
00239|048|D|mg) by 66% and 70%, respectively.  Time to Cmax (Tmax) increased by 70%.(15)|
00239|049|D|This interaction has also been reported in a case report.(16)|
00239|050|D|   In a study in 3 subjects, simultaneous administration of a combination|
00239|051|D|aluminum hydroxide/magnesium hydroxide (30 ml) decreased the AUC of a single|
00239|052|D|dose of ketoconazole (200 mg) by 41%.(172)|
00239|053|D|   In a case report, a patient receiving concurrent ketoconazole with|
00239|054|D|aluminum hydroxide, cimetidine, and sodium bicarbonate did not respond to|
00239|055|D|therapy until cimetidine was discontinued and the administration time of|
00239|056|D|aluminum hydroxide and cimetidine was changed to 2 hours after ketoconazole.|
00239|057|D|In a follow-up study in 2 subjects, concurrent cimetidine and sodium|
00239|058|D|hydroxide lowered ketoconazole levels.(18)|
00239|059|D|   In a study in 14 subjects, simultaneous administration of aluminum|
00239|060|D|hydroxide/magnesium hydroxide (20 ml, 1800 mg/1200 mg) had no significant|
00239|061|D|effects on fluconazole pharmacokinetics.(3)|
00239|062|D|   In a randomized, open-label, cross-over study in 6 subjects, simultaneous|
00239|063|D|administration of itraconazole with buffered didanosine tablets resulted in|
00239|064|D|undetectable levels of itraconazole.(19)|
00239|065|D|   In a randomized cross-over study in 12 HIV-positive subjects,|
00239|066|D|administration of buffered didanosine tablets 2 hours after ketoconazole had|
00239|067|D|no effects on ketoconazole levels.(20)|
00239|068|D|   In a randomized, cross-over, open-label study in 24 healthy subjects,|
00239|069|D|simultaneous administration of enteric-coated didanosine had no effect on|
00239|070|D|ketoconazole pharmacokinetics.(21)|
00239|071|D|   One or more of the drug pairs linked to this monograph have been included|
00239|072|D|in a list of interactions that could be considered for classification as|
00239|073|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
00239|074|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
00239|075|D|Health Information Technology.|
00239|076|B||
00239|077|R|REFERENCES:|
00239|078|B||
00239|079|R|1.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
00239|080|R|  Pharmaceuticals LP June, 2018.|1
00239|081|R|2.Prevacid (lansoprazole) US prescribing information. Takeda Pharmaceuticals|1
00239|082|R|  America, Inc. June, 2018.|1
00239|083|R|3.Van Der Meer JW, Keuning JJ, Scheijgrond HW, Heykants J, Van Cutsem J,|3
00239|084|R|  Brugmans J. The influence of gastric acidity on the bio-availability of|3
00239|085|R|  ketoconazole. J Antimicrob Chemother 1980 Jul;6(4):552-4.|3
00239|086|R|4.Carlson JA, Mann HJ, Canafax DM. Effect of pH on disintegration and|5
00239|087|R|  dissolution of ketoconazole tablets. Am J Hosp Pharm 1983 Aug;|5
00239|088|R|  40(8):1334-6.|5
00239|089|R|5.Jaruratanasirikul S, Sriwiriyajan S. Effect of omeprazole on the|2
00239|090|R|  pharmacokinetics of itraconazole. Eur J Clin Pharmacol 1998 Apr;|2
00239|091|R|  54(2):159-61.|2
00239|092|R|6.Johnson MD, Hamilton CD, Drew RH, Sanders LL, Pennick GJ, Perfect JR. A|2
00239|093|R|  randomized comparative study to determine the effect of omeprazole on the|2
00239|094|R|  peak  serum concentration of itraconazole oral solution. J Antimicrob|2
00239|095|R|  Chemother 2003 Feb;51(2):453-7.|2
00239|096|R|7.Chin TW, Loeb M, Fong IW. Effects of an acidic beverage (Coca-Cola) on|2
00239|097|R|  absorption of ketoconazole. Antimicrob Agents Chemother 1995 Aug;|2
00239|098|R|  39(8):1671-5.|2
00239|099|R|8.Zimmermann T, Yeates RA, Riedel KD, Lach P, Laufen H. The influence of|2
00239|100|R|  gastric pH on the pharmacokinetics of fluconazole: the effect of|2
00239|101|R|  omeprazole. Int J Clin Pharmacol Ther 1994 Sep;32(9):491-6.|2
00239|102|R|9.Wood N, Tan K, Purkins L, Layton G, Hamlin J, Kleinermans D, Nichols D.|2
00239|103|R|  Effect of omeprazole on the steady-state pharmacokinetics of voriconazole.|2
00239|104|R|  Br J Clin Pharmacol 2003 Dec;56 Suppl 1:56-61.|2
00239|105|R|10.Lelawongs P, Barone JA, Colaizzi JL, Hsuan AT, Mechlinski W, Legendre R,|2
00239|106|R|   Guarnieri J. Effect of food and gastric acidity on absorption of orally|2
00239|107|R|   administered ketoconazole. Clin Pharm 1988 Mar;7(3):228-35.|2
00239|108|R|11.Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis|6
00239|109|R|   1990 Mar-Apr;12 Suppl 3:S327-33.|6
00239|110|R|12.Piscitelli SC, Goss TF, Wilton JH, D'Andrea DT, Goldstein H, Schentag JJ.|2
00239|111|R|   Effects of ranitidine and sucralfate on ketoconazole bioavailability.|2
00239|112|R|   Antimicrob Agents Chemother 1991 Sep;35(9):1765-71.|2
00239|113|R|13.Lim SG, Sawyerr AM, Hudson M, Sercombe J, Pounder RE. Short report: the|2
00239|114|R|   absorption of fluconazole and itraconazole under conditions of low|2
00239|115|R|   intragastric acidity. Aliment Pharmacol Ther 1993 Jun;7(3):317-21.|2
00239|116|R|14.Tagamet (cimetidine) US prescribing information. GlaxoSmithKline|1
00239|117|R|   December, 2005.|1
00239|118|R|15.Lohitnavy M, Lohitnavy O, Thangkeattiyanon O, Srichai W. Reduced oral|2
00239|119|R|   itraconazole bioavailability by antacid suspension. J Clin Pharm Ther|2
00239|120|R|   2005 Jun;30(3):201-6.|2
00239|121|R|16.Moreno F, Hardin TC, Rinaldi MG, Graybill JR. Itraconazole-didanosine|3
00239|122|R|   excipient interaction. JAMA 1993 Mar 24-31;269(12):1508.|3
00239|123|R|17.Brass C, Galgiani JN, Blaschke TF, Defelice R, O'Reilly RA, Stevens DA.|2
00239|124|R|   Disposition of ketoconazole, an oral antifungal, in humans. Antimicrob|2
00239|125|R|   Agents Chemother 1982 Jan;21(1):151-8.|2
00239|126|R|18.Thorpe JE, Baker N, Bromet-Petit M. Effect of oral antacid administration|2
00239|127|R|   on the pharmacokinetics of oral fluconazole. Antimicrob Agents Chemother|2
00239|128|R|   1990 Oct;34(10):2032-3.|2
00239|129|R|19.May DB, Drew RH, Yedinak KC, Bartlett JA. Effect of simultaneous|2
00239|130|R|   didanosine administration on itraconazole absorption in healthy|2
00239|131|R|   volunteers. Pharmacotherapy 1994 Sep-Oct;14(5):509-13.|2
00239|132|R|20.Knupp CA, Brater DC, Relue J, Barbhaiya RH. Pharmacokinetics of|2
00239|133|R|   didanosine and ketoconazole after coadministration to patients|2
00239|134|R|   seropositive for the human immunodeficiency virus. J Clin Pharmacol 1993|2
00239|135|R|   Oct;33(10):912-7.|2
00239|136|R|21.Damle BD, Mummaneni V, Kaul S, Knupp C. Lack of effect of simultaneously|2
00239|137|R|   administered didanosine encapsulated enteric bead formulation (Videx EC)|2
00239|138|R|   on oral absorption of indinavir, ketoconazole, or ciprofloxacin.|2
00239|139|R|   Antimicrob Agents Chemother 2002 Feb;46(2):385-91.|2
00239|140|R|22.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
00239|141|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
00239|142|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
00239|143|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
00240|001|T|MONOGRAPH TITLE:  Hydrocortisone, Oral/Bile Acid Sequestrants (mono deleted|
00240|002|T|03/31/2025)|
00240|003|B||
00240|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00240|005|L|of severe adverse interaction.|
00240|006|B||
00240|007|A|MECHANISM OF ACTION:  Interference with the gastrointestinal absorption of|
00240|008|A|hydrocortisone possibly due to binding with cholestyramine.|
00240|009|B||
00240|010|E|CLINICAL EFFECTS:  The pharmacological effects of hydrocortisone decreased.|
00240|011|B||
00240|012|P|PREDISPOSING FACTORS:  None determined.|
00240|013|B||
00240|014|M|PATIENT MANAGEMENT:  Separate the administration times of the drugs by as|
00240|015|M|much as possible and monitor the patient for a decrease in responsiveness to|
00240|016|M|the hydrocortisone. If necessary increase the hydrocortisone dose.|
00240|017|B||
00240|018|D|DISCUSSION:  In 10 healthy subjects, oral administration of 50 mg of|
00240|019|D|hydrocortisone and 4 gm of cholestyramine resulted in a 35% decrease in the|
00240|020|D|area-under-curve (AUC) of hydrocortisone. In addition, the maximum|
00240|021|D|concentration (Cmax) and time to Cmax (Tmax) of hydrocortisone were reduced.|
00240|022|D|The effect was greater following the administration of 8 gm of|
00240|023|D|cholestyramine.|
00240|024|B||
00240|025|R|REFERENCES:|
00240|026|B||
00240|027|R|1.Ware AJ, Combes B. Influence of sodium taurocholate, cholestyramine, and|5
00240|028|R|  mylanta on the intestinal absorption of glucocorticoids in the rat.|5
00240|029|R|  Gastroenterology 1973 Jun;64(6):1150-5.|5
00240|030|R|2.Johansson C, Adamsson U, Stierner U, Lindsten T. Interaction by|2
00240|031|R|  cholestyramine on the uptake of hydrocortisone in the gastrointestinal|2
00240|032|R|  tract. Acta Med Scand 1978;204(6):509-12.|2
00240|033|R|3.Nekl KE, Aron DC. Hydrocortisone-colestipol interaction. Ann Pharmacother|3
00240|034|R|  1993 Jul-Aug;27(7-8):980-1.|3
00241|001|T|MONOGRAPH TITLE:  Levodopa/Iron Salts, Oral|
00241|002|B||
00241|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00241|004|L|of severe adverse interaction.|
00241|005|B||
00241|006|A|MECHANISM OF ACTION:  Iron salts appear to decrease the absorption of|
00241|007|A|levodopa by chelate formation.|
00241|008|B||
00241|009|E|CLINICAL EFFECTS:  The therapeutic effect of levodopa may be decreased.|
00241|010|B||
00241|011|P|PREDISPOSING FACTORS:  None determined.|
00241|012|B||
00241|013|M|PATIENT MANAGEMENT:  Separate the administration times of levodopa and iron|
00241|014|M|by as much as possible. Observe the patient for a decrease in clinical|
00241|015|M|response and adjust the dose of levodopa as necessary.|
00241|016|B||
00241|017|D|DISCUSSION:  Ferrous sulfate administration produced decreases in the serum|
00241|018|D|concentration of levodopa and area-under-curve (AUC). Patients receiving|
00241|019|D|levodopa plus carbidopa also experienced a reduction in the serum|
00241|020|D|concentration and AUC for carbidopa during concurrent administration of|
00241|021|D|ferrous sulfate. In addition, a loss in therapeutic response was|
00241|022|D|demonstrated.|
00241|023|B||
00241|024|R|REFERENCES:|
00241|025|B||
00241|026|R|1.Campbell NR, Hasinoff B. Ferrous sulfate reduces levodopa bioavailability:|2
00241|027|R|  chelation as a possible mechanism. Clin Pharmacol Ther 1989 Mar;|2
00241|028|R|  45(3):220-5.|2
00241|029|R|2.Campbell NR, Rankine D, Goodridge AE, Hasinoff BB, Kara M. Sinemet-ferrous|2
00241|030|R|  sulphate interaction in patients with Parkinson's disease. Br J Clin|2
00241|031|R|  Pharmacol 1990 Oct;30(4):599-605.|2
00243|001|T|MONOGRAPH TITLE:  ACE Inhibitors; ARBs/Lithium|
00243|002|B||
00243|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00243|004|L|of severe adverse interaction.|
00243|005|B||
00243|006|A|MECHANISM OF ACTION:  Angiotensin converting enzyme inhibitors (ACEI) or|
00243|007|A|angiotensin II receptor blocker (ARB)-induced sodium loss or volume|
00243|008|A|depletion may result in decreased renal clearance of lithium.(1)|
00243|009|B||
00243|010|E|CLINICAL EFFECTS:  Concurrent use of ACEI or ARBs may result in elevated|
00243|011|E|lithium levels and lithium toxicity.|
00243|012|E|   Lithium has a narrow therapeutic range. Unintended increases in lithium|
00243|013|E|concentrations may lead to lithium toxicity.  Early symptoms of lithium|
00243|014|E|toxicity may include: lethargy, muscle weakness or stiffness, new onset or|
00243|015|E|coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred|
00243|016|E|vision, bradycardia, tinnitus, or nystagmus.  Severe toxicity may produce|
00243|017|E|multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac|
00243|018|E|arrhythmias, cardiovascular collapse) and may be fatal.(1)|
00243|019|B||
00243|020|P|PREDISPOSING FACTORS:  Risk factors for lithium toxicity include: acute|
00243|021|P|renal impairment, chronic renal disease, dehydration, low sodium diet, and|
00243|022|P|concomitant use of multiple medications which may impair renal elimination|
00243|023|P|of lithium (e.g. ACEI, ARBs, NSAIDs, diuretics).(1)  Patients who require|
00243|024|P|higher therapeutic lithium levels to maintain symptom control are|
00243|025|P|particularly susceptible to these factors.|
00243|026|B||
00243|027|M|PATIENT MANAGEMENT:  If concurrent therapy cannot be avoided, monitor|
00243|028|M|closely.  Evaluate renal function and most recent lithium levels.  If renal|
00243|029|M|function is not stable, whenever possible delay initiation of concurrent|
00243|030|M|therapy until renal function is stable.|
00243|031|M|   The onset of lithium toxicity due to concomitant therapy with an ACEI or|
00243|032|M|ARB may be delayed for 3-5 weeks.(2)  Patients receiving this combination|
00243|033|M|should be observed for signs of lithium toxicity when the ACEI or ARB dose|
00243|034|M|is increased or if additional risk factors for lithium toxicity emerge.|
00243|035|M|   If an ACEI or ARB is required in a patient stabilized on lithium therapy,|
00243|036|M|check baseline lithium concentration, consider empirically lowering the|
00243|037|M|lithium dose, then recheck lithium levels 5 to 7 days after ACEI or ARB|
00243|038|M|initiation. Adjust lithium, ACEI or ARB dose as required and continue|
00243|039|M|frequent (e.g. weekly) monitoring of lithium until levels have stabilized.|
00243|040|M|   If lithium is to be started in a patient stabilized on an ACEI or ARB,|
00243|041|M|consider starting with a lower lithium dose and titrate slowly as half-life|
00243|042|M|may be prolonged.(1)  Monitor lithium concentrations frequently until|
00243|043|M|stabilized on the combination.|
00243|044|M|   If an interacting drug is discontinued, the lithium level may fall.|
00243|045|M|Monitor lithium concentration and adjust dose if needed.(1)|
00243|046|M|   Counsel patient to assure they know signs and symptoms of lithium|
00243|047|M|toxicity and understand the importance of follow-up laboratory testing.|
00243|048|B||
00243|049|D|DISCUSSION:  Elevated lithium levels and lithium toxicity have been reported|
00243|050|D|during concomitant administration of lithium and an ACEI(3-17) or an|
00243|051|D|ARB(18-20). Other factors, such as dehydration, acute or worsening of|
00243|052|D|chronic renal impairment, or acute changes in sodium intake may increase the|
00243|053|D|occurrence of a clinically important interaction.|
00243|054|B||
00243|055|R|REFERENCES:|
00243|056|B||
00243|057|R|1.Lithobid (lithium carbonate) US prescribing information. ANI|1
00243|058|R|  Pharmaceuticals, Inc. May, 2018.|1
00243|059|R|2.Finley PR. Drug Interactions with Lithium: An Update. Clin Pharmacokinet|6
00243|060|R|  2016 Aug;55(8):925-41.|6
00243|061|R|3.Douste-Blazy P, Rostin M, Livarek B, Tordjman E, Montastruc JL, Galinier|3
00243|062|R|  F. Angiotensin converting enzyme inhibitors and lithium treatment. Lancet|3
00243|063|R|  1986 Jun 21;1(8495):1448.|3
00243|064|R|4.Navis GJ, de Jong PE, de Zeeuw D. Volume homeostasis, angiotensin|3
00243|065|R|  converting enzyme inhibition, and lithium therapy. Am J Med 1989 May;|3
00243|066|R|  86(5):621.|3
00243|067|R|5.Baldwin CM, Safferman AZ. A case of lisinopril-induced lithium toxicity.|3
00243|068|R|  DICP 1990 Oct;24(10):946-7.|3
00243|069|R|6.Griffin JH, Hahn SM. Lisinopril-induced lithium toxicity. DICP 1991 Jan;|3
00243|070|R|  25(1):101.|3
00243|071|R|7.Correa FJ, Eiser AR. Angiotensin-converting enzyme inhibitors and lithium|3
00243|072|R|  toxicity. Am J Med 1992 Jul;93(1):108-9.|3
00243|073|R|8.DasGupta K, Jefferson JW, Kobak KA, Greist JH. The effect of enalapril on|2
00243|074|R|  serum lithium levels in healthy men. J Clin Psychiatry 1992 Nov;|2
00243|075|R|  53(11):398-400.|2
00243|076|R|9.Zwanzger P, Marcuse A, Boerner RJ, Walther A, Rupprecht R. Lithium|3
00243|077|R|  intoxication after administration of AT1 blockers. J Clin Psychiatry 2001|3
00243|078|R|  Mar;62(3):208-9.|3
00243|079|R|10.Meyer JM, Dollarhide A, Tuan IL. Lithium toxicity after switch from|3
00243|080|R|   fosinopril to lisinopril. Int Clin Psychopharmacol 2005 Mar;20(2):115-8.|3
00243|081|R|11.Spinewine A, Schoevaerdts D, Mwenge GB, Swine C, Dive A. Drug-induced|3
00243|082|R|   lithium intoxication: a case report. J Am Geriatr Soc 2005 Feb;|3
00243|083|R|   53(2):360-1.|3
00243|084|R|12.Chandragiri SS, Pasol E, Gallagher RM. Lithium ACE inhibitors, NSAIDs,|3
00243|085|R|   and verapamil. A possible fatal combination. Psychosomatics 1998 May-Jun;|3
00243|086|R|   39(3):281-2.|3
00243|087|R|13.Vipond AJ, Bakewell S, Telford R, Nicholls AJ. Lithium toxicity.|3
00243|088|R|   Anaesthesia 1996 Dec;51(12):1156-8.|3
00243|089|R|14.Alderman CP, Lindsay KS. Increased serum lithium concentration secondary|3
00243|090|R|   to treatment with tiaprofenic acid and fosinopril. Ann Pharmacother 1996|3
00243|091|R|   Dec;30(12):1411-3.|3
00243|092|R|15.Teitelbaum M. A significant increase in lithium levels after concomitant|3
00243|093|R|   ACE inhibitor administration. Psychosomatics 1993 Sep-Oct;34(5):450-3.|3
00243|094|R|16.Drouet A, Bouvet O. Lithium and converting enzyme inhibitors. Encephale|3
00243|095|R|   1990 Jan-Feb;16(1):51-2.|3
00243|096|R|17.Rostin M, Douste-Blazy P, Galinier M, Montastruc JL. Lithium and the|3
00243|097|R|   converting enzyme inhibitor: a dangerous combination. Presse Med 1988 Jun|3
00243|098|R|   11;17(23):1218.|3
00243|099|R|18.Leung M, Remick RA. Potential drug interaction between lithium and|3
00243|100|R|   valsartan. J Clin Psychopharmacol 2000 Jun;20(3):392-3.|3
00243|101|R|19.Blanche P, Raynaud E, Kerob D, Galezowski N. Lithium intoxication in an|3
00243|102|R|   elderly patient after combined treatment with losartan. Eur J Clin|3
00243|103|R|   Pharmacol 1997;52(6):501.|3
00243|104|R|20.Su YP, Chang CJ, Hwang TJ. Lithium intoxication after valsartan|3
00243|105|R|   treatment. Psychiatry Clin Neurosci 2007 Apr;61(2):204.|3
00244|001|T|MONOGRAPH TITLE:  Selected Azole Antifungals/Antacids (mono deleted|
00244|002|T|10/30/2014)|
00244|003|B||
00244|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00244|005|L|of severe adverse interaction.|
00244|006|B||
00244|007|A|MECHANISM OF ACTION:  Antacids and buffers in didanosine products increase|
00244|008|A|stomach pH.  Quinapril tablets may contain a high percentage of magnesium.|
00244|009|A|Since some orally administered azole antifungal agents require an acidic|
00244|010|A|medium for optimal absorption, agents may decrease the absorption of azole|
00244|011|A|antifungal agents.|
00244|012|B||
00244|013|E|CLINICAL EFFECTS:  Simultaneous administration of an antacid or buffered|
00244|014|E|didanosine may result in decreased therapeutic effects of the azole|
00244|015|E|antifungal.|
00244|016|B||
00244|017|P|PREDISPOSING FACTORS:  None determined.|
00244|018|B||
00244|019|M|PATIENT MANAGEMENT:  Administer the azole antifungal agent at least two|
00244|020|M|hours before the antacid or buffered didanosine.|
00244|021|B||
00244|022|D|DISCUSSION:  In randomized, open-labeled, cross-over study in 12 healthy|
00244|023|D|subjects, simultaneous administration of an antacid decreased the|
00244|024|D|area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of|
00244|025|D|itraconazole (200 mg) by 66% and 70%, respectively.  Time to Cmax (Tmax)|
00244|026|D|increased by 70%.(1)  This interaction has also been reported in a case|
00244|027|D|report.(2)|
00244|028|D|   In a study in 3 subjects, simultaneous administration of a combination|
00244|029|D|aluminum hydroxide/magnesium hydroxide (30 ml) decreased the AUC of a single|
00244|030|D|dose of ketoconazole (200 mg) by 41%.(3)|
00244|031|D|   In a case report, a patient receiving concurrent ketoconazole with|
00244|032|D|aluminum hydroxide, cimetidine, and sodium bicarbonate did not respond to|
00244|033|D|therapy until cimetidine was discontinued and the administration time of|
00244|034|D|aluminum hydroxide and cimetidine was changed to 2 hours after ketoconazole.|
00244|035|D|In a follow-up study in 2 subjects, concurrent cimetidine and sodium|
00244|036|D|hydroxide lowered ketoconazole levels.(4)|
00244|037|D|   In a study in 14 subjects, simultaneous administration of aluminum|
00244|038|D|hydroxide/magnesium hydroxide (20 ml, 1800 mg/1200 mg) had no significant|
00244|039|D|effects on fluconazole pharmacokinetics.(5)|
00244|040|D|   In a randomized, open-label, cross-over study in 6 subjects, simultaneous|
00244|041|D|administration of itraconazole with buffered didanosine tablets resulted in|
00244|042|D|undetectable levels of itraconazole.(6)|
00244|043|D|   In a randomized cross-over study in 12 HIV-positive subjects,|
00244|044|D|administration of buffered didanosine tablets 2 hours after ketoconazole had|
00244|045|D|no effects on ketoconazole levels.(7)|
00244|046|D|   In a randomized, cross-over, open-label study in 24 healthy subjects,|
00244|047|D|simultaneous administration of enteric-coated didanosine had no effect on|
00244|048|D|ketoconazole pharmacokinetics.(8)|
00244|049|B||
00244|050|R|REFERENCES:|
00244|051|B||
00244|052|R|1.Lohitnavy M, Lohitnavy O, Thangkeattiyanon O, Srichai W. Reduced oral|2
00244|053|R|  itraconazole bioavailability by antacid suspension. J Clin Pharm Ther 2005|2
00244|054|R|  Jun;30(3):201-6.|2
00244|055|R|2.Moreno F, Hardin TC, Rinaldi MG, Graybill JR. Itraconazole-didanosine|3
00244|056|R|  excipient interaction. JAMA 1993 Mar 24-31;269(12):1508.|3
00244|057|R|3.Brass C, Galgiani JN, Blaschke TF, Defelice R, O'Reilly RA, Stevens DA.|2
00244|058|R|  Disposition of ketoconazole, an oral antifungal, in humans. Antimicrob|2
00244|059|R|  Agents Chemother 1982 Jan;21(1):151-8.|2
00244|060|R|4.Van Der Meer JW, Keuning JJ, Scheijgrond HW, Heykants J, Van Cutsem J,|3
00244|061|R|  Brugmans J. The influence of gastric acidity on the bio-availability of|3
00244|062|R|  ketoconazole. J Antimicrob Chemother 1980 Jul;6(4):552-4.|3
00244|063|R|5.Thorpe JE, Baker N, Bromet-Petit M. Effect of oral antacid administration|2
00244|064|R|  on the pharmacokinetics of oral fluconazole. Antimicrob Agents Chemother|2
00244|065|R|  1990 Oct;34(10):2032-3.|2
00244|066|R|6.May DB, Drew RH, Yedinak KC, Bartlett JA. Effect of simultaneous|2
00244|067|R|  didanosine administration on itraconazole absorption in healthy|2
00244|068|R|  volunteers. Pharmacotherapy 1994 Sep-Oct;14(5):509-13.|2
00244|069|R|7.Knupp CA, Brater DC, Relue J, Barbhaiya RH. Pharmacokinetics of didanosine|2
00244|070|R|  and ketoconazole after coadministration to patients seropositive for the|2
00244|071|R|  human immunodeficiency virus. J Clin Pharmacol 1993 Oct;33(10):912-7.|2
00244|072|R|8.Damle BD, Mummaneni V, Kaul S, Knupp C. Lack of effect of simultaneously|2
00244|073|R|  administered didanosine encapsulated enteric bead formulation (Videx EC)|2
00244|074|R|  on oral absorption of indinavir, ketoconazole, or ciprofloxacin.|2
00244|075|R|  Antimicrob Agents Chemother 2002 Feb;46(2):385-91.|2
00245|001|T|MONOGRAPH TITLE:  Selected Antipsychotics/Lithium|
00245|002|B||
00245|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00245|004|L|take action as needed.|
00245|005|B||
00245|006|A|MECHANISM OF ACTION:  The exact mechanism of the interaction is unknown.|
00245|007|A|Neurotoxicity symptoms (confusion, delirium, seizures, encephalopathy, and|
00245|008|A|EEG changes) may be due to potentiation or an additive effect of the|
00245|009|A|antipsychotic agent and lithium.|
00245|010|B||
00245|011|E|CLINICAL EFFECTS:  Concurrent use of lithium and selected antipsychotic|
00245|012|E|agents may produce neurotoxic symptoms, including extrapyramidal symptoms,|
00245|013|E|neuroleptic malignant syndrome, and encephalopathic syndrome.|
00245|014|B||
00245|015|P|PREDISPOSING FACTORS:  Large doses of either drug, pre-existing brain damage|
00245|016|P|or other conditions (e.g. infection, dehydration) may increase the risk for|
00245|017|P|neurotoxicity.|
00245|018|B||
00245|019|M|PATIENT MANAGEMENT:  Lithium and antipsychotic agents are commonly|
00245|020|M|co-prescribed for the acute management of manic or mixed manic episodes|
00245|021|M|associated with bipolar disorder.  Concurrent use should be approached with|
00245|022|M|caution.  Consider additional clinical monitoring for signs and symptoms of|
00245|023|M|neurotoxicity, including confusion, fever, lethargy, tremors, stupor,|
00245|024|M|weakness, leukocytosis, and increased blood urea nitrogen. If signs of|
00245|025|M|neurotoxicity appear, discontinuation of the antipsychotic agent may be|
00245|026|M|required.|
00245|027|M|   The US manufacturer of lithium carbonate states concurrent use with|
00245|028|M|antipsychotic agents, including chlorpromazine, clozapine, fluphenazine,|
00245|029|M|haloperidol, perphenazine, risperidone, and thioridazine, should be|
00245|030|M|monitored closely.|
00245|031|M|   Although uncommon to rare, cases of severe neurotoxicity have been|
00245|032|M|reported with this combination.  Monitoring plasma levels is not always|
00245|033|M|beneficial in preventing neurotoxic symptoms.  Patients may experience|
00245|034|M|neurotoxic symptoms with plasma concentrations in the therapeutic ranges.|
00245|035|M|Close monitoring for signs of neurotoxicity, EEG monitoring, adequate|
00245|036|M|hydration, and electrolyte status are recommended to minimize toxic|
00245|037|M|potential.|
00245|038|B||
00245|039|D|DISCUSSION:  Lithium and antipsychotic agents are commonly co-prescribed for|
00245|040|D|the acute management of manic or mixed manic episodes associated with|
00245|041|D|bipolar disorder.  Several case reports have been published describing acute|
00245|042|D|and irreversible neurotoxicity with the combination of lithium and|
00245|043|D|antipsychotic agents, though these episodes often resemble rare serious|
00245|044|D|events that can be attributed to the administration of either agent alone|
00245|045|D|(e.g., delirium, dysphoria, encephalopathy, dyskinesias, neuroleptic|
00245|046|D|malignant syndrome, etc.).|
00245|047|D|   Signs and symptoms of neurotoxicity associated with concomitant use have|
00245|048|D|included confusion, fever, lethargy, tremors, stupor, weakness,|
00245|049|D|leukocytosis, and increased blood urea nitrogen.|
00245|050|D|   Extrapyramidal effects, which in some cases were irreversible, and|
00245|051|D|permanent brain damage have also been reported.|
00245|052|D|   Selected antipsychotics linked to this monograph include: benperidol,|
00245|053|D|clozapine, haloperidol, and risperidone.|
00245|054|B||
00245|055|R|REFERENCES:|
00245|056|B||
00245|057|R|1.Lithobid (lithium carbonate) US prescribing information. ANI|1
00245|058|R|  Pharmaceuticals, Inc. May, 2018.|1
00245|059|R|2.Lithium carbonate US prescribing information. West-Ward Pharmaceuticals|1
00245|060|R|  Corp. October, 2022.|1
00245|061|R|3.Cohen WJ, Cohen NH. Lithium carbonate, haloperidol, and irreversible brain|3
00245|062|R|  damage. JAMA 1974 Dec 2;230(9):1283-7.|3
00245|063|R|4.Finley PR. Drug Interactions with Lithium: An Update. Clin Pharmacokinet|6
00245|064|R|  2016 Aug;55(8):925-41.|6
00245|065|R|5.Swartz CM. Olanzapine-lithium encephalopathy. Psychosomatics 2001 Jul-Aug;|3
00245|066|R|  42(4):370.|3
00245|067|R|6.Haldol injection (haloperidol) US prescribing information. Janssen|1
00245|068|R|  Pharmaceuticals, Inc. October, 2025.|1
00245|069|R|7.Colvard MD, Gentry JD, Mullis DM. Neurotoxicity with combined use of|3
00245|070|R|  lithium and haloperidol decanoate. Prim Care Companion CNS Disord 2013;|3
00245|071|R|  15(6):.|3
00245|072|R|8.Thornton WE, Pray BJ. Lithium intoxication: a report of two cases. Can|3
00245|073|R|  Psychiatr Assoc J 1975 Jun;20(4):281-2.|3
00245|074|R|9.Loudon JB, Waring H. Toxic reactions to lithium and haloperidol. Lancet|3
00245|075|R|  1976 Nov 13;2(7994):1088.|3
00245|076|R|10.Baastrup PC, Hollnagel P, Sorensen R, Schou M. Adverse reactions in|3
00245|077|R|   treatment with lithium carbonate and haloperidol. JAMA 1976 Dec 6;|3
00245|078|R|   236(23):2645-6.|3
00245|079|R|11.Juhl RP, Tsuang MT, Perry PJ. Concomitant administration of haloperidol|2
00245|080|R|   and lithium carbonate in acute mania. Dis Nerv Syst 1977 Sep;38(9):675-6.|2
00245|081|R|12.Thomas CJ. Brain damage with lithium/haloperidol. Br J Psychiatry 1979|3
00245|082|R|   May;134:552.|3
00245|083|R|13.Biederman J, Lerner Y, Belmaker RH. Combination of lithium carbonate and|2
00245|084|R|   haloperidol in schizo-affective disorder: a controlled study. Arch Gen|2
00245|085|R|   Psychiatry 1979 Mar;36(3):327-33.|2
00245|086|R|14.Thomas C, Tatham A, Jakubowski S. Lithium/haloperidol combinations and|3
00245|087|R|   brain damage. Lancet 1982 Mar 13;1(8272):626.|3
00245|088|R|15.Spring G, Frankel M. New data on lithium and haloperidol incompatibility.|3
00245|089|R|   Am J Psychiatry 1981 Jun;138(6):818-21.|3
00245|090|R|16.Addonizio G. Rapid induction of extrapyramidal side effects with combined|3
00245|091|R|   use of lithium and neuroleptics. J Clin Psychopharmacol 1985 Oct;|3
00245|092|R|   5(5):296-8.|3
00245|093|R|17.Goldney RD, Spence ND. Safety of the combination of lithium and|3
00245|094|R|   neuroleptic drugs. Am J Psychiatry 1986 Jul;143(7):882-4.|3
00245|095|R|18.Saran A, Addy O, Foliart RH, Schubert DS, Halaris A.|2
00245|096|R|   Electroencephalographic changes and other indices of neurotoxicity with|2
00245|097|R|   haloperidol-lithium therapy. Neuropsychobiology 1989;20(3):152-7.|2
00246|001|T|MONOGRAPH TITLE:  Valproic Acid/Carbamazepine|
00246|002|B||
00246|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00246|004|L|take action as needed.|
00246|005|B||
00246|006|A|MECHANISM OF ACTION:  Valproic acid may displace carbamazepine from protein|
00246|007|A|binding sites and inhibit the metabolism of the active metabolite of|
00246|008|A|carbamazepine. In addition, carbamazepine may increase the metabolism of|
00246|009|A|valproic acid.|
00246|010|B||
00246|011|E|CLINICAL EFFECTS:  Loss of seizure control due to decreased serum valproic|
00246|012|E|acid concentrations. Toxicity due to increased concentrations of the active|
00246|013|E|metabolite of carbamazepine.|
00246|014|B||
00246|015|P|PREDISPOSING FACTORS:  None determined.|
00246|016|B||
00246|017|M|PATIENT MANAGEMENT:  Monitor serum concentrations of both drugs. Adjust the|
00246|018|M|dose of either drug as needed.|
00246|019|B||
00246|020|D|DISCUSSION:  After discontinuing carbamazepine therapy, valproic acid levels|
00246|021|D|increased in one patient producing pancreatitis. Acute psychosis was|
00246|022|D|reported in another patient 8 days after adding carbamazepine to the|
00246|023|D|patient's valproic acid regimen. Numerous studies have found that|
00246|024|D|carbamazepine can decrease serum valproic acid concentrations. While the|
00246|025|D|effects of valproic acid on carbamazepine levels are variable, serum|
00246|026|D|concentrations of the active metabolite of carbamazepine are increased.|
00246|027|B||
00246|028|R|REFERENCES:|
00246|029|B||
00246|030|R|1.Adams DJ, Luders H, Pippenger C. Sodium valproate in the treatment of|2
00246|031|R|  intractable seizure disorders: a clinical and electroencephalographic|2
00246|032|R|  study. Neurology 1978 Feb;28(2):152-7.|2
00246|033|R|2.Wilder BJ, Willmore LJ, Bruni J, Villarreal HJ. Valproic acid: interaction|2
00246|034|R|  with other anticonvulsant drugs. Neurology 1978 Sep;28(9 Pt 1):892-6.|2
00246|035|R|3.Schapel GJ, Beran RG, Doecke CJ, O'Reilly WJ, Reece PA, Rischbieth RH,|2
00246|036|R|  Sansom LN, Stanley PE. Pharmacokinetics of sodium valproate in epileptic|2
00246|037|R|  patients: prediction of maintenance dosage by single-dose study. Eur J|2
00246|038|R|  Clin Pharmacol 1980 Jan;17(1):71-7.|2
00246|039|R|4.Reunanen MI, Luoma P, Myllyla VV, Hokkanen E. Low serum valproic acid|2
00246|040|R|  concentrations in epileptic patients on combination therapy. Curr Ther Res|2
00246|041|R|  1980 Sep;28(3):456-62.|2
00246|042|R|5.Hoffmann F, von Unruh GE, Jancik BC. Valproic acid disposition in|2
00246|043|R|  epileptic patients during combined antiepileptic maintenance therapy. Eur|2
00246|044|R|  J Clin Pharmacol 1981;19(5):383-5.|2
00246|045|R|6.Brodie MJ, Forrest G, Rapeport WG. Carbamazepine 10, 11 epoxide|2
00246|046|R|  concentrations in epileptics on carbamazepine alone and in combination|2
00246|047|R|  with other anticonvulsants. Br J Clin Pharmacol 1983 Dec;16(6):747-9.|2
00246|048|R|7.Levy RH, Moreland TA, Morselli PL, Guyot M, Brachet-Liermain A, Loiseau P.|5
00246|049|R|  Carbamazepine/valproic acid interaction in man and rhesus monkey.|5
00246|050|R|  Epilepsia 1984 Jun;25(3):338-45.|5
00246|051|R|8.Jann MW, Fidone GS, Israel MK, Bonadero P. Increased valproate serum|2
00246|052|R|  concentrations upon carbamazepine cessation. Epilepsia 1988 Sep-Oct;|2
00246|053|R|  29(5):578-81.|2
00246|054|R|9.Robbins DK, Wedlund PJ, Kuhn R, Baumann RJ, Levy RH, Chang SL. Inhibition|2
00246|055|R|  of epoxide hydrolase by valproic acid in epileptic patients receiving|2
00246|056|R|  carbamazepine. Br J Clin Pharmacol 1990 Jun;29(6):759-62.|2
00246|057|R|10.Ramsay RE, McManus DQ, Guterman A, Briggle TV, Vazquez D, Perchalski R,|2
00246|058|R|   Yost RA, Wong P. Carbamazepine metabolism in humans: effect of concurrent|2
00246|059|R|   anticonvulsant therapy. Ther Drug Monit 1990 May;12(3):235-41.|2
00246|060|R|11.Johnsen SD, Johns DW. Carbamazepine epoxide toxicity in children|4
00246|061|R|   receiving carbamazepine and valproate. Ann Neurol 1991;30(3):491.|4
00246|062|R|12.Ketter TA, Pazzaglia PJ, Post RM. Synergy of carbamazepine and valproic|3
00246|063|R|   acid in affective illness: case report and review of the literature. J|3
00246|064|R|   Clin Psychopharmacol 1992 Aug;12(4):276-81.|3
00247|001|T|MONOGRAPH TITLE:  Cyclosporine; Sirolimus/Metoclopramide|
00247|002|B||
00247|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00247|004|L|take action as needed.|
00247|005|B||
00247|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown but is possibly due to|
00247|007|A|a metoclopramide-induced increase in gastric emptying time leading to an|
00247|008|A|increase in cyclosporine absorption.(1)|
00247|009|B||
00247|010|E|CLINICAL EFFECTS:  The pharmacological and toxic effects of cyclosporine and|
00247|011|E|sirolimus may be increased.|
00247|012|B||
00247|013|P|PREDISPOSING FACTORS:  None determined.|
00247|014|B||
00247|015|M|PATIENT MANAGEMENT:  Monitor serum cyclosporine or sirolimus concentrations|
00247|016|M|and adjust dose as necessary.|
00247|017|B||
00247|018|D|DISCUSSION:  In a study involving 14 renal transplant patients, a single|
00247|019|D|oral dose of metoclopramide 20 mg produced nearly a 30% increase in|
00247|020|D|cyclosporine bioavailability.(2,3)  Similar results were reported in a|
00247|021|D|patient receiving cyclosporine and metoclopramide concurrently.(4)|
00247|022|D|Additional studies with varying dosage schedules of metoclopramide|
00247|023|D|administration are needed to determine the extent of this interaction.|
00247|024|B||
00247|025|R|REFERENCES:|
00247|026|B||
00247|027|R|1.Reglan (metoclopramide) tablets US prescribing information. ANI|1
00247|028|R|  Pharmaceuticals, Inc. August 29, 2017.|1
00247|029|R|2.Wadhwa NK, Schroeder TJ, O'Flaherty E, Pesce AJ, Myre SA, First MR. The|2
00247|030|R|  effect of oral metoclopramide on the absorption of cyclosporine.|2
00247|031|R|  Transplant Proc 1987 Feb;19(1 Pt 2):1730-3.|2
00247|032|R|3.Wadhwa NK, Schroeder TJ, O'Flaherty E, Pesce AJ, Myre SA, First MR. The|2
00247|033|R|  effect of oral metoclopramide on the absorption of cyclosporine.|2
00247|034|R|  Transplantation 1987 Feb;43(2):211-3.|2
00247|035|R|4.Morse GD, Holdsworth MT, Venuto RC, Gerbasi J, Walshe JJ. Pharmacokinetics|2
00247|036|R|  and clinical tolerance of intravenous and oral cyclosporine in the|2
00247|037|R|  immediate postoperative period. Clin Pharmacol Ther 1988 Dec;44(6):654-64.|2
00248|001|T|MONOGRAPH TITLE:  Cimetidine/Benzodiazepines|
00248|002|B||
00248|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00248|004|L|take action as needed.|
00248|005|B||
00248|006|A|MECHANISM OF ACTION:  Cimetidine may decrease the metabolism of Phase I|
00248|007|A|hepatically metabolized benzodiazepines.  At doses of 800-2400 mg daily,|
00248|008|A|cimetidine is a weak inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6, and|
00248|009|A|CYP3A4.|
00248|010|B||
00248|011|E|CLINICAL EFFECTS:  Concurrent use may result in increased pharmacologic or|
00248|012|E|toxic effects of certain benzodiazepines.  Toxic effects include profound|
00248|013|E|sedation, respiratory depression, coma, and/or death.|
00248|014|B||
00248|015|P|PREDISPOSING FACTORS:  None determined.|
00248|016|B||
00248|017|M|PATIENT MANAGEMENT:  Benzodiazepines that do not undergo extensive Phase I|
00248|018|M|metabolism (lorazepam, oxazepam) may be an alternative to interacting|
00248|019|M|benzodiazepines in patients receiving cimetidine or by administering another|
00248|020|M|H-2 antagonist (e.g., ranitidine, famotidine, nizatidine).|
00248|021|M|   Cimetidine use at higher doses of 200-400 mg four times daily would have|
00248|022|M|an increased risk of inhibiting the metabolism of benzodiazepines.  Lower|
00248|023|M|doses and over-the-counter doses of cimetidine would be expected to have a|
00248|024|M|diminished effect.  Consider using alternative H2 antagonists when long-term|
00248|025|M|concurrent therapy with benzodiazepines is indicated.|
00248|026|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00248|027|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00248|028|M|unresponsiveness.|
00248|029|B||
00248|030|D|DISCUSSION:  Cimetidine increases the half-life and serum concentration and|
00248|031|D|decreases the clearance of benzodiazepines that undergo oxidative metabolism|
00248|032|D|(e.g., alprazolam, bromazepam, diazepam, flurazepam, midazolam, triazolam).|
00248|033|D|   In a clinical study, cimetidine 1,200 mg daily decreased the clearance of|
00248|034|D|bromazepam by 50% and increased its half-life from 23 hours to 29 hours.(22)|
00248|035|D|   The sedative effects of benzodiazepines have been reported to be|
00248|036|D|increased during concurrent administration of cimetidine.  This interaction|
00248|037|D|does not appear to occur with benzodiazepines that undergo glucuronide|
00248|038|D|conjugation.|
00248|039|B||
00248|040|R|REFERENCES:|
00248|041|B||
00248|042|R|1.Desmond PV, Patwardhan RV, Schenker S, Speeg KV Jr. Cimetidine impairs|2
00248|043|R|  elimination of chlordiazepoxide (Librium) in man. Ann Intern Med 1980 Aug;|2
00248|044|R|  93(2):266-8.|2
00248|045|R|2.Klotz U, Reimann I. Delayed clearance of diazepam due to cimetidine. N|2
00248|046|R|  Engl J Med 1980 May 1;302(18):1012-4.|2
00248|047|R|3.Klotz U, Reimann I. Influence of cimetidine on the pharmacokinetics of|2
00248|048|R|  desmethyldiazepam and oxazepam. Eur J Clin Pharmacol 1980 Nov;|2
00248|049|R|  18(6):517-20.|2
00248|050|R|4.Patwardhan RV, Yarborough GW, Desmond PV, Johnson RF, Schenker S, Speeg KV|2
00248|051|R|  Jr. Cimetidine spares the glucuronidation of lorazepam and oxazepam.|2
00248|052|R|  Gastroenterology 1980 Nov;79(5 Pt 1):912-6.|2
00248|053|R|5.Ruffalo RL, Thompson JF, Segal J. Cimetidine-benzodiazepine drug|6
00248|054|R|  interaction. Am J Hosp Pharm 1981 Sep;38(9):1365-6.|6
00248|055|R|6.Patwardhan RV, Johnson RF, Sinclair AP, Schenker S, Speeg KV Jr. Lack of|2
00248|056|R|  tolerance and rapid recovery of cimetidine-inhibited chlordiazepoxide|2
00248|057|R|  (Librium) elimination. Gastroenterology 1981 Sep;81(3):547-51.|2
00248|058|R|7.Klotz U, Reimann I. Elevation of steady-state diazepam levels by|2
00248|059|R|  cimetidine. Clin Pharmacol Ther 1981 Oct;30(4):513-7.|2
00248|060|R|8.Divoll M, Abernethy DR, Greenblatt DJ. Cimetidine impairs drug oxidizing|4
00248|061|R|  capacity in the elderly. Clin Pharmacol Ther 1982 Feb;31(2):218.|4
00248|062|R|9.Gough PA, Curry SH, Araujo OE, Robinson JD, Dallman JJ. Influence of|2
00248|063|R|  cimetidine on oral diazepam elimination with measurement of subsequent|2
00248|064|R|  cognitive change. Br J Clin Pharmacol 1982 Nov;14(5):739-42.|2
00248|065|R|10.Hiss J, Hepler BR, Falkowski AJ, Sunshine I. Fatal bradycardia after|3
00248|066|R|   intentional overdose of cimetidine and diazepam. Lancet 1982 Oct 30;|3
00248|067|R|   2(8305):982.|3
00248|068|R|11.Divoll M, Greenblatt DJ, Abernethy DR, Shader RI. Cimetidine impairs|2
00248|069|R|   clearance of antipyrine and desmethyldiazepam in the elderly. J Am|2
00248|070|R|   Geriatr Soc 1982 Nov;30(11):684-9.|2
00248|071|R|12.Abernethy DR, Greenblatt DJ, Divoll M, Moschitto LJ, Harmatz JS, Shader|2
00248|072|R|   RI. Interaction of cimetidine with the triazolobenzodiazepines alprazolam|2
00248|073|R|   and triazolam. Psychopharmacology (Berl) 1983;80(3):275-8.|2
00248|074|R|13.Greenblatt DJ, Abernethy DR, Morse DS, Harmatz JS, Shader RI. Clinical|2
00248|075|R|   importance of the interaction of diazepam and cimetidine. N Engl J Med|2
00248|076|R|   1984 Jun 21;310(25):1639-43.|2
00248|077|R|14.Greenblatt DJ, Abernethy DR, Morse DS, Harmatz JS, Shader RI. The|4
00248|078|R|   diazepam-cimetidine interaction: is it clinically important?. Clin|4
00248|079|R|   Pharmacol Ther 1984 Feb;35(2):245.|4
00248|080|R|15.Greenblatt DJ, Abernethy DR, Koepke HH, Shader RI. Interaction of|2
00248|081|R|   cimetidine with oxazepam, lorazepam, and flurazepam. J Clin Pharmacol|2
00248|082|R|   1984 Apr;24(4):187-93.|2
00248|083|R|16.Greenblatt DJ, Locniskar A, Scavone JM, Blyden GT, Ochs HR, Harmatz JS,|2
00248|084|R|   Shader RI. Absence of interaction of cimetidine and ranitidine with|2
00248|085|R|   intravenous and oral midazolam. Anesth Analg 1986 Feb;65(2):176-80.|2
00248|086|R|17.Locniskar A, Greenblatt DJ, Harmatz JS, Zinny MA, Shader RI. Interaction|2
00248|087|R|   of diazepam with famotidine and cimetidine, two H2-receptor antagonists.|2
00248|088|R|   J Clin Pharmacol 1986 Apr;26(4):299-303.|2
00248|089|R|18.Friedman H, Greenblatt DJ, Burstein ES, Scavone JM, Harmatz JS, Shader|2
00248|090|R|   RI. Triazolam kinetics: interaction with cimetidine, propranolol, and the|2
00248|091|R|   combination. J Clin Pharmacol 1988 Mar;28(3):228-33.|2
00248|092|R|19.Andersson T, Andren K, Cederberg C, Edvardsson G, Heggelund A, Lundborg|2
00248|093|R|   P. Effect of omeprazole and cimetidine on plasma diazepam levels. Eur J|2
00248|094|R|   Clin Pharmacol 1990;39(1):51-4.|2
00248|095|R|20.Sanders LD, Whitehead C, Gildersleve CD, Rosen M, Robinson JO.|2
00248|096|R|   Interaction of H2-receptor antagonists and benzodiazepine sedation. A|2
00248|097|R|   double-blind placebo-controlled investigation of the effects of|2
00248|098|R|   cimetidine and ranitidine on recovery after intravenous midazolam.|2
00248|099|R|   Anaesthesia 1993 Apr;48(4):286-92.|2
00248|100|R|21.This information is based on an extract from the Certara Drug Interaction|6
00248|101|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00248|102|R|22.Ochs HR, Greenblatt DJ, Friedman H, Burstein ES, Locniskar A, Harmatz JS,|2
00248|103|R|   Shader RI. Bromazepam pharmacokinetics: influence of age, gender, oral|2
00248|104|R|   contraceptives,  cimetidine, and propranolol. Clin Pharmacol Ther 1987|2
00248|105|R|   May;41(5):562-70.|2
00249|001|T|MONOGRAPH TITLE:  Carbamazepine/Cimetidine|
00249|002|B||
00249|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00249|004|L|take action as needed.|
00249|005|B||
00249|006|A|MECHANISM OF ACTION:  Inhibition of carbamazepine metabolism by CYP3A4.|
00249|007|B||
00249|008|E|CLINICAL EFFECTS:  The pharmacologic and toxic effects of carbamazepine may|
00249|009|E|be increased.|
00249|010|B||
00249|011|P|PREDISPOSING FACTORS:  None determined.|
00249|012|B||
00249|013|M|PATIENT MANAGEMENT:  Monitor serum carbamazepine and observe the patient for|
00249|014|M|signs of carbamazepine toxicity when starting, stopping or altering the dose|
00249|015|M|of cimetidine. Administration of an alternative H-2 antagonist, such as|
00249|016|M|famotidine or ranitidine, may circumvent this interaction.|
00249|017|B||
00249|018|D|DISCUSSION:  Elevated plasma carbamazepine concentrations and toxicity have|
00249|019|D|been reported in patients stabilized on carbamazepine after cimetidine has|
00249|020|D|been started. The effects of this interaction appear to dissipate within one|
00249|021|D|week, at which time carbamazepine returns to the level observed prior to the|
00249|022|D|addition of cimetidine. However, toxicity may still occur as long as these|
00249|023|D|drugs are administered concomitantly.|
00249|024|B||
00249|025|R|REFERENCES:|
00249|026|B||
00249|027|R|1.Telerman-Toppet N, Duret ME, Coers C. Cimetidine interaction with|3
00249|028|R|  carbamazepine. Ann Intern Med 1981 Apr;94(4 pt 1):544.|3
00249|029|R|2.Sonne J, Luhdorf K, Larsen NE, Andreasen PB. Lack of interaction between|2
00249|030|R|  cimetidine and carbamazepine. Acta Neurol Scand 1983 Oct;68(4):253-6.|2
00249|031|R|3.Macphee GJ, Thompson GG, Scobie G, Agnew E, Park BK, Murray T, McColl KE,|2
00249|032|R|  Brodie MJ. Effects of cimetidine on carbamazepine auto- and|2
00249|033|R|  hetero-induction in man. Br J Clin Pharmacol 1984 Sep;18(3):411-9.|2
00249|034|R|4.Webster LK, Mihaly GW, Jones DB, Smallwood RA, Phillips JA, Vajda FJ.|2
00249|035|R|  Effect of cimetidine and ranitidine on carbamazepine and sodium valproate|2
00249|036|R|  pharmacokinetics. Eur J Clin Pharmacol 1984;27(3):341-3.|2
00249|037|R|5.Dalton MJ, Powell JR, Messenheimer JA. The influence of cimetidine on|4
00249|038|R|  single dose carbamazepine pharmacokinetics. Clin Pharmacol Ther 1984 Fe;|4
00249|039|R|  35(2):233.|4
00249|040|R|6.Dalton MJ, Powell JR, Messenheimer JA Jr. The influence of cimetidine on|2
00249|041|R|  single-dose carbamazepine pharmacokinetics. Epilepsia 1985 Mar-Apr;|2
00249|042|R|  26(2):127-30.|2
00249|043|R|7.Levine M, Jones MW, Sheppard I. Differential effect of cimetidine on serum|2
00249|044|R|  concentrations of carbamazepine and phenytoin. Neurology 1985 Apr;|2
00249|045|R|  35(4):562-5.|2
00249|046|R|8.Dalton MJ, Powell JR, Messenheimer JA Jr. Ranitidine does not alter|2
00249|047|R|  single-dose carbamazepine pharmacokinetics in healthy adults. Drug Intell|2
00249|048|R|  Clin Pharm 1985 Dec;19(12):941-4.|2
00249|049|R|9.Dalton MJ, Powell JR, Messenheimer JA Jr, Clark J. Cimetidine and|2
00249|050|R|  carbamazepine: a complex drug interaction. Epilepsia 1986 Sep-Oct;|2
00249|051|R|  27(5):553-8.|2
00250|001|T|MONOGRAPH TITLE:  Neuromuscular Blocking Agents/Verapamil|
00250|002|B||
00250|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00250|004|L|of severe adverse interaction.|
00250|005|B||
00250|006|A|MECHANISM OF ACTION:  Unknown.|
00250|007|B||
00250|008|E|CLINICAL EFFECTS:  The neuromuscular blocking effect of nondepolarizing|
00250|009|E|muscle relaxants may be extended, producing profound sedation, respiratory|
00250|010|E|depression, coma, and/or death.|
00250|011|B||
00250|012|P|PREDISPOSING FACTORS:  None determined.|
00250|013|B||
00250|014|M|PATIENT MANAGEMENT:  If possible, avoid administration of nondepolarizing|
00250|015|M|neuromuscular blocking agents to patients receiving verapamil. When both|
00250|016|M|drugs must be given, carefully monitor respiratory function to avoid|
00250|017|M|prolonged neuromuscular blockade. If needed, blockade may be reversed by|
00250|018|M|giving edrophonium.|
00250|019|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00250|020|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00250|021|M|unresponsiveness.|
00250|022|B||
00250|023|D|DISCUSSION:  Patients receiving verapamil have experienced prolonged|
00250|024|D|skeletal muscle paralysis after administration of usual therapeutic doses of|
00250|025|D|a nondepolarizing neuromuscular blocking agent. While muscle paralysis was|
00250|026|D|unresponsive to treatment with neostigmine, reversal of blockade has been|
00250|027|D|achieved by administration of edrophonium.|
00250|028|B||
00250|029|R|REFERENCES:|
00250|030|B||
00250|031|R|1.van Poorten JF, Dhasmana KM, Kuypers RS, Erdmann W. Verapamil and reversal|3
00250|032|R|  of vecuronium neuromuscular blockade. Anesth Analg 1984 Feb;63(2):155-7.|3
00250|033|R|2.Jones RM, Cashman JN, Casson WR, Broadbent MP. Verapamil potentiation of|3
00250|034|R|  neuromuscular blockade: failure of reversal with neostigmine but prompt|3
00250|035|R|  reversal with edrophonium. Anesth Analg 1985 Oct;64(10):1021-5.|3
00250|036|R|3.Carlos R, Erill S. Therapeutic rounds: abnormally prolonged responses to|3
00250|037|R|  neuromuscular blocking agents. Clin Ther 1986;9(1):22-3, 135-6.|3
00250|038|R|4.Wali FA. Interaction of verapamil with d-tubocurarine and cholinergic|5
00250|039|R|  agonists at the avian neuromuscular junction. Acta Anaesthesiol Scand 1987|5
00250|040|R|  Jan;31(1):15-20.|5
00251|001|T|MONOGRAPH TITLE:  Triamterene; Amiloride/Selected NSAIDs|
00251|002|B||
00251|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00251|004|L|take action as needed.|
00251|005|B||
00251|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown; however, nonsteroidal|
00251|007|A|anti-inflammatory (NSAID) inhibition of prostaglandins may allow triamterene|
00251|008|A|or amiloride- induced nephrotoxicity or hyperkalemia to occur in some|
00251|009|A|patients.|
00251|010|B||
00251|011|E|CLINICAL EFFECTS:  Possible renal failure or hyperkalemia.|
00251|012|B||
00251|013|P|PREDISPOSING FACTORS:  Preexisting renal impairment.|
00251|014|B||
00251|015|M|PATIENT MANAGEMENT:  When possible, avoid concurrent therapy with|
00251|016|M|triamterene or amiloride with NSAIDs. If these agents are used concurrently,|
00251|017|M|monitor renal function and serum electrolytes. If decreased renal function|
00251|018|M|or hyperkalemia develops, discontinue both agents.|
00251|019|B||
00251|020|D|DISCUSSION:  Acute renal failure and hyperkalemia have been reported in|
00251|021|D|patients receiving concurrent therapy with therapeutic doses of triamterene|
00251|022|D|or amiloride with NSAIDs. Although a majority of these reports have involved|
00251|023|D|indomethacin, other NSAIDs have been implicated (diclofenac, flurbiprofen,|
00251|024|D|and ibuprofen).|
00251|025|B||
00251|026|R|REFERENCES:|
00251|027|B||
00251|028|R|1.Favre L, Glasson P, Vallotton MB. Reversible acute renal failure from|2
00251|029|R|  combined triamterene and indomethacin: a study in healthy subjects. Ann|2
00251|030|R|  Intern Med 1982 Mar;96(3):317-20.|2
00251|031|R|2.McCarthy JT, Torres VE, Romero JC, Wochos DN, Velosa JA. Acute intrinsic|3
00251|032|R|  renal failure induced by indomethacin: role of prostaglandin synthetase|3
00251|033|R|  inhibition. Mayo Clin Proc 1982 May;57(5):289-96.|3
00251|034|R|3.Favre L, Glasson P, Riondel A, Vallotton MB. Interaction of diuretics and|2
00251|035|R|  non-steroidal anti-inflammatory drugs in man. Clin Sci (Lond) 1983 Apr;|2
00251|036|R|  64(4):407-15.|2
00251|037|R|4.Weinberg MS, Quigg RJ, Salant DJ, Bernard DB. Anuric renal failure|3
00251|038|R|  precipitated by indomethacin and triamterene. Nephron 1985;40(2):216-8.|3
00251|039|R|5.Lynn KL, Bailey RR, Swainson CP, Sainsbury R, Low WI. Renal failure with|3
00251|040|R|  potassium-sparing diuretics. N Z Med J 1985 Aug 14;98(784):629-33.|3
00251|041|R|6.Mathews A, Bailie GR. Acute renal failure and hyperkalemia associated with|3
00251|042|R|  triamterene and indomethacin. Vet Hum Toxicol 1986 Jun;28(3):224-5.|3
00251|043|R|7.Harkonen M, Ekblom-Kullberg S. Reversible deterioration of renal function|3
00251|044|R|  after diclofenac in patient receiving triamterene. Br Med J (Clin Res Ed)|3
00251|045|R|  1986 Sep 1986;293(6548):698-9.|3
00251|046|R|8.Gehr TWB, Sica DA, Steiger BW, Marshall C. Interaction of|4
00251|047|R|  triamterene-hydrochlorothiazide (T-H) and ibuprofen (I). Clin Pharmacol|4
00251|048|R|  Ther 1990 Feb;47(2):200.|4
00251|049|R|9.Glasson P, Vallotton MB. Inhibition of prostaglandins biosynthesis lowers|2
00251|050|R|  antidiuretic hormone excretion in man. Adv Prostaglandin Thromboxane Res|2
00251|051|R|  1980;7:1115-8.|2
00251|052|R|10.Wong DG, Spence JD, Lamki L, Freeman D, McDonald JW. Effect of|3
00251|053|R|   non-steroidal anti-inflammatory drugs on control of hypertension by|3
00251|054|R|   beta-blockers and diuretics. Lancet 1986 May 3;1(8488):997-1001.|3
00251|055|R|11.ter Borg EJ, de Jong PE, Meyer S, van Rijswijk MH, Kallenberg CG.|3
00251|056|R|   Indomethacin and ibuprofen-induced reversible acute renal failure in a|3
00251|057|R|   patient with systemic lupus erythematosus. Neth J Med 1987 Apr;|3
00251|058|R|   30(3-4):181-6.|3
00251|059|R|12.Mor R, Pitlik S, Rosenfeld JB. Indomethacin- and Moduretic--induced|3
00251|060|R|   hyperkalemia. Isr J Med Sci 1983 Jun;19(6):535-7.|3
00251|061|R|13.Maxzide (triamterene/hydrochlorothiazide) US prescribing information.|1
00251|062|R|   Lederle January, 2011.|1
00251|063|R|14.Dyazide (triamterene/hydrochlorothiazide) US prescribing information.|1
00251|064|R|   Glaxo SmithKline February, 2011.|1
00251|065|R|15.Midamor (amiloride) US prescribing information. Merck & Co., Inc.|1
00251|066|R|   November, 2002.|1
00251|067|R|16.Moduretic (amiloride/hydrochlorothiazide) US prescribing information.|1
00251|068|R|   Merck & Co., Inc. November, 2002.|1
00252|001|T|MONOGRAPH TITLE:  Succinylcholine/Cyclophosphamide|
00252|002|B||
00252|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00252|004|L|of severe adverse interaction.|
00252|005|B||
00252|006|A|MECHANISM OF ACTION:  Cyclophosphamide may reduce plasma concentrations of|
00252|007|A|the enzyme that metabolizes succinylcholine, pseudocholinesterase.|
00252|008|B||
00252|009|E|CLINICAL EFFECTS:  The neuromuscular blocking activity of succinylcholine|
00252|010|E|may be prolonged producing profound sedation, respiratory depression, coma,|
00252|011|E|and/or death.|
00252|012|B||
00252|013|P|PREDISPOSING FACTORS:  None determined.|
00252|014|B||
00252|015|M|PATIENT MANAGEMENT:  If possible, avoid administration of succinylcholine to|
00252|016|M|patients receiving cyclophosphamide. When both drugs must be given,|
00252|017|M|carefully monitor neuromuscular function to avoid overdosage of|
00252|018|M|succinylcholine and prolonged apnea.|
00252|019|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00252|020|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00252|021|M|unresponsiveness.|
00252|022|B||
00252|023|D|DISCUSSION:  Case reports and in vitro investigations support that|
00252|024|D|concurrent administration of cyclophosphamide and succinylcholine can|
00252|025|D|produce prolonged neuromuscular blockade. The effect may be greatest when|
00252|026|D|large dosages of cyclophosphamide are given.|
00252|027|B||
00252|028|R|REFERENCES:|
00252|029|B||
00252|030|R|1.Mone JG, Mathie WE. Qualitative defects of pseudocholinesterase activity.|2
00252|031|R|  Anaesthesia 1967 Jan;22(1):55-68.|2
00252|032|R|2.Gurman GM. Prolonged apnea after succinylcholine in a case treated with|3
00252|033|R|  cytostatics for cancer. Anesth Analg 1972 Sep-Oct;51(5):761-5.|3
00252|034|R|3.Zsigmond EK, Robins G. The effect of a series of anti-cancer drugs on|5
00252|035|R|  plasma cholinesterase activity. Can Anaesth Soc J 1972 Jan;19(1):75-82.|5
00252|036|R|4.Walker IR, Zapf PW, Mackay IR. Cyclophosphamide, cholinesterase and|3
00252|037|R|  anaesthesia. Aust N Z J Med 1972 Aug;2(3):247-51.|3
00252|038|R|5.Dillman JB. Safe use of succinylcholine during repeated anesthetics in a|3
00252|039|R|  patient treated with cyclophosphamide. Anesth Analg 1987 Apr;66(4):351-3.|3
00253|001|T|MONOGRAPH TITLE:  Quinolones, Oral/Iron Salts, Oral (mono deleted|
00253|002|T|12/01/2011)|
00253|003|B||
00253|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00253|005|L|of severe adverse interaction.|
00253|006|B||
00253|007|A|MECHANISM OF ACTION:  Uncertain. However, decreased gastrointestinal|
00253|008|A|absorption of quinolones due to complex formation with iron salts appears to|
00253|009|A|be involved.|
00253|010|B||
00253|011|E|CLINICAL EFFECTS:  The anti-infective actions of quinolone antibiotics may|
00253|012|E|be decreased.|
00253|013|B||
00253|014|P|PREDISPOSING FACTORS:  None determined.|
00253|015|B||
00253|016|M|PATIENT MANAGEMENT:  If possible, avoid concomitant use of an oral quinolone|
00253|017|M|antibiotic and an iron salt.  If it is necessary to administer these agents|
00253|018|M|concurrently, follow the manufacturers' recommendations regarding timing of|
00253|019|M|administration of the quinolone and the iron salt.|
00253|020|M|   Manufacturer recommendations regarding the separation of administration|
00253|021|M|times of quinolones and iron salts vary. Do NOT give iron salts:|
00253|022|M|--for 6 hours before or 2 hours after ciprofloxacin.(1)|
00253|023|M|--for 3 hours before or 2 hours after gemifloxacin.(2)|
00253|024|M|--for 2 hours before or 2 hours after levofloxacin.(3)|
00253|025|M|--for 2 hours before or 2 hours after lomefloxacin.(4)|
00253|026|M|--for 8 hours before or 4 hours after moxifloxacin.(5)|
00253|027|M|--for 2 hours before or 2 hours after nalidixic acid.(6)|
00253|028|M|--for 2 hours before or 2 hours after norfloxacin.(7)|
00253|029|M|--for 2 hours before or 2 hours after ofloxacin.(8)|
00253|030|M|--for 2 hours before or 2 hours after trovafloxacin.(9)|
00253|031|B||
00253|032|D|DISCUSSION:  Current documentation is based on the effects of iron salts on|
00253|033|D|ciprofloxacin absorption. However, the interaction is also expected to occur|
00253|034|D|with other quinolone antibiotics. As much as a tenfold reduction in peak and|
00253|035|D|trough ciprofloxacin serum concentrations has been reported during|
00253|036|D|concurrent administration of ciprofloxacin and ferrous sulfate compared to|
00253|037|D|administration of ciprofloxacin alone.|
00253|038|D|   Simultaneous administration of moxifloxacin and ferrous sulfate (100 mg)|
00253|039|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
00253|040|D|moxifloxacin by 39% and 59%, respectively.(5)|
00253|041|B||
00253|042|R|REFERENCES:|
00253|043|B||
00253|044|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
00253|045|R|  Corporation February, 2011.|1
00253|046|R|2.Factive (gemifloxacin mesylate) US prescribing information. Oscient|1
00253|047|R|  Pharmaceuticals February, 2011.|1
00253|048|R|3.Levaquin (levofloxacin) US prescribing information. Ortho-McNeil|1
00253|049|R|  Pharmaceutical, Inc. February, 2011.|1
00253|050|R|4.Maxaquin (lomefloxacin hydrochloride) US prescribing information. Pfizer|1
00253|051|R|  Inc. March, 2004.|1
00253|052|R|5.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
00253|053|R|  Pharmaceuticals Corporation February, 2011.|1
00253|054|R|6.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
00253|055|R|  Inc. November, 2012.|1
00253|056|R|7.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc.|1
00253|057|R|  September, 2011.|1
00253|058|R|8.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
00253|059|R|  Pharmaceutical, Inc. February, 2011.|1
00253|060|R|9.Polk RE, Healy DP, Sahai J, Drwal L, Racht E. Effect of ferrous sulfate|2
00253|061|R|  and multivitamins with zinc on absorption of ciprofloxacin in normal|2
00253|062|R|  volunteers. Antimicrob Agents Chemother 1989 Nov;33(11):1841-4.|2
00253|063|R|10.LePennec MP, Kitzis MD, Terdjman M, Foubard S, Garbarz E, Hanania G.|3
00253|064|R|   Possible interaction of ciprofloxacin with ferrous sulphate. J Antimicrob|3
00253|065|R|   Chemother 1990 Jan;25(1):184-5.|3
00253|066|R|11.Lomaestro BM, Bailie GR. Quinolone-cation interactions: a review. DICP|6
00253|067|R|   1991 Nov;25(11):1249-58.|6
00253|068|R|12.Kara M, Hasinoff BB, McKay DW, Campbell NR. Clinical and chemical|2
00253|069|R|   interactions between iron preparations and ciprofloxacin. Br J Clin|2
00253|070|R|   Pharmacol 1991 Mar;31(3):257-61.|2
00253|071|R|13.Campbell NR, Kara M, Hasinoff BB, Haddara WM, McKay DW. Norfloxacin|2
00253|072|R|   interaction with antacids and minerals. Br J Clin Pharmacol 1992 Jan;|2
00253|073|R|   33(1):115-6.|2
00253|074|R|14.Allen A, Bygate E, Faessel H, Isaac L, Lewis A. The effect of ferrous|2
00253|075|R|   sulphate and sucralfate on the bioavailability of oral gemifloxacin in|2
00253|076|R|   healthy volunteers. Int J Antimicrob Agents 2000 Aug;15(4):283-9.|2
00254|001|T|MONOGRAPH TITLE:  Mitotane/Spironolactone|
00254|002|B||
00254|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00254|004|L|of severe adverse interaction.|
00254|005|B||
00254|006|A|MECHANISM OF ACTION:  The mechanism of this interaction has not been|
00254|007|A|established.  Spironolactone may block the action or increase the|
00254|008|A|elimination of mitotane.(1)|
00254|009|B||
00254|010|E|CLINICAL EFFECTS:  The levels and effectiveness of mitotane may be|
00254|011|E|reduced.(1-2)|
00254|012|B||
00254|013|P|PREDISPOSING FACTORS:  None determined.|
00254|014|B||
00254|015|M|PATIENT MANAGEMENT:  The manufacturer of mitotane states that concomitant|
00254|016|M|use with spironolactone should be avoided.(1)|
00254|017|M|   The Canadian and UK manufacturers of mitotane states that concomitant use|
00254|018|M|with spironolactone is contraindicated.(3-4)|
00254|019|B||
00254|020|D|DISCUSSION:  There are no pharmacokinetic studies on the concomitant use of|
00254|021|D|mitotane and spironolactone.  In a retrospective review of 54 patients on|
00254|022|D|mitotane, 14 patients who received concomitant spironolactone had|
00254|023|D|significantly lower mitotane levels despite higher doses than patients on|
00254|024|D|mitotane alone.(1-2)|
00254|025|D|   In a case report, following addition of mitotane to the treatment|
00254|026|D|schedule of a patient receiving spironolactone, the expected effects of|
00254|027|D|mitotane did not occur.  When spironolactone was stopped, the effects of|
00254|028|D|mitotane were observed.(5)|
00254|029|B||
00254|030|R|REFERENCES:|
00254|031|B||
00254|032|R|1.Lysodren (mitotane) US prescribing information. E.R. Squibb & Sons, L.L.C.|1
00254|033|R|  October, 2024.|1
00254|034|R|2.Haberbosch L, Maurer L, Sandforth A, Wernicke C, Spranger J, Mai K,|6
00254|035|R|  Jumpertz von Schwartzenberg R. Spironolactone is associated with reduced|6
00254|036|R|  mitotane levels in adrenocortical  carcinoma patients. Endocr Relat Cancer|6
00254|037|R|  2022 Feb 3;29(3):121-128.|6
00254|038|R|3.Lysodren (mitotane) CA prescribing information. HRA Pharma Rare Diseases|1
00254|039|R|  December, 2024.|1
00254|040|R|4.Lysodren (mitotane) UK prescribing information. Esteve RD UK & Ireland Ltd|1
00254|041|R|  August, 2023.|1
00254|042|R|5.Wortsman J, Soler NG. Mitotane. Spironolactone antagonism in Cushing's|3
00254|043|R|  syndrome. JAMA 1977 Dec 5;238(23):2527.|3
00255|001|T|MONOGRAPH TITLE:  Deferasirox/Aluminum Salts|
00255|002|B||
00255|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00255|004|L|of severe adverse interaction.|
00255|005|B||
00255|006|A|MECHANISM OF ACTION:  Decreased absorption of deferasirox possibly from|
00255|007|A|complex formation with the aluminum salt.|
00255|008|B||
00255|009|E|CLINICAL EFFECTS:  The therapeutic effects of deferasirox may be reduced.|
00255|010|B||
00255|011|P|PREDISPOSING FACTORS:  None determined.|
00255|012|B||
00255|013|M|PATIENT MANAGEMENT:  The manufacturer of deferasirox states patients taking|
00255|014|M|deferasirox should not take aluminum salts or aluminum-containing antacid|
00255|015|M|products.|
00255|016|B||
00255|017|D|DISCUSSION:  Simultaneous administration of deferasirox and aluminum has not|
00255|018|D|been studied.  Even though deferasirox has a lower affinity for aluminum|
00255|019|D|than iron, it should not be taken with aluminum-containing products.|
00255|020|B||
00255|021|R|REFERENCE:|
00255|022|B||
00255|023|R|1.Exjade (deferasirox) US prescribing information. Novartis Pharmaceuticals|1
00255|024|R|  Corporation July, 2019.|1
00256|001|T|MONOGRAPH TITLE:  HMG-CoA Reductase Inhibitors/Niacin (Greater Than or Equal|
00256|002|T|To 250 mg)|
00256|003|B||
00256|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00256|005|L|of severe adverse interaction.|
00256|006|B||
00256|007|A|MECHANISM OF ACTION:  Unknown.|
00256|008|B||
00256|009|E|CLINICAL EFFECTS:  Myopathy and rhabdomyolysis (muscle aches, tenderness,|
00256|010|E|and weakness) have been associated with concomitant administration of|
00256|011|E|HMG-CoA reductase inhibitors and niacin.|
00256|012|B||
00256|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
00256|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
00256|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
00256|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
00256|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
00256|018|P|transporter OATP1B1 may have increased statin concentrations and be|
00256|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
00256|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
00256|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
00256|022|B||
00256|023|M|PATIENT MANAGEMENT:  The benefit of further alterations in lipid levels with|
00256|024|M|combined use of statins and lipid-lowering dosages of niacin (<= 1000|
00256|025|M|mg/day) should be carefully weighed against the potential risks.(1-10)|
00256|026|M|   The US manufacturer of simvastatin states that dosages of niacin should|
00256|027|M|not exceed 1000 mg daily in patients of Chinese descent.(6)|
00256|028|B||
00256|029|D|DISCUSSION:  The risk of myopathy is increased during concurrent use of|
00256|030|D|HMG-CoA reductase inhibitors and niacin.(1-10)|
00256|031|D|   Concomitant administration of niacin with the immediate release|
00256|032|D|formulation of fluvastatin had no effect on fluvastatin pharmacokinetics.|
00256|033|D|Myopathy was not observed in a trial of concurrent fluvastatin and niacin in|
00256|034|D|74 patients.  Concurrent fluvastatin and niacin results in additive effects|
00256|035|D|on total cholesterol and LDL cholesterol.(9)|
00256|036|D|   In uncontrolled studies, most subjects who developed myopathy while on|
00256|037|D|lovastatin were also taking cyclosporine, gemfibrozil, or niacin.(1)|
00256|038|D|However, a systematic review showed comparable rates of adverse event|
00256|039|D|reports (AERs) including serious adverse events, hepatotoxicity, or|
00256|040|D|rhabdomyolysis for the combination of lovastatin with niacin-extended|
00256|041|D|release (ER) pill relative to either agent alone or to other statins.|
00256|042|D|Therefore, these results did not support a clinically significant adverse|
00256|043|D|drug interaction between niacin-ER and statins.(14)|
00256|044|D|   In clinical trials involving small numbers of patients, no myopathy was|
00256|045|D|reported with concurrent pravastatin and niacin.(10)|
00256|046|D|   There are case reports of myopathy during concurrent lovastatin and|
00256|047|D|niacin.(2,11,12)|
00256|048|D|   Interim HPS2 results showed a higher rate of myopathy in patients of|
00256|049|D|Chinese descent (0.43%) when compared to patients of non-Chinese descent|
00256|050|D|(0.03%) in patients taking simvastatin (40 mg) with cholesterol-lowering|
00256|051|D|doses of niacin.(7)  Kosoglou suggests that there is a small pharmacokinetic|
00256|052|D|drug interaction between ER niacin and ezetimibe/simvastatin but is not|
00256|053|D|clinically significant.(15) However, the HPS2-THRIVE showed a significant|
00256|054|D|four-fold excess risk of myopathy with the addition of ER niacin 2g plus|
00256|055|D|laropiprant 40mg daily (ERN/LRPT) to simvastatin 40mg daily (with or without|
00256|056|D|ezetimibe 10mg daily).  This additional risk is particularly prevalent among|
00256|057|D|Chinese descent versus European descent.(16)|
00256|058|D|   The AIM-HIGH trial randomized 3414 patients to receive niacin|
00256|059|D|extended-release 1500-2000 mg per day or placebo in addition to current|
00256|060|D|therapy of simvastatin 40-80 mg per day and ezetimibe 10 mg per day if|
00256|061|D|needed to achieve a goal LDL of 40-80 mg/dL.  Patients were followed for a|
00256|062|D|mean of 3 years.  The primary efficacy endpoint of composite of the first|
00256|063|D|event of death from coronary heart disease, nonfatal myocardial infarction,|
00256|064|D|ischemic stroke, hospitalization (greater than 23 hours) for an acute|
00256|065|D|coronary syndrome, or symptom-driven coronary or cerebral vascularization,|
00256|066|D|occurred in 16.4% of patients in the niacin group and 16.2% of patients in|
00256|067|D|the placebo group (p=0.80).(17)|
00256|068|D|   The HPS2-THRIVE trial randomized 25,673 patients to receive|
00256|069|D|extended-release niacin 2000 mg with laropiprant 40 mg per day or placebo in|
00256|070|D|addition to current therapy of simvastatin 40 mg per day.  Patients were|
00256|071|D|followed for a median of 3.9 years.  The primary efficacy endpoint of first|
00256|072|D|major vascular event, defined as a major coronary event (nonfatal myocardial|
00256|073|D|infarction or death from coronary causes), stroke of any type, or coronary|
00256|074|D|or noncoronary vascularization, occurred in 13.2% of patients in the|
00256|075|D|niacin-laropiprant group and 13.7% of patients in the placebo group|
00256|076|D|(p=0.29).(18)|
00256|077|D|    A post-hoc analysis of the AIM-HIGH trial showed significant lowering of|
00256|078|D|triglycerides (59 mg/dL) in the extended-release niacin (ERN) group|
00256|079|D|compared to the placebo group (20mg/dL).  High density lipoprotein levels|
00256|080|D|showed improvement in the ERN group compared to the placebo (11.3mg/dL vs.|
00256|081|D|4.7 mg/dL, respectively).  The incidence of cardiovascular disease events|
00256|082|D|was similar in both groups. However, all-cause mortality was significantly|
00256|083|D|higher in the ERN group (15.4%) versus the control group (9.2%).(19)|
00256|084|D|    A meta-analysis investigating the effects of niacin for primary and|
00256|085|D|secondary prevention of cardiovascular events suggests that niacin does not|
00256|086|D|reduce mortality or rates of myocardial infarctions or strokes.  Increased|
00256|087|D|side effects are reported with niacin.  Benefits from niacin therapy in the|
00256|088|D|prevention of cardiovascular disease events are unlikely.(20)|
00256|089|D|     The AIM HIGH trial investigated the effects of ERN added to|
00256|090|D|simvastatin/ezetimibe on glucose and insulin values.  ERN increased fasting|
00256|091|D|glucose from baseline to 1 year in patients with normal (7.9 vs 4.3 mg/dL,|
00256|092|D|respectively) and impaired fasting glucose (4.1 vs 1.4 mg/dL, respectively).|
00256|093|D|There was an increased risk of progressing from normal to impaired fasting|
00256|094|D|glucose in the ERN (58.6% cases) versus placebo (41.5% cases).(21)|
00256|095|D|   One or more of the drug pairs linked to this monograph have been included|
00256|096|D|in a list of interactions that could be considered for classification as|
00256|097|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
00256|098|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
00256|099|D|Health Information Technology.|
00256|100|B||
00256|101|R|REFERENCES:|
00256|102|B||
00256|103|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
00256|104|R|  February, 2014.|1
00256|105|R|2.Niaspan (niacin) US prescribing information. Abbott Laboratories May,|1
00256|106|R|  2022.|1
00256|107|R|3.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
00256|108|R|  2020.|1
00256|109|R|4.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
00256|110|R|  America, Inc. November, 2022.|1
00256|111|R|5.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
00256|112|R|  Pharmaceuticals LP July, 2024.|1
00256|113|R|6.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
00256|114|R|  2023.|1
00256|115|R|7.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
00256|116|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
00256|117|R|8.USFood and Drug Administration. FDA Drug Safety Communication:  Ongoing|1
00256|118|R|  safety review of high-dose Zocor (simvastatin) and increased risk of|1
00256|119|R|  muscle injury. available at:|1
00256|120|R|  http://wayback.archive-it.org/7993/20170112165500/http://www.fda.gov/Safet|1
00256|121|R|  y/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm205404|1
00256|122|R|  .htm March 19, 2010.|1
00256|123|R|9.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
00256|124|R|  Pharmaceuticals Corporation August, 2017.|1
00256|125|R|10.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
00256|126|R|   Squibb Company May, 2022.|1
00256|127|R|11.Norman DJ, Illingworth DR, Munson J, Hosenpud J. Myolysis and acute renal|3
00256|128|R|   failure in a heart-transplant recipient receiving lovastatin. N Engl J|3
00256|129|R|   Med 1988 Jan 7;318(1):46-7.|3
00256|130|R|12.Reaven P, Witztum JL. Lovastatin, nicotinic acid, and rhabdomyolysis. Ann|3
00256|131|R|   Intern Med 1988 Oct 1;109(7):597-8.|3
00256|132|R|13.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
00256|133|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
00256|134|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
00256|135|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
00256|136|R|14.Alsheikh-Ali AA, Karas RH. Safety of lovastatin/extended release niacin|2
00256|137|R|   compared with lovastatin alone, atorvastatin alone, pravastatin alone,|2
00256|138|R|   and simvastatin alone (from the United States Food and Drug|2
00256|139|R|   Administration adverse event reporting system). Am J Cardiol 2007 Feb 1;|2
00256|140|R|   99(3):379-81.|2
00256|141|R|15.Kosoglou T, Zhu Y, Statkevich P, Triantafyllou I, Taggart W, Xuan F, Kim|2
00256|142|R|   KT, Cutler DL. Assessment of potential pharmacokinetic interactions of|2
00256|143|R|   ezetimibe/simvastatin and extended-release niacin tablets in healthy|2
00256|144|R|   subjects. Eur J Clin Pharmacol 2011 May;67(5):483-92.|2
00256|145|R|16.HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk|2
00256|146|R|   patients of ER niacin/laropiprant: trial design, pre-specified muscle and|2
00256|147|R|   liver outcomes, and reasons for stopping study treatment. Eur Heart J|2
00256|148|R|   2013 May;34(17):1279-91.|2
00256|149|R|17.Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P,|2
00256|150|R|   Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low|2
00256|151|R|   HDL cholesterol levels receiving intensive statin therapy. N Engl J Med|2
00256|152|R|   2011 Dec 15;365(24):2255-67.|2
00256|153|R|18.Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J,|2
00256|154|R|   Wallendszus K, Craig M, Jiang L, Collins R, Armitage J. Effects of|2
00256|155|R|   extended-release niacin with laropiprant in high-risk patients. N Engl J|2
00256|156|R|   Med 2014 Jul 17;371(3):203-12.|2
00256|157|R|19.Kalil RS, Wang JH, de Boer IH, Mathew RO, Ix JH, Asif A, Shi X, Boden WE.|2
00256|158|R|   Effect of extended-release niacin on cardiovascular events and kidney|2
00256|159|R|   function in  chronic kidney disease: a post hoc analysis of the AIM-HIGH|2
00256|160|R|   trial. Kidney Int 2015 Jun;87(6):1250-7.|2
00256|161|R|20.Schandelmaier S, Briel M, Saccilotto R, Olu KK, Arpagaus A, Hemkens LG,|6
00256|162|R|   Nordmann AJ. Niacin for primary and secondary prevention of|6
00256|163|R|   cardiovascular events. Cochrane Database Syst Rev 2017 Jun 14;|6
00256|164|R|   6(6):CD009744.|6
00256|165|R|21.Goldberg RB, Bittner VA, Dunbar RL, Fleg JL, Grunberger G, Guyton JR,|2
00256|166|R|   Leiter LA, McBride R, Robinson JG, Simmons DL, Wysham C, Xu P, Boden WE.|2
00256|167|R|   Effects of Extended-Release Niacin Added to Simvastatin/Ezetimibe on|2
00256|168|R|   Glucose and  Insulin Values in AIM-HIGH. Am J Med 2016 Jul;|2
00256|169|R|   129(7):753.e13-22.|2
00257|001|T|MONOGRAPH TITLE:  Methotrexate (Oncology-Injection)/Procarbazine (mono|
00257|002|T|deleted 11/07/2025)|
00257|003|B||
00257|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00257|005|L|of severe adverse interaction.|
00257|006|B||
00257|007|A|MECHANISM OF ACTION:  Unknown.|
00257|008|B||
00257|009|E|CLINICAL EFFECTS:  Impaired renal function may occur.|
00257|010|B||
00257|011|P|PREDISPOSING FACTORS:  None determined.|
00257|012|B||
00257|013|M|PATIENT MANAGEMENT:  Separate the last dose of procarbazine from the|
00257|014|M|initiation of high-dose methotrexate infusion by at least 72 hours.|
00257|015|B||
00257|016|D|DISCUSSION:  Documentation consists of three case histories.  Nephrotoxicity|
00257|017|D|developed in 3 of the first 4 patients with brain tumors during treatment|
00257|018|D|with a new protocol which included procarbazine(100 mg/meter-squared on days|
00257|019|D|1-14) and high-dose methotrexate (2 grams/meter-squared x 3 doses on days|
00257|020|D|15, 22, 29).  No patient had received prior chemotherapy and all patients|
00257|021|D|had normal renal function prior to chemotherapy.  Other side effects did not|
00257|022|D|increase in severity or frequency during concomitant use of these drugs.  A|
00257|023|D|previous protocol in three patients used the same chemotherapy agents and|
00257|024|D|doses but began methotrexate 4 days after the completion of procarbazine;|
00257|025|D|none of these patients developed renal impairment.  Although high-dose|
00257|026|D|methotrexate alone can cause nephrotoxicity the temporal association between|
00257|027|D|administration and the onset of impaired renal function raises the|
00257|028|D|possibility of a drug interaction.(1)|
00257|029|B||
00257|030|R|REFERENCE:|
00257|031|B||
00257|032|R|1.Price P, Thompson H, Bessell EM, Bloom HJ. Renal impairment following the|6
00257|033|R|  combined use of high-dose methotrexate and procarbazine. Cancer Chemother|6
00257|034|R|  Pharmacol 1988;21(3):265-7.|6
00258|001|T|MONOGRAPH TITLE:  Cyclosporine/Calcium Channel Blockers|
00258|002|B||
00258|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00258|004|L|take action as needed.|
00258|005|B||
00258|006|A|MECHANISM OF ACTION:  Calcium channel blockers may inhibit the metabolism of|
00258|007|A|cyclosporine by CYP3A4.|
00258|008|B||
00258|009|E|CLINICAL EFFECTS:  Concurrent use of calcium channel blockers may result in|
00258|010|E|elevated levels of and toxicity from cyclosporine.|
00258|011|B||
00258|012|P|PREDISPOSING FACTORS:  None determined.|
00258|013|B||
00258|014|M|PATIENT MANAGEMENT:  Monitor cyclosporine levels when initiating or|
00258|015|M|discontinuing calcium channel blockers.|
00258|016|B||
00258|017|D|DISCUSSION:  Concurrent administration of cyclosporine and amlodipine,|
00258|018|D|diltiazem, nicardipine, or verapamil has caused elevated cyclosporine|
00258|019|D|levels.  Renal toxicity was seen in some cases.  Upon discontinuation of the|
00258|020|D|calcium channel blocker, cyclosporine concentrations have returned to|
00258|021|D|baseline levels.  With concurrent diltiazem administration, cyclosporine|
00258|022|D|dosage decreases of 15% to 48% were required.|
00258|023|D|   A prospective study in 11 renal transplant patients showed a 40% increase|
00258|024|D|in trough cyclosporine levels when given concomitantly with amlodipine.(29)|
00258|025|B||
00258|026|R|REFERENCES:|
00258|027|B||
00258|028|R|1.Wagner K, Neumayer HH. Prevention of delayed graft function in cadaver|3
00258|029|R|  kidney transplants by diltiazem. Lancet 1985 Dec 14;2(8468):1355-6.|3
00258|030|R|2.Pochet JM, Pirson Y. Cyclosporin-diltiazem interaction. Lancet 1986 Apr|3
00258|031|R|  26;1(8487):979.|3
00258|032|R|3.Grino JM, Sabate I, Castelao AM, Alsina J. Influence of diltiazem on|3
00258|033|R|  cyclosporin clearance. Lancet 1986 Jun 14;1(8494):1387.|3
00258|034|R|4.Bourbigot B, Guiserix J, Airiau J, Bressollette L, Morin JF, Cledes J.|3
00258|035|R|  Nicardipine increases cyclosporin blood levels. Lancet 1986 Jun 21;|3
00258|036|R|  1(8495):1447.|3
00258|037|R|5.Neumayer HH, Wagner K. Diltiazem and economic use of cyclosporin. Lancet|3
00258|038|R|  1986 Aug 30;2(8505):523.|3
00258|039|R|6.Lindholm A, Henricsson S. Verapamil inhibits cyclosporin metabolism.|3
00258|040|R|  Lancet 1987 May 30;1(8544):1262-3.|3
00258|041|R|7.Cantarovich M, Hiesse C, Lockiec F, Charpentier B, Fries D. Confirmation|3
00258|042|R|  of the interaction between cyclosporine and the calcium channel blocker|3
00258|043|R|  nicardipine in renal transplant patients. Clin Nephrol 1987 Oct;|3
00258|044|R|  28(4):190-3.|3
00258|045|R|8.Maggio TG, Bartels DW. Increased cyclosporine blood concentrations due to|3
00258|046|R|  verapamil administration. Drug Intell Clin Pharm 1988 Sep;22(9):705-7.|3
00258|047|R|9.Wagner K, Henkel M, Heinemeyer G, Neumayer HH. Interaction of calcium|2
00258|048|R|  blockers and cyclosporine. Transplant Proc 1988 Apr;20(2 Suppl 2):561-8.|2
00258|049|R|10.Henricsson S, Lindholm A. Inhibition of cyclosporine metabolism by other|5
00258|050|R|   drugs in vitro. Transplant Proc 1988 Apr;20(2 Suppl 2):569-71.|5
00258|051|R|11.Kohlhaw K, Wonigeit K, Frei U, Oldhafer K, Neumann K, Pichlmayr R. Effect|2
00258|052|R|   of the calcium channel blocker diltiazem on cyclosporine A blood levels|2
00258|053|R|   and dose requirements. Transplant Proc 1988 Apr;20(2 Suppl 2):572-4.|2
00258|054|R|12.Kessler M, Netter P, Renoult E, Jonon B, Mur JM, Trechot P, Dousset B.|2
00258|055|R|   Influence of nicardipine on renal function and plasma cyclosporin in|2
00258|056|R|   renal transplant patients. Eur J Clin Pharmacol 1989;36(6):637-8.|2
00258|057|R|13.McNally P, Mistry N, Idle J, Walls J, Feehally J. Calcium channel|3
00258|058|R|   blockers and cyclosporine metabolism. Transplantation 1989 Dec;|3
00258|059|R|   48(6):1071.|3
00258|060|R|14.McFadden JP, Pontin JE, Powles AV, Fry L, Idle JR. Cyclosporin decreases|3
00258|061|R|   nifedipine metabolism. BMJ 1989 Nov 11;299(6709):1224.|3
00258|062|R|15.Kelly JJ, Walker RG, d'Apice AJ, Kincaid-Smith P. A prospective study of|2
00258|063|R|   the effect of diltiazem in renal allograft recipients receiving|2
00258|064|R|   cyclosporine A: preliminary results. Transplant Proc 1990 Oct;|2
00258|065|R|   22(5):2127-8.|2
00258|066|R|16.Tortorice KL, Heim-Duthoy KL, Awni WM, Rao KV, Kasiske BL. The effects of|2
00258|067|R|   calcium channel blockers on cyclosporine and its metabolites in renal|2
00258|068|R|   transplant recipients. Ther Drug Monit 1990 Jul;12(4):321-8.|2
00258|069|R|17.Bourge RC, Kirklin JK, Naftel DC, Figg WD, White-Williams C, Ketchum C.|2
00258|070|R|   Diltiazem-cyclosporine interaction in cardiac transplant recipients:|2
00258|071|R|   impact on cyclosporine dose and medication costs. Am J Med 1991 Mar;|2
00258|072|R|   90(3):402-4.|2
00258|073|R|18.Dy GR, Raja RM, Mendez MM. The clinical and biochemical effect of calcium|2
00258|074|R|   channel blockers in organ transplant recipients on cyclosporine.|2
00258|075|R|   Transplant Proc 1991 Feb;23(1 Pt 2):1258-9.|2
00258|076|R|19.Tenschert W, Harfmann P, Meyer-Moldenhauer WH, Arndt R, Klosterhalfen H.|2
00258|077|R|   Kidney protective effect of diltiazem after renal transplantation with|2
00258|078|R|   long cold ischemia time and triple-drug immunosuppression. Transplant|2
00258|079|R|   Proc 1991 Feb;23(1 Pt 2):1334-5.|2
00258|080|R|20.Endresen L, Bergan S, Holdaas H, Pran T, Sinding-Larsen B, Berg KJ. Lack|2
00258|081|R|   of effect of the calcium antagonist isradipine on cyclosporine|2
00258|082|R|   pharmacokinetics in renal transplant patients. Ther Drug Monit 1991 Nov;|2
00258|083|R|   13(6):490-5.|2
00258|084|R|21.Kunzendorf U, Walz G, Brockmoeller J, Neumayer HH, Jochimsen F, Roots I,|2
00258|085|R|   Offermann G, Strom TB. Effects of diltiazem upon metabolism and|2
00258|086|R|   immunosuppressive action of cyclosporine in kidney graft recipients.|2
00258|087|R|   Transplantation 1991 Aug;52(2):280-4.|2
00258|088|R|22.Chagnac A, Zevin D, Ori Y, Korzets A, Hirsh J, Levi J. The effect of|2
00258|089|R|   high-dose nifedipine on renal hemodynamics of cyclosporine-treated renal|2
00258|090|R|   allograft recipients. Transplantation 1992 Apr;53(4):766-9.|2
00258|091|R|23.Leibbrandt DM, Day RO. Cyclosporin and calcium channel blockers: an|6
00258|092|R|   exploitable drug interaction?. Med J Aust 1992 Sep 7;157(5):296-7.|6
00258|093|R|24.Chrysostomou A, Walker RG, Russ GR, d'Apice AJ, Kincaid-Smith P, Mathew|2
00258|094|R|   TH. Diltiazem in renal allograft recipients receiving cyclosporine.|2
00258|095|R|   Transplantation 1993 Feb;55(2):300-4.|2
00258|096|R|25.Kuzuya T, Kobayashi T, Moriyama N, Nagasaka T, Yokoyama I, Uchida K,|2
00258|097|R|   Nakao A, Nabeshima T. Amlodipine, but not MDR1 polymorphisms, alters the|2
00258|098|R|   pharmacokinetics of cyclosporine A in Japanese kidney transplant|2
00258|099|R|   recipients. Transplantation 2003 Sep 15;76(5):865-8.|2
00258|100|R|26.Pesavento TE, Jones PA, Julian BA, Curtis JJ. Amlodipine increases|2
00258|101|R|   cyclosporine levels in hypertensive renal transplant patients: results of|2
00258|102|R|   a prospective study. J Am Soc Nephrol 1996 Jun;7(6):831-5.|2
00258|103|R|27.Sennesael J, Lamote J, Violet I, Tasse S, Verbeelen D. Comparison of|2
00258|104|R|   perindopril and amlodipine in cyclosporine-treated renal allograft|2
00258|105|R|   recipients. Hypertension 1995 Sep;26(3):436-44.|2
00258|106|R|28.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
00258|107|R|   information. Abbott Pharmaceuticals, Inc. November, 2016.|1
00258|108|R|29.Norvasc (amlodipine) US Prescribing Information. Pfizer Labs October,|1
00258|109|R|   2017.|1
00259|001|T|MONOGRAPH TITLE:  Aminoglutethimide/Dexamethasone|
00259|002|B||
00259|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00259|004|L|take action as needed.|
00259|005|B||
00259|006|A|MECHANISM OF ACTION:  Unknown. However, aminoglutethimide appears to induce|
00259|007|A|hepatic microsomal enzymes, thereby reducing the bioavailability of|
00259|008|A|dexamethasone.|
00259|009|B||
00259|010|E|CLINICAL EFFECTS:  Loss of dexamethasone-induced adrenal suppression,|
00259|011|E|leading to unsuccessful aminoglutethimide adrenalectomy.|
00259|012|B||
00259|013|P|PREDISPOSING FACTORS:  None determined.|
00259|014|B||
00259|015|M|PATIENT MANAGEMENT:  Increase doses of dexamethasone may be required.|
00259|016|M|Monitor dexamethasone response when altering the dose of aminoglutethimide.|
00259|017|B||
00259|018|D|DISCUSSION:  In patients with metastatic breast cancer treated with|
00259|019|D|dexamethasone and aminoglutethimide, a decrease in dexamethasone half-life|
00259|020|D|was observed during aminoglutethimide administration. To achieve successful|
00259|021|D|adrenalectomy without loss of adrenal suppression a two- to three-fold|
00259|022|D|increase in corticosteroid dosage was required. This interaction was not|
00259|023|D|observed with concomitant administration of hydrocortisone and|
00259|024|D|aminoglutethimide. Aminoglutethimide is derived from glutethimide. Therefore|
00259|025|D|glutethimide may be expected to interact with dexamethasone.|
00259|026|B||
00259|027|R|REFERENCES:|
00259|028|B||
00259|029|R|1.Lipton A, Santen RJ. Proceedings: Medical adrenalectomy using|2
00259|030|R|  aminoglutethimide and dexamethasone in advanced breast cancer. Cancer 1974|2
00259|031|R|  Feb;33(2):503-12.|2
00259|032|R|2.Santen RJ, Lipton A, Kendall J. Successful medical adrenalectomy with|2
00259|033|R|  amino-glutethimide. Role of altered drug metabolism. JAMA 1974 Dec 23-30;|2
00259|034|R|  230(12):1661-5.|2
00259|035|R|3.Santen RJ, Wells SA, Runic S, Gupta C, Kendall J, Rudy EB, Samojlik E.|2
00259|036|R|  Adrenal suppression with aminoglutethimide. I. Differential e-fects of|2
00259|037|R|  aminoglutethimide on glucocorticoid metabolism as a rationale for use of|2
00259|038|R|  hydrocortisone. J Clin Endocrinol Metab 1977 Sep;45(3):469-79.|2
00259|039|R|4.Halpern J, Catane R, Baerwald H. A call for caution in the use of|3
00259|040|R|  aminoglutethimide: negative interactions with dexamethasone and beta|3
00259|041|R|  blocker treatment. J Med 1984;15(1):59-63.|3
00259|042|R|5.Kvinssland S, Lonning PE, Ueland PM. Aminoglutethimide as an inducer of|6
00259|043|R|  microsomal enzymes. Part 1: Pharmacological aspects. Breast Cancer Res|6
00259|044|R|  Treat 1986;7 Suppl:S73-6.|6
00260|001|T|MONOGRAPH TITLE:  Sulfonylureas/Diazoxide|
00260|002|B||
00260|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00260|004|L|take action as needed.|
00260|005|B||
00260|006|A|MECHANISM OF ACTION:  Unknown.|
00260|007|B||
00260|008|E|CLINICAL EFFECTS:  In a patient stabilized on a sulfonylurea hypoglycemic|
00260|009|E|agent, hyperglycemia may occur following the addition of diazoxide to the|
00260|010|E|treatment.|
00260|011|B||
00260|012|P|PREDISPOSING FACTORS:  None determined.|
00260|013|B||
00260|014|M|PATIENT MANAGEMENT:  Monitor blood glucose and adjust the dose of the|
00260|015|M|sulfonylurea hypoglycemic agent as needed.|
00260|016|B||
00260|017|D|DISCUSSION:  The concurrent administration of a sulfonylurea hypoglycemic|
00260|018|D|agent and diazoxide has been beneficial in treating chlorpropamide-induced|
00260|019|D|hypoglycemia and diazoxide-induced hyperglycemia. These reports indicate a|
00260|020|D|potential problem if these agents are administered without proper monitoring|
00260|021|D|of the patient's blood glucose.|
00260|022|B||
00260|023|R|REFERENCES:|
00260|024|B||
00260|025|R|1.Wolff F. Diazoxide hyperglycaemia and its continued relief by tolbutamide.|5
00260|026|R|  Lancet 1964 Feb 8;1:309-10.|5
00260|027|R|2.Wales JK, Grant AM, Wolff FW. Reversal of diazoxide effects by|5
00260|028|R|  tolbutamide. Lancet 1967 May 27;1(7500):1137-8.|5
00260|029|R|3.Johnson SF, Schade DS, Peake GT. Chlorpropamide-induced hypoglycemia:|3
00260|030|R|  successful treatment with diazoxide. Am J Med 1977 Nov;63(5):799-804.|3
00260|031|R|4.Pfeifer MA, Wolter CF, Samols E. Management of chlorpropamide-induced|3
00260|032|R|  hypoglycemia with diazoxide. South Med J 1978 May;71(5):606-8.|3
00260|033|R|5.Jeffery WH, Graham EM. Treatment of chlorpropamide overdose with|3
00260|034|R|  diazoxide. Drug Intell Clin Pharm 1983 May;17(5):372-4.|3
00261|001|T|MONOGRAPH TITLE:  Methotrexate; Pralatrexate/Sulfonamide Antibacterials;|
00261|002|T|Trimethoprim|
00261|003|B||
00261|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00261|005|L|of severe adverse interaction.|
00261|006|B||
00261|007|A|MECHANISM OF ACTION:  Sulfonamide antibacterials and/or trimethoprim may|
00261|008|A|decrease the renal clearance of methotrexate and pralatrexate or produce a|
00261|009|A|synergistically-induced folate deficiency.  Sulfonamide antibacterials|
00261|010|A|and/or trimethoprim may decrease protein binding of methotrexate.|
00261|011|B||
00261|012|E|CLINICAL EFFECTS:  Concurrent use of sulfonamide antibacterials and/or|
00261|013|E|trimethoprim may increase levels of and toxicity from methotrexate and|
00261|014|E|pralatrexate, leading to increased risk of severe neurotoxicity, stomatitis,|
00261|015|E|and myelosuppression, including neutropenia.|
00261|016|B||
00261|017|P|PREDISPOSING FACTORS:  Risk factors for methotrexate or pralatrexate|
00261|018|P|toxicity include:|
00261|019|P|- High-dose oncology regimens|
00261|020|P|- Impaired renal function, ascites, or pleural effusions|
00261|021|B||
00261|022|M|PATIENT MANAGEMENT:  Concurrent use of sulfonamide antibiotics or|
00261|023|M|trimethoprim with methotrexate or pralatrexate should be avoided.  If|
00261|024|M|coadministration cannot be avoided, closely monitor patients who are|
00261|025|M|receiving concurrent therapy or patients who have recently finished|
00261|026|M|methotrexate or pralatrexate therapy and who are beginning sulfonamide|
00261|027|M|therapy for signs of toxicity, including bone marrow suppression,|
00261|028|M|pancytopenia, thrombocytopenia, and stomatitis.|
00261|029|B||
00261|030|D|DISCUSSION:  In one study in pediatric leukemia patients, concurrent|
00261|031|D|administration of methotrexate and trimethoprim-sulfamethoxazole resulted in|
00261|032|D|an increase in free methotrexate and a decrease in free methotrexate|
00261|033|D|clearance.  These changes resulted in a 66% increase in systemic exposure to|
00261|034|D|methotrexate, although there were no significant changes in total|
00261|035|D|methotrexate clearance or methotrexate half-life.  In another study in|
00261|036|D|pediatric leukemia patients, concurrent therapy with methotrexate and|
00261|037|D|trimethoprim-sulfamethoxazole did not alter the intestinal absorption,|
00261|038|D|degree of plasma protein binding, or average concentration of methotrexate.|
00261|039|D|Case reports have documented methotrexate toxicities such as bone marrow|
00261|040|D|hypoplasia, pancytopenia, thrombocytopenia, and stomatitis during concurrent|
00261|041|D|therapy and during therapy with trimethoprim-sulfamethoxazole following the|
00261|042|D|conclusion of methotrexate therapy.  Some of these reports involved patients|
00261|043|D|receiving low-dose methotrexate for rheumatoid arthritis. Methotrexate|
00261|044|D|plasma protein binding and renal clearance  have been shown to be decreased|
00261|045|D|by the concurrent administration of sulfisoxazole.|
00261|046|D|   In a retrospective cohort study of 3204 adults taking low-dose|
00261|047|D|methotrexate, the risk of all-cause hospitalization (Risk Ratio (RR) 1.49|
00261|048|D|(95% Confidence Interval (CI) 1.13-1.97) and infection (RR 2.78 (95% CI 1.30|
00261|049|D|- 5.95)) was higher in adults treated with trimethoprim-sulfamethoxazole|
00261|050|D|(n=1602) than those treated with cephalosporins (n=1602).|
00261|051|D|   This interaction has also been reported in patients receiving concurrent|
00261|052|D|methotrexate and trimethoprim without concurrent sulfamethoxazole.|
00261|053|B||
00261|054|R|REFERENCES:|
00261|055|B||
00261|056|R|1.Kobrinsky NL, Ramsay NK. Acute megaloblastic anemia induced by high-dose|3
00261|057|R|  trimethoprim- sulfamethoxazole. Ann Intern Med 1981 Jun;94(6):780-1.|3
00261|058|R|2.Dan M, Shapira I. Possible role of methotrexate in|3
00261|059|R|  trimethoprim-sulfamethoxazole-induced acute megaloblastic anemia. Isr J|3
00261|060|R|  Med Sci 1984 Mar;20(3):262-3.|3
00261|061|R|3.Thomas MH, Gutterman LA. Methotrexate toxicity in a patient receiving|3
00261|062|R|  trimethoprim- sulfamethoxazole. J Rheumatol 1986 Apr;13(2):440-1.|3
00261|063|R|4.Maricic M, Davis M, Gall EP. Megaloblastic pancytopenia in a patient|3
00261|064|R|  receiving concurrent methotrexate and trimethoprim-sulfamethoxazole|3
00261|065|R|  treatment. Arthritis Rheum 1986 Jan;29(1):133-5.|3
00261|066|R|5.Frain JB. Methotrexate toxicity in a patient receiving trimethoprim-|3
00261|067|R|  sulfamethoxazole. J Rheumatol 1987 Feb;14(1):176-7.|3
00261|068|R|6.Ng HW, Macfarlane AW, Graham RM, Verbov JL. Near fatal drug interactions|3
00261|069|R|  with methotrexate given for psoriasis. Br Med J (Clin Res Ed) 1987 Sep 26;|3
00261|070|R|  295(6601):752-3.|3
00261|071|R|7.Groenendal H, Rampen FH. Methotrexate and|3
00261|072|R|  trimethoprim-sulphamethoxazole--a potentially hazardous combination. Clin|3
00261|073|R|  Exp Dermatol 1990 Sep;15(5):358-60.|3
00261|074|R|8.Govert JA, Patton S, Fine RL. Pancytopenia from using trimethoprim and|3
00261|075|R|  methotrexate. Ann Intern Med 1992 Nov 15;117(10):877-8.|3
00261|076|R|9.Beach BJ, Woods WG, Howell SB. Influence of co-trimoxazole on methotrexate|2
00261|077|R|  pharmacokinetics in children with acute lymphoblastic leukemia. Am J|2
00261|078|R|  Pediatr Hematol Oncol 1981 Summer;3(2):115-9.|2
00261|079|R|10.Liegler DG, Henderson ES, Hahn MA, Oliverio VT. The effect of organic|2
00261|080|R|   acids on renal clearance of methotrexate in man. Clin Pharmacol Ther 1969|2
00261|081|R|   Nov-Dec;10(6):849-57.|2
00261|082|R|11.el-Tamtamy S. Letter: Co-trimoxazole and the blood. Lancet 1974 May 11;|3
00261|083|R|   1(7863):929-30.|3
00261|084|R|12.Bernstein LS. Adverse reactions to trimethoprim-sulfamethoxazole, with|6
00261|085|R|   particular reference to long-term therapy. Can Med Assoc J 1975 Jun 14;|6
00261|086|R|   112(13 Spec No):96-8.|6
00261|087|R|13.Haagsma CJ, van Riel PL, de Rooij DJ, Vree TB, Russel FJ, van't Hof MA,|2
00261|088|R|   van de Putte LB. Combination of methotrexate and sulphasalazine vs|2
00261|089|R|   methotrexate alone: a randomized open clinical trial in rheumatoid|2
00261|090|R|   arthritis patients resistant to sulphasalazine therapy. Br J Rheumatol|2
00261|091|R|   1994 Nov;33(11):1049-55.|2
00261|092|R|14.Ferrazzini G, Klein J, Sulh H, Chung D, Griesbrecht E, Koren G.|2
00261|093|R|   Interaction between trimethoprim-sulfamethoxazole and methotrexate in|2
00261|094|R|   children with leukemia. J Pediatr 1990 Nov;117(5):823-6.|2
00261|095|R|15.Steuer A, Gumpel JM. Methotrexate and trimethoprim: a fatal interaction.|3
00261|096|R|   Br J Rheumatol 1998 Jan;37(1):105-6.|3
00261|097|R|16.Folotyn (pralatrexate) US prescribing information. Allos Therapeutics,|1
00261|098|R|   Inc. May, 2016.|1
00261|099|R|17.Sadeghi H, Ahmadi F, McArthur E, Sontrop JM, Abdullah SS, Urquhart BL,|6
00261|100|R|   Kim RB, Muanda FT. Co-prescription of low-dose methotrexate and|6
00261|101|R|   trimethoprim-sulfamethoxazole and the 30-day risk of death among older|6
00261|102|R|   adults: A cohort study. Br J Clin Pharmacol. 2024;1-9.|6
00262|001|T|MONOGRAPH TITLE:  Disopyramide/Selected Macrolides|
00262|002|B||
00262|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00262|004|L|of severe adverse interaction.|
00262|005|B||
00262|006|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
00262|007|A|disopyramide at CYP3A4.(1-6)|
00262|008|B||
00262|009|E|CLINICAL EFFECTS:  Serum disopyramide concentrations may be increased,|
00262|010|E|leading to cardiac arrhythmias including QT prolongation or torsades de|
00262|011|E|pointes.|
00262|012|B||
00262|013|P|PREDISPOSING FACTORS:  Renal and hepatic impairment may increase risk for|
00262|014|P|excessive QTc prolongation as disopyramide is eliminated renally and|
00262|015|P|hepatically. To prevent increased serum levels and risk for ventricular|
00262|016|P|arrhythmias, disopyramide must be dose adjusted in renal and hepatic|
00262|017|P|insufficiency.|
00262|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
00262|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
00262|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
00262|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
00262|022|P|advanced age.(10)|
00262|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00262|024|P|higher systemic concentrations of either QT prolonging drug are additional|
00262|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00262|026|P|drug concentrations include rapid infusion of an intravenous dose or|
00262|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00262|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00262|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(10)|
00262|030|B||
00262|031|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with disopyramide|
00262|032|M|and a macrolide antibiotic that inhibits CYP3A4 should be monitored for|
00262|033|M|changes in cardiac status. The dosage of disopyramide may need to be|
00262|034|M|adjusted.|
00262|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00262|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00262|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00262|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00262|039|B||
00262|040|D|DISCUSSION:  There have been three reports of life-threatening cardiac|
00262|041|D|arrhythmias and one report of severe hypoglycemia and prolonged QTc interval|
00262|042|D|when clarithromycin was added to disopyramide therapy.(1-3,7)  There have|
00262|043|D|been two reports of life-threatening cardiac arrhythmias when erythromycin|
00262|044|D|was added to disopyramide.(4)  The patients had been well controlled on|
00262|045|D|disopyramide alone.  In the cases of cardiac arrhythmias, increased|
00262|046|D|disopyramide concentrations, prolonged QT interval and ventricular|
00262|047|D|tachycardia were observed when the macrolide was added to their treatment.|
00262|048|D|   Erythromycin(5) and troleandomycin(6) have been shown to inhibit|
00262|049|D|disopyramide metabolism in vitro.|
00262|050|D|   Azithromycin has been shown not to inhibit CYP3A4.(8)|
00262|051|B||
00262|052|R|REFERENCES:|
00262|053|B||
00262|054|R|1.Hayashi Y, Ikeda U, Hashimoto T, Watanabe T, Mitsuhashi T, Shimada K.|3
00262|055|R|  Torsades de pointes ventricular tachycardia induced by clarithromycin and|3
00262|056|R|  disopyramide in the presence of hypokalemia. Pacing Clin Electrophysiol|3
00262|057|R|  1999 Apr;22(4 Pt 1):672-4.|3
00262|058|R|2.Iida H, Morita T, Suzuki E, Iwasawa K, Toyo-oka T, Nakajima T.|3
00262|059|R|  Hypoglycemia induced by interaction between clarithromycin and|3
00262|060|R|  disopyramide. Jpn Heart J 1999 Jan;40(1):91-6.|3
00262|061|R|3.Paar D, Terjung B, Sauerbruch T. Life-threatening interaction between|3
00262|062|R|  clarithromycin and disopyramide. Lancet 1997 Feb 1;349(9048):326-7.|3
00262|063|R|4.Ragosta M, Weihl AC, Rosenfeld LE. Potentially fatal interaction between|3
00262|064|R|  erythromycin and disopyramide. Am J Med 1989 Apr;86(4):465-6.|3
00262|065|R|5.Echizen H, Kawasaki H, Chiba K, Tani M, Ishizaki T. A potent inhibitory|5
00262|066|R|  effect of erythromycin and other macrolide antibiotics on the|5
00262|067|R|  mono-N-dealkylation metabolism of disopyramide with human liver|5
00262|068|R|  microsomes. J Pharmacol Exp Ther 1993 Mar;264(3):1425-31.|5
00262|069|R|6.Echizen H, Tanizaki M, Tatsuno J, Chiba K, Berwick T, Tani M, Gonzalez FJ,|5
00262|070|R|  Ishizaki T. Identification of CYP3A4 as the enzyme involved in the|5
00262|071|R|  mono-N-dealkylation of disopyramide enantiomers in humans. Drug Metab|5
00262|072|R|  Dispos 2000 Aug;28(8):937-44.|5
00262|073|R|7.Choudhury L, Grais IM, Passman RS. Torsades de pointes due to drug|3
00262|074|R|  interaction between disopyramide and clarithromycin. Heart Dis 1999|3
00262|075|R|  Sep-Oct;1(4):206-7.|3
00262|076|R|8.Norpace (disopyramide phosphate) US prescribing information. Pfizer Inc.|1
00262|077|R|  December, 2020.|1
00262|078|R|9.Amacher DE, Schomaker SJ, Retsema JA. Comparison of the effects of the new|5
00262|079|R|  azalide antibiotic, azithromycin, and erythromycin estolate on rat liver|5
00262|080|R|  cytochrome P-450. Antimicrob Agents Chemother 1991 Jun;35(6):1186-90.|5
00262|081|R|10.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
00262|082|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
00262|083|R|   hospital settings: a scientific statement from the American Heart|6
00262|084|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
00262|085|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
00263|001|T|MONOGRAPH TITLE:  Amiodarone/Diltiazem; Verapamil|
00263|002|B||
00263|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00263|004|L|of severe adverse interaction.|
00263|005|B||
00263|006|A|MECHANISM OF ACTION:  Concomitant use of amiodarone with diltiazem or|
00263|007|A|verapamil can contribute to depressant effects on the sinus and|
00263|008|A|atrioventricular node and decreased contractility which can potentiate the|
00263|009|A|electrophysiologic and hemodynamic effects of amiodarone.  Diltiazem and|
00263|010|A|verapamil may also increase amiodarone concentrations through CYP3A4|
00263|011|A|inhibition. Therefore, the effects of these drugs on the heart may be|
00263|012|A|additive.(1-2)|
00263|013|B||
00263|014|E|CLINICAL EFFECTS:  Life-threatening effects, including bradycardia, sinus|
00263|015|E|arrest and atrioventricular blockade may occur.|
00263|016|B||
00263|017|P|PREDISPOSING FACTORS:  None determined.|
00263|018|B||
00263|019|M|PATIENT MANAGEMENT:  Carefully monitor patients for cardiac toxicity during|
00263|020|M|combined treatment with amiodarone and diltiazem or verapamil.|
00263|021|B||
00263|022|D|DISCUSSION:  In a single case report, a 61-year-old female patient developed|
00263|023|D|sinus arrest and low cardiac output with decreased urination when amiodarone|
00263|024|D|was added to her treatment regimen of diltiazem and furosemide.  After|
00263|025|D|discontinuing diltiazem and amiodarone, the patient was successfully treated|
00263|026|D|with ventricular pacing and pressor agents. The patient was later managed|
00263|027|D|successfully with furosemide and amiodarone.(3)|
00263|028|D|   In a study, with severe sinus node dysfunction who were all taking|
00263|029|D|diltiazem, six were concomitantly taking amiodarone and/or beta-blocking|
00263|030|D|agents.(4)|
00263|031|B||
00263|032|R|REFERENCES:|
00263|033|B||
00263|034|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
00263|035|R|  Pharmaceuticals October, 2018.|1
00263|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
00263|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00263|038|R|3.Lee TH, Friedman PL, Goldman L, Stone PH, Antman EM. Sinus arrest and|3
00263|039|R|  hypotension with combined amiodarone-diltiazem therapy. Am Heart J 1985|3
00263|040|R|  Jan;109(1):163-4.|3
00263|041|R|4.Andrivet P, Beaslay V, Kiger JP, vu Gnoc C. Complete sinus arrest during|3
00263|042|R|  diltiazem therapy; clinical correlates and efficacy of intravenous|3
00263|043|R|  calcium. Eur Heart J 1994 Mar;15(3):350-4.|3
00264|001|T|MONOGRAPH TITLE:  Procainamide/Amiodarone|
00264|002|B||
00264|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00264|004|L|of severe adverse interaction.|
00264|005|B||
00264|006|A|MECHANISM OF ACTION:  Unknown.  Proposed pharmacokinetic mechanisms for this|
00264|007|A|interaction may stem from inhibition of hepatic cytochromes and/or|
00264|008|A|competitive inhibition of renal elimination via active tubular secretion.(1)|
00264|009|A|   Pharmacodynamic effects have also been described.(1-3)  Procainamide and|
00264|010|A|amiodarone each increase QRS and QTc intervals; these effects may be|
00264|011|A|additive.|
00264|012|B||
00264|013|E|CLINICAL EFFECTS:  Serum procainamide concentrations may be elevated|
00264|014|E|increasing the pharmacologic and toxic effects.  Increased QTc intervals may|
00264|015|E|result in potentially life-threatening arrhythmias such as torsades de|
00264|016|E|pointes.|
00264|017|B||
00264|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00264|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
00264|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00264|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00264|022|P|female gender, or advanced age.(4)|
00264|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00264|024|P|higher systemic concentrations of either QT prolonging drug are additional|
00264|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00264|026|P|drug concentrations include rapid infusion of an intravenous dose or|
00264|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00264|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00264|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
00264|030|B||
00264|031|M|PATIENT MANAGEMENT:  The US manufacturer of amiodarone recommends|
00264|032|M|concomitant therapy be reserved for patients with life-threatening|
00264|033|M|ventricular arrhythmias who are incompletely responsive to a single agent or|
00264|034|M|incompletely responsive to amiodarone.  If concomitant therapy is required,|
00264|035|M|the dosage of procainamide should be reduced by 30 - 50% beginning several|
00264|036|M|days after amiodarone is initiated.(2)|
00264|037|M|   Monitor the serum procainamide concentration and observe the patient for|
00264|038|M|conduction disturbances, exacerbation of tachyarrhythmias and signs of|
00264|039|M|procainamide toxicity.(1,2)|
00264|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00264|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00264|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00264|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00264|044|B||
00264|045|D|DISCUSSION:  Concurrent administration of procainamide and amiodarone can|
00264|046|D|produce increases in the half-life and serum procainamide concentration as|
00264|047|D|well as an increase in the serum level of the active metabolite|
00264|048|D|N-acetylprocainamide. Hypotension and arrhythmias have been reported. In|
00264|049|D|some patients the dose of procainamide may need to be reduced by 20% to 25%.|
00264|050|D|Electrophysiologic effects seem to be additive.|
00264|051|D|   One or more of the drug pairs linked to this monograph have been included|
00264|052|D|in a list of interactions that should be considered "high-priority" for|
00264|053|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00264|054|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00264|055|D|Coordinator (ONC) for Health Information Technology.|
00264|056|B||
00264|057|R|REFERENCES:|
00264|058|B||
00264|059|R|1.Windle J, Prystowsky EN, Miles WM, Heger JJ. Pharmacokinetic and|2
00264|060|R|  electrophysiologic interactions of amiodarone and procainamide. Clin|2
00264|061|R|  Pharmacol Ther 1987 Jun;41(6):603-10.|2
00264|062|R|2.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
00264|063|R|  Pharmaceuticals October, 2018.|1
00264|064|R|3.Saal AK, Werner JA, Greene HL, Sears GK, Graham EL. Effect of amiodarone|2
00264|065|R|  on serum quinidine and procainamide levels. Am J Cardiol 1984 May 1;|2
00264|066|R|  53(9):1264-7.|2
00264|067|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00264|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00264|069|R|  settings: a scientific statement from the American Heart Association and|6
00264|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00264|071|R|  2;55(9):934-47.|6
00264|072|R|5.Marchlinski FE, Buxton AE, Kindwall KE, Miller JM, Rosenthal ME, Gottlieb|2
00264|073|R|  CD, Bloom RB, Josephson ME. Comparison of individual and combined effects|2
00264|074|R|  of procainamide and amiodarone in patients with sustained ventricular|2
00264|075|R|  tachyarrhythmias. Circulation 1988 Sep;78(3):583-91.|2
00264|076|R|6.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00264|077|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00264|078|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00264|079|R|  19(5):735-43.|6
00265|001|T|MONOGRAPH TITLE:  Tricyclic Compounds/Cimetidine|
00265|002|B||
00265|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00265|004|L|take action as needed.|
00265|005|B||
00265|006|A|MECHANISM OF ACTION:  Cimetidine inhibits the hepatic metabolism of|
00265|007|A|tricyclic antidepressants.|
00265|008|B||
00265|009|E|CLINICAL EFFECTS:  The pharmacological and toxic effects of tricyclic|
00265|010|E|antidepressants may be increased.|
00265|011|B||
00265|012|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
00265|013|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
00265|014|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
00265|015|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
00265|016|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
00265|017|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
00265|018|P|systemic steroids).|
00265|019|P|   The risk of anticholinergic toxicities including cognitive decline,|
00265|020|P|delirium, falls and fractures is increased in geriatric patients using more|
00265|021|P|than one medicine with anticholinergic properties.(9)|
00265|022|B||
00265|023|M|PATIENT MANAGEMENT:  Observe the patient for an increased or decreased|
00265|024|M|response to tricyclic antidepressant therapy if cimetidine is started or|
00265|025|M|stopped. Adjust the dose of the tricyclic agent accordingly. This|
00265|026|M|interaction can probably be avoided by administration of an H-2 receptor|
00265|027|M|antagonist other than cimetidine (e.g., famotidine, nizatidine, ranitidine).|
00265|028|B||
00265|029|D|DISCUSSION:  Both controlled studies and case reports have demonstrated that|
00265|030|D|concurrent administration of tricyclic antidepressants and cimetidine can|
00265|031|D|result in an increase in plasma tricyclic antidepressant concentrations.|
00265|032|D|Adverse effects have been reported. Similarity between cyclobenzaprine and|
00265|033|D|TCA's warrants consideration of TCA interactions for cyclobenzaprine.|
00265|034|B||
00265|035|R|REFERENCES:|
00265|036|B||
00265|037|R|1.Miller DD, Macklin M. Cimetidine-imipramine interaction: a case report. Am|3
00265|038|R|  J Psychiatry 1983 Mar;140(3):351-2.|3
00265|039|R|2.Miller DD, Sawyer JB, Duffy JP. Cimetidine's effect on steady-state serum|3
00265|040|R|  nortriptyline concentrations. Drug Intell Clin Pharm 1983 Dec;|3
00265|041|R|  17(12):904-5.|3
00265|042|R|3.Henauer SA, Hollister LE. Cimetidine interaction with imipramine and|2
00265|043|R|  nortriptyline. Clin Pharmacol Ther 1984 Feb;35(2):183-7.|2
00265|044|R|4.Anonymous. Cimetidine-imipramine interaction: case report and comments. Am|3
00265|045|R|  J Psychiatry 1984 Jan;141(1):152-3.|3
00265|046|R|5.Spina E, Koike Y. Differential effects of cimetidine and ranitidine on|5
00265|047|R|  imipramine demethylation and desmethylimipramine hydroxylation by human|5
00265|048|R|  liver microsomes. Eur J Clin Pharmacol 1986;30(2):239-42.|5
00265|049|R|6.Wells BG, Pieper JA, Self TH, Stewart CF, Waldon SL, Bobo L, Warner C. The|2
00265|050|R|  effect of ranitidine and cimetidine on imipramine disposition. Eur J Clin|2
00265|051|R|  Pharmacol 1986;31(3):285-90.|2
00265|052|R|7.Sutherland DL, Remillard AJ, Haight KR, Brown MA, Old L. The influence of|2
00265|053|R|  cimetidine versus ranitidine on doxepin pharmacokinetics. Eur J Clin|2
00265|054|R|  Pharmacol 1987;32(2):159-64.|2
00265|055|R|8.Miller ME, Perry CJ, Siris SG. Psychosis in association with combined|3
00265|056|R|  cimetidine and imipramine treatment. Psychosomatics 1987 Apr;28(4):217-9.|3
00265|057|R|9.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
00265|058|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
00265|059|R|  Soc 2023 Jul;71(7):2052-2081.|6
00266|001|T|MONOGRAPH TITLE:  Selected Calcium Channel Blockers/Cimetidine|
00266|002|B||
00266|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00266|004|L|take action as needed.|
00266|005|B||
00266|006|A|MECHANISM OF ACTION:  Cimetidine may decrease the metabolism of diltiazem,|
00266|007|A|felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and|
00266|008|A|nitrendipine.|
00266|009|B||
00266|010|E|CLINICAL EFFECTS:  The pharmacological effects of the calcium channel|
00266|011|E|blocker may be increased.|
00266|012|B||
00266|013|P|PREDISPOSING FACTORS:  None determined.|
00266|014|B||
00266|015|M|PATIENT MANAGEMENT:  Observe the patient for changes in clinical response to|
00266|016|M|the calcium channel blocker when starting or stopping cimetidine.  The|
00266|017|M|dosage of the calcium channel blocker may need to be adjusted.  Ideally,|
00266|018|M|suggest an alternative H-2 antagonist such as famotidine, nizatidine, or|
00266|019|M|ranitidine.|
00266|020|B||
00266|021|D|DISCUSSION:  Significant effects have been observed during concurrent|
00266|022|D|administration of nifedipine or felodipine with cimetidine.  During combined|
00266|023|D|administration of nifedipine and cimetidine in six healthy volunteers, the|
00266|024|D|area-under-curve (AUC) of nifedipine was increased by 80% compared to|
00266|025|D|nifedipine alone.  Increased heart rate and a drop in mean arterial pressure|
00266|026|D|14 mmHg were also reported.  Ranitidine showed only a nonsignificant 25%|
00266|027|D|rise in peak plasma levels of nifedipine and no effects on blood pressure.|
00266|028|D|Similar results were reported in another study where concurrent|
00266|029|D|administration of felodipine and cimetidine resulted in an increase in|
00266|030|D|felodipine AUC and maximum concentration (Cmax) by 50%.|
00266|031|D|   Concurrent administration of cimetidine has also been shown to increase|
00266|032|D|the AUC and Cmax of diltiazem by 53% and 58%, respectively.|
00266|033|D|   The manufacturers of isradipine and nicardipine recommend carefully|
00266|034|D|monitoring patients receiving concurrent therapy with cimetidine.  The|
00266|035|D|manufacturer of isradipine states that concurrent therapy with cimetidine|
00266|036|D|has been shown to increase the AUC of isradipine by 50%.  The manufacturer|
00266|037|D|of nifedipine states that careful titration is necessary in patients|
00266|038|D|receiving concurrent therapy.  The manufacturers of felodipine and diltiazem|
00266|039|D|state that dosage adjustments may be necessary in patients receiving|
00266|040|D|concurrent therapy.|
00266|041|D|   Ranitidine has much less affinity for CYP metabolism than cimetidine and|
00266|042|D|would therefore be expected to have less of an effect on calcium channel|
00266|043|D|blocker metabolism.  Studies have shown that nizatidine and famotidine do|
00266|044|D|not inhibit CYP3A4 metabolism.|
00266|045|B||
00266|046|R|REFERENCES:|
00266|047|B||
00266|048|R|1.Smith SR, Kendall MJ, Lobo J, Beerahee A, Jack DB, Wilkins MR. Ranitidine|2
00266|049|R|  and cimetidine; drug interactions with single dose and steady-state|2
00266|050|R|  nifedipine administration. Br J Clin Pharmacol 1987 Mar;23(3):311-5.|2
00266|051|R|2.Schwartz JB, Upton RA, Lin ET, Williams RL, Benet LZ. Effect of cimetidine|2
00266|052|R|  or ranitidine administration on nifedipine pharmacokinetics and|2
00266|053|R|  pharmacodynamics. Clin Pharmacol Ther 1988 Jun;43(6):673-80.|2
00266|054|R|3.Khan A, Langley SJ, Mullins FG, Dixon JS, Toon S. The pharmacokinetics and|2
00266|055|R|  pharmacodynamics of nifedipine at steady state during concomitant|2
00266|056|R|  administration of cimetidine or high dose ranitidine. Br J Clin Pharmacol|2
00266|057|R|  1991 Oct;32(4):519-22.|2
00266|058|R|4.Guengerich FP, Brian WR, Iwasaki M, Sari MA, Baarnhielm C, Berntsson P.|5
00266|059|R|  Oxidation of dihydropyridine calcium channel blockers and analogues by|5
00266|060|R|  human liver cytochrome P-450 IIIA4. J Med Chem 1991 Jun;34(6):1838-44.|5
00266|061|R|5.Plendil (felodipine) US prescribing information. AstraZeneca|1
00266|062|R|  Pharmaceuticals LP November, 2003.|1
00266|063|R|6.Humphries TJ. Famotidine: a notable lack of drug interactions. Scand J|6
00266|064|R|  Gastroenterol Suppl 1987;134:55-60.|6
00266|065|R|7.Secor JW, Speeg KV Jr, Meredith CG, Johnson RF, Snowdy P, Schenker S. Lack|2
00266|066|R|  of effect of nizatidine on hepatic drug metabolism in man. Br J Clin|2
00266|067|R|  Pharmacol 1985 Dec;20(6):710-3.|2
00266|068|R|8.Klotz U. Lack of effect of nizatidine on drug metabolism. Scand J|5
00266|069|R|  Gastroenterol Suppl 1987;136:18-23.|5
00266|070|R|9.Lin JH, Los LE, Ulm EH, Duggan DE. Kinetic studies on the competition|5
00266|071|R|  between famotidine and cimetidine in rats. Evidence of multiple renal|5
00266|072|R|  secretory systems for organic cations. Drug Metab Dispos 1988 Jan-Feb;|5
00266|073|R|  16(1):52-6.|5
00266|074|R|10.Wang RW, Miwa GT, Argenbright LS, Lu AY. In vitro studies on the|5
00266|075|R|   interaction of famotidine with liver microsomal cytochrome P-450. Biochem|5
00266|076|R|   Pharmacol 1988 Aug 1;37(15):3049-53.|5
00266|077|R|11.Kirch W, Hoensch H, Janisch HD. Interactions and non-interactions with|6
00266|078|R|   ranitidine. Clin Pharmacokinet 1984 Nov-Dec;9(6):493-510.|6
00266|079|R|12.Renwick AG, Le Vie J, Challenor VF, Waller DG, Gruchy B, George CF.|2
00266|080|R|   Factors affecting the pharmacokinetics of nifedipine. Eur J Clin|2
00266|081|R|   Pharmacol 1987;32(4):351-5.|2
00266|082|R|13.Winship LC, McKenney JM, Wright JT Jr, Wood JH, Goodman RP. The effect of|2
00266|083|R|   ranitidine and cimetidine on single-dose diltiazem pharmacokinetics.|2
00266|084|R|   Pharmacotherapy 1985 Jan-Feb;5(1):16-9.|2
00266|085|R|14.Kirch W, Ramsch K, Janisch HD, Ohnhaus EE. The influence of two histamine|2
00266|086|R|   H2-receptor antagonists, cimetidine and ranitidine, on the plasma levels|2
00266|087|R|   and clinical effect of nifedipine and metoprolol. Arch Toxicol Suppl|2
00266|088|R|   1984;7:256-9.|2
00266|089|R|15.Procardia (nifedipine) US prescribing information. Pfizer Inc. January 9,|1
00266|090|R|   2015.|1
00266|091|R|16.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
00266|092|R|   information. Abbott Pharmaceuticals, Inc. November, 2016.|1
00266|093|R|17.Cardene (nicardipine) US prescribing information. EKR Therapeutics, Inc.|1
00266|094|R|   August, 2016.|1
00266|095|R|18.Dynacirc (isradipine) US prescribing information. Reliant Pharmaceuticals|1
00266|096|R|   December, 2006.|1
00267|001|T|MONOGRAPH TITLE:  Neuromuscular Blocking Agents/Lincosamides|
00267|002|B||
00267|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00267|004|L|take action as needed.|
00267|005|B||
00267|006|A|MECHANISM OF ACTION:  Lincosamides appear to augment the neuromuscular|
00267|007|A|blocking effects of nondepolarizing muscle relaxants.|
00267|008|B||
00267|009|E|CLINICAL EFFECTS:  The effects of nondepolarizing neuromuscular relaxants|
00267|010|E|may be prolonged leading to profound sedation, respiratory depression, coma,|
00267|011|E|and/or death.|
00267|012|B||
00267|013|P|PREDISPOSING FACTORS:  None determined.|
00267|014|B||
00267|015|M|PATIENT MANAGEMENT:  Monitor respiratory function of the patient and provide|
00267|016|M|the necessary support. In patients who have received nondepolarizing muscle|
00267|017|M|relaxants, avoid use of lincosamides in the recovery room.|
00267|018|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00267|019|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00267|020|M|unresponsiveness.|
00267|021|B||
00267|022|D|DISCUSSION:  Lincomycin has been reported to augment the neuromuscular|
00267|023|D|blocking effect of pancuronium in seven anesthetized patients. The effect|
00267|024|D|was readily antagonized by neostigmine administration. In a case report,|
00267|025|D|clindamycin produced prolonged neuromuscular blockade in a patient who had|
00267|026|D|received pancuronium. Neostigmine was ineffective in antagonizing the|
00267|027|D|blockade.|
00267|028|B||
00267|029|R|REFERENCES:|
00267|030|B||
00267|031|R|1.Fogdall RP, Miller RD. Prolongation of a pancuronium-induced neuromuscular|3
00267|032|R|  blockade by clindamycin. Anesthesiology 1974 Oct;41(4):407-8.|3
00267|033|R|2.Booij LH, Miller RD, Crul JF. Neostigmine and 4-aminopyridine antagonism|2
00267|034|R|  of lincomycin-pancuronium neuromuscular blockade in man. Anesth Analg 1978|2
00267|035|R|  May-Jun;57(3):316-21.|2
00268|001|T|MONOGRAPH TITLE:  Procainamide/MATE Inhibitors|
00268|002|B||
00268|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00268|004|L|take action as needed.|
00268|005|B||
00268|006|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
00268|007|A|protein transporters in the kidneys may interfere with the renal elimination|
00268|008|A|of procainamide and its active metabolite, N-acetylprocainamide (NAPA).|
00268|009|B||
00268|010|E|CLINICAL EFFECTS:  The pharmacological and toxic effects of procainamide and|
00268|011|E|NAPA may be increased, including potentially life-threatening cardiac|
00268|012|E|arrhythmias, like torsades de pointes (TdP).|
00268|013|B||
00268|014|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
00268|015|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
00268|016|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
00268|017|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
00268|018|P|concurrent use of agents known to cause QT prolongation.|
00268|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00268|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00268|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00268|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00268|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00268|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00268|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).|
00268|026|B||
00268|027|M|PATIENT MANAGEMENT:  Monitor serum procainamide and NAPA concentrations and|
00268|028|M|observe the patients for signs of toxicity.|
00268|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00268|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00268|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00268|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00268|033|B||
00268|034|D|DISCUSSION:  Administration of trimethoprim to patients receiving|
00268|035|D|procainamide produced an increase in the area under the concentration-time|
00268|036|D|curve and a decrease in the clearance of procainamide. At the same time,|
00268|037|D|serum NAPA concentrations and clearance were decreased.|
00268|038|D|   MATE inhibitors include: pyrimethamine, risdiplam, and trimethoprim.(4)|
00268|039|B||
00268|040|R|REFERENCES:|
00268|041|B||
00268|042|R|1.Kosoglou T, Rocci ML Jr, Vlasses PH. Trimethoprim alters the disposition|2
00268|043|R|  of procainamide and N- acetylprocainamide. Clin Pharmacol Ther 1988 Oct;|2
00268|044|R|  44(4):467-77.|2
00268|045|R|2.Vlasses PH, Kosoglou T, Chase SL, Greenspon AJ, Lottes S, Andress E,|2
00268|046|R|  Ferguson RK, Rocci ML Jr. Trimethoprim inhibition of the renal clearance|2
00268|047|R|  of procainamide and N- acetylprocainamide. Arch Intern Med 1989 Jun;|2
00268|048|R|  149(6):1350-3.|2
00268|049|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00268|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00268|051|R|  settings: a scientific statement from the American Heart Association and|6
00268|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00268|053|R|  2;55(9):934-47.|6
00268|054|R|4.This information is based on an extract from the Certara Drug Interaction|6
00268|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00269|001|T|MONOGRAPH TITLE:  Nondepolarizing Muscle Relaxants/Magnesium Salts,|
00269|002|T|Injectable|
00269|003|B||
00269|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00269|005|L|take action as needed.|
00269|006|B||
00269|007|A|MECHANISM OF ACTION:  Magnesium may reduce postjunctional membrane|
00269|008|A|neuromuscular blocking action of nondepolarizing muscle relaxants.|
00269|009|A|Parenterally administered magnesium may potentiate the effects of the|
00269|010|A|nondepolarizing muscle relaxants.|
00269|011|B||
00269|012|E|CLINICAL EFFECTS:  Increased neuromuscular blockade with profound sedation,|
00269|013|E|respiratory depression, coma, and/or death.|
00269|014|B||
00269|015|P|PREDISPOSING FACTORS:  None determined.|
00269|016|B||
00269|017|M|PATIENT MANAGEMENT:  Monitor respiratory function when parenteral magnesium|
00269|018|M|and nondepolarizing muscle relaxants are administered concurrently. Adjust|
00269|019|M|the dose of the neuromuscular blocking agent accordingly.|
00269|020|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00269|021|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00269|022|M|unresponsiveness.|
00269|023|B||
00269|024|D|DISCUSSION:  The effects of nondepolarizing muscle relaxants have been|
00269|025|D|reported to be increased in laboratory animals and in humans by concomitant|
00269|026|D|administration of magnesium sulfate. Respiratory depression has been|
00269|027|D|reported.|
00269|028|B||
00269|029|R|REFERENCES:|
00269|030|B||
00269|031|R|1.Giesecke AH Jr, Morris RE, Dalton MD, Stephen CR. Of magnesium, muscle|5
00269|032|R|  relaxants, toxemic parturients, and cats. Anesth Analg 1968 Nov-Dec;|5
00269|033|R|  47(6):689-95.|5
00269|034|R|2.Morris R, Giesecke AH Jr. Potentiation of muscle relaxants by magnesium|2
00269|035|R|  sulfate therapy in toxemia of pregnancy. South Med J 1968 Jan;61(1):25-8.|2
00269|036|R|3.Aldrete JA, Zahler A, Aikawa JK. Prevention of succinylcholine-induced|2
00269|037|R|  hyperkalaemia by magnesium sulfate. Can Anaesth Soc J 1970 Sep;|2
00269|038|R|  17(5):477-84.|2
00269|039|R|4.Ghoneim MM, Long JP. The interaction between magnesium and other|5
00269|040|R|  neuromuscular blocking agents. Anesthesiology 1970 Jan;32(1):23-7.|5
00269|041|R|5.Sinatra RS, Philip BK, Naulty JS, Ostheimer GW. Prolonged neuromuscular|3
00269|042|R|  blockade with vecuronium in a patient treated with magnesium sulfate.|3
00269|043|R|  Anesth Analg 1985 Dec;64(12):1220-2.|3
00269|044|R|6.Ostergaard D, Engbaek J, Viby-Mogensen J. Adverse reactions and|6
00269|045|R|  interactions of the neuromuscular blocking drugs. Med Toxicol Adverse Drug|6
00269|046|R|  Exp 1989 Sep-Oct;4(5):351-68.|6
00270|001|T|MONOGRAPH TITLE:  Selected Alpha-1 Blockers/Verapamil|
00270|002|B||
00270|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00270|004|L|take action as needed.|
00270|005|B||
00270|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown. The bioavailability of|
00270|007|A|prazosin and terazosin are increased.|
00270|008|B||
00270|009|E|CLINICAL EFFECTS:  The hypotensive effects of both drugs may be increased.|
00270|010|E|The incidence of postural hypotension may be greater than with either agent|
00270|011|E|alone.|
00270|012|B||
00270|013|P|PREDISPOSING FACTORS:  None determined.|
00270|014|B||
00270|015|M|PATIENT MANAGEMENT:  The combined use of alpha blockers and verapamil may|
00270|016|M|offer therapeutic benefit in the treatment of hypertension. However, blood|
00270|017|M|pressure should be closely monitored when one of these agents is added to|
00270|018|M|the regimen of the other. Adjust the dose of either drug accordingly.|
00270|019|M|   The manufacturer of prazosin states this interaction can be minimized by|
00270|020|M|reducing the prazosin dose to 1 to 2 mg three times a day, by introducing|
00270|021|M|antihypertensive drugs cautiously, and by retitrating prazosin based on|
00270|022|M|clinical response.(6)|
00270|023|B||
00270|024|D|DISCUSSION:  Increased serum concentration and area-under-curve (AUC) of|
00270|025|D|prazosin have been reported when starting verapamil in patients receiving|
00270|026|D|prazosin. Both reclining and standing blood pressure increased as did the|
00270|027|D|occurrence of orthostatic hypotension.|
00270|028|D|   In a study in 24 subjects, the concurrent administration of terazosin and|
00270|029|D|verapamil resulted in increases in terazosin AUC  by 11% after the first|
00270|030|D|dose of verapamil and by 24% after 3 weeks of combined treatment. The time|
00270|031|D|to the maximum concentration (Tmax) of terazosin was decreased. There were|
00270|032|D|no significant changes in verapamil pharmacokinetics.|
00270|033|B||
00270|034|R|REFERENCES:|
00270|035|B||
00270|036|R|1.Pasanisi F, Elliott HL, Meredith PA, McSharry DR, Reid JL. Combined alpha|2
00270|037|R|  adrenoceptor antagonism and calcium channel blockade in normal subjects.|2
00270|038|R|  Clin Pharmacol Ther 1984 Dec;36(6):716-23.|2
00270|039|R|2.Meredith PA, Elliott HL, Pasanisi F, Reid JL. Prazosin and verapamil: a|4
00270|040|R|  pharmacokinetic and pharmacodynamic interaction. Br J Clin Pharmacol 1985|4
00270|041|R|  Sep;21(1):85P.|4
00270|042|R|3.Elliott HL, Meredith PA, Campbell L, Reid JL. The combination of prazosin|2
00270|043|R|  and verapamil in the treatment of essential hypertension. Clin Pharmacol|2
00270|044|R|  Ther 1988 May;43(5):554-60.|2
00270|045|R|4.Meredith PA, Elliott HL. An additive or synergistic drug interaction:|2
00270|046|R|  application of concentration-effect modeling. Clin Pharmacol Ther 1992|2
00270|047|R|  Jun;51(6):708-14.|2
00270|048|R|5.Hytrin (terazosin hydrochloride) US prescribing information. Abbott|1
00270|049|R|  Laboratories July, 2009.|1
00270|050|R|6.Minipress (prazosin hydrochloride) US prescribing information. Pfizer Inc.|1
00270|051|R|  February, 2015.|1
00271|001|T|MONOGRAPH TITLE:  Felbamate/Carbamazepine|
00271|002|B||
00271|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00271|004|L|take action as needed.|
00271|005|B||
00271|006|A|MECHANISM OF ACTION:  Unknown. However, felbamate probably increases the|
00271|007|A|metabolism of carbamazepine to the epoxide metabolite and/or inhibits the|
00271|008|A|conversion of the epoxide metabolite of carbamazepine to the diol|
00271|009|A|metabolite. In addition, carbamazepine increases the metabolism of|
00271|010|A|felbamate.|
00271|011|B||
00271|012|E|CLINICAL EFFECTS:  Both serum carbamazepine and felbamate concentrations may|
00271|013|E|be decreased reducing their therapeutic effects.|
00271|014|B||
00271|015|P|PREDISPOSING FACTORS:  None determined.|
00271|016|B||
00271|017|M|PATIENT MANAGEMENT:  Serum concentrations of both drugs should be monitored|
00271|018|M|and patients should be observed for changes in seizure control if therapy|
00271|019|M|with either agent is started, stopped or altered. Adjust therapy as|
00271|020|M|indicated.|
00271|021|M|   The US manufacturer of felbamate recommends decreasing the dosage of|
00271|022|M|carbamazepine by 20% when initiating felbamate therapy.|
00271|023|B||
00271|024|D|DISCUSSION:  In patients stabilized on carbamazepine monotherapy, addition|
00271|025|D|of felbamate produced a decrease in plasma carbamazepine concentrations. The|
00271|026|D|effect on serum carbamazepine concentrations was evident following one week|
00271|027|D|of felbamate coadministration, reached a plateau between the second and|
00271|028|D|fourth weeks and persisted during concomitant therapy with both|
00271|029|D|anticonvulsants. Serum carbamazepine concentrations returned to original|
00271|030|D|levels within 3 weeks of discontinuing felbamate. Although serum levels of|
00271|031|D|carbamazepine decreased, the active epoxide metabolite of carbamazepine|
00271|032|D|increased by 46%. Addition of carbamazepine to regimen of patients receiving|
00271|033|D|felbamate results in a decrease in felbamate plasma concentrations.|
00271|034|B||
00271|035|R|REFERENCES:|
00271|036|B||
00271|037|R|1.Fuerst RH, Graves NM, Leppik IE, Brundage RC, Holmes GB, Remmel RP.|3
00271|038|R|  Felbamate increases phenytoin but decreases carbamazepine concentrations.|3
00271|039|R|  Epilepsia 1988 Jul-Aug;29(4):488-91.|3
00271|040|R|2.Graves NM, Holmes GB, Fuerst RH, Leppik IE. Effect of felbamate on|2
00271|041|R|  phenytoin and carbamazepine serum concentrations. Epilepsia 1989 Mar-Apr;|2
00271|042|R|  30(2):225-9.|2
00271|043|R|3.Wagner ML, Graves NM, Marienau K, Holmes GB, Remmel RP, Leppik IE.|2
00271|044|R|  Discontinuation of phenytoin and carbamazepine in patients receiving|2
00271|045|R|  felbamate. Epilepsia 1991 May-Jun;32(3):398-406.|2
00271|046|R|4.Albani F, Theodore WH, Washington P, Devinsky O, Bromfield E, Porter RJ,|2
00271|047|R|  Nice FJ. Effect of felbamate on plasma levels of carbamazepine and its|2
00271|048|R|  metabolites. Epilepsia 1991 Jan-Feb;32(1):130-2.|2
00271|049|R|5.Wagner ML, Remmel RP, Graves NM, Leppik IE. Effect of felbamate on|2
00271|050|R|  carbamazepine and its major metabolites. Clin Pharmacol Ther 1993 May;|2
00271|051|R|  53(5):536-43.|2
00271|052|R|6.Felbatrol (felbamate) US prescribing information. MedPoint Pharmaceuticals|1
00271|053|R|  Inc. August 27, 2012.|1
00272|001|T|MONOGRAPH TITLE:  Felbamate/Valproic Acid|
00272|002|B||
00272|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00272|004|L|take action as needed.|
00272|005|B||
00272|006|A|MECHANISM OF ACTION:  Felbamate may inhibit the CYP2C19 metabolism of|
00272|007|A|valproic acid.|
00272|008|B||
00272|009|E|CLINICAL EFFECTS:  The addition of felbamate may result in elevated levels|
00272|010|E|and toxicity from valproic acid.(1,2)|
00272|011|B||
00272|012|P|PREDISPOSING FACTORS:  None determined.|
00272|013|B||
00272|014|M|PATIENT MANAGEMENT:  The US manufacturer of felbamate recommends decreasing|
00272|015|M|the dosage of valproic acid by 20% during the initiation of felbamate|
00272|016|M|therapy.(1)|
00272|017|B||
00272|018|D|DISCUSSION:  Administration of felbamate to 10 epileptic patients stabilized|
00272|019|D|on valproic acid resulted in a dose related increase in felbamate|
00272|020|D|area-under-curve (AUC) and maximum concentration (Cmax).(2)|
00272|021|D|   In a study in 4 subjects with epilepsy receiving valproate, valproate|
00272|022|D|minimum concentration (Cmin) increased by 24% and 52% following the addition|
00272|023|D|of felbamate at dosages of 1200 mg/day an 2400 mg/day, respectively.(1)|
00272|024|D|   In a study in 18 healthy subjects receiving valproate (400 mg/day for 21|
00272|025|D|days) and felbamate (days 8-21 at 1200 mg/day, 2400 mg/day, 3000mg/day, or|
00272|026|D|3600 mg/day) increased valproate Cmax by 38-72% and AUC by 93-108% (except|
00272|027|D|for the 1200 mg/day dose) depending on felbamate dose. Valproate clearance|
00272|028|D|was reduced by 34-54% depending on felbamate dose.(3)|
00272|029|D|   In a study in 10 children on valproic acid with felbamate (mean dose 18.5|
00272|030|D|mg/kg/day), the Cmin and AUC were increased and the valproic acid clearance|
00272|031|D|was reduced 21%.(4)|
00272|032|D|   In a study in 10 subjects with epilepsy stabilized on valproic acid (9.5|
00272|033|D|- 31.7 mg/kg/day) receiving felbamate (600 mg or 1200 mg twice a day)|
00272|034|D|resulted in an increase in Cmax and AUC of 34-55% and 27-54% and a reduction|
00272|035|D|in clearance of 22-33%.(5)|
00272|036|B||
00272|037|R|REFERENCES:|
00272|038|B||
00272|039|R|1.Felbatrol (felbamate) US prescribing information. MedPoint Pharmaceuticals|1
00272|040|R|  Inc. August 27, 2012.|1
00272|041|R|2.Wagner ML, Graves NM, Leppik IE, Remmel RP, Ward DL, Shumaker RC. The|4
00272|042|R|  effect of felbamate on valproate disposition. Epilepsia 1991;32(3):15.|4
00272|043|R|3.Hooper WD, Franklin ME, Glue P, Banfield CR, Radwanski E, McLaughlin DB,|2
00272|044|R|  McIntyre ME, Dickinson RG, Eadie MJ. Effect of felbamate on valproic acid|2
00272|045|R|  disposition in healthy volunteers: inhibition of beta-oxidation. Epilepsia|2
00272|046|R|  1996 Jan;37(1):91-7.|2
00272|047|R|4.Delgado MR. Changes in valproic acid concentrations and dose/level ratios|2
00272|048|R|  by felbamate coadministration in children. Ann Neurol 1994;36:538.|2
00272|049|R|5.Wagner ML, Graves NM, Leppik IE, Remmel RP, Shumaker RC, Ward DL, Perhach|2
00272|050|R|  JL. The effect of felbamate on valproic acid disposition. Clin Pharmacol|2
00272|051|R|  Ther 1994 Nov;56(5):494-502.|2
00273|001|T|MONOGRAPH TITLE:  Adenosine; Regadenoson/Dipyridamole|
00273|002|B||
00273|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00273|004|L|is contraindicated and generally should not be dispensed or administered to|
00273|005|L|the same patient.|
00273|006|B||
00273|007|A|MECHANISM OF ACTION:  Dipyridamole inhibits cellular transport of|
00273|008|A|adenosine.(1-3)  Also, dipyridamole has been shown to increase intrinsic|
00273|009|A|adenosine levels indicating that dipyridamole inhibits the intrinsic|
00273|010|A|metabolism of adenosine.(4)|
00273|011|A|   Regadenoson is a derivative of adenosine.(5)|
00273|012|B||
00273|013|E|CLINICAL EFFECTS:  Concurrent dipyridamole may increase serum concentrations|
00273|014|E|and potentiate the cardiovascular effects of adenosine.  Conversely,|
00273|015|E|significant bradycardia has occurred following rapid bolus injections of|
00273|016|E|adenosine.(1-8)|
00273|017|E|   Dipyridamole may increase the effects of regadenoson.(1,2,5)|
00273|018|B||
00273|019|P|PREDISPOSING FACTORS:  None determined.|
00273|020|B||
00273|021|M|PATIENT MANAGEMENT:  The recommendations for concurrent use of adenosine or|
00273|022|M|regadenoson with dipyridamole is dependent on the indication.|
00273|023|M|   -For Cardioversion:|
00273|024|M|   The Australian manufacturer of adenosine states the use of adenosine for|
00273|025|M|cardioversion is contraindicated in patients receiving dipyridamole.|
00273|026|M|Discontinue the use of dipyridamole 24 hours prior to adenosine bolus|
00273|027|M|dosing.(7)|
00273|028|M|   The US manufacturer of adenosine states smaller doses of adenosine may be|
00273|029|M|effective with dipyridamole.(6)  Lower the dose of adenosine in patients|
00273|030|M|receiving dipyridamole.(1,2)  Monitor for increased effects of adenosine.|
00273|031|M|   -For Stress Testing:|
00273|032|M|   Clinical practice guidelines from the American Society of Nuclear|
00273|033|M|Cardiology state dipyridamole use within the previous 48 hours is a|
00273|034|M|contraindication to adenosine or regadenoson stress testing.(9,10)|
00273|035|M|   The US manufacturer of dipyridamole recommends stopping dipyridamole for|
00273|036|M|48 hours prior to stress testing with intravenous dipyridamole or other|
00273|037|M|adenosinergic agents (e.g. adenosine or regadenoson).(1)|
00273|038|M|   The Australian manufacturer of dipyridamole recommends stopping|
00273|039|M|dipyridamole for 24 hours prior to stress testing with adenosine.(2)|
00273|040|M|   The US manufacturer of regadenoson recommends withholding dipyridamole|
00273|041|M|for at least 2 days prior to regadenoson administration.(5)|
00273|042|B||
00273|043|D|DISCUSSION:  In a prospective, placebo-controlled single blinded study in|
00273|044|D|eight healthy subjects, all patients were randomized to receive adenosine|
00273|045|D|infusion on two separate days.  Heart rate and skin temperature increased in|
00273|046|D|a dose-related manner following adenosine administration.  An increase in|
00273|047|D|heart rate of 15 bpm occurred with 0.005 mg/kg/min of adenosine following|
00273|048|D|administration of dipyridamole but did not change following saline.  Blood|
00273|049|D|pressure remained unchanged throughout the study.(11)|
00273|050|D|   According to another prospective, non-placebo controlled, non-blinded|
00273|051|D|study, five healthy volunteers received a five-day course of oral|
00273|052|D|dipyridamole 100 mg every 6 hours.  Plasma adenosine levels were measured|
00273|053|D|for a five day control period as a baseline and also during the five-day|
00273|054|D|course of dipyridamole.  It was found during the baseline studies that|
00273|055|D|adenosine levels vary significantly between individuals but seem to be|
00273|056|D|constant within the same individual.  During the five-day course, the|
00273|057|D|average increase in endogenous adenosine concentration was 60%. It was|
00273|058|D|concluded that administration of oral dipyridamole significantly increases|
00273|059|D|plasma adenosine levels in normal human subjects.  Also, there was a|
00273|060|D|positive correlation between adenosine and dipyridamole levels (p =|
00273|061|D|0.001).(12)|
00273|062|B||
00273|063|R|REFERENCES:|
00273|064|B||
00273|065|R|1.Persantine (dipyridamole) US prescribing information. Boehringer Ingelheim|1
00273|066|R|  Pharmaceuticals, Inc. December, 2019.|1
00273|067|R|2.Persantin (dipyridamole) Australian product information. Clinect Pty Ltd|1
00273|068|R|  January, 2021.|1
00273|069|R|3.Watt AH, Bernard MS, Webster J, Passani SL, Stephens MR, Routledge PA.|2
00273|070|R|  Intravenous adenosine in the treatment of supraventricular tachycardia: a|2
00273|071|R|  dose-ranging study and interaction with dipyridamole. Br J Clin Pharmacol|2
00273|072|R|  1986 Feb;21(2):227-30.|2
00273|073|R|4.Biaggioni I, Onrot J, Hollister AS, Robertson D. Cardiovascular effects of|2
00273|074|R|  adenosine infusion in man and their modulation by dipyridamole. Life Sci|2
00273|075|R|  1986 Dec 8;39(23):2229-36.|2
00273|076|R|5.Lexiscan (regadenoson) US prescribing information. Astellas Pharma US,|1
00273|077|R|  Inc. May, 2018.|1
00273|078|R|6.Adenoscan (adenosine) US prescribing information. Astellas Pharma US, Inc.|1
00273|079|R|  August, 2014.|1
00273|080|R|7.Adenocar (adenosine) Australian product information. Sanofi-Aventis|1
00273|081|R|  Australia Pty Ltd August, 2022.|1
00273|082|R|8.Adenoscan (adenosine) Australian product information. Sanofi Aventis|1
00273|083|R|  Australia Pty Ltd August, 2022.|1
00273|084|R|9.Weinberg R Bullock-Palmer R. ASNC Practice Point Pharmacological Stress|6
00273|085|R|  Testing - Regadenoson..|6
00273|086|R|10.Weinberg R Bullock-Palmer R. ASNC Practice Point Pharmacological Stress|6
00273|087|R|   Testing - Adenosine..|6
00273|088|R|11.Conradson TB, Dixon CM, Clarke B, Barnes PJ. Cardiovascular effects of|2
00273|089|R|   infused adenosine in man: potentiation by dipyridamole. Acta Physiol|2
00273|090|R|   Scand 1987 Mar;129(3):387-91.|2
00273|091|R|12.German DC, Kredich NM, Bjornsson TD. Oral dipyridamole increases plasma|2
00273|092|R|   adenosine levels in human beings. Clin Pharmacol Ther 1989 Jan;|2
00273|093|R|   45(1):80-4.|2
00274|001|T|MONOGRAPH TITLE:  Alteplase/Nitroglycerin|
00274|002|B||
00274|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00274|004|L|of severe adverse interaction.|
00274|005|B||
00274|006|A|MECHANISM OF ACTION:  Nitroglycerin may increase hepatic blood flow,|
00274|007|A|enhancing the hepatic metabolism of alteplase (t-PA).|
00274|008|B||
00274|009|E|CLINICAL EFFECTS:  The thrombolytic effect of alteplase may be decreased.|
00274|010|B||
00274|011|P|PREDISPOSING FACTORS:  None determined.|
00274|012|B||
00274|013|M|PATIENT MANAGEMENT:  If possible, avoid coadministration of alteplase and|
00274|014|M|nitroglycerin. If both drugs must be given concomitantly use caution when|
00274|015|M|administering these agents. Be aware that the therapeutic effects of|
00274|016|M|alteplase may be impaired.|
00274|017|B||
00274|018|D|DISCUSSION:  In a study, nitroglycerin administration decreased plasma|
00274|019|D|levels of alteplase reducing the thrombolytic effects. In a non-randomized|
00274|020|D|study involving patients with suspected infarction, stable coronary artery|
00274|021|D|reperfusion occurred in 91% of the patients receiving alteplase plus saline|
00274|022|D|solution compared to 44% receiving alteplase plus intravenous nitroglycerin.|
00274|023|D|Patients receiving alteplase and nitroglycerin concomitantly had lower mean|
00274|024|D|plasma t-PA antigen concentrations than patients receiving alteplase alone.|
00274|025|D|The differences persisted for more than 6 hours after completing the|
00274|026|D|alteplase infusion.(1)|
00274|027|D|     In an earlier subset of the above study, patients with acute myocardial|
00274|028|D|infarctions who received alteplase alone demonstrated an earlier peak serum|
00274|029|D|creatine kinase and showed signs of reperfusion more frequently and sooner|
00274|030|D|than did patients receiving alteplase plus nitroglycerin. In addition,|
00274|031|D|patients receiving alteplase and nitroglycerin had a greater incidence of|
00274|032|D|in-hospital adverse events and a higher incidence of reocclusion.(2)|
00274|033|B||
00274|034|R|REFERENCES:|
00274|035|B||
00274|036|R|1.Nicolini FA, Ferrini D, Ottani F, Galvani M, Ronchi A, Behrens PH,|2
00274|037|R|  Rusticali F, Mehta JL. Concurrent nitroglycerin therapy impairs|2
00274|038|R|  tissue-type plasminogen activator-induced thrombolysis in patients with|2
00274|039|R|  acute myocardial infarction. Am J Cardiol 1994 Oct 1;74(7):662-6.|2
00274|040|R|2.Nicolini FA, Vaddi K, Ferrini D, Ottani F, Galvani M, Rusticali F, Mehta|4
00274|041|R|  JL. Nitroglycerin given concurrently decreases the efficacy of t-PA in|4
00274|042|R|  patients with acute myocardial infarction. Circulation 1992 Oct;|4
00274|043|R|  86(4):I-856.|4
00274|044|R|3.Nitrostat (nitroglycerin) US prescribing information. Pfizer January 24,|1
00274|045|R|  2018.|1
00275|001|T|MONOGRAPH TITLE:  Cisapride/Fluconazole; Miconazole|
00275|002|B||
00275|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00275|004|L|is contraindicated and generally should not be dispensed or administered to|
00275|005|L|the same patient.|
00275|006|B||
00275|007|A|MECHANISM OF ACTION:  Inhibition of metabolism of cisapride by azole|
00275|008|A|antifungal agents by CYP3A4.(1)|
00275|009|B||
00275|010|E|CLINICAL EFFECTS:  Increased serum concentrations of cisapride resulting in|
00275|011|E|possible life-threatening cardiotoxicity, including prolongation of the QT|
00275|012|E|interval.|
00275|013|B||
00275|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00275|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00275|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00275|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00275|018|P|female gender, or advanced age.(7)|
00275|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00275|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00275|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00275|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00275|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00275|024|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
00275|025|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)|
00275|026|B||
00275|027|M|PATIENT MANAGEMENT:  Concomitant administration of fluconazole or miconazole|
00275|028|M|with cisapride is contraindicated.|
00275|029|B||
00275|030|D|DISCUSSION:  Elevated plasma levels of cisapride can cause QT prolongation|
00275|031|D|and torsades de pointes-type ventricular tachycardia which may be fatal.|
00275|032|D|Ketoconazole is contraindicated with concurrent administration of cisapride|
00275|033|D|because ketoconazole has resulted in markedly elevated cisapride serum|
00275|034|D|levels and prolonged QT interval.|
00275|035|D|   Serious cardiovascular events, including QT prolongation, torsades de|
00275|036|D|pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have|
00275|037|D|been reported in patients taking cisapride in combination with itraconazole|
00275|038|D|and/or other CYP P-450-3A4 inhibitors.(3)|
00275|039|D|   Cisapride is metabolized by CYP3A4. In vitro studies have shown|
00275|040|D|itraconazole, miconazole, posaconazole, and voriconazole to be potent|
00275|041|D|inhibitors of CYP3A4 and like ketoconazole, these agents are also expected|
00275|042|D|to markedly increase cisapride serum concentrations.|
00275|043|D|   One or more of the drug pairs linked to this monograph have been included|
00275|044|D|in a list of interactions that should be considered "high-priority" for|
00275|045|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00275|046|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00275|047|D|Coordinator (ONC) for Health Information Technology.|
00275|048|B||
00275|049|R|REFERENCES:|
00275|050|B||
00275|051|R|1.Propulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00275|052|R|  January, 2000.|1
00275|053|R|2.Data on file (LMD 110256). Janssen Pharmaceutica Products, L.P. February,|1
00275|054|R|  1995.|1
00275|055|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
00275|056|R|  Products, L.P. February, 2024.|1
00275|057|R|4.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
00275|058|R|5.Noxafil (posaconazole) UK summary of product characteristics.|1
00275|059|R|  Schering-Plough Ltd. January, 2022.|1
00275|060|R|6.Noxafil (posaconazole) US prescribing information. Schering Corporation|1
00275|061|R|  March, 2019.|1
00275|062|R|7.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
00275|063|R|  Pharmaceuticals February, 2014.|1
00275|064|R|8.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00275|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00275|066|R|  settings: a scientific statement from the American Heart Association and|6
00275|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00275|068|R|  2;55(9):934-47.|6
00275|069|R|9.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00275|070|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00275|071|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00275|072|R|  19(5):735-43.|6
00276|001|T|MONOGRAPH TITLE:  Cisapride/Selected Macrolide Antibiotics (mono deleted|
00276|002|T|07/09/2015)|
00276|003|B||
00276|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00276|005|L|is contraindicated and generally should not be dispensed or administered to|
00276|006|L|the same patient.|
00276|007|B||
00276|008|A|MECHANISM OF ACTION:  The macrolide antibiotics may inhibit the metabolism|
00276|009|A|of cisapride at CYP3A4.(1,2)|
00276|010|B||
00276|011|E|CLINICAL EFFECTS:  Concurrent administration of cisapride with the macrolide|
00276|012|E|may result in elevated levels of cisapride, which may produce|
00276|013|E|life-threatening cardiotoxicity.(1-4)|
00276|014|B||
00276|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00276|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
00276|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00276|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00276|019|P|female gender, or advanced age.(6)|
00276|020|P|    Concurrent use of more than one drug known to cause QT prolongation or|
00276|021|P|higher systemic concentrations of either QT prolonging drug are additional|
00276|022|P|risk factors for torsades de pointes.  Factors which may increased systemic|
00276|023|P|drug concentrations include rapid infusion of an intravenous dose or|
00276|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00276|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00276|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
00276|027|B||
00276|028|M|PATIENT MANAGEMENT:  Concomitant administration of cisapride(1) with|
00276|029|M|clarithromycin,(3) erythromycin, or troleandomycin is contraindicated.|
00276|030|M|Concomitant administration of telithromycin with cisapride is|
00276|031|M|contraindicated by the UK and US manufacturers of telithromycin.(4,5)|
00276|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00276|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00276|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00276|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00276|036|B||
00276|037|D|DISCUSSION:  Elevated plasma levels of cisapride can cause QT prolongation|
00276|038|D|and torsades de pointes-type ventricular tachycardia which may be fatal.|
00276|039|D|Ketoconazole is contraindicated with concurrent administration of cisapride|
00276|040|D|because ketoconazole has resulted in markedly elevated cisapride serum|
00276|041|D|levels and prolonged QT interval. Cisapride is metabolized by CYP3A4. In|
00276|042|D|vitro studies have shown troleandomycin to be a potent inhibitor of CYP3A4|
00276|043|D|and like ketoconazole, troleandomycin is also expected to markedly increase|
00276|044|D|cisapride serum concentrations.  Therefore, concurrent use of this product|
00276|045|D|with cisapride is also contraindicated.|
00276|046|D|   Maximum concentrations (Cmax) of cisapride were increased by 95% during|
00276|047|D|concurrent telithromycin.(5)|
00276|048|D|   One or more of the drug pairs linked to this monograph have been included|
00276|049|D|in a list of interactions that should be considered "high-priority" for|
00276|050|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00276|051|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00276|052|D|Coordinator (ONC) for Health Information Technology.|
00276|053|B||
00276|054|R|REFERENCES:|
00276|055|B||
00276|056|R|1.Propulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00276|057|R|  January, 2000.|1
00276|058|R|2.Data on file (LMD 125108). Janssen Pharmaceutica Products, L.P. February,|1
00276|059|R|  1997.|1
00276|060|R|3.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
00276|061|R|  September, 2019.|1
00276|062|R|4.Ketek (telithromycin) UK summary of product characteristics.|1
00276|063|R|  Sanofi-Aventis June 2, 2009.|1
00276|064|R|5.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
00276|065|R|  December, 2010.|1
00276|066|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00276|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00276|068|R|  settings: a scientific statement from the American Heart Association and|6
00276|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00276|070|R|  2;55(9):934-47.|6
00276|071|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00276|072|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00276|073|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00276|074|R|  19(5):735-43.|6
00277|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/SSRIs; Nefazodone|
00277|002|B||
00277|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00277|004|L|is contraindicated and generally should not be dispensed or administered to|
00277|005|L|the same patient.|
00277|006|B||
00277|007|A|MECHANISM OF ACTION:  Concurrent administration may result in the inhibition|
00277|008|A|of the metabolism of astemizole and terfenadine by the SSRIs and nefazodone.|
00277|009|B||
00277|010|E|CLINICAL EFFECTS:  Concurrent administration may result in increased serum|
00277|011|E|levels of astemizole and terfenadine resulting in possible life-threatening|
00277|012|E|cardiotoxicity including QT prolongation or torsades de pointes.|
00277|013|B||
00277|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00277|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00277|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00277|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00277|018|P|female gender, or advanced age.(9)|
00277|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00277|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00277|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00277|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00277|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00277|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00277|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(9)|
00277|026|B||
00277|027|M|PATIENT MANAGEMENT:  Concomitant administration of terfenadine with either|
00277|028|M|fluvoxamine and nefazodone is contraindicated.(1-3)  The manufacturer of|
00277|029|M|terfenadine states that concurrent administration of terfenadine and|
00277|030|M|sertraline is not recommended.(3)  Concomitant administration of astemizole|
00277|031|M|with fluvoxamine and nefazodone is contraindicated by the manufacturers of|
00277|032|M|fluvoxamine and nefazodone.(1,2)  Concomitant administration of astemizole|
00277|033|M|and fluoxetine, fluvoxamine, nefazodone, paroxetine, or sertraline is not|
00277|034|M|recommended by the manufacturer of astemizole.(4)|
00277|035|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00277|036|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00277|037|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00277|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00277|039|B||
00277|040|D|DISCUSSION:  Elevated plasma levels of the nonsedating antihistamines|
00277|041|D|astemizole or terfenadine can cause QT prolongation and torsades de|
00277|042|D|pointes-type ventricular tachycardia which may be fatal. Both astemizole and|
00277|043|D|terfenadine are metabolized by CYP3A4.  Drugs that block the metabolism of|
00277|044|D|astemizole and terfenadine may produce an increase in plasma concentrations|
00277|045|D|of these antihistamines. It has not been demonstrated that fluvoxamine is a|
00277|046|D|potent inhibitor of CYP3A4: however, fluvoxamine is suspected to be. In|
00277|047|D|vitro studies have shown nefazodone to be an inhibitor of CYP3A4.  Therefore|
00277|048|D|the manufacturers of fluvoxamine and nefazodone contraindicate concurrent|
00277|049|D|use with either astemizole or or terfenadine.(1,2)|
00277|050|D|   The manufacturer of astemizole states that concurrent administration of|
00277|051|D|astemizole and fluoxetine, fluvoxamine, nefazodone, paroxetine, or|
00277|052|D|sertraline is not recommended.(4)|
00277|053|D|   In a study, concurrent administration of fluoxetine with a single dose of|
00277|054|D|terfenadine resulted in no changes in terfenadine levels.  The manufacturer|
00277|055|D|of fluoxetine states that fluoxetine inhibition of CYP3A4 is unlikely to be|
00277|056|D|of clinical significance.(5)|
00277|057|D|   In a study, concurrent administration of paroxetine with terfenadine at|
00277|058|D|steady state resulted in no changes in terfenadine levels.  The manufacturer|
00277|059|D|of paroxetine states that paroxetine inhibition of CYP3A4 is unlikely to be|
00277|060|D|of clinical significance.(6,7)|
00277|061|D|   In a study, concurrent administration of sertraline with terfenadine at|
00277|062|D|steady state resulted in no changes in terfenadine levels.  The manufacturer|
00277|063|D|of sertraline states that sertraline inhibition of CYP3A4 is unlikely to be|
00277|064|D|of clinical significance.(8)|
00277|065|B||
00277|066|R|REFERENCES:|
00277|067|B||
00277|068|R|1.Fluvoxamine US prescribing information. Teva Pharmaceuticals November,|1
00277|069|R|  2017.|1
00277|070|R|2.Serzone (nefazodone hydrochloride) US prescribing information.|1
00277|071|R|  Bristol-Myers Squibb Company January, 2005.|1
00277|072|R|3.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00277|073|R|  September, 1997.|1
00277|074|R|4.Hismanal (astemizole) US prescribing information. Janssen Pharmaceutica|1
00277|075|R|  Products, L.P. February, 1998.|1
00277|076|R|5.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
00277|077|R|  and Company August, 2023.|1
00277|078|R|6.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
00277|079|R|  Technologies January, 2017.|1
00277|080|R|7.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
00277|081|R|  Therapeutics, LLC September, 2021.|1
00277|082|R|8.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
00277|083|R|9.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00277|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00277|085|R|  settings: a scientific statement from the American Heart Association and|6
00277|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00277|087|R|  2;55(9):934-47.|6
00278|001|T|MONOGRAPH TITLE:  Selected Benzodiazepines/Fluoxetine; Nefazodone|
00278|002|B||
00278|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00278|004|L|take action as needed.|
00278|005|B||
00278|006|A|MECHANISM OF ACTION:  Fluoxetine, a strong CYP2C19 inhibitor, and|
00278|007|A|nefazodone, a strong CYP3A4 inhibitor, may decrease the metabolism of Phase|
00278|008|A|I hepatically metabolized benzodiazepines.  Benzodiazepines linked to this|
00278|009|A|monograph are metabolized by both CYP2C19 and CYP3A4.|
00278|010|B||
00278|011|E|CLINICAL EFFECTS:  Concurrent use of fluoxetine or nefazodone and selected|
00278|012|E|benzodiazepines may result in increased systemic levels and clinical effects|
00278|013|E|of the benzodiazepine.  Toxic effects of increased benzodiazepine levels|
00278|014|E|include profound sedation, respiratory depression, coma, and/or death.|
00278|015|E|   Benzodiazepines linked to this monograph are chlordiazepoxide,|
00278|016|E|clorazepate, diazepam, flurazepam, halazepam, prazepam and quazepam.|
00278|017|B||
00278|018|P|PREDISPOSING FACTORS:  Patients receiving a medication regimen which|
00278|019|P|includes inhibitors of both major benzodiazepine metabolic pathways (i.e.|
00278|020|P|CYP2C19 and CYP3A4).|
00278|021|B||
00278|022|M|PATIENT MANAGEMENT:  Benzodiazepines that do not undergo extensive Phase I|
00278|023|M|metabolism (lorazepam, oxazepam) may be an alternative to interacting|
00278|024|M|benzodiazepines in patients receiving fluoxetine or nefazodone.|
00278|025|M|   The benzodiazepine dose may need to be decreased during concurrent|
00278|026|M|therapy with fluoxetine or nefazodone.  If nefazodone or fluoxetine is|
00278|027|M|started in a patient already receiving a benzodiazepine metabolized by|
00278|028|M|CYP2C19 and CYP3A4, then monitor closely and anticipate the need to reduce|
00278|029|M|the benzodiazepine dose.|
00278|030|M|   If on review of medication therapy the patient is found to be taking both|
00278|031|M|a strong CYP2C19 and a strong CYP3A4 inhibitor, it would be prudent to|
00278|032|M|convert patient to an alternative benzodiazepine or to an alternative to the|
00278|033|M|inhibiting agent(s).|
00278|034|M|   Counsel patient to report excess drowsiness, confusion, memory problems|
00278|035|M|including sleep-driving behaviors, loss of coordination, slowed or difficult|
00278|036|M|breathing, or unresponsiveness.|
00278|037|B||
00278|038|D|DISCUSSION:  Fluoxetine has been shown to increase the area-under-curve|
00278|039|D|(AUC) and half-life (T1/2) of diazepam and to decrease the plasma clearance|
00278|040|D|and formation of N-desmethyldiazepam.|
00278|041|D|   Benzodiazepines such as lorazepam, oxazepam, which do not undergo|
00278|042|D|extensive Phase I hepatic metabolism, would not be expected to interact with|
00278|043|D|fluoxetine or nefazodone.|
00278|044|D|   Citalopram has been shown not to have clinically significant effects on|
00278|045|D|triazolam.|
00278|046|D|   Sertraline has been shown not to have clinically significant effects on|
00278|047|D|diazepam.|
00278|048|D|   A statistically significant interaction has been shown to occur between|
00278|049|D|venlafaxine and diazepam. However, the magnitude of the effects does not|
00278|050|D|appear to be sufficient to be clinically important.|
00278|051|B||
00278|052|R|REFERENCES:|
00278|053|B||
00278|054|R|1.Lemberger L, Rowe H, Bosomworth JC, Tenbarge JB, Bergstrom RF. The effect|2
00278|055|R|  of fluoxetine on the pharmacokinetics and psychomotor responses of|2
00278|056|R|  diazepam. Clin Pharmacol Ther 1988 Apr;43(4):412-9.|2
00278|057|R|2.Moskowitz H, Burns M. The effects on performance of two antidepressants,|2
00278|058|R|  alone and in combination with diazepam. Prog Neuropsychopharmacol Biol|2
00278|059|R|  Psychiatry 1988;12(5):783-92.|2
00278|060|R|3.Gardner MJ, Baris BA, Wilner KD, Preskorn SH. Effect of sertraline on the|4
00278|061|R|  pharmacokinetics and protein binding of diazepam in healthy volunteers.|4
00278|062|R|  Clin Pharmacokinet 1997;32 Suppl 1:43-9.|4
00278|063|R|4.Troy SM, Lucki I, Peirgies AA, Parker VD, Klockowski PM, Chiang ST.|2
00278|064|R|  Pharmacokinetic and pharmacodynamic evaluation of the potential drug|2
00278|065|R|  interaction between venlafaxine and diazepam. J Clin Pharmacol 1995 Apr;|2
00278|066|R|  35(4):410-9.|2
00278|067|R|5.Nolting A, Abramowitz W. Lack of interaction between citalopram and the|2
00278|068|R|  CYP3A4 substrate triazolam. Pharmacotherapy 2000 Jul;20(7):750-5.|2
00278|069|R|6.Barbhaiya RH, Shukla UA, Kroboth PD, Greene DS. Coadministration of|2
00278|070|R|  nefazodone and benzodiazepines: II. A pharmacokinetic interaction study|2
00278|071|R|  with triazolam. J Clin Psychopharmacol 1995 Oct;15(5):320-6.|2
00278|072|R|7.Kroboth PD, Folan MM, Lush RM, Chaikin PC, Shukla UA, Barbhaiya R, Salazar|2
00278|073|R|  DE. Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic|2
00278|074|R|  assessment. J Clin Psychopharmacol 1995 Oct;15(5):306-19.|2
00278|075|R|8.Greene DS, Salazar DE, Dockens RC, Kroboth P, Barbhaiya RH.|2
00278|076|R|  Coadministration of nefazodone and benzodiazepines: IV. A pharmacokinetic|2
00278|077|R|  interaction study with lorazepam. J Clin Psychopharmacol 1995 Dec;|2
00278|078|R|  15(6):409-16.|2
00278|079|R|9.Greene DS, Salazar DE, Dockens RC, Kroboth P, Barbhaiya RH.|2
00278|080|R|  Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic|2
00278|081|R|  interaction study with alprazolam. J Clin Psychopharmacol 1995 Dec;|2
00278|082|R|  15(6):399-408.|2
00278|083|R|10.Nefazodone Hydrochloride US prescribing information. Teva Pharmaceuticals|1
00278|084|R|   USA Inc. June, 2014.|1
00279|001|T|MONOGRAPH TITLE:  Ketorolac/OAT3 Inhibitors|
00279|002|B||
00279|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00279|004|L|is contraindicated and generally should not be dispensed or administered to|
00279|005|L|the same patient.|
00279|006|B||
00279|007|A|MECHANISM OF ACTION:  Inhibitors of organic anion transporter 3 (OAT3) may|
00279|008|A|inhibit the renal clearance of ketorolac.|
00279|009|B||
00279|010|E|CLINICAL EFFECTS:  Enhanced ketorolac toxicity including gastrointestinal|
00279|011|E|and renal toxicity as well as increased risk of bleeding.|
00279|012|B||
00279|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00279|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00279|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
00279|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00279|017|P|risk for bleeding (e.g. NSAIDs).|
00279|018|B||
00279|019|M|PATIENT MANAGEMENT:  Concomitant administration of ketorolac and organic|
00279|020|M|anion transporter 3 (OAT3) inhibitors are contraindicated by the|
00279|021|M|manufacturer.|
00279|022|M|   If concurrent therapy is deemed medically necessary, monitor patients|
00279|023|M|receiving concurrent therapy for signs of blood loss, including decreased|
00279|024|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
00279|025|M|and promptly evaluate patients with any symptoms.|
00279|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00279|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00279|028|M|anticoagulation in patients with active pathologic bleeding.|
00279|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00279|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00279|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00279|032|M|and/or swelling.|
00279|033|B||
00279|034|D|DISCUSSION:  Probenecid has been reported to increase serum concentrations|
00279|035|D|and toxicity of nonsteroidal anti-inflammatory drugs (e.g., indomethacin,|
00279|036|D|ketoprofen, naproxen).(1-3) Based upon material from the manufacturer of|
00279|037|D|ketorolac, concurrent administration of probenecid and ketorolac also|
00279|038|D|increases serum concentrations of the NSAID ketorolac and produces a 2-fold|
00279|039|D|increase in the half-life of ketorolac and a 3-fold increase in the area|
00279|040|D|under the plasma concentration-time curve.(4) Ketorolac is a potent NSAID|
00279|041|D|analgesic and increasing the serum concentrations may increase the risk of|
00279|042|D|occurrence of serious renal, GI and hematologic side effects.|
00279|043|D|   OAT3 inhibitors linked to this monograph include:  cabotegravir,|
00279|044|D|leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(5)|
00279|045|B||
00279|046|R|REFERENCES:|
00279|047|B||
00279|048|R|1.Runkel R, Mroszczak E, Chaplin M, Sevelius H, Segre E. Naproxen-probenecid|2
00279|049|R|  interaction. Clin Pharmacol Ther 1978 Dec;24(6):706-13.|2
00279|050|R|2.Upton RA, Williams RL, Buskin JN, Jones RM. Effects of probenecid on|2
00279|051|R|  ketoprofen kinetics. Clin Pharmacol Ther 1982 Jun;31(6):705-12.|2
00279|052|R|3.Sinclair H, Gibson T. Interaction between probenecid and indomethacin. Br|3
00279|053|R|  J Rheumatol 1986 Aug;25(3):316-7.|3
00279|054|R|4.Toradol (ketorolac tromethamine) US prescribing information. Roche|1
00279|055|R|  Pharmaceuticals March, 2013.|1
00279|056|R|5.This information is based on an extract from the Certara Drug Interaction|6
00279|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00281|001|T|MONOGRAPH TITLE:  Enoxaparin/Ketorolac (mono deleted 06/24/2004)|
00281|002|B||
00281|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00281|004|L|of severe adverse interaction.|
00281|005|B||
00281|006|A|MECHANISM OF ACTION:  Enoxaparin, a low-molecular weight heparin, exhibits|
00281|007|A|antithrombotic activity through its anti-clotting factor activities on|
00281|008|A|Factor Xa and Factor IIa. Ketorolac inhibits platelet aggregation.|
00281|009|B||
00281|010|E|CLINICAL EFFECTS:  Concurrent therapy may result in an increased risk of|
00281|011|E|hemorrhage.|
00281|012|B||
00281|013|P|PREDISPOSING FACTORS:  None determined.|
00281|014|B||
00281|015|M|PATIENT MANAGEMENT:  Concurrent therapy should be avoided if possible.|
00281|016|M|Patients in whom concurrent therapy cannot be avoided should be closely|
00281|017|M|monitored.|
00281|018|B||
00281|019|D|DISCUSSION:  Although no adverse events were recorded in one randomized|
00281|020|D|study of concurrent therapy with enoxaparin and ketorolac, the manufacturer|
00281|021|D|of enoxaparin recommends that the agents not be used together. The patients|
00281|022|D|in the study were extensively monitored during concurrent therapy and only|
00281|023|D|received five doses of ketorolac with no other NSAID use in the previous|
00281|024|D|four weeks.|
00281|025|B||
00281|026|R|REFERENCES:|
00281|027|B||
00281|028|R|1.Toradol (ketorolac) US prescribing information. Roche Pharmaceuticals|1
00281|029|R|  August, 1997.|1
00281|030|R|2.Lovenox (enoxaparin) US prescribing information. Aventis Pharmaceuticals,|1
00281|031|R|  Inc. December, 2004.|1
00281|032|R|3.Weale AE, Warwick DJ, Durant N, Prothero D. Is there a clinical|2
00281|033|R|  interaction between low molecular weight heparin and non-steroidal|2
00281|034|R|  analgesics after total hip replacement?. Ann R Coll Surg Engl 1995 Jan;|2
00281|035|R|  77(1):35-7.|2
00282|001|T|MONOGRAPH TITLE:  Fluvoxamine/Cisapride|
00282|002|B||
00282|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00282|004|L|is contraindicated and generally should not be dispensed or administered to|
00282|005|L|the same patient.|
00282|006|B||
00282|007|A|MECHANISM OF ACTION:  Fluvoxamine may inhibit the metabolism of cisapride,|
00282|008|A|resulting in elevated cisapride levels.(1,2)|
00282|009|B||
00282|010|E|CLINICAL EFFECTS:  Concurrent administration may result in increased serum|
00282|011|E|cisapride levels resulting in possible life-threatening cardiotoxicity|
00282|012|E|including QT prolongation or torsades de pointes.|
00282|013|B||
00282|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00282|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00282|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00282|017|P|long QT syndrome) hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00282|018|P|female gender, or advanced age.(3)|
00282|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00282|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00282|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00282|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00282|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00282|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00282|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00282|026|B||
00282|027|M|PATIENT MANAGEMENT:  Concurrent administration of fluvoxamine(2) with|
00282|028|M|cisapride is contraindicated.|
00282|029|M|   If alternatives are not available and concurrent therapy is deemed|
00282|030|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
00282|031|M|and monitor ECG at baseline and at regular intervals.  Correct any|
00282|032|M|electrolyte abnormalities.  Instruct patients to report any irregular|
00282|033|M|heartbeat, dizziness, or fainting.|
00282|034|B||
00282|035|D|DISCUSSION:  It has not been demonstrated that fluvoxamine is a potent|
00282|036|D|inhibitor of CYP3A4; however, fluvoxamine is suspected to be.  In vitro|
00282|037|D|studies have shown fluvoxamine to be an inhibitor of CYP3A4.(2)  Therefore|
00282|038|D|the manufacturer of fluvoxamine contraindicates concurrent therapy with|
00282|039|D|cisapride.(2)|
00282|040|D|   In a study, concurrent administration of fluoxetine with a single dose of|
00282|041|D|terfenadine resulted in no changes in terfenadine levels.  The manufacturer|
00282|042|D|of fluoxetine states that fluoxetine inhibition of CYP3A4 is unlikely to be|
00282|043|D|of clinical significance.(4)|
00282|044|D|   In a study, concurrent administration of paroxetine with terfenadine at|
00282|045|D|steady state resulted in no changes in terfenadine levels.  The manufacturer|
00282|046|D|of paroxetine states that paroxetine inhibition of CYP3A4 is unlikely to be|
00282|047|D|of clinical significance.(5,6)|
00282|048|D|   In a study, concurrent administration of sertraline with cisapride at|
00282|049|D|steady state resulted in no changes in cisapride levels.  The manufacturer|
00282|050|D|of sertraline states that sertraline inhibition of CYP3A4 is unlikely to be|
00282|051|D|of clinical significance.(6,7)|
00282|052|B||
00282|053|R|REFERENCES:|
00282|054|B||
00282|055|R|1.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00282|056|R|  Products, L.P. January, 2000.|1
00282|057|R|2.Fluvoxamine maleate US prescribing information. Eon Labs, Inc. March,|1
00282|058|R|  2005.|1
00282|059|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00282|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00282|061|R|  settings: a scientific statement from the American Heart Association and|6
00282|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00282|063|R|  2;55(9):934-47.|6
00282|064|R|4.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
00282|065|R|  and Company August, 2023.|1
00282|066|R|5.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
00282|067|R|  Technologies January, 2017.|1
00282|068|R|6.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
00282|069|R|  Therapeutics, LLC September, 2021.|1
00282|070|R|7.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
00283|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Amiodarone|
00283|002|B||
00283|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00283|004|L|is contraindicated and generally should not be dispensed or administered to|
00283|005|L|the same patient.|
00283|006|B||
00283|007|A|MECHANISM OF ACTION:  Ritonavir-boosted nirmatrelvir(1) or tipranavir(2);|
00283|008|A|ritonavir-boosted or unboosted indinavir(3); or nelfinavir (4) may inhibit|
00283|009|A|the metabolism of amiodarone at CYP3A4.|
00283|010|B||
00283|011|E|CLINICAL EFFECTS:  The concurrent administration of amiodarone with|
00283|012|E|ritonavir-boosted nirmatrelvir(1) or tipranavir(2); ritonavir-boosted or|
00283|013|E|unboosted indinavir(3); or nelfinavir (4) may result in increased levels,|
00283|014|E|clinical effects, and toxicity of amiodarone.|
00283|015|B||
00283|016|P|PREDISPOSING FACTORS:  None determined.|
00283|017|B||
00283|018|M|PATIENT MANAGEMENT:  The concurrent administration of amiodarone with|
00283|019|M|ritonavir-boosted nirmatrelvir(1) or tipranavir(2); ritonavir-boosted or|
00283|020|M|unboosted indinavir(3); or nelfinavir (4) is contraindicated by the|
00283|021|M|manufacturers of these drugs.|
00283|022|B||
00283|023|D|DISCUSSION:  Indinavir has been shown to inhibit CYP3A4.  Therefore, the|
00283|024|D|manufacturer of indinavir states that the concurrent administration of|
00283|025|D|indinavir with amiodarone, which is metabolized by CYP3A4, is|
00283|026|D|contraindicated.(3)|
00283|027|D|   Nelfinavir has been shown to inhibit CYP3A4.  Therefore, the manufacturer|
00283|028|D|of nelfinavir states that the concurrent administration of nelfinavir with|
00283|029|D|amiodarone, which is metabolized by CYP3A4, is contraindicated.(4)|
00283|030|D|   Protease inhibitors linked to this monograph include: indinavir,|
00283|031|D|nelfinavir, nirmatrelvir, and tipranavir.  Ritonavir is always used with|
00283|032|D|another protease inhibitor as a pharmacokinetic booster and is captured as|
00283|033|D|part of the protease inhibitor regimen.|
00283|034|B||
00283|035|R|REFERENCES:|
00283|036|B||
00283|037|R|1.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
00283|038|R|  information. Pfizer Inc. February, 2025.|1
00283|039|R|2.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00283|040|R|  Pharmaceuticals, Inc. April, 2024.|1
00283|041|R|3.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00283|042|R|  September, 2016.|1
00283|043|R|4.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00283|044|R|  Pharmaceuticals, Inc. September, 2016.|1
00284|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Bepridil|
00284|002|B||
00284|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00284|004|L|is contraindicated and generally should not be dispensed or administered to|
00284|005|L|the same patient.|
00284|006|B||
00284|007|A|MECHANISM OF ACTION:  Atazanavir,(1-2) darunavir,(3-4) lopinavir,(5)|
00284|008|A|nirmatrelvir,(6-7) paritaprevir,(8) and tipranavir(9) may inhibit the|
00284|009|A|metabolism of bepridil.|
00284|010|B||
00284|011|E|CLINICAL EFFECTS:  Concurrent administration of atazanavir,(1-2)|
00284|012|E|darunavir,(3-4) lopinavir,(5) nirmatrelvir,(6-7) paritaprevir,(8) or|
00284|013|E|tipranavir(9) may result in increased levels and clinical effects of|
00284|014|E|bepridil.|
00284|015|B||
00284|016|P|PREDISPOSING FACTORS:  None determined.|
00284|017|B||
00284|018|M|PATIENT MANAGEMENT:  The UK manufacturers of atazanavir(2) and darunavir(4)|
00284|019|M|state that concurrent use of bepridil is contraindicated.(1)  The US|
00284|020|M|manufacturers of atazanavir, darunavir, lopinavir, and paritaprevir|
00284|021|M|recommend caution and monitoring of bepridil concentrations during|
00284|022|M|concurrent therapy.(1,3,5,8)|
00284|023|M|   The US manufacturer of tipranavir states that concurrent administration|
00284|024|M|with bepridil is contraindicated.(9)|
00284|025|B||
00284|026|D|DISCUSSION:  The protease inhibitors linked to this monograph inhibit CYP3A4|
00284|027|D|at clinically relevant concentrations.|
00284|028|B||
00284|029|R|REFERENCES:|
00284|030|B||
00284|031|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
00284|032|R|  Squibb Company December, 2024.|1
00284|033|R|2.Reyataz (atazanavir) UK summary of product characteristics. Bristol-Myers|1
00284|034|R|  Squibb Pharmaceuticals Limited September 8, 2008.|1
00284|035|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
00284|036|R|  March, 2023.|1
00284|037|R|4.Prezista (darunavir) UK Summary of product characteristics. Janssen-Cilgat|1
00284|038|R|  LTD August 8, 2008.|1
00284|039|R|5.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00284|040|R|  Laboratories December, 2019.|1
00284|041|R|6.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
00284|042|R|  information. Pfizer Inc. February, 2025.|1
00284|043|R|7.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
00284|044|R|  Monograph. Pfizer Canada ULC October, 2023.|1
00284|045|R|8.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
00284|046|R|  prescribing information. AbbVie Inc. December, 2019.|1
00284|047|R|9.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00284|048|R|  Pharmaceuticals, Inc. April, 2024.|1
00285|001|T|MONOGRAPH TITLE:  Ritonavir/Bupropion (mono deleted 09/20/2022)|
00285|002|B||
00285|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00285|004|L|take action as needed.|
00285|005|B||
00285|006|A|MECHANISM OF ACTION:  Ritonavir may induce the metabolism of bupropion by|
00285|007|A|CYP2B6.(1,2)|
00285|008|B||
00285|009|E|CLINICAL EFFECTS:  Concurrent ritonavir may result in decreased levels of|
00285|010|E|bupropion and its active metabolite, hydroxybupropion, which may result in a|
00285|011|E|decrease in clinical response.(1,2)|
00285|012|B||
00285|013|P|PREDISPOSING FACTORS:  None determined.|
00285|014|B||
00285|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent ritonavir and|
00285|016|M|bupropion for an adequate clinical response to bupropion.(1)  The dosage of|
00285|017|M|bupropion may need to be adjusted; however, the maximum recommended dose of|
00285|018|M|bupropion should not be exceed.(2)  An alternative agent may need to be|
00285|019|M|selected.|
00285|020|B||
00285|021|D|DISCUSSION:  Although ritonavir was shown to inhibit bupropion metabolism in|
00285|022|D|vitro,(3) data in humans is contradictory.|
00285|023|D|   In a study in 7 healthy subjects, pretreatment with ritonavir (200 mg|
00285|024|D|twice daily for 2 days) did not have a significant effect on the|
00285|025|D|pharmacokinetics of a single dose of bupropion (75 mg).(4)|
00285|026|D|   In a study in 13 healthy subjects, subjects received a single dose of|
00285|027|D|bupropion (150 mg) alone and after 3 and 17 days of ritonavir (200 mg 3|
00285|028|D|times daily for 1 day, 300 mg twice daily for 6 days, then 400 mg twice|
00285|029|D|daily).  Treatment with 3 days of ritonavir decreased the area-under-curve|
00285|030|D|(AUC) of racemic, R-bupropion, and S-bupropion by 16%, 14%, and 20%,|
00285|031|D|respectively.  Steady-state ritonavir decreased the AUC of racemic,|
00285|032|D|R-bupropion, and S-bupropion by 33%, 31%, and 40%, respectively.  Apparent|
00285|033|D|oral clearance of racemic, R-bupropion, and S-bupropion increased by|
00285|034|D|1.2-fold after 3 days of ritonavir.  Apparent oral clearance of racemic,|
00285|035|D|R-bupropion, and S-bupropion increased by 1.4-fold, 1.7-fold, and by|
00285|036|D|1.5-fold with steady state ritonavir.(5)|
00285|037|D|   In a study in healthy subjects, ritonavir (100 mg twice daily) decreased|
00285|038|D|the AUC and maximum concentration (Cmax) of bupropion (dosage not stated) by|
00285|039|D|22% and 21%, respectively.  Exposure to the hydroxybupropion,|
00285|040|D|threohydrobupropion, and the erythrohydrobupropion metabolites were|
00285|041|D|decreased by 23%, 38%, and 48%, respectively.(2)|
00285|042|D|   In a study in healthy subjects, ritonavir (600 mg twice daily) decreased|
00285|043|D|the AUC and Cmax of bupropion (dosage not stated) by 66% and 62%,|
00285|044|D|respectively.  Exposure to the hydroxybupropion, threohydrobupropion, and|
00285|045|D|the erythrohydrobupropion metabolites were decreased by 78%, 50%, and 68%,|
00285|046|D|respectively.(2)|
00285|047|D|  In a study in healthy subjects, lopinavir/ritonavir (400/100 mg twice|
00285|048|D|daily) decreased the AUC and Cmax of bupropion (dosage not stated) by 57%|
00285|049|D|each.  The AUC and Cmax of hydroxybupropion decreased by 50% and 31%,|
00285|050|D|respectively.(2)|
00285|051|B||
00285|052|R|REFERENCES:|
00285|053|B||
00285|054|R|1.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00285|055|R|  December, 2019.|1
00285|056|R|2.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
00285|057|R|  GlaxoSmithKline November, 2019.|1
00285|058|R|3.Hesse LM, von Moltke LL, Shader RI, Greenblatt DJ. Ritonavir, efavirenz,|5
00285|059|R|  and nelfinavir inhibit CYP2B6 activity in vitro: potential drug|5
00285|060|R|  interactions with bupropion. Drug Metab Dispos 2001 Feb;29(2):100-2.|5
00285|061|R|4.Hesse LM, Greenblatt DJ, von Moltke LL, Court MH. Ritonavir has minimal|2
00285|062|R|  impact on the pharmacokinetic disposition of a single dose of bupropion|2
00285|063|R|  administered to human volunteers. J Clin Pharmacol 2006 May;46(5):567-76.|2
00285|064|R|5.Kharasch ED, Mitchell D, Coles R, Blanco R. Rapid clinical induction of|2
00285|065|R|  hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents|2
00285|066|R|  Chemother 2008 May;52(5):1663-9.|2
00286|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Inhibitors/Cisapride (mono deleted|
00286|002|T|02/28/2023)|
00286|003|B||
00286|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00286|005|L|is contraindicated and generally should not be dispensed or administered to|
00286|006|L|the same patient.|
00286|007|B||
00286|008|A|MECHANISM OF ACTION:  The metabolism of cisapride may be inhibited by the|
00286|009|A|protease inhibitors(1-12) and cobicistat.(13)|
00286|010|B||
00286|011|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
00286|012|E|of cisapride, which may result in cardiac arrhythmias including QT|
00286|013|E|prolongation or torsades de pointes.(1-13)|
00286|014|B||
00286|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00286|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
00286|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00286|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00286|019|P|female gender, or advanced age.(14)|
00286|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00286|021|P|higher systemic concentrations of either QT prolonging drug are additional|
00286|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00286|023|P|drug concentrations include rapid infusion of an intravenous dose or|
00286|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00286|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00286|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(14)|
00286|027|B||
00286|028|M|PATIENT MANAGEMENT:  The concurrent administration of cisapride with|
00286|029|M|amprenavir,(1) atazanavir,(2,3) darunavir,(4) fosamprenavir,(5)|
00286|030|M|indinavir,(6) nelfinavir,(7) ritonavir,(8,9) the combination of lopinavir|
00286|031|M|and ritonavir,(10) saquinavir,(11) tipranavir coadministered with|
00286|032|M|ritonavir,(12) and cobicistat(13) is contraindicated.|
00286|033|B||
00286|034|D|DISCUSSION:  Ritonavir has a high affinity for several CYP isoenzymes,|
00286|035|D|including CYP3A4.(7)  The combination of lopinavir and ritonavir has also|
00286|036|D|been shown to inhibit CYP3A4 in vitro and in vivo.(8)  The primary site of|
00286|037|D|the metabolism of indinavir is CYPA4.(6)  Nelfinavir is metabolized at|
00286|038|D|multiple CYP isoenzyme sites; however, only CYP3A is inhibited at|
00286|039|D|therapeutic dosages of nelfinavir.(12)  Saquinavir has been shown to inhibit|
00286|040|D|CYP3A.(10)  Fosamprenavir is rapidly converted to amprenavir, which is|
00286|041|D|metabolized by CYP3A4.(5)  Cobicistat has been shown to be a potent|
00286|042|D|inhibitor of CYP3A4.|
00286|043|D|   Elevated plasma levels of cisapride can cause QT prolongation and|
00286|044|D|torsades de pointes-type ventricular tachycardia which may be fatal.(6)|
00286|045|B||
00286|046|R|REFERENCES:|
00286|047|B||
00286|048|R|1.Agenerase (amprenavir) Capsules US prescribing information.|1
00286|049|R|  GlaxoSmithKline May, 2005.|1
00286|050|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
00286|051|R|  Squibb Company December, 2024.|1
00286|052|R|3.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
00286|053|R|  Squibb Pharmaceuticals October 25, 2023.|1
00286|054|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
00286|055|R|  August, 2021.|1
00286|056|R|5.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
00286|057|R|  March, 2019.|1
00286|058|R|6.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00286|059|R|  September, 2016.|1
00286|060|R|7.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00286|061|R|  December, 2019.|1
00286|062|R|8.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00286|063|R|  Products, L.P. January, 2000.|1
00286|064|R|9.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00286|065|R|  Laboratories December, 2019.|1
00286|066|R|10.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00286|067|R|   Laboratories, Inc. March, 2019.|1
00286|068|R|11.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00286|069|R|   Pharmaceuticals, Inc. April, 2024.|1
00286|070|R|12.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00286|071|R|   Pharmaceuticals, Inc. September, 2016.|1
00286|072|R|13.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
00286|073|R|   prescribing information. Gilead Sciences, Inc. September, 2021.|1
00286|074|R|14.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
00286|075|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
00286|076|R|   hospital settings: a scientific statement from the American Heart|6
00286|077|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
00286|078|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
00287|001|T|MONOGRAPH TITLE:  Ritonavir/Clozapine  (mono deleted 05/17/2001)|
00287|002|B||
00287|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00287|004|L|is contraindicated and generally should not be dispensed or administered to|
00287|005|L|the same patient.|
00287|006|B||
00287|007|A|MECHANISM OF ACTION:  Ritonavir may inhibit the metabolism of clozapine.|
00287|008|B||
00287|009|E|CLINICAL EFFECTS:  Increased levels of clozapine.|
00287|010|B||
00287|011|P|PREDISPOSING FACTORS:  None determined.|
00287|012|B||
00287|013|M|PATIENT MANAGEMENT:  Concurrent administration of clozapine and ritonavir is|
00287|014|M|contraindicated by the manufacturer of ritonavir.|
00287|015|B||
00287|016|D|DISCUSSION:  There is no clinical documentation substantiating this|
00287|017|D|potential drug interaction. Ritonavir has a high affinity for several CYP|
00287|018|D|P-450 isoenzymes.|
00287|019|B||
00287|020|R|REFERENCE:|
00287|021|B||
00287|022|R|1.Norvir (ritonavir) US prescribing information. Abbott Laboratories March,|1
00287|023|R|  1997.|1
00288|001|T|MONOGRAPH TITLE:  Nirmatrelvir-Ritonavir; Tipranavir/Flecainide; Propafenone|
00288|002|B||
00288|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00288|004|L|is contraindicated and generally should not be dispensed or administered to|
00288|005|L|the same patient.|
00288|006|B||
00288|007|A|MECHANISM OF ACTION:  Ritonavir-boosted nirmatrelvir and tipranavir may|
00288|008|A|inhibit the metabolism of flecainide by CYP2D6, and of propafenone by CYP2D6|
00288|009|A|and CYP3A4.(1,2)|
00288|010|B||
00288|011|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
00288|012|E|and clinical effects of flecainide and propafenone, including serious and/or|
00288|013|E|life-threatening effects like QT prolongation and torsades de pointes.(1)|
00288|014|B||
00288|015|P|PREDISPOSING FACTORS:  The interaction with tipranavir may be more severe in|
00288|016|P|patients who are CYP2D6 extensive or intermediate metabolizers.|
00288|017|P|   Renal and hepatic impairment may increase risk for excessive QTc|
00288|018|P|prolongation as flecainide and propafenone are both renally and hepatically|
00288|019|P|eliminated.|
00288|020|P|   The risk of QT prolongation or torsades de pointes may be increased in|
00288|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
00288|022|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
00288|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
00288|024|P|advanced age.(2)|
00288|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00288|026|P|higher systemic concentrations of either QT prolonging drug are additional|
00288|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00288|028|P|drug concentrations include rapid infusion of an intravenous dose or|
00288|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00288|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00288|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00288|032|B||
00288|033|M|PATIENT MANAGEMENT:  The concurrent administration of ritonavir-boosted|
00288|034|M|nirmatrelvir or tipranavir and flecainide or propafenone is|
00288|035|M|contraindicated.(1,2)|
00288|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00288|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00288|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00288|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00288|040|B||
00288|041|D|DISCUSSION:  The combination of tipranavir coadministered with ritonavir has|
00288|042|D|been shown to inhibit CYP2D6 and CYP3A4 in vitro and in vivo. Agents that|
00288|043|D|are extensively metabolized by CYP2D6 and CYP3A4 and have high first pass|
00288|044|D|metabolism, like flecainide and propafenone, may be the most susceptible to|
00288|045|D|large increases when coadministered with tipranavir coadministered with|
00288|046|D|ritonavir.(1)|
00288|047|B||
00288|048|R|REFERENCES:|
00288|049|B||
00288|050|R|1.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00288|051|R|  Pharmaceuticals, Inc. April, 2024.|1
00288|052|R|2.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
00288|053|R|  information. Pfizer Inc. February, 2025.|1
00288|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00288|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00288|056|R|  settings: a scientific statement from the American Heart Association and|6
00288|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00288|058|R|  2;55(9):934-47.|6
00289|001|T|MONOGRAPH TITLE:  Ritonavir/Meperidine|
00289|002|B||
00289|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00289|004|L|of severe adverse interaction.|
00289|005|B||
00289|006|A|MECHANISM OF ACTION:  Ritonavir, a moderate CYP2B6 inducer and weak CYP3A4|
00289|007|A|inducer, may induce the metabolism of meperidine to the primary metabolite,|
00289|008|A|normeperidine.(1,2)|
00289|009|B||
00289|010|E|CLINICAL EFFECTS:  Concurrent use of ritonavir and meperidine may result in|
00289|011|E|decreased levels of meperidine, elevated levels of normeperidine, and CNS|
00289|012|E|toxicity, including seizures, profound sedation, respiratory depression,|
00289|013|E|coma, and/or death.(2,3)|
00289|014|B||
00289|015|P|PREDISPOSING FACTORS:  None determined.|
00289|016|B||
00289|017|M|PATIENT MANAGEMENT:  The manufacturer of meperidine states that concomitant|
00289|018|M|use of meperidine and ritonavir should be avoided.(4)  The manufacturer of|
00289|019|M|ritonavir states that dosage increases and long-term use of meperidine in|
00289|020|M|patients receiving ritonavir are not recommended.(2)|
00289|021|M|    Respiratory depression can occur at any time during opioid therapy,|
00289|022|M|especially during therapy initiation and following dosage increases.  The|
00289|023|M|risk of opioid-related overdose or overdose-related death is increased with|
00289|024|M|higher opioid doses, and this risk persists over the course of therapy.|
00289|025|M|Consider these risks when using concurrently with other agents that may|
00289|026|M|cause CNS depression.(5)|
00289|027|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
00289|028|M|patients when prescribing or renewing an opioid analgesic or medicine to|
00289|029|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
00289|030|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
00289|031|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
00289|032|M|as those taking CNS depressants) and when a patient has household|
00289|033|M|members/close contacts at risk for accidental overdose.  Discuss the options|
00289|034|M|for obtaining an opioid reversal agent (e.g., prescription,|
00289|035|M|over-the-counter, or as part of a community-based program).(6)|
00289|036|B||
00289|037|D|DISCUSSION:  In a study in eight healthy subjects, the administration of a|
00289|038|D|single dose of meperidine (50 mg) after 10 days of ritonavir (500 mg twice|
00289|039|D|daily) resulted in decreases in the meperidine area-under-curve (AUC) and|
00289|040|D|maximum concentration (Cmax) by 67% and 60%, respectively.(3)  The AUC and|
00289|041|D|and Cmax of normeperidine increased by 47% and 87%, respectively.(2)|
00289|042|B||
00289|043|R|REFERENCES:|
00289|044|B||
00289|045|R|1.This information is based on an extract from the Certara Drug Interaction|6
00289|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00289|047|R|2.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00289|048|R|  December, 2019.|1
00289|049|R|3.Piscitelli SC, Kress DR, Bertz RJ, Pau A, Davey R. The effect of ritonavir|2
00289|050|R|  on the pharmacokinetics of meperidine and normeperidine. Pharmacotherapy|2
00289|051|R|  2000 May;20(5):549-53.|2
00289|052|R|4.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
00289|053|R|  Pharmaceuticals LLC. December, 2023.|1
00289|054|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
00289|055|R|  prescribing information for all opioid pain medicines to provide|1
00289|056|R|  additional guidance for safe use. Available at:|1
00289|057|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
00289|058|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
00289|059|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
00289|060|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
00289|061|R|  recommends health care professionals discuss naloxone with all patients|1
00289|062|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
00289|063|R|  disorder. Available at:|1
00289|064|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
00289|065|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
00289|066|R|  d-pain July 23, 2020.|1
00290|001|T|MONOGRAPH TITLE:  Protease Inhibitors/Oral Midazolam; Triazolam|
00290|002|B||
00290|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00290|004|L|is contraindicated and generally should not be dispensed or administered to|
00290|005|L|the same patient.|
00290|006|B||
00290|007|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
00290|008|A|the benzodiazepines midazolam and triazolam at CYP3A4.(1-30)|
00290|009|B||
00290|010|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
00290|011|E|and clinical effects of the benzodiazepines, which may result in profound|
00290|012|E|sedation, respiratory depression, coma, and/or death.(1-30) Higher triazolam|
00290|013|E|levels may increase risk for anterograde amnesia, "sleep driving" and other|
00290|014|E|complex behavior disorders.(30)|
00290|015|B||
00290|016|P|PREDISPOSING FACTORS:  The elderly are particularly sensitive to increased|
00290|017|P|plasma concentrations of triazolam.(30)|
00290|018|B||
00290|019|M|PATIENT MANAGEMENT:  The manufacturers of the protease inhibitors and US|
00290|020|M|guidelines on use of antiretroviral agents (31) state that concurrent|
00290|021|M|administration of triazolam or oral midazolam with ritonavir-boosted(1-3)|
00290|022|M|darunavir,(4-6) lopinavir,(7-9) nirmatrelvir,(10) paritaprevir,(11)|
00290|023|M|saquinavir,(12-14) or tipranavir (15-17); ritonavir-boosted or unboosted|
00290|024|M|amprenavir,(18-19) atazanavir,(20-21) fosamprenavir,(22-23)|
00290|025|M|indinavir,(24-26); or nelfinavir,(27-29) is contraindicated.|
00290|026|M|   Midazolam may be administered by the intravenous route in patients with|
00290|027|M|close clinical monitoring for respiratory depression and/or prolonged|
00290|028|M|sedation.  Caution should be exercised and dosage adjustments should be|
00290|029|M|considered if these effects occur.|
00290|030|B||
00290|031|D|DISCUSSION:  In an open-label, randomized study in 14 subjects, lopinavir/|
00290|032|D|ritonavir (400/100 mg twice daily) decreased the metabolism of single doses|
00290|033|D|of oral and intravenous midazolam (0.025 mg/kg and 5 mg, respectively) by|
00290|034|D|77% and 92%, respectively.(32)|
00290|035|D|   In a double-blind, randomized, cross-over study in 12 subjects,|
00290|036|D|concurrent administration of saquinavir base with oral midazolam increased|
00290|037|D|the bioavailability of oral midazolam from 41% to 90%.  The midazolam|
00290|038|D|maximum concentration (Cmax) and area-under-curve (AUC) increased two-fold|
00290|039|D|and five-fold, respectively. The concurrent administration of saquinavir|
00290|040|D|base with intravenous midazolam resulted in a decrease in midazolam|
00290|041|D|clearance by 56% and increased the midazolam half-life from 4.1 hours to 9.5|
00290|042|D|hours.(33)|
00290|043|D|   In a study in 6 healthy subjects, saquinavir base (1200 mg twice daily)|
00290|044|D|increased the AUC and Cmax of a single dose of midazolam (7.5 mg) by 514%|
00290|045|D|and 235%, respectively.(12)|
00290|046|D|   In a study in 16 healthy subjects, saquinavir/ritonavir (1000/100 mg|
00290|047|D|twice daily) increased the AUC and Cmax of a single dose of midazolam (7.5|
00290|048|D|mg) by 1144% and 327%, respectively.(14)|
00290|049|D|   In a double-blind study, ritonavir (four doses of 200 mg) decreased the|
00290|050|D|clearance of a single dose of triazolam (0.125 mg) by 96%.(34)|
00290|051|D|   Amprenavir,(35), lopinavir,(36) and ritonavir(33,34) have been shown to|
00290|052|D|inhibit triazolam metabolism in vitro in human liver microsomes.|
00290|053|D|   In a clinical trial of 13 healthy patients patients receiving concurrent|
00290|054|D|midazolam (3mg) and ritonavir (100 mg three times daily), midazolam AUC|
00290|055|D|increased by a factor of 28.4 +/- 4.2 and oral clearance was reduced to 4.2%|
00290|056|D|of normal.(37)|
00290|057|D|   Protease inhibitors linked to this monograph include: amprenavir,|
00290|058|D|atazanavir, fosamprenavir, darunavir, indinavir, lopinavir, nelfinavir,|
00290|059|D|nirmatrelvir, paritaprevir, saquinavir, and tipranavir. Ritonavir, as a|
00290|060|D|pharmacokinetic booster, will alert through the primary protease inhibitor.|
00290|061|B||
00290|062|R|REFERENCES:|
00290|063|B||
00290|064|R|1.Norvir (ritonavir) Canadian prescribing information. Abbott May 29, 2019.|1
00290|065|R|2.Norvir (ritonavir) UK summary of product characteristics. AbbVie, Ltd.|1
00290|066|R|  July 18, 2019.|1
00290|067|R|3.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00290|068|R|  December, 2019.|1
00290|069|R|4.Prezista (darunavir) Canadian prescribing information. Jannsen-Ortho June,|1
00290|070|R|  2008.|1
00290|071|R|5.Prezista (darunavir) UK Summary of product characteristics. Janssen-Cilgat|1
00290|072|R|  LTD August 8, 2008.|1
00290|073|R|6.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
00290|074|R|  March, 2023.|1
00290|075|R|7.Kaletra (lopinavir/ritonavir) Canadian prescribing information. Abbott|1
00290|076|R|  Limited May 22, 2019.|1
00290|077|R|8.Kaletra (lopinavir/ritonavir) UK summary of product characteristics.|1
00290|078|R|  Abbott Laboratories, Limited July 11, 2008.|1
00290|079|R|9.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00290|080|R|  Laboratories December, 2019.|1
00290|081|R|10.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
00290|082|R|   information. Pfizer Inc. February, 2025.|1
00290|083|R|11.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
00290|084|R|   prescribing information. AbbVie Inc. December, 2019.|1
00290|085|R|12.Invirase (saquinavir mesylate) Canadian prescribing information. Roche|1
00290|086|R|   March, 2007.|1
00290|087|R|13.Invirase (saquinavir mesylate) UK summary of product characteristics.|1
00290|088|R|   Roche Products Limited July 11, 2008.|1
00290|089|R|14.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00290|090|R|   Laboratories, Inc. March, 2019.|1
00290|091|R|15.Aptivus (tipranavir) Canadian prescribing information. Boehringer|1
00290|092|R|   Ingelheim March 5, 2014.|1
00290|093|R|16.Aptivus (tipranavir) UK Summary of product characteristics. Boehringer|1
00290|094|R|   Ingelheim Limited October 3, 2018.|1
00290|095|R|17.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00290|096|R|   Pharmaceuticals, Inc. April, 2024.|1
00290|097|R|18.Agenerase (amprenavir) summary of product characteristics.|1
00290|098|R|   GlaxoSmithKline UK January 18, 2005.|1
00290|099|R|19.Agenerase (amprenavir) Oral Solution US prescribing information.|1
00290|100|R|   GlaxoSmithKline May, 2005.|1
00290|101|R|20.Reyataz (atazanavir) UK summary of product characteristics. Bristol-Myers|1
00290|102|R|   Squibb Pharmaceuticals Limited September 8, 2008.|1
00290|103|R|21.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
00290|104|R|   Squibb Company December, 2024.|1
00290|105|R|22.Telzir (fosamprenavir calcium) UK summary of product characteristics.|1
00290|106|R|   GlaxoSmithKline UK October 18. 2013.|1
00290|107|R|23.Lexiva (fosamprenavir calcium) US prescribing information.|1
00290|108|R|   GlaxoSmithKline March, 2019.|1
00290|109|R|24.Crixivan (indinavir sulfate) Canadian prescribing information. Merck|1
00290|110|R|   Frosst February, 2007.|1
00290|111|R|25.Crixivan (indinavir sulfphate) UK summary of product characteristics.|1
00290|112|R|   Merck Sharp & Dohme Limited September, 2008.|1
00290|113|R|26.Crixivan (indinavir sulfate) US prescribing information. Merck & Co.,|1
00290|114|R|   Inc. September, 2016.|1
00290|115|R|27.Viracept (nelfinavir mesylate) Canadian prescribing information. Pfizer|1
00290|116|R|   September, 2006.|1
00290|117|R|28.Viracept (nelfinavir mesylate) UK summary of product characteristics.|1
00290|118|R|   Roche Products Limited August 4, 2008.|1
00290|119|R|29.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00290|120|R|   Pharmaceuticals, Inc. September, 2016.|1
00290|121|R|30.Halcion (triazolam) US prescribing information. Pharmacia & Upjohn|1
00290|122|R|   Company October, 2019.|1
00290|123|R|31.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
00290|124|R|   for the use of antiretroviral agents in adults and adolescents Living|6
00290|125|R|   with HIV. Department of Health and Human Services. Available at|6
00290|126|R|   https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats|6
00290|127|R|   -new-guidelines June 13, 2021.|6
00290|128|R|32.Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, Eron|2
00290|129|R|   JJ Jr, Klein CE, Rublein JC, Kashuba AD. Lopinavir/ritonavir induces the|2
00290|130|R|   hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2|2
00290|131|R|   but inhibits the hepatic and intestinal activity of CYP3A as measured by|2
00290|132|R|   a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic|2
00290|133|R|   Syndr 2006 May;42(1):52-60.|2
00290|134|R|33.Palkama VJ, Ahonen J, Neuvonen PJ, Olkkola KT. Effect of saquinavir on|2
00290|135|R|   the pharmacokinetics and pharmacodynamics of oral and intravenous|2
00290|136|R|   midazolam. Clin Pharmacol Ther 1999 Jul;66(1):33-9.|2
00290|137|R|34.Greenblatt DJ, von Moltke LL, Harmatz JS, Durol AL, Daily JP, Graf JA,|2
00290|138|R|   Mertzanis P, Hoffman JL, Shader RI. Differential impairment of triazolam|2
00290|139|R|   and zolpidem clearance by ritonavir. J Acquir Immune Defic Syndr 2000 Jun|2
00290|140|R|   1;24(2):129-36.|2
00290|141|R|35.von Moltke LL, Durol AL, Duan SX, Greenblatt DJ. Potent mechanism-based|5
00290|142|R|   inhibition of human CYP3A in vitro by amprenavir and ritonavir:|5
00290|143|R|   comparison with ketoconazole. Eur J Clin Pharmacol 2000 Jun;56(3):259-61.|5
00290|144|R|36.Weemhoff JL, von Moltke LL, Richert C, Hesse LM, Harmatz JS, Greenblatt|5
00290|145|R|   DJ. Apparent mechanism-based inhibition of human CYP3A in-vitro by|5
00290|146|R|   lopinavir. J Pharm Pharmacol 2003 Mar;55(3):381-6.|5
00290|147|R|37.Greenblatt DJ, Peters DE, Oleson LE, Harmatz JS, MacNab MW, Berkowitz N,|2
00290|148|R|   Zinny MA, Court MH. Inhibition of oral midazolam clearance by boosting|2
00290|149|R|   doses of ritonavir, and by 4,4-dimethyl-benziso-(2H)-selenazine|2
00290|150|R|   (ALT-2074), an experimental catalytic mimic of glutathione oxidase. Br J|2
00290|151|R|   Clin Pharmacol 2009 Dec;68(6):920-7.|2
00291|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Propafenone (mono deleted|
00291|002|T|10/24/2013)|
00291|003|B||
00291|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00291|005|L|is contraindicated and generally should not be dispensed or administered to|
00291|006|L|the same patient.|
00291|007|B||
00291|008|A|MECHANISM OF ACTION:  Lopinavir, ritonavir, and tipranavir coadministered|
00291|009|A|with ritonavir may inhibit the metabolism of propafenone.(1-3)|
00291|010|B||
00291|011|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
00291|012|E|and clinical effects of propafenone, including life threatening cardiac|
00291|013|E|arrhythmias.(1-3)|
00291|014|B||
00291|015|P|PREDISPOSING FACTORS:  None determined.|
00291|016|B||
00291|017|M|PATIENT MANAGEMENT:  The concurrent administration of propafenone with the|
00291|018|M|combination of lopinavir and ritonavir is contraindicated by the|
00291|019|M|manufacturer of Kaletra.(1)|
00291|020|M|   The concurrent administration of propafenone and ritonavir is|
00291|021|M|contraindicated by the manufacturer of ritonavir.(2)|
00291|022|M|   The concurrent administration of propafenone and tipranavir|
00291|023|M|coadministered with ritonavir is contraindicated by the manufacturer of|
00291|024|M|tipranavir.(3)|
00291|025|B||
00291|026|D|DISCUSSION:  The combination of lopinavir and ritonavir and tipranavir|
00291|027|D|coadministered with ritonavir has been shown to inhibit CYP P-450-3A4 in|
00291|028|D|vitro and in vivo. Agents that are extensively metabolized by CYP P-450-3A4|
00291|029|D|and have high first pass metabolism may be the most susceptible to large|
00291|030|D|increases when coadministered with the combination of lopinavir and|
00291|031|D|ritonavir and tipranavir coadministered with ritonavir.(1,3)|
00291|032|D|   Ritonavir alone has also been shown to inhibit CYP P-450-3A4 in vitro and|
00291|033|D|in vivo. Agents that are extensively metabolized by CYP P-450-3A4 and have|
00291|034|D|high first pass metabolism may be the most susceptible to large increases|
00291|035|D|when coadministered with ritonavir.(2)|
00291|036|B||
00291|037|R|REFERENCES:|
00291|038|B||
00291|039|R|1.Kaletra (lopinavir/ritonavir) Canadian prescribing information. Abbott|1
00291|040|R|  Limited May 22, 2019.|1
00291|041|R|2.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00291|042|R|  November, 2012.|1
00291|043|R|3.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00291|044|R|  Pharmaceuticals, Inc. February, 2012.|1
00292|001|T|MONOGRAPH TITLE:  Ritonavir/Propoxyphene|
00292|002|B||
00292|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00292|004|L|is contraindicated and generally should not be dispensed or administered to|
00292|005|L|the same patient.|
00292|006|B||
00292|007|A|MECHANISM OF ACTION:  Ritonavir may inhibit the metabolism of propoxyphene.|
00292|008|A|(1-3)|
00292|009|B||
00292|010|E|CLINICAL EFFECTS:  Increased levels and clinical effects of propoxyphene,|
00292|011|E|including profound sedation, respiratory depression, coma, and/or|
00292|012|E|death.(1-3)|
00292|013|B||
00292|014|P|PREDISPOSING FACTORS:  None determined.|
00292|015|B||
00292|016|M|PATIENT MANAGEMENT:  The Australian(1) and UK(2) manufacturers of ritonavir|
00292|017|M|state that concurrent propoxyphene is contraindicated.  The US manufacturer|
00292|018|M|of ritonavir states that a reduction in propoxyphene dosage may be required|
00292|019|M|during concurrent therapy.(3)|
00292|020|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00292|021|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00292|022|M|unresponsiveness.|
00292|023|B||
00292|024|D|DISCUSSION:  There is no clinical documentation substantiating this|
00292|025|D|potential drug interaction. Ritonavir has a high affinity for several CYP|
00292|026|D|hepatic isoenzymes.|
00292|027|B||
00292|028|R|REFERENCES:|
00292|029|B||
00292|030|R|1.Norvir (ritonavir) Australian prescribing information. Abbott Australasia|1
00292|031|R|  Pty. Ltd. January 29, 2004.|1
00292|032|R|2.Norvir (ritonavir) UK summary of product characteristics. AbbVie, Ltd.|1
00292|033|R|  July 18, 2019.|1
00292|034|R|3.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00292|035|R|  December, 2019.|1
00293|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Alprazolam|
00293|002|B||
00293|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00293|004|L|of severe adverse interaction.|
00293|005|B||
00293|006|A|MECHANISM OF ACTION:  Protease inhibitors, including amprenavir, atazanavir,|
00293|007|A|darunavir, fosamprenavir, lopinavir, nelfinavir, nirmatrelvir/ritonavir,|
00293|008|A|paritaprevir, saquinavir, and tipranavir, may inhibit the metabolism of|
00293|009|A|alprazolam by CYP3A4.(1-3)|
00293|010|B||
00293|011|E|CLINICAL EFFECTS:  The concurrent administration of amprenavir, atazanavir,|
00293|012|E|darunavir, fosamprenavir, lopinavir, nelfinavir, nirmatrelvir/ritonavir,|
00293|013|E|paritaprevir, saquinavir, and tipranavir may result in increased levels and|
00293|014|E|clinical effects of alprazolam, which may result in extreme sedation and|
00293|015|E|respiratory depression.(1-3)|
00293|016|B||
00293|017|P|PREDISPOSING FACTORS:  Inhibition of alprazolam may be greater in patients|
00293|018|P|who have recently started therapy with a protease inhibitor.(1)|
00293|019|B||
00293|020|M|PATIENT MANAGEMENT:  Consider alternative benzodiazepines such as lorazepam,|
00293|021|M|temazepam, or oxazepam.  If concurrent use is necessary, patients receiving|
00293|022|M|amprenavir, atazanavir, darunavir, fosamprenavir, lopinavir, nelfinavir,|
00293|023|M|nirmatrelvir/ritonavir, paritaprevir, saquinavir, or tipranavir should be|
00293|024|M|observed for increased alprazolam effects.  The dosage of alprazolam may|
00293|025|M|need to adjusted, or alprazolam may need to be discontinued.(1-3)|
00293|026|B||
00293|027|D|DISCUSSION:  In a study in healthy subjects, the administration of a single|
00293|028|D|dose of alprazolam (1.0 mg) following 12 days of ritonavir therapy (titrated|
00293|029|D|up to 500 mg daily) resulted in a decrease in the alprazolam|
00293|030|D|area-under-curve (AUC) by 12%.(1,3)  The maximum concentration (Cmax) of|
00293|031|D|alprazolam decreased by 16%.(1)|
00293|032|D|   In contrast to this, in a double-blind study in 10 healthy subjects, the|
00293|033|D|administration of a single dose of alprazolam (1.0 mg) following four doses|
00293|034|D|of ritonavir (200 mg) resulted in a decrease in alprazolam clearance by 59%.|
00293|035|D|Ritonavir has been shown to inhibit and induce CYP3A4.(3)|
00293|036|D|   In a study in 17 subjects, telaprevir (750 mg every 8 hours for 10 days)|
00293|037|D|increased the AUC of a single dose of alprazolam (0.5 mg) by 35%.(4)|
00293|038|B||
00293|039|R|REFERENCES:|
00293|040|B||
00293|041|R|1.Xanax (alprazolam) US prescribing information. Pharmacia & Upjohn Company|1
00293|042|R|  February, 2021.|1
00293|043|R|2.This information is based on an extract from the Certara Drug Interaction|6
00293|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00293|045|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
00293|046|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
00293|047|R|  HIV. Department of Health and Human Services. Available at|6
00293|048|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
00293|049|R|  new-guidelines June 13, 2021.|6
00293|050|R|4.Frye R, Bertz R, Granneman GR, Qian J, Lamm J, Dennis S, Valdes J. Effect|2
00293|051|R|  of ritonavir on the pharmacokinetics and pharmacodynamics of alprazolam.|2
00293|052|R|  37th Interscience Conference on Antimicrobial Agents and Chemotherapy|2
00293|053|R|  (ICAAC), Toronto, Canada 1997;37:12.|2
00293|054|R|5.Greenblatt DJ, von Moltke LL, Harmatz JS, Durol AL, Daily JP, Graf JA,|2
00293|055|R|  Mertzanis P, Hoffman JL, Shader RI. Alprazolam-ritonavir interaction:|2
00293|056|R|  implications for product labeling. Clin Pharmacol Ther 2000 Apr;|2
00293|057|R|  67(4):335-41.|2
00294|001|T|MONOGRAPH TITLE:  Ritonavir/Zolpidem (mono deleted 01/08/2015)|
00294|002|B||
00294|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00294|004|L|take action as needed.|
00294|005|B||
00294|006|A|MECHANISM OF ACTION:  Ritonavir may inhibit the metabolism of zolpidem.(1)|
00294|007|B||
00294|008|E|CLINICAL EFFECTS:  Increased levels and clinical effects of zolpidem,(1)|
00294|009|E|which may result in extreme sedation and respiratory depression.|
00294|010|B||
00294|011|P|PREDISPOSING FACTORS:  None determined.|
00294|012|B||
00294|013|M|PATIENT MANAGEMENT:  Concurrent use of ritonavir may require a decrease in|
00294|014|M|the dose of zolpidem.(1)|
00294|015|B||
00294|016|D|DISCUSSION:  In a double-blind study, ritonavir decreased the clearance of a|
00294|017|D|single dose of zolpidem (5 mg) by 22%.(2)|
00294|018|B||
00294|019|R|REFERENCES:|
00294|020|B||
00294|021|R|1.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00294|022|R|  November, 2012.|1
00294|023|R|2.Greenblatt DJ, von Moltke LL, Harmatz JS, Durol AL, Daily JP, Graf JA,|2
00294|024|R|  Mertzanis P, Hoffman JL, Shader RI. Differential impairment of triazolam|2
00294|025|R|  and zolpidem clearance by ritonavir. J Acquir Immune Defic Syndr 2000 Jun|2
00294|026|R|  1;24(2):129-36.|2
00295|001|T|MONOGRAPH TITLE:  Dexfenfluramine; Fenfluramine/Serotoninergic Agents|
00295|002|B||
00295|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00295|004|L|take action as needed.|
00295|005|B||
00295|006|A|MECHANISM OF ACTION:  Concurrent administration may result in additive|
00295|007|A|effects on serotonin, resulting in serotonin syndrome.|
00295|008|B||
00295|009|E|CLINICAL EFFECTS:  May result in serotonin syndrome, a potentially|
00295|010|E|life-threatening syndrome which may include one or more of the following|
00295|011|E|symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus,|
00295|012|E|tachycardia, hyperthermia, and muscle rigidity.|
00295|013|B||
00295|014|P|PREDISPOSING FACTORS:  None determined.|
00295|015|B||
00295|016|M|PATIENT MANAGEMENT:  The manufacturer of fenfluramine states that|
00295|017|M|fenfluramine should be used with caution with other serotonergic agents such|
00295|018|M|as the selective serotonin reuptake inhibitors, sumatriptan, or|
00295|019|M|dihydroergotamine.|
00295|020|M|   If concurrent therapy is warranted, patients should be monitored for|
00295|021|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00295|022|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00295|023|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00295|024|M|coordination, or severe diarrhea.|
00295|025|B||
00295|026|D|DISCUSSION:  This interaction is based on FDA mandated class labeling for|
00295|027|D|these agents. Although there is no clinical documentation for an interaction|
00295|028|D|between dexfenfluramine or fenfluramine and either the selective serotonin|
00295|029|D|reuptake inhibitors, sumatriptan, or dihydroergotamine, caution is still|
00295|030|D|warranted.  This syndrome has been reported with the selective serotonin|
00295|031|D|reuptake inhibitors and other serotonergic agents, including sumatriptan and|
00295|032|D|dihydroergotamine.|
00295|033|B||
00295|034|R|REFERENCES:|
00295|035|B||
00295|036|R|1.Redux (dexfenfluramine) US prescribing information. Wyeth-Ayerst|1
00295|037|R|  Laboratories April 29, 1996.|1
00295|038|R|2.Personal Communication. Wyeth Labs Inc. July 1996.|1
00295|039|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00295|040|R|  352(11):1112-20.|6
00296|001|T|MONOGRAPH TITLE:  Cyclosporine/Amiodarone|
00296|002|B||
00296|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00296|004|L|take action as needed.|
00296|005|B||
00296|006|A|MECHANISM OF ACTION:  Amiodarone may inhibit the metabolism of cyclosporine|
00296|007|A|by CYP3A4.|
00296|008|B||
00296|009|E|CLINICAL EFFECTS:  Increased levels of cyclosporine, which may result in|
00296|010|E|renal toxicity.|
00296|011|B||
00296|012|P|PREDISPOSING FACTORS:  None determined.|
00296|013|B||
00296|014|M|PATIENT MANAGEMENT:  Monitor cyclosporine levels and renal function in|
00296|015|M|patients receiving concurrent therapy. During concurrent therapy with|
00296|016|M|amiodarone, cyclosporine dosages may need to be decreased by over 50%.|
00296|017|B||
00296|018|D|DISCUSSION:  Documentation on this interaction is limited to case reports|
00296|019|D|involving ten transplant patients. In the first report, the dosage of|
00296|020|D|cyclosporine required to maintain a therapeutic trough concentration of|
00296|021|D|200-250 ng/ml (measured by high-performance liquid chromatography) decreased|
00296|022|D|from 5.4-5.8 mg/Kg/day to 2.3 mg/Kg/day following the addition of|
00296|023|D|amiodarone.  Cyclosporine clearance decreased from 0.22 L/hr/Kg to 0.1|
00296|024|D|L/hr/Kg 12 days after the addition of amiodarone.  In the second report,|
00296|025|D|there was a twofold increase in cyclosporine levels following the addition|
00296|026|D|of amiodarone to stabilized cyclosporine therapy.  A retrospective study of|
00296|027|D|eight transplant patients who received concurrent therapy with cyclosporine|
00296|028|D|and amiodarone reported that cyclosporine levels increased in all subjects|
00296|029|D|despite a decrease in cyclosporine dosage (from 6.2 mg/Kg/day to 3.5|
00296|030|D|mg/Kg/day).|
00296|031|B||
00296|032|R|REFERENCES:|
00296|033|B||
00296|034|R|1.Nicolau DP, Uber WE, Crumbley AJ 3rd, Strange C. Amiodarone-cyclosporine|3
00296|035|R|  interaction in a heart transplant patient. J Heart Lung Transplant 1992|3
00296|036|R|  May-Jun;11(3 Pt 1):564-8.|3
00296|037|R|2.Chitwood KK, Abdul-Haqq AJ, Heim-Duthoy KL. Cyclosporine-amiodarone|3
00296|038|R|  interaction. Ann Pharmacother 1993 May;27(5):569-71.|3
00296|039|R|3.Mamprin F, Mullins P, Graham T, Kendall S, Biocine B, Large S, Wallwork J,|3
00296|040|R|  Schofield P. Amiodarone-cyclosporine interaction in cardiac|3
00296|041|R|  transplantation. Am Heart J 1992 Jun;123(6):1725-6.|3
00297|001|T|MONOGRAPH TITLE:  Lithium/Loop Diuretics|
00297|002|B||
00297|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00297|004|L|of severe adverse interaction.|
00297|005|B||
00297|006|A|MECHANISM OF ACTION:  Lithium is eliminated unchanged by the kidney;|
00297|007|A|diuretic induced sodium elimination may lead to decreased renal clearance of|
00297|008|A|lithium.|
00297|009|B||
00297|010|E|CLINICAL EFFECTS:  Lithium has a narrow therapeutic range; even modest,|
00297|011|E|unintended increases in lithium concentration may result in lithium|
00297|012|E|toxicity.|
00297|013|E|   Early symptoms of lithium toxicity may include: lethargy, muscle weakness|
00297|014|E|or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea,|
00297|015|E|confusion, ataxia, blurred vision, tinnitus and nystagmus.  Severe toxicity|
00297|016|E|may produce multiple organ dysfunction (e.g. seizures, coma, renal failure,|
00297|017|E|cardiac arrhythmias, cardiovascular collapse) and may be fatal.|
00297|018|B||
00297|019|P|PREDISPOSING FACTORS:  Risk factors for lithium toxicity include: renal|
00297|020|P|impairment or worsening of existing renal disease, dehydration, low sodium|
00297|021|P|diet, and concomitant use of multiple medications which may impair renal|
00297|022|P|elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics).|
00297|023|P|Patients who require higher therapeutic lithium levels to maintain symptom|
00297|024|P|control are particularly susceptible to these factors.|
00297|025|B||
00297|026|M|PATIENT MANAGEMENT:  Monitor closely to decrease the risk for lithium|
00297|027|M|toxicity.  Evaluate renal function and most recent lithium levels.  If renal|
00297|028|M|function is not stable, it would be prudent to withhold combination therapy|
00297|029|M|until renal function is stable.|
00297|030|M|   If a loop diuretic is started, or if the dose is increased in a patient|
00297|031|M|stabilized on lithium therapy, consider empirically lowering the lithium|
00297|032|M|dose, and recheck lithium levels 5 to 7 days after diuretic initiation.|
00297|033|M|Adjust lithium or diuretic dose as required and continue frequent (e.g.|
00297|034|M|weekly) monitoring of lithium until levels have stabilized.|
00297|035|M|   If lithium is to be started in a patient stabilized on a loop diuretic,|
00297|036|M|consider starting with a lower lithium dose and titrate slowly as half-life|
00297|037|M|may be prolonged.  Monitor lithium concentrations until stabilized on the|
00297|038|M|combination.|
00297|039|M|    Counsel patient to assure they know signs and symptoms of lithium|
00297|040|M|toxicity and understand the importance of follow-up laboratory testing.|
00297|041|B||
00297|042|D|DISCUSSION:  The documentation for this interaction is conflicting. A large|
00297|043|D|epidemiologic study in elderly bipolar patients and case reports describe|
00297|044|D|interactions between lithium and furosemide or bumetanide which resulted in|
00297|045|D|increased levels of lithium and lithium toxicity. Several studies in healthy|
00297|046|D|subjects have found that furosemide had no effect on lithium clearance or|
00297|047|D|lithium serum concentrations. Other studies performed to assess the accuracy|
00297|048|D|of lithium clearance in assessing proximal tubular reabsorption found that|
00297|049|D|furosemide and bumetanide increased lithium clearance.|
00297|050|B||
00297|051|R|REFERENCES:|
00297|052|B||
00297|053|R|1.Oh TE. Frusemide and lithium toxicity. Anaesth Intensive Care 1977 Feb;|3
00297|054|R|  5(1):60-2.|3
00297|055|R|2.Thornton WE, Pray BJ. Lithium intoxication: a report of two cases. Can|3
00297|056|R|  Psychiatr Assoc J 1975 Jun;20(4):281-2.|3
00297|057|R|3.Hurtig HI, Dyson WL. Letter: Lithium toxicity enhanced by diuresis. N Engl|3
00297|058|R|  J Med 1974 Mar 28;290(13):748-9.|3
00297|059|R|4.Kerry RJ, Ludlow JM, Owen G. Diuretics are dangerous with lithium. Br Med|3
00297|060|R|  J 1980 Aug 2;281(6236):371.|3
00297|061|R|5.Huang LG. Lithium intoxication with coadministration of a loop-diuretic. J|3
00297|062|R|  Clin Psychopharmacol 1990 Jun;10(3):228.|3
00297|063|R|6.Shalmi M, Rasmusen H, Amtorp O, Christensen S. Effect of chronic oral|2
00297|064|R|  furosemide administration on the 24-hour cycle of lithium clearance and|2
00297|065|R|  electrolyte excretion in humans. Eur J Clin Pharmacol 1990;38(3):275-80.|2
00297|066|R|7.Saffer D, Coppen A. Frusemide: a safe diuretic during lithium therapy?. J|2
00297|067|R|  Affect Disord 1983 Nov;5(4):289-92.|2
00297|068|R|8.Crabtree BL, Mack JE, Johnson CD, Amyx BC. Comparison of the effects of|2
00297|069|R|  hydrochlorothiazide and furosemide on lithium disposition. Am J Psychiatry|2
00297|070|R|  1991 Aug;148(8):1060-3.|2
00297|071|R|9.Atherton JC, Green R, Hughes S, McFall V, Sharples JA, Solomon LR, Wilson|2
00297|072|R|  L. Lithium clearance in man: effects of dietary salt intake, acute changes|2
00297|073|R|  in extracellular fluid volume, amiloride and frusemide. Clin Sci (Lond)|2
00297|074|R|  1987 Dec;73(6):645-51.|2
00297|075|R|10.Colussi G, Rombola G, Surian M, De Ferrari ME, Airaghi C, Benazzi E,|2
00297|076|R|   Malberti F, Minetti L. Effects of acute administration of acetazolamide|2
00297|077|R|   and frusemide on lithium clearance in humans. Nephrol Dial Transplant|2
00297|078|R|   1989;4(8):707-12.|2
00297|079|R|11.Beutler JJ, Boer WH, Koomans HA, Dorhout Mees EJ. Comparative study of|2
00297|080|R|   the effects of furosemide, ethacrynic acid and bumetanide on the lithium|2
00297|081|R|   clearance and diluting segment reabsorption in humans. J Pharmacol Exp|2
00297|082|R|   Ther 1992 Feb;260(2):768-72.|2
00297|083|R|12.Lithobid (lithium carbonate) US prescribing information. ANI|1
00297|084|R|   Pharmaceuticals, Inc. May, 2018.|1
00297|085|R|13.Finley PR. Drug Interactions with Lithium: An Update. Clin Pharmacokinet|6
00297|086|R|   2016 Aug;55(8):925-41.|6
00297|087|R|14.Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA.|2
00297|088|R|   Drug-induced lithium toxicity in the elderly: a population-based study. J|2
00297|089|R|   Am Geriatr Soc 2004 May;52(5):794-8.|2
00298|001|T|MONOGRAPH TITLE:  Itraconazole/Selected HMG-CoA Reductase Inhibitors|
00298|002|B||
00298|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00298|004|L|is contraindicated and generally should not be dispensed or administered to|
00298|005|L|the same patient.|
00298|006|B||
00298|007|A|MECHANISM OF ACTION:  Itraconazole may inhibit the metabolism of|
00298|008|A|atorvastatin, lovastatin, or simvastatin by CYP3A4.|
00298|009|B||
00298|010|E|CLINICAL EFFECTS:  Concurrent administration of itraconazole may result in|
00298|011|E|increased levels of atorvastatin, lovastatin, or simvastatin, which may|
00298|012|E|result in an increased risk of rhabdomyolysis.|
00298|013|B||
00298|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
00298|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
00298|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
00298|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
00298|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
00298|019|P|transporter OATP1B1 may have increased statin concentrations and be|
00298|020|P|predisposed to myopathy or rhabdomyolysis.|
00298|021|B||
00298|022|M|PATIENT MANAGEMENT:  Do not use lovastatin(1) or simvastatin(2-4) with|
00298|023|M|itraconazole(5).|
00298|024|M|   The manufacturer of atorvastatin states the dose of atorvastatin should|
00298|025|M|be limited to 20 mg in patients receiving itraconazole.(6)  The manufacturer|
00298|026|M|of itraconazole(5) states that concurrent use of atorvastatin should be|
00298|027|M|carefully monitored.|
00298|028|M|   Concurrent therapy with cerivastatin and atorvastatin, lovastatin, or|
00298|029|M|simvastatin is not recommended.(7)|
00298|030|M|   The US manufacturer of itraconazole states that concurrent administration|
00298|031|M|with lovastatin or simvastatin is contraindicated during or two weeks after|
00298|032|M|itraconazole treatment.(5)|
00298|033|B||
00298|034|D|DISCUSSION:  In a study, itraconazole (200 mg daily for 4 days) increased|
00298|035|D|the AUC and Cmax of atorvastatin (40 mg single dose) by 3.3-fold and 20%,|
00298|036|D|respectively.(6)|
00298|037|D|   In a randomized, double-blind, cross-over study, administration of|
00298|038|D|atorvastatin (40 mg single dose) on day 4 of itraconazole (200 mg daily X 5|
00298|039|D|days) increased atorvastatin area-under-curve (AUC) and half-life (T1/2)|
00298|040|D|3-fold.  There were no significant change in atorvastatin maximum|
00298|041|D|concentration (Cmax).  Atorvastatin lactone AUC, Cmax, and T1/2 increased|
00298|042|D|4-fold, 2-fold, and 2-fold respectively.  The AUC of active and total|
00298|043|D|HMG-CoA reductase inhibitors increased 1.6-fold and 1.7-fold,|
00298|044|D|respectively.(8)|
00298|045|D|   In healthy subjects, itraconazole increased atorvastatin T1/2, AUC, and|
00298|046|D|Cmax by 60%, 2.4-fold, and 47%, respectively.  Itraconazole had no effect on|
00298|047|D|pravastatin pharmacokinetics.(9)|
00298|048|D|   In a study in 18 healthy subjects, itraconazole (400 mg) increased the|
00298|049|D|Cmax, AUC, and half-life of a single dose of atorvastatin (20 mg) by 38%,|
00298|050|D|150%, 30%, respectively.(10)|
00298|051|D|   Administration of cerivastatin (0.3 mg) with itraconazole (200 mg daily X|
00298|052|D|10 days) increased cerivastatin AUC and Cmax 38% and 12%, respectively.|
00298|053|D|There was no effect on itraconazole pharmacokinetics. Administration of|
00298|054|D|cerivastatin (0.8 mg single dose) with itraconazole increased cerivastatin|
00298|055|D|AUC and Cmax by 27% and 25%, respectively.(11)|
00298|056|D|   In a randomized, double-blind, cross-over study in 10 healthy subjects,|
00298|057|D|the administration of cerivastatin (0.3 mg single dose) on day 4 of|
00298|058|D|itraconazole (200 mg) increased cerivastatin parent compound AUC 15%.|
00298|059|D|Cerivastatin lactone AUC, Cmax, and T1/2 increased 2.6-fold, 1.8-fold, and|
00298|060|D|3.2-fold, respectively.  The M-23 active metabolite AUC increased 36%.  The|
00298|061|D|AUC and T1/2 of all active cerivastatin derivatives increased 27% and 40%,|
00298|062|D|respectively.(10)|
00298|063|D|   In a double-blind cross-over study in 12 healthy subjects, administration|
00298|064|D|of lovastatin (40 mg single dose) after 4 days of itraconazole (200 mg|
00298|065|D|daily) increased lovastatin Cmax by more than 20-fold.  Lovastatin AUC and|
00298|066|D|T1/2 increased from undetectable levels in all but 3 subjects during placebo|
00298|067|D|phase to 546 ng/ml and 3.6+/-1 hours, respectively, during itraconazole.|
00298|068|D|The lovastatin acid Cmax and AUC increased 13-fold and 23-fold,|
00298|069|D|respectively, during concurrent itraconazole.  The T1/2 of lovastatin acid|
00298|070|D|increased from undetectable levels in the placebo phase to 6+/-1.1 hours in|
00298|071|D|the itraconazole phase.(12)|
00298|072|D|   In a double-blind cross-over study in 10 subjects, administration of|
00298|073|D|lovastatin (40 mg single dose) after 4 days of itraconazole (100 mg daily)|
00298|074|D|increased lovastatin Cmax and AUC by about 15-fold.  The lovastatin Cmax and|
00298|075|D|AUC increased 12-fold and 15-fold, respectively, during itraconazole.  The|
00298|076|D|lovastatin and lovastatin acid T1/2 increased from undetectable levels to|
00298|077|D|3.7+/-3.8 hours and 4.7+/-4.0 hours, respectively, during itraconazole.(13)|
00298|078|D|   In a randomized, double-blind, cross-over study, administration of|
00298|079|D|simvastatin (40 mg single dose) on day 4 of itraconazole (200 mg daily)|
00298|080|D|increased simvastatin AUC and Cmax 10-fold.  Simvastatin acid AUC and Cmax|
00298|081|D|increased 19-fold and 17-fold, respectively.  Simvastatin acid T1/2|
00298|082|D|increased 25%.  The AUC, Cmax, and T1/2 of the HMG-CoA reductase inhibitors|
00298|083|D|increased 5-fold, 3-fold, and 3-fold, respectively.(14)|
00298|084|D|   In a double-blind, cross-over study in 10 subjects, the administration of|
00298|085|D|fluvastatin (40 mg single dose) after 4 days of itraconazole (100 mg daily)|
00298|086|D|had no significant effect on the Cmax or AUC of fluvastatin.  Fluvastatin|
00298|087|D|T1/2 was slightly increased during itraconazole.(13)|
00298|088|D|   In a double-blind, cross-over study in 10 subjects, the administration of|
00298|089|D|pravastatin (40 mg single dose) after 4 days of itraconazole (200 mg daily)|
00298|090|D|had no significant effect on the Cmax, AUC, or T1/2 of pravastatin.(10)|
00298|091|D|   There are case reports of rhabdomyolysis with concurrent itraconazole and|
00298|092|D|lovastatin(18-20)and with concurrent itraconazole and simvastatin(21-25).|
00298|093|D|   One or more of the drug pairs linked to this monograph have been included|
00298|094|D|in a list of interactions that should be considered "high-priority" for|
00298|095|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00298|096|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00298|097|D|Coordinator (ONC) for Health Information Technology.|
00298|098|B||
00298|099|R|REFERENCES:|
00298|100|B||
00298|101|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
00298|102|R|  February, 2014.|1
00298|103|R|2.USFood and Drug Administration. FDA Drug Safety Communication: New|1
00298|104|R|  restrictions, contraindications, and dose limitations for Zocor|1
00298|105|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
00298|106|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
00298|107|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
00298|108|R|  June 8, 2011.|1
00298|109|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
00298|110|R|  2023.|1
00298|111|R|4.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
00298|112|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
00298|113|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
00298|114|R|  Products, L.P. February, 2024.|1
00298|115|R|6.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
00298|116|R|  2020.|1
00298|117|R|7.Baycol (cerivastatin) US prescribing information. Bayer Corporation|1
00298|118|R|  December, 2000.|1
00298|119|R|8.Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the|2
00298|120|R|  pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998 Jul;|2
00298|121|R|  64(1):58-65.|2
00298|122|R|9.Jacobson TA. Comparative pharmacokinetic interaction profiles of|2
00298|123|R|  pravastatin, simvastatin, and atorvastatin when coadministered with|2
00298|124|R|  cytochrome P450 inhibitors. Am J Cardiol 2004 Nov 1;94(9):1140-6.|2
00298|125|R|10.Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P.|2
00298|126|R|   Itraconazole alters the pharmacokinetics of atorvastatin to a greater|2
00298|127|R|   extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000|2
00298|128|R|   Oct;68(4):391-400.|2
00298|129|R|11.Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on|2
00298|130|R|   cerivastatin pharmacokinetics. Eur J Clin Pharmacol 1999 Jan;|2
00298|131|R|   54(11):851-5.|2
00298|132|R|12.Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma|2
00298|133|R|   concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther|2
00298|134|R|   1996 Jul;60(1):54-61.|2
00298|135|R|13.Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on|2
00298|136|R|   the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol|2
00298|137|R|   1998 Jul;46(1):49-53.|2
00298|138|R|14.Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is|2
00298|139|R|   very susceptible to interaction with the CYP3A4 inhibitor itraconazole.|2
00298|140|R|   Clin Pharmacol Ther 1998 Mar;63(3):332-41.|2
00298|141|R|15.Jacobsen W, Kirchner G, Hallensleben K, Mancinelli L, Deters M, Hackbarth|5
00298|142|R|   I, Baner K, Benet LZ, Sewing KF, Christians U. Small intestinal|5
00298|143|R|   metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase|5
00298|144|R|   inhibitor lovastatin and comparison with pravastatin. J Pharmacol Exp|5
00298|145|R|   Ther 1999 Oct;291(1):131-9.|5
00298|146|R|16.Jacobsen W, Kirchner G, Hallensleben K, Mancinelli L, Deters M, Hackbarth|5
00298|147|R|   I, Benet LZ, Sewing KF, Christians U. Comparison of cytochrome|5
00298|148|R|   P-450-dependent metabolism and drug interactions of the|5
00298|149|R|   3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and|5
00298|150|R|   pravastatin in the liver. Drug Metab Dispos 1999 Feb;27(2):173-9.|5
00298|151|R|17.Ishigam M, Uchiyama M, Kondo T, Iwabuchi H, Inoue S, Takasaki W, Ikeda T,|5
00298|152|R|   Komai T, Ito K, Sugiyama Y. Inhibition of in vitro metabolism of|5
00298|153|R|   simvastatin by itraconazole in humans and prediction of in vivo drug-drug|5
00298|154|R|   interactions. Pharm Res 2001 May;18(5):622-31.|5
00298|155|R|18.Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin|3
00298|156|R|   and the antifungal agent itraconazole. N Engl J Med 1995 Sep 7;|3
00298|157|R|   333(10):664-5.|3
00298|158|R|19.Horn M. Coadministration of itraconazole with hypolipidemic agents may|3
00298|159|R|   induce rhabdomyolysis in healthy individuals. Arch Dermatol 1996 Oct;|3
00298|160|R|   132(10):1254.|3
00298|161|R|20.Segaert MF, De Soete C, Vandewiele I, Verbanck J.|3
00298|162|R|   Drug-interaction-induced rhabdomyolysis. Nephrol Dial Transplant 1996|3
00298|163|R|   Sep;11(9):1846-7.|3
00298|164|R|21.Roques S, Lytrivi M, Rusu D, Devriendt J, De Bels D.|3
00298|165|R|   Rhabdomyolysis-induced acute renal failure due to itraconazole and|3
00298|166|R|   simvastatin association. Drug Metabol Drug Interact 2011;26(2):79-80.|3
00298|167|R|22.Tiessen RG, Lagerwey HJ, Jager GJ, Sprenger HG. Drug interaction caused|3
00298|168|R|   by communication problems. Rhabdomyolysis due to a combination of|3
00298|169|R|   itraconazole and simvastatin. Ned Tijdschr Geneeskd 2010;154:A762.|3
00298|170|R|23.Saliba WR, Elias M. Severe myopathy induced by the co-administration of|3
00298|171|R|   simvastatin and itraconazole. Eur J Intern Med 2005 Aug;16(4):305.|3
00298|172|R|24.Vlahakos DV, Manginas A, Chilidou D, Zamanika C, Alivizatos PA.|3
00298|173|R|   Itraconazole-induced rhabdomyolysis and acute renal failure in a heart|3
00298|174|R|   transplant recipient treated with simvastatin and cyclosporine.|3
00298|175|R|   Transplantation 2002 Jun 27;73(12):1962-4.|3
00298|176|R|25.Maxa JL, Melton LB, Ogu CC, Sills MN, Limanni A. Rhabdomyolysis after|3
00298|177|R|   concomitant use of cyclosporine, simvastatin, gemfibrozil, and|3
00298|178|R|   itraconazole. Ann Pharmacother 2002 May;36(5):820-3.|3
00298|179|R|26.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00298|180|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00298|181|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00298|182|R|   19(5):735-43.|6
00299|001|T|MONOGRAPH TITLE:  5-HT1D Agonists/Ergot Alkaloids|
00299|002|B||
00299|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00299|004|L|is contraindicated and generally should not be dispensed or administered to|
00299|005|L|the same patient.|
00299|006|B||
00299|007|A|MECHANISM OF ACTION:  The 5-HT1D agonists and ergot alkaloids can produce|
00299|008|A|vasospastic reactions.|
00299|009|B||
00299|010|E|CLINICAL EFFECTS:  Concurrent therapy may produce additive vasospastic|
00299|011|E|effects.|
00299|012|B||
00299|013|P|PREDISPOSING FACTORS:  None determined.|
00299|014|B||
00299|015|M|PATIENT MANAGEMENT:  The US manufacturer states that sumatriptan should not|
00299|016|M|be used within 24 hours of an ergotamine-containing or ergotamine-like|
00299|017|M|medication (such as dihydroergotamine or methysergide).(1,2)  The|
00299|018|M|Australian(3) and UK(4,5) manufacturers state that 24 hours should elapse|
00299|019|M|before sumatriptan is administered following an ergotamine-containing|
00299|020|M|preparation and 6 hours should elapse before an ergotamine-containing|
00299|021|M|preparation is administered following sumatriptan.|
00299|022|M|   The US manufacturer states that zolmitriptan should not be used within 24|
00299|023|M|hours of an ergotamine-containing or ergotamine-like medication.(6)  The UK|
00299|024|M|manufacturer states that zolmitriptan should not be used within 6 hours of|
00299|025|M|an ergotamine-containing or ergotamine-like medication.(7)  The The|
00299|026|M|Australian manufacturer states that 24 hours should elapse before|
00299|027|M|zolmitriptan is administered following an ergotamine-containing preparation|
00299|028|M|and 6 hours should elapse before an ergotamine-containing medication is|
00299|029|M|administered following zolmitriptan.(8)|
00299|030|M|   The US manufacturer states that the use of rizatriptan within 24 hours of|
00299|031|M|an ergotamine-containing or ergot-type medication is contraindicated.(9)|
00299|032|M|   The US manufacturer states that the use of naratriptan within 24 hours of|
00299|033|M|an ergotamine-containing or ergot-type medication is contraindicated.(10)|
00299|034|M|The Australian manufacturer states that concurrent use of naratriptan and|
00299|035|M|ergotamine or ergotamine derivatives is not recommended.(11)|
00299|036|M|   The US manufacturer states that the use of eletriptan within 24 hours of|
00299|037|M|an ergotamine-containing or ergot-type medication is contraindicated.(12)|
00299|038|M|The UK manufacturer states that the use of eletriptan within 24 hours of an|
00299|039|M|ergotamine-containing or ergot-type medication is not recommended.(13)|
00299|040|B||
00299|041|D|DISCUSSION:  Because of the theoretical risk of additive vasospastic|
00299|042|D|effects, the US manufacturer states that the use of sumatriptan within 24|
00299|043|D|hours of an ergotamine-containing or ergotamine-like medication is|
00299|044|D|contraindicated.(1,2)  The Australian(3) and UK(4,5) manufacturer states|
00299|045|D|that 24 hours should elapse before sumatriptan is administered following an|
00299|046|D|ergotamine-containing preparation and 6 hours should elapse before an|
00299|047|D|ergotamine-containing medication is administered following sumatriptan.|
00299|048|D|   Although the pharmacokinetics of zolmitriptan were not affected by|
00299|049|D|ergotamine, the UK manufacturer of zolmitriptan recommends that 6 hours|
00299|050|D|should elapse between the administration of zolmitriptan and an ergotamine|
00299|051|D|preparation.(7)  The US manufacturer of zolmitriptan states under|
00299|052|D|contraindications that zolmitriptan should not be used within 24 hours of an|
00299|053|D|ergotamine-containing or ergot-type medication.(6)  The Australian|
00299|054|D|manufacturer states that 24 hours should elapse before zolmitriptan is|
00299|055|D|administered following an ergotamine-containing preparation and 6 hours|
00299|056|D|should elapse before an ergotamine-containing medication is administered|
00299|057|D|following zolmitriptan.(8)|
00299|058|D|   Because of the additive risk of prolonged vasospastic reactions, the|
00299|059|D|manufacturers of rizatriptan(9) and naratriptan(10) in the US state that the|
00299|060|D|use of ergotamine-containing or ergot-type medications and these agents is|
00299|061|D|contraindicated.  The Australian manufacturer states that concurrent use of|
00299|062|D|naratriptan and ergotamine or ergotamine derivatives is not recommended.(11)|
00299|063|D|   Administration of oral ergotamine one and two hours after eletriptan|
00299|064|D|resulted in additive increases in blood pressure.(13)|
00299|065|B||
00299|066|R|REFERENCES:|
00299|067|B||
00299|068|R|1.Imitrex Tablets (sumatriptan) US prescribing information. GlaxoSmithKline|1
00299|069|R|  December 14, 2017.|1
00299|070|R|2.Imitrex Injection (sumatriptan) US prescribing information.|1
00299|071|R|  GlaxoSmithKline December 14, 2017.|1
00299|072|R|3.Imigran Tablets, Injection, and Nasal Spray (sumatriptan) Australian|1
00299|073|R|  prescribing information. GlaxoSmithKline February 11, 2002.|1
00299|074|R|4.Imigran Nasal Spray (sumatriptan) UK summary of product characteristics.|1
00299|075|R|  GlaxoSmithKline UK July 8, 2004.|1
00299|076|R|5.Imigran Injection (sumatriptan) UK summary of product characteristics.|1
00299|077|R|  GlaxoSmithKline UK September 19, 2003.|1
00299|078|R|6.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
00299|079|R|  Pharmaceuticals LP September, 2012.|1
00299|080|R|7.Zomig (zolmitriptan) UK summary of product characteristics. Zeneca Limited|1
00299|081|R|  March, 1997.|1
00299|082|R|8.Zomig (zomitriptan) Australian prescribing information. AstraZeneca Pty|1
00299|083|R|  Ltd July 10, 2003.|1
00299|084|R|9.Maxalt (rizatriptan) US prescribing information. Merck & Co., Inc.|1
00299|085|R|  October, 2019.|1
00299|086|R|10.Amerge (naratriptan) US prescribing information. GlaxoSmithKline October,|1
00299|087|R|   2013.|1
00299|088|R|11.Naramig (naratriptan hydrochloride) Australian prescribing information.|1
00299|089|R|   GlaxoSmithKline Australia Pty Ltd. April 30, 2004.|1
00299|090|R|12.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
00299|091|R|   March, 2020.|1
00299|092|R|13.Relpax (eletriptan hydrobromide) UK summary of product characteristics.|1
00299|093|R|   Pfizer Limited September, 2013.|1
00300|001|T|MONOGRAPH TITLE:  Itraconazole; Ketoconazole; Levoketoconazole/Selected|
00300|002|T|Benzodiazepines|
00300|003|B||
00300|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00300|005|L|is contraindicated and generally should not be dispensed or administered to|
00300|006|L|the same patient.|
00300|007|B||
00300|008|A|MECHANISM OF ACTION:  Itraconazole, ketoconazole, and levoketoconazole may|
00300|009|A|inhibit the metabolism of alprazolam, estazolam, midazolam, and triazolam by|
00300|010|A|CYP3A.(1-29)|
00300|011|B||
00300|012|E|CLINICAL EFFECTS:  Inhibition of benzodiazepine metabolism may produce|
00300|013|E|increased levels of these agents, as well as increased clinical effects.|
00300|014|E|Toxic effects of increased benzodiazepine levels include profound sedation,|
00300|015|E|respiratory depression, coma, and/or death.|
00300|016|B||
00300|017|P|PREDISPOSING FACTORS:  None determined.|
00300|018|B||
00300|019|M|PATIENT MANAGEMENT:  The concurrent use of alprazolam,(1) estazolam,(2) or|
00300|020|M|triazolam(3-5) with itraconazole or ketoconazole or levoketoconazole is|
00300|021|M|contraindicated.|
00300|022|M|   The concurrent use of oral midazolam with itraconazole(3) or|
00300|023|M|ketoconazole(4) is contraindicated by the manufacturer of the azole|
00300|024|M|antifungals.  The manufacturer of oral midazolam states that the agents|
00300|025|M|should only be used concurrently if absolutely necessary and if appropriate|
00300|026|M|equipment and personnel are available to respond to respiratory|
00300|027|M|insufficiency.(6)  The concurrent use of injectable midazolam and|
00300|028|M|itraconazole(3,7) or ketoconazole(4,7) should be approached with special|
00300|029|M|precaution and patient monitoring.|
00300|030|M|   The US manufacturer of itraconazole states that concomitant|
00300|031|M|administration with triazolam or oral midazolam is contraindicated during|
00300|032|M|and two weeks after itraconazole treatment.(3)|
00300|033|M|   The US manufacturer of levoketoconazole states concurrent use with|
00300|034|M|sensitive CYP3A4 substrates is contraindicated.(29)|
00300|035|B||
00300|036|D|DISCUSSION:  In a double-blind cross-over study in 10 healthy subjects,|
00300|037|D|itraconazole increased alprazolam area-under-curve (AUC) and half-life by|
00300|038|D|1.67-fold and by 1.56-fold, respectively.  Alprazolam clearance was|
00300|039|D|decreased by 60%.(8)|
00300|040|D|   In a double-blind cross-over study, concurrent ketoconazole decreased|
00300|041|D|alprazolam clearance by 68.6% and increased alprazolam half-life by|
00300|042|D|2.9-fold.(9)  Ketoconazole has also been shown to inhibit alprazolam|
00300|043|D|metabolism in vitro.(10,11)|
00300|044|D|   In a double-blind, randomized cross-over study, itraconazole had no|
00300|045|D|effects on the pharmacokinetics of a single dose of estazolam.(12)  However,|
00300|046|D|itraconazole was shown to inhibit the metabolism of estazolam in vitro(13)|
00300|047|D|and the manufacturer of estazolam states that concurrent use with either|
00300|048|D|itraconazole or ketoconazole is expected to increase estazolam levels and|
00300|049|D|thus concurrent use is contraindicated.(2)|
00300|050|D|   In a study in 9 healthy subjects, itraconazole increased the AUC of oral|
00300|051|D|midazolam by 8-fold.  Increased effects were also noted.(14)  In a|
00300|052|D|double-blind cross-over study in 12 subjects, itraconazole increased the|
00300|053|D|AUC, maximum concentration (Cmax) and half-life of oral midazolam by 6-fold,|
00300|054|D|2.5-fold, and 2-fold, respectively. Increased effects were also noted.(15)|
00300|055|D|In a cross-over study in 12 subjects, one dose of itraconazole increased the|
00300|056|D|AUC and Cmax of oral midazolam by 3.5-fold and by 2-fold, respectively. Six|
00300|057|D|doses of itraconazole increased the AUC of oral midazolam by almost 7-fold.|
00300|058|D|Increased midazolam effects were seen.(16)  In a double-blind, cross-over|
00300|059|D|study, itraconazole increased midazolam AUC by 10-fold.  Subjects also|
00300|060|D|experienced significantly increased sedation and amnesiac effects.(17)|
00300|061|D|Itraconazole has also been shown to inhibit midazolam metabolism in|
00300|062|D|vitro.(18,19)|
00300|063|D|   In a study in healthy subjects, ketoconazole increased the AUC of oral|
00300|064|D|midazolam by 771.9%.(20)  In a double-blind, cross-over study, ketoconazole|
00300|065|D|increased midazolam AUC by 15-fold. Subjects also experienced significantly|
00300|066|D|increased sedation and amnesiac effects.(17)  In a study in 11 healthy|
00300|067|D|subjects, administration of ketoconazole (400 mg daily) for 1 day, 2 days,|
00300|068|D|and 5 days increased the AUC of a single dose of oral midazolam (2 mg) by|
00300|069|D|10.28-fold, 13.14-fold, and 13.96-fold, respectively, and the Cmax by|
00300|070|D|5.01-fold, 5.29-fold, and 5.42-fold, respectively.(21)  In a study in|
00300|071|D|healthy subjects, ketoconazole (200 mg twice daily) reduced the clearance of|
00300|072|D|midazolam 6-fold.(22)  Ketoconazole has also been shown to inhibit the|
00300|073|D|metabolism of midazolam in vitro.(18,19,23-25)|
00300|074|D|   In a randomized, cross-over study in 10 healthy subjects, itraconazole|
00300|075|D|ingested simultaneously, or 3, 12, or 24 hours before triazolam increased|
00300|076|D|triazolam AUC by 3.1-fold, 4.8-fold, 4.6-fold, and 3.8-fold, respectively.|
00300|077|D|The increased in triazolam Cmax ranged from 1.4-fold to 1.8-fold.  Subjects|
00300|078|D|noted increased triazolam effects.(23)  In a double-blind cross-over study|
00300|079|D|in 9 subjects, itraconazole increased triazolam AUC by 27-fold.(24)|
00300|080|D|   In a double-blind cross-over study in 9 subjects, ketoconazole increased|
00300|081|D|triazolam AUC by 22-fold.(24)  In a double-blind cross-over study,|
00300|082|D|concurrent ketoconazole decreased triazolam clearance by 91%.  Triazolam|
00300|083|D|half-life and Cmax increased 5.1-fold and 1.1-fold, respectively.(9)|
00300|084|D|Ketoconazole has also been shown to inhibit triazolam metabolism in|
00300|085|D|vitro.(23,25)|
00300|086|B||
00300|087|R|REFERENCES:|
00300|088|B||
00300|089|R|1.Xanax (alprazolam) US prescribing information. Pharmacia & Upjohn Company|1
00300|090|R|  February, 2021.|1
00300|091|R|2.Prosom (estazolam) US prescribing information. Abbott Laboratories|1
00300|092|R|  January, 2004.|1
00300|093|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
00300|094|R|  Products, L.P. February, 2024.|1
00300|095|R|4.Halcion (triazolam) US prescribing information. Pharmacia & Upjohn Company|1
00300|096|R|  October, 2019.|1
00300|097|R|5.Midazolam Hydrochloride Syrup US Prescribing Information. Padagis US LLC|1
00300|098|R|  December 11, 2021.|1
00300|099|R|6.Versed Injection (midazolam hydrochloride) US prescribing information.|1
00300|100|R|  Roche Pharmaceuticals June, 2000.|1
00300|101|R|7.Yasui N, Kondo T, Otani K, Furukori H, Kaneko S, Ohkubo T, Nagasaki T,|2
00300|102|R|  Sugawara K. Effect of itraconazole on the single oral dose|2
00300|103|R|  pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology|2
00300|104|R|  (Berl) 1998 Oct;139(3):269-73.|2
00300|105|R|8.Greenblatt DJ, Wright CE, von Moltke LL, Harmatz JS, Ehrenberg BL, Harrel|2
00300|106|R|  LM, Corbett K, Counihan M, Tobias S, Shader RI. Ketoconazole inhibition of|2
00300|107|R|  triazolam and alprazolam clearance: differential kinetic and dynamic|2
00300|108|R|  consequences. Clin Pharmacol Ther 1998 Sep;64(3):237-47.|2
00300|109|R|9.Allqvist A, Miura J, Bertilsson L, Mirghani RA. Inhibition of CYP3A4 and|5
00300|110|R|  CYP3A5 catalyzed metabolism of alprazolam and quinine by ketoconazole as|5
00300|111|R|  racemate and four different enantiomers. Eur J Clin Pharmacol 2007 Feb;|5
00300|112|R|  63(2):173-9.|5
00300|113|R|10.von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Harmatz JS, Shader RI.|5
00300|114|R|   Inhibitors of alprazolam metabolism in vitro: effect of serotonin-|5
00300|115|R|   reuptake-inhibitor antidepressants, ketoconazole and quinidine. Br J Clin|5
00300|116|R|   Pharmacol 1994 Jul;38(1):23-31.|5
00300|117|R|11.Otsuji Y, Okuyama N, Aoshima T, Fukasawa T, Kato K, Gerstenberg G, Miura|2
00300|118|R|   M, Ohkubo T, Sugawara K, Otani K. No effect of itraconazole on the single|2
00300|119|R|   oral dose pharmacokinetics and pharmacodynamics of estazolam. Ther Drug|2
00300|120|R|   Monit 2002 Jun;24(3):375-8.|2
00300|121|R|12.Miura M, Otani K, Ohkubo T. Identification of human cytochrome P450|5
00300|122|R|   enzymes involved in the formation of 4-hydroxyestazolam from estazolam.|5
00300|123|R|   Xenobiotica 2005 May;35(5):455-65.|5
00300|124|R|13.Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ. The area under the|2
00300|125|R|   plasma concentration-time curve for oral midazolam is 400-fold larger|2
00300|126|R|   during treatment with itraconazole than with rifampicin. Eur J Clin|2
00300|127|R|   Pharmacol 1998 Mar;54(1):53-8.|2
00300|128|R|14.Ahonen J, Olkkola KT, Neuvonen PJ. Effect of itraconazole and terbinafine|2
00300|129|R|   on the pharmacokinetics and pharmacodynamics of midazolam in healthy|2
00300|130|R|   volunteers. Br J Clin Pharmacol 1995 Sep;40(3):270-2.|2
00300|131|R|15.Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic|2
00300|132|R|   antimycotics, itraconazole and fluconazole, on the pharmacokinetics and|2
00300|133|R|   pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996|2
00300|134|R|   Mar;82(3):511-6.|2
00300|135|R|16.Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in|2
00300|136|R|   patients receiving the systemic antimycotics ketoconazole or|2
00300|137|R|   itraconazole. Clin Pharmacol Ther 1994 May;55(5):481-5.|2
00300|138|R|17.Wang JS, Wen X, Backman JT, Taavitsainen P, Neuvonen PJ, Kivisto KT.|5
00300|139|R|   Midazolam alpha-hydroxylation by human liver microsomes in vitro:|5
00300|140|R|   inhibition by calcium channel blockers, itraconazole and ketoconazole.|5
00300|141|R|   Pharmacol Toxicol 1999 Oct;85(4):157-61.|5
00300|142|R|18.von Moltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS,|5
00300|143|R|   Shader RI. Midazolam hydroxylation by human liver microsomes in vitro:|5
00300|144|R|   inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents.|5
00300|145|R|   J Clin Pharmacol 1996 Sep;36(9):783-91.|5
00300|146|R|19.Lam YW, Alfaro CL, Ereshefsky L, Miller M. Pharmacokinetic and|2
00300|147|R|   pharmacodynamic interactions of oral midazolam with ketoconazole,|2
00300|148|R|   fluoxetine, fluvoxamine, and nefazodone. J Clin Pharmacol 2003 Nov;|2
00300|149|R|   43(11):1274-82.|2
00300|150|R|20.Stoch SA, Friedman E, Maes A, Yee K, Xu Y, Larson P, Fitzgerald M,|2
00300|151|R|   Chodakewitz J, Wagner JA. Effect of different durations of ketoconazole|2
00300|152|R|   dosing on the single-dose pharmacokinetics of midazolam: shortening the|2
00300|153|R|   paradigm. J Clin Pharmacol 2009 Apr;49(4):398-406.|2
00300|154|R|21.Tham LS, Lee HS, Wang L, Yong WP, Fan L, Ong AB, Sukri N, Soo R, Lee SC,|2
00300|155|R|   Goh BC. Ketoconazole renders poor CYP3A phenotype status with midazolam|2
00300|156|R|   as probe drug. Ther Drug Monit 2006 Apr;28(2):255-61.|2
00300|157|R|22.Patki KC, Von Moltke LL, Greenblatt DJ. In vitro metabolism of midazolam,|5
00300|158|R|   triazolam, nifedipine, and testosterone by human liver microsomes and|5
00300|159|R|   recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab|5
00300|160|R|   Dispos 2003 Jul;31(7):938-44.|5
00300|161|R|23.Takano M, Hasegawa R, Fukuda T, Yumoto R, Nagai J, Murakami T.|5
00300|162|R|   Interaction with P-glycoprotein and transport of erythromycin, midazolam|5
00300|163|R|   and ketoconazole in Caco-2 cells. Eur J Pharmacol 1998 Oct 9;|5
00300|164|R|   358(3):289-94.|5
00300|165|R|24.Wrighton SA, Ring BJ. Inhibition of human CYP3A catalyzed 1'-hydroxy|5
00300|166|R|   midazolam formation by ketoconazole, nifedipine, erythromycin,|5
00300|167|R|   cimetidine, and nizatidine. Pharm Res 1994 Jun;11(6):921-4.|5
00300|168|R|25.Neuvonen PJ, Varhe A, Olkkola KT. The effect of ingestion time interval|2
00300|169|R|   on the interaction between itraconazole and triazolam. Clin Pharmacol|2
00300|170|R|   Ther 1996 Sep;60(3):326-31.|2
00300|171|R|26.Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous|2
00300|172|R|   to patients receiving systemic antimycotics ketoconazole or itraconazole.|2
00300|173|R|   Clin Pharmacol Ther 1994 Dec;56(6 Pt 1):601-7.|2
00300|174|R|27.von Moltke LL, Greenblatt DJ, Harmatz JS, Duan SX, Harrel LM,|5
00300|175|R|   Cotreau-Bibbo MM, Pritchard GA, Wright CE, Shader RI. Triazolam|5
00300|176|R|   biotransformation by human liver microsomes in vitro: effects of|5
00300|177|R|   metabolic inhibitors and clinical confirmation of a predicted interaction|5
00300|178|R|   with ketoconazole. J Pharmacol Exp Ther 1996 Feb;276(2):370-9.|5
00300|179|R|28.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
00300|180|R|   Pharmaceuticals February, 2014.|1
00300|181|R|29.Recorlev (levoketoconazole) US prescribing information. Xeris|1
00300|182|R|   Pharmaceuticals, Inc. June, 2023.|1
00301|001|T|MONOGRAPH TITLE:  Cisplatin/Paclitaxel (mono deleted 02/04/2022)|
00301|002|B||
00301|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00301|004|L|take action as needed.|
00301|005|B||
00301|006|A|MECHANISM OF ACTION:  Paclitaxel's cytotoxic effects are thought to be from|
00301|007|A|its effects on the microtubules which are present during mitosis.|
00301|008|A|Administration of cisplatin prior to paclitaxel is thought to decrease the|
00301|009|A|number of cells entering mitosis, thus decreasing the cytotoxic effects of|
00301|010|A|paclitaxel (1).  Administration of paclitaxel following cisplatin has shown|
00301|011|A|to result in a decrease in paclitaxel clearance (2).|
00301|012|B||
00301|013|E|CLINICAL EFFECTS:  Administration of cisplatin prior to paclitaxel has been|
00301|014|E|shown to result in antagonistic effects on cell kills in vitro (1,3-4) and|
00301|015|E|increased neutropenia in vivo (5-6).  Simultaneous administration of|
00301|016|E|cisplatin and paclitaxel without prior administration of paclitaxel has been|
00301|017|E|shown to result in antagonistic effects on cell kills in vitro (5).|
00301|018|E|Administration of paclitaxel before cisplatin (1,4,6) or before concurrent|
00301|019|E|administration of paclitaxel and cisplatin (3) has been shown to result in|
00301|020|E|synergistic cell kills in vitro.|
00301|021|B||
00301|022|P|PREDISPOSING FACTORS:  None determined.|
00301|023|B||
00301|024|M|PATIENT MANAGEMENT:  Paclitaxel should be administered prior to cisplatin or|
00301|025|M|as concurrent therapy with paclitaxel and cisplatin.|
00301|026|B||
00301|027|D|DISCUSSION:  Several in vitro studies have documented synergistic cell-kills|
00301|028|D|when paclitaxel was administered prior to cisplatin (1,4,6) or prior to|
00301|029|D|concurrent therapy with paclitaxel and cisplatin (3).  Administration of|
00301|030|D|paclitaxel after cisplatin has been shown to result in antagonistic effects|
00301|031|D|on cell kills in vivo (1,3-4).  Another in vitro study found that concurrent|
00301|032|D|administration of paclitaxel and cisplatin also resulted in antagonistic|
00301|033|D|effects (4).  In vivo studies have found that administration of cisplatin|
00301|034|D|prior to paclitaxel resulted in more profound neutropenia than|
00301|035|D|administration of cisplatin after paclitaxel (1,2).  In vivo studies have|
00301|036|D|not examined the effects of order of administration on efficacy.|
00301|037|B||
00301|038|R|REFERENCES:|
00301|039|B||
00301|040|R|1.Liebmann JE, Fisher J, Teague D, Cook JA. Sequence dependence of|5
00301|041|R|  paclitaxel (Taxol) combined with cisplatin or alkylators in human cancer|5
00301|042|R|  cells. Oncol Res 1994;6(1):25-31.|5
00301|043|R|2.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
00301|044|R|  Company August, 2010.|1
00301|045|R|3.Jekunen AP, Christen RD, Shalinsky DR, Howell SB. Synergistic interaction|5
00301|046|R|  between cisplatin and taxol in human ovarian carcinoma cells in vitro. Br|5
00301|047|R|  J Cancer 1994 Feb;69(2):299-306.|5
00301|048|R|4.Vanhoefer U, Harstrick A, Wilke H, Schleucher N, Walles H, Schroder J,|5
00301|049|R|  Seeber S. Schedule-dependent antagonism of paclitaxel and cisplatin in|5
00301|050|R|  human gastric and ovarian carcinoma cell lines in vitro. Eur J Cancer|5
00301|051|R|  1995;31A(1):92-7.|5
00301|052|R|5.Rowinsky EK, Gilbert MR, McGuire WP, Noe DA, Grochow LB, Forastiere AA,|2
00301|053|R|  Ettinger DS, Lubejko BG, Clark B, Sartorius SE, et al. Sequences of taxol|2
00301|054|R|  and cisplatin: a phase I and pharmacologic study. J Clin Oncol 1991 Sep;|2
00301|055|R|  9(9):1692-703.|2
00301|056|R|6.Clark JW, Santos-Moore AS, Choy H. Sequencing of taxol and carboplatimum|4
00301|057|R|  therapy. Proc Am Assoc Cancer Res 1995 Mar;36:298.|4
00302|001|T|MONOGRAPH TITLE:  Etoposide/P-glycoprotein (P-gp) Inhibitors|
00302|002|B||
00302|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00302|004|L|take action as needed.|
00302|005|B||
00302|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibition may increase|
00302|007|A|etoposide cellular concentration, decrease biliary or renal elimination, and|
00302|008|A|increase systemic absorption of oral etoposide.(1-4)|
00302|009|B||
00302|010|E|CLINICAL EFFECTS:  Increased cellular or systemic levels of etoposide may|
00302|011|E|result in etoposide toxicity.|
00302|012|B||
00302|013|P|PREDISPOSING FACTORS:  The interaction magnitude may be greater in patients|
00302|014|P|receiving oral etoposide, or with impaired renal or hepatic function.|
00302|015|B||
00302|016|M|PATIENT MANAGEMENT:  Anticipate and monitor for increased hematologic and|
00302|017|M|gastrointestinal toxicities.  Adjust or hold etoposide dose when needed.|
00302|018|M|   In patients receiving high-dose cyclosporine therapy, etoposide dosages|
00302|019|M|should be reduced by 50%.(1)  Monitor for signs of etoposide toxicity.|
00302|020|M|Dosages may need further adjustment.|
00302|021|M|   The manufacturer of vimseltinib states concurrent use with P-gp|
00302|022|M|substrates should be avoided. If concurrent use cannot be avoided, take|
00302|023|M|vimseltinib at least 4 hours prior to etoposide.(5)|
00302|024|B||
00302|025|D|DISCUSSION:  In a study in 16 patients, the administration of etoposide plus|
00302|026|D|cyclosporine increased etoposide area-under-curve (AUC) by 59% and half-life|
00302|027|D|by 73%.  Etoposide renal clearance was decreased by 38% and nonrenal|
00302|028|D|clearance was decreased by 52%.  White blood cell count nadir was|
00302|029|D|significantly lower during concurrent therapy with cyclosporine and|
00302|030|D|etoposide (1200 mm3) when compared to etoposide alone (2500 mm3). There was|
00302|031|D|also a trend for higher dosages of cyclosporine to exert increased effects|
00302|032|D|on etoposide, although this difference did not reach statistical|
00302|033|D|significance.(1)|
00302|034|D|   P-gp inhibitors linked to this monograph are asciminib, asunaprevir,|
00302|035|D|azithromycin, belumosudil, capmatinib, cimetidine, clarithromycin,|
00302|036|D|cyclosporine, daridorexant, danicopan, deutivacaftor, diosmin, flibanserin,|
00302|037|D|fostamatinib, glecaprevir/pibrentasvir, imlunestrant, itraconazole,|
00302|038|D|ivacaftor, josamycin, ketoconazole, lonafarnib, mavorixafor, neratinib,|
00302|039|D|osimertinib, pirtobrutinib, propafenone, quinidine, selpercatinib,|
00302|040|D|sofosbuvir/velpatasvir/voxilaprevir, sotorasib, tepotinib, tucatinib,|
00302|041|D|valbenazine, vemurafenib, verapamil, vimseltinib, and voclosporin.|
00302|042|B||
00302|043|R|REFERENCES:|
00302|044|B||
00302|045|R|1.Lum BL, Kaubisch S, Yahanda AM, Adler KM, Jew L, Ehsan MN, Brophy NA,|2
00302|046|R|  Halsey J, Gosland MP, Sikic BI. Alteration of etoposide pharmacokinetics|2
00302|047|R|  and pharmacodynamics by cyclosporine in a phase I trial to modulate|2
00302|048|R|  multidrug resistance. J Clin Oncol 1992 Oct;10(10):1635-42.|2
00302|049|R|2.Yang J, Bogni A, Schuetz EG, Ratain M, Dolan ME, McLeod H, Gong L, Thorn|6
00302|050|R|  C, Relling MV, Klein TE, Altman RB. Etoposide pathway. Pharmacogenet|6
00302|051|R|  Genomics 2009 Jul;19(7):552-3.|6
00302|052|R|3.Lagas JS, Fan L, Wagenaar E, Vlaming ML, van Tellingen O, Beijnen JH,|5
00302|053|R|  Schinkel AH. P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 determine the|5
00302|054|R|  pharmacokinetics of etoposide. Clin Cancer Res 2010 Jan 01;16(1):130-40.|5
00302|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
00302|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00302|057|R|5.Romvimza (vimseltinib) US prescribing information. Deciphera|1
00302|058|R|  Pharmaceuticals, LLC February, 2025.|1
00303|001|T|MONOGRAPH TITLE:  Sympathomimetics/Rauwolfia Alkaloids|
00303|002|B||
00303|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00303|004|L|take action as needed.|
00303|005|B||
00303|006|A|MECHANISM OF ACTION:  Reserpine depletes catecholamine stores within the|
00303|007|A|peripheral vascular adrenergic nerve endings, thus indirect acting|
00303|008|A|sympathomimetics are unable to trigger the release of catecholamines. The|
00303|009|A|reserpine-induced catecholamine release increases sensitivity to the effects|
00303|010|A|of direct acting sympathomimetics.|
00303|011|B||
00303|012|E|CLINICAL EFFECTS:  Increased effects of direct acting sympathomimetics.|
00303|013|E|Decreased effects of indirect acting sympathomimetics.  Mixed acting|
00303|014|E|sympathomimetics will show effects based on the predominance of either|
00303|015|E|direct or indirect activity.|
00303|016|B||
00303|017|P|PREDISPOSING FACTORS:  None determined.|
00303|018|B||
00303|019|M|PATIENT MANAGEMENT:  If these agents are administered concurrently, monitor|
00303|020|M|blood pressure.  The dose of the sympathomimetic may need to be adjusted.|
00303|021|B||
00303|022|D|DISCUSSION:  This interaction has been well documented in animal studies and|
00303|023|D|human case reports have confirmed the interaction.  Reserpine has been shown|
00303|024|D|to decrease the response to epinephrine administered for hypotension.|
00303|025|D|Reserpine has also been shown to decrease the effectiveness of ophthalmic|
00303|026|D|epinephrine, a direct acting sympathomimetic.  Ophthalmic phenylephrine has|
00303|027|D|been shown to decrease the hypotensive effects of reserpine.|
00303|028|B||
00303|029|R|REFERENCES:|
00303|030|B||
00303|031|R|1.Burn JH, Rand MJ. The action of sympathomimetic amines in animals treated|5
00303|032|R|  with reserpine. J Physiol 1958;144:314-36.|5
00303|033|R|2.Trendelenburg U. Supersensitivity and subsensitivity to sympathomimetic|6
00303|034|R|  amines. Pharmacol Rev 1963;15:225-74.|6
00303|035|R|3.Sneddon JM, Turner P. Ephedrine mydriasis in hypertension and the response|2
00303|036|R|  to treatment. Clin Pharmacol Ther 1969 Jan-Feb;10(1):64-71.|2
00303|037|R|4.Eger EI, Hamilton WK. The effect of reserpine on the action of various|5
00303|038|R|  vasopressors. Anesthesiology 1959 Sep-Oct;20(5):641-5.|5
00303|039|R|5.Maxwell RA, Povalski H, Plummer AJ. A differential effect of reserpine on|5
00303|040|R|  pressor amine activity and its relationship to other agents producing this|5
00303|041|R|  effect. J Pharmacol Exp Ther 1959;125:178-83.|5
00303|042|R|6.Ziegler CH, Lovette JB. Operative complications after therapy with|3
00303|043|R|  reserpine and reserpine compounds. JAMA 1961 Jun 17;176(11):916-9.|3
00303|044|R|7.Stone CA, Ross CA, Wenger HC, Ludden CT, Blessing JA, Totaro JA, Porter|5
00303|045|R|  CC. Effect of alpha-methyl-3,4-dihydroxyphenylalamine (methyldopa),|5
00303|046|R|  reserpine and related agents on some vascular responses in the dog. J|5
00303|047|R|  Pharmacol Exp Ther 1962;136(1):80-8.|5
00303|048|R|8.Moore JI, Moran NC. Cardiac contractile force responses to ephedrine and|5
00303|049|R|  other sympathomimetic amines in dogs after pretreatment with reserpine. J|5
00303|050|R|  Pharmacol Exp Ther 1962;136(1):89-96.|5
00304|001|T|MONOGRAPH TITLE:  Anticoagulants/Dextrothyroxine|
00304|002|B||
00304|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00304|004|L|of severe adverse interaction.|
00304|005|B||
00304|006|A|MECHANISM OF ACTION:  Unknown. However, dextrothyroxine may influence|
00304|007|A|concentrations of vitamin K-dependent clotting factors.|
00304|008|B||
00304|009|E|CLINICAL EFFECTS:  Concurrent therapy may result in increase anticoagulant|
00304|010|E|effects and increase the risk for bleeding.|
00304|011|B||
00304|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00304|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00304|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
00304|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00304|016|P|risk for bleeding (e.g. NSAIDs).|
00304|017|B||
00304|018|M|PATIENT MANAGEMENT:  Monitor prothrombin activity and adjust the|
00304|019|M|anticoagulant dosage accordingly during initiation of warfarin therapy in|
00304|020|M|patients receiving dextrothyroxine therapy.  The dosage of warfarin may be|
00304|021|M|less than expected in patients currently receiving dextrothyroxine.|
00304|022|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00304|023|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00304|024|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00304|025|M|patients with any symptoms.|
00304|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00304|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00304|028|M|anticoagulation in patients with active pathologic bleeding.|
00304|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00304|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00304|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00304|032|M|and/or swelling.|
00304|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00304|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00304|035|M|initiating, altering the dose or discontinuing either drug.|
00304|036|B||
00304|037|D|DISCUSSION:  Any change in thyroid status in patients stabilized on warfarin|
00304|038|D|may necessitate a change in warfarin dosage requirements.  Initiation of|
00304|039|D|dextrothyroxine therapy in patients stabilized on warfarin may result in|
00304|040|D|increases in the effects of warfarin.  A decrease in the dose of warfarin|
00304|041|D|usually becomes necessary within one to four weeks after starting therapy|
00304|042|D|with dextrothyroxine.|
00304|043|B||
00304|044|R|REFERENCES:|
00304|045|B||
00304|046|R|1.Walters MB. The relationship between thyroid function and anticoagulant|3
00304|047|R|  therapy. Am J Cardiol 1963 Jan;11:112-4.|3
00304|048|R|2.Schrogie JJ, Solomon HM. The anticoagulant response to bishydroxycoumarin.|2
00304|049|R|  II. The effect of D- thyroxine, clofibrate, and norethandrolone. Clin|2
00304|050|R|  Pharmacol Ther 1967 Jan-Feb;8(1):70-7.|2
00304|051|R|3.Kimberg DV. The liver. In:  Werner SC, Ingbar SH, ed. Werner and Ingbar's|6
00304|052|R|  The thyroid. New York: Harper & Row; 1971: 569..|6
00304|053|R|4.Feely J, Stevenson IH, Crooks J. Altered plasma protein binding of drugs|5
00304|054|R|  in thyroid disease. Clin Pharmacokinet 1981 Jul-Aug;6(4):298-305.|5
00304|055|R|5.Weintraub M, Breckenridge RT, Griner PF. The effects of dextrothyroxine on|5
00304|056|R|  the kinetics of prothrombin activity: proposed mechanism of the|5
00304|057|R|  potentiation of warfarin by D-thyroxine. J Lab Clin Med 1973 Feb;|5
00304|058|R|  81(2):273-9.|5
00304|059|R|6.Owens JC, Neely WB, Owen WR. Effect of sodium dextrothyroxine in patients|2
00304|060|R|  receiving anticoagulants. N Engl J Med 1962 Jan 11;266(2):76-9.|2
00304|061|R|7.Self T, Weisburst M, Wooten E, Straughn A, Oliver J. Warfarin-induced|3
00304|062|R|  hypoprothrombinemia. Potentiation by hyperthyroidism. JAMA 1975 Mar 17;|3
00304|063|R|  231(11):1165-6.|3
00304|064|R|8.Rice AJ, McIntosh TJ, Fouts JR, Brunk SF, Wilson WR. Decreased sensitivity|2
00304|065|R|  to warfarin in patients with myxedema. Am J Med Sci 1971 Oct;262(4):211-5.|2
00304|066|R|9.Vagenakis AG, Cote R, Miller ME, Braverman LE, Stohlman F Jr. Enhancement|3
00304|067|R|  of warfarin-induced hypoprothrombinemia by thyrotoxicosis. Johns Hopkins|3
00304|068|R|  Med J 1972 Jul;131(1):69-73.|3
00304|069|R|10.Gotta AW, Sullivan CA, Seaman J, Jean-Gilles B. Prolonged intraoperative|3
00304|070|R|   bleeding caused by propylthiouracil-induced hypoprothrombinemia.|3
00304|071|R|   Anesthesiology 1972 Nov;37(5):562-3.|3
00304|072|R|11.Piziak VK, Hahn HB Jr. Isolated menarche in juvenile hypothyroidism. Clin|3
00304|073|R|   Pediatr (Phila) 1984 Mar;23(3):177-9.|3
00305|001|T|MONOGRAPH TITLE:  Selected quinolones/Class IA & III Antiarrhythmics|
00305|002|B||
00305|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00305|004|L|is contraindicated and generally should not be dispensed or administered to|
00305|005|L|the same patient.|
00305|006|B||
00305|007|A|MECHANISM OF ACTION:  Unknown.  Possibly additive or synergistic effects on|
00305|008|A|the QTc interval.|
00305|009|B||
00305|010|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in potentially|
00305|011|E|life-threatening arrhythmias such as torsades de pointes.|
00305|012|B||
00305|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00305|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00305|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00305|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00305|017|P|female gender, or advanced age.(3)|
00305|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00305|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00305|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00305|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00305|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00305|023|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
00305|024|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00305|025|B||
00305|026|M|PATIENT MANAGEMENT:  Concurrent administration of sparfloxacin with Class Ia|
00305|027|M|(disopyramide, moricizine, procainamide, quinidine) or Class III|
00305|028|M|(amiodarone, bretylium, sotalol) antiarrhythmic agents is contraindicated by|
00305|029|M|the manufacturer of sparfloxacin.(1)  Concurrent administration of these|
00305|030|M|agents with grepafloxacin is also contraindicated by the manufacturer of|
00305|031|M|grepafloxacin unless appropriate cardiac monitoring can be assured.(2)|
00305|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00305|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00305|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00305|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00305|036|B||
00305|037|D|DISCUSSION:  The product information for grepafloxacin states that because|
00305|038|D|prolongation of the QTc interval has been observed in healthy subjects|
00305|039|D|receiving grepafloxacin, the concurrent administration of grepafloxacin with|
00305|040|D|medications known to prolong the QTc interval is contraindicated unless|
00305|041|D|appropriate cardiac monitoring can be assured.(2)|
00305|042|D|   Torsades de pointes has been reported in patients receiving sparfloxacin|
00305|043|D|with disopyramide and amiodarone.(1)|
00305|044|B||
00305|045|R|REFERENCES:|
00305|046|B||
00305|047|R|1.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
00305|048|R|  Inc. February, 2003.|1
00305|049|R|2.Raxar (grepafloxacin) US prescribing information. Glaxo Wellcome, Inc.|1
00305|050|R|  November, 1997.|1
00305|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00305|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00305|053|R|  settings: a scientific statement from the American Heart Association and|6
00305|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00305|055|R|  2;55(9):934-47.|6
00306|001|T|MONOGRAPH TITLE:  Grepafloxacin/Erythromycin|
00306|002|B||
00306|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00306|004|L|is contraindicated and generally should not be dispensed or administered to|
00306|005|L|the same patient.|
00306|006|B||
00306|007|A|MECHANISM OF ACTION:  The concurrent use of multiple agents that prolong the|
00306|008|A|QTc interval may result in additive effects on the QTc interval.(2)  In|
00306|009|A|vitro studies indicate that grepafloxacin and sparfloxacin are both potent|
00306|010|A|inhibitors of p-glycoprotein-mediated efflux of erythromycin, which could|
00306|011|A|minimize the metabolism of both the fluoroquinolone and erythromycin.(3,4)|
00306|012|B||
00306|013|E|CLINICAL EFFECTS:  The concurrent use of multiple agents that prolong the|
00306|014|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
00306|015|E|including torsades de pointes.(2)|
00306|016|B||
00306|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00306|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
00306|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00306|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00306|021|P|female gender, or advanced age.(2)|
00306|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00306|023|P|higher systemic concentrations of either QT prolonging drug are additional|
00306|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00306|025|P|drug concentrations include rapid infusion of an intravenous dose or|
00306|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00306|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00306|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00306|029|B||
00306|030|M|PATIENT MANAGEMENT:  Concurrent administration of grepafloxacin and agents|
00306|031|M|known to produce an increase in the QTc interval and/or torsades de pointes|
00306|032|M|such as erythromycin is contraindicated unless appropriate cardiac|
00306|033|M|monitoring can be assured.(1)|
00306|034|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00306|035|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00306|036|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00306|037|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00306|038|B||
00306|039|D|DISCUSSION:  There is no published documentation to support this potential|
00306|040|D|drug interaction.  The product information for grepafloxacin states that|
00306|041|D|prolongation of the QTc interval has been observed in healthy subjects|
00306|042|D|receiving grepafloxacin.(1)|
00306|043|B||
00306|044|R|REFERENCES:|
00306|045|B||
00306|046|R|1.Raxar (grepafloxacin) US prescribing information. Glaxo Wellcome, Inc.|1
00306|047|R|  November, 1997.|1
00306|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00306|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00306|050|R|  settings: a scientific statement from the American Heart Association and|6
00306|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00306|052|R|  2;55(9):934-47.|6
00306|053|R|3.Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-drug interactions. J|6
00306|054|R|  Neuroimmune Pharmacol 2006 Sep;1(3):323-39.|6
00306|055|R|4.Sikri V, Pal D, Jain R, Kalyani D, Mitra AK. Cotransport of macrolide and|5
00306|056|R|  fluoroquinolones, a beneficial interaction reversing P-glycoprotein|5
00306|057|R|  efflux. Am J Ther 2004 Nov-Dec;11(6):433-42.|5
00307|001|T|MONOGRAPH TITLE:  Grepafloxacin; Sparfloxacin/Astemizole; Terfenadine|
00307|002|B||
00307|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00307|004|L|is contraindicated and generally should not be dispensed or administered to|
00307|005|L|the same patient.|
00307|006|B||
00307|007|A|MECHANISM OF ACTION:  Possibly additive or synergistic effects on the QTc|
00307|008|A|interval.(7)|
00307|009|B||
00307|010|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in|
00307|011|E|life-threatening arrhythmias such as torsades de pointes.|
00307|012|B||
00307|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00307|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00307|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00307|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00307|017|P|female gender, or advanced age.(6)|
00307|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00307|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00307|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00307|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00307|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00307|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00307|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
00307|025|B||
00307|026|M|PATIENT MANAGEMENT:  Concurrent administration of grepafloxacin and agents|
00307|027|M|known to produce an increase in the QTc interval and/or torsades de pointes|
00307|028|M|such as astemizole or terfenadine is contraindicated unless appropriate|
00307|029|M|cardiac monitoring can be assured.(1)  Concurrent administration of|
00307|030|M|sparfloxacin and agents known to produce an increase in the QTc interval|
00307|031|M|and/or torsades de pointes is contraindicated.  The manufacturer of|
00307|032|M|sparfloxacin states that concurrent administration of sparfloxacin and|
00307|033|M|either astemizole or terfenadine should be avoided.(2)  The manufacturer of|
00307|034|M|terfenadine states that concurrent administration of terfenadine and|
00307|035|M|sparfloxacin is not recommended.(3)  Fexofenadine and loratadine,|
00307|036|M|nonsedating antihistamines which have been shown to have no effects on|
00307|037|M|cardiac function(4,5), may be alternatives in patients receiving|
00307|038|M|grepafloxacin or sparfloxacin. Sparfloxacin should be administered with|
00307|039|M|caution to patients receiving concomitant medications known to prolong the|
00307|040|M|QTc interval.(7)|
00307|041|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00307|042|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00307|043|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00307|044|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00307|045|B||
00307|046|D|DISCUSSION:  There is no published documentation to support this potential|
00307|047|D|drug interaction.  The product information for grepafloxacin states that|
00307|048|D|prolongation of the QTc interval has been observed in healthy subjects|
00307|049|D|receiving grepafloxacin.(1)  The product information for sparfloxacin states|
00307|050|D|that torsades de pointes has been reported in patients receiving|
00307|051|D|sparfloxacin and disopyramide and amiodarone.  Therefore, concurrent|
00307|052|D|administration of sparfloxacin and agents known to produce an increase in|
00307|053|D|the QTc interval and/or torsades de pointes, such as astemizole and|
00307|054|D|terfenadine, is contraindicated.(2)  The manufacturer of terfenadine states|
00307|055|D|that concurrent administration of terfenadine and sparfloxacin is not|
00307|056|D|recommended.(3) A study in 88 healthy volunteers demonstrated that the|
00307|057|D|concomitant administration of sparfloxacin and terfenadine resulted in an|
00307|058|D|additive effect of prolongation of the QTc interval.(7)|
00307|059|B||
00307|060|R|REFERENCES:|
00307|061|B||
00307|062|R|1.Raxar (grepafloxacin) US prescribing information. Glaxo Wellcome, Inc.|1
00307|063|R|  November, 1997.|1
00307|064|R|2.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
00307|065|R|  Inc. February, 2003.|1
00307|066|R|3.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00307|067|R|  September, 1997.|1
00307|068|R|4.Allegra (fexofenadine hydrochloride) US prescribing information.|1
00307|069|R|  Sanofi-Aventis U.S. LLC October, 2006.|1
00307|070|R|5.Claritin (loratadine) US prescribing information. Schering-Plough|1
00307|071|R|  Corporation January, 1997.|1
00307|072|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00307|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00307|074|R|  settings: a scientific statement from the American Heart Association and|6
00307|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00307|076|R|  2;55(9):934-47.|6
00307|077|R|7.Morganroth J, Hunt T, Dorr MB, Magner D, Talbot GH. The effect of|2
00307|078|R|  terfenadine on the cardiac pharmacodynamics of sparfloxacin. Clin Ther|2
00307|079|R|  1999 Sep;21(9):1514-24.|2
00308|001|T|MONOGRAPH TITLE:  Grepafloxacin; Sparfloxacin/Cisapride|
00308|002|B||
00308|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00308|004|L|is contraindicated and generally should not be dispensed or administered to|
00308|005|L|the same patient.|
00308|006|B||
00308|007|A|MECHANISM OF ACTION:  Possibly additive or synergistic effects on the QTc|
00308|008|A|interval.(5)|
00308|009|B||
00308|010|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in|
00308|011|E|life-threatening arrhythmias such as torsades de pointes.|
00308|012|B||
00308|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00308|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00308|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00308|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00308|017|P|female gender, or advanced age.(4)|
00308|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00308|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00308|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00308|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00308|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00308|023|P|an agent which inhibits  its metabolism or elimination, genetic impairment|
00308|024|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
00308|025|B||
00308|026|M|PATIENT MANAGEMENT:  Concurrent administration of grepafloxacin and agents|
00308|027|M|known to produce an increase in the QTc interval and/or torsades de pointes|
00308|028|M|such as cisapride is contraindicated unless appropriate cardiac monitoring|
00308|029|M|can be assured.(1)  Concurrent administration of sparfloxacin and agents|
00308|030|M|known to produce an increase in the QTc interval and/or torsades de pointes|
00308|031|M|is contraindicated.  The manufacturer of sparfloxacin states that concurrent|
00308|032|M|administration of sparfloxacin and cisapride should be avoided.(2)  The|
00308|033|M|manufacturer of cisapride states that cisapride should not be concomitantly|
00308|034|M|administered with agents known to prolong the QT interval such as|
00308|035|M|sparfloxacin.(3)|
00308|036|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00308|037|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00308|038|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00308|039|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00308|040|B||
00308|041|D|DISCUSSION:  The product information for grepafloxacin states that|
00308|042|D|prolongation of the QTc interval has been observed in healthy subjects|
00308|043|D|receiving grepafloxacin.  Therefore, concurrent administration of|
00308|044|D|grepafloxacin and agents known to produce an increase in the QTc interval|
00308|045|D|and/or torsades de pointes such as cisapride is contraindicated unless|
00308|046|D|appropriate cardiac monitoring can be assured.(1)|
00308|047|D|   The product information for sparfloxacin states that torsades de pointes|
00308|048|D|has been reported in patients receiving sparfloxacin and disopyramide and|
00308|049|D|amiodarone.  Therefore, concurrent administration of sparfloxacin and agents|
00308|050|D|known to produce an increase in the QTc interval and/or torsades de pointes,|
00308|051|D|such as cisapride, is contraindicated.(2)|
00308|052|D|   The manufacturer of cisapride states that QT prolongation, torsades de|
00308|053|D|pointes (sometimes with syncope), cardiac arrest, and sudden death have been|
00308|054|D|reported in patients who were not taking agents known to increase cisapride|
00308|055|D|levels.  Some of these patients were taking agents known to prolong the QT|
00308|056|D|interval, such as sparfloxacin.  The manufacturer of cisapride states that|
00308|057|D|cisapride should not be concomitantly administered with agents known to|
00308|058|D|prolong the QT interval.(3)|
00308|059|D|   A study in 15 healthy volunteers demonstrated that cisapride accelerated|
00308|060|D|the absorption and peak concentration of sparfloxacin. The QTc interval for|
00308|061|D|these patients was prolonged by 7.7% compared to the QTc interval during|
00308|062|D|medication-free periods.(5)|
00308|063|B||
00308|064|R|REFERENCES:|
00308|065|B||
00308|066|R|1.Raxar (grepafloxacin) US prescribing information. Glaxo Wellcome, Inc.|1
00308|067|R|  November, 1997.|1
00308|068|R|2.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
00308|069|R|  Inc. February, 2003.|1
00308|070|R|3.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00308|071|R|  Products, L.P. January, 2000.|1
00308|072|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00308|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00308|074|R|  settings: a scientific statement from the American Heart Association and|6
00308|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00308|076|R|  2;55(9):934-47.|6
00308|077|R|5.Zix JA, Geerdes-Fenge HF, Rau M, Vockler J, Borner K, Koeppe P, Lode H.|2
00308|078|R|  Pharmacokinetics of sparfloxacin and interaction with cisapride and|2
00308|079|R|  sucralfate. Antimicrob Agents Chemother 1997 Aug;41(8):1668-72.|2
00309|001|T|MONOGRAPH TITLE:  Grepafloxacin; Sparfloxacin/Pentamidine|
00309|002|B||
00309|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00309|004|L|is contraindicated and generally should not be dispensed or administered to|
00309|005|L|the same patient.|
00309|006|B||
00309|007|A|MECHANISM OF ACTION:  Possibly additive or synergistic effects on the QTc|
00309|008|A|interval.(4)|
00309|009|B||
00309|010|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in|
00309|011|E|life-threatening arrhythmias such as torsades de pointes.|
00309|012|B||
00309|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00309|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00309|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00309|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00309|017|P|female gender, or advanced age.(3)|
00309|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00309|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00309|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00309|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00309|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00309|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00309|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00309|025|B||
00309|026|M|PATIENT MANAGEMENT:  Concurrent administration of grepafloxacin and agents|
00309|027|M|known to produce an increase in the QTc interval and/or torsades de pointes|
00309|028|M|such as pentamidine is contraindicated unless appropriate cardiac monitoring|
00309|029|M|can be assured.(1)  Concurrent administration of sparfloxacin and agents|
00309|030|M|known to produce an increase in the QTc interval and/or torsades de pointes|
00309|031|M|is contraindicated.  The manufacturer of sparfloxacin states that concurrent|
00309|032|M|administration of sparfloxacin and pentamidine should be avoided.(2)|
00309|033|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00309|034|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00309|035|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00309|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00309|037|B||
00309|038|D|DISCUSSION:  There is no published documentation to support this potential|
00309|039|D|drug interaction.  The product information for grepafloxacin states that|
00309|040|D|prolongation of the QTc interval has been observed in healthy subjects|
00309|041|D|receiving grepafloxacin.(1)  The product information for sparfloxacin states|
00309|042|D|that torsades de pointes has been reported in patients receiving|
00309|043|D|sparfloxacin and disopyramide and amiodarone.  Therefore, concurrent|
00309|044|D|administration of sparfloxacin and agents known to produce an increase in|
00309|045|D|the QTc interval and/or torsades de pointes, such as pentamidine, is|
00309|046|D|contraindicated.(2)|
00309|047|B||
00309|048|R|REFERENCES:|
00309|049|B||
00309|050|R|1.Raxar (grepafloxacin) US prescribing information. Glaxo Wellcome, Inc.|1
00309|051|R|  November, 1997.|1
00309|052|R|2.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
00309|053|R|  Inc. February, 2003.|1
00309|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00309|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00309|056|R|  settings: a scientific statement from the American Heart Association and|6
00309|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00309|058|R|  2;55(9):934-47.|6
00309|059|R|4.Owens RC Jr. QT prolongation with antimicrobial agents: understanding the|6
00309|060|R|  significance. Drugs 2004;64(10):1091-124.|6
00310|001|T|MONOGRAPH TITLE:  Grepafloxacin; Sparfloxacin/Tricyclic Compounds|
00310|002|B||
00310|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00310|004|L|is contraindicated and generally should not be dispensed or administered to|
00310|005|L|the same patient.|
00310|006|B||
00310|007|A|MECHANISM OF ACTION:  Unknown.  Possibly additive or synergistic effects on|
00310|008|A|the QTc interval.|
00310|009|B||
00310|010|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in|
00310|011|E|life-threatening arrhythmias such as torsades de pointes.|
00310|012|B||
00310|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00310|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00310|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00310|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00310|017|P|female gender, or advanced age.(3)|
00310|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00310|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00310|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00310|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00310|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00310|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00310|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00310|025|B||
00310|026|M|PATIENT MANAGEMENT:  Concurrent administration of grepafloxacin and agents|
00310|027|M|known to produce an increase in the QTc interval and/or torsades de pointes|
00310|028|M|such as tricyclic antidepressants is contraindicated unless appropriate|
00310|029|M|cardiac monitoring can be assured.(1)  Concurrent administration of|
00310|030|M|sparfloxacin and agents known to produce an increase in the QTc interval|
00310|031|M|and/or torsades de pointes is contraindicated.  The manufacturer of|
00310|032|M|sparfloxacin states that concurrent administration of sparfloxacin and|
00310|033|M|tricyclic antidepressants should be avoided.(2)|
00310|034|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00310|035|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00310|036|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00310|037|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00310|038|B||
00310|039|D|DISCUSSION:  There is no published documentation to support this potential|
00310|040|D|drug interaction.  The product information for grepafloxacin states that|
00310|041|D|prolongation of the QTc interval has been observed in healthy subjects|
00310|042|D|receiving grepafloxacin.(1)  The product information for sparfloxacin states|
00310|043|D|that torsades de pointes has been reported in patients receiving|
00310|044|D|sparfloxacin and disopyramide and amiodarone.  Therefore, concurrent|
00310|045|D|administration of sparfloxacin and agents known to produce an increase in|
00310|046|D|the QTc interval and/or torsades de pointes, such as tricyclic|
00310|047|D|antidepressants, is contraindicated.(2)|
00310|048|B||
00310|049|R|REFERENCES:|
00310|050|B||
00310|051|R|1.Raxar (grepafloxacin) US prescribing information. Glaxo Wellcome, Inc.|1
00310|052|R|  November, 1997.|1
00310|053|R|2.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
00310|054|R|  Inc. February, 2003.|1
00310|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00310|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00310|057|R|  settings: a scientific statement from the American Heart Association and|6
00310|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00310|059|R|  2;55(9):934-47.|6
00311|001|T|MONOGRAPH TITLE:  Grepafloxacin; Sparfloxacin/Phenothiazines|
00311|002|B||
00311|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00311|004|L|is contraindicated and generally should not be dispensed or administered to|
00311|005|L|the same patient.|
00311|006|B||
00311|007|A|MECHANISM OF ACTION:  Unknown.  Possibly additive or synergistic effects on|
00311|008|A|the QTc interval.|
00311|009|B||
00311|010|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in|
00311|011|E|life-threatening arrhythmias such as torsades de pointes.|
00311|012|B||
00311|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00311|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00311|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00311|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00311|017|P|female gender, or advanced age.(3)|
00311|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00311|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00311|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00311|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00311|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00311|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00311|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00311|025|B||
00311|026|M|PATIENT MANAGEMENT:  Concurrent administration of grepafloxacin and agents|
00311|027|M|known to produce an increase in the QTc interval and/or torsades de pointes|
00311|028|M|such as phenothiazines is contraindicated unless appropriate cardiac|
00311|029|M|monitoring can be assured.(1)  Concurrent administration of sparfloxacin and|
00311|030|M|agents known to produce an increase in the QTc interval and/or torsades de|
00311|031|M|pointes is contraindicated.  The manufacturer of sparfloxacin states that|
00311|032|M|concurrent administration of sparfloxacin and phenothiazines should be|
00311|033|M|avoided.(2)|
00311|034|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00311|035|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00311|036|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00311|037|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00311|038|B||
00311|039|D|DISCUSSION:  There is no published documentation to support this potential|
00311|040|D|drug interaction.  The product information for grepafloxacin states that|
00311|041|D|prolongation of the QTc interval has been observed in healthy subjects|
00311|042|D|receiving grepafloxacin.(1)  The product information for sparfloxacin states|
00311|043|D|that torsades de pointes has been reported in patients receiving|
00311|044|D|sparfloxacin and disopyramide and amiodarone.  Therefore, concurrent|
00311|045|D|administration of sparfloxacin and agents known to produce an increase in|
00311|046|D|the QTc interval and/or torsades de pointes, such as phenothiazines, is|
00311|047|D|contraindicated.(2)|
00311|048|B||
00311|049|R|REFERENCES:|
00311|050|B||
00311|051|R|1.Raxar (grepafloxacin) US prescribing information. Glaxo Wellcome, Inc.|1
00311|052|R|  November, 1997.|1
00311|053|R|2.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
00311|054|R|  Inc. February, 2003.|1
00311|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00311|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00311|057|R|  settings: a scientific statement from the American Heart Association and|6
00311|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00311|059|R|  2;55(9):934-47.|6
00312|001|T|MONOGRAPH TITLE:  Nitrazepam/Fluvoxamine (mono deleted 04/15/2022)|
00312|002|B||
00312|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00312|004|L|take action as needed.|
00312|005|B||
00312|006|A|MECHANISM OF ACTION:  Fluvoxamine, a CYP3A4 inhibitor, may inhibit the|
00312|007|A|metabolism of nitrazepam.|
00312|008|B||
00312|009|E|CLINICAL EFFECTS:  Serum nitrazepam concentration and half-life may be|
00312|010|E|increased, enhancing the CNS side effects of the nitrazepam including|
00312|011|E|profound sedation, respiratory depression, coma, and/or death.|
00312|012|B||
00312|013|P|PREDISPOSING FACTORS:  None determined.|
00312|014|B||
00312|015|M|PATIENT MANAGEMENT:  If sedation is increased or prolonged, it may be|
00312|016|M|necessary to decrease the dose or increase the dosing interval of|
00312|017|M|nitrazepam.  Consider giving a benzodiazepine that is not metabolized by|
00312|018|M|oxidative metabolism (e.g., lorazepam).|
00312|019|B||
00312|020|D|DISCUSSION:  Clinical data supporting this interaction are based on studies|
00312|021|D|involving fluvoxamine and concomitant administration of alprazolam or|
00312|022|D|diazepam.  However, the mechanism of this interaction probably involves|
00312|023|D|inhibition of benzodiazepine oxidative metabolism by fluvoxamine.  Since|
00312|024|D|alprazolam and diazepam as well as nitrazepam undergo oxidative metabolism,|
00312|025|D|this interaction would be expected to occur with nitrazepam.|
00312|026|D|   In healthy volunteers, the half-life and serum concentration of|
00312|027|D|alprazolam and diazepam have been found to be increased while the clearance|
00312|028|D|was decreased by concomitant administration of fluvoxamine.  Diazepam serum|
00312|029|D|levels were increased by 32% and the half life by 131% while the plasma|
00312|030|D|alprazolam level was increased by 100% and the half-life by 70%.|
00312|031|B||
00312|032|R|REFERENCES:|
00312|033|B||
00312|034|R|1.Fleishaker JC, Hulst LK. A pharmacokinetic and pharmacodynamic evaluation|2
00312|035|R|  of the combined administration of alprazolam and fluvoxamine. Eur J Clin|2
00312|036|R|  Pharmacol 1994;46(1):35-9.|2
00312|037|R|2.Perucca E, Gatti G, Cipolla G, Spina E, Barel S, Soback S, Gips M, Bialer|2
00312|038|R|  M. Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic|2
00312|039|R|  study in normal volunteers. Clin Pharmacol Ther 1994 Nov;56(5):471-6.|2
00312|040|R|3.Mizuno K, Katoh M, Okumura H, Nakagawa N, Negishi T, Hashizume T, Nakajima|5
00312|041|R|  M, Yokoi T. Metabolic activation of benzodiazepines by CYP3A4. Drug Metab|5
00312|042|R|  Dispos 2009 Feb;37(2):345-51.|5
00313|001|T|MONOGRAPH TITLE:  Carbamazepine/Selected SSRIs|
00313|002|B||
00313|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00313|004|L|take action as needed.|
00313|005|B||
00313|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  The SSRIs may inhibit|
00313|007|A|the metabolism of carbamazepine, although evidence is conflicting.|
00313|008|B||
00313|009|E|CLINICAL EFFECTS:  Possible increased levels of carbamazepine and clinical|
00313|010|E|toxicity.|
00313|011|B||
00313|012|P|PREDISPOSING FACTORS:  One set of authors speculated that the interaction|
00313|013|P|may be less prevalent in long-term recipients of carbamazepine in whom|
00313|014|P|carbamazepine has resulted in enzyme induction.  Carbamazepine-induced|
00313|015|P|enzyme induction could possibly decrease the amount of SSRI available to|
00313|016|P|interact with carbamazepine.(1)|
00313|017|B||
00313|018|M|PATIENT MANAGEMENT:  Consider monitoring carbamazepine levels when SSRI|
00313|019|M|therapy is initiated or withdrawn.  Patients receiving concurrent therapy|
00313|020|M|should be monitored for clinical signs of toxicity.|
00313|021|B||
00313|022|D|DISCUSSION:  Information on this interaction is conflicting.  In a study in|
00313|023|D|subjects maintained on carbamazepine (CBZ), the addition of fluoxetine or|
00313|024|D|fluvoxamine to their regimens resulted in no changes in either CBZ or|
00313|025|D|carbamazepine-10,11-epoxide (CBZ-E).(1)  Another study compared subjects|
00313|026|D|receiving concurrent therapy with CBZ and fluoxetine to subjects receiving|
00313|027|D|CBZ therapy alone.  There were no differences in the ratios of CBZ to CBZ-E|
00313|028|D|levels between the groups, although there was a trend towards lower CBZ|
00313|029|D|clearance in the group receiving concurrent therapy.  The in-vitro section|
00313|030|D|of this study found that fluoxetine did not inhibit the metabolism of CBZ|
00313|031|D|until fluoxetine reached levels 20 times greater than those found|
00313|032|D|clinically.  In contrast, another study in healthy subjects found a 30%|
00313|033|D|increase in area-under-curve (AUC) of CBZ and CBZ-E during concurrent|
00313|034|D|therapy with fluoxetine.(3) There have been four case reports of|
00313|035|D|parkinsonism developing after the addition of fluoxetine to CBZ therapy.|
00313|036|D|(4-6) There have been two case reports of increased CBZ levels(7) and one|
00313|037|D|report of serotonin syndrome(8) following the addition of fluoxetine|
00313|038|D|therapy.|
00313|039|D|     Information on fluvoxamine is also conflicting.  Although the addition|
00313|040|D|of fluvoxamine to carbamazepine regimens resulted in no changes in either|
00313|041|D|CBZ or CBZ-E levels in one study,(1) there have been five case reports of|
00313|042|D|increases in CBZ levels, with clinical toxicity in two reports, during|
00313|043|D|concurrent therapy.(9-10)|
00313|044|D|     Information on sertraline is also conflicting.  Although the addition|
00313|045|D|of sertraline to carbamazepine regimens resulted in no changes in either CBZ|
00313|046|D|or CBZ-E levels in one study,(11) there has been one case report of|
00313|047|D|increased CBZ levels with clinical toxicity during concurrent therapy.(12)|
00313|048|D|     One study has demonstrated that paroxetine had no effect on CBZ levels|
00313|049|D|or effectiveness.(13)|
00313|050|B||
00313|051|R|REFERENCES:|
00313|052|B||
00313|053|R|1.Spina E, Avenoso A, Pollicino AM, Caputi AP, Fazio A, Pisani F.|2
00313|054|R|  Carbamazepine coadministration with fluoxetine or fluvoxamine. Ther Drug|2
00313|055|R|  Monit 1993 Jun;15(3):247-50.|2
00313|056|R|2.Gidal BE, Anderson GD, Seaton TL, Miyoshi HR, Wilenksy AJ. Evaluation of|5
00313|057|R|  the effect of fluoxetine on the formation of carbamazepine epoxide. Ther|5
00313|058|R|  Drug Monit 1993 Oct;15(5):405-9.|5
00313|059|R|3.Grimsley SR, Jann MW, Carter JG, D'Mello AP, D'Souza MJ. Increased|2
00313|060|R|  carbamazepine plasma concentrations after fluoxetine coadministration.|2
00313|061|R|  Clin Pharmacol Ther 1991 Jul;50(1):10-5.|2
00313|062|R|4.Gernaat HB, Van de Woude J, Touw DJ. Fluoxetine and parkinsonism in|3
00313|063|R|  patients taking carbamazepine. Am J Psychiatry 1991 Nov;148(11):1604-5.|3
00313|064|R|5.Keppel Hesselink JM. Parkinsonism following addition of fluoxetine to|3
00313|065|R|  treatment with neuroleptics or carbamazepine. Ned Tijdschr Geneeskd 1992|3
00313|066|R|  Apr 11;136(15):754-5.|3
00313|067|R|6.Jansen EN, Kolling P. Parkinsonism following addition of fluoxetine to|3
00313|068|R|  treatment with neuroleptics or carbamazepine. Ned Tijdschr Geneeskd 1992|3
00313|069|R|  Apr 11;136(15):755-6.|3
00313|070|R|7.Pearson HJ. Interaction of fluoxetine with carbamazepine. J Clin|3
00313|071|R|  Psychiatry 1990 Mar;51(3):126.|3
00313|072|R|8.Dursun SM, Mathew VM, Reveley MA. Toxic serotonin syndrome after|3
00313|073|R|  fluoxetine plus carbamazepine. Lancet 1993 Aug 14;342(8868):442-3.|3
00313|074|R|9.Fritze J, Unsorg B, Lanczik M. Interaction between carbamazepine and|3
00313|075|R|  fluvoxamine. Acta Psychiatr Scand 1991 Dec;84(6):583-4.|3
00313|076|R|10.Cottencin O, Regnaut N, Thevenon-Gignac C, Thomas P, Goudemand M,|3
00313|077|R|   Debruille C, Robert H. Carbamazepine-fluvoxamine interaction.|3
00313|078|R|   Consequences for the carbamazepine plasma level. Encephale 1995 Mar-Apr;|3
00313|079|R|   21(2):141-5.|3
00313|080|R|11.Rapeport WG, Williams SA, Muirhead DC, Dewland PM, Tanner T, Wesnes K.|2
00313|081|R|   Absence of a sertraline-mediated effect on the pharmacokinetics and|2
00313|082|R|   pharmacodynamics of carbamazepine. J Clin Psychiatry 1996;57 Suppl|2
00313|083|R|   1:20-3.|2
00313|084|R|12.Joblin M. Possible interaction of sertraline with carbamazepine. N Z Med|3
00313|085|R|   J 1994 Feb 9;107(971):43.|3
00313|086|R|13.Andersen BB, Mikkelsen M, Vesterager A, Dam M, Kristensen HB, Pedersen B,|2
00313|087|R|   Lund J, Mengel H. No influence of the antidepressant paroxetine on|2
00313|088|R|   carbamazepine, valproate and phenytoin. Epilepsy Res 1991 Nov-Dec;|2
00313|089|R|   10(2-3):201-4.|2
00314|001|T|MONOGRAPH TITLE:  Metformin/Iodinated Contrast Materials|
00314|002|B||
00314|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00314|004|L|of severe adverse interaction.|
00314|005|B||
00314|006|A|MECHANISM OF ACTION:  Use of iodinated contrast materials may result in|
00314|007|A|acute changes in renal function, resulting in a decrease in metformin|
00314|008|A|clearance.(1-3)|
00314|009|B||
00314|010|E|CLINICAL EFFECTS:  Use of iodinated contrast materials may increase levels|
00314|011|E|of metformin, which may result in lactic acidosis.(1-3)|
00314|012|B||
00314|013|P|PREDISPOSING FACTORS:  Pre-existing renal dysfunction may contribute to|
00314|014|P|decreased clearance of metformin.|
00314|015|P|   Other factors which may increase the risk for lactic acidosis include age|
00314|016|P|greater than 65 years, dehydration, metabolic acidosis, sepsis, a history of|
00314|017|P|hepatic impairment, alcoholism, or heart failure.(1-4)|
00314|018|B||
00314|019|M|PATIENT MANAGEMENT:  Evaluate renal function prior to contrast procedure.|
00314|020|M|   According to manufacturer recommendations, discontinue metformin at the|
00314|021|M|time of, or prior to, the contrast imaging procedure in patients with a|
00314|022|M|history of liver disease, alcoholism, heart failure, or if contrast is to be|
00314|023|M|administered intra-arterially.  When contrast is to be administered by other|
00314|024|M|routes, discontinue metformin at the time of, or prior to, the procedure for|
00314|025|M|patients with an estimated glomerular filtration rate (eGFR) of 30 to 60|
00314|026|M|mL/min/1.73 m2.  Re-evaluate eGFR 48 hours after the imaging procedure and|
00314|027|M|restart metformin if renal function is stable.  Discontinuation of metformin|
00314|028|M|is not required if eGFR is > 60 mL/min/1.73 m2.(4)|
00314|029|M|   According to American College of Radiology guidelines, discontinue|
00314|030|M|metformin at the time of, or prior to, the contrast imaging procedure in|
00314|031|M|patients with acute kidney injury or chronic kidney disease (Stage IV or V|
00314|032|M|or eGFR < 30 mL/min/1.73 m2), or who are undergoing arterial catheter|
00314|033|M|studies that might result in emboli (atheromatous or other) to the renal|
00314|034|M|arteries. Re-evaluate eGFR 48 hours after the imaging procedure and restart|
00314|035|M|metformin if renal function is normal.  Discontinuation of metformin is not|
00314|036|M|required in patients with no evidence of acute kidney injury and with eGFR|
00314|037|M|>= 30 mL/min/m2.(5)|
00314|038|B||
00314|039|D|DISCUSSION:  An FDA review of the medical literature showed that metformin|
00314|040|D|may be safely used in patients with mild or moderate renal impairment,|
00314|041|D|resulting in modifications of prescribing recommendations and method for|
00314|042|D|evaluation of renal function.(4)|
00314|043|D|   A clinical review of 33 patients on metformin who had received contrast|
00314|044|D|media showed elevations in serum creatinine of the four patients with|
00314|045|D|baseline elevations.  The 29 patients with normal baseline renal function|
00314|046|D|showed no elevations after administration of contrast media.  The authors|
00314|047|D|recommend that a baseline serum creatinine is obtained for all patients and|
00314|048|D|that metformin should only be discontinued in patients with baseline|
00314|049|D|elevations.(6)|
00314|050|D|    A retrospective study of ninety-seven patients currently taking|
00314|051|D|metformin underwent a radiologic procedure with contrast media.  Of these|
00314|052|D|patients, 4 developed contrast material associated nephropathy and eight|
00314|053|D|patients had an increased risk of lactic acidosis, with a baseline serum|
00314|054|D|creatinine <1.5mg/dl.(7)|
00314|055|D|   A prospective clinical trial with 50 diabetic patients on metformin with|
00314|056|D|baseline serum creatinine <1.47mg/dl showed no statistical difference in|
00314|057|D|renal function before and 48 hours after administration of contrast media.|
00314|058|D|The authors recommend a baseline serum creatinine for all patients and|
00314|059|D|suggest that temporary discontinuation of metformin may not be necessary|
00314|060|D|when baseline renal function is <1.47mg/dl.(8)|
00314|061|D|   A systematic review of the literature reveals that 17 of 18 case reports|
00314|062|D|of metformin-induced lactic acidosis involved patients with renal|
00314|063|D|dysfunction prior to administration of contrast media.  The authors|
00314|064|D|recommend a baseline serum creatinine in all patients and if renal|
00314|065|D|dysfunction is present, metformin should be discontinued for 48 hours before|
00314|066|D|and after administration of contrast media.  The authors recommend follow-up|
00314|067|D|creatinine measurement in patients with prior renal impairment or known|
00314|068|D|comorbidities affecting lactate levels.(9)|
00314|069|B||
00314|070|R|REFERENCES:|
00314|071|B||
00314|072|R|1.Glucophage (metformin hydrochloride) US prescribing information.|1
00314|073|R|  Bristol-Myers Squibb Company May, 2018.|1
00314|074|R|2.Avandamet (rosiglitazone maleate-metformin HCl) Australia prescribing|1
00314|075|R|  information. GlaxoSmithKline January 11, 2012.|1
00314|076|R|3.Avandamet (rosiglitazone maleate-metformin HCl) Canadian prescribing|1
00314|077|R|  information. GlaxoSmithKline April 18, 2013.|1
00314|078|R|4.USFood and Drug Administration (FDA). FDA Drug Safety Communication: FDA|1
00314|079|R|  revises warnings regarding use of the diabetes medicine metformin in|1
00314|080|R|  certain patients with reduced kidney function. Accessed at:|1
00314|081|R|  http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm April 8, 2016.|1
00314|082|R|5.ACR Committee on Drugs and Contrast Media. ACR Manual on Contrast Media.|6
00314|083|R|  Available at https://www.acr.org/Clinical-Resources/Contrast-Manual.|6
00314|084|R|  American College of Radiology;Version 10.3:.|6
00314|085|R|6.Nawaz S, Cleveland T, Gaines PA, Chan P. Clinical risk associated with|6
00314|086|R|  contrast angiography in metformin treated patients: a clinical review.|6
00314|087|R|  Clin Radiol 1998 May;53(5):342-4.|6
00314|088|R|7.Parra D, Legreid AM, Beckey NP, Reyes S. Metformin monitoring and change|2
00314|089|R|  in serum creatinine levels in patients undergoing radiologic procedures|2
00314|090|R|  involving administration of intravenous contrast media. Pharmacotherapy|2
00314|091|R|  2004 Aug;24(8):987-93.|2
00314|092|R|8.Radwan MA, Al Taweel ES, Al-Moghairi AM, Aloudah NM, Al Babtain MA,|2
00314|093|R|  Al-Amri HS. Monitoring metformin in cardiac patients exposed to contrast|2
00314|094|R|  media using ultra-high-performance liquid chromatography tandem|2
00314|095|R|  mass-spectrometry. Ther Drug Monit 2011 Dec;33(6):742-9.|2
00314|096|R|9.McCartney MM, Gilbert FJ, Murchison LE, Pearson D, McHardy K, Murray AD.|6
00314|097|R|  Metformin and contrast media--a dangerous combination?. Clin Radiol 1999|6
00314|098|R|  Jan;54(1):29-33.|6
00315|001|T|MONOGRAPH TITLE:  Live Typhoid Vaccine/Antimicrobials|
00315|002|B||
00315|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00315|004|L|is contraindicated and generally should not be dispensed or administered to|
00315|005|L|the same patient.|
00315|006|B||
00315|007|A|MECHANISM OF ACTION:  The antimicrobial may be active against the organism|
00315|008|A|in the live-vaccine.  Antimicrobial therapy may prevent the vaccine organism|
00315|009|A|from replicating enough to trigger an immune response.(1)|
00315|010|B||
00315|011|E|CLINICAL EFFECTS:  Vaccination may be ineffective.|
00315|012|B||
00315|013|P|PREDISPOSING FACTORS:  None determined.|
00315|014|B||
00315|015|M|PATIENT MANAGEMENT:  Do not give oral typhoid vaccine until 72 hours after|
00315|016|M|the last dose of antimicrobial.  If possible, to optimize vaccine|
00315|017|M|effectiveness, do not start antibacterial drugs for 72 hours after the last|
00315|018|M|dose of oral typhoid vaccine.  A longer interval should be considered for|
00315|019|M|long-acting antimicrobials, such as azithromycin.(3)|
00315|020|B||
00315|021|D|DISCUSSION:  Because antimicrobial therapy may prevent sufficient|
00315|022|D|vaccine-organism replication to generate an immune response, the|
00315|023|D|manufacturer of live-attenuated typhoid vaccine and the Centers for Disease|
00315|024|D|Control (CDC) state that the vaccine should not be administered to patients|
00315|025|D|receiving antimicrobial therapy.(1-3)|
00315|026|B||
00315|027|R|REFERENCES:|
00315|028|B||
00315|029|R|1.Typhoid Vaccine Live Oral Ty 21a US prescribing information. Berna|1
00315|030|R|  Products Corp. 1997.|1
00315|031|R|2.Centers for Disease Control and Prevention. General Recommendations on|1
00315|032|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
00315|033|R|  Practices (ACIP). MMWR.  Available at:|1
00315|034|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
00315|035|R|  February 17, 2022;60(RR No.2):1-68.|1
00315|036|R|3.Center for Disease Control and Prevention. Updated Recommendations for the|1
00315|037|R|  Use of Typhoid Vaccine - Advisory Committee on Immunization Practices,|1
00315|038|R|  United States, 2015. MMWR.  Available at:|1
00315|039|R|  https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6411a4.htm March 27, 2015;|1
00315|040|R|  64(11):1-24.|1
00316|001|T|MONOGRAPH TITLE:  Lamotrigine/Valproic Acid|
00316|002|B||
00316|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00316|004|L|of severe adverse interaction.|
00316|005|B||
00316|006|A|MECHANISM OF ACTION:  Valproic acid decreases the clearance of|
00316|007|A|lamotrigine.(1)|
00316|008|B||
00316|009|E|CLINICAL EFFECTS:  Concurrent therapy results in increased levels of|
00316|010|E|lamotrigine, requiring dosage adjustments.  Valproic acid levels may also|
00316|011|E|decrease over the first three weeks of therapy.  Coadministration of|
00316|012|E|valproic acid may increase the risk of potentially life-threatening|
00316|013|E|lamotrigine-induced rashes.(1)|
00316|014|B||
00316|015|P|PREDISPOSING FACTORS:  The incidence of lamotrigine-induced rash has been|
00316|016|P|shown to be higher in pediatric patients.  Although yet to proven, exceeding|
00316|017|P|the recommended dosage for lamotrigine, exceeding the recommended dose|
00316|018|P|escalation for lamotrigine, or being positive for the HLA-B*1502 allele may|
00316|019|P|also increase the risk for lamotrigine-induced rash.(1)|
00316|020|B||
00316|021|M|PATIENT MANAGEMENT:  The dosage of lamotrigine should be reduced during|
00316|022|M|concurrent administration of valproic acid.  Refer to the current|
00316|023|M|manufacturer's prescribing information for lamotrigine for dosing guidelines|
00316|024|M|for patients receiving concurrent lamotrigine and valproic acid therapy.(1)|
00316|025|M|     All patients receiving lamotrigine should be instructed to immediately|
00316|026|M|report the development of a rash of any kind to their physician.|
00316|027|M|     The dosage of valproic acid may also need to be adjusted.|
00316|028|B||
00316|029|D|DISCUSSION:  In clinical trials, 6 of 584 (1%) of patients who received|
00316|030|D|lamotrigine with valproate were hospitalized with rash.  Only 4 of 2398|
00316|031|D|patients who received lamotrigine without valproate were hospitalized.  In|
00316|032|D|pediatric patients receiving concurrent valproate, 1.2% experienced a|
00316|033|D|serious rash compared with 0.6% of those not receiving concurrent therapy.|
00316|034|D|(1)|
00316|035|D|   In a study in 103 adult patients with epilepsy, 30% of patients receiving|
00316|036|D|concurrent lamotrigine with valproate developed a rash, while only 8% of|
00316|037|D|patients receiving lamotrigine alone developed a rash.(2) In a study in 56|
00316|038|D|pediatric patients, the addition of lamotrigine to valproate resulted in|
00316|039|D|rash in five patients. When lamotrigine was resumed without concurrent|
00316|040|D|valproate therapy, there was no recurrence of rash.(3)|
00316|041|D|   In a study in 18 healthy subjects, the administration of lamotrigine and|
00316|042|D|valproic acid decreased the trough stead-state levels of valproate by 25%|
00316|043|D|over a 3 week period.  Valproate levels then stabilized.(4)  Valproate|
00316|044|D|increases lamotrigine levels by slightly more than 2-fold.(1)|
00316|045|B||
00316|046|R|REFERENCES:|
00316|047|B||
00316|048|R|1.Lamictal (lamotrigine) US prscribing information. GlaxoSmithKline October,|1
00316|049|R|  2025.|1
00316|050|R|2.Li LM, Russo M, O'Donoghue MF, Duncan JS, Sander JW. Allergic skin rash|2
00316|051|R|  with lamotrigine and concomitant valproate therapy: evidence for an|2
00316|052|R|  increased risk. Arq Neuropsiquiatr 1996 Mar;54(1):47-9.|2
00316|053|R|3.Farrell K, Connolly MB, Munn R, Peng S, MacWilliam LM. Prospective,|2
00316|054|R|  open-label, add-on study of lamotrigine in 56 children with intractable|2
00316|055|R|  generalized epilepsy. Pediatr Neurol 1997 Apr;16(3):201-5.|2
00316|056|R|4.Anderson GD, Yau MK, Gidal BE, Harris SJ, Levy RH, Lai AA, Wolf KB, Wargin|2
00316|057|R|  WA, Dren AT. Bidirectional interaction of valproate and lamotrigine in|2
00316|058|R|  healthy subjects. Clin Pharmacol Ther 1996 Aug;60(2):145-56.|2
00317|001|T|MONOGRAPH TITLE:  Theophylline/Zileuton|
00317|002|B||
00317|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00317|004|L|take action as needed.|
00317|005|B||
00317|006|A|MECHANISM OF ACTION:  Zileuton may inhibit the metabolism of|
00317|007|A|theophylline(1).|
00317|008|B||
00317|009|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
00317|010|E|of theophylline (up to two-fold) with possible theophylline toxicity.(1,2)|
00317|011|B||
00317|012|P|PREDISPOSING FACTORS:  None determined.|
00317|013|B||
00317|014|M|PATIENT MANAGEMENT:  The manufacturer of zileuton recommends that patients|
00317|015|M|receiving concurrent therapy have their theophylline dosages reduced by|
00317|016|M|one-half and that these patients be monitored for theophylline toxicity.(2)|
00317|017|B||
00317|018|D|DISCUSSION:  In a study in 16 subjects, the concurrent administration of|
00317|019|D|theophylline and zileuton resulted in increased levels of theophylline and|
00317|020|D|adverse effects.  During concurrent administration, theophylline|
00317|021|D|area-under-curve (AUC), maximum concentration (Cmax), and minimum|
00317|022|D|concentration (Cmin) increased 92%, 73%, and 125%, respectively.  During|
00317|023|D|administration of theophylline with placebo, eight of 16 subjects reported a|
00317|024|D|single adverse effect, while 14 subjects reported a total of 44 adverse|
00317|025|D|effects during administration of theophylline with zileuton.(1)|
00317|026|B||
00317|027|R|REFERENCES:|
00317|028|B||
00317|029|R|1.Awni WM, Braeckman RA, Granneman GR, Witt G, Dube LM. Pharmacokinetics and|2
00317|030|R|  pharmacodynamics of zileuton after oral administration of single and|2
00317|031|R|  multiple dose regimens of zileuton 600mg in healthy volunteers. Clin|2
00317|032|R|  Pharmacokinet 1995;29 Suppl 2:22-33.|2
00317|033|R|2.Zyflo (zileuton) US prescribing information. Cornerstone Therapeutics,|1
00317|034|R|  Inc. November, 2011.|1
00318|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/Mibefradil|
00318|002|B||
00318|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00318|004|L|is contraindicated and generally should not be dispensed or administered to|
00318|005|L|the same patient.|
00318|006|B||
00318|007|A|MECHANISM OF ACTION:  Mibefradil has been shown to inhibit the activity of|
00318|008|A|CYP3A4 and thus may inhibit the metabolism of astemizole and terfenadine.(1)|
00318|009|B||
00318|010|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
00318|011|E|of astemizole and terfenadine, which may result in life-threatening|
00318|012|E|cardiotoxicity including QT prolongation or torsades de pointes.|
00318|013|B||
00318|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00318|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00318|016|P|failure, myocardial infarction, history of torsades de  pointes, congenital|
00318|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00318|018|P|female gender, or advanced age.(6)|
00318|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00318|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00318|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00318|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00318|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00318|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00318|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
00318|026|B||
00318|027|M|PATIENT MANAGEMENT:  The manufacturer of mibefradil states that concurrent|
00318|028|M|administration of mibefradil with either astemizole or terfenadine is|
00318|029|M|contraindicated.(1)  The manufacturer of terfenadine also states that|
00318|030|M|concurrent administration of terfenadine and mibefradil is contraindicated.|
00318|031|M|(2)|
00318|032|M|   Fexofenadine and loratadine, nonsedating antihistamines which have been|
00318|033|M|shown to have no effects on cardiac function(3,4), may be alternatives in|
00318|034|M|patients receiving mibefradil.|
00318|035|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00318|036|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00318|037|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00318|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00318|039|B||
00318|040|D|DISCUSSION:  There is no published documentation in the medical literature|
00318|041|D|to support this interaction.  According to the manufacturer's prescribing|
00318|042|D|information for terfenadine, concurrent administration of terfenadine and|
00318|043|D|mibefradil resulted in elevated plasma concentrations of terfenadine up to|
00318|044|D|40 ng/ml (normally undetectable) and a 12% increase in mean QTc interval.|
00318|045|D|Since elevated terfenadine levels and increased QTc intervals are associated|
00318|046|D|with life-threatening cardiotoxicity, the manufacturer of terfenadine states|
00318|047|D|that concurrent administration of mibefradil and terfenadine is|
00318|048|D|contra-indicated.(2)  Because mibefradil has been shown to inhibit CYP3A4,|
00318|049|D|the manufacturer of mibefradil has contraindicated the concurrent|
00318|050|D|administration of astemizole and terfenadine, which are metabolized at this|
00318|051|D|cytochrome.(1)|
00318|052|D|   Following the discontinuation of mibefradil, seven to 14 days are|
00318|053|D|required for sufficient elimination of mibefradil metabolites to minimize|
00318|054|D|mibefradil's effect on CYP3A4.(5)|
00318|055|B||
00318|056|R|REFERENCES:|
00318|057|B||
00318|058|R|1.Posicor (mibefradil) US prescribing information. Roche Pharmaceuticals|1
00318|059|R|  June, 1997.|1
00318|060|R|2.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00318|061|R|  September, 1997.|1
00318|062|R|3.Allegra (fexofenadine hydrochloride) US prescribing information.|1
00318|063|R|  Sanofi-Aventis U.S. LLC October, 2006.|1
00318|064|R|4.Claritin (loratadine) US prescribing information. Schering-Plough|1
00318|065|R|  Corporation January, 1997.|1
00318|066|R|5."Dear Doctor" letter on mibefradil. Roche Pharmaceuticals June 12, 1998.|1
00318|067|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00318|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00318|069|R|  settings: a scientific statement from the American Heart Association and|6
00318|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00318|071|R|  2;55(9):934-47.|6
00319|001|T|MONOGRAPH TITLE:  Cisapride/Selected Calcium Channel Blockers|
00319|002|B||
00319|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00319|004|L|is contraindicated and generally should not be dispensed or administered to|
00319|005|L|the same patient.|
00319|006|B||
00319|007|A|MECHANISM OF ACTION:  Mibefradil has been shown to inhibit the activity of|
00319|008|A|CYP3A4 and thus may inhibit the metabolism of cisapride.(1) Concurrent|
00319|009|A|administration of cisapride and either bepridil or terodiline may result in|
00319|010|A|additive effects on the QT interval.(2)|
00319|011|B||
00319|012|E|CLINICAL EFFECTS:  Concurrent administration of mibefradil and cisapride may|
00319|013|E|result in elevated levels of cisapride, which may result in life-threatening|
00319|014|E|cardiotoxicity.  Concurrent administration of cisapride with either bepridil|
00319|015|E|or terodiline may result in prolongation of the QT interval, which may|
00319|016|E|result in potentially life-threatening arrhythmias, including torsades de|
00319|017|E|pointes.(2)|
00319|018|B||
00319|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00319|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
00319|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00319|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00319|023|P|female gender, or advanced age.(4)|
00319|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00319|025|P|higher systemic concentrations of either QT prolonging drug are additional|
00319|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00319|027|P|drug concentrations include rapid infusion of an intravenous dose or|
00319|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00319|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00319|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
00319|031|B||
00319|032|M|PATIENT MANAGEMENT:  The manufacturer of mibefradil states that concurrent|
00319|033|M|administration of mibefradil with cisapride is contraindicated.(1)  The|
00319|034|M|manufacturer of cisapride states that cisapride should not be concomitantly|
00319|035|M|administered with agents known to prolong the QT interval such as bepridil|
00319|036|M|or terodiline.(2)|
00319|037|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00319|038|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00319|039|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00319|040|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00319|041|B||
00319|042|D|DISCUSSION:  The manufacturer of cisapride states that QT prolongation,|
00319|043|D|torsades de pointes (sometimes with syncope), cardiac arrest, and sudden|
00319|044|D|death have been reported in patients who were not taking agents known to|
00319|045|D|increase cisapride levels.  Some of these patients were taking agents known|
00319|046|D|to prolong the QT interval, such as certain antipsychotic medications such|
00319|047|D|as certain phenothiazines and sertindole.  The manufacturer of cisapride|
00319|048|D|states that cisapride should not be concomitantly administered with agents|
00319|049|D|known to prolong the QT interval.(1)|
00319|050|D|   Because mibefradil has been shown to inhibit CYP3A4, the manufacturer of|
00319|051|D|mibefradil has contraindicated the concurrent administration of cisapride,|
00319|052|D|which is metabolized at this cytochrome.(1)  Following the discontinuation|
00319|053|D|of mibefradil, seven to 14 days are required for sufficient elimination of|
00319|054|D|mibefradil metabolites to minimize mibefradil's inhibition of the CYP3A4|
00319|055|D|system.(3)|
00319|056|D|   One or more of the drug pairs linked to this monograph have been included|
00319|057|D|in a list of interactions that should be considered "high-priority" for|
00319|058|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00319|059|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00319|060|D|Coordinator (ONC) for Health Information Technology.|
00319|061|B||
00319|062|R|REFERENCES:|
00319|063|B||
00319|064|R|1.Posicor (mibefradil) US prescribing information. Roche Pharmaceuticals|1
00319|065|R|  June, 1997.|1
00319|066|R|2.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00319|067|R|  Products, L.P. January, 2000.|1
00319|068|R|3."Dear Doctor" letter on mibefradil. Roche Pharmaceuticals June 12, 1998.|1
00319|069|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00319|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00319|071|R|  settings: a scientific statement from the American Heart Association and|6
00319|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00319|073|R|  2;55(9):934-47.|6
00319|074|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00319|075|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00319|076|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00319|077|R|  19(5):735-43.|6
00320|001|T|MONOGRAPH TITLE:  Opioid Antagonists/Opioid Analgesics|
00320|002|B||
00320|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00320|004|L|is contraindicated and generally should not be dispensed or administered to|
00320|005|L|the same patient.|
00320|006|B||
00320|007|A|MECHANISM OF ACTION:  Naltrexone, nalmefene, and samidorphan are opioid|
00320|008|A|antagonists and thus inhibit the effects of opioid analgesics.(1-3)|
00320|009|B||
00320|010|E|CLINICAL EFFECTS:  Concurrent administration or the administration of|
00320|011|E|naltrexone within 7-10 days of opioids may induce acute abstinence syndrome|
00320|012|E|or exacerbate a pre-existing subclinical abstinence syndrome.(1,4)  Patients|
00320|013|E|taking naltrexone may not experience beneficial effects of opioid-containing|
00320|014|E|medications.(4)|
00320|015|E|   Samidorphan can precipitate opioid withdrawal in patients who are|
00320|016|E|dependent on opioids.  In patients who use opioids, delay initiation of|
00320|017|E|samidorphan for a minimum of 7 days after last use of short-acting opioids|
00320|018|E|and 14 days after last use of long-acting opioids.(3)|
00320|019|E|   Concurrent use of nalmefene tablets with opioid agonists may prevent the|
00320|020|E|beneficial effects of the opioid.(2)|
00320|021|B||
00320|022|P|PREDISPOSING FACTORS:  None determined.|
00320|023|B||
00320|024|M|PATIENT MANAGEMENT:  The manufacturer of naltrexone states that the|
00320|025|M|administration of naltrexone concurrently with opioids or to patients|
00320|026|M|dependent on opioids is contraindicated.(1,4)|
00320|027|M|   Patients previously dependent on short-acting opioids should be|
00320|028|M|opioid-free for a minimum of seven to ten days before beginning naltrexone|
00320|029|M|therapy.  Patients previously on buprenorphine or methadone may be|
00320|030|M|vulnerable to withdrawal symptoms for as long as 2 weeks.(1,4)  The|
00320|031|M|manufacturer of naltrexone states that the naloxone challenge test,|
00320|032|M|described in the naltrexone prescribing information, can be administered to|
00320|033|M|determine if patients are opioid free.(1)|
00320|034|M|   The manufacturer of samidorphan states the concurrent use of samidorphan|
00320|035|M|in patients using opioids or undergoing acute opioid withdrawal is|
00320|036|M|contraindicated.  Prior to initiating samidorphan, there should be at least|
00320|037|M|a 7-day opioid free interval from the last use of short-acting opioids, and|
00320|038|M|at least a 14-day opioid free interval from the last use of long-acting|
00320|039|M|opioids.(3)|
00320|040|M|   The UK manufacturer of nalmefene tablets (for reduction of alcohol|
00320|041|M|consumption) states the concurrent use of opioid analgesics is|
00320|042|M|contraindicated.(2)  Suspend the use of nalmefene tablets for 7 days prior|
00320|043|M|to the anticipated use of opioids (e.g., elective surgery).(2)|
00320|044|B||
00320|045|D|DISCUSSION:  A double-blind, randomized, placebo-control study evaluated|
00320|046|D|pain relief and side effects of 35 opioid-naive patients undergoing cesarean|
00320|047|D|section. All patients received spinal anesthesia (bupivacaine and morphine)|
00320|048|D|and were randomized to also receive placebo, naltrexone 3 mg, or naltrexone|
00320|049|D|6 mg. Patients treated with naltrexone experienced shorter duration of pain|
00320|050|D|relief (not statistically significant), however incidence of opioid-induced|
00320|051|D|side effects was reduced.  Patients in the naltrexone 6 mg group had lower|
00320|052|D|rates of pruritus, vomiting, and somnolence (all statistically significant)|
00320|053|D|compared to the placebo group.(5)|
00320|054|D|   In a double-blind, randomized, placebo-control trial ten recreational|
00320|055|D|opioid users were studied to determine the effects of hydromorphone (4 mg|
00320|056|D|and 16 mg), tramadol (87.5 mg, 175 mg, and 350 mg), and placebo after|
00320|057|D|pretreatment with naltrexone (50 mg) or placebo. Results show that lower|
00320|058|D|doses of hydromorphone and tramadol acted similar to placebo. Hydromorphone|
00320|059|D|16 mg alone caused euphoria and miosis which were blocked by naltrexone.|
00320|060|D|Tramadol 350 mg produced a lower magnitude of euphoria and miosis compared|
00320|061|D|to hydromorphone. Naltrexone partially diminished the euphoria caused by|
00320|062|D|tramadol, while it enhanced some of the unpleasant monoaminergic effects|
00320|063|D|(flushing, malaise, vomiting).(6)|
00320|064|D|   A case report describes a 28 year-old ex-heroin addict who was stable on|
00320|065|D|methadone 100 mg daily and simultaneously stopped using heroin and began|
00320|066|D|drinking alcohol. He was admitted to the hospital for alcohol detoxification|
00320|067|D|and, by mistake, was given naltrexone 100 mg instead of methadone 100 mg.|
00320|068|D|The patient experienced withdrawal symptoms including chills, agitation,|
00320|069|D|muscle and abdominal pain, generalized piloerection, and dilated pupils.|
00320|070|D|Treatment of withdrawal was titrated to treat symptoms and required|
00320|071|D|administration 78 mg of parenteral hydromorphone, after which the patient|
00320|072|D|experienced relief for the following six hours.(8)|
00320|073|D|   Intentional administration of an opioid antagonist, naloxone, with opioid|
00320|074|D|analgesics has been performed with close monitoring to lower required opioid|
00320|075|D|dose by inducing withdrawal. Three case reports describe patients who had|
00320|076|D|improved pain relief on significantly reduced doses of opioid analgesics.(8)|
00320|077|D|   In a double-blind controlled trial, 267 trauma patients were randomized|
00320|078|D|to receive 0.05 mg/kg intravenous morphine either alone or in combination|
00320|079|D|with 5 mg naltrexone oral suspension. Evaluated endpoints include reduction|
00320|080|D|of pain and incidence of side effects.  Results indicate that ultra-low dose|
00320|081|D|naltrexone does not alter opioid requirements for pain control, but does|
00320|082|D|lower incidence of nausea [2 (1.16%) vs 16 (11.6%), p<0.001].(9)|
00320|083|B||
00320|084|R|REFERENCES:|
00320|085|B||
00320|086|R|1.Revia (naltrexone) US prescribing information. Duramed Pharmaceuticals,|1
00320|087|R|  Inc. October, 2013.|1
00320|088|R|2.Selincro (nalmefene hydrochloride dihydrate) UK prescribing information.|1
00320|089|R|  Lundbeck Limited February, 2019.|1
00320|090|R|3.Lybalvi (olanzapine-samidorphan) US prescribing information. Alkermes,|1
00320|091|R|  Inc. January, 2024.|1
00320|092|R|4.Vivitrol (naltrexone for extended-release injectable suspension) US|1
00320|093|R|  prescribing information. Aklermes, Inc. March, 2021.|1
00320|094|R|5.Abboud TK, Lee K, Zhu J, Reyes A, Afrasiabi A, Mantilla M, Steffens Z,|2
00320|095|R|  Chai M. Prophylactic oral naltrexone with intrathecal morphine for|2
00320|096|R|  cesarean section: effects on adverse reactions and analgesia. Anesth Analg|2
00320|097|R|  1990 Oct;71(4):367-70.|2
00320|098|R|6.Stoops WW, Lofwall MR, Nuzzo PA, Craig LB, Siegel AJ, Walsh SL.|2
00320|099|R|  Pharmacodynamic profile of tramadol in humans: influence of naltrexone|2
00320|100|R|  pretreatment. Psychopharmacology (Berl) 2012 Oct;223(4):427-38.|2
00320|101|R|7.Volavka J, Resnick RB. Letter: Treatment of accidental naltrexone-induced|3
00320|102|R|  withdrawal. Am J Psychiatry 1976 Feb;133(2):233.|3
00320|103|R|8.Loitman JE. Enhanced analgesia with opioid antagonist administration. J|3
00320|104|R|  Palliat Med 2006 Dec;9(6):1250-3.|3
00320|105|R|9.Farahmand S, Ahmadi O, Dehpour A, Khashayar P. Does adding low doses of|2
00320|106|R|  oral naltrexone to morphine alter the subsequent opioid  requirements and|2
00320|107|R|  side effects in trauma patients?. Am J Emerg Med 2012 Jan;30(1):75-8.|2
00321|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/Cisapride|
00321|002|B||
00321|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00321|004|L|is contraindicated and generally should not be dispensed or administered to|
00321|005|L|the same patient.|
00321|006|B||
00321|007|A|MECHANISM OF ACTION:  Concurrent administration may produce additive effects|
00321|008|A|on the QT interval.|
00321|009|B||
00321|010|E|CLINICAL EFFECTS:  Concurrent usage may increase the risk of cardiotoxicity,|
00321|011|E|including life-threatening arrhythmias such as QT prolongation or torsades|
00321|012|E|de pointes.|
00321|013|B||
00321|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00321|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00321|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00321|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00321|018|P|female gender, or advanced age.(3)|
00321|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00321|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00321|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00321|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00321|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00321|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00321|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00321|026|B||
00321|027|M|PATIENT MANAGEMENT:  Evaluate all patients for predisposing risk factors.|
00321|028|M|The manufacturer of terfenadine states that concurrent administration with|
00321|029|M|cisapride is not recommended.(1)  The manufacturer of cisapride states that|
00321|030|M|cisapride should not be concomitantly administered with agents known to|
00321|031|M|prolong the QT interval such as astemizole.(2)|
00321|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00321|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00321|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00321|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00321|036|B||
00321|037|D|DISCUSSION:  Elevated plasma levels of astemizole, cisapride, and|
00321|038|D|terfenadine can cause QT prolongation and torsades de pointes-type|
00321|039|D|ventricular tachycardia which may be fatal.  Therefore, the manufacturer of|
00321|040|D|terfenadine states that concurrent administration is not recommended.(1)|
00321|041|D|   The manufacturer of cisapride states that QT prolongation, torsades de|
00321|042|D|pointes (sometimes with syncope), cardiac arrest, and sudden death have been|
00321|043|D|reported in patients who were not taking agents known to increase cisapride|
00321|044|D|levels.  Some of these patients were taking agents known to prolong the QT|
00321|045|D|interval, such as astemizole.  The manufacturer of cisapride states that|
00321|046|D|cisapride should not be concomitantly administered with agents known to|
00321|047|D|prolong the QT interval.(2)|
00321|048|D|   One or more of the drug pairs linked to this monograph have been included|
00321|049|D|in a list of interactions that should be considered "high-priority" for|
00321|050|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00321|051|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00321|052|D|Coordinator (ONC) for Health Information Technology.|
00321|053|B||
00321|054|R|REFERENCES:|
00321|055|B||
00321|056|R|1.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00321|057|R|  September, 1997.|1
00321|058|R|2.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00321|059|R|  Products, L.P. January, 2000.|1
00321|060|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00321|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00321|062|R|  settings: a scientific statement from the American Heart Association and|6
00321|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00321|064|R|  2;55(9):934-47.|6
00321|065|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00321|066|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00321|067|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00321|068|R|  19(5):735-43.|6
00322|001|T|MONOGRAPH TITLE:  Terfenadine/Probucol|
00322|002|B||
00322|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00322|004|L|of severe adverse interaction.|
00322|005|B||
00322|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
00322|007|B||
00322|008|E|CLINICAL EFFECTS:  Concurrent usage may increase the risk of cardiotoxicity,|
00322|009|E|including life-threatening arrhythmias such as QT prolongation or torsades|
00322|010|E|de pointes.|
00322|011|B||
00322|012|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00322|013|P|may be increased in patients with cardiovascular disease (e.g. heart|
00322|014|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00322|015|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00322|016|P|female gender, or advanced age.(3)|
00322|017|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00322|018|P|higher systemic concentrations of either QT prolonging drug are additional|
00322|019|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00322|020|P|drug concentrations include rapid infusion of an intravenous dose or|
00322|021|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00322|022|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00322|023|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00322|024|B||
00322|025|M|PATIENT MANAGEMENT:  Evaluate all patients for predisposing risk factors.|
00322|026|M|The manufacturer of terfenadine states that concurrent administration with|
00322|027|M|probucol is not recommended.(1)|
00322|028|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00322|029|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00322|030|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00322|031|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00322|032|B||
00322|033|D|DISCUSSION:  Elevated plasma levels of terfenadine can cause QT prolongation|
00322|034|D|and torsades de pointes-type ventricular tachycardia which may be fatal.(1)|
00322|035|D|Probucol can also induce QT prolongation.(2)  Therefore, the manufacturer of|
00322|036|D|terfenadine states that concurrent administration of terfenadine and|
00322|037|D|probucol is not recommended.(1)|
00322|038|D|   One or more of the drug pairs linked to this monograph have been included|
00322|039|D|in a list of interactions that should be considered "high-priority" for|
00322|040|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00322|041|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00322|042|D|Coordinator (ONC) for Health Information Technology.|
00322|043|B||
00322|044|R|REFERENCES:|
00322|045|B||
00322|046|R|1.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00322|047|R|  September, 1997.|1
00322|048|R|2.Lorelco (Probucol) Canadian prescribing information. Marion Merrell Dow,|1
00322|049|R|  Canada 1996.|1
00322|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00322|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00322|052|R|  settings: a scientific statement from the American Heart Association and|6
00322|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00322|054|R|  2;55(9):934-47.|6
00322|055|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00322|056|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00322|057|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00322|058|R|  19(5):735-43.|6
00323|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/Zileuton|
00323|002|B||
00323|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00323|004|L|of severe adverse interaction.|
00323|005|B||
00323|006|A|MECHANISM OF ACTION:  Zileuton may inhibit the metabolism of astemizole and|
00323|007|A|terfenadine.(1-3)|
00323|008|B||
00323|009|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
00323|010|E|of astemizole and terfenadine, which may result in life-threatening|
00323|011|E|cardiotoxicity including QT prolongation or torsades de pointes.|
00323|012|B||
00323|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00323|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00323|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00323|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00323|017|P|female gender, or advanced age.(4)|
00323|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00323|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00323|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00323|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00323|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00323|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00323|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
00323|025|B||
00323|026|M|PATIENT MANAGEMENT:  Evaluate all patients for predisposing risk factors.|
00323|027|M|The manufacturers of zileuton(1) and terfenadine(2) state that concurrent|
00323|028|M|administration of terfenadine and zileuton is not recommended.  The|
00323|029|M|manufacturer of astemizole states that concurrent administration of|
00323|030|M|astemizole and zileuton is not recommended.(3)|
00323|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00323|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00323|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00323|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00323|035|B||
00323|036|D|DISCUSSION:  There is no published documentation substantiating this|
00323|037|D|possible drug interaction.  In a study in 16 subjects, the concurrent|
00323|038|D|administration of terfenadine and zileuton resulted in a decrease in|
00323|039|D|terfenadine clearance by 22% and a 35% increase in terfenadine|
00323|040|D|area-under-curve (AUC) and maximum concentration (Cmax).(1)  Although there|
00323|041|D|were no significant prolongations of the QTc interval in this small study,|
00323|042|D|the manufacturers of zileuton(1) and terfenadine(2) state that concurrent|
00323|043|D|administration is not recommended.|
00323|044|D|   The manufacturer of astemizole states that concurrent administration of|
00323|045|D|astemizole and zileuton is not recommended.(3)|
00323|046|B||
00323|047|R|REFERENCES:|
00323|048|B||
00323|049|R|1.Zyflo (zileuton) US prescribing information. Abbott Laboratories October,|1
00323|050|R|  2000.|1
00323|051|R|2.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00323|052|R|  September, 1997.|1
00323|053|R|3.Dear Doctor Letter. Janssen Pharmaceutica Products, L.P. February 1998.|1
00323|054|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00323|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00323|056|R|  settings: a scientific statement from the American Heart Association and|6
00323|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00323|058|R|  2;55(9):934-47.|6
00324|001|T|MONOGRAPH TITLE:  Troglitazone/Contraceptives|
00324|002|B||
00324|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00324|004|L|of severe adverse interaction.|
00324|005|B||
00324|006|A|MECHANISM OF ACTION:  Troglitazone may induce the metabolism of the oral|
00324|007|A|contraceptive by CYP3A4.(1,2)|
00324|008|B||
00324|009|E|CLINICAL EFFECTS:  Concurrent administration may result in decreased levels|
00324|010|E|of both the estrogen and progestin components of the oral contraceptive,|
00324|011|E|which may result in breakthrough bleeding and loss of contraception.(1,2)|
00324|012|B||
00324|013|P|PREDISPOSING FACTORS:  None determined.|
00324|014|B||
00324|015|M|PATIENT MANAGEMENT:  Higher contraceptive dosages may be needed in patients|
00324|016|M|receiving troglitazone therapy.  Alternative methods of contraception should|
00324|017|M|also be considered.(1,2)|
00324|018|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
00324|019|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
00324|020|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
00324|021|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
00324|022|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
00324|023|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
00324|024|M|and to seek medical advice if they do become pregnant.(3)|
00324|025|B||
00324|026|D|DISCUSSION:  In a study in 15 healthy women, concurrent troglitazone (600 mg|
00324|027|D|daily) and Ortho Novum 1/35 (35 mcg ethinyl estradiol, 1 mg norethindrone)|
00324|028|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
00324|029|D|ethinyl estradiol by 29% and 32%, respectively.  Concurrent therapy|
00324|030|D|decreased the AUC and Cmax of norethindrone by 30% and 31%.  Troglitazone|
00324|031|D|decreased the plasma unbound AUC of norethindrone by 49%.(1,2)|
00324|032|B||
00324|033|R|REFERENCES:|
00324|034|B||
00324|035|R|1.Rezulin (troglitazone) US prescribing information. Parke-Davis August,|1
00324|036|R|  1997.|1
00324|037|R|2.Loi CM, Stern R, Koup JR, Vassos AB, Knowlton P, Sedman AJ. Effect of|2
00324|038|R|  troglitazone on the pharmacokinetics of an oral contraceptive agent. J|2
00324|039|R|  Clin Pharmacol 1999 Apr;39(4):410-7.|2
00324|040|R|3.Medicines and Healthcare products Regulatory Agency.|1
00324|041|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
00324|042|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
00324|043|R|  available at:|1
00324|044|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
00324|045|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
00324|046|R|  -and-contraceptive-efficacy September 15, 2016..|1
00325|001|T|MONOGRAPH TITLE:  Troglitazone/Cholestyramine|
00325|002|B||
00325|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00325|004|L|take action as needed.|
00325|005|B||
00325|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown; however,|
00325|007|A|cholestyramine may bind with troglitazone in the gastrointestinal tract and|
00325|008|A|prevent its absorption.|
00325|009|B||
00325|010|E|CLINICAL EFFECTS:  Concurrent administration may result in decreased levels|
00325|011|E|of troglitazone and decreased clinical effects.|
00325|012|B||
00325|013|P|PREDISPOSING FACTORS:  None determined.|
00325|014|B||
00325|015|M|PATIENT MANAGEMENT:  The manufacturer of troglitazone states that concurrent|
00325|016|M|administration is not recommended.(1)  If concurrent therapy is necessary,|
00325|017|M|the administration of troglitazone and cholestyramine should be separated as|
00325|018|M|much as possible.|
00325|019|B||
00325|020|D|DISCUSSION:  There is no published documentation to support this|
00325|021|D|interaction.  The manufacturer of troglitazone states that concurrent|
00325|022|D|administration of troglitazone and cholestyramine decreased the absorption|
00325|023|D|of troglitazone by 70%.(1)|
00325|024|B||
00325|025|R|REFERENCE:|
00325|026|B||
00325|027|R|1.Rezulin (troglitazone) US prescribing information. Parke-Davis August,|1
00325|028|R|  1997.|1
00326|001|T|MONOGRAPH TITLE:  Terfenadine/Bepridil|
00326|002|B||
00326|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00326|004|L|of severe adverse interaction.|
00326|005|B||
00326|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
00326|007|B||
00326|008|E|CLINICAL EFFECTS:  Concurrent usage may increase the risk of cardiotoxicity,|
00326|009|E|including life-threatening arrhythmias such as QT prolongation or torsades|
00326|010|E|de pointes.|
00326|011|B||
00326|012|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00326|013|P|may be increased in patients with cardiovascular disease (e.g. heart|
00326|014|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00326|015|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00326|016|P|female gender, or advanced age.(1,3)|
00326|017|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00326|018|P|higher systemic concentrations of either QT prolonging drug are additional|
00326|019|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00326|020|P|drug concentrations include rapid infusion of an intravenous dose or|
00326|021|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00326|022|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00326|023|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00326|024|B||
00326|025|M|PATIENT MANAGEMENT:  Evaluate all patients for predisposing risk factors.|
00326|026|M|The manufacturer of terfenadine states that concurrent administration with|
00326|027|M|bepridil is not recommended.(1)|
00326|028|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00326|029|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00326|030|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00326|031|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00326|032|B||
00326|033|D|DISCUSSION:  Elevated plasma levels of terfenadine can cause QT prolongation|
00326|034|D|and torsades de pointes-type ventricular tachycardia which may be fatal.(1)|
00326|035|D|Bepridil has also been shown to increase the QTc interval.(2) Therefore, the|
00326|036|D|manufacturer of terfenadine states that concurrent administration is not|
00326|037|D|recommended.(1)|
00326|038|D|   One or more of the drug pairs linked to this monograph have been included|
00326|039|D|in a list of interactions that should be considered "high-priority" for|
00326|040|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00326|041|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00326|042|D|Coordinator (ONC) for Health Information Technology.|
00326|043|B||
00326|044|R|REFERENCES:|
00326|045|B||
00326|046|R|1.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00326|047|R|  September, 1997.|1
00326|048|R|2.Vascor (bepridil hydrochloride) US prescribing information. Ortho-McNeil|1
00326|049|R|  Pharmaceutical, Inc. March, 2000.|1
00326|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00326|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00326|052|R|  settings: a scientific statement from the American Heart Association and|6
00326|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00326|054|R|  2;55(9):934-47.|6
00326|055|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00326|056|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00326|057|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00326|058|R|  19(5):735-43.|6
00327|001|T|MONOGRAPH TITLE:  Selected Retinoids/Progestin-Only Oral Contraceptives|
00327|002|B||
00327|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00327|004|L|of severe adverse interaction.|
00327|005|B||
00327|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
00327|007|B||
00327|008|E|CLINICAL EFFECTS:  Concurrent use may result in increased progesterone|
00327|009|E|levels and interference with the effect of the contraceptive.  Major fetal|
00327|010|E|abnormalities have been reported with the administration of acitretin(1) and|
00327|011|E|isotretinoin.(2)|
00327|012|B||
00327|013|P|PREDISPOSING FACTORS:  None determined.|
00327|014|B||
00327|015|M|PATIENT MANAGEMENT:  Use of "mini-pill" progestin preparations are not|
00327|016|M|recommended.   Patients on acitretin(1) or isotretinoin(2) therapy should be|
00327|017|M|using two reliable methods of contraception and should be advised that|
00327|018|M|progestin-only mini-pills may fail.|
00327|019|M|   Consider switching to a combination estrogen-progestin contraceptive|
00327|020|M|agent; intrauterine device (IUD); or  injected, implanted, or inserted|
00327|021|M|hormonal birth control products.  Two methods of contraception are still|
00327|022|M|required.|
00327|023|B||
00327|024|D|DISCUSSION:  According to the manufacturer of acitretin, this interaction|
00327|025|D|has been documented in one patient who received concurrent therapy with|
00327|026|D|acitretin and a progestin-only mini-pill.(1)  Given the severe consequences|
00327|027|D|of contraceptive failure during acitretin or isotretinoin therapy, caution|
00327|028|D|is warranted.  All females of reproductive age should use two reliable forms|
00327|029|D|of contraception unless they have undergone a hysterectomy or practice|
00327|030|D|abstinence.(1,2)|
00327|031|D|   In a study in 26 healthy women, concurrent use of isotretinoin and Ortho|
00327|032|D|Novum 7/7/7 (ethinyl estradiol and norethindrone) resulted in small,|
00327|033|D|inconsistent, although statistically significant, decreases in ethinyl|
00327|034|D|estradiol (9%) and norethindrone (11%).  However, there was large|
00327|035|D|variability of pharmacokinetic and pharmacodynamic markers and the authors|
00327|036|D|stressed that their results reinforced the need for additional contraceptive|
00327|037|D|measures during therapy.(3)|
00327|038|B||
00327|039|R|REFERENCES:|
00327|040|B||
00327|041|R|1.Soriatane (acitretin) US prescribing information. Roche Pharmaceuticals|1
00327|042|R|  February, 2014.|1
00327|043|R|2.Accutane (isotretinoin) US prescribing information. Roche Laboratories,|1
00327|044|R|  Inc. January, 2010.|1
00327|045|R|3.Hendrix CW, Jackson KA, Whitmore E, Guidos A, Kretzer R, Liss CM, Shah LP,|2
00327|046|R|  Khoo KC, McLane J, Trapnell CB. The effect of isotretinoin on the|2
00327|047|R|  pharmacokinetics and pharmacodynamics of ethinyl estradiol and|2
00327|048|R|  norethindrone. Clin Pharmacol Ther 2004 May;75(5):464-75.|2
00328|001|T|MONOGRAPH TITLE:  Acitretin/Methotrexate|
00328|002|B||
00328|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00328|004|L|is contraindicated and generally should not be dispensed or administered to|
00328|005|L|the same patient.|
00328|006|B||
00328|007|A|MECHANISM OF ACTION:  Additive hepatic toxicity.(1-3)|
00328|008|B||
00328|009|E|CLINICAL EFFECTS:  Methotrexate has a risk of causing hepatic fibrosis and|
00328|010|E|cirrhosis.(1)  Concurrent use with another hepatotoxic agent like acitretin|
00328|011|E|increases the risk of hepatotoxicity.(2,3)|
00328|012|B||
00328|013|P|PREDISPOSING FACTORS:  None determined.|
00328|014|B||
00328|015|M|PATIENT MANAGEMENT:  The manufacturer of acitretin states that the|
00328|016|M|concurrent use of acitretin and methotrexate is contraindicated.(2)|
00328|017|B||
00328|018|D|DISCUSSION:  Because of the risk of increased hepatotoxicity during|
00328|019|D|concurrent administration of methotrexate and etretinate, the manufacturer|
00328|020|D|of acitretin states that concurrent administration of methotrexate and|
00328|021|D|acitretin is contraindicated.(2)|
00328|022|B||
00328|023|R|REFERENCES:|
00328|024|B||
00328|025|R|1.McClure SL, Valentine J, Gordon KB. Comparative tolerability of systemic|6
00328|026|R|  treatments for plaque-type psoriasis. Drug Saf 2002;25(13):913-27.|6
00328|027|R|2.Soriatane (acitretin) US prescribing information. Roche Pharmaceuticals|1
00328|028|R|  February, 2014.|1
00328|029|R|3.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
00328|030|R|  Inc. March, 2018.|1
00329|001|T|MONOGRAPH TITLE:  Ketorolac (Non-Injection)/NSAID; Aspirin (Greater Than 300|
00329|002|T|mg); Salicylates|
00329|003|B||
00329|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00329|005|L|is contraindicated and generally should not be dispensed or administered to|
00329|006|L|the same patient.|
00329|007|B||
00329|008|A|MECHANISM OF ACTION:  Possible additive or synergistic side effects.(1,2)|
00329|009|B||
00329|010|E|CLINICAL EFFECTS:  Concurrent use of multiple doses of ketorolac with other|
00329|011|E|non-steroidal anti-inflammatory agents (NSAIDs), salicylates or aspirin may|
00329|012|E|result in an increase in NSAID-related side effects such as bleeding or|
00329|013|E|renal impairment.(1-3)|
00329|014|B||
00329|015|P|PREDISPOSING FACTORS:  Patients with pre-existing renal impairment may be at|
00329|016|P|an increased risk of adverse effects from this interaction.|
00329|017|P|   The risk for bleeding episodes may be greater in patients with multiple|
00329|018|P|disease-associated factors (e.g. thrombocytopenia, advanced liver disease).|
00329|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
00329|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00329|021|P|risk for bleeding (e.g., anticoagulants, antiplatelets, corticosteroids,|
00329|022|P|selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine|
00329|023|P|reuptake inhibitors (SNRIs).|
00329|024|P|   Risk of GI bleed may be increased in patients who are of older age, in|
00329|025|P|poor health status, or who use alcohol or smoke. Risk may also be increased|
00329|026|P|with longer duration of NSAID use and prior history of peptic ulcer disease|
00329|027|P|and/or GI bleeding.|
00329|028|B||
00329|029|M|PATIENT MANAGEMENT:  Manufacturers of ketorolac state that concurrent use of|
00329|030|M|ketorolac with either other NSAIDs or aspirin is contraindicated.(1,2)|
00329|031|M|   If concurrent therapy is deemed medically necessary, monitor patients|
00329|032|M|receiving concurrent therapy for signs of blood loss, including decreased|
00329|033|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
00329|034|M|and promptly evaluate patients with any symptoms.|
00329|035|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
00329|036|M|to monitor efficacy and safety of anticoagulation. Discontinue|
00329|037|M|anticoagulation in patients with active pathologic bleeding.|
00329|038|M|   Conduct periodic monitoring of renal function, especially in patients|
00329|039|M|with renal impairment.|
00329|040|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00329|041|M|unusual bruising; red or black, tarry stools; acute abdominal or joint pain|
00329|042|M|and/or swelling.|
00329|043|B||
00329|044|D|DISCUSSION:  Based upon similar pharmacodynamic effects and potentially|
00329|045|D|cumulative risks of serious NSAID-related adverse events, manufacturers of|
00329|046|D|ketorolac state the concurrent administration of ketorolac with other NSAIDs|
00329|047|D|or aspirin is contraindicated.(1,2)|
00329|048|B||
00329|049|R|REFERENCES:|
00329|050|B||
00329|051|R|1.Toradol (ketorolac tromethamine) US prescribing information. Roche|1
00329|052|R|  Pharmaceuticals March, 2013.|1
00329|053|R|2.Ketorolac tromethamine oral tablets, US prescribing information. Mylan|1
00329|054|R|  Pharmaceuticals Inc. July, 2015.|1
00329|055|R|3.Durlaza (aspirin extended release) US prescribing information. New Haven|1
00329|056|R|  Pharmaceuticals, Inc. September, 2015.|1
00330|001|T|MONOGRAPH TITLE:  Apraclonidine/MAOIs|
00330|002|B||
00330|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00330|004|L|is contraindicated and generally should not be dispensed or administered to|
00330|005|L|the same patient.|
00330|006|B||
00330|007|A|MECHANISM OF ACTION:  Apraclonidine is an alpha-2-adrenergic agonist used to|
00330|008|A|decrease intraocular pressure. The use of apraclonidine ophthalmic solution|
00330|009|A|leads to systemic absorption.(1) As apraclonidine does not cross the blood|
00330|010|A|brain barrier, peripheral alpha-2-adrenergic effects could potentially|
00330|011|A|result in vasoconstriction.(1)|
00330|012|B||
00330|013|E|CLINICAL EFFECTS:  Not described.(1)|
00330|014|B||
00330|015|P|PREDISPOSING FACTORS:  Unknown.|
00330|016|B||
00330|017|M|PATIENT MANAGEMENT:  The manufacturer of apraclonidine states that|
00330|018|M|concurrent administration of apraclonidine to patients on monoamine oxidase|
00330|019|M|inhibitors (MAOI's) is contraindicated.(1)|
00330|020|B||
00330|021|D|DISCUSSION:  There is no clinical documentation to support this interaction.|
00330|022|D|The manufacturer of apraclonidine states that concurrent administration of|
00330|023|D|apraclonidine to patients on MAOI's is contraindicated.(1)|
00330|024|D|   Methylene blue, when administered intravenously, has been shown to reach|
00330|025|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
00330|026|D|   Metaxalone is a weak inhibitor of MAO.|
00330|027|B||
00330|028|R|REFERENCES:|
00330|029|B||
00330|030|R|1.Iopidine (apraclonidine) US prescribing information. Alcon Laboratories,|1
00330|031|R|  Inc. April 6, 2017.|1
00330|032|R|2.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00330|033|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00330|034|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00330|035|R|3.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00330|036|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00330|037|R|  2000 Jun;56(3):247-50.|2
00330|038|R|4.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00330|039|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00330|040|R|  Feb;34(2):346.e5-6.|3
00330|041|R|5.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00330|042|R|  Pfizer Inc. January, 2024.|1
00331|001|T|MONOGRAPH TITLE:  Bupropion; Solriamfetol/MAO Inhibitors|
00331|002|B||
00331|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00331|004|L|is contraindicated and generally should not be dispensed or administered to|
00331|005|L|the same patient.|
00331|006|B||
00331|007|A|MECHANISM OF ACTION:  Bupropion and solriamfetol increase dopamine and|
00331|008|A|norepinephrine concentrations via blockade of the dopamine and|
00331|009|A|norepinephrine reuptake transporters.(1-4)  Monoamine oxidase inhibitors|
00331|010|A|(MAOIs) block the metabolism of norepinephrine and dopamine, also leading to|
00331|011|A|increased neuronal concentrations of norepinephrine and dopamine.(5)|
00331|012|B||
00331|013|E|CLINICAL EFFECTS:  The concurrent administration of bupropion or|
00331|014|E|solriamfetol and MAOIs may increase the risk for hypertensive crisis, severe|
00331|015|E|hypertension, or other adverse reactions,(3-4) including mania, psychosis or|
00331|016|E|agitation with bupropion,(3) and headache, nausea, anorexia, or anxiety with|
00331|017|E|solriamfetol.(4)|
00331|018|B||
00331|019|P|PREDISPOSING FACTORS:  Patients with pre-existing hypertension may be more|
00331|020|P|likely to experience treatment-emergent hypertension.(3)|
00331|021|P|   Patients with moderate to severe renal impairment may be at higher risk|
00331|022|P|for increases in blood pressure and heart rate from solriamfetol due to|
00331|023|P|prolonged drug exposure.(4)|
00331|024|B||
00331|025|M|PATIENT MANAGEMENT:  The US manufacturers of bupropion and solriamfetol|
00331|026|M|state that concurrent use of bupropion or solriamfetol with a MAOI is|
00331|027|M|contraindicated due to the risk for hypertensive reactions.(3,4)  The US|
00331|028|M|manufacturer of phenelzine states that concurrent use of bupropion is|
00331|029|M|contraindicated.(5)|
00331|030|M|   At least 14 days should elapse between the discontinuation of a MAOI and|
00331|031|M|the initiation of bupropion or solriamfetol,(3-5) except in the case of|
00331|032|M|methylene blue.(6)  Do not initiate bupropion or solriamfetol therapy in|
00331|033|M|patients receiving methylene blue until 24 hours after the last dose of|
00331|034|M|these agents.(3,6)|
00331|035|M|   In emergency situations in patients maintained on bupropion or|
00331|036|M|solriamfetol, weigh the availability and safety of alternatives to methylene|
00331|037|M|blue against the risk of acute hypertension.  If methylene blue therapy is|
00331|038|M|required, the patient's bupropion or solriamfetol should be immediately|
00331|039|M|discontinued.  Patients' blood pressure should be closely monitored for 2|
00331|040|M|weeks or until 24 hours after the last dose of methylene blue, whichever|
00331|041|M|comes first.(3,6)|
00331|042|M|   In non-emergency situations in patients maintained on bupropion or|
00331|043|M|solriamfetol when methylene blue therapy is planned, discontinue the|
00331|044|M|patient's bupropion or solriamfetol at least 2 weeks in advance of methylene|
00331|045|M|blue therapy.  The patient's bupropion or solriamfetol therapy may be|
00331|046|M|resumed 24 hours after the last dose of linezolid or methylene blue.(3,6)|
00331|047|M|   If concurrent therapy is warranted, patients should be monitored for|
00331|048|M|signs and symptoms of hypertensive crisis.|
00331|049|B||
00331|050|D|DISCUSSION:  The US manufacturers of bupropion and solriamfetol state that|
00331|051|D|concurrent use of bupropion or solriamfetol with a MAOI is|
00331|052|D|contraindicated.(3,4)  The US manufacturer of phenelzine states that|
00331|053|D|concurrent use of bupropion is contraindicated.(5)|
00331|054|D|   At least 14 days should elapse between the discontinuation of a MAOI and|
00331|055|D|the initiation of bupropion or solriamfetol.(1-5)|
00331|056|D|   Methylene blue, when administered intravenously, has been shown to reach|
00331|057|D|sufficient concentrations to be a potent inhibitor of MAO-A.(6,7)|
00331|058|D|   Metaxalone is a weak inhibitor of MAO.(8,9)|
00331|059|D|   FDA alerts in July 2011(6) described the risk for serotonin syndrome when|
00331|060|D|bupropion is used concurrently with methylene blue or other MAOIs.  In|
00331|061|D|October 2011 FDA updated these alerts, describing the risk for serotonin|
00331|062|D|syndrome when MAOIs are combined with bupropion (and selected other|
00331|063|D|psychiatric agents not associated with case reports of serotonin syndrome)|
00331|064|D|as unclear.(7)  Subsequent bupropion and solriamfetol prescribing|
00331|065|D|information describes an increased risk for hypertensive reactions when|
00331|066|D|co-prescribed with MAOIs.(3,4)|
00331|067|B||
00331|068|R|REFERENCES:|
00331|069|B||
00331|070|R|1.Zhu AZ, Cox LS, Nollen N, Faseru B, Okuyemi KS, Ahluwalia JS, Benowitz NL,|2
00331|071|R|  Tyndale RF. CYP2B6 and bupropion's smoking-cessation pharmacology: the|2
00331|072|R|  role of hydroxybupropion. Clin Pharmacol Ther 2012 Dec;92(6):771-7.|2
00331|073|R|2.Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ,|5
00331|074|R|  Martin BR. Enantioselective effects of hydroxy metabolites of bupropion on|5
00331|075|R|  behavior and on function of monoamine transporters and nicotinic|5
00331|076|R|  receptors. Mol Pharmacol 2004 Sep;66(3):675-82.|5
00331|077|R|3.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
00331|078|R|  GlaxoSmithKline November, 2019.|1
00331|079|R|4.Sunosi (solriamfetol) US Prescribing Information. Jazz Pharmaceuticals,|1
00331|080|R|  Inc. October, 2021.|1
00331|081|R|5.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
00331|082|R|  2007.|1
00331|083|R|6.USFood and Drug Administration. FDA Drug Safety Communication: Serious CNS|1
00331|084|R|  reactions possible when methylene blue is given to patients taking certain|1
00331|085|R|  psychiatric medications. available at:|1
00331|086|R|  http://wayback.archive-it.org/7993/20170722185916/https://www.fda.gov/Drug|1
00331|087|R|  s/DrugSafety/ucm263190.htm July 26, 2011.|1
00331|088|R|7.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
00331|089|R|  information about the drug interaction between methylene blue|1
00331|090|R|  (methylthioninium chloride) and serotonergic psychiatric medications.|1
00331|091|R|  available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
00331|092|R|  21, 2011.|1
00331|093|R|8.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00331|094|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00331|095|R|  Feb;34(2):346.e5-6.|3
00331|096|R|9.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00331|097|R|  Pfizer Inc. January, 2024.|1
00332|001|T|MONOGRAPH TITLE:  Cabergoline/Selected Dopamine Blockers|
00332|002|B||
00332|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00332|004|L|of severe adverse interaction.|
00332|005|B||
00332|006|A|MECHANISM OF ACTION:  Dopamine (D2) blockers such as the phenothiazines,|
00332|007|A|butyrophenones, thioxanthenes and atypical antipsychotics may decrease the|
00332|008|A|effects of cabergoline, a dopamine agonist.(1)|
00332|009|B||
00332|010|E|CLINICAL EFFECTS:  Concurrent administration of cabergoline with dopamine|
00332|011|E|blockers (e.g. phenothiazines, butyrophenones, or thio xanthines) may|
00332|012|E|decrease the effectiveness of cabergoline.(1)  Cabergoline may decrease the|
00332|013|E|effectiveness of antipsychotic treatment.|
00332|014|B||
00332|015|P|PREDISPOSING FACTORS:  None determined.|
00332|016|B||
00332|017|M|PATIENT MANAGEMENT:  The manufacturer of cabergoline states cabergoline(1)|
00332|018|M|should not be administered concurrently with dopamine antagonists. Avoid|
00332|019|M|concurrent use when possible.|
00332|020|M|   If cabergoline is started in a patient receiving long term antipsychotic|
00332|021|M|treatment, monitor closely for loss of antipsychotic efficacy.|
00332|022|M|   If an antipsychotic is required for a patient on long term cabergoline|
00332|023|M|therapy, consider use of a shorter half-life, less potent dopamine (D2)|
00332|024|M|blocking atypical antipsychotic (e.g. clozapine, quetiapine) and monitor|
00332|025|M|closely.|
00332|026|B||
00332|027|D|DISCUSSION:  The manufacturer of cabergoline state that it should not be|
00332|028|D|administered concurrently with dopamine antagonists.|
00332|029|B||
00332|030|R|REFERENCE:|
00332|031|B||
00332|032|R|1.Dostinex (cabergoline) US prescribing information. Pfizer April, 2025.|1
00333|001|T|MONOGRAPH TITLE:  Cabergoline/Metoclopramide  (mono deleted 12/08/2005)|
00333|002|B||
00333|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00333|004|L|is contraindicated and generally should not be dispensed or administered to|
00333|005|L|the same patient.|
00333|006|B||
00333|007|A|MECHANISM OF ACTION:  Dopamine antagonists such as metoclopramide may block|
00333|008|A|the effects of cabergoline, a dopamine agonist.(1)|
00333|009|B||
00333|010|E|CLINICAL EFFECTS:  Concurrent administration of cabergoline with|
00333|011|E|metoclopramide may decrease the effectiveness of cabergoline.(1)|
00333|012|B||
00333|013|P|PREDISPOSING FACTORS:  None determined.|
00333|014|B||
00333|015|M|PATIENT MANAGEMENT:  The manufacturer of cabergoline states that cabergoline|
00333|016|M|should not be administered concurrently with dopamine antagonists such as|
00333|017|M|metoclopramide.(1)|
00333|018|B||
00333|019|D|DISCUSSION:  There is no clinical documentation to support this interaction.|
00333|020|D|The manufacturer of cabergoline states that cabergoline should not be|
00333|021|D|administered concurrently with dopamine antagonists such as|
00333|022|D|metoclopramide.(1)|
00333|023|B||
00333|024|R|REFERENCE:|
00333|025|B||
00333|026|R|1.Dostinex (cabergoline) US prescribing information. Pharmacia & Upjohn|1
00333|027|R|  Company December, 1996.|1
00334|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Nevirapine|
00334|002|B||
00334|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00334|004|L|of severe adverse interaction.|
00334|005|B||
00334|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
00334|007|B||
00334|008|E|CLINICAL EFFECTS:  Concurrent administration of nevirapine with the protease|
00334|009|E|inhibitors amprenavir, fosamprenavir, indinavir, nelfinavir, or saquinavir|
00334|010|E|may decrease plasma concentrations of the protease inhibitor.(1-8)|
00334|011|E|   Decreased plasma concentrations of the protease inhibitor may result in|
00334|012|E|decreased effectiveness and the development of resistance.|
00334|013|B||
00334|014|P|PREDISPOSING FACTORS:  None determined.|
00334|015|B||
00334|016|M|PATIENT MANAGEMENT:  The exact clinical significance is unknown.  Patients|
00334|017|M|receiving concurrent therapy should be closely monitored.|
00334|018|M|   The US manufacturers of fosamprenavir(4) and nevirapine(2) state that|
00334|019|M|concurrent use of nevirapine with fosamprenavir without ritonavir is not|
00334|020|M|recommended.  No dosage adjustment is required when nevirapine is given with|
00334|021|M|fosamprenavir in combination with ritonavir twice daily.(2,4)  The|
00334|022|M|combination of nevirapine with fosamprenavir/ritonavir once daily has not|
00334|023|M|been studied.(4)|
00334|024|M|   One set of investigators recommends that a dose of 1000 mg of indinavir|
00334|025|M|every eight hours be considered in patients receiving concurrent therapy|
00334|026|M|with nevirapine.(1)  The manufacturers of indinavir(8) and nevirapine(2)|
00334|027|M|state that the appropriate doses for this combination have not been|
00334|028|M|established.|
00334|029|M|   Appropriate doses of the combinations of nevirapine with nelfinavir(2,5)|
00334|030|M|or with saquinavir/ritonavir(6) have not been determined.|
00334|031|B||
00334|032|D|DISCUSSION:  In a study in 17 subjects, concurrent nevirapine (200 mg twice|
00334|033|D|daily) and fosamprenavir (1400 mg twice daily) decreased the maximum|
00334|034|D|concentration (Cmax), area-under-curve (AUC), and minimum concentration|
00334|035|D|(Cmin) of amprenavir by 25%, 33%, and 35%, respectively.(2,4)  Nevirapine|
00334|036|D|Cmax, AUC, and Cmin increased by 25%, 29%, and 34%, respectively.(4)  In a|
00334|037|D|study in 17 subjects, concurrent nevirapine (200 mg twice daily) with|
00334|038|D|fosamprenavir (700 mg twice daily) and ritonavir (100 mg twice daily)|
00334|039|D|decreased the AUC and Cmin of amprenavir by 11% and 19%, respectively.(2,4)|
00334|040|D|Nevirapine Cmax, AUC, and Cmin increased by 13%, 14%, and 22%,|
00334|041|D|respectively.(4)|
00334|042|D|   In a study in 19 HIV-infected patients, the concurrent administration of|
00334|043|D|nevirapine with indinavir (800 mg every 8 hours) decreased indinavir AUC,|
00334|044|D|Cmax, and Cmin, by 31%, 15%, and 44%, respectively.(2)  There was a|
00334|045|D|non-significant effect on nevirapine levels.(1)|
00334|046|D|   In a study in 23 HIV-infected patients, the concurrent administration of|
00334|047|D|nevirapine (200 mg daily for 14 days, then 200 mg twice daily) with|
00334|048|D|nelfinavir (750 mg 3 times daily) decreased the Cmin of nelfinavir by 32%.|
00334|049|D|The AUC, Cmax, and Cmin of the M8-metabolite of nelfinavir decreased by 62%,|
00334|050|D|59%, and 66%, respectively.(2)|
00334|051|D|   In a study in 14 HIV-infected patients, the concurrent administration of|
00334|052|D|nevirapine and ritonavir (600 mg twice daily) did not affect the AUC or Cmax|
00334|053|D|of ritonavir.(2)  There was no effect on nevirapine pharmacokinetics.(1)|
00334|054|D|   In a study in 23 HIV-infected patients, the concurrent administration of|
00334|055|D|nevirapine with saquinavir (600 mg three times daily) decreased saquinavir|
00334|056|D|AUC and Cmax by 38% and 32%, respectively.(2)  There was no effect on the|
00334|057|D|pharmacokinetics of nevirapine.(1)|
00334|058|B||
00334|059|R|REFERENCES:|
00334|060|B||
00334|061|R|1.Marino RT. Personal communication. Boehringer Ingelheim Pharmaceuticals,|1
00334|062|R|  Inc. February 7, 2001.|1
00334|063|R|2.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
00334|064|R|  Pharmaceuticals, Inc. June, 2022.|1
00334|065|R|3.Agenerase (amprenavir) Oral Solution US prescribing information.|1
00334|066|R|  GlaxoSmithKline May, 2005.|1
00334|067|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
00334|068|R|  March, 2019.|1
00334|069|R|5.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00334|070|R|  Pharmaceuticals, Inc. September, 2016.|1
00334|071|R|6.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00334|072|R|  Laboratories, Inc. March, 2019.|1
00334|073|R|7.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
00334|074|R|  Inc. December, 2004.|1
00334|075|R|8.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00334|076|R|  September, 2016.|1
00335|001|T|MONOGRAPH TITLE:  Hormonal Contraceptive Agents/Efavirenz; Nevirapine|
00335|002|B||
00335|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00335|004|L|of severe adverse interaction.|
00335|005|B||
00335|006|A|MECHANISM OF ACTION:  Efavirenz(1) and nevirapine(2,3) may induce the|
00335|007|A|metabolism of hormonal contraceptives via CYP3A4.|
00335|008|B||
00335|009|E|CLINICAL EFFECTS:  Concurrent administration of efavirenz(1) or|
00335|010|E|nevirapine(2,3) with a hormonal contraceptive agent may result in decreased|
00335|011|E|plasma concentrations and clinical effectiveness of the contraceptive agent.|
00335|012|B||
00335|013|P|PREDISPOSING FACTORS:  None determined.|
00335|014|B||
00335|015|M|PATIENT MANAGEMENT:  The US manufacturers of efavirenz(1) and nevirapine(2)|
00335|016|M|state that hormonal contraceptives should not be used as the sole method of|
00335|017|M|contraception in women taking these agents.|
00335|018|M|   A reliable method of barrier contraception must be used in addition to|
00335|019|M|hormonal contraception in women taking efavirenz.(1)  Alternative or|
00335|020|M|additional methods of contraception should be considered in women taking|
00335|021|M|nevirapine.(2)|
00335|022|M|   Because of the long half-life of efavirenz, women should continue to use|
00335|023|M|a barrier method of contraception in addition to hormonal contraception for|
00335|024|M|12 weeks after discontinuing efavirenz.(1)|
00335|025|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
00335|026|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
00335|027|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
00335|028|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
00335|029|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3|
00335|030|M|mg.(4)  Advise the patient to have a pregnancy test to exclude pregnancy|
00335|031|M|after use and to seek medical advice if they do become pregnant.|
00335|032|B||
00335|033|D|DISCUSSION:  In a study in 21 subjects, concurrent efavirenz (600 mg daily|
00335|034|D|for 14 days) and ethinyl estradiol/norgestimate (0.035/0.25 mg for 14 days)|
00335|035|D|had no effect on ethinyl estradiol levels.  The maximum concentration|
00335|036|D|(Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of|
00335|037|D|norelgestromin decreased by 46%, 64%, and 82%, respectively.  The Cmax, AUC,|
00335|038|D|and Cmin of levonorgestrel decreased by 80%, 83%, and 86%, respectively.(1)|
00335|039|D|   There have been reports of contraceptive failure in patients with|
00335|040|D|etonogestrel implants who were receiving efavirenz.(1)|
00335|041|D|   In a study in 10 subjects taking Ortho-Novum 1/35, nevirapine decreased|
00335|042|D|the AUC of ethinyl estradiol by 20% and the AUC and Cmax of norethindrone by|
00335|043|D|19% and 16%, respectively.(2)|
00335|044|D|   In a study in 16 HIV-positive females, concurrent nevirapine (200 mg|
00335|045|D|daily, Days 2-15; 200 mg twice daily, Days 16-29) and ethinyl estradiol with|
00335|046|D|norethindrone decreased the AUCs of ethinyl estradiol and norethindrone by|
00335|047|D|29% and 18%, respectively.(3)|
00335|048|D|   A study of 118 HIV-positive females compared levonorgestrel|
00335|049|D|pharmacokinetics and safety between the following groups: 1. levonorgestrel|
00335|050|D|1.5 mg with dolutegravir-based antiretrovirals (ART)(control group), 2.|
00335|051|D|levonorgestrel 1.5 mg with efavirenz-based ART, 3. levonorgestrel 3 mg with|
00335|052|D|efavirenz-based ART, and 4. levonorgestrel 3 mg with rifampin.  While both|
00335|053|D|levonorgestrel 3 mg groups had Cmax and AUC(0-8h) similar to the control|
00335|054|D|group, the half life of levonorgestrel was shorter, resulting in an AUC(inf)|
00335|055|D|that was 53% lower in the efavirenz group and 37% lower in the rifampin|
00335|056|D|group than the control group.  Tolerability was similar between groups.  No|
00335|057|D|pregnancies were reported but it is unknown whether the correction of|
00335|058|D|levonorgestrel levels early in the dosing period is sufficient to maintain|
00335|059|D|overall emergency contraceptive effectiveness.(5)|
00335|060|B||
00335|061|R|REFERENCES:|
00335|062|B||
00335|063|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
00335|064|R|  Company November, 2023.|1
00335|065|R|2.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
00335|066|R|  Pharmaceuticals, Inc. June, 2022.|1
00335|067|R|3.Mildvan D, Yarrish R, Marshak A, Hutman HW, McDonough M, Lamson M,|2
00335|068|R|  Robinson P. Pharmacokinetic interaction between nevirapine and ethinyl|2
00335|069|R|  estradiol/norethindrone when administered concurrently to HIV-infected|2
00335|070|R|  women. J Acquir Immune Defic Syndr 2002 Apr 15;29(5):471-7.|2
00335|071|R|4.Medicines and Healthcare products Regulatory Agency.|1
00335|072|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
00335|073|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
00335|074|R|  available at:|1
00335|075|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
00335|076|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
00335|077|R|  -and-contraceptive-efficacy September 15, 2016..|1
00335|078|R|5.Scarsi KK, Smeaton LM, Podany AT, Olefsky M, Woolley E, Barr E, Pham M,|2
00335|079|R|  Mawlana S, Supparatpinyo K, Gatechompol S, Jalil EM, Gadama L,|2
00335|080|R|  Badal-Faesen S, Belaunzaran-Zamudio PF, Godfrey C, etal. Pharmacokinetics|2
00335|081|R|  of dose-adjusted levonorgestrel emergency contraception combined  with|2
00335|082|R|  efavirenz-based antiretroviral therapy or rifampicin-containing|2
00335|083|R|  tuberculosis  regimens. Contraception 2023 Jan 12;109951.|2
00336|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Selected Macrolide Antibiotics|
00336|002|B||
00336|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00336|004|L|is contraindicated and generally should not be dispensed or administered to|
00336|005|L|the same patient.|
00336|006|B||
00336|007|A|MECHANISM OF ACTION:  The macrolides may inhibit the hepatic metabolism of|
00336|008|A|ergot alkaloids by inhibition of CYP3A4.(1)|
00336|009|B||
00336|010|E|CLINICAL EFFECTS:  Concurrent use may result in increased levels of ergot|
00336|011|E|alkaloids, which may result in clinical signs of ergotism, including|
00336|012|E|vasospasm, dysesthesia, renal ischemia, and peripheral ischemia.|
00336|013|B||
00336|014|P|PREDISPOSING FACTORS:  None determined.|
00336|015|B||
00336|016|M|PATIENT MANAGEMENT:  The manufacturer of ergotamine(2) and dihydroergotamine|
00336|017|M|(3) state that the concurrent use of these agents with clarithromycin,|
00336|018|M|erythromycin, or troleandomycin is contraindicated.|
00336|019|M|   The US manufacturer of methylergonovine states that methylergonovine|
00336|020|M|should not be administered with potent CYP3A4 inhibitors such as the|
00336|021|M|macrolide antibiotics clarithromycin, erythromycin, and troleandomycin.(4)|
00336|022|M|   The US manufacturer of clarithromycin states that concurrent|
00336|023|M|administration of ergotamine or dihydroergotamine is contraindicated.(5)|
00336|024|M|   It would be prudent to avoid the concurrent use of all ergot alkaloids|
00336|025|M|and macrolide antibiotics that inhibit CYP3A4.|
00336|026|M|   Patients receiving concurrent therapy with macrolides and ergot alkaloids|
00336|027|M|should be monitored for clinical signs of ergotism.  One or both agents may|
00336|028|M|need to be discontinued.  Patients should be treated symptomatically for|
00336|029|M|ergotism.|
00336|030|B||
00336|031|D|DISCUSSION:  Three case reports have documented clinical signs of ergotism|
00336|032|D|following concomitant therapy with erythromycin and ergotamine.  Symptoms|
00336|033|D|included vasospasm, dysesthesia, renal ischemia, and peripheral ischemia.|
00336|034|D|Symptoms occurred within one to seven days of concurrent therapy and with|
00336|035|D|small doses of ergotamine.(6-8)  Five case reports have documented|
00336|036|D|peripheral vasospasm following the concurrent administration of ergotamine|
00336|037|D|and troleandomycin.  Ergotamine dosages ranged from single dose to long term|
00336|038|D|therapy.(9-12)  A similar interaction was reported for ergotamine and|
00336|039|D|troleandomycin(13) and ergotamine and clarithromycin.(14)|
00336|040|D|   Other case reports document similar interactions between|
00336|041|D|dihydroergotamine and erythromycin(15-19), troleandomycin(16-19), and|
00336|042|D|ponsinomycin(20).|
00336|043|D|   One or more of the drug pairs linked to this monograph have been included|
00336|044|D|in a list of interactions that should be considered "high-priority" for|
00336|045|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00336|046|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00336|047|D|Coordinator (ONC) for Health Information Technology.|
00336|048|B||
00336|049|R|REFERENCES:|
00336|050|B||
00336|051|R|1.Lu WJ, Huang K, Lai ML, Huang JD. Erythromycin alters the pharmacokinetics|6
00336|052|R|  of bromocriptine by inhibition of organic anion transporting polypeptide|6
00336|053|R|  C-mediated uptake. Clin Pharmacol Ther 2006 Oct;80(4):421-2.|6
00336|054|R|2.D. H. E. 45 (dihydroergotamine mesylate) US prescribing information.|1
00336|055|R|  Valeant Pharmaceuticals North America November 6, 2017.|1
00336|056|R|3.Cafergot (ergotamine tartrate and caffeine) tablets US prescribing|1
00336|057|R|  information. Sandoz Inc May 14, 2012.|1
00336|058|R|4.Methergine (methylergonovine maleate) US prescribing information. Novartis|1
00336|059|R|  Pharmaceuticals Corporation June, 2012.|1
00336|060|R|5.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
00336|061|R|  September, 2019.|1
00336|062|R|6.Francis H, Tyndall A, Webb J. Severe vascular spasm due to|3
00336|063|R|  erythromycin-ergotamine interaction. Clin Rheumatol 1984 Jun;3(2):243-6.|3
00336|064|R|7.Collet AM, Moncharmont D, San Marco JL, Eissinger F, Pinot JJ, Laselve L.|3
00336|065|R|  Iatrogenic ergotism. Responsibility of an ergotamine tartrate-|3
00336|066|R|  erythromycine propionate association (author's transl). Sem Hop 1982 Jul|3
00336|067|R|  1;58(26-27):1624-6.|3
00336|068|R|8.Ghali R, De Lean J, Douville Y, Noel HP, Labbe R. Erythromycin-associated|3
00336|069|R|  ergotamine intoxication: arteriographic and electrophysiologic analysis of|3
00336|070|R|  a rare cause of severe ischemia of the lower extremities and associated|3
00336|071|R|  ischemic neuropathy. Ann Vasc Surg 1993 May;7(3):291-6.|3
00336|072|R|9.Chignier E, Riou R, Descotes J, Meunier P, Courpron P, Vignon G. Acute|3
00336|073|R|  iatrogenic ergotism by drug association. Diagnosis through non- invasive|3
00336|074|R|  exploration (Doppler velocimetry (author's transl). Nouv Presse Med 1978|3
00336|075|R|  Aug 26-Sep 2;7(28):2478.|3
00336|076|R|10.Matthews NT, Havill JH. Ergotism with therapeutic doses of ergotamine|3
00336|077|R|   tartrate. N Z Med J 1979 Jun 27;89(638):476-7.|3
00336|078|R|11.Hayton AC. Precipitation of acute ergotism by triacetyloleandomycin. N Z|3
00336|079|R|   Med J 1969 Jan;69(440):42.|3
00336|080|R|12.Bigorie B, Aimez P, Soria RJ, Samama F, di Maria G, Guy-Grand B, Bour H.|3
00336|081|R|   Is triacetyl oleandomycin-ergotamine tartrate combination dangerous?.|3
00336|082|R|   Nouv Presse Med 1975 Nov 8;4(38):2723-5.|3
00336|083|R|13.Monsarrat M, Lefebvre D, Parraguette J, Vaysse C, Bastide G. Acute|3
00336|084|R|   ergotism caused by an ergotamine-oleandomycin combination. Nouv Presse|3
00336|085|R|   Med 1982 Feb 20;11(8):603.|3
00336|086|R|14.Horowitz RS, Dart RC, Gomez HF. Clinical ergotism with lingual ischemia|3
00336|087|R|   induced by clarithromycin- ergotamine interaction. Arch Intern Med 1996|3
00336|088|R|   Feb 26;156(4):456-8.|3
00336|089|R|15.Leroy F, Asseman P, Pruvost P, Adnet P, Lacroix D, Thery C.|3
00336|090|R|   Dihydroergotamine-erythromycin-induced ergotism. Ann Intern Med 1988 Aug|3
00336|091|R|   1;109(3):249.|3
00336|092|R|16.Franco A, Bourlard P, Massot C, Lecoeur J, Guidicelli H, Bessard G. Acute|3
00336|093|R|   ergotism caused by dihydroergotamine-triacetyloleandomycin association.|3
00336|094|R|   Nouv Presse Med 1978 Jan 21;7(3):205.|3
00336|095|R|17.Vayssairat M, Fiessinger JN, Bequemin MH, Housset E. Dihydroergotamine|3
00336|096|R|   and triacetyloleandomycin combination. Its role in iatrogenic necrosis of|3
00336|097|R|   the fingers. Nouv Presse Med 1978 Jun 10;7(23):2077.|3
00336|098|R|18.Boucharlat J, Franco A, Carpentier P, Charignon Y, Denis B, Hommel M.|3
00336|099|R|   Ergotism in a psychiatric setting caused by combined dihydroergotamine-|3
00336|100|R|   erythromycin propionate. Apropos of a case. Ann Med Psychol (Paris) 1980|3
00336|101|R|   Mar;138(3):292-6.|3
00336|102|R|19.Neveux E, Lesgourgues B, Luton JP, Guilhaume B, Bertagna, Picard J. Acute|3
00336|103|R|   ergotism caused by the interaction of erythromycin propionate and|3
00336|104|R|   dihydroergotamine. Nouv Presse Med 1981 Sep 26;10(34):2830.|3
00336|105|R|20.Couet W, Mathieu HP, Fourtillan JB. Effect of ponsinomycin on the|2
00336|106|R|   pharmacokinetics of dihydroergotamine administered orally. Fundam Clin|2
00336|107|R|   Pharmacol 1991;5(1):47-52.|2
00336|108|R|21.Delaforge M, Riviere R, Sartori E, Doignon JL, Grognet JM. Metabolism of|5
00336|109|R|   dihydroergotamine by a cytochrome P-450 similar to that involved in the|5
00336|110|R|   metabolism of macrolide antibiotics. Xenobiotica 1989 Nov;19(11):1285-95.|5
00336|111|R|22.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00336|112|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00336|113|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00336|114|R|   19(5):735-43.|6
00337|001|T|MONOGRAPH TITLE:  Aspirin With Papaveretum/MAOIs|
00337|002|B||
00337|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00337|004|L|of severe adverse interaction.|
00337|005|B||
00337|006|A|MECHANISM OF ACTION:  Unknown.|
00337|007|B||
00337|008|E|CLINICAL EFFECTS:  May result in either CNS depression or excitation.|
00337|009|B||
00337|010|P|PREDISPOSING FACTORS:  None determined.|
00337|011|B||
00337|012|M|PATIENT MANAGEMENT:  Avoid concurrent therapy with these agents if possible.|
00337|013|M|If concurrent therapy is necessary, monitor patients for signs of CNS|
00337|014|M|depression or excitation.|
00337|015|B||
00337|016|D|DISCUSSION:  The data sheet for papaverine states that the drug is|
00337|017|D|contraindicated in patients receiving therapy with a MAOI agent.|
00337|018|D|   Methylene blue, when administered intravenously, has been shown to reach|
00337|019|D|sufficient concentrations to be a potent inhibitor MAO-A.|
00337|020|D|   Metaxalone is a weak inhibitor of MAO.|
00337|021|B||
00337|022|R|REFERENCES:|
00337|023|B||
00337|024|R|1.Papaverine UK summary of product characteristics. British National|1
00337|025|R|  Formulary, Number 29 March 1995.|1
00337|026|R|2.Aspav (papaveretum) UK summary of product characteristics. ABPI Data Sheet|1
00337|027|R|  (Roussel Laboratories Ltd) 1996.|1
00337|028|R|3.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00337|029|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00337|030|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00337|031|R|4.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00337|032|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00337|033|R|  2000 Jun;56(3):247-50.|2
00337|034|R|5.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00337|035|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00337|036|R|  Feb;34(2):346.e5-6.|3
00337|037|R|6.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00337|038|R|  Pfizer Inc. January, 2024.|1
00338|001|T|MONOGRAPH TITLE:  Grepafloxacin; Sparfloxacin/Bepridil|
00338|002|B||
00338|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00338|004|L|is contraindicated and generally should not be dispensed or administered to|
00338|005|L|the same patient.|
00338|006|B||
00338|007|A|MECHANISM OF ACTION:  Unknown.  Possibly additive or synergistic effects on|
00338|008|A|the QTc interval.|
00338|009|B||
00338|010|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in|
00338|011|E|life-threatening arrhythmias such as torsades de pointes.|
00338|012|B||
00338|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00338|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00338|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00338|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00338|017|P|female gender, or advanced age.(3)|
00338|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00338|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00338|020|P|risk factors for torsades de pointes.  Factors which may increases systemic|
00338|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00338|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00338|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00338|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00338|025|B||
00338|026|M|PATIENT MANAGEMENT:  Concurrent administration of sparfloxacin with bepridil|
00338|027|M|is contraindicated by the manufacturer of sparfloxacin.(1)  Concurrent|
00338|028|M|administration of these agents with grepafloxacin is also contraindicated by|
00338|029|M|the manufacturer of grepafloxacin unless appropriate cardiac monitoring can|
00338|030|M|be assured.(2)|
00338|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00338|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00338|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00338|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00338|035|B||
00338|036|D|DISCUSSION:  There is no published documentation to support this potential|
00338|037|D|drug interaction.  The product information for grepafloxacin states that|
00338|038|D|because prolongation of the QTc interval has been observed in healthy|
00338|039|D|subjects receiving grepafloxacin, concurrent administration of grepafloxacin|
00338|040|D|with medications known to prolong the QTc interval is contraindicated unless|
00338|041|D|appropriate cardiac monitoring can be assured.(2) The product information|
00338|042|D|for sparfloxacin states that torsades de pointes has been reported in|
00338|043|D|patients receiving sparfloxacin and disopyramide and amiodarone.(1)|
00338|044|B||
00338|045|R|REFERENCES:|
00338|046|B||
00338|047|R|1.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
00338|048|R|  Inc. February, 2003.|1
00338|049|R|2.Raxar (grepafloxacin) US prescribing information. Glaxo Wellcome, Inc.|1
00338|050|R|  November, 1997.|1
00338|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00338|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00338|053|R|  settings: a scientific statement from the American Heart Association and|6
00338|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00338|055|R|  2;55(9):934-47.|6
00339|001|T|MONOGRAPH TITLE:  Mibefradil/Selected Agents|
00339|002|B||
00339|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00339|004|L|is contraindicated and generally should not be dispensed or administered to|
00339|005|L|the same patient.|
00339|006|B||
00339|007|A|MECHANISM OF ACTION:  Mibefradil has been shown to inhibit the activity of|
00339|008|A|CYP P-450-3A4 and CYP P-450-2D6 and may inhibit the metabolism of these|
00339|009|A|agents.(1-2)|
00339|010|B||
00339|011|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
00339|012|E|of these agents.(1,2)  Withdrawal of mibefradil may result in decreased|
00339|013|E|levels of these agents.|
00339|014|E|   Concurrent administration of the mibefradil with the HMG-CoA reductase|
00339|015|E|inhibitors may result in elevated levels of the HMG-CoA reductase|
00339|016|E|inhibitors, which may result in rhabdomyolysis.(1)|
00339|017|B||
00339|018|P|PREDISPOSING FACTORS:  None determined.|
00339|019|B||
00339|020|M|PATIENT MANAGEMENT:  Patients who received concurrent therapy with|
00339|021|M|mibefradil and these agents should be monitored for decreased levels and|
00339|022|M|effectiveness of these medications during the two weeks following the|
00339|023|M|withdrawal of mibefradil.  Dosage adjustments of the medications may be|
00339|024|M|necessary.|
00339|025|M|   The manufacturer of mibefradil stated that concurrent administration of|
00339|026|M|mibefradil with either lovastatin or simvastatin was contraindicated and|
00339|027|M|that concurrent administration of mibefradil with either atorvastatin or|
00339|028|M|cerivastatin should have generally been avoided.(1)  Fluvastatin or|
00339|029|M|pravastatin, which are not significantly metabolized by CYP P-450-3A4, may|
00339|030|M|have been used as alternatives in patients receiving mibefradil.|
00339|031|B||
00339|032|D|DISCUSSION:  Mibefradil was shown to inhibit CYP P-450-3A4 and CYP P-450-2D6|
00339|033|D|thus may inhibit the metabolism of agents metabolized at these sites.|
00339|034|D|Withdrawal of mibefradil may result in decreased levels of these agents as|
00339|035|D|the CYP P-450 system returns to normal.  Following the discontinuation of|
00339|036|D|mibefradil, seven to 14 days are required for sufficient elimination of|
00339|037|D|mibefradil metabolites to minimize mibefradil effects on the CYP P-450|
00339|038|D|system.  Dosage adjustments may need to be made during this period.(2)|
00339|039|D|   The manufacturer stated that there were seven reports of rhabdomyolysis|
00339|040|D|in patients receiving concurrent therapy with simvastatin and mibefradil.|
00339|041|D|Four patients were also receiving cyclosporine.  Because lovastatin follows|
00339|042|D|the same metabolic pathway as simvastatin, a similar interaction would be|
00339|043|D|expected.  Atorvastatin and cerivastatin are metabolized by CYP P-450-3A4 to|
00339|044|D|active and inactive metabolites.(1)|
00339|045|B||
00339|046|R|REFERENCES:|
00339|047|B||
00339|048|R|1.Dear Doctor Letter. Roche Pharmaceuticals December 1997.|1
00339|049|R|2."Dear Doctor" letter on mibefradil. Roche Pharmaceuticals June 12, 1998.|1
00340|001|T|MONOGRAPH TITLE:  Clozapine/Selected Dual CYP1A2 and CYP3A4 Inducers|
00340|002|B||
00340|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00340|004|L|of severe adverse interaction.|
00340|005|B||
00340|006|A|MECHANISM OF ACTION:  While clozapine is primarily metabolized by CYP1A2,|
00340|007|A|CYP3A4 also plays a role.(1)  Barbiturates, phenytoin, phenobarbital,|
00340|008|A|primidone and rifampin induce both of these metabolic pathways.|
00340|009|B||
00340|010|E|CLINICAL EFFECTS:  Concomitant administration may result in decreased|
00340|011|E|concentration and effectiveness of clozapine.(1-3)|
00340|012|B||
00340|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00340|014|P|of the inducer for longer than 1-2 weeks.|
00340|015|B||
00340|016|M|PATIENT MANAGEMENT:  If concurrent treatment of clozapine with barbiturates,|
00340|017|M|phenytoin, phenobarbital, primidone or rifampin is required, then close|
00340|018|M|monitoring for decreased clozapine efficacy is needed.  The onset of|
00340|019|M|induction is gradual.  Depending upon the inducing agent, it may take as|
00340|020|M|little as one week to more than 4 weeks to see maximal induction effects.|
00340|021|M|   In stable clozapine patients beginning treatment with an enzyme inducer,|
00340|022|M|consider measurement of clozapine levels prior to start of concomitant|
00340|023|M|therapy with an inducer.  The magnitude of this interaction can be large;|
00340|024|M|combined CYP1A2 and CYP3A4 enzyme inducers may decrease clozapine levels =|
00340|025|M|or > 50%. Adjust clozapine dose accordingly.|
00340|026|M|   After stabilization on concomitant therapy, if the enzyme inducer is|
00340|027|M|subsequently discontinued, then the clozapine dosage will need to be|
00340|028|M|gradually decreased to the original dose as the effects of enzyme induction|
00340|029|M|wane over approximately 2-3 weeks.|
00340|030|B||
00340|031|D|DISCUSSION:  A case report describes a clozapine patient with schizophrenia|
00340|032|D|and a history of smoking 20-30 cigarettes(an inducer of CYP1A2 metabolism)|
00340|033|D|per day who was stable on a clozapine dosage of 400 mg per day.  Clozapine|
00340|034|D|concentrations were approximately 250 micrograms/L.  Due to suspected|
00340|035|D|mycobacteria infection he was started on rifampin, isoniazid, and|
00340|036|D|pyrazinamide.  Three and one-half weeks later his clozapine level was|
00340|037|D|rechecked due to signs of decompensation. Clozapine levels had fallen|
00340|038|D|approximately 80%. An increase of the clozapine dose to 600 mg per day led|
00340|039|D|to minimal improvement in clozapine levels (to approximately 80|
00340|040|D|micrograms/L). Simultaneous discontinuation of rifampin and initiation of|
00340|041|D|ciprofloxacin (a CYP1A2 inhibitor) led to a rapid increase in clozapine|
00340|042|D|concentrations.(2)|
00340|043|B||
00340|044|R|REFERENCES:|
00340|045|B||
00340|046|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
00340|047|R|  Pharmaceuticals Corporation April, 2020.|1
00340|048|R|2.Joos AA, Frank UG, Kaschka WP. Pharmacokinetic interaction of clozapine|3
00340|049|R|  and rifampicin in a forensic patient with an atypical mycobacterial|3
00340|050|R|  infection. J Clin Psychopharmacol 1998 Feb;18(1):83-5.|3
00340|051|R|3.Miller DD. Effect of phenytoin on plasma clozapine concentrations in two|3
00340|052|R|  patients. J Clin Psychiatry 1991 Jan;52(1):23-5.|3
00341|001|T|MONOGRAPH TITLE:  Sibutramine/MAOIs|
00341|002|B||
00341|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00341|004|L|is contraindicated and generally should not be dispensed or administered to|
00341|005|L|the same patient.|
00341|006|B||
00341|007|A|MECHANISM OF ACTION:  Sibutramine is known to be a potent inhibitor of|
00341|008|A|serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake in|
00341|009|A|vivo.(1,2) Concomitant use of sibutramine with MAOIs, which has|
00341|010|A|serotonin-potentiating effects, may increase the level of serotonin and|
00341|011|A|cause serotonin syndrome.(1)|
00341|012|B||
00341|013|E|CLINICAL EFFECTS:  Concurrent use of sibutramine and MAOI's may result in|
00341|014|E|serotonin syndrome, a serious and potentially fatal reaction. Symptoms of|
00341|015|E|serotonin syndrome include tremor, agitation, diaphoresis, hyperreflexia,|
00341|016|E|clonus, tachycardia, hyperthermia, muscle rigidity, hallucinations, and|
00341|017|E|coma.(1,3)|
00341|018|B||
00341|019|P|PREDISPOSING FACTORS:  None determined.|
00341|020|B||
00341|021|M|PATIENT MANAGEMENT:  The concurrent use of sibutramine and MAOI's is|
00341|022|M|contraindicated by the manufacturer of sibutramine.  In addition, at least|
00341|023|M|two weeks should elapse between either discontinuing a MAOI and initiating|
00341|024|M|sibutramine or discontinuing sibutramine and initiating a MAOI.(1)|
00341|025|M|   Patients in whom serotonin syndrome is suspected should receive immediate|
00341|026|M|medical attention.|
00341|027|M|   If concurrent therapy is warranted, patients should be monitored for|
00341|028|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00341|029|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00341|030|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00341|031|M|coordination, or severe diarrhea.|
00341|032|B||
00341|033|D|DISCUSSION:  There is no published documentation to support this|
00341|034|D|interaction.  Because sibutramine inhibits serotonin reuptake and serotonin|
00341|035|D|syndrome has been reported during concomitant use of MAOI's and the|
00341|036|D|selective serotonin reuptake inhibitors, the manufacturer of sibutramine|
00341|037|D|states that concurrent use is contraindicated.  In addition, at least two|
00341|038|D|weeks should elapse between either discontinuing a MAOI and initiating|
00341|039|D|sibutramine or discontinuing sibutramine and initiating a MAOI.(1)|
00341|040|D|   Methylene blue, when administered intravenously, has been shown to reach|
00341|041|D|sufficient concentrations to be a potent inhibitor of MAO-A.(4,5)|
00341|042|D|   Metaxalone is a weak inhibitor of MAO.(6,7)|
00341|043|B||
00341|044|R|REFERENCES:|
00341|045|B||
00341|046|R|1.Meridia (sibutramine hydrochloride monohydrate) US prescribing|1
00341|047|R|  information. Abbott Laboratories August, 2010.|1
00341|048|R|2.Ryan DH. Clinical use of sibutramine. Drugs Today (Barc) 2004 Jan;|6
00341|049|R|  40(1):41-54.|6
00341|050|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00341|051|R|  352(11):1112-20.|6
00341|052|R|4.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00341|053|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00341|054|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00341|055|R|5.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00341|056|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00341|057|R|  2000 Jun;56(3):247-50.|2
00341|058|R|6.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00341|059|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00341|060|R|  Feb;34(2):346.e5-6.|3
00341|061|R|7.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00341|062|R|  Pfizer Inc. January, 2024.|1
00342|001|T|MONOGRAPH TITLE:  Sibutramine/Serotoninergic Agents|
00342|002|B||
00342|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00342|004|L|is contraindicated and generally should not be dispensed or administered to|
00342|005|L|the same patient.|
00342|006|B||
00342|007|A|MECHANISM OF ACTION:  Concurrent administration may result in additive|
00342|008|A|effects on serotonin, resulting in serotonin syndrome.|
00342|009|B||
00342|010|E|CLINICAL EFFECTS:  Concurrent use of sibutramine and agents which effect|
00342|011|E|serotonin may result in serotonin syndrome, a serious and potentially fatal|
00342|012|E|reaction.  Symptoms of serotonin syndrome may include tremor, agitation,|
00342|013|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
00342|014|E|rigidity. (1-5)|
00342|015|B||
00342|016|P|PREDISPOSING FACTORS:  None determined.|
00342|017|B||
00342|018|M|PATIENT MANAGEMENT:  Sibutramine has been removed from the market by the|
00342|019|M|European Medicines Agency and by regulatory agencies in a number of|
00342|020|M|countries including Australia, Canada, Hong Kong, India, Thailand, United|
00342|021|M|Kingdom and the United States.|
00342|022|M|   The Canadian manufacturer of sibutramine formerly stated that concurrent|
00342|023|M|use with antidepressants or serotonergic agents is contraindicated.  At|
00342|024|M|least 14 days should elapse between discontinuation of these agents and|
00342|025|M|initiation of sibutramine.  Five weeks is required following the|
00342|026|M|discontinuation of fluoxetine.(1)|
00342|027|M|   The Australian(2) and UK(3) manufacturers of sibutramine stated that|
00342|028|M|sibutramine is contraindicated within 2 weeks of antidepressant use and|
00342|029|M|should not be used with other serotonergic agents.|
00342|030|M|   The US manufacturer of sibutramine stated that in general, sibutramine|
00342|031|M|should not be administered with other serotonergic agents such as the|
00342|032|M|selective serotonin reuptake inhibitors, sumatriptan or dihydroergotamine.|
00342|033|M|However, if concurrent administration is clinically indicated, the patient|
00342|034|M|should be appropriately observed.(4)|
00342|035|M|   If concurrent therapy is warranted, patients should be monitored for|
00342|036|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00342|037|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00342|038|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00342|039|M|coordination, or severe diarrhea.|
00342|040|M|   Patients in whom serotonin syndrome is suspected should receive immediate|
00342|041|M|medical attention.|
00342|042|B||
00342|043|D|DISCUSSION:  Sibutramine has been removed from the market by the European|
00342|044|D|Medicines Agency and by regulatory agencies in a number of countries|
00342|045|D|including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and|
00342|046|D|the United States.|
00342|047|D|   Sibutramine inhibits serotonin reuptake and serotonin syndrome has been|
00342|048|D|reported during concomitant use of selective serotonin reuptake inhibitors|
00342|049|D|and other selective serotonin reuptake inhibitors, sumatriptan, and|
00342|050|D|dihydroergotamine(1-4)|
00342|051|B||
00342|052|R|REFERENCES:|
00342|053|B||
00342|054|R|1.Meridia (sibutramine hydrochloride monohydrate) Canadian prescribing|1
00342|055|R|  information. Abbott Limited December, 2004.|1
00342|056|R|2.Reductil (sibutramine hydrochloride) Australian prescribing information.|1
00342|057|R|  Abbott Australasia Pty. Ltd. March 5, 2004.|1
00342|058|R|3.Reductil (sibutramine hydrochloride monohydrate) UK summary of product|1
00342|059|R|  characteristics. Abbott Laboratories, Limited January 12, 2005.|1
00342|060|R|4.Meridia (sibutramine hydrochloride monohydrate) US prescribing|1
00342|061|R|  information. Abbott Laboratories August, 2010.|1
00342|062|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00342|063|R|  352(11):1112-20.|6
00343|001|T|MONOGRAPH TITLE:  Sibutramine/Select Opioids|
00343|002|B||
00343|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00343|004|L|is contraindicated and generally should not be dispensed or administered to|
00343|005|L|the same patient.|
00343|006|B||
00343|007|A|MECHANISM OF ACTION:  Concurrent administration may result in additive|
00343|008|A|effects on serotonin, resulting in serotonin syndrome.|
00343|009|B||
00343|010|E|CLINICAL EFFECTS:  Concurrent use of sibutramine and certain opioids may|
00343|011|E|result in serotonin syndrome, a serious and potentially fatal reaction.|
00343|012|E|Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
00343|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,3)|
00343|014|B||
00343|015|P|PREDISPOSING FACTORS:  None determined.|
00343|016|B||
00343|017|M|PATIENT MANAGEMENT:  Sibutramine has been removed from the market by the|
00343|018|M|European Medicines Agency and by regulatory agencies in a number of|
00343|019|M|countries including Australia, Canada, Hong Kong, India, Thailand, United|
00343|020|M|Kingdom and the United States.|
00343|021|M|   The UK manufacturer of sibutramine formerly stated that sibutramine|
00343|022|M|should not be administered with other drugs that raise serotonin levels in|
00343|023|M|the brain, including certain opioids such as dextromethorphan, meperidine,|
00343|024|M|pentazocine, and fentanyl.(2)|
00343|025|M|   The US manufacturer of sibutramine stated that in general, sibutramine|
00343|026|M|should not be administered with other serotonergic agents such as|
00343|027|M|dextromethorphan, meperidine, pentazocine, and fentanyl.  However, if|
00343|028|M|concurrent administration is clinically indicated, the patient should be|
00343|029|M|appropriately observed.(1)|
00343|030|M|   If concurrent therapy is warranted, patients should be monitored for|
00343|031|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00343|032|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00343|033|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00343|034|M|coordination, or severe diarrhea.|
00343|035|M|   Patients in whom serotonin syndrome is suspected should receive immediate|
00343|036|M|medical attention.|
00343|037|B||
00343|038|D|DISCUSSION:  Sibutramine has been removed from the market by the European|
00343|039|D|Medicines Agency and by regulatory agencies in a number of countries|
00343|040|D|including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and|
00343|041|D|the United States.|
00343|042|D|   Because sibutramine inhibits serotonin reuptake and serotonin syndrome|
00343|043|D|has been reported during concomitant use of selective serotonin reuptake|
00343|044|D|inhibitors and certain opioids such as dextromethorphan, meperidine,|
00343|045|D|pentazocine, and fentanyl, the UK manufacturer of sibutramine states that|
00343|046|D|sibutramine should not be administered with these agents.(2)|
00343|047|B||
00343|048|R|REFERENCES:|
00343|049|B||
00343|050|R|1.Meridia (sibutramine hydrochloride monohydrate) US prescribing|1
00343|051|R|  information. Abbott Laboratories August, 2010.|1
00343|052|R|2.Reductil (sibutramine hydrochloride monohydrate) UK summary of product|1
00343|053|R|  characteristics. Abbott Laboratories, Limited January 12, 2005.|1
00343|054|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00343|055|R|  352(11):1112-20.|6
00344|001|T|MONOGRAPH TITLE:  Sibutramine/Lithium|
00344|002|B||
00344|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00344|004|L|is contraindicated and generally should not be dispensed or administered to|
00344|005|L|the same patient.|
00344|006|B||
00344|007|A|MECHANISM OF ACTION:  Concurrent administration may result in additive|
00344|008|A|effects on serotonin, resulting in serotonin syndrome.|
00344|009|B||
00344|010|E|CLINICAL EFFECTS:  Concurrent use of sibutramine and lithium may result in|
00344|011|E|serotonin syndrome, a serious and potentially fatal reaction.  Symptoms of|
00344|012|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
00344|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,3)|
00344|014|B||
00344|015|P|PREDISPOSING FACTORS:  None determined.|
00344|016|B||
00344|017|M|PATIENT MANAGEMENT:  Sibutramine has been removed from the market by the|
00344|018|M|European Medicines Agency and by regulatory agencies in a number of|
00344|019|M|countries including Australia, Canada, Hong Kong, India, Thailand, United|
00344|020|M|Kingdom and the United States.|
00344|021|M|   The UK manufacturer of sibutramine formerly stated that sibutramine|
00344|022|M|should not be administered with other drugs that raise serotonin levels in|
00344|023|M|the brain, such as lithium.(1)|
00344|024|M|   The US manufacturer of sibutramine stated that in general, sibutramine|
00344|025|M|should not be administered with other serotonergic agents such as lithium.|
00344|026|M|However, if concurrent administration is clinically indicated, the patient|
00344|027|M|should be appropriately observed.(1)|
00344|028|M|   If concurrent therapy is warranted, patients should be monitored for|
00344|029|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00344|030|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00344|031|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00344|032|M|coordination, or severe diarrhea.|
00344|033|M|   Patients in whom serotonin syndrome is suspected should receive immediate|
00344|034|M|medical attention.|
00344|035|B||
00344|036|D|DISCUSSION:  Sibutramine has been removed from the market by the European|
00344|037|D|Medicines Agency and by regulatory agencies in a number of countries|
00344|038|D|including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and|
00344|039|D|the United States.|
00344|040|D|   There is no published documentation to support this interaction.  Because|
00344|041|D|sibutramine inhibits serotonin reuptake and serotonin syndrome has been|
00344|042|D|reported during concomitant use of selective serotonin reuptake inhibitors|
00344|043|D|and lithium, the UK manufacturer of sibutramine states that sibutramine|
00344|044|D|should not be administered with lithium.(2)|
00344|045|B||
00344|046|R|REFERENCES:|
00344|047|B||
00344|048|R|1.Meridia (sibutramine hydrochloride monohydrate) US prescribing|1
00344|049|R|  information. Abbott Laboratories August, 2010.|1
00344|050|R|2.Reductil (sibutramine hydrochloride monohydrate) UK summary of product|1
00344|051|R|  characteristics. Abbott Laboratories, Limited January 12, 2005.|1
00344|052|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00344|053|R|  352(11):1112-20.|6
00345|001|T|MONOGRAPH TITLE:  Sibutramine/Tryptophan|
00345|002|B||
00345|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00345|004|L|is contraindicated and generally should not be dispensed or administered to|
00345|005|L|the same patient.|
00345|006|B||
00345|007|A|MECHANISM OF ACTION:  Concurrent administration may result in additive|
00345|008|A|effects on serotonin, resulting in serotonin syndrome.|
00345|009|B||
00345|010|E|CLINICAL EFFECTS:  Concurrent use of sibutramine and tryptophan may result|
00345|011|E|in serotonin syndrome, a serious and potentially fatal reaction.  Symptoms|
00345|012|E|of serotonin syndrome may include tremor, agitation, diaphoresis,|
00345|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,3)|
00345|014|B||
00345|015|P|PREDISPOSING FACTORS:  None determined.|
00345|016|B||
00345|017|M|PATIENT MANAGEMENT:  Sibutramine has been removed from the market by the|
00345|018|M|European Medicines Agency and by regulatory agencies in a number of|
00345|019|M|countries including Australia, Canada, Hong Kong, India, Thailand, United|
00345|020|M|Kingdom and the United States.|
00345|021|M|   The UK manufacturer of sibutramine formerly stated that sibutramine|
00345|022|M|should not be administered with other drugs that raise serotonin levels in|
00345|023|M|the brain, such as tryptophan.(2)|
00345|024|M|   The US manufacturer of sibutramine formerly stated that in general,|
00345|025|M|sibutramine should not be administered with other serotonergic agents such|
00345|026|M|as tryptophan.  However, if concurrent administration is clinically|
00345|027|M|indicated, the patient should be appropriately observed.(1)|
00345|028|M|   If concurrent therapy is warranted, patients should be monitored for|
00345|029|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00345|030|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00345|031|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00345|032|M|coordination, or severe diarrhea.|
00345|033|M|   Patients in whom serotonin syndrome is suspected should receive immediate|
00345|034|M|medical attention.|
00345|035|B||
00345|036|D|DISCUSSION:  Sibutramine has been removed from the market by the European|
00345|037|D|Medicines Agency and by regulatory agencies in a number of countries|
00345|038|D|including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and|
00345|039|D|the United States.|
00345|040|D|   There is no published documentation to support this interaction.  Because|
00345|041|D|sibutramine inhibits serotonin reuptake and serotonin syndrome has been|
00345|042|D|reported during concomitant use of selective serotonin reuptake inhibitors|
00345|043|D|and tryptophan, the UK manufacturer of sibutramine states that sibutramine|
00345|044|D|should not be administered with tryptophan.(2)|
00345|045|B||
00345|046|R|REFERENCES:|
00345|047|B||
00345|048|R|1.Meridia (sibutramine hydrochloride monohydrate) US prescribing|1
00345|049|R|  information. Abbott Laboratories August, 2010.|1
00345|050|R|2.Reductil (sibutramine hydrochloride monohydrate) UK summary of product|1
00345|051|R|  characteristics. Abbott Laboratories, Limited January 12, 2005.|1
00345|052|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00345|053|R|  352(11):1112-20.|6
00346|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors; Cobicistat/Pimozide|
00346|002|B||
00346|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00346|004|L|is contraindicated and generally should not be dispensed or administered to|
00346|005|L|the same patient.|
00346|006|B||
00346|007|A|MECHANISM OF ACTION:  Protease inhibitors(1-13,15) and cobicistat(14) may|
00346|008|A|inhibit the metabolism of pimozide at CYP3A4.|
00346|009|B||
00346|010|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
00346|011|E|of pimozide, which may result in prolongation of the QTc interval and|
00346|012|E|potentially life-threatening ventricular arrhythmias.(1-15)|
00346|013|B||
00346|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00346|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00346|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00346|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00346|018|P|female gender, or advanced age.(17)|
00346|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00346|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00346|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00346|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00346|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00346|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00346|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(17)|
00346|026|P|   The risk of anticholinergic toxicities including cognitive decline,|
00346|027|P|delirium, falls and fractures is increased in geriatric patients using more|
00346|028|P|than one medicine with anticholinergic properties.(18)|
00346|029|B||
00346|030|M|PATIENT MANAGEMENT:  The concurrent use of pimozide and the protease|
00346|031|M|inhibitors amprenavir,(1) atazanavir,(2,3) darunavir,(4) fosamprenavir,(5)|
00346|032|M|indinavir,(6,7) nelfinavir,(6,8) nirmatrelvir coadministered with|
00346|033|M|ritonavir,(15) and tipranavir coadministered with ritonavir(13) and|
00346|034|M|cobicistat(14) is contraindicated.|
00346|035|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00346|036|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00346|037|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00346|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00346|039|B||
00346|040|D|DISCUSSION:  An in vitro study indicates that pimozide is metabolized at|
00346|041|D|CYP3A4.(15)  Elevated levels of pimozide may prolong the QTc interval|
00346|042|D|resulting in life-threatening ventricular arrhythmias.(6)|
00346|043|D|   Selected CYP3A inhibitors linked include: amprenavir, atazanavir,|
00346|044|D|cobicistat, darunavir, fosamprenavir, indinavir, nelfinavir, nirmatrelvir,|
00346|045|D|paritaprevir, and tipranavir.|
00346|046|B||
00346|047|R|REFERENCES:|
00346|048|B||
00346|049|R|1.Agenerase (amprenavir) Oral Solution US prescribing information.|1
00346|050|R|  GlaxoSmithKline May, 2005.|1
00346|051|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
00346|052|R|  Squibb Company December, 2024.|1
00346|053|R|3.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
00346|054|R|  Squibb Pharmaceuticals October 25, 2023.|1
00346|055|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
00346|056|R|  March, 2023.|1
00346|057|R|5.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
00346|058|R|  March, 2019.|1
00346|059|R|6.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
00346|060|R|  2011.|1
00346|061|R|7.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00346|062|R|  September, 2016.|1
00346|063|R|8.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00346|064|R|  Pharmaceuticals, Inc. September, 2016.|1
00346|065|R|9.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00346|066|R|  December, 2019.|1
00346|067|R|10.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
00346|068|R|   Inc. December, 2004.|1
00346|069|R|11.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00346|070|R|   Laboratories, Inc. March, 2019.|1
00346|071|R|12.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00346|072|R|   Laboratories December, 2019.|1
00346|073|R|13.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00346|074|R|   Pharmaceuticals, Inc. April, 2024.|1
00346|075|R|14.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
00346|076|R|   prescribing information. Gilead Sciences, Inc. September, 2021.|1
00346|077|R|15.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
00346|078|R|   information. Pfizer Inc. February, 2025.|1
00346|079|R|16.Desta Z, Kerbusch T, Soukhova N, Richard E, Ko JW, Flockhart DA.|5
00346|080|R|   Identification and characterization of human cytochrome P450 isoforms|5
00346|081|R|   interacting with pimozide. J Pharmacol Exp Ther 1998 May;285(2):428-37.|5
00346|082|R|17.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
00346|083|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
00346|084|R|   hospital settings: a scientific statement from the American Heart|6
00346|085|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
00346|086|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
00346|087|R|18.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
00346|088|R|   potentially  inappropriate medication use in older adults. J Am Geriatr|6
00346|089|R|   Soc 2023 Jul;71(7):2052-2081.|6
00347|001|T|MONOGRAPH TITLE:  Protease Inhibitors/Ergot Alkaloids|
00347|002|B||
00347|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00347|004|L|is contraindicated and generally should not be dispensed or administered to|
00347|005|L|the same patient.|
00347|006|B||
00347|007|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
00347|008|A|the ergot alkaloids by CYP3A4, including dihydroergotamine, ergotamine,|
00347|009|A|ergonovine, and methylergonovine. (1-13)|
00347|010|B||
00347|011|E|CLINICAL EFFECTS:  The concurrent administration of a protease inhibitor|
00347|012|E|with an ergot alkaloid may result in elevated levels, clinical effects, and|
00347|013|E|adverse effects of the ergot alkaloids.(1-13)  Signs of ergotism may include|
00347|014|E|peripheral vasospasm and ischemia.|
00347|015|B||
00347|016|P|PREDISPOSING FACTORS:  None determined.|
00347|017|B||
00347|018|M|PATIENT MANAGEMENT:  The concurrent administration of ergot alkaloids with|
00347|019|M|amprenavir,(1) atazanavir,(2,3) darunavir,(4) fosamprenavir,(5) indinavir,|
00347|020|M|(6) the combination of lopinavir and ritonavir,(7) nelfinavir,(8)|
00347|021|M|nirmatrelvir coadministered with ritonavir,(25) ritonavir, (12)|
00347|022|M|saquinavir,(9,10) and tipranavir coadministered with ritonavir(11) is|
00347|023|M|contraindicated.|
00347|024|M|   The US manufacturer of methylergonovine states that methylergonovine|
00347|025|M|should not be administered with potent CYP3A4 inhibitors such as protease|
00347|026|M|inhibitors.(13)|
00347|027|M|   Protease inhibitors linked include: amprenavir, atazanavir, darunavir,|
00347|028|M|fosamprenavir, indinavir, lopinavir, nelfinavir, nirmatrelvir, ritonavir,|
00347|029|M|saquinavir, and tipranavir.|
00347|030|B||
00347|031|D|DISCUSSION:  There have been several case reports of ergotism developing in|
00347|032|D|patients receiving concurrent ergotamine derivatives with indinavir,(14)|
00347|033|D|nelfinavir,(15) or ritonavir.(16-23)|
00347|034|D|   One or more of the drug pairs linked to this monograph have been included|
00347|035|D|in a list of interactions that should be considered "high-priority" for|
00347|036|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00347|037|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00347|038|D|Coordinator (ONC) for Health Information Technology.|
00347|039|B||
00347|040|R|REFERENCES:|
00347|041|B||
00347|042|R|1.Agenerase (amprenavir) Oral Solution US prescribing information.|1
00347|043|R|  GlaxoSmithKline May, 2005.|1
00347|044|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
00347|045|R|  Squibb Company December, 2024.|1
00347|046|R|3.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
00347|047|R|  Squibb Pharmaceuticals October 25, 2023.|1
00347|048|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
00347|049|R|  March, 2023.|1
00347|050|R|5.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
00347|051|R|  March, 2019.|1
00347|052|R|6.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00347|053|R|  September, 2016.|1
00347|054|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00347|055|R|  Laboratories December, 2019.|1
00347|056|R|8.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00347|057|R|  Pharmaceuticals, Inc. September, 2016.|1
00347|058|R|9.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
00347|059|R|  Inc. December, 2004.|1
00347|060|R|10.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00347|061|R|   Laboratories, Inc. March, 2019.|1
00347|062|R|11.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00347|063|R|   Pharmaceuticals, Inc. April, 2024.|1
00347|064|R|12.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00347|065|R|   December, 2019.|1
00347|066|R|13.Methergine (methylergonovine maleate) US prescribing information.|1
00347|067|R|   Novartis Pharmaceuticals Corporation June, 2012.|1
00347|068|R|14.Rosenthal E, Sala F, Chichmanian RM, Batt M, Cassuto JP. Ergotism related|3
00347|069|R|   to concurrent administration of ergotamine tartrate and indinavir. JAMA|3
00347|070|R|   1999 Mar 17;281(11):987.|3
00347|071|R|15.Mortier E, Pouchot J, Vinceneux P, Lalande M. Ergotism related to|3
00347|072|R|   interaction between nelfinavir and ergotamine. Am J Med 2001 May;|3
00347|073|R|   110(7):594.|3
00347|074|R|16.Montero A, Giovannoni AG, Tvrde PL. Leg ischemia in a patient receiving|3
00347|075|R|   ritonavir and ergotamine. Ann Intern Med 1999 Feb 16;130(4 Pt 1):329-30.|3
00347|076|R|17.Caballero-Granado FJ, Viciana P, Cordero E, Gomez-Vera MJ, del Nozal M,|3
00347|077|R|   Lopez-Cortes LF. Ergotism related to concurrent administration of|3
00347|078|R|   ergotamine tartrate and ritonavir in an AIDS patient. Antimicrob Agents|3
00347|079|R|   Chemother 1997 May;41(5):1207.|3
00347|080|R|18.Blanche P, Rigolet A, Gombert B, Ginsburg C, Salmon D, Sicard D. Ergotism|3
00347|081|R|   related to a single dose of ergotamine tartrate in an AIDS patient|3
00347|082|R|   treated with ritonavir. Postgrad Med J 1999 Sep;75(887):546-7.|3
00347|083|R|19.Liaudet L, Buclin T, Jaccard C, Eckert P. Drug points: severe ergotism|3
00347|084|R|   associated with interaction between ritonavir and ergotamine. BMJ 1999|3
00347|085|R|   Mar 20;318(7186):771.|3
00347|086|R|20.Pardo Rey C, Yebra M, Borrallo M, Vega A, Ramos A, Montero MC.|3
00347|087|R|   Irreversible coma, ergotamine, and ritonavir. Clin Infect Dis 2003 Sep 1;|3
00347|088|R|   37(5):e72-3.|3
00347|089|R|21.Spiegel M, Schmidauer C, Kampfl A, Sarcletti M, Poewe W. Cerebral|3
00347|090|R|   ergotism under treatment with ergotamine and ritonavir. Neurology 2001|3
00347|091|R|   Aug 28;57(4):743-4.|3
00347|092|R|22.Vila A, Mykietiuk A, Bonvehi P, Temporiti E, Uruena A, Herrera F.|3
00347|093|R|   Clinical ergotism induced by ritonavir. Scand J Infect Dis 2001;|3
00347|094|R|   33(10):788-9.|3
00347|095|R|23.Gallo C, de la Fuente B, Garcia-Alcalde ML, Antuna A. Ergotism in a|3
00347|096|R|   patient treated with ritonavir and ergotamine. Med Clin (Barc) 2002 Oct|3
00347|097|R|   26;119(14):558-9.|3
00347|098|R|24.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00347|099|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00347|100|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00347|101|R|   19(5):735-43.|6
00347|102|R|25.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
00347|103|R|   information. Pfizer Inc. February, 2025.|1
00348|001|T|MONOGRAPH TITLE:  Cyclosporine/Selected Androgens|
00348|002|B||
00348|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00348|004|L|of severe adverse interaction.|
00348|005|B||
00348|006|A|MECHANISM OF ACTION:  Danazol and methyltestosterone may inhibit the|
00348|007|A|metabolism of cyclosporine.|
00348|008|B||
00348|009|E|CLINICAL EFFECTS:  Concurrent therapy may result in increased levels of|
00348|010|E|cyclosporine, which may produce hepatic and renal dysfunction.|
00348|011|B||
00348|012|P|PREDISPOSING FACTORS:  None determined.|
00348|013|B||
00348|014|M|PATIENT MANAGEMENT:  If possible, avoid giving patients receiving|
00348|015|M|cyclosporine danazol or methyltestosterone.  If concurrent therapy is|
00348|016|M|warranted, monitor cyclosporine levels as well as renal and hepatic function|
00348|017|M|carefully.  Cyclosporine dosage adjustments may be necessary when these|
00348|018|M|agents are initiated or discontinued, as well as during concurrent therapy.|
00348|019|M|Discontinuation of the androgen may be necessary.|
00348|020|B||
00348|021|D|DISCUSSION:  Four case reports have documented increased cyclosporine levels|
00348|022|D|during concurrent therapy with danazol.(1-4)  In two of these reports,|
00348|023|D|elevated cyclosporine levels persisted even after decreases in cyclosporine|
00348|024|D|dosages.(1,2)  One patient also experienced decreased renal function, as|
00348|025|D|indicated by an increase in serum creatinine levels.(1)  Cyclosporine levels|
00348|026|D|returned to baseline following the discontinuation of danazol.(1-4)|
00348|027|D|     Two case reports have documented increased cyclosporine levels during|
00348|028|D|concurrent therapy with methyltestosterone.  Both patients experienced|
00348|029|D|elevated cyclosporine, bilirubin, and serum creatinine levels during|
00348|030|D|concurrent therapy.(5,6)  In one patient, elevated cyclosporine levels|
00348|031|D|persisted despite a 40% decrease in cyclosporine dosage.(5)  Discontinuation|
00348|032|D|of methyltestosterone resulted in a gradual return of cyclosporine levels to|
00348|033|D|previous values.(5,6)|
00348|034|B||
00348|035|R|REFERENCES:|
00348|036|B||
00348|037|R|1.Ross WB, Roberts D, Griffin PJ, Salaman JR. Cyclosporin interaction with|3
00348|038|R|  danazol and norethisterone. Lancet 1986 Feb 8;1(8476):330.|3
00348|039|R|2.Blatt J, Howrie D, Orlando S, Burckart G. Interaction between cyclosporine|3
00348|040|R|  and danazol in a pediatric patient. J Pediatr Hematol Oncol 1996 Feb;|3
00348|041|R|  18(1):95.|3
00348|042|R|3.Koneru B, Hartner C, Iwatsuki S, Starzl TE. Effect of danazol on|3
00348|043|R|  cyclosporine pharmacokinetics. Transplantation 1988 May;45(5):1001.|3
00348|044|R|4.Passfall J, Schuller I, Keller F. Pharmacokinetics of cyclosporin during|3
00348|045|R|  administration of danazol. Nephrol Dial Transplant 1994;9(12):1807-8.|3
00348|046|R|5.Moller BB, Ekelund B. Toxicity of cyclosporine during treatment with|3
00348|047|R|  androgens. N Engl J Med 1985 Nov 28;313(22):1416.|3
00348|048|R|6.Goffin E, Pirson Y, Geubel A, van Ypersele de Strihou C.|3
00348|049|R|  Cyclosporine-methyltestosterone interaction. Nephron 1991;59(1):174-5.|3
00349|001|T|MONOGRAPH TITLE:  Tobramycin Inhalation/Selected Diuretics|
00349|002|B||
00349|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00349|004|L|take action as needed.|
00349|005|B||
00349|006|A|MECHANISM OF ACTION:  The combination may have additive or synergistic risks|
00349|007|A|for ototoxicity and/or nephrotoxicity.(1,2)|
00349|008|B||
00349|009|E|CLINICAL EFFECTS:  Concurrent use may result in an increased risk of|
00349|010|E|aminoglycoside toxicity.(1)|
00349|011|B||
00349|012|P|PREDISPOSING FACTORS:  Severe renal impairment, sepsis, or concomitant use|
00349|013|P|of additional ototoxic or nephrotoxic agents may further increase the risk|
00349|014|P|for toxicity.|
00349|015|P|   Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G,|
00349|016|P|m.1095T>C, and m.1494C>T) are at greatly increased risk of developing|
00349|017|P|ototoxicity.  An additional risk factor includes patients with a maternal|
00349|018|P|relative known to have a clinically relevant MT-RNR1 variant.  The risk of|
00349|019|P|ototoxicity can occur at standard recommended doses of aminoglycosides.(3)|
00349|020|B||
00349|021|M|PATIENT MANAGEMENT:  Instruct patients to contact their provider for new|
00349|022|M|onset or worsening tinnitus.  Tinnitus may be a sentinel symptom of|
00349|023|M|ototoxicity.  In clinical trials of tobramycin inhalation 8 patients (3%)|
00349|024|M|receiving tobramycin reported tinnitus while no patients in the placebo|
00349|025|M|group reported this symptom.(1)|
00349|026|M|   For renally impaired patients receiving long term tobramycin inhalation|
00349|027|M|therapy, consider measurement of serum tobramycin to assure low systemic|
00349|028|M|levels.|
00349|029|M|   The manufacturer of tobramycin for inhalation states that the product|
00349|030|M|should not be administered concurrently with ethacrynic acid, furosemide,|
00349|031|M|intravenous mannitol, or urea.(1)|
00349|032|B||
00349|033|D|DISCUSSION:  Although systemic absorption of inhaled tobramycin is limited,|
00349|034|D|the manufacturer states that because these diuretics may enhance the risk|
00349|035|D|for aminoglycoside toxicity, they should not be administered concurrently|
00349|036|D|with inhaled tobramycin.(1)|
00349|037|B||
00349|038|R|REFERENCES:|
00349|039|B||
00349|040|R|1.Tobi (tobramycin solution for inhalation) US prescribing information.|1
00349|041|R|  Novartis October, 2018.|1
00349|042|R|2.Lasix (furosemide) US prescribing information. Sanofi-Aventis U.S. LLC|1
00349|043|R|  March, 2016.|1
00349|044|R|3.McDermott JH, Wolf J, Hoshitsuki K, Huddart R, Caudle KE, Whirl-Carrillo|6
00349|045|R|  M, Steyger PS, Smith RJH, Cody N, Rodriguez-Antona C, Klein TE, Newman WG.|6
00349|046|R|  Clinical Pharmacogenetics Implementation Consortium Guideline for the use|6
00349|047|R|  of aminoglycosides based on MT-RNR1 genotype. Clin Pharmacol Ther May,|6
00349|048|R|  2021.|6
00350|001|T|MONOGRAPH TITLE:  Halofantrine/Antimalarials|
00350|002|B||
00350|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00350|004|L|is contraindicated and generally should not be dispensed or administered to|
00350|005|L|the same patient.|
00350|006|B||
00350|007|A|MECHANISM OF ACTION:  Possibly additive effects on the QTc interval.|
00350|008|B||
00350|009|E|CLINICAL EFFECTS:  Concurrent use of halofantrine and other antimalarials,|
00350|010|E|such as quinine, chloroquine, or mefloquine, may predispose patients to|
00350|011|E|development of prolonged QTc intervals.(1)|
00350|012|B||
00350|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00350|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00350|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00350|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00350|017|P|female gender, or advanced age.(5)|
00350|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00350|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00350|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00350|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00350|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00350|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00350|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
00350|025|B||
00350|026|M|PATIENT MANAGEMENT:  The UK manufacturer of halofantrine states under the|
00350|027|M|contraindications section of the prescribing information that unless there|
00350|028|M|are compelling clinical reasons, halofantrine should not be used with other|
00350|029|M|antimalarials, such as quinine, chloroquine, or mefloquine.(1)  The US|
00350|030|M|manufacturer of halofantrine states that halofantrine should not be given|
00350|031|M|with or subsequent to mefloquine.(2)|
00350|032|M|   The US manufacturer of mefloquine states that halofantrine must not be|
00350|033|M|given concurrently with or within 15 weeks of the last dose of|
00350|034|M|mefloquine.(3)|
00350|035|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00350|036|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00350|037|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00350|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00350|039|B||
00350|040|D|DISCUSSION:  Concurrent halofantrine and mefloquine has been reported to|
00350|041|D|result in further prolongation of the QTc interval.(4)|
00350|042|D|   Because concurrent use may predispose patients to prolongation of the QTc|
00350|043|D|interval, the UK manufacturer of halofantrine states under the|
00350|044|D|contraindications section of the prescribing information that halofantrine|
00350|045|D|should not be used with other antimalarials such as quinine, chloroquine, or|
00350|046|D|mefloquine unless compelling clinical reasons exist.(1)  The US manufacturer|
00350|047|D|of halofantrine states that halofantrine should not be given with or|
00350|048|D|subsequent to mefloquine.(2)  The US manufacturer of mefloquine states that|
00350|049|D|halofantrine must not be given with or subsequent to mefloquine.(3)|
00350|050|D|   One or more of the drug pairs linked to this monograph have been included|
00350|051|D|in a list of interactions that should be considered "high-priority" for|
00350|052|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00350|053|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00350|054|D|Coordinator (ONC) for Health Information Technology.|
00350|055|B||
00350|056|R|REFERENCES:|
00350|057|B||
00350|058|R|1.Halfan (halofantrine) UK summary of product characteristics. Smith-Kline|1
00350|059|R|  and French Laboratories, Inc. April, 1997.|1
00350|060|R|2.Halfan (halofantrine hydrochloride) US prescribing information. SmithKline|1
00350|061|R|  Beecham Pharmaceuticals October, 2001.|1
00350|062|R|3.Lariam (mefloquine hydrochloride) US prescribing information. Roche|1
00350|063|R|  Pharmaceuticals August, 2009.|1
00350|064|R|4.Nosten F, ter Kuile FO, Luxemburger C, Woodrow C, Kyle DE,|3
00350|065|R|  Chongsuphajaisiddhi T, White NJ. Cardiac effects of antimalarial treatment|3
00350|066|R|  with halofantrine. Lancet 1993 Apr 24;341(8852):1054-6.|3
00350|067|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00350|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00350|069|R|  settings: a scientific statement from the American Heart Association and|6
00350|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00350|071|R|  2;55(9):934-47.|6
00350|072|R|6.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00350|073|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00350|074|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00350|075|R|  19(5):735-43.|6
00351|001|T|MONOGRAPH TITLE:  Halofantrine/Tricyclic Compounds|
00351|002|B||
00351|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00351|004|L|is contraindicated and generally should not be dispensed or administered to|
00351|005|L|the same patient.|
00351|006|B||
00351|007|A|MECHANISM OF ACTION:  Possibly additive effects on the QTc interval.|
00351|008|B||
00351|009|E|CLINICAL EFFECTS:  Concurrent use of halofantrine and tricyclic|
00351|010|E|antidepressants may pre-dispose patients to development of prolonged QTc|
00351|011|E|intervals.(1)|
00351|012|B||
00351|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00351|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00351|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00351|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00351|017|P|female gender, or advanced age.(2)|
00351|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00351|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00351|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00351|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00351|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00351|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00351|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00351|025|B||
00351|026|M|PATIENT MANAGEMENT:  The manufacturer of halofantrine states under the|
00351|027|M|contraindications section of the prescribing information that unless there|
00351|028|M|are compelling clinical reasons, halofantrine should not be used with|
00351|029|M|tricyclic antidepressants.(1)|
00351|030|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00351|031|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00351|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00351|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00351|034|B||
00351|035|D|DISCUSSION:  There is no published documentation to support this potential|
00351|036|D|interaction.  Because concurrent use may pre-dispose patients to|
00351|037|D|prolongation of the QTc interval, the manufacturer of halofantrine states|
00351|038|D|under the contraindications section of the prescribing information that|
00351|039|D|halofantrine should not be used with tricyclic antidepressants unless|
00351|040|D|compelling clinical reasons exist.(1)|
00351|041|B||
00351|042|R|REFERENCES:|
00351|043|B||
00351|044|R|1.Halfan (halofantrine) UK summary of product characteristics. Smith-Kline|1
00351|045|R|  and French Laboratories, Inc. April, 1997.|1
00351|046|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00351|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00351|048|R|  settings: a scientific statement from the American Heart Association and|6
00351|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00351|050|R|  2;55(9):934-47.|6
00352|001|T|MONOGRAPH TITLE:  Halofantrine/Antipsychotics|
00352|002|B||
00352|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00352|004|L|is contraindicated and generally should not be dispensed or administered to|
00352|005|L|the same patient.|
00352|006|B||
00352|007|A|MECHANISM OF ACTION:  Possibly additive effects on the QTc interval.|
00352|008|B||
00352|009|E|CLINICAL EFFECTS:  Concurrent use of halofantrine and antipsychotics may|
00352|010|E|pre-dispose patients to the development of prolonged QTc intervals.(1)|
00352|011|B||
00352|012|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00352|013|P|may be increased in patients with cardiovascular disease (e.g. heart|
00352|014|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00352|015|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00352|016|P|female gender, or advanced age.(2)|
00352|017|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00352|018|P|higher systemic concentrations of either QT prolonging drug are additional|
00352|019|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00352|020|P|drug concentrations include rapid infusion of an intravenous dose or|
00352|021|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00352|022|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00352|023|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00352|024|B||
00352|025|M|PATIENT MANAGEMENT:  The manufacturer of halofantrine states under the|
00352|026|M|contraindications section of the prescribing information that unless there|
00352|027|M|are compelling clinical reasons, halofantrine should not be used with|
00352|028|M|antipsychotics.(1)|
00352|029|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00352|030|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00352|031|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00352|032|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00352|033|B||
00352|034|D|DISCUSSION:  Because concurrent use may pre-dispose patients to prolongation|
00352|035|D|of the QTc interval, the manufacturer of halofantrine states under the|
00352|036|D|contraindications section of the prescribing information that halofantrine|
00352|037|D|should not be used with antipsychotics unless compelling clinical reasons|
00352|038|D|exist.(1)|
00352|039|D|   One or more of the drug pairs linked to this monograph have been included|
00352|040|D|in a list of interactions that should be considered "high-priority" for|
00352|041|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00352|042|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00352|043|D|Coordinator (ONC) for Health Information Technology.|
00352|044|B||
00352|045|R|REFERENCES:|
00352|046|B||
00352|047|R|1.Halfan (halofantrine) UK summary of product characteristics. Smith-Kline|1
00352|048|R|  and French Laboratories, Inc. April, 1997.|1
00352|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00352|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00352|051|R|  settings: a scientific statement from the American Heart Association and|6
00352|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00352|053|R|  2;55(9):934-47.|6
00352|054|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00352|055|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00352|056|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00352|057|R|  19(5):735-43.|6
00353|001|T|MONOGRAPH TITLE:  Halofantrine/Class I and III Antiarrhythmics|
00353|002|B||
00353|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00353|004|L|is contraindicated and generally should not be dispensed or administered to|
00353|005|L|the same patient.|
00353|006|B||
00353|007|A|MECHANISM OF ACTION:  Possibly additive effects on the QTc interval.|
00353|008|B||
00353|009|E|CLINICAL EFFECTS:  Concurrent use of halofantrine and Class I or III|
00353|010|E|antiarrhythmics may pre-dispose patients to development of prolonged QTc|
00353|011|E|interval.(1)|
00353|012|B||
00353|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00353|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00353|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00353|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00353|017|P|female gender, or advanced age.(2)|
00353|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00353|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00353|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00353|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00353|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00353|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00353|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00353|025|B||
00353|026|M|PATIENT MANAGEMENT:  The manufacturer of halofantrine states under the|
00353|027|M|contraindications section of the prescribing information that unless there|
00353|028|M|are compelling clinical reasons, halofantrine should not be used with Class|
00353|029|M|I and III antiarrhythmics.(1)|
00353|030|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00353|031|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00353|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00353|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00353|034|B||
00353|035|D|DISCUSSION:  Because concurrent use may pre-dispose patients to prolongation|
00353|036|D|of the QTc interval, the manufacturer of halofantrine states in the|
00353|037|D|contraindications section of the prescribing information that halofantrine|
00353|038|D|should not be used with Class I or III antiarrhythmics unless compelling|
00353|039|D|clinical reasons exist.(1)|
00353|040|D|   One or more of the drug pairs linked to this monograph have been included|
00353|041|D|in a list of interactions that should be considered "high-priority" for|
00353|042|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00353|043|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00353|044|D|Coordinator (ONC) for Health Information Technology.|
00353|045|B||
00353|046|R|REFERENCES:|
00353|047|B||
00353|048|R|1.Halfan (halofantrine) UK summary of product characteristics. Smith-Kline|1
00353|049|R|  and French Laboratories, Inc. April, 1997.|1
00353|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00353|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00353|052|R|  settings: a scientific statement from the American Heart Association and|6
00353|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00353|054|R|  2;55(9):934-47.|6
00353|055|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00353|056|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00353|057|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00353|058|R|  19(5):735-43.|6
00354|001|T|MONOGRAPH TITLE:  Halofantrine/Astemizole; Terfenadine|
00354|002|B||
00354|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00354|004|L|is contraindicated and generally should not be dispensed or administered to|
00354|005|L|the same patient.|
00354|006|B||
00354|007|A|MECHANISM OF ACTION:  Possibly additive effects on the QTc interval.|
00354|008|B||
00354|009|E|CLINICAL EFFECTS:  Concurrent use of halofantrine and astemizole or|
00354|010|E|terfenadine may pre-dispose patients to development of prolonged QTc|
00354|011|E|interval.(1)|
00354|012|B||
00354|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00354|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00354|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00354|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00354|017|P|female gender, or advanced age.(4)|
00354|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00354|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00354|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00354|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00354|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00354|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00354|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
00354|025|B||
00354|026|M|PATIENT MANAGEMENT:  The manufacturer of halofantrine states under the|
00354|027|M|contraindications section of the prescribing information that unless there|
00354|028|M|are compelling clinical reasons, halofantrine should not be used with|
00354|029|M|astemizole or terfenadine.(1)  Fexofenadine or loratadine, non-sedating|
00354|030|M|antihistamines which have been shown to have no effect on cardiac|
00354|031|M|function,(2,3) may be alternatives in patients receiving halofantrine.|
00354|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00354|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00354|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00354|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00354|036|B||
00354|037|D|DISCUSSION:  Because concurrent use may pre-dispose patients to prolongation|
00354|038|D|of the QTc interval, the manufacturer of halofantrine states in the|
00354|039|D|contraindications section of the prescribing information that halofantrine|
00354|040|D|should not be used with astemizole or terfenadine unless compelling clinical|
00354|041|D|reasons exist.(1)|
00354|042|D|   One or more of the drug pairs linked to this monograph have been included|
00354|043|D|in a list of interactions that should be considered "high-priority" for|
00354|044|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00354|045|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00354|046|D|Coordinator (ONC) for Health Information Technology.|
00354|047|B||
00354|048|R|REFERENCES:|
00354|049|B||
00354|050|R|1.Halfan (halofantrine) UK summary of product characteristics. Smith-Kline|1
00354|051|R|  and French Laboratories, Inc. April, 1997.|1
00354|052|R|2.Allegra (fexofenadine hydrochloride) US prescribing information.|1
00354|053|R|  Sanofi-Aventis U.S. LLC October, 2006.|1
00354|054|R|3.Claritin (loratadine) US prescribing information. Schering-Plough|1
00354|055|R|  Corporation January, 1997.|1
00354|056|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00354|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00354|058|R|  settings: a scientific statement from the American Heart Association and|6
00354|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00354|060|R|  2;55(9):934-47.|6
00354|061|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00354|062|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00354|063|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00354|064|R|  19(5):735-43.|6
00355|001|T|MONOGRAPH TITLE:  Saquinavir Base/Ergot Derivatives  (mono deleted|
00355|002|T|11/09/2000)|
00355|003|B||
00355|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00355|005|L|is contraindicated and generally should not be dispensed or administered to|
00355|006|L|the same patient.|
00355|007|B||
00355|008|A|MECHANISM OF ACTION:  Saquinavir may inhibit the metabolism of the ergot|
00355|009|A|derivatives.(1)|
00355|010|B||
00355|011|E|CLINICAL EFFECTS:  Concurrent administration of Fortovase and an ergot|
00355|012|E|derivative may result in elevated levels of the ergot derivative and adverse|
00355|013|E|effects.(1)|
00355|014|B||
00355|015|P|PREDISPOSING FACTORS:  None determined.|
00355|016|B||
00355|017|M|PATIENT MANAGEMENT:  The manufacturer of saquinavir states that Fortovase|
00355|018|M|should not be administered with ergot derivatives.(1)|
00355|019|B||
00355|020|D|DISCUSSION:  There is no clinical documentation to support this interaction.|
00355|021|D|Because saquinavir has been shown to inhibit CYP P-450-3A, the manufacturer|
00355|022|D|manufacturer of saquinavir states that Fortovase should not be administered|
00355|023|D|with ergot derivatives.(1)|
00355|024|B||
00355|025|R|REFERENCE:|
00355|026|B||
00355|027|R|1.Fortovase (saquinavir) US prescribing information. Roche Pharmaceuticals|1
00355|028|R|  November, 1997.|1
00356|001|T|MONOGRAPH TITLE:  Pimozide/Phenothiazines|
00356|002|B||
00356|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00356|004|L|is contraindicated and generally should not be dispensed or administered to|
00356|005|L|the same patient.|
00356|006|B||
00356|007|A|MECHANISM OF ACTION:  Concurrent use may possibly result in additive effects|
00356|008|A|on the QTc interval.(1)|
00356|009|B||
00356|010|E|CLINICAL EFFECTS:  Concurrent use may result in prolongation of the QTc|
00356|011|E|interval, which may result in potentially life-threatening arrhythmias.(1)|
00356|012|B||
00356|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00356|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00356|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00356|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00356|017|P|female gender, or advanced age.(2)|
00356|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00356|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00356|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00356|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00356|022|P|impaired metabolism or elimination of the drug (e.e. coadministration with|
00356|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00356|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00356|025|B||
00356|026|M|PATIENT MANAGEMENT:  Concurrent therapy with pimozide and phenothiazines|
00356|027|M|should be avoided.  The manufacturer of pimozide states that concurrent|
00356|028|M|therapy with agents that prolong the QTc interval is contraindicated.(1)|
00356|029|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00356|030|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00356|031|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00356|032|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00356|033|B||
00356|034|D|DISCUSSION:  Pimozide has been shown to prolong the QTc interval.|
00356|035|D|Therefore, the manufacturer of pimozide states that concurrent therapy with|
00356|036|D|agents that prolong the QTc interval is contraindicated because of the risk|
00356|037|D|of additive effects on the QTc interval.(1)  No other clinical documentation|
00356|038|D|is available.|
00356|039|D|   One or more of the drug pairs linked to this monograph have been included|
00356|040|D|in a list of interactions that should be considered "high-priority" for|
00356|041|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00356|042|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00356|043|D|Coordinator (ONC) for Health Information Technology.|
00356|044|B||
00356|045|R|REFERENCES:|
00356|046|B||
00356|047|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
00356|048|R|  2011.|1
00356|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00356|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00356|051|R|  settings: a scientific statement from the American Heart Association and|6
00356|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00356|053|R|  2;55(9):934-47.|6
00356|054|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00356|055|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00356|056|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00356|057|R|  19(5):735-43.|6
00357|001|T|MONOGRAPH TITLE:  Pimozide/Selected Antiarrhythmics|
00357|002|B||
00357|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00357|004|L|is contraindicated and generally should not be dispensed or administered to|
00357|005|L|the same patient.|
00357|006|B||
00357|007|A|MECHANISM OF ACTION:  Concurrent use may possibly result in additive effects|
00357|008|A|on the QTc interval.(1)|
00357|009|B||
00357|010|E|CLINICAL EFFECTS:  Concurrent use may result in prolongation of the QTc|
00357|011|E|interval, which may result in potentially life-threatening arrhythmias.(1)|
00357|012|B||
00357|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00357|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00357|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00357|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00357|017|P|female gender, or advanced age.(2)|
00357|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00357|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00357|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00357|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00357|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00357|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00357|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00357|025|B||
00357|026|M|PATIENT MANAGEMENT:  Concurrent therapy with pimozide and Class IA and III|
00357|027|M|antiarrhythmics should be avoided.  The manufacturer of pimozide states that|
00357|028|M|concurrent therapy with agents that prolong the QTc interval is|
00357|029|M|contraindicated.(1)|
00357|030|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00357|031|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00357|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00357|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00357|034|B||
00357|035|D|DISCUSSION:  Pimozide has been shown to prolong the QTc interval.|
00357|036|D|Therefore, the manufacturer of pimozide states that concurrent therapy with|
00357|037|D|agents that prolong the QTc interval is contraindicated because of the risk|
00357|038|D|of additive effects on the QTc interval.(1)  No other clinical documentation|
00357|039|D|is available.|
00357|040|D|   One or more of the drug pairs linked to this monograph have been included|
00357|041|D|in a list of interactions that should be considered "high-priority" for|
00357|042|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00357|043|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00357|044|D|Coordinator (ONC) for Health Information Technology.|
00357|045|B||
00357|046|R|REFERENCES:|
00357|047|B||
00357|048|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
00357|049|R|  2011.|1
00357|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00357|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00357|052|R|  settings: a scientific statement from the American Heart Association and|6
00357|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00357|054|R|  2;55(9):934-47.|6
00357|055|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00357|056|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00357|057|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00357|058|R|  19(5):735-43.|6
00358|001|T|MONOGRAPH TITLE:  Pimozide/Tricyclic Compounds|
00358|002|B||
00358|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00358|004|L|is contraindicated and generally should not be dispensed or administered to|
00358|005|L|the same patient.|
00358|006|B||
00358|007|A|MECHANISM OF ACTION:  Concurrent use may possibly result in additive effects|
00358|008|A|on the QTc interval.(1)|
00358|009|B||
00358|010|E|CLINICAL EFFECTS:  Concurrent use may result in prolongation of the QTc|
00358|011|E|interval, which may result in potentially life-threatening arrhythmias.(1)|
00358|012|B||
00358|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00358|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00358|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00358|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00358|017|P|female gender, or advanced age.(2)|
00358|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00358|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00358|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00358|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00358|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00358|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00358|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00358|025|B||
00358|026|M|PATIENT MANAGEMENT:  Concurrent therapy with pimozide and tricyclic|
00358|027|M|antidepressants should be avoided.  The manufacturer of pimozide states that|
00358|028|M|concurrent therapy with agents that prolong the QTc interval is|
00358|029|M|contraindicated.(1)|
00358|030|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00358|031|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00358|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00358|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00358|034|B||
00358|035|D|DISCUSSION:  There is no clinical documentation to support this interaction.|
00358|036|D|Pimozide has been shown to prolong the QTc interval.  Therefore, the|
00358|037|D|manufacturer of pimozide states that concurrent therapy with agents that|
00358|038|D|prolong the QTc interval is contraindicated because of the risk of additive|
00358|039|D|effects on the QTc interval.(1)  No other clinical documentation is|
00358|040|D|available.|
00358|041|B||
00358|042|R|REFERENCES:|
00358|043|B||
00358|044|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
00358|045|R|  2011.|1
00358|046|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00358|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00358|048|R|  settings: a scientific statement from the American Heart Association and|6
00358|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00358|050|R|  2;55(9):934-47.|6
00359|001|T|MONOGRAPH TITLE:  Mefloquine/Chloroquine; Hydroxychloroquine; Quinidine;|
00359|002|T|Quinine|
00359|003|B||
00359|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00359|005|L|is contraindicated and generally should not be dispensed or administered to|
00359|006|L|the same patient.|
00359|007|B||
00359|008|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
00359|009|A|additive effects between mefloquine and antimalarials including chloroquine,|
00359|010|A|hydroxychloroquine, quinidine or quinine.|
00359|011|B||
00359|012|E|CLINICAL EFFECTS:  Concurrent administration of mefloquine with chloroquine,|
00359|013|E|hydroxychloroquine, quinidine or quinine may result in electrocardiographic|
00359|014|E|abnormalities, cardiac arrest, and/or an increased risk of convulsions.(1)|
00359|015|B||
00359|016|P|PREDISPOSING FACTORS:  None determined.|
00359|017|B||
00359|018|M|PATIENT MANAGEMENT:  Concurrent use of mefloquine with chloroquine,|
00359|019|M|hydroxychloroquine, quinidine, or quinine is contraindicated.  If these|
00359|020|M|agents are used in the initial treatment of malaria, the administration of|
00359|021|M|mefloquine should be delayed until 12 hours after the last dose of|
00359|022|M|chloroquine, hydroxychloroquine, quinidine, or quinine.(1)|
00359|023|B||
00359|024|D|DISCUSSION:  There is little clinical information to support this|
00359|025|D|interaction.|
00359|026|D|   An in vitro study in human liver microsomes showed that quinine inhibits|
00359|027|D|the metabolism of mefloquine.(2)|
00359|028|D|   The manufacturer of mefloquine states that concurrent administration of|
00359|029|D|mefloquine with quinine or quinidine may produce electrocardiographic|
00359|030|D|abnormalities or cardiac arrest and that the concurrent administration of|
00359|031|D|mefloquine and quinine or chloroquine may increase the risk of|
00359|032|D|convulsions.(1)|
00359|033|D|   The manufacturer of mefloquine states that if quinine or quinidine are|
00359|034|D|used in the treatment of malaria, 12 hours should elapse between the their|
00359|035|D|last dose and the first dose of mefloquine.(1)|
00359|036|B||
00359|037|R|REFERENCES:|
00359|038|B||
00359|039|R|1.Lariam (mefloquine hydrochloride) US prescribing information. Roche|1
00359|040|R|  Pharmaceuticals August, 2009.|1
00359|041|R|2.Bangchang KN, Karbwang J, Back DJ. Mefloquine metabolism by human liver|5
00359|042|R|  microsomes. Effect of other antimalarial drugs. Biochem Pharmacol 1992 May|5
00359|043|R|  8;43(9):1957-61.|5
00360|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
00360|002|T|antagonists)/Propoxyphene; Tramadol|
00360|003|B||
00360|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00360|005|L|take action as needed.|
00360|006|B||
00360|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
00360|008|B||
00360|009|E|CLINICAL EFFECTS:  Concurrent use of propoxyphene or tramadol may result in|
00360|010|E|increased effects of some anticoagulants, including bleeding.|
00360|011|B||
00360|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00360|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00360|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
00360|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00360|016|P|risk for bleeding (e.g. NSAIDs).|
00360|017|B||
00360|018|M|PATIENT MANAGEMENT:  Patients maintained on warfarin who begin therapy with|
00360|019|M|propoxyphene or tramadol containing medication should be monitored closely|
00360|020|M|for signs of increased warfarin effects.  The dosage of warfarin may need to|
00360|021|M|be adjusted or a different opioid may need to be used.|
00360|022|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00360|023|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00360|024|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00360|025|M|patients with any symptoms.|
00360|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00360|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00360|028|M|anticoagulation in patients with active pathologic bleeding.|
00360|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00360|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00360|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00360|032|M|and/or swelling.|
00360|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00360|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00360|035|M|initiating, altering the dose or discontinuing either drug.|
00360|036|B||
00360|037|D|DISCUSSION:  There have been three case reports of patients developing|
00360|038|D|hematuria following the addition of a combination product containing|
00360|039|D|propoxyphene and acetaminophen.(1-2)  In one of these reports, the patient|
00360|040|D|took double the recommended dosage of the product in a four hour period.(1)|
00360|041|D|In another case report, a patient noticed increased bleeding from facial|
00360|042|D|shaving cuts and developed an increased prothrombin time after|
00360|043|D|self-administering nearly twice the recommended dosage of a combination|
00360|044|D|propoxyphene and acetaminophen product and an unknown quantity of ibuprofen|
00360|045|D|over a three day period.(3)  In another report, a patient developed an|
00360|046|D|increased prothrombin time following the addition of a combination|
00360|047|D|propoxyphene and acetaminophen product.(4)|
00360|048|D|   There have been three case reports of increased INR values following the|
00360|049|D|addition of tramadol to warfarin-containing regimens.(5-7)|
00360|050|D|   A large systematic review was performed on 72 warfarin drug-drug|
00360|051|D|interactions studies that reported on bleeding, thromboembolic events, or|
00360|052|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 4 of|
00360|053|D|those studies found a higher rate of clinically significant bleeding in|
00360|054|D|patients on warfarin and non-NSAID analgesics (OR=2.12; 95% CI 1.65-2.73).|
00360|055|D|Increased bleeding risk was also seen in subgroup analyses with opioid|
00360|056|D|analgesics (OR=2.81; 95% CI 1.89-4.17).(8)|
00360|057|D|   A retrospective review associated tramadol use with episodes of major|
00360|058|D|bleeding in patients receiving phenprocoumon or acenocoumarol.(9)  In|
00360|059|D|contrast, a study in 19 patients receiving phenprocoumon found no effect on|
00360|060|D|INR values following the addition of tramadol.(10)|
00360|061|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
00360|062|D|pairs were reviewed and found 14% of drug pairs were associated with a|
00360|063|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
00360|064|D|of warfarin and propoxyphene resulted in a ratio of rate ratios (95% CI) of|
00360|065|D|1.38 (1.08-1.77).(11)|
00360|066|B||
00360|067|R|REFERENCES:|
00360|068|B||
00360|069|R|1.Orme M, Breckenridge A, Cook P. Warfarin and Distalgesic interaction. Br|3
00360|070|R|  Med J 1976 Jan 24;1(6003):200.|3
00360|071|R|2.Jones RV. Letter: Warfarin and distalgesic interaction. Br Med J 1976 Feb|3
00360|072|R|  21;1(6007):460.|3
00360|073|R|3.Justice JL, Kline SS. Analgesics and warfarin. A case that brings up|3
00360|074|R|  questions and cautions. Postgrad Med 1988 Apr;83(5):217-8, 220.|3
00360|075|R|4.Smith R, Prudden D, Hawkes C. Propoxyphene and warfarin interaction. Drug|3
00360|076|R|  Intell Clin Pharm 1984 Oct;18(10):822.|3
00360|077|R|5.Dumo PA, Kielbasa LA. Successful anticoagulation and continuation of|3
00360|078|R|  tramadol therapy in the setting of a tramadol-warfarin interaction.|3
00360|079|R|  Pharmacotherapy 2006 Nov;26(11):1654-7.|3
00360|080|R|6.Sabbe JR, Sims PJ, Sims MH. Tramadol-warfarin interaction. Pharmacotherapy|3
00360|081|R|  1998 Jul-Aug;18(4):871-3.|3
00360|082|R|7.Scher ML, Huntington NH, Vitillo JA. Potential interaction between|3
00360|083|R|  tramadol and warfarin. Ann Pharmacother 1997 May;31(5):646-7.|3
00360|084|R|8.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00360|085|R|  Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00360|086|R|  interactions with warfarin: A systematic review and meta-analysis. Br J|6
00360|087|R|  Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00360|088|R|9.Penning-van Beest F, Erkens J, Petersen KU, Koelz HR, Herings R. Main|2
00360|089|R|  comedications associated with major bleeding during anticoagulant therapy|2
00360|090|R|  with coumarins. Eur J Clin Pharmacol 2005 Jul;61(5-6):439-44.|2
00360|091|R|10.Boeijinga JK, van Meegen E, van den Ende R, Schook CE, Cohen AF. Lack of|2
00360|092|R|   interaction between tramadol and coumarins. J Clin Pharmacol 1998 Oct;|2
00360|093|R|   38(10):966-70.|2
00360|094|R|11.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
00360|095|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
00360|096|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
00360|097|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
00361|001|T|MONOGRAPH TITLE:  5-HT1D Agonists/SSRIs; SNRIs (mono deleted 12/17/2019)|
00361|002|B||
00361|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00361|004|L|take action as needed.|
00361|005|B||
00361|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
00361|007|B||
00361|008|E|CLINICAL EFFECTS:  Concurrent use has been associated with weakness,|
00361|009|E|hyperreflexia, and incoordination.(1) Concurrent use may result in serotonin|
00361|010|E|syndrome. Symptoms of serotonin syndrome may include tremor, agitation,|
00361|011|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
00361|012|E|rigidity.(2)|
00361|013|B||
00361|014|P|PREDISPOSING FACTORS:  None determined.|
00361|015|B||
00361|016|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
00361|017|M|closely,(1,3-15) especially during treatment initiation, during dosage|
00361|018|M|increases, or if another serotonergic agent is added to the patient's|
00361|019|M|regimen.(1)|
00361|020|M|   The FDA states that the risk of serotonin syndrome should be weighed|
00361|021|M|against the potential benefit of concurrent therapy.  The risk of serotonin|
00361|022|M|syndrome should be discussed with the patient and the patient should be|
00361|023|M|instructed to seek immediate medical attention if they develop any signs of|
00361|024|M|serotonin syndrome.(1)|
00361|025|M|   In a 2010 statement, the American Headache Society concluded that|
00361|026|M|existing data was insufficient to support limiting concurrent use of SSRIs|
00361|027|M|or SNRIs with triptans due to concern for serotonin syndrome.  They|
00361|028|M|recommend vigilant symptom monitoring to ensure prompt evaluation and|
00361|029|M|treatment, and submission of case reports to FDA MedWatch and medical|
00361|030|M|journals.(16)|
00361|031|M|   Another group of authors concluded the risk of serotonin syndrome is low|
00361|032|M|and the advisory should be reconsidered.(17)|
00361|033|M|   If concurrent therapy is warranted, patients should be monitored for|
00361|034|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00361|035|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00361|036|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00361|037|M|coordination, or severe diarrhea.|
00361|038|B||
00361|039|D|DISCUSSION:  In a case report, a patient developed serotonin syndrome one|
00361|040|D|hour after taking sumatriptan for an acute migraine.  The patient had also|
00361|041|D|been taking sertraline for migraine prophylaxis for three months.  Over the|
00361|042|D|next month, the patient experienced five similar (but less severe) episodes|
00361|043|D|following the administration of sumatriptan.  Following the discontinuation|
00361|044|D|of sertraline, the patient experienced no side effects from sumatriptan.(18)|
00361|045|D|In another report in the same article, a patient developed serotonin|
00361|046|D|syndrome within ten minutes of a dose of sumatriptan.  The patient was also|
00361|047|D|on sertraline.  The patient experienced no side effects from sumatriptan|
00361|048|D|while on nortriptyline.(18)|
00361|049|D|   One set of authors reviewed 22 adverse event reports submitted to Eli|
00361|050|D|Lilly Canada, Inc. and found that six of the reports provided good evidence|
00361|051|D|of a probable drug-drug interaction between fluoxetine and sumatriptan.(19)|
00361|052|D|In one case report, a patient noted an increase in migraine frequency and a|
00361|053|D|decreased effectiveness of sumatriptan following the initiation of|
00361|054|D|fluoxetine.(20)|
00361|055|D|   In contrast to the above reports, a study in 14 patients reported no|
00361|056|D|adverse events in the 12 subjects who received a total of 91 doses of|
00361|057|D|sumatriptan in conjunction with a selective serotonin reuptake|
00361|058|D|inhibitor.(21)  Another study reported similar results in six subjects.(22)|
00361|059|D|Another study reported no adverse effects during concurrent sumatriptan and|
00361|060|D|paroxetine.(23)  Another study reported no significant alterations in|
00361|061|D|pharmacokinetic or pharmacodynamic parameters during concurrent zolmitriptan|
00361|062|D|and fluoxetine administration.(24)  The manufacturer of rizatriptan states|
00361|063|D|no clinical or pharmacokinetic interactions were observed during concurrent|
00361|064|D|administration with paroxetine.(8)|
00361|065|D|   The American Headache Society evaluated 40 case reports of serotonin|
00361|066|D|syndrome associated with SSRI or SNRI use. Ten of these cases met Sternbach|
00361|067|D|criteria, but none met Hunter criteria for serotonin syndrome. Given the|
00361|068|D|incomplete, inadequate, or conflicting data, the group concluded evidence|
00361|069|D|was insufficient to support limiting concurrent use of SSRIs or SNRIs with|
00361|070|D|triptans due to concern for serotonin syndrome.(16,25)|
00361|071|D|   In a retrospective review of 14 years of patient data (January 1, 2001 to|
00361|072|D|December 31, 2014) found 47,968 unique patients who were prescribed a tripan|
00361|073|D|during the study period.  Of these, 19,017 were also prescribed a SSRI or|
00361|074|D|SNRI.  The percentage of patients receiving co-therapy ranged from 21% to|
00361|075|D|29% during the study period.  There were 17 suspected cases of serotonin|
00361|076|D|syndrome during the study period; however, only 2 were classified as having|
00361|077|D|definite serotonin syndrome and 5 were classified as having possible|
00361|078|D|serotonin syndrome, for an incidence rate of 2.3 cases per 10,000|
00361|079|D|person-years of exposure.(17)|
00361|080|B||
00361|081|R|REFERENCES:|
00361|082|B||
00361|083|R|1.US Food and Drug Administration Center for Drug Evaluations and Research -|1
00361|084|R|  FDA Public Health Advisory. Combined Use of 5-Hydroxytryptamine Receptor|1
00361|085|R|  Agonists (Triptans), Selective Serotonin Reuptake Inhibitors (SSRIs) or|1
00361|086|R|  Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) May Result|1
00361|087|R|  in Life-threatening Serotonin Syndrome. available at:|1
00361|088|R|  http://wayback.archive-it.org/7993/20161022204605/http://www.fda.gov/Drugs|1
00361|089|R|  /DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm1243|1
00361|090|R|  49.htm July 19, 2006.|1
00361|091|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00361|092|R|  352(11):1112-20.|6
00361|093|R|3.Imitrex Injection (sumatriptan) US prescribing information.|1
00361|094|R|  GlaxoSmithKline December 14, 2017.|1
00361|095|R|4.Imitrex Injection/Tablets/Nasal Spray (sumatriptan) Canadian product|1
00361|096|R|  monograph. GlaxoSmithKline, Inc. May 07, 2004.|1
00361|097|R|5.Imitrex Tablets (sumatriptan) US prescribing information. GlaxoSmithKline|1
00361|098|R|  December 14, 2017.|1
00361|099|R|6.Imitrex Nasal Spray (sumatriptan) US prescribing information.|1
00361|100|R|  GlaxoSmithKline December 14, 2017.|1
00361|101|R|7.Amerge (naratriptan) US prescribing information. GlaxoSmithKline October,|1
00361|102|R|  2013.|1
00361|103|R|8.Maxalt (rizatriptan) US prescribing information. Merck & Co., Inc.|1
00361|104|R|  October, 2019.|1
00361|105|R|9.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
00361|106|R|  Pharmaceuticals LP September, 2012.|1
00361|107|R|10.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
00361|108|R|11.Effexor XR (venlafaxine hydrochloride) US prescribing information.|1
00361|109|R|   Viatris August, 2023.|1
00361|110|R|12.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
00361|111|R|   and Company September, 2021.|1
00361|112|R|13.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
00361|113|R|   and Company August, 2023.|1
00361|114|R|14.Symbyax (olanzapine and fluoxetine hydrochloride) US prescribing|1
00361|115|R|   information. Eli Lilly and Company August, 2023.|1
00361|116|R|15.Savella (milnacipran hydrochloride) US prescribing information. Forest|1
00361|117|R|   Pharmaceuticals, Inc. September, 2021.|1
00361|118|R|16.Evans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE. The FDA|6
00361|119|R|   alert on serotonin syndrome with use of triptans combined with selective|6
00361|120|R|   serotonin reuptake inhibitors or selective serotonin-norepinephrine|6
00361|121|R|   reuptake inhibitors: American Headache Society position paper. Headache|6
00361|122|R|   2010 Jun;50(6):1089-99.|6
00361|123|R|17.Orlova Y, Rizzoli P, Loder E. Association of Coprescription of Triptan|2
00361|124|R|   Antimigraine Drugs and Selective Serotonin Reuptake Inhibitor or|2
00361|125|R|   Selective Norepinephrine Reuptake Inhibitor Antidepressants With|2
00361|126|R|   Serotonin Syndrome. JAMA Neurol 2018 Feb 26.|2
00361|127|R|18.Mathew NT, Tietjen GE, Lucker C. Serotonin syndrome complicating migraine|3
00361|128|R|   pharmacotherapy. Cephalalgia 1996 Aug;16(5):323-7.|3
00361|129|R|19.Joffe RT, Sokolov ST. Co-administration of fluoxetine and sumatriptan:|3
00361|130|R|   the Canadian experience. Acta Psychiatr Scand 1997 Jun;95(6):551-2.|3
00361|131|R|20.Szabo CP. Fluoxetine and sumatriptan: possibly a counterproductive|3
00361|132|R|   combination. J Clin Psychiatry 1995 Jan;56(1):37-8.|3
00361|133|R|21.Blier P, Bergeron R. The safety of concomitant use of sumatriptan and|2
00361|134|R|   antidepressant treatments. J Clin Psychopharmacol 1995 Apr;15(2):106-9.|2
00361|135|R|22.Leung M, Ong M. Lack of an interaction between sumatriptan and selective|2
00361|136|R|   serotonin reuptake inhibitors. Headache 1995 Sep;35(8):488-9.|2
00361|137|R|23.Wing YK, Clifford EM, Sheehan BD, Campling GM, Hockney RA, Cowen PJ.|2
00361|138|R|   Paroxetine treatment and the prolactin response to sumatriptan.|2
00361|139|R|   Psychopharmacology (Berl) 1996 Apr;124(4):377-9.|2
00361|140|R|24.Smith DA, Cleary EW, Watkins S, Huffman CS, Polvino WJ. Zolmitriptan|2
00361|141|R|   (311C90) does not interact with fluoxetine in healthy volunteers. Int J|2
00361|142|R|   Clin Pharmacol Ther 1998 Jun;36(6):301-5.|2
00361|143|R|25.Evans RW. The FDA alert on serotonin syndrome with combined use of SSRIs|3
00361|144|R|   or SNRIs and Triptans: an analysis of the 29 case reports. MedGenMed|3
00361|145|R|   2007;9(3):48.|3
00362|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
00362|002|T|antagonists)/Zafirlukast|
00362|003|B||
00362|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00362|005|L|take action as needed.|
00362|006|B||
00362|007|A|MECHANISM OF ACTION:  Zafirlukast may inhibit the CYP2C9 mediated metabolism|
00362|008|A|of warfarin.(1,2)|
00362|009|B||
00362|010|E|CLINICAL EFFECTS:  Concurrent use of select anticoagulants and zafirlukast|
00362|011|E|may increase the risk for bleeding.(1)|
00362|012|B||
00362|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00362|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00362|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
00362|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00362|017|P|risk for bleeding (e.g. NSAIDs).|
00362|018|P|   Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2|
00362|019|P|copies of a reduced function VKORC1 gene are expected to be more susceptible|
00362|020|P|to this interaction.|
00362|021|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00362|022|P|are expected to be less susceptible to effects from this drug combination,|
00362|023|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00362|024|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
00362|025|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
00362|026|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to|
00362|027|P|effective and safe anticoagulation than patients without these CYP2C9|
00362|028|P|variants.|
00362|029|B||
00362|030|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with warfarin and|
00362|031|M|zafirlukast should have their prothrombin or INR values monitored closely|
00362|032|M|and their warfarin dosage adjusted accordingly.(1)|
00362|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00362|034|M|precipitant drug is initiated or discontinued.|
00362|035|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00362|036|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00362|037|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00362|038|M|patients with any symptoms.  Discontinue anticoagulation in patients with|
00362|039|M|active pathologic bleeding.|
00362|040|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00362|041|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00362|042|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00362|043|M|and/or swelling.|
00362|044|B||
00362|045|D|DISCUSSION:  In a study reported in the manufacturer's prescribing|
00362|046|D|information, the administration of a single dose of warfarin (25 mg) during|
00362|047|D|concurrent administration of steady-state zafirlukast resulted in|
00362|048|D|significant increases in the area-under-curve (AUC) and half-life (63% and|
00362|049|D|36%, respectively) of warfarin.  Prothrombin times increased 35% during|
00362|050|D|concurrent administration.(1)|
00362|051|D|     In contrast, concurrent administration of the recommended dose of|
00362|052|D|montelukast with warfarin did not result in clinically significant effects|
00362|053|D|on warfarin. (4)|
00362|054|B||
00362|055|R|REFERENCES:|
00362|056|B||
00362|057|R|1.Accolate (zafirlukast) US prescribing information. AstraZeneca|1
00362|058|R|  Pharmaceuticals LP November, 2013.|1
00362|059|R|2.This information is based on an extract from the Certara Drug Interaction|6
00362|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00362|061|R|3.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
00362|062|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
00362|063|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
00362|064|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
00362|065|R|  Oct;90(4):625-9.|6
00362|066|R|4.Singulair (montelukast) US prescribing information. Merck & Co., Inc.|1
00362|067|R|  February, 2021.|1
00363|001|T|MONOGRAPH TITLE:  CGMP Specific PDE Type-5 Inhibitors/Nitrates|
00363|002|B||
00363|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00363|004|L|is contraindicated and generally should not be dispensed or administered to|
00363|005|L|the same patient.|
00363|006|B||
00363|007|A|MECHANISM OF ACTION:  Nitrates activate guanyl cyclase, an enzyme that|
00363|008|A|increases levels of cyclic guanosine monophosphate (cGMP).  cGMP produces|
00363|009|A|smooth muscle relaxation.  Avanafil,(1) sildenafil,(2) tadalafil,(3,4) and|
00363|010|A|vardenafil (5-7) inhibit phosphodiesterase type 5 (PDE5), which is|
00363|011|A|responsible for the breakdown of cGMP.  Concurrent use of nitrates with|
00363|012|A|avanafil,(1) sildenafil,(2) tadalafil,(3,4) or vardenafil(5-7) results in|
00363|013|A|potentiation of the effect of nitrates.|
00363|014|B||
00363|015|E|CLINICAL EFFECTS:  The concurrent use of CGMP specific PDE type-5 inhibitors|
00363|016|E|and nitrates potentiates the hypotensive effects of nitrates(1-7) which may|
00363|017|E|result in dizziness, syncope, heart attack, or stroke.(4)  The concurrent|
00363|018|E|use of sildenafil and sodium nitroprusside may potentiate the|
00363|019|E|antiaggregatory effect of sodium nitroprusside in addition to increased|
00363|020|E|hypotensive effects.(2)|
00363|021|B||
00363|022|P|PREDISPOSING FACTORS:  Plasma levels of the PDE type-5 inhibitor may be|
00363|023|P|higher in the following patients:  those older than 65, with hepatic|
00363|024|P|impairment, with severe renal impairment, or using concomitant CYP3A4|
00363|025|P|inhibitors.  This may increase the severity of the interaction.|
00363|026|B||
00363|027|M|PATIENT MANAGEMENT:  The administration of avanafil to patients receiving|
00363|028|M|organic nitrates, either regularly and/or intermittently, is|
00363|029|M|contraindicated.  In a patient who has taken avanafil, at least 12 hours|
00363|030|M|should elapse after the last dose of avanafil before nitrate administration|
00363|031|M|is considered and it should only be administered under close medical|
00363|032|M|supervision with appropriate hemodynamic monitoring.(1)|
00363|033|M|   The administration of sildenafil to patients receiving organic nitrates,|
00363|034|M|either regularly and/or intermittently, in any form is contraindicated.(2)|
00363|035|M|   The administration of tadalafil to patients receiving any form of organic|
00363|036|M|nitrate, either regularly and/or intermittently, is contraindicated.(3,4)|
00363|037|M|Patients should be instructed to seek immediate medical attention if they|
00363|038|M|experience anginal chest pain following tadalafil.  In such cases where|
00363|039|M|nitrate administration is considered medically necessary, at least 48 hours|
00363|040|M|should elapse after tadalafil administration before nitrate administration|
00363|041|M|is considered.  In such cases, nitrates should only be administered under|
00363|042|M|close medical supervision with appropriate hemodynamic monitoring.(4)|
00363|043|M|   The administration of vardenafil to patients receiving nitrates or nitric|
00363|044|M|oxide donors is contraindicated.(5-7)  In patients prescribed vardenafil in|
00363|045|M|whom nitrate administration is deemed medically necessary in a|
00363|046|M|life-threatening situation, the Canadian manufacturer of vardenafil states|
00363|047|M|that at least 24 hours should have elapsed after the last dose of vardenafil|
00363|048|M|before the nitrate administration is considered.  Nitrates should only be|
00363|049|M|administered under close medical supervision with appropriate hemodynamic|
00363|050|M|monitoring.(7)|
00363|051|M|   The concomitant use of nicorandil(8) or subinguinal nitroglycerin(9) and|
00363|052|M|PDE type-5 inhibitors is contraindicated.|
00363|053|M|   Treat hypotension resulting from concurrent use as a nitrate overdose,|
00363|054|M|with elevation of the extremities and central volume expansion.(10)|
00363|055|B||
00363|056|D|DISCUSSION:  Nitrates activate guanylate cyclase, an enzyme that increases|
00363|057|D|levels of cGMP.  cGMP produces smooth muscle relaxation.  Avanafil,(1)|
00363|058|D|sildenafil,(2) tadalafil,(3,4) and vardenafil (5-7) inhibit PDE5, which is|
00363|059|D|responsible for the breakdown of cGMP.  Concurrent use of nitrates with|
00363|060|D|avanafil,(1) sildenafil,(2) tadalafil,(3,4) or vardenafil(5-7) results in|
00363|061|D|potentiation of the effect of nitrates.|
00363|062|D|   It is unknown when nitrates, if necessary, can be safely administered to|
00363|063|D|patients who have taken CGMP specific PDE type-5 inhibitors.  Following a|
00363|064|D|single 100 mg oral dose of sildenafil, peak plasma levels are approximately|
00363|065|D|440 ng/mL and levels 24 hours post dose are approximately 2 ng/ml.|
00363|066|D|Sildenafil plasma levels at 24 hours post dose are three to eight times|
00363|067|D|higher in the following patients:  those age greater than 65, those with|
00363|068|D|hepatic impairment, those with severe renal impairment (creatinine clearance|
00363|069|D|less than 30 ml/min), and those with concomitant use of potent CYP P-450-3A4|
00363|070|D|inhibitors (erythromycin).  Although plasma levels of sildenafil are lower|
00363|071|D|at 24 hours post dose, the manufacturer of sildenafil states that it is|
00363|072|D|still unknown whether nitrates can safely be coadministered at that time.(2)|
00363|073|D|   In vitro studies with human platelets have shown that sildenafil|
00363|074|D|potentiates the antiaggregatory effect of sodium nitroprusside.(2)|
00363|075|D|   In a study of 150 subjects who received tadalafil (20 mg) daily for 7|
00363|076|D|days, sublingual nitroglycerin was administered at 2, 4, 8, 24, 48, 72, and|
00363|077|D|96 hours after tadalafil.  A significant interaction between tadalafil and|
00363|078|D|nitroglycerin was observed up to and including 24 hours post-tadalafil.  At|
00363|079|D|48 hours, the interaction was not observed by most hemodynamic measures.|
00363|080|D|After 48 hours, the interaction was not detectable.(4)|
00363|081|D|   In a population-based cohort study of 61,487 men who received nitrates,|
00363|082|D|5,710 (9%) concurrently received PDE Type-5 inhibitors (PDE5i).  Crude|
00363|083|D|hazard ratios found a significant and inverse association between|
00363|084|D|combination use of nitrates and PDE5i and all cause, cardiovascular, and|
00363|085|D|non-cardiovascular mortality.  All-cause mortality incidence rates were 2.69|
00363|086|D|cases per 100 person-years for the nitrate and PDE5i group vs 3.83 cases per|
00363|087|D|100 person-years in the nitrate-only group.  Concurrent use of nitrates and|
00363|088|D|PDE5i found a multivariate adjusted HR for all-cause mortality of 1.39 (95%|
00363|089|D|CI: 1.28-1.51).  Concurrent use of nitrates and PDE5i found an adjusted HR|
00363|090|D|for cardiovascular death, non-cardiovascular death, myocardial infarction,|
00363|091|D|heart failure, revascularization, and major adverse cardiovascular event|
00363|092|D|(MACE) in patients treated with both nitrates and PDE5i was 1.34 (95% CI:|
00363|093|D|1.11-1.62), 1.40 (95% CI: 1.27-1.54), 1.72 (95% CI: 1.55-1.90), 1.67 (95%|
00363|094|D|CI: 1.48-1.90), 1.95 (95% CI: 1.78-2.13), and 1.70 (95% CI: 1.58-1.83),|
00363|095|D|respectively, compared with patients with nitrates only.(11)|
00363|096|B||
00363|097|R|REFERENCES:|
00363|098|B||
00363|099|R|1.Stendra (avanafil) US prescribing information. Vivus, Inc. October, 2022.|1
00363|100|R|2.Viagra (sildenafil) US prescribing information. Pfizer Inc. December 14,|1
00363|101|R|  2017.|1
00363|102|R|3.Cialis (tadalafil) UK summary of product characteristics. Eli Lilly and|1
00363|103|R|  Company Limited September 16, 2008.|1
00363|104|R|4.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
00363|105|R|  February, 2018.|1
00363|106|R|5.Levitra (vardenafil hydrochloride trihydrate) UK summary of product|1
00363|107|R|  characteristics. Bayer plc December 20, 2006.|1
00363|108|R|6.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
00363|109|R|  Pharmaceuticals Corporation March, 2023.|1
00363|110|R|7.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
00363|111|R|  Bayer, Inc. October 24, 2006.|1
00363|112|R|8.Ikorel (nicorandil) Australian prescribing information. Aventis Pharma|1
00363|113|R|  August 13, 2003.|1
00363|114|R|9.Imdur (isosorbide mononitrate) US prescribing information. Key|1
00363|115|R|  Pharmaceuticals, Inc. July, 2002.|1
00363|116|R|10.Nitrostat (nitroglycerin) US prescribing information. Pfizer January 24,|1
00363|117|R|   2018.|1
00363|118|R|11.Trolle Lagerros Y, Grotta A, Freyland S, Grannas D, Andersson DP. Risk of|2
00363|119|R|   Death in Patients With Coronary Artery Disease Taking Nitrates and|2
00363|120|R|   Phosphodiesterase-5 Inhibitors. J Am Coll Cardiol 2024 Jan 23;|2
00363|121|R|   83(3):417-426.|2
00364|001|T|MONOGRAPH TITLE:  Vardenafil (Greater Than 2.5 mg)/Strong CYP3A4 Inhibitors|
00364|002|B||
00364|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00364|004|L|is contraindicated and generally should not be dispensed or administered to|
00364|005|L|the same patient.|
00364|006|B||
00364|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
00364|008|A|vardenafil.(1-3)|
00364|009|B||
00364|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
00364|011|E|increased levels, clinical effects, and side effects of vardenafil.(1-3)|
00364|012|B||
00364|013|P|PREDISPOSING FACTORS:  None determined.|
00364|014|B||
00364|015|M|PATIENT MANAGEMENT:  The US manufacturer of vardenafil states that a maximum|
00364|016|M|dose of 2.5 mg of vardenafil every 24 hours should not be exceeded in|
00364|017|M|patients taking strong CYP3A4 inhibitors.(1)|
00364|018|M|   Note that other countries have different warnings.  The Canadian(3) and|
00364|019|M|UK(3) manufacturer of vardenafil state that vardenafil should not exceed 5|
00364|020|M|mg in patients taking clarithromycin.  The UK manufacturer of vardenafil|
00364|021|M|states that the concurrent use of vardenafil with strong CYP3A4 inhibitors|
00364|022|M|should be avoided.(3)|
00364|023|M|   The US manufacturer of cobicistat states that a maximum dose of 2.5 mg of|
00364|024|M|vardenafil every 72 hours should not be exceeded in patients taking|
00364|025|M|cobicistat.(4)|
00364|026|B||
00364|027|D|DISCUSSION:  Concurrent use of ketoconazole (200 mg, a strong inhibitor of|
00364|028|D|CYP3A4) with vardenafil (5 mg) increased the vardenafil area-under-curve|
00364|029|D|(AUC) and maximum concentration (Cmax) by 10-fold and 4-fold,|
00364|030|D|respectively.(1-3)|
00364|031|D|   Concurrent administration of erythromycin (500 mg three times daily, a|
00364|032|D|moderate inhibitor of CYP3A4) with vardenafil (5 mg) increased the AUC and|
00364|033|D|Cmax of vardenafil by 4-fold and 3-fold, respectively.(1-3)|
00364|034|B||
00364|035|R|REFERENCES:|
00364|036|B||
00364|037|R|1.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
00364|038|R|  Pharmaceuticals Corporation March, 2023.|1
00364|039|R|2.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
00364|040|R|  Bayer, Inc. October 24, 2006.|1
00364|041|R|3.Levitra (vardenafil hydrochloride trihydrate) UK summary of product|1
00364|042|R|  characteristics. Bayer plc December 20, 2006.|1
00364|043|R|4.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
00364|044|R|  June, 2025.|1
00365|001|T|MONOGRAPH TITLE:  Sildenafil (for ED); Tadalafil (for ED)/Selected Strong|
00365|002|T|CYP3A4 Inhibitors|
00365|003|B||
00365|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00365|005|L|take action as needed.|
00365|006|B||
00365|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
00365|008|A|sildenafil(1) and tadalafil.(2)|
00365|009|B||
00365|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
00365|011|E|increased levels, clinical effects, and side effects of sildenafil(1) and|
00365|012|E|tadalafil.(2)|
00365|013|B||
00365|014|P|PREDISPOSING FACTORS:  None determined.|
00365|015|B||
00365|016|M|PATIENT MANAGEMENT:  The US manufacturer of sildenafil recommends a starting|
00365|017|M|dose of 25 mg of sildenafil for erectile dysfunction in patients receiving|
00365|018|M|concomitant therapy with strong CYP3A4 inhibitors.(1)|
00365|019|M|   The US manufacturer of tadalafil states that the maximum recommended dose|
00365|020|M|of as needed tadalafil for erectile dysfunction in patients taking strong|
00365|021|M|inhibitors of CYP3A4 is 10 mg every 72 hours.(2)  The maximum recommended|
00365|022|M|dose of daily tadalafil for erectile dysfunction in patients taking strong|
00365|023|M|inhibitors of CYP3A4 is 2.5 mg.(3)|
00365|024|M|   The US manufacturer of tadalafil chewable tablets (Chewtadzy) states the|
00365|025|M|maximum recommended dose of as needed tadalafil for erectile dysfunction in|
00365|026|M|patients taking strong CYP3A4 inhibitors is 10 mg every 72 hours.  The use|
00365|027|M|of tadalafil chewable tablets (Chewtazdy) for once daily use for erectile|
00365|028|M|dysfunction or benign prostatic hyperplasia (BPH) is not recommended in|
00365|029|M|patients taking strong CYP3A4 inhibitors due to the lack of a 2.5 mg tablet|
00365|030|M|strength.(3)|
00365|031|B||
00365|032|D|DISCUSSION:  Concurrent administration of a single 100 mg dose of sildenafil|
00365|033|D|with erythromycin (500 mg twice daily for five days) resulted in an increase|
00365|034|D|of sildenafil area-under-curve (AUC) by 182%.  Therefore, the manufacturer|
00365|035|D|of sildenafil recommends a starting dose of 25 mg of sildenafil in patients|
00365|036|D|receiving concomitant therapy with other strong CYP3A4 inhibitors such as|
00365|037|D|itraconazole or ketoconazole.(1)|
00365|038|D|   Concurrent administration of a single 20 mg dose of tadalafil with|
00365|039|D|ketoconazole (400 mg daily) increased tadalafil AUC and maximum|
00365|040|D|concentration (Cmax) by 312% and 22%, respectively.  Concurrent|
00365|041|D|administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg|
00365|042|D|daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(2)|
00365|043|D|   Strong CYP3A4 inhibitors include adagrasib, ceritinib, clarithromycin,|
00365|044|D|grapefruit, idelalisib, itraconazole, josamycin, ketoconazole,|
00365|045|D|levoketoconazole, lonafarnib, nefazodone, posaconazole, ribociclib,|
00365|046|D|telithromycin, tucatinib, and voriconazole.(4,5)|
00365|047|B||
00365|048|R|REFERENCES:|
00365|049|B||
00365|050|R|1.Viagra (sildenafil) US prescribing information. Pfizer Inc. December 14,|1
00365|051|R|  2017.|1
00365|052|R|2.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
00365|053|R|  February, 2018.|1
00365|054|R|3.Chewtadzy (tadalafil chewable tablets) US prescribing information. ANI|1
00365|055|R|  Pharmaceuticals, Inc. June, 2024.|1
00365|056|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
00365|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
00365|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
00365|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
00365|060|R|  11/14/2017.|1
00365|061|R|5.This information is based on an extract from the Certara Drug Interaction|6
00365|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00366|001|T|MONOGRAPH TITLE:  Sildenafil/Mibefradil|
00366|002|B||
00366|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00366|004|L|take action as needed.|
00366|005|B||
00366|006|A|MECHANISM OF ACTION:  Mibefradil may inhibit the metabolism of sildenafil at|
00366|007|A|CYP P-450-3A4.(1)|
00366|008|B||
00366|009|E|CLINICAL EFFECTS:  Concurrent use may result in increased levels, clinical|
00366|010|E|effects, and side effects of sildenafil.(1)|
00366|011|B||
00366|012|P|PREDISPOSING FACTORS:  None determined.|
00366|013|B||
00366|014|M|PATIENT MANAGEMENT:  The manufacturer of sildenafil recommends a starting|
00366|015|M|dose of 25 mg of sildenafil in patients receiving concomitant therapy with|
00366|016|M|potent CYP P-450-3A4 inhibitors such as mibefradil.(1)|
00366|017|B||
00366|018|D|DISCUSSION:  Concurrent administration of a single, 100 mg dose of|
00366|019|D|sildenafil with erythromycin (500 mg twice daily for five days) resulted in|
00366|020|D|an increase of sildenafil area-under-curve (AUC) by 182%.  Therefore, the|
00366|021|D|manufacturer of sildenafil recommends a starting dose of 25 mg of sildenafil|
00366|022|D|in patients receiving concomitant therapy with other potent CYP P-450-3A4|
00366|023|D|inhibitors such as mibefradil.(1)|
00366|024|B||
00366|025|R|REFERENCE:|
00366|026|B||
00366|027|R|1.Viagra (sildenafil) US prescribing information. Pfizer Inc. March, 1998.|1
00367|001|T|MONOGRAPH TITLE:  Selected Macrolides/Selected HMG-CoA Reductase Inhibitors|
00367|002|B||
00367|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00367|004|L|is contraindicated and generally should not be dispensed or administered to|
00367|005|L|the same patient.|
00367|006|B||
00367|007|A|MECHANISM OF ACTION:  The macrolides may inhibit the metabolism of the|
00367|008|A|HMG-CoA reductase inhibitors by CYP3A4.|
00367|009|B||
00367|010|E|CLINICAL EFFECTS:  Concurrent therapy may result in increased levels of the|
00367|011|E|HMG-CoA reductase inhibitors, which may produce rhabdomyolysis.  Symptoms of|
00367|012|E|rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine|
00367|013|E|kinase levels, and reddish-brown, heme positive urine.|
00367|014|B||
00367|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
00367|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
00367|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
00367|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
00367|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
00367|020|P|transporter OATP1B1 may have increased statin concentrations and be|
00367|021|P|predisposed to myopathy or rhabdomyolysis.|
00367|022|B||
00367|023|M|PATIENT MANAGEMENT:  The concurrent administration of lovastatin(1) or|
00367|024|M|simvastatin(2,3) with clarithromycin or erythromycin is contraindicated.|
00367|025|M|   If treatment with clarithromycin or erythromycin is required, suspend|
00367|026|M|lovastatin or simvastatin therapy during antibiotic use.|
00367|027|B||
00367|028|D|DISCUSSION:  Concurrent administration of cerivastatin and erythromycin to|
00367|029|D|patients with hypercholesterolemia resulted in increases in cerivastatin|
00367|030|D|steady state AUC and Cmax by 50% and 24%, respectively.(4)  In a study in 12|
00367|031|D|healthy subjects, pretreatment with seven days of erythromycin resulted in|
00367|032|D|increases in the AUC and Cmax of a single dose of cerivastatin (300 mcg) by|
00367|033|D|21% and 13%, respectively.(5)  An in-vitro study in human liver microsomes|
00367|034|D|showed that the metabolism of cerivastatin was inhibited by|
00367|035|D|troleandomycin.(6)|
00367|036|D|   In a study in 12 healthy subjects, pretreatment with erythromycin|
00367|037|D|increased the Cmax and AUC of a single dose of simvastatin by 3.4-fold and|
00367|038|D|6.2-fold, respectively.  Pretreatment with erythromycin also increased the|
00367|039|D|Cmax and AUC of simvastatin acid by 5.0-fold and 3.9-fold, respectively.(7)|
00367|040|D|   In a study in healthy subjects, clarithromycin increased the AUC of|
00367|041|D|simvastatin, atorvastatin, and pravastatin by 10-fold, greater than 4-fold,|
00367|042|D|and almost 2-fold, respectively.(8)|
00367|043|D|   There are several case reports of patients developing rhabdomyolysis|
00367|044|D|(characterized by myalgia, weakness, elevated creatine kinase levels, and|
00367|045|D|heme positive urine) following the addition of erythromycin to lovastatin|
00367|046|D|therapy.(9-13)  Another article reported two cases of rhabdomyolysis, one|
00367|047|D|following the addition of clarithromycin to lovastatin therapy and the other|
00367|048|D|following the addition of azithromycin to lovastatin therapy.(14)|
00367|049|D|   One patient developed rhabdomyolysis and severe myopathy after treatment|
00367|050|D|with roxithromycin and combination simvastatin and gemfibrozil.(15)|
00367|051|D|   One or more of the drug pairs linked to this monograph have been included|
00367|052|D|in a list of interactions that should be considered "high-priority" for|
00367|053|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00367|054|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00367|055|D|Coordinator (ONC) for Health Information Technology.|
00367|056|B||
00367|057|R|REFERENCES:|
00367|058|B||
00367|059|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
00367|060|R|  February, 2014.|1
00367|061|R|2.USFood and Drug Administration. FDA Drug Safety Communication: New|1
00367|062|R|  restrictions, contraindications, and dose limitations for Zocor|1
00367|063|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
00367|064|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
00367|065|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
00367|066|R|  June 8, 2011.|1
00367|067|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
00367|068|R|  2023.|1
00367|069|R|4.Baycol (cerivastatin) US prescribing information. Bayer Corporation|1
00367|070|R|  December, 2000.|1
00367|071|R|5.Muck W, Ochmann K, Rohde G, Unger S, Kuhlmann J. Influence of erythromycin|2
00367|072|R|  pre- and co-treatment on single-dose pharmacokinetics of the HMG-CoA|2
00367|073|R|  reductase inhibitor cerivastatin. Eur J Clin Pharmacol 1998 Feb;|2
00367|074|R|  53(6):469-73.|2
00367|075|R|6.Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, Ploschke J,|5
00367|076|R|  Radtke M. Metabolism of cerivastatin by human liver microsomes in vitro.|5
00367|077|R|  Characterization of primary metabolic pathways and of cytochrome P450|5
00367|078|R|  isozymes involved. Drug Metab Dispos 1997 Mar;25(3):321-31.|5
00367|079|R|7.Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil|2
00367|080|R|  considerably increase serum simvastatin and simvastatin acid|2
00367|081|R|  concentrations. Clin Pharmacol Ther 1998 Aug;64(2):177-82.|2
00367|082|R|8.Jacobson TA. Comparative pharmacokinetic interaction profiles of|2
00367|083|R|  pravastatin, simvastatin, and atorvastatin when coadministered with|2
00367|084|R|  cytochrome P450 inhibitors. Am J Cardiol 2004 Nov 1;94(9):1140-6.|2
00367|085|R|9.Ayanian JZ, Fuchs CS, Stone RM. Lovastatin and rhabdomyolysis. Ann Intern|3
00367|086|R|  Med 1988 Oct 15;109(8):682-3.|3
00367|087|R|10.Spach DH, Bauwens JE, Clark CD, Burke WG. Rhabdomyolysis associated with|3
00367|088|R|   lovastatin and erythromycin use. West J Med 1991 Feb;154(2):213-5.|3
00367|089|R|11.Corpier CL, Jones PH, Suki WN, Lederer ED, Quinones MA, Schmidt SW, Young|3
00367|090|R|   JB. Rhabdomyolysis and renal injury with lovastatin use. Report of two|3
00367|091|R|   cases in cardiac transplant recipients. JAMA 1988 Jul 8;260(2):239-41.|3
00367|092|R|12.Lilley LL, Guanci R. Drug interaction triggers weakness. Am J Nurs 1998|3
00367|093|R|   Apr;98(4):10.|3
00367|094|R|13.Wong PW, Dillard TA, Kroenke K. Multiple organ toxicity from addition of|3
00367|095|R|   erythromycin to long-term lovastatin therapy. South Med J 1998 Feb;|3
00367|096|R|   91(2):202-5.|3
00367|097|R|14.Grunden JW, Fisher KA. Lovastatin-induced rhabdomyolysis possibly|3
00367|098|R|   associated with clarithromycin and azithromycin. Ann Pharmacother 1997|3
00367|099|R|   Jul-Aug;31(7-8):859-63.|3
00367|100|R|15.Huynh T, Cordato D, Yang F, Choy T, Johnstone K, Bagnall F, Hitchens N,|3
00367|101|R|   Dunn R. HMG CoA reductase-inhibitor-related myopathy and the influence of|3
00367|102|R|   drug interactions. Intern Med J 2002 Sep-Oct;32(9-10):486-90.|3
00367|103|R|16.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00367|104|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00367|105|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00367|106|R|   19(5):735-43.|6
00368|001|T|MONOGRAPH TITLE:  Mizolastine/Selected Class I & III Antiarrhythmics|
00368|002|B||
00368|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00368|004|L|is contraindicated and generally should not be dispensed or administered to|
00368|005|L|the same patient.|
00368|006|B||
00368|007|A|MECHANISM OF ACTION:  Unknown.  Possibly additive or synergistic effects on|
00368|008|A|the QTc interval.|
00368|009|B||
00368|010|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in|
00368|011|E|life-threatening arrhythmias such as torsades de pointes.|
00368|012|B||
00368|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00368|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00368|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00368|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00368|017|P|female gender, or advanced age.(2)|
00368|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00368|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00368|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00368|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00368|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00368|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00368|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00368|025|B||
00368|026|M|PATIENT MANAGEMENT:  Concurrent administration of mizolastine with agents|
00368|027|M|known to prolong the QT interval such as the Class I (disopyramide,|
00368|028|M|encainide, flecainide, procainamide, propafenone, quinidine) or Class III|
00368|029|M|(amiodarone, bretylium, ibutilide, sotalol) antiarrhythmic agents is|
00368|030|M|contraindicated by the manufacturer of mizolastine.(1)|
00368|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00368|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00368|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00368|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00368|035|B||
00368|036|D|DISCUSSION:  There is no published documentation to support this potential|
00368|037|D|drug interaction.  The product information for mizolastine states that|
00368|038|D|because mizolastine has a weak potential to prolong the QTc interval,|
00368|039|D|concurrent administration of mizolastine with drugs known to prolong the QTc|
00368|040|D|interval is contraindicated.(1)|
00368|041|B||
00368|042|R|REFERENCES:|
00368|043|B||
00368|044|R|1.Mizollen (mizolastine) US prescribing information. Lorex Synthelab|1
00368|045|R|  September 29, 1997.|1
00368|046|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00368|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00368|048|R|  settings: a scientific statement from the American Heart Association and|6
00368|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00368|050|R|  2;55(9):934-47.|6
00369|001|T|MONOGRAPH TITLE:  Armodafinil; Modafinil/Steroidal Contraceptives|
00369|002|B||
00369|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00369|004|L|of severe adverse interaction.|
00369|005|B||
00369|006|A|MECHANISM OF ACTION:  Modafinil may induce the CYP3A4 mediated metabolism of|
00369|007|A|the steroidal contraceptive.(1-3)  Armodafinil is the R-enantiomer of|
00369|008|A|modafinil.(4)|
00369|009|B||
00369|010|E|CLINICAL EFFECTS:  Armodafinil(4) or modafinil(1-3) may result in decreased|
00369|011|E|levels of steroidal contraceptives and possibly decreased effectiveness of|
00369|012|E|the contraceptive agent during and one(1,4) to two(2-3) months following|
00369|013|E|armodafinil or modafinil therapy.|
00369|014|B||
00369|015|P|PREDISPOSING FACTORS:  None determined.|
00369|016|B||
00369|017|M|PATIENT MANAGEMENT:  The United Kingdom manufacturer of modafinil states|
00369|018|M|that when oral contraceptives are used concurrently with modafinil, a|
00369|019|M|product containing 50 mcg or more of ethinyl estradiol should be used.|
00369|020|M|Adequate contraception requires continuation of the oral contraceptive two|
00369|021|M|months after the discontinuation of modafinil.(2)|
00369|022|M|   The Australian manufacturer of modafinil states that alternative or|
00369|023|M|concomitant methods of contraception are recommended for patients on|
00369|024|M|modafinil until 2 months after discontinuation of modafinil.(3)|
00369|025|M|   The United States manufacturer of armodafinil(4) and modafinil(1) states|
00369|026|M|that because the effectiveness of steroidal contraceptives may be decreased|
00369|027|M|during concurrent therapy, alternative or concomitant methods of|
00369|028|M|contraception are recommended during therapy and for one month following|
00369|029|M|discontinuation of armodafinil or modafinil.|
00369|030|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
00369|031|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
00369|032|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
00369|033|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
00369|034|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
00369|035|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
00369|036|M|and to seek medical advice if they do become pregnant.(5)|
00369|037|B||
00369|038|D|DISCUSSION:  Modafinil is contraindicated during pregnancy and may induce|
00369|039|D|the metabolism of oral,(2) depot, and implantable(1) contraceptives, thus|
00369|040|D|decreasing their effectiveness.|
00369|041|D|   A placebo-controlled, single-blind study in 41 females evaluated the|
00369|042|D|effect of modafinil on the pharmacokinetics of ethinyl estradiol.  The study|
00369|043|D|subjects were controlled on long-term oral contraceptive treatment (0.035 mg|
00369|044|D|ethinyl estradiol) and norgestimate (0.180-0.250 mg). Pharmacokinetic|
00369|045|D|profiles were obtained for ethinyl estradiol on the day before initiation|
00369|046|D|and on the last day of modafinil (200 mg for 7 days, then 400 mg for 21|
00369|047|D|days) or placebo (28 days).  A small, but significant decrease in the|
00369|048|D|ethinyl estradiol area-under-curve (AUC) by 18%, and maximum concentration|
00369|049|D|(Cmax) by 11% were reported.(6)|
00369|050|B||
00369|051|R|REFERENCES:|
00369|052|B||
00369|053|R|1.Provigil (modafinil) US prescribing information. Cephalon, Inc. October,|1
00369|054|R|  2010.|1
00369|055|R|2.Provigil (modafinil) UK summary of product characteristics. Cephalon UK|1
00369|056|R|  Ltd. December 10, 1997.|1
00369|057|R|3.Modavigil (modafinil) Australian Product Information. Teva Pharma|1
00369|058|R|  Australia Pty Limited February, 2020.|1
00369|059|R|4.Nuvigil (armodafinil) US prescribing information. Cephalon, Inc. October,|1
00369|060|R|  2010.|1
00369|061|R|5.Medicines and Healthcare products Regulatory Agency.|1
00369|062|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
00369|063|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
00369|064|R|  available at:|1
00369|065|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
00369|066|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
00369|067|R|  -and-contraceptive-efficacy September 15, 2016..|1
00369|068|R|6.Robertson P Jr, Hellriegel ET, Arora S, Nelson M. Effect of modafinil on|2
00369|069|R|  the pharmacokinetics of ethinyl estradiol and triazolam in healthy|2
00369|070|R|  volunteers. Clin Pharmacol Ther 2002 Jan;71(1):46-56.|2
00370|001|T|MONOGRAPH TITLE:  Arbutamine/Selected Antiarrhythmics|
00370|002|B||
00370|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00370|004|L|is contraindicated and generally should not be dispensed or administered to|
00370|005|L|the same patient.|
00370|006|B||
00370|007|A|MECHANISM OF ACTION:  Arbutamine may have additive or synergistic effects on|
00370|008|A|the proarrhythmic effects of these agents.(1)|
00370|009|B||
00370|010|E|CLINICAL EFFECTS:  Concurrent use may result in precipitation or|
00370|011|E|exacerbation of supraventricular and ventricular arrhythmias.(1)|
00370|012|B||
00370|013|P|PREDISPOSING FACTORS:  Possibly a history of sustained supraventricular or|
00370|014|P|ventricular arrhythmias.(1)|
00370|015|B||
00370|016|M|PATIENT MANAGEMENT:  The manufacturer of arbutamine states that arbutamine|
00370|017|M|should not be administered with Class I antiarrhythmics such as flecainide,|
00370|018|M|lidocaine, and quinidine or with digoxin.(1)|
00370|019|B||
00370|020|D|DISCUSSION:  Because arbutamine may precipitate or exacerbate|
00370|021|D|supraventricular or ventricular arrhythmias, the manufacturer of arbutamine|
00370|022|D|states that it should not be administered with proarrhythmic agents such as|
00370|023|D|Class I antiarrhythmics such as flecainide, lidocaine, or quinidine.(1)  The|
00370|024|D|manufacturer of arbutamine also states that it should not be administered|
00370|025|D|with digoxin.(1)|
00370|026|D|     There is no published documentation for this interaction.|
00370|027|B||
00370|028|R|REFERENCE:|
00370|029|B||
00370|030|R|1.Genesa (arbutamine) US prescribing information. Gensia Automedics August,|1
00370|031|R|  1997.|1
00371|001|T|MONOGRAPH TITLE:  Arbutamine/Atropine|
00371|002|B||
00371|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00371|004|L|is contraindicated and generally should not be dispensed or administered to|
00371|005|L|the same patient.|
00371|006|B||
00371|007|A|MECHANISM OF ACTION:  Arbutamine is a potent non-selective beta-adrenoceptor|
00371|008|A|agonist with mild alpha 1-sympathomimetic activity, resulting in increased|
00371|009|A|heart rate and contractility.(2,4)  Atropine is an antimuscarinic agent|
00371|010|A|which blocks acetylcholine from binding to its receptors, thus increasing|
00371|011|A|heart rate.(3)|
00371|012|B||
00371|013|E|CLINICAL EFFECTS:  Concurrent use may interfere with the determination of|
00371|014|E|the correct dose of arbutamine(1) and may lead to increased chronotropic|
00371|015|E|effect.(4)|
00371|016|B||
00371|017|P|PREDISPOSING FACTORS:  None determined.|
00371|018|B||
00371|019|M|PATIENT MANAGEMENT:  The manufacturer of arbutamine states that arbutamine|
00371|020|M|should not be administered with atropine.  The manufacturer does not|
00371|021|M|recommend the use of atropine to enhance the patient's response to|
00371|022|M|arbutamine.(1)|
00371|023|B||
00371|024|D|DISCUSSION:  Because the dosing of arbutamine is based on the heart rate|
00371|025|D|response of the patient, the manufacturer does not recommend the use of|
00371|026|D|atropine to enhance the response of the patient to arbutamine.  The|
00371|027|D|manufacturer states that arbutamine should not be administered with|
00371|028|D|atropine.(1)|
00371|029|B||
00371|030|R|REFERENCES:|
00371|031|B||
00371|032|R|1.Genesa (arbutamine) US prescribing information. Gensia Automedics August,|1
00371|033|R|  1997.|1
00371|034|R|2.Shehata AR, Ahlberg AW, Gillam LD, Mascitelli VA, Piriz JM, Fleming RA,|2
00371|035|R|  Chen C, Waters DD, Heller GV. Direct comparison of arbutamine and|2
00371|036|R|  dobutamine stress testing with myocardial perfusion imaging and|2
00371|037|R|  echocardiography in patients with coronary artery disease. Am J Cardiol|2
00371|038|R|  1997 Sep 15;80(6):716-20.|2
00371|039|R|3.Wilson ME, Lee GK, Chandra A, Kane GC. Central anticholinergic syndrome|3
00371|040|R|  following dobutamine-atropine stress echocardiography. Echocardiography|3
00371|041|R|  2011 Nov;28(10):E205-6.|3
00371|042|R|4.Ketteler T, Krahwinkel W, Wolfertz J, Godke J, Hoffmeister T, Scheuble L,|6
00371|043|R|  Gulker H. Arbutamine stress echocardiography. Eur Heart J 1997 Jun;18|6
00371|044|R|  Suppl D:D24-30.|6
00372|001|T|MONOGRAPH TITLE:  Arbutamine/Tricyclic Compounds|
00372|002|B||
00372|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00372|004|L|is contraindicated and generally should not be dispensed or administered to|
00372|005|L|the same patient.|
00372|006|B||
00372|007|A|MECHANISM OF ACTION:  The exact mechanism of the interaction is unknown.|
00372|008|B||
00372|009|E|CLINICAL EFFECTS:  The exact clinical effects are not stated.(1)|
00372|010|B||
00372|011|P|PREDISPOSING FACTORS:  None determined.|
00372|012|B||
00372|013|M|PATIENT MANAGEMENT:  The manufacturer of arbutamine states that arbutamine|
00372|014|M|should not be administered with tricyclic antidepressants.(1)|
00372|015|B||
00372|016|D|DISCUSSION:  The manufacturer of arbutamine states that arbutamine should|
00372|017|D|not be administered with tricyclic antidepressants.(1)|
00372|018|D|     There is no published documentation for this interaction.|
00372|019|B||
00372|020|R|REFERENCE:|
00372|021|B||
00372|022|R|1.Genesa (arbutamine) US prescribing information. Gensia Automedics August,|1
00372|023|R|  1997.|1
00373|001|T|MONOGRAPH TITLE:  Arbutamine/Beta-Blockers|
00373|002|B||
00373|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00373|004|L|is contraindicated and generally should not be dispensed or administered to|
00373|005|L|the same patient.|
00373|006|B||
00373|007|A|MECHANISM OF ACTION:  Beta-blockers antagonize the effects of arbutamine, a|
00373|008|A|beta-agonist.(1)|
00373|009|B||
00373|010|E|CLINICAL EFFECTS:  Concurrent use of arbutamine and beta-blockers may|
00373|011|E|attenuate the response to arbutamine.(1)|
00373|012|B||
00373|013|P|PREDISPOSING FACTORS:  None determined.|
00373|014|B||
00373|015|M|PATIENT MANAGEMENT:  The manufacturer of arbutamine states that|
00373|016|M|beta-blockers should be withdrawn at least 48 hours prior to the use of|
00373|017|M|arbutamine.(1)|
00373|018|B||
00373|019|D|DISCUSSION:  Because beta-blockers may antagonize the effects of arbutamine,|
00373|020|D|a beta-agonist, the manufacturer of arbutamine states that beta-blockers|
00373|021|D|should be withdrawn at least 48 hours prior to the use of arbutamine.(1)|
00373|022|D|     There is no published documentation for this interaction.|
00373|023|B||
00373|024|R|REFERENCE:|
00373|025|B||
00373|026|R|1.Genesa (arbutamine) US prescribing information. Gensia Automedics August,|1
00373|027|R|  1997.|1
00374|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Contraceptives|
00374|002|B||
00374|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00374|004|L|of severe adverse interaction.|
00374|005|B||
00374|006|A|MECHANISM OF ACTION:  Ritonavir-boosted protease inhibitors(1-10),|
00374|007|A|fosamprenavir(1), and nelfinavir(2) may induce the metabolism of estrogens.|
00374|008|A|Unboosted atazanavir may inhibit the metabolism of estrogens and|
00374|009|A|progestins.(3)|
00374|010|B||
00374|011|E|CLINICAL EFFECTS:  Concurrent use of ritonavir-boosted protease inhibitors|
00374|012|E|may result in decreased levels and effectiveness of estrogen and increased|
00374|013|E|levels of progestins, which may increase the risk of insulin resistance,|
00374|014|E|dyslipidemia, and acne.(1-10)  Additionally, concurrent use of|
00374|015|E|atazanavir-cobicistat with drospirenone-containing contraceptives may result|
00374|016|E|in elevated levels of and effects from drospirenone, including|
00374|017|E|hyperkalemia.(4)|
00374|018|E|   Atazanavir alone may result in elevated levels of estrogens.(3)|
00374|019|E|   Hormonal contraceptives may decrease the effectiveness of|
00374|020|E|fosamprenavir.(1)  Elevated liver enzymes may also occur.(1)|
00374|021|E|   Concurrent use with tipranavir may increase the risk of rash.(5)|
00374|022|B||
00374|023|P|PREDISPOSING FACTORS:  None determined.|
00374|024|B||
00374|025|M|PATIENT MANAGEMENT:  The US Department of Health and Human Services (DHHS)|
00374|026|M|HIV guidelines recommend that concurrent use of oral contraceptives with|
00374|027|M|atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir be done|
00374|028|M|with a contraceptive product that contains at least 35 mcg ethinyl|
00374|029|M|estradiol.  If atazanavir is used without ritonavir, limit the dose of|
00374|030|M|ethinyl estradiol to 30 mcg.  Atazanavir/cobistat is contraindicated with|
00374|031|M|drospirenone-containing products.  No dose adjustment is needed when|
00374|032|M|atazanavir/cobicistat is used with other oral contraceptives.(11)|
00374|033|M|   Most manufacturer recommendations differ from the DHHS guidelines.|
00374|034|M|   The manufacturer of atazanavir states that if an oral contraceptive agent|
00374|035|M|containing either norgestimate or norethindrone is used with atazanavir|
00374|036|M|without ritonavir, the contraceptive should contain no more than 30 mcg of|
00374|037|M|ethinyl estradiol.  These agents should be used with caution.  Oral|
00374|038|M|contraceptives containing progestins other than norethindrone or|
00374|039|M|norgestimate and hormonal contraceptives other than oral (e.g. patches,|
00374|040|M|rings, injections) have not been studied with atazanavir (boosted or|
00374|041|M|unboosted), and alternative contraceptive methods are recommended.(3,4)|
00374|042|M|   The manufacturers of fosamprenavir,(1) darunavir,(5) and tipranavir(6)|
00374|043|M|state that alternate methods of non-hormonal contraception are recommended.|
00374|044|M|   The manufacturers of the combination of lopinavir and ritonavir,(7)|
00374|045|M|nelfinavir,(2) ritonavir,(8) and saquinavir(9) state that additional or|
00374|046|M|alternate methods of contraception should be used in patients receiving|
00374|047|M|these agents.|
00374|048|M|   The manufacturer of nirmatrelvir/ritonavir states that a non-hormonal|
00374|049|M|method of contraception should be considered during nirmatrelvir/ritonavir|
00374|050|M|therapy until one menstrual cycle after stopping therapy.(10)|
00374|051|M|   The CDC contraceptive guidelines state that intrauterine devices (copper|
00374|052|M|or levonorgestrel) may be used with any antiretroviral agent.(12)|
00374|053|M|   The manufacturer of darunavir/cobicistat states that additional or|
00374|054|M|alternative (non-hormonal) forms of contraception should be considered when|
00374|055|M|estrogen-containing contraceptives are co-administered with|
00374|056|M|darunavir/ritonavir.(17)|
00374|057|B||
00374|058|D|DISCUSSION:  Concurrent administration of unboosted amprenavir (1200 mg|
00374|059|D|twice daily) with ethinyl estradiol/norethindrone (0.035 mg/1 mg daily)|
00374|060|D|decreased the amprenavir area-under-curve (AUC) and minimum concentration|
00374|061|D|(Cmin) by 22% and 20%, respectively.  The Cmin of ethinyl estradiol was|
00374|062|D|increased by 32%. The AUC and Cmin of norethindrone were increased by 18%|
00374|063|D|and 45%, respectively.  Fosamprenavir is a prodrug of amprenavir.(1)|
00374|064|D|   In contrast, a study of fosamprenavir/ritonavir (700/100 mg twice daily)|
00374|065|D|with ethinyl estradiol/norethindrone (0.035/0.5 mg daily) in 25 subjects had|
00374|066|D|no effect on amprenavir levels.   In addition, this combination decreased|
00374|067|D|the Cmax and AUC of ethinyl estradiol by 28% and 37%, respectively.  The|
00374|068|D|Cmax, AUC, and Cmin of norethindrone decreased by 38%, 34%, and 26%,|
00374|069|D|respectively.(1)|
00374|070|D|   Concurrent administration of atazanavir (400 mg daily) with ethinyl|
00374|071|D|estradiol-norethindrone (Ortho-Novum) increased the maximum concentration|
00374|072|D|(Cmax), AUC, and Cmin of ethinyl estradiol by 15%, 48%, and 91%,|
00374|073|D|respectively, and the Cmax, AUC, and Cmin of norethindrone by 67%, 210%, and|
00374|074|D|362%, respectively.(3)|
00374|075|D|  Concurrent administration of atazanavir/ritonavir (300/100 mg daily) with|
00374|076|D|ethinyl estradiol-norgestimate (Ortho Tri-Cyclen) decreased the maximum|
00374|077|D|concentration (Cmax), AUC, and Cmin of ethinyl estradiol by 16%, 19%, and|
00374|078|D|37%, respectively, and increased the Cmax, AUC, and Cmin of norgestimate by|
00374|079|D|68%, 85%, and 202%, respectively.(3)|
00374|080|D|   In a study in 11 subjects, concurrent administration of|
00374|081|D|darunavir/ritonavir (600/100 mg twice daily) with ethinyl|
00374|082|D|estradiol/norethindrone (0.035/1 mg daily) decreased ethinyl estradiol Cmax,|
00374|083|D|AUC, and Cmin by 32%, 44%, and 62%, respectively.  The Cmax, AUC, and Cmin,|
00374|084|D|of norethindrone decreased by 10%, 14%, and 30%, respectively.(6)|
00374|085|D|   The concurrent administration of nelfinavir (2250 mg daily) and ethinyl|
00374|086|D|estradiol (35 mcg daily) and norethindrone (0.4 mg daily) decreased the AUC,|
00374|087|D|Cmax, and Cmin of ethinyl estradiol by 47%, 28%, and 62%, respectively, and|
00374|088|D|decreased the AUC and Cmin of norethindrone by 18% and 46%, respectively.|
00374|089|D|There was no effect on the Cmax of norethindrone.(2)|
00374|090|D|   Concurrent administration of lopinavir/ritonavir (400/100 mg twice daily)|
00374|091|D|and Ortho Novum (once daily) decreased the Cmax, AUC, and Cmin of ethinyl|
00374|092|D|estradiol by 41%, 42%, and 58%, respectively.  The Cmax, AUC, and Cmin, of|
00374|093|D|norethindrone decreased by 16%, 17%, and 32%, respectively.(7)|
00374|094|D|   Concurrent administration of ritonavir (500 mg twice daily) and ethinyl|
00374|095|D|estradiol (50 mcg single dose) decreased ethinyl estradiol AUC and Cmax by|
00374|096|D|40% and 32%, respectively.(8,14)|
00374|097|D|   In a study in 8 healthy females, ethinyl estradiol/gestodene (0.03/0.075|
00374|098|D|mg) had no effect on the pharmacokinetics of a single dose of saquinavir|
00374|099|D|(600 mg).(15)|
00374|100|D|   In a study in 21 subjects, concurrent ethinyl estradiol/norethindrone|
00374|101|D|(0.035/1 mg) and tipranavir-ritonavir (500/100 mg twice daily) decreased|
00374|102|D|tipranavir Cmin by 27%.  Ethinyl estradiol AUC and Cmax decreased by 48% and|
00374|103|D|48%, respectively.  There were no significant effects on norethindrone|
00374|104|D|levels.  In a study in 13 subjects, concurrent ethinyl estradiol/|
00374|105|D|norethindrone (0.035/1 mg) and tipranavir-ritonavir (750/200 mg twice daily)|
00374|106|D|had no significant effects on tipranavir levels.  Ethinyl estradiol AUC and|
00374|107|D|Cmax decreased by 52% and 43%, respectively.  There were no significant|
00374|108|D|effects on norethindrone levels.(6)|
00374|109|D|   Selected protease inhibitors linked to this monograph include:|
00374|110|D|amprenavir, atazanavir, darunavir, fosamprenavir, lopinavir, nelfinavir,|
00374|111|D|nirmatrelvir, and ritonavir.  Although not directly linked, protease|
00374|112|D|inhibitor regimens containing saquinavir and tipranavir also alert.|
00374|113|B||
00374|114|R|REFERENCES:|
00374|115|B||
00374|116|R|1.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
00374|117|R|  March, 2019.|1
00374|118|R|2.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00374|119|R|  Pharmaceuticals, Inc. September, 2016.|1
00374|120|R|3.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
00374|121|R|  Squibb Company December, 2024.|1
00374|122|R|4.Evotaz (atazanavir and cobicistat) US prescribing information.|1
00374|123|R|  Bristol-Myers-Squibb Company May, 2025.|1
00374|124|R|5.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00374|125|R|  Pharmaceuticals, Inc. April, 2024.|1
00374|126|R|6.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
00374|127|R|  March, 2023.|1
00374|128|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00374|129|R|  Laboratories December, 2019.|1
00374|130|R|8.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00374|131|R|  December, 2019.|1
00374|132|R|9.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00374|133|R|  Laboratories, Inc. March, 2019.|1
00374|134|R|10.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
00374|135|R|   information. Pfizer Inc. February, 2025.|1
00374|136|R|11.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
00374|137|R|   for the use of antiretroviral agents in adults and adolescents Living|6
00374|138|R|   with HIV. Department of Health and Human Services. Available at|6
00374|139|R|   https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats|6
00374|140|R|   -new-guidelines June 13, 2021.|6
00374|141|R|12.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
00374|142|R|   Criteria for Contraceptive Use, 2016. MMWR Recomm Rep.  Available at:|6
00374|143|R|   https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf July 29, 2016;|6
00374|144|R|   65(3):.|6
00374|145|R|13.Medicines and Healthcare products Regulatory Agency.|1
00374|146|R|   Levonorgestrel-containing emergency hormonal contraception: advice on|1
00374|147|R|   interactions with hepatic enzyme inducers and contraceptive efficacy.|1
00374|148|R|   available at:|1
00374|149|R|   https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency|1
00374|150|R|   -hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-induce|1
00374|151|R|   rs-and-contraceptive-efficacy September 15, 2016..|1
00374|152|R|14.Ouellet D, Hsu A, Qian J, Locke CS, Eason CJ, Cavanaugh JH, Leonard JM,|2
00374|153|R|   Granneman GR. Effect of ritonavir on the pharmacokinetics of ethinyl|2
00374|154|R|   oestradiol in healthy female volunteers. Br J Clin Pharmacol 1998 Aug;|2
00374|155|R|   46(2):111-6.|2
00374|156|R|15.Frohlich M, Burhenne J, Martin-Facklam M, Weiss J, von Wolff M,|2
00374|157|R|   Strowitzki T, Walter-Sack I, Haefeli WE. Oral contraception does not|2
00374|158|R|   alter single dose saquinavir pharmacokinetics in women. Br J Clin|2
00374|159|R|   Pharmacol 2004 Mar;57(3):244-52.|2
00374|160|R|16.Nor-Q-D (norethindrone) US prescribing information. WatsonPharma March,|1
00374|161|R|   2005.|1
00374|162|R|17.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
00374|163|R|   Pharmaceuticals, Inc. March, 2025.|1
00375|001|T|MONOGRAPH TITLE:  Selected Opioids/Selected Strong CYP3A4 Inducers|
00375|002|B||
00375|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00375|004|L|take action as needed.|
00375|005|B||
00375|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
00375|007|A|alfentanil, benzhydrocodone, buprenorphine,(1) fentanyl, hydrocodone,|
00375|008|A|meperidine,(2-4) morphine,(5) oxycodone, papaveretum, and sufentanil.(6)|
00375|009|B||
00375|010|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer may result in|
00375|011|E|decreased levels of alfentanil, benzhydrocodone, buprenorphine, fentanyl,|
00375|012|E|hydrocodone, meperidine, morphine, oxycodone, papaveretum, and sufentanil,|
00375|013|E|which may result in decreased effectiveness and may precipitate withdrawal|
00375|014|E|symptoms.(1-6)|
00375|015|E|   Induction of meperidine metabolism may result in an increase in levels of|
00375|016|E|normeperidine, the toxic metabolite of meperidine, resulting in a higher|
00375|017|E|risk of excitatory effects, including hallucinations, tremors, and|
00375|018|E|seizures.(2,3)|
00375|019|B||
00375|020|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00375|021|P|of the inducer for longer than 1-2 weeks.|
00375|022|B||
00375|023|M|PATIENT MANAGEMENT:  Patients maintained on alfentanil, benzhydrocodone,|
00375|024|M|buprenorphine, fentanyl, hydrocodone, meperidine, morphine, oxycodone,|
00375|025|M|papaveretum, and sufentanil may require dosage adjustments if a strong|
00375|026|M|CYP3A4 inducer is initiated or discontinued.  The effects of the interaction|
00375|027|M|may last for several weeks after the discontinuation of the inducer.|
00375|028|M|   Patients who transfer to Sublocade (extended release subcutaneous syringe|
00375|029|M|buprenorphine) from transmucosal buprenorphine used concomitantly with|
00375|030|M|CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine|
00375|031|M|level produced by Sublocade is adequate. If patients already on Sublocade|
00375|032|M|require newly-initiated treatment with CYP3A4 inducer, the patient should be|
00375|033|M|monitored for withdrawal. If the dose of Sublocade is not adequate in the|
00375|034|M|absence of the concomitant medication, and the concomitant medication cannot|
00375|035|M|be reduced or discontinued, the patient should be transitioned back to a|
00375|036|M|formulation of buprenorphine that permits dose adjustment. If a patient has|
00375|037|M|been stabilized on Sublocade with a CYP3A4 inducer and the concomitant|
00375|038|M|medication is discontinued, the patient should be monitored for signs and|
00375|039|M|symptoms of over-medication. Within 2 weeks of Sublocade administration, if|
00375|040|M|the dose provided by Sublocade is excessive in the absence of the|
00375|041|M|concomitant inducer, it may be necessary to remove the Sublocade and treat|
00375|042|M|the patient with a formulation of buprenorphine that permits dose|
00375|043|M|adjustments.(15)|
00375|044|M|   The manufacturer of sufentanil sublingual tablets states that if|
00375|045|M|concomitant use with CYP3A4 inducers is necessary, consider use of an|
00375|046|M|alternate agent that allows dose adjustment.(6)|
00375|047|B||
00375|048|D|DISCUSSION:  In a study in 12 opoid-dependent patients, rifampin (600 mg|
00375|049|D|daily) decreased the area-under-curve (AUC) of buprenorphine by 70%.  Half|
00375|050|D|of the subjects experienced withdrawal symptoms.  When compared to|
00375|051|D|historical values, there was no effect on rifampin levels.(1)|
00375|052|D|   In a study of four healthy volunteers, phenytoin increased meperidine|
00375|053|D|clearance from 1017 +/- 225 ml/min (mean +/- SD) to 1280 +/- 130 ml/min and|
00375|054|D|decreased half-life from 6.4 hours to 4.3 hours.  Phenytoin also increased|
00375|055|D|normeperidine AUC by 1.53-fold after IV meperidine and by 1.25-fold after|
00375|056|D|oral meperidine.(3)|
00375|057|D|   In a study in 10 healthy subjects, pretreatment with rifampin (600 mg|
00375|058|D|daily) for 13 days decreased the area-under-curve (AUC) and maximum|
00375|059|D|concentration (Cmax) of a single dose of morphine by 28% and 41%,|
00375|060|D|respectively.  The AUCs of morphine-3-glucuronide and morphine-6-glucuronide|
00375|061|D|were proportionally decreased as well.  Following rifampin pretreatment, no|
00375|062|D|analgesic effects of morphine were seen.(5)|
00375|063|D|   In a randomized controlled trial of 12 healthy participants St. John's|
00375|064|D|wort decreased the oxycodone AUC by 50%, shortened the oxycodone elimination|
00375|065|D|half-life, and decreased the self-reported drug effect of oxycodone compared|
00375|066|D|to placebo.(7)|
00375|067|D|   In a study in 12 healthy subjects, pretreatment with rifampin had no|
00375|068|D|effect on fentanyl Cmax or time to Cmax (Tmax) after administration of oral|
00375|069|D|transmucosal fentanyl.  However, fentanyl AUC decreased 62%.(8)|
00375|070|D|   In a study in 9 healthy subjects, rifampin increased the clearance of|
00375|071|D|alfentanil by 169%.  Alfentanil half-life decreased 61%.(9)|
00375|072|D|   In a study of patients undergoing craniotomy, higher fentanyl maintenance|
00375|073|D|doses were required in patients receiving carbamazepine and phenytoin|
00375|074|D|compared to control subjects not receiving enzyme-inducing agents.(10)|
00375|075|D|   There are case reports of decreased levels and effectiveness of oxycodone|
00375|076|D|with concurrent phenytoin(11) and rifampin(12) and with concurrent fentanyl|
00375|077|D|and rifampin.(13-14)|
00375|078|D|   Selected strong CYP3A4 inducers linked to this monograph include:|
00375|079|D|apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
00375|080|D|ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, and St.|
00375|081|D|John's Wort.|
00375|082|B||
00375|083|R|REFERENCES:|
00375|084|B||
00375|085|R|1.McCance-Katz EF, Moody DE, Prathikanti S, Friedland G, Rainey PM.|2
00375|086|R|  Rifampin, but not rifabutin, may produce opiate withdrawal in|2
00375|087|R|  buprenorphine-maintained patients. Drug Alcohol Depend 2011 Nov 1;|2
00375|088|R|  118(2-3):326-34.|2
00375|089|R|2.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
00375|090|R|  Pharmaceuticals LLC. December, 2023.|1
00375|091|R|3.Pond SM, Kretschzmar KM. Effect of phenytoin on meperidine clearance and|2
00375|092|R|  normeperidine formation. Clin Pharmacol Ther 1981 Nov;30(5):680-6.|2
00375|093|R|4.Stambaugh JE Jr, Wainer IW, Schwartz I. The effect of phenobarbital on the|2
00375|094|R|  metabolism of meperidine in normal volunteers. J Clin Pharmacol 1978 Oct;|2
00375|095|R|  18(10):482-90.|2
00375|096|R|5.Fromm MF, Eckhardt K, Li S, Schanzle G, Hofmann U, Mikus G, Eichelbaum M.|2
00375|097|R|  Loss of analgesic effect of morphine due to coadministration of rifampin.|2
00375|098|R|  Pain 1997 Aug;72(1-2):261-7.|2
00375|099|R|6.Dsuvia (sufentanil) sublingual tablet US prescribing information. AcelRx|1
00375|100|R|  Pharmaceuticals, Inc. December, 2023.|1
00375|101|R|7.Nieminen TH, Hagelberg NM, Saari TI, Neuvonen M, Laine K, Neuvonen PJ,|2
00375|102|R|  Olkkola KT. St John's wort greatly reduces the concentrations of oral|2
00375|103|R|  oxycodone. Eur J Pain 2010 Sep;14(8):854-9.|2
00375|104|R|8.Kharasch ED, Whittington D, Hoffer C. Influence of hepatic and intestinal|2
00375|105|R|  cytochrome P4503A activity on the acute disposition and effects of oral|2
00375|106|R|  transmucosal fentanyl citrate. Anesthesiology 2004 Sep;101(3):729-37.|2
00375|107|R|9.Kharasch ED, Russell M, Mautz D, Thummel KE, Kunze KL, Bowdle A, Cox K.|2
00375|108|R|  The role of cytochrome P450 3A4 in alfentanil clearance. Implications for|2
00375|109|R|  interindividual variability in disposition and perioperative drug|2
00375|110|R|  interactions. Anesthesiology 1997 Jul;87(1):36-50.|2
00375|111|R|10.Tempelhoff R, Modica PA, Spitznagel EL Jr. Anticonvulsant therapy|2
00375|112|R|   increases fentanyl requirements during anaesthesia for craniotomy. Can J|2
00375|113|R|   Anaesth 1990 Apr;37(3):327-32.|2
00375|114|R|11.Pon D, Hwang J, Lo T, Zyl CV. Decreased responsiveness to oxycodone: A|3
00375|115|R|   case of a pharmacokinetic drug interaction?. J Opioid Manag 2015 Jul-Aug;|3
00375|116|R|   11(4):357-61.|3
00375|117|R|12.Lee HK, Lewis LD, Tsongalis GJ, McMullin M, Schur BC, Wong SH, Yeo KT.|3
00375|118|R|   Negative urine opioid screening caused by rifampin-mediated induction of|3
00375|119|R|   oxycodone hepatic metabolism. Clin Chim Acta 2006 May;367(1-2):196-200.|3
00375|120|R|13.Morii H, Chiba M, Konishi H, Endo Y, Yamaji A. Failure of pain control|3
00375|121|R|   using transdermal fentanyl during rifampicin treatment. J Pain Symptom|3
00375|122|R|   Manage 2007 Jan;33(1):5-6.|3
00375|123|R|14.Takane H, Nosaka A, Wakushima H, Hosokawa K, Ieiri I. Rifampin reduces|3
00375|124|R|   the analgesic effect of transdermal fentanyl. Ann Pharmacother 2005 Dec;|3
00375|125|R|   39(12):2139-40.|3
00375|126|R|15.Sublocade (buprenorphine extended release injection) US prescribing|1
00375|127|R|   information. Indivior Inc. February, 2025.|1
00376|001|T|MONOGRAPH TITLE:  Methadone/Phenytoin (mono deleted 02/25/2016)|
00376|002|B||
00376|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00376|004|L|take action as needed.|
00376|005|B||
00376|006|A|MECHANISM OF ACTION:  Phenytoin may induce the metabolism of methadone.|
00376|007|B||
00376|008|E|CLINICAL EFFECTS:  Concurrent administration may result in decreased levels|
00376|009|E|of methadone, which may precipitate withdrawal symptoms.|
00376|010|B||
00376|011|P|PREDISPOSING FACTORS:  None determined.|
00376|012|B||
00376|013|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with methadone|
00376|014|M|and phenytoin may require higher dosages of methadone to prevent the|
00376|015|M|development of withdrawal symptoms.  The dosage of methadone may need to be|
00376|016|M|adjusted if phenytoin is initiated or discontinued.|
00376|017|B||
00376|018|D|DISCUSSION:  In a study in five patients maintained on methadone, the|
00376|019|D|addition of phenytoin to their regimens resulted in moderately severe|
00376|020|D|withdrawal symptoms and a decrease in the area-under-curve (AUC) for|
00376|021|D|methadone. Methadone plasma concentrations returned to baseline levels two|
00376|022|D|to three days after the discontinuation of phenytoin.(1)|
00376|023|B||
00376|024|R|REFERENCE:|
00376|025|B||
00376|026|R|1.Tong TG, Pond SM, Kreek MJ, Jaffery NF, Benowitz NL. Phenytoin-induced|2
00376|027|R|  methadone withdrawal. Ann Intern Med 1981 Mar;94(3):349-51.|2
00377|001|T|MONOGRAPH TITLE:  Cisapride/Selected Class IA & III Antiarrhythmics|
00377|002|B||
00377|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00377|004|L|is contraindicated and generally should not be dispensed or administered to|
00377|005|L|the same patient.|
00377|006|B||
00377|007|A|MECHANISM OF ACTION:  Concurrent administration of cisapride and Class IA or|
00377|008|A|III antiarrhythmics may result in additive effects on the QT interval.(1)|
00377|009|B||
00377|010|E|CLINICAL EFFECTS:  Concurrent administration of cisapride and Class IA or|
00377|011|E|III antiarrhythmics may result in prolongation of the QT interval, which may|
00377|012|E|result in potentially life-threatening arrhythmias.(1)|
00377|013|B||
00377|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00377|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00377|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00377|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00377|018|P|female gender, or advanced age.(3)|
00377|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00377|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00377|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00377|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00377|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00377|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00377|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00377|026|B||
00377|027|M|PATIENT MANAGEMENT:  The US manufacturer of cisapride states that cisapride|
00377|028|M|should not be concomitantly administered with agents known to prolong the QT|
00377|029|M|interval such as the Class IA and Class III antiarrhythmics.(1)|
00377|030|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00377|031|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00377|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00377|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00377|034|B||
00377|035|D|DISCUSSION:  The manufacturer of cisapride states that QT prolongation,|
00377|036|D|torsades de pointes (sometimes with syncope), cardiac arrest, and sudden|
00377|037|D|death have been reported in patients who were not taking agents known to|
00377|038|D|increase cisapride levels.  Some of these patients were taking agents known|
00377|039|D|to prolong the QT interval, such as the Class IA and Class III|
00377|040|D|antiarrhythmics.(1)|
00377|041|D|  Class I antiarrhythmics known to prolong the QT interval are disopyramide,|
00377|042|D|encainide, flecainide, procainamide, propafenone, and quinidine.  Class III|
00377|043|D|antiarrhythmics known to prolong the QT interval are amiodarone and sotalol.|
00377|044|D|  In clinical studies, gastric emptying significantly increased with the|
00377|045|D|combination disopyramide (100mg t.i.d.) and cisapride (2.5mg t.i.d.), which|
00377|046|D|resulted in a two-fold increase in the absorption rate constant of|
00377|047|D|disopyramide compared to disopyramide monotherapy.  In addition, the lag|
00377|048|D|time of disopyramide decreased and was two-fold shorter.(2)|
00377|049|D|   One or more of the drug pairs linked to this monograph have been included|
00377|050|D|in a list of interactions that should be considered "high-priority" for|
00377|051|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00377|052|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00377|053|D|Coordinator (ONC) for Health Information Technology.|
00377|054|B||
00377|055|R|REFERENCES:|
00377|056|B||
00377|057|R|1.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00377|058|R|  Products, L.P. January, 2000.|1
00377|059|R|2.Kuroda T, Yoshihara Y, Nakamura H, Azumi T, Inatome T, Fukuzaki H,|2
00377|060|R|  Takanashi H, Yogo K, Akima M. Effects of cisapride on gastrointestinal|2
00377|061|R|  motor activity and gastric emptying of disopyramide. J Pharmacobiodyn 1992|2
00377|062|R|  Aug;15(8):395-402.|2
00377|063|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00377|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00377|065|R|  settings: a scientific statement from the American Heart Association and|6
00377|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00377|067|R|  2;55(9):934-47.|6
00377|068|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00377|069|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00377|070|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00377|071|R|  19(5):735-43.|6
00378|001|T|MONOGRAPH TITLE:  Cisapride/Tricyclic & Tetracyclic Compounds|
00378|002|B||
00378|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00378|004|L|is contraindicated and generally should not be dispensed or administered to|
00378|005|L|the same patient.|
00378|006|B||
00378|007|A|MECHANISM OF ACTION:  The concurrent use of cisapride with a tricyclic or|
00378|008|A|tetracyclic compound may result in additive effects on the QT interval.(1,2)|
00378|009|B||
00378|010|E|CLINICAL EFFECTS:  Concurrent use may result in prolongation of the QT|
00378|011|E|interval, which may result in potentially life-threatening arrhythmias.(1,2)|
00378|012|B||
00378|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00378|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00378|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00378|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00378|017|P|female gender, or advanced age.(3)|
00378|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00378|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00378|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00378|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00378|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00378|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00378|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00378|025|B||
00378|026|M|PATIENT MANAGEMENT:  The manufacturer of cisapride states that cisapride|
00378|027|M|should not be concomitantly administered with agents known to prolong the QT|
00378|028|M|interval such as certain tricyclic antidepressants and certain tetracyclic|
00378|029|M|antidepressants.(1)  The manufacturer of amitriptyline states under|
00378|030|M|contraindications that amitriptyline should not be given with cisapride.(2)|
00378|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00378|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00378|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00378|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00378|035|B||
00378|036|D|DISCUSSION:  The manufacturer of cisapride states that QT prolongation,|
00378|037|D|torsades de pointes (sometimes with syncope), cardiac arrest, and sudden|
00378|038|D|death have been reported in patients who were not taking agents known to|
00378|039|D|increase cisapride levels.  Some of these patients were taking agents known|
00378|040|D|to prolong the QT interval, such as certain tricyclic antidepressants and|
00378|041|D|certain tetracyclic antidepressants.  The manufacturer of cisapride states|
00378|042|D|that cisapride should not be concomitantly administered with agents known to|
00378|043|D|prolong the QT interval.(1)|
00378|044|D|   The manufacturer of amitriptyline states under contraindications that|
00378|045|D|amitriptyline should not be given with cisapride due to the potential for|
00378|046|D|increased QT interval and increased risk of arrhythmia.(2)|
00378|047|B||
00378|048|R|REFERENCES:|
00378|049|B||
00378|050|R|1.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00378|051|R|  Products, L.P. January, 2000.|1
00378|052|R|2.Amitriptyline hydrochloride, US prescribing information. Sandoz Inc.|1
00378|053|R|  January, 2010.|1
00378|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00378|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00378|056|R|  settings: a scientific statement from the American Heart Association and|6
00378|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00378|058|R|  2;55(9):934-47.|6
00379|001|T|MONOGRAPH TITLE:  Cisapride/Selected Antipsychotics|
00379|002|B||
00379|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00379|004|L|is contraindicated and generally should not be dispensed or administered to|
00379|005|L|the same patient.|
00379|006|B||
00379|007|A|MECHANISM OF ACTION:  Concurrent administration may result in additive|
00379|008|A|effects on the QT interval.(1,2)|
00379|009|B||
00379|010|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
00379|011|E|the QT interval, which may result in potentially life-threatening|
00379|012|E|arrhythmias.(1)|
00379|013|B||
00379|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00379|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00379|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00379|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00379|018|P|female gender, or advanced age.(3)|
00379|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00379|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00379|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00379|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00379|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00379|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00379|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00379|026|B||
00379|027|M|PATIENT MANAGEMENT:  The manufacturer of cisapride states that cisapride|
00379|028|M|should not be concomitantly administered with agents known to prolong the QT|
00379|029|M|interval such as certain antipsychotic medications such as certain|
00379|030|M|phenothiazines (1,2), sertindole (1), and pimozide.(2)|
00379|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00379|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00379|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00379|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00379|035|B||
00379|036|D|DISCUSSION:  The manufacturer of cisapride states that QT prolongation,|
00379|037|D|torsades de pointes (sometimes with syncope), cardiac arrest, and sudden|
00379|038|D|death have been reported in patients who were not taking agents known to|
00379|039|D|increase cisapride levels.  Some of these patients were taking agents known|
00379|040|D|to prolong the QT interval, such as certain antipsychotic medications such|
00379|041|D|as certain phenothiazines, sertindole, and pimozide.  The manufacturer of|
00379|042|D|cisapride states that cisapride should not be concomitantly administered|
00379|043|D|with agents known to prolong the QT interval.(1,2)|
00379|044|D|   One or more of the drug pairs linked to this monograph have been included|
00379|045|D|in a list of interactions that should be considered "high-priority" for|
00379|046|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00379|047|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00379|048|D|Coordinator (ONC) for Health Information Technology.|
00379|049|B||
00379|050|R|REFERENCES:|
00379|051|B||
00379|052|R|1.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00379|053|R|  Products, L.P. January, 2000.|1
00379|054|R|2.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica,|1
00379|055|R|  Canada February, 2000.|1
00379|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00379|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00379|058|R|  settings: a scientific statement from the American Heart Association and|6
00379|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00379|060|R|  2;55(9):934-47.|6
00379|061|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00379|062|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00379|063|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00379|064|R|  19(5):735-43.|6
00380|001|T|MONOGRAPH TITLE:  Cisapride/Potassium Wasting Diuretics|
00380|002|B||
00380|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00380|004|L|is contraindicated and generally should not be dispensed or administered to|
00380|005|L|the same patient.|
00380|006|B||
00380|007|A|MECHANISM OF ACTION:  Concurrent administration may result in additive|
00380|008|A|effects on the QT interval.(1)|
00380|009|B||
00380|010|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
00380|011|E|the QT interval, which may result in potentially life-threatening|
00380|012|E|arrhythmias.(1)|
00380|013|B||
00380|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00380|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00380|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00380|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00380|018|P|female gender, or advanced age.(2)|
00380|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00380|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00380|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00380|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00380|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00380|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00380|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00380|026|B||
00380|027|M|PATIENT MANAGEMENT:  The manufacturer of cisapride states that cisapride|
00380|028|M|should not be used in patients with uncorrected hypokalemia or who might|
00380|029|M|experience a rapid reduction of plasma potassium, such as those patients|
00380|030|M|taking potassium-wasting diuretics in the acute setting.(1)|
00380|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00380|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00380|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00380|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00380|035|B||
00380|036|D|DISCUSSION:  The manufacturer of cisapride states that QT prolongation,|
00380|037|D|torsades de pointes (sometimes with syncope), cardiac arrest, and sudden|
00380|038|D|death have been reported in patients who were not taking agents known to|
00380|039|D|increase cisapride levels.  Some of these patients had uncorrected|
00380|040|D|electrolyte disorders such as hypokalemia.  Therefore, the manufacturer of|
00380|041|D|cisapride states that cisapride should not be used in patients with|
00380|042|D|uncorrected hypokalemia or who might experience a rapid reduction of plasma|
00380|043|D|potassium, such as those patients taking potassium-wasting diuretics in the|
00380|044|D|acute setting.(1)|
00380|045|D|   There is no published documentation to support this interaction.|
00380|046|B||
00380|047|R|REFERENCES:|
00380|048|B||
00380|049|R|1.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
00380|050|R|  Products, L.P. January, 2000.|1
00380|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00380|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00380|053|R|  settings: a scientific statement from the American Heart Association and|6
00380|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00380|055|R|  2;55(9):934-47.|6
00381|001|T|MONOGRAPH TITLE:  Rizatriptan/Propranolol|
00381|002|B||
00381|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00381|004|L|take action as needed.|
00381|005|B||
00381|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
00381|007|B||
00381|008|E|CLINICAL EFFECTS:  Concurrent administration of rizatriptan and propranolol|
00381|009|E|may increase the levels of rizatriptan.(1,2)|
00381|010|B||
00381|011|P|PREDISPOSING FACTORS:  None determined.|
00381|012|B||
00381|013|M|PATIENT MANAGEMENT:  For adult patients receiving propranolol, the|
00381|014|M|manufacturer of rizatriptan states that the 5 mg dose of rizatriptan should|
00381|015|M|be used and that a maximum of three doses (15 mg) should be administered in|
00381|016|M|a 24 hour period.(1)|
00381|017|M|   For pediatric patients receiving propranolol who weigh less than 40 kg|
00381|018|M|(88 lb), rizatriptan should not be given.(1)|
00381|019|M|   For pediatric patients receiving propranolol who weigh at least 40 kg (88|
00381|020|M|lb), a single 5 mg dose of rizatriptan is recommended (maximum dose of 5 mg|
00381|021|M|in a 24 hour period).(1)|
00381|022|B||
00381|023|D|DISCUSSION:  In a study in 11 subjects, the concurrent use of rizatriptan|
00381|024|D|(10 mg) with propranolol (240 mg daily) resulted in an increase in the|
00381|025|D|area-under-curve (AUC) of rizatriptan by 70%.  A 4-fold increase was|
00381|026|D|observed in one subject.  The AUC of the rizatriptan N-monodesmethyl|
00381|027|D|metabolite was not affected by the concurrent administration of|
00381|028|D|propranolol.(1,2)|
00381|029|D|   In a study in 12 healthy subjects, concurrent use of propranolol (80 mg|
00381|030|D|twice daily) with almotriptan (12.5 mg) resulted in statistically|
00381|031|D|significant changes in almotriptan AUC; however, the change was less than 7%|
00381|032|D|and considered unlikely to be clinically significant.(3)|
00381|033|D|   In a study in 10 healthy subjects, concurrent propranolol (80 mg twice|
00381|034|D|daily) with sumatriptan (300 mg) had no effects on the pharmacokinetics or|
00381|035|D|pharmacodynamics of sumatriptan.(4)|
00381|036|D|   In a study in 12 healthy subjects, concurrent use of propranolol (160 mg|
00381|037|D|daily) with zolmitriptan (10 mg) increased the AUC and maximum concentration|
00381|038|D|(Cmax) of zolmitriptan by 56% and 37%, respectively.  Propranolol had no|
00381|039|D|effect on the pressor response to zolmitriptan.  The authors stated that the|
00381|040|D|effects are unlikely to be clinically significant and that no dosage|
00381|041|D|adjustment is required during concurrent therapy.(5)|
00381|042|B||
00381|043|R|REFERENCES:|
00381|044|B||
00381|045|R|1.Maxalt (rizatriptan) US prescribing information. Merck & Co., Inc.|1
00381|046|R|  October, 2019.|1
00381|047|R|2.Goldberg MR, Sciberras D, De Smet M, Lowry R, Tomasko L, Lee Y, Olah TV,|2
00381|048|R|  Zhao J, Vyas KP, Halpin R, Kari PH, James I. Influence of|2
00381|049|R|  beta-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a|2
00381|050|R|  5-HT1B/1D agonist: differential effects of propranolol, nadolol and|2
00381|051|R|  metoprolol. Br J Clin Pharmacol 2001 Jul;52(1):69-76.|2
00381|052|R|3.Fleishaker JC, Sisson TA, Carel BJ, Azie NE. Lack of pharmacokinetic|2
00381|053|R|  interaction between the antimigraine compound, almotriptan, and|2
00381|054|R|  propranolol in healthy volunteers. Cephalalgia 2001 Feb;21(1):61-5.|2
00381|055|R|4.Scott AK, Walley T, Breckenridge AM, Lacey LF, Fowler PA. Lack of an|2
00381|056|R|  interaction between propranolol and sumatriptan. Br J Clin Pharmacol 1991|2
00381|057|R|  Nov;32(5):581-4.|2
00381|058|R|5.Peck RW, Seaber EJ, Dixon R, Gillotin CG, Weatherley BC, Layton G, Posner|2
00381|059|R|  J. The interaction between propranolol and the novel antimigraine agent|2
00381|060|R|  zolmitriptan (311C90). Br J Clin Pharmacol 1997 Dec;44(6):595-9.|2
00382|001|T|MONOGRAPH TITLE:  MAO Inhibitors/Tryptophan|
00382|002|B||
00382|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00382|004|L|is contraindicated and generally should not be dispensed or administered to|
00382|005|L|the same patient.|
00382|006|B||
00382|007|A|MECHANISM OF ACTION:  Concurrent use may result in additive effects on|
00382|008|A|serotonin levels.  MAOIs may potentiate the effects of tryptophan.(1)|
00382|009|B||
00382|010|E|CLINICAL EFFECTS:  Concurrent administration of tryptophan with a MAO|
00382|011|E|Inhibitor may result in serotonin syndrome and/or hypertensive crisis.(1)|
00382|012|E|Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
00382|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(15)|
00382|014|E|In addition to these effects, disorientation, delirium, agitation,|
00382|015|E|hypomania, shivering, ocular oscillation, and Babinski signs have been|
00382|016|E|reported with concurrent tryptophan and phenelzine.(1)|
00382|017|B||
00382|018|P|PREDISPOSING FACTORS:  None determined.|
00382|019|B||
00382|020|M|PATIENT MANAGEMENT:  Patients receiving MAO Inhibitors should not take|
00382|021|M|agents such as tryptophan.|
00382|022|M|   If concurrent therapy is warranted, patients should be monitored for|
00382|023|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00382|024|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00382|025|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00382|026|M|coordination, or severe diarrhea.|
00382|027|B||
00382|028|D|DISCUSSION:  In a study in nine subjects, the administration of a single|
00382|029|D|intravenous dose of tryptophan with tranylcypromine significantly increased|
00382|030|D|the normal prolactin response to tryptophan.  Four of the nine subjects|
00382|031|D|developed a distinctive neuromotor syndrome characterized by hyperreflexia,|
00382|032|D|ankle clonus, nystagmus, incoordination, tremor, myoclonic jerks, and|
00382|033|D|nausea.(2)  Another set of authors reported eight cases of delirium, ranging|
00382|034|D|from mild to severe, in patients who received concurrent tranylcypromine and|
00382|035|D|tryptophan. Symptoms developed within two days to 4 weeks of beginning|
00382|036|D|concurrent therapy.(3)  In a case report, the addition of tryptophan to a|
00382|037|D|tranylcypromine regimen resulted in hypomania.(4)  In another report, a|
00382|038|D|patient developed hyperventilation, shivering, hyperthermia, increased|
00382|039|D|muscle tone, and hyperreflexia when tryptophan was added to tranylcypromine|
00382|040|D|therapy.(5)  There are two reports of fatalities following the concurrent|
00382|041|D|administration of tryptophan and tranylcypromine.  In the first report, a a|
00382|042|D|patient had been receiving chlorpromazine, lithium, and tryptophan when|
00382|043|D|phenelzine was initiated.  Four weeks later, the patient developed|
00382|044|D|neuroleptic malignant syndrome and expired despite resuscitation efforts.(6)|
00382|045|D|In the second report, a patient had been receiving fluoxetine,|
00382|046|D|levothyroxine, propranolol, quinidine, and hydroxyzine.  Fluoxetine was|
00382|047|D|discontinued and tranylcypromine, thioridazine, and tryptophan were|
00382|048|D|initiated.  The patient developed neuroleptic malignant syndrome two and|
00382|049|D|one-half hours after the first tryptophan dose and expired 24 hours later.|
00382|050|D|(7)|
00382|051|D|  In a case report, the addition of tryptophan to a regimen that included|
00382|052|D|phenelzine resulted in an acute behavioral and neurologic syndrome.  The|
00382|053|D|patient's symptoms resolved 24 hours after the discontinuation of both|
00382|054|D|agents.(8)  In another report, a patient developed hypomania following the|
00382|055|D|addition of tryptophan to phenelzine therapy.(4)  Another report describes|
00382|056|D|the development of delirium following the addition of tryptophan to|
00382|057|D|phenelzine.(9)  One set of authors reported three cases of myoclonus,|
00382|058|D|hyperreflexia, and diaphoresis following the addition of tryptophan to|
00382|059|D|phenelzine therapy.(10)|
00382|060|D|   Some studies have shown that the addition of tryptophan to MAO Inhibitor|
00382|061|D|therapy may have beneficial results, including greater improvement in|
00382|062|D|depression and faster onset of effects.(11,12)|
00382|063|D|   Methylene blue, when administered intravenously, has been shown to reach|
00382|064|D|sufficient concentrations to be a potent inhibitor of MAO-A.(13,14)|
00382|065|D|   Metaxalone is a weak inhibitor of MAO.(16,17)|
00382|066|B||
00382|067|R|REFERENCES:|
00382|068|B||
00382|069|R|1.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
00382|070|R|  2007.|1
00382|071|R|2.Price LH, Charney DS, Heninger GR. Effects of tranylcypromine treatment on|2
00382|072|R|  neuroendocrine, behavioral, and autonomic responses to tryptophan in|2
00382|073|R|  depressed patients. Life Sci 1985 Sep 2;37(9):809-18.|2
00382|074|R|3.Pope HG Jr, Jonas JM, Hudson JI, Kafka MP. Toxic reactions to the|3
00382|075|R|  combination of monoamine oxidase inhibitors and tryptophan. Am J|3
00382|076|R|  Psychiatry 1985 Apr;142(4):491-2.|3
00382|077|R|4.Goff DC. Two cases of hypomania following the addition of L-tryptophan to|3
00382|078|R|  a monoamine oxidase inhibitor. Am J Psychiatry 1985 Dec;142(12):1487-8.|3
00382|079|R|5.Price WA, Zimmer B, Kucas P. Serotonin syndrome: a case report. J Clin|3
00382|080|R|  Pharmacol 1986 Jan;26(1):77-8.|3
00382|081|R|6.Staufenberg EF, Tantam D. Malignant hyperpyrexia syndrome in combined|3
00382|082|R|  treatment. Br J Psychiatry 1989 Apr;154:577-8.|3
00382|083|R|7.Kline SS, Mauro LS, Scala-Barnett DM, Zick D. Serotonin syndrome versus|3
00382|084|R|  neuroleptic malignant syndrome as a cause of death. Clin Pharm 1989 Jul;|3
00382|085|R|  8(7):510-4.|3
00382|086|R|8.Thomas JM, Rubin EH. Case report of a toxic reaction from a combination of|3
00382|087|R|  tryptophan and phenelzine. Am J Psychiatry 1984 Feb;141(2):281-3.|3
00382|088|R|9.Alvine G, Black DW, Tsuang D. Case of delirium secondary to|3
00382|089|R|  phenelzine/L-tryptophan combination. J Clin Psychiatry 1990 Jul;51(7):311.|3
00382|090|R|10.Levy AB, Bucher P, Votolato N. Myoclonus, hyperreflexia and diaphoresis|3
00382|091|R|   in patients on phenelzine- tryptophan combination treatment. Can J|3
00382|092|R|   Psychiatry 1985 Oct;30(6):434-6.|3
00382|093|R|11.Ayuso Gutierrez JL, Alino JJ. Tryptophan and an MAOI (nialamide) in the|2
00382|094|R|   treatment of depression. A double-blind study. Int Pharmacopsychiatry|2
00382|095|R|   1971;6(2):92-7.|2
00382|096|R|12.Glassman AH, Platman SR. Potentiation of a monoamine oxidase inhibitor by|2
00382|097|R|   tryptophan. J Psychiatr Res 1969 Dec;7(2):83-8.|2
00382|098|R|13.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00382|099|R|   inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00382|100|R|   prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00382|101|R|14.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00382|102|R|   distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00382|103|R|   2000 Jun;56(3):247-50.|2
00382|104|R|15.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00382|105|R|   352(11):1112-20.|6
00382|106|R|16.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00382|107|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00382|108|R|   Feb;34(2):346.e5-6.|3
00382|109|R|17.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00382|110|R|   Pfizer Inc. January, 2024.|1
00383|001|T|MONOGRAPH TITLE:  ACE Inhibitors; ARBs/Loop Diuretics|
00383|002|B||
00383|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00383|004|L|take action as needed.|
00383|005|B||
00383|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  The initial|
00383|007|A|hypotensive effect of the ACE inhibitors is mainly the result of suppression|
00383|008|A|of the renin-angiotensin-aldosterone system.  The ACE inhibitors inhibit the|
00383|009|A|formation of angiotensin II and angiotensin II receptor antagonists block|
00383|010|A|the action of angiotensin II, thereby lowering aldosterone levels with|
00383|011|A|subsequent sodium and water depletion.  Agents such as the loop diuretics|
00383|012|A|that cause sodium and water loss may exaggerate the hypotensive state.|
00383|013|B||
00383|014|E|CLINICAL EFFECTS:  The addition of an ACE inhibitor to a patient receiving a|
00383|015|E|loop diuretic may result in severe postural hypotension.  This effect is|
00383|016|E|transient and is not expected to occur during long-term dosing.  Symptomatic|
00383|017|E|hypotension may result in patients treated with loop diuretics who are|
00383|018|E|started on an angiotensin II receptor antagonist.|
00383|019|E|    Concurrent use of a renin-angiotensin system (RAS) inhibitor with|
00383|020|E|diuretics and NSAIDs may result in increased risk of acute kidney injury|
00383|021|E|(AKI).|
00383|022|B||
00383|023|P|PREDISPOSING FACTORS:  Addition of an ACE inhibitor or an angiotensin II|
00383|024|P|receptor antagonist to a patient already receiving a diuretic or who is|
00383|025|P|sodium depleted.|
00383|026|P|    Low water intake/dehydration, drug sensitivity, greater than 75 years of|
00383|027|P|age, and renal impairment may increase an individual's susceptibility to|
00383|028|P|AKI.|
00383|029|B||
00383|030|M|PATIENT MANAGEMENT:  In patients without heart failure, it may be advisable|
00383|031|M|to discontinue the diuretic, reduce the dose of the diuretic, or increase|
00383|032|M|salt intake prior to the initiation of the ACE inhibitor.    If hypotension|
00383|033|M|occurs, place the patient in a supine position.  Hypotension is most likely|
00383|034|M|when the ACE inhibitor is initiated.  However, if subsequent hypotension|
00383|035|M|occurs, a dosage adjustment or discontinuation of one agent may be required.|
00383|036|M|   Intravascular volume depletion should be corrected in patients prior to|
00383|037|M|the initiation of an angiotensin II receptor antagonist.|
00383|038|M|   Concurrent use of a RAS inhibitor with loop diuretics and NSAIDs should|
00383|039|M|be used with caution and monitored closely for signs of AKI.|
00383|040|B||
00383|041|D|DISCUSSION:  In a computational study, the risk of AKI using triple therapy|
00383|042|D|with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was|
00383|043|D|assessed.  The study found the following factors may increase an|
00383|044|D|individual's susceptibility to AKI: low water intake, drug sensitivity,|
00383|045|D|greater than 75 years of age, and renal impairment.(4,5)|
00383|046|D|    In an observational study, current use of a triple therapy with a|
00383|047|D|diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of|
00383|048|D|acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI)|
00383|049|D|1.12-1.53). The highest risk of AKI associated with triple therapy were|
00383|050|D|observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (6)|
00383|051|D|    Severe postural hypotension(1,2) and transient postural hypotension(3)|
00383|052|D|has been reported in patients receiving concurrent captopril and furosemide.|
00383|053|D|The effect is transient and may be more prevalent in patients who are|
00383|054|D|sodium depleted.(8)|
00383|055|D|   Reversible renal failure(9) and decreased renal function(10) have been|
00383|056|D|reported in patients receiving concurrent administration with enalapril and|
00383|057|D|furosemide.  In a study in which electrolytes were replaced with saline or|
00383|058|D|Ringer's solution, no postural hypotension was noted; however, significant|
00383|059|D|decreases in diastolic blood pressure occurred at three, four, and six hours|
00383|060|D|after concurrent administration.(11)|
00383|061|B||
00383|062|R|REFERENCES:|
00383|063|B||
00383|064|R|1.Ferguson RK, Vlasses PH, Koplin JR, Shirinian A, Burke JF Jr, Alexander|3
00383|065|R|  JC. Captopril in severe treatment-resistant hypertension. Am Heart J 1980|3
00383|066|R|  May;99(5):579-85.|3
00383|067|R|2.Case DB, Atlas SA, Laragh JH, Sealey JE, Sullivan PA, McKinstry DN.|3
00383|068|R|  Clinical experience with blockade of the renin-angiotensin-aldosterone|3
00383|069|R|  system by an oral converting-enzyme inhibitor (SQ 14,225, captopril) in|3
00383|070|R|  hypertensive patients. Prog Cardiovasc Dis 1978 Nov-Dec;21(3):195-206.|3
00383|071|R|3.Koffer H, Vlasses PH, Ferguson RK, Weis M, Adler AG. Captopril in|2
00383|072|R|  diuretic-treated hypertensive patients. JAMA 1980 Dec 5;244(22):2532-5.|2
00383|073|R|4.Leete J,  Wang C,  Lopez-Hernandez FJ,  Layton AT. Determining risk|6
00383|074|R|  factors for triple whammy acute kidney injury. Math Biosci 2022 Apr 4.|6
00383|075|R|5.Dreischulte T,  Morales DR,  Bell S,  Guthrie B. Combined use of|2
00383|076|R|  nonsteroidal anti-inflammatory drugs with diuretics and/or|2
00383|077|R|  renin-angiotensin system inhibitors in the community increases the risk of|2
00383|078|R|  acute kidney injury. Kidney Int 2015 Aug;88(2):396-403.|2
00383|079|R|6.Lapi F,  Azoulay L,  Yin H,  Nessim SJ,  Suissa S. Concurrent use of|2
00383|080|R|  diuretics, angiotensin converting enzyme inhibitors, and angiotensin|2
00383|081|R|  receptor blockers with non-steroidal anti-inflammatory drugs and risk of|2
00383|082|R|  acute kidney injury: nested case-control study. BMJ 2013 Jan;8(346):.|2
00383|083|R|7.Juhlin T,  Bjorkman S,  Hoglund P. Cyclooxygenase inhibition causes marked|2
00383|084|R|  impairment of renal function in elderly subjects treated with diuretics|2
00383|085|R|  and ACE-inhibitors. Eur J Heart Fail 2005 Oct;7(6):1049-56.|2
00383|086|R|8.Heel RC, Brogden RN, Speight TM, Avery GS. Captopril: a preliminary review|6
00383|087|R|  of its pharmacological properties and therapeutic efficacy. Drugs 1980|6
00383|088|R|  Dec;20(6):409-52.|6
00383|089|R|9.Funck-Brentano C, Chatellier G, Alexandre JM. Reversible renal failure|3
00383|090|R|  after combined treatment with enalapril and frusemide in a patient with|3
00383|091|R|  congestive heart failure. Br Heart J 1986 Jun;55(6):596-8.|3
00383|092|R|10.Anonymous. Reversible renal failure after combined treatment with|3
00383|093|R|   enalapril and frusemide in a patient with congestive heart failure. Br|3
00383|094|R|   Heart J 1986 Nov;56(5):489-90.|3
00383|095|R|11.Van Hecken AM, Verbesselt R, Buntinx A, Cirillo VJ, De Schepper PJ.|2
00383|096|R|   Absence of a pharmacokinetic interaction between enalapril and frusemide.|2
00383|097|R|   Br J Clin Pharmacol 1987 Jan;23(1):84-7.|2
00384|001|T|MONOGRAPH TITLE:  Cytarabine; Methotrexate/Asparaginase|
00384|002|B||
00384|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00384|004|L|of severe adverse interaction.|
00384|005|B||
00384|006|A|MECHANISM OF ACTION:  The exact mechanism of the interaction is unknown and|
00384|007|A|may be a combination of mechanisms.  Asparaginase has been shown to decrease|
00384|008|A|the cellular uptake of methotrexate.  This effect is maximal 24 hours after|
00384|009|A|asparaginase administration and returns to baseline 96 hours later.|
00384|010|A|Asparaginase inhibits DNA synthesis and asparaginase-induced amino acid|
00384|011|A|depletion may cause cells to enter a stationary phase of growth.  Since|
00384|012|A|methotrexate is most toxic against cells that are actively synthesizing DNA,|
00384|013|A|its transport and cytocidal effects may be decreased.(1)|
00384|014|B||
00384|015|E|CLINICAL EFFECTS:  When asparaginase is administered prior to or with|
00384|016|E|cytarabine or methotrexate, asparaginase may diminish the effect of|
00384|017|E|cytarabine or methotrexate on malignant cells (1-3).|
00384|018|B||
00384|019|P|PREDISPOSING FACTORS:  None determined.|
00384|020|B||
00384|021|M|PATIENT MANAGEMENT:  Cytarabine and methotrexate should not be administered|
00384|022|M|with or during the period following asparaginase therapy when asparagine|
00384|023|M|levels are below normal.(2-3)|
00384|024|M|   A synergistic effect was observed when cytarabine was given before|
00384|025|M|asparaginase therapy and was most prominent with a treatment interval of|
00384|026|M|about 120 hours.(4)|
00384|027|M|   The optimal time interval between asparaginase and a subsequent dose of|
00384|028|M|methotrexate has been shown to be 9-10 days.  A 24-hour interval between|
00384|029|M|methotrexate and a subsequent dose of asparaginase allows for the return of|
00384|030|M|methotrexate's effects on malignant cells.(1)|
00384|031|B||
00384|032|D|DISCUSSION:  The effects of asparaginase with cytarabine or methotrexate in|
00384|033|D|combination are schedule-dependent.  When asparaginase is given concurrently|
00384|034|D|with or prior to cytarabine or methotrexate, asparaginase inhibits the|
00384|035|D|cytocidal effects of cytarabine and methotrexate.  However, when given 24|
00384|036|D|hours after larger doses of cytarabine or  methotrexate, asparaginase may|
00384|037|D|decrease some of the toxic effects of cytarabine or methotrexate, allowing|
00384|038|D|the host to tolerate larger doses of chemotherapy.  The sequential|
00384|039|D|administration of cytarabine or methotrexate followed by asparaginase may|
00384|040|D|result in synergistic effects and decreased toxicity (1).|
00384|041|B||
00384|042|R|REFERENCES:|
00384|043|B||
00384|044|R|1.Capizzi RL. Asparaginase-methotrexate in combination chemotherapy:|5
00384|045|R|  schedule- dependent differential effects on normal versus neoplastic|5
00384|046|R|  cells. Cancer Treat Rep 1981;65 Suppl 4:115-21.|5
00384|047|R|2.Elspar (asparaginase) US prescribing information. Merck & Co., Inc. July,|1
00384|048|R|  2006.|1
00384|049|R|3.Erwinase (crisantaspase) UK Summary of Product Characteristics. Porton|1
00384|050|R|  Biopharma Limited April 8, 2021.|1
00384|051|R|4.Spectrila (asparaginase) UK Summary of Product Characteristics. medac GmbH|1
00384|052|R|  June 10, 2021.|1
00385|001|T|MONOGRAPH TITLE:  Altretamine/Pyridoxine|
00385|002|B||
00385|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00385|004|L|is contraindicated and generally should not be dispensed or administered to|
00385|005|L|the same patient.|
00385|006|B||
00385|007|A|MECHANISM OF ACTION:  The mechanism by which pyridoxine adversely affects|
00385|008|A|response duration while coadministering altretamine is not known at this|
00385|009|A|time and requires further investigation.|
00385|010|B||
00385|011|E|CLINICAL EFFECTS:  The coadministration of oral pyridoxine with chemotherapy|
00385|012|E|regimens consisting of oral altretamine adversely affected response|
00385|013|E|duration.(1,2)|
00385|014|B||
00385|015|P|PREDISPOSING FACTORS:  None determined.|
00385|016|B||
00385|017|M|PATIENT MANAGEMENT:  Although pyridoxine administration significantly|
00385|018|M|reduces the neurotoxicity associated with altretamine, it should not be|
00385|019|M|administered with altretamine due to its adverse effect on response|
00385|020|M|duration.(1,2)|
00385|021|B||
00385|022|D|DISCUSSION:  In a study, 248 patients with Stages III-IV ovarian epithelial|
00385|023|D|cancer were randomized to one of four cisplatin and altretamine regimens.|
00385|024|D|In each regimen, oral altretamine (200 mg/m2 daily) was administered on days|
00385|025|D|8-21.  In addition, intravenous cisplatin was administered on day 1 (37.5|
00385|026|D|mg/m2, regimens A and B, or 75 mg/m2, regimens C and D).  Oral pyridoxine|
00385|027|D|(300 mg/m2 daily, days 1-21) was added to regimens B and D.  While|
00385|028|D|pyridoxine did decrease neurologic toxicity and had no effect on response,|
00385|029|D|pyridoxine was found to adversely affect response duration in all patients.|
00385|030|D|This effect was the greatest in previously untreated patients.  In addition,|
00385|031|D|pyridoxine had a slight negative effect on failure-free survival in|
00385|032|D|previously untreated patients.(1)|
00385|033|B||
00385|034|R|REFERENCES:|
00385|035|B||
00385|036|R|1.Wiernik PH, Yeap B, Vogl SE, Kaplan BH, Comis RL, Falkson G, Davis TE,|2
00385|037|R|  Fazzini E, Cheuvart B, Horton J. Hexamethylmelamine and low or moderate|2
00385|038|R|  dose cisplatin with or without pyridoxine for treatment of advanced|2
00385|039|R|  ovarian carcinoma: a study of the Eastern Cooperative Oncology Group.|2
00385|040|R|  Cancer Invest 1992;10(1):1-9.|2
00385|041|R|2.Hexalen (altretamine) US prescribing information. U.S. Bioscience Inc.|1
00385|042|R|  July, 1995.|1
00386|001|T|MONOGRAPH TITLE:  Dipyridamole Injectable/Xanthine Derivatives|
00386|002|B||
00386|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00386|004|L|is contraindicated and generally should not be dispensed or administered to|
00386|005|L|the same patient.|
00386|006|B||
00386|007|A|MECHANISM OF ACTION:  The xanthine derivatives are adenosine receptor|
00386|008|A|antagonists.  Concurrent administration may inhibit dipyridamole-induced|
00386|009|A|increases in endogenous plasma adenosine levels, thus decreasing|
00386|010|A|dipyridamole's vasodilator effects.(1)|
00386|011|B||
00386|012|E|CLINICAL EFFECTS:  Concurrent administration may result in a decrease in|
00386|013|E|dipyridamole's vasodilator effects.  This may produce false-negative results|
00386|014|E|during dipyridamole-thallium imaging tests.(1-3)|
00386|015|B||
00386|016|P|PREDISPOSING FACTORS:  In patients with congestive heart failure and|
00386|017|P|decreased hepatic function, the metabolism of xanthine derivatives may be|
00386|018|P|decreased.  These patients may need a longer xanthine-free period prior to|
00386|019|P|dipyridamole-thallium imaging tests.(2)|
00386|020|B||
00386|021|M|PATIENT MANAGEMENT:  Patients scheduled for dipyridamole-thallium imaging|
00386|022|M|tests should have a xanthine-free period (including caffeine-containing|
00386|023|M|products) for at least 24 hours prior to their exam.(3)|
00386|024|B||
00386|025|D|DISCUSSION:  In a study in eight male subjects with documented coronary|
00386|026|D|artery disease, intravenous dipyridamole administered during a|
00386|027|D|dipyridamole-thallium 201 SPECT image test produced a significant increase|
00386|028|D|in heart rate, a decrease in blood pressure, and angina in seven patients|
00386|029|D|and ST segment depression in four patients.  SPECT imaging showed reversible|
00386|030|D|perfusion defects in myocardial segments supplied by stenotic coronary|
00386|031|D|arteries.  When the exam was repeated when the subjects were receiving|
00386|032|D|therapeutic dosages of theophylline, there was no appearance of angina, ST|
00386|033|D|depression, or hemodynamic changes and SPECT imaging shown total absence of|
00386|034|D|reversible perfusion defects.(1)|
00386|035|D|   A study in eight patients with coronary artery disease evaluated the|
00386|036|D|effects of caffeine on dipyridamole-201Tl myocardial imaging.  The|
00386|037|D|administration of dipyridamole alone resulted in chest pain and ST-segment|
00386|038|D|depression in four patients.  Concurrent caffeine infusion decreased the|
00386|039|D|dipyridamole-induced decrease in blood pressure and heart rate.  No patients|
00386|040|D|experience chest pain or ST-segment depression.  Six patients had false|
00386|041|D|negative test results.(2)  Another study found that the attenuation of the|
00386|042|D|hemodynamic response to dipyridamole by caffeine was dose-dependent.(3)|
00386|043|B||
00386|044|R|REFERENCES:|
00386|045|B||
00386|046|R|1.Daley PJ, Mahn TH, Zielonka JS, Krubsack AJ, Akhtar R, Bamrah VS. Effect|2
00386|047|R|  of maintenance oral theophylline on dipyridamole-thallium-201 myocardial|2
00386|048|R|  imaging using SPECT and dipyridamole-induced hemodynamic changes. Am Heart|2
00386|049|R|  J 1988 Jun;115(6):1185-92.|2
00386|050|R|2.Smits P, Corstens FH, Aengevaeren WR, Wackers FJ, Thien T. False-negative|2
00386|051|R|  dipyridamole-thallium-201 myocardial imaging after caffeine infusion. J|2
00386|052|R|  Nucl Med 1991 Aug;32(8):1538-41.|2
00386|053|R|3.Smits P, Straatman C, Pijpers E, Thien T. Dose-dependent inhibition of the|2
00386|054|R|  hemodynamic response to dipyridamole by caffeine. Clin Pharmacol Ther 1991|2
00386|055|R|  Nov;50(5 Pt 1):529-37.|2
00387|001|T|MONOGRAPH TITLE:  Phentermine/SSRIs; Milnacipran (mono deleted 09/25/2014)|
00387|002|B||
00387|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00387|004|L|of severe adverse interaction.|
00387|005|B||
00387|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
00387|007|A|additive effects on serotonin.|
00387|008|B||
00387|009|E|CLINICAL EFFECTS:  Concurrent administration of phentermine with a selective|
00387|010|E|serotonin reuptake inhibitor or milnacipran may result in serotonin|
00387|011|E|syndrome.  Symptoms of serotonin syndrome may include tremor, agitation,|
00387|012|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
00387|013|E|rigidity.(4)|
00387|014|B||
00387|015|P|PREDISPOSING FACTORS:  None determined.|
00387|016|B||
00387|017|M|PATIENT MANAGEMENT:  The manufacturers of phentermine state that the|
00387|018|M|concurrent use of phentermine with selective serotonin reuptake inhibitors|
00387|019|M|is not recommended.(1,2)|
00387|020|B||
00387|021|D|DISCUSSION:  In a case report, a 22 year-old female had previously been|
00387|022|D|taking phentermine and oral contraceptive agents.  The patient stopped|
00387|023|D|taking phentermine and, after an undetermined length of time, started taking|
00387|024|D|fluoxetine (20 mg daily).  The patient discontinued her fluoxetine after|
00387|025|D|three months.  Eight days later, she took one dose of phentermine (30 mg).|
00387|026|D|Within several hours, she developed jitteriness, stomach cramps, dry eyes,|
00387|027|D|palpitations, and tremors.  The patient received once dose of lorazepam (1.5|
00387|028|D|mg) and her symptoms resolved over night.(3)|
00387|029|D|  The manufacturers of phentermine state that the concurrent administration|
00387|030|D|of phentermine and selective serotonin reuptake inhibitors is not|
00387|031|D|recommended.(1,2)|
00387|032|B||
00387|033|R|REFERENCES:|
00387|034|B||
00387|035|R|1.Fastin (phentermine) US prescribing information. SmithKline Beecham|1
00387|036|R|  Pharmaceuticals March, 1998.|1
00387|037|R|2.Adipex-P (phentermine hydrochloride) US prescribing information. Gate|1
00387|038|R|  Pharmaceuticals November, 2000.|1
00387|039|R|3.Bostwick JM, Brown TM. A toxic reaction from combining fluoxetine and|3
00387|040|R|  phentermine. J Clin Psychopharmacol 1996 Apr;16(2):189-90.|3
00387|041|R|4.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00387|042|R|  352(11):1112-20.|6
00388|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Fluvoxamine|
00388|002|B||
00388|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00388|004|L|take action as needed.|
00388|005|B||
00388|006|A|MECHANISM OF ACTION:  Fluvoxamine has been shown to inhibit the metabolism|
00388|007|A|of methadone at CYP3A4 in vitro.(1,2)|
00388|008|A|   Levomethadone is an enantiomer of methadone.(3)|
00388|009|B||
00388|010|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
00388|011|E|and clinical effects of methadone, which may result in QTc prolongation and|
00388|012|E|life-threatening arrhythmias.|
00388|013|E|   Elevated levels can also cause profound sedation, respiratory depression,|
00388|014|E|coma, and/or death.|
00388|015|E|   The discontinuation of fluvoxamine in patients maintained on methadone|
00388|016|E|may result in symptoms of methadone withdrawal.|
00388|017|E|   Methadone has been associated with serotonin syndrome.  Symptoms of|
00388|018|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
00388|019|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
00388|020|B||
00388|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
00388|022|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
00388|023|P|myocardial infarction, history of torsades de pointes, congenital long QT|
00388|024|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
00388|025|P|gender, or advanced age.(4)|
00388|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00388|027|P|higher systemic concentrations of either QT prolonging drug are additional|
00388|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00388|029|P|drug concentrations include rapid infusion of an intravenous dose or|
00388|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00388|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00388|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
00388|033|B||
00388|034|M|PATIENT MANAGEMENT:  Patients receiving methadone should be monitored|
00388|035|M|closely when fluvoxamine is initiated or withdrawn.  The dosage of methadone|
00388|036|M|may need to be adjusted.|
00388|037|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00388|038|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00388|039|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00388|040|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00388|041|M|   Respiratory depression can occur at any time during opioid therapy,|
00388|042|M|especially during therapy initiation and following dosage increases.  The|
00388|043|M|risk of opioid-related overdose or overdose-related death is increased with|
00388|044|M|higher opioid doses, and this risk persists over the course of therapy.|
00388|045|M|Consider these risks when using concurrently with agents that may increase|
00388|046|M|opioid drug levels.(5)|
00388|047|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00388|048|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00388|049|M|unresponsiveness.|
00388|050|M|   If concurrent therapy is warranted, patients should be monitored for|
00388|051|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00388|052|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00388|053|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00388|054|M|coordination, or severe diarrhea.|
00388|055|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
00388|056|M|patients when prescribing or renewing an opioid analgesic or medicine to|
00388|057|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
00388|058|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
00388|059|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
00388|060|M|as those taking CNS depressants) and when a patient has household|
00388|061|M|members/close contacts at risk for accidental overdose.  Discuss the options|
00388|062|M|for obtaining an opioid reversal agent (e.g., prescription,|
00388|063|M|over-the-counter, or as part of a community-based program).(6)|
00388|064|B||
00388|065|D|DISCUSSION:  Five case reports of concurrent methadone and fluvoxamine were|
00388|066|D|reported in a single article.  In two patients, methadone levels increased|
00388|067|D|20% following the addition of fluvoxamine therapy.  In the remaining three|
00388|068|D|patients, methadone levels increased 40-100%.  One patient experienced|
00388|069|D|symptoms of methadone withdrawal following the discontinuation of|
00388|070|D|fluvoxamine.(7)|
00388|071|D|   Severe cardiovascular events, including QT prolongation, torsades de|
00388|072|D|pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have|
00388|073|D|been reported in patients receiving concurrent therapy with itraconazole and|
00388|074|D|levomethadyl(1) or methadone.(1,7)|
00388|075|D|   In vitro studies have shown that fluvoxamine inhibits the metabolism of|
00388|076|D|methadone at CYP3A4.(1,2)|
00388|077|B||
00388|078|R|REFERENCES:|
00388|079|B||
00388|080|R|1.Iribarne C, Picart D, Dreano Y, Berthou F. In vitro interactions between|5
00388|081|R|  fluoxetine or fluvoxamine and methadone or buprenorphine. Fundam Clin|5
00388|082|R|  Pharmacol 1998;12(2):194-9.|5
00388|083|R|2.Iribarne C, Dreano Y, Bardou LG, Menez JF, Berthou F. Interaction of|5
00388|084|R|  methadone with substrates of human hepatic cytochrome P450 3A4. Toxicology|5
00388|085|R|  1997 Feb 14;117(1):13-23.|5
00388|086|R|3.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
00388|087|R|  Pharma AS November 30, 2018.|1
00388|088|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00388|089|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00388|090|R|  settings: a scientific statement from the American Heart Association and|6
00388|091|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00388|092|R|  2;55(9):934-47.|6
00388|093|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
00388|094|R|  prescribing information for all opioid pain medicines to provide|1
00388|095|R|  additional guidance for safe use. Available at:|1
00388|096|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
00388|097|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
00388|098|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
00388|099|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
00388|100|R|  recommends health care professionals discuss naloxone with all patients|1
00388|101|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
00388|102|R|  disorder. Available at:|1
00388|103|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
00388|104|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
00388|105|R|  d-pain July 23, 2020.|1
00388|106|R|7.Bertschy G, Baumann P, Eap CB, Baettig D. Probable metabolic interaction|3
00388|107|R|  between methadone and fluvoxamine in addict patients. Ther Drug Monit 1994|3
00388|108|R|  Feb;16(1):42-5.|3
00389|001|T|MONOGRAPH TITLE:  Carbamazepine/Monoamine Oxidase Inhibitors|
00389|002|B||
00389|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00389|004|L|is contraindicated and generally should not be dispensed or administered to|
00389|005|L|the same patient.|
00389|006|B||
00389|007|A|MECHANISM OF ACTION:  Carbamazepine is structurally related to the tricyclic|
00389|008|A|antidepressants, which may sensitize adrenergic receptors to amines that can|
00389|009|A|accumulate extra neuronally as a result of MAO inhibition.|
00389|010|B||
00389|011|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine with a MAOI may result in|
00389|012|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
00389|013|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
00389|014|E|and muscle rigidity.(11)|
00389|015|E|   Possible increases in serum carbamazepine levels can be seen predisposing|
00389|016|E|patients to carbamazepine toxicity.  This may increase excitation, delirium,|
00389|017|E|tremor, twitching, convulsions, coma, and circulatory collapse.  It has also|
00389|018|E|been suggested that the combination of carbamazepine and MAOIs may possibly|
00389|019|E|lead to synergistic hepatotoxicity.|
00389|020|B||
00389|021|P|PREDISPOSING FACTORS:  None determined.|
00389|022|B||
00389|023|M|PATIENT MANAGEMENT:  The US manufacturer of carbamazepine states that MAOIs|
00389|024|M|should be discontinued at least 14 days prior to initiation of carbamazepine|
00389|025|M|therapy.(2)|
00389|026|M|   The US manufacturer of tranylcypromine states that concurrent use of|
00389|027|M|dibenzazepine-related entities (such as carbamazepine) is|
00389|028|M|contraindicated.(3)|
00389|029|M|   The US manufacturer of selegiline states that concurrent use of|
00389|030|M|carbamazepine is contraindicated.(4)|
00389|031|M|   If concurrent therapy is warranted, patients should be monitored for|
00389|032|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00389|033|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00389|034|M|heart palpitations, restlessness, confusion, agitation, trouble|
00389|035|M|coordination, or severe diarrhea.|
00389|036|B||
00389|037|D|DISCUSSION:  Carbamazepine's chemical structure is similar to that of the|
00389|038|D|tricyclic antidepressants (TCAs).(1,2)  TCA serum levels have been elevated|
00389|039|D|by coadministration of isoniazid, a monoamine oxidase inhibitor.  Because of|
00389|040|D|these similarities, it has been hypothesized that MAOIs could inhibit the|
00389|041|D|metabolism of carbamazepine.(1,4)|
00389|042|D|   In a study(4) involving 10 patients, CBZ dosing, and subsequent serum|
00389|043|D|levels, were compared to patients receiving phenelzine verses|
00389|044|D|tranylcypromine.  Results showed that the tranylcypromine group required a|
00389|045|D|2.3 times higher dose than the phenelzine group.  In a related study,(1) 10|
00389|046|D|subjects were given a MAOI, with or without lithium, to examine changes in|
00389|047|D|CBZ pharmacokinetics.  Results showed no significant difference in CBZ level|
00389|048|D|or dose when comparing the phenelzine and tranylcypromine group to baseline.|
00389|049|D|There were also no differences in CBZ level or dose when comparing the|
00389|050|D|phenelzine and tranylcypromine group to each other.|
00389|051|D|   In one case report,(5) a 52 year old woman on CBZ was started on|
00389|052|D|tranylcypromine.  Combination therapy was continued for 2 weeks, at which|
00389|053|D|time the patient's mental state improved and tranylcypromine was|
00389|054|D|discontinued.  The patient experienced no adverse events.  The same author|
00389|055|D|reports another case(5) involving a 31 year-old woman on CBZ who was started|
00389|056|D|on tranylcypromine.  Subsequently, her serum CBZ level decreased 35% over|
00389|057|D|following two weeks.  In a related case,(6) a 24 year-old man on CBZ was|
00389|058|D|started on tranylcypromine.  CBZ levels were drawn on 15 separate occasions|
00389|059|D|over 52 days, which resulted in no significant change in CBZ serum level|
00389|060|D|from his baseline.  This patient also experienced no adverse effects.|
00389|061|D|   Because these studies and case reports examined only a small group of|
00389|062|D|patients and their results are conflicting, it is difficult to assess the|
00389|063|D|clinical significance of this interaction.  However, the manufacturer of|
00389|064|D|carbamazepine states that MAOIs be discontinued for a minimum of 14 days|
00389|065|D|before beginning carbamazepine therapy.(2)|
00389|066|D|   Methylene blue, when administered intravenously, has been shown to reach|
00389|067|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
00389|068|D|   Metaxalone is a weak inhibitor of MAO.|
00389|069|B||
00389|070|R|REFERENCES:|
00389|071|B||
00389|072|R|1.Ketter TA, Post RM, Parekh PI, Worthington K. Addition of monoamine|2
00389|073|R|  oxidase inhibitors to carbamazepine: preliminary evidence of safety and|2
00389|074|R|  antidepressant efficacy in treatment-resistant depression. J Clin|2
00389|075|R|  Psychiatry 1995 Oct;56(10):471-5.|2
00389|076|R|2.Tegretol (carbamazepine) US prescribing information. Novartis|1
00389|077|R|  Pharmaceuticals Corporation September, 2023.|1
00389|078|R|3.Parnate (tranylcypromine sulfate) US prescribing information.|1
00389|079|R|  GlaxoSmithKline January 4, 2018.|1
00389|080|R|4.Emsam (selegline) US prescribing information. Somerset July, 2017.|1
00389|081|R|5.Barklage NE, Jefferson JW, Margolis D. Do monoamine oxidase inhibitors|6
00389|082|R|  alter carbamazepine blood levels?. J Clin Psychiatry 1992 Jul;53(7):258.|6
00389|083|R|6.Lydiard RB, White D, Harvey B, Taylor A. Lack of pharmacokinetic|3
00389|084|R|  interaction between tranylcypromine and carbamazepine. J Clin|3
00389|085|R|  Psychopharmacol 1987 Oct;7(5):360.|3
00389|086|R|7.Joffe RT, Post RM, Uhde TW. Lack of pharmacokinetic interaction of|3
00389|087|R|  carbamazepine with tranylcypromine. Arch Gen Psychiatry 1985 Jul;|3
00389|088|R|  42(7):738.|3
00389|089|R|8.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
00389|090|R|  283(13):1679.|1
00389|091|R|9.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00389|092|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00389|093|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00389|094|R|10.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00389|095|R|   distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00389|096|R|   2000 Jun;56(3):247-50.|2
00389|097|R|11.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00389|098|R|   352(11):1112-20.|6
00389|099|R|12.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00389|100|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00389|101|R|   Feb;34(2):346.e5-6.|3
00389|102|R|13.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00389|103|R|   Pfizer Inc. January, 2024.|1
00390|001|T|MONOGRAPH TITLE:  Atorvastatin/Diltiazem|
00390|002|B||
00390|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00390|004|L|take action as needed.|
00390|005|B||
00390|006|A|MECHANISM OF ACTION:  Diltiazem may inhibit the metabolism of atorvastatin|
00390|007|A|by CYP3A4.(1)|
00390|008|B||
00390|009|E|CLINICAL EFFECTS:  Concurrent diltiazem may result in elevated levels of|
00390|010|E|atorvastatin,(1) which may result in rhabdomyolysis.|
00390|011|B||
00390|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
00390|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
00390|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
00390|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
00390|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
00390|017|P|transporter OATP1B1 may have increased statin concentrations and be|
00390|018|P|predisposed to myopathy or rhabdomyolysis.|
00390|019|B||
00390|020|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with diltiazem|
00390|021|M|should be monitored closely for adverse effects of the HMG-CoA reductase|
00390|022|M|inhibitor, including rhabdomyolysis.  The dosage of the HMG-CoA reductase|
00390|023|M|inhibitor may need to be reduced or discontinued.|
00390|024|M|   Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not|
00390|025|M|metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and|
00390|026|M|simvastatin in patients receiving diltiazem.|
00390|027|B||
00390|028|D|DISCUSSION:  There is a case report of rhabdomyolysis following the addition|
00390|029|D|of diltiazem to a patient maintained on atorvastatin.(1)|
00390|030|D|      In a PKPB model, concurrent use of atorvastatin (20 mg daily) with|
00390|031|D|diltiazem (180 mg twice daily for 3 weeks) increased the simulated Cmax|
00390|032|D|ratio and AUC ratio of atorvastatin by 1.32 and 1.77, respectively, and|
00390|033|D|increased the simulated Cmax ratio and AUC ratio of atorvastatin lactone by|
00390|034|D|2.66 and 3.24, respectively.(2)|
00390|035|B||
00390|036|R|REFERENCES:|
00390|037|B||
00390|038|R|1.Lewin JJ 3rd, Nappi JM, Taylor MH. Rhabdomyolysis with concurrent|3
00390|039|R|  atorvastatin and diltiazem. Ann Pharmacother 2002 Oct;36(10):1546-9.|3
00390|040|R|2.Li S, Yu Y, Jin Z, Dai Y, Lin H, Jiao Z, Ma G, Cai W, Han B, Xiang X.|2
00390|041|R|  Prediction of pharmacokinetic drug-drug interactions causing|2
00390|042|R|  atorvastatin-induced rhabdomyolysis using physiologically based|2
00390|043|R|  pharmacokinetic modelling. Biomed Pharmacother 2019 Sep 10;119:109416.|2
00391|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/Delavirdine|
00391|002|B||
00391|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00391|004|L|is contraindicated and generally should not be dispensed or administered to|
00391|005|L|the same patient.|
00391|006|B||
00391|007|A|MECHANISM OF ACTION:  Delavirdine(1) may inhibit the metabolism of|
00391|008|A|astemizole and terfenadine by CYP3A4.|
00391|009|B||
00391|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of|
00391|011|E|astemizole or terfenadine,(1) which may result in potentially|
00391|012|E|life-threatening ventricular arrhythmias including QT prolongation or|
00391|013|E|torsades de pointes.(2,3)|
00391|014|B||
00391|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00391|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
00391|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00391|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00391|019|P|female gender, or advanced age.(4)|
00391|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00391|021|P|higher systemic concentrations of either QT prolonging drug are additional|
00391|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00391|023|P|drug concentrations include rapid infusion of an intravenous dose or|
00391|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00391|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00391|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
00391|027|B||
00391|028|M|PATIENT MANAGEMENT:  The manufacturer of delavirdine states that the|
00391|029|M|concurrent use of delavirdine and astemizole or terfenadine is|
00391|030|M|contraindicated.(1)|
00391|031|M|   Fexofenadine or loratadine, nonsedating antihistamines which have been|
00391|032|M|shown to have no effects on cardiac function,(5-6) may be alternatives to|
00391|033|M|astemizole or terfenadine in patients receiving delavirdine.|
00391|034|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00391|035|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00391|036|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00391|037|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00391|038|B||
00391|039|D|DISCUSSION:  Delavirdine has been shown to inhibit CYP3A4.  Concurrent use|
00391|040|D|of delavirdine with agents that are highly dependent on CYP3A4 for clearance|
00391|041|D|and for which elevated plasma concentrations are associated with serious|
00391|042|D|and/or life-threatening events, such as astemizole or terfenadine, is|
00391|043|D|contraindicated.(1)|
00391|044|B||
00391|045|R|REFERENCES:|
00391|046|B||
00391|047|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
00391|048|R|  Upjohn Company August, 2012.|1
00391|049|R|2.Hismanal (astemizole) US prescribing information. Janssen Pharmaceutica|1
00391|050|R|  Products, L.P. February, 1998.|1
00391|051|R|3.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00391|052|R|  September, 1997.|1
00391|053|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00391|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00391|055|R|  settings: a scientific statement from the American Heart Association and|6
00391|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00391|057|R|  2;55(9):934-47.|6
00391|058|R|5.Allegra (fexofenadine hydrochloride) US prescribing information.|1
00391|059|R|  Sanofi-Aventis U.S. LLC October, 2006.|1
00391|060|R|6.Claritin (loratidine) US prescribing information. Schering-Plough|1
00391|061|R|  Corporation January, 1997.|1
00392|001|T|MONOGRAPH TITLE:  Midazolam; Triazolam/Efavirenz (mono deleted 06/12/2014)|
00392|002|B||
00392|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00392|004|L|is contraindicated and generally should not be dispensed or administered to|
00392|005|L|the same patient.|
00392|006|B||
00392|007|A|MECHANISM OF ACTION:  Efavirenz may inhibit the metabolism of midazolam and|
00392|008|A|triazolam.(1,2)|
00392|009|B||
00392|010|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
00392|011|E|and clinical effects of the benzodiazepines, which may result in prolonged|
00392|012|E|sedation and respiratory depression.|
00392|013|B||
00392|014|P|PREDISPOSING FACTORS:  None determined.|
00392|015|B||
00392|016|M|PATIENT MANAGEMENT:  The manufacturer of efavirenz states that concurrent|
00392|017|M|use of midazolam or triazolam is contraindicated.(1,2)|
00392|018|B||
00392|019|D|DISCUSSION:  Efavirenz has shown to inhibit CYP P-450-3A4.  Competition for|
00392|020|D|this isozyme may result in increased levels of midazolam or triazolam, which|
00392|021|D|may result in prolonged sedation.  The manufacturer of efavirenz states that|
00392|022|D|midazolam and triazolam should not be administered with efavirenz.(1,2)|
00392|023|B||
00392|024|R|REFERENCES:|
00392|025|B||
00392|026|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
00392|027|R|  Company August, 2012.|1
00392|028|R|2.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
00392|029|R|  prescribing information. Gilead Sciences, Inc. October, 2013.|1
00393|001|T|MONOGRAPH TITLE:  Cisapride/Delavirdine|
00393|002|B||
00393|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00393|004|L|is contraindicated and generally should not be dispensed or administered to|
00393|005|L|the same patient.|
00393|006|B||
00393|007|A|MECHANISM OF ACTION:  Delavirdine may inhibit the metabolism of|
00393|008|A|cisapride.(1)|
00393|009|B||
00393|010|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
00393|011|E|of cisapride, which may result in potentially life-threatening ventricular|
00393|012|E|arrhythmias.(1)|
00393|013|B||
00393|014|P|PREDISPOSING FACTORS:  None determined.|
00393|015|B||
00393|016|M|PATIENT MANAGEMENT:  The manufacturer of delavirdine states that the|
00393|017|M|concurrent use of cisapride is contraindicated.(1)|
00393|018|B||
00393|019|D|DISCUSSION:  Delavirdine has been shown to inhibit CYP3A4. Concurrent use of|
00393|020|D|delavirdine with agents that are highly dependent on CYP3A4 for clearance|
00393|021|D|and for which elevated plasma concentrations are associated with serious|
00393|022|D|and/or life-threatening events, such as cisapride, is contraindicated.(1)|
00393|023|B||
00393|024|R|REFERENCE:|
00393|025|B||
00393|026|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
00393|027|R|  Upjohn Company August, 2012.|1
00394|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Delavirdine|
00394|002|B||
00394|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00394|004|L|is contraindicated and generally should not be dispensed or administered to|
00394|005|L|the same patient.|
00394|006|B||
00394|007|A|MECHANISM OF ACTION:  Delavirdine may inhibit the metabolism of the ergot|
00394|008|A|alkaloids by CYP3A4.(1,2)|
00394|009|B||
00394|010|E|CLINICAL EFFECTS:  Concurrent administration with delavirdine may result in|
00394|011|E|increased levels, clinical effects, and possible toxicity of the ergot|
00394|012|E|alkaloids.(1,2)|
00394|013|B||
00394|014|P|PREDISPOSING FACTORS:  None determined.|
00394|015|B||
00394|016|M|PATIENT MANAGEMENT:  The manufacturer of delavirdine states that the|
00394|017|M|concurrent use of ergot alkaloids is contraindicated.(1)|
00394|018|M|   The US manufacturer of methylergonovine states that methylergonovine|
00394|019|M|should not be administered with potent CYP3A4 inhibitors such as|
00394|020|M|delavirdine.(2)|
00394|021|B||
00394|022|D|DISCUSSION:  Delavirdine has been shown to inhibit CYP3A4. Concurrent use of|
00394|023|D|delavirdine with agents that are highly dependent on CYP3A4 for clearance|
00394|024|D|and for which elevated plasma concentrations are associated with serious|
00394|025|D|and/or life-threatening events, such as the ergot alkaloids, is|
00394|026|D|contraindicated.(1)|
00394|027|B||
00394|028|R|REFERENCES:|
00394|029|B||
00394|030|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
00394|031|R|  Upjohn Company August, 2012.|1
00394|032|R|2.Methergine (methylergonovine maleate) US prescribing information. Novartis|1
00394|033|R|  Pharmaceuticals Corporation June, 2012.|1
00395|001|T|MONOGRAPH TITLE:  Sertindole/Quinidine|
00395|002|B||
00395|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00395|004|L|is contraindicated and generally should not be dispensed or administered to|
00395|005|L|the same patient.|
00395|006|B||
00395|007|A|MECHANISM OF ACTION:  Quinidine may inhibit the metabolism of sertindole at|
00395|008|A|CYP2D6.  In addition, concurrent use may result in additive effects on the|
00395|009|A|QTc interval.(1)|
00395|010|B||
00395|011|E|CLINICAL EFFECTS:  Concurrent use may result in increased levels and effects|
00395|012|E|of sertindole and additive effects on the QTc interval.  Increased QTc|
00395|013|E|interval may result in potentially life-threatening arrhythmias.(1)|
00395|014|E|   Concurrent use may increase the risk of extrapyramidal reactions (e.g.|
00395|015|E|acute dystonic reactions, pseudoparkinsonism tremors, akathisia, or tardive|
00395|016|E|dyskinesia) and neuroleptic malignant syndrome. Tardive dyskinesia, which|
00395|017|E|may be permanent, typically effects the facial muscles and may result in|
00395|018|E|uncontrollable lip smacking, chewing, puckering of the mouth, frowning or|
00395|019|E|scowling, sticking out the tongue, blinking and moving the eyes, and shaking|
00395|020|E|of the arms and/or legs. Symptoms of neuroleptic malignant syndrome include|
00395|021|E|hyperpyrexia, muscle rigidity, altered mental status, an autonomic|
00395|022|E|instability (irregular pulse or blood pressure, tachycardia, diaphoresis,|
00395|023|E|and cardiac arrhythmias), elevated creatinine phosphokinase, myoglobinuria|
00395|024|E|(rhabdomyolysis), and acute renal failure.|
00395|025|B||
00395|026|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00395|027|P|may be increased in patients with cardiovascular disease (e.g. heart|
00395|028|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00395|029|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00395|030|P|female gender, or advanced age.(2)|
00395|031|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00395|032|P|higher systemic concentrations of either QT prolonging drug are additional|
00395|033|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00395|034|P|drug concentrations include rapid infusion of an intravenous dose or|
00395|035|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00395|036|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00395|037|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00395|038|B||
00395|039|M|PATIENT MANAGEMENT:  The manufacturer of sertindole states that the|
00395|040|M|concurrent administration of sertindole with agents known to prolong the QT|
00395|041|M|interval is contraindicated.(1)|
00395|042|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00395|043|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00395|044|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00395|045|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00395|046|M|   Symptoms of extrapyramidal reactions, including tardive dyskinesia,|
00395|047|M|include involuntary movements of limbs and facial grimacing, torticollis,|
00395|048|M|oculogyric crisis, rhythmic protrusion of the gone, bulbar  type of speech,|
00395|049|M|trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.|
00395|050|B||
00395|051|D|DISCUSSION:  Sertindole has been shown to prolong the QT interval in some|
00395|052|D|patients.  Prolongation of the QT interval may result in potentially|
00395|053|D|life-threatening arrhythmias, including torsade de pointes.  The risk of QT|
00395|054|D|prolongation is increased in patients taking concomitant medications that|
00395|055|D|increase the QT interval and/or inhibit the metabolism of sertindole.|
00395|056|D|Quinidine has been shown to prolong the QT interval and may inhibit the|
00395|057|D|metabolism of sertindole at CYP2D6.  Therefore, the manufacturer of|
00395|058|D|sertindole states that the concurrent administration of sertindole with|
00395|059|D|quinidine is contraindicated.(1)|
00395|060|B||
00395|061|R|REFERENCES:|
00395|062|B||
00395|063|R|1.Serdolect (sertindole) UK summary of product characteristics. Lundbeck|1
00395|064|R|  Limited October 25, 1996.|1
00395|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00395|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00395|067|R|  settings: a scientific statement from the American Heart Association and|6
00395|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00395|069|R|  2;55(9):934-47.|6
00395|070|R|3.Serdolect (sertindole) Sweden Summary of Product Characteristics. H.|1
00395|071|R|  Lundbeck A S March 4, 2021.|1
00396|001|T|MONOGRAPH TITLE:  Sertindole/Thioridazine|
00396|002|B||
00396|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00396|004|L|is contraindicated and generally should not be dispensed or administered to|
00396|005|L|the same patient.|
00396|006|B||
00396|007|A|MECHANISM OF ACTION:  The concurrent use of sertindole and thioridazine may|
00396|008|A|result in additive effects on the QTc interval.(1) Thioridazine may decrease|
00396|009|A|the efficacy of sertindole through CYP3A4 induction.|
00396|010|B||
00396|011|E|CLINICAL EFFECTS:  Concurrent use may result in prolongation of the QTc|
00396|012|E|interval, which may result in potentially life-threatening arrhythmias.(1)|
00396|013|E|   Coadministration of sertindole with the moderate CYP3A4 inducer|
00396|014|E|thioridazine decreases sertindole plasma concentrations, which may decrease|
00396|015|E|the efficacy of sertindole. It is unknown how decreased levels of sertindole|
00396|016|E|affects the risk of QTc interval prolongation when sertindole is used|
00396|017|E|concurrently with the QT prolonging CYP3A4 inducer thioridazine.|
00396|018|B||
00396|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00396|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
00396|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00396|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00396|023|P|female gender, or advanced age.(2)|
00396|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00396|025|P|higher systemic concentrations of either QT prolonging drug are additional|
00396|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00396|027|P|drug concentrations include rapid infusion of an intravenous dose or|
00396|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00396|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00396|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00396|031|B||
00396|032|M|PATIENT MANAGEMENT:  The manufacturer of sertindole states that the|
00396|033|M|concurrent administration of sertindole with agents known to prolong the QT|
00396|034|M|interval, such as thioridazine, is contraindicated.(1)|
00396|035|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00396|036|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00396|037|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00396|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00396|039|B||
00396|040|D|DISCUSSION:  Sertindole has been shown to prolong the QT interval in some|
00396|041|D|patients.  Prolongation of the QT interval may result in potentially|
00396|042|D|life-threatening arrhythmias, including torsade de pointes.  The risk of QT|
00396|043|D|prolongation is increased in patients taking concomitant medications that|
00396|044|D|increase the QT interval.  Thioridazine has been shown to prolong the QT|
00396|045|D|interval.  Therefore, the manufacturer of sertindole states that the|
00396|046|D|concurrent administration of sertindole with thioridazine is|
00396|047|D|contraindicated.(1)|
00396|048|B||
00396|049|R|REFERENCES:|
00396|050|B||
00396|051|R|1.Serdolect (sertindole) UK summary of product characteristics. Lundbeck|1
00396|052|R|  Limited October 25, 1996.|1
00396|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00396|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00396|055|R|  settings: a scientific statement from the American Heart Association and|6
00396|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00396|057|R|  2;55(9):934-47.|6
00396|058|R|3.Serdolect (sertindole) Sweden Summary of Product Characteristics. H.|1
00396|059|R|  Lundbeck A S March 4, 2021.|1
00397|001|T|MONOGRAPH TITLE:  Sertindole/Itraconazole; Ketoconazole|
00397|002|B||
00397|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00397|004|L|is contraindicated and generally should not be dispensed or administered to|
00397|005|L|the same patient.|
00397|006|B||
00397|007|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
00397|008|A|metabolism of sertindole at CYP3A4.(1)|
00397|009|B||
00397|010|E|CLINICAL EFFECTS:  Concurrent use may result in increased levels of|
00397|011|E|sertindole, which may increase the risk of prolongation of the QT interval.|
00397|012|E|Prolongation of the QT interval may result in potentially life-threatening|
00397|013|E|arrhythmias.(1)|
00397|014|E|   Concurrent use may increase the risk of extrapyramidal reactions (e.g.|
00397|015|E|acute dystonic reactions, pseudoparkinsonism tremors, akathisia, or tardive|
00397|016|E|dyskinesia) and neuroleptic malignant syndrome. Tardive dyskinesia, which|
00397|017|E|may be permanent, typically effects the facial muscles and may result in|
00397|018|E|uncontrollable lip smacking, chewing, puckering of the mouth, frowning or|
00397|019|E|scowling, sticking out the tongue, blinking and moving the eyes, and shaking|
00397|020|E|of the arms and/or legs. Symptoms of neuroleptic malignant syndrome include|
00397|021|E|hyperpyrexia, muscle rigidity, altered mental status, an autonomic|
00397|022|E|instability (irregular pulse or blood pressure, tachycardia, diaphoresis,|
00397|023|E|and cardiac arrhythmias), elevated creating phosphokinase, myoglobinuria|
00397|024|E|(rhabdomyolysis), and acute renal failure.|
00397|025|B||
00397|026|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00397|027|P|may be increased in patients with cardiovascular disease (e.g. heart|
00397|028|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00397|029|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00397|030|P|female gender, or advanced age.(2)|
00397|031|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00397|032|P|higher systemic concentrations of either QT prolonging drug are additional|
00397|033|P|risk factors for torsades de pointes. Factors which may increased systemic|
00397|034|P|drug concentrations include rapid infusion of an intravenous dose or|
00397|035|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00397|036|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00397|037|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00397|038|P|   Effects may be more pronounced in poor CYP2D6 metabolizers as sertindole|
00397|039|P|is metabolized by CYP3A4 and CYP2D6.|
00397|040|B||
00397|041|M|PATIENT MANAGEMENT:  The manufacturer of sertindole states that the|
00397|042|M|concurrent administration of sertindole with itraconazole or ketoconazole is|
00397|043|M|contraindicated.(1)|
00397|044|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00397|045|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00397|046|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00397|047|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00397|048|M|   The manufacturer of sertindole recommends monitoring ECG at initiation,|
00397|049|M|approximately 3 weeks after steady state or when the dose is increased to 16|
00397|050|M|mg, and after 3 months of treatment. During maintenance treatment, an ECG|
00397|051|M|should be taken every 3 months and before and after any dose increase.(3)|
00397|052|M|   Symptoms of extrapyramidal reactions, including tardive dyskinesia,|
00397|053|M|include involuntary movements of limbs and facial grimacing, torticollis,|
00397|054|M|oculogyric crisis, rhythmic protrusion of the gone, bulbar  type of speech,|
00397|055|M|trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.|
00397|056|B||
00397|057|D|DISCUSSION:  Sertindole has been shown to prolong the QT interval in some|
00397|058|D|patients.  Prolongation of the QT interval may result in potentially|
00397|059|D|life-threatening arrhythmias, including torsade de pointes.  The risk of QT|
00397|060|D|prolongation is increased in patients taking concomitant medications that|
00397|061|D|inhibit the metabolism of sertindole.  Itraconazole and ketoconazole may|
00397|062|D|inhibit the metabolism of sertindole at CYP3A4.  Therefore, the manufacturer|
00397|063|D|of sertindole states that the concurrent administration of sertindole with|
00397|064|D|itraconazole or ketoconazole is contraindicated.(1)|
00397|065|B||
00397|066|R|REFERENCES:|
00397|067|B||
00397|068|R|1.Serdolect (sertindole) UK summary of product characteristics. Lundbeck|1
00397|069|R|  Limited October 25, 1996.|1
00397|070|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00397|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00397|072|R|  settings: a scientific statement from the American Heart Association and|6
00397|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00397|074|R|  2;55(9):934-47.|6
00397|075|R|3.Serdolect (sertindole) Sweden Summary of Product Characteristics. H.|1
00397|076|R|  Lundbeck A S March 4, 2021.|1
00398|001|T|MONOGRAPH TITLE:  Sertindole/Astemizole; Terfenadine (mono deleted|
00398|002|T|09/04/2014)|
00398|003|B||
00398|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00398|005|L|is contraindicated and generally should not be dispensed or administered to|
00398|006|L|the same patient.|
00398|007|B||
00398|008|A|MECHANISM OF ACTION:  The concurrent use of sertindole with either|
00398|009|A|astemizole or terfenadine may result in additive effects on the QTc|
00398|010|A|interval.(1)|
00398|011|B||
00398|012|E|CLINICAL EFFECTS:  Concurrent use may result in prolongation of the QTc|
00398|013|E|interval, which may result in potentially life-threatening arrhythmias.(1)|
00398|014|B||
00398|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00398|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
00398|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00398|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00398|019|P|female gender, or advanced age.(2)|
00398|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00398|021|P|higher systemic concentrations of either QT prolonging drug are additional|
00398|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00398|023|P|drug concentrations include rapid infusion of an intravenous dose or|
00398|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00398|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00398|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00398|027|B||
00398|028|M|PATIENT MANAGEMENT:  The manufacturer of sertindole states that the|
00398|029|M|concurrent administration of sertindole with agents known to prolong the QT|
00398|030|M|interval, such as astemizole or terfenadine, is contraindicated.(1)|
00398|031|B||
00398|032|D|DISCUSSION:  Sertindole has been shown to prolong the QT interval in some|
00398|033|D|patients.  Prolongation of the QT interval may result in potentially|
00398|034|D|life-threatening arrhythmias, including torsade de pointes.  The risk of QT|
00398|035|D|prolongation is increased in patients taking concomitant medications that|
00398|036|D|increase the QT interval.  Both astemizole and terfenadine have been shown|
00398|037|D|to prolong the QT interval.  Therefore, the manufacturer of sertindole|
00398|038|D|states that the concurrent administration of sertindole with either|
00398|039|D|astemizole or terfenadine is contraindicated.(1)|
00398|040|B||
00398|041|R|REFERENCES:|
00398|042|B||
00398|043|R|1.Serdolect (sertindole) UK summary of product characteristics. Lundbeck|1
00398|044|R|  Limited October 25, 1996.|1
00398|045|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00398|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00398|047|R|  settings: a scientific statement from the American Heart Association and|6
00398|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00398|049|R|  2;55(9):934-47.|6
00399|001|T|MONOGRAPH TITLE:  Fosphenytoin; Phenytoin/Azapropazone|
00399|002|B||
00399|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00399|004|L|is contraindicated and generally should not be dispensed or administered to|
00399|005|L|the same patient.|
00399|006|B||
00399|007|A|MECHANISM OF ACTION:  Azapropazone may inhibit the CYP2C9 mediated|
00399|008|A|metabolism of phenytoin. (1)|
00399|009|B||
00399|010|E|CLINICAL EFFECTS:  The concurrent administration of azapropazone may result|
00399|011|E|in increased levels of phenytoin.(1) Phenytoin has a narrow therapeutic|
00399|012|E|range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia,|
00399|013|E|dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision,|
00399|014|E|nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g.|
00399|015|E|coma, irreversible cerebellar dysfunction and atrophy, hypotension,|
00399|016|E|bradycardia, seizures, and cardiac arrest) and may be fatal.(2)|
00399|017|B||
00399|018|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
00399|019|P|hypoalbuminemia.|
00399|020|B||
00399|021|M|PATIENT MANAGEMENT:  The manufacturer of azapropazone states under|
00399|022|M|contraindications that azapropazone should not be administered to patients|
00399|023|M|receiving phenytoin.(1)|
00399|024|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
00399|025|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
00399|026|M|vision, nausea, and vomiting).|
00399|027|B||
00399|028|D|DISCUSSION:  In a study in 5 healthy males, concurrent administration of|
00399|029|D|phenytoin (200 or 300 mg daily) with azapropazone (600 mg twice daily)|
00399|030|D|increased the steady-state phenytoin concentration at least 2-fold and|
00399|031|D|decreased the phenytoin clearance by 35-59%.(3)|
00399|032|D|   A 41-year old patient became unsteady, clumsy, and sleepy after|
00399|033|D|concurrent phenytoin (300 mg daily) and azapropazone (600 mg twice daily).|
00399|034|D|She later developed a headache with episodes of blurred and double vision,|
00399|035|D|generalized motor ataxia, and nystagmus. Phenytoin concentrations were found|
00399|036|D|to have increased 60%.(4)|
00399|037|D|   A 60-year old patient developed confusion, nausea, diplopia, and vertigo|
00399|038|D|with concurrent phenytoin (300 mg daily) and azapropazone (600mg twice|
00399|039|D|daily). A subsequent study in 5 healthy volunteers with concurrent phenytoin|
00399|040|D|(dose adjusted to achieve steady state plasma concentrations 20 mcmol/l) and|
00399|041|D|azapropazone (600 mg twice daily) resulted in the phenytoin concentration|
00399|042|D|increasing 2-fold.(5)|
00399|043|B||
00399|044|R|REFERENCES:|
00399|045|B||
00399|046|R|1.Rheumox (azapropazone) UK summary of product characteristics. Wyeth|1
00399|047|R|  Laboratories 1997.|1
00399|048|R|2.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00399|049|R|  March, 2022.|1
00399|050|R|3.Geaney DP, Carver JG, Davies CL, Aronson JK. Pharmacokinetic investigation|3
00399|051|R|  of the interaction of azapropazone with phenytoin. Br J Clin Pharmacol|3
00399|052|R|  1983 Jun;15(6):727-34.|3
00399|053|R|4.Geaney DP, Carver JG, Aronson JK, Warlow CP. Interaction of azapropazone|3
00399|054|R|  with phenytoin. Br Med J (Clin Res Ed) 1982 May 8;284(6326):1373.|3
00399|055|R|5.Roberts CJ, Daneshmend TK, Macfarlane D, Dieppe PA. Anticonvulsant|2
00399|056|R|  intoxication precipitated by azapropazone. Postgrad Med J 1981 Mar;|2
00399|057|R|  57(665):191-2.|2
00400|001|T|MONOGRAPH TITLE:  Clozapine/Citalopram; Escitalopram|
00400|002|B||
00400|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00400|004|L|take action as needed.|
00400|005|B||
00400|006|A|MECHANISM OF ACTION:  The metabolism of clozapine may be inhibited at|
00400|007|A|CYP1A2, 2D6 or 3A4 by citalopram and escitalopram.|
00400|008|A|   Also, concurrent use with citalopram or escitalopram may result in|
00400|009|A|additive effects on the QT interval.|
00400|010|B||
00400|011|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with|
00400|012|E|citalopram or escitalopram may result in elevated levels of clozapine and an|
00400|013|E|increase in clozapine related side effects such as orthostatic hypotension,|
00400|014|E|syncope, QT prolongation, profound sedation and seizures.|
00400|015|E|   Also, concurrent use of clozapine with citalopram or escitalopram may|
00400|016|E|result potentially life-threatening cardiac arrhythmias, including torsades|
00400|017|E|de pointes.|
00400|018|B||
00400|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00400|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
00400|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00400|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00400|023|P|female gender, or advanced age.(5)|
00400|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00400|025|P|higher systemic concentrations of either QT prolonging drug are additional|
00400|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00400|027|P|drug concentrations include rapid infusion of an intravenous dose or|
00400|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00400|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00400|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).|
00400|031|B||
00400|032|M|PATIENT MANAGEMENT:  Clozapine levels should be monitored in patients|
00400|033|M|receiving concurrent therapy with clozapine and either citalopram or|
00400|034|M|escitalopram and patients should be monitored for signs of clozapine|
00400|035|M|toxicity.  The dosage of either clozapine or citalopram or escitalopram may|
00400|036|M|need to be adjusted or one or both agents may need to be discontinued.|
00400|037|M|Clozapine levels should also be monitored following the discontinuation of|
00400|038|M|citalopram or escitalopram from concurrent therapy.|
00400|039|M|   If concurrent therapy is warranted in patients receiving clozapine and|
00400|040|M|either citalopram or escitalopram, consider obtaining serum calcium,|
00400|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00400|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00400|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00400|044|B||
00400|045|D|DISCUSSION:  Although a study(4) in five subjects found no changes in|
00400|046|D|clozapine levels following the addition of citalopram to clozapine therapy,|
00400|047|D|the manufacturer reports that data from the medical literature and its|
00400|048|D|global post-marketing safety database indicate that concurrent use results|
00400|049|D|in clinically significant elevations of clozapine levels.(5,6)|
00400|050|D|   Citalopram has been associated with dose-depended increases in the QTc|
00400|051|D|interval.  In healthy subjects, the maximum mean difference in QTc interval|
00400|052|D|seen with 20 mg of citalopram and 60 mg of citalopram were 8.5 msec and 18.5|
00400|053|D|msec, respectively.  Based on extrapolation, a 40 mg dose of citalopram is|
00400|054|D|expected to produce a mean increase in the QTc interval of 12.6 msec.|
00400|055|B||
00400|056|R|REFERENCES:|
00400|057|B||
00400|058|R|1.Centorrino F, Baldessarini RJ, Kando J, Frankenburg FR, Volpicelli SA,|2
00400|059|R|  Puopolo PR, Flood JG. Serum concentrations of clozapine and its major|2
00400|060|R|  metabolites: effects of cotreatment with fluoxetine or valproate. Am J|2
00400|061|R|  Psychiatry 1994 Jan;151(1):123-5.|2
00400|062|R|2.Centorrino F, Baldessarini RJ, Frankenburg FR, Kando J, Volpicelli SA,|2
00400|063|R|  Flood JG. Serum levels of clozapine and norclozapine in patients treated|2
00400|064|R|  with selective serotonin reuptake inhibitors. Am J Psychiatry 1996 Jun;|2
00400|065|R|  153(6):820-2.|2
00400|066|R|3.Wetzel H, Anghelescu I, Szegedi A, Wiesner J, Weigmann H, Harter S, Hiemke|2
00400|067|R|  C. Pharmacokinetic interactions of clozapine with selective serotonin|2
00400|068|R|  reuptake inhibitors: differential effects of fluvoxamine and paroxetine in|2
00400|069|R|  a prospective study. J Clin Psychopharmacol 1998 Feb;18(1):2-9.|2
00400|070|R|4.Taylor D, Ellison Z, Ementon Shaw L, Wickham H, Murray R.|2
00400|071|R|  Co-administration of citalopram and clozapine: effect on plasma clozapine|2
00400|072|R|  levels. Int Clin Psychopharmacol 1998 Jan;13(1):19-21.|2
00400|073|R|5.Bess AL, Cunningham SR. Dear Healthcare Provider:  Important drug warning|1
00400|074|R|  and new information about Clozaril. Novartis Pharmaceuticals Corporation|1
00400|075|R|  December, 2005.|1
00400|076|R|6.Clozaril (clozapine tablets) US prescribing information. Novartis|1
00400|077|R|  Pharmaceuticals Corporation April, 2020.|1
00400|078|R|7.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
00400|079|R|  Laboratories Inc. August, 2023.|1
00400|080|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
00400|081|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
00400|082|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
00400|083|R|  https://www.fda.gov/media/71372/download October, 2005.|1
00400|084|R|9.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00400|085|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00400|086|R|  settings: a scientific statement from the American Heart Association and|6
00400|087|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00400|088|R|  2;55(9):934-47.|6
00401|001|T|MONOGRAPH TITLE:  Cilostazol (Less Than or Equal To 50 mg BID)/Strong &|
00401|002|T|Moderate 3A4 Inhibitors that Prolong QT|
00401|003|B||
00401|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00401|005|L|take action as needed.|
00401|006|B||
00401|007|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may inhibit|
00401|008|A|the metabolism of cilostazol at CYP3A4.(1)  Both agents have been shown to|
00401|009|A|prolong the QT interval.(1,2)|
00401|010|B||
00401|011|E|CLINICAL EFFECTS:  The concurrent use of cilostazol and strong and moderate|
00401|012|E|inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may|
00401|013|E|produce increased effects of cilostazol and adverse effects.(1)  Concurrent|
00401|014|E|use may also result in potentially life-threatening cardiac arrhythmias,|
00401|015|E|including torsades de pointes(TdP).(2)|
00401|016|B||
00401|017|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
00401|018|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
00401|019|P|failure, myocardial infarction, history of torsade de pointes, congenital|
00401|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00401|021|P|female gender, or advanced age.(1)|
00401|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00401|023|P|higher systemic concentrations of either QT prolonging drug are additional|
00401|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
00401|025|P|drug concentrations include rapid infusion of an intravenous dose or|
00401|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00401|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00401|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
00401|029|P|   This interaction may also be more severe in patients taking inhibitors of|
00401|030|P|CYP2C19.(1)|
00401|031|B||
00401|032|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
00401|033|M|daily in patients receiving concurrent therapy with strong and moderate|
00401|034|M|inhibitors of CYP3A4.(1)|
00401|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00401|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00401|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00401|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00401|039|B||
00401|040|D|DISCUSSION:  In a study in 16 healthy males, the administration of a single|
00401|041|D|dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours)|
00401|042|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
00401|043|D|cilostazol by 47% and 73%, respectively.  The Cmax and AUC of|
00401|044|D|4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(3)|
00401|045|D|   Analysis of population pharmacokinetics indicated that the concurrent|
00401|046|D|administration of diltiazem with cilostazol increased cilostazol|
00401|047|D|concentrations by 53%.(1)  Concurrent administration of diltiazem and|
00401|048|D|cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%,|
00401|049|D|and increased AUC by 40%.|
00401|050|D|   In a study, the administration of a single dose of cilostazol (10 mg)|
00401|051|D|with erythromycin (500 mg every eight hours) increased the Cmax and AUC of|
00401|052|D|cilostazol by 47% and 73%, respectively.  The AUC of|
00401|053|D|4'-trans-hydroxy-cilostazol was increased by 141%.(1)  In an vitro study in|
00401|054|D|human liver microsomes, ketoconazole inhibited the metabolism of|
00401|055|D|cilostazol.(4)|
00401|056|D|   One or more of the drug pairs linked to this monograph have been included|
00401|057|D|in a list of interactions that should be considered "high-priority" for|
00401|058|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00401|059|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00401|060|D|Coordinator (ONC) for Health Information Technology.|
00401|061|B||
00401|062|R|REFERENCES:|
00401|063|B||
00401|064|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
00401|065|R|  Pharmaceutical, Inc. January, 2015.|1
00401|066|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00401|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00401|068|R|  settings: a scientific statement from the American Heart Association and|6
00401|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00401|070|R|  2;55(9):934-47.|6
00401|071|R|3.Suri A, Forbes WP, Bramer SL. Effects of CYP3A inhibition on the|2
00401|072|R|  metabolism of cilostazol. Clin Pharmacokinet 1999;37 Suppl 2:61-8.|2
00401|073|R|4.Abbas R, Chow CP, Browder NJ, Thacker D, Bramer SL, Fu CJ, Forbes W, Odomi|5
00401|074|R|  M, Flockhart DA. In vitro metabolism and interaction of cilostazol with|5
00401|075|R|  human hepatic cytochrome P450 isoforms. Hum Exp Toxicol 2000 Mar;|5
00401|076|R|  19(3):178-84.|5
00401|077|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00401|078|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00401|079|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00401|080|R|  19(5):735-43.|6
00402|001|T|MONOGRAPH TITLE:  Cilostazol (Less Than or Equal To 50 mg BID)/Selected|
00402|002|T|Strong & Moderate CYP3A4 Inhibitors|
00402|003|B||
00402|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00402|005|L|take action as needed.|
00402|006|B||
00402|007|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may inhibit|
00402|008|A|the metabolism of cilostazol.(1)|
00402|009|B||
00402|010|E|CLINICAL EFFECTS:  The concurrent use of cilostazol and strong and moderate|
00402|011|E|inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may|
00402|012|E|produce increased effects of cilostazol and adverse effects.(1)|
00402|013|B||
00402|014|P|PREDISPOSING FACTORS:  None determined.|
00402|015|B||
00402|016|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
00402|017|M|daily in patients receiving concurrent therapy with strong and moderate|
00402|018|M|inhibitors of CYP3A4.(1)|
00402|019|B||
00402|020|D|DISCUSSION:  In a study in 16 healthy males, the administration of a single|
00402|021|D|dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours)|
00402|022|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
00402|023|D|cilostazol by 47% and 73%, respectively.  The Cmax and AUC of|
00402|024|D|4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(2)|
00402|025|D|   Analysis of population pharmacokinetics indicated that the concurrent|
00402|026|D|administration of diltiazem with cilostazol increased cilostazol|
00402|027|D|concentrations by 53%.  Concurrent administration of diltiazem and|
00402|028|D|cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%,|
00402|029|D|and increased AUC by 40%.(1)|
00402|030|D|   In a study, the administration of a single dose of cilostazol (10 mg)|
00402|031|D|with erythromycin (500 mg every eight hours) increased the Cmax and AUC of|
00402|032|D|cilostazol by 47% and 73%, respectively.  The AUC of|
00402|033|D|4'-trans-hydroxy-cilostazol was increased by 141%.(1)  In an vitro study in|
00402|034|D|human liver microsomes, ketoconazole inhibited the metabolism of|
00402|035|D|cilostazol.(3)|
00402|036|B||
00402|037|R|REFERENCES:|
00402|038|B||
00402|039|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
00402|040|R|  Pharmaceutical, Inc. January, 2015.|1
00402|041|R|2.Suri A, Forbes WP, Bramer SL. Effects of CYP3A inhibition on the|2
00402|042|R|  metabolism of cilostazol. Clin Pharmacokinet 1999;37 Suppl 2:61-8.|2
00402|043|R|3.Abbas R, Chow CP, Browder NJ, Thacker D, Bramer SL, Fu CJ, Forbes W, Odomi|5
00402|044|R|  M, Flockhart DA. In vitro metabolism and interaction of cilostazol with|5
00402|045|R|  human hepatic cytochrome P450 isoforms. Hum Exp Toxicol 2000 Mar;|5
00402|046|R|  19(3):178-84.|5
00403|001|T|MONOGRAPH TITLE:  Cilostazol/Itraconazole; Ketoconazole (mono deleted|
00403|002|T|05/30/2019)|
00403|003|B||
00403|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00403|005|L|take action as needed.|
00403|006|B||
00403|007|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
00403|008|A|metabolism of cilostazol at CYP3A4.(1)|
00403|009|B||
00403|010|E|CLINICAL EFFECTS:  The concurrent use of cilostazol with either itraconazole|
00403|011|E|or ketoconazole may result in elevated levels of cilostazol, which may|
00403|012|E|result in increased effects of cilostazol and adverse effects.(1)|
00403|013|B||
00403|014|P|PREDISPOSING FACTORS:  None determined.|
00403|015|B||
00403|016|M|PATIENT MANAGEMENT:  The manufacturer states under the "Dosage and|
00403|017|M|Administration" section in the cilostazol prescribing information that a|
00403|018|M|dose of cilostazol of 50 mg twice daily should be considered in patients|
00403|019|M|receiving concurrent therapy with CYP P-450-3A4 inhibitors such as|
00403|020|M|itraconazole and ketoconazole.(1)|
00403|021|B||
00403|022|D|DISCUSSION:  In a study reported in the manufacturer's prescribing|
00403|023|D|information, the administration of a single dose of cilostazol (10 mg) with|
00403|024|D|erythromycin (500 mg every eight hours) increased the maximum concentration|
00403|025|D|(Cmax) and area-under-curve (AUC) of cilostazol by 47% and 73%,|
00403|026|D|respectively.  The AUC of 4'-trans-hydroxy-cilostazol was increased by|
00403|027|D|141%.(1)  In an vitro study in human liver microsomes, ketoconazole|
00403|028|D|inhibited the metabolism of cilostazol.(2)|
00403|029|D|   Therefore, because itraconazole and ketoconazole are strong inhibitors of|
00403|030|D|CYP P-450-3A4 and they are expected to affect cilostazol levels to an even|
00403|031|D|greater extent than erythromycin, the manufacturer of cilostazol recommends|
00403|032|D|that a cilostazol dose of 50 mg twice daily be used in patients concurrently|
00403|033|D|treated with itraconazole and ketoconazole.(1)|
00403|034|B||
00403|035|R|REFERENCES:|
00403|036|B||
00403|037|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
00403|038|R|  Pharmaceutical, Inc. January, 2015.|1
00403|039|R|2.Abbas R, Chow CP, Browder NJ, Thacker D, Bramer SL, Fu CJ, Forbes W, Odomi|5
00403|040|R|  M, Flockhart DA. In vitro metabolism and interaction of cilostazol with|5
00403|041|R|  human hepatic cytochrome P450 isoforms. Hum Exp Toxicol 2000 Mar;|5
00403|042|R|  19(3):178-84.|5
00404|001|T|MONOGRAPH TITLE:  Cilostazol (Less Than or Equal To 50 mg BID)/Strong &|
00404|002|T|Moderate CYP2C19 Inhibitors that Prolong QT|
00404|003|B||
00404|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00404|005|L|take action as needed.|
00404|006|B||
00404|007|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP2C19 may inhibit|
00404|008|A|the metabolism of cilostazol.(1-4)   Both agents have been shown to prolong|
00404|009|A|the QT interval.(1,5)|
00404|010|B||
00404|011|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate inhibitors of|
00404|012|E|CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a|
00404|013|E|metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)|
00404|014|E|Concurrent use may also result in potentially life-threatening cardiac|
00404|015|E|arrhythmias, including torsades de pointes(TdP).(6)|
00404|016|B||
00404|017|P|PREDISPOSING FACTORS:  None determined.|
00404|018|B||
00404|019|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
00404|020|M|daily in patients receiving concurrent therapy with strong and moderate|
00404|021|M|inhibitors of CYP2C19.(1)|
00404|022|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
00404|023|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
00404|024|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
00404|025|M|patients to report any irregular heartbeat, dizziness, or fainting.|
00404|026|B||
00404|027|D|DISCUSSION:  In a study in 20 subjects examined the effects of omeprazole|
00404|028|D|(40 mg daily) on a single dose of cilostazol (100 mg).  Concurrent|
00404|029|D|omeprazole increased the cilostazol maximum concentration (Cmax) and|
00404|030|D|area-under-curve (AUC) by 18% and 26%, respectively.  The Cmax and AUC of|
00404|031|D|the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%,|
00404|032|D|respectively.  The Cmax and AUC of the OPC-13213 metabolite of cilostazol|
00404|033|D|decreased by 22% and 31%, respectively.(4)|
00404|034|D|   One or more of the drug pairs linked to this monograph have been included|
00404|035|D|in a list of interactions that should be considered "high-priority" for|
00404|036|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00404|037|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00404|038|D|Coordinator (ONC) for Health Information Technology.|
00404|039|B||
00404|040|R|REFERENCES:|
00404|041|B||
00404|042|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
00404|043|R|  Pharmaceutical, Inc. January, 2015.|1
00404|044|R|2.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
00404|045|R|  Pharmaceuticals LP August, 2021.|1
00404|046|R|3.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
00404|047|R|  Pharmaceuticals LP June, 2018.|1
00404|048|R|4.Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol.|2
00404|049|R|  Clin Pharmacokinet 1999;37 Suppl 2:53-9.|2
00404|050|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
00404|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
00404|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
00404|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
00404|054|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00404|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00404|056|R|  settings: a scientific statement from the American Heart Association and|6
00404|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00404|058|R|  2;55(9):934-47.|6
00404|059|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00404|060|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00404|061|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00404|062|R|  19(5):735-43.|6
00405|001|T|MONOGRAPH TITLE:  Alitretinoin; Bexarotene/Diethyltoluamide (DEET)|
00405|002|B||
00405|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00405|004|L|is contraindicated and generally should not be dispensed or administered to|
00405|005|L|the same patient.|
00405|006|B||
00405|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Alitretinoin(1) and|
00405|008|A|bexarotene(2) may increase the absorption of diethyltoluamide (DEET).|
00405|009|B||
00405|010|E|CLINICAL EFFECTS:  The concurrent application of alitretinoin(1) or|
00405|011|E|bexarotene(2) with diethyltoluamide (DEET) may increase the toxicity of|
00405|012|E|diethyltoluamide.|
00405|013|B||
00405|014|P|PREDISPOSING FACTORS:  None determined.|
00405|015|B||
00405|016|M|PATIENT MANAGEMENT:  The manufacturer of alitretinoin states that patients|
00405|017|M|applying alitretinoin should not concurrently use products that contain|
00405|018|M|diethyltoluamide (DEET).(1) The manufacturer of bexarotene states that|
00405|019|M|patients who are applying bexarotene should not concurrently use products|
00405|020|M|that contain DEET.(2)|
00405|021|B||
00405|022|D|DISCUSSION:  Because animal toxicity studies indicated an increase in|
00405|023|D|diethyltoluamide (DEET) toxicity when DEET was included as a part of the|
00405|024|D|alitretinoin formulation, the manufacturer states that patients applying|
00405|025|D|alitretinoin should not concurrently use products containing DEET.(1)|
00405|026|D|   Because animal toxicity studies indicated an increase in DEET toxicity|
00405|027|D|when DEET was included as a part of the bexarotene formulation, the|
00405|028|D|manufacturer states that patients applying bexarotene should not|
00405|029|D|concurrently use products containing DEET.(2)|
00405|030|B||
00405|031|R|REFERENCES:|
00405|032|B||
00405|033|R|1.Panretin (alitretinoin) US prescribing information. Ligand Pharmaceuticals|1
00405|034|R|  Incorporated November, 2013.|1
00405|035|R|2.Targretin (bexarotene) Gel US prescribing information. Ligand|1
00405|036|R|  Pharmaceuticals Incorporated January, 2001.|1
00406|001|T|MONOGRAPH TITLE:  Acarbose; Miglitol/Amylase; Pancreatin|
00406|002|B||
00406|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00406|004|L|is contraindicated and generally should not be dispensed or administered to|
00406|005|L|the same patient.|
00406|006|B||
00406|007|A|MECHANISM OF ACTION:  Digestive enzyme preparations such as amylase or|
00406|008|A|pancreatin may break down acarbose(1) and miglitol.(2)|
00406|009|B||
00406|010|E|CLINICAL EFFECTS:  The concurrent administration digestive enzyme|
00406|011|E|preparations such as amylase or pancreatin may decrease the effectiveness of|
00406|012|E|acarbose(1) and miglitol.(2)|
00406|013|B||
00406|014|P|PREDISPOSING FACTORS:  None determined.|
00406|015|B||
00406|016|M|PATIENT MANAGEMENT:  The manufacturer of acarbose states that digestive|
00406|017|M|enzymes such as amylase or pancreatin should not be taken concomitantly with|
00406|018|M|acarbose.(1)|
00406|019|M|   The manufacturer of miglitol states that digestive enzymes such as|
00406|020|M|amylase or pancreatin should not be taken concomitantly with miglitol.(2)|
00406|021|B||
00406|022|D|DISCUSSION:  Because digestive enzyme preparations such as amylase or|
00406|023|D|pancreatin may break down acarbose(1) and miglitol(2) and decrease their|
00406|024|D|effectiveness, the manufacturer of acarbose(1) and miglitol(2) state they|
00406|025|D|should not be taken concomitantly with these agents.|
00406|026|B||
00406|027|R|REFERENCES:|
00406|028|B||
00406|029|R|1.Precose (arcarbose) US prescribing information. Bayer Pharmaceuticals|1
00406|030|R|  Corporation March, 2015.|1
00406|031|R|2.Glyset (miglitol) US prescribing information. Pharmacia & Upjohn Company|1
00406|032|R|  September, 2012.|1
00407|001|T|MONOGRAPH TITLE:  COMT Inhibitors/Selected MAOIs|
00407|002|B||
00407|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00407|004|L|is contraindicated and generally should not be dispensed or administered to|
00407|005|L|the same patient.|
00407|006|B||
00407|007|A|MECHANISM OF ACTION:  Since MAOI's and COMT are the two major enzymes|
00407|008|A|responsible for the metabolism of catecholamines, the combination of|
00407|009|A|entacapone, tolcapone, or opicapone and a non-selective MAOI may inhibit the|
00407|010|A|majority of catecholamine metabolism pathways.(1-3)|
00407|011|B||
00407|012|E|CLINICAL EFFECTS:  Concurrent administration of entacapone, tolcapone, or|
00407|013|E|opicapone with a non-selective MAOI may result in elevated levels of|
00407|014|E|catecholamines, which may result in elevated heart rate and blood pressure.|
00407|015|B||
00407|016|P|PREDISPOSING FACTORS:  None determined.|
00407|017|B||
00407|018|M|PATIENT MANAGEMENT:  The Canadian(4) and UK(1) manufacturers of entacapone|
00407|019|M|state that concomitant use of either a non-selective MAOI or a selective|
00407|020|M|MAO-A inhibitor with a selective MAO-B inhibitor with entacapone is|
00407|021|M|contraindicated.  Nonselective MAOI should be discontinued at least 2 weeks|
00407|022|M|prior to initiating entacapone therapy.(4)|
00407|023|M|  The UK manufacturer of tolcapone states that tolcapone should not be|
00407|024|M|coadministered with either a non-selective MAOI or a selective MAO-A|
00407|025|M|inhibitor with a selective MAO-B inhibitor.  (5)  The US manufacturer of|
00407|026|M|tolcapone states that patients should not ordinarily be treated|
00407|027|M|concomitantly with tolcapone and a non-selective MAOI. Tolcapone may be|
00407|028|M|concurrently administered with a selective MAO-B inhibitor.(2)|
00407|029|M|   The Middle East and US manufacturers of opicapone state that concomitant|
00407|030|M|use of opicapone with MAO inhibitors other than those for the treatment of|
00407|031|M|Parkinson's disease is contraindicated.(10,11)|
00407|032|B||
00407|033|D|DISCUSSION:  Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)|
00407|034|D|are the two major enzymes systems involved in the metabolism of|
00407|035|D|catecholamines.  Therefore, theoretically, the combination of either|
00407|036|D|entacapone, tolcapone, or opicapone with a non-selective MAO inhibitor will|
00407|037|D|result in inhibition of the majority of catecholamine metabolism|
00407|038|D|pathways.(1,2)|
00407|039|D|   At daily oral doses of 10 mg, selegiline is primarily a selective MAO-B|
00407|040|D|inhibitor; however, at higher doses, selegiline is capable of inhibiting|
00407|041|D|MAO-A.(6)  At dosages administered transdermally for the treatment of|
00407|042|D|depression, selegiline is not selective for MAO-B.(7)|
00407|043|D|   Methylene blue, when administered intravenously, has been shown to reach|
00407|044|D|sufficient concentrations to be a potent inhibitor of MAO-A.(8,9)|
00407|045|D|   Metaxalone is a weak inhibitor of MAO.(12,13)|
00407|046|B||
00407|047|R|REFERENCES:|
00407|048|B||
00407|049|R|1.Comtess (entacapone) UK summary of product characteristics. Orion Pharma,|1
00407|050|R|  UK September 16, 1998.|1
00407|051|R|2.Tasmar (tolcapone) US prescribing information. Valeant Pharmaceuticals|1
00407|052|R|  International May, 2013.|1
00407|053|R|3.Comtan (entacapone) US prescribing information. Orion Corporation|1
00407|054|R|  February, 2016.|1
00407|055|R|4.Comtan (entacapone) Canadian prescribing information. Novartis|1
00407|056|R|  Pharmaceuticals Canada Inc. March, 2006.|1
00407|057|R|5.Tasmar (tolcapone) UK summary of product characteristics. Valeant|1
00407|058|R|  Pharmaceuticals Ltd. Januar 11, 2006.|1
00407|059|R|6.Eldepryl (selegiline) US prescribing information. Somerset Pharmaceuticals|1
00407|060|R|  February, 1997.|1
00407|061|R|7.Emsam (selegiline) US prescribing information. Somerset August, 2007.|1
00407|062|R|8.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00407|063|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00407|064|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00407|065|R|9.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00407|066|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00407|067|R|  2000 Jun;56(3):247-50.|2
00407|068|R|10.Ongentys (opicapone) Middle East prescribing information. Bial-Portela|1
00407|069|R|   and Ca, S.A. 2018.|1
00407|070|R|11.Ongentys (opicapone) US prescribing information. Neurocrine Biosciences,|1
00407|071|R|   Inc. April, 2020.|1
00407|072|R|12.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00407|073|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00407|074|R|   Feb;34(2):346.e5-6.|3
00407|075|R|13.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00407|076|R|   Pfizer Inc. January, 2024.|1
00408|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Rifabutin; Rifapentine|
00408|002|B||
00408|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00408|004|L|of severe adverse interaction.|
00408|005|B||
00408|006|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
00408|007|A|rifabutin by CYP3A4.(1-29)  Rifabutin may induce the metabolism of some|
00408|008|A|protease inhibitors.(1-14)  Rifabutin may decrease the metabolism of|
00408|009|A|darunavir by competitive inhibition at CYP3A4.(17-19)|
00408|010|A|   Rifapentine may induce the metabolism of the protease inhibitor by|
00408|011|A|CYP3A4.(14)|
00408|012|B||
00408|013|E|CLINICAL EFFECTS:  The concurrent administration of amprenavir, atazanavir,|
00408|014|E|boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir,|
00408|015|E|ritonavir, saquinavir, telaprevir or tipranavir with rifabutin may result in|
00408|016|E|increased levels, clinical effects, and side effects (including neutropenia,|
00408|017|E|lymphopenia, and influenza-like illness) of rifabutin.(1-29)  Levels of|
00408|018|E|amprenavir, indinavir, nelfinavir, and saquinavir may be decreased.(1-14)|
00408|019|E|The increased levels of darunavir seen with concurrent rifabutin are not|
00408|020|E|expected to be clinically significant.(17-19)|
00408|021|E|   Concurrent or recent use of rifapentine may result in decreased levels|
00408|022|E|and effectiveness of the protease inhibitor.(14)|
00408|023|B||
00408|024|P|PREDISPOSING FACTORS:  None determined.|
00408|025|B||
00408|026|M|PATIENT MANAGEMENT:  The Department of Health and Human Services (DHHS)|
00408|027|M|Guidelines for the Use of Antiretroviral Agents,(27) the CDC/NIH guidelines|
00408|028|M|on treatment of opportunistic infections (OI) in HIV(28), and the CDC's|
00408|029|M|guidelines on managing drug interactions in HIV-related tuberculosis|
00408|030|M|(TB)(29) all recommend that the dose of rifabutin be reduced to 150 mg once|
00408|031|M|daily, or 300 mg three times weekly (a 50% reduction), when used with|
00408|032|M|boosted or unboosted protease inhibitors.  Previous iterations of the|
00408|033|M|guidelines recommended a rifabutin dose of 150 mg three times weekly, but|
00408|034|M|some studies have found subtherapeutic rifabutin levels as a result.(30-35)|
00408|035|M|Given the risk of rifamycin resistance, the guidelines now recommend a|
00408|036|M|higher dose of rifabutin than previously, but state that clinicians should|
00408|037|M|recognize that there are limited safety data with this dose and patients|
00408|038|M|need to be closely monitored for rifabutin-related toxicities.|
00408|039|M|   The Australian, UK, and US manufacturers of amprenavir,(1,2,3)|
00408|040|M|fosamprenavir,(4,6) indinavir,(7,8,9) and nelfinavir(10,11,12) recommend|
00408|041|M|reducing the dose of rifabutin by at least 50% when used concurrently.  The|
00408|042|M|Australian(7) and US(9) manufacturers of indinavir recommend that the dosage|
00408|043|M|of indinavir be increased to 1,000 mg every eight hours.  The UK|
00408|044|M|manufacturer of indinavir recommends that the dosage of indinavir be|
00408|045|M|increased to 1,000 mg or 1,200 mg every eight hours.(8)  The US manufacturer|
00408|046|M|of nelfinavir(12) and the US manufacturer of rifabutin(14) recommend a|
00408|047|M|dosage of nelfinavir of 1,250 mg twice daily when used with rifabutin.|
00408|048|M|Monitoring of patients should be increased.  Monitor for neutropenia, liver|
00408|049|M|enzyme levels, and consider monitoring rifabutin concentrations.|
00408|050|M|   The Australian, Canadian, UK, and US manufacturers of|
00408|051|M|atazanavir,(15,16,17) darunavir,(18,19,20) fosamprenavir when used with|
00408|052|M|ritonavir,(4,5,6) lopinavir-ritonavir,(21,22,23) saquinavir,(13) and|
00408|053|M|tipranavir (24) recommend that the dosage of rifabutin be reduced by 75%|
00408|054|M|(e.g. 150 mg every other day or 3 times per week) with careful monitoring.|
00408|055|M|Additional dose adjustment may be warranted.  In Australia, the combination|
00408|056|M|of atazanavir with cobicistat is contraindicated with rifabutin.(15)|
00408|057|M|Monitoring of patients should be increased.  Monitor for neutropenia, liver|
00408|058|M|enzyme levels, and consider monitoring rifabutin concentrations.|
00408|059|M|   When ritonavir is used as an antiretroviral agent at 500 mg bid or above,|
00408|060|M|it is contraindicated with rifabutin.(25,26)  When used as a boosting agent,|
00408|061|M|refer to the dosing for the primary protease inhibitor.|
00408|062|M|   Consider alternatives to rifapentine in patients receiving protease|
00408|063|M|inhibitors.   DHHS guidelines state that rifapentine should not be|
00408|064|M|coadministered with any protease inhibitors.(27)  In Australia, the|
00408|065|M|combination of atazanavir with cobicistat is contraindicated with|
00408|066|M|rifapentine.(15)|
00408|067|M|   Selected protease inhibitors linked to this monograph include:|
00408|068|M|amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir,|
00408|069|M|lopinavir, nelfinavir, ritonavir, saquinavir, and telaprevir.|
00408|070|B||
00408|071|D|DISCUSSION:  Two open-label, randomized, cross-over studies, one in South|
00408|072|D|Africa(30) and one in Vietnam(31), comparing rifabutin doses of 300 mg daily|
00408|073|D|alone with 150 mg 3 times weekly or 150 mg daily given with|
00408|074|D|lopinavir-ritonavir (LPVr) found that the 150 mg daily dose with LPVr|
00408|075|D|attained higher rifabutin levels than 300 mg daily alone, and the 150 mg 3|
00408|076|D|times weekly dose with LPVr led to lower rifabutin levels than 300 mg daily|
00408|077|D|alone.  The levels of the rifabutin active metabolite|
00408|078|D|25-O-desacetylrifabutin was markedly elevated with both dosages in both|
00408|079|D|studies.  All 16 patients in the South Africa study and 22/24 patients in|
00408|080|D|the Vietnam study had negative cultures at the end of TB therapy.  Mild|
00408|081|D|adverse events were common.  Two cases of uveitis occurred in the South|
00408|082|D|Africa study and none in the Vietnam study. Grade 3 neutropenia occurred in|
00408|083|D|5 patients and 1 patient in the South Africa and Vietnam study,|
00408|084|D|respectively.|
00408|085|D|   A retrospective cohort study of HIV-TB co-infected patients on|
00408|086|D|ritonavir-boosted atazanavir compared the use of rifabutin 150 mg 3 times|
00408|087|D|weekly (n=118) with rifabutin 150 mg daily (n=174).  Significantly more|
00408|088|D|patients in the rifabutin daily group than the rifabutin three times weekly|
00408|089|D|group achieved clinical cure (73% vs. 44.1%, p<0.001).(36)|
00408|090|D|   A number of other small studies in HIV-TB co-infected patients on|
00408|091|D|ritonavir-based antiretroviral therapy have also found that a rifabutin dose|
00408|092|D|of 150 mg 3 times weekly led to inadequate rifabutin levels but high|
00408|093|D|25-O-desacetylrifabutin levels.  Many patients achieved clinical cure|
00408|094|D|despite the low rifabutin levels, but studies did report patient|
00408|095|D|deterioration, deaths, relapse, or resistance in patients with low rifabutin|
00408|096|D|levels.(32-35)|
00408|097|D|   A case series of 3 patients with AIDS and TB reported that the patients|
00408|098|D|developed acquired rifamycin resistance despite receiving directly observed|
00408|099|D|therapy for TB.  All the patients had been on ritonavir-boosted protease|
00408|100|D|inhibitors and had a rifabutin dose of 150 mg every other day.(37)|
00408|101|D|   In a study in 7 subjects, atazanavir/ritonavir (300/100 mg daily) and|
00408|102|D|rifabutin (150 mg twice weekly) increased the Cmax, AUC, and Cmin of|
00408|103|D|rifabutin by 2.49-fold, 1.48-fold, and 1.40-fold, respectively, when|
00408|104|D|compared to the administration of 150 mg daily of rifabutin.  The Cmax, AUC,|
00408|105|D|and Cmin of 25-O-desacetylrifabutin increased by 7.77-fold, 10.90-fold, and|
00408|106|D|11.45-fold, respectively.(15)|
00408|107|D|   Concurrent darunavir/ritonavir (600/100 mg twice daily) and rifabutin|
00408|108|D|(150 mg every other day) decreased rifabutin Cmax and AUC by 28% and 7%,|
00408|109|D|respectively, and increased rifabutin Cmin by 64% when compared to the|
00408|110|D|administration of rifabutin (300 mg daily) alone.  The Cmax, AUC, and Cmin|
00408|111|D|of 25-O-desacetylrifabutin increased by 4.77-fold, 9.81-fold, and 27.1-fold,|
00408|112|D|respectively.  The Cmax, AUC, and Cmin of darunavir increased 42%, 57%, and|
00408|113|D|75%, respectively.(20)  In a study using concurrent rifabutin (150 mg daily)|
00408|114|D|with darunavir/ritonavir (400/100 mg twice daily), lymphopenia and|
00408|115|D|influenza-like illnesses were reported at a higher frequency than in|
00408|116|D|patients who received rifabutin alone.  One patient experienced a grade 3|
00408|117|D|decrease in white blood cell count during concurrent therapy.(19)|
00408|118|D|   Concurrent fosamprenavir/ritonavir (700/100 mg twice daily) and rifabutin|
00408|119|D|(150 mg every other day) increased amprenavir Cmax, AUC, and Cmin by 36%,|
00408|120|D|35%, and 17%, respectively.  Rifabutin Cmax decreased by 14% and rifabutin|
00408|121|D|Cmin increased by 28%.  The Cmax, AUC, and Cmin of 25-O-desacetylrifabutin|
00408|122|D|increased by 579%, 1120%, and 2510%, respectively.  The AUC of rifabutin|
00408|123|D|plus 25-O-desacetylrifabutin increased by 64%.(6)|
00408|124|D|   In a study in 14 healthy, HIV-negative subjects, concurrent rifabutin|
00408|125|D|(150 mg once daily) and indinavir (800 mg every 8 hours) decreased indinavir|
00408|126|D|Cmax, AUC, and Cmin by 20%, 32%, and 40%, respectively.  Rifabutin Cmax,|
00408|127|D|AUC, and Cmin increased by 1.29-fold, 1.54-fold, and 1.99-fold,|
00408|128|D|respectively.(9,28)  In a study in 18 healthy subjects, concurrent indinavir|
00408|129|D|(1,000 mg three times daily) with rifabutin (150 mg daily) increased|
00408|130|D|rifabutin and 25-O-desacetylrifabutin AUC by 70% and 120%, respectively,|
00408|131|D|when compared to the administration of rifabutin (300 mg daily) alone.  In a|
00408|132|D|study in 10 HIV-positive subjects, concurrent administration of indinavir|
00408|133|D|(1,000 mg three times daily) with rifabutin (150 mg daily) produced|
00408|134|D|indinavir levels similar to indinavir (800 mg three time daily) administered|
00408|135|D|alone.(39)|
00408|136|D|   Concurrent lopinavir/ritonavir (400/100 mg twice daily) with rifabutin|
00408|137|D|(150 mg daily) increased lopinavir Cmax, AUC, and Cmin by 1.08-fold,|
00408|138|D|1.17-fold, and 1.20-fold, respectively.  The Cmax, AUC, and Cmin of|
00408|139|D|rifabutin increased by 2.12-fold, 3.03-fold, and by 4.90-fold, respectively.|
00408|140|D|The Cmax, AUC, and Cmin of 25-O-desacetylrifabutin increased by 23.6-fold,|
00408|141|D|47.5-fold, and by 94.9-fold, respectively.  The Cmax, AUC, and Cmin of|
00408|142|D|rifabutin plus 25-O-desacetylrifabutin increased by 3.46-fold, 5.73-fold,|
00408|143|D|and 9.53-fold, respectively.(23)|
00408|144|D|   Concurrent rifabutin (300 mg daily) and nelfinavir (750 mg every 8 hours)|
00408|145|D|increased rifabutin AUC, Cmax, and Cmin by 207%, 146%, and 305%,|
00408|146|D|respectively.  Nelfinavir AUC, Cmax, and Cmin decreased by 32%, 24%, and|
00408|147|D|53%, respectively.  Concurrent rifabutin (150 mg once daily) and nelfinavir|
00408|148|D|(750 mg every 8 hours) increased rifabutin AUC, Cmax, and Cmin by 83%, 19%,|
00408|149|D|and 177%, respectively.  Nelfinavir AUC, Cmax, and Cmin decreased by 23%,|
00408|150|D|18%, and 25%, respectively.  Concurrent rifabutin (150 mg once daily) and|
00408|151|D|nelfinavir (1,250 mg every 12 hours) decreased nelfinavir Cmin by 15%.|
00408|152|D|There was no effect on nelfinavir AUC or Cmax.(12)|
00408|153|D|   Rifapentine (600 mg twice weekly for 28 days) decreased the|
00408|154|D|area-under-curve (AUC) and maximum concentration (Cmax) of indinavir (800 mg|
00408|155|D|3 times daily on Days 15-28) by 70% and 55%, respectively.  Indinavir|
00408|156|D|clearance increased 3-fold.  There was no affect on indinavir half-life.|
00408|157|D|There were no effects on rifapentine pharmacokinetics.(14)|
00408|158|D|   One or more of the drug pairs linked to this monograph have been included|
00408|159|D|in a list of interactions that should be considered "high-priority" for|
00408|160|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00408|161|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00408|162|D|Coordinator (ONC) for Health Information Technology.|
00408|163|B||
00408|164|R|REFERENCES:|
00408|165|B||
00408|166|R|1.Agenerase (amprenavir) Australian prescribing information. GlaxoSmithKline|1
00408|167|R|  Australia Pty Ltd. November 24, 2004.|1
00408|168|R|2.Agenerase (amprenavir) summary of product characteristics. GlaxoSmithKline|1
00408|169|R|  UK January 18, 2005.|1
00408|170|R|3.Agenerase (amprenavir) Capsules US prescribing information.|1
00408|171|R|  GlaxoSmithKline May, 2005.|1
00408|172|R|4.Telzir (fosamprenavir calcium) Australian prescribing information.|1
00408|173|R|  GlaxoSmithKline Australia Pty Ltd. November 24, 2004.|1
00408|174|R|5.Telzir (fosamprenavir calcium) UK summary of product characteristics.|1
00408|175|R|  GlaxoSmithKline UK October 18. 2013.|1
00408|176|R|6.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
00408|177|R|  March, 2019.|1
00408|178|R|7.Crixivan (indinavir sulfate) Australian prescribing information. Merck|1
00408|179|R|  Sharp & Dohme (Australia) Pty Ltd. August 11, 2003.|1
00408|180|R|8.Crixivan (indinavir sulfphate) UK summary of product characteristics.|1
00408|181|R|  Merck Sharp & Dohme Limited September, 2008.|1
00408|182|R|9.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00408|183|R|  September, 2016.|1
00408|184|R|10.Viracept (nelfinavir mesylate) Australian prescribing information. Roche|1
00408|185|R|   Products Pty Ltd. October 26, 2000.|1
00408|186|R|11.Viracept (nelfinavir mesylate) UK summary of product characteristics.|1
00408|187|R|   Roche Products Limited August 4, 2008.|1
00408|188|R|12.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00408|189|R|   Pharmaceuticals, Inc. September, 2016.|1
00408|190|R|13.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00408|191|R|   Laboratories, Inc. March, 2019.|1
00408|192|R|14.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
00408|193|R|   2021.|1
00408|194|R|15.Reyataz (atazanavir sulfate) Australian product information.|1
00408|195|R|   Bristol-Myers Squibb Pharmaceuticals October 25, 2023.|1
00408|196|R|16.Reyataz (atazanavir) UK summary of product characteristics. Bristol-Myers|1
00408|197|R|   Squibb Pharmaceuticals Limited September 8, 2008.|1
00408|198|R|17.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
00408|199|R|   Squibb Company December, 2024.|1
00408|200|R|18.Prezista (darunavir) Canadian prescribing information. Jannsen-Ortho|1
00408|201|R|   June, 2008.|1
00408|202|R|19.Prezista (darunavir) UK Summary of product characteristics.|1
00408|203|R|   Janssen-Cilgat LTD August 8, 2008.|1
00408|204|R|20.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
00408|205|R|   March, 2023.|1
00408|206|R|21.Kaletra (lopinavir/ritonavir) Australian prescribing information. Abbott|1
00408|207|R|   Australasia Pty. Ltd. April 1, 2004.|1
00408|208|R|22.Kaletra (lopinavir/ritonavir) UK summary of product characteristics.|1
00408|209|R|   Abbott Laboratories, Limited July 11, 2008.|1
00408|210|R|23.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00408|211|R|   Laboratories December, 2019.|1
00408|212|R|24.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00408|213|R|   Pharmaceuticals, Inc. April, 2024.|1
00408|214|R|25.Norvir (ritonavir) Australian prescribing information. Abbott Australasia|1
00408|215|R|   Pty. Ltd. January 29, 2004.|1
00408|216|R|26.Norvir (ritonavir) UK summary of product characteristics. AbbVie, Ltd.|1
00408|217|R|   July 18, 2019.|1
00408|218|R|27.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
00408|219|R|   for the use of antiretroviral agents in adults and adolescents Living|6
00408|220|R|   with HIV. Department of Health and Human Services. Available at|6
00408|221|R|   https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats|6
00408|222|R|   -new-guidelines June 13, 2021.|6
00408|223|R|28.Panel on Opportunistic Infections in Adults and Adolescents with HIV.|6
00408|224|R|   Mycobacterium tuberculosis Infection and Disease. Guidelines for the|6
00408|225|R|   prevention and treatment of opportunistic infections in adults and|6
00408|226|R|   adolescents with HIV: recommendations from the CDC, the NIH, and the HIV|6
00408|227|R|   Medicine Association of the IDSA. Available at|6
00408|228|R|   http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. September|6
00408|229|R|   22, 2017.|6
00408|230|R|29.CDC. Managing Drug Interactions in the Treatment of HIV-Related|6
00408|231|R|   Tuberculosis online. Available at|6
00408|232|R|   https://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/introduction.|6
00408|233|R|   htm June, 2013.|6
00408|234|R|30.Naiker S, Connolly C, Wiesner L, Kellerman T, Reddy T, Harries A,|2
00408|235|R|   McIlleron H, Lienhardt C, Pym A. Randomized pharmacokinetic evaluation of|2
00408|236|R|   different rifabutin doses in African HIV- infected tuberculosis patients|2
00408|237|R|   on lopinavir/ritonavir-based antiretroviral therapy. BMC Pharmacol|2
00408|238|R|   Toxicol 2014 Nov 19;15:61.|2
00408|239|R|31.Lan NT, Thu NT, Barrail-Tran A, Duc NH, Lan NN, Laureillard D, Lien TT,|2
00408|240|R|   Borand L, Quillet C, Connolly C, Lagarde D, Pym A, Lienhardt C, Dung NH,|2
00408|241|R|   Taburet AM, Harries AD. Randomised pharmacokinetic trial of rifabutin|2
00408|242|R|   with lopinavir/ritonavir-antiretroviral therapy in patients with|2
00408|243|R|   HIV-associated tuberculosis in Vietnam. PLoS One 2014;9(1):e84866.|2
00408|244|R|32.Boulanger C, Hollender E, Farrell K, Stambaugh JJ, Maasen D, Ashkin D,|2
00408|245|R|   Symes S, Espinoza LA, Rivero RO, Graham JJ, Peloquin CA. Pharmacokinetic|2
00408|246|R|   evaluation of rifabutin in combination with lopinavir-ritonavir in|2
00408|247|R|   patients with HIV infection and active tuberculosis. Clin Infect Dis 2009|2
00408|248|R|   Nov 1;49(9):1305-11.|2
00408|249|R|33.Khachi H, O'Connell R, Ladenheim D, Orkin C. Pharmacokinetic interactions|3
00408|250|R|   between rifabutin and lopinavir/ritonavir in HIV-infected patients with|3
00408|251|R|   mycobacterial co-infection. J Antimicrob Chemother 2009 Oct;64(4):871-3.|3
00408|252|R|34.Ramachandran G, Bhavani PK, Hemanth Kumar AK, Srinivasan R, Raja K, Sudha|2
00408|253|R|   V, Venkatesh S, Chandrasekaran C, Swaminathan S. Pharmacokinetics of|2
00408|254|R|   rifabutin during atazanavir/ritonavir co-administration in HIV-infected|2
00408|255|R|   TB patients in India. Int J Tuberc Lung Dis 2013 Dec;17(12):1564-8.|2
00408|256|R|35.Tanuma J, Sano K, Teruya K, Watanabe K, Aoki T, Honda H, Yazaki H,|2
00408|257|R|   Tsukada K, Gatanaga H, Kikuchi Y, Oka S. Pharmacokinetics of rifabutin in|2
00408|258|R|   Japanese HIV-infected patients with or without antiretroviral therapy.|2
00408|259|R|   PLoS One 2013;8(8):e70611.|2
00408|260|R|36.Jenks JD, Kumarasamy N, Ezhilarasi C, Poongulali S, Ambrose P, Yepthomi|2
00408|261|R|   T, Devaraj C, Benson CA. Improved tuberculosis outcomes with daily vs.|2
00408|262|R|   intermittent rifabutin in HIV-TB coinfected patients in India. Int J|2
00408|263|R|   Tuberc Lung Dis 2016 Sep;20(9):1181-4.|2
00408|264|R|37.Jenny-Avital ER, Joseph K. Rifamycin-resistant Mycobacterium tuberculosis|3
00408|265|R|   in the highly active antiretroviral therapy era: a report of 3 relapses|3
00408|266|R|   with acquired rifampin resistance following alternate-day rifabutin and|3
00408|267|R|   boosted protease inhibitor therapy. Clin Infect Dis 2009 May 15;|3
00408|268|R|   48(10):1471-4.|3
00408|269|R|38.Kraft WK, McCrea JB, Winchell GA, Carides A, Lowry R, Woolf EJ, Kusma SE,|2
00408|270|R|   Deutsch PJ, Greenberg HE, Waldman SA. Indinavir and rifabutin drug|2
00408|271|R|   interactions in healthy volunteers. J Clin Pharmacol 2004 Mar;|2
00408|272|R|   44(3):305-13.|2
00408|273|R|39.Hamzeh FM, Benson C, Gerber J, Currier J, McCrea J, Deutsch P, Ruan P, Wu|2
00408|274|R|   H, Lee J, Flexner C. Steady-state pharmacokinetic interaction of|2
00408|275|R|   modified-dose indinavir and rifabutin. Clin Pharmacol Ther 2003 Mar;|2
00408|276|R|   73(3):159-69.|2
00408|277|R|40.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00408|278|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00408|279|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00408|280|R|   19(5):735-43.|6
00409|001|T|MONOGRAPH TITLE:  Tadalafil/Protease Inhibitors (mono deleted 06/12/2014)|
00409|002|B||
00409|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00409|004|L|take action as needed.|
00409|005|B||
00409|006|A|MECHANISM OF ACTION:  The metabolism of tadalafil by CYP P-450-3A4 may be|
00409|007|A|inhibited by the protease inhibitors.(1-10)|
00409|008|B||
00409|009|E|CLINICAL EFFECTS:  The concurrent administration of protease inhibitor may|
00409|010|E|result in elevated levels of tadalafil, which may result in increased|
00409|011|E|adverse effects such as hypotension, visual changes, and priapism.(1-10)|
00409|012|B||
00409|013|P|PREDISPOSING FACTORS:  None determined.|
00409|014|B||
00409|015|M|PATIENT MANAGEMENT:  The US manufacturers of tadalafil(12) and the protease|
00409|016|M|inhibitors(2-10) state that the recommended dose of as need tadalafil for|
00409|017|M|the treatment of erectile dysfunction is 10 mg of tadalafil every 72 hours|
00409|018|M|in patients receiving concurrent therapy.|
00409|019|M|   The US manufacturer of tadalafil states that the recommended dose of|
00409|020|M|daily tadalafil for the treatment of erectile dysfunction in patients taking|
00409|021|M|potent inhibitors of CYP3A4 is 2.5 mg.(10)|
00409|022|M|   The US manufacturers of the protease inhibitors state that in patients|
00409|023|M|who have received a protease inhibitor for at least one week, the initial|
00409|024|M|dosage of tadalafil for the treatment of primary pulmonary hypertension|
00409|025|M|should be 20 mg daily.  The dosage may be increased to 40 mg daily based|
00409|026|M|upon tolerability.(2-10)|
00409|027|M|   The US manufacturers of the protease inhibitors state that in patients|
00409|028|M|who have been receiving tadalafil for the treatment of primary pulmonary|
00409|029|M|hypertension, tadalafil should be discontinued for 24 hours before beginning|
00409|030|M|protease inhibitor therapy other than nelfinavir without concurrent|
00409|031|M|ritonavir.  After one week, tadalafil may be resumed at a dosage of 20 mg|
00409|032|M|daily.  The dosage may be increased to 40 mg daily based upon|
00409|033|M|tolerability.(2-9)|
00409|034|M|   In patients who have been receiving tadalafil for the treatment of|
00409|035|M|primary pulmonary hypertension, tadalafil should be adjusted to 20 mg daily|
00409|036|M|prior to beginning therapy with nelfinavir without concurrent ritonavir.|
00409|037|M|The dosage may be increased to 40 mg daily based upon tolerability.(10)|
00409|038|M|   Patients should be counseled that they are at an increased risk of|
00409|039|M|tadalafil adverse effects, including hypotension, syncope, visual changes,|
00409|040|M|and priapism.  Patients experiencing these effects should report them|
00409|041|M|promptly to their physician.|
00409|042|B||
00409|043|D|DISCUSSION:  Concurrent administration of tipranavir/ritonavir (500/200 mg|
00409|044|D|twice daily for 17 doses) had no significant effects on the AUC of a single|
00409|045|D|dose of tadalafil (10 mg).  Tadalafil Cmax decreased 30%.  Tipranavir Cmax,|
00409|046|D|AUC, and Cmin decreased by 10%, 15%, and 19%, respectively.  Administration|
00409|047|D|of a single dose of tipranavir/ritonavir (500/200 mg) increased the AUC of a|
00409|048|D|single dose of tadalafil (10 mg) by 2.33-fold.  Tadalafil Cmax decreased|
00409|049|D|22%.(9)|
00409|050|D|   Concurrent administration of a single dose of tadalafil (20 mg) with|
00409|051|D|ritonavir (200 mg twice daily) increased tadalafil AUC by 124%.(2,7)|
00409|052|D|Concurrent administration of a single dose of tadalafil (20 mg) with|
00409|053|D|ritonavir (500 mg or 600 mg twice daily) increased tadalafil AUC by 32% and|
00409|054|D|decreased tadalafil Cmax by 30%.(1)|
00409|055|B||
00409|056|R|REFERENCES:|
00409|057|B||
00409|058|R|1.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
00409|059|R|  February, 2010.|1
00409|060|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
00409|061|R|  Squibb Company June, 2014.|1
00409|062|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
00409|063|R|  March, 2023.|1
00409|064|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
00409|065|R|  February, 2013.|1
00409|066|R|5.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00409|067|R|  February, 2011.|1
00409|068|R|6.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00409|069|R|  Laboratories December, 2019.|1
00409|070|R|7.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00409|071|R|  November, 2012.|1
00409|072|R|8.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00409|073|R|  Laboratories, Inc. February, 2012.|1
00409|074|R|9.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00409|075|R|  Pharmaceuticals, Inc. February, 2012.|1
00409|076|R|10.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00409|077|R|   Pharmaceuticals, Inc. May, 2013.|1
00410|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Propafenone|
00410|002|B||
00410|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00410|004|L|take action as needed.|
00410|005|B||
00410|006|A|MECHANISM OF ACTION:  Propafenone may inhibit the metabolism of warfarin via|
00410|007|A|CYP1A2.(1,3)|
00410|008|B||
00410|009|E|CLINICAL EFFECTS:  The concurrent administration of warfarin and propafenone|
00410|010|E|may result in increased anticoagulant effects and risk of bleeding.|
00410|011|B||
00410|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00410|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00410|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
00410|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00410|016|P|risk for bleeding (e.g. NSAIDs).|
00410|017|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
00410|018|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
00410|019|P|are expected to be more susceptible to this interaction.|
00410|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00410|021|P|are expected to be less susceptible to effects from this drug combination,|
00410|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00410|023|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
00410|024|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
00410|025|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
00410|026|P|and safe anticoagulation than patients without these CYP2C9 variants.|
00410|027|B||
00410|028|M|PATIENT MANAGEMENT:  The dosage of warfarin may need to be adjusted when|
00410|029|M|propafenone is initiated or discontinued.  The patient INR should be|
00410|030|M|monitored for changes in the effects of warfarin.|
00410|031|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00410|032|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00410|033|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00410|034|M|patients with any symptoms.  Discontinue anticoagulation in patients with|
00410|035|M|active pathologic bleeding.|
00410|036|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00410|037|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00410|038|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00410|039|M|and/or swelling.|
00410|040|B||
00410|041|D|DISCUSSION:  In a study(2) in eight subjects, the concurrent administration|
00410|042|D|of propafenone with warfarin resulted in a 38% increase in the mean|
00410|043|D|steady-state plasma warfarin concentration when compared to the|
00410|044|D|administration of warfarin alone.  There were also significant changes in|
00410|045|D|the mean prothrombin time during concurrent administration.  While three|
00410|046|D|subjects had little change, two subjects experienced a doubling in|
00410|047|D|prothrombin time and three experienced a 50% increase in prothrombin time.|
00410|048|B||
00410|049|R|REFERENCES:|
00410|050|B||
00410|051|R|1.Kates RE, Yee YG, Kirsten EB. Interaction between warfarin and propafenone|2
00410|052|R|  in healthy volunteer subjects. Clin Pharmacol Ther 1987 Sep;42(3):305-11.|2
00410|053|R|2.Hii JT, Duff HJ, Burgess ED. Clinical pharmacokinetics of propafenone.|6
00410|054|R|  Clin Pharmacokinet 1991 Jul;21(1):1-10.|6
00410|055|R|3.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
00410|056|R|  Laboratories March, 2013.|1
00411|001|T|MONOGRAPH TITLE:  Leflunomide; Teriflunomide/Methotrexate (low strength inj,|
00411|002|T|oral)|
00411|003|B||
00411|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00411|005|L|take action as needed.|
00411|006|B||
00411|007|A|MECHANISM OF ACTION:  Teriflunomide inhibits organic anion transporter 3|
00411|008|A|(OAT3).  The combination may also result in additive or synergistic effects|
00411|009|A|on the liver or lung tissue.|
00411|010|B||
00411|011|E|CLINICAL EFFECTS:  The concurrent administration of leflunomide and|
00411|012|E|methotrexate may result in increased levels and toxicity from methotrexate,|
00411|013|E|including hepatotoxicity, pancytopenia, agranulocytosis, or|
00411|014|E|thrombocytopenia.(1)  Both agents can cause interstitial lung disease|
00411|015|E|(ILD).(2)|
00411|016|E|   Teriflunomide is the active metabolite of leflunomide and recommended|
00411|017|E|doses of both agents produce similar concentrations of teriflunomide.(3)|
00411|018|B||
00411|019|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
00411|020|P|- High-dose oncology regimens|
00411|021|P|- Impaired renal function, ascites, or pleural effusions|
00411|022|P|   This interaction should also be considered if leflunomide(1) or|
00411|023|P|teriflunomide is followed by methotrexate if no drug elimination procedure|
00411|024|P|is performed.|
00411|025|B||
00411|026|M|PATIENT MANAGEMENT:  In patients receiving concurrent methotrexate and|
00411|027|M|leflunomide or teriflunomide, platelets, white blood cells, hemoglobin or|
00411|028|M|hematocrit, and ALT (SGPT) should be performed at baseline and at monthly|
00411|029|M|intervals.  American College of Rheumatology (ACR) guidelines for monitoring|
00411|030|M|methotrexate liver toxicity must be followed with ALT, AST, and serum|
00411|031|M|albumin testing monthly. Patients should be monitored for signs and symptoms|
00411|032|M|of hepatotoxicity and bone marrow suppression.  If evidence of bone marrow|
00411|033|M|suppression occurs, treatment with leflunomide or teriflunomide should be|
00411|034|M|discontinued and cholestyramine or charcoal should be used to rapidly|
00411|035|M|decrease plasma concentrations of the active metabolite of leflunomide.|
00411|036|M|   Pulmonary status should be evaluated in patients who have recently|
00411|037|M|received methotrexate and these patients should be closely monitored during|
00411|038|M|therapy.  Patients should be instructed to contact their doctor if any|
00411|039|M|symptoms of ILD occur.  Symptoms include cough and dyspnea, with or without|
00411|040|M|associated fever.(2)  New or worsening pulmonary symptoms may warrant|
00411|041|M|therapy discontinuation.  If leflunomide or teriflunomide therapy is|
00411|042|M|discontinued, consider initiating washout procedures.|
00411|043|B||
00411|044|D|DISCUSSION:  The combined use of leflunomide and methotrexate has not been|
00411|045|D|adequately studied.(1)|
00411|046|D|   In clinical trials, the administration of leflunomide alone has resulted|
00411|047|D|in abnormal liver enzymes in 5% of subjects.  ALT (SGPT) values were greater|
00411|048|D|than 3-fold of normal in 1.5-4.4% of subjects.(1)|
00411|049|D|   In a small trial in 30 subjects, the concurrent administration of|
00411|050|D|leflunomide and methotrexate resulted in a greater than 3-fold increase in|
00411|051|D|liver enzymes in five subjects and a 2- to 3-fold increase in another five|
00411|052|D|subjects.  Three patients met ACR criteria for liver biopsy.  There was no|
00411|053|D|evidence of a pharmacokinetic interaction.(1)|
00411|054|D|   In a 6 month study, an increase in ALT greater than or equal to 3 times|
00411|055|D|the upper limit of normal was observed in 3.8% of patients (n=133) receiving|
00411|056|D|concurrent leflunomide and methotrexate.  In comparison, such increases were|
00411|057|D|only seen in 0.8% of patients (n=130) who received methotrexate with|
00411|058|D|placebo.(1)|
00411|059|D|   There have been rare reports of pancytopenia, agranulocytosis, and|
00411|060|D|thrombocytopenia during leflunomide therapy.  In most of these reports,|
00411|061|D|patients were receiving concurrent therapy with methotrexate and/or another|
00411|062|D|immunosuppressive agent.(1)|
00411|063|D|   ILD has been rarely reported with leflunomide and has been associated|
00411|064|D|with fatal outcomes.(1) Many of these reports are confounded by preexisting|
00411|065|D|pulmonary disease and/or previous or concomitant use of other agents that|
00411|066|D|cause ILD, including methotrexate.(2)|
00411|067|D|   Teriflunomide is the active metabolite of leflunomide and recommended|
00411|068|D|doses of both agents produce similar concentrations of teriflunomide.(3)|
00411|069|B||
00411|070|R|REFERENCES:|
00411|071|B||
00411|072|R|1.Arava (leflunomide) US prescribing information. Aventis Pharmaceuticals,|1
00411|073|R|  Inc. November, 2012.|1
00411|074|R|2.Dear Healthcare Professional:  Arava (leflunomide) and interstitial lung|1
00411|075|R|  disease. Aventis Pharma, Inc. June 21, 2004.|1
00411|076|R|3.Aubagio (teriflunomide) US prescribing information. Genzyme Corporation|1
00411|077|R|  November, 2020.|1
00412|001|T|MONOGRAPH TITLE:  Cyclosporine/Octreotide|
00412|002|B||
00412|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00412|004|L|take action as needed.|
00412|005|B||
00412|006|A|MECHANISM OF ACTION:  Octreotide may interfere with the enterohepatic|
00412|007|A|circulation of cyclosporine or may delay or inhibit the absorption of|
00412|008|A|cyclosporine.(2)|
00412|009|B||
00412|010|E|CLINICAL EFFECTS:  The concurrent administration of octreotide and|
00412|011|E|cyclosporine may result in a decrease in cyclosporine levels.|
00412|012|B||
00412|013|P|PREDISPOSING FACTORS:  None determined.|
00412|014|B||
00412|015|M|PATIENT MANAGEMENT:  Cyclosporine levels should be monitored in patients|
00412|016|M|receiving concurrent therapy with cyclosporine and octreotide.  The dosage|
00412|017|M|of cyclosporine may need to be adjusted if octreotide is added to or|
00412|018|M|discontinued from cyclosporine therapy.  Octreotide may need to be|
00412|019|M|discontinued.|
00412|020|B||
00412|021|D|DISCUSSION:  In a study, 23 of 65 pancreas transplant patients were treated|
00412|022|D|octreotide.  During octreotide therapy, the dosage of oral cyclosporine|
00412|023|D|required to maintain therapeutic levels increased.  In addition 15 patients|
00412|024|D|required supplemental intravenous cyclosporine to maintain cyclosporine|
00412|025|D|levels.(2)|
00412|026|D|   In a case report, a cadaver renal and whole-pancreas transplant recipient|
00412|027|D|was treated for a fistula with octreotide.  Cyclosporine blood levels slowly|
00412|028|D|decreased despite an increase in cyclosporine dosage (from 180 mg to 300 mg|
00412|029|D|daily).  When the cyclosporine level decreased below 100 ng/ml, intravenous|
00412|030|D|cyclosporine was administered.  Octreotide was discontinued when the patient|
00412|031|D|developed graft rejection.  Cyclosporine levels returned to baseline and the|
00412|032|D|rejection was reversed.(1)  In another case report, cyclosporine levels|
00412|033|D|dropped below detection when octreotide was added to his therapy.  The|
00412|034|D|patient was successfully treated for graft rejection and octreotide was|
00412|035|D|discontinued.(3)  These authors reported a total of nine patients in whom|
00412|036|D|cyclosporine levels decreased following the addition of octreotide to|
00412|037|D|cyclosporine.(4)|
00412|038|D|  In a study of 10 patients with severe diarrhea following bone marrow|
00412|039|D|transplantation, cyclosporine dosage requirements increased by 50% in two|
00412|040|D|subjects following the addition of octreotide.(5)|
00412|041|B||
00412|042|R|REFERENCES:|
00412|043|B||
00412|044|R|1.Stratta RJ, Taylor RJ, Lowell JA, Bynon JS, Cattral M, Langnas AN, Shaw BW|2
00412|045|R|  Jr. Selective use of Sandostatin in vascularized pancreas transplantation.|2
00412|046|R|  Am J Surg 1993 Dec;166(6):598-604; discussion 604-5.|2
00412|047|R|2.Rosenberg L, Dafoe DC, Schwartz R, Campbell DA Jr, Turcotte JG, Tsai ST,|3
00412|048|R|  Vinik A. Administration of somatostatin analog (SMS 201-995) in the|3
00412|049|R|  treatment of a fistula occurring after pancreas transplantation.|3
00412|050|R|  Interference with cyclosporine immunosuppression. Transplantation 1987|3
00412|051|R|  May;43(5):764-6.|3
00412|052|R|3.Landgraf R, Landgraf-Leurs MM, Nusser J, Hillebrand G, Illner WD,|3
00412|053|R|  Abendroth D, Land W. Effect of somatostatin analogue (SMS201-995) on|3
00412|054|R|  cyclosporine levels. Transplantation 1987 Nov;44(5):724-5.|3
00412|055|R|4.Landgraf R, Landgraf-Leurs MMC, Burg D, Kampik A, Castro LA, Abendroth A,|3
00412|056|R|  Illner WD, Land W. Long-term follow-up of segmental pancreas|3
00412|057|R|  transplanation in Type I diabetics. Transplant Proc 1986 Oct;|3
00412|058|R|  18(5):1118-24.|3
00412|059|R|5.Morton AJ, Durrant ST. Efficacy of octreotide in controlling refractory|2
00412|060|R|  diarrhea following bone marrow transplantation. Clin Transplant 1995 Jun;|2
00412|061|R|  9(3 Pt 1):205-8.|2
00413|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants;Temsirolimus/Selected|
00413|002|T|Macrolides|
00413|003|B||
00413|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00413|005|L|of severe adverse interaction.|
00413|006|B||
00413|007|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
00413|008|A|cyclosporine, sirolimus, and temsirolimus by CYP3A4.|
00413|009|B||
00413|010|E|CLINICAL EFFECTS:  The concurrent administration of cyclosporine, sirolimus,|
00413|011|E|or temsirolimus with a macrolide that inhibits CYP3A4 may result in elevated|
00413|012|E|levels of cyclosporine, sirolimus, or temsirolimus and possible toxicity.|
00413|013|E|The levels of the macrolide may also be elevated and result in toxicity.|
00413|014|B||
00413|015|P|PREDISPOSING FACTORS:  Progressively decreasing renal/hepatic function.|
00413|016|B||
00413|017|M|PATIENT MANAGEMENT:  Cyclosporine, sirolimus, and temsirolimus levels should|
00413|018|M|be carefully monitored in patients receiving concurrent therapy with|
00413|019|M|macrolide antibiotics.  The dosage of cyclosporine, sirolimus, or|
00413|020|M|temsirolimus may need to be adjusted during and/or after macrolide therapy|
00413|021|M|or the macrolide may need to be discontinued.  The dosage of the macrolide|
00413|022|M|antibiotic may need to be adjusted.|
00413|023|M|   Guidelines from the American Society of Transplantation state that|
00413|024|M|clarithromycin and erythromycin are contraindicated with sirolimus (although|
00413|025|M|product labels do not contraindicate these combinations), and that the use|
00413|026|M|of clarithromycin or erythromycin with cyclosporine should be avoided.  If|
00413|027|M|the combination must be used, lower the dose of the immunosuppressant by up|
00413|028|M|to 50 % upon initiation of the antibiotic and monitor levels daily with|
00413|029|M|cyclosporine or every 3rd day with sirolimus.|
00413|030|M|   The US manufacturer of sirolimus states that concurrent use with|
00413|031|M|erythromycin, clarithromycin, or telithromycin is not recommended and should|
00413|032|M|be avoided.|
00413|033|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
00413|034|M|with strong CYP3A4 inhibitors such as clarithromycin or telithromycin be|
00413|035|M|avoided.  If concurrent use is warranted, a dosage reduction to 12.5 mg/week|
00413|036|M|of temsirolimus should be considered.  If the macrolide is discontinued, a|
00413|037|M|washout period of 1 week should be allowed before adjusting the dosage of|
00413|038|M|temsirolimus to previous levels.|
00413|039|B||
00413|040|D|DISCUSSION:  Concomitant administration of cyclosporine and erythromycin has|
00413|041|D|been shown to increase cyclosporine trough serum levels and clinical|
00413|042|D|symptoms of drug toxicity. Maximum effect may be seen one week after|
00413|043|D|concurrent administration. These effects reverse when erythromycin is|
00413|044|D|discontinued. The interaction probably occurs with troleandomycin also. Case|
00413|045|D|reports have documented increased cyclosporine and creatinine levels during|
00413|046|D|concurrent administration with clarithromycin. Several studies have shown|
00413|047|D|that spiramycin does not affect cyclosporine pharmacokinetics. Because|
00413|048|D|studies in rats have shown that azithromycin does not affect CYP P-450, it|
00413|049|D|would not be expected to interact with cyclosporine.  One case report exists|
00413|050|D|which describes a potential interaction between cyclosporine and|
00413|051|D|azithromycin; however, the time course of the events suggest that other|
00413|052|D|factors, such as the patient's failing renal graft, may have led to the|
00413|053|D|increased cyclosporine levels in this patient.|
00413|054|D|   In a cross-over study in 16 healthy subjects, pretreatment with|
00413|055|D|erythromycin (500 mg 3 times daily for 9 days) increased the maximum|
00413|056|D|concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a|
00413|057|D|single oral dose of everolimus (2 mg on Day 5) by 2.0-fold, 4.4-fold, and|
00413|058|D|39%, respectively.  There were no effects on erythromycin levels.|
00413|059|D|   In a study in 24 healthy subjects, concurrent sirolimus (2 mg daily) and|
00413|060|D|erythromycin ethylsuccinate (800 mg 3 times daily) increased sirolimus Cmax,|
00413|061|D|AUC, and time to Cmax (Tmax) by 4.4-fold, 4.2-fold, and 0.4 hours,|
00413|062|D|respectively.  Erythromycin Cmax, AUC, and Tmax were increased by 1.6-fold,|
00413|063|D|1.7-fold, and 0.3 hours, respectively.  There are case reports of toxicity|
00413|064|D|with concurrent sirolimus and erythromycin.|
00413|065|D|   Concurrent administration of ketoconazole, another inhibitor of CYP3A4,|
00413|066|D|had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax|
00413|067|D|increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of|
00413|068|D|temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is|
00413|069|D|expected to adjust levels to the range observed without inhibitors; however,|
00413|070|D|there are no data available with this dose adjustment.|
00413|071|D|   Azithromycin, a weak CYP3A4 inhibitor, and spiramycin, which does not|
00413|072|D|inhibit the CYP P-450 system, would not be expected to interact with|
00413|073|D|cyclosporine, sirolimus, or temsirolimus.|
00413|074|B||
00413|075|R|REFERENCES:|
00413|076|B||
00413|077|R|1.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
00413|078|R|  Aug, 2022.|1
00413|079|R|2.Kovarik JM, Beyer D, Bizot MN, Jiang Q, Shenouda M, Schmouder RL. Effect|2
00413|080|R|  of multiple-dose erythromycin on everolimus pharmacokinetics. Eur J Clin|2
00413|081|R|  Pharmacol 2005 Mar;61(1):35-8.|2
00413|082|R|3.Claesson K, Brattstrom C, Burke JT. Sirolimus and erythromycin|3
00413|083|R|  interaction: two cases. Transplant Proc 2001 May;33(3):2136.|3
00413|084|R|4.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
00413|085|R|  Inc. March, 2018.|1
00413|086|R|5.Danan G, Descatoire V, Pessayre D. Self-induction by erythromycin of its|5
00413|087|R|  own transformation into a metabolite forming an inactive complex with|5
00413|088|R|  reduced cytochrome P-450. J Pharmacol Exp Ther 1981 Aug;218(2):509-14.|5
00413|089|R|6.Ptachcinski RJ, Carpenter BJ, Burckart GJ, Venkataramanan R, Rosenthal JT.|3
00413|090|R|  Effect of erythromycin on cyclosporine levels. N Engl J Med 1985 Nov 28;|3
00413|091|R|  313(22):1416-7.|3
00413|092|R|7.Kohan DE. Possible interaction between cyclosporine and erythromycin. N|3
00413|093|R|  Engl J Med 1986 Feb 13;314(7):448.|3
00413|094|R|8.Martell R, Heinrichs D, Stiller CR, Jenner M, Keown PA, Dupre J. The|3
00413|095|R|  effects of erythromycin in patients treated with cyclosporine. Ann Intern|3
00413|096|R|  Med 1986 May;104(5):660-1.|3
00413|097|R|9.Grino JM, Sabate J, Castelao AM, Guardia M, Seron D, Alsina J.|3
00413|098|R|  Erythromycin and cyclosporine. Ann Intern Med 1986 Sep;105(3):467-8.|3
00413|099|R|10.Godin JR, Sketris IS, Belitsky P. Erythromycin-cyclosporin interaction.|3
00413|100|R|   Drug Intell Clin Pharm 1986 Jun;20(6):504-5.|3
00413|101|R|11.Kessler M, Louis J, Renoult E, Vigneron B, Netter P. Interaction between|3
00413|102|R|   cyclosporin and erythromycin in a kidney transplant patient. Eur J Clin|3
00413|103|R|   Pharmacol 1986;30(5):633-4.|3
00413|104|R|12.Gonwa TA, Nghiem DD, Schulak JA, Corry RJ. Erythromycin and cyclosporine.|3
00413|105|R|   Transplantation 1986 Jun;41(6):797-9.|3
00413|106|R|13.Freeman DJ, Martell R, Carruthers SG, Heinrichs D, Keown PA, Stiller CR.|2
00413|107|R|   Cyclosporin-erythromycin interaction in normal subjects. Br J Clin|2
00413|108|R|   Pharmacol 1987 Jun;23(6):776-8.|2
00413|109|R|14.Aoki FY,  Yatscoff R, Jeffery J, Rush D, Sitar D. Effects of erythromycin|4
00413|110|R|   on cyclosporine A kinetics in renal transplant patients. Clin Pharmacol|4
00413|111|R|   Ther 1987 Feb;41(2):221.|4
00413|112|R|15.Wadhwa NK, Schroeder TJ, O'Flaherty E, Pesce AJ, Myre SA, Munda R, First|3
00413|113|R|   MR. Interaction between erythromycin and cyclosporine in a kidney and|3
00413|114|R|   pancreas allograft recipient. Ther Drug Monit 1987;9(1):123-5.|3
00413|115|R|16.Vereerstraeten P, Thiry P, Kinnaert P, Toussaint C. Influence of|2
00413|116|R|   erythromycin on cyclosporine pharmacokinetics. Transplantation 1987 Jul;|2
00413|117|R|   44(1):155-6.|2
00413|118|R|17.Harnett JD, Parfrey PS, Paul MD, Gault MH. Erythromycin-cyclosporine|3
00413|119|R|   interaction in renal transplant recipients. Transplantation 1987 Feb;|3
00413|120|R|   43(2):316-8.|3
00413|121|R|18.Jensen CW, Flechner SM, Van Buren CT, Frazier OH, Cooley DA, Lorber MI,|3
00413|122|R|   Kahan BD. Exacerbation of cyclosporine toxicity by concomitant|3
00413|123|R|   administration of erythromycin. Transplantation 1987 Feb;43(2):263-70.|3
00413|124|R|19.Murray BM, Edwards L, Morse GD, Kohli RR, Venuto RC. Clinically important|3
00413|125|R|   interaction of cyclosporine and erythromycin. Transplantation 1987 Apr;|3
00413|126|R|   43(4):602-4.|3
00413|127|R|20.Gupta SK, Bakran A, Johnson RW, Rowland M. Erythromycin enhances the|2
00413|128|R|   absorption of cyclosporin. Br J Clin Pharmacol 1988 Mar;25(3):401-2.|2
00413|129|R|21.Ben-Ari J, Eisenstein B, Davidovits M, Shmueli D, Shapira Z, Stark H.|3
00413|130|R|   Effect of erythromycin on blood cyclosporine concentrations in kidney|3
00413|131|R|   transplant patients. J Pediatr 1988 Jun;112(6):992-3.|3
00413|132|R|22.Lysz K, Rosenberg JC, Kaplan MP, Migdal S, Sillix D. Interaction of|3
00413|133|R|   erythromycin with cyclosporine. Transplant Proc 1988 Apr;20(2 Suppl|3
00413|134|R|   2):543-8.|3
00413|135|R|23.Guillemain R, Billaud E, Dreyfus G, Amrein C, Kitzis M, Jebara VA,|2
00413|136|R|   Kreft-Jais C. The effects of spiramycin on plasma cyclosporin A|2
00413|137|R|   concentrations in heart transplant patients. Eur J Clin Pharmacol 1989;|2
00413|138|R|   36(1):97-8.|2
00413|139|R|24.Gupta SK, Bakran A, Johnson RW, Rowland M. Cyclosporin-erythromycin|2
00413|140|R|   interaction in renal transplant patients. Br J Clin Pharmacol 1989 Apr;|2
00413|141|R|   27(4):475-81.|2
00413|142|R|25.Vernillet L, Bertault-Peres P, Berland Y, Barradas J, Durand A, Olmer M.|2
00413|143|R|   Lack of effect of spiramycin on cyclosporin pharmacokinetics. Br J Clin|2
00413|144|R|   Pharmacol 1989 Jun;27(6):789-94.|2
00413|145|R|26.Marre F, de Sousa G, Orloff AM, Rahmani R. In vitro interaction between|2
00413|146|R|   cyclosporin A and macrolide antibiotics. Br J Clin Pharmacol 1993 Apr;|2
00413|147|R|   35(4):447-8.|2
00413|148|R|27.Moral A, Navasa M, Rimola A, Garcia-Valdecasas JC, Grande L, Visa J,|3
00413|149|R|   Rodes J. Erythromycin ototoxicity in liver transplant patients. Transpl|3
00413|150|R|   Int 1994;7(1):62-4.|3
00413|151|R|28.Koselj M, Bren A, Kandus A, Kovac D. Drug interactions between|2
00413|152|R|   cyclosporine and rifampicin, erythromycin, and azoles in kidney|2
00413|153|R|   recipients with opportunistic infections. Transplant Proc 1994 Oct;|2
00413|154|R|   26(5):2823-4.|2
00413|155|R|29.Zylber-Katz E. Multiple drug interactions with cyclosporine in a heart|3
00413|156|R|   transplant patient. Ann Pharmacother 1995 Feb;29(2):127-31.|3
00413|157|R|30.Kessler M, Netter P, Zerrouki M, Renoult E, Trechot P, Dousset B, Jonon|3
00413|158|R|   B, Mur JM. Spiramycin does not increase plasma cyclosporin concentrations|3
00413|159|R|   in renal transplant patients. Eur J Clin Pharmacol 1988;35(3):331-2.|3
00413|160|R|31.Kessler M, Netter P, Renoul HE, Trechot P, Dousset B, Bannwarth B. Lack|6
00413|161|R|   of effect of spiramycin on cyclosporin pharmacokinetics. Br J Clin|6
00413|162|R|   Pharmacol 1990 Mar;29(3):370-1.|6
00413|163|R|32.Birmele B, Lebranchu Y, Beliveau F, Rateau H, Furet Y, Nivet H, Bagros P.|3
00413|164|R|   Absence of interaction between cyclosporine and spiramycin.|3
00413|165|R|   Transplantation 1989 May;47(5):927-8.|3
00413|166|R|33.Gersema LM, Porter CB, Russell EH. Suspected drug interaction between|3
00413|167|R|   cyclosporine and clarithromycin. J Heart Lung Transplant 1994 Mar-Apr;|3
00413|168|R|   13(2):343-5.|3
00413|169|R|34.Ferrari SL, Goffin E, Mourad M, Wallemacq P, Squifflet JP, Pirson Y. The|3
00413|170|R|   interaction between clarithromycin and cyclosporine in kidney transplant|3
00413|171|R|   recipients. Transplantation 1994 Sep 27;58(6):725-7.|3
00413|172|R|35.Ljutic D, Rumboldt Z. Possible interaction between azithromycin and|3
00413|173|R|   cyclosporin: a case report. Nephron 1995;70(1):130.|3
00413|174|R|36.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
00413|175|R|   immunosuppressants-Guidelines from the American Society of|6
00413|176|R|   Transplantation Infectious Diseases Community of Practice. Clin|6
00413|177|R|   Transplant 2019 Feb 28;e13510.|6
00414|001|T|MONOGRAPH TITLE:  Indinavir/Efavirenz|
00414|002|B||
00414|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00414|004|L|of severe adverse interaction.|
00414|005|B||
00414|006|A|MECHANISM OF ACTION:  Efavirenz induces the metabolism of indinavir at|
00414|007|A|CYP3A4.(1-3)|
00414|008|B||
00414|009|E|CLINICAL EFFECTS:  The concurrent administration of efavirenz and indinavir|
00414|010|E|results in a decrease in the levels of indinavir.(1-3)|
00414|011|B||
00414|012|P|PREDISPOSING FACTORS:  None determined.|
00414|013|B||
00414|014|M|PATIENT MANAGEMENT:  Concurrent use is not recommended.  The optimal dose of|
00414|015|M|indinavir, when given with efavirenz, is not known.  Increased indinavir|
00414|016|M|doses have not improved efficacy when given with efavirenz.(1-3)|
00414|017|B||
00414|018|D|DISCUSSION:  The concurrent administration of efavirenz and indinavir (800|
00414|019|D|mg every 8 hours) resulted in decreases in the indinavir area-under-curve|
00414|020|D|(AUC) and maximum concentration (Cmax) by 31% and 16%, respectively.(2)|
00414|021|D|   In a study in 20 HIV-positive subjects concurrent efavirenz (600 mg|
00414|022|D|daily) and indinavir (1000 mg tid) decreased indinavir AUC by 33%, 37%, and|
00414|023|D|46% after morning, afternoon, and evening doses, respectively, when compared|
00414|024|D|to indinavir (800 mg tid) alone. Indinavir Cmin decreased by 39%, 52%, and|
00414|025|D|57% after morning, afternoon, and evening doses, respectively, when compared|
00414|026|D|to indinavir (800 mg tid) alone. Indinavir Cmax decreased by 29% after the|
00414|027|D|evening dose.  There were no significant changes in efavirenz|
00414|028|D|pharmacokinetics.(1)|
00414|029|B||
00414|030|R|REFERENCES:|
00414|031|B||
00414|032|R|1.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00414|033|R|  September, 2016.|1
00414|034|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
00414|035|R|  Company November, 2023.|1
00414|036|R|3.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
00414|037|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
00415|001|T|MONOGRAPH TITLE:  Pimozide/Selected Macrolide Antibiotics|
00415|002|B||
00415|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00415|004|L|is contraindicated and generally should not be dispensed or administered to|
00415|005|L|the same patient.|
00415|006|B||
00415|007|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
00415|008|A|pimozide by CYP3A4.|
00415|009|B||
00415|010|E|CLINICAL EFFECTS:  Increased levels of pimozide may result in prolongation|
00415|011|E|of the QT-interval, ventricular arrhythmias, and death.|
00415|012|B||
00415|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00415|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00415|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00415|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00415|017|P|female gender, or advanced age.(3)|
00415|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00415|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00415|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00415|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00415|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00415|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00415|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
00415|025|P|   The risk of anticholinergic toxicities including cognitive decline,|
00415|026|P|delirium, falls and fractures is increased in geriatric patients using more|
00415|027|P|than one medicine with anticholinergic properties.(4)|
00415|028|B||
00415|029|M|PATIENT MANAGEMENT:  The manufacturer of pimozide states that concurrent|
00415|030|M|therapy with macrolide antibiotics and pimozide is contraindicated.(1)|
00415|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00415|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00415|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00415|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00415|035|B||
00415|036|D|DISCUSSION:  The manufacturer of pimozide states that two deaths have been|
00415|037|D|linked to the addition of clarithromycin to pimozide therapy.  Therefore,|
00415|038|D|the manufacturer of pimozide states that concurrent therapy with macrolide|
00415|039|D|antibiotics and pimozide is contraindicated.(1)|
00415|040|D|   A study in 12 subjects found that the concurrent administration of|
00415|041|D|pimozide and clarithromycin resulted in significant increases in the|
00415|042|D|pimozide maximum concentration (Cmax) and area-under-curve (AUC) and|
00415|043|D|decreased the clearance of pimozide.  There was also a significant increase|
00415|044|D|in the QTc interval when pimozide was administered with clarithromycin.(5)|
00415|045|D|   One or more of the drug pairs linked to this monograph have been included|
00415|046|D|in a list of interactions that should be considered "high-priority" for|
00415|047|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00415|048|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00415|049|D|Coordinator (ONC) for Health Information Technology.|
00415|050|B||
00415|051|R|REFERENCES:|
00415|052|B||
00415|053|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
00415|054|R|  2011.|1
00415|055|R|2.Dear Healthcare Provider letter:  labeling changes concerning ORAP|1
00415|056|R|  (pimozide). Gate Pharmaceuticals September, 1999.|1
00415|057|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00415|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00415|059|R|  settings: a scientific statement from the American Heart Association and|6
00415|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00415|061|R|  2;55(9):934-47.|6
00415|062|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
00415|063|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
00415|064|R|  Soc 2023 Jul;71(7):2052-2081.|6
00415|065|R|5.Desta Z, Kerbusch T, Flockhart DA. Effect of clarithromycin on the|2
00415|066|R|  pharmacokinetics and pharmacodynamics of pimozide in healthy poor and|2
00415|067|R|  extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Clin Pharmacol|2
00415|068|R|  Ther 1999 Jan;65(1):10-20.|2
00415|069|R|6.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00415|070|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00415|071|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00415|072|R|  19(5):735-43.|6
00416|001|T|MONOGRAPH TITLE:  Indoramin/MAOIs|
00416|002|B||
00416|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00416|004|L|of severe adverse interaction.|
00416|005|B||
00416|006|A|MECHANISM OF ACTION:  Unknown.|
00416|007|B||
00416|008|E|CLINICAL EFFECTS:  Concurrent administration may result in hypotension.|
00416|009|B||
00416|010|P|PREDISPOSING FACTORS:  None determined.|
00416|011|B||
00416|012|M|PATIENT MANAGEMENT:  Avoid concurrent therapy with these agents if possible.|
00416|013|M|If concurrent therapy is necessary, monitor patients for signs of|
00416|014|M|hypotension.|
00416|015|B||
00416|016|D|DISCUSSION:  The data sheet for indoramin states that the drug is|
00416|017|D|contraindicated in patients receiving therapy with a MAOI agent.|
00416|018|D|   Methylene blue, when administered intravenously, has been shown to reach|
00416|019|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
00416|020|D|   Metaxalone is a weak inhibitor of MAO.|
00416|021|B||
00416|022|R|REFERENCES:|
00416|023|B||
00416|024|R|1.Baratol (indoramin hydrochloride) UK summary of product characteristics.|1
00416|025|R|  Shire Pharmaceuticals Limited April 23, 1993.|1
00416|026|R|2.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00416|027|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00416|028|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00416|029|R|3.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00416|030|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00416|031|R|  2000 Jun;56(3):247-50.|2
00416|032|R|4.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00416|033|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00416|034|R|  Feb;34(2):346.e5-6.|3
00416|035|R|5.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00416|036|R|  Pfizer Inc. January, 2024.|1
00417|001|T|MONOGRAPH TITLE:  Bethanidine/MAOIs|
00417|002|B||
00417|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00417|004|L|of severe adverse interaction.|
00417|005|B||
00417|006|A|MECHANISM OF ACTION:  Unknown.|
00417|007|B||
00417|008|E|CLINICAL EFFECTS:  Concurrent administration may result in hypotension.|
00417|009|B||
00417|010|P|PREDISPOSING FACTORS:  None determined.|
00417|011|B||
00417|012|M|PATIENT MANAGEMENT:  Avoid concurrent therapy with these agents if possible.|
00417|013|M|If concurrent therapy is necessary, monitor patients for signs of|
00417|014|M|hypotension.|
00417|015|B||
00417|016|D|DISCUSSION:  The data sheet for bethanidine states that the drug is|
00417|017|D|contraindicated in patients receiving therapy with a MAOI agent.|
00417|018|D|   Methylene blue, when administered intravenously, has been shown to reach|
00417|019|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
00417|020|D|   Metaxalone is a weak inhibitor of MAO.|
00417|021|B||
00417|022|R|REFERENCES:|
00417|023|B||
00417|024|R|1.Bethanidine UK summary of product characteristics. British National|1
00417|025|R|  Formulary, Number 29 March 1995.|1
00417|026|R|2.Bethanidine UK summary of product characteristics. ABPI Data Sheet (Lagap|1
00417|027|R|  Pharm) 1994.|1
00417|028|R|3.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00417|029|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00417|030|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00417|031|R|4.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00417|032|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00417|033|R|  2000 Jun;56(3):247-50.|2
00417|034|R|5.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00417|035|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00417|036|R|  Feb;34(2):346.e5-6.|3
00417|037|R|6.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00417|038|R|  Pfizer Inc. January, 2024.|1
00418|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Propranolol|
00418|002|B||
00418|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00418|004|L|take action as needed.|
00418|005|B||
00418|006|A|MECHANISM OF ACTION:  The exact mechanism of this interaction is unknown.|
00418|007|A|Propranolol may inhibit the hepatic metabolism of warfarin.|
00418|008|B||
00418|009|E|CLINICAL EFFECTS:  Increased serum concentrations of warfarin may result in|
00418|010|E|an increased risk for bleeding.|
00418|011|B||
00418|012|P|PREDISPOSING FACTORS:  Risk for bleeding episodes may be greater in patients|
00418|013|P|with disease-associated bleeding risk (e.g. thrombocytopenia). Drug risk|
00418|014|P|factors include concurrent use of multiple drugs which inhibit warfarin|
00418|015|P|metabolism, or have an inherent risk for bleeding (e.g. NSAIDs).|
00418|016|P|   Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2|
00418|017|P|copies of a reduced function VKORC1 gene are expected to be more susceptible|
00418|018|P|to this interaction.|
00418|019|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00418|020|P|are expected to be less susceptible to effects from this drug combination,|
00418|021|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00418|022|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
00418|023|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
00418|024|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
00418|025|P|and safe anticoagulation than patients without these CYP2C9 variants|
00418|026|B||
00418|027|M|PATIENT MANAGEMENT:  Monitor the INR when propranolol is added to or|
00418|028|M|discontinued from warfarin therapy, particularly when higher doses of|
00418|029|M|propranolol (> 80 mg/dose) are prescribed.|
00418|030|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00418|031|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00418|032|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00418|033|M|patients with any symptoms.|
00418|034|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00418|035|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00418|036|M|anticoagulation in patients with active pathologic bleeding.|
00418|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00418|038|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00418|039|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00418|040|M|and/or swelling.|
00418|041|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00418|042|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00418|043|M|initiating, altering the dose or discontinuing either drug.|
00418|044|B||
00418|045|D|DISCUSSION:  In two studies in healthy subjects, concurrent administration|
00418|046|D|of warfarin and propranolol 80 mg every 12 hours resulted in increases of|
00418|047|D|warfarin area-under-curve (AUC) by 14.7-16.3% and 23% increase in warfarin|
00418|048|D|maximum concentration (Cmax).  There were no significant changes in|
00418|049|D|prothrombin times.  In a case report, a patient's prothrombin time increased|
00418|050|D|after the addition of propranolol to his warfarin therapy.  The prothrombin|
00418|051|D|time decreased to pre-propranolol treatment values when propranolol was|
00418|052|D|discontinued.|
00418|053|D|   Studies have shown that warfarin AUC was unaffected by atenolol,|
00418|054|D|metoprolol, or esmolol.  Warfarin Cmax was unaffected by metoprolol and|
00418|055|D|esmolol, but increased 12.5% with concurrent administration of atenolol.|
00418|056|D|Prothrombin time, plasma clotting factor VII activity, and the mean warfarin|
00418|057|D|elimination half-life were unchanged by either metoprolol or atenolol.  In a|
00418|058|D|study, administration of acebutolol did not result in a significant change|
00418|059|D|in prothrombin time.|
00418|060|B||
00418|061|R|REFERENCES:|
00418|062|B||
00418|063|R|1.Bax ND, Lennard MS, Tucker GT, Woods HF, Porter NR, Malia RG, Preston FE.|2
00418|064|R|  The effect of beta-adrenoceptor antagonists on the pharmacokinetics and|2
00418|065|R|  pharmacodynamics of warfarin after a single dose. Br J Clin Pharmacol 1984|2
00418|066|R|  May;17(5):553-7.|2
00418|067|R|2.Scott AK, Park BK, Breckenridge AM. Interaction between warfarin and|2
00418|068|R|  propranolol. Br J Clin Pharmacol 1984 May;17(5):559-64.|2
00418|069|R|3.Bax NDS, Lennard MS, Al-Asady S, Deacon CS, Tucker GT, Woods HF.|3
00418|070|R|  Inhibition of drug metabolism by beta-adrenoceptor antagonists. Drugs 1983|3
00418|071|R|  Mar;25(Suppl 2):121-6.|3
00418|072|R|4.Ryan JR. Clinical pharmacology of acebutolol. Am Heart J 1985 May;109(5 Pt|6
00418|073|R|  2):1131-6.|6
00418|074|R|5.Lowenthal DT, Porter RS, Saris SD, Bies CM, Slegowski MB, Staudacher A.|6
00418|075|R|  Clinical pharmacology, pharmacodynamics and interactions with esmolol. Am|6
00418|076|R|  J Cardiol 1985 Oct 23;56(11):14F-18F.|6
00418|077|R|6.Spahn H, Kirch W, Mutschler E, Ohnhaus EE, Kitteringham NR, Logering HJ,|2
00418|078|R|  Paar D. Pharmacokinetic and pharmacodynamic interactions between|2
00418|079|R|  phenprocoumon and atenolol or metoprolol. Br J Clin Pharmacol 1984;17|2
00418|080|R|  Suppl 1:97S-102S.|2
00419|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/Selected|
00419|002|T|HMG-CoA Reductase Inhibitors|
00419|003|B||
00419|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00419|005|L|take action as needed.|
00419|006|B||
00419|007|A|MECHANISM OF ACTION:  The exact mechanism of this interaction is unknown.|
00419|008|A|The HMG-CoA reductase inhibitor may inhibit the hepatic hydroxylation of|
00419|009|A|warfarin.  The HMG-CoA reductase inhibitors, which are highly plasma protein|
00419|010|A|bound, may displace warfarin from its binding site.|
00419|011|B||
00419|012|E|CLINICAL EFFECTS:  Increased hypoprothrombinemic effects of warfarin may|
00419|013|E|result in a risk for bleeding.|
00419|014|B||
00419|015|P|PREDISPOSING FACTORS:  Risk for bleeding episodes may be greater in patients|
00419|016|P|with disease-associated bleeding risk (e.g. thrombocytopenia).|
00419|017|P|   Drug risk factors include concurrent use of multiple drugs which inhibit|
00419|018|P|warfarin metabolism, or have an inherent risk for bleeding (e.g. NSAIDs).|
00419|019|B||
00419|020|M|PATIENT MANAGEMENT:  Patients should be monitored for changes in prothrombin|
00419|021|M|time when a HMG Co-A reductase inhibitor is added to or discontinued from|
00419|022|M|warfarin therapy, or if the dosage of the HMG Co-A reductase inhibitor is|
00419|023|M|adjusted.|
00419|024|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00419|025|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00419|026|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00419|027|M|patients with any symptoms.  Discontinue anticoagulation in patients with|
00419|028|M|active pathologic bleeding.|
00419|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00419|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00419|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00419|032|M|and/or swelling.|
00419|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00419|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00419|035|M|initiating, altering the dose or discontinuing either drug.|
00419|036|B||
00419|037|D|DISCUSSION:  Case reports in the medical literature and to the manufacturer|
00419|038|D|have documented an interaction between lovastatin and warfarin. A case|
00419|039|D|report has documented an interaction between pravastatin and fluindione (an|
00419|040|D|orally administered indanedione anticoagulant), suggesting that pravastatin|
00419|041|D|could also interact similarly with warfarin. Information concerning a|
00419|042|D|potential interaction with simvastatin is conflicting. A case report has|
00419|043|D|documented an interaction between simvastatin and acenocoumarol while|
00419|044|D|another case report showed no interaction with warfarin. One group of|
00419|045|D|authors reported three case reports of increased international normalized|
00419|046|D|ratios (INRs) following the addition of fluvastatin to warfarin therapy. The|
00419|047|D|addition of rosuvastatin to patients stabilized on warfarin resulted in|
00419|048|D|clinically significant changes in INR.|
00419|049|D|   A cohort study identified concurrent use of warfarin with atorvastatin,|
00419|050|D|rosuvastatin, and simvastatin.  Concurrent use of warfarin and simvastatin|
00419|051|D|increased INR from 2.4 to 2.71, with INRs peaking at 4 weeks after statin|
00419|052|D|initiation (mean change 0.32 (95% CI 0.25-0.38) and median change 0.2 (IQR|
00419|053|D|-0.3-0.8)).  Concurrent use of warfarin with atorvastatin and rosuvastatin|
00419|054|D|increased INR from 2.42 to 2.69 with a mean change of 0.27 (95% CI|
00419|055|D|0.12-0.42) and from 2.31 to 2.61 with a mean change of 0.3 (95% CI|
00419|056|D|-0.09-0.69), respectively.|
00419|057|D|   One or more of the drug pairs linked to this monograph have been included|
00419|058|D|in a list of interactions that could be considered for classification as|
00419|059|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
00419|060|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
00419|061|D|Health Information Technology.|
00419|062|B||
00419|063|R|REFERENCES:|
00419|064|B||
00419|065|R|1.Ahmad S. Lovastatin. Warfarin interaction. Arch Intern Med 1990 Nov;|3
00419|066|R|  150(11):2407.|3
00419|067|R|2.Hoffman HS. The interaction of lovastatin and warfarin. Conn Med 1992 Feb;|3
00419|068|R|  56(2):107.|3
00419|069|R|3.Iliadis EA, Konwinski MF. Lovastatin during warfarin therapy resulting in|3
00419|070|R|  bleeding. Pa Med 1995 Dec;98(12):31.|3
00419|071|R|4.Personal communication. Merck & Co., Inc. 1991.|1
00419|072|R|5.Trenque T, Choisy H, Germain ML. Pravastatin: interaction with oral|3
00419|073|R|  anticoagulant?. BMJ 1996 Apr 6;312(7035):886.|3
00419|074|R|6.Grau E, Perella M, Pastor E. Simvastatin-oral anticoagulant interaction.|3
00419|075|R|  Lancet 1996 Feb 10;347(8998):405-6.|3
00419|076|R|7.Gaw A, Wosornu D. Simvastatin during warfarin therapy in|3
00419|077|R|  hyperlipoproteinaemia. Lancet 1992 Oct 17;340(8825):979-80.|3
00419|078|R|8.Trilli LE, Kelley CL, Aspinall SL, Kroner BA. Potential interaction|3
00419|079|R|  between warfarin and fluvastatin. Ann Pharmacother 1996 Dec;|3
00419|080|R|  30(12):1399-402.|3
00419|081|R|9.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
00419|082|R|  Pharmaceuticals LP July, 2024.|1
00419|083|R|10.Engell AE, Svendsen ALO, Lind BS, Andersen CL, Andersen JS, Willadsen TG,|2
00419|084|R|   Persson F, PottegNrd A. Drug-drug interaction between warfarin and|2
00419|085|R|   statins: A Danish cohort study..|2
00419|086|R|11.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
00419|087|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
00419|088|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
00419|089|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
00420|001|T|MONOGRAPH TITLE:  Theophyllines/Allopurinol|
00420|002|B||
00420|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00420|004|L|of severe adverse interaction.|
00420|005|B||
00420|006|A|MECHANISM OF ACTION:  Allopurinol may inhibit the metabolism of|
00420|007|A|theophylline.|
00420|008|B||
00420|009|E|CLINICAL EFFECTS:  Increased levels of theophylline may result in|
00420|010|E|theophylline toxicity.|
00420|011|B||
00420|012|P|PREDISPOSING FACTORS:  Larger doses of allopurinol given for greater than|
00420|013|P|two weeks.|
00420|014|B||
00420|015|M|PATIENT MANAGEMENT:  Monitor theophylline levels in patients receiving|
00420|016|M|concurrent therapy with theophylline and allopurinol. The dosage of|
00420|017|M|theophylline may need to be decreased during concurrent therapy.|
00420|018|B||
00420|019|D|DISCUSSION:  Decreased metabolism of theophylline has been reported during|
00420|020|D|concurrent administration with large doses of allopurinol (600 mg daily)|
00420|021|D|given over two weeks. There is one case report of a 38% increase in|
00420|022|D|theophylline levels following the addition of allopurinol (100 mg daily) to|
00420|023|D|therapy. Other authors have reported  no effect on theophylline clearance by|
00420|024|D|allopurinol when allopurinol was administered in smaller doses for shorter|
00420|025|D|courses of therapy.|
00420|026|B||
00420|027|R|REFERENCES:|
00420|028|B||
00420|029|R|1.Manfredi RL, Vesell ES. Inhibition of theophylline metabolism by long-term|2
00420|030|R|  allopurinol administration. Clin Pharmacol Ther 1981 Feb;29(2):224-9.|2
00420|031|R|2.Barry M, Feely J. Allopurinol influences aminophenazone elimination. Clin|3
00420|032|R|  Pharmacokinet 1990 Aug;19(2):167-9.|3
00420|033|R|3.Grygiel JJ, Wing LM, Farkas J, Birkett DJ. Effects of allopurinol on|2
00420|034|R|  theophylline metabolism and clearance. Clin Pharmacol Ther 1979 Nov;|2
00420|035|R|  26(5):660-7.|2
00420|036|R|4.Vozeh S, Powell JR, Cupit GC, Riegelman S, Sheiner LB. Influence of|2
00420|037|R|  allopurinol on theophylline disposition in adults. Clin Pharmacol Ther|2
00420|038|R|  1980 Feb;27(2):194-7.|2
00421|001|T|MONOGRAPH TITLE:  Theophylline Derivatives/Lithium|
00421|002|B||
00421|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00421|004|L|take action as needed.|
00421|005|B||
00421|006|A|MECHANISM OF ACTION:  Theophylline derivatives increase the renal excretion|
00421|007|A|of lithium.|
00421|008|B||
00421|009|E|CLINICAL EFFECTS:  Decreased levels of lithium which may result in decreased|
00421|010|E|clinical effectiveness.|
00421|011|B||
00421|012|P|PREDISPOSING FACTORS:  None determined.|
00421|013|B||
00421|014|M|PATIENT MANAGEMENT:  Lithium levels and response should be monitored in|
00421|015|M|patients in whom theophylline therapy is initiated or withdrawn. Patients|
00421|016|M|receiving concurrent therapy should be monitored for increased adverse|
00421|017|M|effects.|
00421|018|B||
00421|019|D|DISCUSSION:  In a study involving ten volunteers, the concurrent|
00421|020|D|administration of lithium and theophylline resulted in a significant|
00421|021|D|decrease in lithium serum levels. Upon discontinuation of theophylline,|
00421|022|D|lithium levels and half-life increased, and the clearance of lithium|
00421|023|D|decreased. Individual variability in these parameters was significant. The|
00421|024|D|overall incidence of adverse effects was significantly greater with|
00421|025|D|concurrent therapy including restlessness, tremor, and anorexia. In another|
00421|026|D|study in ten normal subjects, lithium (1200 mg/day for seven days) was|
00421|027|D|administered and it was reported that theophylline infusion (dosed to|
00421|028|D|achieve a plasma level of 14 mcg/ml) increased lithium clearances by 51%. In|
00421|029|D|a case report, reduced lithium levels as well as worsening of manic symptoms|
00421|030|D|occurred after increasing doses of theophylline were administered.|
00421|031|D|   It has been shown that aminophylline increases the lithium/creatinine|
00421|032|D|clearance ratio, which may result in decreased serum lithium below the|
00421|033|D|therapeutic level.|
00421|034|D|   Caffeine withdrawal has been reported to increase lithium levels in|
00421|035|D|several case reports.|
00421|036|D|   This interaction is most important to consider in patients who have been|
00421|037|D|previously sensitive to relapse with decreased lithium levels and in whom|
00421|038|D|levels are maintained at the therapeutic/prophylactic borderline.|
00421|039|B||
00421|040|R|REFERENCES:|
00421|041|B||
00421|042|R|1.Perry PJ, Calloway RA, Cook BL, Smith RE. Theophylline precipitated|2
00421|043|R|  alterations of lithium clearance. Acta Psychiatr Scand 1984 Jun;|2
00421|044|R|  69(6):528-37.|2
00421|045|R|2.Holstad SG, Perry PJ, Kathol RG, Carson RW, Krummel SJ. The effects of|2
00421|046|R|  intravenous theophylline infusion versus intravenous sodium bicarbonate|2
00421|047|R|  infusion on lithium clearance in normal subjects. Psychiatry Res 1988 Aug;|2
00421|048|R|  25(2):203-11.|2
00421|049|R|3.Sierles FS, Ossowski MG. Concurrent use of theophylline and lithium in a|3
00421|050|R|  patient with chronic obstructive lung disease and bipolar disorder. Am J|3
00421|051|R|  Psychiatry 1982 Jan;139(1):117-8.|3
00421|052|R|4.Thomsen K, Schou M. Renal lithium excretion in man. Am J Physiol 1968 Oct;|2
00421|053|R|  215(4):823-7.|2
00421|054|R|5.Tondo L, Rudas N. The course of a seasonal bipolar disorder influenced by|3
00421|055|R|  caffeine. J Affect Disord 1991 Aug;22(4):249-51.|3
00421|056|R|6.Jefferson JW. Lithium tremor and caffeine intake: two cases of drinking|3
00421|057|R|  less and shaking more. J Clin Psychiatry 1988 Feb;49(2):72-3.|3
00421|058|R|7.Mester R, Toren P, Mizrachi I, Wolmer L, Karni N, Weizman A. Caffeine|3
00421|059|R|  withdrawal increases lithium blood levels. Biol Psychiatry 1995 Mar 1;|3
00421|060|R|  37(5):348-50.|3
00422|001|T|MONOGRAPH TITLE:  Dexfenfluramine; Fenfluramine/MAOIs|
00422|002|B||
00422|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00422|004|L|is contraindicated and generally should not be dispensed or administered to|
00422|005|L|the same patient.|
00422|006|B||
00422|007|A|MECHANISM OF ACTION:  Concurrent use of serotonergic drugs with MAOIs may|
00422|008|A|result in serotonin syndrome.|
00422|009|B||
00422|010|E|CLINICAL EFFECTS:  Concurrent therapy may result in serotonin syndrome,|
00422|011|E|which may result in death. Symptoms of serotonin syndrome may include|
00422|012|E|tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
00422|013|E|hyperthermia, and muscle rigidity.(5)|
00422|014|B||
00422|015|P|PREDISPOSING FACTORS:  None determined.|
00422|016|B||
00422|017|M|PATIENT MANAGEMENT:  Concurrent administration of these agents should be|
00422|018|M|avoided. The manufacturer of dexfenfluramine recommends a two week wash-out|
00422|019|M|period discontinuing a MAOI and initiating therapy with dexfenfluramine and|
00422|020|M|a three week wash-out between discontinuing dexfenfluramine and initiating a|
00422|021|M|MAOI.|
00422|022|M|   If concurrent therapy is warranted, patients should be monitored for|
00422|023|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
00422|024|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
00422|025|M|heart palpitations, restlessness, confusion, agitation, trouble with|
00422|026|M|coordination, or severe diarrhea.|
00422|027|B||
00422|028|D|DISCUSSION:  Although this interaction has not been reported with|
00422|029|D|dexfenfluramine or fenfluramine, the manufacturer 's product information for|
00422|030|D|dexfenfluramine states that concurrent therapy with MAOI's is|
00422|031|D|contraindicated.|
00422|032|D|   Methylene blue, when administered intravenously, has been shown to reach|
00422|033|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
00422|034|D|   Metaxalone is a weak inhibitor of MAO.|
00422|035|B||
00422|036|R|REFERENCES:|
00422|037|B||
00422|038|R|1.Redux (dexfenfluramine) US prescribing information. Wyeth-Ayerst|1
00422|039|R|  Laboratories April 29, 1996.|1
00422|040|R|2.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
00422|041|R|  2007.|1
00422|042|R|3.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00422|043|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00422|044|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00422|045|R|4.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00422|046|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00422|047|R|  2000 Jun;56(3):247-50.|2
00422|048|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
00422|049|R|  352(11):1112-20.|6
00422|050|R|6.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00422|051|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00422|052|R|  Feb;34(2):346.e5-6.|3
00422|053|R|7.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00422|054|R|  Pfizer Inc. January, 2024.|1
00423|001|T|MONOGRAPH TITLE:  Theophyllines/Carbamazepine|
00423|002|B||
00423|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00423|004|L|of severe adverse interaction.|
00423|005|B||
00423|006|A|MECHANISM OF ACTION:  Theophylline may induce the metabolism of|
00423|007|A|carbamazepine. Carbamazepine may induce the metabolism of theophylline.|
00423|008|B||
00423|009|E|CLINICAL EFFECTS:  Decreased levels of carbamazepine and theophylline may|
00423|010|E|result in decreased clinical effectiveness of these agents.|
00423|011|B||
00423|012|P|PREDISPOSING FACTORS:  None determined.|
00423|013|B||
00423|014|M|PATIENT MANAGEMENT:  During concurrent therapy, theophylline and|
00423|015|M|carbamazepine serum concentrations should be monitored. The dosage of one or|
00423|016|M|both agents may need to be adjusted.|
00423|017|B||
00423|018|D|DISCUSSION:  In one case report, concurrent administration of carbamazepine|
00423|019|D|and theophylline resulted in sub-therapeutic levels of theophylline, a|
00423|020|D|decrease in theophylline half-life, and a worsening of the patient's|
00423|021|D|clinical condition. In another report, a patient maintained on carbamazepine|
00423|022|D|for eight months experienced a convulsion eight days after beginning|
00423|023|D|theophylline therapy. The patient had previously received theophylline three|
00423|024|D|times without adverse effect. In a follow-up study in this patient,|
00423|025|D|concurrent administration of theophylline and carbamazepine resulted in|
00423|026|D|decreases in carbamazepine levels by 29.6-36.7%, a decrease in carbamazepine|
00423|027|D|half-life by 11.8%, and another grand mal seizure. Theophylline levels in|
00423|028|D|this patient were high; however, not enough information is given in the|
00423|029|D|report to determine if carbamazepine inhibited the metabolism of|
00423|030|D|theophylline.|
00423|031|B||
00423|032|R|REFERENCES:|
00423|033|B||
00423|034|R|1.Rosenberry KR, Defusco CJ, Mansmann HC Jr, McGeady SJ. Reduced|3
00423|035|R|  theophylline half-life induced by carbamazepine therapy. J Pediatr 1983|3
00423|036|R|  Mar;102(3):472-4.|3
00423|037|R|2.Mitchell EA, Dower JC, Green RJ. Interaction between carbamazepine and|3
00423|038|R|  theophylline. N Z Med J 1986 Feb 12;99(795):69-70.|3
00424|001|T|MONOGRAPH TITLE:  Digoxin/Selected Antacids; Kaolin; Sucralfate|
00424|002|B||
00424|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00424|004|L|take action as needed.|
00424|005|B||
00424|006|A|MECHANISM OF ACTION:  The aluminum or magnesium salts may bind digoxin in|
00424|007|A|the gastrointestinal tract, preventing the absorption of digoxin.|
00424|008|B||
00424|009|E|CLINICAL EFFECTS:  Concurrent administration may result in decreased digoxin|
00424|010|E|concentrations and possible decreased clinical effectiveness of digoxin.|
00424|011|B||
00424|012|P|PREDISPOSING FACTORS:  None determined.|
00424|013|B||
00424|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with digoxin and|
00424|015|M|aluminum and/or magnesium hydroxide, magnesium trisilicate, or sucralfate|
00424|016|M|should be monitored for signs of decreased effects of digoxin. Digoxin|
00424|017|M|concentrations should be monitored. The administration of digoxin and|
00424|018|M|aluminum and/or magnesium hydroxide or magnesium trisilicate should be|
00424|019|M|separated by at least one to two hours. The administration of digoxin and|
00424|020|M|sucralfate should be separated by at least two hours. The separation of|
00424|021|M|administration times may not be effective in all patients.  The dosage of|
00424|022|M|digoxin may need to be increased by 20% to 40% or the antacid or sucralfate|
00424|023|M|may need to be discontinued.|
00424|024|M|   Some vitamin preparations may contain sufficient quantities of magnesium|
00424|025|M|salts with antacid properties to interact as well.|
00424|026|B||
00424|027|D|DISCUSSION:  Sucralfate was shown to decrease the mean digoxin|
00424|028|D|area-under-curve (AUC) by 19% in a study in 12 healthy males. This|
00424|029|D|difference was not seen when digoxin and sucralfate administration was|
00424|030|D|separated by two hours.(1) In a case report, a patient developed|
00424|031|D|intermittent pressure-like chest pain, shortness of breath, and a|
00424|032|D|generalized feeling of fatigue during concurrent administration of digoxin|
00424|033|D|and sucralfate, despite sucralfate administration being separated from|
00424|034|D|digoxin administration by two hours.(2)|
00424|035|D|   The simultaneous administration of oral antacids containing magnesium|
00424|036|D|trisilicate, magnesium hydroxide, and aluminum hydroxide or kaolin with|
00424|037|D|digoxin tablets has been shown to decrease the gastrointestinal absorption|
00424|038|D|of digoxin.(3-7)  There is some evidence that digoxin capsules may not be|
00424|039|D|affected;(5) however, additional information is needed.|
00424|040|B||
00424|041|R|REFERENCES:|
00424|042|B||
00424|043|R|1.Giesing DH, Lanman RC, Dimmitt DC, Runser DJ. Lack of effect of sucralfate|4
00424|044|R|  on digoxin pharmacokinetics. Gastroenterology 1983 May;84(5 Part 2):1165.|4
00424|045|R|2.Rey AM, Gums JG. Altered absorption of digoxin, sustained-release|3
00424|046|R|  quinidine, and warfarin with sucralfate administration. DICP 1991 Jul-Aug;|3
00424|047|R|  25(7-8):745-6.|3
00424|048|R|3.Brown DD, Juhl RP. Decreased bioavailability of digoxin due to antacids|2
00424|049|R|  and kaolin-pectin. N Engl J Med 1976 Nov 4;295(19):1034-7.|2
00424|050|R|4.McElnay JC, Harron DW, D'Arcy PF, Eagle MR. Interaction of digoxin with|2
00424|051|R|  antacid constituents. Br Med J 1978 Jun 10;1(6126):1554.|2
00424|052|R|5.Allen MD, Greenblatt DJ, Harmatz JS, Smith TW. Effect of|2
00424|053|R|  magnesium--aluminum hydroxide and kaolin--pectin on absorption of digoxin|2
00424|054|R|  from tablets and capsules. J Clin Pharmacol 1981 Jan;21(1):26-30.|2
00424|055|R|6.Albert KS, Ayres JW, DiSanto AR, Weidler DJ, Sakmar E, Hallmark MR, Stoll|2
00424|056|R|  RG, DeSante KA, Wagner JG. Influence of kaolin--pectin suspension on|2
00424|057|R|  digoxin bioavailability. J Pharm Sci 1978 Nov;67(11):1582-6.|2
00424|058|R|7.Albert KS, Elliot WJ, Abbott RD, Gilbertson TJ, Data JL. Influence of|2
00424|059|R|  kaolin-pectin suspension on steady-state plasma digoxin levels. J Clin|2
00424|060|R|  Pharmacol 1981 Oct;21(10):449-55.|2
00424|061|R|8.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00424|062|R|  Pharmaceuticals, Inc. August, 2018.|1
00425|001|T|MONOGRAPH TITLE:  Digoxin/Ibuprofen; Indomethacin|
00425|002|B||
00425|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00425|004|L|take action as needed.|
00425|005|B||
00425|006|A|MECHANISM OF ACTION:  The exact mechanism of this interaction is unknown,|
00425|007|A|but it may involve decreased digoxin renal excretion.|
00425|008|B||
00425|009|E|CLINICAL EFFECTS:  Increased levels of digoxin which may result in digoxin|
00425|010|E|toxicity. Symptoms of digoxin toxicity can include anorexia, nausea,|
00425|011|E|vomiting, headache, fatigue, malaise, drowsiness, generalized muscle|
00425|012|E|weakness, hallucinations, visual disturbances, and arrhythmias.|
00425|013|B||
00425|014|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
00425|015|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00425|016|P|risk of digoxin toxicity.|
00425|017|B||
00425|018|M|PATIENT MANAGEMENT:  Digoxin levels should be monitored and patients should|
00425|019|M|be monitored for signs of digoxin toxicity during concurrent therapy. The|
00425|020|M|dosage of digoxin may need to be decreased by 15-30% or the frequency of|
00425|021|M|administration may be reduced.|
00425|022|B||
00425|023|D|DISCUSSION:  Although the documentation for this interaction is conflicting,|
00425|024|D|caution is warranted.|
00425|025|D|   One study in 12 patients reported that serum digoxin levels were|
00425|026|D|significantly increased (mean 59%) after concurrent administration of|
00425|027|D|ibuprofen (1600 to 1800 mg/day) for seven days. However, there was no|
00425|028|D|significant difference in digoxin levels after 28 days of concomitant|
00425|029|D|therapy. In another study in eight patients, there was no significant change|
00425|030|D|in digoxin serum concentration during concurrent administration of|
00425|031|D|ibuprofen.|
00425|032|D|   Indomethacin-induced digoxin toxicity in three premature infants has been|
00425|033|D|reported in one study. In another study, administration of indomethacin to|
00425|034|D|11 preterm infants who received intravenous digoxin followed by oral|
00425|035|D|maintenance doses of digoxin resulted in a significant increase of digoxin|
00425|036|D|serum concentration by 40.6% with a significant decrease in urine output by|
00425|037|D|47.7%. The digoxin half-life increased 125.5%. This study recommended|
00425|038|D|decreasing the digoxin dosage by 50% when indomethacin is added to digoxin|
00425|039|D|therapy in preterm infants until further assessments of urine output and|
00425|040|D|digoxin levels are obtained. There are two case reports of digoxin toxicity|
00425|041|D|in neonates following the addition of indomethacin to therapy.|
00425|042|D|Administration of indomethacin to ten patients maintained on digoxin|
00425|043|D|resulted in a 39.7% increase in digoxin concentrations. In contrast, the|
00425|044|D|concurrent administration of indomethacin and digoxin in six healthy adults|
00425|045|D|did not result in a significant pharmacokinetic or pharmacodynamic|
00425|046|D|interaction. However, indomethacin did tend to elevate serum digoxin levels,|
00425|047|D|strengthen the digoxin-induced decrease in ECG parameters and heart rate,|
00425|048|D|and reduce the positive inotropic action of digoxin. In another study|
00425|049|D|involving six healthy adults, the administration of indomethacin for three|
00425|050|D|days followed by a single infusion of digoxin (750 mcg) did not affect any|
00425|051|D|pharmacokinetic or pharmacodynamic parameters of digoxin.|
00425|052|B||
00425|053|R|REFERENCES:|
00425|054|B||
00425|055|R|1.Quattrocchi FP, Robinson JD, Curry RW Jr, Grieco ML, Schulman SG. The|2
00425|056|R|  effect of ibuprofen on serum digoxin concentrations. Drug Intell Clin|2
00425|057|R|  Pharm 1983 Apr;17(4):286-8.|2
00425|058|R|2.Jorgensen HS, Christensen HR, Kampmann JP. Interaction between digoxin and|2
00425|059|R|  indomethacin or ibuprofen. Br J Clin Pharmacol 1991 Jan;31(1):108-10.|2
00425|060|R|3.Mayes LC, Boerth RC. Digoxin-indomethacin interaction. Pediatr Res 1980;|4
00425|061|R|  14(4 Part 2):469.|4
00425|062|R|4.Koren G, Zarfin Y, Perlman M, MacLeod SM. Effects of indomethacin on|2
00425|063|R|  digoxin pharmacokinetics in preterm infants. Pediatr Pharmacol (New York)|2
00425|064|R|  1984;4(1):25-30.|2
00425|065|R|5.Haig GM, Brookfield EG. Increase in serum digoxin concentrations after|3
00425|066|R|  indomethacin therapy in a full-term neonate. Pharmacotherapy 1992;|3
00425|067|R|  12(4):334-6.|3
00425|068|R|6.Schimmel MS, Inwood RJ, Eidelman AI, Eylath U. Toxic digitalis levels|3
00425|069|R|  associated with indomethacin therapy in a neonate. Clin Pediatr (Phila)|3
00425|070|R|  1980 Nov;19(11):768-9.|3
00425|071|R|7.Sziegoleit W, Weiss M, Fahr A, Forster W. Are serum levels and cardiac|2
00425|072|R|  effects of digoxin influenced by indometacin?. Pharmazie 1986 May;|2
00425|073|R|  41(5):340-2.|2
00425|074|R|8.Finch MB, Johnston GD, Kelly JG, McDevitt DG. Pharmacokinetics of digoxin|2
00425|075|R|  alone and in the presence of indomethacin therapy. Br J Clin Pharmacol|2
00425|076|R|  1984 Mar;17(3):353-5.|2
00425|077|R|9.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00425|078|R|  Pharmaceuticals, Inc. August, 2018.|1
00427|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Hydantoins|
00427|002|B||
00427|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00427|004|L|take action as needed.|
00427|005|B||
00427|006|A|MECHANISM OF ACTION:  Phenytoin may inhibit the absorption of the digitalis|
00427|007|A|glycosides by inducing P-glycoprotein.|
00427|008|B||
00427|009|E|CLINICAL EFFECTS:  Concurrent or recent use of hydantoins may result in|
00427|010|E|decreased levels of digitalis glycosides and possible decreased clinical|
00427|011|E|effectiveness.|
00427|012|B||
00427|013|P|PREDISPOSING FACTORS:  None determined.|
00427|014|B||
00427|015|M|PATIENT MANAGEMENT:  Digitalis glycoside levels should be monitored in|
00427|016|M|patients receiving concurrent therapy or when concurrent therapy is|
00427|017|M|discontinued.  The dosage of digoxin may need to be increased by 20% to 40%|
00427|018|M|when therapy is initiated.|
00427|019|M|   Hydantoins have been used to treat digitalis-induced arrhythmias.|
00427|020|B||
00427|021|D|DISCUSSION:  Two studies have documented that concurrent administration of|
00427|022|D|phenytoin and digoxin result in decreased digoxin levels and half-life. With|
00427|023|D|appropriate safeguards, phenytoin does appear to be a useful adjunct in the|
00427|024|D|management of digitalis-induced supraventricular arrhythmias.|
00427|025|B||
00427|026|R|REFERENCES:|
00427|027|B||
00427|028|R|1.Rameis H. On the interaction between phenytoin and digoxin. Eur J Clin|6
00427|029|R|  Pharmacol 1985;29(1):49-53.|6
00427|030|R|2.Perrier D, Mayersohn M, Marcus FI. Clinical pharmacokinetics of digitoxin.|2
00427|031|R|  Clin Pharmacokinet 1977 Jul-Aug;2(4):292-311.|2
00427|032|R|3.Helfant RH, Scherlag BJ, Damato AN. The electrophysiological properties of|5
00427|033|R|  diphenylhydantoin sodium as compared to procaine amide in the normal and|5
00427|034|R|  digitalis-intoxicated heart. Circulation 1967 Jul;36(1):108-18.|5
00427|035|R|4.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00427|036|R|  Pharmaceuticals, Inc. August, 2018.|1
00428|001|T|MONOGRAPH TITLE:  Selected Macrolide Antibiotics/Felodipine (mono deleted|
00428|002|T|02/03/2011)|
00428|003|B||
00428|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00428|005|L|take action as needed.|
00428|006|B||
00428|007|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
00428|008|A|felodipine by CYP P-450-3A4.|
00428|009|B||
00428|010|E|CLINICAL EFFECTS:  Concurrent use of macrolides may result in increased|
00428|011|E|levels of felodipine and dehydrofelodipine, which may result in an increase|
00428|012|E|in the clinical effects of felodipine, including palpitations, edema, and|
00428|013|E|hypotension.|
00428|014|B||
00428|015|P|PREDISPOSING FACTORS:  None determined.|
00428|016|B||
00428|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with macrolides|
00428|018|M|should be monitored for an increase in the clinical effects of felodipine.|
00428|019|M|The dosage of felodipine may need to be decreased, or the macrolide may need|
00428|020|M|to be discontinued.|
00428|021|B||
00428|022|D|DISCUSSION:  In a cross-over study in 12 healthy male subjects, the|
00428|023|D|administration of a single dose of felodipine (10 mg extended-release) after|
00428|024|D|four doses of erythromycin (250 mg) resulted in an increase in felodipine|
00428|025|D|area-under-curve (AUC), maximum concentration (Cmax), and half-life by 149%,|
00428|026|D|127%, and 61%, respectively. Concurrent administration increased|
00428|027|D|dehydrofelodipine AUC, Cmax, and half-life by 92%, 56%, and 93%,|
00428|028|D|respectively, when compared to felodipine administration alone. Concurrent|
00428|029|D|administration of felodipine and erythromycin decreased felodipine M3|
00428|030|D|metabolite AUC and Cmax concentrations by 41% and 36%, respectively. The|
00428|031|D|extent of the interaction was extremely variable between subjects. In a case|
00428|032|D|report, a 43 year-old female developed palpitations, flushing, ankle edema,|
00428|033|D|and hypotension 2-4 days after the addition of erythromycin to felodipine|
00428|034|D|therapy. Felodipine levels were found to be elevated.|
00428|035|B||
00428|036|R|REFERENCES:|
00428|037|B||
00428|038|R|1.Bailey DG, Bend JR, Arnold JM, Tran LT, Spence JD. Erythromycin-felodipine|2
00428|039|R|  interaction: magnitude, mechanism, and comparison with grapefruit juice.|2
00428|040|R|  Clin Pharmacol Ther 1996 Jul;60(1):25-33.|2
00428|041|R|2.Plendil (felodipine) US prescribing information. AstraZeneca|1
00428|042|R|  Pharmaceuticals LP November, 2003.|1
00428|043|R|3.Liedholm H, Nordin G. Erythromycin-felodipine interaction. DICP 1991 Sep;|3
00428|044|R|  25(9):1007-8.|3
00429|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Tamoxifen; Toremifene|
00429|002|B||
00429|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00429|004|L|of severe adverse interaction.|
00429|005|B||
00429|006|A|MECHANISM OF ACTION:  Tamoxifen and toremifene may inhibit the CYP2C9|
00429|007|A|mediated metabolism of warfarin.|
00429|008|B||
00429|009|E|CLINICAL EFFECTS:  The concurrent use of tamoxifen or toremifene and|
00429|010|E|warfarin may result in an increased risk for bleeding.|
00429|011|B||
00429|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00429|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00429|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
00429|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00429|016|P|risk for bleeding (e.g. NSAIDs).|
00429|017|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
00429|018|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
00429|019|P|are expected to be more susceptible to this interaction.|
00429|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00429|021|P|are expected to be less susceptible to effects from this drug combination,|
00429|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00429|023|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
00429|024|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
00429|025|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to|
00429|026|P|achieve effective and safe anticoagulation than patients without these|
00429|027|P|CYP2C9 variants.|
00429|028|B||
00429|029|M|PATIENT MANAGEMENT:  Closely monitor INR when tamoxifen or toremifene are|
00429|030|M|added to or discontinued from concurrent anticoagulant therapy.(1,2)|
00429|031|M|   In high risk women taking tamoxifen for a reduction in breast cancer risk|
00429|032|M|and in women with ductal carcinoma in situ (DCIS), concurrent therapy with|
00429|033|M|coumarin anticoagulants is contraindicated.(1)|
00429|034|B||
00429|035|D|DISCUSSION:  There is one case report of an increase in prothrombin time|
00429|036|D|when tamoxifen was added to warfarin therapy.  This case led to a|
00429|037|D|retrospective chart review of five patients.  Two patients also had|
00429|038|D|increases in prothrombin time.  The other three patients required a smaller|
00429|039|D|than normal dose of warfarin to maintain appropriate prothrombin times.(3)|
00429|040|D|   In another case report, a patient developed hematuria and hematemesis|
00429|041|D|three weeks after the addition of tamoxifen to warfarin therapy.(4)|
00429|042|D|   In a retrospective review of 22 patients who received concurrent therapy|
00429|043|D|with warfarin and tamoxifen, no problems were noted.  Two patients had|
00429|044|D|increased prothrombin times with no signs of bleeding.  One patient|
00429|045|D|experienced a subconjunctival hemorrhage, despite no problems with control|
00429|046|D|of prothrombin times.  Another patient experienced difficulty in control of|
00429|047|D|prothrombin times and a thigh hematoma.  Another patient developed an|
00429|048|D|intraocular hemorrhage and hemorrhagic rashes after the addition of|
00429|049|D|tamoxifen to warfarin therapy.(5)|
00429|050|D|   One set of authors postulated that the antitumor activity of tamoxifen|
00429|051|D|may be reduced if warfarin competitively inhibits the formation of the|
00429|052|D|active metabolite of tamoxifen; however, this has not been demonstrated.(3)|
00429|053|D|   In a case report, a 50-year-old woman with a history of breast cancer|
00429|054|D|started warfarin after mitral valve replacement. She had been on toremifene|
00429|055|D|but it was held during hospitalization for the MVR due to unavailable|
00429|056|D|supply.  Warfarin was dosed up to 21 mg/week in the absence of toremifene.|
00429|057|D|After hospital discharge, patient resumed toremifene and warfarin dose had|
00429|058|D|to be reduced by 37.5% to avoid supratherapeutic INR.(6)|
00429|059|B||
00429|060|R|REFERENCES:|
00429|061|B||
00429|062|R|1.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
00429|063|R|  US Inc. September 25, 2018.|1
00429|064|R|2.Fareston (toremifene citrate) US prescribing information. GTx, Inc. March,|1
00429|065|R|  2011.|1
00429|066|R|3.Tenni P, Lalich DL, Byrne MJ. Life threatening interaction between|3
00429|067|R|  tamoxifen and warfarin. BMJ 1989 Jan 14;298(6666):93.|3
00429|068|R|4.Lodwick R, McConkey B, Brown AM. Life threatening interaction between|3
00429|069|R|  tamoxifen and warfarin. Br Med J (Clin Res Ed) 1987 Oct 31;295(6606):1141.|3
00429|070|R|5.Ritchie LD, Grant SM. Tamoxifen-warfarin interaction: the Aberdeen|3
00429|071|R|  hospitals drug file. BMJ 1989 May 6;298(6682):1253.|3
00429|072|R|6.Peng W, Wang Y, Zhang Y, Lin Y. Concomitant administration of warfarin and|3
00429|073|R|  toremifene: A case report. J Clin Pharm Ther 2022 Dec;47(12):2383-2386.|3
00430|001|T|MONOGRAPH TITLE:  Azole Antifungals/Sulfonylureas|
00430|002|B||
00430|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00430|004|L|take action as needed.|
00430|005|B||
00430|006|A|MECHANISM OF ACTION:  Azole antifungals inhibit the metabolism of|
00430|007|A|sulfonylureas.|
00430|008|B||
00430|009|E|CLINICAL EFFECTS:  Increased effectiveness of the sulfonylurea which may|
00430|010|E|result in clinical symptoms of hypoglycemia.|
00430|011|B||
00430|012|P|PREDISPOSING FACTORS:  None determined.|
00430|013|B||
00430|014|M|PATIENT MANAGEMENT:  Monitor blood glucose levels during concurrent therapy.|
00430|015|M|The dose of the sulfonylurea may need to be adjusted.|
00430|016|B||
00430|017|D|DISCUSSION:  Prospective and retrospective studies in healthy subjects have|
00430|018|D|documented an interaction between the sulfonylureas and fluconazole and|
00430|019|D|ketoconazole. In vitro studies have shown the metabolism of sulfonylureas to|
00430|020|D|be inhibited by ketoconazole and clotrimazole.|
00430|021|D|   In 13 healthy males, fluconazole increased the maximum concentration|
00430|022|D|(Cmax) and area-under-curve (AUC) of a single dose of glipizide (2.5 mg) by|
00430|023|D|19% and 49%, respectively.|
00430|024|D|   In 20 healthy males, fluconazole increased the Cmax and AUC of a single|
00430|025|D|dose of glyburide (5 mg) by 19% and 44%, respectively.|
00430|026|D|   In 13 healthy males, fluconazole increased the Cmax and AUC of a single|
00430|027|D|dose of tolbutamide (500 mg) by 11% and 26%, respectively.|
00430|028|D|   Although itraconazole was found to have no effect on tolbutamide|
00430|029|D|clearance in a study in rats, additional information is needed to determine|
00430|030|D|if an interaction occurs.|
00430|031|D|   In healthy subjects, glucose concentrations decreased during concurrent|
00430|032|D|therapy with glipizide and posaconazole.|
00430|033|D|   Voriconazole has been shown to inhibit CYP2C9.|
00430|034|B||
00430|035|R|REFERENCES:|
00430|036|B||
00430|037|R|1.Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis|6
00430|038|R|  1990 Mar-Apr;12 Suppl 3:S327-33.|6
00430|039|R|2.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
00430|040|R|  2024.|1
00430|041|R|3.Krishnaiah YS, Satyanarayana S, Visweswaram D. Interaction between|2
00430|042|R|  tolbutamide and ketoconazole in healthy subjects. Br J Clin Pharmacol 1994|2
00430|043|R|  Feb;37(2):205-7.|2
00430|044|R|4.Back DJ, Stevenson P, Tjia JF. Comparative effects of two antimycotic|5
00430|045|R|  agents, ketoconazole and terbinafine on the metabolism of tolbutamide,|5
00430|046|R|  ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver|5
00430|047|R|  microsomes in vitro. Br J Clin Pharmacol 1989 Aug;28(2):166-70.|5
00430|048|R|5.Back DJ, Tjia JF, Karbwang J, Colbert J. In vitro inhibition studies of|5
00430|049|R|  tolbutamide hydroxylase activity of human liver microsomes by azoles,|5
00430|050|R|  sulphonamides and quinolines. Br J Clin Pharmacol 1988 Jul;26(1):23-9.|5
00430|051|R|6.Damanhouri Z, Gumbleton M, Nicholls PJ, Shaw MA. In-vivo effects of|5
00430|052|R|  itraconazole on hepatic mixed-function oxidase. J Antimicrob Chemother|5
00430|053|R|  1988 Feb;21(2):187-94.|5
00430|054|R|7.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
00430|055|R|8.Noxafil (posaconazole) UK summary of product characteristics.|1
00430|056|R|  Schering-Plough Ltd. January, 2022.|1
00431|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/NSAIDs; Salicylates|
00431|002|B||
00431|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00431|004|L|of severe adverse interaction.|
00431|005|B||
00431|006|A|MECHANISM OF ACTION:  Cyclosporine increases the production of prostaglandin|
00431|007|A|E2 and I2. Prostaglandin E2 has been shown to prevent cyclosporine -induced|
00431|008|A|renal toxicity in animals. NSAIDS and salicylates may increase|
00431|009|A|cyclosporine-induced renal toxicity by blocking the formation of|
00431|010|A|prostaglandins.|
00431|011|A|   Concurrent use of everolimus, sirolimus or tacrolimus with NSAIDs or|
00431|012|A|salicylates may result in additive nephrotoxicity.|
00431|013|B||
00431|014|E|CLINICAL EFFECTS:  Concurrent administration of cyclosporine, everolimus,|
00431|015|E|sirolimus, or tacrolimus and a NSAID or salicylate may result in a decrease|
00431|016|E|in renal function, with or without an alteration in immunosuppressant|
00431|017|E|levels.|
00431|018|B||
00431|019|P|PREDISPOSING FACTORS:  None determined.|
00431|020|B||
00431|021|M|PATIENT MANAGEMENT:  If possible, avoid the concurrent use of NSAIDs or|
00431|022|M|salicylates in patients maintained on cyclosporine, everolimus, sirolimus,|
00431|023|M|or tacrolimus.  If concurrent therapy is warranted, patients should be|
00431|024|M|monitored for a decrease in renal function.  The NSAID or salicylate may|
00431|025|M|need to be discontinued.|
00431|026|B||
00431|027|D|DISCUSSION:  A decrease in renal function has been reported with concurrent|
00431|028|D|cyclosporine and diclofenac, sulindac, mefenamic acid, ketoprofen,|
00431|029|D|piroxicam, and naproxen. Decreasing the cyclosporine dose without|
00431|030|D|discontinuing the NSAID does not appear to improve renal function.|
00431|031|D|   The use of agents which decrease renal function concurrently with|
00431|032|D|everolimus, sirolimus or tacrolimus should be approached with caution.|
00431|033|D|   An observational study of 63 inpatient encounters for 57 transplant|
00431|034|D|patients evaluated concurrent use between calcineurin inhibitor (CNI)|
00431|035|D|therapy and NSAID use.  Patients were matched to 126 transplant patients on|
00431|036|D|CNI therapy without NSAID use.  Patients who received at least one dose of|
00431|037|D|NSAID had a 12.2% rate of treatment emergent acute kidney injury (AKI).  The|
00431|038|D|relative risk ratio for AKI in patient exposed to NSAID therapy was 2.20|
00431|039|D|(95% CI 0.74-6.54).  An increase in 48 hour post NSAID exposure serum|
00431|040|D|creatinine above baseline was documented in 65.9% of patients compared to|
00431|041|D|46% in the non NSAID group (p=0.016).  Multivariate analysis revealed|
00431|042|D|changes in serum creatinine at 48 hours after admission were independently|
00431|043|D|associated with age (p=0.008) and NSAID use (p=0.026).(12)|
00431|044|B||
00431|045|R|REFERENCES:|
00431|046|B||
00431|047|R|1.Deray G, Le Hoang P, Aupetit B, Achour A, Rottembourg J, Baumelou A.|3
00431|048|R|  Enhancement of cyclosporine A nephrotoxicity by diclofenac. Clin Nephrol|3
00431|049|R|  1987 Apr;27(4):213-4.|3
00431|050|R|2.Harris KP, Jenkins D, Walls J. Nonsteroidal antiinflammatory drugs and|3
00431|051|R|  cyclosporine. A potentially serious adverse interaction. Transplantation|3
00431|052|R|  1988 Oct;46(4):598-9.|3
00431|053|R|3.Mueller EA, Kovarik JM, Koelle EU, Merdjan H, Johnston A, Hitzenberger G.|2
00431|054|R|  Pharmacokinetics of cyclosporine and multiple-dose diclofenac during|2
00431|055|R|  coadministration. J Clin Pharmacol 1993 Oct;33(10):936-43.|2
00431|056|R|4.Sesin GP, O'Keefe E, Roberto P. Sulindac-induced elevation of serum|3
00431|057|R|  cyclosporine concentration. Clin Pharm 1989 Jun;8(6):445-6.|3
00431|058|R|5.Agar JW. Cyclosporin A and mefenamic acid in a renal transplant patient.|3
00431|059|R|  Aust N Z J Med 1991 Oct;21(5):784-5.|3
00431|060|R|6.Ludwin D, Bennett KJ, Grace EM, Buchanan WW, Bensen W, Bombardier C,|3
00431|061|R|  Tugwell PX. Nephrotoxicity in patients with rheumatoid arthritis treated|3
00431|062|R|  with cyclosporine. Transplant Proc 1988 Jun;20(3 Suppl 4):367-70.|3
00431|063|R|7.Altman RD, Perez GO, Sfakianakis GN. Interaction of cyclosporine A and|2
00431|064|R|  nonsteroidal anti-inflammatory drugs on renal function in patients with|2
00431|065|R|  rheumatoid arthritis. Am J Med 1992 Oct;93(4):396-402.|2
00431|066|R|8.Prograf (tacrolimus) UK summary of product characteristics. Fujisawa|1
00431|067|R|  Limited November 14, 2002.|1
00431|068|R|9.Prograf (tacrolimus) Canadian prescribing information. Astellas April 27,|1
00431|069|R|  2011.|1
00431|070|R|10.Prograf (tacrolimus) US prescribing information. Fujisawa Healthcare,|1
00431|071|R|   Inc. September, 2004.|1
00431|072|R|11.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
00431|073|R|   Aug, 2022.|1
00431|074|R|12.Delzer LM, Golightly LK, Kiser TH, Biggins SW, Lewis VJ, Kim II.|2
00431|075|R|   Calcineurin Inhibitor and Nonsteroidal Anti-inflammatory Drug|2
00431|076|R|   Interaction: Implications of Changes in Renal Function Associated With|2
00431|077|R|   Concurrent Use. J Clin Pharmacol 2018 Nov;58(11):1443-1451.|2
00431|078|R|13.Afinitor (everolimus) US prescribing information. Novartaris|1
00431|079|R|   Pharmaceuticals Corporation February, 2020.|1
00431|080|R|14.Zortress (everolimus) US prescribing information. Novartis|1
00431|081|R|   Pharmaceuticals Corporation Sept, 2023.|1
00432|001|T|MONOGRAPH TITLE:  Cyclosporine/Carbamazepine (mono deleted 11/01/2012)|
00432|002|B||
00432|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00432|004|L|take action as needed.|
00432|005|B||
00432|006|A|MECHANISM OF ACTION:  Carbamazepine may induce the metabolism of|
00432|007|A|cyclosporine.|
00432|008|B||
00432|009|E|CLINICAL EFFECTS:  Decreased levels of cyclosporine, which may result in a|
00432|010|E|decrease in the immunosuppressive effects of cyclosporine.|
00432|011|B||
00432|012|P|PREDISPOSING FACTORS:  None determined.|
00432|013|B||
00432|014|M|PATIENT MANAGEMENT:  Monitor cyclosporine levels in patients receiving|
00432|015|M|carbamazepine and in patients in whom carbamazepine is discontinued. The|
00432|016|M|dosage of cyclosporine may need to be adjusted.|
00432|017|B||
00432|018|D|DISCUSSION:  Patients receiving concurrent carbamazepine and cyclosporine|
00432|019|D|therapy may need higher dosages of cyclosporine as a result of enzyme|
00432|020|D|induction by carbamazepine.|
00432|021|B||
00432|022|R|REFERENCES:|
00432|023|B||
00432|024|R|1.Schofield OM, Camp RD, Levene GM. Cyclosporin A in psoriasis: interaction|3
00432|025|R|  with carbamazepine. Br J Dermatol 1990 Mar;122(3):425-6.|3
00432|026|R|2.Lele P, Peterson P, Yang S, Jarrell B, Burke JF Jr. Cyclosporine and|4
00432|027|R|  tegretrol -- another drug interaction. Kidney Int 1985;27(1):344.|4
00432|028|R|3.Soto Alvarez J, Sacristan Del Castillo JA, Alsar Ortiz MJ. Effect of|3
00432|029|R|  carbamazepine on cyclosporin blood level. Nephron 1991;58(2):235-6.|3
00432|030|R|4.Cooney GF, Mochon M, Kaiser B, Dunn SP, Goldsmith B. Effects of|2
00432|031|R|  carbamazepine on cyclosporine metabolism in pediatric renal transplant|2
00432|032|R|  recipients. Pharmacotherapy 1995 May-Jun;15(3):353-6.|2
00433|001|T|MONOGRAPH TITLE:  Itraconazole; Ketoconazole/Digoxin|
00433|002|B||
00433|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00433|004|L|of severe adverse interaction.|
00433|005|B||
00433|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but itraconazole and|
00433|007|A|ketoconazole may inhibit the transport of digoxin by p-glycoprotein.|
00433|008|B||
00433|009|E|CLINICAL EFFECTS:  Concurrent use of itraconazole or ketoconazole may result|
00433|010|E|in increased digoxin levels and signs of digoxin toxicity. Symptoms of|
00433|011|E|digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue,|
00433|012|E|malaise, drowsiness, generalized muscle weakness, disorientation,|
00433|013|E|hallucinations, visual disturbances, and arrhythmias.|
00433|014|B||
00433|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
00433|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
00433|017|P|risk of digoxin toxicity.|
00433|018|B||
00433|019|M|PATIENT MANAGEMENT:  Monitor digoxin levels in patients receiving concurrent|
00433|020|M|therapy with itraconazole or ketoconazole.  The dosage of digoxin may need|
00433|021|M|to be adjusted, possibly by as much as a 30% to 75% decrease during|
00433|022|M|concurrent therapy.  Alternatively, the frequency of administration may be|
00433|023|M|decreased.|
00433|024|B||
00433|025|D|DISCUSSION:  In a double-blind, randomized, cross-over study in 10 healthy|
00433|026|D|subjects, itraconazole (200 mg daily for 5 days) increased the area-under|
00433|027|D|curve (AUC) of a single dose of digoxin (0.5 mg on Day 3) by 50%.  The renal|
00433|028|D|clearance of digoxin decreased by 20%.  Increases in digoxin maximum|
00433|029|D|concentration (Cmax) and half-life were not statistically significant.(2)|
00433|030|D|   In a double-blind, randomized, cross-over study in 10 healthy subjects,|
00433|031|D|itraconazole (200 mg daily for 10 days) increased the AUC of digoxin (0.25|
00433|032|D|mg daily for 20 days) by 80%.(3)|
00433|033|D|   There are several published case reports of increased digoxin levels and|
00433|034|D|signs of digoxin toxicity in patients receiving concurrent therapy with|
00433|035|D|itraconazole.(4-13)  In four of these reports, it was documented that there|
00433|036|D|were no changes in serum creatinine or potassium to account for the|
00433|037|D|increased digoxin levels and toxicity observed.(4-8)  In two patients, a|
00433|038|D|reduction in digoxin dosage by 75% resulted in therapeutic levels during|
00433|039|D|concurrent therapy.|
00433|040|D|   In contrast to these reports, itraconazole (200 mg daily) was|
00433|041|D|administered for 36 months with concurrent digoxin (0.125 mg daily) with no|
00433|042|D|changes in digoxin levels.(14)|
00433|043|D|   In a double-blind, randomized, cross-over study in healthy subjects,|
00433|044|D|voriconazole (200 mg twice daily Days 11-22) had no effect on digoxin levels|
00433|045|D|(0.5 mg twice daily, Day 1; 0.25 mg twice daily Day 2; 0.25 mg daily Days|
00433|046|D|3-22).(15)|
00433|047|D|   Concomitant administration of itraconazole and digoxin increased the|
00433|048|D|digoxin serum concentration by 80%.(16)|
00433|049|D|   There are case reports of elevated digoxin levels during concurrent|
00433|050|D|ketoconazole therapy.(17)|
00433|051|B||
00433|052|R|REFERENCES:|
00433|053|B||
00433|054|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
00433|055|R|  Products, L.P. February, 2024.|1
00433|056|R|2.Jalava KM, Partanen J, Neuvonen PJ. Itraconazole decreases renal clearance|2
00433|057|R|  of digoxin. Ther Drug Monit 1997 Dec;19(6):609-13.|2
00433|058|R|3.Partanen J, Jalava KM, Neuvonen PJ. Itraconazole increases serum digoxin|2
00433|059|R|  concentration. Pharmacol Toxicol 1996 Nov;79(5):274-6.|2
00433|060|R|4.Rex J. Itraconazole-digoxin interaction. Ann Intern Med 1992 Mar 15;|3
00433|061|R|  116(6):525.|3
00433|062|R|5.Kauffman CA, Bagnasco FA. Digoxin toxicity associated with itraconazole|3
00433|063|R|  therapy. Clin Infect Dis 1992 Nov;15(5):886-7.|3
00433|064|R|6.Sachs MK, Blanchard LM, Green PJ. Interaction of itraconazole and digoxin.|3
00433|065|R|  Clin Infect Dis 1993 Mar;16(3):400-3.|3
00433|066|R|7.Alderman CP, Jersmann HP. Digoxin-itraconazole interaction. Med J Aust|3
00433|067|R|  1993 Dec 6-20;159(11-12):838-9.|3
00433|068|R|8.McClean KL, Sheehan GJ. Interaction between itraconazole and digoxin. Clin|3
00433|069|R|  Infect Dis 1994 Feb;18(2):259-60.|3
00433|070|R|9.Mathis AS, Friedman GS. Coadministration of digoxin with itraconazole in|3
00433|071|R|  renal transplant recipients. Am J Kidney Dis 2001 Feb;37(2):E18.|3
00433|072|R|10.Wakasugi H, Ishizuka R, Koreeda N, Yano I, Futami T, Nohara R, Sasayama|3
00433|073|R|   S, Inui K. Effect of itraconazole on digoxin clearance in patients with|3
00433|074|R|   congestive heart failure. Yakugaku Zasshi 2000 Sep;120(9):807-11.|3
00433|075|R|11.Alderman CP, Allcroft PD. Digoxin-itraconazole interaction: possible|3
00433|076|R|   mechanisms. Ann Pharmacother 1997 Apr;31(4):438-40.|3
00433|077|R|12.Cone LA, Himelman RB, Hirschberg JN, Hutcheson JW. Itraconazole-related|3
00433|078|R|   amaurosis and vomiting due to digoxin toxicity. West J Med 1996 Nov;|3
00433|079|R|   165(5):322.|3
00433|080|R|13.Meyboom RH, de Jonge K, Veentjer H, Dekens-Konter JA, de Koning GH.|3
00433|081|R|   Potentiation of digoxin by itraconazole. Ned Tijdschr Geneeskd 1994 Nov|3
00433|082|R|   19;138(47):2353-6.|3
00433|083|R|14.Mochizuki M, Murase S, Takahashi K, Shimada S, Kume H, Iizuka T, Fukuda|3
00433|084|R|   M. Serum itraconazole and hydroxyitraconazole concentrations and|3
00433|085|R|   interaction with digoxin in a case of chronic hypertrophic pachymenigitis|3
00433|086|R|   caused by Aspergillus flavus. Nippon Ishinkin Gakkai Zasshi 2000;|3
00433|087|R|   41(1):33-9.|3
00433|088|R|15.Purkins L, Wood N, Kleinermans D, Nichols D. Voriconazole does not affect|2
00433|089|R|   the steady-state pharmacokinetics of digoxin. Br J Clin Pharmacol 2003|2
00433|090|R|   Dec;56 Suppl 1:45-50.|2
00433|091|R|16.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00433|092|R|   Pharmaceuticals, Inc. August, 2018.|1
00433|093|R|17.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
00433|094|R|   Pharmaceuticals February, 2014.|1
00434|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/Rifampin|
00434|002|B||
00434|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00434|004|L|is contraindicated and generally should not be dispensed or administered to|
00434|005|L|the same patient.|
00434|006|B||
00434|007|A|MECHANISM OF ACTION:  Rifampin may increase the metabolism of the protease|
00434|008|A|inhibitors(1-12) and cobicistat(13) by inducing CYP3A4.|
00434|009|B||
00434|010|E|CLINICAL EFFECTS:  Concurrent use of rifampin with protease inhibitors may|
00434|011|E|result in decreased levels and clinical effectiveness of the protease|
00434|012|E|inhibitors(1-12,14) and cobicistat.(13)|
00434|013|E|   Concurrent use of rifampin with the combination of saquinavir/ritonavir|
00434|014|E|may result in drug-induced hepatitis.(1,14-16)|
00434|015|B||
00434|016|P|PREDISPOSING FACTORS:  None determined.|
00434|017|B||
00434|018|M|PATIENT MANAGEMENT:  The manufacturers of atazanavir,(3,4), cobicistat,(12)|
00434|019|M|darunavir,(5) fosamprenavir,(6) the combination of lopinavir and|
00434|020|M|ritonavir,(8) nelfinavir,(9) saquinavir,(1,11) and tipranavir(12) state that|
00434|021|M|concurrent use of rifampin is contraindicated.|
00434|022|M|   The manufacturers of amprenavir,(2) indinavir,(7) and ritonavir(10) state|
00434|023|M|that these agents should not be used with rifampin.|
00434|024|M|   The manufacturer of rifampin states that concurrent use of atazanavir,|
00434|025|M|darunavir, fosamprenavir, saquinavir, and tipranavir is contraindicated.(14)|
00434|026|M|   The Department of Health and Human Services (DHHS) Guidelines for the Use|
00434|027|M|of Antiretroviral Agents states that rifampin is contraindicated for|
00434|028|M|patients on boosted or unboosted protease inhibitors.  Additional ritonavir|
00434|029|M|does not overcome the interaction and may increase hepatotoxicity, and|
00434|030|M|additional cobicistat is not recommended.  DHHS recommends use of rifabutin|
00434|031|M|as an alternative.(17)|
00434|032|M|   The CDC/NIH guidelines on treatment of opportunistic infections (OI) in|
00434|033|M|HIV(18) and the CDC's guidelines on managing drug interactions in|
00434|034|M|HIV-related tuberculosis (TB)(19) provide guidance for the use of rifampin|
00434|035|M|with the combination product of lopinavir/ritonavir when rifabutin is not|
00434|036|M|available.  The OI guidelines recommend increasing the dose of|
00434|037|M|lopinavir/ritonavir by 50%, and subsequently, increasing to a full double|
00434|038|M|dose, when used with rifampin.  Transaminases should be monitored more|
00434|039|M|frequently than usual.  The guidelines on drug interactions in HIV-related|
00434|040|M|TB state that higher doses of lopinavir/ritonavir should be used only when|
00434|041|M|close monitoring for hepatotoxicity is possible, and when there is a|
00434|042|M|pressing need to start antiretroviral therapy and other antiretrovirals are|
00434|043|M|not an option.  In adults, it is recommended to increase the dose of|
00434|044|M|lopinavir/ritonavir by 50% (to 600/150 mg) for one week, then to double the|
00434|045|M|dose (to 800/200 mg).  In children, "super-boosted" lopinavir/ritonavir is|
00434|046|M|recommended, achieved by using pediatric weight-based dosing for|
00434|047|M|lopinavir/ritonavir, plus additional ritonavir to reach milligram to|
00434|048|M|milligram parity of lopinavir and ritonavir doses.  For both double dosing|
00434|049|M|and super-boosting, the guidelines caution that unacceptable rates of|
00434|050|M|hepatotoxicity was seen in healthy volunteers, though early clinical|
00434|051|M|experience in HIV+ adults found that double dosing was reasonably well|
00434|052|M|tolerated.|
00434|053|B||
00434|054|D|DISCUSSION:  The concurrent administration of amprenavir and rifampin|
00434|055|D|decreased amprenavir maximum concentration (Cmax), area-under-curve (AUC),|
00434|056|D|and minimum concentration (Cmin) by 70%, 82%, and 92%, respectively.  There|
00434|057|D|was no change in rifampin Cmax or AUC.(2,6,20)|
00434|058|D|   In a study in 16 subjects, concurrent rifampin (600 mg daily) and|
00434|059|D|atazanavir/ritonavir (300/100 mg daily) decreased atazanavir Cmax, AUC, and|
00434|060|D|Cmin by 53%, 72%, and 98%, respectively.(3)|
00434|061|D|   In a study in 12 healthy, HIV-negative subjects, concurrent rifampin (600|
00434|062|D|mg daily) and indinavir (800 mg three times daily) decreased indinavir Cmax|
00434|063|D|and AUC by 87% and 92%, respectively.(7)  In a study in 6 HIV-positive|
00434|064|D|subjects, concurrent indinavir/ritonavir (800/100 mg twice daily) and|
00434|065|D|rifampin (300 mg daily) decreased the AUC of indinavir and ritonavir by 87%|
00434|066|D|and 94%, respectively.(21)  In a study in 11 HIV-positive subjects,|
00434|067|D|concurrent indinavir (800 mg three times daily) increased the AUC of a dose|
00434|068|D|of rifampin (600 mg) by 73%.(22)|
00434|069|D|   The concurrent administration of lopinavir/ritonavir (400/100 mg twice|
00434|070|D|daily for 20 days) and rifampin (600 mg daily for 10 days) in 22 subjects|
00434|071|D|decreased lopinavir Cmax, AUC, and Cmin by 55%, 75%, and 99%, respectively.|
00434|072|D|Concurrent administration of lopinavir/ritonavir (800/200 mg twice daily for|
00434|073|D|9 days) and rifampin (600 mg daily for 14 days) in 10 subjects did not|
00434|074|D|change lopinavir Cmax and decreased lopinavir AUC and Cmin by 16% and 57%,|
00434|075|D|respectively.  Concurrent lopinavir/ritonavir (400/400 mg twice daily for 9|
00434|076|D|days) and rifampin (600 mg daily for 14 days) in 9 subjects decreased|
00434|077|D|lopinavir Cmax and AUC by 7% and 2%, respectively, and did not change|
00434|078|D|lopinavir Cmin.  In these studies, 28% of subjects experienced a grade 2|
00434|079|D|increase in ALT/AST, of which 7 (21%) prematurely discontinued the study per|
00434|080|D|protocol.(8)  In an open-label, randomized study in 32 healthy subjects, all|
00434|081|D|subjects initially received lopinavir/ritonavir 400/100 mg twice daily.|
00434|082|D|During concurrent rifampin (600 mg daily), subjects received either 800/200|
00434|083|D|mg or 400/400 mg of lopinavir/ritonavir twice daily.  Concurrent 800/200 mg|
00434|084|D|lopinavir/ritonavir and rifampin decreased lopinavir Cmin by 57% but did not|
00434|085|D|affect lopinavir Cmax.  During concurrent 400/400 mg lopinavir/ritonavir and|
00434|086|D|rifampin, lopinavir Cmin and Cmax were similar to levels seen with 400/100|
00434|087|D|mg lopinavir/ritonavir.  Twelve subjects dropped out of the study and 9|
00434|088|D|developed elevated liver enzymes during concurrent therapy with|
00434|089|D|lopinavir/ritonavir and rifampin.(23)  Three studies examining double dosing|
00434|090|D|(800/200 mg) or super-boosting (400/400 mg) of lopinavir/ritonavir with|
00434|091|D|concurrent rifampin in HIV+ patients have been conducted.  A study of double|
00434|092|D|dosing and super-boosting in 18 HIV-TB patients(24) and a study of double|
00434|093|D|dosing in 21 HIV+ patients without TB(25) both found that adequate|
00434|094|D|lopinavir/ritonavir levels were achieved with lopinavir/ritonavir dose|
00434|095|D|adjustments.  In the study of HIV-TB patients, there were 3 isolated|
00434|096|D|subtherapeutic lopinavir levels which were attributed to poor adherence.|
00434|097|D|Ten of the 11 patients who were followed to completion of TB therapy had|
00434|098|D|undetectable viral loads.  There were no grade 3/4 adverse events, and 10|
00434|099|D|patients had mild side effects.  In the study of patients without TB, two|
00434|100|D|patients experienced grade 3/4 transaminitis, and other adverse events were|
00434|101|D|mild.  The third study of 25 HIV-TB patients confirmed the frequent but mild|
00434|102|D|GI toxicity and reported that 2 patients had grade 3 transaminitis.(26)|
00434|103|D|   Concurrent administration of nelfinavir (750 mg three times daily) and|
00434|104|D|rifampin (600 mg daily) in 12 subjects decreased nelfinavir AUC, Cmax, and|
00434|105|D|Cmin by 83%, 76%, and 92%, respectively.(9)|
00434|106|D|   The concurrent administration of ritonavir and rifampin decreased the|
00434|107|D|area-under-curve (AUC), maximum concentration (Cmax), and minimum|
00434|108|D|concentration (Cmin) of ritonavir by 35%, 25%, and 49%, respectively.(10)|
00434|109|D|   The concurrent administration of saquinavir and rifampin in 14 subjects|
00434|110|D|reduced the AUC and Cmax of saquinavir by 70% and 65%, respectively.(1,11)|
00434|111|D|In a study in 28 healthy subjects, concurrent administration of rifampin|
00434|112|D|(600 mg daily) with saquinavir (1000 mg twice daily) and ritonavir (100 mg|
00434|113|D|twice daily), 65% (11/17) of subjects developed significant hepatocellular|
00434|114|D|toxicity during the 28 day study.  Transaminase elevations of up to greater|
00434|115|D|than 20 times the upper limit of normal values were noted.  One subject was|
00434|116|D|admitted to the hospital.  All study medications were discontinued in all|
00434|117|D|subjects and all liver function tests were returning to normal.  No deaths|
00434|118|D|had been reported.(1,15,16)  In an open-label, prospective, single arm|
00434|119|D|study, 32 HIV-positive subjects received concurrent daily didanosine,|
00434|120|D|lamivudine, ritonavir (200 mg), saquinavir (1600 mg), rifampin (600 mg), and|
00434|121|D|isoniazid (300 mg).  After 48 weeks, 62.5% had an HIV RNA level less than 50|
00434|122|D|copies/ml.  Two patients had hepatic toxicity.  In 10 subjects, saquinavir|
00434|123|D|Cmin was less than 0.05 mcg/ml and 5 of these had virologic failure.|
00434|124|D|Saquinavir Cmin was 44% lower during concurrent rifampin.(27)  In an|
00434|125|D|open-label, randomized, cross-over study, rifampin decreased saquinavir AUC|
00434|126|D|by 70% in healthy subjects and by 46% in HIV-positive subjects.(28)|
00434|127|D|   One or more of the drug pairs linked to this monograph have been included|
00434|128|D|in a list of interactions that should be considered "high-priority" for|
00434|129|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00434|130|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00434|131|D|Coordinator (ONC) for Health Information Technology.|
00434|132|B||
00434|133|R|REFERENCES:|
00434|134|B||
00434|135|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00434|136|R|  Laboratories, Inc. March, 2019.|1
00434|137|R|2.Agenerase (amprenavir) Capsules US prescribing information.|1
00434|138|R|  GlaxoSmithKline May, 2005.|1
00434|139|R|3.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
00434|140|R|  Squibb Company December, 2024.|1
00434|141|R|4.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
00434|142|R|  Squibb Pharmaceuticals October 25, 2023.|1
00434|143|R|5.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
00434|144|R|  March, 2023.|1
00434|145|R|6.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
00434|146|R|  March, 2019.|1
00434|147|R|7.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00434|148|R|  September, 2016.|1
00434|149|R|8.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00434|150|R|  Laboratories December, 2019.|1
00434|151|R|9.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00434|152|R|  Pharmaceuticals, Inc. September, 2016.|1
00434|153|R|10.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
00434|154|R|   December, 2019.|1
00434|155|R|11.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
00434|156|R|   Inc. December, 2004.|1
00434|157|R|12.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00434|158|R|   Pharmaceuticals, Inc. April, 2024.|1
00434|159|R|13.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
00434|160|R|   prescribing information. Gilead Sciences, Inc. September, 2021.|1
00434|161|R|14.Rifadin (rifampin) US prescribing information. Sanofi-Aventis U.S. LLC|1
00434|162|R|   October, 2024.|1
00434|163|R|15.Dear Healthcare Provider Letter.  Subject:  Important drug interaction|1
00434|164|R|   warning for saquinavir. Roche Laboratories, Inc. February 9, 2005.|1
00434|165|R|16.Dear Canadian Healthcare Professional letter:  Subject:  Drug-induced|1
00434|166|R|   hepatitis with marked transaminase elevations in healthy volunteers|1
00434|167|R|   receiving rifampin 600 mg once daily in combination with ritonavir 100 mg|1
00434|168|R|   /  saquinavir 1000 mg twice daily. (ritonavir boosted saquinavir)|1
00434|169|R|   Hoffmann-La Roche Limited February 10, 2005.|1
00434|170|R|17.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
00434|171|R|   for the use of antiretroviral agents in adults and adolescents Living|6
00434|172|R|   with HIV. Department of Health and Human Services. Available at|6
00434|173|R|   https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats|6
00434|174|R|   -new-guidelines June 13, 2021.|6
00434|175|R|18.Panel on Opportunistic Infections in Adults and Adolescents with HIV.|6
00434|176|R|   Mycobacterium tuberculosis Infection and Disease. Guidelines for the|6
00434|177|R|   prevention and treatment of opportunistic infections in adults and|6
00434|178|R|   adolescents with HIV: recommendations from the CDC, the NIH, and the HIV|6
00434|179|R|   Medicine Association of the IDSA. Available at|6
00434|180|R|   http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. September|6
00434|181|R|   22, 2017.|6
00434|182|R|19.CDC. Managing Drug Interactions in the Treatment of HIV-Related|6
00434|183|R|   Tuberculosis online. Available at|6
00434|184|R|   https://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/introduction.|6
00434|185|R|   htm June, 2013.|6
00434|186|R|20.Polk RE, Brophy DF, Israel DS, Patron R, Sadler BM, Chittick GE, Symonds|2
00434|187|R|   WT, Lou Y, Kristoff D, Stein DS. Pharmacokinetic Interaction between|2
00434|188|R|   amprenavir and rifabutin or rifampin in healthy males. Antimicrob Agents|2
00434|189|R|   Chemother 2001 Feb;45(2):502-8.|2
00434|190|R|21.Justesen US, Andersen AB, Klitgaard NA, Brosen K, Gerstoft J, Pedersen C.|2
00434|191|R|   Pharmacokinetic interaction between rifampin and the combination of|2
00434|192|R|   indinavir and low-dose ritonavir in HIV-infected patients. Clin Infect|2
00434|193|R|   Dis 2004 Feb 1;38(3):426-9.|2
00434|194|R|22.Jaruratanasirikul S, Sriwiriyajan S. Effect of indinavir on the|2
00434|195|R|   pharmacokinetics of rifampicin in HIV-infected patients. J Pharm|2
00434|196|R|   Pharmacol 2001 Mar;53(3):409-12.|2
00434|197|R|23.la Porte CJ, Colbers EP, Bertz R, Voncken DS, Wikstrom K, Boeree MJ,|2
00434|198|R|   Koopmans PP, Hekster YA, Burger DM. Pharmacokinetics of adjusted-dose|2
00434|199|R|   lopinavir-ritonavir combined with rifampin in healthy volunteers.|2
00434|200|R|   Antimicrob Agents Chemother 2004 May;48(5):1553-60.|2
00434|201|R|24.Decloedt EH, Maartens G, Smith P, Merry C, Bango F, McIlleron H. The|2
00434|202|R|   safety, effectiveness and concentrations of adjusted lopinavir/ritonavir|2
00434|203|R|   in HIV-infected adults on rifampicin-based antitubercular therapy. PLoS|2
00434|204|R|   One 2012;7(3):e32173.|2
00434|205|R|25.Decloedt EH, McIlleron H, Smith P, Merry C, Orrell C, Maartens G.|2
00434|206|R|   Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin|2
00434|207|R|   with adjusted doses of lopinavir-ritonavir tablets. Antimicrob Agents|2
00434|208|R|   Chemother 2011 Jul;55(7):3195-200.|2
00434|209|R|26.Sunpath H, Winternheimer P, Cohen S, Tennant I, Chelin N, Gandhi RT,|2
00434|210|R|   Murphy RA. Double-dose lopinavir-ritonavir in combination with|2
00434|211|R|   rifampicin-based anti-tuberculosis treatment in South Africa. Int J|2
00434|212|R|   Tuberc Lung Dis 2014 Jun;18(6):689-93.|2
00434|213|R|27.Ribera E, Azuaje C, Lopez RM, Domingo P, Soriano A, Pou L, Sanchez P,|2
00434|214|R|   Mallolas J, Sambea MA, Falco V, Ocana I, Lopez-Colomes JL, Gatell JM,|2
00434|215|R|   Pahissa A. Once-daily regimen of saquinavir, ritonavir, didanosine, and|2
00434|216|R|   lamivudine in HIV-infected patients with standard tuberculosis therapy|2
00434|217|R|   (TBQD Study). J Acquir Immune Defic Syndr 2005 Nov 1;40(3):317-23.|2
00434|218|R|28.Grub S, Bryson H, Goggin T, Ludin E, Jorga K. The interaction of|2
00434|219|R|   saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and|2
00434|220|R|   rifampicin: comparison of the effect in healthy volunteers and in|2
00434|221|R|   HIV-infected patients. Eur J Clin Pharmacol 2001 May;57(2):115-21.|2
00434|222|R|29.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00434|223|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00434|224|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00434|225|R|   19(5):735-43.|6
00435|001|T|MONOGRAPH TITLE:  Astemizole/Quinine|
00435|002|B||
00435|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00435|004|L|is contraindicated and generally should not be dispensed or administered to|
00435|005|L|the same patient.|
00435|006|B||
00435|007|A|MECHANISM OF ACTION:  Quinine inhibits the metabolism of astemizole.|
00435|008|B||
00435|009|E|CLINICAL EFFECTS:  Increased levels of astemizole, which have been shown to|
00435|010|E|result in QT prolongation, cardiac arrest, cardiac arrhythmias (including|
00435|011|E|torsades de pointes), and death.|
00435|012|B||
00435|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00435|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
00435|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00435|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00435|017|P|female gender, or advanced age.(2)|
00435|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00435|019|P|higher systemic concentrations of either QT prolonging drug are additional|
00435|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00435|021|P|drug concentrations include rapid infusion of an intravenous dose or|
00435|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00435|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00435|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
00435|025|B||
00435|026|M|PATIENT MANAGEMENT:  Concurrent administration of these agents is|
00435|027|M|contraindicated according to the manufacturer's product information for|
00435|028|M|astemizole.|
00435|029|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00435|030|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00435|031|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00435|032|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00435|033|B||
00435|034|D|DISCUSSION:  Studies have shown that concurrent administration of quinine|
00435|035|D|(430 mg single dose) and astemizole results in increased levels of|
00435|036|D|astemizole and desmethylastemizole, as well as QT prolongation.  Studies in|
00435|037|D|humans have also been shown that beverage containing quinine (up to 80|
00435|038|D|mg/day or 32 ounces of tonic water) can produce increases in astemizole,|
00435|039|D|although the QT interval was not significantly prolonged.|
00435|040|B||
00435|041|R|REFERENCES:|
00435|042|B||
00435|043|R|1.Hismanal (astemizole) US prescribing information. Janssen Pharmaceutica|1
00435|044|R|  Products, L.P. February, 1996.|1
00435|045|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00435|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00435|047|R|  settings: a scientific statement from the American Heart Association and|6
00435|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00435|049|R|  2;55(9):934-47.|6
00436|001|T|MONOGRAPH TITLE:  Selected 5-HT1D Agonists/MAO Inhibitors|
00436|002|B||
00436|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00436|004|L|is contraindicated and generally should not be dispensed or administered to|
00436|005|L|the same patient.|
00436|006|B||
00436|007|A|MECHANISM OF ACTION:  MAOIs inhibit the metabolism of rizatriptan,(1)|
00436|008|A|sumatriptan,(2-9) and zolmitriptan.(10-11)|
00436|009|B||
00436|010|E|CLINICAL EFFECTS:  Concurrent use of MAOIs may result in increased levels|
00436|011|E|and effects of rizatriptan, sumatriptan or zolmitriptan.(1-11)|
00436|012|B||
00436|013|P|PREDISPOSING FACTORS:  Patients with a history of cardiovascular disease,|
00436|014|P|e.g., coronary artery disease (CAD), transient ischemic attack (TIA),|
00436|015|P|stroke, cardiac conduction disorders or poorly controlled hypertension are|
00436|016|P|not considered candidates for 5-HT1D agonist therapy and would be at greater|
00436|017|P|risk for toxicity due to this interaction.|
00436|018|B||
00436|019|M|PATIENT MANAGEMENT:  Concurrent administration of rizatriptan and a MAOI or|
00436|020|M|administration of rizatriptan within two weeks of the discontinuation of a|
00436|021|M|MAOI is contraindicated according to product labeling for rizatriptan.(1)|
00436|022|M|   Concurrent administration of sumatriptan and a MAOI or administration of|
00436|023|M|sumatriptan within two weeks of the discontinuation of a MAOI is|
00436|024|M|contraindicated according to the Australian, Canada, UK, and US product|
00436|025|M|labeling for these agents.(2-9)|
00436|026|M|  Concurrent administration of zolmitriptan and a MAO-A inhibitor or the|
00436|027|M|administration of zolmitriptan within two weeks of discontinuation of a|
00436|028|M|MAO-A inhibitor is contraindicated according to US labeling.(10)  The UK|
00436|029|M|manufacturer states that a maximum of 7.5 mg of zolmitriptan should be|
00436|030|M|administered within 24 hours of a MAO-A inhibitor.(11)|
00436|031|M|  Eletriptan and frovatriptan are not metabolized by MAO-A(12, 13) and may|
00436|032|M|be an alternative in patients who require treatment with an MAO-A inhibitor.|
00436|033|B||
00436|034|D|DISCUSSION:  Rizatriptan is metabolized by the 'A' subtype of monoamine|
00436|035|D|oxidase.  In a study with 12 subjects, the concurrent administration of|
00436|036|D|rizatriptan (10 mg) with moclobemide (450 mg daily, a selective, reversible|
00436|037|D|MAO-A inhibitor) resulted in increases in the rizatriptan area-under-curve|
00436|038|D|(AUC) and maximum concentration (Cmax) by 119% and 41%, respectively.  The|
00436|039|D|AUC of the active metabolite, N-monodesmethyl rizatriptan, increased over|
00436|040|D|400%.  Plasma concentrations of rizatriptan may be increased by selective|
00436|041|D|MAO-A inhibitors or by nonselective MAO-A and MAO-B inhibitors, although the|
00436|042|D|interaction is expected to be greater with selective MAO-A inhibitors.  The|
00436|043|D|manufacturer also states that no interaction is expected with selective|
00436|044|D|MAO-B inhibitors.(1)|
00436|045|D|   Sumatriptan oral bioavailability is approximately 15%, primarily due to|
00436|046|D|presystemic clearance by MAO-A in the gut and liver.  A small study found an|
00436|047|D|approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A|
00436|048|D|inhibitor was given prior to a 25 mg oral dose of sumatriptan.(4)|
00436|049|D|  In another study, pretreatment with an MAO-A inhibitor prior to|
00436|050|D|administration of injectable sumatriptan resulted in a 2-fold increase in|
00436|051|D|sumatriptan AUC and a 40% increase in elimination half-life.(8)|
00436|052|D|Pretreatment with a MAO-B inhibitor did not produce any significant changes|
00436|053|D|in sumatriptan pharmacokinetics.  The effect of a MAOI on nasal sumatriptan|
00436|054|D|systemic absorption is expected to be less than that seen with oral|
00436|055|D|sumatriptan but greater than that seen with injectable sumatriptan.(6)|
00436|056|D|  Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg|
00436|057|D|twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold|
00436|058|D|increase in Cmax and AUC for zolmitriptan's active N-desmethyl|
00436|059|D|metabolite.(10,11)  Administration of selegiline for one week at a dosage of|
00436|060|D|10 mg daily had no effect on the pharmacokinetics of zolmitriptan or its|
00436|061|D|metabolite.(10)|
00436|062|D|  At daily doses of 10 mg, selegiline is primarily a selective MAO-B|
00436|063|D|inhibitor; however, at higher doses, selegiline is capable of inhibiting|
00436|064|D|MAO-A.  Hypertensive reactions to the addition of either tyramine or a|
00436|065|D|sympathomimetic to recommended dosages of selegiline have been reported.(14)|
00436|066|D|Therefore, patients receiving selegiline at dosages of greater than 10 mg|
00436|067|D|daily should be considered to be receiving a MAO-A inhibitor.  It would also|
00436|068|D|be prudent to monitor patients receiving selegiline at recommended dosages|
00436|069|D|for this interaction.|
00436|070|D|   Methylene blue, when administered intravenously, has been shown to reach|
00436|071|D|sufficient concentrations to be a potent inhibitor of MAO-A.(15)|
00436|072|D|   Metaxalone is a weak inhibitor of MAO.(17,18)|
00436|073|D|   One or more of the drug pairs linked to this monograph have been included|
00436|074|D|in a list of interactions that should be considered "high-priority" for|
00436|075|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
00436|076|D|vetted by an expert panel commissioned by the U.S. Office of the National|
00436|077|D|Coordinator (ONC) for Health Information Technology.|
00436|078|B||
00436|079|R|REFERENCES:|
00436|080|B||
00436|081|R|1.Maxalt (rizatriptan) US prescribing information. Merck & Co., Inc.|1
00436|082|R|  October, 2019.|1
00436|083|R|2.Imigran Tablets, Injection, and Nasal Spray (sumatriptan) Australian|1
00436|084|R|  prescribing information. GlaxoSmithKline February 11, 2002.|1
00436|085|R|3.Imigran Radis (sumaptriptan) UK summary of product characteristics.|1
00436|086|R|  GlaxoSmithKline UK June 8, 2004.|1
00436|087|R|4.Imitrex Tablets (sumatriptan) US prescribing information. GlaxoSmithKline|1
00436|088|R|  December 14, 2017.|1
00436|089|R|5.Imigran Nasal Spray (sumatriptan) UK summary of product characteristics.|1
00436|090|R|  GlaxoSmithKline UK July 8, 2004.|1
00436|091|R|6.Imitrex Nasal Spray (sumatriptan) US prescribing information.|1
00436|092|R|  GlaxoSmithKline December 14, 2017.|1
00436|093|R|7.Imigran Injection (sumatriptan) UK summary of product characteristics.|1
00436|094|R|  GlaxoSmithKline UK September 19, 2003.|1
00436|095|R|8.Imitrex Injection (sumatriptan) US prescribing information.|1
00436|096|R|  GlaxoSmithKline December 14, 2017.|1
00436|097|R|9.Imitrex (sumatriptan) CA prescribing information. GlaxoSmithKline Inc.|1
00436|098|R|  September 22, 2011.|1
00436|099|R|10.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
00436|100|R|   Pharmaceuticals LP September, 2012.|1
00436|101|R|11.Zomig (zolmitriptan) UK summary of product characteristics. Zeneca|1
00436|102|R|   Limited March, 1997.|1
00436|103|R|12.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
00436|104|R|   March, 2020.|1
00436|105|R|13.Frova (frovatriptan) US prescribing information. Endo Pharmaceuticals|1
00436|106|R|   August, 2018.|1
00436|107|R|14.Eldepryl (selegiline) US prescribing information. Somerset|1
00436|108|R|   Pharmaceuticals February, 1997.|1
00436|109|R|15.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
00436|110|R|   inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
00436|111|R|   prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
00436|112|R|16.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
00436|113|R|   distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
00436|114|R|   2000 Jun;56(3):247-50.|2
00436|115|R|17.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
00436|116|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
00436|117|R|   Feb;34(2):346.e5-6.|3
00436|118|R|18.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
00436|119|R|   Pfizer Inc. January, 2024.|1
00436|120|R|19.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
00436|121|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
00436|122|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
00436|123|R|   19(5):735-43.|6
00437|001|T|MONOGRAPH TITLE:  Ritonavir/Piroxicam  (mono deleted 05/17/2001)|
00437|002|B||
00437|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00437|004|L|is contraindicated and generally should not be dispensed or administered to|
00437|005|L|the same patient.|
00437|006|B||
00437|007|A|MECHANISM OF ACTION:  Ritonavir may inhibit the metabolism of piroxicam.|
00437|008|B||
00437|009|E|CLINICAL EFFECTS:  Increased levels of piroxicam.|
00437|010|B||
00437|011|P|PREDISPOSING FACTORS:  None determined.|
00437|012|B||
00437|013|M|PATIENT MANAGEMENT:  Concurrent administration of piroxicam and ritonavir is|
00437|014|M|contraindicated by the manufacturer of ritonavir.|
00437|015|B||
00437|016|D|DISCUSSION:  There is no clinical documentation substantiating this|
00437|017|D|potential drug interaction. Ritonavir has a high affinity for several CYP|
00437|018|D|P-450 isoenzymes.|
00437|019|B||
00437|020|R|REFERENCE:|
00437|021|B||
00437|022|R|1.Norvir (ritonavir) US prescribing information. Abbott Laboratories March,|1
00437|023|R|  1997.|1
00438|001|T|MONOGRAPH TITLE:  Saquinavir/Rifabutin (mono deleted 02/17/2011)|
00438|002|B||
00438|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00438|004|L|is contraindicated and generally should not be dispensed or administered to|
00438|005|L|the same patient.|
00438|006|B||
00438|007|A|MECHANISM OF ACTION:  Rifabutin may induce the metabolism of saquinavir at|
00438|008|A|CYP P-450-3A4.(1-6)|
00438|009|B||
00438|010|E|CLINICAL EFFECTS:  The concurrent administration of saquinavir and rifabutin|
00438|011|E|may result in decreased levels and clinical effects of saquinavir.(1-6)|
00438|012|B||
00438|013|P|PREDISPOSING FACTORS:  None determined.|
00438|014|B||
00438|015|M|PATIENT MANAGEMENT:  The US manufacturer of saquinavir base states that|
00438|016|M|Fortovase should not be given as the sole protease inhibitor to patients|
00438|017|M|taking rifabutin.  Appropriate doses of the combination of rifabutin and|
00438|018|M|Fortovase with ritonavir have not been established.(1)|
00438|019|M|   The Australian manufacturer of saquinavir base states that when Fortovase|
00438|020|M|is used as the sole protease inhibitor, it is contraindicated in patients|
00438|021|M|receiving rifabutin.(2)|
00438|022|M|   The UK manufacturer of saquinavir base states that Fortovase should not|
00438|023|M|be administered with rifabutin.(3)|
00438|024|M|   The US manufacturer of saquinavir mesylate states appropriate doses of|
00438|025|M|the combination of rifabutin and saquinavir mesylate/ritonavir have not been|
00438|026|M|established.(4)|
00438|027|M|   The Australian manufacturer of saquinavir mesylate states that Invirase|
00438|028|M|is contraindicated with rifabutin.(5)|
00438|029|M|   The UK manufacturer of saquinavir mesylate states that Invirase should|
00438|030|M|not be administered with rifabutin.(6)|
00438|031|B||
00438|032|D|DISCUSSION:  In a study in 14 patients, concurrent administration of|
00438|033|D|Fortovase (1200 mg 3 times daily) and rifabutin (300 mg daily) decreased the|
00438|034|D|area-under-curve (AUC) and maximum concentration (Cmax) of saquinavir by 47%|
00438|035|D|and 31%, respectively.  Rifabutin AUC and Cmax increased by 44% and 45%,|
00438|036|D|respectively.(1)|
00438|037|D|   In a study in 12 patients, concurrent administration of Fortovase (600 mg|
00438|038|D|3 times daily) and rifabutin (300 mg daily) for 14 days decreased the AUC|
00438|039|D|and Cmax of saquinavir by 43% and 30%, respectively.(2)|
00438|040|D|   In a study in 14 patients, concurrent administration of Fortovase (1200|
00438|041|D|mg 3 times daily) and rifabutin (300 mg daily) for 10 days decreased the AUC|
00438|042|D|and Cmax of saquinavir by 47% and 39%, respectively.  Rifabutin AUC and Cmax|
00438|043|D|increased by 44% and 45%, respectively.(3)|
00438|044|D|   In a study in 24 patients, concurrent administration of Invirase (400 mg|
00438|045|D|twice daily) with ritonavir (400 mg twice daily) and rifabutin (150 mg every|
00438|046|D|3 days or 300 mg every 7 days) increased the saquinavir AUC and Cmax by 19%|
00438|047|D|and 39%, respectively.(4)|
00438|048|B||
00438|049|R|REFERENCES:|
00438|050|B||
00438|051|R|1.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
00438|052|R|  Inc. December, 2004.|1
00438|053|R|2.Fortovase (saquinavir) Australian prescribing information. Roche April 20,|1
00438|054|R|  2004.|1
00438|055|R|3.Fortovase (saquinavir) UK summary of product characteristics. Roche|1
00438|056|R|  Products Limited September 23, 2004.|1
00438|057|R|4.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00438|058|R|  Laboratories, Inc. November, 2010.|1
00438|059|R|5.Invirase (saquinavir mesylate) Australian prescribing information. Roche|1
00438|060|R|  April 20, 2004.|1
00438|061|R|6.Invirase (saquinavir mesylate) UK summary of product characteristics.|1
00438|062|R|  Roche Products Limited July 11, 2008.|1
00439|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Quinidine|
00439|002|B||
00439|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00439|004|L|is contraindicated and generally should not be dispensed or administered to|
00439|005|L|the same patient.|
00439|006|B||
00439|007|A|MECHANISM OF ACTION:  Boceprevir; nelfinavir; and ritonavir-boosted|
00439|008|A|nirmatrelvir and tipranavir are strong inhibitors of CYP3A4.  Quinidine, an|
00439|009|A|antiarrhythmic with a narrow therapeutic range, is metabolized by|
00439|010|A|CYP3A4.(1-5)|
00439|011|B||
00439|012|E|CLINICAL EFFECTS:  Quinidine causes dose-dependent QTc prolongation.|
00439|013|E|Concurrent use with strong inhibitors of CYP3A4 are expected to increase|
00439|014|E|systemic exposure to quinidine, increasing risk for an abnormally long QT|
00439|015|E|interval.  Prolongation of the QT interval may lead to life-threatening|
00439|016|E|ventricular arrhythmias, including torsades de pointes.(6)|
00439|017|B||
00439|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
00439|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
00439|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
00439|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
00439|022|P|gender, or advanced age.(6)|
00439|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00439|024|P|higher systemic concentrations of either QT prolonging drug are additional|
00439|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
00439|026|P|drug concentrations include rapid infusion of an intravenous dose or|
00439|027|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
00439|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00439|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
00439|030|B||
00439|031|M|PATIENT MANAGEMENT:  The concurrent administration of quinidine with either|
00439|032|M|boceprevir; nelfinavir; or ritonavir-boosted nirmatrelvir or tipranavir is|
00439|033|M|contraindicated.(2-5)|
00439|034|M|   The manufacturer of a low-dose quinidine combination|
00439|035|M|product(dextromethorphan 20 mg/quinidine 10 mg) makes the following|
00439|036|M|recommendations for patients receiving concomitant treatment with|
00439|037|M|strong-moderate inhibitors of CYP3A4:|
00439|038|M| - Correct hypokalemia and hypomagnesemia prior to initiating therapy and|
00439|039|M|monitor during treatment.|
00439|040|M| - Perform a baseline ECG evaluation, then repeat ECG 3 to 4 hours after the|
00439|041|M|first dose. Product is contraindicated in patients with a prolonged QT|
00439|042|M|interval.|
00439|043|M| - reevaluate ECG if risk factors for arrhythmia change during treatment|
00439|044|M| - Instruct patients to report symptoms consistent with cardiac arrhythmia,|
00439|045|M|e.g. syncope or palpitations. If reported, discontinue treatment and|
00439|046|M|evaluate patient.(7)|
00439|047|B||
00439|048|D|DISCUSSION:  Boceprevir; nelfinavir; and ritonavir-boosted nirmatrelvir and|
00439|049|D|tipranavir(2-5) inhibit CYP3A4 at clinically relevant concentrations.|
00439|050|D|   Selected protease inhibitors linked to this monograph include:|
00439|051|D|boceprevir, nelfinavir, nirmatrelvir, and tipranavir.  Ritonavir is always|
00439|052|D|used with another protease inhibitor as a pharmacokinetic booster and is|
00439|053|D|captured as part of the protease inhibitor regimen.|
00439|054|B||
00439|055|R|REFERENCES:|
00439|056|B||
00439|057|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
00439|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
00439|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
00439|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
00439|061|R|  11/14/2017.|1
00439|062|R|2.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00439|063|R|  Pharmaceuticals, Inc. September, 2016.|1
00439|064|R|3.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00439|065|R|  Pharmaceuticals, Inc. April, 2024.|1
00439|066|R|4.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
00439|067|R|  January, 2017.|1
00439|068|R|5.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
00439|069|R|  information. Pfizer Inc. February, 2025.|1
00439|070|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
00439|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
00439|072|R|  settings: a scientific statement from the American Heart Association and|6
00439|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
00439|074|R|  2;55(9):934-47.|6
00439|075|R|7.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
00439|076|R|  prescribing information. Avanir  Pharmaceuticals June, 2019.|1
00440|001|T|MONOGRAPH TITLE:  Protease Inhibitors; Cobicistat/Astemizole; Terfenadine|
00440|002|B||
00440|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
00440|004|L|is contraindicated and generally should not be dispensed or administered to|
00440|005|L|the same patient.|
00440|006|B||
00440|007|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
00440|008|A|astemizole(1-9) and terfenadine(2-10) by CYP3A4.|
00440|009|B||
00440|010|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
00440|011|E|of astemizole(1-9) and terfenadine,(2-10) which may result in cardiac|
00440|012|E|arrhythmias including QT prolongation or torsades de pointes.|
00440|013|B||
00440|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
00440|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
00440|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
00440|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
00440|018|P|female gender, or advanced age.(14)|
00440|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
00440|020|P|higher systemic concentrations of either QT prolonging drug are additional|
00440|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
00440|022|P|drug concentrations include rapid infusion of an intravenous dose or|
00440|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
00440|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
00440|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(14)|
00440|026|B||
00440|027|M|PATIENT MANAGEMENT:  The US manufacturer of amprenavir states that|
00440|028|M|concurrent use of astemizole is contraindicated.(1)|
00440|029|M|   The US manufacturers of darunavir(2), the combination of lopinavir/|
00440|030|M|ritonavir,(3) the combination of nirmatrelvir/ritonavir,(15) ritonavir,(4)|
00440|031|M|and tipranavir coadministered with ritonavir(5) state that concurrent use|
00440|032|M|with either astemizole or terfenadine is contraindicated.|
00440|033|M|   The US manufacturers of indinavir,(6) nelfinavir,(7) and saquinavir(8,9)|
00440|034|M|state that these agents should not be used concurrently with terfenadine or|
00440|035|M|astemizole.  The US manufacturer of terfenadine states that concurrent use|
00440|036|M|with indinavir, nelfinavir, ritonavir, or saquinavir is not recommended.(10)|
00440|037|M|   Fexofenadine and loratadine, nonsedating antihistamines that have been|
00440|038|M|shown to have no effects on cardiac function,(11,12) may be alternatives to|
00440|039|M|astemizole and terfenadine in patients receiving protease inhibitors.|
00440|040|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
00440|041|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
00440|042|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
00440|043|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
00440|044|B||
00440|045|D|DISCUSSION:  The concurrent administration of Fortovase (saquinavir base)|
00440|046|D|with terfenadine resulted in increases in the area-under-curve (AUC) and|
00440|047|D|maximum concentration (Cmax) of terfenadine (normally undetectable) by 368%|
00440|048|D|and 253%, respectively.(8,9)  The AUC and Cmax of the terfenadine acid|
00440|049|D|metabolite increased by 120% and 93%, respectively.(9)|
00440|050|D|    Both astemizole and terfenadine are metabolized by CYP3A4.  Drugs that|
00440|051|D|block the metabolism of astemizole and terfenadine may produce an increase|
00440|052|D|in the plasma concentrations of these antihistamines.  Elevated plasma|
00440|053|D|levels of astemizole and terfenadine can cause QT prolongation and torsades|
00440|054|D|de pointes-type ventricular tachycardia, which may be fatal. Fexofenadine|
00440|055|D|and loratadine have been shown to have no effects on cardiac|
00440|056|D|function.(11,12)|
00440|057|D|   Amprenavir, boceprevir, cobicistat, darunavir, indinavir, lopinavir,|
00440|058|D|nelfinavir, nirmatrelvir, paritaprevir, saquinavir, telaprevir, and|
00440|059|D|tipranavir have been shown to inhibit CYP3A4.|
00440|060|D|   Fosamprenavir is a prodrug of amprenavir.(13)|
00440|061|B||
00440|062|R|REFERENCES:|
00440|063|B||
00440|064|R|1.Agenerase (amprenavir) US prescribing information. Glaxo Wellcome, Inc.|1
00440|065|R|  April, 1999.|1
00440|066|R|2.Prezista (darunavir) US prescribing information. Tibotec Inc. June, 2006.|1
00440|067|R|3.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
00440|068|R|  Laboratories September, 2007.|1
00440|069|R|4.Norvir (ritonavir) US prescribing information. Abbott Laboratories March,|1
00440|070|R|  1997.|1
00440|071|R|5.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
00440|072|R|  Pharmaceuticals, Inc. June, 2007.|1
00440|073|R|6.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
00440|074|R|  January, 2004.|1
00440|075|R|7.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
00440|076|R|  Pharmaceuticals, Inc. March, 1997.|1
00440|077|R|8.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
00440|078|R|  Inc. December, 2004.|1
00440|079|R|9.Invirase (saquinavir mesylate) US prescribing information. Roche|1
00440|080|R|  Laboratories, Inc. July, 2007.|1
00440|081|R|10.Seldane (terfenadine) US prescribing information. Hoechst-Marion Roussel|1
00440|082|R|   September, 1997.|1
00440|083|R|11.Allegra (fexofenadine hydrochloride) US prescribing information.|1
00440|084|R|   Sanofi-Aventis U.S. LLC October, 2006.|1
00440|085|R|12.Claritin (loratadine) US prescribing information. Schering-Plough|1
00440|086|R|   Corporation January, 1997.|1
00440|087|R|13.Lexiva (fosamprenavir calcium) US prescribing information.|1
00440|088|R|   GlaxoSmithKline October, 2003.|1
00440|089|R|14.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
00440|090|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
00440|091|R|   hospital settings: a scientific statement from the American Heart|6
00440|092|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
00440|093|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
00440|094|R|15.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
00440|095|R|   information. Pfizer Inc. February, 2025.|1
00440|096|R|16.This information is based on an extract from the Certara Drug Interaction|6
00440|097|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00440|098|R|17.US Food and Drug Administration (FDA). Drug Development and Drug|1
00440|099|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
00440|100|R|   at:|1
00440|101|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
00440|102|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
00440|103|R|   11/14/2017.|1
00441|001|T|MONOGRAPH TITLE:  Ticlopidine/Aspirin|
00441|002|B||
00441|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00441|004|L|take action as needed.|
00441|005|B||
00441|006|A|MECHANISM OF ACTION:  Ticlopidine inhibits adenosine diphosphate mediated|
00441|007|A|platelet aggregation and aspirin inhibits arachidonic acid mediated platelet|
00441|008|A|aggregation. In addition, ticlopidine potentiates the effect of|
00441|009|A|aspirin-induced inhibition of collagen mediated platelet aggregation.|
00441|010|B||
00441|011|E|CLINICAL EFFECTS:  Concurrent therapy may result in increased inhibition of|
00441|012|E|platelet aggregation resulting in increased bleeding times and possible|
00441|013|E|hemorrhage.|
00441|014|B||
00441|015|P|PREDISPOSING FACTORS:  This interaction may be more significant in patients|
00441|016|P|with a predisposition to bleeding, such as those with ulcers.(1)|
00441|017|P|   The risk for bleeding episodes may be greater in patients with|
00441|018|P|disease-associated factors (e.g. thrombocytopenia).|
00441|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
00441|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00441|021|P|risk for bleeding (e.g. NSAIDs).|
00441|022|B||
00441|023|M|PATIENT MANAGEMENT:  Concurrent therapy is indicated to reduce the incidence|
00441|024|M|of subacute stent thrombosis in patients undergoing successful coronary|
00441|025|M|stent implantation; however, safety of concurrent use beyond 30 days has not|
00441|026|M|been established.  Long-term concurrent therapy is not recommended.(1)|
00441|027|M|   When concurrent therapy is warranted, monitor patients receiving|
00441|028|M|concurrent therapy for signs of blood loss, including decreased hemoglobin|
00441|029|M|and/or hematocrit, fecal occult blood, and/or decreased blood pressure and|
00441|030|M|promptly evaluate patients with any symptoms.|
00441|031|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00441|032|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00441|033|M|anticoagulation in patients with active pathologic bleeding.|
00441|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00441|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00441|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00441|037|M|and/or swelling.|
00441|038|B||
00441|039|D|DISCUSSION:  Studies have shown that concurrent ticlopidine and aspirin|
00441|040|D|therapy potentiates inhibition of collagen mediated platelet aggregation.|
00441|041|D|Also, bleeding times were increased during concurrent therapy when compared|
00441|042|D|to baseline, to aspirin given alone, or to ticlopidine given alone. In one|
00441|043|D|study comparing concurrent therapy with aspirin given alone and ticlopidine|
00441|044|D|given alone, there was an increase in hemorrhage in the group receiving|
00441|045|D|concurrent therapy.|
00441|046|B||
00441|047|R|REFERENCES:|
00441|048|B||
00441|049|R|1.Ticlopidine hydrochloride US prescribing information. Teva Pharmaceuticals|1
00441|050|R|  USA June, 2003.|1
00441|051|R|2.De Caterina R, Sicari R, Bernini W, Lazzerini G, Buti Strata G, Giannessi|2
00441|052|R|  D. Benefit/risk profile of combined antiplatelet therapy with ticlopidine|2
00441|053|R|  and aspirin. Thromb Haemost 1991 May 6;65(5):504-10.|2
00441|054|R|3.Thebault JJ, Blatrix CE, Blanchard JF, Panak EA. The interactions of|2
00441|055|R|  ticlopidine and aspirin in normal subjects. J Int Med Res 1977;|2
00441|056|R|  5(6):405-11.|2
00441|057|R|4.Uchiyama S, Sone R, Nagayama T, Shibagaki Y, Kobayashi I, Maruyama S,|2
00441|058|R|  Kusakabe K. Combination therapy with low-dose aspirin and ticlopidine in|2
00441|059|R|  cerebral ischemia. Stroke 1989 Dec;20(12):1643-7.|2
00442|001|T|MONOGRAPH TITLE:  Selected Azole Antifungals/Proton Pump Inhibitors (mono|
00442|002|T|deleted 12/12/2013)|
00442|003|B||
00442|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00442|005|L|of severe adverse interaction.|
00442|006|B||
00442|007|A|MECHANISM OF ACTION:  Proton pump inhibitors increase the pH of the stomach,|
00442|008|A|possibly reducing the dissolution and gastrointestinal absorption of azole|
00442|009|A|antifungal agents.|
00442|010|B||
00442|011|E|CLINICAL EFFECTS:  Concurrent use of a proton pump inhibitor may reduce the|
00442|012|E|absorption and clinical effectiveness of the azole antifungal.|
00442|013|B||
00442|014|P|PREDISPOSING FACTORS:  None determined.|
00442|015|B||
00442|016|M|PATIENT MANAGEMENT:  If the concurrent administration of these two agents|
00442|017|M|cannot be avoided, administer two capsules of glutamic acid hydrochloride or|
00442|018|M|an acidic beverage such as cola 15 minutes before giving the azole|
00442|019|M|antifungal.  Patients should be monitored for decreased effectiveness of the|
00442|020|M|antifungal agent.|
00442|021|B||
00442|022|D|DISCUSSION:  Itraconazole, ketoconazole, and posaconazole require an acidic|
00442|023|D|medium for predictable dissolution and absorption decreases as pH increases|
00442|024|D|and proton pump inhibitors are expected to decrease their absorption.(1-4)|
00442|025|D|   In a study in 11 healthy subjects, omeprazole (40 mg daily) decreased the|
00442|026|D|maximum concentration (Cmax) and area-under-curve (AUC) of itraconazole (200|
00442|027|D|mg single dose) by 66% and 64%, respectively.(5)  In a study in 15 healthy|
00442|028|D|subjects, omeprazole (40 mg daily) had no effect on the pharmacokinetics of|
00442|029|D|itraconazole solution.(6)|
00442|030|D|   In a study in 9 healthy subjects, omeprazole (60 mg) decreased the AUC of|
00442|031|D|ketoconazole (200 mg single dose) by 83.4% compared to control (ketoconazole|
00442|032|D|alone).  Administration of Coca-Cola (240 ml) with ketoconazole and|
00442|033|D|omeprazole raised ketoconazole AUC to 65% of control values.(7)|
00442|034|D|   In a study in 5 healthy subjects, administration of esomeprazole (40 mg|
00442|035|D|daily for 3 days) decreased posaconazole (400 mg single dose) AUC by 37%|
00442|036|D|compared to control (posaconazole alone).  Administration of Coca-Cola (240|
00442|037|D|ml) with posaconazole and esomeprazole raised posaconazole AUC to 81% of|
00442|038|D|control values.(8)|
00442|039|D|   Coadministration with esomeprazole decreased posaconazole|
00442|040|D|area-under-curve (AUC) and maximum concentration (Cmax) by 32% and 46%,|
00442|041|D|respectively.(9,10)|
00442|042|D|   Omeprazole has been shown to have no significant effect on the absorption|
00442|043|D|of fluconazole(11) or voriconazole.(12)|
00442|044|B||
00442|045|R|REFERENCES:|
00442|046|B||
00442|047|R|1.Prilosec (omeprazole) US Prescribing information. AstraZeneca|1
00442|048|R|  Pharmaceuticlas LP March, 2014.|1
00442|049|R|2.Prevacid (lansoprazole) US prescribing information. Takeda Pharmaceuticals|1
00442|050|R|  America, Inc. September, 2012.|1
00442|051|R|3.Carlson JA, Mann HJ, Canafax DM. Effect of pH on disintegration and|5
00442|052|R|  dissolution of ketoconazole tablets. Am J Hosp Pharm 1983 Aug;|5
00442|053|R|  40(8):1334-6.|5
00442|054|R|4.Van Der Meer JW, Keuning JJ, Scheijgrond HW, Heykants J, Van Cutsem J,|3
00442|055|R|  Brugmans J. The influence of gastric acidity on the bio-availability of|3
00442|056|R|  ketoconazole. J Antimicrob Chemother 1980 Jul;6(4):552-4.|3
00442|057|R|5.Jaruratanasirikul S, Sriwiriyajan S. Effect of omeprazole on the|2
00442|058|R|  pharmacokinetics of itraconazole. Eur J Clin Pharmacol 1998 Apr;|2
00442|059|R|  54(2):159-61.|2
00442|060|R|6.Johnson MD, Hamilton CD, Drew RH, Sanders LL, Pennick GJ, Perfect JR. A|2
00442|061|R|  randomized comparative study to determine the effect of omeprazole on the|2
00442|062|R|  peak  serum concentration of itraconazole oral solution. J Antimicrob|2
00442|063|R|  Chemother 2003 Feb;51(2):453-7.|2
00442|064|R|7.Chin TW, Loeb M, Fong IW. Effects of an acidic beverage (Coca-Cola) on|2
00442|065|R|  absorption of ketoconazole. Antimicrob Agents Chemother 1995 Aug;|2
00442|066|R|  39(8):1671-5.|2
00442|067|R|8.Walravens J, Brouwers J, Spriet I, Tack J, Annaert P, Augustijns P. Effect|2
00442|068|R|  of pH and comedication on gastrointestinal absorption of posaconazole:|2
00442|069|R|  monitoring of intraluminal and plasma drug concentrations. Clin|2
00442|070|R|  Pharmacokinet 2011 Nov 1;50(11):725-34.|2
00442|071|R|9.Noxafil (posaconazole) UK summary of product characteristics.|1
00442|072|R|  Schering-Plough Ltd. January, 2022.|1
00442|073|R|10.Noxafil (posaconazole) US prescribing information. Schering Corporation|1
00442|074|R|   June, 2012.|1
00442|075|R|11.Zimmermann T, Yeates RA, Riedel KD, Lach P, Laufen H. The influence of|2
00442|076|R|   gastric pH on the pharmacokinetics of fluconazole: the effect of|2
00442|077|R|   omeprazole. Int J Clin Pharmacol Ther 1994 Sep;32(9):491-6.|2
00442|078|R|12.Wood N, Tan K, Purkins L, Layton G, Hamlin J, Kleinermans D, Nichols D.|2
00442|079|R|   Effect of omeprazole on the steady-state pharmacokinetics of|2
00442|080|R|   voriconazole. Br J Clin Pharmacol 2003 Dec;56 Suppl 1:56-61.|2
00443|001|T|MONOGRAPH TITLE:  Triamterene; Amiloride/Selected NSAIDs; Salicylates|
00443|002|B||
00443|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00443|004|L|take action as needed.|
00443|005|B||
00443|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown; however, nonsteroidal|
00443|007|A|anti-inflammatory (NSAID) inhibition of prostaglandins may allow triamterene|
00443|008|A|or amiloride- induced nephrotoxicity or hyperkalemia to occur in some|
00443|009|A|patients.|
00443|010|B||
00443|011|E|CLINICAL EFFECTS:  Possible renal failure or hyperkalemia.|
00443|012|B||
00443|013|P|PREDISPOSING FACTORS:  None determined.|
00443|014|B||
00443|015|M|PATIENT MANAGEMENT:  When possible, avoid concurrent therapy with|
00443|016|M|triamterene or amiloride with NSAIDs. If these agents are used concurrently,|
00443|017|M|monitor renal function and serum electrolytes. If decreased renal function|
00443|018|M|or hyperkalemia develops, discontinue both agents.|
00443|019|B||
00443|020|D|DISCUSSION:  Although acute renal failure and hyperkalemia have only been|
00443|021|D|reported in studies and case reports involving indomethacin, diclofenac,|
00443|022|D|flurbiprofen, and ibuprofen with either triamterene or amiloride, the|
00443|023|D|proposed mechanism suggests that all nonsteroidal anti-inflammatory agents|
00443|024|D|may be capable of this interaction. Patients receiving diuretics are at an|
00443|025|D|increased risk of NSAID-induced renal failure.|
00443|026|B||
00443|027|R|REFERENCES:|
00443|028|B||
00443|029|R|1.Favre L, Glasson P, Riondel A, Vallotton MB. Interaction of diuretics and|2
00443|030|R|  non-steroidal anti-inflammatory drugs in man. Clin Sci (Lond) 1983 Apr;|2
00443|031|R|  64(4):407-15.|2
00443|032|R|2.Lodine (etodolac) US prescribing information. Wyeth Pharmaceuticals March,|1
00443|033|R|  2006.|1
00443|034|R|3.Nalfon (fenoprofen) US prescribing information. Dista May, 2016.|1
00443|035|R|4.Oruvail (ketoprofen) US prescribing information. Wyeth-Ayerst Laboratories|1
00443|036|R|  March, 2006.|1
00443|037|R|5.Toradol (ketorolac tromethamine) US prescribing information. Roche|1
00443|038|R|  Pharmaceuticals March, 2013.|1
00443|039|R|6.Ponstel (mefenamic acid) US prescribing information. Parke-Davis May,|1
00443|040|R|  2016.|1
00443|041|R|7.Relafen (nabumetone) US prescribing information. GlaxoSmithKline February,|1
00443|042|R|  2006.|1
00443|043|R|8.Daypro (oxaprozin) US prescribing information. Pfizer May, 2021.|1
00443|044|R|9.Clinoril (sulindac) US prescribing information. Merck & Co., Inc.|1
00443|045|R|  December, 2010.|1
00443|046|R|10.Tolectin (tolmetin) US prescribing information. Teva Pharmaceuticals|1
00443|047|R|   June, 2006.|1
00444|001|T|MONOGRAPH TITLE:  Hydantoins/Omeprazole; Esomeprazole|
00444|002|B||
00444|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00444|004|L|of severe adverse interaction.|
00444|005|B||
00444|006|A|MECHANISM OF ACTION:  Omeprazole and esomeprazole may inhibit the CYP2C19|
00444|007|A|metabolism of hydantoins.(1-3)|
00444|008|A|   Hydantoins may induce the CYP3A4 metabolism of omeprazole and|
00444|009|A|esomeprazole.(1-3)|
00444|010|B||
00444|011|E|CLINICAL EFFECTS:  Concurrent administration of omeprazole or esomeprazole|
00444|012|E|and hydantoins may result in elevated levels of the hydantoin.  Phenytoin|
00444|013|E|has a narrow therapeutic range.  Early symptoms of phenytoin toxicity may|
00444|014|E|include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy,|
00444|015|E|slurred speech, blurred vision, nausea, and vomiting.  Severe toxicity may|
00444|016|E|produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction|
00444|017|E|and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may|
00444|018|E|be fatal.(1)|
00444|019|E|   Concurrent use of omeprazole or esomeprazole with CYP3A4 inducers may|
00444|020|E|result in decreased levels and effectiveness of omeprazole or|
00444|021|E|esomeprazole.(1-3)|
00444|022|B||
00444|023|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
00444|024|P|hypoalbuminemia.|
00444|025|B||
00444|026|M|PATIENT MANAGEMENT:  Avoid concomitant use of CYP3A4 inducers with|
00444|027|M|omeprazole or esomeprazole.(2,3)|
00444|028|M|   Patients should be monitored for changes in response to hydantoins when|
00444|029|M|omeprazole or esomeprazole are added to or discontinued from hydantoin|
00444|030|M|therapy.  Serum hydantoin concentration should be monitored to assist in|
00444|031|M|dosage adjustments.(1)|
00444|032|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
00444|033|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
00444|034|M|vision, nausea, and vomiting).|
00444|035|B||
00444|036|D|DISCUSSION:  In a double-blind cross-over study in ten healthy subjects,|
00444|037|D|concurrent phenytoin (300 mg single dose on day seven of omeprazole therapy)|
00444|038|D|and omeprazole (40 mg daily for nine days) therapy resulted in|
00444|039|D|area-under-curve (AUC) increasing 19% when compared to phenytoin and|
00444|040|D|placebo.  There were no significant changes in phenytoin peak concentration,|
00444|041|D|(Cmax) time to Cmax, or half-life.(4)|
00444|042|D|   In another cross-over study on eight healthy subjects, concurrent|
00444|043|D|phenytoin (250 mg single dose administered intravenously over 30 minutes on|
00444|044|D|day seven of omeprazole therapy) and omeprazole (40 mg daily for eight days)|
00444|045|D|resulted in plasma clearance decreasing 15% and half-life increasing 27%|
00444|046|D|when compared to phenytoin and placebo.  There was a small, but not|
00444|047|D|significant, increase in phenytoin plasma concentrations during concurrent|
00444|048|D|omeprazole therapy.(5)|
00444|049|D|   The results of these studies are disputed in a study of eight epileptic|
00444|050|D|patients maintained on phenytoin (dosage range 200-450 mg daily).  There|
00444|051|D|were no significant changes in phenytoin levels or phenytoin urinary|
00444|052|D|excretion after three weeks of concurrent omeprazole (20 mg daily) therapy|
00444|053|D|when compared to previous steady-state values.  The authors speculated that|
00444|054|D|the low dose of omeprazole (20 mg daily) was not enough to produce the|
00444|055|D|inhibition of phenytoin metabolism seen in other studies.(6)|
00444|056|D|   In an interaction study, rifampin 600 mg daily for 7 days decreased|
00444|057|D|omeprazole AUC by 89.5%.(8,9)|
00444|058|B||
00444|059|R|REFERENCES:|
00444|060|B||
00444|061|R|1.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00444|062|R|  March, 2022.|1
00444|063|R|2.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
00444|064|R|  Pharmaceuticals LP June, 2018.|1
00444|065|R|3.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
00444|066|R|  Pharmaceuticals LP August, 2021.|1
00444|067|R|4.Prichard PJ, Walt RP, Kitchingman GK, Somerville KW, Langman MJ, Williams|2
00444|068|R|  J, Richens A. Oral phenytoin pharmacokinetics during omeprazole therapy.|2
00444|069|R|  Br J Clin Pharmacol 1987 Oct;24(4):543-5.|2
00444|070|R|5.Gugler R, Jensen JC. Omeprazole inhibits oxidative drug metabolism.|2
00444|071|R|  Studies with diazepam and phenytoin in vivo and 7-ethoxycoumarin in vitro.|2
00444|072|R|  Gastroenterology 1985 Dec;89(6):1235-41.|2
00444|073|R|6.Andersson T, Lagerstrom PO, Unge P. A study of the interaction between|2
00444|074|R|  omeprazole and phenytoin in epileptic patients. Ther Drug Monit 1990 Jul;|2
00444|075|R|  12(4):329-33.|2
00444|076|R|7.Jensen JC, Gugler R. Inhibition of human liver cytochrome P-450 by|5
00444|077|R|  omeprazole. Br J Clin Pharmacol 1986 Mar;21(3):328-30.|5
00444|078|R|8.This information is based on an extract from the Certara Drug Interaction|6
00444|079|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00444|080|R|9.Bosilkovska M, Samer CF, Deglon J, Rebsamen M, Staub C, Dayer P, Walder B,|2
00444|081|R|  Desmeules JA, Daali Y. Geneva cocktail for cytochrome p450 and|2
00444|082|R|  P-glycoprotein activity assessment using  dried blood spots. Clin|2
00444|083|R|  Pharmacol Ther 2014 Sep;96(3):349-59.|2
00445|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/SSRIs;|
00445|002|T|SNRIs|
00445|003|B||
00445|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00445|005|L|of severe adverse interaction.|
00445|006|B||
00445|007|A|MECHANISM OF ACTION:  SSRI or SNRI inhibition of platelet serotonin uptake|
00445|008|A|may result in impaired platelet aggregation.(1-11)  This effect may be|
00445|009|A|additive or synergistic when combined with other agents which impair|
00445|010|A|hemostasis.|
00445|011|A|   Fluvoxamine is an inhibitor of CYP2C9 mediated metabolism of warfarin.(9)|
00445|012|B||
00445|013|E|CLINICAL EFFECTS:  Concurrent use of selected anticoagulants and SSRIs or|
00445|014|E|SNRIs may increase the risk for bleeding.|
00445|015|B||
00445|016|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00445|017|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
00445|018|P|impairment has been associated with an elevated risk of GI bleed in patients|
00445|019|P|on SSRIs.(11)|
00445|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
00445|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00445|022|P|risk for bleeding (e.g. NSAIDs).|
00445|023|B||
00445|024|M|PATIENT MANAGEMENT:  For the combination of fluvoxamine and warfarin: when|
00445|025|M|possible change to a SSRI which does not inhibit warfarin metabolism (e.g.|
00445|026|M|citalopram or paroxetine).  For patients who require this combination,|
00445|027|M|monitor for an increase in INR when fluvoxamine is started or the dose is|
00445|028|M|increased.  The warfarin dose may need to be reduced.|
00445|029|M|   For all anticoagulant/SSRI or SNRI combinations, if concurrent therapy is|
00445|030|M|warranted, monitor patients receiving concurrent therapy for signs of blood|
00445|031|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
00445|032|M|and/or decreased blood pressure and promptly evaluate patients with any|
00445|033|M|symptoms.|
00445|034|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00445|035|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00445|036|M|anticoagulation in patients with active pathologic bleeding.|
00445|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00445|038|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00445|039|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00445|040|M|and/or swelling.|
00445|041|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00445|042|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00445|043|M|initiating, altering the dose or discontinuing either drug.|
00445|044|B||
00445|045|D|DISCUSSION:  The manufacturer's product information for fluvoxamine reports|
00445|046|D|a study in which the plasma warfarin concentrations increased 98% and|
00445|047|D|prothrombin times were prolonged in patients who received concurrent|
00445|048|D|fluvoxamine and warfarin.(9)|
00445|049|D|   In a single study in 24 healthy patients, concurrent administration of|
00445|050|D|paroxetine and warfarin resulted in clinically significant bleeding in five|
00445|051|D|patients. No changes in paroxetine or warfarin disposition were seen.(13)|
00445|052|D|   In a review describing the bleeding risk with SRIs, warfarin was|
00445|053|D|associated with an increased rate of hemorrhage among SRI users (adjusted|
00445|054|D|relative risk = 1.41).(14)|
00445|055|D|   In a cohort study of patients taking warfarin in combination with an SSRI|
00445|056|D|versus warfarin treatment alone, an analysis including first bleedings|
00445|057|D|revealed a hazard ratio of 3.49 for bleeding during treatment with a|
00445|058|D|combination of SSRI and warfarin compared with warfarin only.(15)|
00445|059|D|   A retrospective study of warfarin-treated patients prescribed or not|
00445|060|D|prescribed an antidepressant showed that use of an SSRI with warfarin was|
00445|061|D|significantly associated with increased risk of any bleed (overall risk|
00445|062|D|(OR)=2.6), major bleeding (OR=4.4), and hospitalization secondary to|
00445|063|D|bleeding (OR=7.0) as compared to those not taking an SSRI.(16)|
00445|064|D|   A population based study of patient outcomes in 176 primary intracerebral|
00445|065|D|hemorrhage patients showed that 19 patients taking SSRI/SNRIs together with|
00445|066|D|warfarin had an increased 30-day case fatality rate of 78.9% compared to|
00445|067|D|warfarin alone (50.7%).(17)|
00445|068|D|   In a study of the Anticoagulation and Risk factors in Atrial fibrillation|
00445|069|D|(ATRIA) cohort, hemorrhage rates were higher during periods of SSRI exposure|
00445|070|D|compared with periods on no antidepressants (2.32 per 100 person-years vs|
00445|071|D|1.35 per 100 person-years).  After adjusting for bleeding risk and time in|
00445|072|D|INR range > 3, SSRI exposure was associated with an increased rate of|
00445|073|D|hemorrhage compared with no antidepressants (adjusted relative risk =|
00445|074|D|1.41).(18)|
00445|075|D|   Increased bleeding risk has been found when patients receive 3 agents|
00445|076|D|which can affect bleeding risk: an anticoagulant, SSRI and NSAID.(19)|
00445|077|D|   In a retrospective review of 5 years of data from the|
00445|078|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
00445|079|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
00445|080|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
00445|081|D|only based on an observed-expected ratio was 4.5 and in a patient using|
00445|082|D|low-dose aspirin only was 2.5.  Concurrent use of a SSRI with NSAIDs or|
00445|083|D|low-dose aspirin increased the risk of bleeding to 12.2 and 5.2,|
00445|084|D|respectively.(19)|
00445|085|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
00445|086|D|in patients receiving concurrent therapy with SSRIs and NSAIDs.  Adjusted|
00445|087|D|relative risk of bleeding with NSAIDs, SSRIs, or both were 3.7, 2.6, or|
00445|088|D|15.6, respectively.(20)|
00445|089|D|   A large systematic review was performed on 72 warfarin drug-drug|
00445|090|D|interactions studies that reported on bleeding, thromboembolic events, or|
00445|091|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 10 of|
00445|092|D|those studies found a higher rate of clinically significant bleeding in|
00445|093|D|patients on warfarin and antidepressants (OR=1.54; 95% CI 1.4-1.7).|
00445|094|D|Increased bleeding risk was also seen in subgroup analyses with SSRIs|
00445|095|D|(OR=1.62; 95% CI 1.42-1.85) but not SNRIs.  There was an increased case|
00445|096|D|fatality rate for intracerebral hemorrhage with SSRIs and SNRIs (OR=3.64;|
00445|097|D|95% CI 1.15-11.53).(21)|
00445|098|D|   There are two published case reports involving increased effects of|
00445|099|D|warfarin following addition of fluoxetine. Another case report is|
00445|100|D|inconclusive. In a study in seven healthy volunteers, neither single dose or|
00445|101|D|eight days of consecutive therapy resulted in alteration of warfarin|
00445|102|D|clearance.(22, 23)|
00445|103|D|   In a parallel group study involving 12 healthy volunteers, the|
00445|104|D|prothrombin time and area-under-curve (AUC) were increased and the|
00445|105|D|normalization of prothrombin time was decreased with concurrent warfarin and|
00445|106|D|sertraline. There was also a clinically insignificant increase in warfarin|
00445|107|D|protein binding.(24)|
00445|108|D|   There is one case report of increased INR during concurrent warfarin and|
00445|109|D|duloxetine.(25)|
00445|110|B||
00445|111|R|REFERENCES:|
00445|112|B||
00445|113|R|1.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
00445|114|R|  and Company August, 2023.|1
00445|115|R|2.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
00445|116|R|  Laboratories Inc. August, 2023.|1
00445|117|R|3.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
00445|118|R|  Pharmaceuticals Inc. May, 2023.|1
00445|119|R|4.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
00445|120|R|  Technologies January, 2017.|1
00445|121|R|5.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
00445|122|R|  Therapeutics, LLC September, 2021.|1
00445|123|R|6.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
00445|124|R|7.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
00445|125|R|  Pharmaceuticals, Inc. August, 2023.|1
00445|126|R|8.Effexor XR (venlafaxine hydrochloride) US prescribing information. Viatris|1
00445|127|R|  August, 2023.|1
00445|128|R|9.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
00445|129|R|  Pharmaceuticals, Inc. August, 2023.|1
00445|130|R|10.Trintellix (vortioxetine) US prescribing information. Takeda|1
00445|131|R|   Pharmaceuticals America, Inc. November, 2020.|1
00445|132|R|11.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
00445|133|R|   and Company September, 2021.|1
00445|134|R|12.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
00445|135|R|   Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
00445|136|R|   by level of kidney function: A population-based cohort study. Br J Clin|2
00445|137|R|   Pharmacol 2018 Sep;84(9):2142-2151.|2
00445|138|R|13.Bannister SJ, Houser VP, Hulse JD, Kisicki JC, Rasmussen JG. Evaluation|2
00445|139|R|   of the potential for interactions of paroxetine with diazepam,|2
00445|140|R|   cimetidine, warfarin, and digoxin. Acta Psychiatr Scand Suppl 1989;|2
00445|141|R|   350:102-6.|2
00445|142|R|14.Bixby AL, VandenBerg A, Bostwick JR. Clinical management of bleeding risk|6
00445|143|R|   with antidepressants. Ann Pharmacother. 2019;53(2):186-194.|6
00445|144|R|15.Wallerstedt SM, Gleerup H, Sundstrom A, Stigendal L, Ny L. Risk of|6
00445|145|R|   clinically relevant bleeding in warfarin-treated patients--influence of|6
00445|146|R|   SSRI treatment. Pharmacoepidemiol Drug Saf. 2009;18:412-416.|6
00445|147|R|16.Cochran KA, Cavallari LH, Shapiro NL, Bishop JR. Bleeding incidence with|6
00445|148|R|   concomitant use of antidepressants and warfarin. Ther Drug Monit 2011;|6
00445|149|R|   33(4):433-438.|6
00445|150|R|17.Lopponen P, Tetri S, Juvela S, Huhtakangas J, Saloheimo P, Bode MK,|6
00445|151|R|   Hillbom M. Association between warfarin combined with|6
00445|152|R|   serotonin-modulating antidepressants and increased case fatality in|6
00445|153|R|   primary intracerebral hemorrhage: a population-based study. J Neurosurg|6
00445|154|R|   2014;120:1358-1363.|6
00445|155|R|18.Quinn GR, Singer DE, Chang Y, Go AS, Borowsky LH, Udaltsova N, Fang MC.|6
00445|156|R|   Effect of selective serotonin reuptake inhibitors on bleeding risk in|6
00445|157|R|   patients with atrial fibrillation taking warfarin. Am J Cardiol 2014;|6
00445|158|R|   114(4):583-586.|6
00445|159|R|19.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
00445|160|R|   Use of selective serotonin reuptake inhibitors and risk of upper|2
00445|161|R|   gastrointestinal tract bleeding: a population-based cohort study. Arch|2
00445|162|R|   Intern Med 2003 Jan 13;163(1):59-64.|2
00445|163|R|20.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
00445|164|R|   serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
00445|165|R|   population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
00445|166|R|21.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00445|167|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00445|168|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
00445|169|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00445|170|R|22.Claire RJ, Servis ME, Cram DL Jr. Potential interaction between warfarin|2
00445|171|R|   sodium and fluoxetine. Am J Psychiatry 1991 Nov;148(11):1604.|2
00445|172|R|23.Woolfrey S, Gammack NS, Dewar MS, Brown PJ. Fluoxetine-warfarin|3
00445|173|R|   interaction. BMJ 1993 Jul 24;307(6898):241.|3
00445|174|R|24.Wilner KD, Lazar LD, Apseloff G, Gerber N, Yurkewick L. The effects of|4
00445|175|R|   sertraline on the pharmacodynamics of warfarin in healthy volunteers.|4
00445|176|R|   Biol Psychiatry 1991;29:354S.|4
00445|177|R|25.Glueck CJ, Khalil Q, Winiarska M, Wang P. Interaction of duloxetine and|3
00445|178|R|   warfarin causing severe elevation of international normalized ratio. JAMA|3
00445|179|R|   2006 Apr 5;295(13):1517-8.|3
00446|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Selected Anticonvulsants|
00446|002|B||
00446|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00446|004|L|of severe adverse interaction.|
00446|005|B||
00446|006|A|MECHANISM OF ACTION:  Carbamazepine is a strong inducer of CYP3A4;|
00446|007|A|oxcarbazepine and rufinamide are weak inducers of CYP3A4.(1)|
00446|008|B||
00446|009|E|CLINICAL EFFECTS:  Concurrent use with carbamazepine, oxcarbazepine or|
00446|010|E|rufinamide may result in decreased contraceptive levels, which may result in|
00446|011|E|menstrual abnormalities or unintended pregnancy.|
00446|012|B||
00446|013|P|PREDISPOSING FACTORS:  Intermittent compliance with oral contraceptives.|
00446|014|B||
00446|015|M|PATIENT MANAGEMENT:  To avoid pregnancy, additional or alternative means of|
00446|016|M|non-hormonal contraception should be utilized.|
00446|017|M|   If larger doses of hormonal contraceptives are utilized, titrating the|
00446|018|M|dose against a response such as lack of spotting or breakthrough bleeding|
00446|019|M|may not guarantee contraceptive efficacy.|
00446|020|M|   In women who wish to continue oral contraceptives with the addition of a|
00446|021|M|second form of contraception, emphasize the importance of not missing doses|
00446|022|M|of the oral contraceptive.|
00446|023|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
00446|024|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
00446|025|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
00446|026|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
00446|027|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
00446|028|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
00446|029|M|and to seek medical advice if they do become pregnant.|
00446|030|B||
00446|031|D|DISCUSSION:  In a study of four epileptic patients receiving an oral|
00446|032|D|contraceptive containing ethinyl estradiol 50 mcg plus levonorgestrel 250|
00446|033|D|mcg carbamazepine reduced the area-under-curve (AUC) for ethinyl estradiol|
00446|034|D|by 42% and for levonorgestrel by 40%. Pregnancy has been reported.|
00446|035|D|   Pregnancy has been reported in a woman receiving low-dose oral|
00446|036|D|contraceptives six weeks after initiation of treatment with carbamazepine.|
00446|037|D|   In a randomized, open label study, concurrent administration of|
00446|038|D|carbamazepine (600 mg daily) and Ortho Novum 1/35 (ethinyl estradiol,|
00446|039|D|norethindrone) decreased the AUC of ethinyl estradiol and norethindrone by|
00446|040|D|42% and 58%, respectively.  The apparent oral clearance of ethinyl estradiol|
00446|041|D|and norethindrone increased by 127% and 69%, respectively.|
00446|042|D|   Concurrent use of rufinamide (800 mg twice daily) and ethinyl estradiol /|
00446|043|D|norethindrone (35 mcg/1 mg) for 14 days decreased the AUC of ethinyl|
00446|044|D|estradiol and norethindrone by 22% and 14%, respectively.  The maximum|
00446|045|D|concentration (Cmax) of ethinyl estradiol and norethindrone decreased by 31%|
00446|046|D|and 18%, respectively.|
00446|047|D|   Double-blind, randomized, crossover study with 24 women (only 20|
00446|048|D|analyzed) given 20 micrograms ethinyl estradiol and 100 micrograms|
00446|049|D|levonorgestrel and either carbamazepine 600 mg or a matched placebo for 4|
00446|050|D|months.  Ethinyl estradiol and levonorgestrel levels were measured and mean|
00446|051|D|AUC was significantly lower in  those taking carbamazepine.  Cmax of ethinyl|
00446|052|D|estradiol was also significantly decreased.  Additionally more cases of|
00446|053|D|breakthrough bleeding and ovulation occurred with concurrent use of the|
00446|054|D|carbamazepine.|
00446|055|D|   In a case report, a patient with an etonogestrel implant became pregnant|
00446|056|D|while taking carbamazepine for epilepsy.|
00446|057|D|   Coadministration of immediate-release oxcarbazepine decreased mean|
00446|058|D|ethinyl estradiol AUC levels in two different studies by 48% and 52%,|
00446|059|D|respectively.  Additionally, mean AUC of levonorgestrel was decreased in two|
00446|060|D|different studies by 32% and 52%, respectively.|
00446|061|B||
00446|062|R|REFERENCES:|
00446|063|B||
00446|064|R|1.This information is based on an extract from the Certara Drug Interaction|6
00446|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00446|066|R|2.Rapport DJ, Calabrese JR. Interactions between carbamazepine and birth|3
00446|067|R|  control pills. Psychosomatics 1989 Fall;30(4):462-4.|3
00446|068|R|3.Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M. The|2
00446|069|R|  interaction of phenytoin and carbamazepine with combined oral|2
00446|070|R|  contraceptive steroids. Br J Clin Pharmacol 1990 Dec;30(6):892-6.|2
00446|071|R|4.Nor-Q-D (norethindrone) US prescribing information. WatsonPharma March,|1
00446|072|R|  2005.|1
00446|073|R|5.Doose DR, Wang SS, Padmanabhan M, Schwabe S, Jacobs D, Bialer M. Effect of|2
00446|074|R|  topiramate or carbamazepine on the pharmacokinetics of an oral|2
00446|075|R|  contraceptive containing norethindrone and ethinyl estradiol in healthy|2
00446|076|R|  obese and nonobese female subjects. Epilepsia 2003 Apr;44(4):540-9.|2
00446|077|R|6.Inovelon (rufinamide) UK summary of product characteristics. Eisai Limited|1
00446|078|R|  January 16, 2007.|1
00446|079|R|7.Banzel (rufinamide) US prescribing information. Eisai Inc. November, 2019.|1
00446|080|R|8.Davis AR, Westhoff CL, Stanczyk FZ. Carbamazepine coadministration with an|2
00446|081|R|  oral contraceptive: Effects on steroid pharmacokinetics, ovulation, and|2
00446|082|R|  bleeding. Epilepsia 2011 Jan 4.|2
00446|083|R|9.Wilbur K, Ensom MH. Pharmacokinetic drug interactions between oral|6
00446|084|R|  contraceptives and second-generation anticonvulsants. Clin Pharmacokinet|6
00446|085|R|  2000 Apr;38(4):355-65.|6
00446|086|R|10.Reddy DS. Clinical pharmacokinetic interactions between antiepileptic|6
00446|087|R|   drugs and hormonal contraceptives. Expert Rev Clin Pharmacol 2010 Mar 1;|6
00446|088|R|   3(2):183-192.|6
00446|089|R|11.Schindlbeck C, Janni W, Friese K. Failure of Implanon contraception in a|3
00446|090|R|   patient taking carbamazepin for epilepsia. Arch Gynecol Obstet 2006 Jan;|3
00446|091|R|   273(4):255-6.|3
00446|092|R|12.Oxtellar XR (oxcarbazepine) extended-release US prescribing information.|1
00446|093|R|   Supernus, Inc. December, 2018.|1
00446|094|R|13.Medicines and Healthcare products Regulatory Agency.|1
00446|095|R|   Levonorgestrel-containing emergency hormonal contraception: advice on|1
00446|096|R|   interactions with hepatic enzyme inducers and contraceptive efficacy.|1
00446|097|R|   available at:|1
00446|098|R|   https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency|1
00446|099|R|   -hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-induce|1
00446|100|R|   rs-and-contraceptive-efficacy September 15, 2016..|1
00447|001|T|MONOGRAPH TITLE:  Hydantoins/Fluoxetine|
00447|002|B||
00447|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00447|004|L|take action as needed.|
00447|005|B||
00447|006|A|MECHANISM OF ACTION:  Hydantoins are metabolized by CYP2C9 and 2C19.(1)|
00447|007|A|Fluoxetine is a moderate inhibitor of CYP2C19.(2)|
00447|008|B||
00447|009|E|CLINICAL EFFECTS:  The pharmacological and toxic effects of hydantoins may|
00447|010|E|be increased due to elevated plasma hydantoin concentrations.(1,3) Phenytoin|
00447|011|E|has a narrow therapeutic range. Early symptoms of phenytoin toxicity may|
00447|012|E|include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy,|
00447|013|E|slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may|
00447|014|E|produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction|
00447|015|E|and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may|
00447|016|E|be fatal.|
00447|017|B||
00447|018|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
00447|019|P|hypoalbuminemia.|
00447|020|B||
00447|021|M|PATIENT MANAGEMENT:  Serum hydantoin concentrations should be monitored and|
00447|022|M|the patient should be observed for changes in seizure control if therapy|
00447|023|M|with fluoxetine is started, stopped or altered.|
00447|024|M|   Monitor patients for hydantoin toxicity if fluoxetine treatment is|
00447|025|M|started or if dose is increased (e.g. nystagmus, ataxia, dysarthria, tremor,|
00447|026|M|hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and|
00447|027|M|vomiting). Adjust the hydantoin dose as indicated.|
00447|028|M|   If long term fluoxetine therapy is discontinued, the hydantoin|
00447|029|M|concentration may decrease.  As fluoxetine is slowly eliminated over 4 to 6|
00447|030|M|weeks after discontinuation, extended monitoring for potential hydantoin|
00447|031|M|dosage increases is recommended.(3)|
00447|032|B||
00447|033|D|DISCUSSION:  In one case, a patient stabilized on phenytoin for two months|
00447|034|D|developed elevated phenytoin serum concentrations (133% increase) as well as|
00447|035|D|signs and symptoms of phenytoin toxicity within 5 days of starting|
00447|036|D|fluoxetine.|
00447|037|D|   In another case, a patient stabilized on phenytoin for one year had a|
00447|038|D|309% increase in plasma phenytoin concentration and signs of phenytoin|
00447|039|D|toxicity 10 days after initiation of treatment with fluoxetine. Similar|
00447|040|D|cases have been reported to the FDA through the Spontaneous Reporting|
00447|041|D|System.|
00447|042|B||
00447|043|R|REFERENCES:|
00447|044|B||
00447|045|R|1.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
00447|046|R|  March, 2022.|1
00447|047|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
00447|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
00447|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
00447|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
00447|051|R|  11/14/2017.|1
00447|052|R|3.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
00447|053|R|  and Company August, 2023.|1
00447|054|R|4.Jalil P. Toxic reaction following the combined administration of|3
00447|055|R|  fluoxetine and phenytoin: two case reports. J Neurol Neurosurg Psychiatry|3
00447|056|R|  1992 May;55(5):412-3.|3
00447|057|R|5.Woods DJ, Coulter DM, Pillans P. Interaction of phenytoin and fluoxetine.|3
00447|058|R|  N Z Med J 1994 Jan 26;107(970):19.|3
00448|001|T|MONOGRAPH TITLE:  Midazolam/Macrolide Antibiotics|
00448|002|B||
00448|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00448|004|L|take action as needed.|
00448|005|B||
00448|006|A|MECHANISM OF ACTION:  Macrolides may inhibit the metabolism of midazolam|
00448|007|A|through inhibition of CYP3A4.|
00448|008|B||
00448|009|E|CLINICAL EFFECTS:  Serum concentrations of midazolam may be increased,|
00448|010|E|enhancing its pharmacological effects.  Toxic effects of increased midazolam|
00448|011|E|levels include profound sedation, respiratory depression, coma, and/or|
00448|012|E|death.|
00448|013|B||
00448|014|P|PREDISPOSING FACTORS:  None determined.|
00448|015|B||
00448|016|M|PATIENT MANAGEMENT:  Patients should be cautioned about possible increased|
00448|017|M|sedation and observed for this side effect.  Decreasing the dose of|
00448|018|M|midazolam may be necessary.|
00448|019|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
00448|020|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
00448|021|M|unresponsiveness.|
00448|022|B||
00448|023|D|DISCUSSION:  In a study of 12 healthy volunteers, clarithromycin (250 mg|
00448|024|D|twice daily for 5 days) increased the area-under-curve (AUC) of oral|
00448|025|D|midazolam (15 mg) by 3.57-fold.(1)|
00448|026|D|   Sixteen elderly volunteers who received clarithromycin pre-treatment (500|
00448|027|D|mg twice daily for 7 days) had increases in the AUC of oral midazolam of|
00448|028|D|8-fold and of IV midazolam of 3.2-fold.(2)|
00448|029|D|   In a study involving 12 healthy volunteers, oral erythromycin (500 mg|
00448|030|D|three times daily for 7 days) was followed by a single oral 15 mg midazolam|
00448|031|D|dose.  Concomitant administration of erythromycin and oral midazolam|
00448|032|D|produced a decrease in midazolam clearance and an increase in the half-life|
00448|033|D|and serum concentration of midazolam, with an AUC increase of 4.4-fold.|
00448|034|D|Sedation produced by midazolam was pronounced and long-lasting.  When|
00448|035|D|midazolam was given IV, first-pass metabolism was avoided and the effects of|
00448|036|D|the interaction were less profound.  A single IV dose of 0.15 mg/kg|
00448|037|D|midazolam given after 1 week of erythromycin 500 mg three times daily|
00448|038|D|resulted in a 54% decrease in midazolam clearance.(3)|
00448|039|D|   Oral use of midazolam and IV erythromycin has been associated with|
00448|040|D|unconsciousness in an 8-year-old boy.(4,5)|
00448|041|D|   In a study of 10 healthy volunteers, roxithromycin (300 mg daily for 6|
00448|042|D|days) increased the AUC of oral midazolam (15 mg) by 1.5-fold.(6)|
00448|043|D|   Concurrent administration of telithromycin increased the AUC of IV and|
00448|044|D|oral midazolam by 2-fold and 6-fold, respectively.(7)|
00448|045|B||
00448|046|R|REFERENCES:|
00448|047|B||
00448|048|R|1.Yeates RA, Laufen H, Zimmermann T. Interaction between midazolam and|2
00448|049|R|  clarithromycin: comparison with azithromycin. Int J Clin Pharmacol Ther|2
00448|050|R|  1996 Sep;34(9):400-5.|2
00448|051|R|2.Quinney SK, Haehner BD, Rhoades MB, Lin Z, Gorski JC, Hall SD. Interaction|2
00448|052|R|  between midazolam and clarithromycin in the elderly. Br J Clin Pharmacol|2
00448|053|R|  2008 Jan;65(1):98-109.|2
00448|054|R|3.Olkkola KT, Aranko K, Luurila H, Hiller A, Saarnivaara L, Himberg JJ,|2
00448|055|R|  Neuvonen PJ. A potentially hazardous interaction between erythromycin and|2
00448|056|R|  midazolam. Clin Pharmacol Ther 1993 Mar;53(3):298-305.|2
00448|057|R|4.Hiller A, Olkkola KT, Isohanni P, Saarnivaara L. Unconsciousness|3
00448|058|R|  associated with midazolam and erythromycin. Br J Anaesth 1990 Dec;|3
00448|059|R|  65(6):826-8.|3
00448|060|R|5.Wood M. Midazolam and erythromycin. Br J Anaesth 1991 Jul;67(1):131.|6
00448|061|R|6.Backman JT, Aranko K, Himberg JJ, Olkkola KT. A pharmacokinetic|2
00448|062|R|  interaction between roxithromycin and midazolam. Eur J Clin Pharmacol|2
00448|063|R|  1994;46(6):551-5.|2
00448|064|R|7.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
00448|065|R|  November, 2015.|1
00449|001|T|MONOGRAPH TITLE:  Tacrine/Cimetidine|
00449|002|B||
00449|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00449|004|L|of severe adverse interaction.|
00449|005|B||
00449|006|A|MECHANISM OF ACTION:  Cimetidine appears to inhibit the activity of CYP|
00449|007|A|P-450-IA2, which is involved with the metabolism of tacrine.|
00449|008|B||
00449|009|E|CLINICAL EFFECTS:  Serum tacrine concentrations may be elevated increasing|
00449|010|E|the pharmacological and toxic effects of tacrine.|
00449|011|B||
00449|012|P|PREDISPOSING FACTORS:  None determined.|
00449|013|B||
00449|014|M|PATIENT MANAGEMENT:  When possible use an alternative H-2 antagonist. This|
00449|015|M|interaction would not be expected to occur with other H-2 antagonists (e.g.,|
00449|016|M|ranitidine). Monitor serum transaminase levels (specifically ALT/SGPT)|
00449|017|M|weekly for at least 6 weeks if cimetidine is started in a patient who is|
00449|018|M|receiving tacrine and observe the patient for a change in therapeutic|
00449|019|M|response. If both drugs are being started at the same time, or if the|
00449|020|M|patient is receiving cimetidine when tacrine is being started, give a|
00449|021|M|conservative dose of tacrine and monitor serum transaminase levels|
00449|022|M|accordingly. In all instances, observe the clinical response of the patient|
00449|023|M|and adjust the dose of tacrine as needed.|
00449|024|B||
00449|025|D|DISCUSSION:  Documentation of this interaction consists of data on file with|
00449|026|D|the manufacturer of tacrine. Concurrent administration of tacrine and|
00449|027|D|cimetidine increased the area under the tacrine plasma concentration-time|
00449|028|D|curve and maximum plasma tacrine concentration by approximately 64% and 54%|
00449|029|D|respectively. In order to minimize the occurrence of tacrine side effects|
00449|030|D|when starting tacrine in a patient who is receiving cimetidine, monitor|
00449|031|D|serum transaminase levels and observe the clinical response of the patient.|
00449|032|D|The dose of tacrine should be adjusted as indicated.|
00449|033|B||
00449|034|R|REFERENCES:|
00449|035|B||
00449|036|R|1.Cognex (tacrine) US prescribing information. Parke-Davis July, 1996.|1
00449|037|R|2.Brunton LL. Agents for control of gastric acidity and treatment of peptic|6
00449|038|R|  ulcers. In Gilman AG, Rall TW, Nies AS, Taylor P, editors: Goodman and|6
00449|039|R|  Gilman's The Phamacological Basis of Therapeutics. 8th edition. Elmsford,|6
00449|040|R|  New York: Pergamon Press, Inc. 1990.|6
00450|001|T|MONOGRAPH TITLE:  Felbamate/Hydantoins; Phenobarbital (mono deleted|
00450|002|T|04/17/2014)|
00450|003|B||
00450|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00450|005|L|take action as needed.|
00450|006|B||
00450|007|A|MECHANISM OF ACTION:  Felbamate may inhibit the metabolism of hydantoins and|
00450|008|A|phenobarbital. In addition, the metabolism of felbamate may be increased by|
00450|009|A|phenytoin and phenobarbital.|
00450|010|B||
00450|011|E|CLINICAL EFFECTS:  The pharmacological and toxic effects of hydantoins|
00450|012|E|and/or phenobarbital may be increased due to elevated plasma concentrations,|
00450|013|E|while the pharmacological effects of felbamate may be reduced as a result of|
00450|014|E|decreased serum felbamate concentrations.|
00450|015|B||
00450|016|P|PREDISPOSING FACTORS:  None determined.|
00450|017|B||
00450|018|M|PATIENT MANAGEMENT:  The US manufacturer of felbamate recommends that the|
00450|019|M|dosage of phenobarbital and phenytoin be reduced by 20-33% when felbamate is|
00450|020|M|initiated.(1)|
00450|021|M|   Serum concentrations of both drugs should be monitored and patients|
00450|022|M|should be observed for changes in seizure control if therapy with either|
00450|023|M|agent is started, stopped or altered.  Adjust therapy as indicated.  Observe|
00450|024|M|patients for hydantoin and/or phenobarbital toxicity if felbamate is|
00450|025|M|started.|
00450|026|B||
00450|027|D|DISCUSSION:  In a study in 10 patients with epilepsy maintained on phenytoin|
00450|028|D|therapy, phenytoin minimum concentration (Cmin) increased by 24% and 47%|
00450|029|D|following the addition of felbamate at dosages of 1200 mg/day and 1800|
00450|030|D|mg/day, respectively.  Phenytoin dosage reductions of 40% were necessary in|
00450|031|D|8 of the 10 subjects in order to achieve a felbamate dosage of 3600 mg/day|
00450|032|D|while limiting adverse effects and maintain phenytoin levels.|
00450|033|D|   In another clinical trial, decreasing the dosage of phenytoin by 20% at|
00450|034|D|the initiation of felbamate therapy resulted in no significant changes in|
00450|035|D|phenytoin levels.|
00450|036|D|   Phenytoin has been shown to almost double the clearance of felbamate,|
00450|037|D|resulting in a 45% decrease in felbamate levels.|
00450|038|D|   In a study in 12 healthy males, administration of felbamate (2400 mg|
00450|039|D|daily) increased phenobarbital levels by 25%.|
00450|040|D|   In a study in 24 healthy subjects, administration of felbamate (2400 mg|
00450|041|D|daily) increased phenobarbital (100 mg daily) area-under-curve (AUC) and|
00450|042|D|maximum concentration (Cmax) levels by 22% and 24%, respectively.|
00450|043|D|   In clinical trials, patients receiving concurrent phenobarbital were|
00450|044|D|found to have felbamate concentrations that were 29% lower than patients not|
00450|045|D|receiving concurrent phenobarbital.  In contrast, a retrospective review of|
00450|046|D|felbamate levels found no effect by barbiturates.|
00450|047|D|   In a case report, felbamate was initiated and titrated to 50 mg/kg/day|
00450|048|D|over three weeks.  At this time, the patient's phenobarbital dosage was|
00450|049|D|decreased 13% (from 230 mg/daily to 200 mg/day).  Despite this, the|
00450|050|D|patient's phenobarbital level increased 42% and the patient developed|
00450|051|D|neurotoxicity.  The patient's phenobarbital dosage was further reduced to|
00450|052|D|35% of the original dosage (to 150 mg daily) and the patient's phenobarbital|
00450|053|D|levels returned to therapeutic range.|
00450|054|B||
00450|055|R|REFERENCES:|
00450|056|B||
00450|057|R|1.Felbatrol (felbamate) US prescribing information. MedPoint Pharmaceuticals|1
00450|058|R|  Inc. August 27, 2012.|1
00450|059|R|2.Fuerst RH, Graves NM, Leppik IE, Brundage RC, Holmes GB, Remmel RP.|3
00450|060|R|  Felbamate increases phenytoin but decreases carbamazepine concentrations.|3
00450|061|R|  Epilepsia 1988 Jul-Aug;29(4):488-91.|3
00450|062|R|3.Graves NM, Holmes GB, Fuerst RH, Leppik IE. Effect of felbamate on|2
00450|063|R|  phenytoin and carbamazepine serum concentrations. Epilepsia 1989 Mar-Apr;|2
00450|064|R|  30(2):225-9.|2
00450|065|R|4.Wagner ML, Graves NM, Marienau K, Holmes GB, Remmel RP, Leppik IE.|2
00450|066|R|  Discontinuation of phenytoin and carbamazepine in patients receiving|2
00450|067|R|  felbamate. Epilepsia 1991 May-Jun;32(3):398-406.|2
00450|068|R|5.Reidenberg P, Glue P, Banfield CR, Colucci RD, Meehan JW, Radwanski E,|2
00450|069|R|  Mojavarian P, Lin CC, Nezamis J, Guillaume M, et al. Effects of felbamate|2
00450|070|R|  on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995 Sep;|2
00450|071|R|  58(3):279-87.|2
00450|072|R|6.Kelley MT, Walson PD, Cox S, Dusci LJ. Population pharmacokinetics of|2
00450|073|R|  felbamate in children. Ther Drug Monit 1997 Feb;19(1):29-36.|2
00450|074|R|7.Gidal BE, Zupanc ML. Potential pharmacokinetic interaction between|3
00450|075|R|  felbamate and phenobarbital. Ann Pharmacother 1994 Apr;28(4):455-8.|3
00451|001|T|MONOGRAPH TITLE:  Theophyllines/Tacrine|
00451|002|B||
00451|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00451|004|L|of severe adverse interaction.|
00451|005|B||
00451|006|A|MECHANISM OF ACTION:  Unknown. However, tacrine alters the elimination of|
00451|007|A|theophylline.|
00451|008|B||
00451|009|E|CLINICAL EFFECTS:  Serum theophylline concentrations may be elevated,|
00451|010|E|increasing the pharmacological and toxic effects of theophylline.|
00451|011|B||
00451|012|P|PREDISPOSING FACTORS:  None determined.|
00451|013|B||
00451|014|M|PATIENT MANAGEMENT:  In patients receiving theophylline, monitor serum|
00451|015|M|theophylline concentrations and observe the patient for a change in|
00451|016|M|therapeutic response if tacrine therapy is initiated or discontinued. If|
00451|017|M|both drugs are being started at the same time, or if the patient is|
00451|018|M|receiving tacrine when theophylline is being started, reduce the dose of|
00451|019|M|theophylline by 25% to 50% and monitor serum theophylline concentrations. In|
00451|020|M|all instances, adjust the dose of theophylline accordingly.|
00451|021|B||
00451|022|D|DISCUSSION:  Documentation for this interaction consists of data on file|
00451|023|D|with the manufacturer of tacrine. Concurrent administration of tacrine and|
00451|024|D|theophylline produced a twofold increase in theophylline elimination|
00451|025|D|half-life and average plasma theophylline concentrations. In order to|
00451|026|D|minimize the occurrence of the theophylline toxicity when starting tacrine|
00451|027|D|in a patient who is receiving theophylline, monitor serum theophylline|
00451|028|D|concentrations and observe the patient for signs and symptoms of|
00451|029|D|theophylline toxicity which may include tachycardia, anorexia, diarrhea,|
00451|030|D|insomnia, restlessness and headache. Other symptoms of toxicity are extreme|
00451|031|D|thirst, agitation, frequent vomiting, arrhythmias, delirium, hyperthermia|
00451|032|D|and diaphoresis. Seizures may occur and may result in death.|
00451|033|B||
00451|034|R|REFERENCES:|
00451|035|B||
00451|036|R|1.Cognex (tacrine) US prescribing information. Parke-Davis July, 1996.|1
00451|037|R|2.de Vries TM, Siedlik P, Smithers JA, Brown RR, Reece PA, Posvar EL, Sedman|4
00451|038|R|  AJ, Koup JR, Forgue ST. Effect of multiple-dose tacrine administration on|4
00451|039|R|  single-dose pharmacokinetics of digoxin, diazepam, and theophylline. Pharm|4
00451|040|R|  Res 1993;10(10):S-333.|4
00452|001|T|MONOGRAPH TITLE:  Cyclosporine/Barbiturates (mono deleted 11/01/2012)|
00452|002|B||
00452|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00452|004|L|of severe adverse interaction.|
00452|005|B||
00452|006|A|MECHANISM OF ACTION:  Probably due to increased hepatic metabolism of|
00452|007|A|cyclosporine.|
00452|008|B||
00452|009|E|CLINICAL EFFECTS:  The pharmacological effects of cyclosporine may be|
00452|010|E|reduced.|
00452|011|B||
00452|012|P|PREDISPOSING FACTORS:  None determined.|
00452|013|B||
00452|014|M|PATIENT MANAGEMENT:  Observe the patient for a change in clinical response|
00452|015|M|if the dose of the barbiturate is altered or if barbiturate therapy is|
00452|016|M|initiated or discontinued. If a patient has been receiving barbiturates|
00452|017|M|chronically and cyclosporine is started, it may be necessary to administer a|
00452|018|M|higher than usual dose of cyclosporine.|
00452|019|B||
00452|020|D|DISCUSSION:  Documentation supporting this interaction is limited to case|
00452|021|D|histories. Serum cyclosporine concentrations were very low during|
00452|022|D|administration of phenobarbital and increased after phenobarbital was|
00452|023|D|discontinued.|
00452|024|B||
00452|025|R|REFERENCES:|
00452|026|B||
00452|027|R|1.Ptachcinski RJ, Venkataramanan R, Rosenthal JT, Burckart GJ, Taylor RJ,|2
00452|028|R|  Hakala TR. Cyclosporine kinetics in renal transplantation. Clin Pharmacol|2
00452|029|R|  Ther 1985 Sep;38(3):296-300.|2
00452|030|R|2.Carstensen H, Jacobsen N, Dieperink H. Interaction between cyclosporin A|3
00452|031|R|  and phenobarbitone. Br J Clin Pharmacol 1986 May;21(5):550-1.|3
00452|032|R|3.Noguchi M, Kiuchi C, Akiyama H, Sakamaki H, Onozawa Y. Interaction between|3
00452|033|R|  cyclosporin A and anticonvulsants. Bone Marrow Transplantation Team. Bone|3
00452|034|R|  Marrow Transplant 1992 May;9(5):391.|3
00453|001|T|MONOGRAPH TITLE:  Select Azole Antifungal Agents/Coumarin Anticoagulants|
00453|002|B||
00453|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00453|004|L|of severe adverse interaction.|
00453|005|B||
00453|006|A|MECHANISM OF ACTION:  The more potent warfarin S-enantiomer is metabolized|
00453|007|A|by CYP2C9 while the weaker R-enantiomer is metabolized by CYP1A2 and CYP3A4.|
00453|008|A|   Miconazole is a moderate-strong inhibitor of CYP2C9; fluconazole is a|
00453|009|A|moderate inhibitor of CYP2C9 and CYP3A4; voriconazole and ketoconazole are|
00453|010|A|both weak inhibitors of CYP2C9 and strong inhibitors of CYP3A4.|
00453|011|B||
00453|012|E|CLINICAL EFFECTS:  Concurrent use of select azole antifungals and coumarin|
00453|013|E|anticoagulants may increase the risk for bleeding.|
00453|014|B||
00453|015|P|PREDISPOSING FACTORS:  The antifungal dose and inhibitory potency,|
00453|016|P|particularly for CYP2C9, are drug factors which affect the magnitude of this|
00453|017|P|interaction.|
00453|018|P|   The risk for bleeding episodes may be greater in patients with|
00453|019|P|disease-associated factors (e.g. thrombocytopenia).|
00453|020|P|   Additional drug associated risk factors include concurrent use of|
00453|021|P|multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or|
00453|022|P|have an inherent risk for bleeding (e.g. NSAIDs).|
00453|023|P|   Azole antifungal inhibition of CYP2C9, may increase the risk of|
00453|024|P|conversion to the CYP2C9 poor metabolizer phenotype.  Patients with CYP2C9|
00453|025|P|intermediate metabolizer genotype are expected to be the most susceptible to|
00453|026|P|this phenoconversion.|
00453|027|P|   Patients with a pre-existing CYP2C9 poor metabolizer genotype would be|
00453|028|P|less susceptible to this interaction.  However, patients with reduced|
00453|029|P|function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) have an|
00453|030|P|inherently higher risk for bleeding at usual anticoagulant doses and thus|
00453|031|P|generally require lower doses to achieve effective and safe anticoagulation.|
00453|032|P|In addition, CYP2C9 poor metabolizers require more a prolonged time (>2 to|
00453|033|P|4 weeks) to achieve maximum INR effect for a given dosage regimen than|
00453|034|P|patients without these CYP2C9 variants.|
00453|035|B||
00453|036|M|PATIENT MANAGEMENT:  In patients receiving warfarin when fluconazole,|
00453|037|M|voriconazole, miconazole or ketoconazole is started, anticipate the need for|
00453|038|M|a dose reduction. Check the baseline INR then closely monitor and adjust the|
00453|039|M|dose of warfarin until the INR has stabilized on the combination.  After the|
00453|040|M|azole therapy is discontinued, close monitoring is again needed as the INR|
00453|041|M|may fall after removal of the inhibitor.|
00453|042|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
00453|043|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
00453|044|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
00453|045|M|patients with any symptoms.  Discontinue anticoagulation in patients with|
00453|046|M|active pathologic bleeding.|
00453|047|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00453|048|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00453|049|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00453|050|M|and/or swelling.|
00453|051|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00453|052|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00453|053|M|initiating, altering the dose or discontinuing either drug.|
00453|054|B||
00453|055|D|DISCUSSION:  Selected azole antifungal agents can cause an increase in the|
00453|056|D|anticoagulant effects of warfarin.  The drug-related risk is dependent on|
00453|057|D|the specific azole, dose and route.|
00453|058|D|   A large systematic review was performed on 72 warfarin drug-drug|
00453|059|D|interactions studies that reported on bleeding, thromboembolic events, or|
00453|060|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 11 of|
00453|061|D|those studies found a higher rate of clinically significant bleeding in|
00453|062|D|patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83).|
00453|063|D|Increased bleeding risk was also seen in subgroup analyses with azole|
00453|064|D|antifungals (OR=1.86; 95% CI 1.40-2.47).|
00453|065|D|   A retrospective review compared the changes in warfarin effects with|
00453|066|D|coadministration of fluconazole, itraconazole, or voriconazole in 18, 6, and|
00453|067|D|5 patients, respectively.  Mean INR increased from 1.4 to 2.94 in patients|
00453|068|D|taking fluconazole (p<0.001) and increased >20% in 15 out of 18 patients.|
00453|069|D|Mean INR increased from 1.95 to 2.89 in patients taking voriconazole|
00453|070|D|(p<0.05) and increased >20% in 4 out of 5 patients.  Mean INR increased|
00453|071|D|slightly from 1.86 to 1.92 in patients taking itraconazole (p=0.37) and did|
00453|072|D|not increase >20% in any patient.|
00453|073|D|   In healthy subjects, the administration of voriconazole (300 mg every 12|
00453|074|D|hours for 12 days) prior to warfarin (30 mg single dose) doubled the|
00453|075|D|prothrombin time when compared to warfarin plus placebo.|
00453|076|D|   A large epidemiologic study evaluated the risk for hospitalization due to|
00453|077|D|gastrointestinal (GI) bleeding in warfarin patients treated with or without|
00453|078|D|various anti-infective agents, including fluconazole.  Warfarin patients|
00453|079|D|treated with fluconazole had an approximately 2-fold increase in risk for|
00453|080|D|hospitalization due to a GI bleed compared with warfarin patients without|
00453|081|D|infection or warfarin patients receiving alternative anti-infective|
00453|082|D|treatment (e.g. cephalexin, amoxicillin).  This risk was highest in patients|
00453|083|D|who received fluconazole 6 to 15 days prior to admission, leading authors to|
00453|084|D|suggest this risk was due to a pharmacokinetic interaction between warfarin|
00453|085|D|and fluconazole, and not due to infection or infection sequelae (e.g. change|
00453|086|D|in diet or gut bacteria).|
00453|087|D|   A drug-drug interaction study was performed to evaluate the effect of a|
00453|088|D|single 150 mg dose of fluconazole on prothrombin times in 6 women who had|
00453|089|D|received warfarin therapy for at least 6 months and had stable, therapeutic|
00453|090|D|INRs.  Three of 6 women had an INR > 4 or had a bleeding episode: one woman|
00453|091|D|had an INR of 4.6 on day 2, one woman had an INR of 5.2 on day 5, and one|
00453|092|D|woman developed a subconjunctival hemorrhage in the absence of trauma or|
00453|093|D|physical straining on day 6 (INR = 3.4).|
00453|094|D|   Miconazole is the most potent known CYP2C9 inhibitor in vivo.  In an|
00453|095|D|interaction study in 6 healthy volunteers, oral miconazole 125 mg daily for|
00453|096|D|18 days increased warfarin exposure (AUC, area-under-curve) 4.7-fold.  Black|
00453|097|D|stools have been reported with warfarin and administration of miconazole|
00453|098|D|oral gel.|
00453|099|D|   Documentation for oral ketoconazole is less conclusive. However, as|
00453|100|D|ketoconazole is considered a moderate CYP2C9 inhibitor an interaction with|
00453|101|D|warfarin would be expected.|
00453|102|B||
00453|103|R|REFERENCES:|
00453|104|B||
00453|105|R|1.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
00453|106|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
00453|107|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
00453|108|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
00453|109|R|  Oct;90(4):625-9.|6
00453|110|R|2.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
00453|111|R|3.Turrentine MA. Single-dose fluconazole for vulvovaginal candidiasis:|2
00453|112|R|  impact on prothrombin time  in women taking warfarin. Obstet Gynecol 2006|2
00453|113|R|  Feb;107(2 Pt 1):310-3.|2
00453|114|R|4.Schelleman H, Bilker WB, Brensinger CM, Han X, Kimmel SE, Hennessy S.|2
00453|115|R|  Warfarin with fluoroquinolones, sulfonamides, or azole antifungals:|2
00453|116|R|  interactions  and the risk of hospitalization for gastrointestinal|2
00453|117|R|  bleeding. Clin Pharmacol Ther 2008 Nov;84(5):581-8.|2
00453|118|R|5.Yamamoto H, Habu Y, Yano I, Ozaki J, Kimura Y, Sato E, Shida A, Fukatsu S,|2
00453|119|R|  Matsubara K. Comparison of the effects of azole antifungal agents on the|2
00453|120|R|  anticoagulant activity of warfarin. Biol Pharm Bull 2014;37(12):1990-3.|2
00453|121|R|6.Smith AG. Potentiation of oral anticoagulants by ketoconazole. Br Med J|3
00453|122|R|  (Clin Res Ed) 1984 Jan 21;288(6412):188-9.|3
00453|123|R|7.O'Reilly RA, Goulart DA, Kunze KL, Neal J, Gibaldi M, Eddy AC, Trager WF.|2
00453|124|R|  Mechanisms of the stereoselective interaction between miconazole and|2
00453|125|R|  racemic warfarin in human subjects. Clin Pharmacol Ther 1992 Jun;|2
00453|126|R|  51(6):656-67.|2
00453|127|R|8.Colquhoun MC, Daly M, Stewart P, Beeley L. Interaction between warfarin|3
00453|128|R|  and miconazole oral gel. Lancet 1987 Mar 21;1(8534):695-6.|3
00453|129|R|9.Shenfield GM, Page M. Potentiation of warfarin action by miconazole oral|3
00453|130|R|  gel. Aust N Z J Med 1991 Dec;21(6):928.|3
00453|131|R|10.Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis|6
00453|132|R|   1990 Mar-Apr;12 Suppl 3:S327-33.|6
00453|133|R|11.Seaton TL, Celum CL, Black DJ. Possible potentiation of warfarin by|3
00453|134|R|   fluconazole. DICP 1990 Dec;24(12):1177-8.|3
00453|135|R|12.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00453|136|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00453|137|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
00453|138|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00454|001|T|MONOGRAPH TITLE:  Select Antipsychotics;Select|
00454|002|T|Phenothiazines/Anticholinergics|
00454|003|B||
00454|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00454|005|L|take action as needed.|
00454|006|B||
00454|007|A|MECHANISM OF ACTION:  Multiple mechanisms may be involved:|
00454|008|A|  1. additive peripheral and CNS blockade of muscarinic receptors.|
00454|009|A|  2. anticholinergic-induced inhibition of gastrointestinal absorption of|
00454|010|A|phenothiazines.|
00454|011|A|  3. antagonism of the dopamine blocking effects of selected antipsychotics|
00454|012|A|and phenothiazines.|
00454|013|B||
00454|014|E|CLINICAL EFFECTS:  The dopamine blocking effects of selected antipsychotic|
00454|015|E|agents or phenothiazines may be decreased while anticholinergic adverse|
00454|016|E|effects may be increased.|
00454|017|B||
00454|018|P|PREDISPOSING FACTORS:  The risk for severe anticholinergic toxicities, e.g.|
00454|019|P|delirium, hyperthermia, paralytic ileus is increased in the elderly and in|
00454|020|P|patients on multiple anticholinergic agents.|
00454|021|B||
00454|022|M|PATIENT MANAGEMENT:  Anticholinergic agents may be required to treat or|
00454|023|M|prevent antipsychotic induced extrapyramidal symptoms.|
00454|024|M|   When other indications lead to co-prescribing of the combination, assess|
00454|025|M|patient response to the combination.  Review patient medication list for|
00454|026|M|other anticholinergic agents. When needed, decrease the dosage or number of|
00454|027|M|prescribed anticholinergic agents, particularly in the elderly.|
00454|028|B||
00454|029|D|DISCUSSION:  Although numerous studies have been published regarding a|
00454|030|D|possible interaction between phenothiazines and anticholinergics, the|
00454|031|D|earlier reports were not double-blind or placebo controlled and patients may|
00454|032|D|have received other drugs concomitantly. These earlier investigations|
00454|033|D|reported increased side effects as well as increased, decreased and no|
00454|034|D|effect on the therapeutic outcome. Double-blind studies have also reported|
00454|035|D|conflicting results. Anticholinergic therapy varied from having no effect on|
00454|036|D|phenothiazine concentration or patient outcome, to increasing phenothiazine|
00454|037|D|levels. The discrepancies reported may be due to interpatient variability|
00454|038|D|including age of the patient, type and duration of illness and treatment|
00454|039|D|setting.|
00454|040|B||
00454|041|R|REFERENCES:|
00454|042|B||
00454|043|R|1.Gershon S, Neubauer H, Sundland DM. Interaction between some|2
00454|044|R|  anticholinergic agents and phenothiazines. Potentiation of phenothiazine|2
00454|045|R|  sedation and its antagonism. Clin Pharmacol Ther 1965 Nov-Dec;6(6):749-56.|2
00454|046|R|2.Warnes H, Lehmann HE, Ban TA. Adynamic ileus during psychoactive|3
00454|047|R|  medication: a report of three fatal and five severe cases. Can Med Assoc J|3
00454|048|R|  1967 Apr 15;96(15):1112-3.|3
00454|049|R|3.Zelman S, Guillan R. Heat stroke in phenothiazine-treated patients: a|3
00454|050|R|  report of three fatalities. Am J Psychiatry 1970 Jun;126(12):1787-90.|3
00454|051|R|4.Singh MM, Smith JM. Reversal of some therapeutic effects of an|2
00454|052|R|  antipsychotic agent by an antiparkinsonism drug. J Nerv Ment Dis 1973 Jul;|2
00454|053|R|  157(1):50-8.|2
00454|054|R|5.Rivera-Calimlim L, Castaneda L, Lasagna L. Effects of mode of management|3
00454|055|R|  on plasma chlorpromazine in psychiatric patients. Clin Pharmacol Ther 1973|3
00454|056|R|  Nov-Dec;14(6):978-86.|3
00454|057|R|6.Loga S, Curry S, Lader M. Interactions of orphenadrine and phenobarbitone|2
00454|058|R|  with chlorpromazine: plasma concentrations and effects in man. Br J Clin|2
00454|059|R|  Pharmacol 1975 Jun;2(3):197-208.|2
00454|060|R|7.Giordano J, Canter JW, Huang A. Fatal paralytic ileus complicating|3
00454|061|R|  phenothiazine therapy. South Med J 1975 Mar;68(3):351-3.|3
00454|062|R|8.DiMascio A. Toward a more rational use of antiparkinson drugs in|6
00454|063|R|  psychiatry. Drug Ther 1971 Sep;1:23-9.|6
00454|064|R|9.Rivera-Calimlim L, Nasrallah H, Strauss J, Lasagna L. Clinical response|2
00454|065|R|  and plasma levels: effect of dose, dosage schedules, and drug interactions|2
00454|066|R|  on plasma chlorpromazine levels. Am J Psychiatry 1976 Jun;133(6):646-52.|2
00454|067|R|10.Kolakowska T, Wiles DH, Gelder MG, McNeilly AS. Clinical significance of|2
00454|068|R|   plasma chlorpromazine levels. II. Plasma levels of the drug, some of its|2
00454|069|R|   metabolites and prolactin in patients receiving long-term phenothiazine|2
00454|070|R|   treatment. Psychopharmacology (Berl) 1976 Aug 26;49(1):101-7.|2
00454|071|R|11.Chouinard G, Annable L, Cooper S. Antiparkinsonian drug administration|3
00454|072|R|   and plasma levels of penfluridol, a new long-acting neuroleptic. Commun|3
00454|073|R|   Psychopharmacol 1977;1(4):325-31.|3
00454|074|R|12.Mann SC, Boger WP. Psychotropic drugs, summer heat and humidity, and|3
00454|075|R|   hyperpyrexia: a danger restated. Am J Psychiatry 1978 Sep;|3
00454|076|R|   135(9):1097-1100.|3
00454|077|R|13.Simpson GM, Cooper TB, Bark N, Sud I, Lee JH. Effect of antiparkinsonian|2
00454|078|R|   medication on plasma levels of chlorpromazine. Arch Gen Psychiatry 1980|2
00454|079|R|   Feb;37(2):205-8.|2
00454|080|R|14.Rockland L, Cooper T, Schwartz F, Weber D, Sullivan T. Effects of|2
00454|081|R|   trihexyphenidyl on plasma chlorpromazine in young schizophrenics. Can J|2
00454|082|R|   Psychiatry 1990 Oct;35(7):604-7.|2
00454|083|R|15.Benztropine mesylate tablet US prescribing information. Bayshore|1
00454|084|R|   Pharmaceuticals LLC December, 2013.|1
00455|001|T|MONOGRAPH TITLE:  Quinine/Aluminum and Magnesium Antacids; Lanthanum|
00455|002|B||
00455|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00455|004|L|take action as needed.|
00455|005|B||
00455|006|A|MECHANISM OF ACTION:  Aluminum and magnesium antacids may delay or decrease|
00455|007|A|the absorption of quinine.|
00455|008|B||
00455|009|E|CLINICAL EFFECTS:  Concurrent use of antacids may result in decreased levels|
00455|010|E|and effectiveness of quinine.|
00455|011|B||
00455|012|P|PREDISPOSING FACTORS:  None determined.|
00455|013|B||
00455|014|M|PATIENT MANAGEMENT:  The US manufacturer of quinine states that concurrent|
00455|015|M|use with aluminum or magnesium containing antacids should be avoided.|
00455|016|M|   Some vitamin preparations may contain sufficient quantities of magnesium|
00455|017|M|salts with antacid properties to interact as well.|
00455|018|B||
00455|019|D|DISCUSSION:  Aluminum and magnesium antacids have been shown to decrease|
00455|020|D|quinine absorption in rats.|
00455|021|B||
00455|022|R|REFERENCES:|
00455|023|B||
00455|024|R|1.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
00455|025|R|  Industries, Inc. August, 2019.|1
00455|026|R|2.Hurwitz A. The effects of antacids on gastrointestinal drug absorption.|5
00455|027|R|  II. Effect on sulfadiazine and quinine. J Pharmacol Exp Ther 1971 Dec;|5
00455|028|R|  179(3):485-9.|5
00456|001|T|MONOGRAPH TITLE:  Sympathomimetics (Direct, Mixed-Acting)/Methyldopa|
00456|002|B||
00456|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00456|004|L|take action as needed.|
00456|005|B||
00456|006|A|MECHANISM OF ACTION:  Unknown.|
00456|007|B||
00456|008|E|CLINICAL EFFECTS:  The pressor response to sympathomimetics may be|
00456|009|E|increased.|
00456|010|B||
00456|011|P|PREDISPOSING FACTORS:  None determined.|
00456|012|B||
00456|013|M|PATIENT MANAGEMENT:  Start with low doses of sympathomimetics and monitor|
00456|014|M|blood pressure of patients during concurrent administration of|
00456|015|M|sympathomimetics and methyldopa.|
00456|016|B||
00456|017|D|DISCUSSION:  The pressor response to sympathomimetics has been reported to|
00456|018|D|be increased during methyldopa administration. In addition to increased|
00456|019|D|duration of pressor response, severe hypertension has been reported.|
00456|020|B||
00456|021|R|REFERENCES:|
00456|022|B||
00456|023|R|1.Pettinger W, Horwitz D, Spector S, Sjoerdsma A. Enhancement by methyldopa|2
00456|024|R|  of tyramine sensitivity in man. Nature 1963 Dec 14;200(4911):1107-8.|2
00456|025|R|2.Dollery CT, Harington M, Hodge JV. Haemodynamic studies with methyldopa:|2
00456|026|R|  effect on cardiac output and response to pressor amines. Br Heart J 1963;|2
00456|027|R|  25(5):670-6.|2
00456|028|R|3.Dollery CT. Physiological and pharmacological interactions of|6
00456|029|R|  antihypertensive drugs. Proc R Soc Med 1965 Nov;58(11 Part 2):983-7.|6
00456|030|R|4.McLaren EH. Severe hypertension produced by interaction of|3
00456|031|R|  phenylpropanolamine with methyldopa and oxprenolol. Br Med J 1976 Jul 31;|3
00456|032|R|  2(6030):283-4.|3
00457|001|T|MONOGRAPH TITLE:  Tolbutamide/Sulfinpyrazone|
00457|002|B||
00457|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00457|004|L|take action as needed.|
00457|005|B||
00457|006|A|MECHANISM OF ACTION:  Sulfinpyrazone inhibits the hepatic metabolism of|
00457|007|A|tolbutamide.|
00457|008|B||
00457|009|E|CLINICAL EFFECTS:  The hypoglycemic effect of tolbutamide may be increased.|
00457|010|B||
00457|011|P|PREDISPOSING FACTORS:  None determined.|
00457|012|B||
00457|013|M|PATIENT MANAGEMENT:  Monitor blood glucose levels and adjust the dose of|
00457|014|M|tolbutamide as needed.|
00457|015|B||
00457|016|D|DISCUSSION:  This interaction has only been studied during concurrent|
00457|017|D|administration of oral sulfinpyrazone and of a single IV dose of|
00457|018|D|tolbutamide. Under these conditions, concurrent administration of|
00457|019|D|sulfinpyrazone and tolbutamide resulted in a 40% decrease in tolbutamide|
00457|020|D|clearance compared to giving tolbutamide alone.|
00457|021|B||
00457|022|R|REFERENCE:|
00457|023|B||
00457|024|R|1.Miners JO, Foenander T, Wanwimolruk S, Gallus AS, Birkett DJ. The effect|2
00457|025|R|  of sulphinpyrazone on oxidative drug metabolism in man: inhibition of|2
00457|026|R|  tolbutamide elimination. Eur J Clin Pharmacol 1982;22(4):321-6.|2
00458|001|T|MONOGRAPH TITLE:  Primidone/Hydantoins|
00458|002|B||
00458|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00458|004|L|take action as needed.|
00458|005|B||
00458|006|A|MECHANISM OF ACTION:  Unknown. However, phenytoin may enhance the metabolism|
00458|007|A|of primidone to phenobarbital and inhibit the metabolism of phenobarbital.|
00458|008|B||
00458|009|E|CLINICAL EFFECTS:  Serum phenobarbital concentrations may be increased.|
00458|010|B||
00458|011|P|PREDISPOSING FACTORS:  None determined.|
00458|012|B||
00458|013|M|PATIENT MANAGEMENT:  Monitor serum phenobarbital levels and observe patients|
00458|014|M|for signs of phenobarbital excess when starting, stopping or altering|
00458|015|M|hydantoin treatment in patients receiving primidone.|
00458|016|B||
00458|017|D|DISCUSSION:  In vivo, primidone is converted to phenobarbital. Concurrent|
00458|018|D|administration of primidone and phenytoin results in higher serum|
00458|019|D|phenobarbital concentrations than administration of primidone alone or|
00458|020|D|primidone plus phenobarbital. Phenobarbital toxicity has been reported in an|
00458|021|D|infant receiving primidone and phenytoin concomitantly.|
00458|022|B||
00458|023|R|REFERENCES:|
00458|024|B||
00458|025|R|1.Gallagher BB, Baumel IP, Mattson RH, Woodbury SG. Primidone,|2
00458|026|R|  diphenylhydantoin and phenobarbital. Aspects of acute and chronic|2
00458|027|R|  toxicity. Neurology 1973 Feb;23(2):145-9.|2
00458|028|R|2.Wilson JT, Wilkinson GR. Chronic and severe phenobarbital intoxication in|3
00458|029|R|  a child treated with primidone and diphenylhydantoin. J Pediatr 1973 Sep;|3
00458|030|R|  83(3):484-9.|3
00458|031|R|3.Fincham RW, Schottelius DD, Sahs AL. The influence of diphenylhydantoin on|2
00458|032|R|  primidone metabolism. Arch Neurol 1974 Mar;30(3):259-62.|2
00458|033|R|4.Schmidt D. The effect of phenytoin and ethosuximide on primidone|2
00458|034|R|  metabolism in patients with epilepsy. J Neurol 1975 Jun 9;209(2):115-23.|2
00458|035|R|5.Reynolds EH, Fenton G, Fenwick P, Johnson AL, Laundy M. Interaction of|2
00458|036|R|  phenytoin and primidone. Br Med J 1975 Jun 14;2(5971):594-5.|2
00458|037|R|6.Callaghan N, Feely M, Duggan F, O'Callaghan M, Seldrup J. The effect of|2
00458|038|R|  anticonvulsant drugs which induce liver microsomal enzymes on derived and|2
00458|039|R|  ingested phenobarbitone levels. Acta Neurol Scand 1977 Jul;56(1):1-6.|2
00458|040|R|7.Garrettson LK, Gomez M. Phenytoin-primidone interaction. Br J Clin|3
00458|041|R|  Pharmacol 1977;4:693-5.|3
00458|042|R|8.Lambie DG, Johnson RH. The effects of phenytoin on phenobarbitone and|2
00458|043|R|  primidone metabolism. J Neurol Neurosurg Psychiatry 1981 Feb;44(2):148-51.|2
00458|044|R|9.Porro MG, Kupferberg HJ, Porter RJ, Theodore WH, Newmark ME. Phenytoin: an|3
00458|045|R|  inhibitor and inducer of primidone metabolism in an epileptic patient. Br|3
00458|046|R|  J Clin Pharmacol 1982 Aug;14(2):294-7.|3
00459|001|T|MONOGRAPH TITLE:  Theophylline/Barbiturates; Hydantoins|
00459|002|B||
00459|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00459|004|L|take action as needed.|
00459|005|B||
00459|006|A|MECHANISM OF ACTION:  Theophylline is primarily metabolized by CYP1A2 with|
00459|007|A|CYP3A4 playing a lesser role in theophylline clearance.(1) Hydantoins (e.g.|
00459|008|A|phenytoin) and barbiturates are inducers of both metabolic pathways.|
00459|009|A|   Primidone is metabolized to phenobarbital.|
00459|010|B||
00459|011|E|CLINICAL EFFECTS:  Concomitant treatment with barbiturates or hydantoins may|
00459|012|E|lower serum theophylline concentrations resulting in reduced pharmacologic|
00459|013|E|effects.|
00459|014|B||
00459|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00459|016|P|of the inducer for longer than 1-2 weeks.|
00459|017|B||
00459|018|M|PATIENT MANAGEMENT:  Monitor serum theophylline concentrations and observe|
00459|019|M|the patient for a change in the therapeutic effects of theophylline when|
00459|020|M|barbiturate or phenytoin therapy is initiated. The onset of induction is|
00459|021|M|gradual but may begin within one week. The time to maximal induction may be|
00459|022|M|2 or more weeks depending upon the half-life and dose of the inducer.|
00459|023|M|Adjust the dose of theophylline accordingly.|
00459|024|M|   If concomitant therapy with a barbiturate or hydantoin is discontinued,|
00459|025|M|theophylline levels will increase over a number of weeks depending upon the|
00459|026|M|elimination half-life of the barbiturate or hydantoin. Substantial lowering|
00459|027|M|of the theophylline dose may be required to prevent toxicity.  Check serum|
00459|028|M|theophylline levels and monitor for signs and symptoms of theophylline|
00459|029|M|toxicity.|
00459|030|B||
00459|031|D|DISCUSSION:  Data reported from infants, children and adults demonstrate|
00459|032|D|that therapeutic doses of barbiturates and hydantoins increase the clearance|
00459|033|D|of theophylline. There appears to be considerable interindividual|
00459|034|D|differences. In some patients the decrease in plasma theophylline|
00459|035|D|concentration may interfere with clinical management.|
00459|036|D|   Discontinuation of chronic barbiturate or hydantoin therapy in patients|
00459|037|D|stabilized on this combination will lead to increased theophylline levels as|
00459|038|D|induction wanes. Monitor closely as theophylline doses may need to be|
00459|039|D|lowered to prevent toxicity.|
00459|040|B||
00459|041|R|REFERENCES:|
00459|042|B||
00459|043|R|1.Levy RH Thummel KE Trager WF. Metabolic Drug Interactions (textbook).|6
00459|044|R|  Metabolic Drug Interactions 2000.|6
00459|045|R|2.Piafsky KM, Sitar DS, Ogilvie RI. Effect of phenobarbital on the|2
00459|046|R|  disposition of intravenous theophylline. Clin Pharmacol Ther 1977 Sep;|2
00459|047|R|  22(3):336-9.|2
00459|048|R|3.Landay RA, Gonzalez MA, Taylor JC. Effect of phenobarbital on theophylline|2
00459|049|R|  disposition. J Allergy Clin Immunol 1978 Jul;62(1):27-9.|2
00459|050|R|4.Paladino JA, Blumer NA, Maddox RR. Effect of secobarbital on theophylline|3
00459|051|R|  clearance. Ther Drug Monit 1983;5(1):135-9.|3
00459|052|R|5.Saccar CL, Danish M, Ragni MC, Rocci ML Jr, Greene J, Yaffe SJ, Mansmann|2
00459|053|R|  HC Jr. The effect of phenobarbital on theophylline disposition in children|2
00459|054|R|  with asthma. J Allergy Clin Immunol 1985 Jun;75(6):716-9.|2
00459|055|R|6.Gibson GA, Blouin RA, Bauer LA, Rapp RP, Tibbs PA. Influence of high-dose|3
00459|056|R|  pentobarbital on theophylline pharmacokinetics: a case report. Ther Drug|3
00459|057|R|  Monit 1985;7(2):181-4.|3
00459|058|R|7.Yazdani M, Kissling GE, Tran TH, Gottschalk SK, Schuth CR. Phenobarbital|2
00459|059|R|  increases the theophylline requirement of premature infants being treated|2
00459|060|R|  for apnea. Am J Dis Child 1987 Jan;141(1):97-9.|2
00459|061|R|8.Wilschanski M, Kaplan M. Phenobarbital increases aminophylline requirement|3
00459|062|R|  in premature infants. Am J Dis Child 1988 Feb;142(2):122-3.|3
00459|063|R|9.Dahlqvist R, Steiner E, Koike Y, von Bahr C, Lind M, Billing B. Induction|2
00459|064|R|  of theophylline metabolism by pentobarbital. Ther Drug Monit 1989;|2
00459|065|R|  11(4):408-10.|2
00459|066|R|10.Kandrotas RJ, Cranfield TL, Gal P, Ransom JL, Weaver RL. Effect of|2
00459|067|R|   phenobarbital administration on theophylline clearance in premature|2
00459|068|R|   neonates. Ther Drug Monit 1990 Mar;12(2):139-43.|2
00459|069|R|11.Nicholson JP, Basile SA, Cury JD. Massive theophylline dosing in a heavy|3
00459|070|R|   smoker receiving both phenytoin and phenobarbital. Ann Pharmacother 1992|3
00459|071|R|   Mar;26(3):334-6.|3
00459|072|R|12.Taylor JW, Hendeles LWeinberger M, Lyon LW, Wyatt R, Riegelman S. The|4
00459|073|R|   interaction of phenytoin and theophylline. Drug Intell Clin Pharm 1980;|4
00459|074|R|   14(9):638.|4
00459|075|R|13.Marquis JF, Carruthers SG, Spence JD, Brownstone YS, Toogood JH.|3
00459|076|R|   Phenytoin-theophylline interaction. N Engl J Med 1982 Nov 4;|3
00459|077|R|   307(19):1189-90.|3
00459|078|R|14.Sklar SJ, Wagner JC. Enhanced theophylline clearance secondary to|3
00459|079|R|   phenytoin therapy. Drug Intell Clin Pharm 1985 Jan;19(1):34-6.|3
00459|080|R|15.Miller M, Cosgriff J, Kwong T, Morken DA. Influence of phenytoin on|2
00459|081|R|   theophylline clearance. Clin Pharmacol Ther 1984 May;35(5):666-9.|2
00459|082|R|16.Crowley JJ, Cusack BJ, Jue SG, Koup JR, Park BK, Vestal RE. Aging and|2
00459|083|R|   drug interactions. II. Effect of phenytoin and smoking on the oxidation|2
00459|084|R|   of theophylline and cortisol in healthy men. J Pharmacol Exp Ther 1988|2
00459|085|R|   May;245(2):513-23.|2
00459|086|R|17.Adebayo GI. Interaction between phenytoin and theophylline in healthy|2
00459|087|R|   volunteers. Clin Exp Pharmacol Physiol 1988 Nov;15(11):883-7.|2
00459|088|R|18.Landsberg K, Shalansky S. Interaction between phenytoin and theophylline.|3
00459|089|R|   Can J Hosp Pharm 1988 Feb;41(1):31-2.|3
00460|001|T|MONOGRAPH TITLE:  Theophyllines/Disulfiram (mono deleted 09/17/2014)|
00460|002|B||
00460|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00460|004|L|take action as needed.|
00460|005|B||
00460|006|A|MECHANISM OF ACTION:  Disulfiram appears to inhibit both the hydroxylation|
00460|007|A|and methylation of theophylline. The hydroxylation pathway is affected more|
00460|008|A|than demethylation.|
00460|009|B||
00460|010|E|CLINICAL EFFECTS:  Serum theophylline concentrations may be elevated|
00460|011|E|increasing the pharmacological and toxic effects of theophylline.|
00460|012|B||
00460|013|P|PREDISPOSING FACTORS:  None determined.|
00460|014|B||
00460|015|M|PATIENT MANAGEMENT:  Monitor serum theophylline concentrations and observe|
00460|016|M|the patient for a change in therapeutic response if disulfiram therapy is|
00460|017|M|initiated or discontinued. Adjust the dose of theophylline accordingly.|
00460|018|B||
00460|019|D|DISCUSSION:  Documentation for this interaction consists of a study in 20|
00460|020|D|recovering alcoholics. Patients received a single IV dose of theophylline|
00460|021|D|while being given either 250 mg or 500 mg of disulfiram daily. Both dosages|
00460|022|D|of disulfiram decreased the clearance of theophylline.  However, the effect|
00460|023|D|was greatest in patients receiving disulfiram 500 mg daily.|
00460|024|B||
00460|025|R|REFERENCE:|
00460|026|B||
00460|027|R|1.Loi CM, Day JD, Jue SG, Bush ED, Costello P, Dewey LV, Vestal RE.|2
00460|028|R|  Dose-dependent inhibition of theophylline metabolism by disulfiram in|2
00460|029|R|  recovering alcoholics. Clin Pharmacol Ther 1989 May;45(5):476-86.|2
00461|001|T|MONOGRAPH TITLE:  Valproic Acid/Salicylates|
00461|002|B||
00461|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00461|004|L|take action as needed.|
00461|005|B||
00461|006|A|MECHANISM OF ACTION:  Multiple mechanisms appear to be involved. Salicylates|
00461|007|A|may displace valproic acid from plasma protein binding sites.  Salicylates|
00461|008|A|may also affect the metabolism of valproate by increasing conjugation and|
00461|009|A|decreasing oxidation of valproic acid.|
00461|010|B||
00461|011|E|CLINICAL EFFECTS:  Concurrent use of salicylates may increase the unbound|
00461|012|E|fraction of serum valproic acid concentration, resulting in toxicity.|
00461|013|B||
00461|014|P|PREDISPOSING FACTORS:  None determined.|
00461|015|B||
00461|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent salicylate therapy should|
00461|017|M|be observed for signs of valproic acid toxicity (e.g., ataxia, drowsiness,|
00461|018|M|nystagmus, tremor).  The dosage of valproic acid may need to be adjusted.|
00461|019|B||
00461|020|D|DISCUSSION:  In two studies involving 6 epileptic children taking valproic|
00461|021|D|acid, concurrent aspirin led to an increase in serum valproic acid free|
00461|022|D|fraction and an increased half-life.  Renal clearance of free valproic acid|
00461|023|D|was found to decrease.(1,2)  In another study involving 5 children,|
00461|024|D|concurrent valproic acid and aspirin resulted in a decrease in free valproic|
00461|025|D|acid clearance although total valproic acid levels did not change|
00461|026|D|significantly.(3)  However, one study reported that the concurrent use of|
00461|027|D|valproic acid and aspirin leads to an increased excretion of valproic acid|
00461|028|D|and a decreased total salicylate excretion.(4)|
00461|029|D|   In 3 case reports, aspirin given to children taking valproic acid|
00461|030|D|resulted in valproic acid toxicity (tremor, nystagmus, truncal ataxia).|
00461|031|D|There was an increase in free valproic acid levels in two cases, however, a|
00461|032|D|reduction in the free fraction and the total valproic acid levels occurred|
00461|033|D|in the third patient.(5)|
00461|034|D|   In another case report, a patient was maintained on divalproex sodium|
00461|035|D|(2500 mg/day) and aspirin (325 mg/day) with a trough valproate level of 24.7|
00461|036|D|ng/ml and a total valproate level of 64.0 ng/ml.  Five days after aspirin|
00461|037|D|was discontinued for a procedure, trough valproate levels fell to 3.9 ng/ml|
00461|038|D|and a total valproate level fell to 36.0 ng/ml with no change in divalproex|
00461|039|D|dosing.(6)|
00461|040|D|   In a study in 7 healthy males, concurrent diflunisal (250 mg twice daily)|
00461|041|D|increased the unbound fraction of valproic acid (200 mg twice daily) by 20%.|
00461|042|D|The area-under-curve (AUC) of 3-oxo-valproic acid increased by 35%.  There|
00461|043|D|were no effects on diflunisal levels.(7)|
00461|044|B||
00461|045|R|REFERENCES:|
00461|046|B||
00461|047|R|1.Orr JM, Abbott FS, Farrell K, Ferguson S, Sheppard I, Godolphin W.|2
00461|048|R|  Interaction between valproic acid and aspirin in epileptic children: serum|2
00461|049|R|  protein binding and metabolic effects. Clin Pharmacol Ther 1982 May;|2
00461|050|R|  31(5):642-9.|2
00461|051|R|2.Abbott FS, Kassam J, Orr JM, Farrell K. The effect of aspirin on valproic|2
00461|052|R|  acid metabolism. Clin Pharmacol Ther 1986 Jul;40(1):94-100.|2
00461|053|R|3.Farrell K, Orr JM, Abbott FS, Ferguson S, Sheppard I, Godolphin W, Bruni|2
00461|054|R|  J. The effect of acetylsalicylic acid on serum free valproate|2
00461|055|R|  concentrations and valproate clearance in children. J Pediatr 1982 Jul;|2
00461|056|R|  101(1):142-4.|2
00461|057|R|4.Schobben F, Vree TB, van der Kleijn E. Pharmacokinetics, metabolism and|2
00461|058|R|  distribution of 2-N-propyl-pentanoate (sodium valproate) and the influence|2
00461|059|R|  of salicylate comedication. In Meinardi, H. //Rowan, A. J. Advances in|2
00461|060|R|  Epileptology Psychology, Pharmacotherapy and New Diagnostic Approaches.|2
00461|061|R|  Amsterdam, Swets & Zeitlinger B. V. 1978;271-7.|2
00461|062|R|5.Goulden KJ, Dooley JM, Camfield PR, Fraser AD. Clinical valproate toxicity|3
00461|063|R|  induced by acetylsalicylic acid. Neurology 1987 Aug;37(8):1392-4.|3
00461|064|R|6.Sandson NB, Marcucci C, Bourke DL, Smith-Lamacchia R. An interaction|3
00461|065|R|  between aspirin and valproate: the relevance of plasma protein|3
00461|066|R|  displacement drug-drug interactions. Am J Psychiatry 2006 Nov;|3
00461|067|R|  163(11):1891-6.|3
00461|068|R|7.Addison RS, Parker-Scott SL, Eadie MJ, Hooper WD, Dickinson RG.|2
00461|069|R|  Steady-state dispositions of valproate and diflunisal alone and|2
00461|070|R|  coadministered to healthy volunteers. Eur J Clin Pharmacol 2000 Dec;|2
00461|071|R|  56(9-10):715-21.|2
00461|072|R|8.Rettenmeier AW, Prickett KS, Gordon WP, Bjorge SM, Chang SL, Levy RH,|5
00461|073|R|  Baillie TA. Studies on the biotransformation in the perfused rat liver of|5
00461|074|R|  2-n- propyl-4-pentenoic acid, a metabolite of the antiepileptic drug|5
00461|075|R|  valproic acid. Evidence for the formation of chemically reactive|5
00461|076|R|  intermediates. Drug Metab Dispos 1985 Jan-Feb;13(1):81-96.|5
00461|077|R|9.Fleitman JS, Bruni J, Perrin JH, Wilder BJ. Albumin-binding interactions|5
00461|078|R|  of sodium valproate. J Clin Pharmacol 1980 Aug-Sep;20(8-9):514-7.|5
00462|001|T|MONOGRAPH TITLE:  Selected Calcium Channel Blockers/Rifamycins|
00462|002|B||
00462|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00462|004|L|of severe adverse interaction.|
00462|005|B||
00462|006|A|MECHANISM OF ACTION:  Multiple mechanisms appear to be involved. Rifampin|
00462|007|A|may increase the hepatic metabolism of the calcium channel blockers,|
00462|008|A|increase first-pass hepatic metabolism of oral calcium channel blockers, and|
00462|009|A|decrease the protein binding of calcium channel blockers.(1-8)|
00462|010|B||
00462|011|E|CLINICAL EFFECTS:  Concurrent use of rifampin may decrease levels and|
00462|012|E|effectiveness of the calcium channel blocker.(1-8)|
00462|013|B||
00462|014|P|PREDISPOSING FACTORS:  None determined.|
00462|015|B||
00462|016|M|PATIENT MANAGEMENT:  Observe the patient for a decrease in the therapeutic|
00462|017|M|effects of the calcium channel blocker if rifampin is initiated.  The dose|
00462|018|M|of the calcium channel blocker may need to be adjusted if rifampin is|
00462|019|M|initiated or discontinued.(1-7)|
00462|020|M|   The US manufacturer of diltiazem states that concurrent use should be|
00462|021|M|avoided.(2)|
00462|022|M|   The manufacturer of lercanidipine states that concurrent use is not|
00462|023|M|recommended.(10)|
00462|024|B||
00462|025|D|DISCUSSION:  In healthy subjects, pretreatment with rifampin (600 mg daily)|
00462|026|D|reduced the concentration of a single dose of isradipine (5 mg) below a|
00462|027|D|detectable level.  The study concluded that the concentrations and effects|
00462|028|D|of isradipine may be either reduced or absent as a result of increased|
00462|029|D|isradipine metabolism.(1)|
00462|030|D|   Concurrent administration of rifampin has been shown to lower diltiazem|
00462|031|D|levels below detectable limits.(2)|
00462|032|D|   In a study in 5 healthy subjects, pretreatment with rifampin (6 days)|
00462|033|D|decreased the area-under-curve (AUC) of a single oral dose of nilvadipine (4|
00462|034|D|mg) by 96.5%.  Pretreatment with rifampin abolished nilvadipine-induced|
00462|035|D|hypotensive effects and tachycardia.(3)|
00462|036|D|   A study in six subjects examined the effects of pretreatment with|
00462|037|D|rifampin (600 mg daily for 15 days) on single doses of verapamil (10 mg|
00462|038|D|intravenously or 120 mg orally).  Rifampin significantly decreased the|
00462|039|D|maximum concentration (Cmax) and AUC of oral verapamil and resulted in no|
00462|040|D|changes in the P-R interval.  There were small decreases in the AUC of|
00462|041|D|intravenous verapamil.(4)|
00462|042|D|   In a study in 8 male subjects, pretreatment with rifampin (600 mg daily|
00462|043|D|for 15 days) increased the systemic clearance of S-verapamil by 1.3-fold and|
00462|044|D|the apparent oral-clearance of S-verapamil by 32-fold.  The bioavailability|
00462|045|D|of S-verapamil decreased 25-fold.  The effect of oral verapamil on AV|
00462|046|D|conduction was almost abolished.  No significant changes were noted for|
00462|047|D|intravenous administration of verapamil.(5)|
00462|048|D|   In a study in 16 hypertensive chronic kidney disease patients, amlodipine|
00462|049|D|levels decreased an average of 82% after initiation of rifampin. In eight of|
00462|050|D|the 16 patients, the levels were undetectable.(9)|
00462|051|D|   There have been case reports of decreased effectiveness of|
00462|052|D|barnidipine,(6) manidipine,(6) nisoldipine,(6) and verapamil(7,8) during|
00462|053|D|concurrent rifampin therapy.|
00462|054|B||
00462|055|R|REFERENCES:|
00462|056|B||
00462|057|R|1.Isradipine US prescribing information. Cobalt Laboratories April, 2007.|1
00462|058|R|2.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
00462|059|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
00462|060|R|3.Saima S, Furuie K, Yoshimoto H, Fukuda J, Hayashi T, Echizen H. The|2
00462|061|R|  effects of rifampicin on the pharmacokinetics and pharmacodynamics of|2
00462|062|R|  orally administered nilvadipine to healthy subjects. Br J Clin Pharmacol|2
00462|063|R|  2002 Feb;53(2):203-6.|2
00462|064|R|4.Barbarash RA, Bauman JL, Fischer JH, Kondos GT, Batenhorst RL. Near-total|2
00462|065|R|  reduction in verapamil bioavailability by rifampin. Electrocardiographic|2
00462|066|R|  correlates. Chest 1988 Nov;94(5):954-9.|2
00462|067|R|5.Fromm MF, Busse D, Kroemer HK, Eichelbaum M. Differential induction of|2
00462|068|R|  prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology|2
00462|069|R|  1996 Oct;24(4):796-801.|2
00462|070|R|6.Yoshimoto H, Takahashi M, Saima S. Influence of rifampicin on|3
00462|071|R|  antihypertensive effects of dihydropiridine calcium-channel blockers in|3
00462|072|R|  four elderly patients. Nippon Ronen Igakkai Zasshi 1996 Sep;33(9):692-6.|3
00462|073|R|7.Rahn KH, Mooy J, Bohm R, vd Vet A. Reduction of bioavailability of|3
00462|074|R|  verapamil by rifampin. N Engl J Med 1985 Apr 4;312(14):920-1.|3
00462|075|R|8.Barbarash RA. Verapamil-rifampin interaction. Drug Intell Clin Pharm 1985|3
00462|076|R|  Jul-Aug;19(7-8):559-60.|3
00462|077|R|9.Agrawal A, Agarwal SK, Kaleekal T, Gupta YK. Rifampicin and|2
00462|078|R|  anti-hypertensive drugs in chronic kidney disease: Pharmacokinetic|2
00462|079|R|  interactions and their clinical impact. Indian J Nephrol 2016 Sep;|2
00462|080|R|  26(5):322-328.|2
00462|081|R|10.Zanidip (lercanidipine) UK prescribing information. Recordati|1
00462|082|R|   Pharmaceuticals Limited October 4, 2019.|1
00463|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Disulfiram|
00463|002|B||
00463|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00463|004|L|take action as needed.|
00463|005|B||
00463|006|A|MECHANISM OF ACTION:  Disulfiram may inhibit the CYP2C9 mediated metabolism|
00463|007|A|of warfarin or other selected vitamin K antagonists.|
00463|008|B||
00463|009|E|CLINICAL EFFECTS:  The anticoagulant effect of warfarin may be increased|
00463|010|E|resulting in bleeding.|
00463|011|B||
00463|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00463|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00463|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
00463|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00463|016|P|risk for bleeding (e.g. NSAIDs).|
00463|017|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
00463|018|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
00463|019|P|are expected to be more susceptible to this interaction.|
00463|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
00463|021|P|are expected to be less susceptible to effects from this drug combination,|
00463|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
00463|023|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
00463|024|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
00463|025|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
00463|026|P|and safe anticoagulation than patients without these CYP2C9 variants.|
00463|027|B||
00463|028|M|PATIENT MANAGEMENT:  Closely monitor patient INR until stabilized and adjust|
00463|029|M|the anticoagulant dose accordingly.  The time of highest risk for a|
00463|030|M|coumarin-type drug interaction is when the precipitant drug is initiated or|
00463|031|M|discontinued.|
00463|032|M|   When concurrent therapy is warranted, monitor patients receiving|
00463|033|M|concurrent therapy for signs of blood loss, including decreased hemoglobin|
00463|034|M|and/or hematocrit, fecal occult blood, and/or decreased blood pressure and|
00463|035|M|promptly evaluate patients with any symptoms.  Discontinue anticoagulation|
00463|036|M|in patients with active pathologic bleeding.|
00463|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00463|038|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00463|039|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00463|040|M|and/or swelling.|
00463|041|B||
00463|042|D|DISCUSSION:  Disulfiram is classified as a weak inhibitor of CYP2C9 by the|
00463|043|D|FDA.  However, given the low therapeutic index of warfarin, even weak CYP2C9|
00463|044|D|inhibitors may have clinically significant effects.|
00463|045|D|  Clinical investigation has substantiated that combined administration of|
00463|046|D|warfarin and disulfiram increases serum warfarin concentrations and produces|
00463|047|D|an increase in the anticoagulant effect of warfarin.  Case reports have|
00463|048|D|documented the occurrence of bleeding.|
00463|049|B||
00463|050|R|REFERENCES:|
00463|051|B||
00463|052|R|1.Rothstein E. Warfarin effect enhanced by disulfiram. JAMA 1968 Nov 11;|3
00463|053|R|  206(7):1574-5.|3
00463|054|R|2.O'Reilly RA. Potentiation of anticoagulant effect by disulfiram|4
00463|055|R|  (Antabuse). Clin Res 1971;19(1):180.|4
00463|056|R|3.O'Reilly RA. Augmentation of long-term warfarin therapy by disulfiram|4
00463|057|R|  (Antabuse). Clin Res 1972;20(2):185.|4
00463|058|R|4.Rothstein E. Warfarin effect enhanced by disulfiram (antabuse). JAMA 1972|3
00463|059|R|  Aug 28;221(9):1052-3.|3
00463|060|R|5.O'Reilly RA. Interaction of sodium warfarin and disulfiram (antabuse) in|2
00463|061|R|  man. Ann Intern Med 1973 Jan;78(1):73-6.|2
00463|062|R|6.O'Reilly RA. Dynamic interaction between disulfiram and separated|2
00463|063|R|  enantiomorphs of racemic warfarin. Clin Pharmacol Ther 1981 Mar;|2
00463|064|R|  29(3):332-6.|2
00464|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Penicillinase Resistant|
00464|002|T|Penicillins|
00464|003|B||
00464|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00464|005|L|of severe adverse interaction.|
00464|006|B||
00464|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown; however, increased|
00464|008|A|hepatic metabolism of warfarin by the penicillins has been postulated.|
00464|009|B||
00464|010|E|CLINICAL EFFECTS:  Penicillinase resistant penicillins may decrease the|
00464|011|E|effects of anticoagulants, increasing the risk of clots.|
00464|012|B||
00464|013|P|PREDISPOSING FACTORS:  None determined.|
00464|014|B||
00464|015|M|PATIENT MANAGEMENT:  Monitor anticoagulant function during combined|
00464|016|M|administration of these classes of drugs and for several weeks after|
00464|017|M|stopping the penicillin.|
00464|018|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00464|019|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
00464|020|M|before initiating, altering the dose or discontinuing either drug.|
00464|021|B||
00464|022|D|DISCUSSION:  A study compared INR measurements of 236 patients taking|
00464|023|D|warfarin or phenprocoumon to before and after dicloxacillin exposure. Prior|
00464|024|D|to dicloxacillin exposure the mean INR level was 2.59 compared to 1.97 after|
00464|025|D|2-4 weeks of dicloxacillin therapy (a mean decrease of 0.62). 61% of|
00464|026|D|patients (n = 144) had subtherapeutic INR levels (less than 2.0) after 2-4|
00464|027|D|weeks of concomitant dicloxacillin and warfarin therapy. Of 64 patients|
00464|028|D|taking phenprocoumon, the mean INR level was 2.61 before dicloxacillin|
00464|029|D|therapy compared to 2.30 after 2-4 weeks of dicloxacillin therapy (a mean|
00464|030|D|decrease of 0.31). 41% of patients (n = 26) had subtherapeutic INR levels|
00464|031|D|after 2-4 weeks of concomitant phenprocoumon and dicloxacillin therapy.(1)|
00464|032|D|   In a study of seven patients receiving long-term warfarin therapy,|
00464|033|D|administration of dicloxacillin sodium (500mg four times daily for seven|
00464|034|D|days) resulted in a significant reduction in the PT.  All patients had a|
00464|035|D|decrease in PT from baseline values.  The mean decrease was 1.9+/-1.8|
00464|036|D|seconds, but one patient had a decrease of 5.6 seconds (24.3%).(2)|
00464|037|D|   A large systematic review was performed on 72 warfarin drug-drug|
00464|038|D|interactions studies that reported on bleeding, thromboembolic events, or|
00464|039|D|death. Most studies were retrospective cohorts.  A meta-analysis of 11 of|
00464|040|D|those studies found a higher rate of clinically significant bleeding in|
00464|041|D|patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83).|
00464|042|D|Increased bleeding risk was also seen in subgroup analyses with penicillins|
00464|043|D|(OR=1.59; 95% CI 1.14-2.20).(21)|
00464|044|D|   In a retrospective review, five patients with durable, continuous flow|
00464|045|D|left ventricular assist devices who were maintained on warfarin required an|
00464|046|D|mean increase in weekly warfarin dosage of 51.8% to maintain a therapeutic|
00464|047|D|INR during dicloxacillin therapy.  Dicloxacillin was discontinued in three|
00464|048|D|patients and these patients required a decrease in weekly warfarin dosage by|
00464|049|D|30.6% to maintain a therapeutic INR.(3)|
00464|050|D|   In a retrospective, observational, cohort study four patients had their|
00464|051|D|warfarin dose increased 57-130% with concomitant flucloxacillin|
00464|052|D|administration.(4)|
00464|053|D|   Several case reports have documented a decrease in the anticoagulant|
00464|054|D|effects of warfarin during concurrent administration of|
00464|055|D|penicillinase-resistant penicillins, including four reports with|
00464|056|D|cloxacillin,(5-6) three with dicloxacillin,(7-9) three with|
00464|057|D|flucloxacillin,(10-12) and eight with nafcillin.(13-19)  The effects of the|
00464|058|D|interaction have been reported to be delayed up to nine days after taking|
00464|059|D|both drugs concurrently and the effects of the interaction may persist for|
00464|060|D|up to one month after stopping the antibiotic.  In the case of|
00464|061|D|dicloxacillin, some patients required twice their normal dosage of warfarin|
00464|062|D|to maintain therapeutic INRs.  One patient taking flucloxacillin developed a|
00464|063|D|cardioembolic ischemic stroke.  In the case of nafcillin, one patient|
00464|064|D|required 4.5 times the normal dosage of warfarin.|
00464|065|D|   Conversely, there is one report of increased warfarin effects following|
00464|066|D|the addition of cloxacillin to therapy.(20)|
00464|067|D|   In a cohort study of 1023 patients, short- and long-term dicloxacillin|
00464|068|D|treatments decreased INR levels by a mean of -0.65 and -0.76, respectively.|
00464|069|D|The effect of dicloxacillin on INR levels was largest after 2 weeks and more|
00464|070|D|than 90% of patients had a subtherapeutic INR level (INR below 2) after|
00464|071|D|long-term dicloxacillin treatment.  The initiation of dicloxacillin|
00464|072|D|decreased the mean INR from 2.5 to 1.84 within 1-3 weeks of exposure.|
00464|073|D|Flucloxacillin decreased INR levels by -0.37.  Subtherapeutic INR levels|
00464|074|D|were noted in 42% of patients on flucloxacillin.(22)|
00464|075|B||
00464|076|R|REFERENCES:|
00464|077|B||
00464|078|R|1.Pottegard A, Henriksen DP, Madsen KG, Hellfritzsch M, Damkier P, Stage TB.|2
00464|079|R|  Change in International Normalized Ratio Among Patients Treated With|2
00464|080|R|  Dicloxacillin and Vitamin K Antagonists. JAMA 2015 Jul 21;314(3):296-7.|2
00464|081|R|2.Krstenansky PM, Jones WN, Garewal HS. Effect of dicloxacillin sodium on|3
00464|082|R|  the hypoprothrombinemic response to warfarin sodium. Clin Pharm 1987 Oct;|3
00464|083|R|  6(10):804-6.|3
00464|084|R|3.Buhlinger KM, Hollis IB. Effects of Dicloxacillin on Warfarin Dose in|3
00464|085|R|  Patients With a Left Ventricular Assist Device. J Pharm Pract 2018 Jan 1;|3
00464|086|R|  897190018772978.|3
00464|087|R|4.Chaudhuri A, Wade SL. Flucloxacillin-warfarin interaction: an|3
00464|088|R|  under-appreciated phenomenon. Intern Med J 2018 Jul;48(7):860-863.|3
00464|089|R|5.Khalili H, Nikvarz N, Najmeddin F, Dashti-Khavidaki S. A probable|3
00464|090|R|  clinically significant interaction between warfarin and cloxacillin: three|3
00464|091|R|  case reports. Eur J Clin Pharmacol 2012 Sep 4.|3
00464|092|R|6.Ibrahim OM, Allam A. Warfarin resistance in a patient with prosthetic|3
00464|093|R|  valve endocarditis treated with cloxacillin. Saudi Pharm J 1996;4:56-59.|3
00464|094|R|7.Lacey CS. Interaction of dicloxacillin with warfarin. Ann Pharmacother|3
00464|095|R|  2004 May;38(5):898.|3
00464|096|R|8.Mailloux AT, Gidal BE, Sorkness CA. Potential interaction between warfarin|3
00464|097|R|  and dicloxacillin. Ann Pharmacother 1996 Dec;30(12):1402-7.|3
00464|098|R|9.Halvorsen S, Husebye T, Arnesen H. Prosthetic heart valve thrombosis|3
00464|099|R|  during dicloxacillin therapy. Scand Cardiovasc J 1999;33(6):366-8.|3
00464|100|R|10.Choi PY, Phillips KL, Rae I. High-dose intravenous flucloxacillin may|3
00464|101|R|   affect warfarin therapy. Med J Aust 2011 Jun 6;194(11):613.|3
00464|102|R|11.Merwick A, Hannon N, Kelly PJ, O'Rourke K. Warfarin-flucloxacillin|3
00464|103|R|   interaction presenting as cardioembolic ischemic stroke. Eur J Clin|3
00464|104|R|   Pharmacol 2010 Jun;66(6):643-4.|3
00464|105|R|12.Garg A, Mohammed M. Decreased INR response secondary to|3
00464|106|R|   warfarin-flucloxacillin interaction. Ann Pharmacother 2009 Jul;|3
00464|107|R|   43(7):1374-5.|3
00464|108|R|13.Qureshi GD, Reinders TP, Somori GJ, Evans HJ. Warfarin resistance with|3
00464|109|R|   nafcillin therapy. Ann Intern Med 1984 Apr;100(4):527-9.|3
00464|110|R|14.Fraser GL, Miller M, Kane K. Warfarin resistance associated with|3
00464|111|R|   nafcillin therapy. Am J Med 1989 Aug;87(2):237-8.|3
00464|112|R|15.Davis RL, Berman W Jr, Wernly JA, Kelly HW. Warfarin-nafcillin|3
00464|113|R|   interaction. J Pediatr 1991 Feb;118(2):300-3.|3
00464|114|R|16.Shovick VA, Rihn TL. Decreased hypoprothrombinemic response to warfarin|3
00464|115|R|   secondary to the warfarin-nafcillin interaction. DICP 1991 Jun;|3
00464|116|R|   25(6):598-600.|3
00464|117|R|17.Kim KY, Frey RJ, Epplen K, Foruhari F. Interaction between warfarin and|3
00464|118|R|   nafcillin: case report and review of the literature. Pharmacotherapy 2007|3
00464|119|R|   Oct;27(10):1467-70.|3
00464|120|R|18.Taylor AT, Pritchard DC, Goldstein AO, Fletcher JL Jr. Continuation of|3
00464|121|R|   warfarin-nafcillin interaction during dicloxacillin therapy. J Fam Pract|3
00464|122|R|   1994 Aug;39(2):182-5.|3
00464|123|R|19.Heilker GM, Fowler JW Jr, Self TH. Possible nafcillin-warfarin|3
00464|124|R|   interaction. Arch Intern Med 1994 Apr 11;154(7):822-4.|3
00464|125|R|20.Marusic S, Gojo-Tomic N, Bacic-Vrca V, Franic M. Enhanced anticoagulant|3
00464|126|R|   effect of warfarin in a patient treated with cloxacillin. Int J Clin|3
00464|127|R|   Pharmacol Ther 2012 Jun;50(6):431-3.|3
00464|128|R|21.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00464|129|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00464|130|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
00464|131|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00464|132|R|22.Jarvinen E, Dalgard Dunvald AC, Ernst MT, Hammer HS, Potz O, Pottegard A,|2
00464|133|R|   Stage TB. Dicloxacillin-warfarin drug-drug interaction-A register-based|2
00464|134|R|   study and in vitro  investigations in 3D spheroid primary human|2
00464|135|R|   hepatocytes. Br J Clin Pharmacol 2023 Aug;89(8):2614-2624.|2
00465|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antag)/Selected Penicillins|
00465|002|B||
00465|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00465|004|L|take action as needed.|
00465|005|B||
00465|006|A|MECHANISM OF ACTION:  Unknown.|
00465|007|B||
00465|008|E|CLINICAL EFFECTS:  Large doses of parenterally administered penicillins and|
00465|009|E|oral amoxicillin appear to increase the risk of bleeding during concurrent|
00465|010|E|administration of anticoagulants.|
00465|011|B||
00465|012|P|PREDISPOSING FACTORS:  Renal failure may predispose patients to|
00465|013|P|penicillin-induced coagulation abnormalities.   A study suggests that|
00465|014|P|various inflammatory syndromes or the nature of the infection can affect INR|
00465|015|P|levels.|
00465|016|P|   The risk for bleeding episodes may be greater in patients with additional|
00465|017|P|disease-associated factors (e.g. thrombocytopenia).|
00465|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
00465|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00465|020|P|risk for bleeding (e.g. NSAIDs).|
00465|021|B||
00465|022|M|PATIENT MANAGEMENT:  Monitor patient INR for an increase in the|
00465|023|M|hypoprothrombinemic response to anticoagulants during concomitant|
00465|024|M|administration of penicillins. Adjust the dose of warfarin accordingly.|
00465|025|M|   When concurrent therapy is warranted, monitor patients receiving|
00465|026|M|concurrent therapy for signs of blood loss, including decreased hemoglobin|
00465|027|M|and/or hematocrit, fecal occult blood, and/or decreased blood pressure and|
00465|028|M|promptly evaluate patients with any symptoms.  Discontinue anticoagulation|
00465|029|M|in patients with active pathologic bleeding.|
00465|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00465|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00465|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00465|033|M|and/or swelling.|
00465|034|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00465|035|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00465|036|M|initiating, altering the dose or discontinuing either drug.|
00465|037|B||
00465|038|D|DISCUSSION:  High dose parenteral administration of penicillins and oral|
00465|039|D|amoxicillin have been reported to cause an increase in the|
00465|040|D|hypoprothrombinemic effects of warfarin producing bleeding.  Significant|
00465|041|D|clinical effects have been reported with combined administration of warfarin|
00465|042|D|and either carbenicillin or penicillin G.|
00465|043|D|   There have been several case reports and retrospective reviews|
00465|044|D|documenting increased acenocoumarol and warfarin effects, including|
00465|045|D|bleeding, following the addition of amoxicillin, with and without clavulanic|
00465|046|D|acid, to therapy.  In a randomized controlled trial, adult ambulatory|
00465|047|D|patients that had no recent and ongoing infectious or inflammatory|
00465|048|D|conditions received warfarin to a target INR between 2 and 3 with|
00465|049|D|amoxicillin-clavulanic acid (1 gram twice daily for seven days) or placebo.|
00465|050|D|The results showed the mean maximum INR increase from baseline to day 10 did|
00465|051|D|not differ between amoxicillin/clavulanic acid (0.22 +/- 0.3) and the|
00465|052|D|placebo period (0.24 +/- 0.6, p = 0.94).  No patient experienced an INR of|
00465|053|D|greater than 3.5.  No bleeding events were reported during the entire study.|
00465|054|D|   A prospective cross-sectional observational study in 120 patients|
00465|055|D|evaluated warfarin drug interactions, particularly with high-dose|
00465|056|D|amoxicillin/clavulanate.  The study found that patients on|
00465|057|D|amoxicillin/clavulanate had a relative risk of having an INR >=4 of 4.8|
00465|058|D|compared to patients not on amoxicillin/clavulanate (95% CI 2.1-11.3, p <|
00465|059|D|0.001).  This risk was primarily driven by patients on high-dose|
00465|060|D|amoxicillin/clavulanate, who were 5.8 times more likely to have INR >=4 (95%|
00465|061|D|CI 3.5-9.6, p<0.001).  Significantly more patients on high-dose than normal|
00465|062|D|dose amoxicillin/clavulanate had an INR value >= 4 (87.5% v. 28.9%,|
00465|063|D|respectively).  Nine out of ten patients who experienced bleeding during|
00465|064|D|hospitalization were prescribed amoxicillin/clavulanate.|
00465|065|D|   A large systematic review was performed on 72 warfarin drug-drug|
00465|066|D|interactions studies that reported on bleeding, thromboembolic events, or|
00465|067|D|death. Most studies were retrospective cohorts.  A meta-analysis of 11 of|
00465|068|D|those studies found a higher rate of clinically significant bleeding in|
00465|069|D|patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83).|
00465|070|D|Increased bleeding risk was also seen in subgroup analyses with penicillins|
00465|071|D|(OR=1.59; 95% CI 1.14-2.20) and amoxicillin (OR=1.78; 95% CI 1.14-2.79).|
00465|072|D|   A case-control nested cohort study of Medicare beneficiaries with|
00465|073|D|warfarin prescriptions was evaluated for antibiotic use and warfarin|
00465|074|D|toxicity in older adults.  An increased risk of bleeding was associated with|
00465|075|D|penicillins with an adjusted odds ratio of 1.92.|
00465|076|D|   Parenteral penicillins linked to this monograph include: almecillin,|
00465|077|D|amdinocillin, amoxicillin, ampicillin, azlocillin,  bacampicillin,|
00465|078|D|carbenicillin, cyclacillin, hetacillin, mezlocillin, penicillin, penicillin|
00465|079|D|G, penicillin V, phenethicillin, piperacillin, and ticarcillin.|
00465|080|D|   Oral penicillins linked to this monograph include: amoxicillin and|
00465|081|D|penicillin.|
00465|082|B||
00465|083|R|REFERENCES:|
00465|084|B||
00465|085|R|1.Brown CH 3rd, Natelson EA, Bradshaw W, Williams TW Jr, Alfrey CP Jr. The|2
00465|086|R|  hemostatic defect produced by carbenicillin. N Engl J Med 1974 Aug 8;|2
00465|087|R|  291(6):265-70.|2
00465|088|R|2.Brown CH 3rd, Natelson EA, Bradshaw MW, Alfrey C P Jr, Williams TW Jr.|2
00465|089|R|  Study of the effects of ticarcillin on blood coagulation and platelet|2
00465|090|R|  function. Antimicrob Agents Chemother 1975 May;7(5):652-7.|2
00465|091|R|3.Brown CH 3rd, Bradshaw MJ, Natelson EA, Alfrey CP Jr, Williams TW Jr.|2
00465|092|R|  Defective platelet function following the administration of penicillin|2
00465|093|R|  compounds. Blood 1976 Jun;47(6):949-56.|2
00465|094|R|4.Andrassy K, Ritz E, Hasper B, Scherz M, Walter E, Storch H.|3
00465|095|R|  Penicillin-induced coagulation disorder. Lancet 1976 Nov 13;|3
00465|096|R|  2(7994):1039-41.|3
00465|097|R|5.Dijkmans BA, Van Der Meer JW, Boekhout-Mussert MJ, Zaal-De Jong M, Mattie|3
00465|098|R|  H. Prolonged bleeding time during azlocillin therapy. J Antimicrob|3
00465|099|R|  Chemother 1980 Jul;6(4):554-6.|3
00465|100|R|6.Gentry LO, Jemsek JG, Natelson EA. Effects of sodium piperacillin on|2
00465|101|R|  platelet function in normal volunteers. Antimicrob Agents Chemother 1981|2
00465|102|R|  Apr;19(4):532-3.|2
00465|103|R|7.Alexander DP, Russo ME, Fohrman DE, Rothstein G. Nafcillin-induced|3
00465|104|R|  platelet dysfunction and bleeding. Antimicrob Agents Chemother 1983 Jan;|3
00465|105|R|  23(1):59-62.|3
00465|106|R|8.Delavenne X, Laporte S, Demasles S, Mallouk N, Basset T, Tod M, Girard P,|2
00465|107|R|  Mismetti P. Investigation of PK-PD drug-drug interaction between|2
00465|108|R|  acenocoumarol and amoxicillin plus clavulanic acid. Fundam Clin Pharmacol|2
00465|109|R|  2009 Feb;23(1):127-35.|2
00465|110|R|9.Kelly M, Moran J, Byrne S. Formation of rectus sheath hematoma with|3
00465|111|R|  antibiotic use and warfarin therapy: a case report. Am J Geriatr|3
00465|112|R|  Pharmacother 2005 Dec;3(4):266-9.|3
00465|113|R|10.Davydov L, Yermolnik M, Cuni LJ. Warfarin and amoxicillin/clavulanate|3
00465|114|R|   drug interaction. Ann Pharmacother 2003 Mar;37(3):367-70.|3
00465|115|R|11.Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Drug|2
00465|116|R|   interactions as a cause of overanticoagulation on phenprocoumon or|2
00465|117|R|   acenocoumarol predominantly concern antibacterial drugs. Clin Pharmacol|2
00465|118|R|   Ther 2001 Jun;69(6):451-7.|2
00465|119|R|12.Bandrowsky T, Vorono AA, Borris TJ, Marcantoni HW. Amoxicillin-related|3
00465|120|R|   postextraction bleeding in an anticoagulated patient with tranexamic acid|3
00465|121|R|   rinses. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996 Dec;|3
00465|122|R|   82(6):610-2.|3
00465|123|R|13.Tung JY, Johnson JL, Liacouras CA. Portal-mesenteric pylephlebitis with|3
00465|124|R|   hepatic abscesses in a patient with Crohn's disease treated successfully|3
00465|125|R|   with anticoagulation and antibiotics. J Pediatr Gastroenterol Nutr 1996|3
00465|126|R|   Nov;23(4):474-8.|3
00465|127|R|14.Soto J, Sacristan JA, Alsar MJ, Fernandez-Viadero C, Verduga R. Probable|3
00465|128|R|   acenocoumarol-amoxycillin interaction. Acta Haematol 1993;90(4):195-7.|3
00465|129|R|15.Penning-van Beest FJ, Koerselman J, Herings RM. Risk of major bleeding|2
00465|130|R|   during concomitant use of antibiotic drugs and coumarin anticoagulants. J|2
00465|131|R|   Thromb Haemost 2008 Feb;6(2):284-90.|2
00465|132|R|16.Zhang Q, Simoneau G, Verstuyft C, Drouet L, Bal dit Sollier C, Alvarez|2
00465|133|R|   JC, Rizzo-Padoin N, Bergmann JF, Becquemont L, Mouly S.|2
00465|134|R|   Amoxicillin/clavulanic acid-warfarin drug interaction: a randomized|2
00465|135|R|   controlled trial. Br J Clin Pharmacol 2011 Feb;71(2):232-6.|2
00465|136|R|17.Baillargeon J, Holmes HM, Lin YL, Raji MA, Sharma G, Kuo YF. Concurrent|2
00465|137|R|   use of warfarin and antibiotics and the risk of bleeding in older adults.|2
00465|138|R|   Am J Med 2012 Feb;125(2):183-9.|2
00465|139|R|18.Larsen TR, Gelaye A, Durando C. Acute warfarin toxicity: An unanticipated|3
00465|140|R|   consequence of amoxicillin/clavulanate  administration. Am J Case Rep|3
00465|141|R|   2014;15:45-8.|3
00465|142|R|19.Abdel-Aziz MI, Ali MA, Hassan AK, Elfaham TH. Warfarin-drug interactions:|2
00465|143|R|   An emphasis on influence of polypharmacy and high doses of|2
00465|144|R|   amoxicillin/clavulanate. J Clin Pharmacol 2016 Jan;56(1):39-46.|2
00465|145|R|20.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00465|146|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00465|147|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
00465|148|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00466|001|T|MONOGRAPH TITLE:  Thioridazine/Phenylpropanolamine|
00466|002|B||
00466|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00466|004|L|of severe adverse interaction.|
00466|005|B||
00466|006|A|MECHANISM OF ACTION:  Unknown.|
00466|007|B||
00466|008|E|CLINICAL EFFECTS:  Death in a patient has been reported.|
00466|009|B||
00466|010|P|PREDISPOSING FACTORS:  None determined.|
00466|011|B||
00466|012|M|PATIENT MANAGEMENT:  If possible, avoid concurrent administration of these|
00466|013|M|classes of agents. If it is necessary, do so cautiously and monitor the|
00466|014|M|patient.|
00466|015|B||
00466|016|D|DISCUSSION:  Documentation for this interaction consists of a single case|
00466|017|D|history of a patient who was taking thioridazine 100 mg daily and died after|
00466|018|D|taking a single dose of a combination product containing phenylpropanolamine|
00466|019|D|and chlorpheniramine. Sudden death has been reported with phenothiazine|
00466|020|D|administration alone including thioridazine.|
00466|021|B||
00466|022|R|REFERENCES:|
00466|023|B||
00466|024|R|1.Giles TD, Modlin RK. Death associated with ventricular arrhythmia and|3
00466|025|R|  thioridazine hydrochloride. JAMA 1968 Jul 8;205(2):108-10.|3
00466|026|R|2.Chouinard G, Ghadirian AM, Jones BD. Death attributed to ventricular|3
00466|027|R|  arrhythmia induced by thioridazine in combination with a single Contac C|3
00466|028|R|  capsule. Can Med Assoc J 1978 Oct 7;119(7):729-30.|3
00467|001|T|MONOGRAPH TITLE:  Hydantoins, Oral/Sucralfate|
00467|002|B||
00467|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00467|004|L|take action as needed.|
00467|005|B||
00467|006|A|MECHANISM OF ACTION:  Sucralfate can bind to phenytoin resulting in reduced|
00467|007|A|absorption of phenytoin.|
00467|008|B||
00467|009|E|CLINICAL EFFECTS:  The pharmacological effects of phenytoin may be|
00467|010|E|decreased.|
00467|011|B||
00467|012|P|PREDISPOSING FACTORS:  None determined.|
00467|013|B||
00467|014|M|PATIENT MANAGEMENT:  Monitor serum phenytoin concentrations when starting or|
00467|015|M|stopping sucralfate treatment. Adjust the dose of phenytoin as needed.|
00467|016|B||
00467|017|D|DISCUSSION:  In controlled studies sucralfate administration produced a 10%|
00467|018|D|to 20% reduction in the bioavailability of phenytoin. Although these|
00467|019|D|decreases in phenytoin bioavailability are slight, they may be clinically|
00467|020|D|important in some patients.|
00467|021|B||
00467|022|R|REFERENCES:|
00467|023|B||
00467|024|R|1.Smart HL, Somerville KW, Williams J, Richens A, Langman MJ. The effects of|2
00467|025|R|  sucralfate upon phenytoin absorption in man. Br J Clin Pharmacol 1985 Sep;|2
00467|026|R|  20(3):238-40.|2
00467|027|R|2.Hall TG, Cuddy PG, Glass CJ, Melethil S. Effect of sucralfate on phenytoin|2
00467|028|R|  bioavailability. Drug Intell Clin Pharm 1986 Jul-Aug;20(7-8):607-11.|2
00468|001|T|MONOGRAPH TITLE:  Hydantoins/Selected Antineoplastics|
00468|002|B||
00468|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00468|004|L|take action as needed.|
00468|005|B||
00468|006|A|MECHANISM OF ACTION:  Antineoplastic agents may decrease the absorption and|
00468|007|A|increase the metabolism of phenytoin.|
00468|008|B||
00468|009|E|CLINICAL EFFECTS:  The pharmacological effects of phenytoin may be|
00468|010|E|decreased.|
00468|011|B||
00468|012|P|PREDISPOSING FACTORS:  None determined.|
00468|013|B||
00468|014|M|PATIENT MANAGEMENT:  Monitor serum phenytoin concentrations when starting or|
00468|015|M|discontinuing cancer chemotherapy. Adjust the dose of phenytoin as needed.|
00468|016|B||
00468|017|D|DISCUSSION:  Decreased plasma phenytoin concentrations and loss of seizure|
00468|018|D|control have been reported after starting chemotherapy in patients receiving|
00468|019|D|phenytoin. In order to maintain adequate levels of phenytoin during|
00468|020|D|chemotherapy, it may be necessary to increase the dose of phenytoin.|
00468|021|B||
00468|022|R|REFERENCES:|
00468|023|B||
00468|024|R|1.Fincham RW, Schottelius DD. Decreased phenytoin levels in antineoplastic|3
00468|025|R|  therapy. Ther Drug Monit 1979;1(2):277-83.|3
00468|026|R|2.Bollini P, Riva R, Albani F, Ida N, Cacciari L, Bollini C, Baruzzi A.|3
00468|027|R|  Decreased phenytoin level during antineoplastic therapy: a case report.|3
00468|028|R|  Epilepsia 1983 Feb;24(1):75-8.|3
00468|029|R|3.Sylvester RK, Lewis FB, Caldwell KC, Lobell M, Perri R, Sawchuk RA.|3
00468|030|R|  Impaired phenytoin bioavailability secondary to cisplatinum, vinblastine,|3
00468|031|R|  and bleomycin. Ther Drug Monit 1984;6(3):302-5.|3
00468|032|R|4.Neef C, de Voogd-van der Straaten I. An interaction between cytostatic and|3
00468|033|R|  anticonvulsant drugs. Clin Pharmacol Ther 1988 Apr;43(4):372-5.|3
00468|034|R|5.Grossman SA, Sheidler VR, Gilbert MR. Decreased phenytoin levels in|2
00468|035|R|  patients receiving chemotherapy. Am J Med 1989 Nov;87(5):505-10.|2
00468|036|R|6.Dofferhoff AS, Berendsen HH, vd Naalt J, Haaxma-Reiche H, Smit EF, Postmus|3
00468|037|R|  PE. Decreased phenytoin level after carboplatin treatment. Am J Med 1990|3
00468|038|R|  Aug;89(2):247-8.|3
00469|001|T|MONOGRAPH TITLE:  Metronidazole/Barbiturates|
00469|002|B||
00469|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00469|004|L|take action as needed.|
00469|005|B||
00469|006|A|MECHANISM OF ACTION:  The metabolism of metronidazole may be increased by|
00469|007|A|barbiturate administration via induction of CYP2A6.|
00469|008|A|   Primidone is metabolized to phenobarbital.|
00469|009|B||
00469|010|E|CLINICAL EFFECTS:  Serum metronidazole concentrations may be reduced|
00469|011|E|producing a decrease in the therapeutic effects of metronidazole.|
00469|012|B||
00469|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00469|014|P|of the inducer for longer than 1-2 weeks.|
00469|015|B||
00469|016|M|PATIENT MANAGEMENT:  Observe the patient for possible metronidazole|
00469|017|M|treatment failure. Adjust the dose of metronidazole accordingly.|
00469|018|B||
00469|019|D|DISCUSSION:  Therapeutic failure with corresponding increases in|
00469|020|D|metronidazole elimination rate has been reported with concurrent|
00469|021|D|administration of phenobarbital.|
00469|022|B||
00469|023|R|REFERENCES:|
00469|024|B||
00469|025|R|1.Mead PB, Gibson M, Schentag JJ, Ziemniak JA. Possible alteration of|3
00469|026|R|  metronidazole metabolism by phenobarbital. N Engl J Med 1982 Jun 17;|3
00469|027|R|  306(24):1490.|3
00469|028|R|2.Gupte S. Phenobarbital and metabolism of metronidazole. N Engl J Med 1983|3
00469|029|R|  Mar 3;308(9):529.|3
00469|030|R|3.Loft S, Sonne J, Poulsen HE, Petersen KT, Jorgensen BG, Dossing M.|2
00469|031|R|  Inhibition and induction of metronidazole and antipyrine metabolism. Eur J|2
00469|032|R|  Clin Pharmacol 1987;32(1):35-41.|2
00470|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Quinolones|
00470|002|B||
00470|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00470|004|L|of severe adverse interaction.|
00470|005|B||
00470|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Some quinolones may|
00470|007|A|affect the metabolism of anticoagulants or the infection process may be|
00470|008|A|responsible for the changes seen.|
00470|009|B||
00470|010|E|CLINICAL EFFECTS:  Concurrent use of quinolones may be associated with an|
00470|011|E|increase in hypoprothrombinemic effects of anticoagulants, which may result|
00470|012|E|in an increased risk of bleeding.|
00470|013|B||
00470|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
00470|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
00470|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
00470|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00470|018|P|risk for bleeding (e.g. NSAIDs).|
00470|019|B||
00470|020|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
00470|021|M|receiving concurrent therapy for signs of blood loss, including decreased|
00470|022|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
00470|023|M|and promptly evaluate patients with any symptoms.  A study suggested not|
00470|024|M|preemptively reducing the dose of warfarin upon initiation of levofloxacin,|
00470|025|M|but instead just a short-term INR follow-up appears reasonable.(33)|
00470|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00470|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00470|028|M|anticoagulation in patients with active pathologic bleeding.|
00470|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00470|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00470|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00470|032|M|and/or swelling.|
00470|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00470|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00470|035|M|initiating, altering the dose or discontinuing either drug.|
00470|036|B||
00470|037|D|DISCUSSION:  A large systematic review was performed on 72 warfarin|
00470|038|D|drug-drug interactions studies that reported on bleeding, thromboembolic|
00470|039|D|events, or death.  Most studies were retrospective cohorts.  A meta-analysis|
00470|040|D|of 11 of those studies found a higher rate of clinically significant|
00470|041|D|bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI|
00470|042|D|1.45-1.83).  Increased bleeding risk was also seen in subgroup analyses with|
00470|043|D|fluoroquinolones (OR=1.68; 95% CI 1.34-2.11).(42)|
00470|044|D|   In a study in 16 patients stabilized on warfarin therapy, the addition of|
00470|045|D|ciprofloxacin (500 mg twice daily for 10 days) had no significant effects on|
00470|046|D|INR values and no patients experienced a bleeding event.(1)  In a study in|
00470|047|D|36 patients stabilized on warfarin therapy, the addition of ciprofloxacin|
00470|048|D|(750 mg twice daily for 12 days) had no effects on the amount of S-warfarin.|
00470|049|D|Levels of R-warfarin increased 1.15-fold, concentrations of clotting|
00470|050|D|factors decreased, and the mean PT ratio increased slightly.  However, no|
00470|051|D|patient required warfarin dosage adjustment and no bleeding episodes were|
00470|052|D|reported.(2)  In contrast to these studies, there have been several case|
00470|053|D|reports of bleeding episodes following the addition of ciprofloxacin to|
00470|054|D|warfarin therapy,(3-9) including 66 reports to the FDA from 1987 to 1997.(4)|
00470|055|D|Of these 66 reports, 15 resulted in hospitalization, 25 in bleeding, and 1|
00470|056|D|in death.(4)  As of January 14, 2004, Health Canada had received 10 case|
00470|057|D|reports of interactions between warfarin and ciprofloxacin.  Four of these|
00470|058|D|patients died.(10)|
00470|059|D|   Another study showed that ciprofloxacin prolonged release (PR)|
00470|060|D|concomitantly administered with warfarin does not alter the pharmacokinetics|
00470|061|D|and pharmacodynamics of warfarin.(31)|
00470|062|D|   In a study in 6 healthy males, concurrent enoxacin did not affect the|
00470|063|D|hypothrombinemic effects of warfarin, but did decrease the clearance of|
00470|064|D|R-warfarin.(11)  In a case report, enoxacin did interact with warfarin.(12)|
00470|065|D|   Gatifloxacin has been reported to interact with warfarin in a case|
00470|066|D|report.(13)  As of January 14, 2004, Health Canada had received 13 reports|
00470|067|D|of interactions between warfarin and gatifloxacin.  Two of these patients|
00470|068|D|died.(10)|
00470|069|D|   In a study in 16 healthy subjects, the addition of grepafloxacin (600 mg|
00470|070|D|daily for 14 days) had no effects on the pharmacodynamics of warfarin or the|
00470|071|D|pharmacokinetics of grepafloxacin.(14)|
00470|072|D|   In a study in 6 patients stabilized on warfarin therapy, the addition of|
00470|073|D|levofloxacin had no effect on INR values.(15)  In a study in 16 healthy|
00470|074|D|subjects, levofloxacin (500 mg twice daily for 6 days) had no effects on the|
00470|075|D|pharmacokinetics or pharmacodynamics of a single dose of warfarin (30|
00470|076|D|mg).(16)  In contrast, there are several case reports documenting an|
00470|077|D|interaction between levofloxacin and warfarin.(17-19)  As of January 14,|
00470|078|D|2004, Health Canada had received 16 reports of interactions between warfarin|
00470|079|D|and levofloxacin.  One of these patients died.(10)|
00470|080|D|   In a retrospective study, the addition of levofloxacin to warfarin|
00470|081|D|therapy showed an increase in INR.(35) However, in another retrospective|
00470|082|D|study, the addition of levofloxacin to long-term warfarin therapy showed no|
00470|083|D|interaction.(34) An article on the pharmacokinetics of levofloxacin states|
00470|084|D|that with warfarin there were no pharmacokinetic alterations detected for|
00470|085|D|either the R- or S-enantiomers and there were no significant differences in|
00470|086|D|prothrombin times.(32)|
00470|087|D|   There are several reports of an interaction between moxifloxacin and|
00470|088|D|warfarin.(20-21) As of January 14, 2004, Health Canada had received 12|
00470|089|D|reports of interactions between warfarin and moxifloxacin.(10)|
00470|090|D|   According to the Institute of Clinical Pharmacology, moxifloxacin shows|
00470|091|D|no pharmacokinetic interaction with warfarin.(38,39) According to|
00470|092|D|moxifloxacin official package insert, warfarin did not significantly affect|
00470|093|D|the pharmacokinetics of moxifloxacin because the in vitro studies suggest|
00470|094|D|that moxifloxacin is unlikely to significantly alter the metabolic clearance|
00470|095|D|of drugs metabolized by the cytochrome P450 system.(41)|
00470|096|D|   One case report, of an elderly female concomitantly administered|
00470|097|D|moxifloxacin and warfarin, observed an INR increase from 2.3 to 5.1 and|
00470|098|D|development of hemoperitoneum and left abdominal wall hematoma.(40)|
00470|099|D|   Another case report of an elderly female concomitantly administered|
00470|100|D|warfarin and moxifloxacin observed a prolonged INR level despite withholding|
00470|101|D|warfarin for 6 days; however, the INR did decrease after 2 days upon|
00470|102|D|discontinuing moxifloxacin.(36,37) Two case reports show an interaction|
00470|103|D|between moxifloxacin and warfarin due to evidence of elevated PT and INR|
00470|104|D|following coadministration.(36)|
00470|105|D|   There are case reports documenting interactions between nalidixic acid|
00470|106|D|and warfarin(22-24) and nicoumalone.(25)|
00470|107|D|   In a study in 10 healthy subjects, norfloxacin (400 mg twice daily for 6|
00470|108|D|days) had no effects on the pharmacokinetics or pharmacodynamics of a single|
00470|109|D|dose of warfarin (30 mg).(26)  In a case report, norfloxacin did interact|
00470|110|D|with warfarin.(27)  As of January 14, 2004, Health Canada had received 6|
00470|111|D|reports of interactions between warfarin and norfloxacin.(10)|
00470|112|D|   There are reports of an interaction between ofloxacin and|
00470|113|D|warfarin.(28-29)|
00470|114|D|   In a study in 10 healthy subjects, temafloxacin (600 mg twice daily for 4|
00470|115|D|days) had no effects on prothrombin times.(30)|
00470|116|B||
00470|117|R|REFERENCES:|
00470|118|B||
00470|119|R|1.Bianco TM, Bussey HI, Farnett LE, Linn WD, Roush MK, Wong YW. Potential|2
00470|120|R|  warfarin-ciprofloxacin interaction in patients receiving long- term|2
00470|121|R|  anticoagulation. Pharmacotherapy 1992;12(6):435-9.|2
00470|122|R|2.Israel DS, Stotka J, Rock W, Sintek CD, Kamada AK, Klein C, Swaim WR,|2
00470|123|R|  Pluhar RE, Toscano JP, Lettieri JT, Heller AH, Polk RE. Effect of|2
00470|124|R|  ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin.|2
00470|125|R|  Clin Infect Dis 1996 Feb;22(2):251-6.|2
00470|126|R|3.Mott FE, Murphy S, Hunt V. Ciprofloxacin and warfarin. Ann Intern Med 1989|3
00470|127|R|  Sep 15;111(6):542-3.|3
00470|128|R|4.Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin-warfarin coagulopathy: a|3
00470|129|R|  case series. Am J Hematol 2000 Jan;63(1):28-31.|3
00470|130|R|5.Kamada AK. Possible interaction between ciprofloxacin and warfarin. DICP|3
00470|131|R|  1990 Jan;24(1):27-8.|3
00470|132|R|6.Linville D 2nd, Emory C, Graves L 3rd. Ciprofloxacin and warfarin|3
00470|133|R|  interaction. Am J Med 1991 Jun;90(6):765.|3
00470|134|R|7.Renzi R, Finkbeiner S. Ciprofloxacin interaction with sodium warfarin: a|3
00470|135|R|  potentially dangerous side effect. Am J Emerg Med 1991 Nov;9(6):551-2.|3
00470|136|R|8.Byrd DC, Gaskins SE, Parrish AM, Freeman LB. Warfarin and ciprofloxacin|3
00470|137|R|  interaction: case report and controversy. J Am Board Fam Pract 1999|3
00470|138|R|  Nov-Dec;12(6):486-8.|3
00470|139|R|9.Dugoni-Kramer BM. Ciprofloxacin-warfarin interaction. DICP 1991 Dec;|3
00470|140|R|  25(12):1397.|3
00470|141|R|10.Morawiecka I, Djelouah I, Willcox D. Fluoroquinolones and warfarin:|1
00470|142|R|   suspected interactions. Canadian Adverse Reaction Newsletter 2004 Jul;|1
00470|143|R|   14(3):1-2.|1
00470|144|R|11.Toon S, Hopkins KJ, Garstang FM, Aarons L, Sedman A, Rowland M.|2
00470|145|R|   Enoxacin-warfarin interaction: pharmacokinetic and stereochemical|2
00470|146|R|   aspects. Clin Pharmacol Ther 1987 Jul;42(1):33-41.|2
00470|147|R|12.McLeod AD, Burgess C. Drug interaction between warfarin and enoxacin. N Z|3
00470|148|R|   Med J 1988 Apr 27;101(844):216.|3
00470|149|R|13.Artymowicz RJ, Cino BJ, Rossi JG, Walker JL, Moore S. Possible|3
00470|150|R|   interaction between gatifloxacin and warfarin. Am J Health Syst Pharm|3
00470|151|R|   2002 Jun 15;59(12):1205-6.|3
00470|152|R|14.Efthymiopoulos C, Bramer SL, Maroli A, Blum B. Theophylline and warfarin|2
00470|153|R|   interaction studies with grepafloxacin. Clin Pharmacokinet 1997;33 Suppl|2
00470|154|R|   1:39-46.|2
00470|155|R|15.Yamreudeewong W, Lower DL, Kilpatrick DM, Enlow AM, Burrows MM, Greenwood|2
00470|156|R|   MC. Effect of levofloxacin coadministration on the international|2
00470|157|R|   normalized ratios during warfarin therapy. Pharmacotherapy 2003 Mar;|2
00470|158|R|   23(3):333-8.|2
00470|159|R|16.Liao S, Palmer M, Fowler C, Nayak RK. Absence of an effect of|2
00470|160|R|   levofloxacin on warfarin pharmacokinetics and anticoagulation in male|2
00470|161|R|   volunteers. J Clin Pharmacol 1996 Nov;36(11):1072-7.|2
00470|162|R|17.Ravnan SL, Locke C. Levofloxacin and warfarin interaction.|3
00470|163|R|   Pharmacotherapy 2001 Jul;21(7):884-5.|3
00470|164|R|18.Gheno G, Cinetto L. Levofloxacin-warfarin interaction. Eur J Clin|3
00470|165|R|   Pharmacol 2001 Aug;57(5):427.|3
00470|166|R|19.Jones CB, Fugate SE. Levofloxacin and warfarin interaction. Ann|3
00470|167|R|   Pharmacother 2002 Oct;36(10):1554-7.|3
00470|168|R|20.Elbe DH, Chang SW. Moxifloxacin-Warfarin Interaction: A Series of Five|3
00470|169|R|   Case Reports (February). Ann Pharmacother 2005 Jan 4.|3
00470|170|R|21.O'Connor KA, O'Mahony D. The interaction of moxifloxacin and warfarin in|3
00470|171|R|   three elderly patients. Eur J Intern Med 2003 Jul;14(4):255-257.|3
00470|172|R|22.Leor J, Levartowsky D, Sharon C. Interaction between nalidixic acid and|3
00470|173|R|   warfarin. Ann Intern Med 1987 Oct;107(4):601.|3
00470|174|R|23.Gullov AL, Koefoed BG, Petersen P. Interaction between warfarin and|3
00470|175|R|   nalidic acid. Ugeskr Laeger 1996 Sep 9;158(37):5174-5.|3
00470|176|R|24.Hoffbrand BI. Letter: Interaction of nalidixic acid and warfarin. Br Med|3
00470|177|R|   J 1974 Jun 22;2(920):666.|3
00470|178|R|25.Potasman I, Bassan H. Nicoumalone and nalidixic acid interaction. Ann|3
00470|179|R|   Intern Med 1980 Apr;92(4):571.|3
00470|180|R|26.Rocci ML Jr, Vlasses PH, Distlerath LM, Gregg MH, Wheeler SC, Zing W,|2
00470|181|R|   Bjornsson TD. Norfloxacin does not alter warfarin's disposition or|2
00470|182|R|   anticoagulant effect. J Clin Pharmacol 1990 Aug;30(8):728-32.|2
00470|183|R|27.Linville T, Matanin D. Norfloxacin and warfarin. Ann Intern Med 1989 May|3
00470|184|R|   1;110(9):751-2.|3
00470|185|R|28.Leor J, Matetzki S. Ofloxacin and warfarin. Ann Intern Med 1988 Nov 1;|3
00470|186|R|   109(9):761.|3
00470|187|R|29.Baciewicz AM, Ashar BH, Locke TW. Interaction of ofloxacin and warfarin.|3
00470|188|R|   Ann Intern Med 1993 Dec 15;119(12):1223.|3
00470|189|R|30.Millar E, Coles S, Wyld P, Nimmo W. Temafloxacin does not potentiate the|2
00470|190|R|   anticoagulant effect of warfarin in healthy subjects. Clin Pharmacokinet|2
00470|191|R|   1992;22 Suppl 1:102-6.|2
00470|192|R|31.Washington C, Hou SY, Hughes NC, Campanella C, Berner B. Ciprofloxacin|2
00470|193|R|   prolonged-release tablets do not affect warfarin pharmacokinetics and|2
00470|194|R|   pharmacodynamics. J Clin Pharmacol 2007 Oct;47(10):1320-6.|2
00470|195|R|32.Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin|6
00470|196|R|   Pharmacokinet 1997 Feb;32(2):101-19.|6
00470|197|R|33.Ahmed A, Stephens JC, Kaus CA, Fay WP. Impact of preemptive warfarin dose|2
00470|198|R|   reduction on anticoagulation after initiation  of|2
00470|199|R|   trimethoprim-sulfamethoxazole or levofloxacin. J Thromb Thrombolysis 2008|2
00470|200|R|   Aug;26(1):44-8.|2
00470|201|R|34.McCall KL, Scott JC, Anderson HG. Retrospective evaluation of a possible|2
00470|202|R|   interaction between warfarin and levofloxacin. Pharmacotherapy 2005 Jan;|2
00470|203|R|   25(1):67-73.|2
00470|204|R|35.Mercadal Orfila G, Gracia Garcia B, Leiva Badosa E, Perayre Badia M,|6
00470|205|R|   Reynaldo Martinez C, Jodar Masanes R. Retrospective assessment of|6
00470|206|R|   potential interaction between levofloxacin and warfarin. Pharm World Sci|6
00470|207|R|   2009 Apr;31(2):224-9.|6
00470|208|R|36.Ji Y, Hokayem Y. Moxifloxacin-warfarin interaction. J Community Hosp|3
00470|209|R|   Intern Med Perspect 2011;1(4):.|3
00470|210|R|37.Yew KL, Lee WC. Moxifloxacin-warfarin interaction. Med J Malaysia 2012|3
00470|211|R|   Aug;67(4):420-1.|3
00470|212|R|38.Stass H, Kubitza D. Profile of moxifloxacin drug interactions. Clin|2
00470|213|R|   Infect Dis 2001 Mar 15;32 Suppl 1:S47-50.|2
00470|214|R|39.Muijsers RB, Jarvis B. Moxifloxacin in uncomplicated skin and skin|6
00470|215|R|   structure infections. Drugs 2002;62(6):967-73; discussion 974-5.|6
00470|216|R|40.Chao CM, Lin SH, Lai CC. Abdominal wall hematoma and hemoperitoneum in an|3
00470|217|R|   individual with concomitant use  of warfarin and moxifloxacin. J Am|3
00470|218|R|   Geriatr Soc 2013 Aug;61(8):1432-3.|3
00470|219|R|41.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
00470|220|R|   Pharmaceuticals Corporation October 18, 2018.|1
00470|221|R|42.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00470|222|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00470|223|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
00470|224|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00471|001|T|MONOGRAPH TITLE:  Digoxin/Hydroxychloroquine|
00471|002|B||
00471|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00471|004|L|of severe adverse interaction.|
00471|005|B||
00471|006|A|MECHANISM OF ACTION:  Unknown. However, hydroxychloroquine may reduce the|
00471|007|A|renal and non-renal clearance of digoxin.|
00471|008|B||
00471|009|E|CLINICAL EFFECTS:  Plasma digoxin concentrations may be elevated, increasing|
00471|010|E|the toxic effects of digoxin. Symptoms of digoxin toxicity can include|
00471|011|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
00471|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
00471|013|E|disturbances, and arrhythmias.|
00471|014|B||
00471|015|P|PREDISPOSING FACTORS:  None determined.|
00471|016|B||
00471|017|M|PATIENT MANAGEMENT:  Monitor serum digoxin concentrations and observe the|
00471|018|M|patient for signs of toxicity when starting or stopping hydroxychloroquine.|
00471|019|M|Adjust the dose of digoxin as needed.|
00471|020|B||
00471|021|D|DISCUSSION:  Two patients stabilized on digoxin therapy experienced an|
00471|022|D|increase in serum digoxin levels when hydroxychloroquine was added to their|
00471|023|D|treatment. Plasma digoxin levels decreased when hydroxychloroquine was|
00471|024|D|discontinued.|
00471|025|B||
00471|026|R|REFERENCE:|
00471|027|B||
00471|028|R|1.Leden I. Digoxin-hydroxychloroquine interaction?. Acta Med Scand 1982;|3
00471|029|R|  211(5):411-2.|3
00472|001|T|MONOGRAPH TITLE:  Methyldopa/Beta-Blockers (Nonselective)|
00472|002|B||
00472|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00472|004|L|of severe adverse interaction.|
00472|005|B||
00472|006|A|MECHANISM OF ACTION:  Unopposed alpha-adrenergic vasoconstriction produced|
00472|007|A|by alpha-methylnorepinephrine in the presence of beta-blockade.|
00472|008|B||
00472|009|E|CLINICAL EFFECTS:  Severe hypertension.|
00472|010|B||
00472|011|P|PREDISPOSING FACTORS:  None determined.|
00472|012|B||
00472|013|M|PATIENT MANAGEMENT:  Monitor blood pressure during concomitant|
00472|014|M|administration of methyldopa and a nonselective beta-blocker. If|
00472|015|M|hypertension occurs, treatment with phentolamine should be considered.|
00472|016|B||
00472|017|D|DISCUSSION:  Although methyldopa and propranolol have been used together to|
00472|018|D|treat hypertension, severe increases in blood pressure, including death in|
00472|019|D|one patient, has been reported during administration of these drugs. In|
00472|020|D|addition, methyldopa alone has been reported to cause paradoxical|
00472|021|D|hypertension. Additional studies are needed to define the specific|
00472|022|D|population at risk.|
00472|023|B||
00472|024|R|REFERENCES:|
00472|025|B||
00472|026|R|1.Nies AS, Shand DG. Hypertensive response to propranolol in a patient|5
00472|027|R|  treated with methyldopa--a proposed mechansim. Clin Pharmacol Ther 1973|5
00472|028|R|  Sep-Oct;14(5):823-6.|5
00472|029|R|2.Petrie JC, Galloway DB, Jeffers TA, Millar HR, Smith MC, Wood RA, Lewis|2
00472|030|R|  JA, Simpson WT. Methyldopa and propranolol or practolol in moderate|2
00472|031|R|  hypertension. Br Med J 1976 Jul 17;2(6028):137-9.|2
00472|032|R|3.McLaren EH. Severe hypertension produced by interaction of|3
00472|033|R|  phenylpropanolamine with methyldopa and oxprenolol. Br Med J 1976 Jul 31;|3
00472|034|R|  2(6030):283-4.|3
00472|035|R|4.Zehnle CG. Paradoxical hypertension experienced during methyldopa therapy.|3
00472|036|R|  Am J Hosp Pharm 1981 Nov;38(11):1774-5.|3
00473|001|T|MONOGRAPH TITLE:  Selected Opioid Analgesics/Cimetidine|
00473|002|B||
00473|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00473|004|L|take action as needed.|
00473|005|B||
00473|006|A|MECHANISM OF ACTION:  The metabolism of selected opioid analgesics may be|
00473|007|A|inhibited by cimetidine.(1-15)  At doses of 800-2400 mg daily, cimetidine is|
00473|008|A|a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP1A2, CYP2C19,|
00473|009|A|CYP2C9, and CYP2D6.(16)|
00473|010|A|   Benzhydrocodone is a prodrug of hydrocodone.(12)|
00473|011|B||
00473|012|E|CLINICAL EFFECTS:  The effect of selected opioid analgesics may be increased|
00473|013|E|including profound sedation, respiratory depression, coma, and/or death.|
00473|014|E|   Opioid analgesics have been associated with histamine release and is|
00473|015|E|dependent on dose, route of administration, and rate of administration.|
00473|016|E|Histamine release can cause arteriole dilation and contribute to a profound|
00473|017|E|decrease in systemic blood pressure.  The cardiovascular effects of|
00473|018|E|histamine release occurring with the opioid analgesics may be decreased by|
00473|019|E|giving cimetidine concurrently.()|
00473|020|B||
00473|021|P|PREDISPOSING FACTORS:  None determined.|
00473|022|B||
00473|023|M|PATIENT MANAGEMENT:  Cimetidine use at higher doses of 200-400 mg four times|
00473|024|M|daily would have an increased risk of inhibiting the metabolism of opioid|
00473|025|M|analgesics.  Lower doses and over-the-counter doses of cimetidine would be|
00473|026|M|expected to have a diminished effect.  Consider using alternative H2|
00473|027|M|antagonists when long-term concurrent therapy with opioid analgesics is|
00473|028|M|indicated.|
00473|029|M|   The manufacturer of sufentanil sublingual tablets states that if|
00473|030|M|concomitant use with CYP3A4 inhibitors is necessary, consider use of an|
00473|031|M|alternate agent that allows dose adjustment.(15)|
00473|032|M|   Respiratory depression can occur at any time during opioid therapy,|
00473|033|M|especially during therapy initiation and following dosage increases.  The|
00473|034|M|risk of opioid-related overdose or overdose-related death is increased with|
00473|035|M|higher opioid doses, and this risk persists over the course of therapy.|
00473|036|M|Consider these risks when using concurrently with other agents that may|
00473|037|M|cause CNS depression.(17)|
00473|038|M|   Monitor the patient for increased adverse effects of the opioid analgesic|
00473|039|M|including respiratory and central nervous system depression, unusual|
00473|040|M|dizziness or lightheadedness, extreme sleepiness, slowed or difficult|
00473|041|M|breathing, or unresponsiveness.|
00473|042|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
00473|043|M|patients when prescribing or renewing an opioid analgesic or medicine to|
00473|044|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
00473|045|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
00473|046|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
00473|047|M|as those taking CNS depressants) and when a patient has household|
00473|048|M|members/close contacts at risk for accidental overdose.  Discuss the options|
00473|049|M|for obtaining an opioid reversal agent (e.g., prescription,|
00473|050|M|over-the-counter, or as part of a community-based program).(18)|
00473|051|B||
00473|052|D|DISCUSSION:  Severe respiratory depression has been reported with the|
00473|053|D|concurrent administration of opioid analgesics and cimetidine.  Systemic|
00473|054|D|levels of opioid analgesics metabolized by CYP3A4 may be increased during|
00473|055|D|concurrent use with cimetidine, a CYP3A4 inhibitor.(1-15)|
00473|056|D|   In a study of 6 healthy subjects, the effects of ketoconazole (a strong|
00473|057|D|CYP3A4 inhibitor) 400 mg daily for 3 days on alfentanil were studied.  The|
00473|058|D|maximum concentration (Cmax) and area-under-curve (AUC) of alfentanil were|
00473|059|D|increased with both sequential and simultaneous dosing of alfentanil with|
00473|060|D|concurrent ketoconazole.(19)|
00473|061|D|   In a study of 16 healthy subjects, the effects of ketoconazole 300 mg|
00473|062|D|twice daily for 2 days on fentanyl 5 mcg/kg single dose were examined.|
00473|063|D|Fentanyl AUC was increased by 133% and clearance was reduced to 78%.  The|
00473|064|D|metabolism of fentanyl to norfentanyl by CYP3A4 was delayed and partial|
00473|065|D|metabolic clearance decreased by 18% with concurrent ketoconazole.(20)|
00473|066|D|   In vitro results of the effects of ketoconazole on hydrocodone confirmed|
00473|067|D|CYP3A4 is responsible for the metabolism of hydrocodone to|
00473|068|D|norhydrocodone.(21)|
00473|069|D|   A review discussed the metabolism of hydrocodone by CYP2D6 to|
00473|070|D|O-demethylated hydromorphone and by CYP3A4 to N-demethylated norhydrocodone.|
00473|071|D|CYP3A4 activity is reported as higher in women resulting in higher|
00473|072|D|fractions of the norhydrocodone metabolite in women than in men.(22)|
00473|073|D|   A case report of a 46 year old hemodialysis patient was on routine|
00473|074|D|therapy with phenytoin 100 mg three times daily and cimetidine 300 mg three|
00473|075|D|times daily.  Four days after starting cimetidine, morphine 15 mg IM every 4|
00473|076|D|hours was initiated for pain.  After the sixth dose of morphine, the patient|
00473|077|D|was apneic with a respiratory rate of 3 breaths/minute and had a grand mal|
00473|078|D|seizure.  The patient responded to naloxone 0.4 mg IV single dose with|
00473|079|D|improvement in respiratory rate to 12 breaths/minute.  Cimetidine was|
00473|080|D|stopped and phenytoin decreased to 100 mg twice daily with improvement after|
00473|081|D|80 hours from initial episode.  A month later the patient required surgery|
00473|082|D|and was given cimetidine 150 mg twice daily followed by Pantopon 15 mg IM|
00473|083|D|every 3-6 hours postoperatively for pain.  The patient again became apneic,|
00473|084|D|confused, and developed muscle twitching which responded to naloxone 0.4 mg|
00473|085|D|for 4 doses over the next 24 hours with complete recovery.(23)|
00473|086|D|   In a study of 8 healthy subjects, the effects of cimetidine on morphine|
00473|087|D|were studied.  Subjects were evaluated in three study periods: morphine 10|
00473|088|D|mg IM single dose; cimetidine 600 mg oral given one hour before morphine 10|
00473|089|D|mg IM single dose; and cimetidine 600 mg oral single dose.  Morphine reduced|
00473|090|D|resting ventilation and increased end-tidal CO2 with peak effects at 120|
00473|091|D|minutes and resolution at 12 hours.  Morphine with cimetidine pretreatment|
00473|092|D|had similar effects on resting ventilation and end-tidal CO2, however the|
00473|093|D|recovery ratio from 120 to 720 minutes was significantly different than|
00473|094|D|morphine alone (p<0.05).(24)|
00473|095|D|   In a study of 7 healthy subjects, the effects of cimetidine 300 mg oral|
00473|096|D|four times daily for 4 days on morphine 10 mg IV single dose were evaluated.|
00473|097|D|No significant differences were found in morphine concentrations at any|
00473|098|D|time point from zero to ten hours after dose administration with and without|
00473|099|D|cimetidine.  Morphine elimination half-life (t1/2), systemic clearance,|
00473|100|D|volume of distribution, and AUC with and without cimetidine had no|
00473|101|D|statistical differences.(25)|
00473|102|D|   In a study of 40 patients undergoing elective coronary artery bypass|
00473|103|D|graft surgery were randomized to receive either cimetidine 4 mg/kg,|
00473|104|D|diphenhydramine 1 mg/kg, a combination of both cimetidine and|
00473|105|D|diphenhydramine, or placebo, followed by morphine 1 mg/kg.  Patients were|
00473|106|D|randomized to one of four groups: 1. placebo plus morphine; 2. cimetidine|
00473|107|D|plus morphine; 3. diphenhydramine plus morphine; or 4. cimetidine plus|
00473|108|D|diphenhydramine plus morphine.  Patients in group 1 had a 10-fold increase|
00473|109|D|in plasma histamine levels within 2 minutes of morphine with a decrease in|
00473|110|D|mean BP, diastolic BP, and systemic vascular resistance (SVR).  Group 2 has|
00473|111|D|similar effects with a peak change in SVR and plasma histamine rise within 2|
00473|112|D|minutes of morphine.  The change in SVR was significant when compared to|
00473|113|D|placebo but less than group 1.  Group 3 patients had an increase in heart|
00473|114|D|rate (HR) from diphenhydramine alone as well as peak effects within 2|
00473|115|D|minutes of morphine with decreases in BP and SVR but were less than morphine|
00473|116|D|alone.  Group 4 patients had a 7-fold increase in histamine with a|
00473|117|D|significant increase in HR, diastolic BP, and BP.  When group 4 is compared|
00473|118|D|to group 1, patients had a decrease in SVR and diastolic BP that was|
00473|119|D|significantly less despite comparable increases in plasma histamine.(26)|
00473|120|D|   In vitro testing of oxycodone and methadone, cimetidine caused a greater|
00473|121|D|than 50% inhibition in all pathways: CYP2B6, CYP3A4, CYP2C18, and CYP2D6.|
00473|122|D|Cimetidine was found to be a weak reversible inhibitor in vitro.|
00473|123|D|Extrapolation of the data to in vivo inhibition is unlikely to produce|
00473|124|D|significant inhibition unless concentrations exceed normal doses by|
00473|125|D|10-fold.(27)|
00473|126|D|   Two studies examined the effects of CYP2D6 and CYP3A4 on the metabolism|
00473|127|D|of oxycodone as well as genetic polymorphism influences.  After concurrent|
00473|128|D|administration of oxycodone with ketoconazole, the Cmax of the metabolites|
00473|129|D|noroxycodone and noroxymorphone were decreased by 80% from baseline.(28,29)|
00473|130|D|   A review discussed the metabolism of oxycodone by CYP3A4 to noroxycodone,|
00473|131|D|the major metabolite with weak antinociceptive properties, and by CYP2D6 to|
00473|132|D|the active minor metabolite oxymorphone.()|
00473|133|D|   In a study of 8 male subjects, effects of cimetidine 600 mg twice daily|
00473|134|D|for seven days on pethidine 70 mg IV single dose was evaluated.  Concurrent|
00473|135|D|use with cimetidine was associated with a 22% decrease in clearance, 11%|
00473|136|D|decrease in elimination rate, and a 13% decrease in volume of distribution|
00473|137|D|of pethidine.  Changes were also seen in norpethidine, the primary|
00473|138|D|metabolite, with a 23% decrease in AUC and 29% decrease in Cmax.(30)|
00473|139|D|   Opioid analgesics linked to this monograph include: alfentanil,|
00473|140|D|benzhydrocodone, dihydrocodeine, fentanyl, hydrocodone, meperidine,|
00473|141|D|meptazinol, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene,|
00473|142|D|and sufentanil.|
00473|143|B||
00473|144|R|REFERENCES:|
00473|145|B||
00473|146|R|1.Tagamet (cimetidine) US prescribing information. GlaxoSmithKline December,|1
00473|147|R|  2005.|1
00473|148|R|2.Soleimanpour H, Safari S, Shahsavari Nia K, Sanaie S, Alavian SM. Opioid|6
00473|149|R|  Drugs in Patients With Liver Disease: A Systematic Review. Hepat Mon 2016|6
00473|150|R|  Apr;16(4):e32636.|6
00473|151|R|3.MacKenzie M, Zed PJ, Ensom MH. Opioid Pharmacokinetics-Pharmacodynamics:|6
00473|152|R|  Clinical Implications in Acute Pain Management in Trauma. Ann Pharmacother|6
00473|153|R|  2016 Mar;50(3):209-18.|6
00473|154|R|4.Kotlinska-Lemieszek A, Klepstad P, Haugen DF. Clinically significant|6
00473|155|R|  drug-drug interactions involving opioid analgesics used for pain treatment|6
00473|156|R|  in patients with cancer: a systematic review. Drug Des Devel Ther 2015;|6
00473|157|R|  9:5255-67.|6
00473|158|R|5.Stadol (butorphanol tartrate) US prescribing information. Bristol-Myers|1
00473|159|R|  Squibb April, 2002.|1
00473|160|R|6.Zohydro ER (hydrocodone bitarate) US prescribing information. Zogenix Inc.|1
00473|161|R|  October, 2019.|1
00473|162|R|7.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
00473|163|R|  Pharmaceuticals LLC. December, 2023.|1
00473|164|R|8.Nubain (nalbuphine hydrochloride) US prescribing information. Endo|1
00473|165|R|  Pharmaceuticals Inc. October, 2019.|1
00473|166|R|9.OxyContin (oxycodone hydrochloride) US prescribing information. Perdue|1
00473|167|R|  Pharma L.P. October, 2021.|1
00473|168|R|10.Opana ER (oxymorphone hydrochloride) US prescribing information. Endo|1
00473|169|R|   Pharmaceuticals, Inc. October, 2019.|1
00473|170|R|11.Dilaudid (hydromorphone) US prescribing information. Fresenius Kabi USA,|1
00473|171|R|   LLC October, 2019.|1
00473|172|R|12.Apadaz (benzhydrocodone and acetaminophen) US prescribing information.|1
00473|173|R|   KemPharm, Inc.. December, 2023.|1
00473|174|R|13.Actiq (fentanyl citrate) Australian prescribing information. Orphan|1
00473|175|R|   Australia Pty Ltd. November 2, 2002.|1
00473|176|R|14.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
00473|177|R|   Inc. October, 2019.|1
00473|178|R|15.Dsuvia (sufentanil) sublingual tablet US prescribing information. AcelRx|1
00473|179|R|   Pharmaceuticals, Inc. December, 2023.|1
00473|180|R|16.This information is based on an extract from the Certara Drug Interaction|6
00473|181|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00473|182|R|17.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
00473|183|R|   updates prescribing information for all opioid pain medicines to provide|1
00473|184|R|   additional guidance for safe use. Available at:|1
00473|185|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescr|1
00473|186|R|   ibing-information-all-opioid-pain-medicines-provide-additional-guidance-s|1
00473|187|R|   afe-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
00473|188|R|18.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
00473|189|R|   recommends health care professionals discuss naloxone with all patients|1
00473|190|R|   when prescribing opioid pain relievers or medicines to treat opioid use|1
00473|191|R|   disorder. Available at:|1
00473|192|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-hea|1
00473|193|R|   lth-care-professionals-discuss-naloxone-all-patients-when-prescribing-opi|1
00473|194|R|   oid-pain July 23, 2020.|1
00473|195|R|19.Kharasch ED, Vangveravong S, Buck N, London A, Kim T, Blood J, Mach RH.|2
00473|196|R|   Concurrent assessment of hepatic and intestinal cytochrome P450 3A|2
00473|197|R|   activities using deuterated alfentanil. Clin Pharmacol Ther 2011 Apr;|2
00473|198|R|   89(4):562-70.|2
00473|199|R|20.Ziesenitz VC, Konig SK, Mahlke NS, Skopp G, Haefeli WE, Mikus G.|2
00473|200|R|   Pharmacokinetic interaction of intravenous fentanyl with ketoconazole. J|2
00473|201|R|   Clin Pharmacol 2015 Jun;55(6):708-17.|2
00473|202|R|21.Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA. CYP2D6 and|5
00473|203|R|   CYP3A4 involvement in the primary oxidative metabolism of hydrocodone  by|5
00473|204|R|   human liver microsomes. Br J Clin Pharmacol 2004 Mar;57(3):287-97.|5
00473|205|R|22.Graziani M, Nistico R. Gender difference in prescription opioid abuse: A|6
00473|206|R|   focus on oxycodone and hydrocodone. Pharmacol Res 2016 Apr 20;108:31-38.|6
00473|207|R|23.Fine A, Churchill DN. Potentially lethal interaction of cimetidine and|3
00473|208|R|   morphine. Can Med Assoc J 1981 Jun 1;124(11):1434-6.|3
00473|209|R|24.Lam AM, Clement JL. Effect of cimetidine premedication on|2
00473|210|R|   morphine-induced ventilatory depression. Can Anaesth Soc J 1984 Jan;|2
00473|211|R|   31(1):36-43.|2
00473|212|R|25.Mojaverian P, Fedder IL, Vlasses PH, Rotmensch HH, Rocci ML Jr, Swanson|2
00473|213|R|   BN, Ferguson RK. Cimetidine does not alter morphine disposition in man.|2
00473|214|R|   Br J Clin Pharmacol 1982 Dec;14(6):809-13.|2
00473|215|R|26.Philbin DM, Moss J, Akins CW, Rosow CE, Kono K, Schneider RC, VerLee TR,|2
00473|216|R|   Savarese JJ. The use of H1 and H2 histamine antagonists with morphine|2
00473|217|R|   anesthesia: a double-blind study. Anesthesiology 1981 Sep;55(3):292-6.|2
00473|218|R|27.Moody DE, Liu F, Fang WB. In vitro inhibition of methadone and oxycodone|5
00473|219|R|   cytochrome P450-dependent metabolism: reversible inhibition by|5
00473|220|R|   H2-receptor agonists and proton-pump inhibitors. J Anal Toxicol 2013 Oct;|5
00473|221|R|   37(8):476-85.|5
00473|222|R|28.Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier|2
00473|223|R|   MF, Hochstrasser D, Dayer P, Desmeules JA. The effects of CYP2D6 and|2
00473|224|R|   CYP3A activities on the pharmacokinetics of immediate release oxycodone.|2
00473|225|R|   Br J Pharmacol 2010 Jun;160(4):907-18.|2
00473|226|R|29.Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier|2
00473|227|R|   MF, Hochstrasser D, Dayer P, Desmeules JA. Genetic polymorphisms and drug|2
00473|228|R|   interactions modulating CYP2D6 and CYP3A activities have a major effect|2
00473|229|R|   on oxycodone analgesic efficacy and safety. Br J Pharmacol 2010 Jun;|2
00473|230|R|   160(4):919-30.|2
00473|231|R|30.Guay DR, Meatherall RC, Chalmers JL, Grahame GR. Cimetidine alters|2
00473|232|R|   pethidine disposition in man. Br J Clin Pharmacol 1984 Dec;18(6):907-14.|2
00474|001|T|MONOGRAPH TITLE:  Felodipine/Selected Strong CYP3A4 Inducers|
00474|002|B||
00474|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00474|004|L|of severe adverse interaction.|
00474|005|B||
00474|006|A|MECHANISM OF ACTION:  Felodipine is designated as a sensitive CYP3A4|
00474|007|A|substrate.  Strong CYP3A4 inducers may induce the metabolism of felodipine|
00474|008|A|and decrease exposure (area-under-curve, AUC) by 80% or more.(1-2)|
00474|009|A|   Primidone is metabolized to phenobarbital.|
00474|010|B||
00474|011|E|CLINICAL EFFECTS:  Serum levels and bioavailability of felodipine may be|
00474|012|E|decreased resulting in a decrease or loss of antihypertensive or antianginal|
00474|013|E|effects.|
00474|014|B||
00474|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00474|016|P|of the inducer for longer than 1-2 weeks.|
00474|017|B||
00474|018|M|PATIENT MANAGEMENT:  The US manufacturer of felodipine states that|
00474|019|M|alternative antihypertensive agents should be considered in patients taking|
00474|020|M|anticonvulsants that induce CYP3A4.(1)  Although there are no specific|
00474|021|M|recommendations for other strong CYP3A4 inducers, a clinically significant|
00474|022|M|interaction can be expected and a similar approach is reasonable with|
00474|023|M|concurrent use.|
00474|024|M|   Monitor antihypertensive response and adjust the dose of felodipine as|
00474|025|M|needed.|
00474|026|M|   In patients already receiving felodipine when the CYP3A4 inducer is|
00474|027|M|started, the onset of this interaction may be delayed, and maximal induction|
00474|028|M|effects may not be seen for 2 or more weeks.  Monitor antihypertensive|
00474|029|M|response and adjust the dose of felodipine as needed.|
00474|030|M|   In patients stabilized on the CYP3A4 inducer therapy, the addition of|
00474|031|M|felodipine may not be effective for treatment of hypertension or angina.|
00474|032|B||
00474|033|D|DISCUSSION:  A study in healthy subjects compared felodipine exposure in|
00474|034|D|patients receiving felodipine alone or with another strong CYP3A4 inducer|
00474|035|D|(phenytoin).  Combination therapy reduced felodipine exposure|
00474|036|D|(area-under-curve, AUC) by 94%.(3)|
00474|037|D|   Felodipine levels have been shown to be reduced by 90% in patients taking|
00474|038|D|anticonvulsants such as carbamazepine.|
00474|039|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
00474|040|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
00474|041|D|mitotane, phenobarbital, phenytoin and primidone.(2,4)|
00474|042|B||
00474|043|R|REFERENCES:|
00474|044|B||
00474|045|R|1.Plendil (felodipine) US prescribing information. AstraZeneca|1
00474|046|R|  Pharmaceuticals LP November, 2003.|1
00474|047|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
00474|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
00474|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
00474|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
00474|051|R|  11/14/2017.|1
00474|052|R|3.Capewell S, Freestone S, Critchley JA, Pottage A, Prescott LF. Reduced|2
00474|053|R|  felodipine bioavailability in patients taking anticonvulsants. Lancet 1988|2
00474|054|R|  Aug 27;2(8609):480-2.|2
00474|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
00474|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
00475|001|T|MONOGRAPH TITLE:  Felodipine/Hydantoins (mono deleted 06/09/2011)|
00475|002|B||
00475|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00475|004|L|of severe adverse interaction.|
00475|005|B||
00475|006|A|MECHANISM OF ACTION:  Hydantoins may induce the metabolism of felodipine.|
00475|007|B||
00475|008|E|CLINICAL EFFECTS:  Concurrent use of hydantoins may result in dramatically|
00475|009|E|reduced levels of felodipine, resulting in a lack of antihypertensive|
00475|010|E|effects.|
00475|011|B||
00475|012|P|PREDISPOSING FACTORS:  None determined.|
00475|013|B||
00475|014|M|PATIENT MANAGEMENT:  The US manufacturer of felodipine state that|
00475|015|M|alternative antihypertensive agents should be considered in patients taking|
00475|016|M|phenytoin.(1)|
00475|017|B||
00475|018|D|DISCUSSION:  In a study comparing patients receiving felodipine with|
00475|019|D|enzyme-inducing anticonvulsants such as phenytoin with felodipine levels in|
00475|020|D|healthy subjects, felodipine area-under-curve (AUC) was decreased by 94%.(1)|
00475|021|D|   Compared to control patients receiving felodipine alone, decreased serum|
00475|022|D|concentrations, bioavailability and half-life of felodipine in two epileptic|
00475|023|D|patients during concurrent administration of phenytoin.  A similar effect|
00475|024|D|was noted in other epileptic patients who were receiving felodipine with|
00475|025|D|other anticonvulsant drugs that were also potent inducers of hepatic mixed|
00475|026|D|function oxidases. The same pharmacokinetic effects occurred in three|
00475|027|D|patients receiving felodipine during concurrent administration of phenytoin|
00475|028|D|and carbamazepine.(2)|
00475|029|B||
00475|030|R|REFERENCES:|
00475|031|B||
00475|032|R|1.Plendil (felodipine) US prescribing information. AstraZeneca|1
00475|033|R|  Pharmaceuticals LP November, 2003.|1
00475|034|R|2.Capewell S, Freestone S, Critchley JA, Pottage A, Prescott LF. Reduced|2
00475|035|R|  felodipine bioavailability in patients taking anticonvulsants. Lancet 1988|2
00475|036|R|  Aug 27;2(8609):480-2.|2
00476|001|T|MONOGRAPH TITLE:  Gemfibrozil/Anticoagulants  (mono deleted 09/27/2001)|
00476|002|B||
00476|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00476|004|L|of severe adverse interaction.|
00476|005|B||
00476|006|A|MECHANISM OF ACTION:  Unknown.|
00476|007|B||
00476|008|E|CLINICAL EFFECTS:  The hypoprothrombinemic response to anticoagulants may be|
00476|009|E|increased.|
00476|010|B||
00476|011|P|PREDISPOSING FACTORS:  None determined.|
00476|012|B||
00476|013|M|PATIENT MANAGEMENT:  Monitor anticoagulant activity when initiating or|
00476|014|M|discontinuing treatment with gemfibrozil in patients receiving|
00476|015|M|anticoagulants. Adjust the dose of anticoagulant as needed.|
00476|016|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00476|017|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00476|018|M|initiating, altering the dose or discontinuing either drug.|
00476|019|B||
00476|020|D|DISCUSSION:  A single report of an increase in prothrombin time was reported|
00476|021|D|in a 38-year-old woman stabilized on warfarin 5 mg daily following the|
00476|022|D|addition of gemfibrozil 1.2 gm daily to her therapy. In order to maintain an|
00476|023|D|adequate response to warfarin the dose was decreased to 2.5 mg daily.|
00476|024|B||
00476|025|R|REFERENCE:|
00476|026|B||
00476|027|R|1.Ahmad S. Gemfibrozil interaction with warfarin sodium (coumadin). Chest|3
00476|028|R|  1990 Oct;98(4):1041-2.|3
00477|001|T|MONOGRAPH TITLE:  Theophyllines/Thiabendazole|
00477|002|B||
00477|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00477|004|L|take action as needed.|
00477|005|B||
00477|006|A|MECHANISM OF ACTION:  Unknown. Possibly inhibition of theophylline|
00477|007|A|metabolism by thiabendazole.|
00477|008|B||
00477|009|E|CLINICAL EFFECTS:  Possible theophylline toxicity.|
00477|010|B||
00477|011|P|PREDISPOSING FACTORS:  None determined.|
00477|012|B||
00477|013|M|PATIENT MANAGEMENT:  Monitor serum theophylline concentrations and observe|
00477|014|M|the patient for signs of theophylline toxicity when thiabendazole is|
00477|015|M|started. Adjust the dose of theophylline as needed.|
00477|016|B||
00477|017|D|DISCUSSION:  Three case reports and the results of a randomized crossover|
00477|018|D|study in 6 healthy volunteers have found theophylline concentrations to be|
00477|019|D|increased by the administration of thiabendazole. The crossover study also|
00477|020|D|demonstrated that thiabendazole increased theophylline half-life and|
00477|021|D|decreased the clearance and elimination rate constant of theophylline.|
00477|022|D|Symptoms of theophylline toxicity were observed in some cases.|
00477|023|B||
00477|024|R|REFERENCES:|
00477|025|B||
00477|026|R|1.Sugar AM, Kearns PJ Jr, Haulk AA, Rushing JL. Possible|3
00477|027|R|  thiabendazole-induced theophylline toxicity. Am Rev Respir Dis 1980 Sep;|3
00477|028|R|  122(3):501-3.|3
00477|029|R|2.Lew G, Murray WE, Lane JR, Haeger E. Theophylline-thiabendazole drug|3
00477|030|R|  interaction. Clin Pharm 1989 Mar;8(3):225-7.|3
00477|031|R|3.Schneider D, Gannon R, Sweeney K, Shore E. Theophylline and antiparasitic|2
00477|032|R|  drug interactions. A case report and study of the influence of|2
00477|033|R|  thiabendazole and mebendazole on theophylline pharmacokinetics in adults.|2
00477|034|R|  Chest 1990 Jan;97(1):84-7.|2
00478|001|T|MONOGRAPH TITLE:  Levodopa/Hydantoins (mono deleted 02/03/2022)|
00478|002|B||
00478|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00478|004|L|take action as needed.|
00478|005|B||
00478|006|A|MECHANISM OF ACTION:  Unknown.|
00478|007|B||
00478|008|E|CLINICAL EFFECTS:  The pharmacological effects of levodopa may be decreased.|
00478|009|B||
00478|010|P|PREDISPOSING FACTORS:  None determined.|
00478|011|B||
00478|012|M|PATIENT MANAGEMENT:  If this drug combination cannot be avoided, it may be|
00478|013|M|necessary to use a larger than usual dose of levodopa.|
00478|014|B||
00478|015|D|DISCUSSION:  In 5 parkinsonism patients and 2 patients with chronic|
00478|016|D|manganese poisoning, administration of phenytoin reversed the therapeutic|
00478|017|D|benefits of levodopa.|
00478|018|B||
00478|019|R|REFERENCES:|
00478|020|B||
00478|021|R|1.Mendez JS, Cotzias GC, Mena I, Papavasiliou PS. Diphenylhydantoin.|2
00478|022|R|  Blocking of levodopa effects. Arch Neurol 1975 Jan;32(1):44-6.|2
00478|023|R|2.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
00478|024|R|  February, 2011.|1
00479|001|T|MONOGRAPH TITLE:  Selected Azole Antifungal Agents/Hydantoins (mono deleted|
00479|002|T|10/01/2014)|
00479|003|B||
00479|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00479|005|L|of severe adverse interaction.|
00479|006|B||
00479|007|A|MECHANISM OF ACTION:  Fluconazole and miconazole are suspected to inhibit|
00479|008|A|the hepatic metabolism of phenytoin.  Phenytoin is believed to induce the|
00479|009|A|metabolism of itraconazole and voriconazole, while itraconazole and|
00479|010|A|voriconazole may inhibit the metabolism of phenytoin.|
00479|011|B||
00479|012|E|CLINICAL EFFECTS:  The pharmacological and adverse effects of phenytoin may|
00479|013|E|be increased during fluconazole, itraconazole, miconazole, or voriconazole|
00479|014|E|therapy.  The pharmacological effects of itraconazole and voriconazole may|
00479|015|E|be decreased during concurrent therapy with phenytoin.|
00479|016|B||
00479|017|P|PREDISPOSING FACTORS:  None determined.|
00479|018|B||
00479|019|M|PATIENT MANAGEMENT:  Monitor plasma phenytoin concentrations and observe the|
00479|020|M|patient for symptoms of phenytoin toxicity when fluconazole, itraconazole,|
00479|021|M|miconazole, or voriconazole are initiated.  If the azole antifungal is|
00479|022|M|discontinued, there may be a decrease in phenytoin efficacy requiring|
00479|023|M|another dosage adjustment.|
00479|024|M|   If concurrent therapy with itraconazole and phenytoin is required, the|
00479|025|M|manufacturer of itraconazole recommends monitoring itraconazole levels and|
00479|026|M|adjusting itraconazole dosage if necessary.|
00479|027|M|   The manufacturer recommends that the dosage of voriconazole be increased|
00479|028|M|from 4 mg/kg to 5 mg/kg intravenously every 12 hours or from 200 mg to 400|
00479|029|M|mg orally every 12 hours (from 100 mg to 200 mg every 12 hours in patients|
00479|030|M|less than 40 kg).|
00479|031|B||
00479|032|D|DISCUSSION:  Case reports have documented the occurrence of phenytoin|
00479|033|D|toxicity when miconazole was added to the treatment of patients receiving|
00479|034|D|phenytoin.|
00479|035|D|   In healthy subjects, phenytoin (300 mg once daily) decreased the|
00479|036|D|voriconazole (200 mg every 12 hours for 14 days) maximum concentration|
00479|037|D|(Cmax) and AUC by 50% and 70% respectively.  Administration of voriconazole|
00479|038|D|at a dose of 400 mg twice daily resulted in comparable levels of|
00479|039|D|voriconazole when voriconazole 200 mg twice daily was given without|
00479|040|D|phenytoin.  In healthy subjects, voriconazole (400 mg every 12 hours for 10|
00479|041|D|days) increased phenytoin (300 mg daily) Cmax and AUC by 70% and 80%,|
00479|042|D|respectively.  Phenytoin Cmax and AUC may be expected to double when given|
00479|043|D|with voriconazole.|
00479|044|B||
00479|045|R|REFERENCES:|
00479|046|B||
00479|047|R|1.Rolan PE, Somogyi AA, Drew MJ, Cobain WG, South D, Bochner F. Phenytoin|3
00479|048|R|  intoxication during treatment with parenteral miconazole. Br Med J (Clin|3
00479|049|R|  Res Ed) 1983 Dec 10;287(6407):1760.|3
00479|050|R|2.Vfend (voriconazole) US prescribing information. Pfizer Inc. November,|1
00479|051|R|  2011.|1
00480|001|T|MONOGRAPH TITLE:  Disopyramide/Selected Hydantoins|
00480|002|B||
00480|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00480|004|L|take action as needed.|
00480|005|B||
00480|006|A|MECHANISM OF ACTION:  The hepatic metabolism of disopyramide may be|
00480|007|A|increased.|
00480|008|B||
00480|009|E|CLINICAL EFFECTS:  The pharmacologic effects of disopyramide may be|
00480|010|E|decreased while anticholinergic side effects associated with the metabolite|
00480|011|E|of disopyramide may occur.|
00480|012|B||
00480|013|P|PREDISPOSING FACTORS:  None determined.|
00480|014|B||
00480|015|M|PATIENT MANAGEMENT:  Monitor serum disopyramide concentrations when starting|
00480|016|M|or stopping phenytoin. Adjust the dose of disopyramide accordingly.|
00480|017|B||
00480|018|D|DISCUSSION:  Administration of phenytoin to the therapeutic regimen of|
00480|019|D|patients receiving disopyramide has been reported to produce a decrease in|
00480|020|D|plasma disopyramide concentration, half-life and area under the serum|
00480|021|D|concentration-time curve. Disopyramide concentration increases after|
00480|022|D|discontinuing phenytoin. Coinciding with the decrease in disopyramide levels|
00480|023|D|is an increase in the concentration of the mono-N-dealkyldisopyramide|
00480|024|D|metabolite. The metabolite possess anticholinergic activity. Anticholinergic|
00480|025|D|effects have been reported during concurrent administration of disopyramide|
00480|026|D|and phenytoin.|
00480|027|B||
00480|028|R|REFERENCES:|
00480|029|B||
00480|030|R|1.Aitio ML, Vuorenmaa T. Enhanced metabolism and diminished efficacy of|2
00480|031|R|  disopyramide by enzyme induction?. Br J Clin Pharmacol 1980 Feb;|2
00480|032|R|  9(2):149-52.|2
00480|033|R|2.Aitio ML, Mansury L, Tala E, Haataja M, Aitio A. The effect of enzyme|2
00480|034|R|  induction on the metabolism of disopyramide in man. Br J Clin Pharmacol|2
00480|035|R|  1981 Mar;11(3):279-85.|2
00480|036|R|3.Aitio ML. Plasma concentrations and protein binding of disopyramide and|2
00480|037|R|  mono-N- dealkyldisopyramide during chronic oral disopyramide therapy. Br J|2
00480|038|R|  Clin Pharmacol 1981 Apr;11(4):369-75.|2
00480|039|R|4.Matos JA, Fisher JD, Kim SG. Disopyramide - phenytoin interaction. Clin|4
00480|040|R|  Res 1981;29(3):655A.|4
00480|041|R|5.Kessler JM, Keys PW, Stafford RW. Disopyramide and phenytoin interaction.|3
00480|042|R|  Clin Pharm 1982 May-Jun;1(3):263-4.|3
00480|043|R|6.Nightingale J, Nappi JM. Effect of phenytoin on serum disopyramide|2
00480|044|R|  concentrations. Clin Pharm 1987 Jan;6(1):46-50.|2
00481|001|T|MONOGRAPH TITLE:  Selected Beta-Blockers/Hydralazine (mono deleted|
00481|002|T|02/03/2022)|
00481|003|B||
00481|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00481|005|L|take action as needed.|
00481|006|B||
00481|007|A|MECHANISM OF ACTION:  Hydralazine, a weak CY2D6 inhibitor, may increase|
00481|008|A|systemic availability of certain beta-blockers (e.g., metoprolol or|
00481|009|A|propranolol).|
00481|010|B||
00481|011|E|CLINICAL EFFECTS:  The pharmacologic and toxic effects of certain|
00481|012|E|beta-blockers may be increased in fasting subjects taking hydralazine.|
00481|013|B||
00481|014|P|PREDISPOSING FACTORS:  None determined.|
00481|015|B||
00481|016|M|PATIENT MANAGEMENT:  Observe the response of the patient to propranolol and|
00481|017|M|hydralazine when treatment with hydralazine is started or stopped.|
00481|018|M|Administration of a sustained-release form of the beta-blocker may|
00481|019|M|circumvent this interaction.|
00481|020|B||
00481|021|D|DISCUSSION:  Beta-blockers and hydralazine may be used concurrently for the|
00481|022|D|treatment of hypertension. In fasting subjects, concomitant administration|
00481|023|D|of hydralazine and propranolol increased the bioavailability and peak plasma|
00481|024|D|concentration of propranolol. This effect did not occur when hydralazine was|
00481|025|D|given to non-fasting subjects or with sustained-release propranolol.|
00481|026|D|Hydralazine has also been reported to increase the area under metoprolol|
00481|027|D|concentration-time curve.|
00481|028|B||
00481|029|R|REFERENCES:|
00481|030|B||
00481|031|R|1.Zacest R, Gilmore E, Koch-Weser J. Treatment of essential hypertension|2
00481|032|R|  with combined vasodilation and beta- adrenergic blockade. N Engl J Med|2
00481|033|R|  1972 Mar 23;286(12):617-22.|2
00481|034|R|2.Guevara J, Velasco M, Hernandez-Pieretti O. Treatment of severe essential|2
00481|035|R|  hypretension with combined hydralazine and propranolol. Curr Ther Res 1977|2
00481|036|R|  Mar;21(3):277-281.|2
00481|037|R|3.McLean AJ, Skews H, Bobik A, Dudley FJ. Interaction between oral|2
00481|038|R|  propranolol and hydralazine. Clin Pharmacol Ther 1980 Jun;27(6):726-32.|2
00481|039|R|4.Jackman GP, McLean AJ, Jennings GL, Bobik A. No stereoselective first-pass|2
00481|040|R|  hepatic extraction of propranolol. Clin Pharmacol Ther 1981 Sep;|2
00481|041|R|  30(3):291-6.|2
00481|042|R|5.Schneck DW, Vary JE. Mechanism by which hydralazine increases propranolol|2
00481|043|R|  bioavailability. Clin Pharmacol Ther 1984 Apr;35(4):447-53.|2
00481|044|R|6.Byrne AJ, McNeil JJ, Harrison PM, Louis W, Tonkin AM, McLean AJ. Stable|2
00481|045|R|  oral availability of sustained release propranolol when co- administered|2
00481|046|R|  with hydralazine or food: evidence implicating substrate delivery rate as|2
00481|047|R|  a determinant of presystemic drug interactions. Br J Clin Pharmacol 1984;|2
00481|048|R|  17 Suppl 1:45S-50S.|2
00481|049|R|7.Lindeberg S, Holm B, Lundborg P, Regardh CG, Sandstrom B. The effect of|2
00481|050|R|  hydralazine on steady-state plasma concentrations of metoprolol in|2
00481|051|R|  pregnant hypertensive women. Eur J Clin Pharmacol 1988;35(2):131-5.|2
00482|001|T|MONOGRAPH TITLE:  Digoxin, Oral/Antineoplastics|
00482|002|B||
00482|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00482|004|L|take action as needed.|
00482|005|B||
00482|006|A|MECHANISM OF ACTION:  Decreased gastrointestinal digoxin absorption.|
00482|007|B||
00482|008|E|CLINICAL EFFECTS:  The pharmacologic effects of digoxin may be decreased.|
00482|009|B||
00482|010|P|PREDISPOSING FACTORS:  None determined.|
00482|011|B||
00482|012|M|PATIENT MANAGEMENT:  Monitor serum digoxin concentrations and observe the|
00482|013|M|patient for a decrease in pharmacologic activity. Adjust the dose of digoxin|
00482|014|M|accordingly. Substituting digitoxin or digoxin capsules for digoxin tablets|
00482|015|M|may circumvent this interaction.|
00482|016|B||
00482|017|D|DISCUSSION:  There are a number of factors affecting the outcome of this|
00482|018|D|interaction. The effects of antineoplastic therapy on the gastrointestinal|
00482|019|D|absorption of digoxin have only been studied with certain chemotherapeutic|
00482|020|D|agents or regimens (e.g., bleomycin, carmustine, cyclophosphamide,|
00482|021|D|cytarabine, doxorubicin, methotrexate, procarbazine, vincristine). The|
00482|022|D|interaction appears to occur with the administration of oral digoxin tablets|
00482|023|D|as opposed to digoxin capsules. The gastrointestinal absorption of digitoxin|
00482|024|D|does not seem to be altered by antineoplastic therapy.|
00482|025|B||
00482|026|R|REFERENCES:|
00482|027|B||
00482|028|R|1.Kuhlmann J, Zilly W, Wilke J. Effects of cytostatic drugs on plasma level|2
00482|029|R|  and renal excretion of beta- acetyldigoxin. Clin Pharmacol Ther 1981 Oct;|2
00482|030|R|  30(4):518-27.|2
00482|031|R|2.Kuhlmann J, Wilke J, Rietbrock N. Cytostatic drugs are without significant|2
00482|032|R|  effect on digitoxin plasma level and renal excretion. Clin Pharmacol Ther|2
00482|033|R|  1982 Nov;32(5):646-51.|2
00482|034|R|3.Bjornsson TD, Huang AT, Roth P, Jacob DS, Christenson R. Effects of|2
00482|035|R|  high-dose cancer chemotherapy on the absorption of digoxin in two|2
00482|036|R|  different formulations. Clin Pharmacol Ther 1986 Jan;39(1):25-8.|2
00483|001|T|MONOGRAPH TITLE:  Beta-Blockers/Propafenone|
00483|002|B||
00483|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00483|004|L|take action as needed.|
00483|005|B||
00483|006|A|MECHANISM OF ACTION:  Propafenone increases the serum concentration of|
00483|007|A|certain beta-blockers (e.g., metoprolol and propranolol) by decreasing the|
00483|008|A|first-pass metabolism and by inhibition of metabolism.|
00483|009|B||
00483|010|E|CLINICAL EFFECTS:  The pharmacologic effect of certain beta-blockers may be|
00483|011|E|increased.|
00483|012|B||
00483|013|P|PREDISPOSING FACTORS:  None determined.|
00483|014|B||
00483|015|M|PATIENT MANAGEMENT:  Monitor cardiac function of patients receiving|
00483|016|M|beta-blockers when starting or stopping propafenone. Adjust the dose of the|
00483|017|M|beta-blocker accordingly.|
00483|018|B||
00483|019|D|DISCUSSION:  Serum concentrations of both metoprolol and propranolol have|
00483|020|D|been found to be increased by concurrent administration of propafenone. A|
00483|021|D|twofold increase in the steady state plasma level of propranolol was|
00483|022|D|measured while metoprolol concentrations increased from two to fivefold.|
00483|023|B||
00483|024|R|REFERENCES:|
00483|025|B||
00483|026|R|1.Wagner F, Kalusche D, Trenk D, Jahnchen E, Roskamm H. Drug interaction|2
00483|027|R|  between propafenone and metoprolol. Br J Clin Pharmacol 1987 Aug;|2
00483|028|R|  24(2):213-20.|2
00483|029|R|2.Kowey PR, Kirsten EB, Fu CH, Mason WD. Interaction between propranolol and|2
00483|030|R|  propafenone in healthy volunteers. J Clin Pharmacol 1989 Jun;29(6):512-7.|2
00484|001|T|MONOGRAPH TITLE:  Digoxin/Penicillamine|
00484|002|B||
00484|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00484|004|L|take action as needed.|
00484|005|B||
00484|006|A|MECHANISM OF ACTION:  Unknown.|
00484|007|B||
00484|008|E|CLINICAL EFFECTS:  Serum digoxin concentrations may be decreased.|
00484|009|B||
00484|010|P|PREDISPOSING FACTORS:  None determined.|
00484|011|B||
00484|012|M|PATIENT MANAGEMENT:  Monitor serum digoxin concentrations and observe the|
00484|013|M|patient for a decrease in pharmacologic activity when concurrent treatment|
00484|014|M|with penicillamine is started or stopped. Adjust the dose of digoxin|
00484|015|M|accordingly.  The dosage of digoxin may need to be increased by 20% to 40%.|
00484|016|B||
00484|017|D|DISCUSSION:  Penicillamine administration to adults or children has been|
00484|018|D|shown to decrease serum concentrations. The decrease occurred whether|
00484|019|D|digoxin was given orally or intravenously.|
00484|020|B||
00484|021|R|REFERENCES:|
00484|022|B||
00484|023|R|1.Moezzi B, Fatourechi V, Khozain R, Eslami B. The effect of penicillamine|2
00484|024|R|  on serum digoxin levels. Jpn Heart J 1978 May;19(3):366-75.|2
00484|025|R|2.Moezzi B, Khozein R, Pooymehr F, Shakibi JG. Reversal of digoxin-induced|2
00484|026|R|  changes in erythrocyte electrolyte concentrations by penicillamine in|2
00484|027|R|  children. Jpn Heart J 1980 May;21(3):335-9.|2
00484|028|R|3.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
00484|029|R|  Pharmaceuticals, Inc. August, 2018.|1
00485|001|T|MONOGRAPH TITLE:  Halothane/Rifampin|
00485|002|B||
00485|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00485|004|L|of severe adverse interaction.|
00485|005|B||
00485|006|A|MECHANISM OF ACTION:  Unknown.|
00485|007|B||
00485|008|E|CLINICAL EFFECTS:  Possible increased risk of hepatoxicity.|
00485|009|B||
00485|010|P|PREDISPOSING FACTORS:  None determined.|
00485|011|B||
00485|012|M|PATIENT MANAGEMENT:  Because of the seriousness of this interaction, avoid|
00485|013|M|the use of rifampin directly before or after halothane.|
00485|014|B||
00485|015|D|DISCUSSION:  Documentation for this interaction is very limited and may|
00485|016|D|involve the combined use of rifampin and isoniazid contiguously with|
00485|017|D|halothane.|
00485|018|B||
00485|019|R|REFERENCES:|
00485|020|B||
00485|021|R|1.Most JA, Markle GB 4th. A nearly fatal hepatotoxic reaction to rifampin|3
00485|022|R|  after halothane anesthesia. Am J Surg 1974 May;127(5):593-5.|3
00485|023|R|2.Pessayre D, Bentata M, Degott C, Nouel O, Miguet JP, Rueff B, Benhamou JP.|3
00485|024|R|  Isoniazid-rifampin fulminant hepatitis. A possible consequence of the|3
00485|025|R|  enhancement of isoniazid hepatotoxicity by enzyme induction.|3
00485|026|R|  Gastroenterology 1977 Feb;72(2):284-9.|3
00485|027|R|3.Bartelink AK, Lenders JW, van Herwaarden CL, van Haelst UJ, van Tongeren|3
00485|028|R|  JH. Fatal hepatitis after treatment with isoniazid and rifampicin in a|3
00485|029|R|  patient on anticonvulsant therapy. Tubercle 1983 Jun;64(2):125-8.|3
00486|001|T|MONOGRAPH TITLE:  Theophylline/Rifampin|
00486|002|B||
00486|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00486|004|L|of severe adverse interaction.|
00486|005|B||
00486|006|A|MECHANISM OF ACTION:  The hepatic metabolism of theophyllines is increased|
00486|007|A|by rifampin.|
00486|008|B||
00486|009|E|CLINICAL EFFECTS:  Serum theophylline concentrations are reduced, possibly|
00486|010|E|resulting in a decrease in therapeutic effects.|
00486|011|B||
00486|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00486|013|P|of the inducer for longer than 1-2 weeks.|
00486|014|B||
00486|015|M|PATIENT MANAGEMENT:  Monitor the patients for a change in therapeutic|
00486|016|M|response to theophylline if rifampin therapy is started or stopped. Adjust|
00486|017|M|the dose of theophylline accordingly.|
00486|018|B||
00486|019|D|DISCUSSION:  Concurrent administration of theophylline and rifampin can|
00486|020|D|produce a clinically significant increase in theophylline clearance. This|
00486|021|D|interaction has been documented in adult and pediatric patients.|
00486|022|B||
00486|023|R|REFERENCES:|
00486|024|B||
00486|025|R|1.Hauser AR, Lee C, Teague RB, Mullins C. The effect of rifampin on|4
00486|026|R|  theophylline disposition. Clin Pharmacol Ther 1983 Feb;33(2):254.|4
00486|027|R|2.Robson RA, Miners JO, Wing LM, Birkett DJ. Theophylline-rifampicin|2
00486|028|R|  interaction: non-selective induction of theophylline metabolic pathways.|2
00486|029|R|  Br J Clin Pharmacol 1984 Sep;18(3):445-8.|2
00486|030|R|3.Straughn AB, Henderson RP, Lieberman PL, Self TH. Effect of rifampin on|2
00486|031|R|  theophylline disposition. Ther Drug Monit 1984;6(2):153-6.|2
00486|032|R|4.Powell-Jackson PR, Jamieson AP, Gray BJ, Moxham J, Williams R. Effect of|2
00486|033|R|  rifampicin administration on theophylline pharmacokinetics in humans. Am|2
00486|034|R|  Rev Respir Dis 1985 Jun;131(6):939-40.|2
00486|035|R|5.Boyce EG, Dukes GE, Rollins DE, Sudds TW. The effect of rifampin on|2
00486|036|R|  theophylline kinetics. J Clin Pharmacol 1986 Nov-Dec;26(8):696-9.|2
00486|037|R|6.Brocks DR, Lee KC, Weppler CP, Tam YK. Theophylline-rifampin interaction|3
00486|038|R|  in a pediatric patient. Clin Pharm 1986 Jul;5:602-4.|3
00486|039|R|7.Adebayo GI, Akintonwa A, Mabadeje AF. Attenuation of rifampicin-induced|2
00486|040|R|  theophylline metabolism by diltiazem/rifampicin coadministration in|2
00486|041|R|  healthy volunteers. Eur J Clin Pharmacol 1989;37(2):127-31.|2
00487|001|T|MONOGRAPH TITLE:  Hydantoins/Valproic Acid (mono deleted 12/26/2013)|
00487|002|B||
00487|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00487|004|L|take action as needed.|
00487|005|B||
00487|006|A|MECHANISM OF ACTION:  Multiple mechanisms appear to be involved.|
00487|007|A|        1. Valproic acid displaces phenytoin from protein binding sites.|
00487|008|A|        2. Valproic acid may inhibit the hepatic metabolism of phenytoin.|
00487|009|A|        2. Phenytoin may stimulate the hepatic metabolism of valproic acid.|
00487|010|B||
00487|011|E|CLINICAL EFFECTS:  The pharmacological and toxic effects of phenytoin may be|
00487|012|E|increased while the pharmacological effects of valproic acid may be|
00487|013|E|decreased.|
00487|014|B||
00487|015|P|PREDISPOSING FACTORS:  None determined.|
00487|016|B||
00487|017|M|PATIENT MANAGEMENT:  Monitor serum phenytoin and valproic acid|
00487|018|M|concentrations. Observe the patient for loss of seizure control and symptoms|
00487|019|M|of phenytoin toxicity. Adjust the dose of either agent as needed.|
00487|020|B||
00487|021|D|DISCUSSION:  The outcome of this interaction in individual patients is|
00487|022|D|variable. In most patients the active form of phenytoin (the unbound drug)|
00487|023|D|is not significantly changed by valproic acid. Decreased serum phenytoin|
00487|024|D|concentrations have been reported, as have symptoms of phenytoin toxicity.|
00487|025|D|Increases in frequency of seizures have also been reported. Patients|
00487|026|D|receiving phenytoin and valproic acid concurrently tend to have lower serum|
00487|027|D|valproic acid concentrations than patients taking valproic acid alone.|
00487|028|B||
00487|029|R|REFERENCES:|
00487|030|B||
00487|031|R|1.Windorfer A Jr, Sauer W, Gadeke R. Elevation of diphenylhydantoin and|3
00487|032|R|  primidone serum concentration by addition of dipropylacetate, a new|3
00487|033|R|  anticonvulsant drug. Acta Paediatr Scand 1975 Sep;64(5):771-2.|3
00487|034|R|2.Bardy A, Hari R, Lehtovaara R, Majuri H. Valproate may lower|3
00487|035|R|  serum-phenytoin. Lancet 1976 Dec 11;2(7998):1297-8.|3
00487|036|R|3.Patsalos PN, Lascelles PT. Valproate may lower serum-phenytoin. Lancet|5
00487|037|R|  1977 Jan 1;1(8001):50-1.|5
00487|038|R|4.Patsalos PN, Lascelles PT. Effect of sodium valproate on plasma protein|5
00487|039|R|  binding of diphenylhydantoin. J Neurol Neurosurg Psychiatry 1977 Jun;|5
00487|040|R|  40(6):570-4.|5
00487|041|R|5.Wilder BJ, Willmore LJ, Bruni J, Villarreal HJ. Valproic acid: interaction|2
00487|042|R|  with other anticonvulsant drugs. Neurology 1978 Sep;28(9 Pt 1):892-6.|2
00487|043|R|6.Dahlqvist R, Borga O, Rane A, Walsh Z, Sjoqvist F. Decreased plasma|2
00487|044|R|  protein binding of phenytoin in patients on valproic acid. Br J Clin|2
00487|045|R|  Pharmacol 1979 Dec;8(6):547-52.|2
00487|046|R|7.Reunanen MI, Luoma P, Myllyla VV, Hokkanen E. Low serum valproic acid|2
00487|047|R|  concentrations in epileptic patients on combination therapy. Curr Ther Res|2
00487|048|R|  1980 Sep;28(3):456-62.|2
00487|049|R|8.Sansom LN, Beran RC, Schapel GJ. Interaction between phenytoin and|3
00487|050|R|  valproate. Med J Aust 1980 Aug 23;2(4):212.|3
00487|051|R|9.Monks A, Richens A. Effect of single doses of sodium valproate on serum|2
00487|052|R|  phenytoin levels and protein binding in epileptic patients. Clin Pharmacol|2
00487|053|R|  Ther 1980 Jan;27(1):89-95.|2
00487|054|R|10.Bruni J, Gallo JM, Lee CS, Perchalski RJ, Wilder BJ. Interactions of|2
00487|055|R|   valproic acid with phenytoin. Neurology 1980 Nov;30(11):1233-6.|2
00487|056|R|11.Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on|2
00487|057|R|   sodium valproate - a 5- year follow-up study in 100 children with|2
00487|058|R|   epilepsy. Acta Neurol Scand 1982 May;65(5):504-23.|2
00487|059|R|12.Palm R, Silseth C, Alvan G. Phenytoin intoxication as the first symptom|3
00487|060|R|   of fatal liver damage induced by sodium valproate. Br J Clin Pharmacol|3
00487|061|R|   1984 May;17(5):597-9.|3
00487|062|R|13.Riva R, Albani F, Contin M, Perucca E, Ambrosetto G, Gobbi G, Santucci M,|2
00487|063|R|   Procaccianti G, Baruzzi A. Time-dependent interaction between phenytoin|2
00487|064|R|   and valproic acid. Neurology 1985 Apr;35(4):510-5.|2
00487|065|R|14.Miles MV, Snead OC 3rd, Thorn MD. Predictability of unbound antiepileptic|2
00487|066|R|   drug concentrations in children treated with valproic acid and phenytoin.|2
00487|067|R|   Clin Pharm 1988 Sep;7(9):688-93.|2
00487|068|R|15.Haidukewych D, Rodin EA, Zielinski JJ. Derivation and evaluation of an|2
00487|069|R|   equation for prediction of free phenytoin concentration in patients|2
00487|070|R|   co-medicated with valproic acid. Ther Drug Monit 1989;11(2):134-9.|2
00487|071|R|16.Johnson GJ, Kilpatrick CJ, Bury RW, Fullinfaw RO, Moulds RF. Unbound|2
00487|072|R|   phenytoin plasma concentrations in patients comedicated with sodium|2
00487|073|R|   valproate--the predictive value of plasma albumin concentration. Br J|2
00487|074|R|   Clin Pharmacol 1989 Jun;27(6):843-9.|2
00487|075|R|17.May T, Rambeck B. Fluctuations of unbound and total phenytoin|2
00487|076|R|   concentrations during the day in epileptic patients on valproic acid|2
00487|077|R|   comedication. Ther Drug Monit 1990 Mar;12(2):124-8.|2
00488|001|T|MONOGRAPH TITLE:  Calcium Channel Blockers/Calcium Supplements (mono deleted|
00488|002|T|05/12/2016)|
00488|003|B||
00488|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00488|005|L|take action as needed.|
00488|006|B||
00488|007|A|MECHANISM OF ACTION:  Administration of calcium may increase the|
00488|008|A|extracellular calcium concentration, antagonizing the pharmacologic effects|
00488|009|A|of calcium channel blockers.|
00488|010|B||
00488|011|E|CLINICAL EFFECTS:  The pharmacologic and toxic effects of calcium channel|
00488|012|E|blockers may be antagonized.|
00488|013|B||
00488|014|P|PREDISPOSING FACTORS:  None determined.|
00488|015|B||
00488|016|M|PATIENT MANAGEMENT:  Observe the patient for loss of the therapeutic effect|
00488|017|M|of calcium channel blocker. Alternative therapy may be necessary.|
00488|018|B||
00488|019|D|DISCUSSION:  In one patient the clinical effects of verapamil (ie., control|
00488|020|D|of atrial fibrillation) was reversed by administration of a calcium|
00488|021|D|supplement and calciferol. In a study, 20 patients with hypertension|
00488|022|D|controlled on verapamil were given a one time IV dose of 1375 mg calcium|
00488|023|D|gluconate. Mean arterial blood pressure did not change and no relationship|
00488|024|D|was found between calcium and verapamil plasma concentrations. However,|
00488|025|D|individual response varied and some patients showed substantial changes in|
00488|026|D|mean arterial blood pressure. Administration of calcium gluconate to five|
00488|027|D|patients with multifocal atrial tachycardia reduced the antihypertensive|
00488|028|D|effect of verapamil but did not alter the antiarrhythmic effect.|
00488|029|D|    The beneficial effects of this interaction have been utilized to treat|
00488|030|D|verapamil, nifedipine, and diltiazem overdoses and acute hypotension. In one|
00488|031|D|case a patient survived after ingesting 24 grams of verapamil with the use|
00488|032|D|of IV calcium gluconate.|
00488|033|B||
00488|034|R|REFERENCES:|
00488|035|B||
00488|036|R|1.Perkins CM. Serious verapamil poisoning: treatment with intravenous|3
00488|037|R|  calcium gluconate. Br Med J 1978 Oct 21;2(6145):1127.|3
00488|038|R|2.Woie L, Storstein L. Successful treatment of suicidal verapamil poisoning|3
00488|039|R|  with calcium gluconate. Eur Heart J 1981 Jun;2(3):239-42.|3
00488|040|R|3.Bar-Or D, Gasiel Y. Calcium and calciferol antagonise effect of verapamil|3
00488|041|R|  in atrial fibrillation. Br Med J (Clin Res Ed) 1981 May 16;|3
00488|042|R|  282(6276):1585-6.|3
00488|043|R|4.Chimienti M, Previtali M, Medicia A, Piccinini M. Acute verapamil|3
00488|044|R|  poisoning: successful treatment with epinephrine. Clin Cardiol 1982 Mar;|3
00488|045|R|  5(3):219-22.|3
00488|046|R|5.Lipman J, Jardine I, Roos C, Dreosti L. Intravenous Calcium chloride as an|3
00488|047|R|  antidote to verapamil-induced hypotension. Intensive Care Med 1982 Jan;|3
00488|048|R|  8(1):55-7.|3
00488|049|R|6.Weiss AT, Lewis BS, Halon DA, Hasin Y, Gotsman MS. The use of calcium with|2
00488|050|R|  verapamil in the management of supraventricular tachyarrhythmias. Int J|2
00488|051|R|  Cardiol 1983 Oct;4(3):275-84.|2
00488|052|R|7.Morris DL, Goldschlager N. Calcium infusion for reversal of adverse|3
00488|053|R|  effects of intravenous verapamil. JAMA 1983 Jun 17;249(23):3212-3.|3
00488|054|R|8.Malcolm N, Callegari P, Goldberg J, Strauss H, Caille G, Vezina M, Spenard|3
00488|055|R|  J. Massive diltiazem overdosage: clinical and pharmacokinetic|3
00488|056|R|  observations. Drug Intell Clin Pharm 1986 Nov;20(11):888.|3
00488|057|R|9.Salerno DM, Anderson B, Sharkey PJ, Iber C. Intravenous verapamil for|2
00488|058|R|  treatment of multifocal atrial tachycardia with and without calcium|2
00488|059|R|  pretreatment. Ann Intern Med 1987 Nov;107(5):623-8.|2
00488|060|R|10.Guadagnino V, Greengart A, Hollander G, Solar M, Shani J, Lichstein E.|3
00488|061|R|   Treatment of severe left ventricular dysfunction with calcium chloride in|3
00488|062|R|   patients receiving verapamil. J Clin Pharmacol 1987 May-Jun;27(5):407-9.|3
00488|063|R|11.Midtbo K, Hals O. Can blood pressure reduction induced by slow calcium|2
00488|064|R|   channel blockade (verapamil) be reversed by calcium infusion?. Pharmacol|2
00488|065|R|   Toxicol 1987 May;60(5):330-2.|2
00488|066|R|12.Ashraf M, Chaudhary K, Nelson J, Thompson W. Massive overdose of|3
00488|067|R|   sustained-release verapamil: a case report and review of literature. Am J|3
00488|068|R|   Med Sci 1995 Dec;310(6):258-63.|3
00488|069|R|13.Haddad LM. Resuscitation after nifedipine overdose exclusively with|3
00488|070|R|   intravenous calcium chloride. Am J Emerg Med 1996 Oct;14(6):602-3.|3
00489|001|T|MONOGRAPH TITLE:  Selected Anticonvulsants; Barbiturates/Estrogens|
00489|002|B||
00489|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00489|004|L|take action as needed.|
00489|005|B||
00489|006|A|MECHANISM OF ACTION:  Enzyme induction, causing increased hepatic metabolism|
00489|007|A|of estrogens.|
00489|008|B||
00489|009|E|CLINICAL EFFECTS:  Decreased effectiveness of estrogens may lead to|
00489|010|E|spotting, breakthrough bleeding, vaginitis and may increase the risk for|
00489|011|E|osteoporosis.|
00489|012|B||
00489|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
00489|014|P|of the inducer for longer than 1-2 weeks.|
00489|015|B||
00489|016|M|PATIENT MANAGEMENT:  Increasing the dose of estrogen may be sufficient.|
00489|017|B||
00489|018|D|DISCUSSION:  Decreased effectiveness of estrogens characterized by spotting,|
00489|019|D|breakthrough bleeding or vaginitis have been documented during concurrent|
00489|020|D|administration of barbiturates and hydantoins.  Primidone is metabolized to|
00489|021|D|phenobarbital.  Additionally, lowered estrogen levels may increase the risk|
00489|022|D|of osteoporosis.  Often, patients are receiving multiple anticonvulsant|
00489|023|D|drugs making it difficult to quantify the frequency of this interaction.|
00489|024|D|However, decreases in the area under the plasma concentration-time curves|
00489|025|D|for ethinyl estradiol and levonorgestrel have been documented during|
00489|026|D|concurrent administration of phenytoin.|
00489|027|B||
00489|028|R|REFERENCES:|
00489|029|B||
00489|030|R|1.Janz D, Schmidt D. Letter: Anti-epileptic drugs and failure of oral|3
00489|031|R|  contraceptives. Lancet 1974 Jun 1;1(7866):1113.|3
00489|032|R|2.Laengner H, Detering K. Letter: Anti-epileptic drugs and failure of oral|3
00489|033|R|  contraceptives. Lancet 1974 Sep 7;2(7880):600.|3
00489|034|R|3.Hempel E, Klinger W. Drug stimulated biotransformation of hormonal steroid|6
00489|035|R|  contraceptives: clinical implications. Drugs 1976 Dec;12(6):442-8.|6
00489|036|R|4.Roberton YR, Johnson ES. Interactions between oral contraceptives and|6
00489|037|R|  other drugs: a review. Curr Med Res Opin 1976;3(9):647-61.|6
00489|038|R|5.Coulam CB, Annegers JF. Do anticonvulsants reduce the efficacy of oral|3
00489|039|R|  contraceptives?. Epilepsia 1979 Oct;20(5):519-25.|3
00489|040|R|6.Back DJ, Bates M, Bowden A, Breckenridge AM, Hall MJ, Jones H, MacIver M,|2
00489|041|R|  Orme M, Perucca E, Richens A, Rowe PH, Smith E. The interaction of|2
00489|042|R|  phenobarbital and other anticonvulsants with oral contraceptive steroid|2
00489|043|R|  therapy. Contraception 1980 Nov;22(5):495-503.|2
00489|044|R|7.Anonymous. Drug interaction with oral contraceptive steroids. Br Med J|6
00489|045|R|  1980 Jul 12;281(6233):93-4.|6
00489|046|R|8.Mattson RH, Cramer JA, Darney PD, Naftolin F. Use of oral contraceptives|6
00489|047|R|  by women with epilepsy. JAMA 1986 Jul 11;256(2):238-40.|6
00490|001|T|MONOGRAPH TITLE:  Barbiturates/Estrogens (mono deleted 06/09/2011)|
00490|002|B||
00490|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00490|004|L|take action as needed.|
00490|005|B||
00490|006|A|MECHANISM OF ACTION:  Enzyme induction, causing increased hepatic metabolism|
00490|007|A|of estrogens.|
00490|008|B||
00490|009|E|CLINICAL EFFECTS:  Decreased effectiveness of estrogens may lead to|
00490|010|E|spotting, breakthrough bleeding, vaginitis and may increase the risk for|
00490|011|E|osteoporosis.|
00490|012|B||
00490|013|P|PREDISPOSING FACTORS:  None determined.|
00490|014|B||
00490|015|M|PATIENT MANAGEMENT:  Increasing the dose of estrogen may be sufficient.|
00490|016|B||
00490|017|D|DISCUSSION:  Decreased effectiveness of estrogens characterized by spotting,|
00490|018|D|breakthrough bleeding or vaginitis have been documented during concurrent|
00490|019|D|administration of barbiturates. Additionally, lowered estrogen levels may|
00490|020|D|increase the risk of osteoporosis. Often, patients are receiving multiple|
00490|021|D|anticonvulsant drugs making it difficult to quantify the frequency of this|
00490|022|D|interaction.|
00490|023|B||
00490|024|R|REFERENCES:|
00490|025|B||
00490|026|R|1.Janz D, Schmidt D. Letter: Anti-epileptic drugs and failure of oral|3
00490|027|R|  contraceptives. Lancet 1974 Jun 1;1(7866):1113.|3
00490|028|R|2.Laengner H, Detering K. Letter: Anti-epileptic drugs and failure of oral|3
00490|029|R|  contraceptives. Lancet 1974 Sep 7;2(7880):600.|3
00490|030|R|3.Hempel E, Klinger W. Drug stimulated biotransformation of hormonal steroid|6
00490|031|R|  contraceptives: clinical implications. Drugs 1976 Dec;12(6):442-8.|6
00490|032|R|4.Roberton YR, Johnson ES. Interactions between oral contraceptives and|6
00490|033|R|  other drugs: a review. Curr Med Res Opin 1976;3(9):647-61.|6
00490|034|R|5.Coulam CB, Annegers JF. Do anticonvulsants reduce the efficacy of oral|3
00490|035|R|  contraceptives?. Epilepsia 1979 Oct;20(5):519-25.|3
00490|036|R|6.Back DJ, Bates M, Bowden A, Breckenridge AM, Hall MJ, Jones H, MacIver M,|2
00490|037|R|  Orme M, Perucca E, Richens A, Rowe PH, Smith E. The interaction of|2
00490|038|R|  phenobarbital and other anticonvulsants with oral contraceptive steroid|2
00490|039|R|  therapy. Contraception 1980 Nov;22(5):495-503.|2
00490|040|R|7.Anonymous. Drug interaction with oral contraceptive steroids. Br Med J|6
00490|041|R|  1980 Jul 12;281(6233):93-4.|6
00490|042|R|8.Mattson RH, Cramer JA, Darney PD, Naftolin F. Use of oral contraceptives|6
00490|043|R|  by women with epilepsy. JAMA 1986 Jul 11;256(2):238-40.|6
00491|001|T|MONOGRAPH TITLE:  Azole Antifungal Agents/Selected Rifamycins|
00491|002|B||
00491|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00491|004|L|of severe adverse interaction.|
00491|005|B||
00491|006|A|MECHANISM OF ACTION:  Multiple mechanisms may be involved:|
00491|007|A|   1) Rifampin or rifapentine appear to increase the CYP3A4 metabolism of|
00491|008|A|the azole antifungal agents.|
00491|009|A|   2) The azole antifungals may interfere with the gastrointestinal|
00491|010|A|absorption of the rifamycins.|
00491|011|B||
00491|012|E|CLINICAL EFFECTS:  The pharmacological effects of both the azole antifungal|
00491|013|E|and the rifamycin may be decreased.|
00491|014|B||
00491|015|P|PREDISPOSING FACTORS:  None determined.|
00491|016|B||
00491|017|M|PATIENT MANAGEMENT:  Rifampin or rifapentine is not recommended two weeks|
00491|018|M|before and during treatment with itraconazole or ketoconazole.(11-12)|
00491|019|M|Concurrent therapy should only be undertaken if benefits are considered to|
00491|020|M|outweigh risks.|
00491|021|M|   If concurrent therapy is necessary, observe the patient for a decrease in|
00491|022|M|the therapeutic effect of both drugs.  It may be necessary to increase the|
00491|023|M|dose of the antifungal agent.(13)|
00491|024|B||
00491|025|D|DISCUSSION:  Rifampin administration has been shown to decrease serum|
00491|026|D|concentrations of fluconazole, itraconazole and ketoconazole.  The majority|
00491|027|D|of documentation supports a clinically significant interaction with|
00491|028|D|ketoconazole demonstrating a greater than 50% decrease in ketoconazole|
00491|029|D|concentrations.|
00491|030|D|   In a clinical study of eight volunteers, administration of a single oral|
00491|031|D|dose of 200 mg fluconazole after 15 days of rifampin 600 mg daily resulted|
00491|032|D|in a significant decrease in mean fluconazole area-under-curve (AUC) of 23%|
00491|033|D|and fluconazole half-life from 33.4 to 26.8 hours.(13)|
00491|034|D|   Documentation for the interaction with itraconazole is less dramatic.|
00491|035|D|   Ketoconazole can also cause greater than 50% reduction in rifampin|
00491|036|D|levels.|
00491|037|B||
00491|038|R|REFERENCES:|
00491|039|B||
00491|040|R|1.Brass C, Galgiani JN, Blaschke TF, Defelice R, O'Reilly RA, Stevens DA.|2
00491|041|R|  Disposition of ketoconazole, an oral antifungal, in humans. Antimicrob|2
00491|042|R|  Agents Chemother 1982 Jan;21(1):151-8.|2
00491|043|R|2.Drouhet E, Dupont B. Laboratory and clinical assessment of ketoconazole in|3
00491|044|R|  deep-seated mycoses. Am J Med 1983 Jan 24;74(1B):30-47.|3
00491|045|R|3.Engelhard D, Stutman HR, Marks MI. Interaction of ketoconazole with|3
00491|046|R|  rifampin and isoniazid. N Engl J Med 1984 Dec 27;311(26):1681-3.|3
00491|047|R|4.Meunier F. Serum fungistatic and fungicidal activity in volunteers|2
00491|048|R|  receiving antifungal agents. Eur J Clin Microbiol 1986 Feb;5(1):103-9.|2
00491|049|R|5.Doble N, Shaw R, Rowland-Hill C, Lush M, Warnock DW, Keal EE.|2
00491|050|R|  Pharmacokinetic study of the interaction between rifampicin and|2
00491|051|R|  ketoconazole. J Antimicrob Chemother 1988 May;21(5):633-5.|2
00491|052|R|6.Abadie-Kemmerly S, Pankey GA, Dalovisio JR, Dalvisio JR. Failure of|3
00491|053|R|  ketoconazole treatment of Blastomyces dermatitidis. Ann Intern Med 1988|3
00491|054|R|  Nov 15;109(10):844-5.|3
00491|055|R|7.Blomley M, Teare EL, de Belder A, Thway Y, Weston M. Itraconazole and|3
00491|056|R|  anti-tuberculosis drugs. Lancet 1990 Nov 17;336(8725):1255.|3
00491|057|R|8.Coker RJ, Tomlinson DR, Parkin J, Harris JR, Pinching AJ. Interaction|3
00491|058|R|  between fluconazole and rifampicin. BMJ 1990 Oct 6;301(6755):818.|3
00491|059|R|9.Apseloff G, Hilligoss DM, Gardner MJ, Henry EB, Inskeep PB, Gerber N,|2
00491|060|R|  Lazar JD. Induction of fluconazole metabolism by rifampin: in vivo study|2
00491|061|R|  in humans. J Clin Pharmacol 1991 Apr;31(4):358-61.|2
00491|062|R|10.Tucker RM, Denning DW, Hanson LH, Rinaldi MG, Graybill JR, Sharkey PK,|3
00491|063|R|   Pappagianis D, Stevens DA. Interaction of azoles with rifampin,|3
00491|064|R|   phenytoin, and carbamazepine: in vitro and clinical observations. Clin|3
00491|065|R|   Infect Dis 1992 Jan;14(1):165-74.|3
00491|066|R|11.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
00491|067|R|   Products, L.P. February, 2024.|1
00491|068|R|12.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
00491|069|R|   Pharmaceuticals February, 2014.|1
00491|070|R|13.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
00491|071|R|   2024.|1
00492|001|T|MONOGRAPH TITLE:  Methoxyflurane/Barbiturates|
00492|002|B||
00492|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00492|004|L|of severe adverse interaction.|
00492|005|B||
00492|006|A|MECHANISM OF ACTION:  Barbiturates may increase hepatic metabolism of|
00492|007|A|methoxyflurane to nephrotoxic metabolites.|
00492|008|A|   Primidone is metabolized to phenobarbital.|
00492|009|B||
00492|010|E|CLINICAL EFFECTS:  Nephrotoxicity of methoxyflurane may be increased.|
00492|011|B||
00492|012|P|PREDISPOSING FACTORS:  None determined.|
00492|013|B||
00492|014|M|PATIENT MANAGEMENT:  When possible, avoid administering methoxyflurane to|
00492|015|M|patients who are receiving enzyme inducing drugs. Since enzyme induction|
00492|016|M|dissipates slowly, allow up to three weeks for metabolic status to return to|
00492|017|M|normal.|
00492|018|B||
00492|019|D|DISCUSSION:  Since methoxyflurane is nephrotoxic, a causal relationship is|
00492|020|D|difficult to establish. The majority of documentation for this interaction|
00492|021|D|is based on animal studies. However, renal insufficiency has been reported|
00492|022|D|in two barbiturate treated patients who were given methoxyflurane.|
00492|023|B||
00492|024|R|REFERENCES:|
00492|025|B||
00492|026|R|1.Son SL, Colella JJ Jr, Brown BR Jr. The effect of phenobarbitone on the|5
00492|027|R|  metabolism of methoxyflurane to oxalic acid in the rat. Br J Anaesth 1972|5
00492|028|R|  Dec;44(12):1224-8.|5
00492|029|R|2.Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. A study of dose|3
00492|030|R|  response in man. JAMA 1973 Sep 24;225(13):1611-6.|3
00492|031|R|3.Cousins MJ, Mazze RI, Kosek JC, Hitt BA, Love FV. The etiology of|5
00492|032|R|  methoxyflurane nephrotoxicity. J Pharmacol Exp Ther 1974 Sep;|5
00492|033|R|  190(3):530-41.|5
00492|034|R|4.Churchill D, Knaack J, Chirito E, Barre P, Cole C, Muehrcke R, Gault MH.|3
00492|035|R|  Persisting renal insufficiency after methoxyflurane anesthesia. Report of|3
00492|036|R|  two cases and review of literature. Am J Med 1974 Apr;56(4):575-82.|3
00492|037|R|5.Churchill D, Yacoub JM, Siu KP, Symes A, Gault MH. Toxic nephropathy after|3
00492|038|R|  low-dose methoxyflurane anesthesia: drug interaction with secobarbital?.|3
00492|039|R|  Can Med Assoc J 1976 Feb 21;114(4):326-8, 333.|3
00493|001|T|MONOGRAPH TITLE:  Guanethidine/Sympathomimetics (Indirect Acting)|
00493|002|B||
00493|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00493|004|L|of severe adverse interaction.|
00493|005|B||
00493|006|A|MECHANISM OF ACTION:  Indirect-acting sympathomimetics may displace|
00493|007|A|guanethidine from adrenergic neurons, thereby antagonizing the clinical|
00493|008|A|effect.|
00493|009|B||
00493|010|E|CLINICAL EFFECTS:  Blood pressure may be increased.|
00493|011|B||
00493|012|P|PREDISPOSING FACTORS:  None determined.|
00493|013|B||
00493|014|M|PATIENT MANAGEMENT:  When possible, use an alternative antihypertensive|
00493|015|M|agent or sympathomimetic.|
00493|016|B||
00493|017|D|DISCUSSION:  This interaction has been demonstrated with concomitant|
00493|018|D|administration of anorexiant-type indirect-acting sympathomimetics and|
00493|019|D|guanethidine. Increased blood pressure has been reported.|
00493|020|B||
00493|021|R|REFERENCES:|
00493|022|B||
00493|023|R|1.Day MD. Effect of sympathomimetic amines on the blocking action of|5
00493|024|R|  guanethidine, bretylium and xylocholine. Br J Pharmacol 1962;18:421-39.|5
00493|025|R|2.Day MD, Rand MJ. Antagonism of guanethidine by dexamphetamine and other|5
00493|026|R|  related sympathomimetic amines. J Pharm Pharmacol 1962 Sep;14:541-9.|5
00493|027|R|3.Gokhale SD, Gulati OD, Udwadia BP. Antagonism of the adrenergic neurone|5
00493|028|R|  blocking action of guanethidine by certain antidepressant and|5
00493|029|R|  antihistamine drugs. Arch Int Pharmacodyn Ther 1966 Apr;160(2):321-9.|5
00493|030|R|4.Gulati OD, Dave BT, Gokhale SD, Shah KM. Antagonism of adrenergic neuron|2
00493|031|R|  blockade in hypertensive subjects. Clin Pharmacol Ther 1966 Jul-Aug;|2
00493|032|R|  7(4):510-4.|2
00493|033|R|5.Misage JR, McDonald RH Jr. Antagonism of hypotensive action of bethanidine|3
00493|034|R|  by "common cold" remedy. Br Med J 1970 Nov 7;4(731):347.|3
00493|035|R|6.Starke K. Interactions of guanethidine and indirect-acting sympathomimetic|5
00493|036|R|  amines. Arch Int Pharmacodyn Ther 1972 Feb;195(2):309-14.|5
00493|037|R|7.Ober KF, Wang RI. Drug interactions with guanethidine. Clin Pharmacol Ther|2
00493|038|R|  1973 Mar-Apr;14(2):190-5.|2
00494|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
00494|002|T|antagonists)/Aminoglutethimide|
00494|003|B||
00494|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00494|005|L|take action as needed.|
00494|006|B||
00494|007|A|MECHANISM OF ACTION:  Aminoglutethimide may increase the metabolism of|
00494|008|A|warfarin by CYP1A2.|
00494|009|B||
00494|010|E|CLINICAL EFFECTS:  The hypoprothrombinemic response to warfarin may be|
00494|011|E|decreased.|
00494|012|B||
00494|013|P|PREDISPOSING FACTORS:  None determined.|
00494|014|B||
00494|015|M|PATIENT MANAGEMENT:  Monitor anticoagulant function when starting, stopping|
00494|016|M|or altering the dose of aminoglutethimide. Adjust the dose of warfarin|
00494|017|M|accordingly.|
00494|018|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00494|019|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00494|020|M|initiating, altering the dose or discontinuing either drug.|
00494|021|B||
00494|022|D|DISCUSSION:  Case reports and limited studies indicate that|
00494|023|D|aminoglutethimide  increases the clearance of warfarin. In order to maintain|
00494|024|D|adequate anticoagulation during the concurrent administration of|
00494|025|D|aminoglutethimide, larger doses of warfarin may be needed than when the|
00494|026|D|anticoagulant is administered alone.|
00494|027|B||
00494|028|R|REFERENCES:|
00494|029|B||
00494|030|R|1.Murray RM, Pitt P, Jerums G. Medical adrenalectomy with aminoglutethimide|3
00494|031|R|  in the management of advanced breast cancer. Med J Aust 1981 Feb 21;|3
00494|032|R|  1(4):179-81.|3
00494|033|R|2.Bruning PF, Bonfrer JG. Aminoglutethimide and oral anticoagulant therapy.|3
00494|034|R|  Lancet 1983 Sep 3;2(8349):582.|3
00494|035|R|3.Lonning PE, Kvinnsland S, Jahren G. Aminoglutethimide and warfarin. A new|3
00494|036|R|  important drug interaction. Cancer Chemother Pharmacol 1984;12(1):10-2.|3
00494|037|R|4.Lonning PE, Ueland PM, Kvinnsland S. The influence of a graded dose|2
00494|038|R|  schedule of aminoglutethimide on the disposition of the optical|2
00494|039|R|  enantiomers of warfarin in patients with breast cancer. Cancer Chemother|2
00494|040|R|  Pharmacol 1986;17(2):177-81.|2
00495|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
00495|002|T|antagonists)/Carbamazepine|
00495|003|B||
00495|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00495|005|L|take action as needed.|
00495|006|B||
00495|007|A|MECHANISM OF ACTION:  Carbamazepine may induce the metabolism of warfarin by|
00495|008|A|CYP2C9 and CYP3A4.(1)|
00495|009|B||
00495|010|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine may result in decreased|
00495|011|E|levels and effectiveness of warfarin, which may increase the risk of|
00495|012|E|clotting.(1)|
00495|013|B||
00495|014|P|PREDISPOSING FACTORS:  None determined.|
00495|015|B||
00495|016|M|PATIENT MANAGEMENT:  Monitor INR response closely in patients maintained on|
00495|017|M|warfarin when initiating, titrating, and discontinuing carbamazepine.|
00495|018|M|Patients maintained on carbamazepine may require higher dosages of|
00495|019|M|warfarin.(1)|
00495|020|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00495|021|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00495|022|M|initiating, altering the dose or discontinuing either drug.|
00495|023|B||
00495|024|D|DISCUSSION:  A retrospective cohort study in 57 patients had an increase in|
00495|025|D|warfarin dose with concurrent carbamazepine use.  After initiation of|
00495|026|D|carbamazepine, the mean weekly warfarin dose and ratio of dose/INR increased|
00495|027|D|by 7.6 mg (24%) and 5.7 mg/INR (43%), respectively.  Patients experienced no|
00495|028|D|bleeding or thromboembolic events during the study period.(2)|
00495|029|D|   This interaction has also been documented in case reports.(3-7)|
00495|030|B||
00495|031|R|REFERENCES:|
00495|032|B||
00495|033|R|1.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
00495|034|R|  Squibb Company September, 2016.|1
00495|035|R|2.Clark NP, Hoang K, Delate T, Horn JR, Witt DM. Warfarin Interaction With|2
00495|036|R|  Hepatic Cytochrome P-450 Enzyme-Inducing Anticonvulsants. Clin Appl Thromb|2
00495|037|R|  Hemost 2018 Jan;24(1):172-178.|2
00495|038|R|3.Hansen JM, Siersboek-Nielsen K, Skovsted L. Carbamazepine-induced|2
00495|039|R|  acceleration of diphenylhydantoin and warfarin metabolism in man. Clin|2
00495|040|R|  Pharmacol Ther 1971 May-Jun;12(3):539-43.|2
00495|041|R|4.Ross JR, Beeley L. Interaction between carbamazepine and warfarin. Br Med|3
00495|042|R|  J 1980 Jun 14;280(6229):1415-6.|3
00495|043|R|5.Kendall AG, Boivin M. Warfarin-carbamazepine interaction. Ann Intern Med|3
00495|044|R|  1981 Feb;94(2):280.|3
00495|045|R|6.Massey EW. Effect of carbamazepine on Coumadin metabolism. Ann Neurol 1983|3
00495|046|R|  Jun;13(6):691-2.|3
00495|047|R|7.Denbow CE, Fraser HS. Clinically significant hemorrhage due to|3
00495|048|R|  warfarin-carbamazepine interaction. South Med J 1990 Aug;83(8):981.|3
00496|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/NSAIDs|
00496|002|B||
00496|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00496|004|L|of severe adverse interaction.|
00496|005|B||
00496|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Some NSAIDs may|
00496|007|A|displace anticoagulants from plasma protein binding sites.  NSAIDs also have|
00496|008|A|the potential to produce gastrointestinal ulceration and bleeding.  Some|
00496|009|A|NSAIDs may impair platelet function and prolong bleeding times.|
00496|010|B||
00496|011|E|CLINICAL EFFECTS:  Concurrent use of anticoagulants and NSAIDs may increase|
00496|012|E|the risk for bleeding.|
00496|013|B||
00496|014|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with renal|
00496|015|P|impairment and in patients older than 75 years.|
00496|016|P|   The risk for bleeding episodes may be greater in patients with multiple|
00496|017|P|disease-associated factors (e.g. thrombocytopenia, advanced liver disease).|
00496|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
00496|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
00496|020|P|risk for bleeding (e.g., other anticoagulants, antiplatelets,|
00496|021|P|corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or|
00496|022|P|serotonin-norepinephrine  reuptake inhibitors (SNRIs).  Risk of GI bleed may|
00496|023|P|be increased in patients who are of older age, in poor health status, or who|
00496|024|P|use alcohol or smoke.  Risk may also be increased with longer duration of|
00496|025|P|NSAID use and prior history of peptic ulcer disease and/or GI bleeding.|
00496|026|B||
00496|027|M|PATIENT MANAGEMENT:  If concurrent therapy with anticoagulants and NSAIDs is|
00496|028|M|warranted, patients should be closely monitored for signs of blood loss,|
00496|029|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
00496|030|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
00496|031|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
00496|032|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
00496|033|M|anticoagulation in patients with active pathologic bleeding.|
00496|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
00496|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
00496|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
00496|037|M|and/or swelling.|
00496|038|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00496|039|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00496|040|M|initiating, altering the dose or discontinuing either drug.|
00496|041|B||
00496|042|D|DISCUSSION:  The effects of NSAIDs on the hypoprothrombinemic response to|
00496|043|D|anticoagulants appears to vary between patients as well as with different|
00496|044|D|NSAIDs.  Documentation is frequently contradictory - while studies have|
00496|045|D|shown several NSAIDs to have no effect on the pharmacokinetics of warfarin,|
00496|046|D|case reports have documented increased effects with and without bleeding|
00496|047|D|when these same NSAIDs were administered concurrently with warfarin.|
00496|048|D|   While celecoxib has been shown not to affect platelet aggregation or|
00496|049|D|bleeding times and had no effects on the anticoagulant effect of warfarin in|
00496|050|D|healthy subjects, increased prothrombin times and bleeding episodes, some of|
00496|051|D|which were fatal, have been reported, predominantly in the elderly, in|
00496|052|D|patients receiving concurrent therapy with celecoxib and warfarin.|
00496|053|D|   Rofecoxib has been shown to increase prothrombin times in subjects who|
00496|054|D|received concurrent warfarin therapy.|
00496|055|D|   A post hoc analysis of nonselective NSAIDs in the RE-LY study (compared|
00496|056|D|dabigatran 150 and 110 mg twice daily with warfarin in atrial fibrillation)|
00496|057|D|assessed clinical outcomes by comparing nonselective NSAID use (at least|
00496|058|D|once during trial) with no NSAID use in 2279 patients. The use of NSAIDs was|
00496|059|D|associated an increased risk of major bleeding (hazard ratio (HR) 1.68),|
00496|060|D|gastrointestinal major bleeding (HR 1.81), stroke or systemic embolism (HR|
00496|061|D|1.50), and hospitalization (HR 1.64).(22)|
00496|062|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
00496|063|D|pairs were reviewed and found 14% of drug pairs were associated with a|
00496|064|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
00496|065|D|of warfarin and sulindac resulted in a ratio of rate ratios (RR) (95% CI) of|
00496|066|D|3.7 (1.79-7.62); warfarin and etodolac ratio of RR 2.61 (1.6-4.25); warfarin|
00496|067|D|and ibuprofen ratio of RR 1.94 (1.5-2.5); warfarin and naproxen ratio of RR|
00496|068|D|1.72 (1.35-2.19); warfarin and indomethacin ratio of RR 1.62 (1.03-2.55);|
00496|069|D|warfarin and diclofenac ratio of RR 1.43 (1.07-1.92; warfarin and celecoxib|
00496|070|D|ratio of RR 1.24 (1.02-1.53); and warfarin and meloxicam ratio of RR 1.23|
00496|071|D|(1.02-1.47).(23)|
00496|072|D|   In a nationwide cohort study, patients were evaluated for thromboembolic|
00496|073|D|cardiovascular and clinically relevant bleeding events with concurrent|
00496|074|D|antithrombotic and ongoing NSAID treatment.  A total of 108,232 patients|
00496|075|D|were followed for a mean of 2.3 +/- 1.8 years after diagnosis of myocardial|
00496|076|D|infarction.  Concomitant NSAID treatment significantly increased the risk|
00496|077|D|for cardiovascular events (hazard ratio (HR) 6.96; 95% CI 6.24 - 6.77;|
00496|078|D|p<0.001) and bleeding events (HR 4.08; 95% CI 3.51 - 4.73; p<0.001) compared|
00496|079|D|to no NSAID treatment.  NSAIDs were further evaluated and revealed the use|
00496|080|D|of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI:|
00496|081|D|2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68|
00496|082|D|to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively)|
00496|083|D|had the lowest risk for cardiovascular and bleeding events, receptively.|
00496|084|D|   A large systematic review was performed on 72 warfarin drug-drug|
00496|085|D|interactions studies that reported on bleeding, thromboembolic events, or|
00496|086|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 8 of|
00496|087|D|those studies found a higher rate of clinically significant bleeding in|
00496|088|D|patients on warfarin and NSAIDs (OR=1.83; 95% CI 1.29-2.59).  Increased|
00496|089|D|bleeding risk was seen in subgroup analyses with non-selective NSAIDs|
00496|090|D|(OR=1.86; 95% CI 1.10-3.17) and COX-2 inhibitors (OR=1.81; 95% CI|
00496|091|D|1.3-2.52).(24)|
00496|092|D|   If concurrent therapy with anticoagulants and NSAIDs is warranted, it|
00496|093|D|would be prudent to monitor patients closely for increased anticoagulant|
00496|094|D|effects.|
00496|095|B||
00496|096|R|REFERENCES:|
00496|097|B||
00496|098|R|1.Thilo D, Nyman D. A study of the effects of the anti-rheumatic drug|2
00496|099|R|  ibuprofen (Brufen) on patients being treated with the oral anti-coagulant|2
00496|100|R|  phenprocoumon (Marcoumar). J Int Med Res 1974;2:276-8.|2
00496|101|R|2.Boekhout-Mussert MJ, Loeliger EA. Influence of ibuprofen on oral|2
00496|102|R|  anti-coagulant with phenprocoumon. J Int Med Res 1974;2:279-83.|2
00496|103|R|3.Penner JA, Abbrecht PH. Lack of interaction between ibuprofen and|2
00496|104|R|  warfarin. Curr Ther Res Clin Exp 1975 Dec;18(6):862-71.|2
00496|105|R|4.Michot F, Ajdacic K, Glaus L. A double-blind clinical trial to determine|2
00496|106|R|  if an interaction exists between diclofenac sodium and the oral|2
00496|107|R|  anticoagulant acenocoumarol (nicoumalone). J Int Med Res 1975;3(3):153-7.|2
00496|108|R|5.Marbet GA, Duckert F, Walter M, Six P, Airenne H. Interaction study|2
00496|109|R|  between phenprocoumon and flurbiprofen. Curr Med Res Opin 1977;5(1):26-31.|2
00496|110|R|6.Slattery JT, Levy G, Jain A, McMahon FG. Effect of naproxen on the|2
00496|111|R|  kinetics of elimination and anticoagulant activity of a single dose or|2
00496|112|R|  warfarin. Clin Pharmacol Ther 1979 Jan;25(1):51-60.|2
00496|113|R|7.Jain A, McMahon FG, Slattery JT, Levy G. Effect of naproxen on the|2
00496|114|R|  steady-state serum concentration and anticoagulant activity of warfarin.|2
00496|115|R|  Clin Pharmacol Ther 1979 Jan;25(1):61-6.|2
00496|116|R|8.Loftin JP, Vesell ES. Interaction between sulindac and warfarin: different|3
00496|117|R|  results in normal subjects and in an unusual patient with a|3
00496|118|R|  potassium-losing renal tubular defect. J Clin Pharmacol 1979 Nov-Dec;|3
00496|119|R|  19(11-12):733-42.|3
00496|120|R|9.Carter SA. Potential effect of sulindac on response of prothrombin-time to|3
00496|121|R|  oral anticoagulants. Lancet 1979 Sep 29;2(8144):698-9.|3
00496|122|R|10.Ross JR, Beeley L. Sulindac, prothrombin time, and anticoagulants. Lancet|3
00496|123|R|   1979 Nov 17;2(8151):1075.|3
00496|124|R|11.Stricker BH, Delhez JL. Interactions between flurbiprofen and coumarins.|3
00496|125|R|   Br Med J (Clin Res Ed) 1982 Sep 18;285(6344):812-3.|3
00496|126|R|12.Dahl SL, Ward JR. Pharmacology, clinical efficacy, and adverse effects of|6
00496|127|R|   piroxicam, a new nonsteroidal anti-inflammatory agent. Pharmacotherapy|6
00496|128|R|   1982 Mar-Apr;2(2):80-90.|6
00496|129|R|13.Rhodes RS, Rhodes PJ, Klein C, Sintek CD. A warfarin-piroxicam drug|3
00496|130|R|   interaction. Drug Intell Clin Pharm 1985 Jul-Aug;19(7-8):556-8.|3
00496|131|R|14.Flessner MF, Knight H. Prolongation of prothrombin time and severe|3
00496|132|R|   gastrointestinal bleeding associated with combined use of warfarin and|3
00496|133|R|   ketoprofen. JAMA 1988 Jan 15;259(3):353.|3
00496|134|R|15.Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal|2
00496|135|R|   anti-inflammatory drug use and increased risk for peptic ulcer disease in|2
00496|136|R|   elderly persons. Ann Intern Med 1991 Feb 15;114(4):257-63.|2
00496|137|R|16.Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious|6
00496|138|R|   gastrointestinal complications related to use of nonsteroidal|6
00496|139|R|   anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991 Nov 15;|6
00496|140|R|   115(10):787-96.|6
00496|141|R|17.Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of|2
00496|142|R|   nonsteroidal anti-inflammatory drugs and oral anticoagulants places|2
00496|143|R|   elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch|2
00496|144|R|   Intern Med 1993 Jul 26;153(14):1665-70.|2
00496|145|R|18.Hilleman DE, Mohiuddin SM, Lucas BD Jr. Nonsteroidal antiinflammatory|6
00496|146|R|   drug use in patients receiving warfarin: emphasis on nabumetone. Am J Med|6
00496|147|R|   1993 Aug 9;95(2A):30S-34S.|6
00496|148|R|19.Mieszczak C, Winther K. Lack of interaction of ketoprofen with warfarin.|2
00496|149|R|   Eur J Clin Pharmacol 1993;44(2):205-6.|2
00496|150|R|20.Celebrex (celecoxib) US prescribing information. Pfizer Inc. May, 2019.|1
00496|151|R|21.Vioxx (rofecoxib) US prescribing information. Merck & Co., Inc. May,|1
00496|152|R|   2016.|1
00496|153|R|22.Kent AP, Brueckmann M, Fraessdorf M, Connolly SJ, Yusuf S, Eikelboom JW,|2
00496|154|R|   Oldgren J, Reilly PA, Wallentin L, Ezekowitz MD. Concomitant Oral|2
00496|155|R|   Anticoagulant and Nonsteroidal Anti-Inflammatory Drug Therapy in Patients|2
00496|156|R|   With Atrial Fibrillation. J Am Coll Cardiol 2018 Jul 17;72(3):255-267.|2
00496|157|R|23.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
00496|158|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
00496|159|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
00496|160|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
00496|161|R|24.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
00496|162|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
00496|163|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
00496|164|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
00497|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/Vitamin K|
00497|002|B||
00497|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00497|004|L|of severe adverse interaction.|
00497|005|B||
00497|006|A|MECHANISM OF ACTION:  Anticoagulants interfere with the activation of|
00497|007|A|vitamin K-dependent clotting factors. Vitamin K administration may reverse|
00497|008|A|this effect.|
00497|009|B||
00497|010|E|CLINICAL EFFECTS:  The pharmacological effect of anticoagulants may be|
00497|011|E|reversed resulting in thrombus formation.|
00497|012|B||
00497|013|P|PREDISPOSING FACTORS:  None determined.|
00497|014|B||
00497|015|M|PATIENT MANAGEMENT:  Patients receiving anticoagulants should avoid eating|
00497|016|M|unusual increases in foods high in vitamin K content.|
00497|017|M|   The time of highest risk for a coumarin-type drug interaction is when the|
00497|018|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
00497|019|M|initiating, altering the dose or discontinuing either drug.|
00497|020|B||
00497|021|D|DISCUSSION:  Numerous reports have demonstrated that vitamin K interferes|
00497|022|D|with the hypoprothrombinemic effects of anticoagulants. However, reports of|
00497|023|D|clinically important consequences are uncommon. A clearer understanding of|
00497|024|D|the mechanism by which these drugs act has made it possible to use vitamin K|
00497|025|D|to control bleeding side effects of warfarin therapy. One should be aware of|
00497|026|D|the vitamin K content of enteral feeding products being administered to|
00497|027|D|patients on anticoagulant therapy. Prothrombin time should be monitored when|
00497|028|D|these products are given.|
00497|029|B||
00497|030|R|REFERENCES:|
00497|031|B||
00497|032|R|1.Anonymous. Anticoagulant therapyn - a clinical dilemma. JAMA 1964 Feb 15;|6
00497|033|R|  187(7):27-30.|6
00497|034|R|2.Andersen P, Godal HC. Predictable reduction in anticoagulant activity of|2
00497|035|R|  warfarin by small amounts of vitamin K. Acta Med Scand 1975 Oct;|2
00497|036|R|  198(4):269-70.|2
00497|037|R|3.Fletcher DC. Clotting factors in vitamin K-rich vegetables hinder|6
00497|038|R|  anticoagulant therapy?. JAMA 1977 Apr 25;237(17):1871.|6
00497|039|R|4.Kempin SJ. Warfarin resistance caused by broccoli. N Engl J Med 1983 May|3
00497|040|R|  19;308(20):1229-30.|3
00497|041|R|5.Karlson B, Leijd B, Hellstrom K. On the influence of vitamin K-rich|2
00497|042|R|  vegetables and wine on the effectiveness of warfarin treatment. Acta Med|2
00497|043|R|  Scand 1986;220(4):347-50.|2
00497|044|R|6.Walker FB 4th. Myocardial infarction after diet-induced warfarin|3
00497|045|R|  resistance. Arch Intern Med 1984 Oct;144(10):2089-90.|3
00497|046|R|7.Martin JE, Lutomski DM. Warfarin resistance and enteral feedings. JPEN J|3
00497|047|R|  Parenter Enteral Nutr 1989 Mar-Apr;13(2):206-8.|3
00497|048|R|8.Suttie JW. Warfarin and vitamin K. Clin Cardiol 1990 Apr;13(4 Suppl|6
00497|049|R|  6):VI16-8.|6
00497|050|R|9.Chow WH, Chow TC, Tse TM, Tai YT, Lee WT. Anticoagulation instability with|3
00497|051|R|  life-threatening complication after dietary modification. Postgrad Med J|3
00497|052|R|  1990 Oct;66(780):855-7.|3
00497|053|R|10.Pedersen FM, Hamberg O, Hess K, Ovesen L. The effect of dietary vitamin K|2
00497|054|R|   on warfarin-induced anticoagulation. J Intern Med 1991 Jun;229(6):517-20.|2
00498|001|T|MONOGRAPH TITLE:  Warfarin/Vitamin E (Alpha Tocopherol) Greater Than or|
00498|002|T|Equal To 800 Units|
00498|003|B||
00498|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
00498|005|L|of severe adverse interaction.|
00498|006|B||
00498|007|A|MECHANISM OF ACTION:  Vitamin E may decrease vitamin K-dependent clotting|
00498|008|A|factors, resulting in additive effects with warfarin.(1)|
00498|009|B||
00498|010|E|CLINICAL EFFECTS:  Dose of vitamin E of 800 units/day or more may increase|
00498|011|E|the pharmacologic effects of warfarin.(1-7)|
00498|012|B||
00498|013|P|PREDISPOSING FACTORS:  None determined.|
00498|014|B||
00498|015|M|PATIENT MANAGEMENT:  Patients receiving vitamin E supplements of 800|
00498|016|M|units/day or more may require lower dosages of warfarin.  In patients|
00498|017|M|maintained on warfarin who initiate vitamin E supplements in dosages of 800|
00498|018|M|units/day or more, measured INR one to two weeks after initiation of vitamin|
00498|019|M|E and also every two to four weeks during the first two months.(2)|
00498|020|B||
00498|021|D|DISCUSSION:  Vitamin E doses up to 400 units/day is believed not to affect|
00498|022|D|the prothrombin time in patients concomitantly receiving warfarin.(2)|
00498|023|D|Vitamin E doses of 800 International Units/day and more have been reported|
00498|024|D|to increase the hypoprothrombinemic effect of warfarin.  However, in a|
00498|025|D|double blind clinical trial, with only 13 subjects completing the study,|
00498|026|D|patients who had received chronic warfarin therapy with the addition of|
00498|027|D|vitamin E dose as high as 1,200 IU/day for 1 month saw negligible change in|
00498|028|D|the INR or prothrombin time.(3)|
00498|029|D|   Selumetinib capsules contain a significant amount of vitamin E.  Each 10|
00498|030|D|mg capsule contains 32 mg (48 units) and each 25 mg capsule contains (54|
00498|031|D|units) of vitamin E.  The daily dose of selumetinib may contain up to 256 mg|
00498|032|D|(384 units) of vitamin E.  Vitamin E supplementation is not recommended if|
00498|033|D|it will result in a daily vitamin E intake exceeding recommended or safe|
00498|034|D|amounts.(4)|
00498|035|D|   Agenerase brand of amprenavir capsules and oral solution contain a|
00498|036|D|significant amount of vitamin E.  Each 150 mg capsule contains 109|
00498|037|D|International Units vitamin E, with a total of 1,744 International Units of|
00498|038|D|vitamin E in the recommended daily adult dose.  Each mL of oral solution|
00498|039|D|contains 46 International Units of vitamin E.(5)|
00498|040|D|   One or more of the drug pairs linked to this monograph have been included|
00498|041|D|in a list of interactions that could be considered for classification as|
00498|042|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
00498|043|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
00498|044|D|Health Information Technology.|
00498|045|B||
00498|046|R|REFERENCES:|
00498|047|B||
00498|048|R|1.Corrigan JJ Jr, Ulfers LL. Effect of vitamin E on prothrombin levels in|2
00498|049|R|  warfarin-induced vitamin K deficiency. Am J Clin Nutr 1981 Sep;|2
00498|050|R|  34(9):1701-5.|2
00498|051|R|2.Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative|6
00498|052|R|  therapies and warfarin. Am J Health Syst Pharm 2000 Jul 1;57(13):1221-7;|6
00498|053|R|  quiz 1228-30.|6
00498|054|R|3.Kim JM, White RH. Effect of vitamin E on the anticoagulant response to|2
00498|055|R|  warfarin. Am J Cardiol 1996 Mar 1;77(7):545-6.|2
00498|056|R|4.Koselugo (selumetinib) US prescribing information. AstraZeneca|1
00498|057|R|  Pharmaceuticals LP December, 2021.|1
00498|058|R|5.Agenerase (amprenavir) Capsules US prescribing information.|1
00498|059|R|  GlaxoSmithKline May, 2005.|1
00498|060|R|6.Corrigan JJ Jr, Marcus FI. Coagulopathy associated with vitamin E|3
00498|061|R|  ingestion. JAMA 1974 Dec 2;230(9):1300-1.|3
00498|062|R|7.Schrogie JJ. Letter: Coagulopathy and fat-soluble vitamins. JAMA 1975 Apr|2
00498|063|R|  7;232(1):19.|2
00498|064|R|8.Anonymous. Vitamin K, vitamin E and the coumarin drugs. Nutr Rev 1982 Jun;|3
00498|065|R|  40(6):180-2.|3
00498|066|R|9.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
00498|067|R|  Middleton B, Bates DW. Drug-drug interactions that should be|6
00498|068|R|  non-interruptive in order to reduce alert fatigue in electronic health|6
00498|069|R|  records. J Am Med Inform Assoc 2012 Sep 25.|6
00499|001|T|MONOGRAPH TITLE:  Theophyllines/Ticlopidine (mono deleted 09/17/2014)|
00499|002|B||
00499|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
00499|004|L|take action as needed.|
00499|005|B||
00499|006|A|MECHANISM OF ACTION:  Interference with theophylline elimination.|
00499|007|B||
00499|008|E|CLINICAL EFFECTS:  Possible increase in theophylline side effects.|
00499|009|B||
00499|010|P|PREDISPOSING FACTORS:  None determined.|
00499|011|B||
00499|012|M|PATIENT MANAGEMENT:  Monitor theophylline serum levels. Observe patient for|
00499|013|M|theophylline toxicity.|
00499|014|B||
00499|015|D|DISCUSSION:  Increases in serum theophylline concentration and half-life|
00499|016|D|have been reported during concurrent administration of theophylline and|
00499|017|D|ticlopidine.|
00499|018|B||
00499|019|R|REFERENCE:|
00499|020|B||
00499|021|R|1.Colli A, Buccino G, Cocciolo M, Parravicini R, Elli GM, Scaltrini G.|2
00499|022|R|  Ticlopidine-theophylline interaction. Clin Pharmacol Ther 1987 Mar;|2
00499|023|R|  41(3):358-62.|2
01000|001|T|MONOGRAPH TITLE:  Pimozide/Strong CYP3A4 Inhibitors|
01000|002|B||
01000|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01000|004|L|is contraindicated and generally should not be dispensed or administered to|
01000|005|L|the same patient.|
01000|006|B||
01000|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
01000|008|A|pimozide at CYP3A.|
01000|009|B||
01000|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
01000|011|E|the levels and effects of pimozide including QTc prolongation and|
01000|012|E|potentially life-threatening cardiac arrhythmias like torsades de pointes.|
01000|013|E|   Concurrent use may also result in extrapyramidal symptoms such as|
01000|014|E|akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and|
01000|015|E|oculogyric crisis.(1)|
01000|016|B||
01000|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01000|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
01000|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01000|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01000|021|P|female gender, or advanced age.(8)|
01000|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01000|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01000|024|P|risk factors for torsades de pointes.  Factors which may increased systemic|
01000|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01000|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01000|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01000|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(8)|
01000|029|P|   The risk of anticholinergic toxicities including cognitive decline,|
01000|030|P|delirium, falls and fractures is increased in geriatric patients using more|
01000|031|P|than one medicine with anticholinergic properties.(9)|
01000|032|B||
01000|033|M|PATIENT MANAGEMENT:  The use of pimozide with strong CYP3A4 inhibitors is|
01000|034|M|contraindicated, especially when other risk factors for QT prolongation are|
01000|035|M|present.|
01000|036|M|   The manufacturer of pimozide states that concomitant treatment with|
01000|037|M|strong CYP3A4 inhibitors is contraindicated and treatment with less potent|
01000|038|M|inhibitors of CYP3A4 should also be avoided.(1)|
01000|039|M|   If concurrent use cannot be avoided, then correct or minimize QT|
01000|040|M|prolonging risk factors, use the lowest effective dose of pimozide, and|
01000|041|M|discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if|
01000|042|M|possible.|
01000|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01000|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01000|045|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
01000|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01000|047|B||
01000|048|D|DISCUSSION:  An in vitro study indicates that pimozide is metabolized at|
01000|049|D|CYP3A.  Elevated levels of pimozide may prolong the QTc interval, resulting|
01000|050|D|in life-threatening ventricular arrhythmias.(1)|
01000|051|D|   Serious cardiovascular events, including QT prolongation, torsades de|
01000|052|D|pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have|
01000|053|D|been reported in patients taking pimozide in combination with itraconazole|
01000|054|D|and/or other CYP3A4 inhibitors.(3)|
01000|055|D|   Strong CYP3A4 inhibitors include: idelalisib, itraconazole, ketoconazole,|
01000|056|D|and tucatinib.(5,6)|
01000|057|D|   One or more of the drug pairs linked to this monograph have been included|
01000|058|D|in a list of interactions that should be considered "high-priority" for|
01000|059|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01000|060|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01000|061|D|Coordinator (ONC) for Health Information Technology.|
01000|062|B||
01000|063|R|REFERENCES:|
01000|064|B||
01000|065|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
01000|066|R|  2011.|1
01000|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01000|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01000|069|R|  settings: a scientific statement from the American Heart Association and|6
01000|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01000|071|R|  2;55(9):934-47.|6
01000|072|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01000|073|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01000|074|R|  Soc 2023 Jul;71(7):2052-2081.|6
01000|075|R|4.Desta Z, Kerbusch T, Soukhova N, Richard E, Ko JW, Flockhart DA.|5
01000|076|R|  Identification and characterization of human cytochrome P450 isoforms|5
01000|077|R|  interacting with pimozide. J Pharmacol Exp Ther 1998 May;285(2):428-37.|5
01000|078|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
01000|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01000|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01000|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01000|082|R|  11/14/2017.|1
01000|083|R|6.This information is based on an extract from the Certara Drug Interaction|6
01000|084|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01000|085|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01000|086|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01000|087|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01000|088|R|  19(5):735-43.|6
01001|001|T|MONOGRAPH TITLE:  Pimozide/SSRIs; Nefazodone|
01001|002|B||
01001|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01001|004|L|is contraindicated and generally should not be dispensed or administered to|
01001|005|L|the same patient.|
01001|006|B||
01001|007|A|MECHANISM OF ACTION:  Fluvoxamine,(1) nefazodone,(2,3) may inhibit the|
01001|008|A|metabolism of pimozide at CYP3A4.  The mechanisms for the interactions|
01001|009|A|between citalopram,(4) escitalopram,(5) and sertraline(6) and pimozide are|
01001|010|A|unknown.|
01001|011|B||
01001|012|E|CLINICAL EFFECTS:  Concurrent use may result in prolongation of the QTc|
01001|013|E|interval and potentially life-threatening ventricular arrhythmias.(1-9)|
01001|014|E|Concurrent use may also result in extrapyramidal symptoms such as akathisia,|
01001|015|E|bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric|
01001|016|E|crisis.(7)|
01001|017|B||
01001|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01001|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
01001|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01001|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01001|022|P|female gender, or advanced age.(8)|
01001|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01001|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01001|025|P|risk factors for torsades de pointes.  Factors which may increased systemic|
01001|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01001|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01001|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01001|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(8)|
01001|030|P|   The risk of anticholinergic toxicities including cognitive decline,|
01001|031|P|delirium, falls and fractures is increased in geriatric patients using more|
01001|032|P|than one medicine with anticholinergic properties.(9)|
01001|033|B||
01001|034|M|PATIENT MANAGEMENT:  The concurrent use of pimozide with citalopram,(3-5)|
01001|035|M|escitalopram,(3-5) fluvoxamine,(1,3) nefazodone,(2,3) or sertraline(3,6) is|
01001|036|M|contraindicated.|
01001|037|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01001|038|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01001|039|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01001|040|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01001|041|B||
01001|042|D|DISCUSSION:  An in vitro study indicates that pimozide is metabolized at|
01001|043|D|CYP3A4.(7)|
01001|044|D|   In a controlled study, the administration of a single dose of pimozide (2|
01001|045|D|mg) with citalopram (40 mg daily for 11 days) increased mean QTc values by|
01001|046|D|10 msec compared to pimozide administered alone.  There was no change in|
01001|047|D|pimozide area-under-curve (AUC) or maximum concentration (Cmax).(4,5)|
01001|048|D|   In a controlled study, the administration of sertraline (200 mg daily)|
01001|049|D|with a single dose of pimozide (2 mg) resulted in 40% increases in both the|
01001|050|D|AUC and Cmax of pimozide, but was not associated with EKG changes.  However,|
01001|051|D|given the narrow therapeutic index of pimozide, their concurrent use is|
01001|052|D|contraindicated by the manufacturer of sertraline.(6)|
01001|053|D|   One or more of the drug pairs linked to this monograph have been included|
01001|054|D|in a list of interactions that should be considered "high-priority" for|
01001|055|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01001|056|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01001|057|D|Coordinator (ONC) for Health Information Technology.|
01001|058|B||
01001|059|R|REFERENCES:|
01001|060|B||
01001|061|R|1.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
01001|062|R|  Pharmaceuticals, Inc. August, 2023.|1
01001|063|R|2.Serzone (nefazodone hydrochloride) US prescribing information.|1
01001|064|R|  Bristol-Myers Squibb Company January, 2005.|1
01001|065|R|3.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
01001|066|R|  2011.|1
01001|067|R|4.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
01001|068|R|  Laboratories Inc. August, 2023.|1
01001|069|R|5.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
01001|070|R|  Pharmaceuticals Inc. May, 2023.|1
01001|071|R|6.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
01001|072|R|7.Desta Z, Kerbusch T, Soukhova N, Richard E, Ko JW, Flockhart DA.|5
01001|073|R|  Identification and characterization of human cytochrome P450 isoforms|5
01001|074|R|  interacting with pimozide. J Pharmacol Exp Ther 1998 May;285(2):428-37.|5
01001|075|R|8.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01001|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01001|077|R|  settings: a scientific statement from the American Heart Association and|6
01001|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01001|079|R|  2;55(9):934-47.|6
01001|080|R|9.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01001|081|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01001|082|R|  Soc 2023 Jul;71(7):2052-2081.|6
01001|083|R|10.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01001|084|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01001|085|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01001|086|R|   19(5):735-43.|6
01002|001|T|MONOGRAPH TITLE:  Pimozide/Zileuton|
01002|002|B||
01002|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01002|004|L|is contraindicated and generally should not be dispensed or administered to|
01002|005|L|the same patient.|
01002|006|B||
01002|007|A|MECHANISM OF ACTION:  Zileuton may inhibit the metabolism of pimozide at|
01002|008|A|CYP3A.(1)|
01002|009|B||
01002|010|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
01002|011|E|of pimozide, which may result in prolongation of the QTc interval and|
01002|012|E|potentially life-threatening ventricular arrhythmias.(1)|
01002|013|B||
01002|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01002|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01002|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01002|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01002|018|P|female gender, or advanced age.(3)|
01002|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01002|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01002|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01002|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01002|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01002|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01002|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01002|026|P|   The risk of anticholinergic toxicities including cognitive decline,|
01002|027|P|delirium, falls and fractures is increased in geriatric patients using more|
01002|028|P|than one medicine with anticholinergic properties.(4)|
01002|029|B||
01002|030|M|PATIENT MANAGEMENT:  The concurrent administration of pimozide and zileuton|
01002|031|M|is contraindicated by the manufacturer of pimozide.(1)|
01002|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01002|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01002|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01002|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01002|036|B||
01002|037|D|DISCUSSION:  An in vitro study indicates that pimozide is metabolized at|
01002|038|D|CYP3A.(2)  Because elevated levels of pimozide may prolong the QTc interval,|
01002|039|D|resulting in life-threatening ventricular arrhythmias, the manufacturer of|
01002|040|D|pimozide states that the concurrent administration of pimozide with|
01002|041|D|inhibitors of CYP3A such as zileuton is contraindicated.(1)|
01002|042|B||
01002|043|R|REFERENCES:|
01002|044|B||
01002|045|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
01002|046|R|  2011.|1
01002|047|R|2.Desta Z, Kerbusch T, Soukhova N, Richard E, Ko JW, Flockhart DA.|5
01002|048|R|  Identification and characterization of human cytochrome P450 isoforms|5
01002|049|R|  interacting with pimozide. J Pharmacol Exp Ther 1998 May;285(2):428-37.|5
01002|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01002|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01002|052|R|  settings: a scientific statement from the American Heart Association and|6
01002|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01002|054|R|  2;55(9):934-47.|6
01002|055|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01002|056|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01002|057|R|  Soc 2023 Jul;71(7):2052-2081.|6
01003|001|T|MONOGRAPH TITLE:  Tapentadol/SSRIs; SNRIs|
01003|002|B||
01003|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01003|004|L|take action as needed.|
01003|005|B||
01003|006|A|MECHANISM OF ACTION:  The concurrent administration of tapentadol(1) with a|
01003|007|A|selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine|
01003|008|A|reuptake inhibitor (SNRI) may result in additive blockade of serotonin|
01003|009|A|reuptake, leading to central serotonergic hyperstimulation.(1)|
01003|010|A|   The combination of tapentadol and SSRIs or SNRIs may impact seizure|
01003|011|A|control.(1)|
01003|012|B||
01003|013|E|CLINICAL EFFECTS:  Concurrent administration may increase the risk for|
01003|014|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
01003|015|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
01003|016|E|and muscle rigidity.(2)|
01003|017|E|   Concurrent administration may increase the risk for seizures, especially|
01003|018|E|in susceptible individuals.(1)|
01003|019|B||
01003|020|P|PREDISPOSING FACTORS:  Treatment with multiple medications which increase|
01003|021|P|serotonin levels or with medications which inhibit the metabolism of|
01003|022|P|serotonin increasing drugs are risk factors for serotonin syndrome.(2)|
01003|023|B||
01003|024|M|PATIENT MANAGEMENT:  If concurrent therapy of tapentadol with a SSRI or SNRI|
01003|025|M|is warranted, patients should be closely monitored for signs and symptoms of|
01003|026|M|serotonin syndrome or increased seizure frequency.  Tapentadol may need to|
01003|027|M|be discontinued.|
01003|028|B||
01003|029|D|DISCUSSION:  Concurrent use of tapentadol with SSRIs or SNRIs may result in|
01003|030|D|additive blockage of serotonin reuptake, leading to central serotonergic|
01003|031|D|hyperstimulation.  Cases of serotonin syndrome have been reported with|
01003|032|D|tapentadol in combination with other serotonergic drugs.(1)|
01003|033|D|   Use of tapentadol has been associated with increased seizure frequency in|
01003|034|D|patients with seizure disorders.(1)|
01003|035|D|   SSRIs and SNRIs linked to this monograph are: citalopram, desvenlafaxine,|
01003|036|D|duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,|
01003|037|D|sertraline, sibutramine, venlafaxine, vilazodone, and vortioxetine.|
01003|038|B||
01003|039|R|REFERENCES:|
01003|040|B||
01003|041|R|1.Nucynta ER (tapentadol) US prescribing information. Janssen|1
01003|042|R|  Pharmaceuticals December, 2023.|1
01003|043|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01003|044|R|  352(11):1112-20.|6
01004|001|T|MONOGRAPH TITLE:  Digoxin/St. John's wort|
01004|002|B||
01004|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01004|004|L|take action as needed.|
01004|005|B||
01004|006|A|MECHANISM OF ACTION:  St. John's wort may induce P-glycoprotein, which|
01004|007|A|mediates the intestinal absorption, distribution, and renal excretion of|
01004|008|A|digoxin.(1)|
01004|009|B||
01004|010|E|CLINICAL EFFECTS:  The concurrent administration of digoxin and St. John's|
01004|011|E|wort may result in decreased levels and clinical effects of digoxin.(1)|
01004|012|B||
01004|013|P|PREDISPOSING FACTORS:  None determined.|
01004|014|B||
01004|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with digoxin and|
01004|016|M|St. John's wort should be monitored for decreased levels and clinical|
01004|017|M|effects of digoxin.  The dosage of digoxin may need to be adjusted if St.|
01004|018|M|John's wort is added to or removed from concurrent therapy with digoxin.|
01004|019|M|The dosage of digoxin may need to be increased by 20% to 40%.|
01004|020|B||
01004|021|D|DISCUSSION:  A single-blind study in 25 subjects compared the concurrent|
01004|022|D|administration of digoxin (0.25 mg daily) with hypericum (300 mg dried|
01004|023|D|hypericum extract) to the administration of digoxin with placebo.|
01004|024|D|Administration of a single dose of hypericum had no effect on digoxin|
01004|025|D|pharmacokinetics.  After 7 and 10 days of concurrent administration, digoxin|
01004|026|D|trough values decreased by 19% and 33%, respectively, when compared to the|
01004|027|D|placebo group.  Digoxin area-under-curve (AUC) decreased 33% after 10 days|
01004|028|D|of concurrent administration.  Within the hypericum group, digoxin maximum|
01004|029|D|concentration (Cmax) and AUC decreased 26% and 28%, respectively, following|
01004|030|D|10 days of concurrent administration.(1)|
01004|031|D|  St. John's wort is a common name for the flowering plant Hypericum|
01004|032|D|perforatum.  Other common names include klamath weed, amber touch-and-heal,|
01004|033|D|goatweed, rosin rose, and millepertuis.|
01004|034|B||
01004|035|R|REFERENCES:|
01004|036|B||
01004|037|R|1.Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I.|2
01004|038|R|  Pharmacokinetic interaction of digoxin with an herbal extract from St|2
01004|039|R|  John's wort (Hypericum perforatum). Clin Pharmacol Ther 1999 Oct;|2
01004|040|R|  66(4):338-45.|2
01004|041|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
01004|042|R|  Pharmaceuticals, Inc. August, 2018.|1
01006|001|T|MONOGRAPH TITLE:  Disopyramide; Quinidine/Selected Azole Antifungals|
01006|002|B||
01006|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01006|004|L|is contraindicated and generally should not be dispensed or administered to|
01006|005|L|the same patient.|
01006|006|B||
01006|007|A|MECHANISM OF ACTION:  Fluconazole,(1) itraconazole,(2) ketoconazole,(3)|
01006|008|A|posaconazole,(4,5) and voriconazole (6) may inhibit the metabolism of|
01006|009|A|disopyramide and quinidine by CYP3A4.|
01006|010|A|   Fluconazole, posaconazole, and voriconazole may also have additive|
01006|011|A|effects on the QT interval.|
01006|012|B||
01006|013|E|CLINICAL EFFECTS:  The concurrent use of fluconazole,(1) itraconazole,(2)|
01006|014|E|ketoconazole,(3) posaconazole,(4,5) or voriconazole(6) with disopyramide or|
01006|015|E|quinidine may result in elevated plasma levels of these antiarrhythmics,|
01006|016|E|which may result in potentially serious or life-threatening adverse effects,|
01006|017|E|including QT prolongation.|
01006|018|E|   Concurrent use of itraconazole and quinidine may also result in transient|
01006|019|E|or permanent hearing loss.(2)|
01006|020|B||
01006|021|P|PREDISPOSING FACTORS:  Renal and hepatic impairment decrease elimination of|
01006|022|P|disopyramide and quinidine and may increase risk for excessive QTc|
01006|023|P|prolongation.  To prevent increased serum levels and risk for ventricular|
01006|024|P|arrhythmias, disopyramide and quinidine must be dose adjusted in renal and|
01006|025|P|hepatic insufficiency.|
01006|026|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01006|027|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01006|028|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01006|029|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01006|030|P|advanced age.(7)|
01006|031|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01006|032|P|higher systemic concentrations of either QT prolonging drug are additional|
01006|033|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01006|034|P|drug concentrations include rapid infusion of an intravenous dose or|
01006|035|P|impaired metabolism or elimination of the drug (e.g coadministration with an|
01006|036|P|agent which inhibits its metabolism or elimination, genetic impairment in|
01006|037|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)|
01006|038|B||
01006|039|M|PATIENT MANAGEMENT:  The manufacturers of fluconazole(1) and|
01006|040|M|posaconazole(4,5) state that administration with agents metabolized by|
01006|041|M|CYP3A4 that are known QT prolonging agents is contraindicated.  The|
01006|042|M|manufacturer of itraconazole(2) and ketoconazole(3) state that|
01006|043|M|administration with disopyramide is contraindicated.|
01006|044|M|   The manufacturers of fluconazole,(1) itraconazole,(2) ketoconazole,(3)|
01006|045|M|posaconazole,(4,5) and voriconazole(6) state that the concurrent use of|
01006|046|M|quinidine is contraindicated.|
01006|047|M|   The US manufacturer of itraconazole states that disopyramide or quinidine|
01006|048|M|should not be administered until at least 2 weeks after itraconazole|
01006|049|M|treatment.(2)|
01006|050|M|   If concurrent therapy is deemed medically necessary, obtain serum|
01006|051|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
01006|052|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01006|053|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01006|054|B||
01006|055|D|DISCUSSION:  Azole antifungals that inhibit CYP3A4 would be expected to|
01006|056|D|increase levels of disopyramide.(1-5)  Life threatening reactions have been|
01006|057|D|reported with other CYP3A4 inhibitors such as clarithromycin and|
01006|058|D|erythromycin.(8)|
01006|059|D|   Serious cardiovascular events, including QT prolongation, torsades de|
01006|060|D|pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have|
01006|061|D|been reported in patients taking quinidine in combination with itraconazole|
01006|062|D|and/or other CYP3A4 inhibitors. Transient or permanent hearing loss has been|
01006|063|D|reported with itraconazole use, several of these reports involved concurrent|
01006|064|D|quinidine.(2)|
01006|065|D|   Posaconazole has been shown to inhibit CYP3A4.(4)|
01006|066|D|   Voriconazole has been shown to increase levels of sirolimus, which is|
01006|067|D|metabolized by the same isoenzyme that quinidine is.  Therefore, the|
01006|068|D|manufacturer of voriconazole states that the concurrent use of voriconazole|
01006|069|D|and quinidine is contraindicated.(6)|
01006|070|D|   One or more of the drug pairs linked to this monograph have been included|
01006|071|D|in a list of interactions that should be considered "high-priority" for|
01006|072|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01006|073|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01006|074|D|Coordinator (ONC) for Health Information Technology.|
01006|075|B||
01006|076|R|REFERENCES:|
01006|077|B||
01006|078|R|1.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
01006|079|R|  2024.|1
01006|080|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01006|081|R|  Products, L.P. February, 2024.|1
01006|082|R|3.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01006|083|R|  Pharmaceuticals February, 2014.|1
01006|084|R|4.Noxafil (posaconazole) UK summary of product characteristics.|1
01006|085|R|  Schering-Plough Ltd. January, 2022.|1
01006|086|R|5.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01006|087|R|  January, 2022.|1
01006|088|R|6.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01006|089|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01006|090|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01006|091|R|  settings: a scientific statement from the American Heart Association and|6
01006|092|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01006|093|R|  2;55(9):934-47.|6
01006|094|R|8.Norpace (disopyramide phosphate) US prescribing information. Pfizer Inc.|1
01006|095|R|  December, 2020.|1
01006|096|R|9.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01006|097|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01006|098|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01006|099|R|  19(5):735-43.|6
01007|001|T|MONOGRAPH TITLE:  Selected Antiarrhythmics/Quinupristin-Dalfopristin;|
01007|002|T|Pristinamycin|
01007|003|B||
01007|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01007|005|L|of severe adverse interaction.|
01007|006|B||
01007|007|A|MECHANISM OF ACTION:  Quinupristin-dalfopristin and pristinamycin may|
01007|008|A|inhibit the metabolism of amiodarone, disopyramide, and quinidine at|
01007|009|A|CYP3A4.(1)|
01007|010|B||
01007|011|E|CLINICAL EFFECTS:  The concurrent administration of|
01007|012|E|quinupristin-dalfopristin or pristinamycin with amiodarone, disopyramide, or|
01007|013|E|quinidine may result in elevated levels of these agents, which may result in|
01007|014|E|prolongation of the QTc interval and possibly life-threatening|
01007|015|E|arrhythmias.(1)|
01007|016|B||
01007|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01007|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
01007|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01007|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01007|021|P|female gender, or advanced age.(2)|
01007|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01007|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01007|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01007|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01007|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01007|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01007|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01007|029|B||
01007|030|M|PATIENT MANAGEMENT:  The manufacturer of quinupristin-dalfopristin states|
01007|031|M|that the concurrent administration of quinupristin-dalfopristin with agents|
01007|032|M|that are known to be metabolized by CYP3A4 and to prolong the QTc interval,|
01007|033|M|such as amiodarone, disopyramide, and quinidine, should be avoided.(1)|
01007|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01007|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01007|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01007|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01007|038|B||
01007|039|D|DISCUSSION:  Quinupristin-dalfopristin has been shown to inhibit CYP3A4.|
01007|040|D|Because of the risk that elevated levels of agents that are known to prolong|
01007|041|D|the QTc interval may result in potentially life-threatening arrhythmias, the|
01007|042|D|manufacturer of quinupristin-dalfopristin states that the concurrent|
01007|043|D|administration of quinupristin-dalfopristin with such agents that are also|
01007|044|D|metabolized by CYP3A4 should be avoided.(1)|
01007|045|D|   Pristinamycin has been shown to inhibit CYP3A4.(3)|
01007|046|B||
01007|047|R|REFERENCES:|
01007|048|B||
01007|049|R|1.Synercid (quinupristin-dalfopristin) US prescribing information.|1
01007|050|R|  Rhone-Poulenc Rorer Pharmaceuticals, Inc. September 21, 1999.|1
01007|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01007|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01007|053|R|  settings: a scientific statement from the American Heart Association and|6
01007|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01007|055|R|  2;55(9):934-47.|6
01007|056|R|3.Pyostacin (pristinamycin) Australian product information. SANOFI WINTHROP|1
01007|057|R|  INDUSTRIE May 5, 2010.|1
01008|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/Quinupristin-Dalfopristin;|
01008|002|T|Pristinamycin|
01008|003|B||
01008|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01008|005|L|of severe adverse interaction.|
01008|006|B||
01008|007|A|MECHANISM OF ACTION:  Quinupristin-dalfopristin and pristinamycin may|
01008|008|A|inhibit the metabolism of astemizole and terfenadine at CYP3A4.(1)|
01008|009|B||
01008|010|E|CLINICAL EFFECTS:  The concurrent administration of|
01008|011|E|quinupristin-dalfopristin or pristinamycin with astemizole or terfenadine|
01008|012|E|may result in elevated levels of unmetabolized astemizole and terfenadine,|
01008|013|E|which have been shown to result in prolongation of QTc interval and|
01008|014|E|life-threatening arrhythmias.(1)|
01008|015|B||
01008|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01008|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
01008|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01008|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01008|020|P|female gender, or advanced age.(2)|
01008|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01008|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01008|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01008|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01008|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01008|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01008|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01008|028|B||
01008|029|M|PATIENT MANAGEMENT:  The manufacturer of quinupristin-dalfopristin states|
01008|030|M|that the concurrent administration of quinupristin-dalfopristin with agents|
01008|031|M|that are known to be metabolized by CYP3A4 and to prolong the QTc interval,|
01008|032|M|such as astemizole and terfenadine, should be avoided.(1)|
01008|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01008|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01008|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01008|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01008|037|B||
01008|038|D|DISCUSSION:  Quinupristin-dalfopristin has been shown to inhibit CYP3A4.|
01008|039|D|Because of the risk that elevated levels of agents that are known to prolong|
01008|040|D|the QTc interval may result in potentially life-threatening arrhythmias, the|
01008|041|D|manufacturer of quinupristin-dalfopristin states that the concurrent|
01008|042|D|administration of quinupristin-dalfopristin with such agents that are also|
01008|043|D|metabolized by CYP3A4 should be avoided.(1)|
01008|044|D|   Pristinamycin has been shown to inhibit CYP3A4.(3)|
01008|045|B||
01008|046|R|REFERENCES:|
01008|047|B||
01008|048|R|1.Synercid (quinupristin-dalfopristin) US prescribing information.|1
01008|049|R|  Rhone-Poulenc Rorer Pharmaceuticals, Inc. September 21, 1999.|1
01008|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01008|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01008|052|R|  settings: a scientific statement from the American Heart Association and|6
01008|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01008|054|R|  2;55(9):934-47.|6
01008|055|R|3.Pyostacin (pristinamycin) Australian product information. SANOFI WINTHROP|1
01008|056|R|  INDUSTRIE May 5, 2010.|1
01009|001|T|MONOGRAPH TITLE:  Cisapride/Quinupristin-Dalfopristin; Pristinamycin|
01009|002|B||
01009|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01009|004|L|of severe adverse interaction.|
01009|005|B||
01009|006|A|MECHANISM OF ACTION:  Quinupristin-dalfopristin and pristinamycin may|
01009|007|A|inhibit the metabolism of cisapride at CYP3A4.(1)|
01009|008|B||
01009|009|E|CLINICAL EFFECTS:  The concurrent administration of|
01009|010|E|quinupristin-dalfopristin or pristinamycin with cisapride may result in|
01009|011|E|elevated levels of unmetabolized cisapride, which have been shown to result|
01009|012|E|in prolongation of the QTc interval and life-threatening arrhythmias.(1)|
01009|013|B||
01009|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01009|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01009|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01009|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01009|018|P|female gender, or advanced age.(2)|
01009|019|P|   concurrent use of more than one drug known to cause QT prolongation or|
01009|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01009|021|P|risk factors for torsades de pointes.  Factors which may increased systemic|
01009|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01009|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01009|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01009|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01009|026|B||
01009|027|M|PATIENT MANAGEMENT:  The manufacturer of quinupristin-dalfopristin states|
01009|028|M|that the concurrent administration of quinupristin-dalfopristin with agents|
01009|029|M|that are known to be metabolized by CYP3A4 and to prolong the QTc interval,|
01009|030|M|such as cisapride, should be avoided.(1)|
01009|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01009|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01009|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01009|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01009|035|B||
01009|036|D|DISCUSSION:  Quinupristin-dalfopristin has been shown to inhibit CYP3A4.|
01009|037|D|Because of the risk that elevated levels of agents that are known to prolong|
01009|038|D|the QTc interval may result in potentially life-threatening arrhythmias, the|
01009|039|D|manufacturer of quinupristin-dalfopristin states that the concurrent|
01009|040|D|administration of quinupristin-dalfopristin with such agents that are also|
01009|041|D|metabolized by CYP3A4 should be avoided.(1)|
01009|042|D|   Pristinamycin has been shown to inhibit CYP3A4.(3)|
01009|043|B||
01009|044|R|REFERENCES:|
01009|045|B||
01009|046|R|1.Synercid (quinupristin-dalfopristin) US prescribing information.|1
01009|047|R|  Rhone-Poulenc Rorer Pharmaceuticals, Inc. September 21, 1999.|1
01009|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01009|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01009|050|R|  settings: a scientific statement from the American Heart Association and|6
01009|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01009|052|R|  2;55(9):934-47.|6
01009|053|R|3.Pyostacin (pristinamycin) Australian product information. SANOFI WINTHROP|1
01009|054|R|  INDUSTRIE May 5, 2010.|1
01010|001|T|MONOGRAPH TITLE:|
01010|002|T|Clarithromycin;Erythromycin/Quinupristin-Dalfopristin;Pristinamycin|
01010|003|B||
01010|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01010|005|L|of severe adverse interaction.|
01010|006|B||
01010|007|A|MECHANISM OF ACTION:  Quinupristin-dalfopristin and pristinamycin may|
01010|008|A|inhibit the metabolism of clarithromycin and erythromycin at CYP3A4.(1)|
01010|009|B||
01010|010|E|CLINICAL EFFECTS:  The concurrent administration of|
01010|011|E|quinupristin-dalfopristin or pristinamycin with clarithromycin or|
01010|012|E|erythromycin may result in elevated levels of these agents, which may result|
01010|013|E|in prolongation of the QTc interval and possibly life-threatening|
01010|014|E|arrhythmias.(1)|
01010|015|B||
01010|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01010|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
01010|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01010|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01010|020|P|female gender, or advanced age.(2)|
01010|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01010|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01010|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01010|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01010|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01010|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01010|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01010|028|B||
01010|029|M|PATIENT MANAGEMENT:  The manufacturer of quinupristin-dalfopristin states|
01010|030|M|that the concurrent administration of quinupristin-dalfopristin with agents|
01010|031|M|that are known to be metabolized by CYP3A4 and to prolong the QTc interval,|
01010|032|M|such as clarithromycin and erythromycin, should be avoided.(1)|
01010|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01010|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01010|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01010|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01010|037|B||
01010|038|D|DISCUSSION:  Quinupristin-dalfopristin has been shown to inhibit CYP3A4.|
01010|039|D|Because of the risk that elevated levels of agents that are known to prolong|
01010|040|D|the QTc interval may result in potentially life-threatening arrhythmias, the|
01010|041|D|manufacturer of quinupristin-dalfopristin states that the concurrent|
01010|042|D|administration of quinupristin-dalfopristin with such agents that are also|
01010|043|D|metabolized by CYP3A4 should be avoided.(1)|
01010|044|D|   Pristinamycin has been shown to inhibit CYP3A4.(3)|
01010|045|B||
01010|046|R|REFERENCES:|
01010|047|B||
01010|048|R|1.Synercid (quinupristin-dalfopristin) US prescribing information.|1
01010|049|R|  Rhone-Poulenc Rorer Pharmaceuticals, Inc. September 21, 1999.|1
01010|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01010|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01010|052|R|  settings: a scientific statement from the American Heart Association and|6
01010|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01010|054|R|  2;55(9):934-47.|6
01010|055|R|3.Pyostacin (pristinamycin) Australian product information. SANOFI WINTHROP|1
01010|056|R|  INDUSTRIE May 5, 2010.|1
01011|001|T|MONOGRAPH TITLE:  Haloperidol; Pimozide/Quinupristin-Dalfopristin;|
01011|002|T|Pristinamycin|
01011|003|B||
01011|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01011|005|L|of severe adverse interaction.|
01011|006|B||
01011|007|A|MECHANISM OF ACTION:  Quinupristin-dalfopristin and pristinamycin may|
01011|008|A|inhibit the metabolism of haloperidol and pimozide at CYP3A4.(1)|
01011|009|B||
01011|010|E|CLINICAL EFFECTS:  The concurrent administration of|
01011|011|E|quinupristin-dalfopristin or pristinamycin with haloperidol or pimozide may|
01011|012|E|result in elevated levels of these agents, which may result in prolongation|
01011|013|E|of the QTc interval and possibly life-threatening arrhythmias.(1)|
01011|014|B||
01011|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01011|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01011|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01011|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01011|019|P|female gender, or advanced age.(2)|
01011|020|P|  Concurrent use of more than one drug known to cause QT prolongation or|
01011|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01011|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01011|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01011|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01011|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01011|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01011|027|P|   The risk of anticholinergic toxicities including cognitive decline,|
01011|028|P|delirium, falls and fractures is increased in geriatric patients using more|
01011|029|P|than one medicine with anticholinergic properties.(3)|
01011|030|B||
01011|031|M|PATIENT MANAGEMENT:  The manufacturer of quinupristin-dalfopristin states|
01011|032|M|that the concurrent administration of quinupristin-dalfopristin with agents|
01011|033|M|that are known to be metabolized by CYP3A4 and to prolong the QTc interval,|
01011|034|M|such as haloperidol and pimozide, should be avoided.(1)|
01011|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01011|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01011|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01011|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01011|039|B||
01011|040|D|DISCUSSION:  Quinupristin-dalfopristin has been shown to inhibit CYP3A4.|
01011|041|D|Because of the risk that elevated levels of agents that are known to prolong|
01011|042|D|the QTc interval may result in potentially life-threatening arrhythmias, the|
01011|043|D|manufacturer of quinupristin-dalfopristin states that the concurrent|
01011|044|D|administration of quinupristin-dalfopristin with such agents that are also|
01011|045|D|metabolized by CYP3A4 should be avoided.(1)|
01011|046|D|   Pristinamycin has been shown to inhibit CYP3A4.(4)|
01011|047|B||
01011|048|R|REFERENCES:|
01011|049|B||
01011|050|R|1.Synercid (quinupristin-dalfopristin) US prescribing information.|1
01011|051|R|  Rhone-Poulenc Rorer Pharmaceuticals, Inc. September 21, 1999.|1
01011|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01011|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01011|054|R|  settings: a scientific statement from the American Heart Association and|6
01011|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01011|056|R|  2;55(9):934-47.|6
01011|057|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01011|058|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01011|059|R|  Soc 2023 Jul;71(7):2052-2081.|6
01011|060|R|4.Pyostacin (pristinamycin) Australian product information. SANOFI WINTHROP|1
01011|061|R|  INDUSTRIE May 5, 2010.|1
01012|001|T|MONOGRAPH TITLE:  Sirolimus; Temsirolimus/Cyclosporine|
01012|002|B||
01012|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01012|004|L|take action as needed.|
01012|005|B||
01012|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Temsirolimus is a|
01012|007|A|pro-drug of sirolimus.(1)|
01012|008|B||
01012|009|E|CLINICAL EFFECTS:  The concurrent administration of sirolimus and|
01012|010|E|cyclosporine may result in elevated levels of sirolimus and cyclosporine.|
01012|011|E|Elevated levels of sirolimus may be seen as soon as after one concurrent|
01012|012|E|dose.  Elevated levels of cyclosporine may take several weeks to develop.(2)|
01012|013|E|   Sirolimus may increase the risk of calcineurin-induced hemolytic uremic|
01012|014|E|syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.(2)|
01012|015|E|   In liver transplant patients, concurrent sirolimus and cyclosporine has|
01012|016|E|been associated with an increase in hepatic artery thrombosis (HAT).  Most|
01012|017|E|cases occurred within 30 days post-transplantation and most led to graft|
01012|018|E|loss or death.(2)|
01012|019|B||
01012|020|P|PREDISPOSING FACTORS:  None determined.|
01012|021|B||
01012|022|M|PATIENT MANAGEMENT:  The manufacturer of sirolimus recommends that sirolimus|
01012|023|M|be administered four hours after cyclosporine oral solution (MODIFIED) and|
01012|024|M|cyclosporine capsules (MODIFIED).(2)  Blood levels of sirolimus and|
01012|025|M|cyclosporine and renal function should be carefully monitored in patients|
01012|026|M|receiving concurrent therapy with these agents.  The dosages of one or both|
01012|027|M|both agents may need to be adjusted.|
01012|028|M|   The manufacturer of sirolimus recommends that sirolimus not be used in|
01012|029|M|liver transplant patients.(2)|
01012|030|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
01012|031|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
01012|032|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
01012|033|M|inhibitors should be avoided.(3)|
01012|034|M|   Since temsirolimus is a pro-drug of sirolimus, it would be prudent to|
01012|035|M|monitor cyclosporine levels during concurrent therapy.|
01012|036|B||
01012|037|D|DISCUSSION:  In a single dose study in 24 healthy subjects, simultaneous|
01012|038|D|administration of sirolimus oral solution (10 mg) and cyclosporine capsules|
01012|039|D|(300 mg, MODIFIED) resulted in increases in the sirolimus maximum|
01012|040|D|concentration (Cmax) and area-under-curve (AUC) by 116% and 230%,|
01012|041|D|respectively. Sirolimus four hours after the administration of cyclosporine|
01012|042|D|capsules (MODIFIED) resulted in increases in sirolimus Cmax and AUC by 37%|
01012|043|D|and 80%, respectively.  Cyclosporine Cmax and AUC were initially not|
01012|044|D|significantly affected; however, after multiple doses, the clearance of|
01012|045|D|cyclosporine was decreased and lower doses of cyclosporine were required.(2)|
01012|046|D|   In a single dose study in 24 healthy subjects, simultaneous|
01012|047|D|administration of sirolimus tablets (10 mg) and cyclosporine capsules (300|
01012|048|D|mg) resulted in increases of sirolimus Cmax and AUC by 512% and 148%,|
01012|049|D|respectively. Sirolimus four hours after the administration of cyclosporine|
01012|050|D|capsules resulted in increases of only 33%. (2)|
01012|051|D|   In a single dose cross-over study in 33 healthy subjects, sirolimus (5|
01012|052|D|mg) was administered alone, 2 hours before cyclosporine capsules (300 mg,|
01012|053|D|MODIFIED), and 2 hours after cyclosporine capsules (300 mg, MODIFIED). There|
01012|054|D|was no significant difference in sirolimus Cmax and AUC when administered 2|
01012|055|D|hours before cyclosporine; however, sirolimus Cmax and AUC increased by 126%|
01012|056|D|and 141%, respectively, when given 2 hours after cyclosporine.(2)|
01012|057|D|   The concurrent administration of sirolimus and cyclosporine oral solution|
01012|058|D|resulted in increases in sirolimus trough concentrations by 67%-86%.  There|
01012|059|D|was no significant effect on cyclosporine concentrations.(2)|
01012|060|B||
01012|061|R|REFERENCES:|
01012|062|B||
01012|063|R|1.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01012|064|R|  Inc. March, 2018.|1
01012|065|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
01012|066|R|  Aug, 2022.|1
01012|067|R|3.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
01012|068|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
01013|001|T|MONOGRAPH TITLE:  Sirolimus/Voriconazole|
01013|002|B||
01013|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01013|004|L|of severe adverse interaction.|
01013|005|B||
01013|006|A|MECHANISM OF ACTION:  Voriconazole may inhibit the metabolism of sirolimus|
01013|007|A|by CYP3A4.(1,2)|
01013|008|B||
01013|009|E|CLINICAL EFFECTS:  The concurrent administration of sirolimus and|
01013|010|E|voriconazole may result in elevated levels of sirolimus and toxicity.(1,2)|
01013|011|B||
01013|012|P|PREDISPOSING FACTORS:  None determined.|
01013|013|B||
01013|014|M|PATIENT MANAGEMENT:  The manufacturer of voriconazole states that concurrent|
01013|015|M|use of sirolimus is contraindicated.(1)|
01013|016|M|   The manufacturer of sirolimus states that concurrent use of voriconazole|
01013|017|M|is not recommended and should be avoided.(2)|
01013|018|M|   If concurrent therapy is warranted, sirolimus levels should be closely|
01013|019|M|monitored.(3)|
01013|020|B||
01013|021|D|DISCUSSION:  In healthy subjects, voriconazole (400 mg every 12 hours Day 1,|
01013|022|D|200 mg every 12 hours on Days 2-9) increased the maximum concentration|
01013|023|D|(Cmax) and area-under-curve (AUC) of sirolimus (2 mg single dose) by 7-fold|
01013|024|D|and 11-fold, respectively.(1)|
01013|025|D|   One set of authors reports 2 case of concurrent sirolimus and|
01013|026|D|voriconazole.  Concurrent voriconazole required dosage reductions of 75% to|
01013|027|D|87.5% in sirolimus dosage.(3)|
01013|028|D|   Another set of authors reports 3 cases of concurrent sirolimus and|
01013|029|D|voriconazole.  In the first, concurrent voriconazole increased sirolimus AUC|
01013|030|D|by 4.5-fold.  In the second, concurrent voriconazole increased sirolimus|
01013|031|D|trough concentrations (Cmin) by 1.5-fold, despite a 75% reduction in|
01013|032|D|sirolimus dose.  In the third report, voriconazole increased sirolimus Cmin|
01013|033|D|by 45% and the dose of sirolimus was decreased by two-thirds.  Following the|
01013|034|D|discontinuation of voriconazole, sirolimus levels were undetectable.(4)|
01013|035|D|   A study in 67 allogenic hematopoetic stem-cell transplant patients were|
01013|036|D|coadministered voriconazole prophylaxis in combination with sirolimus.|
01013|037|D|Concurrent voriconazole prompted an empiric dose reduction of sirolimus of|
01013|038|D|90% and all patients received concurrent therapy.  Median sirolimus trough|
01013|039|D|levels before and at steady state of coadministration with voriconazole were|
01013|040|D|5.8 ng/mL and 6.1 ng/mL, respectively (p=0.45).(5)|
01013|041|B||
01013|042|R|REFERENCES:|
01013|043|B||
01013|044|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01013|045|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
01013|046|R|  Aug, 2022.|1
01013|047|R|3.Mathis AS, Shah NK, Friedman GS. Combined use of sirolimus and|3
01013|048|R|  voriconazole in renal transplantation: a report of two cases. Transplant|3
01013|049|R|  Proc 2004 Nov;36(9):2708-9.|3
01013|050|R|4.Sadaba B, Campanero MA, Quetglas EG, Azanza JR. Clinical relevance of|3
01013|051|R|  sirolimus drug interactions in transplant patients. Transplant Proc 2004|3
01013|052|R|  Dec;36(10):3226-8.|3
01013|053|R|5.Ceberio I, Dai K, Devlin SM, Barker JN, Castro-Malaspina H, Goldberg JD,|2
01013|054|R|  Giralt S, Adel NG, Perales MA. Safety of voriconazole and sirolimus|2
01013|055|R|  coadministration after allogeneic hematopoietic SCT. Bone Marrow|2
01013|056|R|  Transplant 2015 Mar;50(3):438-43.|2
01014|001|T|MONOGRAPH TITLE:  Dofetilide/Verapamil|
01014|002|B||
01014|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01014|004|L|is contraindicated and generally should not be dispensed or administered to|
01014|005|L|the same patient.|
01014|006|B||
01014|007|A|MECHANISM OF ACTION:  Dofetilide is primarily excreted in the urine via both|
01014|008|A|glomerular filtration and active tubular secretion via the cation transport|
01014|009|A|system.  Verapamil is believed to inhibit the cation transport system and|
01014|010|A|thus may inhibit the active tubular secretion of dofetilide.(1)|
01014|011|B||
01014|012|E|CLINICAL EFFECTS:  The concurrent administration of dofetilide with|
01014|013|E|verapamil may result in elevated levels and increased effects of dofetilide,|
01014|014|E|including torsades de pointes.(1,2)|
01014|015|B||
01014|016|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
01014|017|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
01014|018|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
01014|019|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
01014|020|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01014|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01014|022|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01014|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01014|024|P|advanced age.(3)|
01014|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01014|026|P|higher systemic concentrations of either QT prolonging drug are additional|
01014|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01014|028|P|drug concentrations include rapid infusion of an intravenous dose or|
01014|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01014|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01014|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01014|032|B||
01014|033|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that the|
01014|034|M|concurrent administration of dofetilide with verapamil is contraindicated.|
01014|035|M|If dofetilide is to be discontinued, a washout of at least 2 days is|
01014|036|M|recommended prior to starting verapamil.(1)|
01014|037|M|   If alternatives are not available and concurrent therapy is deemed|
01014|038|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
01014|039|M|and monitor ECG at baseline and at regular intervals.  Correct any|
01014|040|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01014|041|M|heartbeat, dizziness, or fainting.|
01014|042|B||
01014|043|D|DISCUSSION:  The concurrent administration of dofetilide and verapamil|
01014|044|D|resulted in an increase in dofetilide peak plasma levels by 42%.  Concurrent|
01014|045|D|administration was also associated with a higher occurrence of torsades de|
01014|046|D|pointes.(1)|
01014|047|D|   A study in twelve healthy subjects examined the effects of combination|
01014|048|D|therapy with verapamil and dofetilide. Though no clinically adverse effects|
01014|049|D|were observed, concurrent use of both drugs increased plasma concentration|
01014|050|D|of dofetilide by 43%.(2)|
01014|051|B||
01014|052|R|REFERENCES:|
01014|053|B||
01014|054|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01014|055|R|  2013.|1
01014|056|R|2.Johnson BF, Cheng SL, Venitz J. Transient kinetic and dynamic interactions|2
01014|057|R|  between verapamil and dofetilide, a class III antiarrhythmic. J Clin|2
01014|058|R|  Pharmacol 2001 Nov;41(11):1248-56.|2
01014|059|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01014|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01014|061|R|  settings: a scientific statement from the American Heart Association and|6
01014|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01014|063|R|  2;55(9):934-47.|6
01015|001|T|MONOGRAPH TITLE:  Dofetilide/MATE Inhibitors|
01015|002|B||
01015|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01015|004|L|is contraindicated and generally should not be dispensed or administered to|
01015|005|L|the same patient.|
01015|006|B||
01015|007|A|MECHANISM OF ACTION:  The active tubular secretion of dofetilide is|
01015|008|A|inhibited by renal cation transport inhibitors.(1)|
01015|009|B||
01015|010|E|CLINICAL EFFECTS:  The concurrent administration of dofetilide with renal|
01015|011|E|cation transport inhibitors may result in elevated levels and increased|
01015|012|E|effects of dofetilide including QT prolongation or torsades de pointes.(1)|
01015|013|B||
01015|014|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
01015|015|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
01015|016|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
01015|017|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
01015|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01015|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01015|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01015|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01015|022|P|advanced age.(2)|
01015|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01015|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01015|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01015|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01015|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01015|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01015|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01015|030|B||
01015|031|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that the|
01015|032|M|concurrent administration of dofetilide with renal cation transport|
01015|033|M|inhibitors is contraindicated.  The manufacturer suggests that agents that|
01015|034|M|have no effect on dofetilide plasma levels, such as aluminum and magnesium|
01015|035|M|hydroxide antacids, omeprazole, or ranitidine, be used as alternatives to|
01015|036|M|cimetidine.  If dofetilide is to be discontinued, a washout of at least 2|
01015|037|M|days is recommendation prior to starting cimetidine.(1)|
01015|038|B||
01015|039|D|DISCUSSION:  Dofetilide is primarily excreted in the urine via both|
01015|040|D|glomerular filtration and active tubular secretion via the cation transport|
01015|041|D|system.  Cimetidine is believed to inhibit the cation transport system.(1)|
01015|042|D|   The concurrent administration of dofetilide (500 mcg twice daily) with|
01015|043|D|cimetidine (400 mg twice daily) resulted in an increase in dofetilide plasma|
01015|044|D|levels by 58%.  The concurrent administration of dofetilide (500 mcg single|
01015|045|D|dose) with cimetidine (100 mg twice daily) resulted in an increase in|
01015|046|D|dofetilide plasma levels by 13%.(1)|
01015|047|D|   Therefore, the manufacturer of dofetilide states that the concurrent|
01015|048|D|administration of dofetilide and cimetidine is contraindicated.  The|
01015|049|D|manufacturer suggests that agents that have no effect on dofetilide plasma|
01015|050|D|levels, such as aluminum and magnesium hydroxide antacids, omeprazole, or|
01015|051|D|ranitidine, be used as alternatives to cimetidine.(1)|
01015|052|D|   MATE renal transport inhibitors include: cimetidine, pyrimethamine,|
01015|053|D|risdiplam, and vandetanib.(3)|
01015|054|B||
01015|055|R|REFERENCES:|
01015|056|B||
01015|057|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01015|058|R|  2013.|1
01015|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01015|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01015|061|R|  settings: a scientific statement from the American Heart Association and|6
01015|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01015|063|R|  2;55(9):934-47.|6
01015|064|R|3.This information is based on an extract from the Certara Drug Interaction|6
01015|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01016|001|T|MONOGRAPH TITLE:  Dofetilide/Trimethoprim|
01016|002|B||
01016|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01016|004|L|is contraindicated and generally should not be dispensed or administered to|
01016|005|L|the same patient.|
01016|006|B||
01016|007|A|MECHANISM OF ACTION:  The active tubular secretion of dofetilide is|
01016|008|A|inhibited by trimethoprim.(1)|
01016|009|B||
01016|010|E|CLINICAL EFFECTS:  The concurrent administration of dofetilide with|
01016|011|E|trimethoprim may result in elevated levels and increased effects of|
01016|012|E|dofetilide, including QT prolongation or torsades de pointes.(1)|
01016|013|B||
01016|014|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
01016|015|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
01016|016|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
01016|017|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
01016|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01016|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01016|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01016|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01016|022|P|advanced age.(2)|
01016|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01016|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01016|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01016|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01016|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01016|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01016|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01016|030|B||
01016|031|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that the|
01016|032|M|concurrent administration of dofetilide with trimethoprim (alone or in|
01016|033|M|combination with sulfamethoxazole) is contraindicated.  If dofetilide is to|
01016|034|M|be discontinued, a washout of at least 2 days is recommended prior to|
01016|035|M|starting trimethoprim.(1)|
01016|036|B||
01016|037|D|DISCUSSION:  Dofetilide is primarily excreted in the urine via both|
01016|038|D|glomerular filtration and active tubular secretion via the cation transport|
01016|039|D|system.  Trimethoprim is believed to inhibit the cation transport system.|
01016|040|D|The concurrent administration of dofetilide (500 mcg twice daily) with|
01016|041|D|trimethoprim-sulfamethoxazole (160 mg-800 mg twice daily) for four days|
01016|042|D|resulted in an increase in dofetilide area-under-curve (AUC) and maximum|
01016|043|D|concentration (Cmax) by 93% and 103%, respectively.(1)|
01016|044|D|   Therefore, the manufacturer of dofetilide states that the concurrent|
01016|045|D|administration of dofetilide and trimethoprim is contraindicated.(1)|
01016|046|B||
01016|047|R|REFERENCES:|
01016|048|B||
01016|049|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01016|050|R|  2013.|1
01016|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01016|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01016|053|R|  settings: a scientific statement from the American Heart Association and|6
01016|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01016|055|R|  2;55(9):934-47.|6
01017|001|T|MONOGRAPH TITLE:  Dofetilide/Itraconazole; Ketoconazole(Oral)|
01017|002|B||
01017|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01017|004|L|is contraindicated and generally should not be dispensed or administered to|
01017|005|L|the same patient.|
01017|006|B||
01017|007|A|MECHANISM OF ACTION:  Although dofetilide is primarily eliminated unchanged|
01017|008|A|in the urine, a portion is metabolized via CYP3A4.(1)  Systemic ketoconazole|
01017|009|A|inhibits active renal tubular secretion of dofetilide via the cation|
01017|010|A|transport system.(1)  Itraconazole and ketoconazole are both strong|
01017|011|A|inhibitors of CYP3A4.(2)|
01017|012|A|   Dofetilide is a Class III antiarrhythmic agent which must be initiated in|
01017|013|A|the hospital due to the risk for serious ventricular arrhythmias including|
01017|014|A|torsades de pointes. There is a linear relationship between dofetilide|
01017|015|A|plasma concentration and QT prolongation.(1)|
01017|016|B||
01017|017|E|CLINICAL EFFECTS:  The concurrent administration of dofetilide with|
01017|018|E|itraconazole(3) or ketoconazole(4) may result in elevated levels and|
01017|019|E|increased effects of dofetilide, including prolongation of the QT interval|
01017|020|E|and torsades de pointes.|
01017|021|B||
01017|022|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
01017|023|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
01017|024|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
01017|025|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
01017|026|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01017|027|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01017|028|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01017|029|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01017|030|P|advanced age.(5)|
01017|031|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01017|032|P|higher systemic concentrations of either QT prolonging drug are additional|
01017|033|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01017|034|P|drug concentrations include rapid infusion of an intravenous dose or|
01017|035|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01017|036|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01017|037|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
01017|038|B||
01017|039|M|PATIENT MANAGEMENT:  The concurrent use of dofetilide with either|
01017|040|M|itraconazole(3) or ketoconazole(1,4) is contraindicated.  If dofetilide is|
01017|041|M|to be discontinued, a washout of at least 2 days is recommended prior to|
01017|042|M|starting azole therapy.(1)|
01017|043|M|   The concurrent use of dofetilide with itraconazole is contraindicated|
01017|044|M|during and two weeks after itraconazole treatment.(3)|
01017|045|M|   If concurrent therapy is deemed medically necessary, obtain serum|
01017|046|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
01017|047|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01017|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01017|049|B||
01017|050|D|DISCUSSION:  The concurrent administration of dofetilide (500 mcg twice|
01017|051|D|daily) with ketoconazole (400 mg daily) for seven days resulted in increases|
01017|052|D|in the dofetilide maximum concentration (Cmax) and area-under-curve (AUC) by|
01017|053|D|53% and 41%, respectively, in males and by 97% and 69%, respectively, in|
01017|054|D|females.(1)|
01017|055|B||
01017|056|R|REFERENCES:|
01017|057|B||
01017|058|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01017|059|R|  2013.|1
01017|060|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
01017|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01017|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01017|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01017|064|R|  11/14/2017.|1
01017|065|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01017|066|R|  Products, L.P. February, 2024.|1
01017|067|R|4.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01017|068|R|  Pharmaceuticals February, 2014.|1
01017|069|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01017|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01017|071|R|  settings: a scientific statement from the American Heart Association and|6
01017|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01017|073|R|  2;55(9):934-47.|6
01018|001|T|MONOGRAPH TITLE:  Dofetilide/Prochlorperazine|
01018|002|B||
01018|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01018|004|L|is contraindicated and generally should not be dispensed or administered to|
01018|005|L|the same patient.|
01018|006|B||
01018|007|A|MECHANISM OF ACTION:  The active tubular secretion of dofetilide may be|
01018|008|A|inhibited by prochlorperazine.(1)|
01018|009|B||
01018|010|E|CLINICAL EFFECTS:  The concurrent administration of dofetilide with|
01018|011|E|prochlorperazine may result in elevated levels and increased effects of|
01018|012|E|dofetilide, including QT prolongation or torsades de pointes.(1)|
01018|013|B||
01018|014|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
01018|015|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
01018|016|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
01018|017|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
01018|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01018|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01018|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01018|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01018|022|P|advanced age.(2)|
01018|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01018|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01018|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01018|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01018|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01018|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01018|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01018|030|B||
01018|031|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that|
01018|032|M|prochlorperazine should not be used in patients on dofetilide.  If|
01018|033|M|dofetilide is to be discontinued, a washout of at least 2 days is|
01018|034|M|recommended prior to starting prochlorperazine.(1)|
01018|035|B||
01018|036|D|DISCUSSION:  Dofetilide is primarily excreted in the urine via both|
01018|037|D|glomerular filtration and active tubular secretion via the cation transport|
01018|038|D|system.  Prochlorperazine is believed to inhibit the cation transport|
01018|039|D|system.  Other agents that inhibit this system, including cimetidine,|
01018|040|D|ketoconazole, trimethoprim, and verapamil, have been shown to increase|
01018|041|D|dofetilide levels.  Therefore, the manufacturer of dofetilide states that|
01018|042|D|prochlorperazine should not be used in patients on dofetilide.(1)|
01018|043|B||
01018|044|R|REFERENCES:|
01018|045|B||
01018|046|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01018|047|R|  2013.|1
01018|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01018|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01018|050|R|  settings: a scientific statement from the American Heart Association and|6
01018|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01018|052|R|  2;55(9):934-47.|6
01019|001|T|MONOGRAPH TITLE:  Dofetilide/Megestrol|
01019|002|B||
01019|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01019|004|L|is contraindicated and generally should not be dispensed or administered to|
01019|005|L|the same patient.|
01019|006|B||
01019|007|A|MECHANISM OF ACTION:  The active tubular secretion of dofetilide may be|
01019|008|A|inhibited by megestrol.(1)|
01019|009|B||
01019|010|E|CLINICAL EFFECTS:  The concurrent administration of dofetilide with|
01019|011|E|megestrol may result in elevated levels and increased effects of dofetilide,|
01019|012|E|including QT prolongation or torsades de pointes.(1)|
01019|013|B||
01019|014|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
01019|015|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
01019|016|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
01019|017|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
01019|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01019|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01019|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01019|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01019|022|P|advanced age.(2)|
01019|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01019|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01019|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01019|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01019|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01019|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01019|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01019|030|B||
01019|031|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that megestrol|
01019|032|M|should not be used in patients on dofetilide.  If dofetilide is to be|
01019|033|M|discontinued, a washout of at least 2 days is recommended prior to starting|
01019|034|M|megestrol.(1)|
01019|035|B||
01019|036|D|DISCUSSION:  Dofetilide is primarily excreted in the urine via both|
01019|037|D|glomerular filtration and active tubular secretion via the cation transport|
01019|038|D|system.  Megestrol is believed to inhibit the cation transport system. Other|
01019|039|D|agents that inhibit this system, including cimetidine, ketoconazole,|
01019|040|D|trimethoprim, and verapamil, have been shown to increase dofetilide levels.|
01019|041|D|Therefore, the manufacturer of dofetilide states that megestrol should not|
01019|042|D|be used in patients on dofetilide.(1)|
01019|043|B||
01019|044|R|REFERENCES:|
01019|045|B||
01019|046|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01019|047|R|  2013.|1
01019|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01019|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01019|050|R|  settings: a scientific statement from the American Heart Association and|6
01019|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01019|052|R|  2;55(9):934-47.|6
01020|001|T|MONOGRAPH TITLE:  Dofetilide/Class Ia And Class III Antiarrhythmics|
01020|002|B||
01020|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01020|004|L|is contraindicated and generally should not be dispensed or administered to|
01020|005|L|the same patient.|
01020|006|B||
01020|007|A|MECHANISM OF ACTION:  Dofetilide has been shown to prolong the QTc interval.|
01020|008|A|Concurrent use with other agents that prolong the QTc interval may result|
01020|009|A|in additive effects on the QTc interval.(1)|
01020|010|B||
01020|011|E|CLINICAL EFFECTS:  The concurrent use of dofetilide with other agents that|
01020|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01020|013|E|arrhythmias, including torsades de pointes.(1)|
01020|014|B||
01020|015|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
01020|016|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
01020|017|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
01020|018|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
01020|019|P|   The risk of QT prolongation may be increased by reduced creatinine|
01020|020|P|clearance, female gender, larger doses of sotalol, and a history of|
01020|021|P|cardiomegaly or congestive heart failure.(1-2)  Risk may also be increased|
01020|022|P|in patients with cardiovascular disease (e.g. myocardial infarction, history|
01020|023|P|of torsades de pointes, congenital long QT syndrome), hypokalemia,|
01020|024|P|hypomagnesemia, hypocalcemia, bradycardia, or advanced age.(3)|
01020|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01020|026|P|higher systemic concentrations of either QT prolonging drug are additional|
01020|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01020|028|P|drug concentrations include rapid infusion of an intravenous dose or|
01020|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01020|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01020|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01020|032|B||
01020|033|M|PATIENT MANAGEMENT:  Class Ia or Class III antiarrhythmic agents should be|
01020|034|M|withheld for at least three half-lives prior to initiating dofetilide.|
01020|035|M|Dofetilide has been administered to patients previously treated with|
01020|036|M|amiodarone when amiodarone levels were below 0.3 mg/L or amiodarone had been|
01020|037|M|withdrawn for at least 3 months.(1)|
01020|038|M|   The manufacturer of propafenone states that Class Ia or Class III|
01020|039|M|antiarrhythmic agents should be withheld for at least 5 half-lives prior to|
01020|040|M|initiating propafenone.(2)|
01020|041|M|   If concurrent therapy is deemed medically necessary, obtain serum|
01020|042|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
01020|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01020|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01020|045|B||
01020|046|D|DISCUSSION:  Because of the risk of adverse effects, Class Ia or Class III|
01020|047|D|antiarrhythmic agents should be withheld for at least three half-lives prior|
01020|048|D|to initiating dofetilide. Dofetilide has been administered to patients|
01020|049|D|previously treated with amiodarone when amiodarone levels were below 0.3|
01020|050|D|mg/L or amiodarone had been withdrawn for at least three months.(1)|
01020|051|D|   Agents that are linked to this monograph may have varying degrees of|
01020|052|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
01020|053|D|been shown to prolong the QTc interval either through their mechanism of|
01020|054|D|action, through studies on their effects on the QTc interval, or through|
01020|055|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01020|056|D|and/or postmarketing reports.(4)|
01020|057|D|   One or more of the drug pairs linked to this monograph have been included|
01020|058|D|in a list of interactions that should be considered "high-priority" for|
01020|059|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01020|060|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01020|061|D|Coordinator (ONC) for Health Information Technology.|
01020|062|B||
01020|063|R|REFERENCES:|
01020|064|B||
01020|065|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01020|066|R|  2013.|1
01020|067|R|2.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
01020|068|R|  Laboratories March, 2013.|1
01020|069|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01020|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01020|071|R|  settings: a scientific statement from the American Heart Association and|6
01020|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01020|073|R|  2;55(9):934-47.|6
01020|074|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
01020|075|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01020|076|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01020|077|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01020|078|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01020|079|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01020|080|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01020|081|R|  19(5):735-43.|6
01021|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/St. John's Wort|
01021|002|B||
01021|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01021|004|L|is contraindicated and generally should not be dispensed or administered to|
01021|005|L|the same patient.|
01021|006|B||
01021|007|A|MECHANISM OF ACTION:  St. John's wort may induce CYP3A4 and induce the|
01021|008|A|metabolism of the protease inhibitors(1-11) and cobicistat.(12)|
01021|009|B||
01021|010|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort and a protease|
01021|011|E|inhibitor(1-11) or cobicistat(12) may result in decreased levels of these|
01021|012|E|agents, which may lead to the development of resistant HIV and treatment|
01021|013|E|failure.(1-12)|
01021|014|B||
01021|015|P|PREDISPOSING FACTORS:  None determined.|
01021|016|B||
01021|017|M|PATIENT MANAGEMENT:  The manufacturers of amprenavir(1), indinavir,(2) and|
01021|018|M|saquinavir(3,4) state that St. John's wort should not be used by patients|
01021|019|M|receiving these agents.|
01021|020|M|   The manufacturers of atazanavir,(5) darunavir,(6) fosamprenavir,(7) the|
01021|021|M|combination of lopinavir and ritonavir,(8) nelfinavir,(9) ritonavir,(10)|
01021|022|M|tipranavir,(11) and cobicistat(12) state that concurrent use of St. John's|
01021|023|M|wort is contraindicated.|
01021|024|B||
01021|025|D|DISCUSSION:  In a study in eight healthy, HIV negative subjects,|
01021|026|D|pretreatment with St. John's wort (300 mg tablets, 0.3% hypericin) decreased|
01021|027|D|the indinavir area-under-curve (AUC) and maximum concentration (Cmax) by 57%|
01021|028|D|and 28%, respectively.(13)|
01021|029|D|   In another study in eight healthy, HIV-negative subjects, concurrent St.|
01021|030|D|John's wort (300 mg tablets, 0.3% hypericin three times daily) and indinavir|
01021|031|D|(800 mg three times daily) decreased indinavir AUC and minimum concentration|
01021|032|D|(Cmin) by 54% and 81%, respectively.(2)|
01021|033|D|   One or more of the drug pairs linked to this monograph have been included|
01021|034|D|in a list of interactions that should be considered "high-priority" for|
01021|035|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01021|036|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01021|037|D|Coordinator (ONC) for Health Information Technology.|
01021|038|B||
01021|039|R|REFERENCES:|
01021|040|B||
01021|041|R|1.Agenerase (amprenavir) Oral Solution US prescribing information.|1
01021|042|R|  GlaxoSmithKline May, 2005.|1
01021|043|R|2.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01021|044|R|  September, 2016.|1
01021|045|R|3.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
01021|046|R|  Inc. December, 2004.|1
01021|047|R|4.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01021|048|R|  Laboratories, Inc. March, 2019.|1
01021|049|R|5.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01021|050|R|  Squibb Company December, 2024.|1
01021|051|R|6.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01021|052|R|  March, 2023.|1
01021|053|R|7.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01021|054|R|  March, 2019.|1
01021|055|R|8.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01021|056|R|  Laboratories December, 2019.|1
01021|057|R|9.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01021|058|R|  Pharmaceuticals, Inc. September, 2016.|1
01021|059|R|10.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01021|060|R|   December, 2019.|1
01021|061|R|11.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01021|062|R|   Pharmaceuticals, Inc. April, 2024.|1
01021|063|R|12.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
01021|064|R|   prescribing information. Gilead Sciences, Inc. September, 2021.|1
01021|065|R|13.Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir|2
01021|066|R|   concentrations and St John's wort. Lancet 2000 Feb 12;355(9203):547-8.|2
01021|067|R|14.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01021|068|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01021|069|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01021|070|R|   19(5):735-43.|6
01022|001|T|MONOGRAPH TITLE:  Cisapride/Cimetidine|
01022|002|B||
01022|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01022|004|L|is contraindicated and generally should not be dispensed or administered to|
01022|005|L|the same patient.|
01022|006|B||
01022|007|A|MECHANISM OF ACTION:  Cimetidine may inhibit the metabolism of cisapride.(1)|
01022|008|A|Cimetidine inhibits the hepatic drug metabolizing enzymes by binding to CYP|
01022|009|A|enzymes.(2)  Therefore, certain drugs which are substrates of CYP enzymes|
01022|010|A|can have delayed elimination and increased blood levels when used|
01022|011|A|concurrently with cimetidine.|
01022|012|B||
01022|013|E|CLINICAL EFFECTS:  Increased levels of cisapride which may result in cardiac|
01022|014|E|arrhythmias including QT prolongation or torsades de pointes.(1)|
01022|015|B||
01022|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01022|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
01022|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01022|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01022|020|P|female gender, or advanced age.(4)|
01022|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01022|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01022|023|P|risk factors for torsades de pointes.  Factors which may increased systemic|
01022|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01022|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01022|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01022|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01022|028|B||
01022|029|M|PATIENT MANAGEMENT:  The concurrent administration of cimetidine and|
01022|030|M|cisapride is contraindicated by the Canadian manufacturer of cisapride.(1)|
01022|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01022|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01022|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01022|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01022|035|B||
01022|036|D|DISCUSSION:  Elevated plasma levels of cisapride can cause QT prolongation|
01022|037|D|and torsades de pointes-type ventricular tachycardia which may be fatal.|
01022|038|D|Cisapride is metabolized by CYP enzymes.  Cimetidine inhibits the hepatic|
01022|039|D|drug metabolizing enzymes by binding to CYP enzymes.(2)  Therefore, certain|
01022|040|D|drugs which are substrates of CYP enzymes can have delayed elimination and|
01022|041|D|increased blood levels when used concurrently with cimetidine.  The|
01022|042|D|manufacturers of cisapride state that coadministration with cimetidine leads|
01022|043|D|to an increased peak plasma concentration and area-under-curve (AUC) of|
01022|044|D|cisapride.(1,3)  The Canadian manufacturer of Cisapride state the concurrent|
01022|045|D|administration of cimetidine and cisapride is contraindicated.(1)|
01022|046|B||
01022|047|R|REFERENCES:|
01022|048|B||
01022|049|R|1.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica,|1
01022|050|R|  Canada February, 2000.|1
01022|051|R|2.Tagamet (cimetidine) US prescribing information. GlaxoSmithKline December,|1
01022|052|R|  2005.|1
01022|053|R|3.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
01022|054|R|  Products, L.P. January, 2000.|1
01022|055|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01022|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01022|057|R|  settings: a scientific statement from the American Heart Association and|6
01022|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01022|059|R|  2;55(9):934-47.|6
01023|001|T|MONOGRAPH TITLE:  Amprenavir-Propylene Glycol/Disulfiram|
01023|002|B||
01023|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01023|004|L|is contraindicated and generally should not be dispensed or administered to|
01023|005|L|the same patient.|
01023|006|B||
01023|007|A|MECHANISM OF ACTION:  Disulfiram inhibits the alcohol and aldehyde|
01023|008|A|dehydrogenase pathway, which is responsible for the metabolism of propylene|
01023|009|A|glycol.(1)|
01023|010|B||
01023|011|E|CLINICAL EFFECTS:  The concurrent administration of propylene glycol and|
01023|012|E|disulfiram may result in the accumulation of propylene glycol, resulting in|
01023|013|E|adverse effects such as seizures, stupor, tachycardia, hyperosmolality,|
01023|014|E|lactic acidosis, renal toxicity, and hemolysis.(1,2)|
01023|015|B||
01023|016|P|PREDISPOSING FACTORS:  Certain ethnic populations (Asians, Eskimos, and|
01023|017|P|Native Americans) and women may have a decreased ability to metabolize|
01023|018|P|propylene glycol.(1,2)|
01023|019|B||
01023|020|M|PATIENT MANAGEMENT:  Because of the high concentration of propylene glycol|
01023|021|M|in the oral solution formulation of amprenavir, the manufacturer states that|
01023|022|M|the concurrent administration of amprenavir oral solution and disulfiram is|
01023|023|M|contraindicated.  Patients receiving treatment with disulfiram should|
01023|024|M|receive the capsule formulation of amprenavir.  If the capsule formulation|
01023|025|M|of amprenavir or another protease inhibitor formulation is not an option,|
01023|026|M|then disulfiram should be discontinued.(1,2)|
01023|027|B||
01023|028|D|DISCUSSION:  The Agenerase oral solution formulation of amprenavir contains|
01023|029|D|550 mg of propylene glycol per mL.  The recommended daily dosage of|
01023|030|D|amprenavir results in an intake of propylene glycol of 1650 mg/kg per day.|
01023|031|D|Propylene glycol is metabolized by the alcohol and aldehyde dehydrogenase|
01023|032|D|enzyme pathway.  Disulfiram inhibits this pathway.  The concurrent|
01023|033|D|administration of disulfiram and amprenavir oral solution may result in the|
01023|034|D|accumulation of propylene glycol and toxicity.  Therefore, the manufacturer|
01023|035|D|of amprenavir oral solution states that the concurrent use of amprenavir|
01023|036|D|oral solution with disulfiram is contraindicated.  Patients receiving|
01023|037|D|treatment with disulfiram should receive the oral capsule formulation of|
01023|038|D|amprenavir.  If the oral capsule formulation of amprenavir or another|
01023|039|D|protease inhibitor formulation is not an option, then disulfiram should be|
01023|040|D|discontinued.(1,2)|
01023|041|B||
01023|042|R|REFERENCES:|
01023|043|B||
01023|044|R|1.Dear Healthcare Professional letter. RE:  Potential safety concerns with|1
01023|045|R|  the large amount of propylene glycol in AGENERASE (amprenavir) oral|1
01023|046|R|  solution. Glaxo Wellcome, Inc. May, 2000.|1
01023|047|R|2.Agenerase (amprenavir) Oral Solution US prescribing information.|1
01023|048|R|  GlaxoSmithKline May, 2005.|1
01024|001|T|MONOGRAPH TITLE:  Propylene Glycol/Metronidazole; Tinidazole|
01024|002|B||
01024|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01024|004|L|is contraindicated and generally should not be dispensed or administered to|
01024|005|L|the same patient.|
01024|006|B||
01024|007|A|MECHANISM OF ACTION:  Metronidazole(1) and tinidazole(2) inhibit the alcohol|
01024|008|A|and aldehyde dehydrogenase pathway, which is responsible for the metabolism|
01024|009|A|of propylene glycol.(1,2)|
01024|010|B||
01024|011|E|CLINICAL EFFECTS:  The concurrent administration of metronidazole(1) and|
01024|012|E|tinidazole(2) may result in the accumulation of propylene glycol, which may|
01024|013|E|result in adverse effects such as seizures, stupor, tachycardia,|
01024|014|E|hyperosmolality, lactic acidosis, renal toxicity, and hemolysis.|
01024|015|B||
01024|016|P|PREDISPOSING FACTORS:  Certain ethnic populations (Asians, Eskimos, and|
01024|017|P|Native Americans) and women may have a decreased ability to metabolize|
01024|018|P|propylene glycol.(1,2)|
01024|019|B||
01024|020|M|PATIENT MANAGEMENT:  Patients should be advised of the possible affects that|
01024|021|M|may result from ingestion or application of products that contain propylene|
01024|022|M|glycol while taking metronidazole or tinidazole.(1,2)|
01024|023|M|   Patients receiving metronidazole or tinidazole should be instructed to|
01024|024|M|avoid products containing propylene glycol during and for 3 days after|
01024|025|M|taking metronidazole or tinidazole.(1,2)|
01024|026|M|   Patients should be informed about unsuspected sources of propylene glycol|
01024|027|M|such as elixirs and topical preparations.|
01024|028|M|   Caution is also warranted when using intravenous preparations containing|
01024|029|M|propylene glycol solvents in patients receiving metronidazole or tinidazole.|
01024|030|B||
01024|031|D|DISCUSSION:  Concurrent use of products that contain propylene glycol may|
01024|032|D|cause a disulfiram-like reaction to alcohol when used with metronidazole or|
01024|033|D|tinidazole.|
01024|034|B||
01024|035|R|REFERENCES:|
01024|036|B||
01024|037|R|1.Flagyl (metronidazole) US prescribing information. G.D. Searle LLC|1
01024|038|R|  Division of Pfizer Inc. October, 2018.|1
01024|039|R|2.Tinidazole US prescribing information. Rising Pharmaceuticals, Inc..|1
01024|040|R|  October 12, 2017.|1
01025|001|T|MONOGRAPH TITLE:  Codeine/Strong CYP2D6 Inhibitors|
01025|002|B||
01025|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01025|004|L|take action as needed.|
01025|005|B||
01025|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2D6 may inhibit the metabolism|
01025|007|A|of codeine to its active form, morphine.|
01025|008|B||
01025|009|E|CLINICAL EFFECTS:  The concurrent administration of codeine and a strong|
01025|010|E|inhibitor of CYP2D6 may result in decreased efficacy of codeine.|
01025|011|E|   If a strong CYP2D6 inhibitor is discontinued, the effects of codeine may|
01025|012|E|be increased, including respiratory depression.|
01025|013|B||
01025|014|P|PREDISPOSING FACTORS:  Patients with CYP2D6 ultrarapid, normal, and|
01025|015|P|intermediate metabolizer phenotypes may be affected to a greater extent by|
01025|016|P|CYP2D6 inhibitors.  For patients on strong CYP2D6 inhibitors, the predicted|
01025|017|P|phenotype is a CYP2D6 poor metabolizer.|
01025|018|P|   Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are|
01025|019|P|not affected by CYP2D6 inhibition.|
01025|020|B||
01025|021|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with codeine and|
01025|022|M|a strong CYP2D6 inhibitor should be observed for decreased effectiveness of|
01025|023|M|codeine.  Dose increase of codeine may be required, or an alternative|
01025|024|M|analgesic, such as morphine, may need to be considered.|
01025|025|M|   After discontinuation of a CYP2D6 inhibitor, consider reducing the dosage|
01025|026|M|of codeine and monitor the patient for signs and symptoms of respiratory|
01025|027|M|depression or sedation.|
01025|028|B||
01025|029|D|DISCUSSION:  Strong inhibitors of CYP2D6 have been shown to decrease the|
01025|030|D|metabolism of codeine to morphine at CYP2D6.  Quinidine has also been shown|
01025|031|D|to decrease cerebrospinal fluid levels of morphine after codeine|
01025|032|D|administration.  Concurrent administration resulted in decreased effects of|
01025|033|D|codeine.|
01025|034|D|   Strong CYP2D6 inhibitors linked to this monograph are: bupropion,|
01025|035|D|dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and|
01025|036|D|terbinafine.|
01025|037|B||
01025|038|R|REFERENCES:|
01025|039|B||
01025|040|R|1.Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects|2
01025|041|R|  of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996|2
01025|042|R|  Sep;278(3):1165-74.|2
01025|043|R|2.Sindrup SH, Arendt-Nielsen L, Brosen K, Bjerring P, Angelo HR, Eriksen B,|2
01025|044|R|  Gram LF. The effect of quinidine on the analgesic effect of codeine. Eur J|2
01025|045|R|  Clin Pharmacol 1992;42(6):587-91.|2
01025|046|R|3.Sindrup SH, Hofmann U, Asmussen J, Mikus G, Brosen K, Nielsen F, Ingwersen|2
01025|047|R|  SH, Broen Christensen C. Impact of quinidine on plasma and cerebrospinal|2
01025|048|R|  fluid concentrations of codeine and morphine after codeine intake. Eur J|2
01025|049|R|  Clin Pharmacol 1996;49(6):503-9.|2
01025|050|R|4.Desmeules J, Gascon MP, Dayer P, Magistris M. Impact of environmental and|4
01025|051|R|  genetic factors on codeine analgesia. Eur J Clin Pharmacol 1991;|4
01025|052|R|  41(1):23-6.|4
01025|053|R|5.Crews KR, Monte AA, Huddart R, Caudle KE, Kharasch ED. Clinical|6
01025|054|R|  Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1,|6
01025|055|R|  and COMT Genotypes and Select Opioid Therapy. Clin Pharmacol Ther 2021|6
01025|056|R|  Oct;110(4):888-896.|6
01025|057|R|6.This information is based on an extract from the Certara Drug Interaction|6
01025|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01025|059|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
01025|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01025|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01025|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01025|063|R|  11/14/2017.|1
01026|001|T|MONOGRAPH TITLE:  Tacrolimus; Temsirolimus/Azole Antifungals (mono deleted|
01026|002|T|10/24/2013)|
01026|003|B||
01026|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01026|005|L|of severe adverse interaction.|
01026|006|B||
01026|007|A|MECHANISM OF ACTION:  The azole antifungal may inhibit the metabolism of|
01026|008|A|tacrolimus or temsirolimus by CYP P-450-3A4 in the intestines and the liver.|
01026|009|B||
01026|010|E|CLINICAL EFFECTS:  Concurrent administration of an azole antifungal may|
01026|011|E|result in elevated levels of and toxicity from tacrolimus or temsirolimus.|
01026|012|B||
01026|013|P|PREDISPOSING FACTORS:  None determined.|
01026|014|B||
01026|015|M|PATIENT MANAGEMENT:  Tacrolimus and temsirolimus levels and renal function|
01026|016|M|should be monitored if an azole antifungal is initiated or discontinued from|
01026|017|M|concurrent therapy.  The dosage of tacrolimus or temsirolimus may need to be|
01026|018|M|adjusted.|
01026|019|M|   The UK(1) and US(2) manufacturers of posaconazole recommend that the dose|
01026|020|M|of tacrolimus be reduced to about one-third its original dose when|
01026|021|M|posaconazole is initiated.  Tacrolimus levels should be closely monitored|
01026|022|M|during and after therapy.  The dosage of tacrolimus may need to be adjusted|
01026|023|M|following posaconazole therapy.|
01026|024|M|   The manufacturer of voriconazole recommends that the dosage of tacrolimus|
01026|025|M|be reduced to one-third its original dose when voriconazole is initiated.|
01026|026|M|Tacrolimus levels should be closely monitored during and after therapy.  The|
01026|027|M|dosage of tacrolimus may need to be adjusted following the completion of|
01026|028|M|voriconazole therapy.(3)|
01026|029|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
01026|030|M|with strong CYP P-450-3A4 inhibitors such as itraconazole, ketoconazole, or|
01026|031|M|voriconazole be avoided.  If concurrent use is warranted, a dosage reduction|
01026|032|M|to 12.5 mg/week of temsirolimus should be considered.  If the azole is|
01026|033|M|discontinued, a washout period of 1 week should be allowed before adjusting|
01026|034|M|the dosage of temsirolimus to previous levels.(4)|
01026|035|B||
01026|036|D|DISCUSSION:  In a study in 20 patients, the addition of fluconazole to|
01026|037|D|tacrolimus therapy resulted in the need for a 56% dosage reduction in|
01026|038|D|tacrolimus. Acute renal dysfunction was seen in three patients and acute|
01026|039|D|mental status changes were seen in two subjects.(5) Another study found a|
01026|040|D|16% increase in tacrolimus levels with concurrent fluconazole.(6)|
01026|041|D|   There have been several case reports of increased tacrolimus levels|
01026|042|D|during the concurrent administration of itraconazole.(7-11)|
01026|043|D|   In a study in six subjects, the administration of ketoconazole ten hours|
01026|044|D|before tacrolimus did not significantly affect the clearance, volume of|
01026|045|D|distribution, or hepatic bioavailability of tacrolimus. However, there was|
01026|046|D|100% increase in oral bioavailability of tacrolimus when administered ten|
01026|047|D|hours after ketoconazole.(12)  In a study in six subjects, concurrent|
01026|048|D|administration of ketoconazole (200 mg) increased tacrolimus oral|
01026|049|D|bioavailability by 114%.  Oral tacrolimus clearance decreased by 65.6%.|
01026|050|D|There was no significant effect on the clearance of intravenous|
01026|051|D|tacrolimus.(13)  In a case report, a patient's trough tacrolimus level|
01026|052|D|increased from 0.25 ng/ml to 1.9 ng/ml following the addition of|
01026|053|D|ketoconazole to her therapy.(14)|
01026|054|D|   In a case report, a patient's tacrolimus plasma concentrations increased|
01026|055|D|to 3.5 ng/ml within 24 hours of initiating clotrimazole troches. Eight days|
01026|056|D|after clotrimazole was started, her tacrolimus level increased to 9.0 ng/ml.|
01026|057|D|The area-under-curve (AUC) of tacrolimus increased two-fold during|
01026|058|D|concurrent therapy.(15)|
01026|059|D|   One study looked at the effects of posaconazole on the metabolism of|
01026|060|D|tacrolimus when both medications were administered concurrently in healthy|
01026|061|D|individuals.  The coadministration resulted in an increase in both the AUC|
01026|062|D|and the maximum concentration (Cmax) of tacrolimus by 358% and 121%,|
01026|063|D|respectively, as well as an increase in the elimination half-life and a|
01026|064|D|decrease in total body clearance.  The changes in the pharmacokinetics of|
01026|065|D|the drug led to an increased incidence of adverse reactions associated with|
01026|066|D|the elevated levels of tacrolimus.  The occurrence of adverse reactions was|
01026|067|D|83% for patients taking the combination compared to 39% and 67% for patients|
01026|068|D|taking either tacrolimus or posaconazole alone, respectively.  In efficacy|
01026|069|D|studies, clinically significant interactions resulting in hospitalization|
01026|070|D|and/or posaconazole discontinuation were reported.(1,16)|
01026|071|D|   In healthy subjects, voriconazole (400 mg every 12 hours Day 1, 200 mg|
01026|072|D|every 12 hours Days 2-7) increased tacrolimus (0.1 mg/kg single dose) Cmax|
01026|073|D|and AUC by 2-fold and 3-fold, respectively.(3)|
01026|074|D|   Concurrent administration of ketoconazole had no effects on temsirolimus|
01026|075|D|AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and|
01026|076|D|2.2-fold, respectively.  Dosage adjustment of temsirolimus to 12.5 mg/week|
01026|077|D|in the presence of strong CYP P-450-3A4 inhibitors is expected to adjust|
01026|078|D|levels to the range observed without inhibitors; however, there are no data|
01026|079|D|available with this dose adjustment.(4)|
01026|080|D|   One study looked at the effects of posaconazole on the metabolism of|
01026|081|D|tacrolimus when both medications were administered concurrently in healthy|
01026|082|D|individuals.  The coadministration resulted in an increase in both the Cmax|
01026|083|D|and the AUC for tacrolimus by 121% and 358% respectively, as well as an|
01026|084|D|increase in the elimination half-life and a decrease in total body|
01026|085|D|clearance.  The changes in the pharmacokinetics of the drug led to an|
01026|086|D|increased incidence of adverse reactions associated with the elevated levels|
01026|087|D|of tacrolimus.  In patients taking the combination of medications 83%|
01026|088|D|experienced adverse events compared to 39% and 67% for patients taking|
01026|089|D|tacrolimus or posaconazole alone, respectively.(16)|
01026|090|D|   In a case report, a patient's tacrolimus plasma concentration increased|
01026|091|D|from 12.4ng/ml on 6 mg/day of tacrolimus to 26.5ng/ml following 3mg|
01026|092|D|tacrolimus and 400mg/day in divided doses of voriconazole on day one, and|
01026|093|D|then further to 44.0ng/ml on day two despite discontinuation of|
01026|094|D|tacrolimus.(17)|
01026|095|D|   In a retrospective study of lung transplant patients, those who had|
01026|096|D|voriconazole discontinued while on tacrolimus required a 64% increase in|
01026|097|D|dose to maintain therapeutic levels, (p = 0.002).   Patients who had|
01026|098|D|itraconazole discontinued while on tacrolimus required a 76% increase in|
01026|099|D|dose to maintain therapeutic levels, (p < 0.0001).(18)|
01026|100|D|   In a trial involving bone marrow transplant patients, those who were|
01026|101|D|given voriconazole while on a stable dose of tacrolimus had their median|
01026|102|D|concentration/dose (C/D) ratio of tacrolimus increase by as much as 116%, (p|
01026|103|D|< 0.001).(19)|
01026|104|B||
01026|105|R|REFERENCES:|
01026|106|B||
01026|107|R|1.Noxafil (posaconazole) UK summary of product characteristics.|1
01026|108|R|  Schering-Plough Ltd. January, 2022.|1
01026|109|R|2.Noxafil (posaconazole) US prescribing information. Schering Corporation|1
01026|110|R|  June, 2012.|1
01026|111|R|3.Vfend (voriconazole) US prescribing information. Pfizer Inc. November,|1
01026|112|R|  2011.|1
01026|113|R|4.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01026|114|R|  Inc. May, 2012.|1
01026|115|R|5.Manez R, Martin M, Raman D, Silverman D, Jain A, Warty V, Gonzalez-Pinto|2
01026|116|R|  I, Kusne S, Starzl TE. Fluconazole therapy in transplant recipients|2
01026|117|R|  receiving FK506. Transplantation 1994 May 27;57(10):1521-3.|2
01026|118|R|6.Osowski CL, Dix SP, Lin LS, Mullins RE, Geller RB, Wingard JR. Evaluation|2
01026|119|R|  of the drug interaction between intravenous high-dose fluconazole and|2
01026|120|R|  cyclosporine or tacrolimus in bone marrow transplant patients.|2
01026|121|R|  Transplantation 1996 Apr 27;61(8):1268-72.|2
01026|122|R|7.Capone D, Gentile A, Imperatore P, Palmiero G, Basile V. Effects of|3
01026|123|R|  itraconazole on tacrolimus blood concentrations in a renal transplant|3
01026|124|R|  recipient. Ann Pharmacother 1999 Oct;33(10):1124-5.|3
01026|125|R|8.Billaud EM, Guillemain R, Tacco F, Chevalier P. Evidence for a|3
01026|126|R|  pharmacokinetic interaction between itraconazole and tacrolimus in organ|3
01026|127|R|  transplant patients. Br J Clin Pharmacol 1998 Sep;46(3):271-2.|3
01026|128|R|9.Furlan V, Parquin F, Penaud JF, Cerrina J, Ladurie FL, Dartevelle P,|3
01026|129|R|  Taburet AM. Interaction between tacrolimus and itraconazole in a|3
01026|130|R|  heart-lung transplant recipient. Transplant Proc 1998 Feb;30(1):187-8.|3
01026|131|R|10.Kramer MR, Merin G, Rudis E, Bar I, Nesher T, Bublil M, Milgalter E. Dose|3
01026|132|R|   adjustment and cost of itraconazole prophylaxis in lung transplant|3
01026|133|R|   recipients receiving cyclosporine and tacrolimus (FK 506). Transplant|3
01026|134|R|   Proc 1997 Sep;29(6):2657-9.|3
01026|135|R|11.Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C,|3
01026|136|R|   Gritsch A, McCauley J, Starzl T, Demetris AJ, Randhawa PS. Clinical|3
01026|137|R|   features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney|3
01026|138|R|   transplant recipients. Clin Transplant 1997 Jun;11(3):237-42.|3
01026|139|R|12.Floren LC, Bekersky I, Benet LZ, Mekki Q, Dressler D, Lee JW, Roberts JP,|2
01026|140|R|   Hebert MF. Tacrolimus oral bioavailability doubles with coadministration|2
01026|141|R|   of ketoconazole. Clin Pharmacol Ther 1997 Jul;62(1):41-9.|2
01026|142|R|13.Prograf (tacrolimus) US prescribing information. Fujisawa Healthcare,|1
01026|143|R|   Inc. November, 2022.|1
01026|144|R|14.Assan R, Fredj G, Larger E, Feutren G, Bismuth H. FK 506/fluconazole|3
01026|145|R|   interaction enhances FK 506 nephrotoxicity. Diabete Metab 1994 Jan-Feb;|3
01026|146|R|   20(1):49-52.|3
01026|147|R|15.Mieles L, Venkataramanan R, Yokoyama I, Warty VJ, Starzl TE. Interaction|3
01026|148|R|   between FK506 and clotrimazole in a liver transplant recipient.|3
01026|149|R|   Transplantation 1991 Dec;52(6):1086-7.|3
01026|150|R|16.Sansone-Parsons A, Krishna G, Martinho M, Kantesaria B, Gelone S, Mant|2
01026|151|R|   TG. Effect of oral posaconazole on the pharmacokinetics of cyclosporine|2
01026|152|R|   and tacrolimus. Pharmacotherapy 2007 Jun;27(6):825-34.|2
01026|153|R|17.Capone D, Tarantino G, Gentile A, Sabbatini M, Polichetti G, Santangelo|3
01026|154|R|   M, Nappi R, Ciotola A, D'Alessandro V, Renda A, Basile V, Federico S.|3
01026|155|R|   Effects of voriconazole on tacrolimus metabolism in a kidney transplant|3
01026|156|R|   recipient. J Clin Pharm Ther 2010 Feb;35(1):121-4.|3
01026|157|R|18.Kramer MR, Amital A, Fuks L, Shitrit D. Voriconazole and itraconazole in|2
01026|158|R|   lung transplant recipients receiving tacrolimus (FK 506): efficacy and|2
01026|159|R|   drug interaction. Clin Transplant 2010 Dec 16.|2
01026|160|R|19.Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S. Drug interaction|2
01026|161|R|   between voriconazole and calcineurin inhibitors in allogeneic|2
01026|162|R|   hematopoietic stem cell transplant recipients. Bone Marrow Transplant|2
01026|163|R|   2009 Sep;44(6):371-4.|2
01027|001|T|MONOGRAPH TITLE:  Atorvastatin; Cerivastatin/Nefazodone|
01027|002|B||
01027|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01027|004|L|of severe adverse interaction.|
01027|005|B||
01027|006|A|MECHANISM OF ACTION:  Nefazodone has been shown to inhibit CYP3A4.|
01027|007|A|Nefazodone may inhibit the metabolism of HMG-CoA reductase inhibitors|
01027|008|A|metabolized at this isoenzyme.(1)|
01027|009|B||
01027|010|E|CLINICAL EFFECTS:  The concurrent administration of nefazodone with a|
01027|011|E|HMG-CoA reductase inhibitor metabolized by CYP3A4 may result in elevated|
01027|012|E|levels of the HMG CoA reductase inhibitor. Elevated levels of the HMG-CoA|
01027|013|E|reductase inhibitor may result in rhabdomyolysis.(1-4)|
01027|014|B||
01027|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01027|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01027|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01027|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01027|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01027|020|P|transporter OATP1B1 may have increased statin concentrations and be|
01027|021|P|predisposed to myopathy or rhabdomyolysis.|
01027|022|B||
01027|023|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, the dosage of|
01027|024|M|atorvastatin and cerivastatin should be reduced when administered with|
01027|025|M|nefazodone.(1)  Patients should be carefully monitored for signs and|
01027|026|M|symptoms of muscle pain, tenderness, or weakness.(2)  Atorvastatin or|
01027|027|M|cerivastatin may need to be discontinued.|
01027|028|M|   Fluvastatin and pravastatin, HMG-CoA reductase inhibitors that are not|
01027|029|M|extensively metabolized by CYP3A4, may be alternatives to other HMG-CoA|
01027|030|M|reductase inhibitors in patients taking nefazodone.(1)|
01027|031|B||
01027|032|D|DISCUSSION:  In a single-dose study, the administration of simvastatin (40|
01027|033|D|mg) or atorvastatin (40 mg) following six days of nefazodone (200 mg twice|
01027|034|D|daily) resulted in a 20-fold increase in simvastatin and simvastatin acid|
01027|035|D|levels and 3- to 4-fold increase in atorvastatin and atorvastatin lactone|
01027|036|D|levels.(1)|
01027|037|D|   There are case reports of rhabdomyolysis in patients receiving concurrent|
01027|038|D|nefazodone with lovastatin(1) and simvastatin(1,3-6) therapy.|
01027|039|B||
01027|040|R|REFERENCES:|
01027|041|B||
01027|042|R|1.Serzone (nefazodone hydrochloride) US prescribing information.|1
01027|043|R|  Bristol-Myers Squibb Company January, 2005.|1
01027|044|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01027|045|R|  February, 2014.|1
01027|046|R|3.Jacobson RH, Wang P, Glueck CJ. Myositis and rhabdomyolysis associated|3
01027|047|R|  with concurrent use of simvastatin and nefazodone. JAMA 1997 Jan 22-29;|3
01027|048|R|  277(4):296-7.|3
01027|049|R|4.Karnik NS, Maldonado JR. Antidepressant and statin interactions: a review|3
01027|050|R|  and case report of simvastatin and nefazodone-induced rhabdomyolysis and|3
01027|051|R|  transaminitis. Psychosomatics 2005 Nov-Dec;46(6):565-8.|3
01027|052|R|5.Skrabal MZ, Stading JA, Monaghan MS. Rhabdomyolysis associated with|3
01027|053|R|  simvastatin-nefazodone therapy. South Med J 2003 Oct;96(10):1034-5.|3
01027|054|R|6.Thompson M, Samuels S. Rhabdomyolysis with simvastatin and nefazodone. Am|3
01027|055|R|  J Psychiatry 2002 Sep;159(9):1607.|3
01028|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/Danshen|
01028|002|B||
01028|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01028|004|L|take action as needed.|
01028|005|B||
01028|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Danshen may decrease|
01028|007|A|the elimination of warfarin.(1)  In vitro tests have shown that danshen|
01028|008|A|inhibits platelet aggregation.(2)|
01028|009|B||
01028|010|E|CLINICAL EFFECTS:  The concurrent administration of warfarin and danshen may|
01028|011|E|result in increased hypoprothrombic effects of warfarin, including|
01028|012|E|bleeding.(3-5)|
01028|013|B||
01028|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01028|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01028|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
01028|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01028|018|P|risk for bleeding (e.g. NSAIDs).|
01028|019|B||
01028|020|M|PATIENT MANAGEMENT:  If possible, the concurrent administration of warfarin|
01028|021|M|and danshen should be avoided.  If concurrent therapy is warranted, monitor|
01028|022|M|patients for signs of blood loss, including decreased hemoglobin,|
01028|023|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
01028|024|M|evaluate patients with any symptoms.  The dosage of warfarin may need to be|
01028|025|M|adjusted.  Danshen and/or warfarin may need to be discontinued.|
01028|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01028|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01028|028|M|anticoagulation in patients with active pathologic bleeding.|
01028|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01028|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01028|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01028|032|M|and/or swelling.|
01028|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01028|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01028|035|M|initiating, altering the dose or discontinuing either drug.|
01028|036|B||
01028|037|D|DISCUSSION:  There are several case reports of increased warfarin effects|
01028|038|D|following the addition of danshen to warfarin therapy.  All of these|
01028|039|D|patients required the administration of blood products to reverse clotting|
01028|040|D|abnormalities.|
01028|041|D|   In the first report, the patient developed a massive right pleural|
01028|042|D|effusion, from which 4.5 liters of non-clotted blood was drained, two weeks|
01028|043|D|following the addition of danshen to warfarin therapy.  The patient's INR|
01028|044|D|was 8.4.  Both warfarin and danshen were discontinued and the patient's INR|
01028|045|D|dropped to 2.0 following the administration of fresh frozen plasma and|
01028|046|D|packed red blood cells.(3)|
01028|047|D|   In the second report, the patient developed a decreased hemoglobin of 5.3|
01028|048|D|G/dl and an INR of greater than 5.62 following the intermittent|
01028|049|D|administration of danshen with warfarin.  Both agents were discontinued and|
01028|050|D|fresh frozen plasma was administered.  The patient's clotting abnormalities|
01028|051|D|resolved after five days.(4)|
01028|052|D|  In the third report, a patient presented with melena following the|
01028|053|D|addition of danshen and the concurrent administration of a 15% methyl|
01028|054|D|salicylate medicated oil.  His INR was over 5.5 and his hemoglobin level was|
01028|055|D|7.6 G/dl.  The patient received 12 units of fresh frozen plasma and seven|
01028|056|D|units of packed red blood cells.  The patient was diagnosed with|
01028|057|D|adenocarcinoma.(5)|
01028|058|D|  A study in rats revealed that danshen increased the absorption rate|
01028|059|D|constant, area-under-curve (AUC), maximum concentration (Cmax), and|
01028|060|D|elimination half-life of warfarin and decreased the clearance and apparent|
01028|061|D|volume of distribution of warfarin.  Prothrombin times were prolonged.(1)|
01028|062|B||
01028|063|R|REFERENCES:|
01028|064|B||
01028|065|R|1.Chan K, Lo AC, Yeung JH, Woo KS. The effects of Danshen (Salvia|5
01028|066|R|  miltiorrhiza) on warfarin pharmacodynamics and pharmacokinetics of|5
01028|067|R|  warfarin enantiomers in rats. J Pharm Pharmacol 1995 May;47(5):402-6.|5
01028|068|R|2.Wang Z, Roberts JM, Grant PG, Colman RW, Schreiber AD. The effect of a|5
01028|069|R|  medicinal Chinese herb on platelet function. Thromb Haemost 1982 Dec 27;|5
01028|070|R|  48(3):301-6.|5
01028|071|R|3.Izzat MB, Yim AP, El-Zufari MH. A taste of Chinese medicine!. Ann Thorac|3
01028|072|R|  Surg 1998 Sep;66(3):941-2.|3
01028|073|R|4.Yu CM, Chan JC, Sanderson JE. Chinese herbs and warfarin potentiation by|3
01028|074|R|  'danshen'. J Intern Med 1997 Apr;241(4):337-9.|3
01028|075|R|5.Tam LS, Chan TY, Leung WK, Critchley JA. Warfarin interactions with|3
01028|076|R|  Chinese traditional medicines: danshen and methyl salicylate medicated|3
01028|077|R|  oil. Aust N Z J Med 1995 Jun;25(3):258.|3
01029|001|T|MONOGRAPH TITLE:  Mycophenolate/Aluminum & Magnesium Antacids; Lanthanum;|
01029|002|T|Sevelamer|
01029|003|B||
01029|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01029|005|L|take action as needed.|
01029|006|B||
01029|007|A|MECHANISM OF ACTION:  Aluminum or magnesium antacids and non-calcium|
01029|008|A|containing phosphate binders such as lanthanum and sevelamer decrease the|
01029|009|A|absorption of mycophenolate.(1-3)|
01029|010|B||
01029|011|E|CLINICAL EFFECTS:  The simultaneous administration of mycophenolate with|
01029|012|E|aluminum or magnesium antacids and non-calcium containing phosphate binders|
01029|013|E|such as lanthanum and sevelamer may decrease the levels of mycophenolate and|
01029|014|E|its clinical effects.|
01029|015|B||
01029|016|P|PREDISPOSING FACTORS:  None determined.|
01029|017|B||
01029|018|M|PATIENT MANAGEMENT:  The US manufacturer of mycophenolate mofetil states|
01029|019|M|that calcium free phosphate binders, such as sevelamer, should not be|
01029|020|M|administered simultaneously with mycophenolate mofetil.  Administer|
01029|021|M|sevelamer at least 2 hours after administration of mycophenolate mofetil to|
01029|022|M|decrease the extent of the interaction.(1)|
01029|023|M|   The US manufacturer of mycophenolate sodium states that mycophenolate|
01029|024|M|sodium should not be administered simultaneously with antacids.  Administer|
01029|025|M|aluminum or magnesium containing antacids at least 2 hours after|
01029|026|M|mycophenolate.(2)|
01029|027|M|   Close monitoring of mycophenolic acid levels may be warranted in patients|
01029|028|M|on mycophenolate mofetil therapy that are initiating or discontinuing|
01029|029|M|concurrent therapy with these agents.  Patients on concurrent therapies may|
01029|030|M|also require higher doses of mycophenolate mofetil in order to achieve|
01029|031|M|desired blood levels.|
01029|032|B||
01029|033|D|DISCUSSION:  In a study in 10 rheumatoid arthritis patients, the|
01029|034|D|simultaneous administration of mycophenolate and Maalox TC (an antacid|
01029|035|D|containing magnesium and aluminum hydroxide) resulted in decreases in the|
01029|036|D|maximum concentration (Cmax) and area-under-curve (AUC) of mycophenolate by|
01029|037|D|33% and 17%, respectively.(1,2)|
01029|038|D|   In a study of 3 adult patients and 6 pediatric patients with stable renal|
01029|039|D|graft function receiving mycophenolate mofetil, sevelamer (3-4 capsules of|
01029|040|D|403 mg twice daily) decreased the AUC and Cmax of mycophenolic acid by 26%|
01029|041|D|and 36%, respectively.(1,3)|
01029|042|D|   In a study in 12 stable renal transplant patients, administration of|
01029|043|D|magnesium-aluminum-containing antacids (30 ml) increased the Cmax and AUC of|
01029|044|D|a single dose of mycophenolate sodium by 25% and 37%, respectively.(2)|
01029|045|B||
01029|046|R|REFERENCES:|
01029|047|B||
01029|048|R|1.CellCept (mycophenolate mofetil) US prescribing information. Roche|1
01029|049|R|  Pharmaceuticals June, 2022.|1
01029|050|R|2.Myfortic (mycophenolate acid) US prescribing information. Novartis|1
01029|051|R|  Pharmaceuticals Corporation September, 2013.|1
01029|052|R|3.Bullingham R, Shah J, Goldblum R, Schiff M. Effects of food and antacid on|2
01029|053|R|  the pharmacokinetics of single doses of mycophenolate mofetil in|2
01029|054|R|  rheumatoid arthritis patients. Br J Clin Pharmacol 1996 Jun;41(6):513-6.|2
01029|055|R|4.Pieper AK, Buhle F, Bauer S, Mai I, Budde K, Haffner D, Neumayer HH,|2
01029|056|R|  Querfeld U. The effect of sevelamer on the pharmacokinetics of cyclosporin|2
01029|057|R|  A and mycophenolate mofetil after renal transplantation. Nephrol Dial|2
01029|058|R|  Transplant 2004 Oct;19(10):2630-3.|2
01030|001|T|MONOGRAPH TITLE:  Mycophenolate/Bile Acid Sequestrants|
01030|002|B||
01030|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01030|004|L|of severe adverse interaction.|
01030|005|B||
01030|006|A|MECHANISM OF ACTION:  Bile acid sequestrants may bind mycophenolate in the|
01030|007|A|intestine, preventing the absorption of the oral formulation of|
01030|008|A|mycophenolate and the enterohepatic recirculation of both the oral and|
01030|009|A|intravenous formulations of mycophenolate.(1)|
01030|010|B||
01030|011|E|CLINICAL EFFECTS:  The concurrent administration of mycophenolate and a bile|
01030|012|E|acid sequestrant may decrease the levels and clinical effects of|
01030|013|E|mycophenolate.(1,2)|
01030|014|B||
01030|015|P|PREDISPOSING FACTORS:  None determined.|
01030|016|B||
01030|017|M|PATIENT MANAGEMENT:  The manufacturers of mycophenolate state that the|
01030|018|M|concurrent administration of mycophenolate and bile acid sequestrants is not|
01030|019|M|recommended.(1,2)  Consider the use of other agents in patients receiving|
01030|020|M|mycophenolate therapy.|
01030|021|B||
01030|022|D|DISCUSSION:  In a study in 12 healthy subjects, the administration of|
01030|023|D|mycophenolate (1.5 grams) following pretreatment with cholestyramine (4|
01030|024|D|grams three times daily) resulted in a 40% decrease in the area-under-curve|
01030|025|D|(AUC) of mycophenolate.  The interaction is also expected to occur with|
01030|026|D|intravenous mycophenolate, because it also undergoes enterohepatic|
01030|027|D|circulation.(1)|
01030|028|B||
01030|029|R|REFERENCES:|
01030|030|B||
01030|031|R|1.CellCept (mycophenolate mofetil) US prescribing information. Roche|1
01030|032|R|  Pharmaceuticals June, 2022.|1
01030|033|R|2.Myfortic (mycophenolate acid) US prescribing information. Novartis|1
01030|034|R|  Pharmaceuticals Corporation September, 2013.|1
01031|001|T|MONOGRAPH TITLE:  Stavudine; Zidovudine/Ribavirin|
01031|002|B||
01031|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01031|004|L|of severe adverse interaction.|
01031|005|B||
01031|006|A|MECHANISM OF ACTION:  Ribavirin is believed to inhibit the phosphorylation|
01031|007|A|of zidovudine to its active form, zidovudine triphosphate, by reducing the|
01031|008|A|activity of thymidine kinase.(1)  Ribavirin is also believed to inhibit the|
01031|009|A|phosphorylation of stavudine to its active form.(2)|
01031|010|B||
01031|011|E|CLINICAL EFFECTS:  Concurrent use of ribavirin with stavudine may result in|
01031|012|E|decreased efficacy of stavudine(2,3) or hepatic failure.(4)|
01031|013|E|   Concurrent use of ribavirin and zidovudine may result in decreased|
01031|014|E|efficacy of zidovudine,(3,5,6) hepatic failure,(4) neutropenia,(4) or|
01031|015|E|anemia.(4)|
01031|016|B||
01031|017|P|PREDISPOSING FACTORS:  None determined.|
01031|018|B||
01031|019|M|PATIENT MANAGEMENT:  The manufacturer of zidovudine states that concurrent|
01031|020|M|use with ribavirin should be avoided.(3,5)  The manufacturer of Rebetol|
01031|021|M|(ribavirin) states that the combination should be used with caution.(6)|
01031|022|M|Patients receiving concurrent therapy with zidovudine and ribavirin should|
01031|023|M|be closely monitored for hepatic failure, neutropenia, and anemia.|
01031|024|M|   The manufacturer of stavudine states that concurrent use with ribavirin|
01031|025|M|should be approached with caution.(7)  The manufacturer of Rebetrol|
01031|026|M|(ribavirin) states that the combination should be used with caution.(6)|
01031|027|M|Patients receiving concurrent therapy with stavudine and ribavirin should be|
01031|028|M|closely monitored for hepatic failure.|
01031|029|B||
01031|030|D|DISCUSSION:  Zidovudine is converted to its active form by a series of|
01031|031|D|phosphorylations. Ribavirin reduces the activity of thymidine kinase,|
01031|032|D|resulting in higher levels of the natural nucleoside thymidine triphosphate|
01031|033|D|and decreased levels of zidovudine triphosphate. Zidovudine triphosphate|
01031|034|D|competes with thymidine triphosphate for insertion in the viral DNA chain.|
01031|035|D|(3)  Several in-vitro studies have shown that the concurrent administration|
01031|036|D|of ribavirin results in decreased phosphorylation of zidovudine(1,8-10),|
01031|037|D|increased sensitivity to zidovudine toxicity,(8) and decreased sensitivity|
01031|038|D|to zidovudine.(9,10)  However, no pharmacokinetic or pharmacodynamic changes|
01031|039|D|were seen in a study of 6 subjects receiving concurrent ribavirin and|
01031|040|D|zidovudine.(4)  In study NR15961, patients receiving concurrent ribavirin,|
01031|041|D|interferon, and zidovudine developed severe neutropenia (ANC less than 500,|
01031|042|D|15% versus 9%) and severe anemia (hemoglobin less than 8 g/dL, 5% versus 1%)|
01031|043|D|more frequently than patients not receiving zidovudine.(4)|
01031|044|D|   Stavudine is also converted to its active form by a series of|
01031|045|D|phosphorylations.(7)  In vitro studies have shown that ribavirin inhibits|
01031|046|D|this process.(2,4,7)  However, no pharmacokinetic or pharmacodynamic changes|
01031|047|D|were seen in a study of 10 subjects receiving concurrent ribavirin and|
01031|048|D|stavudine.(4)|
01031|049|D|   In study NR15961, 14 (11%) of 129 HIV-positive chronic hepatitis C|
01031|050|D|patients receiving HAART developed hepatic decompensation.  All 14 patients|
01031|051|D|were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and|
01031|052|D|lamivudine.(4)|
01031|053|B||
01031|054|R|REFERENCES:|
01031|055|B||
01031|056|R|1.Hoggard PG, Veal GJ, Wild MJ, Barry MG, Back DJ. Drug interactions with|5
01031|057|R|  zidovudine phosphorylation in vitro. Antimicrob Agents Chemother 1995 Jun;|5
01031|058|R|  39(6):1376-8.|5
01031|059|R|2.Hoggard PG, Kewn S, Barry MG, Khoo SH, Back DJ. Effects of drugs on|5
01031|060|R|  2',3'-dideoxy-2',3'-didehydrothymidine phosphorylation in vitro.|5
01031|061|R|  Antimicrob Agents Chemother 1997 Jul;41(6):1231-6.|5
01031|062|R|3.Stotka RA. Personal communication. Glaxo Wellcome, Inc. June 1, 2000.|1
01031|063|R|4.Copegus (ribavirin) US prescribing information. Roche Laboratories, Inc.|1
01031|064|R|  August, 2015.|1
01031|065|R|5.Retrovir (zidovudine) US prescribing information. GlaxoSmithKline|1
01031|066|R|  September, 2018.|1
01031|067|R|6.Rebetol (ribavirin) US prescribing information. Merck & Co., Inc. May,|1
01031|068|R|  2019.|1
01031|069|R|7.Zerit (stavudine) US prescribing information. Bristol-Myers Squibb Company|1
01031|070|R|  December 19, 2017.|1
01031|071|R|8.Sim SM, Hoggard PG, Sales SD, Phiboonbanakit D, Hart CA, Back DJ. Effect|5
01031|072|R|  of ribavirin on zidovudine efficacy and toxicity in vitro: a|5
01031|073|R|  concentration-dependent interaction. AIDS Res Hum Retroviruses 1998 Dec|5
01031|074|R|  20;14(18):1661-7.|5
01031|075|R|9.Baba M, Pauwels R, Balzarini J, Herdewijn P, De Clercq E, Desmyter J.|5
01031|076|R|  Ribavirin antagonizes inhibitory effects of pyrimidine 2',3'-|5
01031|077|R|  dideoxynucleosides but enhances inhibitory effects of purine 2',3'-|5
01031|078|R|  dideoxynucleosides on replication of human immunodeficiency virus in|5
01031|079|R|  vitro. Antimicrob Agents Chemother 1987 Oct;31(10):1613-7.|5
01031|080|R|10.Vogt MW, Hartshorn KL, Furman PA, Chou TC, Fyfe JA, Coleman LA,|5
01031|081|R|   Crumpacker C, Schooley RT, Hirsch MS. Ribavirin antagonizes the effect of|5
01031|082|R|   azidothymidine on HIV replication. Science 1987 Mar 13;235(4794):1376-9.|5
01032|001|T|MONOGRAPH TITLE:  Ropinirole/Ciprofloxacin|
01032|002|B||
01032|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01032|004|L|take action as needed.|
01032|005|B||
01032|006|A|MECHANISM OF ACTION:  Ciprofloxacin inhibits the metabolism of ropinirole at|
01032|007|A|CYP1A2.(1-3)|
01032|008|B||
01032|009|E|CLINICAL EFFECTS:  The concurrent administration of ciprofloxacin and|
01032|010|E|ropinirole may result in elevated levels of ropinirole, increased clinical|
01032|011|E|effects, and signs of toxicity.(1-3)|
01032|012|B||
01032|013|P|PREDISPOSING FACTORS:  None determined.|
01032|014|B||
01032|015|M|PATIENT MANAGEMENT:  In patients receiving ciprofloxacin who are started on|
01032|016|M|ropinirole, ropinirole may be titrated to effect according to the|
01032|017|M|manufacturer's dosage instructions. If ciprofloxacin is started or|
01032|018|M|discontinued in a patient receiving ropinirole, the dosage of ropinirole may|
01032|019|M|need to be adjusted.(1-2)|
01032|020|B||
01032|021|D|DISCUSSION:  In a study in 12 subjects, the concurrent administration of|
01032|022|D|ropinirole with ciprofloxacin resulted in increases in the maximum|
01032|023|D|concentration (Cmax) and area-under-curve (AUC) of ropinirole by 84% and|
01032|024|D|60%, respectively.  The major pathway for ropinirole metabolism has been|
01032|025|D|shown to be CYP1A2.(1-3)|
01032|026|B||
01032|027|R|REFERENCES:|
01032|028|B||
01032|029|R|1.ReQuip (ropinirole hydrochloride) Canadian prescribing information.|1
01032|030|R|  GlaxoSmithKline November 4, 2008.|1
01032|031|R|2.Requip (ropinirole hydrochloride) UK summary of product characteristics.|1
01032|032|R|  GlaxoSmithKline UK October 30, 2008.|1
01032|033|R|3.Requip (ropinirole hydrochloride) US prescribing information.|1
01032|034|R|  GlaxoSmithKline July, 2021.|1
01033|001|T|MONOGRAPH TITLE:  Selected Benzodiazepines/Posaconazole|
01033|002|B||
01033|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01033|004|L|take action as needed.|
01033|005|B||
01033|006|A|MECHANISM OF ACTION:  Posaconazole may inhibit the metabolism of|
01033|007|A|benzodiazepines by CYP3A4.(1,2)|
01033|008|B||
01033|009|E|CLINICAL EFFECTS:  The concurrent administration of posaconazole with|
01033|010|E|benzodiazepines metabolized by CYP3A4 may result in elevated levels of and|
01033|011|E|increased clinical effects from the benzodiazepines.(1,2)  Toxic effects of|
01033|012|E|increased levels of benzodiazepines include profound sedation, respiratory|
01033|013|E|depression, coma, and/or death.|
01033|014|B||
01033|015|P|PREDISPOSING FACTORS:  None determined.|
01033|016|B||
01033|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with posaconazole|
01033|018|M|should be monitored for increased benzodiazepine effects.  The dosage of the|
01033|019|M|benzodiazepine may need to be decreased or the benzodiazepine may need to be|
01033|020|M|discontinued.|
01033|021|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
01033|022|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
01033|023|M|unresponsiveness.|
01033|024|B||
01033|025|D|DISCUSSION:  Posaconazole (200 mg daily for 10 days) increased the AUC of a|
01033|026|D|single dose of intravenous midazolam (30 minute infusion of 0.05 mg/kg) by|
01033|027|D|83%.(1)|
01033|028|D|   Posaconazole (200 mg twice daily for 7 days) increased the Cmax and AUC|
01033|029|D|of a single dose of intravenous midazolam (0.4 mg) by 30% and 362%,|
01033|030|D|respectively.  Posaconazole (200 mg twice daily for 7 days) increased the|
01033|031|D|Cmax and AUC of a single dose of oral midazolam (2 mg) by 169% and 470%,|
01033|032|D|respectively.  Posaconazole (400 mg twice daily for 7 days) increased the|
01033|033|D|Cmax and AUC of a single dose of intravenous midazolam (0.4 mg) by 62% and|
01033|034|D|524%, respectively.  Posaconazole (400 mg twice daily for 7 days) increased|
01033|035|D|the Cmax and AUC of a single dose of oral midazolam (2 mg) by 138% and 397%,|
01033|036|D|respectively.(2)|
01033|037|D|   In a study of 12 healthy volunteers (11 male and 1 female), posaconazole|
01033|038|D|(200mg twice daily for 7 days and 400mg twice daily for 7 days) increased|
01033|039|D|midazolam Cmax up to 1.3 and 2.4 fold, respectively, and midazolam AUC 4.6|
01033|040|D|and 6.2 fold, respectively.  Midazolam half-life was also increased.(3)|
01033|041|B||
01033|042|R|REFERENCES:|
01033|043|B||
01033|044|R|1.Noxafil (posaconazole) UK summary of product characteristics.|1
01033|045|R|  Schering-Plough Ltd. January, 2022.|1
01033|046|R|2.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01033|047|R|  January, 2022.|1
01033|048|R|3.Krishna G, Moton A, Ma L, Savant I, Martinho M, Seiberling M, McLeod J.|2
01033|049|R|  Effects of oral posaconazole on the pharmacokinetic properties of oral and|2
01033|050|R|  intravenous midazolam: a phase I, randomized, open-label, crossover study|2
01033|051|R|  in healthy volunteers. Clin Ther 2009 Feb;31(2):286-98.|2
01033|052|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
01033|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01033|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01033|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01033|056|R|  11/14/2017.|1
01034|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Calcium; Iron; Sucralfate|
01034|002|B||
01034|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01034|004|L|take action as needed.|
01034|005|B||
01034|006|A|MECHANISM OF ACTION:  The mechanism by which malabsorption of thyroid|
01034|007|A|preparations occurs from calcium-containing products is presumed to be a|
01034|008|A|binding of the medication to the thyroid hormone, forming an insoluble or|
01034|009|A|nonabsorbable complex.(1-3)|
01034|010|A|   Iron may form a ferric-thyroxine complex with thyroid agents, preventing|
01034|011|A|their absorption from the gastrointestinal tract.(1,4)|
01034|012|A|   Sucralfate binds to other agents in the gastrointestinal tract and alters|
01034|013|A|absorption of other drugs, including thyroid agents.(1,5)|
01034|014|B||
01034|015|E|CLINICAL EFFECTS:  The simultaneous administration of thyroid preparations|
01034|016|E|with calcium, iron, or sucralfate may result in decreased levels and|
01034|017|E|clinical effects of thyroid preparations.(1)|
01034|018|B||
01034|019|P|PREDISPOSING FACTORS:  None determined.|
01034|020|B||
01034|021|M|PATIENT MANAGEMENT:  Instruct patients to separate the administration time|
01034|022|M|of thyroid preparations from calcium or iron by as much time as possible,|
01034|023|M|preferably by at least four hours.(1)  Administer thyroid preparations at|
01034|024|M|least 2 hours before sucralfate.(5)|
01034|025|M|   Patients taking thyroid preparations and calcium- or iron-containing|
01034|026|M|products or sucralfate should be monitored for changes in thyroid function.|
01034|027|M|The dosage of the thyroid preparation may need to be increased.  Separating|
01034|028|M|the administration times of the thyroid preparation and the calcium- or|
01034|029|M|iron-containing products or sucralfate may decrease the effects of the|
01034|030|M|interaction.(1-5)|
01034|031|B||
01034|032|D|DISCUSSION:  In a pharmacokinetic study 8 healthy, euthyroid adults were|
01034|033|D|given levothyroxine alone and levothyroxine coadministered with calcium|
01034|034|D|carbonate, calcium citrate, or calcium acetate in doses containing 500 mg|
01034|035|D|elemental calcium.  The coadministration of each of the three calcium|
01034|036|D|preparations significantly reduced levothyroxine absorption by about 20%-25%|
01034|037|D|compared with levothyroxine given alone.(3)|
01034|038|D|   In a study in 14 subjects, the simultaneous administration of thyroxine|
01034|039|D|with ferrous sulfate for 12 weeks resulted in an increase in the mean level|
01034|040|D|of thyroid stimulating hormone (TSH) from 1.6+/-0.4 mU/L to 5.4+/-2.8 mU/L.|
01034|041|D|Mixing thyroxine with ferrous sulfate in vitro resulted in a poorly soluble|
01034|042|D|complex.(4)|
01034|043|D|   In a study in 20 hypothyroid patients, the simultaneous administration of|
01034|044|D|levothyroxine and calcium carbonate (1200 mg) daily for three months|
01034|045|D|resulted in reductions in the mean free T4 and total T4 levels.  These|
01034|046|D|values increased in most patients following the discontinuation of calcium|
01034|047|D|carbonate.  A concurrent in-vitro study found that calcium carbonate|
01034|048|D|adsorbed levothyroxine in solution at a pH of 2, gastric pH, but not at a pH|
01034|049|D|of 7.4.(6)|
01034|050|D|   One author reported three cases of decreased levothyroxine efficacy|
01034|051|D|following the addition of calcium carbonate to therapy.(7)|
01034|052|D|   In a study in 5 healthy subjects, levothyroxine (five 200 mcg tablets)|
01034|053|D|was administered in 3 different dosing regimens: after an overnight fast,|
01034|054|D|with the fifth and final dose of sucralfate (1 gram every 6 hours) and 8|
01034|055|D|hours after the second and final dose of sucralfate (2 grams every 12|
01034|056|D|hours).  When administered alone, 80% of levothyroxine was absorbed within 6|
01034|057|D|hours of administration, compared to 23% when administered concurrently with|
01034|058|D|sucralfate.  There was no difference in levothyroxine absorption when|
01034|059|D|administered alone or 8 hours after sucralfate.(8)|
01034|060|D|   There are several case reports documenting decreased effects of thyroid|
01034|061|D|supplementation as the result of simultaneous administration of|
01034|062|D|sucralfate.(9,10)|
01034|063|D|   One or more of the drug pairs linked to this monograph have been included|
01034|064|D|in a list of interactions that could be considered for classification as|
01034|065|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
01034|066|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
01034|067|D|Health Information Technology.|
01034|068|B||
01034|069|R|REFERENCES:|
01034|070|B||
01034|071|R|1.Synthroid (levothyroxine sodium) US prescribing information. Abbott|1
01034|072|R|  Laboratories February, 2024.|1
01034|073|R|2.Phoslyra (calcium acetate) US prescribing information. Fresenius Medical|1
01034|074|R|  Care North America April, 2015.|1
01034|075|R|3.Zamfirescu I, Carlson HE. Absorption of levothyroxine when coadministered|2
01034|076|R|  with various calcium formulations. Thyroid 2011 May;21(5):483-6.|2
01034|077|R|4.Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate|2
01034|078|R|  reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med|2
01034|079|R|  1992 Dec 15;117(12):1010-3.|2
01034|080|R|5.Carafate (sucralfate) US prescribing information. Allergan, Inc. June,|1
01034|081|R|  2023.|1
01034|082|R|6.Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the|2
01034|083|R|  absorption of levothyroxine. JAMA 2000 Jun 7;283(21):2822-5.|2
01034|084|R|7.Schneyer CR. Calcium carbonate and reduction of levothyroxine efficacy.|3
01034|085|R|  JAMA 1998 Mar 11;279(10):750.|3
01034|086|R|8.Sherman SI, Tielens ET, Ladenson PW. Sucralfate causes malabsorption of|2
01034|087|R|  L-thyroxine. Am J Med 1994 Jun;96(6):531-5.|2
01034|088|R|9.Havrankova J, Lahaie R. Levothyroxine binding by sucralfate. Ann Intern|3
01034|089|R|  Med 1992 Sep 1;117(5):445-6.|3
01034|090|R|10.Vick K, Wennerberg P. Sucralfate-levothyroxine drug interaction..|4
01034|091|R|11.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
01034|092|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
01034|093|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
01034|094|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
01035|001|T|MONOGRAPH TITLE:  Thioridazine/Selected SSRIs; Duloxetine|
01035|002|B||
01035|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01035|004|L|is contraindicated and generally should not be dispensed or administered to|
01035|005|L|the same patient.|
01035|006|B||
01035|007|A|MECHANISM OF ACTION:  Dapoxetine,(1) duloxetine,(2) fluoxetine,(3-7) and|
01035|008|A|paroxetine(3,4) may inhibit the metabolism of thioridazine by CYP2D6.|
01035|009|A|Fluvoxamine may inhibit the metabolism of thioridazine by CYP2C19 and/or|
01035|010|A|CYP1A2.(8)|
01035|011|B||
01035|012|E|CLINICAL EFFECTS:  The concurrent administration of dapoxetine, duloxetine,|
01035|013|E|fluoxetine, fluvoxamine, or paroxetine with thioridazine may result in|
01035|014|E|elevated levels of thioridazine.  Elevated levels of thioridazine may|
01035|015|E|augment thioridazine-induced prolongation of the QTc interval, which may|
01035|016|E|increase the risk of serious, potentially fatal, cardiac arrhythmias such as|
01035|017|E|torsades de pointes.(3,4)|
01035|018|B||
01035|019|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers may|
01035|020|P|be affected to a greater extent by CYP2D6 inhibitors.  Patients who are|
01035|021|P|CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6|
01035|022|P|inhibition.|
01035|023|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01035|024|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01035|025|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01035|026|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01035|027|P|advanced age.(15)|
01035|028|P|     Concurrent use of more than one drug known to cause QT prolongation or|
01035|029|P|higher systemic concentrations of either QT prolonging drug are additional|
01035|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01035|031|P|drug concentrations include rapid infusion of an intravenous dose or|
01035|032|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
01035|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01035|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(15)|
01035|035|B||
01035|036|M|PATIENT MANAGEMENT:  Use an alternative antipsychotic agent.  The concurrent|
01035|037|M|use of thioridazine with dapoxetine,(1) duloxetine,(2) fluoxetine,(3-5,7)|
01035|038|M|fluvoxamine,(3,4,8) or paroxetine(3,4,9,10) is contraindicated.|
01035|039|M|   If thioridazine cannot be discontinued, use an alternative to the|
01035|040|M|interacting SSRI or duloxetine and evaluate patient for predisposing risk|
01035|041|M|factors for QT prolongation. Correct modifiable risk factors and monitor for|
01035|042|M|QT prolongation as appropriate throughout treatment with thioridazine.|
01035|043|M|   If alternative treatment is not possible and concurrent therapy is deemed|
01035|044|M|medically necessary, strongly consider obtaining serum calcium, magnesium,|
01035|045|M|and potassium levels and monitoring ECG at baseline and at regular|
01035|046|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
01035|047|M|report any irregular heartbeat, dizziness, or fainting.|
01035|048|M|   At least 7 days should elapse following the discontinuation of dapoxetine|
01035|049|M|before thioridazine is initiated and at least 14 days should elapse|
01035|050|M|following the discontinuation of thioridazine before dapoxetine is|
01035|051|M|initiated.(1)|
01035|052|M|   At least five weeks should elapse following the discontinuation of|
01035|053|M|fluoxetine before thioridazine is initiated.(5-7)|
01035|054|B||
01035|055|D|DISCUSSION:  In a study, pretreatment with duloxetine (60 mg twice daily)|
01035|056|D|increased the area-under-curve (AUC) of a single dose of desipramine (50 mg)|
01035|057|D|by 3-fold.  Desipramine is metabolized by CYP2D6.(2)|
01035|058|D|   In a study in 10 patients, concurrent fluvoxamine (25 mg twice daily)|
01035|059|D|resulted in a 3-fold increase in the levels of thioridazine and its two|
01035|060|D|active metabolites, mesoridazine and sulforidazine.(11)|
01035|061|D|   A study in six slow and 13 rapid metabolizers of debrisoquin showed that|
01035|062|D|slow metabolizers of debrisoquin had 2.4-fold and 4.5-fold higher|
01035|063|D|thioridazine maximum concentration (Cmax) and AUC, respectively, than rapid|
01035|064|D|metabolizers.(5,6,12)  Slow metabolizers of debrisoquin have a genetic|
01035|065|D|defect that results in low levels of CYP2D6.(3)|
01035|066|D|   A study in healthy subjects showed a thioridazine dose-related|
01035|067|D|prolongation of the QTc interval.(13)|
01035|068|D|   A study in schizophrenic patients found no changes in thioridazine levels|
01035|069|D|following the addition of citalopram.(14)|
01035|070|B||
01035|071|R|REFERENCES:|
01035|072|B||
01035|073|R|1.Priligy (dapoxetine hydrochloride) Australian prescribing information.|1
01035|074|R|  Ortho-McNeil Pharmaceutical March 19, 2013.|1
01035|075|R|2.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
01035|076|R|  and Company September, 2021.|1
01035|077|R|3.Dear Doctor Letter. Re:  Important drug warning about Mellarill. Novartis|1
01035|078|R|  Pharmaceuticals Corporation July 7, 2000.|1
01035|079|R|4.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
01035|080|R|  September, 2014.|1
01035|081|R|5.Sarafem (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
01035|082|R|  and Company September, 2021.|1
01035|083|R|6.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
01035|084|R|  and Company August, 2023.|1
01035|085|R|7.Symbyax (olanzapine and fluoxetine hydrochloride) US prescribing|1
01035|086|R|  information. Eli Lilly and Company August, 2023.|1
01035|087|R|8.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
01035|088|R|  Pharmaceuticals, Inc. August, 2023.|1
01035|089|R|9.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
01035|090|R|  Technologies January, 2017.|1
01035|091|R|10.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
01035|092|R|   Therapeutics, LLC September, 2021.|1
01035|093|R|11.Carrillo JA, Ramos SI, Herraiz AG, Llerena A, Agundez JA, Berecz R, Duran|2
01035|094|R|   M, Benitez J. Pharmacokinetic interaction of fluvoxamine and thioridazine|2
01035|095|R|   in schizophrenic patients. J Clin Psychopharmacol 1999 Dec;19(6):494-9.|2
01035|096|R|12.von Bahr C, Movin G, Nordin C, Liden A, Hammarlund-Udenaes M, Hedberg A,|2
01035|097|R|   Ring H, Sjoqvist F. Plasma levels of thioridazine and metabolites are|2
01035|098|R|   influenced by the debrisoquin hydroxylation phenotype. Clin Pharmacol|2
01035|099|R|   Ther 1991 Mar;49(3):234-40.|2
01035|100|R|13.Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH.|2
01035|101|R|   Concentration-related pharmacodynamic effects of thioridazine and its|2
01035|102|R|   metabolites in humans. Clin Pharmacol Ther 1996 Nov;60(5):543-53.|2
01035|103|R|14.Syvalahti EK, Taiminen T, Saarijarvi S, Lehto H, Niemi H, Ahola V, Dahl|2
01035|104|R|   ML, Salokangas RK. Citalopram causes no significant alterations in plasma|2
01035|105|R|   neuroleptic levels in schizophrenic patients. J Int Med Res 1997 Jan-Feb;|2
01035|106|R|   25(1):24-32.|2
01035|107|R|15.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
01035|108|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
01035|109|R|   hospital settings: a scientific statement from the American Heart|6
01035|110|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
01035|111|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
01035|112|R|16.Wojcikowski J, Maurel P, Daniel WA. Characterization of human cytochrome|5
01035|113|R|   p450 enzymes involved in the metabolism of the piperidine-type|5
01035|114|R|   phenothiazine neuroleptic thioridazine. Drug Metab Dispos 2006 Mar;|5
01035|115|R|   34(3):471-6.|5
01036|001|T|MONOGRAPH TITLE:  Cyclosporine/Orlistat|
01036|002|B||
01036|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01036|004|L|of severe adverse interaction.|
01036|005|B||
01036|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown. Orlistat may bind with|
01036|007|A|cyclosporine in the stomach or small intestine, thus decreasing the|
01036|008|A|absorption of cyclosporine.|
01036|009|B||
01036|010|E|CLINICAL EFFECTS:  The concurrent administration of cyclosporine and|
01036|011|E|orlistat may result in a decrease in the levels and clinical effects of|
01036|012|E|cyclosporine.(1,2)|
01036|013|B||
01036|014|P|PREDISPOSING FACTORS:  None determined.|
01036|015|B||
01036|016|M|PATIENT MANAGEMENT:  The US manufacturer of orlistat states that|
01036|017|M|cyclosporine should be administered either at least 3 hours before or after|
01036|018|M|orlistat and that cyclosporine levels should be carefully monitored.(1)|
01036|019|B||
01036|020|D|DISCUSSION:  In a case report, a heart-transplant patient experienced a|
01036|021|D|decrease in cyclosporine trough concentration, maximum concentration (Cmax),|
01036|022|D|and area-under-curve (AUC) by 47%, 86%, and 75%, respectively, following the|
01036|023|D|addition of orlistat to his regimen.(3)|
01036|024|D|   In a case report, larger than normal doses of cyclosporine were required|
01036|025|D|in a renal transplant patient who had been maintained on orlistat.(4)|
01036|026|D|   In a case report, a renal transplant patient experienced decreased|
01036|027|D|cyclosporine levels following the addition of orlistat to her regimen,|
01036|028|D|despite the administration of orlistat 2 hours before cyclosporine.|
01036|029|D|However, the authors note that the patient did not follow a low-fat diet and|
01036|030|D|experienced severe diarrhea which may have also contributed to poor|
01036|031|D|cyclosporine absorption.(5)|
01036|032|D|   There are other case reports of decreased cyclosporine levels following|
01036|033|D|the addition of orlistat,(6-9) including six reports received by the US Food|
01036|034|D|and Drug Administration.(6)|
01036|035|D|   In a multiple dose study, orlistat (120 mg TID) decreased the Cmax and|
01036|036|D|AUC of cyclosporine (50 mg BID) by 25% and 31%, respectively.  When|
01036|037|D|separated by 3 hours, orlistat (120 mg TID) decreased the Cmax and AUC of|
01036|038|D|cyclosporine (50 mg BID) by 4% and 17%, respectively.(1,10)|
01036|039|B||
01036|040|R|REFERENCES:|
01036|041|B||
01036|042|R|1.Xenical (orlistat) US prescribing information. Roche Laboratories, Inc.|1
01036|043|R|  November, 2022.|1
01036|044|R|2.Alli (orlistat) US prescribing information. GSK Consumer Healthcare May,|1
01036|045|R|  2017.|1
01036|046|R|3.Nagele H, Petersen B, Bonacker U, Rodiger W. Effect of orlistat on blood|3
01036|047|R|  cyclosporin concentration in an obese heart transplant patient. Eur J Clin|3
01036|048|R|  Pharmacol 1999 Nov;55(9):667-9.|3
01036|049|R|4.Evans S, Michael R, Wells H, Maclean D, Gordon I, Taylor J, Goldsmith D.|3
01036|050|R|  Drug interaction in a renal transplant patient: cyclosporin-Neoral and|3
01036|051|R|  orlistat. Am J Kidney Dis 2003 Feb;41(2):493-6.|3
01036|052|R|5.Barbaro D, Orsini P, Pallini S, Piazza F, Pasquini C. Obesity in|3
01036|053|R|  transplant patients: case report showing interference of orlistat with|3
01036|054|R|  absorption of cyclosporine and review of literature. Endocr Pract 2002|3
01036|055|R|  Mar-Apr;8(2):124-6.|3
01036|056|R|6.Colman E, Fossler M. Reduction in blood cyclosporine concentrations by|3
01036|057|R|  orlistat. N Engl J Med 2000 Apr 13;342(15):1141-2.|3
01036|058|R|7.Errasti P, Garcia I, Lavilla J, Ballester B, Manrique J, Purroy A.|3
01036|059|R|  Reduction in blood cyclosporine concentration by orlistat in two renal|3
01036|060|R|  transplant patients. Transplant Proc 2002 Feb;34(1):137-9.|3
01036|061|R|8.Le Beller C, Bezie Y, Chabatte C, Guillemain R, Amrein C, Billaud EM.|3
01036|062|R|  Co-administration of orlistat and cyclosporine in a heart transplant|3
01036|063|R|  recipient. Transplantation 2000 Nov 27;70(10):1541-2.|3
01036|064|R|9.Schnetzler B, Kondo-Oestreicher M, Vala D, Khatchatourian G, Faidutti B.|3
01036|065|R|  Orlistat decreases the plasma level of cyclosporine and may be responsible|3
01036|066|R|  for the development of acute rejection episodes. Transplantation 2000 Nov|3
01036|067|R|  27;70(10):1540-1.|3
01036|068|R|10.Zhi J, Moore R, Kanitra L, Mulligan TE. Pharmacokinetic evaluation of the|2
01036|069|R|   possible interaction between selected concomitant medications and|2
01036|070|R|   orlistat at steady state in healthy subjects. J Clin Pharmacol 2002 Sep;|2
01036|071|R|   42(9):1011-9.|2
01037|001|T|MONOGRAPH TITLE:  Delavirdine/Antacids|
01037|002|B||
01037|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01037|004|L|take action as needed.|
01037|005|B||
01037|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown. Antacids decrease the|
01037|007|A|absorption of delavirdine.(1)|
01037|008|B||
01037|009|E|CLINICAL EFFECTS:  The simultaneous administration of delavirdine with an|
01037|010|E|antacid may decrease the absorption of delavirdine, which may result in|
01037|011|E|subtherapeutic levels.|
01037|012|B||
01037|013|P|PREDISPOSING FACTORS:  None determined.|
01037|014|B||
01037|015|M|PATIENT MANAGEMENT:  The administration of delavirdine and antacids should|
01037|016|M|be separated by at least one hour.(1)|
01037|017|M|   Some vitamin preparations may contain sufficient quantities of magnesium|
01037|018|M|salts with antacid properties to interact as well.|
01037|019|B||
01037|020|D|DISCUSSION:  In a single dose study in 12 healthy subjects, the simultaneous|
01037|021|D|administration of delavirdine with an alumina and magnesia oral suspension|
01037|022|D|(20 ml) decreased the delavirdine area-under-curve (AUC) and maximum|
01037|023|D|concentration (Cmax) by 44% and 52%, respectively.(1)|
01037|024|B||
01037|025|R|REFERENCE:|
01037|026|B||
01037|027|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01037|028|R|  Upjohn Company August, 2012.|1
01038|001|T|MONOGRAPH TITLE:  Delavirdine/Rifampin; Rifabutin|
01038|002|B||
01038|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01038|004|L|is contraindicated and generally should not be dispensed or administered to|
01038|005|L|the same patient.|
01038|006|B||
01038|007|A|MECHANISM OF ACTION:  Rifampin and rifabutin may induce the metabolism of|
01038|008|A|delavirdine at CYP3A4.(1) Delavirdine may inhibit the metabolism of|
01038|009|A|rifabutin.(1)|
01038|010|B||
01038|011|E|CLINICAL EFFECTS:  The concurrent administration of rifampin or rifabutin|
01038|012|E|with delavirdine may result in drastically reduced levels of delavirdine and|
01038|013|E|therapeutic failure.(1) The concurrent administration of rifabutin and|
01038|014|E|delavirdine may result in elevated levels of rifabutin.(1)|
01038|015|B||
01038|016|P|PREDISPOSING FACTORS:  None determined.|
01038|017|B||
01038|018|M|PATIENT MANAGEMENT:  The manufacturer of delavirdine states that rifampin|
01038|019|M|and rifabutin should not be used in patients receiving delavirdine.(1)|
01038|020|M|   The US manufacturer of rifabutin states that concomitant use of rifabutin|
01038|021|M|with delavirdine is contraindicated. (3)|
01038|022|B||
01038|023|D|DISCUSSION:  In a study in seven HIV-1 infected patients, the concurrent|
01038|024|D|administration of delavirdine (400 mg three times daily) with rifampin (600|
01038|025|D|mg once daily) resulted in a decrease in the delavirdine area-under-curve|
01038|026|D|(AUC), maximum concentration (Cmax), and minimum concentration (Cmin) by|
01038|027|D|97%, 90%, and 100%, respectively.(1)|
01038|028|D|   In a study in seven HIV-1 infected patients, the concurrent|
01038|029|D|administration of delavirdine (400 mg three times daily) with rifabutin (300|
01038|030|D|mg once daily) decreased delavirdine AUC, Cmax, and Cmin by 82%, 72%, and|
01038|031|D|94%, respectively.  The AUC, Cmax, and Cmin of rifabutin were increased by|
01038|032|D|230%, 128%, and 452%, respectively.(1,2)|
01038|033|B||
01038|034|R|REFERENCES:|
01038|035|B||
01038|036|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01038|037|R|  Upjohn Company August, 2012.|1
01038|038|R|2.Borin MT, Chambers JH, Carel BJ, Freimuth WW, Aksentijevich S, Piergies|2
01038|039|R|  AA. Pharmacokinetic study of the interaction between rifabutin and|2
01038|040|R|  delavirdine mesylate in HIV-1 infected patients. Antiviral Res 1997 Jun;|2
01038|041|R|  35(1):53-63.|2
01038|042|R|3.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
01038|043|R|  2021.|1
01039|001|T|MONOGRAPH TITLE:  Sildenafil/Delavirdine|
01039|002|B||
01039|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01039|004|L|take action as needed.|
01039|005|B||
01039|006|A|MECHANISM OF ACTION:  Delavirdine may inhibit the metabolism of sildenafil|
01039|007|A|at CYP3A4.(1)|
01039|008|B||
01039|009|E|CLINICAL EFFECTS:  The concurrent administration of delavirdine and|
01039|010|E|sildenafil may result in elevated levels of sildenafil and an increased risk|
01039|011|E|for sildenafil adverse effects, including hypotension, visual changes, and|
01039|012|E|prolonged erections.(1)|
01039|013|B||
01039|014|P|PREDISPOSING FACTORS:  None determined.|
01039|015|B||
01039|016|M|PATIENT MANAGEMENT:  The manufacturer of delavirdine states that if|
01039|017|M|delavirdine and sildenafil are used concurrently, a maximum dosage of 25 mg|
01039|018|M|of sildenafil in a 48 hour period should not be exceeded.(1)|
01039|019|M|   Patients should be counseled that they are at an increased risk of|
01039|020|M|sildenafil adverse effects, including hypotension, visual changes, and|
01039|021|M|priapism.(1)|
01039|022|B||
01039|023|D|DISCUSSION:  Delavirdine has been shown to be a potent inhibitor of CYP3A4.|
01039|024|D|Sildenafil is metabolized by this isoenzyme. Because ritonavir, which also|
01039|025|D|inhibits this isoenzyme, was shown to inhibit the metabolism of sildenafil,|
01039|026|D|the manufacturer of delavirdine recommends that the sildenafil dosage|
01039|027|D|recommended by the manufacturer of sildenafil for concurrent administration|
01039|028|D|with ritonavir be observed for use with delavirdine.(1)|
01039|029|B||
01039|030|R|REFERENCE:|
01039|031|B||
01039|032|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01039|033|R|  Upjohn Company August, 2012.|1
01040|001|T|MONOGRAPH TITLE:  Aspirin; Aloxiprin/Ginkgo Biloba|
01040|002|B||
01040|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01040|004|L|Assess the risk to the patient and take action as needed.|
01040|005|B||
01040|006|A|MECHANISM OF ACTION:  The mechanism of the interaction between ginkgo biloba|
01040|007|A|and aspirin is not known. Ginkgo biloba contains a component that has been|
01040|008|A|shown to be a potent inhibitor of platelet-activating factor,(1-3) which may|
01040|009|A|be responsible for the interaction.|
01040|010|B||
01040|011|E|CLINICAL EFFECTS:  The concurrent administration of ginkgo biloba with|
01040|012|E|aspirin or aloxiprin may result in an increase in bleeding times and|
01040|013|E|hemorrhagic complications.|
01040|014|B||
01040|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01040|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01040|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
01040|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01040|019|P|risk for bleeding (e.g. NSAIDs).|
01040|020|B||
01040|021|M|PATIENT MANAGEMENT:  Patients receiving either aspirin or aloxiprin with|
01040|022|M|ginkgo biloba should be alerted to the possibility of increased bleeding and|
01040|023|M|risk of hemorrhagic complications. Consider monitoring for these|
01040|024|M|complications during concurrent therapy. The dosage of aspirin or aloxiprin|
01040|025|M|may need to be adjusted if ginkgo biloba is added to, or discontinued from,|
01040|026|M|concurrent therapy. Ginkgo biloba may need to be discontinued.|
01040|027|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01040|028|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01040|029|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01040|030|M|patients with any symptoms.|
01040|031|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01040|032|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01040|033|M|anticoagulation in patients with active pathologic bleeding.|
01040|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01040|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01040|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01040|037|M|and/or swelling.|
01040|038|B||
01040|039|D|DISCUSSION:  In a single case report, an elderly patient who had been taking|
01040|040|D|325 mg of aspirin daily for 3 years developed blurred vision one week after|
01040|041|D|he started a twice daily regimen of ginkgo biloba. Exam revealed a fine|
01040|042|D|stream of blood oozing down from the margin of the iris into the inferior|
01040|043|D|angle. There was no history of trauma, ischemia, or vascular occlusion and|
01040|044|D|bleeding stopped spontaneously.(4)|
01040|045|B||
01040|046|R|REFERENCES:|
01040|047|B||
01040|048|R|1.Chung KF, Dent G, McCusker M, Guinot P, Page CP, Barnes PJ. Effect of a|2
01040|049|R|  ginkgolide mixture (BN 52063) in antagonising skin and platelet responses|2
01040|050|R|  to platelet activating factor in man. Lancet 1987 Jan 31;1(8527):248-51.|2
01040|051|R|2.Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated|3
01040|052|R|  with chronic Ginkgo biloba ingestion. Neurology 1996 Jun;46(6):1775-6.|3
01040|053|R|3.Belougne E, Aguejouf O, Imbault P, Azougagh Oualane F, Doutremepuich F,|5
01040|054|R|  Droy-Lefaix MT, Doutremepuich C. Experimental thrombosis model induced by|5
01040|055|R|  laser beam. Application of aspirin and an extract of Ginkgo biloba: EGb|5
01040|056|R|  761. Thromb Res 1996 Jun 1;82(5):453-8.|5
01040|057|R|4.Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of|3
01040|058|R|  Ginkgo biloba extract. N Engl J Med 1997 Apr 10;336(15):1108.|3
01041|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Dong Quai|
01041|002|B||
01041|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01041|004|L|Assess the risk to the patient and take action as needed.|
01041|005|B||
01041|006|A|MECHANISM OF ACTION:  Though the exact mechanism is not known, it has been|
01041|007|A|suggested that the dong quai root contains natural coumarin derivatives and|
01041|008|A|may potentiate the effect of anticoagulants.(1)|
01041|009|B||
01041|010|E|CLINICAL EFFECTS:  The concurrent administration of anticoagulants and dong|
01041|011|E|quai may result in an increased risk for bleeding.(1)|
01041|012|B||
01041|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01041|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01041|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01041|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01041|017|P|risk for bleeding (e.g. NSAIDs).|
01041|018|B||
01041|019|M|PATIENT MANAGEMENT:  Patients receiving both an anticoagulant and dong quai|
01041|020|M|should be alerted to the possibility of increased effects of the|
01041|021|M|anticoagulant. Consider monitoring INR levels more frequently when dong quai|
01041|022|M|is added to or discontinued from concurrent therapy. The dose of the|
01041|023|M|anticoagulant may need to be adjusted if dong quai is added to or|
01041|024|M|discontinued from concurrent therapy. Dong quai may need to be discontinued.|
01041|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01041|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01041|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01041|028|M|patients with any symptoms.|
01041|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01041|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01041|031|M|anticoagulation in patients with active pathologic bleeding.|
01041|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01041|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01041|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01041|035|M|and/or swelling.|
01041|036|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01041|037|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01041|038|M|initiating, altering the dose or discontinuing either drug.|
01041|039|B||
01041|040|D|DISCUSSION:  In a case report, the addition of dong quai to the therapy of a|
01041|041|D|patient maintained on a stable warfarin regimen resulted in significant|
01041|042|D|increases in the patient's INR. One month after the addition of dong quai|
01041|043|D|(565 mg one to two times daily for perimenopausal symptoms) to her warfarin|
01041|044|D|regimen, her INR had increased to 4.05.  One month later, her INR was 4.9.|
01041|045|D|Two weeks after the discontinuation of dong quai, her INR had decreased to|
01041|046|D|3.41 and four weeks after dong quai discontinuation, her INR was 2.48.(1)|
01041|047|B||
01041|048|R|REFERENCE:|
01041|049|B||
01041|050|R|1.Page RL 2nd, Lawrence JD. Potentiation of warfarin by dong quai.|3
01041|051|R|  Pharmacotherapy 1999 Jul;19(7):870-6.|3
01042|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Ginkgo Biloba|
01042|002|B||
01042|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01042|004|L|Assess the risk to the patient and take action as needed.|
01042|005|B||
01042|006|A|MECHANISM OF ACTION:  The mechanism of the interaction between ginkgo biloba|
01042|007|A|and anticoagulants is not known. Ginkgo biloba contains a component that has|
01042|008|A|been shown to be a potent inhibitor of platelet-activating factor, which may|
01042|009|A|be responsible for the interaction.(1-3)|
01042|010|B||
01042|011|E|CLINICAL EFFECTS:  The concurrent administration of ginkgo biloba with an|
01042|012|E|anticoagulant may result in an increase in bleeding times and hemorrhagic|
01042|013|E|complications.|
01042|014|B||
01042|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01042|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01042|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
01042|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01042|019|P|risk for bleeding (e.g. NSAIDs).|
01042|020|B||
01042|021|M|PATIENT MANAGEMENT:  Patients receiving both an anticoagulant and ginkgo|
01042|022|M|biloba should be alerted to the possibility of increased bleeding times and|
01042|023|M|hemorrhagic complications. Consider monitoring for these complications|
01042|024|M|during concurrent therapy. The dosage of the anticoagulant may need to be|
01042|025|M|adjusted if ginkgo biloba is added to, or discontinued from, concurrent|
01042|026|M|therapy. Ginkgo biloba may need to be discontinued.|
01042|027|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01042|028|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01042|029|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01042|030|M|patients with any symptoms.|
01042|031|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01042|032|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01042|033|M|anticoagulation in patients with active pathologic bleeding.|
01042|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01042|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01042|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01042|037|M|and/or swelling.|
01042|038|M|      The time of highest risk for a coumarin-type drug interaction is when|
01042|039|M|the precipitant drug is initiated or discontinued. Contact the prescriber|
01042|040|M|before initiating, altering the dose or discontinuing either drug.|
01042|041|B||
01042|042|D|DISCUSSION:  In a single case report, an elderly patient who had been|
01042|043|D|maintained on warfarin for 5 years, was admitted with a 2-day history of|
01042|044|D|inability to feed herself, severe apraxia, and a change in cognitive|
01042|045|D|deficits. A CT scan showed a left parietal hemorrhage, her PT was 16.9 and|
01042|046|D|her PTT was 35.5. The patient had been taking ginkgo biloba for 2 months. It|
01042|047|D|is not known whether an interaction would occur between ginkgo biloba and|
01042|048|D|the other anticoagulants, but patients should be warned of the possibility|
01042|049|D|of a drug interaction resulting in a spontaneous bleeding episode.(4)|
01042|050|D|   In a retrospective chart analysis of 143,360 patients, patients on|
01042|051|D|concurrent warfarin and ginkgo had a higher bleeding event rate than|
01042|052|D|warfarin alone (22.6% vs 18%, respectively) with a hazard ratio of 1.38 (95%|
01042|053|D|CI 1.2-1.58, p<0.001).(5)|
01042|054|D|   In contrast, in an open-label, cross-over study in 12 healthy subjects,|
01042|055|D|pretreatment with ginkgo (2 g ginkgo biloba leaf, 9.6 mg ginkgo|
01042|056|D|flavonglycosides, 2.4mg ginkgolides and bilobalide 3 times daily) for 1 week|
01042|057|D|had no effect on the pharmacokinetics or pharmacodynamics of a single dose|
01042|058|D|of warfarin (25 mg).(6)|
01042|059|B||
01042|060|R|REFERENCES:|
01042|061|B||
01042|062|R|1.Gilbert GJ. Ginkgo biloba. Neurology 1997 Apr;48(4):1137.|3
01042|063|R|2.Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of|3
01042|064|R|  Ginkgo biloba extract. N Engl J Med 1997 Apr 10;336(15):1108.|3
01042|065|R|3.Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated|3
01042|066|R|  with chronic Ginkgo biloba ingestion. Neurology 1996 Jun;46(6):1775-6.|3
01042|067|R|4.Matthews MK Jr. Association of Ginkgo biloba with intracerebral|3
01042|068|R|  hemorrhage. Neurology 1998 Jun;50(6):1933-4.|3
01042|069|R|5.Stoddard GJ, Archer M, Shane-McWhorter L, Bray BE, Redd DF, Proulx J,|2
01042|070|R|  Zeng-Treitler Q. Ginkgo and Warfarin Interaction in a Large Veterans|2
01042|071|R|  Administration Population..|2
01042|072|R|6.Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO,|2
01042|073|R|  McLachlan AJ. Effect of ginkgo and ginger on the pharmacokinetics and|2
01042|074|R|  pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2005|2
01042|075|R|  Apr;59(4):425-32.|2
01043|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/Ginseng|
01043|002|B||
01043|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01043|004|L|Assess the risk to the patient and take action as needed.|
01043|005|B||
01043|006|A|MECHANISM OF ACTION:  The exact mechanism of is unknown.|
01043|007|B||
01043|008|E|CLINICAL EFFECTS:  The concurrent administration of anticoagulants and|
01043|009|E|ginseng may result in decreased INR values and clinical effects of the|
01043|010|E|anticoagulant.|
01043|011|B||
01043|012|P|PREDISPOSING FACTORS:  None determined.|
01043|013|B||
01043|014|M|PATIENT MANAGEMENT:  Patients receiving both an anticoagulant and ginseng|
01043|015|M|should be alerted to the possibility of decreased effects of the|
01043|016|M|anticoagulant. Consider monitoring INRs more frequently during concurrent|
01043|017|M|therapy. The dosage of the anticoagulant may need to be adjusted if ginseng|
01043|018|M|is added to or discontinued from concurrent therapy. Ginseng may need to be|
01043|019|M|discontinued.|
01043|020|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01043|021|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01043|022|M|anticoagulation in patients with active pathologic bleeding.|
01043|023|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01043|024|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
01043|025|M|before initiating, altering the dose or discontinuing either drug.|
01043|026|B||
01043|027|D|DISCUSSION:  In a case report, a patient was maintained on a regimen of|
01043|028|D|warfarin with an INR ranging from 3.0 to 4.0 for the nine months prior to|
01043|029|D|the patient starting to take ginseng. Two weeks after starting ginseng, his|
01043|030|D|INR dropped to 1.5 (was measured at 3.1 four weeks before). The INR returned|
01043|031|D|to 3.3 in the two weeks following discontinuation of the ginseng.(1)|
01043|032|D|  Conversely, in a crossover study of 12 healthy male subjects who received|
01043|033|D|warfarin alone and with ginseng, INR and platelet aggregation were not|
01043|034|D|affected by ginseng treatment.(2)  In a study, 24 subjects received a single|
01043|035|D|warfarin dose (25mg) with either St. John's wort, Asian ginseng, Ginkgo|
01043|036|D|biloba, or ginger.  Asian ginseng produced only a moderate increase in|
01043|037|D|warfarin apparent clearance (1.14+/-0.04 compared to control).  Other|
01043|038|D|pharmacokinetic and pharmacodynamic parameters were unaffected.(3)|
01043|039|D|  In a randomized double-blind crossover study, 31 cardiac valve replacement|
01043|040|D|patients on warfarin therapy with a stable INR were included to study the|
01043|041|D|effects of ginseng on warfarin.  One group was given 1g of Korean red|
01043|042|D|ginseng for 6 weeks.  After a 3-week washout period, they then received|
01043|043|D|warfarin and placebo.  The other group received the same treatments in|
01043|044|D|opposite order.  The mean INR change at baseline to week 3 and baseline to|
01043|045|D|week 6 showed no statistically significant differences in mean INR change|
01043|046|D|(p=0.72, p=0.21).(4)|
01043|047|D|  In an open-label randomized control trial, 25 ischemic stroke patients|
01043|048|D|received oral warfarin (2 mg daily for 7 days then 5 mg daily for 7 days)|
01043|049|D|and P. ginseng (0.5 mg aqueous extract three times daily) or placebo for two|
01043|050|D|weeks.  Ginseng did not produce any significant differences in peak PT and|
01043|051|D|INR values compared to the placebo.(5)|
01043|052|D|  In a randomized, double-blind, placebo-controlled trial, 20 healthy|
01043|053|D|patients received warfarin (5 mg for 3 consecutive days in weeks 1 and 4).|
01043|054|D|In addition, the patients either received American ginseng (1 g twice daily)|
01043|055|D|or placebo in weeks 2-4.  A statistically significant reduction in INR was|
01043|056|D|observed in the ginseng group compared to the placebo group (p=0.0012).(6)|
01043|057|B||
01043|058|R|REFERENCES:|
01043|059|B||
01043|060|R|1.Janetzky K, Morreale AP. Probable interaction between warfarin and|3
01043|061|R|  ginseng. Am J Health Syst Pharm 1997 Mar 15;54(6):692-3.|3
01043|062|R|2.Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO,|2
01043|063|R|  McLachlan AJ. Effect of St John's wort and ginseng on the pharmacokinetics|2
01043|064|R|  and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol|2
01043|065|R|  2004 May;57(5):592-9.|2
01043|066|R|3.Jiang X, Blair EY, McLachlan AJ. Investigation of the effects of herbal|2
01043|067|R|  medicines on warfarin response in healthy subjects: a population|2
01043|068|R|  pharmacokinetic-pharmacodynamic modeling approach. J Clin Pharmacol 2006|2
01043|069|R|  Nov;46(11):1370-8.|2
01043|070|R|4.Lee YH, Lee BK, Choi YJ, Yoon IK, Chang BC, Gwak HS. Interaction between|2
01043|071|R|  warfarin and Korean red ginseng in patients with cardiac valve|2
01043|072|R|  replacement. Int J Cardiol 2010 Nov 19;145(2):275-6.|2
01043|073|R|5.Lee SH, Ahn YM, Ahn SY, Doo HK, Lee BC. Interaction between warfarin and|2
01043|074|R|  Panax ginseng in ischemic stroke patients. J Altern Complement Med 2008|2
01043|075|R|  Jul;14(6):715-21.|2
01043|076|R|6.Yuan CS, Wei G, Dey L, Karrison T, Nahlik L, Maleckar S, Kasza K, Ang-Lee|2
01043|077|R|  M, Moss J. Brief communication: American ginseng reduces warfarin's effect|2
01043|078|R|  in healthy patients: a randomized, controlled Trial. Ann Intern Med 2004|2
01043|079|R|  Jul 6;141(1):23-7.|2
01044|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/Green Tea|
01044|002|B||
01044|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01044|004|L|Assess the risk to the patient and take action as needed.|
01044|005|B||
01044|006|A|MECHANISM OF ACTION:  Green tea is high in vitamin K, which is essential for|
01044|007|A|for the production of certain clotting factors. Warfarin acts by inhibiting|
01044|008|A|the synthesis of these clotting factors.(1,2) An increase in the vitamin K|
01044|009|A|content of the diet may antagonize the effects of warfarin.(3)|
01044|010|B||
01044|011|E|CLINICAL EFFECTS:  Vitamin K may antagonize the effects of warfarin, which|
01044|012|E|may result in significant decreases in a patient's International Normalized|
01044|013|E|Ratio (INR) and an increased risk of the patient developing a blood clot.|
01044|014|B||
01044|015|P|PREDISPOSING FACTORS:  None determined.|
01044|016|B||
01044|017|M|PATIENT MANAGEMENT:  Patients maintained on warfarin should be cautioned of|
01044|018|M|the risk of altering the effects of warfarin by changing the amounts of|
01044|019|M|foods high in vitamin K (such as green tea) in their diet. Patients should|
01044|020|M|be encouraged to be consistent with their vitamin K intake.(4-6) More|
01044|021|M|frequent monitoring of INRs may be required and dosage adjustments of|
01044|022|M|warfarin made accordingly.  Discontinuation of green tea may also be|
01044|023|M|required.|
01044|024|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01044|025|M|to monitor efficacy and safety of anticoagulation.|
01044|026|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01044|027|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01044|028|M|initiating, altering the dose or discontinuing either drug.|
01044|029|B||
01044|030|D|DISCUSSION:  In a case report, a patient who had been stabilized on warfarin|
01044|031|D|experienced a dramatic decrease in his INR after he had started drinking|
01044|032|D|one-half to one gallon of green tea daily. The patient's INR decreased from|
01044|033|D|between 3.20 and 3.79 to 1.37 one week after beginning to consume green tea.|
01044|034|D|One month later, his INR had decreased to 1.14. After discontinuing green|
01044|035|D|tea, the patient's INR increased to 2.55. Dry green tea leaves contain 1,428|
01044|036|D|mg of vitamin K per 100 grams.(7)|
01044|037|B||
01044|038|R|REFERENCES:|
01044|039|B||
01044|040|R|1.Carlisle DM, Blaschke TF. Vitamin K1, vitamin K1 epoxide and warfarin|5
01044|041|R|  interrelationships in the dog. Biochem Pharmacol 1981 Nov 1;30(21):2931-6.|5
01044|042|R|2.Shearer MJ, Barkhan P. Vitamin K1 and therapy of massive warfarin|2
01044|043|R|  overdose. Lancet 1979 Feb 3;1(8110):266-7.|2
01044|044|R|3.Weser JK, Sellers E. Drug interactions with coumarin anticoagulants. 2. N|6
01044|045|R|  Engl J Med 1971 Sep 2;285(10):547-58.|6
01044|046|R|4.Fletcher DC. Clotting factors in vitamin K-rich vegetables hinder|6
01044|047|R|  anticoagulant therapy?. JAMA 1977 Apr 25;237(17):1871.|6
01044|048|R|5.Kempin SJ. Warfarin resistance caused by broccoli. N Engl J Med 1983 May|3
01044|049|R|  19;308(20):1229-30.|3
01044|050|R|6.Blickstein D, Shaklai M, Inbal A. Warfarin antagonism by avocado. Lancet|3
01044|051|R|  1991 Apr 13;337(8746):914-5.|3
01044|052|R|7.Taylor JR, Wilt VM. Probable antagonism of warfarin by green tea. Ann|3
01044|053|R|  Pharmacother 1999 Apr;33(4):426-8.|3
01045|001|T|MONOGRAPH TITLE:  SSRIs; SNRIs; Nefazodone/Ayahuasca|
01045|002|B||
01045|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01045|004|L|Assess the risk to the patient and take action as needed.|
01045|005|B||
01045|006|A|MECHANISM OF ACTION:  One of the major plant components in this psychoactive|
01045|007|A|beverage contains harmala alkaloids (including harmaline and harmine) which|
01045|008|A|block the enzymatic activity of monoamine oxidase.  Another plant component|
01045|009|A|in this beverage contains N,N-dimethyltryptamine (DMT), a potent and short|
01045|010|A|acting psychedelic agent which is normally not active orally due to its|
01045|011|A|rapid oxidation by monoamine oxidase.(1,2)|
01045|012|B||
01045|013|E|CLINICAL EFFECTS:  The concurrent administration of selective or|
01045|014|E|non-selective serotonin reuptake inhibitors and ayahuasca may result in|
01045|015|E|serotonin syndrome.  Symptoms of serotonin  syndrome may include tremor,|
01045|016|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
01045|017|E|and muscle rigidity.(4)|
01045|018|B||
01045|019|P|PREDISPOSING FACTORS:  None determined.|
01045|020|B||
01045|021|M|PATIENT MANAGEMENT:  Patients maintained on a selective serotonin reuptake|
01045|022|M|inhibitor, nefazodone, venlafaxine, or milnacipran should be warned about|
01045|023|M|the potential for developing serotonin syndrome if ayahuasca is used|
01045|024|M|concurrently.  The use of ayahuasca may have to be discontinued while the|
01045|025|M|patient is maintained on the antidepressant.|
01045|026|M|   If concurrent therapy is warranted, patients should be monitored for|
01045|027|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
01045|028|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
01045|029|M|heart palpitations, restlessness, confusion, agitation, trouble with|
01045|030|M|coordination, or severe diarrhea.|
01045|031|B||
01045|032|D|DISCUSSION:  In a case report, a patient maintained on fluoxetine for|
01045|033|D|several months participated in a ceremonial ritual which involved ingesting|
01045|034|D|100 ml of ayahuasca.  Within one hour of ingesting the beverage, the patient|
01045|035|D|experienced symptoms typical of serotonin syndrome, including tremors,|
01045|036|D|sweating, shivering, confusion, and severe nausea and vomiting. Four hours|
01045|037|D|after ingesting ayahuasca, the patient rapidly became asymptomatic without|
01045|038|D|treatment.(3)|
01045|039|B||
01045|040|R|REFERENCES:|
01045|041|B||
01045|042|R|1.Callaway JC, Raymon LP, Hearn WL, McKenna DJ, Grob CS, Brito GS, Mash DC.|5
01045|043|R|  Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human|5
01045|044|R|  plasma after oral dosing with ayahuasca. J Anal Toxicol 1996 Oct;|5
01045|045|R|  20(6):492-7.|5
01045|046|R|2.Callaway JC, Airaksinen MM, McKenna DJ, Brito GS, Grob CS. Platelet|2
01045|047|R|  serotonin uptake sites increased in drinkers of ayahuasca.|2
01045|048|R|  Psychopharmacology (Berl) 1994 Nov;116(3):385-7.|2
01045|049|R|3.Callaway JC, Grob CS. Ayahuasca preparations and serotonin reuptake|3
01045|050|R|  inhibitors: a potential combination for severe adverse interactions. J|3
01045|051|R|  Psychoactive Drugs 1998 Oct-Dec;30(4):367-9.|3
01045|052|R|4.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01045|053|R|  352(11):1112-20.|6
01046|001|T|MONOGRAPH TITLE:  SSRIs; SNRIs/St. John's Wort|
01046|002|B||
01046|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01046|004|L|Assess the risk to the patient and take action as needed.|
01046|005|B||
01046|006|A|MECHANISM OF ACTION:  The exact mechanism for this interaction is unknown|
01046|007|A|because the mechanism of action of St. John's wort is unknown. While early|
01046|008|A|studies showed that St. John's wort inhibited monoamine oxidase,(1,2) other|
01046|009|A|studies have shown that the MAOI effects of St. John's wort are too weak to|
01046|010|A|explain its therapeutic effects.(3,4) The active component of St. John's|
01046|011|A|wort is thought to be hypericin,(5) a weak MAO inhibitor(1) whose|
01046|012|A|concentration in humans may not reach the levels required to inhibit MAO.(2)|
01046|013|A|Another study theorized that St. John's wort may inhibit serotonin|
01046|014|A|reuptake.(6)|
01046|015|B||
01046|016|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort and a selective or|
01046|017|E|non-selective serotonin reuptake inhibitor may result in serotonin syndrome.|
01046|018|E|Symptoms of serotonin syndrome may include irritability, altered|
01046|019|E|consciousness, double vision, nausea, confusion, anxiety, hyperthermia,|
01046|020|E|increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital|
01046|021|E|signs, and coma. Serotonin syndrome may result in death.|
01046|022|B||
01046|023|P|PREDISPOSING FACTORS:  None determined.|
01046|024|B||
01046|025|M|PATIENT MANAGEMENT:  Consider a 14 day washout period for patients who have|
01046|026|M|taken St. John's wort before initiating a selective or non-selective|
01046|027|M|serotonin reuptake inhibitor.  Patients on these antidepressants should be|
01046|028|M|cautioned about and observed for the potential of developing serotonin|
01046|029|M|syndrome if they add St. John's wort to their regimen.|
01046|030|M|   If concurrent therapy is warranted, patients should be monitored for|
01046|031|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
01046|032|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
01046|033|M|heart palpitations, restlessness, confusion, agitation, trouble with|
01046|034|M|coordination, or severe diarrhea.|
01046|035|B||
01046|036|D|DISCUSSION:  In a case report, a patient had stopped taking paroxetine ten|
01046|037|D|days prior to initiating St. John's wort. The evening after initiating St.|
01046|038|D|John's wort, the patient took a paroxetine because she was having trouble|
01046|039|D|sleeping. At noon the next day, the patient was able to be awakened, but was|
01046|040|D|incoherent, groggy, slow-moving, and almost unable to get up. Two hours|
01046|041|D|later during an examination, she was groggy and lethargic, but able to|
01046|042|D|respond appropriately. She complained of nausea, weakness, and fatigue. Her|
01046|043|D|vital signs and physical exam were normal, except for a slow response time|
01046|044|D|and limp muscle tone. She did not take any additional paroxetine and was|
01046|045|D|normal the next day.(7)|
01046|046|D|   Serotonin syndrome has also been reported with concurrent St. John's wort|
01046|047|D|and nefazodone,(8) sertraline,(8) and venlafaxine.(9)  Mania has also been|
01046|048|D|reported with concurrent St. John's wort and sertraline.(10)|
01046|049|B||
01046|050|R|REFERENCES:|
01046|051|B||
01046|052|R|1.Muller WE, Rolli M, Schafer C, Hafner U. Effects of hypericum extract (LI|5
01046|053|R|  160) in biochemical models of antidepressant activity. Pharmacopsychiatry|5
01046|054|R|  1997 Sep;30 Suppl 2:102-7.|5
01046|055|R|2.Cott JM. In vitro receptor binding and enzyme inhibition by Hypericum|5
01046|056|R|  perforatum extract. Pharmacopsychiatry 1997 Sep;30 Suppl 2:108-12.|5
01046|057|R|3.Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and|5
01046|058|R|  hypericin. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S54-6.|5
01046|059|R|4.Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of|5
01046|060|R|  hypericum extract. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S57-9.|5
01046|061|R|5.Anonymous. St. John's wort. Med Lett Drugs Ther 1997 Nov 21;|6
01046|062|R|  39(1014):107-8.|6
01046|063|R|6.Perovic S, Muller WE. Pharmacological profile of hypericum extract. Effect|5
01046|064|R|  on serotonin uptake by postsynaptic receptors. Arzneimittelforschung 1995|5
01046|065|R|  Nov;45(11):1145-8.|5
01046|066|R|7.Gordon JB. SSRIs and St.John's Wort: possible toxicity?. Am Fam Physician|3
01046|067|R|  1998 Mar 1;57(5):950,953.|3
01046|068|R|8.Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant|3
01046|069|R|  drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999 Spring;|3
01046|070|R|  12(1):7-10.|3
01046|071|R|9.Prost N, Tichadou L, Rodor F, Nguyen N, David JM, Jean-Pastor MJ. St.|3
01046|072|R|  Johns wort-venlafaxine interaction. Presse Med 2000 Jul 1;29(23):1285-6.|3
01046|073|R|10.Barbenel DM, Yusufi B, O'Shea D, Bench CJ. Mania in a patient receiving|3
01046|074|R|   testosterone replacement postorchidectomy taking St John's wort and|3
01046|075|R|   sertraline. J Psychopharmacol 2000 Mar;14(1):84-6.|3
01047|001|T|MONOGRAPH TITLE:  Monoamine Oxidase Inhibitors/Ginseng|
01047|002|B||
01047|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01047|004|L|Assess the risk to the patient and take action as needed.|
01047|005|B||
01047|006|A|MECHANISM OF ACTION:  It has been shown that glycosides found in ginseng|
01047|007|A|(ginsenosides) inhibit cyclic adenosine monophosphate (AMP)|
01047|008|A|phosphodiesterase and may also affect cortical steroid secretion. These|
01047|009|A|effects are thought to partly account for the psychoactive effects of|
01047|010|A|ginsenosides.(4)|
01047|011|B||
01047|012|E|CLINICAL EFFECTS:  The concurrent administration of a monoamine oxidase|
01047|013|E|inhibitor and ginseng may result in changes in efficacy or unexpected toxic|
01047|014|E|effects of the monoamine oxidase inhibitor.|
01047|015|B||
01047|016|P|PREDISPOSING FACTORS:  None determined.|
01047|017|B||
01047|018|M|PATIENT MANAGEMENT:  Patients receiving both a monoamine oxidase inhibitor|
01047|019|M|(MAOI) and ginseng should be alerted to the possibility of toxicity or|
01047|020|M|changes in the effects of the MAOI. Consider monitoring the patient for|
01047|021|M|changes in clinical status or signs of toxicity (irritability, insomnia,|
01047|022|M|restlessness, hallucinations, movement disorders, severe headache, etc). The|
01047|023|M|dosage of the MAOI may need to be adjusted if ginseng is added to, or|
01047|024|M|discontinued from, concurrent therapy. Ginseng may need to be discontinued.|
01047|025|B||
01047|026|D|DISCUSSION:  Two cases of an interaction between ginseng and phenelzine have|
01047|027|D|been reported. In both cases, the patients developed signs of toxicity and|
01047|028|D|experienced changes in the effects of phenelzine after taking ginseng. In|
01047|029|D|the first case report, the patient was rechallenged with phenelzine alone|
01047|030|D|and experienced no side effects.(1) The second patient had previously taken|
01047|031|D|ginseng alone with no adverse effects and was also able to take phenelzine|
01047|032|D|with no adverse effects. Her symptoms returned upon rechallenge with the|
01047|033|D|combination of phenelzine and ginseng.(2,3)|
01047|034|D|   Methylene blue, when administered intravenously, has been shown to reach|
01047|035|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
01047|036|D|   Metaxalone is a weak inhibitor of MAO.|
01047|037|B||
01047|038|R|REFERENCES:|
01047|039|B||
01047|040|R|1.Nikaido T, Ohmoto T, Sankawa U, Tanaka O, Kasai R, Shoji J, Sanada S, Hiai|5
01047|041|R|  S, Yokoyama H, Oura H, et al. Inhibitors of cyclic AMP phosphodiesterase|5
01047|042|R|  in Panax ginseng C. A. Meyer and Panax japonicus C. A. Meyer. Chem Pharm|5
01047|043|R|  Bull (Tokyo) 1984 Apr;32(4):1477-83.|5
01047|044|R|2.Jones BD, Runikis AM. Interaction of ginseng with phenelzine. J Clin|3
01047|045|R|  Psychopharmacol 1987 Jun;7(3):201-2.|3
01047|046|R|3.Shader RI, Greenblatt DJ. Phenelzine and the dream machine--ramblings and|3
01047|047|R|  reflections. J Clin Psychopharmacol 1985 Apr;5(2):65.|3
01047|048|R|4.Shader RI, Greenblatt DJ. Bees, ginseng and MAOIs revisited. J Clin|3
01047|049|R|  Psychopharmacol 1988 Aug;8(4):235.|3
01047|050|R|5.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
01047|051|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
01047|052|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
01047|053|R|6.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
01047|054|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
01047|055|R|  2000 Jun;56(3):247-50.|2
01047|056|R|7.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
01047|057|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
01047|058|R|  Feb;34(2):346.e5-6.|3
01047|059|R|8.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
01047|060|R|  Pfizer Inc. January, 2024.|1
01048|001|T|MONOGRAPH TITLE:  Penicillins/Guar Gum; Khat|
01048|002|B||
01048|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01048|004|L|Assess the risk to the patient and take action as needed.|
01048|005|B||
01048|006|A|MECHANISM OF ACTION:  Guar gum may decrease the absorption of penicillins by|
01048|007|A|delaying gastric emptying along with possible mechanical interference in the|
01048|008|A|small intestine.(1)|
01048|009|A|   It has been suggested that penicillin-like antibiotics combine with|
01048|010|A|tannins, one of the alkaloids in khat leaves, to form an insoluble and|
01048|011|A|poorly absorbed complex. The tannins may also interfere with the|
01048|012|A|gastrointestinal absorption process.(2)|
01048|013|B||
01048|014|E|CLINICAL EFFECTS:  Concurrent use of penicillin antibiotics and khat may|
01048|015|E|decrease levels of the antibiotic leading to decreased efficacy.(2)|
01048|016|B||
01048|017|P|PREDISPOSING FACTORS:  None determined.|
01048|018|B||
01048|019|M|PATIENT MANAGEMENT:  The concurrent use of penicillins and guar gum is not|
01048|020|M|recommended. Separating the drugs by two to four hours may reduce the|
01048|021|M|decrease in absorption.  Patients should be monitored for decreased|
01048|022|M|penicillin levels and decreased efficacy.  The dose of penicillin may need|
01048|023|M|to be increased or the guar gum discontinued until the course of penicillin|
01048|024|M|is finished.(1)|
01048|025|M|   Separating the dosing of antibiotics by two hours after chewing khat may|
01048|026|M|reduce the potential for decreased absorption. Monitoring of antibiotic|
01048|027|M|levels and/or efficacy may be required.(2)|
01048|028|B||
01048|029|D|DISCUSSION:  In one study involving ten healthy patients, it was found that|
01048|030|D|the concurrent administration of penicillin V with guar gum resulted in|
01048|031|D|decreases in the penicillin area-under-curve (AUC) and maximum concentration|
01048|032|D|(Cmax) by 28.4% and 24.9%, respectively.(1)|
01048|033|D|   In one study involving eight patients it was shown that the absorption of|
01048|034|D|ampicillin was significantly reduced when given concurrently with khat. The|
01048|035|D|same study also showed a significant decrease in the absorption of|
01048|036|D|amoxicillin under the same circumstances, but to a lesser extent than with|
01048|037|D|ampicillin.(2)|
01048|038|B||
01048|039|R|REFERENCES:|
01048|040|B||
01048|041|R|1.Attef OA, Ali AA, Ali HM. Effect of Khat chewing on the bioavailability of|2
01048|042|R|  ampicillin and amoxycillin. J Antimicrob Chemother 1997 Apr;39(4):523-5.|2
01048|043|R|2.Huupponen R, Seppala P, Iisalo E. Effect of guar gum, a fibre preparation,|2
01048|044|R|  on digoxin and penicillin absorption in man. Eur J Clin Pharmacol 1984;|2
01048|045|R|  26(2):279-81.|2
01049|001|T|MONOGRAPH TITLE:  Penicillins/Guar Gum (mono deleted 12/26/2013)|
01049|002|B||
01049|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01049|004|L|Assess the risk to the patient and take action as needed.|
01049|005|B||
01049|006|A|MECHANISM OF ACTION:  Guar gum may decrease the absorption of penicillins by|
01049|007|A|delaying gastric emptying along with possible mechanical interference in the|
01049|008|A|small intestine.(1)|
01049|009|B||
01049|010|E|CLINICAL EFFECTS:  The concurrent use of penicillins and guar gum may result|
01049|011|E|in decreased absorption of penicillins causing a decrease in serum|
01049|012|E|levels.(1)|
01049|013|B||
01049|014|P|PREDISPOSING FACTORS:  None determined.|
01049|015|B||
01049|016|M|PATIENT MANAGEMENT:  The concurrent use of penicillins and guar gum is not|
01049|017|M|recommended. Separating the drugs by two to four hours may reduce the|
01049|018|M|decrease in absorption.  Patients should be monitored for decreased|
01049|019|M|penicillin levels and decreased efficacy.  The dose of penicillin may need|
01049|020|M|to be increased or the guar gum discontinued until the course of penicillin|
01049|021|M|is finished.(1)|
01049|022|B||
01049|023|D|DISCUSSION:  In one study involving ten healthy patients, it was found that|
01049|024|D|the concurrent administration of penicillin V with guar gum resulted in|
01049|025|D|decreases in the penicillin area-under-curve (AUC) and maximum concentration|
01049|026|D|(Cmax) by 28.4% and 24.9%, respectively.(1)|
01049|027|B||
01049|028|R|REFERENCE:|
01049|029|B||
01049|030|R|1.Huupponen R, Seppala P, Iisalo E. Effect of guar gum, a fibre preparation,|2
01049|031|R|  on digoxin and penicillin absorption in man. Eur J Clin Pharmacol 1984;|2
01049|032|R|  26(2):279-81.|2
01050|001|T|MONOGRAPH TITLE:  Benzodiazepines/Kava|
01050|002|B||
01050|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01050|004|L|Assess the risk to the patient and take action as needed.|
01050|005|B||
01050|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown. The alpha-pyrones in|
01050|007|A|kava may have a synergistic effect on other sedatives that mediate the gamma|
01050|008|A|amino-butyric acid (GABA) receptors.(1-2)|
01050|009|B||
01050|010|E|CLINICAL EFFECTS:  The concurrent administration of benzodiazepines and kava|
01050|011|E|may result in increased effects of these agents, including lethargy and|
01050|012|E|disorientation.(1)  Concurrent use may result in additive CNS depression and|
01050|013|E|may result in profound sedation, respiratory depression, coma, and/or death.|
01050|014|B||
01050|015|P|PREDISPOSING FACTORS:  None determined.|
01050|016|B||
01050|017|M|PATIENT MANAGEMENT:  Patients receiving both benzodiazepines and kava should|
01050|018|M|be alerted to the possibility of increased effects of these agents. One or|
01050|019|M|both agents may need to be discontinued.|
01050|020|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
01050|021|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
01050|022|M|unresponsiveness.|
01050|023|B||
01050|024|D|DISCUSSION:  In a single case report, a 54 year-old male presented to the|
01050|025|D|emergency room in a lethargic, disoriented, and semicomatose state three|
01050|026|D|days after the addition of kava to his medication regimen that included|
01050|027|D|alprazolam.  The patient became more alert over several hours.(3)|
01050|028|B||
01050|029|R|REFERENCES:|
01050|030|B||
01050|031|R|1.Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper|5
01050|032|R|  methysticum as modulator of the GABA binding site in different regions of|5
01050|033|R|  rat brain. Psychopharmacology (Berl) 1994 Dec;116(4):469-74.|5
01050|034|R|2.Jamieson DD, Duffield PH. The antinociceptive actions of kava components|5
01050|035|R|  in mice. Clin Exp Pharmacol Physiol 1990 Jul;17(7):495-507.|5
01050|036|R|3.Almeida JC, Grimsley EW. Coma from the health food store: interaction|3
01050|037|R|  between kava and alprazolam. Ann Intern Med 1996 Dec 1;125(11):940-1.|3
01051|001|T|MONOGRAPH TITLE:  Lithium/Psyllium|
01051|002|B||
01051|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01051|004|L|Assess the risk to the patient and take action as needed.|
01051|005|B||
01051|006|A|MECHANISM OF ACTION:  It has been suggested that psyllium maintains hydrated|
01051|007|A|feces, therefore a greater amount of lithium remains ionized and cannot be|
01051|008|A|absorbed.(1)|
01051|009|B||
01051|010|E|CLINICAL EFFECTS:  The concurrent use of lithium and psyllium may result in|
01051|011|E|decreased lithium levels and decreased efficacy.(1)|
01051|012|B||
01051|013|P|PREDISPOSING FACTORS:  None determined.|
01051|014|B||
01051|015|M|PATIENT MANAGEMENT:  Patient's lithium levels should be carefully monitored.|
01051|016|M|Dosage adjustments of lithium may be necessary. It may also be necessary to|
01051|017|M|consider an alternative laxative choice.(1)|
01051|018|B||
01051|019|D|DISCUSSION:  In a case report, a patient was initiated on lithium and|
01051|020|D|psyllium containing laxative. The lithium level four days later was|
01051|021|D|insufficient, at 0.53 mmol/L. The lithium dose was increased, but the|
01051|022|D|patient's lithium level continued to decrease, to 0.40 mmol/L five days|
01051|023|D|later. The psyllium was discontinued and the lithium dose was maintained at|
01051|024|D|the same dose. The lithium level rose after four days to 0.76 mmol/L.(1)|
01051|025|B||
01051|026|R|REFERENCE:|
01051|027|B||
01051|028|R|1.Perlman BB. Interaction between lithium salts and ispaghula husk. Lancet|3
01051|029|R|  1990 Feb 17;335(8686):416.|3
01052|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Ginseng|
01052|002|B||
01052|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01052|004|L|Assess the risk to the patient and take action as needed.|
01052|005|B||
01052|006|A|MECHANISM OF ACTION:  Ginseng contains eleutherosides, which are chemically|
01052|007|A|related to digitalis glycosides, such as digoxin, and may have an additive|
01052|008|A|effect with digoxin.(1)|
01052|009|B||
01052|010|E|CLINICAL EFFECTS:  The concurrent administration of digitalis glycosides and|
01052|011|E|ginseng may result in increased serum levels of digoxin and possible|
01052|012|E|digitalis glycoside toxicity. Symptoms of digoxin toxicity can include|
01052|013|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
01052|014|E|generalized muscle weakness, disorientation, hallucinations, visual|
01052|015|E|disturbances, and arrhythmias.|
01052|016|B||
01052|017|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
01052|018|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
01052|019|P|risk of digoxin toxicity.|
01052|020|B||
01052|021|M|PATIENT MANAGEMENT:  Patients receiving both a digitalis glycoside and|
01052|022|M|ginseng should be alerted to the possibility of increased levels and|
01052|023|M|possible digitalis glycoside toxicity. Consider monitoring digitalis|
01052|024|M|glycoside levels during concurrent therapy. The dosage of the digitalis|
01052|025|M|glycoside may need to be adjusted if ginseng is added to or discontinued|
01052|026|M|from concurrent therapy. Ginseng may need to be discontinued.|
01052|027|B||
01052|028|D|DISCUSSION:  In a case report, ginseng was shown to increase serum digoxin|
01052|029|D|levels in a patient. The patient had previously had stable digoxin levels|
01052|030|D|between 0.9 and 2.2 nmol/L for over ten years. On a routine office visit,|
01052|031|D|the patient's digoxin level was found to be 5.2 nmol/L, with no signs of|
01052|032|D|digoxin toxicity.  Digoxin was stopped, then resumed at a decrease dosage,|
01052|033|D|and finally discontinued on day 10.  On day 25, the patient's digoxin level|
01052|034|D|was 4.5 nmol/L.  The patient reported that he had been taking Siberian|
01052|035|D|ginseng since the previous summer.  Ginseng was discontinued and the|
01052|036|D|patient's digoxin level decreased to 4.0 nmol/L on day 28 and to 2.2 nmol/L|
01052|037|D|on day 33.  Digoxin was reintroduced at a dosage of 0.125 mg alternating|
01052|038|D|with 0.25 mg, with a digoxin level between 0.8 and 1.1 nmol/L.  Thirty-six|
01052|039|D|days after restarting ginseng, the patient's digoxin level had increased to|
01052|040|D|1.9 nmol/L.  This further increased to 3.2 nmol/L 53 days later.  The|
01052|041|D|ginseng was discontinued and six days later the patient's digoxin level was|
01052|042|D|1.2 nmol/L.  No digoxin or digitoxin contamination was found in the ginseng|
01052|043|D|capsules.(1)|
01052|044|B||
01052|045|R|REFERENCE:|
01052|046|B||
01052|047|R|1.McRae S. Elevated serum digoxin levels in a patient taking digoxin and|3
01052|048|R|  Siberian ginseng. CMAJ 1996 Aug 1;155(3):293-5.|3
01053|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Guar Gum|
01053|002|B||
01053|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01053|004|L|Assess the risk to the patient and take action as needed.|
01053|005|B||
01053|006|A|MECHANISM OF ACTION:  Guar gum may bind to bile acids, causing a decrease in|
01053|007|A|serum digitalis glycoside levels.(1)|
01053|008|B||
01053|009|E|CLINICAL EFFECTS:  Concurrent use of guar gum and digitalis glycosides may|
01053|010|E|result in significantly lower levels of the digitalis glycoside, potentially|
01053|011|E|causing a decrease in efficacy.(1)|
01053|012|B||
01053|013|P|PREDISPOSING FACTORS:  None determined.|
01053|014|B||
01053|015|M|PATIENT MANAGEMENT:  Separating the dose of the digitalis glycoside from the|
01053|016|M|guar gum by two to four hours may help reduce the potential for decreased|
01053|017|M|absorption. Patients on both medications should be monitored for decreased|
01053|018|M|digitalis glycoside levels and decreased efficacy.(1)|
01053|019|B||
01053|020|D|DISCUSSION:  In one study involving 10 patients it was found that concurrent|
01053|021|D|use of digoxin and guar gum resulted in a decrease in digoxin|
01053|022|D|area-under-curve (AUC) and maximum concentration (Cmax) by 16% and 21%,|
01053|023|D|respectively.(1) In another study in 11 patients, there was found to be no|
01053|024|D|significant decrease in serum digoxin concentrations when given with guar(2)|
01053|025|D|gum.|
01053|026|B||
01053|027|R|REFERENCE:|
01053|028|B||
01053|029|R|1.Huupponen R, Seppala P, Iisalo E. Effect of guar gum, a fibre preparation,|2
01053|030|R|  on digoxin and penicillin absorption in man. Eur J Clin Pharmacol 1984;|2
01053|031|R|  26(2):279-81.|2
01054|001|T|MONOGRAPH TITLE:  Selected Digitalis Glycosides/St. John's Wort|
01054|002|B||
01054|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01054|004|L|Assess the risk to the patient and take action as needed.|
01054|005|B||
01054|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of digitalis|
01054|007|A|glycosides by the CYP P-450 isoenzyme system.(1)|
01054|008|B||
01054|009|E|CLINICAL EFFECTS:  The concurrent administration of digitalis glycosides and|
01054|010|E|St. John's wort may result in decreased levels and clinical effects of|
01054|011|E|digoxin/digitoxin.(1)|
01054|012|B||
01054|013|P|PREDISPOSING FACTORS:  None determined.|
01054|014|B||
01054|015|M|PATIENT MANAGEMENT:  Patients receiving both a digitalis glycoside and St.|
01054|016|M|John's wort should be alerted to the possibility of decreased effects of the|
01054|017|M|cardiac glycoside.(1) Consider monitoring digitalis glycoside levels during|
01054|018|M|concurrent therapy. The dosage of the digitalis glycoside may need to be|
01054|019|M|adjusted if St. John's wort is added to or discontinued from concurrent|
01054|020|M|therapy. St. John's wort may need to be discontinued.|
01054|021|B||
01054|022|D|DISCUSSION:  St. John's wort has been shown to decrease levels of indinavir|
01054|023|D|in healthy subjects.(2)  Because the digitalis glycosides are metabolized by|
01054|024|D|the same metabolic pathway, the FDA recommends that patients taking digoxin|
01054|025|D|or digitoxin be alerted to the possibility of a drug interaction resulting|
01054|026|D|in decreased levels of the digitalis glycoside.(1)|
01054|027|B||
01054|028|R|REFERENCES:|
01054|029|B||
01054|030|R|1.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
01054|031|R|  283(13):1679.|1
01054|032|R|2.Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir|2
01054|033|R|  concentrations and St John's wort. Lancet 2000 Feb 12;355(9203):547-8.|2
01055|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Kyushin|
01055|002|B||
01055|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01055|004|L|Assess the risk to the patient and take action as needed.|
01055|005|B||
01055|006|A|MECHANISM OF ACTION:  Kyushin is composed mostly of chan-su, which contains|
01055|007|A|bufalin.(1,2) Bufalin has a chemical structure similar to digoxin. This can|
01055|008|A|cause laboratory values for the digitalis glycosides to be falsely elevated|
01055|009|A|or decreased.|
01055|010|B||
01055|011|E|CLINICAL EFFECTS:  Serum monitoring is an important part of therapy.|
01055|012|E|Inaccurate values could lead to inappropriate changes in therapy, causing|
01055|013|E|insufficient or excessive digitalis glycoside dosages. Symptoms of digoxin|
01055|014|E|toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise,|
01055|015|E|drowsiness, generalized muscle weakness, disorientation, hallucinations,|
01055|016|E|visual disturbances, and arrhythmias.|
01055|017|B||
01055|018|P|PREDISPOSING FACTORS:  None determined.|
01055|019|B||
01055|020|M|PATIENT MANAGEMENT:  Serum levels should be carefully evaluated in patients|
01055|021|M|receiving both digitalis glycosides and kyushin and the patient's clinical|
01055|022|M|status should be carefully assessed.|
01055|023|B||
01055|024|D|DISCUSSION:  In a case report a patient with heart failure was treated with|
01055|025|D|digoxin. The patient was also self-medicating with kyushin. Digoxin|
01055|026|D|monitoring revealed an elevated level without signs or symptoms of toxicity.|
01055|027|D|(3) A study found that in patients receiving kyushin alone digoxin|
01055|028|D|monitoring revealed a near therapeutic digoxin level.(1) Another study|
01055|029|D|showed that bufalin falsely decreased serum digoxin levels.(4) The same|
01055|030|D|study found that bufalin falsely elevated serum digoxin levels when using a|
01055|031|D|different assessment tool.(4)|
01055|032|B||
01055|033|R|REFERENCES:|
01055|034|B||
01055|035|R|1.Fushimi R, Koh T, Iyama S, Yasuhara M, Tachi J, Kohda K, Amino N, Miyai K.|5
01055|036|R|  Digoxin-like immunoreactivity in Chinese medicine. Ther Drug Monit 1990|5
01055|037|R|  May;12(3):242-5.|5
01055|038|R|2.Bagrov AY, Roukoyatkina NI, Fedorova OV, Pinaev AG, Ukhanova MV.|5
01055|039|R|  Digitalis-like and vasoconstrictor effects of endogenous digoxin-like|5
01055|040|R|  factor(s) from the venom of Bufo marinus toad. Eur J Pharmacol 1993 Apr 6;|5
01055|041|R|  234(2-3):165-72.|5
01055|042|R|3.Fushimi R, Tachi J, Amino N, Miyai K. Chinese medicine interfering with|3
01055|043|R|  digoxin immunoassays. Lancet 1989 Feb 11;1(8633):339.|3
01055|044|R|4.Dasgupta A, Scott J. Unexpected suppression of total digoxin|5
01055|045|R|  concentrations by cross- reactants in the microparticle enzyme|5
01055|046|R|  immunoassay: elimination of interference by monitoring free digoxin|5
01055|047|R|  concentration. Am J Clin Pathol 1998 Jul;110(1):78-82.|5
01056|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Psyllium|
01056|002|B||
01056|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01056|004|L|Assess the risk to the patient and take action as needed.|
01056|005|B||
01056|006|A|MECHANISM OF ACTION:  Psyllium may bind physically to the digitalis|
01056|007|A|glycosides, preventing their absorption.(1)|
01056|008|B||
01056|009|E|CLINICAL EFFECTS:  Decreased absorption may result in significantly lower|
01056|010|E|digitalis glycoside levels and thus a decrease in efficacy.(1)|
01056|011|B||
01056|012|P|PREDISPOSING FACTORS:  None determined.|
01056|013|B||
01056|014|M|PATIENT MANAGEMENT:  A two hour interval between dosage with these drugs may|
01056|015|M|prevent the interaction.  Patients should be monitored for decreased|
01056|016|M|digitalis glycoside levels and decreased efficacy.  It may be necessary to|
01056|017|M|discontinue psyllium use.(1)|
01056|018|B||
01056|019|D|DISCUSSION:  In a single dose study in 10 normal adults it was found that|
01056|020|D|coadministration of psyllium and digoxin reduced the bioavailability of|
01056|021|D|digoxin when compared to the administration of digoxin alone.(1)|
01056|022|D|Conversely, in another study focusing on the influence of a psyllium|
01056|023|D|formulation (vi-Siblin S, Parke-Davis) on the steady state concentrations of|
01056|024|D|plasma digoxin in geriatric patients, digoxin levels were not significantly|
01056|025|D|affected at 2 and 4 weeks.(2)|
01056|026|B||
01056|027|R|REFERENCES:|
01056|028|B||
01056|029|R|1.Brown DD, Juhl RP. Altered bioavailability of digoxin produced by|2
01056|030|R|  gastrointestinal medications. Clin Res 1979;27:610A.|2
01056|031|R|2.Nordstrom M, Melander A, Robertsson E, Steen B. Influence of wheat bran|2
01056|032|R|  and of a bulk-forming ispaghula cathartic on the bioavailability of|2
01056|033|R|  digoxin in geriatric in-patients. Drug Nutr Interact 1987;5(2):67-9.|2
01057|001|T|MONOGRAPH TITLE:  Loop Diuretics/Ginseng|
01057|002|B||
01057|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01057|004|L|Assess the risk to the patient and take action as needed.|
01057|005|B||
01057|006|A|MECHANISM OF ACTION:  The long-term use of germanium, a component of many|
01057|007|A|ginseng preparations, has been associated with chronic renal failure.(1)|
01057|008|A|Damage to the thick ascending loop of Henle may lessen the effect of loop|
01057|009|A|diuretics.(1,2)|
01057|010|B||
01057|011|E|CLINICAL EFFECTS:  The concurrent administration of loop diuretics and|
01057|012|E|ginseng preparations may result in significant fluid retention resulting in|
01057|013|E|edema and/or hypertension.|
01057|014|B||
01057|015|P|PREDISPOSING FACTORS:  None determined.|
01057|016|B||
01057|017|M|PATIENT MANAGEMENT:  Patients maintained on loop diuretics should be|
01057|018|M|cautioned that the concurrent use of ginseng preparations may result in|
01057|019|M|renal failure. The patient's renal status should be carefully monitored.|
01057|020|M|Ginseng may need to be discontinued.|
01057|021|B||
01057|022|D|DISCUSSION:  In a case report, a patient maintained on furosemide and|
01057|023|D|cyclosporine was hospitalized with significant weight gain and hypertension|
01057|024|D|after initiating nutritional supplements including 10 to 12 tablets daily of|
01057|025|D|germanium-containing Korean ginseng. The patient's ginseng was discontinued|
01057|026|D|and the patient was stabilized and discharged. The patient restarted the|
01057|027|D|ginseng after discharge. He was readmitted with the same symptoms 14 days|
01057|028|D|later. Symptoms resolved when nutritional supplements were discontinued and|
01057|029|D|intravenous diuretics were administered.(3)|
01057|030|B||
01057|031|R|REFERENCES:|
01057|032|B||
01057|033|R|1.Sanai T, Okuda S, Onoyama K, Oochi N, Oh Y, Kobayashi K, Shimamatsu K,|3
01057|034|R|  Fujimi S, Fujishima M. Germanium dioxide-induced nephropathy: a new type|3
01057|035|R|  of renal disease. Nephron 1990;54(1):53-60.|3
01057|036|R|2.Okada K, Okagawa K, Kawakami K, Kuroda Y, Morizumi K, Sato H, Morita H,|3
01057|037|R|  Shimomura S, Saito S. Renal failure caused by long-term use of a germanium|3
01057|038|R|  preparation as an elixir. Clin Nephrol 1989 Apr;31(4):219-24.|3
01057|039|R|3.Becker BN, Greene J, Evanson J, Chidsey G, Stone WJ. Ginseng-induced|3
01057|040|R|  diuretic resistance. JAMA 1996 Aug 28;276(8):606-7.|3
01058|001|T|MONOGRAPH TITLE:  Corticosteroids/Glycyrrhiza (Licorice)|
01058|002|B||
01058|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01058|004|L|Assess the risk to the patient and take action as needed.|
01058|005|B||
01058|006|A|MECHANISM OF ACTION:  Glycyrrhizic acid, the active form of glycyrrhizin (a|
01058|007|A|compound found in licorice), has been shown to inhibit the enzyme which|
01058|008|A|catalyzes the oxidation of the 11-betahydroxycorticosteroids to their|
01058|009|A|inactive metabolites.(1,2)|
01058|010|B||
01058|011|E|CLINICAL EFFECTS:  The concurrent administration of corticosteroids|
01058|012|E|(prednisolone, beclomethasone, betamethasone, budesonide, etc) with products|
01058|013|E|containing glycyrrhiza (commonly known as licorice) may result in increased,|
01058|014|E|decreased, or no changes in corticosteroid levels.|
01058|015|B||
01058|016|P|PREDISPOSING FACTORS:  None determined.|
01058|017|B||
01058|018|M|PATIENT MANAGEMENT:  Patients receiving both a corticosteroid and|
01058|019|M|glycyrrhizic-containing compounds should be altered to the possibility of|
01058|020|M|increased or decreased effects of the corticosteroid. Observe the patient|
01058|021|M|for loss of the therapeutic effect or increased side effects of the|
01058|022|M|corticosteroid during concurrent therapy. The dose of the corticosteroid may|
01058|023|M|need to be adjusted if glycyrrhiza is added to or discontinued from|
01058|024|M|concurrent therapy. Glycyrrhiza may need to be discontinued.|
01058|025|B||
01058|026|D|DISCUSSION:  Glycyrrhiza has been shown to alter the pharmacokinetics of|
01058|027|D|prednisolone in healthy subjects. Three different preparations containing|
01058|028|D|glycyrrhizin were shown to increase, decrease, or not change the AUC of|
01058|029|D|prednisolone, as well as the concentration ratio of prednisone to|
01058|030|D|prednisolone.(3) Because other corticosteroids are pharmacologically and|
01058|031|D|structurally similar to prednisolone, an interaction may be expected to|
01058|032|D|occur between glycyrrhiza and other corticosteroids (beclomethasone,|
01058|033|D|betamethasone, budesonide, etc).|
01058|034|B||
01058|035|R|REFERENCES:|
01058|036|B||
01058|037|R|1.Monder C, Stewart PM, Lakshmi V, Valentino R, Burt D, Edwards CR. Licorice|5
01058|038|R|  inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: in|5
01058|039|R|  vivo and in vitro studies. Endocrinology 1989 Aug;125(2):1046-53.|5
01058|040|R|2.Edwards CR, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, de Kloet|5
01058|041|R|  ER, Monder C. Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue|5
01058|042|R|  specific protector of the mineralocorticoid receptor. Lancet 1988 Oct 29;|5
01058|043|R|  2(8618):986-9.|5
01058|044|R|3.Homma M, Oka K, Ikeshima K, Takahashi N, Niitsuma T, Fukuda T, Itoh H.|2
01058|045|R|  Different effects of traditional Chinese medicines containing similar|2
01058|046|R|  herbal constituents on prednisolone pharmacokinetics. J Pharm Pharmacol|2
01058|047|R|  1995 Aug;47(8):687-92.|2
01059|001|T|MONOGRAPH TITLE:  Antidiabetic Agents/Fenugreek|
01059|002|B||
01059|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01059|004|L|Assess the risk to the patient and take action as needed.|
01059|005|B||
01059|006|A|MECHANISM OF ACTION:  The mechanism of action of fenugreek's hypoglycemic|
01059|007|A|effect is not known.|
01059|008|B||
01059|009|E|CLINICAL EFFECTS:  The additive glucose lowering effect resulting from|
01059|010|E|concurrent use of these agents may result in hypoglycemia.|
01059|011|B||
01059|012|P|PREDISPOSING FACTORS:  The antidiabetic effects of fenugreek may be greater|
01059|013|P|in patients with mild diabetes.|
01059|014|B||
01059|015|M|PATIENT MANAGEMENT:  Patients receiving both antidiabetic agents and|
01059|016|M|fenugreek should be alerted to the possibility of the occurrence of|
01059|017|M|hypoglycemic events and how to respond if they experience hypoglycemia. The|
01059|018|M|dosage of antidiabetic agents may need to be adjusted and/or the fenugreek|
01059|019|M|may need to be discontinued.|
01059|020|B||
01059|021|D|DISCUSSION:  In a study involving 80 patients with type 2 diabetes mellitus|
01059|022|D|it was found that fenugreek significantly decreased fasting and postprandial|
01059|023|D|blood sugars in patients with mild diabetes. After one month, fasting and|
01059|024|D|post-prandial blood sugar measurements decreased from 174.4+/-9.3 to|
01059|025|D|142.0+/-9.5 and from 246.4+/-8.7 to 213+/-9.6, respectively. While there|
01059|026|D|were small changes in fasting and post-prandial blood sugar measurements|
01059|027|D|after one month of fenugreek in patients with severe type 2 diabetes|
01059|028|D|mellitus, these changes were not statistically significant.(1)|
01059|029|D|  In a study involving patients with type 1 diabetes mellitus, the addition|
01059|030|D|of fenugreek (100 grams daily) significantly reduced fasting blood sugar and|
01059|031|D|improved the glucose tolerance test. There was a 54 per cent reduction in|
01059|032|D|the 24 hour urinary glucose excretion.(2)|
01059|033|B||
01059|034|R|REFERENCES:|
01059|035|B||
01059|036|R|1.Bordia A, Verma SK, Srivastava KC. Effect of ginger (Zingiber officinale|2
01059|037|R|  Rosc.) and fenugreek (Trigonella foenumgraecum L.) on blood lipids, blood|2
01059|038|R|  sugar and platelet aggregation in patients with coronary artery disease.|2
01059|039|R|  Prostaglandins Leukot Essent Fatty Acids 1997 May;56(5):379-84.|2
01059|040|R|2.Sharma RD, Raghuram TC, Rao NS. Effect of fenugreek seeds on blood glucose|2
01059|041|R|  and serum lipids in type I diabetes. Eur J Clin Nutr 1990 Apr;44(4):301-6.|2
01060|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants; Temsirolimus/St. John's Wort|
01060|002|T|(mono deleted 11/01/2012)|
01060|003|B||
01060|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01060|005|L|take action as needed.|
01060|006|B||
01060|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01060|008|A|cyclosporine, sirolimus, tacrolimus, and temsirolimus.(1,2)|
01060|009|B||
01060|010|E|CLINICAL EFFECTS:  The concurrent administration of St. John's wort may|
01060|011|E|result in decreased levels and clinical effectiveness of cyclosporine,|
01060|012|E|sirolimus, tacrolimus, and temsirolimus.(1)|
01060|013|B||
01060|014|P|PREDISPOSING FACTORS:  None determined.|
01060|015|B||
01060|016|M|PATIENT MANAGEMENT:  The US manufacturer of temsirolimus states that|
01060|017|M|patients receiving temsirolimus should not take St. John's wort.(2)  It|
01060|018|M|would be prudent to follow this advice for cyclosporine, sirolimus, and|
01060|019|M|tacrolimus.|
01060|020|M|   Patients who insist on taking St. John's wort should be alerted to the|
01060|021|M|possibility of decreased effects of cyclosporine, sirolimus, tacrolimus, and|
01060|022|M|temsirolimus and possible therapeutic failure, including, in the case of|
01060|023|M|cyclosporine, sirolimus, and tacrolimus, possible graft loss.(1)|
01060|024|M|   Monitor blood levels during concurrent therapy.  Dosages may need to be|
01060|025|M|adjusted if St. John's wort is added to or discontinued from concurrent|
01060|026|M|therapy. St. John's wort may need to be discontinued.|
01060|027|B||
01060|028|D|DISCUSSION:  In an open-label study in 11 renal transplant patients,|
01060|029|D|subjects received St. John's wort (600 mg daily) for 14 days in addition to|
01060|030|D|their normal cyclosporine regimen.  After 14 days of St. John's wort,|
01060|031|D|dose-corrected cyclosporine area-under-curve (AUC), maximum concentration|
01060|032|D|(Cmax), and minimum concentration (Cmin) decreased by 46%, 42%, and 41%,|
01060|033|D|respectively.  Mean cyclosporine dose increased from 2.7 mg/kg/day at 4.2|
01060|034|D|mg/kg/day at the end of the study.  Subjects required their first|
01060|035|D|cyclosporine dosage adjustment at Day 3.(3)|
01060|036|D|   In a study in 10 healthy subjects, pretreatment with St. John's wort (300|
01060|037|D|mg 3 times daily for 18 days) decreased the AUC of a single dose of|
01060|038|D|tacrolimus (0.1 mg/kg) by 35.3%.  Tacrolimus apparent oral clearance and|
01060|039|D|volume of distribution increased by 68% and 53%, respectively.(4)|
01060|040|D|   In a study in 10 renal transplant patients, concurrent St. John's wort|
01060|041|D|(600 mg daily) for 2 weeks increased tacrolimus dose requirements from a|
01060|042|D|baseline of 4.5 mg/day to 8.0 mg/day.  Dose-correct tacrolimus AUC decreased|
01060|043|D|by 57.8%.(5)|
01060|044|D|   There have been several case reports of interactions between St. John's|
01060|045|D|wort and cyclosporine(6-16) and tacrolimus.(17)|
01060|046|B||
01060|047|R|REFERENCES:|
01060|048|B||
01060|049|R|1.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
01060|050|R|  283(13):1679.|1
01060|051|R|2.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01060|052|R|  Inc. May, 2012.|1
01060|053|R|3.Bauer S, Stormer E, Johne A, Kruger H, Budde K, Neumayer HH, Roots I, Mai|2
01060|054|R|  I. Alterations in cyclosporin A pharmacokinetics and metabolism during|2
01060|055|R|  treatment with St John's wort in renal transplant patients. Br J Clin|2
01060|056|R|  Pharmacol 2003 Feb;55(2):203-11.|2
01060|057|R|4.Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John's|2
01060|058|R|  wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy|2
01060|059|R|  volunteers. J Clin Pharmacol 2004 Jan;44(1):89-94.|2
01060|060|R|5.Mai I, Stormer E, Bauer S, Kruger H, Budde K, Roots I. Impact of St John's|2
01060|061|R|  wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid|2
01060|062|R|  in renal transplant patients. Nephrol Dial Transplant 2003 Apr;|2
01060|063|R|  18(4):819-22.|2
01060|064|R|6.Alscher DM, Klotz U. Drug interaction of herbal tea containing St. John's|3
01060|065|R|  wort with cyclosporine. Transpl Int 2003 Jul;16(7):543-4.|3
01060|066|R|7.Turton-Weeks SM, Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz|3
01060|067|R|  SR. St John's wort: a hidden risk for transplant patients. Prog Transplant|3
01060|068|R|  2001 Jun;11(2):116-20.|3
01060|069|R|8.Moschella C, Jaber BL. Interaction between cyclosporine and Hypericum|3
01060|070|R|  perforatum (St. John's wort) after organ transplantation. Am J Kidney Dis|3
01060|071|R|  2001 Nov;38(5):1105-7.|3
01060|072|R|9.Beer AM, Ostermann T. St. John's wort: interaction with cyclosporine|3
01060|073|R|  increases risk of rejection for the kidney transplant and raises daily|3
01060|074|R|  cost of medication. Med Klin (Munich) 2001 Aug 15;96(8):480-3.|3
01060|075|R|10.Ahmed SM, Banner NR, Dubrey SW. Low cyclosporin-A level due to|3
01060|076|R|   Saint-John's-wort in heart transplant patients. J Heart Lung Transplant|3
01060|077|R|   2001 Jul;20(7):795.|3
01060|078|R|11.Karliova M, Treichel U, Malago M, Frilling A, Gerken G, Broelsch CE.|3
01060|079|R|   Interaction of Hypericum perforatum (St. John's wort) with cyclosporin A|3
01060|080|R|   metabolism in a patient after liver transplantation. J Hepatol 2000 Nov;|3
01060|081|R|   33(5):853-5.|3
01060|082|R|12.Mai I, Kruger H, Budde K, Johne A, Brockmoller J, Neumayer HH, Roots I.|3
01060|083|R|   Hazardous pharmacokinetic interaction of Saint John's wort (Hypericum|3
01060|084|R|   perforatum) with the immunosuppressant cyclosporin. Int J Clin Pharmacol|3
01060|085|R|   Ther 2000 Oct;38(10):500-2.|3
01060|086|R|13.Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. Drug|3
01060|087|R|   interaction between St. John's wort and cyclosporine. Ann Pharmacother|3
01060|088|R|   2000 Sep;34(9):1013-6.|3
01060|089|R|14.Mandelbaum A, Pertzborn F, Martin-Facklam M, Wiesel M. Unexplained|3
01060|090|R|   decrease of cyclosporin trough levels in a compliant renal transplant|3
01060|091|R|   patient. Nephrol Dial Transplant 2000 Sep;15(9):1473-4.|3
01060|092|R|15.Breidenbach T, Kliem V, Burg M, Radermacher J, Hoffmann MW, Klempnauer J.|3
01060|093|R|   Profound drop of cyclosporin A whole blood trough levels caused by St.|3
01060|094|R|   John's wort (Hypericum perforatum). Transplantation 2000 May 27;|3
01060|095|R|   69(10):2229-30.|3
01060|096|R|16.Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G. Acute heart|3
01060|097|R|   transplant rejection due to Saint John's wort. Lancet 2000 Feb 12;|3
01060|098|R|   355(9203):548-9.|3
01060|099|R|17.Bolley R, Zulke C, Kammerl M, Fischereder M, Kramer BK.|3
01060|100|R|   Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4|3
01060|101|R|   system with St John's wort. Transplantation 2002 Mar 27;73(6):1009.|3
01061|001|T|MONOGRAPH TITLE:  Delavirdine; Nevirapine/St. John's Wort|
01061|002|B||
01061|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01061|004|L|is contraindicated and generally should not be dispensed or administered to|
01061|005|L|the same patient.|
01061|006|B||
01061|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01061|008|A|delavirdine and nevirapine by CYP3A4.(1-3)|
01061|009|B||
01061|010|E|CLINICAL EFFECTS:  The concurrent administration of delavirdine or|
01061|011|E|nevirapine and St. John's wort may result in decreased levels and clinical|
01061|012|E|effects of delavirdine and nevirapine.(1-3)|
01061|013|B||
01061|014|P|PREDISPOSING FACTORS:  None determined.|
01061|015|B||
01061|016|M|PATIENT MANAGEMENT:  The US manufacturers of delavirdine(2) and|
01061|017|M|nevirapine(3) state that these agents should not be administered with St.|
01061|018|M|John's wort.|
01061|019|M|   Patients receiving both of these medications should be alerted to the the|
01061|020|M|possibility of decreased effects of the NNRTI.(1)  Consider monitoring blood|
01061|021|M|levels of the NNRTI, as well as the CD4 count and viral load during|
01061|022|M|concurrent therapy.  The dosage of the NNRTI may need to be adjusted if St.|
01061|023|M|John's wort is added to or discontinued from concurrent therapy.  St. John's|
01061|024|M|wort may need to be discontinued.|
01061|025|B||
01061|026|D|DISCUSSION:  In a study of 5 patients who had been receiving concurrent|
01061|027|D|nevirapine and St. John's wort for several months, concurrent St. John's|
01061|028|D|wort increased nevirapine clearance by 35% compared to periods when the|
01061|029|D|patients were not receiving St. John's wort.(4)|
01061|030|D|   St. John's wort is expected to lower concentrations of delavirdine(2) as|
01061|031|D|well.|
01061|032|B||
01061|033|R|REFERENCES:|
01061|034|B||
01061|035|R|1.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
01061|036|R|  283(13):1679.|1
01061|037|R|2.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01061|038|R|  Upjohn Company August, 2012.|1
01061|039|R|3.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
01061|040|R|  Pharmaceuticals, Inc. June, 2022.|1
01061|041|R|4.de Maat MM, Hoetelmans RM, Math t RA, van Gorp EC, Meenhorst PL, Mulder|2
01061|042|R|  JW, Beijnen JH. Drug interaction between St John's wort and nevirapine.|2
01061|043|R|  AIDS 2001 Feb 16;15(3):420-1.|2
01062|001|T|MONOGRAPH TITLE:  Saquinavir/St. John's Wort (mono deleted 01/26/2006)|
01062|002|B||
01062|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01062|004|L|is contraindicated and generally should not be dispensed or administered to|
01062|005|L|the same patient.|
01062|006|B||
01062|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01062|008|A|saquinavir by the CYP P-450 isoenzyme system.(1,2)|
01062|009|B||
01062|010|E|CLINICAL EFFECTS:  The concurrent administration of saquinavir and St.|
01062|011|E|John's wort may result in suboptimal saquinavir concentrations, which may|
01062|012|E|lead to loss of virologic response and development of resistance or class|
01062|013|E|cross-resistance.(1,2)|
01062|014|B||
01062|015|P|PREDISPOSING FACTORS:  None determined.|
01062|016|B||
01062|017|M|PATIENT MANAGEMENT:  The manufacturer of saquinavir states that St. John's|
01062|018|M|wort should not be used in patients receiving saquinavir.(2,3)|
01062|019|B||
01062|020|D|DISCUSSION:  St. John's wort has been shown to decrease levels of indinavir|
01062|021|D|in healthy subjects.(4)  Because the other protease inhibitors are|
01062|022|D|metabolized by the same metabolic pathway, the FDA recommends that patients|
01062|023|D|taking any protease inhibitor be alerted to the possibility of a drug|
01062|024|D|interaction resulting in decreased levels and/or effects of the protease|
01062|025|D|inhibitor.(1)|
01062|026|B||
01062|027|R|REFERENCES:|
01062|028|B||
01062|029|R|1.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
01062|030|R|  283(13):1679.|1
01062|031|R|2.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01062|032|R|  Laboratories, Inc. November, 2010.|1
01062|033|R|3.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
01062|034|R|  Inc. December, 2004.|1
01062|035|R|4.Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir|2
01062|036|R|  concentrations and St John's wort. Lancet 2000 Feb 12;355(9203):547-8.|2
01063|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/St. John's Wort|
01063|002|B||
01063|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01063|004|L|of severe adverse interaction.|
01063|005|B||
01063|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01063|007|A|hormonal-containing contraceptives by CYP3A4.(1-8)|
01063|008|B||
01063|009|E|CLINICAL EFFECTS:  The concurrent administration of St. John's wort may|
01063|010|E|result in reduced levels and clinical effectiveness of hormonal-containing|
01063|011|E|contraceptives.(1-8)|
01063|012|B||
01063|013|P|PREDISPOSING FACTORS:  None determined.|
01063|014|B||
01063|015|M|PATIENT MANAGEMENT:  Women taking hormonal contraception should be alerted|
01063|016|M|to the possibility of decreased effects of their hormonal-containing|
01063|017|M|contraceptive if they take St. John's wort.|
01063|018|M|   Consider monitoring for menstrual irregularities and pregnancy during|
01063|019|M|concurrent therapy.  The dosage of the contraceptive may need to be adjusted|
01063|020|M|if St. John's wort is added to or discontinued from concurrent therapy, or|
01063|021|M|another form of birth control may need to be considered.  St. John's wort|
01063|022|M|may need to be|
01063|023|M|discontinued.|
01063|024|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
01063|025|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
01063|026|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
01063|027|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
01063|028|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
01063|029|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
01063|030|M|and to seek medical advice if they do become pregnant.|
01063|031|B||
01063|032|D|DISCUSSION:  The FDA and CDC recommend that patients taking|
01063|033|D|estrogen-containing oral contraceptives be alerted to the possibility of a|
01063|034|D|drug interaction resulting in decreased levels and/or effects of the oral|
01063|035|D|contraceptive.(1,2)|
01063|036|D|   In a study in 12 healthy women taking ethinyl estradiol-norethindrone,|
01063|037|D|administration of St. John's wort (300 mg 3 times daily) increased the oral|
01063|038|D|clearance of norethindrone and decreased the half-life of ethinyloestradiol.|
01063|039|D|Serum concentrations of follicle-stimulating hormone, luteinizing hormone,|
01063|040|D|and progesterone were not significantly affected by St. John's wort.|
01063|041|D|Breakthrough bleeding occurred in 2 of 12 subjects in the control phase and|
01063|042|D|7 of 12 women during the St. John's wort phase.(3)|
01063|043|D|   In a study in 17 healthy women, subjects receiving|
01063|044|D|ethinyloestradiol-desogestrel alone, with 300 mg St. John's wort twice|
01063|045|D|daily, and with 300 mg St. John's wort 3 times daily.  There was no|
01063|046|D|significant changes in follicle maturation, serum estrogen, or serum|
01063|047|D|progesterone concentrations during St. John's wort.  During the control|
01063|048|D|phase, 6 women reported breakthrough bleeding, compared with 13 women while|
01063|049|D|taking St. John's wort twice daily and 15 women while taking St. John's wort|
01063|050|D|3 times daily.  There were no changes in the area-under-curve (AUC) or|
01063|051|D|maximum concentration (Cmax) of ethinyloestradiol.  However, the AUC and|
01063|052|D|Cmax of 3-ketodesogestrel decreased by 43.9% and by 17.8%, respectively|
01063|053|D|during twice daily St. John's wort and by 41.7% and by 22.8%, respectively|
01063|054|D|during 3 times daily St. John's wort.(4)|
01063|055|D|   In a study in 16 healthy women, concurrent St. John's wort (300 mg three|
01063|056|D|times daily) decreased the exposure from Loestrin 1/20 (estradiol with|
01063|057|D|norethindrone) by 13% to 15%.  Breakthrough bleeding and evidence of|
01063|058|D|follicle growth and probable ovulation increased during concurrent St.|
01063|059|D|John's wort.(6)|
01063|060|D|   Unplanned pregnancies have been reported during concurrent St. John's|
01063|061|D|wort and hormonal contraception.(4,7)|
01063|062|D|   In a study in 15 healthy women, concurrent St. John's wort and Loestrin|
01063|063|D|1/20 did not affect androgen levels when compared to Loestrin 1/20 alone,|
01063|064|D|suggesting that concurrent therapy would not impair treatment of acne or|
01063|065|D|hirsutism.(8)|
01063|066|B||
01063|067|R|REFERENCES:|
01063|068|B||
01063|069|R|1.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
01063|070|R|  283(13):1679.|1
01063|071|R|2.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
01063|072|R|  Criteria for Contraceptive Use, 2016. MMWR Recomm Rep.  Available at:|6
01063|073|R|  https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf July 29, 2016;|6
01063|074|R|  65(3):.|6
01063|075|R|3.Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, Hilligoss JK,|2
01063|076|R|  Miller M, Gorski JC. The interaction between St John's wort and an oral|2
01063|077|R|  contraceptive. Clin Pharmacol Ther 2003 Dec;74(6):525-35.|2
01063|078|R|4.Pfrunder A, Schiesser M, Gerber S, Haschke M, Bitzer J, Drewe J.|2
01063|079|R|  Interaction of St John's wort with low-dose oral contraceptive therapy: a|2
01063|080|R|  randomized controlled trial. Br J Clin Pharmacol 2003 Dec;56(6):683-90.|2
01063|081|R|5.Nor-Q-D (norethindrone) US prescribing information. WatsonPharma March,|1
01063|082|R|  2005.|1
01063|083|R|6.Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's|2
01063|084|R|  Wort with oral contraceptives: effects on the pharmacokinetics of|2
01063|085|R|  norethindrone and ethinyl estradiol, ovarian activity and breakthrough|2
01063|086|R|  bleeding. Contraception 2005 Jun;71(6):402-8.|2
01063|087|R|7.Schwarz UI, Buschel B, Kirch W. Unwanted pregnancy on self-medication with|3
01063|088|R|  St John's wort despite hormonal contraception. Br J Clin Pharmacol 2003|3
01063|089|R|  Jan;55(1):112-3.|3
01063|090|R|8.Fogle RH, Murphy PA, Westhoff CL, Stanczyk FZ. Does St. John's wort|2
01063|091|R|  interfere with the antiandrogenic effect of oral contraceptive pills?.|2
01063|092|R|  Contraception 2006 Sep;74(3):245-8.|2
01063|093|R|9.Medicines and Healthcare products Regulatory Agency.|1
01063|094|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
01063|095|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
01063|096|R|  available at:|1
01063|097|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
01063|098|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
01063|099|R|  -and-contraceptive-efficacy September 15, 2016..|1
01064|001|T|MONOGRAPH TITLE:  Diltiazem; Felodipine; Verapamil/St. John's Wort|
01064|002|B||
01064|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01064|004|L|of severe adverse interaction.|
01064|005|B||
01064|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01064|007|A|diltiazem, felodipine and verapamil by the CYP3A4.(1-3)|
01064|008|B||
01064|009|E|CLINICAL EFFECTS:  The concurrent administration of St. John's wort may|
01064|010|E|result in decreased levels and clinical effects of diltiazem, felodipine and|
01064|011|E|verapamil.(1-3)|
01064|012|B||
01064|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01064|014|P|of the inducer for longer than 1-2 weeks.|
01064|015|B||
01064|016|M|PATIENT MANAGEMENT:  Concurrent use is not recommended.  Patients receiving|
01064|017|M|both a selected calcium channel blocker and St. John's wort should be|
01064|018|M|alerted to the possibility of decreased effects of the calcium channel|
01064|019|M|blocker.(1)  Observe the patient for loss of the therapeutic effect of the|
01064|020|M|calcium channel blocker.  The dose of the calcium channel blocker may need|
01064|021|M|to be adjusted if St. John's wort is added to or discontinued from|
01064|022|M|concurrent therapy.  St. John's wort may need to be discontinued.|
01064|023|B||
01064|024|D|DISCUSSION:  One study looked at the effects of St. John's wort on the|
01064|025|D|metabolism of S- and R-verapamil in eight healthy male subjects.  The|
01064|026|D|patients underwent jejunal perfusion with verapamil before and after taking|
01064|027|D|St. John's wort (300 mg three times daily) for 14 days.  The study concluded|
01064|028|D|that St. John's wort decreased the area-under-curve (AUC) and the maximum|
01064|029|D|plasma concentration (Cmax) of both the S- and R-enantiomers by 80% and 78%,|
01064|030|D|respectively.  The induction of first pass verapamil metabolism by St.|
01064|031|D|John's wort was shown to significantly decrease the bioavailability of the|
01064|032|D|medication.(2)|
01064|033|D|   St. John's wort has been shown to decrease levels of indinavir in healthy|
01064|034|D|subjects.(3)  Because selected calcium channel blockers (diltiazem,|
01064|035|D|felodipine) are metabolized by the same metabolic pathway, the FDA|
01064|036|D|recommends that patients taking these calcium channel blockers be alerted to|
01064|037|D|the possibility of a drug interaction resulting in decreased levels and/or|
01064|038|D|effects of the calcium channel blocker.(1)|
01064|039|B||
01064|040|R|REFERENCES:|
01064|041|B||
01064|042|R|1.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
01064|043|R|  283(13):1679.|1
01064|044|R|2.Tannergren C, Engman H, Knutson L, Hedeland M, Bondesson U, Lennernas H.|2
01064|045|R|  St John's wort decreases the bioavailability of R- and S-verapamil through|2
01064|046|R|  induction of the first-pass metabolism. Clin Pharmacol Ther 2004 Apr;|2
01064|047|R|  75(4):298-309.|2
01064|048|R|3.Plendil (felodipine) US prescribing information. AstraZeneca|1
01064|049|R|  Pharmaceuticals LP November, 2003.|1
01064|050|R|4.Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir|2
01064|051|R|  concentrations and St John's wort. Lancet 2000 Feb 12;355(9203):547-8.|2
01065|001|T|MONOGRAPH TITLE:  Tricyclic Antidepressants/St. John's Wort|
01065|002|B||
01065|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01065|004|L|take action as needed.|
01065|005|B||
01065|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of tricyclic|
01065|007|A|antidepressants (TCAs) by the CYP P-450 isoenzyme system.(1)|
01065|008|B||
01065|009|E|CLINICAL EFFECTS:  The concurrent administration of TCAs and St. John's wort|
01065|010|E|may result in decreased levels and clinical effects of the TCA.(1)|
01065|011|B||
01065|012|P|PREDISPOSING FACTORS:  None determined.|
01065|013|B||
01065|014|M|PATIENT MANAGEMENT:  Patients receiving both of these medications should be|
01065|015|M|alerted to the possibility of decreased effects of the TCA.(1)  Observe the|
01065|016|M|patient for loss of the therapeutic effect of the TCA and consider|
01065|017|M|monitoring TCA levels during concurrent therapy.  The dosage of the TCA may|
01065|018|M|need to be adjusted if St. John's wort is added to or discontinued from|
01065|019|M|concurrent therapy.  St. John's wort may need to be discontinued.|
01065|020|B||
01065|021|D|DISCUSSION:  St. John's wort has been shown to decrease levels of indinavir|
01065|022|D|in healthy subjects.(2)  Because TCAs (amitriptyline, amoxapine, imipramine)|
01065|023|D|are metabolized by the same metabolic pathway, the FDA recommends that|
01065|024|D|patients taking tricyclic antidepressants be alerted to the possibility of a|
01065|025|D|drug interaction resulting in decreased levels and/or effects of the TCA.(1)|
01065|026|D|   In a study in 12 subjects, the addition of St. John's wort (900 mg day)|
01065|027|D|decreased the area-under-curve (AUC) of amitriptyline (75 mg twice daily) by|
01065|028|D|22%.  The AUC of nortriptyline decreased 41%.(3)|
01065|029|B||
01065|030|R|REFERENCES:|
01065|031|B||
01065|032|R|1.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
01065|033|R|  283(13):1679.|1
01065|034|R|2.Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir|2
01065|035|R|  concentrations and St John's wort. Lancet 2000 Feb 12;355(9203):547-8.|2
01065|036|R|3.Johne A, Schmider J, Brockmoller J, Stadelmann AM, Stormer E, Bauer S,|2
01065|037|R|  Scholler G, Langheinrich M, Roots I. Decreased plasma levels of|2
01065|038|R|  amitriptyline and its metabolites on comedication with an extract from St.|2
01065|039|R|  John's wort ( Hypericum perforatum ). J Clin Psychopharmacol 2002 Feb;|2
01065|040|R|  22(1):46-54.|2
01066|001|T|MONOGRAPH TITLE:  Selected Anticonvulsants/St. John's Wort|
01066|002|B||
01066|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01066|004|L|Assess the risk to the patient and take action as needed.|
01066|005|B||
01066|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01066|007|A|perampanel, phenytoin, phenobarbital, primidone, and tiagabine by the CYP3A4|
01066|008|A|isoenzyme system.(1-3)|
01066|009|B||
01066|010|E|CLINICAL EFFECTS:  The concurrent administration of  perampanel, phenytoin,|
01066|011|E|phenobarbital, primidone, and tiagabine with St. John's wort may result in|
01066|012|E|reduced levels and clinical effects of the anticonvulsant.(1-3)|
01066|013|B||
01066|014|P|PREDISPOSING FACTORS:  None determined.|
01066|015|B||
01066|016|M|PATIENT MANAGEMENT:  Patients maintained on perampanel, phenytoin,|
01066|017|M|phenobarbital, primidone, or tiagabine should be cautioned about the risk of|
01066|018|M|decreased anticonvulsant effects if St. John's wort is initiated.(1-3)|
01066|019|M|Consider monitoring blood levels of the anticonvulsant, as well as seizure|
01066|020|M|activity, during concurrent therapy.  The dosage of the anticonvulsant may|
01066|021|M|need to be adjusted if St. John's wort is added to or discontinued from|
01066|022|M|concurrent therapy.  St. John's wort may need to be discontinued.|
01066|023|B||
01066|024|D|DISCUSSION:  St. John's wort has been shown to decrease levels of indinavir|
01066|025|D|in healthy subjects.(4)  Because some anticonvulsants (phenytoin,|
01066|026|D|phenobarbital and primidone) are metabolized by the same metabolic pathway,|
01066|027|D|the FDA recommends that patients taking selected anticonvulsants be alerted|
01066|028|D|to the possibility of a drug interaction resulting in decreased levels|
01066|029|D|and/or effects of the anticonvulsant.(1)|
01066|030|D|   St. John's wort is expected to decrease levels of perampanel and|
01066|031|D|tiagabine as well.(2-3)|
01066|032|B||
01066|033|R|REFERENCES:|
01066|034|B||
01066|035|R|1.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
01066|036|R|  283(13):1679.|1
01066|037|R|2.Fycompa (perampanel) UK summary of product characteristics. Eisai Ltd|1
01066|038|R|  August, 2021.|1
01066|039|R|3.Gabitril (tiagabine) US prescribing information. Cephalon, LLC September,|1
01066|040|R|  2021.|1
01066|041|R|4.Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir|2
01066|042|R|  concentrations and St John's wort. Lancet 2000 Feb 12;355(9203):547-8.|2
01067|001|T|MONOGRAPH TITLE:  Cyclophosphamide/St. John's Wort|
01067|002|B||
01067|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01067|004|L|Assess the risk to the patient and take action as needed.|
01067|005|B||
01067|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01067|007|A|cyclophosphamide by CYP2B6 and CYP3A4, resulting in increased formation of|
01067|008|A|active and cytotoxic metabolites.(1)|
01067|009|B||
01067|010|E|CLINICAL EFFECTS:  The concurrent administration of cyclophosphamide and St.|
01067|011|E|John's wort may result in increased levels and toxicity of cyclophosphamide|
01067|012|E|metabolites.(1)|
01067|013|B||
01067|014|P|PREDISPOSING FACTORS:  None determined.|
01067|015|B||
01067|016|M|PATIENT MANAGEMENT:  Patients receiving both of these medications should be|
01067|017|M|alerted to the possibility of increased toxicity from cyclophosphamide.(1)|
01067|018|M|Monitor closely for signs of toxicity during concurrent therapy.  The dosage|
01067|019|M|of cyclophosphamide may need to be adjusted if St. John's wort is added to|
01067|020|M|or discontinued from concurrent therapy.  St. John's wort may need to be|
01067|021|M|discontinued.|
01067|022|B||
01067|023|D|DISCUSSION:  St. John's wort may induce the formation the active and|
01067|024|D|cytotoxic metabolites of cyclophosphamide, resulting in increased|
01067|025|D|toxicity.(1)|
01067|026|B||
01067|027|R|REFERENCE:|
01067|028|B||
01067|029|R|1.Procytox (cyclophosphamide) Canadian prescribing information. Baxter|1
01067|030|R|  Corporation September 7, 2012.|1
01068|001|T|MONOGRAPH TITLE:  Beta-Blockers/St. John's Wort|
01068|002|B||
01068|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01068|004|L|Assess the risk to the patient and take action as needed.|
01068|005|B||
01068|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of beta|
01068|007|A|blockers by CYP3A4.(1)|
01068|008|B||
01068|009|E|CLINICAL EFFECTS:  The concurrent administration of beta blockers and St.|
01068|010|E|John's wort may result in decreased levels and clinical effects of the beta|
01068|011|E|blocker.(1)|
01068|012|B||
01068|013|P|PREDISPOSING FACTORS:  None determined.|
01068|014|B||
01068|015|M|PATIENT MANAGEMENT:  Patients receiving both of these medications should be|
01068|016|M|alerted to the possibility of decreased effects of the beta blocker.(1)|
01068|017|M|Observe the patient for loss of the therapeutic effect of the beta blocker|
01068|018|M|during concurrent therapy. The dosage of the beta blocker may need to be|
01068|019|M|adjusted if St. John's wort is added to or discontinued from concurrent|
01068|020|M|therapy. St. John's wort may need to be discontinued.|
01068|021|B||
01068|022|D|DISCUSSION:  St. John's wort has been shown to decrease levels of indinavir|
01068|023|D|in healthy subjects.(2)  Because some beta blockers are metabolized by the|
01068|024|D|same metabolic pathway, the FDA recommends that patients taking beta|
01068|025|D|blockers be alerted to the possibility of a drug interaction resulting in|
01068|026|D|decreased levels and/or effects of the beta blocker.(1)|
01068|027|B||
01068|028|R|REFERENCES:|
01068|029|B||
01068|030|R|1.Anonymous. From the Food and Drug Administration. JAMA 2000 Apr 5;|1
01068|031|R|  283(13):1679.|1
01068|032|R|2.Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir|2
01068|033|R|  concentrations and St John's wort. Lancet 2000 Feb 12;355(9203):547-8.|2
01069|001|T|MONOGRAPH TITLE:  Xanthine Derivatives/St. John's Wort|
01069|002|B||
01069|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01069|004|L|Assess the risk to the patient and take action as needed.|
01069|005|B||
01069|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of the|
01069|007|A|xanthine derivatives by CYP1A2.(1)|
01069|008|B||
01069|009|E|CLINICAL EFFECTS:  The concurrent administration of St. John's wort and a|
01069|010|E|xanthine derivative may result in decreased levels and clinical effects of|
01069|011|E|the xanthine derivative.(1)  Short-term (<2 weeks) administration of St.|
01069|012|E|John's wort does not appear to significantly alter the plasma levels of|
01069|013|E|theophylline, but longer exposure (4 or more weeks) might increase the|
01069|014|E|magnitude of the interaction.(2)|
01069|015|B||
01069|016|P|PREDISPOSING FACTORS:  None determined.|
01069|017|B||
01069|018|M|PATIENT MANAGEMENT:  Serum levels should be carefully monitored if St.|
01069|019|M|John's wort is added to or discontinued from concurrent therapy with a|
01069|020|M|xanthine derivative.|
01069|021|B||
01069|022|D|DISCUSSION:  In a case report, a 42 year-old female was maintained on|
01069|023|D|theophylline (300 mg twice daily) for several months. Two months after she|
01069|024|D|began taking St. John's wort (300 mg daily, 0.3% hypericum), she required a|
01069|025|D|dosage increase of theophylline (to 800 mg twice daily) to maintain a|
01069|026|D|theophylline level of 9.2 mcg/ml. Seven days after discontinuing St. John's|
01069|027|D|wort, the patient's theophylline level was 19.6 mcg/ml and her dosage of|
01069|028|D|theophylline was reduced.(1)|
01069|029|D|   In a randomized, open-labeled, crossover study in 12 Japanese males,|
01069|030|D|subjects received St. John's wort (300 mg three times daily for 15 days).|
01069|031|D|St. John's wort did not significantly affect the pharmacokinetics of|
01069|032|D|theophylline (400 mg single dose) in plasma.  Overall, the fractions of|
01069|033|D|metabolites in the urine remained unchanged with the exception of|
01069|034|D|1-methyluric acid (1U).  The 1U urinary metabolite ratio increased in the|
01069|035|D|presence of St. John's Wort.  However, the short length of the study led the|
01069|036|D|researchers to believe an interaction may be seen after a longer duration.|
01069|037|D|It may take 4 weeks or more to see an induction of enzymes that would affect|
01069|038|D|theophylline.  Further studies are needed.(2)|
01069|039|B||
01069|040|R|REFERENCES:|
01069|041|B||
01069|042|R|1.Nebel A, Schneider BJ, Baker RK, Kroll DJ. Potential metabolic interaction|3
01069|043|R|  between St. John's wort and theophylline. Ann Pharmacother 1999 Apr;|3
01069|044|R|  33(4):502.|3
01069|045|R|2.Morimoto T, Kotegawa T, Tsutsumi K, Ohtani Y, Imai H, Nakano S. Effect of|2
01069|046|R|  St. John's wort on the pharmacokinetics of theophylline in healthy|2
01069|047|R|  volunteers. J Clin Pharmacol 2004 Jan;44(1):95-101.|2
01070|001|T|MONOGRAPH TITLE:  Delavirdine; Rilpivirine/Didanosine|
01070|002|B||
01070|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01070|004|L|take action as needed.|
01070|005|B||
01070|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01070|007|B||
01070|008|E|CLINICAL EFFECTS:  The simultaneous administration of delavirdine or|
01070|009|E|rilpivirine and didanosine may result in decreased levels and effectiveness|
01070|010|E|of the NNRTI and didanosine.(1-3)|
01070|011|B||
01070|012|P|PREDISPOSING FACTORS:  None determined.|
01070|013|B||
01070|014|M|PATIENT MANAGEMENT:  The manufacturers of delavirdine(1) and didanosine(2)|
01070|015|M|recommend that the administration of delavirdine and didanosine be separated|
01070|016|M|by at least one hour.|
01070|017|M|   The manufacturer of rilpivirine recommends that didanosine be|
01070|018|M|administered at least 2 hours before or 4 hours after rilpivirine.(3)|
01070|019|B||
01070|020|D|DISCUSSION:  In a study in nine HIV-1 infected patients, the simultaneous|
01070|021|D|administration of delavirdine (400 mg three times daily) with didanosine|
01070|022|D|(either 125 mg or 250 mg twice daily) for 4 weeks decreased the maximum|
01070|023|D|concentration (Cmax) and area-under-curve (AUC) of didanosine by 20% and|
01070|024|D|21%, respectively.  The Cmax and AUC of delavirdine decreased by 32% and|
01070|025|D|19%, respectively.(1)|
01070|026|D|   In a study in 12 HIV-infected patients, the simultaneous administration|
01070|027|D|of delavirdine (400 mg single dose) with didanosine (125 mg or 200 mg every|
01070|028|D|12 hours) decreased delavirdine Cmax and AUC by 53% and 32%, respectively.|
01070|029|D|Administration of delavirdine (400 mg single dose) 1 hour before didanosine|
01070|030|D|(125 mg or 200 mg every 12 hours) increased delavirdine Cmax and AUC by 18%|
01070|031|D|and 20%, respectively.(2)|
01070|032|D|   In a study in 21 subjects, administration of didanosine (400 mg|
01070|033|D|delayed-release capsule daily) 2 hours before rilpivirine (150 mg daily) had|
01070|034|D|no effect on the Cmax, AUC, or minimum concentration (Cmin) of rilpivirine.|
01070|035|D|There were no significant effects on the Cmax or AUC of didanosine.(3)|
01070|036|B||
01070|037|R|REFERENCES:|
01070|038|B||
01070|039|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01070|040|R|  Upjohn Company August, 2012.|1
01070|041|R|2.Videx (didanosine) US prescribing information. Bristol-Myers Squibb|1
01070|042|R|  Company November, 2011.|1
01070|043|R|3.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
01070|044|R|  March, 2024.|1
01071|001|T|MONOGRAPH TITLE:  Itraconazole; Ketoconazole/Nevirapine|
01071|002|B||
01071|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01071|004|L|of severe adverse interaction.|
01071|005|B||
01071|006|A|MECHANISM OF ACTION:  Nevirapine may induce the metabolism of itraconazole|
01071|007|A|or ketoconazole by CYP3A4.(1,2,3)  Ketoconazole may inhibit the metabolism|
01071|008|A|of nevirapine at CYP3A4.(1)|
01071|009|B||
01071|010|E|CLINICAL EFFECTS:  The concurrent administration of nevirapine and either|
01071|011|E|itraconazole or ketoconazole may result in decreased levels of itraconazole|
01071|012|E|or ketoconazole, resulting in a loss of efficacy.(1)  Ketoconazole may|
01071|013|E|increase levels of nevirapine, although the clinical significance of this is|
01071|014|E|unknown.(1)|
01071|015|B||
01071|016|P|PREDISPOSING FACTORS:  None determined.|
01071|017|B||
01071|018|M|PATIENT MANAGEMENT:  Recommendations differ:|
01071|019|M| - The manufacturer of nevirapine states that nevirapine should not be|
01071|020|M|administered with itraconazole or ketoconazole.(1)|
01071|021|M| - The manufacturer of oral ketoconazole states concomitant administration|
01071|022|M|with nevirapine is not recommended.(2)|
01071|023|M| - The manufacturer of itraconazole states concomitant treatment with|
01071|024|M|nevirapine is not recommended.(3)|
01071|025|M| - US guidelines for the use of antiretroviral agents in adults and|
01071|026|M|adolescents recommend the following(4):|
01071|027|M|Ketoconazole should not be used with nevirapine.|
01071|028|M|Avoid concomitant use of nevirapine and itraconazole if possible. If|
01071|029|M|co-administered, monitor itraconazole concentration and adjust dose|
01071|030|M|accordingly.|
01071|031|M|   The US manufacturer of itraconazole states that concurrent administration|
01071|032|M|with nevirapine is not recommended two weeks before and during itraconazole|
01071|033|M|treatment.(3)|
01071|034|B||
01071|035|D|DISCUSSION:  In a study in 21 HIV-infected patients, the concurrent|
01071|036|D|administration of nevirapine (200 mg twice daily) and ketoconazole (400 mg|
01071|037|D|once daily) resulted in decreases in the area-under-curve (AUC) and maximum|
01071|038|D|concentration (Cmax) of ketoconazole by 72% and 44%, respectively.(1)|
01071|039|B||
01071|040|R|REFERENCES:|
01071|041|B||
01071|042|R|1.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
01071|043|R|  Pharmaceuticals, Inc. June, 2022.|1
01071|044|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01071|045|R|  Pharmaceuticals February, 2014.|1
01071|046|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01071|047|R|  Products, L.P. February, 2024.|1
01071|048|R|4.Department of Health and Human Services. Table 15b. Drug Interactions|1
01071|049|R|  between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs.|1
01071|050|R|  Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults|1
01071|051|R|  and Adolescents 02/12/2013.|1
01071|052|R|5.This information is based on an extract from the Certara Drug Interaction|6
01071|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01072|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Didanosine|
01072|002|B||
01072|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01072|004|L|take action as needed.|
01072|005|B||
01072|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01072|007|B||
01072|008|E|CLINICAL EFFECTS:  The simultaneous administration of buffered didanosine|
01072|009|E|with atazanavir or indinavir may result in dramatically decreased levels of|
01072|010|E|the protease inhibitor and loss of efficacy.(1-3)|
01072|011|E|   The simultaneous administration of enteric-coated didanosine with|
01072|012|E|atazanavir,(2) darunavir,(4) lopinavir/ritonavir(5) or ritonavir(6) may|
01072|013|E|result in decreased levels and efficacy of didanosine.|
01072|014|B||
01072|015|P|PREDISPOSING FACTORS:  None determined.|
01072|016|B||
01072|017|M|PATIENT MANAGEMENT:  The manufacturer of atazanavir(2) recommends that|
01072|018|M|enteric-coated didanosine be administered at a different time than|
01072|019|M|atazanavir.  Buffered didanosine should be administered 1 hour before or 2|
01072|020|M|hours after atazanavir.|
01072|021|M|   The manufacturers of didanosine(1) and indinavir(3) recommend that the|
01072|022|M|administration of buffered didanosine and indinavir be separated by at least|
01072|023|M|one hour.|
01072|024|M|   The US manufacturer of darunavir recommends that didanosine be given one|
01072|025|M|hour before or two hours after darunavir/ritonavir or|
01072|026|M|darunavir/cobicistat.(4,8)|
01072|027|M|   The US manufacturer of lopinavir/ritonavir recommends that didanosine be|
01072|028|M|given one hour before or two hours after lopinavir/ritonavir capsules or|
01072|029|M|oral solution.(5)  Lopinavir/ritonavir tablets may be taken concurrently|
01072|030|M|with didanosine.(7)|
01072|031|B||
01072|032|D|DISCUSSION:  Atazanavir 400 mg daily decreased the maximum concentration|
01072|033|D|(Cmax) and area-under-curve (AUC) of enteric-coated didanosine 400 mg single|
01072|034|D|dose by 36% and 34%, respectively.  Coadministration of enteric-coated|
01072|035|D|didanosine with atazanavir 300 mg daily with ritonavir 100 mg daily resulted|
01072|036|D|in similar decreases in didanosine exposure.  Simultaneous administration of|
01072|037|D|single-dose buffered didanosine 200 mg with atazanavir 400 mg decreased|
01072|038|D|atazanavir's Cmax by 89% and AUC by 87%.  Administering atazanavir 1 hour|
01072|039|D|after didanosine mitigated the interaction.(2)|
01072|040|D|   Concurrent administration of darunavir/ritonavir (600/100 mg twice daily)|
01072|041|D|and didanosine (400 mg daily) decreased darunavir Cmax by 7%.  Didanosine|
01072|042|D|Cmax and AUC decreased by 16% and 9%, respectively.(4)|
01072|043|D|   The simultaneous administration of didanosine and indinavir decreased the|
01072|044|D|Cmax and AUC of indinavir by 82% and 84%, respectively.(1)|
01072|045|D|   The simultaneous administration of didanosine and ritonavir decreased the|
01072|046|D|AUC and maximum concentration (Cmax) of didanosine by 13% and 16%,|
01072|047|D|respectively.  There were no significant changes in ritonavir|
01072|048|D|pharmacokinetics.(6)|
01072|049|B||
01072|050|R|REFERENCES:|
01072|051|B||
01072|052|R|1.Videx (didanosine) US prescribing information. Bristol-Myers Squibb|1
01072|053|R|  Company November, 2011.|1
01072|054|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01072|055|R|  Squibb Company December, 2024.|1
01072|056|R|3.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01072|057|R|  September, 2016.|1
01072|058|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01072|059|R|  March, 2023.|1
01072|060|R|5.Kaletra (lopinavir/ritonavir capsules) US prescribing information. Abbott|1
01072|061|R|  Laboratories September, 2016.|1
01072|062|R|6.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01072|063|R|  December, 2019.|1
01072|064|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01072|065|R|  Laboratories December, 2019.|1
01072|066|R|8.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
01072|067|R|  Pharmaceuticals, Inc. March, 2025.|1
01073|001|T|MONOGRAPH TITLE:  Indinavir/Itraconazole; Ketoconazole|
01073|002|B||
01073|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01073|004|L|take action as needed.|
01073|005|B||
01073|006|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
01073|007|A|metabolism of indinavir at CYP3A4.(1)|
01073|008|B||
01073|009|E|CLINICAL EFFECTS:  The concurrent administration of itraconazole and|
01073|010|E|ketoconazole with indinavir may result in elevated levels of indinavir and|
01073|011|E|toxicity.(1)|
01073|012|B||
01073|013|P|PREDISPOSING FACTORS:  None determined.|
01073|014|B||
01073|015|M|PATIENT MANAGEMENT:  The manufacturer of indinavir recommends that when|
01073|016|M|indinavir is administered with either itraconazole or ketoconazole, the|
01073|017|M|dosage of indinavir be reduced to 600 mg of indinavir every eight hours.(1)|
01073|018|B||
01073|019|D|DISCUSSION:  In a study in 12 healthy, HIV-negative subjects, concurrent|
01073|020|D|itraconazole (200 mg twice daily) and indinavir (600 mg three times daily)|
01073|021|D|decreased indinavir maximum concentration (Cmax) by 22% and increased|
01073|022|D|indinavir minimum concentration (Cmin) by 1.49-fold, when compared to|
01073|023|D|indinavir (800 mg three times daily) alone.(1)|
01073|024|D|   In a study in 12 healthy, HIV-negative subjects, concurrent ketoconazole|
01073|025|D|(400 mg daily) and indinavir (600 mg three times daily) decreased indinavir|
01073|026|D|Cmax and AUC, by 31% and 20%, respectively, and increased indinavir Cmin by|
01073|027|D|1.29-fold, when compared to indinavir (800 mg three times daily) alone.(1)|
01073|028|D|   In a study in 12 healthy, HIV-negative subjects, concurrent ketoconazole|
01073|029|D|(400 mg daily) and indinavir (400 mg three times daily) decreased indinavir|
01073|030|D|Cmax and AUC, by 58%, 56%, and 27%, respectively, when compared to indinavir|
01073|031|D|(800 mg three times daily) alone.(1)|
01073|032|B||
01073|033|R|REFERENCE:|
01073|034|B||
01073|035|R|1.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01073|036|R|  September, 2016.|1
01074|001|T|MONOGRAPH TITLE:  Slt Low Strength Antimuscarinics/Strong CYP3A4 Inhibitors|
01074|002|B||
01074|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01074|004|L|take action as needed.|
01074|005|B||
01074|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
01074|007|A|darifenacin,(1) fesoterodine,(2) and solifenacin.(3,4)|
01074|008|B||
01074|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong inhibitor of|
01074|010|E|CYP3A4 may result in elevated levels of and signs of toxicity from|
01074|011|E|darifenacin,(1) fesoterodine,(2) and solifenacin.(3,4)|
01074|012|B||
01074|013|P|PREDISPOSING FACTORS:  None determined.|
01074|014|B||
01074|015|M|PATIENT MANAGEMENT:  The US manufacturer of darifenacin states that the|
01074|016|M|daily dose of darifenacin should not exceed 7.5 mg in patients receiving|
01074|017|M|potent CYP3A4 inhibitors.(1)|
01074|018|M|   The US manufacturer of fesoterodine states that the daily dose of|
01074|019|M|fesoterodine should not exceed 4 mg in adult patients receiving potent|
01074|020|M|CYP3A4 inhibitors.  In pediatric patients, the daily dose of fesoterodine|
01074|021|M|taking strong CYP3A4 inhibitors should be reduced to 4 mg in patients|
01074|022|M|weighing greater than 35 kilograms. Use of fesoterodine in pediatric|
01074|023|M|patients weighing greater than 25 kilograms and up to 35 kilograms is not|
01074|024|M|recommended.(2)|
01074|025|M|   The US and Swedish manufacturers of solifenacin state the daily dose|
01074|026|M|should be limited to 5 mg in adults and should not exceed the starting dose|
01074|027|M|in children and adolescents when administered with strong CYP3A4 inhibitors.|
01074|028|M|The starting dose of solifenacin is 2 mg for patients weighing up to 15 kg,|
01074|029|M|3 mg for patients over 15 kg to 45 kg, 4 mg for patients over 45 kg to 60|
01074|030|M|kg, and 5 mg for patients over 60 kg.(3,4)  The Swedish manufacturer of the|
01074|031|M|combination product of tamsulosin-solifenacin states that the daily dose of|
01074|032|M|solifenacin should not exceed 6 mg in patients receiving potent CYP3A4|
01074|033|M|inhibitors.(5)|
01074|034|B||
01074|035|D|DISCUSSION:  In a study in 10 extensive CYP2D6 metabolizers and 1 poor|
01074|036|D|CYP2D6 metabolizer, concurrent administration of ketoconazole (400 mg)|
01074|037|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
01074|038|D|darifenacin (7.5 mg daily) by 3.9-fold and 4.6-fold, respectively, in|
01074|039|D|extensive metabolizers and by 12.9-fold and 12-fold, respectively, in the|
01074|040|D|poor metabolizer, compared to historical controls.  The concurrent|
01074|041|D|administration of ketoconazole (400 mg) and darifenacin (15 mg daily)|
01074|042|D|increased darifenacin AUC and Cmax by 11.5-fold and 10.73-fold,|
01074|043|D|respectively, in extensive metabolizers and by 4.9-fold and 4.9-fold,|
01074|044|D|respectively, in the poor metabolizer, compared to historical controls.(1)|
01074|045|D|   Concurrent administration of darifenacin (30 mg daily) and erythromycin,|
01074|046|D|a moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 128% and|
01074|047|D|95%, respectively.  Administration of darifenacin (30 mg daily) and|
01074|048|D|fluconazole, another moderate CYP3A4 inhibitor, increased darifenacin AUC|
01074|049|D|and Cmax by 84% and 88%, respectively.  No dosage adjustment is recommended|
01074|050|D|during concurrent therapy with moderate inhibitors of CYP3A4.(1)|
01074|051|D|   In a study, co-administration of ketoconazole (200 mg twice a day)|
01074|052|D|increased the Cmax and AUC of the active metabolite of fesoterodine 2.0 and|
01074|053|D|2.3-fold in CYP2D6 extensive metabolizers and 2.1 and 2.5-fold in CYP2D6|
01074|054|D|poor metabolizers, respectively.  Fesoterodine Cmax and AUC were 4.5-fold|
01074|055|D|and 5.7-fold higher in subjects who were CYP2D6 poor metabolizers and taking|
01074|056|D|ketoconazole when compared to extensive CYP2D6 metabolizers not taking|
01074|057|D|ketoconazole.(2)|
01074|058|D|   In another study, ketoconazole (200 mg daily) increased the Cmax and AUC|
01074|059|D|of the active metabolite of fesoterodine 2.2-fold in CYP2D6 extensive|
01074|060|D|metabolizers and 1.5-fold and 1.9-fold in CYP2D6 poor metabolizers,|
01074|061|D|respectively.(1,2)  Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold|
01074|062|D|higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole|
01074|063|D|when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2)|
01074|064|D|   Based on a controlled randomized study in 28 healthy adults, oral|
01074|065|D|fluconazole (200 mg daily) taken with oral fesoterodine (8 mg daily)  was|
01074|066|D|generally well tolerated in patients.  A slightly non-clinically significant|
01074|067|D|rise in plasma fesoterodine levels did occur.  No clinically significant|
01074|068|D|side effects were reported.  The most common side effects reported by|
01074|069|D|patients include: dizziness, blurred vision and abdominal distension when|
01074|070|D|fluconazole was taken with fesoterodine.(6)|
01074|071|D|   Concurrent use of ketoconazole (400 mg daily for 21 days) increased the|
01074|072|D|Cmax and AUC of solifenacin (10 mg) by 1.5-fold and|
01074|073|D|2.7-fold,respectively.(3)|
01074|074|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
01074|075|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
01074|076|D|josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
01074|077|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
01074|078|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
01074|079|D|tucatinib, and voriconazole.(7)|
01074|080|B||
01074|081|R|REFERENCES:|
01074|082|B||
01074|083|R|1.Enablex (darifenacin) US prescribing information. Warner Chilcott (US),|1
01074|084|R|  LLC July, 2021.|1
01074|085|R|2.Toviaz (fesoterodine fumarate) US prescribing information. Pfizer June,|1
01074|086|R|  2021.|1
01074|087|R|3.Vesicare (solifenacin succinate) US prescribing information. Astella|1
01074|088|R|  Pharma US, Inc. May, 2020.|1
01074|089|R|4.Vesicare (solifenacin) Swedish prescribing information. Astellas Pharma|1
01074|090|R|  March 2018.|1
01074|091|R|5.Urizia (tamsulosin-solifenacin) Swedish prescribing information. Astellas|1
01074|092|R|  Pharma December 5, 2013.|1
01074|093|R|6.Malhotra B, Dickins M, Alvey C, Jumadilova Z, Li X, Duczynski G, Gandelman|2
01074|094|R|  K. Effects of the Moderate CYP3A4 Inhibitor, Fluconazole, on the|2
01074|095|R|  Pharmacokinetics of Fesoterodine in Healthy Subjects. Br J Clin Pharmacol|2
01074|096|R|  2011 May 5.|2
01074|097|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
01074|098|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01074|099|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01074|100|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01074|101|R|  11/14/2017.|1
01075|001|T|MONOGRAPH TITLE:  Tolterodine/Selected Macrolide Antibiotics (mono deleted|
01075|002|T|01/12/2012)|
01075|003|B||
01075|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01075|005|L|take action as needed.|
01075|006|B||
01075|007|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
01075|008|A|tolterodine by CYP P-450-3A4.(1,2)|
01075|009|B||
01075|010|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with a|
01075|011|E|macrolide antibiotic may result in elevated levels of tolterodine and signs|
01075|012|E|of toxicity.(1,2)|
01075|013|B||
01075|014|P|PREDISPOSING FACTORS:  None determined.|
01075|015|B||
01075|016|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
01075|017|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
01075|018|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
01075|019|M|used in patients receiving concurrent therapy with macrolide antibiotics|
01075|020|M|that inhibit CYP P-450-3A4, such as clarithromycin and erythromycin.|
01075|021|B||
01075|022|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP|
01075|023|D|P-450-2D6, the concurrent administration of tolterodine (2 mg) with|
01075|024|D|ketoconazole (200 mg once daily for four days), another inhibitor of CYP|
01075|025|D|P-450-3A4, resulted in a 60% decrease in tolterodine clearance.(3)|
01075|026|D|Tolterodine AUC and Cmax increased 2.5-fold and 2-fold, respectively.(2)|
01075|027|B||
01075|028|R|REFERENCES:|
01075|029|B||
01075|030|R|1.Detrol (tolterodine tartrate) US prescribing information. Pharmacia &|1
01075|031|R|  Upjohn Company April, 2009.|1
01075|032|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pharmacia &|1
01075|033|R|  Upjohn Company September, 2008.|1
01075|034|R|3.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
01075|035|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
01075|036|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
01076|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Selected CYP3A4 Inhibitors|
01076|002|B||
01076|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01076|004|L|is contraindicated and generally should not be dispensed or administered to|
01076|005|L|the same patient.|
01076|006|B||
01076|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
01076|008|A|HMG-CoA reductase inhibitors that are metabolized by CYP3A4.|
01076|009|B||
01076|010|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated HMG|
01076|011|E|levels, which may increase the risk of myopathy, including|
01076|012|E|rhabdomyolysis.(1-18)|
01076|013|B||
01076|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01076|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01076|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01076|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01076|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01076|019|P|transporter OATP1B1 may have increased statin concentrations and be|
01076|020|P|predisposed to myopathy or rhabdomyolysis.|
01076|021|B||
01076|022|M|PATIENT MANAGEMENT:  Do not use simvastatin with protease inhibitors,(1-3)|
01076|023|M|with or without cobicistat(2,3) or ritonavir. The manufacturer of|
01076|024|M|simvastatin states that the concurrent use of strong CYP3A4 inhibitors is|
01076|025|M|contraindicated.|
01076|026|M|   The manufacturer of lovastatin states that the concurrent use of strong|
01076|027|M|CYP3A4 inhibitors is contraindicated, including protease inhibitors, with or|
01076|028|M|without cobicistat or ritonavir.(4, 25)|
01076|029|M|   The manufacturers of atazanavir,(5) cobicistat,(18) darunavir,(6)|
01076|030|M|fosamprenavir,(7) indinavir,(8) the combination of lopinavir with|
01076|031|M|ritonavir,(9) the combination of nirmatrelvir with ritonavir,(17)|
01076|032|M|saquinavir,(11) and tipranavir(12) state that concurrent use of lovastatin|
01076|033|M|or simvastatin is contraindicated.|
01076|034|M|   The manufacturer of nirmatrelvir/ritonavir recommends discontinuing use|
01076|035|M|of lovastatin and simvastatin at least 12 hours prior to|
01076|036|M|initiation of nirmatrelvir/ritonavir and holding statin therapy until 5 days|
01076|037|M|after completing nirmatrelvir/ritonavir therapy.(17)|
01076|038|M|   The manufacturers of amprenavir(13) and nelfinavir(14) state that|
01076|039|M|lovastatin and simvastatin should not be used with these agents.|
01076|040|M|   It would be prudent to utilize fluvastatin in patients treated with|
01076|041|M|protease inhibitors who require HMG-CoA reductase therapy.|
01076|042|B||
01076|043|D|DISCUSSION:  A study in 15 subjects found that darunavir/ritonavir (300/100|
01076|044|D|mg twice daily) decreased the maximum concentration (Cmax) and area-under|
01076|045|D|curve (AUC) of atorvastatin (10 mg daily) by 64% and 15%, when compared to|
01076|046|D|atorvastatin (40 mg daily) administered alone.  Atorvastatin minimum|
01076|047|D|concentration (Cmin) increased by 81% during concurrent therapy.(6)|
01076|048|D|   A study in 16 subjects found that fosamprenavir increased atorvastatin|
01076|049|D|Cmax and AUC by 304% and 130%, respectively.  Atorvastatin Cmin decreased by|
01076|050|D|10%.(7)|
01076|051|D|   A study in 12 subjects found that lopinavir increased atorvastatin Cmax,|
01076|052|D|AUC, and Cmin by 4.67-fold, 5.88-fold, and 2.28-fold, respectively.|
01076|053|D|Atorvastatin had no clinically significant effect on lopinavir|
01076|054|D|pharmacokinetics.(9)|
01076|055|D|   A study in 12 subjects found that lopinavir increased pravastatin Cmax|
01076|056|D|and AUC by 1.26-fold and 1.33-fold, respectively.  Pravastatin had no|
01076|057|D|clinically significant effect on lopinavir pharmacokinetics.(9)|
01076|058|D|   A randomized, controlled trial in healthy subjects examined the effects|
01076|059|D|of a combination of ritonavir and saquinavir on the pharmacokinetics of|
01076|060|D|atorvastatin, pravastatin, and simvastatin and the effects of pravastatin on|
01076|061|D|nelfinavir pharmacokinetics.  The combination of ritonavir and saquinavir|
01076|062|D|decreased pravastatin levels by 50% and increased atorvastatin and|
01076|063|D|simvastatin levels by 79% and 3059%, respectively.  Pravastatin had no|
01076|064|D|statistically significant effect on nelfinavir pharmacokinetics.(14)|
01076|065|D|   An open-label study in healthy subjects examined the effects of|
01076|066|D|nelfinavir on atorvastatin and simvastatin pharmacokinetics.  Nelfinavir|
01076|067|D|increased atorvastatin AUC, Cmax, and Cmin by 74%, 122%, and 39%,|
01076|068|D|respectively.  Nelfinavir increased simvastatin AUC and Cmax by 505% and|
01076|069|D|517%, respectively.  There was no effect on nelfinavir pharmacokinetics when|
01076|070|D|compared to historical controls.(14,16)|
01076|071|D|   A study in 14 healthy HIV-seronegative adults found that nelfinavir|
01076|072|D|decreased median pravastatin AUC by 46.5%. Nelfinavir also decreased median|
01076|073|D|pravastatin Cmax by 40.1%.(19)|
01076|074|D|   In a study of 25 HIV-positive patients, 13 patients were treated with|
01076|075|D|pravastatin and 12 patients were treated with fluvastatin. Within the 25|
01076|076|D|patients, 8 patients were also on concomitant indinavir-containing highly|
01076|077|D|active antiretroviral therapy (HAART). Indinavir plasma levels were not|
01076|078|D|significantly influenced by pravastatin or fluvastatin therapy.(20)|
01076|079|D|   Rhabdomyolysis has been reported during concurrent use of simvastatin and|
01076|080|D|nelfinavir(21) or ritonavir.(22)|
01076|081|D|   Lovastatin was tested in a single dose, open-labeled, randomized|
01076|082|D|crossover study of ten healthy volunteers.  Grapefruit juice increased Cmax|
01076|083|D|of lovastatin 12-fold, and the area under the AUC 15-fold. Likewise, the|
01076|084|D|active metabolite lovastatin acid demonstrated a 4-fold increase in Cmax and|
01076|085|D|a 5-fold increase in AUC. Lovastatin and lovastatin acid concentrations and|
01076|086|D|AUC increased in each subject.(23)|
01076|087|D|   A study found that itraconazole (200 mg for 4 days) increased lovastatin|
01076|088|D|(40 mg on day 4)Cmax by greater than 25-fold and lovastatin acid AUC and|
01076|089|D|Cmax by greater than 20-fold and 13-fold. A study found that itraconazole|
01076|090|D|(100 mg for 4 days) increased lovastatin (40 mg on day 4) AUC and Cmax by|
01076|091|D|greater than 14.8-fold and lovastatin acid AUC and Cmax by 15.4 and|
01076|092|D|11.5-fold.(25)|
01076|093|D|   One or more of the drug pairs linked to this monograph have been included|
01076|094|D|in a list of interactions that should be considered "high-priority" for|
01076|095|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01076|096|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01076|097|D|Coordinator (ONC) for Health Information Technology.|
01076|098|B||
01076|099|R|REFERENCES:|
01076|100|B||
01076|101|R|1.USFood and Drug Administration. FDA Drug Safety Communication: New|1
01076|102|R|  restrictions, contraindications, and dose limitations for Zocor|1
01076|103|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
01076|104|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01076|105|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
01076|106|R|  June 8, 2011.|1
01076|107|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
01076|108|R|  2023.|1
01076|109|R|3.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
01076|110|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
01076|111|R|4.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01076|112|R|  February, 2014.|1
01076|113|R|5.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01076|114|R|  Squibb Company December, 2024.|1
01076|115|R|6.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01076|116|R|  March, 2023.|1
01076|117|R|7.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01076|118|R|  March, 2019.|1
01076|119|R|8.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01076|120|R|  September, 2016.|1
01076|121|R|9.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01076|122|R|  Laboratories December, 2019.|1
01076|123|R|10.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01076|124|R|   December, 2019.|1
01076|125|R|11.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01076|126|R|   Laboratories, Inc. March, 2019.|1
01076|127|R|12.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01076|128|R|   Pharmaceuticals, Inc. April, 2024.|1
01076|129|R|13.Agenerase (amprenavir) Capsules US prescribing information.|1
01076|130|R|   GlaxoSmithKline May, 2005.|1
01076|131|R|14.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01076|132|R|   Pharmaceuticals, Inc. September, 2016.|1
01076|133|R|15.Fichtenbaum CJ, Gerber JG, Rosenkranz SL, Segal Y, Aberg JA, Blaschke T,|2
01076|134|R|   Alston B, Fang F, Kosel B, Aweeka F. Pharmacokinetic interactions between|2
01076|135|R|   protease inhibitors and statins in HIV seronegative volunteers: ACTG|2
01076|136|R|   Study A5047. AIDS 2002 Mar 8;16(4):569-77.|2
01076|137|R|16.Hsyu PH, Schultz-Smith MD, Lillibridge JH, Lewis RH, Kerr BM.|2
01076|138|R|   Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-|2
01076|139|R|   methylglutaryl coenzyme A reductase inhibitors atorvastatin and|2
01076|140|R|   simvastatin. Antimicrob Agents Chemother 2001 Dec;45(12):3445-50.|2
01076|141|R|17.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01076|142|R|   information. Pfizer Inc. February, 2025.|1
01076|143|R|18.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
01076|144|R|   prescribing information. Gilead Sciences, Inc. September, 2021.|1
01076|145|R|19.Aberg JA, Rosenkranz SL, Fichtenbaum CJ, Alston BL, Brobst SW, Segal Y,|2
01076|146|R|   Gerber JG. Pharmacokinetic interaction between nelfinavir and pravastatin|2
01076|147|R|   in HIV-seronegative volunteers: ACTG Study A5108. AIDS 2006 Mar 21;|2
01076|148|R|   20(5):725-9.|2
01076|149|R|20.Benesic A, Zilly M, Kluge F, Weissbrich B, Winzer R, Klinker H, Langmann|2
01076|150|R|   P. Lipid lowering therapy with fluvastatin and pravastatin in patients|2
01076|151|R|   with HIV infection and antiretroviral therapy: comparison of efficacy and|2
01076|152|R|   interaction with indinavir. Infection 2004 Aug;32(4):229-33.|2
01076|153|R|21.Hare CB, Vu MP, Grunfeld C, Lampiris HW. Simvastatin-nelfinavir|3
01076|154|R|   interaction implicated in rhabdomyolysis and death. Clin Infect Dis 2002|3
01076|155|R|   Nov 15;35(10):e111-2.|3
01076|156|R|22.Cheng CH, Miller C, Lowe C, Pearson VE. Rhabdomyolysis due to probable|3
01076|157|R|   interaction between simvastatin and ritonavir. Am J Health Syst Pharm|3
01076|158|R|   2002 Apr 15;59(8):728-30.|3
01076|159|R|23.Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases|2
01076|160|R|   serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol|2
01076|161|R|   Ther 1998 Apr;63(4):397-402.|2
01076|162|R|24.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01076|163|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01076|164|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01076|165|R|   19(5):735-43.|6
01076|166|R|25.Altoprev (lovastatin) US prescribing information. Covis Pharma March|1
01076|167|R|   2024.|1
01077|001|T|MONOGRAPH TITLE:  Lopinavir/Efavirenz; Nevirapine|
01077|002|B||
01077|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01077|004|L|take action as needed.|
01077|005|B||
01077|006|A|MECHANISM OF ACTION:  Efavirenz(1-3) and nevirapine(1,2,4) may induce the|
01077|007|A|metabolism of lopinavir via CYP3A4.|
01077|008|B||
01077|009|E|CLINICAL EFFECTS:  The concurrent administration of efavirenz(1-3) or|
01077|010|E|nevirapine(1,2,4) with lopinavir may result in decreased levels and clinical|
01077|011|E|effectiveness of lopinavir.|
01077|012|B||
01077|013|P|PREDISPOSING FACTORS:  None determined.|
01077|014|B||
01077|015|M|PATIENT MANAGEMENT:  Lopinavir/ritonavir should not be administered once|
01077|016|M|daily in combination with either efavirenz or nevirapine.  Administration of|
01077|017|M|lopinavir/ritonavir with either efavirenz or nevirapine in patients less|
01077|018|M|than 6 months of age is not recommended.(1)|
01077|019|M|   The US manufacturer of lopinavir/ritonavir states that the dose of|
01077|020|M|lopinavir/ritonavir tablets should be 500/125 mg (two 200/50 mg tablets and|
01077|021|M|one 100/25 mg tablet) twice daily in adults receiving concurrent|
01077|022|M|efavirenz.(1)  The US manufacturer of efavirenz states that a dosage|
01077|023|M|increase to 600/150 mg of lopinavir/ritonavir twice daily may be considered|
01077|024|M|in treatment-experienced patients receiving combination therapy in whom|
01077|025|M|decreased susceptibility to lopinavir is suspected.(3)|
01077|026|M|   The US manufacturers of lopinavir/ritonavir(1) and nevirapine(4) states|
01077|027|M|that the dose of lopinavir/ritonavir tablets should be 500/125 mg (two|
01077|028|M|200/50 mg tablets and one 100/25 mg tablet) twice daily in adults receiving|
01077|029|M|concurrent nevirapine.|
01077|030|M|   The dose of lopinavir/ritonavir oral solution should be 520/130 mg (6.5|
01077|031|M|ml) twice daily in adults receiving concurrent efavirenz or nevirapine.(1,4)|
01077|032|M|   The US manufacturer of lopinavir/ritonavir states that pediatric patients|
01077|033|M|aged 6 months to 18 years receiving efavirenz or nevirapine require a dosage|
01077|034|M|increase to 300/75 mg/m2 of oral solution twice daily (not to exceed the|
01077|035|M|recommended adult dose).(1)  If weight-based dosing is preferred, patients|
01077|036|M|weighing less than 15 kg should receive 13/3.25 mg/kg of lopinavir/ritonavir|
01077|037|M|oral solution twice daily with food and patients weighing 15 kg to 45 kg|
01077|038|M|should receive 11/2.75 mg/kg of lopinavir/ritonavir oral solution twice|
01077|039|M|daily with food.(1,4)  Refer to the current Kaletra tablet labeling for|
01077|040|M|information on dosing Kaletra tablets in pediatric patients who can swallow|
01077|041|M|tablets.(1)|
01077|042|B||
01077|043|D|DISCUSSION:  A study in 11 subjects examined the effects of concurrent|
01077|044|D|administration of efavirenz (600 mg daily) with lopinavir/ritonavir (400/100|
01077|045|D|mg twice daily). When compared to 7 controls, concurrent administration|
01077|046|D|resulted in decreases in the area-under-curve (AUC) and and minimum|
01077|047|D|concentration (Cmin) lopinavir by 19% and 39%, respectively.  Efavirenz AUC|
01077|048|D|and Cmin decreased 16% and 16%, respectively.(1-3)  There was no effect on|
01077|049|D|ritonavir levels.(3)|
01077|050|D|   In a study in 19 subjects, concurrent efavirenz (600 mg daily) with|
01077|051|D|lopinavir/ritonavir (500/125 mg twice daily) increased lopinavir maximum|
01077|052|D|concentration (Cmax) and AUC by 12% and 6%, respectively, and decreased|
01077|053|D|lopinavir Cmin by 10% when compared to lopinavir/ritonavir 400/100 mg twice|
01077|054|D|daily alone.(1)|
01077|055|D|   In a study in 23 subjects, concurrent efavirenz (600 mg daily) with|
01077|056|D|lopinavir/ritonavir (600/150 mg twice daily) increased lopinavir Cmax, AUC,|
01077|057|D|and Cmin by 36%, 36%, and 32%, respectively, when compared to|
01077|058|D|lopinavir/ritonavir (400/100 mg twice daily) without concurrent|
01077|059|D|efavirenz.(1)|
01077|060|D|   A study compared 22 subjects taking concurrent nevirapine (200 mg twice|
01077|061|D|daily) with lopinavir/ritonavir (400/100 mg twice daily) with 19 subjects|
01077|062|D|taking lopinavir/ritonavir alone.  Concurrent therapy decreased lopinavir|
01077|063|D|Cmax, AUC, and Cmin by 19%, 27%, and 51%, respectively.  Another study|
01077|064|D|compared 12 subjects taking concurrent nevirapine (7 mg/kg or 4 mg/kg daily|
01077|065|D|for 2 weeks, twice daily for 1 week) and lopinavir/ritonavir (300/75 mg/m2)|
01077|066|D|with 15 subjects taking lopinavir/ritonavir alone.  Concurrent therapy|
01077|067|D|decreased lopinavir Cmax, AUC, and Cmin by 14%, 22%, and 55%,|
01077|068|D|respectively.(4)  Another study compared 5 subjects taking concurrent|
01077|069|D|nevirapine (200 mg daily for 14 days, twice daily for 6 days) with 6|
01077|070|D|subjects taking lopinavir/ ritonavir alone. Concurrent therapy increased|
01077|071|D|nevirapine Cmax, AUC, and Cmin by 5%, 8%, and 15% respectively.(1-3)|
01077|072|D|   In pediatric patients aged 6 months to 12 years, administration of|
01077|073|D|230/57.5 mg/m2 twice daily of lopinavir/ritonavir without nevirapine and|
01077|074|D|300/73 mg/m2 twice daily of lopinavir/ritonavir with nevirapine provided|
01077|075|D|similar lopinavir plasma concentrations.(1)|
01077|076|B||
01077|077|R|REFERENCES:|
01077|078|B||
01077|079|R|1.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01077|080|R|  Laboratories December, 2019.|1
01077|081|R|2.Kaletra (lopinavir/ritonavir capsules) US prescribing information. Abbott|1
01077|082|R|  Laboratories September, 2016.|1
01077|083|R|3.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01077|084|R|  Company November, 2023.|1
01077|085|R|4.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
01077|086|R|  Pharmaceuticals, Inc. June, 2022.|1
01078|001|T|MONOGRAPH TITLE:  Clarithromycin/Selected Protease Inhibitors; Cobicistat|
01078|002|B||
01078|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01078|004|L|take action as needed.|
01078|005|B||
01078|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  The metabolism of|
01078|007|A|clarithromycin by CYP3A4 may be inhibited.|
01078|008|B||
01078|009|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
01078|010|E|of clarithromycin(1-11), reduced levels of 14-OH-clarithromycin,(1-5) and|
01078|011|E|QTc prolongation.(1,2)|
01078|012|B||
01078|013|P|PREDISPOSING FACTORS:  Patients with decreased renal function (as shown by a|
01078|014|P|creatinine clearance (CrCL) of 60 ml/min or less are more susceptible to|
01078|015|P|effects of the interaction.(2-4,6-8)|
01078|016|P|   The risk of QT prolongation or torsade de pointes may be increased in|
01078|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01078|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01078|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01078|020|P|advanced age.(12)|
01078|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01078|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01078|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01078|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01078|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01078|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01078|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(12)|
01078|028|B||
01078|029|M|PATIENT MANAGEMENT:  The manufacturer of atazanavir recommends consideration|
01078|030|M|of a 50% reduction in clarithromycin dosage in patients receiving|
01078|031|M|atazanavir.  For indications other than Mycobacterium avium complex,|
01078|032|M|consider an alternative to clarithromycin.(1,2)|
01078|033|M|   The manufacturer of cobicistat says that alternative antibiotics should|
01078|034|M|be considered with concomitant use of cobicistat coadministered with|
01078|035|M|atazanavir or darunavir.(9)|
01078|036|M|   The manufacturers of darunavir,(6) the combination of lopinavir and|
01078|037|M|ritonavir,(7) ritonavir,(4) and tipranavir coadministered with ritonavir(5)|
01078|038|M|recommend that the dose of clarithromycin be reduced by 50% in patients with|
01078|039|M|a CrCl of 30 ml/min to 60 ml/min.  For patients with a CrCl of less than 30|
01078|040|M|ml/min, the dose of clarithromycin should be reduced by 75%. No adjustment|
01078|041|M|is necessary in patients with normal renal function.|
01078|042|M|   The manufacturer of the combination of elvitegravir, cobicistat,|
01078|043|M|emtricitabine, and tenofovir disoproxil states that no adjustment is|
01078|044|M|necessary in patients with a CrCl greater than or equal to 60 ml/min.  In|
01078|045|M|patients with a CrCl of 50 ml/min to 60 ml/min, the dose of clarithromycin|
01078|046|M|should be reduced by 50%.(8)|
01078|047|M|   The manufacturer of clarithromycin states that in patients receiving|
01078|048|M|ritonavir, the dose of clarithromycin be reduced by 50% in patients with a|
01078|049|M|CrCl of 30 ml/min to 60 ml/min. For patients with a CrCl of less than 30|
01078|050|M|ml/min, the dose of clarithromycin should be reduced by 75%. No dosage|
01078|051|M|adjustment is necessary in patients with normal renal function.(3)|
01078|052|M|   Dosages of clarithromycin in excess of 1000 mg per day should not be used|
01078|053|M|in patients taking protease inhibitors.(3)|
01078|054|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01078|055|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01078|056|M|regular intervals.  Correct any electrolyte abnormalities.|
01078|057|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
01078|058|M|fainting.|
01078|059|B||
01078|060|D|DISCUSSION:  In a study in 29 subjects, clarithromycin (500 mg twice daily)|
01078|061|D|increased the maximum concentration (Cmax), area-under-curve (AUC), and|
01078|062|D|minimum concentration (Cmin) of atazanavir (400 mg daily) by 6%, 28%, and|
01078|063|D|91%, respectively.  In a study in 21 subjects, atazanavir (400 mg daily)|
01078|064|D|increased the Cmax, AUC, and Cmin of clarithromycin by 50%, 94%, and 160%,|
01078|065|D|respectively, and decreased the Cmax, AUC, and Cmin of OH-clarithromycin by|
01078|066|D|72%, 70%, and 62%, respectively.(1)|
01078|067|D|   In a study in 17 subjects, concurrent clarithromycin (500 mg twice daily)|
01078|068|D|and darunavir/ritonavir (400/100 mg twice daily) decreased the Cmax and AUC|
01078|069|D|of darunavir by 17%, 13%, respectively.  Clarithromycin Cmax, AUC, and Cmin|
01078|070|D|increased by 1.26-fold, 1.57-fold, and 2.74-fold, respectively.(6)|
01078|071|D|   In a study in 22 subjects, concurrent clarithromycin and ritonavir|
01078|072|D|increased clarithromycin AUC,(1,4) Cmax,(4) and Cmin(4) by 77%, 31%, and|
01078|073|D|2.8-fold, respectively.  The AUC,(1,3) Cmax,(3) and Cmin(3) of|
01078|074|D|14-OH-clarithromycin decreased by 100%, 99%, and 100%, respectively.|
01078|075|D|Ritonavir AUC, Cmax, Cmin increased by 12%, 15%, 14%, respectively.(4)|
01078|076|D|   In a study in 24 subjects, concurrent clarithromycin (500 mg twice daily)|
01078|077|D|and tipranavir/ritonavir (500/200 mg twice daily) increased tipranavir Cmax,|
01078|078|D|AUC, and Cmin by 1.40-fold, 1.66-fold, 2.00-fold, respectively.  The AUC and|
01078|079|D|Cmin of clarithromycin increased 1.19-fold and 1.68-fold, respectively.  The|
01078|080|D|Cmax, AUC, and Cmin of 14-OH-clarithromycin decreased by 97%, 97%, and 95%,|
01078|081|D|respectively.(5)|
01078|082|D|   In a controlled study in 21 healthy volunteers the use of|
01078|083|D|tipranavir/ritonavir (500/200 for 7 days) concurrently with clarithromycin|
01078|084|D|(500mg twice daily for 14 days) led to increased TPV/r Cmax, AUC, and Cp12h|
01078|085|D|by 40%, 66%, and 100% respectively.  The formation of the active metabolite|
01078|086|D|14-OH-CLR was decreased by 95%, and both AUC and Cmax of 14-OH-CLR were|
01078|087|D|decreased by 97% in the presence of tipranavir.  Single dose|
01078|088|D|tipranavir/ritonavir result in no statistical change in clarithromycin AUC|
01078|089|D|or Cmax, but a 50% increase in Cp12h was identified.  Multiple dose|
01078|090|D|tipranavir/ritonavir showed a 19% increase in clarithromycin AUC, no change|
01078|091|D|in Cmax, and a 68% increase in Cp12h versus clarithromycin alone.(13)|
01078|092|D|   Selected protease inhibitors linked to this monograph include:|
01078|093|D|atazanavir, boceprevir, cobicistat, darunavir, lopinavir, ritonavir,|
01078|094|D|telaprevir, and tipranavir.|
01078|095|B||
01078|096|R|REFERENCES:|
01078|097|B||
01078|098|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01078|099|R|  Squibb Company December, 2024.|1
01078|100|R|2.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01078|101|R|  Squibb Pharmaceuticals October 25, 2023.|1
01078|102|R|3.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
01078|103|R|  September, 2019.|1
01078|104|R|4.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01078|105|R|  December, 2019.|1
01078|106|R|5.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01078|107|R|  Pharmaceuticals, Inc. April, 2024.|1
01078|108|R|6.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01078|109|R|  March, 2023.|1
01078|110|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01078|111|R|  Laboratories December, 2019.|1
01078|112|R|8.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
01078|113|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
01078|114|R|9.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
01078|115|R|  June, 2025.|1
01078|116|R|10.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
01078|117|R|   Incorporated October, 2013.|1
01078|118|R|11.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
01078|119|R|   January, 2017.|1
01078|120|R|12.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
01078|121|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
01078|122|R|   hospital settings: a scientific statement from the American Heart|6
01078|123|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
01078|124|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
01078|125|R|13.la Porte CJ, Sabo JP, Elgadi M, Cameron DW. Interaction studies of|2
01078|126|R|   tipranavir-ritonavir with clarithromycin, fluconazole, and rifabutin in|2
01078|127|R|   healthy volunteers. Antimicrob Agents Chemother 2009 Jan;53(1):162-73.|2
01078|128|R|14.Brophy DF, Israel DS, Pastor A, Gillotin C, Chittick GE, Symonds WT, Lou|2
01078|129|R|   Y, Sadler BM, Polk RE. Pharmacokinetic interaction between amprenavir and|2
01078|130|R|   clarithromycin in healthy male volunteers. Antimicrob Agents Chemother|2
01078|131|R|   2000 Apr;44(4):978-84.|2
01078|132|R|15.Boruchoff SE, Sturgill MG, Grasing KW, Seibold JR, McCrea J, Winchell GA,|2
01078|133|R|   Kusma SE, Deutsch PJ. The steady-state disposition of indinavir is not|2
01078|134|R|   altered by the concomitant administration of clarithromycin. Clin|2
01078|135|R|   Pharmacol Ther 2000 Apr;67(4):351-9.|2
01078|136|R|16.Ouellet D, Hsu A, Granneman GR, Carlson G, Cavanaugh J, Guenther H,|2
01078|137|R|   Leonard JM. Pharmacokinetic interaction between ritonavir and|2
01078|138|R|   clarithromycin. Clin Pharmacol Ther 1998 Oct;64(4):355-62.|2
01079|001|T|MONOGRAPH TITLE:  Fosphenytoin; Phenytoin/Ciprofloxacin|
01079|002|B||
01079|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01079|004|L|take action as needed.|
01079|005|B||
01079|006|A|MECHANISM OF ACTION:  The exact mechanism in unknown, but several possible|
01079|007|A|mechanisms have been proposed.  Ciprofloxacin may decrease phenytoin|
01079|008|A|concentrations by inducing phenytoin metabolism.(1)  Ciprofloxacin may also|
01079|009|A|disrupt the enterohepatic circulation of phenytoin(2) or shift the phenytoin|
01079|010|A|volume of distribution.(3)  Ciprofloxacin may also increase the renal|
01079|011|A|excretion of phenytoin by inhibiting its tubular reabsorption.(4)|
01079|012|B||
01079|013|E|CLINICAL EFFECTS:  Ciprofloxacin may decrease serum phenytoin levels or|
01079|014|E|increase seizure frequency.|
01079|015|B||
01079|016|P|PREDISPOSING FACTORS:  None determined.|
01079|017|B||
01079|018|M|PATIENT MANAGEMENT:  Phenytoin plasma levels and seizure frequency should be|
01079|019|M|monitored closely when ciprofloxacin is added to or discontinued from|
01079|020|M|therapy. The phenytoin dose should be adjusted as needed based on phenytoin|
01079|021|M|levels and symptoms of seizure activity.  Phenytoin doses may need to be|
01079|022|M|readjusted when ciprofloxacin is discontinued from therapy.|
01079|023|B||
01079|024|D|DISCUSSION:  There are two case reports of seizures occurring in patients|
01079|025|D|maintained on phenytoin following the addition of ciprofloxacin to their|
01079|026|D|therapy.  There were no changes in phenytoin levels.(5)  There are eight|
01079|027|D|reports of decreased phenytoin levels and seizures following the addition of|
01079|028|D|ciprofloxacin to therapy.(1-4,6,7)|
01079|029|D|   In contrast to the above reports, one study in seven subjects found an|
01079|030|D|increase in phenytoin levels following the addition of ciprofloxacin to|
01079|031|D|therapy.  There were no changes in seizure activity.(8)|
01079|032|D|   In another case report, phenytoin levels increased following the addition|
01079|033|D|of ciprofloxacin to therapy.(9)|
01079|034|D|   In a study in four subjects, there were no overall changes in phenytoin|
01079|035|D|pharmacokinetics overall during concurrent ciprofloxacin administration.  In|
01079|036|D|one subject, phenytoin maximum concentration (Cmax) and area-under-curve|
01079|037|D|(AUC) significantly decreased.(10)|
01079|038|B||
01079|039|R|REFERENCES:|
01079|040|B||
01079|041|R|1.Dillard ML, Fink RM, Parkerson R. Ciprofloxacin-phenytoin interaction. Ann|3
01079|042|R|  Pharmacother 1992 Feb;26(2):263.|3
01079|043|R|2.Brouwers PJ, de Boer LE, Guchelaar HJ. Ciprofloxacin-phenytoin|3
01079|044|R|  interaction. Ann Pharmacother 1997 Apr;31(4):498.|3
01079|045|R|3.Pollak PT, Slayter KL. Comment: ciprofloxacin-phenytoin interaction. Ann|6
01079|046|R|  Pharmacother 1997 Dec;31(12):1549-50.|6
01079|047|R|4.McLeod R, Trinkle R. Comment: unexpectedly low phenytoin concentration in|3
01079|048|R|  a patient receiving ciprofloxacin. Ann Pharmacother 1998 Oct;|3
01079|049|R|  32(10):1110-1.|3
01079|050|R|5.Slavich IL, Gleffe RF, Haas EJ. Grand mal epileptic seizures during|3
01079|051|R|  ciprofloxacin therapy. JAMA 1989 Jan 27;261(4):558-9.|3
01079|052|R|6.Springuel P. Risk of seizures from concomitant use of ciprofloxacin and|6
01079|053|R|  phenytoin in patients with epilepsy. CMAJ 1998 Jan 13;158(1):104-5, 108-9.|6
01079|054|R|7.Otero MJ, Moran D, Valverde MP. Interaction between phenytoin and|3
01079|055|R|  ciprofloxacin. Ann Pharmacother 1999 Feb;33(2):251-2.|3
01079|056|R|8.Schroeder D, Frye J, Alldredge B, Messing R, Flaherty J Jr. Effect of|2
01079|057|R|  ciprofloxacin on serum phenytoin concentrations in eplieptic patients.|2
01079|058|R|  Pharmacotherapy 1991;11(3):275.|2
01079|059|R|9.Hull RL. Possible phenytoin-ciprofloxacin interaction. Ann Pharmacother|3
01079|060|R|  1993 Oct;27(10):1283.|3
01079|061|R|10.Job ML, Arn SK, Strom JG, Jacobs NF, D'Souza MJ. Effect of ciprofloxacin|2
01079|062|R|   on the pharmacokinetics of multiple-dose phenytoin serum concentrations.|2
01079|063|R|   Ther Drug Monit 1994 Aug;16(4):427-31.|2
01080|001|T|MONOGRAPH TITLE:  Selected Cephalosporins & Penicillins/Probenecid|
01080|002|B||
01080|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01080|004|L|take action as needed.|
01080|005|B||
01080|006|A|MECHANISM OF ACTION:  Probenecid impairs the clearance of some|
01080|007|A|cephalosporins and penicillins via inhibition of renal anion transporters in|
01080|008|A|the proximal tubule.(49)  It has also been hypothesized that probenecid may|
01080|009|A|affect tissue distribution of cephalosporins.(1-5)|
01080|010|B||
01080|011|E|CLINICAL EFFECTS:  The concurrent administration of probenecid may result in|
01080|012|E|increased maximum concentration (Cmax), area-under-curve (AUC), and|
01080|013|E|half-life of the cephalosporin or penicillin.(49) While this may improve|
01080|014|E|antibiotic efficacy,(46-48) increased levels may also increase the risk for|
01080|015|E|antibiotic-associated nephrotoxicity.(4)|
01080|016|B||
01080|017|P|PREDISPOSING FACTORS:  Underlying renal dysfunction may increase the risk|
01080|018|P|for nephrotoxicity.|
01080|019|B||
01080|020|M|PATIENT MANAGEMENT:  In patients receiving the combination to improve|
01080|021|M|antibiotic efficacy, monitor for antibiotic adverse effects and consider|
01080|022|M|monitoring renal function.|
01080|023|M|   In patients receiving probenecid therapy to prevent or treat|
01080|024|M|hyperuricemia, exposure to the antibiotic will be increased. A decrease in|
01080|025|M|antibiotic dose or frequency may be required.|
01080|026|M|   The US manufacturer of piperacillin-tazobactam states probenecid should|
01080|027|M|not be coadministered with piperacillin-tazobactam unless the benefit|
01080|028|M|outweighs the risk.(50)|
01080|029|B||
01080|030|D|DISCUSSION:  Concurrent use of probenecid with a cephalosporin or penicillin|
01080|031|D|may cause an increase in the Cmax, AUC, and an increased elimination half|
01080|032|D|life of the antibiotic.(6-8,49)  This may be beneficial or necessary in|
01080|033|D|difficult to treat infections,(46-48) but an increased risk for adverse|
01080|034|D|effects should be expected.  Antibiotics not dose adjusted for concurrent|
01080|035|D|use with probenecid may be associated with an increased risk for adverse|
01080|036|D|effects, such as nephrotoxicity.|
01080|037|D|   Probenecid administered concurrently with piperacillin-tazobactam|
01080|038|D|prolongs the half-life of piperacillin by 21% and tazobactam by 71%.|
01080|039|D|   In a study in 8 healthy males, concurrent administration of probenecid (1|
01080|040|D|g) with piperacillin (1 g IM) increased piperacillin's Cmax  and AUC by 30%|
01080|041|D|and 60%. Renal clearance was reduced by 40%.(51)|
01080|042|D|   The cephalosporins affected by probenecid include cefazolin,(9-11)|
01080|043|D|cephacetrile,(12,13) cephaloglycin,(14,15) cephalexin,(16-21) cephradine,|
01080|044|D|(22-23) cefoxitin,(24-28) cefadroxil(29), cefaclor,(23) cefamandole,(30)|
01080|045|D|ceftizoxime,(31,32) cefuroxime,(33,34) cefprozil,(35) cefonicid,(36)|
01080|046|D|cefmetazole,(37) cefmenoxime,(38) and cefditoren.(39)|
01080|047|D|   Probenecid has been shown not to affect moxalactam,(4,40,41) ceforanide,|
01080|048|D|(4,42), cefoperazone, ceftazidime(4,34,43) or ceftriaxone.(4)|
01080|049|B||
01080|050|R|REFERENCES:|
01080|051|B||
01080|052|R|1.Hoffstedt B, Haidl S, Walder M. Influence of probenecid on serum and|2
01080|053|R|  subcutaneous tissue fluid concentrations of benzylpenicillin and|2
01080|054|R|  ceftazidime in human volunteers. Eur J Clin Microbiol 1983 Dec;2(6):604-6.|2
01080|055|R|2.Stoeckel K, Trueb V, Dubach UC, McNamara PJ. Effect of probenecid on the|2
01080|056|R|  elimination and protein binding of ceftriaxone. Eur J Clin Pharmacol 1988;|2
01080|057|R|  34(2):151-6.|2
01080|058|R|3.Gibaldi M, Schwartz MA. Apparent effect of probenecid on the distribution|2
01080|059|R|  of penicillins in man. Clin Pharmacol Ther 1968 May-Jun;9(3):345-9.|2
01080|060|R|4.Brown GR. Cephalosporin-probenecid drug interactions. Clin Pharmacokinet|6
01080|061|R|  1993 Apr;24(4):289-300.|6
01080|062|R|5.Welling PG, Dean S, Selen A, Kendall MJ, Wise R. Probenecid: an|2
01080|063|R|  unexplained effect on cephalosporin pharmacology. Br J Clin Pharmacol 1979|2
01080|064|R|  Nov;8(5):491-5.|2
01080|065|R|6.Tuano SB, Brodie JL, Kirby WM. Cephaloridine versus cephalothin: relation|2
01080|066|R|  of the kidney to blood level differences after parenteral administration.|2
01080|067|R|  Antimicrobial Agents Chemother 1966;6:101-6.|2
01080|068|R|7.Kaplan K, Reisberg BE, Weinstein L. Cephaloridine: antimicrobial activity|2
01080|069|R|  and pharmacologic behavior. Am J Med Sci 1967 Jun;253(6):667-74.|2
01080|070|R|8.Kump J, Moskowitz J, Ehrenkranz NJ, Panunzio Y. Cephaloridine in the|2
01080|071|R|  treatment of streptococcal endocarditis: a preliminary evaluation. South|2
01080|072|R|  Med J 1969 Apr;62(4):461-4.|2
01080|073|R|9.Duncan WC. Treatment of gonorrhea with cefazolin plus probenecid. J Infect|2
01080|074|R|  Dis 1974 Oct;130(4):398-401.|2
01080|075|R|10.Spina SP, Dillon EC Jr. Effect of chronic probenecid therapy on cefazolin|2
01080|076|R|   serum concentrations. Ann Pharmacother 2003 May;37(5):621-4.|2
01080|077|R|11.Brown G, Zemcov SJ, Clarke AM. Effect of probenecid on cefazolin serum|2
01080|078|R|   concentrations. J Antimicrob Chemother 1993 Jun;31(6):1009-11.|2
01080|079|R|12.Westenfelder SR, Naber KG, Madsen PO. Pharmacokinetics of a new|2
01080|080|R|   cephalosporin, cephacetrile, in patients with normal and impaired renal|2
01080|081|R|   function. Arzneimittelforschung 1974 Sep;24(9b):1481-5.|2
01080|082|R|13.Wise R, Reeves DS. Pharmacological studies on cephacetrile in human|2
01080|083|R|   volunteers. Curr Med Res Opin 1974;2(5):249-55.|2
01080|084|R|14.Pitt J, Siasoco R, Kaplan K, Weinstein L. Antimicrobial activity and|6
01080|085|R|   pharmacological behavior of cephaloglycine. Antimicrobial Agents|6
01080|086|R|   Chemother 1967;7:630-5.|6
01080|087|R|15.Applestein JM, Crosby EB, Johnson WD, Kaye D. In vitro antimicrobial|2
01080|088|R|   activity and human pharmacology of cephaloglycin. Appl Microbiol 1968|2
01080|089|R|   Jul;16(7):1006-10.|2
01080|090|R|16.Thornhill TS, Levison ME, Johnson WD, Kaye D. In vitro antimicrobial|2
01080|091|R|   activity and human pharmacology of cephalexin, a new orally absorbed|2
01080|092|R|   cephalosporin C antibiotic. Appl Microbiol 1969 Mar;17(3):457-61.|2
01080|093|R|17.Meyers BR, Kaplan K, Weinstein L. Cephalexin: microbiological effects and|2
01080|094|R|   pharmacologic parameters in man. Clin Pharmacol Ther 1969 Nov-Dec;|2
01080|095|R|   10(6):810-6.|2
01080|096|R|18.Taylor WA, Holloway WJ. Cephalexin in the treatment of gonorrhea. Int J|2
01080|097|R|   Clin Pharmacol 1972 Apr;6(1):7-9.|2
01080|098|R|19.Sales JE, Sutcliffe M, O'Grady F. Cephalexin levels in human bile in|2
01080|099|R|   presence of biliary tract disease. Br Med J 1972 Aug 19;3(824):441-3.|2
01080|100|R|20.Regamey C, Libke RD, Clarke JT, Kirby WM. Pharmacokinetics of parenteral|2
01080|101|R|   sodium cephalexin in comparison with cephalothin and cefazolin. Infection|2
01080|102|R|   1974;2(3):132-6.|2
01080|103|R|21.Oller LZ, Smith HG, Marshall MJ. Cephaloridine and cephalexin in|2
01080|104|R|   venereological practice. Postgrad Med J 1970 Oct;Suppl:99-102.|2
01080|105|R|22.Mischler TW, Sugerman AA, Willard DA, Brannick LJ, Neiss ES. Influence of|2
01080|106|R|   probenecid and food on the bioavailability of cephradine in normal male|2
01080|107|R|   subjects. J Clin Pharmacol 1974 Nov-Dec;14(11-12):604-11.|2
01080|108|R|23.Roberts DH, Kendall MJ, Jack DB, Welling PG. Pharmacokinetics of|2
01080|109|R|   cephradine given intravenously with and without probenecid. Br J Clin|2
01080|110|R|   Pharmacol 1981 Jun;11(6):561-4.|2
01080|111|R|24.Reeves DS, Bullock DW, Bywater MJ, Holt HA, White LO, Thornhill DP. The|2
01080|112|R|   effect of probenecid on the pharmacokinetics and distribution of|2
01080|113|R|   cefoxitin in healthy volunteers. Br J Clin Pharmacol 1981 Apr;|2
01080|114|R|   11(4):353-9.|2
01080|115|R|25.Goodwin CS, Raftery EB, Goldberg AD, Skeggs H, Till AE, Martin CM.|2
01080|116|R|   Effects of rate of infusion and probenecid on serum levels, renal|2
01080|117|R|   excretion, and tolerance of intravenous doses of cefoxitin in humans:|2
01080|118|R|   comparison with cephalothin. Antimicrob Agents Chemother 1974 Sep;|2
01080|119|R|   6(3):338-46.|2
01080|120|R|26.Bint AJ, Reeves DS, Holt HA. Effect of probenecid on serum cefoxitin|2
01080|121|R|   concentrations. J Antimicrob Chemother 1977 Nov;3(6):627-8.|2
01080|122|R|27.Arvidsson A, Borga O, Kager L, Pieper R. Renal elimination of cefoxitin|2
01080|123|R|   and effect of probenecid after single and repeated doses. J Antimicrob|2
01080|124|R|   Chemother 1981 Apr;7(4):423-30.|2
01080|125|R|28.Vlasses PH, Holbrook AM, Schrogie JJ, Rogers JD, Ferguson RK, Abrams WB.|2
01080|126|R|   Effect of orally administered probenecid on the pharmacokinetics of|2
01080|127|R|   cefoxitin. Antimicrob Agents Chemother 1980 May;17(5):847-55.|2
01080|128|R|29.Marino EL, Dominguez-Gil A. The pharmacokinetics of cefadroxil associated|2
01080|129|R|   with probenecid. Int J Clin Pharmacol Ther Toxicol 1981 Nov;19(11):506-8.|2
01080|130|R|30.Griffith RS, Black HR, Brier GL, Wolny JD. Effect of probenecid on the|2
01080|131|R|   blood levels and urinary excretion of cefamandole. Antimicrob Agents|2
01080|132|R|   Chemother 1977 May;11(5):809-12.|2
01080|133|R|31.LeBel M, Paone RP, Lewis GP. Effect of probenecid on the pharmacokinetics|2
01080|134|R|   of ceftizoxime. J Antimicrob Chemother 1983 Aug;12(2):147-55.|2
01080|135|R|32.Adam D, Timmler R. Pharmacokinetics of ceftizoxime with and without|2
01080|136|R|   probenecid. Arzneimittelforschung 1982;32(4):416-9.|2
01080|137|R|33.Garton AM, Rennie RP, Gilpin J, Marrelli M, Shafran SD. Comparison of|2
01080|138|R|   dose doubling with probenecid for sustaining serum cefuroxime levels. J|2
01080|139|R|   Antimicrob Chemother 1997 Dec;40(6):903-6.|2
01080|140|R|34.Verhagen CA, Mattie H, Van Strijen E. The renal clearance of cefuroxime|2
01080|141|R|   and ceftazidime and the effect of probenecid on their tubular excretion.|2
01080|142|R|   Br J Clin Pharmacol 1994 Feb;37(2):193-7.|2
01080|143|R|35.Shukla UA, Pittman KA, Barbhaiya RH. Pharmacokinetic interactions of|2
01080|144|R|   cefprozil with food, propantheline, metoclopramide, and probenecid in|2
01080|145|R|   healthy volunteers. J Clin Pharmacol 1992 Aug;32(8):725-31.|2
01080|146|R|36.Pitkin D, Dubb J, Actor P, Alexander F, Ehrlich S, Familiar R, Stote R.|2
01080|147|R|   Kinetics and renal handling of cefonicid. Clin Pharmacol Ther 1981 Nov;|2
01080|148|R|   30(5):587-93.|2
01080|149|R|37.Ko H, Cathcart KS, Griffith DL, Peters GR, Adams WJ. Pharmacokinetics of|2
01080|150|R|   intravenously administered cefmetazole and cefoxitin and effects of|2
01080|151|R|   probenecid on cefmetazole elimination. Antimicrob Agents Chemother 1989|2
01080|152|R|   Mar;33(3):356-61.|2
01080|153|R|38.Sennello LT, Quinn D, Rollins DE, Tolman KG, Sonders RC. Effect of|2
01080|154|R|   probenecid on the pharmacokinetics of cefmenoxime. Antimicrob Agents|2
01080|155|R|   Chemother 1983 Jun;23(6):803-7.|2
01080|156|R|39.Spectracef (cefditoren pivoxil) US prescribing information. Cornerstone|1
01080|157|R|   BioPharma, Inc. July, 2008.|1
01080|158|R|40.Shimada J, Ueda Y. Moxalactam--absorption, excretion, distribution, and|2
01080|159|R|   metabolism. Rev Infect Dis 1982 Nov-Dec;4 Suppl:S569-80.|2
01080|160|R|41.DeSante KA, Israel KS, Brier GL, Wolny JD, Hatcher BL. Effect of|2
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01080|164|R|   to alter the pharmacokinetics of ceforanide. Antimicrob Agents Chemother|2
01080|165|R|   1981 Oct;20(4):530-2.|2
01080|166|R|43.Fortaz (ceftazidime) US prescribing information. GlaxoSmithKline|1
01080|167|R|   February, 2020.|1
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01080|173|R|   High-Dose Oral Amoxicillin Plus Probenecid Is Highly Effective for|2
01080|174|R|   Syphilis in Patients With HIV Infection. Clin Infect Dis 2015 Jul 15;|2
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01080|179|R|   2012.|1
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01081|001|T|MONOGRAPH TITLE:  Lithium/Selected Phenothiazines|
01081|002|B||
01081|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01081|004|L|take action as needed.|
01081|005|B||
01081|006|A|MECHANISM OF ACTION:  The exact mechanism of the interaction is unknown.|
01081|007|A|Neurotoxicity symptoms (confusion, delirium, seizures, encephalopathy, and|
01081|008|A|EEG changes) may be due to potentiation or an additive effect of the|
01081|009|A|antipsychotic agent and the lithium.(1)  Cardiotoxic effects may be the|
01081|010|A|result of additive effects from thioridazine, and lithium.  Lithium may|
01081|011|A|lower intracellular potassium levels, which may increase the potential for|
01081|012|A|thioridazine toxcity.(2)|
01081|013|B||
01081|014|E|CLINICAL EFFECTS:  Phenothiazines and lithium may produce electrocardiogram|
01081|015|E|changes and neurotoxic symptoms.(1,3-5)  Ventricular arrhythmia, sinus|
01081|016|E|bradycardia, and first degree AV block have been seen with concurrent use of|
01081|017|E|thioridazine and lithium.(2)|
01081|018|B||
01081|019|P|PREDISPOSING FACTORS:  Large doses of either drug, pre-existing brain damage|
01081|020|P|or other conditions (e.g. infection, dehydration) may increase the risk for|
01081|021|P|neurotoxicity.|
01081|022|B||
01081|023|M|PATIENT MANAGEMENT:  Lithium and phenothiazines or other antipsychotics are|
01081|024|M|commonly co-prescribed in the treatment of bipolar disorder.  Although|
01081|025|M|uncommon to rare, cases of severe neurotoxicity have been reported with this|
01081|026|M|combination.  During initiation of concurrent treatment with lithium and|
01081|027|M|haloperidol, observe the patient closely for signs of neurotoxic or|
01081|028|M|extrapyramidal effects.|
01081|029|M|   Monitoring plasma levels is not always beneficial in preventing|
01081|030|M|neurotoxic symptoms.  Patients may experience neurotoxic symptoms with|
01081|031|M|plasma concentrations in the therapeutic ranges.  EEG monitoring may be of|
01081|032|M|benefit in the prevention of neurotoxicity. Consider avoiding concurrent|
01081|033|M|therapy.|
01081|034|B||
01081|035|D|DISCUSSION:  Neurotoxicity symptoms, ventricular arrhythmia, sinus|
01081|036|D|bradycardia, first degree AV block, and sleepwalking have been observed with|
01081|037|D|concurrent use of lithium carbonate and thioridazine.(1,3-5)|
01081|038|D|   Neurotoxicity symptoms and sleepwalking have also been seen when lithium|
01081|039|D|was given with thiothixene(4,5), fluphenazine(3,5-7), perphenazine(5,8), and|
01081|040|D|chlorpromazine.(5)|
01081|041|D|   It is unknown if the toxicities seen with thioridazine and lithium are|
01081|042|D|due to concomitant use of the drugs or from just one agent.  Ventricular|
01081|043|D|arrhythmia, sinus bradycardia, and first degree AV block resolved when one|
01081|044|D|of the agents was removed or the dose decreased.(2)|
01081|045|D|   It is best if these agents are not used concomitantly.  If necessary,|
01081|046|D|close monitoring of EEG status and neurotoxic symptoms should be practiced.|
01081|047|B||
01081|048|R|REFERENCES:|
01081|049|B||
01081|050|R|1.Spring GK. Neurotoxicity with combined use of lithium and thioridazine. J|3
01081|051|R|  Clin Psychiatry 1979 Mar;40(3):135-8.|3
01081|052|R|2.Liberatore MA, Robinson DS. Torsade de pointes: a mechanism for sudden|3
01081|053|R|  death associated with neuroleptic drug therapy?. J Clin Psychopharmacol|3
01081|054|R|  1984 Jun;4(3):143-6.|3
01081|055|R|3.Spring GK. EEG observations in confirming neurotoxicity. Am J Psychiatry|6
01081|056|R|  1979 Aug;136(8):1099-100.|6
01081|057|R|4.Prakash R, Kelwala S, Ban TA. Neurotoxicity with combined administration|3
01081|058|R|  of lithium and a neuroleptic. Compr Psychiatry 1982 Nov-Dec;23(6):567-71.|3
01081|059|R|5.Charney DS, Kales A, Soldatos CR, Nelson JC. Somnambulistic-like episodes|3
01081|060|R|  secondary to combined lithium-neuroleptic treatment. Br J Psychiatry 1979|3
01081|061|R|  Nov;135:418-24.|3
01081|062|R|6.Kamlana SH, Kerry RJ, Khan IA. Lithium: some drug interactions.|3
01081|063|R|  Practitioner 1980 Dec;224(1350):1291-2.|3
01081|064|R|7.Singh SV. Lithium carbonate/fluphenazine decanoate producing irreversible|3
01081|065|R|  brain damage. Lancet 1982 Jul 31;2(8292):278.|3
01081|066|R|8.Thornton WE, Pray BJ. Lithium intoxication: a report of two cases. Can|3
01081|067|R|  Psychiatr Assoc J 1975 Jun;20(4):281-2.|3
01082|001|T|MONOGRAPH TITLE:  Anesthetics/Aminoglycosides|
01082|002|B||
01082|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01082|004|L|of severe adverse interaction.|
01082|005|B||
01082|006|A|MECHANISM OF ACTION:  The neuromuscular blocking activity of aminoglycosides|
01082|007|A|results from a decreased sensitivity at the postjunctional membrane and|
01082|008|A|interfere with transmitter release.(1)  These actions produce a synergistic|
01082|009|A|effect with anesthetic agents that produce neuromuscular blockade.(2,3) Some|
01082|010|A|anesthetics cause renal failure due to release of fluoride ion.|
01082|011|A|Aminoglycosides cause nephrotoxicity when high doses are given.(4,5)|
01082|012|B||
01082|013|E|CLINICAL EFFECTS:  Increased neuromuscular blockade activity, profound|
01082|014|E|sedation, respiratory depression, coma, and/or death.  Circulatory collapse|
01082|015|E|may also occur secondary to the neuromuscular blockade.(6-10)  Decreased|
01082|016|E|urinary output and increased BUN and serum creatinine may indicate renal|
01082|017|E|impairment.|
01082|018|B||
01082|019|P|PREDISPOSING FACTORS:  Patients in respiratory distress, history of renal|
01082|020|P|impairment and high doses of aminoglycosides and anesthetics.|
01082|021|B||
01082|022|M|PATIENT MANAGEMENT:  Monitor neuromuscular blockade with train-of-four|
01082|023|M|stimulus.  Monitor vital signs, and respiratory rate.  Intravenous|
01082|024|M|neostigmine (0.2 to 2.5 mg), calcium (1 G), and possibly sodium bicarbonate|
01082|025|M|(dose not reported) may be beneficial in reversal of neuromuscular blockade|
01082|026|M|and respiratory depression.(6-10)  Supportive care and ventilation should be|
01082|027|M|utilized until the neuromuscular blockade is resolved.  Volume replacement|
01082|028|M|may be necessary for circulatory collapse.(6-10)  Monitor BUN, serum|
01082|029|M|creatinine, and urinary output and adjust aminoglycoside and anesthetic|
01082|030|M|doses according to renal function.|
01082|031|B||
01082|032|D|DISCUSSION:  Aminoglycosides including kanamycin(6,11), streptomycin(6,13),|
01082|033|D|amikacin(13), gentamicin(7,13-15), neomycin, and tobramycin(13) have been|
01082|034|D|documented to have neuromuscular blocking activity.  There is no|
01082|035|D|documentation with netilmicin and paromomycin, though it is assumed that|
01082|036|D|they produce the same effects as the other members of this class.  Neomycin|
01082|037|D|has been shown to interact with cyclopropane(8,9), halothane(6),|
01082|038|D|methoxyflurane(6), and nitrous oxide(6).  Enflurane, ethylene, and|
01082|039|D|isoflurane share similar properties to the previous inhalation anesthetics|
01082|040|D|and would likely interact with neomycin.  Kanamycin(6,11) and streptomycin|
01082|041|D|(6,12) are known to interact with ether.  Gentamicin has been reported to|
01082|042|D|potentiate atracurium.(16)  Therefore it is hypothesized that all|
01082|043|D|aminoglycosides interact with the inhaled anesthetics.  One study evaluating|
01082|044|D|gentamicin and halothane in animals did not exhibit a decrease in muscle|
01082|045|D|strength.(17)  Aminoglycosides have been proven to be nephrotoxic at high|
01082|046|D|doses.  Anesthetics containing fluoride also produce renal dysfunction.|
01082|047|D|Nephrotoxicity occurred more often when gentamicin or tobramycin were given|
01082|048|D|with enflurane than when enflurane was given alone or in patients who|
01082|049|D|received nitrous oxide and opioid anesthesia.(4)|
01082|050|B||
01082|051|R|REFERENCES:|
01082|052|B||
01082|053|R|1.Waud BE, Waud DR. Comparison of the effects of general anesthethics on the|3
01082|054|R|  end-plate of skeletal muscle. Anesthesiology 1975 Nov;43(5):540-7.|3
01082|055|R|2.Corrado AP, Ramos AO, de Escobar CT. Neuro-muscular blockade by neomycin|3
01082|056|R|  potentiation by ether anesthesia and d-tubocurarine and antagonism by|3
01082|057|R|  calcium and prostigmine. Arch Int Pharmacodyn Ther 1959;121(3-4):380-394.|3
01082|058|R|3.Vital Brazil O, Prado-Franceschi J. The nature of neuromuscular block|3
01082|059|R|  produced by neomycin and gentamicin. Arch Int Pharmacodyn Ther 1969 May;|3
01082|060|R|  179(1):78-85.|3
01082|061|R|4.Motuz DJ, Watson WA, Barlow JC, Velasquez NV, Schentag JJ. The increase in|3
01082|062|R|  urinary alanine aminopeptidase excretion associated with enflurane|3
01082|063|R|  anesthesia is increased further by aminoglycosides. Anesth Analg 1988 Aug;|3
01082|064|R|  67(8):770-4.|3
01082|065|R|5.Merino GE, Buselmeier TJ, Kjellstrand CM. Postoperative chronic renal|3
01082|066|R|  failure: a new syndrome?. Ann Surg 1975 Jul;182(1):37-44.|3
01082|067|R|6.Pittinger CB, Eryasa Y, Adamson R. Antibiotic-induced paralysis. Anesth|6
01082|068|R|  Analg 1970 May-Jun;49(3):487-501.|6
01082|069|R|7.Pittinger C, Adamson R. Antibiotic blockade of neuromuscular function.|6
01082|070|R|  Annu Rev Pharmacol 1972;12:169-84.|6
01082|071|R|8.Webber BM. Respiratory arrest following intraperitoneal administration of|3
01082|072|R|  neomycin. A M A Arch Surg 1957;75:174-6.|3
01082|073|R|9.Jones WPG. Calcium treatment for ineffective respiration resulting from|3
01082|074|R|  administration of neomycin. J Am Med Assoc 1959 Jun 20;170(8):943-4.|3
01082|075|R|10.Wright EA, McQuillen MP. Antibiotic-induced neuromuscular blockade. Ann N|3
01082|076|R|   Y Acad Sci 1971 Sep 15;183:358-68.|3
01082|077|R|11.Brady JP, Williams HC. Magnesium intoxication in a premature infant.|3
01082|078|R|   Pediatrics 1967 Jul;40(1):100-3.|3
01082|079|R|12.Levanen J, Nordman R. Complete respiratory paralysis caused by a large|3
01082|080|R|   dose of streptomycin and its treatment with calcium chloride. Ann Clin|3
01082|081|R|   Res 1975 Feb;7(1):47-9.|3
01082|082|R|13.L'Hommedieu CS, Nicholas D, Armes DA, Jones P, Nelson T, Pickering LK.|3
01082|083|R|   Potentiation of magnesium sulfate--induced neuromuscular weakness by|3
01082|084|R|   gentamicin, tobramycin, and amikacin. J Pediatr 1983 Apr;102(4):629-31.|3
01082|085|R|14.Warner WA, Sanders E. Neuromuscular blockade associated with gentamicin|3
01082|086|R|   therapy. JAMA 1971 Feb 15;215(7):1153-4.|3
01082|087|R|15.Holtzman JL. Letter: Gentamicin and neuromuscular blockade. Ann Intern|3
01082|088|R|   Med 1976 Jan;84(1):55.|3
01082|089|R|16.Martinez EA, Mealey KL, Wooldridge AA, Mercer DE, Cooper J, Slater MR,|5
01082|090|R|   Hartsfield SM. Pharmacokinetics, effects on renal function, and|5
01082|091|R|   potentiation of atracurium-induced neuromuscular blockade after|5
01082|092|R|   administration of a high dose of gentamicin in isoflurane-anesthetized|5
01082|093|R|   dogs. Am J Vet Res 1996 Nov;57(11):1623-6.|5
01082|094|R|17.Hague BA, Martinez EA, Hartsfield SM. Effects of high-dose gentamicin|5
01082|095|R|   sulfate on neuromuscular blockade in halothane-anesthetized horses. Am J|5
01082|096|R|   Vet Res 1997 Nov;58(11):1324-6.|5
01083|001|T|MONOGRAPH TITLE:  Xanthine Derivatives/Charcoal|
01083|002|B||
01083|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01083|004|L|take action as needed.|
01083|005|B||
01083|006|A|MECHANISM OF ACTION:  Theophylline is absorbed by activated charcoal.(1) The|
01083|007|A|absorption results in decreased theophylline absorption from the|
01083|008|A|gastrointestinal tract, decreased enterohepatic recirculation, and increased|
01083|009|A|theophylline clearance.(1-14)|
01083|010|B||
01083|011|E|CLINICAL EFFECTS:  Theophylline absorption is decreased and clearance is|
01083|012|E|increased as charcoal absorbs the theophylline.|
01083|013|B||
01083|014|P|PREDISPOSING FACTORS:  None determined.|
01083|015|B||
01083|016|M|PATIENT MANAGEMENT:  In a theophylline overdose the charcoal should be|
01083|017|M|administered as soon as possible.  Theophylline clearance may increase with|
01083|018|M|continued administration.  If the charcoal is not being given for|
01083|019|M|theophylline overdose, a higher dose of theophylline should be given, or|
01083|020|M|administration times should be separated.|
01083|021|B||
01083|022|D|DISCUSSION:  Activated charcoal is more effective than gastric lavage,|
01083|023|D|emesis, or sorbitol catharsis and is considered first line therapy for|
01083|024|D|sustained-release theophylline overdose.(15,16)  Theophylline half-life has|
01083|025|D|been reported to be decreased up to 52%, and clearance increased up to 96%.|
01083|026|D|(5) Mean plasma level of a single dose of slow-release theophylline|
01083|027|D|decreased by 39%.(2)  Activated charcoal is also effective in treating|
01083|028|D|aminophylline overdose.(17)|
01083|029|B||
01083|030|R|REFERENCES:|
01083|031|B||
01083|032|R|1.Sintek C, Hendeles L, Weinberger M. Inhibition of theophylline absorption|3
01083|033|R|  by activated charcoal. J Pediatr 1979 Feb;94(2):314-6.|3
01083|034|R|2.Helliwell M, Berry D. Theophylline absorption by effervescent activated|2
01083|035|R|  charcoal (Medicoal). J Int Med Res 1981;9(3):222-5.|2
01083|036|R|3.Ginoza GW, Strauss AA, Iskra MK, Modanlou HD. Potential treatment of|2
01083|037|R|  theophylline toxicity by high surface area activated charcoal. J Pediatr|2
01083|038|R|  1987 Jul;111(1):140-2.|2
01083|039|R|4.Goldberg MJ, Spector R, Park GD, Johnson GF, Roberts P. The effect of|2
01083|040|R|  sorbitol and activated charcoal on serum theophylline concentrations after|2
01083|041|R|  slow-release theophylline. Clin Pharmacol Ther 1987 Jan;41(1):108-11.|2
01083|042|R|5.True RJ, Berman JM, Mahutte CK. Treatment of theophylline toxicity with|3
01083|043|R|  oral activated charcoal. Crit Care Med 1984 Feb;12(2):113-4.|3
01083|044|R|6.Berlinger WG, Spector R, Goldberg MJ, Johnson GF, Quee CK, Berg MJ.|2
01083|045|R|  Enhancement of theophylline clearance by oral activated charcoal. Clin|2
01083|046|R|  Pharmacol Ther 1983 Mar;33(3):351-4.|2
01083|047|R|7.Park GD, Radomski L, Goldberg MJ, Spector R, Johnson GF, Quee CK. Effects|2
01083|048|R|  of size and frequency of oral doses of charcoal on theophylline clearance.|2
01083|049|R|  Clin Pharmacol Ther 1983 Nov;34(5):663-6.|2
01083|050|R|8.Mahutte CK, True RJ, Michiels TM, Berman JM, Light RW. Increased serum|2
01083|051|R|  theophylline clearance with orally administered activated charcoal. Am Rev|2
01083|052|R|  Respir Dis 1983 Nov;128(5):820-2.|2
01083|053|R|9.Radomski L, Park GD, Goldberg MJ, Spector R, Johnson GF, Quee CK. Model|2
01083|054|R|  for theophylline overdose treatment with oral activated charcoal. Clin|2
01083|055|R|  Pharmacol Ther 1984 Mar;35(3):402-8.|2
01083|056|R|10.Gal P, Miller A, McCue JD. Oral activated charcoal to enhance|3
01083|057|R|   theophylline elimination in an acute overdose. JAMA 1984 Jun 15;|3
01083|058|R|   251(23):3130-1.|3
01083|059|R|11.Sessler CN, Glauser FL, Cooper KR. Treatment of theophylline toxicity|2
01083|060|R|   with oral activated charcoal. Chest 1985 Mar;87(3):325-9.|2
01083|061|R|12.Davis R, Ellsworth A, Justus RE, Bauer LA. Reversal of theophylline|3
01083|062|R|   toxicity using oral activated charcoal. J Fam Pract 1985 Jan;20(1):73-4.|3
01083|063|R|13.Amitai Y, Yeung AC, Moye J, Lovejoy FH Jr. Repetitive oral activated|3
01083|064|R|   charcoal and control of emesis in severe theophylline toxicity. Ann|3
01083|065|R|   Intern Med 1986 Sep;105(3):386-7.|3
01083|066|R|14.Shannon M, Amitai Y, Lovejoy FH Jr. Multiple dose activated charcoal for|3
01083|067|R|   theophylline poisoning in young infants. Pediatrics 1987 Sep;|3
01083|068|R|   80(3):368-70.|3
01083|069|R|15.Minton NA, Glucksman E, Henry JA. Prevention of drug absorption in|6
01083|070|R|   simulated theophylline overdose. Hum Exp Toxicol 1995 Feb;14(2):170-4.|6
01083|071|R|16.Minton NA, Henry JA. Prevention of drug absorption in simulated|2
01083|072|R|   theophylline overdose. J Toxicol Clin Toxicol 1995;33(1):43-9.|2
01083|073|R|17.Jain R, Tholl DA. Activated charcoal for theophylline toxicity in a|3
01083|074|R|   premature infant on the second day of life. Dev Pharmacol Ther 1992;|3
01083|075|R|   19(2-3):106-10.|3
01084|001|T|MONOGRAPH TITLE:  Mifepristone/Corticosteroids|
01084|002|B||
01084|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01084|004|L|of severe adverse interaction.|
01084|005|B||
01084|006|A|MECHANISM OF ACTION:  Mifepristone is an antagonist of the progesterone and|
01084|007|A|glucocorticoid (GR-II) receptors, but has little effect at the|
01084|008|A|mineralocorticoid (GR-I) receptor.  Mifepristone has a higher affinity for|
01084|009|A|the glucocorticoid receptor than either dexamethasone or cortisol and will|
01084|010|A|displace both endogenous and exogenous glucocorticoids from their binding|
01084|011|A|sites.|
01084|012|B||
01084|013|E|CLINICAL EFFECTS:  Although serum cortisol levels rise, antagonism of the|
01084|014|E|glucocorticoid receptor may lead to adrenal insufficiency. Efficacy of|
01084|015|E|locally administered corticosteroids may be diminished.|
01084|016|B||
01084|017|P|PREDISPOSING FACTORS:  None determined.|
01084|018|B||
01084|019|M|PATIENT MANAGEMENT:  The manufacturers of mifepristone states that|
01084|020|M|mifepristone is contraindicated in patients receiving concurrent long-term|
01084|021|M|corticosteroid therapy.(1-2)  Due to its long mean half-life of 85 hours(2),|
01084|022|M|even short term mifepristone use may have an extended duration of effect.|
01084|023|B||
01084|024|D|DISCUSSION:  The manufacturers of mifepristone states that mifepristone is|
01084|025|D|contraindicated in patients receiving concurrent long-term corticosteroid|
01084|026|D|therapy.(1-2)|
01084|027|B||
01084|028|R|REFERENCES:|
01084|029|B||
01084|030|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
01084|031|R|  November, 2019.|1
01084|032|R|2.Mifeprex (mifepristone) US prescribing information. Danco Laboratories,|1
01084|033|R|  LLC January, 2023.|1
01085|001|T|MONOGRAPH TITLE:  Mifepristone/Anticoagulants; Antiplatelets|
01085|002|B||
01085|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01085|004|L|is contraindicated and generally should not be dispensed or administered to|
01085|005|L|the same patient.|
01085|006|B||
01085|007|A|MECHANISM OF ACTION:  Anticoagulants may result in excessive bleeding|
01085|008|A|following the abortion.|
01085|009|B||
01085|010|E|CLINICAL EFFECTS:  The concurrent use of mifepristone with anticoagulants|
01085|011|E|may result in excessive bleeding following the abortion.|
01085|012|B||
01085|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01085|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01085|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01085|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01085|017|P|risk for bleeding (e.g. NSAIDs).|
01085|018|B||
01085|019|M|PATIENT MANAGEMENT:  The manufacturer of mifepristone states that|
01085|020|M|mifepristone is contraindicated in patients receiving concurrent|
01085|021|M|anticoagulant therapy.(1)|
01085|022|M|   If concurrent therapy is deemed medically necessary, monitor patients|
01085|023|M|receiving concurrent therapy for signs of blood loss, including decreased|
01085|024|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
01085|025|M|and promptly evaluate patients with any symptoms.|
01085|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01085|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01085|028|M|anticoagulation in patients with active pathologic bleeding.|
01085|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01085|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01085|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01085|032|M|and/or swelling.|
01085|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01085|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01085|035|M|initiating, altering the dose or discontinuing either drug.|
01085|036|B||
01085|037|D|DISCUSSION:  The manufacturer of mifepristone states that mifepristone is|
01085|038|D|contraindicated in patients receiving concurrent anticoagulant therapy.(1)|
01085|039|B||
01085|040|R|REFERENCE:|
01085|041|B||
01085|042|R|1.Mifeprex (mifepristone) US prescribing information. Danco Laboratories,|1
01085|043|R|  LLC January, 2023.|1
01086|001|T|MONOGRAPH TITLE:  Mifepristone/Strong CYP3A4 Inducers|
01086|002|B||
01086|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01086|004|L|of severe adverse interaction.|
01086|005|B||
01086|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may accelerate the metabolism|
01086|007|A|of mifepristone by CYP3A4.(1,2)|
01086|008|B||
01086|009|E|CLINICAL EFFECTS:  The concurrent use of mifepristone and strong CYP3A4|
01086|010|E|inducers may result in decreased levels and effectiveness of|
01086|011|E|mifepristone.(1,2)|
01086|012|B||
01086|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01086|014|P|of the inducer for longer than 1-2 weeks.|
01086|015|B||
01086|016|M|PATIENT MANAGEMENT:  Avoid co-administration of mifepristone with strong|
01086|017|M|CYP3A4 inducers.(1-3)|
01086|018|M|   If mifepristone is used as a progestin antagonist and concurrent use|
01086|019|M|cannot be avoided, conduct post-treatment assessment as detailed in the|
01086|020|M|mifepristone prescribing information to verify treatment success.(1,3)|
01086|021|B||
01086|022|D|DISCUSSION:  In a study, rifampin decreased mifepristone area-under-curve|
01086|023|D|(AUC) by 6.3-fold.  The AUC of mifepristone active metabolites|
01086|024|D|22-hydroxy-mifepristone and N-demethyl-mifepristone decreased by 20-fold and|
01086|025|D|5.9-fold, respectively.(4)|
01086|026|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
01086|027|D|barbiturates, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
01086|028|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's|
01086|029|D|Wort.(5)|
01086|030|B||
01086|031|R|REFERENCES:|
01086|032|B||
01086|033|R|1.Mifeprex (mifepristone) US prescribing information. Danco Laboratories,|1
01086|034|R|  LLC January, 2023.|1
01086|035|R|2.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
01086|036|R|  November, 2019.|1
01086|037|R|3.Rifadin (rifampin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01086|038|R|  October, 2024.|1
01086|039|R|4.Rifadin (rifampin) UK Summary of Product Characteristics. Sanofi July 2,|1
01086|040|R|  2024.|1
01086|041|R|5.This information is based on an extract from the Certara Drug Interaction|6
01086|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01087|001|T|MONOGRAPH TITLE:  Trazodone/Ginkgo Biloba|
01087|002|B||
01087|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01087|004|L|Assess the risk to the patient and take action as needed.|
01087|005|B||
01087|006|A|MECHANISM OF ACTION:  Trazodone is metabolized by CYP3A4 to an active form,|
01087|007|A|1-(m-chlorophenyl)piperazine (mCPP), which enhances the release of GABA.|
01087|008|A|Flavonoids in ginkgo may possess GABAergic activity and may increase the|
01087|009|A|production of mCCP, leading to an excess of GABA activity.(1)|
01087|010|B||
01087|011|E|CLINICAL EFFECTS:  The concurrent use of trazodone and ginkgo may result in|
01087|012|E|excess GABA activity in the central nervous system (CNS), leading to|
01087|013|E|increased sedation and possible coma.(1)|
01087|014|B||
01087|015|P|PREDISPOSING FACTORS:  None determined.|
01087|016|B||
01087|017|M|PATIENT MANAGEMENT:  Patients receiving trazodone should be cautioned about|
01087|018|M|the potential for increased sedation and possibly coma with concurrent use|
01087|019|M|of ginkgo. One or both agents may need to be discontinued. Flumazenil may be|
01087|020|M|useful in reversing trazodone/ginkgo-induced coma.|
01087|021|B||
01087|022|D|DISCUSSION:  In a single case report, an 80 year-old female Alzheimer's|
01087|023|D|patient was treated with bromazepam, vitamin E, and donepezil. These agents|
01087|024|D|were discontinued and replaced with trazodone (20 mg twice daily) and ginkgo|
01087|025|D|(80 mg twice daily). Over the next two days, the patient's care giver noted|
01087|026|D|improvement in the patient's anxiety without sedation or other adverse|
01087|027|D|effects. On the third day at 6PM, the patient developed gait instability and|
01087|028|D|drowsiness. One hour later, she fell asleep and was not able to be aroused.|
01087|029|D|The patient had received 100 mg of trazodone and 320 mg of ginkgo in the|
01087|030|D|previous 50 hours. The patient awoke following the administration of 1 mg of|
01087|031|D|flumazenil. Trazodone and ginkgo were discontinued.(1)|
01087|032|B||
01087|033|R|REFERENCE:|
01087|034|B||
01087|035|R|1.Galluzzi S, Zanetti O, Binetti G, Trabucchi M, Frisoni GB. Coma in a|3
01087|036|R|  patient with Alzheimer's disease taking low dose trazodone and gingko|3
01087|037|R|  biloba. J Neurol Neurosurg Psychiatry 2000 May;68(5):679-80.|3
01088|001|T|MONOGRAPH TITLE:  Antidiabetic Agents/Ginseng|
01088|002|B||
01088|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01088|004|L|Assess the risk to the patient and take action as needed.|
01088|005|B||
01088|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown. Ginseng may slow the|
01088|007|A|digestion of food, thus decreasing the rate of carbohydrate metabolism into|
01088|008|A|portal hepatic circulation. Ginseng may also affect glucose transport.|
01088|009|B||
01088|010|E|CLINICAL EFFECTS:  The additive glucose lowering effect resulting from|
01088|011|E|concurrent use of these agents may result in hypoglycemia.|
01088|012|B||
01088|013|P|PREDISPOSING FACTORS:  None determined.|
01088|014|B||
01088|015|M|PATIENT MANAGEMENT:  Patients receiving both antidiabetic agents and ginseng|
01088|016|M|should be alerted to the possibility of the occurrence of hypoglycemic|
01088|017|M|events and how to respond if they experience hypoglycemia. The dosage of the|
01088|018|M|antidiabetic agent may need to be adjusted and/or ginseng may need to be|
01088|019|M|discontinued. The dosage of the antidiabetic agent may need to be adjusted|
01088|020|M|if ginseng is discontinued.|
01088|021|B||
01088|022|D|DISCUSSION:  In a placebo-controlled, randomized, cross-over study, the|
01088|023|D|effects of ginseng on glucose levels were examined in 10 non-diabetic|
01088|024|D|subjects and nine subjects with non-insulin dependent diabetes mellitus|
01088|025|D|(NIDDM). The two test treatments consisted of 3 grams of ginseng either 40|
01088|026|D|minutes before or together with a glucose challenge (300 ml containing 25|
01088|027|D|grams of glucose).  The control treatments consisted of a placebo either 40|
01088|028|D|minutes before or together with the glucose challenge.|
01088|029|D|   In non-diabetic subjects, there was no difference in glucose levels|
01088|030|D|between placebo and ginseng when ginseng was administered together with the|
01088|031|D|glucose challenge. In non-diabetic subjects, the glucose area-under-curve|
01088|032|D|(AUC) was reduced by 18% when ginseng was administered 40 minutes prior to|
01088|033|D|the glucose challenge when compared to placebo.|
01088|034|D|   In patients with NIDDM, the glucose AUC was decreased by 19% and 22% when|
01088|035|D|ginseng was administered before or together with the glucose challenge,|
01088|036|D|respectively, when compared to placebo.(1)|
01088|037|B||
01088|038|R|REFERENCE:|
01088|039|B||
01088|040|R|1.Vuksan V, Sievenpiper JL, Koo VY, Francis T, Beljan-Zdravkovic U, Xu Z,|2
01088|041|R|  Vidgen E. American ginseng (Panax quinquefolius L) reduces postprandial|2
01088|042|R|  glycemia in nondiabetic subjects and subjects with type 2 diabetes|2
01088|043|R|  mellitus. Arch Intern Med 2000 Apr 10;160(7):1009-13.|2
01089|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin (Greater Than 20 mg)/Azithromycin|
01089|002|B||
01089|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01089|004|L|take action as needed.|
01089|005|B||
01089|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Other macrolides|
01089|007|A|(e.g. erythromycin, clarithromycin) which are moderate or strong inhibitors|
01089|008|A|of CYP3A4 have been shown to increase levels of the HMG-CoA reductase|
01089|009|A|inhibitors (statins); however, azithromycin is a much weaker inhibitor of|
01089|010|A|this isoenzyme.(1,2)|
01089|011|A|   FDA has classified lovastatin and simvastatin as sensitive substrates at|
01089|012|A|CYP3A4.  Sensitive substrates are drugs whose plasma exposure|
01089|013|A|(area-under-curve or AUC) has been shown to increase > or = 5-fold  when|
01089|014|A|co-administered with a strong inhibitor of a specific enzyme.  A weak|
01089|015|A|inhibitor increases AUC of a sensitive substrate > 1.25-fold but < 2-fold.|
01089|016|A|Azithromycin is classified as a weak inhibitor of CYP3A4.(1)|
01089|017|B||
01089|018|E|CLINICAL EFFECTS:  Concurrent therapy may result in rhabdomyolysis. Symptoms|
01089|019|E|of rhabdomyolysis include muscle pain, tenderness, weakness, elevated|
01089|020|E|creatine kinase levels, and reddish-brown, heme positive urine.|
01089|021|B||
01089|022|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01089|023|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01089|024|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01089|025|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01089|026|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01089|027|P|transporter OATP1B1 may have increased statin concentrations and be|
01089|028|P|predisposed to myopathy or rhabdomyolysis.|
01089|029|B||
01089|030|M|PATIENT MANAGEMENT:  In patients with one or more predisposing risk factors|
01089|031|M|for statin associated myopathy it may be prudent to suspend lovastatin or|
01089|032|M|simvastatin during azithromycin therapy.  Rhabdomyolysis has been reported|
01089|033|M|with the combination of lovastatin or simvastatin and azithromycin.|
01089|034|M|   If temporary discontinuation of the HMG-CoA reductase inhibitor is not|
01089|035|M|possible, patients should be instructed to report any unexplained muscle|
01089|036|M|pain, tenderness, weakness, or discoloration of the urine.(3,4)|
01089|037|B||
01089|038|D|DISCUSSION:  A systematic screening of the World Health Organization Adverse|
01089|039|D|Drug Reaction database found case reports suggestive of an interaction|
01089|040|D|between azithromycin and statins.  The authors found 5 lovastatin and 20|
01089|041|D|simvastatin case reports and used a disproportionality measure which found|
01089|042|D|report rates were 1.88 and 3.55 times higher respectively than predicted.(5)|
01089|043|D|   A case report describes rhabdomyolysis in a 73 year old man with chronic|
01089|044|D|renal impairment, diabetes, hypertension, gout and hyperlipidemia with|
01089|045|D|regular medications which included allopurinol 100 mg daily, prednisone 5 mg|
01089|046|D|daily, labetalol, bumetanide, insulin, amlodipine (a weak CYP3A4 inhibitor)|
01089|047|D|and simvastatin 80 mg daily. Azithromycin 500 mg X1 day, then 250 mg daily|
01089|048|D|X4 days was prescribed for acute bronchitis.  One week later patient was|
01089|049|D|admitted to the hospital with a 5 day history of severe weakness and pain in|
01089|050|D|his arms and legs. He developed acute renal insufficiency (creatinine|
01089|051|D|baseline 1.7 increased to 3.8) and rhabdomyolysis (CPK 11,240 units/L).|
01089|052|D|Treatment led to resolution of symptoms in 3 weeks.  Simvastatin was|
01089|053|D|restarted at 40 mg daily and subsequently increased back to 80 mg daily|
01089|054|D|without recurrence of symptoms.(6)|
01089|055|D|   A case report describes a 56 year old man receiving buspirone, nefazodone|
01089|056|D|(a strong CYP3A4 inhibitor), lisinopril, aspirin and simvastatin 80 mg daily|
01089|057|D|without reported problems.  Azithromycin and fexofenadine were prescribed|
01089|058|D|for sinusitis.  He was admitted to the hospital 5 days later with a 2-3 day|
01089|059|D|history of generalized back,leg, and flank pain along with coca-cola colored|
01089|060|D|urine.  AST, ALT and creatine kinase were 2,324, 700, and 10,738|
01089|061|D|respectively. Patient was discharged after 8 days. His simvastatin was not|
01089|062|D|resumed.(7)|
01089|063|D|   An article reported two cases of rhabdomyolysis, one following the|
01089|064|D|addition of clarithromycin to lovastatin therapy and the other following the|
01089|065|D|addition of azithromycin to lovastatin therapy.(8)|
01089|066|B||
01089|067|R|REFERENCES:|
01089|068|B||
01089|069|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
01089|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01089|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01089|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01089|073|R|  11/14/2017.|1
01089|074|R|2.This information is based on an extract from the Certara Drug Interaction|6
01089|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01089|076|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01089|077|R|  February, 2014.|1
01089|078|R|4.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
01089|079|R|  2023.|1
01089|080|R|5.Strandell J, Bate A, Hagg S, Edwards IR. Rhabdomyolysis a result of|2
01089|081|R|  azithromycin and statins: an unrecognized interaction. Br J Clin Pharmacol|2
01089|082|R|  2009 Sep;68(3):427-34.|2
01089|083|R|6.Alreja G, Inayatullah S, Goel S, Braden G. Rhabdomyolysis caused by an|3
01089|084|R|  unusual interaction between azithromycin and simvastatin. J Cardiovasc Dis|3
01089|085|R|  Res 2012 Oct;3(4):319-22.|3
01089|086|R|7.Skrabal MZ, Stading JA, Cannella CA, Monaghan MS. Two cases of|3
01089|087|R|  rhabdomyolysis associated with high-dose simvastatin. Am J Health Syst|3
01089|088|R|  Pharm 2003 Mar 15;60(6):578-81.|3
01089|089|R|8.Grunden JW, Fisher KA. Lovastatin-induced rhabdomyolysis possibly|3
01089|090|R|  associated with clarithromycin and azithromycin. Ann Pharmacother 1997|3
01089|091|R|  Jul-Aug;31(7-8):859-63.|3
01089|092|R|9.Ayanian JZ, Fuchs CS, Stone RM. Lovastatin and rhabdomyolysis. Ann Intern|3
01089|093|R|  Med 1988 Oct 15;109(8):682-3.|3
01089|094|R|10.Lilley LL, Guanci R. Drug interaction triggers weakness. Am J Nurs 1998|3
01089|095|R|   Apr;98(4):10.|3
01090|001|T|MONOGRAPH TITLE:  Cerivastatin/Fibrates|
01090|002|B||
01090|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01090|004|L|is contraindicated and generally should not be dispensed or administered to|
01090|005|L|the same patient.|
01090|006|B||
01090|007|A|MECHANISM OF ACTION:  The mechanism of action may involve multiple pathways|
01090|008|A|and may be different depending on which fibrate is involved. Both statins|
01090|009|A|and fibric acid derivatives can cause myalgia and can produce an additive|
01090|010|A|effect when taken together. Fenofibrate and derivatives are known inhibitors|
01090|011|A|of CYP2A6, CYP2C8, and CYP2C9 which could increase plasma concentration of|
01090|012|A|several statins including cerivastatin, rosuvastatin, and fluvastatin.|
01090|013|A|Interactions between statins and gemfibrozil are not likely due to|
01090|014|A|gemfibrozil's inhibitory effect on the CYP system, but rather by its|
01090|015|A|impairment of the hepatic glucuronidation pathway. Gemfibrozil is a strong|
01090|016|A|inhibitor of the glucuronidation-mediated lactonization of several statins|
01090|017|A|thereby increasing the concentration of active statin acid.(12-16)|
01090|018|B||
01090|019|E|CLINICAL EFFECTS:  The concurrent administration of cerivastatin with a|
01090|020|E|fibric acid derivative may result in rhabdomyolysis and/or renal failure.|
01090|021|E|Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness,|
01090|022|E|elevated creatine kinase levels, and reddish-brown, hemepositive urine.|
01090|023|B||
01090|024|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01090|025|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01090|026|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01090|027|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01090|028|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01090|029|P|transporter OATP1B1 may have increased statin concentrations and be|
01090|030|P|predisposed to myopathy or rhabdomyolysis.|
01090|031|B||
01090|032|M|PATIENT MANAGEMENT:  The concurrent administration of cerivastatin with|
01090|033|M|gemfibrozil is contraindicated.(1,2)|
01090|034|M|   The concurrent administration of cerivastatin with other fibrates should|
01090|035|M|be avoided.(1)  Consider the use of an alternative statin in patients whom|
01090|036|M|require fibric acid derivative therapy.|
01090|037|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
01090|038|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
01090|039|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
01090|040|M|urine, and/or discolored urine.|
01090|041|B||
01090|042|D|DISCUSSION:  Rhabdomyolysis(3-7) and renal failure(3,4) have been reported|
01090|043|D|in patients receiving concurrent cerivastatin and gemfibrozil.|
01090|044|D|Rhabdomyolysis and renal failure have also been reported with the|
01090|045|D|combination of cerivastatin and bezafibrate(8).|
01090|046|D|   In a retrospective cohort study of 252,460 patients, cerivastatin in|
01090|047|D|combination with fibrate resulted in a rhabdomyolysis risk of 1 in 10|
01090|048|D|treated patients per year.  The risk of hospitalization due to|
01090|049|D|rhabdomyolysis for patients aged 65 or older with diabetes treated with a|
01090|050|D|statin and a fibrate increased 1411-fold compared to stain monotherapy.(9)|
01090|051|D|   A case-crossover study consisting of 93,831 patients evaluated statin and|
01090|052|D|statin/fibrate use and their association with myopathy.  The study showed|
01090|053|D|that cerivastatin had an increased relative risk (2.05, 95% CI 1.2-3.5) for|
01090|054|D|myopathy over atorvastatin at 12 weeks.(10)|
01090|055|D|   A review of case reports submitted to the FDA's AERS database for statin-|
01090|056|D|and statin/gemfibrozil-associated rhabdomyolysis and showed that the|
01090|057|D|reporting rates for patients taking cerivastatin were higher than other|
01090|058|D|statins at 4.24/100,000 prescriptions vs. < 1/100,000 prescriptions,|
01090|059|D|respectively.(11)|
01090|060|D|   The ACCORD trial was a randomized trial of 5518 patients with type 2|
01090|061|D|diabetes receiving simvastatin (40 mg per day or less) and either|
01090|062|D|fenofibrate (initial dose of 160 mg per day, dose adjusted for renal|
01090|063|D|function) or placebo.  At the mean follow up of 4.7 years, the primary|
01090|064|D|efficacy endpoint of first occurrence of a major cardiovascular event,|
01090|065|D|including nonfatal myocardial infarction, nonfatal stroke, or death from|
01090|066|D|cardiovascular causes, occurred at an annual rate of 2.2% in the fenofibrate|
01090|067|D|group and 2.4 % in the placebo group (p=0.32).(17)|
01090|068|B||
01090|069|R|REFERENCES:|
01090|070|B||
01090|071|R|1.Baycol (cerivastatin) US prescribing information. Bayer Corporation|1
01090|072|R|  December, 2000.|1
01090|073|R|2.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
01090|074|R|  Ltd. November, 2014.|1
01090|075|R|3.Ozdemir O, Boran M, Gokce V, Uzun Y, Kocak B, Korkmaz S. A case with|3
01090|076|R|  severe rhabdomyolysis and renal failure associated with|3
01090|077|R|  cerivastatin-gemfibrozil combination therapy--a case report. Angiology|3
01090|078|R|  2000 Aug;51(8):695-7.|3
01090|079|R|4.Pogson GW, Kindred LH, Carper BG. Rhabdomyolysis and renal failure|3
01090|080|R|  associated with cerivastatin- gemfibrozil combination therapy. Am J|3
01090|081|R|  Cardiol 1999 Apr 1;83(7):1146.|3
01090|082|R|5.Bermingham RP, Whitsitt TB, Smart ML, Nowak DP, Scalley RD. Rhabdomyolysis|3
01090|083|R|  in a patient receiving the combination of cerivastatin and gemfibrozil. Am|3
01090|084|R|  J Health Syst Pharm 2000 Mar 1;57(5):461-4.|3
01090|085|R|6.Alexandridis G, Pappas GA, Elisaf MS. Rhabdomyolysis due to combination|3
01090|086|R|  therapy with cerivastatin and gemfibrozil. Am J Med 2000 Aug 15;|3
01090|087|R|  109(3):261-2.|3
01090|088|R|7.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of a|3
01090|089|R|  statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
01090|090|R|  2002;101(7):53-6.|3
01090|091|R|8.Plotkin E, Bernheim J, Ben-Chetrit S, Mor A, Korzets Z. Influenza|3
01090|092|R|  vaccine--a possible trigger of rhabdomyolysis induced acute renal failure|3
01090|093|R|  due to the combined use of cerivastatin and bezafibrate. Nephrol Dial|3
01090|094|R|  Transplant 2000 May;15(5):740-1.|3
01090|095|R|9.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
01090|096|R|  Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized|2
01090|097|R|  rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004|2
01090|098|R|  Dec 1;292(21):2585-90.|2
01090|099|R|10.Molokhia M, McKeigue P, Curcin V, Majeed A. Statin induced myopathy and|2
01090|100|R|   myalgia: time trend analysis and comparison of risk associated with|2
01090|101|R|   statin class from 1991-2006. PLoS One 2008;3(6):e2522.|2
01090|102|R|11.Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA|2
01090|103|R|   reductase inhibitors and gemfibrozil combination therapy.|2
01090|104|R|   Pharmacoepidemiol Drug Saf 2004 Jul;13(7):417-26.|2
01090|105|R|12.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
01090|106|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
01090|107|R|13.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
01090|108|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
01090|109|R|   95(1):120-2.|2
01090|110|R|14.Corsini A, Bellosta S, Davidson MH. Pharmacokinetic interactions between|6
01090|111|R|   statins and fibrates. Am J Cardiol 2005 Nov 7;96(9A):44K-49K; discussion|6
01090|112|R|   34K-35K.|6
01090|113|R|15.Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Effects of|5
01090|114|R|   fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos|5
01090|115|R|   2002 Nov;30(11):1280-7.|5
01090|116|R|16.Ballantyne CM, Davidson MH. Possible differences between fibrates in|6
01090|117|R|   pharmacokinetic interactions with statins. Arch Intern Med 2003 Oct 27;|6
01090|118|R|   163(19):2394-5.|6
01090|119|R|17.Ginsberg HN, Elam MB, Lovato LC, Crouse JRetal. Effects of combination|2
01090|120|R|   lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010 Apr 29;|2
01090|121|R|   362(17):1563-74.|2
01091|001|T|MONOGRAPH TITLE:  Ketoconazole/Sucralfate|
01091|002|B||
01091|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01091|004|L|take action as needed.|
01091|005|B||
01091|006|A|MECHANISM OF ACTION:  Sucralfate may decrease the absorption of ketoconazole|
01091|007|A|by binding to ketoconazole(1,2) or by decreasing gastric pH.(3)|
01091|008|B||
01091|009|E|CLINICAL EFFECTS:  The simultaneous administration of sucralfate and|
01091|010|E|ketoconazole may decrease the absorption of ketoconazole, which may result|
01091|011|E|in therapeutic failures.|
01091|012|B||
01091|013|P|PREDISPOSING FACTORS:  None determined.|
01091|014|B||
01091|015|M|PATIENT MANAGEMENT:  The administration of sucralfate and ketoconazole|
01091|016|M|should be separated by two hours.(1)|
01091|017|B||
01091|018|D|DISCUSSION:  In a randomized cross-over study in six subjects, the|
01091|019|D|simultaneous administration of a sucralfate suspension (1 g in 30 ml of|
01091|020|D|water) and ketoconazole (400 mg) decreased ketoconazole maximum|
01091|021|D|concentration (Cmax) and area-under-curve (AUC) by 34.3% (from 8.20 ug/ml to|
01091|022|D|5.39 ug.ml) and 21.3%, respectively, when compared to the administration of|
01091|023|D|ketoconazole alone.(3)|
01091|024|D|   In a randomized cross-over study in 12 subjects, the simultaneous|
01091|025|D|administration of ketoconazole with sucralfate decreased the ketoconazole|
01091|026|D|Cmax and AUC by 27.7% (from 12.34 ug/ml to 8.92 ug/ml) and 24% (from 78.12|
01091|027|D|ugxh/ml to 59.32 ugxh/ml), respectively, when compared to the administration|
01091|028|D|of ketoconazole alone. When the administration of ketoconazole and|
01091|029|D|sucralfate were separated by two hours, there was no significant difference|
01091|030|D|in the pharmacokinetic parameters of ketoconazole when compared to the|
01091|031|D|administration of ketoconazole alone.(1)|
01091|032|D|   An in vitro study found that sucralfate decreased the solubility of|
01091|033|D|ketoconazole.(2)|
01091|034|B||
01091|035|R|REFERENCES:|
01091|036|B||
01091|037|R|1.Carver PL, Berardi RR, Knapp MJ, Rider JM, Kauffman CA, Bradley SF, Atassi|2
01091|038|R|  M. In vivo interaction of ketoconazole and sucralfate in healthy|2
01091|039|R|  volunteers. Antimicrob Agents Chemother 1994 Feb;38(2):326-9.|2
01091|040|R|2.Hoeschele JD, Roy AK, Pecoraro VL, Carver PL. In vitro analysis of the|5
01091|041|R|  interaction between sucralfate and ketoconazole. Antimicrob Agents|5
01091|042|R|  Chemother 1994 Feb;38(2):319-25.|5
01091|043|R|3.Piscitelli SC, Goss TF, Wilton JH, D'Andrea DT, Goldstein H, Schentag JJ.|2
01091|044|R|  Effects of ranitidine and sucralfate on ketoconazole bioavailability.|2
01091|045|R|  Antimicrob Agents Chemother 1991 Sep;35(9):1765-71.|2
01092|001|T|MONOGRAPH TITLE:  Azathioprine/ACE Inhibitors|
01092|002|B||
01092|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01092|004|L|take action as needed.|
01092|005|B||
01092|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown. Azathioprine-induced|
01092|007|A|impairment of hematopoiesis and ACE inhibitor-induced decreases in|
01092|008|A|erythropoietin may result in additive effects on bone marrow.(1,2)|
01092|009|B||
01092|010|E|CLINICAL EFFECTS:  The concurrent use of azathioprine and an ACE inhibitor|
01092|011|E|may result in anemia or leucopenia.(1-6)  ACE inhibitors have been used to|
01092|012|E|correct post-transplantation erythrocytosis in patients who also received|
01092|013|E|azathioprine.(7)|
01092|014|B||
01092|015|P|PREDISPOSING FACTORS:  Patients with reduced or absent thiopurine|
01092|016|P|S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are|
01092|017|P|at higher risk of accumulating thiopurine metabolites and severe|
01092|018|P|myelosuppression.  Approximately 0.3 % of patients of European, Latino, or|
01092|019|P|African descent have mutations of the TPMT gene resulting in little to no|
01092|020|P|TPMT activity (homozygous deficiency), and approximately 10 % have|
01092|021|P|intermediate TPMT activity (heterozygous deficiency).  NUDT15 deficiency is|
01092|022|P|not seen in patients of African descent and is seen in less than 1 % of|
01092|023|P|patients of European descent.  Approximately 1 % of patients of East Asian|
01092|024|P|descent, 0.5 % of patients of central/south Asian descent, and 2 % of|
01092|025|P|patients of Latino descent have homozygous NUDT15 deficiency.  About 17 % of|
01092|026|P|patients of East Asian descent, 13 % of patients of central/south Asian|
01092|027|P|descent, and 8 % of patients of Latino descent have heterozygous NUDT15|
01092|028|P|deficiency.(8)|
01092|029|B||
01092|030|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with azathioprine|
01092|031|M|and an ACE inhibitor should be closely monitored for hematological changes.|
01092|032|M|One of the agents may need to be discontinued.|
01092|033|B||
01092|034|D|DISCUSSION:  In a study in 15 kidney-transplant patients receiving|
01092|035|D|azathioprine, enalapril and captopril were replaced by nifedipine or|
01092|036|D|clonidine.  Hematocrit and hemoglobin levels increased from 37.5% to 39.7%|
01092|037|D|and from 12.8 g/dl to 13.5 g/dl, respectively,10 to 12 weeks after ACE|
01092|038|D|inhibitor withdrawal.  Reticulocytes and erythropoietin concentrations rose|
01092|039|D|from 14.1/1000 to 20.6/1000 and from 14.3 mU/ml to 29.3m U/ml, respectively.|
01092|040|D|There were no changes in azathioprine levels.(1)|
01092|041|D|   A retrospective review compared azathioprine-treated patients to patients|
01092|042|D|receiving azathioprine and ACE inhibitors.  Hematocrit, hemoglobin, and|
01092|043|D|haptoglobin levels were significantly lower in the group receiving ACE|
01092|044|D|inhibitors, 19.7%, 17.2%, and 45%, respectively.(2)|
01092|045|D|   Three case reports document the development of leucopenia during the|
01092|046|D|concurrent administration of captopril and azathioprine.(3-5)  Another case|
01092|047|D|report documented the development of anemia with concurrent enalapril and|
01092|048|D|azathioprine.(6)|
01092|049|D|   Enalapril has been used to treat post-renal transplant erythrocytosis in|
01092|050|D|patients receiving azathioprine.(7)|
01092|051|B||
01092|052|R|REFERENCES:|
01092|053|B||
01092|054|R|1.Gossmann J, Thurmann P, Bachmann T, Weller S, Kachel HG, Schoeppe W,|2
01092|055|R|  Scheuermann EH. Mechanism of angiotensin converting enzyme|2
01092|056|R|  inhibitor-related anemia in renal transplant recipients. Kidney Int 1996|2
01092|057|R|  Sep;50(3):973-8.|2
01092|058|R|2.Gossmann J, Kachel HG, Schoeppe W, Scheuermann EH. Anemia in renal|2
01092|059|R|  transplant recipients caused by concomitant therapy with azathioprine and|2
01092|060|R|  angiotensin-converting enzyme inhibitors. Transplantation 1993 Sep;|2
01092|061|R|  56(3):585-9.|2
01092|062|R|3.Gronhagen-Riska C, Fyhrquist F, Ahonen J, von Willebrand E, Hayry P.|3
01092|063|R|  Angiotensin I-converting enzyme inhibition after renal transplantation.|3
01092|064|R|  Scand J Urol Nephrol Suppl 1984;79:63-7.|3
01092|065|R|4.Shindo K, Matsuya F, Ura T, Jodai A, Shimomae H, Kuniyoshi M, Hirose T,|3
01092|066|R|  Kusaba Y, Saito Y. Captopril-associated granulocytopenia in hypertension|3
01092|067|R|  after renal transplantation. Clin Nephrol 1984 Dec;22(6):314-6.|3
01092|068|R|5.Anonymous. Successful low dose captopril rechallenge following|3
01092|069|R|  drug-induced leucopenia. Lancet 1981 Jun 20;1(8234):1362-3.|3
01092|070|R|6.Kuriyama R, Kogure H, Itoh S, Kikuchi K, Ichikawa N, Nomura Y, Degawa H,|3
01092|071|R|  Meigata K, Watanabe K, Beck Y, Tomikawa S, Nagao T, Uchida H. Angiotensin|3
01092|072|R|  converting enzyme inhibitor induced anemia in a kidney transplant|3
01092|073|R|  recipient. Transplant Proc 1996 Jun;28(3):1635.|3
01092|074|R|7.Rostaing L, Boisseau M, Huyn A, Durand D. Correction of post-renal|2
01092|075|R|  transplant erythrocytosis by enalapril. Scand J Urol Nephrol 1995 Dec;|2
01092|076|R|  29(4):399-406.|2
01092|077|R|8.Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM,|6
01092|078|R|  Moyer AM, Evans WE, Klein TE, Antillon-Klussmann FG, Caudle KE, Kato M,|6
01092|079|R|  Yeoh AEJ, Schmiegelow K, Yang JJ. Clinical Pharmacogenetics Implementation|6
01092|080|R|  Consortium Guideline for Thiopurine Dosing  Based on TPMT and NUDT15|6
01092|081|R|  Genotypes: 2018 Update. Clin Pharmacol Ther 2019 May;105(5):1095-1105.|6
01093|001|T|MONOGRAPH TITLE:  Protease Inhibitors/Carbamazepine|
01093|002|B||
01093|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01093|004|L|of severe adverse interaction.|
01093|005|B||
01093|006|A|MECHANISM OF ACTION:  Carbamazepine may induce the metabolism of the|
01093|007|A|protease inhibitors at CYP3A4.(1-7)  Ritonavir may inhibit the metabolism of|
01093|008|A|carbamazepine by CYP3A4.(8,9)|
01093|009|B||
01093|010|E|CLINICAL EFFECTS:  The concurrent use of indinavir and carbamazepine may|
01093|011|E|result in higher than anticipated carbamazepine levels, decreased indinavir|
01093|012|E|plasma levels, and antiretroviral therapy failure.(1,2)|
01093|013|E|   The concurrent use of amprenavir, fosamprenavir, lopinavir, nelfinavir,|
01093|014|E|and saquinavir may result in decreased levels of these agents and|
01093|015|E|antiretroviral therapy failure.(3-7)|
01093|016|E|   The concurrent use of darunavir/ritonavir(11) or ritonavir(7,9,11) and|
01093|017|E|carbamazepine may result in elevated levels of carbamazepine and signs of|
01093|018|E|carbamazepine toxicity.|
01093|019|B||
01093|020|P|PREDISPOSING FACTORS:  None determined.|
01093|021|B||
01093|022|M|PATIENT MANAGEMENT:  Consider avoiding the concurrent use of carbamazepine|
01093|023|M|and amprenavir, fosamprenavir, indinavir, lopinavir, nelfinavir, or|
01093|024|M|saquinavir.  If concurrent therapy is warranted, carbamazepine and protease|
01093|025|M|inhibitor levels, as well as antiretroviral response, should be closely|
01093|026|M|monitored.|
01093|027|M|   In patients receiving concurrent therapy with carbamazepine and|
01093|028|M|darunavir/ritonavir(10) or ritonavir(8), carbamazepine levels should be|
01093|029|M|closely monitored and the patient should be observed for signs of|
01093|030|M|carbamazepine toxicity.  The dosage of carbamazepine may need to be adjusted|
01093|031|M|or carbamazepine may need to be discontinued.|
01093|032|M|   The manufacturer of lopinavir states that lopinavir/ritonavir should not|
01093|033|M|be administered once daily to patients receiving carbamazepine.(5)|
01093|034|B||
01093|035|D|DISCUSSION:  In a study in 16 subjects, concurrent carbamazepine (200 mg|
01093|036|D|twice daily) with darunavir/ritonavir (600/100 mg twice daily) had no|
01093|037|D|significant effects on darunavir pharmacokinetics.  The maximum|
01093|038|D|concentration (Cmax), area-under-curve (AUC), and minimum concentration|
01093|039|D|(Cmin) of carbamazepine increased by 43%, 45%, and 54%, respectively.  The|
01093|040|D|Cmax, AUC, and Cmin of carbamazepine epoxide decreased by 54%, 54%, and 52%,|
01093|041|D|respectively.(10)|
01093|042|D|   In a case report, an HIV-positive male restarted antiretroviral therapy|
01093|043|D|with indinavir (800 mg every 8 hours), lamivudine (150 mg twice daily), and|
01093|044|D|zidovudine (200 mg three times daily) in November of 1997.  In January of|
01093|045|D|1998, carbamazepine (200 mg daily) was started for post-herpetic neuralgia.|
01093|046|D|Despite the low dose of carbamazepine, carbamazepine levels were 6.7 mg/L|
01093|047|D|and 8.9 mg/L in February, 1998 and March, 1998, respectively.  At the end of|
01093|048|D|March, 1998, carbamazepine was discontinued.  In January and February of|
01093|049|D|1998, the patient's viral load was undetectable and his CD4+ count was|
01093|050|D|340x106/L and 400x106/L, respectively.  By April of 1998, his HIV-RNA level|
01093|051|D|had risen to 6x103 copies/ml and his CD4+ count decreased to 200x106/L.  His|
01093|052|D|HIV-RNA level increased to 300x103 copies/ml three months later.  Prior to|
01093|053|D|carbamazepine therapy, the patient's indinavir levels had been 61% of the|
01093|054|D|reference population.  During carbamazepine therapy, his indinavir levels|
01093|055|D|decreased to a value of 4% of the reference population. Two weeks after|
01093|056|D|carbamazepine was discontinued, his indinavir levels increased to a value of|
01093|057|D|173% of the reference population.(2)|
01093|058|D|   In a case report, a 36 year-old male HIV-positive patient was treated|
01093|059|D|with phenytoin (400 mg/day) and carbamazepine (600 mg/day) in addition to|
01093|060|D|his antiretroviral regimen that included zidovudine and zalcitabine. His HIV|
01093|061|D|regimen was changed to stavudine, lamivudine, and indinavir, which resulted|
01093|062|D|in a partial viral-load response.  This regimen was then replaced with|
01093|063|D|lamivudine, didanosine, ritonavir, and saquinavir, which resulted in the|
01093|064|D|patient's viral load becoming undetectable.  Levels of carbamazepine at this|
01093|065|D|time were normal (6.5 mcg/ml).  Over the next two months, the patient|
01093|066|D|developed a progressive gait disorder and dizziness. His carbamazepine level|
01093|067|D|increased to 18 mcg/ml.  Carbamazepine was replaced with primidone.(9)|
01093|068|D|   In a case report, a 20 year-old male had been HIV-positive since age 8|
01093|069|D|and been maintained on carbamazepine (350 mg twice daily) since age 12.  The|
01093|070|D|patient was admitted for changes to his antiretroviral regimen. On day 2,|
01093|071|D|his carbamazepine level was 9.5 mcg/ml and his aminotransferase (ALT) value|
01093|072|D|was normal. On day 8, a single dose of ritonavir (200 mg) was administered.|
01093|073|D|Within 12 hours, his carbamazepine level increased to 17.8 mcg/ml.  On day|
01093|074|D|9, ritonavir (200 mg three times daily), but ritonavir was discontinued on|
01093|075|D|day 10 because of intractable nausea and vertigo.  On day 12, the patient's|
01093|076|D|ALT level was 141 International Units/L.  On day 13, ritonavir (200 mg every|
01093|077|D|24 hours) was restarted.  The patient's carbamazepine level increased to|
01093|078|D|16.3 mcg/ml and ritonavir was discontinued.(10)|
01093|079|D|   One or more of the drug pairs linked to this monograph have been included|
01093|080|D|in a list of interactions that should be considered "high-priority" for|
01093|081|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01093|082|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01093|083|D|Coordinator (ONC) for Health Information Technology.|
01093|084|B||
01093|085|R|REFERENCES:|
01093|086|B||
01093|087|R|1.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01093|088|R|  September, 2016.|1
01093|089|R|2.Hugen PW, Burger DM, Brinkman K, ter Hofstede HJ, Schuurman R, Koopmans|3
01093|090|R|  PP, Hekster YA. Carbamazepine--indinavir interaction causes antiretroviral|3
01093|091|R|  therapy failure. Ann Pharmacother 2000 Apr;34(4):465-70.|3
01093|092|R|3.Agenerase (amprenavir) Oral Solution US prescribing information.|1
01093|093|R|  GlaxoSmithKline May, 2005.|1
01093|094|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01093|095|R|  March, 2019.|1
01093|096|R|5.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01093|097|R|  Laboratories December, 2019.|1
01093|098|R|6.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01093|099|R|  Pharmaceuticals, Inc. September, 2016.|1
01093|100|R|7.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01093|101|R|  Laboratories, Inc. March, 2019.|1
01093|102|R|8.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01093|103|R|  December, 2019.|1
01093|104|R|9.Berbel Garcia A, Latorre Ibarra A, Porta Etessam J, Martinez Salio A,|3
01093|105|R|  Perez Martinez D, Siaz Diaz R, Toledo Heras M. Protease inhibitor-induced|3
01093|106|R|  carbamazepine toxicity. Clin Neuropharmacol 2000 Jul-Aug;23(4):216-8.|3
01093|107|R|10.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01093|108|R|   March, 2023.|1
01093|109|R|11.Kato Y, Fujii T, Mizoguchi N, Takata N, Ueda K, Feldman MD, Kayser SR.|3
01093|110|R|   Potential interaction between ritonavir and carbamazepine.|3
01093|111|R|   Pharmacotherapy 2000 Jul;20(7):851-4.|3
01093|112|R|12.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01093|113|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01093|114|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01093|115|R|   19(5):735-43.|6
01094|001|T|MONOGRAPH TITLE:  Propafenone/Fluoxetine|
01094|002|B||
01094|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01094|004|L|take action as needed.|
01094|005|B||
01094|006|A|MECHANISM OF ACTION:  Fluoxetine may inhibit propafenone metabolism by|
01094|007|A|CYP2D6.(1)|
01094|008|B||
01094|009|E|CLINICAL EFFECTS:  The concurrent administration of fluoxetine and|
01094|010|E|propafenone may result in elevated levels of propafenone and increased|
01094|011|E|clinical and toxic effects of propafenone.(1)|
01094|012|B||
01094|013|P|PREDISPOSING FACTORS:  None determined.|
01094|014|B||
01094|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with fluoxetine|
01094|016|M|and propafenone should be carefully monitored for increased propafenone|
01094|017|M|effects and toxicity.  The dosage of propafenone may need to be decreased.|
01094|018|B||
01094|019|D|DISCUSSION:  A study in nine healthy, extensive CYP2D6 metabolizers examined|
01094|020|D|the effects of fluoxetine (20 mg daily for 10 days) on a single dose of|
01094|021|D|propafenone (400 mg).  Fluoxetine increased the half-life (T1/2, from|
01094|022|D|3.44+/-0.74 hours to 4.47+/-1.00 hours), the maximum concentration (Cmax,|
01094|023|D|from 435.71+/-37.1 ng/ml to 580.41+/-43.2 ng/ml), and area-under-curve (AUC,|
01094|024|D|from 2238.37+/-25.2 mcg x h/L to 3371.29+/-86.7 mcg x h/L) of S-propafenone|
01094|025|D|when compared to baseline.  S-propafenone clearance decreased from|
01094|026|D|75.01+/-17.69 L/h to 49.36+/-8.62 L/h.  Fluoxetine increased the T 1/2 (from|
01094|027|D|3.24+/-0.9 hours to 3.98+/-0.58 hours), Cmax (from 304.71+/-09.9 ng/ml to|
01094|028|D|461.91+/-34.8 ng/ml) and AUC (from 1576.35+/-73.1 mcg x h/L to|
01094|029|D|2370.7+/-704.5 mcg x h/L) of R-propafenone when compared to baseline.|
01094|030|D|R-propafenone clearance decreased from 107.62+/-33.82 L/h to 70.60+/-12.42|
01094|031|D|L/h.(1)|
01094|032|B||
01094|033|R|REFERENCE:|
01094|034|B||
01094|035|R|1.Cai WM, Chen B, Zhou Y, Zhang YD. Fluoxetine impairs the CYP2D6-mediated|2
01094|036|R|  metabolism of propafenone enantiomers in healthy Chinese volunteers. Clin|2
01094|037|R|  Pharmacol Ther 1999 Nov;66(5):516-21.|2
01095|001|T|MONOGRAPH TITLE:  Quinolones, Oral/Didanosine Pediatric Solution & Antacid|
01095|002|B||
01095|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01095|004|L|take action as needed.|
01095|005|B||
01095|006|A|MECHANISM OF ACTION:  Aluminum and magnesium may form chelation compounds|
01095|007|A|with the quinolones.(1-15)|
01095|008|B||
01095|009|E|CLINICAL EFFECTS:  Simultaneous administration or administration of aluminum|
01095|010|E|or magnesium products close to the administration time of an oral quinolone|
01095|011|E|may result in decreased absorption and clinical effectiveness of the|
01095|012|E|quinolone.|
01095|013|B||
01095|014|P|PREDISPOSING FACTORS:  None determined.|
01095|015|B||
01095|016|M|PATIENT MANAGEMENT:  If possible, avoid concomitant use of an oral quinolone|
01095|017|M|antibiotic and Videx (didanosine) pediatric oral solution, which is mixed|
01095|018|M|with Maximum Strength Mylanta Liquid, which contains aluminum and magnesium|
01095|019|M|hydroxide.  If it necessary to administer these agents concurrently, follow|
01095|020|M|the manufacturers' recommendations regarding the timing of administration of|
01095|021|M|the quinolone with Videx pediatric suspension or aluminum- or magnesium|
01095|022|M|containing compounds.|
01095|023|M|   Manufacturer recommendations regarding the separation of administration|
01095|024|M|times of quinolones and products containing aluminum and magnesium vary:|
01095|025|M|---Do not give ciprofloxacin for at least 2 hours before or 6 hours after|
01095|026|M|oral cations.(1)|
01095|027|M|---Do not give delafloxacin for at least 2 hours before or 6 hours after|
01095|028|M|oral cations.(2)|
01095|029|M|---Do not give enoxacin for at least 2 hours before or 8 hours after oral|
01095|030|M|cations.(3)|
01095|031|M|---Do not give gatifloxacin for at least 4 hours before oral cations.(4)|
01095|032|M|---Do not give gemifloxacin for at least 2 hours before or 3 hours after|
01095|033|M|oral cations.(5)|
01095|034|M|---Do not give levofloxacin for at least 2 hours before or 2 hours after|
01095|035|M|oral cations.(6)|
01095|036|M|---Do not give lomefloxacin for at least 2 hours before or 4 hours after|
01095|037|M|oral cations.(7)|
01095|038|M|---Do not give moxifloxacin for at least 4 hours before or 8 hours after|
01095|039|M|oral cations.(8)|
01095|040|M|---Do not give nalidixic acid for at least 2 hours before or 2 hours after|
01095|041|M|oral cations.(9)|
01095|042|M|---Do not give norfloxacin for at least 2 hours before or 2 hours after oral|
01095|043|M|cations.(10)|
01095|044|M|---Do not give ofloxacin for at least 2 hours before or 2 hours after oral|
01095|045|M|cations.(11)|
01095|046|M|---Do not give prulifloxacin for at least 2 hours before or 4 hours after|
01095|047|M|oral cations.(12)|
01095|048|M|---Do not give sparfloxacin for at least 4 hours before oral cations.(13)|
01095|049|M|---Do not give trovafloxacin for at least 2 hours before or after oral|
01095|050|M|cations.(14)|
01095|051|M|---Do not give sitafloxacin for at least 2 hours before or after oral|
01095|052|M|cations.(15)|
01095|053|B||
01095|054|D|DISCUSSION:  Magnesium and aluminum compounds have been shown to form|
01095|055|D|chelation compounds with quinolone antibiotics, resulting in decreased|
01095|056|D|absorption of the quinolone.(1-28)  Concurrent administration of an antacid|
01095|057|D|with ciprofloxacin has been shown to reduce the bioavailability of|
01095|058|D|ciprofloxacin by as much as 90% and administration of an antacid 2 hours|
01095|059|D|prior to ciprofloxacin has been shown to decrease ciprofloxacin|
01095|060|D|concentrations by 20-50%.  Magnesium- and aluminum-containing antacids have|
01095|061|D|been shown to decrease the bioavailability of lomefloxacin by 48%.|
01095|062|D|   The chewable/dispersible formulation of Videx (didanosine) contains|
01095|063|D|magnesium hydroxide and magnesium stearate.  The administration of|
01095|064|D|ciprofloxacin 2 hours prior to Videx chewable/dispersible tablets decreased|
01095|065|D|ciprofloxacin concentrations by 26%.(31)|
01095|066|D|   Manufacturer recommendations regarding the separation of aluminum and/or|
01095|067|D|magnesium compounds and quinolone antibiotic vary.  The manufacturers'|
01095|068|D|recommendations for the separating of Videx pediatric suspension are the|
01095|069|D|same as for aluminum- or magnesium-containing antacids.|
01095|070|B||
01095|071|R|REFERENCES:|
01095|072|B||
01095|073|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
01095|074|R|  Corporation March, 2022.|1
01095|075|R|2.Baxdela (delafloxacin) US prescribing information. Melinta Therapeutics,|1
01095|076|R|  Inc. June 19, 2017.|1
01095|077|R|3.Penetrex (enoxacin) US prescribing information. Aventis Pharmaceuticals,|1
01095|078|R|  Inc. July, 1998.|1
01095|079|R|4.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
01095|080|R|  Company January, 2006.|1
01095|081|R|5.Factive (gemifloxacin mesylate) US prescribing information. Merus Labs|1
01095|082|R|  International, Inc. October, 2018.|1
01095|083|R|6.Levaquin (levofloxacin) US prescribing information. Janssen|1
01095|084|R|  Pharmaceuticals, Inc. October 18, 2018.|1
01095|085|R|7.Maxaquin (lomefloxacin hydrochloride) US prescribing information. Pfizer|1
01095|086|R|  Inc. January, 2005.|1
01095|087|R|8.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
01095|088|R|  Pharmaceuticals Corporation October 18, 2018.|1
01095|089|R|9.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
01095|090|R|  Inc. November, 2012.|1
01095|091|R|10.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
01095|092|R|   2016.|1
01095|093|R|11.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
01095|094|R|   Pharmaceutical, Inc. February, 2011.|1
01095|095|R|12.Unidrox (prulifloxacin) HK prescribing information. Lee's Pharmaceutical|1
01095|096|R|   (HK) Limited.|1
01095|097|R|13.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
01095|098|R|   Inc. February, 2003.|1
01095|099|R|14.Trovan (trovafloxacin mesylate) US prescribing information. Roerig April,|1
01095|100|R|   2000.|1
01095|101|R|15.Gracevit (sitafloxacin) Japanese prescribing information. Daiichi-Sankyo|1
01095|102|R|   Co., Ltd March 2025.|1
01095|103|R|16.Hoffken G, Borner K, Glatzel PD, Koeppe P, Lode H. Reduced enteral|2
01095|104|R|   absorption of ciprofloxacin in the presence of antacids. Eur J Clin|2
01095|105|R|   Microbiol 1985 Jun;4(3):345.|2
01095|106|R|17.Golper TA, Hartstein AI, Morthland VH, Christensen JM. Effects of|2
01095|107|R|   antacids and dialysate dwell times on multiple-dose pharmacokinetics of|2
01095|108|R|   oral ciprofloxacin in patients on continuous ambulatory peritoneal|2
01095|109|R|   dialysis. Antimicrob Agents Chemother 1987 Nov;31(11):1787-90.|2
01095|110|R|18.Maesen FP, Davies BI, Geraedts WH, Sumajow CA. Ofloxacin and antacids. J|2
01095|111|R|   Antimicrob Chemother 1987 Jun;19(6):848-50.|2
01095|112|R|19.Nix DE, Watson WA, Lener ME, Frost RW, Krol G, Goldstein H, Lettieri J,|2
01095|113|R|   Schentag JJ. Effects of aluminum and magnesium antacids and ranitidine on|2
01095|114|R|   the absorption of ciprofloxacin. Clin Pharmacol Ther 1989 Dec;|2
01095|115|R|   46(6):700-5.|2
01095|116|R|20.Grasela TH Jr, Schentag JJ, Sedman AJ, Wilton JH, Thomas DJ, Schultz RW,|2
01095|117|R|   Lebsack ME, Kinkel AW. Inhibition of enoxacin absorption by antacids or|2
01095|118|R|   ranitidine. Antimicrob Agents Chemother 1989 May;33(5):615-7.|2
01095|119|R|21.Nix DE, Wilton JH, Ronald B, Distlerath L, Williams VC, Norman A.|2
01095|120|R|   Inhibition of norfloxacin absorption by antacids. Antimicrob Agents|2
01095|121|R|   Chemother 1990 Mar;34(3):432-5.|2
01095|122|R|22.Flor S, Guay DR, Opsahl JA, Tack K, Matzke GR. Effects of|2
01095|123|R|   magnesium-aluminum hydroxide and calcium carbonate antacids on|2
01095|124|R|   bioavailability of ofloxacin. Antimicrob Agents Chemother 1990 Dec;|2
01095|125|R|   34(12):2436-8.|2
01095|126|R|23.Martinez Cabarga M, Sanchez Navarro A, Colino Gandarillas CI,|2
01095|127|R|   Dominguez-Gil A. Effects of two cations on gastrointestinal absorption of|2
01095|128|R|   ofloxacin. Antimicrob Agents Chemother 1991 Oct;35(10):2102-5.|2
01095|129|R|24.Akerele JO, Okhamafe AO. Influence of oral co-administered metallic drugs|2
01095|130|R|   on ofloxacin pharmacokinetics. J Antimicrob Chemother 1991 Jul;|2
01095|131|R|   28(1):87-94.|2
01095|132|R|25.Frost RW, Lasseter KC, Noe AJ, Shamblen EC, Lettieri JT. Effects of|2
01095|133|R|   aluminum hydroxide and calcium carbonate antacids on the bioavailability|2
01095|134|R|   of ciprofloxacin. Antimicrob Agents Chemother 1992 Apr;36(4):830-2.|2
01095|135|R|26.Campbell NR, Kara M, Hasinoff BB, Haddara WM, McKay DW. Norfloxacin|2
01095|136|R|   interaction with antacids and minerals. Br J Clin Pharmacol 1992 Jan;|2
01095|137|R|   33(1):115-6.|2
01095|138|R|27.Shimada J, Shiba K, Oguma T, Miwa H, Yoshimura Y, Nishikawa T, Okabayashi|2
01095|139|R|   Y, Kitagawa T, Yamamoto S. Effect of antacid on absorption of the|2
01095|140|R|   quinolone lomefloxacin. Antimicrob Agents Chemother 1992 Jun;|2
01095|141|R|   36(6):1219-24.|2
01095|142|R|28.Nix DE, Lebsack ME, Chapelsky M, Sedman AJ, Busch J, Norman A. Effect of|2
01095|143|R|   oral antacids on disposition of intravenous enoxacin. Antimicrob Agents|2
01095|144|R|   Chemother 1993 Apr;37(4):775-7.|2
01095|145|R|29.Sahai J, Gallicano K, Oliveras L, Khaliq S, Hawley-Foss N, Garber G.|2
01095|146|R|   Cations in the didanosine tablet reduce ciprofloxacin bioavailability.|2
01095|147|R|   Clin Pharmacol Ther 1993 Mar;53(3):292-7.|2
01095|148|R|30.Lehto P, Kivisto KT. Different effects of products containing metal ions|2
01095|149|R|   on the absorption of lomefloxacin. Clin Pharmacol Ther 1994 Nov;|2
01095|150|R|   56(5):477-82.|2
01095|151|R|31.Allen A, Vousden M, Porter A, Lewis A. Effect of Maalox on the|2
01095|152|R|   bioavailability of oral gemifloxacin in healthy volunteers. Chemotherapy|2
01095|153|R|   1999 Nov-Dec;45(6):504-11.|2
01095|154|R|32.Videx (didanosine) US prescribing information. Bristol-Myers Squibb|1
01095|155|R|   Company November, 2011.|1
01096|001|T|MONOGRAPH TITLE:  Gatifloxacin/Didanosine Buffered Solution|
01096|002|B||
01096|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01096|004|L|of severe adverse interaction.|
01096|005|B||
01096|006|A|MECHANISM OF ACTION:  The buffers in the didanosine buffered solution may|
01096|007|A|bind to gatifloxacin, preventing its absorption.|
01096|008|B||
01096|009|E|CLINICAL EFFECTS:  Simultaneous administration may result in decreased|
01096|010|E|levels and clinical effectiveness of gatifloxacin.|
01096|011|B||
01096|012|P|PREDISPOSING FACTORS:  None determined.|
01096|013|B||
01096|014|M|PATIENT MANAGEMENT:  The manufacturer of gatifloxacin states that patients|
01096|015|M|receiving concurrent therapy with gatifloxacin and didanosine buffered|
01096|016|M|solution should take gatifloxacin four hours before the didanosine buffered|
01096|017|M|solution.(1)|
01096|018|B||
01096|019|D|DISCUSSION:  The manufacturer of gatifloxacin states that patients receiving|
01096|020|D|concurrent therapy with gatifloxacin and didanosine buffered solution should|
01096|021|D|take gatifloxacin four hours before the didanosine buffered solution.(1)|
01096|022|B||
01096|023|R|REFERENCE:|
01096|024|B||
01096|025|R|1.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
01096|026|R|  Company January, 2006.|1
01097|001|T|MONOGRAPH TITLE:  Melatonin/Strong CYP1A2 Inhibitors|
01097|002|B||
01097|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01097|004|L|Assess the risk to the patient and take action as needed.|
01097|005|B||
01097|006|A|MECHANISM OF ACTION:  Strong CYP1A2 inhibitors may significantly increase|
01097|007|A|the area-under-curve (AUC) of melatonin by inhibiting CYP1A2.(1,2)|
01097|008|A|   Fluvoxamine, a strong CYP1A2 inhibitor, has also been shown to increase|
01097|009|A|endogenous melatonin levels.|
01097|010|A|   The use of sertraline with melatonin may have resulted in an imbalance of|
01097|011|A|melatonin and dopamine in the retina.|
01097|012|B||
01097|013|E|CLINICAL EFFECTS:  The concurrent administration of melatonin and strong|
01097|014|E|CYP1A2 inhibitors may result in significantly increased melatonin levels and|
01097|015|E|subsequent side effects.(1-4)|
01097|016|E|   In addition, the use of sertraline and melatonin has resulted in vision|
01097|017|E|changes.(5)|
01097|018|B||
01097|019|P|PREDISPOSING FACTORS:  None determined.|
01097|020|B||
01097|021|M|PATIENT MANAGEMENT:  The UK manufacturer of melatonin recommends against the|
01097|022|M|concurrent use of melatonin and CYP1A2 inhibitors.(1)|
01097|023|M|   The Australian manufacturer of melatonin states concurrent use of|
01097|024|M|melatonin and CYP1A2 inhibitors should be avoided.(2)|
01097|025|M|   Patients should be monitored for increased effects of melatonin when|
01097|026|M|melatonin and CYP1A2 inhibitors are used concurrently.|
01097|027|B||
01097|028|D|DISCUSSION:  In a study, fluvoxamine increased the area-under-curve (AUC)|
01097|029|D|and concentration maximum (Cmax) of melatonin by 17-fold and 12-fold,|
01097|030|D|respectively.(2)|
01097|031|D|   In a case report, a 51 year old female with chronic primary insomnia who|
01097|032|D|received 5 mg melatonin at bedtime and 75 mg fluvoxamine in the afternoon|
01097|033|D|experienced increased nocturnal sleep, from 2.5 hours (drug free) to 4.2|
01097|034|D|hours (melatonin alone) up to 5.5 hours per night (melatonin with|
01097|035|D|fluvoxamine).  Both melatonin and fluvoxamine alone increased melatonin|
01097|036|D|levels; however administration of melatonin alone increased melatonin levels|
01097|037|D|more than fluvoxamine alone.  Concurrent use of melatonin and fluvoxamine|
01097|038|D|increased melatonin levels 20-fold when compared to the administration of|
01097|039|D|melatonin alone.(3)|
01097|040|D|   In a study involving five males, 5 mg of melatonin daily was given for|
01097|041|D|one week, then 50 mg of fluvoxamine was added (administered three hours|
01097|042|D|apart.  The AUC of melatonin increased at least nine-fold (p<0.05).  The|
01097|043|D|Cmax increased at least six-fold in melatonin (p<0.01), versus the Cmax in|
01097|044|D|patients who received melatonin alone.(4)|
01097|045|D|   One case report indicated that sertraline and melatonin (doses unknown)|
01097|046|D|with a high protein diet caused visual acuity loss, dyschromatopsia and|
01097|047|D|altered light adaptation.  Visual acuity and color vision returned to|
01097|048|D|baseline two months after the discontinuation of melatonin and the diet.(5)|
01097|049|D|   Strong CYP1A2 inhibitors include: enasidenib, fluvoxamine, sertraline,|
01097|050|D|and viloxazine.(6)|
01097|051|B||
01097|052|R|REFERENCES:|
01097|053|B||
01097|054|R|1.Circadin (melatonin) UK summary of product characteristics. Lundberg|1
01097|055|R|  Limited May, 2008.|1
01097|056|R|2.Circadin (melatonin) Australian product information. Neurim|1
01097|057|R|  Pharmaceuticals November, 2020.|1
01097|058|R|3.Grozinger M, Hartter S, Wang X, Roschke J, Hiemke C, Rose DM. Fluvoxamine|3
01097|059|R|  strongly inhibits melatonin metabolism in a patient with low-amplitude|3
01097|060|R|  melatonin profile. Arch Gen Psychiatry 2000 Aug;57(8):812-3.|3
01097|061|R|4.Hartter S, Grozinger M, Weigmann H, Roschke J, Hiemke C. Increased|2
01097|062|R|  bioavailability of oral melatonin after fluvoxamine coadministration. Clin|2
01097|063|R|  Pharmacol Ther 2000 Jan;67(1):1-6.|2
01097|064|R|5.Lehman NL, Johnson LN. Toxic optic neuropathy after concomitant use of|3
01097|065|R|  melatonin, zoloft, and a high-protein diet. J Neuroophthalmol 1999 Dec;|3
01097|066|R|  19(4):232-4.|3
01097|067|R|6.This information is based on an extract from the Certara Drug Interaction|6
01097|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01098|001|T|MONOGRAPH TITLE:  S-Adenosylmethionine (SAM-e)/SSRIs; SNRIs; Clomipramine|
01098|002|B||
01098|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01098|004|L|Assess the risk to the patient and take action as needed.|
01098|005|B||
01098|006|A|MECHANISM OF ACTION:  S-adenosylmethionine (SAM), SSRIs, SNRIs and|
01098|007|A|clomipramine are suggested to have similar effects on the serotonin pathway,|
01098|008|A|therefore their use together may result in additive or synergistic effects.|
01098|009|B||
01098|010|E|CLINICAL EFFECTS:  Concomitant use of S-adenosylmethionine and|
01098|011|E|antidepressants which inhibit neuronal serotonin reuptake may result in|
01098|012|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
01098|013|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
01098|014|E|and muscle rigidity.(2)|
01098|015|B||
01098|016|P|PREDISPOSING FACTORS:  None determined.|
01098|017|B||
01098|018|M|PATIENT MANAGEMENT:  Concurrent use of S-adenosylmethionine and SSRIs,|
01098|019|M|SNRIs, or clomipramine should be approached with caution.  Patients should|
01098|020|M|be monitored for signs of serotonin syndrome.  One or both agents may need|
01098|021|M|to be discontinued.|
01098|022|M|   If concurrent therapy is warranted, patients should be monitored for|
01098|023|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
01098|024|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
01098|025|M|heart palpitations, restlessness, confusion, agitation, trouble with|
01098|026|M|coordination, or severe diarrhea.|
01098|027|B||
01098|028|D|DISCUSSION:  A case report reviewed a 71 year old female with a history of|
01098|029|D|major affective disorder.  She received intramuscular S-adenosylmethionine|
01098|030|D|(100 mg/day) and oral clomipramine (25 mg/day) with no other drugs reported.|
01098|031|D|Ten days later clomipramine was increased to 75 mg/day and within 72 hours|
01098|032|D|of the increase the patient became anxious, agitated and confused.  She was|
01098|033|D|admitted to the hospital and given the diagnosis of serotonin syndrome; her|
01098|034|D|medications were stopped.  She was treated with intravenous dantrolene (50|
01098|035|D|mg) every 6 hours) for 48 hours, fluids and supportive care.  Her condition|
01098|036|D|improved over the next 4 days.(1)|
01098|037|B||
01098|038|R|REFERENCES:|
01098|039|B||
01098|040|R|1.Iruela LM, Minguez L, Merino J, Monedero G. Toxic interaction of|3
01098|041|R|  S-adenosylmethionine and clomipramine. Am J Psychiatry 1993 Mar;|3
01098|042|R|  150(3):522.|3
01098|043|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01098|044|R|  352(11):1112-20.|6
01099|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Co-Enzyme Q|
01099|002|T|(Ubiquinone)|
01099|003|B||
01099|004|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01099|005|L|Assess the risk to the patient and take action as needed.|
01099|006|B||
01099|007|A|MECHANISM OF ACTION:  It is currently unknown how Co-enzyme Q effects|
01099|008|A|warfarin. It is proposed that since Co-enzyme Q is chemically related to|
01099|009|A|vitamin K, it may too antagonize the effects of warfarin(1,2) and other|
01099|010|A|coumarin anticoagulants.|
01099|011|B||
01099|012|E|CLINICAL EFFECTS:  The concurrent administration of Co-enzyme Q and|
01099|013|E|anticoagulants may result in unpredictable effects on the the international|
01099|014|E|normalized ratio (INR) and prothrombin time.  Studies and case reports have|
01099|015|E|shown no effect, decreased effects, and increased affects of warfarin with|
01099|016|E|concurrent use of Co-enzyme Q.|
01099|017|B||
01099|018|P|PREDISPOSING FACTORS:  None determined.|
01099|019|B||
01099|020|M|PATIENT MANAGEMENT:  Patients should be made aware of Co-enzyme Q's possible|
01099|021|M|effects on anticoagulant therapy.  For the accurate and consistent INR or|
01099|022|M|prothrombin times, the coadministration of Co-enzyme Q and anticoagulants is|
01099|023|M|not recommended.  Patients receiving anticoagulant therapy should be closely|
01099|024|M|monitored if Co-enzyme Q is initiated or discontinued.|
01099|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01099|026|M|to monitor efficacy and safety of anticoagulation.|
01099|027|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01099|028|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01099|029|M|initiating, altering the dose or discontinuing either drug.|
01099|030|B||
01099|031|D|DISCUSSION:  Three separate patients taking over the counter Co-enzyme Q|
01099|032|D|were reported to have a significant decrease in INR levels with concurrent|
01099|033|D|administration with warfarin.  In one case, a 68 year old man was stable on|
01099|034|D|warfarin after several episodes of pulmonary emboli for 6 years (INR between|
01099|035|D|2.5 and 4.0).  After taking Co-enzyme Q 30 mg a day for two weeks, his INR|
01099|036|D|had dropped to 1.31.  Co-enzyme Q was subsequently discontinued.(1)|
01099|037|D|   In an animal study, rats were given a single oral dose of warfarin 1.5|
01099|038|D|mg/kg either alone or on day 4 of an 8 day-day oral dosing regimen of 10|
01099|039|D|mg/kg Co-enzyme Q.  Serum plasma levels were drawn over a 96-hour period|
01099|040|D|following warfarin administration and it was found that Co-enzyme Q|
01099|041|D|significantly augmented warfarin metabolism, but showed little effect on|
01099|042|D|absorption.  However, another study found that vitamin K reversed the|
01099|043|D|prothrombin time increase, but that Co-enzyme Q did not reverse the|
01099|044|D|increase, differentiating it biologically from its structural similarity to|
01099|045|D|vitamin K.(4)|
01099|046|D|   Conversely, in a study of the risk of bleeding and INR levels as affected|
01099|047|D|by complementary and alternative medicine, the use of Co-enzyme Q was|
01099|048|D|associated with a self reported increase of bleeding events.  However, this|
01099|049|D|same study indicated that Co-enzyme Q was not associated with increased|
01099|050|D|INRs.  The increase in bleeding events could be attributed to reporting|
01099|051|D|bias.  The fact that patients volunteered to keep diaries would indicate|
01099|052|D|that they are probably more likely to report minor events more often.  This|
01099|053|D|could also be due to chance due to the fact that only 15 patients|
01099|054|D|participated in the study.(5)|
01099|055|D|   One study suggests that Co-enzyme Q did not have significant impact on|
01099|056|D|INRs when administered with anticoagulants.  Patients were stable on|
01099|057|D|warfarin treatment for several months prior to the study period.  No|
01099|058|D|significant effects on INRs were observed after twenty-one patients|
01099|059|D|completed a 4 week treatment of Co-enzyme Q 100mg daily along with their|
01099|060|D|warfarin therapy.(6)|
01099|061|B||
01099|062|R|REFERENCES:|
01099|063|B||
01099|064|R|1.Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet 1994|3
01099|065|R|  Nov 12;344(8933):1372-3.|3
01099|066|R|2.Landbo C, Almdal TP. Interaction between warfarin and coenzyme Q10. Ugeskr|3
01099|067|R|  Laeger 1998 May 25;160(22):3226-7.|3
01099|068|R|3.Zhou Q, Chan E. Accuracy of repeated blood sampling in rats: a new|6
01099|069|R|  technique applied in pharmacokinetic/pharmacodynamic studies of the|6
01099|070|R|  interaction between warfarin and co-enzyme Q10. J Pharmacol Toxicol|6
01099|071|R|  Methods 1998 Nov;40(4):191-9.|6
01099|072|R|4.Combs AB, Porter TH, Folkers K. Anticoagulant activity of a naphthoquinone|5
01099|073|R|  analog of vitamin K and an inhibitor of coenzyme Q10- enzyme systems. Res|5
01099|074|R|  Commun Chem Pathol Pharmacol 1976 Jan;13(1):109-14.|5
01099|075|R|5.Shalansky S, Lynd L, Richardson K, Ingaszewski A, Kerr C. Risk of|6
01099|076|R|  warfarin-related bleeding events and supratherapeutic international|6
01099|077|R|  normalized ratios associated with complementary and alternative medicine:|6
01099|078|R|  a longitudinal analysis. Pharmacotherapy 2007 Sep;27(9):1237-47.|6
01099|079|R|6.Gebhart BC, Barker BC, Markewitz BA. Decreased serum linezolid levels in a|3
01099|080|R|  critically ill patient receiving concomitant linezolid and rifampin.|3
01099|081|R|  Pharmacotherapy 2007 Mar;27(3):476-9.|3
01100|001|T|MONOGRAPH TITLE:  Caspofungin/Cyclosporine|
01100|002|B||
01100|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01100|004|L|of severe adverse interaction.|
01100|005|B||
01100|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01100|007|B||
01100|008|E|CLINICAL EFFECTS:  The concurrent use of caspofungin and cyclosporine may|
01100|009|E|result in elevated levels of caspofungin, as well as increases in alanine|
01100|010|E|transaminase (ALT) and aspartate transaminase (AST) levels.|
01100|011|B||
01100|012|P|PREDISPOSING FACTORS:  None determined.|
01100|013|B||
01100|014|M|PATIENT MANAGEMENT:  Caspofungin and cyclosporine should only be used|
01100|015|M|concurrently if the potential benefits outweigh the potential risk to the|
01100|016|M|patient.  Patients receiving concurrent therapy who develop elevated liver|
01100|017|M|function tests should be monitored and the risk/benefit of continuing|
01100|018|M|concurrent therapy should be evaluated.(1)|
01100|019|B||
01100|020|D|DISCUSSION:  In a clinical study, four subjects received two 3 mg/kg doses|
01100|021|D|of cyclosporine on Day 10 of caspofungin (70 mg daily).  Three of the four|
01100|022|D|subjects developed transient elevations of ALT on Day 11 that were 2-3 times|
01100|023|D|the upper limit of normal.  AST levels were also elevated, but to a lesser|
01100|024|D|magnitude.  Eight subjects received cyclosporine (3 mg/kg) twice on Day 1 of|
01100|025|D|caspofungin (35 mg daily for 3 days).  Two of these subjects had a small|
01100|026|D|increase in ALT (slightly above the upper limit of normal) and a slight|
01100|027|D|elevation in AST.  Cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) has|
01100|028|D|been shown to increase the area-under-curve (AUC) of caspofungin by 35%.(1)|
01100|029|D|   In a study in 40 immunocompromised patients, subjects received concurrent|
01100|030|D|caspofungin and cyclosporine from 1 to 290 days (median 17.5 days).  Of|
01100|031|D|these, 14 (35%) developed transaminase elevations greater than 5 times the|
01100|032|D|upper limit of normal or greater than 3 times baseline during concurrent|
01100|033|D|therapy or the 14 days afterwards.  Five were considered possibly related to|
01100|034|D|concurrent therapy.  None developed clinical evidence of hepatotoxicity or|
01100|035|D|serious hepatic events.  Discontinuation of therapy because of abnormalities|
01100|036|D|in hepatic enzymes from any cause occurred in 4 patients, 2 were considered|
01100|037|D|related to concurrent therapy.(1)|
01100|038|D|   In prospective invasive aspergillosis and compassionate use studies,|
01100|039|D|there were 4 patients who received concurrent therapy for 2 to 56 days.|
01100|040|D|None developed increased hepatic enzymes.(1)|
01100|041|B||
01100|042|R|REFERENCE:|
01100|043|B||
01100|044|R|1.Cancidas (caspofungin acetate) US prescribing information. Merck & Co.,|1
01100|045|R|  Inc. January, 2013.|1
01101|001|T|MONOGRAPH TITLE:  Caspofungin/Efavirenz; Nevirapine|
01101|002|B||
01101|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01101|004|L|take action as needed.|
01101|005|B||
01101|006|A|MECHANISM OF ACTION:  Efavirenz and nevirapine may induce the metabolism of|
01101|007|A|caspofungin via induction of unspecified hepatic CYP enzymes.(1)|
01101|008|B||
01101|009|E|CLINICAL EFFECTS:  The concurrent administration of caspofungin with either|
01101|010|E|efavirenz or nevirapine may result in decreased levels and clinical|
01101|011|E|effectiveness of caspofungin.(1)|
01101|012|B||
01101|013|P|PREDISPOSING FACTORS:  None determined.|
01101|014|B||
01101|015|M|PATIENT MANAGEMENT:  In adult patients receiving concurrent therapy with|
01101|016|M|efavirenz or nevirapine, the US manufacturer of caspofungin recommends that|
01101|017|M|an increase in the daily dose of caspofungin to 70 mg (following the usual|
01101|018|M|70 mg loading dose) be considered.(1)|
01101|019|M|   In pediatric patients receiving concurrent therapy with efavirenz or|
01101|020|M|nevirapine, the US manufacturer of caspofungin recommends that an increase|
01101|021|M|in the daily dose of caspofungin to 70 mg/m2 (to a maximum of 70 mg daily,|
01101|022|M|following the usual 70 mg/m2 loading dose) be considered.(1)|
01101|023|B||
01101|024|D|DISCUSSION:  Regression analyses of patient pharmacokinetic data suggests|
01101|025|D|that administration of caspofungin with inducers and or mixed inducers/|
01101|026|D|inhibitors of drug clearance may result in clinically significant decreases|
01101|027|D|in caspofungin concentrations.  Therefore, the manufacturer of caspofungin|
01101|028|D|recommends that an increase in the daily dose of caspofungin to 70 mg|
01101|029|D|(following the usual 70 mg loading dose) be considered in patients receiving|
01101|030|D|concurrent therapy with efavirenz or nevirapine.  The efficacy of a 70 mg|
01101|031|D|daily dose in patients who are not responding to the 50 mg daily dose is not|
01101|032|D|known, but limited safety data suggests that it is well tolerated.(1)|
01101|033|B||
01101|034|R|REFERENCE:|
01101|035|B||
01101|036|R|1.Cancidas (caspofungin acetate) US prescribing information. Merck & Co.,|1
01101|037|R|  Inc. January, 2013.|1
01102|001|T|MONOGRAPH TITLE:  Caspofungin/Nelfinavir (mono deleted 05/29/2003)|
01102|002|B||
01102|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01102|004|L|take action as needed.|
01102|005|B||
01102|006|A|MECHANISM OF ACTION:  Nelfinavir may induce the metabolism of|
01102|007|A|caspofungin.(1)|
01102|008|B||
01102|009|E|CLINICAL EFFECTS:  The concurrent administration of caspofungin with|
01102|010|E|nelfinavir may result in decreased levels and clinical effectiveness of|
01102|011|E|caspofungin.(1)|
01102|012|B||
01102|013|P|PREDISPOSING FACTORS:  None determined.|
01102|014|B||
01102|015|M|PATIENT MANAGEMENT:  The manufacturer of caspofungin recommends that an|
01102|016|M|increase in the daily dose of caspofungin to 70 mg (following the usual 70|
01102|017|M|mg loading dose) be considered in patients receiving concurrent therapy with|
01102|018|M|nelfinavir who are not clinically responding to caspofungin.(1)|
01102|019|B||
01102|020|D|DISCUSSION:  Regression analyses of patient pharmacokinetic data suggests|
01102|021|D|that administration of caspofungin with inducers and or mixed inducers/|
01102|022|D|inhibitors of drug clearance may result in clinically significant decreases|
01102|023|D|in caspofungin concentrations.  Therefore, the manufacturer of caspofungin|
01102|024|D|recommends that an increase in the daily dose of caspofungin to 70 mg|
01102|025|D|(following the usual 70 mg loading dose) be considered in patients receiving|
01102|026|D|concurrent therapy with nelfinavir who are not clinically responding to|
01102|027|D|caspofungin.  The efficacy of a 70 mg daily dose in patients who are not|
01102|028|D|responding to the 50 mg daily dose is not known, but limited safety data|
01102|029|D|suggests that it is well tolerated.(1)|
01102|030|B||
01102|031|R|REFERENCE:|
01102|032|B||
01102|033|R|1.Cancidas (caspofungin acetate) US prescribing information. Merck & Co.,|1
01102|034|R|  Inc. January, 2001.|1
01103|001|T|MONOGRAPH TITLE:  Caspofungin/Fosphenytoin; Phenytoin|
01103|002|B||
01103|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01103|004|L|take action as needed.|
01103|005|B||
01103|006|A|MECHANISM OF ACTION:  Phenytoin may induce the metabolism of caspofungin by|
01103|007|A|CYP3A4.(1)|
01103|008|B||
01103|009|E|CLINICAL EFFECTS:  The concurrent administration of caspofungin with|
01103|010|E|phenytoin may result in decreased levels and clinical effectiveness of|
01103|011|E|caspofungin.(1)|
01103|012|B||
01103|013|P|PREDISPOSING FACTORS:  None determined.|
01103|014|B||
01103|015|M|PATIENT MANAGEMENT:  In adult patients receiving concurrent therapy with|
01103|016|M|phenytoin, the US manufacturer of caspofungin recommends that an increase in|
01103|017|M|the daily dose of caspofungin to 70 mg (following the usual 70 mg loading|
01103|018|M|dose) be considered.(1)|
01103|019|M|   In pediatric patients receiving concurrent therapy with phenytoin, the US|
01103|020|M|manufacturer of caspofungin recommends that an increase in the daily dose of|
01103|021|M|caspofungin to 70 mg/m2 (to a maximum of 70 mg daily, following the usual 70|
01103|022|M|mg/m2 loading dose) be considered.(1)|
01103|023|B||
01103|024|D|DISCUSSION:  Regression analyses of patient pharmacokinetic data suggests|
01103|025|D|that administration of caspofungin with inducers and or mixed inducers/|
01103|026|D|inhibitors of drug clearance may result in clinically significant decreases|
01103|027|D|in caspofungin concentrations.  Therefore, the manufacturer of caspofungin|
01103|028|D|recommends that an increase in the daily dose of caspofungin to 70 mg|
01103|029|D|(following the usual 70 mg loading dose) be considered in patients receiving|
01103|030|D|concurrent therapy with phenytoin.  The efficacy of a 70 mg daily dose in|
01103|031|D|patients who are not responding to the 50 mg daily dose is not known, but|
01103|032|D|limited safety data suggests that it is well tolerated.(1)|
01103|033|B||
01103|034|R|REFERENCE:|
01103|035|B||
01103|036|R|1.Cancidas (caspofungin acetate) US prescribing information. Merck & Co.,|1
01103|037|R|  Inc. January, 2013.|1
01104|001|T|MONOGRAPH TITLE:  Caspofungin/Rifampin|
01104|002|B||
01104|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01104|004|L|take action as needed.|
01104|005|B||
01104|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of caspofungin by|
01104|007|A|CYP3A4.(1)|
01104|008|B||
01104|009|E|CLINICAL EFFECTS:  The concurrent administration of caspofungin with|
01104|010|E|rifampin may result in decreased levels and clinical effectiveness of|
01104|011|E|caspofungin.(1)|
01104|012|B||
01104|013|P|PREDISPOSING FACTORS:  None determined.|
01104|014|B||
01104|015|M|PATIENT MANAGEMENT:  In adult patients receiving concurrent therapy with|
01104|016|M|rifampin, the US manufacturer of caspofungin states that a daily dose of 70|
01104|017|M|mg of caspofungin should be used.(1)|
01104|018|M|   In pediatric patients receiving concurrent therapy with rifampin, the US|
01104|019|M|manufacturer of caspofungin recommends that an increase in the daily dose of|
01104|020|M|caspofungin to 70 mg/m2 (to a maximum of 70 mg daily, following the usual 70|
01104|021|M|mg/m2 loading dose) be considered.(1)|
01104|022|B||
01104|023|D|DISCUSSION:  In a study in healthy volunteers, rifampin decreased|
01104|024|D|caspofungin trough concentrations by 30%.(1)|
01104|025|B||
01104|026|R|REFERENCE:|
01104|027|B||
01104|028|R|1.Cancidas (caspofungin acetate) US prescribing information. Merck & Co.,|1
01104|029|R|  Inc. January, 2013.|1
01105|001|T|MONOGRAPH TITLE:  Caspofungin/Dexamethasone|
01105|002|B||
01105|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01105|004|L|take action as needed.|
01105|005|B||
01105|006|A|MECHANISM OF ACTION:  Dexamethasone may induce the metabolism of caspofungin|
01105|007|A|by CYP3A4.(1)|
01105|008|B||
01105|009|E|CLINICAL EFFECTS:  The concurrent administration of caspofungin with|
01105|010|E|dexamethasone may result in decreased levels and clinical effectiveness of|
01105|011|E|caspofungin.(1)|
01105|012|B||
01105|013|P|PREDISPOSING FACTORS:  None determined.|
01105|014|B||
01105|015|M|PATIENT MANAGEMENT:  In adult patients receiving concurrent therapy with|
01105|016|M|dexamethasone, the US manufacturer of caspofungin recommends that an|
01105|017|M|increase in the daily dose of caspofungin to 70 mg (following the usual 70|
01105|018|M|mg loading dose) be considered.(1)|
01105|019|M|   In pediatric patients receiving concurrent therapy with dexamethasone,|
01105|020|M|the US manufacturer of caspofungin recommends that an increase in the daily|
01105|021|M|dose of caspofungin to 70 mg/m2 (to a maximum of 70 mg daily, following the|
01105|022|M|usual 70 mg/m2 loading dose) be considered.(1)|
01105|023|B||
01105|024|D|DISCUSSION:  Regression analyses of patient pharmacokinetic data suggests|
01105|025|D|that administration of caspofungin with inducers and or mixed inducers/|
01105|026|D|inhibitors of drug clearance may result in clinically significant decreases|
01105|027|D|in caspofungin concentrations.  Therefore, the manufacturer of caspofungin|
01105|028|D|recommends that an increase in the daily dose of caspofungin to 70 mg|
01105|029|D|(following the usual 70 mg loading dose) be considered in patients receiving|
01105|030|D|concurrent therapy with dexamethasone.  The efficacy of a 70 mg daily dose|
01105|031|D|in patients who are not responding to the 50 mg daily dose is not known, but|
01105|032|D|limited safety data suggests that it is well tolerated.(1)|
01105|033|B||
01105|034|R|REFERENCE:|
01105|035|B||
01105|036|R|1.Cancidas (caspofungin acetate) US prescribing information. Merck & Co.,|1
01105|037|R|  Inc. January, 2013.|1
01106|001|T|MONOGRAPH TITLE:  Caspofungin/Carbamazepine|
01106|002|B||
01106|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01106|004|L|take action as needed.|
01106|005|B||
01106|006|A|MECHANISM OF ACTION:  Carbamazepine may induce the metabolism of caspofungin|
01106|007|A|by CYP3A4.(1)|
01106|008|B||
01106|009|E|CLINICAL EFFECTS:  The concurrent administration of caspofungin with|
01106|010|E|carbamazepine may result in decreased levels and clinical effectiveness of|
01106|011|E|caspofungin.(1)|
01106|012|B||
01106|013|P|PREDISPOSING FACTORS:  None determined.|
01106|014|B||
01106|015|M|PATIENT MANAGEMENT:  In adult patients receiving concurrent therapy with|
01106|016|M|carbamazepine, the US manufacturer of caspofungin recommends that an|
01106|017|M|increase in the daily dose of caspofungin to 70 mg (following the usual 70|
01106|018|M|mg loading dose) be considered.(1)|
01106|019|M|   In pediatric patients receiving concurrent therapy with carbamazepine,|
01106|020|M|the US manufacturer of caspofungin recommends that an increase in the daily|
01106|021|M|dose of caspofungin to 70 mg/m2 (to a maximum of 70 mg daily, following the|
01106|022|M|usual 70 mg/m2 loading dose) be considered.(1)|
01106|023|B||
01106|024|D|DISCUSSION:  Regression analyses of patient pharmacokinetic data suggests|
01106|025|D|that administration of caspofungin with inducers and or mixed inducers/|
01106|026|D|inhibitors of drug clearance may result in clinically significant decreases|
01106|027|D|in caspofungin concentrations.  Therefore, the manufacturer of caspofungin|
01106|028|D|recommends that an increase in the daily dose of caspofungin to 70 mg|
01106|029|D|(following the usual 70 mg loading dose) be considered.  The efficacy of a|
01106|030|D|70 mg daily dose in patients who are not responding to the 50 mg daily dose|
01106|031|D|is not known, but limited safety data suggests that it is well tolerated.(1)|
01106|032|B||
01106|033|R|REFERENCE:|
01106|034|B||
01106|035|R|1.Cancidas (caspofungin acetate) US prescribing information. Merck & Co.,|1
01106|036|R|  Inc. January, 2013.|1
01107|001|T|MONOGRAPH TITLE:  Didanosine/Allopurinol|
01107|002|B||
01107|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01107|004|L|is contraindicated and generally should not be dispensed or administered to|
01107|005|L|the same patient.|
01107|006|B||
01107|007|A|MECHANISM OF ACTION:  Didanosine is broken down to hypoxanthine by purine|
01107|008|A|nucleoside phosphorylase (PNP) and uric acid by xanthene oxidase.|
01107|009|A|Allopurinol is a xanthene oxidase inhibitor and therefore inhibits the|
01107|010|A|metabolism of didanosine.(1,2)|
01107|011|B||
01107|012|E|CLINICAL EFFECTS:  The concurrent administration of allopurinol and|
01107|013|E|didanosine may result in elevated levels of and toxicity from|
01107|014|E|didanosine.(3,4)|
01107|015|B||
01107|016|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01107|017|P|renal insufficiency.  Renal impairment may significantly increase the plasma|
01107|018|P|half-life of oxypurinol, the main and active metabolite of allopurinol.|
01107|019|B||
01107|020|M|PATIENT MANAGEMENT:  The manufacturer of didanosine states that the|
01107|021|M|concurrent use of allopurinol is contraindicated.(3,4)|
01107|022|B||
01107|023|D|DISCUSSION:  In two patients with renal impairment, the administration of|
01107|024|D|didanosine (200 mg single dose) with allopurinol (300 mg daily) increased|
01107|025|D|the area-under-curve (AUC) and maximum concentration (Cmax) of didanosine by|
01107|026|D|312% and 232%, respectively.  In 14 healthy subjects, the administration of|
01107|027|D|didanosine (400 mg single dose) with allopurinol (300 mg daily for 7 days)|
01107|028|D|increased the AUC and Cmax of didanosine by 113% and 69%, respectively.(3,4)|
01107|029|D|   In a small study in four treatment-naive patients, the addition of|
01107|030|D|allopurinol (300 mg daily) allowed the dose of didanosine to be decreased|
01107|031|D|50%.  Didanosine plasma levels and HIV-1-RNA levels were unchanged after 4|
01107|032|D|and 17-20 months.(5)|
01107|033|B||
01107|034|R|REFERENCES:|
01107|035|B||
01107|036|R|1.Back DJ, Ormesher S, Tjia JF, Macleod R. Metabolism of|5
01107|037|R|  2',3'-dideoxyinosine (ddI) in human blood. Br J Clin Pharmacol 1992 Mar;|5
01107|038|R|  33(3):319-22.|5
01107|039|R|2.Ray AS, Olson L, Fridland A. Role of purine nucleoside phosphorylase in|5
01107|040|R|  interactions between 2',3'-dideoxyinosine and allopurinol, ganciclovir, or|5
01107|041|R|  tenofovir. Antimicrob Agents Chemother 2004 Apr;48(4):1089-95.|5
01107|042|R|3.Videx EC (didanosine) US prescribing information. Bristol-Myers Squibb|1
01107|043|R|  Company January 25, 2018.|1
01107|044|R|4.Videx (didanosine) US prescribing information. Bristol-Myers Squibb|1
01107|045|R|  Company November, 2011.|1
01107|046|R|5.Boelaert JR, Dom GM, Huitema AD, Beijnen JH, Lange JM. The boosting of|2
01107|047|R|  didanosine by allopurinol permits a halving of the didanosine dosage. AIDS|2
01107|048|R|  2002 Nov 8;16(16):2221-3.|2
01108|001|T|MONOGRAPH TITLE:  Didanosine/Hydroxyurea|
01108|002|B||
01108|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01108|004|L|of severe adverse interaction.|
01108|005|B||
01108|006|A|MECHANISM OF ACTION:  Hydroxyurea may potentiate the intracellular toxicity|
01108|007|A|of didanosine.(1)|
01108|008|B||
01108|009|E|CLINICAL EFFECTS:  The concurrent administration of hydroxyurea and|
01108|010|E|didanosine may increase the risk of pancreatitis, severe peripheral|
01108|011|E|neuropathy, hepatotoxicity, and hepatic failure.(2-4)|
01108|012|B||
01108|013|P|PREDISPOSING FACTORS:  The incidence rate of pancreatitis or neuropathy may|
01108|014|P|be higher in patients receiving therapy with didanosine, hydroxyurea, and|
01108|015|P|stavudine.|
01108|016|B||
01108|017|M|PATIENT MANAGEMENT:  The US manufacturer of didanosine states that the|
01108|018|M|concurrent use of didanosine and hydroxyurea, with or without stavudine,|
01108|019|M|should be avoided.(2)  The US manufacturer of hydroxyurea states that the|
01108|020|M|combination of hydroxyurea, didanosine, and stavudine should be avoided.(3)|
01108|021|M|   Monitor patients receiving concurrent therapy for signs and symptoms of|
01108|022|M|pancreatitis, peripheral neuropathy, and hepatotoxicity.|
01108|023|B||
01108|024|D|DISCUSSION:  The US manufacturer of didanosine states that the risk of|
01108|025|D|pancreatitis and neuropathy with didanosine is increased with the concurrent|
01108|026|D|use of agents that also cause these effects.(2)|
01108|027|D|   In a clinical trial, 2 of 68 patients who received didanosine, stavudine,|
01108|028|D|and hydroxyurea died of pancreatitis.  In an early access program, fatal|
01108|029|D|pancreatitis occurred in one patient receiving didanosine, hydroxyurea,|
01108|030|D|stavudine, ritonavir, indinavir, and efavirenz.(2)|
01108|031|D|   In a case report, a 26 year-old HIV positive male developed malaise and|
01108|032|D|upper abdominal pain 42 days after the addition of hydroxyurea to his|
01108|033|D|didanosine, stavudine and nevirapine.  Three weeks after discontinuing|
01108|034|D|hydroxyurea, symptoms worsened and a CT scan revealed pancreatitis.  The|
01108|035|D|patient did eventually recover.(1)|
01108|036|D|   An additional study found that sensory neuropathy was more prevalent in|
01108|037|D|patients on combination therapy with hydroxyurea.  Of the 1116 patients in|
01108|038|D|the study, there were 117 cases of neuropathy.  The crude incidence rate of|
01108|039|D|neuropathy per 100 person-years was 6.8 for didanosine alone, 8.8 for|
01108|040|D|didanosine in combination with hydroxyurea, 9.8 for stavudine alone, 17.5|
01108|041|D|for didanosine in combination with stavudine, and 28.6 for didanosine in|
01108|042|D|combination with hydroxyurea and stavudine.(3)|
01108|043|B||
01108|044|R|REFERENCES:|
01108|045|B||
01108|046|R|1.Longhurst HJ, Pinching AJ. Drug Points: pancreatitis associated with|3
01108|047|R|  hydroxyurea in combination with didanosine. BMJ 2001 Jan 13;322(7278):81.|3
01108|048|R|2.Videx EC (didanosine) US prescribing information. Bristol-Myers Squibb|1
01108|049|R|  Company January 25, 2018.|1
01108|050|R|3.Hydrea (hydroxyurea) US prescribing information. Bristol-Myers Squibb|1
01108|051|R|  Company November, 2023.|1
01108|052|R|4.Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in|2
01108|053|R|  HIV-infected patients on monotherapy versus those on combination therapy|2
01108|054|R|  with didanosine, stavudine and hydroxyurea. AIDS 2000 Feb 18;14(3):273-8.|2
01109|001|T|MONOGRAPH TITLE:  Nitrofurantoin/Magnesium Trisilicate|
01109|002|B||
01109|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01109|004|L|of severe adverse interaction.|
01109|005|B||
01109|006|A|MECHANISM OF ACTION:  Magnesium trisilicate may bind to nitrofurantoin in|
01109|007|A|the gastrointestinal tract, preventing its absorption.(1,2)|
01109|008|B||
01109|009|E|CLINICAL EFFECTS:  The concurrent administration of nitrofurantoin and|
01109|010|E|magnesium trisilicate may result in decreased levels and effectiveness of|
01109|011|E|nitrofurantoin.(1,2)|
01109|012|B||
01109|013|P|PREDISPOSING FACTORS:  None determined.|
01109|014|B||
01109|015|M|PATIENT MANAGEMENT:  The manufacturer of nitrofurantoin states that patients|
01109|016|M|receiving nitrofurantoin should be instructed not to use magnesium|
01109|017|M|trisilicate.(1,2)  If concurrent therapy cannot be avoided, the doses of|
01109|018|M|nitrofurantoin and magnesium trisilicate should be separated by as much time|
01109|019|M|as possible.|
01109|020|B||
01109|021|D|DISCUSSION:  In a study in 6 subjects, the concurrent administration of a|
01109|022|D|single dose of nitrofurantoin (100 mg) with a single dose of magnesium|
01109|023|D|trisilicate (5 G) resulted in a decrease in both the rate and extent of|
01109|024|D|absorption of nitrofurantoin.  The time that nitrofurantoin was above its|
01109|025|D|minimum effective concentration in the urine was also decreased.  In vitro|
01109|026|D|studies confirmed magnesium trisilicate bound nitrofurantoin.  In vitro|
01109|027|D|studies found that bismuth oxycarbonate, talc, kaolin, and magnesium oxide|
01109|028|D|had intermediate absorptive powers when compared to magnesium trisilicate.|
01109|029|D|Aluminum hydroxide and calcium carbonate had low to no absorptive powers.(3)|
01109|030|B||
01109|031|R|REFERENCES:|
01109|032|B||
01109|033|R|1.Macrodantin (nitrofurantoin macrocrystals) US prescribing information.|1
01109|034|R|  Almatica Pharma, Inc. September, 2013.|1
01109|035|R|2.Macrobid (nitrofurantoin monohydrate/macrocrystals) US prescribing|1
01109|036|R|  information. Almatica Pharma, Inc. September, 2013.|1
01109|037|R|3.Naggar VF, Khalil SA. Effect of magnesium trisilicate on nitrofurantoin|2
01109|038|R|  absorption. Clin Pharmacol Ther 1979 Jun;25(6):857-63.|2
01110|001|T|MONOGRAPH TITLE:  Selected NSAIDs/Selected CYP2C9 Inhibitors|
01110|002|B||
01110|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01110|004|L|take action as needed.|
01110|005|B||
01110|006|A|MECHANISM OF ACTION:  The major metabolic pathway for many non-steroidal|
01110|007|A|anti-inflammatory agents (NSAIDs) is CYP2C9. Inhibitors of CYP2C9 include:|
01110|008|A|amiodarone, asciminib, diosmin, fluconazole, ketoconazole, miconazole,|
01110|009|A|nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2)|
01110|010|B||
01110|011|E|CLINICAL EFFECTS:  Concurrent use of NSAIDs with inhibitors of CYP2C9 may|
01110|012|E|result in increased levels of and adverse effects from NSAIDs, including|
01110|013|E|increased risk for bleeding.|
01110|014|E|   NSAIDs linked to this monograph are celecoxib, diclofenac, flurbiprofen,|
01110|015|E|ibuprofen, meloxicam, naproxen, parecoxib, piroxicam and valdecoxib.|
01110|016|B||
01110|017|P|PREDISPOSING FACTORS:  Higher doses of either agent would be expected to|
01110|018|P|increase the risk for serious adverse effects such as gastrointestinal|
01110|019|P|bleeding (GIB) or renal failure.|
01110|020|P|   Patients who smoke, are elderly, debilitated, dehydrated, have renal|
01110|021|P|impairment, or who have a history of GIB due to NSAIDs are also at increased|
01110|022|P|risk for serious adverse events.(3-7)|
01110|023|P|   The risk for bleeding episodes may be greater in patients with|
01110|024|P|disease-associated factors (e.g. thrombocytopenia).|
01110|025|P|   Drug associated risk factors include concurrent use of multiple drugs|
01110|026|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01110|027|P|risk for bleeding (e.g. NSAIDs).|
01110|028|B||
01110|029|M|PATIENT MANAGEMENT:  Patients on routine NSAID therapy when an inhibitor of|
01110|030|M|CYP2C9 is started should be evaluated for patient-specific risk factors for|
01110|031|M|NSAID toxicity.  Based upon this risk assessment, consider dose reduction of|
01110|032|M|the NSAID or close monitoring for adverse effects.|
01110|033|M|   For a patient already receiving a CYP2C9 inhibitor when an NSAID is|
01110|034|M|started, consider initiating the NSAID at a lower than usual dose,|
01110|035|M|particularly when predisposing risk factors for harm are present.|
01110|036|M|   The manufacturer of celecoxib recommends that celecoxib be introduced at|
01110|037|M|the lowest recommended dose in patients receiving fluconazole therapy.(3)|
01110|038|M|The manufacturer of fluconazole states that half the dose of celecoxib may|
01110|039|M|be necessary when fluconazole is added.(4)  It would be prudent to follow|
01110|040|M|this recommendation with other CYP2C9 inhibitors and to decrease the dose of|
01110|041|M|celecoxib in patients in whom CYP2C9 inhibitors are added to celecoxib|
01110|042|M|therapy.|
01110|043|M|   The manufacturer of diclofenac-misoprostol states that the total daily|
01110|044|M|dose of diclofenac should not exceed the lowest recommended dose of 50 mg|
01110|045|M|twice daily in patients taking CYP2C9 inhibitors.(5)  It would be prudent to|
01110|046|M|use the lowest recommended dose of other diclofenac formulations in patients|
01110|047|M|taking CYP2C9 inhibitors.|
01110|048|M|   The manufacturer of parecoxib states that the dose of parecoxib should be|
01110|049|M|reduced in those patients who are receiving fluconazole therapy.(6)  It|
01110|050|M|would be prudent to follow this recommendation with other CYP2C9 inhibitors.|
01110|051|M|   The manufacturer of nitisinone recommends reducing the dosage of a CYP2C9|
01110|052|M|substrate by one-half.(7)|
01110|053|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01110|054|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01110|055|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01110|056|M|patients with any symptoms.|
01110|057|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01110|058|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01110|059|M|anticoagulation in patients with active pathologic bleeding.|
01110|060|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01110|061|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01110|062|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01110|063|M|and/or swelling.|
01110|064|B||
01110|065|D|DISCUSSION:  The concomitant administration of celecoxib and fluconazole|
01110|066|D|(200 mg daily) resulted in a 2-fold increase in celecoxib plasma|
01110|067|D|concentration.(3)|
01110|068|D|   In vitro studies in human hepatocytes found that amiodarone inhibited|
01110|069|D|diclofenac metabolism.(8)|
01110|070|D|   In two separate studies, single doses of diclofenac (50 mg) or ibuprofen|
01110|071|D|(400 mg) were coadministered with the last dose of voriconazole (400 mg q12h|
01110|072|D|on Day 1, followed by 200 mg q12h on Day 2). Voriconazole increased the mean|
01110|073|D|AUC of diclofenac by 78% and increased the AUC of the active isomer of|
01110|074|D|ibuprofen by 100%.(9-11)|
01110|075|D|   Coadministration of diosmin increased diclofenac levels by 63%.(2)|
01110|076|D|   Coadministration of flurbiprofen or ibuprofen with fluconazole increased|
01110|077|D|the AUC of flurbiprofen by 81% and of the active ibuprofen by 82% compared|
01110|078|D|with either agent alone.(4)|
01110|079|D|   Concurrent voriconazole increased meloxicam AUC by 47%.(12,13)|
01110|080|D|   The concurrent administration of fluconazole and parecoxib resulted in|
01110|081|D|increases in the area-under-curve (AUC) and maximum concentration (Cmax) of|
01110|082|D|valdecoxib (the active metabolite of parecoxib) by 62% and 19%,|
01110|083|D|respectively.(6)|
01110|084|D|   In a study, single dose diclofenac (50mg) given concurrently with the|
01110|085|D|last dose of voriconazole (400 mg every 12 hours on Day 1, 200 mg every 12|
01110|086|D|hours on Day 2) increased Cmax and AUC by 2.1-fold and 1.8-fold,|
01110|087|D|respectively. (5)|
01110|088|D|   Inhibitors of CYP2C9 include:  amiodarone, asciminib, diosmin,|
01110|089|D|fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine,|
01110|090|D|voriconazole, and zafirlukast.(1,2)|
01110|091|B||
01110|092|R|REFERENCES:|
01110|093|B||
01110|094|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
01110|095|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01110|096|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01110|097|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01110|098|R|  11/14/2017.|1
01110|099|R|2.Rajnarayana K, Venkatesham A, Krishna DR. Bioavailability of diclofenac|2
01110|100|R|  sodium after pretreatment with diosmin in healthy volunteers. Drug Metabol|2
01110|101|R|  Drug Interact 2007;22(2-3):165-74.|2
01110|102|R|3.Celebrex (celecoxib) US prescribing information. Pfizer Inc. May, 2019.|1
01110|103|R|4.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
01110|104|R|  2024.|1
01110|105|R|5.Arthrotec (diclofenac sodium/misoprostol) US prescribing information.|1
01110|106|R|  Pfizer, Inc. December, 2022.|1
01110|107|R|6.Dynastat (parecoxib) UK summary of product characteristics. Pfizer Limited|1
01110|108|R|  June 26, 2020.|1
01110|109|R|7.Harliku (nitisinone) US prescribing information. Cycle Pharmaceuticals Ltd|1
01110|110|R|  June, 2025.|1
01110|111|R|8.McGinnity DF, Tucker J, Trigg S, Riley RJ. Prediction of CYP2C9-mediated|5
01110|112|R|  drug-drug interactions: a comparison using data from recombinant enzymes|5
01110|113|R|  and human hepatocytes. Drug Metab Dispos 2005 Nov;33(11):1700-7.|5
01110|114|R|9.Hynninen VV, Olkkola KT, Leino K, Lundgren S, Neuvonen PJ, Rane A,|2
01110|115|R|  Valtonen M, Laine K. Effect of voriconazole on the pharmacokinetics of|2
01110|116|R|  diclofenac. Fundam Clin Pharmacol 2007 Dec;21(6):651-6.|2
01110|117|R|10.Hynninen VV, Olkkola KT, Leino K, Lundgren S, Neuvonen PJ, Rane A,|2
01110|118|R|   Valtonen M, Vyyrylainen H, Laine K. Effects of the antifungals|2
01110|119|R|   voriconazole and fluconazole on the pharmacokinetics of s-(+)- and|2
01110|120|R|   R-(-)-Ibuprofen. Antimicrob Agents Chemother 2006 Jun;50(6):1967-72.|2
01110|121|R|11.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01110|122|R|12.Hynninen VV, Olkkola KT, Bertilsson L, Kurkinen KJ, Korhonen T, Neuvonen|1
01110|123|R|   PJ, Laine K. Voriconazole increases while itraconazole decreases plasma|1
01110|124|R|   meloxicam concentrations. Antimicrob Agents Chemother 2009 Feb;|1
01110|125|R|   53(2):587-92.|1
01110|126|R|13.Mobic (meloxicam) US prescribing information. Boehringer Ingelheim May,|1
01110|127|R|   2016.|1
01110|128|R|14.Feldene (piroxicam) US prescribing information. Pfizer Inc. May, 2019.|1
01111|001|T|MONOGRAPH TITLE:  Selected Retinoids (Systemic)/Tetracyclines|
01111|002|B||
01111|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01111|004|L|is contraindicated and generally should not be dispensed or administered to|
01111|005|L|the same patient.|
01111|006|B||
01111|007|A|MECHANISM OF ACTION:  Both systemic tetracyclines(1-4,14) and systemic|
01111|008|A|retinoids(5-14) have been independently associated with medication-induced|
01111|009|A|intracranial hypertension.|
01111|010|B||
01111|011|E|CLINICAL EFFECTS:  The concurrent use of oral retinoids(5-12) with|
01111|012|E|tetracyclines has been associated with pseudotumor cerebri (benign|
01111|013|E|intracranial hypertension).  Early signs of pseudotumor cerebri include|
01111|014|E|papilledema (inflammation of the optic nerve), headache, nausea, vomiting,|
01111|015|E|and visual disturbances such as blurred vision, double vision, and loss of|
01111|016|E|vision.(15)|
01111|017|B||
01111|018|P|PREDISPOSING FACTORS:  Women of childbearing age who are overweight or have|
01111|019|P|a previous history of intracranial hypertension are at a greater risk of|
01111|020|P|developing intracranial hypertension.(15)|
01111|021|B||
01111|022|M|PATIENT MANAGEMENT:  The UK(5) and US(6) manufacturers of acitretin state|
01111|023|M|state that concurrent use with tetracyclines is contraindicated.|
01111|024|M|   The UK manufacturer of isotretinoin states that concurrent use with|
01111|025|M|tetracyclines is contraindicated.(7)  The US manufacturer of isotretinoin|
01111|026|M|states that the concurrent use of tetracyclines should be avoided.(8)  The|
01111|027|M|US manufacturer of minocycline states that the administration of|
01111|028|M|isotretinoin should be avoided shortly before, during and shortly after|
01111|029|M|minocycline therapy.(2)|
01111|030|M|   The UK manufacturers of oral tretinoin and alitretinoin states that|
01111|031|M|concurrent use with tetracyclines is contraindicated.(9,11)|
01111|032|M|   The Canadian manufacturer of palovarotene states that coadministration of|
01111|033|M|tetracycline derivatives should be avoided.(12)|
01111|034|M|   Patients who present with symptoms of pseudotumor cerebri should be|
01111|035|M|screened for papilledema.  If papilledema is present, they should|
01111|036|M|discontinue the drug and be referred to a neurologist for further|
01111|037|M|treatment.(5-13)|
01111|038|B||
01111|039|D|DISCUSSION:  The concurrent use of isotretinoin and tetracyclines has been|
01111|040|D|associated with pseudotumor cerebri.(5-13)  A review of ocular side effects|
01111|041|D|from the National Registry of Drug-Induced Ocular Side Effects, the World|
01111|042|D|Health Organization, the Food and Drug Administration, and medical journals|
01111|043|D|from 1979 to 2003 found 6 patients who developed intracranial hypertension|
01111|044|D|while taking concurrent minocycline or tetracycline with tretinoin,|
01111|045|D|acitretin, or etretinate.(13)|
01111|046|B||
01111|047|R|REFERENCES:|
01111|048|B||
01111|049|R|1.Doryx (doxycycline)  US prescribing information. Mayne Pharma|1
01111|050|R|  International Pty Ltd February, 2020.|1
01111|051|R|2.Minocin (minocycline hydrochloride oral suspension) US prescribing|1
01111|052|R|  information. Triax Pharmaceuticals November, 2018.|1
01111|053|R|3.Solodyn (minocycline ext-rel) US prescribing information. Bausch Health|1
01111|054|R|  US, LLC March, 2025.|1
01111|055|R|4.Tygacil (tigecycline) US prescribing information. Wyeth Pharmaceuticals|1
01111|056|R|  Inc. June, 2020.|1
01111|057|R|5.Neotigason (acitretin) UK summary of product characteristics. Roche|1
01111|058|R|  Products Limited April 5, 2006.|1
01111|059|R|6.Soriatane (acitretin) US prescribing information. Roche Pharmaceuticals|1
01111|060|R|  February, 2014.|1
01111|061|R|7.Roaccutane (isotretinoin) UK summary of product characteristics. Roche|1
01111|062|R|  Products Limited February 14, 2006.|1
01111|063|R|8.Accutane (isotretinoin) US prescribing information. Roche Laboratories,|1
01111|064|R|  Inc. January, 2010.|1
01111|065|R|9.Vesanoid (tretinoin) UK summary of product characteristics. Roche Products|1
01111|066|R|  Limited March 20, 2006.|1
01111|067|R|10.Vesanoid (tretinoin) US prescribing information. Roche Laboratories, Inc.|1
01111|068|R|   February, 2023.|1
01111|069|R|11.Toctino (alitretinoin) UK summary of product characteristics. Basilea|1
01111|070|R|   Pharmaceuticals Ltd September 19, 2008.|1
01111|071|R|12.Sohonos (palovarotene) Canadian Product Monograph. Ipsen|1
01111|072|R|   Biopharmaceuticals Canada Inc. January, 2022.|1
01111|073|R|13.Fraunfelder FW, Fraunfelder FT. Evidence for a probable causal|3
01111|074|R|   relationship between tretinoin, acitretin, and etretinate and|3
01111|075|R|   intracranial hypertension. J Neuroophthalmol 2004 Sep;24(3):214-6.|3
01111|076|R|14.Xu C, Zhang J, Zhang Y, Sun Q, Yang X, Fang W. Drug-Induced Intracranial|6
01111|077|R|   Pressure Increase: Disproportionality Analysis of the Public Version of|6
01111|078|R|   the FDA Event Reporting System. Acta Neurologica Scandinavica September|6
01111|079|R|   2024.|6
01111|080|R|15.Vibramycin (doxycycline) US prescribing information. Pfizer Labs August,|1
01111|081|R|   2025.|1
01112|001|T|MONOGRAPH TITLE:  Methotrexate/Penicillins|
01112|002|B||
01112|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01112|004|L|of severe adverse interaction.|
01112|005|B||
01112|006|A|MECHANISM OF ACTION:  Penicillins may compete with the renal tubular|
01112|007|A|secretion of methotrexate.|
01112|008|B||
01112|009|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and penicillins may|
01112|010|E|result in elevated levels of methotrexate and methotrexate toxicity, leading|
01112|011|E|to increased risk of severe neurotoxicity, stomatitis, and myelosuppression.|
01112|012|B||
01112|013|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
01112|014|P|- High-dose oncology regimens|
01112|015|P|- Impaired renal function, ascites, or pleural effusions|
01112|016|B||
01112|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with methotrexate|
01112|018|M|and penicillins should be monitored closely for elevated methotrexate levels|
01112|019|M|and methotrexate toxicity.  The dose and duration of leucovorin rescue|
01112|020|M|therapy may need to be increased.|
01112|021|B||
01112|022|D|DISCUSSION:  Elevated methotrexate levels, signs of methotrexate toxicity,|
01112|023|D|and death have been reported following the concurrent use of methotrexate|
01112|024|D|(both low dose and high dose) and penicillin derivatives.|
01112|025|D|   In a patient being treated with high-dose methotrexate (8 G/m2), the|
01112|026|D|concurrent use of amoxicillin resulted in a 56% decrease in the clearance of|
01112|027|D|methotrexate and signs of methotrexate toxicity.(1)  There are two cases of|
01112|028|D|methotrexate toxicity following the addition of amoxicillin to low-dose|
01112|029|D|methotrexate therapy (7.5 mg-10 mg weekly) for psoriasis.  In another case,|
01112|030|D|a patient was found to have a toxic methotrexate level 12 days after her|
01112|031|D|last dose of weekly methotrexate (7.5 mg).  The patient had been treated|
01112|032|D|with amoxicillin followed by flucloxacillin.(2)|
01112|033|D|   In a case report, dicloxacillin decreased methotrexate clearance 93%.(4)|
01112|034|D|   Flucloxacillin was shown to increase the area-under-curve (AUC) of|
01112|035|D|methotrexate by 7.3% in a study in 10 subjects.(5)  In a case report, a|
01112|036|D|patient on low-dose methotrexate (5 mg) developed methotrexate pneumonia|
01112|037|D|following the addition of flucloxacillin to his regimen.(5)|
01112|038|D|   In a patient being treated with high-dose methotrexate (12 G/m2), the|
01112|039|D|concurrent use of mezlocillin increased the half-life of methotrexate from|
01112|040|D|10.1 to 27.2 hours.(6)|
01112|041|D|   In a case report, a patient developed methotrexate toxicity following the|
01112|042|D|addition of penicillin V potassium to his methotrexate (50 mg weekly).(7)|
01112|043|D|   In a case report, penicillin decreased methotrexate clearance 36%.(4)|
01112|044|D|   In one report, leucovorin rescue therapy had to be continued for 192|
01112|045|D|hours following the concurrent use of methotrexate (3 G/m2) and|
01112|046|D|piperacillin.  During cycles without concurrent piperacillin, leucovorin|
01112|047|D|rescue therapy was only required for 72 hours.(8)  There are two reports of|
01112|048|D|neutropenia and death following the concurrent use of piperacillin and|
01112|049|D|low-dose methotrexate (2.5 mg three times weekly in one patient, 5 mg weekly|
01112|050|D|in another) for psoriasis.  One of these patients also received|
01112|051|D|flucloxacillin. (3)  In another case report, the concurrent use of|
01112|052|D|piperacillin decreased methotrexate clearance by 67%.(4)|
01112|053|D|   In a case report, ticarcillin decreased methotrexate clearance by 60%.(4)|
01112|054|B||
01112|055|R|REFERENCES:|
01112|056|B||
01112|057|R|1.Ronchera CL, Hernandez T, Peris JE, Torres F, Granero L, Jimenez NV, Pla|3
01112|058|R|  JM. Pharmacokinetic interaction between high-dose methotrexate and|3
01112|059|R|  amoxycillin. Ther Drug Monit 1993 Oct;15(5):375-9.|3
01112|060|R|2.Engelbrecht JA, Calhoon SL, Scherrer JJ. Methotrexate pneumonitis after|3
01112|061|R|  low-dose therapy for rheumatoid arthritis. Arthritis Rheum 1983 Oct;|3
01112|062|R|  26(10):1275-8.|3
01112|063|R|3.Mayall B, Poggi G, Parkin JD. Neutropenia due to low-dose methotrexate|3
01112|064|R|  therapy for psoriasis and rheumatoid arthritis may be fatal. Med J Aust|3
01112|065|R|  1991 Oct 7;155(7):480-4.|3
01112|066|R|4.Bloom EJ, Ignoffo RJ, Reis CA, Cadman E. Delayed clearance (CL) of|4
01112|067|R|  methotrexate (MTX) associated with  antibiotics and antiinflammatory|4
01112|068|R|  agents. Clin Res 1986;34(2):560A.|4
01112|069|R|5.Herrick AL, Grennan DM, Griffen K, Aarons L, Gifford LA. Lack of|2
01112|070|R|  interaction between flucloxacillin and methotrexate in patients with|2
01112|071|R|  rheumatoid arthritis. Br J Clin Pharmacol 1996 Mar;41(3):223-7.|2
01112|072|R|6.Dean R, Nachman J, Lorenzana AN. Possible methotrexate-mezlocillin|3
01112|073|R|  interaction. Am J Pediatr Hematol Oncol 1992 Spring;14(1):88-9.|3
01112|074|R|7.Nierenberg DW, Mamelok RD. Toxic reaction to methotrexate in a patient|3
01112|075|R|  receiving penicillin and furosemide: a possible interaction. Arch Dermatol|3
01112|076|R|  1983 Jun;119(6):449-50.|3
01112|077|R|8.Yamamoto K, Sawada Y, Matsushita Y, Moriwaki K, Bessho F, Iga T. Delayed|3
01112|078|R|  elimination of methotrexate associated with piperacillin administration.|3
01112|079|R|  Ann Pharmacother 1997 Oct;31(10):1261-2.|3
01113|001|T|MONOGRAPH TITLE:  Live Viral Vaccines/Alemtuzumab (mono deleted 04/26/2012)|
01113|002|B||
01113|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01113|004|L|is contraindicated and generally should not be dispensed or administered to|
01113|005|L|the same patient.|
01113|006|B||
01113|007|A|MECHANISM OF ACTION:  Alemtuzumab-induced immunosuppression may prevent an|
01113|008|A|immune response to the vaccine.(1)|
01113|009|B||
01113|010|E|CLINICAL EFFECTS:  The use of live viral vaccines in patients who have|
01113|011|E|recently received alemtuzumab may be ineffective and may result in|
01113|012|E|infection.(1)|
01113|013|B||
01113|014|P|PREDISPOSING FACTORS:  None determined.|
01113|015|B||
01113|016|M|PATIENT MANAGEMENT:  The manufacturer of alemtuzumab states that patients|
01113|017|M|who have recently received alemtuzumab should not be immunized with live|
01113|018|M|viral vaccines.(1)|
01113|019|B||
01113|020|D|DISCUSSION:  The manufacturer of alemtuzumab states that the safety of|
01113|021|D|immunization with live viral vaccines following alemtuzumab therapy has not|
01113|022|D|been studied.  The ability to generate a primary or anamnestic humoral|
01113|023|D|response to any vaccine following alemtuzumab has not been studied.|
01113|024|D|Therefore, the manufacturer of alemtuzumab states that because of their|
01113|025|D|immunosuppression, patients who have recently received alemtuzumab should|
01113|026|D|not be immunized with live viral vaccines.(1)|
01113|027|B||
01113|028|R|REFERENCE:|
01113|029|B||
01113|030|R|1.Campath (alemtuzumab) US prescribing information. Berlex Laboratories|1
01113|031|R|  March, 2009.|1
01114|001|T|MONOGRAPH TITLE:  Ziprasidone/Selected Antiarrhythmics|
01114|002|B||
01114|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01114|004|L|is contraindicated and generally should not be dispensed or administered to|
01114|005|L|the same patient.|
01114|006|B||
01114|007|A|MECHANISM OF ACTION:  Dofetilide, quinidine, sotalol and ziprasidone have|
01114|008|A|been shown to prolong the QTc interval.  The concurrent use of ziprasidone|
01114|009|A|with these agents may result in additive effects on the QTc interval.(1)|
01114|010|B||
01114|011|E|CLINICAL EFFECTS:  The concurrent use of ziprasidone with dofetilide,|
01114|012|E|quinidine, or sotalol may result in additive prolongation of the QTc|
01114|013|E|interval and potentially life-threatening arrhythmias.(1)|
01114|014|B||
01114|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01114|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01114|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01114|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01114|019|P|female gender, or advanced age.(2)|
01114|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01114|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01114|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01114|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01114|024|P|impaired metabolism or elimination of the drug (e.g coadministration with an|
01114|025|P|agent which inhibits its metabolism or elimination, genetic impairment in|
01114|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01114|027|B||
01114|028|M|PATIENT MANAGEMENT:  The manufacturer of ziprasidone states under|
01114|029|M|contraindications that ziprasidone should not be used with other drugs that|
01114|030|M|prolong the QTc interval, including dofetilide, quinidine, or sotalol.(1)|
01114|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01114|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01114|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01114|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01114|035|B||
01114|036|D|DISCUSSION:  Ziprasidone has been shown to prolong the QTc interval in a|
01114|037|D|dose-related fashion.  Therefore, the manufacturer of ziprasidone states|
01114|038|D|under contraindications that ziprasidone should not be used with other drugs|
01114|039|D|that prolong the QTc interval, including dofetilide, quinidine, or|
01114|040|D|sotalol.(1)|
01114|041|B||
01114|042|R|REFERENCES:|
01114|043|B||
01114|044|R|1.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
01114|045|R|  May, 2021.|1
01114|046|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01114|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01114|048|R|  settings: a scientific statement from the American Heart Association and|6
01114|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01114|050|R|  2;55(9):934-47.|6
01115|001|T|MONOGRAPH TITLE:  Ziprasidone/Pimozide; Thioridazine|
01115|002|B||
01115|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01115|004|L|is contraindicated and generally should not be dispensed or administered to|
01115|005|L|the same patient.|
01115|006|B||
01115|007|A|MECHANISM OF ACTION:  Pimozide, thioridazine and ziprasidone have all been|
01115|008|A|shown to prolong the QTc interval.  The concurrent use of ziprasidone with|
01115|009|A|these agents may result in additive effects on the QTc interval.(1)|
01115|010|B||
01115|011|E|CLINICAL EFFECTS:  The concurrent use of ziprasidone with pimozide or|
01115|012|E|thioridazine may result in additive prolongation of the QTc interval and|
01115|013|E|potentially life-threatening arrhythmias.(1)|
01115|014|B||
01115|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01115|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01115|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01115|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01115|019|P|female gender, or advanced age.(2)|
01115|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01115|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01115|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01115|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01115|024|P|impaired metabolism or elimination of the drug (e.g coadministration with an|
01115|025|P|agent which inhibits its metabolism or elimination, genetic impairment in|
01115|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01115|027|B||
01115|028|M|PATIENT MANAGEMENT:  The manufacturer of ziprasidone states under|
01115|029|M|contraindications that ziprasidone should not be used with other drugs that|
01115|030|M|prolong the QTc interval, including pimozide or thioridazine.(1)|
01115|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01115|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01115|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01115|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01115|035|B||
01115|036|D|DISCUSSION:  Ziprasidone has been shown to prolong the QTc interval in a|
01115|037|D|dose-related fashion.  Therefore, the manufacturer of ziprasidone states|
01115|038|D|under contraindications that ziprasidone should not be used with other drugs|
01115|039|D|that prolong the QTc interval, including pimozide or thioridazine.(1)|
01115|040|B||
01115|041|R|REFERENCES:|
01115|042|B||
01115|043|R|1.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
01115|044|R|  May, 2021.|1
01115|045|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01115|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01115|047|R|  settings: a scientific statement from the American Heart Association and|6
01115|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01115|049|R|  2;55(9):934-47.|6
01116|001|T|MONOGRAPH TITLE:  Ziprasidone/Moxifloxacin; Sparfloxacin|
01116|002|B||
01116|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01116|004|L|is contraindicated and generally should not be dispensed or administered to|
01116|005|L|the same patient.|
01116|006|B||
01116|007|A|MECHANISM OF ACTION:  Moxifloxacin, sparfloxacin, and ziprasidone have been|
01116|008|A|shown to prolong the QTc interval.  The concurrent use of ziprasidone with|
01116|009|A|these agents may result in additive effects on the QTc interval.(1)|
01116|010|B||
01116|011|E|CLINICAL EFFECTS:  The concurrent use of ziprasidone with moxifloxacin or|
01116|012|E|sparfloxacin may result in additive prolongation of the QTc interval and|
01116|013|E|potentially life-threatening arrhythmias.(1)|
01116|014|B||
01116|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01116|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01116|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01116|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01116|019|P|female gender, or advanced age.(2)|
01116|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01116|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01116|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01116|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01116|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01116|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01116|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01116|027|B||
01116|028|M|PATIENT MANAGEMENT:  The manufacturer of ziprasidone states under|
01116|029|M|contraindications that ziprasidone should not be used with other drugs that|
01116|030|M|prolong the QTc interval, including moxifloxacin and sparfloxacin.(1)|
01116|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01116|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01116|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01116|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01116|035|B||
01116|036|D|DISCUSSION:  Ziprasidone has been shown to prolong the QTc interval in a|
01116|037|D|dose-related fashion.  Therefore, the manufacturer of ziprasidone states|
01116|038|D|under contraindications that ziprasidone should not be used with other drugs|
01116|039|D|that prolong the QTc interval, including moxifloxacin or sparfloxacin.(1)|
01116|040|B||
01116|041|R|REFERENCES:|
01116|042|B||
01116|043|R|1.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
01116|044|R|  May, 2021.|1
01116|045|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01116|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01116|047|R|  settings: a scientific statement from the American Heart Association and|6
01116|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01116|049|R|  2;55(9):934-47.|6
01117|001|T|MONOGRAPH TITLE:  Thioridazine/QT Prolonging Agents|
01117|002|B||
01117|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01117|004|L|of severe adverse interaction.|
01117|005|B||
01117|006|A|MECHANISM OF ACTION:  Thioridazine has been shown to prolong the QTc|
01117|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01117|008|A|may result in additive effects on the QTc interval.(1)|
01117|009|B||
01117|010|E|CLINICAL EFFECTS:  The concurrent use of thioridazine with other agents that|
01117|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01117|012|E|arrhythmias, including torsades de pointes.(1)|
01117|013|B||
01117|014|P|PREDISPOSING FACTORS:  Use of thioridazine in patients with reduced CYP2D6|
01117|015|P|activity (either through genetic predisposition or use of drugs that inhibit|
01117|016|P|CYP2D6 activity) may increase the risk of torsades de pointes and/or sudden|
01117|017|P|death in patients taking thioridazine.(1)|
01117|018|P|   The risk of QT prolongation or torsade de pointes may be increased in|
01117|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01117|020|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
01117|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01117|022|P|advanced age.(4)|
01117|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01117|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01117|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01117|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01117|027|P|impaired metabolism or elimination of the drug (e.g. impairment in the drug|
01117|028|P|metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01117|029|B||
01117|030|M|PATIENT MANAGEMENT:  The manufacturer of thioridazine states under|
01117|031|M|contraindications that the use of thioridazine should be avoided in|
01117|032|M|combination with other drugs that are known to prolong the QTc interval.|
01117|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01117|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01117|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01117|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01117|037|B||
01117|038|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01117|039|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01117|040|D|monograph have been shown to prolong the QTc interval either through their|
01117|041|D|mechanism of action, through studies on their effects on the QTc interval,|
01117|042|D|or through reports of QTc prolongation and/or torsades de pointes in|
01117|043|D|clinical trials and/or postmarketing reports.(2)|
01117|044|D|   One or more of the drug pairs linked to this monograph have been included|
01117|045|D|in a list of interactions that should be considered "high-priority" for|
01117|046|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01117|047|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01117|048|D|Coordinator (ONC) for Health Information Technology.|
01117|049|B||
01117|050|R|REFERENCES:|
01117|051|B||
01117|052|R|1.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
01117|053|R|  September, 2014.|1
01117|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01117|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01117|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01117|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01117|058|R|3.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
01117|059|R|  November, 2017.|1
01117|060|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01117|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01117|062|R|  settings: a scientific statement from the American Heart Association and|6
01117|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01117|064|R|  2;55(9):934-47.|6
01117|065|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01117|066|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01117|067|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01117|068|R|  19(5):735-43.|6
01118|001|T|MONOGRAPH TITLE:  Bepridil/QT Prolonging Agents|
01118|002|B||
01118|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01118|004|L|is contraindicated and generally should not be dispensed or administered to|
01118|005|L|the same patient.|
01118|006|B||
01118|007|A|MECHANISM OF ACTION:  Bepridil has been shown to prolong the QTc interval.|
01118|008|A|Concurrent use with other agents that prolong the QTc interval may result in|
01118|009|A|additive effects on the QTc interval.(1)|
01118|010|B||
01118|011|E|CLINICAL EFFECTS:  The concurrent use of bepridil with other agents that|
01118|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01118|013|E|arrhythmias, including torsades de pointes.(1)|
01118|014|B||
01118|015|P|PREDISPOSING FACTORS:  Hypokalemia, the use of potassium wasting diuretics,|
01118|016|P|and the presence of antecedent bradycardia may increase the risk of torsades|
01118|017|P|de pointes.(1)|
01118|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01118|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01118|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01118|021|P|hypokalemia, hypomagnesemia, hypocalcemia, female gender, or advanced|
01118|022|P|age.(3)|
01118|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01118|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01118|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01118|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01118|027|P|impaired metabolism or elimination of the drug (e.g. coadministration  with|
01118|028|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
01118|029|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01118|030|B||
01118|031|M|PATIENT MANAGEMENT:  The manufacturer of bepridil states under|
01118|032|M|contraindications that bepridil is contraindicated in patients taking other|
01118|033|M|drugs that prolong the QT interval.(1)|
01118|034|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01118|035|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01118|036|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01118|037|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01118|038|B||
01118|039|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01118|040|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01118|041|D|monograph have been shown to prolong the QTc interval either through their|
01118|042|D|mechanism of action, through studies on their effects on the QTc interval,|
01118|043|D|or through reports of QTc prolongation and/or torsades de pointes in|
01118|044|D|clinical trials and/or postmarketing reports.(2)|
01118|045|D|   One or more of the drug pairs linked to this monograph have been included|
01118|046|D|in a list of interactions that should be considered "high-priority" for|
01118|047|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01118|048|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01118|049|D|Coordinator (ONC) for Health Information Technology.|
01118|050|B||
01118|051|R|REFERENCES:|
01118|052|B||
01118|053|R|1.Vascor (bepridil hydrochloride) US prescribing information. Ortho-McNeil|1
01118|054|R|  Pharmaceutical, Inc. March, 2000.|1
01118|055|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01118|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01118|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01118|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01118|059|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01118|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01118|061|R|  settings: a scientific statement from the American Heart Association and|6
01118|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01118|063|R|  2;55(9):934-47.|6
01118|064|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01118|065|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01118|066|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01118|067|R|  19(5):735-43.|6
01119|001|T|MONOGRAPH TITLE:  Ziprasidone/Selected QT Prolonging Agents|
01119|002|B||
01119|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01119|004|L|is contraindicated and generally should not be dispensed or administered to|
01119|005|L|the same patient.|
01119|006|B||
01119|007|A|MECHANISM OF ACTION:  Ziprasidone has been shown to prolong the QTc|
01119|008|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01119|009|A|may result in additive effects on the QTc interval.(1)|
01119|010|B||
01119|011|E|CLINICAL EFFECTS:  The concurrent use of ziprasidone with other agents that|
01119|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01119|013|E|arrhythmias, including torsades de pointes.(1)|
01119|014|B||
01119|015|P|PREDISPOSING FACTORS:  Bradycardia, hypokalemia, hypomagnesemia, and the|
01119|016|P|presence of congenital prolongation of the QT interval may increase the risk|
01119|017|P|of torsades de pointes and/or sudden death.(1)|
01119|018|P|   The risk of QT prolongation or torsade de pointes may also be increased|
01119|019|P|in patients with cardiovascular disease (e.g. heart failure, myocardial|
01119|020|P|infarction, history of torsade de pointes), hypocalcemia, female gender, or|
01119|021|P|advanced age.(3)|
01119|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01119|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01119|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01119|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01119|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01119|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01119|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction.(3)|
01119|029|B||
01119|030|M|PATIENT MANAGEMENT:  The manufacturer of ziprasidone states under|
01119|031|M|contraindications that ziprasidone should not be used with other drugs that|
01119|032|M|prolong the QT interval such as dofetilide, sotalol, quinidine, other Class|
01119|033|M|Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine,|
01119|034|M|droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin,|
01119|035|M|halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl|
01119|036|M|acetate, dolasetron mesylate, probucol or tacrolimus.(1)|
01119|037|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01119|038|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01119|039|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01119|040|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01119|041|B||
01119|042|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01119|043|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01119|044|D|monograph have been shown to prolong the QTc interval either through their|
01119|045|D|mechanism of action, through studies on their effects on the QTc interval,|
01119|046|D|or through reports of QTc prolongation and/or torsades de pointes in|
01119|047|D|clinical trials and/or postmarketing reports.(2)|
01119|048|B||
01119|049|R|REFERENCES:|
01119|050|B||
01119|051|R|1.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
01119|052|R|  May, 2021.|1
01119|053|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01119|054|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01119|055|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01119|056|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01119|057|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01119|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01119|059|R|  settings: a scientific statement from the American Heart Association and|6
01119|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01119|061|R|  2;55(9):934-47.|6
01120|001|T|MONOGRAPH TITLE:  Mesoridazine/QT Prolonging Agents|
01120|002|B||
01120|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01120|004|L|of severe adverse interaction.|
01120|005|B||
01120|006|A|MECHANISM OF ACTION:  Mesoridazine has been shown to prolong the QTc|
01120|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01120|008|A|may result in additive effects on the QTc interval.(1)|
01120|009|B||
01120|010|E|CLINICAL EFFECTS:  The concurrent use of mesoridazine with other agents that|
01120|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01120|012|E|arrhythmias, including torsades de pointes.(1)|
01120|013|B||
01120|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01120|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01120|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01120|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01120|018|P|gender, or advanced age.(3)|
01120|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01120|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01120|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01120|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01120|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01120|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01120|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01120|026|B||
01120|027|M|PATIENT MANAGEMENT:  The manufacturer of mesoridazine states under|
01120|028|M|contraindications that the use of mesoridazine should be avoided in|
01120|029|M|combination with other drugs that are known to prolong the QTc interval.(1)|
01120|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01120|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01120|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01120|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01120|034|B||
01120|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01120|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01120|037|D|monograph have been shown to prolong the QTc interval either through their|
01120|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01120|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01120|040|D|clinical trials and/or postmarketing reports.(2)|
01120|041|D|   One or more of the drug pairs linked to this monograph have been included|
01120|042|D|in a list of interactions that should be considered "high-priority" for|
01120|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01120|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01120|045|D|Coordinator (ONC) for Health Information Technology.|
01120|046|B||
01120|047|R|REFERENCES:|
01120|048|B||
01120|049|R|1.Serentil (mesoridazine besylate) US prescribing information. Novartis|1
01120|050|R|  Pharmaceuticals Corporation August, 2000.|1
01120|051|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01120|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01120|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01120|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01120|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01120|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01120|057|R|  settings: a scientific statement from the American Heart Association and|6
01120|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01120|059|R|  2;55(9):934-47.|6
01120|060|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01120|061|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01120|062|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01120|063|R|  19(5):735-43.|6
01121|001|T|MONOGRAPH TITLE:  Pimozide/QT Prolonging Agents|
01121|002|B||
01121|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01121|004|L|is contraindicated and generally should not be dispensed or administered to|
01121|005|L|the same patient.|
01121|006|B||
01121|007|A|MECHANISM OF ACTION:  Pimozide has been shown to prolong the QTc interval.|
01121|008|A|Concurrent use with other agents that prolong the QTc interval may result in|
01121|009|A|additive effects on the QTc interval.(1)|
01121|010|B||
01121|011|E|CLINICAL EFFECTS:  The concurrent use of pimozide with other agents that|
01121|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01121|013|E|arrhythmias, including torsades de pointes.(1)|
01121|014|B||
01121|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01121|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01121|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01121|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01121|019|P|gender, or advanced age.(3)|
01121|020|P|   Concurrent use of more than one drug know to cause QT prolongation or|
01121|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01121|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01121|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01121|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01121|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01121|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction.(3)|
01121|027|B||
01121|028|M|PATIENT MANAGEMENT:  The manufacturer of pimozide states under|
01121|029|M|contraindications that the use of pimozide is contraindicated in patients|
01121|030|M|taking other drugs which prolong the QT interval.(1)|
01121|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01121|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01121|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01121|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01121|035|B||
01121|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01121|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01121|038|D|monograph have been shown to prolong the QTc interval either through their|
01121|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01121|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01121|041|D|clinical trials and/or postmarketing reports.(2)|
01121|042|D|   One or more of the drug pairs linked to this monograph have been included|
01121|043|D|in a list of interactions that should be considered "high-priority" for|
01121|044|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01121|045|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01121|046|D|Coordinator (ONC) for Health Information Technology.|
01121|047|B||
01121|048|R|REFERENCES:|
01121|049|B||
01121|050|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
01121|051|R|  2011.|1
01121|052|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01121|053|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01121|054|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01121|055|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01121|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01121|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01121|058|R|  settings: a scientific statement from the American Heart Association and|6
01121|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01121|060|R|  2;55(9):934-47.|6
01121|061|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01121|062|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01121|063|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01121|064|R|  19(5):735-43.|6
01122|001|T|MONOGRAPH TITLE:  Selected Beta-Blockers/Amiodarone; Dronedarone|
01122|002|B||
01122|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01122|004|L|take action as needed.|
01122|005|B||
01122|006|A|MECHANISM OF ACTION:  The mechanism by which carvedilol, metoprolol,|
01122|007|A|nebivolol, and propranolol and amiodarone produce severe bradycardia and|
01122|008|A|hypotension is due to depressant effects on the sinus and AV node.  Since|
01122|009|A|these beta-blockers are cleared by CYP2D6 metabolism and amiodarone is a|
01122|010|A|weak 2D6 inhibitor; amiodarone may decrease their metabolism.(1,3)|
01122|011|A|   Dronedarone is a moderate CYP2D6 inhibitor therefore may inhibit the|
01122|012|A|metabolism of carvedilol, metoprolol, nebivolol and propranolol since these|
01122|013|A|beta-blockers are cleared by CYP2D6 metabolism.(2-3)|
01122|014|B||
01122|015|E|CLINICAL EFFECTS:  The concurrent administration of hepatically metabolized|
01122|016|E|beta-blockers with amiodarone(1) or dronedarone may result in bradycardia|
01122|017|E|and hypotension.(1)|
01122|018|B||
01122|019|P|PREDISPOSING FACTORS:  None determined.|
01122|020|B||
01122|021|M|PATIENT MANAGEMENT:  Use low doses of beta-blockers initially.  Only|
01122|022|M|increase the dosage of the beta-blocker after ECG verification of good|
01122|023|M|tolerability.(2)|
01122|024|M|   Patients receiving a concurrent therapy should be closely monitored for|
01122|025|M|adverse effects, such as bradycardia and hypotension. Patients experiencing|
01122|026|M|this drug interaction should have their beta-adrenergic blocking drug|
01122|027|M|discontinued.  Supportive therapy with sympathomimetic agents may be|
01122|028|M|required.|
01122|029|B||
01122|030|D|DISCUSSION:  In one case report, a patient taking amiodarone developed|
01122|031|D|hypotension and atropine-resistant sinus bradycardia after receiving a|
01122|032|D|single dose of metoprolol.  Three hours after receiving the metoprolol dose,|
01122|033|D|the patient experienced dizziness, weakness, and blurred vision.(1)|
01122|034|D|  Another report described two patients who exhibited an interaction between|
01122|035|D|amiodarone and propranolol.  One patient maintained on amiodarone|
01122|036|D|experienced cardiac arrest after a single oral dose of propranolol.  The|
01122|037|D|second patient received intravenous amiodarone followed by 2 doses of oral|
01122|038|D|propranolol and developed severe bradycardia followed by ventricular|
01122|039|D|fibrillation.(4)|
01122|040|D|   The stereoselective effect of amiodarone on the pharmacokinetics of|
01122|041|D|racemic carvedilol was evaluated in 106 patients, where 52 received|
01122|042|D|carvedilol monotherapy and 54 received carvedilol with amiodarone.  There|
01122|043|D|was no significant differences between the serum concentration to dose ratio|
01122|044|D|between the 2 groups.  However, there was an increase in the ratio of|
01122|045|D|S-carvedilol to R-carvedilol.  During amiodarone, the concentration of|
01122|046|D|S-carvedilol increased from 3.03 ng/ml to 6.54 ng/ml.(5)|
01122|047|D|   Several studies have shown that the addition of carvedilol to congestive|
01122|048|D|heart failure patients currently receiving amiodarone resulted in improved|
01122|049|D|hypotension/dizziness, primary AV block, and aggravated angina.(6-8)|
01122|050|D|   Dronedarone increased propranolol and metoprolol (exact dosages not|
01122|051|D|stated) by 1.3-fold and 1.6-fold, respectively.(2)|
01122|052|D|   Amiodarone increased metoprolol maximum concentration (Cmax) from 40|
01122|053|D|mcg/L to 70 mcg/L and area-under-curve (AUC) from 767 mcg x h/L to 1387 mcg|
01122|054|D|x h/L after an amiodarone loading dose of 1.2 g.  The interaction was noted|
01122|055|D|to be more pronounced in patients with >/= 2 compared to 1 functional CYP2D6|
01122|056|D|alleles.(9)|
01122|057|D|   Concomitant use of dronedarone and metoprolol were studied in 49 health|
01122|058|D|subjects with four differing CYP2D6 mutations.  Thirty-nine were extensive|
01122|059|D|metabolizers of CYP2D6 with Cmax significantly increased from baseline|
01122|060|D|(134.1 ng/mL) on day 13 to 162.6 ng/mL, 195.58 ng/mL, and 180.9 ng/mL after|
01122|061|D|administration of dronedarone 800 mg, 1200 mg, and 1600 mg dose,|
01122|062|D|respectively.(10)|
01122|063|B||
01122|064|R|REFERENCES:|
01122|065|B||
01122|066|R|1.Leor J, Levartowsky D, Sharon C, Farfel Z. Amiodarone and beta-adrenergic|3
01122|067|R|  blockers: an interaction with metoprolol but not with atenolol. Am Heart J|3
01122|068|R|  1988 Jul;116(1 Pt 1):206-7.|3
01122|069|R|2.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01122|070|R|  November, 2020.|1
01122|071|R|3.This information is based on an extract from the Certara Drug Interaction|6
01122|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01122|073|R|4.Derrida JP, Ollagnier J, Benaim R, Haiat R, Chiche P. Amiodarone and|3
01122|074|R|  propanolol: a dangerous combination?. Nouv Presse Med 1979 Apr 14;|3
01122|075|R|  8(17):1429.|3
01122|076|R|5.Fukumoto K, Kobayashi T, Komamura K, Kamakura S, Kitakaze M, Ueno K.|2
01122|077|R|  Stereoselective effect of amiodarone on the pharmacokinetics of racemic|2
01122|078|R|  carvedilol. Drug Metab Pharmacokinet 2005 Dec;20(6):423-7.|2
01122|079|R|6.Nagele H, Bohlmann M, Eck U, Petersen B, Rodiger W. Combination therapy|2
01122|080|R|  with carvedilol and amiodarone in patients with severe heart failure. Eur|2
01122|081|R|  J Heart Fail 2000 Mar;2(1):71-9.|2
01122|082|R|7.Macdonald PS, Keogh AM, Aboyoun C, Lund M, Amor R, McCaffrey D. Impact of|2
01122|083|R|  concurrent amiodarone treatment on the tolerability and efficacy of|2
01122|084|R|  carvedilol in patients with chronic heart failure. Heart 1999 Nov;|2
01122|085|R|  82(5):589-93.|2
01122|086|R|8.Krum H, Shusterman N, MacMahon S, Sharpe N. Efficacy and safety of|2
01122|087|R|  carvedilol in patients with chronic heart failure receiving concomitant|2
01122|088|R|  amiodarone therapy. Australia/New Zealand Heart Failure Research|2
01122|089|R|  Collaborative Group. J Card Fail 1998 Dec;4(4):281-8.|2
01122|090|R|9.Werner D, Wuttke H, Fromm MF, Schaefer S, Eschenhagen T, Brune K, Daniel|2
01122|091|R|  WG, Werner U. Effect of amiodarone on the plasma levels of metoprolol. Am|2
01122|092|R|  J Cardiol 2004 Nov 15;94(10):1319-21.|2
01122|093|R|10.Damy T, Pousset F, Caplain H, Hulot JS, Lechat P. Pharmacokinetic and|2
01122|094|R|   pharmacodynamic interactions between metoprolol and dronedarone in|2
01122|095|R|   extensive and poor CYP2D6 metabolizers healthy subjects. Fundam Clin|2
01122|096|R|   Pharmacol 2004 Feb;18(1):113-23.|2
01123|001|T|MONOGRAPH TITLE:  Halofantrine/QT Prolonging Agents|
01123|002|B||
01123|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01123|004|L|is contraindicated and generally should not be dispensed or administered to|
01123|005|L|the same patient.|
01123|006|B||
01123|007|A|MECHANISM OF ACTION:  Halofantrine has been shown to prolong the QTc|
01123|008|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01123|009|A|may result in additive effects on the QTc interval.(1)|
01123|010|B||
01123|011|E|CLINICAL EFFECTS:  The concurrent use of halofantrine with other agents that|
01123|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01123|013|E|arrhythmias, including torsades de pointes.(1)|
01123|014|B||
01123|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01123|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01123|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01123|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01123|019|P|gender, or advanced age.(3)|
01123|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01123|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01123|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01123|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01123|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01123|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01123|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction.(3)|
01123|027|B||
01123|028|M|PATIENT MANAGEMENT:  The manufacturer of halofantrine states in a black box|
01123|029|M|warning that halofantrine is not recommended for use in combination with|
01123|030|M|drugs known to prolong the QTc interval.  Under precautions, drug|
01123|031|M|interactions, the manufacturer states that halofantrine should not be|
01123|032|M|administered with drugs known to prolong the QTc interval.(1)|
01123|033|B||
01123|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01123|035|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01123|036|D|monograph have been shown to prolong the QTc interval either through their|
01123|037|D|mechanism of action, through studies on their effects on the QTc interval,|
01123|038|D|or through reports of QTc prolongation and/or torsades de pointes in|
01123|039|D|clinical trials and/or postmarketing reports.(2)|
01123|040|D|   One or more of the drug pairs linked to this monograph have been included|
01123|041|D|in a list of interactions that should be considered "high-priority" for|
01123|042|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01123|043|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01123|044|D|Coordinator (ONC) for Health Information Technology.|
01123|045|B||
01123|046|R|REFERENCES:|
01123|047|B||
01123|048|R|1.Halfan (halofantrine hydrochloride) US prescribing information. SmithKline|1
01123|049|R|  Beecham Pharmaceuticals October, 2001.|1
01123|050|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01123|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01123|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01123|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01123|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01123|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01123|056|R|  settings: a scientific statement from the American Heart Association and|6
01123|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01123|058|R|  2;55(9):934-47.|6
01123|059|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01123|060|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01123|061|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01123|062|R|  19(5):735-43.|6
01124|001|T|MONOGRAPH TITLE:  Sparfloxacin/QT Prolonging Agents|
01124|002|B||
01124|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01124|004|L|is contraindicated and generally should not be dispensed or administered to|
01124|005|L|the same patient.|
01124|006|B||
01124|007|A|MECHANISM OF ACTION:  Sparfloxacin has been shown to prolong the QTc|
01124|008|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01124|009|A|may result in additive effects on the QTc interval.(1)|
01124|010|B||
01124|011|E|CLINICAL EFFECTS:  The concurrent use of sparfloxacin with other agents that|
01124|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01124|013|E|arrhythmias, including torsades de pointes.(1)|
01124|014|B||
01124|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01124|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01124|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01124|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01124|019|P|gender, or advanced age.(3)|
01124|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01124|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01124|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01124|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01124|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01124|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01124|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01124|027|B||
01124|028|M|PATIENT MANAGEMENT:  The manufacturer of sparfloxacin states under|
01124|029|M|contraindications that sparfloxacin is contraindicated in patients being|
01124|030|M|treated concomitantly with medications known to produce an increase in the|
01124|031|M|QTc interval and/or torsade de pointes.(1)|
01124|032|B||
01124|033|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01124|034|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01124|035|D|monograph have been shown to prolong the QTc interval either through their|
01124|036|D|mechanism of action, through studies on their effects on the QTc interval,|
01124|037|D|or through reports of QTc prolongation and/or torsades de pointes in|
01124|038|D|clinical trials and/or postmarketing reports.(2)|
01124|039|B||
01124|040|R|REFERENCES:|
01124|041|B||
01124|042|R|1.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
01124|043|R|  Inc. February, 2003.|1
01124|044|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01124|045|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01124|046|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01124|047|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01124|048|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01124|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01124|050|R|  settings: a scientific statement from the American Heart Association and|6
01124|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01124|052|R|  2;55(9):934-47.|6
01125|001|T|MONOGRAPH TITLE:  Levomethadyl/QT Prolonging Agents|
01125|002|B||
01125|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01125|004|L|is contraindicated and generally should not be dispensed or administered to|
01125|005|L|the same patient.|
01125|006|B||
01125|007|A|MECHANISM OF ACTION:  Levomethadyl has been shown to prolong the QTc|
01125|008|A|interval and induce torsade de pointes.  Concurrent use with other agents|
01125|009|A|that prolong the QTc interval may result in additive effects on the QTc|
01125|010|A|interval.(1)|
01125|011|B||
01125|012|E|CLINICAL EFFECTS:  The concurrent use of levomethadyl with other agents that|
01125|013|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01125|014|E|arrhythmias, including torsades de pointes.(1)|
01125|015|B||
01125|016|P|PREDISPOSING FACTORS:  Congestive heart failure, bradycardia, diuretic use,|
01125|017|P|cardiac hypertrophy, hypokalemia, or hypomagnesemia may increase the risk of|
01125|018|P|torsade de pointes and/or sudden death.(1)  The risk of QT prolongation may|
01125|019|P|also be increased in patients with other cardiovascular diseases (e.g.|
01125|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01125|021|P|syndrome), hypocalcemia, female gender, or advanced age.(3)|
01125|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01125|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01125|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01125|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01125|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01125|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01125|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01125|029|B||
01125|030|M|PATIENT MANAGEMENT:  The manufacturer of levomethadyl states under|
01125|031|M|contraindications that levomethadyl is contraindicated in patients being|
01125|032|M|treated concomitantly with other drug products known to prolong the QT|
01125|033|M|interval.(1)|
01125|034|B||
01125|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01125|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01125|037|D|monograph have been shown to prolong the QTc interval either through their|
01125|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01125|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01125|040|D|clinical trials and/or postmarketing reports.(2)|
01125|041|D|   One or more of the drug pairs linked to this monograph have been included|
01125|042|D|in a list of interactions that should be considered "high-priority" for|
01125|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01125|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01125|045|D|Coordinator (ONC) for Health Information Technology.|
01125|046|B||
01125|047|R|REFERENCES:|
01125|048|B||
01125|049|R|1.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
01125|050|R|  Roxane Laboratories, Inc. May, 2001.|1
01125|051|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01125|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01125|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01125|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01125|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01125|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01125|057|R|  settings: a scientific statement from the American Heart Association and|6
01125|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01125|059|R|  2;55(9):934-47.|6
01125|060|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01125|061|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01125|062|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01125|063|R|  19(5):735-43.|6
01126|001|T|MONOGRAPH TITLE:  Felodipine; Nisoldipine/Selected Azole Antifungals|
01126|002|B||
01126|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01126|004|L|take action as needed.|
01126|005|B||
01126|006|A|MECHANISM OF ACTION:  Azole antifungal agents may inhibit the first-pass and|
01126|007|A|elimination metabolism of calcium channel blockers by CYP3A4.|
01126|008|B||
01126|009|E|CLINICAL EFFECTS:  The concurrent administration of azole antifungals with|
01126|010|E|calcium channel blockers metabolized by CYP3A4 may result in elevated levels|
01126|011|E|of the calcium channel blocker and adverse effects, including hypotension|
01126|012|E|and edema.|
01126|013|B||
01126|014|P|PREDISPOSING FACTORS:  None determined.|
01126|015|B||
01126|016|M|PATIENT MANAGEMENT:  The concurrent use of azole antifungals with calcium|
01126|017|M|channel blockers should be approached with caution.  When these agents are|
01126|018|M|used concurrently, the dose of the calcium channel blocker may need to be|
01126|019|M|decreased and patients should be observed for increased effects.  If the|
01126|020|M|azole antifungal is discontinued, the dose of the calcium channel blocker|
01126|021|M|may need to be increased and patients should be observed for decreased|
01126|022|M|effects.|
01126|023|B||
01126|024|D|DISCUSSION:  A double-blind, randomized, two-phase crossover study in nine|
01126|025|D|subjects examined the effects of itraconazole on felodipine.  The half-life|
01126|026|D|of felodipine increased by 71% during concurrent itraconazole.  In seven of|
01126|027|D|the nine subjects, the maximum concentration (Cmax) of felodipine when|
01126|028|D|administered with placebo was lower than the 32-hour concentration of|
01126|029|D|felodipine when administered with itraconazole.  Concurrent use also|
01126|030|D|resulted in significantly greater effects on both blood pressure and heart|
01126|031|D|rate.(1,2) There are two case reports of patients developing edema following|
01126|032|D|the addition of itraconazole to felodipine therapy.  In the second report,|
01126|033|D|the patient was rechallenged with concurrent itraconazole and again|
01126|034|D|developed edema.(3)|
01126|035|D|   In a case report, following the withdrawal of fluconazole from concurrent|
01126|036|D|nifedipine therapy, a loss in blood-pressure control occurred.(4)  In|
01126|037|D|another report, a patient developed edema following the addition of|
01126|038|D|itraconazole to nifedipine therapy.(5)|
01126|039|D|   A randomized cross-over trial in seven subjects examined the effects of|
01126|040|D|ketoconazole (200 mg daily for 4 days) on nisoldipine (5 mg daily).  The|
01126|041|D|concurrent use of ketoconazole increased the nisoldipine area-under-curve|
01126|042|D|(AUC) and Cmax by 24-fold and 11-fold, respectively.  Increases in the M9|
01126|043|D|nisoldipine metabolite were similar.(6)|
01126|044|D|   Posaconazole has been shown to inhibit CYP3A4.(7,8)|
01126|045|D|   Voriconazole has been shown to inhibit the metabolism of felodipine in|
01126|046|D|vitro.(9)|
01126|047|B||
01126|048|R|REFERENCES:|
01126|049|B||
01126|050|R|1.Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma|2
01126|051|R|  concentrations and effects of felodipine. Clin Pharmacol Ther 1997 Apr;|2
01126|052|R|  61(4):410-5.|2
01126|053|R|2.Plendil (felodipine) US prescribing information. AstraZeneca|1
01126|054|R|  Pharmaceuticals LP November, 2003.|1
01126|055|R|3.Neuvonen PJ, Suhonen R. Itraconazole interacts with felodipine. J Am Acad|3
01126|056|R|  Dermatol 1995 Jul;33(1):134-5.|3
01126|057|R|4.Kremens B, Brendel E, Bald M, Czyborra P, Michel MC. Loss of blood|3
01126|058|R|  pressure control on withdrawal of fluconazole during nifedipine therapy.|3
01126|059|R|  Br J Clin Pharmacol 1999 Jun;47(6):707-8.|3
01126|060|R|5.Tailor SA, Gupta AK, Walker SE, Shear NH. Peripheral edema due to|3
01126|061|R|  nifedipine-itraconazole interaction: a case report. Arch Dermatol 1996|3
01126|062|R|  Mar;132(3):350-2.|3
01126|063|R|6.Noxafil (posaconazole) UK summary of product characteristics.|1
01126|064|R|  Schering-Plough Ltd. January, 2022.|1
01126|065|R|7.Heinig R, Adelmann HG, Ahr G. The effect of ketoconazole on the|2
01126|066|R|  pharmacokinetics, pharmacodynamics and safety of nisoldipine. Eur J Clin|2
01126|067|R|  Pharmacol 1999 Mar;55(1):57-60.|2
01126|068|R|8.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01126|069|R|  January, 2022.|1
01126|070|R|9.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01127|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors and NNRTIs/Garlic|
01127|002|B||
01127|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01127|004|L|of severe adverse interaction.|
01127|005|B||
01127|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Garlic may induce the|
01127|007|A|metabolism of protease inhibitors and non-nucleoside reverse transcriptase|
01127|008|A|inhibitors (NNRTIs) by CYP3A4.  P-glycoproteins may also be involved.(1,2)|
01127|009|B||
01127|010|E|CLINICAL EFFECTS:  Concurrent use of garlic and a protease inhibitor or|
01127|011|E|NNRTI may result in decreased levels and effectiveness of the protease|
01127|012|E|inhibitor or NNRTI therapy.(2-3)|
01127|013|B||
01127|014|P|PREDISPOSING FACTORS:  None determined.|
01127|015|B||
01127|016|M|PATIENT MANAGEMENT:  Patients taking a protease inhibitor or NNRTI should|
01127|017|M|avoid taking garlic supplements.  Garlic from food sources is not likely to|
01127|018|M|cause a problem, although there may be some concern if patients are|
01127|019|M|ingesting a large quantity of garlic on a regular basis.|
01127|020|B||
01127|021|D|DISCUSSION:  A study in nine HIV-negative subjects examined the effects of|
01127|022|D|the concurrent use of a garlic supplement (taken twice daily) on saquinavir|
01127|023|D|(1200 mg twice daily).  Concurrent use resulted in a decrease in saquinavir|
01127|024|D|area-under-curve (AUC), maximum concentration (Cmax), and trough|
01127|025|D|concentration (Cmin) by 51%, 49%, and 54%, respectively, when compared to|
01127|026|D|the administration of saquinavir alone.  Following a garlic washout period,|
01127|027|D|saquinavir levels only returned to 60-70% of baseline.(2)|
01127|028|D|   In a study in 10 healthy subjects, the administration of garlic (10 mg|
01127|029|D|twice daily) for four days had no significant effects on a single dose of|
01127|030|D|ritonavir (400 mg).  Ritonavir AUC and Cmax decreased by 17% and by 25%,|
01127|031|D|respectively.  However, the authors cautioned that their results should not|
01127|032|D|be extrapolated to steady-state conditions.(4)|
01127|033|B||
01127|034|R|REFERENCES:|
01127|035|B||
01127|036|R|1.Piscitelli SC, Burstein AH, Welden N, Gallicano KD, Falloon J. The effect|2
01127|037|R|  of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect|2
01127|038|R|  Dis 2002 Jan 15;34(2):234-8.|2
01127|039|R|2.Tinggaard M, David KP, Gerstoft J, Hansen AE, Kirk O, Lebech AM, Lindhardt|6
01127|040|R|  BA, Rose MV, Ryom L, Weis N, Benfield T. Potential drug-drug interactions|6
01127|041|R|  between antiretroviral drugs and comedications,  including dietary|6
01127|042|R|  supplements, among people living with HIV: A clinical survey. HIV Med 2022|6
01127|043|R|  May 6.|6
01127|044|R|3.Gregory PJ. Personal Communication. Pharmacist's Letter March, 2001.|4
01127|045|R|4.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
01127|046|R|  Inc. December, 2004.|1
01127|047|R|5.Gallicano K, Foster B, Choudhri S. Effect of short-term administration of|2
01127|048|R|  garlic supplements on single- dose ritonavir pharmacokinetics in healthy|2
01127|049|R|  volunteers. Br J Clin Pharmacol 2003 Feb;55(2):199-202.|2
01128|001|T|MONOGRAPH TITLE:  Nefazodone/Carbamazepine|
01128|002|B||
01128|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01128|004|L|is contraindicated and generally should not be dispensed or administered to|
01128|005|L|the same patient.|
01128|006|B||
01128|007|A|MECHANISM OF ACTION:  Carbamazepine may induce the metabolism of|
01128|008|A|nefazodone.(1-3)  Nefazodone may inhibit the metabolism of|
01128|009|A|carbamazepine.(1,2)|
01128|010|B||
01128|011|E|CLINICAL EFFECTS:  Concurrent administration of carbamazepine and nefazodone|
01128|012|E|may result in decreased levels of nefazodone(1-3) and elevated levels of|
01128|013|E|carbamazepine.(1,2)  Nefazodone may be ineffective when administered to|
01128|014|E|patients receiving carbamazepine.(1,3)|
01128|015|B||
01128|016|P|PREDISPOSING FACTORS:  None determined.|
01128|017|B||
01128|018|M|PATIENT MANAGEMENT:  The concurrent use of carbamazepine and nefazodone is|
01128|019|M|contraindicated by their manufacturers.(1,2)|
01128|020|B||
01128|021|D|DISCUSSION:  A study in 12 subjects examined the effects of concurrent|
01128|022|D|administration of nefazodone (200 mg twice daily) and carbamazepine (200 mg|
01128|023|D|twice daily).  Concurrent use decreased the steady state nefazodone maximum|
01128|024|D|concentration (Cmax) and area-under-curve (AUC) by 86% and 93%,|
01128|025|D|respectively.  The Cmax and AUC of hydroxynefazodone, an active metabolite|
01128|026|D|of nefazodone, decreased 85% and 94%, respectively.  The Cmax and AUC of two|
01128|027|D|other nefazodone metabolites, meta-chlorophenylpiperazine and a|
01128|028|D|triazole-dione metabolite, were also decreased, by 13%, 44%, 28%, and 57%,|
01128|029|D|respectively.  The Cmax and AUC of carbamazepine were each increased by 23%.|
01128|030|D|The Cmax and AUC of the 10,11 epoxycarbamazepine metabolite decreased by 21%|
01128|031|D|and 20%, respectively.(1)|
01128|032|D|   The concurrent administration of carbamazepine and nefazodone is expected|
01128|033|D|to result in insufficient nefazodone levels to produce a clinical|
01128|034|D|effect.(1,3)|
01128|035|D|   There are published case reports of carbamazepine toxicity in patient|
01128|036|D|receiving concurrent nefazodone therapy, including somnolence and|
01128|037|D|dizziness.(4,5)|
01128|038|B||
01128|039|R|REFERENCES:|
01128|040|B||
01128|041|R|1.Serzone (nefazodone hydrochloride) US prescribing information.|1
01128|042|R|  Bristol-Myers Squibb Company January, 2005.|1
01128|043|R|2.Tegretol (carbamazepine) US prescribing information. Novartis|1
01128|044|R|  Pharmaceuticals Corporation September, 2023.|1
01128|045|R|3.Laroudie C, Salazar DE, Cosson JP, Cheuvart B, Istin B, Girault J, Ingrand|2
01128|046|R|  I, Decourt JP. Carbamazepine-nefazodone interaction in healthy subjects. J|2
01128|047|R|  Clin Psychopharmacol 2000 Feb;20(1):46-53.|2
01128|048|R|4.Ashton AK, Wolin RE. Nefazodone-induced carbamazepine toxicity. Am J|3
01128|049|R|  Psychiatry 1996 May;153(5):733.|3
01128|050|R|5.Roth L, Bertschy G. Nefazodone may inhibit the metabolism of|3
01128|051|R|  carbamazepine: three case reports. Eur Psychiatry 2001 Aug;16(5):320-1.|3
01129|001|T|MONOGRAPH TITLE:  Zaleplon/Cimetidine|
01129|002|B||
01129|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01129|004|L|take action as needed.|
01129|005|B||
01129|006|A|MECHANISM OF ACTION:  Cimetidine inhibits the metabolism of zaleplon by|
01129|007|A|aldehyde oxidase and by CYP3A4.(1)|
01129|008|B||
01129|009|E|CLINICAL EFFECTS:  The concurrent use of cimetidine and zaleplon may result|
01129|010|E|in increased levels and clinical effects of zaleplon, including profound|
01129|011|E|sedation, respiratory depression, coma, and/or death.(1)|
01129|012|B||
01129|013|P|PREDISPOSING FACTORS:  None determined.|
01129|014|B||
01129|015|M|PATIENT MANAGEMENT:  The manufacturer of zaleplon recommends that an initial|
01129|016|M|dose of 5 mg of zaleplon be used in patients being concomitantly treated|
01129|017|M|with cimetidine.(1)|
01129|018|B||
01129|019|D|DISCUSSION:  Concomitant administration of zaleplon (10 mg) and cimetidine|
01129|020|D|(800 mg) resulted in an 85% increase in zaleplon maximum concentration|
01129|021|D|(Cmax) and area-under-curve (AUC).  Therefore, the manufacturer of zaleplon|
01129|022|D|recommends that an initial dose of 5 mg of zaleplon be used in patients|
01129|023|D|being concomitantly treated with cimetidine.(1)|
01129|024|B||
01129|025|R|REFERENCE:|
01129|026|B||
01129|027|R|1.Sonata (zaleplon) US prescribing information. Wyeth Pharmaceuticals|1
01129|028|R|  August, 2019.|1
01130|001|T|MONOGRAPH TITLE:  Selected Xanthine Derivatives/Fluvoxamine|
01130|002|B||
01130|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01130|004|L|take action as needed.|
01130|005|B||
01130|006|A|MECHANISM OF ACTION:  Fluvoxamine may inhibit the metabolism of the xanthine|
01130|007|A|derivatives by CYP1A2.(1,2)|
01130|008|B||
01130|009|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine and xanthine derivatives|
01130|010|E|may result in elevated levels of the xanthine derivative and toxicity.|
01130|011|B||
01130|012|P|PREDISPOSING FACTORS:  None determined.|
01130|013|B||
01130|014|M|PATIENT MANAGEMENT:  The manufacturer of fluvoxamine recommends that the|
01130|015|M|dose of theophylline be decreased to one-third of the usual daily dose in|
01130|016|M|patients receiving concurrent therapy.  Theophylline levels should be|
01130|017|M|closely monitored and patients should be observed for signs of theophylline|
01130|018|M|toxicity.(3)  The dosage of theophylline may need to be adjusted if|
01130|019|M|fluvoxamine is discontinued.|
01130|020|M|   Patients receiving fluvoxamine should be instructed to consume caffeine|
01130|021|M|containing beverages and/or medications with caution.|
01130|022|B||
01130|023|D|DISCUSSION:  In a study in 12 healthy subjects, the administration of a|
01130|024|D|single dose of theophylline ethylenediamine (300 mg) on Day 4 of fluvoxamine|
01130|025|D|(50 mg Day 1, 100 mg daily Days 2-6) decreased theophylline total clearance|
01130|026|D|by 70%.  The half-life of theophylline increased 2.3-fold (from 6.6 hours to|
01130|027|D|22 hours).(1)  In a study in 12 healthy males, the administration of a|
01130|028|D|single dose of theophylline (375 mg given as 442 mg aminophylline) with|
01130|029|D|fluvoxamine (50 mg twice daily at steady state) decreased theophylline|
01130|030|D|clearance by 3-fold.(3)  Fluvoxamine has been shown to inhibit the|
01130|031|D|metabolism of theophylline in vitro.(2)  There are four case reports of|
01130|032|D|theophylline toxicity during concurrent fluvoxamine therapy.(4-7)|
01130|033|D|   In a study in eight healthy subjects, the administration of a single dose|
01130|034|D|of caffeine (200 mg) on Day 8 of fluvoxamine (50 mg daily Days 1-4, 100 mg|
01130|035|D|daily Days 5-12) decreased caffeine clearance by 80%.  The half-life of|
01130|036|D|caffeine increased 5.2-fold (from 5 hours to 31 hours).(8)|
01130|037|D|  In a study, seven reports of impaired caffeine clearance were reported in|
01130|038|D|patients whom received single 250mg doses of caffeine together with|
01130|039|D|fluvoxamine (four doses of 100mg over two days).  Fluvoxamine reduced the|
01130|040|D|apparent oral clearance of caffeine by 91.3%, and prolonged its elimination|
01130|041|D|half-life by 11.4-fold (from 4.9 hours to 56 hours).  There were no changes|
01130|042|D|in the pharmacodynamic effects of caffeine.(9)|
01130|043|B||
01130|044|R|REFERENCES:|
01130|045|B||
01130|046|R|1.Rasmussen BB, Jeppesen U, Gaist D, Brosen K. Griseofulvin and fluvoxamine|2
01130|047|R|  interactions with the metabolism of theophylline. Ther Drug Monit 1997|2
01130|048|R|  Feb;19(1):56-62.|2
01130|049|R|2.Rasmussen BB, Maenpaa J, Pelkonen O, Loft S, Poulsen HE, Lykkesfeldt J,|5
01130|050|R|  Brosen K. Selective serotonin reuptake inhibitors and theophylline|5
01130|051|R|  metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br|5
01130|052|R|  J Clin Pharmacol 1995 Feb;39(2):151-9.|5
01130|053|R|3.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
01130|054|R|  Pharmaceuticals, Inc. August, 2023.|1
01130|055|R|4.Sperber AD. Toxic interaction between fluvoxamine and sustained release|3
01130|056|R|  theophylline in an 11-year-old boy. Drug Saf 1991 Nov-Dec;6(6):460-2.|3
01130|057|R|5.Diot P, Jonville AP, Gerard F, Bonnelle M, Autret E, Breteau M, Lemarie E,|3
01130|058|R|  Lavandier M. Possible interaction between theophylline and fluvoxamine.|3
01130|059|R|  Therapie 1991 Mar-Apr;46(2):170-1.|3
01130|060|R|6.van den Brekel AM, Harrington L. Toxic effects of theophylline caused by|3
01130|061|R|  fluvoxamine. CMAJ 1994 Nov 1;151(9):1289-90.|3
01130|062|R|7.DeVane CL, Markowitz JS, Hardesty SJ, Mundy S, Gill HS.|3
01130|063|R|  Fluvoxamine-induced theophylline toxicity. Am J Psychiatry 1997 Sep;|3
01130|064|R|  154(9):1317-8.|3
01130|065|R|8.Jeppesen U, Loft S, Poulsen HE, Brsen K. A fluvoxamine-caffeine|2
01130|066|R|  interaction study. Pharmacogenetics 1996 Jun;6(3):213-22.|2
01130|067|R|9.Culm-Merdek KE, von Moltke LL, Harmatz JS, Greenblatt DJ. Fluvoxamine|2
01130|068|R|  impairs single-dose caffeine clearance without altering caffeine|2
01130|069|R|  pharmacodynamics. Br J Clin Pharmacol 2005 Nov;60(5):486-93.|2
01131|001|T|MONOGRAPH TITLE:  Tolterodine (Less Than or Equal To 1 mg or Less Than or|
01131|002|T|Equal To 2 mg ER)/Selected CYP3A4 Inhibitors|
01131|003|B||
01131|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01131|005|L|take action as needed.|
01131|006|B||
01131|007|A|MECHANISM OF ACTION:  Cyclosporine, erythromycin, miconazole, and|
01131|008|A|vinblastine may inhibit the metabolism of tolterodine by CYP3A4.(1,2)|
01131|009|B||
01131|010|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with|
01131|011|E|cyclosporine, erythromycin, miconazole, or vinblastine may result in|
01131|012|E|elevated levels of tolterodine and signs of toxicity.(1,2)|
01131|013|B||
01131|014|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers may be at|
01131|015|P|increased risk.(1,2)|
01131|016|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01131|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01131|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01131|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01131|020|P|advanced age.(3)|
01131|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01131|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01131|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01131|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01131|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01131|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01131|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01131|028|P|   The risk of anticholinergic toxicities including cognitive decline,|
01131|029|P|delirium, falls and fractures is increased in geriatric patients using more|
01131|030|P|than one medicine with anticholinergic properties.(4)|
01131|031|B||
01131|032|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
01131|033|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
01131|034|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
01131|035|M|used in patients receiving concurrent therapy with cyclosporine,|
01131|036|M|erythromycin, miconazole, or vinblastine.|
01131|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01131|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01131|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01131|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01131|041|B||
01131|042|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP2D6, the|
01131|043|D|concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg|
01131|044|D|once daily for four days), another inhibitor of CYP3A4, resulted in a 60%|
01131|045|D|decrease in tolterodine clearance.(5)  Tolterodine AUC and Cmax increased|
01131|046|D|2.5-fold and 2-fold, respectively.(2)|
01131|047|D|   In a study of the effect of tolterodine immediate release tablets, the|
01131|048|D|effect on the QT interval appeared greater for 8 mg/day (two times the|
01131|049|D|therapeutic dose) compared to 4 mg/day.  Tolterodine 2 mg BID and|
01131|050|D|tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and|
01131|051|D|11.84 msec (7.11-16.58 msec), respectively.  The change in QT interval was|
01131|052|D|more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers|
01131|053|D|(EMs).(1,2)|
01131|054|B||
01131|055|R|REFERENCES:|
01131|056|B||
01131|057|R|1.Detrol (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
01131|058|R|  August, 2012.|1
01131|059|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
01131|060|R|  July, 2018.|1
01131|061|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01131|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01131|063|R|  settings: a scientific statement from the American Heart Association and|6
01131|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01131|065|R|  2;55(9):934-47.|6
01131|066|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01131|067|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01131|068|R|  Soc 2023 Jul;71(7):2052-2081.|6
01131|069|R|5.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
01131|070|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
01131|071|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
01132|001|T|MONOGRAPH TITLE:  Tolterodine/Vinblastine (mono deleted 01/12/2012)|
01132|002|B||
01132|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01132|004|L|take action as needed.|
01132|005|B||
01132|006|A|MECHANISM OF ACTION:  Vinblastine may inhibit the metabolism of tolterodine|
01132|007|A|by CYP P-450-3A4.(1,2)|
01132|008|B||
01132|009|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with|
01132|010|E|vinblastine may result in elevated levels of tolterodine and signs of|
01132|011|E|toxicity.(1,2)|
01132|012|B||
01132|013|P|PREDISPOSING FACTORS:  None determined.|
01132|014|B||
01132|015|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
01132|016|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
01132|017|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
01132|018|M|used in patients receiving concurrent therapy with vinblastine.|
01132|019|B||
01132|020|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP|
01132|021|D|P-450-2D6, the concurrent administration of tolterodine (2 mg) with|
01132|022|D|ketoconazole (200 mg once daily for four days), another inhibitor of CYP|
01132|023|D|P-450-3A4, resulted in a 60% decrease in tolterodine clearance.(3)|
01132|024|D|Tolterodine AUC and Cmax increased 2.5-fold and 2-fold, respectively.(2)|
01132|025|B||
01132|026|R|REFERENCES:|
01132|027|B||
01132|028|R|1.Detrol (tolterodine tartrate) US prescribing information. Pharmacia &|1
01132|029|R|  Upjohn Company April, 2009.|1
01132|030|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pharmacia &|1
01132|031|R|  Upjohn Company September, 2008.|1
01132|032|R|3.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
01132|033|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
01132|034|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
01133|001|T|MONOGRAPH TITLE:  Stavudine/Zidovudine|
01133|002|B||
01133|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01133|004|L|of severe adverse interaction.|
01133|005|B||
01133|006|A|MECHANISM OF ACTION:  Zidovudine may inhibit the phosphorylation of|
01133|007|A|stavudine to its active form by competing for thymidine kinase.(1,2)|
01133|008|B||
01133|009|E|CLINICAL EFFECTS:  The concurrent use of zidovudine and stavudine may result|
01133|010|E|in decreased antiretroviral effectiveness.(1-4)|
01133|011|B||
01133|012|P|PREDISPOSING FACTORS:  None determined.|
01133|013|B||
01133|014|M|PATIENT MANAGEMENT:  The manufacturers of stavudine(4) and zidovudine(3)|
01133|015|M|state than concurrent use of these agents should be avoided.|
01133|016|B||
01133|017|D|DISCUSSION:  Both zidovudine and stavudine undergo a series of|
01133|018|D|phosphorylations to their active forms.  During this process, they compete|
01133|019|D|for thymidine kinase.  An in vitro study showed that the presence of|
01133|020|D|zidovudine decreased intracellular phosphate metabolites of stavudine by|
01133|021|D|41-83%, depending on the concentration of zidovudine. There was no effect on|
01133|022|D|zidovudine phosphorylation.(1)|
01133|023|D|   In a study in 145 HIV-positive subjects, subjects were randomized to one|
01133|024|D|of four treatment arms: zidovudine with stavudine, zidovudine with|
01133|025|D|didanosine, didanosine alone, or stavudine alone.  Patients in the stavudine|
01133|026|D|plus zidovudine arm had progressive declines in CD4 counts.  Patients in all|
01133|027|D|other arms had stable or increased CD4 counts.  Mean levels of stavudine|
01133|028|D|triphosphate were 10fmol/10x6 cells in patients receiving concurrent|
01133|029|D|zidovudine.  Mean levels of stavudine triphosphate were 65fmol/10x6 in|
01133|030|D|patients receiving stavudine alone.  There was no difference in zidovudine|
01133|031|D|monophosphate or zidovudine triphosphate levels in patients receiving|
01133|032|D|zidovudine alone or with stavudine.(2)|
01133|033|B||
01133|034|R|REFERENCES:|
01133|035|B||
01133|036|R|1.Hoggard P, Khoo S, Barry M, Back D. Intracellular metabolism of zidovudine|5
01133|037|R|  and stavudine in combination. J Infect Dis 1996 Sep;174(3):671-2.|5
01133|038|R|2.Havlir DV, Tierney C, Friedland GH, Pollard RB, Smeaton L, Sommadossi JP,|2
01133|039|R|  Fox L, Kessler H, Fife KH, Richman DD. In vivo antagonism with zidovudine|2
01133|040|R|  plus stavudine combination therapy. J Infect Dis 2000 Jul;182(1):321-5.|2
01133|041|R|3.Retrovir (zidovudine) US prescribing information. GlaxoSmithKline|1
01133|042|R|  September, 2018.|1
01133|043|R|4.Zerit (stavudine) US prescribing information. Bristol-Myers Squibb Company|1
01133|044|R|  December 19, 2017.|1
01134|001|T|MONOGRAPH TITLE:  Stavudine; Zidovudine/Doxorubicin|
01134|002|B||
01134|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01134|004|L|of severe adverse interaction.|
01134|005|B||
01134|006|A|MECHANISM OF ACTION:  Doxorubicin may inhibit the phosphorylation of|
01134|007|A|stavudine(1,2) and zidovudine(3) to their active forms.  Prolonged use of|
01134|008|A|zidovudine may result in the resistance of tumor cells to doxorubicin.(4)|
01134|009|B||
01134|010|E|CLINICAL EFFECTS:  The concurrent use of doxorubicin may result in decreased|
01134|011|E|levels and effectiveness of stavudine(1) and zidovudine.(3)  Prolonged use|
01134|012|E|of zidovudine may result in decreased effectiveness of doxorubicin.(4)|
01134|013|B||
01134|014|P|PREDISPOSING FACTORS:  None determined.|
01134|015|B||
01134|016|M|PATIENT MANAGEMENT:  The US manufacturer of stavudine states that concurrent|
01134|017|M|use of doxorubicin should be approached with caution.(2)|
01134|018|M|   The US manufacturer of zidovudine states that the concomitant use of|
01134|019|M|zidovudine and doxorubicin should be avoided.(5)|
01134|020|B||
01134|021|D|DISCUSSION:  An in vitro study showed that doxorubicin inhibits the|
01134|022|D|intracellular phosphorylation of stavudine to its active form at clinically|
01134|023|D|relevant concentrations.(1)|
01134|024|D|An in vitro study showed that doxorubicin inhibits the intracellular|
01134|025|D|phosphorylation of zidovudine to its active form.(3)  Another in vitro study|
01134|026|D|found that long-term exposure to zidovudine decreased cell sensitivity to|
01134|027|D|doxorubicin.(4)|
01134|028|B||
01134|029|R|REFERENCES:|
01134|030|B||
01134|031|R|1.Hoggard PG, Kewn S, Barry MG, Khoo SH, Back DJ. Effects of drugs on|5
01134|032|R|  2',3'-dideoxy-2',3'-didehydrothymidine phosphorylation in vitro.|5
01134|033|R|  Antimicrob Agents Chemother 1997 Jul;41(6):1231-6.|5
01134|034|R|2.Zerit (stavudine) US prescribing information. Bristol-Myers Squibb Company|1
01134|035|R|  December 19, 2017.|1
01134|036|R|3.Hoggard PG, Veal GJ, Wild MJ, Barry MG, Back DJ. Drug interactions with|5
01134|037|R|  zidovudine phosphorylation in vitro. Antimicrob Agents Chemother 1995 Jun;|5
01134|038|R|  39(6):1376-8.|5
01134|039|R|4.Cinatl J Jr, Kotchetkov R, Groschel B, Cinatl J, Driever PH, Kabickova H,|5
01134|040|R|  Kornhuber B, Schwabe D, Doerr HW. Azidothymidine resistance of H9 human|5
01134|041|R|  T-cell lymphoma cells is associated with decreased sensitivity to|5
01134|042|R|  antitumor agents and inhibition of apoptosis. Int J Mol Med 1998 Dec;|5
01134|043|R|  2(6):685-91.|5
01134|044|R|5.Retrovir (zidovudine) US prescribing information. GlaxoSmithKline|1
01134|045|R|  September, 2018.|1
01135|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Imatinib|
01135|002|B||
01135|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01135|004|L|is contraindicated and generally should not be dispensed or administered to|
01135|005|L|the same patient.|
01135|006|B||
01135|007|A|MECHANISM OF ACTION:  Imatinib may inhibit the metabolism of warfarin by|
01135|008|A|CYP2C9.(1)|
01135|009|B||
01135|010|E|CLINICAL EFFECTS:  The concurrent use of imatinib and warfarin may result in|
01135|011|E|an increased risk for bleeding.|
01135|012|B||
01135|013|P|PREDISPOSING FACTORS:  Risk for bleeding episodes may be greater in patients|
01135|014|P|with disease-associated bleeding risk (e.g. thrombocytopenia).|
01135|015|P|  Drug associated risk factors include concurrent use of multiple drugs|
01135|016|P|which inhibit anticoagulant/antiplatelet metabolism, and drugs which have an|
01135|017|P|inherent risk for bleeding (e.g. NSAIDs).|
01135|018|P|  Pharmacogenomic risk variables:|
01135|019|P|  Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2|
01135|020|P|copies of a reduced function VKORC1 gene are expected to be more susceptible|
01135|021|P|to this interaction.|
01135|022|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
01135|023|P|are expected to be less susceptible to effects from this drug combination,|
01135|024|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
01135|025|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
01135|026|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
01135|027|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
01135|028|P|and safe anticoagulation than patients without these CYP2C9 variants.|
01135|029|B||
01135|030|M|PATIENT MANAGEMENT:  The manufacturer of imatinib states under the "Drug|
01135|031|M|Interaction" section of the imatinib prescribing information that patients|
01135|032|M|receiving imatinib who require anticoagulation should receive low-molecular|
01135|033|M|weight or standard heparin instead of warfarin.(1) If imatinib and warfarin|
01135|034|M|are used together, INR values should be closely monitored when imatinib is|
01135|035|M|initiated and discontinued.  Patients should be observed for signs of|
01135|036|M|excessive anticoagulation during concurrent therapy.|
01135|037|M|   If concurrent therapy is deemed medically necessary, monitor patients|
01135|038|M|receiving concurrent therapy for signs of blood loss, including decreased|
01135|039|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
01135|040|M|and promptly evaluate patients with any symptoms.|
01135|041|M|    When applicable, perform agent-specific laboratory tests (e.g. INR,|
01135|042|M|aPTT) to monitor efficacy and safety of anticoagulation. Discontinue|
01135|043|M|anticoagulation in patients with active pathologic bleeding.|
01135|044|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01135|045|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01135|046|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01135|047|M|and/or swelling.|
01135|048|M|      The time of highest risk for a coumarin-type drug interaction is when|
01135|049|M|the precipitant drug is initiated or discontinued. Contact the prescriber|
01135|050|M|before initiating, altering the dose or discontinuing either drug.|
01135|051|B||
01135|052|D|DISCUSSION:  Because imatinib has been shown to inhibit CYP2C9 in vitro, the|
01135|053|D|manufacturer states under the "Drug Interaction" section of the imatinib|
01135|054|D|prescribing information that patients receiving imatinib who require|
01135|055|D|anticoagulation should receive low-molecular weight or standard heparin|
01135|056|D|instead of warfarin.(1)|
01135|057|B||
01135|058|R|REFERENCE:|
01135|059|B||
01135|060|R|1.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
01135|061|R|  Pharmaceuticals Corporation August, 2022.|1
01136|001|T|MONOGRAPH TITLE:  Imatinib/St. John's wort (mono deleted 09/01/2011)|
01136|002|B||
01136|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01136|004|L|take action as needed.|
01136|005|B||
01136|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of imatinib|
01136|007|A|by CYP P-450-3A4.(1-2)|
01136|008|B||
01136|009|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort with imatinib may|
01136|010|E|result in decreased levels and clinical effectiveness of imatinib.(1-2)|
01136|011|B||
01136|012|P|PREDISPOSING FACTORS:  None determined.|
01136|013|B||
01136|014|M|PATIENT MANAGEMENT:  The concurrent use of imatinib and St. John's wort|
01136|015|M|should be approached with caution.  Consider an alternative agent to St.|
01136|016|M|John's wort, if possible, or consider increasing the dose of imatinib.(1)|
01136|017|B||
01136|018|D|DISCUSSION:  In a study in 12 healthy subjects, administration of a single|
01136|019|D|oral dose of imatinib (400 mg) on Day 10 of a 14 day course of St. John's|
01136|020|D|wort (300 mg 3 times daily) increased imatinib clearance by 40%.  Imatinib|
01136|021|D|area-under-curve (AUC) decreased by 30%.  Imatinib maximum concentration|
01136|022|D|(Cmax) and half-life were significantly decreased as well.(1)|
01136|023|D|   In a study in 10 healthy subjects, administration of a single oral dose|
01136|024|D|of imatinib (400 mg) following 2 weeks of St. John's wort (300 mg 3 times|
01136|025|D|daily) decreased imatinib AUC, Cmax, and half-life by 32%, 29%, and 21%,|
01136|026|D|respectively.(2,3)|
01136|027|B||
01136|028|R|REFERENCES:|
01136|029|B||
01136|030|R|1.Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, Egorin MJ. Effect of St|2
01136|031|R|  John's wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther|2
01136|032|R|  2004 Nov;76(4):323-9.|2
01136|033|R|2.Smith P. The influence of St. John's wort on the pharmacokinetics and|2
01136|034|R|  protein binding of imatinib mesylate. Pharmacotherapy 2004 Nov;|2
01136|035|R|  24(11):1508-14.|2
01136|036|R|3.Smith PF, Bullock JM, Booker BM, Haas CE, Berenson CS, Jusko WJ. Induction|2
01136|037|R|  of imatinib metabolism by hypericum perforatum. Blood 2004 Aug 15;|2
01136|038|R|  104(4):1229-30.|2
01137|001|T|MONOGRAPH TITLE:  Rifampin/Pyrazinamide|
01137|002|B||
01137|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01137|004|L|of severe adverse interaction.|
01137|005|B||
01137|006|A|MECHANISM OF ACTION:  The concurrent use of rifampin and pyrazinamide for|
01137|007|A|the treatment of latent tuberculosis (TB prophylaxis) may result in additive|
01137|008|A|or synergistic hepatotoxicity.(1,2)|
01137|009|B||
01137|010|E|CLINICAL EFFECTS:  The concurrent use of rifampin and pyrazinamide for the|
01137|011|E|treatment of latent tuberculosis (TB prophylaxis) may result in|
01137|012|E|hepatotoxicity and death.(2)|
01137|013|B||
01137|014|P|PREDISPOSING FACTORS:  Underlying liver disease, concurrent therapy with|
01137|015|P|agents associated with liver injury, alcoholism, and/or a previous history|
01137|016|P|of isoniazid-associated liver injury may predispose patients to liver damage|
01137|017|P|from the combination of rifampin and pyrazinamide when used for the|
01137|018|P|treatment of latent tuberculosis (TB prophylaxis).(1)|
01137|019|B||
01137|020|M|PATIENT MANAGEMENT:  The combination of rifampin and pyrazinamide is|
01137|021|M|recommended by the Centers for Disease Control (CDC) as part of a standard|
01137|022|M|4-drug regimen for the treatment of active TB disease.(1,2)|
01137|023|M|   The American Thoracic Society (ATS) and the CDC state that the|
01137|024|M|combination of rifampin and pyrazinamide should generally not be offered to|
01137|025|M|patients with latent tuberculosis infection for either HIV-negative or|
01137|026|M|HIV-positive persons.(2)|
01137|027|M|   The combination of rifampin and pyrazinamide for the treatment of latent|
01137|028|M|tuberculosis should never be offered to patients who are 1) concurrently|
01137|029|M|taking other medicines associated with liver injury, 2) drink excessive|
01137|030|M|amounts of alcohol (even if alcohol use is discontinued during therapy), 3)|
01137|031|M|have underlying liver disease, or 4) have a history of underlying isoniazid|
01137|032|M|associated liver injury.(2)|
01137|033|M|   The combination of rifampin and pyrazinamide for the treatment of latent|
01137|034|M|tuberculosis may be considered if the potential benefit outweigh the risk of|
01137|035|M|severe liver injury and death, but only if 1) the preferred or alternative|
01137|036|M|regimens are not likely to be completed and 2) oversight by a clinician with|
01137|037|M|experience in the treatment of latent tuberculosis can be provided.(1)|
01137|038|M|   When used as therapy for latent TB (TB prophylaxis), the ATS and CDC|
01137|039|M|recommend that the combination of rifampin and pyrazinamide be used with the|
01137|040|M|following cautions.  No more than a two-week supply of rifampin-pyrazinamide|
01137|041|M|should be dispensed at one time.  The daily pyrazinamide dose should not|
01137|042|M|exceed 20 mg/kg/day or a maximum of 2 grams/day and the twice weekly dose|
01137|043|M|should not exceed 50 mg/kg/day or a maximum of 4 grams/day. Patients, serum|
01137|044|M|AT, and bilirubin should be assessed at 2, 4, 6, and 8 weeks of therapy.|
01137|045|M|Therapy should be discontinued and should not be resumed if the AT is 5|
01137|046|M|times the upper limit of normal range in asymptomatic patients, or if the AT|
01137|047|M|is above normal range when accompanied by symptoms of hepatitis, or if serum|
01137|048|M|bilirubin is greater than the normal range.  Patients should be instructed|
01137|049|M|to stop taking the combination and seek medical attention if they develop|
01137|050|M|abdominal pain, emesis, jaundice, or other hepatitis symptoms.(2)|
01137|051|M|   These recommendations have been endorsed by the Infectious Diseases|
01137|052|M|Society of America (IDSA).(2)|
01137|053|B||
01137|054|D|DISCUSSION:  From October of 2000 to June of 2003, 48 cases of liver injury|
01137|055|D|(defined as clinical and laboratory findings consistent with hepatitis|
01137|056|D|leading to hospital admission or death) associated with the combination of|
01137|057|D|rifampin and pyrazinamide for the treatment of latent tuberculosis were were|
01137|058|D|reported to the CDC.  Of these 48 cases, 37 patients recovered and 11 died|
01137|059|D|of liver failure.  Of these 48 cases, 33% occurred in the second month of|
01137|060|D|treatment.  Of the 7,737 patients who started combination rifampin and|
01137|061|D|pyrazinamide during this period, 204 discontinued the regimen because of|
01137|062|D|elevated AST concentration greater than 5 times the upper limit of normal|
01137|063|D|(rate 26.4 per 1,000 initiations) and an additional 146 patients|
01137|064|D|discontinued the regimen because of symptoms of hepatitis (rate 18.9 per|
01137|065|D|1,000 initiations).  The estimated rates of hospitalization and death during|
01137|066|D|this period were 3.0 per 1,000 initiations and 0.9 per 1,000 initiations,|
01137|067|D|respectively.(2)|
01137|068|B||
01137|069|R|REFERENCES:|
01137|070|B||
01137|071|R|1.Anonymous. Update: Fatal and severe liver injuries associated with|1
01137|072|R|  rifampin and pyrazinamide for latent tuberculosis infection, and revisions|1
01137|073|R|  in American Thoracic Society/CDC recommendations--United States, 2001.|1
01137|074|R|  MMWR Morb Mortal Wkly Rep 2001 Aug 31;50(34):733-5.|1
01137|075|R|2.Anonymous. Update: adverse event data and revised American Thoracic|1
01137|076|R|  Society/CDC recommendations against the use of rifampin and pyrazinamide|1
01137|077|R|  for treatment of latent tuberculosis infection--United States, 2003. MMWR|1
01137|078|R|  Morb Mortal Wkly Rep 2003 Aug 8;52(31):735-9.|1
01138|001|T|MONOGRAPH TITLE:  Brivaracetam; Lamotrigine; Perampanel/Rifampin;|
01138|002|T|Rifapentine|
01138|003|B||
01138|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01138|005|L|of severe adverse interaction.|
01138|006|B||
01138|007|A|MECHANISM OF ACTION:  Rifampin and rifapentine may induce the metabolism of|
01138|008|A|brivaracetam by CYP2C19(1) and lamotrigine(2,3) and perampanel(4) by CYP3A4.|
01138|009|B||
01138|010|E|CLINICAL EFFECTS:  The concurrent use of rifampin or rifapentine with|
01138|011|E|brivaracetam,(1) lamotrigine,(2,3) or perampanel(4) may result in decreased|
01138|012|E|levels and clinical effectiveness of the anticonvulsant.|
01138|013|B||
01138|014|P|PREDISPOSING FACTORS:  None determined.|
01138|015|B||
01138|016|M|PATIENT MANAGEMENT:  Patients receiving rifampin or rifapentine concurrently|
01138|017|M|with brivaracetam, lamotrigine, or perampanel should be observed for|
01138|018|M|decreased anticonvulsant levels and clinical effectiveness.  The dose of the|
01138|019|M|anticonvulsant may need to be adjusted if the rifamycin is added to or|
01138|020|M|removed from therapy.  Refer to the current anticonvulsant prescribing|
01138|021|M|information for information on dosage adjustments.|
01138|022|B||
01138|023|D|DISCUSSION:  Concurrent rifampin decreases brivaracetam levels by 45%.(1)|
01138|024|D|   A study in 10 healthy subjects examined the effects of rifampin (600 mg|
01138|025|D|daily for five days) on a single dose of lamotrigine (25 mg). Pretreatment|
01138|026|D|with rifampin decreased the lamotrigine area-under-curve (AUC) and half-life|
01138|027|D|(T1/2) by 43.7% and 40.8%, respectively.  Lamotrigine clearance over|
01138|028|D|bioavailability increased 98.3%.  The amount of lamotrigine excreted as the|
01138|029|D|glucuronide metabolite increased 36%.(2)|
01138|030|D|   A study in 10 healthy subjects examining the effects of rifampin (600 mg|
01138|031|D|daily for 5 days) on a single dose of lamotrigine (25 mg) showed that|
01138|032|D|rifampin increased the apparent clearance of lamotrigine by approximately|
01138|033|D|2-fold and  decreased the AUC by 40%.(3)|
01138|034|D|   Rifampin and rifapentine are expected to decrease perampanel|
01138|035|D|concentrations.(4)|
01138|036|B||
01138|037|R|REFERENCES:|
01138|038|B||
01138|039|R|1.Briviact (brivaracetam) US prescribing information. UCB, Inc. May, 2018.|1
01138|040|R|2.Ebert U, Thong NQ, Oertel R, Kirch W. Effects of rifampicin and cimetidine|2
01138|041|R|  on pharmacokinetics and pharmacodynamics of lamotrigine in healthy|2
01138|042|R|  subjects. Eur J Clin Pharmacol 2000 Jul;56(4):299-304.|2
01138|043|R|3.Lamictal (lamotrigine) US prscribing information. GlaxoSmithKline October,|1
01138|044|R|  2025.|1
01138|045|R|4.Fycompa (perampanel) UK summary of product characteristics. Eisai Ltd|1
01138|046|R|  August, 2021.|1
01139|001|T|MONOGRAPH TITLE:  Repaglinide/Rifampin (mono deleted 07/23/2014)|
01139|002|B||
01139|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01139|004|L|take action as needed.|
01139|005|B||
01139|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of repaglinide by|
01139|007|A|CYP P-450-3A4.(1)|
01139|008|B||
01139|009|E|CLINICAL EFFECTS:  The concurrent use of rifampin and repaglinide may result|
01139|010|E|in decreased levels and clinical effectiveness of repaglinide.(1)|
01139|011|B||
01139|012|P|PREDISPOSING FACTORS:  None determined.|
01139|013|B||
01139|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with rifampin and|
01139|015|M|repaglinide should be observed for decreased repaglinide levels and clinical|
01139|016|M|effectiveness.  The dose of repaglinide may need to be adjusted if rifampin|
01139|017|M|is added to or removed from repaglinide therapy.|
01139|018|B||
01139|019|D|DISCUSSION:  A study in 9 healthy subjects examined the effects of rifampin|
01139|020|D|(600 mg daily for five days) on a single dose of repaglinide (0.5 mg).|
01139|021|D|Pretreatment with rifampin decreased the repaglinide area-under-curve (AUC),|
01139|022|D|maximum concentration (Cmax), and half-life (T1/2) by 57%, 41%, and 40%,|
01139|023|D|respectively.  The maximum decrease in blood glucose was reduced from 1.6|
01139|024|D|mmol/L to 1.0 mmol/L.(1)|
01139|025|B||
01139|026|R|REFERENCE:|
01139|027|B||
01139|028|R|1.Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivisto KT. Rifampin|2
01139|029|R|  decreases the plasma concentrations and effects of repaglinide. Clin|2
01139|030|R|  Pharmacol Ther 2000 Nov;68(5):495-500.|2
01140|001|T|MONOGRAPH TITLE:  Slt HMG-CoA Reductase Inhibitors/Rifampin (mono deleted|
01140|002|T|11/20/2020)|
01140|003|B||
01140|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01140|005|L|take action as needed.|
01140|006|B||
01140|007|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of the HMG-CoA|
01140|008|A|reductase inhibitors by CYP3A4 in the intestine and liver.(1,2)|
01140|009|B||
01140|010|E|CLINICAL EFFECTS:  The concurrent use of rifampin and an HMG-CoA reductase|
01140|011|E|inhibitor metabolized by CYP3A4 may result in decreased levels and clinical|
01140|012|E|effectiveness of the HMG-CoA reductase inhibitor.(1,2)|
01140|013|B||
01140|014|P|PREDISPOSING FACTORS:  None determined.|
01140|015|B||
01140|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with rifampin and|
01140|017|M|an HMG-CoA reductase inhibitor that is metabolized by CYP3A4 should be|
01140|018|M|observed for decreased effectiveness of the HMG-CoA reductase inhibitor.(1)|
01140|019|M|If long term rifampin therapy is indicated, consider an increase in the|
01140|020|M|dosage of the HMG-CoA reductase inhibitor(2) or using a HMG-CoA reductase|
01140|021|M|inhibitor that is not metabolized by CYP3A4 may be necessary.|
01140|022|M|   Patients maintained on atorvastatin should be instructed to take their|
01140|023|M|atorvastatin and rifampin at the same time.(3)|
01140|024|M|   Pravastatin, which is not metabolized by CYP3A4,(4) may be an alternative|
01140|025|M|to other HMG-CoA reductase inhibitors in patients receiving long-term|
01140|026|M|rifampin therapy; however, dosage adjustments may still be necessary.|
01140|027|B||
01140|028|D|DISCUSSION:  In a study in 10 healthy subjects, pretreatment with rifampin|
01140|029|D|(600 mg daily for 5 days) decreased the area-under-curve (AUC) and half life|
01140|030|D|(T1/2) of a single dose of atorvastatin by 80% and 74%, respectively.  The|
01140|031|D|AUC of active metabolites 2-hydroxyatorvastatin acid and|
01140|032|D|4-hydroxyatorvastatin by 43% and 81%, respectively.(2)|
01140|033|D|   In a study, coadministration of rifampin (600 mg daily for 7 days) and|
01140|034|D|atorvastatin (40 mg single dose) increased the Cmax and AUC of atorvastatin|
01140|035|D|by 2.7-fold and 30%, respectively. Rifampin (600mg daily for 5 days, doses|
01140|036|D|separated) and atorvastatin (40 mg single dose) decreased atorvastatin Cmax|
01140|037|D|and AUC by 80% and 40%, respectively. Delayed administration of atorvastatin|
01140|038|D|after administration of rifampin has been associated with a significant|
01140|039|D|reduction in atorvastatin plasma concentrations. (3)|
01140|040|D|   In a study in 10 healthy subjects, pretreatment with rifampin (600 mg|
01140|041|D|daily for 5 days) decreased the AUC of simvastatin and simvastatin acid (an|
01140|042|D|active metabolite of simvastatin) from a single dose of simvastatin (40 mg)|
01140|043|D|by 87% and 97%, respectively.  The Cmax of both simvastatin and simvastatin|
01140|044|D|acid were decreased by 90%.(1)|
01140|045|D|   Pretreatment with rifampin decreased the Cmax and AUC of fluvastatin by|
01140|046|D|42% and 53%, respectively.(5)|
01140|047|D|   In a randomized, cross-over study in 10 healthy subjects, pretreatment|
01140|048|D|with rifampin (600 mg daily) decreased the AUC of a single dose of|
01140|049|D|pravastatin by 31%.  In 5 of 10 subjects, pravastatin AUC was 50% or less of|
01140|050|D|the AUC seen during the placebo phase.  However, there was wide|
01140|051|D|inter-subject variability.(6)|
01140|052|B||
01140|053|R|REFERENCES:|
01140|054|B||
01140|055|R|1.Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ.|2
01140|056|R|  Rifampin greatly reduces plasma simvastatin and simvastatin acid|2
01140|057|R|  concentrations. Clin Pharmacol Ther 2000 Dec;68(6):592-7.|2
01140|058|R|2.Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly|2
01140|059|R|  decreases and gemfibrozil increases the plasma concentrations of|2
01140|060|R|  atorvastatin and its metabolites. Clin Pharmacol Ther 2005 Aug;|2
01140|061|R|  78(2):154-67.|2
01140|062|R|3.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
01140|063|R|  2020.|1
01140|064|R|4.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
01140|065|R|  Squibb Company May, 2022.|1
01140|066|R|5.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
01140|067|R|  Pharmaceuticals Corporation August, 2017.|1
01140|068|R|6.Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Effect of rifampicin on|2
01140|069|R|  pravastatin pharmacokinetics in healthy subjects. Br J Clin Pharmacol 2004|2
01140|070|R|  Feb;57(2):181-7.|2
01141|001|T|MONOGRAPH TITLE:  Buspirone/Nefazodone|
01141|002|B||
01141|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01141|004|L|take action as needed.|
01141|005|B||
01141|006|A|MECHANISM OF ACTION:  Nefazodone inhibits the metabolism of buspirone by|
01141|007|A|CYP3A4.(1,2)  Buspirone may interfere with the metabolism of nefazodone.|
01141|008|B||
01141|009|E|CLINICAL EFFECTS:  Concurrent use of nefazodone and buspirone may result in|
01141|010|E|elevated levels of and increased effects from buspirone, including|
01141|011|E|lightheadedness, asthenia, dizziness, and somnolence.(1,2)  Concurrent use|
01141|012|E|of higher doses of buspirone with nefazodone may result in increased levels|
01141|013|E|and effects of nefazodone.(1)|
01141|014|B||
01141|015|P|PREDISPOSING FACTORS:  None determined.|
01141|016|B||
01141|017|M|PATIENT MANAGEMENT:  The manufacturer of nefazodone and buspirone recommends|
01141|018|M|a low dose of buspirone (2.5 mg daily) in patients receiving concurrent|
01141|019|M|therapy with these agents.(1,2)  Patients receiving concurrent therapy|
01141|020|M|should be monitored for increased effects of both agents.  The dosage of|
01141|021|M|buspirone may need to be adjusted if nefazodone is withdrawn from therapy.|
01141|022|B||
01141|023|D|DISCUSSION:  In a study in healthy subjects, concurrent use of buspirone|
01141|024|D|(2.5 mg or 5 mg twice daily) with nefazodone (250 mg twice daily) resulted|
01141|025|D|in increases in the maximum concentration (Cmax) and area-under-curve (AUC)|
01141|026|D|of buspirone, up to 20-fold and up to 50-fold, respectively.  The|
01141|027|D|concentration of 1-pyrimidinylpiperazine (a buspirone metabolite) decreased|
01141|028|D|50%.  In subjects taking 2.5 mg of buspirone with nefazodone, the side|
01141|029|D|effect profile was similar to those of subjects taking either drug alone. In|
01141|030|D|subjects taking 5 mg of buspirone, the AUC of nefazodone, of the|
01141|031|D|hydroxynefazodone metabolite of nefazodone, and of the|
01141|032|D|meta-chlorophenylpiperazine metabolite of nefazodone increased by 23%, 17%,|
01141|033|D|and 9%, respectively.(1,2)  The Cmax of nefazodone and hydroxynefazodone|
01141|034|D|increased by 8% and 11%, respectively.(2)  Subjects also reported side|
01141|035|D|effects of lightheadedness, asthenia, dizziness, and somnolence.(1,2)|
01141|036|B||
01141|037|R|REFERENCES:|
01141|038|B||
01141|039|R|1.Serzone (nefazodone hydrochloride) US prescribing information.|1
01141|040|R|  Bristol-Myers Squibb Company January, 2005.|1
01141|041|R|2.BuSpar (buspirone hydrochloride) US prescribing information. Bristol Myers|1
01141|042|R|  Squibb Company September, 2007.|1
01142|001|T|MONOGRAPH TITLE:  Didanosine/Tenofovir|
01142|002|B||
01142|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01142|004|L|take action as needed.|
01142|005|B||
01142|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01142|007|B||
01142|008|E|CLINICAL EFFECTS:  Concurrent use of tenofovir and didanosine may result in|
01142|009|E|elevated levels of didanosine(1-5) and toxicities(4-7) such as pancreatitis,|
01142|010|E|symptomatic hyperlactatemia/lactic acidosis, peripheral neuropathy,(3-5) and|
01142|011|E|renal failure.(8)  Suppression of CD4 cell counts has been observed in|
01142|012|E|patient receiving concurrent therapy.(1)|
01142|013|E|   Concurrent use of tenofovir, didanosine, and a non-nucleoside reverse|
01142|014|E|transcriptase inhibitor (NNRTI) such as efavirenz or nevirapine may result|
01142|015|E|in virological failure and the development of resistance.(3)|
01142|016|B||
01142|017|P|PREDISPOSING FACTORS:  None determined.|
01142|018|B||
01142|019|M|PATIENT MANAGEMENT:  The manufacturers of tenofovir(1-3) and didanosine(4,5)|
01142|020|M|state that these agents should be coadministered with caution and patients|
01142|021|M|should be closely monitored for didanosine-related adverse events(1-5) and|
01142|022|M|efficacy.(4)|
01142|023|M|   Caution should be used when coadministering reduced-dose didanosine,|
01142|024|M|tenofovir, and an NNRTI in treatment-naive patients with high viral loads at|
01142|025|M|baseline since such use has been associated with reports of a high rate of|
01142|026|M|virologic failure and emergence of resistance at an early stage. All|
01142|027|M|patients receiving tenofovir disoproxil fumarate and didanosine|
01142|028|M|concomitantly should be closely monitored for didanosine-related adverse|
01142|029|M|events and clinical response.(4)|
01142|030|M|   In patients weighing 60 kg or more(1-5) with creatinine clearance equal|
01142|031|M|to or greater than 60 ml/min,(4,5) the daily dosage of didanosine should be|
01142|032|M|decreased to 250 mg.(3,5)|
01142|033|M|   In patients weighing less than 60 kg with creatinine clearance equal to|
01142|034|M|or greater than 60 ml/min who are receiving tenofovir or the combination|
01142|035|M|product of tenofovir/emtricitabine, the daily dosage of didanosine should be|
01142|036|M|decreased to 200 mg.(4,5)  Data are not available to recommend a dosage|
01142|037|M|adjustment in patients weighing less than 60 kg and receiving the|
01142|038|M|combination product of tenofovir/emtricitabine/efavirenz.(3)|
01142|039|M|   When coadministered, tenofovir or tenofovir/emtricitabine with enteric|
01142|040|M|coated didanosine may be taken under fasted conditions or with a light meal|
01142|041|M|consisting of less than 400 kcal and 20% fat.  When coadministered,|
01142|042|M|tenofovir or tenofovir/emtricitabine and the buffered formulation of|
01142|043|M|didanosine should be taken in the fasted state.(1,2)|
01142|044|M|   Didanosine should be discontinued in patients who develop didanosine|
01142|045|M|related adverse effects.(1,4)|
01142|046|B||
01142|047|D|DISCUSSION:  In a study in 26 subjects, the administration of tenofovir (300|
01142|048|D|mg daily) two hours after the administration of a single dose of didanosine|
01142|049|D|(400 mg, enteric coated) on an empty stomach increased both the didanosine|
01142|050|D|maximum concentration (Cmax) and area-under-curve (AUC) by 48%.|
01142|051|D|   In a study in 25 subjects, simultaneous administration of tenofovir (300|
01142|052|D|mg daily) with a single dose of didanosine (400 mg, enteric coated) with|
01142|053|D|food increased the didanosine Cmax and AUC by 64% and 60%,|
01142|054|D|respectively.(1,4)  There were no effects on tenofovir pharmacokinetics.(1)|
01142|055|D|   In a study in 14 subjects, administration of didanosine (250 mg or 400 mg|
01142|056|D|once daily for 7 days) with tenofovir (300 mg daily) had no effects on|
01142|057|D|tenofovir pharmacokinetics.  The Cmax and AUC of didanosine increased 28%|
01142|058|D|and 44%, respectively.(1)|
01142|059|D|   In a study in 28 subjects, the administration of tenofovir (300 mg daily)|
01142|060|D|with didanosine 250 mg enteric coated capsules, didanosine levels were|
01142|061|D|similar to those seen with didanosine 400 mg enteric coated capsules alone|
01142|062|D|under fasted conditions.(1)|
01142|063|D|   In a study in 33 subjects, simultaneous administration of tenofovir (300|
01142|064|D|mg daily) with a single dose of didanosine (200 mg, enteric coated) with|
01142|065|D|food increased the AUC of didanosine by 16% and decreased didanosine Cmax by|
01142|066|D|12% when compared to a single 250 mg dose of didanosine.(5)|
01142|067|D|   In a study in 33 subjects, simultaneous administration of tenofovir (300|
01142|068|D|mg daily) with a single dose of didanosine (250 mg, enteric coated) with|
01142|069|D|food had no effect on the AUC of didanosine and decreased didanosine Cmax by|
01142|070|D|20% when compared to a single 400 mg dose of didanosine.(5)|
01142|071|D|   In a study in 33 subjects, simultaneous administration of tenofovir (300|
01142|072|D|mg daily) with a single dose of didanosine (325 mg, enteric coated) with|
01142|073|D|food increased the AUC of didanosine by 13% and decreased didanosine Cmax by|
01142|074|D|11% when compared to a single 400 mg dose of didanosine.(5)|
01142|075|D|   Pancreatitis,(7) fatal lactic acidosis,(6,8) and acute renal failure(8)|
01142|076|D|have been reported in patients receiving concurrent therapy with tenofovir|
01142|077|D|and didanosine.|
01142|078|D|   Virologic failure appears to be limited to the use of tenofovir and|
01142|079|D|didanosine with either efavirenz or nevirapine. Data exist that support the|
01142|080|D|efficacy of tenofovir with efavirenz and didanosine and efavirenz.(3)|
01142|081|B||
01142|082|R|REFERENCES:|
01142|083|B||
01142|084|R|1.Viread (tenofovir disoproxil fumarate) US prescribing information. Gilead|1
01142|085|R|  Sciences, Inc. December, 2018.|1
01142|086|R|2.Truvada (emtricitabine/tenofovir disoproxil fumarate) US prescribing|1
01142|087|R|  information. Gilead Sciences, Inc. June, 2020.|1
01142|088|R|3.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01142|089|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01142|090|R|4.Dear Canadian Healthcare Professional letter: Subject: New safety|1
01142|091|R|  information regarding the co-administration of Videx and Viread, and|1
01142|092|R|  either Sustiva or Viramune. Bristol-Myers Squibb Canada and Gilead June 9,|1
01142|093|R|  2005.|1
01142|094|R|5.Videx EC (didanosine) US prescribing information. Bristol-Myers Squibb|1
01142|095|R|  Company January 25, 2018.|1
01142|096|R|6.Guo Y, Fung HB. Fatal lactic acidosis associated with coadministration of|3
01142|097|R|  didanosine and tenofovir disoproxil fumarate. Pharmacotherapy 2004 Aug;|3
01142|098|R|  24(8):1089-94.|3
01142|099|R|7.Blanchard JN, Wohlfeiler M, Canas A, King K, Lonergan JT. Pancreatitis|3
01142|100|R|  treated with didanosine and tenofovir disoproxil fumarate. Clin Infect Dis|3
01142|101|R|  2003 Sep 1;37(5):e57-62.|3
01142|102|R|8.Murphy MD, O'Hearn M, Chou S. Fatal lactic acidosis and acute renal|3
01142|103|R|  failure after addition of tenofovir to an antiretroviral regimen|3
01142|104|R|  containing didanosine. Clin Infect Dis 2003 Apr 15;36(8):1082-5.|3
01143|001|T|MONOGRAPH TITLE:  Clozapine/Ciprofloxacin|
01143|002|B||
01143|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01143|004|L|of severe adverse interaction.|
01143|005|B||
01143|006|A|MECHANISM OF ACTION:  Ciprofloxacin may inhibit the metabolism of clozapine|
01143|007|A|by CYP1A2.(1)  Both agents have been shown to prolong the QT interval.(2,3)|
01143|008|B||
01143|009|E|CLINICAL EFFECTS:  Concurrent use of ciprofloxacin and clozapine may result|
01143|010|E|in elevated levels of clozapine and possible toxicity including orthostatic|
01143|011|E|hypotension, syncope, QT prolongation, profound sedation and seizures.|
01143|012|E|Concurrent use may also result in QT prolongation, which may result in|
01143|013|E|potentially life-threatening cardiac arrhythmias, including torsades de|
01143|014|E|pointes.(2)|
01143|015|B||
01143|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01143|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01143|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01143|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01143|020|P|gender, or advanced age.(4)|
01143|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01143|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01143|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01143|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01143|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01143|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01143|027|P|dysfunction).(4)|
01143|028|P|   The risk of anticholinergic toxicities including cognitive decline,|
01143|029|P|delirium, falls and fractures is increased in geriatric patients using more|
01143|030|P|than one medicine with anticholinergic properties.(5)|
01143|031|B||
01143|032|M|PATIENT MANAGEMENT:  The manufacturer recommends reducing the clozapine dose|
01143|033|M|to one-third the original dose with concurrent ciprofloxacin.  When|
01143|034|M|ciprofloxacin is discontinued, the clozapine dose should be increased to|
01143|035|M|original clozapine dose.|
01143|036|M|   Clozapine levels should be monitored in patients receiving concurrent|
01143|037|M|therapy with ciprofloxacin.  Patients receiving concurrent therapy should be|
01143|038|M|monitored for adverse clozapine effects and QT prolongation.|
01143|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01143|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01143|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01143|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01143|043|B||
01143|044|D|DISCUSSION:  A randomized, double-blind study in seven patients examined the|
01143|045|D|effects of ciprofloxacin (250 mg twice daily for 7 days) on clozapine (the|
01143|046|D|patients' usual dosages).  Concurrent ciprofloxacin increased the|
01143|047|D|concentration of clozapine and N-desmethylclozapine by 29% and 31%,|
01143|048|D|respectively.(1,6)|
01143|049|D|   There are also several case reports of toxicity with concurrent|
01143|050|D|therapy.(7-11)|
01143|051|D|   Ciprofloxacin is a moderate to strong CYP1A2 inhibitor.(12)|
01143|052|B||
01143|053|R|REFERENCES:|
01143|054|B||
01143|055|R|1.Raaska K, Neuvonen PJ. Ciprofloxacin increases serum clozapine and|2
01143|056|R|  N-desmethylclozapine: a study in patients with schizophrenia. Eur J Clin|2
01143|057|R|  Pharmacol 2000 Nov;56(8):585-9.|2
01143|058|R|2.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
01143|059|R|  Corporation March, 2022.|1
01143|060|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01143|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01143|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01143|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01143|064|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01143|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01143|066|R|  settings: a scientific statement from the American Heart Association and|6
01143|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01143|068|R|  2;55(9):934-47.|6
01143|069|R|5.Clozaril (clozapine tablets) US prescribing information. Novartis|1
01143|070|R|  Pharmaceuticals Corporation April, 2020.|1
01143|071|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01143|072|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01143|073|R|  Soc 2023 Jul;71(7):2052-2081.|6
01143|074|R|7.Sandson NB, Cozza KL, Armstrong SC, Eckermann G, Fischer BA, Phillips B.|3
01143|075|R|  Clozapine case series. Psychosomatics 2007 Mar-Apr;48(2):170-5.|3
01143|076|R|8.Sambhi RS, Puri R, Jones G. Interaction of clozapine and ciprofloxacin: a|3
01143|077|R|  case report. Eur J Clin Pharmacol 2007 Sep;63(9):895-6.|3
01143|078|R|9.Brouwers EE, Sohne M, Kuipers S, van Gorp EC, Schellens JH, Koks CH,|3
01143|079|R|  Beijnen JH, Huitema AD. Ciprofloxacin strongly inhibits clozapine|3
01143|080|R|  metabolism: two case reports. Clin Drug Investig 2009;29(1):59-63.|3
01143|081|R|10.Espnes KA, Heimdal KO, Spigset O. A puzzling case of increased serum|3
01143|082|R|   clozapine levels in a patient with inflammation and infection. Ther Drug|3
01143|083|R|   Monit 2012 Oct;34(5):489-92.|3
01143|084|R|11.Meyer JM, Proctor G, Cummings MA, Dardashti LJ, Stahl SM. Ciprofloxacin|3
01143|085|R|   and Clozapine: A Potentially Fatal but Underappreciated Interaction. Case|3
01143|086|R|   Rep Psychiatry 2016;2016:5606098.|3
01143|087|R|12.This information is based on an extract from the Certara Drug Interaction|6
01143|088|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01144|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
01144|002|T|antagonists)/Capecitabine; Fluorouracil|
01144|003|B||
01144|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01144|005|L|of severe adverse interaction.|
01144|006|B||
01144|007|A|MECHANISM OF ACTION:  Capecitabine inhibits the CYP2C9 mediated metabolism|
01144|008|A|of warfarin.(1)  The interaction mechanism with fluorouracil is not clear.|
01144|009|B||
01144|010|E|CLINICAL EFFECTS:  Concurrent use of fluorouracil (5-FU) or its prodrug,|
01144|011|E|capecitabine, and a Vitamin K antagonist anticoagulant may result in|
01144|012|E|elevated levels of the anticoagulant(2-10) and increase the risk for|
01144|013|E|bleeding.|
01144|014|B||
01144|015|P|PREDISPOSING FACTORS:  Patients who are older than 60 years of age may be|
01144|016|P|predisposed to this interaction.(2)|
01144|017|P|   The risk for bleeding episodes may be greater in patients with|
01144|018|P|disease-associated factors (e.g. thrombocytopenia).|
01144|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
01144|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01144|021|P|risk for bleeding (e.g. NSAIDs).|
01144|022|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
01144|023|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
01144|024|P|are expected to be more susceptible to this interaction.|
01144|025|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
01144|026|P|are expected to be less susceptible to effects from this drug combination,|
01144|027|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
01144|028|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
01144|029|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
01144|030|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
01144|031|P|and safe anticoagulation than patients without these CYP2C9 variants.|
01144|032|B||
01144|033|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with capecitabine|
01144|034|M|or fluorouracil and a Vitamin K antagonist anticoagulant (e.g. warfarin)|
01144|035|M|should have their INR closely monitored and adjusted for an extended period|
01144|036|M|of time as the maximal increase in INR may not occur for 30 - 40 days or|
01144|037|M|more.(10)|
01144|038|M|   If patient has been stabilized on the combination of a Vitamin K|
01144|039|M|antagonist and fluorouracil or capecitabine, and the fluoropyrimidine is|
01144|040|M|subsequently discontinued, the dosage of anticoagulant may need to be|
01144|041|M|gradually increased to maintain a therapeutic INR.|
01144|042|M|   When concurrent therapy is warranted, monitor patients receiving|
01144|043|M|concurrent therapy for signs of blood loss, including decreased hemoglobin|
01144|044|M|and/or hematocrit, fecal occult blood, and/or decreased blood pressure and|
01144|045|M|promptly evaluate patients with any symptoms.|
01144|046|M|   When applicable, perform agent-specific laboratory test (e.g. INR) to|
01144|047|M|monitor efficacy and safety of anticoagulation.  Discontinue anticoagulation|
01144|048|M|in patients with active pathologic bleeding.|
01144|049|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01144|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01144|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01144|052|M|and/or swelling.|
01144|053|B||
01144|054|D|DISCUSSION:  In four patients with cancer, concurrent use of capecitabine|
01144|055|D|(1250 mg/m2 twice daily) with a single dose of warfarin (20 mg) increased|
01144|056|D|the area-under-curve (AUC) of the more active S-isomer of warfarin by 57%.|
01144|057|D|The clearance S-warfarin was decreased by 37%.  The baseline corrected AUC|
01144|058|D|of the International Normalized Ration (INR) and the maximum observed mean|
01144|059|D|INR value increase by 2.8-fold and 91%, respectively.|
01144|060|D|   A retrospective cohort study evaluated changes in INR for 24 patients|
01144|061|D|treated with either 5-fluorouracil or capecitabine and warfarin over a 90|
01144|062|D|day period.  The median change in INR was 2.8.|
01144|063|D|   Altered coagulation parameters and/or bleeding, including death have been|
01144|064|D|reported in patients taking capecitabine with warfarin or phenprocoumon.|
01144|065|D|There have been postmarketing reports of clinically significant increases in|
01144|066|D|prothrombin time and INR in patients who were previously stabilized on|
01144|067|D|anticoagulants when capecitabine was introduced.  These events occurred|
01144|068|D|within several days or months of beginning concurrent therapy or within a|
01144|069|D|month of discontinuing concurrent therapy.(1)|
01144|070|D|   There are several case reports of elevated warfarin response, including|
01144|071|D|hemorrhage, during the concurrent administration of warfarin and|
01144|072|D|fluorouracil.(2-8)|
01144|073|B||
01144|074|R|REFERENCES:|
01144|075|B||
01144|076|R|1.This information is based on an extract from the Certara Drug Interaction|6
01144|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01144|078|R|2.Xeloda (capecitabine) US prescribing information. Roche Pharmaceuticals|1
01144|079|R|  October, 2025.|1
01144|080|R|3.Wajima T, Mukhopadhyay P. Possible interactions between warfarin and|3
01144|081|R|  5-fluorouracil. Am J Hematol 1992 Jul;40(3):238.|3
01144|082|R|4.Scarfe MA, Israel MK. Possible drug interaction between warfarin and|3
01144|083|R|  combination of levamisole and fluorouracil. Ann Pharmacother 1994 Apr;|3
01144|084|R|  28(4):464-7.|3
01144|085|R|5.Brown MC. Multisite mucous membrane bleeding due to a possible interaction|3
01144|086|R|  between warfarin and 5-fluorouracil. Pharmacotherapy 1997 May-Jun;|3
01144|087|R|  17(3):631-3.|3
01144|088|R|6.Brown MC. Interaction between warfarin and 5-fluorouracil, not between|3
01144|089|R|  warfarin and levamisole. Clin Pharmacol Ther 1998 Aug;64(2):233.|3
01144|090|R|7.Brown MC. An adverse interaction between warfarin and 5-fluorouracil: A|3
01144|091|R|  case report and review of the literature. Chemotherapy 1999 Sep-Oct;|3
01144|092|R|  45(5):392-5.|3
01144|093|R|8.Kolesar JM, Johnson CL, Freeberg BL, Berlin JD, Schiller JH. Warfarin-5-FU|3
01144|094|R|  interaction--a consecutive case series. Pharmacotherapy 1999 Dec;|3
01144|095|R|  19(12):1445-9.|3
01144|096|R|9.Aki Z, Kotiloglu G, Ozyilkan O. A patient with a prolonged prothrombin|3
01144|097|R|  time due to an adverse interaction between 5-fluorouracil and warfarin. Am|3
01144|098|R|  J Gastroenterol 2000 Apr;95(4):1093-4.|3
01144|099|R|10.Shah SR, Martin R, Dowell JE, Ussery SM. Comparison of the|2
01144|100|R|   5-fluorouracil-warfarin and capecitabine-warfarin drug interactions.|2
01144|101|R|   Pharmacotherapy 2010 Dec;30(12):1259-65.|2
01145|001|T|MONOGRAPH TITLE:  Alteplase/Selected Anticoagulants (Vitamin K antagonists);|
01145|002|T|Heparins|
01145|003|B||
01145|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01145|005|L|of severe adverse interaction.|
01145|006|B||
01145|007|A|MECHANISM OF ACTION:  The concurrent use of alteplase and anticoagulants may|
01145|008|A|increase the risk of bleeding.(1)|
01145|009|B||
01145|010|E|CLINICAL EFFECTS:  The concurrent use of alteplase and anticoagulants may|
01145|011|E|result in bleeding episodes.(1)|
01145|012|B||
01145|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01145|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01145|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01145|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01145|017|P|risk for bleeding (e.g. NSAIDs).|
01145|018|B||
01145|019|M|PATIENT MANAGEMENT:  The manufacturer of alteplase states that the use of|
01145|020|M|alteplase for an indication of acute ischemic stroke is contraindicated in|
01145|021|M|patients receiving anticoagulants.(1)|
01145|022|M|   Concurrent use of alteplase and anticoagulants is dependent on the|
01145|023|M|therapeutic indication.|
01145|024|M|   In Acute Ischemic Stroke:|
01145|025|M|   - Clinical practice guidelines for acute ischemic stroke state the use of|
01145|026|M|thrombolytic therapy for an indication of acute ischemic stroke is|
01145|027|M|contraindicated in patients who have received warfarin and have an elevated|
01145|028|M|activated partial thromboplastin time (aPTT) > 40 seconds, prothrombin time|
01145|029|M|(PT) > 15 seconds, INR > 1.7, or platelets <100,000/mm3 at presentation.|
01145|030|M|   In Acute Myocardial Infarction:|
01145|031|M|   - Patients who are receiving alteplase for an indication of acute|
01145|032|M|myocardial infarction should be carefully monitored for signs of bleeding,|
01145|033|M|especially at arterial puncture sites, if heparin is used concurrently.|
01145|034|M|   - The use of alteplase in patients with acute myocardial infarction|
01145|035|M|should follow standard management of myocardial infarction, including|
01145|036|M|minimizing arterial and venous puncture; avoid noncompressible arterial|
01145|037|M|puncture; and minimize internal jugular and subclavian venous punctures to|
01145|038|M|decrease bleeding from the noncompressible sites.|
01145|039|M|   For all indications:|
01145|040|M|   - In the event of serious bleeding, anticoagulants should be discontinued|
01145|041|M|immediately.|
01145|042|M|   - If concurrent therapy is warranted, monitor patients receiving|
01145|043|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
01145|044|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
01145|045|M|evaluate patients with any symptoms.|
01145|046|M|   - When applicable, perform agent-specific laboratory test (e.g. INR,|
01145|047|M|aPTT) to monitor efficacy and safety of anticoagulation.  Discontinue|
01145|048|M|anticoagulation in patients with active pathologic bleeding.|
01145|049|M|   - Instruct patients to report any signs and symptoms of bleeding, such as|
01145|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01145|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01145|052|M|and/or swelling.|
01145|053|B||
01145|054|D|DISCUSSION:  The manufacturer of alteplase states that the use of alteplase|
01145|055|D|for an indication of acute ischemic stroke is contraindicated in patients|
01145|056|D|receiving anticoagulants.(1)  Patients who are receiving alteplase for an|
01145|057|D|indication of acute myocardial infarction or pulmonary embolism should be|
01145|058|D|carefully monitored for signs of bleeding if anticoagulants are being used|
01145|059|D|concurrently or have recently been used.|
01145|060|D|   In a retrospective review of 107 acute ischemic stroke patients receiving|
01145|061|D|tPA with or without warfarin the incidence of symptomatic intracerebral|
01145|062|D|hemorrhage(sICH) was found to be much greater in patients receiving|
01145|063|D|warfarin, 30.8% in patients receiving warfarin compared to 3.2% in patients|
01145|064|D|not undergoing warfarin therapy.(2)|
01145|065|B||
01145|066|R|REFERENCES:|
01145|067|B||
01145|068|R|1.Activase (alteplase, recombinant) US prescribing information. Genentech,|1
01145|069|R|  Inc. February, 2018.|1
01145|070|R|2.Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC. Guidelines|6
01145|071|R|  for the Early Management of Patients With Acute Ischemic Stroke: 2019|6
01145|072|R|  Update to the 2018 Guidelines for the Early Management of Acute Ischemic|6
01145|073|R|  Stroke:  A Guideline for Healthcare Professionals From the AHA/ASA. Stroke|6
01145|074|R|  2019 Dec;50(12):e344-e418.|6
01145|075|R|3.Prabhakaran S, Rivolta J, Vieira JR, Rincon F, Stillman J, Marshall RS,|2
01145|076|R|  Chong JY. Symptomatic Intracerebral Hemorrhage Among Eligible|2
01145|077|R|  Warfarin-Treated Patients Receiving Intravenous Tissue Plasminogen|2
01145|078|R|  Activator for Acute Ischemic Stroke. Arch Neurol 2010 Mar 8.|2
01146|001|T|MONOGRAPH TITLE:  Alteplase/Heparins|
01146|002|B||
01146|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01146|004|L|of severe adverse interaction.|
01146|005|B||
01146|006|A|MECHANISM OF ACTION:  The concurrent use of alteplase and heparins may|
01146|007|A|increase the risk of bleeding.|
01146|008|B||
01146|009|E|CLINICAL EFFECTS:  The concurrent use of alteplase and heparins may result|
01146|010|E|in bleeding episodes.|
01146|011|B||
01146|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01146|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01146|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
01146|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01146|016|P|risk for bleeding (e.g. NSAIDs).|
01146|017|B||
01146|018|M|PATIENT MANAGEMENT:  Use of alteplase and anticoagulants, including|
01146|019|M|heparins, may increase the risk of bleeding if administered prior to,|
01146|020|M|during, or after alteplase therapy.  Concurrent use of alteplase and|
01146|021|M|heparins is dependent on the therapeutic indication.|
01146|022|M|   In Acute Ischemic Stroke:|
01146|023|M|   - Clinical practice guidelines for acute ischemic stroke state the use of|
01146|024|M|thrombolytic therapy for an indication of acute ischemic stroke is|
01146|025|M|contraindicated in patients who have received full treatment doses of|
01146|026|M|heparins within 24 hours preceding the onset of stroke or who have an|
01146|027|M|elevated activated partial thromboplastin time (aPTT) > 40 seconds,|
01146|028|M|prothrombin time (PT) > 15 seconds, INR > 1.7, or platelets <100,000/mm3 at|
01146|029|M|presentation.|
01146|030|M|   In Acute Myocardial Infarction:|
01146|031|M|   - Patients who are receiving alteplase for an indication of acute|
01146|032|M|myocardial infarction should be carefully monitored for signs of bleeding,|
01146|033|M|especially at arterial puncture sites, if heparin is used concurrently.|
01146|034|M|   - The use of alteplase in patients with acute myocardial infarction|
01146|035|M|should follow standard management of myocardial infarction, including|
01146|036|M|minimizing arterial and venous puncture; avoid noncompressible arterial|
01146|037|M|puncture; and minimize internal jugular and subclavian venous punctures to|
01146|038|M|decrease bleeding from the noncompressible sites.|
01146|039|M|   For all indications:|
01146|040|M|   - In the event of serious bleeding, heparins should be discontinued|
01146|041|M|immediately and consider protamine administration for reversal of heparin.|
01146|042|M|   - If concurrent therapy is warranted, monitor patients receiving|
01146|043|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
01146|044|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
01146|045|M|evaluate patients with any symptoms.|
01146|046|M|   - When applicable, perform agent-specific laboratory test (e.g. INR,|
01146|047|M|aPTT) to monitor efficacy and safety of anticoagulation.  Discontinue|
01146|048|M|anticoagulation in patients with active pathologic bleeding.|
01146|049|M|   - Instruct patients to report any signs and symptoms of bleeding, such as|
01146|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01146|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01146|052|M|and/or swelling.|
01146|053|B||
01146|054|D|DISCUSSION:  The manufacturer of alteplase states that the use of alteplase|
01146|055|D|for an indication of acute ischemic stroke is contraindicated in patients|
01146|056|D|who have received heparin within 24 hours preceding the onset of stroke and|
01146|057|D|who have an elevated activated partial thromboplastin time (aPTT) at|
01146|058|D|presentation.|
01146|059|D|   Heparin has been administered concomitantly and following alteplase in|
01146|060|D|the treatment of acute myocardial infarction.  Patients who are receiving|
01146|061|D|alteplase with heparin should be carefully monitored for signs of bleeding,|
01146|062|D|especially at arterial puncture sites, if heparin is used concurrently.|
01146|063|B||
01146|064|R|REFERENCES:|
01146|065|B||
01146|066|R|1.Activase (alteplase, recombinant) US prescribing information. Genentech,|1
01146|067|R|  Inc. February, 2018.|1
01146|068|R|2.Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC. Guidelines|6
01146|069|R|  for the Early Management of Patients With Acute Ischemic Stroke: 2019|6
01146|070|R|  Update to the 2018 Guidelines for the Early Management of Acute Ischemic|6
01146|071|R|  Stroke:  A Guideline for Healthcare Professionals From the AHA/ASA. Stroke|6
01146|072|R|  2019 Dec;50(12):e344-e418.|6
01147|001|T|MONOGRAPH TITLE:  Topiramate/Carbonic Anhydrase Inhibitors|
01147|002|B||
01147|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01147|004|L|of severe adverse interaction.|
01147|005|B||
01147|006|A|MECHANISM OF ACTION:  Topiramate is a weak carbonic anhydrase inhibitor and|
01147|007|A|can induce renal bicarbonate loss, resulting in metabolic acidosis.  It can|
01147|008|A|also reduce urinary citrate excretion and increase urinary pH, posing a risk|
01147|009|A|for nephrolithiasis.  As well, carbonic anhydrase inhibitors can cause|
01147|010|A|decreased sweating and elevated body temperature, predisposing patients to|
01147|011|A|heat-related disorders.(1)|
01147|012|B||
01147|013|E|CLINICAL EFFECTS:  The concurrent use of topiramate with another carbonic|
01147|014|E|anhydrase inhibitor may increase the risk of metabolic acidosis and kidney|
01147|015|E|stone formation.(1)|
01147|016|E|   Concurrent use of topiramate with other carbonic anhydrase inhibitors may|
01147|017|E|increase the incidence of oligohidrosis and hyperthermia, especially in|
01147|018|E|pediatric or adolescent patients.(1-2)  Overheating and dehydration can lead|
01147|019|E|to brain damage and death.|
01147|020|B||
01147|021|P|PREDISPOSING FACTORS:  Patients with conditions that predispose to acidosis|
01147|022|P|(such as renal disease, severe respiratory disorders, status epilepticus,|
01147|023|P|diarrhea, and being on a ketogenic diet) may be at increased risk of|
01147|024|P|experiencing adverse effects from concurrent carbonic anhydrase|
01147|025|P|inhibitors.(1)|
01147|026|P|   Pediatric and adolescent patients and patients with dehydration may be|
01147|027|P|more likely to experience heat-related disorders.(1)|
01147|028|B||
01147|029|M|PATIENT MANAGEMENT:  The US manufacturer of topiramate states that the|
01147|030|M|concurrent use of topiramate with other carbonic anhydrase inhibitors should|
01147|031|M|be avoided.  Patients receiving concurrent therapy should be monitored for|
01147|032|M|the appearance of or worsening of metabolic acidosis, nephrolithiasis, and|
01147|033|M|hyperthermia.(1)|
01147|034|M|   Check serum bicarbonate at baseline and periodically during treatment.|
01147|035|M|Monitor for signs and symptoms of metabolic acidosis: hyperventilation,|
01147|036|M|fatigue, anorexia, arrhythmias, stupor.|
01147|037|M|   Monitor for signs and symptoms of heat stroke: skin feels very hot with|
01147|038|M|little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid|
01147|039|M|breathing.|
01147|040|M|   Monitor for signs and symptoms of dehydration: dry mouth, urinating less|
01147|041|M|than usual, dark-colored urine, dry skin, feeling tired, dizziness, or|
01147|042|M|irritability.|
01147|043|M|   If signs or symptoms of metabolic acidosis, dehydration, oligohidrosis,|
01147|044|M|or elevated body temperature occur, a decreased dose or discontinuation of|
01147|045|M|zonisamide should be considered.|
01147|046|B||
01147|047|D|DISCUSSION:  Topiramate is a weak carbonic anhydrase inhibitor.  Carbonic|
01147|048|D|anhydrase inhibitors increase urinary bicarbonate excretion, reduce urinary|
01147|049|D|citrate excretion and increase urinary pH.  Concurrent use of topiramate|
01147|050|D|with other carbonic anhydrase inhibitors may increase the risk of metabolic|
01147|051|D|acidosis and kidney stone formation and should therefore be avoided.(1)|
01147|052|D|   Case reports of decreased sweating and elevated temperature have been|
01147|053|D|reported, especially in pediatric patients.  Some cases resulted in heat|
01147|054|D|stroke that required hospital treatment.(1)|
01147|055|B||
01147|056|R|REFERENCE:|
01147|057|B||
01147|058|R|1.Topamax (topiramate) US prescribing information. Janssen Pharmaceuticals,|1
01147|059|R|  Inc. May, 2023.|1
01148|001|T|MONOGRAPH TITLE:  Live Vaccines/Anakinra; Canakinumab; Rilonacept (mono|
01148|002|T|deleted 04/26/2012)|
01148|003|B||
01148|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01148|005|L|is contraindicated and generally should not be dispensed or administered to|
01148|006|L|the same patient.|
01148|007|B||
01148|008|A|MECHANISM OF ACTION:  Anakinra,(1) canakinumab,(2) and rilonacept(3)|
01148|009|A|interfere with the normal immune response to new antigens.|
01148|010|B||
01148|011|E|CLINICAL EFFECTS:  Live vaccines may not be effective in patients treated|
01148|012|E|with anakinra,(1) canakinumab,(2) or rilonacept(3)|
01148|013|B||
01148|014|P|PREDISPOSING FACTORS:  None determined.|
01148|015|B||
01148|016|M|PATIENT MANAGEMENT:  The US manufacturers of anakinra,(1) canakinumab,(2)|
01148|017|M|and rilonacept(3) state that live vaccines should not be given concurrently|
01148|018|M|with these agents.|
01148|019|B||
01148|020|D|DISCUSSION:  There are no data available on the effects of live vaccines in|
01148|021|D|patients receiving these agents or the secondary transmission of infection|
01148|022|D|by live vaccines in patients receiving these agents.  Because these agents|
01148|023|D|interfere with the normal immune response to new antigens, vaccination may|
01148|024|D|not be effective in patients treated with them.(1-3)|
01148|025|B||
01148|026|R|REFERENCES:|
01148|027|B||
01148|028|R|1.Kineret (anakinra) US prescribing information. Amgen Inc. December, 2006.|1
01148|029|R|2.Ilaris (canakinumab) US prescribing information. Novartis Pharmaceuticals|1
01148|030|R|  Corporation August, 2023.|1
01148|031|R|3.Arcalyst (rilonacept) US prescribing information. Regeneron|1
01148|032|R|  Pharmaceuticals, Inc. March, 2021.|1
01149|001|T|MONOGRAPH TITLE:  Live Vaccines/Etanercept (mono deleted 04/26/2012)|
01149|002|B||
01149|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01149|004|L|is contraindicated and generally should not be dispensed or administered to|
01149|005|L|the same patient.|
01149|006|B||
01149|007|A|MECHANISM OF ACTION:  Etanercept may interfere with the normal immune|
01149|008|A|response to new antigens.(1)|
01149|009|B||
01149|010|E|CLINICAL EFFECTS:  Live vaccines may not be effective in patients treated|
01149|011|E|with etanercept and may cause infection.(1)|
01149|012|B||
01149|013|P|PREDISPOSING FACTORS:  None determined.|
01149|014|B||
01149|015|M|PATIENT MANAGEMENT:  The manufacturer of etanercept states that live|
01149|016|M|vaccines should not be given concurrently with etanercept.  Patients should|
01149|017|M|be brought up-to-date on all immunizations prior to etanercept therapy.(1)|
01149|018|B||
01149|019|D|DISCUSSION:  Because etanercept interferes with the normal immune response,|
01149|020|D|vaccination may not be effective and may cause disease in patients treated|
01149|021|D|with etanercept.  Therefore, the manufacturer of etanercept states that live|
01149|022|D|vaccines should not be given concurrently with etanercept.  Patients should|
01149|023|D|be brought up-to-date on all immunizations prior to etanercept therapy.(1)|
01149|024|B||
01149|025|R|REFERENCE:|
01149|026|B||
01149|027|R|1.Enbrel (etanercept) US prescribing information. Amgen December, 2023.|1
01150|001|T|MONOGRAPH TITLE:  Cyclosporine/Quinupristin-Dalfopristin; Pristinamycin|
01150|002|B||
01150|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01150|004|L|of severe adverse interaction.|
01150|005|B||
01150|006|A|MECHANISM OF ACTION:  Quinupristin-dalfopristin and pristinamycin may|
01150|007|A|inhibit the metabolism of cyclosporine by CYP3A4.(1,2)|
01150|008|B||
01150|009|E|CLINICAL EFFECTS:  Concurrent use of quinupristin-dalfopristin or|
01150|010|E|pristinamycin and cyclosporine may result in elevated levels of cyclosporine|
01150|011|E|and toxicity.(1)|
01150|012|B||
01150|013|P|PREDISPOSING FACTORS:  None determined.|
01150|014|B||
01150|015|M|PATIENT MANAGEMENT:  Cyclosporine levels should be carefully monitored when|
01150|016|M|quinupristin-dalfopristin or pristinamycin is added to or discontinued from|
01150|017|M|concurrent cyclosporine therapy.(1,2)  The dosage of cyclosporine may need|
01150|018|M|to be adjusted.|
01150|019|B||
01150|020|D|DISCUSSION:  In a study in 24 subjects, the administration of|
01150|021|D|quinupristin-dalfopristin (7.5 mg/kg three times daily for 2 days) and|
01150|022|D|cyclosporine (300 mg on Day 3) resulted in increases in cyclosporine|
01150|023|D|area-under-curve (AUC), maximum concentration (Cmax), and half-life by 63%,|
01150|024|D|30%, and 77%, respectively.  There was a 33% decrease in cyclosporine|
01150|025|D|clearance.(1)|
01150|026|D|   In a case report, a patient's trough cyclosporine levels increased from a|
01150|027|D|range of 80-105 ng/ml to 261 ng/ml and 291 ng/ml two and three days after|
01150|028|D|the addition of quinupristin-dalfopristin.  The patient's cyclosporine|
01150|029|D|dosage was decreased by one-third.  Following the completion of|
01150|030|D|quinupristin-dalfopristin therapy, cyclosporine levels decreased and the|
01150|031|D|cyclosporine dosage was increased to prior levels.(2)|
01150|032|D|   In vitro studies have shown that quinupristin-dalfopristin significantly|
01150|033|D|inhibits CYP3A4 metabolism, including that of cyclosporine.(1)|
01150|034|B||
01150|035|R|REFERENCES:|
01150|036|B||
01150|037|R|1.Synercid (quinupristin-dalfopristin) US prescribing information. Aventis|1
01150|038|R|  Pharmaceuticals, Inc. December, 2000.|1
01150|039|R|2.Stamatakis MK, Richards JG. Interaction between quinupristin/dalfopristin|3
01150|040|R|  and cyclosporine. Ann Pharmacother 1997 May;31(5):576-8.|3
01150|041|R|3.Pyostacin (pristinamycin) Australian product information. SANOFI WINTHROP|1
01150|042|R|  INDUSTRIE May 5, 2010.|1
01150|043|R|4.Gagnadoux MF, Loirat C, Pillion G, Bertheleme JP, Pouliquen M, Guest G,|3
01150|044|R|  Broyer M. Nephrotoxicity of pristinamycin-cyclosporin interaction in renal|3
01150|045|R|  transplant  patients. Presse Med 1987 Oct 24;16(35):1761.|3
01150|046|R|5.Herbrecht R, Garcia JJ, Bergerat JP, Oberling F. Effect of pristinamycin|3
01150|047|R|  on cyclosporin levels in bone marrow transplant  recipients. Bone Marrow|3
01150|048|R|  Transplant 1989 Jul;4(4):457-8.|3
01151|001|T|MONOGRAPH TITLE:  Dofetilide/Thiazide Diuretics|
01151|002|B||
01151|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01151|004|L|is contraindicated and generally should not be dispensed or administered to|
01151|005|L|the same patient.|
01151|006|B||
01151|007|A|MECHANISM OF ACTION:  Thiazide diuretics may decrease the excretion of|
01151|008|A|dofetilide and may decrease potassium levels.(1)|
01151|009|B||
01151|010|E|CLINICAL EFFECTS:  Concurrent use of dofetilide with a thiazide diuretic may|
01151|011|E|result in elevated levels and clinical effects of dofetilide, as well as|
01151|012|E|prolongation of the QT interval.(1)|
01151|013|B||
01151|014|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
01151|015|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
01151|016|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
01151|017|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
01151|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01151|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01151|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01151|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and|
01151|022|P|advanced age.(2)|
01151|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01151|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01151|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01151|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01151|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01151|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01151|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01151|030|B||
01151|031|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that the|
01151|032|M|concurrent use of dofetilide with hydrochlorothiazide, alone or in|
01151|033|M|combination with triamterene, is contraindicated.(1)  Other thiazides should|
01151|034|M|also be considered contraindicated as well.|
01151|035|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01151|036|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01151|037|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01151|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01151|039|B||
01151|040|D|DISCUSSION:  In a study, hydrochlorothiazide (50 mg daily) alone or|
01151|041|D|hydrochlorothiazide/triamterene (50 mg/100 mg daily) was administered with|
01151|042|D|dofetilide (500 mcg twice daily) for 5 days following 2 days of diuretic use|
01151|043|D|at half-dose.  In patients receiving hydrochlorothiazide alone, the|
01151|044|D|area-under-curve (AUC) and maximum concentration (Cmax) of dofetilide|
01151|045|D|increased by 27% and by 21%, respectively.  The pharmacodynamic effects of|
01151|046|D|dofetilide increased by 197% (QTc increase over time) and by 95% (maximum|
01151|047|D|QTc increase).  In patients on combination hydrochlorothiazide/triamterene,|
01151|048|D|dofetilide AUC and Cmax increased by 30% and by 16%, respectively.  The|
01151|049|D|pharmacodynamic effects of dofetilide increased by 190% (QTc increase over|
01151|050|D|time) and by 84% (maximum QTc increase).(1)|
01151|051|D|   Dofetilide clearance was 16% lower in patients receiving thiazide|
01151|052|D|diuretics.(1)|
01151|053|B||
01151|054|R|REFERENCES:|
01151|055|B||
01151|056|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01151|057|R|  2013.|1
01151|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01151|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01151|060|R|  settings: a scientific statement from the American Heart Association and|6
01151|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01151|062|R|  2;55(9):934-47.|6
01152|001|T|MONOGRAPH TITLE:  Bosentan; Sitaxsentan/Cyclosporine|
01152|002|B||
01152|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01152|004|L|is contraindicated and generally should not be dispensed or administered to|
01152|005|L|the same patient.|
01152|006|B||
01152|007|A|MECHANISM OF ACTION:  Bosentan may induce the metabolism of cyclosporine by|
01152|008|A|CYP3A4.(1)  The exact mechanisms behind the increased levels of bosentan is|
01152|009|A|unknown, but may involve competitive inhibition for CYP3A4.(1)|
01152|010|A|   The exact mechanism behind the increased levels of sitaxsentan is|
01152|011|A|unknown;(2,3) however, sitaxsentan may be a substrate of the OATP|
01152|012|A|transporter system.(2)|
01152|013|B||
01152|014|E|CLINICAL EFFECTS:  Concurrent use of bosentan and cyclosporine may result in|
01152|015|E|elevated levels of and effects from bosentan, including severe headache,|
01152|016|E|nausea, and vomiting, and may increase the risk of liver damage.  Concurrent|
01152|017|E|use may result in decreased levels and effectiveness of cyclosporine.(1)|
01152|018|E|   Concurrent use of sitaxsentan and cyclosporine may result in elevated|
01152|019|E|levels of and effects from sitaxsentan, including severe headache, nausea,|
01152|020|E|and vomiting, and may increase the risk of liver damage.(2)|
01152|021|B||
01152|022|P|PREDISPOSING FACTORS:  None determined.|
01152|023|B||
01152|024|M|PATIENT MANAGEMENT:  The US manufacturer of bosentan states that the|
01152|025|M|concurrent use of bosentan and cyclosporine is contraindicated.(1)|
01152|026|M|   The Canadian(3) and UK(2) manufacturers of sitaxsentan state that the|
01152|027|M|concurrent use of sitaxsentan and cyclosporine is contraindicated.|
01152|028|B||
01152|029|D|DISCUSSION:  On the first day of concurrent bosentan (500 mg and 1000 mg|
01152|030|D|twice daily) and cyclosporine therapy, bosentan trough concentrations (Cmin)|
01152|031|D|increased 30-fold.  Steady-state bosentan concentrations were 3- to 4-fold|
01152|032|D|higher during concurrent cyclosporine.  Side effects reported during|
01152|033|D|concurrent therapy included severe headache, nausea, and vomiting.  Mild|
01152|034|D|decreases in blood pressure and heart rate were observed.  Cyclosporine|
01152|035|D|concentrations were decreased by 50%.(1)|
01152|036|D|   In a study in healthy subjects, administration of bosentan (250 mg to|
01152|037|D|1000 mg twice daily) and cyclosporine (300 mg twice daily, adjusted to|
01152|038|D|achieve a Cmin of 200-250 ng/ml) increased dose-normalized bosentan Cmin on|
01152|039|D|Day 1 and Day 8 by approximately 21-fold and 2-fold, respectively, when|
01152|040|D|compared to bosentan administration alone.  Cyclosporine mean|
01152|041|D|dose-normalized maximum concentration (Cmax), area-under-curve (AUC), and|
01152|042|D|Cmin decreased by 30%, 50%, and 60%, respectively, when compared to|
01152|043|D|cyclosporine administration alone.(4,5)|
01152|044|D|   Concurrent use of sitaxsentan (100 mg daily) and cyclosporine (3.5 mg/kg|
01152|045|D|twice daily) increased the minimum concentration (Cmin) of sitaxsentan by|
01152|046|D|6-fold.  There were no effects on cyclosporine clearance.(2,3)|
01152|047|B||
01152|048|R|REFERENCES:|
01152|049|B||
01152|050|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
01152|051|R|  US, Inc. September 5, 2017.|1
01152|052|R|2.Thelin (sitaxentan sodium) UK summary of product characteristics. Encysive|1
01152|053|R|  (UK) Limited August 10, 2006.|1
01152|054|R|3.Gehshan A. Dear Canadian Healthcare Professional letter:  Subject:  Saftey|1
01152|055|R|  information regarding Thelin (sitaxsentan sodium) and the ocurrence of|1
01152|056|R|  liver toxicity, risks to the fetus, and important drug-drug interactions.|1
01152|057|R|  Encysive Pharmaceuticals July 9, 2007.|1
01152|058|R|4.Sandimmune (cyclosporine) US prescribing information. Novartis|1
01152|059|R|  Pharmaceuticals Corporation September 2023.|1
01152|060|R|5.Binet I, Wallnofer A, Weber C, Jones R, Thiel G. Renal hemodynamics and|3
01152|061|R|  pharmacokinetics of bosentan with and without cyclosporine A. Kidney Int|3
01152|062|R|  2000 Jan;57(1):224-31.|3
01153|001|T|MONOGRAPH TITLE:  Bosentan/Glyburide|
01153|002|B||
01153|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01153|004|L|is contraindicated and generally should not be dispensed or administered to|
01153|005|L|the same patient.|
01153|006|B||
01153|007|A|MECHANISM OF ACTION:  The mechanism behind the increased risk of elevated|
01153|008|A|liver aminotransferases is unknown.|
01153|009|B||
01153|010|E|CLINICAL EFFECTS:  Concurrent use of bosentan and glyburide may increase the|
01153|011|E|risk of liver enzyme elevations.(1,2)|
01153|012|B||
01153|013|P|PREDISPOSING FACTORS:  None determined.|
01153|014|B||
01153|015|M|PATIENT MANAGEMENT:  The US manufacturers of bosentan and glyburide state|
01153|016|M|that the concurrent use of these agents is contraindicated(1,2) and that|
01153|017|M|alternative hypoglycemic agents should be considered.(1)|
01153|018|B||
01153|019|D|DISCUSSION:  An increased risk of liver enzyme elevation was seen in|
01153|020|D|patients receiving concurrent bosentan and glyburide.(1,2)|
01153|021|B||
01153|022|R|REFERENCES:|
01153|023|B||
01153|024|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
01153|025|R|  US, Inc. September 5, 2017.|1
01153|026|R|2.Diabeta (glyburide) US prescribing information. Sanofi-Aventis U.S. LLC|1
01153|027|R|  October, 2013.|1
01154|001|T|MONOGRAPH TITLE:  Hormonal Contraceptive Agents/Bosentan|
01154|002|B||
01154|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01154|004|L|of severe adverse interaction.|
01154|005|B||
01154|006|A|MECHANISM OF ACTION:  Bosentan may induce the metabolism of hormonal|
01154|007|A|contraceptive agents by CYP3A4.(1,2)|
01154|008|B||
01154|009|E|CLINICAL EFFECTS:  Concurrent use of bosentan and hormonal contraceptive|
01154|010|E|agents may decrease the effectiveness of the hormonal contraceptive agent,|
01154|011|E|which may result in contraceptive failure.(1,2)  Bosentan is likely to cause|
01154|012|E|major birth defects if used by pregnant women.(1)|
01154|013|B||
01154|014|P|PREDISPOSING FACTORS:  None determined.|
01154|015|B||
01154|016|M|PATIENT MANAGEMENT:  Women receiving bosentan therapy should not rely solely|
01154|017|M|on hormonal contraceptive agents (including oral, implantable, injectable,|
01154|018|M|or transdermal agents) because they may not be effective.  Consider|
01154|019|M|consulting a gynecologist or similar expert for advice on adequate|
01154|020|M|contraception.(1)|
01154|021|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
01154|022|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
01154|023|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
01154|024|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
01154|025|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
01154|026|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
01154|027|M|and to seek medical advice if they do become pregnant.|
01154|028|B||
01154|029|D|DISCUSSION:  Concurrent use of bosentan and Ortho-Novum (norethindrone and|
01154|030|D|ethinyl estradiol) resulted in average decreases of norethindrone and|
01154|031|D|ethinyl estradiol by 14% and 31%, respectively.  However, individual|
01154|032|D|subjects experienced decreases in norethindrone and ethinyl estradiol by as|
01154|033|D|much as 56% and 66%, respectively.  Therefore, hormonal contraceptive agents|
01154|034|D|may not be reliable in patients taking bosentan.(1,2)|
01154|035|B||
01154|036|R|REFERENCES:|
01154|037|B||
01154|038|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
01154|039|R|  US, Inc. September 5, 2017.|1
01154|040|R|2.van Giersbergen PL, Halabi A, Dingemanse J. Pharmacokinetic interaction|2
01154|041|R|  between bosentan and the oral contraceptives norethisterone and ethinyl|2
01154|042|R|  estradiol. Int J Clin Pharmacol Ther 2006 Mar;44(3):113-8.|2
01154|043|R|3.Medicines and Healthcare products Regulatory Agency.|1
01154|044|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
01154|045|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
01154|046|R|  available at:|1
01154|047|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
01154|048|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
01154|049|R|  -and-contraceptive-efficacy September 15, 2016..|1
01155|001|T|MONOGRAPH TITLE:  Risperidone/Selected Strong CYP2D6 Inhibitors|
01155|002|B||
01155|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01155|004|L|take action as needed.|
01155|005|B||
01155|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
01155|007|A|risperidone by CYP2D6.(1)|
01155|008|B||
01155|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2D6 inhibitors may result in|
01155|010|E|elevated levels of risperidone and an increase in risperidone side|
01155|011|E|effects.(1)|
01155|012|B||
01155|013|P|PREDISPOSING FACTORS:  None determined.|
01155|014|B||
01155|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with strong|
01155|016|M|CYP2D6 inhibitors with risperidone should be observed for increases in|
01155|017|M|risperidone side effects, including extrapyramidal and Parkinsonian|
01155|018|M|symptoms.|
01155|019|M|   The US manufacturer of risperidone (Risperdal) recommends that when|
01155|020|M|CYP2D6 inhibitors are co-administered with risperidone that the dose should|
01155|021|M|be reduced. The risperidone dose should not exceed 8 mg per day when|
01155|022|M|co-administered with CYP2D6 inhibitors. When initiating therapy with|
01155|023|M|risperidone, the dose of risperidone should be titrated slowly. It may be|
01155|024|M|necessary to increase the risperidone dose, when CYP2D6 inhibitors are|
01155|025|M|discontinued.(1)|
01155|026|M|   One set of authors recommended a low initial dose of paroxetine of 10|
01155|027|M|mg/day to 20 mg/day in patients receiving risperidone.(2)|
01155|028|B||
01155|029|D|DISCUSSION:  In a study in 7 patients maintained on risperidone (doses|
01155|030|D|ranged from 2 mg daily to 4 mg daily), the addition of duloxetine (60 mg|
01155|031|D|daily) increased risperidone levels by 25%.  The mean plasma|
01155|032|D|risperidone/9-hydroxyrisperidone ratio increased 1.95-fold.  One patient|
01155|033|D|developed mild extrapyramidal symptoms.  His risperidone level at the time|
01155|034|D|was 72 ng/ml.(3)  In contrast, a retrospective chart review compared 7|
01155|035|D|patients receiving concurrent risperidone and duloxetine to control patients|
01155|036|D|receiving only risperidone and found no significant effect on risperidone|
01155|037|D|levels.(4)|
01155|038|D|   A study in 10 patients examined the effects of fluoxetine (20 mg daily)|
01155|039|D|on risperidone (4-6 mg/day).  One patient dropped out following the|
01155|040|D|development of severe akathisia after one week of fluoxetine.  Her|
01155|041|D|risperidone levels had increased 457%.  In the remaining patients,|
01155|042|D|fluoxetine increased risperidone levels by 308% at two weeks and by 733% at|
01155|043|D|four weeks.  Levels of the active moiety increased by 75% by four weeks.|
01155|044|D|During the second week of fluoxetine therapy, two patients developed|
01155|045|D|Parkinsonian symptoms.(5)|
01155|046|D|   Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone|
01155|047|D|plasma concentrations.(5)|
01155|048|D|   A study in 3 poor metabolizer and 8 extensive metabolizers examined the|
01155|049|D|effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily).|
01155|050|D|Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone|
01155|051|D|and the active moiety by 29% and by 100%, respectively, in poor|
01155|052|D|metabolizers.  In extensive metabolizers, the AUC of risperidone and the|
01155|053|D|active moiety increased by 70% and 41%, respectively.(6)|
01155|054|D|   A study in 10 patients examined the effects of paroxetine (20 mg daily)|
01155|055|D|on risperidone (4-8 mg/day).  After two and four weeks of concurrent|
01155|056|D|therapy, risperidone concentrations increased 388% and 453%, respectively.|
01155|057|D|Plasma concentrations of the active moiety increased 39.4% and 44.5% after|
01155|058|D|two and four weeks of concurrent therapy, respectively.  No symptoms of|
01155|059|D|risperidone toxicity or change in extrapyramidal effects were noted.  One|
01155|060|D|patient developed Parkinsonism.(2)|
01155|061|D|   Paroxetine has been shown to lower 9-hydroxyrisperidone plasma|
01155|062|D|concentrations by 10%.(2)|
01155|063|D|   Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib,|
01155|064|D|fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(7)|
01155|065|B||
01155|066|R|REFERENCES:|
01155|067|B||
01155|068|R|1.Risperdal (risperidone) US prescribing information. Janssen Pharmaceutical|1
01155|069|R|  Ltd. February 2021.|1
01155|070|R|2.Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A. Plasma|2
01155|071|R|  concentrations of risperidone and 9-hydroxyrisperidone during combined|2
01155|072|R|  treatment with paroxetine. Ther Drug Monit 2001 Jun;23(3):223-7.|2
01155|073|R|3.Santoro V, D'Arrigo C, Spina E, Mico U, Muscatello MR, Zoccali R. Effect|2
01155|074|R|  of adjunctive duloxetine on the plasma concentrations of clozapine,|2
01155|075|R|  olanzapine, and risperidone in patients with psychotic disorders. J Clin|2
01155|076|R|  Psychopharmacol 2010 Oct;30(5):634-6.|2
01155|077|R|4.Hendset M, Molden E, Enoksen TB, Refsum H, Hermann M. The effect of|2
01155|078|R|  coadministration of duloxetine on steady-state serum concentration of|2
01155|079|R|  risperidone and aripiprazole: a study based on therapeutic drug monitoring|2
01155|080|R|  data. Ther Drug Monit 2010 Dec;32(6):787-90.|2
01155|081|R|5.Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E.|2
01155|082|R|  Inhibition of risperidone metabolism by fluoxetine in patients with|2
01155|083|R|  schizophrenia: a clinically relevant pharmacokinetic drug interaction. J|2
01155|084|R|  Clin Psychopharmacol 2002 Aug;22(4):419-23.|2
01155|085|R|6.Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The|2
01155|086|R|  effect of fluoxetine on the pharmacokinetics and safety of risperidone in|2
01155|087|R|  psychiatric patients. Pharmacopsychiatry 2002 Mar;35(2):50-6.|2
01155|088|R|7.This information is based on an extract from the Certara Drug Interaction|6
01155|089|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01156|001|T|MONOGRAPH TITLE:  Interleukin-1 Blocker/Tumor Necrosis Factor (TNF)|
01156|002|T|Inhibitors|
01156|003|B||
01156|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01156|005|L|of severe adverse interaction.|
01156|006|B||
01156|007|A|MECHANISM OF ACTION:  Possibly additive or synergistic effects on the immune|
01156|008|A|system.|
01156|009|B||
01156|010|E|CLINICAL EFFECTS:  Concurrent use of anakinra, canakinumab, or rilonacept|
01156|011|E|and a tumor necrosis factor (TNF) inhibitor may increase the risk of severe|
01156|012|E|infection and/or neutropenia(1-9) without providing any clinical|
01156|013|E|benefit.(4-6)|
01156|014|B||
01156|015|P|PREDISPOSING FACTORS:  None determined.|
01156|016|B||
01156|017|M|PATIENT MANAGEMENT:  The US manufacturer of anakinra states that concurrent|
01156|018|M|use of anakinra with tumor necrosis factor (TNF) blocking agents|
01156|019|M|certolizumab, etanercept, and infliximab is not recommended.(1)|
01156|020|M|   The Canadian(2) and US(3) manufacturers of adalimumab, the US|
01156|021|M|manufacturer of certolizumab,(4) and the US manufacturer of golimumab,(4)|
01156|022|M|and the US manufacturer of infliximab(7) state that concurrent therapy with|
01156|023|M|anakinra is not recommended.|
01156|024|M|   The Australian manufacturers of infliximab, adalimumab, etanercept, and|
01156|025|M|golimumab state that concurrent use with anakinra is contraindicated.(11-14)|
01156|026|M|The Australian manufacturer of anakinra states that concurrent therapy with|
01156|027|M|TNF inhibitors is contraindicated.(15)|
01156|028|M|   The US manufacturers of rilonacept(8) and canakinumab(9) state that|
01156|029|M|concurrent use with TNF blocking agents is not recommended.|
01156|030|M|   Patients receiving concurrent therapy should be closely monitored for|
01156|031|M|signs of infection and neutropenia.(10)|
01156|032|B||
01156|033|D|DISCUSSION:  Preliminary data suggest a higher rate of serious infections|
01156|034|D|(7%) in patients treated concurrently with anakinra and etanercept compared|
01156|035|D|to when anakinra is administered alone (2%)(1) or when etanercept is|
01156|036|D|administered alone (0%).(5,8)  The most common infections were bacterial|
01156|037|D|pneumonia (4 cases) and cellulitis (4 cases).  One patient with pulmonary|
01156|038|D|fibrosis and pneumonia died from respiratory failure.(6)  Preliminary data|
01156|039|D|also suggest a higher rate of neutropenia (2-3%) when anakinra is|
01156|040|D|administered with etanercept.(1,6)  Data also suggest that the combination|
01156|041|D|provides no added clinical benefit.(6)|
01156|042|B||
01156|043|R|REFERENCES:|
01156|044|B||
01156|045|R|1.Kineret (anakinra) US prescribing information. Amgen Inc. May, 2016.|1
01156|046|R|2.Dear Canadian Healthcare Professional Letter.  Subject:  Updated safety|1
01156|047|R|  information on hematologic events associated with HUMIRA and the risk of|1
01156|048|R|  infections associated with the concurrent use of HUMIRA and anakinra.|1
01156|049|R|  Abbott Laboratories, Limited February 2, 2005.|1
01156|050|R|3.Humira (adalimumab) US prescribing information. Abbott Laboratories|1
01156|051|R|  December, 2018.|1
01156|052|R|4.Cimzia (certolizumab pegol) US prescribing information. UCB, Inc.|1
01156|053|R|  February, 2019.|1
01156|054|R|5.Simponi (golimumab) US prescribing information. Centocor Ortho Biotech|1
01156|055|R|  Inc. March, 2018.|1
01156|056|R|6.Enbrel (etanercept) US prescribing information. Amgen December, 2023.|1
01156|057|R|7.Remicade (infliximab) US prescribing information. Janssen Biotech, Inc.|1
01156|058|R|  May, 2020.|1
01156|059|R|8.Arcalyst (rilonacept) US prescribing information. Regeneron|1
01156|060|R|  Pharmaceuticals, Inc. March, 2021.|1
01156|061|R|9.Ilaris (canakinumab) US prescribing information. Novartis Pharmaceuticals|1
01156|062|R|  Corporation August, 2023.|1
01156|063|R|10.Enbrel (etanercept) Canadian prescribing information. Amgen July, 2007.|1
01156|064|R|11.Remsima (infliximab) Australian prescribing information. Celltrion|1
01156|065|R|   Healthcare Australia Pty Ltd Jan 3, 2024.|1
01156|066|R|12.Enbrel (etanercept) Australian prescribing information. Pfizer Australia|1
01156|067|R|   Pty Ltd May 13, 2024.|1
01156|068|R|13.Simponi (golimumab) Australian prescribing information. Janssen-Cilag Pty|1
01156|069|R|   Ltd Feb 8, 2021.|1
01156|070|R|14.Humira (adalimumab) Australian prescribing information. AbbVie Pty Ltd|1
01156|071|R|   Jan 8, 2025.|1
01156|072|R|15.Kineret (anakinra) Australian prescribing information. Swedish Orphan|1
01156|073|R|   Biovitrum Pty Ltd Dec 9, 2024.|1
01157|001|T|MONOGRAPH TITLE:  Eletriptan/Selected Macrolide; Ketolide Antibiotics|
01157|002|B||
01157|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01157|004|L|is contraindicated and generally should not be dispensed or administered to|
01157|005|L|the same patient.|
01157|006|B||
01157|007|A|MECHANISM OF ACTION:  Macrolide or ketolide antibiotics which are|
01157|008|A|moderately-strong to strong inhibitors of CYP3A4 may inhibit the metabolism|
01157|009|A|of eletriptan.(1-3)|
01157|010|B||
01157|011|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
01157|012|E|adverse effects from eletriptan.(1,2)|
01157|013|E|   Antibiotic agents linked to this monograph are clarithromycin,|
01157|014|E|erythromycin, josamycin, telithromycin and troleandomycin.|
01157|015|B||
01157|016|P|PREDISPOSING FACTORS:  None determined.|
01157|017|B||
01157|018|M|PATIENT MANAGEMENT:  The US manufacturer of eletriptan states that|
01157|019|M|eletriptan should not be used within at least 72 hours of treatment with|
01157|020|M|strong CYP3A4 inhibitors such as clarithromycin or troleandomycin.(2)  The|
01157|021|M|UK manufacturer of eletriptan states that eletriptan should not be used|
01157|022|M|together with clarithromycin, erythromycin, or josamycin.(1)|
01157|023|M|   If migraine treatment is needed during macrolide or ketolide antibiotic|
01157|024|M|therapy use triptans not metabolized by CYP3A4 such as frovatriptan,|
01157|025|M|sumatriptan, or zolmitriptan.(4-7)|
01157|026|B||
01157|027|D|DISCUSSION:  In a clinical study with a moderate to strong CYP3A4 inhibitor,|
01157|028|D|erythromycin 1000 mg increased the eletriptan maximum concentration (Cmax)|
01157|029|D|and area-under-curve (AUC) by 2-fold and 3.6-fold, respectively.  The|
01157|030|D|half-life of eletriptan increased from 4.6 hours to 7.1 hours.(1)|
01157|031|D|   In a clinical study with a strong CYP3A4 inhibitor, ketoconazole (400 mg)|
01157|032|D|increased the eletriptan maximum concentration (Cmax) and area-under-curve|
01157|033|D|(AUC) by 2.7-fold and 5.9-fold, respectively.  The half-life of eletriptan|
01157|034|D|increased from 4.8 hours to 8.3 hours.(1)  The time to Cmax (Tmax) increased|
01157|035|D|from 2.8 hours to 5.4 hours.(2)|
01157|036|B||
01157|037|R|REFERENCES:|
01157|038|B||
01157|039|R|1.Relpax (eletriptan hydrobromide) UK summary of product characteristics.|1
01157|040|R|  Pfizer Limited September, 2013.|1
01157|041|R|2.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
01157|042|R|  March, 2020.|1
01157|043|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01157|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01157|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01157|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01157|047|R|  11/14/2017.|1
01157|048|R|4.Imitrex Tablets (sumatriptan) US prescribing information. GlaxoSmithKline|1
01157|049|R|  December 14, 2017.|1
01157|050|R|5.Frova (frovatriptan) US prescribing information. Endo Pharmaceuticals|1
01157|051|R|  August, 2018.|1
01157|052|R|6.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
01157|053|R|  Pharmaceuticals LP September, 2012.|1
01157|054|R|7.Yu AM. Indolealkylamines: biotransformations and potential drug-drug|6
01157|055|R|  interactions. AAPS J 2008 Jun;10(2):242-53.|6
01158|001|T|MONOGRAPH TITLE:  Eletriptan/Selected Azole Antifungals|
01158|002|B||
01158|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01158|004|L|is contraindicated and generally should not be dispensed or administered to|
01158|005|L|the same patient.|
01158|006|B||
01158|007|A|MECHANISM OF ACTION:  Itraconazole, ketoconazole, posaconazole and|
01158|008|A|voriconazole are strong inhibitors of CYP3A4 and may inhibit the metabolism|
01158|009|A|of eletriptan via this pathway.(1-3)|
01158|010|B||
01158|011|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
01158|012|E|adverse effects from eletriptan.(1,2)|
01158|013|B||
01158|014|P|PREDISPOSING FACTORS:  None determined.|
01158|015|B||
01158|016|M|PATIENT MANAGEMENT:  The US manufacturer of eletriptan states that|
01158|017|M|eletriptan should not be used within at least 72 hours of administration of|
01158|018|M|a strong CYP3A4 inhibitor.(2)  The UK manufacturer of eletriptan states that|
01158|019|M|eletriptan should not be used together with itraconazole or ketoconazole.(1)|
01158|020|M|If migraine treatment is needed during azole antifungal therapy use|
01158|021|M|triptans not metabolized by CYP3A4 such as frovatriptan, sumatriptan, or|
01158|022|M|zolmitriptan.(4-7)|
01158|023|B||
01158|024|D|DISCUSSION:  In clinical studies, ketoconazole (400 mg) increased the|
01158|025|D|eletriptan maximum concentration (Cmax) and area-under-curve (AUC) by|
01158|026|D|2.7-fold and 5.9-fold, respectively.  The half-life of eletriptan increased|
01158|027|D|from 4.8 hours to 8.3 hours.(1)  The time to Cmax (Tmax) increased from 2.8|
01158|028|D|hours to 5.4 hours.(2)|
01158|029|B||
01158|030|R|REFERENCES:|
01158|031|B||
01158|032|R|1.Relpax (eletriptan hydrobromide) UK summary of product characteristics.|1
01158|033|R|  Pfizer Limited September, 2013.|1
01158|034|R|2.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
01158|035|R|  March, 2020.|1
01158|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01158|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01158|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01158|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01158|040|R|  11/14/2017.|1
01158|041|R|4.Frova (frovatriptan) US prescribing information. Endo Pharmaceuticals|1
01158|042|R|  August, 2018.|1
01158|043|R|5.Imitrex Tablets (sumatriptan) US prescribing information. GlaxoSmithKline|1
01158|044|R|  December 14, 2017.|1
01158|045|R|6.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
01158|046|R|  Pharmaceuticals LP September, 2012.|1
01158|047|R|7.Yu AM. Indolealkylamines: biotransformations and potential drug-drug|6
01158|048|R|  interactions. AAPS J 2008 Jun;10(2):242-53.|6
01159|001|T|MONOGRAPH TITLE:  Eletriptan/Selected Protease Inhibitors; Cobicistat|
01159|002|B||
01159|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01159|004|L|is contraindicated and generally should not be dispensed or administered to|
01159|005|L|the same patient.|
01159|006|B||
01159|007|A|MECHANISM OF ACTION:  Cobicistat or protease inhibitors which are strong|
01159|008|A|inhibitors of CYP3A4 may reduce the CYP3A4 mediated metabolism of|
01159|009|A|eletriptan.(1-6)|
01159|010|B||
01159|011|E|CLINICAL EFFECTS:  Concurrent use of eletriptan with strong inhibitors of|
01159|012|E|CYP3A4(1-7) may result in elevated levels of and adverse effects from|
01159|013|E|eletriptan.(1-6)|
01159|014|E|   Agents linked to this monograph are: atazanavir, boceprevir, cobicistat,|
01159|015|E|indinavir, lopinavir, nelfinavir, nirmatrelvir, paritaprevir, saquinavir,|
01159|016|E|telaprevir, and tipranavir.|
01159|017|B||
01159|018|P|PREDISPOSING FACTORS:  None determined.|
01159|019|B||
01159|020|M|PATIENT MANAGEMENT:  The US manufacturer of eletriptan states that|
01159|021|M|eletriptan should not be used within at least 72 hours of potent inhibitors|
01159|022|M|of CYP3A4.(2) The UK manufacturer of eletriptan states that eletriptan|
01159|023|M|should not be used together with indinavir, nelfinavir, or ritonavir.(1)|
01159|024|M|   If migraine treatment is needed during protease inhibitor therapy, use|
01159|025|M|triptans not metabolized by CYP3A4 such as frovatriptan, sumatriptan, or|
01159|026|M|zolmitriptan.(8-11)|
01159|027|B||
01159|028|D|DISCUSSION:  In a clinical trial, another strong CYP3A4 inhibitor|
01159|029|D|ketoconazole 400 mg, increased the eletriptan maximum concentration (Cmax)|
01159|030|D|and exposure (area-under-curve, AUC) by 2.7-fold and 5.9-fold, respectively.|
01159|031|D|The half-life of eletriptan increased from 4.8 hours to 8.3 hours.(1)|
01159|032|D|   In another trial, a high dose of a moderate to strong CYP3A4 inhibitor,|
01159|033|D|erythromycin (1000 mg), increased the eletriptan Cmax and AUC by 2-fold and|
01159|034|D|3.6-fold, respectively.  The half-life of eletriptan increased from 4.6|
01159|035|D|hours to 7.1 hours.(2)|
01159|036|B||
01159|037|R|REFERENCES:|
01159|038|B||
01159|039|R|1.Relpax (eletriptan hydrobromide) UK summary of product characteristics.|1
01159|040|R|  Pfizer Limited September, 2013.|1
01159|041|R|2.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
01159|042|R|  March, 2020.|1
01159|043|R|3.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
01159|044|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
01159|045|R|4.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
01159|046|R|  Incorporated October, 2013.|1
01159|047|R|5.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
01159|048|R|  January, 2017.|1
01159|049|R|6.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01159|050|R|  information. Pfizer Inc. February, 2025.|1
01159|051|R|7.This information is based on an extract from the Certara Drug Interaction|6
01159|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01159|053|R|8.Frova (frovatriptan) US prescribing information. Endo Pharmaceuticals|1
01159|054|R|  August, 2018.|1
01159|055|R|9.Imitrex Tablets (sumatriptan) US prescribing information. GlaxoSmithKline|1
01159|056|R|  December 14, 2017.|1
01159|057|R|10.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
01159|058|R|   Pharmaceuticals LP September, 2012.|1
01159|059|R|11.Yu AM. Indolealkylamines: biotransformations and potential drug-drug|6
01159|060|R|   interactions. AAPS J 2008 Jun;10(2):242-53.|6
01160|001|T|MONOGRAPH TITLE:  Eletriptan/St. John's Wort (mono deleted 03/17/2022)|
01160|002|B||
01160|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01160|004|L|Assess the risk to the patient and take action as needed.|
01160|005|B||
01160|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.(1)|
01160|007|B||
01160|008|E|CLINICAL EFFECTS:  Concurrent use may result in adverse effects from|
01160|009|E|eletriptan.(1)|
01160|010|B||
01160|011|P|PREDISPOSING FACTORS:  None determined.|
01160|012|B||
01160|013|M|PATIENT MANAGEMENT:  Patients receiving eletriptan should be cautioned that|
01160|014|M|undesirable eletriptan side effects may be more likely to occur if they are|
01160|015|M|using St. John's wort.|
01160|016|B||
01160|017|D|DISCUSSION:  The manufacturer states that undesirable side effects may be|
01160|018|D|more common during concurrent use of St. John's wort.(1)|
01160|019|B||
01160|020|R|REFERENCE:|
01160|021|B||
01160|022|R|1.Relpax (eletriptan hydrobromide) UK summary of product characteristics.|1
01160|023|R|  Pfizer Limited September, 2013.|1
01161|001|T|MONOGRAPH TITLE:  Droperidol/QT Prolonging Agents|
01161|002|B||
01161|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01161|004|L|is contraindicated and generally should not be dispensed or administered to|
01161|005|L|the same patient.|
01161|006|B||
01161|007|A|MECHANISM OF ACTION:  Droperidol has been shown to prolong the QTc interval.|
01161|008|A|Concurrent use with other agents that prolong the QTc interval may result in|
01161|009|A|additive effects on the QTc interval.(1)|
01161|010|B||
01161|011|E|CLINICAL EFFECTS:  The concurrent use of droperidol with other agents that|
01161|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01161|013|E|arrhythmias, including torsades de pointes.(1)|
01161|014|B||
01161|015|P|PREDISPOSING FACTORS:  Congestive heart failure, bradycardia, use of a|
01161|016|P|diuretic, cardiac hypertrophy, hypokalemia, hypomagnesemia, age over 65|
01161|017|P|years, alcohol abuse, and the use of agents such as benzodiazepines,|
01161|018|P|volatile anesthetics, and intravenous opiate may predispose patients to the|
01161|019|P|development of prolonged QT syndrome.(1)  Risk may also be increased in|
01161|020|P|patients with other cardiovascular diseases (e.g. myocardial infarction,|
01161|021|P|history of torsade de pointes, congenital long QT syndrome), hypocalcemia,|
01161|022|P|or female gender.(3)|
01161|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01161|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01161|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01161|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01161|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01161|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01161|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01161|030|B||
01161|031|M|PATIENT MANAGEMENT:  The manufacturer of droperidol states under precautions|
01161|032|M|drug interactions that drugs known to have the potential to prolong the QT|
01161|033|M|interval should not be used together with droperidol.(1)|
01161|034|B||
01161|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01161|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01161|037|D|monograph have been shown to prolong the QTc interval either through their|
01161|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01161|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01161|040|D|clinical trials and/or postmarketing reports.(2)|
01161|041|D|   One or more of the drug pairs linked to this monograph have been included|
01161|042|D|in a list of interactions that should be considered "high-priority" for|
01161|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01161|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01161|045|D|Coordinator (ONC) for Health Information Technology.|
01161|046|B||
01161|047|R|REFERENCES:|
01161|048|B||
01161|049|R|1.Inapsine (droperidol) US prescribing information. Akorn, Inc. November,|1
01161|050|R|  2001.|1
01161|051|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01161|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01161|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01161|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01161|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01161|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01161|057|R|  settings: a scientific statement from the American Heart Association and|6
01161|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01161|059|R|  2;55(9):934-47.|6
01161|060|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01161|061|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01161|062|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01161|063|R|  19(5):735-43.|6
01162|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Telithromycin|
01162|002|B||
01162|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01162|004|L|is contraindicated and generally should not be dispensed or administered to|
01162|005|L|the same patient.|
01162|006|B||
01162|007|A|MECHANISM OF ACTION:  Telithromycin may inhibit the metabolism of the ergot|
01162|008|A|alkaloids at CYP3A4.(1,2)|
01162|009|B||
01162|010|E|CLINICAL EFFECTS:  Concurrent use of telithromycin and an ergot alkaloid may|
01162|011|E|result in ergotism (severe vasoconstriction) with possible necrosis of the|
01162|012|E|extremities.(1,2)|
01162|013|B||
01162|014|P|PREDISPOSING FACTORS:  None determined.|
01162|015|B||
01162|016|M|PATIENT MANAGEMENT:  The UK manufacturer of telithromycin states that the|
01162|017|M|concurrent use of telithromycin and ergot alkaloids is contraindicated.(1)|
01162|018|M|The US manufacturer of telithromycin states that concurrent use is not|
01162|019|M|recommended.(2)|
01162|020|B||
01162|021|D|DISCUSSION:  Concurrent administration of macrolides such as erythromycin|
01162|022|D|and josamycin with ergot alkaloids has resulted in severe vasoconstriction|
01162|023|D|and necrosis of the extremities.  Telithromycin is a potent inhibitor of|
01162|024|D|CYP3A4.(1,2)|
01162|025|D|   One or more of the drug pairs linked to this monograph have been included|
01162|026|D|in a list of interactions that should be considered "high-priority" for|
01162|027|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01162|028|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01162|029|D|Coordinator (ONC) for Health Information Technology.(3)|
01162|030|B||
01162|031|R|REFERENCES:|
01162|032|B||
01162|033|R|1.Ketek (telithromycin) UK summary of product characteristics.|1
01162|034|R|  Sanofi-Aventis June 2, 2009.|1
01162|035|R|2.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01162|036|R|  November, 2015.|1
01162|037|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01162|038|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01162|039|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01162|040|R|  19(5):735-43.|6
01163|001|T|MONOGRAPH TITLE:  Selected HMG-CoA Reductase Inhibitors/Telithromycin|
01163|002|B||
01163|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01163|004|L|is contraindicated and generally should not be dispensed or administered to|
01163|005|L|the same patient.|
01163|006|B||
01163|007|A|MECHANISM OF ACTION:  Telithromycin may inhibit the metabolism of some|
01163|008|A|HMG-CoA reductase inhibitors by CYP3A4.(1-7)|
01163|009|B||
01163|010|E|CLINICAL EFFECTS:  Concurrent use of telithromycin with HMG-CoA reductase|
01163|011|E|inhibitors that are metabolized by CYP3A4 may result in elevated levels of|
01163|012|E|the HMG-CoA reductase inhibitor and myopathy.(1-7)|
01163|013|B||
01163|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01163|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01163|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01163|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01163|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01163|019|P|transporter OATP1B1 may have increased statin concentrations and be|
01163|020|P|predisposed to myopathy or rhabdomyolysis.|
01163|021|B||
01163|022|M|PATIENT MANAGEMENT:  Do not use atorvastatin,(1,2) lovastatin,(1-3) or|
01163|023|M|simvastatin(1,2,4-6) with telithromycin.  If telithromycin therapy cannot be|
01163|024|M|avoided, suspend statin therapy during the course of the antibiotic.(1-6)|
01163|025|M|   Cerivastatin should be used with caution during telithromycin therapy.|
01163|026|M|Patients receiving concurrent therapy with cerivastatin and telithromycin|
01163|027|M|should be carefully monitored and instructed to report any signs or symptoms|
01163|028|M|of myopathy.(7)|
01163|029|B||
01163|030|D|DISCUSSION:  Simultaneous administration of telithromycin and simvastatin|
01163|031|D|resulted in increases in the simvastatin area-under-curve (AUC) and maximum|
01163|032|D|concentration (Cmax) by 8.9-fold and 5.3-fold, respectively.  The AUC and|
01163|033|D|Cmax of simvastatin acid increased 12-fold and 15-fold, respectively.(1-3)|
01163|034|D|   Administration of telithromycin and simvastatin 12 hours apart resulted|
01163|035|D|in increases in the simvastatin AUC and Cmax by 4.0-fold and by 3.4-fold,|
01163|036|D|respectively.  The AUC and Cmax of simvastatin acid increased 4.3-fold and|
01163|037|D|3.2-fold, respectively.(2)|
01163|038|D|   One or more of the drug pairs linked to this monograph have been included|
01163|039|D|in a list of interactions that should be considered "high-priority" for|
01163|040|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01163|041|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01163|042|D|Coordinator (ONC) for Health Information Technology.|
01163|043|B||
01163|044|R|REFERENCES:|
01163|045|B||
01163|046|R|1.Ketek (telithromycin) UK summary of product characteristics.|1
01163|047|R|  Sanofi-Aventis June 2, 2009.|1
01163|048|R|2.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01163|049|R|  November, 2015.|1
01163|050|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01163|051|R|  February, 2014.|1
01163|052|R|4.USFood and Drug Administration. FDA Drug Safety Communication: New|1
01163|053|R|  restrictions, contraindications, and dose limitations for Zocor|1
01163|054|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
01163|055|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01163|056|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
01163|057|R|  June 8, 2011.|1
01163|058|R|5.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
01163|059|R|  2023.|1
01163|060|R|6.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
01163|061|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
01163|062|R|7.Baycol (cerivastatin) US prescribing information. Bayer Corporation|1
01163|063|R|  December, 2000.|1
01163|064|R|8.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01163|065|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01163|066|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01163|067|R|  19(5):735-43.|6
01164|001|T|MONOGRAPH TITLE:  Rifampin; Rifapentine/Clarithromycin; Erythromycin;|
01164|002|T|Telithromycin|
01164|003|B||
01164|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01164|005|L|of severe adverse interaction.|
01164|006|B||
01164|007|A|MECHANISM OF ACTION:  Rifampin and rifapentine may induce the metabolism of|
01164|008|A|clarithromycin, erythromycin, and telithromycin by CYP3A4.(1-5)|
01164|009|B||
01164|010|E|CLINICAL EFFECTS:  Concurrent use of rifampin or rifapentine may result in|
01164|011|E|decreased levels and effectiveness of clarithromycin, erythromycin, and|
01164|012|E|telithromycin.(1-5)|
01164|013|B||
01164|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01164|015|P|of the inducer for longer than 1-2 weeks.|
01164|016|B||
01164|017|M|PATIENT MANAGEMENT:  Concurrent use of rifampin or rifapentine with|
01164|018|M|clarithromycin should be approached with caution and may require|
01164|019|M|clarithromycin dose adjustment.(1)  Consideration of alternative therapies|
01164|020|M|to rifamycins may be required.(1-2)|
01164|021|M|   The UK manufacturer of erythromycin states erythromycin should not be|
01164|022|M|used during and two weeks after treatment with CYP3A4 inducers.(3)|
01164|023|M|   Concurrent treatment of rifampin or rifapentine with telithromycin should|
01164|024|M|be avoided.(4-5)  The UK manufacturer of telithromycin states that treatment|
01164|025|M|with telithromycin should be avoided during and for two weeks after|
01164|026|M|treatment with rifampin.(4)|
01164|027|M|   If concurrent use cannot be avoided, monitor patients receiving|
01164|028|M|concurrent therapy for decreased antibiotic efficacy.|
01164|029|B||
01164|030|D|DISCUSSION:  Clarithromycin and its active metabolite (14-OH-clarithromycin)|
01164|031|D|have different microbiologic activities.  Induction of clarithromycin|
01164|032|D|metabolism lowers clarithromycin exposure while increasing the active|
01164|033|D|metabolite exposure.  Depending on the infection being treated, CYP3A4|
01164|034|D|inducers may or may not have an impact on therapeutic efficacy.(2)|
01164|035|D|   Concurrent use of telithromycin with rifampin decreased the maximum|
01164|036|D|concentration (Cmax) and area-under-curve (AUC) of telithromycin by 79% and|
01164|037|D|by 86%, respectively.(5)|
01164|038|D|   The induction effect decreases during the two weeks following the|
01164|039|D|discontinuation of the inducer.(4)|
01164|040|B||
01164|041|R|REFERENCES:|
01164|042|B||
01164|043|R|1.Clarithromycin UK Summary of Product Characteristics. Ranbaxy (UK) Limited|1
01164|044|R|  January 26, 2022.|1
01164|045|R|2.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
01164|046|R|  September, 2019.|1
01164|047|R|3.Erythrocin (erythromycin) UK prescribing information. ADVANZ Pharma|1
01164|048|R|  February 2023.|1
01164|049|R|4.Ketek (telithromycin) UK summary of product characteristics.|1
01164|050|R|  Sanofi-Aventis June 2, 2009.|1
01164|051|R|5.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01164|052|R|  November, 2015.|1
01164|053|R|6.Hafner R, Bethel J, Power M, Landry B, Banach M, Mole L, Standiford HC,|2
01164|054|R|  Follansbee S, Kumar P, Raasch R, Cohn D, Mushatt D, Drusano G. Tolerance|2
01164|055|R|  and pharmacokinetic interactions of rifabutin and clarithromycin in human|2
01164|056|R|  immunodeficiency virus-infected volunteers. Antimicrob Agents Chemother|2
01164|057|R|  1998 Mar;42(3):631-9.|2
01165|001|T|MONOGRAPH TITLE:  Selected Anticonvulsants; Barbiturates/Telithromycin|
01165|002|B||
01165|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01165|004|L|of severe adverse interaction.|
01165|005|B||
01165|006|A|MECHANISM OF ACTION:  Barbiturates, phenobarbital, primidone, and phenytoin|
01165|007|A|may induce the metabolism of telithromycin by CYP3A4.(1,2)|
01165|008|B||
01165|009|E|CLINICAL EFFECTS:  Concurrent use of barbiturates, phenobarbital, primidone|
01165|010|E|or phenytoin with telithromycin may result in decreased levels and|
01165|011|E|effectiveness of telithromycin.(1,2)|
01165|012|B||
01165|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01165|014|P|of the inducer for longer than 1-2 weeks.|
01165|015|B||
01165|016|M|PATIENT MANAGEMENT:  The UK manufacturer of telithromycin states that|
01165|017|M|treatment with telithromycin should be avoided during and for two weeks|
01165|018|M|after treatment with phenobarbital, primidone or phenytoin.(1)|
01165|019|M|   The US manufacturer of telithromycin states that concurrent use should be|
01165|020|M|avoided with phenobarbital, primidone or phenytoin.(2)|
01165|021|B||
01165|022|D|DISCUSSION:  Concurrent use of telithromycin with potent CYP3A4 inducers|
01165|023|D|such as phenytoin could result in major reductions of telithromycin plasma|
01165|024|D|concentrations and decreased telithromycin clinical effectiveness.  The|
01165|025|D|induction effect decreases during the two weeks following the|
01165|026|D|discontinuation of the inducer.(1)|
01165|027|B||
01165|028|R|REFERENCES:|
01165|029|B||
01165|030|R|1.Ketek (telithromycin) UK summary of product characteristics.|1
01165|031|R|  Sanofi-Aventis June 2, 2009.|1
01165|032|R|2.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01165|033|R|  November, 2015.|1
01166|001|T|MONOGRAPH TITLE:  St. John's Wort/Telithromycin|
01166|002|B||
01166|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01166|004|L|of severe adverse interaction.|
01166|005|B||
01166|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01166|007|A|telithromycin by CYP P-450-3A4.(1)|
01166|008|B||
01166|009|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort with telithromycin may|
01166|010|E|result in decreased levels and effectiveness of telithromycin.(1)|
01166|011|B||
01166|012|P|PREDISPOSING FACTORS:  None determined.|
01166|013|B||
01166|014|M|PATIENT MANAGEMENT:  The UK manufacturer of telithromycin states that|
01166|015|M|treatment with telithromycin should be avoided during and for two weeks|
01166|016|M|after treatment with St. John's wort.(1)|
01166|017|B||
01166|018|D|DISCUSSION:  Concurrent use of telithromycin with potent CYP P-450-3A4|
01166|019|D|inducers such as St. John's wort could result in major reductions of|
01166|020|D|telithromycin plasma concentrations and decreased telithromycin clinical|
01166|021|D|effectiveness. The induction effect decreases during the two weeks following|
01166|022|D|the discontinuation of the inducer.(1)|
01166|023|B||
01166|024|R|REFERENCE:|
01166|025|B||
01166|026|R|1.Ketek (telithromycin) UK summary of product characteristics.|1
01166|027|R|  Sanofi-Aventis June 2, 2009.|1
01167|001|T|MONOGRAPH TITLE:  Sertindole/QT Prolonging Agents|
01167|002|B||
01167|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01167|004|L|is contraindicated and generally should not be dispensed or administered to|
01167|005|L|the same patient.|
01167|006|B||
01167|007|A|MECHANISM OF ACTION:  Sertindole has been shown to prolong the QTc interval.|
01167|008|A|Concurrent use with other agents that prolong the QTc interval may result in|
01167|009|A|additive effects on the QTc interval.(1)|
01167|010|B||
01167|011|E|CLINICAL EFFECTS:  The concurrent use of sertindole with other agents that|
01167|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01167|013|E|arrhythmias, including torsades de pointes.(1)|
01167|014|B||
01167|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01167|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01167|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01167|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01167|019|P|gender, or advanced age.(3)|
01167|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01167|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01167|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01167|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01167|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01167|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01167|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01167|027|B||
01167|028|M|PATIENT MANAGEMENT:  The manufacturer of sertindole states that sertindole|
01167|029|M|is contraindicated in patients receiving drugs known to prolong the QT|
01167|030|M|interval.(1)|
01167|031|B||
01167|032|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01167|033|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01167|034|D|monograph have been shown to prolong the QTc interval either through their|
01167|035|D|mechanism of action, through studies on their effects on the QTc interval,|
01167|036|D|or through reports of QTc prolongation and/or torsades de pointes in|
01167|037|D|clinical trials and/or postmarketing reports.(2)|
01167|038|B||
01167|039|R|REFERENCES:|
01167|040|B||
01167|041|R|1.Serdolect (sertindole) UK summary of product characteristics. Lundbeck|1
01167|042|R|  Limited October 25, 1996.|1
01167|043|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01167|044|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01167|045|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01167|046|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01167|047|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01167|048|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01167|049|R|  settings: a scientific statement from the American Heart Association and|6
01167|050|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01167|051|R|  2;55(9):934-47.|6
01167|052|R|4.Serdolect (sertindole) Sweden Summary of Product Characteristics. H.|1
01167|053|R|  Lundbeck A S March 4, 2021.|1
01168|001|T|MONOGRAPH TITLE:  Vitamin A/Selected Retinoids|
01168|002|B||
01168|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01168|004|L|of severe adverse interaction.|
01168|005|B||
01168|006|A|MECHANISM OF ACTION:  The retinoids are structurally related to vitamin A.|
01168|007|A|(1-6)|
01168|008|B||
01168|009|E|CLINICAL EFFECTS:  Concurrent use of retinoids with vitamin A supplements|
01168|010|E|may result in signs of vitamin A toxicity.(1-6)  Symptoms of vitamin A|
01168|011|E|toxicity include nausea, vomiting, loss of appetite, weakness, dry or itchy|
01168|012|E|skin or lips, irritability, and hair loss.|
01168|013|B||
01168|014|P|PREDISPOSING FACTORS:  None determined.|
01168|015|B||
01168|016|M|PATIENT MANAGEMENT:  The manufacturer of acitretin states that concomitant|
01168|017|M|use of vitamin A supplements should be avoided.(1)|
01168|018|M|   The manufacturer of bexarotene states that patients should be advised to|
01168|019|M|limit vitamin A supplements.  In clinical studies, patients were advised to|
01168|020|M|limit their vitamin A intake to less than or equal to 15,000 International|
01168|021|M|Units/day.(2)|
01168|022|M|   The manufacturer of isotretinoin states that patients should be advised|
01168|023|M|against taking vitamin A supplements.(3)|
01168|024|M|   The manufacturer of palovarotene states that concomitant use of vitamin A|
01168|025|M|must be avoided.(4)|
01168|026|M|   The manufacturer of tretinoin states that tretinoin must not be|
01168|027|M|administered in combination with vitamin A.(5)|
01168|028|M| The UK manufacturer of alitretinoin states that tretinoin must not be|
01168|029|M|administered in combination with vitamin A.(6)|
01168|030|B||
01168|031|D|DISCUSSION:  The retinoids are structurally related to vitamin A.  The|
01168|032|D|concurrent use of retinoids with vitamin A may result in signs and symptoms|
01168|033|D|of vitamin A toxicity.(1-6)|
01168|034|B||
01168|035|R|REFERENCES:|
01168|036|B||
01168|037|R|1.Soriatane (acitretin) US prescribing information. Roche Pharmaceuticals|1
01168|038|R|  February, 2014.|1
01168|039|R|2.Targretin (bexarotene) Capsules US prescribing information. Valeant|1
01168|040|R|  Pharmaceuticals North America LLC July, 2015.|1
01168|041|R|3.Accutane (isotretinoin) US prescribing information. Roche Laboratories,|1
01168|042|R|  Inc. January, 2010.|1
01168|043|R|4.Sohonos (palovarotene) Canadian Product Monograph. Ipsen|1
01168|044|R|  Biopharmaceuticals Canada Inc. January, 2022.|1
01168|045|R|5.Vesanoid (tretinoin) US prescribing information. Roche Laboratories, Inc.|1
01168|046|R|  February, 2023.|1
01168|047|R|6.Toctino (alitretinoin) UK summary of product characteristics. Basilea|1
01168|048|R|  Pharmaceuticals Ltd September 19, 2008.|1
01169|001|T|MONOGRAPH TITLE:  Lithium/SSRIs; SNRIs (mono deleted 05/26/2022)|
01169|002|B||
01169|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01169|004|L|take action as needed.|
01169|005|B||
01169|006|A|MECHANISM OF ACTION:  The combination of lithium with the selective|
01169|007|A|serotonin reuptake inhibitors or serotonin norepinephrine reuptake|
01169|008|A|inhibitors may have additive effects on serotonin levels.|
01169|009|B||
01169|010|E|CLINICAL EFFECTS:  Some patients may develop an increase in serotonergic|
01169|011|E|activity in the CNS, which could result in serotonin syndrome. Symptoms of|
01169|012|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
01169|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(15)|
01169|014|B||
01169|015|P|PREDISPOSING FACTORS:  Use of multiple drugs which increase serotonin|
01169|016|P|levels.(15)|
01169|017|B||
01169|018|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
01169|019|M|observed for signs of increased serotonergic side effects.  When clinically|
01169|020|M|appropriate, consider monitoring serum concentrations of one or both|
01169|021|M|medicines for toxicity.|
01169|022|M|   Counsel patients to report new or worsening muscle twitching, tremors,|
01169|023|M|shivering or stiffness, fever, heavy sweating, heart palpitations,|
01169|024|M|restlessness, confusion, agitation, decreased coordination, or severe|
01169|025|M|diarrhea.|
01169|026|M|   Lithium and SSRIs or SNRIs have been used together and found to be|
01169|027|M|effective in the treatment of affective disorders (e.g. depression, bipolar|
01169|028|M|disorder).  Although toxicity has been reported, based upon the long history|
01169|029|M|of concomitant use, and evaluation of cases and interaction studies, the|
01169|030|M|likelihood of a drug-drug interaction appears to be uncommon, perhaps|
01169|031|M|rare.(16)|
01169|032|B||
01169|033|D|DISCUSSION:  Lithium and SSRIs or SNRIs have been used together and found to|
01169|034|D|be effective in the treatment of affective disorders (e.g. depression,|
01169|035|D|bipolar disorder).|
01169|036|D|   Although toxicity has been reported, based upon cases and interaction|
01169|037|D|studies the likelihood of a drug-drug interaction appears to be uncommon,|
01169|038|D|perhaps rare.(16)  Some of the reported cases may represent drug-disease|
01169|039|D|interactions (e.g. mania with lithium and antidepressant).|
01169|040|D|   There is one report of serotonin syndrome one week after the addition of|
01169|041|D|lithium to fluoxetine therapy.  The patient had taken fluoxetine for three|
01169|042|D|months with no adverse effects.(1)  In another report, a patient with|
01169|043|D|previously stable lithium levels over a 20-year period developed elevated|
01169|044|D|lithium levels and signs of lithium toxicity following the addition of|
01169|045|D|fluoxetine to his regimen.(2)  In another report, a patient developed|
01169|046|D|absence seizures following the addition of fluoxetine to lithium.(3)  Other|
01169|047|D|reports describe mania(4) and encephalopathy(5) during concurrent lithium|
01169|048|D|and fluoxetine.   In contrast, a study in 10 subjects found that concurrent|
01169|049|D|fluoxetine and lithium decreased the maximum concentration (Cmax) of|
01169|050|D|lithium; however, there were no significant effects on lithium|
01169|051|D|area-under-curve (AUC), total clearance, or renal clearance.(6)|
01169|052|D|   There is one report of serotonin syndrome with concurrent fluvoxamine and|
01169|053|D|lithium.  The patient had been treated with lithium for nine years.  She|
01169|054|D|developed serotonin syndrome after 10 days of concurrent therapy.  There was|
01169|055|D|no change in her lithium serum levels.(7)  Another report described|
01169|056|D|somnolence during concurrent fluvoxamine and lithium.(8)|
01169|057|D|   There is one report of serotonin syndrome with concurrent paroxetine and|
01169|058|D|lithium.  The patient had been on paroxetine for three weeks when lithium|
01169|059|D|was added.  She developed symptoms of serotonin syndrome six days later. Her|
01169|060|D|paroxetine level was found to be 690 ng/ml (normal range, 80-115 ng/ml).|
01169|061|D|Paroxetine was reduced from 30 mg/day to 10 mg/day and her symptoms resolved|
01169|062|D|in five days.  Her paroxetine level at that time was 390 ng/ml.  She had|
01169|063|D|previously taken lithium for 21 years with no adverse effects.(9)  A study|
01169|064|D|in 14 depressed patients found an increase in tremors following the addition|
01169|065|D|of paroxetine to lithium therapy.(10)|
01169|066|D|   There is one report of priapism occurring in a patient with sexual|
01169|067|D|dysfunction during concurrent sertraline and lithium.  The patient had been|
01169|068|D|maintained on sertraline (50 mg/day) with lithium for one year.  Two weeks|
01169|069|D|after the dose of sertraline was increased to 100 mg/day, the patient|
01169|070|D|presented with priapism, which was treated with phenylephrine.(11)  A study|
01169|071|D|in eight subjects found that concurrent sertraline had no effect on lithium|
01169|072|D|pharmacokinetics; however, seven of the subjects reported side effects that|
01169|073|D|are usually associated with lithium toxicity.(12)|
01169|074|D|   There is one report of serotonin syndrome during concurrent venlafaxine|
01169|075|D|and lithium.  The patient had previously taken lithium with no adverse|
01169|076|D|effects.(13)|
01169|077|D|   There is one report of serotonin syndrome during therapy with|
01169|078|D|vortioxetine.  Vortioxetine was discontinued and the patient was treated|
01169|079|D|with cyproheptadine with resolution of symptoms.(18)|
01169|080|B||
01169|081|R|REFERENCES:|
01169|082|B||
01169|083|R|1.Muly EC, McDonald W, Steffens D, Book S. Serotonin syndrome produced by a|3
01169|084|R|  combination of fluoxetine and lithium. Am J Psychiatry 1993 Oct;|3
01169|085|R|  150(10):1565.|3
01169|086|R|2.Salama AA, Shafey M. A case of severe lithium toxicity induced by combined|3
01169|087|R|  fluoxetine and lithium carbonate. Am J Psychiatry 1989 Feb;146(2):278.|3
01169|088|R|3.Sacristan JA, Iglesias C, Arellano F, Lequerica J. Absence seizures|3
01169|089|R|  induced by lithium: possible interaction with fluoxetine. Am J Psychiatry|3
01169|090|R|  1991 Jan;148(1):146-7.|3
01169|091|R|4.Hadley A, Cason MP. Mania resulting from lithium-fluoxetine combination.|3
01169|092|R|  Am J Psychiatry 1989 Dec;146(12):1637-8.|3
01169|093|R|5.Noveske FG, Hahn KR, Flynn RJ. Possible toxicity of combined fluoxetine|3
01169|094|R|  and lithium. Am J Psychiatry 1989 Nov;146(11):1515.|3
01169|095|R|6.Breuel HP, Muller-Oerlinghausen B, Nickelsen T, Heine PR. Pharmacokinetic|2
01169|096|R|  interactions between lithium and fluoxetine after single and repeated|2
01169|097|R|  fluoxetine administration in young healthy volunteers. Int J Clin|2
01169|098|R|  Pharmacol Ther 1995 Jul;33(7):415-9.|2
01169|099|R|7.Ohman R, Spigset O. Serotonin syndrome induced by fluvoxamine-lithium|3
01169|100|R|  interaction. Pharmacopsychiatry 1993 Nov;26(6):263-4.|3
01169|101|R|8.Evans M, Marwick P. Fluvoxamine and lithium: an unusual interaction. Br J|3
01169|102|R|  Psychiatry 1990 Feb;156:286.|3
01169|103|R|9.Sobanski T, Bagli M, Laux G, Rao ML. Serotonin syndrome after lithium|3
01169|104|R|  add-on medication to paroxetine. Pharmacopsychiatry 1997 May;30(3):106-7.|3
01169|105|R|10.Zaninelli R, Bauer M, Jobert M, Muller-Oerlinghausen B. Changes in|2
01169|106|R|   quantitatively assessed tremor during treatment of major depression with|2
01169|107|R|   lithium augmented by paroxetine or amitriptyline. J Clin Psychopharmacol|2
01169|108|R|   2001 Apr;21(2):190-8.|2
01169|109|R|11.Mendelson WB, Franko T. Priapism with sertraline and lithium. J Clin|3
01169|110|R|   Psychopharmacol 1994 Dec;14(6):434-5.|3
01169|111|R|12.Apseloff G, Wilner KD, von Deutsch DA, Henry EB, Tremaine LM, Gerber N,|2
01169|112|R|   Lazar JD. Sertraline does not alter steady-state concentrations or renal|2
01169|113|R|   clearance of lithium in healthy volunteers. J Clin Pharmacol 1992 Jul;|2
01169|114|R|   32(7):643-6.|2
01169|115|R|13.Mekler G, Woggon B. A case of serotonin syndrome caused by venlafaxine|3
01169|116|R|   and lithium. Pharmacopsychiatry 1997 Nov;30(6):272-3.|3
01169|117|R|14.Savella (milnacipran hydrochloride) US prescribing information. Forest|1
01169|118|R|   Pharmaceuticals, Inc. September, 2021.|1
01169|119|R|15.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01169|120|R|   352(11):1112-20.|6
01169|121|R|16.Finley PR. Drug Interactions with Lithium: An Update. Clin Pharmacokinet|6
01169|122|R|   2016 Aug;55(8):925-41.|6
01169|123|R|17.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
01169|124|R|   and Company September, 2021.|1
01169|125|R|18.Ong CY, Vasanwala FF. Diaphoresis: A Presentation of Serotonin Syndrome|3
01169|126|R|   From Vortioxetine..|3
01170|001|T|MONOGRAPH TITLE:  Anastrozole; Letrozole/Tamoxifen|
01170|002|B||
01170|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01170|004|L|is contraindicated and generally should not be dispensed or administered to|
01170|005|L|the same patient.|
01170|006|B||
01170|007|A|MECHANISM OF ACTION:  Tamoxifen may induce the metabolism of anastrozole(1)|
01170|008|A|and letrozole(2) by induction of CYP3A4.|
01170|009|B||
01170|010|E|CLINICAL EFFECTS:  Concurrent use of tamoxifen may result in decreased|
01170|011|E|plasma levels and effectiveness of anastrozole(1,3) and letrozole.(2,3)|
01170|012|B||
01170|013|P|PREDISPOSING FACTORS:  None determined.|
01170|014|B||
01170|015|M|PATIENT MANAGEMENT:  The manufacturers of anastrozole(1) and tamoxifen(3)|
01170|016|M|state that these agents should not be coadministered.|
01170|017|M|   The manufacturer of letrozole does not recommend concurrent therapy with|
01170|018|M|tamoxifen(4) and the manufacturer of tamoxifen states they should not be|
01170|019|M|used concurrently.(3)  Patients may benefit more from sequential therapy,|
01170|020|M|rather than concurrent therapy.(2,5)|
01170|021|B||
01170|022|D|DISCUSSION:  Based on clinical and pharmacokinetic data from the ATAC trial,|
01170|023|D|tamoxifen should not be administered with anastrozole.  Concurrent use|
01170|024|D|decreased anastrozole plasma levels by 27%.  The combination had no efficacy|
01170|025|D|benefit when compared to tamoxifen administration alone.  Tamoxifen|
01170|026|D|pharmacokinetics were not affected.(1,3)|
01170|027|D|   A study in 12 subjects examined the concurrent administration of|
01170|028|D|tamoxifen and letrozole for six weeks.  Concurrent use decreased the mean|
01170|029|D|concentration of letrozole by 37.6%.(3,4)  Although suppression of|
01170|030|D|estradiol, estrone, and estrone sulfate were not effected, the authors|
01170|031|D|speculated that patients may not receive the full benefit of combination|
01170|032|D|therapy.(4)  A study in 23 patients found that letrozole had no effect on|
01170|033|D|tamoxifen levels. However, the antitumor effects of combination therapy were|
01170|034|D|less than expected.(6)  The therapeutic effect of letrozole is not affected|
01170|035|D|if letrozole is administered immediately after tamoxifen.(5)|
01170|036|B||
01170|037|R|REFERENCES:|
01170|038|B||
01170|039|R|1.Antoniou T, Tseng AL. Interactions between antiretrovirals and|6
01170|040|R|  antineoplastic drug therapy. Clin Pharmacokinet 2005;44(2):111-45.|6
01170|041|R|2.Arimidex (anastrozole) US prescribing information. AstraZeneca|1
01170|042|R|  Pharmaceuticals LP May, 2013.|1
01170|043|R|3.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
01170|044|R|  US Inc. September 25, 2018.|1
01170|045|R|4.Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA,|2
01170|046|R|  Gundacker H, Sioufi A, Smith IE. Impact of tamoxifen on the|2
01170|047|R|  pharmacokinetics and endocrine effects of the aromatase inhibitor|2
01170|048|R|  letrozole in postmenopausal women with breast cancer. Clin Cancer Res 1999|2
01170|049|R|  Sep;5(9):2338-43.|2
01170|050|R|5.Weiss L. Personnal communication. Novartis Pharmaceuticals Corporation|1
01170|051|R|  January 3, 2002.|1
01170|052|R|6.Femara (letrozole) US prescribing information. Novartis Pharmaceuticals|1
01170|053|R|  Corporation September, 2017.|1
01170|054|R|7.Dowsett M, Cuzick J, Howell A, Jackson I. Pharmacokinetics of anastrozole|2
01170|055|R|  and tamoxifen alone, and in combination, during adjuvant endocrine therapy|2
01170|056|R|  for early breast cancer in postmenopausal women: a sub-protocol of the|2
01170|057|R|  'Arimidex and tamoxifen alone or in combination' (ATAC) trial. Br J Cancer|2
01170|058|R|  2001 Aug 3;85(3):317-24.|2
01170|059|R|8.Dowsett M, Tobias JS, Howell A, Blackman GM, Welch H, King N, Ponzone R,|2
01170|060|R|  von Euler M, Baum M. The effect of anastrozole on the pharmacokinetics of|2
01170|061|R|  tamoxifen in post-menopausal women with early breast cancer. Br J Cancer|2
01170|062|R|  1999 Jan;79(2):311-5.|2
01170|063|R|9.Bonanni B, Serrano D, Gandini S, Guerrieri-Gonzaga A, Johansson H, Macis|2
01170|064|R|  D, Cazzaniga M, Luini A, Cassano E, Oldani S, Lien EA, Pelosi G, Decensi|2
01170|065|R|  A. Randomized biomarker trial of anastrozole or low-dose tamoxifen or|2
01170|066|R|  their combination in subjects with breast intraepithelial neoplasia. Clin|2
01170|067|R|  Cancer Res 2009 Nov 15;15(22):7053-60.|2
01170|068|R|10.Ingle JN, Suman VJ, Johnson PA, Krook JE, Mailliard JA, Wheeler RH,|2
01170|069|R|   Loprinzi CL, Perez EA, Jordan VC, Dowsett M. Evaluation of tamoxifen plus|2
01170|070|R|   letrozole with assessment of pharmacokinetic interaction in|2
01170|071|R|   postmenopausal women with metastatic breast cancer. Clin Cancer Res 1999|2
01170|072|R|   Jul;5(7):1642-9.|2
01171|001|T|MONOGRAPH TITLE:  BCG Vaccines/Mefloquine|
01171|002|B||
01171|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01171|004|L|is contraindicated and generally should not be dispensed or administered to|
01171|005|L|the same patient.|
01171|006|B||
01171|007|A|MECHANISM OF ACTION:  Mefloquine may attenuate the immunization response to|
01171|008|A|vaccines with attenuated live bacteria, such as BCG vaccine.(1)|
01171|009|B||
01171|010|E|CLINICAL EFFECTS:  Concurrent use may make the vaccine ineffective.(1)|
01171|011|B||
01171|012|P|PREDISPOSING FACTORS:  None determined.|
01171|013|B||
01171|014|M|PATIENT MANAGEMENT:  The manufacturer of mefloquine states that vaccinations|
01171|015|M|with vaccines containing attenuated live bacteria should be completed three|
01171|016|M|days before the initiation of mefloquine.(1)|
01171|017|B||
01171|018|D|DISCUSSION:  The manufacturer of mefloquine states that attenuation of|
01171|019|D|immunization response to vaccines with attenuated live bacteria cannot be|
01171|020|D|excluded and therefore the manufacturer of mefloquine states that|
01171|021|D|vaccinations with vaccines containing attenuated live bacteria should be|
01171|022|D|completed three days before the initiation of mefloquine.(1)|
01171|023|B||
01171|024|R|REFERENCE:|
01171|025|B||
01171|026|R|1.Lariam (mefloquine hydrochloride) US prescribing information. Roche|1
01171|027|R|  Pharmaceuticals August, 2009.|1
01172|001|T|MONOGRAPH TITLE:  Penicillamine/Gold Salts|
01172|002|B||
01172|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01172|004|L|is contraindicated and generally should not be dispensed or administered to|
01172|005|L|the same patient.|
01172|006|B||
01172|007|A|MECHANISM OF ACTION:  Both agents have similar hematologic and renal adverse|
01172|008|A|effects.(1)|
01172|009|B||
01172|010|E|CLINICAL EFFECTS:  Concurrent use may result in hematologic and/or renal|
01172|011|E|toxicity.(1)|
01172|012|B||
01172|013|P|PREDISPOSING FACTORS:  None determined.|
01172|014|B||
01172|015|M|PATIENT MANAGEMENT:  The manufacturers of penicillamine(1) and|
01172|016|M|aurothioglucose(2) state that penicillamine and gold salts should not be|
01172|017|M|used simultaneously.|
01172|018|B||
01172|019|D|DISCUSSION:  Because penicillamine and the gold salts have similar|
01172|020|D|hematologic and renal adverse effects, the manufacturers of penicillamine(1)|
01172|021|D|and aurothioglucose(2) state that penicillamine and gold salts should not be|
01172|022|D|used simultaneously.  Penicillamine has been shown not to chelate gold to a|
01172|023|D|significant extent.(3-5)|
01172|024|B||
01172|025|R|REFERENCES:|
01172|026|B||
01172|027|R|1.Cuprimine (penicillamine) US prescribing information. Merck & Co., Inc.|1
01172|028|R|  March, 2004.|1
01172|029|R|2.Solganal (aurothioglucose) US prescribing information. Schering-Plough|1
01172|030|R|  Corporation March, 1996.|1
01172|031|R|3.Aaron S, Davis P, Biggs D. D-penicillamine does not chelate gold. J|2
01172|032|R|  Rheumatol 1984 Dec;11(6):869-70.|2
01172|033|R|4.Kean W, Lock CJ. Penicillamine does not chelate gold (I). J Rheumatol 1983|2
01172|034|R|  Aug;10(4):527-30.|2
01172|035|R|5.Davis P, Barraclough D. Interaction of D-penicillamine with gold salts: in|2
01172|036|R|  vivo studies on gold chelation and in vitro studies on protein binding.|2
01172|037|R|  Arthritis Rheum 1977 Sep-Oct;20(7):1413-8.|2
01173|001|T|MONOGRAPH TITLE:  Antifibrinolytics/Factor IX; Anti-Inhibitor Coagulant Conc|
01173|002|B||
01173|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01173|004|L|is contraindicated and generally should not be dispensed or administered to|
01173|005|L|the same patient.|
01173|006|B||
01173|007|A|MECHANISM OF ACTION:  Concurrent use may result in additive or synergistic|
01173|008|A|effects on the coagulation pathways.(1-3)|
01173|009|B||
01173|010|E|CLINICAL EFFECTS:  Concurrent use may result in thrombosis.(1-3)|
01173|011|B||
01173|012|P|PREDISPOSING FACTORS:  None determined.|
01173|013|B||
01173|014|M|PATIENT MANAGEMENT:  The manufacturer of aminocaproic acid states that|
01173|015|M|aminocaproic acid should not be administered concomitantly with Factor IX|
01173|016|M|Complex concentrates or with Anti-inhibitor Coagulant concentrates.(1)|
01173|017|M|   The manufacturer of tranexamic acid states that tranexamic acid should|
01173|018|M|not be administered concomitantly with Factor IX Complex concentrates or|
01173|019|M|with Anti-inhibitor Coagulant concentrates.(2,3)|
01173|020|M|   Concurrent use may be warranted in select patients with hemophilia A or|
01173|021|M|hemophilia B.  Monitor patients closely for signs of thrombosis,|
01173|022|M|disseminated intravascular coagulation, and hypercoagulability if concurrent|
01173|023|M|use is deemed necessary.(4-6)|
01173|024|B||
01173|025|D|DISCUSSION:  Because of the increased risk of thrombosis, the manufacturer|
01173|026|D|of aminocaproic acid states that aminocaproic acid should not be|
01173|027|D|administered concomitantly with Factor IX Complex concentrates or with|
01173|028|D|Anti-inhibitor Coagulant concentrates.(1)|
01173|029|D|   Because of the increased risk of thrombosis, the manufacturer of|
01173|030|D|tranexamic acid states that tranexamic acid should not be administered|
01173|031|D|concomitantly with Factor IX Complex concentrates or with Anti-inhibitor|
01173|032|D|Coagulant concentrates.(2,3)|
01173|033|D|   In a study, eight hemophilia B patients undergoing dental extraction|
01173|034|D|procedures received combination therapy with aminocaproic acid or tranexamic|
01173|035|D|acid and monoclonal antibody purified factor IX for bleeding prophylaxis.|
01173|036|D|All patients achieved hemostasis without clinical evidence of thrombosis as|
01173|037|D|well as no changes were seen in hemoglobin, hematocrit, or in markers of|
01173|038|D|hemostatic system activation.(4)|
01173|039|D|   In a study, seven hemophilia A patients with inhibitors and one with|
01173|040|D|acquired hemophilia patient received activated prothrombin complex|
01173|041|D|concentrate (APCC) and tranexamic acid for management of bleeding episodes|
01173|042|D|and prevention of hemorrhage during surgery.  Hemostatic outcomes were rated|
01173|043|D|excellent or good in 10 out of 11 (91%) treatment episodes.  No episodes of|
01173|044|D|thrombosis or disseminated intravascular coagulation occurred during|
01173|045|D|treatment.(5)|
01173|046|D|   A study in six hemophilia A patients and five healthy volunteers|
01173|047|D|evaluated the use of tranexamic acid as an adjunct to APCC to control|
01173|048|D|bleeding.  Patients who received tranexamic acid had a significant increase|
01173|049|D|in maximum clot firmness compared to healthy controls.  No clinical or|
01173|050|D|laboratory signs of thromboembolic events, disseminated intravascular|
01173|051|D|coagulation, or hypercoagulability were observed.(6)|
01173|052|B||
01173|053|R|REFERENCES:|
01173|054|B||
01173|055|R|1.Amicar (aminocaproic acid) US prescribing information. Clover Pharms|1
01173|056|R|  August, 2008.|1
01173|057|R|2.Cyklokapron (tranexamic acid) US prescribing information. Pharmacia|1
01173|058|R|  Corporation February, 2021.|1
01173|059|R|3.Lysteda (tranexamic acid) US prescribing information. Ferring|1
01173|060|R|  Pharmaceuticals, Inc. October, 2013.|1
01173|061|R|4.Djulbegovic B, Marasa M, Pesto A, Kushner GM, Hadley T, Joseph G,|2
01173|062|R|  Goldsmith G. Safety and efficacy of purified factor IX concentrate and|2
01173|063|R|  antifibrinolytic agents for dental extractions in hemophilia B. Am J|2
01173|064|R|  Hematol 1996 Feb;51(2):168-70.|2
01173|065|R|5.Holmstrom M, Tran HT, Holme PA. Combined treatment with APCC (FEIBA(R))|2
01173|066|R|  and tranexamic acid in patients with haemophilia A with inhibitors and in|2
01173|067|R|  patients with acquired haemophilia A--a two-centre experience. Haemophilia|2
01173|068|R|  2012 Jul;18(4):544-9.|2
01173|069|R|6.Tran HT, Sorensen B, Rea CJ, Bjornsen S, Ueland T, Pripp AH, Tjonnfjord|2
01173|070|R|  GE, Holme PA. Tranexamic acid as adjunct therapy to bypassing agents in|2
01173|071|R|  haemophilia A patients  with inhibitors. Haemophilia 2014 May;|2
01173|072|R|  20(3):369-75.|2
01174|001|T|MONOGRAPH TITLE:  Zalcitabine/Pentamidine Injection|
01174|002|B||
01174|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01174|004|L|is contraindicated and generally should not be dispensed or administered to|
01174|005|L|the same patient.|
01174|006|B||
01174|007|A|MECHANISM OF ACTION:  Concurrent use may result in additive or synergistic|
01174|008|A|effects on the pancreas.(1)|
01174|009|B||
01174|010|E|CLINICAL EFFECTS:  Concurrent use may result in pancreatitis and death.(1)|
01174|011|B||
01174|012|P|PREDISPOSING FACTORS:  Patients with a history of pancreatitis or known risk|
01174|013|P|factors for pancreatitis may be at a greater risk of developing pancreatitis|
01174|014|P|during zalcitabine therapy.(1)|
01174|015|B||
01174|016|M|PATIENT MANAGEMENT:  The manufacturer of zalcitabine states that if|
01174|017|M|intravenous pentamidine is required, treatment with zalcitabine should be|
01174|018|M|interrupted.(1)|
01174|019|B||
01174|020|D|DISCUSSION:  Fulminant pancreatitis resulting in death has been reported|
01174|021|D|with intravenous pentamidine and zalcitabine.  Pancreatitis is an uncommon|
01174|022|D|complication of zalcitabine therapy, occurring in 1.1% of patients.  In|
01174|023|D|patients with a history of pancreatitis or elevated amylases, the incidence|
01174|024|D|of pancreatitis was found to be 5.3%, with an additional 4.4% developing an|
01174|025|D|asymptomatic elevated serum amylase.  The manufacturer states that treatment|
01174|026|D|with zalcitabine should be interrupted if treatment with another drug known|
01174|027|D|to cause pancreatitis, such as pentamidine, is required.(1)|
01174|028|B||
01174|029|R|REFERENCE:|
01174|030|B||
01174|031|R|1.Hivid (zalcitabine) US prescribing information. Roche Pharmaceuticals|1
01174|032|R|  September, 2002.|1
01175|001|T|MONOGRAPH TITLE:  Amiodarone/St. John's wort (mono deleted 02/16/2017)|
01175|002|B||
01175|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01175|004|L|Assess the risk to the patient and take action as needed.|
01175|005|B||
01175|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01175|007|A|amiodarone by CYP P-450-3A4.(1)|
01175|008|B||
01175|009|E|CLINICAL EFFECTS:  Concurrent use of amiodarone and St. John's wort may|
01175|010|E|result in decreased levels and clinical effectiveness of amiodarone.(1)|
01175|011|B||
01175|012|P|PREDISPOSING FACTORS:  None determined.|
01175|013|B||
01175|014|M|PATIENT MANAGEMENT:  Patients should be counseled that concurrent use of|
01175|015|M|amiodarone and St. John's wort may reduce levels and effectiveness of|
01175|016|M|amiodarone.|
01175|017|B||
01175|018|D|DISCUSSION:  The manufacturer of amiodarone states that because St. John's|
01175|019|D|wort has been shown to induce CYP P-450-3A4, concurrent use with amiodarone|
01175|020|D|may result in decreased amiodarone levels.(1)|
01175|021|B||
01175|022|R|REFERENCE:|
01175|023|B||
01175|024|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
01175|025|R|  Pharmaceuticals October, 2018.|1
01176|001|T|MONOGRAPH TITLE:  Pioglitazone/Insulin|
01176|002|B||
01176|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01176|004|L|take action as needed.|
01176|005|B||
01176|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may be the result|
01176|007|A|of additive fluid retention.(1,2)|
01176|008|B||
01176|009|E|CLINICAL EFFECTS:  The concurrent use of pioglitazone with insulin may|
01176|010|E|increase the risk of edema and heart failure.(1,2)|
01176|011|B||
01176|012|P|PREDISPOSING FACTORS:  Specific risk factors for heart failure could not be|
01176|013|P|determined.  Patients with ongoing edema are more likely to have|
01176|014|P|edema-associated adverse effects with combination therapy.(1)|
01176|015|B||
01176|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
01176|017|M|monitored for cardiovascular adverse events.  If signs and symptoms of|
01176|018|M|congestive heart failure develop, patients should be treated according to|
01176|019|M|current standards of care.  Consideration should be given to lowering the|
01176|020|M|dosage of or discontinuing pioglitazone.(1,2)|
01176|021|B||
01176|022|D|DISCUSSION:  In a clinical trial, two of 191 (1.1%) of patients receiving|
01176|023|D|pioglitazone (15 mg) and insulin and two of 188 (1.1%) of patients receiving|
01176|024|D|pioglitazone (30 mg) and insulin developed congestive heart failure.  None|
01176|025|D|of the patients receiving insulin alone developed congestive heart|
01176|026|D|failure.(1)|
01176|027|B||
01176|028|R|REFERENCES:|
01176|029|B||
01176|030|R|1.Actos (pioglitazone hydrochloride) US prescribing information. Takeda|1
01176|031|R|  Pharmaceuticals Inc. November, 2013.|1
01176|032|R|2.Humalog (insulin lispro) US prescribing information. Eli Lilly and Company|1
01176|033|R|  July, 2023.|1
01177|001|T|MONOGRAPH TITLE:  Nifedipine/Melatonin|
01177|002|B||
01177|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01177|004|L|Assess the risk to the patient and take action as needed.|
01177|005|B||
01177|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but melatonin might|
01177|007|A|effect calcium signaling.(1)|
01177|008|B||
01177|009|E|CLINICAL EFFECTS:  Concurrent use of melatonin with nifedipine may result in|
01177|010|E|an increase in systolic blood pressure, diastolic blood pressure, and heart|
01177|011|E|rate.(1)|
01177|012|B||
01177|013|P|PREDISPOSING FACTORS:  None determined.|
01177|014|B||
01177|015|M|PATIENT MANAGEMENT:  Patients maintained on nifedipine therapy should be|
01177|016|M|cautioned before beginning melatonin therapy.  Patients taking melatonin|
01177|017|M|with nifedipine should be observed for a decrease in blood pressure control.|
01177|018|B||
01177|019|D|DISCUSSION:  In a study in 47 patients receiving nifedipine (30 mg/day or 60|
01177|020|D|mg/day), patients received melatonin (5 mg at bedtime) for four weeks. After|
01177|021|D|four weeks of concurrent therapy, systolic blood pressure, diastolic blood|
01177|022|D|pressure, and heart rate increased 6.5 mmHg, 4.9 mmHg, and 3.9 beats/min,|
01177|023|D|respectively.  The increases seen in diastolic blood pressure and heart rate|
01177|024|D|were greatest in the morning.(1)|
01177|025|B||
01177|026|R|REFERENCE:|
01177|027|B||
01177|028|R|1.Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in|2
01177|029|R|  hypertensive patients well controlled by nifedipine: a 24-hour study. Br J|2
01177|030|R|  Clin Pharmacol 2000 May;49(5):423-7.|2
01178|001|T|MONOGRAPH TITLE:  Fluorouracil/Metronidazole; Tinidazole|
01178|002|B||
01178|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01178|004|L|of severe adverse interaction.|
01178|005|B||
01178|006|A|MECHANISM OF ACTION:  Metronidazole(1) and tinidazole(2) may decrease the|
01178|007|A|clearance of fluorouracil.|
01178|008|B||
01178|009|E|CLINICAL EFFECTS:  Concurrent use of metronidazole(1) or tinidazole with|
01178|010|E|fluorouracil may result in elevated levels of fluorouracil and toxicity,|
01178|011|E|including severe and fatal myelosuppression including neutropenia,|
01178|012|E|thrombocytopenia, or anemia, severe diarrhea, cardiotoxicity, or|
01178|013|E|neurotoxicity.|
01178|014|B||
01178|015|P|PREDISPOSING FACTORS:  Patients who are intermediate or poor|
01178|016|P|dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no|
01178|017|P|DPYD function.  Since DPYD is the rate-limiting enzyme involved in|
01178|018|P|fluoropyrimidine metabolism, these patients may be more susceptible to the|
01178|019|P|effects of this interaction.(3)|
01178|020|B||
01178|021|M|PATIENT MANAGEMENT:  Avoid using metronidazole as an adjunct agent to|
01178|022|M|fluorouracil therapy.  If possible, also avoid treating infections with|
01178|023|M|metronidazole or tinidazole in patients receiving fluorouracil.  If|
01178|024|M|concurrent therapy for the treatment of infection is required, the dosage of|
01178|025|M|fluorouracil may need to be reduced.  Patients receiving concurrent therapy|
01178|026|M|should be closely monitored for signs of fluorouracil toxicity.|
01178|027|B||
01178|028|D|DISCUSSION:  In a study in 27 patients, metronidazole (750 mg/m2) was given|
01178|029|D|one hour before fluorouracil (600 mg/m2) daily for five days.  The regimen|
01178|030|D|was repeated every 4 weeks.  Fluorouracil toxicity was greatly enhanced,|
01178|031|D|with 74% of patients experiencing granulocytopenia (less than 1500/ml).|
01178|032|D|Pharmacokinetic studies showed that metronidazole decreased fluorouracil|
01178|033|D|clearance by 26.9%.  In vitro studies revealed no synergism with the two|
01178|034|D|agents on the HCT-8 colon cancer cell line.(1)|
01178|035|B||
01178|036|R|REFERENCES:|
01178|037|B||
01178|038|R|1.Bardakji Z, Jolivet J, Langelier Y, Besner JG, Ayoub J.|2
01178|039|R|  5-Fluorouracil-metronidazole combination therapy in metastatic colorectal|2
01178|040|R|  cancer. Clinical, pharmacokinetic and in vitro cytotoxicity studies.|2
01178|041|R|  Cancer Chemother Pharmacol 1986;18(2):140-4.|2
01178|042|R|2.Tinidazole US prescribing information. Rising Pharmaceuticals, Inc..|1
01178|043|R|  October 12, 2017.|1
01178|044|R|3.Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ,|6
01178|045|R|  Klein TE, McLeod HL, Caudle KE, Diasio RB, Schwab M. Clinical|6
01178|046|R|  Pharmacogenetics Implementation Consortium (CPIC) Guideline for|6
01178|047|R|  Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017|6
01178|048|R|  Update. Clin Pharmacol Ther 2018 Feb;103(2):210-216.|6
01179|001|T|MONOGRAPH TITLE:  Tacrolimus/Cyclosporine|
01179|002|B||
01179|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01179|004|L|is contraindicated and generally should not be dispensed or administered to|
01179|005|L|the same patient.|
01179|006|B||
01179|007|A|MECHANISM OF ACTION:  Both tacrolimus and cyclosporine are nephrotoxic.|
01179|008|A|Additionally, both drugs are highly protein bound, and extensively|
01179|009|A|metabolized by CYP3A4, increasing risk for elevated serum concentrations.|
01179|010|A|When taken together they may cause additive or synergistic|
01179|011|A|nephrotoxicity.(1-3)|
01179|012|B||
01179|013|E|CLINICAL EFFECTS:  Concurrent use of tacrolimus and cyclosporine may result|
01179|014|E|in nephrotoxicity.(1-3)|
01179|015|B||
01179|016|P|PREDISPOSING FACTORS:  Patients with baseline hypertension and/or taking|
01179|017|P|high doses of cyclosporine may have an increased risk of an adverse|
01179|018|P|effect.(4)|
01179|019|B||
01179|020|M|PATIENT MANAGEMENT:  The manufacturer of tacrolimus states that tacrolimus|
01179|021|M|should not be used simultaneously with cyclosporine.  When switching|
01179|022|M|patients from one agent to another, the first agent should be discontinued|
01179|023|M|for at least 24 hours prior to beginning the new agent.  In patients with|
01179|024|M|elevated levels of tacrolimus or cyclosporine, allow additional time between|
01179|025|M|agents.(1)|
01179|026|M|   If concurrent therapy is used, renal function, specifically serum|
01179|027|M|creatinine, should be closely monitored.  If severe impairment occurs,|
01179|028|M|consider a dose reduction of tacrolimus or alternative treatment.(2-3)|
01179|029|B||
01179|030|D|DISCUSSION:  Tacrolimus is extremely nephrotoxic.  Initial clinical|
01179|031|D|experience with concurrent tacrolimus and cyclosporine resulted in additive/|
01179|032|D|synergistic nephrotoxicity.(1)|
01179|033|D|   A prospective study evaluated treatment regimens for patients who had a|
01179|034|D|liver transplant within the last year and had calcineurin inhibitor|
01179|035|D|(CNI)-induced renal dysfunction. 75 patients were randomized to either|
01179|036|D|continue their current CNI dose or switch to mycophenolate mofetil (MMF)|
01179|037|D|with a reduced CNI dose. Compared to baseline there was a statistically|
01179|038|D|significant improvement in renal function in the MMF group.  Changes in|
01179|039|D|renal function for the CNI group were not statistically significant. This|
01179|040|D|study suggests an alternative treatment regimen for patients with|
01179|041|D|CNI-induced renal impairment.(5)|
01179|042|B||
01179|043|R|REFERENCES:|
01179|044|B||
01179|045|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
01179|046|R|  August, 2023.|1
01179|047|R|2.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
01179|048|R|  Corporation September, 2023.|1
01179|049|R|3.Sandimmune (cyclosporine) US prescribing information. Novartis|1
01179|050|R|  Pharmaceuticals Corporation September 2023.|1
01179|051|R|4.Sinha A, Sharma A, Mehta A, Gupta R, Gulati A, Hari P, Dinda AK, Bagga A.|2
01179|052|R|  Calcineurin inhibitor induced nephrotoxicity in steroid resistant|2
01179|053|R|  nephrotic syndrome. Indian J Nephrol 2013 Jan;23(1):41-6.|2
01179|054|R|5.Cicinnati VR, Yu Z, Klein CG, Sotiropoulos GC, Saner F, Malago M, Frilling|2
01179|055|R|  A, Gerken G, Broelsch CE, Beckebaum S. Clinical trial: switch to combined|2
01179|056|R|  mycophenolate mofetil and minimal dose calcineurin inhibitor in stable|2
01179|057|R|  liver transplant patients--assessment of renal and allograft function,|2
01179|058|R|  cardiovascular risk factors and immune monitoring. Aliment Pharmacol Ther|2
01179|059|R|  2007 Nov 1;26(9):1195-208.|2
01180|001|T|MONOGRAPH TITLE:  Live Vaccines/Selected Immunosuppressants; Temsirolimus|
01180|002|T|(mono deleted 04/26/2012)|
01180|003|B||
01180|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01180|005|L|of severe adverse interaction.|
01180|006|B||
01180|007|A|MECHANISM OF ACTION:  Cyclosporine, sirolimus, tacrolimus, and temsirolimus|
01180|008|A|may affect the response to the vaccination.(1-4)|
01180|009|B||
01180|010|E|CLINICAL EFFECTS:  Live vaccines given during cyclosporine, sirolimus,|
01180|011|E|tacrolimus, or temsirolimus therapy may result in disease or vaccination|
01180|012|E|failure.(1-4)|
01180|013|B||
01180|014|P|PREDISPOSING FACTORS:  None determined.|
01180|015|B||
01180|016|M|PATIENT MANAGEMENT:  The manufacturers of cyclosporine,(1) sirolimus(2),|
01180|017|M|systemic tacrolimus,(3) and temsirolimus(4) state that live vaccines should|
01180|018|M|be avoided during therapy with these agents.  Patients receiving these|
01180|019|M|agents should also avoid close contact with people who have received live|
01180|020|M|vaccines.(4)|
01180|021|B||
01180|022|D|DISCUSSION:  Immunosuppressants may affect the response to vaccinations.|
01180|023|D|Some vaccines may be less effective.  Live vaccines may result in disease.|
01180|024|D|Therefore, the manufacturers of cyclosporine,(1) sirolimus,(2) systemic|
01180|025|D|tacrolimus,(3) and temsirolimus(4) state that live vaccines should be|
01180|026|D|avoided during therapy.|
01180|027|B||
01180|028|R|REFERENCES:|
01180|029|B||
01180|030|R|1.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
01180|031|R|  Corporation May, 2013.|1
01180|032|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
01180|033|R|  March, 2013.|1
01180|034|R|3.Prograf (tacrolimus) US prescribing information. Fujisawa Healthcare, Inc.|1
01180|035|R|  November, 2022.|1
01180|036|R|4.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01180|037|R|  Inc. June, 2011.|1
01181|001|T|MONOGRAPH TITLE:  Cyclosporine;Tacrolimus/Potassium-Sparing Diuretics|
01181|002|B||
01181|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01181|004|L|of severe adverse interaction.|
01181|005|B||
01181|006|A|MECHANISM OF ACTION:  Concurrent use of cyclosporine(1) or tacrolimus(2)|
01181|007|A|with a potassium-sparing diuretic may result in additive or synergistic|
01181|008|A|effects on potassium levels.|
01181|009|B||
01181|010|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine(1) or tacrolimus(2) with a|
01181|011|E|potassium-sparing diuretic may result in severe hyperkalemia.|
01181|012|B||
01181|013|P|PREDISPOSING FACTORS:  Renal impairment increases the risk for hyperkalemia.|
01181|014|B||
01181|015|M|PATIENT MANAGEMENT:  The US manufacturers of cyclosporine(1) and|
01181|016|M|tacrolimus(2) state that potassium-sparing diuretics should not be used|
01181|017|M|during therapy with these agents.|
01181|018|B||
01181|019|D|DISCUSSION:  Hyperkalemia has been reported with cyclosporine, therefore,|
01181|020|D|the US manufacturer states that potassium-sparing diuretics should not be|
01181|021|D|used with cyclosporine.(1)|
01181|022|D|   In tacrolimus clinical trials, mild to severe hyperkalemia was reported|
01181|023|D|in 31% of kidney transplant patients, 45% of US liver transplant patients,|
01181|024|D|and 13% of European liver transplant patients.  The manufacturer of|
01181|025|D|tacrolimus states that potassium levels should be closely monitored in all|
01181|026|D|patients maintained on tacrolimus and that potassium-sparing diuretics|
01181|027|D|should be avoided during tacrolimus therapy.(2)|
01181|028|B||
01181|029|R|REFERENCES:|
01181|030|B||
01181|031|R|1.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
01181|032|R|  Corporation September, 2023.|1
01181|033|R|2.Prograf (tacrolimus) Canadian prescribing information. Astellas April 27,|1
01181|034|R|  2011.|1
01182|001|T|MONOGRAPH TITLE:  Irinotecan/St. John's Wort|
01182|002|B||
01182|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01182|004|L|is contraindicated and generally should not be dispensed or administered to|
01182|005|L|the same patient.|
01182|006|B||
01182|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01182|008|A|irinotecan by CYP3A4.(1-3)|
01182|009|B||
01182|010|E|CLINICAL EFFECTS:  Concurrent use of irinotecan and St. John's wort may|
01182|011|E|result in decreased levels of the active metabolite of irinotecan and|
01182|012|E|possibly decreased effectiveness.(1-3)|
01182|013|B||
01182|014|P|PREDISPOSING FACTORS:  None determined.|
01182|015|B||
01182|016|M|PATIENT MANAGEMENT:  St. John's wort is contraindicated during irinotecan|
01182|017|M|therapy and should be discontinued at least 2 weeks prior to the first cycle|
01182|018|M|of irinotecan.(1)|
01182|019|B||
01182|020|D|DISCUSSION:  A randomized, controlled trial in three subjects examined the|
01182|021|D|effects of St. John's wort on irinotecan.  Concurrent use of St. John's wort|
01182|022|D|decreased the area-under-curve (AUC) of the active metabolite of irinotecan|
01182|023|D|by over 50%.  The AUC of irinotecan was not affected.  The clearance of APC,|
01182|024|D|an inactive metabolite of irinotecan, increased 37% and the extent of|
01182|025|D|glucuronidation of the active metabolite increased 82%.(2)|
01182|026|D|   In an unblinded, randomized crossover study of ten subjects studied the|
01182|027|D|effects of St. John's wort on the metabolism of irinotecan. In the first|
01182|028|D|five patients, leukocyte and neutrophil levels decreased by 56% and 63%,|
01182|029|D|respectively when on irinotecan therapy alone. When given irinotecan with|
01182|030|D|St. John's wort, leukocyte and neutrophils only dropped by 8.6% and 4.3%|
01182|031|D|respectively. Also, concurrent use of irinotecan and St. John's wort caused|
01182|032|D|the active metabolite of irinotecan, SN-38, to decrease by 42% which may|
01182|033|D|decrease the effect of antitumor activity exhibited by irinotecan.(3)|
01182|034|B||
01182|035|R|REFERENCES:|
01182|036|B||
01182|037|R|1.Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia|1
01182|038|R|  & Upjohn Company January, 2020.|1
01182|039|R|2.Mathijssen RHJ, Verweij J, De Bruijn P, De Jonge MJA, Sparreboom A.|4
01182|040|R|  Modulation of irinotecan (CPT-11) metabolism by st. john's wort cancer|4
01182|041|R|  patients. 93rd Annual Meeting of the American Association for Cancer|4
01182|042|R|  Research, San Francisco, CA 2002 Apr 8.|4
01182|043|R|3.Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A. Effects of|2
01182|044|R|  St. John's wort on irinotecan metabolism. J Natl Cancer Inst 2002 Aug 21;|2
01182|045|R|  94(16):1247-9.|2
01183|001|T|MONOGRAPH TITLE:  Rofecoxib/Rifampin|
01183|002|B||
01183|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01183|004|L|take action as needed.|
01183|005|B||
01183|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of rofecoxib by CYP|
01183|007|A|P-450.(1)|
01183|008|B||
01183|009|E|CLINICAL EFFECTS:  The concurrent use of rofecoxib and rifampin may decrease|
01183|010|E|rofecoxib levels by 50%.(1)|
01183|011|B||
01183|012|P|PREDISPOSING FACTORS:  None determined.|
01183|013|B||
01183|014|M|PATIENT MANAGEMENT:  The manufacturer of rofecoxib recommends a starting|
01183|015|M|dose of 25 mg of rofecoxib for the treatment of osteoarthritis in patients|
01183|016|M|receiving rifampin.(1)|
01183|017|B||
01183|018|D|DISCUSSION:  The concurrent use of rofecoxib and rifampin, a potent inducer|
01183|019|D|of CYP P-450, resulted in a 50% decrease in the plasma concentration of|
01183|020|D|rofecoxib.  Therefore, the manufacturer of rofecoxib recommends a starting|
01183|021|D|dose of 25 mg of rofecoxib for the treatment of osteoarthritis in patients|
01183|022|D|receiving rifampin.(1)|
01183|023|B||
01183|024|R|REFERENCE:|
01183|025|B||
01183|026|R|1.Vioxx (rofecoxib) US prescribing information. Merck & Co., Inc. May, 2016.|1
01184|001|T|MONOGRAPH TITLE:  Theophylline Derivatives/Rofecoxib (mono deleted|
01184|002|T|09/17/2014)|
01184|003|B||
01184|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01184|005|L|take action as needed.|
01184|006|B||
01184|007|A|MECHANISM OF ACTION:  Rofecoxib may inhibit the metabolism of theophylline|
01184|008|A|by CYP P-450-1A2.(1)|
01184|009|B||
01184|010|E|CLINICAL EFFECTS:  Concurrent use of rofecoxib and theophylline may result|
01184|011|E|in elevated theophylline levels and theophylline toxicity.(1)|
01184|012|B||
01184|013|P|PREDISPOSING FACTORS:  None determined.|
01184|014|B||
01184|015|M|PATIENT MANAGEMENT:  Theophylline levels should be monitored in patients|
01184|016|M|maintained on theophylline if rofecoxib is initiated, adjusted, or|
01184|017|M|discontinued.(1)  The dosage of theophylline may need to be adjusted.|
01184|018|B||
01184|019|D|DISCUSSION:  In healthy subjects, rofecoxib (12.5 mg/day, 25 mg/day, or 50|
01184|020|D|mg/day for seven days) increased the area-under-curve (AUC) of a single dose|
01184|021|D|of theophylline (300 mg) by 38% to 60%.  Therefore, the manufacturer of|
01184|022|D|rofecoxib recommends that theophylline levels be monitored if rofecoxib is|
01184|023|D|initiated or changed in patients receiving theophylline.(1)|
01184|024|B||
01184|025|R|REFERENCE:|
01184|026|B||
01184|027|R|1.Vioxx (rofecoxib) US prescribing information. Merck & Co., Inc. May, 2016.|1
01185|001|T|MONOGRAPH TITLE:  Alprazolam; Midazolam; Triazolam/Delavirdine|
01185|002|B||
01185|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01185|004|L|is contraindicated and generally should not be dispensed or administered to|
01185|005|L|the same patient.|
01185|006|B||
01185|007|A|MECHANISM OF ACTION:  Delavirdine may inhibit the metabolism of alprazolam,|
01185|008|A|midazolam, and triazolam by CYP3A4.(1)|
01185|009|B||
01185|010|E|CLINICAL EFFECTS:  Concurrent use of delavirdine with alprazolam, midazolam,|
01185|011|E|or triazolam may result in elevated levels of alprazolam, midazolam, or|
01185|012|E|triazolam and toxicity, including profound sedation, respiratory depression,|
01185|013|E|coma, and/or death.(1)|
01185|014|B||
01185|015|P|PREDISPOSING FACTORS:  None determined.|
01185|016|B||
01185|017|M|PATIENT MANAGEMENT:  The manufacturer of delavirdine states that concurrent|
01185|018|M|use of delavirdine with alprazolam, midazolam, or triazolam is|
01185|019|M|contraindicated.(1)|
01185|020|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
01185|021|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
01185|022|M|unresponsiveness.|
01185|023|B||
01185|024|D|DISCUSSION:  Because delavirdine inhibits CYP3A4, the concurrent use of|
01185|025|D|agents that are highly dependent on CYP3A4 for clearance and for which|
01185|026|D|elevated plasma concentration are associated with serious and/or|
01185|027|D|life-threatening events, such as alprazolam, midazolam, or triazolam, is|
01185|028|D|contraindicated by the manufacturer of delavirdine.(1)|
01185|029|B||
01185|030|R|REFERENCE:|
01185|031|B||
01185|032|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01185|033|R|  Upjohn Company August, 2012.|1
01186|001|T|MONOGRAPH TITLE:  Pimozide/Delavirdine|
01186|002|B||
01186|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01186|004|L|is contraindicated and generally should not be dispensed or administered to|
01186|005|L|the same patient.|
01186|006|B||
01186|007|A|MECHANISM OF ACTION:  Delavirdine may inhibit the metabolism of pimozide by|
01186|008|A|CYP3A4.(1)|
01186|009|B||
01186|010|E|CLINICAL EFFECTS:  Concurrent use of delavirdine with pimozide may result in|
01186|011|E|elevated levels of pimozide, which may result in prolongation of the QTc|
01186|012|E|interval and potentially life-threatening ventricular arrhythmias.(1)|
01186|013|B||
01186|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01186|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01186|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01186|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01186|018|P|female gender, or advanced age.(2)|
01186|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01186|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01186|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01186|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01186|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01186|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01186|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01186|026|P|   The risk of anticholinergic toxicities including cognitive decline,|
01186|027|P|delirium, falls and fractures is increased in geriatric patients using more|
01186|028|P|than one medicine with anticholinergic properties.(3)|
01186|029|B||
01186|030|M|PATIENT MANAGEMENT:  The US manufacturer of delavirdine states that the|
01186|031|M|concurrent use of pimozide is contraindicated.(1)|
01186|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01186|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01186|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01186|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01186|036|B||
01186|037|D|DISCUSSION:  Because delavirdine inhibits CYP3A4, the concurrent use of|
01186|038|D|agents that are highly dependent on CYP3A4 for clearance and for which|
01186|039|D|elevated plasma concentration are associated with serious and/or|
01186|040|D|life-threatening events, such as pimozide, is contraindicated by the US|
01186|041|D|manufacturer of delavirdine.(1)|
01186|042|D|    Elevated levels of pimozide may result in prolongation of the QTc|
01186|043|D|interval and potentially life-threatening ventricular arrhythmias.(4)|
01186|044|B||
01186|045|R|REFERENCES:|
01186|046|B||
01186|047|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01186|048|R|  Upjohn Company August, 2012.|1
01186|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01186|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01186|051|R|  settings: a scientific statement from the American Heart Association and|6
01186|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01186|053|R|  2;55(9):934-47.|6
01186|054|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01186|055|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01186|056|R|  Soc 2023 Jul;71(7):2052-2081.|6
01186|057|R|4.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
01186|058|R|  2011.|1
01187|001|T|MONOGRAPH TITLE:  Delavirdine; Etravirine/Selected Strong CYP3A4 Inducers|
01187|002|B||
01187|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01187|004|L|is contraindicated and generally should not be dispensed or administered to|
01187|005|L|the same patient.|
01187|006|B||
01187|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
01187|008|A|delavirdine(1) and etravirine(2) by CYP3A4.|
01187|009|B||
01187|010|E|CLINICAL EFFECTS:  Concurrent use of delavirdine(1) or etravirine(2) with|
01187|011|E|strong CYP3A4 inducers may result in sub-therapeutic levels of the|
01187|012|E|non-nucleoside reverse transcriptase inhibitor (NNRTI) and the development|
01187|013|E|of resistance to antiretroviral agents.|
01187|014|B||
01187|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01187|016|P|of the inducer for longer than 1-2 weeks.|
01187|017|B||
01187|018|M|PATIENT MANAGEMENT:  The US manufacturers of delavirdine(1) and etravirine|
01187|019|M|(2) state that strong CYP3A4 inducers should not be used in combination with|
01187|020|M|delavirdine and etravirine.|
01187|021|B||
01187|022|D|DISCUSSION:  In a study in 8 subjects, administration of various doses of|
01187|023|D|barbiturates, carbamazepine, phenytoin, and phenobarbital with delavirdine|
01187|024|D|(300-400 mg 3 times daily) decreased the minimum concentration (Cmin) of|
01187|025|D|delavirdine by 90%.(1)|
01187|026|D|   In a study of 12 subjects, rifabutin (300 mg daily), a moderate CYP3A4|
01187|027|D|inducer, decreased both the area-under-curve (AUC) and maximum concentration|
01187|028|D|(Cmax) of etravirine by 37%.(2)|
01187|029|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
01187|030|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
01187|031|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and|
01187|032|D|primidone.(3)|
01187|033|B||
01187|034|R|REFERENCES:|
01187|035|B||
01187|036|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01187|037|R|  Upjohn Company August, 2012.|1
01187|038|R|2.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01187|039|R|  August, 2014.|1
01187|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
01187|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01188|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Delavirdine|
01188|002|B||
01188|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01188|004|L|is contraindicated and generally should not be dispensed or administered to|
01188|005|L|the same patient.|
01188|006|B||
01188|007|A|MECHANISM OF ACTION:  Delavirdine may inhibit the metabolism of lovastatin|
01188|008|A|and simvastatin by CYP3A4.(1)|
01188|009|B||
01188|010|E|CLINICAL EFFECTS:  Concurrent use of delavirdine with lovastatin or|
01188|011|E|simvastatin may result in elevated levels of lovastatin and simvastatin and|
01188|012|E|an increased risk of rhabdomyolysis.(1)|
01188|013|B||
01188|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01188|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01188|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01188|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01188|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01188|019|P|transporter OATP1B1 may have increased statin concentrations and be|
01188|020|P|predisposed to myopathy or rhabdomyolysis.|
01188|021|B||
01188|022|M|PATIENT MANAGEMENT:  The manufacturer of delavirdine states that lovastatin|
01188|023|M|and simvastatin should not be coadministered with delavirdine.(1)|
01188|024|B||
01188|025|D|DISCUSSION:  Because delavirdine inhibits CYP3A4, the concurrent use of|
01188|026|D|delavirdine with lovastatin or simvastatin may result in elevated levels of|
01188|027|D|these agents and an increased risk of rhabdomyolysis.  Therefore, the|
01188|028|D|manufacturer of delavirdine states that lovastatin and simvastatin should|
01188|029|D|not be coadministered with delavirdine.(1)|
01188|030|B||
01188|031|R|REFERENCE:|
01188|032|B||
01188|033|R|1.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01188|034|R|  Upjohn Company August, 2012.|1
01189|001|T|MONOGRAPH TITLE:  Voriconazole/Rifampin; Rifabutin (mono deleted 03/29/2012)|
01189|002|B||
01189|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01189|004|L|is contraindicated and generally should not be dispensed or administered to|
01189|005|L|the same patient.|
01189|006|B||
01189|007|A|MECHANISM OF ACTION:  Rifampin and rifabutin induce the metabolism of|
01189|008|A|voriconazole by CYP P-450 isoenzyme system.(1)|
01189|009|B||
01189|010|E|CLINICAL EFFECTS:  The concurrent use of either rifampin or rifabutin with|
01189|011|E|voriconazole may result in severely reduced levels of voriconazole and|
01189|012|E|therapeutic failure.(1)|
01189|013|B||
01189|014|P|PREDISPOSING FACTORS:  None determined.|
01189|015|B||
01189|016|M|PATIENT MANAGEMENT:  The manufacturer of voriconazole states that the|
01189|017|M|concurrent use of voriconazole with either rifampin or rifabutin is|
01189|018|M|contraindicated.(1)|
01189|019|B||
01189|020|D|DISCUSSION:  The concurrent use of rifampin (600 mg once daily) with|
01189|021|D|voriconazole (200 mg every 12 hours for 7 days) decreased the maximum|
01189|022|D|concentration (Cmax) and area-under-curve (AUC) of voriconazole by 93% and|
01189|023|D|96%, respectively.  Doubling the dose of voriconazole did not restore|
01189|024|D|adequate exposure to voriconazole during rifampin.(1)|
01189|025|D|   The concurrent use of rifabutin (300 mg once daily) with voriconazole|
01189|026|D|(200 mg twice daily) decreased the Cmax and AUC of voriconazole by 67% and|
01189|027|D|79%, respectively.  The concurrent use of rifabutin (300 mg once daily) with|
01189|028|D|voriconazole (400 mg twice daily) increased the Cmax and AUC of voriconazole|
01189|029|D|to twice that seen with voriconazole alone at 200 mg twice daily.  However,|
01189|030|D|the Cmax and AUC of rifabutin were 3-fold and 4-fold higher, respectively,|
01189|031|D|when given with voriconazole at 400 mg twice daily.(1)|
01189|032|B||
01189|033|R|REFERENCE:|
01189|034|B||
01189|035|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. November,|1
01189|036|R|  2011.|1
01190|001|T|MONOGRAPH TITLE:  Isavuconazonium; Voriconazole/Selected CYP3A4 Inducers|
01190|002|B||
01190|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01190|004|L|is contraindicated and generally should not be dispensed or administered to|
01190|005|L|the same patient.|
01190|006|B||
01190|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 and rifabutin may increase|
01190|008|A|the metabolism of isavuconazonium(1,2) and voriconazole.(3)|
01190|009|B||
01190|010|E|CLINICAL EFFECTS:  The concurrent use of strong inducers of CYP3A4 or|
01190|011|E|rifabutin with isavuconazonium(1,2) or voriconazole(3) may result in|
01190|012|E|severely reduced levels of the azole antifungal and therapeutic failure.|
01190|013|B||
01190|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01190|015|P|of the inducer for longer than 1-2 weeks.|
01190|016|B||
01190|017|M|PATIENT MANAGEMENT:  The concurrent use of isavuconazonium(1,2) or|
01190|018|M|voriconazole(3) with strong inducers of CYP3A4 is contraindicated.  The|
01190|019|M|concurrent use of voriconazole with rifabutin is also contraindicated.(3,4)|
01190|020|M|   The UK manufacturer of voriconazole states that concurrent use with|
01190|021|M|rifabutin should be avoided. If concurrent use is necessary, the maintenance|
01190|022|M|dose of voriconazole may be increased from 200 mg to 350 mg orally twice|
01190|023|M|daily. If the patient weighs less than 40 kg, the maintenance dose of|
01190|024|M|voriconazole may be increased from 100 mg to 200 mg orally twice daily. If|
01190|025|M|concurrent use is necessary, the maintenance dose of intravenous|
01190|026|M|voriconazole can be increased to 5 mg/kg intravenously twice daily.(9)|
01190|027|M|   The US manufacturer of isavuconazonium does not make any recommendations|
01190|028|M|for concurrent use with rifabutin,(1) but the UK manufacturer states that|
01190|029|M|concurrent use of rifabutin is contraindicated.(2)|
01190|030|B||
01190|031|D|DISCUSSION:  The concurrent use of rifampin (600 mg) with isavuconazonium|
01190|032|D|(multiple doses) decreased the maximum concentration (Cmax) and|
01190|033|D|area-under-curve (AUC) of voriconazole by 75% and 97%, respectively.(1)|
01190|034|D|   The concurrent use of rifampin (600 mg once daily) with voriconazole (200|
01190|035|D|mg every 12 hours for 7 days) decreased the Cmax and AUC of voriconazole by|
01190|036|D|93% and 96%, respectively.  Doubling the dose of voriconazole did not|
01190|037|D|restore adequate exposure to voriconazole during rifampin.(3)|
01190|038|D|   The concurrent use of rifabutin (300 mg once daily) with voriconazole|
01190|039|D|(200 mg twice daily) decreased the Cmax and AUC of voriconazole by 67% and|
01190|040|D|79%, respectively.  The concurrent use of rifabutin (300 mg once daily) with|
01190|041|D|voriconazole (400 mg twice daily) increased the Cmax and AUC of voriconazole|
01190|042|D|to twice that seen with voriconazole alone at 200 mg twice daily.  However,|
01190|043|D|the Cmax and AUC of rifabutin were 3-fold and 4-fold higher, respectively,|
01190|044|D|when given with voriconazole at 400 mg twice daily.(3)|
01190|045|D|   In a study in 16 subjects, subjects received single doses of voriconazole|
01190|046|D|(400 mg) alone, after one dose of St. John's wort (300 mg), and after 15|
01190|047|D|days of St. John's wort (300 mg daily).  After 10 hours of St. John's wort,|
01190|048|D|voriconazole area-under-curve (AUC) increased 22%.  After 15 days of St.|
01190|049|D|John's wort, voriconazole AUC decreased 59%.(5)|
01190|050|D|   Therapeutic failures have been reported with voriconazole in patients|
01190|051|D|treated concurrently with carbamazepine,(6) phenobarbital,(7) and|
01190|052|D|rifampin.(8)|
01190|053|D|   In a study in 12 healthy male subjects, voriconazole (400 mg twice daily|
01190|054|D|for 7 days) with rifabutin (300 mg daily for 7 days) increased rifabutin's|
01190|055|D|AUC and Cmax by 331% and 195%, respectively. The AUC and Cmax of|
01190|056|D|voriconazole were increased by approximately 100%.(4)|
01190|057|D|   Selected CYP3A4 inducers linked to this monograph include apalutamide,|
01190|058|D|barbiturates, carbamazepine, encorafenib, enzalutamide, ivosidenib,|
01190|059|D|lumacaftor, mitotane, phenobarbital, primidone, rifabutin, rifampin,|
01190|060|D|rifapentine, and St. John's wort.|
01190|061|B||
01190|062|R|REFERENCES:|
01190|063|B||
01190|064|R|1.Cresemba (isavuconazonium sulfate) US prescribing information. Astellas|1
01190|065|R|  Pharma US, Inc. May, 2021.|1
01190|066|R|2.Cresemba (isavuconazonium sulfate) UK Summary of Product Characteristics.|1
01190|067|R|  Pfizer Limited June 28, 2021.|1
01190|068|R|3.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01190|069|R|4.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
01190|070|R|  2021.|1
01190|071|R|5.Rengelshausen J, Banfield M, Riedel KD, Burhenne J, Weiss J, Thomsen T,|2
01190|072|R|  Walter-Sack I, Haefeli WE, Mikus G. Opposite effects of short-term and|2
01190|073|R|  long-term St John's wort intake on voriconazole pharmacokinetics. Clin|2
01190|074|R|  Pharmacol Ther 2005 Jul;78(1):25-33.|2
01190|075|R|6.Malingre MM, Godschalk PC, Klein SK. A case report of voriconazole therapy|4
01190|076|R|  failure in a homozygous ultrarapid CYP2C19*17/*17 patient comedicated with|4
01190|077|R|  carbamazepine. Br J Clin Pharmacol 2012 Jul;74(1):205-6.|4
01190|078|R|7.Muldrew KM, Maples HD, Stowe CD, Jacobs RF. Intravenous voriconazole|3
01190|079|R|  therapy in a preterm infant. Pharmacotherapy 2005 Jun;25(6):893-8.|3
01190|080|R|8.Geist MJ, Egerer G, Burhenne J, Riedel KD, Mikus G. Induction of|3
01190|081|R|  voriconazole metabolism by rifampin in a patient with acute myeloid|3
01190|082|R|  leukemia: importance of interdisciplinary communication to prevent|3
01190|083|R|  treatment errors with complex medications. Antimicrob Agents Chemother|3
01190|084|R|  2007 Sep;51(9):3455-6.|3
01190|085|R|9.Vfend (voriconazole) UK summary of product characteristics. Pfizer Limited|1
01190|086|R|  March, 2022.|1
01191|001|T|MONOGRAPH TITLE:  Voriconazole/Long-Acting Barbiturates (mono deleted|
01191|002|T|03/29/2012)|
01191|003|B||
01191|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01191|005|L|is contraindicated and generally should not be dispensed or administered to|
01191|006|L|the same patient.|
01191|007|B||
01191|008|A|MECHANISM OF ACTION:  Long acting barbiturates may induce the metabolism of|
01191|009|A|voriconazole by CYP P-450.(1)|
01191|010|B||
01191|011|E|CLINICAL EFFECTS:  The concurrent use of long acting barbiturates and|
01191|012|E|voriconazole may result in severely reduced levels of voriconazole and|
01191|013|E|therapeutic failure.(1)|
01191|014|B||
01191|015|P|PREDISPOSING FACTORS:  None determined.|
01191|016|B||
01191|017|M|PATIENT MANAGEMENT:  The manufacturer of voriconazole states that the|
01191|018|M|concurrent use of voriconazole with long acting barbiturates is|
01191|019|M|contraindicated.(1)|
01191|020|B||
01191|021|D|DISCUSSION:  The concurrent use of rifampin (600 mg once daily) with|
01191|022|D|voriconazole (200 mg every 12 hours for 7 days) decreased the maximum|
01191|023|D|concentration (Cmax) and area-under-curve (AUC) of voriconazole by 93% and|
01191|024|D|96%, respectively.  Doubling the dose of voriconazole did not restore|
01191|025|D|adequate exposure to voriconazole during rifampin.(1)|
01191|026|D|   Because long acting barbiturates are also potent inducers of CYP P-450,|
01191|027|D|the manufacturer of voriconazole states that the concurrent use of|
01191|028|D|voriconazole and long acting barbiturates is contraindicated.(1)|
01191|029|B||
01191|030|R|REFERENCE:|
01191|031|B||
01191|032|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. November,|1
01191|033|R|  2011.|1
01192|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Posaconazole; Voriconazole|
01192|002|B||
01192|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01192|004|L|is contraindicated and generally should not be dispensed or administered to|
01192|005|L|the same patient.|
01192|006|B||
01192|007|A|MECHANISM OF ACTION:  Posaconazole(1,2) and voriconazole(3,4) may inhibit|
01192|008|A|the metabolism of the ergot alkaloids by CYP3A4.|
01192|009|B||
01192|010|E|CLINICAL EFFECTS:  The concurrent use of posaconazole(1,2) or voriconazole|
01192|011|E|(3,4) and ergot alkaloids may result in elevated levels of the ergot|
01192|012|E|alkaloids and ergotism.|
01192|013|B||
01192|014|P|PREDISPOSING FACTORS:  None determined.|
01192|015|B||
01192|016|M|PATIENT MANAGEMENT:  The UK(1) and US(2) manufacturers of posaconazole state|
01192|017|M|that the concurrent use of ergot alkaloids is contraindicated.|
01192|018|M|   The manufacturer of voriconazole states that the concurrent use of|
01192|019|M|voriconazole and ergot alkaloids is contraindicated.(3)|
01192|020|M|   The US manufacturer of methylergonovine states that methylergonovine|
01192|021|M|should not be administered with potent CYP3A4 inhibitors such as|
01192|022|M|voriconazole.(4)|
01192|023|B||
01192|024|D|DISCUSSION:  Posaconazole has been shown to inhibit the CYP3A4 mediated|
01192|025|D|metabolism of midazolam by 83%.(1)|
01192|026|D|   Voriconazole (400 mg every 12 hours for one day, then 200 mg every 12|
01192|027|D|hours for 8 days) increased the maximum concentration (Cmax) and|
01192|028|D|area-under-curve (AUC) of a single dose of sirolimus (2 mg) by 7-fold and|
01192|029|D|11-fold, respectively.  Ergot alkaloids are metabolized by the same|
01192|030|D|isoenzyme system.(3)|
01192|031|D|   One or more of the drug pairs linked to this monograph have been included|
01192|032|D|in a list of interactions that should be considered "high-priority" for|
01192|033|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01192|034|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01192|035|D|Coordinator (ONC) for Health Information Technology.|
01192|036|B||
01192|037|R|REFERENCES:|
01192|038|B||
01192|039|R|1.Noxafil (posaconazole) UK summary of product characteristics.|1
01192|040|R|  Schering-Plough Ltd. January, 2022.|1
01192|041|R|2.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01192|042|R|  January, 2022.|1
01192|043|R|3.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01192|044|R|4.Methergine (methylergonovine maleate) US prescribing information. Novartis|1
01192|045|R|  Pharmaceuticals Corporation June, 2012.|1
01192|046|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01192|047|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01192|048|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01192|049|R|  19(5):735-43.|6
01193|001|T|MONOGRAPH TITLE:  Omeprazole; Pantoprazole/Voriconazole|
01193|002|B||
01193|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01193|004|L|take action as needed.|
01193|005|B||
01193|006|A|MECHANISM OF ACTION:  Voriconazole is a strong CYP3A4 inhibitor and a|
01193|007|A|moderate inhibitor of CYP2C19.  Omeprazole and pantoprazole are|
01193|008|A|predominantly metabolized by CYP2C19 but are also a substrate of CYP3A4.|
01193|009|A|Voriconazole may inhibit the metabolism of omeprazole and pantoprazole by|
01193|010|A|CYP2C19 and CYP3A4.(1-3)|
01193|011|B||
01193|012|E|CLINICAL EFFECTS:  The concurrent use of voriconazole and either omeprazole|
01193|013|E|or pantoprazole may result in elevated levels of omeprazole and|
01193|014|E|pantoprazole, and increase the risk of proton pump inhibitor (PPI) related|
01193|015|E|side effects including gastroenteritis, Clostridioides difficile associated|
01193|016|E|diarrhea, fractures, hypomagnesemia and vitamin B12 deficiency.(1-3)|
01193|017|B||
01193|018|P|PREDISPOSING FACTORS:  None determined.|
01193|019|B||
01193|020|M|PATIENT MANAGEMENT:  The manufacturer of voriconazole states that when|
01193|021|M|voriconazole is initiated in patients receiving dosages of omeprazole of 40|
01193|022|M|mg/day or greater, the dosage of omeprazole should be reduced by|
01193|023|M|one-half.(1)|
01193|024|M|   The manufacturer of voriconazole states concurrent use of other proton|
01193|025|M|pump inhibitors (PPIs) that are CYP2C19 substrates such as pantoprazole may|
01193|026|M|also require a dose adjustment.(1)|
01193|027|B||
01193|028|D|DISCUSSION:  In healthy subjects, concurrent voriconazole (400 mg every 12|
01193|029|D|hours Day 1, 200 mg Days 2-7) with omeprazole (40 mg daily for Days 1-7)|
01193|030|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
01193|031|D|omeprazole by 2-fold and 4-fold, respectively.  Therefore, the manufacturer|
01193|032|D|of voriconazole recommends that when voriconazole is initiated in patients|
01193|033|D|receiving dosages of omeprazole of 40 mg/day or greater, the dosage of|
01193|034|D|omeprazole should be reduced by one-half.(1)|
01193|035|D|   In healthy subjects, concurrent voriconazole (400 mg every 12 hours Day|
01193|036|D|1, 200 mg Days 2-10) with omeprazole (40 mg once daily) increased the Cmax|
01193|037|D|and AUC of voriconazole by 15% and 40%, respectively.  The manufacturer of|
01193|038|D|voriconazole does not recommend a dosage adjustment of voriconazole when|
01193|039|D|administered with omeprazole.(1)|
01193|040|B||
01193|041|R|REFERENCES:|
01193|042|B||
01193|043|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01193|044|R|2.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
01193|045|R|  Pharmaceuticals LP June, 2018.|1
01193|046|R|3.Protonix (pantoprazole sodium) US prescribing information. Wyeth|1
01193|047|R|  Pharmaceuticals, Inc. August, 2024.|1
01194|001|T|MONOGRAPH TITLE:  Atorvastatin; Lovastatin (Less than or Equal To 40 mg);|
01194|002|T|Simvastatin (Less Than or Equal To 20 mg)/Amiodarone|
01194|003|B||
01194|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01194|005|L|take action as needed.|
01194|006|B||
01194|007|A|MECHANISM OF ACTION:  Amiodarone may inhibit the metabolism of|
01194|008|A|atorvastatin,(1) lovastatin(2) and simvastatin(3-6) by CYP3A4.|
01194|009|B||
01194|010|E|CLINICAL EFFECTS:  Concurrent use of amiodarone(2) with certain HMG CoA|
01194|011|E|reductase inhibitors may increase the risk of rhabdomyolysis.|
01194|012|B||
01194|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01194|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01194|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01194|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01194|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01194|018|P|transporter OATP1B1 may have increased statin concentrations and be|
01194|019|P|predisposed to myopathy or rhabdomyolysis.|
01194|020|B||
01194|021|M|PATIENT MANAGEMENT:  Use the lowest dose of atorvastatin necessary in|
01194|022|M|patients receiving concurrent amiodarone therapy.(1)|
01194|023|M|   The US manufacturers of amiodarone(1) and lovastatin(2) recommend that|
01194|024|M|the dose of lovastatin not exceed 40 mg daily in patients receiving|
01194|025|M|concurrent amiodarone unless the potential benefit outweighs the increased|
01194|026|M|risk of myopathy.|
01194|027|M|   The US manufacturers of amiodarone(1) and simvastatin(3-6) recommend that|
01194|028|M|the dose of simvastatin not exceed 20 mg daily in patients receiving|
01194|029|M|concurrent amiodarone unless the potential benefit outweighs the increased|
01194|030|M|risk of myopathy.|
01194|031|B||
01194|032|D|DISCUSSION:  Rhabdomyolysis has been reported with concurrent amiodarone and|
01194|033|D|atorvastatin and simvastatin.(1)|
01194|034|D|   In a case report, a 63 year-old male developed rhabdomyolysis 4 weeks|
01194|035|D|after starting simvastatin therapy and 2 weeks after starting amiodarone.(7)|
01194|036|D|   In a clinical trial, myopathy was been reported in 6% of patients|
01194|037|D|receiving concurrent simvastatin (80 mg) and amiodarone.(3)|
01194|038|D|   In a randomized, cross-over study in 12 healthy subjects, subjects|
01194|039|D|received amiodarone (400 mg daily) with either simvastatin (40 mg) or|
01194|040|D|pravastatin (40 mg).  Amiodarone increased simvastatin area-under-curve|
01194|041|D|(AUC) by 73%, maximum concentration (Cmax) by 100%, and half-life by 48%.|
01194|042|D|There were no significant effects on pravastatin pharmacokinetics.(8)|
01194|043|D|   In a case report, a 72 year-old male developed rhabdomyolysis 10 weeks|
01194|044|D|after starting amiodarone (200 mg daily) therapy and 6 weeks after starting|
01194|045|D|simvastatin (80 mg daily).(9)|
01194|046|D|   In a retrospective review of patients receiving amiodarone, the rate of|
01194|047|D|adverse events in combination with a statin was 1.0%, 0.7%, and 0.4% for|
01194|048|D|simvastatin, atorvastatin, and pravastatin, respectively.  The most commonly|
01194|049|D|reported adverse effect was muscle soreness, which was present in 77% of|
01194|050|D|reports and was found more often in older male patients.(10)|
01194|051|B||
01194|052|R|REFERENCES:|
01194|053|B||
01194|054|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
01194|055|R|  Pharmaceuticals October, 2018.|1
01194|056|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01194|057|R|  February, 2014.|1
01194|058|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
01194|059|R|  2023.|1
01194|060|R|4.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
01194|061|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
01194|062|R|5.USFood and Drug Administration. FDA Drug Safety Communication: New|1
01194|063|R|  restrictions, contraindications, and dose limitations for Zocor|1
01194|064|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
01194|065|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01194|066|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
01194|067|R|  June 8, 2011.|1
01194|068|R|6.Ede M. Dear Canadian Healthcare Professional:  Subject:  ZOCOR|1
01194|069|R|  (simvastatin) - New Safety Recommendations on Dosage Associated with the|1
01194|070|R|  Increased Risk of Myopathy/Rhabdomyolysis. Merck Canada Inc. November 7,|1
01194|071|R|  2012.|1
01194|072|R|7.Roten L, Schoenenberger RA, Krahenbuhl S, Schlienger RG. Rhabdomyolysis in|3
01194|073|R|  association with simvastatin and amiodarone. Ann Pharmacother 2004 Jun;|3
01194|074|R|  38(6):978-81.|3
01194|075|R|8.Becquemont L, Neuvonen M, Verstuyft C, Jaillon P, Letierce A, Neuvonen PJ,|2
01194|076|R|  Funck-Brentano C. Amiodarone interacts with simvastatin but not with|2
01194|077|R|  pravastatin disposition kinetics. Clin Pharmacol Ther 2007 May;|2
01194|078|R|  81(5):679-84.|2
01194|079|R|9.Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin-amiodarone|3
01194|080|R|  interaction resulting in rhabdomyolysis, azotemia, and possible|3
01194|081|R|  hepatotoxicity. Ann Pharmacother 2006 Apr;40(4):753-7.|3
01194|082|R|10.Alsheikh-Ali AA, Karas RH. Adverse events with concomitant amiodarone and|2
01194|083|R|   statin therapy. Prev Cardiol 2005 Spring;8(2):95-7.|2
01195|001|T|MONOGRAPH TITLE:  Selected Oral Quinolones/Oral Calcium Products (mono|
01195|002|T|deleted 12/01/2011)|
01195|003|B||
01195|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01195|005|L|take action as needed.|
01195|006|B||
01195|007|A|MECHANISM OF ACTION:  Calcium may form chelation compounds with the|
01195|008|A|quinolones.(1-6)|
01195|009|B||
01195|010|E|CLINICAL EFFECTS:  Simultaneous administration or administration of calcium|
01195|011|E|products close to the administration time of certain oral quinolones may|
01195|012|E|result in decreased absorption and clinical effectiveness of the quinolone.|
01195|013|B||
01195|014|P|PREDISPOSING FACTORS:  None determined.|
01195|015|B||
01195|016|M|PATIENT MANAGEMENT:  If possible, avoid concomitant use of an oral quinolone|
01195|017|M|antibiotic and a calcium-containing antacid or supplement.  If it is|
01195|018|M|necessary to administer these agents concurrently, follow the manufacturer's|
01195|019|M|recommendations regarding timing of administration of the quinolone and the|
01195|020|M|calcium.|
01195|021|M|   Manufacturer recommendations regarding the separation of administration|
01195|022|M|times of quinolones and calcium-containing products vary.  Do NOT give|
01195|023|M|calcium-containing products:|
01195|024|M|--for 6 hours before or 2 hours after ciprofloxacin(1)|
01195|025|M|--for 8 hours before or 2 hours after enoxacin(2)|
01195|026|M|--for 2 hours before or 2 hours after levofloxacin(3)|
01195|027|M|--for 2 hours before or 2 hours after nalidixic acid(4)|
01195|028|M|--for 2 hours before or 2 hours after ofloxacin(5)|
01195|029|M|--until 4 hours after sparfloxacin(6)|
01195|030|B||
01195|031|D|DISCUSSION:  Calcium-containing compounds have been shown to form chelation|
01195|032|D|compounds with quinolone antibiotics, resulting in decreased absorption of|
01195|033|D|the quinolone.(1-6)  Concurrent administration of calcium has been shown to|
01195|034|D|decrease the bioavailability of ciprofloxacin by 40%.(7,8)  Concurrent|
01195|035|D|calcium has been shown to decrease the bioavailability of norfloxacin by|
01195|036|D|37.5%.(9)|
01195|037|D|   In a study in 12 subjects, calcium had no clinically significant effect|
01195|038|D|on the bioavailability of moxifloxacin.(10)|
01195|039|D|   Manufacturer recommendations regarding the separation of quinolones and|
01195|040|D|calcium-containing products vary.|
01195|041|B||
01195|042|R|REFERENCES:|
01195|043|B||
01195|044|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
01195|045|R|  Corporation February, 2011.|1
01195|046|R|2.Penetrex (enoxacin) US prescribing information. Aventis Pharmaceuticals,|1
01195|047|R|  Inc. July, 1998.|1
01195|048|R|3.Levaquin (levofloxacin) Canadian prescribing information. Janssen-Ortho|1
01195|049|R|  Inc. February 4, 2005.|1
01195|050|R|4.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
01195|051|R|  Inc. November, 2012.|1
01195|052|R|5.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
01195|053|R|  Pharmaceutical, Inc. February, 2011.|1
01195|054|R|6.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
01195|055|R|  Inc. February, 2003.|1
01195|056|R|7.Frost RW, Lasseter KC, Noe AJ, Shamblen EC, Lettieri JT. Effects of|2
01195|057|R|  aluminum hydroxide and calcium carbonate antacids on the bioavailability|2
01195|058|R|  of ciprofloxacin. Antimicrob Agents Chemother 1992 Apr;36(4):830-2.|2
01195|059|R|8.Sahai J, Healy DP, Stotka J, Polk RE. The influence of chronic|2
01195|060|R|  administration of calcium carbonate on the bioavailability of oral|2
01195|061|R|  ciprofloxacin. Br J Clin Pharmacol 1993 Mar;35(3):302-4.|2
01195|062|R|9.Nix DE, Wilton JH, Ronald B, Distlerath L, Williams VC, Norman A.|2
01195|063|R|  Inhibition of norfloxacin absorption by antacids. Antimicrob Agents|2
01195|064|R|  Chemother 1990 Mar;34(3):432-5.|2
01195|065|R|10.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
01195|066|R|   Pharmaceuticals Corporation February, 2011.|1
01196|001|T|MONOGRAPH TITLE:  Selected Oral Quinolones/Oral Zinc Products (mono deleted|
01196|002|T|12/01/2011)|
01196|003|B||
01196|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01196|005|L|take action as needed.|
01196|006|B||
01196|007|A|MECHANISM OF ACTION:  Zinc may form chelation compounds with the quinolones.|
01196|008|A|(1-11)|
01196|009|B||
01196|010|E|CLINICAL EFFECTS:  Simultaneous administration or administration of zinc|
01196|011|E|products close to the administration time of an oral quinolone may result in|
01196|012|E|decreased absorption and clinical effectiveness of the quinolone.|
01196|013|B||
01196|014|P|PREDISPOSING FACTORS:  None determined.|
01196|015|B||
01196|016|M|PATIENT MANAGEMENT:  If possible, avoid concomitant use of an oral quinolone|
01196|017|M|antibiotic and a zinc-containing product.  If it is necessary to administer|
01196|018|M|these agents concurrently, follow the manufacturers' recommendations|
01196|019|M|regarding timing of administration of the quinolone and the zinc product.|
01196|020|M|   Manufacturer recommendations regarding the separation of administration|
01196|021|M|times of quinolones and zinc-containing products: Do NOT give zinc:|
01196|022|M|--for 6 hours before or 2 hours after ciprofloxacin(1)|
01196|023|M|--for 8 hours before or 2 hours after enoxacin(2)|
01196|024|M|--until 4 hours after gatifloxacin(3)|
01196|025|M|--for 3 hours before or 2 hours after gemifloxacin(4)|
01196|026|M|--for 2 hours before or 2 hours after levofloxacin(5)|
01196|027|M|--for 2 hours before or 2 hours after lomefloxacin(6)|
01196|028|M|--for 8 hours before or 4 hours after moxifloxacin(7)|
01196|029|M|--for 2 hours before or 2 hours after nalidixic acid(8)|
01196|030|M|--for 2 hours before or 2 hours after norfloxacin(9)|
01196|031|M|--for 2 hours before or 2 hours after ofloxacin(10)|
01196|032|M|--until 4 hours after sparfloxacin(11)|
01196|033|B||
01196|034|D|DISCUSSION:  Zinc-containing compounds have been shown to form chelation|
01196|035|D|compounds with quinolone antibiotics, resulting in decreased absorption of|
01196|036|D|the quinolone.(1-11)  Concurrent administration of zinc has been shown to|
01196|037|D|decrease the bioavailability of ciprofloxacin.(12)  Concurrent zinc has been|
01196|038|D|shown to decrease the bioavailability of norfloxacin.(13)|
01196|039|B||
01196|040|R|REFERENCES:|
01196|041|B||
01196|042|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
01196|043|R|  Corporation February, 2011.|1
01196|044|R|2.Penetrex (enoxacin) US prescribing information. Aventis Pharmaceuticals,|1
01196|045|R|  Inc. July, 1998.|1
01196|046|R|3.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
01196|047|R|  Company January, 2006.|1
01196|048|R|4.Factive (gemifloxacin mesylate) US prescribing information. Oscient|1
01196|049|R|  Pharmaceuticals February, 2011.|1
01196|050|R|5.Levaquin (levofloxacin) US prescribing information. Ortho-McNeil|1
01196|051|R|  Pharmaceutical, Inc. February, 2011.|1
01196|052|R|6.Maxaquin (lomefloxacin hydrochloride) US prescribing information. Pfizer|1
01196|053|R|  Inc. January, 2005.|1
01196|054|R|7.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
01196|055|R|  Pharmaceuticals Corporation February, 2011.|1
01196|056|R|8.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
01196|057|R|  Inc. November, 2012.|1
01196|058|R|9.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc.|1
01196|059|R|  September, 2011.|1
01196|060|R|10.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
01196|061|R|   Pharmaceutical, Inc. February, 2011.|1
01196|062|R|11.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
01196|063|R|   Inc. February, 2003.|1
01196|064|R|12.Polk RE, Healy DP, Sahai J, Drwal L, Racht E. Effect of ferrous sulfate|2
01196|065|R|   and multivitamins with zinc on absorption of ciprofloxacin in normal|2
01196|066|R|   volunteers. Antimicrob Agents Chemother 1989 Nov;33(11):1841-4.|2
01196|067|R|13.Campbell NR, Kara M, Hasinoff BB, Haddara WM, McKay DW. Norfloxacin|2
01196|068|R|   interaction with antacids and minerals. Br J Clin Pharmacol 1992 Jan;|2
01196|069|R|   33(1):115-6.|2
01197|001|T|MONOGRAPH TITLE:  Artemether;Lumefantrine/Strong CYP3A4 Inhib; Protease|
01197|002|T|Inhib|
01197|003|B||
01197|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01197|005|L|take action as needed.|
01197|006|B||
01197|007|A|MECHANISM OF ACTION:  Potent inhibitors of CYP3A4 may inhibit the metabolism|
01197|008|A|of artemether and lumefantrine.(1)|
01197|009|B||
01197|010|E|CLINICAL EFFECTS:  Concurrent use of potent CYP3A4 inhibitors with|
01197|011|E|artemether-lumefantrine may result in elevated levels of the antimalarial|
01197|012|E|agents and toxicity, including prolongation of the QT interval which may|
01197|013|E|result in life threatening arrhythmia and death.(1)|
01197|014|B||
01197|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01197|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01197|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01197|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01197|019|P|female gender, or advanced age.(2)|
01197|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01197|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01197|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01197|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01197|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01197|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01197|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01197|027|B||
01197|028|M|PATIENT MANAGEMENT:  The manufacturer of artemether-lumefantrine states that|
01197|029|M|concurrent use with potent CYP3A4 inhibitors should be approached with|
01197|030|M|caution.(1)|
01197|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01197|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01197|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01197|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01197|035|B||
01197|036|D|DISCUSSION:  In a study in 13 healthy subjects, administration of|
01197|037|D|ketoconazole (400 mg Day 1, 200 mg Days 2-5, a potent inhibitor of CYP3A4)|
01197|038|D|with a single dose of artemether-lumefantrine (20 mg/120 mg) increased the|
01197|039|D|area-under-curve (AUC) of artemether and lumefantrine by 2.3-fold and|
01197|040|D|1.6-fold, respectively.(1)|
01197|041|D|    CYP3A4 inhibitors linked to this monograph include: atazanavir,|
01197|042|D|boceprevir, cobicistat, darunavir, fosamprenavir, idelalisib, indinavir,|
01197|043|D|itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone,|
01197|044|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir,|
01197|045|D|and tucatinib.(3,4)|
01197|046|B||
01197|047|R|REFERENCES:|
01197|048|B||
01197|049|R|1.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01197|050|R|  Pharmaceuticals Corporation August, 2019.|1
01197|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01197|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01197|053|R|  settings: a scientific statement from the American Heart Association and|6
01197|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01197|055|R|  2;55(9):934-47.|6
01197|056|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01197|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01197|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01197|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01197|060|R|  11/14/2017.|1
01197|061|R|4.This information is based on an extract from the Certara Drug Interaction|6
01197|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01198|001|T|MONOGRAPH TITLE:  Artemether; Lumefantrine/Selected Azole Antifungals (mono|
01198|002|T|deleted 10/04/2012)|
01198|003|B||
01198|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01198|005|L|take action as needed.|
01198|006|B||
01198|007|A|MECHANISM OF ACTION:  Some azole antifungals may inhibit the metabolism of|
01198|008|A|artemether and lumefantrine by CYP P-450-3A4.(1)|
01198|009|B||
01198|010|E|CLINICAL EFFECTS:  Concurrent use of CYP P-450-3A4 inhibitors with|
01198|011|E|artemether and lumefantrine may result in elevated levels of the|
01198|012|E|antimalarial agents and toxicity.(1)|
01198|013|B||
01198|014|P|PREDISPOSING FACTORS:  None determined.|
01198|015|B||
01198|016|M|PATIENT MANAGEMENT:  The US manufacturer of artemether-lumefantrine states|
01198|017|M|that the concurrent use of artemether-lumefantrine with agents that inhibit|
01198|018|M|CYP P-450-3A4, such as itraconazole or ketoconazole, should be approached|
01198|019|M|with caution.(1)|
01198|020|M|   Dosage adjustments are not necessary.(1,2)|
01198|021|B||
01198|022|D|DISCUSSION:  In a study in 15 healthy subjects, concurrent ketoconazole|
01198|023|D|resulted in a moderate increase (less than/equal to 2 -fold) in artemether,|
01198|024|D|lumefantrine, and dihydroartemisinin following a single dose of|
01198|025|D|artemether-lumefantrine.(1,2)  There were no increases in side effects or|
01198|026|D|electrocardiographic parameters.(2)|
01198|027|B||
01198|028|R|REFERENCES:|
01198|029|B||
01198|030|R|1.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
01198|031|R|  Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
01198|032|R|2.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01198|033|R|  Pharmaceuticals Corporation April, 2009.|1
01199|001|T|MONOGRAPH TITLE:  Artemether; Lumefantrine/Cimetidine (mono deleted|
01199|002|T|10/04/2012)|
01199|003|B||
01199|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01199|005|L|take action as needed.|
01199|006|B||
01199|007|A|MECHANISM OF ACTION:  Cimetidine may inhibit the metabolism of artemether|
01199|008|A|and lumefantrine by CYP P-450-3A4.(1)|
01199|009|B||
01199|010|E|CLINICAL EFFECTS:  Concurrent use of CYP P-450-3A4 inhibitors with|
01199|011|E|artemether and lumefantrine may result in elevated levels of the|
01199|012|E|antimalarial agents and toxicity.(1)|
01199|013|B||
01199|014|P|PREDISPOSING FACTORS:  None determined.|
01199|015|B||
01199|016|M|PATIENT MANAGEMENT:  The US manufacturer of artemether-lumefantrine states|
01199|017|M|that the concurrent use of artemether-lumefantrine with agents that inhibit|
01199|018|M|CYP P-450-3A4, such as cimetidine, should be approached with caution.(1)|
01199|019|B||
01199|020|D|DISCUSSION:  Artemether and lumefantrine are metabolized by CYP P-450-3A4.|
01199|021|D|Because there is a lack of clinical data and the effects on safety are|
01199|022|D|unknown, the manufacturer of artemether-lumefantrine states that the|
01199|023|D|concurrent use of artemether-lumefantrine with agents that inhibit CYP|
01199|024|D|P-450-3A4, such as cimetidine, should be approached with caution.(1)|
01199|025|B||
01199|026|R|REFERENCE:|
01199|027|B||
01199|028|R|1.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01199|029|R|  Pharmaceuticals Corporation April, 2009.|1
01200|001|T|MONOGRAPH TITLE:  Artemether; Lumefantrine/Protease Inhibitors (mono deleted|
01200|002|T|10/04/2012)|
01200|003|B||
01200|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01200|005|L|take action as needed.|
01200|006|B||
01200|007|A|MECHANISM OF ACTION:  Protease inhibitors have varying patterns of|
01200|008|A|inhibition, induction, and competition for CYP P-450-3A4.  Artemether and|
01200|009|A|lumefantrine are metabolized by CYP P-450-3A4 and artemether has been shown|
01200|010|A|to induce CYP P-450-3A4.(1)|
01200|011|B||
01200|012|E|CLINICAL EFFECTS:  The clinical effects seen with this interaction may vary|
01200|013|E|depending on the protease inhibitor(s) used.  Concurrent use with artemether|
01200|014|E|and lumefantrine may result in 1) elevated levels of and toxicity from|
01200|015|E|lumefantrine (including QTc prolongation and torsade de pointes), 2)|
01200|016|E|decreased levels and efficacy of artemether-lumefantrine, and/or 3)|
01200|017|E|decreased levels and efficacy of the protease inhibitor.(1)|
01200|018|B||
01200|019|P|PREDISPOSING FACTORS:  None determined.|
01200|020|B||
01200|021|M|PATIENT MANAGEMENT:  Concurrent use of artemether-lumefantrine with a|
01200|022|M|protease inhibitor should be approached with caution.(1)  Patients should be|
01200|023|M|monitored for clinical response and undesirable effects of both agents.(2)|
01200|024|B||
01200|025|D|DISCUSSION:  Artemether and lumefantrine are metabolized by CYP P-450-3A4|
01200|026|D|and artemether has been shown to induce CYP P-450-3A4. Protease inhibitors|
01200|027|D|have varying patterns of inhibition, induction, and competition for CYP|
01200|028|D|P-450-3A4.(1)|
01200|029|B||
01200|030|R|REFERENCES:|
01200|031|B||
01200|032|R|1.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
01200|033|R|  Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
01200|034|R|2.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01200|035|R|  Pharmaceuticals Corporation April, 2009.|1
01201|001|T|MONOGRAPH TITLE:  Flecainide/Lumefantrine|
01201|002|B||
01201|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01201|004|L|is contraindicated and generally should not be dispensed or administered to|
01201|005|L|the same patient.|
01201|006|B||
01201|007|A|MECHANISM OF ACTION:  Lumefantrine may inhibit the metabolism of flecainide|
01201|008|A|by CYP2D6.(1,2)|
01201|009|B||
01201|010|E|CLINICAL EFFECTS:  Concurrent administration of lumefantrine and flecainide|
01201|011|E|may result in elevated levels of flecainide and toxicity.(1,2)|
01201|012|B||
01201|013|P|PREDISPOSING FACTORS:  None determined.|
01201|014|B||
01201|015|M|PATIENT MANAGEMENT:  The UK manufacturer of artemether-lumefantrine states|
01201|016|M|that the concurrent use of artemether-lumefantrine is contraindicated in|
01201|017|M|patients receiving drugs that are metabolized by CYP2D6, such as|
01201|018|M|flecainide.(1)|
01201|019|M|   The US manufacturer of artemether-lumefantrine states that the concurrent|
01201|020|M|use of artemether-lumefantrine should be avoided in patients receiving drugs|
01201|021|M|that are metabolized by CYP2D6, such as flecainide.(2)|
01201|022|B||
01201|023|D|DISCUSSION:  Lumefantrine has been shown in vitro to inhibit CYP2D6.  This|
01201|024|D|may be clinically relevant for agents with a low therapeutic index that also|
01201|025|D|have cardiac effects.(1,2)|
01201|026|B||
01201|027|R|REFERENCES:|
01201|028|B||
01201|029|R|1.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
01201|030|R|  Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
01201|031|R|2.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01201|032|R|  Pharmaceuticals Corporation August, 2019.|1
01202|001|T|MONOGRAPH TITLE:  Metoprolol/Lumefantrine|
01202|002|B||
01202|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01202|004|L|is contraindicated and generally should not be dispensed or administered to|
01202|005|L|the same patient.|
01202|006|B||
01202|007|A|MECHANISM OF ACTION:  Lumefantrine may inhibit the metabolism of metoprolol|
01202|008|A|by inhibition of CYP2D6.(1)|
01202|009|B||
01202|010|E|CLINICAL EFFECTS:  Concurrent administration of lumefantrine and metoprolol|
01202|011|E|may result in elevated metoprolol plasma concentrations, increasing risk of|
01202|012|E|toxicity (bradycardia and hypotension) and decreasing cardioselectivity of|
01202|013|E|metoprolol.(2)|
01202|014|B||
01202|015|P|PREDISPOSING FACTORS:  Poor metabolizers of CYP2D6 and/or patients taking|
01202|016|P|other CYP2D6 inhibitors are at increased risk for a drug interaction between|
01202|017|P|metoprolol and lumefantrine.|
01202|018|B||
01202|019|M|PATIENT MANAGEMENT:  The UK manufacturer of artemether-lumefantrine states|
01202|020|M|that the concurrent use of artemether-lumefantrine is contraindicated in|
01202|021|M|patients receiving drugs that are metabolized by CYP2D6, such as metoprolol.|
01202|022|M|(1)|
01202|023|M|   The US manufacturer of artemether-lumefantrine states that|
01202|024|M|co-administration of artemether-lumefantrine and medications metabolized by|
01202|025|M|CYP2D6 is not recommended.(3)|
01202|026|B||
01202|027|D|DISCUSSION:  Lumefantrine has been shown in vitro to inhibit CYP2D6. Because|
01202|028|D|this may be clinically relevant for agents with a low therapeutic index, the|
01202|029|D|manufacturer of artemether-lumefantrine states that the concurrent use of|
01202|030|D|artemether-lumefantrine is contraindicated in patients receiving drugs that|
01202|031|D|are metabolized by CYP2D6, such as metoprolol. (1)|
01202|032|D|   The manufacturer of metoprolol states that patients who are poor|
01202|033|D|metabolizers of CYP2D6 may experience much higher plasma concentrations of|
01202|034|D|metoprolol than those with normal CYP2D6 activity, and that|
01202|035|D|co-administration of potent CYP2D6 inhibitors would mimic the|
01202|036|D|pharmacokinetics of CYP2D6 poor metabolizers.(2)|
01202|037|B||
01202|038|R|REFERENCES:|
01202|039|B||
01202|040|R|1.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
01202|041|R|  Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
01202|042|R|2.Lopressor (metoprolol tartrate) US prescribing information. Validus|1
01202|043|R|  Pharmaceuticals. LLC July, 2023.|1
01202|044|R|3.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01202|045|R|  Pharmaceuticals Corporation August, 2019.|1
01203|001|T|MONOGRAPH TITLE:  Selected Tricyclic Compounds/Lumefantrine|
01203|002|B||
01203|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01203|004|L|is contraindicated and generally should not be dispensed or administered to|
01203|005|L|the same patient.|
01203|006|B||
01203|007|A|MECHANISM OF ACTION:  Lumefantrine may inhibit the metabolism of some|
01203|008|A|tricyclic antidepressants by CYP2D6.(1,2)|
01203|009|B||
01203|010|E|CLINICAL EFFECTS:  Concurrent administration of lumefantrine and some|
01203|011|E|tricyclic antidepressants may result in elevated levels of the tricyclic|
01203|012|E|antidepressants and toxicity.(1,2)|
01203|013|B||
01203|014|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
01203|015|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
01203|016|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
01203|017|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
01203|018|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
01203|019|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
01203|020|P|systemic steroids).|
01203|021|P|   The risk of anticholinergic toxicities including cognitive decline,|
01203|022|P|delirium, falls and fractures is increased in geriatric patients using more|
01203|023|P|than one medicine with anticholinergic properties.(3)|
01203|024|B||
01203|025|M|PATIENT MANAGEMENT:  The UK manufacturer of artemether-lumefantrine states|
01203|026|M|that the concurrent use of artemether-lumefantrine is contraindicated in|
01203|027|M|patients receiving drugs that are metabolized by CYP2D6, such as some|
01203|028|M|tricyclic antidepressants.(1)|
01203|029|M|   The US manufacturer of artemether-lumefantrine states that the concurrent|
01203|030|M|use of artemether-lumefantrine should be avoided in patients receiving drugs|
01203|031|M|that are metabolized by CYP2D6, such as some tricyclic antidepressants.(2)|
01203|032|B||
01203|033|D|DISCUSSION:  Lumefantrine has been shown in vitro to inhibit CYP2D6.  This|
01203|034|D|may be clinically relevant for agents with a low therapeutic index that have|
01203|035|D|cardiac effects.(1,2)|
01203|036|B||
01203|037|R|REFERENCES:|
01203|038|B||
01203|039|R|1.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
01203|040|R|  Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
01203|041|R|2.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01203|042|R|  Pharmaceuticals Corporation August, 2019.|1
01203|043|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01203|044|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01203|045|R|  Soc 2023 Jul;71(7):2052-2081.|6
01204|001|T|MONOGRAPH TITLE:  Artemether; Lumefantrine/Antimalarials|
01204|002|B||
01204|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01204|004|L|is contraindicated and generally should not be dispensed or administered to|
01204|005|L|the same patient.|
01204|006|B||
01204|007|A|MECHANISM OF ACTION:  Halofantrine and quinine may inhibit the metabolism of|
01204|008|A|lumefantrine by CYP2D6.(1)  The combination of artemether-lumefantrine and|
01204|009|A|antimalarials may result in additive effects on the QT interval.(1)|
01204|010|B||
01204|011|E|CLINICAL EFFECTS:  Concurrent use may result in toxicity and/or prolongation|
01204|012|E|of the QT interval, which may result in life-threatening arrhythmias.(1,2)|
01204|013|B||
01204|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01204|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01204|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01204|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01204|018|P|female gender, or advanced age.(3)|
01204|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01204|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01204|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01204|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01204|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01204|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01204|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01204|026|B||
01204|027|M|PATIENT MANAGEMENT:  The UK manufacturer of artemether-lumefantrine states|
01204|028|M|that the concurrent use of artemether-lumefantrine with other antimalarials|
01204|029|M|is contraindicated.(1)|
01204|030|M|   The US manufacturer of artemether-lumefantrine states that|
01204|031|M|artemether-lumefantrine should not be given concurrently with|
01204|032|M|antimalarials.(2)|
01204|033|M|   If a patient deteriorates during artemether-lumefantrine therapy and|
01204|034|M|requires another antimalarial agent, it may be started immediately, but the|
01204|035|M|UK manufacturer of artemether-lumefantrine recommends ECG and potassium|
01204|036|M|monitoring.(1)|
01204|037|M|   In patients who have previously received halofantrine, both the UK and US|
01204|038|M|manufacturers of artemether-lumefantrine recommends that one month elapse|
01204|039|M|between the last dose of halofantrine and the initiation of|
01204|040|M|artemether-lumefantrine.(1)|
01204|041|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01204|042|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01204|043|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01204|044|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01204|045|B||
01204|046|D|DISCUSSION:  In a study in 14 healthy subjects, administration of a single|
01204|047|D|intravenous dose of quinine (10 mg/kg) 2 hours after the sixth dose of|
01204|048|D|artemether-lumefantrine had no effect on lumefantrine or dihydroartemisinin|
01204|049|D|levels.  Artemether levels were decreased; however, this was not believed to|
01204|050|D|be clinically significant.(1,2)  Concurrent quinine and|
01204|051|D|artemether-lumefantrine produced a slight, but significant increase on the|
01204|052|D|QTc interval.(1)|
01204|053|B||
01204|054|R|REFERENCES:|
01204|055|B||
01204|056|R|1.Giao PT, de Vries PJ. Pharmacokinetic interactions of antimalarial agents.|6
01204|057|R|  Clin Pharmacokinet 2001;40(5):343-73.|6
01204|058|R|2.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01204|059|R|  Pharmaceuticals Corporation August, 2019.|1
01204|060|R|3.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
01204|061|R|  Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
01204|062|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01204|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01204|064|R|  settings: a scientific statement from the American Heart Association and|6
01204|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01204|066|R|  2;55(9):934-47.|6
01204|067|R|5.Lefevre G, Bindschedler M, Ezzet F, Schaeffer N, Meyer I, Thomsen MS.|2
01204|068|R|  Pharmacokinetic interaction trial between co-artemether and mefloquine.|2
01204|069|R|  Eur J Pharm Sci 2000 Apr;10(2):141-51.|2
01204|070|R|6.van Agtmael MA, Van Der Graaf CA, Dien TK, Koopmans RP, van Boxtel CJ. The|2
01204|071|R|  contribution of the enzymes CYP2D6 and CYP2C19 in the demethylation of|2
01204|072|R|  artemether in healthy subjects. Eur J Drug Metab Pharmacokinet 1998|2
01204|073|R|  Jul-Sep;23(3):429-36.|2
01204|074|R|7.Tan-ariya P, Na-Bangchang K, Ubalee R, Thanavibul A, Thipawangkosol P,|2
01204|075|R|  Karbwang J. Pharmacokinetic interactions of artemether and pyrimethamine|2
01204|076|R|  in healthy male Thais. Southeast Asian J Trop Med Public Health 1998 Mar;|2
01204|077|R|  29(1):18-23.|2
01205|001|T|MONOGRAPH TITLE:  Tapentadol/Tricyclic Compounds; Carbamazepine|
01205|002|B||
01205|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01205|004|L|of severe adverse interaction.|
01205|005|B||
01205|006|A|MECHANISM OF ACTION:  Tapentadol and tricyclic compounds may lower the|
01205|007|A|seizure threshold.(1)|
01205|008|A|   Tapentadol and tricyclic compounds may result in additive effects on|
01205|009|A|serotonin levels.(1)|
01205|010|A|   Although not used therapeutically as an antidepressant, carbamazepine is|
01205|011|A|a tricyclic compound.|
01205|012|B||
01205|013|E|CLINICAL EFFECTS:  Concurrent use of tapentadol and a tricyclic compound may|
01205|014|E|result in seizures or serotonin syndrome.(1)|
01205|015|B||
01205|016|P|PREDISPOSING FACTORS:  Risk of seizures may be increased in patients with|
01205|017|P|epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol|
01205|018|P|or drug withdrawal, or infections of the central nervous system.(1)|
01205|019|B||
01205|020|M|PATIENT MANAGEMENT:  Tapentadol should be used with caution in patients|
01205|021|M|taking tricyclic compounds, including carbamazepine.  Monitor patients|
01205|022|M|closely for serotonin syndrome.(1)|
01205|023|B||
01205|024|D|DISCUSSION:  Concurrent use of tapentadol with tricyclic compounds may|
01205|025|D|result in additive blockage of serotonin reuptake, leading to central|
01205|026|D|serotonergic hyperstimulation.  Cases of serotonin syndrome have been|
01205|027|D|reported with tapentadol in combination with other serotonergic drugs.(1)|
01205|028|D|   Use of tapentadol has been associated with increased seizure frequency in|
01205|029|D|patients with seizure disorders.(1)|
01205|030|B||
01205|031|R|REFERENCES:|
01205|032|B||
01205|033|R|1.Nucynta ER (tapentadol) US prescribing information. Janssen|1
01205|034|R|  Pharmaceuticals December, 2023.|1
01205|035|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01205|036|R|  352(11):1112-20.|6
01206|001|T|MONOGRAPH TITLE:  Tramadol/MAOIs|
01206|002|B||
01206|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01206|004|L|is contraindicated and generally should not be dispensed or administered to|
01206|005|L|the same patient.|
01206|006|B||
01206|007|A|MECHANISM OF ACTION:  Tramadol and MAO inhibitors (MAOIs) may lower the|
01206|008|A|seizure threshold.(1-3)|
01206|009|A|   Both tramadol and MAOIs may increase serotonin and norepinephrine.|
01206|010|A|Tramadol inhibits neuronal reuptake of serotonin and norepinephrine, while|
01206|011|A|MAOIs impair metabolism of serotonin and norepinephrine via inhibition of|
01206|012|A|monoamine oxidase(MAO).(1-3)|
01206|013|B||
01206|014|E|CLINICAL EFFECTS:  Concurrent use of tramadol and an inhibitor of monoamine|
01206|015|E|oxidase may result in seizures or serotonin syndrome.(1-3)  Symptoms of|
01206|016|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
01206|017|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)|
01206|018|B||
01206|019|P|PREDISPOSING FACTORS:  CYP2D6 poor metabolizers, or patients also taking|
01206|020|P|strong CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine,|
01206|021|P|terbinafine) will inhibit tramadol metabolism leading higher systemic levels|
01206|022|P|of tramadol.|
01206|023|P|   Risk of seizures may be increased in patients with epilepsy, a history of|
01206|024|P|seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or|
01206|025|P|infections of the central nervous system.(3)  The risk of seizure may also|
01206|026|P|be increased in patients receiving more than the upper daily dose limit of|
01206|027|P|tramadol or in patients taking other medications that lower seizure|
01206|028|P|threshold.(1-2)|
01206|029|B||
01206|030|M|PATIENT MANAGEMENT:  The Australian manufacturers of tramadol state that it|
01206|031|M|is contraindicated in patients who are currently receiving monoamine oxidase|
01206|032|M|inhibitors or who have received them in the previous 14 days.(1,2)|
01206|033|M|   The US manufacturer of tramadol states that tramadol should be used with|
01206|034|M|caution in patients taking monoamine oxidase inhibitors and in patients|
01206|035|M|receiving antidepressants.(3)|
01206|036|B||
01206|037|D|DISCUSSION:  The use of tramadol in patients taking monoamine oxidase|
01206|038|D|inhibitors may increase the risk of seizures, serotonin syndrome, and|
01206|039|D|suicide.(3)|
01206|040|D|   Methylene blue, when administered intravenously, has been shown to reach|
01206|041|D|sufficient concentrations to be a potent inhibitor of MAO-A.(4,5)|
01206|042|D|   Metaxalone is a weak inhibitor of MAO.(7,8)|
01206|043|D|   One or more of the drug pairs linked to this monograph have been included|
01206|044|D|in a list of interactions that should be considered "high-priority" for|
01206|045|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01206|046|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01206|047|D|Coordinator (ONC) for Health Information Technology.|
01206|048|B||
01206|049|R|REFERENCES:|
01206|050|B||
01206|051|R|1.Zydol (tramadol hydrochloride) Australian prescribing information. CSL|1
01206|052|R|  Limited November 27, 2002.|1
01206|053|R|2.Tramal (tramadol hydrochloride) Australian prescribing information. CSL|1
01206|054|R|  Limited November 27, 2002.|1
01206|055|R|3.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
01206|056|R|  October, 2019.|1
01206|057|R|4.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
01206|058|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
01206|059|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
01206|060|R|5.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
01206|061|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
01206|062|R|  2000 Jun;56(3):247-50.|2
01206|063|R|6.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01206|064|R|  352(11):1112-20.|6
01206|065|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01206|066|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01206|067|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01206|068|R|  19(5):735-43.|6
01207|001|T|MONOGRAPH TITLE:  Gabapentin/Aluminum; Magnesium-Containing Compounds|
01207|002|B||
01207|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01207|004|L|take action as needed.|
01207|005|B||
01207|006|A|MECHANISM OF ACTION:  Aluminum or magnesium containing products may reduce|
01207|007|A|the bioavailability of gabapentin.(1)|
01207|008|B||
01207|009|E|CLINICAL EFFECTS:  Simultaneous administration of aluminum or magnesium|
01207|010|E|containing products and gabapentin may result in decreased absorption of|
01207|011|E|gabapentin by 20% and reduce its clinical effectiveness.(1)|
01207|012|B||
01207|013|P|PREDISPOSING FACTORS:  None determined.|
01207|014|B||
01207|015|M|PATIENT MANAGEMENT:  If the use of both medications is unavoidable, it is|
01207|016|M|recommended that gabapentin be taken at least 2 hours following the|
01207|017|M|administration of aluminum or magnesium containing products.(1)|
01207|018|B||
01207|019|D|DISCUSSION:  In 16 subjects, Maalox reduced the bioavailability of|
01207|020|D|gabapentin by about 20%.  The reduction was only 5% when gabapentin was|
01207|021|D|administered 2 hours after the Maalox dose.  It is for this reason that the|
01207|022|D|manufacturer of gabapentin recommends that it be taken at least 2 hours|
01207|023|D|after the administration of aluminum or magnesium containing products.(1)|
01207|024|B||
01207|025|R|REFERENCE:|
01207|026|B||
01207|027|R|1.Neurontin (gabapentin) US prescribing information. Pfizer, Inc. December,|1
01207|028|R|  2020.|1
01208|001|T|MONOGRAPH TITLE:  Irinotecan/Strong CYP3A4 Inhibitors; Darunavir|
01208|002|B||
01208|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01208|004|L|is contraindicated and generally should not be dispensed or administered to|
01208|005|L|the same patient.|
01208|006|B||
01208|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
01208|008|A|SN-38, the active metabolite of irinotecan.|
01208|009|A|   Strong CYP3A4 inhibitors and darunavir may prevent the breakdown of SN-38|
01208|010|A|to its inactive metabolites APC, NPC, M2, M3, and M4.(1,2)|
01208|011|B||
01208|012|E|CLINICAL EFFECTS:  Coadministration of irinotecan with a strong CYP3A4|
01208|013|E|inhibitor may result in increased irinotecan plasma concentration, and|
01208|014|E|therefore increased exposure to its active metabolite SN-38. Increased SN-38|
01208|015|E|exposure may lead to serious toxicity, including severe neutropenia,|
01208|016|E|interstitial pulmonary disease, and even death.(3)|
01208|017|B||
01208|018|P|PREDISPOSING FACTORS:  None determined.|
01208|019|B||
01208|020|M|PATIENT MANAGEMENT:  Concurrent use of irinotecan and strong CYP3A4|
01208|021|M|inhibitors or darunavir is contraindicated.(2-4)  Strong CYP3A4 inhibitors|
01208|022|M|should be discontinued at least 1 week prior to starting irinotecan.(4)|
01208|023|M|   The US manufacturer of itraconazole states that concomitant|
01208|024|M|administration with irinotecan is contra-indicated during and two weeks|
01208|025|M|after itraconazole treatment.(5)|
01208|026|M|   If concurrent therapy is warranted, consider a four-fold reduction in|
01208|027|M|irinotecan dose.(3)  Patients receiving concurrent therapy should be closely|
01208|028|M|monitored for toxicity.|
01208|029|B||
01208|030|D|DISCUSSION:  A randomized cross-over study involving seven patients was|
01208|031|D|performed in which each was given irinotecan 350 mg/m2 IV alone for 90|
01208|032|D|minutes and followed 3 weeks later by irinotecan 100 mg/m2 given with|
01208|033|D|ketoconazole 200 mg orally 1 hour before or 23 hours after the infusion of|
01208|034|D|irinotecan, or both cycles were given vice versa.  With ketoconazole|
01208|035|D|coadministration, the conversion of irinotecan to its inactive metabolite|
01208|036|D|was reduced by 87%, whereas the relative exposure to the active prodrug was|
01208|037|D|increased by 109%.  Both hematologic (degree of myelosuppression; percent|
01208|038|D|decrease in neutrophil count) and nonhematologic (nausea, vomiting, and|
01208|039|D|diarrhea) parameters were similar between the courses, despite a 3.5 fold|
01208|040|D|reduced irinotecan dose when given in combination with ketoconazole.  The|
01208|041|D|authors concluded that the coadministration of various CYP3A4 inhibitors|
01208|042|D|could potentiate a fatal outcome.(3)|
01208|043|D|   A prospective, open-label, randomized study was conducted to determine|
01208|044|D|the pharmacokinetics of lopinavir (LPV)/ritonavir (RTV) administration with|
01208|045|D|irinotecan (CPT11). Eight HIV-infected, Caucasian male patients with|
01208|046|D|Kaposi's sarcoma, stage IV (according to New York University classification)|
01208|047|D|were administered highly active antiretroviral therapy (HAART). HAART|
01208|048|D|consisted of 400 mg lopinavir/ 100 mg ritonavir (Kaletra) twice daily|
01208|049|D|(b.i.d) in association with NRTIs b.i.d. for at least 1 month before the|
01208|050|D|start of anticancer chemotherapy. Patients were then treated with irinotecan|
01208|051|D|as a single agent (150 mg/m2) over a 90 min infusion at days 1 and 10, every|
01208|052|D|3 weeks. Concomitant LPV/RTV treatment reduced the irinotecan clearance from|
01208|053|D|21.3 +/- 6.3 to 11.3 +/- 3.5 l/h/m2 (P=0.0008) causing an 89% increase of|
01208|054|D|CPT11 AUC (P=0.001) and a 20% increase in the Cmax of CPT11 (p=0.02). The|
01208|055|D|LPV/RTV treatment increased the AUC of SN38 by 204% (p=0.0001) and AUC of|
01208|056|D|SN38G by 94% (P=0.002).  Conversely, LPV/RTV treatment caused an 81%|
01208|057|D|reduction in AUC of APC (p=0.02).  Overall, the authors concluded that|
01208|058|D|CYP3A4 inhibitors like LPV/RTV decrease CPT11 clearance and increase SN-38|
01208|059|D|exposure, potentially leading to CPT11 toxicity if not monitored closely.(7)|
01208|060|D|   Strong CYP3A4 Inhibitors include:  adagrasib, boceprevir, ceritinib,|
01208|061|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
01208|062|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
01208|063|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
01208|064|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
01208|065|D|tucatinib, and voriconazole.(8)|
01208|066|D|   One or more of the drug pairs linked to this monograph have been included|
01208|067|D|in a list of interactions that should be considered "high-priority" for|
01208|068|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01208|069|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01208|070|D|Coordinator (ONC) for Health Information Technology.|
01208|071|B||
01208|072|R|REFERENCES:|
01208|073|B||
01208|074|R|1.Santos A, Zanetta S, Cresteil T, Deroussent A, Pein F, Raymond E,|2
01208|075|R|  Vernillet L, Risse ML, Boige V, Gouyette A, Vassal G. Metabolism of|2
01208|076|R|  irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res 2000|2
01208|077|R|  May;6(5):2012-20.|2
01208|078|R|2.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01208|079|R|  March, 2023.|1
01208|080|R|3.Kehrer DF, Mathijssen RH, Verweij J, de Bruijn P, Sparreboom A. Modulation|2
01208|081|R|  of irinotecan metabolism by ketoconazole. J Clin Oncol 2002 Jul 15;|2
01208|082|R|  20(14):3122-9.|2
01208|083|R|4.Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia|1
01208|084|R|  & Upjohn Company January, 2020.|1
01208|085|R|5.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01208|086|R|  Pharmaceuticals February, 2014.|1
01208|087|R|6.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01208|088|R|  Products, L.P. February, 2024.|1
01208|089|R|7.Corona G, Vaccher E, Sandron S, Sartor I, Tirelli U, Innocenti F, Toffoli|2
01208|090|R|  G. Lopinavir-ritonavir dramatically affects the pharmacokinetics of|2
01208|091|R|  irinotecan in HIV patients with Kaposi's sarcoma. Clin Pharmacol Ther 2008|2
01208|092|R|  Apr;83(4):601-6.|2
01208|093|R|8.This information is based on an extract from the Certara Drug Interaction|6
01208|094|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01208|095|R|9.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01208|096|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01208|097|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01208|098|R|  19(5):735-43.|6
01209|001|T|MONOGRAPH TITLE:  Sodium Oxybate/Sedative Hypnotics; Alcohol|
01209|002|B||
01209|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01209|004|L|is contraindicated and generally should not be dispensed or administered to|
01209|005|L|the same patient.|
01209|006|B||
01209|007|A|MECHANISM OF ACTION:  Oxybate may be associated with respiratory depression.|
01209|008|A|As oxybate is taken at bedtime, concurrent use with alcohol or hypnotics may|
01209|009|A|increase the risk for respiratory depression or loss of consciousness.(1-3)|
01209|010|A|   Primidone is metabolized to phenobarbital.|
01209|011|B||
01209|012|E|CLINICAL EFFECTS:  Concurrent use of sodium oxybate and sedative hypnotics|
01209|013|E|or alcohol may  further increase the risk for respiratory depression and|
01209|014|E|profound sedation or coma.(1,2)  Fatalities have been reported.(3)|
01209|015|B||
01209|016|P|PREDISPOSING FACTORS:  Based upon FDA evaluation of deaths in patients|
01209|017|P|taking sodium oxybate, risk factors may include: use of multiple drugs which|
01209|018|P|depress the CNS, more rapid than recommended oxybate dose titration,|
01209|019|P|exceeding the maximum recommended oxybate dose, and prescribing for|
01209|020|P|unapproved uses such as fibromyalgia, insomnia or migraine. Note that in|
01209|021|P|oxybate clinical trials for narcolepsy 78% - 85% of patients were also|
01209|022|P|receiving concomitant CNS stimulants.(1-3)|
01209|023|B||
01209|024|M|PATIENT MANAGEMENT:  The FDA states that sodium oxybate is contraindicated|
01209|025|M|in patients also taking hypnotics or alcohol.(1,2)|
01209|026|M|   Significant quantities of alcohol may be present in medicinal products.|
01209|027|M|Alcohol is is used to improve docetaxel and paclitaxel solubility.|
01209|028|M|   - The quantity of alcohol in paclitaxel injection formulations|
01209|029|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01209|030|M|dose contains approximately 13 grams of alcohol.|
01209|031|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01209|032|M|3-fold depending upon the manufacturer. FDA data on alcohol content (4):|
01209|033|M|   Product                      Manufacturer         Alcohol/200 mg dose|
01209|034|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01209|035|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01209|036|M|   Docetaxel Inj.               Accord                  4.0 grams|
01209|037|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01209|038|M|    formulation|
01209|039|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01209|040|M|   Docefrez                     Sun Pharma              2.9 grams|
01209|041|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01209|042|M|    formulation|
01209|043|B||
01209|044|D|DISCUSSION:  The FDA evaluated sodium oxybate postmarket fatal adverse event|
01209|045|D|reports from the FDA Adverse Event Reporting System(AERS)and from the|
01209|046|D|manufacturer. Although report documentation was not always optimal or|
01209|047|D|complete, useful information was obtained.|
01209|048|D|   Factors which may have contributed to fatal outcome: concomitant use of|
01209|049|D|one or more drugs which depress the CNS, more rapid than recommended upward|
01209|050|D|dose titration, exceeding the maximum recommended oxybate dose, and|
01209|051|D|prescribing for unapproved uses such as fibromyalgia, insomnia or migraine.|
01209|052|D|   Many deaths occurred in patients with serious psychiatric disorders such|
01209|053|D|as depression and substance abuse. Other concomitant diseases may have also|
01209|054|D|contributed to respiratory and CNS depressant effects of oxybate.(3)|
01209|055|B||
01209|056|R|REFERENCES:|
01209|057|B||
01209|058|R|1.Xyrem (sodium oxybate) US prescribing information. Jazz Pharmaceuticals,|1
01209|059|R|  Inc. April, 2023.|1
01209|060|R|2.Lumryz (sodium oxybate extended-release oral suspension) US prescribing|1
01209|061|R|  information. Avadel CNS Pharmaceuticals, LLC May, 2023.|1
01209|062|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Warning|1
01209|063|R|  against use of Xyrem (sodium oxybate) with alcohol or drugs causing|1
01209|064|R|  respiratory depression. available at:|1
01209|065|R|  http://www.fda.gov/Drugs/DrugSafety/ucm332029.htm December 17, 2012.|1
01209|066|R|4.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
01209|067|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
01209|068|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01209|069|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
01209|070|R|  20, 2014.|1
01210|001|T|MONOGRAPH TITLE:  Eplerenone/Potassium Supplements|
01210|002|B||
01210|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01210|004|L|of severe adverse interaction.|
01210|005|B||
01210|006|A|MECHANISM OF ACTION:  Eplerenone increases serum potassium levels.(1)|
01210|007|B||
01210|008|E|CLINICAL EFFECTS:  Concurrent use of eplerenone with a potassium supplement|
01210|009|E|may result in hyperkalemia.(1)|
01210|010|B||
01210|011|P|PREDISPOSING FACTORS:  Renal impairment.|
01210|012|B||
01210|013|M|PATIENT MANAGEMENT:  The manufacturer of eplerenone states that the use of|
01210|014|M|eplerenone for the treatment of hypertension in patients receiving potassium|
01210|015|M|supplements is contraindicated.(1)|
01210|016|B||
01210|017|D|DISCUSSION:  The main risk of eplerenone therapy is hyperkalemia.  The risk|
01210|018|D|of hyperkalemia can be reduced by avoiding potassium supplements during|
01210|019|D|eplerenone therapy.(1)|
01210|020|B||
01210|021|R|REFERENCE:|
01210|022|B||
01210|023|R|1.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
01211|001|T|MONOGRAPH TITLE:  Aldosterone Receptor Antagonists/Potassium Sparing|
01211|002|T|Diuretics|
01211|003|B||
01211|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01211|005|L|of severe adverse interaction.|
01211|006|B||
01211|007|A|MECHANISM OF ACTION:  Aldosterone receptor antagonists increase serum|
01211|008|A|potassium levels, as do potassium-sparing diuretics.(1-3)|
01211|009|B||
01211|010|E|CLINICAL EFFECTS:  Concurrent use of aldosterone receptor antagonists with a|
01211|011|E|potassium sparing diuretic may result in hyperkalemia.(1-3)|
01211|012|B||
01211|013|P|PREDISPOSING FACTORS:  Renal impairment|
01211|014|B||
01211|015|M|PATIENT MANAGEMENT:  The manufacturer of eplerenone states that the use of|
01211|016|M|eplerenone for the treatment of hypertension in patients receiving|
01211|017|M|potassium-sparing diuretics is contraindicated.(1)|
01211|018|M|   The US manufacturer of spironolactone states that spironolactone should|
01211|019|M|not be used with potassium-sparing diuretics.(2)|
01211|020|M|   The US manufacturer of finerenone states that more frequent monitoring of|
01211|021|M|potassium may be necessary in patients on concomitant medications that|
01211|022|M|impair potassium excretion or increase serum potassium levels.(3)|
01211|023|B||
01211|024|D|DISCUSSION:  The one of the main risks of aldosterone receptor antagonist|
01211|025|D|therapy is hyperkalemia.  The risk of hyperkalemia can be reduced by|
01211|026|D|avoiding potassium sparing diuretics during therapy.(1-3)|
01211|027|B||
01211|028|R|REFERENCES:|
01211|029|B||
01211|030|R|1.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
01211|031|R|2.Aldactone (spironolactone) US prescribing information. Pfizer November,|1
01211|032|R|  2025.|1
01211|033|R|3.KERENDIA (finerenone) US prescribing information. Bayer HealthCare|1
01211|034|R|  Pharmaceuticals Inc. July, 2025.|1
01212|001|T|MONOGRAPH TITLE:  Eplerenone/Strong CYP3A4 Inhibitors; Protease Inhibitors|
01212|002|B||
01212|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01212|004|L|is contraindicated and generally should not be dispensed or administered to|
01212|005|L|the same patient.|
01212|006|B||
01212|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 and protease inhibitors|
01212|008|A|may inhibit the metabolism of eplerenone.(1-3)|
01212|009|B||
01212|010|E|CLINICAL EFFECTS:  Concurrent use of eplerenone with a strong inhibitor of|
01212|011|E|CYP3A4 or a protease inhibitor may result in 5-fold increases in eplerenone|
01212|012|E|concentrations and toxicity (e.g. hyperkalemia, hypotension).(1-3)|
01212|013|B||
01212|014|P|PREDISPOSING FACTORS:  Severe renal disease increases the risk for|
01212|015|P|hyperkalemia.|
01212|016|B||
01212|017|M|PATIENT MANAGEMENT:  The manufacturer of eplerenone states that the|
01212|018|M|concurrent use of strong CYP3A4 inhibitors is contraindicated.(1)  The US|
01212|019|M|Department of Health and Human Services HIV guidelines state that protease|
01212|020|M|inhibitors are contraindicated with eplerenone.(3)|
01212|021|M|   The US manufacturer of itraconazole states that concurrent use of|
01212|022|M|eplerenone is contraindicated during and two weeks after itraconazole|
01212|023|M|treatment.(4)|
01212|024|M|   The starting dose of eplerenone for hypertension should be reduced to 25|
01212|025|M|mg in patients receiving moderate CYP3A4 inhibitors.(1)|
01212|026|M|   In all patients taking eplerenone who start taking a moderate CYP3A4|
01212|027|M|inhibitor, check serum potassium and creatinine levels after 3-7 days of|
01212|028|M|concurrent therapy.(1)|
01212|029|B||
01212|030|D|DISCUSSION:  Ketoconazole (200 mg BID) increased the maximum concentration|
01212|031|D|(Cmax) and area-under-curve (AUC) of a single dose of eplerenone (100 mg) by|
01212|032|D|1.7-fold and 5.4-fold, respectively.(1)|
01212|033|D|   The concurrent use of eplerenone with less potent CYP3A4 inhibitors|
01212|034|D|(erythromycin 500 mg BID, fluconazole 200 mg daily, saquinavir 1200 mg TID,|
01212|035|D|and verapamil 240 mg daily) increased the Cmax of eplerenone by 1.4-fold to|
01212|036|D|1.6-fold and the AUC of eplerenone by 2.0-fold and 2.9-fold.(1)|
01212|037|D|   Strong inhibitors of CYP3A4 and protease inhibitors linked to this|
01212|038|D|monograph include:  adagrasib, amprenavir, atazanavir, boceprevir,|
01212|039|D|ceritinib, clarithromycin, cobicistat, darunavir, fosamprenavir, idelalisib,|
01212|040|D|indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir,|
01212|041|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
01212|042|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
01212|043|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1,2)|
01212|044|B||
01212|045|R|REFERENCES:|
01212|046|B||
01212|047|R|1.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
01212|048|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01212|049|R|  Pharmaceuticals February, 2014.|1
01212|050|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01212|051|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01212|052|R|  HIV. Department of Health and Human Services. Available at:|6
01212|053|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
01212|054|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
01212|055|R|4.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01212|056|R|  Products, L.P. February, 2024.|1
01212|057|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
01212|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01212|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01212|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01212|061|R|  11/14/2017.|1
01213|001|T|MONOGRAPH TITLE:  Eplerenone/Selected Moderate CYP3A4 Inhibitors|
01213|002|B||
01213|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01213|004|L|of severe adverse interaction.|
01213|005|B||
01213|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
01213|007|A|metabolism of eplerenone.(1)|
01213|008|B||
01213|009|E|CLINICAL EFFECTS:  Concurrent use of moderate inhibitors of CYP3A4 may|
01213|010|E|result in a 2-fold increase in eplerenone concentration and toxicity (e.g.|
01213|011|E|hyperkalemia, hypotension).(1)|
01213|012|B||
01213|013|P|PREDISPOSING FACTORS:  Severe renal disease increases the risk for|
01213|014|P|hyperkalemia.|
01213|015|B||
01213|016|M|PATIENT MANAGEMENT:  The starting dose of eplerenone for hypertension should|
01213|017|M|be reduced to 25 mg in patients receiving moderate CYP3A4 inhibitors. For|
01213|018|M|inadequate blood pressure response, dosing may be increased to a maximum of|
01213|019|M|25 mg twice daily. Do not exceed 25 mg once daily in post-MI CHF patients|
01213|020|M|receiving a moderate CYP3A4 inhibitor.(1)|
01213|021|M|   In all patients taking eplerenone who start taking a moderate CYP3A4|
01213|022|M|inhibitor, check serum potassium and creatinine levels after 3-7 days of|
01213|023|M|concurrent therapy.(1)|
01213|024|B||
01213|025|D|DISCUSSION:  Ketoconazole (200 mg BID) increased the maximum concentration|
01213|026|D|(Cmax) and area-under-curve (AUC) of a single dose of eplerenone (100 mg) by|
01213|027|D|1.7-fold and 5.4-fold, respectively.(1)|
01213|028|D|   The concurrent use of eplerenone with less potent CYP3A4 inhibitors|
01213|029|D|(erythromycin 500 mg BID, fluconazole 200 mg daily, saquinavir 1200 mg TID,|
01213|030|D|and verapamil 240 mg daily) increased the Cmax of eplerenone by 1.4-fold to|
01213|031|D|1.6-fold and the AUC of eplerenone by 2.0-fold and 2.9-fold.(1)|
01213|032|D|   Moderate inhibitors of CYP3A4 include:  aprepitant, avacopan,|
01213|033|D|berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, duvelisib,|
01213|034|D|erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib,|
01213|035|D|isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib,|
01213|036|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and|
01213|037|D|verapamil.(1-3)|
01213|038|B||
01213|039|R|REFERENCES:|
01213|040|B||
01213|041|R|1.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
01213|042|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
01213|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01213|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01213|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01213|046|R|  11/14/2017.|1
01213|047|R|3.This information is based on an extract from the Certara Drug Interaction|6
01213|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01214|001|T|MONOGRAPH TITLE:  Eplerenone/Selected Macrolide Antibiotics (mono deleted|
01214|002|T|03/01/2012)|
01214|003|B||
01214|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01214|005|L|take action as needed.|
01214|006|B||
01214|007|A|MECHANISM OF ACTION:  Certain macrolide antibiotics may inhibit the|
01214|008|A|metabolism of eplerenone by CYP P-450-3A4.(1)|
01214|009|B||
01214|010|E|CLINICAL EFFECTS:  Concurrent use of eplerenone with an inhibitor of CYP|
01214|011|E|P-450-3A4 may result in a 2-fold increase in eplerenone concentration and|
01214|012|E|toxicity.(1)|
01214|013|B||
01214|014|P|PREDISPOSING FACTORS:  None determined.|
01214|015|B||
01214|016|M|PATIENT MANAGEMENT:  The starting dose of eplerenone should be reduced to 25|
01214|017|M|mg in patients receiving weak CYP P-450-3A4 inhibitors.(1)|
01214|018|B||
01214|019|D|DISCUSSION:  The concurrent use of eplerenone and erythromycin resulted in|
01214|020|D|an approximate 2-fold increase in eplerenone concentrations.  Therefore, the|
01214|021|D|manufacturer of eplerenone states that the starting dose of eplerenone|
01214|022|D|should be reduced to 25 mg in patients receiving weak CYP P-450-3A4|
01214|023|D|inhibitors such as erythromycin.(1)  Telithromycin has also been shown to|
01214|024|D|inhibit CYP P-450-3A4.(2,3)|
01214|025|B||
01214|026|R|REFERENCES:|
01214|027|B||
01214|028|R|1.Inspra (eplerenone) US prescribing information. Pfizer Inc. March, 2011.|1
01214|029|R|2.Ketek (telithromycin) UK summary of product characteristics.|1
01214|030|R|  Sanofi-Aventis June 2, 2009.|1
01214|031|R|3.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01214|032|R|  December, 2010.|1
01215|001|T|MONOGRAPH TITLE:  Eplerenone/Saquinavir (mono deleted 03/01/2012)|
01215|002|B||
01215|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01215|004|L|take action as needed.|
01215|005|B||
01215|006|A|MECHANISM OF ACTION:  Saquinavir may inhibit the metabolism of eplerenone by|
01215|007|A|CYP P-450-3A4.(1)|
01215|008|B||
01215|009|E|CLINICAL EFFECTS:  Concurrent use of eplerenone with saquinavir may result|
01215|010|E|in a 2-fold increase in eplerenone concentration and toxicity.(1)|
01215|011|B||
01215|012|P|PREDISPOSING FACTORS:  None determined.|
01215|013|B||
01215|014|M|PATIENT MANAGEMENT:  The starting dose of eplerenone should be reduced to 25|
01215|015|M|mg in patients receiving weak CYP P-450-3A4 inhibitors.(1)|
01215|016|B||
01215|017|D|DISCUSSION:  The concurrent use of eplerenone and saquinavir resulted in an|
01215|018|D|approximate 2-fold increase in eplerenone concentrations.  Therefore, the|
01215|019|D|manufacturer of eplerenone states that the starting dose of eplerenone|
01215|020|D|should be reduced to 25 mg in patients receiving weak CYP P-450-3A4|
01215|021|D|inhibitors such as saquinavir.(1)|
01215|022|B||
01215|023|R|REFERENCE:|
01215|024|B||
01215|025|R|1.Inspra (eplerenone) US prescribing information. Pfizer Inc. March, 2011.|1
01216|001|T|MONOGRAPH TITLE:  Eplerenone/Verapamil (mono deleted 03/01/2012)|
01216|002|B||
01216|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01216|004|L|take action as needed.|
01216|005|B||
01216|006|A|MECHANISM OF ACTION:  Verapamil may inhibit the metabolism of eplerenone by|
01216|007|A|CYP P-450-3A4.(1)|
01216|008|B||
01216|009|E|CLINICAL EFFECTS:  Concurrent use of eplerenone with verapamil may result in|
01216|010|E|a 2-fold increase in eplerenone concentration and toxicity.(1)|
01216|011|B||
01216|012|P|PREDISPOSING FACTORS:  None determined.|
01216|013|B||
01216|014|M|PATIENT MANAGEMENT:  The starting dose of eplerenone should be reduced to 25|
01216|015|M|mg in patients receiving weak CYP P-450-3A4 inhibitors.(1)|
01216|016|B||
01216|017|D|DISCUSSION:  The concurrent use of eplerenone and verapamil resulted in an|
01216|018|D|approximate 2-fold increase in eplerenone concentrations.  Therefore, the|
01216|019|D|manufacturer of eplerenone states that the starting dose of eplerenone|
01216|020|D|should be reduced to 25 mg in patients receiving weak CYP P-450-3A4|
01216|021|D|inhibitors such as verapamil.(1)|
01216|022|B||
01216|023|R|REFERENCE:|
01216|024|B||
01216|025|R|1.Inspra (eplerenone) US prescribing information. Pfizer Inc. March, 2011.|1
01217|001|T|MONOGRAPH TITLE:  CGMP Specific PDE Type-5 Inhibitors/Alpha-Blockers|
01217|002|B||
01217|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01217|004|L|take action as needed.|
01217|005|B||
01217|006|A|MECHANISM OF ACTION:  Concurrent use of avanafil,(1) sildenafil,(2-5)|
01217|007|A|tadalafil,(6-9) or vardenafil(10-14) and an alpha-blocker may result in|
01217|008|A|additive or synergistic effects on blood pressure.|
01217|009|B||
01217|010|E|CLINICAL EFFECTS:  Concurrent use of avanafil,(1) sildenafil,(2-5)|
01217|011|E|tadalafil,(6-9) or vardenafil(10-14)) and an alpha-blocker may result in|
01217|012|E|symptomatic hypotension.|
01217|013|B||
01217|014|P|PREDISPOSING FACTORS:  Patients who have a history of hemodynamic|
01217|015|P|instability on alpha-blocker therapy prior to initiating avanafil,|
01217|016|P|sildenafil, tadalafil, or vardenafil may be at an increased risk of|
01217|017|P|symptomatic hypotension during concurrent therapy.|
01217|018|B||
01217|019|M|PATIENT MANAGEMENT:  The US manufacturer of avanafil states that patients|
01217|020|M|taking alpha-blockers should be stabilized on their alpha-blocker prior to|
01217|021|M|beginning avanafil therapy.  Avanafil should be initiated at the 50 mg|
01217|022|M|dosage.  In patients stabilized on avanafil therapy, alpha-blocker therapy|
01217|023|M|should be initiated at the lowest possible dosage.(1)|
01217|024|M|   The US, Australian, Canadian, and UK manufacturers of sildenafil state|
01217|025|M|that patients taking alpha-blockers should be stabilized on their|
01217|026|M|alpha-blocker prior to beginning sildenafil therapy.  Sildenafil should be|
01217|027|M|initiated at the lowest possible dosage.  In patients stabilized on|
01217|028|M|sildenafil therapy, alpha-blocker therapy should be initiated at the lowest|
01217|029|M|possible dosage.(2-5)|
01217|030|M|   The US manufacturer of tadalafil states that patients taking tadalafil|
01217|031|M|for erectile dysfunction (ED) and alpha-blockers should be stabilized on|
01217|032|M|their alpha-blocker prior to beginning tadalafil therapy.  Tadalafil should|
01217|033|M|be initiated at the lowest possible dosage.  In patients stabilized on|
01217|034|M|tadalafil therapy, alpha-blocker therapy should be initiated at the lowest|
01217|035|M|possible dose. The combination of tadalafil and an alpha-blocker for|
01217|036|M|treatment of benign prostatic hyperplasia (BPH) is not recommended. Patients|
01217|037|M|on alpha-blocker therapy for BPH should discontinue their alpha-blocker at|
01217|038|M|least one day prior to starting tadalafil for once daily use for the|
01217|039|M|treatment of BPH.(6)|
01217|040|M|   The Australian manufacturer of tadalafil states that tadalafil should be|
01217|041|M|used with caution in patients taking alpha-blockers.(7)|
01217|042|M|   The Canadian manufacturer of tadalafil states that it may be used with|
01217|043|M|tamsulosin and should be used with caution with other alpha-blockers.(8)|
01217|044|M|   The UK manufacturer of tadalafil states that concurrent use with|
01217|045|M|alpha-blockers is not recommended.(9)|
01217|046|M|   The US, Canadian, and UK manufacturers of vardenafil state that patients|
01217|047|M|taking alpha-blockers should be stabilized on their alpha-blocker prior to|
01217|048|M|beginning vardenafil therapy.  Vardenafil should be initiated at the lowest|
01217|049|M|possible dosage.  In patients stabilized on vardenafil therapy,|
01217|050|M|alpha-blocker therapy should be initiated at the lowest possible|
01217|051|M|dosage.(10-12)|
01217|052|M|   The UK manufacturer of vardenafil states that vardenafil may be give at|
01217|053|M|any time in relation to tamsulosin; however, a dose separation period of 6|
01217|054|M|hour should be considered for other alpha-blockers.(12)|
01217|055|M|   The Australian manufacturer of vardenafil states that concurrent use with|
01217|056|M|alpha-blockers is not recommended.(13)|
01217|057|M|   The US manufacturers of doxazosin,(14) prazosin(15) and terazosin(16)|
01217|058|M|state that PDE-5 inhibitor therapy should be initiated at the lowest dose.|
01217|059|B||
01217|060|D|DISCUSSION:  In a study in 24 subjects, concurrent use of avanafil (200 mg)|
01217|061|D|with doxazosin (1 mg on Day 1, titrated to 8 mg for Days 8-18) resulted in 7|
01217|062|D|subjects experiencing potentially clinically significant changes in blood|
01217|063|D|pressure.(1)|
01217|064|D|   In a study in 24 subjects, concurrent use of avanafil (200 mg) with|
01217|065|D|tamsulosin (0.4 mg Days 1-11) resulted in 5 subjects experiencing|
01217|066|D|potentially clinically significant changes in blood pressure.(1)|
01217|067|D|   Simultaneous administration of sildenafil (25 mg) and doxazosin (4 mg)|
01217|068|D|resulted in mean additional reductions of supine blood pressure of 7 mmHg|
01217|069|D|systolic and 7 mmHg diastolic.  When doxazosin (4 mg) was simultaneously|
01217|070|D|administered with higher doses of sildenafil, there were reports of|
01217|071|D|symptomatic postural hypotension within one to four hours.(2)|
01217|072|D|   In a study, concurrent administration of a single dose of tadalafil (20|
01217|073|D|mg) to healthy subjects receiving alfuzosin (10 mg daily) resulted in mean|
01217|074|D|maximum decreases in standing and supine systolic blood pressure by 2.2 mmHg|
01217|075|D|and 4.4 mmHg, respectively.  There were no subjects with a decrease from|
01217|076|D|baseline standing systolic blood pressure greater than 30 mmHg.(6)|
01217|077|D|   In a study, concurrent administration of a single dose of tadalafil (20|
01217|078|D|mg) to 18 healthy subjects receiving doxazosin (8 mg daily) resulted in|
01217|079|D|significant augmentation of the blood-pressure lowering effects of doxazosin|
01217|080|D|(by 9.8 mmHg).  The number of subjects with a standing blood pressure of|
01217|081|D|less than 85 mmHg was greater after concurrent doxazosin and tadalafil than|
01217|082|D|when compared to doxazosin with placebo (28% versus 6%).  One subject|
01217|083|D|reported vertigo and another reported dizziness.  No syncope was|
01217|084|D|reported.(5,14)  In a second study, concurrent administration of a single|
01217|085|D|dose of tadalafil (20 mg) to healthy subjects receiving doxazosin (4-8 mg|
01217|086|D|daily) also resulted in augmentation of the blood-pressure lowering affects|
01217|087|D|of doxazosin.  One subject reported symptomatic hypotension and another|
01217|088|D|reported dizziness with concurrent therapy.(6)|
01217|089|D|   In a study, concurrent administration of a single dose of tadalafil (20|
01217|090|D|mg) to healthy subjects receiving tamsulosin (0.4 mg daily) resulted in no|
01217|091|D|significant decreases in blood pressure.(6,17)|
01217|092|D|   Hypotension has been reported with concurrent use of terazosin and|
01217|093|D|phosphodiesterase-5 inhibitors.(16)|
01217|094|D|   With simultaneous administration of vardenafil (10 mg) and terazosin (10|
01217|095|D|mg), 6 of 8 healthy subjects experienced a standing systolic blood pressure|
01217|096|D|of less than 85 mmHg.  With simultaneous vardenafil (20 mg) and terazosin|
01217|097|D|(10 mg), 2 of 9 subjects experienced a standing systolic blood pressure of|
01217|098|D|less than 85 mmHg.  When vardenafil (20 mg) was administered 6 hours apart|
01217|099|D|from terazosin (10 mg), 7 of 28 subjects experienced a standing systolic|
01217|100|D|blood pressure of less than 85 mmHg.(10)|
01217|101|D|   With simultaneous administration of vardenafil (10 mg) and tamsulosin|
01217|102|D|(0.4 mg), two of 16 subjects experienced a standing systolic blood pressure|
01217|103|D|of less than 85 mmHg.  When vardenafil (20 mg) was administered six hours|
01217|104|D|apart from tamsulosin (0.4 mg), one of 24 subjects experienced a standing|
01217|105|D|systolic blood pressure of less than 85 mmHg.(10)|
01217|106|D|   In a study in subjects with benign prostatic hyperplasia (BPH) on stable|
01217|107|D|tamsulosin or terazosin therapy, simultaneous vardenafil (5 mg) and|
01217|108|D|tamsulosin resulted in no effects on blood pressure.  Simultaneous|
01217|109|D|vardenafil (5 mg) with terazosin resulted in hypotension in some subjects.|
01217|110|D|This effect did not occur when vardenafil and terazosin were separated by 6|
01217|111|D|hours.(12)|
01217|112|D|   In a placebo controlled, crossover study in 22 subjects with benign|
01217|113|D|prostatic hyperplasia receiving tamsulosin, subjects received single doses|
01217|114|D|of vardenafil (10 mg and 20 mg).  No patients exhibited symptomatic|
01217|115|D|hypotension.  Three patients receiving 20 mg of vardenafil reported|
01217|116|D|dizziness, but none had a systolic blood pressure of less than 95 mmHg.(18)|
01217|117|D|   In a placebo-controlled study in 24 health male subjects, administration|
01217|118|D|of sildenafil (100 mg) or tadalafil (20 mg) with silodosin resulted in an|
01217|119|D|increase in positive orthostatic tests in the 12 hours after concurrent|
01217|120|D|administration when compared with the administration of silodosin alone.|
01217|121|D|There were no reports of symptomatic orthostasis or dizziness.(19)|
01217|122|B||
01217|123|R|REFERENCES:|
01217|124|B||
01217|125|R|1.Viagra (sildenafil) US prescribing information. Pfizer Inc. December 14,|1
01217|126|R|  2017.|1
01217|127|R|2.Viagra (sildenafil) Australian prescribing information. Pfizer October 17,|1
01217|128|R|  2006.|1
01217|129|R|3.Viagra (sildenafil citrate) Canadian prescribing information. Pfizer March|1
01217|130|R|  9, 2006.|1
01217|131|R|4.Viagra (sildenafil citrate) UK summary of product characteristics. Pfizer|1
01217|132|R|  Limited July 11, 2006.|1
01217|133|R|5.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
01217|134|R|  February, 2018.|1
01217|135|R|6.Cialis (tadalafil) Australian prescribing information. Eli Lilly Pty Ltd|1
01217|136|R|  July 3, 2006.|1
01217|137|R|7.Cialis (tadalafil) Canadian prescribing information. Lilly August 30,|1
01217|138|R|  2005.|1
01217|139|R|8.Cialis (tadalafil) UK summary of product characteristics. Eli Lilly and|1
01217|140|R|  Company Limited September 16, 2008.|1
01217|141|R|9.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
01217|142|R|  Pharmaceuticals Corporation March, 2023.|1
01217|143|R|10.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
01217|144|R|   Bayer, Inc. October 24, 2006.|1
01217|145|R|11.Levitra (vardenafil hydrochloride trihydrate) UK summary of product|1
01217|146|R|   characteristics. Bayer plc December 20, 2006.|1
01217|147|R|12.Levitra (vardenafil hydrochloride trihydrate) Australian prescribing|1
01217|148|R|   information. Bayer Australia Limited November 2, 2006.|1
01217|149|R|13.Cardura (doxazosin hydrochloride) US prescribing information. Pfizer,|1
01217|150|R|   Inc. June, 2016.|1
01217|151|R|14.Minipress (prazosin hydrochloride) US prescribing information. Pfizer|1
01217|152|R|   Inc. February, 2015.|1
01217|153|R|15.Hytrin (terazosin hydrochloride) US prescribing information. Abbott|1
01217|154|R|   Laboratories July, 2009.|1
01217|155|R|16.Kloner RA, Jackson G, Emmick JT, Mitchell MI, Bedding A, Warner MR,|2
01217|156|R|   Pereira A. Interaction between the phosphodiesterase 5 inhibitor,|2
01217|157|R|   tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy|2
01217|158|R|   normotensive men. J Urol 2004 Nov;172(5 Pt 1):1935-40.|2
01217|159|R|17.Auerbach SM, Gittelman M, Mazzu A, Cihon F, Sundaresan P, White WB.|2
01217|160|R|   Simultaneous administration of vardenafil and tamsulosin does not induce|2
01217|161|R|   clinically significant hypotension in patients with benign prostatic|2
01217|162|R|   hyperplasia. Urology 2004 Nov;64(5):998-1003; discussion 1003-4.|2
01217|163|R|18.Rapaflo (silodosin) US prescribing information. Watson Laboratories, Inc.|1
01217|164|R|   July, 2013.|1
01218|001|T|MONOGRAPH TITLE:  Ezetimibe/Bile Acid Sequestrants|
01218|002|B||
01218|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01218|004|L|take action as needed.|
01218|005|B||
01218|006|A|MECHANISM OF ACTION:  Bile acid sequestrants may prevent the absorption of|
01218|007|A|ezetimibe.(1)|
01218|008|B||
01218|009|E|CLINICAL EFFECTS:  Simultaneous administration of a bile acid sequestrant|
01218|010|E|and ezetimibe may result in decreased levels and clinical effectiveness of|
01218|011|E|ezetimibe.(1)|
01218|012|B||
01218|013|P|PREDISPOSING FACTORS:  None determined.|
01218|014|B||
01218|015|M|PATIENT MANAGEMENT:  In patients receiving concurrent therapy, the|
01218|016|M|manufacturer of ezetimibe recommends that ezetimibe be administered either 2|
01218|017|M|or more hours before or 4 or more hours after a bile acid sequestrant.(1)|
01218|018|B||
01218|019|D|DISCUSSION:  In a study in 40 subjects, the simultaneous administration of|
01218|020|D|ezetimibe and cholestyramine decreased the area-under-curve (AUC) of total|
01218|021|D|ezetimibe and ezetimibe by 55% and 80%, respectively.  This may reduce the|
01218|022|D|effectiveness of ezetimibe.  Therefore, the manufacturer of ezetimibe|
01218|023|D|recommends that ezetimibe be administered either 2 or more hours before or 4|
01218|024|D|or more hours after a bile acid sequestrant.(1)|
01218|025|B||
01218|026|R|REFERENCE:|
01218|027|B||
01218|028|R|1.Zetia (ezetimibe) US prescribing information. Merck/Schering-Plough|1
01218|029|R|  Pharmaceuticals July, 2023.|1
01219|001|T|MONOGRAPH TITLE:  Ezetimibe/Fibrates|
01219|002|B||
01219|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01219|004|L|take action as needed.|
01219|005|B||
01219|006|A|MECHANISM OF ACTION:  Both ezetimibe and fibrates may increase cholesterol|
01219|007|A|excretion in the bile.  Fibrates may inhibit the metabolism of ezetimibe.(1)|
01219|008|B||
01219|009|E|CLINICAL EFFECTS:  Concurrent administration of ezetimibe may result in|
01219|010|E|cholelithiasis, elevated levels of ezetimibe, and toxicity.(1)|
01219|011|B||
01219|012|P|PREDISPOSING FACTORS:  None determined.|
01219|013|B||
01219|014|M|PATIENT MANAGEMENT:  The US manufacturer of ezetimibe states that the|
01219|015|M|concurrent use of ezetimibe and fibrates other than fenofibrate is not|
01219|016|M|recommended.(1)|
01219|017|M|   The Australian manufacturer of ezetimibe states that concurrent use with|
01219|018|M|fenofibrate in patients with gall bladder disease is contraindicated.(2)|
01219|019|M|   Patients receiving concurrent therapy with any fibrate should be|
01219|020|M|monitored for cholelithiasis and increased ezetimibe side effects.  If|
01219|021|M|cholelithiasis is suspected, gallbladder studies are indicated and|
01219|022|M|alternative therapy may need to be utilized.(1)|
01219|023|B||
01219|024|D|DISCUSSION:  Fibrates have been shown to increase cholesterol excretion into|
01219|025|D|the bile, leading to cholelithiasis.  Ezetimibe has been shown in dogs to|
01219|026|D|increase cholesterol in the gallbladder bile.(1)|
01219|027|D|   In a study in 32 subjects, concurrent fenofibrate and ezetimibe increased|
01219|028|D|the maximum concentration (Cmax) and area-under-curve (AUC) of total|
01219|029|D|ezetimibe by 64% and 48%, respectively.  There was no significant effect on|
01219|030|D|fenofibrate pharmacokinetics.  Concomitant fenofibrate increased total|
01219|031|D|ezetimibe concentrations by 1.5-fold.(1)|
01219|032|D|   In a study in 625 patients for up to 12 weeks and 576 patients for up to|
01219|033|D|an additional 48 weeks, concurrent ezetimibe and fenofibrate was effective|
01219|034|D|at lowering total cholesterol, LDL-C, Apo B, and non-HDL-C.  The number of|
01219|035|D|patients was inadequate to assess gallbladder risk; however, 0.6% of|
01219|036|D|patients in the fenofibrate monotherapy group experienced cholecystectomy|
01219|037|D|versus 1.7% during concurrent therapy.(1)|
01219|038|D|   In a study in 12 healthy subjects, concurrent gemfibrozil and ezetimibe|
01219|039|D|increased the bioavailability of ezetimibe by 1.7-fold.  There was no|
01219|040|D|significant effect on gemfibrozil pharmacokinetics.(1)|
01219|041|B||
01219|042|R|REFERENCES:|
01219|043|B||
01219|044|R|1.Zetia (ezetimibe) US prescribing information. Merck/Schering-Plough|1
01219|045|R|  Pharmaceuticals July, 2023.|1
01219|046|R|2.Ezetimibe Australian product information. Pharmacor Pty Limited March 5,|1
01219|047|R|  2025.|1
01220|001|T|MONOGRAPH TITLE:  Topotecan/Granulocyte Colony Stimulating Factors (mono|
01220|002|T|deleted 02/04/2022)|
01220|003|B||
01220|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01220|005|L|take action as needed.|
01220|006|B||
01220|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01220|008|B||
01220|009|E|CLINICAL EFFECTS:  Concurrent use of topotecan and granulocyte colony|
01220|010|E|stimulating factor (G-CSF) may prolong the duration of neutropenia.(1)|
01220|011|B||
01220|012|P|PREDISPOSING FACTORS:  None determined.|
01220|013|B||
01220|014|M|PATIENT MANAGEMENT:  If G-CSF is to be used in topotecan-treated patients,|
01220|015|M|the manufacturer of topotecan states that it should not be initiated until|
01220|016|M|Day 6 of therapy, 24 hours after the completion of topotecan treatment.(1)|
01220|017|M|It would be prudent to follow this recommendation for granulocyte macrophage|
01220|018|M|colony stimulating factor (GM-CSF) as well.|
01220|019|B||
01220|020|D|DISCUSSION:  Because concurrent use of topotecan and G-CSF may prolong the|
01220|021|D|duration of neutropenia, the manufacturer of topotecan states that if G-CSF|
01220|022|D|is used in topotecan-treated patients, it should not be initiated until Day|
01220|023|D|6 of therapy, 24 hours after the completion of topotecan treatment.(1)|
01220|024|B||
01220|025|R|REFERENCE:|
01220|026|B||
01220|027|R|1.Hycamtin Injection (topotecan hydrochloride) US prescribing information.|1
01220|028|R|  GlaxoSmithKline June, 2015.|1
01221|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Itraconazole; Ketoconazole|
01221|002|B||
01221|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01221|004|L|is contraindicated and generally should not be dispensed or administered to|
01221|005|L|the same patient.|
01221|006|B||
01221|007|A|MECHANISM OF ACTION:  Itraconazole(1,2) and ketoconazole(3-5) may inhibit|
01221|008|A|the metabolism of ergot alkaloids by CYP3A4.|
01221|009|B||
01221|010|E|CLINICAL EFFECTS:  Concurrent use may result in increased levels of ergot|
01221|011|E|alkaloids, which may result in clinical signs of ergotism, including|
01221|012|E|vasospasm, dysesthesia, renal ischemia, and peripheral ischemia.|
01221|013|B||
01221|014|P|PREDISPOSING FACTORS:  None determined.|
01221|015|B||
01221|016|M|PATIENT MANAGEMENT:  The manufacturers of itraconazole(1) and|
01221|017|M|ketoconazole(5) state that concurrent administration with ergot alkaloids|
01221|018|M|metabolized by CYP3A4 is contraindicated. The US manufacturer of|
01221|019|M|itraconazole also states that concurrent administration of ergot alkaloids|
01221|020|M|is contraindicated during and two weeks after itraconazole treatment.(1)|
01221|021|M|   The manufacturers of dihydroergotamine(3) and ergotamine(4) state that|
01221|022|M|the concurrent use of these agents with strong inhibitors of CYP3A4 such as|
01221|023|M|itraconazole, ketoconazole, or levoketoconazole is contraindicated.|
01221|024|M|   The US manufacturer of methylergonovine states that methylergonovine|
01221|025|M|should not be administered with potent CYP3A4 inhibitors such as|
01221|026|M|itraconazole, ketoconazole, or levoketoconazole.(2)|
01221|027|B||
01221|028|D|DISCUSSION:  Coadministration of dihydroergotamine(3) and ergotamine(4) with|
01221|029|D|potent inhibitors of CYP3A4 such as clarithromycin, erythromycin, indinavir,|
01221|030|D|nelfinavir, ritonavir, and troleandomycin has resulted in ergotism,|
01221|031|D|characterized by vasospasm and ischemia of the extremities.|
01221|032|D|   One or more of the drug pairs linked to this monograph have been included|
01221|033|D|in a list of interactions that should be considered "high-priority" for|
01221|034|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01221|035|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01221|036|D|Coordinator (ONC) for Health Information Technology.|
01221|037|B||
01221|038|R|REFERENCES:|
01221|039|B||
01221|040|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01221|041|R|  Products, L.P. February, 2024.|1
01221|042|R|2.Methergine (methylergonovine maleate) US prescribing information. Novartis|1
01221|043|R|  Pharmaceuticals Corporation June, 2012.|1
01221|044|R|3.D. H. E. 45 (dihydroergotamine mesylate) US prescribing information.|1
01221|045|R|  Valeant Pharmaceuticals North America November 6, 2017.|1
01221|046|R|4.Cafergot (ergotamine tartrate and caffeine) tablets US prescribing|1
01221|047|R|  information. Sandoz Inc May 14, 2012.|1
01221|048|R|5.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01221|049|R|  Pharmaceuticals February, 2014.|1
01221|050|R|6.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01221|051|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01221|052|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01221|053|R|  19(5):735-43.|6
01221|054|R|7.Christensen J, Dupont E, OStergaard K. Cabergoline plasma concentration is|3
01221|055|R|  increased during concomitant treatment with itraconazole. Mov Disord 2002|3
01221|056|R|  Nov;17(6):1360-2.|3
01222|001|T|MONOGRAPH TITLE:  Aripiprazole IR/Strong CYP3A4 Inhib; Atazanavir; Darunavir|
01222|002|B||
01222|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01222|004|L|take action as needed.|
01222|005|B||
01222|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
01222|007|A|aripiprazole.(1-2)|
01222|008|B||
01222|009|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
01222|010|E|may result in elevated levels of and toxicity from aripiprazole.(1-2)|
01222|011|B||
01222|012|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01222|013|P|patients who are CYP2D6 poor metabolizers, or who receive concomitant|
01222|014|P|treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine,|
01222|015|P|paroxetine, quinidine) in addition to treatment with a strong CYP3A4|
01222|016|P|inhibitor.(1-2)|
01222|017|B||
01222|018|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole states that the|
01222|019|M|dose of immediate release oral or injectable aripiprazole should be reduced|
01222|020|M|to one-half of its normal dose when strong CYP3A4 inhibitors are|
01222|021|M|coadministered, unless aripiprazole is being administered as adjunctive|
01222|022|M|therapy for Major Depressive Disorder.  If the patient is also receiving a|
01222|023|M|strong CYP2D6 inhibitor or is a known CYP2D6 poor metabolizer, the dose of|
01222|024|M|aripiprazole should be reduced to one-fourth its normal dose.  When the|
01222|025|M|inhibitors are discontinued, the dose of aripiprazole should be|
01222|026|M|increased.(1)|
01222|027|M|   The US Department of Health and Human Services HIV guidelines state that|
01222|028|M|patients on ritonavir- or cobicistat-boosted protease inhibitors should have|
01222|029|M|their dose of aripiprazole decreased to one-fourth of the usual dose.|
01222|030|M|Patients on unboosted atazanavir should have their aripiprazole decreased to|
01222|031|M|one-half of the usual dose.(2)|
01222|032|B||
01222|033|D|DISCUSSION:  The coadministration of ketoconazole (200 mg daily for 14 days)|
01222|034|D|with a single oral dose of aripiprazole (15 mg) resulted in increases in the|
01222|035|D|area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and|
01222|036|D|77%, respectively.  In simulations, the combination of strong CYP2D6 and|
01222|037|D|CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by|
01222|038|D|4.5-fold.  The concurrent use of strong CYP3A4 inhibitors in poor CYP2D6|
01222|039|D|metabolizers is predicted to increase aripiprazole Cmax and AUC by|
01222|040|D|3-fold.(1)|
01222|041|D|   CYP3A4 inhibitors linked to this monograph include: adagrasib,|
01222|042|D|atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir,|
01222|043|D|grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
01222|044|D|levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone,|
01222|045|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
01222|046|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
01222|047|D|troleandomycin, tucatinib, and voriconazole.(3)|
01222|048|B||
01222|049|R|REFERENCES:|
01222|050|B||
01222|051|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
01222|052|R|  Pharmaceutical, Inc. August, 2019.|1
01222|053|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01222|054|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01222|055|R|  HIV. Department of Health and Human Services. Available at|6
01222|056|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
01222|057|R|  new-guidelines June 13, 2021.|6
01222|058|R|3.This information is based on an extract from the Certara Drug Interaction|6
01222|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01223|001|T|MONOGRAPH TITLE:  Aripiprazole/Quinidine (mono deleted 04/23/2015)|
01223|002|B||
01223|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01223|004|L|take action as needed.|
01223|005|B||
01223|006|A|MECHANISM OF ACTION:  Quinidine may inhibit the metabolism of aripiprazole|
01223|007|A|by CYP2D6.(1)|
01223|008|B||
01223|009|E|CLINICAL EFFECTS:  Concurrent administration of quinidine with aripiprazole|
01223|010|E|may result in elevated levels of aripiprazole and toxicity.(1)|
01223|011|B||
01223|012|P|PREDISPOSING FACTORS:  This interaction is expected to me more severe in|
01223|013|P|patients also taking a strong CYP3A4 inhibitor.(1)|
01223|014|B||
01223|015|M|PATIENT MANAGEMENT:  The manufacturer of aripiprazole states that the dose|
01223|016|M|of aripiprazole should be reduced to one-half of its normal dose when|
01223|017|M|quinidine is coadministered, unless aripiprazole is being administered as|
01223|018|M|adjunctive therapy for Major Depressive Disorder.(1)|
01223|019|M|  If the patient is also receiving a strong CYP3A4 inhibitor, the dose of|
01223|020|M|aripiprazole should be reduced to one-fourth its normal dose.|
01223|021|M|  When the inhibitor(s) is(are) discontinued, the dose of aripiprazole|
01223|022|M|should be increased.(1)|
01223|023|B||
01223|024|D|DISCUSSION:  The administration of quinidine (166 mg daily for 13 days) with|
01223|025|D|a single dose of aripiprazole (10 mg) resulted in a 112% increase in the|
01223|026|D|area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of|
01223|027|D|dehydro-aripiprazole, the active metabolite of aripiprazole.(1)|
01223|028|B||
01223|029|R|REFERENCE:|
01223|030|B||
01223|031|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
01223|032|R|  Pharmaceutical, Inc. December, 2014.|1
01224|001|T|MONOGRAPH TITLE:  Aripiprazole Immediate Release/Slt Strong CYP2D6|
01224|002|T|Inhibitors|
01224|003|B||
01224|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01224|005|L|take action as needed.|
01224|006|B||
01224|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
01224|008|A|aripiprazole.(1)|
01224|009|B||
01224|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
01224|011|E|with aripiprazole may result in elevated levels of and toxicity from|
01224|012|E|aripiprazole.(1)|
01224|013|B||
01224|014|P|PREDISPOSING FACTORS:  The interaction is expected to be more severe in|
01224|015|P|patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6|
01224|016|P|inhibitor.(1)|
01224|017|B||
01224|018|M|PATIENT MANAGEMENT:  The US manufacturer of oral aripiprazole states that|
01224|019|M|the dose of aripiprazole should be reduced to one-half of its normal dose|
01224|020|M|when strong CYP2D6 inhibitors such as bupropion, fluoxetine, paroxetine and|
01224|021|M|quinidine are coadministered, unless aripiprazole is being used as|
01224|022|M|adjunctive therapy for Major Depressive Disorder.  If the patient is also|
01224|023|M|receiving a strong CYP3A4 inhibitor, the dose of aripiprazole should be|
01224|024|M|reduced to one-fourth its normal dose.  When the inhibitor(s) is(are)|
01224|025|M|discontinued, the dose of aripiprazole should be increased.(1)|
01224|026|B||
01224|027|D|DISCUSSION:  The administration of quinidine (166 mg daily for 13 days, a|
01224|028|D|strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg)|
01224|029|D|resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole|
01224|030|D|and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite|
01224|031|D|of aripiprazole.(1)|
01224|032|D|   Strong CYP2D6 inhibitors linked to this monograph are dacomitinib,|
01224|033|D|fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)|
01224|034|B||
01224|035|R|REFERENCES:|
01224|036|B||
01224|037|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
01224|038|R|  Pharmaceutical, Inc. August, 2019.|1
01224|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
01224|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01224|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01224|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01224|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01224|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01224|045|R|  11/14/2017.|1
01225|001|T|MONOGRAPH TITLE:  Aripiprazole/Carbamazepine;Phenobarbital;Phenytoin (mono|
01225|002|T|deleted 01/10/2013)|
01225|003|B||
01225|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01225|005|L|take action as needed.|
01225|006|B||
01225|007|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital or phenytoin may induce|
01225|008|A|the metabolism of aripiprazole by CYP3A4.(1,2)|
01225|009|B||
01225|010|E|CLINICAL EFFECTS:  Concurrent administration of carbamazepine, phenobarbital|
01225|011|E|or phenytoin with aripiprazole may result in decreased levels of|
01225|012|E|aripiprazole and therapeutic failure.(1)|
01225|013|B||
01225|014|P|PREDISPOSING FACTORS:  None determined.|
01225|015|B||
01225|016|M|PATIENT MANAGEMENT:  The manufacturer of aripiprazole states that the dose|
01225|017|M|of aripiprazole should be doubled (to 20 mg-30 mg daily) if a CYP3A4 inducer|
01225|018|M|is added to aripiprazole therapy.  Additional dosage increases should be|
01225|019|M|based on clinical observation of the patient.  If carbamazepine,|
01225|020|M|phenobarbital or phenytoin is withdrawn from concurrent therapy, the dosage|
01225|021|M|of aripiprazole should be gradually reduced (to 10 mg-15 mg daily).(1)|
01225|022|B||
01225|023|D|DISCUSSION:  The concurrent administration of carbamazepine (200 mg twice|
01225|024|D|daily) with aripiprazole (30 mg daily) resulted in 70% decreases in the|
01225|025|D|area-under-curve (AUC) and maximum concentration (Cmax) of both aripiprazole|
01225|026|D|and dehydro-aripiprazole, its active metabolite.(1)|
01225|027|D|   Based upon FDA criteria, carbamazepine, phenobarbital and phenytoin are|
01225|028|D|strong inducers of CYP3A4.(2)|
01225|029|B||
01225|030|R|REFERENCES:|
01225|031|B||
01225|032|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
01225|033|R|  Pharmaceutical, Inc. July, 2014.|1
01225|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
01225|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01225|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01225|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01225|038|R|  11/14/2017.|1
01226|001|T|MONOGRAPH TITLE:  Colchicine/Cyclosporine|
01226|002|B||
01226|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01226|004|L|of severe adverse interaction.|
01226|005|B||
01226|006|A|MECHANISM OF ACTION:  Colchicine is metabolized and transported by CYP3A4|
01226|007|A|and P-glycoprotein (P-gp) respectively.  Cyclosporine is an inhibitor of|
01226|008|A|both of these pathways.  Studies indicate that cyclosporine may inhibit|
01226|009|A|renal secretion(4) of colchicine and decrease the hepatic secretion(5) of|
01226|010|A|colchicine into the bile.|
01226|011|B||
01226|012|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine may result in elevated|
01226|013|E|levels of and toxicity from colchicine.  Symptoms of colchicine toxicity|
01226|014|E|include muscle weakness or pain; numbness or tingling in the fingers or|
01226|015|E|toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting;|
01226|016|E|feeling weak or tired; increased infections; and pale or gray color of the|
01226|017|E|lips, tongue, or palms of hands.(1,2)  Patients with familial Mediterranean|
01226|018|E|fever (FMF) may experience a higher incidence of colchicine-related|
01226|019|E|gastrointestinal effects.|
01226|020|B||
01226|021|P|PREDISPOSING FACTORS:  Serum colchicine levels and the risk of colchicine|
01226|022|P|myopathy may be increased by renal dysfunction,(2) which may occur in renal|
01226|023|P|transplant patients(3) and is common in gout.(2)  This interaction is|
01226|024|P|expected to be more severe in patients with renal and/or hepatic|
01226|025|P|impairment(1,2) and may occur more frequently in patients with familial|
01226|026|P|Mediterranean fever (FMF).|
01226|027|B||
01226|028|M|PATIENT MANAGEMENT:  The concurrent use of strong P-gp inhibitors such as|
01226|029|M|cyclosporine is contraindicated in patients with renal or hepatic|
01226|030|M|impairment.(6,7)|
01226|031|M|   In patients without renal or hepatic impairment who are currently taking|
01226|032|M|or have taken strong P-gp inhibitors such as cyclosporine in the previous 14|
01226|033|M|days, the dosage of colchicine should be reduced.  For gout flares, the|
01226|034|M|recommended dosage is 0.6 mg (1 tablet) for one dose.  This dose should be|
01226|035|M|repeated no earlier than in 3 days.  For gout prophylaxis, if the original|
01226|036|M|dosage was 0.6 mg twice daily, use 0.3 mg daily.  If the original dosage was|
01226|037|M|0.6 mg daily, use 0.3 mg every other day.  For Familial Mediterranean fever|
01226|038|M|(FMF), the recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg|
01226|039|M|twice a day).(6,7)|
01226|040|M|   Patients should be instructed to immediately report any signs of|
01226|041|M|colchicine toxicity, such as abdominal pain; significant nausea or vomiting;|
01226|042|M|diarrhea; muscle weakness/pain; numbness/tingling in fingers/toes; unusual|
01226|043|M|bleeding or bruising, infections, unusual weakness/tiredness, or pale/gray|
01226|044|M|color of the lips/tongue/palms of hands.|
01226|045|B||
01226|046|D|DISCUSSION:  In a study in 23 subjects, concurrent administration of a|
01226|047|D|single dose of cyclosporine (100 mg) increased the maximum concentration|
01226|048|D|(Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by|
01226|049|D|270% (range 62% to 606.9%) and by 259% (range 75.8% to 511.9%),|
01226|050|D|respectively.(7)|
01226|051|D|   In a case report, a renal transplant patient's cyclosporine level|
01226|052|D|increased more than 9-fold the day after the initiation of colchicine. The|
01226|053|D|patient also developed renal dysfunction.(1)  In another report, a renal|
01226|054|D|transplant patient developed renal dysfunction and myopathy two weeks after|
01226|055|D|a three-day course of colchicine.(8)  In a case report, a renal transplant|
01226|056|D|patient developed myopathy four weeks after the addition of colchicine to|
01226|057|D|his cyclosporine regimen.  Prior to his transplant, he had taken colchicine|
01226|058|D|for almost five years with no adverse effects.(9)  In another report, a|
01226|059|D|renal transplant patient developed myopathy two weeks after the addition of|
01226|060|D|colchicine to cyclosporine therapy.(10)  Another report describes three|
01226|061|D|cases of myopathy during concurrent cyclosporine and colchicine.  The|
01226|062|D|patients had taken the combination for six weeks, one year, and eight years|
01226|063|D|prior to developing myopathy.(11)|
01226|064|D|   In a retrospective review, five of ten patients (50%) who received|
01226|065|D|concurrent cyclosporine and colchicine developed myopathy. There were no|
01226|066|D|differences in age, transplant duration, or serum creatinine between those|
01226|067|D|patients who developed myopathy and those who did not.(12)|
01226|068|D|   In a study in four patients with familial Mediterranean fever (FMF) who|
01226|069|D|were receiving colchicine, an attempt was made to convert azathioprine to|
01226|070|D|cyclosporine.  All four patients developed pronounced side effects,|
01226|071|D|including diarrhea and elevated serum lactic acid; three had elevated serum|
01226|072|D|alanine aminotransferase (ALT) and hyperbilirubinemia; two had elevated|
01226|073|D|serum creatinines; and one was hospitalized with myopathy.  No patients|
01226|074|D|reached therapeutic levels of cyclosporine.  The authors had previously|
01226|075|D|converted three colchicine-treated FMF patients to cyclosporine.(13)|
01226|076|D|   Another article reported that only one of eight patients with FMF|
01226|077|D|tolerated concurrent cyclosporine and colchicine following renal|
01226|078|D|transplantation.  Two subjects only had gastrointestinal side effects, the|
01226|079|D|other five had myopathy in addition to gastrointestinal side effects.(14)|
01226|080|D|   In another case report, a 59 year-old male renal transplant patient|
01226|081|D|maintained on cyclosporine developed rhabdomyolysis with progressive|
01226|082|D|quadriparesis, hematologic toxicity, and acute renal failure following the|
01226|083|D|addition of colchicine (3 mg daily for 7 days) to his regimen.(15)|
01226|084|B||
01226|085|R|REFERENCES:|
01226|086|B||
01226|087|R|1.This information is based on an extract from the Certara Drug Interaction|6
01226|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01226|089|R|2.Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M. Colchicine|3
01226|090|R|  myopathy and neuropathy. N Engl J Med 1987 Jun 18;316(25):1562-8.|3
01226|091|R|3.Rumpf KW, Henning HV. Is myopathy in renal transplant patients induced by|3
01226|092|R|  cyclosporin or colchicine?. Lancet 1990 Mar 31;335(8692):800-1.|3
01226|093|R|4.Speeg KV, Maldonado AL, Liaci J, Muirhead D. Effect of cyclosporine on|5
01226|094|R|  colchicine secretion by the kidney multidrug transporter studied in vivo.|5
01226|095|R|  J Pharmacol Exp Ther 1992 Apr;261(1):50-5.|5
01226|096|R|5.Speeg KV, Maldonado AL, Liaci J, Muirhead D. Effect of cyclosporine on|5
01226|097|R|  colchicine secretion by a liver canalicular transporter studied in vivo.|5
01226|098|R|  Hepatology 1992 May;15(5):899-903.|5
01226|099|R|6.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01226|100|R|  2011.|1
01226|101|R|7.Anonymous. Information for Healthcare Professionals: New Safety|1
01226|102|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01226|103|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01226|104|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01226|105|R|8.Lee BI, Shin SJ, Yoon SN, Choi YJ, Yang CW, Bang BK. Acute myopathy|3
01226|106|R|  induced by colchicine in a cyclosporine-treated renal transplant|3
01226|107|R|  recipient--a case report and review of the literature. J Korean Med Sci|3
01226|108|R|  1997 Apr;12(2):160-1.|3
01226|109|R|9.Jonsson J, Gelpi JR, Light JA, Aquino A, Maszaros S. Colchicine-induced|3
01226|110|R|  myoneuropathy in a renal transplant patient. Transplantation 1992 Jun;|3
01226|111|R|  53(6):1369-71.|3
01226|112|R|10.Jagose JT, Bailey RR. Muscle weakness due to colchicine in a renal|3
01226|113|R|   transplant recipient. N Z Med J 1997 Sep 12;110(1051):343.|3
01226|114|R|11.Rana SS, Giuliani MJ, Oddis CV, Lacomis D. Acute onset of colchicine|3
01226|115|R|   myoneuropathy in cardiac transplant recipients: case studies of three|3
01226|116|R|   patients. Clin Neurol Neurosurg 1997 Dec;99(4):266-70.|3
01226|117|R|12.Ducloux D, Schuller V, Bresson-Vautrin C, Chalopin JM. Colchicine|3
01226|118|R|   myopathy in renal transplant recipients on cyclosporin. Nephrol Dial|3
01226|119|R|   Transplant 1997 Nov;12(11):2389-92.|3
01226|120|R|13.Yussim A, Bar-Nathan N, Lustig S, Shaharabani E, Geier E, Shmuely D,|2
01226|121|R|   Nakache R, Shapira Z. Gastrointestinal, hepatorenal, and neuromuscular|2
01226|122|R|   toxicity caused by cyclosporine-colchicine interaction in renal|2
01226|123|R|   transplantation. Transplant Proc 1994 Oct;26(5):2825-6.|2
01226|124|R|14.Cohen SL, Boner G, Shmueli D, Yusim A, Rosenfeld J, Shapira Z.|3
01226|125|R|   Cyclosporin: poorly tolerated in familial Mediterranean fever. Nephrol|3
01226|126|R|   Dial Transplant 1989;4(3):201-4.|3
01226|127|R|15.Garrouste C, Philipponnet C, Kaysi S, Enache I, Tiple A, Heng AE. Severe|3
01226|128|R|   colchicine intoxication in a renal transplant recipient on cyclosporine.|3
01226|129|R|   Transplant Proc 2012 Nov;44(9):2851-2.|3
01227|001|T|MONOGRAPH TITLE:  Memantine/N-Methyl-D-Aspartate (NMDA) Antagonists|
01227|002|B||
01227|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01227|004|L|of severe adverse interaction.|
01227|005|B||
01227|006|A|MECHANISM OF ACTION:  N-methyl-D-aspartate (NMDA) antagonists act at the|
01227|007|A|same receptor system as does memantine.(1,2)|
01227|008|B||
01227|009|E|CLINICAL EFFECTS:  Concurrent use may result in more frequent and more|
01227|010|E|pronounced side effects, especially CNS-related effects.(1)|
01227|011|B||
01227|012|P|PREDISPOSING FACTORS:  None determined.|
01227|013|B||
01227|014|M|PATIENT MANAGEMENT:  The UK manufacturer of memantine states that the|
01227|015|M|concurrent use of memantine with N-methyl-D-aspartate (NMDA) antagonists|
01227|016|M|such as amantadine or ketamine should be avoided.(1)  The US manufacturer of|
01227|017|M|memantine states that concurrent use should be approached with caution.(2)|
01227|018|B||
01227|019|D|DISCUSSION:  Because N-methyl-D-aspartate (NMDA) antagonists act at the same|
01227|020|D|receptor system as does memantine, concurrent use may result in more|
01227|021|D|frequent and more pronounced side effects, especially CNS-related effects.|
01227|022|D|Therefore, the UK manufacturer of memantine states that the concurrent use|
01227|023|D|of memantine with NMDA antagonists such as amantadine or ketamine should be|
01227|024|D|avoided.(1)  The US manufacturer of memantine states that concurrent use|
01227|025|D|should be approached with caution.(2)|
01227|026|D|   In a study in 52 healthy subjects, concurrent memantine (20 mg daily) and|
01227|027|D|dextromethorphan/quinidine (30/30 mg daily) resulted in no changes in|
01227|028|D|dextromethorphan or memantine levels.  There was a slight increase in|
01227|029|D|dizziness as measured by the dizziness visual analog scale (VAS) when|
01227|030|D|compared to memantine alone but not the combination of|
01227|031|D|dextromethorphan/quinidine alone.  For other pharmacodynamic assessments,|
01227|032|D|there was either no effect or improvement on some subscales.(3)|
01227|033|B||
01227|034|R|REFERENCES:|
01227|035|B||
01227|036|R|1.Ebixa (memantine hydrochloride) UK summary of product characteristics. H.|1
01227|037|R|  Lundbeck A/S September 27, 2002.|1
01227|038|R|2.Namenda (memantine hydrochloride) US prescribing information. Forest|1
01227|039|R|  Pharmaceuticals Inc. July, 2014.|1
01227|040|R|3.Pope LE, Kaye R, Hepner A, Schoedel KA, Bartlett C, Sellers EM. A study of|2
01227|041|R|  potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions|2
01227|042|R|  between dextromethorphan/quinidine and memantine. Presented at the 163rd|2
01227|043|R|  Metting of the American Psychiatric Association. May 22-26, 2010; New|2
01227|044|R|  Orleans, LA..|2
01228|001|T|MONOGRAPH TITLE:  Atomoxetine; Reboxetine; Viloxazine/Monoamine Oxidase|
01228|002|T|Inhib|
01228|003|B||
01228|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01228|005|L|is contraindicated and generally should not be dispensed or administered to|
01228|006|L|the same patient.|
01228|007|B||
01228|008|A|MECHANISM OF ACTION:  Monoamine oxidase Inhibitors (MAOIs) block the enzymes|
01228|009|A|that degrade monoamine neurotransmitters-norepinephrine and serotonin.|
01228|010|A|Atomoxetine, reboxetine, and viloxazine inhibit the pre-synaptic|
01228|011|A|norepinephrine transporter.  Concomitant use of atomoxetine, reboxetine, or|
01228|012|A|viloxazine with MAOIs may potentiate the release of norepinephrine and other|
01228|013|A|monoamines from adrenergic nerve endings.(1-3)|
01228|014|B||
01228|015|E|CLINICAL EFFECTS:  Concurrent use may result in serious and sometimes fatal|
01228|016|E|reactions including hyperthermia, rigidity, myoclonus, autonomic instability|
01228|017|E|with possible rapid fluctuations of vital signs, and mental status changes|
01228|018|E|that include extreme agitation progressing to delirium and coma.(1-3)|
01228|019|B||
01228|020|P|PREDISPOSING FACTORS:  None determined.|
01228|021|B||
01228|022|M|PATIENT MANAGEMENT:  The manufacturers of atomoxetine and viloxazine state|
01228|023|M|that the concurrent use of atomoxetine or viloxazine with a monoamine|
01228|024|M|oxidase inhibitor (MAOI) is contraindicated.  At least a two-week washout|
01228|025|M|period should occur between switching a patient from a MAOI to atomoxetine|
01228|026|M|or viloxazine, or from atomoxetine to a MAOI.(1,3)|
01228|027|M|   The Australian manufacturer of reboxetine states that concurrent use with|
01228|028|M|an MAOI is contraindicated.(2)|
01228|029|B||
01228|030|D|DISCUSSION:  Because the use of other drugs that affect brain monoamine|
01228|031|D|concentrations with monoamine oxidase inhibitors has resulted in serious and|
01228|032|D|sometimes fatal reactions, the manufacturer of atomoxetine states that the|
01228|033|D|concurrent use of atomoxetine with a MAOI is contraindicated.  At least a|
01228|034|D|two-week washout period should occur between switching a patient from a MAOI|
01228|035|D|to atomoxetine or from atomoxetine to a MAOI.(1)|
01228|036|D|   The Australian manufacturer of reboxetine and the US manufacturer of|
01228|037|D|viloxazine state that concurrent use with an MAOI is contraindicated.(2-3)|
01228|038|D|   Methylene blue, when administered intravenously, has been shown to reach|
01228|039|D|sufficient concentrations to be a potent inhibitor of MAO-A.(4-5)|
01228|040|D|   Metaxalone is a weak inhibitor of MAO.(8,9)|
01228|041|D|   One or more of the drug pairs linked to this monograph have been included|
01228|042|D|in a list of interactions that should be considered "high-priority" for|
01228|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01228|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01228|045|D|Coordinator (ONC) for Health Information Technology.|
01228|046|B||
01228|047|R|REFERENCES:|
01228|048|B||
01228|049|R|1.Strattera (atomoxetine hydrochloride) US prescribing information. Eli|1
01228|050|R|  Lilly and Company January, 2022.|1
01228|051|R|2.Edronax (reboxetine mesylate) Australian prescribing information. Pfizer|1
01228|052|R|  Australia Pty Ltd. November 8, 2022.|1
01228|053|R|3.Qelbree (viloxazine) US prescribing information. Catalent Pharma|1
01228|054|R|  Solutions, LLC April, 2021.|1
01228|055|R|4.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
01228|056|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
01228|057|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
01228|058|R|5.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
01228|059|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
01228|060|R|  2000 Jun;56(3):247-50.|2
01228|061|R|6.Fisar Z, Hroudova J, Raboch J. Inhibition of monoamine oxidase activity by|5
01228|062|R|  antidepressants and mood stabilizers. Neuro Endocrinol Lett 2010;|5
01228|063|R|  31(5):645-56.|5
01228|064|R|7.Aggarwal A, Kulkarni G, Jahan S. Potential serious adverse interactions|3
01228|065|R|  between linezolid and atomoxetine. J Child Adolesc Psychopharmacol 2012|3
01228|066|R|  Oct;22(5):405.|3
01228|067|R|8.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
01228|068|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
01228|069|R|  Feb;34(2):346.e5-6.|3
01228|070|R|9.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
01228|071|R|  Pfizer Inc. January, 2024.|1
01228|072|R|10.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01228|073|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01228|074|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01228|075|R|   19(5):735-43.|6
01229|001|T|MONOGRAPH TITLE:  Atomoxetine; Vortioxetine/Strong 2D6 Inhibitors|
01229|002|B||
01229|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01229|004|L|of severe adverse interaction.|
01229|005|B||
01229|006|A|MECHANISM OF ACTION:  FDA designates atomoxetine as a 'sensitive substrate'|
01229|007|A|at CYP2D6. Sensitive substrates are drugs whose area-under-curve (AUC)|
01229|008|A|increases 5-fold or higher when given a strong inhibitor of a particular|
01229|009|A|enzyme.(1)|
01229|010|A|   Although metabolized via several CYP P-450 pathways, vortioxetine appears|
01229|011|A|primarily metabolized via CYP2D6.(2-3)|
01229|012|A|   Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine are strong|
01229|013|A|inhibitors of CYP2D6. Terbinafine is a moderate to strong inhibitors of|
01229|014|A|CYP2D6.(1,4)|
01229|015|B||
01229|016|E|CLINICAL EFFECTS:  Concurrent use of bupropion, dacomitinib, fluoxetine,|
01229|017|E|paroxetine, quinidine, or terbinafine may result in elevated levels and|
01229|018|E|adverse effects of atomoxetine or vortioxetine.  Atomoxetine adverse effects|
01229|019|E|may include elevated blood pressure, tachycardia, insomnia, irritability,|
01229|020|E|nausea/vomiting, or appetite suppression.(5,7)  Vortioxetine adverse effects|
01229|021|E|may include headache, nausea, vomiting, dizziness, or abnormal dreams.(2,3)|
01229|022|B||
01229|023|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers may|
01229|024|P|be affected to a greater extent by CYP2D6 inhibitors.  Patients who are|
01229|025|P|CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6|
01229|026|P|inhibition.|
01229|027|B||
01229|028|M|PATIENT MANAGEMENT:  When a strong CYP2D6 inhibitor is added to existing|
01229|029|M|atomoxetine therapy, exposure to atomoxetine may increase greater than|
01229|030|M|5-fold, depending upon the dosage and specific CYP2D6 inhibitor involved.|
01229|031|M|The manufacturer of atomoxetine recommends downward dosage adjustments when|
01229|032|M|patients receive concomitant treatment with strong CYP2D6 inhibitors.(5)|
01229|033|M|   When initiating atomoxetine in children and adolescents weighing up to 70|
01229|034|M|Kg who are already receiving strong CYP2D6 inhibitors, the atomoxetine dose|
01229|035|M|should be initiated at 0.5 mg/kg/day and only increased to the usual target|
01229|036|M|dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the|
01229|037|M|initial dose is well tolerated.(5)|
01229|038|M|   When initiating atomoxetine in children and adolescents weighing over 70|
01229|039|M|Kg and adults who are receiving strong CYP2D6 inhibitors, atomoxetine should|
01229|040|M|be initiated at 40 mg/day and only increased to the usual target dose of 80|
01229|041|M|mg/day if symptoms fail to improve after 4 weeks and the initial dose is|
01229|042|M|well tolerated.(5)|
01229|043|M|   The manufacturer of vortioxetine recommends reducing vortioxetine dose by|
01229|044|M|half when a strong CYP2D6 inhibitor is coadministered.(2)|
01229|045|B||
01229|046|D|DISCUSSION:  In a single-blind study in 22 healthy subjects, the concurrent|
01229|047|D|administration of paroxetine (20 mg twice daily in one arm, 20 mg one daily|
01229|048|D|in another arm) with atomoxetine (20 mg twice daily) resulted in increases|
01229|049|D|in the maximum concentration (Cmax), area-under-curve (AUC), and half-life|
01229|050|D|of atomoxetine by 3.5-fold, 6.5-fold, and 2.5-fold, respectively.  There|
01229|051|D|were no changes in paroxetine pharmacokinetics.(4)|
01229|052|D|   In extensive metabolizers administered paroxetine(2,3) or fluoxetine(2)|
01229|053|D|with atomoxetine, the AUC of atomoxetine is approximately 6-fold to 8-fold|
01229|054|D|and the Cmax is about 3-fold to 4-fold greater than with atomoxetine alone.|
01229|055|D|   In vitro studies suggest that administration of CYP P-450 inhibitors to|
01229|056|D|poor metabolizers would not increase plasma atomoxetine concentrations.(2)|
01229|057|D|   A drug interaction study conducted over 28 days evaluated the effect of|
01229|058|D|bupropion 150 mg twice daily on the tolerance and steady-state kinetics of|
01229|059|D|vortioxetine 10 mg daily in 28 healthy subjects.  Vortioxetine AUC and Cmax|
01229|060|D|increased by 2.3 and 2.1 fold respectively.(3)|
01229|061|D|   Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine are strong|
01229|062|D|inhibitors of CYP2D6. Terbinafine is a moderate to strong inhibitors of|
01229|063|D|CYP2D6.(1,4)|
01229|064|B||
01229|065|R|REFERENCES:|
01229|066|B||
01229|067|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
01229|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01229|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01229|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01229|071|R|  11/14/2017.|1
01229|072|R|2.Trintellix (vortioxetine) US prescribing information. Takeda|1
01229|073|R|  Pharmaceuticals America, Inc. November, 2020.|1
01229|074|R|3.Chen G, Lee R, Hojer AM, Buchbjerg JK, Serenko M, Zhao Z. Pharmacokinetic|2
01229|075|R|  Drug Interactions Involving Vortioxetine (Lu AA21004), a Multimodal|2
01229|076|R|  Antidepressant. Clin Drug Investig 2013 Oct;33(10):727-36.|2
01229|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
01229|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01229|079|R|5.Strattera (atomoxetine hydrochloride) US prescribing information. Eli|1
01229|080|R|  Lilly and Company January, 2022.|1
01229|081|R|6.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
01229|082|R|  Therapeutics, LLC September, 2021.|1
01229|083|R|7.Belle DJ, Ernest CS, Sauer JM, Smith BP, Thomasson HR, Witcher JW. Effect|2
01229|084|R|  of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics.|2
01229|085|R|  J Clin Pharmacol 2002 Nov;42(11):1219-27.|2
01230|001|T|MONOGRAPH TITLE:  Atomoxetine/Quinidine (mono deleted 05/12/2011)|
01230|002|B||
01230|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01230|004|L|take action as needed.|
01230|005|B||
01230|006|A|MECHANISM OF ACTION:  Quinidine may inhibit atomoxetine's metabolism by CYP|
01230|007|A|P-450-2D6.(1)|
01230|008|B||
01230|009|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of|
01230|010|E|atomoxetine and increased side effects.(1)|
01230|011|B||
01230|012|P|PREDISPOSING FACTORS:  None determined.|
01230|013|B||
01230|014|M|PATIENT MANAGEMENT:  The manufacturer of atomoxetine recommends dosage|
01230|015|M|adjustments of atomoxetine in patients receiving strong CYP P-450-2D6|
01230|016|M|inhibitors such as quinidine.(1)|
01230|017|M|   In children and adolescents weighing up to 70 kg who are receiving|
01230|018|M|quinidine, atomoxetine should be initiated at 0.5 mg/kg/day and only|
01230|019|M|increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to|
01230|020|M|improve after 4 weeks and the initial dose is well tolerated.(1)|
01230|021|M|   In children and adolescents weighing over 70 kg and adults who are|
01230|022|M|receiving quinidine, atomoxetine should be initiated at 40 mg/day and only|
01230|023|M|increased to the usual target dose of 80 mg/day if symptoms fail to improve|
01230|024|M|after 4 weeks and the initial dose is well tolerated.(1)|
01230|025|B||
01230|026|D|DISCUSSION:  In extensive metabolizers administered paroxetine or fluoxetine|
01230|027|D|with atomoxetine, the AUC of atomoxetine is approximately 6-fold to 8-fold|
01230|028|D|and the Cmax is about 3-fold to 4-fold greater than with atomoxetine alone.|
01230|029|D|Therefore, the manufacturer of atomoxetine recommends dosage adjustments|
01230|030|D|when atomoxetine is given with potent CYP P-450-2D6 inhibitors such as|
01230|031|D|quinidine.(1)|
01230|032|D|   In vitro studies suggest that administration of CYP P-450 inhibitors to|
01230|033|D|poor metabolizers would not increase plasma atomoxetine concentrations.(1)|
01230|034|B||
01230|035|R|REFERENCE:|
01230|036|B||
01230|037|R|1.Strattera (atomoxetine hydrochloride) US prescribing information. Eli|1
01230|038|R|  Lilly and Company January, 2022.|1
01231|001|T|MONOGRAPH TITLE:  Trimetrexate/Zidovudine|
01231|002|B||
01231|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01231|004|L|is contraindicated and generally should not be dispensed or administered to|
01231|005|L|the same patient.|
01231|006|B||
01231|007|A|MECHANISM OF ACTION:  Both trimetrexate and zidovudine can result in|
01231|008|A|hepatotoxicity and hematologic toxicity.(1)|
01231|009|B||
01231|010|E|CLINICAL EFFECTS:  Concurrent use may result in hepatotoxicity or|
01231|011|E|hematologic toxicity, which may limit the dose of trimetrexate than can be|
01231|012|E|safely administered.(1)|
01231|013|B||
01231|014|P|PREDISPOSING FACTORS:  None determined.|
01231|015|B||
01231|016|M|PATIENT MANAGEMENT:  The manufacturer of trimetrexate states that to allow|
01231|017|M|for full therapeutic doses of trimetrexate, zidovudine therapy should be|
01231|018|M|discontinued during trimetrexate therapy.(1)|
01231|019|B||
01231|020|D|DISCUSSION:  Patients receiving trimetrexate may experience severe hepatic,|
01231|021|D|hematologic, renal, and gastrointestinal toxicities. Caution should be used|
01231|022|D|in treating patients with impaired hematologic, renal, or hepatic function.|
01231|023|D|To allow for full therapeutic doses of trimetrexate, treatment with|
01231|024|D|zidovudine should be discontinued during trimetrexate therapy.(1)|
01231|025|B||
01231|026|R|REFERENCE:|
01231|027|B||
01231|028|R|1.Neutrexin (trimetrexate glucuronate for injection) US prescribing|1
01231|029|R|  information. MedImmune Oncology, Inc. January, 2005..|1
01232|001|T|MONOGRAPH TITLE:  Lamivudine/Zalcitabine|
01232|002|B||
01232|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01232|004|L|is contraindicated and generally should not be dispensed or administered to|
01232|005|L|the same patient.|
01232|006|B||
01232|007|A|MECHANISM OF ACTION:  Lamivudine and zalcitabine may inhibit the|
01232|008|A|intracellular phosphorylation of each other.(1-6)|
01232|009|B||
01232|010|E|CLINICAL EFFECTS:  Concurrent administration of lamivudine and zalcitabine|
01232|011|E|may result in decreased clinical efficacy of one or both agents.|
01232|012|B||
01232|013|P|PREDISPOSING FACTORS:  None determined.|
01232|014|B||
01232|015|M|PATIENT MANAGEMENT:  The manufacturer of lamivudine states that the|
01232|016|M|concurrent use of lamivudine and zalcitabine is not recommended.(1-3)|
01232|017|B||
01232|018|D|DISCUSSION:  Both lamivudine(1-3) and zalcitabine(7) undergo a series of|
01232|019|D|phosphorylations to their active metabolites.|
01232|020|D|   In an in vitro study, the presence of lamivudine significantly decreased|
01232|021|D|the phosphorylation of zalcitabine, resulting in a 50% decrease in|
01232|022|D|zalcitabine triphosphate levels.(4)|
01232|023|D|   In an in vitro study in peripheral blood mononuclear cells (PBMCs) and|
01232|024|D|U937 cells, zalcitabine significantly inhibited the phosphorylation of|
01232|025|D|lamivudine.  No lamivudine triphosphate was found in the PBMCs and the|
01232|026|D|amount of lamivudine triphosphate was decreased 33% when compared to control|
01232|027|D|values in the U937 cell line.(5)|
01232|028|D|   In another in vitro study, lamivudine decreased total zalcitabine|
01232|029|D|phosphates by 57%.  There was no effect on lamivudine phosphorylation.(6)|
01232|030|B||
01232|031|R|REFERENCES:|
01232|032|B||
01232|033|R|1.Epivir (lamivudine) US prescribing information. GlaxoSmithKline May, 2019.|1
01232|034|R|2.Trizivir (abacavir sulfate, lamivudine, and zidovudine) US prescribing|1
01232|035|R|  information. GlaxoSmithKline April, 2018.|1
01232|036|R|3.Epzicom (abacavir sulfate and lamivudine) US prescribing information.|1
01232|037|R|  GlaxoSmithKline February, 2021.|1
01232|038|R|4.Veal GJ, Barry MG, Khoo SH, Back DJ. In vitro screening of nucleoside|5
01232|039|R|  analog combinations for potential use in anti-HIV therapy. AIDS Res Hum|5
01232|040|R|  Retroviruses 1997 Apr 10;13(6):481-4.|5
01232|041|R|5.Kewn S, Veal GJ, Hoggard PG, Barry MG, Back DJ. Lamivudine (3TC)|5
01232|042|R|  phosphorylation and drug interactions in vitro. Biochem Pharmacol 1997 Sep|5
01232|043|R|  1;54(5):589-95.|5
01232|044|R|6.Hoggard PG, Sales SD, Kewn S, Sunderland D, Khoo SH, Hart CA, Back DJ.|5
01232|045|R|  Correlation between intracellular pharmacological activation of nucleoside|5
01232|046|R|  analogues and HIV suppression in vitro. Antivir Chem Chemother 2000 Nov;|5
01232|047|R|  11(6):353-8.|5
01232|048|R|7.Hivid (zalcitabine) US prescribing information. Roche Pharmaceuticals|1
01232|049|R|  September, 2002.|1
01233|001|T|MONOGRAPH TITLE:  Abciximab/Dextran|
01233|002|B||
01233|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01233|004|L|is contraindicated and generally should not be dispensed or administered to|
01233|005|L|the same patient.|
01233|006|B||
01233|007|A|MECHANISM OF ACTION:  Abciximab inhibits platelet aggregation by preventing|
01233|008|A|the binding of fibrinogen, von Willebrand factor, and other adhesive|
01233|009|A|molecules to GP IIb/IIIa receptor sites on activated platelets.(1) Dextran|
01233|010|A|also has an inhibitory effect on platelet function by effecting changes in|
01233|011|A|electrophoretic mobility and/or interfering with the factor VIII/von|
01233|012|A|Willebrand factor complex.(2,3) Concurrent use of abciximab and dextran may|
01233|013|A|have additive antiplatelet effects and an increase the risk of bleeding.|
01233|014|B||
01233|015|E|CLINICAL EFFECTS:  Concurrent use of abciximab and dextran may result in|
01233|016|E|bleeding.(1)|
01233|017|B||
01233|018|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01233|019|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01233|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
01233|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01233|022|P|risk for bleeding (e.g. NSAIDs).|
01233|023|B||
01233|024|M|PATIENT MANAGEMENT:  The manufacturer of abciximab states that abciximab is|
01233|025|M|contraindicated with the use of intravenous dextran before percutaneous|
01233|026|M|coronary intervention (PCI) or if there is intent to use it during an|
01233|027|M|intervention.(1)|
01233|028|M|   If concurrent therapy is deemed medically necessary, monitor patients|
01233|029|M|receiving concurrent therapy for signs of blood loss, including decreased|
01233|030|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
01233|031|M|and promptly evaluate patients with any symptoms.|
01233|032|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01233|033|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01233|034|M|anticoagulation in patients with active pathologic bleeding.|
01233|035|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01233|036|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01233|037|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01233|038|M|and/or swelling.|
01233|039|B||
01233|040|D|DISCUSSION:  In the EPIC trial, 11 patients received concurrent abciximab|
01233|041|D|and low molecular weight dextran.  Five had major bleeding events and four|
01233|042|D|had minor bleeding events.  None of the five placebo patients treated with|
01233|043|D|low molecular weight dextran had a major or minor bleeding event.(1)|
01233|044|B||
01233|045|R|REFERENCES:|
01233|046|B||
01233|047|R|1.ReoPro (abciximab) US prescribing information. Eli Lilly and Company|1
01233|048|R|  November 25, 2013.|1
01233|049|R|2.Harker LA, Fuster V. Pharmacology of platelet inhibitors. J Am Coll|6
01233|050|R|  Cardiol 1986 Dec;8(6 Suppl B):21B-32B.|6
01233|051|R|3.Nazzal M, Owunwanne A, Christenson JT. Direct platelet effect of low|2
01233|052|R|  molecular weight dextran in small calibre PTFE grafts. Eur J Vasc Surg|2
01233|053|R|  1991 Apr;5(2):169-72.|2
01234|001|T|MONOGRAPH TITLE:  Imipenem-Cilastatin/Ganciclovir,Valganciclovir|
01234|002|B||
01234|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01234|004|L|of severe adverse interaction.|
01234|005|B||
01234|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
01234|007|A|additive or synergistic effects on the seizure threshold.|
01234|008|B||
01234|009|E|CLINICAL EFFECTS:  Concurrent use of imipenem-cilastatin with ganciclovir|
01234|010|E|may result in generalized seizures.(1)|
01234|011|B||
01234|012|P|PREDISPOSING FACTORS:  None determined.|
01234|013|B||
01234|014|M|PATIENT MANAGEMENT:  The manufacturer of imipenem-cilastatin states that|
01234|015|M|imipenem-cilastatin and ganciclovir should not be coadministered unless the|
01234|016|M|potential benefits outweigh the risks of seizures.(1)|
01234|017|B||
01234|018|D|DISCUSSION:  Generalized seizures have been reported in patients who|
01234|019|D|received ganciclovir and imipenem-cilastatin.(1)|
01234|020|B||
01234|021|R|REFERENCES:|
01234|022|B||
01234|023|R|1.Primaxin I.V. (imipenem and cilastatin for injection) US prescribing|1
01234|024|R|  information. Merck & Co., Inc. October, 2006.|1
01234|025|R|2.Cytovene IV (ganciclovir) US prescribing information. Genentech Inc.|1
01234|026|R|  August, 2018.|1
01235|001|T|MONOGRAPH TITLE:  Adenosine; Hexobendine; Regadenoson/Xanthine Derivatives|
01235|002|B||
01235|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01235|004|L|of severe adverse interaction.|
01235|005|B||
01235|006|A|MECHANISM OF ACTION:  Xanthine derivatives may antagonize the effects of|
01235|007|A|endogenous(1) and exogenous adenosine,(2,3) regadenoson,(4) and|
01235|008|A|hexobendine.(5)|
01235|009|B||
01235|010|E|CLINICAL EFFECTS:  Concurrent use of a xanthine derivative use may result in|
01235|011|E|decreased effectiveness of adenosine, hexobendine and regadenoson.|
01235|012|E|Aminophylline may increase the risk of adenosine-induced seizures.(3)|
01235|013|B||
01235|014|P|PREDISPOSING FACTORS:  None determined.|
01235|015|B||
01235|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with adenosine|
01235|017|M|and a xanthine derivative should be monitored for decreased effectiveness of|
01235|018|M|adenosine.  The dosage of adenosine may need to be increased.  Whenever|
01235|019|M|possible, withhold xanthine derivatives for 5 half-lives prior to using|
01235|020|M|adenosine in cardiac stress tests.(6)  Methylxanthines should not be used to|
01235|021|M|reverse the effects of adenosine in patients who experience|
01235|022|M|adenosine-induced seizures.(3)|
01235|023|M|   Concurrent therapy with hexobendine and a xanthine oxidase derivative|
01235|024|M|should also be monitored for decreased effectiveness of hexobendine.(5)|
01235|025|M|   The US manufacturer of regadenoson recommends that patients avoid|
01235|026|M|methylxanthines (e.g. caffeine, pentoxifylline, and theophylline) for 12|
01235|027|M|hours prior to regadenoson administration.  Aminophylline may be used to|
01235|028|M|attenuate severe and/or persistent adverse reactions to regadenoson.(4)|
01235|029|B||
01235|030|D|DISCUSSION:  In a study in six healthy subjects, theophylline significantly|
01235|031|D|reduced the heart-rate response to adenosine.  In addition, theophylline|
01235|032|D|reduced the amount of abdominal and chest discomfort reported by subjects,|
01235|033|D|allowing significantly higher infusion rates of adenosine.(7)  Theophylline|
01235|034|D|has also been reported to antagonize the vasorelaxant action of adenosine in|
01235|035|D|human forearm arterioles.(8)  In a study in five subjects, theophylline|
01235|036|D|decreased the amounts of adenosine-induced side effects, including chest|
01235|037|D|pain.  There was no change in blood pressure or respiratory rate during|
01235|038|D|concurrent adenosine and theophylline.(9)|
01235|039|D|   In a study in ten dog and twelve human subjects, the administration of|
01235|040|D|adenosine after hexobendine increased coronary sinus blood flow.|
01235|041|D|Aminophylline administration significantly decreased the coronary|
01235|042|D|vasodilation response to adenosine and hexobendine.(5)|
01235|043|D|   In a study in ten healthy subjects, caffeine reduced the mean|
01235|044|D|adenosine-induced increases in systolic blood pressure by 7.2 mmHg and heart|
01235|045|D|rate by 8.4 beats/min when compared to placebo.(2)  In another study in ten|
01235|046|D|healthy subjects, caffeine was shown to lower the adenosine-induced response|
01235|047|D|of blood pressure and heart rate.(3)  Caffeine has also been reported to|
01235|048|D|reduced adenosine-induced changes in minute ventilation and tidal volume.(3)|
01235|049|D|   Aminophylline has been shown to shorten the duration of coronary blood|
01235|050|D|flow response to regadenoson.(3)|
01235|051|D|   Coronary flow reserve was 8% lower in patients who received caffeine (200|
01235|052|D|mg single dose) 2 hours prior to regadenoson administration when compared to|
01235|053|D|subjects who received placebo instead of caffeine.(4)|
01235|054|B||
01235|055|R|REFERENCES:|
01235|056|B||
01235|057|R|1.Fredholm BB. On the mechanism of action of theophylline and caffeine. Acta|6
01235|058|R|  Med Scand 1985;217(2):149-53.|6
01235|059|R|2.Smits P, Schouten J, Thien T. Cardiovascular effects of two xanthines and|2
01235|060|R|  the relation to adenosine antagonism. Clin Pharmacol Ther 1989 Jun;|2
01235|061|R|  45(6):593-9.|2
01235|062|R|3.Adenoscan (adenosine) US prescribing information. Astellas Pharma US, Inc.|1
01235|063|R|  August, 2014.|1
01235|064|R|4.Lexiscan (regadenoson) US prescribing information. Astellas Pharma US,|1
01235|065|R|  Inc. May, 2018.|1
01235|066|R|5.Hansing CE, Folts JD, Afonso S, Rowe GG. Systemic and coronary hemodynamic|5
01235|067|R|  effects of hexobendine and its interaction with adenosine and|5
01235|068|R|  aminophylline. J Pharmacol Exp Ther 1972 Jun;181(3):498-511.|5
01235|069|R|6.Maxwell DL, Fuller RW, Conradson TB, Dixon CM, Aber V, Hughes JM, Barnes|3
01235|070|R|  PJ. Contrasting effects of two xanthines, theophylline and enprofylline,|3
01235|071|R|  on the cardio-respiratory stimulation of infused adenosine in man. Acta|3
01235|072|R|  Physiol Scand 1987 Nov;131(3):459-65.|3
01235|073|R|7.Taddei S, Pedrinelli R, Salvetti A. Theophylline is an antagonist of|2
01235|074|R|  adenosine in human forearm arterioles. Am J Hypertens 1991 Mar;4(3 Pt|2
01235|075|R|  1):256-9.|2
01235|076|R|8.Minton NA, Henry JA. Pharmacodynamic interactions between infused|2
01235|077|R|  adenosine and oral theophylline. Hum Exp Toxicol 1991 Nov;10(6):411-8.|2
01235|078|R|9.Smits P, Boekema P, De Abreu R, Thien T, van 't Laar A. Evidence for an|2
01235|079|R|  antagonism between caffeine and adenosine in the human cardiovascular|2
01235|080|R|  system. J Cardiovasc Pharmacol 1987 Aug;10(2):136-43.|2
01235|081|R|10.Smits P, Schouten J, Thien T. Respiratory stimulant effects of adenosine|2
01235|082|R|   in man after caffeine and enprofylline. Br J Clin Pharmacol 1987 Dec;|2
01235|083|R|   24(6):816-9.|2
01236|001|T|MONOGRAPH TITLE:  Moricizine/Cimetidine|
01236|002|B||
01236|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01236|004|L|take action as needed.|
01236|005|B||
01236|006|A|MECHANISM OF ACTION:  Cimetidine may inhibit moricizine's metabolism.(1)|
01236|007|B||
01236|008|E|CLINICAL EFFECTS:  Concurrent use of cimetidine and moricizine may result in|
01236|009|E|increased moricizine levels and effects.|
01236|010|B||
01236|011|P|PREDISPOSING FACTORS:  None determined.|
01236|012|B||
01236|013|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with moricizine|
01236|014|M|and cimetidine should be closely monitored for electrocardiographic (ECG)|
01236|015|M|changes.  The dose of moricizine may need to be adjusted if cimetidine is|
01236|016|M|added to or withdrawn from therapy.|
01236|017|B||
01236|018|D|DISCUSSION:  In a study of eight normal fasting volunteers taking no other|
01236|019|D|medications, cimetidine administration increased the elimination half-life|
01236|020|D|of moricizine by 35% and reduced the clearance by 48.5%.  The|
01236|021|D|area-under-curve (AUC) of moricizine was increased 39% and the apparent|
01236|022|D|volume of distribution of moricizine was decreased 26% with concurrent|
01236|023|D|administration of cimetidine.  ECG readings, heart rate, and blood pressure|
01236|024|D|were not altered significantly by co-administration of cimetidine and|
01236|025|D|moricizine when compared to moricizine alone.(1)|
01236|026|B||
01236|027|R|REFERENCE:|
01236|028|B||
01236|029|R|1.Biollaz J, Shaheen O, Wood AJ. Cimetidine inhibition of ethmozine|2
01236|030|R|  metabolism. Clin Pharmacol Ther 1985 Jun;37(6):665-8.|2
01237|001|T|MONOGRAPH TITLE:  Selected Theophylline Derivatives/Moricizine|
01237|002|B||
01237|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01237|004|L|take action as needed.|
01237|005|B||
01237|006|A|MECHANISM OF ACTION:  Moricizine may induce the metabolism of hepatically|
01237|007|A|metabolized theophylline derivatives.(1)|
01237|008|B||
01237|009|E|CLINICAL EFFECTS:  Concurrent use of moricizine may result in reduced|
01237|010|E|theophylline levels and clinical effectiveness.(1)|
01237|011|B||
01237|012|P|PREDISPOSING FACTORS:  None determined.|
01237|013|B||
01237|014|M|PATIENT MANAGEMENT:  Theophylline levels should be carefully monitored if|
01237|015|M|moricizine is added to or withdrawn from concurrent therapy.  The dose of|
01237|016|M|theophylline may need to be adjusted.|
01237|017|B||
01237|018|D|DISCUSSION:  In a study in 12 healthy subjects, the effects of moricizine|
01237|019|D|(250 mg every 8 hours) on single doses of immediate-release aminophylline|
01237|020|D|and controlled-release theophylline was examined.  Theophylline clearance|
01237|021|D|increased for both the aminophylline and the controlled-release theophylline|
01237|022|D|preparation (43% and 66%, respectively).  Theophylline half-life decreased,|
01237|023|D|although the magnitude of decrease was less with the controlled-release|
01237|024|D|formulation than with the aminophylline formulation (20% and 33%,|
01237|025|D|respectively).  The theophylline area-under-curve (AUC) was decreased for|
01237|026|D|both the aminophylline and theophylline (32% and 36%, respectively).|
01237|027|D|Moricizine also decreased the maximum concentration (Cmax) of theophylline|
01237|028|D|with the controlled-release theophylline, but not with aminophylline.(1)|
01237|029|B||
01237|030|R|REFERENCE:|
01237|031|B||
01237|032|R|1.Pieniaszek HJ Jr, Davidson AF, Benedek IH. Effect of moricizine on the|2
01237|033|R|  pharmacokinetics of single-dose theophylline in healthy subjects. Ther|2
01237|034|R|  Drug Monit 1993 Jun;15(3):199-203.|2
01238|001|T|MONOGRAPH TITLE:  Propafenone/Selected Class IA And III Antiarrhythmics|
01238|002|B||
01238|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01238|004|L|is contraindicated and generally should not be dispensed or administered to|
01238|005|L|the same patient.|
01238|006|B||
01238|007|A|MECHANISM OF ACTION:  Concurrent use of propafenone with other Class IA or|
01238|008|A|III antiarrhythmics may result in additive or synergistic effects on the QTc|
01238|009|A|interval.(1)|
01238|010|A|   In addition to additive or synergistic effects on the QTc interval,|
01238|011|A|concurrent amiodarone and propafenone may affect conduction and|
01238|012|A|repolarization.(1)|
01238|013|B||
01238|014|E|CLINICAL EFFECTS:  Concurrent use of propafenone with other Class IA and III|
01238|015|E|antiarrhythmics may result in prolongation of the QTc interval and|
01238|016|E|life-threatening cardiac arrhythmias.|
01238|017|E|   In addition to these effects, concurrent amiodarone may affect conduction|
01238|018|E|and repolarization.(1)|
01238|019|B||
01238|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01238|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
01238|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01238|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01238|024|P|female gender, or advanced age.(2)|
01238|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01238|026|P|higher systemic concentrations of either QT prolonging drug are additional|
01238|027|P|risk factors for torsades de pointes.  Factors which may increased systemic|
01238|028|P|drug concentrations include rapid infusion of an intravenous dose or|
01238|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01238|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01238|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01238|032|B||
01238|033|M|PATIENT MANAGEMENT:  The manufacturer of propafenone states that concurrent|
01238|034|M|use of Class IA and III Antiarrhythmics is not recommended and these agents|
01238|035|M|should be withheld for at least 5 half-lives prior to dosing with|
01238|036|M|propafenone.(1)|
01238|037|M|   If alternatives are not available and concurrent therapy is deemed|
01238|038|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
01238|039|M|and monitor ECG at baseline and at regular intervals.  Correct any|
01238|040|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01238|041|M|heartbeat, dizziness, or fainting.|
01238|042|B||
01238|043|D|DISCUSSION:  Two studies evaluated the safety of adding ibutilide to|
01238|044|D|propafenone for cardioversion.  Although positive clinical results were|
01238|045|D|observed, ten patients reported significant bradycardia and one patient|
01238|046|D|experienced torsades de pointes.(4,5)|
01238|047|D|   A study assessed the use of propafenone in patients with|
01238|048|D|amiodarone-resistant ventricular tachycardia.  Two cases reported suppressed|
01238|049|D|ventricular tachycardia after the addition of propafenone to amiodarone.|
01238|050|D|Four cases reported worsening of spontaneous tachycardia with combined|
01238|051|D|administration, and one case degenerated to ventricular fibrillation. The|
01238|052|D|combination may be useful but is often associated with undesirable,|
01238|053|D|significant side-effects.  The combination may be limited to patients|
01238|054|D|without severely depressed left ventricular function and a reduced|
01238|055|D|probability of inducing ventricular tachycardia.(6)|
01238|056|B||
01238|057|R|REFERENCES:|
01238|058|B||
01238|059|R|1.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
01238|060|R|  Laboratories March, 2013.|1
01238|061|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01238|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01238|063|R|  settings: a scientific statement from the American Heart Association and|6
01238|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01238|065|R|  2;55(9):934-47.|6
01238|066|R|3.Klein RC, Huang SK, Marcus FI, Horwitz L, Fenster PE, Rushforth N, Kirsten|2
01238|067|R|  EB. Enhanced antiarrhythmic efficacy of propafenone when used in|2
01238|068|R|  combination with procainamide or quinidine. Am Heart J 1987 Sep;|2
01238|069|R|  114(3):551-8.|2
01238|070|R|4.Korantzopoulos P, Kolettis TM, Papathanasiou A, Naka KK, Kolios P,|2
01238|071|R|  Leontaridis I, Draganigos A, Katsouras CS, Goudevenos JA. Propafenone|2
01238|072|R|  added to ibutilide increases conversion rates of persistent atrial|2
01238|073|R|  fibrillation. Heart 2006 May;92(5):631-4.|2
01238|074|R|5.Chiladakis JA, Kalogeropoulos A, Patsouras N, Manolis AS. Ibutilide added|2
01238|075|R|  to propafenone for the conversion of atrial fibrillation and atrial|2
01238|076|R|  flutter. J Am Coll Cardiol 2004 Aug 18;44(4):859-63.|2
01238|077|R|6.Morgera T, Dreas L, Humar F, Maras P, Chersevani D, Camerini F. The use of|2
01238|078|R|  associated propafenone in patients with amiodarone-resistant ventricular|2
01238|079|R|  tachycardia. Int J Cardiol 1991 May;31(2):187-97.|2
01239|001|T|MONOGRAPH TITLE:  Lithium/Carbonic Anhydrase Inhibitors|
01239|002|B||
01239|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01239|004|L|take action as needed.|
01239|005|B||
01239|006|A|MECHANISM OF ACTION:  Carbonic anhydrase inhibitors may increase the renal|
01239|007|A|excretion of lithium, either by alkalinization of the urine or by impairing|
01239|008|A|the proximal tubular reabsorption of lithium.|
01239|009|B||
01239|010|E|CLINICAL EFFECTS:  Concurrent use of a carbonic anhydrase inhibitor may|
01239|011|E|result in decreased levels and clinical effectiveness of lithium.|
01239|012|B||
01239|013|P|PREDISPOSING FACTORS:  None determined.|
01239|014|B||
01239|015|M|PATIENT MANAGEMENT:  Lithium levels should be monitored in patients|
01239|016|M|receiving concurrent therapy or if the carbonic anhydrase inhibitor is|
01239|017|M|withdrawn from concurrent therapy.  The dose of lithium may need to be|
01239|018|M|adjusted.|
01239|019|B||
01239|020|D|DISCUSSION:  One study involving six subjects showed that the concurrent use|
01239|021|D|of a single dose of both lithium carbonate and acetazolamide caused a 27% to|
01239|022|D|31% increase in the urinary excretion of lithium.(1)|
01239|023|D|   Acetazolamide has been used in combination with other agents to treat|
01239|024|D|lithium toxicity.(2)|
01239|025|B||
01239|026|R|REFERENCES:|
01239|027|B||
01239|028|R|1.Thomsen K, Schou M. Renal lithium excretion in man. Am J Physiol 1968 Oct;|2
01239|029|R|  215(4):823-7.|2
01239|030|R|2.Horowitz LC, Fisher GU. Acute lithium toxicity. N Engl J Med 1969 Dec 11;|3
01239|031|R|  281(24):1369.|3
01240|001|T|MONOGRAPH TITLE:  Selected Inhalation Anesthetic Agents/Sympathomimetics|
01240|002|B||
01240|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01240|004|L|of severe adverse interaction.|
01240|005|B||
01240|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  The anesthetics|
01240|007|A|produce conduction changes that increase impulse re-entry into the|
01240|008|A|myocardial tissue.(1)  The anesthetics' ability to precipitate arrhythmias|
01240|009|A|is enhanced by elevated arterial blood pressure, tachycardia, hypercapnia,|
01240|010|A|and/or hypoxia, events that stimulate the release of endogenous|
01240|011|A|catecholamines.(1)|
01240|012|B||
01240|013|E|CLINICAL EFFECTS:  Concurrent use of inhalation anesthetic agents and|
01240|014|E|sympathomimetics may result in ventricular arrhythmias or sudden blood|
01240|015|E|pressure and heart rate increase during surgery.(2)|
01240|016|B||
01240|017|P|PREDISPOSING FACTORS:  None determined.|
01240|018|B||
01240|019|M|PATIENT MANAGEMENT:  Monitor blood pressure and avoid use of|
01240|020|M|sympathomimetics in patients being treated with anesthetics on the day of|
01240|021|M|surgery.(2)|
01240|022|M|   Intravenous use of epinephrine during surgery with halothane and related|
01240|023|M|halogenated general anesthetics should be strongly discouraged.  When|
01240|024|M|intravenous epinephrine is necessary, nitrous oxide anesthesia supplemented|
01240|025|M|with ether, muscle relaxants, or opioids should be used instead of|
01240|026|M|halothane.(3,4)|
01240|027|M|   Epinephrine may safely be used subcutaneously with the following|
01240|028|M|precautions: the patient is adequately ventilated to prevent hypoxia or|
01240|029|M|respiratory acidosis; the total dose of epinephrine is limited to 100 mcg/10|
01240|030|M|minute period or 300 mcg/hour in adults, 3.5 mcg/Kg in infants, 2.5 mcg/Kg|
01240|031|M|in children up to two years of age, and 1.45 mcg/Kg in children over two|
01240|032|M|years of age; a minimum effective concentration of anesthetic is maintained;|
01240|033|M|the drugs are not co-administered in patients with hypertension or other|
01240|034|M|cardiovascular disorders; and the cardiac rhythm is continuously monitored|
01240|035|M|during and after injection.(3-10)|
01240|036|M|   If arrhythmias occur after the administration of the epinephrine, the|
01240|037|M|drugs of choice are lidocaine or propranolol, depending on the type of|
01240|038|M|arrhythmia.(1)|
01240|039|B||
01240|040|D|DISCUSSION:  Administration of epinephrine during halothane anesthesia may|
01240|041|D|may lead to serious ventricular arrhythmias.(3-6,11-18)  This has occurred|
01240|042|D|when epinephrine was administered intravenously,(6) when it was administered|
01240|043|D|with lidocaine as a dental block,(11,14) or when it was administered|
01240|044|D|supraperiosteally.(5)|
01240|045|D|   Norepinephrine has been shown to interact with halothane in a manner|
01240|046|D|similar to epinephrine.(1)|
01240|047|D|   In two case reports, patients were given terbutaline (0.25 to 0.35 mg)|
01240|048|D|for wheezing following induction of anesthesia with halothane.  One|
01240|049|D|patient's heart rate increased from 68 to 100 beats/minute, and the ECG|
01240|050|D|showed premature ventricular contractions and bigeminy, while the other|
01240|051|D|patient developed multiple unifocal premature ventricular contractions and|
01240|052|D|bigeminy.  The arrhythmias resolved in both patients following lidocaine|
01240|053|D|administration.(19)|
01240|054|D|   Although not documented, isoproterenol causes effects on the heart|
01240|055|D|similar to terbutaline(20) and would probably interact with halothane in a|
01240|056|D|similar manner.|
01240|057|D|   Other inhalation anesthetics that increase the incidence of arrhythmias|
01240|058|D|with epinephrine include chloroform,(20) methoxyflurane,(20) and|
01240|059|D|enflurane.(12)|
01240|060|D|   A similar interaction may be expected between the other inhalation|
01240|061|D|anesthetics and sympathomimetics.|
01240|062|B||
01240|063|R|REFERENCES:|
01240|064|B||
01240|065|R|1.Weiner N. Norepinephrine, epinephrine, and the sympathomimetic amines. In|6
01240|066|R|  Gilman AG, Goodman LS, Rall TW, Murad F, eds. Goodman and Gilman's The|6
01240|067|R|  Pharmacological Basis of Therapeutics. 7th ed. New York: MacMillan|6
01240|068|R|  Publishing Company. 1985.|6
01240|069|R|2.Concerta (methylphenidate) Extended-Release prescribing information.|1
01240|070|R|  Janssen Pharmaceuticals October, 2023.|1
01240|071|R|3.Katz RL, Matteo RS, Papper EM. The injection of epinephrine during general|2
01240|072|R|  anesthesia with halogenated hydrocarbons and cyclopropane in man.|2
01240|073|R|  Anesthesiology 1962 Sep Oct;23(5):597-600.|2
01240|074|R|4.Johnstone M. Adrenaline and noradrenaline during anaesthesia. Anaesthesia|2
01240|075|R|  1953;8:32-42.|2
01240|076|R|5.Hirshom WI, Taylor RG, Sheehan JC. Arrhythmias produced by combinations of|2
01240|077|R|  halothane and small amounts of vasopressor. Br J Oral Surg 1965;2:131-36.|2
01240|078|R|6.Andersen N, Johansen SH. Incidence of catechol-amine-induced arrhythmias|2
01240|079|R|  during halothane anesthesia. Anesthesiology 1963 Jan Feb;24(1):51-56.|2
01240|080|R|7.Matteo RS, Katz RL, Papper EM. The injection of epinephrine during general|2
01240|081|R|  anesthesia. Anesthesiology 1962;23:360-64.|2
01240|082|R|8.Joas TA, Stevens WC. Comparison of the arrhythmic doses of epinephrine|5
01240|083|R|  during Forane, halothane, and fluroxene anesthesia in dogs. Anesthesiology|5
01240|084|R|  1971 Jul;35(1):48-53.|5
01240|085|R|9.Wallbank WA. Cardiac effects of halothane and adrenaline in hare-lip and|3
01240|086|R|  cleft- palate surgery. Br J Anaesth 1970 Jun;42(6):548-52.|3
01240|087|R|10.Melgrave AP. The use of epinephrine in the presence of halothane in|3
01240|088|R|   children. Can Anaesth Soc J 1970 May;17(3):256-60.|3
01240|089|R|11.Forbes AM. Halothane, adrenaline and cardiac arrest. Anaesthesia 1966|2
01240|090|R|   Jan;21(1):22-7.|2
01240|091|R|12.Reisner LS, Lippmann M. Ventricular arrhythmias after epinephrine|2
01240|092|R|   injection in enflurane and in halothane anesthesia. Anesth Analg 1975|2
01240|093|R|   Jul-Aug;54(4):468-70.|2
01240|094|R|13.Ikezono E, Yasuda K, Hattori Y. Effects of propranolol on|2
01240|095|R|   epinephrine-induced arrhythmias during halothane anesthesia in man and|2
01240|096|R|   cats. Anesth Analg 1969 Jul-Aug;48(4):598-604.|2
01240|097|R|14.Ueda W, Hirakawa M, Mae O. Appraisal of epinephrine administration to|2
01240|098|R|   patients under halothane anesthesia for closure of cleft palate.|2
01240|099|R|   Anesthesiology 1983 Jun;58(6):574-6.|2
01240|100|R|15.Kaufman L. Unforeseen complications encountered during dental|2
01240|101|R|   anaesthesia. Cardiac arrhythmias during dental anaesthesia. Proc R Soc|2
01240|102|R|   Med 1966 Aug;59(8):731-4.|2
01240|103|R|16.Alexander JP. Dysrhythmia and oral surgery. Br J Anaesth 1971 Aug;|2
01240|104|R|   43(8):773-8.|2
01240|105|R|17.Alexander JP, Bekheit S, Fletcher E. Dysrhythmia and oral surgery. II.|2
01240|106|R|   Junctional rhythms. Br J Anaesth 1972 Nov;44(11):1179-82.|2
01240|107|R|18.Katz RL, Katz GJ. Surgical infiltration of pressor drugs and their|6
01240|108|R|   interaction with volatile anaesthetics. Br J Anaesth 1966 Sep;|6
01240|109|R|   38(9):712-8.|6
01240|110|R|19.Thiagarajah S, Grynsztejn M, Lear E, Azar I. Ventricular arrhythmias|3
01240|111|R|   after terbutaline administration to patients anesthetized with halothane.|3
01240|112|R|   Anesth Analg 1986 Apr;65(4):417-8.|3
01240|113|R|20.Katz RL, Epstein RA. The interaction of anesthetic agents and adrenergic|6
01240|114|R|   drugs to produce cardiac arrhythmias. Anesthesiology 1968 Jul-Aug;|6
01240|115|R|   29(4):763-84.|6
01241|001|T|MONOGRAPH TITLE:  Oral Phosphate Supplements; Urinary pH Modifiers/Aluminum;|
01241|002|T|Calcium; Magnesium|
01241|003|B||
01241|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01241|005|L|of severe adverse interaction.|
01241|006|B||
01241|007|A|MECHANISM OF ACTION:  Medications containing significant amounts of|
01241|008|A|aluminum, calcium, or magnesium may bind to the phosphate and prevent its|
01241|009|A|absorption.(1)|
01241|010|B||
01241|011|E|CLINICAL EFFECTS:  Concurrent use of medications containing significant|
01241|012|E|amounts of aluminum, calcium, or magnesium may result in decreased|
01241|013|E|effectiveness of phosphate supplements and urinary pH modifiers high in|
01241|014|E|phosphate.(1)|
01241|015|B||
01241|016|P|PREDISPOSING FACTORS:  None determined.|
01241|017|B||
01241|018|M|PATIENT MANAGEMENT:  Patients receiving phosphate supplements or urinary pH|
01241|019|M|modifiers high in phosphate should be instructed to avoid medications|
01241|020|M|containing aluminum, calcium, or magnesium.(1)|
01241|021|M|   If concurrent use cannot be avoided, separate the administration of|
01241|022|M|phosphate containing products by as much time as possible from medications|
01241|023|M|containing aluminum, calcium, or magnesium.|
01241|024|M|   Some phosphate laxative products used as phosphate supplements may|
01241|025|M|contain sufficient quantities of phosphate to interact as well.|
01241|026|B||
01241|027|D|DISCUSSION:  The manufacturer of K-Phos states that products containing|
01241|028|D|aluminum, calcium, or magnesium may bind to the phosphate and prevent its|
01241|029|D|absorption.  Therefore, patients receiving phosphate supplements and urinary|
01241|030|D|pH modifiers high in phosphate should be instructed to avoid products|
01241|031|D|containing aluminum, calcium, or magnesium.(1)|
01241|032|B||
01241|033|R|REFERENCE:|
01241|034|B||
01241|035|R|1.K-Phos Neutral (phosphorous) US prescribing information. Beach 2002.|1
01242|001|T|MONOGRAPH TITLE:  Rifabutin/Efavirenz|
01242|002|B||
01242|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01242|004|L|take action as needed.|
01242|005|B||
01242|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of rifabutin via|
01242|007|A|CYP3A4.(1,2)|
01242|008|B||
01242|009|E|CLINICAL EFFECTS:  Concurrent use of efavirenz may result in decreased|
01242|010|E|levels and therapeutic failure of rifabutin.(1,2)|
01242|011|B||
01242|012|P|PREDISPOSING FACTORS:  None determined.|
01242|013|B||
01242|014|M|PATIENT MANAGEMENT:  The manufacturer of efavirenz recommends increasing the|
01242|015|M|dose of rifabutin by 50% in patients receiving concurrent efavirenz.  In|
01242|016|M|regimens when rifabutin is only given 2 or 3 times per week, the|
01242|017|M|manufacturer of efavirenz recommends doubling the dose of rifabutin.(1,2)|
01242|018|B||
01242|019|D|DISCUSSION:  In a study in 9 subjects, concurrent efavirenz (600 mg daily)|
01242|020|D|and rifabutin (300 mg daily) decreased the rifabutin maximum concentration|
01242|021|D|(Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 32%,|
01242|022|D|38%, and by 45%, respectively.  The efavirenz Cmin decreased by 12%.(1,2)|
01242|023|D|   In a study in 21 patients with tuberculosis and HIV infection,|
01242|024|D|administration of twice weekly rifabutin (600 mg) with isoniazid (15 mg/kg)|
01242|025|D|with efavirenz produced levels that adequately compensated for the efavirenz|
01242|026|D|interaction.  Efavirenz levels were 10% higher than in historical|
01242|027|D|controls.(3)|
01242|028|D|   In a case report, a patient receiving efavirenz (600 mg daily, increased|
01242|029|D|to 800 mg daily) had subtherapeutic efavirenz levels during concomitant use|
01242|030|D|of rifabutin (450 mg daily).  Expected clinical outcomes of efavirenz were|
01242|031|D|seen 12 days after discontinuation of rifabutin.(4)|
01242|032|D|   In another case report, a patient receiving efavirenz experienced|
01242|033|D|treatment failure with rifabutin.(5)|
01242|034|B||
01242|035|R|REFERENCES:|
01242|036|B||
01242|037|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01242|038|R|  Company November, 2023.|1
01242|039|R|2.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01242|040|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01242|041|R|3.Weiner M, Benator D, Peloquin CA, Burman W, Vernon A, Engle M, Khan A,|2
01242|042|R|  Zhao Z. Evaluation of the drug interaction between rifabutin and efavirenz|2
01242|043|R|  in patients with HIV infection and tuberculosis. Clin Infect Dis 2005 Nov|2
01242|044|R|  1;41(9):1343-9.|2
01242|045|R|4.Hsu O, Hill CJ, Kim M, Tan B, O'Brien JG. Decreased plasma efavirenz|3
01242|046|R|  concentrations in a patient receiving rifabutin. Am J Health Syst Pharm|3
01242|047|R|  2010 Oct 1;67(19):1611-4.|3
01242|048|R|5.Edelstein HE, Cuadros Y. Failure of treatment of tuberculous adenitis due|3
01242|049|R|  to an unexpected drug interaction with rifabutin and efavirenz. AIDS 2004|3
01242|050|R|  Aug 20;18(12):1748-9.|3
01243|001|T|MONOGRAPH TITLE:  Selected NSAIDs/Probenecid|
01243|002|B||
01243|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01243|004|L|take action as needed.|
01243|005|B||
01243|006|A|MECHANISM OF ACTION:  Probenecid may inhibit the renal tubular secretion of|
01243|007|A|some NSAIDs.  Probenecid may also prevent biliary clearance of NSAIDs.|
01243|008|B||
01243|009|E|CLINICAL EFFECTS:  The decreased clearance of NSAIDs may lead to increased|
01243|010|E|blood levels and an increase in adverse effects.|
01243|011|B||
01243|012|P|PREDISPOSING FACTORS:  None determined.|
01243|013|B||
01243|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
01243|015|M|monitored for an increase in NSAID-related adverse effects, including renal|
01243|016|M|insufficiency.  The dose of the NSAID may need to be decreased or probenecid|
01243|017|M|may need to be discontinued.|
01243|018|B||
01243|019|D|DISCUSSION:  Probenecid has been reported to increase the blood levels of|
01243|020|D|indomethacin by 2-fold to 6-fold.(1,2)  Probenecid has been reported to|
01243|021|D|increase levels of oral ketoprofen by 93%;(3) however, no effect was seen on|
01243|022|D|intramuscular ketoprofen in another study.(4)  Probenecid has also been|
01243|023|D|shown to increase naproxen levels.(5)  Probenecid has been shown to increase|
01243|024|D|the maximum concentration (Cmax) of tenoxicam.  No other pharmacokinetic|
01243|025|D|parameters were affected.(6)|
01243|026|D|   This interaction may result in clinical benefits in some patients.|
01243|027|B||
01243|028|R|REFERENCES:|
01243|029|B||
01243|030|R|1.Brooks PM, Bell MA, Sturrock RD, Famaey JP, Dick WC. The clinical|2
01243|031|R|  significance of indomethacin-probenecid interaction. Br J Pharmacol 1974;|2
01243|032|R|  1:287-90.|2
01243|033|R|2.Skeith MD, Simkin PA, Healey LA. The renal excretion of indomethacin and|2
01243|034|R|  its inhibition by probenecid. Clin Pharmacol Ther 1968 Jan-Feb;9(1):89-93.|2
01243|035|R|3.Upton RA, Williams RL, Buskin JN, Jones RM. Effects of probenecid on|2
01243|036|R|  ketoprofen kinetics. Clin Pharmacol Ther 1982 Jun;31(6):705-12.|2
01243|037|R|4.Wollheim FA, Stenberg P, Nilsson B, Mellbin G. Clinical and methodological|2
01243|038|R|  studies on intramuscular ketoprofen in postoperative rheumatic pain. Eur J|2
01243|039|R|  Clin Pharmacol 1981;20(6):423-5.|2
01243|040|R|5.Runkel R, Mroszczak E, Chaplin M, Sevelius H, Segre E. Naproxen-probenecid|2
01243|041|R|  interaction. Clin Pharmacol Ther 1978 Dec;24(6):706-13.|2
01243|042|R|6.Day RO, Geisslinger G, Paull P, Williams KM. Neither cimetidine nor|2
01243|043|R|  probenecid affect the pharmacokinetics of tenoxicam in normal volunteers.|2
01243|044|R|  Br J Clin Pharmacol 1994 Jan;37(1):79-81.|2
01244|001|T|MONOGRAPH TITLE:  Eletriptan/Nefazodone|
01244|002|B||
01244|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01244|004|L|is contraindicated and generally should not be dispensed or administered to|
01244|005|L|the same patient.|
01244|006|B||
01244|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of eletriptan by|
01244|008|A|CYP3A4.(1)|
01244|009|B||
01244|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
01244|011|E|adverse effects from eletriptan.(1)|
01244|012|B||
01244|013|P|PREDISPOSING FACTORS:  None determined.|
01244|014|B||
01244|015|M|PATIENT MANAGEMENT:  The US manufacturer of eletriptan states that|
01244|016|M|eletriptan should not be used within at least 72 hours of nefazodone.(1)|
01244|017|B||
01244|018|D|DISCUSSION:  Concurrent use with ketoconazole, another potent inhibitor of|
01244|019|D|CYP3A4, resulted in about a 3-fold increase in the maximum concentration|
01244|020|D|(Cmax) and about a 6-fold increase in the area-under-curve (AUC) of|
01244|021|D|eletriptan.  Eletriptan half-life increased from 5 hours to 8 hours and the|
01244|022|D|time to Cmax (Tmax) increased from 2.8 hours to 5.4 hours.(1)|
01244|023|D|   Concurrent use with erythromycin, also an inhibitor of CYP3A4, increased|
01244|024|D|the Cmax and AUC of eletriptan by about 2-fold and about 4-fold,|
01244|025|D|respectively.(1)|
01244|026|B||
01244|027|R|REFERENCES:|
01244|028|B||
01244|029|R|1.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
01244|030|R|  March, 2020.|1
01244|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
01244|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01245|001|T|MONOGRAPH TITLE:  Imatinib/Carbamazepine; Phenobarbital; Phenytoin (mono|
01245|002|T|deleted 09/08/2008)|
01245|003|B||
01245|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01245|005|L|of severe adverse interaction.|
01245|006|B||
01245|007|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital, and phenytoin may induce|
01245|008|A|the metabolism of imatinib at the CYP P-450-3A4 isoenzyme.(1)|
01245|009|B||
01245|010|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, phenobarbital, or|
01245|011|E|phenytoin with imatinib without a dosage adjustment may result in decreased|
01245|012|E|levels of and clinical response to imatinib.(1)|
01245|013|B||
01245|014|P|PREDISPOSING FACTORS:  None determined.|
01245|015|B||
01245|016|M|PATIENT MANAGEMENT:  The US manufacturer of imatinib states that concurrent|
01245|017|M|use of strong CYP P-450-3A4 inhibitors such carbamazepine, phenobarbital, or|
01245|018|M|phenytoin should be avoided.  If concurrent therapy is required, the dosage|
01245|019|M|of imatinib be increased by 50% and clinical response be carefully|
01245|020|M|monitored.(1)|
01245|021|B||
01245|022|D|DISCUSSION:  Imatinib is mainly metabolized by the CYP P-450-3A4 isoenzyme.|
01245|023|D|Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 8 days)|
01245|024|D|increased the clearance of a single dose of imatinib (400 mg) by 3.8-fold.|
01245|025|D|The area-under-curve (AUC) and maximum concentration (Cmax) decreased by 74%|
01245|026|D|and 54%, respectively.  Similar effects are expected with carbamazepine,|
01245|027|D|phenobarbital, and phenytoin, which are also potent inducers of CYP|
01245|028|D|P-450-3A4.(1)|
01245|029|B||
01245|030|R|REFERENCE:|
01245|031|B||
01245|032|R|1.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
01245|033|R|  Pharmaceuticals Corporation February, 2013.|1
01246|001|T|MONOGRAPH TITLE:  Imatinib; Pazopanib/Rifamycins (mono deleted 04/21/2011)|
01246|002|B||
01246|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01246|004|L|of severe adverse interaction.|
01246|005|B||
01246|006|A|MECHANISM OF ACTION:  Rifamycins may induce the metabolism of imatinib(1,2)|
01246|007|A|and pazopanib(3) by the CYP P-450-3A4 isoenzyme.|
01246|008|B||
01246|009|E|CLINICAL EFFECTS:  Concurrent use of rifamycins and imatinib without a|
01246|010|E|dosage adjustment may result in decreased levels of and clinical response to|
01246|011|E|imatinib(1) and pazopanib.(3)|
01246|012|B||
01246|013|P|PREDISPOSING FACTORS:  None determined.|
01246|014|B||
01246|015|M|PATIENT MANAGEMENT:  The US manufacturer of imatinib states that concurrent|
01246|016|M|use of strong CYP P-450-3A4 inducers such as rifampin and rifabutin be|
01246|017|M|avoided.  If concurrent use is required, the dosage of imatinib be increased|
01246|018|M|by 50% and clinical response be carefully monitored.(1)|
01246|019|M|   The US manufacturer of pazopanib states that the concurrent use of strong|
01246|020|M|CYP P-450-3A4 inducers should be avoided.  Pazopanib should not be|
01246|021|M|administered to patients who cannot avoid chronic use of strong CYP|
01246|022|M|P-450-3A4 inducers.(3)|
01246|023|B||
01246|024|D|DISCUSSION:  Imatinib is mainly metabolized by the CYP P-450-3A4 isoenzyme.|
01246|025|D|Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10 days)|
01246|026|D|increased the clearance of a single dose of imatinib (400 mg) by 3.8-fold.|
01246|027|D|The area-under-curve (AUC) and maximum concentration (Cmax) decreased by 74%|
01246|028|D|and 54%, respectively.(1,2)  The Cmax of the CGP74588 metabolite increased|
01246|029|D|by 88.6%, but the AUC of CGP74588 decreased by 11%.(2)|
01246|030|D|   Pazopanib is primarily metabolized by CYP P-450-3A4.(3)|
01246|031|B||
01246|032|R|REFERENCES:|
01246|033|B||
01246|034|R|1.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
01246|035|R|  Pharmaceuticals Corporation February, 2013.|1
01246|036|R|2.Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U,|2
01246|037|R|  Seiberling M. Effect of rifampicin on the pharmacokinetics of imatinib|2
01246|038|R|  mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol|2
01246|039|R|  2004 Feb;53(2):102-6.|2
01246|040|R|3.Votrient (pazopanib) US prescribing information. GlaxoSmithKline October,|1
01246|041|R|  2009.|1
01247|001|T|MONOGRAPH TITLE:  Theophyllines/Interferon (mono deleted 09/17/2014)|
01247|002|B||
01247|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01247|004|L|take action as needed.|
01247|005|B||
01247|006|A|MECHANISM OF ACTION:  Interferons may inhibit the metabolism of|
01247|007|A|theophyllines.(1-6)|
01247|008|B||
01247|009|E|CLINICAL EFFECTS:  The concurrent administration of theophyllines with|
01247|010|E|interferons may result in increased levels and toxicity of theophyllines.|
01247|011|E|(1-6)|
01247|012|B||
01247|013|P|PREDISPOSING FACTORS:  None determined.|
01247|014|B||
01247|015|M|PATIENT MANAGEMENT:  Theophylline levels should be closely monitored in|
01247|016|M|patients receiving concurrent interferon therapy.  The dosage of|
01247|017|M|theophylline may need to be adjusted if interferon is initiated or|
01247|018|M|discontinued.|
01247|019|B||
01247|020|D|DISCUSSION:  A study in 5 patients with active hepatitis B and 4 healthy|
01247|021|D|subjects examined the effects of a single dose of interferon alpha (9|
01247|022|D|megaunits in 8 subjects, 18 megaunits in 1 subject).  There was no effect on|
01247|023|D|theophylline in 1 subject.  In the other 8 subjects, interferon increased|
01247|024|D|theophylline half-life by 70% and decreased theophylline clearance by 49%|
01247|025|D|(range 33% to 81%).(1)|
01247|026|D|   A study in 11 healthy subjects examined the effects of interferon alpha|
01247|027|D|(3 x 10x6 International Units daily for 3 days) on a single aminophylline (4|
01247|028|D|mg/kg) infusion.  Interferon increased the half-life, area-under-curve|
01247|029|D|(AUC), and mean residence time by 13.7%, 17.9%, and 16.3%, respectively.|
01247|030|D|Theophylline clearance decreased by 9.1%.(2)|
01247|031|D|   In a study in healthy males, peginterferon alfa-2a (180 mcg once weekly|
01247|032|D|for 4 weeks) increased theophylline AUC by 25%.(3,4)|
01247|033|D|   Concurrent interferon alfa has been shown to increase theophylline levels|
01247|034|D|by 100%.(5)|
01247|035|D|   A study in 7 patients with chronic hepatitis C examined the effects of|
01247|036|D|interferon beta (3 x 10x6 to 9 x 10X6 International Units daily for 8 weeks)|
01247|037|D|on theophylline ethylenediamine (single 250 mg infusion).  Interferon|
01247|038|D|decreased theophylline clearance by 26.3% and increased theophylline|
01247|039|D|half-life by 39.3%.  There was no correlation between interferon dose and|
01247|040|D|effect. The greatest effect was seen in a patient who received 3 x 10x6|
01247|041|D|International Units daily, while no effect was seen in a patient who|
01247|042|D|received 9 x 10x6 International Units daily.(6)|
01247|043|D|   In a study in 18 patients with chronic hepatitis B and 5 patients with|
01247|044|D|chronic hepatitis C, there was no statistically significant change in|
01247|045|D|caffeine clearance, but caffeine clearance tended to be increased in|
01247|046|D|patients who responded to interferon.(7)|
01247|047|B||
01247|048|R|REFERENCES:|
01247|049|B||
01247|050|R|1.Williams SJ, Baird-Lambert JA, Farrell GC. Inhibition of theophylline|2
01247|051|R|  metabolism by interferon. Lancet 1987 Oct 24;2(8565):939-41.|2
01247|052|R|2.Jonkman JH, Nicholson KG, Farrow PR, Eckert M, Grasmeijer G, Oosterhuis B,|2
01247|053|R|  De Noord OE, Guentert TW. Effects of alpha-interferon on theophylline|2
01247|054|R|  pharmacokinetics and metabolism. Br J Clin Pharmacol 1989 Jun;|2
01247|055|R|  27(6):795-802.|2
01247|056|R|3.Pegasys 135 PFS (interferon alfa-2a) UK summary of product|1
01247|057|R|  characteristics. Roche Products Limited June 20, 2002.|1
01247|058|R|4.Pegasys (peginterferon alfa-2a) US prescribing information. Genentech USA,|1
01247|059|R|  Inc. September, 2014.|1
01247|060|R|5.Intron A (interfeon alfa-2b) US prescribing information. Schering|1
01247|061|R|  Corporation December, 2011.|1
01247|062|R|6.Okuno H, Takasu M, Kano H, Seki T, Shiozaki Y, Inoue K. Depression of|2
01247|063|R|  drug-metabolizing activity in the human liver by interferon-beta.|2
01247|064|R|  Hepatology 1993 Jan;17(1):65-9.|2
01247|065|R|7.Wittayalertpanya S, Mahachai V. Caffeine clearance in patients with|2
01247|066|R|  chronic viral hepatitis: before and after interferon therapy. J Med Assoc|2
01247|067|R|  Thai 2001 Jun;84 Suppl 1:S189-96.|2
01248|001|T|MONOGRAPH TITLE:  Itraconazole; Ketoconazole; Levoketoconazole/Isoniazid|
01248|002|B||
01248|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01248|004|L|is contraindicated and generally should not be dispensed or administered to|
01248|005|L|the same patient.|
01248|006|B||
01248|007|A|MECHANISM OF ACTION:  Isoniazid may induce the metabolism of itraconazole(1,|
01248|008|A|ketoconazole(2-4), and levoketoconazole(5) by CYP3A4.|
01248|009|B||
01248|010|E|CLINICAL EFFECTS:  The concurrent administration of itraconazole,|
01248|011|E|ketoconazole, or levoketoconazole with isoniazid may result in decreased|
01248|012|E|levels and clinical effectiveness of itraconazole(1) or ketoconazole(2-4) or|
01248|013|E|levoketoconazole.(5)|
01248|014|B||
01248|015|P|PREDISPOSING FACTORS:  None determined.|
01248|016|B||
01248|017|M|PATIENT MANAGEMENT:  Concurrent administration of itraconazole and isoniazid|
01248|018|M|is not recommended by the manufacturer of itraconazole. Concurrent|
01248|019|M|administration is not recommended two weeks before and during itraconazole|
01248|020|M|treatment.(1)|
01248|021|M|   The manufacturer of ketoconazole states that isoniazid should not be|
01248|022|M|administered with ketoconazole.(3)|
01248|023|M|   The manufacturer of levoketoconazole states that concurrent use of|
01248|024|M|isoniazid with levoketoconazole should be avoided for 2 weeks before and|
01248|025|M|during treatment with levoketoconazole.(5)|
01248|026|B||
01248|027|D|DISCUSSION:  In a case report in a 3 year-old male, the administration of|
01248|028|D|isoniazid decreased ketoconazole area-under-curve (AUC) by 80% when|
01248|029|D|administered simultaneously with ketoconazole and by 82.5% when administered|
01248|030|D|12 hours apart from ketoconazole.(3)|
01248|031|D|   In a study in 8 male tuberculosis patients, the administration of|
01248|032|D|isoniazid decreased ketoconazole plasma concentrations by 75% at 2 hours|
01248|033|D|after administration and by 85% at 5 hours after administration.(4)|
01248|034|D|   Similar effects are expected with itraconazole.(1)|
01248|035|B||
01248|036|R|REFERENCES:|
01248|037|B||
01248|038|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01248|039|R|  Products, L.P. February, 2024.|1
01248|040|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01248|041|R|  Pharmaceuticals February, 2014.|1
01248|042|R|3.Engelhard D, Stutman HR, Marks MI. Interaction of ketoconazole with|3
01248|043|R|  rifampin and isoniazid. N Engl J Med 1984 Dec 27;311(26):1681-3.|3
01248|044|R|4.Pilheu JA, Galati MR, Yunis AS, De Salvo MC, Negroni R, Garcia Fernandez|2
01248|045|R|  JC, Mingolla L, Rubio MC, Masana M, Acevedo C. Pharmacokinetic interaction|2
01248|046|R|  of ketoconazole, isoniazid and rifampicin. Medicina (B Aires) 1989;|2
01248|047|R|  49(1):43-7.|2
01248|048|R|5.Recorlev (levoketoconazole) US prescribing information. Xeris|1
01248|049|R|  Pharmaceuticals, Inc. June, 2023.|1
01249|001|T|MONOGRAPH TITLE:  Raloxifene/Cholestyramine; Colestipol|
01249|002|B||
01249|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01249|004|L|of severe adverse interaction.|
01249|005|B||
01249|006|A|MECHANISM OF ACTION:  Cholestyramine and colestipol may reduce the|
01249|007|A|absorption and enterohepatic recycling of raloxifene.(1)|
01249|008|B||
01249|009|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
01249|010|E|clinical effects of raloxifene.(1)|
01249|011|B||
01249|012|P|PREDISPOSING FACTORS:  None determined.|
01249|013|B||
01249|014|M|PATIENT MANAGEMENT:  The US manufacturer of raloxifene states that|
01249|015|M|concurrent use with cholestyramine is not recommended and raloxifene should|
01249|016|M|not be coadministered with other anion exchange resins.(1)|
01249|017|B||
01249|018|D|DISCUSSION:  Cholestyramine was found to decrease the absorption and|
01249|019|D|enterohepatic circulation of raloxifene by 60% after only one dose.  Other|
01249|020|D|anion exchange resins, such as colestipol, are thought to produce similar|
01249|021|D|effects.(1)|
01249|022|B||
01249|023|R|REFERENCE:|
01249|024|B||
01249|025|R|1.Evista (raloxifene hydrochloride) US prescribing information. Eli Lilly|1
01249|026|R|  and Company June, 2018.|1
01250|001|T|MONOGRAPH TITLE:  Atovaquone/Rifabutin|
01250|002|B||
01250|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01250|004|L|of severe adverse interaction.|
01250|005|B||
01250|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown but likely involves|
01250|007|A|rifabutin-induced increase in the metabolism of atovaquone.(1,2)|
01250|008|B||
01250|009|E|CLINICAL EFFECTS:  Concurrent administration of atovaquone with rifabutin|
01250|010|E|may result in decreased levels and clinical effects of atovaquone(1,2).|
01250|011|B||
01250|012|P|PREDISPOSING FACTORS:  None determined.|
01250|013|B||
01250|014|M|PATIENT MANAGEMENT:  The administration of rifabutin during atovaquone|
01250|015|M|therapy is not recommended.(1,2)  Consider alternative agents to rifabutin|
01250|016|M|during atovaquone therapy.(1)|
01250|017|M|   If coadministration is necessary, the National Institute of Health|
01250|018|M|Opportunistic Infections guidelines recommend patients take atovaquone with|
01250|019|M|a fatty meal and monitor for decreased atovaquone efficacy.(3)|
01250|020|B||
01250|021|D|DISCUSSION:  In a study of 13 HIV-positive patients, rifampin (600 mg every|
01250|022|D|24 hours) and atovaquone (750 mg every 12 hours) resulted in a decrease in|
01250|023|D|average atovaquone steady-state plasma concentration by 52% and an increase|
01250|024|D|in average rifampin steady-state plasma concentration by 37%.(1)|
01250|025|D|   In a trial of 24 healthy volunteers, rifabutin 300 mg once daily with|
01250|026|D|atovaquone oral suspension 750 mg twice daily resulted in a 34% decrease in|
01250|027|D|the mean steady-state plasma atovaquone concentration and a 19% decrease in|
01250|028|D|the mean steady-state plasma rifabutin concentration.(1)|
01250|029|B||
01250|030|R|REFERENCES:|
01250|031|B||
01250|032|R|1.Mepron (atovaquone) US prescribing information. GlaxoSmithKline July,|1
01250|033|R|  2019.|1
01250|034|R|2.Malarone (atovaquone and proguanil hydrochloride) US prescribing|1
01250|035|R|  information. GlaxoSmithKline March, 2010.|1
01250|036|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01250|037|R|  for the prevention and treatment of opportunistic infections in adults and|6
01250|038|R|  adolescents with HIV. Department of Health and Human Services. Available|6
01250|039|R|  at|6
01250|040|R|  https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/Adul|6
01250|041|R|  t_OI.pdf Accessed October 26, 2020..|6
01251|001|T|MONOGRAPH TITLE:  Fluvastatin (Less Than or Equal To 20 mg BID); Pravastatin|
01251|002|T|(Less Than or Equal To 20 mg); Rosuvastatin (Less Than or Equal To 5|
01251|003|T|mg)/Cyclosporine|
01251|004|B||
01251|005|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01251|006|L|take action as needed.|
01251|007|B||
01251|008|A|MECHANISM OF ACTION:  Cyclosporine is a CYP3A4, P-glycoprotein, and OATP|
01251|009|A|inhibitor, while statins are CYP3A4, P-glycoprotein, and OATP substrates.|
01251|010|A|(1,2) When a statin is combined with cyclosporine, statin clearance is|
01251|011|A|reduced and elevated statin concentrations remain in the peripheral blood|
01251|012|A|and muscle cells.(3)|
01251|013|B||
01251|014|E|CLINICAL EFFECTS:  Myopathy and muscle aches, tenderness and weakness|
01251|015|E|(rhabdomyolysis) may occur with concurrent administration of HMG-CoA|
01251|016|E|reductase inhibitors and cyclosporine.|
01251|017|B||
01251|018|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01251|019|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01251|020|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01251|021|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01251|022|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01251|023|P|transporter OATP1B1 may have increased statin concentrations and be|
01251|024|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
01251|025|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
01251|026|P|may have increased rosuvastatin concentrations and risk of myopathy.|
01251|027|P|Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may|
01251|028|P|have increased fluvastatin concentrations and  risk of myopathy.|
01251|029|B||
01251|030|M|PATIENT MANAGEMENT:  The dosage of fluvastatin should not exceed 20 mg BID|
01251|031|M|in patients receiving cyclosporine.(4)|
01251|032|M|   The dosage of pravastatin should not exceed 20 mg in patients receiving|
01251|033|M|cyclosporine.(5)|
01251|034|M|   The dosage of rosuvastatin should not exceed 5 mg in patients receiving|
01251|035|M|cyclosporine.(6)|
01251|036|M|   Patients receiving concurrent therapy should be instructed to report|
01251|037|M|symptoms of muscle pain, tenderness, or weakness.|
01251|038|B||
01251|039|D|DISCUSSION:  Since this reaction may occur with HMG-CoA-reductase inhibitors|
01251|040|D|alone, a causal relationship is difficult to establish.  However, the|
01251|041|D|incidence of myopathy and rhabdomyolysis appears to increase with concurrent|
01251|042|D|administration of cyclosporine.|
01251|043|D|   In a study, administration of pravastatin in 11 heart transplant patients|
01251|044|D|receiving cyclosporine was compared to 8 control subjects not receiving|
01251|045|D|cyclosporine.  Pravastatin AUC and Cmax were 7-8-fold and 12-fold higher,|
01251|046|D|respectively, in subjects taking cyclosporine.(7)|
01251|047|D|   In a double-blind, randomized, cross-over study in 44 renal transplant|
01251|048|D|patients, neither lovastatin nor pravastatin affected cyclosporine levels.|
01251|049|D|Pravastatin levels after 1 day and after 28 days of concurrent therapy were|
01251|050|D|5-fold higher than historical controls.  Lovastatin levels accumulated over|
01251|051|D|the course of the study and by Day 28 were 20-fold higher than historical|
01251|052|D|controls.(8)|
01251|053|D|   In a study in 31 renal transplant patients, neither pravastatin nor|
01251|054|D|simvastatin affected cyclosporine levels.(9)  In contrast, in a study in 44|
01251|055|D|heart transplant subjects, cyclosporine clearance was increased following|
01251|056|D|the addition of simvastatin.(10)|
01251|057|D|   In a study, a single dose of cyclosporine (5 mg/kg) increased the Cmax|
01251|058|D|and AUC of a single dose of pravastatin (40 mg) by 327% and 282%,|
01251|059|D|respectively.(6)|
01251|060|D|   Several studies have found no effect from fluvastatin on cyclosporine|
01251|061|D|pharmacokinetics.(11-15)  One of these also noted no affects of cyclosporine|
01251|062|D|on fluvastatin levels.(11)  In contrast, a study that compared the|
01251|063|D|administration of fluvastatin in 10 heart transplant to 10 healthy control|
01251|064|D|subjects found that fluvastatin AUC and Cmax were 2.55-fold and 3.10-fold|
01251|065|D|higher than in control subjects.(16)  In another study, stable cyclosporine|
01251|066|D|doses increased the Cmax and AUC of fluvastatin (20 mg daily for 14 weeks)|
01251|067|D|by 30% and 90%, respectively.(4)|
01251|068|D|   In an open-label study in 10 heart transplant patients, concurrent|
01251|069|D|cyclosporine increased rosuvastatin AUC and Cmax by 7.1-fold and 10.6-fold,|
01251|070|D|respectively, when compared to historical controls.  There were no effects|
01251|071|D|on cyclosporine levels.(7,17)|
01251|072|B||
01251|073|R|REFERENCES:|
01251|074|B||
01251|075|R|1.Simonson SG, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CD, Windass|2
01251|076|R|  AS, Schneck DW. Rosuvastatin pharmacokinetics in heart transplant|2
01251|077|R|  recipients administered an antirejection regimen including cyclosporine.|2
01251|078|R|  Clin Pharmacol Ther 2004 Aug;76(2):167-77.|2
01251|079|R|2.Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering|6
01251|080|R|  drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006 Dec;|6
01251|081|R|  80(6):565-81.|6
01251|082|R|3.Yang WH, Zeng ZS, Ren XW, Li YP, Shang WJ, Feng GW, Zhang LR.|3
01251|083|R|  Simvastatin-induced myopathy with concomitant use of cyclosporine: case|3
01251|084|R|  report. Int J Clin Pharmacol Ther 2011 Dec;49(12):772-7.|3
01251|085|R|4.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
01251|086|R|  Pharmaceuticals Corporation August, 2017.|1
01251|087|R|5.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
01251|088|R|  Squibb Company May, 2022.|1
01251|089|R|6.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
01251|090|R|  Pharmaceuticals LP July, 2024.|1
01251|091|R|7.Park JW, Siekmeier R, Merz M, Krell B, Harder S, Marz W, Seidel D, Schuler|2
01251|092|R|  S, Gross W. Pharmacokinetics of pravastatin in heart-transplant patients|2
01251|093|R|  taking cyclosporin A. Int J Clin Pharmacol Ther 2002 Oct;40(10):439-50.|2
01251|094|R|8.Olbricht C, Wanner C, Eisenhauer T, Kliem V, Doll R, Boddaert M, O'Grady|2
01251|095|R|  P, Krekler M, Mangold B, Christians U. Accumulation of lovastatin, but not|2
01251|096|R|  pravastatin, in the blood of cyclosporine-treated kidney graft patients|2
01251|097|R|  after multiple doses. Clin Pharmacol Ther 1997 Sep;62(3):311-21.|2
01251|098|R|9.Capone D, Stanziale P, Gentile A, Imperatore P, Pellegrino T, Basile V.|2
01251|099|R|  Effects of simvastatin and pravastatin on hyperlipidemia and cyclosporin|2
01251|100|R|  blood levels in renal transplant recipients. Am J Nephrol 1999;|2
01251|101|R|  19(3):411-5.|2
01251|102|R|10.Akhlaghi F, McLachlan AJ, Keogh AM, Brown KF. Effect of simvastatin on|2
01251|103|R|   cyclosporine unbound fraction and apparent blood clearance in heart|2
01251|104|R|   transplant recipients. Br J Clin Pharmacol 1997 Dec;44(6):537-42.|2
01251|105|R|11.Holdaas H, Hagen E, Asberg A, Lund K, Hartman A, Vaidyanathan S, Prasad|2
01251|106|R|   P, He YL, Yeh CM, Bigler H, Rouilly M, Denouel J. Evaluation of the|2
01251|107|R|   pharmacokinetic interaction between fluvastatin XL and cyclosporine in|2
01251|108|R|   renal transplant recipients. Int J Clin Pharmacol Ther 2006 Apr;|2
01251|109|R|   44(4):163-71.|2
01251|110|R|12.Locsey L, Asztalos L, Kincses Z, Balazs G. Fluvastatin (Lescol) treatment|2
01251|111|R|   of hyperlipidaemia in patients with renal transplants. Int Urol Nephrol|2
01251|112|R|   1997;29(1):95-106.|2
01251|113|R|13.Li PK, Mak TW, Chan TH, Wang A, Lam CW, Lai KN. Effect of fluvastatin on|2
01251|114|R|   lipoprotein profiles in treating renal transplant recipients with|2
01251|115|R|   dyslipoproteinemia. Transplantation 1995 Oct 15;60(7):652-6.|2
01251|116|R|14.Holdaas H, Hartmann A, Stenstrom J, Dahl KJ, Borge M, Pfister P. Effect|2
01251|117|R|   of fluvastatin for safely lowering atherogenic lipids in renal transplant|2
01251|118|R|   patients receiving cyclosporine. Am J Cardiol 1995 Jul 13;|2
01251|119|R|   76(2):102A-106A.|2
01251|120|R|15.Li PK, Mak TW, Wang AY, Lee YT, Leung CB, Lui SF, Lam CW, Lai KN. The|2
01251|121|R|   interaction of fluvastatin and cyclosporin A in renal transplant|2
01251|122|R|   patients. Int J Clin Pharmacol Ther 1995 Apr;33(4):246-8.|2
01251|123|R|16.Park JW, Siekmeier R, Lattke P, Merz M, Mix C, Schuler S, Jaross W.|2
01251|124|R|   Pharmacokinetics and pharmacodynamics of fluvastatin in heart transplant|2
01251|125|R|   recipients taking cyclosporine A. J Cardiovasc Pharmacol Ther 2001 Oct;|2
01251|126|R|   6(4):351-61.|2
01252|001|T|MONOGRAPH TITLE:  Topotecan/Phenytoin|
01252|002|B||
01252|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01252|004|L|of severe adverse interaction.|
01252|005|B||
01252|006|A|MECHANISM OF ACTION:  Phenytoin may increase the intracellular efflux of|
01252|007|A|topotecan(1) by P-glycoprotein (P-gp).|
01252|008|B||
01252|009|E|CLINICAL EFFECTS:  Concurrent use of phenytoin with topotecan may result in|
01252|010|E|decreased levels of topotecan and active metabolites and clinical|
01252|011|E|effectiveness.|
01252|012|B||
01252|013|P|PREDISPOSING FACTORS:  None determined.|
01252|014|B||
01252|015|M|PATIENT MANAGEMENT:  Levels of topotecan, and its active metabolites should|
01252|016|M|be monitored in patients receiving concurrent phenytoin. If phenytoin is|
01252|017|M|added to or discontinued from concurrent topotecan therapy, the dosage of|
01252|018|M|topotecan may need to be adjusted to ensure therapeutic effects or prevent|
01252|019|M|toxicity.|
01252|020|B||
01252|021|D|DISCUSSION:  In a case report, phenytoin increased the clearance of|
01252|022|D|topotecan and topotecan lactone by 47.1% and 44.9%, respectively.(1)|
01252|023|B||
01252|024|R|REFERENCE:|
01252|025|B||
01252|026|R|1.Zamboni WC, Gajjar AJ, Heideman RL, Beijnen JH, Rosing H, Houghton PJ,|3
01252|027|R|  Stewart CF. Phenytoin alters the disposition of topotecan and N-desmethyl|3
01252|028|R|  topotecan in a patient with medulloblastoma. Clin Cancer Res 1998 Mar;|3
01252|029|R|  4(3):783-9.|3
01253|001|T|MONOGRAPH TITLE:  Volatile Anesthetic Agents/St. John's Wort|
01253|002|B||
01253|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01253|004|L|Assess the risk to the patient and take action as needed.|
01253|005|B||
01253|006|A|MECHANISM OF ACTION:  Hyperphorin, the active metabolite of hypericin in St.|
01253|007|A|John's wort, and the volatile anesthetic agents may compete for the|
01253|008|A|gamma-aminobutyric acid receptor sites.|
01253|009|B||
01253|010|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort with a volatile|
01253|011|E|anesthetic agent may result in prolonged sedation and/or cardiovascular|
01253|012|E|collapse.|
01253|013|B||
01253|014|P|PREDISPOSING FACTORS:  None determined.|
01253|015|B||
01253|016|M|PATIENT MANAGEMENT:  Patients should be instructed to discontinue the use of|
01253|017|M|St. John's wort at least five days prior to anesthesia with volatile|
01253|018|M|anesthetics.(1)|
01253|019|B||
01253|020|D|DISCUSSION:  In a case report, a 21 year-old female who had been taking St.|
01253|021|D|John's wort (1000 mg three times daily) experienced delayed emergence from|
01253|022|D|sevoflurane anesthesia.  She remained sedated 30 minutes post-anesthesia,|
01253|023|D|even when painful stimuli were introduced.  Forty-five minutes|
01253|024|D|post-anesthesia, she was able to flex and responded with incoherent sounds|
01253|025|D|to painful stimuli.  Ninety minutes post-anesthesia, the patient was|
01253|026|D|completely arousable and oriented to person, place, and time.(1)|
01253|027|D|   In a case report, a 23 year-old female on St. John's wort experienced|
01253|028|D|decreased blood pressure (to 60/20 mmHg) and heart rate (to 60 bpm) during|
01253|029|D|isoflurane anesthesia.  She had previously undergone surgery with isoflurane|
01253|030|D|anesthesia with no problems noted.(2)|
01253|031|B||
01253|032|R|REFERENCES:|
01253|033|B||
01253|034|R|1.Crowe S, McKeating K. Delayed emergence and St. John's wort.|3
01253|035|R|  Anesthesiology 2002 Apr;96(4):1025-7.|3
01253|036|R|2.Irefin S, Sprung J. A possible cause of cardiovascular collapse during|3
01253|037|R|  anesthesia: long- term use of St. John's Wort. J Clin Anesth 2000 Sep;|3
01253|038|R|  12(6):498-9.|3
01254|001|T|MONOGRAPH TITLE:  Clopidogrel/Atorvastatin (mono deleted 03/21/2013)|
01254|002|B||
01254|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01254|004|L|take action as needed.|
01254|005|B||
01254|006|A|MECHANISM OF ACTION:  Atorvastatin may inhibit the metabolism of clopidogrel|
01254|007|A|to its pharmacologically active form by CYP P-450-3A4.(1)|
01254|008|B||
01254|009|E|CLINICAL EFFECTS:  Concurrent use of atorvastatin and clopidogrel may result|
01254|010|E|in a decrease in clopidogrel-mediated platelet aggregation inhibition.|
01254|011|B||
01254|012|P|PREDISPOSING FACTORS:  None determined.|
01254|013|B||
01254|014|M|PATIENT MANAGEMENT:  Alternatives to atorvastatin, such as pravastatin,|
01254|015|M|should be considered in clopidogrel treated patients.  If concurrent|
01254|016|M|clopidogrel and atorvastatin is warranted, consider monitoring platelet|
01254|017|M|function testing.(1)|
01254|018|B||
01254|019|D|DISCUSSION:  In a study in 35 patients, platelet aggregation inhibition was|
01254|020|D|significantly attenuated in patients receiving concurrent clopidogrel and|
01254|021|D|atorvastatin when compared to clopidogrel alone.  In patients taking|
01254|022|D|clopidogrel alone, platelet aggregation fell from 92.5% prior to the|
01254|023|D|initiation of clopidrogel to 34% 24 hours after clopidogrel initiation. In|
01254|024|D|patients receiving atorvastatin, platelet aggregation fell from 92% prior to|
01254|025|D|the initiation of clopidogrel to 77% 24 hours after clopidogrel initiation,|
01254|026|D|a nonstatistically significant change.  Atorvastatin's attenuation of|
01254|027|D|clopidogrel's antiplatelet activity was dose dependent. Platelet aggregation|
01254|028|D|values 24 hours after the initiation of clopidogrel in patients receiving no|
01254|029|D|atorvastatin, atorvastatin 10 mg (n=7), atorvastatin 20 mg (n=7), and|
01254|030|D|atorvastatin 40 mg (n=5) were 34%, 58%, 74%, and 89% (complete inhibition of|
01254|031|D|clopidogrel's effect), respectively. Six to eight days after stent|
01254|032|D|placement, inhibition of platelet aggregation continued to be attenuated in|
01254|033|D|patients taking atorvastatin (41% platelet aggregation with clopidogrel|
01254|034|D|alone, N=13, versus 74% platelet aggregation in patients taking clopidogrel|
01254|035|D|and atorvastatin, n=13).(1)|
01254|036|D|   In contrast to this report, a study in 75 patients found no significant|
01254|037|D|effects on clopidogrel-induced platelet aggregation inhibition.  Patients|
01254|038|D|receiving no statin (n=25), patients taking atorvastatin (n=25, mean dose|
01254|039|D|27.915.5 mg), and patients taking other statins (simvastatin, n=20, mean|
01254|040|D|dose 33.99.2 mg; pravastatin, n=8, mean dose 29.312.1 mg; lovastatin n=5,|
01254|041|D|all on 20 mg; fluvastatin, n=2, one on 20 mg, one on 80 mg) were compared at|
01254|042|D|baseline, four hours after clopidogrel initiation, and 24 hours after|
01254|043|D|clopidogrel initiation.  There were no significant differences in the|
01254|044|D|platelet measures between groups, with the exception of the diminished|
01254|045|D|expression of the anti protease-activated G-protein-coupled thrombin|
01254|046|D|receptor as measured by SPAN12 antibody in statin-treated patients.(2)|
01254|047|B||
01254|048|R|REFERENCES:|
01254|049|B||
01254|050|R|1.Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR,|2
01254|051|R|  Carville DG, Guyer KE, Bates ER. Atorvastatin reduces the ability of|2
01254|052|R|  clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.|2
01254|053|R|  Circulation 2003 Jan 7;107(1):32-7.|2
01254|054|R|2.Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane DC,|4
01254|055|R|  Tanguay JF, SteinhublSR, Berger PB, O'Connor CM, Hennekens CC.|4
01254|056|R|  Atorvastatin does not affect the antiplatelet properties of clopidogrel in|4
01254|057|R|  patients undergoing coronary stenting in randomized data from the|4
01254|058|R|  interaction of atorvastatin and clopidogrel (INTERACTION) trial. Presented|4
01254|059|R|  at the 52nd Annual Scientific Session of the American College of|4
01254|060|R|  Cardiology: Chicago, Illinois.  March 30-April 2, 2003..|4
01255|001|T|MONOGRAPH TITLE:  Fexofenadine/St. John's Wort|
01255|002|B||
01255|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01255|004|L|Assess the risk to the patient and take action as needed.|
01255|005|B||
01255|006|A|MECHANISM OF ACTION:  St. John's wort may inhibit the transportation of|
01255|007|A|fexofenadine into the intestinal lumen via p-glycoprotein.(1)|
01255|008|B||
01255|009|E|CLINICAL EFFECTS:  Short-term use of St. John's wort and fexofenadine may|
01255|010|E|result in increases in fexofenadine levels.  Long-term use may result in|
01255|011|E|either no significant changes in or decreased fexofenadine levels.|
01255|012|B||
01255|013|P|PREDISPOSING FACTORS:  None determined.|
01255|014|B||
01255|015|M|PATIENT MANAGEMENT:  Patients maintained on fexofenadine should be aware of|
01255|016|M|possible transient increases in fexofenadine levels in the short-term when|
01255|017|M|St. John's wort is added to therapy and possible decreased fexofenadine|
01255|018|M|effectiveness with long-term use.|
01255|019|B||
01255|020|D|DISCUSSION:  In a study in 12 patients, a single dose of St. John's wort|
01255|021|D|increased fexofenadine maximum concentration (Cmax) by 45% and decreased|
01255|022|D|fexofenadine oral clearance 20%.  Long-term St. John's wort had no effect on|
01255|023|D|fexofenadine pharmacokinetics when compared to the control phase; however,|
01255|024|D|long-term St. John's wort decreased fexofenadine Cmax by 35% and increased|
01255|025|D|fexofenadine clearance by 47% when compared to single dose levels.(1)|
01255|026|D|   In a study in 10 subjects, a single dose of St. John's wort increased|
01255|027|D|fexofenadine Cmax by 58%.  Multiple doses of St. John's wort had no effect|
01255|028|D|on fexofenadine Cmax.(2)|
01255|029|D|   In a study in six subjects, St. John's wort markedly decreased the|
01255|030|D|fexofenadine's area-under-curve (AUC).(3)|
01255|031|B||
01255|032|R|REFERENCES:|
01255|033|B||
01255|034|R|1.Wang Z, Hamman MA, Huang SM, Lesko LJ, Hall SD. Effect of St John's wort|2
01255|035|R|  on the pharmacokinetics of fexofenadine. Clin Pharmacol Ther 2002 Jun;|2
01255|036|R|  71(6):414-20.|2
01255|037|R|2.Hamman MA, Wang Z, Honig P, Collins J, Lesko L, Huang S-M, Hall SD.|4
01255|038|R|  Effects of acute and chronic Saint John's Wort (SJW) administration on|4
01255|039|R|  fexofenadine (FEX) disposition. Clin Pharmacol Ther 2001 Jan;69(1):P53.|4
01255|040|R|3.Dresser GK, Schwarz UI, Wilkinson GR, Kim RB. St. John's Wort induces|4
01255|041|R|  intestinal and hepatic CYP3A4 and p-glycoprotein in healthy volunteers.|4
01255|042|R|  Clin Pharmacol Ther 2001 Jan;69(1):P23.|4
01256|001|T|MONOGRAPH TITLE:  Selected Vinca Alkaloids/Slt Azole Antifungal;|
01256|002|T|Levoketoconazole|
01256|003|B||
01256|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01256|005|L|of severe adverse interaction.|
01256|006|B||
01256|007|A|MECHANISM OF ACTION:  Itraconazole, ketoconazole, posaconazole,|
01256|008|A|voriconazole, or levoketoconazole may inhibit the metabolism of vinca|
01256|009|A|alkaloids by CYP3A4.(1-6,15-16)|
01256|010|B||
01256|011|E|CLINICAL EFFECTS:  Concurrent use of itraconazole, ketoconazole,|
01256|012|E|posaconazole, voriconazole, or levoketoconazole may result in elevated|
01256|013|E|levels of and toxicity from the vinca alkaloids.|
01256|014|B||
01256|015|P|PREDISPOSING FACTORS:  None determined.|
01256|016|B||
01256|017|M|PATIENT MANAGEMENT:  If possible, consider alternatives to itraconazole,|
01256|018|M|ketoconazole, posaconazole, voriconazole, and levoketoconazole in patients|
01256|019|M|treated with vinca alkaloids.  If concurrent therapy is warranted, patients|
01256|020|M|should be monitored closely for toxicity.  The dosage of the vinca alkaloid|
01256|021|M|may need to be adjusted during concurrent therapy.|
01256|022|M|   The US manufacturer of itraconazole states that concurrent use with vinca|
01256|023|M|alkaloids is not recommended during and two weeks after itraconazole|
01256|024|M|treatment.(15)|
01256|025|B||
01256|026|D|DISCUSSION:  Severe neurotoxicity has been reported in 21 patients treated|
01256|027|D|with vincristine in whom itraconazole was initiated.(7-14)  Toxicity was|
01256|028|D|more severe and developed earlier during concurrent therapy than during|
01256|029|D|vincristine alone.|
01256|030|D|   Vincristine toxicity, including severe peripheral neuropathy, abdominal|
01256|031|D|cramps, constipation, fluctuations in consciousness, and seizures, was|
01256|032|D|reported in a 9 year-old female after she received vincristine following|
01256|033|D|pre-treatment with posaconazole.(13)|
01256|034|D|   A retrospective review examined 50 patients who received vincristine|
01256|035|D|therapy.  Twenty-nine patients received concurrent azole antifungals.  In|
01256|036|D|the azole group, vincristine dosage adjustments were more common (average|
01256|037|D|reduction of 46.5%) and patients were more likely to fail to complete their|
01256|038|D|vincristine course (48.3% versus 9.5%).  Patients receiving azole were more|
01256|039|D|likely to experience decreased peristalsis (65.5% versus 28.6%).  Decreased|
01256|040|D|peristalsis symptoms occurred in 50%, 75%, and 66.6% of patients receiving|
01256|041|D|fluconazole, voriconazole, and posaconazole, respectively.(14)|
01256|042|D|   Vinorelbine toxicity, including constipation, oral mucositis, and|
01256|043|D|granulocytopenia, believed to contribute to the patient's death was reported|
01256|044|D|in a 72 year-old man after he received vinorelbine and itraconazole.(17)|
01256|045|D|   Vindesine toxicity, including paralytic ileus and neurotoxicity, was|
01256|046|D|reported in a 20 year-old male after she received vindesine on day 4 and day|
01256|047|D|11 with itraconazole on day 2.(18)|
01256|048|D|   Vindesine toxicity, including neurotoxicity (limbs anesthesia, abdominal|
01256|049|D|pain, abdominal bloating, cramps, inability to pass flatus, or stool), was|
01256|050|D|reported in a 37 year-old female after she received vindesine on day 1 and|
01256|051|D|day 8 and itraconazole on day 9.(18)|
01256|052|D|   Vindesine toxicity, including abdominal distention and pain,|
01256|053|D|constipation, loss of appetite and weight, paralysis of the extremities,|
01256|054|D|anemia, thrombocytopenia, and neutropenia, and neurotoxicity (trismus, neck|
01256|055|D|rigidity, syndrome of inappropriate antidiuretic hormone secretion) was|
01256|056|D|reported in a 4 year-old male after starting itraconazole on day 1 of cycle|
01256|057|D|3 with vindesine.(19)|
01256|058|B||
01256|059|R|REFERENCES:|
01256|060|B||
01256|061|R|1.Zhou-Pan XR, Seree E, Zhou XJ, Placidi M, Maurel P, Barra Y, Rahmani R.|4
01256|062|R|  Involvement of human liver cytochrome P450 3A in vinblastine metabolism:|4
01256|063|R|  drug interactions. Cancer Res 1993 Nov 1;53(21):5121-6.|4
01256|064|R|2.Noxafil (posaconazole) UK summary of product characteristics.|1
01256|065|R|  Schering-Plough Ltd. January, 2022.|1
01256|066|R|3.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01256|067|R|  January, 2022.|1
01256|068|R|4.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01256|069|R|5.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01256|070|R|  Pharmaceuticals February, 2014.|1
01256|071|R|6.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
01256|072|R|  Pierre Fabre Limited September 21, 2009.|1
01256|073|R|7.Gillies J, Hung KA, Fitzsimons E, Soutar R. Severe vincristine toxicity in|3
01256|074|R|  combination with itraconazole. Clin Lab Haematol 1998 Apr;20(2):123-4.|3
01256|075|R|8.Jeng MR, Feusner J. Itraconazole-enhanced vincristine neurotoxicity in a|3
01256|076|R|  child with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2001 Mar;|3
01256|077|R|  18(2):137-42.|3
01256|078|R|9.Bohme A, Ganser A, Hoelzer D. Aggravation of vincristine-induced|3
01256|079|R|  neurotoxicity by itraconazole in the treatment of adult ALL. Ann Hematol|3
01256|080|R|  1995 Dec;71(6):311-2.|3
01256|081|R|10.Murphy JA, Ross LM, Gibson BE. Vincristine toxicity in five children with|3
01256|082|R|   acute lymphoblastic leukaemia. Lancet 1995 Aug 12;346(8972):443.|3
01256|083|R|11.Sathiapalan RK, El-Solh H. Enhanced vincristine neurotoxicity from drug|3
01256|084|R|   interactions: case report and review of literature. Pediatr Hematol Oncol|3
01256|085|R|   2001 Dec;18(8):543-6.|3
01256|086|R|12.Kamaluddin M, McNally P, Breatnach F, O'Marcaigh A, Webb D, O'Dell E,|3
01256|087|R|   Scanlon P, Butler K, O'Meara A. Potentiation of vincristine toxicity by|3
01256|088|R|   itraconazole in children with lymphoid malignancies. Acta Paediatr 2001|3
01256|089|R|   Oct;90(10):1204-7.|3
01256|090|R|13.Eiden C, Palenzuela G, Hillaire-Buys D, Margueritte G, Cociglio M,|3
01256|091|R|   Hansel-Esteller S, Peyriere H. Posaconazole-increased vincristine|3
01256|092|R|   neurotoxicity in a child: a case report. J Pediatr Hematol Oncol 2009|3
01256|093|R|   Apr;31(4):292-5.|3
01256|094|R|14.Harnicar S, Adel N, Jurcic J. Modification of vincristine dosing during|3
01256|095|R|   concomitant azole therapy in adult acute lymphoblastic leukemia patients.|3
01256|096|R|   J Oncol Pharm Pract 2009 Mar 12.|3
01256|097|R|15.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01256|098|R|   Products, L.P. February, 2024.|1
01256|099|R|16.Recorlev (levoketoconazole) US prescribing information. Xeris|1
01256|100|R|   Pharmaceuticals, Inc. June, 2023.|1
01256|101|R|17.Bosque E. Possible drug interaction between itraconazole and vinorelbine|3
01256|102|R|   tartrate leading to death after one dose of chemotherapy. Ann Intern Med|3
01256|103|R|   2001 Mar 6;134(5):427.|3
01256|104|R|18.Chen S, Wu D, Sun A, Qiu H, Jin Z, Tang X, Miao M, Fu Z, Ma X, Han Y, Hu|3
01256|105|R|   X. Itraconazole-enhanced vindesine neurotoxicity in adult acute|3
01256|106|R|   lymphoblastic leukaemia. Am J Hematol 2007 Oct;82(10):942.|3
01256|107|R|19.Zhou H, Li L, Zhou Y, Han Y. Syndrome of inappropriate antidiuretic|3
01256|108|R|   hormone secretion from concomitant use of  itraconazole and vindesine. J|3
01256|109|R|   Clin Pharm Ther 2018 Feb;43(1):137-140.|3
01257|001|T|MONOGRAPH TITLE:  Atazanavir/Ritonavir (mono deleted 10/02/2015)|
01257|002|B||
01257|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01257|004|L|take action as needed.|
01257|005|B||
01257|006|A|MECHANISM OF ACTION:  Ritonavir may inhibit the metabolism of atazanavir|
01257|007|A|(1,2) at CYP P-450-3A4.|
01257|008|B||
01257|009|E|CLINICAL EFFECTS:  Concurrent use of ritonavir and atazanavir may result in|
01257|010|E|elevated levels of atazanavir.(1,2)|
01257|011|B||
01257|012|P|PREDISPOSING FACTORS:  None determined.|
01257|013|B||
01257|014|M|PATIENT MANAGEMENT:  Administration of atazanavir without ritonavir is not|
01257|015|M|recommended in treatment-experienced patients with prior virologic|
01257|016|M|failure.(1)|
01257|017|M|   The US manufacturer of atazanavir states that if atazanavir is|
01257|018|M|administered with ritonavir, dosages of 300 mg atazanavir with 100 mg of|
01257|019|M|ritonavir once daily with food should be used.(1,2)  Use of doses of|
01257|020|M|ritonavir greater than 100 mg daily are not recommended.(1)|
01257|021|B||
01257|022|D|DISCUSSION:  In a study in 28 subjects, administration of atazanavir (300 mg|
01257|023|D|daily) with ritonavir (100 mg daily) increased atazanavir maximum|
01257|024|D|concentration (Cmax), area-under-curve (AUC), and minimum concentration|
01257|025|D|(Cmin) by 18%, 103%, and 671%, respectively, when compared to the|
01257|026|D|administration of 400 mg of atazanavir alone.(1,2)|
01257|027|B||
01257|028|R|REFERENCES:|
01257|029|B||
01257|030|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01257|031|R|  Squibb Company September, 2016.|1
01257|032|R|2.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01257|033|R|  Squibb Pharmaceuticals October 25, 2023.|1
01258|001|T|MONOGRAPH TITLE:  Budesonide/Itraconazole; Ketoconazole (mono deleted|
01258|002|T|05/01/2008)|
01258|003|B||
01258|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01258|005|L|take action as needed.|
01258|006|B||
01258|007|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
01258|008|A|metabolism of budesonide by CYP P-450-3A4.|
01258|009|B||
01258|010|E|CLINICAL EFFECTS:  Concurrent use of itraconazole or ketoconazole with|
01258|011|E|budesonide may result in increased levels of and toxicity from budesonide.|
01258|012|B||
01258|013|P|PREDISPOSING FACTORS:  None determined.|
01258|014|B||
01258|015|M|PATIENT MANAGEMENT:  If concurrent therapy is required, patients should be|
01258|016|M|closely monitored for increased signs and/or symptoms of hypercorticism.(1)|
01258|017|M|Separate the administration times by as much time as possible to minimize|
01258|018|M|the interaction.  The dosage of budesonide may need to be adjusted if|
01258|019|M|itraconazole or ketoconazole are added to or withdrawn from concurrent|
01258|020|M|therapy.|
01258|021|B||
01258|022|D|DISCUSSION:  The concurrent use of ketoconazole has been shown to increase|
01258|023|D|budesonide area-under-curve (AUC) by eight-fold.(1)|
01258|024|D|   In a study in eight healthy subjects, the simultaneous administration of|
01258|025|D|ketoconazole increased budesonide AUC by 6.5-fold.  Administering the two|
01258|026|D|agents 12 hours apart increased budesonide AUC by 3.8-fold.(2)|
01258|027|D|   In a study, 11 of 25 cystic fibrosis patients treated with concurrent|
01258|028|D|itraconazole and budesonide were found to have adrenal suppression.(3)|
01258|029|B||
01258|030|R|REFERENCES:|
01258|031|B||
01258|032|R|1.Entocort EC (budesonide) US prescribing information. AstraZeneca|1
01258|033|R|  Pharmaceuticals LP April, 2016.|1
01258|034|R|2.Seidegard J. Reduction of the inhibitory effect of ketoconazole on|2
01258|035|R|  budesonide pharmacokinetics by separation of their time of administration.|2
01258|036|R|  Clin Pharmacol Ther 2000 Jul;68(1):13-7.|2
01258|037|R|3.Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S. Iatrogenic|2
01258|038|R|  adrenal insufficiency as a side-effect of combined treatment of|2
01258|039|R|  itraconazole and budesonide. Eur Respir J 2002 Jul;20(1):127-33.|2
01259|001|T|MONOGRAPH TITLE:  Agalsidase/Chloroquine|
01259|002|B||
01259|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01259|004|L|of severe adverse interaction.|
01259|005|B||
01259|006|A|MECHANISM OF ACTION:  Chloroquine may inhibit the intracellular activity of|
01259|007|A|alpha-galactosidase.(1,2)|
01259|008|B||
01259|009|E|CLINICAL EFFECTS:  Concurrent use of agalsidase with chloroquine may result|
01259|010|E|in decreased effectiveness of agalsidase.(1,2)|
01259|011|B||
01259|012|P|PREDISPOSING FACTORS:  None determined.|
01259|013|B||
01259|014|M|PATIENT MANAGEMENT:  The manufacturer of agalsidase alpha in Canada(1) and|
01259|015|M|the manufacturer of agalsidase beta in the United Kingdom(2) state that|
01259|016|M|agalsidase should not be administered with chloroquine.|
01259|017|B||
01259|018|D|DISCUSSION:  Because of a theoretical risk of inhibited intracellular|
01259|019|D|activity of alpha-galactosidase activity, the manufacturer of agalsidase|
01259|020|D|alpha in Canada(1) and the manufacturer of agalsidase beta in the United|
01259|021|D|Kingdom(2) state that agalsidase should not be administered with|
01259|022|D|chloroquine.|
01259|023|B||
01259|024|R|REFERENCES:|
01259|025|B||
01259|026|R|1.Replagal (agalsidase alfa) Canadian prescribing information. Paladin Labs,|1
01259|027|R|  Inc. January, 2004.|1
01259|028|R|2.Fabrazyme (agalsidase beta) UK summary of product characteristics. Genzyme|1
01259|029|R|  Europe July, 2021.|1
01260|001|T|MONOGRAPH TITLE:  Agalsidase/Amiodarone|
01260|002|B||
01260|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01260|004|L|of severe adverse interaction.|
01260|005|B||
01260|006|A|MECHANISM OF ACTION:  Amiodarone may inhibit the intracellular activity of|
01260|007|A|alpha-galactosidase.(1,2)|
01260|008|B||
01260|009|E|CLINICAL EFFECTS:  Concurrent use of agalsidase with amiodarone may result|
01260|010|E|in decreased effectiveness of agalsidase.(1,2)|
01260|011|B||
01260|012|P|PREDISPOSING FACTORS:  None determined.|
01260|013|B||
01260|014|M|PATIENT MANAGEMENT:  The manufacturer of agalsidase alpha in Canada(1) and|
01260|015|M|the manufacturer of agalsidase beta in the United Kingdom(2) state that|
01260|016|M|agalsidase should not be administered with amiodarone.|
01260|017|B||
01260|018|D|DISCUSSION:  Because of a theoretical risk of inhibited intracellular|
01260|019|D|activity of alpha-galactosidase activity, the manufacturer of agalsidase|
01260|020|D|alpha in Canada(1) and the manufacturer of agalsidase beta in the United|
01260|021|D|Kingdom(2) state that agalsidase should not be administered with amiodarone.|
01260|022|B||
01260|023|R|REFERENCES:|
01260|024|B||
01260|025|R|1.Replagal (agalsidase alfa) Canadian prescribing information. Paladin Labs,|1
01260|026|R|  Inc. January, 2004.|1
01260|027|R|2.Fabrazyme (agalsidase beta) UK summary of product characteristics. Genzyme|1
01260|028|R|  Europe July, 2021.|1
01261|001|T|MONOGRAPH TITLE:  Agalsidase/Monobenzone (Benoquin)|
01261|002|B||
01261|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01261|004|L|of severe adverse interaction.|
01261|005|B||
01261|006|A|MECHANISM OF ACTION:  Monobenzone (benoquin) may inhibit the intracellular|
01261|007|A|activity of alpha-galactosidase.(1,2)|
01261|008|B||
01261|009|E|CLINICAL EFFECTS:  Concurrent use of agalsidase with monobenzone (benoquin)|
01261|010|E|may result in decreased effectiveness of agalsidase.(1,2)|
01261|011|B||
01261|012|P|PREDISPOSING FACTORS:  None determined.|
01261|013|B||
01261|014|M|PATIENT MANAGEMENT:  The manufacturer of agalsidase alpha in Canada(1) and|
01261|015|M|the manufacturer of agalsidase beta in the United Kingdom(2) state that|
01261|016|M|agalsidase should not be administered with monobenzone (benoquin).|
01261|017|B||
01261|018|D|DISCUSSION:  Because of a theoretical risk of inhibited intracellular|
01261|019|D|activity of alpha-galactosidase activity, the manufacturer of agalsidase|
01261|020|D|alpha in Canada(1) and the manufacturer of agalsidase beta in the United|
01261|021|D|Kingdom(2) state that agalsidase should not be administered with monobenzone|
01261|022|D|(benoquin).|
01261|023|B||
01261|024|R|REFERENCES:|
01261|025|B||
01261|026|R|1.Replagal (agalsidase alfa) Canadian prescribing information. Paladin Labs,|1
01261|027|R|  Inc. January, 2004.|1
01261|028|R|2.Fabrazyme (agalsidase beta) UK summary of product characteristics. Genzyme|1
01261|029|R|  Europe July, 2021.|1
01262|001|T|MONOGRAPH TITLE:  Agalsidase/Gentamicin|
01262|002|B||
01262|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01262|004|L|of severe adverse interaction.|
01262|005|B||
01262|006|A|MECHANISM OF ACTION:  Gentamicin may inhibit the intracellular activity of|
01262|007|A|alpha-galactosidase.(1,2)|
01262|008|B||
01262|009|E|CLINICAL EFFECTS:  Concurrent use of agalsidase with gentamicin may result|
01262|010|E|in decreased effectiveness of agalsidase.(1,2)|
01262|011|B||
01262|012|P|PREDISPOSING FACTORS:  None determined.|
01262|013|B||
01262|014|M|PATIENT MANAGEMENT:  The manufacturer of agalsidase alpha in Canada(1) and|
01262|015|M|the manufacturer of agalsidase beta in the United Kingdom(2) state that|
01262|016|M|agalsidase should not be administered with gentamicin.|
01262|017|B||
01262|018|D|DISCUSSION:  Because of a theoretical risk of inhibited intracellular|
01262|019|D|activity of alpha-galactosidase activity, the manufacturer of agalsidase|
01262|020|D|alpha in Canada(1) and the manufacturer of agalsidase beta in the United|
01262|021|D|Kingdom(2) state that agalsidase should not be administered with gentamicin.|
01262|022|B||
01262|023|R|REFERENCES:|
01262|024|B||
01262|025|R|1.Replagal (agalsidase alfa) Canadian prescribing information. Paladin Labs,|1
01262|026|R|  Inc. January, 2004.|1
01262|027|R|2.Fabrazyme (agalsidase beta) UK summary of product characteristics. Genzyme|1
01262|028|R|  Europe July, 2021.|1
01263|001|T|MONOGRAPH TITLE:  Penicillamine/Oxyphenbutazone; Phenylbutazone|
01263|002|B||
01263|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01263|004|L|is contraindicated and generally should not be dispensed or administered to|
01263|005|L|the same patient.|
01263|006|B||
01263|007|A|MECHANISM OF ACTION:  Concurrent use may result in additive or synergistic|
01263|008|A|effects on the blood and kidneys.(1)|
01263|009|B||
01263|010|E|CLINICAL EFFECTS:  Concurrent use of penicillamine and oxyphenbutazone or|
01263|011|E|phenylbutazone may result in serious hematologic or renal toxicity.(1)|
01263|012|B||
01263|013|P|PREDISPOSING FACTORS:  None determined.|
01263|014|B||
01263|015|M|PATIENT MANAGEMENT:  The manufacturer of penicillamine states that|
01263|016|M|penicillamine should not be used in patients receiving concurrent|
01263|017|M|oxyphenbutazone or phenylbutazone.(1)|
01263|018|B||
01263|019|D|DISCUSSION:  Because oxyphenbutazone and phenylbutazone are associated with|
01263|020|D|hematologic and renal toxicity, the manufacturer of penicillamine states|
01263|021|D|that penicillamine should not be used in patients receiving concurrent|
01263|022|D|oxyphenbutazone or phenylbutazone.(1)|
01263|023|B||
01263|024|R|REFERENCE:|
01263|025|B||
01263|026|R|1.Cuprimine (penicillamine) US prescribing information. Merck & Co., Inc.|1
01263|027|R|  March, 2004.|1
01264|001|T|MONOGRAPH TITLE:  Penicillamine/Antimalarial Agents|
01264|002|B||
01264|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01264|004|L|is contraindicated and generally should not be dispensed or administered to|
01264|005|L|the same patient.|
01264|006|B||
01264|007|A|MECHANISM OF ACTION:  Concurrent use may result in additive or synergistic|
01264|008|A|effects on the blood and kidneys(1) or increased penicillamine levels.(2)|
01264|009|B||
01264|010|E|CLINICAL EFFECTS:  Concurrent use of penicillamine with antimalarials may|
01264|011|E|result in serious hematologic or renal toxicity(1,2) or elevated levels of|
01264|012|E|penicillamine.(2)|
01264|013|B||
01264|014|P|PREDISPOSING FACTORS:  None determined.|
01264|015|B||
01264|016|M|PATIENT MANAGEMENT:  The manufacturer of penicillamine states that|
01264|017|M|penicillamine should not be used in patients receiving concurrent therapy|
01264|018|M|with antimalarial agents.(1)|
01264|019|B||
01264|020|D|DISCUSSION:  In patients with rheumatoid arthritis, concurrent chloroquine|
01264|021|D|increased penicillamine plasma concentrations by 34% when compared to|
01264|022|D|penicillamine alone.(2)|
01264|023|D|   In a 2-year controlled, double-blind trial of penicillamine,|
01264|024|D|hydroxychloroquine, or combination therapy, patients on combination therapy|
01264|025|D|did not do as well as patients receiving penicillamine alone.(3)|
01264|026|D|   Because antimalarial agents are associated with hematologic and renal|
01264|027|D|toxicity, the manufacturer of penicillamine states that penicillamine should|
01264|028|D|not be used in patients receiving concurrent antimalarials.(1)|
01264|029|B||
01264|030|R|REFERENCES:|
01264|031|B||
01264|032|R|1.Cuprimine (penicillamine) US prescribing information. Merck & Co., Inc.|1
01264|033|R|  March, 2004.|1
01264|034|R|2.Seideman P, Lindstrom B. Pharmacokinetic interactions of penicillamine in|2
01264|035|R|  rheumatoid arthritis. J Rheumatol 1989 Apr;16(4):473-4.|2
01264|036|R|3.Bunch TW, O'Duffy JD, Tompkins RB, O'Fallon WM. Controlled trial of|3
01264|037|R|  hydroxychloroquine and D-penicillamine singly and in combination in the|3
01264|038|R|  treatment of rheumatoid arthritis. Arthritis Rheum 1984 Mar;27(3):267-76.|3
01265|001|T|MONOGRAPH TITLE:  Anticoagulants/Corticosteroids|
01265|002|B||
01265|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01265|004|L|take action as needed.|
01265|005|B||
01265|006|A|MECHANISM OF ACTION:  Corticosteroids may increase the coagulability of|
01265|007|A|blood, thus decreasing the effect of the anticoagulant.(1,2) Corticosteroids|
01265|008|A|may also lower vascular integrity, which could increase the risk of|
01265|009|A|hemorrhage.(3,4)|
01265|010|B||
01265|011|E|CLINICAL EFFECTS:  Concurrent use of corticosteroids may result in either|
01265|012|E|increased (increased risk of bleeding) or decreased effects (increased risk|
01265|013|E|of treatment failure) of anticoagulants.|
01265|014|B||
01265|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01265|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01265|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
01265|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01265|019|P|risk for bleeding (e.g. NSAIDs).|
01265|020|B||
01265|021|M|PATIENT MANAGEMENT:  The patient's clotting times should be monitored|
01265|022|M|closely, along with any clinical signs of hemorrhage or clot formation. The|
01265|023|M|dosage of the anticoagulant may need to be adjusted accordingly.|
01265|024|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01265|025|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01265|026|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01265|027|M|patients with any symptoms.|
01265|028|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01265|029|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01265|030|M|anticoagulation in patients with active pathologic bleeding.|
01265|031|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01265|032|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01265|033|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01265|034|M|and/or swelling.|
01265|035|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01265|036|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01265|037|M|initiating, altering the dose or discontinuing either drug.|
01265|038|B||
01265|039|D|DISCUSSION:  Corticotropin and other corticosteroids have been shown to both|
01265|040|D|increase (3,5-11) and decrease (1,12,13) the effects of acenocoumarol,|
01265|041|D|dicumarol, fluindione, and warfarin.  Hemorrhagic episodes have been|
01265|042|D|associated with concurrent use of these medications.(3,5)|
01265|043|D|   One or more of the drug pairs linked to this monograph have been included|
01265|044|D|in a list of interactions that could be considered for classification as|
01265|045|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
01265|046|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
01265|047|D|Health Information Technology.|
01265|048|B||
01265|049|R|REFERENCES:|
01265|050|B||
01265|051|R|1.Cosgriff SW, Diefenbach AF, Vogt W Jr. Hypercoagulability of the blood|2
01265|052|R|  associated with ACTH and cortisone therapy. American Journal of Medicine|2
01265|053|R|  1950 Dec;752-56.|2
01265|054|R|2.Ozsoylu S, Strauss HS, Diamond LK. Effects of corticosteroids on|2
01265|055|R|  coagulation of the blood. Nature 1962 Sept 22;195:1214-15.|2
01265|056|R|3.Van Cauwenberge H, Jaques LB. Hemorrhagic effect of ACTH with|5
01265|057|R|  anticoagulants. Can Med Assoc J 1958 Oct 1;79:536-40.|5
01265|058|R|4.Hamblin TJ. Interaction between warfarin and phenformin. Lancet 1971 Dec|3
01265|059|R|  11;2(7737):1323.|3
01265|060|R|5.O'Connell TX, Aston SJ. Acute adrenal hemorrhage complicating|3
01265|061|R|  anticoagulant therapy. Surg Gynecol Obstet 1974 Sep;139(3):355-7.|3
01265|062|R|6.Hellem AJ, Solem JH. The influence of ACTH on prothrombin-proconvertin|2
01265|063|R|  values in blood during treatment with dicumarol and phenylindanedione.|2
01265|064|R|  Acta Medica Scandinavica 1954;150:389-93.|2
01265|065|R|7.Sievers J, Johansson BW, Nilsson SE. The corticosteroid treatment of acute|2
01265|066|R|  myocardial infarction. Cardiologia 1964;45(2):65-76.|2
01265|067|R|8.Brozovic M, Gurd LJ. Prothrombin during warfarin treatment. Br J Haematol|2
01265|068|R|  1973 May;24(5):579-88.|2
01265|069|R|9.Costedoat-Chalumeau N, Amoura Z, Aymard G, Sevin O, Wechsler B, Cacoub P,|2
01265|070|R|  Du LT, Diquet B, Ankri A, Piette JC. Potentiation of vitamin K antagonists|2
01265|071|R|  by high-dose intravenous methylprednisolone. Ann Intern Med 2000 Apr 18;|2
01265|072|R|  132(8):631-5.|2
01265|073|R|10.Stading JA. Effects of prednisone on the International Normalized Ratio.|3
01265|074|R|   Am J Health Syst Pharm 2006 Dec 1;63(23):2354-6.|3
01265|075|R|11.Kaufman M. Treatment of multiple sclerosis with high-dose corticosteroids|3
01265|076|R|   may prolong the prothrombin time to dangerous levels in patients taking|3
01265|077|R|   warfarin. Mult Scler 1997 Aug;3(4):248-9.|3
01265|078|R|12.Chatterjea JB, Salomon L. Antagonistic effect of ACTH and cortisone on|2
01265|079|R|   the anticoagulant activity of ethyl biscoumacetate. Br Med J 1954 Oct 2;|2
01265|080|R|   2:790-92.|2
01265|081|R|13.Menczel J, Dreyfuss F, . Effect of prednisone on blood coagulation time|2
01265|082|R|   in patients on dicumarol therapy. J Lab & Clin Med 1960 Jul;56(1):14-20.|2
01265|083|R|14.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
01265|084|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
01265|085|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
01265|086|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
01266|001|T|MONOGRAPH TITLE:  Vardenafil (Greater Than 2.5 mg)/Selected Protease|
01266|002|T|Inhibitors|
01266|003|B||
01266|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01266|005|L|is contraindicated and generally should not be dispensed or administered to|
01266|006|L|the same patient.|
01266|007|B||
01266|008|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01266|009|A|vardenafil by CYP3A4.|
01266|010|B||
01266|011|E|CLINICAL EFFECTS:  Concurrent use of vardenafil with protease inhibitors may|
01266|012|E|result in increased levels of and adverse effects from vardenafil, including|
01266|013|E|hypotension, visual changes, and sustained erections.|
01266|014|B||
01266|015|P|PREDISPOSING FACTORS:  None determined.|
01266|016|B||
01266|017|M|PATIENT MANAGEMENT:  US guidelines for the use of antiretroviral agents|
01266|018|M|recommends patients receiving protease inhibitors should receive no more|
01266|019|M|than 2.5 mg of vardenafil every 72 hours.|
01266|020|M|   US labeling recommendations for concurrent use of vardenafil with|
01266|021|M|protease inhibitors state:|
01266|022|M|   -Patients receiving any ritonavir- or cobicistat-containing regimens,|
01266|023|M|including atazanavir, darunavir, fosamprenavir, indinavir, lopinavir,|
01266|024|M|nirmatrelvir, paritaprevir, saquinavir, and tipranavir should receive no|
01266|025|M|more than 2.5 mg of vardenafil every 72 hours.|
01266|026|M|   -Patients receiving unboosted atazanavir, unboosted fosamprenavir,|
01266|027|M|unboosted indinavir, or nelfinavir should take no more than 2.5 mg of|
01266|028|M|vardenafil every 24 hours.|
01266|029|M|   Canadian labeling contraindicates concurrent use of atazanavir/ritonavir,|
01266|030|M|lopinavir/ritonavir, and nirmatrelvir/ritonavir with vardenafil.(6,13,17)|
01266|031|M|   Patients should be counseled that they are at an increased risk of|
01266|032|M|vardenafil adverse effects, including hypotension, visual changes, and|
01266|033|M|priapism.|
01266|034|B||
01266|035|D|DISCUSSION:  Concurrent use of indinavir (800 mg three times daily) with|
01266|036|D|vardenafil (10 mg) increased the vardenafil area-under-curve (AUC) and|
01266|037|D|maximum concentration (Cmax) by 16-fold and 7-fold, respectively.|
01266|038|D|Vardenafil half-life increased 2-fold.  At 24-hours post-dose, vardenafil|
01266|039|D|levels fell to approximately 4% of vardenafil Cmax.  The AUC and Cmax of|
01266|040|D|indinavir decreased by 30% and 40%, respectively.|
01266|041|D|   Concurrent use of ritonavir (600 mg twice daily)with vardenafil (5 mg)|
01266|042|D|increased vardenafil AUC and Cmax by 49-fold and 13-fold, respectively.  The|
01266|043|D|half-life of vardenafil increased to 26 hours.  The ritonavir AUC and Cmax|
01266|044|D|decreased by 20%.|
01266|045|B||
01266|046|R|REFERENCES:|
01266|047|B||
01266|048|R|1.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
01266|049|R|  Bayer, Inc. October 24, 2006.|1
01266|050|R|2.Levitra (vardenafil hydrochloride trihydrate) UK summary of product|1
01266|051|R|  characteristics. Bayer plc December 20, 2006.|1
01266|052|R|3.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
01266|053|R|  Pharmaceuticals Corporation March, 2023.|1
01266|054|R|4.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01266|055|R|  September, 2016.|1
01266|056|R|5.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01266|057|R|  Laboratories December, 2019.|1
01266|058|R|6.Kaletra (lopinavir/ritonavir) Canadian prescribing information. Abbott|1
01266|059|R|  Limited May 22, 2019.|1
01266|060|R|7.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01266|061|R|  March, 2023.|1
01266|062|R|8.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01266|063|R|  March, 2019.|1
01266|064|R|9.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01266|065|R|  Pharmaceuticals, Inc. September, 2016.|1
01266|066|R|10.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
01266|067|R|   Inc. December, 2004.|1
01266|068|R|11.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01266|069|R|   Laboratories, Inc. March, 2019.|1
01266|070|R|12.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01266|071|R|   information. Pfizer Inc. February, 2025.|1
01266|072|R|13.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
01266|073|R|   Monograph. Pfizer Canada ULC October, 2023.|1
01266|074|R|14.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
01266|075|R|   prescribing information. AbbVie Inc. December, 2019.|1
01266|076|R|15.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01266|077|R|   Pharmaceuticals, Inc. April, 2024.|1
01266|078|R|16.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01266|079|R|   Squibb Company December, 2024.|1
01266|080|R|17.Reyataz (atazanavir) Canadian prescribing information. Bristol-Myers|1
01266|081|R|   Squibb Canada August 31, 2023.|1
01266|082|R|18.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01266|083|R|   for the use of antiretroviral agents in adults and adolescents Living|6
01266|084|R|   with HIV. Department of Health and Human Services. Available at|6
01266|085|R|   https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats|6
01266|086|R|   -new-guidelines June 13, 2021.|6
01266|087|R|19.This information is based on an extract from the Certara Drug Interaction|6
01266|088|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01267|001|T|MONOGRAPH TITLE:  Vardenafil (Greater Than 5 mg)/Selected CYP3A4 Inhibitors|
01267|002|B||
01267|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01267|004|L|is contraindicated and generally should not be dispensed or administered to|
01267|005|L|the same patient.|
01267|006|B||
01267|007|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
01267|008|A|vardenafil by CYP3A4.(1-4)|
01267|009|B||
01267|010|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
01267|011|E|increased levels of and adverse effects from vardenafil, including|
01267|012|E|hypotension, visual changes, and sustained erections.(1-4)|
01267|013|B||
01267|014|P|PREDISPOSING FACTORS:  The interaction may be more severe in men older than|
01267|015|P|75 years.(4)|
01267|016|B||
01267|017|M|PATIENT MANAGEMENT:  The US manufacturer of vardenafil states that a maximum|
01267|018|M|dose of 2.5 mg of vardenafil every 24 hours should not be exceeded in|
01267|019|M|patients taking 400 mg of itraconazole or ketoconazole and that a maximum|
01267|020|M|dose of 5 mg of vardenafil every 24 hours should not be exceeded in patients|
01267|021|M|taking 200 mg of itraconazole or ketoconazole.(1)|
01267|022|M|   For moderate CYP3A4 inhibitors, do not exceed a maximum dose of 5 mg of|
01267|023|M|vardenafil every 24 hours.(1)|
01267|024|M|   Note that other countries have stricter warnings.  The Australian|
01267|025|M|manufacturer of vardenafil states that vardenafil must not be taken with|
01267|026|M|dosages of itraconazole or ketoconazole greater than 200 mg.  A maximum dose|
01267|027|M|of 5 mg of vardenafil should not be exceeded if used with lower dosages of|
01267|028|M|itraconazole and ketoconazole.(2)  The Canadian manufacturer of vardenafil|
01267|029|M|states that the concurrent use of vardenafil with itraconazole or|
01267|030|M|ketoconazole is contraindicated and that the dosage should not exceed 5 mg|
01267|031|M|in patients taking erythromycin.(3)  The UK manufacturer of vardenafil|
01267|032|M|states that the concurrent use of vardenafil with either oral itraconazole|
01267|033|M|or oral ketoconazole is contraindicated in men older than 75 years and|
01267|034|M|should be avoided in all patients.  The dosage of vardenafil should not|
01267|035|M|exceed 5 mg in patients taking erythromycin.(4)|
01267|036|B||
01267|037|D|DISCUSSION:  Concurrent use of ketoconazole (200 mg) with vardenafil (5 mg)|
01267|038|D|increased the vardenafil area-under-curve (AUC) and maximum concentration|
01267|039|D|(Cmax) by 10-fold and 4-fold, respectively.(1-4)|
01267|040|D|   Concurrent administration of erythromycin (500 mg three times daily) with|
01267|041|D|vardenafil (5 mg) increased the AUC and Cmax of vardenafil by 4-fold and|
01267|042|D|3-fold, respectively.(1-4)|
01267|043|B||
01267|044|R|REFERENCES:|
01267|045|B||
01267|046|R|1.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
01267|047|R|  Pharmaceuticals Corporation March, 2023.|1
01267|048|R|2.Levitra (vardenafil hydrochloride trihydrate) Australian prescribing|1
01267|049|R|  information. Bayer Australia Limited November 2, 2006.|1
01267|050|R|3.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
01267|051|R|  Bayer, Inc. October 24, 2006.|1
01267|052|R|4.Levitra (vardenafil hydrochloride trihydrate) UK summary of product|1
01267|053|R|  characteristics. Bayer plc December 20, 2006.|1
01268|001|T|MONOGRAPH TITLE:  Sirolimus; Temsirolimus/Tacrolimus|
01268|002|B||
01268|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01268|004|L|of severe adverse interaction.|
01268|005|B||
01268|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Temsirolimus is a|
01268|007|A|pro-drug of sirolimus.(1)|
01268|008|B||
01268|009|E|CLINICAL EFFECTS:  Concurrent use of sirolimus may result in decreased|
01268|010|E|tacrolimus levels,(2,3) as well as an increased risk of wound healing|
01268|011|E|complications, renal function impairment, and insulin dependent post|
01268|012|E|transplant diabetes.(2)|
01268|013|E|   Sirolimus may increase the risk of calcineurin-induced hemolytic uremic|
01268|014|E|syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.(4)|
01268|015|E|   Concurrent use of sirolimus and tacrolimus in liver transplant patients|
01268|016|E|may result in hepatic artery thrombosis (HAT), graft loss, and death.(4,5)|
01268|017|E|Most cases of HAT occurred within 30 days of transplantation and most lead|
01268|018|E|to graft loss or death.(4)|
01268|019|E|   Concurrent use of sirolimus and tacrolimus in lung transplant patients|
01268|020|E|may result in fatal bronchial anastomotic dehiscence.(4)|
01268|021|B||
01268|022|P|PREDISPOSING FACTORS:  Adverse hepatic effects were noted in liver|
01268|023|P|transplant patients.  Adverse renal effects were noted in renal transplant|
01268|024|P|patients and heart transplant patients.|
01268|025|B||
01268|026|M|PATIENT MANAGEMENT:  The US manufacturer of tacrolimus states that|
01268|027|M|concurrent use with sirolimus is not recommended.(2)  It may be prudent to|
01268|028|M|avoid concurrent use of sirolimus and tacrolimus in liver and lung|
01268|029|M|transplant patients.  If concurrent use is warranted, monitor patients and|
01268|030|M|tacrolimus levels closely.|
01268|031|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
01268|032|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
01268|033|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
01268|034|M|inhibitors should be avoided.(6)|
01268|035|M|   Since temsirolimus is converted to sirolimus,(1) it would be prudent to|
01268|036|M|follow this advice with concurrent temsirolimus and tacrolimus.|
01268|037|B||
01268|038|D|DISCUSSION:  Two transplant centers have reported cases of bronchial|
01268|039|D|anastomotic dehiscence, including fatal cases, in lung transplant patients|
01268|040|D|treated with a combination of sirolimus and tacrolimus.  In one center, four|
01268|041|D|out of 15 patients developed bronchia anastomotic dehiscence, three of these|
01268|042|D|four patients died.  The second center reported two cases of bronchial|
01268|043|D|anastomotic dehiscence, one of these patients died.(4)|
01268|044|D|   In two studies of liver transplant patients, concurrent sirolimus and|
01268|045|D|tacrolimus was associated with an increase in hepatic artery thrombosis,|
01268|046|D|graft loss, and excess mortality.(4,5)  In a study in de novo liver|
01268|047|D|transplant patients, concurrent use of sirolimus and tacrolimus resulted in|
01268|048|D|excess mortality and graft loss (22% with combination therapy versus 9% with|
01268|049|D|tacrolimus alone).  Many of these patients had evidence of infection at or|
01268|050|D|near death.  In this study and another study, concurrent sirolimus and|
01268|051|D|tacrolimus was associated with an increase in HAT (7% with combination|
01268|052|D|therapy versus 2% in the control arm).(4)|
01268|053|D|   In renal transplant patients, coadministration of tacrolimus and|
01268|054|D|sirolimus (2 or 5 mg daily) resulted in decreases in tacrolimus|
01268|055|D|area-under-curve (AUC) and trough concentration (Cmin) by 30%.  Tacrolimus|
01268|056|D|AUC and Cmin decreased 3% and 11%, respectively, following concurrent|
01268|057|D|sirolimus at 1 mg daily.(2)|
01268|058|D|   In a study in eight pediatric renal transplant patients, the addition of|
01268|059|D|sirolimus increased tacrolimus dosage requirements by 71.2%.(3)|
01268|060|D|   Concurrent use in heart transplant patients was associated with renal|
01268|061|D|function impairment, wound healing complications, and insulin depended post|
01268|062|D|transplant diabetes.(2)|
01268|063|D|   Temsirolimus is a pro-drug of sirolimus.(1)|
01268|064|B||
01268|065|R|REFERENCES:|
01268|066|B||
01268|067|R|1.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01268|068|R|  Inc. March, 2018.|1
01268|069|R|2.Filler G, Womiloju T, Feber J, Lepage N, Christians U. Adding sirolimus to|2
01268|070|R|  tacrolimus-based immunosuppression in pediatric renal transplant|2
01268|071|R|  recipients reduces tacrolimus exposure. Am J Transplant 2005 Aug;|2
01268|072|R|  5(8):2005-10.|2
01268|073|R|3.Dear Healthcare Provider letter on Rapamune (sirolimus). Wyeth|1
01268|074|R|  Laboratories February, 2003.|1
01268|075|R|4.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
01268|076|R|  Aug, 2022.|1
01268|077|R|5.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
01268|078|R|  August, 2023.|1
01268|079|R|6.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
01268|080|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
01269|001|T|MONOGRAPH TITLE:  Selected Antidiabetic Agents/Clarithromycin; Telithromycin|
01269|002|B||
01269|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01269|004|L|take action as needed.|
01269|005|B||
01269|006|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01269|007|A|metabolism of glipizide(1) and glyburide(1,2) by CYP3A4.|
01269|008|B||
01269|009|E|CLINICAL EFFECTS:  Concurrent use of glipizide or glyburide and|
01269|010|E|clarithromycin or telithromycin may result in elevated levels of and effects|
01269|011|E|from glipizide and glyburide, including hypoglycemia.|
01269|012|B||
01269|013|P|PREDISPOSING FACTORS:  None determined.|
01269|014|B||
01269|015|M|PATIENT MANAGEMENT:  Patients maintained on glipizide or glyburide should be|
01269|016|M|closely monitored if clarithromycin or telithromycin is added to or|
01269|017|M|withdrawn from concurrent therapy.  A dosage adjustment of the antidiabetic|
01269|018|M|agent may be required during macrolide therapy.|
01269|019|B||
01269|020|D|DISCUSSION:  In a study in 12 healthy subjects, clarithromycin (250 mg twice|
01269|021|D|daily) increased the area-under-curve (AUC) and maximum concentration (Cmax)|
01269|022|D|of a single dose of glyburide (0.875 mg) by 1.35-fold and 1.25-fold,|
01269|023|D|respectively.(2)|
01269|024|D|   Severe hypoglycemia has been reported in patients following the addition|
01269|025|D|of clarithromycin to glipizide and glyburide therapy.(1)|
01269|026|B||
01269|027|R|REFERENCES:|
01269|028|B||
01269|029|R|1.Bussing R, Gende A. Severe hypoglycemia from clarithromycin-sulfonylurea|3
01269|030|R|  drug interaction. Diabetes Care 2002 Sep;25(9):1659-61.|3
01269|031|R|2.Lilja JJ, Niemi M, Fredrikson H, Neuvonen PJ. Effects of clarithromycin|2
01269|032|R|  and grapefruit juice on the pharmacokinetics of glibenclamide. Br J Clin|2
01269|033|R|  Pharmacol 2007 Jun;63(6):732-40.|2
01270|001|T|MONOGRAPH TITLE:  Eplerenone/St. John's Wort|
01270|002|B||
01270|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01270|004|L|Assess the risk to the patient and take action as needed.|
01270|005|B||
01270|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01270|007|A|eplerenone by CYP3A4.(1)|
01270|008|B||
01270|009|E|CLINICAL EFFECTS:  Concurrent use of eplerenone and St. John's wort may|
01270|010|E|result in decreased effectiveness of eplerenone.(1)|
01270|011|B||
01270|012|P|PREDISPOSING FACTORS:  None determined.|
01270|013|B||
01270|014|M|PATIENT MANAGEMENT:  Patients taking eplerenone should be cautioned that the|
01270|015|M|use of St. John's wort may decrease the effects of eplerenone.|
01270|016|B||
01270|017|D|DISCUSSION:  Concurrent St. John's wort decreased the eplerenone|
01270|018|D|area-under-curve (AUC) by 30%.(1)|
01270|019|B||
01270|020|R|REFERENCE:|
01270|021|B||
01270|022|R|1.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
01271|001|T|MONOGRAPH TITLE:  Pimozide/Aprepitant|
01271|002|B||
01271|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01271|004|L|is contraindicated and generally should not be dispensed or administered to|
01271|005|L|the same patient.|
01271|006|B||
01271|007|A|MECHANISM OF ACTION:  Aprepitant may inhibit the metabolism of pimozide by|
01271|008|A|CYP3A4.(1)|
01271|009|B||
01271|010|E|CLINICAL EFFECTS:  Concurrent use of aprepitant and pimozide may result in|
01271|011|E|elevated levels of pimozide, which may result in cardiac arrhythmias,|
01271|012|E|including life-threatening torsades de pointes.(1)|
01271|013|B||
01271|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01271|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01271|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01271|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01271|018|P|female gender, or advanced age.(2)|
01271|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01271|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01271|021|P|risk factors for torsades de pointes.  Factors which may increased systemic|
01271|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01271|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01271|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01271|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01271|026|P|   The risk of anticholinergic toxicities including cognitive decline,|
01271|027|P|delirium, falls and fractures is increased in geriatric patients using more|
01271|028|P|than one medicine with anticholinergic properties.(3)|
01271|029|B||
01271|030|M|PATIENT MANAGEMENT:  The manufacturer of aprepitant states that the|
01271|031|M|concurrent use of aprepitant and pimozide is contraindicated.(1)|
01271|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01271|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01271|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01271|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01271|036|B||
01271|037|D|DISCUSSION:  Aprepitant is a moderate inhibitor of CYP3A4.  Elevated levels|
01271|038|D|of pimozide have been shown to increase the QTc interval, which may result|
01271|039|D|in life-threatening arrhythmias, including torsades de pointes. Therefore,|
01271|040|D|the manufacturer of aprepitant states that the concurrent use of aprepitant|
01271|041|D|and pimozide is contraindicated.(1)|
01271|042|B||
01271|043|R|REFERENCES:|
01271|044|B||
01271|045|R|1.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
01271|046|R|  September, 2019.|1
01271|047|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01271|048|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01271|049|R|  settings: a scientific statement from the American Heart Association and|6
01271|050|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01271|051|R|  2;55(9):934-47.|6
01271|052|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01271|053|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01271|054|R|  Soc 2023 Jul;71(7):2052-2081.|6
01272|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/Aprepitant|
01272|002|B||
01272|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01272|004|L|is contraindicated and generally should not be dispensed or administered to|
01272|005|L|the same patient.|
01272|006|B||
01272|007|A|MECHANISM OF ACTION:  Aprepitant may inhibit the metabolism of astemizole|
01272|008|A|and terfenadine by CYP3A4.(1)|
01272|009|B||
01272|010|E|CLINICAL EFFECTS:  Concurrent use of aprepitant and either astemizole or|
01272|011|E|terfenadine may result in elevated levels of astemizole or terfenadine,|
01272|012|E|which may result in cardiac arrhythmias, including life-threatening torsades|
01272|013|E|de pointes.(1)|
01272|014|B||
01272|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01272|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01272|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01272|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01272|019|P|female gender, or advanced age.(2)|
01272|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01272|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01272|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01272|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01272|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01272|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01272|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01272|027|B||
01272|028|M|PATIENT MANAGEMENT:  The manufacturer of aprepitant states that the|
01272|029|M|concurrent use of aprepitant with either astemizole or terfenadine is|
01272|030|M|contraindicated.(1)|
01272|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01272|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01272|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01272|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01272|035|B||
01272|036|D|DISCUSSION:  Aprepitant is a moderate inhibitor of CYP3A4.  Elevated levels|
01272|037|D|of astemizole and terfenadine have been shown to increase the QTc interval,|
01272|038|D|which may result in life-threatening arrhythmias, including torsades de|
01272|039|D|pointes.  Therefore, the manufacturer of aprepitant states that the|
01272|040|D|concurrent use of aprepitant and astemizole or terfenadine is|
01272|041|D|contraindicated.(1)|
01272|042|B||
01272|043|R|REFERENCES:|
01272|044|B||
01272|045|R|1.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
01272|046|R|  September, 2019.|1
01272|047|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01272|048|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01272|049|R|  settings: a scientific statement from the American Heart Association and|6
01272|050|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01272|051|R|  2;55(9):934-47.|6
01273|001|T|MONOGRAPH TITLE:  Cisapride/Aprepitant|
01273|002|B||
01273|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01273|004|L|is contraindicated and generally should not be dispensed or administered to|
01273|005|L|the same patient.|
01273|006|B||
01273|007|A|MECHANISM OF ACTION:  Aprepitant may inhibit the metabolism of cisapride by|
01273|008|A|CYP3A4.(1)|
01273|009|B||
01273|010|E|CLINICAL EFFECTS:  Concurrent use of aprepitant and cisapride may result in|
01273|011|E|elevated levels of cisapride, which may result in cardiac arrhythmias,|
01273|012|E|including life-threatening torsades de pointes.(1)|
01273|013|B||
01273|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01273|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01273|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01273|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01273|018|P|female gender, or advanced age.(2)|
01273|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01273|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01273|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01273|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01273|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01273|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01273|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01273|026|B||
01273|027|M|PATIENT MANAGEMENT:  The manufacturer of aprepitant states that the|
01273|028|M|concurrent use of aprepitant and cisapride is contraindicated.(1)|
01273|029|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01273|030|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01273|031|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01273|032|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01273|033|B||
01273|034|D|DISCUSSION:  Aprepitant is a moderate inhibitor of CYP3A4.  Elevated levels|
01273|035|D|of cisapride have been shown to increase the QTc interval, which may result|
01273|036|D|in life-threatening arrhythmias, including torsades de pointes. Therefore,|
01273|037|D|the manufacturer of aprepitant states that the concurrent use of aprepitant|
01273|038|D|and cisapride is contraindicated.(1)|
01273|039|B||
01273|040|R|REFERENCES:|
01273|041|B||
01273|042|R|1.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
01273|043|R|  September, 2019.|1
01273|044|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01273|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01273|046|R|  settings: a scientific statement from the American Heart Association and|6
01273|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01273|048|R|  2;55(9):934-47.|6
01274|001|T|MONOGRAPH TITLE:  Steroidal Contraceptives/Aprepitant; Fosaprepitant|
01274|002|B||
01274|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01274|004|L|of severe adverse interaction.|
01274|005|B||
01274|006|A|MECHANISM OF ACTION:  Aprepitant and fosaprepitant may induce the CYP3A4|
01274|007|A|mediated metabolism of hormonal contraceptives.(1,2)|
01274|008|B||
01274|009|E|CLINICAL EFFECTS:  The effectiveness of hormonal contraceptives may be|
01274|010|E|reduced during and for 28 days following aprepitant and fosaprepitant|
01274|011|E|use.(1,2)|
01274|012|B||
01274|013|P|PREDISPOSING FACTORS:  None determined.|
01274|014|B||
01274|015|M|PATIENT MANAGEMENT:  Patients taking hormonal contraceptives should be|
01274|016|M|instructed to use alternative or back-up methods of contraception while|
01274|017|M|using aprepitant or fosaprepitant and for 1 month after the last dose of|
01274|018|M|aprepitant or fosaprepitant.(1,2)|
01274|019|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
01274|020|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
01274|021|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
01274|022|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
01274|023|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
01274|024|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
01274|025|M|and to seek medical advice if they do become pregnant.|
01274|026|B||
01274|027|D|DISCUSSION:  The concurrent use of aprepitant (100 mg daily for 14 days)|
01274|028|D|with an oral contraceptive (ethinyl estradiol, 35 mcg and norethindrone, 1|
01274|029|D|mg) decreased the area-under-curve (AUC) of ethinyl estradiol and|
01274|030|D|norethindrone by 43% and 8%, respectively.(1)|
01274|031|D|   In another study, an oral contraceptive (ethinyl estradiol and|
01274|032|D|norethindrone, dosages not stated) was administered on Days 1 through 21.|
01274|033|D|Subjects also received aprepitant (125 mg Day 8, 80 mg daily Days 9 and 10),|
01274|034|D|ondansetron (32 mg Day 8), dexamethasone (12 mg Day 8, 8 mg daily Days 9|
01274|035|D|through 11).  The AUC of ethinyl estradiol decreased by 19% on Day 10 and by|
01274|036|D|as much as 64% on Days 9 through 21.  There was no effect on the AUC of|
01274|037|D|norethindrone on Day 10, but there was as much as a 60% decrease in|
01274|038|D|norethindrone minimum concentration (Cmin) during Days 9 through 21.(1)|
01274|039|D|   In another study, an oral contraceptive (ethinyl estradiol and|
01274|040|D|norgestimate, dosages not stated) was administered on Days 1 through 21.|
01274|041|D|Subjects also received aprepitant (40 mg Day 8).  The AUC of ethinyl|
01274|042|D|estradiol decreased by 4% and 29% on Days 8 and 12, respectively.  The AUC|
01274|043|D|of norelgestromin (norgestimate is converted to norelgestromin) increased by|
01274|044|D|18% on Day 8 and decreased by 10% on Day 12.  Trough concentrations of|
01274|045|D|ethinyl estradiol and norelgestromin on Days 8 through 21 were generally|
01274|046|D|lower following aprepitant.(1)|
01274|047|B||
01274|048|R|REFERENCES:|
01274|049|B||
01274|050|R|1.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
01274|051|R|  September, 2019.|1
01274|052|R|2.Emend (fosaprepitant) US prescribing information. Merck Sharp & Dohme|1
01274|053|R|  Corp. March, 2018.|1
01274|054|R|3.Medicines and Healthcare products Regulatory Agency.|1
01274|055|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
01274|056|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
01274|057|R|  available at:|1
01274|058|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
01274|059|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
01274|060|R|  -and-contraceptive-efficacy September 15, 2016..|1
01275|001|T|MONOGRAPH TITLE:  Dexamethasone; Methylprednisolone/Aprepitant (Greater Than|
01275|002|T|40 mg); Fosaprepitant|
01275|003|B||
01275|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01275|005|L|take action as needed.|
01275|006|B||
01275|007|A|MECHANISM OF ACTION:  Aprepitant and fosaprepitant may inhibit the|
01275|008|A|metabolism of dexamethasone and methylprednisolone by CYP3A4.(1,2)|
01275|009|B||
01275|010|E|CLINICAL EFFECTS:  Concurrent use with multiple dose of aprepitant or|
01275|011|E|fosaprepitant without dosage adjustments of the corticosteroid may result in|
01275|012|E|elevated levels of the corticosteroids and adverse effects.(1,2)|
01275|013|B||
01275|014|P|PREDISPOSING FACTORS:  The effects of the interaction are greater when the|
01275|015|P|corticosteroids are administered orally versus intravenously.(1)|
01275|016|B||
01275|017|M|PATIENT MANAGEMENT:  The US manufacturer states that the dosage of oral|
01275|018|M|dexamethasone should be reduced by 50% when administered with the 125/80 mg|
01275|019|M|regimen of aprepitant(1) or with fosaprepitant.(2)  No dosage adjustment is|
01275|020|M|required with single 40 mg doses of aprepitant.(1)|
01275|021|M|   The US manufacturer states that the dosage of oral methylprednisolone|
01275|022|M|should be reduced by 50% and that the dosage of intravenous|
01275|023|M|methylprednisolone should be reduced by 25% when methylprednisolone is|
01275|024|M|administered with the 125/80 mg regimen of aprepitant(1) or with|
01275|025|M|fosaprepitant.(2) No dosage adjustment is required with single 40 mg doses|
01275|026|M|of aprepitant.(1)|
01275|027|B||
01275|028|D|DISCUSSION:  In a clinical trial, the administration of oral dexamethasone|
01275|029|D|(20 mg on Day 1, then 8 mg Days 2-5) and aprepitant (125 mg on Day 1, then|
01275|030|D|80 mg Days 2-5) increased the dexamethasone area-under-curve (AUC) by|
01275|031|D|2.2-fold on Days 1 and 5.  A single dose of aprepitant (40 mg) increased the|
01275|032|D|AUC of a single dose of dexamethasone (20 mg) by 1.45-fold.(1)|
01275|033|D|   In another clinical trial, the administration of methylprednisolone (125|
01275|034|D|mg intravenously on Day 1, then 40 mg orally Days 2-3) and aprepitant (125|
01275|035|D|mg on Day 1, then 80 mg Days 2-3) increased methylprednisolone AUC by|
01275|036|D|1.34-fold on Day 1 and by 2.5-fold on Day 3.(1)|
01275|037|D|   In a study in 440 subjects receiving aprepitant (40 mg or 125 mg), the|
01275|038|D|clearance of single dose intravenous dexamethasone was decreased by 24.7%|
01275|039|D|and 47.5% when coadministered with aprepitant 40 mg or 125 mg, respectively,|
01275|040|D|compared to dexamethasone alone.(3)|
01275|041|B||
01275|042|R|REFERENCES:|
01275|043|B||
01275|044|R|1.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
01275|045|R|  September, 2019.|1
01275|046|R|2.Emend (fosaprepitant) US prescribing information. Merck Sharp & Dohme|1
01275|047|R|  Corp. March, 2018.|1
01275|048|R|3.Nakade S, Ohno T, Kitagawa J, Hashimoto Y, Katayama M, Awata H, Kodama Y,|2
01275|049|R|  Miyata Y. Population pharmacokinetics of aprepitant and dexamethasone in|2
01275|050|R|  the prevention of  chemotherapy-induced nausea and vomiting. Cancer|2
01275|051|R|  Chemother Pharmacol 2008 Dec;63(1):75-83.|2
01276|001|T|MONOGRAPH TITLE:  Rolapitant/Strong CYP3A4 Inducers|
01276|002|B||
01276|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01276|004|L|of severe adverse interaction.|
01276|005|B||
01276|006|A|MECHANISM OF ACTION:  Rolapitant is metabolized primarily by CYP3A4.  Strong|
01276|007|A|inducers of CYP3A4 may increase the metabolism and clearance via CYP3A4.(1)|
01276|008|B||
01276|009|E|CLINICAL EFFECTS:  Concurrent use with strong inducers of CYP3A4 may result|
01276|010|E|in significantly decreased levels and effectiveness of rolapitant.(1)|
01276|011|B||
01276|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01276|013|P|of the inducer for longer than 1-2 weeks.|
01276|014|B||
01276|015|M|PATIENT MANAGEMENT:  The manufacturer of rolapitant states concurrent use|
01276|016|M|with strong CYP3A4 inducers should be avoided.(1)  Patients treated|
01276|017|M|concurrently with a strong CYP3A4 inducer should be monitored for decreased|
01276|018|M|antiemetic efficacy.  When possible and clinically appropriate, consider use|
01276|019|M|of an alternative antiemetic or alternatives to the strong CYP3A4|
01276|020|M|inducer.(1)|
01276|021|B||
01276|022|D|DISCUSSION:  Rifampin (600 mg daily for 14 days) decreased the Cmax and AUC|
01276|023|D|of a single dose of rolapitant (180 mg on Day 7) by 30% and 85%,|
01276|024|D|respectively.  The half-life of rolapitant decreased from 176 hours to 41|
01276|025|D|hours.(1)|
01276|026|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
01276|027|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
01276|028|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
01276|029|D|rifampin, rifapentine, and St. John's Wort.(2,3)|
01276|030|D|   FDA defines a Strong CYP inducer as an agent which decreases the|
01276|031|D|area-under-curve (AUC) of a Sensitive Substrate by > or = 80 per cent.(2)|
01276|032|B||
01276|033|R|REFERENCES:|
01276|034|B||
01276|035|R|1.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
01276|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
01276|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01276|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01276|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01276|040|R|  11/14/2017.|1
01276|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
01276|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01277|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Chlorella Algae|
01277|002|B||
01277|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01277|004|L|Assess the risk to the patient and take action as needed.|
01277|005|B||
01277|006|A|MECHANISM OF ACTION:  Chlorella is rich in Vitamin K.  Coumarin|
01277|007|A|anticoagulants (e.g. warfarin) interfere with the activation of vitamin|
01277|008|A|K-dependent clotting factors. Vitamin K administration may reverse this|
01277|009|A|effect.|
01277|010|B||
01277|011|E|CLINICAL EFFECTS:  Concurrent use of coumarin anticoagulants and chlorella|
01277|012|E|may result in decreased clinical effects of the anticoagulant.(1)|
01277|013|B||
01277|014|P|PREDISPOSING FACTORS:  None determined.|
01277|015|B||
01277|016|M|PATIENT MANAGEMENT:  Patients treated with coumarin anticoagulants should be|
01277|017|M|cautioned about adding or removing chlorella products from concurrent|
01277|018|M|therapy.  Patients should be monitored for changes in anticoagulant effects|
01277|019|M|if chlorella is added to or removed from concurrent therapy.  The dosage of|
01277|020|M|the anticoagulant may need to be adjusted.|
01277|021|B||
01277|022|D|DISCUSSION:  In a single case report, a 77 year-old male had been maintained|
01277|023|D|on warfarin.  After the initiation of chlorella, his thrombotest results|
01277|024|D|indicated sub-therapeutic response to warfarin.(1)|
01277|025|B||
01277|026|R|REFERENCE:|
01277|027|B||
01277|028|R|1.Ohkawa S, Yoneda Y, Ohsumi Y, Tabuchi M. Warfarin therapy and chlorella.|3
01277|029|R|  Rinsho Shinkeigaku 1995 Jul;35(7):806-7.|3
01278|001|T|MONOGRAPH TITLE:  Clozapine/Benzodiazepines|
01278|002|B||
01278|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01278|004|L|of severe adverse interaction.|
01278|005|B||
01278|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Some benzodiazepines|
01278|007|A|may increase clozapine levels.(1)|
01278|008|B||
01278|009|E|CLINICAL EFFECTS:  Concurrent administration of clozapine with a|
01278|010|E|benzodiazepine may result in orthostatic hypotension, delirium, collapse,|
01278|011|E|profound sedation, respiratory arrest, and/or cardiac arrest.(2-3)|
01278|012|B||
01278|013|P|PREDISPOSING FACTORS:  Patients with preexisting cardiovascular, liver,|
01278|014|P|organic brain disease(1) or sleep apnea may be predisposed to the|
01278|015|P|interaction.  The interaction may be more likely when initiating clozapine|
01278|016|P|therapy, when restarting clozapine after a brief clozapine-free interval, or|
01278|017|P|when adding clozapine to benzodiazepine therapy.(1,2)|
01278|018|B||
01278|019|M|PATIENT MANAGEMENT:  The concurrent use of clozapine with benzodiazepines|
01278|020|M|should be approached with caution, especially in patients who have recently|
01278|021|M|started or restarted clozapine therapy.|
01278|022|M|   Monitor patients for excessive sedation, decreased respiratory rate, and|
01278|023|M|ataxia.(3)|
01278|024|B||
01278|025|D|DISCUSSION:  Collapse has been reported in a patients in whom clozapine and|
01278|026|D|clonazepam were initiated simultaneously.(4)  Somnolence, confusion, ataxia,|
01278|027|D|and disorientation were reported in a patient following the addition of|
01278|028|D|clozapine to clonazepam therapy.(5)|
01278|029|D|   Collapse has been reported in three patients maintained on diazepam in|
01278|030|D|whom clozapine was initiated.(6,7)|
01278|031|D|   Cardiac arrest and death during sleep were reported in a patient in whom|
01278|032|D|clozapine and oxazepam were initiated simultaneously.(4)|
01278|033|D|   Delirium has been reported in four clozapine-treated patients in whom|
01278|034|D|lorazepam was initiated.(5,8)  Respiratory arrest and death were reported in|
01278|035|D|one patient in whom clozapine was initiated who had been maintained on oral|
01278|036|D|lorazepam.  The patient received three supplemental doses of intravenous|
01278|037|D|lorazepam for increased psychosis and was found dead 12 hours later.(9)|
01278|038|B||
01278|039|R|REFERENCES:|
01278|040|B||
01278|041|R|1.Faisal I, lindenmayer JP, Taintor Z, Cancro R. Clozapine-benzodiazepine|6
01278|042|R|  interactions. J Clin Psychiatry 1997 Dec;58(12):547-8.|6
01278|043|R|2.Clozaril (clozapine tablets) US prescribing information. Novartis|1
01278|044|R|  Pharmaceuticals Corporation April, 2020.|1
01278|045|R|3.Ativan (lorazepam injection) US prescribing information. Biovail|1
01278|046|R|  Laboratories International SRL April 27, 2017.|1
01278|047|R|4.Borentain S, Millet B, Olie JP. Cardiac risk at the onset of treatment in|3
01278|048|R|  patients treated with benzodiazepines and clozapine. Eur Psychiatry 2002|3
01278|049|R|  Nov;17(7):419-20.|3
01278|050|R|5.Jackson CW, Markowitz JS, Brewerton TD. Delirium associated with clozapine|3
01278|051|R|  and benzodiazepine combinations. Ann Clin Psychiatry 1995 Sep;7(3):139-41.|3
01278|052|R|6.Sassim N, Grohmann R. Adverse drug reactions with clozapine and|3
01278|053|R|  simultaneous application of benzodiazepines. Pharmacopsychiatry 1988 Nov;|3
01278|054|R|  21(6):306-7.|3
01278|055|R|7.Tupala E, Niskanen L, Tiihonen J. Transient syncope and ECG changes|3
01278|056|R|  associated with the concurrent administration of clozapine and diazepam. J|3
01278|057|R|  Clin Psychiatry 1999 Sep;60(9):619-20.|3
01278|058|R|8.Cobb CD, Anderson CB, Seidel DR. Possible interaction between clozapine|3
01278|059|R|  and lorazepam. Am J Psychiatry 1991 Nov;148(11):1606-7.|3
01278|060|R|9.Klimke A, Klieser E. Sudden death after intravenous application of|3
01278|061|R|  lorazepam in a patient treated with clozapine. Am J Psychiatry 1994 May;|3
01278|062|R|  151(5):780.|3
01279|001|T|MONOGRAPH TITLE:  Cyclosporine/Selected Quinolones|
01279|002|B||
01279|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01279|004|L|take action as needed.|
01279|005|B||
01279|006|A|MECHANISM OF ACTION:  Cyclosporine and quinolones may result in synergistic|
01279|007|A|nephrotoxicity.(1,2)  Quinolones may inhibit the metabolism of cyclosporine|
01279|008|A|and may interfere with the renal tubular excretion of cyclosporine.(2)|
01279|009|B||
01279|010|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine with quinolones may result|
01279|011|E|in elevated levels of cyclosporine and nephrotoxicity.|
01279|012|B||
01279|013|P|PREDISPOSING FACTORS:  None determined.|
01279|014|B||
01279|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with cyclosporine|
01279|016|M|and a quinolone should be monitored for increased cyclosporine levels and|
01279|017|M|signs of nephrotoxicity.|
01279|018|B||
01279|019|D|DISCUSSION:  Nephrotoxicity with(1) and without(2) elevated cyclosporine|
01279|020|D|levels has been reported in patients maintained in cyclosporine in whom|
01279|021|D|ciprofloxacin was initiated.  A retrospective review found a significantly|
01279|022|D|greater percentage of cases of biopsy-proven rejection in patients who|
01279|023|D|received concurrent cyclosporine and ciprofloxacin (45%) than in matched|
01279|024|D|controls who did not receive ciprofloxacin (19%).(3)  In contrast to these|
01279|025|D|reports, three studies found no effect on cyclosporine levels or rates of|
01279|026|D|nephrotoxicity with concurrent ciprofloxacin.(4-6)|
01279|027|D|   In a study in 12 healthy subjects, levofloxacin had no effect on the|
01279|028|D|pharmacokinetics of a single dose of cyclosporine.(7)|
01279|029|D|   In a study in pediatric patients, the dose of cyclosporine needed to|
01279|030|D|maintain cyclosporine trough levels between 150 ng/ml and 400 ng/ml was|
01279|031|D|found to be 4.5 mg/kg/day in patients receiving concurrent norfloxacin and|
01279|032|D|7.4 mg/kg/day in patients not receiving norfloxacin.(8)  Elevated levels of|
01279|033|D|cyclosporine were noted in a patient following the addition of norfloxacin|
01279|034|D|to his cyclosporine regimen.(9)|
01279|035|B||
01279|036|R|REFERENCES:|
01279|037|B||
01279|038|R|1.Avent CK, Krinsky D, Kirklin JK, Bourge RC, Figg WD. Synergistic|3
01279|039|R|  nephrotoxicity due to ciprofloxacin and cyclosporine. Am J Med 1988 Sep;|3
01279|040|R|  85(3):452-3.|3
01279|041|R|2.Elston RA, Taylor J. Possible interaction of ciprofloxacin with|3
01279|042|R|  cyclosporin A. J Antimicrob Chemother 1988 May;21(5):679-80.|3
01279|043|R|3.Wrishko RE, Levine M, Primmett DR, Kim S, Partovi N, Lewis S, Landsberg D,|2
01279|044|R|  Keown PA. Investigation of a possible interaction between ciprofloxacin|2
01279|045|R|  and cyclosporine in renal transplant patients. Transplantation 1997 Oct|2
01279|046|R|  15;64(7):996-9.|2
01279|047|R|4.Kruger HU, Schuler U, Proksch B, Gobel M, Ehninger G. Investigation of|2
01279|048|R|  potential interaction of ciprofloxacin with cyclosporine in bone marrow|2
01279|049|R|  transplant recipients. Antimicrob Agents Chemother 1990 Jun;34(6):1048-52.|2
01279|050|R|5.Lang J, Finaz de Villaine J, Garraffo R, Touraine JL. Cyclosporine|2
01279|051|R|  (cyclosporin A) pharmacokinetics in renal transplant patients receiving|2
01279|052|R|  ciprofloxacin. Am J Med 1989 Nov 30;87(5A):82S-85S.|2
01279|053|R|6.de Witte T, Novakova I, Branolte J, Muytjens H, de Pauw B. Long-term oral|2
01279|054|R|  ciprofloxacin for infection prophylaxis in allogeneic bone marrow|2
01279|055|R|  transplantation. Pharm Weekbl Sci 1987 Dec 11;9 Suppl:S48-52.|2
01279|056|R|7.Doose DR, Walker SA, Chien SC, Williams RR, Nayak RK. Levofloxacin does|2
01279|057|R|  not alter cyclosporine disposition. J Clin Pharmacol 1998 Jan;38(1):90-3.|2
01279|058|R|8.McLellan RA, Drobitch RK, McLellan H, Acott PD, Crocker JF, Renton KW.|2
01279|059|R|  Norfloxacin interferes with cyclosporine disposition in pediatric patients|2
01279|060|R|  undergoing renal transplantation. Clin Pharmacol Ther 1995 Sep;|2
01279|061|R|  58(3):322-7.|2
01279|062|R|9.Thomson DJ, Menkis AH, McKenzie FN. Norfloxacin-cyclosporine interaction.|3
01279|063|R|  Transplantation 1988 Aug;46(2):312-3.|3
01280|001|T|MONOGRAPH TITLE:  Thyroid/Iron Salts, Oral (mono deleted 12/05/2019)|
01280|002|B||
01280|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01280|004|L|take action as needed.|
01280|005|B||
01280|006|A|MECHANISM OF ACTION:  Iron may form a ferric-thyroxine complex with thyroid|
01280|007|A|agents, preventing their absorption from the gastrointestinal tract.(1,2)|
01280|008|B||
01280|009|E|CLINICAL EFFECTS:  Simultaneous administration of thyroid agents with iron|
01280|010|E|may result in decreased levels and clinical effectiveness of the thyroid|
01280|011|E|agent.(1,2)|
01280|012|B||
01280|013|P|PREDISPOSING FACTORS:  None determined.|
01280|014|B||
01280|015|M|PATIENT MANAGEMENT:  The administration times of thyroid agents and iron|
01280|016|M|supplements should be separated by four hours.(1)|
01280|017|B||
01280|018|D|DISCUSSION:  In a study in 14 subjects, the simultaneous administration of|
01280|019|D|thyroxine with ferrous sulfate for 12 weeks resulted in an increase in the|
01280|020|D|mean level of thyroid stimulating hormone (TSH) from 1.6+/-0.4 mU/L to|
01280|021|D|5.4+/-2.8 mU/L. Mixing thyroxine with ferrous sulfate in vitro resulted in a|
01280|022|D|poorly soluble complex.(2)|
01280|023|D|   One or more of the drug pairs linked to this monograph have been included|
01280|024|D|in a list of interactions that could be considered for classification as|
01280|025|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
01280|026|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
01280|027|D|Health Information Technology.|
01280|028|B||
01280|029|R|REFERENCES:|
01280|030|B||
01280|031|R|1.Synthroid (levothyroxine sodium) US prescribing information. Abbott|1
01280|032|R|  Laboratories February, 2024.|1
01280|033|R|2.Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate|2
01280|034|R|  reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med|2
01280|035|R|  1992 Dec 15;117(12):1010-3.|2
01280|036|R|3.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
01280|037|R|  Middleton B, Bates DW. Drug-drug interactions that should be|6
01280|038|R|  non-interruptive in order to reduce alert fatigue in electronic health|6
01280|039|R|  records. J Am Med Inform Assoc 2012 Sep 25.|6
01281|001|T|MONOGRAPH TITLE:  Gefitinib/Phenytoin (mono deleted 09/01/2011)|
01281|002|B||
01281|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01281|004|L|take action as needed.|
01281|005|B||
01281|006|A|MECHANISM OF ACTION:  Phenytoin may induce the metabolism of gefitinib by|
01281|007|A|CYP P-450-3A4.(1)|
01281|008|B||
01281|009|E|CLINICAL EFFECTS:  Concurrent use of gefitinib and phenytoin without dosage|
01281|010|E|gefitinib may result in decreased levels of and clinical effects from|
01281|011|E|gefitinib.(1)|
01281|012|B||
01281|013|P|PREDISPOSING FACTORS:  None determined.|
01281|014|B||
01281|015|M|PATIENT MANAGEMENT:  The manufacturer of gefitinib recommends that in|
01281|016|M|patients receiving a potent CYP P-450-3A4 inducer such as phenytoin, a dose|
01281|017|M|increase to 500 mg daily of gefitinib be considered in the absence of severe|
01281|018|M|adverse drug reaction.  Clinical response and adverse events should be|
01281|019|M|closely monitored.(1)|
01281|020|B||
01281|021|D|DISCUSSION:  In a study in healthy male volunteers, rifampicin decreased the|
01281|022|D|area-under-curve (AUC) of gefitinib by 85%.  Other potent CYP P-450-3A4|
01281|023|D|isoenzyme inducers such as phenytoin are expected to have similar effects.|
01281|024|D|(1)|
01281|025|B||
01281|026|R|REFERENCE:|
01281|027|B||
01281|028|R|1.Iressa (gefitinib tablets) US prescribing information. AstraZeneca|1
01281|029|R|  Pharmaceuticals LP April 7, 2004.|1
01282|001|T|MONOGRAPH TITLE:  Gefitinib/Rifampin (mono deleted 09/01/2011)|
01282|002|B||
01282|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01282|004|L|take action as needed.|
01282|005|B||
01282|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of gefitinib by CYP|
01282|007|A|P-450-3A4.(1)|
01282|008|B||
01282|009|E|CLINICAL EFFECTS:  Concurrent use of gefitinib and rifampin without a dosage|
01282|010|E|increase in gefitinib may result in decreased levels of and clinical effects|
01282|011|E|from gefitinib.(1)|
01282|012|B||
01282|013|P|PREDISPOSING FACTORS:  None determined.|
01282|014|B||
01282|015|M|PATIENT MANAGEMENT:  The manufacturer of gefitinib recommends that in|
01282|016|M|patients receiving a potent CYP P-450-3A4 inducer such as rifampin, a dose|
01282|017|M|increase to 500 mg daily of gefitinib be considered in the absence of severe|
01282|018|M|adverse drug reaction.  Clinical response and adverse events should be|
01282|019|M|closely monitored.(1)|
01282|020|B||
01282|021|D|DISCUSSION:  In a study in healthy male volunteers, rifampicin decreased the|
01282|022|D|area-under-curve (AUC) of gefitinib by 85%.(1)|
01282|023|B||
01282|024|R|REFERENCE:|
01282|025|B||
01282|026|R|1.Iressa (gefitinib tablets) US prescribing information. AstraZeneca|1
01282|027|R|  Pharmaceuticals LP April 7, 2004.|1
01283|001|T|MONOGRAPH TITLE:  Repaglinide/Gemfibrozil|
01283|002|B||
01283|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01283|004|L|is contraindicated and generally should not be dispensed or administered to|
01283|005|L|the same patient.|
01283|006|B||
01283|007|A|MECHANISM OF ACTION:  Gemfibrozil inhibits the OATP1B1 transporter and is a|
01283|008|A|strong inhibitor of CYP2C8, leading to inhibition of repaglinide transport|
01283|009|A|and metabolism by these pathways.(1,6)|
01283|010|B||
01283|011|E|CLINICAL EFFECTS:  Concurrent use of gemfibrozil and repaglinide may result|
01283|012|E|in elevated levels and clinical effects of repaglinide.(1)|
01283|013|B||
01283|014|P|PREDISPOSING FACTORS:  Concurrent administration of itraconazole may further|
01283|015|P|increase repaglinide levels.(1,3)|
01283|016|B||
01283|017|M|PATIENT MANAGEMENT:  The US manufacturers of gemfibrozil(2) and|
01283|018|M|repaglinide,(3) and the Canadian manufacturer of repaglinide(4) state that|
01283|019|M|concurrent use of gemfibrozil and repaglinide is contraindicated.|
01283|020|M|   Consider the use of fenofibrate in patients treated with repaglinide who|
01283|021|M|require fibrate therapy.|
01283|022|B||
01283|023|D|DISCUSSION:  In a randomized, cross-over study in 12 healthy subjects,|
01283|024|D|gemfibrozil (600 mg twice daily) increased the area-under-curve (AUC) and|
01283|025|D|half-life of repaglinide by 8.1-fold and 1.8-fold, respectively.(1,3)  At|
01283|026|D|seven hours post dose, gemfibrozil increased plasma repaglinide levels by|
01283|027|D|28.6-fold.  The blood-glucose lowering effects of repaglinide were also|
01283|028|D|increased by gemfibrozil.(1)|
01283|029|D|   In a study, concurrent administration of gemfibrozil (600 mg twice daily)|
01283|030|D|and itraconazole (100 mg twice daily) for three days increased repaglinide|
01283|031|D|AUC and Cmax by 19-fold and 2.8-fold, respectively.(2)|
01283|032|D|   In a randomized, cross-over study in 9 healthy subjects, concurrent|
01283|033|D|gemfibrozil (600 mg twice daily) and itraconazole (200 mg once, then 100 mg|
01283|034|D|twice daily) increased the AUC and maximum concentration (Cmax) of|
01283|035|D|nateglinide (30 mg) by 47% and 30%, respectively.  The AUC and Cmax of a|
01283|036|D|nateglinide metabolite were also increased by 166% and 92%, respectively.|
01283|037|D|However, the blood-glucose lowering effects of nateglinide were not|
01283|038|D|significantly altered.(5)|
01283|039|D|  An in vitro study used human liver subcellular fractions, fresh human|
01283|040|D|hepatocytes, and recombinant enzymes to study repaglinide metabolism.  This|
01283|041|D|study concluded that repaglinide undergoes direct glucuronidation and that|
01283|042|D|gemfibrozil inhibited both glucuronide and M4 formation with minor M2|
01283|043|D|inhibition.  This resulted in a 80% decrease in turnover of repaglinide.(8)|
01283|044|D|  In a randomized crossover study, ten healthy volunteers were given 0.25 mg|
01283|045|D|orally of repaglinide then, 1 hour later, a single oral 30 mg, 100 mg, 300|
01283|046|D|mg, or 900 mg dose of gemfibrozil or placebo.  The mean AUC of repaglinide|
01283|047|D|was increased 1.9-fold,4.5-fold, 6.7-fold, or 8.3-fold after a single dose|
01283|048|D|of gemfibrozil 30 mg, 100 mg, 300 mg, or 900 mg, respectively (p<0.001).|
01283|049|D|The Cmax of repaglinide increased 1.4-fold, 1.7-fold, 2.1-fold, and|
01283|050|D|2.4-fold, respectively, after the single oral dose of gemfibrozil|
01283|051|D|(p<0.05).(8)|
01283|052|D|  In a randomized cross-over study, 12 healthy patients received bezafibrate|
01283|053|D|(400 mg daily), fenofibrate (200 mg daily), or placebo (once daily) for 5|
01283|054|D|days.  On day 5, the patient also took a single dose of repaglinide (0.25|
01283|055|D|mg) one hour after the fibrate dose.   Bezafibrate and fenofibrate had no|
01283|056|D|statistically significant effects on the Cmax, Tmax, AUC, or T1/2 of|
01283|057|D|repaglinide, nor did it affect blood glucose concentrations.(9)|
01283|058|B||
01283|059|R|REFERENCES:|
01283|060|B||
01283|061|R|1.Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil,|2
01283|062|R|  itraconazole, and their combination on the pharmacokinetics and|2
01283|063|R|  pharmacodynamics of repaglinide: potentially hazardous interaction between|2
01283|064|R|  gemfibrozil and repaglinide. Diabetologia 2003 Mar;46(3):347-51.|2
01283|065|R|2.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
01283|066|R|  Ltd. December, 2020.|1
01283|067|R|3.Prandin (repaglinide) US prescribing information. Novo Nordisk|1
01283|068|R|  Pharmaceuticals, Inc. February 8, 2017.|1
01283|069|R|4.GlucoNorm (repaglinide) Canadian prescribing information. NovoNordisk|1
01283|070|R|  March 1, 2005.|1
01283|071|R|5.Niemi M, Backman JT, Juntti-Patinen L, Neuvonen M, Neuvonen PJ.|2
01283|072|R|  Coadministration of gemfibrozil and itraconazole has only a minor effect|2
01283|073|R|  on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide. Br|2
01283|074|R|  J Clin Pharmacol 2005 Aug;60(2):208-17.|2
01283|075|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
01283|076|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01283|077|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01283|078|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01283|079|R|  11/14/2017.|1
01283|080|R|7.Gan J, Chen W, Shen H, Gao L, Hong Y, Tian Y, Li W, Zhang Y, Tang Y, Zhang|5
01283|081|R|  H, Humphreys WG, Rodrigues AD. Repaglinide-gemfibrozil drug interaction:|5
01283|082|R|  inhibition of repaglinide glucuronidation as a potential additional|5
01283|083|R|  contributing mechanism. Br J Clin Pharmacol 2010 Dec;70(6):870-80.|5
01283|084|R|8.Honkalammi J, Niemi M, Neuvonen PJ, Backman JT. Dose-dependent interaction|2
01283|085|R|  between gemfibrozil and repaglinide in humans: strong  inhibition of|2
01283|086|R|  CYP2C8 with subtherapeutic gemfibrozil doses. Drug Metab Dispos 2011 Oct;|2
01283|087|R|  39(10):1977-86.|2
01283|088|R|9.Kajosaari LI, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ. Lack of|2
01283|089|R|  effect of bezafibrate and fenofibrate on the pharmacokinetics and|2
01283|090|R|  pharmacodynamics of repaglinide. Br J Clin Pharmacol 2004 Oct;58(4):390-6.|2
01284|001|T|MONOGRAPH TITLE:  Vardenafil/Alpha-Blockers (mono deleted 06/28/2007)|
01284|002|B||
01284|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01284|004|L|of severe adverse interaction.|
01284|005|B||
01284|006|A|MECHANISM OF ACTION:  Concurrent use of vardenafil and an alpha-blocker may|
01284|007|A|result in additive or synergistic effects on blood pressure.(1-4)|
01284|008|B||
01284|009|E|CLINICAL EFFECTS:  Simultaneous administration of vardenafil with an|
01284|010|E|alpha-blocker may result in symptomatic hypotension.(1-4)|
01284|011|B||
01284|012|P|PREDISPOSING FACTORS:  None determined.|
01284|013|B||
01284|014|M|PATIENT MANAGEMENT:  The US manufacturer of vardenafil states that|
01284|015|M|vardenafil is cautioned in patients taking alpha-blockers. Patients should|
01284|016|M|be stabilized on alpha-blocker therapy prior to beginning vardenafil and|
01284|017|M|vardenafil should be initiated at the lowest recommended starting dose.  In|
01284|018|M|patients stabilized on alpha-blockers, vardenafil should be initiated at the|
01284|019|M|lowest starting dose.  A maximum dose of 5 mg of vardenafil should be used|
01284|020|M|in patients taking alpha-blockers without any other medications that inhibit|
01284|021|M|CYP P-450-3A4.  A maximum dose of 2.5 mg of vardenafil should be used in|
01284|022|M|patients taking alpha-blockers with other medications that inhibit CYP|
01284|023|M|P-450-3A4.(1)|
01284|024|M|   The Canadian manufacturer of vardenafil states that the concurrent use of|
01284|025|M|vardenafil and alpha-blockers is not recommended.(2)|
01284|026|M|   The UK manufacturer of vardenafil states that the concurrent therapy with|
01284|027|M|vardenafil and alpha-blockers should only be done if the patient is|
01284|028|M|stabilized on alpha-blocker therapy.  A maximum dose of 5 mg vardenafil|
01284|029|M|should not be exceeded in patients taking an alpha-blocker.  Vardenafil|
01284|030|M|should not be taken within 6 hours of any alpha-blocker, with the exception|
01284|031|M|of tamsulosin.(3)|
01284|032|B||
01284|033|D|DISCUSSION:  With simultaneous administration of vardenafil (10 mg) and|
01284|034|D|terazosin (10 mg), six of eight healthy subjects experienced a standing|
01284|035|D|systolic blood pressure of less than 85 mmHg.  With simultaneous vardenafil|
01284|036|D|(20 mg) and terazosin (10 mg), two of nine subjects experienced a standing|
01284|037|D|systolic blood pressure of less than 85 mmHg.  When vardenafil (20 mg) was|
01284|038|D|administered six hours apart from terazosin (10 mg), seven of 28 subjects|
01284|039|D|experienced a standing systolic blood pressure of less than 85 mmHg.(1)|
01284|040|D|   With simultaneous administration of vardenafil (10 mg) and tamsulosin|
01284|041|D|(0.4 mg), two of 16 subjects experienced a standing systolic blood pressure|
01284|042|D|of less than 85 mmHg.  When vardenafil (20 mg) was administered six hours|
01284|043|D|apart from tamsulosin (0.4 mg), one of 24 subjects experienced a standing|
01284|044|D|systolic blood pressure of less than 85 mmHg.(1)|
01284|045|D|   In a study in subjects with benign prostatic hyperplasia (BPH) on stable|
01284|046|D|tamsulosin or terazosin therapy, simultaneous vardenafil (5 mg) and|
01284|047|D|tamsulosin resulted in no effects on blood pressure.  Simultaneous|
01284|048|D|vardenafil (5 mg) with terazosin resulted in hypotension in some subjects.|
01284|049|D|This effect did not occur when vardenafil and terazosin were separated by 6|
01284|050|D|hours.(3)|
01284|051|D|   In a placebo controlled, crossover study in 22 subjects with benign|
01284|052|D|prostatic hyperplasia receiving tamsulosin, subjects received single doses|
01284|053|D|of vardenafil (10 mg and 20 mg).  No patients exhibited symptomatic|
01284|054|D|hypotension.  Three patients receiving 20 mg of vardenafil reported|
01284|055|D|dizziness, but none had a systolic blood pressure of less than 95 mmHg.(5)|
01284|056|D|   Hypotension has been reported with concurrent use of terazosin and|
01284|057|D|phosphodiesterase-5 inhibitors.(4)|
01284|058|B||
01284|059|R|REFERENCES:|
01284|060|B||
01284|061|R|1.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
01284|062|R|  Pharmaceuticals Corporation August, 2013.|1
01284|063|R|2.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
01284|064|R|  Bayer, Inc. October 24, 2006.|1
01284|065|R|3.Levitra (vardenafil hydrochloride trihydrate) UK summary of product|1
01284|066|R|  characteristics. Bayer plc December 20, 2006.|1
01284|067|R|4.Hytrin (terazosin hydrochloride) US prescribing information. Abbott|1
01284|068|R|  Laboratories February, 2006.|1
01284|069|R|5.Auerbach SM, Gittelman M, Mazzu A, Cihon F, Sundaresan P, White WB.|2
01284|070|R|  Simultaneous administration of vardenafil and tamsulosin does not induce|2
01284|071|R|  clinically significant hypotension in patients with benign prostatic|2
01284|072|R|  hyperplasia. Urology 2004 Nov;64(5):998-1003; discussion 1003-4.|2
01285|001|T|MONOGRAPH TITLE:  Vardenafil/Class IA And III Antiarrhythmics (mono deleted|
01285|002|T|03/26/2021)|
01285|003|B||
01285|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01285|005|L|of severe adverse interaction.|
01285|006|B||
01285|007|A|MECHANISM OF ACTION:  The concurrent use of vardenafil and Class IA or III|
01285|008|A|antiarrhythmics may result in additive or synergistic effects on the QTc|
01285|009|A|interval.(1,2)|
01285|010|B||
01285|011|E|CLINICAL EFFECTS:  Concurrent use of vardenafil and Class IA or III|
01285|012|E|antiarrhythmics may result in prolongation of the QTc interval, which may|
01285|013|E|result in potentially life-threatening arrhythmias.(1,2)|
01285|014|B||
01285|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01285|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01285|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01285|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01285|019|P|female gender, or advanced age.(3)|
01285|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01285|021|P|higher systemic concentrations of either QT prolonging drug ar additional|
01285|022|P|risk factors for torsades de pointes.  Factors which may increased systemic|
01285|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01285|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01285|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01285|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01285|027|B||
01285|028|M|PATIENT MANAGEMENT:  The Canadian(1) and US(2) manufacturers of vardenafil|
01285|029|M|state that patients receiving Class IA or III antiarrhythmics should avoid|
01285|030|M|using vardenafil.|
01285|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01285|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01285|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01285|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01285|035|B||
01285|036|D|DISCUSSION:  In a study in 59 healthy males, vardenafil (10 mg, therapeutic|
01285|037|D|dose and 80 mg, supratherapeutic dose) and moxifloxacin (400 mg) produced|
01285|038|D|similar increases in the QTc interval.(2)|
01285|039|B||
01285|040|R|REFERENCES:|
01285|041|B||
01285|042|R|1.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
01285|043|R|  Bayer, Inc. October 24, 2006.|1
01285|044|R|2.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
01285|045|R|  Pharmaceuticals Corporation March, 2023.|1
01285|046|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01285|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01285|048|R|  settings: a scientific statement from the American Heart Association and|6
01285|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01285|050|R|  2;55(9):934-47.|6
01286|001|T|MONOGRAPH TITLE:  Irinotecan/UGT1A1 Inhibitors|
01286|002|B||
01286|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01286|004|L|is contraindicated and generally should not be dispensed or administered to|
01286|005|L|the same patient.|
01286|006|B||
01286|007|A|MECHANISM OF ACTION:  Inhibitors of UGT1A1 may inhibit the metabolism of|
01286|008|A|SN-38, the active metabolite of irinotecan.(1)|
01286|009|A|   Atazanavir may inhibit the metabolism of irinotecan by UGT1A1.(1,2)  This|
01286|010|A|increases the system exposure to SN-38, the active metabolite of|
01286|011|A|irinotecan.(3)|
01286|012|B||
01286|013|E|CLINICAL EFFECTS:  Concurrent use of UGT1A1 inhibitors may result in|
01286|014|E|increased exposure to and toxicity from irinotecan.(1)|
01286|015|B||
01286|016|P|PREDISPOSING FACTORS:  None determined.|
01286|017|B||
01286|018|M|PATIENT MANAGEMENT:  The US manufacturer of irinotecan states do not|
01286|019|M|administer UGT1A1 inhibitors with irinotecan unless there are no therapeutic|
01286|020|M|alternatives.  The increased exposure to the active metabolite should be|
01286|021|M|taken into consideration when co-administering these agents.(1)|
01286|022|M|   The US manufacturer of atazanavir states that concurrent use of|
01286|023|M|irinotecan is contraindicated.(2)  The Australian manufacturer of atazanavir|
01286|024|M|states that irinotecan should not be administered with atazanavir.(3)|
01286|025|B||
01286|026|D|DISCUSSION:  Because atazanavir inhibits UGT1A1 at therapeutic|
01286|027|D|concentrations, it is expected to interfere with the metabolism of|
01286|028|D|irinotecan.  Therefore, the manufacturer of atazanavir states that|
01286|029|D|irinotecan should not be administered with atazanavir.(1,2)|
01286|030|D|   UGT1A1 inhibitors linked to this monograph include: atazanavir,|
01286|031|D|capivasertib, belumosudil, erlotinib, gemfibrozil, lapatinib, nilotinib,|
01286|032|D|pazopanib, probenecid, regorafenib, and sorafenib.|
01286|033|D|   One or more of the drug pairs linked to this monograph have been included|
01286|034|D|in a list of interactions that should be considered "high-priority" for|
01286|035|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01286|036|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01286|037|D|Coordinator (ONC) for Health Information Technology.|
01286|038|B||
01286|039|R|REFERENCES:|
01286|040|B||
01286|041|R|1.Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia|1
01286|042|R|  & Upjohn Company January, 2020.|1
01286|043|R|2.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01286|044|R|  Squibb Pharmaceuticals October 25, 2023.|1
01286|045|R|3.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01286|046|R|  Squibb Company December, 2024.|1
01286|047|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01286|048|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01286|049|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01286|050|R|  19(5):735-43.|6
01287|001|T|MONOGRAPH TITLE:  Atazanavir; Nelfinavir/Proton Pump Inhibitors|
01287|002|B||
01287|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01287|004|L|is contraindicated and generally should not be dispensed or administered to|
01287|005|L|the same patient.|
01287|006|B||
01287|007|A|MECHANISM OF ACTION:  Proton pump inhibitors increase gastric pH.  As|
01287|008|A|gastric pH increases, the solubility of atazanavir and nelfinavir|
01287|009|A|decreases.(1,2)|
01287|010|A|   Omeprazole has been shown to inhibit nelfinavir metabolism by CYP2C19.(3)|
01287|011|B||
01287|012|E|CLINICAL EFFECTS:  Concurrent use of atazanavir(1-2,4-8) or|
01287|013|E|nelfinavir(3,8-9) and a proton pump inhibitor may result in decreased levels|
01287|014|E|and effectiveness of atazanavir or nelfinavir.|
01287|015|B||
01287|016|P|PREDISPOSING FACTORS:  None determined.|
01287|017|B||
01287|018|M|PATIENT MANAGEMENT:  The US and Australian manufacturer of atazanavir states|
01287|019|M|that treatment naive patients requiring a proton pump inhibitor should|
01287|020|M|receive 300 mg atazanavir with 100 mg ritonavir.  The proton pump inhibitor|
01287|021|M|should not exceed a dose comparable to omeprazole 20 mg daily and should be|
01287|022|M|administered 12 hours before atazanavir/ritonavir.(1,2)|
01287|023|M|   Atazanavir should not be administered with proton pump inhibitors without|
01287|024|M|concurrent ritonavir in adults or pediatric patients of at least 13 years of|
01287|025|M|age and weighing at least 40 kg.(1,2)|
01287|026|M|   The US and Australian manufacturer of atazanavir states that proton pump|
01287|027|M|inhibitors should not be administered with atazanavir in treatment|
01287|028|M|experienced patients.(1,2)|
01287|029|M|   Data are insufficient to recommend a dose of atazanavir in patients|
01287|030|M|weighing less than 40 kg and receiving a proton pump inhibitor.(1)|
01287|031|M|   The Canadian and UK manufacturer of atazanavir states that the|
01287|032|M|coadministration of atazanavir and proton pump inhibitors is not|
01287|033|M|recommended.  If coadministration is necessary, the dose of atazanavir|
01287|034|M|should be increased to 400 mg daily taken with ritonavir 100 mg daily, and|
01287|035|M|the dose of the proton pump inhibitor should not exceed the equivalent of|
01287|036|M|omeprazole 20 mg.(10,11)|
01287|037|M|   The UK manufacturer of esomeprazole states that concurrent use with|
01287|038|M|atazanavir is contraindicated.(9)|
01287|039|M|   The US manufacturer of esomeprazole(4) and omeprazole(5) states that|
01287|040|M|concurrent use of atazanavir or nelfinavir is not recommended.|
01287|041|M|   The US manufacturers of dexlansoprazole (6), lansoprazole,(7) and|
01287|042|M|pantoprazole(8) state that atazanavir and nelfinavir should not be|
01287|043|M|coadministered with proton pump inhibitors.|
01287|044|B||
01287|045|D|DISCUSSION:  In a study of 16 subjects, atazanavir (400 mg daily)|
01287|046|D|area-under-curve (AUC), maximum concentration (Cmax) and minimum|
01287|047|D|concentration (Cmin) decreased 94%, 96% and 95% respectively, when given|
01287|048|D|with omeprazole (40 mg daily).  Omeprazole AUC and Cmax increased 145% and|
01287|049|D|124% respectively.(1)|
01287|050|D|   In a study of 15 subjects, atazanavir AUC, Cmax and Cmin decreased 76%,|
01287|051|D|72% and 78% respectively, when given with omeprazole (40 mg daily) and|
01287|052|D|ritonavir (100 mg daily).(1)|
01287|053|D|   In a study in 13 subjects, administration of omeprazole (20 mg daily) 12|
01287|054|D|hours before atazanavir/ritonavir (300/100 mg daily) decreased atazanavir|
01287|055|D|Cmax, AUC, and Cmin by 39%, 42%, and 46%, respectively; however, the|
01287|056|D|atazanavir AUC and Cmin were 10% and 2.4-fold higher than average levels|
01287|057|D|seen with atazanavir 400 mg alone.(1)|
01287|058|D|   In a study in 14 subjects, administration of omeprazole (20 mg daily) 1|
01287|059|D|hour before atazanavir/ritonavir (400/100 mg daily) decreased atazanavir|
01287|060|D|Cmax, AUC, and Cmin by 31%, 30%, and 31%, respectively; however, the|
01287|061|D|atazanavir AUC and Cmin were 32% and 3.3-fold higher than average levels|
01287|062|D|seen with atazanavir 400 mg alone.(1)|
01287|063|D|   In a study in 10 healthy subjects, concurrent administration of|
01287|064|D|lansoprazole (60 mg daily for 2 days) with atazanavir (400 mg) decreased|
01287|065|D|atazanavir AUC by 94%.(14)|
01287|066|D|   In a case report, concurrent esomeprazole decreased atazanavir, but not|
01287|067|D|fosamprenavir levels in a 65 year-old HIV-positive male.(15)|
01287|068|D|   In a study in 16 healthy, HIV-negative subjects, the concurrent|
01287|069|D|administration of omeprazole or ranitidine with ritonavir-boosted darunavir|
01287|070|D|had no effect on darunavir pharmacokinetics.(16)|
01287|071|D|   In a study in healthy subjects, the concurrent administration of|
01287|072|D|esomeprazole (20 mg daily) with either fosamprenavir (1400 mg twice daily)|
01287|073|D|or fosamprenavir (700 mg twice daily) and ritonavir (100 mg twice daily) for|
01287|074|D|14 days had no effect on amprenavir pharmacokinetics.(17)|
01287|075|D|   In a study in 19 subjects, concurrent omeprazole (40 mg daily) and|
01287|076|D|nelfinavir (1250 mg twice daily) for 4 days decreased nelfinavir AUC, Cmax,|
01287|077|D|and Cmin by 36%, 37%, and 39%.(7,17)  The AUC, Cmax, and Cmin of the active|
01287|078|D|M8 metabolite of nelfinavir decreased by 92%, 89%, and 75%,|
01287|079|D|respectively.(4,17)  A retrospective review of nelfinavir levels found|
01287|080|D|concurrent use of omeprazole decreased the median M8/nelfinavir ratio.(12)|
01287|081|D|   In a case report a 56 year old HIV infected male received omeprazole|
01287|082|D|(40mg daily) and atazanavir/ritonavir (300/100mg) for ten months.|
01287|083|D|Investigators used Bayesian models to determine atazanavir exposure, and|
01287|084|D|found atazanavir levels to be in the 25th percentile of boosted levels, but|
01287|085|D|still above the 75th percentile for unboosted atazanavir.(20)|
01287|086|D|   A retrospective review of 76 patients taking proton pump inhibitors and|
01287|087|D|66 patients not using proton pump inhibitors found no association with a|
01287|088|D|higher virologic failure rate in patients receiving proton pump|
01287|089|D|inhibitors.(21)|
01287|090|D|   In a case report, a 50 year-old HIV-infected male with a CD4 count of|
01287|091|D|1095 cells/ml and an HIV load of 88 copies/ml on a nelfinavir based regimen|
01287|092|D|was switched to an atazanavir/ritonavir (300/100mg daily) regimen. The|
01287|093|D|patient was taking omeprazole (20mg daily) and admitted to taking the|
01287|094|D|atazanavir at 150mg twice daily.  The patients CD4 count dropped to 830|
01287|095|D|cells/ml, but his HIV load dropped to <75 copies/ml.  The investigators|
01287|096|D|summarized concurrent use of omeprazole did not adversely affect this|
01287|097|D|patient's virologic load.(22)|
01287|098|D|   In a study in 18 healthy subjects, concurrent omeprazole (40 mg daily)|
01287|099|D|with saquinavir/ritonavir (1000/100 mg twice daily) for 4 days increased|
01287|100|D|saquinavir AUC by 83%.  No toxicities were noted.(18)|
01287|101|D|   In a study in 12 healthy subjects, concurrent omeprazole (40 mg daily)|
01287|102|D|with saquinavir/ritonavir (1000/100 mg twice daily) for 7 weeks increased|
01287|103|D|saquinavir AUC, Cmin, and Cmax by 54%, 73%, 55% respectively.  Omeprazole 2|
01287|104|D|hours prior to saquinavir/ritonavir increased saquinavir AUC, Cmin, and Cmax|
01287|105|D|by 67%, 97%, and 65% respectively.  No toxicities were noted.(23)|
01287|106|D|   In a study of 14 healthy subjects, concurrent omeprazole (20 mg daily and|
01287|107|D|40 mg daily) with indinavir (800mg daily) for 7 days decreased indinavir AUC|
01287|108|D|by 34% and 47% respectively and no statistical changes were seen in the Cmax|
01287|109|D|or Tmax of indinavir.  When omeprazole (40mg daily) was given with|
01287|110|D|indinavir/ritonavir (800mg/200mg daily) for 7 days indinavir AUC increased|
01287|111|D|by 55% and no statistical changes were seen in indinavir Cmax or Tmax.|
01287|112|D|Omeprazole (40mg daily) showed a Cmax increase of 50% and a half-life|
01287|113|D|increase of 100% in the presence of ritonavir.(24)|
01287|114|D|   In a study of 19 healthy subjects, concurrent omeprazole (20 mg daily)|
01287|115|D|with fosamprenavir/ritonavir (1400/200 mg daily) or atazanavir/ritonavir|
01287|116|D|(300/100)for 3 weeks showed no effect on amprenavir pharmacokinetics, but|
01287|117|D|decreased atazanavir  AUC and Cmin by 27%.(25)|
01287|118|D|   In a retrospective review of 15 HIV-infected patients receiving indinavir|
01287|119|D|(800mg three times daily), nine patients were also receiving omeprazole|
01287|120|D|(20-40mg daily).  Of these nine patients, four  had plasma concentrations of|
01287|121|D|indinavir below the 95% confidence interval of plasmas concentration in|
01287|122|D|patients receiving indinavir alone, four were within the 95% confidence|
01287|123|D|interval, and one was above the 95% confidence interval.(26)|
01287|124|D|   In a case report, a 40 year-old HIV-infected male with extensive|
01287|125|D|antiretroviral history and virological failure began atazanavir/ritonavir|
01287|126|D|(300/100mg daily).  The patient was restarted on lansoprazole during|
01287|127|D|atazanavir/ritonavir therapy, and despite lansoprazole and tenofovir therapy|
01287|128|D|the patients plasma concentrations of atazanavir remained consistent with|
01287|129|D|historical values, and the patients Cmin stayed well above the established|
01287|130|D|values for the combination of atazanavir/ritonavir with tenofovir.(27)|
01287|131|D|   In a study of 68 healthy subjects, coadministration of omeprazole (40mg|
01287|132|D|daily) with lopinavir/ritonavir (400/100mg twice daily or 800/200mg once|
01287|133|D|daily) showed no statistical change in pharmacokinetics.(28,29)  However,|
01287|134|D|when given with atazanavir/ritonavir (300/100 daily) bioavailability of|
01287|135|D|atazanavir decreased by 48-62%.(28)|
01287|136|D|   One or more of the drug pairs linked to this monograph have been included|
01287|137|D|in a list of interactions that should be considered "high-priority" for|
01287|138|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01287|139|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01287|140|D|Coordinator (ONC) for Health Information Technology.|
01287|141|B||
01287|142|R|REFERENCES:|
01287|143|B||
01287|144|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01287|145|R|  Squibb Company December, 2024.|1
01287|146|R|2.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01287|147|R|  Squibb Pharmaceuticals October 25, 2023.|1
01287|148|R|3.Hirani VN, Raucy JL, Lasker JM. Conversion of the HIV protease inhibitor|5
01287|149|R|  nelfinavir to a bioactive metabolite by human liver CYP2C19. Drug Metab|5
01287|150|R|  Dispos 2004 Dec;32(12):1462-7.|5
01287|151|R|4.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
01287|152|R|  Pharmaceuticals LP August, 2021.|1
01287|153|R|5.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
01287|154|R|  Pharmaceuticals LP June, 2018.|1
01287|155|R|6.Dexilant (dexlansoprazole) US prescribing information. Takeda|1
01287|156|R|  Pharmaceuticals North America, Inc. October, 2017.|1
01287|157|R|7.Prevacid (lansoprazole) US prescribing information. Takeda Pharmaceuticals|1
01287|158|R|  America, Inc. June, 2018.|1
01287|159|R|8.Protonix (pantoprazole sodium) US prescribing information. Wyeth|1
01287|160|R|  Pharmaceuticals, Inc. August, 2024.|1
01287|161|R|9.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01287|162|R|  Pharmaceuticals, Inc. September, 2016.|1
01287|163|R|10.Baede-van Dijk PA, Hugen PW, Verweij-van Wissen CP, Koopmans PP, Burger|2
01287|164|R|   DM, Hekster YA. Analysis of variation in plasma concentrations of|2
01287|165|R|   nelfinavir and its active metabolite M8 in HIV-positive patients. AIDS|2
01287|166|R|   2001 May 25;15(8):991-8.|2
01287|167|R|11.Reyataz (atazanavir) Canadian prescribing information. Bristol-Myers|1
01287|168|R|   Squibb Canada August 31, 2023.|1
01287|169|R|12.Reyataz (atazanavir) UK summary of product characteristics. Bristol-Myers|1
01287|170|R|   Squibb Pharmaceuticals Limited September 8, 2008.|1
01287|171|R|13.Nexium (esomeprazole) UK summary of product characteristics. AstraZeneca|1
01287|172|R|   UK Limited April 25, 2008.|1
01287|173|R|14.Tomilo DL, Smith PF, Ogundele AB, Difrancesco R, Berenson CS, Eberhardt|2
01287|174|R|   E, Bednarczyk E, Morse GD. Inhibition of atazanavir oral absorption by|2
01287|175|R|   lansoprazole gastric acid suppression in healthy volunteers.|2
01287|176|R|   Pharmacotherapy 2006 Mar;26(3):341-6.|2
01287|177|R|15.Kiser JJ, Lichtenstein KA, Anderson PL, Fletcher CV. Effects of|3
01287|178|R|   esomeprazole on the pharmacokinetics of atazanavir and fosamprenavir in a|3
01287|179|R|   patient with human immunodeficiency virus infection. Pharmacotherapy 2006|3
01287|180|R|   Apr;26(4):511-4.|3
01287|181|R|16.Sekar VJ, Lefebvre E, De Paepe E, De Marez T, De Pauw M, Parys W,|2
01287|182|R|   Hoetelmans RM. Pharmacokinetic Interaction between Darunavir Boosted with|2
01287|183|R|   Ritonavir and Omeprazole or Ranitidine in Human Immunodeficiency|2
01287|184|R|   Virus-Negative Healthy Volunteers. Antimicrob Agents Chemother 2007 Mar;|2
01287|185|R|   51(3):958-61.|2
01287|186|R|17.Shelton MJ, Ford SL, Borland J, Lou Y, Wire MB, Min SS, Xue ZG, Yuen G.|2
01287|187|R|   Coadministration of esomeprazole with fosamprenavir has no impact on|2
01287|188|R|   steady-state plasma amprenavir pharmacokinetics. J Acquir Immune Defic|2
01287|189|R|   Syndr 2006 May;42(1):61-7.|2
01287|190|R|18.Fang AF, Damle BD, LaBadie RR, Crownover PH, Hewlett D Jr, Glue PW.|2
01287|191|R|   Significant decrease in nelfinavir systemic exposure after omeprazole|2
01287|192|R|   coadministration in healthy subjects. Pharmacotherapy 2008 Jan;|2
01287|193|R|   28(1):42-50.|2
01287|194|R|19.Winston A, Back D, Fletcher C, Robinson L, Unsworth J, Tolowinska I,|2
01287|195|R|   Schutz M, Pozniak AL, Gazzard B, Boffito M. Effect of omeprazole on the|2
01287|196|R|   pharmacokinetics of saquinavir-500 mg formulation with ritonavir in|2
01287|197|R|   healthy male and female volunteers. AIDS 2006 Jun 26;20(10):1401-6.|2
01287|198|R|20.Goicoechea M, Best B, Capparelli E, Caperna J, Ballard C, Haubrich R.|3
01287|199|R|   Therapeutic ritonavir-boosted atazanavir plasma concentration and|3
01287|200|R|   concurrent omeprazole use. AIDS 2006 Oct 24;20(16):2127-8.|3
01287|201|R|21.Furtek KJ, Crum NF, Olson PE, Wallace MR. Proton pump inhibitor therapy|6
01287|202|R|   in atazanavir-treated patients: contraindicated?. J Acquir Immune Defic|6
01287|203|R|   Syndr 2006 Mar;41(3):394-6.|6
01287|204|R|22.Chan-Tack KM, Edozien A. Ritonavir-boosted atazanavir may be efficacious|3
01287|205|R|   in HIV-infected patients concurrently receiving omeprazole. Clin Infect|3
01287|206|R|   Dis 2006 May 1;42(9):1344.|3
01287|207|R|23.Singh K, Dickinson L, Chaikan A, Back D, Fletcher C, Pozniak A, Moyle G,|2
01287|208|R|   Nelson M, Gazzard B, Herath D, Boffito M. Pharmacokinetics and safety of|2
01287|209|R|   saquinavir/ritonavir and omeprazole in HIV-infected subjects. Clin|2
01287|210|R|   Pharmacol Ther 2008 Jun;83(6):867-72.|2
01287|211|R|24.Tappouni HL, Rublein JC, Donovan BJ, Hollowell SB, Tien HC, Min SS,|2
01287|212|R|   Theodore D, Rezk NL, Smith PC, Tallman MN, Raasch RH, Kashuba AD. Effect|2
01287|213|R|   of omeprazole on the plasma concentrations of indinavir when administered|2
01287|214|R|   alone and in combination with ritonavir. Am J Health Syst Pharm 2008 Mar|2
01287|215|R|   1;65(5):422-8.|2
01287|216|R|25.Luber AD, Brower R, Kim D, Silverman R, Peloquin CA, Frank I.|2
01287|217|R|   Steady-state pharmacokinetics of once-daily fosamprenavir/ritonavir and|2
01287|218|R|   atazanavir/ritonavir alone and in combination with 20 mg omeprazole in|2
01287|219|R|   healthy volunteers. HIV Med 2007 Oct;8(7):457-64.|2
01287|220|R|26.Burger DM, Hugen PW, Kroon FP, Groeneveld P, Brinkman K, Foudraine NA,|6
01287|221|R|   Sprenger H, Koopmans PP, Hekster YA. Pharmacokinetic interaction between|6
01287|222|R|   the proton pump inhibitor omeprazole and the HIV protease inhibitor|6
01287|223|R|   indinavir. AIDS 1998 Oct 22;12(15):2080-2.|6
01287|224|R|27.Kosel BW, Storey SS, Collier AC. Lack of interaction between atazanavir|3
01287|225|R|   and lansoprazole. AIDS 2005 Mar 24;19(6):637-8.|3
01287|226|R|28.Klein CE, Chiu YL, Cai Y, Beck K, King KR, Causemaker SJ, Doan T,|2
01287|227|R|   Esslinger HU, Podsadecki TJ, Hanna GJ. Effects of acid-reducing agents on|2
01287|228|R|   the pharmacokinetics of lopinavir/ritonavir and ritonavir-boosted|2
01287|229|R|   atazanavir. J Clin Pharmacol 2008 May;48(5):553-62.|2
01287|230|R|29.Chiu YL, Klein CE, Woodward WC, King KR, Naylor C, Awni W, Brun S. Lack|2
01287|231|R|   of effect of gastric acid-reducing agents on the pharmacokinetics of|2
01287|232|R|   lopinavir/ritonavir in HIV-infected patients. AIDS Patient Care STDS 2007|2
01287|233|R|   Apr;21(4):247-51.|2
01287|234|R|30.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01287|235|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01287|236|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01287|237|R|   19(5):735-43.|6
01288|001|T|MONOGRAPH TITLE:  Atazanavir/Indinavir|
01288|002|B||
01288|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01288|004|L|is contraindicated and generally should not be dispensed or administered to|
01288|005|L|the same patient.|
01288|006|B||
01288|007|A|MECHANISM OF ACTION:  Both atazanavir and indinavir are associated with|
01288|008|A|indirect (unconjugated) hyperbilirubinemia (1-3) by inhibiting UDP|
01288|009|A|glucuronyl transferase (UGT).(4)  The mechanism is thought to involve this|
01288|010|A|inhibition.|
01288|011|B||
01288|012|E|CLINICAL EFFECTS:  Concurrent use of atazanavir and indinavir may result in|
01288|013|E|higher levels of indirect (unconjugated) bilirubin, leading to|
01288|014|E|hyperbilirubinemia,(1-3) by inhibiting UDP glucuronyl transferase.(4)  When|
01288|015|E|atazanavir or indinavir are taken separately, this is usually asymptomatic|
01288|016|E|and reversible upon discontinuation of the drug.(5,6)  However, if these two|
01288|017|E|drugs are combined, higher levels of unconjugated hyperbilirubinemia may|
01288|018|E|present in patients and lead to jaundice.|
01288|019|B||
01288|020|P|PREDISPOSING FACTORS:  Patients who are homozygous for the UGT1A1*28 allele|
01288|021|P|(abnormality causing reduced UGT1A1 enzymes needed for bilirubin metabolism)|
01288|022|P|may be at a higher risk for developing hyperbilirubinemia and jaundice when|
01288|023|P|exposed to certain protease inhibitors.(5)  It is important to note that|
01288|024|P|patients with a condition called Gilbert's Syndrome (a condition|
01288|025|P|characterized by chronic hyperbilirubinemia) have the UGT1A1*28 allele.(7)|
01288|026|B||
01288|027|M|PATIENT MANAGEMENT:  The US manufacturer of atazanavir states that|
01288|028|M|concurrent use of indinavir is contraindicated.(1)|
01288|029|M|   The Australian manufacturer of atazanavir(2) and the US manufacturer of|
01288|030|M|indinavir(3) state that indinavir should not be administered with|
01288|031|M|atazanavir.|
01288|032|B||
01288|033|D|DISCUSSION:  Because atazanavir and indinavir are associated with indirect|
01288|034|D|(unconjugated) hyperbilirubinemia, the manufacturers of atazanavir(1,2) and|
01288|035|D|indinavir(3) state that indinavir should not be administered with|
01288|036|D|atazanavir.|
01288|037|D|   Rotger M et al. studied the contribution of UGT1A1*28 and|
01288|038|D|anti-antiretroviral therapy to hyperbilirubinemia by monitoring 1386 total|
01288|039|D|bilirubin and 226 unconjugated bilirubin levels in 96 patients with human|
01288|040|D|immunodeficiency virus (HIV) during a median time period of 6 years.|
01288|041|D|Researchers estimated the average bilirubin level to be 8.8 mcmol/L (0.51|
01288|042|D|mg/dL).  Results showed that atazanavir increased bilirubin levels by 15|
01288|043|D|mcmol/L (0.87 mg/dL) and indinavir increased bilirubin levels by 8 mcmol/L|
01288|044|D|(0.46 mg/dL).  Furthermore, the homozygous UGT1A1*28 allele caused an|
01288|045|D|increase in bilirubin levels by 5.2 mcmol/L (0.3 mg/dL).  There were 27|
01288|046|D|participants (28%) that had > 2 bilirubin levels in the jaundice range (from|
01288|047|D|>43 mcmol/L to >2.5 mg/dL]).  Furthermore, 6 (67%) of the 9 patients in this|
01288|048|D|clinical trial, who were homozygous for UGT1A1*28 and received atazanavir or|
01288|049|D|indinavir, had bilirubin levels in the jaundice range.  This is compared to|
01288|050|D|4 (7%) of the 54 HIV-infected patients, with elevated bilirubin levels, who|
01288|051|D|were not homozygous for UGT1A1*28 and did not receive either atazanavir or|
01288|052|D|indinavir (p<0.001).(8)|
01288|053|B||
01288|054|R|REFERENCES:|
01288|055|B||
01288|056|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01288|057|R|  Squibb Company December, 2024.|1
01288|058|R|2.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01288|059|R|  Squibb Pharmaceuticals October 25, 2023.|1
01288|060|R|3.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01288|061|R|  September, 2016.|1
01288|062|R|4.Wensing AM, van Maarseveen NM, Nijhuis M. Fifteen years of HIV Protease|6
01288|063|R|  Inhibitors: raising the barrier to resistance. Antiviral Res 2010 Jan;|6
01288|064|R|  85(1):59-74.|6
01288|065|R|5.Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P, Feinberg J,|2
01288|066|R|  Sherman KE. Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl|2
01288|067|R|  Acad Sci U S A 2001 Oct 23;98(22):12671-6.|2
01288|068|R|6.Sulkowski MS. Drug-induced liver injury associated with antiretroviral|6
01288|069|R|  therapy that includes HIV-1 protease inhibitors. Clin Infect Dis 2004 Mar|6
01288|070|R|  1;38 Suppl 2:S90-7.|6
01288|071|R|7.Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout|2
01288|072|R|  D, Tytgat GN, Jansen PL, Oude Elferink RP, et al. The genetic basis of the|2
01288|073|R|  reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's|2
01288|074|R|  syndrome. N Engl J Med 1995 Nov 2;333(18):1171-5.|2
01288|075|R|8.Rotger M, Taffe P, Bleiber G, Gunthard HF, Furrer H, Vernazza P, Drechsler|2
01288|076|R|  H, Bernasconi E, Rickenbach M, Telenti A. Gilbert syndrome and the|2
01288|077|R|  development of antiretroviral therapy-associated hyperbilirubinemia. J|2
01288|078|R|  Infect Dis 2005 Oct 15;192(8):1381-6.|2
01289|001|T|MONOGRAPH TITLE:  Fosamprenavir; Saquinavir/Efavirenz|
01289|002|B||
01289|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01289|004|L|of severe adverse interaction.|
01289|005|B||
01289|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of|
01289|007|A|fosamprenavir,(1-3) and saquinavir (1,2,4) via CYP3A4.|
01289|008|B||
01289|009|E|CLINICAL EFFECTS:  Concurrent use of fosamprenavir and efavirenz without the|
01289|010|E|correct amount of concurrent ritonavir may result in decreased levels of|
01289|011|E|amprenavir.(1-3)  Concurrent use of saquinavir as the sole protease|
01289|012|E|inhibitor with efavirenz may result in decreased saquinavir levels and|
01289|013|E|effectiveness.(1,2,4)  Saquinavir may decrease efavirenz levels.(1,4)|
01289|014|B||
01289|015|P|PREDISPOSING FACTORS:  None determined.|
01289|016|B||
01289|017|M|PATIENT MANAGEMENT:  An additional 100 mg/day (300 mg total) of ritonavir is|
01289|018|M|recommended when efavirenz is administered with fosamprenavir/ritonavir once|
01289|019|M|daily.  No change in the ritonavir dose is required when efavirenz is|
01289|020|M|administered with fosamprenavir/ritonavir twice daily.  Appropriate doses of|
01289|021|M|fosamprenavir and efavirenz administered without ritonavir have not been|
01289|022|M|established.(1-3)|
01289|023|M|   Saquinavir should not be used as the sole protease inhibitor in patients|
01289|024|M|receiving efavirenz.(1,2)  Appropriate doses of the combination of efavirenz|
01289|025|M|and saquinavir mesylate/ritonavir have not been determined.(4)|
01289|026|B||
01289|027|D|DISCUSSION:  In a study in 16 subjects, concurrent use of efavirenz (600 mg|
01289|028|D|daily) with fosamprenavir (1400 mg daily) with ritonavir (200 mg daily)|
01289|029|D|decreased the amprenavir AUC and minimum concentration (Cmin) by 13% and|
01289|030|D|36%, respectively.  Administration of an additional 100 mg of ritonavir|
01289|031|D|daily increased amprenavir Cmax and AUC by 18% and 11%, respectively.(3)|
01289|032|D|   In a study in 16 subjects, concurrent use of efavirenz (600 mg daily)|
01289|033|D|with fosamprenavir (700 mg twice daily) with ritonavir (100 mg twice daily)|
01289|034|D|decreased amprenavir Cmin by 17% but had no effect on amprenavir AUC or|
01289|035|D|Cmax.(3)|
01289|036|D|   In a study in 12 subjects, concurrent use of efavirenz (600 mg daily)|
01289|037|D|with saquinavir (1200 mg every 8 hours) decreased the saquinavir AUC, Cmax,|
01289|038|D|and Cmin by 62%, 50%, and 56%, respectively.  Efavirenz AUC, Cmax, and Cmin|
01289|039|D|were decreased by 12%, 13%, and 14%, respectively.(1,4)|
01289|040|B||
01289|041|R|REFERENCES:|
01289|042|B||
01289|043|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01289|044|R|  Company November, 2023.|1
01289|045|R|2.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01289|046|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01289|047|R|3.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01289|048|R|  March, 2019.|1
01289|049|R|4.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01289|050|R|  Laboratories, Inc. March, 2019.|1
01290|001|T|MONOGRAPH TITLE:  Amprenavir; Atazanavir/Antacids; Buffered Formulations|
01290|002|B||
01290|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01290|004|L|take action as needed.|
01290|005|B||
01290|006|A|MECHANISM OF ACTION:  Antacids increase gastric pH.  As gastric pH|
01290|007|A|increases, the solubility of atazanavir decreases.(1,2)  The exact mechanism|
01290|008|A|behind the interaction between amprenavir and antacids is unknown.|
01290|009|B||
01290|010|E|CLINICAL EFFECTS:  Simultaneous administration of amprenavir or atazanavir|
01290|011|E|with antacids or buffered formulations may result in decreased levels and|
01290|012|E|effectiveness of amprenavir(3) and atazanavir.(1,2)|
01290|013|B||
01290|014|P|PREDISPOSING FACTORS:  None determined.|
01290|015|B||
01290|016|M|PATIENT MANAGEMENT:  The manufacturer of amprenavir states that amprenavir|
01290|017|M|should be administered 1 hour before or after antacids or buffered|
01290|018|M|formulations such as didanosine.(3)|
01290|019|M|   The manufacturer of atazanavir states that atazanavir should be|
01290|020|M|administered 2 hours before or 1 hour after antacids or buffered|
01290|021|M|formulations.(1,2)|
01290|022|M|   Some vitamin preparations may contain sufficient quantities of calcium|
01290|023|M|and/or magnesium salts with antacid properties to interact as well.|
01290|024|B||
01290|025|D|DISCUSSION:  Simultaneous administration of atazanavir with didanosine|
01290|026|D|buffered tablets decreased atazanavir area-under-curve (AUC), maximum|
01290|027|D|concentration (Cmax) and minimum concentration (Cmin) by 87%, 89% and 84%,|
01290|028|D|respectively.  Administration of atazanavir 1 hour after didanosine buffered|
01290|029|D|tablets had no significant effect on atazanavir pharmacokinetics.(1)|
01290|030|D|   Other buffered formulations and antacids are expected to substantially|
01290|031|D|decrease atazanavir concentrations and therapeutic effectiveness as|
01290|032|D|well.(1,2)|
01290|033|B||
01290|034|R|REFERENCES:|
01290|035|B||
01290|036|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01290|037|R|  Squibb Company December, 2024.|1
01290|038|R|2.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01290|039|R|  Squibb Pharmaceuticals October 25, 2023.|1
01290|040|R|3.Agenerase (amprenavir) Oral Solution US prescribing information.|1
01290|041|R|  GlaxoSmithKline May, 2005.|1
01291|001|T|MONOGRAPH TITLE:  Slt Calcium Channel|
01291|002|T|Blockers/Atazanavir;Darunavir;Fosamprenavir|
01291|003|B||
01291|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01291|005|L|take action as needed.|
01291|006|B||
01291|007|A|MECHANISM OF ACTION:  Atazanavir, darunavir, and fosamprenavir may inhibit|
01291|008|A|the CYP3A4-mediated metabolism of calcium channel blockers.(1-5)|
01291|009|B||
01291|010|E|CLINICAL EFFECTS:  Concurrent use of atazanavir, darunavir, or fosamprenavir|
01291|011|E|may result in increased levels of calcium channel blockers.|
01291|012|E|   The combination of atazanavir with non-dihydropyridines may result in an|
01291|013|E|additive effect on the PR interval.(1-2,6-7)|
01291|014|B||
01291|015|P|PREDISPOSING FACTORS:  None determined.|
01291|016|B||
01291|017|M|PATIENT MANAGEMENT:  The US Department of Health and Human Services HIV|
01291|018|M|guidelines recommend that concurrent use of calcium channel blockers with|
01291|019|M|protease inhibitors be monitored closely.  The dose of the calcium channel|
01291|020|M|blocker should be titrated to clinical response and adverse events.(5)|
01291|021|M|   Additional recommendations apply to patients on atazanavir.  EKG|
01291|022|M|monitoring is recommended for patients on concurrent therapy with calcium|
01291|023|M|channel blockers.  A dose reduction of diltiazem by 50% should be considered|
01291|024|M|for patients starting atazanavir.(1,2,5)|
01291|025|B||
01291|026|D|DISCUSSION:  In a study in 28 subjects, concurrent atazanavir (400 mg daily)|
01291|027|D|with diltiazem (180 mg daily) increased the diltiazem area-under-curve (AUC)|
01291|028|D|and maximum concentration (Cmax) by 225% and 98%, respectively.(1,2)|
01291|029|D|Diltiazem minimum concentration (Cmin) increased by 242%.  The Cmax, AUC,|
01291|030|D|and Cmin of desacetyl-diltiazem increased by 272%, 265%, and 221%,|
01291|031|D|respectively.  There were no significant effects on atazanavir levels.(1)|
01291|032|B||
01291|033|R|REFERENCES:|
01291|034|B||
01291|035|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01291|036|R|  Squibb Company December, 2024.|1
01291|037|R|2.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01291|038|R|  Squibb Pharmaceuticals October 25, 2023.|1
01291|039|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01291|040|R|  August, 2021.|1
01291|041|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01291|042|R|  March, 2019.|1
01291|043|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01291|044|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01291|045|R|  HIV. Department of Health and Human Services. Available at:|6
01291|046|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
01291|047|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
01291|048|R|6.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
01291|049|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
01291|050|R|7.Covera-HS (verapamil hydrochloride) US prescribing information. G.D.|1
01291|051|R|  Searle LLC September, 2017.|1
01292|001|T|MONOGRAPH TITLE:  Atazanavir/H2 Antagonists|
01292|002|B||
01292|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01292|004|L|take action as needed.|
01292|005|B||
01292|006|A|MECHANISM OF ACTION:  H-2 antagonists increase gastric pH.  As gastric pH|
01292|007|A|increases, the solubility of atazanavir decreases.(1,2)|
01292|008|B||
01292|009|E|CLINICAL EFFECTS:  Concurrent use of atazanavir and a H-2 antagonist may|
01292|010|E|result in decreased levels and effectiveness of atazanavir.(1,2)|
01292|011|B||
01292|012|P|PREDISPOSING FACTORS:  None determined.|
01292|013|B||
01292|014|M|PATIENT MANAGEMENT:  The Australian and US manufacturers of atazanavir(1,2)|
01292|015|M|and cobicistat(3,4) state that patients who require H-2 antagonist therapy|
01292|016|M|should receive atazanavir 300 mg daily with ritonavir 100 mg daily or|
01292|017|M|cobicistat 150 mg daily, taken with and/or at least 10 hours after the H-2|
01292|018|M|antagonist dose.  Patients who are also on tenofovir in addition to|
01292|019|M|atazanavir and a H-2 antagonist should receive atazanavir 400 mg daily with|
01292|020|M|ritonavir 100 mg daily or cobicistat 150 mg daily.(2,3,5)  The dose of the|
01292|021|M|H-2 antagonist should not exceed the equivalent of famotidine 40 mg twice|
01292|022|M|daily in treatment-naive patients, and 20 mg twice daily in|
01292|023|M|treatment-experienced patients.(2-5)|
01292|024|M|   Treatment-experienced pregnant patients in the second or third trimester|
01292|025|M|on concurrent tenofovir disoproxil should have their atazanavir dose|
01292|026|M|increased to 400 mg with ritonavir 100 mg daily.  The use of atazanavir with|
01292|027|M|both a H2-antagonist and tenofovir in treatment-experienced pregnant women|
01292|028|M|is not recommended.(2)|
01292|029|M|   The Australian manufacturer of atazanavir states that atazanavir without|
01292|030|M|ritonavir is not recommended when co-administered with H-2 antagonists.(1)|
01292|031|M|   The US manufacturer of atazanavir states that treatment-naive patients|
01292|032|M|who are unable to tolerate ritonavir or cobicistat should receive atazanavir|
01292|033|M|400 mg daily with food at least 2 hours before and at least 10 hours after|
01292|034|M|the H-2 antagonist.  The H-2 antagonist dose should not exceed the|
01292|035|M|equivalent of a 20 mg single dose of famotidine and the total daily dose|
01292|036|M|should not exceed a 40 mg equivalent dose of famotidine.|
01292|037|M|Treatment-experienced patients should not use unboosted atazanavir with a|
01292|038|M|H-2 antagonist.(2)|
01292|039|M|   The US manufacturer of atazanavir states that atazanavir should not be|
01292|040|M|administered without ritonavir in pediatric patients at least 13 years of|
01292|041|M|age who weigh at least 40 kg who are receiving a H2 antagonist.  Data are|
01292|042|M|not sufficient to recommend a dose of atazanavir in patients weighing less|
01292|043|M|than 40 kg.(2)|
01292|044|B||
01292|045|D|DISCUSSION:  In a study in 15 subjects, simultaneous administration of|
01292|046|D|atazanavir (400 mg daily) with famotidine (40 mg twice daily) decreased the|
01292|047|D|atazanavir maximum concentration (Cmax), area-under-curve (AUC), and minimum|
01292|048|D|concentration (Cmin) by 47%, 41%, and 42%, respectively.(2)|
01292|049|D|   In a study in 14 subjects, atazanavir (400 mg daily) was administered 2|
01292|050|D|hours before and 10 hours after famotidine (40 mg twice daily).  Atazanavir|
01292|051|D|Cmax increased 8%.  Atazanavir AUC and Cmin decreased by 5% and 21%,|
01292|052|D|respectively.(2)|
01292|053|D|   In a study in 14 subjects, atazanavir (300 mg daily) and ritonavir (100|
01292|054|D|mg daily) were administered simultaneously with famotidine (40 mg twice|
01292|055|D|daily).  Atazanavir Cmax, AUC, and Cmin decreased by 14%, 18%, and 28%,|
01292|056|D|respectively, compared to the same regimen alone.  However, atazanavir Cmax|
01292|057|D|was similar to levels seen with atazanavir 400 mg alone.  Atazanavir AUC and|
01292|058|D|Cmin were 1.79-fold and 4.46-fold higher than levels seen with atazanavir|
01292|059|D|400 mg alone.(2)|
01292|060|D|   In a study in 18 subjects, simultaneous administration of famotidine (20|
01292|061|D|mg twice daily) and atazanavir/ritonavir (300/100 mg daily) decreased the|
01292|062|D|Cmax, AUC, and Cmin of atazanavir by 9%, 10%, and 19%, respectively.(2)|
01292|063|D|   In a study in 20 subjects, administration of|
01292|064|D|atazanavir/ritonavir/tenofovir (300/100/300 mg daily) 12 hours after|
01292|065|D|famotidine (40 mg daily) decreased the Cmax, AUC, and Cmin of atazanavir by|
01292|066|D|11%, 12%, and 23%, respectively.(2)|
01292|067|D|   In a study in 18 subjects, administration of|
01292|068|D|atazanavir/ritonavir/tenofovir (300/100/300 mg daily) 12 hours after the|
01292|069|D|evening dose and two hours before the morning dose of famotidine (40 mg|
01292|070|D|twice daily) decreased the Cmax, AUC, and Cmin of atazanavir by 26%, 21%,|
01292|071|D|and 28%, respectively.(2)|
01292|072|D|   In a study in 15 subjects, administration of atazanavir/ritonavir|
01292|073|D|(400/100 mg) with famotidine (40 mg twice daily) decreased atazanavir Cmin|
01292|074|D|by 14%.  There were no significant effects on atazanavir Cmax or AUC.(2)|
01292|075|B||
01292|076|R|REFERENCES:|
01292|077|B||
01292|078|R|1.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01292|079|R|  Squibb Pharmaceuticals October 25, 2023.|1
01292|080|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01292|081|R|  Squibb Company December, 2024.|1
01292|082|R|3.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
01292|083|R|  June, 2025.|1
01292|084|R|4.Evotaz (atazanavir and cobicistat) US prescribing information.|1
01292|085|R|  Bristol-Myers-Squibb Company May, 2025.|1
01292|086|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01292|087|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01292|088|R|  HIV. Department of Health and Human Services. Available at|6
01292|089|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
01292|090|R|  new-guidelines June 13, 2021.|6
01293|001|T|MONOGRAPH TITLE:  Atazanavir/Tenofovir disoproxil|
01293|002|B||
01293|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01293|004|L|take action as needed.|
01293|005|B||
01293|006|A|MECHANISM OF ACTION:  Tenofovir disoproxil may induce the metabolism of|
01293|007|A|atazanavir.(1) It is unknown how atazanavir increases tenofovir disoproxil|
01293|008|A|levels.(2)|
01293|009|B||
01293|010|E|CLINICAL EFFECTS:  Concurrent use of atazanavir and tenofovir disoproxil|
01293|011|E|without concurrent ritonavir or cobicistat may result in decreased levels|
01293|012|E|and effectiveness of atazanavir.(1-3)  Concurrent use of atazanavir may|
01293|013|E|result in increased levels and toxicity from tenofovir disoproxil.(2)|
01293|014|B||
01293|015|P|PREDISPOSING FACTORS:  None determined.|
01293|016|B||
01293|017|M|PATIENT MANAGEMENT:  The US manufacturer of atazanavir states that patients|
01293|018|M|on concurrent tenofovir disoproxil 300 mg daily should receive atazanavir|
01293|019|M|300 mg and ritonavir 100 mg once daily all as a single daily dose with food.|
01293|020|M|Treatment-experienced patients on both tenofovir disoproxil and a H-2|
01293|021|M|antagonist should have their atazanavir dose increased to 400 mg with|
01293|022|M|ritonavir 100 mg daily.  Treatment-experienced pregnant patients in the|
01293|023|M|second or third trimester on concurrent tenofovir disoproxil should also|
01293|024|M|have their atazanavir dose increased to 400 mg with ritonavir 100 mg|
01293|025|M|daily.(1)|
01293|026|M|   Atazanavir should not be administered with tenofovir disoproxil without|
01293|027|M|concurrent ritonavir in adults or pediatric patients of at least 13 years of|
01293|028|M|age and weighing at least 40 kg.(1-3)|
01293|029|M|   There are no data to recommend a dose of atazanavir with tenofovir|
01293|030|M|disoproxil in pediatric patients weighing less than 40 kg.(1)|
01293|031|M|   Patients receiving concurrent therapy should be monitored for tenofovir|
01293|032|M|associated adverse events and tenofovir should be discontinued in patients|
01293|033|M|who experience adverse events.(1-2)|
01293|034|M|   The combination product containing efavirenz/emtricitabine/tenofovir|
01293|035|M|disoproxil is not recommended for use in patients receiving atazanavir.(4)|
01293|036|M|   No dosage adjustment is required with the use of tenofovir|
01293|037|M|alafenamide.(5)|
01293|038|B||
01293|039|D|DISCUSSION:  In a study in healthy subjects, concurrent atazanavir (400 mg|
01293|040|D|daily) with tenofovir disoproxil fumarate (300 mg daily) decreased|
01293|041|D|atazanavir area-under-curve (AUC), maximum concentration (Cmax), and minimum|
01293|042|D|concentration (Cmin) by 25%, 21%, and 40%, respectively.   The AUC, Cmax,|
01293|043|D|and Cmin of tenofovir increased by 24%, 14%, and 22%, respectively.(1,2)|
01293|044|D|   In another study, atazanavir AUC, Cmax, and Cmin decreased by 25%, 28%,|
01293|045|D|and 23%, respectively, when atazanavir (300 mg daily), ritonavir (100 mg|
01293|046|D|daily), and tenofovir disoproxil fumarate (300 mg daily) were|
01293|047|D|coadministered, when compared to the administration of atazanavir and|
01293|048|D|ritonavir alone. However, these decreased levels were approximately 2.3-fold|
01293|049|D|and 4-fold higher that the respective values for atazanavir (400 mg daily)|
01293|050|D|alone.(1,2)  Interim data suggests that rate of moderate or severe adverse|
01293|051|D|effects is similar between atazanavir-treated patients and unboosted|
01293|052|D|atazanavir-treated patients.(1)|
01293|053|D|    In a study of 12 subjects, the AUC, Cmax and Cmin of tenofovir|
01293|054|D|disoproxil fumarate (300 mg daily) increased 37%, 34% and 29% respectively,|
01293|055|D|when given with atazanavir (300 mg daily) and ritonavir (100 mg daily).(1)|
01293|056|D|   Because both efavirenz and tenofovir disoproxil decrease atazanavir|
01293|057|D|concentrations and the effect of taking both on atazanavir pharmacokinetics|
01293|058|D|has not been studied, the use of atazanavir with the combination product|
01293|059|D|efavirenz/emtricitabine/tenofovir disoproxil is not recommended.(4)|
01293|060|B||
01293|061|R|REFERENCES:|
01293|062|B||
01293|063|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01293|064|R|  Squibb Company December, 2024.|1
01293|065|R|2.Truvada (emtricitabine/tenofovir disoproxil fumarate) US prescribing|1
01293|066|R|  information. Gilead Sciences, Inc. June, 2020.|1
01293|067|R|3.Viread (tenofovir disoproxil fumarate) US prescribing information. Gilead|1
01293|068|R|  Sciences, Inc. December, 2018.|1
01293|069|R|4.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01293|070|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01293|071|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01293|072|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01293|073|R|  HIV. Department of Health and Human Services. Available at|6
01293|074|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
01293|075|R|  new-guidelines June 13, 2021.|6
01294|001|T|MONOGRAPH TITLE:  Ibutilide/Class IA and III Antiarrhythmics|
01294|002|B||
01294|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01294|004|L|is contraindicated and generally should not be dispensed or administered to|
01294|005|L|the same patient.|
01294|006|B||
01294|007|A|MECHANISM OF ACTION:  Concurrent use of ibutilide with Class IA or III|
01294|008|A|antiarrhythmics may result in additive or synergistic effects on the QTc|
01294|009|A|interval.(1)|
01294|010|B||
01294|011|E|CLINICAL EFFECTS:  Concurrent use of ibutilide with Class IA or III|
01294|012|E|antiarrhythmics may result in life-threatening ventricular arrhythmias,|
01294|013|E|including torsades de pointes.(1)|
01294|014|B||
01294|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01294|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01294|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01294|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01294|019|P|female gender, or advanced age.(4)|
01294|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01294|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01294|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01294|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01294|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01294|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01294|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01294|027|B||
01294|028|M|PATIENT MANAGEMENT:  The manufacturer of ibutilide states that Class IA or|
01294|029|M|III antiarrhythmics should not be used concomitantly with ibutilide or|
01294|030|M|within 4 hours post-infusion.(1)|
01294|031|M|   If concurrent therapy is deemed medically necessary, obtain serum|
01294|032|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
01294|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01294|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01294|035|B||
01294|036|D|DISCUSSION:  In clinical trials, Class IA and III antiarrhythmics were|
01294|037|D|withheld for 5 half-lives prior to the administration of ibutilide and for 4|
01294|038|D|hours after.(1)|
01294|039|D|   In separate clinical trials, concomitant use of ibutilide with amiodarone|
01294|040|D|resulted in significantly prolonged QTc intervals.(2,3)|
01294|041|D|   One or more of the drug pairs linked to this monograph have been included|
01294|042|D|in a list of interactions that should be considered "high-priority" for|
01294|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01294|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01294|045|D|Coordinator (ONC) for Health Information Technology.|
01294|046|B||
01294|047|R|REFERENCES:|
01294|048|B||
01294|049|R|1.Corvert (ibutilide fumarate) US prescribing information. Pharmacia &|1
01294|050|R|  Upjohn Company July, 2002.|1
01294|051|R|2.Fragakis N, Papadopoulos N, Papanastasiou S, Kozirakis M, Maligkos G,|2
01294|052|R|  Tsaritsaniotis E, Katsaris G. Efficacy and safety of ibutilide for|2
01294|053|R|  cardioversion of atrial flutter and fibrillation in patients receiving|2
01294|054|R|  amiodarone or propafenone. Pacing Clin Electrophysiol 2005 Sep;|2
01294|055|R|  28(9):954-61.|2
01294|056|R|3.Glatter K, Yang Y, Chatterjee K, Modin G, Cheng J, Kayser S, Scheinman MM.|2
01294|057|R|  Chemical cardioversion of atrial fibrillation or flutter with ibutilide in|2
01294|058|R|  patients receiving amiodarone therapy. Circulation 2001 Jan 16;|2
01294|059|R|  103(2):253-7.|2
01294|060|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01294|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01294|062|R|  settings: a scientific statement from the American Heart Association and|6
01294|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01294|064|R|  2;55(9):934-47.|6
01294|065|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01294|066|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01294|067|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01294|068|R|  19(5):735-43.|6
01295|001|T|MONOGRAPH TITLE:  Quetiapine/Selected Azole Antifungals (mono deleted|
01295|002|T|06/19/2014)|
01295|003|B||
01295|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01295|005|L|take action as needed.|
01295|006|B||
01295|007|A|MECHANISM OF ACTION:  Azole antifungals may inhibit the metabolism of|
01295|008|A|quetiapine by CYP P-450-3A4.(1)|
01295|009|B||
01295|010|E|CLINICAL EFFECTS:  Concurrent use of azole antifungals and quetiapine may|
01295|011|E|result in elevated levels of and toxicity from quetiapine.(1)|
01295|012|B||
01295|013|P|PREDISPOSING FACTORS:  None determined.|
01295|014|B||
01295|015|M|PATIENT MANAGEMENT:  The manufacturer of quetiapine states that quetiapine|
01295|016|M|dosage adjustments are required in patients receiving concurrent|
01295|017|M|fluconazole, itraconazole, or ketoconazole.(1)|
01295|018|B||
01295|019|D|DISCUSSION:  In a study, concurrent use of ketoconazole (200 mg daily for 4|
01295|020|D|days) and quetiapine resulted in an increase in quetiapine Cmax and AUC by|
01295|021|D|3.35-fold and 6.2-fold, respectively. Ketoconazole also decreased the mean|
01295|022|D|apparent oral clearance of quetiapine by 84%, and increased quetiapine mean|
01295|023|D|elimination half-life by 2.6-fold.(1,2)|
01295|024|B||
01295|025|R|REFERENCES:|
01295|026|B||
01295|027|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
01295|028|R|  Pharmaceuticals LP July, 2011.|1
01295|029|R|2.Grimm SW, Richtand NM, Winter HR, Stams KR, Reele SB. Effects of|2
01295|030|R|  cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine|2
01295|031|R|  pharmacokinetics. Br J Clin Pharmacol 2006 Jan;61(1):58-69.|2
01296|001|T|MONOGRAPH TITLE:  Selected Antipsychotics/Strong CYP3A4 Inducers|
01296|002|B||
01296|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01296|004|L|of severe adverse interaction.|
01296|005|B||
01296|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
01296|007|A|clearance of aripiprazole(1), brexpiprazole(2), and risperidone.(3)|
01296|008|B||
01296|009|E|CLINICAL EFFECTS:  Strong CYP3A4 inducers may result in decreased levels and|
01296|010|E|effectiveness of aripiprazole, brexpiprazole, and risperidone.(1-3)|
01296|011|B||
01296|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01296|013|P|of the inducer for longer than 1-2 weeks.|
01296|014|B||
01296|015|M|PATIENT MANAGEMENT:  The dose of immediate release aripiprazole should be|
01296|016|M|doubled over 1-2 weeks if a CYP3A4 inducer is added to aripiprazole therapy.|
01296|017|M|Additional dosage increases should be based on clinical observation of the|
01296|018|M|patient.  If the inducer is withdrawn from concurrent therapy, the dosage of|
01296|019|M|aripiprazole should be gradually reduced to the original level over 1-2|
01296|020|M|weeks.(1)|
01296|021|M|   The dose of brexpiprazole should be doubled over 1-2 weeks in patients|
01296|022|M|taking strong CYP3A4 inducers.  If the inducer is discontinued, reduce the|
01296|023|M|dosage of brexpiprazole to the original level over 1-2 weeks.(2)|
01296|024|M|   The US manufacturer of risperidone (Risperdal) recommends that patients|
01296|025|M|increase the dose of risperidone up to double the patient's usual dose when|
01296|026|M|taken concurrently with a CYP3A4 inducer.  Do not exceed twice the patient's|
01296|027|M|usual dose. It may be necessary to decrease the risperidone dose when the|
01296|028|M|CYP3A4 inducer is discontinued.(3)|
01296|029|B||
01296|030|D|DISCUSSION:  The concurrent administration of carbamazepine (200 mg twice|
01296|031|D|daily) with aripiprazole (30 mg daily) resulted in 70% decreases in the|
01296|032|D|area-under-curve (AUC) and maximum concentration (Cmax) of both aripiprazole|
01296|033|D|and dehydro-aripiprazole, its active metabolite.(1)|
01296|034|D|   Rifampin decreased the AUC of brexpiprazole by approximately 75%.(2)|
01296|035|D|   A study in 11 schizophrenic inpatients examined the effects of the|
01296|036|D|addition of carbamazepine (200 mg twice daily) for one week to risperidone|
01296|037|D|(3 mg twice daily).  Concurrent carbamazepine decreased plasma|
01296|038|D|concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by|
01296|039|D|50%, 44%, and 45%, respectively.(4)|
01296|040|D|   A study compared 23 patients receiving risperidone alone to 11 patients|
01296|041|D|receiving concurrent risperidone and carbamazepine.  The groups were matched|
01296|042|D|for sex, age, body weight, and risperidone dosage.  Plasma concentrations of|
01296|043|D|9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone|
01296|044|D|were significantly lower in patients receiving concurrent carbamazepine.|
01296|045|D|Five subjects received risperidone with and without carbamazepine.  In these|
01296|046|D|patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone|
01296|047|D|concentrations were lower during concurrent carbamazepine.(5)|
01296|048|D|   In a case report, a patient developed an exacerbation of psychotic|
01296|049|D|symptoms four weeks after the addition of carbamazepine (800 mg daily) to|
01296|050|D|his regimen.  Plasma levels of risperidone and 9-hydroxyrisperidone had|
01296|051|D|decreased by 77% and 63%, respectively.(6)|
01296|052|D|   In an open, randomized cross-over study in 10 healthy males, pretreatment|
01296|053|D|with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC)|
01296|054|D|and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg)|
01296|055|D|by 72% and 50%, respectively.(7)|
01296|056|D|   In a study in 10 healthy males, pretreatment with rifampin (600 mg daily|
01296|057|D|for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone|
01296|058|D|(1 mg) by 51% and 38%, respectively.  The AUC of 9-hydroxyrisperidone and|
01296|059|D|the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43%|
01296|060|D|and 45%, respectively.  The Cmax of 9-hydroxyrisperidone and the active|
01296|061|D|moieties decreased by 46% and 41%, respectively.(8)|
01296|062|D|   Strong CYP3A4 inducers linked to this monograph are:  apalutamide,|
01296|063|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
01296|064|D|mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St.|
01296|065|D|John's Wort.(9,10)|
01296|066|B||
01296|067|R|REFERENCES:|
01296|068|B||
01296|069|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
01296|070|R|  Pharmaceutical, Inc. August, 2019.|1
01296|071|R|2.Rexulti (brexpiprazole) US prescribing information. Otsuka Pharmaceutical|1
01296|072|R|  Co., Ltd. June, 2020.|1
01296|073|R|3.Risperdal (risperidone) US prescribing information. Janssen Pharmaceutical|1
01296|074|R|  Ltd. February 2021.|1
01296|075|R|4.Ono S, Mihara K, Suzuki A, Kondo T, Yasui-Furukori N, Furukori H, de Vries|2
01296|076|R|  R, Kaneko S. Significant pharmacokinetic interaction between risperidone|2
01296|077|R|  and carbamazepine: its relationship with CYP2D6 genotypes.|2
01296|078|R|  Psychopharmacology (Berl) 2002 Jun;162(1):50-4.|2
01296|079|R|5.Spina E, Avenoso A, Facciola G, Salemi M, Scordo MG, Giacobello T, Madia|2
01296|080|R|  AG, Perucca E. Plasma concentrations of risperidone and|2
01296|081|R|  9-hydroxyrisperidone: effect of comedication with carbamazepine or|2
01296|082|R|  valproate. Ther Drug Monit 2000 Aug;22(4):481-5.|2
01296|083|R|6.Mahatthanatrakul W, Nontaput T, Ridtitid W, Wongnawa M, Sunbhanich M.|2
01296|084|R|  Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of|2
01296|085|R|  antipsychotic risperidone in healthy volunteers. J Clin Pharm Ther 2007|2
01296|086|R|  Apr;32(2):161-7.|2
01296|087|R|7.Spina E, Scordo MG, Avenoso A, Perucca E. Adverse drug interaction between|3
01296|088|R|  risperidone and carbamazepine in a patient with chronic schizophrenia and|3
01296|089|R|  deficient CYP2D6 activity. J Clin Psychopharmacol 2001 Feb;21(1):108-9.|3
01296|090|R|8.Kim KA, Park PW, Liu KH, Kim KB, Lee HJ, Shin JG, Park JY. Effect of|2
01296|091|R|  rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics|2
01296|092|R|  of risperidone. J Clin Pharmacol 2008 Jan;48(1):66-72.|2
01296|093|R|9.US Food and Drug Administration (FDA). Drug Development and Drug|1
01296|094|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01296|095|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01296|096|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01296|097|R|  11/14/2017.|1
01296|098|R|10.This information is based on an extract from the Certara Drug Interaction|6
01296|099|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01297|001|T|MONOGRAPH TITLE:  Influenza Virus Vaccine Live/Salicylates|
01297|002|B||
01297|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01297|004|L|of severe adverse interaction.|
01297|005|B||
01297|006|A|MECHANISM OF ACTION:  Use of salicylates during influenza infection has been|
01297|007|A|associated with Reye's Syndrome.(1,2)|
01297|008|B||
01297|009|E|CLINICAL EFFECTS:  Use of the live influenza virus vaccine in children and|
01297|010|E|adolescents (patients age 2-17 years) receiving salicylate therapy may|
01297|011|E|increase the risk of Reye's Syndrome.(1,2)  Symptoms of Reye's syndrome|
01297|012|E|include drowsiness, confusion, seizures, coma.  In severe cases, Reye's|
01297|013|E|syndrome can result in death.|
01297|014|B||
01297|015|P|PREDISPOSING FACTORS:  None determined.|
01297|016|B||
01297|017|M|PATIENT MANAGEMENT:  The use of live influenza virus vaccine in children and|
01297|018|M|adolescents (patients age 2-17 years) receiving salicylate therapy is|
01297|019|M|contraindicated.(1,2) Use of salicylates should be avoided for 4 weeks after|
01297|020|M|administration of live influenza vaccine.(1)|
01297|021|B||
01297|022|D|DISCUSSION:  Because the use of salicylates during influenza infection has|
01297|023|D|been associated with Reye's Syndrome, the use of live influenza virus|
01297|024|D|vaccine in children and adolescents (patients age 2-17 years) receiving|
01297|025|D|salicylate therapy is contraindicated.(1,2)|
01297|026|B||
01297|027|R|REFERENCES:|
01297|028|B||
01297|029|R|1.FluMist (influenza virus vaccine live, intranasal) US prescribing|1
01297|030|R|  information. MedImmune LLC July, 2010.|1
01297|031|R|2.Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal US prescribing|1
01297|032|R|  information. MedImmune, LLC September, 2009.|1
01298|001|T|MONOGRAPH TITLE:  Aldesleukin/Glucocorticoids|
01298|002|B||
01298|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01298|004|L|of severe adverse interaction.|
01298|005|B||
01298|006|A|MECHANISM OF ACTION:  Corticosteroids may suppress interleukin-2-induced|
01298|007|A|tumor necrosis factor (TNF) synthesis.(1)|
01298|008|B||
01298|009|E|CLINICAL EFFECTS:  Concurrent use of corticosteroids may reduce the|
01298|010|E|antitumor effectiveness of aldesleukin.(2)|
01298|011|B||
01298|012|P|PREDISPOSING FACTORS:  None determined.|
01298|013|B||
01298|014|M|PATIENT MANAGEMENT:  The manufacturer of aldesleukin states that concurrent|
01298|015|M|administration of corticosteroids and aldesleukin should be avoided.(2)|
01298|016|B||
01298|017|D|DISCUSSION:  Corticosteroids have been shown to reduce aldesleukin-related|
01298|018|D|side effects such as fever, renal insufficiency, hyperbilirubinemia,|
01298|019|D|confusion, and dyspnea.(1,2)  However, dexamethasone has been shown to|
01298|020|D|reduce aldesleukin-induced TNF synthesis.(1)|
01298|021|B||
01298|022|R|REFERENCES:|
01298|023|B||
01298|024|R|1.Mier JW, Vachino G, Klempner MS, Aronson FR, Noring R, Smith S, Brandon|2
01298|025|R|  EP, Laird W, Atkins MB. Inhibition of interleukin-2-induced tumor necrosis|2
01298|026|R|  factor release by dexamethasone: prevention of an acquired neutrophil|2
01298|027|R|  chemotaxis defect and differential suppression of interleukin-2-associated|2
01298|028|R|  side effects. Blood 1990 Nov 15;76(10):1933-40.|2
01298|029|R|2.Proleukin (aldesleukin) US prescribing information. Prometheus|1
01298|030|R|  Laboratories, Inc. July, 2012.|1
01299|001|T|MONOGRAPH TITLE:  Delavirdine/Amprenavir; Fosamprenavir|
01299|002|B||
01299|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01299|004|L|is contraindicated and generally should not be dispensed or administered to|
01299|005|L|the same patient.|
01299|006|B||
01299|007|A|MECHANISM OF ACTION:  Amprenavir which may induce the metabolism of|
01299|008|A|delavirdine by CYP3A4.(1,2)  Fosamprenavir is a prodrug of amprenavir.(2)|
01299|009|B||
01299|010|E|CLINICAL EFFECTS:  Concurrent administration of amprenavir or fosamprenavir|
01299|011|E|and delavirdine may result in decreased levels of, decreased clinical|
01299|012|E|effectiveness of, and possible resistance to delavirdine.(1,2)|
01299|013|B||
01299|014|P|PREDISPOSING FACTORS:  None determined.|
01299|015|B||
01299|016|M|PATIENT MANAGEMENT:  The manufacturer of amprenavir(1) states that|
01299|017|M|delavirdine should not be coadministered with amprenavir.|
01299|018|M|   The manufacturer of fosamprenavir states that concurrent use of|
01299|019|M|delavirdine is contraindicated.(2)|
01299|020|B||
01299|021|D|DISCUSSION:  In a study in 9 subjects, concurrent amprenavir (600 mg twice|
01299|022|D|daily) and delavirdine (600 mg twice daily) increased the amprenavir maximum|
01299|023|D|concentration (Cmax), area-under-curve (AUC), and minimum concentration|
01299|024|D|(Cmin) by 40%, 130%, and 125%, respectively.  The delavirdine Cmax, AUC, and|
01299|025|D|Cmin were decreased by 47%, 61%, and 88%, respectively.(1,2)|
01299|026|B||
01299|027|R|REFERENCES:|
01299|028|B||
01299|029|R|1.Agenerase (amprenavir) Oral Solution US prescribing information.|1
01299|030|R|  GlaxoSmithKline May, 2005.|1
01299|031|R|2.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01299|032|R|  March, 2019.|1
01300|001|T|MONOGRAPH TITLE:  Vardenafil (Less Than or Equal To 2.5 mg)/Selected|
01300|002|T|Protease Inhibitors|
01300|003|B||
01300|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01300|005|L|take action as needed.|
01300|006|B||
01300|007|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01300|008|A|vardenafil by CYP3A4.|
01300|009|B||
01300|010|E|CLINICAL EFFECTS:  Concurrent use of vardenafil with protease inhibitors may|
01300|011|E|result in increased levels of and adverse effects from vardenafil, including|
01300|012|E|hypotension, visual changes, and sustained erections.|
01300|013|B||
01300|014|P|PREDISPOSING FACTORS:  None determined.|
01300|015|B||
01300|016|M|PATIENT MANAGEMENT:  US guidelines for the use of antiretroviral agents|
01300|017|M|recommends patients receiving protease inhibitors should receive no more|
01300|018|M|than 2.5 mg of vardenafil every 72 hours.|
01300|019|M|   US labeling recommendations for concurrent use of vardenafil with|
01300|020|M|protease inhibitors state:|
01300|021|M|   -Patients receiving any ritonavir- or cobicistat-containing regimens,|
01300|022|M|including atazanavir, darunavir, fosamprenavir, indinavir, lopinavir,|
01300|023|M|nirmatrelvir, paritaprevir, saquinavir, and tipranavir should receive no|
01300|024|M|more than 2.5 mg of vardenafil every 72 hours.|
01300|025|M|   -Patients receiving unboosted atazanavir, unboosted fosamprenavir,|
01300|026|M|unboosted indinavir, or nelfinavir should take no more than 2.5 mg of|
01300|027|M|vardenafil every 24 hours.|
01300|028|M|   Canadian labeling contraindicates concurrent use of atazanavir/ritonavir,|
01300|029|M|lopinavir/ritonavir, and nirmatrelvir/ritonavir with vardenafil.(3,12,14)|
01300|030|M|   Patients should be counseled that they are at an increased risk of|
01300|031|M|vardenafil adverse effects, including hypotension, visual changes, and|
01300|032|M|priapism.|
01300|033|B||
01300|034|D|DISCUSSION:  Concurrent use of indinavir (800 mg three times daily) with|
01300|035|D|vardenafil (10 mg) increased the vardenafil area-under-curve (AUC) and|
01300|036|D|maximum concentration (Cmax) by 16-fold and 7-fold, respectively.|
01300|037|D|Vardenafil half-life increased 2-fold.  At 24-hours post-dose, vardenafil|
01300|038|D|levels fell to approximately 4% of vardenafil Cmax.  The AUC and Cmax of|
01300|039|D|indinavir decreased by 30% and 40%, respectively.|
01300|040|D|   Concurrent use of ritonavir (600 mg twice daily)with vardenafil (5 mg)|
01300|041|D|increased vardenafil AUC and Cmax by 49-fold and 13-fold, respectively.  The|
01300|042|D|half-life of vardenafil increased to 26 hours.  The ritonavir AUC and Cmax|
01300|043|D|decreased by 20%.|
01300|044|B||
01300|045|R|REFERENCES:|
01300|046|B||
01300|047|R|1.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
01300|048|R|  Bayer, Inc. October 24, 2006.|1
01300|049|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01300|050|R|  Squibb Company December, 2024.|1
01300|051|R|3.Reyataz (atazanavir) Canadian prescribing information. Bristol-Myers|1
01300|052|R|  Squibb Canada August 31, 2023.|1
01300|053|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01300|054|R|  March, 2023.|1
01300|055|R|5.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01300|056|R|  March, 2019.|1
01300|057|R|6.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01300|058|R|  Pharmaceuticals, Inc. September, 2016.|1
01300|059|R|7.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
01300|060|R|  Inc. December, 2004.|1
01300|061|R|8.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01300|062|R|  Laboratories, Inc. March, 2019.|1
01300|063|R|9.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01300|064|R|  Pharmaceuticals, Inc. April, 2024.|1
01300|065|R|10.Crixivan (indinavir sulfate) US prescribing information. Merck & Co.,|1
01300|066|R|   Inc. September, 2016.|1
01300|067|R|11.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01300|068|R|   Laboratories December, 2019.|1
01300|069|R|12.Kaletra (lopinavir/ritonavir) Canadian prescribing information. Abbott|1
01300|070|R|   Limited May 22, 2019.|1
01300|071|R|13.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01300|072|R|   information. Pfizer Inc. February, 2025.|1
01300|073|R|14.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
01300|074|R|   Monograph. Pfizer Canada ULC October, 2023.|1
01300|075|R|15.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
01300|076|R|   prescribing information. AbbVie Inc. December, 2019.|1
01300|077|R|16.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01300|078|R|   for the use of antiretroviral agents in adults and adolescents Living|6
01300|079|R|   with HIV. Department of Health and Human Services. Available at|6
01300|080|R|   https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats|6
01300|081|R|   -new-guidelines June 13, 2021.|6
01300|082|R|17.This information is based on an extract from the Certara Drug Interaction|6
01300|083|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01301|001|T|MONOGRAPH TITLE:  Atorvastatin/Selected Protease Inhibitors|
01301|002|B||
01301|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01301|004|L|take action as needed.|
01301|005|B||
01301|006|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01301|007|A|atorvastatin by CYP3A4.(1-5)|
01301|008|B||
01301|009|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors may result in|
01301|010|E|elevated levels of atorvastatin, which could result in rhabdomyolysis.(1-5)|
01301|011|B||
01301|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01301|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01301|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01301|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01301|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01301|017|P|transporter OATP1B1 may have increased statin concentrations and be|
01301|018|P|predisposed to myopathy or rhabdomyolysis.|
01301|019|B||
01301|020|M|PATIENT MANAGEMENT:  In patients receiving protease inhibitors, consider the|
01301|021|M|use of fluvastatin.|
01301|022|M|   If atorvastatin is used with a protease inhibitor, use the lowest dose|
01301|023|M|possible of the HMG-CoA reductase inhibitor with careful monitoring.(1-5)|
01301|024|B||
01301|025|D|DISCUSSION:  A study in 12 subjects found that lopinavir increased|
01301|026|D|atorvastatin maximum concentration (Cmax), area-under-curve (AUC), and|
01301|027|D|minimum concentration (Cmin) by 4.67-fold, 5.88-fold, and 2.28-fold,|
01301|028|D|respectively.  Atorvastatin had no clinically significant effect on|
01301|029|D|lopinavir pharmacokinetics.(5)|
01301|030|B||
01301|031|R|REFERENCES:|
01301|032|B||
01301|033|R|1.Agenerase (amprenavir) Capsules US prescribing information.|1
01301|034|R|  GlaxoSmithKline May, 2005.|1
01301|035|R|2.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
01301|036|R|  June, 2025.|1
01301|037|R|3.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01301|038|R|  September, 2016.|1
01301|039|R|4.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01301|040|R|  December, 2019.|1
01301|041|R|5.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
01301|042|R|  2020.|1
01302|001|T|MONOGRAPH TITLE:  Latanoprost/Thimerosal|
01302|002|B||
01302|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01302|004|L|take action as needed.|
01302|005|B||
01302|006|A|MECHANISM OF ACTION:  Latanoprost is physically incompatible with|
01302|007|A|thimerosal.|
01302|008|B||
01302|009|E|CLINICAL EFFECTS:  The simultaneous application of these products may result|
01302|010|E|in a precipitate forming in the eye.(1)|
01302|011|B||
01302|012|P|PREDISPOSING FACTORS:  None determined.|
01302|013|B||
01302|014|M|PATIENT MANAGEMENT:  Patients should be instructed to separate the|
01302|015|M|administration of latanoprost eye drops and other eye drops that contain|
01302|016|M|thimerosal by at least 5 minutes.(1)|
01302|017|B||
01302|018|D|DISCUSSION:  In vitro studies have shown that precipitation occurs when eye|
01302|019|D|drops containing thimerosal are mixed with latanoprost eye drops.(1)|
01302|020|B||
01302|021|R|REFERENCE:|
01302|022|B||
01302|023|R|1.Xalatan (latanoprost ophthalmic solution) US prescribing information.|1
01302|024|R|  Pharmacia & Upjohn Company September, 2020.|1
01303|001|T|MONOGRAPH TITLE:  Aspartame; Phenylalanine; Tyrosine/Nitisinone|
01303|002|B||
01303|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01303|004|L|of severe adverse interaction.|
01303|005|B||
01303|006|A|MECHANISM OF ACTION:  Aspartame contains phenylalanine, which is metabolized|
01303|007|A|into tyrosine.  Nitisinone prevents the breakdown of tyrosine.(1)|
01303|008|B||
01303|009|E|CLINICAL EFFECTS:  Elevated levels of tyrosine can cause vision changes|
01303|010|E|(cornea ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and|
01303|011|E|photophobia), skin problems (painful hyperkeratotic plaques on the soles and|
01303|012|E|palms), and nervous system toxicity (variable degrees of mental retardation|
01303|013|E|and developmental delay).|
01303|014|B||
01303|015|P|PREDISPOSING FACTORS:  None determined.|
01303|016|B||
01303|017|M|PATIENT MANAGEMENT:  Patients receiving nitisinone should following dietary|
01303|018|M|restrictions concerning the consumption of aspartame, phenylalanine, and|
01303|019|M|tyrosine, including medications that contain these ingredients.(1)|
01303|020|B||
01303|021|D|DISCUSSION:  In most patients, eye symptoms resulting from elevated tyrosine|
01303|022|D|levels were transient, lasting less than one week; however, six patients had|
01303|023|D|prolonged episodes lasting up to almost 2 years.(1)|
01303|024|B||
01303|025|R|REFERENCE:|
01303|026|B||
01303|027|R|1.Orfadin (nitisinone) US prescribing information. Rare Diseases|1
01303|028|R|  Therapeutics, Inc. May, 2019.|1
01304|001|T|MONOGRAPH TITLE:  Non-Live or Non-Replicating Vaccines/Efalizumab|
01304|002|B||
01304|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01304|004|L|is contraindicated and generally should not be dispensed or administered to|
01304|005|L|the same patient.|
01304|006|B||
01304|007|A|MECHANISM OF ACTION:  Efalizumab-induced immunosuppression may prevent|
01304|008|A|proper immune response to the vaccine.(1)|
01304|009|B||
01304|010|E|CLINICAL EFFECTS:  The use of vaccines in patients who have recently|
01304|011|E|received efalizumab may be ineffective.(1)|
01304|012|B||
01304|013|P|PREDISPOSING FACTORS:  None determined.|
01304|014|B||
01304|015|M|PATIENT MANAGEMENT:  Patients should receive all appropriate immunizations|
01304|016|M|prior to beginning efalizumab therapy.  The use of vaccines in patients who|
01304|017|M|have recently received efalizumab may be ineffective.(1)  Patients who are|
01304|018|M|vaccinated within the 14 days prior to initiating immunosuppressive therapy|
01304|019|M|should be considered unvaccinated and should be revaccinated at least 3|
01304|020|M|months after immunosuppressive therapy is discontinued when immune|
01304|021|M|competence is restored.(2)|
01304|022|B||
01304|023|D|DISCUSSION:  In a small study with intravenous efalizumab, a single dose of|
01304|024|D|0.3 mg/kg of efalizumab given before primary immunization with a neoantigen|
01304|025|D|decreased the secondary immune response, and a dose of 1 mg/kg almost|
01304|026|D|completely ablated it.  (This dose has comparable pharmacodynamic effects to|
01304|027|D|the recommended subcutaneous dose of 1 mg/kg.)  In chimpanzees treated with|
01304|028|D|greater than 10 times the normal clinical exposure level of efalizumab,|
01304|029|D|antibody responses were decreased following immunization with tetanus toxoid|
01304|030|D|compared with untreated control animals.(1)|
01304|031|B||
01304|032|R|REFERENCES:|
01304|033|B||
01304|034|R|1.Raptiva (efalizumab) US prescribing information. Genentech, Inc. March 13,|1
01304|035|R|  2009.|1
01304|036|R|2.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
01304|037|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
01304|038|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
01304|039|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
01304|040|R|  recs.pdf February 10, 2023;1-197.|6
01305|001|T|MONOGRAPH TITLE:  Eplerenone/Nefazodone (mono deleted 03/01/2012)|
01305|002|B||
01305|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01305|004|L|is contraindicated and generally should not be dispensed or administered to|
01305|005|L|the same patient.|
01305|006|B||
01305|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of eplerenone by|
01305|008|A|CYP P-450-3A4.(1)|
01305|009|B||
01305|010|E|CLINICAL EFFECTS:  Concurrent use of eplerenone with nefazodone may result|
01305|011|E|in 5-fold increases in eplerenone concentrations and toxicity.(1)|
01305|012|B||
01305|013|P|PREDISPOSING FACTORS:  None determined.|
01305|014|B||
01305|015|M|PATIENT MANAGEMENT:  The manufacturer of eplerenone states that the|
01305|016|M|concurrent use of eplerenone with potent inhibitors of CYP P-450-3A4 such as|
01305|017|M|nefazodone is contraindicated.  The starting dose of eplerenone should be|
01305|018|M|reduced to 25 mg in patients receiving weak CYP P-450-3A4 inhibitors.(1)|
01305|019|B||
01305|020|D|DISCUSSION:  Concurrent use of eplerenone with ketoconazole resulted in a|
01305|021|D|5-fold increase in eplerenone concentrations.  Therefore, the manufacturer|
01305|022|D|of eplerenone states that the concurrent use of eplerenone with potent|
01305|023|D|inhibitors of CYP P-450-3A4 such as nefazodone is contraindicated.(1)|
01305|024|D|   The concurrent use of eplerenone with less potent CYP P-450-3A4|
01305|025|D|inhibitors (erythromycin, fluconazole, saquinavir, and verapamil) caused an|
01305|026|D|approximate 2-fold increase in eplerenone concentrations.  Therefore, the|
01305|027|D|manufacturer of eplerenone states that the starting dose of eplerenone|
01305|028|D|should be reduced to 25 mg in patients receiving weak CYP P-450-3A4|
01305|029|D|inhibitors.(1)|
01305|030|B||
01305|031|R|REFERENCE:|
01305|032|B||
01305|033|R|1.Inspra (eplerenone) US prescribing information. Pfizer Inc. March, 2011.|1
01306|001|T|MONOGRAPH TITLE:  Eplerenone/Clarithromycin; Troleandomycin (mono deleted|
01306|002|T|03/01/2012)|
01306|003|B||
01306|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01306|005|L|is contraindicated and generally should not be dispensed or administered to|
01306|006|L|the same patient.|
01306|007|B||
01306|008|A|MECHANISM OF ACTION:  Clarithromycin and troleandomycin may inhibit the|
01306|009|A|metabolism of eplerenone by CYP P-450-3A4.(1)|
01306|010|B||
01306|011|E|CLINICAL EFFECTS:  Concurrent use of eplerenone with clarithromycin or|
01306|012|E|troleandomycin may result in 5-fold increases in eplerenone concentrations|
01306|013|E|and toxicity.(1)|
01306|014|B||
01306|015|P|PREDISPOSING FACTORS:  None determined.|
01306|016|B||
01306|017|M|PATIENT MANAGEMENT:  The manufacturer of eplerenone states that the|
01306|018|M|concurrent use of eplerenone with potent inhibitors of CYP P-450-3A4 such as|
01306|019|M|clarithromycin or troleandomycin is contraindicated.  The starting dose of|
01306|020|M|eplerenone should be reduced to 25 mg in patients receiving weak CYP|
01306|021|M|P-450-3A4 inhibitors.(1)|
01306|022|B||
01306|023|D|DISCUSSION:  Concurrent use of eplerenone with ketoconazole resulted in a|
01306|024|D|5-fold increase in eplerenone concentrations.  Therefore, the manufacturer|
01306|025|D|of eplerenone states that the concurrent use of eplerenone with potent|
01306|026|D|inhibitors of CYP P-450-3A4 such as clarithromycin or troleandomycin is|
01306|027|D|contraindicated.(1)|
01306|028|D|   The concurrent use of eplerenone with less potent CYP P-450-3A4|
01306|029|D|inhibitors (erythromycin, fluconazole, saquinavir, and verapamil) caused an|
01306|030|D|approximate 2-fold increase in eplerenone concentrations.  Therefore, the|
01306|031|D|manufacturer of eplerenone states that the starting dose of eplerenone|
01306|032|D|should be reduced to 25 mg in patients receiving weak CYP P-450-3A4|
01306|033|D|inhibitors.(1)|
01306|034|B||
01306|035|R|REFERENCE:|
01306|036|B||
01306|037|R|1.Inspra (eplerenone) US prescribing information. Pfizer Inc. March, 2011.|1
01307|001|T|MONOGRAPH TITLE:  Eplerenone/Nelfinavir; Ritonavir (mono deleted 03/01/2012)|
01307|002|B||
01307|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01307|004|L|is contraindicated and generally should not be dispensed or administered to|
01307|005|L|the same patient.|
01307|006|B||
01307|007|A|MECHANISM OF ACTION:  Nelfinavir and ritonavir may inhibit the metabolism of|
01307|008|A|eplerenone by CYP P-450-3A4.(1)|
01307|009|B||
01307|010|E|CLINICAL EFFECTS:  Concurrent use of eplerenone with nelfinavir or ritonavir|
01307|011|E|may result in 5-fold increases in eplerenone concentrations and toxicity.(1)|
01307|012|B||
01307|013|P|PREDISPOSING FACTORS:  None determined.|
01307|014|B||
01307|015|M|PATIENT MANAGEMENT:  The manufacturer of eplerenone states that the|
01307|016|M|concurrent use of eplerenone with potent inhibitors of CYP P-450-3A4 such as|
01307|017|M|nelfinavir or ritonavir is contraindicated.  The starting dose of eplerenone|
01307|018|M|should be reduced to 25 mg in patients receiving weak CYP P-450-3A4|
01307|019|M|inhibitors.(1)|
01307|020|B||
01307|021|D|DISCUSSION:  Concurrent use of eplerenone with ketoconazole resulted in a|
01307|022|D|5-fold increase in eplerenone concentrations.  Therefore, the manufacturer|
01307|023|D|of eplerenone states that the concurrent use of eplerenone with potent|
01307|024|D|inhibitors of CYP P-450-3A4 such as nelfinavir or ritonavir is|
01307|025|D|contraindicated.(1)|
01307|026|D|   The concurrent use of eplerenone with less potent CYP P-450-3A4|
01307|027|D|inhibitors (erythromycin, fluconazole, saquinavir, and verapamil) caused an|
01307|028|D|approximate 2-fold increase in eplerenone concentrations.  Therefore, the|
01307|029|D|manufacturer of eplerenone states that the starting dose of eplerenone|
01307|030|D|should be reduced to 25 mg in patients receiving weak CYP P-450-3A4|
01307|031|D|inhibitors.(1)|
01307|032|B||
01307|033|R|REFERENCE:|
01307|034|B||
01307|035|R|1.Inspra (eplerenone) US prescribing information. Pfizer Inc. March, 2011.|1
01308|001|T|MONOGRAPH TITLE:  Pioglitazone (Less Than or Equal To 15 mg);|
01308|002|T|Rosiglitazone/Strong CYP2C8 Inhibitor|
01308|003|B||
01308|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01308|005|L|of severe adverse interaction.|
01308|006|B||
01308|007|A|MECHANISM OF ACTION:  Strong CYP2C8 inhibitors may inhibit the metabolism of|
01308|008|A|pioglitazone(1-5) and rosiglitazone.(6)|
01308|009|B||
01308|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2C8 inhibitors may result in|
01308|011|E|elevated levels of and clinical effects, including severe hypoglycemia, from|
01308|012|E|pioglitazone(1-5) or rosiglitazone.(6,7)|
01308|013|B||
01308|014|P|PREDISPOSING FACTORS:  None determined.|
01308|015|B||
01308|016|M|PATIENT MANAGEMENT:  Consider avoiding strong inhibitors of CYP2C8 in|
01308|017|M|patients maintained on pioglitazone or rosiglitazone.  The maximum|
01308|018|M|recommended dosage of pioglitazone is 15 mg daily when used concurrently|
01308|019|M|with gemfibrozil or other strong CYP2C8 inhibitors.(2)  The dosage of|
01308|020|M|pioglitazone(2) or rosiglitazone(7) may need to be adjusted if gemfibrozil|
01308|021|M|is initiated or discontinued.|
01308|022|M|  If concurrent therapy is warranted, patients should be closely monitored|
01308|023|M|for increased response to pioglitazone or rosiglitazone.|
01308|024|B||
01308|025|D|DISCUSSION:  In a randomized, cross-over study in 10 healthy subjects,|
01308|026|D|pretreatment with gemfibrozil (600 mg daily for 3 days) increased the the|
01308|027|D|area-under-curve (AUC) of a single dose of pioglitazone (30 mg) by 3.4-fold.|
01308|028|D|The AUC of the ratios of the M-III metabolite/pioglitazone and M-IV|
01308|029|D|metabolite/pioglitazone were reduced by 71% and by 65%, respectively. (1,2)|
01308|030|D|   In a randomized, double-blind, cross-over study in 12 healthy subjects,|
01308|031|D|pretreatment with gemfibrozil (600 mg daily for 3 days) increased the AUC|
01308|032|D|and half-life (T1/2) of a single dose of pioglitazone (15 mg) by 3.2-fold|
01308|033|D|(range 2.3-fold to 6.5-fold) and by 1.7-fold, respectively.  There was no|
01308|034|D|significant effect on pioglitazone maximum concentration (Cmax).  The 0-48|
01308|035|D|hour AUC of the M-III and M-IV metabolites were decreased by 42% and by 45%,|
01308|036|D|respectively; however, there was no significant effect on their 0-infinity|
01308|037|D|AUC.(3)|
01308|038|D|   In a randomized, cross-over study, gemfibrozil (600 mg twice daily for 4|
01308|039|D|days) increased the AUC of a single dose of pioglitazone (15 mg) by|
01308|040|D|4.3-fold.  The increase was variable between CYP2C8 genotypes.  Individuals|
01308|041|D|who were CYP2C8*3 carriers had a 5.2-fold increase in pioglitazone, while|
01308|042|D|CYP2C8*1 homozygotes had a 3.3-fold increase in pioglitazone.(5)|
01308|043|D|   In a randomized crossover study in 10 subjects, gemfibrozil (600 mg twice|
01308|044|D|daily) increased the rosiglitazone (4 mg single dose) AUC by 2.3-fold and|
01308|045|D|increased rosiglitazone T1/2 from 3.6 hours to 7.6 hours. Rosiglitazone Cmax|
01308|046|D|increased 1.2-fold.  At 24 hours post dose, the rosiglitazone concentration|
01308|047|D|was 9.8-fold greater when it was taken with gemfibrozil.  Gemfibrozil|
01308|048|D|increased the time to Cmax (Tmax) of N-desmethylrosiglitazone from 7 hours|
01308|049|D|to 12 hours and decreased its AUC by 38%.(6)|
01308|050|D|   Concurrent use of gemfibrozil (600 mg twice daily) with rosiglitazone (4|
01308|051|D|mg daily) increased rosiglitazone AUC by 127%.(7)|
01308|052|D|   Strong inhibitors of CYP2C8 include: gemfibrozil.(8,9)|
01308|053|B||
01308|054|R|REFERENCES:|
01308|055|B||
01308|056|R|1.Deng LJ, Wang F, Li HD. Effect of gemfibrozil on the pharmacokinetics of|2
01308|057|R|  pioglitazone. Eur J Clin Pharmacol 2005 Dec;61(11):831-6.|2
01308|058|R|2.Actos (pioglitazone hydrochloride) US prescribing information. Takeda|1
01308|059|R|  Pharmaceuticals Inc. November, 2013.|1
01308|060|R|3.Jaakkola T, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil,|2
01308|061|R|  itraconazole, and their combination on the pharmacokinetics of|2
01308|062|R|  pioglitazone. Clin Pharmacol Ther 2005 May;77(5):404-14.|2
01308|063|R|4.Jaakkola T, Laitila J, Neuvonen PJ, Backman JT. Pioglitazone is|5
01308|064|R|  metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with|5
01308|065|R|  CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol 2006 Jul;99(1):44-51.|5
01308|066|R|5.Aquilante CL, Kosmiski LA, Bourne DW, Bushman L, Daily EB, Hammond KP,|2
01308|067|R|  Hopley CW, Kadam RS, Kanack AT, Kompella UB, Le M, Predhomme JA, Rower JE,|2
01308|068|R|  Sidhom MS. Impact of the CYP2C8*3 polymorphism on the drug-drug|2
01308|069|R|  interaction between gemfibrozil and pioglitazone. Br J Clin Pharmacol 2012|2
01308|070|R|  May 25.|2
01308|071|R|6.Niemi M, Backman JT, Granfors M, Laitila J, Neuvonen M, Neuvonen PJ.|2
01308|072|R|  Gemfibrozil considerably increases the plasma concentrations of|2
01308|073|R|  rosiglitazone. Diabetologia 2003 Oct;46(10):1319-23.|2
01308|074|R|7.Avandia (rosiglitazone) US prescribing information. GlaxoSmithKline May,|1
01308|075|R|  2012.|1
01308|076|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
01308|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01308|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01308|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01308|080|R|  11/14/2017.|1
01308|081|R|9.This information is based on an extract from the Certara Drug Interaction|6
01308|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01309|001|T|MONOGRAPH TITLE:  Phenytoin/Eslicarbazepine; Oxcarbazepine (mono deleted|
01309|002|T|04/17/2014)|
01309|003|B||
01309|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01309|005|L|take action as needed.|
01309|006|B||
01309|007|A|MECHANISM OF ACTION:  Eslicarbazepine and oxcarbazepine may inhibit the|
01309|008|A|CYP2C19 mediated metabolism of phenytoin. (1-3)  Phenytoin may induce the|
01309|009|A|metabolism of eslicarbazepine and oxcarbazepine.(1,3)|
01309|010|B||
01309|011|E|CLINICAL EFFECTS:  Concurrent use of eslicarbazepine or oxcarbazepine and|
01309|012|E|phenytoin may result in decreased levels of eslicarbazepine and|
01309|013|E|oxcarbazepine and increased levels of phenytoin.(1,3)|
01309|014|B||
01309|015|P|PREDISPOSING FACTORS:  None determined.|
01309|016|B||
01309|017|M|PATIENT MANAGEMENT:  For patients stabilized on phenytoin, monitor for|
01309|018|M|increased phenytoin levels approximately 4 to 7 days after initiation or|
01309|019|M|after an increase in the eslicarbazepine or oxcarbazepine dose.|
01309|020|M|   If phenytoin is added to a patient stabilized on eslicarbazepine or|
01309|021|M|oxcarbazepine, the eslicarbazepine or oxcarbazepine dose may need to be|
01309|022|M|increased. Onset of phenytoin induction is gradual and may not be maximal|
01309|023|M|for days or weeks.|
01309|024|M|   Patients stabilized on the combination may need a dose adjustment if|
01309|025|M|either drug is discontinued.|
01309|026|B||
01309|027|D|DISCUSSION:  In interaction studies, eslicarbazepine or oxcarbazepine|
01309|028|D|increased phenytoin concentrations 30 to 40% and phenytoin decreased|
01309|029|D|eslicarbazepine or oxcarbazepine concentrations approximately 30%(1,3).|
01309|030|D|   An in vitro study in human liver microsomes found that oxcarbazepine|
01309|031|D|inhibited CYP P-450-2C19 mediated phenytoin metabolism.(2)|
01309|032|D|   In a study of oxcarbazepine (900 mg daily) and phenytoin, no effects on|
01309|033|D|phenytoin levels were seen.(4)|
01309|034|B||
01309|035|R|REFERENCES:|
01309|036|B||
01309|037|R|1.Trileptal (oxcarbazepine) US prescribing information. Novartis|1
01309|038|R|  Pharmaceuticals Corporation November, 2017.|1
01309|039|R|2.Lakehal F, Wurden CJ, Kalhorn TF, Levy RH. Carbamazepine and oxcarbazepine|5
01309|040|R|  decrease phenytoin metabolism through inhibition of CYP2C19. Epilepsy Res|5
01309|041|R|  2002 Dec;52(2):79-83.|5
01309|042|R|3.Aptiom (eslicarbazepine) US prescribing information. Sunovian|1
01309|043|R|  Pharmaceuticals Inc. August 27, 2015.|1
01309|044|R|4.McKee PJ, Blacklaw J, Forrest G, Gillham RA, Walker SM, Connelly D, Brodie|2
01309|045|R|  MJ. A double-blind, placebo-controlled interaction study between|2
01309|046|R|  oxcarbazepine and carbamazepine, sodium valproate and phenytoin in|2
01309|047|R|  epileptic patients. Br J Clin Pharmacol 1994 Jan;37(1):27-32.|2
01310|001|T|MONOGRAPH TITLE:  Selected Antiarrhythmics/Selected Protease Inhibitors|
01310|002|B||
01310|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01310|004|L|take action as needed.|
01310|005|B||
01310|006|A|MECHANISM OF ACTION:  Darunavir (coadministered with cobicistat or|
01310|007|A|ritonavir)(1), fosamprenavir (with or without ritonavir),(2)|
01310|008|A|lopinavir-ritonavir(3), and ombitasvir-paritaprevir-ritonavir(4) are CYP3A4|
01310|009|A|inhibitors and may decrease the metabolism of ajmaline, amiodarone, and|
01310|010|A|quinidine.|
01310|011|B||
01310|012|E|CLINICAL EFFECTS:  Concurrent use of darunavir (coadministered with|
01310|013|E|cobicistat or ritonavir)(1), fosamprenavir (with or without ritonavir),(2)|
01310|014|E|lopinavir-ritonavir(3), or ombitasvir-paritaprevir-ritonavir(4) with|
01310|015|E|ajmaline, amiodarone, or quinidine may result in elevated levels of these|
01310|016|E|antiarrhythmics and serious and/or life-threatening arrhythmias, including|
01310|017|E|torsades de pointes.|
01310|018|B||
01310|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01310|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01310|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01310|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01310|023|P|gender, or advanced age.(5)|
01310|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01310|025|P|higher systemic concentrations of either QT prolonging drug are additional|
01310|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01310|027|P|drug concentrations include rapid infusion of an intravenous dose or|
01310|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01310|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01310|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
01310|031|B||
01310|032|M|PATIENT MANAGEMENT:  Darunavir (coadministered with cobicistat or|
01310|033|M|ritonavir),(1) fosamprenavir (with or without ritonavir),(2)|
01310|034|M|lopinavir-ritonavir,(3) and ombitasvir-paritaprevir-ritonavir(4) should be|
01310|035|M|used with caution with ajmaline, amiodarone, and quinidine, along with|
01310|036|M|concentration monitoring of these agents.|
01310|037|M|   The US Department of Health and Human Services HIV guidelines state that|
01310|038|M|amiodarone should not be coadministered with darunavir or lopinavir unless|
01310|039|M|benefits outweigh risks, and that quinidine should not be coadministered|
01310|040|M|with protease inhibitors.(12)|
01310|041|M|   The Canadian and UK manufacturers of darunavir,(6,7) fosamprenavir,(8,9)|
01310|042|M|and lopinavir-ritonavir(10,11) state that concurrent use of amiodarone is|
01310|043|M|contraindicated.  The UK manufacturers of darunavir(7) and fosamprenavir(9)|
01310|044|M|state that concurrent use of quinidine is contraindicated.|
01310|045|M|   If used concurrently, consider obtaining serum calcium, magnesium, and|
01310|046|M|potassium levels and monitoring ECG at baseline and at regular intervals.|
01310|047|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
01310|048|M|irregular heartbeat, dizziness, or fainting.|
01310|049|B||
01310|050|D|DISCUSSION:  Darunavir and fosamprenavir are moderate inhibitors of CYP3A4.|
01310|051|D|Lopinavir-ritonavir is a strong inhibitor of CYP3A4.(13)|
01310|052|B||
01310|053|R|REFERENCES:|
01310|054|B||
01310|055|R|1.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01310|056|R|  March, 2023.|1
01310|057|R|2.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01310|058|R|  March, 2019.|1
01310|059|R|3.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01310|060|R|  Laboratories December, 2019.|1
01310|061|R|4.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
01310|062|R|  prescribing information. AbbVie Inc. December, 2019.|1
01310|063|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01310|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01310|065|R|  settings: a scientific statement from the American Heart Association and|6
01310|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01310|067|R|  2;55(9):934-47.|6
01310|068|R|6.Prezista (darunavir) Canadian prescribing information. Jannsen-Ortho June,|1
01310|069|R|  2008.|1
01310|070|R|7.Prezista (darunavir) UK Summary of product characteristics. Janssen-Cilgat|1
01310|071|R|  LTD August 8, 2008.|1
01310|072|R|8.Telzir (fosamprenavir calcium) Canadian product monograph. ViiV Healthcare|1
01310|073|R|  ULC February 11, 2014.|1
01310|074|R|9.Telzir (fosamprenavir calcium) UK summary of product characteristics.|1
01310|075|R|  GlaxoSmithKline UK October 18. 2013.|1
01310|076|R|10.Kaletra (lopinavir/ritonavir) Canadian prescribing information. Abbott|1
01310|077|R|   Limited May 22, 2019.|1
01310|078|R|11.Kaletra (lopinavir/ritonavir) UK summary of product characteristics.|1
01310|079|R|   Abbott Laboratories, Limited July 11, 2008.|1
01310|080|R|12.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01310|081|R|   for the use of antiretroviral agents in adults and adolescents Living|6
01310|082|R|   with HIV. Department of Health and Human Services. Available at:|6
01310|083|R|   https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-|6
01310|084|R|   and-adolescent-arv/whats-new March 23, 2023.|6
01310|085|R|13.This information is based on an extract from the Certara Drug Interaction|6
01310|086|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01311|001|T|MONOGRAPH TITLE:  Tricyclic Compounds/Fosamprenavir; Tipranavir|
01311|002|B||
01311|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01311|004|L|take action as needed.|
01311|005|B||
01311|006|A|MECHANISM OF ACTION:  Fosamprenavir and tipranavir may inhibit the|
01311|007|A|metabolism of tricyclic compounds.(1,2)|
01311|008|B||
01311|009|E|CLINICAL EFFECTS:  Concurrent use of fosamprenavir(1) or tipranavir(2) with|
01311|010|E|tricyclic compounds may result in elevated levels of the tricyclic agents|
01311|011|E|and serious and/or life-threatening effects.|
01311|012|B||
01311|013|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
01311|014|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
01311|015|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
01311|016|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
01311|017|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
01311|018|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
01311|019|P|systemic steroids).|
01311|020|P|   The risk of anticholinergic toxicities including cognitive decline,|
01311|021|P|delirium, falls and fractures is increased in geriatric patients using more|
01311|022|P|than one medicine with anticholinergic properties.(4)|
01311|023|B||
01311|024|M|PATIENT MANAGEMENT:  The manufacturer of fosamprenavir(1) recommends caution|
01311|025|M|with concurrent use of these agents with tricyclic compounds, along with|
01311|026|M|concentration monitoring of the tricyclics.|
01311|027|M|   The manufacturer of tipranavir recommends dosage reduction and|
01311|028|M|concentration monitoring of desipramine when coadministered with|
01311|029|M|tipranavir/ritonavir.(2)|
01311|030|B||
01311|031|D|DISCUSSION:  Amprenavir has been shown to be a potent inhibitor of|
01311|032|D|CYP3A4.(1,3)  Fosamprenavir is a prodrug of amprenavir.(1)  Therefore, the|
01311|033|D|manufacturer of amprenavir(3) and fosamprenavir(1) recommends caution with|
01311|034|D|concurrent use of these agents with tricyclic compounds, along with|
01311|035|D|concentration monitoring of the tricyclic compounds.|
01311|036|D|   No interaction studies have been performed on the combination of|
01311|037|D|tipranavir-ritonavir and desipramine.  Desipramine is a sensitive substrate|
01311|038|D|of CYP2D6 while tipranavir-ritonavir is a moderate CYP2D6 inhibitor.(5,6)|
01311|039|D|In one clinical study, six subjects were given 50 mg desipramine on three|
01311|040|D|occasions: alone, after a 60 mg dose of fluoxetine (strong CYP2D6|
01311|041|D|inhibitor), and after eight daily 60 mg doses of fluoxetine.  Fluoxetine|
01311|042|D|significantly reduced oral clearance of desipramine by up to 10-fold and|
01311|043|D|prolonged the half-life of desipramine by up to 4-fold.(7)|
01311|044|B||
01311|045|R|REFERENCES:|
01311|046|B||
01311|047|R|1.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01311|048|R|  March, 2019.|1
01311|049|R|2.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01311|050|R|  Pharmaceuticals, Inc. April, 2024.|1
01311|051|R|3.Agenerase (amprenavir) Capsules US prescribing information.|1
01311|052|R|  GlaxoSmithKline May, 2005.|1
01311|053|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01311|054|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01311|055|R|  Soc 2023 Jul;71(7):2052-2081.|6
01311|056|R|5.This information is based on an extract from the Certara Drug Interaction|6
01311|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01311|058|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
01311|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01311|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01311|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01311|062|R|  11/14/2017.|1
01311|063|R|7.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
01311|064|R|  fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
01311|065|R|  1992 Mar;51(3):239-48.|2
01312|001|T|MONOGRAPH TITLE:  Tadalafil/Tamsulosin (mono deleted 04/28/2005)|
01312|002|B||
01312|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01312|004|L|take action as needed.|
01312|005|B||
01312|006|A|MECHANISM OF ACTION:  Concurrent use of tadalafil and an alpha-blocker may|
01312|007|A|result in additive effects on blood pressure.(1-3)|
01312|008|B||
01312|009|E|CLINICAL EFFECTS:  Simultaneous administration of tadalafil and an|
01312|010|E|alpha-blocker may result in symptomatic hypotension.(1-3)|
01312|011|B||
01312|012|P|PREDISPOSING FACTORS:  Volume depletion and other concurrent|
01312|013|P|anti-hypertensive agents.|
01312|014|B||
01312|015|M|PATIENT MANAGEMENT:  The US manufacturer of tadalafil states that in|
01312|016|M|patients already receiving alpha-blockers, patients should be stabilized on|
01312|017|M|alpha-blocker therapy prior to initiating tadalafil and tadalafil should be|
01312|018|M|initiated at the lowest recommended dose.(1)|
01312|019|M|   The US manufacturer also states that in patients receiving tadalafil,|
01312|020|M|alpha-blocker therapy should be initiated at the lowest dose.(1)|
01312|021|M|   The Australian manufacturer of tadalafil states that tadalafil should be|
01312|022|M|used with caution in patients taking alpha-blockers.(2)|
01312|023|M|   The UK manufacturer of tadalafil states that concurrent use with|
01312|024|M|alpha-blockers is not recommended.(3)|
01312|025|B||
01312|026|D|DISCUSSION:  In a study, concurrent administration of a single dose of|
01312|027|D|tadalafil (20 mg) to healthy subjects receiving doxazosin (8 mg daily)|
01312|028|D|resulted in significant augmentation of the blood-pressure lowering effects|
01312|029|D|of doxazosin.  One subject reported vertigo and another reported dizziness.|
01312|030|D|No syncope was reported.(1)  In a second study, concurrent administration of|
01312|031|D|a single dose of tadalafil (20 mg) to healthy subjects receiving doxazosin|
01312|032|D|(4-8 mg daily) also resulted in augmentation of the blood-pressure lowering|
01312|033|D|affects of doxazosin.  One subject reported symptomatic hypotension and|
01312|034|D|another reported dizziness with concurrent therapy.(1)|
01312|035|D|   In a study, concurrent administration of a single dose of tadalafil (20|
01312|036|D|mg) to healthy subjects receiving tamsulosin (0.4 mg daily) resulted in no|
01312|037|D|significant decreases in blood pressure.(1)|
01312|038|B||
01312|039|R|REFERENCE:|
01312|040|B||
01312|041|R|1.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
01312|042|R|  February, 2010.|1
01313|001|T|MONOGRAPH TITLE:  Tadalafil/Alpha Blockers (mono deleted 04/18/2005)|
01313|002|B||
01313|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01313|004|L|take action as needed.|
01313|005|B||
01313|006|A|MECHANISM OF ACTION:  Concurrent use of tadalafil and an alpha-blocker may|
01313|007|A|result in additive effects on blood pressure.(1-3)|
01313|008|B||
01313|009|E|CLINICAL EFFECTS:  Simultaneous administration of tadalafil and an|
01313|010|E|alpha-blocker may result in symptomatic hypotension.(1-3)|
01313|011|B||
01313|012|P|PREDISPOSING FACTORS:  Volume depletion and other concurrent|
01313|013|P|anti-hypertensive agents.|
01313|014|B||
01313|015|M|PATIENT MANAGEMENT:  The US manufacturer of tadalafil states that in|
01313|016|M|patients already receiving alpha-blockers, patients should be stabilized on|
01313|017|M|alpha-blocker therapy prior to initiating tadalafil and tadalafil should be|
01313|018|M|initiated at the lowest recommended dose.(1)|
01313|019|M|   The US manufacturer also states that in patients receiving tadalafil,|
01313|020|M|alpha-blocker therapy should be initiated at the lowest dose.(1)|
01313|021|M|   The Australian manufacturer of tadalafil states that tadalafil should be|
01313|022|M|used with caution in patients taking alpha-blockers.(2)|
01313|023|M|   The UK manufacturer of tadalafil states that concurrent use with|
01313|024|M|alpha-blockers is not recommended.(3)|
01313|025|B||
01313|026|D|DISCUSSION:  In a study, concurrent administration of a single dose of|
01313|027|D|tadalafil (20 mg) to healthy subjects receiving doxazosin (8 mg daily)|
01313|028|D|resulted in significant augmentation of the blood-pressure lowering effects|
01313|029|D|of doxazosin.  One subject reported vertigo and another reported dizziness.|
01313|030|D|No syncope was reported.(1)  In a second study, concurrent administration of|
01313|031|D|a single dose of tadalafil (20 mg) to healthy subjects receiving doxazosin|
01313|032|D|(4-8 mg daily) also resulted in augmentation of the blood-pressure lowering|
01313|033|D|affects of doxazosin.  One subject reported symptomatic hypotension and|
01313|034|D|another reported dizziness with concurrent therapy.(1)|
01313|035|D|   In a study, concurrent administration of a single dose of tadalafil (20|
01313|036|D|mg) to healthy subjects receiving tamsulosin (0.4 mg daily) resulted in no|
01313|037|D|significant decreases in blood pressure.(1)|
01313|038|B||
01313|039|R|REFERENCES:|
01313|040|B||
01313|041|R|1.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
01313|042|R|  February, 2010.|1
01313|043|R|2.Cialis (tadalafil) Australian prescribing information. Eli Lilly Pty Ltd|1
01313|044|R|  July 3, 2006.|1
01313|045|R|3.Cialis (tadalafil) UK summary of product characteristics. Eli Lilly and|1
01313|046|R|  Company Limited September 16, 2008.|1
01314|001|T|MONOGRAPH TITLE:  Pemetrexed/Long Half-Life NSAIDs; Diflunisal|
01314|002|B||
01314|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01314|004|L|of severe adverse interaction.|
01314|005|B||
01314|006|A|MECHANISM OF ACTION:  NSAIDs may decrease the clearance of pemetrexed.(1)|
01314|007|A|This decreased clearance may be the result of chronic renal toxicity from|
01314|008|A|NSAIDs or NSAIDs may compete with pemetrexed for tubular secretion.(2)|
01314|009|B||
01314|010|E|CLINICAL EFFECTS:  Concurrent use of pemetrexed and NSAIDs may result in|
01314|011|E|elevated levels of and toxicity from pemetrexed, including myelosuppression,|
01314|012|E|neutropenia, renal toxicity, and gastrointestinal toxicity.(1)|
01314|013|B||
01314|014|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01314|015|P|patients with mild to moderate renal insufficiency (creatine clearance|
01314|016|P|(CrCl) of 45 ml/min to 79 ml/min) and/or patients taking long acting NSAIDs.|
01314|017|P|(1)|
01314|018|B||
01314|019|M|PATIENT MANAGEMENT:  NSAIDs and salicylates with long half-lives should be|
01314|020|M|avoided for at least 5 days before, the day of, and 2 days following|
01314|021|M|pemetrexed administration in all patients.(1,2)  If NSAIDs are required,|
01314|022|M|patients should be monitored for pemetrexed toxicity, especially|
01314|023|M|myelosuppression, renal toxicity, and gastrointestinal toxicity.(1)|
01314|024|M|   In patients with normal renal function (CrCl equal to or greater than 80|
01314|025|M|ml/min), ibuprofen (400 mg 4 times daily) can be administered with|
01314|026|M|pemetrexed.(1)|
01314|027|M|   In patients with mild to moderate renal insufficiency (CrCl from 45|
01314|028|M|ml/min to 79 ml/min), NSAIDs with short half-lives should be avoided for 2|
01314|029|M|days before, the day of, and 2 days after pemetrexed administration.|
01314|030|M|Ibuprofen should be administered with caution in these patients.(1)|
01314|031|B||
01314|032|D|DISCUSSION:  In patients with normal renal function, ibuprofen (400 mg 4|
01314|033|D|times daily) decreased the clearance of pemetrexed by 20% and increased its|
01314|034|D|area-under-curve (AUC) by 20%.(1)|
01314|035|D|   In a Phase I clinical trial, two patients receiving high dose pemetrexed|
01314|036|D|therapy experienced severe toxicity, both were receiving a NSAID.  Following|
01314|037|D|these reports, all patients were required to stop aspirin or other NSAIDs 2|
01314|038|D|days before and not resume these agents until 2 days after pemetrexed.(2)|
01314|039|D|   In two randomized, controlled cross-over trials, 27 cancer patients with|
01314|040|D|a creatinine clearance (CrCl) less than or equal to 60 ml/min received|
01314|041|D|pemetrexed (500 mg/m2) infusion on Day 1 of a 21-day cycle and either|
01314|042|D|aspirin 325 mg or ibuprofen 400 mg orally every 6 hours starting 2 days|
01314|043|D|before pemetrexed administration. Coadministration of aspirin did not affect|
01314|044|D|pemetrexed pharmacokinetics. Ibuprofen decreased the clearance of pemetrexed|
01314|045|D|by 16%, increased its maximum concentration (Cmax) by 15%, and increased the|
01314|046|D|AUC by 20%.(3)|
01314|047|B||
01314|048|R|REFERENCES:|
01314|049|B||
01314|050|R|1.Alimta (pemetrexed for injection) US prescribing information. Eli Lilly|1
01314|051|R|  and Company June, 2018.|1
01314|052|R|2.Personal Communication:  Alimta - Use with nsaids or aspirin. Eli Lilly|1
01314|053|R|  and Company February 10, 2004.|1
01314|054|R|3.Sweeney CJ, Takimoto CH, Latz JE, Baker SD, Murry DJ, Krull JH, Fife K,|2
01314|055|R|  Battiato L, Cleverly A, Chaudhary AK, Chaudhuri T, Sandler A, Mita AC,|2
01314|056|R|  Rowinsky EK. Two drug interaction studies evaluating the pharmacokinetics|2
01314|057|R|  and toxicity of pemetrexed when coadministered with aspirin or Ibuprofen|2
01314|058|R|  in patients with advanced cancer. Clin Cancer Res 2006 Jan 15;|2
01314|059|R|  12(2):536-42.|2
01315|001|T|MONOGRAPH TITLE:  Pemetrexed/Selected NSAIDs; Aspirin (Greater Than 325 mg)|
01315|002|B||
01315|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01315|004|L|of severe adverse interaction.|
01315|005|B||
01315|006|A|MECHANISM OF ACTION:  NSAIDs may decrease the clearance of pemetrexed.(1)|
01315|007|A|This decreased clearance may be the result of chronic renal toxicity from|
01315|008|A|NSAIDs or NSAIDs may compete with pemetrexed for tubular secretion.(2)|
01315|009|B||
01315|010|E|CLINICAL EFFECTS:  Concurrent use of pemetrexed and NSAIDs may result in|
01315|011|E|elevated levels of and toxicity from pemetrexed, including myelosuppression,|
01315|012|E|neutropenia, renal toxicity, and gastrointestinal toxicity.(1)|
01315|013|B||
01315|014|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01315|015|P|patients with mild to moderate renal insufficiency (creatine clearance|
01315|016|P|(CrCl) of 45 ml/min to 79 ml/min) and/or patients taking long acting NSAIDs.|
01315|017|P|(1)|
01315|018|B||
01315|019|M|PATIENT MANAGEMENT:  In patients with normal renal function (CrCl equal to|
01315|020|M|or greater than 80 ml/min), ibuprofen (400 mg 4 times daily) can be|
01315|021|M|administered with pemetrexed.  Aspirin in low to moderate doses (325 mg|
01315|022|M|every 6 hours) does not affect the pharmacokinetics of pemetrexed.(1)|
01315|023|M|   In patients with mild to moderate renal insufficiency (CrCl from 45|
01315|024|M|ml/min to 79 ml/min), NSAIDs with short half-lives should be avoided for 2|
01315|025|M|days before, the day of, and 2 days after pemetrexed administration.|
01315|026|M|Ibuprofen should be administered with caution in these patients.(1)|
01315|027|M|   NSAIDs and salicylates with long half-lives should be avoided for at|
01315|028|M|least 5 days before, the day of, and 2 days following pemetrexed|
01315|029|M|administration in all patients.(1,2)  If NSAIDs are required, patients|
01315|030|M|should be monitored for pemetrexed toxicity, especially myelosuppression,|
01315|031|M|renal toxicity, and gastrointestinal toxicity.(1)|
01315|032|B||
01315|033|D|DISCUSSION:  In patients with normal renal function, ibuprofen (400 mg 4|
01315|034|D|times daily) decreased the clearance of pemetrexed by 20% and increased its|
01315|035|D|area-under-curve (AUC) by 20%.(1)|
01315|036|D|   In a Phase I clinical trial, two patients receiving high dose pemetrexed|
01315|037|D|therapy experienced severe toxicity, both were receiving a NSAID.  Following|
01315|038|D|these reports, all patients were required to stop aspirin or other NSAIDs 2|
01315|039|D|days before and not resume these agents until 2 days after pemetrexed.(2)|
01315|040|D|    In two randomized, controlled cross-over trials, 27 cancer patients with|
01315|041|D|a creatinine clearance (CrCl) less than or equal to 60 ml/min received|
01315|042|D|pemetrexed (500 mg/m2) infusion on Day 1 of a 21-day cycle and either|
01315|043|D|aspirin 325 mg or ibuprofen 400 mg orally every 6 hours starting 2 days|
01315|044|D|before pemetrexed administration. Coadministration of aspirin did not affect|
01315|045|D|pemetrexed pharmacokinetics. Ibuprofen decreased the clearance of pemetrexed|
01315|046|D|by 16%, increased its maximum concentration (Cmax) by 15%, and increased the|
01315|047|D|AUC by 20%.(3)|
01315|048|D|   Aspirin products linked to this monograph are single ingredient aspirin|
01315|049|D|products with greater than 325 mg strength, and aspirin combination products|
01315|050|D|(e.g. opioid-aspirin or cough/cold/allergy products) with a reasonable|
01315|051|D|likelihood of a total daily aspirin dose > or = 1,300 mg per day.|
01315|052|B||
01315|053|R|REFERENCES:|
01315|054|B||
01315|055|R|1.Alimta (pemetrexed for injection) US prescribing information. Eli Lilly|1
01315|056|R|  and Company June, 2018.|1
01315|057|R|2.Personal Communication:  Alimta - Use with nsaids or aspirin. Eli Lilly|1
01315|058|R|  and Company February 10, 2004.|1
01315|059|R|3.Sweeney CJ, Takimoto CH, Latz JE, Baker SD, Murry DJ, Krull JH, Fife K,|2
01315|060|R|  Battiato L, Cleverly A, Chaudhary AK, Chaudhuri T, Sandler A, Mita AC,|2
01315|061|R|  Rowinsky EK. Two drug interaction studies evaluating the pharmacokinetics|2
01315|062|R|  and toxicity of pemetrexed when coadministered with aspirin or Ibuprofen|2
01315|063|R|  in patients with advanced cancer. Clin Cancer Res 2006 Jan 15;|2
01315|064|R|  12(2):536-42.|2
01316|001|T|MONOGRAPH TITLE:  Live Vaccines/Mycophenolate (mono deleted 04/26/2012)|
01316|002|B||
01316|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01316|004|L|of severe adverse interaction.|
01316|005|B||
01316|006|A|MECHANISM OF ACTION:  Mycophenolate-induced immunosuppression may prevent an|
01316|007|A|immune response to the vaccine.(1-3)|
01316|008|B||
01316|009|E|CLINICAL EFFECTS:  The use of live vaccines in patients who are receiving|
01316|010|E|mycophenolate may be ineffective and may result in infection.(1-3)|
01316|011|B||
01316|012|P|PREDISPOSING FACTORS:  None determined.|
01316|013|B||
01316|014|M|PATIENT MANAGEMENT:  The manufacturers of mycophenolate states that live|
01316|015|M|vaccines should be avoided in patients receiving mycophenolate.(1-3)|
01316|016|B||
01316|017|D|DISCUSSION:  Immune response to influenza vaccination was studied in 15|
01316|018|D|patients treated with prednisolone, cyclosporine, azathioprine; 13 patients|
01316|019|D|treated with prednisolone, cyclosporine, and mycophenolate, and 20 healthy|
01316|020|D|subjects.  A 4-fold rise in titre to 50% of the immunizing antigens was seen|
01316|021|D|in control subjects, compared to 33% of patients treated with azathioprine|
01316|022|D|and only 10% of patients treated with mycophenolate.  No patient receiving|
01316|023|D|mycophenolate responded to all three antigens and many failed to respond to|
01316|024|D|any antigen.(4)|
01316|025|B||
01316|026|R|REFERENCES:|
01316|027|B||
01316|028|R|1.CellCept (mycophenolate mofetil) US prescribing information. Roche|1
01316|029|R|  Pharmaceuticals September, 2013.|1
01316|030|R|2.Myfortic (mycophenolic acid) Australian prescribing information. Novartis|1
01316|031|R|  Pharmaceutical Australia Pty Ltd February 27, 2003.|1
01316|032|R|3.Myfortic (mycophenolate acid) US prescribing information. Novartis|1
01316|033|R|  Pharmaceuticals Corporation September, 2013.|1
01316|034|R|4.Smith KG, Isbel NM, Catton MG, Leydon JA, Becker GJ, Walker RG.|2
01316|035|R|  Suppression of the humoral immune response by mycophenolate mofetil.|2
01316|036|R|  Nephrol Dial Transplant 1998 Jan;13(1):160-4.|2
01317|001|T|MONOGRAPH TITLE:  Antidiabetic Agents/Gymnema|
01317|002|B||
01317|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01317|004|L|of severe adverse interaction.|
01317|005|B||
01317|006|A|MECHANISM OF ACTION:  Gymnema has been shown to increase the number of|
01317|007|A|insulin-secreting beta cells in animals.  It has also been shown to increase|
01317|008|A|the activity of enzymes responsible for glucose uptake and utilization and|
01317|009|A|inhibit peripheral utilization of glucose.(1)|
01317|010|B||
01317|011|E|CLINICAL EFFECTS:  Use of gymnema may result in decreased requirements of|
01317|012|E|antidiabetic agents.(2-4)|
01317|013|B||
01317|014|P|PREDISPOSING FACTORS:  None determined.|
01317|015|B||
01317|016|M|PATIENT MANAGEMENT:  Diabetic patients should be carefully monitored if|
01317|017|M|gymnema is initiated or discontinued from concurrent therapy.  The dosage of|
01317|018|M|the patient's antidiabetic agent(s) may need to be adjusted.(2)|
01317|019|B||
01317|020|D|DISCUSSION:  In a study in 22 non-insulin-dependent patients, patients had|
01317|021|D|decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma|
01317|022|D|proteins during gymnema therapy.  Patients were able to decrease the dosage|
01317|023|D|of their conventional antidiabetic therapy and five patients were able to|
01317|024|D|discontinue their conventional antidiabetic therapy.(3)|
01317|025|D|   In a study in 27 insulin-dependent patients, patients had decreased|
01317|026|D|insulin requirements, fasting blood glucose, glycosylated hemoglobin, and|
01317|027|D|glycosylated plasma protein levels.(4)|
01317|028|B||
01317|029|R|REFERENCES:|
01317|030|B||
01317|031|R|1.Anonymous. Gymnema sylvestre. Altern Med Rev 1999 Feb;4(1):46-7.|6
01317|032|R|2.Gymnema (gymnema) Australian prescribing information. MediHerb August,|1
01317|033|R|  2000.|1
01317|034|R|3.Baskaran K, Kizar Ahamath B, Radha Shanmugasundaram K, Shanmugasundaram|2
01317|035|R|  ER. Antidiabetic effect of a leaf extract from Gymnema sylvestre in|2
01317|036|R|  non-insulin-dependent diabetes mellitus patients. J Ethnopharmacol 1990|2
01317|037|R|  Oct;30(3):295-300.|2
01317|038|R|4.Shanmugasundaram ER, Rajeswari G, Baskaran K, Rajesh Kumar BR, Radha|2
01317|039|R|  Shanmugasundaram K, Kizar Ahmath B. Use of Gymnema sylvestre leaf extract|2
01317|040|R|  in the control of blood glucose in insulin-dependent diabetes mellitus. J|2
01317|041|R|  Ethnopharmacol 1990 Oct;30(3):281-94.|2
01318|001|T|MONOGRAPH TITLE:  Selected Chemotherapy Agents/Turmeric (Curcumin)|
01318|002|B||
01318|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01318|004|L|of severe adverse interaction.|
01318|005|B||
01318|006|A|MECHANISM OF ACTION:  Curcumin, the major component of turmeric, has been|
01318|007|A|shown to decrease chemotherapy-induced apoptosis by inhibition of reactive|
01318|008|A|oxygen species generation and blockade of the c-Jun NH2-terminal kinase|
01318|009|A|pathway.(1)|
01318|010|B||
01318|011|E|CLINICAL EFFECTS:  Concurrent use of turmeric (curcumin) may decrease the|
01318|012|E|effectiveness of some chemotherapy agents.(1)|
01318|013|B||
01318|014|P|PREDISPOSING FACTORS:  None determined.|
01318|015|B||
01318|016|M|PATIENT MANAGEMENT:  Patients receiving cytotoxic therapy for breast cancer|
01318|017|M|should be excluded from curcumin-based chemotherapy.(1)  It would be prudent|
01318|018|M|to instruct patients to avoid or limit consumption of curcumin or turmeric.|
01318|019|B||
01318|020|D|DISCUSSION:  In vitro studies in MCF-7 cancer cell lines showed that|
01318|021|D|curcumin decreased camptothecin-induced, doxorubicin-induced, and|
01318|022|D|mechlorethamine-induced apoptosis.  In vivo tests in mice xenograft models|
01318|023|D|of human breast cancer, dietary curcumin decreased cyclophosphamide-induced|
01318|024|D|tumor regression.(1)|
01318|025|B||
01318|026|R|REFERENCE:|
01318|027|B||
01318|028|R|1.Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ.|5
01318|029|R|  Dietary curcumin inhibits chemotherapy-induced apoptosis in models of|5
01318|030|R|  human breast cancer. Cancer Res 2002 Jul 1;62(13):3868-75.|5
01319|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants; Temsirolimus/Rifamycins (mono|
01319|002|T|deleted 11/01/2012)|
01319|003|B||
01319|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01319|005|L|of severe adverse interaction.|
01319|006|B||
01319|007|A|MECHANISM OF ACTION:  Rifamycins may induce the metabolism of everolimus,|
01319|008|A|sirolimus, tacrolimus, and temsirolimus by CYP P-450-3A4 in the liver and in|
01319|009|A|the intestines.(1-9)|
01319|010|B||
01319|011|E|CLINICAL EFFECTS:  Concurrent use of rifamycins and everolimus, sirolimus,|
01319|012|E|tacrolimus, or temsirolimus may result in decreased levels and effectiveness|
01319|013|E|of everolimus, sirolimus, tacrolimus, or temsirolimus.(1-9)|
01319|014|B||
01319|015|P|PREDISPOSING FACTORS:  None determined.|
01319|016|B||
01319|017|M|PATIENT MANAGEMENT:  The US manufacturer of everolimus states that|
01319|018|M|concurrent use with strong CYP P-450-3A4 inducers such as carbamazepine,|
01319|019|M|phenobarbital, or phenytoin should be avoided.  If concurrent use is|
01319|020|M|warranted, consider increasing the dose of everolimus from 10 mg daily to 20|
01319|021|M|mg daily in 5 mg increments.  If the inducer is discontinued, the dosage of|
01319|022|M|everolimus should be returned to the dosage used prior to the use of the|
01319|023|M|strong inducer.(1)|
01319|024|M|   The US manufacturer of sirolimus states that concurrent use of rifampin|
01319|025|M|or rifabutin is not recommended and should be avoided.(2)|
01319|026|M|   The US manufacturer of temsirolimus states that concurrent use of strong|
01319|027|M|inducers of CYP P-450-3A4, such as rifabutin, rifampicin, or rifampin should|
01319|028|M|should be avoided.  If concurrent therapy is warranted, consider increasing|
01319|029|M|the dosage of temsirolimus from 25 mg/week to 50 mg/week.  If the inducer is|
01319|030|M|discontinued, the dosage of temsirolimus should be returned to the previous|
01319|031|M|dose.(3)|
01319|032|M|   Drug levels should be carefully monitored in patients receiving|
01319|033|M|concurrent therapy with rifamycins.  The dosage of these agents may need to|
01319|034|M|be adjusted during and/or after rifamycins or the rifamycin may need to be|
01319|035|M|discontinued.|
01319|036|B||
01319|037|D|DISCUSSION:  In a cross-over study in 12 healthy subjects, pretreatment with|
01319|038|D|rifampin (600 mg daily for 8 days) decreased the maximum concentration|
01319|039|D|(Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of|
01319|040|D|everolimus by 58%, 63%, and 25%, respectively.  The apparent oral clearance|
01319|041|D|of everolimus increased by 172%.(4)|
01319|042|D|   In a study in 14 healthy subjects, pretreatment with rifampin (600 mg|
01319|043|D|daily for 14 days) decreased the AUC and Cmax of a single dose of sirolimus|
01319|044|D|(20 mg) by 82% and 71%, respectively.  The oral clearance of sirolimus|
01319|045|D|increased by 5.5-fold.(2)|
01319|046|D|   A study in six healthy subjects examined the effects of rifampin on|
01319|047|D|single doses of oral (0.1 mg/kg) and intravenous (0.025 mg/kg/4 hours)|
01319|048|D|tacrolimus.  Rifampin increased tacrolimus clearance by 47% and decreased|
01319|049|D|tacrolimus bioavailability by 51%.(5)|
01319|050|D|   There have been several case reports of decreased tacrolimus levels|
01319|051|D|following the addition of rifampin.(6-9)  In one of these reports, renal|
01319|052|D|allograft dysfunction was reported.(9)|
01319|053|D|   Concurrent rifampin had no significant effects on the AUC or Cmax of|
01319|054|D|temsirolimus; however, sirolimus AUC and Cmax decreased by 56% and 65%,|
01319|055|D|respectively.  A dosage adjustment to 50 mg/week of temsirolimus in the|
01319|056|D|presence of strong CYP P-450-3A4 inducers is predicted to adjust levels to|
01319|057|D|those seen without inducers; however, there are no clinical data in patients|
01319|058|D|using this dose.(2)|
01319|059|D|  In a case report, a 60-year-old cadaveric kidney transplant patient was|
01319|060|D|maintained on sirolimus (4 mg daily) for several months.  After developing a|
01319|061|D|Mycobacterium tuberculosis infection, the patient was started on a|
01319|062|D|combination of rifampin, isoniazid, pyrazinamide, and ethambutol.  The dose|
01319|063|D|of sirolimus was proactively increased to 30 mg daily to maintain levels|
01319|064|D|above 10 ng/mL.  The patient remained stable and, upon follow-up, he|
01319|065|D|maintained good renal function and successfully eradicated the TB|
01319|066|D|infection.(10)|
01319|067|D|  In a case report, a 28-year-old cadaveric kidney transplant patient was|
01319|068|D|maintained on a steady dose of sirolimus (4-6 mg daily).  Upon development|
01319|069|D|of a TB infection the patient was started on anti-TB treatment including|
01319|070|D|rifampin.  The serum levels of sirolimus decreased from 12 ng/mL to 5.2|
01319|071|D|ng/mL after treatment with rifampin.   When the sirolimus dosage was|
01319|072|D|increased to 25 mg daily the patient maintained renal function and showed no|
01319|073|D|signs of TB infection.(10)|
01319|074|D|  In an open-label clinical trial, 10 male patients received ridaforolimus|
01319|075|D|(40 mg daily, days 1 and 14) and rifampin (600 mg daily, days 1-21).|
01319|076|D|Administration of rifampin resulted in a reduction in the mean whole-blood|
01319|077|D|concentration of ridaforolimus (AUC-GMR 0.57, Cmax- GMR 0.66).  The mean|
01319|078|D|whole-blood concentration of ridaforolimus increased 1.5-fold following|
01319|079|D|ketoconazole administration.(11)|
01319|080|D|  In a case report, a 44-year-old cadaveric kidney transplant patient had|
01319|081|D|been stabilized on immunosuppressive treatment regimen that included 10 mg|
01319|082|D|oral prednisone, 16 mg tacrolimus, and 1.5 g of mycophenolate mofetil.  The|
01319|083|D|patient developed a Mycobacterium tuberculosis infection and was|
01319|084|D|subsequently started on therapy including rifampin (600 mg), pyrazinamide|
01319|085|D|(300 mg), ethambutol (400 mg), and isoniazid (300 mg).  After initiating the|
01319|086|D|rifampin regimen, tacrolimus levels decreased to as low as 3.7 ng/mL.  As a|
01319|087|D|result, the patient switched from rifampin to rifabutin.  The tacrolimus|
01319|088|D|levels gradually increased to reach adequate levels (10-15 ng/mL).  The|
01319|089|D|patient's kidney function remained stable and the TB infection resolved.(12)|
01319|090|B||
01319|091|R|REFERENCES:|
01319|092|B||
01319|093|R|1.Afinitor (everolimus) US prescribing information. Novartis Pharmaceuticals|1
01319|094|R|  Corporation March, 2009.|1
01319|095|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
01319|096|R|  March, 2013.|1
01319|097|R|3.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01319|098|R|  Inc. May, 2012.|1
01319|099|R|4.Kovarik JM, Hartmann S, Figueiredo J, Rouilly M, Port A, Rordorf C. Effect|2
01319|100|R|  of rifampin on apparent clearance of everolimus. Ann Pharmacother 2002|2
01319|101|R|  Jun;36(6):981-5.|2
01319|102|R|5.Hebert MF, Fisher RM, Marsh CL, Dressler D, Bekersky I. Effects of|2
01319|103|R|  rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin|2
01319|104|R|  Pharmacol 1999 Jan;39(1):91-6.|2
01319|105|R|6.Kiuchi T, Tanaka K, Inomata Y, Uemoto S, Satomura K, Egawa H, Uyama S,|3
01319|106|R|  Sano K, Okajima H, Yamaoka Y. Experience of tacrolimus-based|3
01319|107|R|  immunosuppression in living-related liver transplantation complicated with|3
01319|108|R|  graft tuberculosis: interaction with rifampicin and side effects.|3
01319|109|R|  Transplant Proc 1996 Dec;28(6):3171-2.|3
01319|110|R|7.Furlan V, Perello L, Jacquemin E, Debray D, Taburet AM. Interactions|3
01319|111|R|  between FK506 and rifampicin or erythromycin in pediatric liver|3
01319|112|R|  recipients. Transplantation 1995 Apr 27;59(8):1217-8.|3
01319|113|R|8.Bhaloo S, Prasad GV. Severe reduction in tacrolimus levels with rifampin|3
01319|114|R|  despite multiple cytochrome P450 inhibitors: a case report. Transplant|3
01319|115|R|  Proc 2003 Nov;35(7):2449-51.|3
01319|116|R|9.Chenhsu RY, Loong CC, Chou MH, Lin MF, Yang WC. Renal allograft|3
01319|117|R|  dysfunction associated with rifampin-tacrolimus interaction. Ann|3
01319|118|R|  Pharmacother 2000 Jan;34(1):27-31.|3
01319|119|R|10.Ngo BT, Pascoe M, Kahn D. Drug interaction between rifampicin and|3
01319|120|R|   sirolimus in transplant patients. Saudi J Kidney Dis Transpl 2011|3
01319|121|R|   Jan-Feb;22(1):112-5.|3
01319|122|R|11.Stroh M, Palcza J, McCrea J, Marsilio S, Breidinger S, Panebianco D,|2
01319|123|R|   Johnson-Levonas A, Kraft WK, Orford K, Murphy G, Agrawal N, Trucksis M,|2
01319|124|R|   Wagner JA, Iwamoto M. The effect of multiple doses of rifampin and|2
01319|125|R|   ketoconazole on the single-dose pharmacokinetics of ridaforolimus. Cancer|2
01319|126|R|   Chemother Pharmacol 2012 May;69(5):1247-53.|2
01319|127|R|12.Lopez-Montes A, Gallego E, Lopez E, Perez J, Lorenzo I, Llamas F, Serrano|3
01319|128|R|   A, Andres E, Illescas L, Gomez C. Treatment of tuberculosis with|3
01319|129|R|   rifabutin in a renal transplant recipient. Am J Kidney Dis 2004 Oct;|3
01319|130|R|   44(4):e59-63.|3
01320|001|T|MONOGRAPH TITLE:  Phenytoin/Sulthiame|
01320|002|B||
01320|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01320|004|L|of severe adverse interaction.|
01320|005|B||
01320|006|A|MECHANISM OF ACTION:  Sulthiame may inhibit the CYP2C19 mediated metabolism|
01320|007|A|of phenytoin.(1-4)|
01320|008|B||
01320|009|E|CLINICAL EFFECTS:  Concurrent use of sulthiame and phenytoin may result in|
01320|010|E|elevated levels of phenytoin and phenytoin toxicity.(1-4) Phenytoin has a|
01320|011|E|narrow therapeutic range. Early symptoms of phenytoin toxicity may include|
01320|012|E|nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred|
01320|013|E|speech, blurred vision, nausea, and vomiting. Severe toxicity may produce|
01320|014|E|organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and|
01320|015|E|atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be|
01320|016|E|fatal.(5)|
01320|017|B||
01320|018|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
01320|019|P|hypoalbuminemia.|
01320|020|B||
01320|021|M|PATIENT MANAGEMENT:  Patients maintained on phenytoin should be carefully|
01320|022|M|monitored if sulthiame is initiated or discontinued.  The dosage of|
01320|023|M|phenytoin may need to be adjusted.|
01320|024|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
01320|025|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
01320|026|M|vision, nausea, and vomiting).|
01320|027|B||
01320|028|D|DISCUSSION:  In a study in four epileptic patients who had been maintained|
01320|029|D|on phenytoin (300 mg daily) for 12 months, the addition of sulthiame (200|
01320|030|D|mg, 400 mg, 600 mg, or 800 mg daily) increased phenytoin levels by an|
01320|031|D|average of 136% (range 85% to 175%).  Phenytoin levels rose above 20 mcg/ml|
01320|032|D|in three patients and all three experienced mild symptoms of phenytoin|
01320|033|D|toxicity, including apathy and dizziness.  In one patient, phenytoin levels|
01320|034|D|had not returned to baseline one month after sulthiame withdrawal.  The|
01320|035|D|effect of sulthiame on phenytoin half-life was examined in four other|
01320|036|D|subjects who were not on phenytoin therapy.  Sulthiame increased phenytoin|
01320|037|D|half-life from 8 hours to 12 hours in one patient (200 mg sulthiame daily),|
01320|038|D|from 8 hours to 13 hours in another (400 mg daily), from 15 hours to 18|
01320|039|D|hours in another (600 mg daily), and from 12 to 35 hours in another (800 mg|
01320|040|D|daily).(1)|
01320|041|D|   A study in seven patients found elevated phenytoin levels and symptoms of|
01320|042|D|phenytoin toxicity (sleepiness, dizziness, moodiness, loss of initiative,|
01320|043|D|ataxia, nystagmus, and shortness of breath) following the addition of|
01320|044|D|sulthiame (400 mg daily for one week, then 600 mg daily).(2)|
01320|045|D|   In a study in six patients, phenytoin levels decreased, phenytoin|
01320|046|D|half-life decreased, and the ratio of 5-(p-hydroxyphenyl)-5-phenylhydantion|
01320|047|D|to phenytoin in the urine changed in favor of the metabolite one month after|
01320|048|D|the withdrawal of sulthiame.(3)|
01320|049|D|   In a prospective review of 137 patients receiving phenytoin who were|
01320|050|D|admitted to a hospital specializing in epilepsy, 20 patients were also|
01320|051|D|taking sulthiame (100 mg/day to 800 mg/day).  Of these 20 patients, 40% had|
01320|052|D|toxic phenytoin levels (defined as 25 mcg/ml), in comparison to only 13% of|
01320|053|D|patients who were not taking sulthiame who had toxic phenytoin levels.(4)|
01320|054|B||
01320|055|R|REFERENCES:|
01320|056|B||
01320|057|R|1.Hansen JM, Kristensen M, Skovsted L. Sulthiame (Ospolot) as inhibitor of|2
01320|058|R|  diphenylhydatoin metabolism. Epilepsia 1968 Mar;9(1):17-22.|2
01320|059|R|2.Olesen OV, Jensen ON. Drug--interaction between sulthiame (Ospolot (R))|2
01320|060|R|  and phenytoin in the treatment of epilepsy. Dan Med Bull 1969 May;|2
01320|061|R|  16(5):154-8.|2
01320|062|R|3.Houghton GW, Richens A. Proceedings: Inhibition of phenytoin metabolism by|2
01320|063|R|  sulthiame. Br J Pharmacol 1973 Sep;49(1):157P-158P.|2
01320|064|R|4.Houghton GW, Richens A. Phenytoin intoxication induced by sulthiame in|3
01320|065|R|  epileptic patients. J Neurol Neurosurg Psychiatry 1974 Mar;37(3):275-81.|3
01320|066|R|5.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
01320|067|R|  March, 2022.|1
01321|001|T|MONOGRAPH TITLE:  Fotemustine/Dacarbazine|
01321|002|B||
01321|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01321|004|L|of severe adverse interaction.|
01321|005|B||
01321|006|A|MECHANISM OF ACTION:  Dacarbazine depletes the O6alkyl DNA alkyltransferase|
01321|007|A|(O6AT) system and may deplete cytosolic and/or nuclear glutathione.  This|
01321|008|A|may result in increased alkylating effects of fotemustine and may prevent|
01321|009|A|cells from detoxifying dacarbazine and fotemustine.(1)|
01321|010|B||
01321|011|E|CLINICAL EFFECTS:  Sequential administration of dacarbazine and fotemustine|
01321|012|E|may result in severe toxicities, including acute respiratory distress|
01321|013|E|syndrome.(1-4)|
01321|014|B||
01321|015|P|PREDISPOSING FACTORS:  None determined.|
01321|016|B||
01321|017|M|PATIENT MANAGEMENT:  The Australian manufacturer of fotemustine states that|
01321|018|M|the sequential administration of dacarbazine and fotemustine should be|
01321|019|M|avoided.(2)|
01321|020|M|   The combination of dacarbazine and fotemustine, administered on different|
01321|021|M|treatment days, is used in the treatment of cancer.|
01321|022|B||
01321|023|D|DISCUSSION:  Several studies have reported severe, rapidly fatal pulmonary|
01321|024|D|toxicity following the sequential administration of dacarbazine and|
01321|025|D|fotemustine.(1,3-4)  Pretreatment with corticosteroids was not effective in|
01321|026|D|preventing lung toxicity.  Lung function monitoring did not predict|
01321|027|D|toxicity.(1)|
01321|028|B||
01321|029|R|REFERENCES:|
01321|030|B||
01321|031|R|1.Gerard B, Aamdal S, Lee SM, Leyvraz S, Lucas C, D'Incalci M, Bizzari JP.|2
01321|032|R|  Activity and unexpected lung toxicity of the sequential administration of|2
01321|033|R|  two alkylating agents--dacarbazine and fotemustine--in patients with|2
01321|034|R|  melanoma. Eur J Cancer 1993;29A(5):711-9.|2
01321|035|R|2.Muphoran (fotemustine) Australian prescribing information. Servier August|1
01321|036|R|  21, 2001.|1
01321|037|R|3.Aamdal S, Gerard B, Bohman T, D'Incalci M. Sequential administration of|2
01321|038|R|  dacarbazine and fotemustine in patients with disseminated malignant|2
01321|039|R|  melanoma--an effective combination with unexpected toxicity. Eur J Cancer|2
01321|040|R|  1992;28(2-3):447-50.|2
01321|041|R|4.Lee SM, Margison GP, Woodcock AA, Thatcher N. Sequential administration of|2
01321|042|R|  varying doses of dacarbazine and fotemustine in advanced malignant|2
01321|043|R|  melanoma. Br J Cancer 1993 Jun;67(6):1356-60.|2
01322|001|T|MONOGRAPH TITLE:  Perhexiline/Selected CYP2D6 Inhibitors|
01322|002|B||
01322|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01322|004|L|take action as needed.|
01322|005|B||
01322|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2D6 may inhibit the metabolism of|
01322|007|A|perhexiline by CYP2D6.|
01322|008|B||
01322|009|E|CLINICAL EFFECTS:  Concurrent use of perhexiline and a CYP2D6 inhibitor may|
01322|010|E|result in elevated levels of perhexiline and toxicity, including risk of QT|
01322|011|E|prolongation or torsade de pointes.|
01322|012|B||
01322|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01322|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01322|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01322|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01322|017|P|gender, or advanced age.(1,2)|
01322|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01322|019|P|higher systemic concentrations of either QT prolonging drug are additional|
01322|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01322|021|P|drug concentrations include rapid infusion of an intravenous dose or|
01322|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01322|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01322|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01322|025|B||
01322|026|M|PATIENT MANAGEMENT:  Patients maintained on perhexiline should be carefully|
01322|027|M|monitored if a CYP2D6 inhibitor is initiated or discontinued.  The dosage of|
01322|028|M|perhexiline may need to be adjusted.|
01322|029|M|   If concurrent therapy is warranted, monitor ECG more frequently and|
01322|030|M|consider obtaining serum calcium, magnesium, and potassium levels at|
01322|031|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01322|032|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01322|033|B||
01322|034|D|DISCUSSION:  The Adverse Drug Reactions Advisory Committee has received five|
01322|035|D|reports of an interaction between perhexiline and SSRIs.(1)|
01322|036|D|   In one report, an 82 year-old male developed symptoms of perhexiline|
01322|037|D|toxicity ten days after the addition of citalopram to his regimen.|
01322|038|D|Citalopram was discontinued on Day 10.  The patient's perhexiline level,|
01322|039|D|previously stable between 0.29 mg/L and 0.34 mg/l, was found to be 0.82 mg/L|
01322|040|D|on day 15.  Perhexiline dosage was reduced.(1)|
01322|041|D|   In another report, a 62 year-old male developed perhexiline toxicity|
01322|042|D|following the addition of paroxetine to his regimen.  After paroxetine was|
01322|043|D|discontinued, perhexiline levels returned to baseline.(3)|
01322|044|D|   In another report, an 84 year-old female developed perhexiline toxicity|
01322|045|D|following the addition of fluoxetine to her regimen.  Despite the|
01322|046|D|discontinuation of fluoxetine, perhexiline levels were slow to return to|
01322|047|D|baseline.(3)|
01322|048|D|   Selected CYP2D6 inhibitors linked to this monograph include: bupropion,|
01322|049|D|citalopram, dacomitinib, escitalopram, fluoxetine, hydroquinidine,|
01322|050|D|paroxetine, quinidine, and terbinafine.(4)|
01322|051|B||
01322|052|R|REFERENCES:|
01322|053|B||
01322|054|R|1.Nyfort-Hansen K. Perhexiline toxicity related to citalopram use. Med J|3
01322|055|R|  Aust 2002 Jun 3;176(11):560-1.|3
01322|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01322|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01322|058|R|  settings: a scientific statement from the American Heart Association and|6
01322|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01322|060|R|  2;55(9):934-47.|6
01322|061|R|3.Alderman CP, Hundertmark JD, Soetratma TW. Interaction of serotonin|3
01322|062|R|  re-uptake inhibitors with perhexiline. Aust N Z J Psychiatry 1997 Aug;|3
01322|063|R|  31(4):601-3.|3
01322|064|R|4.This information is based on an extract from the Certara Drug Interaction|6
01322|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01323|001|T|MONOGRAPH TITLE:  Tirilazad/Ketoconazole|
01323|002|B||
01323|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01323|004|L|take action as needed.|
01323|005|B||
01323|006|A|MECHANISM OF ACTION:  Ketoconazole may inhibit the metabolism of tirilazad|
01323|007|A|by CYP P-450-3A4.(1-3)|
01323|008|B||
01323|009|E|CLINICAL EFFECTS:  Concurrent use of ketoconazole may result in elevated|
01323|010|E|levels of and toxicity from tirilazad.(1)|
01323|011|B||
01323|012|P|PREDISPOSING FACTORS:  None determined.|
01323|013|B||
01323|014|M|PATIENT MANAGEMENT:  Patients maintained on tirilazad should be carefully|
01323|015|M|monitored if ketoconazole is initiated or discontinued.  The dosage of|
01323|016|M|tirilazad may need to be adjusted.|
01323|017|B||
01323|018|D|DISCUSSION:  A study in 12 healthy subjects examined the effects of|
01323|019|D|ketoconazole (200 mg daily for 7 days) on single doses of oral (10 mg/kg)|
01323|020|D|and intravenous  (2 mg/kg) tirilazad.  Tirilazad was administered on the|
01323|021|D|fourth day of ketoconazole.  Area-under-curve (AUC) of oral and intravenous|
01323|022|D|tirilazad increased by 67% and by 309%, respectively.  The maximum|
01323|023|D|concentration (Cmax) of oral tirilazad increased by 263%.  Ketoconazole also|
01323|024|D|increased the AUC of U-89678, an active metabolite of tirilazad, after oral|
01323|025|D|and intravenous tirilazad by 472% and by 720%, respectively.  U-89678 Cmax|
01323|026|D|increased by 196% and by 623% after oral and intravenous administration of|
01323|027|D|tirilazad, respectively, during ketoconazole.  Ketoconazole also increased|
01323|028|D|the AUC and Cmax of U-87999 following oral and intravenous tirilazad.(2)|
01323|029|D|   In vitro studies have shown ketoconazole to inhibit tirilazad metabolism|
01323|030|D|in human liver microsomes.(3)|
01323|031|B||
01323|032|R|REFERENCES:|
01323|033|B||
01323|034|R|1.Freedox (tirilazad mesylate) Australian prescribing information. Pharmacia|1
01323|035|R|  Australia April 29, 1996.|1
01323|036|R|2.Fleishaker JC, Pearson PG, Wienkers LC, Pearson LK, Peters GR.|2
01323|037|R|  Biotransformation of tirilazad in human: 2. Effect of ketoconazole on|2
01323|038|R|  tirilazad clearance and oral bioavailability. J Pharmacol Exp Ther 1996|2
01323|039|R|  May;277(2):991-8.|2
01323|040|R|3.Wienkers LC, Steenwyk RC, Sanders PE, Pearson PG. Biotransformation of|5
01323|041|R|  tirilazad in human: 1. Cytochrome P450 3A-mediated hydroxylation of|5
01323|042|R|  tirilazad mesylate in human liver microsomes. J Pharmacol Exp Ther 1996|5
01323|043|R|  May;277(2):982-90.|5
01324|001|T|MONOGRAPH TITLE:  Tirilazad/Selected Strong CYP3A4 Inducers|
01324|002|B||
01324|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01324|004|L|take action as needed.|
01324|005|B||
01324|006|A|MECHANISM OF ACTION:  Barbiturates, phenobarbital, phenytoin and primidone|
01324|007|A|may induce the metabolism of tirilazad by CYP3A4.(1)|
01324|008|B||
01324|009|E|CLINICAL EFFECTS:  Concurrent use of barbiturates, phenobarbital, phenytoin|
01324|010|E|or primidone may result in decreased levels and clinical effectiveness of|
01324|011|E|tirilazad.(1)|
01324|012|B||
01324|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01324|014|P|of the inducer for longer than 1-2 weeks.|
01324|015|B||
01324|016|M|PATIENT MANAGEMENT:  Patients receiving tirilazad therapy should be|
01324|017|M|carefully monitored if barbiturates, phenobarbital, phenytoin or primidone|
01324|018|M|is initiated or discontinued from concurrent therapy.  The dosage of|
01324|019|M|tirilazad may need to be adjusted.|
01324|020|B||
01324|021|D|DISCUSSION:  A study in 15 healthy subjects examined the effects of|
01324|022|D|phenobarbital on tirilazad pharmacokinetics.  Subjects received tirilazad|
01324|023|D|(1.5 mg/kg every 6 hours) for 29 doses alone and during an 8 day course of|
01324|024|D|phenobarbital (100 mg daily).  There was no effect on the first dose|
01324|025|D|pharmacokinetics of tirilazad or U-89678, an active metabolite of tirilazad.|
01324|026|D|After the completion of 29 doses, tirilazad and U-89678 clearance increased|
01324|027|D|by 25% in males and by 29% in females during phenobarbital administration.|
01324|028|D|The area-under-curve (AUC) of tirilazad and U-89678 decreased by 51% in|
01324|029|D|males and by 69% in females during phenobarbital.  The difference between|
01324|030|D|genders was not statistically significant.(1)|
01324|031|D|   A study in 12 healthy males examined the effects of phenytoin (200 mg 3|
01324|032|D|times daily for 11 doses, then 100 mg 3 times daily for 5 doses) on|
01324|033|D|tirilazad (1.5 mg/kg every 6 hours for 21 doses) pharmacokinetics. Phenytoin|
01324|034|D|decreased the area-under-curve (AUC) of tirilazad by 35% at the end of|
01324|035|D|tirilazad administration.  The AUC of U-89678, an active metabolite of|
01324|036|D|tirilazad, decreased by 87%.(1)  The amount of circulating active moieties|
01324|037|D|during phenytoin administration decreased by 47%.(2)|
01324|038|D|  In a study in 12 healthy subjects (6 male, 6 female), phenytoin (200 mg 3|
01324|039|D|times daily for 9 doses, then 100 mg 3 times daily for 13 doses) increased|
01324|040|D|tirilazad (1.5 mg/kg every 6 hours for 29 doses) clearance by 91.8%.  The|
01324|041|D|AUC of tirilazad and U-89678 after the last tirilazad decreased by 93.1%|
01324|042|D|during phenytoin administration.(3)|
01324|043|B||
01324|044|R|REFERENCES:|
01324|045|B||
01324|046|R|1.Fleishaker JC, Pearson LK, Peters GR. Gender does not affect the degree of|2
01324|047|R|  induction of tirilazad clearance by phenobarbital. Eur J Clin Pharmacol|2
01324|048|R|  1996;50(1-2):139-45.|2
01324|049|R|2.Freedox (tirilazad mesylate) Australian prescribing information. Pharmacia|1
01324|050|R|  Australia April 29, 1996.|1
01324|051|R|3.Fleishaker JC, Pearson LK, Peters GR. Induction of tirilazad clearance by|2
01324|052|R|  phenytoin. Biopharm Drug Dispos 1998 Mar;19(2):91-6.|2
01325|001|T|MONOGRAPH TITLE:  Tirilazad/Phenytoin (mono deleted 06/16/2011)|
01325|002|B||
01325|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01325|004|L|take action as needed.|
01325|005|B||
01325|006|A|MECHANISM OF ACTION:  Phenytoin may induce the metabolism of tirilazad by|
01325|007|A|CYP P-450-3A4.(1-3)|
01325|008|B||
01325|009|E|CLINICAL EFFECTS:  Concurrent use of phenytoin may result in decreased|
01325|010|E|levels and clinical effectiveness of tirilazad.(1-3)|
01325|011|B||
01325|012|P|PREDISPOSING FACTORS:  None determined.|
01325|013|B||
01325|014|M|PATIENT MANAGEMENT:  Patients receiving tirilazad therapy should be|
01325|015|M|carefully monitored if phenytoin is initiated or discontinued from|
01325|016|M|concurrent therapy.  The dosage of tirilazad may need to be adjusted.|
01325|017|B||
01325|018|D|DISCUSSION:  A study in 12 healthy males examined the effects of phenytoin|
01325|019|D|(200 mg 3 times daily for 11 doses, then 100 mg 3 times daily for 5 doses)|
01325|020|D|on tirilazad (1.5 mg/kg every 6 hours for 21 doses) pharmacokinetics.|
01325|021|D|Phenytoin decreased the area-under-curve (AUC) of tirilazad by 35% at the|
01325|022|D|end of tirilazad administration.  The AUC of U-89678, an active metabolite|
01325|023|D|of tirilazad, decreased by 87%.(1)  The amount of circulating active|
01325|024|D|moieties during phenytoin administration decreased by 47%.(2)|
01325|025|D|  In a study in 12 healthy subjects (6 male, 6 female), phenytoin (200 mg 3|
01325|026|D|times daily for 9 doses, then 100 mg 3 times daily for 13 doses) increased|
01325|027|D|tirilazad (1.5 mg/kg every 6 hours for 29 doses) clearance by 91.8%.  The|
01325|028|D|AUC of tirilazad and U-89678 after the last tirilazad decreased by 93.1%|
01325|029|D|during phenytoin administration.(3)|
01325|030|B||
01325|031|R|REFERENCES:|
01325|032|B||
01325|033|R|1.Fleishaker JC, Hulst LK, Peters GR. The effect of phenytoin on the|2
01325|034|R|  pharmacokinetics of tirilazad mesylate in healthy male volunteers. Clin|2
01325|035|R|  Pharmacol Ther 1994 Oct;56(4):389-97.|2
01325|036|R|2.Freedox (tirilazad mesylate) Australian prescribing information. Pharmacia|1
01325|037|R|  Australia April 29, 1996.|1
01325|038|R|3.Fleishaker JC, Pearson LK, Peters GR. Induction of tirilazad clearance by|2
01325|039|R|  phenytoin. Biopharm Drug Dispos 1998 Mar;19(2):91-6.|2
01326|001|T|MONOGRAPH TITLE:  Risperidone/Carbamazepine; Phenobarbital; Phenytoin (mono|
01326|002|T|deleted 01/10/2013)|
01326|003|B||
01326|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01326|005|L|take action as needed.|
01326|006|B||
01326|007|A|MECHANISM OF ACTION:  Carbamazepine,(1,2) phenobarbital,(1) and phenytoin(1)|
01326|008|A|may induce the metabolism of risperidone by CYP P-450-3A4.  Risperidone may|
01326|009|A|inhibit the metabolism of carbamazepine.(3)|
01326|010|B||
01326|011|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
01326|012|E|effectiveness of risperidone(1,2,4-5) and elevated levels of|
01326|013|E|carbamazepine.(3)|
01326|014|B||
01326|015|P|PREDISPOSING FACTORS:  None determined.|
01326|016|B||
01326|017|M|PATIENT MANAGEMENT:  Patients receiving risperidone should be closely|
01326|018|M|monitored if carbamazepine, phenobarbital, or phenytoin is initiated or|
01326|019|M|discontinued from concurrent therapy.  The dosage of risperidone may need to|
01326|020|M|be adjusted.|
01326|021|M|   The US manufacturer of extended release risperidone microspheres for|
01326|022|M|injection (Risperdal Consta) recommends that patients maintained on this|
01326|023|M|product be closely monitored during the first 4-8 weeks of concurrent|
01326|024|M|therapy if carbamazepine, phenobarbital, or phenytoin is initiated.|
01326|025|M|Patients may need a dosage increase of this product or additional oral|
01326|026|M|risperidone.  If carbamazepine, phenobarbital, or phenytoin is discontinued,|
01326|027|M|the manufacturer recommends that patients maintained on the recommended 25|
01326|028|M|mg dose continue to receive this dose, unless clinical judgment necessitates|
01326|029|M|lowering the dose or interrupting therapy.  If a decision is made to lower|
01326|030|M|the dose, the dose may be lowered to 12.5 mg 2 to 4 weeks before the|
01326|031|M|discontinuation of carbamazepine, phenobarbital, or phenytoin although the|
01326|032|M|efficacy of this dose has not been confirmed in clinical trials.(1)|
01326|033|M|   Patients receiving carbamazepine should be closely monitored if|
01326|034|M|risperidone is initiated or discontinued from concurrent therapy.  The|
01326|035|M|dosage of carbamazepine may need to be adjusted.|
01326|036|B||
01326|037|D|DISCUSSION:  A study in 11 schizophrenic inpatients examined the effects of|
01326|038|D|the addition of carbamazepine (200 mg twice daily) for one week to|
01326|039|D|risperidone (3 mg twice daily).  Concurrent carbamazepine decreased plasma|
01326|040|D|concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by|
01326|041|D|50%, 44%, and 45%, respectively.(2)|
01326|042|D|   A study compared 23 patients receiving risperidone alone to 11 patients|
01326|043|D|receiving concurrent risperidone and carbamazepine.  The groups were matched|
01326|044|D|for sex, age, body weight, and risperidone dosage.  Plasma concentrations of|
01326|045|D|9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone|
01326|046|D|were significantly lower in patients receiving concurrent carbamazepine.|
01326|047|D|Five subjects received risperidone with and without carbamazepine.  In these|
01326|048|D|patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone|
01326|049|D|concentrations were lower during concurrent carbamazepine.(4)|
01326|050|D|   A study in eight patients examined the effects of the addition of|
01326|051|D|risperidone (1 mg daily) to carbamazepine (400 mg to 1200 mg daily).  After|
01326|052|D|two weeks of risperidone, carbamazepine levels increased 19%.(3)|
01326|053|D|   In a case report, a patient developed an exacerbation of psychotic|
01326|054|D|symptoms four weeks after the addition of carbamazepine (800 mg daily) to|
01326|055|D|his regimen.  Plasma levels of risperidone and 9-hydroxyrisperidone had|
01326|056|D|decreased by 77% and 63%, respectively.(5)|
01326|057|B||
01326|058|R|REFERENCES:|
01326|059|B||
01326|060|R|1.Risperdal Consta (risperidone long acting injection) US prescribing|1
01326|061|R|  information. Janssen Pharmaceutical Ltd. September, 2011.|1
01326|062|R|2.Ono S, Mihara K, Suzuki A, Kondo T, Yasui-Furukori N, Furukori H, de Vries|2
01326|063|R|  R, Kaneko S. Significant pharmacokinetic interaction between risperidone|2
01326|064|R|  and carbamazepine: its relationship with CYP2D6 genotypes.|2
01326|065|R|  Psychopharmacology (Berl) 2002 Jun;162(1):50-4.|2
01326|066|R|3.Mula M, Monaco F. Carbamazepine-risperidone interactions in patients with|2
01326|067|R|  epilepsy. Clin Neuropharmacol 2002 Mar-Apr;25(2):97-100.|2
01326|068|R|4.Spina E, Avenoso A, Facciola G, Salemi M, Scordo MG, Giacobello T, Madia|2
01326|069|R|  AG, Perucca E. Plasma concentrations of risperidone and|2
01326|070|R|  9-hydroxyrisperidone: effect of comedication with carbamazepine or|2
01326|071|R|  valproate. Ther Drug Monit 2000 Aug;22(4):481-5.|2
01326|072|R|5.Spina E, Scordo MG, Avenoso A, Perucca E. Adverse drug interaction between|3
01326|073|R|  risperidone and carbamazepine in a patient with chronic schizophrenia and|3
01326|074|R|  deficient CYP2D6 activity. J Clin Psychopharmacol 2001 Feb;21(1):108-9.|3
01327|001|T|MONOGRAPH TITLE:  Voriconazole/Atazanavir; Cobicistat; Ritonavir|
01327|002|B||
01327|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01327|004|L|of severe adverse interaction.|
01327|005|B||
01327|006|A|MECHANISM OF ACTION:  Ritonavir may induce the metabolism of voriconazole by|
01327|007|A|CYP2C9 and CYP2C19.(1,2)  Voriconazole may induce the metabolism of low-dose|
01327|008|A|ritonavir.(1)|
01327|009|A|   Voriconazole may inhibit the metabolism of cobicistat by CYP3A4.(1,3)|
01327|010|A|   There is no data on the concurrent use of atazanavir and voriconazole but|
01327|011|A|their interaction is likely mediated by CYP3A4.(4,5)|
01327|012|B||
01327|013|E|CLINICAL EFFECTS:  Concurrent use of ritonavir may result in decreased|
01327|014|E|levels of voriconazole and therapeutic failure.  Concurrent use of|
01327|015|E|voriconazole and low-dose ritonavir may also result in decreased levels of|
01327|016|E|ritonavir.(1,2)|
01327|017|E|   The combination of voriconazole with cobicistat may result in increased|
01327|018|E|levels and toxicity of cobicistat.(3)|
01327|019|B||
01327|020|P|PREDISPOSING FACTORS:  None determined.|
01327|021|B||
01327|022|M|PATIENT MANAGEMENT:  The US Department of Health and Human Services HIV|
01327|023|M|treatment guidelines recommend not to coadminister voriconazole with|
01327|024|M|ritonavir or cobicistat unless benefit outweighs risk.  If unboosted|
01327|025|M|atazanavir is used concurrently with voriconazole, monitoring of|
01327|026|M|voriconazole concentrations is recommended.(5)|
01327|027|M|   The US manufacturers of voriconazole(1) and ritonavir(2) state that|
01327|028|M|concurrent use of voriconazole with ritonavir (400 mg twice daily) is|
01327|029|M|contraindicated.  The concurrent use of voriconazole with low-dose ritonavir|
01327|030|M|(100 mg twice daily) should be avoided, unless the potential benefits|
01327|031|M|justifies the risk to the patient.(2,5)|
01327|032|M|   The Canadian manufacturer of nirmatrelvir/ritonavir states that|
01327|033|M|concurrent use with voriconazole is contraindicated due to a risk of|
01327|034|M|reduction in voriconazole plasma concentrations and possible loss of|
01327|035|M|effect.(6)|
01327|036|B||
01327|037|D|DISCUSSION:  In a study in healthy subjects, ritonavir (400 mg twice daily)|
01327|038|D|decreased voriconazole (400 mg twice daily) maximum concentration (Cmax) and|
01327|039|D|area-under-curve (AUC) by 66% and by 82%, respectively.  There were no|
01327|040|D|significant effects on ritonavir Cmax or AUC.(1,2)|
01327|041|D|   In a study in healthy subjects, ritonavir (100 mg twice daily) decreased|
01327|042|D|voriconazole (400 mg twice daily for one day, then 200 mg twice daily) Cmax|
01327|043|D|and AUC by 24% and 39%, respectively.  Ritonavir Cmax and AUC decreased by|
01327|044|D|24% and 14%, respectively.(1)|
01327|045|D|   Conversely, in a study of 20 healthy subjects, ritonavir (300 mg twice|
01327|046|D|daily for 2 days) increased voriconazole (400 mg single dose) Cmax and AUC|
01327|047|D|by 17.5% and 3.5 fold respectively.(7)|
01327|048|B||
01327|049|R|REFERENCES:|
01327|050|B||
01327|051|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01327|052|R|2.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01327|053|R|  December, 2019.|1
01327|054|R|3.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
01327|055|R|  June, 2025.|1
01327|056|R|4.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01327|057|R|  Squibb Company December, 2024.|1
01327|058|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01327|059|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01327|060|R|  HIV. Department of Health and Human Services. Available at|6
01327|061|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
01327|062|R|  new-guidelines June 13, 2021.|6
01327|063|R|6.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
01327|064|R|  Monograph. Pfizer Canada ULC October, 2023.|1
01327|065|R|7.Mikus G, Schowel V, Drzewinska M, Rengelshausen J, Ding R, Riedel KD,|2
01327|066|R|  Burhenne J, Weiss J, Thomsen T, Haefeli WE. Potent cytochrome P450 2C19|2
01327|067|R|  genotype-related interaction between voriconazole and the cytochrome P450|2
01327|068|R|  3A4 inhibitor ritonavir. Clin Pharmacol Ther 2006 Aug;80(2):126-35.|2
01328|001|T|MONOGRAPH TITLE:  Voriconazole/Efavirenz|
01328|002|B||
01328|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01328|004|L|of severe adverse interaction.|
01328|005|B||
01328|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of voriconazole by|
01328|007|A|CYP3A4.  Voriconazole may inhibit the metabolism of efavirenz by|
01328|008|A|CYP3A4.(1,2)|
01328|009|B||
01328|010|E|CLINICAL EFFECTS:  Concurrent use of efavirenz and voriconazole may result|
01328|011|E|in decreased levels of voriconazole, therapeutic failure of voriconazole,|
01328|012|E|elevated levels of efavirenz, and efavirenz toxicity.(1,2)|
01328|013|B||
01328|014|P|PREDISPOSING FACTORS:  None determined.|
01328|015|B||
01328|016|M|PATIENT MANAGEMENT:  The US manufacturers of efavirenz(1) and voriconazole|
01328|017|M|(2) state that concurrent use of standard doses of voriconazole and|
01328|018|M|efavirenz are contraindicated.|
01328|019|M|   When coadministered, the dose of voriconazole should be increased to 400|
01328|020|M|mg every 12 hours and the dose of efavirenz should be decreased to 300 mg|
01328|021|M|daily(1,2) using the capsule formulation.(1)  Efavirenz tablets should not|
01328|022|M|be broken.(1)|
01328|023|M|   The UK and US manufacturers of the combination product containing|
01328|024|M|efavirenz/emtricitabine/tenofovir disoproxil fumarate states that this|
01328|025|M|product should not be used with voriconazole because it is a fixed dose of|
01328|026|M|efavirenz that cannot be adjusted.(3,4)|
01328|027|B||
01328|028|D|DISCUSSION:  In a study in healthy subjects, efavirenz (400 mg daily)|
01328|029|D|decreased voriconazole (400 mg twice daily for 1 day, then 200 mg twice|
01328|030|D|daily) maximum concentration (Cmax) and area-under-curve (AUC) by 61% and by|
01328|031|D|77%, respectively.  Efavirenz Cmax and AUC increased by 38% and by 44%,|
01328|032|D|respectively.(1,2)|
01328|033|D|   In a study in healthy males, concurrent administration of voriconazole|
01328|034|D|(300 mg twice daily) with efavirenz (300 mg daily) decreased voriconazole|
01328|035|D|AUC and Cmax by 55% and 36%, when compared to levels achieved with|
01328|036|D|voriconazole 200 mg twice daily.  When compared to levels achieved with|
01328|037|D|efavirenz 600 mg daily, efavirenz AUC was equivalent and Cmax decreased by|
01328|038|D|14%.(1,2)|
01328|039|D|   In a study in healthy males, concurrent administration of voriconazole|
01328|040|D|(400 mg twice daily) with efavirenz (300 mg daily) decreased voriconazole|
01328|041|D|AUC by 7% and increased voriconazole Cmax by 23%, when compared to levels|
01328|042|D|achieved with voriconazole 200 mg twice daily.  When compared to levels|
01328|043|D|achieved with efavirenz 600 mg daily, efavirenz Cmax was equivalent and AUC|
01328|044|D|increased by 17%.(1,2)|
01328|045|B||
01328|046|R|REFERENCES:|
01328|047|B||
01328|048|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01328|049|R|  Company November, 2023.|1
01328|050|R|2.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01328|051|R|3.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) UK summary|1
01328|052|R|  of product characteristics. Gilead  Sciences Ltd July 8, 2020.|1
01328|053|R|4.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01328|054|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01329|001|T|MONOGRAPH TITLE:  Cinacalcet/Strong CYP3A4 Inhibitors|
01329|002|B||
01329|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01329|004|L|take action as needed.|
01329|005|B||
01329|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
01329|007|A|cinacalcet by CYP3A4.(1)|
01329|008|B||
01329|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
01329|010|E|elevated levels of and toxicity from cinacalcet.(1)|
01329|011|B||
01329|012|P|PREDISPOSING FACTORS:  None determined.|
01329|013|B||
01329|014|M|PATIENT MANAGEMENT:  PTH and serum calcium concentrations should be closely|
01329|015|M|monitored if a strong CYP3A4 inhibitor is initiated or discontinued in|
01329|016|M|patients receiving cinacalcet therapy.  The dosage of cinacalcet may need to|
01329|017|M|be adjusted.(1)|
01329|018|B||
01329|019|D|DISCUSSION:  In a study, administration of cinacalcet on day 5 of a seven|
01329|020|D|day course of ketoconazole (200 mg twice daily) increased cinacalcet|
01329|021|D|area-under-curve (AUC) and maximum concentration (Cmax) by 2.3-fold and by|
01329|022|D|2.2-fold, respectively.(1)|
01329|023|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
01329|024|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
01329|025|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
01329|026|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
01329|027|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib|
01329|028|D|and voriconazole.(2)|
01329|029|B||
01329|030|R|REFERENCES:|
01329|031|B||
01329|032|R|1.Sensipar (cinacalcet hydrochloride) US prescribing information. Amgen Inc.|1
01329|033|R|  March, 2019.|1
01329|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
01329|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01330|001|T|MONOGRAPH TITLE:  Chlorpromazine/Pindolol; Propranolol|
01330|002|B||
01330|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01330|004|L|take action as needed.|
01330|005|B||
01330|006|A|MECHANISM OF ACTION:  Pindolol and propranolol may inhibit the metabolism of|
01330|007|A|chlorpromazine.  Chlorpromazine may inhibit the metabolism of pindolol.|
01330|008|B||
01330|009|E|CLINICAL EFFECTS:  Increased plasma levels with resultant enhanced|
01330|010|E|pharmacologic response of each or both drugs as well as increased risk of|
01330|011|E|toxicity.|
01330|012|B||
01330|013|P|PREDISPOSING FACTORS:  None determined.|
01330|014|B||
01330|015|M|PATIENT MANAGEMENT:  If both drugs are administered, adjust the dose of one|
01330|016|M|or both drugs as needed based on patient response.  Dosage adjustments may|
01330|017|M|also be required if one agent is discontinued.|
01330|018|B||
01330|019|D|DISCUSSION:  In study in five subjects, propranolol's bioavailability|
01330|020|D|increased up to 33% with concurrent chlorpromazine administration.  The|
01330|021|D|plasma levels of propranolol were increased in three of the subjects.(1)|
01330|022|D|Conversely, chlorpromazine levels have been reported to increase with|
01330|023|D|concomitant propranolol therapy.(2,3)  In one study, ten patients received|
01330|024|D|propranolol (mean dose 8.1 mg/Kg/day) and chlorpromazine (mean dose 6.7|
01330|025|D|mg/Kg/day). In six of the patients, chlorpromazine levels increased|
01330|026|D|five-fold compared to chlorpromazine alone; the active metabolites of|
01330|027|D|chlorpromazine were increased as well.(2)  In a case report, a patient|
01330|028|D|maintained on chlorpromazine (800 mg/day) and thiothixene developed|
01330|029|D|delirium, hallucinations, a grand mal seizure, and photosensitivity two|
01330|030|D|weeks after the initiation of propranolol (1200 mg/day).  When propranolol|
01330|031|D|was discontinued and the dose of chlorpromazine was decreased, the patient's|
01330|032|D|symptoms resolved.(3)|
01330|033|D|   In another study in seven patients, pindolol levels were found to be|
01330|034|D|increased when administered with thioridazine.(4)|
01330|035|B||
01330|036|R|REFERENCES:|
01330|037|B||
01330|038|R|1.Vestal RE, Kornhauser DM, Hollifield JW, Shand DG. Inhibition of|2
01330|039|R|  propranolol metabolism by chlorpromazine. Clin Pharmacol Ther 1979 Jan;|2
01330|040|R|  25(1):19-24.|2
01330|041|R|2.Peet M, Middlemiss DN, Yates RA. Propranolol in schizophrenia. II.|2
01330|042|R|  Clinical and biochemical aspects of combining propranolol with|2
01330|043|R|  chlorpromazine. Br J Psychiatry 1981 Aug;139:112-7.|2
01330|044|R|3.Miller FA, Rampling D. Adverse effects of combined propranolol and|3
01330|045|R|  chlorpromazine therapy. Am J Psychiatry 1982 Sep;139(9):1198-9.|3
01330|046|R|4.Greendyke RM, Gulya A. Effect of pindolol administration on serum levels|2
01330|047|R|  of thioridazine, haloperidol, phenytoin, and phenobarbital. J Clin|2
01330|048|R|  Psychiatry 1988 Mar;49(3):105-7.|2
01331|001|T|MONOGRAPH TITLE:  Levomethadone; Levomethadyl; Methadone/Itraconazole;|
01331|002|T|Ketoconazole|
01331|003|B||
01331|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01331|005|L|is contraindicated and generally should not be dispensed or administered to|
01331|006|L|the same patient.|
01331|007|B||
01331|008|A|MECHANISM OF ACTION:  Itraconazole(1) and ketoconazole(2) may inhibit the|
01331|009|A|metabolism of levomethadyl and methadone by CYP3A4.|
01331|010|A|   Levomethadone is an enantiomer of methadone.(3)|
01331|011|B||
01331|012|E|CLINICAL EFFECTS:  Concurrent administration of itraconazole(1) and|
01331|013|E|ketoconazole(2) may result in elevated levels of levomethadyl and methadone,|
01331|014|E|which may result in QTc prolongation and life-threatening arrhythmias.|
01331|015|E|   Elevated levels can also cause profound sedation, respiratory depression,|
01331|016|E|coma, and/or death.|
01331|017|E|   Methadone has been associated with serotonin syndrome.  Symptoms of|
01331|018|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
01331|019|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
01331|020|B||
01331|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01331|022|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01331|023|P|myocardial infarction, history of torsades de pointes, congenital long QT|
01331|024|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01331|025|P|gender, or advanced age.(4)|
01331|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01331|027|P|higher systemic concentrations of either QT prolonging drug are additional|
01331|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01331|029|P|drug concentrations include rapid infusion of an intravenous dose or|
01331|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01331|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01331|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01331|033|B||
01331|034|M|PATIENT MANAGEMENT:  The concurrent administration of itraconazole with|
01331|035|M|levomethadyl or methadone is contraindicated.(1)|
01331|036|M|   The US manufacturer of itraconazole states that methadone should not be|
01331|037|M|administered until at least 2 weeks after itraconazole treatment.(1)|
01331|038|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01331|039|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01331|040|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01331|041|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01331|042|M|   Respiratory depression can occur at any time during opioid therapy,|
01331|043|M|especially during therapy initiation and following dosage increases.  The|
01331|044|M|risk of opioid-related overdose or overdose-related death is increased with|
01331|045|M|higher opioid doses, and this risk persists over the course of therapy.|
01331|046|M|Consider these risks when using concurrently with agents that may increase|
01331|047|M|opioid drug levels.(5)|
01331|048|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
01331|049|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
01331|050|M|unresponsiveness.|
01331|051|M|   If concurrent therapy is warranted, patients should be monitored for|
01331|052|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
01331|053|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
01331|054|M|heart palpitations, restlessness, confusion, agitation, trouble with|
01331|055|M|coordination, or severe diarrhea.|
01331|056|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
01331|057|M|patients when prescribing or renewing an opioid analgesic or medicine to|
01331|058|M|treat opioid use disorder (OUD).  Consider prescribing opioid reversal|
01331|059|M|agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
01331|060|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
01331|061|M|as those taking CNS depressants) and when a patient has household|
01331|062|M|members/close contacts at risk for accidental overdose.  Discuss the options|
01331|063|M|for obtaining an opioid reversal agent (e.g., prescription,|
01331|064|M|over-the-counter, or as part of a community-based program).(6)|
01331|065|B||
01331|066|D|DISCUSSION:  Severe cardiovascular events, including QT prolongation,|
01331|067|D|torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden|
01331|068|D|death have been reported in patients receiving concurrent therapy with|
01331|069|D|itraconazole and levomethadyl(1) or methadone.(1,7)|
01331|070|D|   Ketoconazole is expected to increase methadone levels as well.(2)|
01331|071|B||
01331|072|R|REFERENCES:|
01331|073|B||
01331|074|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01331|075|R|  Products, L.P. February, 2024.|1
01331|076|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01331|077|R|  Pharmaceuticals February, 2014.|1
01331|078|R|3.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
01331|079|R|  Pharma AS November 30, 2018.|1
01331|080|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01331|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01331|082|R|  settings: a scientific statement from the American Heart Association and|6
01331|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01331|084|R|  2;55(9):934-47.|6
01331|085|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
01331|086|R|  prescribing information for all opioid pain medicines to provide|1
01331|087|R|  additional guidance for safe use. Available at:|1
01331|088|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
01331|089|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
01331|090|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
01331|091|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
01331|092|R|  recommends health care professionals discuss naloxone with all patients|1
01331|093|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
01331|094|R|  disorder. Available at:|1
01331|095|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
01331|096|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
01331|097|R|  d-pain July 23, 2020.|1
01331|098|R|7.NoorZurani MH, Vicknasingam B, Narayanan S. Itraconazole-induced torsade|3
01331|099|R|  de pointes in a patient receiving methadone substitution therapy. Drug|3
01331|100|R|  Alcohol Rev 2009 Nov;28(6):688-90.|3
01332|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Tibolone|
01332|002|B||
01332|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01332|004|L|take action as needed.|
01332|005|B||
01332|006|A|MECHANISM OF ACTION:  Tibolone may lower fibrinogen levels and increase|
01332|007|A|antithrombin III, plasminogen, and fibrinolytic activity(1) and it may|
01332|008|A|decrease factor VIIa, a vitamin K dependent coagulation factor.(2)|
01332|009|B||
01332|010|E|CLINICAL EFFECTS:  Concurrent use of tibolone and vitamin K antagonists may|
01332|011|E|increase the risk for bleeding.|
01332|012|B||
01332|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01332|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01332|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01332|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01332|017|P|risk for bleeding (e.g. NSAIDs).|
01332|018|B||
01332|019|M|PATIENT MANAGEMENT:  Patients maintained on anticoagulants should be closely|
01332|020|M|monitored if tibolone is initiated, adjusted, or discontinued.(1)  The|
01332|021|M|dosage of the anticoagulant may need to be adjusted.|
01332|022|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01332|023|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01332|024|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01332|025|M|patients with any symptoms.|
01332|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01332|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01332|028|M|anticoagulation in patients with active pathologic bleeding.|
01332|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01332|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01332|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01332|032|M|and/or swelling.|
01332|033|B||
01332|034|D|DISCUSSION:  A retrospective review identified five women in whom INR values|
01332|035|D|were elevated following the addition of tibolone to their warfarin (four|
01332|036|D|women) or phenindione (one woman) therapy.  Elevated INR values were seen|
01332|037|D|one to two weeks following the addition of tibolone.  In another patient,|
01332|038|D|INR values decreased following the discontinuation of tibolone from|
01332|039|D|concurrent warfarin therapy, necessitating a warfarin dosage increase from 6|
01332|040|D|mg/day to 7.5 mg/day.(2)|
01332|041|B||
01332|042|R|REFERENCES:|
01332|043|B||
01332|044|R|1.Livial (tibolone) Australian prescribing information. Merck Sharp & Dohme|1
01332|045|R|  (Australia) Pty Limited May 17, 2016.|1
01332|046|R|2.McLintock LA, Dykes A, Tait RC, Walker ID. Interaction between hormone|3
01332|047|R|  replacement therapy preparations and oral anticoagulant therapy. BJOG 2003|3
01332|048|R|  Aug;110(8):777-9.|3
01333|001|T|MONOGRAPH TITLE:  Selected Steroids/Antiretroviral CYP3A4 Inhibitors|
01333|002|B||
01333|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01333|004|L|of severe adverse interaction.|
01333|005|B||
01333|006|A|MECHANISM OF ACTION:  Antiretroviral CYP3A4 inhibitors may inhibit the|
01333|007|A|metabolism of corticosteroids metabolized by CYP3A4.|
01333|008|A|   Dexamethasone may induce metabolism of agents that are substrates of|
01333|009|A|CYP3A4.(1-13,50)|
01333|010|B||
01333|011|E|CLINICAL EFFECTS:  Concurrent use of antiretroviral CYP3A4 inhibitors may|
01333|012|E|result in increased systemic exposure to and effects from corticosteroids|
01333|013|E|metabolized by CYP3A4, including Cushing's syndrome and adrenal suppression.|
01333|014|E|   Concurrent dexamethasone may result in decreased levels and effectiveness|
01333|015|E|of CYP3A4 substrates.|
01333|016|B||
01333|017|P|PREDISPOSING FACTORS:  None determined.|
01333|018|B||
01333|019|M|PATIENT MANAGEMENT:  If possible, avoid concurrent therapy of betamethasone,|
01333|020|M|budesonide, ciclesonide, fluticasone, dexamethasone, methylprednisolone, or|
01333|021|M|triamcinolone with antiretroviral CYP3A4 inhibitors.  Alternative|
01333|022|M|corticosteroids that are less affected by CYP3A4 inhibitors should be|
01333|023|M|considered, like beclomethasone, prednisone, and prednisolone.  If|
01333|024|M|concurrent therapy is warranted, patients should be closely monitored for|
01333|025|M|systemic effects.  The corticosteroid may need to be discontinued.|
01333|026|M|   Patients receiving concurrent therapy with dexamethasone and substrates|
01333|027|M|of CYP3A4 should also be monitored for decreased effectiveness of the CYP3A4|
01333|028|M|substrate.|
01333|029|M|   The manufacturers of nasal fluticasone(14-16) and fluticasone for|
01333|030|M|inhalation(17) state that concurrent use of fluticasone and atazanavir,|
01333|031|M|indinavir, nelfinavir, ritonavir or saquinavir is not recommended.|
01333|032|M|   The US manufacturers of atazanavir,(1) fosamprenavir,(5) indinavir(6) and|
01333|033|M|nelfinavir(8) recommend caution with concurrent use of inhaled or nasal|
01333|034|M|fluticasone. Consider alternatives to fluticasone if long-term use is|
01333|035|M|required.|
01333|036|B||
01333|037|D|DISCUSSION:  In a study, boceprevir (800 mg TID for 7 days) increased the|
01333|038|D|area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%.  The|
01333|039|D|maximum concentration (Cmax) and AUC of prednisolone increased by 16% and|
01333|040|D|37%, respectively.(2)|
01333|041|D|   A study of 14 healthy adults found that concurrent use of ketoconazole|
01333|042|D|with ciclesonide increased the AUC of ciclesonide's active metabolite,|
01333|043|D|des-ciclesonide, by approximately 3.6-fold at steady state, while levels of|
01333|044|D|ciclesonide remained unchanged.  However, the study concluded that no dosage|
01333|045|D|adjustments were required because ciclesonide has a very low potential to|
01333|046|D|cause side effects.(18)|
01333|047|D|   A study in 18 healthy subjects examined the effects of ritonavir (100 mg|
01333|048|D|twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects,|
01333|049|D|fluticasone was undetectable (<10 pg/ml) when administered alone.  In|
01333|050|D|subjects in whom fluticasone was detectable when given alone, Cmax and|
01333|051|D|area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively.|
01333|052|D|With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml|
01333|053|D|and 3102.6 pg x hr/ml, respectively.(7,11,14) This reflects increases in|
01333|054|D|Cmax and AUC by 25-fold and 350-fold, respectively.(3)  The cortisol AUC|
01333|055|D|decreased by 86%.(6,14-16)|
01333|056|D|   In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4|
01333|057|D|and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold|
01333|058|D|and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(19)|
01333|059|D|   There have been several case reports of Cushing's syndrome in patients|
01333|060|D|treated concurrently with ritonavir and inhaled budesonide,(19-20)|
01333|061|D|dexamethasone,(22) injectable triamcinolone,(23-26) nasal|
01333|062|D|fluticasone.(28-46)  Hepatitis has also been reported with concurrent|
01333|063|D|budesonide and ritonavir.(47)|
01333|064|D|   In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3|
01333|065|D|days) increased the AUC, Cmax, and elimination half-life of|
01333|066|D|methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(48)|
01333|067|D|   In a study in 8 healthy subjects, following nefazodone administration the|
01333|068|D|following changes were seen with methylprednisolone: mean (+/-SD) area under|
01333|069|D|the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966|
01333|070|D|+/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs.|
01333|071|D|14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was|
01333|072|D|longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(49)|
01333|073|D|   Selected steroids linked to this monograph include: betamethasone,|
01333|074|D|budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, and|
01333|075|D|triamcinolone.(50)|
01333|076|D|   Selected CYP3A4 inhibitors and substrates linked to this monograph|
01333|077|D|include:  atazanavir, cobicistat, darunavir, fosamprenavir, indinavir,|
01333|078|D|lenacapavir, lopinavir, nelfinavir, saquinavir, and tipranavir.(50)|
01333|079|B||
01333|080|R|REFERENCES:|
01333|081|B||
01333|082|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01333|083|R|  Squibb Company December, 2024.|1
01333|084|R|2.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
01333|085|R|  January, 2017.|1
01333|086|R|3.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
01333|087|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
01333|088|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01333|089|R|  March, 2023.|1
01333|090|R|5.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01333|091|R|  March, 2019.|1
01333|092|R|6.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01333|093|R|  September, 2016.|1
01333|094|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01333|095|R|  Laboratories December, 2019.|1
01333|096|R|8.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01333|097|R|  Pharmaceuticals, Inc. September, 2016.|1
01333|098|R|9.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01333|099|R|  December, 2019.|1
01333|100|R|10.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01333|101|R|   Laboratories, Inc. March, 2019.|1
01333|102|R|11.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
01333|103|R|   Incorporated October, 2013.|1
01333|104|R|12.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01333|105|R|   Pharmaceuticals, Inc. April, 2024.|1
01333|106|R|13.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
01333|107|R|   November 2024.|1
01333|108|R|14.Flovent HFA inhalation (fluticasone propionate) US prescribing|1
01333|109|R|   information. GlaxoSmithKline January, 2019.|1
01333|110|R|15.Flovent Rotadisk (fluticasone propionate) US prescribing information.|1
01333|111|R|   GlaxoSmithKline March, 2004.|1
01333|112|R|16.Flonase Nasal Spray (fluticasone propionate) US prescribing information.|1
01333|113|R|   GlaxoSmithKline January, 2019.|1
01333|114|R|17.Flovent Diskus (fluticasone propionate) US prescribing information.|1
01333|115|R|   GlaxoSmithKline January, 2019.|1
01333|116|R|18.Bohmer GM, Drollmann A, Gleiter CH, Nave R. Effect of coadministered|2
01333|117|R|   ketoconazole, a strong cytochrome P450 3A4 enzyme inhibitor, on the|2
01333|118|R|   pharmacokinetics of ciclesonide and its active metabolite|2
01333|119|R|   desisobutyryl-ciclesonide. Clin Pharmacokinet 2008;47(5):343-9.|2
01333|120|R|19.Penzak SR, Formentini E, Alfaro RM, Long M, Natarajan V, Kovacs J.|2
01333|121|R|   Prednisolone pharmacokinetics in the presence and absence of ritonavir|2
01333|122|R|   after oral prednisone administration to healthy volunteers. J Acquir|2
01333|123|R|   Immune Defic Syndr 2005 Dec 15;40(5):573-80.|2
01333|124|R|20.Kedem E, Shahar E, Hassoun G, Pollack S. Iatrogenic Cushing's syndrome|3
01333|125|R|   due to coadministration of ritonavir and inhaled budesonide in an|3
01333|126|R|   asthmatic human immunodeficiency virus infected patient. J Asthma 2010|3
01333|127|R|   Sep;47(7):830-1.|3
01333|128|R|21.Gray D, Roux P, Carrihill M, Klein M. Adrenal suppression and Cushing's|3
01333|129|R|   syndrome secondary to ritonavir and budesonide. S Afr Med J 2010 May;|3
01333|130|R|   100(5):296-7.|3
01333|131|R|22.Ebright JR, Stellini MA, Tselis AC. Spinal epidural lipomatosis in a|3
01333|132|R|   human immunodeficiency virus-positive patient receiving steroids and|3
01333|133|R|   protease inhibitor therapy. Clin Infect Dis 2001 Mar 1;32(5):E90-1.|3
01333|134|R|23.Herold MA, Gunthard HF. Cushing syndrome after steroid-infiltration in|3
01333|135|R|   two HIV-patients with antiretroviral therapy. Praxis (Bern 1994) 2010 Jul|3
01333|136|R|   7;99(14):863-5.|3
01333|137|R|24.Danaher PJ, Salsbury TL, Delmar JA. Metabolic derangement after injection|3
01333|138|R|   of triamcinolone into the hip of an HIV-infected patient receiving|3
01333|139|R|   ritonavir. Orthopedics 2009 Jun;32(6):450.|3
01333|140|R|25.Dort K, Padia S, Wispelwey B, Moore CC. Adrenal suppression due to an|3
01333|141|R|   interaction between ritonavir and injected triamcinolone: a case report.|3
01333|142|R|   AIDS Res Ther 2009;6:10.|3
01333|143|R|26.Ramanathan R, Pau AK, Busse KH, Zemskova M, Nieman L, Kwan R, Hammer JH,|3
01333|144|R|   Mican JM, Maldarelli F. Iatrogenic Cushing syndrome after epidural|3
01333|145|R|   triamcinolone injections in an HIV type 1-infected patient receiving|3
01333|146|R|   therapy with ritonavir-lopinavir. Clin Infect Dis 2008 Dec 15;|3
01333|147|R|   47(12):e97-9.|3
01333|148|R|27.Yombi JC, Maiter D, Belkhir L, Nzeusseu A, Vandercam B. Iatrogenic|3
01333|149|R|   Cushing's syndrome and secondary adrenal insufficiency after a single|3
01333|150|R|   intra-articular administration of triamcinolone acetonide in HIV-infected|3
01333|151|R|   patients treated with ritonavir. Clin Rheumatol 2008 Dec;27 Suppl|3
01333|152|R|   2:S79-82.|3
01333|153|R|28.Rouanet I, Peyriere H, Mauboussin JM, Vincent D. Cushing's syndrome in a|3
01333|154|R|   patient treated by ritonavir/lopinavir and inhaled fluticasone. HIV Med|3
01333|155|R|   2003 Apr;4(2):149-50.|3
01333|156|R|29.Clevenbergh P, Corcostegui M, Gerard D, Hieronimus S, Mondain V,|3
01333|157|R|   Chichmanian RM, Sadoul JL, Dellamonica P. Iatrogenic Cushing's syndrome|3
01333|158|R|   in an HIV-infected patient treated with inhaled corticosteroids|3
01333|159|R|   (fluticasone propionate) and low dose ritonavir enhanced PI containing|3
01333|160|R|   regimen. J Infect 2002 Apr;44(3):194-5.|3
01333|161|R|30.Chen F, Kearney T, Robinson S, Daley-Yates PT, Waldron S, Churchill DR.|3
01333|162|R|   Cushing's syndrome and severe adrenal suppression in patients treated|3
01333|163|R|   with ritonavir and inhaled nasal fluticasone. Sex Transm Infect 1999 Aug;|3
01333|164|R|   75(4):274.|3
01333|165|R|31.Hillebrand-Haverkort ME, Prummel MF, ten Veen JH. Ritonavir-induced|3
01333|166|R|   Cushing's syndrome in a patient treated with nasal fluticasone. AIDS 1999|3
01333|167|R|   Sep 10;13(13):1803.|3
01333|168|R|32.Dupont C, Giraud V, Leporrier J, Greffe S, Rouveix E, Chinet T. Cushing's|3
01333|169|R|   syndrome induced by combined treatment with inhaled fluticasone and oral|3
01333|170|R|   ritonavir. Rev Mal Respir 2009 Sep;26(7):779-82.|3
01333|171|R|33.Collet-Gaudillat C, Roussin-Bretagne S, Desforges-Bullet V, Petit-Aubert|3
01333|172|R|   G, Doll J, Beressi JP. Iatrogenic Cushing's syndrome, diabetes mellitus|3
01333|173|R|   and secondary adrenal failure in a human immunodeficiency virus patient|3
01333|174|R|   treated with ritonavir boosted atazanavir and fluticasone. Ann Endocrinol|3
01333|175|R|   (Paris) 2009 Sep;70(4):252-5.|3
01333|176|R|34.Valin N, De Castro N, Garrait V, Bergeron A, Bouche C, Molina JM.|3
01333|177|R|   Iatrogenic Cushing's syndrome in HIV-infected patients receiving|3
01333|178|R|   ritonavir and inhaled fluticasone: description of 4 new cases and review|3
01333|179|R|   of the literature. J Int Assoc Physicians AIDS Care (Chic) 2009 Mar-Apr;|3
01333|180|R|   8(2):113-21.|3
01333|181|R|35.Bouldouyre MA, Moachon L, Guillevin L, Launay O. Iatrogenic Cushing|3
01333|182|R|   syndrome in an HIV-infected female patient: be careful about interaction|3
01333|183|R|   inhaled corticosteroids-ritonavir!. Presse Med 2008 Dec;37(12):1834-5.|3
01333|184|R|36.Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and|3
01333|185|R|   Cushing's syndrome secondary to an interaction between ritonavir and|3
01333|186|R|   fluticasone: a review of the literature. HIV Med 2008 Jul;9(6):389-96.|3
01333|187|R|37.Jinno S, Goshima C. Progression of Kaposi sarcoma associated with|3
01333|188|R|   iatrogenic Cushing syndrome in a person with HIV/AIDS. AIDS Read 2008|3
01333|189|R|   Feb;18(2):100-4.|3
01333|190|R|38.St Germain RM, Yigit S, Wells L, Girotto JE, Salazar JC. Cushing syndrome|3
01333|191|R|   and severe adrenal suppression caused by fluticasone and protease|3
01333|192|R|   inhibitor combination in an HIV-infected adolescent. AIDS Patient Care|3
01333|193|R|   STDS 2007 Jun;21(6):373-7.|3
01333|194|R|39.Bhumbra NA, Sahloff EG, Oehrtman SJ, Horner JM. Exogenous Cushing|3
01333|195|R|   syndrome with inhaled fluticasone in a child receiving|3
01333|196|R|   lopinavir/ritonavir. Ann Pharmacother 2007 Jul;41(7):1306-9.|3
01333|197|R|40.Pessanha TM, Campos JM, Barros AC, Pone MV, Garrido JR, Pone SM.|3
01333|198|R|   Iatrogenic Cushing's syndrome in a adolescent with AIDSs on ritonavir and|3
01333|199|R|   inhaled fluticasone. Case report and literature review. AIDS 2007 Feb 19;|3
01333|200|R|   21(4):529-32.|3
01333|201|R|41.Arrington-Sanders R, Hutton N, Siberry GK. Ritonavir-fluticasone|3
01333|202|R|   interaction causing Cushing syndrome in HIV-infected children and|3
01333|203|R|   adolescents. Pediatr Infect Dis J 2006 Nov;25(11):1044-8.|3
01333|204|R|42.Johnson SR, Marion AA, Vrchoticky T, Emmanuel PJ, Lujan-Zilbermann J.|3
01333|205|R|   Cushing syndrome with secondary adrenal insufficiency from concomitant|3
01333|206|R|   therapy with ritonavir and fluticasone. J Pediatr 2006 Mar;148(3):386-8.|3
01333|207|R|43.Gillett MJ, Cameron PU, Nguyen HV, Hurley DM, Mallal SA. Iatrogenic|3
01333|208|R|   Cushing's syndrome in an HIV-infected patient treated with ritonavir and|3
01333|209|R|   inhaled fluticasone. AIDS 2005 Apr 29;19(7):740-1.|3
01333|210|R|44.Samaras K, Pett S, Gowers A, McMurchie M, Cooper DA. Iatrogenic Cushing's|3
01333|211|R|   syndrome with osteoporosis and secondary adrenal failure in human|3
01333|212|R|   immunodeficiency virus-infected patients receiving inhaled|3
01333|213|R|   corticosteroids and ritonavir-boosted protease inhibitors: six cases. J|3
01333|214|R|   Clin Endocrinol Metab 2005 Jul;90(7):4394-8.|3
01333|215|R|45.Soldatos G, Sztal-Mazer S, Woolley I, Stockigt J. Exogenous|3
01333|216|R|   glucocorticoid excess as a result of ritonavir-fluticasone interaction.|3
01333|217|R|   Intern Med J 2005 Jan;35(1):67-8.|3
01333|218|R|46.Gupta SK, Dube MP. Exogenous cushing syndrome mimicking human|3
01333|219|R|   immunodeficiency virus lipodystrophy. Clin Infect Dis 2002 Sep 15;|3
01333|220|R|   35(6):E69-71.|3
01333|221|R|47.Sagir A, Wettstein M, Oette M, Erhardt A, Haussinger D.|3
01333|222|R|   Budesonide-induced acute hepatitis in an HIV-positive patient with|3
01333|223|R|   ritonavir as a co-medication. AIDS 2002 May 24;16(8):1191-2.|3
01333|224|R|48.Varis T, Backman JT, Kivisto KT, Neuvonen PJ. Diltiazem and mibefradil|2
01333|225|R|   increase the plasma concentrations and greatly enhance the|2
01333|226|R|   adrenal-suppressant effect of oral methylprednisolone. Clin Pharmacol|2
01333|227|R|   Ther 2000 Mar;67(3):215-21.|2
01333|228|R|49.Kotlyar M, Brewer ER, Golding M, Carson SW. Nefazodone inhibits|2
01333|229|R|   methylprednisolone disposition and enhances its adrenal-suppressant|2
01333|230|R|   effect. J Clin Psychopharmacol 2003 Dec;23(6):652-6.|2
01333|231|R|50.This information is based on an extract from the Certara Drug Interaction|6
01333|232|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01334|001|T|MONOGRAPH TITLE:  Methadone; Oxycodone/St. John's Wort (mono deleted|
01334|002|T|02/25/2016)|
01334|003|B||
01334|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01334|005|L|take action as needed.|
01334|006|B||
01334|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01334|008|A|methadone(1,2) and oxycodone(3) by CYP3A4.|
01334|009|B||
01334|010|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
01334|011|E|methadone(1,2) and oxycodone(3) concentrations and effectiveness.  Some|
01334|012|E|patients may result in withdrawal symptoms.(1,2)|
01334|013|B||
01334|014|P|PREDISPOSING FACTORS:  None determined.|
01334|015|B||
01334|016|M|PATIENT MANAGEMENT:  Patients maintained on methadone or oxycodone should be|
01334|017|M|advised that St. John's wort may lower drug serum levels, resulting in|
01334|018|M|withdrawal symptoms.  Patients should be observed for withdrawal symptoms.|
01334|019|M|The dosage of methadone or oxycodone may need to be adjusted if St. John's|
01334|020|M|wort is initiated or discontinued.|
01334|021|B||
01334|022|D|DISCUSSION:  In a study in four patients in a methadone maintenance program,|
01334|023|D|the addition of St. John's wort (900 mg daily) decreased methadone levels by|
01334|024|D|47% (range: 19%-60%).  Two patients reported withdrawal symptoms.(1)|
01334|025|D|   In a randomized controlled trial of 12 healthy participants St. John's|
01334|026|D|wort decreased the oxycodone AUC by 50%, shortened the oxycodone elimination|
01334|027|D|half-life, and decreased the self-reported drug effect of oxycodone compared|
01334|028|D|to placebo.(3)|
01334|029|B||
01334|030|R|REFERENCES:|
01334|031|B||
01334|032|R|1.Eich-Hochli D, Oppliger R, Golay KP, Baumann P, Eap CB. Methadone|2
01334|033|R|  maintenance treatment and St. John's Wort - a case report.|2
01334|034|R|  Pharmacopsychiatry 2003 Jan;36(1):35-7.|2
01334|035|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
01334|036|R|  Pharmaceuticals Corp. December, 2016.|1
01334|037|R|3.Nieminen TH, Hagelberg NM, Saari TI, Neuvonen M, Laine K, Neuvonen PJ,|2
01334|038|R|  Olkkola KT. St John's wort greatly reduces the concentrations of oral|2
01334|039|R|  oxycodone. Eur J Pain 2010 Sep;14(8):854-9.|2
01335|001|T|MONOGRAPH TITLE:  Trazodone/Selected CYP3A4 Inhibitors|
01335|002|B||
01335|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01335|004|L|of severe adverse interaction.|
01335|005|B||
01335|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
01335|007|A|trazodone.(1)  Trazodone has been shown to prolong the QT interval.|
01335|008|A|Trazodone's active metabolite meta-chlorophenylpiperazine (m-CPP) is|
01335|009|A|metabolized by CYP2D6. Cobicistat is also a weak CYP2D6 inhibitor.(1)|
01335|010|B||
01335|011|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
01335|012|E|elevated levels of and adverse effects from trazodone, including nausea,|
01335|013|E|dizziness, hypotension, syncope, serotonin syndrome,(9) and cardiac|
01335|014|E|arrhythmias including QT prolongation or torsades de pointes, which may be|
01335|015|E|life-threatening.(1)|
01335|016|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
01335|017|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
01335|018|E|rigidity.|
01335|019|B||
01335|020|P|PREDISPOSING FACTORS:  This interaction may be more severe with larger|
01335|021|P|and/or routine doses of trazodone.|
01335|022|P|   The risk of QT prolongation or torsades de pointes may be increased in|
01335|023|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01335|024|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01335|025|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01335|026|P|advanced age.(10)|
01335|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01335|028|P|higher systemic concentrations of either QT prolonging drug are additional|
01335|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01335|030|P|drug concentrations include rapid infusion of an intravenous dose or|
01335|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01335|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01335|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(10)|
01335|034|B||
01335|035|M|PATIENT MANAGEMENT:  A lower dose of trazodone should be considered in|
01335|036|M|patients receiving CYP3A4 inhibitors.(1-7)  Instruct patients to report|
01335|037|M|dizziness, any irregular heartbeat, fainting episodes or excessive daytime|
01335|038|M|sedation.|
01335|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01335|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01335|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01335|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01335|043|M|   In addition to QT prolongation, patients should be monitored for signs|
01335|044|M|and symptoms of serotonin syndrome.  Instruct patients to report muscle|
01335|045|M|twitching, tremors, shivering and stiffness, fever, heavy sweating, heart|
01335|046|M|palpitations, restlessness, confusion, agitation, trouble with coordination,|
01335|047|M|or severe diarrhea.|
01335|048|B||
01335|049|D|DISCUSSION:  In a cross-over study in 10 healthy subjects, pretreatment with|
01335|050|D|clarithromycin (500 mg, 4 doses given over 32 hours) increased the maximum|
01335|051|D|concentration, (Cmax) half-life, and area-under-curve (AUC) of a single dose|
01335|052|D|of trazodone (50 mg) by 35% (p<0.005), 96% (p<0.02), and 99% (p<0.001),|
01335|053|D|respectively.  Trazodone oral clearance decreased by 46% (p<0.001).|
01335|054|D|Pharmacodynamic effects of trazodone were also increased, as shown by|
01335|055|D|changes in self-rated sedation, observer-rated sedation, digit-symbol|
01335|056|D|substitution test (DSST) scores.(11)|
01335|057|D|   In a study in 10 healthy subjects, short-term ritonavir (four doses of|
01335|058|D|200 mg twice daily) increased the AUC and half-life of a single dose of|
01335|059|D|trazodone (50 mg) by 2.4-fold and 2.2-fold, respectively.  The Cmax of|
01335|060|D|trazodone increased 34% and its clearance decreased 52%.  Three subjects|
01335|061|D|experienced nausea, dizziness, or hypotension and one of these subjects also|
01335|062|D|experienced syncope during concurrent administration.(3)|
01335|063|D|   In a single case report, a female experienced serotonin syndrome|
01335|064|D|characterized by high blood pressure (240/120 mmHg); intermittent numbness|
01335|065|D|of the right side of her lips and nose and fingers of the right hand;|
01335|066|D|nausea; loose stools; flushed, pruritic skin; confusion; and difficulty|
01335|067|D|concentrating four days after the addition of trazodone (25-50 mg daily) to|
01335|068|D|nefazodone.(9)|
01335|069|D|   An in vitro study in human liver microsomes showed that indinavir,|
01335|070|D|ketoconazole, and ritonavir inhibited the metabolism of trazodone.(8)|
01335|071|D|   Amprenavir, atazanavir, boceprevir, cobicistat, darunavir, fosamprenavir,|
01335|072|D|grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
01335|073|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir,|
01335|074|D|paritaprevir, tipranavir, telaprevir, and tucatinib are considered to be|
01335|075|D|potent inhibitors of the CYP3A4 isoenzyme.(12)|
01335|076|B||
01335|077|R|REFERENCES:|
01335|078|B||
01335|079|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
01335|080|R|  Labopharm Inc. November, 2012.|1
01335|081|R|2.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01335|082|R|  September, 2016.|1
01335|083|R|3.Greenblatt DJ, von Moltke LL, Harmatz JS, Fogelman SM, Chen G, Graf JA,|2
01335|084|R|  Mertzanis P, Byron S, Culm KE, Granda BW, Daily JP, Shader RI. Short-term|2
01335|085|R|  exposure to low-dose ritonavir impairs clearance and enhances adverse|2
01335|086|R|  effects of trazodone. J Clin Pharmacol 2003 Apr;43(4):414-22.|2
01335|087|R|4.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01335|088|R|  December, 2019.|1
01335|089|R|5.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01335|090|R|  Laboratories December, 2019.|1
01335|091|R|6.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01335|092|R|  March, 2019.|1
01335|093|R|7.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01335|094|R|  Squibb Company December, 2024.|1
01335|095|R|8.Zalma A, von Moltke LL, Granda BW, Harmatz JS, Shader RI, Greenblatt DJ.|5
01335|096|R|  In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and|5
01335|097|R|  human immunodeficiency viral protease inhibitors. Biol Psychiatry 2000 Apr|5
01335|098|R|  1;47(7):655-61.|5
01335|099|R|9.Margolese HC, Chouinard G. Serotonin syndrome from addition of low-dose|3
01335|100|R|  trazodone to nefazodone. Am J Psychiatry 2000 Jun;157(6):1022.|3
01335|101|R|10.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
01335|102|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
01335|103|R|   hospital settings: a scientific statement from the American Heart|6
01335|104|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
01335|105|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
01335|106|R|11.Farkas D, Volak LP, Harmatz JS, von Moltke LL, Court MH, Greenblatt DJ.|2
01335|107|R|   Short-term clarithromycin administration impairs clearance and enhances|2
01335|108|R|   pharmacodynamic effects of trazodone but not of zolpidem. Clin Pharmacol|2
01335|109|R|   Ther 2009 Jun;85(6):644-50.|2
01335|110|R|12.US Food and Drug Administration (FDA). Drug Development and Drug|1
01335|111|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
01335|112|R|   at:|1
01335|113|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
01335|114|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01335|115|R|   11/14/2017.|1
01335|116|R|13.Kharasch ED, Walker A, Hoffer C, Sheffels P. Sensitivity of intravenous|5
01335|117|R|   and oral alfentanil and pupillary miosis as minimally  invasive and|5
01335|118|R|   noninvasive probes for hepatic and first-pass CYP3A activity. J Clin|5
01335|119|R|   Pharmacol 2005 Oct;45(10):1187-97.|5
01335|120|R|14.This information is based on an extract from the Certara Drug Interaction|6
01335|121|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01336|001|T|MONOGRAPH TITLE:  Trazodone/Itraconazole; Ketoconazole (mono deleted|
01336|002|T|12/01/2011)|
01336|003|B||
01336|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01336|005|L|of severe adverse interaction.|
01336|006|B||
01336|007|A|MECHANISM OF ACTION:  Itraconazole(1) and ketoconazole(1,2) may inhibit the|
01336|008|A|metabolism of trazodone by CYP P-450-3A4.  Trazodone has been shown to|
01336|009|A|prolong the QTc interval.(1)|
01336|010|B||
01336|011|E|CLINICAL EFFECTS:  Concurrent use of itraconazole or ketoconazole may result|
01336|012|E|in elevated levels of and adverse effects from trazodone,(1,2) including the|
01336|013|E|potential for life-threatening cardiac arrhythmias.(1)|
01336|014|B||
01336|015|P|PREDISPOSING FACTORS:  This interaction may be more severe with larger|
01336|016|P|and/or routine doses of trazodone.|
01336|017|B||
01336|018|M|PATIENT MANAGEMENT:  A lower dose of trazodone should be considered in|
01336|019|M|patients receiving potent CYP P-450-3A4 inhibitors such as itraconazole or|
01336|020|M|ketoconazole.(1)  Instruct patients to report any irregular heartbeat or|
01336|021|M|fainting episodes.|
01336|022|B||
01336|023|D|DISCUSSION:  An in vitro study in human liver microsomes showed that|
01336|024|D|ketoconazole inhibited the metabolism of trazodone.(1,2)|
01336|025|D|   In a study in 10 healthy subjects, short-term ritonavir (four doses of|
01336|026|D|200 mg twice daily), another potent inhibitor of CYP P-450-3A4, increased th|
01336|027|D|area-under-curve (AUC) and half-life of a single dose of trazodone (50 mg)|
01336|028|D|by 2.4-fold and 2.2-fold, respectively.  The maximum concentration (Cmax) of|
01336|029|D|trazodone increased 34% and its clearance decreased 52%.  Three subjects|
01336|030|D|experienced nausea, dizziness, or hypotension and one of these subjects also|
01336|031|D|experienced syncope during concurrent administration.(1,3)|
01336|032|D|   Therefore, the manufacturer of trazodone states that a lower dose of|
01336|033|D|trazodone should be considered in patients receiving potent CYP P-450-3A4|
01336|034|D|inhibitors such as itraconazole or ketoconazole.(1)|
01336|035|B||
01336|036|R|REFERENCES:|
01336|037|B||
01336|038|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
01336|039|R|  Labopharm Inc. November, 2012.|1
01336|040|R|2.Zalma A, von Moltke LL, Granda BW, Harmatz JS, Shader RI, Greenblatt DJ.|5
01336|041|R|  In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and|5
01336|042|R|  human immunodeficiency viral protease inhibitors. Biol Psychiatry 2000 Apr|5
01336|043|R|  1;47(7):655-61.|5
01336|044|R|3.Greenblatt DJ, von Moltke LL, Harmatz JS, Fogelman SM, Chen G, Graf JA,|2
01336|045|R|  Mertzanis P, Byron S, Culm KE, Granda BW, Daily JP, Shader RI. Short-term|2
01336|046|R|  exposure to low-dose ritonavir impairs clearance and enhances adverse|2
01336|047|R|  effects of trazodone. J Clin Pharmacol 2003 Apr;43(4):414-22.|2
01337|001|T|MONOGRAPH TITLE:  Trazodone/Nefazodone (mono deleted 12/01/2011)|
01337|002|B||
01337|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01337|004|L|of severe adverse interaction.|
01337|005|B||
01337|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of trazodone by|
01337|007|A|CYP P-450-3A4.  Trazodone has been shown to prolong the QTc interval.(1)|
01337|008|B||
01337|009|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in elevated|
01337|010|E|levels of and adverse effects from trazodone, including the potential for|
01337|011|E|life-threatening cardiac arrhythmias(1) or in serotonin syndrome.(2)|
01337|012|E|Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
01337|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)|
01337|014|B||
01337|015|P|PREDISPOSING FACTORS:  This interaction may be more severe with larger|
01337|016|P|and/or routine doses of trazodone.|
01337|017|B||
01337|018|M|PATIENT MANAGEMENT:  A lower dose of trazodone should be considered in|
01337|019|M|patients receiving potent CYP P-450-3A4 inhibitors such as nefazodone.(1)|
01337|020|M|Patients should be observed for signs and symptoms of serotonin syndrome.|
01337|021|M|Instruct patients to report any irregular heartbeat or fainting episodes.|
01337|022|B||
01337|023|D|DISCUSSION:  In a single case report, a female experienced serotonin|
01337|024|D|syndrome characterized by high blood pressure (240/120 mmHg); intermittent|
01337|025|D|numbness of the right side of her lips and nose and fingers of the right|
01337|026|D|hand; nausea; loose stools; flushed, pruritic skin; confusion; and|
01337|027|D|difficulty concentrating four days after the addition of trazodone (25-50 mg|
01337|028|D|daily) to nefazodone.(2)|
01337|029|D|   An in vitro study in human liver microsomes showed that indinavir,|
01337|030|D|ketoconazole, and ritonavir, other potent inhibitors of CYP P-450-3A4,|
01337|031|D|inhibited the metabolism of trazodone.(1,3)|
01337|032|D|   In a study in 10 healthy subjects, short-term ritonavir (four doses of|
01337|033|D|200 mg twice daily), increased the area-under-curve (AUC) and half-life of a|
01337|034|D|single dose of trazodone (50 mg) by 2.4-fold and 2.2-fold, respectively. The|
01337|035|D|maximum concentration (Cmax) of trazodone increased 34% and its clearance|
01337|036|D|decreased 50%.  Three subjects experienced nausea, dizziness, or hypotension|
01337|037|D|and one of these subjects also experienced syncope during concurrent|
01337|038|D|administration.(1,4)|
01337|039|D|   Therefore, the manufacturer of trazodone states that a lower dose of|
01337|040|D|trazodone should be considered in patients receiving potent CYP P-450-3A4|
01337|041|D|inhibitors such as itraconazole or ketoconazole.(1)|
01337|042|B||
01337|043|R|REFERENCES:|
01337|044|B||
01337|045|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
01337|046|R|  Labopharm Inc. November, 2012.|1
01337|047|R|2.Margolese HC, Chouinard G. Serotonin syndrome from addition of low-dose|3
01337|048|R|  trazodone to nefazodone. Am J Psychiatry 2000 Jun;157(6):1022.|3
01337|049|R|3.Zalma A, von Moltke LL, Granda BW, Harmatz JS, Shader RI, Greenblatt DJ.|5
01337|050|R|  In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and|5
01337|051|R|  human immunodeficiency viral protease inhibitors. Biol Psychiatry 2000 Apr|5
01337|052|R|  1;47(7):655-61.|5
01337|053|R|4.Greenblatt DJ, von Moltke LL, Harmatz JS, Fogelman SM, Chen G, Graf JA,|2
01337|054|R|  Mertzanis P, Byron S, Culm KE, Granda BW, Daily JP, Shader RI. Short-term|2
01337|055|R|  exposure to low-dose ritonavir impairs clearance and enhances adverse|2
01337|056|R|  effects of trazodone. J Clin Pharmacol 2003 Apr;43(4):414-22.|2
01337|057|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01337|058|R|  352(11):1112-20.|6
01338|001|T|MONOGRAPH TITLE:  Class IA & III Antiarrhythmics/Telithromycin|
01338|002|B||
01338|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01338|004|L|of severe adverse interaction.|
01338|005|B||
01338|006|A|MECHANISM OF ACTION:  Telithromycin may prolong the QT interval.(1)|
01338|007|A|Telithromycin may affect the absorption of sotalol.(1)|
01338|008|B||
01338|009|E|CLINICAL EFFECTS:  Concurrent administration of telithromycin with a Class|
01338|010|E|IA or III antiarrhythmic may result in prolongation of the QTc interval,|
01338|011|E|which may result in potentially life-threatening arrhythmias.(1)  Levels of|
01338|012|E|sotalol may be reduced.(1)|
01338|013|B||
01338|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01338|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01338|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01338|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01338|018|P|female gender, or advanced age.(2)|
01338|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01338|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01338|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01338|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01338|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01338|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01338|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01338|026|B||
01338|027|M|PATIENT MANAGEMENT:  The US manufacturer of telithromycin states that|
01338|028|M|telithromycin should be avoided in patients taking Class IA or III|
01338|029|M|antiarrhythmics.(1)|
01338|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01338|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01338|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01338|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01338|034|B||
01338|035|D|DISCUSSION:  Telithromycin may prolong the QT interval.  Concurrent|
01338|036|D|administration with a Class IA or III antiarrhythmic may result in|
01338|037|D|prolongation of the QTc interval, which may result in potentially|
01338|038|D|life-threatening arrhythmias, and should be avoided.(1)|
01338|039|D|   Telithromycin has been shown to decrease the maximum concentration (Cmax)|
01338|040|D|and area-under-curve (AUC) of sotalol by 34% and 20%, respectively.(1)|
01338|041|B||
01338|042|R|REFERENCES:|
01338|043|B||
01338|044|R|1.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01338|045|R|  November, 2015.|1
01338|046|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01338|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01338|048|R|  settings: a scientific statement from the American Heart Association and|6
01338|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01338|050|R|  2;55(9):934-47.|6
01339|001|T|MONOGRAPH TITLE:  Silodosin; Tamsulosin/Strong CYP3A4 Inhibitors|
01339|002|B||
01339|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01339|004|L|is contraindicated and generally should not be dispensed or administered to|
01339|005|L|the same patient.|
01339|006|B||
01339|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
01339|008|A|silodosin and tamsulosin.(1,2)|
01339|009|B||
01339|010|E|CLINICAL EFFECTS:  Coadministration of a strong CYP3A4 inhibitor may cause|
01339|011|E|an increase in silodosin and tamsulosin levels and effects, including severe|
01339|012|E|hypotension.(1,2)|
01339|013|B||
01339|014|P|PREDISPOSING FACTORS:  In patients receiving tamsulosin, the interaction may|
01339|015|P|be worse in patients who are CYP2D6 poor metabolizers because tamsulosin|
01339|016|P|also undergoes metabolism by this pathway.(2)|
01339|017|B||
01339|018|M|PATIENT MANAGEMENT:  The US manufacturer of silodosin states that concurrent|
01339|019|M|use of strong CYP3A4 inhibitors is contraindicated.(1)|
01339|020|M|   The US manufacturer of tamsulosin states that tamsulosin should not be|
01339|021|M|used with strong CYP3A4 inhibitors.(2)|
01339|022|M|   The US manufacturer of itraconazole states that silodosin or tamsulosin|
01339|023|M|should not be administered until at least 2 weeks after itraconazole|
01339|024|M|treatment.(3)|
01339|025|B||
01339|026|D|DISCUSSION:  Administration of ketoconazole (200 mg daily for 4 days)|
01339|027|D|increased the Cmax and AUC of a single dose of silodosin (4 mg) by 3.7-fold|
01339|028|D|and 2.9-fold, respectively.(1)|
01339|029|D|   Administration of ketoconazole (400 mg daily for 4 days) increased the|
01339|030|D|Cmax and AUC of a single dose of silodosin (8 mg) by 3.8-fold and 3.2-fold,|
01339|031|D|respectively.(1)|
01339|032|D|   In a study in 24 healthy male subjects, administration of ketoconazole|
01339|033|D|(400 mg daily for 5 days) increased the Cmax and AUC of a single dose of|
01339|034|D|tamsulosin (0.4 mg) by 2.2-fold (90% CI 1.96, 2.45) and 2.8-fold (90% CI|
01339|035|D|2.56, 3.07), respectively.  No serous adverse events were reported when|
01339|036|D|subjects took tamsulosin with ketoconazole.(2,4)|
01339|037|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
01339|038|D|clarithromycin, cobicistat, idelalisib, itraconazole, josamycin,|
01339|039|D|ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone,|
01339|040|D|posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin,|
01339|041|D|tucatinib and voriconazole.(5,6)|
01339|042|B||
01339|043|R|REFERENCES:|
01339|044|B||
01339|045|R|1.Rapaflo (silodosin) US prescribing information. Watson Laboratories, Inc.|1
01339|046|R|  July, 2013.|1
01339|047|R|2.Flomax (tamsulosin hydrochloride) US prescribing information. Boehringer|1
01339|048|R|  Ingelheim Pharmaceuticals, Inc. October 20. 2014.|1
01339|049|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01339|050|R|  Products, L.P. February, 2024.|1
01339|051|R|4.Troost J, Tatami S, Tsuda Y, Mattheus M, Mehlburger L, Wein M, Michel MC.|2
01339|052|R|  Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole,|2
01339|053|R|  on the  pharmacokinetics and cardiovascular safety of tamsulosin. Br J|2
01339|054|R|  Clin Pharmacol 2011 Aug;72(2):247-56.|2
01339|055|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
01339|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01339|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01339|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01339|059|R|  11/14/2017.|1
01339|060|R|6.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
01339|061|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
01340|001|T|MONOGRAPH TITLE:  Alfuzosin;Silodosin;Tamsulosin/Protease Inhibitors|
01340|002|B||
01340|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01340|004|L|is contraindicated and generally should not be dispensed or administered to|
01340|005|L|the same patient.|
01340|006|B||
01340|007|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
01340|008|A|alfuzosin,(1) silodosin,(2) and tamsulosin(3) by CYP3A4.|
01340|009|B||
01340|010|E|CLINICAL EFFECTS:  Co-administration of a protease inhibitor may result in|
01340|011|E|increased alfuzosin,(1) silodosin,(2) and tamsulosin(3) levels and serious|
01340|012|E|effects such as hypotension.|
01340|013|B||
01340|014|P|PREDISPOSING FACTORS:  In patients receiving tamsulosin, the interaction may|
01340|015|P|be worse in patients who are CYP2D6 poor metabolizers because tamsulosin|
01340|016|P|also undergoes metabolism by this pathway.(3)|
01340|017|B||
01340|018|M|PATIENT MANAGEMENT:  The US manufacturers of alfuzosin(1) and silodosin(2)|
01340|019|M|state that concurrent use of strong CYP3A4 inhibitors is contraindicated.|
01340|020|M|   The US manufacturer of tamsulosin states that tamsulosin should not be|
01340|021|M|used with strong CYP3A4 inhibitors.(3)|
01340|022|M|   The US manufacturers of atazanavir,(4) darunavir,(5) fosamprenavir,(6)|
01340|023|M|indinavir,(7) lopinavir/ritonavir,(8) nelfinavir,(9),|
01340|024|M|nirmatrelvir/ritonavir,(10 paritaprevir, (11) saquinavir,(12) and|
01340|025|M|tipranavir(13) state that concurrent use of alfuzosin is contraindicated.|
01340|026|B||
01340|027|D|DISCUSSION:  Administration of ketoconazole (400 mg daily), another|
01340|028|D|inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
01340|029|D|area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and|
01340|030|D|3.2-fold, respectively.(1)|
01340|031|D|   Administration of ketoconazole (200 mg daily) increased the Cmax and AUC|
01340|032|D|of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold,|
01340|033|D|respectively.(1)|
01340|034|D|   Administration of ketoconazole (200 mg daily for 4 days), increased the|
01340|035|D|Cmax and AUC of a single dose of silodosin (4 mg) by 3.7-fold and 2.9-fold,|
01340|036|D|respectively.(2)|
01340|037|D|   Administration of ketoconazole (400 mg daily for 4 days) increased the|
01340|038|D|Cmax and AUC of a single dose of silodosin (8 mg) by 3.8-fold and 3.2-fold,|
01340|039|D|respectively.(2)|
01340|040|D|   In a study in 24 healthy subjects, administration of ketoconazole (400 mg|
01340|041|D|daily for 5 days) increased the Cmax and AUC of a single dose of tamsulosin|
01340|042|D|(0.4 mg) by 2.2-fold and 2.8-fold, respectively.(3)|
01340|043|B||
01340|044|R|REFERENCES:|
01340|045|B||
01340|046|R|1.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
01340|047|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
01340|048|R|2.Rapaflo (silodosin) US prescribing information. Watson Laboratories, Inc.|1
01340|049|R|  July, 2013.|1
01340|050|R|3.Flomax (tamsulosin hydrochloride) US prescribing information. Boehringer|1
01340|051|R|  Ingelheim Pharmaceuticals, Inc. October 20. 2014.|1
01340|052|R|4.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01340|053|R|  Squibb Company December, 2024.|1
01340|054|R|5.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01340|055|R|  March, 2023.|1
01340|056|R|6.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01340|057|R|  March, 2019.|1
01340|058|R|7.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01340|059|R|  September, 2016.|1
01340|060|R|8.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01340|061|R|  Laboratories December, 2019.|1
01340|062|R|9.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01340|063|R|  Pharmaceuticals, Inc. September, 2016.|1
01340|064|R|10.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01340|065|R|   information. Pfizer Inc. February, 2025.|1
01340|066|R|11.Technivie (ombitasvir-paritaprevir-ritonavir) US prescribing information.|1
01340|067|R|   Abbvie Inc. December, 2019.|1
01340|068|R|12.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01340|069|R|   Laboratories, Inc. March, 2019.|1
01340|070|R|13.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01340|071|R|   Pharmaceuticals, Inc. April, 2024.|1
01341|001|T|MONOGRAPH TITLE:  Platelet Aggregation Inhibitors/Selected Anticoagulants|
01341|002|T|(Vitamin K antagonists); Heparins|
01341|003|B||
01341|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01341|005|L|take action as needed.|
01341|006|B||
01341|007|A|MECHANISM OF ACTION:  Platelet aggregation inhibitors work by irreversibly|
01341|008|A|modifying the platelet ADP receptor and inhibiting the activation of GP|
01341|009|A|IIb/IIIa complex.(1)  Concurrent use with anticoagulants may result in|
01341|010|A|additive effects on the clotting cascade.|
01341|011|B||
01341|012|E|CLINICAL EFFECTS:  The concurrent use of platelet aggregation inhibitors and|
01341|013|E|anticoagulants may result in an increased risk of bleeding.|
01341|014|B||
01341|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01341|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01341|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
01341|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01341|019|P|risk for bleeding (e.g. NSAIDs).|
01341|020|B||
01341|021|M|PATIENT MANAGEMENT:  Use caution when administering platelet aggregation|
01341|022|M|inhibitors concurrently with anticoagulants.(1)  Careful monitoring of|
01341|023|M|appropriate laboratory values for the patient's anticoagulant (e.g. PTT for|
01341|024|M|heparin, anti Xa levels for low-molecular weight heparins, INR for warfarin)|
01341|025|M|as well as signs and symptoms of bleeding is warranted.|
01341|026|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01341|027|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01341|028|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01341|029|M|patients with any symptoms.|
01341|030|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01341|031|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01341|032|M|anticoagulation in patients with active pathologic bleeding.|
01341|033|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01341|034|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01341|035|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01341|036|M|and/or swelling.|
01341|037|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01341|038|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01341|039|M|initiating, altering the dose or discontinuing either drug.|
01341|040|B||
01341|041|D|DISCUSSION:  Although a study in patients on long-term warfarin therapy|
01341|042|D|found that the stable anticoagulation status was unaffected by concurrent|
01341|043|D|clopidogrel use,(2) careful monitoring would be prudent.|
01341|044|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
01341|045|D|pairs were reviewed and found 14% of drug pairs were associated with a|
01341|046|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
01341|047|D|of warfarin and dipyridamole resulted in a ratio of rate ratios (95% CI) of|
01341|048|D|2.07 (1.65-2.6); and warfarin and clopidogrel ratio of rate ratios 1.69|
01341|049|D|(1.56-1.84).|
01341|050|D|   A large systematic review was performed on 72 warfarin drug-drug|
01341|051|D|interactions studies that reported on bleeding, thromboembolic events, or|
01341|052|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 38 of|
01341|053|D|those studies found a higher rate of clinically significant bleeding in|
01341|054|D|patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94).|
01341|055|D|Increased bleeding risk was also seen in subgroup analyses with aspirin|
01341|056|D|(OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and|
01341|057|D|aspirin plus clopidogrel or ticlopidine  (OR=2.07, 95% CI 1.33-3.21).(4)|
01341|058|B||
01341|059|R|REFERENCES:|
01341|060|B||
01341|061|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01341|062|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01341|063|R|2.Lidell C, Svedberg LE, Lindell P, Bandh S, Job B, Wallentin L. Clopidogrel|2
01341|064|R|  and warfarin: absence of interaction in patients receiving long-term|2
01341|065|R|  anticoagulant therapy for non-valvular atrial fibrillation. Thromb Haemost|2
01341|066|R|  2003 May;89(5):842-6.|2
01341|067|R|3.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
01341|068|R|  Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
01341|069|R|  Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
01341|070|R|  Pharmacol Ther 2020 Aug;108(2):377-386.|2
01341|071|R|4.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
01341|072|R|  Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
01341|073|R|  interactions with warfarin: A systematic review and meta-analysis. Br J|6
01341|074|R|  Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
01342|001|T|MONOGRAPH TITLE:  Eptifibatide/Platelet Aggregation Inhibitors|
01342|002|B||
01342|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01342|004|L|take action as needed.|
01342|005|B||
01342|006|A|MECHANISM OF ACTION:  Eptifibatide reversibly inhibits platelet aggregation|
01342|007|A|by preventing the binding of fibrinogen, von Willebrand factor, and other|
01342|008|A|adhesive ligands to GP IIb/IIIa.(1) Platelet aggregation inhibitors, such as|
01342|009|A|clopidogrel, inhibit aggregation by inhibiting the binding of ADP to its|
01342|010|A|platelet receptor.(2)|
01342|011|B||
01342|012|E|CLINICAL EFFECTS:  Concurrent use of eptifibatide and platelet aggregation|
01342|013|E|inhibitors may cause additive effects and increase the risk of bleeding.(1)|
01342|014|B||
01342|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01342|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01342|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
01342|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01342|019|P|risk for bleeding (e.g. NSAIDs).|
01342|020|B||
01342|021|M|PATIENT MANAGEMENT:  The manufacturer of eptifibatide recommends employing|
01342|022|M|caution when using eptifibatide with other drugs that affect hemostasis,|
01342|023|M|such as eptifibatide.(1)|
01342|024|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01342|025|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01342|026|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01342|027|M|patients with any symptoms.|
01342|028|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01342|029|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01342|030|M|anticoagulation in patients with active pathologic bleeding.|
01342|031|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01342|032|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01342|033|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01342|034|M|and/or swelling.|
01342|035|B||
01342|036|D|DISCUSSION:  The ESPRIT study observed the use of eptifibatide and|
01342|037|D|clopidogrel or ticlopidine and found that when patients were carefully|
01342|038|D|monitored there was no increase in risk of bleeding;(1) however, caution is|
01342|039|D|still warranted.|
01342|040|B||
01342|041|R|REFERENCES:|
01342|042|B||
01342|043|R|1.Integrilin (eptifibatide) US prescribing information. Schering Corporation|1
01342|044|R|  March, 2011.|1
01342|045|R|2.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01342|046|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01343|001|T|MONOGRAPH TITLE:  Bupropion/Antipsychotics|
01343|002|B||
01343|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01343|004|L|take action as needed.|
01343|005|B||
01343|006|A|MECHANISM OF ACTION:  Both bupropion and the antipsychotics are known to|
01343|007|A|lower the seizure threshold.(1,2)  Bupropion is also a strong inhibitor of|
01343|008|A|CYP2D6.(3)|
01343|009|B||
01343|010|E|CLINICAL EFFECTS:  Concurrent use of bupropion and an antipsychotic may|
01343|011|E|result in additive effects on the seizure threshold, increasing the risk of|
01343|012|E|seizures.(1,2)|
01343|013|B||
01343|014|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
01343|015|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
01343|016|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
01343|017|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
01343|018|P|total daily dose of bupropion greater than 450 mg or single doses greater|
01343|019|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
01343|020|P|oral hypoglycemics or insulin; or with concomitant medications known to|
01343|021|P|lower seizure threshold (antidepressants, theophylline, systemic|
01343|022|P|steroids).(1,2)|
01343|023|P|   The risk of anticholinergic toxicities including cognitive decline,|
01343|024|P|delirium, falls and fractures is increased in geriatric patients using more|
01343|025|P|than one medicine with anticholinergic properties.(3)|
01343|026|B||
01343|027|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics|
01343|028|M|should be undertaken only with extreme caution and with low initial|
01343|029|M|bupropion dosing and small gradual dosage increases.(1,2)  Single doses|
01343|030|M|should not exceed 150 mg.(1,2)  The maximum daily dose of bupropion should|
01343|031|M|not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)|
01343|032|B||
01343|033|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
01343|034|D|other agents that lower seizure threshold, the manufacturer of bupropion|
01343|035|D|states that the concurrent use of bupropion and antipsychotics should be|
01343|036|D|undertaken only with extreme caution and with low initial bupropion dosing|
01343|037|D|and small gradual dosage increases.(1)|
01343|038|B||
01343|039|R|REFERENCES:|
01343|040|B||
01343|041|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
01343|042|R|  GlaxoSmithKline November, 2019.|1
01343|043|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
01343|044|R|  GlaxoSmithKline July, 2019.|1
01343|045|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01343|046|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01343|047|R|  Soc 2023 Jul;71(7):2052-2081.|6
01343|048|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
01343|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01343|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01343|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01343|052|R|  11/14/2017.|1
01344|001|T|MONOGRAPH TITLE:  Bupropion/Selected Antidepressants|
01344|002|B||
01344|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01344|004|L|take action as needed.|
01344|005|B||
01344|006|A|MECHANISM OF ACTION:  Depending upon the antidepressant, one or two|
01344|007|A|mechanisms may be involved.|
01344|008|A|   Both bupropion and antidepressants are known to lower the seizure|
01344|009|A|threshold.(1,2)|
01344|010|A|   Bupropion, a strong inhibitor of CYP2D6 may increase systemic exposure|
01344|011|A|(AUC, area-under-curve) to antidepressants metabolized by this pathway. The|
01344|012|A|tricyclic antidepressants, the SSRIs, and the SNRIs are the most sensitive|
01344|013|A|to CYP2D6 inhibition and are addressed in separate monographs.|
01344|014|A|Antidepressants which are metabolized by CYP2D6 but less susceptible to|
01344|015|A|CYP2D6 inhibition are: mianserin, mirtazapine, nefazodone active metabolite|
01344|016|A|(mCPP), and trazodone active metabolite (mCPP).(3)|
01344|017|B||
01344|018|E|CLINICAL EFFECTS:  Concurrent use of bupropion and an antidepressant may|
01344|019|E|result in additive effects on the seizure threshold, increasing the risk of|
01344|020|E|seizures.(1,2)|
01344|021|E|   Concurrent use may also increase levels of and side effects from|
01344|022|E|antidepressants metabolized by CYP2D6, such as mianserin, mirtazepine,|
01344|023|E|nefazodone, and trazodone.(3)|
01344|024|B||
01344|025|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
01344|026|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
01344|027|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
01344|028|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
01344|029|P|total daily dose of bupropion greater than 450 mg or single doses greater|
01344|030|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
01344|031|P|oral hypoglycemics or insulin; or with concomitant medications known to|
01344|032|P|lower seizure threshold (antipsychotics, theophylline, systemic|
01344|033|P|steroids).(1,2)|
01344|034|B||
01344|035|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antidepressants|
01344|036|M|should be undertaken only with extreme caution and with low initial|
01344|037|M|bupropion dosing and small gradual dosage increases.(1,2)  Single doses|
01344|038|M|should not exceed 150 mg.(1,2)  The maximum daily dose of bupropion should|
01344|039|M|not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)|
01344|040|B||
01344|041|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
01344|042|D|other agents that lower seizure threshold, the manufacturer of bupropion|
01344|043|D|states that the concurrent use of bupropion and antidepressants should be|
01344|044|D|undertaken only with extreme caution and with low initial bupropion dosing|
01344|045|D|and small gradual dosage increases.(1,2)|
01344|046|D|   In a study in 15 male subjects who were extensive metabolizers of CYP2D6,|
01344|047|D|bupropion (150 mg twice daily) increased the maximum concentration (Cmax),|
01344|048|D|area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine|
01344|049|D|(50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2)|
01344|050|B||
01344|051|R|REFERENCES:|
01344|052|B||
01344|053|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
01344|054|R|  GlaxoSmithKline November, 2019.|1
01344|055|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
01344|056|R|  GlaxoSmithKline July, 2019.|1
01344|057|R|3.This information is based on an extract from the Certara Drug Interaction|6
01344|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01344|059|R|4.Koyama E, Chiba K, Tani M, Ishizaki T. Identification of human cytochrome|5
01344|060|R|  P450 isoforms involved in the stereoselective  metabolism of mianserin|5
01344|061|R|  enantiomers. J Pharmacol Exp Ther 1996 Jul;278(1):21-30.|5
01344|062|R|5.Stormer E, von Moltke LL, Shader RI, Greenblatt DJ. Metabolism of the|5
01344|063|R|  antidepressant mirtazapine in vitro: contribution of cytochromes P-450|5
01344|064|R|  1A2, 2D6, and 3A4. Drug Metab Dispos 2000 Oct;28(10):1168-75.|5
01345|001|T|MONOGRAPH TITLE:  Bupropion/Theophylline|
01345|002|B||
01345|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01345|004|L|take action as needed.|
01345|005|B||
01345|006|A|MECHANISM OF ACTION:  Both bupropion and theophylline are known to lower the|
01345|007|A|seizure threshold.(1,2)|
01345|008|B||
01345|009|E|CLINICAL EFFECTS:  Concurrent use of bupropion and theophylline may result|
01345|010|E|in additive effects on the seizure threshold, increasing the risk of|
01345|011|E|seizures.(1,2)|
01345|012|B||
01345|013|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
01345|014|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
01345|015|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
01345|016|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
01345|017|P|total daily dose of bupropion greater than 450 mg or single doses greater|
01345|018|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
01345|019|P|oral hypoglycemics or insulin; or with concomitant medications known to|
01345|020|P|lower seizure threshold (antidepressants, antipsychotics, systemic|
01345|021|P|steroids).(1,2)|
01345|022|B||
01345|023|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and theophylline should|
01345|024|M|be undertaken only with extreme caution and with low initial dosing of|
01345|025|M|bupropion and small gradual dosage increases.(1,2)  Single doses should not|
01345|026|M|exceed 150 mg.(1,2)  The maximum daily dose of bupropion should not exceed|
01345|027|M|300 mg for smoking cessation(2) or 450 mg for depression.(1)|
01345|028|B||
01345|029|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
01345|030|D|other agents that lower seizure threshold, the manufacturer of bupropion|
01345|031|D|states that the concurrent use of bupropion and theophylline should be|
01345|032|D|undertaken only with extreme caution and with low initial bupropion dosing|
01345|033|D|and small, gradual dosage increases.(1,2)|
01345|034|B||
01345|035|R|REFERENCES:|
01345|036|B||
01345|037|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
01345|038|R|  GlaxoSmithKline November, 2019.|1
01345|039|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
01345|040|R|  GlaxoSmithKline July, 2019.|1
01346|001|T|MONOGRAPH TITLE:  Bupropion/Steroids|
01346|002|B||
01346|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01346|004|L|take action as needed.|
01346|005|B||
01346|006|A|MECHANISM OF ACTION:  Both bupropion and systemic steroids are known to|
01346|007|A|lower the seizure threshold.(1,2)|
01346|008|B||
01346|009|E|CLINICAL EFFECTS:  Concurrent use of bupropion and systemic steroids may|
01346|010|E|result in additive effects on the seizure threshold, increasing the risk of|
01346|011|E|seizures.(1,2)|
01346|012|B||
01346|013|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
01346|014|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
01346|015|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
01346|016|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
01346|017|P|total daily dose of bupropion greater than 450 mg or single doses greater|
01346|018|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
01346|019|P|oral hypoglycemics or insulin; or with concomitant medications known to|
01346|020|P|lower seizure threshold (antidepressants, antipsychotics,|
01346|021|P|theophylline).(1,2)|
01346|022|B||
01346|023|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and systemic steroids|
01346|024|M|should be undertaken only with extreme caution and with low initial|
01346|025|M|bupropion dosing and small gradual dosage increases.(1,2)  Single doses|
01346|026|M|should not exceed 150 mg.(1,2)  The maximum daily dose of bupropion should|
01346|027|M|not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)|
01346|028|B||
01346|029|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
01346|030|D|other agents that lower seizure threshold, the manufacturer of bupropion|
01346|031|D|states that the concurrent use of bupropion and systemic steroids should be|
01346|032|D|undertaken only with extreme caution and with low initial bupropion dosing|
01346|033|D|and small gradual dosage increases.(1,2)|
01346|034|B||
01346|035|R|REFERENCES:|
01346|036|B||
01346|037|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
01346|038|R|  GlaxoSmithKline November, 2019.|1
01346|039|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
01346|040|R|  GlaxoSmithKline July, 2019.|1
01347|001|T|MONOGRAPH TITLE:  Bupropion/Hypoglycemics; Insulin|
01347|002|B||
01347|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01347|004|L|take action as needed.|
01347|005|B||
01347|006|A|MECHANISM OF ACTION:  Bupropion can lower the seizure threshold and when|
01347|007|A|given concurrently with other medications that also lower the threshold|
01347|008|A|there is an increased risk of seizure.(1,2)|
01347|009|B||
01347|010|E|CLINICAL EFFECTS:  Concurrent use of bupropion and hypoglycemics or insulin|
01347|011|E|may increase the risk of seizure.(1,2)|
01347|012|B||
01347|013|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
01347|014|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
01347|015|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
01347|016|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
01347|017|P|total daily dose of bupropion greater than 450 mg or single doses greater|
01347|018|P|than 150 mg; rapid escalation of bupropion dosage; or with concomitant|
01347|019|P|medications known to lower seizure threshold (antidepressants,|
01347|020|P|antipsychotics, systemic steroids, theophylline).(1,2)|
01347|021|B||
01347|022|M|PATIENT MANAGEMENT:  The use of bupropion in patients treated with oral|
01347|023|M|hypoglycemic agents or insulin should be undertaken only with extreme|
01347|024|M|caution and with low initial bupropion dosing and small gradual dosage|
01347|025|M|increases.(1,2)  Single doses should not exceed 150 mg.(1,2)  The maximum|
01347|026|M|daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or|
01347|027|M|450 mg for depression.(1)|
01347|028|B||
01347|029|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
01347|030|D|other agents that lower seizure threshold, the manufacturer of bupropion|
01347|031|D|states that the concurrent use of bupropion and oral hypoglycemic agents or|
01347|032|D|insulin should be undertaken only with extreme caution and with low initial|
01347|033|D|bupropion dosing and small gradual dosage increases.(1,2)|
01347|034|B||
01347|035|R|REFERENCES:|
01347|036|B||
01347|037|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
01347|038|R|  GlaxoSmithKline November, 2019.|1
01347|039|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
01347|040|R|  GlaxoSmithKline July, 2019.|1
01348|001|T|MONOGRAPH TITLE:  Tramadol/Neuroleptics (mono deleted 04/20/2017)|
01348|002|B||
01348|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01348|004|L|take action as needed.|
01348|005|B||
01348|006|A|MECHANISM OF ACTION:  Tramadol can lower the seizure threshold at and above|
01348|007|A|the recommended dosage range.(1)  Neuroleptics also lower the seizure|
01348|008|A|threshold.|
01348|009|B||
01348|010|E|CLINICAL EFFECTS:  Concomitant use of tramadol with neuroleptics may|
01348|011|E|increase the risk of seizure.(1)|
01348|012|B||
01348|013|P|PREDISPOSING FACTORS:  Seizure risk may be increased in patients with|
01348|014|P|epilepsy, history of seizure, or in patients with a recognized risk for|
01348|015|P|seizure (head trauma, metabolic disorder, alcohol and drug withdrawal, or|
01348|016|P|CNS infections).(1)|
01348|017|B||
01348|018|M|PATIENT MANAGEMENT:  Use caution when administering tramadol concurrently|
01348|019|M|with neuroleptics.|
01348|020|B||
01348|021|D|DISCUSSION:  In a case report a 36 year old male died after developing a|
01348|022|D|seizure while being treated with tramadol, promethazine, and other|
01348|023|D|medications.(2)|
01348|024|B||
01348|025|R|REFERENCES:|
01348|026|B||
01348|027|R|1.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
01348|028|R|  October, 2019.|1
01348|029|R|2.Ripple MG, Pestaner JP, Levine BS, Smialek JE. Lethal combination of|3
01348|030|R|  tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol|3
01348|031|R|  2000 Dec;21(4):370-4.|3
01349|001|T|MONOGRAPH TITLE:  Entacapone; Opicapone/COMT-Metabolized Agents|
01349|002|B||
01349|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01349|004|L|take action as needed.|
01349|005|B||
01349|006|A|MECHANISM OF ACTION:  Entacapone and opicapone are selective and reversible|
01349|007|A|inhibitors of catechol-O-methyltransferase (COMT) and drugs that are|
01349|008|A|metabolized by COMT can not be fully metabolized when given with entacapone|
01349|009|A|or opicapone.(1)|
01349|010|B||
01349|011|E|CLINICAL EFFECTS:  COMT-metabolized agents can interact with entacapone or|
01349|012|E|opicapone and may result in an increased heart rates, arrhythmias, or an|
01349|013|E|excessive change in blood pressure.(1)|
01349|014|B||
01349|015|P|PREDISPOSING FACTORS:  None determined.|
01349|016|B||
01349|017|M|PATIENT MANAGEMENT:  The manufacturers of entacapone and opicapone recommend|
01349|018|M|using caution when administering entacapone or opicapone and a|
01349|019|M|COMT-metabolized agent regardless of the route of administration (including|
01349|020|M|inhalation).(1-3)|
01349|021|B||
01349|022|D|DISCUSSION:  In an interaction study, ventricular tachycardia was observed|
01349|023|D|after epinephrine and entacapone administration.(1)|
01349|024|D|   Another study on the effect of entacapone given with isoproterenol and|
01349|025|D|epinephrine concluded that entacapone may potentiate the chronotropic and|
01349|026|D|arrhythmogenic effects of isoproterenol and epinephrine.(4)|
01349|027|B||
01349|028|R|REFERENCES:|
01349|029|B||
01349|030|R|1.Comtan (entacapone) US prescribing information. Orion Corporation|1
01349|031|R|  February, 2016.|1
01349|032|R|2.Ongentys (opicapone) Middle East prescribing information. Bial-Portela and|1
01349|033|R|  Ca, S.A. 2018.|1
01349|034|R|3.Ongentys (opicapone) US prescribing information. Neurocrine Biosciences,|1
01349|035|R|  Inc. April, 2020.|1
01349|036|R|4.Illi A, Sundberg S, Ojala-Karlsson P, Korhonen P, Scheinin M, Gordin A.|2
01349|037|R|  The effect of entacapone on the disposition and hemodynamic effects of|2
01349|038|R|  intravenous isoproterenol and epinephrine. Clin Pharmacol Ther 1995 Aug;|2
01349|039|R|  58(2):221-7.|2
01350|001|T|MONOGRAPH TITLE:  Lepirudin/Coumarin Anticoagulants|
01350|002|B||
01350|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01350|004|L|take action as needed.|
01350|005|B||
01350|006|A|MECHANISM OF ACTION:  Lepirudin is a highly specific direct inhibitor of|
01350|007|A|thrombin.(1) Coumarin anticoagulants are vitamin K antagonists that affect|
01350|008|A|clotting function.|
01350|009|B||
01350|010|E|CLINICAL EFFECTS:  Concurrent use of lepirudin and coumarin anticoagulants|
01350|011|E|may increase the risk of bleeding.(1)|
01350|012|B||
01350|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01350|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01350|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01350|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01350|017|P|risk for bleeding (e.g. NSAIDs).|
01350|018|B||
01350|019|M|PATIENT MANAGEMENT:  The manufacturer recommends close monitoring of|
01350|020|M|patients taking lepirudin and coumarin anticoagulants.(1)|
01350|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01350|022|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01350|023|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01350|024|M|patients with any symptoms.|
01350|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01350|026|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01350|027|M|anticoagulation in patients with active pathologic bleeding.|
01350|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01350|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01350|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01350|031|M|and/or swelling.|
01350|032|M|   In patients scheduled for a switch to oral anticoagulation, the dosage of|
01350|033|M|lepirudin should be decreased until the aPTT ratio reaches just above 1.5|
01350|034|M|before initiating oral anticoagulation.  Coumarin derivatives should be|
01350|035|M|initiated after platelet counts are normalizing and without a loading dose.|
01350|036|M|Parenteral anticoagulant should be continued for 4-5 days to avoid|
01350|037|M|prothrombic effects.(1)|
01350|038|M|      The time of highest risk for a coumarin-type drug interaction is when|
01350|039|M|the precipitant drug is initiated or discontinued. Contact the prescriber|
01350|040|M|before initiating, altering the dose or discontinuing either drug.|
01350|041|B||
01350|042|D|DISCUSSION:  Concurrent use of lepirudin and coumarin anticoagulants may|
01350|043|D|increase the risk of bleeding.  The manufacturer recommends close monitoring|
01350|044|D|of patients taking lepirudin and coumarin anticoagulants.  In patients|
01350|045|D|scheduled for a switch to oral anticoagulation, the dosage of lepirudin|
01350|046|D|should be decreased until the aPTT ratio reaches just above 1.5 before|
01350|047|D|initiating oral anticoagulation.  Coumarin derivatives should be initiated|
01350|048|D|after platelet counts are normalizing and without a loading dose. Parenteral|
01350|049|D|anticoagulant should be continued for 4-5 days to avoid prothrombic|
01350|050|D|effects.(1)|
01350|051|B||
01350|052|R|REFERENCE:|
01350|053|B||
01350|054|R|1.Refludan (lepirudin (rDNA)) US prescribing information. Berlex|1
01350|055|R|  Laboratories October, 2002.|1
01351|001|T|MONOGRAPH TITLE:  Lepirudin/Platelet Aggregation Inhibitors|
01351|002|B||
01351|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01351|004|L|take action as needed.|
01351|005|B||
01351|006|A|MECHANISM OF ACTION:  Lepirudin is a highly specific direct inhibitor of|
01351|007|A|thrombin.(1) Platelet aggregation inhibitors enhance the effects of|
01351|008|A|lepirudin.|
01351|009|B||
01351|010|E|CLINICAL EFFECTS:  Concurrent use of lepirudin and platelet aggregation|
01351|011|E|inhibitors may increase the risk of bleeding complications and may enhance|
01351|012|E|the effect of lepirudin on aPTT prolongation.(1)|
01351|013|B||
01351|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01351|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01351|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
01351|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01351|018|P|risk for bleeding (e.g. NSAIDs).|
01351|019|B||
01351|020|M|PATIENT MANAGEMENT:  The manufacturer recommends close monitoring of|
01351|021|M|patients taking this combination.(1)|
01351|022|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01351|023|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01351|024|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01351|025|M|patients with any symptoms.|
01351|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01351|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01351|028|M|anticoagulation in patients with active pathologic bleeding.|
01351|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01351|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01351|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01351|032|M|and/or swelling.|
01351|033|B||
01351|034|D|DISCUSSION:  A study using lepirudin in combination with platelet|
01351|035|D|aggregation inhibitors concluded that caution should be exercised when using|
01351|036|D|this combination because of the increased risk of bleeding complications.(2)|
01351|037|B||
01351|038|R|REFERENCES:|
01351|039|B||
01351|040|R|1.Refludan (lepirudin (rDNA)) US prescribing information. Berlex|1
01351|041|R|  Laboratories October, 2002.|1
01351|042|R|2.Cochran K, DeMartini TJ, Lewis BE, O Brien J, Steen LH, Grassman ED, Leya|2
01351|043|R|  F. Use of lepirudin during percutaneous vascular interventions in patients|2
01351|044|R|  with heparin-induced thrombocytopenia. J Invasive Cardiol 2003 Nov;|2
01351|045|R|  15(11):617-21.|2
01352|001|T|MONOGRAPH TITLE:  Reteplase/Selected Anticoagulants (Vitamin K antagonists);|
01352|002|T|Heparins|
01352|003|B||
01352|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01352|005|L|take action as needed.|
01352|006|B||
01352|007|A|MECHANISM OF ACTION:  Reteplase catalyzes the cleavage of endogenous|
01352|008|A|plasminogen to generate plasmin which degrades the fibrin matrix of a|
01352|009|A|thrombus.(1)|
01352|010|B||
01352|011|E|CLINICAL EFFECTS:  The concurrent use of reteplase and anticoagulants may|
01352|012|E|increase the risk of bleeding.(1)|
01352|013|B||
01352|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01352|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01352|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
01352|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01352|018|P|risk for bleeding (e.g. NSAIDs).|
01352|019|B||
01352|020|M|PATIENT MANAGEMENT:  Carefully weigh the benefit of reteplase versus the|
01352|021|M|risks in patients receiving anticoagulants.  Use caution with administering|
01352|022|M|these agents together.|
01352|023|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01352|024|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01352|025|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01352|026|M|patients with any symptoms.|
01352|027|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01352|028|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01352|029|M|anticoagulation in patients with active pathologic bleeding.|
01352|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01352|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01352|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01352|033|M|and/or swelling.|
01352|034|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01352|035|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01352|036|M|initiating, altering the dose or discontinuing either drug.|
01352|037|B||
01352|038|D|DISCUSSION:  The most common adverse reaction with reteplase is bleeding.|
01352|039|D|Information regarding use concurrent use of reteplase and anticoagulants is|
01352|040|D|lacking.  The manufacturer of reteplase states that studies of concurrent|
01352|041|D|reteplase and anticoagulants have not been conducted.(1)|
01352|042|B||
01352|043|R|REFERENCE:|
01352|044|B||
01352|045|R|1.Retavase (reteplase recombinant) US prescribing information. Centocor,|1
01352|046|R|  Inc. November, 2000.|1
01353|001|T|MONOGRAPH TITLE:  Heparins/Selected Anticoagulants (Vitamin K antagonists);|
01353|002|T|Citrates|
01353|003|B||
01353|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01353|005|L|take action as needed.|
01353|006|B||
01353|007|A|MECHANISM OF ACTION:  Heparin inhibits thrombosis by inactivating activated|
01353|008|A|Factor X and inhibiting the conversion of prothrombin to thrombin.(1)|
01353|009|B||
01353|010|E|CLINICAL EFFECTS:  Concurrent use of anticoagulants with heparin can enhance|
01353|011|E|the effects of heparin and may increase the risk of bleeding.(1)|
01353|012|B||
01353|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01353|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01353|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01353|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01353|017|P|risk for bleeding (e.g. NSAIDs).|
01353|018|B||
01353|019|M|PATIENT MANAGEMENT:  The manufacturer recommends baseline and periodic|
01353|020|M|platelet counts and hematocrits for the entire duration of heparin|
01353|021|M|administration.(1)|
01353|022|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
01353|023|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
01353|024|M|blood pressure and promptly evaluate patients with any symptoms.|
01353|025|M|Discontinue heparin in patients with active pathological bleeding unless the|
01353|026|M|benefits outweigh the potential risk.(1)|
01353|027|M|   Partial thromboplastin time (aPTT) or whole-blood clotting time (WBC) may|
01353|028|M|be monitored to assess coagulation status.(1)|
01353|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01353|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01353|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01353|032|M|and/or swelling.|
01353|033|B||
01353|034|D|DISCUSSION:  A study of the use of heparin and warfarin in DVT patients|
01353|035|D|concluded that it is safe to use heparin in combination with warfarin(2)|
01353|036|D|with proper monitoring.|
01353|037|B||
01353|038|R|REFERENCES:|
01353|039|B||
01353|040|R|1.Heparin Sodium Injection, USP US prescribing information. B. Braun Medical|1
01353|041|R|  Inc. December, 2023.|1
01353|042|R|2.Harrison L, McGinnis J, Crowther M, Ginsberg J, Hirsh J. Assessment of|2
01353|043|R|  outpatient treatment of deep-vein thrombosis with low-molecular-weight|2
01353|044|R|  heparin. Arch Intern Med 1998 Oct 12;158(18):2001-3.|2
01354|001|T|MONOGRAPH TITLE:  Heparins/NSAIDs|
01354|002|B||
01354|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01354|004|L|take action as needed.|
01354|005|B||
01354|006|A|MECHANISM OF ACTION:  Heparin inhibits thrombosis by inactivating activated|
01354|007|A|Factor X and inhibiting the conversion of prothrombin to thrombin.(1)|
01354|008|A|   NSAIDs inhibit coagulation by interfering with platelet-aggregation,|
01354|009|A|while inhibition of prostaglandin synthesis increases the risk for|
01354|010|A|gastrointestinal bleeding.|
01354|011|B||
01354|012|E|CLINICAL EFFECTS:  Concurrent use of heparin and an NSAID may increase the|
01354|013|E|risk for bleeding.(1,2)|
01354|014|B||
01354|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01354|016|P|patients with multiple disease-associated factors (e.g. thrombocytopenia,|
01354|017|P|advanced liver disease).|
01354|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
01354|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01354|020|P|risk for bleeding (e.g., other anticoagulants, antiplatelets,|
01354|021|P|corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or|
01354|022|P|serotonin-norepinephrine  reuptake inhibitors (SNRIs).|
01354|023|P|   Risk of GI bleed may be increased in patients who are of older age, in|
01354|024|P|poor health status, or who use alcohol or smoke.  Risk may also be increased|
01354|025|P|with longer duration of NSAID use and prior history of peptic ulcer disease|
01354|026|P|and/or GI bleeding.|
01354|027|B||
01354|028|M|PATIENT MANAGEMENT:  Manufacturers recommend caution and monitoring when|
01354|029|M|using this combination of drugs.(1,2)|
01354|030|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01354|031|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01354|032|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01354|033|M|patients with any symptoms.|
01354|034|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01354|035|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01354|036|M|anticoagulation in patients with active pathologic bleeding.|
01354|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01354|038|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01354|039|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01354|040|M|and/or swelling.|
01354|041|B||
01354|042|D|DISCUSSION:  Based upon drug mechanisms of action, careful monitoring would|
01354|043|D|be prudent.|
01354|044|B||
01354|045|R|REFERENCES:|
01354|046|B||
01354|047|R|1.Heparin Sodium Injection, USP US prescribing information. B. Braun Medical|1
01354|048|R|  Inc. December, 2023.|1
01354|049|R|2.Naprosyn (naproxen) US prescribing information. Atnahs Pharma May, 2021.|1
01355|001|T|MONOGRAPH TITLE:  Heparins/Sulfinpyrazone|
01355|002|B||
01355|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01355|004|L|take action as needed.|
01355|005|B||
01355|006|A|MECHANISM OF ACTION:  Sulfinpyrazone and its metabolite inhibit platelet|
01355|007|A|aggregation induced by sodium arachidonate.(1)|
01355|008|B||
01355|009|E|CLINICAL EFFECTS:  Concurrent use of heparin derivatives and sulfinpyrazone|
01355|010|E|may result in bleeding.|
01355|011|B||
01355|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01355|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01355|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
01355|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01355|016|P|risk for bleeding (e.g. NSAIDs).|
01355|017|B||
01355|018|M|PATIENT MANAGEMENT:  Unless really needed, agents which may increase the|
01355|019|M|risk of hemorrhage, such as sulfinpyrazone, should be discontinued prior to|
01355|020|M|the initiation of heparin derivatives.(2)|
01355|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01355|022|M|therapy for signs or risks for blood loss, including platelet count,|
01355|023|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
01355|024|M|and promptly evaluate patients with any symptoms.|
01355|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01355|026|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01355|027|M|anticoagulation in patients with active pathologic bleeding.|
01355|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01355|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01355|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01355|031|M|and/or swelling.|
01355|032|B||
01355|033|D|DISCUSSION:  Sulfinpyrazone and its metabolite inhibit platelet aggregation|
01355|034|D|induced by sodium arachidonate.(1)  Unless really needed, agents which may|
01355|035|D|increase the risk of hemorrhage, such as sulfinpyrazone, should be|
01355|036|D|discontinued prior to the initiation of heparin derivatives.(2)  Periodic|
01355|037|D|complete blood counts, including platelet count, and stool occult blood|
01355|038|D|tests are recommended during therapy.(2)|
01355|039|B||
01355|040|R|REFERENCES:|
01355|041|B||
01355|042|R|1.Pay GF, Wallis RB, Zelaschi D. The effect of sulphinpyrazone and its|5
01355|043|R|  metabolites on platelet function in vitro and ex vivo. Haemostasis 1981;|5
01355|044|R|  10(3):165-75.|5
01355|045|R|2.Lovenox (enoxaparin sodium) US prescribing information. Sanofi-Aventis|1
01355|046|R|  U.S. LLC October, 2013.|1
01356|001|T|MONOGRAPH TITLE:  Abciximab/Thrombolytics|
01356|002|B||
01356|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01356|004|L|take action as needed.|
01356|005|B||
01356|006|A|MECHANISM OF ACTION:  Thrombolytics decrease plasma fibrinogen levels.(1)|
01356|007|A|When thrombolytics are administered with abciximab, there is enhanced|
01356|008|A|inhibition of platelet aggregation.|
01356|009|B||
01356|010|E|CLINICAL EFFECTS:  Concurrent use of abciximab and thrombolytics may result|
01356|011|E|in greater inhibition of platelet aggregation which may lead to an increased|
01356|012|E|risk of bleeding.|
01356|013|B||
01356|014|P|PREDISPOSING FACTORS:  Active internal bleed, thrombocytopenia, recent major|
01356|015|P|surgery or trauma, severe uncontrolled hypertension, use of IV dextran|
01356|016|P|before PCI, and history of cerebrovascular accident within two years(2)|
01356|017|P|   Other drug associated risk factors include concurrent use of multiple|
01356|018|P|drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an|
01356|019|P|inherent risk for bleeding (e.g. NSAIDs).|
01356|020|B||
01356|021|M|PATIENT MANAGEMENT:  Because of effects on bleeding, abciximab should be|
01356|022|M|used judiciously in patients who have received thrombolytics.  In all|
01356|023|M|patients receiving abciximab, potential bleeding sites should be checked. It|
01356|024|M|is also recommended to monitor the patients closely.(2)|
01356|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01356|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01356|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01356|028|M|patients with any symptoms.|
01356|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01356|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01356|031|M|anticoagulation in patients with active pathologic bleeding.|
01356|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01356|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01356|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01356|035|M|and/or swelling.|
01356|036|B||
01356|037|D|DISCUSSION:  In the GUSTO V trial, the incidence of moderate or severe non|
01356|038|D|intracranial bleeding was increased in patients receiving half-dose|
01356|039|D|Reteplase with abciximab (4.6%) when compared to patients receiving|
01356|040|D|full-dose Reteplase alone (2.3%).(2,3)|
01356|041|B||
01356|042|R|REFERENCES:|
01356|043|B||
01356|044|R|1.Streptase (streptokinase) US prescribing information. Aventis Behring|1
01356|045|R|  June, 2002.|1
01356|046|R|2.ReoPro (abciximab) US prescribing information. Eli Lilly and Company|1
01356|047|R|  November 25, 2013.|1
01356|048|R|3.Retavase (reteplase recombinant) US prescribing information. Centocor,|1
01356|049|R|  Inc. November, 2000.|1
01357|001|T|MONOGRAPH TITLE:  Apomorphine/5-HT3 Antagonists that Prolong QT|
01357|002|B||
01357|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01357|004|L|is contraindicated and generally should not be dispensed or administered to|
01357|005|L|the same patient.|
01357|006|B||
01357|007|A|MECHANISM OF ACTION:  The mechanism for risk of profound hypotension or loss|
01357|008|A|of consciousness is not known.|
01357|009|A|   There is data to suggest that apomorphine (1), as well as dolasetron,(2)|
01357|010|A|granisetron,(3) ondansetron,(4) and tropisetron(3) cause QT prolongation.|
01357|011|A|Although QTc prolongation with apomorphine is not likely at therapeutic|
01357|012|A|doses,(1) additive effects may be possible with concurrent administration of|
01357|013|A|5-HT3 antagonists.|
01357|014|B||
01357|015|E|CLINICAL EFFECTS:  Concurrent use of apomorphine with a 5-HT3 antagonist may|
01357|016|E|result in profound hypotension,(1) loss of consciousness,(1) and QT|
01357|017|E|prolongation.(1-4)|
01357|018|B||
01357|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01357|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01357|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01357|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01357|023|P|gender, or advanced age.(5)|
01357|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01357|025|P|higher systemic concentrations of either QT prolonging drug are additional|
01357|026|P|factors for torsade de pointes.  Factors which may increase systemic drug|
01357|027|P|concentrations include rapid infusion of an intravenous dose or impaired|
01357|028|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
01357|029|P|which inhibits its metabolism or elimination, genetic impairment in drug|
01357|030|P|metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
01357|031|B||
01357|032|M|PATIENT MANAGEMENT:  The manufacturer of apomorphine states that concurrent|
01357|033|M|use with 5-HT3 antagonists is contraindicated.(1)  The US manufacturer of|
01357|034|M|ondansetron states that concurrent use of apomorphine is contraindicated.(2)|
01357|035|M|Alternative agents, such as trimethobenzamide, are recommended for|
01357|036|M|prevention of nausea and vomiting caused by apomorphine.(6)|
01357|037|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01357|038|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01357|039|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01357|040|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01357|041|B||
01357|042|D|DISCUSSION:  Profound hypotension and loss of consciousness have been|
01357|043|D|reported with the concurrent use of apomorphine and ondansetron.(1,2)|
01357|044|D|Apomorphine and some 5-HT3 antagonists (dolasetron, granisetron,|
01357|045|D|ondansetron, and tropisetron) have been shown to prolong the QTc|
01357|046|D|interval;(1-4); additive effects may be possible with the concurrent|
01357|047|D|administration of apomorphine and 5-HT3 antagonists.|
01357|048|D|   Known 5-HT3 Antagonists that have been associated with QT prolongation|
01357|049|D|include:  dolasetron, granisetron, ondansetron, and tropisetron.|
01357|050|B||
01357|051|R|REFERENCES:|
01357|052|B||
01357|053|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
01357|054|R|  Inc. May, 2019.|1
01357|055|R|2.USFood and Drug Administration. FDA Drug Safety Communication: Abnormal|1
01357|056|R|  heart rhythms associated with use of Anzemet (dolasetron mesylate).|1
01357|057|R|  Available at: http://www.fda.gov/Drugs/DrugSafety/ucm237081.htm December|1
01357|058|R|  17, 2010.|1
01357|059|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01357|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01357|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01357|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01357|063|R|4.Zofran (ondansetron) US prescribing information. GlaxoSmithKline October,|1
01357|064|R|  2021.|1
01357|065|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01357|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01357|067|R|  settings: a scientific statement from the American Heart Association and|6
01357|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01357|069|R|  2;55(9):934-47.|6
01357|070|R|6.Bowron A. Practical considerations in the use of apomorphine injectable.|6
01357|071|R|  Neurology 2004 Mar 23;62(6 Suppl 4):S32-6.|6
01358|001|T|MONOGRAPH TITLE:  Selected Platelet Aggregation Inhibitors/NSAIDs;|
01358|002|T|Salicylates|
01358|003|B||
01358|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01358|005|L|of severe adverse interaction.|
01358|006|B||
01358|007|A|MECHANISM OF ACTION:  Abciximab, cangrelor, cilostazol, clopidogrel,|
01358|008|A|dipyridamole, eptifibatide, prasugrel, ticagrelor, vorapaxar and NSAIDs or|
01358|009|A|salicylates inhibit platelet aggregation.|
01358|010|B||
01358|011|E|CLINICAL EFFECTS:  Concurrent use of platelet aggregation inhibitors and|
01358|012|E|NSAIDs or salicylates may increase the risk of bleeding.|
01358|013|B||
01358|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01358|015|P|patients with multiple disease-associated factors (e.g. thrombocytopenia,|
01358|016|P|advanced liver disease).|
01358|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
01358|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01358|019|P|risk for bleeding (e.g., anticoagulants, other antiplatelets,|
01358|020|P|corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or|
01358|021|P|serotonin-norepinephrine  reuptake inhibitors (SNRIs).|
01358|022|P|   Risk of GI bleed may be increased in patients who are of older age, in|
01358|023|P|poor health status, or who use alcohol or smoke.  Risk may also be increased|
01358|024|P|with longer duration of NSAID use and prior history of peptic ulcer disease|
01358|025|P|and/or GI bleeding. Risk increases as the number of risk factors increases.|
01358|026|B||
01358|027|M|PATIENT MANAGEMENT:  Use caution when administering platelet aggregation|
01358|028|M|inhibitors with NSAIDs or salicylates.(1-5)  It would be prudent to monitor|
01358|029|M|patients more closely during concurrent therapy and to use the lowest NSAID|
01358|030|M|or salicylate dose possible.|
01358|031|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
01358|032|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
01358|033|M|and/or decreased blood pressure and promptly evaluate patients with any|
01358|034|M|symptoms.|
01358|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01358|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01358|037|M|anticoagulation in patients with active pathologic bleeding.|
01358|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01358|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01358|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01358|041|M|and/or swelling.|
01358|042|M|   The 2010 ACCF/ACG/AHA Consensus guidelines recommend the use of proton|
01358|043|M|pump inhibitors (PPIs) in patients with multiple risk factors for GI|
01358|044|M|bleeding who require antiplatelet therapy.  However, esomeprazole and|
01358|045|M|omeprazole should be avoided with clopidogrel as they are expected to reduce|
01358|046|M|the effectiveness of clopidogrel.  Use of other PPIs should be approached|
01358|047|M|with caution, as they may reduce the effectiveness of clopidogrel.|
01358|048|B||
01358|049|D|DISCUSSION:  Because of the increased risk of bleeding, caution is warranted|
01358|050|D|when using this combination.|
01358|051|D|   In a nationwide cohort study, patients were evaluated for thromboembolic|
01358|052|D|cardiovascular and clinically relevant bleeding events with concurrent|
01358|053|D|antithrombotic and ongoing NSAID treatment.  A total of 108,232 patients|
01358|054|D|were followed for a mean of 2.3 +/- 1.8 years after diagnosis of myocardial|
01358|055|D|infarction.  Concomitant NSAID treatment significantly increased the risk|
01358|056|D|for cardiovascular events (hazard ratio (HR) 6.96; 95% CI 6.24 - 6.77;|
01358|057|D|p<0.001) and bleeding events (HR 4.08; 95% CI 3.51 - 4.73; p<0.001) compared|
01358|058|D|to no NSAID treatment.  NSAIDs were further evaluated and revealed the use|
01358|059|D|of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI:|
01358|060|D|2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68|
01358|061|D|to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively)|
01358|062|D|had the lowest risk for cardiovascular and bleeding events, receptively.|
01358|063|B||
01358|064|R|REFERENCES:|
01358|065|B||
01358|066|R|1.ReoPro (abciximab) US prescribing information. Eli Lilly and Company|1
01358|067|R|  November 25, 2013.|1
01358|068|R|2.Kengreal (cangrelor) US prescribing information. The Medicines Company|1
01358|069|R|  October, 2019.|1
01358|070|R|3.Plavix (clopidogrel hydrogen sulfate) Australian prescribing information.|1
01358|071|R|  Sanofi-Synthelabo Australia Pty Limited May, 2022.|1
01358|072|R|4.Plavix (clopidogrel hydrogen sulphate) UK summary of product|1
01358|073|R|  characteristics. Sanofi Pharma Bristol-Myers Squibb SNC July 23, 2020.|1
01358|074|R|5.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01358|075|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01358|076|R|6.Integrilin (eptifibatide) US prescribing information. Schering Corporation|1
01358|077|R|  March, 2011.|1
01358|078|R|7.Abraham NS, et al. ACCF-ACG-AHA 2010 Expert Consensus Document on the|6
01358|079|R|  concomitant use of proton pump inhibitors & thienopyridines: a focused|6
01358|080|R|  update of the ACCF-ACG-AHA 2008 expert consensus document. Circulation|6
01358|081|R|  2010 Dec 14;122(24):2619-33.|6
01358|082|R|8.Kang DO, An H, Park GU, Yum Y, Park EJ, Park Y, Jang WY, Kim W, Choi JY,|2
01358|083|R|  Roh SY, Na JO, Kim JW, Kim EJ, Rha SW, Park CG, Seo HS, Choi CU.|2
01358|084|R|  Cardiovascular and Bleeding Risks Associated With Nonsteroidal|2
01358|085|R|  Anti-Inflammatory  Drugs After Myocardial Infarction. J Am Coll Cardiol|2
01358|086|R|  2020 Aug 4;76(5):518-529.|2
01359|001|T|MONOGRAPH TITLE:  Abciximab/Selected Platelet Inhibitors|
01359|002|B||
01359|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01359|004|L|take action as needed.|
01359|005|B||
01359|006|A|MECHANISM OF ACTION:  Dipyridamole, prasugrel, and ticlopidine inhibit|
01359|007|A|platelet aggregation.  Dipyridamole inhibits the uptake of adenosine, which|
01359|008|A|increases the local concentration of adenosine and causes platelet|
01359|009|A|aggregation inhibition.(1)  Prasugrel irreversibly binds to the ADP|
01359|010|A|receptors on platelets.(2)  Ticlopidine interferes with platelet membrane|
01359|011|A|function by inhibiting ADP-induced platelet-fibrinogen binding.(3)|
01359|012|A|Abciximab inhibits platelet aggregation by preventing the binding of|
01359|013|A|fibrinogen, von Willebrand factor, and other adhesive molecules on activated|
01359|014|A|platelets.(4)|
01359|015|B||
01359|016|E|CLINICAL EFFECTS:  Concurrent usage of these agents may result in an|
01359|017|E|increased risk of bleeding.|
01359|018|B||
01359|019|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01359|020|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01359|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
01359|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01359|023|P|risk for bleeding (e.g. NSAIDs).|
01359|024|B||
01359|025|M|PATIENT MANAGEMENT:  It is not recommended to administer dipyridamole,|
01359|026|M|ticlopidine, or prasugrel with abciximab because of the increased risk of|
01359|027|M|bleeds.|
01359|028|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01359|029|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01359|030|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01359|031|M|patients with any symptoms.|
01359|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01359|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01359|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01359|035|M|and/or swelling.|
01359|036|B||
01359|037|D|DISCUSSION:  A study including 21 patients taking ticlopidine and abciximab|
01359|038|D|showed that ticlopidine elicited a subtle potentiation of the|
01359|039|D|platelet-inhibitory capacity of abciximab.(5)|
01359|040|B||
01359|041|R|REFERENCES:|
01359|042|B||
01359|043|R|1.Aggrenox (aspirin/extended-release dipyridamole) US prescribing|1
01359|044|R|  information. Boehringer Ingelheim Pharmaceuticals, Inc. May, 2021.|1
01359|045|R|2.Efient (prasugrel hydrochloride) UK summary of product characteristics.|1
01359|046|R|  Eli Lilly and Company February 25, 2009.|1
01359|047|R|3.Ticlopidine hydrochloride US prescribing information. Teva Pharmaceuticals|1
01359|048|R|  USA June, 2003.|1
01359|049|R|4.ReoPro (abciximab) US prescribing information. Eli Lilly and Company|1
01359|050|R|  November 25, 2013.|1
01359|051|R|5.Kleiman NS, Graziadei N, Jordan RE, Lance ET, Fischer A, Maresh K, Edwards|5
01359|052|R|  A, Mascelli MA. Ticlopidine enhances the platelet inhibitory capacity of|5
01359|053|R|  abciximab in vitro. J Thromb Thrombolysis 2000 Jan;9(1):29-36.|5
01360|001|T|MONOGRAPH TITLE:  Ethyl Alcohol/Disulfiram Derivatives|
01360|002|B||
01360|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01360|004|L|is contraindicated and generally should not be dispensed or administered to|
01360|005|L|the same patient.|
01360|006|B||
01360|007|A|MECHANISM OF ACTION:  Disulfiram alters the intermediary metabolism of|
01360|008|A|alcohol.  Acetaldehyde is produced as a result of an initial metabolism of|
01360|009|A|alcohol in the liver.  Acetaldehyde is normally further oxidized by aldehyde|
01360|010|A|dehydrogenase.  However, this step is slowed by disulfiram and results in|
01360|011|A|elevated acetaldehyde levels in the blood, which produces the undesirable|
01360|012|A|effects.(1-2)|
01360|013|B||
01360|014|E|CLINICAL EFFECTS:  Patients taking preparations that contain alcohol or|
01360|015|E|using topical preparations that contain alcohol while taking disulfiram or|
01360|016|E|agents related to it may experience throbbing in the head and neck,|
01360|017|E|palpitations, tachycardia, hypotension, sweating, nausea, and vomiting.(3)|
01360|018|B||
01360|019|P|PREDISPOSING FACTORS:  None determined.|
01360|020|B||
01360|021|M|PATIENT MANAGEMENT:  The US manufacturer recommends that disulfiram never be|
01360|022|M|administered to a patient who is in a state of alcohol intoxication.|
01360|023|M|Patients should be advised that even small amounts of alcohol may trigger|
01360|024|M|the reaction. U.S. manufacturer states that taking any alcohol containing|
01360|025|M|products during the course of therapy with disulfiram or its derivatives is|
01360|026|M|contraindicated.(2)|
01360|027|M|   Patients should be informed about unsuspected sources of alcohol such as|
01360|028|M|elixirs and topical preparations.(2)|
01360|029|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
01360|030|M|   - The quantity of alcohol in paclitaxel injection formulations|
01360|031|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01360|032|M|dose contains approximately 13 grams of alcohol.|
01360|033|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01360|034|M|3-fold depending upon the manufacturer. FDA data on alcohol content (13):|
01360|035|M|   Product                      Manufacturer           Alcohol/200 mg dose|
01360|036|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01360|037|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01360|038|M|   Docetaxel Inj.               Accord                  4.0 grams|
01360|039|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01360|040|M|    formulation|
01360|041|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01360|042|M|   Docefrez                     Sun Pharma              2.9 grams|
01360|043|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01360|044|M|    formulation|
01360|045|B||
01360|046|D|DISCUSSION:  Disulfiram is used therapeutically in the treatment of|
01360|047|D|alcoholism.  The quantity of alcohol required to elicit the interaction|
01360|048|D|varies with individuals.(2,4-5)  Consumption of even small doses (e.g., 15|
01360|049|D|ml may lead to this interaction; therefore, concomitant administration|
01360|050|D|should be avoided. Patients have suffered from this interaction from|
01360|051|D|ingest-ing cough mixtures(6) and using topical preparations such as|
01360|052|D|aftershave lotions(7) and antipsoriatic preparations(8) that contained|
01360|053|D|alcohol.|
01360|054|D|   The duration of this interaction varies from 30 to 60 minutes to several|
01360|055|D|hours, depending on the amount of alcohol consumed.(2,9) An overdose of|
01360|056|D|disulfiram and alcohol may have caused a case of severe polyneuritis in one|
01360|057|D|report,(10) and another report attributes the death of a patient to this|
01360|058|D|interaction.(11)|
01360|059|D|   This interaction has also been reported in patients who came in contact|
01360|060|D|with other organic solvents (e.g., paint, "mineral spirits") through|
01360|061|D|inhalation; therefore, patients should be advised of this potential hazard|
01360|062|D|as well.(12)|
01360|063|B||
01360|064|R|REFERENCES:|
01360|065|B||
01360|066|R|1.Malcolm MT. Alcohol-disulfiram reactions. Br J Psychiatry 1984 May;|3
01360|067|R|  144:555.|3
01360|068|R|2.Antabuse (disulfiram) US prescribing information. Teva Women's Health,|1
01360|069|R|  Inc. February, 2013.|1
01360|070|R|3.Kwentus J, Major LF. Disulfiram in the treatment of alcoholism; a review.|6
01360|071|R|  J Stud Alcohol 1979 May;40(5):428-46.|6
01360|072|R|4.Rothstein E. Use of disulfiram (Antabuse) in alcoholism. N Engl J Med 1970|6
01360|073|R|  Oct 22;283(17):936.|6
01360|074|R|5.Stoll D, King LE Jr. Disulfiram-alcohol skin reaction to beer-containing|3
01360|075|R|  shampoo. JAMA 1980 Nov 7;244(18):2045.|3
01360|076|R|6.Koff RS, Papadimas I, Honig EG. Alcohol in cough medicines hazard to|3
01360|077|R|  disulfiram user. JAMA 1971 Mar 22;215(12):1988-9.|3
01360|078|R|7.Mercurio F. Antabuse(R)-alcohol reaction following use of after-shave|3
01360|079|R|  lotion. JAMA 1952 May 3;149:82.|3
01360|080|R|8.Ellis CN, Mitchell AJ, Beardsley GR Jr. Tar gel interaction with|3
01360|081|R|  disulfiram. Arch Dermatol 1979 Nov;115(11):1367-8.|3
01360|082|R|9.Hald J, Jacobsen E, Larsen V. The sensitizing effect of|2
01360|083|R|  tetraethylthiuramdisulphide (Antabuse) by ethylalcohol. Acta Pharmacol|2
01360|084|R|  1948;4:285-96.|2
01360|085|R|10.Rothrock JF, Johnson PC, Rothrock SM, Merkley R. Fulminant polyneuritis|3
01360|086|R|   after overdose of disulfiram and ethanol. Neurology 1984 Mar;34(3):357-9.|3
01360|087|R|11.van Ieperen L. Sudden death during disulfiram-ethanol reaction. S Afr Med|3
01360|088|R|   J 1984 Aug 4;66(5):165.|3
01360|089|R|12.Scott GE, Little FW. Disulfiram reaction to organic solvents other than|3
01360|090|R|   ethanol. N Engl J Med 1985 Mar 21;312(12):790.|3
01360|091|R|13.USFood and Drug Administration (FDA). Docetaxel: Drug Safety|1
01360|092|R|   Communication - May Cause Symptoms of Alcohol Intoxication. available at:|1
01360|093|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-co|1
01360|094|R|   mmunication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol|1
01360|095|R|   June 20, 2014.|1
01361|001|T|MONOGRAPH TITLE:  Ethyl Alcohol/Fexinidazole;Metronidazole;Tinidazole|
01361|002|B||
01361|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01361|004|L|of severe adverse interaction.|
01361|005|B||
01361|006|A|MECHANISM OF ACTION:  In vitro studies show that metronidazole produces an|
01361|007|A|inhibition of aldehyde dehydrogenase and other alcohol-oxidizing|
01361|008|A|enzymes.(1-5)  This results in the accumulation of acetaldehyde, which is|
01361|009|A|responsible for the disulfiram-like reaction.|
01361|010|A|   A similar process may occur with fexinidazole(6) and tinidazole.(7)|
01361|011|B||
01361|012|E|CLINICAL EFFECTS:  Concurrent use of oral metronidazole with alcohol has|
01361|013|E|been associated with a disulfiram-type reaction resulting in symptoms of|
01361|014|E|hypotension, tachycardia, nausea, sweating, facial flushing, headache, and|
01361|015|E|vomiting.(7-10)  It has been suggested that some patients find this|
01361|016|E|combination of agents a pleasant experience, citing giddiness and excitement|
01361|017|E|as rationale for abuse.(11)|
01361|018|B||
01361|019|P|PREDISPOSING FACTORS:  None determined.|
01361|020|B||
01361|021|M|PATIENT MANAGEMENT:  Patients receiving fexinidazole should be instructed to|
01361|022|M|avoid alcohol during and for at least 48 hours after taking fexinidazole.(6)|
01361|023|M|   Patients should be advised of the possible affects that may result from|
01361|024|M|ingestion or application of products that contain alcohol while taking|
01361|025|M|metronidazole.|
01361|026|M|   Patients receiving tinidazole should be instructed to avoid alcohol|
01361|027|M|during and for 3 days after taking tinidazole.(7)|
01361|028|M|   Patients should be informed about unsuspected sources of alcohol such as|
01361|029|M|elixirs and topical preparations.|
01361|030|M|   Caution is also warranted when using intravenous preparations containing|
01361|031|M|alcohol solvents in patients receiving metronidazole or tinidazole.|
01361|032|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
01361|033|M|   - The quantity of alcohol in paclitaxel injection formulations|
01361|034|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01361|035|M|dose contains approximately 13 grams of alcohol.|
01361|036|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01361|037|M|3-fold depending upon the manufacturer. FDA data on alcohol content (22):|
01361|038|M|   Product                      Manufacturer           Alcohol/200 mg dose|
01361|039|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01361|040|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01361|041|M|   Docetaxel Inj.               Accord                  4.0 grams|
01361|042|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01361|043|M|    formulation|
01361|044|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01361|045|M|   Docefrez                     Sun Pharma              2.9 grams|
01361|046|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01361|047|M|    formulation|
01361|048|B||
01361|049|D|DISCUSSION:  In a case report,(13) a patient developed disulfiram-like|
01361|050|D|reactions after receiving concurrent metronidazole and intravenous|
01361|051|D|sulfamethoxazole-trimethoprim, which is solubilized in a 10% alcohol base.|
01361|052|D|In another case report, a female patient using vaginal inserts containing|
01361|053|D|metronidazole once daily at bedtime ingested two or three drinks containing|
01361|054|D|30ml of vodka on the fifth day of metronidazole therapy.(14)  About a half|
01361|055|D|hour later, the patient inserted the metronidazole vaginal tablet and awoke|
01361|056|D|one hour later with a severe burning sensation in her stomach, a severe|
01361|057|D|headache, and nausea accompanied by a cold sweat.  These symptoms resolved|
01361|058|D|in about four hours.  Other studies have failed to observe a disulfiram-like|
01361|059|D|reaction between alcohol and metronidazole.(15-21)|
01361|060|B||
01361|061|R|REFERENCES:|
01361|062|B||
01361|063|R|1.Gupta NK, Woodley CL, Fried R. Effect of metronidazole on liver alcohol|5
01361|064|R|  dehydrogenase. Biochem Pharmacol 1970 Oct;19(10):2805-8.|5
01361|065|R|2.Kitson TM. The disulfiram--ethanol reaction: a review. J Stud Alcohol 1977|5
01361|066|R|  Jan;38(1):96-113.|5
01361|067|R|3.Edwards JA, Price J. Metronidazole and atypical human alcohol|5
01361|068|R|  dehydrogenase. Biochem Pharmacol 1967 Oct;16(10):2026-7.|5
01361|069|R|4.Fried R, Fried LW. The effect of Flagyl on xanthine oxidase and alcohol|5
01361|070|R|  dehydrogenase. Biochem Pharmacol 1966;15:1890-94.|5
01361|071|R|5.Paltrinieri E. Inhibitory action of|5
01361|072|R|  hydroxy-2-ethyl-1-methyl-2-nitro-5-imidazole on alcohol-dehydrogenase.|5
01361|073|R|  Farmaco Sci 1967 Dec;22(12):1054-6.|5
01361|074|R|6.Fexinidazole US prescribing information. Sanofi-Aventis U.S. LLC July,|1
01361|075|R|  2021.|1
01361|076|R|7.Tinidazole US prescribing information. Rising Pharmaceuticals, Inc..|1
01361|077|R|  October 12, 2017.|1
01361|078|R|8.Penick SB, Carrier RN, Sheldon JB. Metronidazole in the treatment of|3
01361|079|R|  alcoholism. Am J Psychiatry 1969 Feb;125(8):1063-6.|3
01361|080|R|9.Taylor JA. Metronidazole--a new agent for combined somatic and psychic|3
01361|081|R|  therapy of alcoholism. A case study and preliminary report. Bull Los Angel|3
01361|082|R|  Neuro Soc 1964 Sep;29:158-62.|3
01361|083|R|10.Lehmann HE, Ban TA, Naltchayan E. Metronidazole in the treatment of the|3
01361|084|R|   alcoholic. Psychiatr Neurol (Basel) 1966;152(6):395-401.|3
01361|085|R|11.Alexander I. 'Alcohol-antabuse' syndrome in patients receiving|3
01361|086|R|   metronidazole during gynaecological treatment. Br J Clin Pract 1985 Jul;|3
01361|087|R|   39(7):292-3.|3
01361|088|R|12.Giannini AJ, DeFrance DT. Metronidazole and alcohol--potential for|3
01361|089|R|   combinative abuse. J Toxicol Clin Toxicol 1983 Jul;20(5):509-15.|3
01361|090|R|13.Edwards DL, Fink PC, Van Dyke PO. Disulfiram-like reaction associated|3
01361|091|R|   with intravenous trimethoprim-sulfamethoxazole and metronidazole. Clin|3
01361|092|R|   Pharm 1986 Dec;5(12):999-1000.|3
01361|093|R|14.Plosker GL. Possible interaction between ethanol and vaginally|3
01361|094|R|   administered metronidazole. Clin Pharm 1987 Mar;6(3):189, 192-3.|3
01361|095|R|15.Gelder MG, Edwards G. Metronidazole in the treatment of alcohol|2
01361|096|R|   addiction. A controlled trial. Br J Psychiatry 1968 Apr;114(509):473-5.|2
01361|097|R|16.Goodwin DW. Metronidazole in the treatment of alcoholism: a negative|2
01361|098|R|   report. Am J Psychiatry 1967 Apr;123(10):1276-8.|2
01361|099|R|17.Egan WP, Goetz R. Effect of metronidazole on drinking by alcoholics. Q J|2
01361|100|R|   Stud Alcohol 1968 Dec;29(4):899-902.|2
01361|101|R|18.Gallant DM, Bishop MP, Camp E, Tisdale C. A six-month controlled|2
01361|102|R|   evaluation of metronidazole (Flagyl) in chronic alcoholic patients. Curr|2
01361|103|R|   Ther Res Clin Exp 1968 Feb;10(2):82-7.|2
01361|104|R|19.Platz A, Panepinto WC, Kissin B, Charnoff SM. Metronidazole and|2
01361|105|R|   alcoholism. (An evaluation of specific and non specific factors in drug|2
01361|106|R|   treatment). Dis Nerv Syst 1970 Sep;31(9):631-6.|2
01361|107|R|20.Strassman HD, Adams B, Pearson AW. Metronidazole effect on social|2
01361|108|R|   drinkers. Q J Stud Alcohol 1970 Jun;31(2):394-8.|2
01361|109|R|21.Lowenstam I. Metronidazole and placebo in the treatment of chronic|2
01361|110|R|   alcoholism. A comparative study. Psychosomatics 1969 May-Jun;10(3):43-5.|2
01361|111|R|22.USFood and Drug Administration (FDA). Docetaxel: Drug Safety|1
01361|112|R|   Communication - May Cause Symptoms of Alcohol Intoxication. available at:|1
01361|113|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-co|1
01361|114|R|   mmunication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol|1
01361|115|R|   June 20, 2014.|1
01362|001|T|MONOGRAPH TITLE:  Hydantoins/Ethyl Alcohol|
01362|002|B||
01362|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01362|004|L|take action as needed.|
01362|005|B||
01362|006|A|MECHANISM OF ACTION:  Chronic alcohol ingestion may result in alterations in|
01362|007|A|the metabolism of phenytoin.|
01362|008|B||
01362|009|E|CLINICAL EFFECTS:  Chronic alcohol ingestion may result in either elevated|
01362|010|E|phenytoin levels, which may result in increased phenytoin adverse effects,|
01362|011|E|or in a decrease in phenytoin levels, which may result in decreased seizure|
01362|012|E|control.|
01362|013|B||
01362|014|P|PREDISPOSING FACTORS:  None determined.|
01362|015|B||
01362|016|M|PATIENT MANAGEMENT:  Phenytoin levels should be monitored in patients who|
01362|017|M|ingest alcohol chronically and in patients who discontinue alcohol|
01362|018|M|consumption.|
01362|019|B||
01362|020|D|DISCUSSION:  It has been reported that long-term alcohol ingestion may|
01362|021|D|increase the metabolism and clearance of phenytoin.(1-3)  However, it has|
01362|022|D|also been postulated that long term alcohol ingestion may inhibit phenytoin|
01362|023|D|metabolism, causing phenytoin levels to increase.  Phenytoin clearance may|
01362|024|D|increase during alcohol withdrawal, resulting in a decrease in serum serum|
01362|025|D|phenytoin levels.(4)  The use of small amounts of alcohol does not produce|
01362|026|D|these effects.(3)|
01362|027|B||
01362|028|R|REFERENCES:|
01362|029|B||
01362|030|R|1.Birkett DJ, Graham GG, Chinwah PM, Wade DN, Hickie JB. Multiple drug|2
01362|031|R|  interactions with phenytoin. Med J Aust 1977 Oct 1;2(14):467-8.|2
01362|032|R|2.Kater RM, Roggin G, Tobon F, Zieve P, Iber FL. Increased rate of clearance|2
01362|033|R|  of drugs from the circulation of alcoholics. Am J Med Sci 1969 Jul;|2
01362|034|R|  258(1):35-9.|2
01362|035|R|3.Schmidt D. Effect of ethanol intake on phenytoin metabolism in volunteers.|2
01362|036|R|  Experientia 1975 Nov 15;31(11):1313-4.|2
01362|037|R|4.Sandor P, Sellers EM, Dumbrell M, Khouw V. Effect of short- and long-term|2
01362|038|R|  alcohol use on phenytoin kinetics in chronic alcoholics. Clin Pharmacol|2
01362|039|R|  Ther 1981 Sep;30(3):390-7.|2
01363|001|T|MONOGRAPH TITLE:  Brinzolamide/Carbonic Anhydrase Inhibitors|
01363|002|B||
01363|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01363|004|L|take action as needed.|
01363|005|B||
01363|006|A|MECHANISM OF ACTION:  Brinzolamide and other carbonic anhydrase inhibitors|
01363|007|A|cause a decrease in aqueous humor secretion by slowing the formation of|
01363|008|A|bicarbonate ions with a subsequent reduction of sodium and fluid transport|
01363|009|A|which results in a reduction of intraocular pressure.(1)|
01363|010|B||
01363|011|E|CLINICAL EFFECTS:  If brinzolamide is given with other carbonic anhydrase|
01363|012|E|inhibitors it may cause electrolyte disturbances, because brinzolamide can|
01363|013|E|be absorbed systemically.(1)|
01363|014|B||
01363|015|P|PREDISPOSING FACTORS:  Patients with conditions that predispose to acidosis|
01363|016|P|(such as renal disease, severe respiratory disorders, status epilepticus,|
01363|017|P|diarrhea, and being on a ketogenic diet) may be at increased risk of|
01363|018|P|experiencing adverse effects from concurrent carbonic anhydrase inhibitors.|
01363|019|B||
01363|020|M|PATIENT MANAGEMENT:  It is not recommended to use brinzolamide with systemic|
01363|021|M|carbonic anhydrase inhibitors.|
01363|022|B||
01363|023|D|DISCUSSION:  Although no human data is available, electrolyte imbalance,|
01363|024|D|development of an acidotic state, and possible nervous system effects may|
01363|025|D|occur following oral administration of brinzolamide and another carbonic|
01363|026|D|anhydrase inhibitor.(1)|
01363|027|B||
01363|028|R|REFERENCE:|
01363|029|B||
01363|030|R|1.Azopt (brinzolamide) US prescribing information. Alcon Labs September,|1
01363|031|R|  2006.|1
01364|001|T|MONOGRAPH TITLE:  Raloxifene/Estrogen|
01364|002|B||
01364|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01364|004|L|take action as needed.|
01364|005|B||
01364|006|A|MECHANISM OF ACTION:  Raloxifene binds to estrogen receptors and activates|
01364|007|A|certain estrogenic pathways while blocking others.(1)|
01364|008|B||
01364|009|E|CLINICAL EFFECTS:  Concurrent use of raloxifene and estrogen may result in|
01364|010|E|an unpredictable response.|
01364|011|B||
01364|012|P|PREDISPOSING FACTORS:  None determined.|
01364|013|B||
01364|014|M|PATIENT MANAGEMENT:  The manufacturer of raloxifene does not recommend the|
01364|015|M|use of systemic estrogen or hormone replacement therapy with raloxifene.(1)|
01364|016|B||
01364|017|D|DISCUSSION:  Information on the interaction between raloxifene and estrogen|
01364|018|D|is lacking and the manufacturer of raloxifene states that the concurrent use|
01364|019|D|of these medications has not been studied in prospective clinical trials.(1)|
01364|020|B||
01364|021|R|REFERENCE:|
01364|022|B||
01364|023|R|1.Evista (raloxifene hydrochloride) US prescribing information. Eli Lilly|1
01364|024|R|  and Company June, 2018.|1
01365|001|T|MONOGRAPH TITLE:  Amiodarone/QT Prolonging Agents|
01365|002|B||
01365|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01365|004|L|of severe adverse interaction.|
01365|005|B||
01365|006|A|MECHANISM OF ACTION:  Amiodarone has been shown to prolong the QTc interval.|
01365|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01365|008|A|additive effects on the QTc interval.(1-3)|
01365|009|B||
01365|010|E|CLINICAL EFFECTS:  The concurrent use of amiodarone with other agents that|
01365|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01365|012|E|arrhythmias, including torsades de pointes.(1-3)|
01365|013|B||
01365|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01365|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01365|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01365|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01365|018|P|gender, or advanced age.(6)|
01365|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01365|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01365|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01365|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01365|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01365|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01365|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
01365|026|B||
01365|027|M|PATIENT MANAGEMENT:  The US manufacturer of amiodarone states that the|
01365|028|M|concurrent use of QT prolonging agents should be avoided and that the need|
01365|029|M|to co-administer amiodarone with any other drug known to prolong the QTc|
01365|030|M|interval must be based on a careful assessment of the potential risks and|
01365|031|M|benefits of doing so for each patient.(3)|
01365|032|M|   The Australian(1) and UK(2) manufacturers of amiodarone states that|
01365|033|M|concurrent use of agents known to cause torsades de pointes is|
01365|034|M|contraindicated.|
01365|035|B||
01365|036|D|DISCUSSION:  QTc prolongation has been reported during concurrent amiodarone|
01365|037|D|and azole antifungals, fluoroquinolones, and macrolide antibiotics.(3)|
01365|038|D|   A retrospective review of patients who received concurrent amiodarone and|
01365|039|D|haloperidol over a 24 month period found 49 patients who received concurrent|
01365|040|D|therapy for 381 exposures.  The mean increase in QTc interval was 9.8 msec;|
01365|041|D|the average change in QTc interval per patient was 23.6 msec.(4)|
01365|042|D|   Agents that are linked to this monograph may have varying degrees of|
01365|043|D|potential to prolong the QTc interval but are generally accepted to have a|
01365|044|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
01365|045|D|been shown to prolong the QTc interval either through their mechanism of|
01365|046|D|action, through studies on their effects on the QTc interval, or through|
01365|047|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01365|048|D|and/or postmarketing reports.(5)|
01365|049|D|   One or more of the drug pairs linked to this monograph have been included|
01365|050|D|in a list of interactions that should be considered "high-priority" for|
01365|051|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01365|052|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01365|053|D|Coordinator (ONC) for Health Information Technology.|
01365|054|B||
01365|055|R|REFERENCES:|
01365|056|B||
01365|057|R|1.Cordarone X (amiodarone hydrochloride) Australian prescribing information.|1
01365|058|R|  Sanofi-Synthelabo Australia Pty Limited Augsut 15, 2007.|1
01365|059|R|2.Cordarone X (amiodarone hydrochloride) UK summary of product|1
01365|060|R|  characteristics. Sanofi-Aventis July 6, 2010.|1
01365|061|R|3.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
01365|062|R|  Pharmaceuticals October, 2018.|1
01365|063|R|4.Bush SE, Hatton RC, Winterstein AG, Thomson MR, Woo GW. Effects of|3
01365|064|R|  concomitant amiodarone and haloperidol on Q-Tc interval prolongation. Am J|3
01365|065|R|  Health Syst Pharm 2008 Dec 1;65(23):2232-6.|3
01365|066|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
01365|067|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01365|068|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01365|069|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01365|070|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01365|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01365|072|R|  settings: a scientific statement from the American Heart Association and|6
01365|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01365|074|R|  2;55(9):934-47.|6
01365|075|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01365|076|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01365|077|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01365|078|R|  19(5):735-43.|6
01366|001|T|MONOGRAPH TITLE:  Arsenic/Possible QT Prolonging Agents|
01366|002|B||
01366|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01366|004|L|take action as needed.|
01366|005|B||
01366|006|A|MECHANISM OF ACTION:  Arsenic has been shown to prolong the QTc interval.|
01366|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01366|008|A|additive effects on the QTc interval.(1)|
01366|009|B||
01366|010|E|CLINICAL EFFECTS:  The concurrent use of arsenic with other agents that|
01366|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01366|012|E|arrhythmias, including torsades de pointes.(1)|
01366|013|B||
01366|014|P|PREDISPOSING FACTORS:  The risk of torsade de pointes is related to the|
01366|015|P|extent of QT prolongation, concomitant administration of QT prolonging|
01366|016|P|drugs, a history of torsade de pointes, preexisting QT interval|
01366|017|P|prolongation, congestive heart failure, use of potassium-wasting diuretics,|
01366|018|P|or other conditions that result in hypokalemia or hypomagnesemia.(1) Risk|
01366|019|P|may also be increased in patients with other cardiovascular disease (e.g.|
01366|020|P|myocardial infarction, congenital long QT syndrome), hypocalcemia,|
01366|021|P|bradycardia, female gender, or advanced age.(2)|
01366|022|P|   Higher systemic concentrations of either QT prolonging drug are|
01366|023|P|additional risk factors for torsade de pointes.  Factors which may increase|
01366|024|P|systemic drug concentrations include rapid infusion of an intravenous dose|
01366|025|P|or impaired metabolism or elimination of the drug (e.g. coadministration|
01366|026|P|with an agent which inhibits its metabolism or elimination, genetic|
01366|027|P|impairment in drug metabolism or elimination, and/or renal/hepatic|
01366|028|P|dysfunction).(2)|
01366|029|B||
01366|030|M|PATIENT MANAGEMENT:  The manufacturer of arsenic trioxide states that, if|
01366|031|M|possible, drugs that are known to prolong the QT interval should be|
01366|032|M|discontinued prior to therapy and caution is advised during|
01366|033|M|coadministration.(1)|
01366|034|M|   In patients who reach a QTc interval value > 450 msec in men or >460 msec|
01366|035|M|in women, withhold arsenic and any other QT prolonging agents.  Monitor|
01366|036|M|electrolytes and correct abnormalities.  After the QTc normalizes, follow|
01366|037|M|manufacturer instructions concerning restarting arsenic and escalation of|
01366|038|M|dosing.(1)|
01366|039|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
01366|040|M|fainting.|
01366|041|B||
01366|042|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01366|043|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01366|044|D|monograph have been shown to prolong the QTc interval either through their|
01366|045|D|mechanism of action, through studies on their effects on the QTc interval,|
01366|046|D|or through reports of QTc prolongation and/or torsades de pointes in|
01366|047|D|clinical trials and/or postmarketing reports.(3)|
01366|048|B||
01366|049|R|REFERENCES:|
01366|050|B||
01366|051|R|1.Trisenox (arsenic trioxide) US Prescribing information. Teva|1
01366|052|R|  Pharmaceuticals USA, Inc. October, 2020.|1
01366|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01366|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01366|055|R|  settings: a scientific statement from the American Heart Association and|6
01366|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01366|057|R|  2;55(9):934-47.|6
01366|058|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01366|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01366|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01366|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01367|001|T|MONOGRAPH TITLE:  Dofetilide/Possible QT Prolonging Agents|
01367|002|B||
01367|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01367|004|L|take action as needed.|
01367|005|B||
01367|006|A|MECHANISM OF ACTION:  Dofetilide has been shown to prolong the QTc interval|
01367|007|A|in a dose-dependent fashion.  Concurrent use with other agents that prolong|
01367|008|A|the QTc interval may result in additive effects on the QTc interval.(1)|
01367|009|B||
01367|010|E|CLINICAL EFFECTS:  The concurrent use of dofetilide with other agents that|
01367|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01367|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
01367|013|B||
01367|014|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
01367|015|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
01367|016|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
01367|017|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
01367|018|P|   In general, the risk of QT prolongation or torsade de pointes may be|
01367|019|P|increased in patients with cardiovascular disease (e.g. heart failure,|
01367|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01367|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01367|022|P|gender, or advanced age.(2)|
01367|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01367|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01367|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01367|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01367|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01367|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01367|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01367|030|B||
01367|031|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that the use of|
01367|032|M|dofetilide with other agents known to prolong the QTc interval is not|
01367|033|M|recommended.(1)|
01367|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01367|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01367|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01367|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01367|038|M|   If dofetilide dose is increased or if dofetilide therapy is reinitiated|
01367|039|M|after an interruption, the patient should be hospitalized for continuous ECG|
01367|040|M|monitoring.(1)|
01367|041|B||
01367|042|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01367|043|D|degrees of potential to prolong the QTc interval but are generally accepted|
01367|044|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
01367|045|D|monograph have been shown to prolong the QTc interval either through their|
01367|046|D|mechanism of action, through studies on their effects on the QTc interval,|
01367|047|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
01367|048|D|clinical trials and/or post-marketing reports.(3)|
01367|049|B||
01367|050|R|REFERENCES:|
01367|051|B||
01367|052|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01367|053|R|  2013.|1
01367|054|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01367|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01367|056|R|  settings: a scientific statement from the American Heart Association and|6
01367|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01367|058|R|  2;55(9):934-47.|6
01367|059|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01367|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01367|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01367|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01368|001|T|MONOGRAPH TITLE:  Gatifloxacin/QT Prolonging Agents|
01368|002|B||
01368|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01368|004|L|take action as needed.|
01368|005|B||
01368|006|A|MECHANISM OF ACTION:  Gatifloxacin has been shown to prolong the QTc|
01368|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01368|008|A|may result in additive effects on the QTc interval.(1)|
01368|009|B||
01368|010|E|CLINICAL EFFECTS:  The concurrent use of gatifloxacin with other agents that|
01368|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01368|012|E|arrhythmias, including torsades de pointes.(1)|
01368|013|B||
01368|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01368|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01368|016|P|myocardial infarction, history of torsade de pointes. congenital long QT|
01368|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01368|018|P|gender, or advanced age.(3)|
01368|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01368|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01368|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01368|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01368|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01368|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01368|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01368|026|B||
01368|027|M|PATIENT MANAGEMENT:  The manufacturer of gatifloxacin states that|
01368|028|M|gatifloxacin should be used with caution when given with other agents known|
01368|029|M|to prolong the QT interval, including erythromycin, phenothiazines, and|
01368|030|M|tricyclics.(1)|
01368|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01368|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01368|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01368|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01368|035|B||
01368|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01368|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01368|038|D|monograph have been shown to prolong the QTc interval either through their|
01368|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01368|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01368|041|D|clinical trials and/or postmarketing reports.(2)|
01368|042|B||
01368|043|R|REFERENCES:|
01368|044|B||
01368|045|R|1.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
01368|046|R|  Company January, 2006.|1
01368|047|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01368|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01368|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01368|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01368|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01368|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01368|053|R|  settings: a scientific statement from the American Heart Association and|6
01368|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01368|055|R|  2;55(9):934-47.|6
01369|001|T|MONOGRAPH TITLE:  Moxifloxacin/Possible QT Prolonging Agents|
01369|002|B||
01369|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01369|004|L|take action as needed.|
01369|005|B||
01369|006|A|MECHANISM OF ACTION:  Moxifloxacin has been shown to prolong the QTc|
01369|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01369|008|A|may result in additive effects on the QTc interval.(1)|
01369|009|B||
01369|010|E|CLINICAL EFFECTS:  The concurrent use of moxifloxacin with other agents that|
01369|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01369|012|E|arrhythmias, including torsades de pointes.(1)|
01369|013|B||
01369|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01369|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01369|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01369|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01369|018|P|gender, or advanced age.(3)|
01369|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01369|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01369|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01369|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01369|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01369|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01369|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01369|026|B||
01369|027|M|PATIENT MANAGEMENT:  The manufacturer of moxifloxacin states that|
01369|028|M|moxifloxacin should be avoided in patients taking agents known to prolong|
01369|029|M|the QT interval.(1)|
01369|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01369|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01369|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01369|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01369|034|B||
01369|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01369|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01369|037|D|monograph have been shown to prolong the QTc interval either through their|
01369|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01369|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01369|040|D|clinical trials and/or postmarketing reports.(2)|
01369|041|B||
01369|042|R|REFERENCES:|
01369|043|B||
01369|044|R|1.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
01369|045|R|  Pharmaceuticals Corporation October 18, 2018.|1
01369|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01369|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01369|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01369|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01369|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01369|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01369|052|R|  settings: a scientific statement from the American Heart Association and|6
01369|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01369|054|R|  2;55(9):934-47.|6
01370|001|T|MONOGRAPH TITLE:  Sotalol/Possible QT Prolonging Agents|
01370|002|B||
01370|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01370|004|L|take action as needed.|
01370|005|B||
01370|006|A|MECHANISM OF ACTION:  Sotalol has been shown to prolong the QTc interval.|
01370|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01370|008|A|additive effects on the QTc interval.(1)|
01370|009|B||
01370|010|E|CLINICAL EFFECTS:  The concurrent use of sotalol with other agents that|
01370|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01370|012|E|arrhythmias, including torsades de pointes.(1)|
01370|013|B||
01370|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by|
01370|015|P|reduced creatinine clearance, female gender, larger doses of sotalol, and a|
01370|016|P|history of cardiomegaly or congestive heart failure.(1)  Risk may also be|
01370|017|P|increased in patients with cardiovascular disease (e.g. myocardial|
01370|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01370|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, or advanced age.(3)|
01370|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01370|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01370|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01370|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01370|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01370|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01370|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01370|027|B||
01370|028|M|PATIENT MANAGEMENT:  The manufacturer of sotalol states that concurrent use|
01370|029|M|with other agents known to prolong the QT interval is not recommended.(1)|
01370|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01370|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01370|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01370|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01370|034|B||
01370|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01370|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01370|037|D|monograph have been shown to prolong the QTc interval either through their|
01370|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01370|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01370|040|D|clinical trials and/or postmarketing reports.(2)|
01370|041|B||
01370|042|R|REFERENCES:|
01370|043|B||
01370|044|R|1.Betapace (sotalol hydrochloride) US prescribing information. Bayer|1
01370|045|R|  Healthcare Inc. June, 2021.|1
01370|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01370|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01370|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01370|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01370|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01370|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01370|052|R|  settings: a scientific statement from the American Heart Association and|6
01370|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01370|054|R|  2;55(9):934-47.|6
01371|001|T|MONOGRAPH TITLE:  Risperidone/QT Prolonging Agents (mono deleted 11/07/2019)|
01371|002|B||
01371|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01371|004|L|take action as needed.|
01371|005|B||
01371|006|A|MECHANISM OF ACTION:  Risperidone has been shown to prolong the QTc|
01371|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01371|008|A|may result in additive effects on the QTc interval.(1)|
01371|009|B||
01371|010|E|CLINICAL EFFECTS:  The concurrent use of risperidone with other agents that|
01371|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01371|012|E|arrhythmias, including torsades de pointes.(1)|
01371|013|B||
01371|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01371|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01371|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01371|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01371|018|P|gender, or advanced age.(3)|
01371|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01371|020|P|higher systemic concentration of either QT prolonging drug are additional|
01371|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01371|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01371|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01371|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01371|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01371|026|B||
01371|027|M|PATIENT MANAGEMENT:  The UK manufacturer of risperidone states that|
01371|028|M|risperidone should be used with caution when given with other agents known|
01371|029|M|to prolong the QT interval.(1)|
01371|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01371|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01371|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01371|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01371|034|B||
01371|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01371|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01371|037|D|monograph have been shown to prolong the QTc interval either through their|
01371|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01371|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01371|040|D|clinical trials and/or postmarketing reports.(2)|
01371|041|B||
01371|042|R|REFERENCES:|
01371|043|B||
01371|044|R|1.Risperidal (risperidone) UK summary of product characteristics.|1
01371|045|R|  Janssen-Cilag, UK Limited May 14, 2004.|1
01371|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01371|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01371|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01371|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01371|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01371|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01371|052|R|  settings: a scientific statement from the American Heart Association and|6
01371|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01371|054|R|  2;55(9):934-47.|6
01372|001|T|MONOGRAPH TITLE:  Dolasetron/QT Prolonging Agents|
01372|002|B||
01372|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01372|004|L|take action as needed.|
01372|005|B||
01372|006|A|MECHANISM OF ACTION:  Dolasetron has been shown to prolong the QTc interval.|
01372|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01372|008|A|additive effects on the QTc interval.(1)|
01372|009|B||
01372|010|E|CLINICAL EFFECTS:  The concurrent use of dolasetron with other agents that|
01372|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01372|012|E|arrhythmias, including torsades de pointes.(1)|
01372|013|B||
01372|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01372|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01372|016|P|myocardial infarction, anthracycline-induced cardiotoxicity, history of|
01372|017|P|torsade de pointes, congenital long QT syndrome), hypokalemia,|
01372|018|P|hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced|
01372|019|P|age.(1,3)|
01372|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01372|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01372|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01372|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01372|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01372|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01372|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01372|027|B||
01372|028|M|PATIENT MANAGEMENT:  The manufacturer of dolasetron states that dolasetron|
01372|029|M|should be used with caution when given with other agents known to prolong|
01372|030|M|the QT interval.(1)|
01372|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01372|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01372|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01372|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01372|035|B||
01372|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01372|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01372|038|D|monograph have been shown to prolong the QTc interval either through their|
01372|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01372|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01372|041|D|clinical trials and/or postmarketing reports.(2)|
01372|042|B||
01372|043|R|REFERENCES:|
01372|044|B||
01372|045|R|1.Anzemet (dolasetron mesylate) US prescribing information. Sanofi-Aventis|1
01372|046|R|  Us.S. LLC September, 2014.|1
01372|047|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01372|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01372|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01372|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01372|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01372|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01372|053|R|  settings: a scientific statement from the American Heart Association and|6
01372|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01372|055|R|  2;55(9):934-47.|6
01373|001|T|MONOGRAPH TITLE:  Ethyl Alcohol/Selected Cephalosporins|
01373|002|B||
01373|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01373|004|L|of severe adverse interaction.|
01373|005|B||
01373|006|A|MECHANISM OF ACTION:  Certain cephalosporins have a methyltetrazolethiol|
01373|007|A|side chain that resembles part of the disulfiram molecule.  It has been|
01373|008|A|suggested that the cephalosporins with this side chain interfere with the|
01373|009|A|activity of the alcohol-metabolizing enzyme, aldehyde dehydrogenase,|
01373|010|A|resulting in elevated concentrations of acetaldehyde and a "disulfiram-like"|
01373|011|A|reaction.(1)|
01373|012|B||
01373|013|E|CLINICAL EFFECTS:  A disulfiram-like reaction may occur in patients who|
01373|014|E|ingest alcohol during and after taking some cephalosporins. Symptoms include|
01373|015|E|throbbing in the head and neck, palpitations, tachycardia, hypotension,|
01373|016|E|sweating, nausea, and vomiting.|
01373|017|B||
01373|018|P|PREDISPOSING FACTORS:  None determined.|
01373|019|B||
01373|020|M|PATIENT MANAGEMENT:  Patients receiving cephalosporins with a|
01373|021|M|methyltetrazolethiol side chain should be cautioned about consuming alcohol|
01373|022|M|during and for several days after therapy.  Patients should be informed|
01373|023|M|about unsuspected sources of alcohol such as elixirs and topical|
01373|024|M|preparations.|
01373|025|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
01373|026|M|   - The quantity of alcohol in paclitaxel injection formulations|
01373|027|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01373|028|M|dose contains approximately 13 grams of alcohol.|
01373|029|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01373|030|M|3-fold depending upon the manufacturer. FDA data on alcohol content (17) :|
01373|031|M|   Product                      Manufacturer           Alcohol/200 mg dose|
01373|032|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01373|033|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01373|034|M|   Docetaxel Inj.               Accord                  4.0 grams|
01373|035|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01373|036|M|    formulation|
01373|037|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01373|038|M|   Docefrez                     Sun Pharma              2.9 grams|
01373|039|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01373|040|M|    formulation|
01373|041|B||
01373|042|D|DISCUSSION:  A disulfiram-like reaction has been reported following the|
01373|043|D|ingestion of alcohol by patients receiving cefamandole,(2-4) cefoperazone,|
01373|044|D|(5-7) cefotetan,(8) and moxalactam.(9-11)  The reaction has been reported in|
01373|045|D|patients who had been receiving the antibiotic periodically or continuously|
01373|046|D|before alcohol consumption.  The reaction occurred within 30 minutes of|
01373|047|D|alcohol consumption.(5-7)  In one patient, the reaction occurred after an|
01373|048|D|injection of 15 ml of a 67% alcohol into the paraaortic space for celiac|
01373|049|D|plexus alcohol block.(11)|
01373|050|D|   Cefonicid and ceforanide have exhibited these effects in animal studies.|
01373|051|D|(12)  However, another study showed that cefonicid did not interact with|
01373|052|D|alcohol.(13)|
01373|053|D|   No interaction was found with cefazolin, cefotaxime, cefoxitin,|
01373|054|D|cephalothin, or cephradine in animal studies.(14-15)  A study in humans|
01373|055|D|found no interaction with ceftizoxime.(1)  These cephalosporins do not have|
01373|056|D|a methyltetrazolethiol side chain.|
01373|057|D|   A single case reported a disulfiram-like reaction in a patient taking|
01373|058|D|cefonicid therapy on two separate occasions.(16)|
01373|059|B||
01373|060|R|REFERENCES:|
01373|061|B||
01373|062|R|1.Elenbaas RM, Ryan JL, Robinson WA, Singsank MJ, Harvey MJ, Klaassen CD. On|3
01373|063|R|  the disulfiram-like activity of moxalactam. Clin Pharmacol Ther 1982 Sep;|3
01373|064|R|  32(3):347-55.|3
01373|065|R|2.Portier H, Chalopin JM, Freysz M, Tanter Y. Interaction between|3
01373|066|R|  cephalosporins and alcohol. Lancet 1980 Aug 2;2(8188):263.|3
01373|067|R|3.Drummer S, Hauser WE Jr, Remington JS. Antabuse-like effect of beta-lactam|3
01373|068|R|  antibiotics. N Engl J Med 1980 Dec 11;303(24):1417-8.|3
01373|069|R|4.Rotoli B, De Rosa G, Selleri C, Luciano L. Alcohol and cephamandole.|3
01373|070|R|  Haematologica 1985 Jul-Aug;70(4):372-3.|3
01373|071|R|5.Foster TS, Raehl CL, Wilson HD. Disulfiram-like reaction associated with a|3
01373|072|R|  parenteral cephalosporin. Am J Hosp Pharm 1980 Jun;37(6):858-9.|3
01373|073|R|6.Reeves DS, Davies AJ. Antabuse effect with cephalosporins. Lancet 1980 Sep|3
01373|074|R|  6;2(8193):540.|3
01373|075|R|7.McMahon FG. Disulfiram-like reaction to a cephalosporin. JAMA 1980 Jun 20;|3
01373|076|R|  243(23):2397.|3
01373|077|R|8.Norrby SR. Adverse reactions and interactions with newer cephalosporin and|3
01373|078|R|  cephamycin antibiotics. Med Toxicol 1986 Jan-Feb;1(1):32-46.|3
01373|079|R|9.Neu HC, Prince AS. Interaction between moxalactam and alcohol. Lancet 1980|3
01373|080|R|  Jun 28;1(8183):1422.|3
01373|081|R|10.Brown KR, Guglielmo BJ, Pons VG, Jacobs RA. Theophylline elixir,|3
01373|082|R|   moxalactam, and a disulfiram reaction. Ann Intern Med 1982 Oct;|3
01373|083|R|   97(4):621-2.|3
01373|084|R|11.Umeda S, Arai T. Disulfiram-like reaction to moxalactam after celiac|3
01373|085|R|   plexus alcohol block. Anesth Analg 1985 Mar;64(3):377.|3
01373|086|R|12.Fromtling RA, Gadebusch HH. Ethanol-cephalosporin antibiotic|5
01373|087|R|   interactions: an animal model for the detection of disulfiram|5
01373|088|R|   (Antabuse)-like effects. Methods Find Exp Clin Pharmacol 1983 Nov;|5
01373|089|R|   5(9):595-600.|5
01373|090|R|13.McMahon FG, Noveck RJ. Lack of disulfiram--like reactions with|5
01373|091|R|   ceftizoxime. J Antimicrob Chemother 1982 Nov;10 Suppl C:129-33.|5
01373|092|R|14.Buening MK, Wold JS. Ethanol-moxalactam interactions in vivo. Rev Infect|5
01373|093|R|   Dis 1982 Nov-Dec;4 Suppl:S555-63.|5
01373|094|R|15.Buening MK, Wold JS, Israel KS, Krammer RB. Disulfiram-like reaction to|3
01373|095|R|   beta-lactams. JAMA 1981 May 22-29;245(20):2027.|3
01373|096|R|16.Marcon G, Spolaor A, Scevola M, Zolli M, Carlassara GB. Disulfiram-like|3
01373|097|R|   effect of cefonicid: first observation. Recenti Prog Med 1990 Jan;|3
01373|098|R|   81(1):47-8.|3
01373|099|R|17.USFood and Drug Administration (FDA). Docetaxel: Drug Safety|1
01373|100|R|   Communication - May Cause Symptoms of Alcohol Intoxication. available at:|1
01373|101|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-co|1
01373|102|R|   mmunication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol|1
01373|103|R|   June 20, 2014.|1
01374|001|T|MONOGRAPH TITLE:  Ethyl Alcohol/Benzodiazepines|
01374|002|B||
01374|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01374|004|L|of severe adverse interaction.|
01374|005|B||
01374|006|A|MECHANISM OF ACTION:  Concurrent use may result in additive central nervous|
01374|007|A|system depressant effects.  Concurrent use may also result in altered|
01374|008|A|absorption, altered distribution, or decreased elimination leading to higher|
01374|009|A|concentrations of the benzodiazepine in the brain.(1-4)|
01374|010|B||
01374|011|E|CLINICAL EFFECTS:  Concurrent use of benzodiazepines and alcohol-containing|
01374|012|E|products may result in enhanced disruption of psychomotor performance and|
01374|013|E|increased central nervous system depression.  Increased CNS depression may|
01374|014|E|result in profound sedation, respiratory depression, coma, and/or death.|
01374|015|B||
01374|016|P|PREDISPOSING FACTORS:  None determined.|
01374|017|B||
01374|018|M|PATIENT MANAGEMENT:  Patients should be informed that alcohol consumption|
01374|019|M|may result in significant decreased psychomotor performance and its|
01374|020|M|associated risks.|
01374|021|M|   Use of a short acting benzodiazepine may minimize the potential for|
01374|022|M|extreme effects.|
01374|023|M|   If suicide or drug abuse is a concern, benzodiazepine use may be ill|
01374|024|M|advised, since alcohol tends to greatly increase benzodiazepine-induced CNS|
01374|025|M|depression in acute overdosage.|
01374|026|M|   Patients should be informed about unsuspected sources of alcohol such as|
01374|027|M|medications.|
01374|028|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
01374|029|M|   - The quantity of alcohol in paclitaxel injection formulations|
01374|030|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01374|031|M|dose contains approximately 13 grams of alcohol.|
01374|032|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01374|033|M|3-fold depending upon the manufacturer. FDA data on alcohol content (18):|
01374|034|M|   Product                      Manufacturer           Alcohol/200 mg dose|
01374|035|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01374|036|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01374|037|M|   Docetaxel Inj.               Accord                  4.0 grams|
01374|038|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01374|039|M|    formulation|
01374|040|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01374|041|M|   Docefrez                     Sun Pharma              2.9 grams|
01374|042|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01374|043|M|    formulation|
01374|044|B||
01374|045|D|DISCUSSION:  Several articles have detailed enhanced disruption of|
01374|046|D|psychomotor performance and increased CNS depression with concurrent use of|
01374|047|D|diazepam and alcohol.(1-6)|
01374|048|D|   Evidence shows that temazepam and the other short-acting or|
01374|049|D|intermediate-acting benzodiazepines (e.g., alprazolam, halazepam, triazolam)|
01374|050|D|tend to result in less profound alcohol interactions.(7)  Although one study|
01374|051|D|showed no effect on triazolam pharmacokinetics, a clinically significant|
01374|052|D|pharmacodynamic interaction cannot be ruled out.(8)  Other reports have|
01374|053|D|shown clinically significant effects from concurrent triazolam and alcohol|
01374|054|D|use.(9,10)|
01374|055|D|   In 8 healthy subjects, concurrent midazolam and alcohol resulted in|
01374|056|D|impairment of immediate recall.(11)  In a similar study, the hypnotic effect|
01374|057|D|of midazolam was augmented by alcohol.(12)  In a study involving 9 subjects,|
01374|058|D|measurements of total reaction time were longer after concurrent alcohol and|
01374|059|D|lorazepam as compared to the use of either agent alone.(13)  Reports have|
01374|060|D|been conflicting regarding the actions of chlordiazepoxide when combined|
01374|061|D|with alcohol.  Differences in time of exposure, dosage, and response|
01374|062|D|parameters have been used to explain the inconsistent findings with|
01374|063|D|chlordiazepoxide.(14)|
01374|064|B||
01374|065|R|REFERENCES:|
01374|066|B||
01374|067|R|1.Hayes SL, Pablo G, Radomski T, Palmer RF. Ethanol and oral diazepam|2
01374|068|R|  absorption. N Engl J Med 1977 Jan 27;296(4):186-9.|2
01374|069|R|2.Thiessen JJ, Sellers EM, Denbeigh P, Dolman L. Plasma protein binding of|2
01374|070|R|  diazepam and tolbutamide in chronic alcoholics. J Clin Pharmacol 1976 Jul;|2
01374|071|R|  16(7):345-51.|2
01374|072|R|3.Desmond PV, Patwardhan RV, Schenker S, Hoyumpa AM. Short-term ethanol|2
01374|073|R|  administration impairs the elimination of chlordiazepoxide (Librium|2
01374|074|R|  inverted question mark) in man. Eur J Clin Pharmacol 1980 Oct;18(3):275-8.|2
01374|075|R|4.Sellers EM, Naranjo CA, Giles HG, Frecker RC, Beeching M. Intravenous|2
01374|076|R|  diazepam and oral ethanol interaction. Clin Pharmacol Ther 1980 Nov;|2
01374|077|R|  28(5):638-45.|2
01374|078|R|5.Greenblatt DJ, Laughren TP, Allen MD, Harmatz JS, Shader RI. Plasma|2
01374|079|R|  diazepam and desmethyldiazepam concentrations during long-term diazepam|2
01374|080|R|  therapy. Br J Clin Pharmacol 1981 Jan;11(1):35-40.|2
01374|081|R|6.Linnoila M, Saario I, Maki M. Effect of treatment with diazepam or lithium|2
01374|082|R|  and alcohol on psychomotor skills related to driving. Eur J Clin Pharmacol|2
01374|083|R|  1974 Aug 23;7(5):337-42.|2
01374|084|R|7.Lehmann W, Liljenberg B. Effect of temazepam and temazepam-ethanol on|2
01374|085|R|  sleep. Eur J Clin Pharmacol 1981;20(3):201-5.|2
01374|086|R|8.Ochs HR, Greenblatt DJ, Arendt RM, Hubbel W, Shader RI. Pharmacokinetic|2
01374|087|R|  noninteraction of triazolam and ethanol. J Clin Psychopharmacol 1984 Apr;|2
01374|088|R|  4(2):106-7.|2
01374|089|R|9.Morris HH 3rd, Estes ML. Traveler's amnesia. Transient global amnesia|3
01374|090|R|  secondary to triazolam. JAMA 1987 Aug 21;258(7):945-6.|3
01374|091|R|10.Dorian P, Sellers EM, Kaplan HL, Hamilton C, Greenblatt DJ, Abernethy D.|2
01374|092|R|   Triazolam and ethanol interaction: kinetic and dynamic consequences. Clin|2
01374|093|R|   Pharmacol Ther 1985 May;37(5):558-62.|2
01374|094|R|11.Subhan Z, Hindmarch I. The effects of midazolam in conjunction with|2
01374|095|R|   alcohol on iconic memory and free-recall. Neuropsychobiology 1983;|2
01374|096|R|   9(4):230-4.|2
01374|097|R|12.Hindmarch I, Subhan Z. The effects of midazolam in conjunction with|2
01374|098|R|   alcohol on sleep, psychomotor performance and car driving ability. Int J|2
01374|099|R|   Clin Pharmacol Res 1983;3(5):323-9.|2
01374|100|R|13.Aucamp AK, Weis OF, Muller FO, Gill CE, Malan J. Oxprenolol plus ethanol|2
01374|101|R|   causes no central nervous system depression--a comparison with lorazepam|2
01374|102|R|   plus ethanol. S Afr Med J 1984 Sep 22;66(12):445-6.|2
01374|103|R|14.Ascione FJ. Benzodiazepines with alcohol. Drug Ther 1978 Jan;8:58-71.|2
01374|104|R|15.Harvey SC. Hypnotics and sedatives. 1980;339-75.|2
01374|105|R|16.Van Gorder PN, Hoffman WE, Baughman V, Albrecht RF, Miletich DJ, Guzman|2
01374|106|R|   F, Cook JM. Midazolam-ethanol interactions and reversal with a|2
01374|107|R|   benzodiazepine antagonist. Anesth Analg 1985 Feb;64(2):129-35.|2
01374|108|R|17.Divoll M, Greenblatt DJ, Lacasse Y, Shader RI. Benzodiazepine overdosage:|2
01374|109|R|   plasma concentrations and clinical outcome. Psychopharmacology (Berl)|2
01374|110|R|   1981;73(4):381-3.|2
01374|111|R|18.USFood and Drug Administration (FDA). Docetaxel: Drug Safety|1
01374|112|R|   Communication - May Cause Symptoms of Alcohol Intoxication. available at:|1
01374|113|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-co|1
01374|114|R|   mmunication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol|1
01374|115|R|   June 20, 2014.|1
01375|001|T|MONOGRAPH TITLE:  Glinides; Sulfonylureas/Ethyl Alcohol|
01375|002|B||
01375|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01375|004|L|take action as needed.|
01375|005|B||
01375|006|A|MECHANISM OF ACTION:  Alcohol can induce hypoglycemia and interfere with|
01375|007|A|gluconeogenesis in the liver by means of intrinsic hypoglycemic|
01375|008|A|activity.(1-3)  Some alcoholic beverages may increase serum glucose levels|
01375|009|A|from their high carbohydrate content.(4)  Chronic alcohol intake may|
01375|010|A|decrease half-life of sulfonylureas by increasing liver metabolism.(1, 5-8)|
01375|011|B||
01375|012|E|CLINICAL EFFECTS:  Alcohol consumption while on a glinide or sulfonylureas|
01375|013|E|may result in unpredictable and varied reactions, ranging from mild flushing|
01375|014|E|to severe hypoglycemic reactions.|
01375|015|E|  Alcohol consumption during chlorpropamide therapy has resulted in a|
01375|016|E|disulfiram-like reaction.|
01375|017|B||
01375|018|P|PREDISPOSING FACTORS:  None determined.|
01375|019|B||
01375|020|M|PATIENT MANAGEMENT:  Diabetics should be cautioned about the effects of|
01375|021|M|alcohol consumption on diabetic control, possible flushing with concurrent|
01375|022|M|use, and about unsuspected sources of alcohol such as medications.|
01375|023|M|   Patients on chlorpropamide therapy should be counseled about the|
01375|024|M|possibility of a disulfiram-like reaction to alcohol consumption.|
01375|025|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
01375|026|M|   - The quantity of alcohol in paclitaxel injection formulations|
01375|027|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01375|028|M|dose contains approximately 13 grams of alcohol.|
01375|029|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01375|030|M|3-fold depending upon the manufacturer. FDA data on alcohol content (21):|
01375|031|M|   Product                      Manufacturer           Alcohol/200 mg dose|
01375|032|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01375|033|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01375|034|M|   Docetaxel Inj.               Accord                  4.0 grams|
01375|035|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01375|036|M|    formulation|
01375|037|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01375|038|M|   Docefrez                     Sun Pharma              2.9 grams|
01375|039|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01375|040|M|    formulation|
01375|041|B||
01375|042|D|DISCUSSION:  Chlorpropamide has been reported to induce facial flushing|
01375|043|D|(5,9-18) and a disulfiram-like reaction(4,9,10,18,19) following alcohol|
01375|044|D|consumption.|
01375|045|D|   Tolbutamide has been shown to interact with alcohol in nonalcoholic|
01375|046|D|diabetic patients, alcoholics, and normal subjects.(2,3,6-8,16,17)  There is|
01375|047|D|one report of reduced tolerance for alcohol in a patient on tolazamide|
01375|048|D|therapy.(20)  In a study in 10 normal subjects, administration of ethanol|
01375|049|D|with glipizide resulted in a delay in return to fasting glucose levels. The|
01375|050|D|time of onset and the extent of hypoglycemia were not altered.(21) Glipizide|
01375|051|D|and glyburide have been reported to have a very low incidence of|
01375|052|D|disulfiram-like reactions with concurrent alcohol; however, in one study, 5|
01375|053|D|of 11 patients taking glyburide developed flushing after a test dose of|
01375|054|D|alcohol.(18)|
01375|055|B||
01375|056|R|REFERENCES:|
01375|057|B||
01375|058|R|1.Arky RA, Veverbrants E, Abramson EA. Irreversible hypoglycemia. A|3
01375|059|R|  complication of alcohol and insulin. JAMA 1968 Oct 14;206(3):575-8.|3
01375|060|R|2.Dornhorst A, Ouyang A. Effect of alcohol on glucose tolerance. Lancet 1971|3
01375|061|R|  Oct 30;2(7731):957-9.|3
01375|062|R|3.Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea|3
01375|063|R|  hypoglycaemic agents: part 2. Drugs 1981 Oct;22(4):295-320.|3
01375|064|R|4.Walsh CH, O'Sullivan DJ. Effect of moderate alcohol intake on control of|3
01375|065|R|  diabetes. Diabetes 1974 May;23(5):440-2.|3
01375|066|R|5.Barnett AH, Gonzalez-Auvert C, Pyke DA, Saunders JB, Williams R, Dickenson|3
01375|067|R|  CJ, Rawlins MD. Blood concentrations of acetaldehyde during|3
01375|068|R|  chlorpropamide-alcohol flush. Br Med J (Clin Res Ed) 1981 Oct 10;|3
01375|069|R|  283(6297):939-41.|3
01375|070|R|6.Shah MN, Clancy BA, Iber FL. Comparison of blood clearance of ethanol and|3
01375|071|R|  tolbutamide and the activity of hepatic ethanol-oxidizing and|3
01375|072|R|  drug-metabolizing enzymes in chronic alcoholic subjects. Am J Clin Nutr|3
01375|073|R|  1972 Feb;25(2):135-9.|3
01375|074|R|7.Iber FL. Drug metabolism in heavy consumers of ethyl alcohol. Clin|3
01375|075|R|  Pharmacol Ther 1977 Nov;22(5 Pt 2):735-42.|3
01375|076|R|8.Kater RM, Tobon F, Iber FL. Increased rate of tolbutamide metabolism in|3
01375|077|R|  alcoholic patients. JAMA 1969 Jan 13;207(2):363-5.|3
01375|078|R|9.Medbak S, Wass JA, Clement-Jones V, Cooke ED, Bowcock SA, Cudworth AG,|3
01375|079|R|  Rees LH. Chlorpropamide alcohol flush and circulating met-enkephalin: a|3
01375|080|R|  positive link. Br Med J (Clin Res Ed) 1981 Oct 10;283(6297):937-9.|3
01375|081|R|10.Leslie RD, Pyke DA. Chlorpropamide-alcohol flushing: a dominantly|3
01375|082|R|   inherited trait associated with diabetes. Br Med J 1978 Dec 2;|3
01375|083|R|   2(6151):1519-21.|3
01375|084|R|11.Kobberling J, Bengsch N, Bruggeboes B, Schwarck H, Tillil H, Weber M. The|3
01375|085|R|   chlorpropamide alcohol flush. Lack of specificity for familial|3
01375|086|R|   non-insulin dependent diabetes. Diabetologia 1980 Oct;19(4):359-63.|3
01375|087|R|12.deSilva NE, Tunbridge WM, Alberti KG. Low incidence of|3
01375|088|R|   chlorpropamide-alcohol flushing in diet-treated, non-insulin-dependent|3
01375|089|R|   diabetes. Lancet 1981 Jan 17;1(8212):128-31.|3
01375|090|R|13.Strakosch CR, Jefferys DB, Keen H. Blockade of chlorpropamide alcohol|3
01375|091|R|   flush by aspirin. Lancet 1980 Feb 23;1(8165):394-6.|3
01375|092|R|14.Leslie RD, Bellamy D, Pyke DA. Asthma induced by enkephalin. Br Med J|3
01375|093|R|   1980 Jan 5;280(6206):16-8.|3
01375|094|R|15.Barnett AH, Pyke DA. Chlorpropamide-alcohol flushing and large-vessel|3
01375|095|R|   disease in non-insulin-dependent diabetes. Br Med J 1980 Jul 26;|3
01375|096|R|   281(6235):261-2.|3
01375|097|R|16.Harris EL. Adverse reactions to oral antidiabetic agents. Br Med J 1971|3
01375|098|R|   Jul 3;3(765):29-30.|3
01375|099|R|17.Capretti L, Speroni G, Girone M, Coscelli C, Butturini U, Rocca G.|3
01375|100|R|   Chlorpropamide- and tolbutamide-alcohol flushing in non-insulin-dependent|3
01375|101|R|   diabetes. Br Med J (Clin Res Ed) 1981 Nov 21;283(6303):1361-2.|3
01375|102|R|18.Wardle EN, Richardson GO. Alcohol and glibenclamide. Br Med J 1971 Jul 3;|3
01375|103|R|   3:309.|3
01375|104|R|19.FITZGERALD MG, GADDIE R, MALINS JM, O'SULLIVANDJ. Alcohol sensitivity in|3
01375|105|R|   diabetics receiving chlorpropromide. Diabetes 1962 Jan-Feb;11:40-3.|3
01375|106|R|20.McKendry JB, Gfeller KF. Clinical experience with the oral antidiabetic|3
01375|107|R|   compound, tolazamide. Can Med Assoc J 1967 Mar 4;96(9):531-5.|3
01375|108|R|21.USFood and Drug Administration (FDA). Docetaxel: Drug Safety|1
01375|109|R|   Communication - May Cause Symptoms of Alcohol Intoxication. available at:|1
01375|110|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-co|1
01375|111|R|   mmunication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol|1
01375|112|R|   June 20, 2014.|1
01376|001|T|MONOGRAPH TITLE:  Chloral Hydrate Derivatives/Ethyl Alcohol|
01376|002|B||
01376|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01376|004|L|take action as needed.|
01376|005|B||
01376|006|A|MECHANISM OF ACTION:  Alcohol stimulates the reduction of chloral hydrate to|
01376|007|A|trichloroethanol, which is longer-acting than the parent compound.(1)|
01376|008|A|Trichloroethanol in turn inhibits the oxidation of alcohol to acetaldehyde|
01376|009|A|by alcohol dehydrogenase.  Enhanced CNS depression occurs.|
01376|010|A|   The mechanism for the development of vasodilation is not known but is not|
01376|011|A|related to increased acetaldehyde levels.(1,2,4)|
01376|012|B||
01376|013|E|CLINICAL EFFECTS:  Concurrent ingestion of chloral hydrate and alcohol|
01376|014|E|results in greater CNS depression than that occurring when either agent is|
01376|015|E|taken alone.(2,3)  In addition, a disulfiram-like reaction characterized by|
01376|016|E|vasodilation, flushing, tachycardia, hypotension, or headache may occur when|
01376|017|E|alcohol is ingested by a patient who has been receiving chloral hydrate for|
01376|018|E|several days.(1,2)|
01376|019|B||
01376|020|P|PREDISPOSING FACTORS:  None determined.|
01376|021|B||
01376|022|M|PATIENT MANAGEMENT:  All patients taking chloral hydrate should be warned|
01376|023|M|that the CNS depressant effects of both chloral hydrate and alcohol are|
01376|024|M|increased by concurrent ingestion and the possibility of a disulfiram-like|
01376|025|M|reaction.  Patients should be informed about unsuspected sources of alcohol|
01376|026|M|such as medications.|
01376|027|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
01376|028|M|   - The quantity of alcohol in paclitaxel injection formulations|
01376|029|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01376|030|M|dose contains approximately 13 grams of alcohol.|
01376|031|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01376|032|M|3-fold depending upon the manufacturer. FDA data on alcohol content (5):|
01376|033|M|   Product                      Manufacturer           Alcohol/200 mg dose|
01376|034|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01376|035|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01376|036|M|   Docetaxel Inj.               Accord                  4.0 grams|
01376|037|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01376|038|M|    formulation|
01376|039|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01376|040|M|   Docefrez                     Sun Pharma              2.9 grams|
01376|041|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01376|042|M|    formulation|
01376|043|B||
01376|044|D|DISCUSSION:  Patients with cardiovascular disease who receive chloral|
01376|045|D|hydrate long-term should be especially careful about ingesting alcohol in|
01376|046|D|view of the tachycardia and hypotension that can result from the|
01376|047|D|vasodilation reaction.|
01376|048|B||
01376|049|R|REFERENCES:|
01376|050|B||
01376|051|R|1.Sellers EM, Lang M, Koch-Weser J, LeBlanc E, Kalant H. Interaction of|2
01376|052|R|  chloral hydrate and ethanol in man. I. Metabolism. Clin Pharmacol Ther|2
01376|053|R|  1972 Jan-Feb;13(1):37-49.|2
01376|054|R|2.Sellers EM, Carr G, Bernstein JG, Sellers S, Koch-Weser J. Interaction of|2
01376|055|R|  chloral hydrate and ethanol in man. II. Hemodynamics and performance. Clin|2
01376|056|R|  Pharmacol Ther 1972 Jan-Feb;13(1):50-8.|2
01376|057|R|3.Gessner PK, Cabana BE. Chloral alcoholate: reevaluation of its role in the|2
01376|058|R|  interaction between the hypnotic effects of chloral hydrate and ethanol. J|2
01376|059|R|  Pharmacol Exp Ther 1967 Jun;156(3):602-5.|2
01376|060|R|4.Asmussen E, Hald J, Larsen V. The pharmacological action of acetaldehyde|2
01376|061|R|  on the human organism. Acta Pharmacol 1948;4:311-20.|2
01376|062|R|5.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
01376|063|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
01376|064|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01376|065|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
01376|066|R|  20, 2014.|1
01377|001|T|MONOGRAPH TITLE:  Ethyl Alcohol/Levamisole|
01377|002|B||
01377|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01377|004|L|of severe adverse interaction.|
01377|005|B||
01377|006|A|MECHANISM OF ACTION:  The exact mechanism of this interaction is unknown.|
01377|007|B||
01377|008|E|CLINICAL EFFECTS:  Levamisole hydrochloride has been reported to produce|
01377|009|E|disulfiram-like side effects following the ingestion of alcohol.  Some signs|
01377|010|E|of this interaction include throbbing in the head and neck, flushing,|
01377|011|E|palpitations, tachycardia, hypotension, sweating, nausea, and vomiting.|
01377|012|B||
01377|013|P|PREDISPOSING FACTORS:  None determined.|
01377|014|B||
01377|015|M|PATIENT MANAGEMENT:  Patients should be advised of the possible affects that|
01377|016|M|may result from the concurrent use of levamisole and alcohol or alcohol|
01377|017|M|containing products.  Patients should be informed about unsuspected sources|
01377|018|M|of alcohol such as medications.|
01377|019|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
01377|020|M|   - The quantity of alcohol in paclitaxel injection formulations|
01377|021|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01377|022|M|dose contains approximately 13 grams of alcohol.|
01377|023|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01377|024|M|3-fold depending upon the manufacturer. FDA data on alcohol content (2):|
01377|025|M|   Product                      Manufacturer           Alcohol/200 mg dose|
01377|026|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01377|027|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01377|028|M|   Docetaxel Inj.               Accord                  4.0 grams|
01377|029|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01377|030|M|    formulation|
01377|031|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01377|032|M|   Docefrez                     Sun Pharma              2.9 grams|
01377|033|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01377|034|M|    formulation|
01377|035|B||
01377|036|D|DISCUSSION:  The duration of this interaction may vary depending on the|
01377|037|D|amount of alcohol consumed.  The quantity of alcohol needed to elicit this|
01377|038|D|interaction varies with individuals.|
01377|039|B||
01377|040|R|REFERENCES:|
01377|041|B||
01377|042|R|1.Ergamisol (levamisole) Australian product information. Janssen-Cilag Pty|1
01377|043|R|  Limited March 26, 1999.|1
01377|044|R|2.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
01377|045|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
01377|046|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01377|047|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
01377|048|R|  20, 2014.|1
01378|001|T|MONOGRAPH TITLE:  Fomepizole/Ethyl Alcohol|
01378|002|B||
01378|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01378|004|L|of severe adverse interaction.|
01378|005|B||
01378|006|A|MECHANISM OF ACTION:  Fomepizole inhibits the activity of alcohol|
01378|007|A|dehydrogenase, an enzyme needed to help eliminate alcohol.  Additionally,|
01378|008|A|alcohol can decrease the rate of elimination of fomepizole by the same|
01378|009|A|mechanism.|
01378|010|B||
01378|011|E|CLINICAL EFFECTS:  This interaction may cause an increase in the adverse|
01378|012|E|events associated with both increased alcohol levels as well as increased|
01378|013|E|fomepizole levels.  Increase fomepizole levels may result in headache,|
01378|014|E|nausea, dizziness, and drowsiness.  Increased alcohol levels may cause|
01378|015|E|sedation, decreased motor skills, and loss of consciousness.|
01378|016|B||
01378|017|P|PREDISPOSING FACTORS:  None determined.|
01378|018|B||
01378|019|M|PATIENT MANAGEMENT:  Patients should be advised of this potential hazard and|
01378|020|M|should be encouraged not to ingest alcohol containing products during the|
01378|021|M|course of therapy with fomepizole.  Patients should be informed about|
01378|022|M|unsuspected sources of alcohol, such as medications.|
01378|023|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
01378|024|M|   - The quantity of alcohol in paclitaxel injection formulations|
01378|025|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01378|026|M|dose contains approximately 13 grams of alcohol.|
01378|027|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01378|028|M|3-fold depending upon the manufacturer. FDA data on alcohol content (2):|
01378|029|M|   Product                      Manufacturer           Alcohol/200 mg dose|
01378|030|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01378|031|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01378|032|M|   Docetaxel Inj.               Accord                  4.0 grams|
01378|033|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01378|034|M|    formulation|
01378|035|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01378|036|M|   Docefrez                     Sun Pharma              2.9 grams|
01378|037|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01378|038|M|    formulation|
01378|039|B||
01378|040|D|DISCUSSION:  Fomepizole (10-20 mg/kg) significantly reduced the rate of|
01378|041|D|elimination of ethanol by approximately 40%, given in moderate doses to|
01378|042|D|healthy volunteers.  This occurred because of inhibition of alcohol|
01378|043|D|dehydrogenase.  Similarly, ethanol decreased the rate of elimination of|
01378|044|D|fomepizole by approximately 50%, by the same mechanism.(1)|
01378|045|B||
01378|046|R|REFERENCES:|
01378|047|B||
01378|048|R|1.Antizol (fomepizole) US prescribing information. Orphan Medical, Inc.|1
01378|049|R|  December, 2000.|1
01378|050|R|2.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
01378|051|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
01378|052|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01378|053|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
01378|054|R|  20, 2014.|1
01379|001|T|MONOGRAPH TITLE:  Propafenone/Possible QT Prolonging Agents|
01379|002|B||
01379|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01379|004|L|take action as needed.|
01379|005|B||
01379|006|A|MECHANISM OF ACTION:  Propafenone has been shown to prolong the QTc|
01379|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01379|008|A|may result in additive effects on the QTc interval.(1)|
01379|009|B||
01379|010|E|CLINICAL EFFECTS:  The concurrent use of propafenone with other agents that|
01379|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01379|012|E|arrhythmias, including torsades de pointes.(1)|
01379|013|B||
01379|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01379|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01379|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01379|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01379|018|P|gender, or advanced age.(3)|
01379|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01379|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01379|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01379|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01379|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01379|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01379|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01379|026|B||
01379|027|M|PATIENT MANAGEMENT:  The manufacturer of propafenone states that the use of|
01379|028|M|propafenone with other agents known to prolong the QT interval should be|
01379|029|M|avoided.(1)|
01379|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01379|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01379|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01379|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01379|034|B||
01379|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01379|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01379|037|D|monograph have been shown to prolong the QTc interval either through their|
01379|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01379|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01379|040|D|clinical trials and/or postmarketing reports.(2)|
01379|041|B||
01379|042|R|REFERENCES:|
01379|043|B||
01379|044|R|1.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
01379|045|R|  Laboratories March, 2013.|1
01379|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01379|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01379|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01379|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01379|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01379|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01379|052|R|  settings: a scientific statement from the American Heart Association and|6
01379|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01379|054|R|  2;55(9):934-47.|6
01380|001|T|MONOGRAPH TITLE:  Abarelix/Class IA and III Antiarrhythmics|
01380|002|B||
01380|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01380|004|L|take action as needed.|
01380|005|B||
01380|006|A|MECHANISM OF ACTION:  Abarelix has been shown to prolong the QTc interval.|
01380|007|A|Concurrent use with Class IA or III antiarrhythmics may result in additive|
01380|008|A|effects on the QTc interval.(1)|
01380|009|B||
01380|010|E|CLINICAL EFFECTS:  The concurrent use of abarelix with Class IA or III|
01380|011|E|antiarrhythmics may result in potentially life-threatening cardiac|
01380|012|E|arrhythmias, including torsades de pointes.(1)|
01380|013|B||
01380|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01380|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01380|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01380|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01380|018|P|female gender, or advanced age.(2)|
01380|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01380|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01380|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01380|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01380|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01380|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01380|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01380|026|B||
01380|027|M|PATIENT MANAGEMENT:  The manufacturer of abarelix states that physicians|
01380|028|M|should consider if the risks of QTc prolongation outweigh the benefits of|
01380|029|M|abarelix therapy in patients taking Class IA or III antiarrhythmics.(1)|
01380|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01380|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01380|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01380|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01380|034|B||
01380|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01380|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01380|037|D|monograph have been shown to prolong the QTc interval either through their|
01380|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01380|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01380|040|D|clinical trials and/or postmarketing reports.(2)|
01380|041|B||
01380|042|R|REFERENCES:|
01380|043|B||
01380|044|R|1.Plenaxis (abarelix) US prescribing information. Praecis Pharmaceuticals|1
01380|045|R|  Incorporated November, 2003.|1
01380|046|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01380|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01380|048|R|  settings: a scientific statement from the American Heart Association and|6
01380|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01380|050|R|  2;55(9):934-47.|6
01381|001|T|MONOGRAPH TITLE:  Busulfan/Thioguanine|
01381|002|B||
01381|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01381|004|L|take action as needed.|
01381|005|B||
01381|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01381|007|B||
01381|008|E|CLINICAL EFFECTS:  Co-administration of busulfan and thioguanine may result|
01381|009|E|in portal hypertension(1,2) and esophageal varices(3) with abnormal liver|
01381|010|E|function tests.(1,3)|
01381|011|B||
01381|012|P|PREDISPOSING FACTORS:  None determined.|
01381|013|B||
01381|014|M|PATIENT MANAGEMENT:  Concurrent busulfan and thioguanine should be|
01381|015|M|approached with caution and not used routinely.(1)|
01381|016|B||
01381|017|D|DISCUSSION:  In a study of 674 patients treated for chronic myeloid|
01381|018|D|leukemia, patients were randomized to receive either busulfan alone (n=338)|
01381|019|D|or busulfan and thioguanine (n=337).  In the combination group, 17 patients|
01381|020|D|developed varices and 7 developed ascites.  In the busulfan group, no|
01381|021|D|patients developed varices and only once case of ascites was noted.(1)|
01381|022|D|   One set of authors reported two patients who developed esophageal varices|
01381|023|D|and abnormal liver function tests after 21 months of treatment with busulfan|
01381|024|D|and thioguanine.  Another patient treated with this combination developed|
01381|025|D|hepatotoxicity 17 months and bleeding esophageal varices 25 months after|
01381|026|D|treatment initiation.(2)|
01381|027|D|   In another report, five patients receiving busulfan and thioguanine for|
01381|028|D|chronic myeloid leukemia demonstrated esophageal varices associated with|
01381|029|D|abnormal liver function tests in all subjects reviewed.  Three of these|
01381|030|D|presented with gastrointestinal hemorrhage and one died.(3)|
01381|031|B||
01381|032|R|REFERENCES:|
01381|033|B||
01381|034|R|1.Shepherd PC, Fooks J, Gray R, Allan NC. Thioguanine used in maintenance|2
01381|035|R|  therapy of chronic myeloid leukaemia causes non-cirrhotic portal|2
01381|036|R|  hypertension. Results from MRC CML. II. Trial comparing busulphan with|2
01381|037|R|  busulphan and thioguanine. Br J Haematol 1991 Oct;79(2):185-92.|2
01381|038|R|2.Shepherd P, Harrison DJ. Idiopathic portal hypertension associated with|3
01381|039|R|  cytotoxic drugs. J Clin Pathol 1990 Mar;43(3):206-10.|3
01381|040|R|3.Key NS, Kelly PM, Emerson PM, Chapman RW, Allan NC, McGee JO. Oesophageal|3
01381|041|R|  varices associated with busulphan-thioguanine combination therapy for|3
01381|042|R|  chronic myeloid leukaemia. Lancet 1987 Nov 7;2(8567):1050-2.|3
01382|001|T|MONOGRAPH TITLE:  Live Vaccines/Selected Monoclonal Antibodies (mono deleted|
01382|002|T|04/26/2012)|
01382|003|B||
01382|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01382|005|L|is contraindicated and generally should not be dispensed or administered to|
01382|006|L|the same patient.|
01382|007|B||
01382|008|A|MECHANISM OF ACTION:  Monoclonal antibody-induced immunosuppression may|
01382|009|A|prevent an immune response to the vaccine.(1-9)|
01382|010|B||
01382|011|E|CLINICAL EFFECTS:  The use of live vaccines in patients who have recently|
01382|012|E|received adalimumab,(1) belimumab,(2) certolizumab,(3) golimumab,(4)|
01382|013|E|infliximab,(5) ofatumumab,(6) rituximab,(7) tocilizumab,(8) or|
01382|014|E|ustekinumab(9,10) may be ineffective and may result in infection.|
01382|015|B||
01382|016|P|PREDISPOSING FACTORS:  None determined.|
01382|017|B||
01382|018|M|PATIENT MANAGEMENT:  Live vaccines should not be administered prior to or|
01382|019|M|with adalimumab,(1) belimumab,(2) certolizumab,(3) golimumab,(4)|
01382|020|M|infliximab,(5) ofatumumab,(6) rituximab,(7) tocilizumab,(8) or|
01382|021|M|ustekinumab(9,10) or to patients who have recently received these agents.|
01382|022|M|   The US manufacturer of ustekinumab states that patients receiving|
01382|023|M|ustekinumab should not receive live vaccines.  BCG vaccines should not be|
01382|024|M|given in the year prior to, during, or the year after ustekinumab|
01382|025|M|therapy.(9)  The UK manufacturer of ustekinumab states that live viral or|
01382|026|M|live bacterial vaccines should be withheld for 15 weeks after the last dose|
01382|027|M|of ustekinumab.  Ustekinumab may be resumed 2 weeks after vaccination.(10)|
01382|028|B||
01382|029|D|DISCUSSION:  No data are available on the effects of vaccination or on the|
01382|030|D|secondary transmission of infection by live vaccines in patients receiving|
01382|031|D|adalimumab,(1), belimumab,(2) certolizumab,(3), golimumab,(4) infliximab,(5)|
01382|032|D|or tocilizumab.(8)|
01382|033|D|   The safety of immunization with live viral vaccine in patients receiving|
01382|034|D|ofatumumab,(6) rituximab(7) or ustekinumab(9,10) has not been studied.|
01382|035|B||
01382|036|R|REFERENCES:|
01382|037|B||
01382|038|R|1.Humira (adalimumab) US prescribing information. Abbott Laboratories May,|1
01382|039|R|  2013.|1
01382|040|R|2.Benlysta (belimumab) US prescribing information. GlaxoSmithKline December,|1
01382|041|R|  2020.|1
01382|042|R|3.Cimzia (certolizumab pegol) US prescribing information. UCB, Inc.|1
01382|043|R|  February, 2019.|1
01382|044|R|4.Simponi (golimumab) US prescribing information. Centocor Ortho Biotech|1
01382|045|R|  Inc. February, 2014.|1
01382|046|R|5.Remicade (infliximab) US prescribing information. Janssen Biotech, Inc.|1
01382|047|R|  May, 2020.|1
01382|048|R|6.Arzerra (ofatumumab) US prescribing information. GlaxoSmithKline October,|1
01382|049|R|  2009.|1
01382|050|R|7.Rituxan (rituximab) US prescribing information. Genentech, Inc. June,|1
01382|051|R|  2018.|1
01382|052|R|8.Actemra (tocilizumab) US prescribing information. Genentech, Inc. June,|1
01382|053|R|  2019.|1
01382|054|R|9.Stelara (ustekinumab) US prescribing information. Centocor Ortho Biotech,|1
01382|055|R|  Inc. September, 2009.|1
01382|056|R|10.Stelara (ustekinumab) UK summary of product characteristics.|1
01382|057|R|   Janssen-Cilag Ltd January 16, 2009.|1
01383|001|T|MONOGRAPH TITLE:  Inhaled Indirect-Acting Sympathomimetics/Tricyclic|
01383|002|T|Compounds|
01383|003|B||
01383|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01383|005|L|take action as needed.|
01383|006|B||
01383|007|A|MECHANISM OF ACTION:  Unknown. However, it is speculated that|
01383|008|A|indirect-acting sympathomimetics would have decreased activity due to|
01383|009|A|tricyclic blockage of their uptake into the adrenergic neuron.|
01383|010|B||
01383|011|E|CLINICAL EFFECTS:  Decreased effect of indirect acting sympathomimetics.|
01383|012|B||
01383|013|P|PREDISPOSING FACTORS:  None determined.|
01383|014|B||
01383|015|M|PATIENT MANAGEMENT:  The concurrent use of inhaled sympathomimetics and|
01383|016|M|tricyclic compounds or the use of these agents within 14 days of each other|
01383|017|M|should be approached with extreme caution.|
01383|018|B||
01383|019|D|DISCUSSION:  Epinephrine and other direct-acting sympathomimetic amines|
01383|020|D|exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and|
01383|021|D|tachycardia) in individuals concurrently receiving or previously treated|
01383|022|D|with tricyclic antidepressants.|
01383|023|D|   Similarity between cyclobenzaprine and the tricyclic antidepressants|
01383|024|D|warrants consideration of tricyclic antidepressant interactions for|
01383|025|D|cyclobenzaprine.|
01383|026|B||
01383|027|R|REFERENCES:|
01383|028|B||
01383|029|R|1.Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN.|2
01383|030|R|  Interactions between sympathomimetic amines and antidepressant agents in|2
01383|031|R|  man. Br Med J 1973 Feb 10;1(5849):311-5.|2
01383|032|R|2.Ghose K. Sympathomimetic amines and tricyclic antidepressant drugs.|2
01383|033|R|  Neuropharmacology 1980 Dec;19(12):1251-4.|2
01383|034|R|3.Svedmyr N. The influence of a tricyclic antidepressive agent|2
01383|035|R|  (protriptyline) on some of the circulatory effects of noradrenaline and|2
01383|036|R|  adrenaline in man. Life Sci 1968 Jan 1;7(1):77-84.|2
01383|037|R|4.Bonaccorsi A, Garattini S. Effect of desipramine on directly or indirectly|5
01383|038|R|  elicited catecholamine pressor responses in rats. J Pharm Pharmacol 1966|5
01383|039|R|  Jul;18(7):443-8.|5
01383|040|R|5.Cairncross KD. On the peripheral pharmacology of amitriptyline. Arch Int|5
01383|041|R|  Pharmacodyn Ther 1965 Apr;154(2):438-48.|5
01383|042|R|6.Ghose K, Gifford LA, Turner P, Leighton M. Studies of the interaction of|2
01383|043|R|  desmethylimipramine with tyramine in man after a single oral dose, and its|2
01383|044|R|  correlation with plasma concentration. Br J Clin Pharmacol 1976 Apr;|2
01383|045|R|  3(2):334-7.|2
01383|046|R|7.Jefferson JW. A review of the cardiovascular effects and toxicity of|6
01383|047|R|  tricyclic antidepressants. Psychosom Med 1975 Mar-Apr;37(2):160-79.|6
01383|048|R|8.Ragheb M. Drug interactions in psychiatric practice. Int|6
01383|049|R|  Pharmacopsychiatry 1981;16(2):92-118.|6
01383|050|R|9.Risch SC, Groom GP, Janowsky DS. Interfaces of psychopharmacology and|6
01383|051|R|  cardiology--part one. J Clin Psychiatry 1981 Jan;42(1):23-34.|6
01383|052|R|10.Maxwell RA, Keenan PD, Chaplin E, Roth B, Eckhardt SB. Molecular features|5
01383|053|R|   affecting the potency of tricyclic antidepressants and structurally|5
01383|054|R|   related compounds as inhibitors of the uptake of tritiated norepinephrine|5
01383|055|R|   by rabbit aortic strips. J Pharmacol Exp Ther 1969 Apr;166(2):320-9.|5
01383|056|R|11.Ventolin (albuterol) inhalation aerosol US prescribing information.|1
01383|057|R|   GlaxoSmithKline August, 2021.|1
01384|001|T|MONOGRAPH TITLE:  Inhl Sympathomimetics (Indirect & Mixed Acting)/MAOIs|
01384|002|T|(mono deleted 04/28/2011)|
01384|003|B||
01384|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01384|005|L|of severe adverse interaction.|
01384|006|B||
01384|007|A|MECHANISM OF ACTION:  Catecholamine stores increased by MAOIs can be|
01384|008|A|released by indirect acting sympathomimetics such as ephedrine and|
01384|009|A|amphetamine. MAO inhibitors also interfere with gut and liver metabolism of|
01384|010|A|direct acting sympathomimetics (eg oral phenylephrine).|
01384|011|B||
01384|012|E|CLINICAL EFFECTS:  Potentiation of sympathomimetic effect may be observed,|
01384|013|E|including hypertensive crisis.  Fatalities have occurred with concurrent use|
01384|014|E|of MAOIs and systemic sympathomimetics.|
01384|015|B||
01384|016|P|PREDISPOSING FACTORS:  None determined.|
01384|017|B||
01384|018|M|PATIENT MANAGEMENT:  The manufacturers of inhaled sympathomimetics states|
01384|019|M|that these agents should be used with extreme caution during concurrent|
01384|020|M|therapy with or within 14 days of MAOI use.|
01384|021|B||
01384|022|D|DISCUSSION:  Indirect acting sympathomimetic amines may cause abrupt|
01384|023|D|elevation of blood pressure when administered to patients taking monoamine|
01384|024|D|oxidase inhibitors, resulting in a potentially fatal hypertensive crisis.|
01384|025|D|   Mixed (direct and indirect) acting sympathomimetics have also been shown|
01384|026|D|to interact with monoamine oxidase inhibitors depending on their degree of|
01384|027|D|indirect action.  The direct-acting sympathomimetics have not been reported|
01384|028|D|to interact.  Dopamine is metabolized by monoamine oxidase, and its pressor|
01384|029|D|effect is enhanced by monoamine oxidase inhibitors.|
01384|030|D|   Since procarbazine, an antineoplastic agent, is a weak monoamine oxidase|
01384|031|D|inhibitor, hypertensive reactions may result from its concurrent use with|
01384|032|D|indirect and mixed acting sympathomimetics.|
01384|033|D|   Furazolidone, an antibacterial with monoamine oxidase inhibitor action,|
01384|034|D|has also been shown to interact with indirect acting sympathomimetics.|
01384|035|D|   Linezolid is another antibacterial with monoamine oxidase inhibitor|
01384|036|D|properties.|
01384|037|D|   Foods containing large amounts of tyramine have also been implicated in|
01384|038|D|this interaction.|
01384|039|D|   Methylene blue, when administered intravenously, has been shown to reach|
01384|040|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
01384|041|B||
01384|042|R|REFERENCES:|
01384|043|B||
01384|044|R|1.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
01384|045|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
01384|046|R|2.Pettinger WA, Soyangco FG, Oates JA. Inhibition of monoamine oxidase in|2
01384|047|R|  man by furazolidone. Clin Pharmacol Ther 1968 Jul-Aug;9(4):442-7.|2
01384|048|R|3.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
01384|049|R|  2007.|1
01384|050|R|4.Adderall XR (amphetamine) US prescribing information. Shire US Inc.|1
01384|051|R|  December, 2013.|1
01384|052|R|5.Marplan (isocarboxazid) US prescribing information. Validus|1
01384|053|R|  Pharmaceuticals August, 2007.|1
01384|054|R|6.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
01384|055|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
01384|056|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
01384|057|R|7.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
01384|058|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
01384|059|R|  2000 Jun;56(3):247-50.|2
01384|060|R|8.Parnate (tranylcypromine sulfate) US prescribing information.|1
01384|061|R|  GlaxoSmithKline May, 2010.|1
01385|001|T|MONOGRAPH TITLE:  Inhaled Mixed & Direct Acting Sympathomimetics/Linezolid|
01385|002|B||
01385|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01385|004|L|take action as needed.|
01385|005|B||
01385|006|A|MECHANISM OF ACTION:  Catecholamine stores increased by MAOIs can be|
01385|007|A|released by indirect acting sympathomimetics.  MAO inhibitors also interfere|
01385|008|A|with gut and liver metabolism of direct acting sympathomimetics.|
01385|009|B||
01385|010|E|CLINICAL EFFECTS:  Potentiation of sympathomimetic effect may be observed.|
01385|011|B||
01385|012|P|PREDISPOSING FACTORS:  None determined.|
01385|013|B||
01385|014|M|PATIENT MANAGEMENT:  Inhaled sympathomimetics should be used with extreme|
01385|015|M|caution during concurrent therapy with or within 14 days of MAOI use.|
01385|016|B||
01385|017|D|DISCUSSION:  Indirect acting sympathomimetic amines may cause abrupt|
01385|018|D|elevation of blood pressure when administered to patients taking monoamine|
01385|019|D|oxidase inhibitors, resulting in a potentially fatal hypertensive crisis.|
01385|020|D|   Mixed (direct and indirect) acting sympathomimetics have also been shown|
01385|021|D|to interact with monoamine oxidase inhibitors depending on their degree of|
01385|022|D|indirect action.  The direct-acting sympathomimetics have not been reported|
01385|023|D|to interact.  Dopamine is metabolized by monoamine oxidase, and its pressor|
01385|024|D|effect is enhanced by monoamine oxidase inhibitors.|
01385|025|D|   Linezolid is an antibacterial with monoamine oxidase inhibitor|
01385|026|D|properties.|
01385|027|B||
01385|028|R|REFERENCES:|
01385|029|B||
01385|030|R|1.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
01385|031|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
01385|032|R|2.Pettinger WA, Soyangco FG, Oates JA. Inhibition of monoamine oxidase in|2
01385|033|R|  man by furazolidone. Clin Pharmacol Ther 1968 Jul-Aug;9(4):442-7.|2
01385|034|R|3.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
01385|035|R|  2007.|1
01385|036|R|4.Adderall XR (amphetamine) US prescribing information. Shire US Inc. April,|1
01385|037|R|  2015.|1
01385|038|R|5.Ventolin (albuterol) inhalation aerosol US prescribing information.|1
01385|039|R|  GlaxoSmithKline August, 2021.|1
01386|001|T|MONOGRAPH TITLE:  Amphetamines; Phentermine/SSRIs; SNRIs|
01386|002|B||
01386|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01386|004|L|take action as needed.|
01386|005|B||
01386|006|A|MECHANISM OF ACTION:  Amphetamines may affect serotonin release and/or|
01386|007|A|reuptake, depending on their molecular structure.  Ring substitution tends|
01386|008|A|to increase amphetamine-induced release of endogenous serotonin.  However,|
01386|009|A|the effect on serotonin release may also be dose related and is more likely|
01386|010|A|if the amphetamine is taken in doses greater than those approved and|
01386|011|A|generally employed in treating Attention-deficit-hyperactivity-disorder, or|
01386|012|A|if abused, especially over long periods of time.(1)|
01386|013|A|   Amphetamines, phentermine and serotonin-norepinephrine reuptake|
01386|014|A|inhibitors(SNRIs) may have additive effects on blood pressure.|
01386|015|B||
01386|016|E|CLINICAL EFFECTS:  Concurrent use of amphetamines with agents that affect|
01386|017|E|serotonin may increase the risk of serotonin syndrome.  Symptoms of|
01386|018|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
01386|019|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(8)|
01386|020|E|   Concurrent use of amphetamines or phentermine and a SNRI may increase the|
01386|021|E|risk for high blood pressure or make hypertension more difficult to control.|
01386|022|E|   SSRIs and SNRIs linked to this monograph are: citalopram, desvenlafaxine,|
01386|023|E|duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran,|
01386|024|E|milnacipran, paroxetine, sertraline, venlafaxine, vilazodone and|
01386|025|E|vortioxetine.|
01386|026|B||
01386|027|P|PREDISPOSING FACTORS:  High doses or long-term abuse of amphetamines may|
01386|028|P|increase the risk of this interaction.|
01386|029|B||
01386|030|M|PATIENT MANAGEMENT:  The concurrent use of amphetamines with SSRIs or SNRIs|
01386|031|M|should be approached with appropriate monitoring.|
01386|032|M|   Instruct patients receiving concurrent therapy to report any signs or|
01386|033|M|symptoms of serotonin syndrome immediately.|
01386|034|M|   Monitor blood pressure during concurrent therapy and adjust dosage or|
01386|035|M|change medication for persistent increases in blood pressure.|
01386|036|M|   If concurrent therapy is warranted, patients should be monitored for|
01386|037|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
01386|038|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
01386|039|M|heart palpitations, restlessness, confusion, agitation, trouble with|
01386|040|M|coordination, or severe diarrhea.|
01386|041|B||
01386|042|D|DISCUSSION:  In a case report, a 13 year-old female experienced tachycardia|
01386|043|D|when amphetamine was added to her sertraline regimen.(2)|
01386|044|D|   Increased side effects have also been reported in patients maintained on|
01386|045|D|fluoxetine who ingested illicit amphetamines.(3)|
01386|046|D|   In a case report, a 22 year-old female had previously been taking|
01386|047|D|phentermine and oral contraceptive agents.  The patient stopped taking|
01386|048|D|phentermine and, after an undetermined length of time, started taking|
01386|049|D|fluoxetine (20 mg daily).  The patient discontinued her fluoxetine after|
01386|050|D|three months.  Eight days later, she took one dose of phentermine (30 mg).|
01386|051|D|Within several hours, she developed jitteriness, stomach cramps, dry eyes,|
01386|052|D|palpitations, and tremors.  The patient received once dose of lorazepam (1.5|
01386|053|D|mg) and her symptoms resolved over night.(4)|
01386|054|D|   In a case report, a 32 year-old male developed agitation, anxiety,|
01386|055|D|shivering, tremors, and diaphoresis two weeks after adding venlafaxine to|
01386|056|D|his dexamphetamine.(5)|
01386|057|D|   There have also been reports of safe and effective use of amphetamines|
01386|058|D|with fluoxetine,(6) dextroamphetamine and sertraline,(6) and|
01386|059|D|dextroamphetamine with fluoxetine.(7)|
01386|060|B||
01386|061|R|REFERENCES:|
01386|062|B||
01386|063|R|1.Anonymous. Personal communication:  Adderall XR and SSRI's. Shire US Inc.|1
01386|064|R|  August 11, 2004.|1
01386|065|R|2.Gracious BL. Atrioventricular nodal re-entrant tachycardia associated with|3
01386|066|R|  stimulant treatment. J Child Adolesc Psychopharmacol 1999;9(2):125-8.|3
01386|067|R|3.Barrett J, Meehan O, Fahy T. SSRI and sympathominetic interaction. Br J|3
01386|068|R|  Psychiatry 1996 Feb;168(2):253.|3
01386|069|R|4.Bostwick JM, Brown TM. A toxic reaction from combining fluoxetine and|3
01386|070|R|  phentermine. J Clin Psychopharmacol 1996 Apr;16(2):189-90.|3
01386|071|R|5.Prior FH, Isbister GK, Dawson AH, Whyte IM. Serotonin toxicity with|3
01386|072|R|  therapeutic doses of dexamphetamine and venlafaxine. Med J Aust 2002 Mar|3
01386|073|R|  4;176(5):240-1.|3
01386|074|R|6.Findling RL. Open-label treatment of comorbid depression and attentional|2
01386|075|R|  disorders with co-administration of serotonin reuptake inhibitors and|2
01386|076|R|  psychostimulants in children, adolescents, and adults: a case series. J|2
01386|077|R|  Child Adolesc Psychopharmacol 1996 Fall;6(3):165-75.|2
01386|078|R|7.Linet LS. Treatment of a refractory depression with a combination of|3
01386|079|R|  fluoxetine and d-amphetamine. Am J Psychiatry 1989 Jun;146(6):803-4.|3
01386|080|R|8.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01386|081|R|  352(11):1112-20.|6
01387|001|T|MONOGRAPH TITLE:  Solifenacin/Nelfinavir; Ritonavir (mono deleted|
01387|002|T|04/05/2012)|
01387|003|B||
01387|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01387|005|L|of severe adverse interaction.|
01387|006|B||
01387|007|A|MECHANISM OF ACTION:  Nelfinavir and ritonavir may inhibit the metabolism of|
01387|008|A|solifenacin by CYP P-450-3A4.(1)|
01387|009|B||
01387|010|E|CLINICAL EFFECTS:  Concurrent use of nelfinavir or ritonavir without a|
01387|011|E|dosage adjustment of solifenacin may result in elevated levels of and|
01387|012|E|toxicity from solifenacin.(1)|
01387|013|B||
01387|014|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01387|015|P|patients with severe renal impairment or moderate hepatic impairment.(1)|
01387|016|B||
01387|017|M|PATIENT MANAGEMENT:  The UK manufacturer of solifenacin states that the|
01387|018|M|maximum dose of solifenacin should be restricted to 5 mg when used with|
01387|019|M|potent inhibitors of CYP P-450-3A4 such as nelfinavir or ritonavir.(1)|
01387|020|M|  The UK manufacturer of solifenacin states that concurrent use with potent|
01387|021|M|inhibitors of CYP P-450-3A4 such as nelfinavir or ritonavir is|
01387|022|M|contraindicated in patients with severe renal impairment or moderate hepatic|
01387|023|M|impairment.(1)|
01387|024|B||
01387|025|D|DISCUSSION:  Concurrent use of ketoconazole, a potent inhibitor of CYP|
01387|026|D|P-450-3A4, at a dose of 200 mg daily increased the area-under-curve (AUC) of|
01387|027|D|solifenacin by 2-fold.  Concurrent use of ketoconazole at a dose of 400 mg|
01387|028|D|daily increased the AUC of solifenacin by 3-fold.(1)|
01387|029|B||
01387|030|R|REFERENCE:|
01387|031|B||
01387|032|R|1.Vesicare (solifenacin succinate) UK summary of product characteristics.|1
01387|033|R|  Yamanouchi Pharma Ltd. August, 2021.|1
01388|001|T|MONOGRAPH TITLE:  Selected Anti-Aromatase Agents/Estrogens|
01388|002|B||
01388|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01388|004|L|is contraindicated and generally should not be dispensed or administered to|
01388|005|L|the same patient.|
01388|006|B||
01388|007|A|MECHANISM OF ACTION:  Aromatase inhibitors(1-6) and inactivators(7-10) treat|
01388|008|A|breast cancer by inhibiting estrogen synthesis therefore lowering serum|
01388|009|A|estrone and estradiol levels.|
01388|010|A|   In postmenopausal women, androgens are metabolized to estrogens via the|
01388|011|A|primary pathway of the aromatase enzyme.|
01388|012|B||
01388|013|E|CLINICAL EFFECTS:  Concurrent administration of estrogen may decrease the|
01388|014|E|effectiveness of aromatase inhibitors.(1-6)|
01388|015|B||
01388|016|P|PREDISPOSING FACTORS:  None determined.|
01388|017|B||
01388|018|M|PATIENT MANAGEMENT:  The Canadian,(1) UK,(2) and US(3) manufacturers of|
01388|019|M|anastrozole state that estrogen containing therapies should not be used|
01388|020|M|during anastrozole therapy.|
01388|021|M|   The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of|
01388|022|M|exemestane state that exemestane should not be administered with estrogen|
01388|023|M|containing therapies.|
01388|024|M|   The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen|
01388|025|M|containing therapies should be avoided during letrozole therapy.|
01388|026|B||
01388|027|D|DISCUSSION:  Many breast cancers have estrogen receptors and their growth|
01388|028|D|can be stimulated by estrogen.  Anastrozole is a potent and selective|
01388|029|D|non-steroidal aromatase inhibitor that lowers serum estradiol levels.|
01388|030|D|Concurrent use of estrogen may diminish the effects of anastrozole.(1-3)|
01388|031|D|   Exemestane is a steroidal aromatase inactivator that lowers serum|
01388|032|D|estradiol levels.  Concurrent use of estrogen may diminish the effects of|
01388|033|D|exemestane.(7-10)|
01388|034|B||
01388|035|R|REFERENCES:|
01388|036|B||
01388|037|R|1.Arimidex (anastrozole) Canadian prescribing information. Sanis Health Inc.|1
01388|038|R|  July, 2015.|1
01388|039|R|2.Arimidex (anastrozole) UK summary of product characteristics. AstraZeneca|1
01388|040|R|  UK Ltd June, 2021.|1
01388|041|R|3.Arimidex (anastrozole) US prescribing information. AstraZeneca|1
01388|042|R|  Pharmaceuticals LP May, 2013.|1
01388|043|R|4.Femara (letrozole) Canadian prescribing information. Novartis|1
01388|044|R|  Pharmaceuticals Canada Inc. April, 2014.|1
01388|045|R|5.Femara (letrozole) UK summary of product characteristics. Novartis|1
01388|046|R|  Pharmaceuticals Corporation May, 2012.|1
01388|047|R|6.Femara (letrozole) US prescribing information. Novartis Pharmaceuticals|1
01388|048|R|  Corporation September, 2017.|1
01388|049|R|7.Aromasin (exemestane) Australian prescribing information. Pharmacia|1
01388|050|R|  Australia August 18, 2003.|1
01388|051|R|8.Aromasin (exemestane) Canadian prescribing information. Pfizer Canada Inc.|1
01388|052|R|  March 01, 2005.|1
01388|053|R|9.Aromasin (exemestane) UK summary of product characteristics. Pharmacia|1
01388|054|R|  Limited December 17, 2004.|1
01388|055|R|10.Aromasin (exemestane) US prescribing information. Pharmacia & Upjohn|1
01388|056|R|   Company July, 2016.|1
01389|001|T|MONOGRAPH TITLE:  Solifenacin/Itraconazole; Ketoconazole (mono deleted|
01389|002|T|04/05/2012)|
01389|003|B||
01389|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01389|005|L|of severe adverse interaction.|
01389|006|B||
01389|007|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
01389|008|A|metabolism of solifenacin by CYP P-450-3A4.(1)|
01389|009|B||
01389|010|E|CLINICAL EFFECTS:  Concurrent use of itraconazole or ketoconazole without a|
01389|011|E|dosage adjustment of solifenacin may result in elevated levels of and|
01389|012|E|toxicity from solifenacin.(1)|
01389|013|B||
01389|014|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01389|015|P|patients with severe renal impairment or moderate hepatic impairment.(1)|
01389|016|B||
01389|017|M|PATIENT MANAGEMENT:  The UK manufacturer of solifenacin states that the|
01389|018|M|maximum dose of solifenacin should be restricted to 5 mg when used with|
01389|019|M|potent inhibitors of CYP P-450-3A4 such as itraconazole or ketoconazole.(1)|
01389|020|M|   The UK manufacturer of solifenacin states that concurrent use with potent|
01389|021|M|inhibitors of CYP P-450-3A4 such as itraconazole or ketoconazole is|
01389|022|M|contraindicated in patients with severe renal impairment or moderate hepatic|
01389|023|M|impairment.(1)|
01389|024|M|   The US manufacturer of solifenacin states that the dosage of solifenacin|
01389|025|M|should not exceed 5 mg when used with potent inhibitors of CYP P-450-3A4|
01389|026|M|such as ketoconazole.(2)|
01389|027|B||
01389|028|D|DISCUSSION:  Concurrent use of ketoconazole, a potent inhibitor of CYP|
01389|029|D|P-450-3A4, at a dose of 200 mg daily increased the area-under-curve (AUC) of|
01389|030|D|solifenacin by 2-fold.  Concurrent use of ketoconazole at a dose of 400 mg|
01389|031|D|daily increased the AUC of solifenacin by 3-fold.(1)|
01389|032|B||
01389|033|R|REFERENCES:|
01389|034|B||
01389|035|R|1.Vesicare (solifenacin succinate) UK summary of product characteristics.|1
01389|036|R|  Yamanouchi Pharma Ltd. August, 2021.|1
01389|037|R|2.Vesicare (solifenacin succinate) US prescribing information. Astellas|1
01389|038|R|  Pharma US, Inc. November, 2008.|1
01390|001|T|MONOGRAPH TITLE:  Cabergoline; Pergolide/Metoclopramide|
01390|002|B||
01390|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01390|004|L|is contraindicated and generally should not be dispensed or administered to|
01390|005|L|the same patient.|
01390|006|B||
01390|007|A|MECHANISM OF ACTION:  Dopamine antagonists such as metoclopramide may block|
01390|008|A|the effects of cabergoline(1) and pergolide(2,3), dopamine agonists.|
01390|009|B||
01390|010|E|CLINICAL EFFECTS:  Concurrent administration of cabergoline or pergolide|
01390|011|E|with metoclopramide may decrease the effectiveness of cabergoline(1) and|
01390|012|E|pergolide.(2,3)|
01390|013|B||
01390|014|P|PREDISPOSING FACTORS:  None determined.|
01390|015|B||
01390|016|M|PATIENT MANAGEMENT:  The manufacturers of cabergoline and pergolide state|
01390|017|M|that cabergoline(1) and pergolide(2) should not be administered concurrently|
01390|018|M|with dopamine antagonists such as metoclopramide.|
01390|019|B||
01390|020|D|DISCUSSION:  The manufacturers of cabergoline and pergolide state that these|
01390|021|D|agents should not be administered concurrently with dopamine antagonists|
01390|022|D|such as metoclopramide.(1-3)|
01390|023|B||
01390|024|R|REFERENCES:|
01390|025|B||
01390|026|R|1.Dostinex (cabergoline) US prescribing information. Pfizer April, 2025.|1
01390|027|R|2.Celance (pergolide mesylate) UK summary of product characteristics. Eli|1
01390|028|R|  Lilly and Company 1997.|1
01390|029|R|3.Permax (pergolide) US prescribing information. Eli Lilly and Company July|1
01390|030|R|  12, 2004.|1
01391|001|T|MONOGRAPH TITLE:  Apomorphine/QT Prolonging Agents|
01391|002|B||
01391|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01391|004|L|take action as needed.|
01391|005|B||
01391|006|A|MECHANISM OF ACTION:  Apomorphine has been shown to prolong the QTc|
01391|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01391|008|A|may result in additive effects on the QTc interval.(1)|
01391|009|B||
01391|010|E|CLINICAL EFFECTS:  The concurrent use of apomorphine with other agents that|
01391|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01391|012|E|arrhythmias, including torsades de pointes.(1)|
01391|013|B||
01391|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01391|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01391|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01391|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01391|018|P|gender, or advanced age.(3)|
01391|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01391|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01391|021|P|factors for torsade de pointes.  Factors which may increase systemic drug|
01391|022|P|concentrations include rapid infusion of an intravenous dose or impaired|
01391|023|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
01391|024|P|which inhibits its metabolism or elimination, genetic impairment in drug|
01391|025|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01391|026|B||
01391|027|M|PATIENT MANAGEMENT:  The manufacturer of apomorphine states that the use of|
01391|028|M|apomorphine with other agents known to prolong the QT interval should be|
01391|029|M|done with caution.(1)|
01391|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01391|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01391|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01391|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01391|034|B||
01391|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01391|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01391|037|D|monograph have been shown to prolong the QTc interval either through their|
01391|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01391|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01391|040|D|clinical trials and/or postmarketing reports.(2)|
01391|041|B||
01391|042|R|REFERENCES:|
01391|043|B||
01391|044|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
01391|045|R|  Inc. May, 2019.|1
01391|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01391|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01391|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01391|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01391|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01391|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01391|052|R|  settings: a scientific statement from the American Heart Association and|6
01391|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01391|054|R|  2;55(9):934-47.|6
01392|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Possible QT Prolonging Agents|
01392|002|B||
01392|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01392|004|L|take action as needed.|
01392|005|B||
01392|006|A|MECHANISM OF ACTION:  Levomethadone and methadone have been shown to prolong|
01392|007|A|the QTc interval. Concurrent use with other agents that prolong the QTc|
01392|008|A|interval may result in additive effects on the QTc interval.(1,2)|
01392|009|B||
01392|010|E|CLINICAL EFFECTS:  The concurrent use of levomethadone or methadone with|
01392|011|E|other agents that prolong the QTc interval may result in potentially|
01392|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)|
01392|013|B||
01392|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01392|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01392|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01392|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01392|018|P|gender, or advanced age.(3)|
01392|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01392|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01392|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01392|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01392|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01392|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01392|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01392|026|B||
01392|027|M|PATIENT MANAGEMENT:  Concurrent use of levomethadone or methadone with other|
01392|028|M|agents known to prolong the QT interval should be approached with extreme|
01392|029|M|caution.(1,2)|
01392|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01392|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01392|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01392|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01392|034|B||
01392|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01392|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01392|037|D|monograph have been shown to prolong the QTc interval either through their|
01392|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01392|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01392|040|D|clinical trials and/or postmarketing reports.(3)|
01392|041|D|   Most cases of methadone-induced QT prolongation are associated with, but|
01392|042|D|not limited to, higher dose treatment (greater than 200 mg daily) and most|
01392|043|D|involve patients being treated for pain with large, multiple daily doses.|
01392|044|D|Cases have been reported in patients treated with doses commonly used for|
01392|045|D|maintenance treatment of opioid addiction.(2)|
01392|046|D|   Levomethadone should be used with caution in patients with a history of|
01392|047|D|QT prolongation, advanced heart disease, concomitant CYP3A4 inhibitors, or|
01392|048|D|electrolyte abnormalities.  Cases of QT prolongation and torsades de pointes|
01392|049|D|have been reported, most commonly with high doses.(1)|
01392|050|B||
01392|051|R|REFERENCES:|
01392|052|B||
01392|053|R|1.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
01392|054|R|  Pharma AS November 30, 2018.|1
01392|055|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
01392|056|R|  Pharmaceuticals Corp. June, 2021.|1
01392|057|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01392|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01392|059|R|  settings: a scientific statement from the American Heart Association and|6
01392|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01392|061|R|  2;55(9):934-47.|6
01392|062|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
01392|063|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01392|064|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01392|065|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01393|001|T|MONOGRAPH TITLE:  Erythromycin; Telithromycin/Itraconazole; Ketoconazole|
01393|002|B||
01393|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01393|004|L|of severe adverse interaction.|
01393|005|B||
01393|006|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
01393|007|A|metabolism of erythromycin(1) and telithromycin(2-4) by CYP3A4.|
01393|008|A|Erythromycin and telithromycin have been shown to prolong the QTc interval,|
01393|009|A|which may result in torsades de pointes.(1-4)|
01393|010|A|   Erythromycin may also increase levels of itraconazole.(2)|
01393|011|B||
01393|012|E|CLINICAL EFFECTS:  Concurrent use of erythromycin or telithromycin with|
01393|013|E|potent inhibitors of CYP3A4 such as itraconazole or ketoconazole may result|
01393|014|E|in elevated levels of erythromycin and telithromycin and risk of QT|
01393|015|E|prolongation or torsades de pointes leading to sudden death from cardiac|
01393|016|E|causes.(1-4)|
01393|017|B||
01393|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01393|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
01393|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01393|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01393|022|P|female gender, or advanced age.(5)|
01393|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01393|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01393|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01393|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01393|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01393|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01393|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
01393|030|B||
01393|031|M|PATIENT MANAGEMENT:  It has been suggested that the concurrent use of|
01393|032|M|erythromycin with potent inhibitors of CYP3A4, such as itraconazole, and|
01393|033|M|ketoconazole, should be avoided.(1)|
01393|034|M|   The concurrent use of itraconazole(2,3) or ketoconazole(3,4) with|
01393|035|M|telithromycin should be avoided.|
01393|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01393|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01393|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01393|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01393|040|B||
01393|041|D|DISCUSSION:  A retrospective review examined sudden cardiac death in|
01393|042|D|Tennessee Medicaid patients.  Erythromycin use increased the risk of sudden|
01393|043|D|cardiac death by 1.79-fold.  Concurrent use of erythromycin with a potent|
01393|044|D|inhibitor of CYP3A4 (diltiazem, fluconazole, itraconazole, ketoconazole,|
01393|045|D|troleandomycin, or verapamil) increased the risk of sudden cardiac death by|
01393|046|D|5.35-fold when compared to patients receiving no antibiotic therapy.  There|
01393|047|D|was one death in 106 person-years among concurrent users of diltiazem and|
01393|048|D|erythromycin.  There were two deaths in 78 person-years among concurrent|
01393|049|D|users of verapamil and erythromycin.  There were no sudden cardiac deaths|
01393|050|D|among concurrent users of erythromycin and other calcium channel blockers|
01393|051|D|that do not inhibit CYP3A4.(1)|
01393|052|D|   Itraconazole increased the maximum concentration (Cmax) and|
01393|053|D|area-under-curve (AUC) of telithromycin by 22% and 54%, respectively.(3)|
01393|054|D|   Ketoconazole increased the Cmax and AUC of telithromycin by 51% and 95%,|
01393|055|D|respectively.(3)|
01393|056|B||
01393|057|R|REFERENCES:|
01393|058|B||
01393|059|R|1.Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral|2
01393|060|R|  erythromycin and the risk of sudden death from cardiac causes. N Engl J|2
01393|061|R|  Med 2004 Sep 9;351(11):1089-96.|2
01393|062|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01393|063|R|  Products, L.P. February, 2024.|1
01393|064|R|3.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01393|065|R|  November, 2015.|1
01393|066|R|4.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01393|067|R|  Pharmaceuticals February, 2014.|1
01393|068|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01393|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01393|070|R|  settings: a scientific statement from the American Heart Association and|6
01393|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01393|072|R|  2;55(9):934-47.|6
01394|001|T|MONOGRAPH TITLE:  Selected Macrolides/Selected Calcium Channel Blockers|
01394|002|B||
01394|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01394|004|L|of severe adverse interaction.|
01394|005|B||
01394|006|A|MECHANISM OF ACTION:  Some macrolides may inhibit metabolism of calcium|
01394|007|A|channel blockers.(1)  In some patients, calcium channel blockers may inhibit|
01394|008|A|the metabolism of the macrolide.  Some macrolides have been associated with|
01394|009|A|cardiac arrhythmias, including torsades de pointes.(2)|
01394|010|B||
01394|011|E|CLINICAL EFFECTS:  In some patients, concurrent use may result in elevated|
01394|012|E|levels of and effects from the calcium channel blockers, including|
01394|013|E|hypotension,(2,3) shock,(2) and acute kidney failure.(3)  In others,|
01394|014|E|elevated levels of the macrolide may occur, which may increase the risk of|
01394|015|E|sudden death from cardiac causes.(1)|
01394|016|B||
01394|017|P|PREDISPOSING FACTORS:  None determined.|
01394|018|B||
01394|019|M|PATIENT MANAGEMENT:  If possible, avoid the concurrent use of calcium|
01394|020|M|channel blockers with macrolides that inhibit CYP.(1,2)  Depending on the|
01394|021|M|infection, azithromycin may be an alternative in patients maintained on|
01394|022|M|calcium channel blockers.(1)  If concurrent use is required, monitor|
01394|023|M|patients for and instruct them to report signs of hypotension, cardiac|
01394|024|M|arrhythmias, or renal failure.|
01394|025|B||
01394|026|D|DISCUSSION:  A retrospective review examined sudden cardiac death in|
01394|027|D|Tennessee Medicaid patients.  Erythromycin use increased the risk of sudden|
01394|028|D|cardiac death by 1.79-fold.  Concurrent use of erythromycin with a potent|
01394|029|D|inhibitor of CYP3A4 (diltiazem, fluconazole, itraconazole, ketoconazole,|
01394|030|D|troleandomycin, or verapamil) increased the risk of sudden cardiac death by|
01394|031|D|5.35-fold when compared to patients receiving no antibiotic therapy.(2)|
01394|032|D|   In a retrospective review of residents of Ontario, Canada aged 66 or|
01394|033|D|older who were receiving calcium channel blockers, use of clarithromycin and|
01394|034|D|erythromycin were associated with an increased risk of hospitalization for|
01394|035|D|hypotension (odds ratio 3.7 and 5.8, respectively).  There was no|
01394|036|D|association between use of azithromycin and hospitalization for|
01394|037|D|hypotension.(2)|
01394|038|D|   In a retrospective review of residents of Ontario, Canada aged 65 or|
01394|039|D|older who were receiving calcium channel blockers, use of clarithromycin was|
01394|040|D|associated with an increased risk of hospitalization with acute kidney|
01394|041|D|injury when compared to use of azithromycin (0.44% of patients versus 0.22%|
01394|042|D|- odds ratio 1.98).  Risk was highest with the use of nifedipine (odds ratio|
01394|043|D|5.33).  Use of clarithromycin was also associated with a higher risk of|
01394|044|D|hospitalization with hypotension (0.12% of patients versus 0.07%, odds ratio|
01394|045|D|1.60) and all-cause mortality (1.02% of patients versus 0.59%, odds ratio|
01394|046|D|1.74).(3)|
01394|047|D|   In a cross-over study in 12 healthy male subjects, the administration of|
01394|048|D|a single dose of felodipine (10 mg extended-release) after four doses of|
01394|049|D|erythromycin (250 mg) resulted in an increase in felodipine area-under-curve|
01394|050|D|(AUC), maximum concentration (Cmax), and half-life by 149%, 127%, and 61%,|
01394|051|D|respectively. Concurrent administration increased dehydrofelodipine AUC,|
01394|052|D|Cmax, and half-life by 92%, 56%, and 93%, respectively, when compared to|
01394|053|D|felodipine administration alone. Concurrent administration of felodipine and|
01394|054|D|erythromycin decreased felodipine M3 metabolite AUC and Cmax concentrations|
01394|055|D|by 41% and 36%, respectively. The extent of the interaction was extremely|
01394|056|D|variable between subjects.(4)|
01394|057|D|   In a case report, a 43 year-old female developed palpitations, flushing,|
01394|058|D|ankle edema, and hypotension 2-4 days after the addition of erythromycin to|
01394|059|D|felodipine therapy. Felodipine levels were found to be elevated.(5)|
01394|060|D|   In a case report, a 77 year-old male developed shock, heart block, and|
01394|061|D|multi-organ failure two days after the addition of clarithromycin to|
01394|062|D|nifedipine therapy.(6)|
01394|063|D|   In a case report, a 76 year-old female developed hypotension,|
01394|064|D|bradycardia, shortness of breath, and weakness two days after the addition|
01394|065|D|of telithromycin to verapamil therapy.(7)|
01394|066|B||
01394|067|R|REFERENCES:|
01394|068|B||
01394|069|R|1.Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral|2
01394|070|R|  erythromycin and the risk of sudden death from cardiac causes. N Engl J|2
01394|071|R|  Med 2004 Sep 9;351(11):1089-96.|2
01394|072|R|2.Wright AJ, Gomes T, Mamdani MM, Horn JR, Juurlink DN. The risk of|2
01394|073|R|  hypotension following co-prescription of macrolide antibiotics and|2
01394|074|R|  calcium-channel blockers. CMAJ 2011 Jan 17.|2
01394|075|R|3.Gandhi S, Fleet JL, Bailey DG, McArthur E, Wald R, Rehman F, Garg AX.|2
01394|076|R|  Calcium-channel blocker-clarithromycin drug interactions and acute kidney|2
01394|077|R|  injury. JAMA 2013 Dec 18;310(23):2544-53.|2
01394|078|R|4.Bailey DG, Bend JR, Arnold JM, Tran LT, Spence JD. Erythromycin-felodipine|2
01394|079|R|  interaction: magnitude, mechanism, and comparison with grapefruit juice.|2
01394|080|R|  Clin Pharmacol Ther 1996 Jul;60(1):25-33.|2
01394|081|R|5.Geronimo-Pardo M, Cuartero-del-Pozo AB, Jimenez-Vizuete JM, Cortinas-Saez|3
01394|082|R|  M, Peyro-Garcia R. Clarithromycin-nifedipine interaction as possible cause|3
01394|083|R|  of vasodilatory shock. Ann Pharmacother 2005 Mar;39(3):538-42.|3
01394|084|R|6.Reed M, Wall GC, Shah NP, Heun JM, Hicklin GA. Verapamil toxicity|3
01394|085|R|  resulting from a probable interaction with telithromycin. Ann Pharmacother|3
01394|086|R|  2005 Feb;39(2):357-60.|3
01394|087|R|7.Liedholm H, Nordin G. Erythromycin-felodipine interaction. DICP 1991 Sep;|3
01394|088|R|  25(9):1007-8.|3
01395|001|T|MONOGRAPH TITLE:  Erythromycin/Troleandomycin|
01395|002|B||
01395|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01395|004|L|of severe adverse interaction.|
01395|005|B||
01395|006|A|MECHANISM OF ACTION:  Troleandomycin may inhibit the metabolism of|
01395|007|A|erythromycin by CYP3A4.  Erythromycin has been shown to prolong the QTc|
01395|008|A|interval and result in torsades de pointes.(1)|
01395|009|B||
01395|010|E|CLINICAL EFFECTS:  Concurrent use of erythromycin with potent inhibitors of|
01395|011|E|CYP3A4 such as troleandomycin, may result in elevated levels of erythromycin|
01395|012|E|and risk of QT prolongation or torsades de pointes leading to sudden death|
01395|013|E|from cardiac causes.(1)|
01395|014|B||
01395|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01395|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01395|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01395|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01395|019|P|female gender, or advanced age.(2)|
01395|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01395|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01395|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01395|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01395|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01395|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01395|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01395|027|B||
01395|028|M|PATIENT MANAGEMENT:  It has been suggested that the concurrent use of|
01395|029|M|erythromycin with potent inhibitors of CYP3A4, such as troleandomycin,|
01395|030|M|should be avoided.(1)|
01395|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01395|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01395|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01395|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01395|035|B||
01395|036|D|DISCUSSION:  A retrospective review examined sudden cardiac death in|
01395|037|D|Tennessee Medicaid patients.  Erythromycin use increased the risk of sudden|
01395|038|D|cardiac death by 1.79-fold.  Concurrent use of erythromycin with a potent|
01395|039|D|inhibitor of CYP3A4 (diltiazem, fluconazole, itraconazole, ketoconazole,|
01395|040|D|troleandomycin, or verapamil) increased the risk of sudden cardiac death by|
01395|041|D|5.35-fold when compared to patients receiving no antibiotic therapy.(1)|
01395|042|B||
01395|043|R|REFERENCES:|
01395|044|B||
01395|045|R|1.Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral|2
01395|046|R|  erythromycin and the risk of sudden death from cardiac causes. N Engl J|2
01395|047|R|  Med 2004 Sep 9;351(11):1089-96.|2
01395|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01395|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01395|050|R|  settings: a scientific statement from the American Heart Association and|6
01395|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01395|052|R|  2;55(9):934-47.|6
01396|001|T|MONOGRAPH TITLE:  Lamotrigine/Estrogen-Containing Contraceptives|
01396|002|B||
01396|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01396|004|L|of severe adverse interaction.|
01396|005|B||
01396|006|A|MECHANISM OF ACTION:  Estrogens increase glucuronidation mediated metabolism|
01396|007|A|of lamotrigine.  Lamotrigine may modestly induce the metabolism of hormonal|
01396|008|A|contraceptives.(1,2)|
01396|009|B||
01396|010|E|CLINICAL EFFECTS:  Concurrent use of lamotrigine and estrogen-containing|
01396|011|E|contraceptives may result in decreased levels and effectiveness of both|
01396|012|E|agents.  Increased seizure rates have been reported in patients taking|
01396|013|E|lamotrigine for epilepsy.(1,2)|
01396|014|B||
01396|015|P|PREDISPOSING FACTORS:  Increased seizure risk is more likely when|
01396|016|P|lamotrigine is used as monotherapy for treatment of epilepsy.|
01396|017|P|   The risk for an increase in seizure rate is lower in patients already|
01396|018|P|stabilized on a combination of lamotrigine and an enzyme inducing agent such|
01396|019|P|as carbamazepine, phenytoin, phenobarbital, or primidone.|
01396|020|P|   The risk for contraceptive failure may be greater in patients also taking|
01396|021|P|other enzyme inducing agents such as carbamazepine, phenytoin,|
01396|022|P|phenobarbital, primidone, or rifampin.|
01396|023|B||
01396|024|M|PATIENT MANAGEMENT:  During initiation of lamotrigine therapy, no|
01396|025|M|adjustments to the recommended lamotrigine dose escalation guidelines are|
01396|026|M|recommended in patients taking estrogen-containing contraceptives.(1)|
01396|027|M|   Dose adjustments will be necessary in most patients who start or stop an|
01396|028|M|estrogen-containing oral contraceptive in patients taking maintenance doses|
01396|029|M|of lamotrigine.  The lamotrigine dosage may need to be increased by as much|
01396|030|M|as 2-fold according to clinical response when estrogen-containing|
01396|031|M|contraceptives are initiated in patients NOT taking other drugs which induce|
01396|032|M|glucuronidation such as carbamazepine, phenytoin, phenobarbital, primidone,|
01396|033|M|lopinavir/ritonavir, atazanavir/ritonavir, or rifampin.  If|
01396|034|M|estrogen-containing contraceptives are discontinued, the dosage of|
01396|035|M|lamotrigine may need to be decreased by 50%.(1)  Initiate changes in|
01396|036|M|lamotrigine dosage at the same time estrogen containing products are started|
01396|037|M|or stopped.(1)|
01396|038|M|   In patients also taking carbamazepine, phenytoin, phenobarbital,|
01396|039|M|primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin, no|
01396|040|M|lamotrigine maintenance dosage adjustments should be necessary if|
01396|041|M|estrogen-containing contraceptives are initiated or discontinued.(1)|
01396|042|M|   Patients should be instructed to promptly report any changes in their|
01396|043|M|menstrual cycle, such as break-through bleeding.(1)|
01396|044|B||
01396|045|D|DISCUSSION:  In a study in 16 females, concurrent ethinylestradiol (30 mcg)|
01396|046|D|and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) increased|
01396|047|D|lamotrigine clearance by 2-fold, with a mean decrease in lamotrigine|
01396|048|D|area-under-curve (AUC) and maximum concentration (Cmax) by 52% and 39%,|
01396|049|D|respectively.  Serum trough lamotrigine levels were two-fold higher at the|
01396|050|D|end of the week of inactive tablets when compared to lamotrigine levels at|
01396|051|D|the end of the active hormonal cycle.  This effect should be expected in|
01396|052|D|women not taking carbamazepine, phenytoin, phenobarbital, primidone, or|
01396|053|D|rifampin.(1)|
01396|054|D|   In a study in 16 females, concurrent ethinylestradiol (30 mcg) and|
01396|055|D|levonorgestrel (150 mcg) with lamotrigine (300 mg per day) had no effect on|
01396|056|D|ethinylestradiol levels.  Levonorgestrel AUC and Cmax decreased by 19% and|
01396|057|D|12%, respectively.  Though there was no hormonal evidence of ovulation,|
01396|058|D|there was some loss of suppression of the hypothalamic-pituitary-ovarian|
01396|059|D|axis.(1)|
01396|060|D|   In a study, mean steady-state lamotrigine levels were 13 micro mol/L in|
01396|061|D|22 women taking oral contraceptives compared to 28 micro mol/L in 30 women|
01396|062|D|who were not taking oral contraceptives.  The lamotrigine dose/body weight/|
01396|063|D|plasma concentration was 2.1 L/kg/day in patients taking oral contraceptives|
01396|064|D|compared to 0.8 L/kg/day in patients without oral contraceptives.(3)|
01396|065|D|   One set of authors reported seven cases of decreased lamotrigine levels|
01396|066|D|in patients receiving oral contraceptives.  Lamotrigine levels were|
01396|067|D|decreased by 41% to 64%, average 49%.  Most patients either experienced|
01396|068|D|increased seizure frequency or recurrence of seizures after the addition of|
01396|069|D|the oral contraceptive, or increased lamotrigine adverse effects following|
01396|070|D|the discontinuation of the oral contraceptive.(4)|
01396|071|D|   A study in 45 females compared lamotrigine pharmacokinetics in patients|
01396|072|D|taking an ethinyl estradiol-containing contraceptive (n=11) to patients|
01396|073|D|taking a progestin-only contraceptive (n=16) and to patients taking no|
01396|074|D|contraceptives (n=18).  The lamotrigine serum concentration to dose ratio|
01396|075|D|was significantly lower in patients taking ethinyl estradiol-containing|
01396|076|D|contraceptives.  There was no significant difference between patients taking|
01396|077|D|progestin-only contraceptives and those using no contraceptives.(5)|
01396|078|D|   In a double-blind, placebo-controlled study, women with epilepsy were|
01396|079|D|treated with lamotrigine monotherapy, or lamotrigine plus oral|
01396|080|D|contraceptive.  After 21 days, the mean dose-corrected lamotrigine|
01396|081|D|concentration was 84% higher in the monotherapy group verses the combined|
01396|082|D|treatment group.(6)|
01396|083|D|   Another study in 8 epileptic females assessed the pharmacokinetics of|
01396|084|D|lamotrigine in combination with hormonal contraceptives.  Serum samples were|
01396|085|D|drawn on days 18 and 21 of hormonal contraceptive therapy and during days 5|
01396|086|D|and 7 of the placebo week (hormonal contraceptive free week). Analysis found|
01396|087|D|statistically significant elevations (approximately 27%) in lamotrigine|
01396|088|D|plasma concentrations during the hormone-free week, than during cycle|
01396|089|D|intake.(7)|
01396|090|D|   In a study, 22 enrolled females took lamotrigine titrated up to 300 mg/d|
01396|091|D|for a period of 130 days and either combined it with an oral contraceptive|
01396|092|D|or took lamotrigine monotherapy.  Both ethinyl estradiol and lamotrigine|
01396|093|D|serum levels were drawn in the presence or absence of combined therapy.|
01396|094|D|Laboratory serum data showed the ratios of lamotrigine AUC (0-24h) and Cmax|
01396|095|D|at 0.48 for coadministration (lamotrigine plus oral contraceptive) and a|
01396|096|D|ratio of 0.61 for lamotrigine monotherapy.  There were no changes in ethinyl|
01396|097|D|estradiol levels.  Levonorgestrel levels decreased 19% and 7 of 22 patients|
01396|098|D|reported break-through bleeding; however, suppression of ovulation was|
01396|099|D|maintained.(8)|
01396|100|D|   In an interaction study, lamotrigine decreased exposure to the progestin|
01396|101|D|component (levonorgestrel) of an oral contraceptive by 19%, but suppression|
01396|102|D|of ovulation was not affected. The manufacturer of lamotrigine states that|
01396|103|D|the possibility of decreased contraceptive efficacy in some patients cannot|
01396|104|D|be excluded.(1)|
01396|105|D|   The 2010 CDC and 2015 WHO contraceptive guidelines do not mention|
01396|106|D|evidence of reduced contraceptive efficacy with concurrent therapy with|
01396|107|D|lamotrigine.(9,10)|
01396|108|D|   The 2018 Faculty of Sexual and Reproductive Healthcare contraceptive|
01396|109|D|guidelines state that lamotrigine is not thought to be an enzyme-inducing|
01396|110|D|drug but that contraceptive efficacy may be reduced by concurrent use with|
01396|111|D|lamotrigine. The clinical significance of this effect is unknown. The|
01396|112|D|guideline recommends caution when administering lamotrigine and|
01396|113|D|contraceptives concurrently.(11)|
01396|114|B||
01396|115|R|REFERENCES:|
01396|116|B||
01396|117|R|1.Lamictal (lamotrigine) US prscribing information. GlaxoSmithKline October,|1
01396|118|R|  2025.|1
01396|119|R|2.Dear Healthcare Professional, Subject:  Important new safety information|1
01396|120|R|  concerning the antiepileptic, LAMICTAL (lamotrigine). GlaxoSmithKline|1
01396|121|R|  Canada September, 2004.|1
01396|122|R|3.Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce|2
01396|123|R|  lamotrigine plasma levels. Neurology 2003 Aug 26;61(4):570-1.|2
01396|124|R|4.Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels|3
01396|125|R|  reduced by oral contraceptives. Epilepsy Res 2001 Nov;47(1-2):151-4.|3
01396|126|R|5.Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not progestogens,|2
01396|127|R|  reduces lamotrigine serum concentrations. Epilepsia 2005 Sep;46(9):1414-7.|2
01396|128|R|6.Christensen J, Petrenaite V, Atterman J, Sidenius P, Ohman I, Tomson T,|2
01396|129|R|  Sabers A. Oral contraceptives induce lamotrigine metabolism: evidence from|2
01396|130|R|  a double-blind, placebo-controlled trial. Epilepsia 2007 Mar;48(3):484-9.|2
01396|131|R|7.Contin M, Albani F, Ambrosetto G, Avoni P, Bisulli F, Riva R, Tinuper P,|2
01396|132|R|  Baruzzi A. Variation in lamotrigine plasma concentrations with hormonal|2
01396|133|R|  contraceptive monthly cycles in patients with epilepsy. Epilepsia 2006|2
01396|134|R|  Sep;47(9):1573-5.|2
01396|135|R|8.Sidhu J, Job S, Singh S, Philipson R. The pharmacokinetic and|2
01396|136|R|  pharmacodynamic consequences of the co-administration of lamotrigine and a|2
01396|137|R|  combined oral contraceptive in healthy female subjects. Br J Clin|2
01396|138|R|  Pharmacol 2006 Feb;61(2):191-9.|2
01396|139|R|9.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
01396|140|R|  Criteria for Contraceptive Use, 2010. MMWR Early Release 2010;59:1-86.|6
01396|141|R|10.Department of Reproductive Health World Health Organization. Medical|6
01396|142|R|   eligibility criteria for contraceptive use. Fifth Edition 2015.|6
01396|143|R|11.Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness|6
01396|144|R|   Unit. Clinical guidance drug interactions with hormonal contraception.|6
01396|145|R|   January, 2018.|6
01397|001|T|MONOGRAPH TITLE:  Itraconazole; Ketoconazole/Selected CYP3A4 Inhibitors|
01397|002|B||
01397|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01397|004|L|take action as needed.|
01397|005|B||
01397|006|A|MECHANISM OF ACTION:  Atazanavir,(1) cobicistat,(2) darunavir with|
01397|007|A|cobicistat or ritonavir,(3) fosamprenavir,(4) lopinavir/ritonavir,(5)|
01397|008|A|nirmatrelvir/ritonavir,(6) saquinavir,(7) and tipranavir/ritonavir(8) may|
01397|009|A|inhibit the metabolism of itraconazole and ketoconazole.  Itraconazole and|
01397|010|A|ketoconazole may inhibit the metabolism of the protease inhibitors and|
01397|011|A|elvitegravir/cobicistat.(2,9-11)|
01397|012|B||
01397|013|E|CLINICAL EFFECTS:  Concurrent use may result in increased levels of and|
01397|014|E|toxicity from itraconazole, ketoconazole, the protease inhibitors, or|
01397|015|E|elvitegravir/cobicistat.(1-11)|
01397|016|B||
01397|017|P|PREDISPOSING FACTORS:  None determined.|
01397|018|B||
01397|019|M|PATIENT MANAGEMENT:  The concurrent use of boosted protease inhibitors or|
01397|020|M|elvitegravir/cobicistat with high doses of ketoconazole or itraconazole|
01397|021|M|greater than 200 mg daily is not recommended.(1-11)  Use of high doses of|
01397|022|M|itraconazole should be guided by itraconazole concentrations.(11)|
01397|023|M|   The US Department of Health and Human Service HIV guidelines state that|
01397|024|M|dosing of itraconazole when used concurrently with unboosted atazanavir|
01397|025|M|should be guided by itraconazole concentrations.(11)|
01397|026|M|   The manufacturer of fosamprenavir states that a dose reduction of|
01397|027|M|itraconazole or ketoconazole may be needed for patients receiving more than|
01397|028|M|400 mg of these agents a day with unboosted fosamprenavir.(4)|
01397|029|M|   The manufacturer of saquinavir states that concurrent use with|
01397|030|M|itraconazole should be monitored for saquinavir toxicity due to the risk of|
01397|031|M|cardiac arrhythmias.(7)|
01397|032|M|   Monitor for adverse effects from either the antifungal or the protease|
01397|033|M|inhibitor.|
01397|034|B||
01397|035|D|DISCUSSION:  A study of 14 subjects found that ketoconazole (200 mg daily)|
01397|036|D|used concurrently with atazanavir (400 mg daily) had negligible effects on|
01397|037|D|atazanavir area-under-curve (AUC) and maximum concentration (Cmax).(1)|
01397|038|D|   In a study of 18 subjects, ketoconazole (200 mg twice daily) increased|
01397|039|D|the Cmax and AUC of elvitegravir by 1.17-fold and 1.48-fold.(2)|
01397|040|D|   In a study in 14 subjects, concurrent ketoconazole (200 mg twice daily)|
01397|041|D|and darunavir/ritonavir (400/100 mg twice daily) increased darunavir Cmax,|
01397|042|D|AUC, and minimum concentration (Cmin) by 1.21-fold, 1.42-fold, and|
01397|043|D|1.73-fold, respectively.  Ketoconazole Cmax, AUC, and Cmin increased by|
01397|044|D|2.11-fold, 3.12-fold, and 9.68-fold, respectively.(3)|
01397|045|D|   In a study in 12 subjects, administration of a single dose of|
01397|046|D|ketoconazole (400 mg) with a single dose of amprenavir (1200 mg) decreased|
01397|047|D|the amprenavir Cmax by 16%.  Amprenavir AUC was increased by 31%.|
01397|048|D|Ketoconazole Cmax and AUC were increased by 19% and 44%, respectively.(4)|
01397|049|D|   In a study in 15 subjects, concurrent ketoconazole (200 mg daily) with|
01397|050|D|fosamprenavir/ritonavir (700/100 mg twice daily) resulted in no changes in|
01397|051|D|amprenavir levels.  Ketoconazole Cmax and AUC increased by 25% and 169%,|
01397|052|D|respectively.(4)|
01397|053|D|   In a study in 12 subjects, administration of a single dose of|
01397|054|D|ketoconazole (200 mg) after 16 days of lopinavir with ritonavir (400 mg with|
01397|055|D|100 mg twice daily) decreased lopinavir Cmax, AUC, Cmin levels 11%, 13%, and|
01397|056|D|25%, respectively.  Ketoconazole Cmax and AUC were increased 1.13-fold and|
01397|057|D|3.04-fold, respectively.(5)|
01397|058|D|   A study of 11 subjects found that itraconazole (200 mg daily) increased|
01397|059|D|the Cmax and AUC of nirmatrelvir by 119% and 139%, respectively.(6)|
01397|060|D|   In a study in 12 subjects, administration of ketoconazole (200 mg daily)|
01397|061|D|and saquinavir (1000 mg twice daily) with ritonavir (100 mg twice daily)|
01397|062|D|resulted in no changes in saquinavir levels.  Ketoconazole AUC and Cmax|
01397|063|D|increased by 168% and 45%, respectively.(7)|
01397|064|D|   Ketoconazole has been shown to increase the Cmax and AUC of telithromycin|
01397|065|D|by 51% and 95%, respectively.(9)|
01397|066|D|   Selected CYP3A4 inhibitors linked to this monograph include: atazanavir,|
01397|067|D|cobicistat, darunavir, fosamprenavir, lopinavir, nirmatrelvir/ritonavir,|
01397|068|D|saquinavir, and tipranavir.|
01397|069|B||
01397|070|R|REFERENCES:|
01397|071|B||
01397|072|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01397|073|R|  Squibb Company December, 2024.|1
01397|074|R|2.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
01397|075|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
01397|076|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01397|077|R|  March, 2023.|1
01397|078|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01397|079|R|  March, 2019.|1
01397|080|R|5.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01397|081|R|  Laboratories December, 2019.|1
01397|082|R|6.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01397|083|R|  information. Pfizer Inc. February, 2025.|1
01397|084|R|7.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01397|085|R|  Laboratories, Inc. March, 2019.|1
01397|086|R|8.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01397|087|R|  Pharmaceuticals, Inc. April, 2024.|1
01397|088|R|9.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01397|089|R|  Pharmaceuticals February, 2014.|1
01397|090|R|10.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01397|091|R|   Products, L.P. February, 2024.|1
01397|092|R|11.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01397|093|R|   for the use of antiretroviral agents in adults and adolescents Living|6
01397|094|R|   with HIV. Department of Health and Human Services. Available at:|6
01397|095|R|   https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-|6
01397|096|R|   and-adolescent-arv/whats-new March 23, 2023.|6
01398|001|T|MONOGRAPH TITLE:  Didanosine/Ribavirin|
01398|002|B||
01398|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01398|004|L|is contraindicated and generally should not be dispensed or administered to|
01398|005|L|the same patient.|
01398|006|B||
01398|007|A|MECHANISM OF ACTION:  Ribavirin increases levels of the active metabolite of|
01398|008|A|didanosine, dideoxyadenosine 5'-triphosphate.(1-3)|
01398|009|B||
01398|010|E|CLINICAL EFFECTS:  Concurrent administration with ribavirin may result in|
01398|011|E|elevated levels of dideoxyadenosine 5'-triphosphate and toxicities such as|
01398|012|E|fatal hepatic failure, peripheral neuropathy, pancreatitis, and symptomatic|
01398|013|E|hyperlactatemia/lactic acidosis.(1,2)|
01398|014|B||
01398|015|P|PREDISPOSING FACTORS:  None determined.|
01398|016|B||
01398|017|M|PATIENT MANAGEMENT:  The manufacturers of didanosine(2) and ribavirin(1,3)|
01398|018|M|state that concurrent therapy is contraindicated.|
01398|019|M|   If concurrent therapy is used, monitor patients closely, especially|
01398|020|M|amylase levels.(4)|
01398|021|B||
01398|022|D|DISCUSSION:  In 39 patients who received concurrent didanosine (400 mg daily|
01398|023|D|in 86%) and ribavirin (10 mg/kg daily or greater in 91%), 20 (57%) developed|
01398|024|D|one or more adverse events after a mean of 87 days.  Hyperamylasemia|
01398|025|D|occurred in 18 (51%) patients.  Hyperlactatemia occurred in 8 (23%)|
01398|026|D|patients.  Acute pancreatitis and symptomatic hyperlactatemia developed in|
01398|027|D|10 (28%) and 6 (17%) patients, respectively.  Two patients with pancreatitis|
01398|028|D|and severe lactic acidosis died.  The other patients recovered, even with|
01398|029|D|continuation of hepatitis therapy in 83% and withdrawal of didanosine in|
01398|030|D|40%.(4)|
01398|031|D|   In study NR15961, 14 (11%) of 129 HIV-positive chronic hepatitis C|
01398|032|D|patients receiving HAART developed hepatic decompensation.  All 14 patients|
01398|033|D|were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and|
01398|034|D|lamivudine.(3)|
01398|035|D|   Fatal hepatic failure, peripheral neuropathy, pancreatitis, and|
01398|036|D|symptomatic hyperlactatemia/lactic acidosis have been reported with|
01398|037|D|concurrent therapy.(1)|
01398|038|B||
01398|039|R|REFERENCES:|
01398|040|B||
01398|041|R|1.Rebetol (ribavirin) US prescribing information. Merck & Co., Inc. May,|1
01398|042|R|  2019.|1
01398|043|R|2.Videx EC (didanosine) US prescribing information. Bristol-Myers Squibb|1
01398|044|R|  Company January 25, 2018.|1
01398|045|R|3.Copegus (ribavirin) US prescribing information. Roche Laboratories, Inc.|1
01398|046|R|  August, 2015.|1
01398|047|R|4.Moreno A, Quereda C, Moreno L, Perez-Elias MJ, Muriel A, Casado JL, Antela|2
01398|048|R|  A, Dronda F, Navas E, Barcena R, Moreno S. High rate of didanosine-related|2
01398|049|R|  mitochondrial toxicity in HIV/HCV-coinfected patients receiving ribavirin.|2
01398|050|R|  Antivir Ther 2004 Feb;9(1):133-8.|2
01399|001|T|MONOGRAPH TITLE:  SSRIs; SNRIs/Selected NSAIDs; Aspirin|
01399|002|B||
01399|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01399|004|L|take action as needed.|
01399|005|B||
01399|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
01399|007|A|hemostasis.(1,2)  The increased risk of bleeding may be a result of a|
01399|008|A|decrease in serotonin reuptake by platelets.|
01399|009|B||
01399|010|E|CLINICAL EFFECTS:  Concurrent use of a selective serotonin reuptake|
01399|011|E|inhibitor(1-7,13) or a serotonin-norepinephrine reuptake inhibitor(8-10) and|
01399|012|E|a NSAID may result in bleeding.|
01399|013|B||
01399|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01399|015|P|patients with multiple disease-associated factors (e.g. thrombocytopenia,|
01399|016|P|advanced liver disease).|
01399|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
01399|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01399|019|P|risk for bleeding (e.g., anticoagulants, antiplatelets, or corticosteroids.|
01399|020|P|   Risk of GI bleed may be increased in patients who are of older age, in|
01399|021|P|poor health status, or who use alcohol or smoke. Risk may also be increased|
01399|022|P|with longer duration of NSAID use and prior history of peptic ulcer disease|
01399|023|P|and/or GI bleeding.   Renal impairment has been associated with an elevated|
01399|024|P|risk of GI bleed in patients on SSRIs.(15)|
01399|025|B||
01399|026|M|PATIENT MANAGEMENT:  Selective serotonin reuptake inhibitors(1-7,13) or|
01399|027|M|serotonin-norepinephrine reuptake inhibitors(8-10) and NSAIDs should be used|
01399|028|M|concurrently with caution.  Patients should be warned about the increased|
01399|029|M|risk of bleeding and be educated about signs and symptoms of|
01399|030|M|bleeding.(1-11,13)|
01399|031|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01399|032|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01399|033|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01399|034|M|patients with any symptoms.|
01399|035|M|   Discontinue anti-platelet agents in patients with active pathologic|
01399|036|M|bleeding.|
01399|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01399|038|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01399|039|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01399|040|M|and/or swelling.|
01399|041|B||
01399|042|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
01399|043|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
01399|044|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
01399|045|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
01399|046|D|only based on an observed-expected ratio was 4.5 and in a patient using|
01399|047|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
01399|048|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
01399|049|D|bleeding to 12.2 and 5.2, respectively.(11)|
01399|050|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
01399|051|D|in patients receiving concurrent therapy with selective serotonin reuptake|
01399|052|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
01399|053|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
01399|054|D|respectively.(12)|
01399|055|B||
01399|056|R|REFERENCES:|
01399|057|B||
01399|058|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
01399|059|R|  Laboratories Inc. August, 2023.|1
01399|060|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
01399|061|R|  Pharmaceuticals Inc. May, 2023.|1
01399|062|R|3.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
01399|063|R|  and Company August, 2023.|1
01399|064|R|4.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
01399|065|R|  Technologies January, 2017.|1
01399|066|R|5.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
01399|067|R|  Therapeutics, LLC September, 2021.|1
01399|068|R|6.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
01399|069|R|7.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
01399|070|R|  Pharmaceuticals, Inc. August, 2023.|1
01399|071|R|8.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
01399|072|R|  Pharmaceuticals, Inc. August, 2023.|1
01399|073|R|9.Effexor XR (venlafaxine hydrochloride) US prescribing information. Viatris|1
01399|074|R|  August, 2023.|1
01399|075|R|10.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
01399|076|R|   and Company September, 2021.|1
01399|077|R|11.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
01399|078|R|   Use of selective serotonin reuptake inhibitors and risk of upper|2
01399|079|R|   gastrointestinal tract bleeding: a population-based cohort study. Arch|2
01399|080|R|   Intern Med 2003 Jan 13;163(1):59-64.|2
01399|081|R|12.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
01399|082|R|   serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
01399|083|R|   population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
01399|084|R|13.Trintellix (vortioxetine) US prescribing information. Takeda|1
01399|085|R|   Pharmaceuticals America, Inc. November, 2020.|1
01399|086|R|14.Russo NW, Petrucci G, Rocca B. Aspirin, stroke and drug-drug|6
01399|087|R|   interactions. Vascul Pharmacol 2016 Dec;87:14-22.|6
01399|088|R|15.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
01399|089|R|   Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
01399|090|R|   by level of kidney function: A population-based cohort study. Br J Clin|2
01399|091|R|   Pharmacol 2018 Sep;84(9):2142-2151.|2
01400|001|T|MONOGRAPH TITLE:  Strontium/Oral Calcium Products|
01400|002|B||
01400|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01400|004|L|take action as needed.|
01400|005|B||
01400|006|A|MECHANISM OF ACTION:  Calcium may prevent the absorption of strontium.(1,2)|
01400|007|B||
01400|008|E|CLINICAL EFFECTS:  Simultaneous administration of strontium with oral|
01400|009|E|calcium products may result in decreased levels and effectiveness of|
01400|010|E|strontium.(1,2)|
01400|011|B||
01400|012|P|PREDISPOSING FACTORS:  None determined.|
01400|013|B||
01400|014|M|PATIENT MANAGEMENT:  The administration of strontium and oral calcium|
01400|015|M|products should be separated by at least 2 hours.(1,2)|
01400|016|B||
01400|017|D|DISCUSSION:  Simultaneous administration of strontium with calcium or food|
01400|018|D|decreased the bioavailability of strontium by 60-70% when compared to|
01400|019|D|administration 3 hours after a meal.(1,2)|
01400|020|B||
01400|021|R|REFERENCES:|
01400|022|B||
01400|023|R|1.Protelos (strontium ranelate) UK summary of product characteristics. Les|1
01400|024|R|  Laboratoires Servier September 21, 2004.|1
01400|025|R|2.Bonisara (strontium gluconate) US prescribing information. Zylera|1
01400|026|R|  Pharmaceuticals September, 2006.|1
01401|001|T|MONOGRAPH TITLE:  Strontium/Aluminum and Magnesium Antacids|
01401|002|B||
01401|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01401|004|L|take action as needed.|
01401|005|B||
01401|006|A|MECHANISM OF ACTION:  Aluminum and magnesium containing antacids may reduce|
01401|007|A|the absorption of strontium.(1,2)|
01401|008|B||
01401|009|E|CLINICAL EFFECTS:  Simultaneous administration of strontium with antacids|
01401|010|E|containing aluminum or magnesium may result in decreased levels and|
01401|011|E|effectiveness of strontium.(1,2)|
01401|012|B||
01401|013|P|PREDISPOSING FACTORS:  None determined.|
01401|014|B||
01401|015|M|PATIENT MANAGEMENT:  The UK manufacturer of strontium states that|
01401|016|M|administration of strontium and antacids containing aluminum or magnesium|
01401|017|M|should be separated by at least 2 hours when practical.(1)|
01401|018|M|   The US manufacturer of strontium states that it is preferable to take|
01401|019|M|antacids containing aluminum and magnesium at least 2 hours after strontium.|
01401|020|M|However, when this dosing regimen is impractical due to the recommended|
01401|021|M|administration of strontium at bedtime, concomitant intake remains|
01401|022|M|acceptable.(2)|
01401|023|M|   Some vitamin preparations may contain sufficient quantities of magnesium|
01401|024|M|salts with antacid properties to interact as well.|
01401|025|B||
01401|026|D|DISCUSSION:  Simultaneous administration of strontium with aluminum and|
01401|027|D|magnesium hydroxides 2 hours before or together with strontium decreased the|
01401|028|D|area-under-curve (AUC) of strontium by 20%-25%.   Absorption was almost|
01401|029|D|unaffected when the antacid was given 2 hours after strontium.(1)|
01401|030|B||
01401|031|R|REFERENCES:|
01401|032|B||
01401|033|R|1.Protelos (strontium ranelate) UK summary of product characteristics. Les|1
01401|034|R|  Laboratoires Servier September 21, 2004.|1
01401|035|R|2.Bonisara (strontium gluconate) US prescribing information. Zylera|1
01401|036|R|  Pharmaceuticals September, 2006.|1
01402|001|T|MONOGRAPH TITLE:  Strontium Ranelate/Oral Tetracyclines|
01402|002|B||
01402|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01402|004|L|is contraindicated and generally should not be dispensed or administered to|
01402|005|L|the same patient.|
01402|006|B||
01402|007|A|MECHANISM OF ACTION:  Strontium may form a complex with oral tetracyclines,|
01402|008|A|preventing their absorption.(1,2)|
01402|009|B||
01402|010|E|CLINICAL EFFECTS:  Simultaneous administration of strontium with oral|
01402|011|E|tetracyclines may result in decreased levels and effectiveness of the|
01402|012|E|tetracycline.(1,2)|
01402|013|B||
01402|014|P|PREDISPOSING FACTORS:  None determined.|
01402|015|B||
01402|016|M|PATIENT MANAGEMENT:  The UK(1) and US(2) manufacturers of strontium states|
01402|017|M|that strontium therapy should be suspended during the treatment with an oral|
01402|018|M|tetracycline.|
01402|019|B||
01402|020|D|DISCUSSION:  Divalent cations such as strontium can form complexes with oral|
01402|021|D|tetracyclines.(1,2)|
01402|022|B||
01402|023|R|REFERENCES:|
01402|024|B||
01402|025|R|1.Protelos (strontium ranelate) UK summary of product characteristics. Les|1
01402|026|R|  Laboratoires Servier September 21, 2004.|1
01402|027|R|2.Bonisara (strontium gluconate) US prescribing information. Zylera|1
01402|028|R|  Pharmaceuticals September, 2006.|1
01403|001|T|MONOGRAPH TITLE:  Strontium Gluconate and Ranelate/Oral Quinolones|
01403|002|B||
01403|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01403|004|L|is contraindicated and generally should not be dispensed or administered to|
01403|005|L|the same patient.|
01403|006|B||
01403|007|A|MECHANISM OF ACTION:  Strontium may form a complex with oral quinolones,|
01403|008|A|preventing their absorption.(1,2)|
01403|009|B||
01403|010|E|CLINICAL EFFECTS:  Simultaneous administration of strontium with oral|
01403|011|E|quinolones may result in decreased levels and effectiveness of the oral|
01403|012|E|quinolone.(1,2)|
01403|013|B||
01403|014|P|PREDISPOSING FACTORS:  None determined.|
01403|015|B||
01403|016|M|PATIENT MANAGEMENT:  The UK(1) and US(2) manufacturers of strontium states|
01403|017|M|that strontium therapy should be suspended during treatment with an oral|
01403|018|M|quinolone.|
01403|019|B||
01403|020|D|DISCUSSION:  Divalent cations such as strontium can form complexes with oral|
01403|021|D|quinolones.(1,2)|
01403|022|B||
01403|023|R|REFERENCES:|
01403|024|B||
01403|025|R|1.Protelos (strontium ranelate) UK summary of product characteristics. Les|1
01403|026|R|  Laboratoires Servier September 21, 2004.|1
01403|027|R|2.Bonisara (strontium gluconate) US prescribing information. Zylera|1
01403|028|R|  Pharmaceuticals September, 2006.|1
01404|001|T|MONOGRAPH TITLE:  Dorzolamide/Carbonic Anhydrase Inhibitors|
01404|002|B||
01404|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01404|004|L|take action as needed.|
01404|005|B||
01404|006|A|MECHANISM OF ACTION:  Dorzolamide and other carbonic anhydrase inhibitors|
01404|007|A|cause a decrease in aqueous humor secretion by slowing the formation of|
01404|008|A|bicarbonate ions with a subsequent reduction of sodium and fluid transport|
01404|009|A|which results in a reduction of intraocular pressure.(1)|
01404|010|B||
01404|011|E|CLINICAL EFFECTS:  If dorzolamide is given with other carbonic anhydrase|
01404|012|E|inhibitors it may cause electrolyte disturbances, because dorzolamide can be|
01404|013|E|absorbed systemically.(1)|
01404|014|B||
01404|015|P|PREDISPOSING FACTORS:  Patients with conditions that predispose to acidosis|
01404|016|P|(such as renal disease, severe respiratory disorders, status epilepticus,|
01404|017|P|diarrhea, and being on a ketogenic diet) may be at increased risk of|
01404|018|P|experiencing adverse effects from concurrent carbonic anhydrase inhibitors.|
01404|019|B||
01404|020|M|PATIENT MANAGEMENT:  The manufacturer of dorzolamide states that concurrent|
01404|021|M|use with oral carbonic anhydrase inhibitors is not recommended.(1)|
01404|022|B||
01404|023|D|DISCUSSION:  Although no human data is available, electrolyte imbalance,|
01404|024|D|development of an acidotic state, and possible nervous system effects may|
01404|025|D|occur following administration of dorzolamide and oral carbonic anhydrase|
01404|026|D|inhibitors.(1)|
01404|027|B||
01404|028|R|REFERENCE:|
01404|029|B||
01404|030|R|1.Trusopt (dorzolamide hydrochloride) US prescribing information. Merck &|1
01404|031|R|  Co., Inc. June, 2010.|1
01405|001|T|MONOGRAPH TITLE:  Selected Oral Benzodiazepines/Aprepitant (Greater Than 40|
01405|002|T|mg); Netupitant|
01405|003|B||
01405|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01405|005|L|take action as needed.|
01405|006|B||
01405|007|A|MECHANISM OF ACTION:  Netupitant and aprepitant doses greater than 40 mg per|
01405|008|A|day are classified as moderate inhibitors of CYP3A4 and may inhibit the|
01405|009|A|CYP3A4 mediated absorption and metabolism of midazolam or triazolam.(1-4)|
01405|010|B||
01405|011|E|CLINICAL EFFECTS:  Concurrent administration of aprepitant or netupitant may|
01405|012|E|result in increased levels of and effects from the benzodiazepines.(1-4)|
01405|013|E|Toxic effects of increased levels of benzodiazepines include profound|
01405|014|E|sedation, respiratory depression, coma, and/or death.|
01405|015|B||
01405|016|P|PREDISPOSING FACTORS:  None determined.|
01405|017|B||
01405|018|M|PATIENT MANAGEMENT:  Depending on patient tolerance, the benzodiazepine|
01405|019|M|dosage may need to be reduced or an alternative agent not metabolized by|
01405|020|M|CYP3A4 (e.g. lorazepam, temazepam) may be used.|
01405|021|M|   Patients receiving concurrent therapy with aprepitant or netupitant and|
01405|022|M|midazolam or triazolam should be closely monitored and counseled regarding|
01405|023|M|possible adverse effects due to increased benzodiazepine exposure.  Due to|
01405|024|M|its long half-life, the effects of a single dose of netupitant persist for 4|
01405|025|M|or more days.|
01405|026|B||
01405|027|D|DISCUSSION:  In an open-label, randomized single-period study in 16 healthy|
01405|028|D|subjects, administration of aprepitant (125 mg on Day 1, 80 mg on Days 2-5)|
01405|029|D|increased the area-under-curve (AUC) of a single oral dose of midazolam (2|
01405|030|D|mg on Day 1 and Day 5) by 2.3-fold on Day 1 and by 3.3-fold on Day 5 when|
01405|031|D|compared to midazolam alone.  Midazolam maximum concentration (Cmax)|
01405|032|D|increased by 1.5-fold on Day 1 and by 1.9-fold on Day 5.(1,5)  Midazolam|
01405|033|D|half-life increased from 1.7 hours for midazolam alone to 3.3 hours on Day 1|
01405|034|D|and Day 5.  In the second group, administration of aprepitant (40 mg on Day|
01405|035|D|1, 25 mg on Days 2-5) with midazolam had no significant effects on midazolam|
01405|036|D|AUC, Cmax, or half-life.(6)|
01405|037|D|   In a study, administration of a single dose of aprepitant (40 mg)|
01405|038|D|increased the AUC of a single dose of oral midazolam (2 mg) by 1.2-fold.|
01405|039|D|This was not considered clinically significant.(1)|
01405|040|D|   In a study in 12 healthy subjects, administration of aprepitant (125 mg|
01405|041|D|on Day 1, 80 mg on Days 2-3) increased the AUC of a single dose of|
01405|042|D|intravenous midazolam (2 mg on Days 4, 8, and 15) by 25% on Day 4.  The AUC|
01405|043|D|of midazolam was decreased by 19% on Day 8.  These effects were not|
01405|044|D|considered clinically significant.(1,5)|
01405|045|D|   In a study, administration of a single dose of intravenous midazolam (2|
01405|046|D|mg) 1 hour after a single dose of aprepitant (125 mg) increased midazolam|
01405|047|D|AUC by 1.5-fold.(1)|
01405|048|D|   In a study, co-administration of a single dose of netupitant 300 mg and|
01405|049|D|oral midazolam 7.5 mg led to an increase in the Cmax and AUC of midazolam by|
01405|050|D|36% and 126% respectively.(4)|
01405|051|B||
01405|052|R|REFERENCES:|
01405|053|B||
01405|054|R|1.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
01405|055|R|  September, 2019.|1
01405|056|R|2.Emend (aprepitant) Australian prescribing information. MSD April 5, 2004.|1
01405|057|R|3.Emend (aprepitant) UK summary of product characteristics. Merck Sharp &|1
01405|058|R|  Dohme Limited January 10. 2005.|1
01405|059|R|4.Akynzeo (netupitant and palonsetron). Helsinn Birex Pharmaceuticals June,|1
01405|060|R|  2021.|1
01405|061|R|5.Majumdar AK, McCrea JB, Panebianco DL, Hesney M, Dru J, Constanzer M,|2
01405|062|R|  Goldberg MR, Murphy G, Gottesdiener KM, Lines CR, Petty KJ, Blum RA.|2
01405|063|R|  Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a|2
01405|064|R|  probe. Clin Pharmacol Ther 2003 Sep;74(2):150-6.|2
01405|065|R|6.Shadle CR, Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, Evans|2
01405|066|R|  JK, Blum RA. Evaluation of potential inductive effects of aprepitant on|2
01405|067|R|  cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol 2004 Apr;|2
01405|068|R|  44(3):215-23.|2
01406|001|T|MONOGRAPH TITLE:  Erlotinib/Rifamycins (mono deleted 04/21/2011)|
01406|002|B||
01406|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01406|004|L|of severe adverse interaction.|
01406|005|B||
01406|006|A|MECHANISM OF ACTION:  Rifamycins may induce the metabolism of erlotinib by|
01406|007|A|CYP P-450-3A4.(1)|
01406|008|B||
01406|009|E|CLINICAL EFFECTS:  Concurrent use of rifamycins may result in decreased|
01406|010|E|levels and effectiveness of erlotinib.(1)|
01406|011|B||
01406|012|P|PREDISPOSING FACTORS:  None determined.|
01406|013|B||
01406|014|M|PATIENT MANAGEMENT:  Consider alternatives to rifamycins in patients|
01406|015|M|receiving erlotinib.  If concurrent therapy cannot be avoided, consider|
01406|016|M|increasing the dosage of erlotinib as tolerated at two week intervals while|
01406|017|M|closely monitoring the patient.  The highest dosage studied with concurrent|
01406|018|M|rifampin is 450 mg.(1)|
01406|019|M|   If the dosage of erlotinib is increased, it will need to be decreased|
01406|020|M|when the rifamycin is discontinued.(1)|
01406|021|B||
01406|022|D|DISCUSSION:  Pretreatment and concurrent therapy with rifampin increased|
01406|023|D|erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve|
01406|024|D|(AUC) by 66% to 80%.  This is equivalent to a dose of about 30 mg to 50 mg|
01406|025|D|in NSCLC patients.(1)|
01406|026|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
01406|027|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
01406|028|D|150 mg dose of erlotinib.(1)|
01406|029|B||
01406|030|R|REFERENCE:|
01406|031|B||
01406|032|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. April,|1
01406|033|R|  2010.|1
01407|001|T|MONOGRAPH TITLE:  Erlotinib/Selected Anticonvulsants (mono deleted|
01407|002|T|04/21/2011)|
01407|003|B||
01407|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01407|005|L|of severe adverse interaction.|
01407|006|B||
01407|007|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital, and phenytoin may induce|
01407|008|A|the metabolism of erlotinib by CYP P-450-3A4.(1)|
01407|009|B||
01407|010|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, phenobarbital, and/or|
01407|011|E|phenytoin may result in decreased levels and effectiveness of erlotinib.(1)|
01407|012|B||
01407|013|P|PREDISPOSING FACTORS:  None determined.|
01407|014|B||
01407|015|M|PATIENT MANAGEMENT:  Consider alternatives to carbamazepine, phenobarbital,|
01407|016|M|and phenytoin in patients receiving erlotinib.  If concurrent therapy cannot|
01407|017|M|be avoided, consider increasing the dosage of erlotinib as tolerated at two|
01407|018|M|week intervals while closely monitoring the patient.  The highest dosage|
01407|019|M|studied with a concurrent CYP P-450-3A4 inducer (rifampin) is 450 mg.(1)|
01407|020|M|   If the dosage of erlotinib is increased, it will need to be decreased if|
01407|021|M|carbamazepine, phenobarbital, or phenytoin is discontinued.(1)|
01407|022|B||
01407|023|D|DISCUSSION:  Pretreatment and concurrent therapy with rifampin, another CYP|
01407|024|D|P-450-3A4 inducer, increased erlotinib clearance by 3-fold and decreased the|
01407|025|D|erlotinib area-under-curve (AUC) by 66% to 80%.  This is equivalent to a|
01407|026|D|dose of about 30 mg to 50 mg in NSCLC.(1)|
01407|027|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
01407|028|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
01407|029|D|150 mg dose of erlotinib.(1)|
01407|030|D|   Carbamazepine, phenobarbital, and phenytoin, potent inducers of CYP|
01407|031|D|P-450-3A4, are expected to have similar effects.(1)|
01407|032|B||
01407|033|R|REFERENCE:|
01407|034|B||
01407|035|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. April,|1
01407|036|R|  2010.|1
01408|001|T|MONOGRAPH TITLE:  Selected Antineoplastic Systemic Enzyme Inhibitors/St.|
01408|002|T|John's Wort|
01408|003|B||
01408|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01408|005|L|of severe adverse interaction.|
01408|006|B||
01408|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01408|008|A|antineoplastic systemic enzyme inhibitors, including bortezomib,(1)|
01408|009|A|bosutinib,(2) ceritinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6)|
01408|010|A|gefitinib,(7) ibrutinib,(15) idelalisib,(8) imatinib,(9) lapatinib,(10)|
01408|011|A|pazopanib,(11) sorafenib,(12) and vandetanib(13) by CYP3A4.|
01408|012|B||
01408|013|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
01408|014|E|levels and effectiveness of antineoplastic systemic enzyme inhibitors,|
01408|015|E|including bortezomib,(1) bosutinib,(2) ceritinib,(3) crizotinib,(4)|
01408|016|E|dasatinib,(5) erlotinib,(6) gefitinib,(7) ibrutinib,(15) idelalisib,(8)|
01408|017|E|imatinib,(9) lapatinib,(10) pazopanib,(11) sorafenib,(12) and|
01408|018|E|vandetanib.(13)|
01408|019|B||
01408|020|P|PREDISPOSING FACTORS:  None determined.|
01408|021|B||
01408|022|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers such|
01408|023|M|as St. John's wort in patients receiving therapy with antineoplastic enzyme|
01408|024|M|inhibitors.  Consider the use of alternative agents with less enzyme|
01408|025|M|induction potential.(1-13,15)|
01408|026|M|   If concurrent use of dasatinib is warranted, consider increasing the dose|
01408|027|M|of dasatinib.(5)|
01408|028|M|   If concurrent therapy with erlotinib cannot be avoided, consider|
01408|029|M|increasing the dosage of erlotinib as tolerated at two week intervals while|
01408|030|M|closely monitoring the patient.  The highest dosage studied with concurrent|
01408|031|M|rifampin is 450 mg.  If the dosage of erlotinib is increased, it will need|
01408|032|M|to be decreased when St. John's wort is discontinued.(6)|
01408|033|M|   In patients receiving a potent CYP3A4 inducer, a dose increase to 500 mg|
01408|034|M|daily of gefitinib should be considered in the absence of severe adverse|
01408|035|M|drug reaction.  Clinical response and adverse events should be closely|
01408|036|M|monitored.(7)|
01408|037|M|   If concurrent therapy with imatinib is warranted, the dose of imatinib|
01408|038|M|should be increased by at least 50% and clinical response should be|
01408|039|M|carefully monitored.  Dosages up to 1200 mg/day (600 mg twice daily) have|
01408|040|M|been used in patients receiving concurrent therapy with strong CYP3A4|
01408|041|M|inducers.(9)|
01408|042|M|   If concurrent therapy with lapatinib is warranted, the dose of lapatinib|
01408|043|M|should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2|
01408|044|M|positive metastatic breast cancer indication) or from 1,500 mg/day up to|
01408|045|M|5,500 mg/day (hormone receptor positive, HER2 positive breast cancer|
01408|046|M|indication) based on patient tolerability. If St. John's wort is|
01408|047|M|discontinued, the dose of lapatinib should be adjusted to the normal|
01408|048|M|dose.(10)|
01408|049|M|   Pazopanib should not be administered to patients who cannot avoid chronic|
01408|050|M|use of strong CYP3A4 inducers.(11)|
01408|051|B||
01408|052|D|DISCUSSION:  Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased|
01408|053|D|bortezomib area-under-curve (AUC) by 45%.(1)|
01408|054|D|   In a study in 24 healthy subjects, rifampin decreased bosutinib AUC and|
01408|055|D|maximum concentration (Cmax) by 94% and 86%.(2)|
01408|056|D|   In a study in 19 healthy subjects, rifampin (600 mg daily for 14 days)|
01408|057|D|decreased the Cmax and AUC of a single dose of ceritinib by 44% and 70%,|
01408|058|D|respectively.(3)|
01408|059|D|   Rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of|
01408|060|D|crizotinib (250 mg) by 69% and 82%, respectively.(4)|
01408|061|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily)|
01408|062|D|decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%,|
01408|063|D|respectively.(5)|
01408|064|D|   Pretreatment and concurrent therapy with rifampin increased erlotinib|
01408|065|D|clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by|
01408|066|D|66% to 80%.  This is equivalent to a dose of about 30 mg to 50 mg in|
01408|067|D|NSCLC.(6)|
01408|068|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
01408|069|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
01408|070|D|150 mg dose of erlotinib.(6)|
01408|071|D|   In a study in healthy male volunteers, rifampicin decreased the AUC of|
01408|072|D|gefitinib by 85%.(7)|
01408|073|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
01408|074|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
01408|075|D|75%, respectively.(8)|
01408|076|D|   Concurrent St. John's wort decreased the AUC of imatinib by 30%.(9)|
01408|077|D|   In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200|
01408|078|D|mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of|
01408|079|D|lapatinib by 72%.  The dose adjustment recommendations are based on|
01408|080|D|pharmacokinetic studies and are predicted to adjust lapatinib AUC to the|
01408|081|D|range observed without concurrent CYP3A4 inducers; however, there are no|
01408|082|D|clinical data with these doses in patients receiving strong CYP3A4|
01408|083|D|inducers.(10)|
01408|084|D|   Pazopanib is primarily metabolized by CYP3A4.(11)|
01408|085|D|   Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a|
01408|086|D|single dose of sorafenib (400 mg) by 37%.(12)|
01408|087|D|   Strong CYP3A4 inducers are expected to alter vandetanib|
01408|088|D|concentrations.(13)|
01408|089|D|   Rifampin, a strong CYP3A4 inducer, decreased ibrutinib's Cmax and AUC by|
01408|090|D|more than 13-fold and 10-fold.(15)|
01408|091|B||
01408|092|R|REFERENCES:|
01408|093|B||
01408|094|R|1.Velcade (bortezomib) US prescribing information. Mellennium|1
01408|095|R|  Pharmaceuticals, Inc. October, 2021.|1
01408|096|R|2.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
01408|097|R|  2023.|1
01408|098|R|3.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
01408|099|R|  Corporation August, 2021.|1
01408|100|R|4.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
01408|101|R|  2023.|1
01408|102|R|5.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01408|103|R|  Company February, 2023.|1
01408|104|R|6.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
01408|105|R|  2016.|1
01408|106|R|7.Iressa (gefitinib tablets) US prescribing information. AstraZeneca|1
01408|107|R|  Pharmaceuticals LP April 7, 2004.|1
01408|108|R|8.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
01408|109|R|  October, 2020.|1
01408|110|R|9.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
01408|111|R|  Pharmaceuticals Corporation August, 2022.|1
01408|112|R|10.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
01408|113|R|   2018.|1
01408|114|R|11.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
01408|115|R|   2020.|1
01408|116|R|12.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
01408|117|R|   Corporation July, 2020.|1
01408|118|R|13.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
01408|119|R|   Pharmaceuticals LP October, 2018.|1
01408|120|R|14.Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U,|2
01408|121|R|   Seiberling M. Effect of rifampicin on the pharmacokinetics of imatinib|2
01408|122|R|   mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother|2
01408|123|R|   Pharmacol 2004 Feb;53(2):102-6.|2
01408|124|R|15.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
01408|125|R|   August, 2022.|1
01409|001|T|MONOGRAPH TITLE:  Efalizumab; Natalizumab/Immunosuppressives;|
01409|002|T|Immunomodulators|
01409|003|B||
01409|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01409|005|L|is contraindicated and generally should not be dispensed or administered to|
01409|006|L|the same patient.|
01409|007|B||
01409|008|A|MECHANISM OF ACTION:  Natalizumab,(1-3) efalizumab,(4) immunosuppressives,|
01409|009|A|and immunomodulators all suppress the immune system.|
01409|010|B||
01409|011|E|CLINICAL EFFECTS:  Concurrent use of natalizumab(1-3) or efalizumab(4) with|
01409|012|E|immunosuppressives or immunomodulators may result in an increased risk of|
01409|013|E|infections, including progressive multifocal leukoencephalopathy (PML), an|
01409|014|E|opportunistic infection caused by the JC virus (JCV).|
01409|015|B||
01409|016|P|PREDISPOSING FACTORS:  Previous JCV infection, longer duration of|
01409|017|P|natalizumab treatment - especially if greater than 2 years, and prior or|
01409|018|P|concomitant treatment with immunosuppressant medication are all independent|
01409|019|P|risk factors which increase the risk for PML.(1,5)|
01409|020|P|   The FDA has estimated PML incidence stratified by risk factors:|
01409|021|P|   If anti-JCV antibody positive, no prior immunosuppressant use and|
01409|022|P|natalizumab treatment less than 25 months, incidence <1/1,000.|
01409|023|P|   If anti-JCV antibody positive, history of prior immunosuppressant use and|
01409|024|P|natalizumab treatment less than 25 months, incidence 2/1,000|
01409|025|P|   If anti-JCV antibody positive, no prior immunosuppressant use and|
01409|026|P|natalizumab treatment 25-48 months, incidence 4/1,000|
01409|027|P|   If anti-JCV antibody positive, history of prior immunosuppressant use and|
01409|028|P|natalizumab treatment 25-48 months, incidence 11/1,000.|
01409|029|B||
01409|030|M|PATIENT MANAGEMENT:  The US manufacturer of natalizumab states patients with|
01409|031|M|Crohn's disease should not receive concurrent immunosuppressants, with the|
01409|032|M|exception of limited overlap of corticosteroids, due to the increased risk|
01409|033|M|for PML.  For new natalizumab patients currently receiving chronic oral|
01409|034|M|corticosteroids for Crohn's Disease, begin corticosteroid taper when|
01409|035|M|therapeutic response to natalizumab has occurred.  If corticosteroids cannot|
01409|036|M|be discontinued within six months of starting natalizumab, discontinue|
01409|037|M|natalizumab.(3)|
01409|038|M|   The US manufacturer of natalizumab states that natalizumab should not|
01409|039|M|ordinarily be used in multiple sclerosis patients receiving|
01409|040|M|immunosuppressants or immunomodulators due to the increased risk for PML.|
01409|041|M|Immunosuppressives include, but are not limited to azathioprine,|
01409|042|M|cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone,|
01409|043|M|mycophenolate, and corticosteroids.(3,6)|
01409|044|M|   The UK manufacturer of natalizumab states that concurrent use with|
01409|045|M|immunosuppressives or antineoplastic agents is contraindicated.(1)|
01409|046|M|   The Canadian manufacturer of natalizumab states that natalizumab should|
01409|047|M|not be used with immunosuppressive or immunomodulatory agents.(2)|
01409|048|M|   The US manufacturer of certolizumab states that concurrent therapy with|
01409|049|M|natalizumab is not recommended.(7)|
01409|050|B||
01409|051|D|DISCUSSION:  Progressive multifocal leukoencephalopathy has been reported in|
01409|052|D|patients receiving concurrent natalizumab were recently or concomitantly|
01409|053|D|taking immunomodulators or immunosuppressants.(1-5,8,9)|
01409|054|D|   In a retrospective cohort study of multiple sclerosis patients newly|
01409|055|D|initiated on a disease-modifying therapy, use of high-efficacy agents|
01409|056|D|(alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of|
01409|057|D|overall infections as moderate-efficacy agents, but there was an elevated|
01409|058|D|risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95%|
01409|059|D|confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI =|
01409|060|D|1.14-1.30).(10)|
01409|061|B||
01409|062|R|REFERENCES:|
01409|063|B||
01409|064|R|1.Tysabri (natalizumab) UK summary of product characteristics. Biogen Idec|1
01409|065|R|  Ltd July, 2021.|1
01409|066|R|2.Tysabri (natalizumab) Canadian prescribing information. Biogen Idec|1
01409|067|R|  Canada, Inc. January 9, 2009.|1
01409|068|R|3.Tysabri (natalizumab) US prescribing information. Biogen Idec, Inc. June,|1
01409|069|R|  2020.|1
01409|070|R|4.Raptiva (efalizumab) US prescribing information. Genentech, Inc. March 13,|1
01409|071|R|  2009.|1
01409|072|R|5.USFood and Drug Administration. FDA Drug Safety Communication: New risk|1
01409|073|R|  factor for Progressive Multifocal Leukoencephalopathy (PML) associated|1
01409|074|R|  with Tysabri (natalizumab). available at:|1
01409|075|R|  http://www.fda.gov/Drugs/DrugSafety/ucm288186.htm January 20, 2012.|1
01409|076|R|6.Medical Information. Personal communication. Biogen Idec, Inc. December 1,|1
01409|077|R|  2004.|1
01409|078|R|7.Cimzia (certolizumab pegol) US prescribing information. UCB, Inc.|1
01409|079|R|  February, 2019.|1
01409|080|R|8.Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal|3
01409|081|R|  leukoencephalopathy complicating treatment with natalizumab and interferon|3
01409|082|R|  beta-1a for multiple sclerosis. N Engl J Med 2005 Jul 28;353(4):369-74.|3
01409|083|R|9.Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive|3
01409|084|R|  multifocal leukoencephalopathy in a patient treated with natalizumab. N|3
01409|085|R|  Engl J Med 2005 Jul 28;353(4):375-81.|3
01409|086|R|10.Li J, Hutton GJ, Varisco TJ, Lin Y, Essien EJ, Aparasu RR. Infection Risk|2
01409|087|R|   Associated with High-Efficacy Disease-Modifying Agents in Multiple|2
01409|088|R|   Sclerosis: A Retrospective Cohort Study. Clin Pharmacol Ther 2024 Nov 15.|2
01410|001|T|MONOGRAPH TITLE:  Eszopiclone; Zopiclone/Erythromycin|
01410|002|B||
01410|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01410|004|L|take action as needed.|
01410|005|B||
01410|006|A|MECHANISM OF ACTION:  Erythromycin may increase the absorption of|
01410|007|A|zopiclone(1) and eszopiclone and inhibit their metabolism by CYP3A4.(2)|
01410|008|B||
01410|009|E|CLINICAL EFFECTS:  Concurrent use of erythromycin and eszopiclone or|
01410|010|E|zopiclone may result in a faster onset of hypnotic effects(1,2) and an|
01410|011|E|increase in effects, including profound sedation, respiratory depression,|
01410|012|E|coma, and/or death.(2)|
01410|013|B||
01410|014|P|PREDISPOSING FACTORS:  None determined.|
01410|015|B||
01410|016|M|PATIENT MANAGEMENT:  Patients should be counseled that concurrent use of|
01410|017|M|erythromycin and eszopiclone or zopiclone may result in faster onset of in|
01410|018|M|faster onset and an increase in effects from the hypnotic.  The dosage of|
01410|019|M|the hypnotic may need to be adjusted during erythromycin therapy.|
01410|020|B||
01410|021|D|DISCUSSION:  In a study in 10 healthy subjects, erythromycin (500 mg 3 times|
01410|022|D|daily for 6 days) increased the area-under-curve (AUC) of a single oral dose|
01410|023|D|of zopiclone (7.5 mg) by 80%.  Zopiclone concentrations at 30 minutes and 60|
01410|024|D|minutes post dose were increased 4-fold and 2-fold, respectively. The|
01410|025|D|AUC(0-1 hour) and AUC(0-2 hour) were increased by 3-fold and 2-fold,|
01410|026|D|respectively.  Time to maximum concentration (Cmax) was decreased from 2|
01410|027|D|hours to 1 hour.  An increase in pharmacodynamic effects was also noted.(1)|
01410|028|D|   Zopiclone is a racemic mixture of eszopiclone and its isomer.(3)|
01410|029|B||
01410|030|R|REFERENCES:|
01410|031|B||
01410|032|R|1.Aranko K, Luurila H, Backman JT, Neuvonen PJ, Olkkola KT. The effect of|2
01410|033|R|  erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone. Br|2
01410|034|R|  J Clin Pharmacol 1994 Oct;38(4):363-7.|2
01410|035|R|2.Imovane (zopiclone) Australian prescribing information. Aventis Pharma|1
01410|036|R|  March 9, 2004.|1
01410|037|R|3.Lunesta (eszopiclone) US prescribing information. Sunovion Pharmaceuticals|1
01410|038|R|  Inc. August, 2019.|1
01411|001|T|MONOGRAPH TITLE:  Formoterol/QT Prolonging Agents (mono deleted 07/02/2019)|
01411|002|B||
01411|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01411|004|L|take action as needed.|
01411|005|B||
01411|006|A|MECHANISM OF ACTION:  Concurrent use of formoterol with other agents that|
01411|007|A|prolong the QTc interval may result in additive effects on the QTc interval.|
01411|008|A|(1,2)|
01411|009|B||
01411|010|E|CLINICAL EFFECTS:  The concurrent use of formoterol with other agents that|
01411|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01411|012|E|arrhythmias, including torsades de pointes.(1,2)|
01411|013|B||
01411|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01411|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01411|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01411|017|P|syndrome), hypocalcemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01411|018|P|gender, or advanced age.(4)|
01411|019|P|   Concurrent use of more than one drug know to cause QT prolongation or|
01411|020|P|higher systemic concentrations or either QT prolonging drug are additional|
01411|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01411|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01411|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01411|024|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
01411|025|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01411|026|B||
01411|027|M|PATIENT MANAGEMENT:  Concurrent use of formoterol with other agents known to|
01411|028|M|prolong the QT interval should be approached with extreme caution.(1,2)|
01411|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01411|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01411|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01411|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01411|033|B||
01411|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01411|035|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01411|036|D|monograph have been shown to prolong the QTc interval either through their|
01411|037|D|mechanism of action, through studies on their effects on the QTc interval,|
01411|038|D|or through reports of QTc prolongation and/or torsades de pointes in|
01411|039|D|clinical trials and/or postmarketing reports.(3)|
01411|040|B||
01411|041|R|REFERENCES:|
01411|042|B||
01411|043|R|1.Foradil Aerolizer (formoterol fumarate) US prescribing information.|1
01411|044|R|  Schering Corporation September, 2012.|1
01411|045|R|2.Symbicort Turbuhaler (budesonide-eformoterol fumarate dihydrate)|1
01411|046|R|  Australian prescribing information. AstraZeneca Pty Ltd April 30, 2004.|1
01411|047|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01411|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01411|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01411|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01411|051|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01411|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01411|053|R|  settings: a scientific statement from the American Heart Association and|6
01411|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01411|055|R|  2;55(9):934-47.|6
01412|001|T|MONOGRAPH TITLE:  Sodium Tetradecyl Sulfate/Estrogens|
01412|002|B||
01412|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01412|004|L|is contraindicated and generally should not be dispensed or administered to|
01412|005|L|the same patient.|
01412|006|B||
01412|007|A|MECHANISM OF ACTION:  Patients taking estrogen-containing hormonal|
01412|008|A|contraceptives or hormone replacement therapy have a higher risk of clotting|
01412|009|A|problems.(1)|
01412|010|B||
01412|011|E|CLINICAL EFFECTS:  Use of sodium tetradecyl sulfate on patients taking|
01412|012|E|estrogen-containing hormonal contraceptives or hormone replacement therapy|
01412|013|E|may increase the risk of deep vein thrombosis.(1)|
01412|014|B||
01412|015|P|PREDISPOSING FACTORS:  None determined.|
01412|016|B||
01412|017|M|PATIENT MANAGEMENT:  The manufacturer of sodium tetradecyl sulfate states|
01412|018|M|that its use in patients taking contraceptives or hormone replacement|
01412|019|M|therapy is contraindicated.(2)|
01412|020|B||
01412|021|D|DISCUSSION:  Factors which may increase the risk of deep vein thrombosis|
01412|022|D|after sclerotherapy should be avoided.(1)  Therefore, its use in patients|
01412|023|D|taking estrogen-containing contraceptives or hormone replacement therapy is|
01412|024|D|contraindicated.(2)|
01412|025|B||
01412|026|R|REFERENCES:|
01412|027|B||
01412|028|R|1.Watkins M. Personal communication:  Fibro-Vein. STD Pharmaceutical|1
01412|029|R|  Products Ltd. December 20, 2004.|1
01412|030|R|2.Fibro-Vein (sodium tetradecyl sulphate) UK summary of product|1
01412|031|R|  characteristics. STD Pharmaceutical Products Ltd. March 14, 2003.|1
01413|001|T|MONOGRAPH TITLE:  Selected Antihistamines/Selected MAOIs|
01413|002|B||
01413|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01413|004|L|is contraindicated and generally should not be dispensed or administered to|
01413|005|L|the same patient.|
01413|006|B||
01413|007|A|MECHANISM OF ACTION:  MAOIs prolong and intensify the effects of|
01413|008|A|antihistamines.(1-6)|
01413|009|B||
01413|010|E|CLINICAL EFFECTS:  Concurrent use of antihistamines and a MAOI may result in|
01413|011|E|severe hypotension.(1-6)|
01413|012|B||
01413|013|P|PREDISPOSING FACTORS:  None determined.|
01413|014|B||
01413|015|M|PATIENT MANAGEMENT:  Concurrent use of antihistamines and a MAOI is|
01413|016|M|contraindicated.(1-6)|
01413|017|B||
01413|018|D|DISCUSSION:  MAOIs may prolong and intensify the effects of antihistamines,|
01413|019|D|resulting in severe hypotension.(1-6)|
01413|020|D|   A case report describes a patient having cyproheptadine added to their|
01413|021|D|phenelzine therapy in an attempt to relieve the patients anorgasmia. The|
01413|022|D|patient began to suddenly experience visual hallucination after taking the|
01413|023|D|cyproheptadine for two months.  Once the medication was terminated, the|
01413|024|D|hallucinations stopped occurring within 48 hours.(7)|
01413|025|D|   Methylene blue, when administered intravenously, has been shown to reach|
01413|026|D|sufficient concentrations to be a potent inhibitor of MAO-A.(8,9)|
01413|027|B||
01413|028|R|REFERENCES:|
01413|029|B||
01413|030|R|1.Zadine (azatadine maleate) Australian prescribing information.|1
01413|031|R|  Schering-Plough Corporation January, 1992.|1
01413|032|R|2.Ambi 1000/5 (guaifenesin/carbetapentane) US prescribing information. AMBI|1
01413|033|R|  Pharmaceuticals, Inc. March, 2006.|1
01413|034|R|3.PediaTan (chlorpheniramine tannate) US prescribing information. ProEthic|1
01413|035|R|  Pharmaceuticals, Inc. June, 2006.|1
01413|036|R|4.Carbinoxamine maleate US prescribing information. Zeris Pharma, L.L.C.|1
01413|037|R|  February, 2007.|1
01413|038|R|5.Cyproheptadine hydrochloride US prescribing information. Cypress|1
01413|039|R|  Pharmaceutical, Inc. November, 2006.|1
01413|040|R|6.Bonjesta (doxylamine and pyridoxine) US prescribing information.|1
01413|041|R|  Duchesnay, Inc. June, 2018.|1
01413|042|R|7.Kahn DA. Possible toxic interaction between cyproheptadine and phenelzine.|3
01413|043|R|  Am J Psychiatry 1987 Sep;144(9):1242-3.|3
01413|044|R|8.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
01413|045|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
01413|046|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
01413|047|R|9.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
01413|048|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
01413|049|R|  2000 Jun;56(3):247-50.|2
01414|001|T|MONOGRAPH TITLE:  Foslevodopa; Levodopa/Deutetrabenazine; Tetrabenazine|
01414|002|B||
01414|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01414|004|L|of severe adverse interaction.|
01414|005|B||
01414|006|A|MECHANISM OF ACTION:  Deutetrabenazine and tetrabenazine antagonize the|
01414|007|A|action of levodopa by inhibiting monoamine reuptake in the presynaptic|
01414|008|A|terminals, thereby depleting dopamine in the central nervous system.(1-4)|
01414|009|A|   Foslevodopa is a prodrug of levodopa.(5)|
01414|010|B||
01414|011|E|CLINICAL EFFECTS:  Concurrent administration with deutetrabenazine or|
01414|012|E|tetrabenazine may result in decreased effectiveness of levodopa.(1-4)|
01414|013|B||
01414|014|P|PREDISPOSING FACTORS:  None determined.|
01414|015|B||
01414|016|M|PATIENT MANAGEMENT:  Recommendations for concurrent use of levodopa with|
01414|017|M|tetrabenazine or deutetrabenazine vary in different regions.|
01414|018|M|   The Australian manufacturer of tetrabenazine states that concurrent use|
01414|019|M|of levodopa is contraindicated.   Levodopa should not be used concurrently|
01414|020|M|with or within one day of discontinuing tetrabenazine.(1)  The Australian|
01414|021|M|and UK manufacturers of tetrabenazine state that tetrabenazine is|
01414|022|M|contraindicated in patients with Parkinson's Disease.(1,2)|
01414|023|M|   Patients with levodopa-induced dyskinetic or choreiform movements should|
01414|024|M|have their levodopa dose reduced rather than start concurrent therapy with|
01414|025|M|tetrabenazine or deutetrabenazine.(3)  If concurrent use is necessary,|
01414|026|M|monitor patients for symptoms of parkinsonism.  A dose reduction or|
01414|027|M|discontinuation of tetrabenazine or deutetrabenazine may be required.(2-4)|
01414|028|B||
01414|029|D|DISCUSSION:  Deutetrabenazine and tetrabenazine can antagonize the effect of|
01414|030|D|levodopa.(1-4)  Most manufacturers either recommend against concurrent|
01414|031|D|use(2,3) or state that concurrent use is contraindicated.(4)  The|
01414|032|D|combination has been used in the treatment of levodopa-induced peak dose|
01414|033|D|dyskinesias.(6)|
01414|034|B||
01414|035|R|REFERENCES:|
01414|036|B||
01414|037|R|1.Tetrabenazine Australian prescribing information. iNova Pharmaceuticals|1
01414|038|R|  (Aust) Pty Ltd April 12, 2017.|1
01414|039|R|2.Tardiben (tetrabenazine) UK summary of product characteristics. AOP Orphan|1
01414|040|R|  Pharmaceuticals AG April 4, 2017.|1
01414|041|R|3.Nitoman (tetrabenazine) Canadian prescribing information. Valeant Canada|1
01414|042|R|  LP September 4, 2014.|1
01414|043|R|4.Austedo (deutetrabenazine) US prescribing information. Teva|1
01414|044|R|  Pharmaceutical, Inc. July, 2024.|1
01414|045|R|5.Vyalev (foslevodopa/foscarbidopa) Canadian product monograph. AbbVie|1
01414|046|R|  Corporation May, 2023.|1
01414|047|R|6.Brusa L, Orlacchio A, Stefani A, Galati S, Pierantozzi M, Iani C, Mercuri|2
01414|048|R|  NB. Tetrabenazine improves levodopa-induced peak-dose dyskinesias in|2
01414|049|R|  patients with Parkinson's disease. Funct Neurol 2013 Apr-May;28(2):101-5.|2
01415|001|T|MONOGRAPH TITLE:  Reserpine/Deutetrabenazine; Tetrabenazine|
01415|002|B||
01415|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01415|004|L|is contraindicated and generally should not be dispensed or administered to|
01415|005|L|the same patient.|
01415|006|B||
01415|007|A|MECHANISM OF ACTION:  Deutetrabenazine and tetrabenazine reversibly inhibit|
01415|008|A|human vesicular monoamine transporter type 2 (VMAT2).  Reserpine|
01415|009|A|irreversibly binds to VMAT2.(1,2)|
01415|010|B||
01415|011|E|CLINICAL EFFECTS:  Concurrent use of deutetrabenazine or tetrabenazine and|
01415|012|E|reserpine may result in overdosage and major depletion of serotonin and|
01415|013|E|norepinephrine in the central nervous system.(1,2)|
01415|014|B||
01415|015|P|PREDISPOSING FACTORS:  None determined.|
01415|016|B||
01415|017|M|PATIENT MANAGEMENT:  The US manufacturers of deutetrabenazine(1) and|
01415|018|M|tetrabenazine(2) states that concurrent use of reserpine is contraindicated.|
01415|019|M|Switching patients from reserpine to deutetrabenazine or tetrabenazine|
01415|020|M|should be done with caution and at least 20 days should elapse after|
01415|021|M|discontinuing reserpine before initiating deutetrabenazine or tetrabenazine.|
01415|022|M|Chorea should re-emerge before initiating deutetrabenazine or|
01415|023|M|tetrabenazine.(1,2)|
01415|024|M|   The Australian manufacturer of tetrabenazine states under|
01415|025|M|contraindications that tetrabenazine should not be given closer than one day|
01415|026|M|before or in combination with reserpine.(3)|
01415|027|B||
01415|028|D|DISCUSSION:  Deutetrabenazine and tetrabenazine reversibly inhibit human|
01415|029|D|vesicular monoamine transporter type 2 (VMAT2).  Reserpine irreversibly|
01415|030|D|binds to VMAT2.  Concurrent use of deutetrabenazine or tetrabenazine and|
01415|031|D|reserpine may result in overdosage and major depletion of serotonin and|
01415|032|D|norepinephrine in the central nervous system.(1,2)|
01415|033|B||
01415|034|R|REFERENCES:|
01415|035|B||
01415|036|R|1.Austedo (deutetrabenazine) US prescribing information. Teva|1
01415|037|R|  Pharmaceutical, Inc. July, 2024.|1
01415|038|R|2.Xenazine (tetrabenazine) US prescribing information. Valeant International|1
01415|039|R|  September, 2017.|1
01415|040|R|3.Tetrabenazine Australian prescribing information. iNova Pharmaceuticals|1
01415|041|R|  (Aust) Pty Ltd April 12, 2017.|1
01416|001|T|MONOGRAPH TITLE:  Deutetrabenazine; Tetrabenazine/MAOIs|
01416|002|B||
01416|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01416|004|L|is contraindicated and generally should not be dispensed or administered to|
01416|005|L|the same patient.|
01416|006|B||
01416|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01416|008|B||
01416|009|E|CLINICAL EFFECTS:  Concurrent use of deutetrabenazine or tetrabenazine with|
01416|010|E|an MAOI may result in restlessness, disorientation, and confusion.(1)|
01416|011|B||
01416|012|P|PREDISPOSING FACTORS:  None determined.|
01416|013|B||
01416|014|M|PATIENT MANAGEMENT:  Concurrent use of deutetrabenazine or tetrabenazine|
01416|015|M|with a MAOI is contraindicated.(1-3)  A two-week washout period should|
01416|016|M|elapse between discontinuing a MAOI and the initiation of deutetrabenazine|
01416|017|M|or tetrabenazine.(1-3)|
01416|018|B||
01416|019|D|DISCUSSION:  Because concurrent use of deutetrabenazine or tetrabenazine|
01416|020|D|with an MAOI may result in restlessness, disorientation, and confusion,|
01416|021|D|tetrabenazine should not be given after a course of any of the MAOI's.(1-3)|
01416|022|D|   Methylene blue, when administered intravenously, has been shown to reach|
01416|023|D|sufficient concentrations to be a potent inhibitor of MAO-A.(4,5)|
01416|024|D|   Metaxalone is a weak inhibitor of MAO.(6,7)|
01416|025|B||
01416|026|R|REFERENCES:|
01416|027|B||
01416|028|R|1.Austedo (deutetrabenazine) US prescribing information. Teva|1
01416|029|R|  Pharmaceutical, Inc. July, 2024.|1
01416|030|R|2.Tetrabenazine Australian prescribing information. iNova Pharmaceuticals|1
01416|031|R|  (Aust) Pty Ltd April 12, 2017.|1
01416|032|R|3.Xenazine (tetrabenazine) US prescribing information. Valeant International|1
01416|033|R|  September, 2017.|1
01416|034|R|4.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
01416|035|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
01416|036|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
01416|037|R|5.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
01416|038|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
01416|039|R|  2000 Jun;56(3):247-50.|2
01416|040|R|6.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
01416|041|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
01416|042|R|  Feb;34(2):346.e5-6.|3
01416|043|R|7.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
01416|044|R|  Pfizer Inc. January, 2024.|1
01417|001|T|MONOGRAPH TITLE:  Iomeprol/Neuroleptics|
01417|002|B||
01417|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01417|004|L|is contraindicated and generally should not be dispensed or administered to|
01417|005|L|the same patient.|
01417|006|B||
01417|007|A|MECHANISM OF ACTION:  Neuroleptics may lower seizure threshold.(1)|
01417|008|B||
01417|009|E|CLINICAL EFFECTS:  Use of iomeprol in a patient receiving a neuroleptic may|
01417|010|E|increase the risk of seizure.(1)|
01417|011|B||
01417|012|P|PREDISPOSING FACTORS:  None determined.|
01417|013|B||
01417|014|M|PATIENT MANAGEMENT:  The manufacturer of iomeprol states that neuroleptics|
01417|015|M|should be discontinued 48 hours before iomeprol use.  Treatment with a|
01417|016|M|neuroleptic should not be resumed until 24 hours post-procedure.(1)|
01417|017|B||
01417|018|D|DISCUSSION:  Because neuroleptics may lower seizure threshold, neuroleptics|
01417|019|D|should be discontinued 48 hours before iomeprol use.  Treatment with a|
01417|020|D|neuroleptic should not be resumed until 24 hours post-procedure.(1)|
01417|021|B||
01417|022|R|REFERENCE:|
01417|023|B||
01417|024|R|1.Iomeron (iomeprol) Australian prescribing information. Regional HCP April|1
01417|025|R|  3, 1998.|1
01418|001|T|MONOGRAPH TITLE:  Iomeprol/Selected Antidepressants|
01418|002|B||
01418|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01418|004|L|is contraindicated and generally should not be dispensed or administered to|
01418|005|L|the same patient.|
01418|006|B||
01418|007|A|MECHANISM OF ACTION:  Both iomeprol and selected antidepressants may lower|
01418|008|A|the seizure threshold.(1)|
01418|009|B||
01418|010|E|CLINICAL EFFECTS:  Use of iomeprol in a patient receiving selected|
01418|011|E|antidepressants may increase the risk of seizure.(1)|
01418|012|E|   Antidepressants included in this monograph are tricyclic antidepressants|
01418|013|E|(except formulations which also include benzodiazepines), bupropion, and|
01418|014|E|oral monoamine oxidase(MAO) inhibitors used to treat depression.|
01418|015|B||
01418|016|P|PREDISPOSING FACTORS:  Iomeprol associated seizures are more likely in|
01418|017|P|patients with intracranial tumors or epilepsy.(1)|
01418|018|B||
01418|019|M|PATIENT MANAGEMENT:  The manufacturer of iomeprol states that tricyclic|
01418|020|M|antidepressants and MAO inhibitors should be discontinued 48 hours before|
01418|021|M|iomeprol use. Treatment with an antidepressant should not be resumed until|
01418|022|M|24 hours post-procedure.(1)|
01418|023|M|   The UK manufacturer of bupropion states that it must not be used in the|
01418|024|M|presence of predisposing risk factors such as medicinals which are known to|
01418|025|M|lower the seizure threshold unless there is a compelling clinical|
01418|026|M|justification that concurrent use outweighs the potential increased risk of|
01418|027|M|seizure.(2)|
01418|028|B||
01418|029|D|DISCUSSION:  Because selected antidepressants may lower seizure threshold,|
01418|030|D|antidepressants should be discontinued 48 hours before iomeprol use.|
01418|031|D|Treatment with an antidepressant should not be resumed until 24 hours|
01418|032|D|post-procedure.(1)|
01418|033|B||
01418|034|R|REFERENCES:|
01418|035|B||
01418|036|R|1.Iomeron 250 (iomeprol) UK Summary of Product Characteristics. Bracco UK|1
01418|037|R|  Limited July 3, 2014.|1
01418|038|R|2.Zyban (bupropion) prolonged release tablets, UK Summary of Product|1
01418|039|R|  Characteristics. GlaxoSmithKline UK June, 2021.|1
01419|001|T|MONOGRAPH TITLE:  Eszopiclone; Zopiclone; Zolpidem/Strong CYP3A4 Inhibitors|
01419|002|B||
01419|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01419|004|L|take action as needed.|
01419|005|B||
01419|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 impair the metabolism of|
01419|007|A|eszopiclone, zopiclone, and zolpidem.(1-5,8)|
01419|008|B||
01419|009|E|CLINICAL EFFECTS:  Concurrent use of eszopiclone, zopiclone, or zolpidem|
01419|010|E|with a strong CYP3A4 inhibitor may result in an increase in hypnotic levels|
01419|011|E|and clinical effects, as well as toxic effects such as profound sedation,|
01419|012|E|respiratory depression, coma, and/or death.|
01419|013|B||
01419|014|P|PREDISPOSING FACTORS:  Systemic exposure may also be increased in patients|
01419|015|P|with severe hepatic impairment.|
01419|016|P|   Elderly and debilitated patients are more likely to have impaired motor|
01419|017|P|or cognitive performance when treated with hypnotics.|
01419|018|B||
01419|019|M|PATIENT MANAGEMENT:  The US manufacturer of eszopiclone states the total|
01419|020|M|dose should not exceed 2 mg in patients taking strong CYP3A4 inhibitors.(1)|
01419|021|M|   The Canadian manufacturer of zopiclone states the prescribed dose should|
01419|022|M|not exceed 5 mg in patients treated with strong CYP3A4 inhibitors.(8)|
01419|023|M|   Patients should be counseled that concurrent use of a strong CYP3A4|
01419|024|M|inhibitor with eszopiclone, zopiclone, or zolpidem may result in an increase|
01419|025|M|in side effects such as confusion, memory loss, sleep-walking or|
01419|026|M|sleep-driving behaviors, or daytime drowsiness.|
01419|027|B||
01419|028|D|DISCUSSION:  Concurrent administration of ketoconazole (400 mg daily for 5|
01419|029|D|days) increased the area-under-curve (AUC) of eszopiclone by 2.2-fold.|
01419|030|D|Eszopiclone maximum concentration (Cmax) and half-life were increased|
01419|031|D|1.4-fold and 1.3-fold, respectively.(1)|
01419|032|D|   An in vitro study in human liver microsomes found that ketoconazole|
01419|033|D|inhibited the metabolism of zopiclone.(2)|
01419|034|D|   In a study in 10 subjects, itraconazole (200 mg daily for 4 days)|
01419|035|D|increased the AUC, Cmax, and half-life of zopiclone by 73%, 29%, and 40%,|
01419|036|D|respectively.  However, there were no significant differences in clinical|
01419|037|D|effects when compared to placebo.(6)|
01419|038|D|   In a randomized, double-blind, cross-over study in 12 healthy subjects,|
01419|039|D|concurrent use of ketoconazole (200 mg twice daily) and zolpidem (5 mg)|
01419|040|D|decreased zolpidem clearance by 64% and increased its AUC 1.83-fold.  In the|
01419|041|D|same study, concurrent use of itraconazole and fluconazole with zolpidem had|
01419|042|D|no clinically significant effects on zolpidem pharmacokinetics.(3,5)|
01419|043|D|   In a randomized, cross-over study in 10 healthy subjects, concurrent use|
01419|044|D|of itraconazole (200 mg daily for 4 days) with a single dose of zolpidem (10|
01419|045|D|mg on day 4) increased the AUC of zolpidem by 34% when compared to placebo.|
01419|046|D|However, there were no significant differences in clinical effects when|
01419|047|D|compared to placebo.(5,7)|
01419|048|D|    Strong CYP3A4 inhibitors linked to this monograph are: adagrasib,|
01419|049|D|boceprevir, ceritinib, clarithromycin,  cobicistat, idelalisib, indinavir,|
01419|050|D|itraconazole, josamycin, lonafarnib, nefazodone, nelfinavir,|
01419|051|D|nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir, telaprevir,|
01419|052|D|telithromycin, troleandomycin, tucatinib, and voriconazole.|
01419|053|B||
01419|054|R|REFERENCES:|
01419|055|B||
01419|056|R|1.Lunesta (eszopiclone) US prescribing information. Sunovion Pharmaceuticals|1
01419|057|R|  Inc. August, 2019.|1
01419|058|R|2.Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Brentano C, Jaillon|5
01419|059|R|  P. Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism. Drug|5
01419|060|R|  Metab Dispos 1999 Sep;27(9):1068-73.|5
01419|061|R|3.Greenblatt DJ, von Moltke LL, Harmatz JS, Mertzanis P, Graf JA, Durol AL,|2
01419|062|R|  Counihan M, Roth-Schechter B, Shader RI. Kinetic and dynamic interaction|2
01419|063|R|  study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin|2
01419|064|R|  Pharmacol Ther 1998 Dec;64(6):661-71.|2
01419|065|R|4.Von Moltke LL, Greenblatt DJ, Granda BW, Duan SX, Grassi JM,|5
01419|066|R|  Venkatakrishnan K, Harmatz JS, Shader RI. Zolpidem metabolism in vitro:|5
01419|067|R|  responsible cytochromes, chemical inhibitors, and in vivo correlations. Br|5
01419|068|R|  J Clin Pharmacol 1999 Jul;48(1):89-97.|5
01419|069|R|5.Ambien CR (zolpidem tartrate) US prescribing information. Sanofi-Aventis|1
01419|070|R|  U.S. LLC August, 2019.|1
01419|071|R|6.Jalava KM, Olkkola KT, Neuvonen PJ. Effect of itraconazole on the|2
01419|072|R|  pharmacokinetics and pharmacodynamics of zopiclone. Eur J Clin Pharmacol|2
01419|073|R|  1996;51(3-4):331-4.|2
01419|074|R|7.Luurila H, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the|2
01419|075|R|  pharmacokinetics and pharmacodynamics of zolpidem. Eur J Clin Pharmacol|2
01419|076|R|  1998 Apr;54(2):163-6.|2
01419|077|R|8.Imovane (zopiclone) Canada prescribing information. Sanofi-Aventis Canada|1
01419|078|R|  Inc. October 20, 2014.|1
01420|001|T|MONOGRAPH TITLE:  Select Sedative Hypnotics; Buspirone/Strong CYP3A4|
01420|002|T|Inducers|
01420|003|B||
01420|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01420|005|L|take action as needed.|
01420|006|B||
01420|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
01420|008|A|buspirone,(1-3) eszopiclone,(4) zopiclone,(5) and zolpidem.(6)|
01420|009|B||
01420|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
01420|011|E|decreased levels and clinical effectiveness of buspirone,(1-3)|
01420|012|E|eszopiclone,(4) zopiclone,(5) and zolpidem.(6)|
01420|013|B||
01420|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01420|015|P|of the inducer for longer than 1-2 weeks.|
01420|016|B||
01420|017|M|PATIENT MANAGEMENT:  The dose of buspirone may need adjusting to maintain|
01420|018|M|anxiolytic effect.(1)|
01420|019|M|   Concurrent use of strong CYP3A4 inducers with zolpidem is not|
01420|020|M|recommended.(6)|
01420|021|M|   If concomitant therapy is warranted, patients should be counseled about|
01420|022|M|possible decreased buspirone or hypnotic effectiveness.|
01420|023|B||
01420|024|D|DISCUSSION:  In a randomized, placebo-controlled, cross-over study in 10|
01420|025|D|subjects, rifampin (600 mg daily) decreased buspirone (30 mg single dose)|
01420|026|D|maximum concentration (Cmax), area-under-curve (AUC), and half-life by|
01420|027|D|89.6%, 83.7%, and 54%, respectively.  During the placebo phase, all subjects|
01420|028|D|had measurable plasma buspirone concentrations at 10 hours after|
01420|029|D|administration; however, no subject had measurable plasma buspirone|
01420|030|D|concentrations at 6 hours after administration during the rifampin phase.(2)|
01420|031|D|The Cmax of the buspirone piperazine metabolite increased by 35%.(3)  There|
01420|032|D|were significant decreases in the effects of buspirone in the postural sway|
01420|033|D|test with eyes closed, the visual analogue scale (VAS) test for subjective|
01420|034|D|drowsiness, and the VAS test for overall drug effect during concurrent|
01420|035|D|rifampin.  Buspirone side effects were reported more often during the|
01420|036|D|placebo phase.(2)|
01420|037|D|   In a study in 8 subjects, rifampin (600 mg daily for 6 days) decreased|
01420|038|D|the area-under-curve (AUC) of a single dose of zopiclone (10 mg) by 82%.|
01420|039|D|The maximum concentration (Cmax) and half-life of zopiclone were decreased|
01420|040|D|by 71% and 15%, respectively.  A significant reduction in zopiclone effects|
01420|041|D|were seen in 3 of 5 psychomotor tests.(5)|
01420|042|D|   In a randomized cross-over study in 8 subjects, rifampin (600 mg daily|
01420|043|D|for 6 days) decreased the AUC, Cmax, and half-life of a single dose of|
01420|044|D|zolpidem (20 mg) by 73%, 58%, and 36%, respectively.  A significant|
01420|045|D|reduction in zolpidem effects were seen in all 6 psychomotor tests.(6,7)|
01420|046|D|   Similar effects are expected with eszopiclone.(4)|
01420|047|B||
01420|048|R|REFERENCES:|
01420|049|B||
01420|050|R|1.Buspar (buspirone hydrochloride) Australian prescribing information.|1
01420|051|R|  Bristol-Myers Squibb Australia Pty Ltd. October 10, 2001.|1
01420|052|R|2.Lamberg TS, Kivisto KT, Neuvonen PJ. Concentrations and effects of|2
01420|053|R|  buspirone are considerably reduced by rifampicin. Br J Clin Pharmacol 1998|2
01420|054|R|  Apr;45(4):381-5.|2
01420|055|R|3.Kivisto KT, Lamberg TS, Neuvonen PJ. Interactions of buspirone with|2
01420|056|R|  itraconazole and rifampicin: effects on the pharmacokinetics of the active|2
01420|057|R|  1-(2-pyrimidinyl)-piperazine metabolite of buspirone. Pharmacol Toxicol|2
01420|058|R|  1999 Feb;84(2):94-7.|2
01420|059|R|4.Lunesta (eszopiclone) US prescribing information. Sunovion Pharmaceuticals|1
01420|060|R|  Inc. August, 2019.|1
01420|061|R|5.Villikka K, Kivisto KT, Lamberg TS, Kantola T, Neuvonen PJ. Concentrations|2
01420|062|R|  and effects of zopiclone are greatly reduced by rifampicin. Br J Clin|2
01420|063|R|  Pharmacol 1997 May;43(5):471-4.|2
01420|064|R|6.Ambien CR (zolpidem tartrate) US prescribing information. Sanofi-Aventis|1
01420|065|R|  U.S. LLC August, 2019.|1
01420|066|R|7.Villikka K, Kivisto KT, Luurila H, Neuvonen PJ. Rifampin reduces plasma|2
01420|067|R|  concentrations and effects of zolpidem. Clin Pharmacol Ther 1997 Dec;|2
01420|068|R|  62(6):629-34.|2
01421|001|T|MONOGRAPH TITLE:  Gemifloxacin/QT Prolonging Agents|
01421|002|B||
01421|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01421|004|L|take action as needed.|
01421|005|B||
01421|006|A|MECHANISM OF ACTION:  Gemifloxacin has been shown to prolong the QTc|
01421|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01421|008|A|may result in additive effects on the QTc interval.(1)|
01421|009|B||
01421|010|E|CLINICAL EFFECTS:  The concurrent use of gemifloxacin with other agents that|
01421|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01421|012|E|arrhythmias, including torsades de pointes.(1)|
01421|013|B||
01421|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01421|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01421|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01421|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01421|018|P|gender, or advanced age.(3)|
01421|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01421|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01421|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01421|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01421|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01421|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01421|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01421|026|B||
01421|027|M|PATIENT MANAGEMENT:  The manufacturer of gemifloxacin states that|
01421|028|M|gemifloxacin should be used with caution when given with other agents known|
01421|029|M|to prolong the QT interval.(1)|
01421|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01421|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01421|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01421|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01421|034|B||
01421|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01421|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01421|037|D|monograph have been shown to prolong the QTc interval either through their|
01421|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01421|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01421|040|D|clinical trials and/or postmarketing reports.(2)|
01421|041|B||
01421|042|R|REFERENCES:|
01421|043|B||
01421|044|R|1.Factive (gemifloxacin mesylate) US prescribing information. Merus Labs|1
01421|045|R|  International, Inc. October, 2018.|1
01421|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01421|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01421|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01421|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01421|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01421|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01421|052|R|  settings: a scientific statement from the American Heart Association and|6
01421|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01421|054|R|  2;55(9):934-47.|6
01422|001|T|MONOGRAPH TITLE:  Norfloxacin/QT Prolonging Agents|
01422|002|B||
01422|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01422|004|L|take action as needed.|
01422|005|B||
01422|006|A|MECHANISM OF ACTION:  Norfloxacin has been shown to prolong the QTc|
01422|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01422|008|A|may result in additive effects on the QTc interval.(1)|
01422|009|B||
01422|010|E|CLINICAL EFFECTS:  The concurrent use of norfloxacin with other agents that|
01422|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01422|012|E|arrhythmias, including torsades de pointes.(1)|
01422|013|B||
01422|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01422|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01422|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01422|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01422|018|P|gender, or advanced age.(3)|
01422|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01422|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01422|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01422|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01422|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01422|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01422|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01422|026|B||
01422|027|M|PATIENT MANAGEMENT:  The manufacturer of norfloxacin states that norfloxacin|
01422|028|M|should be used with caution when given with other agents known to prolong|
01422|029|M|the QT interval.(1)|
01422|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01422|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01422|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01422|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01422|034|B||
01422|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01422|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01422|037|D|monograph have been shown to prolong the QTc interval either through their|
01422|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01422|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01422|040|D|clinical trials and/or postmarketing reports.(2)|
01422|041|B||
01422|042|R|REFERENCES:|
01422|043|B||
01422|044|R|1.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
01422|045|R|  2016.|1
01422|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01422|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01422|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01422|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01422|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01422|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01422|052|R|  settings: a scientific statement from the American Heart Association and|6
01422|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01422|054|R|  2;55(9):934-47.|6
01423|001|T|MONOGRAPH TITLE:  Nalidixic Acid/QT Prolonging Agents (mono deleted|
01423|002|T|09/03/2020)|
01423|003|B||
01423|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01423|005|L|take action as needed.|
01423|006|B||
01423|007|A|MECHANISM OF ACTION:  Nalidixic Acid has been shown to prolong the QTc|
01423|008|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01423|009|A|may result in additive effects on the QTc interval.(1)|
01423|010|B||
01423|011|E|CLINICAL EFFECTS:  The concurrent use of nalidixic acid with other agents|
01423|012|E|that prolong the QTc interval may result in potentially life-threatening|
01423|013|E|cardiac arrhythmias, including torsades de pointes.(1)|
01423|014|B||
01423|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01423|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01423|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01423|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01423|019|P|gender, or advanced age.(3)|
01423|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01423|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01423|022|P|factors for torsade de pointes.  Factors which may increase systemic drug|
01423|023|P|concentrations include rapid infusion of an intravenous dose or impaired|
01423|024|P|metabolism or elimination of the drug (i.e. coadministration with an agent|
01423|025|P|which inhibits its metabolism or elimination, genetic impairment in drug|
01423|026|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01423|027|B||
01423|028|M|PATIENT MANAGEMENT:  The manufacturer of nalidixic acid states that|
01423|029|M|nalidixic acid should be used with caution when given with other agents|
01423|030|M|known to prolong the QT interval.(1)|
01423|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01423|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01423|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01423|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01423|035|B||
01423|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01423|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01423|038|D|monograph have been shown to prolong the QTc interval either through their|
01423|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01423|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01423|041|D|clinical trials and/or postmarketing reports.(2)|
01423|042|B||
01423|043|R|REFERENCES:|
01423|044|B||
01423|045|R|1.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
01423|046|R|  Inc. November, 2012.|1
01423|047|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01423|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01423|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01423|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01423|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01423|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01423|053|R|  settings: a scientific statement from the American Heart Association and|6
01423|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01423|055|R|  2;55(9):934-47.|6
01424|001|T|MONOGRAPH TITLE:  Alkylating Agents/Nalidixic Acid|
01424|002|B||
01424|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01424|004|L|is contraindicated and generally should not be dispensed or administered to|
01424|005|L|the same patient.|
01424|006|B||
01424|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01424|008|B||
01424|009|E|CLINICAL EFFECTS:  Concurrent use of nalidixic acid in patients undergoing|
01424|010|E|therapy with an alkylating agent may result in serious gastrointestinal|
01424|011|E|toxicity such as hemorrhagic ulcerative colitis or intestinal necrosis.(1-2)|
01424|012|B||
01424|013|P|PREDISPOSING FACTORS:  None determined.|
01424|014|B||
01424|015|M|PATIENT MANAGEMENT:  The manufacturer of nalidixic acid states that the|
01424|016|M|concurrent use of nalidixic acid with an alkylating agent is|
01424|017|M|contraindicated.(1)|
01424|018|M|   The manufacturer of intravenous melphalan states that when given|
01424|019|M|simultaneously with nalidixic acid, the incidence of severe hemorrhagic|
01424|020|M|necrotic enterocolitis has been reported to increase in pediatric|
01424|021|M|patients.(2)|
01424|022|B||
01424|023|D|DISCUSSION:  Concurrent use of nalidixic acid in patients undergoing therapy|
01424|024|D|with  may result in serious gastrointestinal toxicity such as hemorrhagic|
01424|025|D|ulcerative colitis or intestinal necrosis.(1,2) Therefore, the manufacturer|
01424|026|D|of nalidixic acid states that the concurrent use of nalidixic acid with an|
01424|027|D|alkylating agent is contraindicated.(1)|
01424|028|B||
01424|029|R|REFERENCES:|
01424|030|B||
01424|031|R|1.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
01424|032|R|  Inc. November, 2012.|1
01424|033|R|2.Alkeran (melphalan hydrochloride) US prescribing information. Celgene|1
01424|034|R|  Corporation October, 2005.|1
01425|001|T|MONOGRAPH TITLE:  Selected Antiarrhythmics/Saquinavir|
01425|002|B||
01425|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01425|004|L|is contraindicated and generally should not be dispensed or administered to|
01425|005|L|the same patient.|
01425|006|B||
01425|007|A|MECHANISM OF ACTION:  Saquinavir coadministered with ritonavir acts as a|
01425|008|A|strong CYP3A4 inhibitor and may decrease the metabolism of some|
01425|009|A|antiarrhythmics.  Concurrent use of saquinavir/ritonavir and some|
01425|010|A|antiarrhythmics may result in additive effects on the QTc interval.(1,2)|
01425|011|B||
01425|012|E|CLINICAL EFFECTS:  Concurrent use of saquinavir/ritonavir with amiodarone,|
01425|013|E|bepridil, disopyramide, flecainide, propafenone, or quinidine may result in|
01425|014|E|elevated levels of and adverse events from (including life-threatening|
01425|015|E|reactions such as QT prolongation or torsades de pointes) the|
01425|016|E|antiarrhythmics.(1,2)|
01425|017|B||
01425|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01425|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
01425|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01425|021|P|long QT syndrome), hypokalemia, hypomagnesemia, Hypocalcemia, bradycardia,|
01425|022|P|female gender, or advanced age.(3)|
01425|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01425|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01425|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01425|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01425|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01425|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01425|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01425|030|B||
01425|031|M|PATIENT MANAGEMENT:  The US manufacturer of saquinavir mesylate states that|
01425|032|M|the antiarrhythmics amiodarone, bepridil, disopyramide, flecainide,|
01425|033|M|propafenone, and quinidine are contraindicated in patients receiving|
01425|034|M|saquinavir/ritonavir.(1)|
01425|035|M|   If concurrent therapy is deemed medically necessary, obtain serum|
01425|036|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
01425|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01425|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01425|039|B||
01425|040|D|DISCUSSION:  The US manufacturer of saquinavir mesylate states that the|
01425|041|D|antiarrhythmics amiodarone, bepridil, disopyramide, flecainide, propafenone,|
01425|042|D|and quinidine are contraindicated in patients receiving|
01425|043|D|saquinavir/ritonavir.(1)|
01425|044|B||
01425|045|R|REFERENCES:|
01425|046|B||
01425|047|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01425|048|R|  Laboratories, Inc. March, 2019.|1
01425|049|R|2.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
01425|050|R|  Inc. December, 2004.|1
01425|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01425|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01425|053|R|  settings: a scientific statement from the American Heart Association and|6
01425|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01425|055|R|  2;55(9):934-47.|6
01426|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Lopinavir|
01426|002|B||
01426|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01426|004|L|take action as needed.|
01426|005|B||
01426|006|A|MECHANISM OF ACTION:  Lopinavir may inhibit the metabolism of amprenavir,|
01426|007|A|fosamprenavir, indinavir, nelfinavir, and saquinavir.  Amprenavir and|
01426|008|A|fosamprenavir may inhibit the metabolism of lopinavir.  Nelfinavir may|
01426|009|A|induce the metabolism of lopinavir.(1-4)|
01426|010|B||
01426|011|E|CLINICAL EFFECTS:  Concurrent administration of lopinavir with indinavir,|
01426|012|E|nelfinavir, or saquinavir may result in elevated levels of indinavir,|
01426|013|E|nelfinavir, and saquinavir.|
01426|014|E|   Concurrent administration of lopinavir with amprenavir or fosamprenavir|
01426|015|E|may result in decreased levels of amprenavir or fosamprenavir.|
01426|016|E|   Concurrent amprenavir, fosamprenavir may result in may result in|
01426|017|E|increased levels of lopinavir.|
01426|018|E|   Concurrent nelfinavir may result in decreased levels of lopinavir.(1-4)|
01426|019|B||
01426|020|P|PREDISPOSING FACTORS:  None determined.|
01426|021|B||
01426|022|M|PATIENT MANAGEMENT:  Appropriate doses of fosamprenavir with|
01426|023|M|lopinavir/ritonavir have not been established.(1,4)|
01426|024|M|   When used concurrently, the dosage of indinavir should be 600 mg twice|
01426|025|M|daily and the dosage of lopinavir/ritonavir should be 400/100 mg twice|
01426|026|M|daily.(1,2)|
01426|027|M|   Lopinavir/ritonavir should not be administered once daily in combination|
01426|028|M|with nelfinavir.  Administration of lopinavir/ritonavir with nelfinavir in|
01426|029|M|patients less than 6 months of age is not recommended.(1)|
01426|030|M|   The dose of lopinavir/ritonavir tablets should be 500/125 mg (two 200/50|
01426|031|M|mg tablets and one 100/25 mg tablet) in adults receiving concurrent|
01426|032|M|nelfinavir.(1)|
01426|033|M|   The dose of lopinavir/ritonavir oral solution should be 520/130 mg (6.5|
01426|034|M|ml) twice daily in adults receiving concurrent nelfinavir.(1,2)|
01426|035|M|   The US manufacturer of lopinavir/ritonavir states that pediatric patients|
01426|036|M|aged 6 months to 18 years receiving nelfinavir require a dosage increase to|
01426|037|M|300/75 mg/m2 of oral solution (not to exceed the recommended adult dose).(1)|
01426|038|M|If weight-based dosing is preferred, patients weighing less than 15 kg|
01426|039|M|should receive 13/3.25 mg/kg of lopinavir/ritonavir oral solution twice|
01426|040|M|daily with food and patients weighing 15 kg to 45 kg should receive 11/2.75|
01426|041|M|mg/kg of lopinavir/ritonavir oral solution twice daily with food.(1)  Refer|
01426|042|M|to the current Kaletra tablet labeling for information on dosing Kaletra|
01426|043|M|tablets in pediatric patients taking nelfinavir who can swallow tablets.(1)|
01426|044|M|   Concurrent use of saquinavir and lopinavir/ritonavir does not require|
01426|045|M|dose adjustment, but should be approached with caution due to additive|
01426|046|M|effects on the QT interval.(1-3)|
01426|047|B||
01426|048|D|DISCUSSION:  In a study in 12 subjects, the concurrent administration of|
01426|049|D|amprenavir (750 mg twice daily) with lopinavir/ritonavir (400/100 mg twice|
01426|050|D|daily) decreased the lopinavir maximum concentration (Cmax),|
01426|051|D|area-under-curve (AUC), and minimum concentration (Cmin) by 28%, 38%, and|
01426|052|D|57%, respectively.  The Cmax, AUC, and Cmin of amprenavir increased by 12%,|
01426|053|D|72%, and 457%, respectively.(1)|
01426|054|D|   In a study in 18 subjects, the concurrent administration of fosamprenavir|
01426|055|D|(700 mg twice daily with 100 mg ritonavir twice daily) and lopinavir/|
01426|056|D|ritonavir (400/100 mg twice daily) increased the lopinavir Cmax, AUC, and|
01426|057|D|Cmin by 30%, 37%, and 52%, respectively.  The Cmax, AUC, and Cmin of|
01426|058|D|amprenavir decreased by 58%, 63%, and 65%, respectively.(1,4)|
01426|059|D|   A 3-arm, randomized cross-over study in healthy subjects examined the|
01426|060|D|pharmacokinetics of lopinavir and amprenavir during concurrent therapy.|
01426|061|D|Amprenavir Cmax, AUC, and Cmin were 13%, 26%, and 42% lower when|
01426|062|D|administered with lopinavir/ritonavir than with ritonavir.(4)|
01426|063|D|  In a study in 13 subjects, concurrent indinavir (600 mg twice daily) and|
01426|064|D|lopinavir/ritonavir (400/100 mg twice daily) decreased indinavir maximum|
01426|065|D|concentration (Cmax) and area-under-curve (AUC) by 29% and 9%, respectively.|
01426|066|D|The minimum concentration (Cmin) of indinavir increased by 3.47-fold.(1,2)|
01426|067|D|   In a study in 13 subjects, concurrent nelfinavir (1000 mg twice daily)|
01426|068|D|and lopinavir/ritonavir (400/100 mg twice daily) decreased lopinavir Cmax,|
01426|069|D|AUC, and Cmin by 21%, 27%, and 38%, respectively.  The AUC and Cmin of|
01426|070|D|nelfinavir increased by 7% and by 86%, respectively.  The Cmax of nelfinavir|
01426|071|D|decreased 7%.  The Cmax, AUC, and Cmin of the M8 metabolite of nelfinavir|
01426|072|D|increased by 2.36-fold, 3.46-fold, and 7.49-fold, respectively.(1,2)|
01426|073|D|   In a study in 14 subjects, concurrent saquinavir (800 mg twice daily)|
01426|074|D|with lopinavir/ritonavir (400/100 mg twice daily) increased the Cmax, AUC,|
01426|075|D|and Cmin of saquinavir by 634%, 962%, and 1674%, respectively.  In a study|
01426|076|D|in 10 subjects, concurrent saquinavir (1200 mg twice daily) with lopinavir/|
01426|077|D|ritonavir (400/100 mg twice daily) increased the Cmax, AUC, and Cmin of|
01426|078|D|saquinavir by 644%, 991%, and by 1654%, respectively.(1,2)|
01426|079|D|   Data from trials indicates that saquinavir concentrations achieved with|
01426|080|D|concurrent saquinavir (1000 mg) with lopinavir/ritonavir (400/100 mg) twice|
01426|081|D|daily are similar to those seen with saquinavir/ritonavir (1000/100 mg)|
01426|082|D|twice daily.(5)|
01426|083|B||
01426|084|R|REFERENCES:|
01426|085|B||
01426|086|R|1.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01426|087|R|  Laboratories December, 2019.|1
01426|088|R|2.Kaletra (lopinavir/ritonavir capsules) US prescribing information. Abbott|1
01426|089|R|  Laboratories September, 2016.|1
01426|090|R|3.Agenerase (amprenavir) Capsules US prescribing information.|1
01426|091|R|  GlaxoSmithKline May, 2005.|1
01426|092|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01426|093|R|  March, 2019.|1
01426|094|R|5.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01426|095|R|  Laboratories, Inc. March, 2019.|1
01427|001|T|MONOGRAPH TITLE:  Amprenavir; Fosamprenavir/Tipranavir|
01427|002|B||
01427|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01427|004|L|of severe adverse interaction.|
01427|005|B||
01427|006|A|MECHANISM OF ACTION:  Tipranavir may induce the CYP3A4-mediated metabolism|
01427|007|A|of amprenavir.(1)  Fosamprenavir is a prodrug of amprenavir.(2)|
01427|008|B||
01427|009|E|CLINICAL EFFECTS:  Concurrent use of tipranavir coadministered with|
01427|010|E|ritonavir may result in decreased levels of amprenavir.(1)|
01427|011|B||
01427|012|P|PREDISPOSING FACTORS:  None determined.|
01427|013|B||
01427|014|M|PATIENT MANAGEMENT:  The US manufacturer of tipranavir states that|
01427|015|M|concurrent administration of fosamprenavir is not recommended.(3)|
01427|016|B||
01427|017|D|DISCUSSION:  In a study in 16 subjects, concurrent amprenavir/ritonavir|
01427|018|D|(600/100 mg twice daily) and tipranavir/ritonavir (500/200 mg twice daily)|
01427|019|D|decreased the Cmax, AUC, and Cmin of amprenavir by 39%, 44%, and 55%,|
01427|020|D|respectively.(3)|
01427|021|B||
01427|022|R|REFERENCES:|
01427|023|B||
01427|024|R|1.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01427|025|R|  Pharmaceuticals, Inc. April, 2024.|1
01427|026|R|2.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01427|027|R|  March, 2019.|1
01427|028|R|3.Agenerase (amprenavir) Capsules US prescribing information.|1
01427|029|R|  GlaxoSmithKline May, 2005.|1
01428|001|T|MONOGRAPH TITLE:  Etravirine; Nevirapine/Rifampin; Rifapentine|
01428|002|B||
01428|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01428|004|L|is contraindicated and generally should not be dispensed or administered to|
01428|005|L|the same patient.|
01428|006|B||
01428|007|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of etravirine(1)|
01428|008|A|and nevirapine by CYP3A4.(2-4)|
01428|009|B||
01428|010|E|CLINICAL EFFECTS:  Concurrent use of rifampin may result in decreased levels|
01428|011|E|and clinical effectiveness of etravirine(1) and nevirapine.(2-4)|
01428|012|B||
01428|013|P|PREDISPOSING FACTORS:  None determined.|
01428|014|B||
01428|015|M|PATIENT MANAGEMENT:  The US manufacturer of etravirine states that it should|
01428|016|M|not be used with rifampin or rifapentine.(1)|
01428|017|M|   The Australian, UK, and US manufacturers of nevirapine state that|
01428|018|M|rifampin should not be coadministered with nevirapine.(2-4)|
01428|019|M|   The Canadian manufacturer of nevirapine states that nevirapine should|
01428|020|M|only be used in combination with rifampin if clearly indicated and with|
01428|021|M|careful monitoring.(5)|
01428|022|M|   Rifabutin may be an alternative to rifampin.(2-4)|
01428|023|B||
01428|024|D|DISCUSSION:  In a study in 14 subjects, concurrent nevirapine and rifampin|
01428|025|D|decreased nevirapine area-under-curve (AUC), maximum concentration (Cmax),|
01428|026|D|and minimum concentration (Cmin) of nevirapine by 58%, 50%, and 68%,|
01428|027|D|respectively.(3)  There were no significant changes to rifampin Cmax or AUC.|
01428|028|D|(3,4)|
01428|029|D|   In a study in 10 HIV-positive tuberculosis patients, concurrent rifampin|
01428|030|D|and nevirapine decreased nevirapine AUC and Cmax by 31% and by 36%,|
01428|031|D|respectively.  There was a non-statistically significant decrease in|
01428|032|D|nevirapine Cmin by 21%.(6)|
01428|033|B||
01428|034|R|REFERENCES:|
01428|035|B||
01428|036|R|1.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01428|037|R|  August, 2014.|1
01428|038|R|2.Viramune (nevirapine) Australian prescribing information. Boehringer|1
01428|039|R|  Ingelheim Pty Ltd. October 24, 2003.|1
01428|040|R|3.Viramune (nevirapine) UK summary of product characteristics. Boehringer|1
01428|041|R|  Ingelheim Limited April, 2007.|1
01428|042|R|4.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
01428|043|R|  Pharmaceuticals, Inc. June, 2022.|1
01428|044|R|5.Viramune (nevirapine) Canadian prescribing information. Boehringer|1
01428|045|R|  Ingelheim 2002.|1
01428|046|R|6.Ribera E, Pou L, Lopez RM, Crespo M, Falco V, Ocana I, Ruiz I, Pahissa A.|2
01428|047|R|  Pharmacokinetic interaction between nevirapine and rifampicin in|2
01428|048|R|  HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr 2001|2
01428|049|R|  Dec 15;28(5):450-3.|2
01429|001|T|MONOGRAPH TITLE:  Ezetimibe/Cyclosporine|
01429|002|B||
01429|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01429|004|L|take action as needed.|
01429|005|B||
01429|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01429|007|B||
01429|008|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine with ezetimibe may result|
01429|009|E|in elevated levels of and side effects from ezetimibe and cyclosporine.(1)|
01429|010|B||
01429|011|P|PREDISPOSING FACTORS:  Patients with severe renal insufficiency may|
01429|012|P|experience larger increases in ezetimibe levels.(1)|
01429|013|B||
01429|014|M|PATIENT MANAGEMENT:  Carefully weigh the risk of elevated levels of|
01429|015|M|ezetimibe and cyclosporine against benefits of ezetimibe in patients|
01429|016|M|maintained on cyclosporine.  Patients receiving concurrent therapy should be|
01429|017|M|monitored for adverse effects.  Ezetimibe may need to be discontinued.(1)|
01429|018|B||
01429|019|D|DISCUSSION:  In a study in 8 post-renal transplant patients with mildly|
01429|020|D|impaired or normal renal function (CrCL greater than 50ml/min), stable|
01429|021|D|cyclosporine doses (75 to 150 mg twice daily) increased ezetimibe|
01429|022|D|area-under-curve (AUC) and maximum concentration (Cmax) values by 240% and|
01429|023|D|by 290%, respectively, compared to historical healthy controls.  In another|
01429|024|D|study, a renal transplant patient with severe renal impairment (CrCl = 13.2)|
01429|025|D|maintained on cyclosporine experienced a 12-fold greater exposure to|
01429|026|D|ezetimibe than healthy subjects.(1)|
01429|027|D|   In a study in 12 healthy subjects, ezetimibe (20 mg daily for 8 days)|
01429|028|D|increased the AUC of a single dose of cyclosporine (100 mg) by 15%.(1)|
01429|029|B||
01429|030|R|REFERENCE:|
01429|031|B||
01429|032|R|1.Zetia (ezetimibe) US prescribing information. Merck/Schering-Plough|1
01429|033|R|  Pharmaceuticals July, 2023.|1
01430|001|T|MONOGRAPH TITLE:  Sirolimus/Selected Azole Antifungals (mono deleted|
01430|002|T|10/24/2013)|
01430|003|B||
01430|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01430|005|L|of severe adverse interaction.|
01430|006|B||
01430|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Ketoconazole has been|
01430|008|A|shown to increase the rate and extent of sirolimus absorption.(1)|
01430|009|B||
01430|010|E|CLINICAL EFFECTS:  The concurrent administration of sirolimus with|
01430|011|E|fluconazole, itraconazole, or ketoconazole may result in elevated levels of|
01430|012|E|sirolimus and toxicity.(1)|
01430|013|B||
01430|014|P|PREDISPOSING FACTORS:  None determined.|
01430|015|B||
01430|016|M|PATIENT MANAGEMENT:  The manufacturer of sirolimus states that the|
01430|017|M|concurrent use of itraconazole or ketoconazole is not recommended and should|
01430|018|M|be avoided.(1)|
01430|019|M|   If concurrent use is warranted, sirolimus concentrations should be|
01430|020|M|closely monitored during and after antifungal therapy.  The dosage of|
01430|021|M|sirolimus may need adjusting.|
01430|022|B||
01430|023|D|DISCUSSION:  The concurrent administration of ketoconazole with sirolimus in|
01430|024|D|multiple-dose studies resulted in increases in the sirolimus maximum|
01430|025|D|concentration (Cmax), time to Cmax (Tmax), and area-under-curve (AUC) by|
01430|026|D|4.3-fold, 38%, and 10.9-fold, respectively.(1)|
01430|027|D|   In a case report, concurrent fluconazole increased sirolimus trough|
01430|028|D|levels (Cmin) by 3.7-fold after 22 days of concurrent therapy.(2)|
01430|029|D|   In a case report, a patient's sirolimus dose had to be increased from|
01430|030|D|0.75 mg daily to 1.5 mg daily to maintain therapeutic levels following the|
01430|031|D|discontinuation of concurrent itraconazole.(2)|
01430|032|D|   In a case report, a patient received oral itraconazole 200 mg every 12|
01430|033|D|hours and sirolimus at a dosage of 7 mg/day on days 76-80 and 5 mg/day on|
01430|034|D|days 81 and 82 of therapy. The patient's sirolimus whole blood trough levels|
01430|035|D|were 17.5 and 35.6 ng/ml on days 80 and 82, respectively (normal range 5-15|
01430|036|D|ng/ml). Sirolimus was then withheld on days 83-90. On day 90, the patient's|
01430|037|D|sirolimus trough level had normalized to 4.4 ng/ml. Sirolimus was then|
01430|038|D|resumed at 1-2 mg/day and adjusted to maintain trough levels of 10-15|
01430|039|D|ng/ml.(3)|
01430|040|D|   In a study in 6 patients, ketoconazole was successfully used to augment|
01430|041|D|sirolimus levels.  Patients were able to receive one-eight to one-fourth|
01430|042|D|(0.25 - 0.50 mg daily) of the usual sirolimus dose while taking 100 to 200|
01430|043|D|mg of ketoconazole daily.(4)|
01430|044|B||
01430|045|R|REFERENCES:|
01430|046|B||
01430|047|R|1.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
01430|048|R|  March, 2013.|1
01430|049|R|2.Sadaba B, Campanero MA, Quetglas EG, Azanza JR. Clinical relevance of|3
01430|050|R|  sirolimus drug interactions in transplant patients. Transplant Proc 2004|3
01430|051|R|  Dec;36(10):3226-8.|3
01430|052|R|3.Said A, Garnick JJ, Dieterle N, Peres E, Abidi MH, Ibrahim RB.|3
01430|053|R|  Sirolimus-itraconazole interaction in a hematopoietic stem cell transplant|3
01430|054|R|  recipient. Pharmacotherapy 2006 Feb;26(2):289-95.|3
01430|055|R|4.Thomas PP, Manivannan J, John GT, Jacob CK. Sirolimus and ketoconazole|2
01430|056|R|  co-prescription in renal transplant recipients. Transplantation 2004 Feb|2
01430|057|R|  15;77(3):474-5.|2
01431|001|T|MONOGRAPH TITLE:  Cefdinir/Oral Iron|
01431|002|B||
01431|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01431|004|L|take action as needed.|
01431|005|B||
01431|006|A|MECHANISM OF ACTION:  Iron may form a chelation complex with cefdinir,|
01431|007|A|preventing its absorption.(1,2)|
01431|008|B||
01431|009|E|CLINICAL EFFECTS:  Simultaneous administration of cefdinir with iron may|
01431|010|E|result in decreased levels and clinical effectiveness of cefdinir.(1,2)|
01431|011|E|Concurrent use may also result in a reddish color of stools.(1)|
01431|012|B||
01431|013|P|PREDISPOSING FACTORS:  None determined.|
01431|014|B||
01431|015|M|PATIENT MANAGEMENT:  Cefdinir should be taken at least 2 hours before or|
01431|016|M|after iron supplements, including multivitamins containing iron.(1)|
01431|017|M|   Patients should be counseled that their stool may turn reddish during|
01431|018|M|treatment with cefdinir.|
01431|019|M|   Cefdinir may be administered simultaneously with iron-fortified infant|
01431|020|M|formula.(1)|
01431|021|B||
01431|022|D|DISCUSSION:  Simultaneous administration of cefdinir with a therapeutic iron|
01431|023|D|supplement containing 60 mg of elemental iron as ferrous sulfate or vitamins|
01431|024|D|containing 10 mg of elemental iron decreased cefdinir absorption by 80% and|
01431|025|D|31%, respectively.(1)|
01431|026|D|   Simultaneous administration of iron with cefdinir (200 mg) decreased|
01431|027|D|cefdinir area-under-curve (AUC) by 93%.(2)|
01431|028|D|   There have been reports of reddish stools in patients taking cefdinir,|
01431|029|D|most of these patients were taking iron-containing products.(1)|
01431|030|B||
01431|031|R|REFERENCES:|
01431|032|B||
01431|033|R|1.Omnicef (cefdinir) US prescribing information. Abbott Laboratories|1
01431|034|R|  December, 2008.|1
01431|035|R|2.Ueno K, Tanaka K, Tsujimura K, Morishima Y, Iwashige H, Yamazaki K, Nakata|2
01431|036|R|  I. Impairment of cefdinir absorption by iron ion. Clin Pharmacol Ther 1993|2
01431|037|R|  Nov;54(5):473-5.|2
01432|001|T|MONOGRAPH TITLE:  Selected Cephalosporins/Aluminum; Magnesium Compounds|
01432|002|B||
01432|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01432|004|L|take action as needed.|
01432|005|B||
01432|006|A|MECHANISM OF ACTION:  Aluminum and magnesium containing antacids may form|
01432|007|A|chelation complexes with some cephalosporins, preventing their|
01432|008|A|absorption.(1,2)|
01432|009|B||
01432|010|E|CLINICAL EFFECTS:  Simultaneous administration of an aluminum and/or|
01432|011|E|magnesium containing antacid with some cephalosporins may result in|
01432|012|E|decreased levels and effectiveness of the cephalosporin.(1,2)|
01432|013|B||
01432|014|P|PREDISPOSING FACTORS:  None determined.|
01432|015|B||
01432|016|M|PATIENT MANAGEMENT:  The manufacturer of cefdinir recommends that cefdinir|
01432|017|M|be taken at least 2 hours before or after an aluminum and/or magnesium|
01432|018|M|containing antacid.(1)|
01432|019|M|   It would be prudent to separate the administration of cefaclor by at|
01432|020|M|least this amount of time as well.(2)|
01432|021|B||
01432|022|D|DISCUSSION:  Simultaneous administration of cefdinir (300 mg) with Maalox TC|
01432|023|D|(30 ml) decreased cefdinir area-under-curve (AUC) and maximum concentration|
01432|024|D|(Cmax) by 40%.(1)|
01432|025|D|   In a study in 15 healthy subjects, simultaneous administration of|
01432|026|D|cefaclor advanced formulation (500 mg) with Maalox TC decreased the extent|
01432|027|D|of cefaclor absorption.(2)|
01432|028|B||
01432|029|R|REFERENCES:|
01432|030|B||
01432|031|R|1.Omnicef (cefdinir) US prescribing information. Abbott Laboratories|1
01432|032|R|  December, 2008.|1
01432|033|R|2.Satterwhite JH, Cerimele BJ, Coleman DL, Hatcher BL, Kisicki J, DeSante|2
01432|034|R|  KA. Pharmacokinetics of cefaclor AF: effects of age, antacids and|2
01432|035|R|  H2-receptor antagonists. Postgrad Med J 1992;68 Suppl 3:S3-9.|2
01433|001|T|MONOGRAPH TITLE:  Topical Sodium Sulfacetamide/Topical Silver|
01433|002|B||
01433|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01433|004|L|of severe adverse interaction.|
01433|005|B||
01433|006|A|MECHANISM OF ACTION:  Topical sodium sulfacetamide and topical silver are|
01433|007|A|physically incompatible.(1,2)|
01433|008|B||
01433|009|E|CLINICAL EFFECTS:  Concurrent application of topical sodium sulfacetamide|
01433|010|E|and topical silver preparations may result in decreased clinical|
01433|011|E|effectiveness of the products.(1,2)|
01433|012|B||
01433|013|P|PREDISPOSING FACTORS:  None determined.|
01433|014|B||
01433|015|M|PATIENT MANAGEMENT:  Avoid using topical silver preparations on the same|
01433|016|M|location as topical sodium sulfacetamide products.(1,2)|
01433|017|B||
01433|018|D|DISCUSSION:  Topical sodium sulfacetamide and topical silver are physically|
01433|019|D|incompatible.(1,2)|
01433|020|B||
01433|021|R|REFERENCES:|
01433|022|B||
01433|023|R|1.Rosula NS (sodium sulfacetamide/urea) US prescribing information. Doak|1
01433|024|R|  Dermatologics July, 2004.|1
01433|025|R|2.Seb-Prev (sodium sulfacetamide) US prescribing information. Glades|1
01433|026|R|  Pharmaceuticals September, 2005.|1
01434|001|T|MONOGRAPH TITLE:  Fenoldopam/Beta-Blockers|
01434|002|B||
01434|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01434|004|L|of severe adverse interaction.|
01434|005|B||
01434|006|A|MECHANISM OF ACTION:  Beta-blockers may inhibit the sympathetic reflex|
01434|007|A|response to fenoldopam.(1)|
01434|008|B||
01434|009|E|CLINICAL EFFECTS:  Concurrent use of fenoldopam and a beta-blocker may|
01434|010|E|result in unexpected hypotension.(1)|
01434|011|B||
01434|012|P|PREDISPOSING FACTORS:  None determined.|
01434|013|B||
01434|014|M|PATIENT MANAGEMENT:  The manufacturer of fenoldopam states that concurrent|
01434|015|M|use with beta-blockers should be avoided.  If concurrent use is necessary,|
01434|016|M|caution should be exercised.(1)|
01434|017|B||
01434|018|D|DISCUSSION:  Because beta-blockers may inhibit the sympathetic reflex|
01434|019|D|response to fenoldopam, the manufacturer of fenoldopam states that|
01434|020|D|concurrent use should be avoided.(1)|
01434|021|D|   One set of authors suggests that fenoldopam may be added to labetalol or|
01434|022|D|esmolol therapy in the treatment of hypertensive crisis during acute|
01434|023|D|myocardial ischemia if blood pressure is controlled poorly alone with|
01434|024|D|labetalol or esmolol.(2)|
01434|025|B||
01434|026|R|REFERENCES:|
01434|027|B||
01434|028|R|1.Corlopam (fenoldopam mesylate) US prescribing information. Abbott|1
01434|029|R|  Laboratories September, 2020.|1
01434|030|R|2.Varon J, Marik PE. The diagnosis and management of hypertensive crises.|6
01434|031|R|  Chest 2000 Jul;118(1):214-27.|6
01435|001|T|MONOGRAPH TITLE:  Sibutramine/Antidepressants|
01435|002|B||
01435|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01435|004|L|is contraindicated and generally should not be dispensed or administered to|
01435|005|L|the same patient.|
01435|006|B||
01435|007|A|MECHANISM OF ACTION:  Sibutramine has demonstrated antidepressant effects.|
01435|008|A|(1)|
01435|009|B||
01435|010|E|CLINICAL EFFECTS:  Concurrent use of sibutramine and an antidepressant may|
01435|011|E|result in additive or synergistic central nervous system (CNS) effects.|
01435|012|B||
01435|013|P|PREDISPOSING FACTORS:  None determined.|
01435|014|B||
01435|015|M|PATIENT MANAGEMENT:  Sibutramine has been removed from the market by the|
01435|016|M|European Medicines Agency and by regulatory agencies in a number of|
01435|017|M|countries including Australia, Canada, Hong Kong, India, Thailand, United|
01435|018|M|Kingdom and the United States.|
01435|019|M|   The Australian,(2) Canadian,(1) and UK(3) manufacturers of sibutramine|
01435|020|M|formerly stated that concurrent use with antidepressants is contraindicated.|
01435|021|M|The Canadian manufacturer also states that concurrent use of St. John's|
01435|022|M|wort is contraindicated.(1)|
01435|023|B||
01435|024|D|DISCUSSION:  Sibutramine has been removed from the market by the European|
01435|025|D|Medicines Agency and by regulatory agencies in a number of countries|
01435|026|D|including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and|
01435|027|D|the United States.|
01435|028|D|    The use of sibutramine with other CNS-active agents has not been|
01435|029|D|evaluated.(1-3)|
01435|030|B||
01435|031|R|REFERENCES:|
01435|032|B||
01435|033|R|1.Meridia (sibutramine hydrochloride monohydrate) Canadian prescribing|1
01435|034|R|  information. Abbott Limited December, 2004.|1
01435|035|R|2.Reductil (sibutramine hydrochloride) Australian prescribing information.|1
01435|036|R|  Abbott Australasia Pty. Ltd. March 5, 2004.|1
01435|037|R|3.Reductil (sibutramine hydrochloride monohydrate) UK summary of product|1
01435|038|R|  characteristics. Abbott Laboratories, Limited January 12, 2005.|1
01436|001|T|MONOGRAPH TITLE:  Sibutramine/Antipsychotics|
01436|002|B||
01436|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01436|004|L|is contraindicated and generally should not be dispensed or administered to|
01436|005|L|the same patient.|
01436|006|B||
01436|007|A|MECHANISM OF ACTION:  Sibutramine has demonstrated antidepressant effects.|
01436|008|A|(1)|
01436|009|B||
01436|010|E|CLINICAL EFFECTS:  Concurrent use of sibutramine and an antipsychotic may|
01436|011|E|result in additive or synergistic central nervous system (CNS) effects.|
01436|012|B||
01436|013|P|PREDISPOSING FACTORS:  None determined.|
01436|014|B||
01436|015|M|PATIENT MANAGEMENT:  The Australian,(2) Canadian,(1) and UK(3) manufacturers|
01436|016|M|of sibutramine state that concurrent use with antipsychotics is|
01436|017|M|contraindicated.|
01436|018|B||
01436|019|D|DISCUSSION:  The use of sibutramine with other CNS-active agents has not|
01436|020|D|been evaluated.(1-3)|
01436|021|B||
01436|022|R|REFERENCES:|
01436|023|B||
01436|024|R|1.Meridia (sibutramine hydrochloride monohydrate) Canadian prescribing|1
01436|025|R|  information. Abbott Limited December, 2004.|1
01436|026|R|2.Reductil (sibutramine hydrochloride) Australian prescribing information.|1
01436|027|R|  Abbott Australasia Pty. Ltd. March 5, 2004.|1
01436|028|R|3.Reductil (sibutramine hydrochloride monohydrate) UK summary of product|1
01436|029|R|  characteristics. Abbott Laboratories, Limited January 12, 2005.|1
01437|001|T|MONOGRAPH TITLE:  Selected Live Viral Vaccines/Selected Immunoglobulins|
01437|002|B||
01437|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01437|004|L|is contraindicated and generally should not be dispensed or administered to|
01437|005|L|the same patient.|
01437|006|B||
01437|007|A|MECHANISM OF ACTION:  Immune globulin(IG) products may prevent the immune|
01437|008|A|system from properly responding to the vaccine.(1-19)|
01437|009|B||
01437|010|E|CLINICAL EFFECTS:  Administration of selected live viral vaccines after|
01437|011|E|immunoglobulins may impair the efficacy of the vaccine.(1-19)|
01437|012|E|   Administration of immunoglobulins within 2-4 weeks after selected live|
01437|013|E|viral vaccines impair the efficacy of the vaccine.(1-4,15)|
01437|014|B||
01437|015|P|PREDISPOSING FACTORS:  The amount of antigen-specific antibody present in|
01437|016|P|the administered immunoglobulin product determines the duration of this|
01437|017|P|interaction.(15)|
01437|018|B||
01437|019|M|PATIENT MANAGEMENT:  The recommendations regarding this interaction are|
01437|020|M|conflicting.|
01437|021|M|   The Centers for Disease Control and Prevention(CDC) immunization|
01437|022|M|recommendations for spacing of live vaccines and antibody-containing|
01437|023|M|products include the following(15):|
01437|024|M|   - Live attenuated influenza vaccine, rotavirus, zoster and Ty21a typhoid|
01437|025|M|vaccines may be given any time before, concurrent, with, or after|
01437|026|M|administration of any immune globulin. Yellow fever vaccine may also be|
01437|027|M|given in areas where donor blood products are unlikely to contain a|
01437|028|M|substantial quantity of yellow fever antibody.|
01437|029|M|   -  Administration of measles or varicella containing vaccines should be|
01437|030|M|postponed for the following intervals after immunoglobulin therapy:|
01437|031|M|      Hepatitis B IG, Tetanus IG - 3 months|
01437|032|M|      Rabies IG - 4 months|
01437|033|M|      Varicella IG - 5 months|
01437|034|M|      Measles prophylaxis IG - 6 months if nonimmunocompromised|
01437|035|M|      Botulinum IG Intravenous, CMV IG Intravenous, Hepatitis A IG - 6|
01437|036|M|months|
01437|037|M|      Intravenous Immune Globulin(IVIG) - 8 to 11 months depending|
01437|038|M|         upon the dose|
01437|039|M|      Monoclonal antibody to RSV F protein (palivizumab) - none|
01437|040|M|    - Administration of antibody-containing products should be delayed 2|
01437|041|M|weeks after administration of live vaccines, except for influenza,|
01437|042|M|rotavirus, zoster and typhoid vaccines as noted above.|
01437|043|M|   CDC guidelines state that in circumstances where there is high-risk of|
01437|044|M|vaccine-preventable disease, it is acceptable to administer a dose of|
01437|045|M|vaccine prior to completion of these intervals.(16)|
01437|046|M|   Manufacturer recommendations are as follows:|
01437|047|M|   Administration of a live viral vaccine should be postponed for at least|
01437|048|M|three months in patients who have received the following immunoglobulin|
01437|049|M|therapy: anthrax immunoglobulin,(19) cytomegalovirus immunoglobulin,(1)|
01437|050|M|hepatitis B immunoglobulin,(5,6) rabies immunoglobulin,(7) tetanus|
01437|051|M|immunoglobulin,(8-11) vaccinia immunoglobulin,(18) and zoster|
01437|052|M|immunoglobulin.(2)|
01437|053|M|   Administration of a live viral vaccine should be postponed for at least|
01437|054|M|six months in patients who have received the following immunoglobulin|
01437|055|M|therapy: botulinum neurotoxin a/b immune globulin.(17)|
01437|056|M|   The US manufacturer of human immunoglobulin states that live viral|
01437|057|M|vaccines should be postponed for three months in patients who have received|
01437|058|M|human immunoglobulin.  The Australian and Canadian manufacturers of human|
01437|059|M|immunoglobulin advise postponing live viral vaccines for 3-6 months in|
01437|060|M|patients who have received human immunoglobulin.(6,12,13,18) The UK|
01437|061|M|manufacturer states that vaccines may be compromised for one year and|
01437|062|M|vaccines should be postponed in children for at least seven months.(14)  The|
01437|063|M|US manufacturer of immune globulin-hyaluronidase states that immune response|
01437|064|M|to live attenuated vaccines may be impaired for up to 6 months, or for a|
01437|065|M|year or more in the case of measles vaccine.(15)|
01437|066|M|   Cytomegalovirus immunoglobulin(1) or human immunoglobulin(3) should not|
01437|067|M|be administered to patients who have received a live vaccine in the previous|
01437|068|M|two weeks.|
01437|069|M|   If a live viral vaccine is given within two weeks of zoster|
01437|070|M|immunoglobulin,(1) repetition of the vaccination three months after the|
01437|071|M|completion of immunoglobulin should be considered.|
01437|072|B||
01437|073|D|DISCUSSION:  CDC Immunization Recommendations(15)provide discussion, charts,|
01437|074|D|and further details regarding appropriate use and timing of vaccine|
01437|075|D|therapy.(16)|
01437|076|B||
01437|077|R|REFERENCES:|
01437|078|B||
01437|079|R|1.CMV immunoglobulin-VF Australian prescribing information. CSL May 13,|1
01437|080|R|  2005.|1
01437|081|R|2.Zoster Immunoglobulin-VF Australian prescribing information. CSL Behring|1
01437|082|R|  (Australia) Pty Ltd September 22, 2014.|1
01437|083|R|3.Normal immunoglobulin-VF Australian prescribing information. CSL August|1
01437|084|R|  10, 2006.|1
01437|085|R|4.RespiGam (respiratory syncytial virus) US prescribing information.|1
01437|086|R|  MedImmune, Inc. May, 2000.|1
01437|087|R|5.Hepatitis B immunoglobulin-VF Australian prescribing information. CSL July|1
01437|088|R|  25, 2006.|1
01437|089|R|6.HyperHEP B (hepatitis B immune globulin (human)) US prescribing|1
01437|090|R|  information. Talecris Biotherapeutics Inc. January, 2005.|1
01437|091|R|7.Human rabies immunoglobulin UK summary of product characteristics. Bio|1
01437|092|R|  Products laboratory August 3, 2004.|1
01437|093|R|8.BatTet (human tetatus immune globulin) US prescribing information. Bayer|1
01437|094|R|  Corporation March, 2004.|1
01437|095|R|9.Tetanus immunoglobulin Australian prescribing information. CSL July 25,|1
01437|096|R|  2006.|1
01437|097|R|10.Baytet (human tetanus immune globulin) Canadian prescribing information.|1
01437|098|R|   Bayer 2004.|1
01437|099|R|11.Human tetanus immunoglobulin UK summary of product characteristics. Bio|1
01437|100|R|   Products Laboratory August 3, 2004.|1
01437|101|R|12.BayGam (human immune globulin) US prescribing information. Bayer|1
01437|102|R|   Corporation January, 2003.|1
01437|103|R|13.Bayhep B (human hepatits B immune globulin) Canadian prescribing|1
01437|104|R|   information. Bayer 2004.|1
01437|105|R|14.Sandoglobulin NF (human normal immunoglobulin) UK summary of product|1
01437|106|R|   characteristics. CSL Behring UK Limited Februray 13, 2006.|1
01437|107|R|15.Hyqvia (Immune Globulin 10% with Recombinant Hyaluronidase) Solution|1
01437|108|R|   Prescribing Information. Baxter Healthcare Corporation September, 2014.|1
01437|109|R|16.Centers for Disease Control and Prevention. General Recommendations on|1
01437|110|R|   Immunization.  Recommendations of the Advisory Committee on Immunization|1
01437|111|R|   Practices (ACIP). MMWR.  Available at:|1
01437|112|R|   https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
01437|113|R|   February 17, 2022;60(RR No.2):1-68.|1
01437|114|R|17.Babybig (botulinum neurotoxin a/b immune globulin) US prescribing|1
01437|115|R|   information. California Department of Public Health June, 2021.|1
01437|116|R|18.Vigiv (vaccinia immune globulin intravenous, human) US prescribing|1
01437|117|R|   information. Emergent BioSolutions Canada Inc. November, 2018.|1
01437|118|R|19.Anthrasil (anthrax immune globulin human liquid) US prescribing|1
01437|119|R|   information. Emergent BioSolutions Canada Inc. May, 2018.|1
01438|001|T|MONOGRAPH TITLE:  Alosetron/Selected Dual CYP1A2 and CYP3A4 Inhibitors|
01438|002|B||
01438|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01438|004|L|is contraindicated and generally should not be dispensed or administered to|
01438|005|L|the same patient.|
01438|006|B||
01438|007|A|MECHANISM OF ACTION:  Dual inhibitors of CYP1A2 and CYP3A4 may inhibit the|
01438|008|A|metabolism of alosetron.(1,2)|
01438|009|B||
01438|010|E|CLINICAL EFFECTS:  Concurrent administration with dual CYP1A2 and CYP3A4|
01438|011|E|inhibitors may result in 6-fold increases in alosetron levels and|
01438|012|E|toxicity.(1,2)|
01438|013|B||
01438|014|P|PREDISPOSING FACTORS:  None determined.|
01438|015|B||
01438|016|M|PATIENT MANAGEMENT:  The manufacturers of alosetron states that concurrent|
01438|017|M|use is contraindicated.(1)|
01438|018|B||
01438|019|D|DISCUSSION:  In a study in 40 healthy females, pretreatment with fluvoxamine|
01438|020|D|(escalating doses from 50 mg to 200 mg daily for 16 days) increased the|
01438|021|D|area-under-curve (AUC) and half-life of alosetron by 6-fold and 3-fold,|
01438|022|D|respectively.(1,2)|
01438|023|D|   Selected dual CYP1A2 and CYP3A4 inhibitors linked include: enasidenib and|
01438|024|D|fluvoxamine.(3,4)|
01438|025|B||
01438|026|R|REFERENCES:|
01438|027|B||
01438|028|R|1.Lotronex (alosetron hydrochloride) US prescribing information. Prometheus|1
01438|029|R|  Labs April, 2019.|1
01438|030|R|2.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
01438|031|R|  Pharmaceuticals, Inc. August, 2023.|1
01438|032|R|3.This information is based on an extract from the Certara Drug Interaction|6
01438|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01438|034|R|4.Idhifa (enasidenib) US prescribing information. Celgene Corporation|1
01438|035|R|  November, 2020.|1
01439|001|T|MONOGRAPH TITLE:  Exemestane/Strong CYP3A4 Inducers|
01439|002|B||
01439|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01439|004|L|of severe adverse interaction.|
01439|005|B||
01439|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
01439|007|A|exemestane.(1)|
01439|008|B||
01439|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer may result in|
01439|010|E|decreased levels and effectiveness of exemestane.(1)|
01439|011|B||
01439|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01439|013|P|of the inducer for longer than 1-2 weeks.|
01439|014|B||
01439|015|M|PATIENT MANAGEMENT:  The US manufacturer of exemestane recommends that|
01439|016|M|patients receiving concurrent therapy with a strong CYP3A4 inducer receive|
01439|017|M|50 mg of exemestane daily after a meal.(1)  The dosage of exemestane may|
01439|018|M|need to be adjusted if the inducer is discontinued.|
01439|019|B||
01439|020|D|DISCUSSION:  In a study in 10 healthy postmenopausal subjects, pretreatment|
01439|021|D|with rifampin (600 mg daily for 14 days) decreased the area-under-curve|
01439|022|D|(AUC) and maximum concentration (Cmax) of a single dose of exemestane (25|
01439|023|D|mg) by 54% and 41%, respectively.(1)|
01439|024|D|   Strong inducers of CYP3A4 would be expected to decrease the AUC of a|
01439|025|D|sensitive 3A4 substrate by 80% or more and include:  apalutamide,|
01439|026|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
01439|027|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
01439|028|D|rifampin, rifapentine and St. John's wort.(1-3)|
01439|029|D|   Moderate inducers of CYP3A4 would be expected to decrease the AUC of a|
01439|030|D|sensitive 3A4 substrate by 50-80% and include:  bosentan, efavirenz,|
01439|031|D|etravirine, modafinil, nafcillin, rifabutin, and thioridazine.(2,3)|
01439|032|D|   Weak inducers of CYP3A4 would be expected to decrease the AUC of a|
01439|033|D|sensitive 3A4 substrate by 20-50% and include:  aprepitant, armodafinil,|
01439|034|D|bexarotene, boceprevir, clobazam, danshen, dexamethasone, echinacea, garlic,|
01439|035|D|gingko, ginseng, glycyrrhizin, nevirapine, oxcarbazepine, pioglitazone,|
01439|036|D|prednisone, quercetin, raltegravir, rufinamide, sorafenib, sulfinpyrazone,|
01439|037|D|telaprevir, terbinafine, ticagrelor, ticlopidine, vemurafenib, and|
01439|038|D|vinblastine.(2,3)|
01439|039|B||
01439|040|R|REFERENCES:|
01439|041|B||
01439|042|R|1.Aromasin (exemestane) US prescribing information. Pharmacia & Upjohn|1
01439|043|R|  Company July, 2016.|1
01439|044|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
01439|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01439|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01439|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01439|048|R|  11/14/2017.|1
01439|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
01439|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01440|001|T|MONOGRAPH TITLE:  Exemestane/Selected Anticonvulsants (mono deleted|
01440|002|T|07/31/2014)|
01440|003|B||
01440|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01440|005|L|take action as needed.|
01440|006|B||
01440|007|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital, and phenytoin may induce|
01440|008|A|the metabolism of exemestane by CYP P-450-3A4.(1)|
01440|009|B||
01440|010|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, phenobarbital, or|
01440|011|E|phenytoin may result in decreased levels and effectiveness of exemestane.(1)|
01440|012|B||
01440|013|P|PREDISPOSING FACTORS:  None determined.|
01440|014|B||
01440|015|M|PATIENT MANAGEMENT:  The US manufacturer of exemestane recommends that|
01440|016|M|patients receiving concurrent therapy with a potent CYP P-450-3A4 inducer|
01440|017|M|such as carbamazepine, phenobarbital, or phenytoin receive 50 mg of|
01440|018|M|exemestane daily after a meal.(1)  The dosage of exemestane may need to be|
01440|019|M|adjusted if carbamazepine, phenobarbital, or phenytoin is discontinued.|
01440|020|B||
01440|021|D|DISCUSSION:  In a study in 10 healthy postmenopausal subjects, pretreatment|
01440|022|D|with rifampin (600 mg daily for 14 days), another inducer of CYP P-450-3A4,|
01440|023|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a|
01440|024|D|single dose of exemestane (25 mg) by 54% and 41%, respectively.(1)|
01440|025|B||
01440|026|R|REFERENCE:|
01440|027|B||
01440|028|R|1.Aromasin (exemestane) US prescribing information. Pharmacia & Upjohn|1
01440|029|R|  Company July, 2016.|1
01441|001|T|MONOGRAPH TITLE:  Exemestane/St. John's Wort (mono deleted 07/31/2014)|
01441|002|B||
01441|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01441|004|L|take action as needed.|
01441|005|B||
01441|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01441|007|A|exemestane by CYP P-450-3A4.(1)|
01441|008|B||
01441|009|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
01441|010|E|levels and effectiveness of exemestane.(1)|
01441|011|B||
01441|012|P|PREDISPOSING FACTORS:  None determined.|
01441|013|B||
01441|014|M|PATIENT MANAGEMENT:  The US manufacturer of exemestane recommends that|
01441|015|M|patients receiving concurrent therapy with a potent CYP P-450-3A4 inducer|
01441|016|M|such as St. John's wort receive 50 mg of exemestane daily after a meal.(1)|
01441|017|M|The dosage of exemestane may need to be adjusted if St. John's wort is is|
01441|018|M|discontinued.|
01441|019|B||
01441|020|D|DISCUSSION:  In a study in 10 healthy postmenopausal subjects, pretreatment|
01441|021|D|with rifampin (600 mg daily for 14 days), another inducer of CYP P-450-3A4,|
01441|022|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a|
01441|023|D|single dose of exemestane (25 mg) by 54% and 41%, respectively.(1)|
01441|024|B||
01441|025|R|REFERENCE:|
01441|026|B||
01441|027|R|1.Aromasin (exemestane) US prescribing information. Pharmacia & Upjohn|1
01441|028|R|  Company July, 2016.|1
01442|001|T|MONOGRAPH TITLE:  Selected Antidiabetic Agents/Selected Quinolones|
01442|002|B||
01442|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01442|004|L|take action as needed.|
01442|005|B||
01442|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01442|007|B||
01442|008|E|CLINICAL EFFECTS:  Concurrent use of quinolones and antidiabetic agents may|
01442|009|E|result in severe hypoglycemia.(1-7) Hypoglycemia can lead to coma.|
01442|010|B||
01442|011|P|PREDISPOSING FACTORS:  Elderly patients, especially those with decreased|
01442|012|P|renal function may be predisposed to this interaction.(5)|
01442|013|B||
01442|014|M|PATIENT MANAGEMENT:  Patients maintained on antidiabetic agents who require|
01442|015|M|concurrent therapy with a quinolone should be closely monitored for|
01442|016|M|hypoglycemia.(1-4)  Patients should be instructed to discontinue quinolone|
01442|017|M|use and contact their doctor if hypoglycemia occurs.(2,4)|
01442|018|M|   Signs of hypoglycemia may include confusion, dizziness, feeling shaky,|
01442|019|M|unusual hunger, headaches, irritability, pounding heart or very fast pulse,|
01442|020|M|pale skin, sweating, trembling, weakness, or unusual anxiety.|
01442|021|B||
01442|022|D|DISCUSSION:  Hypoglycemia has been reported with concurrent ciprofloxacin|
01442|023|D|and glyburide,(1,8,9) levofloxacin and glyburide,(2,10,11) norfloxacin and|
01442|024|D|glyburide,(3) levofloxacin and glipizide (12) as well as levofloxacin and|
01442|025|D|metformin-glibenclamide.(14)  There has been one report of fatal|
01442|026|D|hypoglycemia with concurrent levofloxacin and glyburide(9) and one of the|
01442|027|D|above reports of hypoglycemia with concurrent levofloxacin and glyburide|
01442|028|D|resulted in hypoxic brain injury.(11)|
01442|029|D|   A review of postmarketing adverse event data for the fluoroquinolones and|
01442|030|D|hypoglycemic coma identified 56 reports in FAERS search from October 1987-|
01442|031|D|April 2017 and 11 additional cases in the medical literature. Most patients|
01442|032|D|had risk factors for hypoglycemia. 41 patients were taking one or more|
01442|033|D|hypoglycemic drugs. 13 deaths occurred (some of these patients had renal|
01442|034|D|insufficiency). 9 patients did not fully recover and had resultant|
01442|035|D|disability.(13)|
01442|036|B||
01442|037|R|REFERENCES:|
01442|038|B||
01442|039|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
01442|040|R|  Corporation March, 2022.|1
01442|041|R|2.Levaquin (levofloxacin) US prescribing information. Janssen|1
01442|042|R|  Pharmaceuticals, Inc. October 18, 2018.|1
01442|043|R|3.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
01442|044|R|  2016.|1
01442|045|R|4.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
01442|046|R|  Pharmaceutical, Inc. February, 2011.|1
01442|047|R|5.Dear Canadian Healthcare Professional letter:  Subject:  Updated safety|1
01442|048|R|  information for TEQUIN (gatifloxacin) and serious hypoglycemia and|1
01442|049|R|  hyperglycemia. Bristol-Myers Squibb Canada May 12, 2006.|1
01442|050|R|6.Letourneau G, Morrison B, McMorran M. Gatifloxacin (Tequin):  hypoglycemia|1
01442|051|R|  and hyperglycemia. Canadian Adverse Reaction Newsletter 2003 Jul;|1
01442|052|R|  13(2):1-2.|1
01442|053|R|7.Lewis-Hall F. Dear Healthcare Provider letter. Bristol-Myers Squibb|1
01442|054|R|  February 15, 2006.|1
01442|055|R|8.Roberge RJ, Kaplan R, Frank R, Fore C. Glyburide-ciprofloxacin interaction|3
01442|056|R|  with resistant hypoglycemia. Ann Emerg Med 2000 Aug;36(2):160-3.|3
01442|057|R|9.Lin G, Hays DP, Spillane L. Refractory hypoglycemia from ciprofloxacin and|3
01442|058|R|  glyburide interaction. J Toxicol Clin Toxicol 2004;42(3):295-7.|3
01442|059|R|10.Friedrich LV, Dougherty R. Fatal hypoglycemia associated with|3
01442|060|R|   levofloxacin. Pharmacotherapy 2004 Dec;24(12):1807-12.|3
01442|061|R|11.Lawrence KR, Adra M, Keir C. Hypoglycemia-induced anoxic brain injury|3
01442|062|R|   possibly associated with levofloxacin. J Infect 2006 Jun;52(6):e177-80.|3
01442|063|R|12.Garber SM, Pound MW, Miller SM. Hypoglycemia associated with the use of|3
01442|064|R|   levofloxacin. Am J Health Syst Pharm 2009 Jun 1;66(11):1014-9.|3
01442|065|R|13.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
01442|066|R|   reinforces safety information about serious low blood sugar levels and|1
01442|067|R|   mental health side effects with fluoroquinolone antibiotics; requires|1
01442|068|R|   label changes. available at:|1
01442|069|R|   https://www.fda.gov/Drugs/DrugSafety/ucm611032.htm?utm_campaign=New%20FDA|1
01442|070|R|   %20Drug%20Safety%20Communication%20for%20fluoroquinolone%20antibiotics-%2|1
01442|071|R|   0Drug%20Information%20Update&utm_medium=email&utm_source=Eloqua July 10,|1
01442|072|R|   2018.|1
01442|073|R|14.Micheli L, Sbrilli M, Nencini C. Severe hypoglycemia associated with|3
01442|074|R|   levofloxacin in Type 2 diabetic patients receiving polytherapy: two case|3
01442|075|R|   reports. Int J Clin Pharmacol Ther 2012 Apr;50(4):302-6.|3
01443|001|T|MONOGRAPH TITLE:  Quinolones/Corticosteroids|
01443|002|B||
01443|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01443|004|L|take action as needed.|
01443|005|B||
01443|006|A|MECHANISM OF ACTION:  Quinolone-induced arthropathy is a class effect of the|
01443|007|A|quinolones.(1)  Exactly how corticosteroid use increases the risk of tendon|
01443|008|A|rupture is unknown.|
01443|009|B||
01443|010|E|CLINICAL EFFECTS:  Concurrent use of quinolones and corticosteroids may|
01443|011|E|increase the risk of tendonitis and/or tendon rupture.  This affect is most|
01443|012|E|common in the Achilles tendon, but has been reported in the rotator cuff|
01443|013|E|(shoulder), hand, biceps, thumb, and other tendons.(2-9)|
01443|014|B||
01443|015|P|PREDISPOSING FACTORS:  Risk factors for tendinitis and tendon rupture|
01443|016|P|include age greater than 60; a history of kidney, heart, or lung|
01443|017|P|transplantation, strenuous physical activity, renal failure, and previous|
01443|018|P|tendon disorders such as rheumatoid arthritis.|
01443|019|B||
01443|020|M|PATIENT MANAGEMENT:  Quinolone use should be discontinued if the patient|
01443|021|M|experiences pain, inflammation, or rupture of a tendon.  Patients should be|
01443|022|M|instructed to rest and refrain from exercise until the diagnosis of|
01443|023|M|tendonitis tendon rupture has been excluded.(2-9)|
01443|024|B||
01443|025|D|DISCUSSION:  Ruptures of the shoulder, hand, Achilles tendon, or other|
01443|026|D|tendons that required surgical repair or resulted in prolonged disability|
01443|027|D|have been reported in patients receiving ciprofloxacin,(2) gatifloxacin,(3)|
01443|028|D|levofloxacin,(4) lomefloxacin,(5) moxifloxacin,(6) nalidixic acid,(7)|
01443|029|D|norfloxacin,(8) and ofloxacin.(9)|
01443|030|D|   A retrospective review of the IMS Health database examined quinolone use|
01443|031|D|use from July 1, 1992 to June 30, 1998.  The adjusted relative risk of|
01443|032|D|tendon disorder with concurrent quinolone use was 1.9.  Relative risk|
01443|033|D|increased to 3.2 in patients aged 60 or older compared to 0.9 in patients|
01443|034|D|aged less than 60.  In patients aged 60 or older who used corticosteroids|
01443|035|D|and quinolones concurrently, relative risk increased to 6.2.(10)|
01443|036|D|   In contrast, another retrospective review examined patients from a health|
01443|037|D|insurance claims database and found no apparent effect from concurrent|
01443|038|D|quinolone and corticosteroid use.(11)|
01443|039|D|   In a review of the follow-up to 42 spontaneously reported case of|
01443|040|D|quinolone-associated tendon disorders in the Netherlands between January,|
01443|041|D|1988 and January, 1998, risk factors for tendon disorders included age older|
01443|042|D|than 60, oral corticosteroid use, and existing joint problems.(12)|
01443|043|D|   In a review of the Swiss Drug Monitoring system, four of seven cases of|
01443|044|D|levofloxacin-associated tendon problems also involved concurrent oral or|
01443|045|D|inhaled corticosteroids.(13)|
01443|046|D|   In a review of the Medline database from 1966-2001, 98 case reports of|
01443|047|D|tendinopathy associated with quinolones were located.  Thirty-two (32.7%) of|
01443|048|D|the patients had received systemic or inhaled corticosteroids before and|
01443|049|D|during quinolone therapy.  Of the 40 patients who suffered a tendon rupture,|
01443|050|D|21 (52.5%) were receiving corticosteroids.(14)|
01443|051|D|   Other authors have reported cases of tendon disorders in patients|
01443|052|D|receiving concurrent corticosteroids and ciprofloxacin,(15) levofloxacin,|
01443|053|D|(16-20) and ofloxacin.(21)|
01443|054|B||
01443|055|R|REFERENCES:|
01443|056|B||
01443|057|R|1.Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: a review focusing|6
01443|058|R|  on newer agents. Clin Infect Dis 1999 Feb;28(2):352-64.|6
01443|059|R|2.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
01443|060|R|  Corporation March, 2022.|1
01443|061|R|3.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
01443|062|R|  Company January, 2006.|1
01443|063|R|4.Levaquin (levofloxacin) US prescribing information. Janssen|1
01443|064|R|  Pharmaceuticals, Inc. October 18, 2018.|1
01443|065|R|5.Maxaquin (lomefloxacin hydrochloride) US prescribing information. Pfizer|1
01443|066|R|  Inc. January, 2005.|1
01443|067|R|6.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
01443|068|R|  Pharmaceuticals Corporation October 18, 2018.|1
01443|069|R|7.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
01443|070|R|  Inc. November, 2012.|1
01443|071|R|8.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
01443|072|R|  2016.|1
01443|073|R|9.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
01443|074|R|  Pharmaceutical, Inc. February, 2011.|1
01443|075|R|10.van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HG, Stricker BH.|2
01443|076|R|   Fluoroquinolones and risk of Achilles tendon disorders: case-control|2
01443|077|R|   study. BMJ 2002 Jun 1;324(7349):1306-7.|2
01443|078|R|11.Seeger JD, West WA, Fife D, et al. A case-controlled study describing the|4
01443|079|R|   epidemiology of Achilles tendon rupture with a focus on fluroquinolone|4
01443|080|R|   antibiotics. Abstract #A-519. 43rd Interscience Conference on|4
01443|081|R|   Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, IL September 17,|4
01443|082|R|   2003.|4
01443|083|R|12.van der Linden PD, van Puijenbroek EP, Feenstra J, Veld BA, Sturkenboom|3
01443|084|R|   MC, Herings RM, Leufkens HG, Stricker BH. Tendon disorders attributed to|3
01443|085|R|   fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to|3
01443|086|R|   1998. Arthritis Rheum 2001 Jun;45(3):235-9.|3
01443|087|R|13.Fleisch F, Hartmann K, Kuhn M. Fluoroquinolone-induced tendinopathy: also|3
01443|088|R|   occurring with levofloxacin. Infection 2000 Jul-Aug;28(4):256-7.|3
01443|089|R|14.Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical|6
01443|090|R|   review of the literature. Clin Infect Dis 2003 Jun 1;36(11):1404-10.|6
01443|091|R|15.Chhajed PN, Plit ML, Hopkins PM, Malouf MA, Glanville AR. Achilles tendon|2
01443|092|R|   disease in lung transplant recipients: association with ciprofloxacin.|2
01443|093|R|   Eur Respir J 2002 Mar;19(3):469-71.|2
01443|094|R|16.Filippucci E, Farina A, Bartolucci F, Spallacci C, Busilacchi P, Grassi|3
01443|095|R|   W. Levofloxacin-induced bilateral rupture of the Achilles tendon:|3
01443|096|R|   clinical and sonographic findings. Reumatismo 2003 Oct-Dec;55(4):267-9.|3
01443|097|R|17.Mathis AS, Chan V, Gryszkiewicz M, Adamson RT, Friedman GS.|3
01443|098|R|   Levofloxacin-associated Achilles tendon rupture. Ann Pharmacother 2003|3
01443|099|R|   Jul-Aug;37(7-8):1014-7.|3
01443|100|R|18.Butler MW, Griffin JF, Quinlan WR, McDonnell TJ. Quinolone-associated|3
01443|101|R|   tendonitis: a potential problem in COPD?. Ir J Med Sci 2001 Jul-Sep;|3
01443|102|R|   170(3):198-9.|3
01443|103|R|19.Haddow LJ, Chandra Sekhar M, Hajela V, Gopal Rao G. Spontaneous Achilles|3
01443|104|R|   tendon rupture in patients treated with levofloxacin. J Antimicrob|3
01443|105|R|   Chemother 2003 Mar;51(3):747-8.|3
01443|106|R|20.Cebrian P, Manjon P, Caba P. Ultrasonography of non-traumatic rupture of|3
01443|107|R|   the Achilles tendon secondary to levofloxacin. Foot Ankle Int 2003 Feb;|3
01443|108|R|   24(2):122-4.|3
01443|109|R|21.Schwald N, Debray-Meignan S. Suspected role of ofloxacin in a case of|3
01443|110|R|   arthalgia, myalgia, and multiple tendinopathy. Rev Rhum Engl Ed 1999|3
01443|111|R|   Jul-Sep;66(7-9):419-21.|3
01443|112|R|22.European Medicines Agency Science Medicines Health. Disabling and|6
01443|113|R|   potentially permanenet side effects lead to suspension or restrictions of|6
01443|114|R|   quinolone and fluoroquinolone antibiotics. available at:|6
01443|115|R|   https://www.ema.europa.eu/en/news/disabling-potentially-permanent-side-ef|6
01443|116|R|   fects-lead-suspension-restrictions-quinolone-fluoroquinolone November 11,|6
01443|117|R|   2018.|6
01444|001|T|MONOGRAPH TITLE:  Selected Quinolones/Class IA & III Antiarrhythmics|
01444|002|B||
01444|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01444|004|L|of severe adverse interaction.|
01444|005|B||
01444|006|A|MECHANISM OF ACTION:  Unknown.  Possibly additive or synergistic effects on|
01444|007|A|the QTc interval.  Proposed mechanisms for this interaction may stem from|
01444|008|A|quinolone inhibition of hepatic cytochromes and/or competitive inhibition of|
01444|009|A|renal elimination via active tubular secretion. Ciprofloxacin and|
01444|010|A|norfloxacin are moderate inhibitors of CYP3A4. Quinidine is metabolized by|
01444|011|A|CYP3A4.|
01444|012|B||
01444|013|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in potentially|
01444|014|E|life-threatening arrhythmias such as torsades de pointes.|
01444|015|B||
01444|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01444|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
01444|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01444|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01444|020|P|female gender, or advanced age.(15)|
01444|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01444|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01444|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01444|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01444|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01444|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01444|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(15)|
01444|028|B||
01444|029|M|PATIENT MANAGEMENT:  The manufacturers of ciprofloxacin,(1) gatifloxacin,(2)|
01444|030|M|gemifloxacin,(3) levofloxacin,(4) lomefloxacin,(5), moxifloxacin,(6)|
01444|031|M|nalidixic acid,(7) norfloxacin(8) and ofloxacin(9) state that these agents|
01444|032|M|should be avoided in patients receiving Class IA and III antiarrhythmic|
01444|033|M|agents.|
01444|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01444|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01444|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01444|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01444|038|B||
01444|039|D|DISCUSSION:  Ciprofloxacin,(1) gatifloxacin,(2) gemifloxacin,(3)|
01444|040|D|levofloxacin,(4) lomefloxacin,(5), moxifloxacin,(6) nalidixic acid,(7)|
01444|041|D|norfloxacin(8) and ofloxacin(9) have the potential to prolong the QTc|
01444|042|D|interval.|
01444|043|D|   Torsades de pointes has been reported during post-marketing surveillance|
01444|044|D|in patients receiving lomefloxacin.(5)|
01444|045|D|   There are reports of prolonged QTc intervals with levofloxacin and|
01444|046|D|amiodarone(9) and ciprofloxacin(11) with amiodarone or sotalol.  However, a|
01444|047|D|randomized, crossover study evaluated seven healthy males in which quinidine|
01444|048|D|sulfate (400 mg) were administered alone then crossed over with|
01444|049|D|ciprofloxacin (750 mg b.i.d. for 5 days) pretreatment.  No significant|
01444|050|D|significant differences were found in the quinidine clearance, half-life, or|
01444|051|D|or Cmax or in QRS or QTc prolongation.(10)|
01444|052|D|   Another randomized, crossover study was conducted to determine|
01444|053|D|pharmacokinetic interactions between levofloxacin plus procainamide and|
01444|054|D|ciprofloxacin with procainamide.  Levofloxacin significantly decreased renal|
01444|055|D|clearance and the renal clearance/creatinine clearance ratios of|
01444|056|D|procainamide and N-acetylprocainamide (NAPA), the major metabolite of|
01444|057|D|procainamide; however, ciprofloxacin only changed the renal clearance of|
01444|058|D|procainamide and NAPA.(13)|
01444|059|D|   A pharmacokinetic and pharmacodynamic study evaluated the interaction|
01444|060|D|between ofloxacin and procainamide.  Nine healthy volunteers randomly|
01444|061|D|received one dose of procainamide 1 G, including or excluding pretreatment|
01444|062|D|with ofloxacin (400 mg b.i.d. for 5 doses).  A 12-point EKG monitored for|
01444|063|D|any pharmacodynamic abnormalities and blood urine samples evaluated for|
01444|064|D|pharmacokinetic variations.  The AUC and Cmax for procainamide were|
01444|065|D|increased by 27% and 21% with clearance diminished by 22%.(14)|
01444|066|D|   One or more of the drug pairs linked to this monograph have been included|
01444|067|D|in a list of interactions that should be considered "high-priority" for|
01444|068|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01444|069|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01444|070|D|Coordinator (ONC) for Health Information Technology.|
01444|071|B||
01444|072|R|REFERENCES:|
01444|073|B||
01444|074|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
01444|075|R|  Corporation March, 2022.|1
01444|076|R|2.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
01444|077|R|  Company January, 2006.|1
01444|078|R|3.Factive (gemifloxacin mesylate) US prescribing information. Merus Labs|1
01444|079|R|  International, Inc. October, 2018.|1
01444|080|R|4.Levaquin (levofloxacin) US prescribing information. Janssen|1
01444|081|R|  Pharmaceuticals, Inc. October 18, 2018.|1
01444|082|R|5.Maxaquin (lomefloxacin hydrochloride) US prescribing information. Pfizer|1
01444|083|R|  Inc. January, 2005.|1
01444|084|R|6.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
01444|085|R|  Pharmaceuticals Corporation October 18, 2018.|1
01444|086|R|7.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
01444|087|R|  Inc. November, 2012.|1
01444|088|R|8.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
01444|089|R|  2016.|1
01444|090|R|9.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
01444|091|R|  Pharmaceutical, Inc. February, 2011.|1
01444|092|R|10.Maxa JL, Hebeler RF, Adeeko MA. Torsades de pointes following concurrent|3
01444|093|R|   amiodarone and levofloxacin therapy. Proc (Bayl Univ Med Cent) 2006 Oct;|3
01444|094|R|   19(4):345-6.|3
01444|095|R|11.Prabhakar M, Krahn AD. Ciprofloxacin-induced acquired long QT syndrome.|3
01444|096|R|   Heart Rhythm 2004 Nov;1(5):624-6.|3
01444|097|R|12.Bleske BE, Carver PL, Annesley TM, Bleske JR, Morady F. The effect of|2
01444|098|R|   ciprofloxacin on the pharmacokinetic and ECG parameters of quinidine. J|2
01444|099|R|   Clin Pharmacol 1990 Oct;30(10):911-5.|2
01444|100|R|13.Bauer LA, Black DJ, Lill JS, Garrison J, Raisys VA, Hooton TM.|2
01444|101|R|   Levofloxacin and ciprofloxacin decrease procainamide and|2
01444|102|R|   N-acetylprocainamide renal clearances. Antimicrob Agents Chemother 2005|2
01444|103|R|   Apr;49(4):1649-51.|2
01444|104|R|14.Martin DE, Shen J, Griener J, Raasch R, Patterson JH, Cascio W. Effects|2
01444|105|R|   of ofloxacin on the pharmacokinetics and pharmacodynamics of|2
01444|106|R|   procainamide. J Clin Pharmacol 1996 Jan;36(1):85-91.|2
01444|107|R|15.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
01444|108|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
01444|109|R|   hospital settings: a scientific statement from the American Heart|6
01444|110|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
01444|111|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
01444|112|R|16.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01444|113|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01444|114|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01444|115|R|   19(5):735-43.|6
01445|001|T|MONOGRAPH TITLE:  Lomefloxacin/QT Prolongating Agents  (mono deleted|
01445|002|T|06/30/2005)|
01445|003|B||
01445|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01445|005|L|take action as needed.|
01445|006|B||
01445|007|A|MECHANISM OF ACTION:  Torsades de pointes has been reported with|
01445|008|A|lomefloxacin.  Concurrent use with other agents that prolong the QTc|
01445|009|A|interval may result in additive effects on the QTc interval.(1)|
01445|010|B||
01445|011|E|CLINICAL EFFECTS:  The concurrent use of lomefloxacin with other agents that|
01445|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01445|013|E|arrhythmias, including torsades de pointes.(1)|
01445|014|B||
01445|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by|
01445|016|P|cardiovascular disease, hypokalemia, hypomagnesemia, bradycardia, age,|
01445|017|P|female gender, and/or use of multiple medications.|
01445|018|B||
01445|019|M|PATIENT MANAGEMENT:  The manufacturer of lomefloxacin states that|
01445|020|M|lomefloxacin should be used with caution when given with other agents known|
01445|021|M|to prolong the QT interval.(1)|
01445|022|B||
01445|023|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01445|024|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01445|025|D|monograph have been shown to prolong the QTc interval either through their|
01445|026|D|mechanism of action, through studies on their effects on the QTc interval,|
01445|027|D|or through reports of QTc prolongation and/or torsades de pointes in|
01445|028|D|clinical trials and/or postmarketing reports.(2)|
01445|029|B||
01445|030|R|REFERENCES:|
01445|031|B||
01445|032|R|1.Maxaquin (lomefloxacin hydrochloride) US prescribing information. Pfizer|1
01445|033|R|  Inc. March, 2004.|1
01445|034|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01445|035|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01445|036|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01445|037|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01446|001|T|MONOGRAPH TITLE:  Metformin/MATE Inhibitors|
01446|002|B||
01446|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01446|004|L|take action as needed.|
01446|005|B||
01446|006|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
01446|007|A|protein transporters in the kidneys may interfere with the renal tubular|
01446|008|A|secretion of metformin.(1)|
01446|009|B||
01446|010|E|CLINICAL EFFECTS:  Concurrent use may result in increased plasma levels of|
01446|011|E|metformin and toxicity such as lactic acidosis.  Untreated lactic acidosis|
01446|012|E|may be fatal. Symptoms of lactic acidosis include malaise, myalgias,|
01446|013|E|respiratory distress, low pH, increased anion gap and elevated blood|
01446|014|E|lactate.|
01446|015|B||
01446|016|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
01446|017|P|include renal impairment,sepsis, dehydration, excessive alcohol intake,|
01446|018|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
01446|019|P|failure, metformin plasma levels > 5 micrograms/mL, and conditions which may|
01446|020|P|lead to tissue hypoxia.  Geriatric patients may also be at higher risk due|
01446|021|P|to slower metformin clearance and increased half-life in this population.|
01446|022|P|   The risk for metabolic acidosis is higher with increased doses of either|
01446|023|P|agent.|
01446|024|B||
01446|025|M|PATIENT MANAGEMENT:  Use an alternative agent if possible.|
01446|026|M|   If both drugs are given, monitor patient's renal function and for signs|
01446|027|M|and symptoms of metformin toxicity (lactic acidosis) such as malaise,|
01446|028|M|myalgias, respiratory distress, increasing somnolence, and respiratory|
01446|029|M|distress. Laboratory results which may signal lactic acidosis include: low|
01446|030|M|pH, an increased anion gap, and increased lactate to pyruvate ratio.  Dosage|
01446|031|M|of either agent may need to be adjusted.(1)|
01446|032|B||
01446|033|D|DISCUSSION:  In a study of normal healthy volunteers, concurrent metformin|
01446|034|D|and oral cimetidine increased metformin maximum concentration (Cmax) in|
01446|035|D|plasma and whole blood by 60% and increased metformin area-under-curve (AUC)|
01446|036|D|levels in plasma and whole blood by 40%.(1)|
01446|037|D|   In a study in 7 subjects, concurrent metformin (250 mg daily) with|
01446|038|D|cimetidine (400 mg twice daily) increased metformin AUC by 50%.  Metformin|
01446|039|D|renal clearance over 24 hours was reduced by 27%.(2)|
01446|040|D|   MATE inhibitors include: cimetidine, pyrimethamine, and risdiplam.(3)|
01446|041|B||
01446|042|R|REFERENCES:|
01446|043|B||
01446|044|R|1.Glucophage (metformin hydrochloride) US prescribing information.|1
01446|045|R|  Bristol-Myers Squibb Company May, 2018.|1
01446|046|R|2.Somogyi A, Stockley C, Keal J, Rolan P, Bochner F. Reduction of metformin|2
01446|047|R|  renal tubular secretion by cimetidine in man. Br J Clin Pharmacol 1987|2
01446|048|R|  May;23(5):545-51.|2
01446|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
01446|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01447|001|T|MONOGRAPH TITLE:  Methyldopa/MAOIs|
01447|002|B||
01447|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01447|004|L|is contraindicated and generally should not be dispensed or administered to|
01447|005|L|the same patient.|
01447|006|B||
01447|007|A|MECHANISM OF ACTION:  Monoamine oxidase inhibitors (MAOI's) may inhibit the|
01447|008|A|antihypertensive effects of methyldopa.(1)|
01447|009|B||
01447|010|E|CLINICAL EFFECTS:  Concurrent use of MAOI's and methyldopa may result in|
01447|011|E|hypertensive crisis(2) and/or hallucinations.(3)|
01447|012|B||
01447|013|P|PREDISPOSING FACTORS:  None determined.|
01447|014|B||
01447|015|M|PATIENT MANAGEMENT:  The Australian,(4) UK,(1) and US(5,6) manufacturers of|
01447|016|M|methyldopa state that concurrent use of MAOI's is contraindicated.  The US|
01447|017|M|manufacturer of phenelzine states that concurrent use of methyldopa is|
01447|018|M|contraindicated.(2)|
01447|019|B||
01447|020|D|DISCUSSION:  In a case report, a patient maintained on pargyline developed|
01447|021|D|hallucinations following the increase of her methyldopa from 250 mg daily to|
01447|022|D|250 mg twice daily.(2)|
01447|023|D|   Methylene blue, when administered intravenously, has been shown to reach|
01447|024|D|sufficient concentrations to be a potent inhibitor of MAO-A.(7,8)|
01447|025|D|   Metaxalone is a weak inhibitor of MAO.(9,10)|
01447|026|B||
01447|027|R|REFERENCES:|
01447|028|B||
01447|029|R|1.Aldomet (methyldopa) UK summary of product characteristics. Merck Sharp &|1
01447|030|R|  Dohme Limited August 16, 2001.|1
01447|031|R|2.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
01447|032|R|  2007.|1
01447|033|R|3.Paykel ES. Hallucinosis on combined methyldopa and pargyline. Br Med J|3
01447|034|R|  1966 Mar 26;5490:803.|3
01447|035|R|4.Hydopa (methyldopa) Australian prescribing information. Alphapharm March|1
01447|036|R|  12, 1999.|1
01447|037|R|5.Methyldopa US prescribing information. Mylan Pharmaceuticals Inc. October,|1
01447|038|R|  2012.|1
01447|039|R|6.Aldoril (methyldopa-hydrochlorothiazide) US prescribing information. Merck|1
01447|040|R|  & Co., Inc. February, 2004.|1
01447|041|R|7.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
01447|042|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
01447|043|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
01447|044|R|8.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
01447|045|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
01447|046|R|  2000 Jun;56(3):247-50.|2
01447|047|R|9.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
01447|048|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
01447|049|R|  Feb;34(2):346.e5-6.|3
01447|050|R|10.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
01447|051|R|   Pfizer Inc. January, 2024.|1
01448|001|T|MONOGRAPH TITLE:  Metformin/Cephalexin|
01448|002|B||
01448|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01448|004|L|take action as needed.|
01448|005|B||
01448|006|A|MECHANISM OF ACTION:  Cephalexin may inhibit the renal tubular secretion of|
01448|007|A|metformin.(1,2)|
01448|008|B||
01448|009|E|CLINICAL EFFECTS:  Concurrent use of cephalexin may result in increased|
01448|010|E|levels and clinical effects of metformin,(1,2) as well as an increased risk|
01448|011|E|of lactic acidosis.|
01448|012|B||
01448|013|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
01448|014|P|include renal impairment, sepsis, dehydration, excessive alcohol intake,|
01448|015|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
01448|016|P|failure, metformin plasma levels > 5 micrograms/mL, and conditions which may|
01448|017|P|lead to tissue hypoxia.  Geriatric patients may also be at higher risk due|
01448|018|P|to slower metformin clearance and increased half-life in this population.|
01448|019|B||
01448|020|M|PATIENT MANAGEMENT:  Patients maintained on metformin should be closely|
01448|021|M|monitored when cephalexin is initiated and discontinued.  The dosage of|
01448|022|M|metformin may need to be adjusted.(1)|
01448|023|B||
01448|024|D|DISCUSSION:  In a randomized, cross-over study in 12 healthy subjects,|
01448|025|D|concurrent metformin (500 mg) and cephalexin (500 mg) increased the maximum|
01448|026|D|concentration (Cmax) and area-under-curve (AUC) of metformin by 34% and 24%,|
01448|027|D|respectively.  Metformin renal clearance decreased by 14%.(1,2)|
01448|028|B||
01448|029|R|REFERENCES:|
01448|030|B||
01448|031|R|1.Keflex (cephalexin) US prescribing information. Advancis Pharmaceutical|1
01448|032|R|  Corporation December, 2018.|1
01448|033|R|2.Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C,|2
01448|034|R|  Madhusudan Rao Y. Effect of cephalexin on the pharmacokinetics of|2
01448|035|R|  metformin in healthy human volunteers. Drug Metabol Drug Interact 2002;|2
01448|036|R|  19(1):41-8.|2
01449|001|T|MONOGRAPH TITLE:  Sirolimus;Temsirolimus/Selected Calcium Channel Blockers|
01449|002|B||
01449|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01449|004|L|take action as needed.|
01449|005|B||
01449|006|A|MECHANISM OF ACTION:  Some calcium channel blockers may inhibit the|
01449|007|A|metabolism of sirolimus and temsirolimus by CYP3A4.(1-3)|
01449|008|B||
01449|009|E|CLINICAL EFFECTS:  Concurrent use of calcium channel blockers may result in|
01449|010|E|elevated levels of and side effects from sirolimus and temsirolimus.(1-3)|
01449|011|E|Concurrent sirolimus and verapamil may result in elevated levels of and|
01449|012|E|effects from verapamil.(1)  Sirolimus is the active metabolite of|
01449|013|E|temsirolimus,(3) therefore, temsirolimus should be expected to act in the|
01449|014|E|same manner as sirolimus.|
01449|015|B||
01449|016|P|PREDISPOSING FACTORS:  None determined.|
01449|017|B||
01449|018|M|PATIENT MANAGEMENT:  Patients maintained on sirolimus should be closely|
01449|019|M|monitored if calcium channel blockers such as diltiazem, nicardipine, or|
01449|020|M|verapamil are initiated or discontinued.  The dosage of sirolimus or|
01449|021|M|tacrolimus may need to be adjusted or the calcium channel blocker may need|
01449|022|M|to be discontinued.|
01449|023|M|   Patients receiving concurrent sirolimus and verapamil should be observed|
01449|024|M|for increased verapamil effects.|
01449|025|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
01449|026|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
01449|027|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
01449|028|M|inhibitors should be avoided.(4)|
01449|029|M|   Sirolimus is the active metabolite of temsirolimus,(3) therefore,|
01449|030|M|temsirolimus is expected to act in the same manner as sirolimus.|
01449|031|B||
01449|032|D|DISCUSSION:  In an open, randomized, cross-over trial in 18 healthy|
01449|033|D|subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10|
01449|034|D|mg) increased sirolimus area-under-curve (AUC) and maximum concentration|
01449|035|D|(Cmax) by 60% and by 43%, respectively.  Sirolimus apparent oral clearance|
01449|036|D|and volume of distribution decreased by 38% and 45%, respectively.  There|
01449|037|D|were no effects on diltiazem pharmacokinetics or pharmacodynamics.(1,2)|
01449|038|D|   In a study in 24 healthy subjects, concurrent single doses of nifedipine|
01449|039|D|(60 mg) and sirolimus (10 mg) had no effect on sirolimus levels.(1)|
01449|040|D|   Nicardipine may increase sirolimus levels.(1)|
01449|041|D|   In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with|
01449|042|D|verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold|
01449|043|D|and 2.3-fold, respectively.  The AUC and Cmax of the active S-enantiomer of|
01449|044|D|verapamil each increased by 1.5-fold.  Verapamil time to Cmax (Tmax) was|
01449|045|D|increased by 1.2 hours.(1)|
01449|046|D|   Sirolimus is the active metabolite of temsirolimus,(2) therefore,|
01449|047|D|temsirolimus is expected to act in the same manner as sirolimus.|
01449|048|D|   In a study in 25 healthy subjects, concurrent sirolimus with verapamil|
01449|049|D|increased sirolimus Cmax and AUC 130% and 120%, respectively.(5)|
01449|050|B||
01449|051|R|REFERENCES:|
01449|052|B||
01449|053|R|1.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
01449|054|R|  Aug, 2022.|1
01449|055|R|2.Bottiger Y, Sawe J, Brattstrom C, Tollemar J, Burke JT, Hass G, Zimmerman|2
01449|056|R|  JJ. Pharmacokinetic interaction between single oral doses of diltiazem and|2
01449|057|R|  sirolimus in healthy volunteers. Clin Pharmacol Ther 2001 Jan;69(1):32-40.|2
01449|058|R|3.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01449|059|R|  Inc. March, 2018.|1
01449|060|R|4.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
01449|061|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
01449|062|R|5.Covera-HS (verapamil hydrochloride) US prescribing information. G.D.|1
01449|063|R|  Searle LLC September, 2017.|1
01450|001|T|MONOGRAPH TITLE:  Estramustine/Oral Calcium Products|
01450|002|B||
01450|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01450|004|L|take action as needed.|
01450|005|B||
01450|006|A|MECHANISM OF ACTION:  Calcium may bind to estramustine in the|
01450|007|A|gastro-intestinal tract, preventing its absorption.(1-4)|
01450|008|B||
01450|009|E|CLINICAL EFFECTS:  Simultaneous administration of oral calcium products may|
01450|010|E|result in decreased levels and clinical effectiveness of estramustine.(1-4)|
01450|011|B||
01450|012|P|PREDISPOSING FACTORS:  None determined.|
01450|013|B||
01450|014|M|PATIENT MANAGEMENT:  The UK(1) and US(2) manufacturers of estramustine state|
01450|015|M|that calcium containing products should not be taken simultaneously with|
01450|016|M|estramustine.  One Australian manufacturer of calcium carbonate recommends|
01450|017|M|separating administration by at least 3 hours.(3)|
01450|018|B||
01450|019|D|DISCUSSION:  In a randomized, cross-over study in 6 patients, simultaneous|
01450|020|D|administration of estramustine (420 mg) with milk (200 ml containing 120 mg|
01450|021|D|calcium) decreased the area-under-curve (AUC) and maximum concentration|
01450|022|D|(Cmax) of estromustine (a metabolite of estramustine) by 59% and 68%,|
01450|023|D|respectively.  The AUC of estrone (another estramustine metabolite) was|
01450|024|D|decreased by 63%.(4)|
01450|025|B||
01450|026|R|REFERENCES:|
01450|027|B||
01450|028|R|1.Estracyt (estramustine phosphate) UK summary of product characteristics.|1
01450|029|R|  Pharmacia Limited June 3, 2004.|1
01450|030|R|2.Emcyt (estramustine phosphate sodium) US prescribing information.|1
01450|031|R|  Pharmacia March, 2003.|1
01450|032|R|3.Sandocal (calcium carbonate) Australian prescribing information. Novartis|1
01450|033|R|  Consumer Health July, 1998.|1
01450|034|R|4.Gunnarsson PO, Davidsson T, Andersson SB, Backman C, Johansson SA.|2
01450|035|R|  Impairment of estramustine phosphate absorption by concurrent intake of|2
01450|036|R|  milk and food. Eur J Clin Pharmacol 1990;38(2):189-93.|2
01451|001|T|MONOGRAPH TITLE:  Topical Collagenase; Papain/Topical Heavy Metals|
01451|002|B||
01451|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01451|004|L|of severe adverse interaction.|
01451|005|B||
01451|006|A|MECHANISM OF ACTION:  Heavy metal ions may inactivate collagenase(1) and|
01451|007|A|papain(2-10).|
01451|008|B||
01451|009|E|CLINICAL EFFECTS:  Application of heavy metal ions such as lead, mercury,|
01451|010|E|and silver may inactivate collagenase(1) and papain,(2-8) limiting their|
01451|011|E|effectiveness.|
01451|012|B||
01451|013|P|PREDISPOSING FACTORS:  None determined.|
01451|014|B||
01451|015|M|PATIENT MANAGEMENT:  Avoid applying topical products that contain heavy|
01451|016|M|metals such as lead, mercury, or silver to the same wound areas as|
01451|017|M|collagenase(1) and papain.(2-10)|
01451|018|B||
01451|019|D|DISCUSSION:  The enzymatic activity of collagenase is adversely affected by|
01451|020|D|heavy metal ions such as mercury and silver, which are used in some|
01451|021|D|antiseptics.(1)|
01451|022|D|   Papain may be inactivated by heavy metal ions such as lead, mercury, and|
01451|023|D|silver.(2-10)|
01451|024|B||
01451|025|R|REFERENCES:|
01451|026|B||
01451|027|R|1.Santyl (collagenase) US prescribing information. Ross Products Division,|1
01451|028|R|  Abbott Laboratories, Inc. December, 2003.|1
01451|029|R|2.Accuzyme (papain, urea) ointment US prescribing information. Healthpoint,|1
01451|030|R|  Ltd. November, 2004.|1
01451|031|R|3.Accuzyme (papain, urea) spray US prescribing information. Healthpoint,|1
01451|032|R|  Ltd. March, 2004.|1
01451|033|R|4.Ethezyme, Ethezyme 830 (papain, urea) ointment US prescribing information.|1
01451|034|R|  Ethex Corporation July, 2004.|1
01451|035|R|5.Gladase (papain, urea) ointment US prescribing information. Smith &|1
01451|036|R|  Nephew, Inc. March, 2005.|1
01451|037|R|6.Gladase-C (papain, urea) ointment US prescribing information. Smith &|1
01451|038|R|  Nephew, Inc. March, 2005.|1
01451|039|R|7.Kovia (papain, urea) ointment US prescribing information. Stratus|1
01451|040|R|  Pharmaceuticals Inc. December, 1999.|1
01451|041|R|8.Panafil (papain, urea, chlorophylin copper complex sodium) ointment US|1
01451|042|R|  prescribing information. Healthpoint, Ltd. December, 2004.|1
01451|043|R|9.Panafil (papain, urea, chlorophylin copper complex sodium) ointment US|1
01451|044|R|  prescribing information. Healthpoint, Ltd. March, 2004.|1
01451|045|R|10.Ziox (papain, urea, chlorophylin copper complex sodium) ointment US|1
01451|046|R|   prescribing information. Stratus Pharmaceuticals Inc. August, 2000.|1
01452|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Efavirenz; Nevirapine|
01452|002|B||
01452|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01452|004|L|take action as needed.|
01452|005|B||
01452|006|A|MECHANISM OF ACTION:  Efavirenz(1-4) and nevirapine(4-6) may induce the|
01452|007|A|metabolism of methadone by CYP2B6.|
01452|008|A|   Levomethadone is an enantiomer of methadone.(7)|
01452|009|B||
01452|010|E|CLINICAL EFFECTS:  Concurrent use of efavirenz or nevirapine may result in|
01452|011|E|decreased levels and effectiveness of methadone and withdrawal symptoms.|
01452|012|B||
01452|013|P|PREDISPOSING FACTORS:  None determined.|
01452|014|B||
01452|015|M|PATIENT MANAGEMENT:  Patients receiving efavirenz or nevirapine should be|
01452|016|M|monitored for decreased effectiveness of methadone and symptoms of methadone|
01452|017|M|withdrawal.  The dosage of methadone may need to be adjusted.|
01452|018|B||
01452|019|D|DISCUSSION:  In a study, efavirenz (600 mg daily) given for 3 weeks led to a|
01452|020|D|decrease of levomethadone maximum concentration (Cmax) and area-under-curve|
01452|021|D|(AUC) of 48 % and 57 %, respectively.(7)|
01452|022|D|   In a study of 11 patients receiving methadone maintenance therapy, the|
01452|023|D|addition of efavirenz to their regimen decreased methadone Cmax and AUC by|
01452|024|D|45% and by 52%, respectively.  Nine patients experienced withdrawal symptoms|
01452|025|D|beginning at Day 8 of concurrent therapy.(1)  The manufacturer of efavirenz|
01452|026|D|states that concurrent use resulted in decreased methadone levels and signs|
01452|027|D|of withdrawal.  Subjects required an average methadone dosage increase of|
01452|028|D|22% to relieve symptoms.(2)  There are case reports of methadone withdrawal|
01452|029|D|symptoms in patients receiving efavirenz.(8,9)|
01452|030|D|   In a study in 20 HIV-positive patients receiving methadone maintenance|
01452|031|D|therapy, the addition of nevirapine to their regimen decreased methadone AUC|
01452|032|D|by 41%.  Reductions in AUC were similar for racemic methadone (37%) and|
01452|033|D|(R)-methadone (44%).  Changes in AUC ranged from mild increases in three|
01452|034|D|patients to decreases of up to 70%.  Fourteen subjects experienced|
01452|035|D|withdrawal symptoms and required methadone dosage adjustments.  The median|
01452|036|D|dosage adjustment was 15%.(5)  In a study in 8 HIV-positive patients|
01452|037|D|receiving methadone maintenance therapy, the addition of nevirapine resulted|
01452|038|D|in withdrawal symptoms after 5-10 days of concurrent therapy.(6) In a study|
01452|039|D|in 9 patients receiving methadone, the addition of nevirapine (200 mg daily|
01452|040|D|for 14 days, then 200 mg twice daily for at least 7 days) increased the|
01452|041|D|clearance of methadone by 3-fold and withdrawal symptoms. Dosage adjustments|
01452|042|D|were required in 7 patients.(10)  There are several case reports of|
01452|043|D|methadone withdrawal following the addition of nevirapine.(11-15)|
01452|044|B||
01452|045|R|REFERENCES:|
01452|046|B||
01452|047|R|1.Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ.|2
01452|048|R|  The pharmacokinetics of methadone in HIV-positive patients receiving the|2
01452|049|R|  non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin|2
01452|050|R|  Pharmacol 2001 Mar;51(3):213-7.|2
01452|051|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01452|052|R|  Company November, 2023.|1
01452|053|R|3.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01452|054|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01452|055|R|4.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
01452|056|R|  Pharmaceuticals Corp. June, 2021.|1
01452|057|R|5.Stocker H, Kruse G, Kreckel P, Herzmann C, Arasteh K, Claus J, Jessen H,|2
01452|058|R|  Cordes C, Hintsche B, Schlote F, Schneider L, Kurowski M. Nevirapine|2
01452|059|R|  significantly reduces the levels of racemic methadone and (R)-methadone in|2
01452|060|R|  human immunodeficiency virus-infected patients. Antimicrob Agents|2
01452|061|R|  Chemother 2004 Nov;48(11):4148-53.|2
01452|062|R|6.Bano Rodrigo MD, Agujetas Rodriguez M, Lopez Garcia ML, Guillen Llera JL.|2
01452|063|R|  Nevirapine induces abstinence symptoms in patients on a methadone|2
01452|064|R|  maintenance program with HIV infection. Rev Clin Esp 2000 Jan;200(1):12-4.|2
01452|065|R|7.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
01452|066|R|  Pharma AS November 30, 2018.|1
01452|067|R|8.Pinzani V, Faucherre V, Peyriere H, Blayac JP. Methadone withdrawal|3
01452|068|R|  symptoms with nevirapine and efavirenz. Ann Pharmacother 2000 Mar;|3
01452|069|R|  34(3):405-7.|3
01452|070|R|9.Marzolini C, Troillet N, Telenti A, Baumann P, Decosterd LA, Eap CB.|3
01452|071|R|  Efavirenz decreases methadone blood concentrations. AIDS 2000 Jun 16;|3
01452|072|R|  14(9):1291-2.|3
01452|073|R|10.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
01452|074|R|   Pharmaceuticals, Inc. June, 2022.|1
01452|075|R|11.de la Cruz Pellin M, Esteban J, Gimeno C, Mora E. Interaction between|3
01452|076|R|   methadone and antiretrovirals (stavudine, indinavir, ritonavir,|3
01452|077|R|   nevirapine). Med Clin (Barc) 2003 Oct 4;121(11):439.|3
01452|078|R|12.Bachiller Luque P, Flores AM, de Hoyos Llorente M, Navarro Canadas C.|3
01452|079|R|   Methadone withdrawal syndrome induced by nevirapine. Med Clin (Barc) 2000|3
01452|080|R|   Mar 18;114(10):399.|3
01452|081|R|13.Otero MJ, Fuertes A, Sanchez R, Luna G. Nevirapine-induced withdrawal|3
01452|082|R|   symptoms in HIV patients on methadone maintenance programme: an alert.|3
01452|083|R|   AIDS 1999 May 28;13(8):1004-5.|3
01452|084|R|14.Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral|3
01452|085|R|   regimen including nevirapine. Pharmacotherapy 1999 Apr;19(4):471-2.|3
01452|086|R|15.Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal|3
01452|087|R|   among injection drug users with HIV infection receiving methadone. AIDS|3
01452|088|R|   1999 May 28;13(8):957-62.|3
01452|089|R|16.Younis IR, Lakota EA, Volpe DA, Patel V, Xu Y, Sahajwalla CG. Drug-Drug|6
01452|090|R|   Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned. J|6
01452|091|R|   Clin Pharmacol 2019 Aug;59(8):1035-1043.|6
01453|001|T|MONOGRAPH TITLE:  Selected Nucleoside Analogues/Levomethadone; Methadone|
01453|002|T|(mono deleted 02/04/2022)|
01453|003|B||
01453|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01453|005|L|take action as needed.|
01453|006|B||
01453|007|A|MECHANISM OF ACTION:  Methadone may decrease the bioavailability of|
01453|008|A|didanosine(1-3) and stavudine.(1)  Methadone may decrease the|
01453|009|A|glucuronidation of zidovudine to its inactive form.(4)|
01453|010|A|   Levomethadone is an enantiomer of methadone.(5)|
01453|011|B||
01453|012|E|CLINICAL EFFECTS:  Concurrent use of methadone may result in decreased|
01453|013|E|levels and effectiveness of didanosine(1-3) and stavudine.(1)|
01453|014|E|   Concurrent use of methadone may result in increased levels of and|
01453|015|E|toxicity from zidovudine.(4-9)|
01453|016|B||
01453|017|P|PREDISPOSING FACTORS:  None determined.|
01453|018|B||
01453|019|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with methadone|
01453|020|M|may require larger doses of didanosine and stavudine.|
01453|021|M|  Methadone should not be coadministered with the pediatric powder|
01453|022|M|formulation of didanosine.  Instead, use the enteric coated formulation of|
01453|023|M|didanosine and monitor for changes in HIV RNA viral load in patients|
01453|024|M|requiring concurrent therapy.(2,3)|
01453|025|M|   Patients receiving concurrent therapy with methadone may require|
01453|026|M|decreased doses of zidovudine.|
01453|027|B||
01453|028|D|DISCUSSION:  In a study in healthy subjects, the addition of didanosine and|
01453|029|D|stavudine to 17 patients stabilized on methadone and 10 untreated controls|
01453|030|D|decreased the area-under-curve (AUC) of didanosine and stavudine by 57% and|
01453|031|D|by 25%, respectively.  The maximum concentration (Cmax) of didanosine and|
01453|032|D|stavudine were decreased by 66% and by 44%, respectively.(1)|
01453|033|D|   In a study in 8 recently detoxified, heroin-addicted, HIV-positive|
01453|034|D|subjects, the acute addition of methadone increased oral and intravenous|
01453|035|D|zidovudine AUC by 41% and by 19%, respectively.  Oral and intravenous|
01453|036|D|zidovudine clearance was decreased by 21% and by 19%, respectively.  Chronic|
01453|037|D|methadone increased oral and intravenous zidovudine AUC by 29% and by 41%,|
01453|038|D|respectively.  Clearance for both oral and intravenous zidovudine was|
01453|039|D|decreased by 26%.(7)|
01453|040|D|   In a prospective study in 68 HIV-positive patients, concurrent methadone|
01453|041|D|increased zidovudine levels.(8)|
01453|042|D|   In a study in 14 HIV-positive subjects, the addition of zidovudine to|
01453|043|D|methadone in 9 subjects had no effect on methadone levels.  Zidovudine serum|
01453|044|D|levels were 43% higher in the 9 patients receiving methadone compared to the|
01453|045|D|5 subjects not receiving methadone.(9)|
01453|046|D|   In a study in 16 methadone-maintained, HIV-negative subjects, the|
01453|047|D|administration of a single dose of a lamivudine-zidovudine (150 mg-300 mg)|
01453|048|D|tablet had no effect on methadone pharmacokinetics.(10)|
01453|049|D|   In a study in human liver microsomes, methadone decreased the|
01453|050|D|glucuronidation of zidovudine to its inactive form.(4)|
01453|051|B||
01453|052|R|REFERENCES:|
01453|053|B||
01453|054|R|1.Rainey PM, Friedland G, McCance-Katz EF, Andrews L, Mitchell SM, Charles|2
01453|055|R|  C, Jatlow P. Interaction of methadone with didanosine and stavudine. J|2
01453|056|R|  Acquir Immune Defic Syndr 2000 Jul 1;24(3):241-8.|2
01453|057|R|2.Videx (didanosine) US prescribing information. Bristol-Myers Squibb|1
01453|058|R|  Company November, 2011.|1
01453|059|R|3.Videx EC (didanosine) US prescribing information. Bristol-Myers Squibb|1
01453|060|R|  Company January 25, 2018.|1
01453|061|R|4.Trapnell CB, Klecker RW, Jamis-Dow C, Collins JM. Glucuronidation of|5
01453|062|R|  3'-azido-3'-deoxythymidine (zidovudine) by human liver microsomes:|5
01453|063|R|  relevance to clinical pharmacokinetic interactions with atovaquone,|5
01453|064|R|  fluconazole, methadone, and valproic acid. Antimicrob Agents Chemother|5
01453|065|R|  1998 Jul;42(7):1592-6.|5
01453|066|R|5.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
01453|067|R|  Pharma AS November 30, 2018.|1
01453|068|R|6.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
01453|069|R|  Pharmaceuticals Corp. June, 2021.|1
01453|070|R|7.McCance-Katz EF, Rainey PM, Jatlow P, Friedland G. Methadone effects on|2
01453|071|R|  zidovudine disposition (AIDS Clinical Trials Group 262). J Acquir Immune|2
01453|072|R|  Defic Syndr Hum Retrovirol 1998 Aug 15;18(5):435-43.|2
01453|073|R|8.Burger DM, Meenhorst PL, ten Napel CH, Mulder JW, Neef C, Koks CH, Bult A,|2
01453|074|R|  Beijnen JH. Pharmacokinetic variability of zidovudine in HIV-infected|2
01453|075|R|  individuals: subgroup analysis and drug interactions. AIDS 1994 Dec;|2
01453|076|R|  8(12):1683-9.|2
01453|077|R|9.Schwartz EL, Brechbuhl AB, Kahl P, Miller MA, Selwyn PA, Friedland GH.|2
01453|078|R|  Pharmacokinetic interactions of zidovudine and methadone in intravenous|2
01453|079|R|  drug-using patients with HIV infection. J Acquir Immune Defic Syndr 1992;|2
01453|080|R|  5(6):619-26.|2
01453|081|R|10.Rainey PM, Friedland GH, Snidow JW, McCance-Katz EF, Mitchell SM, Andrews|2
01453|082|R|   L, Lane B, Jatlow P. The pharmacokinetics of methadone following|2
01453|083|R|   co-administration with a lamivudine/zidovudine combination tablet in|2
01453|084|R|   opiate-dependent subjects. Am J Addict 2002 Winter;11(1):66-74.|2
01454|001|T|MONOGRAPH TITLE:  Pramlintide/Anticholinergics; Antispasmodics|
01454|002|B||
01454|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01454|004|L|is contraindicated and generally should not be dispensed or administered to|
01454|005|L|the same patient.|
01454|006|B||
01454|007|A|MECHANISM OF ACTION:  Pramlintide slows gastric emptying.  Anticholinergics|
01454|008|A|and antispasmodics may result in additive or synergistic effects on gastric|
01454|009|A|emptying.|
01454|010|B||
01454|011|E|CLINICAL EFFECTS:  Concurrent use of pramlintide and anticholinergics or|
01454|012|E|antispasmodics may result in additive or synergistic effects on gastric|
01454|013|E|emptying.|
01454|014|B||
01454|015|P|PREDISPOSING FACTORS:  None determined.|
01454|016|B||
01454|017|M|PATIENT MANAGEMENT:  The manufacturer of pramlintide states that pramlintide|
01454|018|M|therapy should not be considered in patients requiring the use of drugs that|
01454|019|M|alter gastrointestinal motility.(1)|
01454|020|M|   Patients receiving anticholinergics and antispasmodics should be|
01454|021|M|evaluated for signs of systemic effects which may include constipation.|
01454|022|B||
01454|023|D|DISCUSSION:  Patients using drugs that alter gastrointestinal motility have|
01454|024|D|not been studied in clinical trials for pramlintide.(1)|
01454|025|D|   Constipation has been reported as a side effect of anticholinergics and|
01454|026|D|antispasmodics.|
01454|027|B||
01454|028|R|REFERENCE:|
01454|029|B||
01454|030|R|1.Symlin (pramlintide acetate) US prescribing information. Amylin|1
01454|031|R|  Pharmaceuticals Inc. March, 2005.|1
01455|001|T|MONOGRAPH TITLE:  Pramlintide/Alpha-Glucosidase Inhibitors|
01455|002|B||
01455|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01455|004|L|is contraindicated and generally should not be dispensed or administered to|
01455|005|L|the same patient.|
01455|006|B||
01455|007|A|MECHANISM OF ACTION:  Pramlintide slows gastric emptying.  Alpha-glucosidase|
01455|008|A|inhibitors slow the absorption of nutrients.(1)|
01455|009|B||
01455|010|E|CLINICAL EFFECTS:  Concurrent use of pramlintide and alpha-glucosidase|
01455|011|E|inhibitors may result in additive or synergistic effects.(1)|
01455|012|B||
01455|013|P|PREDISPOSING FACTORS:  None determined.|
01455|014|B||
01455|015|M|PATIENT MANAGEMENT:  The manufacturer of pramlintide states that pramlintide|
01455|016|M|therapy should not be considered in patients taking alpha-glucosidase|
01455|017|M|inhibitors.(1)|
01455|018|B||
01455|019|D|DISCUSSION:  Patients using alpha-glucosidase inhibitors have not been|
01455|020|D|studied in clinical trials for pramlintide.(1)|
01455|021|B||
01455|022|R|REFERENCE:|
01455|023|B||
01455|024|R|1.Symlin (pramlintide acetate) US prescribing information. Amylin|1
01455|025|R|  Pharmaceuticals Inc. March, 2005.|1
01456|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Voriconazole|
01456|002|B||
01456|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01456|004|L|is contraindicated and generally should not be dispensed or administered to|
01456|005|L|the same patient.|
01456|006|B||
01456|007|A|MECHANISM OF ACTION:  Voriconazole may inhibit the metabolism of lovastatin|
01456|008|A|and simvastatin by CYP3A4.(1-3)|
01456|009|B||
01456|010|E|CLINICAL EFFECTS:  Concurrent use of voriconazole may result in elevated|
01456|011|E|levels of lovastatin and simvastatin and increase the risk of|
01456|012|E|rhabdomyolysis.(1-3)|
01456|013|B||
01456|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01456|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01456|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01456|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01456|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01456|019|P|transporter OATP1B1 may have increased statin concentrations and be|
01456|020|P|predisposed to myopathy or rhabdomyolysis.|
01456|021|B||
01456|022|M|PATIENT MANAGEMENT:  Concurrent use of voriconazole with lovastatin or|
01456|023|M|simvastatin is contraindicated.(1,2)  Therapy with lovastatin or simvastatin|
01456|024|M|should be suspended during voriconazole therapy.|
01456|025|M|  In patients requiring long-term therapy with voriconazole, consider the|
01456|026|M|use of pravastatin or reduced dosages of atorvastatin or fluvastatin, using|
01456|027|M|the lowest dose possible(3,4)  Patients should be carefully monitored for|
01456|028|M|and instructed to report any signs of myopathy.|
01456|029|B||
01456|030|D|DISCUSSION:  Voriconazole has been shown to inhibit the metabolism of|
01456|031|D|lovastatin in human liver microsomes in vitro.(3)|
01456|032|D|   A case report details the development of rhabdomyolysis and dyspnea in a|
01456|033|D|allogeneic stem cell transplant patient taking voriconazole for fungal|
01456|034|D|prophylaxis due to their immunosuppressant therapy while being started on|
01456|035|D|simvastatin for high cholesterol.(5)|
01456|036|D|   One or more of the drug pairs linked to this monograph have been included|
01456|037|D|in a list of interactions that should be considered "high-priority" for|
01456|038|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01456|039|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01456|040|D|Coordinator (ONC) for Health Information Technology.|
01456|041|B||
01456|042|R|REFERENCES:|
01456|043|B||
01456|044|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01456|045|R|  February, 2014.|1
01456|046|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
01456|047|R|  2023.|1
01456|048|R|3.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01456|049|R|4.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
01456|050|R|  2020.|1
01456|051|R|5.Cool RM, Gulbis AM. Rhabdomyolysis after concomitant ese of simvastatin|3
01456|052|R|  and voriconazole in an allogeneic stem cell transplant patient. J Pharm|3
01456|053|R|  Technol May/June 2013;29(3):135-8.|3
01456|054|R|6.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01456|055|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01456|056|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01456|057|R|  19(5):735-43.|6
01457|001|T|MONOGRAPH TITLE:  Tizanidine/Fluvoxamine (mono deleted 03/13/2024)|
01457|002|B||
01457|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01457|004|L|is contraindicated and generally should not be dispensed or administered to|
01457|005|L|the same patient.|
01457|006|B||
01457|007|A|MECHANISM OF ACTION:  Fluvoxamine inhibits the metabolism of tizanidine by|
01457|008|A|CYP1A2.(1-4)|
01457|009|B||
01457|010|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine may result in elevated|
01457|011|E|levels of and effects from tizanidine, including hypotension, bradycardia,|
01457|012|E|drowsiness, sedation, and decreased psychomotor function.(1-3)|
01457|013|B||
01457|014|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
01457|015|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
01457|016|P|patients using more than one medicine with anticholinergic properties.(5)|
01457|017|B||
01457|018|M|PATIENT MANAGEMENT:  The US manufacturers of fluvoxamine(1) and|
01457|019|M|tizanidine(2) state that concurrent use of these agents is contraindicated.|
01457|020|B||
01457|021|D|DISCUSSION:  In a study in 10 healthy subjects, pretreatment with|
01457|022|D|fluvoxamine (100 mg daily for 4 days) increased the area-under-curve (AUC)|
01457|023|D|and maximum concentration (Cmax) of a single dose of tizanidine (4 mg) by|
01457|024|D|33-fold (range:  14-fold to 103-fold) and by 12-fold (range 5-fold to|
01457|025|D|33-fold), respectively.  Tizanidine half-life increased from 1.5 hours to|
01457|026|D|4.3 hours.  The mean decrease in systolic blood pressure was 35 mmHg.  The|
01457|027|D|mean decrease in diastolic blood pressure was 20 mmHg.  Heart rate decreased|
01457|028|D|by 4 beats/minute.  There were also significant effects on the Digit|
01457|029|D|Substitution Test, subjective drug effects, and drowsiness.(1,3)|
01457|030|D|   There is one case report of an interaction between tizanidine and|
01457|031|D|fluvoxamine.(6)|
01457|032|D|   In a study in human liver microsomes, fluvoxamine inhibited the|
01457|033|D|metabolism of tizanidine.(4)|
01457|034|D|   One or more of the drug pairs linked to this monograph have been included|
01457|035|D|in a list of interactions that should be considered "high-priority" for|
01457|036|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01457|037|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01457|038|D|Coordinator (ONC) for Health Information Technology.|
01457|039|B||
01457|040|R|REFERENCES:|
01457|041|B||
01457|042|R|1.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
01457|043|R|  Pharmaceuticals, Inc. August, 2023.|1
01457|044|R|2.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
01457|045|R|  Pharma Inc. November 22, 2024.|1
01457|046|R|3.Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine|2
01457|047|R|  drastically increases concentrations and effects of tizanidine: a|2
01457|048|R|  potentially hazardous interaction. Clin Pharmacol Ther 2004 Apr;|2
01457|049|R|  75(4):331-41.|2
01457|050|R|4.Granfors MT, Backman JT, Laitila J, Neuvonen PJ. Tizanidine is mainly|5
01457|051|R|  metabolized by cytochrome p450 1A2 in vitro. Br J Clin Pharmacol 2004 Mar;|5
01457|052|R|  57(3):349-53.|5
01457|053|R|5.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01457|054|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01457|055|R|  Soc 2023 Jul;71(7):2052-2081.|6
01457|056|R|6.Momo K, Doki K, Hosono H, Homma M, Kohda Y. Drug interaction of tizanidine|3
01457|057|R|  and fluvoxamine. Clin Pharmacol Ther 2004 Nov;76(5):509-10.|3
01457|058|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01457|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01457|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01457|061|R|  19(5):735-43.|6
01458|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Imatinib|
01458|002|B||
01458|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01458|004|L|take action as needed.|
01458|005|B||
01458|006|A|MECHANISM OF ACTION:  Imatinib may inhibit the metabolism of lovastatin and|
01458|007|A|simvastatin by CYP3A4.(1)|
01458|008|B||
01458|009|E|CLINICAL EFFECTS:  Concurrent use of imatinib may result in elevated levels|
01458|010|E|and side effects of lovastatin or simvastatin, including|
01458|011|E|rhabdomyolysis.(1,2)|
01458|012|B||
01458|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01458|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01458|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01458|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01458|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01458|018|P|transporter OATP1B1 may have increased statin concentrations and be|
01458|019|P|predisposed to myopathy or rhabdomyolysis.|
01458|020|B||
01458|021|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with imatinib and|
01458|022|M|lovastatin or simvastatin should be carefully monitored for adverse effects,|
01458|023|M|including rhabdomyolysis.  Consider reducing the dosage of the HMG Co-A|
01458|024|M|reductase inhibitor or using an alternative agent such as fluvastatin or|
01458|025|M|pravastatin in patients receiving concurrent imatinib therapy.  Instruct|
01458|026|M|patients to report any signs of myopathy.|
01458|027|B||
01458|028|D|DISCUSSION:  In a study in 20 patients with chronic myeloid leukemia,|
01458|029|D|subjects received a single dose of simvastatin (40 mg) alone and after 7|
01458|030|D|days of imatinib (400 mg daily).  Imatinib increased the area-under-curve|
01458|031|D|(AUC) and maximum concentration (Cmax) of simvastatin by 3.5-fold and by|
01458|032|D|2-fold, respectively.  Simvastatin total body clearance decreased by 70%.(2)|
01458|033|B||
01458|034|R|REFERENCES:|
01458|035|B||
01458|036|R|1.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
01458|037|R|  Pharmaceuticals Corporation August, 2022.|1
01458|038|R|2.O'Brien SG, Meinhardt P, Bond E, Beck J, Peng B, Dutreix C, Mehring G,|2
01458|039|R|  Milosavljev S, Huber C, Capdeville R, Fischer T. Effects of imatinib|2
01458|040|R|  mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a|2
01458|041|R|  cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia.|2
01458|042|R|  Br J Cancer 2003 Nov 17;89(10):1855-9.|2
01459|001|T|MONOGRAPH TITLE:  Duloxetine/Strong CYP1A2 Inhibitors|
01459|002|B||
01459|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01459|004|L|of severe adverse interaction.|
01459|005|B||
01459|006|A|MECHANISM OF ACTION:  Inhibitors of CYP1A2 may inhibit the metabolism of|
01459|007|A|duloxetine.(1)|
01459|008|B||
01459|009|E|CLINICAL EFFECTS:  Concurrent use of inhibitors of CYP1A2 may result in|
01459|010|E|elevated levels of and toxicity from duloxetine.(1)|
01459|011|B||
01459|012|P|PREDISPOSING FACTORS:  None determined.|
01459|013|B||
01459|014|M|PATIENT MANAGEMENT:  The manufacturer of duloxetine states that concurrent|
01459|015|M|use with strong inhibitors of CYP1A2 should be avoided.(1)|
01459|016|B||
01459|017|D|DISCUSSION:  In a study in 14 male subjects, concurrent fluvoxamine|
01459|018|D|increased duloxetine area-under-curve (AUC), maximum concentration (Cmax),|
01459|019|D|and half-life by over 5-fold, about 2.5-fold, and approximately 3-fold,|
01459|020|D|respectively.(1)|
01459|021|D|   In a study in 14 subjects who were poor metabolizers of CYP2D6,|
01459|022|D|fluvoxamine (100 mg) increased the AUC and Cmax of duloxetine (40 mg BID) by|
01459|023|D|6-fold each.(1)|
01459|024|B||
01459|025|R|REFERENCE:|
01459|026|B||
01459|027|R|1.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
01459|028|R|  and Company September, 2021.|1
01460|001|T|MONOGRAPH TITLE:  Duloxetine/Quinolones (mono deleted 10/11/2012)|
01460|002|B||
01460|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01460|004|L|of severe adverse interaction.|
01460|005|B||
01460|006|A|MECHANISM OF ACTION:  Quinolones may inhibit the metabolism of duloxetine by|
01460|007|A|CYP P-450-1A2.(1)|
01460|008|B||
01460|009|E|CLINICAL EFFECTS:  Concurrent use of quinolones may result in elevated|
01460|010|E|levels of and toxicity from duloxetine.(1)|
01460|011|B||
01460|012|P|PREDISPOSING FACTORS:  None determined.|
01460|013|B||
01460|014|M|PATIENT MANAGEMENT:  The manufacturer of duloxetine states that concurrent|
01460|015|M|use with quinolones should be avoided.(1)|
01460|016|B||
01460|017|D|DISCUSSION:  In a study in 14 male subjects, concurrent fluvoxamine, an|
01460|018|D|inhibitor of CYP P-450-1A2, increased duloxetine area-under curve (AUC),|
01460|019|D|maximum concentration (Cmax), and half-life by over 5-fold, about 2.5-fold,|
01460|020|D|and approximately 3-fold, respectively.  Quinolone antibiotics are expected|
01460|021|D|to have similar effects.(1)|
01460|022|B||
01460|023|R|REFERENCE:|
01460|024|B||
01460|025|R|1.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
01460|026|R|  and Company August, 2023.|1
01461|001|T|MONOGRAPH TITLE:  Tricyclic Compounds/Terbinafine|
01461|002|B||
01461|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01461|004|L|take action as needed.|
01461|005|B||
01461|006|A|MECHANISM OF ACTION:  Terbinafine may inhibit the metabolism of tricyclic|
01461|007|A|compounds by CYP2D6.(1-5)|
01461|008|B||
01461|009|E|CLINICAL EFFECTS:  Concurrent use of terbinafine may result in elevated|
01461|010|E|levels of and toxicity from the tricyclic agent.|
01461|011|B||
01461|012|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
01461|013|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
01461|014|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
01461|015|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
01461|016|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
01461|017|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
01461|018|P|systemic steroids).|
01461|019|P|   The risk of anticholinergic toxicities including cognitive decline,|
01461|020|P|delirium, falls and fractures is increased in geriatric patients using more|
01461|021|P|than one medicine with anticholinergic properties.(6)|
01461|022|B||
01461|023|M|PATIENT MANAGEMENT:  Monitor tricyclic levels in patients receiving|
01461|024|M|concurrent therapy with terbinafine.  The dose of the tricyclic agent may|
01461|025|M|need to be adjusted if terbinafine is initiated or discontinued.  The effect|
01461|026|M|of terbinafine on tricyclics may last for up to four weeks after terbinafine|
01461|027|M|discontinuation.|
01461|028|B||
01461|029|D|DISCUSSION:  In a study in 12 healthy subjects, a single dose of desipramine|
01461|030|D|(50 mg) was given alone, after 21 days of terbinafine (250 mg daily), and 2|
01461|031|D|and 4 weeks after discontinuation of terbinafine.  Administration after 21|
01461|032|D|days of terbinafine therapy increased the area-under-curve (AUC) and maximum|
01461|033|D|concentration (Cmax) of desipramine by 5-fold and 2-fold, respectively.  The|
01461|034|D|AUC and Cmax of desipramine were still elevated when desipramine was|
01461|035|D|administered 4 weeks after the completion of terbinafine therapy.(1,2)|
01461|036|D|   There are case reports of toxicity during concurrent terbinafine and|
01461|037|D|desipramine,(3) imipramine,(4) and nortriptyline.(5,7-8)|
01461|038|D|   In the UK manufacturer states that terbinafine decreased the clearance of|
01461|039|D|desipramine by 82%.(9)|
01461|040|B||
01461|041|R|REFERENCES:|
01461|042|B||
01461|043|R|1.Lamisil (terbinafine hydrochloride) tablet US prescribing information.|1
01461|044|R|  Novartis Pharmaceuticals Corporation June, 2013.|1
01461|045|R|2.Madani S, Barilla D, Cramer J, Wang Y, Paul C. Effect of terbinafine on|2
01461|046|R|  the pharmacokinetics and pharmacodynamics of desipramine in healthy|2
01461|047|R|  volunteers identified as cytochrome P450 2D6 (CYP2D6) extensive|2
01461|048|R|  metabolizers. J Clin Pharmacol 2002 Nov;42(11):1211-8.|2
01461|049|R|3.O'Reardon JP, Hetznecker JM, Rynn MA, Baldassano CF, Szuba MP. Desipramine|3
01461|050|R|  toxicity with terbinafine. Am J Psychiatry 2002 Mar;159(3):492.|3
01461|051|R|4.Teitelbaum ML, Pearson VE. Imipramine toxicity and terbinafine. Am J|3
01461|052|R|  Psychiatry 2001 Dec;158(12):2086.|3
01461|053|R|5.Van Der Kuy PH, Van Den Heuvel HA, Kempen RW, Vanmolkot LM.|3
01461|054|R|  Pharmacokinetic interaction between nortriptyline and terbinafine. Ann|3
01461|055|R|  Pharmacother 2002 Nov;36(11):1712-4.|3
01461|056|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01461|057|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01461|058|R|  Soc 2023 Jul;71(7):2052-2081.|6
01461|059|R|7.van der Kuy PH, Hooymans PM. Nortriptyline intoxication induced by|3
01461|060|R|  terbinafine. BMJ 1998 Feb 7;316(7129):441.|3
01461|061|R|8.Schmutz JL, Barbaud A, Trechot P. Overdose of nortriptyline during|3
01461|062|R|  treatment with terbinafine (1st reported case). Ann Dermatol Venereol 1999|3
01461|063|R|  Aug-Sep;126(8-9):647.|3
01461|064|R|9.Lamisil (terbinafine) UK summary  of product characteristics. Novartis|1
01461|065|R|  Pharmaceutical UK Ltd June, 2008.|1
01462|001|T|MONOGRAPH TITLE:  Selected Nephrotoxic Agents/Cidofovir|
01462|002|B||
01462|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01462|004|L|is contraindicated and generally should not be dispensed or administered to|
01462|005|L|the same patient.|
01462|006|B||
01462|007|A|MECHANISM OF ACTION:  Cidofovir is nephrotoxic.  Concurrent administration|
01462|008|A|of other nephrotoxic agents may result in additive or synergistic effects on|
01462|009|A|renal function.(1-3)|
01462|010|B||
01462|011|E|CLINICAL EFFECTS:  Concurrent use of cidofovir with nephrotoxic agents such|
01462|012|E|as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet,|
01462|013|E|intravenous pentamidine, tenofovir, vancomycin, voclosporin and|
01462|014|E|non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3)|
01462|015|E|Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate,|
01462|016|E|high-dose methotrexate, and streptozocin.|
01462|017|B||
01462|018|P|PREDISPOSING FACTORS:  None determined.|
01462|019|B||
01462|020|M|PATIENT MANAGEMENT:  The Australian,(1) UK,(2) and US(3) manufacturers of|
01462|021|M|cidofovir state that concurrent administration of potentially nephrotoxic|
01462|022|M|agents such as adefovir, intravenous aminoglycosides, amphotericin B,|
01462|023|M|foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and|
01462|024|M|non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3)|
01462|025|M|Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate,|
01462|026|M|high-dose methotrexate, and streptozocin.  These agents should be|
01462|027|M|discontinued at least 7 days before the administration of cidofovir.|
01462|028|B||
01462|029|D|DISCUSSION:  The safety of cidofovir has not been studied in patients|
01462|030|D|receiving other known potentially nephrotoxic agents.  Renal impairment is|
01462|031|D|the major toxicity of cidofovir.(1-3)|
01462|032|B||
01462|033|R|REFERENCES:|
01462|034|B||
01462|035|R|1.Vistide (cidofovir) Australian prescribing information. Pfizer Australia|1
01462|036|R|  Pty Ltd. July 28, 2004.|1
01462|037|R|2.Vistide (cidofovir) UK summary of product characteristics. Gilead Sciences|1
01462|038|R|  Ltd January, 2011.|1
01462|039|R|3.Vistide (cidofovir) US prescribing information. Gilead Sciences, Inc.|1
01462|040|R|  September, 2000.|1
01463|001|T|MONOGRAPH TITLE:  Haloperidol/QT Prolonging Agents|
01463|002|B||
01463|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01463|004|L|take action as needed.|
01463|005|B||
01463|006|A|MECHANISM OF ACTION:  Torsades de pointes has been reported with|
01463|007|A|haloperidol.  Concurrent use with other agents that prolong the QTc interval|
01463|008|A|may result in additive effects on the QTc interval.(1-3)|
01463|009|B||
01463|010|E|CLINICAL EFFECTS:  The concurrent use of haloperidol with other agents that|
01463|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01463|012|E|arrhythmias, including torsades de pointes.(1-3)|
01463|013|B||
01463|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by:|
01463|015|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, use|
01463|016|P|of multiple medications, intravenous haloperidol, or higher than recommended|
01463|017|P|dosages of haloperidol.|
01463|018|P|   The risk of QT prolongation or torsade de pointes may also be increased|
01463|019|P|in patients with cardiovascular disease (e.g. heart failure, myocardial|
01463|020|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
01463|021|P|bradycardia, or advanced age.(5)|
01463|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01463|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01463|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01463|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01463|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01463|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01463|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
01463|029|B||
01463|030|M|PATIENT MANAGEMENT:  The Australian,(1) UK(2) and US(3) manufacturers of|
01463|031|M|haloperidol state that haloperidol should be used with caution when given|
01463|032|M|with other agents known to prolong the QT interval.|
01463|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01463|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01463|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01463|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01463|037|B||
01463|038|D|DISCUSSION:  Sudden death, QT-prolongation, and torsades de pointes have|
01463|039|D|been reported with haloperidol.(3)|
01463|040|D|   Agents that are linked to this monograph may have varying degrees of|
01463|041|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
01463|042|D|been shown to prolong the QTc interval either through their mechanism of|
01463|043|D|action, through studies on their effects on the QTc interval, or through|
01463|044|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01463|045|D|and/or postmarketing reports.(4)|
01463|046|D|   One or more of the drug pairs linked to this monograph have been included|
01463|047|D|in a list of interactions that should be considered "high-priority" for|
01463|048|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01463|049|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01463|050|D|Coordinator (ONC) for Health Information Technology.|
01463|051|B||
01463|052|R|REFERENCES:|
01463|053|B||
01463|054|R|1.Serenace (haloperidol) Australian prescribing information. Sigma|1
01463|055|R|  Pharmaceuticals Pty Ltd. June 5, 2001.|1
01463|056|R|2.Dozic (haloperidol) UK summary of product characteristics. Rosemont|1
01463|057|R|  Pharmaceuticals Limited September 10, 2007.|1
01463|058|R|3.Haldol injection (haloperidol) US prescribing information. Janssen|1
01463|059|R|  Pharmaceuticals, Inc. October, 2025.|1
01463|060|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
01463|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01463|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01463|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01463|064|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01463|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01463|066|R|  settings: a scientific statement from the American Heart Association and|6
01463|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01463|068|R|  2;55(9):934-47.|6
01463|069|R|6.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01463|070|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01463|071|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01463|072|R|  19(5):735-43.|6
01464|001|T|MONOGRAPH TITLE:  Moclobemide/Cimetidine|
01464|002|B||
01464|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01464|004|L|take action as needed.|
01464|005|B||
01464|006|A|MECHANISM OF ACTION:  Cimetidine may decrease the clearance of moclobemide.|
01464|007|A|(1)|
01464|008|B||
01464|009|E|CLINICAL EFFECTS:  Concurrent use of cimetidine may result in elevated|
01464|010|E|levels of and toxicity from moclobemide.(1)|
01464|011|B||
01464|012|P|PREDISPOSING FACTORS:  None determined.|
01464|013|B||
01464|014|M|PATIENT MANAGEMENT:  If moclobemide is initiated in a patient maintained on|
01464|015|M|cimetidine, moclobemide should be initiated at the lowest possible dose.  If|
01464|016|M|cimetidine is added to moclobemide therapy, the dose of moclobemide may need|
01464|017|M|to be decreased by 50%.(1)|
01464|018|B||
01464|019|D|DISCUSSION:  In a study in 8 healthy subjects, single intravenous and oral|
01464|020|D|doses of moclobemide (100 mg) were administered after 2 weeks of cimetidine|
01464|021|D|therapy (200 mg 5 times daily).  Cimetidine decreased the clearance of|
01464|022|D|intravenous moclobemide by 39.3% and increased moclobemide half-life by|
01464|023|D|43.75%.  Cimetidine increased the oral bioavailability of moclobemide from|
01464|024|D|54% to 68% and increased the maximum concentration (Cmax) of moclobemide by|
01464|025|D|36.9%.(2)|
01464|026|B||
01464|027|R|REFERENCES:|
01464|028|B||
01464|029|R|1.Arima (moclobemide) Australian prescribing information. Alphapharm Pty|1
01464|030|R|  Ltd. March 27, 2000.|1
01464|031|R|2.Schoerlin MP, Mayersohn M, Hoevels B, Eggers H, Dellenbach M, Pfefen JP.|2
01464|032|R|  Cimetidine alters the disposition kinetics of the monoamine oxidase-A|2
01464|033|R|  inhibitor moclobemide. Clin Pharmacol Ther 1991 Jan;49(1):32-8.|2
01465|001|T|MONOGRAPH TITLE:  Warfarin/Aprepitant|
01465|002|B||
01465|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01465|004|L|of severe adverse interaction.|
01465|005|B||
01465|006|A|MECHANISM OF ACTION:  Aprepitant may induce the metabolism of S-warfarin by|
01465|007|A|CYP2C9.(1-3)|
01465|008|B||
01465|009|E|CLINICAL EFFECTS:  Use of aprepitant in patients maintained on warfarin may|
01465|010|E|result in decreased levels and effectiveness of warfarin 7-10 days after|
01465|011|E|initiation of aprepitant.(1-3)|
01465|012|B||
01465|013|P|PREDISPOSING FACTORS:  None determined.|
01465|014|B||
01465|015|M|PATIENT MANAGEMENT:  The manufacturers of aprepitant recommend careful|
01465|016|M|monitoring of INR values in the 2 week period, particularly at 7-10 days,|
01465|017|M|following initiation of the 3 day course of aprepitant therapy with each|
01465|018|M|chemotherapy cycle.(1-3)|
01465|019|B||
01465|020|D|DISCUSSION:  In a study in healthy subjects maintained on warfarin, a single|
01465|021|D|125 mg dose of aprepitant was administered on Day 1, followed by single 80|
01465|022|D|mg doses on Days 2 and 3.  There was no effect on the area-under-curve (AUC)|
01465|023|D|of R-warfarin or S-warfarin on Day 3.  However, there was a 34% decrease in|
01465|024|D|S-warfarin AUC and a 14% decrease in INR 5 days after the completion of|
01465|025|D|aprepitant therapy (Day 8).(1-3)|
01465|026|B||
01465|027|R|REFERENCES:|
01465|028|B||
01465|029|R|1.Emend (aprepitant) Australian prescribing information. MSD April 5, 2004.|1
01465|030|R|2.Emend (aprepitant) UK summary of product characteristics. Merck Sharp &|1
01465|031|R|  Dohme Limited January 10. 2005.|1
01465|032|R|3.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
01465|033|R|  September, 2019.|1
01466|001|T|MONOGRAPH TITLE:  Sodium Fusidate/Acetaminophen|
01466|002|B||
01466|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01466|004|L|of severe adverse interaction.|
01466|005|B||
01466|006|A|MECHANISM OF ACTION:  Sodium fusidate and acetaminophen may inhibit the|
01466|007|A|biotransformation of each other by CYP P-450-3A4.(1)|
01466|008|B||
01466|009|E|CLINICAL EFFECTS:  Concurrent use may result in toxicity from sodium|
01466|010|E|fusidate and acetaminophen.(1)|
01466|011|B||
01466|012|P|PREDISPOSING FACTORS:  None determined.|
01466|013|B||
01466|014|M|PATIENT MANAGEMENT:  The Australian manufacturer of sodium fusidate states|
01466|015|M|that concurrent use of sodium fusidate and CYP P-450-3A4 biotransformed|
01466|016|M|drugs such as acetaminophen should be avoided.(1)|
01466|017|B||
01466|018|D|DISCUSSION:  Although the specifics of sodium fusidate metabolic pathways|
01466|019|D|are not known, an interaction between sodium fusidate and drugs that are|
01466|020|D|biotransformed by CYP P-450-3A4 is suspected.(1)|
01466|021|B||
01466|022|R|REFERENCE:|
01466|023|B||
01466|024|R|1.Fucidin (fusidic acid) Australian prescribing information. CSL Limited|1
01466|025|R|  January 9, 2003.|1
01467|001|T|MONOGRAPH TITLE:  Sodium Fusidate/Digitoxin|
01467|002|B||
01467|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01467|004|L|of severe adverse interaction.|
01467|005|B||
01467|006|A|MECHANISM OF ACTION:  Sodium fusidate and digitoxin may inhibit the|
01467|007|A|biotransformation of each other by CYP P-450-3A4.(1)|
01467|008|B||
01467|009|E|CLINICAL EFFECTS:  Concurrent use may result in toxicity from sodium|
01467|010|E|fusidate and digitoxin.(1)|
01467|011|B||
01467|012|P|PREDISPOSING FACTORS:  None determined.|
01467|013|B||
01467|014|M|PATIENT MANAGEMENT:  The Australian manufacturer of sodium fusidate states|
01467|015|M|that concurrent use of sodium fusidate and CYP P-450-3A4 biotransformed|
01467|016|M|drugs such as digitoxin should be avoided.(1)|
01467|017|B||
01467|018|D|DISCUSSION:  Although the specifics of sodium fusidate metabolic pathways|
01467|019|D|are not known, an interaction between sodium fusidate and drugs that are|
01467|020|D|biotransformed by CYP P-450-3A4 is suspected.(1)|
01467|021|B||
01467|022|R|REFERENCE:|
01467|023|B||
01467|024|R|1.Fucidin (fusidic acid) Australian prescribing information. CSL Limited|1
01467|025|R|  January 9, 2003.|1
01468|001|T|MONOGRAPH TITLE:  Sodium Fusidate/Selected Steroids|
01468|002|B||
01468|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01468|004|L|of severe adverse interaction.|
01468|005|B||
01468|006|A|MECHANISM OF ACTION:  Sodium fusidate and steroids may inhibit the|
01468|007|A|biotransformation of each other by CYP P-450-3A4.(1)|
01468|008|B||
01468|009|E|CLINICAL EFFECTS:  Concurrent use may result in toxicity from sodium|
01468|010|E|fusidate and steroids.(1)|
01468|011|B||
01468|012|P|PREDISPOSING FACTORS:  None determined.|
01468|013|B||
01468|014|M|PATIENT MANAGEMENT:  The Australian manufacturer of sodium fusidate states|
01468|015|M|that concurrent use of sodium fusidate and CYP P-450-3A4 biotransformed|
01468|016|M|drugs such as steroids should be avoided.(1)|
01468|017|B||
01468|018|D|DISCUSSION:  Although the specifics of sodium fusidate metabolic pathways|
01468|019|D|are not known, an interaction between sodium fusidate and drugs that are|
01468|020|D|biotransformed by CYP P-450-3A4 is suspected.(1)|
01468|021|B||
01468|022|R|REFERENCE:|
01468|023|B||
01468|024|R|1.Fucidin (fusidic acid) Australian prescribing information. CSL Limited|1
01468|025|R|  January 9, 2003.|1
01469|001|T|MONOGRAPH TITLE:  Quetiapine/Selected Macrolide Antibiotics|
01469|002|B||
01469|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01469|004|L|take action as needed.|
01469|005|B||
01469|006|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
01469|007|A|quetiapine via CYP3A4.  Quetiapine is a sensitive substrate for CYP3A4.|
01469|008|A|Sensitive substrates will have at least a 5-fold increase in|
01469|009|A|area-under-curve(AUC) when given with a strong inhibitor of the enzyme.(1)|
01469|010|B||
01469|011|E|CLINICAL EFFECTS:  Concurrent use of a macrolide antibiotic which is a weak|
01469|012|E|inhibitor of CYP3A4 may result in elevated levels of and toxicity from|
01469|013|E|quetiapine including QT prolongation or torsades de pointes.(2-3)|
01469|014|E|   Agents linked to this monograph are weak or minimal inhibitors of CYP3A4:|
01469|015|E|dirithromycin, josamycin, midecamycin, miocamycin(5), roxithromycin(4), and|
01469|016|E|spiramycin. Based upon its interactions with other CYP3A4 sensitive|
01469|017|E|substrates, roxithromycin may increase quetiapine levels by approximately|
01469|018|E|30% and 50% respectively.(4)|
01469|019|B||
01469|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01469|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01469|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01469|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01469|024|P|gender, or advanced age.(1)|
01469|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01469|026|P|higher systemic concentrations of either QT prolonging drug are additional|
01469|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01469|028|P|drug concentrations include rapid infusion of an intravenous dose or|
01469|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01469|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01469|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
01469|032|B||
01469|033|M|PATIENT MANAGEMENT:  Monitor patients for quetiapine adverse effects, e.g.|
01469|034|M|somnolence, dizziness, hypotension, and adjust dose accordingly.|
01469|035|M|   If concurrent therapy with quetiapine and macrolides is warranted,|
01469|036|M|consider obtaining serum calcium, magnesium, and potassium levels and|
01469|037|M|monitoring ECG at baseline and at regular intervals.  Correct any|
01469|038|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01469|039|M|heartbeat, dizziness, or fainting.|
01469|040|B||
01469|041|D|DISCUSSION:  Macrolides linked to this monograph are expected to have|
01469|042|D|significantly less effect on quetiapine AUC than moderate or strong CYP3A4|
01469|043|D|inhibitors such as erythromycin and clarithromycin respectively.|
01469|044|D|   For example, in a study in 19 Chinese patients with schizophrenia,|
01469|045|D|patients received quetiapine (200 mg twice daily) alone and with|
01469|046|D|erythromycin (500 mg 3 times daily).  Erythromycin increased the quetiapine|
01469|047|D|maximum concentration (Cmax), area-under-curve (AUC), and half-life by 68%,|
01469|048|D|129%, and 92%, respectively.  Quetiapine clearance decreased 52%.  The Cmax|
01469|049|D|and AUC of quetiapine sulfoxide decreased 64% and 23%, respectively.  The|
01469|050|D|half-life of quetiapine sulfoxide increased 203%.  The Cmax and AUC of|
01469|051|D|7-hydroxy-quetiapine decreased by 36% and 40%, respectively.(7)|
01469|052|B||
01469|053|R|REFERENCES:|
01469|054|B||
01469|055|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
01469|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01469|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01469|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01469|059|R|  11/14/2017.|1
01469|060|R|2.Seroquel (quetiapine) US prescribing information. AstraZeneca|1
01469|061|R|  Pharmaceuticals LP September, 2020.|1
01469|062|R|3.Seroquel (quetiapine) Canada prescribing information. AstraZeneca Canada|1
01469|063|R|  Inc. May 15,2013.|1
01469|064|R|4.This information is based on an extract from the Certara Drug Interaction|6
01469|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01469|066|R|5.Kasahara M, Suzuki H, Komiya I. Studies on the cytochrome P450|5
01469|067|R|  (CYP)-mediated metabolic properties of miocamycin: evaluation of the|5
01469|068|R|  possibility of a metabolic intermediate complex formation with  CYP, and|5
01469|069|R|  identification of the human CYP isoforms. Drug Metab Dispos 2000 Apr;|5
01469|070|R|  28(4):409-17.|5
01469|071|R|6.Li KY, Li X, Cheng ZN, Zhang BK, Peng WX, Li HD. Effect of erythromycin on|2
01469|072|R|  metabolism of quetiapine in Chinese suffering from schizophrenia. Eur J|2
01469|073|R|  Clin Pharmacol 2005 Jan;60(11):791-5.|2
01469|074|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01469|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01469|076|R|  settings: a scientific statement from the American Heart Association and|6
01469|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01469|078|R|  2;55(9):934-47.|6
01470|001|T|MONOGRAPH TITLE:  Digoxin/Metoclopramide|
01470|002|B||
01470|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01470|004|L|take action as needed.|
01470|005|B||
01470|006|A|MECHANISM OF ACTION:  Metoclopramide stimulates the smooth muscle in the|
01470|007|A|gastrointestinal tract to increase peristalsis.  This action may reduce the|
01470|008|A|time digoxin is at the absorption site, causing less drug to be absorbed|
01470|009|A|since digoxin absorption is dissolution rate-limited.(1-3)  Metoclopramide|
01470|010|A|may alter digoxin levels by increasing digoxin biliary excretion.(4)|
01470|011|B||
01470|012|E|CLINICAL EFFECTS:  Concurrent use of metoclopramide with digoxin may result|
01470|013|E|in decreased levels and effectiveness of digoxin.(5-7)|
01470|014|B||
01470|015|P|PREDISPOSING FACTORS:  None determined.|
01470|016|B||
01470|017|M|PATIENT MANAGEMENT:  Separate the administration time of metoclopramide and|
01470|018|M|digoxin by as much time as possible.  Monitor digoxin levels if|
01470|019|M|metoclopramide is initiated or discontinued.  The dosage of digoxin may need|
01470|020|M|to be increased by 20% to 40%.|
01470|021|B||
01470|022|D|DISCUSSION:  Steady-state serum digoxin concentrations were reduced by|
01470|023|D|approximately one-third in a group of elderly female patients receiving|
01470|024|D|metoclopramide.  When metoclopramide was discontinued, digoxin|
01470|025|D|concentrations returned to previous levels.(8)|
01470|026|D|   In a study, 6 healthy subjects received digoxin (0.25 mg twice daily) for|
01470|027|D|for 1 week alone and during concurrent metoclopramide (10 mg 3 times daily).|
01470|028|D|Metoclopramide decreased digoxin maximum concentration (Cmax) and AUC by 27%|
01470|029|D|and 19%, respectively.  Metoclopramide prolonged time to reach Cmax (Tmax)|
01470|030|D|by 35%.(9)|
01470|031|D|   In a study involving 16 healthy subjects who received digoxin (two 0.25|
01470|032|D|mg tablets), a single dose of metoclopramide reduced digoxin's|
01470|033|D|area-under-curve (AUC) and cumulative urinary digoxin excretion as compared|
01470|034|D|to digoxin alone.  However, metoclopramide did not affect the same|
01470|035|D|parameters for the soft gelatin capsule form of digoxin (two 0.2 mg|
01470|036|D|capsules).  Metoclopramide reduced digoxin Tmax for both dosage forms.(10)|
01470|037|D|   In a study in 10 healthy subjects, a single dose of metoclopramide (10|
01470|038|D|mg) given 30 minutes before a single dose of digoxin (two standard Lanoxin|
01470|039|D|0.25 mg tablets) decreased digoxin urinary excretion by 8%.(11)|
01470|040|B||
01470|041|R|REFERENCES:|
01470|042|B||
01470|043|R|1.Manninen V, Apajalahti A, Simonen H, Reissell P. Effect of propantheline|2
01470|044|R|  and metoclopramide on absorption of digoxin. Lancet 1973 May 19;|2
01470|045|R|  1(7812):1118-9.|2
01470|046|R|2.Medin S, Nyberg L. Effect of propantheline and metoclopramide on|5
01470|047|R|  absorption of digoxin. Lancet 1973 Jun 16;1(7816):1393.|5
01470|048|R|3.Fraser EJ, Leach RH, Poston JW, Bold AM, Culank LS, Lipede AB.|5
01470|049|R|  Dissolution-rates and bioavailability of digoxin tablets. Lancet 1973 Jun|5
01470|050|R|  16;1(7816):1393.|5
01470|051|R|4.Thompson WG. Altered absorption of digoxin in patients given propantheline|6
01470|052|R|  and metoclopramide. Lancet 1973 Apr 7;1(7806):783-4.|6
01470|053|R|5.Lanoxicaps (digoxin solution in capsules) US prescribing information.|1
01470|054|R|  GlaxoSmithKline October, 2003.|1
01470|055|R|6.Lanoxin (digoxin) Elixir US prescribing information. GlaxoSmithKline|1
01470|056|R|  August, 2018.|1
01470|057|R|7.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
01470|058|R|  Pharmaceuticals, Inc. August, 2018.|1
01470|059|R|8.Manninen V, Apajalahti A, Melin J, Karesoja M. Altered absorption of|2
01470|060|R|  digoxin in patients given propantheline and metoclopramide. Lancet 1973|2
01470|061|R|  Feb 24;1(7800):398-400.|2
01470|062|R|9.Kirch W, Janisch HD, Santos SR, Duhrsen U, Dylewicz P, Ohnhaus EE. Effect|2
01470|063|R|  of cisapride and metoclopramide on digoxin bioavailability. Eur J Drug|2
01470|064|R|  Metab Pharmacokinet 1986 Oct-Dec;11(4):249-50.|2
01470|065|R|10.Johnson BF, Bustrack JA, Urbach DR, Hull JH, Marwaha R. Effect of|2
01470|066|R|   metoclopramide on digoxin absorption from tablets and capsules. Clin|2
01470|067|R|   Pharmacol Ther 1984 Dec;36(6):724-30.|2
01470|068|R|11.Johnson BF, O'Grady J, Bye C. The influence of digoxin particle size on|2
01470|069|R|   absorption of digoxin and the effect of propantheline and metoclopramide.|2
01470|070|R|   Br J Clin Pharmacol 1978 May;5(5):465-7.|2
01471|001|T|MONOGRAPH TITLE:  Warfarin/Azathioprine|
01471|002|B||
01471|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01471|004|L|take action as needed.|
01471|005|B||
01471|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Azathioprine has been|
01471|007|A|shown to decrease warfarin concentrations.(1)|
01471|008|B||
01471|009|E|CLINICAL EFFECTS:  Concurrent use of azathioprine may result in decreased|
01471|010|E|effectiveness of warfarin.|
01471|011|B||
01471|012|P|PREDISPOSING FACTORS:  None determined.|
01471|013|B||
01471|014|M|PATIENT MANAGEMENT:  Patients maintained on warfarin should be closely|
01471|015|M|monitored if azathioprine is initiated or discontinued.  The dosage of|
01471|016|M|warfarin may need to be adjusted.|
01471|017|B||
01471|018|D|DISCUSSION:  In a case report, a 50 year-old female had been maintained on|
01471|019|D|warfarin at a dosage of 40 mg weekly for 2 years with INR values around 3.|
01471|020|D|During azathioprine therapy, her warfarin dosage requirements increased to|
01471|021|D|100-150 mg weekly with resultant INR values of 1.5-1.95.  Following the|
01471|022|D|discontinuation of azathioprine, her INR value increased to 8.3 and the dose|
01471|023|D|of warfarin was decreased to 40 mg weekly.(1)|
01471|024|D|   In a case report, a 32 year-old female had received a six week course of|
01471|025|D|warfarin at a dosage of 35 mg weekly.  Ten days after warfarin completion,|
01471|026|D|azathioprine was initiated and 9 days later the patient developed a deep|
01471|027|D|vein thrombosis.  While on azathioprine, the patient required a dose of|
01471|028|D|warfarin of 120 mg weekly to maintain an INR of 2.0-3.0.(2)|
01471|029|D|   In a case report, a 41 year-old female had been maintained on warfarin at|
01471|030|D|a dosage of 5 mg daily with therapeutic INR values.  Following the addition|
01471|031|D|of azathioprine to her regimen, she required a daily dose of warfarin of 12|
01471|032|D|mg to achieve a therapeutic INR.(3)|
01471|033|D|   In a case report, a patient maintained on azathioprine required a daily|
01471|034|D|dose of warfarin of 17 mg daily to maintain a therapeutic prothrombin time.|
01471|035|D|Following the discontinuation of azathioprine, the patient developed|
01471|036|D|intermittent epistaxis over a 6 week period.  The patient was admitted with|
01471|037|D|hematemesis and a prothrombin time of 32 seconds.  Warfarin was held and|
01471|038|D|later restarted at a daily dose of 5 mg.(4)|
01471|039|D|   In a case report, a 30 year-old female maintained on azathioprine and|
01471|040|D|prednisolone required a daily warfarin dose of 20 mg.  Warfarin dosage|
01471|041|D|required decreasing to 11 mg daily during azathioprine tapering from 150 mg|
01471|042|D|to 50 mg daily.  When azathioprine was reintroduced, the patient's INR fell|
01471|043|D|to 1.3 and warfarin had to be increased to 17 mg daily to maintain and INR|
01471|044|D|of 2.4.(5)|
01471|045|D|  In a case report, a 67 year-old female was treated with warfarin (24 mg|
01471|046|D|weekly) for over three years. After the initiation of azathioprine (150 mg|
01471|047|D|daily), warfarin dosage was increased to a mean dose of 60 to 75 mg weekly|
01471|048|D|over the next 18 months. Her dose of azathioprine was then increased to 200|
01471|049|D|mg daily and her warfarin dosage was increased to a mean dose of 130 mg|
01471|050|D|weekly to compensate for subtherapeutic INR levels. Her INR value before|
01471|051|D|azathioprine discontinuation was 1.8. Four weeks following azathioprine|
01471|052|D|discontinuation her INR was 14.0.(6)|
01471|053|B||
01471|054|R|REFERENCES:|
01471|055|B||
01471|056|R|1.Rotenberg M, Levy Y, Shoenfeld Y, Almog S, Ezra D. Effect of azathioprine|3
01471|057|R|  on the anticoagulant activity of warfarin. Ann Pharmacother 2000 Jan;|3
01471|058|R|  34(1):120-2.|3
01471|059|R|2.Havrda DE, Rathbun S, Scheid D. A case report of warfarin resistance due|3
01471|060|R|  to azathioprine and review of the literature. Pharmacotherapy 2001 Mar;|3
01471|061|R|  21(3):355-7.|3
01471|062|R|3.Walker J, Mendelson H, McClure A, Smith MD. Warfarin and azathioprine:|3
01471|063|R|  clinically significant drug interaction. J Rheumatol 2002 Feb;29(2):398-9.|3
01471|064|R|4.Singleton JD, Conyers L. Warfarin and azathioprine: an important drug|3
01471|065|R|  interaction. Am J Med 1992 Feb;92(2):217.|3
01471|066|R|5.Rivier G, Khamashta MA, Hughes GR. Warfarin and azathioprine: a drug|3
01471|067|R|  interaction does exist. Am J Med 1993 Sep;95(3):342.|3
01471|068|R|6.Ng HJ, Crowther MA. Azathioprine and inhibition of the anticoagulant|3
01471|069|R|  effect of warfarin: evidence from a case report and a literature review.|3
01471|070|R|  Am J Geriatr Pharmacother 2006 Mar;4(1):75-7.|3
01472|001|T|MONOGRAPH TITLE:  Valproic Acid/Carbapenem Antibiotics|
01472|002|B||
01472|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01472|004|L|of severe adverse interaction.|
01472|005|B||
01472|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Carbapenems may|
01472|007|A|inhibit the absorption of valproic acid from the gastrointestinal|
01472|008|A|tract.(1-3)  Meropenem may accelerate the renal excretion of valproate.(4)|
01472|009|A|Carbapenems may increase valproic acid intake by erythrocytes.(5,6)|
01472|010|A|Carbapenems may inhibit the metabolite of valproic acid, valproic|
01472|011|A|acid-glucuronide, from being converted back into the active parent|
01472|012|A|form.(7-9)|
01472|013|B||
01472|014|E|CLINICAL EFFECTS:  Concurrent use of carbapenems and valproic acid without|
01472|015|E|supplemental antiepileptic therapy is not recommended because it results in|
01472|016|E|rapid, significant reductions in serum levels of valproic acid to|
01472|017|E|non-therapeutic levels which may result in seizures.  Dose escalation of|
01472|018|E|valproic acid formulations does not counteract the decrease in serum levels|
01472|019|E|and patients will require additional antiepileptic therapy.  The effects may|
01472|020|E|persist for several days beyond discontinuation of the carbapenem.|
01472|021|B||
01472|022|P|PREDISPOSING FACTORS:  None determined.|
01472|023|B||
01472|024|M|PATIENT MANAGEMENT:  Avoid the use of carbapenem antibiotics in patients|
01472|025|M|maintained on valproic acid when possible.|
01472|026|M|   If concurrent therapy is warranted, patients will require the addition of|
01472|027|M|a supplemental anti-epileptic agent until valproic acid levels return to|
01472|028|M|therapeutic range.|
01472|029|B||
01472|030|D|DISCUSSION:  In a retrospective review of an 18 month period, charts of 39|
01472|031|D|patients who received concurrent therapy with valproate and meropenem were|
01472|032|D|examined.  A pharmacokinetic interaction was observed in all 39 patients,|
01472|033|D|with an average decrease in valproate levels of 66%.  The decrease occurred|
01472|034|D|within 24 hours of the initiation of concurrent therapy.  Electroclinical|
01472|035|D|deterioration was seen in 55% of patients.(10)|
01472|036|D|   A prospective study evaluated ICU patients given levetiracetam or|
01472|037|D|valproic acid to control seizures.  Twenty-four of the 35 patients required|
01472|038|D|meropenem.  Each patient that was on valproic acid had valproic acid levels|
01472|039|D|decrease following the addition of meropenum. (13)|
01472|040|D|   In a study in 23 healthy male subjects, concurrent doripenem (500 mg|
01472|041|D|every 8 hours) decreased the maximum concentration, (Cmax) area-under-curve|
01472|042|D|(AUC), and minimum concentration (Cmin) of valproic acid by 44.5%, 63% and|
01472|043|D|77.7%, respectively.(14)|
01472|044|D|   There are several case reports of decreased valproic acid levels|
01472|045|D|following the addition of meropenem to therapy.(4,11,12,15-21)  Some|
01472|046|D|patients experienced increased seizures.(4 ,11,15,16,20)  In some cases,|
01472|047|D|decreased levels persisted despite increased doses of valproic|
01472|048|D|acid.(11,12,15,17,18,21)  Others required additional anti-seizure|
01472|049|D|medications during concurrent therapy.(16)|
01472|050|D|   Decreased valproic acid levels have also been reported during concurrent|
01472|051|D|ertapenem.(22-25) Seizures were reported in two patients.(22,25)  In one|
01472|052|D|patient, valproic acid levels returned to therapeutic levels within three|
01472|053|D|days of discontinuation of ertapenem, despite no change in valproic acid|
01472|054|D|dose.(25)|
01472|055|D|   Decreased valproic acid levels have also been reported during concurrent|
01472|056|D|imipenem.(26)|
01472|057|D|   A retrospective study evaluated 52 patients given valproic acid and a|
01472|058|D|carbapenem over a five year period.  Patients received either ertapenem,|
01472|059|D|imipenem/cilastatin, or meropenem (9, 17, and 26 patients, respectively).|
01472|060|D|The average serum valproic acid concentration before and after carbapenem|
01472|061|D|use was 58.6 +/- 19.2 and 23.7 +/- 16.3 mg/dL, respectively, which|
01472|062|D|represented a decrease of 60% +/- 23% (p<0.001).  Valproic acid|
01472|063|D|concentrations were reduced with both intravenous and oral formulations of|
01472|064|D|valproic acid (52% +/- 16% and 61% +/-24%, respectively).  Valproic acid|
01472|065|D|serum concentrations were subtherapeutic (<50 mg/L) in 90% of patients|
01472|066|D|during carbapenem concurrent use.  Use during ertapenem,|
01472|067|D|imipenem/cilastatin, and meropenem decreased valproic acid concentrations by|
01472|068|D|72% +/- 17%, 42% +/- 22%, and 67% +/- 19%, respectively.(28)|
01472|069|D|   A retrospective study in 54 patients treated with valproic acid for at|
01472|070|D|least three months for seizure control were evaluated for changes in|
01472|071|D|valproic acid with concurrent carbapenem therapy.  The mean change in|
01472|072|D|valproic acid levels was 80%, 68%, and 51% in the meropenem, ertapenem, and|
01472|073|D|imipenem group, respectively.  During concurrent therapy, 48.1% of patients|
01472|074|D|experienced aggravation of seizures and 25.9% died.  Valproic acid levels of|
01472|075|D|those experiencing aggravation of seizures were 17.7 +/- 9.9 mcg/mL versus|
01472|076|D|17.9 +/- 12.6 mcg/mL in those without aggravation (p=0.944).(29)|
01472|077|D|   A retrospective study in 381 neurosurgery inpatients evaluated valproic|
01472|078|D|acid levels with concurrent meropenem therapy.  Patients were grouped based|
01472|079|D|on valproic acid dose of 1.2 g/day or 1.6 g/day with and without meropenem.|
01472|080|D|In both 1.2 g/day and 1.6 g/day valproic acid groups, valproic acid levels|
01472|081|D|were decreased after initiation of meropenem (67.3 +/- 4.6 mcg/mL v. 15.3|
01472|082|D|+/- 1.9 mcg/mL; 78.2% decrease, p<0.001 for 1.2 g/day valproic acid; 67.6|
01472|083|D|+/- 1.2 mcg/mL v. 18.1 +/- 2.6 mcg/mL; 72.5% decrease, p<0.001 for 1.6 g/day|
01472|084|D|valproic acid.  Valproic acid concentrations recovered to levels comparable|
01472|085|D|to valproic acid alone more than seven days after meropenem|
01472|086|D|discontinuation.(30)|
01472|087|B||
01472|088|R|REFERENCES:|
01472|089|B||
01472|090|R|1.Torii M, Takiguchi Y, Izumi M, Fukushima T, Yokota M. Carbapenem|5
01472|091|R|  antibiotics inhibit valproic acid transport in Caco-2 cell monolayers. Int|5
01472|092|R|  J Pharm 2002 Feb 21;233(1-2):253-6.|5
01472|093|R|2.Nakajima Y, Mizobuchi M, Nakamura M, Takagi H, Inagaki H, Kominami G,|5
01472|094|R|  Koike M, Yamaguchi T. Mechanism of the drug interaction between valproic|5
01472|095|R|  acid and carbapenem antibiotics in monkeys and rats. Drug Metab Dispos|5
01472|096|R|  2004 Dec;32(12):1383-91.|5
01472|097|R|3.Torii M, Takiguchi Y, Saito F, Izumi M, Yokota M. Inhibition by carbapenem|5
01472|098|R|  antibiotic imipenem of intestinal absorption of valproic acid in rats. J|5
01472|099|R|  Pharm Pharmacol 2001 Jun;53(6):823-9.|5
01472|100|R|4.Santucci M, Parmeggiani A, Riva R. Seizure worsening caused by decreased|3
01472|101|R|  serum valproate during meropenem therapy. J Child Neurol 2005 May;|3
01472|102|R|  20(5):456-7.|3
01472|103|R|5.Omoda K, Murakami T, Yumoto R, Nagai J, Maeda Y, Kiribayashi Y, Takano M.|3
01472|104|R|  Increased erythrocyte distribution of valproic acid in pharmacokinetic|3
01472|105|R|  interaction with carbapenem antibiotics in rat and human. J Pharm Sci 2005|3
01472|106|R|  Aug;94(8):1685-93.|3
01472|107|R|6.Ogawa K, Yumoto R, Hamada N, Nagai J, Takano M. Interaction of valproic|5
01472|108|R|  acid and carbapenem antibiotics with multidrug resistance-associated|5
01472|109|R|  proteins in rat erythrocyte membranes. Epilepsy Res 2006 Sep;71(1):76-87.|5
01472|110|R|7.Suzuki E, Yamamura N, Ogura Y, Nakai D, Kubota K, Kobayashi N, Miura S,|5
01472|111|R|  Okazaki O. Identification of valproic Acid glucuronide hydrolase as a key|5
01472|112|R|  enzyme for the interaction of valproic Acid with carbapenem antibiotics.|5
01472|113|R|  Drug Metab Dispos 2010 Sep;38(9):1538-44.|5
01472|114|R|8.Yokogawa K, Iwashita S, Kubota A, Sasaki Y, Ishizaki J, Kawahara M,|5
01472|115|R|  Matsushita R, Kimura K, Ichimura F, Miyamoto K. Effect of meropenem on|5
01472|116|R|  disposition kinetics of valproate and its metabolites in rabbits. Pharm|5
01472|117|R|  Res 2001 Sep;18(9):1320-6.|5
01472|118|R|9.Masuo Y, Ito K, Yamamoto T, Hisaka A, Honma M, Suzuki H. Characterization|5
01472|119|R|  of inhibitory effect of carbapenem antibiotics on the deconjugation of|5
01472|120|R|  valproic acid glucuronide. Drug Metab Dispos 2010 Oct;38(10):1828-35.|5
01472|121|R|10.Spriet I, Goyens J, Meersseman W, Wilmer A, Willems L, Van Paesschen W.|2
01472|122|R|   Interaction between valproate and meropenem: a retrospective study. Ann|2
01472|123|R|   Pharmacother 2007 Jul;41(7):1130-6.|2
01472|124|R|11.Coves-Orts FJ, Borras-Blasco J, Navarro-Ruiz A, Murcia-Lopez A,|3
01472|125|R|   Palacios-Ortega F. Acute seizures due to a probable interaction between|3
01472|126|R|   valproic acid and meropenem. Ann Pharmacother 2005 Mar;39(3):533-7.|3
01472|127|R|12.De Turck BJ, Diltoer MW, Cornelis PJ, Maes V, Spapen HD, Camu F, Huyghens|3
01472|128|R|   LP. Lowering of plasma valproic acid concentrations during concomitant|3
01472|129|R|   therapy with meropenem and amikacin. J Antimicrob Chemother 1998 Oct;|3
01472|130|R|   42(4):563-4.|3
01472|131|R|13.Mink S, Muroi C, Seule M, Bjeljac M, Keller E. Levetiracetam compared to|2
01472|132|R|   valproic acid: plasma concentration levels, adverse effects and|2
01472|133|R|   interactions in aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg|2
01472|134|R|   2011 Oct;113(8):644-8.|2
01472|135|R|14.Doribax (doripenem) US prescribing information. Shionogi, Inc. August,|1
01472|136|R|   2015.|1
01472|137|R|15.Fudio S, Carcas A, Pinana E, Ortega R. Epileptic seizures caused by low|3
01472|138|R|   valproic acid levels from an interaction with meropenem. J Clin Pharm|3
01472|139|R|   Ther 2006 Aug;31(4):393-6.|3
01472|140|R|16.Spriet I, Meersseman W, De Troy E, Wilmer A, Casteels M, Willems L.|3
01472|141|R|   Meropenem -valproic acid interaction in patients with cefepime-associated|3
01472|142|R|   status epilepticus. Am J Health Syst Pharm 2007 Jan 1;64(1):54-8.|3
01472|143|R|17.Clause D, Decleire PY, Vanbinst R, Soyer A, Hantson P. Pharmacokinetic|3
01472|144|R|   interaction between valproic acid and meropenem. Intensive Care Med 2005|3
01472|145|R|   Sep;31(9):1293-4.|3
01472|146|R|18.Nacarkucuk E, Saglam H, Okan M. Meropenem decreases serum level of|3
01472|147|R|   valproic acid. Pediatr Neurol 2004 Sep;31(3):232-4.|3
01472|148|R|19.Sala Pinol F, Padulles Zamora N, Hidalgo Albert E, Clemente Bautista S,|3
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01472|150|R|   interaction between valproic acid and meropenem. An Pediatr (Barc) 2006|3
01472|151|R|   Jan;64(1):93-5.|3
01472|152|R|20.Gu J, Huang Y. Effect of concomitant administration of meropenem and|3
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01472|154|R|   2009 Feb;7(1):26-33.|3
01472|155|R|21.Muzyk AJ, Candeloro CL, Christopher EJ. Drug interaction between|3
01472|156|R|   carbapenems and extended-release divalproex sodium in a  patient with|3
01472|157|R|   schizoaffective disorder. Gen Hosp Psychiatry 2010 Sep-Oct;|3
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01472|162|R|23.Invanz (ertapenem) US prescribing information. Merck & Co., Inc.|1
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01473|001|T|MONOGRAPH TITLE:  Busulfan/Selected Azole Antifungals; Levoketoconazole|
01473|002|B||
01473|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01473|004|L|take action as needed.|
01473|005|B||
01473|006|A|MECHANISM OF ACTION:  Itraconazole, ketoconazole, posaconazole,|
01473|007|A|voriconazole, and levoketoconazole may inhibit the metabolism of busulfan|
01473|008|A|via CYP3A4.(1-6)|
01473|009|B||
01473|010|E|CLINICAL EFFECTS:  Concurrent use of itraconazole, ketoconazole,|
01473|011|E|posaconazole, voriconazole, or levoketoconazole may result in elevated|
01473|012|E|levels of and toxicity from busulfan.(1-4)|
01473|013|B||
01473|014|P|PREDISPOSING FACTORS:  None determined.|
01473|015|B||
01473|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be closely|
01473|017|M|monitored for toxicity.(3)  The dosage of busulfan may need to be adjusted.|
01473|018|B||
01473|019|D|DISCUSSION:  In a study in patients undergoing bone marrow transplantation,|
01473|020|D|13 patients receiving concurrent busulfan and itraconazole were compared to|
01473|021|D|26 matched controls who did not receive an antifungal.  Busulfan clearance|
01473|022|D|was 20% lower in patients receiving concurrent itraconazole.(1)|
01473|023|D|   Itraconazole has been shown to decrease busulfan clearance by up to 25%|
01473|024|D|in patients receiving concurrent therapy(2,3) and may result in busulfan|
01473|025|D|area-under-curve (AUC) greater than 1,500 microM/min in some patients.(3)|
01473|026|B||
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01473|040|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
01473|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01473|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01473|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01473|044|R|  11/14/2017.|1
01473|045|R|6.Palmer J, McCune JS, Perales MA, Marks D, Bubalo J, Mohty M, Wingard JR,|6
01473|046|R|  Paci A, Hassan M, Bredeson C, Pidala J, Shah N, Shaughnessy P, Majhail N,|6
01473|047|R|  Schriber J, Savani BN, Carpenter PA. Personalizing busulfan-based|6
01473|048|R|  conditioning: considerations from the American Society for Blood and|6
01473|049|R|  Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow|6
01473|050|R|  Transplant 2016;1915-1925.|6
01474|001|T|MONOGRAPH TITLE:  Busulfan/Metronidazole|
01474|002|B||
01474|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01474|004|L|of severe adverse interaction.|
01474|005|B||
01474|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01474|007|B||
01474|008|E|CLINICAL EFFECTS:  Concurrent use of metronidazole may result in elevated|
01474|009|E|levels of and toxicity from busulfan.(1,2)|
01474|010|B||
01474|011|P|PREDISPOSING FACTORS:  None determined.|
01474|012|B||
01474|013|M|PATIENT MANAGEMENT:  The concurrent use of metronidazole and high-dose|
01474|014|M|busulfan is not recommended.(1)|
01474|015|B||
01474|016|D|DISCUSSION:  A study in stem-cell transplantation recipients examined 3|
01474|017|D|groups of patients.  Group A (n=5) received concurrent metronidazole and|
01474|018|D|busulfan.  Group B (n=9) received busulfan alone for 2 days, then concurrent|
01474|019|D|busulfan and metronidazole for 2 days.  Group C (n=10) received busulfan|
01474|020|D|without metronidazole.  Busulfan levels were 87% higher in Group A compared|
01474|021|D|Group C.  In Group B, busulfan levels were 79% higher during metronidazole|
01474|022|D|therapy than during busulfan alone.  In Group A, elevated liver|
01474|023|D|transaminases and bilirubin were seen in all patients, 1 patient died of|
01474|024|D|multiorgan failure, 3 developed veno-occlusive disease, and 1 developed|
01474|025|D|hemorrhagic cystitis.  In Group B, 6 patients had elevated liver function|
01474|026|D|tests, but there were no reports of veno-occlusive disease.(2)|
01474|027|B||
01474|028|R|REFERENCES:|
01474|029|B||
01474|030|R|1.Myleran (busulfan) US prescribing information. GlaxoSmithKline February,|1
01474|031|R|  2005.|1
01474|032|R|2.Nilsson C, Aschan J, Hentschke P, Ringden O, Ljungman P, Hassan M. The|2
01474|033|R|  effect of metronidazole on busulfan pharmacokinetics in patients|2
01474|034|R|  undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant|2
01474|035|R|  2003 Mar;31(6):429-35.|2
01475|001|T|MONOGRAPH TITLE:  Cisapride/QT Prolonging Agents|
01475|002|B||
01475|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01475|004|L|is contraindicated and generally should not be dispensed or administered to|
01475|005|L|the same patient.|
01475|006|B||
01475|007|A|MECHANISM OF ACTION:  Torsades de pointes has been reported with cisapride.|
01475|008|A|Concurrent use with other agents that prolong the QTc interval may result in|
01475|009|A|additive effects on the QTc interval.(1)|
01475|010|B||
01475|011|E|CLINICAL EFFECTS:  The concurrent use of cisapride with other agents that|
01475|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01475|013|E|arrhythmias, including torsades de pointes.(1)|
01475|014|B||
01475|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01475|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01475|017|P|failure, myocardial infarction, history of torsade de pointes, congenital|
01475|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01475|019|P|female gender, or advanced age.(3)|
01475|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01475|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01475|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01475|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01475|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01475|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01475|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01475|027|B||
01475|028|M|PATIENT MANAGEMENT:  The Australian manufacturer of cisapride states that|
01475|029|M|concurrent use of agents known to prolong the QTc interval with cisapride is|
01475|030|M|contraindicated.(1)|
01475|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01475|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01475|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01475|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01475|035|B||
01475|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01475|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01475|038|D|monograph have been shown to prolong the QTc interval either through their|
01475|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01475|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01475|041|D|clinical trials and/or postmarketing reports.(2)|
01475|042|D|   One or more of the drug pairs linked to this monograph have been included|
01475|043|D|in a list of interactions that should be considered "high-priority" for|
01475|044|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01475|045|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01475|046|D|Coordinator (ONC) for Health Information Technology.|
01475|047|B||
01475|048|R|REFERENCES:|
01475|049|B||
01475|050|R|1.Prepulsid (cisapride) Australian prescribing information. Janssen-Cilag|1
01475|051|R|  Pty Limited January 25, 2003.|1
01475|052|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01475|053|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01475|054|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01475|055|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01475|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01475|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01475|058|R|  settings: a scientific statement from the American Heart Association and|6
01475|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01475|060|R|  2;55(9):934-47.|6
01475|061|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01475|062|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01475|063|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01475|064|R|  19(5):735-43.|6
01476|001|T|MONOGRAPH TITLE:  Olanzapine/Fluvoxamine|
01476|002|B||
01476|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01476|004|L|take action as needed.|
01476|005|B||
01476|006|A|MECHANISM OF ACTION:  Fluvoxamine may inhibit the metabolism of olanzapine|
01476|007|A|by CYP1A2.(1-5)|
01476|008|B||
01476|009|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine may result in elevated|
01476|010|E|levels of and toxicity from olanzapine.|
01476|011|B||
01476|012|P|PREDISPOSING FACTORS:  None determined.|
01476|013|B||
01476|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
01476|015|M|monitored for olanzapine side effects.  The dose of olanzapine may need to|
01476|016|M|be adjusted if fluvoxamine is initiated or discontinued.|
01476|017|B||
01476|018|D|DISCUSSION:  In a study in 10 male smokers with schizophrenia, pretreatment|
01476|019|D|with fluvoxamine (100 mg daily for 10 days) increased olanzapine|
01476|020|D|area-under-curve (AUC), maximum concentration (Cmax), and half-life by|
01476|021|D|30-50%, 12-64%, and by 25-32%, respectively.  Olanzapine volume of|
01476|022|D|distribution and clearance were decreased by 4-26% and 26-38%,|
01476|023|D|respectively.(1)|
01476|024|D|   In a study in 8 schizophrenic patients, the addition of fluvoxamine (100|
01476|025|D|mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from|
01476|026|D|12-112%.  N-desmethylolanzapine levels were not significantly affected.(2)|
01476|027|D|   In a retrospective review, 10 patients receiving concurrent fluvoxamine|
01476|028|D|and olanzapine were compared to 134 patients receiving olanzapine alone. The|
01476|029|D|ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients|
01476|030|D|receiving concurrent fluvoxamine.(3)|
01476|031|D|   Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and|
01476|032|D|by 52%, respectively, in female nonsmokers.  Fluvoxamine has been shown to|
01476|033|D|increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male|
01476|034|D|smokers.(4,5)|
01476|035|B||
01476|036|R|REFERENCES:|
01476|037|B||
01476|038|R|1.Chiu CC, Lane HY, Huang MC, Liu HC, Jann MW, Hon YY, Chang WH, Lu ML.|2
01476|039|R|  Dose-dependent alternations in the pharmacokinetics of olanzapine during|2
01476|040|R|  coadministration of fluvoxamine in patients with schizophrenia. J Clin|2
01476|041|R|  Pharmacol 2004 Dec;44(12):1385-90.|2
01476|042|R|2.Hiemke C, Peled A, Jabarin M, Hadjez J, Weigmann H, Hartter S, Modai I,|2
01476|043|R|  Ritsner M, Silver H. Fluvoxamine augmentation of olanzapine in chronic|2
01476|044|R|  schizophrenia: pharmacokinetic interactions and clinical effects. J Clin|2
01476|045|R|  Psychopharmacol 2002 Oct;22(5):502-6.|2
01476|046|R|3.Weigmann H, Gerek S, Zeisig A, Muller M, Hartter S, Hiemke C. Fluvoxamine|2
01476|047|R|  but not sertraline inhibits the metabolism of olanzapine: evidence from a|2
01476|048|R|  therapeutic drug monitoring service. Ther Drug Monit 2001 Aug;23(4):410-3.|2
01476|049|R|4.Zyprexa (olanzapine) Australian prescribing information. Eli Lilly Pty Ltd|1
01476|050|R|  November 30, 2006.|1
01476|051|R|5.Zyprexa Relprevv (olanzapine ext-rel IM susp.) US prescribing information.|1
01476|052|R|  Eli Lilly and Company February, 2017.|1
01477|001|T|MONOGRAPH TITLE:  Buspirone/Strong CYP3A4 Inhibitors|
01477|002|B||
01477|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01477|004|L|take action as needed.|
01477|005|B||
01477|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
01477|007|A|of buspirone.(1-4)|
01477|008|B||
01477|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
01477|010|E|elevated levels of and increased effects from buspirone, including|
01477|011|E|lightheadedness, asthenia, dizziness, and somnolence.(1-4)|
01477|012|B||
01477|013|P|PREDISPOSING FACTORS:  None determined.|
01477|014|B||
01477|015|M|PATIENT MANAGEMENT:  The Australian,(2) UK,(3) and US(4) manufacturers of|
01477|016|M|buspirone recommend a lower dose of 2.5 mg twice daily of buspirone in|
01477|017|M|patients receiving strong CYP3A4 inhibitors.|
01477|018|B||
01477|019|D|DISCUSSION:  In a study in 8 healthy subjects, pretreatment with 4 days of|
01477|020|D|erythromycin (1.5 g/day) increased the area-under curve (AUC) and maximum|
01477|021|D|concentration (Cmax) of a single dose of buspirone (10 mg) by 6-fold and|
01477|022|D|5-fold, respectively.  The relative increase in buspirone AUC varied by|
01477|023|D|15-fold. There was a significant difference in scores on the Digit Symbol|
01477|024|D|Substitution test when buspirone was administered with erythromycin.(1)|
01477|025|D|   In a study in 8 healthy subjects, pretreatment with itraconazole (200 mg|
01477|026|D|daily for 4 days) increased the Cmax and AUC of buspirone by 13-fold and|
01477|027|D|19-fold, respectively.(1,2)  However, only the Critical Flicker Fusion test|
01477|028|D|showed statistically significant differences when compared to the|
01477|029|D|administration of buspirone alone.(1)|
01477|030|D|   In a study in 6 subjects, pretreatment with itraconazole (200 mg daily|
01477|031|D|for 4 days) increased the Cmax and AUC of buspirone by 10.5-fold and|
01477|032|D|14.5-fold, respectively.  The Cmax and AUC of the piperazine metabolite of|
01477|033|D|buspirone increased by 57% and 50%, respectively.(3)|
01477|034|D|   In a study in healthy subjects, concurrent use of buspirone (2.5 mg or 5|
01477|035|D|mg twice daily) with nefazodone (250 mg twice daily) resulted in increases|
01477|036|D|in the Cmax and AUC of buspirone, up to 20-fold and up to 50-fold,|
01477|037|D|respectively.  The concentration of 1-pyrimidinylpiperazine (a buspirone|
01477|038|D|metabolite) decreased 50%.(4)|
01477|039|B||
01477|040|R|REFERENCES:|
01477|041|B||
01477|042|R|1.Kivisto KT, Lamberg TS, Kantola T, Neuvonen PJ. Plasma buspirone|2
01477|043|R|  concentrations are greatly increased by erythromycin and itraconazole.|2
01477|044|R|  Clin Pharmacol Ther 1997 Sep;62(3):348-54.|2
01477|045|R|2.Buspar (buspirone hydrochloride) Australian prescribing information.|1
01477|046|R|  Bristol-Myers Squibb Australia Pty Ltd. October 10, 2001.|1
01477|047|R|3.Buspar (buspirone hydrochloride) UK summary of product characteristics.|1
01477|048|R|  Bristol-Myers Squibb Pharmaceuticals Limited August 6, 2002.|1
01477|049|R|4.BuSpar (buspirone hydrochloride) US prescribing information. Bristol Myers|1
01477|050|R|  Squibb Company September, 2007.|1
01477|051|R|5.Kivisto KT, Lamberg TS, Neuvonen PJ. Interactions of buspirone with|2
01477|052|R|  itraconazole and rifampicin: effects on the pharmacokinetics of the active|2
01477|053|R|  1-(2-pyrimidinyl)-piperazine metabolite of buspirone. Pharmacol Toxicol|2
01477|054|R|  1999 Feb;84(2):94-7.|2
01478|001|T|MONOGRAPH TITLE:  Disopyramide/QT Prolonging Agents|
01478|002|B||
01478|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01478|004|L|is contraindicated and generally should not be dispensed or administered to|
01478|005|L|the same patient.|
01478|006|B||
01478|007|A|MECHANISM OF ACTION:  Concurrent use of disopyramide and agents known to|
01478|008|A|prolong the QT interval may result in additive or synergistic effects on the|
01478|009|A|QTc interval.(1)|
01478|010|B||
01478|011|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01478|012|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01478|013|E|torsades de pointes.|
01478|014|B||
01478|015|P|PREDISPOSING FACTORS:  The risk of torsades de pointes may be increased in|
01478|016|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01478|017|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
01478|018|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
01478|019|P|advanced age.(3)|
01478|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01478|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01478|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01478|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01478|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01478|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01478|026|P|drug metabolism or and/or renal/hepatic dysfunction).(3)|
01478|027|B||
01478|028|M|PATIENT MANAGEMENT:  The Australian manufacturer of disopyramide states that|
01478|029|M|concurrent use with agents liable to produce torsades de pointes, including|
01478|030|M|tricyclic or tetracyclic antidepressants, erythromycin, vincamine, and|
01478|031|M|sultopride, is contraindicated.(1)|
01478|032|M|   If alternatives are not available and concurrent therapy is deemed|
01478|033|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
01478|034|M|and monitor ECG at baseline and at regular intervals.  Correct any|
01478|035|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01478|036|M|heartbeat, dizziness, or fainting.|
01478|037|B||
01478|038|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01478|039|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01478|040|D|monograph have been shown to prolong the QTc interval either through their|
01478|041|D|mechanism of action, through studies on their effects on the QTc interval,|
01478|042|D|or through reports of QTc prolongation and/or torsades de pointes in|
01478|043|D|clinical trials and/or postmarketing reports.(2)|
01478|044|D|   One or more of the drug pairs linked to this monograph have been included|
01478|045|D|in a list of interactions that should be considered "high-priority" for|
01478|046|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01478|047|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01478|048|D|Coordinator (ONC) for Health Information Technology.|
01478|049|B||
01478|050|R|REFERENCES:|
01478|051|B||
01478|052|R|1.Rythmodan (disopyramide) Australian prescribing information. Aventis|1
01478|053|R|  Pharma Pty Ltd. September 22, 2000.|1
01478|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01478|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01478|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01478|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01478|058|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01478|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01478|060|R|  settings: a scientific statement from the American Heart Association and|6
01478|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01478|062|R|  2;55(9):934-47.|6
01478|063|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01478|064|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01478|065|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01478|066|R|  19(5):735-43.|6
01479|001|T|MONOGRAPH TITLE:  Disopyramide/Class Ia and III Antiarrhythmics|
01479|002|B||
01479|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01479|004|L|is contraindicated and generally should not be dispensed or administered to|
01479|005|L|the same patient.|
01479|006|B||
01479|007|A|MECHANISM OF ACTION:  Disopyramide has been shown to prolong the QTc|
01479|008|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01479|009|A|may result in additive effects on the QTc interval.(1)|
01479|010|B||
01479|011|E|CLINICAL EFFECTS:  The concurrent use of disopyramide with other agents that|
01479|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01479|013|E|arrhythmias, including torsades de pointes.(1)|
01479|014|B||
01479|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by|
01479|016|P|reduced creatinine clearance, female gender, larger doses of sotalol, and a|
01479|017|P|history of cardiomegaly or congestive heart failure.(1)  Risk may also be|
01479|018|P|increased in patients with cardiovascular disease (e.g. myocardial|
01479|019|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
01479|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, or advanced age.(2)|
01479|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01479|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01479|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01479|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01479|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01479|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01479|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01479|028|B||
01479|029|M|PATIENT MANAGEMENT:  The Australian manufacturer of disopyramide states that|
01479|030|M|the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV|
01479|031|M|is contraindicated.(1)|
01479|032|M|   If concurrent therapy is deemed medically necessary, obtain serum|
01479|033|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
01479|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01479|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01479|036|B||
01479|037|D|DISCUSSION:  Because combinations of antiarrhythmics are not well researched|
01479|038|D|and concurrent use may result in unpredictable effects, the Australian|
01479|039|D|manufacturer of disopyramide states that the concurrent use of other|
01479|040|D|antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1)|
01479|041|D|   Agents that are linked to this monograph may have varying degrees of|
01479|042|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
01479|043|D|been shown to prolong the QTc interval either through their mechanism of|
01479|044|D|action, through studies on their effects on the QTc interval, or through|
01479|045|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01479|046|D|and/or postmarketing reports.(3)|
01479|047|D|   One or more of the drug pairs linked to this monograph have been included|
01479|048|D|in a list of interactions that should be considered "high-priority" for|
01479|049|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01479|050|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01479|051|D|Coordinator (ONC) for Health Information Technology.|
01479|052|B||
01479|053|R|REFERENCES:|
01479|054|B||
01479|055|R|1.Rythmodan (disopyramide) Australian prescribing information. Aventis|1
01479|056|R|  Pharma Pty Ltd. September 22, 2000.|1
01479|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01479|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01479|059|R|  settings: a scientific statement from the American Heart Association and|6
01479|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01479|061|R|  2;55(9):934-47.|6
01479|062|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01479|063|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01479|064|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01479|065|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01479|066|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01479|067|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01479|068|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01479|069|R|  19(5):735-43.|6
01480|001|T|MONOGRAPH TITLE:  Fentanyl/MAOIs|
01480|002|B||
01480|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01480|004|L|is contraindicated and generally should not be dispensed or administered to|
01480|005|L|the same patient.|
01480|006|B||
01480|007|A|MECHANISM OF ACTION:  Fentanyl may inhibit neuronal reuptake of serotonin.|
01480|008|A|MAOIs increase neuronal serotonin concentration via inhibition of MAO-A.|
01480|009|B||
01480|010|E|CLINICAL EFFECTS:  The concurrent use of fentanyl with MAOIs may result in|
01480|011|E|symptoms of serotonin syndrome, including hypertension, hyperpyrexia,|
01480|012|E|sedation, somnolence, and death.(1-4)|
01480|013|B||
01480|014|P|PREDISPOSING FACTORS:  Higher opioid concentrations as may occur due to|
01480|015|P|inhibition of opioid clearance, patient specific genomic factors (e.g. poor|
01480|016|P|metabolizer status for a specific P450 enzyme), or high opioid dosage may|
01480|017|P|increase the risk for a severe interaction.|
01480|018|B||
01480|019|M|PATIENT MANAGEMENT:  The Australian manufacturers of fentanyl injection(4)|
01480|020|M|and fentanyl lozenges(5) state that concurrent use with or use within 2|
01480|021|M|weeks of discontinuation of an MAOI is contraindicated.|
01480|022|M|   The US manufacturers of fentanyl lozenges(6) and patches(7) state that|
01480|023|M|use in patients who have received an MAOI in the previous 14 days is not|
01480|024|M|recommended.  The US manufacturer of fentanyl injection states that use in|
01480|025|M|patients who have received an MAOI in the previous 14 days should be|
01480|026|M|monitored and vasodilators and beta-blockers should be available for the|
01480|027|M|treatment of hypertension.(8)|
01480|028|B||
01480|029|D|DISCUSSION:  The interaction between another opioid, meperidine, and MAOIs|
01480|030|D|has been well documented.(9,10)  There are two reports of potential|
01480|031|D|interactions between MAOIs and dextromethorphan.(1,2)|
01480|032|D|   At least one fatality has been reported from the use of fentanyl during|
01480|033|D|surgery in a patient receiving an MAOI.(3)|
01480|034|D|   Furazolidone is known to inhibit MAO.|
01480|035|D|   One or more of the drug pairs linked to this monograph have been included|
01480|036|D|in a list of interactions that should be considered "high-priority" for|
01480|037|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01480|038|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01480|039|D|Coordinator (ONC) for Health Information Technology.|
01480|040|B||
01480|041|R|REFERENCES:|
01480|042|B||
01480|043|R|1.Rivers N, Horner B. Possible lethal reaction between Nardil and|3
01480|044|R|  dextromethorphan. Can Med Assoc J 1970 Jul;103:85.|3
01480|045|R|2.Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine|3
01480|046|R|  oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988 Dec 22;|3
01480|047|R|  319(25):1671.|3
01480|048|R|3.Noble WH, Baker A. MAO inhibitors and coronary artery surgery: a patient|3
01480|049|R|  death. Can J Anaesth 1992 Dec;39(10):1061-6.|3
01480|050|R|4.DBL fentanyl injection Australian prescribing information. FH Faulding &|1
01480|051|R|  Co Limited t/a David Bull Laboratories October 31, 2003.|1
01480|052|R|5.Actiq (fentanyl citrate) Australian prescribing information. Orphan|1
01480|053|R|  Australia Pty Ltd. November 2, 2002.|1
01480|054|R|6.Actiq (fentanyl citrate) US prescribing information. Cephalon, Inc.|1
01480|055|R|  October, 2019.|1
01480|056|R|7.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
01480|057|R|  Inc. October, 2019.|1
01480|058|R|8.Sublimaze (fentanyl citrate) US prescribing information. Akorn, Inc.|1
01480|059|R|  October, 2019.|1
01480|060|R|9.Huang V, Gortney JS. Risk of serotonin syndrome with concomitant|6
01480|061|R|  administration of linezolid and serotonin agonists. Pharmacotherapy 2006|6
01480|062|R|  Dec;26(12):1784-93.|6
01480|063|R|10.Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin|6
01480|064|R|   toxicity. Br J Anaesth 2005 Oct;95(4):434-41.|6
01480|065|R|11.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
01480|066|R|   warns about several safety issues with opioid pain medicines; requires|1
01480|067|R|   label changes. available at:|1
01480|068|R|   http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
01480|069|R|12.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01480|070|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01480|071|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01480|072|R|   19(5):735-43.|6
01481|001|T|MONOGRAPH TITLE:  Amiodarone/Fentanyl|
01481|002|B||
01481|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01481|004|L|take action as needed.|
01481|005|B||
01481|006|A|MECHANISM OF ACTION:  Fentanyl, a potent opioid with a narrow therapeutic|
01481|007|A|window, is metabolized via CYP3A4.  Amiodarone is a weak inhibitor of|
01481|008|A|CYP3A4.(1)|
01481|009|B||
01481|010|E|CLINICAL EFFECTS:  Concurrent use of amiodarone may result in increased|
01481|011|E|levels and toxicity of fentanyl.(2)|
01481|012|B||
01481|013|P|PREDISPOSING FACTORS:  Interaction effects may be magnified in patients on|
01481|014|P|more than one inhibitor of CYP3A4. Heat.|
01481|015|B||
01481|016|M|PATIENT MANAGEMENT:  If co-administration is necessary, caution is advised|
01481|017|M|when initiating or discontinuing concurrent treatment, particularly if the|
01481|018|M|patient is also receiving concurrent treatment with other CYP3A4 inhibitors|
01481|019|M|(e.g. systemic azole antifungals, clarithromycin, protease inhibitors).(2)|
01481|020|M|   Respiratory depression can occur at any time during opioid therapy,|
01481|021|M|especially during therapy initiation and following dosage increases.  The|
01481|022|M|risk of opioid-related overdose or overdose-related death is increased with|
01481|023|M|higher opioid doses, and this risk persists over the course of therapy.|
01481|024|M|Consider these risks when using concurrently with agents that may increase|
01481|025|M|opioid drug levels.(3)|
01481|026|M|   Monitor for increased adverse effects such as respiratory suppression or|
01481|027|M|increased sedation if amiodarone is added to existing fentanyl therapy.|
01481|028|M|Patients already receiving amiodarone and newly starting on fentanyl therapy|
01481|029|M|may be more sensitive to fentanyl effects and may need lower than usual|
01481|030|M|doses.(2)|
01481|031|M|   Evaluate patients at frequent intervals and consider dose adjustments|
01481|032|M|until stable drug effects are achieved.|
01481|033|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
01481|034|M|patients when prescribing or renewing an opioid analgesic or medicine to|
01481|035|M|treat opioid use disorder (OUD).  Consider prescribing opioid reversal|
01481|036|M|agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
01481|037|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
01481|038|M|as those taking CNS depressants) and when a patient has household|
01481|039|M|members/close contacts at risk for accidental overdose. Discuss the options|
01481|040|M|for obtaining an opioid reversal agent (e.g., prescription,|
01481|041|M|over-the-counter, or as part of a community-based program).(4)|
01481|042|M|   Avoid exposing the fentanyl patch application site and surrounding area|
01481|043|M|to direct external heat sources as there have been reports of overdose and|
01481|044|M|death as a result of exposure to heat.(2)|
01481|045|B||
01481|046|D|DISCUSSION:  Studies and case reports of concomitant amiodarone and fentanyl|
01481|047|D|administration focus on perioperative use.|
01481|048|D|   A study was performed to evaluate the combination of amiodarone and|
01481|049|D|fentanyl in the operative setting.(5)  This was a prospective, randomized,|
01481|050|D|double-blind placebo controlled trial to evaluate the risk for hemodynamic|
01481|051|D|compromise in 84 cardiac patients undergoing bypass or valve surgery.|
01481|052|D|Patients were started on one of two oral amiodarone loading regimens or|
01481|053|D|placebo 1 to 5 days prior to surgery.  All patients received fentanyl as a|
01481|054|D|component of anesthesia therapy during the procedure.  Although systolic BP|
01481|055|D|was lower in amiodarone patients both pre-fentanyl and post-bypass, there|
01481|056|D|were no adverse events.|
01481|057|D|   A retrospective study compared patients who received concurrent|
01481|058|D|amiodarone and fentanyl anesthesia to patients who received fentanyl alone.|
01481|059|D|Patients who received concurrent amiodarone had more episodes of low|
01481|060|D|systemic vascular resistance and required more hemodynamic support with|
01481|061|D|intra-arterial balloon placement.  In the group receiving concurrent|
01481|062|D|amiodarone, 66% developed bradycardia, complete heart block, or became|
01481|063|D|pacemaker-dependent compared to 17% of patients who did not receive|
01481|064|D|amiodarone.(6)|
01481|065|D|   There are several reports of serious complications including bradycardia,|
01481|066|D|hypotension, marked reduction in cardiac output, and sinus arrest in|
01481|067|D|patients receiving concurrent amiodarone and fentanyl anesthesia.(7-11)|
01481|068|D|   A study in healthy subjects shown that the application of heat over the|
01481|069|D|fentanyl patch system increased mean overall fentanyl exposure by 120% and|
01481|070|D|average maximum fentanyl level by 61%.(2)|
01481|071|B||
01481|072|R|REFERENCES:|
01481|073|B||
01481|074|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
01481|075|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01481|076|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01481|077|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01481|078|R|  11/14/2017.|1
01481|079|R|2.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
01481|080|R|  Inc. October, 2019.|1
01481|081|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
01481|082|R|  prescribing information for all opioid pain medicines to provide|1
01481|083|R|  additional guidance for safe use. Available at:|1
01481|084|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
01481|085|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
01481|086|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
01481|087|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
01481|088|R|  recommends health care professionals discuss naloxone with all patients|1
01481|089|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
01481|090|R|  disorder. Available at:|1
01481|091|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
01481|092|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
01481|093|R|  d-pain July 23, 2020.|1
01481|094|R|5.White CM, Dunn A, Tsikouris J, Waberski W, Felton K, Freeman-Bosco L, Giri|2
01481|095|R|  S, Kluger J. An assessment of the safety of short-term amiodarone therapy|2
01481|096|R|  in cardiac surgical  patients with fentanyl-isoflurane anesthesia. Anesth|2
01481|097|R|  Analg 1999 Sep;89(3):585-9.|2
01481|098|R|6.Liberman BA, Teasdale SJ. Anaesthesia and amiodarone. Can Anaesth Soc J|2
01481|099|R|  1985 Nov;32(6):629-38.|2
01481|100|R|7.Gallagher JD, Lieberman RW, Meranze J, Spielman SR, Ellison N.|3
01481|101|R|  Amiodarone-induced complications during coronary artery surgery.|3
01481|102|R|  Anesthesiology 1981 Aug;55(2):186-8.|3
01481|103|R|8.MacKinnon G, Landymore R, Marble A. Should oral amiodarone be used for|3
01481|104|R|  sustained ventricular tachycardia in patients requiring open-heart|3
01481|105|R|  surgery?. Can J Surg 1983 Jul;26(4):355-7.|3
01481|106|R|9.Navalgund AA, Alifimoff JK, Jakymec AJ, Bleyaert AL. Amiodarone-induced|3
01481|107|R|  sinus arrest successfully treated with ephedrine and isoproterenol. Anesth|3
01481|108|R|  Analg 1986 Apr;65(4):414-6.|3
01481|109|R|10.Koblin DD, Romanoff ME, Martin DE, Hensley FA Jr, Larach DR, Stauffer RA,|3
01481|110|R|   Luck JC Jr. Anesthetic management of the parturient receiving amiodarone.|3
01481|111|R|   Anesthesiology 1987 Apr;66(4):551-3.|3
01481|112|R|11.Meulendyk J. Anesthetic considerations with amiodarone: report of a case.|3
01481|113|R|   J Am Osteopath Assoc 1984 Apr;83(8):585-8.|3
01482|001|T|MONOGRAPH TITLE:  ACE Inhibitors/High-Dose Aspirin|
01482|002|B||
01482|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01482|004|L|take action as needed.|
01482|005|B||
01482|006|A|MECHANISM OF ACTION:  Aspirin's inhibition of prostaglandin synthesis may|
01482|007|A|inhibit the release of vasodilating prostaglandins by ACE inhibitors.|
01482|008|B||
01482|009|E|CLINICAL EFFECTS:  Concurrent use of aspirin may result in decreased|
01482|010|E|antihypertensive effects of the ACE inhibitor.|
01482|011|B||
01482|012|P|PREDISPOSING FACTORS:  None determined.|
01482|013|B||
01482|014|M|PATIENT MANAGEMENT:  Monitor patients receiving doses of aspirin higher than|
01482|015|M|150 mg daily for decreased antihypertensive effects of their ACE inhibitor.|
01482|016|M|The use of alternative agents may need to be considered.|
01482|017|B||
01482|018|D|DISCUSSION:  Several studies have documented decreased effectiveness of|
01482|019|D|various ACE inhibitors, including captopril, enalapril, and lisinopril|
01482|020|D|following the addition of aspirin therapy.  Conflicting evidence exists on|
01482|021|D|the use of small (less than 150 mg) daily doses of aspirin with ACE|
01482|022|D|inhibitors, although some guidelines still suggest they may be beneficial.|
01482|023|D|   One or more of the drug pairs linked to this monograph have been included|
01482|024|D|in a list of interactions that could be considered for classification as|
01482|025|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
01482|026|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
01482|027|D|Health Information Technology.|
01482|028|B||
01482|029|R|REFERENCES:|
01482|030|B||
01482|031|R|1.Dzeka TN, Townley R, Arnold JM. Effects of enalaprilat on venoconstriction|2
01482|032|R|  to norepinephrine: role of prostaglandins. Cardiovasc Res 2003 Jul 1;|2
01482|033|R|  59(1):250-6.|2
01482|034|R|2.Viecili PR, Pamplona D, Park M, Silva SR, Ramires JA, Da Luz PL.|2
01482|035|R|  Antagonism of the acute hemodynamic effects of captopril in decompensated|2
01482|036|R|  congestive heart failure by aspirin administration. Braz J Med Biol Res|2
01482|037|R|  2003 Jun;36(6):771-80.|2
01482|038|R|3.Savenkov MP, Ivanov SN, Brodskaia SA. Antihypertensive effect of enalapril|2
01482|039|R|  and lisinopril administered in combination with nonsteroid|2
01482|040|R|  anti-inflammatory agents. Ter Arkh 2001;73(9):27-31.|2
01482|041|R|4.Nawarskas JJ, Townsend RR, Cirigliano MD, Spinler SA. Effect of aspirin on|2
01482|042|R|  blood pressure in hypertensive patients taking enalapril or losartan. Am J|2
01482|043|R|  Hypertens 1999 Aug;12(8 Pt 1):784-9.|2
01482|044|R|5.Guazzi M, Pontone G, Agostoni P. Aspirin worsens exercise performance and|2
01482|045|R|  pulmonary gas exchange in patients with heart failure who are taking|2
01482|046|R|  angiotensin-converting enzyme inhibitors. Am Heart J 1999 Aug;138(2 Pt|2
01482|047|R|  1):254-60.|2
01482|048|R|6.Katz SD, Radin M, Graves T, Hauck C, Block A, LeJemtel TH. Effect of|2
01482|049|R|  aspirin and ifetroban on skeletal muscle blood flow in patients with|2
01482|050|R|  congestive heart failure treated with Enalapril. Ifetroban Study Group. J|2
01482|051|R|  Am Coll Cardiol 1999 Jul;34(1):170-6.|2
01482|052|R|7.Leor J, Reicher-Reiss H, Goldbourt U, Boyko V, Gottlieb S, Battler A,|2
01482|053|R|  Behar S. Aspirin and mortality in patients treated with|2
01482|054|R|  angiotensin-converting enzyme inhibitors: a cohort study of 11,575|2
01482|055|R|  patients with coronary artery disease. J Am Coll Cardiol 1999 Jun;|2
01482|056|R|  33(7):1920-5.|2
01482|057|R|8.Guazzi MD, Campodonico J, Celeste F, Guazzi M, Santambrogio G, Rossi M,|2
01482|058|R|  Trabattoni D, Alimento M. Antihypertensive efficacy of angiotensin|2
01482|059|R|  converting enzyme inhibition and aspirin counteraction. Clin Pharmacol|2
01482|060|R|  Ther 1998 Jan;63(1):79-86.|2
01482|061|R|9.Alimento M, Campodonico J, Santambrogio G, Rossi M, Trabattoni D, Celeste|2
01482|062|R|  F, Guazzi M. The antagonistic effect of aspirin on the expression of|2
01482|063|R|  prostaglandin participation in the antihypertensive activity of ACE|2
01482|064|R|  inhibitors. Cardiologia 1997 Jun;42(6):605-10.|2
01482|065|R|10.Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and|2
01482|066|R|   aspirin on mortality after acute myocardial infarction: subgroup analysis|2
01482|067|R|   of the Cooperative New Scandinavian Enalapril Survival Study II|2
01482|068|R|   (CONSENSUS II). Am J Cardiol 1997 Jan 15;79(2):115-9.|2
01482|069|R|11.Boger RH, Bode-Boger SM, Kramme P, Tsikas D, Gutzki FM, Frolich JC.|2
01482|070|R|   Effect of captopril on prostacyclin and nitric oxide formation in healthy|2
01482|071|R|   human subjects: interaction with low dose acetylsalicylic acid. Br J Clin|2
01482|072|R|   Pharmacol 1996 Dec;42(6):721-7.|2
01482|073|R|12.Hall D, Zeitler H, Rudolph W. Counteraction of the vasodilator effects of|2
01482|074|R|   enalapril by aspirin in severe heart failure. J Am Coll Cardiol 1992 Dec;|2
01482|075|R|   20(7):1549-55.|2
01482|076|R|13.MacIntrye IM, Jhund PS, McMurray JJ. Aspirin inhibits the acute arterial|2
01482|077|R|   and venous vasodilator response to captopril in patients with chronic|2
01482|078|R|   heart failure. Cardiovasc Drugs Ther 2005 Aug;19(4):261-5.|2
01482|079|R|14.Di Gennaro FP, Cingolani OH, Abbate AF, Toblli JE, Vilches A. High doses|2
01482|080|R|   of aspirin reduce natriuresis in hypertensive patients treated with|2
01482|081|R|   enalapril. Medicina (B Aires) 2004;64(4):301-5.|2
01482|082|R|15.Meune C, Mahe I, Mourad JJ, Cohen-Solal A, Levy B, Kevorkian JP, Jondeau|2
01482|083|R|   G, Habib A, Lebret M, Knellwolf AL, Simoneau G, Caulin C, Bergmann JF.|2
01482|084|R|   Aspirin alters arterial function in patients with chronic heart failure|2
01482|085|R|   treated with ACE inhibitors: a dose-mediated deleterious effect. Eur J|2
01482|086|R|   Heart Fail 2003 Jun;5(3):271-9.|2
01482|087|R|16.Ahmed A. Interaction between aspirin and angiotensin-converting enzyme|6
01482|088|R|   inhibitors: should they be used together in older adults with heart|6
01482|089|R|   failure?. J Am Geriatr Soc 2002 Jul;50(7):1293-6.|6
01482|090|R|17.Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup|6
01482|091|R|   M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA,|6
01482|092|R|   Stevenson LW, Yancy CW. 2009 Focused update incorporated into the ACC/AHA|6
01482|093|R|   2005 Guidelines for the Diagnosis and Management of Heart Failure in|6
01482|094|R|   Adults A Report of the ACC/AHA Task Force on Practice Guidelines|6
01482|095|R|   Developed in Collaboration With the ISLHT. J Am Coll Cardiol 2009 Apr 14;|6
01482|096|R|   53(15):e1-e90.|6
01482|097|R|18.National Collaborating Centre for Acute and Chronic Conditions. Chronic|6
01482|098|R|   heart failure. Management of chronic heart failure in adults in primary|6
01482|099|R|   and secondary care (Clinical guideline; no. 108). London (UK): National|6
01482|100|R|   Institute for Health and Clinical Excellence (NICE) Aug, 2010.|6
01482|101|R|19.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
01482|102|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
01482|103|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
01482|104|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
01483|001|T|MONOGRAPH TITLE:  Tizanidine/Ciprofloxacin (mono deleted 03/13/2024)|
01483|002|B||
01483|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01483|004|L|is contraindicated and generally should not be dispensed or administered to|
01483|005|L|the same patient.|
01483|006|B||
01483|007|A|MECHANISM OF ACTION:  Ciprofloxacin may inhibit the metabolism of tizanidine|
01483|008|A|by CYP1A2.(1-3)|
01483|009|B||
01483|010|E|CLINICAL EFFECTS:  Concurrent use of ciprofloxacin may result in elevated|
01483|011|E|levels of and effects from tizanidine, including hypotension, bradycardia,|
01483|012|E|drowsiness, sedation, and decreased psychomotor function.(1-3)|
01483|013|B||
01483|014|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
01483|015|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
01483|016|P|patients using more than one medicine with anticholinergic properties.(4)|
01483|017|B||
01483|018|M|PATIENT MANAGEMENT:  The US manufacturer of ciprofloxacin states that|
01483|019|M|concurrent use of tizanidine is contraindicated.(3)|
01483|020|B||
01483|021|D|DISCUSSION:  In a double-blind, randomized, cross-over study in 10 healthy|
01483|022|D|subjects, pretreatment with ciprofloxacin (500 mg twice daily) for 3 days|
01483|023|D|increased the tizanidine area-under-curve (AUC) and maximum concentration|
01483|024|D|(Cmax) 10-fold (range 6-fold to 24-fold) and by 7-fold (range 4-fold to|
01483|025|D|21-fold), respectively, when compared to administration with placebo. During|
01483|026|D|the ciprofloxacin phase, tizanidine pharmacodynamic effects were also|
01483|027|D|increased. During ciprofloxacin, the mean decreases in systolic and|
01483|028|D|diastolic blood pressure were 35 mmHg and 24 mmHg, respectively.  During|
01483|029|D|placebo, the mean decreases in systolic and diastolic blood pressure were 15|
01483|030|D|mmHg and 11 mmHg, respectively.  During ciprofloxacin, there were|
01483|031|D|significant increases in sedation as shown by the Digit Symbol Substitution|
01483|032|D|Test, subjective drug effect, and subjective drowsiness.(1)|
01483|033|D|   In a case report, a 45 year old woman on maintenance tizanidine therapy|
01483|034|D|was given ciprofloxacin which reduced her systolic and diastolic blood|
01483|035|D|pressure 22 and 14 mmHg, respectively, on the day of ciprofloxacin|
01483|036|D|administration. On day three the patient's blood pressure was reported low|
01483|037|D|at 92/54 mmHg. On days 5 and 6, her body temperature and urine volume|
01483|038|D|decreased 1.1 C and 496 ml/dl, respectively.  The patient's symptoms|
01483|039|D|improved immediately after ciprofloxacin was discontinued.(5)|
01483|040|D|   A retrospective study looked at adverse reaction case reports in the WHO|
01483|041|D|pharmacovigilance database with concurrent tizanidine and ciprofloxacin|
01483|042|D|administration. 57.1% of the adverse reactions were qualified as serious|
01483|043|D|because of hospitalization. The most frequently observed reactions included|
01483|044|D|hypotension, somnolence, fatigue, and asthenia.(6)|
01483|045|D|   A retrospective cohort study assessed the impart of concurrent|
01483|046|D|administration of tizanidine and ciprofloxacin on outpatient physician|
01483|047|D|visits and hospitalizations and found a significant association between|
01483|048|D|exposure to tizanidine and ciprofloxacin and outpatient physician visits at|
01483|049|D|14 and 30 days (odds ratio (OR) = 1.61, (95%CI = 1.17-2.24)(p= 0.004); OR =|
01483|050|D|1.59 (95%CI = 1.1-2.34)(p= 0.016)) and a trend for increased risk of|
01483|051|D|hospitalization for all evaluated time periods (OR = 1.68 (95%CI =|
01483|052|D|0.84-3.17), OR = 1.52 (95%CI = 0.63-3.33), OR = 2.19 (95%CI =|
01483|053|D|0.88-5.02)).(7)|
01483|054|D|   One or more of the drug pairs linked to this monograph have been included|
01483|055|D|in a list of interactions that should be considered "high-priority" for|
01483|056|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01483|057|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01483|058|D|Coordinator (ONC) for Health Information Technology.|
01483|059|B||
01483|060|R|REFERENCES:|
01483|061|B||
01483|062|R|1.Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ. Ciprofloxacin greatly|2
01483|063|R|  increases concentrations and hypotensive effect of tizanidine by|2
01483|064|R|  inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin|2
01483|065|R|  Pharmacol Ther 2004 Dec;76(6):598-606.|2
01483|066|R|2.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
01483|067|R|  Pharma Inc. November 22, 2024.|1
01483|068|R|3.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
01483|069|R|  Corporation March, 2022.|1
01483|070|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01483|071|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01483|072|R|  Soc 2023 Jul;71(7):2052-2081.|6
01483|073|R|5.Momo K, Homma M, Kohda Y, Ohkoshi N, Yoshizawa T, Tamaoka A. Drug|3
01483|074|R|  interaction of tizanidine and ciprofloxacin: case report. Clin Pharmacol|3
01483|075|R|  Ther 2006 Dec;80(6):717-9.|3
01483|076|R|6.Rudolph A, Dahmke H, Kupferschmidt H, Burden A, Weiler S. Coadministration|6
01483|077|R|  of tizanidine and ciprofloxacin: a retrospective analysis of the WHO|6
01483|078|R|  pharmacovigilance database. Eur J Clin Pharmacol 2021 Jun;77(6):895-902.|6
01483|079|R|7.Jodicke AM, Curkovic I, Zellweger U, Tomka IT, Neuer T, Kullak-Ublick GA,|6
01483|080|R|  Roos M, Egbring M. Analysis of Drug-Drug Interactions in Swiss Claims Data|6
01483|081|R|  Using Tizanidine and Ciprofloxacin as a Prototypical Contraindicated|6
01483|082|R|  Combination. Ann Pharmacother 2018 Oct;52(10):983-991.|6
01483|083|R|8.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01483|084|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01483|085|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01483|086|R|  19(5):735-43.|6
01484|001|T|MONOGRAPH TITLE:  Interferon-Alpha/Colchicine (mono deleted 02/25/2022)|
01484|002|B||
01484|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01484|004|L|take action as needed.|
01484|005|B||
01484|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01484|007|B||
01484|008|E|CLINICAL EFFECTS:  Concurrent use of colchicine may decrease the|
01484|009|E|effectiveness of interferon-alpha in the treatment of hepatitis.(1)|
01484|010|E|   Concurrent colchicine and interferon-alpha has been shown to be effective|
01484|011|E|in the treatment of colchicine-resistant familial Mediterranean fever(2-3)|
01484|012|E|and Behcet's disease.(4)|
01484|013|B||
01484|014|P|PREDISPOSING FACTORS:  None determined.|
01484|015|B||
01484|016|M|PATIENT MANAGEMENT:  Avoid concurrent use of colchicine and interferon-alpha|
01484|017|M|in the treatment of hepatitis.|
01484|018|M|   Concurrent colchicine and interferon-alpha has been shown to be effective|
01484|019|M|in the treatment of colchicine-resistant familial Mediterranean fever(2-3)|
01484|020|M|and Behcet's disease.(4)|
01484|021|B||
01484|022|D|DISCUSSION:  In a trial in 65 HCV-RNA positive patients with chronic|
01484|023|D|hepatitis, subjects were randomized to receive interferon-alpha (6 million|
01484|024|D|units 3 times weekly) for 6 months followed by interferon-alpha (3 million|
01484|025|D|units 3 times weekly) for an additional 6 months with (n=31) or without|
01484|026|D|(n=34) colchicine (1 mg daily) 6 days a week for 3 years.  The trial was|
01484|027|D|halted after 18 months.  The amount of patients who achieved alanine|
01484|028|D|transaminase normalization or undetectable HCV-RNA at 6 months was higher in|
01484|029|D|the group that did not receive colchicine (68% versus 32% and 47% versus|
01484|030|D|32%, respectively).  End-of-treatment biochemical and virological response|
01484|031|D|occurred in 41% and 29% of the group that received interferon alone versus|
01484|032|D|19% and 10% of the colchicine group, respectively.  Sustained biochemical|
01484|033|D|response occurred in 26% of the interferon alone group and 6% of the|
01484|034|D|colchicine group.  Corresponding percentages of sustained HCV-RNA loss were|
01484|035|D|21% and 3%, respectively.(1)|
01484|036|D|   Concurrent colchicine and interferon-alpha has been shown to be effective|
01484|037|D|in the treatment of colchicine-resistant familial Mediterranean fever(2-3)|
01484|038|D|and Behcet's disease.(4)|
01484|039|B||
01484|040|R|REFERENCES:|
01484|041|B||
01484|042|R|1.Angelico M, Cepparulo M, Barlattani A, Liuti A, Gentile S, Hurtova M,|2
01484|043|R|  Ombres D, Guarascio P, Rocchi G, Angelico F. Unfavourable effects of|2
01484|044|R|  colchicine in combination with interferon-alpha in the treatment of|2
01484|045|R|  chronic hepatitis C. Aliment Pharmacol Ther 2000 Nov;14(11):1459-67.|2
01484|046|R|2.Tunca M, Akar S, Soyturk M, Kirkali G, Resmi H, Akhunlar H, Gonen O,|2
01484|047|R|  Gallimore JR, Hawkins PN, Tankurt E. The effect of interferon alpha|2
01484|048|R|  administration on acute attacks of familial Mediterranean fever: A|2
01484|049|R|  double-blind, placebo-controlled trial. Clin Exp Rheumatol 2004 Jul-Aug;|2
01484|050|R|  22(4 Suppl 34):S37-40.|2
01484|051|R|3.Tunca M, Tankurt E, Akbaylar Akpinar H, Akar S, Hizli N, Gonen O. The|2
01484|052|R|  efficacy of interferon alpha on colchicine-resistant familial|2
01484|053|R|  Mediterranean fever attacks: a pilot study. Br J Rheumatol 1997 Sep;|2
01484|054|R|  36(9):1005-8.|2
01484|055|R|4.Calguneri M, Apras S, Ozbalkan Z, Ozturk MA, Ertenli I, Kiraz S. The|2
01484|056|R|  efficacy of continuous interferon alpha administration as an adjunctive|2
01484|057|R|  agent to colchicine-resistant familial Mediterranean fever patients. Clin|2
01484|058|R|  Exp Rheumatol 2004 Jul-Aug;22(4 Suppl 34):S41-4.|2
01485|001|T|MONOGRAPH TITLE:  Carbamazepine/Isoniazid|
01485|002|B||
01485|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01485|004|L|of severe adverse interaction.|
01485|005|B||
01485|006|A|MECHANISM OF ACTION:  Isoniazid may inhibit carbamazepine metabolism by|
01485|007|A|CYP3A4.|
01485|008|B||
01485|009|E|CLINICAL EFFECTS:  Concurrent use of isoniazid may result in elevated levels|
01485|010|E|of and toxicity from carbamazepine and possibly isoniazid-induced|
01485|011|E|hepatotoxicity.|
01485|012|B||
01485|013|P|PREDISPOSING FACTORS:  None determined.|
01485|014|B||
01485|015|M|PATIENT MANAGEMENT:  If both drugs are administered, monitor plasma|
01485|016|M|carbamazepine levels and observe the patient for signs and symptoms of|
01485|017|M|carbamazepine and isoniazid toxicity.  Adjust the doses of the drugs|
01485|018|M|accordingly.|
01485|019|B||
01485|020|D|DISCUSSION:  Several case reports have documented carbamazepine toxicity as|
01485|021|D|shown by ataxia, nystagmus, lethargy, and somnolence during concurrent|
01485|022|D|isoniazid.(1-10)  Reports have also found isoniazid-induced hepatotoxicity|
01485|023|D|during concurrent therapy.(1-5)|
01485|024|B||
01485|025|R|REFERENCES:|
01485|026|B||
01485|027|R|1.Wright JM, Stokes EF, Sweeney VP. Isoniazid-induced carbamazepine toxicity|3
01485|028|R|  and vice versa: a double drug interaction. N Engl J Med 1982 Nov 18;|3
01485|029|R|  307(21):1325-7.|3
01485|030|R|2.van der Grient AJ, Kelderman CS. Fatal liver cell necrosis after|3
01485|031|R|  short-term administration of isoniazid and rifampicin to a patient already|3
01485|032|R|  under treatment with anti-epileptic agents. Ned Tijdschr Geneeskd 1983 May|3
01485|033|R|  21;127(21):931.|3
01485|034|R|3.Berkowitz FE, Henderson SL, Fajman N, Schoen B, Naughton M. Acute liver|3
01485|035|R|  failure caused by isoniazid in a child receiving carbamazepine. Int J|3
01485|036|R|  Tuberc Lung Dis 1998 Jul;2(7):603-6.|3
01485|037|R|4.Campos-Franco J, Gonzalez-Quintela A, Alende-Sixto MR. Isoniazid-induced|3
01485|038|R|  hyperacute liver failure in a young patient receiving carbamazepine. Eur J|3
01485|039|R|  Intern Med 2004 Oct;15(6):396-397.|3
01485|040|R|5.Barbare JC, Lallement PY, Vorhauer W, Veyssier P. Hepatotoxicity of|3
01485|041|R|  isoniazid: influence of carbamazepine?. Gastroenterol Clin Biol 1986|3
01485|042|R|  Jun-Jul;10(6-7):523-4.|3
01485|043|R|6.Fleenor ME, Harden JW, Curtis G. Interaction between carbamazepine and|3
01485|044|R|  antituberculosis agents. Chest 1991 Jun;99(6):1554.|3
01485|045|R|7.Poo Arguelles P, Samarra Riera JM, Gairi Tahull JM, Vernet Bori A.|3
01485|046|R|  Carbamazepine-tuberculostatics interaction. Med Clin (Barc) 1984 Dec 15;|3
01485|047|R|  83(20):867-8.|3
01485|048|R|8.Garcia B, Zaborras E, Areas V, Obeso G, Jimenez I, de Juana P, Bermejo T.|3
01485|049|R|  Interaction between isoniazid and carbamazepine potentiated by cimetidine.|3
01485|050|R|  Ann Pharmacother 1992 Jun;26(6):841-2.|3
01485|051|R|9.Valsalan VC, Cooper GL. Carbamazepine intoxication caused by interaction|3
01485|052|R|  with isoniazid. Br Med J (Clin Res Ed) 1982 Jul 24;285(6337):261-2.|3
01485|053|R|10.Block SH. Carbamazepine-isoniazid interaction. Pediatrics 1982 Apr;|3
01485|054|R|   69(4):494-5.|3
01486|001|T|MONOGRAPH TITLE:  Digoxin/Spironolactone|
01486|002|B||
01486|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01486|004|L|take action as needed.|
01486|005|B||
01486|006|A|MECHANISM OF ACTION:  Spironolactone may decrease the renal clearance of|
01486|007|A|digoxin.  Spironolactone may also interfere with some digoxin assays.|
01486|008|B||
01486|009|E|CLINICAL EFFECTS:  Concurrent spironolactone may result in elevated levels|
01486|010|E|of and toxicity from digoxin.  Symptoms of digoxin toxicity can include|
01486|011|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
01486|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
01486|013|E|disturbances, and arrhythmias.|
01486|014|E|   Spironolactone may also interfere with some digoxin assays, resulting in|
01486|015|E|falsely elevated levels.|
01486|016|B||
01486|017|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
01486|018|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
01486|019|P|risk of digoxin toxicity.|
01486|020|B||
01486|021|M|PATIENT MANAGEMENT:  Concurrent administration of spironolactone and digoxin|
01486|022|M|should be closely monitored, and potassium and digoxin concentrations should|
01486|023|M|be measured frequently.  Patients should be monitored for changes in|
01486|024|M|therapeutic effects.  The dosage of digoxin may need to be decreased by|
01486|025|M|15-30% or the frequency of administration may be reduced.(8)|
01486|026|B||
01486|027|D|DISCUSSION:  Simultaneous administration of spironolactone and digoxin has|
01486|028|D|been shown to decrease in digoxin's volume of distribution, plasma|
01486|029|D|clearance, and renal clearance, with corresponding increases in the plasma|
01486|030|D|digoxin concentration.|
01486|031|D|   Although the influence of spironolactone on digoxin's pharmacodynamic|
01486|032|D|effects has not been as extensively evaluated as its pharmacokinetic|
01486|033|D|effects, in two studies the inotropic action of digoxin was reduced during|
01486|034|D|spironolactone administration as measured by preejection period index.|
01486|035|D|However, one study reported that in patients for whom potassium depletion|
01486|036|D|may lead to digoxin toxicity, a potassium-sparing diuretic may safely be|
01486|037|D|used to reduce potassium excretion and thereby reduce the risk of|
01486|038|D|arrhythmias.|
01486|039|D|   Spironolactone has been reported to interfere with some digoxin assays.|
01486|040|D|   Concomitant administration of spironolactone and digoxin increased the|
01486|041|D|digoxin serum concentration 25%. (8)|
01486|042|B||
01486|043|R|REFERENCES:|
01486|044|B||
01486|045|R|1.Steiness E. Renal tubular secretion of digoxin. Circulation 1974 Jul;|2
01486|046|R|  50(1):103-7.|2
01486|047|R|2.Waldorff S, Andersen JD, Heeboll-Nielsen N, Nielsen OG, Moltke E, Sorensen|2
01486|048|R|  U, Steiness E. Spironolactone-induced changes in digoxin kinetics. Clin|2
01486|049|R|  Pharmacol Ther 1978 Aug;24(2):162-7.|2
01486|050|R|3.Paladino JA, Davidson KH, McCall BB. Influence of spironolactone on serum|3
01486|051|R|  digoxin concentration. JAMA 1984 Jan 27;251(4):470-1.|3
01486|052|R|4.Fenster PE, Hager WD, Goodman MM. Digoxin-quinidine-spironolactone|2
01486|053|R|  interaction. Clin Pharmacol Ther 1984 Jul;36(1):70-3.|2
01486|054|R|5.Waldorff S, Hansen PB, Egeblad H, Berning J, Buch J, Kjaergard H, Steiness|2
01486|055|R|  E. Interactions between digoxin and potassium-sparing diuretics. Clin|2
01486|056|R|  Pharmacol Ther 1983 Apr;33(4):418-23.|2
01486|057|R|6.Waldorff S, Berning J, Buch J, Steiness E. Systolic time intervals during|2
01486|058|R|  spironolactone treatment of digitalized and non-digitalized patients with|2
01486|059|R|  ischaemic heart disease. Eur J Clin Pharmacol 1982;21(4):269-73.|2
01486|060|R|7.Finnegan TP, Spence JD, Cape RD. Potassium-sparing diuretics: interaction|2
01486|061|R|  with digoxin in elderly men. J Am Geriatr Soc 1984 Feb;32(2):129-31.|2
01486|062|R|8.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
01486|063|R|  Pharmaceuticals, Inc. August, 2018.|1
01487|001|T|MONOGRAPH TITLE:  Thyroid/Aluminum;Magnesium;Lanthanum;Simeth (mono deleted|
01487|002|T|12/05/2019)|
01487|003|B||
01487|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01487|005|L|take action as needed.|
01487|006|B||
01487|007|A|MECHANISM OF ACTION:  Aluminum-containing compounds (including sucralfate),|
01487|008|A|lanthanum, magnesium-containing compounds, and simethicone may bind to|
01487|009|A|thyroid preparations in the gastrointestinal tract, preventing their|
01487|010|A|absorption, or may delay the absorption of thyroid preparations.(1,2)|
01487|011|B||
01487|012|E|CLINICAL EFFECTS:  Simultaneous administration of aluminum, lanthanum,|
01487|013|E|magnesium, simethicone, or sucralfate may result in decreased levels and|
01487|014|E|effectiveness of thyroid preparations.(1,2)|
01487|015|B||
01487|016|P|PREDISPOSING FACTORS:  None determined.|
01487|017|B||
01487|018|M|PATIENT MANAGEMENT:  Instruct patients to separate the administration time|
01487|019|M|of thyroid preparations from aluminum, magnesium, simethicone, or sucralfate|
01487|020|M|by as much time as possible, preferably by at least four hours.(1)  Separate|
01487|021|M|the administration time of lanthanum by at least two hours.(2)|
01487|022|B||
01487|023|D|DISCUSSION:  In a study in 5 healthy subjects, levothyroxine (five 200 mcg|
01487|024|D|tablets) was administered in 3 different dosing regimens: after an overnight|
01487|025|D|fast, with the fifth and final dose of sucralfate (1 G every 6 hours) and 8|
01487|026|D|hours after the second and final dose of sucralfate (2 G every 12 hours).|
01487|027|D|When administered alone, 80% of levothyroxine was absorbed within 6 hours of|
01487|028|D|administration, compared to 23% when administered concurrently with|
01487|029|D|sucralfate.  There was no difference in levothyroxine absorption when|
01487|030|D|administered alone or 8 hours after sucralfate.(3)|
01487|031|D|   In a study in patients stabilized on levothyroxine, administration of 2-4|
01487|032|D|weeks of an aluminum hydroxide-containing preparation resulted in a 174%|
01487|033|D|increase in TSH levels.(4)|
01487|034|D|   There are several case reports documenting decreased effects of thyroid|
01487|035|D|supplementation as the result of simultaneous administration of sucralfate|
01487|036|D|(5,6) and aluminum compounds.(7,8)|
01487|037|B||
01487|038|R|REFERENCES:|
01487|039|B||
01487|040|R|1.Synthroid (levothyroxine sodium) US prescribing information. Abbott|1
01487|041|R|  Laboratories February, 2024.|1
01487|042|R|2.Fosrenol (lanthanum carbonate) US prescribing information. Shire US Inc.|1
01487|043|R|  May, 2020.|1
01487|044|R|3.Sherman SI, Tielens ET, Ladenson PW. Sucralfate causes malabsorption of|2
01487|045|R|  L-thyroxine. Am J Med 1994 Jun;96(6):531-5.|2
01487|046|R|4.Liel Y, Sperber AD, Shany S. Nonspecific intestinal adsorption of|2
01487|047|R|  levothyroxine by aluminum hydroxide. Am J Med 1994 Oct;97(4):363-5.|2
01487|048|R|5.Havrankova J, Lahaie R. Levothyroxine binding by sucralfate. Ann Intern|3
01487|049|R|  Med 1992 Sep 1;117(5):445-6.|3
01487|050|R|6.Vick K, Wennerberg P. Sucralfate-levothyroxine drug interaction..|4
01487|051|R|7.Sperber AD, Liel Y. Evidence for interference with the intestinal|3
01487|052|R|  absorption of levothyroxine sodium by aluminum hydroxide. Arch Intern Med|3
01487|053|R|  1992 Jan;152(1):183-4.|3
01487|054|R|8.Mersebach H, Rasmussen AK, Kirkegaard L, Feldt-Rasmussen U. Intestinal|3
01487|055|R|  adsorption of levothyroxine by antacids and laxatives: case stories and in|3
01487|056|R|  vitro experiments. Pharmacol Toxicol 1999 Mar;84(3):107-9.|3
01488|001|T|MONOGRAPH TITLE:  Rifabutin/Ritonavir (mono deleted 07/31/2019)|
01488|002|B||
01488|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01488|004|L|is contraindicated and generally should not be dispensed or administered to|
01488|005|L|the same patient.|
01488|006|B||
01488|007|A|MECHANISM OF ACTION:  Ritonavir may inhibit the metabolism of rifabutin at|
01488|008|A|CYP P-450-3A4.(1-3)|
01488|009|B||
01488|010|E|CLINICAL EFFECTS:  The concurrent administration of ritonavir may result in|
01488|011|E|elevated levels, clinical effects, and side effects (including neutropenia)|
01488|012|E|of rifabutin.(1-3)|
01488|013|B||
01488|014|P|PREDISPOSING FACTORS:  None determined.|
01488|015|B||
01488|016|M|PATIENT MANAGEMENT:  The Australian(1) and UK(2) manufacturers of ritonavir|
01488|017|M|state that concurrent administration with rifabutin is contraindicated.|
01488|018|M|   The US manufacturer of ritonavir (3)  and the US manufacturer of|
01488|019|M|rifabutin (5) states that rifabutin dosage should be reduced by at least 75%|
01488|020|M|(to 150 mg every other day or 3 times per week) during concurrent use.|
01488|021|M|Further decreases may be necessary.|
01488|022|B||
01488|023|D|DISCUSSION:  Concurrent ritonavir (500 mg twice daily) increased the|
01488|024|D|area-under-curve (AUC) of rifabutin and 25-O-desacetyl rifabutin by 4-fold|
01488|025|D|and 38-fold, respectively.(1,3)  The maximum concentration (Cmax) of|
01488|026|D|rifabutin and 25-O-desacetyl rifabutin increased by 2.5-fold and 16-fold,|
01488|027|D|respectively.  The minimum concentration (Cmin) of rifabutin and|
01488|028|D|25-O-desacetyl rifabutin increased by 6-fold and 181-fold, respectively.(3)|
01488|029|D|   Concurrent ritonavir (500 mg twice daily for 10 days) with rifabutin (150|
01488|030|D|mg daily for 16 days) in 5 healthy subjects increased the AUC and Cmax of|
01488|031|D|rifabutin by 300 and 150%, respectively. (5)|
01488|032|D|   One or more of the drug pairs linked to this monograph have been included|
01488|033|D|in a list of interactions that should be considered "high-priority" for|
01488|034|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01488|035|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01488|036|D|Coordinator (ONC) for Health Information Technology.|
01488|037|B||
01488|038|R|REFERENCES:|
01488|039|B||
01488|040|R|1.Norvir (ritonavir) Australian prescribing information. Abbott Australasia|1
01488|041|R|  Pty. Ltd. January 29, 2004.|1
01488|042|R|2.Norvir (ritonavir) UK summary of product characteristics. AbbVie, Ltd.|1
01488|043|R|  July 18, 2019.|1
01488|044|R|3.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01488|045|R|  December, 2019.|1
01488|046|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01488|047|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01488|048|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01488|049|R|  19(5):735-43.|6
01488|050|R|5.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
01488|051|R|  2021.|1
01489|001|T|MONOGRAPH TITLE:  Tacrolimus/Danazol|
01489|002|B||
01489|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01489|004|L|take action as needed.|
01489|005|B||
01489|006|A|MECHANISM OF ACTION:  Danazol may inhibit the metabolism of tacrolimus by|
01489|007|A|CYP3A4.(1-3)|
01489|008|B||
01489|009|E|CLINICAL EFFECTS:  Concurrent use of danazol may result in elevated levels|
01489|010|E|of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity,|
01489|011|E|and prolongation of the QTc interval and life-threatening cardiac|
01489|012|E|arrhythmias, including torsades de pointes.(1-3)|
01489|013|B||
01489|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01489|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01489|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01489|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01489|018|P|gender, or advanced age.|
01489|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01489|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01489|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01489|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01489|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01489|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01489|025|P|dysfunction).|
01489|026|B||
01489|027|M|PATIENT MANAGEMENT:  Monitor tacrolimus levels in patients receiving|
01489|028|M|concurrent danazol.  The dosage of tacrolimus may need to be adjusted if|
01489|029|M|danazol is initiated or discontinued.(1)|
01489|030|M|   When concurrent therapy of danazol and tacrolimus is warranted, consider|
01489|031|M|obtaining serum calcium, magnesium, and potassium levels and monitoring ECG|
01489|032|M|at baseline and at regular intervals.  Correct any electrolyte|
01489|033|M|abnormalities.  Instruct patients to report any irregular heartbeat,|
01489|034|M|dizziness, or fainting.|
01489|035|B||
01489|036|D|DISCUSSION:  Concurrent danazol has been shown to increase tacrolimus trough|
01489|037|D|concentrations (Cmin) by more than 5-fold in patients and by 3-fold in|
01489|038|D|rats.(1)|
01489|039|B||
01489|040|R|REFERENCES:|
01489|041|B||
01489|042|R|1.Prograf (tacrolimus) Australian prescribing information. Janssen-Cilag Pty|1
01489|043|R|  Limited December 27, 2000.|1
01489|044|R|2.Prograf (tacrolimus) UK summary of product characteristics. Fujisawa|1
01489|045|R|  Limited November 14, 2002.|1
01489|046|R|3.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
01489|047|R|  August, 2023.|1
01489|048|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01489|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01489|050|R|  settings: a scientific statement from the American Heart Association and|6
01489|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01489|052|R|  2;55(9):934-47.|6
01490|001|T|MONOGRAPH TITLE:  Ketorolac/Anticoagulants|
01490|002|B||
01490|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01490|004|L|of severe adverse interaction.|
01490|005|B||
01490|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Ketorolac impairs|
01490|007|A|platelet function and may prolong bleeding time.(1)  Ketorolac also has the|
01490|008|A|potential to produce gastrointestinal ulceration and bleeding.(1-3)|
01490|009|B||
01490|010|E|CLINICAL EFFECTS:  Concurrent use of ketorolac and anticoagulants may|
01490|011|E|increase the risk of bleeding complications.(1-3)|
01490|012|B||
01490|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01490|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01490|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01490|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01490|017|P|risk for bleeding (e.g. NSAIDs).|
01490|018|B||
01490|019|M|PATIENT MANAGEMENT:  The Australian(1) and UK(2) manufacturers of ketorolac|
01490|020|M|state that the use of ketorolac in patients on anticoagulants, including|
01490|021|M|low-dose heparin,(2) is contraindicated.|
01490|022|M|   The US manufacturer of ketorolac states that concurrent therapy with|
01490|023|M|anticoagulants should be undertaken with extreme caution after carefully|
01490|024|M|weighing the benefits of concurrent therapy against the risks and that|
01490|025|M|patients receiving concurrent therapy should be closely monitored.(3)|
01490|026|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01490|027|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01490|028|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01490|029|M|patients with any symptoms.|
01490|030|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01490|031|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01490|032|M|anticoagulation in patients with active pathologic bleeding.|
01490|033|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01490|034|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01490|035|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01490|036|M|and/or swelling.|
01490|037|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01490|038|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01490|039|M|initiating, altering the dose or discontinuing either drug.|
01490|040|B||
01490|041|D|DISCUSSION:  Ketorolac has been shown to inhibit platelet aggregation and|
01490|042|D|may prolong bleeding times.  Ketorolac-induced inhibition of platelet|
01490|043|D|function disappears within 24 to 48 hours after ketorolac discontinuation.|
01490|044|D|Ketorolac does not affect platelet count, prothrombin time (PT), or partial|
01490|045|D|thromboplastin time (PTT).(1)|
01490|046|D|   Ketorolac has been shown in vitro to only slightly reduce warfarin|
01490|047|D|protein binding (from 99.5% to 99.3%.(3)|
01490|048|D|   In a study in 12 subjects, ketorolac had no effects on the|
01490|049|D|pharmacokinetics or pharmacodynamics of a single dose of warfarin (25 mg).|
01490|050|D|In another study in 11 subjects, ketorolac increased the mean template|
01490|051|D|bleeding time for 2 doses of heparin from 6.0 to 6.4 minutes.(3)|
01490|052|B||
01490|053|R|REFERENCES:|
01490|054|B||
01490|055|R|1.Toradol (ketorolac trometamol) Australian prescribing information. Roche|1
01490|056|R|  Products Pty Ltd. December 17, 2002.|1
01490|057|R|2.Toradol (ketorolac trometamol) UK summary of product characteristics.|1
01490|058|R|  Roche Products Limited September 22, 2003.|1
01490|059|R|3.Toradol (ketorolac tromethamine) US prescribing information. Roche|1
01490|060|R|  Pharmaceuticals March, 2013.|1
01491|001|T|MONOGRAPH TITLE:  Tenecteplase/Oral Anticoagulants; Warfarin|
01491|002|B||
01491|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01491|004|L|is contraindicated and generally should not be dispensed or administered to|
01491|005|L|the same patient.|
01491|006|B||
01491|007|A|MECHANISM OF ACTION:  Tenecteplase catalyzes the cleavage of endogenous|
01491|008|A|plasminogen to generate plasmin which degrades the fibrin matrix of a|
01491|009|A|thrombus.(1-3)|
01491|010|B||
01491|011|E|CLINICAL EFFECTS:  The concurrent use of tenecteplase and warfarin or oral|
01491|012|E|anticoagulants may increase the risk of bleeding.(1-4)|
01491|013|B||
01491|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01491|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01491|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
01491|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01491|018|P|risk for bleeding (e.g. NSAIDs).|
01491|019|B||
01491|020|M|PATIENT MANAGEMENT:  The Australian(1), Canadian(2) and UK(3) manufacturers|
01491|021|M|of tenecteplase state that use in patients on current oral anticoagulants|
01491|022|M|(INR > 1.3) is contraindicated.|
01491|023|M|   The US manufacturer of tenecteplase states that the risks of concurrent|
01491|024|M|therapy with oral anticoagulants must be weighed against the anticipated|
01491|025|M|benefits.(4)|
01491|026|M|   Concurrent use of tenecteplase and anticoagulants is dependent on the|
01491|027|M|therapeutic indication.|
01491|028|M|   In Acute Ischemic Stroke:|
01491|029|M|   - Clinical practice guidelines for acute ischemic stroke state the use of|
01491|030|M|thrombolytic therapy for an indication of acute ischemic stroke is|
01491|031|M|contraindicated in patients who have received warfarin and have an elevated|
01491|032|M|activated partial thromboplastin time (aPTT) > 40 seconds, prothrombin time|
01491|033|M|(PT) > 15 seconds, INR > 1.7, or platelets <100,000/mm3 at presentation.|
01491|034|M|   In Acute Myocardial Infarction:|
01491|035|M|   - Patients who are receiving tenecteplase for an indication of acute|
01491|036|M|myocardial infarction should be carefully monitored for signs of bleeding,|
01491|037|M|especially at arterial puncture sites, if heparin is used concurrently.|
01491|038|M|   - The use of tenecteplase in patients with acute myocardial infarction|
01491|039|M|should follow standard management of myocardial infarction, including|
01491|040|M|minimizing arterial and venous puncture; avoid noncompressible arterial|
01491|041|M|puncture; and minimize internal jugular and subclavian venous punctures to|
01491|042|M|decrease bleeding from the noncompressible sites.|
01491|043|M|   For all indications:|
01491|044|M|   - In the event of serious bleeding, anticoagulants should be discontinued|
01491|045|M|immediately.|
01491|046|M|   - If concurrent therapy is warranted, monitor patients receiving|
01491|047|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
01491|048|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
01491|049|M|evaluate patients with any symptoms.|
01491|050|M|   - When applicable, perform agent-specific laboratory test (e.g. INR,|
01491|051|M|aPTT) to monitor efficacy and safety of anticoagulation.  Discontinue|
01491|052|M|anticoagulation in patients with active pathologic bleeding.|
01491|053|M|   - Instruct patients to report any signs and symptoms of bleeding, such as|
01491|054|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01491|055|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01491|056|M|and/or swelling.|
01491|057|B||
01491|058|D|DISCUSSION:  Patients receiving warfarin were excluded from participation in|
01491|059|D|thrombolytic clinical trials due to bleeding risk.(1-4)|
01491|060|B||
01491|061|R|REFERENCES:|
01491|062|B||
01491|063|R|1.Metalyse (tenecteplase) Australian prescribing information. Boehringer|1
01491|064|R|  Ingelheim Pty Ltd. September 5, 2003.|1
01491|065|R|2.Metalyse (tenecteplase) UK summary of product characteristics. Boehringer|1
01491|066|R|  Ingelheim Limited April 4, 2011.|1
01491|067|R|3.TNKase (tenecteplase) Canada Product Monographh. Genentech, Inc. May 27,|1
01491|068|R|  2008.|1
01491|069|R|4.TNKase (tenecteplase) US prescribing information. Genentech, Inc.|1
01491|070|R|  February, 2018.|1
01491|071|R|5.Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC. Guidelines|6
01491|072|R|  for the Early Management of Patients With Acute Ischemic Stroke: 2019|6
01491|073|R|  Update to the 2018 Guidelines for the Early Management of Acute Ischemic|6
01491|074|R|  Stroke:  A Guideline for Healthcare Professionals From the AHA/ASA. Stroke|6
01491|075|R|  2019 Dec;50(12):e344-e418.|6
01492|001|T|MONOGRAPH TITLE:  Epirubicin/Cimetidine|
01492|002|B||
01492|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01492|004|L|is contraindicated and generally should not be dispensed or administered to|
01492|005|L|the same patient.|
01492|006|B||
01492|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but it is not believed|
01492|008|A|to involve decreased CYP P-450 activity or decreased liver blood flow.(1)|
01492|009|B||
01492|010|E|CLINICAL EFFECTS:  Concurrent use of cimetidine may result in elevated|
01492|011|E|levels of and toxicity from epirubicin.(1,2)|
01492|012|B||
01492|013|P|PREDISPOSING FACTORS:  None determined.|
01492|014|B||
01492|015|M|PATIENT MANAGEMENT:  The manufacturer of epirubicin states that cimetidine|
01492|016|M|therapy should be discontinued prior to epirubicin use.(2)|
01492|017|B||
01492|018|D|DISCUSSION:  In a study in 8 patients, subjects received epirubicin (100|
01492|019|D|mg/m2) every 3 weeks with and without oral cimetidine (400 mg twice daily)|
01492|020|D|for 7 days starting 5 days before epirubicin.  Cimetidine increased the|
01492|021|D|area-under-curve (AUC) of epirubicin, epirubicinol, and|
01492|022|D|7-deoxy-doxorubicinol aglycone by 50%, 41%, and 357%, respectively.(1)  The|
01492|023|D|clearance of epirubicin decreased by 30%.(2)|
01492|024|B||
01492|025|R|REFERENCES:|
01492|026|B||
01492|027|R|1.Murray LS, Jodrell DI, Morrison JG, Cook A, Kerr DJ, Whiting B, Kaye SB,|2
01492|028|R|  Cassidy J. The effect of cimetidine on the pharmacokinetics of epirubicin|2
01492|029|R|  in patients with advanced breast cancer: preliminary evidence of a|2
01492|030|R|  potentially common drug interaction. Clin Oncol (R Coll Radiol) 1998;|2
01492|031|R|  10(1):35-8.|2
01492|032|R|2.Ellence (epirubicin hydrochloride) US prescribing information. Pharmacia|1
01492|033|R|  Corporation July, 2019.|1
01493|001|T|MONOGRAPH TITLE:  Indomethacin/Diflunisal|
01493|002|B||
01493|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01493|004|L|is contraindicated and generally should not be dispensed or administered to|
01493|005|L|the same patient.|
01493|006|B||
01493|007|A|MECHANISM OF ACTION:  Diflunisal may inhibit the metabolism(1,2) and renal|
01493|008|A|excretion(1) of indomethacin.   In an in vitro study using human liver|
01493|009|A|microsomes (HLM) and human intestine microsomes (HIM), diflunisal was shown|
01493|010|A|to inhibit indomethacin glucuronidation in both HLM and HIM with inhibition|
01493|011|A|being more potent in the HIM, suggesting that the decreased clearance of|
01493|012|A|indomethacin may be attributed to the inhibition of the glucuronidation of|
01493|013|A|indomethacin by diflunisal in the intestine.(3)|
01493|014|B||
01493|015|E|CLINICAL EFFECTS:  Concurrent use of diflunisal may result in elevated|
01493|016|E|levels of indomethacin.  Fatal gastrointestinal bleeding has been|
01493|017|E|reported.(4)|
01493|018|B||
01493|019|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01493|020|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01493|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
01493|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01493|023|P|risk for bleeding (e.g. NSAIDs).|
01493|024|B||
01493|025|M|PATIENT MANAGEMENT:  The manufacturer of indomethacin states that diflunisal|
01493|026|M|and indomethacin should not be used concomitantly.(4)|
01493|027|M|   If concurrent therapy is deemed medically necessary, monitor patients|
01493|028|M|receiving concurrent therapy for signs of blood loss, including decreased|
01493|029|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
01493|030|M|and promptly evaluate patients with any symptoms.|
01493|031|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01493|032|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01493|033|M|anticoagulation in patients with active pathologic bleeding.|
01493|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01493|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01493|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01493|037|M|and/or swelling.|
01493|038|B||
01493|039|D|DISCUSSION:  In a study in 24 subjects, patients received a single dose of|
01493|040|D|indomethacin (100 mg) rectally before and after receiving diflunisal at one|
01493|041|D|of three dosages:  500 mg orally (n=8), 500 mg in the morning and 1000 mg at|
01493|042|D|night (n=8), or 500 mg twice daily (n=8).  High dose diflunisal (1500 mg|
01493|043|D|daily) decreased the renal clearance of indomethacin by 92%.  Indomethacin|
01493|044|D|area-under-curve (AUC) and maximum concentration (Cmax) increased by 119%|
01493|045|D|and 40%, respectively.  Similar results were seen when diflunisal was given|
01493|046|D|at 500 mg daily, but the magnitude of change was smaller.(1)|
01493|047|D|   In a study in 16 healthy subjects, concurrent diflunisal and indomethacin|
01493|048|D|increased indomethacin AUC by 3-fold.(2)|
01493|049|D|   Concurrent indomethacin and diflunisal has been associated with fatal|
01493|050|D|gastrointestinal hemorrhage.(4)|
01493|051|B||
01493|052|R|REFERENCES:|
01493|053|B||
01493|054|R|1.Eriksson LO, Wahlin-Boll E, Liedholm H, Seideman P, Melander A. Influence|2
01493|055|R|  of chronic diflunisal treatment on the plasma levels, metabolism and|2
01493|056|R|  excretion of indomethacin. Eur J Clin Pharmacol 1989;37(1):7-15.|2
01493|057|R|2.Van Hecken A, Verbesselt R, Tjandra-Maga TB, De Schepper PJ.|2
01493|058|R|  Pharmacokinetic interaction between indomethacin and diflunisal. Eur J|2
01493|059|R|  Clin Pharmacol 1989;36(5):507-12.|2
01493|060|R|3.Mano Y, Usui T, Kamimura H. In vitro drug interaction between diflunisal|5
01493|061|R|  and indomethacin via glucuronidation in humans. Biopharm Drug Dispos 2006|5
01493|062|R|  Sep;27(6):267-73.|5
01493|063|R|4.Indocin (indomethacin) US prescribing information. Merck & Co., Inc.|1
01493|064|R|  March, 2019.|1
01494|001|T|MONOGRAPH TITLE:  Atazanavir/Amiodarone; Ajmaline; Quinidine|
01494|002|B||
01494|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01494|004|L|of severe adverse interaction.|
01494|005|B||
01494|006|A|MECHANISM OF ACTION:  Atazanavir (unboosted or boosted with cobicistat or|
01494|007|A|ritonavir) may inhibit the metabolism of ajmaline, amiodarone, and quinidine|
01494|008|A|at CYP3A4.(1-4)|
01494|009|B||
01494|010|E|CLINICAL EFFECTS:  Concurrent use of atazanavir (unboosted or boosted with|
01494|011|E|cobicistat or ritonavir) with ajmaline, amiodarone, or quinidine may result|
01494|012|E|in increased levels of these antiarrhythmics and serious and/or life|
01494|013|E|threatening arrhythmias including torsades de pointes.(1-4)|
01494|014|B||
01494|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01494|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01494|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01494|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01494|019|P|gender, or advanced age.(5)|
01494|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01494|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01494|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01494|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01494|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01494|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01494|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
01494|027|B||
01494|028|M|PATIENT MANAGEMENT:  The US manufacturer of atazanavir states that the|
01494|029|M|coadministration of atazanavir-ritonavir with amiodarone or quinidine is|
01494|030|M|contraindicated.(1)  If unboosted atazanavir is used concurrently with|
01494|031|M|amiodarone, use caution and perform therapeutic concentration monitoring.(1)|
01494|032|M|The Canadian and UK manufacturers of atazanavir contraindicate use of|
01494|033|M|atazanavir with quinidine.(2-3)|
01494|034|M|   The US manufacturer of atazanavir-cobicistat states that clinical|
01494|035|M|monitoring is recommended when coadministered with amiodarone or|
01494|036|M|quinidine.(6)  The UK manufacturer of atazanavir-cobicistat states that|
01494|037|M|concurrent amiodarone and quinidine are contraindicated.(7)|
01494|038|M|   If concurrent use is warranted, consider obtaining serum calcium,|
01494|039|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01494|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01494|041|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01494|042|B||
01494|043|D|DISCUSSION:  Atazanavir is a moderate inhibitor of CYP3A4.(8)|
01494|044|B||
01494|045|R|REFERENCES:|
01494|046|B||
01494|047|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01494|048|R|  Squibb Company December, 2024.|1
01494|049|R|2.Reyataz (atazanavir) Canadian prescribing information. Bristol-Myers|1
01494|050|R|  Squibb Canada August 31, 2023.|1
01494|051|R|3.Reyataz (atazanavir) UK summary of product characteristics. Bristol-Myers|1
01494|052|R|  Squibb Pharmaceuticals Limited September 8, 2008.|1
01494|053|R|4.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01494|054|R|  Squibb Pharmaceuticals October 25, 2023.|1
01494|055|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01494|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01494|057|R|  settings: a scientific statement from the American Heart Association and|6
01494|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01494|059|R|  2;55(9):934-47.|6
01494|060|R|6.Evotaz (atazanavir and cobicistat) US prescribing information.|1
01494|061|R|  Bristol-Myers-Squibb Company May, 2025.|1
01494|062|R|7.Evotaz (atazanavir and cobicistat) UK summary of product characteristics.|1
01494|063|R|  Bristol-Myers-Squibb Company March, 2016.|1
01494|064|R|8.This information is based on an extract from the Certara Drug Interaction|6
01494|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01495|001|T|MONOGRAPH TITLE:  Gentamicin, Amikacin, Tobramycin/Amphotericin|
01495|002|B||
01495|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01495|004|L|take action as needed.|
01495|005|B||
01495|006|A|MECHANISM OF ACTION:  The ototoxic or nephrotoxic effects of gentamicin,|
01495|007|A|amikacin, or tobramycin may be additive with those of amphotericin.|
01495|008|B||
01495|009|E|CLINICAL EFFECTS:  The concurrent administration of gentamicin, amikacin, or|
01495|010|E|tobramycin with amphotericin may result in additive ototoxic or nephrotoxic|
01495|011|E|effects.(1)|
01495|012|B||
01495|013|P|PREDISPOSING FACTORS:  Preexisting renal impairment, sepsis, extended|
01495|014|P|duration of aminoglycoside therapy, greater than one aminoglycoside dose per|
01495|015|P|day, or concomitant use of additional nephrotoxic agents such as iodinated|
01495|016|P|contrast media or vancomycin appear to increase the risk for nephrotoxicity|
01495|017|P|and ototoxicity.(1-6).|
01495|018|P|   Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G,|
01495|019|P|m.1095T>C, and m.1494C>T) are at increased risk of developing ototoxicity.|
01495|020|P|An additional risk factor includes patients with a maternal relative known|
01495|021|P|to have a clinically relevant MT-RNR1 variant.  The risk of ototoxicity can|
01495|022|P|occur at standard recommended doses of aminoglycosides.(7)|
01495|023|B||
01495|024|M|PATIENT MANAGEMENT:  The Australian manufacturer of gentamicin, amikacin,|
01495|025|M|and tobramycin state that the concurrent use of gentamicin, amikacin, or|
01495|026|M|tobramycin and amphotericin should be avoided.(1,4,5)|
01495|027|B||
01495|028|D|DISCUSSION:  The Australian and U.K. manufacturers of gentamicin, amikacin,|
01495|029|D|and tobramycin state that since the ototoxic or nephrotoxic effects of|
01495|030|D|gentamicin, amikacin, or tobramycin may be additive, avoid concurrent or|
01495|031|D|sequential use of other neurotoxic and/or nephrotoxic agents including|
01495|032|D|amphotericin.(1,3,4,5)|
01495|033|B||
01495|034|R|REFERENCES:|
01495|035|B||
01495|036|R|1.Gentamicin injection B.P. Australian prescribing information. Pharmacia|1
01495|037|R|  September, 2002.|1
01495|038|R|2.McDermott JH, Wolf J, Hoshitsuki K, Huddart R, Caudle KE, Whirl-Carrillo|6
01495|039|R|  M, Steyger PS, Smith RJH, Cody N, Rodriguez-Antona C, Klein TE, Newman WG.|6
01495|040|R|  Clinical Pharmacogenetics Implementation Consortium Guideline for the use|6
01495|041|R|  of aminoglycosides based on MT-RNR1 genotype. Clin Pharmacol Ther May,|6
01495|042|R|  2021.|6
01495|043|R|3.Gentamicin injection UK summary of product characteristics. Mayne Pharma|1
01495|044|R|  Plc February, 2004.|1
01495|045|R|4.Tobramycin Australian product information. Pfizer Australia Pty Ltd Nov|1
01495|046|R|  18, 2024.|1
01495|047|R|5.Amikacin XSP (amikacin sulfate) solution for injection Australian product|1
01495|048|R|  information. Southern XP IP Pty Ltd June 5, 2023.|1
01496|001|T|MONOGRAPH TITLE:  Selected Nephrotoxic Agents/Cisplatin|
01496|002|B||
01496|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01496|004|L|take action as needed.|
01496|005|B||
01496|006|A|MECHANISM OF ACTION:  The nephrotoxic effects of aminoglycosides or|
01496|007|A|non-steroidal anti-inflammatory drugs (NSAIDs) may be additive to those of|
01496|008|A|cisplatin.|
01496|009|B||
01496|010|E|CLINICAL EFFECTS:  The concurrent administration of amikacin, gentamicin,|
01496|011|E|tobramycin, or NSAIDs with cisplatin may result in additive nephrotoxic|
01496|012|E|effects.(1,2,5,6)|
01496|013|B||
01496|014|P|PREDISPOSING FACTORS:  Pre-existing renal insufficiency, advanced age,|
01496|015|P|dehydration may increase the risk of nephrotoxicity.(1,5,6)|
01496|016|B||
01496|017|M|PATIENT MANAGEMENT:  The US labeling for aminoglycosides and cisplatin|
01496|018|M|states that the concurrent use of aminoglycosides and cisplatin should be|
01496|019|M|avoided.(1,3,4,6)|
01496|020|M|   Inform patients that concurrent cisplatin and aminoglycosides or NSAIDs|
01496|021|M|can cause nephrotoxicity and that renal function and electrolyte monitoring|
01496|022|M|during treatment is necessary.(2)|
01496|023|B||
01496|024|D|DISCUSSION:  The US manufacturers of amikacin, gentamicin and tobramycin|
01496|025|D|state that since the nephrotoxic effects of these medications may be|
01496|026|D|additive, avoid concurrent or sequential use of other neurotoxic and/or|
01496|027|D|nephrotoxic agents including cisplatin.(1,3,6)|
01496|028|B||
01496|029|R|REFERENCES:|
01496|030|B||
01496|031|R|1.Amikacin sulfate injection US prescribing information. Heritage|1
01496|032|R|  Pharmaceuticals, Inc. June, 2020.|1
01496|033|R|2.Cisplatin injection US prescribing information. WG Critical Care February,|1
01496|034|R|  2019.|1
01496|035|R|3.Gentamicin injection B.P. Australian prescribing information. Pharmacia|1
01496|036|R|  September, 2002.|1
01496|037|R|4.Gentamicin injection UK summary of product characteristics. Mayne Pharma|1
01496|038|R|  Plc February, 2004.|1
01496|039|R|5.Gentamicin injection US prescribing information,. Fresenius Kabi USA, LLC.|1
01496|040|R|  October, 2015,.|1
01496|041|R|6.Tobramycin US prescribing information. X-GEN Pharmaceuticals, Inc.|1
01496|042|R|  September, 2011.|1
01497|001|T|MONOGRAPH TITLE:  Gentamicin, Amikacin, Tobramycin/Vancomycin|
01497|002|B||
01497|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01497|004|L|take action as needed.|
01497|005|B||
01497|006|A|MECHANISM OF ACTION:  The ototoxic or nephrotoxic effects of gentamicin,|
01497|007|A|amikacin, or tobramycin may be additive with those of vancomycin.|
01497|008|B||
01497|009|E|CLINICAL EFFECTS:  The concurrent administration of gentamicin, amikacin, or|
01497|010|E|tobramycin with vancomycin may result in additive ototoxic or nephrotoxic|
01497|011|E|effects.(1)|
01497|012|B||
01497|013|P|PREDISPOSING FACTORS:  Preexisting renal impairment, sepsis, extended|
01497|014|P|duration of aminoglycoside therapy, greater than one aminoglycoside dose per|
01497|015|P|day, or concomitant use of additional nephrotoxic agents such as iodinated|
01497|016|P|contrast media or vancomycin appear to increase the risk for nephrotoxicity|
01497|017|P|and ototoxicity.(1-5).|
01497|018|P|   Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G,|
01497|019|P|m.1095T>C, and m.1494C>T) are at increased risk of developing ototoxicity.|
01497|020|P|An additional risk factor includes patients with a maternal relative known|
01497|021|P|to have a clinically relevant MT-RNR1 variant.  The risk of ototoxicity can|
01497|022|P|occur at standard recommended doses of aminoglycosides.|
01497|023|B||
01497|024|M|PATIENT MANAGEMENT:  The Australian manufacturer of gentamicin, amikacin,|
01497|025|M|and tobramycin state that the concurrent use of gentamicin, amikacin, or|
01497|026|M|tobramycin and vancomycin should be avoided.(1,4,5)|
01497|027|B||
01497|028|D|DISCUSSION:  The Australian and U.K. manufacturers of gentamicin, amikacin,|
01497|029|D|and tobramycin state that since the ototoxic or nephrotoxic effects of|
01497|030|D|gentamicin, amikacin, or tobramycin may be additive, avoid concurrent or|
01497|031|D|sequential use of other neurotoxic and/or nephrotoxic agents including|
01497|032|D|vancomycin.(1,3,4,5)|
01497|033|B||
01497|034|R|REFERENCES:|
01497|035|B||
01497|036|R|1.Gentamicin injection B.P. Australian prescribing information. Pharmacia|1
01497|037|R|  September, 2002.|1
01497|038|R|2.McDermott JH, Wolf J, Hoshitsuki K, Huddart R, Caudle KE, Whirl-Carrillo|6
01497|039|R|  M, Steyger PS, Smith RJH, Cody N, Rodriguez-Antona C, Klein TE, Newman WG.|6
01497|040|R|  Clinical Pharmacogenetics Implementation Consortium Guideline for the use|6
01497|041|R|  of aminoglycosides based on MT-RNR1 genotype. Clin Pharmacol Ther May,|6
01497|042|R|  2021.|6
01497|043|R|3.Gentamicin injection UK summary of product characteristics. Mayne Pharma|1
01497|044|R|  Plc February, 2004.|1
01497|045|R|4.Tobramycin Australian product information. Pfizer Australia Pty Ltd Nov|1
01497|046|R|  18, 2024.|1
01497|047|R|5.Amikacin XSP (amikacin sulfate) solution for injection Australian product|1
01497|048|R|  information. Southern XP IP Pty Ltd June 5, 2023.|1
01498|001|T|MONOGRAPH TITLE:  Hydantoins/Select Neuromuscular Blocking Agents|
01498|002|B||
01498|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01498|004|L|take action as needed.|
01498|005|B||
01498|006|A|MECHANISM OF ACTION:  It has been suggested that phenytoin increases|
01498|007|A|end-plate anticholinesterase activity, resulting in higher acetylcholine|
01498|008|A|concentration at the neuromuscular junction.(1)|
01498|009|B||
01498|010|E|CLINICAL EFFECTS:  A higher plasma concentration of the neuromuscular|
01498|011|E|blocking agent was required to effect a given level of neuromuscular|
01498|012|E|blockade in patients receiving phenytoin.(2,3)|
01498|013|B||
01498|014|P|PREDISPOSING FACTORS:  None determined.|
01498|015|B||
01498|016|M|PATIENT MANAGEMENT:  Patients receiving hydantoin anticonvulsants should be|
01498|017|M|monitored for a decreased response to the neuromuscular blocking agent. The|
01498|018|M|dose of the neuromuscular blocking agent may need to be increased and/or|
01498|019|M|given more frequently.(9)|
01498|020|B||
01498|021|D|DISCUSSION:  In a study, patients receiving phenytoin were administered|
01498|022|D|metocurine, attained 83% of maximum neuromuscular blockade compared with 98%|
01498|023|D|in the control group.(1) In another study, patients maintained on phenytoin|
01498|024|D|for more than one week had a significantly higher pancuronium requirement|
01498|025|D|than those patients not receiving phenytoin.(1)|
01498|026|D|   In two separate case reports, patients maintained on phenytoin|
01498|027|D|demonstrated a resistance to pancuronium and a decreased duration of|
01498|028|D|neuromuscular blockade.(3,4)|
01498|029|D|   In a study, patients maintained on phenytoin and receiving vecuronium had|
01498|030|D|a significantly shorter total duration and effect of neuromuscular blockade|
01498|031|D|compared to those patients not receiving phenytoin.(5) In contrast, neither|
01498|032|D|the effect nor duration of atracurium's neuromuscular blockade was affected|
01498|033|D|by phenytoin.(5)|
01498|034|D|  Two in vitro studies showed that the neuromuscular blockade of curare and|
01498|035|D|tubocurarine was potentiated by the use of phenytoin.(6,7)|
01498|036|D|  Ten children received a bolus dose of vecuronium 0.15mg/Kg while on|
01498|037|D|phenytoin and showed a significantly increased clearance of vecuronium|
01498|038|D|compared to the control group, 15.1 and 9.0 ml/Kg/min, respectively.(8)|
01498|039|D|   In a case report, a 58 year-old male previously stabilized on phenytoin|
01498|040|D|(400 mg daily) was given an injection of vecuronium (8 mg) to induce muscle|
01498|041|D|blockade during bowel surgery.  While monitoring the effectiveness of|
01498|042|D|vecuronium only 75% twitch height blockade was noted after seven minutes.|
01498|043|D|The medication, due to its short duration and impaired effectiveness, had to|
01498|044|D|be given more frequently throughout the surgery in order to maintain|
01498|045|D|adequate muscle block.(9)|
01498|046|D|   A separate case report records a decreased response to pancuronium in a|
01498|047|D|15 year-old male, previously stabilized on phenytoin (350 mg daily), while|
01498|048|D|undergoing surgery to remove a parietal tumor.  Pancuronium (0.7 mg/kg) was|
01498|049|D|given as a relaxant during the surgery and monitored using the train-of-four|
01498|050|D|method.  Intermittent doses of pancuronium (0.17 mg/kg) were given for the|
01498|051|D|first hour of surgery without successful blockade apparent by the return of|
01498|052|D|all four twitches within ten minutes of each dose.  A second attempt at|
01498|053|D|muscular blockade was made with continuous infusion atracurium (0.26-0.55|
01498|054|D|mg/kg/hour) for the duration of the surgery.  Only 16 minutes after stopping|
01498|055|D|the infusion, all four twitches were visible.(10)|
01498|056|B||
01498|057|R|REFERENCES:|
01498|058|B||
01498|059|R|1.Chen J Kim YD Dubois M Kammerer W Macnamara TE. The increased requirement|6
01498|060|R|  of pancuronium in neurosurgical patients receiving Dilantin chronically.|6
01498|061|R|  Anesthesiology Sept 1983;59(3):A288.|6
01498|062|R|2.Ornstein E, Matteo RS, Young WL, Diaz J. Resistance to metocurine-induced|6
01498|063|R|  neuromuscular blockade in patients receiving phenytoin. Anesthesiology|6
01498|064|R|  1985 Sep;63(3):294-8.|6
01498|065|R|3.Liberman BA, Norman P, Hardy BG. Pancuronium-phenytoin interaction: a case|3
01498|066|R|  of decreased duration of neuromuscular blockade. Int J Clin Pharmacol Ther|3
01498|067|R|  Toxicol 1988 Aug;26(8):371-4.|3
01498|068|R|4.Hickey DR, Sangwan S, Bevan JC. Phenytoin-induced resistance to|3
01498|069|R|  pancuronium. Use of atracurium infusion in management of a neurosurgical|3
01498|070|R|  patient. Anaesthesia 1988 Sep;43(9):757-9.|3
01498|071|R|5.Ornstein E, Matteo RS, Schwartz AE, Silverberg PA, Young WL, Diaz J. The|6
01498|072|R|  effect of phenytoin on the magnitude and duration of neuromuscular block|6
01498|073|R|  following atracurium or vecuronium. Anesthesiology 1987 Aug;67(2):191-6.|6
01498|074|R|6.NORRIS FH Jr, COLELLA J, MCFARLIN D. EFFECT OF DIPHENYLHYDANTOIN ON|6
01498|075|R|  NEUROMUSCULAR SYNAPSE. Neurology 1964 Sep;14:869-76.|6
01498|076|R|7.Gandhi IC, Jindal MN, Patel VK. Mechaism of neuromuscular blockade with|6
01498|077|R|  some antiepileptic drugs. Arzneimittelforschung 1976 Feb;26(2):258-61.|6
01498|078|R|8.Soriano SG, Sullivan LJ, Venkatakrishnan K, Greenblatt DJ, Martyn JA.|2
01498|079|R|  Pharmacokinetics and pharmacodynamics of vecuronium in children receiving|2
01498|080|R|  phenytoin or carbamazepine for chronic anticonvulsant therapy. Br J|2
01498|081|R|  Anaesth 2001 Feb;86(2):223-9.|2
01498|082|R|9.Gough JD, Smith A, Wise CC. Phenytoin-induced resistance to vecuronium.|3
01498|083|R|  Anaesthesia 1989 Jun;44(6):520.|3
01498|084|R|10.Kumar CM, Lawler PG. Phenytoin-induced resistance to vecuronium.|3
01498|085|R|   Anaesthesia 1989 Mar;44(3):263-4.|3
01499|001|T|MONOGRAPH TITLE:  Orlistat/Fat Soluble Vitamins|
01499|002|B||
01499|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01499|004|L|take action as needed.|
01499|005|B||
01499|006|A|MECHANISM OF ACTION:  The acetate ester forms of vitamin A and vitamin E|
01499|007|A|must undergo hydrolysis for absorption from the gastrointestinal tract.(1)|
01499|008|A|The enzyme responsible for this hydrolysis is inhibited by orlistat.(2)|
01499|009|B||
01499|010|E|CLINICAL EFFECTS:  Orlistat may reduce absorption of fat soluble vitamins,|
01499|011|E|leading to a deficiency state.|
01499|012|B||
01499|013|P|PREDISPOSING FACTORS:  A pre-existing deficiency of fat soluble vitamins|
01499|014|P|(A,D,E and K) or chronic malabsorption syndrome.|
01499|015|B||
01499|016|M|PATIENT MANAGEMENT:  The inhibition of fat soluble vitamin absorption by|
01499|017|M|orlistat should be borne in mind during implementation of a vitamin|
01499|018|M|supplementation strategy.  Patients should be strongly encouraged to take a|
01499|019|M|multivitamin supplement which contains fat soluble vitamins, particularly|
01499|020|M|Vitamin D as it appears most susceptible to this interaction.(4,5)|
01499|021|M|Multivitamin supplements should be taken at least two hours before or after|
01499|022|M|the dose of orlistat, or at bedtime.(4)|
01499|023|M|   Patients with chronic malabsorption syndromes should not receive|
01499|024|M|orlistat.(4)|
01499|025|B||
01499|026|D|DISCUSSION:  Adult patients taking orlistat without supplementation showed a|
01499|027|D|greater reduction in vitamin A,D,E and beta-carotene levels compared to|
01499|028|D|placebo during two or more consecutive visits in studies of 1-2 years|
01499|029|D|duration; these patients had normal baseline values prior to orlistat|
01499|030|D|therapy.  Low vitamin values in orlistat patients were as follows: low|
01499|031|D|Vitamin D 12%, low beta-carotene 6.1%, low Vitamin E 5.8%, low Vitamin A|
01499|032|D|2.2%.(4)|
01499|033|D|   A pharmacokinetic interaction study showed a 30% reduction in|
01499|034|D|beta-carotene supplement absorption and a 60% decreased in vitamin E acetate|
01499|035|D|absorption with concomitant orlistat.(4)|
01499|036|D|   In a study, orlistat produced the vitamin net concentration by|
01499|037|D|approximately 43%.(1)|
01499|038|D|   In a study, no statistically significant decrease in vitamin A absorption|
01499|039|D|was observed with concurrent orlistat.(2)|
01499|040|D|   In a study, mean vitamin D levels were significantly reduced compared|
01499|041|D|with baseline after one month of orlistat therapy despite multivitamin|
01499|042|D|supplementation.(5)|
01499|043|B||
01499|044|R|REFERENCES:|
01499|045|B||
01499|046|R|1.Borgstrom B. Mode of action of tetrahydrolipstatin: a derivative of the|6
01499|047|R|  naturally occurring lipase inhibitor lipstatin. Biochim Biophys Acta 1988|6
01499|048|R|  Oct 14;962(3):308-16.|6
01499|049|R|2.Melia AT, Koss-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of|6
01499|050|R|  dietary fat absorption, on the absorption of vitamins A and E in healthy|6
01499|051|R|  volunteers. J Clin Pharmacol 1996 Jul;36(7):647-53.|6
01499|052|R|3.Xenical (orlistat) Australian rescribing information. Roche May 30, 2002.|1
01499|053|R|4.Xenical (orlistat) US prescribing information. Roche Laboratories, Inc.|1
01499|054|R|  November, 2022.|1
01499|055|R|5.McDuffie JR, Calis KA, Booth SL, Uwaifo GI, Yanovski JA. Effects of|6
01499|056|R|  orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy|6
01499|057|R|  2002 Jul;22(7):814-22.|6
01499|058|R|6.Alli (orlistat) US prescribing information. GSK Consumer Healthcare May,|1
01499|059|R|  2017.|1
01500|001|T|MONOGRAPH TITLE:  Selected Opioids/Selected CYP3A4 Inhibitors|
01500|002|B||
01500|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01500|004|L|of severe adverse interaction.|
01500|005|B||
01500|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
01500|007|A|alfentanil,(1,2) benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4)|
01500|008|A|oxycodone,(5) and sufentanil.(6)  Benzhydrocodone is a prodrug of|
01500|009|A|hydrocodone.(3)|
01500|010|B||
01500|011|E|CLINICAL EFFECTS:  The concurrent administration of a CYP3A4 inhibitor may|
01500|012|E|result in elevated levels of and toxicity from alfentanil,(1,2)|
01500|013|E|benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4) oxycodone,(5) and|
01500|014|E|sufentanil,(6) including profound sedation, respiratory depression, coma,|
01500|015|E|and/or death.|
01500|016|B||
01500|017|P|PREDISPOSING FACTORS:  Heat.|
01500|018|B||
01500|019|M|PATIENT MANAGEMENT:  Monitor patients receiving potent or moderate CYP3A4|
01500|020|M|inhibitors for an extended period of time.  Dosage adjustments should be|
01500|021|M|made if warranted.|
01500|022|M|   The manufacturer of itraconazole states that concomitant administration|
01500|023|M|of fentanyl is not recommended during and 2 weeks after itraconazole|
01500|024|M|treatment.(7)|
01500|025|M|   Avoid exposing the fentanyl patch application site and surrounding area|
01500|026|M|to direct external heat sources as there have been reports of overdose and|
01500|027|M|death as a result of exposure to heat.|
01500|028|M|   The manufacturer of sufentanil sublingual tablets states that if|
01500|029|M|concomitant use with CYP3A4 inhibitors is necessary, consider use of an|
01500|030|M|alternate agent that allows dose adjustment.(6)|
01500|031|M|   Respiratory depression can occur at any time during opioid therapy,|
01500|032|M|especially during therapy initiation and following dosage increases.  The|
01500|033|M|risk of opioid-related overdose or overdose-related death is increased with|
01500|034|M|higher opioid doses, and this risk persists over the course of therapy.|
01500|035|M|Consider these risks when using concurrently with other agents that may|
01500|036|M|cause CNS depression.(8)|
01500|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
01500|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
01500|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
01500|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
01500|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
01500|042|M|as those taking CNS depressants) and when a patient has household|
01500|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
01500|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
01500|045|M|over-the-counter, or as part of a community-based program).(9)|
01500|046|B||
01500|047|D|DISCUSSION:  In a randomized, placebo-controlled trial in 20 healthy|
01500|048|D|subjects, clarithromycin (500 mg twice daily) increased the area-under-curve|
01500|049|D|(AUC) of a single oral dose of oxycodone (10 mg) by 2-fold and 2.3-fold in|
01500|050|D|young and elderly subjects, respectively.(10)|
01500|051|D|   In a controlled cross-over study in 6 subjects, 7 days of pretreatment|
01500|052|D|with erythromycin decreased the clearance of alfentanil by 25%.  Alfentanil|
01500|053|D|half-life increased by 56%.(11)|
01500|054|D|   Erythromycin has been shown to inhibit fentanyl metabolism in vitro.(12)|
01500|055|D|   In a randomized, double-blind, placebo-controlled crossover study in 9|
01500|056|D|subjects, single doses of intravenous fluconazole (400 mg) and oral|
01500|057|D|fluconazole (400 mg) decreased the clearance of a single dose of alfentanil|
01500|058|D|(20 mcg/kg) by 58% and 55%, respectively.  Alfentanil half-life almost|
01500|059|D|doubled after both intravenous and oral fluconazole.  Both intravenous and|
01500|060|D|oral fluconazole increased subjective effects of alfentanil and increased|
01500|061|D|alfentanil-induced respiratory depression.(13)|
01500|062|D|   In a cross-over study, pretreatment with itraconazole (200 mg daily for 4|
01500|063|D|days) had no effect on a single dose of intravenous fentanyl (3 mcg/kg).(14)|
01500|064|D|   In a cross-over study in 12 healthy subjects, itraconazole (200 mg daily|
01500|065|D|for 5 days) increased the AUC and Cmax of a single oral dose of oxycodone|
01500|066|D|(10 mg) by 144% and 45%, respectively.  The AUC of noroxycodone decreased|
01500|067|D|49% and the AUC of oxymorphone increased 359% with concurrent itraconazole|
01500|068|D|and oral oxycodone.  Itraconazole increased the AUC of a single intravenous|
01500|069|D|dose of oxycodone (0.1 mg/kg) by 51%.(15)|
01500|070|D|   In a randomized cross-over study in 12 healthy subjects, ketoconazole|
01500|071|D|increased the AUC of oxycodone by 2-fold to 3-fold and also increased|
01500|072|D|oxycodone-related nausea, drowsiness, and pruritus.(16)|
01500|073|D|   In a randomized cross-over study in 10 healthy subjects, ketoconazole|
01500|074|D|increased the AUC of oxymorphone by 3-fold following a single dose of|
01500|075|D|oxycodone (0.2 mg/kg).  Increased side effects were also noted.(17,18)|
01500|076|D|   Ketoconazole has been shown to inhibit the metabolism of alfentanil,(19)|
01500|077|D|fentanyl,(12) and oxycodone(20) in vitro.|
01500|078|D|   In a study of 11 subjects, ritonavir reduced the clearance of fentanyl|
01500|079|D|67% and increased the AUC 174%.  Eight subjects reported nausea during the|
01500|080|D|study.(21)|
01500|081|D|   In a randomized cross-over study in 16 healthy subjects, ritonavir (300|
01500|082|D|mg twice daily for 4 days) and lopinavir/ritonavir (400/100 mg twice daily|
01500|083|D|for 4 days) increased the AUC of a single dose of oxycodone (10 mg) by|
01500|084|D|3.0-fold and 2.6-fold, respectively.  Oxycodone half-life increased 55% and|
01500|085|D|58%, respectively, with concurrent ritonavir or lopinavir/ritonavir.  Both|
01500|086|D|regimens also increased self-reported oxycodone effects.(22)|
01500|087|D|   The Australian manufacturer of ritonavir states that the AUC of fentanyl|
01500|088|D|may be potentially increased 3-fold with concurrent ritonavir.(23)|
01500|089|D|   In a randomized cross-over study in 11 healthy subjects, telithromycin|
01500|090|D|(800 mg daily for 4 days) increased the AUC of a single dose of oxycodone|
01500|091|D|(10 mg immediate-release) by 80%.  The AUC of noroxycodone was decreased by|
01500|092|D|46%.  There was a modest increase in the pharmacodynamic effects of|
01500|093|D|oxycodone.(24)|
01500|094|D|   In a randomized cross-over study in 10 healthy subjects, troleandomycin|
01500|095|D|increased the AUC of alfentanil by 135%.(25)|
01500|096|D|   In a randomized cross-over study in 12 healthy subjects, troleandomycin|
01500|097|D|increased the AUC of a single dose of fentanyl (oral transmucosal, 10|
01500|098|D|mcg/kg) by 76%.(26)|
01500|099|D|   Troleandomycin has been shown to inhibit alfentanil(18) and fentanyl(27)|
01500|100|D|metabolism in vitro.|
01500|101|D|   In a randomized, cross-over study in 12 healthy subjects, concurrent use|
01500|102|D|of voriconazole and alfentanil increased the AUC of alfentanil 6-fold and|
01500|103|D|decreased its clearance by 85%.(23,28)|
01500|104|D|   In a randomized, cross-over study in 12 healthy subjects, voriconazole|
01500|105|D|(400 mg twice daily, Day 1; 200 mg twice daily, Day 2) and fluconazole (400|
01500|106|D|mg daily, Day 1; 200 mg daily, Day 2) decreased the clearance of a single|
01500|107|D|dose of intravenous fentanyl (5 mcg/kg) by 23% and 16%, respectively.(29)|
01500|108|D|   In a randomized cross-over study in 12 healthy subjects, pretreatment|
01500|109|D|with voriconazole for 4 days increased the AUC, Cmax, and half-life of a|
01500|110|D|single dose of oxycodone (10 mg) by 3.6-fold, 1.7-fold, 2.0-fold,|
01500|111|D|respectively.(30)|
01500|112|D|   There are case reports of interactions between alfentanil and|
01500|113|D|erythromycin,(31) fentanyl and clarithromycin,(32) fentanyl and|
01500|114|D|fluconazole,(33) fentanyl and itraconazole,(34) and oxycodone and|
01500|115|D|voriconazole.(35)  In the case report with fentanyl and fluconazole, the|
01500|116|D|patient died of respiratory depression.(33)|
01500|117|D|   A study in healthy subjects shown that the application of heat over the|
01500|118|D|fentanyl patch system increased mean overall fentanyl exposure by 120% and|
01500|119|D|average maximum fentanyl level by 61%.(2)|
01500|120|D|   In a single dose study of sufentanil sublingual tablet 15 mcg with a|
01500|121|D|strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC|
01500|122|D|and Cmax values of sufentanil, respectively, compared to its administration|
01500|123|D|alone.(6)|
01500|124|D|   Strong CYP3A4 inhibitors that have been documented to interact with|
01500|125|D|alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone or|
01500|126|D|would be expected to interact with these agents include:  boceprevir,|
01500|127|D|clarithromycin, cobicistat, elvitegravir, grapefruit, idelalisib, indinavir,|
01500|128|D|itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil,|
01500|129|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
01500|130|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
01500|131|D|troleandomycin, tucatinib, voriconazole.(36)|
01500|132|D|   Moderate CYP3A4 inhibitors that have been documented to interact with|
01500|133|D|alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone|
01500|134|D|include:  erythromycin and fluconazole.(36)|
01500|135|B||
01500|136|R|REFERENCES:|
01500|137|B||
01500|138|R|1.Actiq (fentanyl citrate) Australian prescribing information. Orphan|1
01500|139|R|  Australia Pty Ltd. November 2, 2002.|1
01500|140|R|2.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
01500|141|R|  Inc. October, 2019.|1
01500|142|R|3.Apadaz (benzhydrocodone and acetaminophen) US prescribing information.|1
01500|143|R|  KemPharm, Inc.. December, 2023.|1
01500|144|R|4.Zohydro ER (hydrocodone bitarate) US prescribing information. Zogenix Inc.|1
01500|145|R|  October, 2019.|1
01500|146|R|5.OxyContin (oxycodone hydrochloride) US prescribing information. Perdue|1
01500|147|R|  Pharma L.P. October, 2021.|1
01500|148|R|6.Dsuvia (sufentanil) sublingual tablet US prescribing information. AcelRx|1
01500|149|R|  Pharmaceuticals, Inc. December, 2023.|1
01500|150|R|7.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01500|151|R|  Products, L.P. February, 2024.|1
01500|152|R|8.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
01500|153|R|  prescribing information for all opioid pain medicines to provide|1
01500|154|R|  additional guidance for safe use. Available at:|1
01500|155|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
01500|156|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
01500|157|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
01500|158|R|9.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
01500|159|R|  recommends health care professionals discuss naloxone with all patients|1
01500|160|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
01500|161|R|  disorder. Available at:|1
01500|162|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
01500|163|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
01500|164|R|  d-pain July 23, 2020.|1
01500|165|R|10.Liukas A, Hagelberg NM, Kuusniemi K, Neuvonen PJ, Olkkola KT. Inhibition|2
01500|166|R|   of cytochrome P450 3A by clarithromycin uniformly affects the|2
01500|167|R|   pharmacokinetics and pharmacodynamics of oxycodone in young and elderly|2
01500|168|R|   volunteers. J Clin Psychopharmacol 2011 Jun;31(3):302-8.|2
01500|169|R|11.Bartkowski RR, Goldberg ME, Larijani GE, Boerner T. Inhibition of|2
01500|170|R|   alfentanil metabolism by erythromycin. Clin Pharmacol Ther 1989 Jul;|2
01500|171|R|   46(1):99-102.|2
01500|172|R|12.Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid|5
01500|173|R|   analgesic, by human liver microsomes. Role of CYP3A4. Drug Metab Dispos|5
01500|174|R|   1996 Sep;24(9):932-9.|5
01500|175|R|13.Palkama VJ, Isohanni MH, Neuvonen PJ, Olkkola KT. The effect of|2
01500|176|R|   intravenous and oral fluconazole on the pharmacokinetics and|2
01500|177|R|   pharmacodynamics of intravenous alfentanil. Anesth Analg 1998 Jul;|2
01500|178|R|   87(1):190-4.|2
01500|179|R|14.Palkama VJ, Neuvonen PJ, Olkkola KT. The CYP 3A4 inhibitor itraconazole|2
01500|180|R|   has no effect on the pharmacokinetics of i.v. fentanyl. Br J Anaesth 1998|2
01500|181|R|   Oct;81(4):598-600.|2
01500|182|R|15.Saari TI, Gronlund J, Hagelberg NM, Neuvonen M, Laine K, Neuvonen PJ,|2
01500|183|R|   Olkkola KT. Effects of itraconazole on the pharmacokinetics and|2
01500|184|R|   pharmacodynamics of intravenously and orally administered oxycodone. Eur|2
01500|185|R|   J Clin Pharmacol 2010 Apr;66(4):387-97.|2
01500|186|R|16.Kummer O, Hammann F, Moser C, Schaller O, Drewe J, Krahenbuhl S. Effect|2
01500|187|R|   of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and|2
01500|188|R|   pharmacodynamics of oxycodone. Eur J Clin Pharmacol 2011 Jan;67(1):63-71.|2
01500|189|R|17.Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier|2
01500|190|R|   MF, Hochstrasser D, Dayer P, Desmeules JA. The effects of CYP2D6 and|2
01500|191|R|   CYP3A activities on the pharmacokinetics of immediate release oxycodone.|2
01500|192|R|   Br J Pharmacol 2010 Jun;160(4):907-18.|2
01500|193|R|18.Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier|2
01500|194|R|   MF, Hochstrasser D, Dayer P, Desmeules JA. Genetic polymorphisms and drug|2
01500|195|R|   interactions modulating CYP2D6 and CYP3A activities have a major effect|2
01500|196|R|   on oxycodone analgesic efficacy and safety. Br J Pharmacol 2010 Jun;|2
01500|197|R|   160(4):919-30.|2
01500|198|R|19.Klees TM, Sheffels P, Dale O, Kharasch ED. Metabolism of alfentanil by|5
01500|199|R|   cytochrome p4503a (cyp3a) enzymes. Drug Metab Dispos 2005 Mar;|5
01500|200|R|   33(3):303-11.|5
01500|201|R|20.Lalovic B, Phillips B, Risler LL, Howald W, Shen DD. Quantitative|5
01500|202|R|   contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver|5
01500|203|R|   and intestinal microsomes. Drug Metab Dispos 2004 Apr;32(4):447-54.|5
01500|204|R|21.Olkkola KT, Palkama VJ, Neuvonen PJ. Ritonavir's role in reducing|2
01500|205|R|   fentanyl clearance and prolonging its half-life. Anesthesiology 1999 Sep;|2
01500|206|R|   91(3):681-5.|2
01500|207|R|22.Nieminen TH, Hagelberg NM, Saari TI, Neuvonen M, Neuvonen PJ, Laine K,|2
01500|208|R|   Olkkola KT. Oxycodone concentrations are greatly increased by the|2
01500|209|R|   concomitant use of ritonavir or lopinavir/ritonavir. Eur J Clin Pharmacol|2
01500|210|R|   2010 Oct;66(10):977-85.|2
01500|211|R|23.Norvir (ritonavir) Australian prescribing information. Abbott Australasia|1
01500|212|R|   Pty. Ltd. January 29, 2004.|1
01500|213|R|24.Gronlund J, Saari T, Hagelberg N, Martikainen IK, Neuvonen PJ, Olkkola|2
01500|214|R|   KT, Laine K. Effect of telithromycin on the pharmacokinetics and|2
01500|215|R|   pharmacodynamics of oral oxycodone. J Clin Pharmacol 2010 Jan;|2
01500|216|R|   50(1):101-8.|2
01500|217|R|25.Kharasch ED, Walker A, Hoffer C, Sheffels P. Intravenous and oral|2
01500|218|R|   alfentanil as in vivo probes for hepatic and first-pass cytochrome P450|2
01500|219|R|   3A activity: noninvasive assessment by use of pupillary miosis. Clin|2
01500|220|R|   Pharmacol Ther 2004 Nov;76(5):452-66.|2
01500|221|R|26.Kharasch ED, Whittington D, Hoffer C. Influence of hepatic and intestinal|2
01500|222|R|   cytochrome P4503A activity on the acute disposition and effects of oral|2
01500|223|R|   transmucosal fentanyl citrate. Anesthesiology 2004 Sep;101(3):729-37.|2
01500|224|R|27.Tateishi T, Krivoruk Y, Ueng YF, Wood AJ, Guengerich FP, Wood M.|5
01500|225|R|   Identification of human liver cytochrome P-450 3A4 as the enzyme|5
01500|226|R|   responsible for fentanyl and sufentanil N-dealkylation. Anesth Analg 1996|5
01500|227|R|   Jan;82(1):167-72.|5
01500|228|R|28.Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT.|2
01500|229|R|   Voriconazole, but not terbinafine, markedly reduces alfentanil clearance|2
01500|230|R|   and prolongs its half-life. Clin Pharmacol Ther 2006 Nov;80(5):502-8.|2
01500|231|R|29.Saari TI, Laine K, Neuvonen M, Neuvonen PJ, Olkkola KT. Effect of|2
01500|232|R|   voriconazole and fluconazole on the pharmacokinetics of intravenous|2
01500|233|R|   fentanyl. Eur J Clin Pharmacol 2008 Jan;64(1):25-30.|2
01500|234|R|30.Hagelberg NM, Nieminen TH, Saari TI, Neuvonen M, Neuvonen PJ, Laine K,|2
01500|235|R|   Olkkola KT. Voriconazole drastically increases exposure to oral|2
01500|236|R|   oxycodone. Eur J Clin Pharmacol 2009 Mar;65(3):263-71.|2
01500|237|R|31.Bartkowski RR, McDonnell TE. Prolonged alfentanil effect following|3
01500|238|R|   erythromycin administration. Anesthesiology 1990 Sep;73(3):566-8.|3
01500|239|R|32.Horton R, Barber C. Opioid-induced respiratory depression resulting from|3
01500|240|R|   transdermal fentanyl-clarithromycin drug interaction in a patient with|3
01500|241|R|   advanced COPD. J Pain Symptom Manage 2009 Jun;37(6):e2-5.|3
01500|242|R|33.Hallberg P, Marten L, Wadelius M. Possible fluconazole-fentanyl|3
01500|243|R|   interaction-a case report. Eur J Clin Pharmacol 2006 Jun;62(6):491-2.|3
01500|244|R|34.Mercadante S, Villari P, Ferrera P. Itraconazole-fentanyl interaction in|3
01500|245|R|   a cancer patient. J Pain Symptom Manage 2002 Sep;24(3):284-6.|3
01500|246|R|35.Watanabe M, Homma M, Momo K, Okoshi Y, Wada T, Hara A, Chiba S, Kohda Y.|3
01500|247|R|   Effects of voriconazole co-administration on oxycodone-induced adverse|3
01500|248|R|   events: a case in the retrospective survey. Eur J Clin Pharmacol 2011 Jan|3
01500|249|R|   8.|3
01500|250|R|36.This information is based on an extract from the Certara Drug Interaction|6
01500|251|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01501|001|T|MONOGRAPH TITLE:  Clarithromycin; Erythromycin/Rifabutin|
01501|002|B||
01501|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01501|004|L|take action as needed.|
01501|005|B||
01501|006|A|MECHANISM OF ACTION:  Clarithromycin and erythromycin inhibit CYP3A4|
01501|007|A|isoenzymes and may inhibit the CYP3A4 mediated metabolism of rifabutin.(1-5)|
01501|008|A|Rifabutin has been shown to induce CYP3A4 isoenzymes and therefore may|
01501|009|A|accelerate the metabolism of clarithromycin and erythromycin and may|
01501|010|A|decrease the plasma concentrations of both agents.(2,3)|
01501|011|B||
01501|012|E|CLINICAL EFFECTS:  The clinical effects of clarithromycin or erythromycin|
01501|013|E|may be decreased.  Rifabutin plasma levels may be increased possibly leading|
01501|014|E|to toxicity.|
01501|015|B||
01501|016|P|PREDISPOSING FACTORS:  In patients with hepatic impairment or severe renal|
01501|017|P|impairment, increased rifabutin levels from this interaction may have an|
01501|018|P|even greater impact.|
01501|019|B||
01501|020|M|PATIENT MANAGEMENT:  The US manufacturer of rifabutin recommends using|
01501|021|M|caution and monitoring for adverse events when rifabutin is given with|
01501|022|M|CYP3A4 inhibitors.  Reduce the dose or suspend use of rifabutin if toxicity|
01501|023|M|is suspected.(1)|
01501|024|M|   The Australian manufacturer of rifabutin recommends reducing the dose of|
01501|025|M|rifabutin to 300 mg daily when given concomitantly with clarithromycin.(2)|
01501|026|M|   The US manufacturer of clarithromycin states the concomitant use of|
01501|027|M|clarithromycin and rifabutin should be approached with caution.(5)|
01501|028|B||
01501|029|D|DISCUSSION:  Concurrent use of clarithromycin and rifabutin in 12|
01501|030|D|HIV-infected patients resulted in the rifabutin area-under-curve (AUC)|
01501|031|D|increasing by 75% and the clarithromycin AUC decreasing by 50%.(1)|
01501|032|D|   In a study in 34 subjects, rifabutin (300 mg daily) decreased|
01501|033|D|clarithromycin area-under-curve (AUC) by 44%.  The AUC of|
01501|034|D|14-hydroxyclarithromycin was 57% higher.(6)|
01501|035|D|   The Australian and U.K. manufacturers of rifabutin have stated that|
01501|036|D|rifabutin has been shown to induce CYP3A4 isoenzymes and may decrease the|
01501|037|D|plasma concentrations of erythromycin.(2,3)|
01501|038|D|   The Australian manufacturer of erythromycin has stated that erythromycin|
01501|039|D|is an inhibitor of CYP3A4 isoenzymes and there have been published reports|
01501|040|D|and spontaneous reports of CYP3A4 based interactions with erythromycin and|
01501|041|D|rifabutin.(2)|
01501|042|B||
01501|043|R|REFERENCES:|
01501|044|B||
01501|045|R|1.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
01501|046|R|  2021.|1
01501|047|R|2.Mycobutin (rifabutin) Australian prescribing information. Pharmacia|1
01501|048|R|  Australia December 14, 2023.|1
01501|049|R|3.Mycobutin (rifabutin) UK summary of products. Farmitalia Carbo Erba Ltd.|1
01501|050|R|  July 30, 1997.|1
01501|051|R|4.Erythromycin lactobionate for IV infusion Australian prescribing|1
01501|052|R|  information. Mayne Pharma October 31, 2003.|1
01501|053|R|5.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
01501|054|R|  September, 2019.|1
01501|055|R|6.Hafner R, Bethel J, Power M, Landry B, Banach M, Mole L, Standiford HC,|2
01501|056|R|  Follansbee S, Kumar P, Raasch R, Cohn D, Mushatt D, Drusano G. Tolerance|2
01501|057|R|  and pharmacokinetic interactions of rifabutin and clarithromycin in human|2
01501|058|R|  immunodeficiency virus-infected volunteers. Antimicrob Agents Chemother|2
01501|059|R|  1998 Mar;42(3):631-9.|2
01502|001|T|MONOGRAPH TITLE:  Systemic Corticosteroids; Corticotropin (ACTH)/Live|
01502|002|T|Vaccines|
01502|003|B||
01502|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01502|005|L|of severe adverse interaction.|
01502|006|B||
01502|007|A|MECHANISM OF ACTION:  Corticosteroids and corticotropin suppress the immune|
01502|008|A|system.  In severely immunocompromised patients, virus replication after|
01502|009|A|administration of live, attenuated-virus vaccines can be enhanced and/or the|
01502|010|A|immune response to the vaccine may be decreased.(1)|
01502|011|B||
01502|012|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained|
01502|013|E|and/or the vaccine may result in illness.(1)|
01502|014|B||
01502|015|P|PREDISPOSING FACTORS:  Patients receiving immunosuppressive doses of|
01502|016|P|corticosteroids or corticotropin for equal to or greater than 14 consecutive|
01502|017|P|days.(1)|
01502|018|B||
01502|019|M|PATIENT MANAGEMENT:  The Centers for Disease Control's (CDC) Advisory|
01502|020|M|Committee on Immunization Practices (ACIP) states that live-virus and live,|
01502|021|M|attenuated vaccines should not be administered to patients who are severely|
01502|022|M|immunosuppressed, including those who are receiving or have received|
01502|023|M|high-dose, systemic steroids for greater than or equal to 14 consecutive|
01502|024|M|days.  Live vaccines should be deferred for at least 1 month after|
01502|025|M|discontinuation of high-dose systemic steroids administered for 14|
01502|026|M|consecutive days.  When initiating immunosuppressives doses of|
01502|027|M|corticosteroids, wait 4 weeks after a live vaccines is administered.|
01502|028|M|However, if patients require therapy for chronic inflammatory conditions, do|
01502|029|M|not delay therapy due to past vaccines.  Patients who are vaccinated within|
01502|030|M|the 14 days prior to initiating immunosuppressive therapy should be|
01502|031|M|considered unvaccinated and should be revaccinated at least 3 months after|
01502|032|M|immunosuppressive therapy is discontinued.(1)|
01502|033|M|   The US manufacturer of corticotropin(2) and triamcinolone(3) and the|
01502|034|M|Australian manufacturer of dexamethasone(4) state that administration of|
01502|035|M|live or live-attenuated vaccines is contraindicated in patients receiving|
01502|036|M|immunosuppressive doses of corticosteroids or corticotropin.|
01502|037|M|   The manufacturer of deflazacort states that live or live-attenuated|
01502|038|M|vaccines should be administered at least 4 to 6 weeks prior to initiation of|
01502|039|M|therapy with deflazacort.(5)|
01502|040|B||
01502|041|D|DISCUSSION:  Many clinicians consider a dose equivalent to either 2 mg/kg of|
01502|042|D|body weight or a total of 20 mg/day of prednisone as sufficiently|
01502|043|D|immunosuppressive to raise safety concerns about live-virus vaccines.(1)|
01502|044|D|   Immunization procedures may be undertaken in patients receiving|
01502|045|D|corticosteroids when the therapy is short term (less than 2 weeks); low to|
01502|046|D|moderate dose; long-term, alternate-day treatment with short-acting|
01502|047|D|preparations; maintenance physiologic doses (replacement therapy); or|
01502|048|D|administered topically (skin or eyes), by aerosol, or by intra-articular,|
01502|049|D|bursal, or tendon injection.(1)|
01502|050|D|   Killed or inactivated vaccines do not pose a danger to immunocompromised|
01502|051|D|patients.(1)|
01502|052|B||
01502|053|R|REFERENCES:|
01502|054|B||
01502|055|R|1.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
01502|056|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
01502|057|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
01502|058|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
01502|059|R|  recs.pdf February 10, 2023;1-197.|6
01502|060|R|2.Acthar Gel (repository corticotropin injection). Mallinckrodt|1
01502|061|R|  Pharmaceuticals October, 2021.|1
01502|062|R|3.Aristospan (triamcinolone hexacetonide) US prescribing information.|1
01502|063|R|  Fujisawa Healthcare, Inc. June, 2024.|1
01502|064|R|4.Dexamethasone sodium phosphate injection Australian prescribing|1
01502|065|R|  information. Mayne Pharma October 30, 2003.|1
01502|066|R|5.Emflaza (deflazacort) US prescribing information. Marathon|1
01502|067|R|  Pharmaceuticals, LLC July, 2020.|1
01503|001|T|MONOGRAPH TITLE:  Selected Corticosteroids/Selected Azole Antifungal Agents|
01503|002|B||
01503|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01503|004|L|take action as needed.|
01503|005|B||
01503|006|A|MECHANISM OF ACTION:  Itraconazole, ketoconazole, posaconazole, and|
01503|007|A|voriconazole may inhibit the CYP3A4 mediated metabolism of some|
01503|008|A|corticosteroids, resulting in increased systemic exposure.  Itraconazole and|
01503|009|A|ketoconazole may also suppress endogenous cortisol output.|
01503|010|B||
01503|011|E|CLINICAL EFFECTS:  Concurrent use of itraconazole, ketoconazole,|
01503|012|E|posaconazole, or voriconazole may result in elevated levels of and effects|
01503|013|E|from the corticosteroid, including Cushing syndrome.  These effects have|
01503|014|E|been seen with systemic as well as inhaled corticosteroids.|
01503|015|B||
01503|016|P|PREDISPOSING FACTORS:  None determined.|
01503|017|B||
01503|018|M|PATIENT MANAGEMENT:  Patients should be carefully monitored with concurrent|
01503|019|M|administration of these agents, or when itraconazole, ketoconazole,|
01503|020|M|posaconazole, or voriconazole is added to corticosteroid therapy. The dose|
01503|021|M|of the corticosteroid may need to be adjusted or alternative therapy|
01503|022|M|considered.|
01503|023|B||
01503|024|D|DISCUSSION:  In a randomized, double-blind, cross-over study in 10 healthy|
01503|025|D|subjects, pretreatment with itraconazole (200 mg daily for 5 days) increased|
01503|026|D|the area-under-curve (AUC) and maximum concentration (Cmax) of a single|
01503|027|D|inhaled dose of budesonide (1000 mcg) by 4.2-fold and 1.6-fold,|
01503|028|D|respectively.  Suppression of cortisol production was increased 43%.(1)|
01503|029|D|   A study examined adrenal insufficiency in 25 cystic fibrosis patients|
01503|030|D|treated with itraconazole and inhaled budesonide and in 12 patients|
01503|031|D|receiving itraconazole alone.  Eleven of the 25 patients receiving|
01503|032|D|concurrent itraconazole and budesonide and none of the patients receiving|
01503|033|D|only itraconazole had adrenal insufficiency.(2)|
01503|034|D|   There are case reports of Cushing syndrome in patients receiving|
01503|035|D|concurrent itraconazole (range 200 mg to 800 mg daily) and inhaled|
01503|036|D|budesonide (range 400 mcg to 1400 mcg daily).(3-5)|
01503|037|D|   The concurrent use of ketoconazole has been shown to increase budesonide|
01503|038|D|area-under-curve (AUC) by eight-fold.(6)|
01503|039|D|   In a study in eight healthy subjects, the simultaneous administration of|
01503|040|D|ketoconazole increased budesonide AUC by 6.5-fold.  Administering the two|
01503|041|D|agents 12 hours apart increased budesonide AUC by 3.8-fold.(7)|
01503|042|D|   There are case reports of Cushing syndrome in patients receiving|
01503|043|D|concurrent itraconazole (range 100 mg to 400 mg daily) and inhaled|
01503|044|D|fluticasone (range 250 mcg to 1.5 mg daily).(8,9)|
01503|045|D|   In a randomized, placebo-controlled, crossover, four phase study in 8|
01503|046|D|healthy subjects, itraconazole decreased the systemic clearance of|
01503|047|D|intravenous dexamethasone by 68%, increased the area-under-curve (AUC) of|
01503|048|D|dexamethasone by 3.3-fold, and prolonged its half-life by 3.2-fold. The AUC|
01503|049|D|of oral dexamethasone was increased 3.7-fold, maximum concentration (Cmax)|
01503|050|D|was increased by 1.7-fold, and the elimination half-life was prolonged|
01503|051|D|2.8-fold by itraconazole.(10)|
01503|052|D|   In a randomized, cross-over study in 14 healthy subjects, pretreatment|
01503|053|D|with itraconazole (400 mg Day 1, 200 mg Days 2-4) increased the AUC of a|
01503|054|D|single oral dose of methylprednisolone by 1.5-fold.  Cortisol levels were|
01503|055|D|significantly lower after concurrent therapy than with methylprednisolone|
01503|056|D|alone.(11)|
01503|057|D|   There is a case report of Cushing syndrome following the addition of|
01503|058|D|itraconazole (400 mg daily) to methylprednisolone (12 mg/day).(12)|
01503|059|D|   In a study in 6 healthy subjects, pretreatment with ketoconazole (200 mg|
01503|060|D|daily) increased the AUC of a single intravenous dose of methylprednisolone|
01503|061|D|(20 mg) by 135% and decreased its clearance by 60%.  Concurrent ketoconazole|
01503|062|D|also increased the reduction in 24-hour cortisol AUC and suppressed morning|
01503|063|D|cortisol concentrations.(13)|
01503|064|D|   In a study in 8 healthy subjects, ketoconazole decreased the clearance of|
01503|065|D|methylprednisolone by 46% and increased mean residence time by 37%.(14)|
01503|066|D|   In a randomized, cross-over study in 14 healthy subjects, pretreatment|
01503|067|D|with itraconazole (400 mg Day 1, 200 mg Days 2-4) had no effect on the|
01503|068|D|pharmacokinetics of a single oral dose of prednisone (60 mg).(11)|
01503|069|D|   In a randomized, cross-over study in 6 healthy subjects, pretreatment|
01503|070|D|with ketoconazole (200 mg daily for 6 days) had no effect on the|
01503|071|D|pharmacokinetics of a single intravenous dose of prednisolone (14.8 mg).(15)|
01503|072|D|   In a randomized, double-blind, cross-over study in 10 healthy subjects,|
01503|073|D|pretreatment with itraconazole (200 mg daily for 4 days) increased the AUC|
01503|074|D|and half-life of a single oral dose of prednisolone (20 mg) by 24% and 29%,|
01503|075|D|respectively.(16)|
01503|076|D|   In a study, concurrent oral ketoconazole increased the AUC of|
01503|077|D|des-ciclesonide from orally inhaled ciclesonide by 3.6-fold.  There were no|
01503|078|D|changes in ciclesonide levels.(17)|
01503|079|D|   In a study in 24 healthy subjects, subjects were randomized to receive|
01503|080|D|either ketoconazole (200 mg BID) or placebo on Days 4-9 of a a 9 day course|
01503|081|D|of mometasone (400 mcg BID).  No subject had mometasone levels greater than|
01503|082|D|150 pcg/ml on Day 3.  Four of 12 subjects who received ketoconazole had|
01503|083|D|mometasone Cmax levels greater than 200 mcg/ml on Day 9.  Plasma cortisol|
01503|084|D|levels appeared to decrease as well.(18)|
01503|085|D|   In a cross-over study in 15 healthy subjects, subjects were randomized to|
01503|086|D|receive fluticasone furoate and vilanterol on days 5-11 with either|
01503|087|D|ketoconazole (200mg once daily) or placebo for days 1-11 with a washout|
01503|088|D|period of 7-14 days.  Fluticasone furoate AUC was increased by 36%, Cmax was|
01503|089|D|increased by 33%, and decreased systemic cortisol levels by 27%.  There were|
01503|090|D|no effects on heart rate and blood potassium levels.  There was a small|
01503|091|D|increase in QTc which was 7.6ms greater when compared to placebo; however,|
01503|092|D|ketoconazole has been reported to increase QTc by 5-6ms.  Vilanterol AUC was|
01503|093|D|increased by 65% and Cmax was increased by 22%.  There were no effects on|
01503|094|D|heart rate and blood potassium levels.  No serious adverse events occurred|
01503|095|D|and no subjects withdrew from the study due to adverse events.  The most|
01503|096|D|common adverse event reported was headache. (19)|
01503|097|D|   Coadministration of orally inhaled fluticasone (1000 mcg) and|
01503|098|D|ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma|
01503|099|D|fluticasone exposure and a 45% decrease in plasma cortisol AUC.(20)|
01503|100|D|   There is a case report of Cushing syndrome following the addition of|
01503|101|D|voriconazole (200 mg twice daily for 21 days for 2 courses) to|
01503|102|D|budesonide,(21) as well as voriconazole added to intranasal mometasone(22)|
01503|103|D|and inhaled fluticasone.(22)|
01503|104|D|   There is a case report of Cushing syndrome following the addition of|
01503|105|D|posaconazole (200 mg three times daily) to inhaled fluticasone.(23)|
01503|106|B||
01503|107|R|REFERENCES:|
01503|108|B||
01503|109|R|1.Raaska K, Niemi M, Neuvonen M, Neuvonen PJ, Kivisto KT. Plasma|2
01503|110|R|  concentrations of inhaled budesonide and its effects on plasma cortisol|2
01503|111|R|  are increased by the cytochrome P4503A4 inhibitor itraconazole. Clin|2
01503|112|R|  Pharmacol Ther 2002 Oct;72(4):362-9.|2
01503|113|R|2.Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S. Iatrogenic|2
01503|114|R|  adrenal insufficiency as a side-effect of combined treatment of|2
01503|115|R|  itraconazole and budesonide. Eur Respir J 2002 Jul;20(1):127-33.|2
01503|116|R|3.Bolland MJ, Bagg W, Thomas MG, Lucas JA, Ticehurst R, Black PN. Cushing's|3
01503|117|R|  syndrome due to interaction between inhaled corticosteroids and|3
01503|118|R|  itraconazole. Ann Pharmacother 2004 Jan;38(1):46-9.|3
01503|119|R|4.Main KM, Skov M, Sillesen IB, Dige-Petersen H, Muller J, Koch C, Lanng S.|3
01503|120|R|  Cushing's syndrome due to pharmacological interaction in a cystic fibrosis|3
01503|121|R|  patient. Acta Paediatr 2002;91(9):1008-11.|3
01503|122|R|5.De Wachter E, Malfroot A, De Schutter I, Vanbesien J, De Schepper J.|3
01503|123|R|  Inhaled budesonide induced Cushing's syndrome in cystic fibrosis patients,|3
01503|124|R|  due to drug inhibition of cytochrome P450. J Cyst Fibros 2003 Jun;|3
01503|125|R|  2(2):72-5.|3
01503|126|R|6.Entocort HC (budesonide) US prescribing information. AstraZeneca AB June,|1
01503|127|R|  2009.|1
01503|128|R|7.Seidegard J. Reduction of the inhibitory effect of ketoconazole on|2
01503|129|R|  budesonide pharmacokinetics by separation of their time of administration.|2
01503|130|R|  Clin Pharmacol Ther 2000 Jul;68(1):13-7.|2
01503|131|R|8.Parmar JS, Howell T, Kelly J, Bilton D. Profound adrenal suppression|3
01503|132|R|  secondary to treatment with low dose inhaled steroids and itraconazole in|3
01503|133|R|  allergic bronchopulmonary aspergillosis in cystic fibrosis. Thorax 2002|3
01503|134|R|  Aug;57(8):749-50.|3
01503|135|R|9.Woods DR, Arun CS, Corris PA, Perros P. Cushing's syndrome without excess|3
01503|136|R|  cortisol. BMJ 2006 Feb 25;332(7539):469-70.|3
01503|137|R|10.Varis T, Kivisto KT, Backman JT, Neuvonen PJ. The cytochrome P450 3A4|2
01503|138|R|   inhibitor itraconazole markedly increases the plasma concentrations of|2
01503|139|R|   dexamethasone and enhances its adrenal-suppressant effect. Clin Pharmacol|2
01503|140|R|   Ther 2000 Nov;68(5):487-94.|2
01503|141|R|11.Lebrun-Vignes B, Archer VC, Diquet B, Levron JC, Chosidow O, Puech AJ,|2
01503|142|R|   Warot D. Effect of itraconazole on the pharmacokinetics of prednisolone|2
01503|143|R|   and methylprednisolone and cortisol secretion in healthy subjects. Br J|2
01503|144|R|   Clin Pharmacol 2001 May;51(5):443-50.|2
01503|145|R|12.Linthoudt H, Van Raemdonck D, Lerut T, Demedts M, Verleden G. The|3
01503|146|R|   association of itraconazole and methylprednisolone may give rise to|3
01503|147|R|   important steroid-related side effects. J Heart Lung Transplant 1996 Nov;|3
01503|148|R|   15(11):1165.|3
01503|149|R|13.Glynn AM, Slaughter RL, Brass C, D'Ambrosio R, Jusko WJ. Effects of|2
01503|150|R|   ketoconazole on methylprednisolone pharmacokinetics and cortisol|2
01503|151|R|   secretion. Clin Pharmacol Ther 1986 Jun;39(6):654-9.|2
01503|152|R|14.Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ. Ketoconazole effects on|2
01503|153|R|   methylprednisolone disposition and their joint suppression of endogenous|2
01503|154|R|   cortisol. Clin Pharmacol Ther 1987 Oct;42(4):465-70.|2
01503|155|R|15.Yamashita SK, Ludwig EA, Middleton E Jr, Jusko WJ. Lack of|2
01503|156|R|   pharmacokinetic and pharmacodynamic interactions between ketoconazole and|2
01503|157|R|   prednisolone. Clin Pharmacol Ther 1991 May;49(5):558-70.|2
01503|158|R|16.Varis T, Kivisto KT, Neuvonen PJ. The effect of itraconazole on the|2
01503|159|R|   pharmacokinetics and pharmacodynamics of oral prednisolone. Eur J Clin|2
01503|160|R|   Pharmacol 2000 Apr;56(1):57-60.|2
01503|161|R|17.Omnaris (ciclesonide) US prescribing information. Nycomed US Inc.|1
01503|162|R|   November 20, 2007.|1
01503|163|R|18.Dulera (mometasone furoate/formoterol) US prescribing information. Merck|1
01503|164|R|   & Co., Inc. August, 2019.|1
01503|165|R|19.Kempsford R, Allen A, Bal J, Rubin D, Tombs L. The effect of ketoconazole|2
01503|166|R|   on the pharmacokinetics and pharmacodynamics of inhaled fluticasone|2
01503|167|R|   furoate and vilanterol trifenatate in healthy subjects. Br J Clin|2
01503|168|R|   Pharmacol 2013 Jun;75(6):1478-87.|2
01503|169|R|20.Flovent Diskus (fluticasone propionate) US prescribing information.|1
01503|170|R|   GlaxoSmithKline January, 2019.|1
01503|171|R|21.Jones W, Chastain CA, Wright PW. Iatrogenic cushing syndrome secondary to|3
01503|172|R|   a probable interaction between voriconazole and budesonide.|3
01503|173|R|   Pharmacotherapy 2014 Jul;34(7):e116-9.|3
01503|174|R|22.Duman AK, Fulco PP. Adrenal Insufficiency With Voriconazole and|3
01503|175|R|   Inhaled/Intranasal Corticosteroids: Case Report and Systematic Review. J|3
01503|176|R|   Pharm Pract 2016 May 04.|3
01503|177|R|23.Pilmis B, Coignard-Biehler H, Jullien V, Hermine O, Touraine P, Lecuit M,|3
01503|178|R|   Lortholary O. Iatrogenic Cushing's syndrome induced by posaconazole.|3
01503|179|R|   Antimicrob Agents Chemother 2013 Nov;57(11):5727-8.|3
01504|001|T|MONOGRAPH TITLE:  Dexamethasone/Praziquantel|
01504|002|B||
01504|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01504|004|L|is contraindicated and generally should not be dispensed or administered to|
01504|005|L|the same patient.|
01504|006|B||
01504|007|A|MECHANISM OF ACTION:  Dexamethasone may induce the metabolism of|
01504|008|A|praziquantel by CYP3A4.(1-3)|
01504|009|B||
01504|010|E|CLINICAL EFFECTS:  Concurrent or recent use of dexamethasone may decrease|
01504|011|E|the levels and effectiveness of praziquantel.|
01504|012|B||
01504|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01504|014|P|of the inducer for longer than 1-2 weeks.|
01504|015|B||
01504|016|M|PATIENT MANAGEMENT:  The concurrent use of praziquantel and strong inducers|
01504|017|M|of CYP3A4, such as dexamethasone, is contraindicated.(1)|
01504|018|M|   In patients receiving dexamethasone who need immediate treatment for|
01504|019|M|schistosomiasis, alternative agents for schistosomiasis should be used.  If|
01504|020|M|praziquantel is required,  increase monitoring for praziquantel efficacy.|
01504|021|M|If schistosomiasis treatment can be delayed, discontinue dexamethasone at|
01504|022|M|least 2 to 4 weeks before administration of praziquantel.  Dexamethasone|
01504|023|M|therapy may be resumed 1 day after completion of praziquantel therapy.(1)|
01504|024|B||
01504|025|D|DISCUSSION:  In a study in eight subjects, concurrent dexamethasone|
01504|026|D|decreased praziquantel levels by 50%.(3)|
01504|027|B||
01504|028|R|REFERENCES:|
01504|029|B||
01504|030|R|1.Biltricide (praziquantel) US prescribing information. Bayer HealthCare|1
01504|031|R|  Pharmaceuticals Inc. January, 2019.|1
01504|032|R|2.Biltricide (praziquantel) Australian prescribing information. Bayer|1
01504|033|R|  November 30, 2003.|1
01504|034|R|3.Vazquez ML, Jung H, Sotelo J. Plasma levels of praziquantel decrease when|2
01504|035|R|  dexamethasone is given simultaneously. Neurology 1987 Sep;37(9):1561-2.|2
01505|001|T|MONOGRAPH TITLE:  Selected Quinolones/Enteral Nutrition|
01505|002|B||
01505|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01505|004|L|take action as needed.|
01505|005|B||
01505|006|A|MECHANISM OF ACTION:  Absorption of orally administered quinolones may be|
01505|007|A|decreased with concurrent enteral nutrition administration.|
01505|008|B||
01505|009|E|CLINICAL EFFECTS:  Administration of a quinolone during enteral nutritional|
01505|010|E|therapy may result in a decrease in clinical effect of the quinolone as a|
01505|011|E|result of lower serum and urine levels.|
01505|012|B||
01505|013|P|PREDISPOSING FACTORS:  None determined.|
01505|014|B||
01505|015|M|PATIENT MANAGEMENT:  Quinolone blood levels should be carefully monitored if|
01505|016|M|the patient is receiving concurrent enteral nutrition.  An alternate|
01505|017|M|antibiotic agent may need to be considered.|
01505|018|B||
01505|019|D|DISCUSSION:  In a study, concurrent administration of ciprofloxacin,|
01505|020|D|levofloxacin, and ofloxacin with Ensure resulted in average decreases in|
01505|021|D|quinolone serum levels of 82.5%, 61.3% and 45.7% respectively.(1)  In|
01505|022|D|another study, concurrent Ensure reduced the percent of relative|
01505|023|D|bioavailability of ciprofloxacin significantly more than ofloxacin.(2)|
01505|024|D|   In a study in 26 hospitalized patients, administration of ciprofloxacin|
01505|025|D|via jejunostomy tube with an enteral formula decreased ciprofloxacin mean|
01505|026|D|bioavailability by 67%.(3)  Conversely, a study showed that ciprofloxacin is|
01505|027|D|well absorbed after administration via a nasogastric tube in the presence of|
01505|028|D|enteral feeding compared with an orally administered tablet.(4)|
01505|029|D|   Gatifloxacin administration with concomitant gastric tube feeding did not|
01505|030|D|affect gatifloxacin bioavailability, but critical illness resulted in|
01505|031|D|significant variability in bioavailability.(5)  Conversely, administration|
01505|032|D|with Ensure significantly decreased gatifloxacin maximum concentration|
01505|033|D|(Cmax) by 44.6%, time to reach Cmax (Tmax) by 60%, area-under-curve (AUC) by|
01505|034|D|26.2%, and relative oral bioavailability by 26%.(6)|
01505|035|D|   In a study, the oral bioavailability of moxifloxacin administered as a|
01505|036|D|crushed tablet was not affected by concomitant enteral feeding through a|
01505|037|D|nasogastric tube.(7)|
01505|038|D|   The relative bioavailability of temafloxacin was not affected by enteral|
01505|039|D|nutrition.(8)|
01505|040|B||
01505|041|R|REFERENCES:|
01505|042|B||
01505|043|R|1.Wright DH, Pietz SL, Konstantinides FN, Rotschafer JC. Decreased in vitro|2
01505|044|R|  fluoroquinolone concentrations after admixture with an enteral feeding|2
01505|045|R|  formulation. JPEN J Parenter Enteral Nutr 2000 Jan-Feb;24(1):42-8.|2
01505|046|R|2.Mueller BA, Brierton DG, Abel SR, Bowman L. Effect of enteral feeding with|2
01505|047|R|  ensure on oral bioavailabilities of ofloxacin and ciprofloxacin.|2
01505|048|R|  Antimicrob Agents Chemother 1994 Sep;38(9):2101-5.|2
01505|049|R|3.Healy DP, Brodbeck MC, Clendening CE. Ciprofloxacin absorption is impaired|2
01505|050|R|  in patients given enteral feedings orally and via gastrostomy and|2
01505|051|R|  jejunostomy tubes. Antimicrob Agents Chemother 1996 Jan;40(1):6-10.|2
01505|052|R|4.Yuk JH, Nightingale CH, Sweeney KR, Quintiliani R, Lettieri JT, Frost RW.|2
01505|053|R|  Relative bioavailability in healthy volunteers of ciprofloxacin|2
01505|054|R|  administered through a nasogastric tube with and without enteral feeding.|2
01505|055|R|  Antimicrob Agents Chemother 1989 Jul;33(7):1118-20.|2
01505|056|R|5.Kanji S, McKinnon PS, Barletta JF, Kruse JA, Devlin JW. Bioavailability of|2
01505|057|R|  gatifloxacin by gastric tube administration with and without concomitant|2
01505|058|R|  enteral feeding in critically ill patients. Crit Care Med 2003 May;|2
01505|059|R|  31(5):1347-52.|2
01505|060|R|6.Kays MB, Overholser BR, Lagvankar S, Goldman M, Sowinski KM. Effect of|2
01505|061|R|  ensure on the oral bioavailability of gatifloxacin in healthy volunteers.|2
01505|062|R|  Pharmacotherapy 2005 Nov;25(11):1530-5.|2
01505|063|R|7.Burkhardt O, Stass H, Thuss U, Borner K, Welte T. Effects of enteral|2
01505|064|R|  feeding on the oral bioavailability of moxifloxacin in healthy volunteers.|2
01505|065|R|  Clin Pharmacokinet 2005;44(9):969-76.|2
01505|066|R|8.Lubowski TJ, Nightingale CH, Sweeney K, Quintiliani R. The relative|2
01505|067|R|  bioavailability of temafloxacin administered through a nasogastric tube|2
01505|068|R|  with and without enteral feeding. Clin Pharmacokinet 1992;22 Suppl 1:43-7.|2
01506|001|T|MONOGRAPH TITLE:  Propofol/Fentanyl|
01506|002|B||
01506|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01506|004|L|take action as needed.|
01506|005|B||
01506|006|A|MECHANISM OF ACTION:  Propofol and fentanyl may result in synergistic|
01506|007|A|effects.(1)  Propofol may inhibit the metabolism of fentanyl.(21)|
01506|008|B||
01506|009|E|CLINICAL EFFECTS:  Concurrent use of fentanyl may result in decreased oxygen|
01506|010|E|saturation(3) or respiratory depression and increased propofol effects,|
01506|011|E|including anesthetic and sedative effects, as well as more pronounced|
01506|012|E|decreases in systolic, diastolic, and mean arterial pressures and cardiac|
01506|013|E|output.(4)|
01506|014|B||
01506|015|P|PREDISPOSING FACTORS:  Pediatric patients may be more susceptible to the|
01506|016|P|effects of the combination, especially bradycardia.(5)|
01506|017|B||
01506|018|M|PATIENT MANAGEMENT:  Patients receiving fentanyl may require a lower|
01506|019|M|induction dose of propofol.  Patients receiving concurrent therapy should be|
01506|020|M|closely monitored, especially pediatric patients.|
01506|021|M|   Limit prescribing opioid analgesics with CNS depressants such as|
01506|022|M|benzodiazepines to patients for whom alternative are ineffective, not|
01506|023|M|tolerated, or would be otherwise inadequate to provide sufficient management|
01506|024|M|of pain.|
01506|025|M|   If concurrent use is necessary, limit the dosages and duration of each|
01506|026|M|drug to the minimum possible while achieving the desired clinical effect. If|
01506|027|M|starting a CNS depressant (for an indication other than epilepsy) with an|
01506|028|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
01506|029|M|indicated in the absence of an opioid and titrate based upon clinical|
01506|030|M|response. If an opioid analgesic is indicated in a patient already taking a|
01506|031|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
01506|032|M|clinical response.|
01506|033|M|   Respiratory depression can occur at any time during opioid therapy,|
01506|034|M|especially during therapy initiation and following dosage increases.  The|
01506|035|M|risk of opioid-related overdose or overdose-related death is increased with|
01506|036|M|higher opioid doses, and this risk persists over the course of therapy.|
01506|037|M|Consider these risks when using concurrently with other agents that may|
01506|038|M|cause CNS depression.|
01506|039|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
01506|040|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
01506|041|M|unresponsiveness.|
01506|042|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
01506|043|M|patients when prescribing or renewing an opioid analgesic or medicine to|
01506|044|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
01506|045|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
01506|046|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
01506|047|M|as those taking CNS depressants) and when a patient has household|
01506|048|M|members/close contacts at risk for accidental overdose.  Discuss the options|
01506|049|M|for obtaining an opioid reversal agent (e.g., prescription,|
01506|050|M|over-the-counter, or as part of a community-based program).|
01506|051|B||
01506|052|D|DISCUSSION:  In a study, it was found that fentanyl plasma levels affected|
01506|053|D|the concentrations of propofol required to regain consciousness. The greater|
01506|054|D|the fentanyl concentration, the lower the propofol concentration was upon|
01506|055|D|regaining consciousness.(5)|
01506|056|D|   A study of 10 patients found maximal hypotension preintubation occurred|
01506|057|D|with a fentanyl dose of 2 mcg/Kg and maximal hypertension postintubation|
01506|058|D|decreased when the fentanyl dosage increased to 4 mcg/Kg. Hemodynamic|
01506|059|D|changes were not observed when the propofol dose was increased to 2-3.5|
01506|060|D|mg/Kg either during preintubation or postintubation.(6)|
01506|061|D|   A study of 20 patients found when alfentanil concentrations increased|
01506|062|D|from 0-500 ng/ml, the EC(50) of propofol decreased from 2.07 to 0/83 mcg/ml|
01506|063|D|for the loss of eyelash reflex and from 3.62 to 1.55 mcg/ml for loss of|
01506|064|D|consciousness.  Alfentanil was found to potentiate the depressant effect of|
01506|065|D|propofol on systolic blood pressure and heart rate.(7)|
01506|066|D|   Time to return of consciousness after discontinuation of propofol-opioid|
01506|067|D|infusion of various duration can be reduced using optimal propofol-opioid|
01506|068|D|concentrations.  The optimal target concentration of propofol is 5 mcg/ml in|
01506|069|D|combination with fentanyl 3.5 mcg/ml in the presence of alfentanil and|
01506|070|D|sufentanil and 2.5 mcg/ml in the presence of remifentanil.(8)|
01506|071|D|   Elderly patients were shown to have significantly reduced depressor|
01506|072|D|slopes compared to younger patients, 60% and 40%, respectively, upon|
01506|073|D|concurrent administration of propofol and fentanyl.  In both patient|
01506|074|D|populations, elderly and younger patients, a decreased reflex sensitivity of|
01506|075|D|38% and 41%, respectively, was found upon administration of propofol. There|
01506|076|D|was a further decrease in reflex sensitivity in the younger population upon|
01506|077|D|administration of fentanyl.  There were no changes noted in the elderly|
01506|078|D|population.  Acute changes in posture or circulating blood volume during|
01506|079|D|propofol anesthesia could result in cardiovascular instability in older|
01506|080|D|patients due to the impairment of circulatory control systems.(9)|
01506|081|D|   In a study of 64 patients, in Group A, 32 received xylocaine 1 mg/Kg|
01506|082|D|followed by propofol 2 mg/Kg over 20 seconds and 32 patients in Group B|
01506|083|D|received xylocaine 1 mg/Kg and fentanyl 1.5 mcg/Kg followed by propofol 2|
01506|084|D|mg/Kg over 20 seconds.  The patients in Group A experienced more side|
01506|085|D|effects such as: cough, hiccup, hypertonus, twitching, or tremors compared|
01506|086|D|to Group B.  In Group B, fentanyl was found to provide cardio-vascular|
01506|087|D|stability, deepen the anesthesia level, decrease the awareness and decrease|
01506|088|D|the excitatory effects of propofol.(10)|
01506|089|D|   A study of 56 patients found a ceiling effect in the Cp50i for propofol|
01506|090|D|at fentanyl concentrations greater than 3 ng/ml.  The propofol Cp50i was|
01506|091|D|decreased by 63% with fentanyl 1 ng/ml and 89% with fentanyl 3 ng/ml.(11)|
01506|092|D|   Alfentanil in combination with propofol was found to decrease the|
01506|093|D|propofol concentration at which patients regain consciousness.  Alfentanil|
01506|094|D|concentrations increasing from 10 to 150 ng/ml decreased the EC50 for|
01506|095|D|propofol from 3.8 to 0.8 mcg/ml.(12)|
01506|096|D|   In 55 patients, concurrent administration of propofol and fentanyl did|
01506|097|D|not show a decrease in systolic or diastolic blood pressure or heart rate|
01506|098|D|based on the speed of induction.  Rapid injection of propofol after fentanyl|
01506|099|D|was effective to decrease the induction time without increasing the|
01506|100|D|postinduction hypotension or bradycardia.(13)|
01506|101|D|   Eight patients showed no significant difference in blood concentration of|
01506|102|D|propofol compared to 8 patients who did not receive propofol upon|
01506|103|D|administration of fentanyl.(14)|
01506|104|D|   Propofol is suggested to prevent fentanyl-induced bronchoconstriction in|
01506|105|D|20 patients randomized to receive either thiopental 5 mg/Kg, followed by a|
01506|106|D|15 mg/Kg/h continuous infusion or propofol 2.5 mg/Kg, followed by a 9|
01506|107|D|mg/Kg/h continuous infusion.(15)|
01506|108|D|   Eight female patients received pretreatment with fentanyl before a single|
01506|109|D|bolus dose of propofol.  All 8 patients experienced prolonged apnea compared|
01506|110|D|to 9 patients who did not receive fentanyl.  There were no pharmacokinetic|
01506|111|D|differences of propofol between the groups.(16)|
01506|112|D|   Increasing the dose of fentanyl was found to reduce propofol Cp50si,|
01506|113|D|Cp50pi, and Cp50ret for somatic response, suggesting a potentiating effect|
01506|114|D|of propofol and fentanyl.  Concurrent use caused an increase in systolic|
01506|115|D|blood pressure.(17)|
01506|116|D|   Propofol was found to decrease the elimination clearance of alfentanil by|
01506|117|D|15%, rapid distribution clearance by 68%, and slow distribution clearance by|
01506|118|D|62%.  During concurrent use of propofol and alfentanil, mean arterial|
01506|119|D|pressure and systemic vascular resistance were significantly lower.(18)|
01506|120|D|   Alfentanil was found to decrease the elimination of propofol from 2.1|
01506|121|D|L/min to 1.9 L/min, the distribution clearance from 2.7 L/min to 2 L/min,|
01506|122|D|and the peripheral volume of distribution from 179 L to 141 L in a study of|
01506|123|D|8 male volunteers.(19)|
01506|124|D|   A study of 10 male volunteers found that concurrent administration of|
01506|125|D|alfentanil and propofol resulted in greater analgesia and increased|
01506|126|D|sedation.  Nausea occurred in 50% of patients during alfentanil monotherapy,|
01506|127|D|while combination therapy resulted in no patients reporting nausea.(20)|
01506|128|D|   Sufentanil and propofol in combination showed no supra-additive|
01506|129|D|interaction regarding loss of consciousness.(21)|
01506|130|D|   A study found that concurrent administration of fentanyl and propofol|
01506|131|D|reduced the blood concentration of propofol required to achieve adequate|
01506|132|D|anesthesia for tracheal intubation.(22)|
01506|133|D|   Another study found that with administration of propofol in combination|
01506|134|D|with fentanyl, loss of consciousness was achieved with lower effect-site|
01506|135|D|concentrations of propofol and a higher bispectral index compared to placebo|
01506|136|D|alone.(23)|
01506|137|D|   Alfentanil was not found to decrease the concentration of propofol needed|
01506|138|D|for loss of consciousness or lack of recall.(24)|
01506|139|B||
01506|140|R|REFERENCES:|
01506|141|B||
01506|142|R|1.Fentanyl Australian prescribing information. Mayne Pharma October 31,|1
01506|143|R|  2003.|1
01506|144|R|2.Vuyk J. Pharmacokinetic and pharmacodynamic interactions between opioids|6
01506|145|R|  and propofol. J Clin Anesth 1997 Sep;9(6 Suppl):23S-26S.|6
01506|146|R|3.Diprivan (propofol) Australian prescribing information. AstraZeneca Pty|1
01506|147|R|  Ltd January 10, 2005.|1
01506|148|R|4.Diprivan (propofol) US prescribing information. AstraZeneca|1
01506|149|R|  Pharmaceuticals LP August, 2022.|1
01506|150|R|5.Mi W, Sakai T, Kudo T, Kudo M, Matsuki A. The interaction between fentanyl|2
01506|151|R|  and propofol during emergence from anesthesia: monitoring with the|2
01506|152|R|  EEG-Bispectral index. J Clin Anesth 2003 Mar;15(2):103-7.|2
01506|153|R|6.Billard V, Moulla F, Bourgain JL, Megnigbeto A, Stanski DR. Hemodynamic|2
01506|154|R|  response to induction and intubation. Propofol/fentanyl interaction.|2
01506|155|R|  Anesthesiology 1994 Dec;81(6):1384-93.|2
01506|156|R|7.Vuyk J, Engbers FH, Burm AG, Vletter AA, Griever GE, Olofsen E, Bovill JG.|2
01506|157|R|  Pharmacodynamic interaction between propofol and alfentanil when given for|2
01506|158|R|  induction of anesthesia. Anesthesiology 1996 Feb;84(2):288-99.|2
01506|159|R|8.Vuyk J. Clinical interpretation of pharmacokinetic and pharmacodynamic|2
01506|160|R|  propofol-opioid interactions. Acta Anaesthesiol Belg 2001;52(4):445-51.|2
01506|161|R|9.Larsen B, Buch U, Wilhelm W, Larsen R. Effects of propofol and fentanyl on|2
01506|162|R|  the baroreceptor reflex in geriatric patients. Anasthesiol Intensivmed|2
01506|163|R|  Notfallmed Schmerzther 1994 Nov;29(7):408-12.|2
01506|164|R|10.Ghabash M, Matta M, Kehhaleh J. Depression of excitatory effects of|2
01506|165|R|   propofol induction by fentanyl. Middle East J Anesthesiol 1996 Feb;|2
01506|166|R|   13(4):419-25.|2
01506|167|R|11.Smith C, McEwan AI, Jhaveri R, Wilkinson M, Goodman D, Smith LR, Canada|2
01506|168|R|   AT, Glass PS. The interaction of fentanyl on the Cp50 of propofol for|2
01506|169|R|   loss of consciousness and skin incision. Anesthesiology 1994 Oct;|2
01506|170|R|   81(4):820-8; discussion 26A.|2
01506|171|R|12.Vuyk J, Lim T, Engbers FH, Burm AG, Vletter AA, Bovill JG. The|2
01506|172|R|   pharmacodynamic interaction of propofol and alfentanil during lower|2
01506|173|R|   abdominal surgery in women. Anesthesiology 1995 Jul;83(1):8-22.|2
01506|174|R|13.Kobayashi Y, Tsuchida A, Kamada Y, Seki S, Ichimiya T, Namiki A. Effects|2
01506|175|R|   of speed of injection on anesthesia induction with propofol and fentanyl.|2
01506|176|R|   Masui 1999 Aug;48(8):847-51.|2
01506|177|R|14.Dixon J, Roberts FL, Tackley RM, Lewis GT, Connell H, Prys-Roberts C.|2
01506|178|R|   Study of the possible interaction between fentanyl and propofol using a|2
01506|179|R|   computer-controlled infusion of propofol. Br J Anaesth 1990 Feb;|2
01506|180|R|   64(2):142-7.|2
01506|181|R|15.Cigarini I, Bonnet F, Lorino AM, Harf A, Desmonts JM. Comparison of the|2
01506|182|R|   effects of fentanyl on respiratory mechanics under propofol or thiopental|2
01506|183|R|   anaesthesia. Acta Anaesthesiol Scand 1990 May;34(4):253-6.|2
01506|184|R|16.Gill SS, Wright EM, Reilly CS. Pharmacokinetic interaction of propofol|2
01506|185|R|   and fentanyl: single bolus injection study. Br J Anaesth 1990 Dec;|2
01506|186|R|   65(6):760-5.|2
01506|187|R|17.Kazama T, Ikeda K, Morita K. The pharmacodynamic interaction between|2
01506|188|R|   propofol and fentanyl with respect to the suppression of somatic or|2
01506|189|R|   hemodynamic responses to skin incision, peritoneum incision, and|2
01506|190|R|   abdominal wall retraction. Anesthesiology 1998 Oct;89(4):894-906.|2
01506|191|R|18.Mertens MJ, Vuyk J, Olofsen E, Bovill JG, Burm AG. Propofol alters the|2
01506|192|R|   pharmacokinetics of alfentanil in healthy male volunteers. Anesthesiology|2
01506|193|R|   2001 Jun;94(6):949-57.|2
01506|194|R|19.Mertens MJ, Olofsen E, Burm AG, Bovill JG, Vuyk J. Mixed-effects modeling|2
01506|195|R|   of the influence of alfentanil on propofol pharmacokinetics.|2
01506|196|R|   Anesthesiology 2004 Apr;100(4):795-805.|2
01506|197|R|20.Pavlin DJ, Coda B, Shen DD, Tschanz J, Nguyen Q, Schaffer R, Donaldson G,|2
01506|198|R|   Jacobson RC, Chapman CR. Effects of combining propofol and alfentanil on|2
01506|199|R|   ventilation, analgesia, sedation, and emesis in human volunteers.|2
01506|200|R|   Anesthesiology 1996 Jan;84(1):23-37.|2
01506|201|R|21.Schraag S, Mohl U, Bothner U, Georgieff M. Interaction modeling of|2
01506|202|R|   propofol and sufentanil on loss of consciousness. J Clin Anesth 1999 Aug;|2
01506|203|R|   11(5):391-6.|2
01506|204|R|22.Kazama T, Ikeda K, Morita K, Katoh T, Kikura M. Propofol concentration|2
01506|205|R|   required for endotracheal intubation with a laryngoscope or fiberscope|2
01506|206|R|   and its interaction with fentanyl. Anesth Analg 1998 Apr;86(4):872-9.|2
01506|207|R|23.Lysakowski C, Dumont L, Pellegrini M, Clergue F, Tassonyi E. Effects of|2
01506|208|R|   fentanyl, alfentanil, remifentanil and sufentanil on loss of|2
01506|209|R|   consciousness and bispectral index during propofol induction of|2
01506|210|R|   anaesthesia. Br J Anaesth 2001 Apr;86(4):523-7.|2
01506|211|R|24.Iselin-Chaves IA, Flaishon R, Sebel PS, Howell S, Gan TJ, Sigl J,|2
01506|212|R|   Ginsberg B, Glass PS. The effect of the interaction of propofol and|2
01506|213|R|   alfentanil on recall, loss of consciousness, and the Bispectral Index.|2
01506|214|R|   Anesth Analg 1998 Oct;87(4):949-55.|2
01507|001|T|MONOGRAPH TITLE:  Levofloxacin/QT Prolonging Agents|
01507|002|B||
01507|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01507|004|L|take action as needed.|
01507|005|B||
01507|006|A|MECHANISM OF ACTION:  Concurrent use of levofloxacin and agents known to|
01507|007|A|prolong the QT interval may result in additive or synergistic effects on the|
01507|008|A|QTc Interval.(1)|
01507|009|B||
01507|010|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01507|011|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01507|012|E|torsades de pointes.|
01507|013|B||
01507|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01507|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01507|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01507|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01507|018|P|gender, or advanced age.(3)|
01507|019|P|   Concurrent use of more than one drug know to cause QT prolongation or|
01507|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01507|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01507|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01507|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01507|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01507|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01507|026|B||
01507|027|M|PATIENT MANAGEMENT:  The U.S. manufacturer of levofloxacin states that|
01507|028|M|levofloxacin should be used with caution when given with other agents known|
01507|029|M|to prolong the QT interval.(1)|
01507|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01507|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01507|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01507|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01507|034|B||
01507|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01507|036|D|degrees of potential to prolong the QTc interval. Agents linked to this|
01507|037|D|monograph have been shown to prolong the QTc interval either through their|
01507|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01507|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01507|040|D|clinical trials and/or postmarketing reports.(2)|
01507|041|D|   One or more of the drug pairs linked to this monograph have been included|
01507|042|D|in a list of interactions that should be considered "high-priority" for|
01507|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01507|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01507|045|D|Coordinator (ONC) for Health Information Technology.|
01507|046|B||
01507|047|R|REFERENCES:|
01507|048|B||
01507|049|R|1.Levaquin (levofloxacin) US prescribing information. Janssen|1
01507|050|R|  Pharmaceuticals, Inc. October 18, 2018.|1
01507|051|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01507|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01507|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01507|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01507|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01507|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01507|057|R|  settings: a scientific statement from the American Heart Association and|6
01507|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01507|059|R|  2;55(9):934-47.|6
01507|060|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01507|061|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01507|062|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01507|063|R|  19(5):735-43.|6
01508|001|T|MONOGRAPH TITLE:  Colchicine (for Gout & FMF)/Strong CYP3A4 Inhibitors|
01508|002|B||
01508|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01508|004|L|of severe adverse interaction.|
01508|005|B||
01508|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
01508|007|A|colchicine.(1,2)|
01508|008|B||
01508|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
01508|010|E|elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
01508|011|E|toxicity include muscle weakness or pain; numbness or tingling in the|
01508|012|E|fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea|
01508|013|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
01508|014|E|color of the lips, tongue, or palms of hands.(1,2)|
01508|015|B||
01508|016|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01508|017|P|patients with renal and/or hepatic impairment(1,2) and in patients who|
01508|018|P|receive concurrent therapy.|
01508|019|B||
01508|020|M|PATIENT MANAGEMENT:  The concurrent use of a strong CYP3A4 inhibitor with|
01508|021|M|colchicine is contraindicated in patients with renal or hepatic|
01508|022|M|impairment.(1-3)  Avoid concurrent use in other patients, if possible.(3)|
01508|023|M|In patients without renal or hepatic impairment who are currently taking or|
01508|024|M|have taken strong CYP3A4 inhibitors in the previous 14 days, the dosage of|
01508|025|M|colchicine should be reduced.|
01508|026|M|   For gout flares, the recommended colchicine dosage is 0.6 mg (1 tablet)|
01508|027|M|for one dose, then 0.3 mg (half tablet) 1 hour later.  This dose should be|
01508|028|M|repeated no earlier than in 3 days.(1,2)|
01508|029|M|   For gout prophylaxis, if the original colchicine dosage was 0.6 mg twice|
01508|030|M|daily, use 0.3 mg daily.  If the original dosage was 0.6 mg daily, use 0.3|
01508|031|M|mg every other day.(3-11)|
01508|032|M|   For Familial Mediterranean fever (FMF), the recommended maximum daily|
01508|033|M|dose of colchicine is 0.6 mg (may be given as 0.3 mg twice a day).(1,2)|
01508|034|M|   Patients should be instructed to immediately report any signs of|
01508|035|M|colchicine toxicity, such as muscle weakness/pain, numbness/tingling in|
01508|036|M|fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness,|
01508|037|M|pale/gray color of the lips/tongue/palms of hands, and/or severe|
01508|038|M|diarrhea/vomiting.|
01508|039|B||
01508|040|D|DISCUSSION:  In a study in 21 subjects, pretreatment with azithromycin (500|
01508|041|D|mg Day 1, then 250 mg daily Days 2-5) increased the maximum concentration|
01508|042|D|(Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by|
01508|043|D|21.6% (range -41.7% to 222%) and by 57.1% (range -24.3% to 241.1%),|
01508|044|D|respectively.(1)|
01508|045|D|   There are several reports of colchicine toxicity(4-6) and death(7,8)|
01508|046|D|following the addition of clarithromycin to therapy.  In a retrospective|
01508|047|D|review of 116 patients who received clarithromycin and colchicine during the|
01508|048|D|same hospitalization, 10.2% (9/88) of patients who received simultaneous|
01508|049|D|therapy died, compared to 3.6% (1/28) of patients who received sequential|
01508|050|D|therapy.(9)|
01508|051|D|   An FDA review of 117 colchicine-related deaths that were not attributable|
01508|052|D|to overdose found that 60 deaths (51%) involved concurrent use of|
01508|053|D|clarithromycin.(2)|
01508|054|D|   In a study in 23 subjects, pretreatment with clarithromycin (250 mg twice|
01508|055|D|daily for 7 days) increased the maximum concentration (Cmax) and|
01508|056|D|area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 227.2%|
01508|057|D|(range 65.7% to 591.1%) and by 281.5% (range 88.7% to 851.6%),|
01508|058|D|respectively.(1)|
01508|059|D|   In a study in 24 subjects, pretreatment with ketoconazole (200 mg twice|
01508|060|D|daily for 5 days) increased the Cmax and AUC of a single dose of colchicine|
01508|061|D|(0.6 mg) by 101.7% (range 19.6% to 219%) and by 212.2% (range 76.7% to|
01508|062|D|419.6%), respectively.(1)|
01508|063|D|   In a study in 18 subjects, pretreatment with ritonavir (100 mg twice|
01508|064|D|daily for 5 days) increased the Cmax and AUC of a single dose of colchicine|
01508|065|D|(0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to|
01508|066|D|924.4%), respectively.(1)|
01508|067|D|   Colchicine toxicity has been reported with concurrent use of CYP3A4 and|
01508|068|D|P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem,|
01508|069|D|erythromycin, and verapamil.(1,2)|
01508|070|D|   Strong inhibitors of CYP3A4 include: adagrasib, atazanavir, boceprevir,|
01508|071|D|ceritinib, clarithromycin, cobicistat, darunavir, idelalisib, indinavir,|
01508|072|D|itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib,|
01508|073|D|lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
01508|074|D|nirmatrelvir, posaconazole, ribociclib, ritonavir, saquinavir, telaprevir,|
01508|075|D|telithromycin, tipranavir, tucatinib, and voriconazole.(1,10)|
01508|076|B||
01508|077|R|REFERENCES:|
01508|078|B||
01508|079|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01508|080|R|  2011.|1
01508|081|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
01508|082|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01508|083|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01508|084|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01508|085|R|3.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01508|086|R|  November, 2015.|1
01508|087|R|4.van der Velden W, Huussen J, Ter Laak H, de Sevaux R. Colchicine-induced|3
01508|088|R|  neuromyopathy in a patient with chronic renal failure: the role of|3
01508|089|R|  clarithromycin. Neth J Med 2008 May;66(5):204-6.|3
01508|090|R|5.Akdag I, Ersoy A, Kahvecioglu S, Gullulu M, Dilek K. Acute colchicine|3
01508|091|R|  intoxication during clarithromycin administration in patients with chronic|3
01508|092|R|  renal failure. J Nephrol 2006 Jul-Aug;19(4):515-7.|3
01508|093|R|6.Rollot F, Pajot O, Chauvelot-Moachon L, Nazal EM, Kelaidi C, Blanche P.|3
01508|094|R|  Acute colchicine intoxication during clarithromycin administration. Ann|3
01508|095|R|  Pharmacother 2004 Dec;38(12):2074-7.|3
01508|096|R|7.Cheng VC, Ho PL, Yuen KY. Two probable cases of serious drug interaction|3
01508|097|R|  between clarithromycin and colchicine. South Med J 2005 Aug;98(8):811-3.|3
01508|098|R|8.Dogukan A, Oymak FS, Taskapan H, Guven M, Tokgoz B, Utas C. Acute fatal|3
01508|099|R|  colchicine intoxication in a patient on continuous ambulatory peritoneal|3
01508|100|R|  dialysis (CAPD). Possible role of clarithromycin administration. Clin|3
01508|101|R|  Nephrol 2001 Feb;55(2):181-2.|3
01508|102|R|9.Hung IF, Wu AK, Cheng VC, Tang BS, To KW, Yeung CK, Woo PC, Lau SK, Cheung|2
01508|103|R|  BM, Yuen KY. Fatal interaction between clarithromycin and colchicine in|2
01508|104|R|  patients with renal insufficiency: a retrospective study. Clin Infect Dis|2
01508|105|R|  2005 Aug 1;41(3):291-300.|2
01508|106|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
01508|107|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
01508|108|R|   at:|1
01508|109|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
01508|110|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01508|111|R|   11/14/2017.|1
01508|112|R|11.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01508|113|R|   Squibb Company December, 2024.|1
01508|114|R|12.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01508|115|R|   March, 2023.|1
01508|116|R|13.Crixivan (indinavir sulfate) US prescribing information. Merck & Co.,|1
01508|117|R|   Inc. September, 2016.|1
01508|118|R|14.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01508|119|R|   Laboratories December, 2019.|1
01508|120|R|15.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01508|121|R|   Pharmaceuticals, Inc. September, 2016.|1
01508|122|R|16.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01508|123|R|   December, 2019.|1
01508|124|R|17.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01508|125|R|   Laboratories, Inc. March, 2019.|1
01508|126|R|18.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01508|127|R|   Pharmaceuticals, Inc. April, 2024.|1
01508|128|R|19.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
01508|129|R|   January, 2017.|1
01508|130|R|20.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
01508|131|R|   Incorporated October, 2013.|1
01509|001|T|MONOGRAPH TITLE:  Ramelteon/Fluvoxamine|
01509|002|B||
01509|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01509|004|L|is contraindicated and generally should not be dispensed or administered to|
01509|005|L|the same patient.|
01509|006|B||
01509|007|A|MECHANISM OF ACTION:  Fluvoxamine may inhibit the metabolism of ramelteon by|
01509|008|A|CYP1A2.(1)|
01509|009|B||
01509|010|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine may result in elevated|
01509|011|E|levels of and toxicity from ramelteon.(1)|
01509|012|B||
01509|013|P|PREDISPOSING FACTORS:  None determined.|
01509|014|B||
01509|015|M|PATIENT MANAGEMENT:  The US manufacturer of ramelteon states that concurrent|
01509|016|M|use of fluvoxamine is contraindicated.(1)  The US manufacturer of|
01509|017|M|fluvoxamine states that ramelteon should not be used with fluvoxamine.(2)|
01509|018|B||
01509|019|D|DISCUSSION:  Pretreatment for 3 days with fluvoxamine (100 mg twice daily)|
01509|020|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of a|
01509|021|D|single dose of ramelteon (16 mg) by 190-fold and 70-fold, respectively.(1,2)|
01509|022|D|   One or more of the drug pairs linked to this monograph have been included|
01509|023|D|in a list of interactions that should be considered "high-priority" for|
01509|024|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01509|025|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01509|026|D|Coordinator (ONC) for Health Information Technology.|
01509|027|B||
01509|028|R|REFERENCES:|
01509|029|B||
01509|030|R|1.Rozerem (ramelteon) US prescribing information. Takeda Pharmaceuticals|1
01509|031|R|  America Inc. November, 2010.|1
01509|032|R|2.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
01509|033|R|  Pharmaceuticals, Inc. August, 2023.|1
01509|034|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01509|035|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01509|036|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01509|037|R|  19(5):735-43.|6
01510|001|T|MONOGRAPH TITLE:  Ramelteon/Rifampin (mono deleted 10/23/2014)|
01510|002|B||
01510|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01510|004|L|take action as needed.|
01510|005|B||
01510|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of ramelteon by CYP|
01510|007|A|P-450.(1)|
01510|008|B||
01510|009|E|CLINICAL EFFECTS:  Concurrent use of rifampin may result in decreased levels|
01510|010|E|and effectiveness of ramelteon.(1)|
01510|011|B||
01510|012|P|PREDISPOSING FACTORS:  None determined.|
01510|013|B||
01510|014|M|PATIENT MANAGEMENT:  Patients receiving ramelteon should be monitored for|
01510|015|M|decreased ramelteon effectiveness when rifampin is initiated and increased|
01510|016|M|effects if rifampin is discontinued. The dosage of ramelteon may need to be|
01510|017|M|adjusted.|
01510|018|B||
01510|019|D|DISCUSSION:  Pretreatment for 11 days with rifampin (600 mg daily) decreased|
01510|020|D|total exposure to ramelteon and its M-II metabolite by 80% (both|
01510|021|D|area-under-curve (AUC) and maximum concentration (Cmax)).(1)|
01510|022|B||
01510|023|R|REFERENCE:|
01510|024|B||
01510|025|R|1.Rozerem (ramelteon) US prescribing information. Takeda Pharmaceuticals|1
01510|026|R|  America Inc. November, 2010.|1
01511|001|T|MONOGRAPH TITLE:  Voriconazole/St. John's Wort (mono deleted 03/29/2012)|
01511|002|B||
01511|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01511|004|L|is contraindicated and generally should not be dispensed or administered to|
01511|005|L|the same patient.|
01511|006|B||
01511|007|A|MECHANISM OF ACTION:  Initially, St. John's wort may inhibit the metabolism|
01511|008|A|of voriconazole; however, long-term use may result in the induction of|
01511|009|A|voriconazole metabolism by CYP P-450-3A4 and P-450-2C19.(1)|
01511|010|B||
01511|011|E|CLINICAL EFFECTS:  The addition of St. John's Wort to voriconazole may|
01511|012|E|initially result in elevated levels of and toxicity from voriconazole.|
01511|013|E|However, continued concurrent use or the initiation of voriconazole in a|
01511|014|E|patient who has been taking St. John's wort may result in decreased levels|
01511|015|E|and effectiveness of voriconazole.|
01511|016|B||
01511|017|P|PREDISPOSING FACTORS:  None determined.|
01511|018|B||
01511|019|M|PATIENT MANAGEMENT:  Concurrent use of St. John's wort and voriconazole is|
01511|020|M|contraindicated.(2)  Advise patients not to initiate therapy with St. John's|
01511|021|M|wort during voriconazole therapy.  If patients have been taking St. John's|
01511|022|M|wort, monitor for decreased voriconazole effectiveness.|
01511|023|B||
01511|024|D|DISCUSSION:  In a study in 16 subjects, subjects received single doses of|
01511|025|D|voriconazole (400 mg) alone, after one dose of St. John's wort (300 mg), and|
01511|026|D|after 15 days of St. John's wort (300 mg daily).  After 10 hours of St.|
01511|027|D|John's wort, voriconazole area-under-curve (AUC) increased 22%.  After 15|
01511|028|D|days of St. John's wort, voriconazole AUC decreased 59%.(1)|
01511|029|B||
01511|030|R|REFERENCES:|
01511|031|B||
01511|032|R|1.Rengelshausen J, Banfield M, Riedel KD, Burhenne J, Weiss J, Thomsen T,|2
01511|033|R|  Walter-Sack I, Haefeli WE, Mikus G. Opposite effects of short-term and|2
01511|034|R|  long-term St John's wort intake on voriconazole pharmacokinetics. Clin|2
01511|035|R|  Pharmacol Ther 2005 Jul;78(1):25-33.|2
01511|036|R|2.Vfend (voriconazole) US prescribing information. Pfizer Inc. November,|1
01511|037|R|  2011.|1
01512|001|T|MONOGRAPH TITLE:  Lovastatin (Less than or Equal To 20 mg)/Danazol|
01512|002|B||
01512|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01512|004|L|take action as needed.|
01512|005|B||
01512|006|A|MECHANISM OF ACTION:  Danazol may inhibit the metabolism of lovastatin by|
01512|007|A|CYP3A4.(1)|
01512|008|B||
01512|009|E|CLINICAL EFFECTS:  Concurrent use of danazol may result in elevated levels|
01512|010|E|of lovastatin and toxicity, including rhabdomyolysis.(1) One case report|
01512|011|E|also states pancreatitis may possibly be caused by the lovastatin danazol|
01512|012|E|interaction.(4)|
01512|013|B||
01512|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01512|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01512|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01512|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01512|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01512|019|P|transporter OATP1B1 may have increased statin concentrations and be|
01512|020|P|predisposed to myopathy or rhabdomyolysis.|
01512|021|B||
01512|022|M|PATIENT MANAGEMENT:  The US manufacturer of lovastatin states that in|
01512|023|M|patients receiving danazol, lovastatin should be started at a dose of 10 mg|
01512|024|M|daily and that the dose of lovastatin should not exceed 20 mg daily.  The|
01512|025|M|benefits of concurrent use should be carefully weighed against the risk of|
01512|026|M|the combination.(1)|
01512|027|B||
01512|028|D|DISCUSSION:  Concurrent use of danazol with lovastatin increases the risk of|
01512|029|D|rhabdomyolysis.(1)|
01512|030|D|   Rhabdomyolysis(2-4) and pancreatitis(2) have been reported with|
01512|031|D|concurrent lovastatin and danazol.|
01512|032|B||
01512|033|R|REFERENCES:|
01512|034|B||
01512|035|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01512|036|R|  February, 2014.|1
01512|037|R|2.Hsieh CY, Chen CH. Rhabdomyolysis and pancreatitis associated with|3
01512|038|R|  coadministration of danazol 600 mg/d and lovastatin 40 mg/d. Clin Ther|3
01512|039|R|  2008 Jul;30(7):1330-5.|3
01512|040|R|3.Khanna S, Mundell WC. Rhadbomyolysis associated with co-administration of|3
01512|041|R|  danazol and lovastatin. Br J Clin Pharmacol 2011 Jul;72(1):166-7.|3
01512|042|R|4.Dallaire M, Chamberland M. Severe rhabdomyolysis in a patient receiving|3
01512|043|R|  lovastatin, danazol, and doxycycline. CMAJ 1994 Jun 15;150(12):1991-4.|3
01513|001|T|MONOGRAPH TITLE:  Amiodarone/Possible QT Prolonging Agents|
01513|002|B||
01513|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01513|004|L|take action as needed.|
01513|005|B||
01513|006|A|MECHANISM OF ACTION:  Amiodarone has been shown to prolong the QTc interval.|
01513|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01513|008|A|additive effects on the QTc interval.(1-3)|
01513|009|B||
01513|010|E|CLINICAL EFFECTS:  The concurrent use of amiodarone with other agents that|
01513|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01513|012|E|arrhythmias, including torsades de pointes.(1-3)|
01513|013|B||
01513|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01513|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01513|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01513|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01513|018|P|gender, or advanced age.(5)|
01513|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01513|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01513|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01513|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01513|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01513|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01513|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
01513|026|B||
01513|027|M|PATIENT MANAGEMENT:  The Australian(1) and UK(2) manufacturers of amiodarone|
01513|028|M|states that concurrent use of agents known to cause torsades de pointes is|
01513|029|M|contraindicated.|
01513|030|M|   The US manufacturer of amiodarone states that the concurrent use of QT|
01513|031|M|prolonging drugs should be avoided and that need to co-administer amiodarone|
01513|032|M|with any other drug known to prolong the QTc interval must be based on a|
01513|033|M|careful assessment of the potential risks and benefits of doing so for each|
01513|034|M|patient.(3)|
01513|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01513|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01513|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01513|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01513|039|B||
01513|040|D|DISCUSSION:  QTc prolongation has been reported during concurrent amiodarone|
01513|041|D|and fluoroquinolones and macrolide antibiotics.|
01513|042|D|   Agents that are linked to this monograph may have been associated with|
01513|043|D|Torsades de Pointes and/or QT prolongation but at this time lack substantial|
01513|044|D|evidence for causing Torsades de Pointes.(4)|
01513|045|D|   One or more of the drug pairs linked to this monograph have been included|
01513|046|D|in a list of interactions that should be considered "high-priority" for|
01513|047|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01513|048|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01513|049|D|Coordinator (ONC) for Health Information Technology.|
01513|050|B||
01513|051|R|REFERENCES:|
01513|052|B||
01513|053|R|1.Cordarone X (amiodarone hydrochloride) Australian prescribing information.|1
01513|054|R|  Sanofi-Synthelabo Australia Pty Limited Augsut 15, 2007.|1
01513|055|R|2.Cordarone X (amiodarone hydrochloride) UK summary of product|1
01513|056|R|  characteristics. Sanofi-Aventis July 6, 2010.|1
01513|057|R|3.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
01513|058|R|  Pharmaceuticals October, 2018.|1
01513|059|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
01513|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01513|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01513|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01513|063|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01513|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01513|065|R|  settings: a scientific statement from the American Heart Association and|6
01513|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01513|067|R|  2;55(9):934-47.|6
01513|068|R|6.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01513|069|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01513|070|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01513|071|R|  19(5):735-43.|6
01514|001|T|MONOGRAPH TITLE:  Thioridazine/Possible QT Prolonging Agents|
01514|002|B||
01514|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01514|004|L|take action as needed.|
01514|005|B||
01514|006|A|MECHANISM OF ACTION:  Thioridazine has been shown to prolong the QTc|
01514|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01514|008|A|may result in additive effects on the QTc interval.(1)|
01514|009|B||
01514|010|E|CLINICAL EFFECTS:  The concurrent use of thioridazine with other agents that|
01514|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01514|012|E|arrhythmias, including torsades de pointes.(1)|
01514|013|B||
01514|014|P|PREDISPOSING FACTORS:  Hypokalemia, bradycardia, the presence of congenital|
01514|015|P|prolongation of the QT interval, or use of thioridazine in patients with|
01514|016|P|reduced CYP2D6 activity (either through genetic predisposition or use of|
01514|017|P|drugs that inhibit CYP2D6 activity) may increase the risk of torsades de|
01514|018|P|pointes and/or sudden death in patients taking thioridazine.(1)|
01514|019|P|   The risk of QT prolongation or torsade de pointes may also be increased|
01514|020|P|in patients with cardiovascular disease (e.g. heart failure, myocardial|
01514|021|P|infarction, history of torsade de pointes), hypomagnesemia, hypocalcemia,|
01514|022|P|female gender, or advanced age.(2)|
01514|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01514|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01514|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01514|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01514|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01514|028|P|an agent which inhibits its metabolism or elimination, and/or renal/hepatic|
01514|029|P|dysfunction).(2)|
01514|030|B||
01514|031|M|PATIENT MANAGEMENT:  The manufacturer of thioridazine states under|
01514|032|M|contraindications that the use of thioridazine should be avoided in|
01514|033|M|combination with other drugs that are known to prolong the QTc interval.(1)|
01514|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01514|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01514|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01514|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01514|038|B||
01514|039|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01514|040|D|associated with Torsades de Pointes and/or QT prolongation but at this time|
01514|041|D|lack substantial evidence for causing Torsades de Pointes.(4)|
01514|042|D|   One or more of the drug pairs linked to this monograph have been included|
01514|043|D|in a list of interactions that should be considered "high-priority" for|
01514|044|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01514|045|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01514|046|D|Coordinator (ONC) for Health Information Technology.|
01514|047|B||
01514|048|R|REFERENCES:|
01514|049|B||
01514|050|R|1.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
01514|051|R|  September, 2014.|1
01514|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01514|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01514|054|R|  settings: a scientific statement from the American Heart Association and|6
01514|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01514|056|R|  2;55(9):934-47.|6
01514|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01514|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01514|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01514|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01514|061|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01514|062|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01514|063|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01514|064|R|  19(5):735-43.|6
01515|001|T|MONOGRAPH TITLE:  Oral Fluoroquinolones/Sevelamer|
01515|002|B||
01515|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01515|004|L|take action as needed.|
01515|005|B||
01515|006|A|MECHANISM OF ACTION:  Sevelamer may bind to oral fluoroquinolones,|
01515|007|A|preventing its absorption.(1)|
01515|008|B||
01515|009|E|CLINICAL EFFECTS:  Simultaneous administration of sevelamer may result in|
01515|010|E|decreased levels and clinical effectiveness of oral fluoroquinolones.(1)|
01515|011|B||
01515|012|P|PREDISPOSING FACTORS:  None determined.|
01515|013|B||
01515|014|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, the oral|
01515|015|M|fluoroquinolone should be administered at least two hours before or six|
01515|016|M|hours after sevelamer.(2)|
01515|017|B||
01515|018|D|DISCUSSION:  In a study in 15 subjects, simultaneous administration of|
01515|019|D|ciprofloxacin (750 mg) and sevelamer (seven 403 mg capsules) decreased the|
01515|020|D|bioavailability of ciprofloxacin by 48%.(1,2)|
01515|021|D|  Oral fluoroquinolones linked to this monograph are: balofloxacin,|
01515|022|D|cinoxacin, ciprofloxacin, delafloxacin, enoxacin, fleroxacin, flumequine,|
01515|023|D|gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin,|
01515|024|D|nadifloxacin, nalidixic acid, nitroxoline, norfloxacin, ofloxacin,|
01515|025|D|pefloxacin, pipemidic acid, prulifloxacin, rosoxacin, sparfloxacin,|
01515|026|D|temafloxacin, tosufloxacin, and trovafloxacin.|
01515|027|B||
01515|028|R|REFERENCES:|
01515|029|B||
01515|030|R|1.Kays MB, Overholser BR, Mueller BA, Moe SM, Sowinski KM. Effects of|2
01515|031|R|  sevelamer hydrochloride and calcium acetate on the oral bioavailability of|2
01515|032|R|  ciprofloxacin. Am J Kidney Dis 2003 Dec;42(6):1253-9.|2
01515|033|R|2.Renagel (sevelamer hydrochloride) US prescribing information. Genzyme|1
01515|034|R|  Corporation March 9, 2016.|1
01516|001|T|MONOGRAPH TITLE:  Alfentanil; Fentanyl; Oxycodone/Selected Antifungals (mono|
01516|002|T|deleted 03/15/2012)|
01516|003|B||
01516|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01516|005|L|of severe adverse interaction.|
01516|006|B||
01516|007|A|MECHANISM OF ACTION:  Fluconazole, itraconazole, ketoconazole, and|
01516|008|A|voriconazole may inhibit the metabolism of alfentanil, fentanyl and|
01516|009|A|oxycodone by CYP P-450-3A4.(1-6)|
01516|010|B||
01516|011|E|CLINICAL EFFECTS:  Concurrent use of fluconazole, itraconazole,|
01516|012|E|ketoconazole, or voriconazole may result in increased or prolonged drug|
01516|013|E|effects of the opiate and possible potentially fatal respiratory|
01516|014|E|depression.(1-6)|
01516|015|B||
01516|016|P|PREDISPOSING FACTORS:  None determined.|
01516|017|B||
01516|018|M|PATIENT MANAGEMENT:  The US manufacturers of fentanyl(1) and oxycodone(2)|
01516|019|M|recommend that patients receiving CYP P-450-3A4 inhibitors such as|
01516|020|M|fluconazole, itraconazole, or ketoconazole be carefully monitored for an|
01516|021|M|extended period of time and dosage adjustments should be made if warranted.|
01516|022|M|   The UK(3) and US(4) manufacturers of voriconazole recommend reducing the|
01516|023|M|dose of short acting opiates that are metabolized by CYP P-450-3A4 (e.g.,|
01516|024|M|alfentanil, fentanyl, oxycodone) when given concurrently with voriconazole.|
01516|025|B||
01516|026|D|DISCUSSION:  In a randomized, double-blind, placebo-controlled crossover|
01516|027|D|study in 9 subjects, single doses of intravenous fluconazole (400 mg) and|
01516|028|D|oral fluconazole (400 mg) decreased the clearance of a single dose of|
01516|029|D|alfentanil (20 mcg/kg) by 58% and 55%, respectively.  Alfentanil half-life|
01516|030|D|almost doubled after both intravenous and oral fluconazole.  Both|
01516|031|D|intravenous and oral fluconazole increased subjective effects of alfentanil|
01516|032|D|and increased alfentanil-induced respiratory depression.(7)|
01516|033|D|   In a randomized, cross-over study in 12 healthy subjects, concurrent use|
01516|034|D|of voriconazole and alfentanil increased the AUC of alfentanil 6-fold and|
01516|035|D|decreased its clearance by 85%.(3,4,8)|
01516|036|D|   In a cross-over study, pretreatment with itraconazole (200 mg daily for 4|
01516|037|D|days) had no effect on a single dose of intravenous fentanyl (3 mcg/kg).(9)|
01516|038|D|In contrast, there is a report of adverse effects following the addition of|
01516|039|D|itraconazole to fentanyl.(10)|
01516|040|D|   In a randomized, cross-over study in 12 healthy subjects, voriconazole|
01516|041|D|(400 mg twice daily, Day 1; 200 mg twice daily, Day 2) and fluconazole (400|
01516|042|D|mg daily, Day 1; 200 mg daily, Day 2) decreased the clearance of a single|
01516|043|D|dose of intravenous fentanyl (5 mcg/kg) by 23% and 16%, respectively.(11)|
01516|044|D|   In a case report, 3 weeks after increasing from a 100 mcg/hour fentanyl|
01516|045|D|patch to a 150 mcg/hour fentanyl patch, a patient was started on fluconazole|
01516|046|D|(50 mg daily).  Three days later, the patient died in his sleep.  Autopsy|
01516|047|D|revealed a toxic fentanyl concentration of 2.4 mcg/g.(12)|
01516|048|D|   In a cross-over study in 12 healthy subjects, itraconazole (200 mg daily|
01516|049|D|for 5 days) increase the AUC and Cmax of a single oral dose of oxycodone (10|
01516|050|D|mg) by 144% and 45%, respectively.  The AUC of noroxycodone decreased 49%|
01516|051|D|and the AUC of oxymorphone increased 359% with concurrent itraconazole and|
01516|052|D|oral oxycodone.  Itraconazole increased the AUC of a single intravenous dose|
01516|053|D|of oxycodone (0.1 mg/kg) by 51%.(13)|
01516|054|D|   In a randomized cross-over study in 10 healthy subjects, ketoconazole|
01516|055|D|increased the AUC of oxymorphone by 3-fold following a single dose of|
01516|056|D|oxycodone (0.2 mg/kg).  Increased side effects were also noted.(14,15)|
01516|057|D|   In a randomized cross-over study in 12 healthy subjects, pretreatment|
01516|058|D|with voriconazole for 4 days increased the AUC, Cmax, and half-life of a|
01516|059|D|single dose of oxycodone (10 mg) by 3.6-fold, 1.7-fold, 2.0-fold,|
01516|060|D|respectively.(16)  This effect has been noted in cancer patients as|
01516|061|D|well.(17)|
01516|062|D|   Ketoconazole has been shown to inhibit the metabolism of alfentanil,(18)|
01516|063|D|fentanyl,(19) and oxycodone(20) in vitro.|
01516|064|B||
01516|065|R|REFERENCES:|
01516|066|B||
01516|067|R|1.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
01516|068|R|  Inc. October, 2019.|1
01516|069|R|2.OxyContin (oxycodone hydrochloride) US prescribing information. Perdue|1
01516|070|R|  Pharma L.P. October, 2021.|1
01516|071|R|3.Vfend (voriconazole) UK summary of product characteristics. Pfizer Limited|1
01516|072|R|  March 25, 2008.|1
01516|073|R|4.Vfend (voriconazole) US prescribing information. Pfizer November, 2010.|1
01516|074|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01516|075|R|  Products, L.P. February, 2024.|1
01516|076|R|6.Nizoral (ketoconazole) US prescribing information. Janssen Pharmaceutica,|1
01516|077|R|  Inc. February, 2002.|1
01516|078|R|7.Palkama VJ, Isohanni MH, Neuvonen PJ, Olkkola KT. The effect of|2
01516|079|R|  intravenous and oral fluconazole on the pharmacokinetics and|2
01516|080|R|  pharmacodynamics of intravenous alfentanil. Anesth Analg 1998 Jul;|2
01516|081|R|  87(1):190-4.|2
01516|082|R|8.Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT.|2
01516|083|R|  Voriconazole, but not terbinafine, markedly reduces alfentanil clearance|2
01516|084|R|  and prolongs its half-life. Clin Pharmacol Ther 2006 Nov;80(5):502-8.|2
01516|085|R|9.Palkama VJ, Neuvonen PJ, Olkkola KT. The CYP 3A4 inhibitor itraconazole|2
01516|086|R|  has no effect on the pharmacokinetics of i.v. fentanyl. Br J Anaesth 1998|2
01516|087|R|  Oct;81(4):598-600.|2
01516|088|R|10.Mercadante S, Villari P, Ferrera P. Itraconazole-fentanyl interaction in|3
01516|089|R|   a cancer patient. J Pain Symptom Manage 2002 Sep;24(3):284-6.|3
01516|090|R|11.Saari TI, Laine K, Neuvonen M, Neuvonen PJ, Olkkola KT. Effect of|2
01516|091|R|   voriconazole and fluconazole on the pharmacokinetics of intravenous|2
01516|092|R|   fentanyl. Eur J Clin Pharmacol 2008 Jan;64(1):25-30.|2
01516|093|R|12.Hallberg P, Marten L, Wadelius M. Possible fluconazole-fentanyl|3
01516|094|R|   interaction-a case report. Eur J Clin Pharmacol 2006 Jun;62(6):491-2.|3
01516|095|R|13.Saari TI, Gronlund J, Hagelberg NM, Neuvonen M, Laine K, Neuvonen PJ,|2
01516|096|R|   Olkkola KT. Effects of itraconazole on the pharmacokinetics and|2
01516|097|R|   pharmacodynamics of intravenously and orally administered oxycodone. Eur|2
01516|098|R|   J Clin Pharmacol 2010 Apr;66(4):387-97.|2
01516|099|R|14.Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier|2
01516|100|R|   MF, Hochstrasser D, Dayer P, Desmeules JA. The effects of CYP2D6 and|2
01516|101|R|   CYP3A activities on the pharmacokinetics of immediate release oxycodone.|2
01516|102|R|   Br J Pharmacol 2010 Jun;160(4):907-18.|2
01516|103|R|15.Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier|2
01516|104|R|   MF, Hochstrasser D, Dayer P, Desmeules JA. Genetic polymorphisms and drug|2
01516|105|R|   interactions modulating CYP2D6 and CYP3A activities have a major effect|2
01516|106|R|   on oxycodone analgesic efficacy and safety. Br J Pharmacol 2010 Jun;|2
01516|107|R|   160(4):919-30.|2
01516|108|R|16.Hagelberg NM, Nieminen TH, Saari TI, Neuvonen M, Neuvonen PJ, Laine K,|2
01516|109|R|   Olkkola KT. Voriconazole drastically increases exposure to oral|2
01516|110|R|   oxycodone. Eur J Clin Pharmacol 2009 Mar;65(3):263-71.|2
01516|111|R|17.Watanabe M, Homma M, Momo K, Okoshi Y, Wada T, Hara A, Chiba S, Kohda Y.|3
01516|112|R|   Effects of voriconazole co-administration on oxycodone-induced adverse|3
01516|113|R|   events: a case in the retrospective survey. Eur J Clin Pharmacol 2011 Jan|3
01516|114|R|   8.|3
01516|115|R|18.Klees TM, Sheffels P, Dale O, Kharasch ED. Metabolism of alfentanil by|5
01516|116|R|   cytochrome p4503a (cyp3a) enzymes. Drug Metab Dispos 2005 Mar;|5
01516|117|R|   33(3):303-11.|5
01516|118|R|19.Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid|5
01516|119|R|   analgesic, by human liver microsomes. Role of CYP3A4. Drug Metab Dispos|5
01516|120|R|   1996 Sep;24(9):932-9.|5
01516|121|R|20.Lalovic B, Phillips B, Risler LL, Howald W, Shen DD. Quantitative|5
01516|122|R|   contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver|5
01516|123|R|   and intestinal microsomes. Drug Metab Dispos 2004 Apr;32(4):447-54.|5
01517|001|T|MONOGRAPH TITLE:  Fentanyl; Oxycodone/Selected Macrolide Antibiotics (mono|
01517|002|T|deleted 03/16/2012)|
01517|003|B||
01517|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01517|005|L|of severe adverse interaction.|
01517|006|B||
01517|007|A|MECHANISM OF ACTION:  Clarithromycin, erythromycin, telithromycin, and|
01517|008|A|troleandomycin may inhibit the metabolism of fentanyl(1) and oxycodone(2) by|
01517|009|A|CYP P-450-3A4.|
01517|010|B||
01517|011|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin, erythromycin,|
01517|012|E|telithromycin, or troleandomycin may result in increased or prolonged drug|
01517|013|E|effects of fentanyl(1) and oxycodone(2), including potentially fatal|
01517|014|E|respiratory depression.|
01517|015|B||
01517|016|P|PREDISPOSING FACTORS:  None determined.|
01517|017|B||
01517|018|M|PATIENT MANAGEMENT:  The US manufacturers of fentanyl(1) and oxycodone(2)|
01517|019|M|recommend that patients receiving potent or moderate CYP P-450-3A4|
01517|020|M|inhibitors, such as clarithromycin, erythromycin, telithromycin, or|
01517|021|M|troleandomycin, be carefully monitored for an extended period of time and|
01517|022|M|dosage adjustments should be made if warranted.|
01517|023|B||
01517|024|D|DISCUSSION:  In a controlled cross-over study in 6 subjects, 7 days of|
01517|025|D|pretreatment with erythromycin decreased the clearance of alfentanil by 25%.|
01517|026|D|Alfentanil half-life increased by 56%.(3)|
01517|027|D|   In a randomized cross-over study in 10 healthy subjects, troleandomycin|
01517|028|D|increased the AUC of alfentanil by 135%.(4)|
01517|029|D|   In a randomized cross-over study in 12 healthy subjects, troleandomycin|
01517|030|D|increased the AUC of a single dose of fentanyl (oral transmucosal, 10|
01517|031|D|mcg/kg) by 76%.(5)|
01517|032|D|   In a randomized cross-over study in 11 healthy subjects, telithromycin|
01517|033|D|(800 mg daily for 4 days) increased the area-under-curve (AUC) of a single|
01517|034|D|dose of oxycodone (10 mg immediate-release) by 80%.  The AUC of noroxycodone|
01517|035|D|was decreased by 46%.  There was a modest increase in the pharmacodynamic|
01517|036|D|effects of oxycodone.(6)|
01517|037|D|   Prolonged alfentanil effects have been reported with concurrent|
01517|038|D|erythromycin.(7)  Respiratory depression has been reported with concurrent|
01517|039|D|oxycodone and clarithromycin.(8)|
01517|040|D|   Erythromycin has been shown to inhibit fentanyl metabolism in vitro.(9)|
01517|041|D|Troleandomycin has been shown to inhibit alfentanil(10) and fentanyl(11)|
01517|042|D|metabolism in vitro.|
01517|043|B||
01517|044|R|REFERENCES:|
01517|045|B||
01517|046|R|1.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
01517|047|R|  Inc. October, 2019.|1
01517|048|R|2.OxyContin (oxycodone hydrochloride) US prescribing information. Perdue|1
01517|049|R|  Pharma L.P. October, 2021.|1
01517|050|R|3.Bartkowski RR, Goldberg ME, Larijani GE, Boerner T. Inhibition of|2
01517|051|R|  alfentanil metabolism by erythromycin. Clin Pharmacol Ther 1989 Jul;|2
01517|052|R|  46(1):99-102.|2
01517|053|R|4.Kharasch ED, Walker A, Hoffer C, Sheffels P. Intravenous and oral|2
01517|054|R|  alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A|2
01517|055|R|  activity: noninvasive assessment by use of pupillary miosis. Clin|2
01517|056|R|  Pharmacol Ther 2004 Nov;76(5):452-66.|2
01517|057|R|5.Kharasch ED, Whittington D, Hoffer C. Influence of hepatic and intestinal|2
01517|058|R|  cytochrome P4503A activity on the acute disposition and effects of oral|2
01517|059|R|  transmucosal fentanyl citrate. Anesthesiology 2004 Sep;101(3):729-37.|2
01517|060|R|6.Gronlund J, Saari T, Hagelberg N, Martikainen IK, Neuvonen PJ, Olkkola KT,|2
01517|061|R|  Laine K. Effect of telithromycin on the pharmacokinetics and|2
01517|062|R|  pharmacodynamics of oral oxycodone. J Clin Pharmacol 2010 Jan;50(1):101-8.|2
01517|063|R|7.Bartkowski RR, McDonnell TE. Prolonged alfentanil effect following|3
01517|064|R|  erythromycin administration. Anesthesiology 1990 Sep;73(3):566-8.|3
01517|065|R|8.Horton R, Barber C. Opioid-induced respiratory depression resulting from|3
01517|066|R|  transdermal fentanyl-clarithromycin drug interaction in a patient with|3
01517|067|R|  advanced COPD. J Pain Symptom Manage 2009 Jun;37(6):e2-5.|3
01517|068|R|9.Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid|5
01517|069|R|  analgesic, by human liver microsomes. Role of CYP3A4. Drug Metab Dispos|5
01517|070|R|  1996 Sep;24(9):932-9.|5
01517|071|R|10.Klees TM, Sheffels P, Dale O, Kharasch ED. Metabolism of alfentanil by|5
01517|072|R|   cytochrome p4503a (cyp3a) enzymes. Drug Metab Dispos 2005 Mar;|5
01517|073|R|   33(3):303-11.|5
01517|074|R|11.Tateishi T, Krivoruk Y, Ueng YF, Wood AJ, Guengerich FP, Wood M.|5
01517|075|R|   Identification of human liver cytochrome P-450 3A4 as the enzyme|5
01517|076|R|   responsible for fentanyl and sufentanil N-dealkylation. Anesth Analg 1996|5
01517|077|R|   Jan;82(1):167-72.|5
01518|001|T|MONOGRAPH TITLE:  Fentanyl; Oxycodone/Nefazodone (mono deleted 03/15/2012)|
01518|002|B||
01518|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01518|004|L|of severe adverse interaction.|
01518|005|B||
01518|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of fentanyl(1,2)|
01518|007|A|and oxycodone(3) by CYP P-450-3A4.|
01518|008|B||
01518|009|E|CLINICAL EFFECTS:  The concurrent administration of nefazodone may result in|
01518|010|E|elevated levels of fentanyl(1,2) and oxycodone(3), including somnolence and|
01518|011|E|potentially fatal respiratory depression.|
01518|012|B||
01518|013|P|PREDISPOSING FACTORS:  None determined.|
01518|014|B||
01518|015|M|PATIENT MANAGEMENT:  The US manufacturers of fentanyl(1) and oxycodone(2)|
01518|016|M|recommend that patients potent CYP P-450-3A4 inhibitors such as nefazodone|
01518|017|M|should be monitored for an extended period of time and dosage adjustments|
01518|018|M|made if warranted.|
01518|019|B||
01518|020|D|DISCUSSION:  Fentanyl(1) and oxycodone(2) are metabolized by the CYP|
01518|021|D|P-450-3A4 isoenzyme.  Moderate and strong inhibitors of this isoenzyme are|
01518|022|D|expected to increase fentanyl(1) and oxycodone(2) levels.|
01518|023|D|  In a study of 11 subjects, ritonavir, another CYP 3A4 inhibitor, reduced|
01518|024|D|the clearance of fentanyl 67% and increased the area-under-curve (AUC) 174%.|
01518|025|D|Eight subjects reported nausea during the study.(4)|
01518|026|B||
01518|027|R|REFERENCES:|
01518|028|B||
01518|029|R|1.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
01518|030|R|  Inc. October, 2019.|1
01518|031|R|2.Serzone (nefazodone hydrochloride) US prescribing information.|1
01518|032|R|  Bristol-Myers Squibb Company January, 2005.|1
01518|033|R|3.OxyContin (oxycodone hydrochloride) US prescribing information. Perdue|1
01518|034|R|  Pharma L.P. October, 2021.|1
01518|035|R|4.Olkkola KT, Palkama VJ, Neuvonen PJ. Ritonavir's role in reducing fentanyl|2
01518|036|R|  clearance and prolonging its half-life. Anesthesiology 1999 Sep;|2
01518|037|R|  91(3):681-5.|2
01519|001|T|MONOGRAPH TITLE:  Bepridil/Possible QT Prolonging Agents|
01519|002|B||
01519|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01519|004|L|of severe adverse interaction.|
01519|005|B||
01519|006|A|MECHANISM OF ACTION:  Bepridil has shown to prolong the QTc interval.|
01519|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01519|008|A|additive effects on the QTc interval.(1)|
01519|009|B||
01519|010|E|CLINICAL EFFECTS:  The concurrent use of bepridil with other agents that|
01519|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01519|012|E|arrhythmias, including torsades de pointes.(1)|
01519|013|B||
01519|014|P|PREDISPOSING FACTORS:  Hypokalemia, the use of potassium wasting diuretics,|
01519|015|P|and the presence of antecedent bradycardia may increase the risk of torsades|
01519|016|P|de pointes.(1)|
01519|017|P|   The risk of QT prolongation or torsade de pointes may also be increased|
01519|018|P|in patients with cardiovascular disease (e.g. heart failure, myocardial|
01519|019|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
01519|020|P|hypomagnesemia, hypocalcemia, female gender, or advanced age.(3)|
01519|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01519|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01519|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01519|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01519|025|P|impaired metabolism or elimination of the drug (e.g coadministration with an|
01519|026|P|agent which inhibitors its metabolism or elimination, genetic impairment in|
01519|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01519|028|B||
01519|029|M|PATIENT MANAGEMENT:  The manufacturer of bepridil states that under|
01519|030|M|contraindications that bepridil is contraindicated in patients taking other|
01519|031|M|drugs that prolong the QT interval.(1)|
01519|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01519|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01519|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01519|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01519|036|B||
01519|037|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01519|038|D|associated with torsades de pointes and/or QT prolongation but at this time|
01519|039|D|lack substantial evidence for causing torsades de pointes.(2)|
01519|040|D|   One or more of the drug pairs linked to this monograph have been included|
01519|041|D|in a list of interactions that should be considered "high-priority" for|
01519|042|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01519|043|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01519|044|D|Coordinator (ONC) for Health Information Technology.|
01519|045|B||
01519|046|R|REFERENCES:|
01519|047|B||
01519|048|R|1.Vascor (bepridil hydrochloride) US prescribing information. Ortho-McNeil|1
01519|049|R|  Pharmaceutical, Inc. March, 2000.|1
01519|050|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01519|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01519|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01519|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01519|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01519|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01519|056|R|  settings: a scientific statement from the American Heart Association and|6
01519|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01519|058|R|  2;55(9):934-47.|6
01519|059|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01519|060|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01519|061|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01519|062|R|  19(5):735-43.|6
01520|001|T|MONOGRAPH TITLE:  Mesoridazine/Possible QT Prolonging Agents|
01520|002|B||
01520|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01520|004|L|take action as needed.|
01520|005|B||
01520|006|A|MECHANISM OF ACTION:  Mesoridazine has been shown to prolong the QTc|
01520|007|A|interval. Concurrent use with other agents that prolong the QTc interval may|
01520|008|A|result in additive effects on the QTc interval.(1)|
01520|009|B||
01520|010|E|CLINICAL EFFECTS:  The concurrent use of mesoridazine with other agents that|
01520|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01520|012|E|arrhythmias, including torsades de pointes.(1)|
01520|013|B||
01520|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01520|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01520|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01520|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01520|018|P|gender, or advanced age.(2)|
01520|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01520|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01520|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01520|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01520|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01520|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01520|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01520|026|B||
01520|027|M|PATIENT MANAGEMENT:  The manufacturer of mesoridazine states under|
01520|028|M|contraindications that the use of mesoridazine should be avoided in|
01520|029|M|combination with other drugs that are known to prolong the QTc interval.(1)|
01520|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01520|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01520|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01520|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01520|034|B||
01520|035|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01520|036|D|associated with torsades de pointes and/or QT prolongation but at this time|
01520|037|D|lack substantial evidence for causing torsades de pointes.(3)|
01520|038|D|   One or more of the drug pairs linked to this monograph have been included|
01520|039|D|in a list of interactions that should be considered "high-priority" for|
01520|040|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01520|041|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01520|042|D|Coordinator (ONC) for Health Information Technology.|
01520|043|B||
01520|044|R|REFERENCES:|
01520|045|B||
01520|046|R|1.Serentil (mesoridazine besylate) US prescribing information. Novartis|1
01520|047|R|  Pharmaceuticals Corporation August, 2000.|1
01520|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01520|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01520|050|R|  settings: a scientific statement from the American Heart Association and|6
01520|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01520|052|R|  2;55(9):934-47.|6
01520|053|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01520|054|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01520|055|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01520|056|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01520|057|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01520|058|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01520|059|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01520|060|R|  19(5):735-43.|6
01521|001|T|MONOGRAPH TITLE:  Pimozide/Possible QT Prolonging Agents|
01521|002|B||
01521|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01521|004|L|of severe adverse interaction.|
01521|005|B||
01521|006|A|MECHANISM OF ACTION:  Pimozide has shown to prolong the QTc interval.|
01521|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01521|008|A|additive effects on the QTc interval.(1)|
01521|009|B||
01521|010|E|CLINICAL EFFECTS:  The concurrent use of pimozide with other agents that|
01521|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01521|012|E|arrhythmias, including torsades de pointes.(1)|
01521|013|B||
01521|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01521|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01521|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01521|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01521|018|P|female gender, or advanced age.(3)|
01521|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01521|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01521|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01521|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01521|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01521|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01521|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01521|026|B||
01521|027|M|PATIENT MANAGEMENT:  The manufacturer of pimozide states that the use of|
01521|028|M|pimozide is contraindicated in patients taking other drugs which prolong the|
01521|029|M|QT interval.(1)|
01521|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01521|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01521|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01521|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01521|034|B||
01521|035|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01521|036|D|associated with torsades de pointes and/or QT prolongation but at this time|
01521|037|D|lack substantial evidence for causing torsades de pointes.(2)|
01521|038|D|   One or more of the drug pairs linked to this monograph have been included|
01521|039|D|in a list of interactions that should be considered "high-priority" for|
01521|040|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01521|041|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01521|042|D|Coordinator (ONC) for Health Information Technology.|
01521|043|B||
01521|044|R|REFERENCES:|
01521|045|B||
01521|046|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
01521|047|R|  2011.|1
01521|048|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01521|049|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01521|050|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01521|051|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01521|052|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01521|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01521|054|R|  settings: a scientific statement from the American Heart Association and|6
01521|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01521|056|R|  2;55(9):934-47.|6
01521|057|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01521|058|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01521|059|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01521|060|R|  19(5):735-43.|6
01522|001|T|MONOGRAPH TITLE:  Halofantrine/Possible QT Prolonging Agents|
01522|002|B||
01522|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01522|004|L|of severe adverse interaction.|
01522|005|B||
01522|006|A|MECHANISM OF ACTION:  Halofantrine has been shown to prolong the QTc|
01522|007|A|interval. Concurrent use with other agents that prolong the QTc interval may|
01522|008|A|result in additive effects on the QTc interval.(1)|
01522|009|B||
01522|010|E|CLINICAL EFFECTS:  The concurrent use of halofantrine with other agents that|
01522|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01522|012|E|arrhythmias, including torsades de pointes.(1)|
01522|013|B||
01522|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01522|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01522|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01522|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01522|018|P|gender, or advanced age.(3)|
01522|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01522|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01522|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01522|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01522|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01522|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01522|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01522|026|B||
01522|027|M|PATIENT MANAGEMENT:  The manufacturer of halofantrine states in a black box|
01522|028|M|warning that halofantrine is not recommended for use in combination with|
01522|029|M|drugs known to prolong the QTc interval. Under precautions, drug|
01522|030|M|interactions, the manufacturer states that halofantrine should not be|
01522|031|M|administered with drugs known to prolong the QTc interval.(1)|
01522|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01522|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01522|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01522|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01522|036|B||
01522|037|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01522|038|D|associated with torsades de pointes and/or QT prolongation but at this time|
01522|039|D|lack substantial evidence for causing torsades de pointes.(2)|
01522|040|D|   One or more of the drug pairs linked to this monograph have been included|
01522|041|D|in a list of interactions that should be considered "high-priority" for|
01522|042|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01522|043|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01522|044|D|Coordinator (ONC) for Health Information Technology.|
01522|045|B||
01522|046|R|REFERENCES:|
01522|047|B||
01522|048|R|1.Halfan (halofantrine hydrochloride) US prescribing information. SmithKline|1
01522|049|R|  Beecham Pharmaceuticals October, 2001.|1
01522|050|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01522|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01522|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01522|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01522|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01522|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01522|056|R|  settings: a scientific statement from the American Heart Association and|6
01522|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01522|058|R|  2;55(9):934-47.|6
01522|059|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01522|060|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01522|061|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01522|062|R|  19(5):735-43.|6
01523|001|T|MONOGRAPH TITLE:  Sparfloxacin/Possible QT Prolonging Agents|
01523|002|B||
01523|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01523|004|L|of severe adverse interaction.|
01523|005|B||
01523|006|A|MECHANISM OF ACTION:  Sparfloxacin has been shown to prolong the QTc|
01523|007|A|interval. Concurrent use with other agents that prolong the QTc interval may|
01523|008|A|result in additive effects on the QTc interval.(1)|
01523|009|B||
01523|010|E|CLINICAL EFFECTS:  The concurrent use of sparfloxacin with other agents that|
01523|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01523|012|E|arrhythmics, including torsades de pointes.|
01523|013|B||
01523|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01523|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01523|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01523|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01523|018|P|gender, or advanced age.(3)|
01523|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01523|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01523|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01523|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01523|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01523|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01523|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01523|026|B||
01523|027|M|PATIENT MANAGEMENT:  The manufacturer of sparfloxacin states under|
01523|028|M|contraindications that sparfloxacin is contraindicated in patients being|
01523|029|M|treated concomitantly with medications known to produce an increase in the|
01523|030|M|QTc interval and/or torsades de pointes.(1)|
01523|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01523|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01523|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01523|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01523|035|B||
01523|036|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01523|037|D|associated with torsades de pointes and/or QT prolongation but at this time|
01523|038|D|lack substantial evidence for causing torsades de pointes.(2)|
01523|039|B||
01523|040|R|REFERENCES:|
01523|041|B||
01523|042|R|1.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
01523|043|R|  Inc. February, 2003.|1
01523|044|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01523|045|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01523|046|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01523|047|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01523|048|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01523|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01523|050|R|  settings: a scientific statement from the American Heart Association and|6
01523|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01523|052|R|  2;55(9):934-47.|6
01524|001|T|MONOGRAPH TITLE:  Levomethadyl/Possible QT Prolonging Agents|
01524|002|B||
01524|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01524|004|L|of severe adverse interaction.|
01524|005|B||
01524|006|A|MECHANISM OF ACTION:  Levomethadyl has been shown to prolong the QTc|
01524|007|A|interval and induce torsades de pointes. Concurrent use with other agents|
01524|008|A|that prolong the QTc interval may result in additive effects on the QTc|
01524|009|A|interval.(1)|
01524|010|B||
01524|011|E|CLINICAL EFFECTS:  The concurrent use of levomethadyl with other agents that|
01524|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01524|013|E|arrhythmias, including torsades de pointes.(1)|
01524|014|B||
01524|015|P|PREDISPOSING FACTORS:  Congestive heart failure, bradycardia, diuretic use,|
01524|016|P|cardiac hypertrophy, hypokalemia, or hypomagnesemia may increase the risk of|
01524|017|P|torsades de pointes and/or sudden death.(1)|
01524|018|P|   The risk of QT prolongation or torsade de pointes may also be increased|
01524|019|P|in patients with cardiovascular disease (e.g. myocardial infarction, history|
01524|020|P|of torsade de pointes, congenital long QT syndrome), hypocalcemia, female|
01524|021|P|gender, or advanced age.(3)|
01524|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01524|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01524|024|P|risk factors for torsade de pointes.   Factors which may increase systemic|
01524|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01524|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01524|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01524|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01524|029|B||
01524|030|M|PATIENT MANAGEMENT:  The manufacturer of levomethadyl states under|
01524|031|M|contraindications that levomethadyl is contraindicated in patients being|
01524|032|M|treated concomitantly with other drug products known to prolong the QT|
01524|033|M|interval.(1)|
01524|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01524|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01524|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01524|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01524|038|B||
01524|039|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01524|040|D|associated with torsades de pointes and/or QT prolongation but at this time|
01524|041|D|lack substantial evidence for causing torsades de pointes.(2)|
01524|042|D|   One or more of the drug pairs linked to this monograph have been included|
01524|043|D|in a list of interactions that should be considered "high-priority" for|
01524|044|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01524|045|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01524|046|D|Coordinator (ONC) for Health Information Technology.|
01524|047|B||
01524|048|R|REFERENCES:|
01524|049|B||
01524|050|R|1.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
01524|051|R|  Roxane Laboratories, Inc. May, 2001.|1
01524|052|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01524|053|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01524|054|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01524|055|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01524|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01524|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01524|058|R|  settings: a scientific statement from the American Heart Association and|6
01524|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01524|060|R|  2;55(9):934-47.|6
01524|061|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01524|062|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01524|063|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01524|064|R|  19(5):735-43.|6
01525|001|T|MONOGRAPH TITLE:  Droperidol/Possible QT Prolonging Agents|
01525|002|B||
01525|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01525|004|L|of severe adverse interaction.|
01525|005|B||
01525|006|A|MECHANISM OF ACTION:  Droperidol has been shown to prolong the QTc interval.|
01525|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01525|008|A|additive effects on the QTc interval.(1)|
01525|009|B||
01525|010|E|CLINICAL EFFECTS:  The concurrent use of droperidol with other agents that|
01525|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01525|012|E|arrhythmias, including torsades de pointes.(1)|
01525|013|B||
01525|014|P|PREDISPOSING FACTORS:  Congestive heart failure, bradycardia, use of a|
01525|015|P|diuretic, cardiac hypertrophy, hypokalemia, hypomagnesemia, age over 65|
01525|016|P|years, alcohol abuse, and the use of agents such as benzodiazepines,|
01525|017|P|volatile anesthetics, and intravenous opiates may predispose patients to the|
01525|018|P|development of prolonged QT syndrome.(1)|
01525|019|P|   The risk of QT prolongation or torsade de pointes may also be increased|
01525|020|P|in patients with cardiovascular disease (e.g. myocardial infarction, history|
01525|021|P|of torsade de pointes, congenital long QT syndrome), hypocalcemia, or female|
01525|022|P|gender.(3)|
01525|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01525|024|P|higher systemic concentrations of either QT prolonging drug are additional|
01525|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01525|026|P|drug concentrations include rapid infusion of an intravenous dose or|
01525|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01525|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01525|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01525|030|B||
01525|031|M|PATIENT MANAGEMENT:  The manufacturer of droperidol states under|
01525|032|M|precautions/drug interactions that drugs known to have the potential to|
01525|033|M|prolong the QT interval should not be used together with droperidol.(1)|
01525|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01525|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01525|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01525|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01525|038|B||
01525|039|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01525|040|D|associated with torsades de pointes and/or QT prolongation but at this time|
01525|041|D|lack substantial evidence for causing torsades de pointes.(2)|
01525|042|D|   One or more of the drug pairs linked to this monograph have been included|
01525|043|D|in a list of interactions that should be considered "high-priority" for|
01525|044|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01525|045|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01525|046|D|Coordinator (ONC) for Health Information Technology.|
01525|047|B||
01525|048|R|REFERENCES:|
01525|049|B||
01525|050|R|1.Inapsine (droperidol) US prescribing information. Akorn, Inc. November,|1
01525|051|R|  2001.|1
01525|052|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01525|053|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01525|054|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01525|055|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01525|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01525|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01525|058|R|  settings: a scientific statement from the American Heart Association and|6
01525|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01525|060|R|  2;55(9):934-47.|6
01525|061|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01525|062|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01525|063|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01525|064|R|  19(5):735-43.|6
01526|001|T|MONOGRAPH TITLE:  Sertindole/Possible QT Prolonging Agents|
01526|002|B||
01526|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01526|004|L|of severe adverse interaction.|
01526|005|B||
01526|006|A|MECHANISM OF ACTION:  Sertindole has been shown to prolong the QTc interval.|
01526|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01526|008|A|additive effects of the QTc interval.(1)|
01526|009|B||
01526|010|E|CLINICAL EFFECTS:  The concurrent use of sertindole with other agents that|
01526|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01526|012|E|arrhythmias, including torsades de pointes.(1)|
01526|013|B||
01526|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01526|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01526|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01526|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01526|018|P|gender, or advanced age.(3)|
01526|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01526|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01526|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01526|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01526|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01526|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01526|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01526|026|B||
01526|027|M|PATIENT MANAGEMENT:  The manufacturer of sertindole state that sertindole is|
01526|028|M|contraindicated in patients receiving drugs known to prolong the QT|
01526|029|M|interval.(1)|
01526|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01526|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01526|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01526|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01526|034|B||
01526|035|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01526|036|D|associated with torsades de pointes and/or QT prolongation but at this time|
01526|037|D|lack substantial evidence for causing torsades de pointes.(2)|
01526|038|B||
01526|039|R|REFERENCES:|
01526|040|B||
01526|041|R|1.Serdolect (sertindole) UK summary of product characteristics. Lundbeck|1
01526|042|R|  Limited October 25, 1996.|1
01526|043|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01526|044|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01526|045|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01526|046|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01526|047|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01526|048|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01526|049|R|  settings: a scientific statement from the American Heart Association and|6
01526|050|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01526|051|R|  2;55(9):934-47.|6
01526|052|R|4.Serdolect (sertindole) Sweden Summary of Product Characteristics. H.|1
01526|053|R|  Lundbeck A S March 4, 2021.|1
01527|001|T|MONOGRAPH TITLE:  Ziprasidone/Selected QT Prolonging Agents|
01527|002|B||
01527|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01527|004|L|of severe adverse interaction.|
01527|005|B||
01527|006|A|MECHANISM OF ACTION:  Ziprasidone has been shown to prolong the QTc|
01527|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
01527|008|A|may result in additive effects on the QTc interval.(1)|
01527|009|B||
01527|010|E|CLINICAL EFFECTS:  The concurrent use of ziprasidone with other agents that|
01527|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01527|012|E|arrhythmias, including torsades de pointes.(1)|
01527|013|B||
01527|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01527|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01527|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01527|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01527|018|P|gender, or advanced age.(1,3)|
01527|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01527|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01527|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01527|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01527|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01527|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01527|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01527|026|B||
01527|027|M|PATIENT MANAGEMENT:  The manufacturer of ziprasidone states under|
01527|028|M|contraindications that ziprasidone should not be used with other drugs that|
01527|029|M|prolong the QT interval such as dofetilide, sotalol, quinidine, other Class|
01527|030|M|Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine,|
01527|031|M|droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin,|
01527|032|M|halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl|
01527|033|M|acetate, dolasetron mesylate, probucol or tacrolimus.(1)  It would be|
01527|034|M|prudent to avoid the use of ziprasidone with medicines suspected of|
01527|035|M|prolonging the QT interval.|
01527|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01527|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01527|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01527|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01527|040|B||
01527|041|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01527|042|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01527|043|D|monograph have been shown to prolong the QTc interval either through their|
01527|044|D|mechanism of action, through studies on their effects on the QTc interval,|
01527|045|D|or through reports of QTc prolongation and/or torsades de pointes in|
01527|046|D|clinical trials and/or postmarketing reports.(2)|
01527|047|B||
01527|048|R|REFERENCES:|
01527|049|B||
01527|050|R|1.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
01527|051|R|  May, 2021.|1
01527|052|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01527|053|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01527|054|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01527|055|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01527|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01527|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01527|058|R|  settings: a scientific statement from the American Heart Association and|6
01527|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01527|060|R|  2;55(9):934-47.|6
01528|001|T|MONOGRAPH TITLE:  Abciximab/Selected Anticoagulants (Vitamin K antagonists);|
01528|002|T|Heparins|
01528|003|B||
01528|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01528|005|L|of severe adverse interaction.|
01528|006|B||
01528|007|A|MECHANISM OF ACTION:  Concurrent use of abciximab and anticoagulants may|
01528|008|A|result in additive effects on clotting mechanisms.(1)|
01528|009|B||
01528|010|E|CLINICAL EFFECTS:  Use of abciximab within 7 days of oral anticoagulants or|
01528|011|E|concurrently with other anticoagulants may increase the risk of bleeding.(1)|
01528|012|B||
01528|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01528|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01528|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01528|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01528|017|P|risk for bleeding (e.g. NSAIDs).|
01528|018|B||
01528|019|M|PATIENT MANAGEMENT:  The US manufacturer of abciximab states that the use of|
01528|020|M|abciximab in patients who have received oral anticoagulants in the previous|
01528|021|M|7 days is contraindicated unless prothrombin time is less than or equal to|
01528|022|M|1.2 times control values.  Concurrent use with other anticoagulants should|
01528|023|M|be approached with caution.(1)|
01528|024|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01528|025|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01528|026|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01528|027|M|patients with any symptoms.|
01528|028|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01528|029|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01528|030|M|anticoagulation in patients with active pathologic bleeding.|
01528|031|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01528|032|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01528|033|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01528|034|M|and/or swelling.|
01528|035|B||
01528|036|D|DISCUSSION:  Abciximab has the potential to increase the risk of bleeding,|
01528|037|D|especially with concurrent anticoagulation, including from heparin, other|
01528|038|D|anticoagulants, or thrombolytics.(1)|
01528|039|D|   A large systematic review was performed on 72 warfarin drug-drug|
01528|040|D|interactions studies that reported on bleeding, thromboembolic events, or|
01528|041|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 38 of|
01528|042|D|those studies found a higher rate of clinically significant bleeding in|
01528|043|D|patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94).(2)|
01528|044|B||
01528|045|R|REFERENCES:|
01528|046|B||
01528|047|R|1.ReoPro (abciximab) US prescribing information. Eli Lilly and Company|1
01528|048|R|  November 25, 2013.|1
01528|049|R|2.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
01528|050|R|  Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
01528|051|R|  interactions with warfarin: A systematic review and meta-analysis. Br J|6
01528|052|R|  Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
01529|001|T|MONOGRAPH TITLE:  Ivabradine/Strong CYP3A4 Inhibitors; Protease Inhibitors|
01529|002|B||
01529|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01529|004|L|is contraindicated and generally should not be dispensed or administered to|
01529|005|L|the same patient.|
01529|006|B||
01529|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 and protease inhibitors|
01529|008|A|may inhibit the metabolism of ivabradine.  Increased levels of ivabradine|
01529|009|A|may cause ivabradine-induced reduction in heart rate which can contribute to|
01529|010|A|increased QT prolongation risk.(1,2)|
01529|011|B||
01529|012|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 or protease|
01529|013|E|inhibitors may result in elevated levels of and toxicity from ivabradine|
01529|014|E|including a reduction in heart rate which can contribute to QT prolongation|
01529|015|E|or torsades de pointes.(1,2)|
01529|016|B||
01529|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01529|018|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01529|019|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01529|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01529|021|P|gender, or advanced age.(3)|
01529|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01529|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01529|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01529|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01529|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01529|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01529|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01529|029|B||
01529|030|M|PATIENT MANAGEMENT:  The manufacturer of ivabradine states that concurrent|
01529|031|M|use with strong CYP3A4 inhibitors is contraindicated.(1,2)  Guideline|
01529|032|M|recommendations state ivabradine should not be used with protease|
01529|033|M|inhibitors.(4,5)|
01529|034|M|   The US manufacturer of itraconazole states that concurrent use with|
01529|035|M|ivabradine is contraindicated during and two weeks after itraconazole|
01529|036|M|treatment.(6)|
01529|037|M|   If concurrent therapy is deemed medically necessary, monitor patients|
01529|038|M|receiving concurrent therapy for bradycardia (heart rate less than 50 bpm),|
01529|039|M|dizziness, fatigue, hypotension, and/or symptoms of atrial fibrillation|
01529|040|M|(heart palpitations, chest pressure, shortness of breath).|
01529|041|B||
01529|042|D|DISCUSSION:  Concurrent use of potent CYP3A4 inhibitors ketoconazole (200 mg|
01529|043|D|daily) and josamycin (1000 mg twice daily) increased mean ivabradine plasma|
01529|044|D|exposure by 7- to 8-fold.(1)|
01529|045|D|   CYP3A4 inhibitors linked to this monograph include:  atazanavir,|
01529|046|D|boceprevir, cobicistat, darunavir, idelalisib, indinavir, itraconazole,|
01529|047|D|josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir,|
01529|048|D|nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir,|
01529|049|D|troleandomycin, and tucatinib.|
01529|050|B||
01529|051|R|REFERENCES:|
01529|052|B||
01529|053|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01529|054|R|  Les Laboratoires Servier March, 2015.|1
01529|055|R|2.Corlanor (ivabradine) US prescribing information. Amgen, Inc. August,|1
01529|056|R|  2021.|1
01529|057|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01529|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01529|059|R|  settings: a scientific statement from the American Heart Association and|6
01529|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01529|061|R|  2;55(9):934-47.|6
01529|062|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01529|063|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01529|064|R|  HIV. Department of Health and Human Services. Available at|6
01529|065|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
01529|066|R|  new-guidelines June 13, 2021.|6
01529|067|R|5.Liverpool Drug Interactions Group. HIV Drug Interactions. Available at:|6
01529|068|R|  https://hiv-druginteractions.org/.|6
01529|069|R|6.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01529|070|R|  Products, L.P. February, 2024.|1
01530|001|T|MONOGRAPH TITLE:  Selected Extended-Release Opioids/Alcohol|
01530|002|B||
01530|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01530|004|L|is contraindicated and generally should not be dispensed or administered to|
01530|005|L|the same patient.|
01530|006|B||
01530|007|A|MECHANISM OF ACTION:  Use of alcohol may result in an acceleration of opioid|
01530|008|A|release from Avinza (morphine) extended-release capsules,(1) Opana|
01530|009|A|(oxymorphone) extended-release tablets,(2) Nucynta (tapentadol)|
01530|010|A|extended-release tablets,(3) and Zohydro (hydrocodone) extended-release|
01530|011|A|capsules.(4)|
01530|012|B||
01530|013|E|CLINICAL EFFECTS:  Use of alcohol may result in the rapid release and|
01530|014|E|absorption of a potentially fatal dose of morphine,(1) oxymorphone,(2)|
01530|015|E|tapentadol,(3) or hydrocodone.(4)  Toxic effects of rapid release include|
01530|016|E|profound sedation, respiratory depression, coma, and/or death.|
01530|017|B||
01530|018|P|PREDISPOSING FACTORS:  The increased release may be alcohol|
01530|019|P|concentration-dependent.(1,2)|
01530|020|B||
01530|021|M|PATIENT MANAGEMENT:  The US manufacturer of Avinza brand of morphine|
01530|022|M|extended-release capsules states that patients should not consume alcohol|
01530|023|M|and must not use prescription or non-prescription medications that contain|
01530|024|M|alcohol while on Avinza.(1)|
01530|025|M|   The US manufacturer of Opana ER brand of oxymorphone extended-release|
01530|026|M|tablets states that patients should not consume alcohol and must not use|
01530|027|M|prescription or non-prescription medications that contain alcohol while on|
01530|028|M|Opana ER.(2)|
01530|029|M|   The US manufacturer of Nucynta ER brand of tapentadol extended-release|
01530|030|M|tablets states that patients should not consume alcohol and must not use|
01530|031|M|prescription or non-prescription medications that contain alcohol while on|
01530|032|M|Nucynta ER.(2)|
01530|033|M|   The US manufacturer of Zohydro ER brand of hydrocodone extended-release|
01530|034|M|capsules states that patients must not consume alcohol or any prescription|
01530|035|M|or non-prescription products containing alcohol while taking Zohydro ER.(4)|
01530|036|M|   Respiratory depression can occur at any time during opioid therapy,|
01530|037|M|especially during therapy initiation and following dosage increases.  The|
01530|038|M|risk of opioid-related overdose or overdose-related death is increased with|
01530|039|M|higher opioid doses, and this risk persists over the course of therapy.|
01530|040|M|Consider these risks when using concurrently with other agents that may|
01530|041|M|cause CNS depression.|
01530|042|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
01530|043|M|patients when prescribing or renewing an opioid analgesic or medicine to|
01530|044|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
01530|045|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
01530|046|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
01530|047|M|as those taking CNS depressants) and when a patient has household|
01530|048|M|members/close contacts at risk for accidental overdose.  Discuss the options|
01530|049|M|for obtaining an opioid reversal agent (e.g., prescription,|
01530|050|M|over-the-counter, or as part of a community-based program).(5)|
01530|051|B||
01530|052|D|DISCUSSION:  In vitro studies showed that mixing Avinza capsules with 900 ml|
01530|053|D|of either a 20% or 40% ethanol solution resulted in an alcohol-concentration|
01530|054|D|dependent increase in release of morphine.  This acceleration of release may|
01530|055|D|result in rapid release of the total morphine dose in vivo, which could|
01530|056|D|result in the absorption of a fatal dose of morphine.(1)|
01530|057|D|   In an in vivo study in healthy subjects, administration of Opana ER|
01530|058|D|(oxymorphone) with 240 ml of 40% alcohol, the area-under-curve (AUC) of|
01530|059|D|oxymorphone increased 13%.  There was no effect on oxymorphone AUC with 20%|
01530|060|D|or 4% alcohol.  The maximum concentration (Cmax) of oxymorphone increased by|
01530|061|D|70% (range -50% to +270%), 31% (range up to 260%), 7% (range up to 110%)|
01530|062|D|with concurrent ingestion of 40%, 20% and 4% alcohol.(2)|
01530|063|D|   In an in vivo study in healthy subjects, administration of Nucynta ER|
01530|064|D|(100 mg tapentadol) with 240 ml of 40% alcohol, the Cmax of tapentadol|
01530|065|D|increased 48% (range 99% to 4.38-fold) and the AUC increased 17%.|
01530|066|D|Administration of Nucynta ER (250 mg tapentadol) with 240 ml of 40% alcohol,|
01530|067|D|the Cmax of tapentadol increased 28% (range 90% to 2.67-fold) and the AUC|
01530|068|D|increased 16%.(3)|
01530|069|D|   In an in vivo study in healthy subjects Zohydro ER (hydrocodone) 50 mg|
01530|070|D|was given on an empty stomach with a 240 mL solution of 40% alcohol/orange|
01530|071|D|juice. The average peak hydrocodone maximum concentration (Cmax) increased|
01530|072|D|by 2.4-fold and systemic absorption was increased by an average of|
01530|073|D|1.2-fold.(4)|
01530|074|B||
01530|075|R|REFERENCES:|
01530|076|B||
01530|077|R|1.Avinza (morphine extended-release capsules) US prescribing information.|1
01530|078|R|  Ligand Pharmaceuticals Incorporated April, 2014.|1
01530|079|R|2.Opana ER (oxymorphone hydrochloride) US prescribing information. Endo|1
01530|080|R|  Pharmaceuticals, Inc. October, 2019.|1
01530|081|R|3.Nucynta ER (tapentadol) US prescribing information. Janssen|1
01530|082|R|  Pharmaceuticals December, 2023.|1
01530|083|R|4.Zohydro ER (hydrocodone bitarate) US prescribing information. Zogenix Inc.|1
01530|084|R|  October, 2019.|1
01530|085|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
01530|086|R|  recommends health care professionals discuss naloxone with all patients|1
01530|087|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
01530|088|R|  disorder. Available at:|1
01530|089|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
01530|090|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
01530|091|R|  d-pain July 23, 2020.|1
01531|001|T|MONOGRAPH TITLE:  Ivabradine/Selected Macrolide Antibiotics (mono deleted|
01531|002|T|11/24/2015)|
01531|003|B||
01531|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01531|005|L|is contraindicated and generally should not be dispensed or administered to|
01531|006|L|the same patient.|
01531|007|B||
01531|008|A|MECHANISM OF ACTION:  Some macrolide antibiotics may inhibit the metabolism|
01531|009|A|of ivabradine by CYP P-450-3A4.(1)|
01531|010|B||
01531|011|E|CLINICAL EFFECTS:  Concurrent use of some macrolide antibiotics may result|
01531|012|E|in elevated levels of and toxicity from ivabradine.(1)|
01531|013|B||
01531|014|P|PREDISPOSING FACTORS:  None determined.|
01531|015|B||
01531|016|M|PATIENT MANAGEMENT:  The manufacturer of ivabradine states that concurrent|
01531|017|M|use with potent CYP P-450-3A4 inhibitors such as clarithromycin, oral|
01531|018|M|erythromycin, josamycin, or telithromycin is contraindicated.(1)|
01531|019|B||
01531|020|D|DISCUSSION:  Concurrent use of potent CYP P-450-3A4 inhibitors ketoconazole|
01531|021|D|(200 mg daily) and josamycin (1000 mg twice daily) increased mean ivabradine|
01531|022|D|plasma exposure by 7- to 8-fold.(1)|
01531|023|B||
01531|024|R|REFERENCE:|
01531|025|B||
01531|026|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01531|027|R|  Les Laboratoires Servier March, 2015.|1
01532|001|T|MONOGRAPH TITLE:  Ivabradine/Nelfinavir; Ritonavir (mono deleted 11/24/2015)|
01532|002|B||
01532|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01532|004|L|is contraindicated and generally should not be dispensed or administered to|
01532|005|L|the same patient.|
01532|006|B||
01532|007|A|MECHANISM OF ACTION:  Nelfinavir and ritonavir may inhibit the metabolism of|
01532|008|A|ivabradine by CYP P-450-3A4.(1)|
01532|009|B||
01532|010|E|CLINICAL EFFECTS:  Concurrent use of nelfinavir or ritonavir may result in|
01532|011|E|elevated levels of and toxicity from ivabradine.(1)|
01532|012|B||
01532|013|P|PREDISPOSING FACTORS:  None determined.|
01532|014|B||
01532|015|M|PATIENT MANAGEMENT:  The manufacturer of ivabradine states that concurrent|
01532|016|M|use with potent CYP P-450-3A4 inhibitors such as nelfinavir or ritonavir is|
01532|017|M|contraindicated.(1)|
01532|018|B||
01532|019|D|DISCUSSION:  Concurrent use of potent CYP P-450-3A4 inhibitors ketoconazole|
01532|020|D|(200 mg daily) and josamycin (1000 mg twice daily) increased mean ivabradine|
01532|021|D|plasma exposure by 7- to 8-fold.(1)|
01532|022|B||
01532|023|R|REFERENCE:|
01532|024|B||
01532|025|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01532|026|R|  Les Laboratoires Servier March, 2015.|1
01533|001|T|MONOGRAPH TITLE:  Ivabradine/Nefazodone (mono deleted 11/24/2015)|
01533|002|B||
01533|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01533|004|L|is contraindicated and generally should not be dispensed or administered to|
01533|005|L|the same patient.|
01533|006|B||
01533|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of ivabradine by|
01533|008|A|CYP P-450-3A4.(1)|
01533|009|B||
01533|010|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in elevated|
01533|011|E|levels of and toxicity from ivabradine.(1)|
01533|012|B||
01533|013|P|PREDISPOSING FACTORS:  None determined.|
01533|014|B||
01533|015|M|PATIENT MANAGEMENT:  The manufacturer of ivabradine states that concurrent|
01533|016|M|use with potent CYP P-450-3A4 inhibitors such as nefazodone is|
01533|017|M|contraindicated.(1)|
01533|018|B||
01533|019|D|DISCUSSION:  Concurrent use of potent CYP P-450-3A4 inhibitors ketoconazole|
01533|020|D|(200 mg daily) and josamycin (1000 mg twice daily) increased mean ivabradine|
01533|021|D|plasma exposure by 7- to 8-fold.(1)|
01533|022|B||
01533|023|R|REFERENCE:|
01533|024|B||
01533|025|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01533|026|R|  Les Laboratoires Servier March, 2015.|1
01534|001|T|MONOGRAPH TITLE:  Ivabradine/Fluconazole (mono deleted 11/24/2015)|
01534|002|B||
01534|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01534|004|L|take action as needed.|
01534|005|B||
01534|006|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of ivabradine|
01534|007|A|by CYP P-450-3A4.(1)|
01534|008|B||
01534|009|E|CLINICAL EFFECTS:  Concurrent use of fluconazole may result in elevated|
01534|010|E|levels of and toxicity from ivabradine.(1)|
01534|011|B||
01534|012|P|PREDISPOSING FACTORS:  None determined.|
01534|013|B||
01534|014|M|PATIENT MANAGEMENT:  The manufacturer of ivabradine states that concurrent|
01534|015|M|use with moderate CYP P-450-3A4 inhibitors such as fluconazole may be|
01534|016|M|considered at a starting dose of 2.5 mg twice daily if resting heart rate is|
01534|017|M|above 60 bpm.  Heart rate should be closely monitored.(1)|
01534|018|B||
01534|019|D|DISCUSSION:  Concurrent use of potent CYP P-450-3A4 inhibitors ketoconazole|
01534|020|D|(200 mg daily) and josamycin (1000 mg twice daily) increased mean ivabradine|
01534|021|D|plasma exposure by 7- to 8-fold.  Concurrent use of moderate CYP P-450-3A4|
01534|022|D|inhibitors diltiazem and verapamil increased ivabradine area-under-curve|
01534|023|D|(AUC) by 2- to 3-fold.(1)|
01534|024|B||
01534|025|R|REFERENCE:|
01534|026|B||
01534|027|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01534|028|R|  Les Laboratoires Servier March, 2015.|1
01535|001|T|MONOGRAPH TITLE:  Ivabradine/Strong CYP3A4 Inducers|
01535|002|B||
01535|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01535|004|L|of severe adverse interaction.|
01535|005|B||
01535|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
01535|007|A|ivabradine.(1,2)|
01535|008|B||
01535|009|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 may result in|
01535|010|E|decreased levels and effectiveness of ivabradine.(1,2)|
01535|011|B||
01535|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01535|013|P|of the inducer for longer than 1-2 weeks.|
01535|014|B||
01535|015|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inducers should be|
01535|016|M|avoided during ivabradine therapy.(1,2)  If concurrent use is necessary,|
01535|017|M|monitor patients for signs and symptoms of worsening heart failure and heart|
01535|018|M|rate greater than 60 bpm.|
01535|019|B||
01535|020|D|DISCUSSION:  Concurrent use of St. John's wort with ivabradine (10 mg twice|
01535|021|D|daily) decreased ivabradine area-under-curve (AUC) by 50%.(1,2)|
01535|022|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
01535|023|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
01535|024|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
01535|025|D|St. John's wort.|
01535|026|B||
01535|027|R|REFERENCES:|
01535|028|B||
01535|029|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01535|030|R|  Les Laboratoires Servier March, 2015.|1
01535|031|R|2.Corlanor (ivabradine) US prescribing information. Amgen, Inc. August,|1
01535|032|R|  2021.|1
01536|001|T|MONOGRAPH TITLE:  Ivabradine/Moderate CYP3A4 Inhibitors|
01536|002|B||
01536|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01536|004|L|of severe adverse interaction.|
01536|005|B||
01536|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
01536|007|A|metabolism of ivabradine.  Increased levels of ivabradine may cause|
01536|008|A|ivabradine-induced reduction in heart rate which can contribute to increased|
01536|009|A|QT prolongation risk.(1-3)|
01536|010|B||
01536|011|E|CLINICAL EFFECTS:  Concurrent use of moderate inhibitors may result in|
01536|012|E|elevated levels of and toxicity from ivabradine including a reduction in|
01536|013|E|heart rate which can contribute to QT prolongation or torsades de|
01536|014|E|pointes.(1-3)|
01536|015|B||
01536|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01536|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01536|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01536|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01536|020|P|gender, or advanced age.(4)|
01536|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01536|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01536|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01536|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01536|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01536|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01536|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01536|028|B||
01536|029|M|PATIENT MANAGEMENT:  The US manufacturer of ivabradine states that|
01536|030|M|concurrent use of moderate inhibitors of CYP3A4, including diltiazem and|
01536|031|M|verapamil, should be avoided.(1)|
01536|032|M|   The Australian and UK manufacturers of ivabradine state that concurrent|
01536|033|M|use of diltiazem or verapamil is contraindicated but that other moderate|
01536|034|M|inhibitors of CYP3A4 may be considered with monitoring of heart rate and|
01536|035|M|with a starting dose of 2.5 mg ivabradine twice daily if resting heart rate|
01536|036|M|is above 70 bpm.(2-3)|
01536|037|M|   Monitor patients receiving concurrent therapy for bradycardia (heart rate|
01536|038|M|less than 50 bpm), dizziness, fatigue, hypotension, and/or symptoms of|
01536|039|M|atrial fibrillation (heart palpitations, chest pressure, shortness of|
01536|040|M|breath).|
01536|041|B||
01536|042|D|DISCUSSION:  Concurrent use of potent CYP3A4 inhibitors ketoconazole (200 mg|
01536|043|D|daily) and josamycin (1000 mg twice daily) increased mean ivabradine plasma|
01536|044|D|exposure by 7- to 8-fold.  Concurrent use of moderate CYP3A4 inhibitors|
01536|045|D|diltiazem and verapamil increased ivabradine area-under-curve (AUC) by 2- to|
01536|046|D|3-fold and reduced heart rate by an additional 5 bpm.(2)|
01536|047|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  amprenavir,|
01536|048|D|aprepitant, avacopan, berotralstat, conivaptan, diltiazem, duvelisib,|
01536|049|D|fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
01536|050|D|isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat,|
01536|051|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and|
01536|052|D|verapamil.(5)|
01536|053|B||
01536|054|R|REFERENCES:|
01536|055|B||
01536|056|R|1.Corlanor (ivabradine) US prescribing information. Amgen, Inc. August,|1
01536|057|R|  2021.|1
01536|058|R|2.Coralan (ivabradine) Australian Product Information. Servier Laboratories|1
01536|059|R|  (Aust.) Pty. Ltd. June, 2022.|1
01536|060|R|3.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01536|061|R|  Les Laboratoires Servier March, 2015.|1
01536|062|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01536|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01536|064|R|  settings: a scientific statement from the American Heart Association and|6
01536|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01536|066|R|  2;55(9):934-47.|6
01536|067|R|5.This information is based on an extract from the Certara Drug Interaction|6
01536|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01537|001|T|MONOGRAPH TITLE:  Ivabradine/QT Prolonging Agents|
01537|002|B||
01537|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01537|004|L|of severe adverse interaction.|
01537|005|B||
01537|006|A|MECHANISM OF ACTION:  QT prolongation may be exacerbated by|
01537|007|A|ivabradine-induced reduction in heart rate.(1)|
01537|008|B||
01537|009|E|CLINICAL EFFECTS:  Concurrent use of ivabradine and agents known to prolong|
01537|010|E|the QT interval may exacerbate QT prolongation.(1)|
01537|011|B||
01537|012|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01537|013|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01537|014|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01537|015|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01537|016|P|gender, or advanced age.(3)|
01537|017|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01537|018|P|higher systemic concentrations of either QT prolonging drug are additional|
01537|019|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01537|020|P|drug concentrations include rapid infusion of an intravenous dose or|
01537|021|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01537|022|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01537|023|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01537|024|B||
01537|025|M|PATIENT MANAGEMENT:  The UK, AU, and Canadian manufacturer of ivabradine|
01537|026|M|states that concurrent use with cardiovascular and non-cardiovascular QT|
01537|027|M|prolonging agents should be avoided.(1,4,5)|
01537|028|M|   The Canadian manufacturer states that if concurrent therapy is deemed|
01537|029|M|necessary, close cardiac monitoring (12-lead ECG) is required. Depending on|
01537|030|M|the ECG results, ivabradine dosing may need to be decreased or stopped.(4)|
01537|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01537|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01537|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01537|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01537|035|B||
01537|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01537|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01537|038|D|monograph have been shown to prolong the QTc interval either through their|
01537|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01537|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01537|041|D|clinical trials and/or postmarketing reports.(2)|
01537|042|B||
01537|043|R|REFERENCES:|
01537|044|B||
01537|045|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01537|046|R|  Les Laboratoires Servier March, 2015.|1
01537|047|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01537|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01537|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01537|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01537|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01537|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01537|053|R|  settings: a scientific statement from the American Heart Association and|6
01537|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01537|055|R|  2;55(9):934-47.|6
01537|056|R|4.Lancora (ivabradine) Canadian prescribing  information. Servier Canada|1
01537|057|R|  Inc. December 20, 2016.|1
01537|058|R|5.Coralan (ivabradine) AU prescribing information. Servier Laboratories|1
01537|059|R|  (Aust.) PTY LTD September 11, 2017.|1
01538|001|T|MONOGRAPH TITLE:  Cisapride/Possible QT Prolonging Agents|
01538|002|B||
01538|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01538|004|L|of severe adverse interaction.|
01538|005|B||
01538|006|A|MECHANISM OF ACTION:  Torsades de pointes has been reported with cisapride.|
01538|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01538|008|A|additive effects on the QTc interval.(1)|
01538|009|B||
01538|010|E|CLINICAL EFFECTS:  The concurrent use of cisapride with other agents that|
01538|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01538|012|E|arrhythmias, including torsades de pointes.(1)|
01538|013|B||
01538|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01538|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01538|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01538|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01538|018|P|gender, or advanced age.(3)|
01538|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01538|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01538|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01538|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01538|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01538|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01538|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01538|026|B||
01538|027|M|PATIENT MANAGEMENT:  The Australian manufacturer of cisapride states that|
01538|028|M|concurrent use of agents known to prolong the QTc interval with cisapride is|
01538|029|M|contraindicated.(1)|
01538|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01538|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01538|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01538|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01538|034|B||
01538|035|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01538|036|D|associated with torsades de pointes and/or QT prolongation but at this time|
01538|037|D|lack substantial evidence for causing torsades de pointes.(2)|
01538|038|D|   One or more of the drug pairs linked to this monograph have been included|
01538|039|D|in a list of interactions that should be considered "high-priority" for|
01538|040|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01538|041|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01538|042|D|Coordinator (ONC) for Health Information Technology.|
01538|043|B||
01538|044|R|REFERENCES:|
01538|045|B||
01538|046|R|1.Prepulsid (cisapride) Australian prescribing information. Janssen-Cilag|1
01538|047|R|  Pty Limited January 25, 2003.|1
01538|048|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01538|049|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01538|050|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01538|051|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01538|052|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01538|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01538|054|R|  settings: a scientific statement from the American Heart Association and|6
01538|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01538|056|R|  2;55(9):934-47.|6
01538|057|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01538|058|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01538|059|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01538|060|R|  19(5):735-43.|6
01539|001|T|MONOGRAPH TITLE:  Disopyramide/Possible QT Prolonging Agents|
01539|002|B||
01539|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01539|004|L|of severe adverse interaction.|
01539|005|B||
01539|006|A|MECHANISM OF ACTION:  Concurrent use of disopyramide and agents known to|
01539|007|A|prolong the QT interval may result in additive or synergistic effects on the|
01539|008|A|QTc interval.(1)|
01539|009|B||
01539|010|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01539|011|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01539|012|E|torsades de pointes.|
01539|013|B||
01539|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01539|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01539|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01539|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01539|018|P|gender, or advanced age.(2)|
01539|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01539|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01539|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01539|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01539|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01539|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01539|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01539|026|B||
01539|027|M|PATIENT MANAGEMENT:  The Australian manufacturer of disopyramide states that|
01539|028|M|concurrent use with agents liable to produce torsades de pointes, including|
01539|029|M|tricyclic or tetracyclic antidepressants, erythromycin, vincamine, and|
01539|030|M|sultopride, is contraindicated.(1)|
01539|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01539|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01539|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01539|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01539|035|B||
01539|036|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01539|037|D|associated with torsades de pointes and/or QT prolongation but at this time|
01539|038|D|lack substantial evidence for causing torsades de pointes.(3)|
01539|039|D|   One or more of the drug pairs linked to this monograph have been included|
01539|040|D|in a list of interactions that should be considered "high-priority" for|
01539|041|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01539|042|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01539|043|D|Coordinator (ONC) for Health Information Technology.|
01539|044|B||
01539|045|R|REFERENCES:|
01539|046|B||
01539|047|R|1.Rythmodan (disopyramide) Australian prescribing information. Aventis|1
01539|048|R|  Pharma Pty Ltd. September 22, 2000.|1
01539|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01539|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01539|051|R|  settings: a scientific statement from the American Heart Association and|6
01539|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01539|053|R|  2;55(9):934-47.|6
01539|054|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01539|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01539|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01539|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01539|058|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01539|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01539|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01539|061|R|  19(5):735-43.|6
01540|001|T|MONOGRAPH TITLE:  Ivabradine/Possible QT Prolonging Agents|
01540|002|B||
01540|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01540|004|L|take action as needed.|
01540|005|B||
01540|006|A|MECHANISM OF ACTION:  QT prolongation may be exacerbated by|
01540|007|A|ivabradine-induced reduction in heart rate.(1)|
01540|008|B||
01540|009|E|CLINICAL EFFECTS:  Concurrent use of ivabradine and agents known to prolong|
01540|010|E|the QT interval may exacerbate QT prolongation.(1)|
01540|011|B||
01540|012|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01540|013|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01540|014|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01540|015|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01540|016|P|gender, or advanced age.(3)|
01540|017|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01540|018|P|higher systemic concentrations of either QT prolonging drug are additional|
01540|019|P|risk factors for torsade de pointes.   Factors which may increase systemic|
01540|020|P|drug concentrations include rapid infusion of an intravenous dose or|
01540|021|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01540|022|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01540|023|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01540|024|B||
01540|025|M|PATIENT MANAGEMENT:  The UK, AU, and Canadian manufacturer of ivabradine|
01540|026|M|states that concurrent use with cardiovascular and non-cardiovascular QT|
01540|027|M|prolonging agents should be avoided.(1)|
01540|028|M|   The Canadian manufacturer states that if concurrent therapy is deemed|
01540|029|M|necessary, close cardiac monitoring (12-lead ECG) is required. Depending on|
01540|030|M|the ECG results, ivabradine dosing may need to be decreased or stopped.(4)|
01540|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01540|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01540|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01540|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01540|035|B||
01540|036|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01540|037|D|associated with torsades de pointes and/or QT prolongation but at this time|
01540|038|D|lack substantial evidence for causing torsades de pointes.(2)|
01540|039|B||
01540|040|R|REFERENCES:|
01540|041|B||
01540|042|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01540|043|R|  Les Laboratoires Servier March, 2015.|1
01540|044|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01540|045|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01540|046|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01540|047|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01540|048|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01540|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01540|050|R|  settings: a scientific statement from the American Heart Association and|6
01540|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01540|052|R|  2;55(9):934-47.|6
01540|053|R|4.Lancora (ivabradine) Canadian prescribing  information. Servier Canada|1
01540|054|R|  Inc. December 20, 2016.|1
01540|055|R|5.Coralan (ivabradine) AU prescribing information. Servier Laboratories|1
01540|056|R|  (Aust.) PTY LTD September 11, 2017.|1
01541|001|T|MONOGRAPH TITLE:  Erlotinib; Gefitinib; Sorafenib/Warfarin|
01541|002|B||
01541|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01541|004|L|take action as needed.|
01541|005|B||
01541|006|A|MECHANISM OF ACTION:  Bleeding has been reported with the use of|
01541|007|A|erlotinib,(1) gefitinib,(2) and sorafenib(3) alone.  Concurrent use of|
01541|008|A|warfarin may result in additive effects.|
01541|009|B||
01541|010|E|CLINICAL EFFECTS:  Concurrent use of erlotinib,(1) gefitinib,(2) or|
01541|011|E|sorafenib(3) and warfarin may increase the risk of bleeding.|
01541|012|B||
01541|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01541|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01541|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01541|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01541|017|P|risk for bleeding (e.g. NSAIDs).|
01541|018|B||
01541|019|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with erlotinib,|
01541|020|M|gefitinib, or sorafenib and warfarin should be closely monitored for changes|
01541|021|M|in International Normalized Ratio (INR) and signs of bleeding.  Permanent|
01541|022|M|discontinuation of erlotinib, gefitinib, and sorafenib should be considered|
01541|023|M|in patients who experience a bleeding event that requires medical|
01541|024|M|intervention.|
01541|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01541|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01541|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01541|028|M|patients with any symptoms.|
01541|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01541|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01541|031|M|anticoagulation in patients with active pathologic bleeding.|
01541|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01541|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01541|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01541|035|M|and/or swelling.|
01541|036|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01541|037|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01541|038|M|initiating, altering the dose or discontinuing either drug.|
01541|039|B||
01541|040|D|DISCUSSION:  Increased INR and bleeding events, including gastrointestinal|
01541|041|D|and non-gastrointestinal (including fatalities) have been reported with|
01541|042|D|concurrent erlotinib and warfarin.(1,4)|
01541|043|D|   Elevated INR and bleeding events have also been reported with|
01541|044|D|gefitinib(2,5,6) and sorafenib(3,7,8)|
01541|045|D|   Bleeding has been reported with erlotinib,(1) gefitinib,(2) and|
01541|046|D|sorafenib(3) alone.(3)|
01541|047|B||
01541|048|R|REFERENCES:|
01541|049|B||
01541|050|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
01541|051|R|  2016.|1
01541|052|R|2.Iressa (gefitinib) US prescribing information. AstraZeneca March 6, 2012.|1
01541|053|R|3.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
01541|054|R|  Corporation July, 2020.|1
01541|055|R|4.Thomas KS, Billingsley A, Amarshi N, Nair BA. Elevated international|3
01541|056|R|  normalized ratio associated with concomitant warfarin and erlotinib. Am J|3
01541|057|R|  Health Syst Pharm 2010 Sep 1;67(17):1426-9.|3
01541|058|R|5.Arai S, Mitsufuji H, Nishii Y, Onoda S, Ryuge S, Wada M, Katono K, Iwasaki|3
01541|059|R|  M, Takakura A, Otani S, Yamamoto M, Yanaihara T, Yokoba M, Kubota M,|3
01541|060|R|  Katagiri M, Fukui T, Kobayashi H. Yanase N, Hataishi R, Masuda, N.  Effect|3
01541|061|R|  of gefitinib on warfarin antithrombotic activity. Int J Clin Oncol 2009|3
01541|062|R|  Aug;14(4):332-6.|3
01541|063|R|6.Onoda S, Mitsufuji H, Yanase N, Ryuge S, Kato E, Wada M, Ishii K, Hagiri|3
01541|064|R|  S, Yamamoto M, Yokoba M, Yanaihara T, Kuboto M, Takada N, Katagiri M, Abe|3
01541|065|R|  T, Tanaka N, Kobayashi H, Masuda N. Drug interaction between gefitinib and|3
01541|066|R|  warfarin. Jpn J Clin Oncol 2005 Aug;35(8):478-82.|3
01541|067|R|7.Shiozawa K, Watanabe M, Hirano N, Wakui N, Kikuchi Y, Hara F, Ishii K,|3
01541|068|R|  Iida K, Sumino Y. Gastrointestinal hemorrhage associated with concurrent|3
01541|069|R|  use of sorafenib and warfarin for hepatocellular carcinoma. Gan To Kagaku|3
01541|070|R|  Ryoho 2011 Oct;38(10):1713-5.|3
01541|071|R|8.Moretti LV, Montalvo RO. Elevated International Normalized Ratio|3
01541|072|R|  associated with concurrent use of sorafenib and warfarin. Am J Health Syst|3
01541|073|R|  Pharm 2009 Dec 1;66(23):2123-5.|3
01542|001|T|MONOGRAPH TITLE:  Abatacept/Selected Biologic DMARDs|
01542|002|B||
01542|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01542|004|L|is contraindicated and generally should not be dispensed or administered to|
01542|005|L|the same patient.|
01542|006|B||
01542|007|A|MECHANISM OF ACTION:  Possibly additive or synergistic effects on the immune|
01542|008|A|system.|
01542|009|B||
01542|010|E|CLINICAL EFFECTS:  Concurrent use of abatacept with anakinra, rituximab, or|
01542|011|E|a tumor necrosis factor (TNF) blocking agent may increase the risk of severe|
01542|012|E|infections without providing any clinical benefit.(1-5)|
01542|013|B||
01542|014|P|PREDISPOSING FACTORS:  None determined.|
01542|015|B||
01542|016|M|PATIENT MANAGEMENT:  The manufacturer of abatacept states that abatacept|
01542|017|M|should not be used with TNF blocking agents or other biologic DMARDs.|
01542|018|M|Patients transitioning from TNF blocking agent therapy to abatacept should|
01542|019|M|be closely monitored for signs of infection.(1)|
01542|020|M|   The US manufacturers of adalimumab,(2) certolizumab,(3) golimumab,(4) and|
01542|021|M|infliximab(5) state that concurrent therapy with abatacept is not|
01542|022|M|recommended.|
01542|023|B||
01542|024|D|DISCUSSION:  In clinical trials, patients who received concurrent abatacept|
01542|025|D|and TNF blocking agents experienced more infections (63% versus 43%) and|
01542|026|D|more serious infections (4.4% versus 0.8%) than patients who received TNF|
01542|027|D|agents alone.  There was no significant additional efficacy over use of TNF|
01542|028|D|agents alone.(1)|
01542|029|D|   In other trials, infections and serious infections were reported in 54%|
01542|030|D|and 3%, respectively, of patients who received abatacept alone.(1)|
01542|031|B||
01542|032|R|REFERENCES:|
01542|033|B||
01542|034|R|1.Orencia (abatacept) US prescribing information. Bristol-Myers Squibb|1
01542|035|R|  Company December, 2021.|1
01542|036|R|2.Humira (adalimumab) US prescribing information. Abbott Laboratories|1
01542|037|R|  December, 2018.|1
01542|038|R|3.Cimzia (certolizumab pegol) US prescribing information. UCB, Inc.|1
01542|039|R|  February, 2019.|1
01542|040|R|4.Simponi (golimumab) US prescribing information. Centocor Ortho Biotech|1
01542|041|R|  Inc. March, 2018.|1
01542|042|R|5.Remicade (infliximab) US prescribing information. Janssen Biotech, Inc.|1
01542|043|R|  May, 2020.|1
01543|001|T|MONOGRAPH TITLE:  Live Vaccines/Abatacept (mono deleted 04/26/2012)|
01543|002|B||
01543|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01543|004|L|is contraindicated and generally should not be dispensed or administered to|
01543|005|L|the same patient.|
01543|006|B||
01543|007|A|MECHANISM OF ACTION:  Abatacept may interfere with the normal immune|
01543|008|A|response to new antigens.(1)|
01543|009|B||
01543|010|E|CLINICAL EFFECTS:  Live vaccines may not be effective in patients treated|
01543|011|E|with abatacept.(1)|
01543|012|B||
01543|013|P|PREDISPOSING FACTORS:  None determined.|
01543|014|B||
01543|015|M|PATIENT MANAGEMENT:  The manufacturer of abatacept states that live vaccines|
01543|016|M|should not be given concurrently with abatacept or within 3 months of its|
01543|017|M|discontinuation.(1)|
01543|018|B||
01543|019|D|DISCUSSION:  Because abatacept interferes with the normal immune response,|
01543|020|D|vaccination may not be effective.  Therefore, the manufacturer of abatacept|
01543|021|D|states that live vaccines should not be given concurrently with abatacept or|
01543|022|D|within 3 months of its discontinuation.(1)|
01543|023|B||
01543|024|R|REFERENCE:|
01543|025|B||
01543|026|R|1.Orencia (abatacept) US prescribing information. Bristol-Myers Squibb|1
01543|027|R|  Company January, 2012.|1
01544|001|T|MONOGRAPH TITLE:  Tolvaptan/Strong CYP3A4 Inhibitors|
01544|002|B||
01544|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01544|004|L|is contraindicated and generally should not be dispensed or administered to|
01544|005|L|the same patient.|
01544|006|B||
01544|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
01544|008|A|of tolvaptan.(1)  Toxicity may result from an overly rapid correction of|
01544|009|A|serum sodium.|
01544|010|B||
01544|011|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
01544|012|E|in increased levels of tolvaptan.(1)|
01544|013|E|   Elevated levels of tolvaptan may lead to increased clinical effects such|
01544|014|E|as hypotension, hypovolemia, and thirst, as well as toxicity in the form of|
01544|015|E|neurologic sequelae such as osmotic demyelination syndrome (ODS).  ODS can|
01544|016|E|lead to coma and death.  Symptoms of ODS include dysarthria, mutism,|
01544|017|E|dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and|
01544|018|E|coma.(1)|
01544|019|B||
01544|020|P|PREDISPOSING FACTORS:  None determined.|
01544|021|B||
01544|022|M|PATIENT MANAGEMENT:  Concurrent use of tolvaptan and strong CYP3A4|
01544|023|M|inhibitors is contraindicated.(1)|
01544|024|M|   The US manufacturer of itraconazole states that concurrent use with|
01544|025|M|tolvaptan is contraindicated during and two weeks after itraconazole|
01544|026|M|treatment.(2)|
01544|027|B||
01544|028|D|DISCUSSION:  Tolvaptan is a substrate of CYP3A4.|
01544|029|D|   Concurrent administration of ketoconazole (200 mg daily) increased|
01544|030|D|tolvaptan exposure by 5-fold.  Administration of ketoconazole at dosages of|
01544|031|D|400 mg daily would be expected to produce greater increases, as would|
01544|032|D|concurrent administration with other strong CYP3A4 inhibitors.(1)|
01544|033|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
01544|034|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
01544|035|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
01544|036|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
01544|037|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib,|
01544|038|D|and voriconazole.(3)|
01544|039|B||
01544|040|R|REFERENCES:|
01544|041|B||
01544|042|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01544|043|R|  Ltd. April, 2018.|1
01544|044|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01544|045|R|  Products, L.P. February, 2024.|1
01544|046|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01544|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01544|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01544|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01544|050|R|  11/14/2017.|1
01545|001|T|MONOGRAPH TITLE:  Conivaptan/Clarithromycin; Telithromycin (mono deleted|
01545|002|T|04/12/2012)|
01545|003|B||
01545|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01545|005|L|is contraindicated and generally should not be dispensed or administered to|
01545|006|L|the same patient.|
01545|007|B||
01545|008|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01545|009|A|metabolism of conivaptan via CYP P-450-3A4.  Toxicity may result from an|
01545|010|A|overly rapid correction of serum sodium.(1)|
01545|011|B||
01545|012|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin or telithromycin may|
01545|013|E|result in increased levels of conivaptan, which may lead to increased|
01545|014|E|clinical effects such as hypotension, hypovolemia, and thirst, as well as|
01545|015|E|toxicity in the form of neurologic sequelae such as osmotic demyelination|
01545|016|E|syndrome.(1)|
01545|017|B||
01545|018|P|PREDISPOSING FACTORS:  None determined.|
01545|019|B||
01545|020|M|PATIENT MANAGEMENT:  The US manufacturer of conivaptan states that the|
01545|021|M|combination of potent CYP P-450-3A4 inhibitors, such as clarithromycin and|
01545|022|M|telithromycin, and conivaptan is contraindicated.(1)|
01545|023|B||
01545|024|D|DISCUSSION:  Conivaptan is a sensitive substrate of CYP P-450-3A4.|
01545|025|D|Coadministration of conivaptan and ketoconazole, another CYP P-450-3A4|
01545|026|D|inhibitor, resulted in a 4-fold increase in the area under the curve (AUC)|
01545|027|D|and an 11-fold increase in the maximum concentration (Cmax) of|
01545|028|D|conivaptan.(1)|
01545|029|B||
01545|030|R|REFERENCE:|
01545|031|B||
01545|032|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
01545|033|R|  Pharma US, Inc. February, 2012.|1
01546|001|T|MONOGRAPH TITLE:  Conivaptan/Selected Protease Inhibitors (mono deleted|
01546|002|T|04/12/2012)|
01546|003|B||
01546|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01546|005|L|is contraindicated and generally should not be dispensed or administered to|
01546|006|L|the same patient.|
01546|007|B||
01546|008|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01546|009|A|conivaptan via CYP P-450-3A4.  Toxicity may result from an overly rapid|
01546|010|A|correction of serum sodium.(1)|
01546|011|B||
01546|012|E|CLINICAL EFFECTS:  Concurrent use of a protease inhibitor may result in|
01546|013|E|increased levels of conivaptan, which may lead to increased clinical effects|
01546|014|E|such as hypotension, hypovolemia, and thirst, as well as toxicity in the|
01546|015|E|form of neurologic sequelae such as osmotic demyelination syndrome.(1)|
01546|016|B||
01546|017|P|PREDISPOSING FACTORS:  None determined.|
01546|018|B||
01546|019|M|PATIENT MANAGEMENT:  The US manufacturer of conivaptan states that the|
01546|020|M|combination of potent CYP P-450-3A4 inhibitors, such as atazanavir,|
01546|021|M|indinavir, nelfinavir, ritonavir, and saquinavir, and conivaptan is|
01546|022|M|contraindicated.(1)|
01546|023|B||
01546|024|D|DISCUSSION:  Conivaptan is a sensitive substrate of CYP P-450-3A4.|
01546|025|D|Coadministration of conivaptan and ketoconazole, another CYP P-450-3A4|
01546|026|D|inhibitor, resulted in a 4-fold increase in the area under the curve (AUC)|
01546|027|D|and an 11-fold increase in the maximum concentration (Cmax)of conivaptan.(1)|
01546|028|B||
01546|029|R|REFERENCE:|
01546|030|B||
01546|031|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
01546|032|R|  Pharma US, Inc. February, 2012.|1
01547|001|T|MONOGRAPH TITLE:  Midazolam/Conivaptan|
01547|002|B||
01547|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01547|004|L|of severe adverse interaction.|
01547|005|B||
01547|006|A|MECHANISM OF ACTION:  Conivaptan may inhibit the metabolism of midazolam via|
01547|007|A|CYP3A4.(1)|
01547|008|B||
01547|009|E|CLINICAL EFFECTS:  Concurrent use of midazolam and conivaptan may result in|
01547|010|E|increased levels of midazolam, which may lead to increased clinical effects|
01547|011|E|and toxicity, including respiratory depression.(1)|
01547|012|B||
01547|013|P|PREDISPOSING FACTORS:  None determined.|
01547|014|B||
01547|015|M|PATIENT MANAGEMENT:  The US manufacturer of conivaptan states the concurrent|
01547|016|M|use of agents primarily metabolized by CYP3A4, such as midazolam, should be|
01547|017|M|avoided.  Treatment with midazolam may be initiated no sooner than 1 week|
01547|018|M|after the infusion of conivaptan is completed.(1)|
01547|019|B||
01547|020|D|DISCUSSION:  Conivaptan is a potent inhibitor of CYP3A4.  In an evaluation|
01547|021|D|of the combination of intravenous conivaptan (40 mg) with either an|
01547|022|D|intravenous dose of midazolam (1 mg) or an oral dose of midazolam (2 mg),|
01547|023|D|mean area under the curve (AUC) values of midazolam were increased 2- and|
01547|024|D|3-fold, respectively.(1)|
01547|025|B||
01547|026|R|REFERENCE:|
01547|027|B||
01547|028|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
01547|029|R|  Pharma US, Inc. October, 2016.|1
01548|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Conivaptan|
01548|002|B||
01548|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01548|004|L|of severe adverse interaction.|
01548|005|B||
01548|006|A|MECHANISM OF ACTION:  Conivaptan is a moderate CYP3A4 inhibitor and may|
01548|007|A|inhibit the metabolism of lovastatin(1,2) and simvastatin(2,3) via CYP3A4.|
01548|008|B||
01548|009|E|CLINICAL EFFECTS:  Concurrent use of conivaptan may result in increased|
01548|010|E|levels of lovastatin(1,2) or simvastatin,(2,3) which may lead to increased|
01548|011|E|clinical effects and toxicity, including rhabdomyolysis.|
01548|012|B||
01548|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01548|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01548|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01548|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01548|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01548|018|P|transporter OATP1B1 may have increased statin concentrations and be|
01548|019|P|predisposed to myopathy or rhabdomyolysis.|
01548|020|B||
01548|021|M|PATIENT MANAGEMENT:  Concurrent use of lovastatin(1) or simvastatin(3) with|
01548|022|M|inhibitors of CYP3A4 may increase the risk of myopathy.  The manufacturer of|
01548|023|M|conivaptan recommends avoiding concurrent use of drugs primarily metabolized|
01548|024|M|by CYP3A4.(2)  Therapy with lovastatin and simvastatin may be initiated no|
01548|025|M|sooner than 1 week after the infusion of conivaptan is completed.(2)|
01548|026|B||
01548|027|D|DISCUSSION:  Conivaptan is a moderate inhibitor of CYP3A4.  In an evaluation|
01548|028|D|of the combination of intravenous conivaptan (30 mg) and simvastatin, the|
01548|029|D|area-under-curve (AUC) of simvastatin was increased 3-fold.  Two cases of|
01548|030|D|rhabdomyolysis occurred in patients who were also receiving a CYP3A4|
01548|031|D|metabolized HMG-CoA reductase inhibitor.(3)|
01548|032|B||
01548|033|R|REFERENCES:|
01548|034|B||
01548|035|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01548|036|R|  February, 2014.|1
01548|037|R|2.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
01548|038|R|  Pharma US, Inc. October, 2016.|1
01548|039|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
01548|040|R|  2023.|1
01549|001|T|MONOGRAPH TITLE:  Amlodipine; Levamlodipine/Conivaptan|
01549|002|B||
01549|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01549|004|L|of severe adverse interaction.|
01549|005|B||
01549|006|A|MECHANISM OF ACTION:  Conivaptan may inhibit the metabolism of amlodipine|
01549|007|A|via CYP3A4.(1)|
01549|008|A|   Levamlodipine is the active isomer of amlodipine.(2)|
01549|009|B||
01549|010|E|CLINICAL EFFECTS:  Concurrent use of amlodipine or levamlodipine and|
01549|011|E|conivaptan may result in increased levels of amlodipine or levamlodipine,|
01549|012|E|which may lead to increased clinical effects and toxicity.(1)|
01549|013|B||
01549|014|P|PREDISPOSING FACTORS:  None determined.|
01549|015|B||
01549|016|M|PATIENT MANAGEMENT:  The US manufacturer of conivaptan states that|
01549|017|M|concurrent use of agents primarily metabolized by CYP3A4, such as amlodipine|
01549|018|M|or levamlodipine, should be avoided.  Amlodipine or levamlodipine may be|
01549|019|M|initiated no sooner than 1 week after the infusion of conivaptan is|
01549|020|M|completed.(1)|
01549|021|B||
01549|022|D|DISCUSSION:  Conivaptan is a potent inhibitor of CYP3A4.  In an evaluation|
01549|023|D|of the combination of oral conivaptan (80 mg/day) and amlodipine, the|
01549|024|D|area-under-curve (AUC) and half life of amlodipine were both increased|
01549|025|D|2-fold.(1)|
01549|026|B||
01549|027|R|REFERENCES:|
01549|028|B||
01549|029|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
01549|030|R|  Pharma US, Inc. October, 2016.|1
01549|031|R|2.Conjupri (levamlodipine) US prescribing information. CSPC Ouyi|1
01549|032|R|  Pharmaceutical Co., Ltd. December, 2019.|1
01550|001|T|MONOGRAPH TITLE:  Digoxin/Conivaptan|
01550|002|B||
01550|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01550|004|L|take action as needed.|
01550|005|B||
01550|006|A|MECHANISM OF ACTION:  Conivaptan may inhibit the metabolism of digoxin via|
01550|007|A|P-glycoprotein (P-gp).(1)|
01550|008|B||
01550|009|E|CLINICAL EFFECTS:  Concurrent use of conivaptan and digoxin may result in an|
01550|010|E|increased concentration of digoxin, which may lead to increased clinical|
01550|011|E|effects and toxicity.  Symptoms of digoxin toxicity can include anorexia,|
01550|012|E|nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle|
01550|013|E|weakness, disorientation, hallucinations, visual disturbances, and|
01550|014|E|arrhythmias.(1)|
01550|015|B||
01550|016|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
01550|017|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
01550|018|P|risk of digoxin toxicity.|
01550|019|B||
01550|020|M|PATIENT MANAGEMENT:  Dosage of digoxin may need to be altered based on the|
01550|021|M|individual patient response.  Monitor for signs and symptoms of digoxin|
01550|022|M|toxicity and adjust dose accordingly.(1)|
01550|023|M|   The manufacturer of digoxin recommends reducing digoxin concentrations by|
01550|024|M|decreasing the dose by approximately 15-30% or by modifying the dosing|
01550|025|M|frequency of digoxin.(2)|
01550|026|B||
01550|027|D|DISCUSSION:  Conivaptan is a P-gp inhibitor.  Digoxin is a P-glycoprotein|
01550|028|D|substrate.|
01550|029|D|   Coadministration of conivaptan (80 mg/day) and digoxin (0.5 mg) resulted|
01550|030|D|in a 30% decrease in the clearance, 79% increase in the maximum|
01550|031|D|concentration (Cmax), and a 43% increase in the area under the curve (AUC)|
01550|032|D|of digoxin.(1)|
01550|033|B||
01550|034|R|REFERENCES:|
01550|035|B||
01550|036|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
01550|037|R|  Pharma US, Inc. October, 2016.|1
01550|038|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
01550|039|R|  Pharmaceuticals, Inc. August, 2018.|1
01551|001|T|MONOGRAPH TITLE:  Saquinavir/Loperamide|
01551|002|B||
01551|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01551|004|L|of severe adverse interaction.|
01551|005|B||
01551|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but loperamide may|
01551|007|A|decrease saquinavir absorption.(1)  Saquinavir may increase loperamide|
01551|008|A|absorption.(2)|
01551|009|B||
01551|010|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
01551|011|E|effectiveness of saquinavir(1,2) and elevated levels of loperamide, which|
01551|012|E|may result in respiratory depression.(2)|
01551|013|B||
01551|014|P|PREDISPOSING FACTORS:  None determined.|
01551|015|B||
01551|016|M|PATIENT MANAGEMENT:  Consider avoiding the use of loperamide, especially for|
01551|017|M|long-term use, in patients receiving saquinavir.(1)|
01551|018|M|   If concurrent use is warranted, monitor for decrease saquinavir levels|
01551|019|M|and efficacy.(2)  The dosage of saquinavir may need adjusting.|
01551|020|M|   Consider lower doses of loperamide in these patients and monitor for|
01551|021|M|adverse effects, including respiratory depression.|
01551|022|B||
01551|023|D|DISCUSSION:  In a study in 12 healthy subjects, administration of a single|
01551|024|D|dose of loperamide (16 mg) with a single dose of saquinavir (600 mg)|
01551|025|D|decreased the saquinavir area-under-curve (AUC) and maximum concentration|
01551|026|D|(Cmax) by 54% and 46%, respectively.(1)|
01551|027|D|   Loperamide AUC increased by 40%.(1)|
01551|028|B||
01551|029|R|REFERENCES:|
01551|030|B||
01551|031|R|1.USFood and Drug Administration. FDA Drug Safety Communication:  FDA warns|1
01551|032|R|  about serious heart problems with high doses of the antidiarrheal medicine|1
01551|033|R|  loperamide (Imodium), including from abuse and misuse. available at:|1
01551|034|R|  http://www.fda.gov/downloads/Drugs/DrugSafety/UCM505108.pdf June 7, 2016.|1
01551|035|R|2.Mikus G, Schmidt L, Burhenne J, Ding R, Riedel KD, Tayrouz Y, Weiss J,|2
01551|036|R|  Haefeli WE. Reduction of saquinavir exposure by coadministration of|2
01551|037|R|  loperamide: a two-way pharmacokinetic interaction. Clin Pharmacokinet|2
01551|038|R|  2004;43(14):1015-24.|2
01552|001|T|MONOGRAPH TITLE:  Loperamide/CYP3A4; CYP2C8; P-glycoprotein (P-gp)|
01552|002|T|Inhibitors|
01552|003|B||
01552|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01552|005|L|take action as needed.|
01552|006|B||
01552|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase|
01552|008|A|loperamide systemic absorption and facilitate entry into central nervous|
01552|009|A|system (CNS).(1)|
01552|010|B||
01552|011|E|CLINICAL EFFECTS:  Concurrent use of inhibitors of CYP3A4, CYP2C8, and/or|
01552|012|E|P-gp may increase levels of loperamide, resulting in respiratory|
01552|013|E|depression.(1)|
01552|014|B||
01552|015|P|PREDISPOSING FACTORS:  None determined.|
01552|016|B||
01552|017|M|PATIENT MANAGEMENT:  Use loperamide with caution in patients receiving|
01552|018|M|inhibitors of CYP3A4, CYP2C8, and/or P-gp.  Consider lower doses of|
01552|019|M|loperamide in these patients and monitor for adverse effects.|
01552|020|M|   The manufacturer of lonafarnib recommends starting loperamide at a dose|
01552|021|M|of 1 mg and slowly increasing the dose as needed.(2)|
01552|022|B||
01552|023|D|DISCUSSION:  In a randomized, cross-over study in 12 healthy subjects,|
01552|024|D|itraconazole (100 mg twice daily for 5 days - first dose 200 mg),|
01552|025|D|gemfibrozil (600 mg twice daily), and the combination of itraconazole and|
01552|026|D|gemfibrozil (same dosages) increased the area-under-curve (AUC) of single|
01552|027|D|doses of loperamide (4 mg) by 2.9-fold, 1.6-fold, and 4.2-fold,|
01552|028|D|respectively.(3)|
01552|029|D|   In a study of healthy subjects, lonafarnib (100 mg twice daily for 5|
01552|030|D|days) increased the AUC and maximum concentration (Cmax) of single dose|
01552|031|D|loperamide (2 mg) by 299% and 214%, respectively.(3)|
01552|032|D|   In a study in 18 healthy males, quinidine increased the AUC of a single|
01552|033|D|dose of loperamide by 2.2-fold and markedly decreased pupil size.(4)|
01552|034|D|   In a study in 8 healthy subjects, subjects experienced respiratory|
01552|035|D|depression when a single dose of loperamide (16 mg) was administered with a|
01552|036|D|single dose of quinidine (600 mg) but not when loperamide was administered|
01552|037|D|alone.(6)  Loperamide plasma levels increased 2-fold to 3-fold.(5)|
01552|038|B||
01552|039|R|REFERENCES:|
01552|040|B||
01552|041|R|1.USFood and Drug Administration. FDA Drug Safety Communication:  FDA warns|1
01552|042|R|  about serious heart problems with high doses of the antidiarrheal medicine|1
01552|043|R|  loperamide (Imodium), including from abuse and misuse. available at:|1
01552|044|R|  http://www.fda.gov/downloads/Drugs/DrugSafety/UCM505108.pdf June 7, 2016.|1
01552|045|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
01552|046|R|  Inc. November, 2020.|1
01552|047|R|3.Kim TE, Lee H, Lim KS, Lee S, Yoon SH, Park KM, Han H, Shin SG, Jang IJ,|2
01552|048|R|  Yu KS, Cho JY. Effects of HM30181, a P-glycoprotein inhibitor, on the|2
01552|049|R|  pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers.|2
01552|050|R|  Br J Clin Pharmacol 2014 Sep;78(3):556-64.|2
01552|051|R|4.Niemi M, Tornio A, Pasanen MK, Fredrikson H, Neuvonen PJ, Backman JT.|2
01552|052|R|  Itraconazole, gemfibrozil and their combination markedly raise the plasma|2
01552|053|R|  concentrations of loperamide. Eur J Clin Pharmacol 2006 Jun;62(6):463-72.|2
01552|054|R|5.Sadeque AJ, Wandel C, He H, Shah S, Wood AJ. Increased drug delivery to|2
01552|055|R|  the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 2000 Sep;|2
01552|056|R|  68(3):231-7.|2
01552|057|R|6.Imodium (loperamide hydrochloride) US prescribing information. Johnson &|1
01552|058|R|  Johnson Consumer Inc. October, 2016.|1
01553|001|T|MONOGRAPH TITLE:  Tolterodine/Class IA & III Antiarrhythmics|
01553|002|B||
01553|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01553|004|L|take action as needed.|
01553|005|B||
01553|006|A|MECHANISM OF ACTION:  Concurrent use of tolterodine and Class IA or III|
01553|007|A|antiarrhythmics may result in additive effects on the QTc interval.(1)|
01553|008|B||
01553|009|E|CLINICAL EFFECTS:  Concurrent use of tolterodine and Class IA or III|
01553|010|E|antiarrhythmics may result in QTc prolongation and life-threatening cardiac|
01553|011|E|arrhythmias, including torsades de pointes.(1)|
01553|012|B||
01553|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01553|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
01553|015|P|failure, myocardial infarction, history of torsades de pointes, congential|
01553|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01553|017|P|female gender, advanced age, and/or patients who are poor CYP P-450-2D6|
01553|018|P|metabolizers.(2)|
01553|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01553|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01553|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01553|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01553|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01553|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01553|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01553|026|B||
01553|027|M|PATIENT MANAGEMENT:  Use tolterodine with caution in patients maintained on|
01553|028|M|Class IA or III antiarrhythmics.(1)|
01553|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01553|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01553|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01553|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01553|033|B||
01553|034|D|DISCUSSION:  The effects of tolterodine on the QTc interval were studied in|
01553|035|D|45 healthy subjects.  Effects were compared to moxifloxacin, a known QTc|
01553|036|D|prolonging agent.  Tolterodine's effect on the QTc interval correlated with|
01553|037|D|tolterodine plasma concentration.  There was a greater increase in QTc in|
01553|038|D|patients who were CYP P-450-2D6 poor metabolizers.  There has been no|
01553|039|D|associated with tolterodine and torsades in the international post-marketing|
01553|040|D|experience of Detrol or Detrol LA.(1)|
01553|041|B||
01553|042|R|REFERENCES:|
01553|043|B||
01553|044|R|1.Detrol LA (tolterodine tartrate) US prescribing information. Pharmacia &|1
01553|045|R|  Upjohn Company September, 2008.|1
01553|046|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01553|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01553|048|R|  settings: a scientific statement from the American Heart Association and|6
01553|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01553|050|R|  2;55(9):934-47.|6
01554|001|T|MONOGRAPH TITLE:  Warfarin/Selected Herbals That May Increase Warfarin|
01554|002|T|Effects|
01554|003|B||
01554|004|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01554|005|L|Assess the risk to the patient and take action as needed.|
01554|006|B||
01554|007|A|MECHANISM OF ACTION:  Concurrent use of some alternative therapy agents may|
01554|008|A|result in additive or synergistic effects with warfarin.  Some alternative|
01554|009|A|therapy agents may cause bleeding when taken alone and may contain coumarins|
01554|010|A|and/or salicylates and/or have anticoagulant, antiplatelet, and/or|
01554|011|A|fibrinolytic properties.(1)|
01554|012|B||
01554|013|E|CLINICAL EFFECTS:  Concurrent use of warfarin and some alternative therapy|
01554|014|E|agents may result in elevated INR values and increased risk of bleeding.|
01554|015|B||
01554|016|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01554|017|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01554|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
01554|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01554|020|P|risk for bleeding (e.g. NSAIDs).|
01554|021|B||
01554|022|M|PATIENT MANAGEMENT:  Advise patients against using alternative therapy|
01554|023|M|agents with warfarin and to report the initiation or discontinuation of any|
01554|024|M|alternative therapy agents.|
01554|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01554|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01554|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01554|028|M|patients with any symptoms.|
01554|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01554|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01554|031|M|anticoagulation in patients with active pathologic bleeding.|
01554|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01554|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01554|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01554|035|M|and/or swelling.|
01554|036|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01554|037|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01554|038|M|initiating, altering the dose or discontinuing either drug.|
01554|039|B||
01554|040|D|DISCUSSION:  The following alternative therapy agents contain coumarins with|
01554|041|D|potential anticoagulant effects:  alfalfa, angelica (dong quai), aniseed,|
01554|042|D|arnica, asa foetida, bogbean, boldo, buchu, capsicum, cassia, celery,|
01554|043|D|chamomile (German and Roman), dandelion, fenugreek, horse chestnut,|
01554|044|D|horseradish, licorice, meadowsweet, nettle, parsley, passion flower, prickly|
01554|045|D|ash (northern), quassia, red clover, sweet clover, sweet woodruff, tonka|
01554|046|D|beans, wild carrot, and wild lettuce.(1)|
01554|047|D|   The following alternative therapy agents have anticoagulant properties:|
01554|048|D|bladder wrack (Fucus), pau d'arco, and yarrow.(1)|
01554|049|D|   The following alternative therapy agents contain salicylates and/or have|
01554|050|D|antiplatelet properties:  agrimony, aloe gel, aspen, black cohosh, black|
01554|051|D|haw, bogbean, cassia, clove, dandelion, European mistletoe, feverfew,|
01554|052|D|garlic, German sarsaparilla, ginger, ginkgo biloba, ginseng (Panax),|
01554|053|D|licorice, meadowsweet, onion, policosanol, poplar, senega, tamarind, willow,|
01554|054|D|wintergreen.(1)|
01554|055|D|   The following alternative therapy agents have fibrinolytic properties:|
01554|056|D|bromelains, capsicum, garlic, ginseng (Panax), goldenseal, inositol|
01554|057|D|nicotinate, and onion.(1)|
01554|058|D|   The following alternative therapy agents have been associated with|
01554|059|D|increased risk of self-reported bleeding:  cayenne, ginger, and willow|
01554|060|D|bark.(2)|
01554|061|D|   There is one case report of elevated INR and bleeding following the use|
01554|062|D|of a brand of guilinggao (essence of tortoise shell) that contained beimu|
01554|063|D|(Fritillaria spp.), chishao (Paeoniae rubra, Chinese peony), jinyinhua|
01554|064|D|(Lonicera japonica), and jishi (Poncirus trifoliata).(3)|
01554|065|D|   There are also case reports of elevated warfarin effects with concurrent|
01554|066|D|Lycium (Chinese boxthorn)(4-6) and with papaya.(7-8)|
01554|067|B||
01554|068|R|REFERENCES:|
01554|069|B||
01554|070|R|1.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
01554|071|R|  Squibb Company September, 2016.|1
01554|072|R|2.Shalansky S, Lynd L, Richardson K, Ingaszewski A, Kerr C. Risk of|6
01554|073|R|  warfarin-related bleeding events and supratherapeutic international|6
01554|074|R|  normalized ratios associated with complementary and alternative medicine:|6
01554|075|R|  a longitudinal analysis. Pharmacotherapy 2007 Sep;27(9):1237-47.|6
01554|076|R|3.Wong AL, Chan TY. Interaction between warfarin and the herbal product|3
01554|077|R|  quilinggao. Ann Pharmacother 2003 Jun;37(6):836-8.|3
01554|078|R|4.Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative|6
01554|079|R|  therapies and warfarin. Am J Health Syst Pharm 2000 Jul 1;57(13):1221-7;|6
01554|080|R|  quiz 1228-30.|6
01554|081|R|5.Izzo AA, Di Carlo G, Borrelli F, Ernst E. Cardiovascular pharmacotherapy|3
01554|082|R|  and herbal medicines: the risk of drug interaction. Int J Cardiol 2005|3
01554|083|R|  Jan;98(1):1-14.|3
01554|084|R|6.Rivera CA, Ferro CL, Bursua AJ, Gerber BS. Probable interaction between|3
01554|085|R|  Lycium barbarum (goji) and warfarin. Pharmacotherapy 2012 Mar;32(3):e50-3.|3
01554|086|R|7.Leung H, Hung A, Hui AC, Chan TY. Warfarin overdose due to the possible|3
01554|087|R|  effects of Lycium barbarum L. Food Chem Toxicol 2008 May;46(5):1860-2.|3
01554|088|R|8.Lam AY, Elmer GW, Mohutsky MA. Possible interaction between warfarin and|3
01554|089|R|  Lycium barbarum L. Ann Pharmacother 2001 Oct;35(10):1199-201.|3
01555|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants; Temsirolimus/Protease|
01555|002|T|Inhibitors; Cobicistat|
01555|003|B||
01555|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01555|005|L|of severe adverse interaction.|
01555|006|B||
01555|007|A|MECHANISM OF ACTION:  HIV and HCV protease inhibitors as well as cobicistat|
01555|008|A|may inhibit the metabolism of cyclosporine, sirolimus, and temsirolimus by|
01555|009|A|CYP3A4.(1-15)|
01555|010|B||
01555|011|E|CLINICAL EFFECTS:  Concurrent use of HIV or HCV protease inhibitors as well|
01555|012|E|as cobicistat may result in increased levels of cyclosporine, sirolimus, or|
01555|013|E|temsirolimus.(1-15)|
01555|014|B||
01555|015|P|PREDISPOSING FACTORS:  None determined.|
01555|016|B||
01555|017|M|PATIENT MANAGEMENT:  For patients concurrently taking cyclosporine,|
01555|018|M|sirolimus, or temsirolimus and either a HIV or HCV protease inhibitor or|
01555|019|M|cobicistat, therapeutic concentration monitoring of the immunosuppressant is|
01555|020|M|recommended.  Depending upon the agents involved, dose decreases of the|
01555|021|M|immunosuppressant agent may be required.(1-15)|
01555|022|M|   Guidelines from the American Society of Transplantation recommend|
01555|023|M|avoiding the use of ritonavir- or cobicistat-based HIV or HCV antiviral|
01555|024|M|regimens with cyclosporine or sirolimus due to an increased risk of graft|
01555|025|M|loss and death, as well as the availability of HIV integrase inhibitors that|
01555|026|M|avoid interactions with immunosuppressants.  If the combination must be|
01555|027|M|used, lower the dose of cyclosporine to 25-50 mg daily or sirolimus to 1 mg|
01555|028|M|once or twice weekly.  Monitor drug concentrations closely.(1)|
01555|029|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
01555|030|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
01555|031|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
01555|032|M|inhibitors should be avoided.(16)|
01555|033|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
01555|034|M|with strong CYP3A4 inhibitors such as protease inhibitors be avoided. If|
01555|035|M|concurrent use is warranted, a dosage reduction to 12.5 mg/week of|
01555|036|M|temsirolimus should be considered.  If the protease inhibitor is|
01555|037|M|discontinued, a washout period of 1 week should be allowed before adjusting|
01555|038|M|the dosage of temsirolimus to previous levels.(2)|
01555|039|M|   The selected immunosuppressants linked to this monograph include:|
01555|040|M|cyclosporine, sirolimus, and temsirolimus.|
01555|041|M|   The protease inhibitors linked to this monograph include: amprenavir,|
01555|042|M|atazanavir, boceprevir, cobicistat, darunavir, fosamprenavir, indinavir,|
01555|043|M|lopinavir, nelfinavir, ritonavir, telaprevir, and tipranavir.|
01555|044|B||
01555|045|D|DISCUSSION:  A retrospective study of 42 HIV+ kidney transplant recipients|
01555|046|D|examined rejection rates in patients on ritonavir-boosted protease inhibitor|
01555|047|D|(PI) antiretroviral regimens compared to patients on other antiretroviral|
01555|048|D|regimens.  Immunosuppression therapy consisted of cyclosporine in 7 patients|
01555|049|D|(17%) and tacrolimus in 32 patients (76%).  The remaining 3 patients were|
01555|050|D|transitioning between drugs.  Over 3 years, 65% of patients on PI-based|
01555|051|D|antiretroviral therapy experienced rejection, compared with 36% of patients|
01555|052|D|on other antiretroviral therapies (p<0.001).  There was no difference in|
01555|053|D|patient or graft survival at 3 years.(17)|
01555|054|D|   Cyclosporine:|
01555|055|D|   Boceprevir (800 mg TID for 7 days) increased the Cmax and AUC of|
01555|056|D|cyclosporine (100 mg single dose) by 2-fold and 2.68-fold, respectively.|
01555|057|D|Boceprevir AUC increased 16%.(4)|
01555|058|D|   In a case report, cyclosporine dosage requirements decreased 12-fold|
01555|059|D|following the addition of amprenavir/ritonavir.  In another patient,|
01555|060|D|cyclosporine dosage requirements decreased 3.5-fold following the addition|
01555|061|D|of fosamprenavir.(18)|
01555|062|D|   In a study in 3 HIV+ transplant patients who were receiving lopinavir/|
01555|063|D|ritonavir, cyclosporine doses were reduced to 5-20% of standard doses to|
01555|064|D|prevent toxicity.(19)|
01555|065|D|   In a clinical study, 7 HIV+ patients concurrently taking cyclosporine and|
01555|066|D|nelfinavir experienced a 19% increase in time to Cmax (Tmax) and a 2-fold|
01555|067|D|increase in AUC of cyclosporine when nelfinavir was added.(20)|
01555|068|D|   In a case report, cyclosporine levels tripled and signs of toxicity|
01555|069|D|developed 3 days after the addition of saquinavir (1200 mg 3 times daily) to|
01555|070|D|cyclosporine (150 mg twice daily).  Cyclosporine and saquinavir dosages were|
01555|071|D|decreased to 75 mg twice daily and 600 mg 3 times daily, respectively.|
01555|072|D|Cyclosporine Cmin levels were 90% of those seen with 150 mg twice daily.|
01555|073|D|Saquinavir AUC was 4.3-fold higher than in patients taking saquinavir 600 mg|
01555|074|D|twice daily without cyclosporine and 11.1-fold higher than literature|
01555|075|D|values.(21)|
01555|076|D|   In a study in 9 subjects, the concurrent administration of telaprevir|
01555|077|D|(750 mg TID) decreased the Cmax and AUC of a single dose of cyclosporine (10|
01555|078|D|mg) by 87% and 54%, respectively, when compared to levels achieved with a|
01555|079|D|single 100 mg dose of cyclosporine.  Extrapolated to level expected with the|
01555|080|D|100 mg dose, cyclosporine Cmax and AUC would have increased by 32% and|
01555|081|D|4.64-fold, respectively.(5)|
01555|082|D|   Sirolimus:|
01555|083|D|   Boceprevir (800 mg TID for 9 days) increased the Cmax and AUC of|
01555|084|D|sirolimus (2 mg single dose) by 4.84-fold and 8.121-fold, respectively.|
01555|085|D|Boceprevir Cmin increased 21%.(4)|
01555|086|D|   In a case report, the pharmacokinetics of a liver transplant patient|
01555|087|D|concurrently taking nelfinavir (250 mg) and sirolimus (2 mg) were compared|
01555|088|D|to the pharmacokinetics in 3 other liver transplant patients that were also|
01555|089|D|taking sirolimus, but not nelfinavir.  The maximum concentration (Cmax) was|
01555|090|D|3.2 times higher, the area-under-curve (AUC) was 1.6 times higher, the half|
01555|091|D|life was prolonged by 60%, and the 0-hr and 24-hour trough levels (Cmin) of|
01555|092|D|sirolimus were 9-fold and 5-fold higher, respectively, in patients|
01555|093|D|concurrently taking nelfinavir and sirolimus.(22)|
01555|094|D|   Temsirolimus:|
01555|095|D|   Concurrent administration of ketoconazole, another inhibitor of CYP3A4,|
01555|096|D|had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax|
01555|097|D|increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of|
01555|098|D|temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is|
01555|099|D|expected to adjust levels to the range observed without inhibitors; however,|
01555|100|D|there are no data available with this dose adjustment.(3)|
01555|101|B||
01555|102|R|REFERENCES:|
01555|103|B||
01555|104|R|1.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
01555|105|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
01555|106|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
01555|107|R|  e13510.|6
01555|108|R|2.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01555|109|R|  Inc. March, 2018.|1
01555|110|R|3.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
01555|111|R|  January, 2017.|1
01555|112|R|4.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
01555|113|R|  Incorporated October, 2013.|1
01555|114|R|5.Agenerase (amprenavir) Capsules US prescribing information.|1
01555|115|R|  GlaxoSmithKline May, 2005.|1
01555|116|R|6.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01555|117|R|  Squibb Company December, 2024.|1
01555|118|R|7.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
01555|119|R|  June, 2025.|1
01555|120|R|8.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01555|121|R|  March, 2023.|1
01555|122|R|9.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01555|123|R|  March, 2019.|1
01555|124|R|10.Crixivan (indinavir sulfate) US prescribing information. Merck & Co.,|1
01555|125|R|   Inc. September, 2016.|1
01555|126|R|11.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01555|127|R|   Laboratories December, 2019.|1
01555|128|R|12.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01555|129|R|   Pharmaceuticals, Inc. September, 2016.|1
01555|130|R|13.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01555|131|R|   December, 2019.|1
01555|132|R|14.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01555|133|R|   Laboratories, Inc. March, 2019.|1
01555|134|R|15.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01555|135|R|   Pharmaceuticals, Inc. April, 2024.|1
01555|136|R|16.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
01555|137|R|   prescribing information. Aadi Bioscience, Inc. November, 2021.|1
01555|138|R|17.Rollins B, Farouk S, DeBoccardo G, Lerner S, Rana M, Huprikar S, Miko L,|2
01555|139|R|   Delaney V, Florman S, Shapiro R. Higher rates of rejection in|2
01555|140|R|   HIV-infected kidney transplant recipients on ritonavir-boosted protease|2
01555|141|R|   inhibitors: 3-year follow-up study. Clin Transplant 2019 Jun;|2
01555|142|R|   33(6):e13534.|2
01555|143|R|18.Guaraldi G, Cocchi S, Codeluppi M, Di Benedetto F, Bonora S, Motta A,|3
01555|144|R|   Luzi K, Pecorari M, Gennari W, Masetti M, Gerunda GE, Esposito R.|3
01555|145|R|   Pharmacokinetic interaction between Amprenavir/Ritonavir and|3
01555|146|R|   FosAmprenavir on cyclosporine in two patients with human immunodeficiency|3
01555|147|R|   virus infection undergoing orthotopic liver transplantation. Transplant|3
01555|148|R|   Proc 2006 May;38(4):1138-40.|3
01555|149|R|19.Vogel M, Voigt E, Michaelis HC, Sudhop T, Wolff M, Turler A, Sauerbruch|2
01555|150|R|   T, Rockstroh JK, Spengler U. Management of drug-to-drug interactions|2
01555|151|R|   between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in|2
01555|152|R|   liver-transplanted HIV-infected patients. Liver Transpl 2004 Jul;|2
01555|153|R|   10(7):939-44.|2
01555|154|R|20.Frassetto L, Thai T, Aggarwal AM, Bucher P, Jacobsen W, Christians U,|2
01555|155|R|   Benet LZ, Floren LC. Pharmacokinetic interactions between cyclosporine|2
01555|156|R|   and protease inhibitors in HIV+ subjects. Drug Metab Pharmacokinet 2003;|2
01555|157|R|   18(2):114-20.|2
01555|158|R|21.Brinkman K, Huysmans F, Burger DM. Pharmacokinetic interaction between|3
01555|159|R|   saquinavir and cyclosporine. Ann Intern Med 1998 Dec 1;129(11):914-5.|3
01555|160|R|22.Jain AK, Venkataramanan R, Fridell JA, Gadomski M, Shaw LM, Ragni M,|3
01555|161|R|   Korecka M, Fung J. Nelfinavir, a protease inhibitor, increases sirolimus|3
01555|162|R|   levels in a liver transplantation patient: a case report. Liver Transpl|3
01555|163|R|   2002 Sep;8(9):838-40.|3
01556|001|T|MONOGRAPH TITLE:  Hydroxyurea/Interferon|
01556|002|B||
01556|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01556|004|L|of severe adverse interaction.|
01556|005|B||
01556|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01556|007|B||
01556|008|E|CLINICAL EFFECTS:  Concurrent or recent use of interferon may increase the|
01556|009|E|risk of cutaneous vascular toxicities, including vasculitic ulcerations and|
01556|010|E|gangrene.(1,2)|
01556|011|B||
01556|012|P|PREDISPOSING FACTORS:  The interaction has been noted in patients treated|
01556|013|P|with hydroxyurea for myeloproliferative disorders.(1,2)|
01556|014|B||
01556|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy and|
01556|016|M|patients receiving hydroxyurea alone who have recently received interferon|
01556|017|M|closely for cutaneous vasculitic ulcerations.  Discontinue hydroxyurea in|
01556|018|M|patients who develop cutaneous vasculitic ulcerations.(1,2)|
01556|019|B||
01556|020|D|DISCUSSION:  Cutaneous vasculitic toxicities, including vasculitic|
01556|021|D|ulcerations and gangrene, have occurred in patients with myeloproliferative|
01556|022|D|disorders during therapy with hydroxyurea.  These vasculitic toxicities were|
01556|023|D|reported most often in patients with a history of, or currently receiving,|
01556|024|D|interferon therapy.(1,2)|
01556|025|B||
01556|026|R|REFERENCES:|
01556|027|B||
01556|028|R|1.Smyth AC. Dear Healthcare Provider:  Droxia (hydroxyurea). Bristol-Myers|1
01556|029|R|  Squibb Company January 20, 2006.|1
01556|030|R|2.Smyth AC. Dear Healthcare Provider:  Hydrea (hydroxyurea). Bristol-Myers|1
01556|031|R|  Squibb Company January 20, 2006.|1
01557|001|T|MONOGRAPH TITLE:  Selected Antineoplastic Systemic Enzyme Inhibitors/Strong|
01557|002|T|3A4 Inhibitors (mono deleted 03/05/2015)|
01557|003|B||
01557|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01557|005|L|of severe adverse interaction.|
01557|006|B||
01557|007|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
01557|008|A|the metabolism of axitinib,(1) bosutinib,(2) cabozantinib,(3) ceritinib,(4)|
01557|009|A|crizotinib,(5) dabrafenib,(6) dasatinib,(7) ibrutinib,(8) idelalisib,(9)|
01557|010|A|lapatinib,(10) nilotinib,(11) olaparib,(12) palbociclib,(13) pazopanib,(14)|
01557|011|A|ponatinib,(15) ruxolitinib,(16) sunitinib,(17) and tofacitinib.(18)|
01557|012|B||
01557|013|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
01557|014|E|levels of and effects from axitinib,(1) bosutinib,(2) cabozantinib,(3)|
01557|015|E|ceritinib,(4) crizotinib,(5) dabrafenib,(6) dasatinib,(7) ibrutinib,(8)|
01557|016|E|idelalisib,(9) lapatinib,(10) nilotinib,(11) olaparib,(12) palbociclib,(13)|
01557|017|E|pazopanib,(14) ponatinib,(15) ruxolitinib,(16) sunitinib,(17) and|
01557|018|E|tofacitinib.(18)|
01557|019|E|    In addition, elevated levels of ceritinib,(4) crizotinib,(5)|
01557|020|E|dabrafenib,(6) dasatinib,(7) lapatinib,(10) nilotinib,(11) pazopanib,(14)|
01557|021|E|and sunitinib(17) may result in prolongation of the QTc interval, which may|
01557|022|E|result in potentially life-threatening cardiac arrhythmias, including|
01557|023|E|torsades de pointes|
01557|024|B||
01557|025|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01557|026|P|may be increased in patients with cardiovascular disease (e.g. heart|
01557|027|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01557|028|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01557|029|P|female gender, or advanced age.(19)|
01557|030|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01557|031|P|higher systemic concentrations of either QT prolonging drug are additional|
01557|032|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01557|033|P|drug concentrations include rapid infusion of an intravenous dose or|
01557|034|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01557|035|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01557|036|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(19)|
01557|037|P|   In patients taking ruxolitinib, this interaction may be more severe in|
01557|038|P|patients with a low platelet count.(16)|
01557|039|B||
01557|040|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
01557|041|M|undergoing therapy with axitinib,(1) bosutinib,(2) cabozantinib,(3)|
01557|042|M|ceritinib,(4) crizotinib,(5) dabrafenib,(6) dasatinib,(7) ibrutinib,(8)|
01557|043|M|idelalisib,(9) lapatinib,(10) nilotinib,(11) olaparib,(12) palbociclib,(13)|
01557|044|M|pazopanib,(14) ponatinib,(15) ruxolitinib,(16) sunitinib,(17) and|
01557|045|M|tofacitinib.(18)  Consider alternatives with no or minimal enzyme|
01557|046|M|inhibition.(1,6,15)|
01557|047|M|   If concurrent use of axitinib and a strong inhibitor of CYP3A4 is|
01557|048|M|warranted, consider decreasing the dose of axitinib by one-half (e.g. start|
01557|049|M|with an initial dose of 2 mg twice daily).  Subsequent doses may be|
01557|050|M|increased or decreased based on patient response.  When the 3A4 inhibitor|
01557|051|M|has been discontinued, allow a washout period equal to 3-5 half-lives of the|
01557|052|M|inhibitor before increasing the dose of axitinib.(1)|
01557|053|M|   If concurrent use of cabozantinib and a strong inhibitor of CYP3A4 is|
01557|054|M|warranted, the dose of cabozantinib should be reduced by 40 mg (from 140 mg|
01557|055|M|to 100 mg daily or from 100 mg to 60 mg daily).  When the 3A4 inhibitor has|
01557|056|M|been discontinued, resume the dose of cabozantinib that was used previously|
01557|057|M|2-3 days after discontinuation of the inhibitor.(32)|
01557|058|M|   If concurrent use of ceritinib and a strong inhibitor of CYP3A4 is|
01557|059|M|unavoidable, reduce the dosage of ceritinib by one-third, rounding to the|
01557|060|M|nearest 150 mg dosage strength.  If the strong CYP3A4 inhibitor is|
01557|061|M|discontinued, resume the dose that was taken prior to using the|
01557|062|M|inhibitor.(4)|
01557|063|M|   If concurrent use of dasatinib and a strong inhibitor of CYP3A4 is|
01557|064|M|warranted, consider decreasing the dose of dasatinib to 20 mg daily in|
01557|065|M|patients taking dasatinib 100 mg daily and to 40 mg daily in patients taking|
01557|066|M|dasatinib 140 mg daily.  If this dose is not tolerated, either the strong|
01557|067|M|3A4 inhibitor must be discontinued or dasatinib should be stopped until|
01557|068|M|therapy with the 3A4 inhibitor has been completed.  When the 3A4 inhibitor|
01557|069|M|has been discontinued, a one-week washout period should be allowed before|
01557|070|M|the dosage of dasatinib is increased.(7)|
01557|071|M|   The concurrent chronic use of strong CYP3A4 inhibitors with ibrutinib is|
01557|072|M|not recommended.  For short-term use of strong CYP3A4 inhibitors, such as 7|
01557|073|M|days or less of antibiotics/antifungals, consider interruption of ibrutinib|
01557|074|M|therapy.  If a moderate CYP3A4 inhibitor is required, reduce the dose of|
01557|075|M|ibrutinib to 140 mg daily.(8)|
01557|076|M|   If concurrent use of idelalisib and a strong inhibitor of CYP3A4 is|
01557|077|M|warranted, monitor patients for toxicity and follow toxicity dose|
01557|078|M|modification guidelines.(9)|
01557|079|M|   If concurrent use of lapatinib and a strong inhibitor of CYP3A4 is|
01557|080|M|warranted, a dose reduction to 500 mg/day should be considered.  If the 3A4|
01557|081|M|inhibitor is discontinued, at least 1 week should elapse before the|
01557|082|M|lapatinib dose is adjusted upward.(10)|
01557|083|M|   Consider interrupting nilotinib therapy if a strong CYP3A4 inhibitor is|
01557|084|M|needed.  If concurrent use is warranted, a dose reduction to 300 mg once|
01557|085|M|daily in patients with resistant or intolerant Ph+CML or to 200 mg once|
01557|086|M|daily in patients with newly diagnosed Ph+CML-CP should be considered.  If|
01557|087|M|the 3A4 inhibitor is discontinued, a washout period should occur before the|
01557|088|M|nilotinib dose is adjusted upward.(11)|
01557|089|M|   If concomitant use of olaparib and a strong CYP3A4 inhibitor cannot be|
01557|090|M|avoided, reduce the olaparib dose to 150 mg taken twice daily.(12)|
01557|091|M|   If concurrent use of palbociclib and a strong CYP3A4 inhibitor cannot be|
01557|092|M|avoided, reduce the dose of palbociclib to 75 mg daily.  If the 3A4|
01557|093|M|inhibitor is discontinued, a washout period of 3-5 half-lives of the|
01557|094|M|inhibitor should occur before the palbociclib dose is adjusted upward.(13)|
01557|095|M|   If concurrent administration of pazopanib and a strong CYP3A4 inhibitor|
01557|096|M|is warranted, the dosage of pazopanib should be reduced to 400 mg.|
01557|097|M|Additional dosage reductions may be required if adverse events occur.(14)|
01557|098|M|   If concurrent administration of ponatinib and a strong CPY3A4 inhibitors|
01557|099|M|is warranted, the recommended ponatinib dose should be reduced to 30 mg once|
01557|100|M|daily during concomitant treatment.  Even with the dose reduction, patients|
01557|101|M|receiving concomitant therapy may be at increased risk for adverse|
01557|102|M|reactions.  Assure recommended monitoring (e.g. complete blood counts, liver|
01557|103|M|function, lipase, blood pressure measurement) is scheduled and patient is|
01557|104|M|aware of signs of thrombosis (e.g. symptoms of myocardial infarction or|
01557|105|M|stroke).  If the ponatinib dose has been reduced due to coadministration of|
01557|106|M|a CYP3A4 inhibitor, and the inhibitor is subsequently discontinued,|
01557|107|M|reevaluate ponatinib efficacy and safety to determine if a dose increase is|
01557|108|M|appropriate.(15)|
01557|109|M|   In patients with a platelet count greater than or equal to 100 X 10x9/L|
01557|110|M|who are receiving a strong inhibitor of CYP3A4, the recommended starting|
01557|111|M|dose of ruxolitinib is 10 mg twice daily.  In patients with a platelet count|
01557|112|M|greater than 50 X 10x9/L to less than 100 X 10x9/L who are receiving a|
01557|113|M|strong inhibitor of CYP3A4, the recommended starting dose of ruxolitinib is|
01557|114|M|5 mg twice daily.  In patients stabilized on ruxolitinib of 10 mg twice|
01557|115|M|daily or more in whom a strong 3A4 inhibitor is initiated, reduce the dose|
01557|116|M|of ruxolitinib by 50% (rounded up to the closest available tablet strength).|
01557|117|M|In patients stabilized on ruxolitinib of 5 mg twice daily in whom a strong|
01557|118|M|3A4 inhibitor is initiated, reduce the dose of ruxolitinib to 5 mg daily.|
01557|119|M|In patients stabilized on ruxolitinib of 5 mg daily, avoid the use of strong|
01557|120|M|CYP3A4 inhibitors or interrupt ruxolitinib therapy for the duration of the|
01557|121|M|CYP3A4 inhibitor treatment.  The dose should be adjusted based on monitoring|
01557|122|M|of safety and efficacy.(16)|
01557|123|M|   If concurrent therapy is warranted with sunitinib and a strong CYP3A4|
01557|124|M|inhibitor, a dosage reduction of sunitinib to a minimum of 37.5 mg daily in|
01557|125|M|patients with gastrointestinal stromal tumors (GIST) or advanced renal cell|
01557|126|M|carcinoma (RCC) or to a minimum of 25 mg in patients with pancreatic|
01557|127|M|neuroendocrine tumors (pNET) should be considered.(17)|
01557|128|M|   In patients taking a strong CYP3A4 inhibitor, the starting dose of|
01557|129|M|tofacitinib should be reduced to 5 mg daily.(16)|
01557|130|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor with|
01557|131|M|ceritinib,(4) crizotinib,(5) dabrafenib,(6) dasatinib,(7) lapatinib,(10)|
01557|132|M|nilotinib,(11) pazopanib,(14) and sunitinib(17) should be monitored for|
01557|133|M|prolongation of the QTc interval.|
01557|134|B||
01557|135|D|DISCUSSION:  Ketoconazole (400 mg twice daily, a strong inhibitor of CYP3A4)|
01557|136|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
01557|137|D|axitinib (5 mg) by approximately 1.5-fold and 2-fold, respectively.  There|
01557|138|D|were no large (> 20 msec) changes in QTc interval.  Recommended dosage|
01557|139|D|adjustments are expected to produce AUC levels comparable to axitinib|
01557|140|D|administered without a strong CYP3A4 inhibitor; however, no data is|
01557|141|D|available.(1)|
01557|142|D|   In a study in 24 healthy subjects, ketoconazole (400 mg daily for 5 days)|
01557|143|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
01557|144|D|bosutinib (100 mg) by 5.2-fold and 8.6-fold, respectively.(2)|
01557|145|D|   In a study in healthy subjects, ketoconazole (400 mg daily for 27 days)|
01557|146|D|increased the AUC of a single dose of cabozantinib by 38%.(3)|
01557|147|D|   In a study in 19 healthy subjects, ketoconazole (200 mg twice daily for|
01557|148|D|14 days) increased the Cmax and AUC of a single dose of ceritinib (450 mg)|
01557|149|D|by 22% and 2.9-fold, respectively.  The steady-state AUC of ceritinib at|
01557|150|D|reduced doses after concurrent ketoconazole was predicted by simulations to|
01557|151|D|be similar to the steady-state AUC of ceritinib alone.(4)|
01557|152|D|   Ketoconazole (200 mg twice daily) increased the Cmax and AUC of a single|
01557|153|D|dose of crizotinib (150 mg) by 1.4-fold and 3.2-fold, respectively.(5)|
01557|154|D|   Ketoconazole (400 mg daily for 4 days) increased the AUC of dabrafenib|
01557|155|D|(75 mg BID) by 71%.  The AUC of hydroxy-dabrafenib and desmethyl-dabrafenib|
01557|156|D|increased by 82% and 68%, respectively.(6)|
01557|157|D|   In a study in healthy subjects, concurrent ketoconazole (200 mg twice|
01557|158|D|daily) with dasatinib (20 mg) increased dasatinib Cmax and AUC by 4-fold and|
01557|159|D|5-fold, respectively.  Recommended dosage adjustments are expected to adjust|
01557|160|D|the dasatinib AUC to ranges observed without CYP3A4 inhibitors; however,|
01557|161|D|there are no clinical data available.(7)|
01557|162|D|   In a study in 18 healthy subjects, ketoconazole (400 mg daily for 7 days)|
01557|163|D|increased the Cmax and AUC of ibrutinib (single 40 mg dose) by 24-fold and|
01557|164|D|29-fold, respectively.(8)|
01557|165|D|   In a study in healthy subjects, ketoconazole (400 mg daily for 4 days)|
01557|166|D|increased the AUC of idelalisib (400 mg single dose) by 1.8-fold.(9)|
01557|167|D|   In a study in healthy subjects, ketoconazole (200 mg twice daily for 7|
01557|168|D|days) increased lapatinib AUC and half-life (T1/2) by 3.6-fold and 1.7-fold,|
01557|169|D|respectively.  The dosage adjustment to 500 mg/day is based on|
01557|170|D|pharmacokinetic studies and is predicted to adjust lapatinib AUC to the|
01557|171|D|range observed without inhibitors; however, there are no clinical data with|
01557|172|D|this dosage adjustment in patients receiving strong CYP3A4 inhibitors.(10)|
01557|173|D|   In a study in healthy subjects, concurrent ketoconazole (400 mg daily)|
01557|174|D|increased nilotinib AUC 3-fold.(11)|
01557|175|D|   In an interaction study, the AUC and Cmax of olaparib was increased 2.7|
01557|176|D|and 1.4-fold respectively when it was administered with itraconazole (dose|
01557|177|D|not specified), a strong CYP3A4 inhibitor.(12)|
01557|178|D|   In a study in 12 healthy subjects, itraconazole (200 mg daily) increased|
01557|179|D|the Cmax and AUC of a single dose of palbociclib by 34% and 87%,|
01557|180|D|respectively.(13)|
01557|181|D|   Administration of multiple doses of oral pazopanib (400 mg) with multiple|
01557|182|D|doses of oral ketoconazole (400 mg) increased the AUC and Cmax of pazopanib|
01557|183|D|by 1.7-fold and 1.5-fold, respectively.  Administration of a single dose of|
01557|184|D|pazopanib ophthalmic drops and ketoconazole, an inhibitor of CYP3A4 and Pgp,|
01557|185|D|increase the AUC and Cmax of pazopanib by 220% and 150%, respectively.|
01557|186|D|Administration of lapatinib (1500 mg), a weak inhibitor of CYP3A4, Pgp, and|
01557|187|D|BCRP, increased the AUC and Cmax of pazopanib (800 mg) by 50% and 60%,|
01557|188|D|respectively.  Decreasing the dosage of pazopanib to 400 mg in patients|
01557|189|D|receiving strong CYP P3A4 inhibitors is expected to adjust the AUC of|
01557|190|D|pazopanib to the normal range; however, there are no clinical data available|
01557|191|D|to support this.(14)|
01557|192|D|   In 22 healthy volunteers, ketoconazole (400 mg once daily) increased the|
01557|193|D|Cmax and AUC of a single 15 mg dose of ponatinib by 47% and 78%,|
01557|194|D|respectively.(15)|
01557|195|D|   In healthy subjects, ketoconazole (200 mg twice daily for 4 days)|
01557|196|D|increased the Cmax, AUC, and half-life of a single dose of ruxolitinib (10|
01557|197|D|mg) by 33%, 91%, and 62%, respectively.  There was also a corresponding|
01557|198|D|increase in pSTAT3 inhibition, a pharmacodynamic marker for ruxolitinib.(16)|
01557|199|D|   In healthy subjects, erythromycin (a moderate inhibitor of CYP3A4, 500 mg|
01557|200|D|twice daily for 4 days) increased the Cmax and AUC of a single dose of|
01557|201|D|ruxolitinib (10 mg) by 8% and 27%, respectively.  Therefore, no dosage|
01557|202|D|adjustment is recommended with moderate or mild inhibitors of CYP3A4.(16)|
01557|203|D|   In a study in healthy subjects, concurrent ketoconazole increased the|
01557|204|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 49% and|
01557|205|D|51%, respectively, of a single dose of sunitinib.(17)|
01557|206|D|   In a study, administration of ketoconazole, increased the AUC of|
01557|207|D|tofacitinib by more than 2-fold.(18)|
01557|208|D|   Strong CYP3A4 inhibitors include:  boceprevir, clarithromycin,|
01557|209|D|conivaptan, idelalisib, indinavir, itraconazole, ketoconazole,|
01557|210|D|lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, olaparib,|
01557|211|D|posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and|
01557|212|D|voriconazole.(19)|
01557|213|D|   One or more of the drug pairs linked to this monograph have been included|
01557|214|D|in a list of interactions that should be considered "high-priority" for|
01557|215|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01557|216|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01557|217|D|Coordinator (ONC) for Health Information Technology.|
01557|218|B||
01557|219|R|REFERENCES:|
01557|220|B||
01557|221|R|1.Inlyta (axitinib) US prescribing information. Pfizer Inc. June, 2020.|1
01557|222|R|2.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
01557|223|R|  2013.|1
01557|224|R|3.Cometriq (cabozantinib) US prescribing information. Exelixix, Inc.|1
01557|225|R|  November, 2012.|1
01557|226|R|4.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
01557|227|R|  Corporation April, 2014.|1
01557|228|R|5.Xalkori (crizotinib) US prescribing information. Pfizer Inc. November,|1
01557|229|R|  2013.|1
01557|230|R|6.Tafinlar (dabrafenib) US prescribing information. Novartis Pharmaceuticals|1
01557|231|R|  Corporation May, 2023.|1
01557|232|R|7.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01557|233|R|  Company June 2013.|1
01557|234|R|8.Imbruvica (ibrutinib) US Prescribing information. Janssen Biotech Inc.|1
01557|235|R|  November, 2013.|1
01557|236|R|9.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
01557|237|R|  October, 2020.|1
01557|238|R|10.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
01557|239|R|   2018.|1
01557|240|R|11.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01557|241|R|   Corporation September, 2014.|1
01557|242|R|12.Lynparza (olaparib) US prescribing information. AstraZenica|1
01557|243|R|   Pharmaceuticals December, 2014.|1
01557|244|R|13.Ibrance (palbociclib) US prescribing information. Pfizer Labs February 3,|1
01557|245|R|   2015.|1
01557|246|R|14.Votrient (pazopanib) US prescribing information. GlaxoSmithKline April,|1
01557|247|R|   2015.|1
01557|248|R|15.Iclusig (ponatinib) US prescribing information. ARIAD Pharmaceuticals|1
01557|249|R|   Inc. June, 2020.|1
01557|250|R|16.Jakafi (ruxolitinib) US prescribing information. Incyte Corporation|1
01557|251|R|   September, 2021.|1
01557|252|R|17.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. April,|1
01557|253|R|   2015.|1
01557|254|R|18.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. November,|1
01557|255|R|   2012.|1
01557|256|R|19.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
01557|257|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
01557|258|R|   hospital settings: a scientific statement from the American Heart|6
01557|259|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
01557|260|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
01557|261|R|20.US Food and Drug Administration (FDA). Drug Development and Drug|1
01557|262|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
01557|263|R|   at:|1
01557|264|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
01557|265|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01557|266|R|   11/14/2017.|1
01557|267|R|21.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01557|268|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01557|269|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01557|270|R|   19(5):735-43.|6
01558|001|T|MONOGRAPH TITLE:  Selected Antineoplastic Systemic Enzyme|
01558|002|T|Inhibitors/Selected Macrolides (mono deleted 09/01/2011)|
01558|003|B||
01558|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01558|005|L|of severe adverse interaction.|
01558|006|B||
01558|007|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01558|008|A|metabolism of dasatinib,(1) lapatinib,(2) nilotinib,(3) pazopanib,(4) and|
01558|009|A|sunitinib(5) by CYP P-450-3A4.|
01558|010|B||
01558|011|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin or telithromycin may|
01558|012|E|result in increase levels of and effects from dasatinib,(1) lapatinib(2),|
01558|013|E|nilotinib,(3) pazopanib,(4) or sunitinib,(5) including prolongation of the|
01558|014|E|QTc interval which may result in potentially life-threatening cardiac|
01558|015|E|arrhythmias, including torsades de pointes.|
01558|016|B||
01558|017|P|PREDISPOSING FACTORS:  None determined.|
01558|018|B||
01558|019|M|PATIENT MANAGEMENT:  The US manufacturer of dasatinib states that concurrent|
01558|020|M|use of CYP P-450-3A4 inhibitors such as clarithromycin or telithromycin|
01558|021|M|should be avoided.  If concurrent use is warranted, consider decreasing the|
01558|022|M|dose of dasatinib to 20 mg daily in patients taking dasatinib 100 mg daily|
01558|023|M|and to 40 mg daily in patients taking dasatinib 140 mg daily.  If this dose|
01558|024|M|is not tolerated, either the macrolide must be discontinued or dasatinib|
01558|025|M|should be stopped until macrolide therapy has been completed.  When the|
01558|026|M|macrolide has been discontinued, a one-week washout period should be allowed|
01558|027|M|before the dosage of dasatinib is increased.(1)|
01558|028|M|   The US manufacturer of lapatinib states that concurrent use of CYP|
01558|029|M|P-450-3A4 inhibitors such as clarithromycin or telithromycin should be|
01558|030|M|avoided.  If concurrent use is warranted, a dose reduction of lapatinib to|
01558|031|M|500 mg/day should be considered.  If the macrolide is discontinued, at least|
01558|032|M|1 week should elapse before the lapatinib dose is adjusted upward.(2)|
01558|033|M|   The US manufacturer of nilotinib states that concurrent use of CYP|
01558|034|M|P-450-3A4 inhibitors such as clarithromycin or telithromycin should be|
01558|035|M|avoided  and recommends that therapy with nilotinib be interrupted.  If|
01558|036|M|concurrent use is warranted, a dose reduction of nilotinib to 300 mg once|
01558|037|M|daily in patients with resistant or intolerant Ph+CML or to 200 mg once|
01558|038|M|daily in patients with newly diagnosed Ph+CML-CP should be considered.  If|
01558|039|M|the macrolide is discontinued, a washout period should occur before the|
01558|040|M|nilotinib dose is adjusted upward.(3)|
01558|041|M|   The US manufacturer of pazopanib states that the concurrent use of strong|
01558|042|M|CYP P-450-3A4 inhibitors should be avoided.  If concurrent administration is|
01558|043|M|warranted, the dosage of pazopanib should be reduced to 400 mg.  Additional|
01558|044|M|dosage reductions may be required if adverse events occur.(4)|
01558|045|M|   The US manufacturer of sunitinib recommends considering alternative|
01558|046|M|agents with no or minimal enzyme inhibition in place of CYP P-450-3A4|
01558|047|M|inhibitors such as clarithromycin or telithromycin.  If concurrent therapy|
01558|048|M|is warranted, a dosage reduction of sunitinib to a minimum of 37.5 mg daily|
01558|049|M|daily should be considered.(5)|
01558|050|M|   Patients receiving concurrent therapy should be monitored for QTc|
01558|051|M|prolongation.|
01558|052|B||
01558|053|D|DISCUSSION:  In a study in healthy subjects, concurrent ketoconazole (200 mg|
01558|054|D|twice daily), another CYP P-450-3A4 inhibitor, with dasatinib (20 mg)|
01558|055|D|increased dasatinib maximum concentration (Cmax) and area-under-curve (AUC)|
01558|056|D|by 4-fold and 5-fold, respectively.  Recommended dosage adjustments are|
01558|057|D|expected to adjust the dasatinib AUC to ranges observed without CYP|
01558|058|D|P-450-3A4 inhibitors; however, there are no clinical data available.(1)|
01558|059|D|   In a study in healthy subjects, ketoconazole (200 mg twice daily for 7|
01558|060|D|days) increased lapatinib AUC and half-life (T1/2) by 3.6-fold and 1.7-fold,|
01558|061|D|respectively.  The dosage adjustment to 500 mg/day is based on|
01558|062|D|pharmacokinetic studies and is predicted to adjust lapatinib AUC to the|
01558|063|D|range observed without inhibitors; however, there are no clinical data with|
01558|064|D|this dosage adjustment in patients receiving strong CYP P-450-3A4|
01558|065|D|inhibitors.(2)|
01558|066|D|   In a study in healthy subjects, concurrent ketoconazole (400 mg daily)|
01558|067|D|increased nilotinib AUC 3-fold.(3)|
01558|068|D|   Concurrent administration of oral pazopanib and CYP P-450-3A4 inhibitors|
01558|069|D|has resulted in elevated levels of pazopanib.  Administration of a single|
01558|070|D|dose of pazopanib ophthalmic drops and ketoconazole, an inhibitor of CYP|
01558|071|D|P-450-3A4 and Pgp, increase the AUC and Cmax of pazopanib by 220% and 150%,|
01558|072|D|respectively.  Administration of lapatinib (1500 mg), a weak inhibitor of|
01558|073|D|CYP P-450-3A4, Pgp, and BCRP, increased the AUC and Cmax of pazopanib (800|
01558|074|D|mg) by 50% and 60%, respectively.  Decreasing the dosage of pazopanib to 400|
01558|075|D|mg in patients receiving strong CYP P-450-3A4 inhibitors is expected to|
01558|076|D|adjust the AUC of pazopanib to the normal range; however, there are no|
01558|077|D|clinical data available to support this.(4)|
01558|078|D|  In a study in healthy subjects, concurrent ketoconazole increased the|
01558|079|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 49% and|
01558|080|D|51%, respectively, of a single dose of sunitinib.(5)|
01558|081|B||
01558|082|R|REFERENCES:|
01558|083|B||
01558|084|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01558|085|R|  Company October, 2010.|1
01558|086|R|2.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline January 29,|1
01558|087|R|  2010.|1
01558|088|R|3.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01558|089|R|  Corporation January, 2011.|1
01558|090|R|4.Votrient (pazopanib) US prescribing information. GlaxoSmithKline October,|1
01558|091|R|  2009.|1
01558|092|R|5.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. July,|1
01558|093|R|  2010.|1
01559|001|T|MONOGRAPH TITLE:  Slt Antineoplastic Systemic Enzyme Inhib/Nefazodone (mono|
01559|002|T|deleted 09/01/2011)|
01559|003|B||
01559|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01559|005|L|of severe adverse interaction.|
01559|006|B||
01559|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of dasatinib,(1)|
01559|008|A|lapatinib,(2) nilotinib,(3) pazopanib,(4) and sunitinib(5) by CYP P-450-3A4.|
01559|009|B||
01559|010|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may increase levels of and|
01559|011|E|effects from dasatinib,(1) lapatinib,(2) nilotinib,(3) pazopanib,(4) and|
01559|012|E|sunitinib.(5)|
01559|013|B||
01559|014|P|PREDISPOSING FACTORS:  None determined.|
01559|015|B||
01559|016|M|PATIENT MANAGEMENT:  The US manufacturer of dasatinib states that concurrent|
01559|017|M|use of CYP P-450-3A4 inhibitors such as nefazodone should be avoided.  If|
01559|018|M|concurrent use is warranted, consider decreasing the dose of dasatinib to 20|
01559|019|M|mg daily in patients taking dasatinib 100 mg daily and to 40 mg daily in|
01559|020|M|patients taking dasatinib 140 mg daily.  If this dose is not tolerated,|
01559|021|M|either nefazodone must be discontinued or dasatinib should be stopped until|
01559|022|M|nefazodone therapy has been completed.  When the nefazodone has been|
01559|023|M|discontinued, a one-week washout period should be allowed before the dosage|
01559|024|M|of dasatinib is increased.(1)|
01559|025|M|   The US manufacturer of lapatinib states that concurrent use of CYP|
01559|026|M|P-450-3A4 inhibitors such as nefazodone should be avoided.  If concurrent|
01559|027|M|use is warranted, a dose reduction of lapatinib to 500 mg/day should be|
01559|028|M|considered.  If nefazodone is discontinued, at least 1 week should elapse|
01559|029|M|before the lapatinib dose is adjusted upward.(2)|
01559|030|M|   The US manufacturer of nilotinib states that concurrent use of CYP|
01559|031|M|P-450-3A4 inhibitors such as nefazodone should be avoided and recommends|
01559|032|M|that therapy with nilotinib be interrupted.  If concurrent use is warranted,|
01559|033|M|a dose reduction of nilotinib to 300 mg once daily in patients with|
01559|034|M|resistant or intolerant Ph+CML or to 200 mg once daily in patients with|
01559|035|M|newly diagnosed Ph+CML-CP should be considered.  If nefazodone is|
01559|036|M|discontinued, a washout period should occur before the nilotinib dose is|
01559|037|M|adjusted upward.(3)|
01559|038|M|   The US manufacturer of pazopanib states that the concurrent use of strong|
01559|039|M|CYP P-450-3A4 inhibitors should be avoided.  If concurrent administration is|
01559|040|M|warranted, the dosage of pazopanib should be reduced to 400 mg.  Additional|
01559|041|M|dosage reductions may be required if adverse events occur.(4)|
01559|042|M|   The US manufacturer of sunitinib recommends considering alternative|
01559|043|M|agents with no or minimal enzyme inhibition in place of CYP P-450-3A4|
01559|044|M|inhibitors such as nefazodone.  If concurrent therapy is warranted, a dosage|
01559|045|M|reduction of sunitinib to a minimum of 37.5 mg daily should be|
01559|046|M|considered.(5)|
01559|047|M|   Patients receiving concurrent therapy should be monitored for QTc|
01559|048|M|prolongation.|
01559|049|B||
01559|050|D|DISCUSSION:  In a study in healthy subjects, concurrent ketoconazole (200 mg|
01559|051|D|twice daily), another CYP P-450-3A4 inhibitor, with dasatinib (20 mg)|
01559|052|D|increased dasatinib maximum concentration (Cmax) and area-under-curve (AUC)|
01559|053|D|by 4-fold and 5-fold, respectively.  Recommended dosage adjustments are|
01559|054|D|expected to adjust the dasatinib AUC to ranges observed without CYP|
01559|055|D|P-450-3A4 inhibitors; however, there are no clinical data available.(1)|
01559|056|D|   In a study in healthy subjects, ketoconazole (200 mg twice daily for 7|
01559|057|D|days) increased lapatinib AUC and half-life (T1/2) by 3.6-fold and 1.7-fold,|
01559|058|D|respectively.  The dosage adjustment to 500 mg/day is based on|
01559|059|D|pharmacokinetic studies and is predicted to adjust lapatinib AUC to the|
01559|060|D|range observed without inhibitors; however, there are no clinical data with|
01559|061|D|this dosage adjustment in patients receiving strong CYP P-450-3A4|
01559|062|D|inhibitors.(2)|
01559|063|D|   In a study in healthy subjects, concurrent ketoconazole (400 mg daily)|
01559|064|D|increased nilotinib AUC 3-fold.(3)|
01559|065|D|   Concurrent administration of oral pazopanib and CYP P-450-3A4 inhibitors|
01559|066|D|has resulted in elevated levels of pazopanib.  Administration of a single|
01559|067|D|dose of pazopanib ophthalmic drops and ketoconazole, an inhibitor of CYP|
01559|068|D|P-450-3A4 and Pgp, increase the AUC and Cmax of pazopanib by 220% and 150%,|
01559|069|D|respectively.  Administration of lapatinib (1500 mg), a weak inhibitor of|
01559|070|D|CYP P-450-3A4, Pgp, and BCRP, increased the AUC and Cmax of pazopanib (800|
01559|071|D|mg) by 50% and 60%, respectively.  Decreasing the dosage of pazopanib to 400|
01559|072|D|mg in patients receiving strong CYP P-450-3A4 inhibitors is expected to|
01559|073|D|adjust the AUC of pazopanib to the normal range; however, there are no|
01559|074|D|clinical data available to support this.(4)|
01559|075|D|  In a study in healthy subjects, concurrent ketoconazole increased the|
01559|076|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 49% and|
01559|077|D|51%, respectively, of a single dose of sunitinib.(5)|
01559|078|B||
01559|079|R|REFERENCES:|
01559|080|B||
01559|081|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01559|082|R|  Company October, 2010.|1
01559|083|R|2.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline January 29,|1
01559|084|R|  2010.|1
01559|085|R|3.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01559|086|R|  Corporation January, 2011.|1
01559|087|R|4.Votrient (pazopanib) US prescribing information. GlaxoSmithKline October,|1
01559|088|R|  2009.|1
01559|089|R|5.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. July,|1
01559|090|R|  2010.|1
01560|001|T|MONOGRAPH TITLE:  Slt Antineo Systemic Enzyme Inhib/Slt Protease Inh (mono|
01560|002|T|deleted 09/01/2011)|
01560|003|B||
01560|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01560|005|L|of severe adverse interaction.|
01560|006|B||
01560|007|A|MECHANISM OF ACTION:  Atazanavir, indinavir, nelfinavir, ritonavir, and|
01560|008|A|saquinavir may inhibit the metabolism of dasatinib,(1) lapatinib,(2)|
01560|009|A|nilotinib,(3) pazopanib,(4) and sunitinib(5) by CYP P-450-3A4.|
01560|010|B||
01560|011|E|CLINICAL EFFECTS:  Concurrent use of atazanavir, indinavir, nelfinavir,|
01560|012|E|ritonavir, or saquinavir may increase levels of and effects from dasatinib,|
01560|013|E|(1) lapatinib,(2) nilotinib,(3) pazopanib,(4) or sunitinib.(5)|
01560|014|B||
01560|015|P|PREDISPOSING FACTORS:  None determined.|
01560|016|B||
01560|017|M|PATIENT MANAGEMENT:  The US manufacturer of dasatinib states that concurrent|
01560|018|M|use of CYP P-450-3A4 inhibitors such as atazanavir, indinavir, nelfinavir,|
01560|019|M|ritonavir, or saquinavir should be avoided.  If concurrent use is warranted,|
01560|020|M|consider decreasing the dose of dasatinib to 20 mg daily in patients taking|
01560|021|M|dasatinib 100 mg daily and to 40 mg daily in patients taking dasatinib 140|
01560|022|M|mg daily.  If this dose is not tolerated, either the protease inhibitor must|
01560|023|M|be discontinued or dasatinib should be stopped until protease inhibitor|
01560|024|M|therapy is discontinued.  When the protease inhibitor has been discontinued,|
01560|025|M|a one-week washout period should be allowed before the dosage of dasatinib|
01560|026|M|is increased.(1)|
01560|027|M|   The US manufacturer of lapatinib states that concurrent use of CYP|
01560|028|M|P-450-3A4 inhibitors such as atazanavir, indinavir, nelfinavir, ritonavir,|
01560|029|M|or saquinavir be avoided.  If concurrent use is warranted, a dose reduction|
01560|030|M|of lapatinib to 500 mg/day should be considered.  If the protease inhibitor|
01560|031|M|is discontinued, at least 1 week should elapse before the lapatinib dose is|
01560|032|M|adjusted upward.(2)|
01560|033|M|   The US manufacturer of nilotinib states that concurrent use of CYP|
01560|034|M|P-450-3A4 inhibitors such as atazanavir, indinavir, nelfinavir, ritonavir,|
01560|035|M|or saquinavir be avoided and recommends that therapy with nilotinib be|
01560|036|M|interrupted.  If concurrent use is warranted, a dose reduction of nilotinib|
01560|037|M|to 300 mg once daily in patients with resistant or intolerant Ph+CML or to|
01560|038|M|200 mg once daily in patients with newly diagnosed Ph+CML-CP should be|
01560|039|M|considered.  If the protease inhibitor is discontinued, a washout period|
01560|040|M|should occur before the nilotinib dose is adjusted upward.(3)|
01560|041|M|   The US manufacturer of pazopanib states that the concurrent use of strong|
01560|042|M|CYP P-450-3A4 inhibitors should be avoided.  If concurrent administration is|
01560|043|M|warranted, the dosage of pazopanib should be reduced to 400 mg.  Additional|
01560|044|M|dosage reductions may be required if adverse events occur.(4)|
01560|045|M|   The US manufacturer of sunitinib recommends considering alternative|
01560|046|M|agents with no or minimal enzyme inhibition in place of CYP P-450-3A4|
01560|047|M|inhibitors such as atazanavir, indinavir, nelfinavir, ritonavir, or|
01560|048|M|saquinavir.  If concurrent therapy is warranted, a dosage reduction of|
01560|049|M|sunitinib to a minimum of 37.5 mg daily should be considered.(5)|
01560|050|M|   Patients receiving concurrent therapy should be monitored for QTc|
01560|051|M|prolongation.|
01560|052|B||
01560|053|D|DISCUSSION:  In a study in healthy subjects, concurrent ketoconazole (200 mg|
01560|054|D|twice daily), another CYP P-450-3A4 inhibitor, with dasatinib (20 mg)|
01560|055|D|increased dasatinib maximum concentration (Cmax) and area-under-curve (AUC)|
01560|056|D|by 4-fold and 5-fold, respectively.  Recommended dosage adjustments are|
01560|057|D|expected to adjust the dasatinib AUC to ranges observed without CYP|
01560|058|D|P-450-3A4 inhibitors; however, there are no clinical data available.(1)|
01560|059|D|   In a study in healthy subjects, ketoconazole (200 mg twice daily for 7|
01560|060|D|days) increased lapatinib AUC and half-life (T1/2) by 3.6-fold and 1.7-fold,|
01560|061|D|respectively.  The dosage adjustment to 500 mg/day is based on|
01560|062|D|pharmacokinetic studies and is predicted to adjust lapatinib AUC to the|
01560|063|D|range observed without inhibitors; however, there are no clinical data with|
01560|064|D|this dosage adjustment in patients receiving strong CYP P-450-3A4|
01560|065|D|inhibitors.(2)|
01560|066|D|   In a study in healthy subjects, concurrent ketoconazole (400 mg daily)|
01560|067|D|increased nilotinib AUC 3-fold.(3)|
01560|068|D|   Concurrent administration of oral pazopanib and CYP P-450-3A4 inhibitors|
01560|069|D|has resulted in elevated levels of pazopanib.  Administration of a single|
01560|070|D|dose of pazopanib ophthalmic drops and ketoconazole, an inhibitor of CYP|
01560|071|D|P-450-3A4 and Pgp, increase the AUC and Cmax of pazopanib by 220% and 150%,|
01560|072|D|respectively.  Administration of lapatinib (1500 mg), a weak inhibitor of|
01560|073|D|CYP P-450-3A4, Pgp, and BCRP, increased the AUC and Cmax of pazopanib (800|
01560|074|D|mg) by 50% and 60%, respectively.  Decreasing the dosage of pazopanib to 400|
01560|075|D|mg in patients receiving strong CYP P-450-3A4 inhibitors is expected to|
01560|076|D|adjust the AUC of pazopanib to the normal range; however, there are no|
01560|077|D|clinical data available to support this.(4)|
01560|078|D|  In a study in healthy subjects, concurrent ketoconazole increased the|
01560|079|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 49% and|
01560|080|D|51%, respectively, of a single dose of sunitinib.(5)|
01560|081|B||
01560|082|R|REFERENCES:|
01560|083|B||
01560|084|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01560|085|R|  Company October, 2010.|1
01560|086|R|2.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline January 29,|1
01560|087|R|  2010.|1
01560|088|R|3.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01560|089|R|  Corporation January, 2011.|1
01560|090|R|4.Votrient (pazopanib) US prescribing information. GlaxoSmithKline October,|1
01560|091|R|  2009.|1
01560|092|R|5.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. July,|1
01560|093|R|  2010.|1
01561|001|T|MONOGRAPH TITLE:  Bosutinib/Strong CYP3A4 Inducers|
01561|002|B||
01561|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01561|004|L|of severe adverse interaction.|
01561|005|B||
01561|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
01561|007|A|metabolism of bosutinib.(1)|
01561|008|B||
01561|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
01561|010|E|levels and effectiveness of bosutinib.(1)|
01561|011|B||
01561|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01561|013|P|of the inducer for longer than 1-2 weeks.|
01561|014|B||
01561|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
01561|016|M|patients receiving therapy with bosutinib.  Consider the use of alternative|
01561|017|M|agents with less enzyme induction potential.(1)|
01561|018|B||
01561|019|D|DISCUSSION:  In a study in 24 healthy subjects, rifampin decreased bosutinib|
01561|020|D|area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%.(1)|
01561|021|D|   In a study, 24 healthy subjects received a single dose of bosutinib 500|
01561|022|D|mg (days 1 and 14) and rifampin 600 mg (days 8-17). Bosutinib Cmax and AUC|
01561|023|D|decreased by 86% and 92%, respectively.  Bosutinib clearance increased by|
01561|024|D|13-fold.(2)|
01561|025|D|   Strong inducers of CYP3A4 include:  barbiturates, encorafenib,|
01561|026|D|enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin,|
01561|027|D|primidone, rifampin, and rifapentine.(3,4)|
01561|028|B||
01561|029|R|REFERENCES:|
01561|030|B||
01561|031|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
01561|032|R|  2023.|1
01561|033|R|2.Abbas R, Boni J, Sonnichsen D. Effect of rifampin on the pharmacokinetics|2
01561|034|R|  of bosutinib, a dual Src/Abl tyrosine  kinase inhibitor, when administered|2
01561|035|R|  concomitantly to healthy subjects. Drug Metab Pers Ther 2015 Mar;|2
01561|036|R|  30(1):57-63.|2
01561|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
01561|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01561|039|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
01561|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01561|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01561|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01561|043|R|  11/14/2017.|1
01562|001|T|MONOGRAPH TITLE:  Selected Antineoplastic Systemic Enzyme|
01562|002|T|Inhibitors/Selected Anticonvulsants (mono deleted 09/01/2011)|
01562|003|B||
01562|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01562|005|L|of severe adverse interaction.|
01562|006|B||
01562|007|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital, and phenytoin may induce|
01562|008|A|the metabolism of antineoplastic systemic enzyme inhibitors, including|
01562|009|A|dasatinib,(1) erlotinib,(2) imatinib,(3) lapatinib,(4) nilotinib,(5)|
01562|010|A|pazopanib,(6) sorafenib,(7) sunitinib,(8) and vandetanib(9) by CYP|
01562|011|A|P-450-3A4.|
01562|012|B||
01562|013|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, phenobarbital, or|
01562|014|E|phenytoin may decrease the levels and effectiveness of antineoplastic|
01562|015|E|systemic enzyme inhibitors, including dasatinib,(1) erlotinib,(2)|
01562|016|E|imatinib,(3) lapatinib,(4) nilotinib,(5) pazopanib,(6) sorafenib,(7)|
01562|017|E|sunitinib,(8) and vandetanib(9)|
01562|018|B||
01562|019|P|PREDISPOSING FACTORS:  None determined.|
01562|020|B||
01562|021|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP P-450-3A4 such|
01562|022|M|as carbamazepine, phenobarbital, and phenytoin in patients receiving therapy|
01562|023|M|with antineoplastic enzyme inhibitors.  Consider the use of alternative|
01562|024|M|agents with less enzyme induction potential.(1-9)|
01562|025|M|   If concurrent use with dasatinib is warranted, consider increasing the|
01562|026|M|dose of dasatinib.(1)|
01562|027|M|   If concurrent therapy with erlotinib cannot be avoided, consider|
01562|028|M|increasing the dosage of erlotinib as tolerated at two week intervals while|
01562|029|M|closely monitoring the patient.  The highest dosage studied with a|
01562|030|M|concurrent CYP P-450-3A4 inducer (rifampin) is 450 mg.  If the dosage of|
01562|031|M|erlotinib is increased, it will need to be decreased if carbamazepine,|
01562|032|M|phenobarbital, or phenytoin is discontinued.(2)|
01562|033|M|   If concurrent therapy with imatinib is required, the dosage of imatinib|
01562|034|M|should be increased by 50% and clinical response be carefully monitored.|
01562|035|M|Dosages up to 1200 mg/day (600 mg twice daily) have been used in patients|
01562|036|M|receiving concurrent therapy with strong CYP P-450-3A4 inducers.(3)|
01562|037|M|   If concurrent therapy with lapatinib is warranted, the dose of lapatinib|
01562|038|M|should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2|
01562|039|M|positive metastatic breast cancer indication) or from 1,500 mg/day up to|
01562|040|M|5,500 mg/day (hormone receptor positive, HER2 positive breast cancer|
01562|041|M|indication) based on patient tolerability.  If carbamazepine, phenobarbital,|
01562|042|M|or phenytoin is discontinued, the dose of lapatinib should be adjusted to|
01562|043|M|the normal dose.(4)|
01562|044|M|   Because of the nonlinear pharmacokinetic profile of nilotinib, increasing|
01562|045|M|its dose is unlikely to compensate for enzyme induction.(5)|
01562|046|M|   Pazopanib should not be administered to patients who cannot avoid chronic|
01562|047|M|use of strong CYP P-450-3A4 inducers.(6)|
01562|048|M|   If concurrent therapy with sorafenib is warranted, a dosage increase of|
01562|049|M|sorafenib should be considered and the patient monitored carefully for|
01562|050|M|toxicity.(7)|
01562|051|M|   If concurrent therapy with sunitinib is warranted, a dosage increase of|
01562|052|M|sunitinib to a maximum of 87.5 mg daily should be considered.(8)|
01562|053|B||
01562|054|D|DISCUSSION:  In a study in healthy subjects, concurrent rifampin (600 mg|
01562|055|D|daily), another CYP P-450-3A4 inducer, decreased the maximum concentration|
01562|056|D|(Cmax) and area-under-curve (AUC) of a single dose of dasatinib by 81% and|
01562|057|D|82%, respectively.(1)|
01562|058|D|   Pretreatment and concurrent therapy with rifampin increased erlotinib|
01562|059|D|clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by|
01562|060|D|66% to 80%.  This is equivalent to a dose of about 30 mg to 50 mg in|
01562|061|D|NSCLC.(2)|
01562|062|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
01562|063|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
01562|064|D|150 mg dose of erlotinib.(2)|
01562|065|D|   In a preclinical trial with imatinib, pretreatment of 14 healthy subjects|
01562|066|D|with rifampin (600 mg daily for 8 days) increased the clearance of a single|
01562|067|D|dose of imatinib (400 mg) by 3.8-fold. The area-under-curve (AUC) and|
01562|068|D|maximum concentration (Cmax) decreased by 74% and 54%, respectively.(3)|
01562|069|D|   In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200|
01562|070|D|mg twice daily for 17 days), another CYP P-450-3A4 inducer, decreased the|
01562|071|D|AUC of lapatinib by 72%.  The dose adjustment recommendations are based on|
01562|072|D|pharmacokinetic studies and are predicted to adjust lapatinib AUC to the|
01562|073|D|range observed without concurrent CYP P-450-3A4 inducers; however, there are|
01562|074|D|no clinical data with these doses in patients receiving strong CYP P-450-3A4|
01562|075|D|inducers.(4)|
01562|076|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily for 12|
01562|077|D|days) decreased nilotinib AUC by 80%.(5)|
01562|078|D|   Pazopanib is primarily metabolized by CYP P-450-3A4.(6)|
01562|079|D|   Concurrent rifampin decreased sorafenib AUC by 37%.(7)|
01562|080|D|   In a study in healthy subjects, concurrent rifampin decreased the|
01562|081|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and|
01562|082|D|46%, respectively, of a single dose of sunitinib.(8)|
01562|083|D|   Strong CYP P-450-3A4 inducers are expected to alter vandetanib|
01562|084|D|concentrations.(9)|
01562|085|B||
01562|086|R|REFERENCES:|
01562|087|B||
01562|088|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01562|089|R|  Company October, 2010.|1
01562|090|R|2.Tarceva (erlotinib) US prescribing information. Genentech, Inc. April,|1
01562|091|R|  2010.|1
01562|092|R|3.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
01562|093|R|  Pharmaceuticals Corporation February, 2013.|1
01562|094|R|4.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline January 29,|1
01562|095|R|  2010.|1
01562|096|R|5.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01562|097|R|  Corporation January, 2011.|1
01562|098|R|6.Votrient (pazopanib) US prescribing information. GlaxoSmithKline October,|1
01562|099|R|  2009.|1
01562|100|R|7.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
01562|101|R|  Corporation March, 2011.|1
01562|102|R|8.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. July,|1
01562|103|R|  2010.|1
01562|104|R|9.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
01562|105|R|  Pharmaceuticals LP June, 2020.|1
01563|001|T|MONOGRAPH TITLE:  Selected Antineoplastic Systemic Enzyme|
01563|002|T|Inhibitors/Rifamycins (mono deleted 09/01/2011)|
01563|003|B||
01563|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01563|005|L|of severe adverse interaction.|
01563|006|B||
01563|007|A|MECHANISM OF ACTION:  Rifabutin, rifampin, and rifapentine may induce the|
01563|008|A|metabolism of antineoplastic systemic enzyme inhibitors, including|
01563|009|A|dasatinib,(1) erlotinib,(2) imatinib,(3) lapatinib,(4) nilotinib,(5)|
01563|010|A|pazopanib,(6) sorafenib,(7) sunitinib,(8) and vandetanib(9) by CYP|
01563|011|A|P-450-3A4.|
01563|012|B||
01563|013|E|CLINICAL EFFECTS:  Concurrent or recent use of rifabutin, rifampin, or|
01563|014|E|rifapentine may decrease the levels and effectiveness of antineoplastic|
01563|015|E|systemic enzyme inhibitors, including dasatinib,(1) erlotinib,(2)|
01563|016|E|imatinib,(3) lapatinib,(4) nilotinib,(5) pazopanib,(6) sorafenib,(7)|
01563|017|E|sunitinib,(8) and vandetanib(9)|
01563|018|B||
01563|019|P|PREDISPOSING FACTORS:  None determined.|
01563|020|B||
01563|021|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP P-450-3A4|
01563|022|M|inducers such as rifamycins in patients receiving therapy with|
01563|023|M|antineoplastic enzyme inhibitors.  Consider the use of alternative agents|
01563|024|M|with less enzyme induction potential.(1-9)|
01563|025|M|   If concurrent therapy with dasatinib is warranted, consider increasing|
01563|026|M|the dose of dasatinib.(1)|
01563|027|M|   If concurrent therapy with erlotinib cannot be avoided, consider|
01563|028|M|increasing the dosage of erlotinib as tolerated at two week intervals while|
01563|029|M|closely monitoring the patient.  The highest dosage studied with concurrent|
01563|030|M|rifampin is 450 mg.  If the dosage of erlotinib is increased, it will need|
01563|031|M|to be decreased when the rifamycin is discontinued.(2)|
01563|032|M|   If concurrent use with imatinib is required, the dosage of imatinib|
01563|033|M|should be increased by 50% and clinical response be carefully monitored.|
01563|034|M|Dosages up to 1200 mg/day (600 mg twice daily) have been used in patients|
01563|035|M|receiving concurrent therapy with strong CYP P-450-3A4 inducers.(3)|
01563|036|M|   If concurrent therapy with lapatinib is warranted, the dose of lapatinib|
01563|037|M|should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2|
01563|038|M|positive metastatic breast cancer indication) or from 1,500 mg/day up to|
01563|039|M|5,500 mg/day (hormone receptor positive, HER2 positive breast cancer|
01563|040|M|indication) based on patient tolerability.  If rifabutin, rifampin, or|
01563|041|M|rifapentine is discontinued, the dose of lapatinib should be adjusted to the|
01563|042|M|normal dose.(4)|
01563|043|M|   Because of the nonlinear pharmacokinetic profile of nilotinib, increasing|
01563|044|M|the dose of nilotinib is unlikely to compensate for enzyme induction.(5)|
01563|045|M|   Pazopanib should not be administered to patients who cannot avoid chronic|
01563|046|M|use of strong CYP P-450-3A4 inducers.(6)|
01563|047|M|   If concurrent therapy with sorafenib is warranted, a dosage increase of|
01563|048|M|sorafenib should be considered and the patient monitored carefully for|
01563|049|M|toxicity.(7)|
01563|050|M|   If concurrent therapy with sunitinib is warranted, a dosage increase of|
01563|051|M|sunitinib to a maximum of 87.5 mg daily should be considered.(8)|
01563|052|B||
01563|053|D|DISCUSSION:  In a study in healthy subjects, concurrent rifampin (600 mg|
01563|054|D|daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC)|
01563|055|D|of a single dose of dasatinib by 81% and 82%, respectively.(1)|
01563|056|D|   Pretreatment and concurrent therapy with rifampin increased erlotinib|
01563|057|D|clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by|
01563|058|D|66% to 80%.  This is equivalent to a dose of about 30 mg to 50 mg in NSCLC|
01563|059|D|patients.(2)|
01563|060|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
01563|061|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
01563|062|D|150 mg dose of erlotinib.(2)|
01563|063|D|   Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10|
01563|064|D|days) increased the clearance of a single dose of imatinib (400 mg) by|
01563|065|D|3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax)|
01563|066|D|decreased by 74% and 54%, respectively.(3,10)  The Cmax of the CGP74588|
01563|067|D|metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(10)|
01563|068|D|   In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200|
01563|069|D|mg twice daily for 17 days), another CYP P-450-3A4 inducer, decreased the|
01563|070|D|AUC of lapatinib by 72%.  The dose adjustment recommendations are based on|
01563|071|D|pharmacokinetic studies and are predicted to adjust lapatinib AUC to the|
01563|072|D|range observed without concurrent CYP P-450-3A4 inducers; however, there are|
01563|073|D|no clinical data with these doses in patients receiving strong CYP P-450-3A4|
01563|074|D|inducers.(4)|
01563|075|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily for 12|
01563|076|D|days) decreased nilotinib AUC by 80%.(5)|
01563|077|D|   Pazopanib is primarily metabolized by CYP P-450-3A4.(6)|
01563|078|D|   Concurrent rifampin decreased sorafenib AUC by 37%.(7)|
01563|079|D|   In a study in healthy subjects, concurrent rifampin decreased the|
01563|080|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and|
01563|081|D|46%, respectively, of a single dose of sunitinib.(8)|
01563|082|D|   Strong CYP P-450-3A4 inducers are expected to alter vandetanib|
01563|083|D|concentrations.(9)|
01563|084|B||
01563|085|R|REFERENCES:|
01563|086|B||
01563|087|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01563|088|R|  Company October, 2010.|1
01563|089|R|2.Tarceva (erlotinib) US prescribing information. Genentech, Inc. April,|1
01563|090|R|  2010.|1
01563|091|R|3.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
01563|092|R|  Pharmaceuticals Corporation February, 2013.|1
01563|093|R|4.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline January 29,|1
01563|094|R|  2010.|1
01563|095|R|5.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01563|096|R|  Corporation January, 2011.|1
01563|097|R|6.Votrient (pazopanib) US prescribing information. GlaxoSmithKline October,|1
01563|098|R|  2009.|1
01563|099|R|7.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
01563|100|R|  Corporation March, 2011.|1
01563|101|R|8.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. July,|1
01563|102|R|  2010.|1
01563|103|R|9.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
01563|104|R|  Pharmaceuticals LP June, 2020.|1
01563|105|R|10.Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U,|2
01563|106|R|   Seiberling M. Effect of rifampicin on the pharmacokinetics of imatinib|2
01563|107|R|   mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother|2
01563|108|R|   Pharmacol 2004 Feb;53(2):102-6.|2
01564|001|T|MONOGRAPH TITLE:  Selected Antineoplastic Systemic Enzyme Inhibitors/St.|
01564|002|T|John's Wort|
01564|003|B||
01564|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01564|005|L|is contraindicated and generally should not be dispensed or administered to|
01564|006|L|the same patient.|
01564|007|B||
01564|008|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01564|009|A|cabozantinib,(1) nilotinib,(2) and sunitinib(3) by CYP3A4.|
01564|010|B||
01564|011|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in|
01564|012|E|unpredictable decreases in the levels and effectiveness of cabozantinib,(1)|
01564|013|E|nilotinib,(2) and sunitinib.(3)|
01564|014|B||
01564|015|P|PREDISPOSING FACTORS:  None determined.|
01564|016|B||
01564|017|M|PATIENT MANAGEMENT:  The US manufacturers of cabozantinib,(1) nilotinib,(2)|
01564|018|M|and sunitinib(3) state that patients receiving these agents should not take|
01564|019|M|St. John's wort.|
01564|020|B||
01564|021|D|DISCUSSION:  In a study in healthy subjects, concurrent rifampin (600 mg|
01564|022|D|daily for 31 days, another potent inducer of CYP3A4) decreased the|
01564|023|D|area-under-curve (AUC) of a single dose of cabozantinib by 77%.(1)|
01564|024|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily for 12|
01564|025|D|days) decreased nilotinib AUC by 80%.(2)|
01564|026|D|   In a study in healthy subjects, concurrent rifampin decreased the|
01564|027|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and|
01564|028|D|46%, respectively, of a single dose of sunitinib.(3)|
01564|029|B||
01564|030|R|REFERENCES:|
01564|031|B||
01564|032|R|1.Cometriq (cabozantinib) US prescribing information. Exelixix, Inc.|1
01564|033|R|  January, 2020.|1
01564|034|R|2.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01564|035|R|  Corporation September, 2021.|1
01564|036|R|3.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
01564|037|R|  2021.|1
01565|001|T|MONOGRAPH TITLE:  Ranolazine/QT Prolonging Agents|
01565|002|B||
01565|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01565|004|L|take action as needed.|
01565|005|B||
01565|006|A|MECHANISM OF ACTION:  Ranolazine prolongs the QTc interval in a dose-related|
01565|007|A|manner.  Use with other agents that prolong the QTc interval may result in|
01565|008|A|additive effects.(1)|
01565|009|B||
01565|010|E|CLINICAL EFFECTS:  Concurrent use of ranolazine and agents known to prolong|
01565|011|E|the QTc interval may result in prolongation of the QTc interval and|
01565|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
01565|013|B||
01565|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01565|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01565|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01565|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01565|018|P|gender, or advanced age.(4)|
01565|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01565|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01565|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01565|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01565|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01565|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01565|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01565|026|B||
01565|027|M|PATIENT MANAGEMENT:  The UK manufacturer of ranolazine states that|
01565|028|M|concurrent use with agents known to prolong the QT interval should be|
01565|029|M|approached with caution.(1)|
01565|030|M|   Patients should be instructed to inform their physician if they are|
01565|031|M|receiving any drugs that prolong the QTc interval.(2)|
01565|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01565|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01565|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01565|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01565|036|B||
01565|037|D|DISCUSSION:  Ranolazine has been shown to prolong the QTc interval in a|
01565|038|D|dose-related manner.(1,2)|
01565|039|D|   Agents that are linked to this monograph may have varying degrees of|
01565|040|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
01565|041|D|been shown to prolong the QTc interval either through their mechanism of|
01565|042|D|action, through studies on their effects on the QTc interval, or through|
01565|043|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01565|044|D|and/or postmarketing reports.(3)|
01565|045|B||
01565|046|R|REFERENCES:|
01565|047|B||
01565|048|R|1.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01565|049|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01565|050|R|2.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
01565|051|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01565|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01565|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01565|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01565|055|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01565|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01565|057|R|  settings: a scientific statement from the American Heart Association and|6
01565|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01565|059|R|  2;55(9):934-47.|6
01566|001|T|MONOGRAPH TITLE:  Ranolazine/Possible QT Prolonging Agents (mono deleted|
01566|002|T|02/18/2009)|
01566|003|B||
01566|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01566|005|L|of severe adverse interaction.|
01566|006|B||
01566|007|A|MECHANISM OF ACTION:  Ranolazine prolongs the QTc interval in a dose-related|
01566|008|A|manner.  Use with other agents that prolong the QTc interval may result in|
01566|009|A|additive effects.(1)|
01566|010|B||
01566|011|E|CLINICAL EFFECTS:  Concurrent use of ranolazine and agents known to prolong|
01566|012|E|the QTc interval may result in prolongation of the QTc interval and|
01566|013|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
01566|014|B||
01566|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by|
01566|016|P|cardiovascular disease, hypokalemia, hypomagnesemia, bradycardia, age,|
01566|017|P|female gender, and/or use of multiple medications.|
01566|018|B||
01566|019|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that|
01566|020|M|concurrent use with agents known to prolong the QT interval is|
01566|021|M|contraindicated.(1)|
01566|022|B||
01566|023|D|DISCUSSION:  Ranolazine has been shown to prolong the QTc interval in a|
01566|024|D|dose-related manner.(1)|
01566|025|D|   Agents that are linked to this monograph may have been associated with|
01566|026|D|torsades de pointes and/or QT prolongation but at this time lack substantial|
01566|027|D|evidence for causing torsades de pointes.(2)|
01566|028|B||
01566|029|R|REFERENCE:|
01566|030|B||
01566|031|R|1.Ranexa (ranolazine) US prescribing information. CV Therapeutics, Inc.|1
01566|032|R|  July, 2011.|1
01567|001|T|MONOGRAPH TITLE:  Ranolazine (Less than or Equal To 500 mg BID)/Moderate|
01567|002|T|CYP3A4 Inhibitors|
01567|003|B||
01567|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01567|005|L|take action as needed.|
01567|006|B||
01567|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
01567|008|A|metabolism of ranolazine.  Verapamil may also increase the absorption of|
01567|009|A|ranolazine by inhibiting P-glycoprotein.(1)|
01567|010|B||
01567|011|E|CLINICAL EFFECTS:  Concurrent use of moderate inhibitors of CYP3A4 may|
01567|012|E|result in elevated levels of and clinical effects from ranolazine.  Elevated|
01567|013|E|ranolazine levels may result in QTc prolongation, which may result in|
01567|014|E|life-threatening cardiac arrhythmia, including torsades de pointes.(1)|
01567|015|B||
01567|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01567|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
01567|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01567|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01567|020|P|female gender, or advanced age.(5)|
01567|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01567|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01567|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01567|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01567|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01567|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01567|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01567|028|B||
01567|029|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
01567|030|M|dosage of ranolazine should be limited to 500 mg twice daily in patients|
01567|031|M|receiving moderate inhibitors of CYP3A4.(1)|
01567|032|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
01567|033|M|monitoring ECG at baseline and at regular intervals.  Correct any|
01567|034|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01567|035|M|heartbeat, dizziness, or fainting.|
01567|036|B||
01567|037|D|DISCUSSION:  Concurrent use of diltiazem, a moderate inhibitor of CYP3A4, at|
01567|038|D|daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000|
01567|039|D|mg twice daily) by 50% and 130%, respectively.(1,3)  In healthy subjects,|
01567|040|D|concurrent ranolazine (1000 mg twice daily) had no effects on the|
01567|041|D|pharmacokinetics of diltiazem (60 mg three times daily).(1)|
01567|042|D|   Concurrent use of verapamil (120 mg three times daily) increased plasma|
01567|043|D|levels of ranolazine (750 mg twice daily) by 100%.(1)|
01567|044|D|   In a study in 12 healthy males, ranolazine immediate release (IR, 240 mg|
01567|045|D|three times daily) had no effect on diltiazem (60 mg three times daily)|
01567|046|D|pharmacokinetics. However, at ranolazine IR steady state, diltiazem|
01567|047|D|increased ranolazine IR area under the curve (AUC) by 85%, on average, and|
01567|048|D|increased maximum concentration (Cmax) by 1.9-fold and minimum concentration|
01567|049|D|(Cmin) by 2.1-fold.(4)|
01567|050|D|   In a study in 12 subjects, ranolazine sustained release (SR, 500 mg twice|
01567|051|D|daily) had no effect on diltiazem (60 mg three times daily)|
01567|052|D|pharmacokinetics. However, at ranolazine steady state, diltiazem increased|
01567|053|D|ranolazine SR Cmax, concentration minimum (Cmin), AUC by 80%, 216%, and 90%,|
01567|054|D|on average, respectively.(4)|
01567|055|D|   In a study in 8 healthy males, diltiazem modified release (MR, 180 mg, or|
01567|056|D|240 mg, or 360 mg, once daily) increased ranolazine sustained release (SR,|
01567|057|D|1000 mg twice daily) AUC by 52%, 93%, and 139%, respectively. Ranolazine|
01567|058|D|half-lives did not show any consistent trend of changes with increasing|
01567|059|D|doses of diltiazem.(4)|
01567|060|D|   In a study of patients with severe chronic angina, the addition of|
01567|061|D|ranolazine 750 mg twice daily or 1,000 mg twice daily along with their|
01567|062|D|standard dose of diltiazem (180 mg once daily) provided additional|
01567|063|D|antianginal relief, without evident adverse, long-term survival consequences|
01567|064|D|over 1 to 2 years of therapy.(5)|
01567|065|D|   Ranolazine-induced QTc prolongation is dose and concentration-related.(1)|
01567|066|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant, avacopan,|
01567|067|D|berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, erythromycin,|
01567|068|D|dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosamprenavir,|
01567|069|D|fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir,|
01567|070|D|letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol,|
01567|071|D|treosulfan and verapamil.(1,3,6,7)|
01567|072|B||
01567|073|R|REFERENCES:|
01567|074|B||
01567|075|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
01567|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01567|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01567|078|R|  settings: a scientific statement from the American Heart Association and|6
01567|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01567|080|R|  2;55(9):934-47.|6
01567|081|R|3.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01567|082|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01567|083|R|4.Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to|2
01567|084|R|  investigate the pharmacokinetic interactions between ranolazine and|2
01567|085|R|  ketoconazole, diltiazem, or simvastatin during combined administration in|2
01567|086|R|  healthy subjects. J Clin Pharmacol 2005 Apr;45(4):422-33.|2
01567|087|R|5.Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W,|2
01567|088|R|  Skettino SL, Wolff AA. Effects of ranolazine with atenolol, amlodipine, or|2
01567|089|R|  diltiazem on exercise tolerance and angina frequency in patients with|2
01567|090|R|  severe chronic angina: a randomized controlled trial. JAMA 2004 Jan 21;|2
01567|091|R|  291(3):309-16.|2
01567|092|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
01567|093|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01567|094|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01567|095|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01567|096|R|  11/14/2017.|1
01567|097|R|7.This information is based on an extract from the Certara Drug Interaction|6
01567|098|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01568|001|T|MONOGRAPH TITLE:  Ranolazine/Strong CYP3A4 Inhibitors; Protease Inhibitors|
01568|002|B||
01568|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01568|004|L|is contraindicated and generally should not be dispensed or administered to|
01568|005|L|the same patient.|
01568|006|B||
01568|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 and protease inhibitors|
01568|008|A|may inhibit the metabolism of ranolazine.(1,2)|
01568|009|B||
01568|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 or protease|
01568|011|E|inhibitors may result in elevated levels of and clinical effects from|
01568|012|E|ranolazine.  Elevated ranolazine levels may result in QTc prolongation,|
01568|013|E|which may result in life-threatening cardiac arrhythmia, including torsades|
01568|014|E|de pointes.(1,2)|
01568|015|B||
01568|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01568|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
01568|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01568|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01568|020|P|female gender, or advanced age.(3)|
01568|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01568|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01568|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01568|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01568|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01568|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01568|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01568|028|B||
01568|029|M|PATIENT MANAGEMENT:  The concurrent use of ranolazine with strong CYP3A4|
01568|030|M|inhibitors or protease inhibitors is contraindicated.(1,2,4-8)|
01568|031|M|   The US HIV guidelines state that ranolazine (regardless of dose) is|
01568|032|M|contraindicated with atazanavir when it is boosted with ritonavir.  If|
01568|033|M|atazanavir is not boosted with ritonavir, ranolazine should not be|
01568|034|M|coadministered.(8)|
01568|035|M|   The US manufacturer of itraconazole states that concurrent administration|
01568|036|M|of ranolazine is contraindicated during and two weeks after itraconazole|
01568|037|M|treatment.(9)|
01568|038|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01568|039|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01568|040|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01568|041|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01568|042|B||
01568|043|D|DISCUSSION:  Concurrent use of ketoconazole (200 mg twice daily), a strong|
01568|044|D|CYP3A4 inhibitor, increased plasma levels of ranolazine (1000 mg twice|
01568|045|D|daily) by 220%.(1)|
01568|046|D|   Concurrent use of diltiazem, a moderate inhibitor of CYP3A4 inhibitor, at|
01568|047|D|daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000|
01568|048|D|mg twice daily) by 50% and 140%, respectively.(1,2)   Concurrent use of|
01568|049|D|ranolazine (1000 mg twice daily) did not affect the pharmacokinetics of|
01568|050|D|diltiazem (60 mg TID).(1)|
01568|051|D|   Concurrent use of verapamil (120 mg three times daily), a moderate|
01568|052|D|inhibitor of CYP3A4 increased plasma levels of ranolazine (750 mg twice|
01568|053|D|daily) by 100%.(1)|
01568|054|D|   Ranolazine-induced QTc prolongation is dose and|
01568|055|D|concentration-related.(1,2)|
01568|056|D|   Strong CYP3A4 inhibitors and protease inhibitors linked to this monograph|
01568|057|D|include: boceprevir; cobicistat; idelalisib; itraconazole; josamycin;|
01568|058|D|ketoconazole; mibefradil; mifepristone; nefazodone; telaprevir;|
01568|059|D|troleandomycin; tucatinib; ritonavir-boosted darunavir, nirmatrelvir,|
01568|060|D|paritaprevir, and tipranavir; ritonavir-boosted or unboosted atazanavir or|
01568|061|D|indinavir; and nelfinavir.(1,2,10,11)  Ritonavir is always used with another|
01568|062|D|protease inhibitor as a pharmacokinetic booster and is captured as part of|
01568|063|D|the protease inhibitor regimen.|
01568|064|B||
01568|065|R|REFERENCES:|
01568|066|B||
01568|067|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
01568|068|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01568|069|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01568|070|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01568|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01568|072|R|  settings: a scientific statement from the American Heart Association and|6
01568|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01568|074|R|  2;55(9):934-47.|6
01568|075|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01568|076|R|  March, 2023.|1
01568|077|R|5.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01568|078|R|  Pharmaceuticals February, 2014.|1
01568|079|R|6.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01568|080|R|  Laboratories December, 2019.|1
01568|081|R|7.Liverpool Drug Interactions Group. HIV Drug Interactions. Available at:|6
01568|082|R|  https://hiv-druginteractions.org/.|6
01568|083|R|8.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01568|084|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01568|085|R|  HIV. Department of Health and Human Services. Available at|6
01568|086|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
01568|087|R|  new-guidelines June 13, 2021.|6
01568|088|R|9.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01568|089|R|  Products, L.P. February, 2024.|1
01568|090|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
01568|091|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
01568|092|R|   at:|1
01568|093|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
01568|094|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01568|095|R|   11/14/2017.|1
01568|096|R|11.This information is based on an extract from the Certara Drug Interaction|6
01568|097|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01569|001|T|MONOGRAPH TITLE:  Ranolazine/Protease Inhibitors (mono deleted 01/30/2014)|
01569|002|B||
01569|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01569|004|L|is contraindicated and generally should not be dispensed or administered to|
01569|005|L|the same patient.|
01569|006|B||
01569|007|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01569|008|A|ranolazine by CYP P-450-3A4.(1,2)|
01569|009|B||
01569|010|E|CLINICAL EFFECTS:  Concurrent protease inhibitors may result in elevated|
01569|011|E|levels of and clinical effects from ranolazine.  Elevated ranolazine levels|
01569|012|E|may result in QTc prolongation, which may result in life-threatening cardiac|
01569|013|E|arrhythmia, including torsades de pointes.(1,2)|
01569|014|B||
01569|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01569|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01569|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01569|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01569|019|P|female gender, or advanced age.(2)|
01569|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01569|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01569|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01569|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01569|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01569|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01569|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01569|027|B||
01569|028|M|PATIENT MANAGEMENT:  The US and UK manufacturer of ranolazine states that|
01569|029|M|concurrent use with potent CYP P-450-3A4 inhibitors including protease|
01569|030|M|inhibitors is contraindicated.(1,2)|
01569|031|B||
01569|032|D|DISCUSSION:  Concurrent use of diltiazem, another CYP P-450-3A4 inhibitor,|
01569|033|D|at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine|
01569|034|D|(1000 mg twice daily) by 1.5-fold and 2.4-fold, respectively.(2)|
01569|035|D|   Concurrent use of ketoconazole (200 mg twice daily), another CYP|
01569|036|D|P-450-3A4 inhibitor, increased plasma levels of ranolazine (1000 mg twice|
01569|037|D|daily) 3.2-fold.(1)|
01569|038|D|   Concurrent use of verapamil (120 mg three times daily) increased plasma|
01569|039|D|levels of ranolazine (1000 mg twice daily) by 2.2-fold.(2)|
01569|040|D|   Ranolazine-induced QTc prolongation is dose and|
01569|041|D|concentration-related.(1,2)|
01569|042|B||
01569|043|R|REFERENCES:|
01569|044|B||
01569|045|R|1.Ranexa (ranolazine) US prescribing information. CV Therapeutics, Inc.|1
01569|046|R|  July, 2011.|1
01569|047|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01569|048|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01569|049|R|  settings: a scientific statement from the American Heart Association and|6
01569|050|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01569|051|R|  2;55(9):934-47.|6
01570|001|T|MONOGRAPH TITLE:  Simvastatin (Less than or Equal To 20 mg);|
01570|002|T|Lovastatin/Ranolazine|
01570|003|B||
01570|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01570|005|L|take action as needed.|
01570|006|B||
01570|007|A|MECHANISM OF ACTION:  Ranolazine may inhibit the metabolism of lovastatin(3)|
01570|008|A|and simvastatin by CYP3A4.(1,2,4-6)|
01570|009|B||
01570|010|E|CLINICAL EFFECTS:  Concurrent ranolazine may result in elevated levels of|
01570|011|E|lovastatin(3) and simvastatin,(1,2,4-6) which may result in myopathy and|
01570|012|E|rhabdomyolysis.|
01570|013|B||
01570|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01570|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01570|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01570|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01570|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01570|019|P|transporter OATP1B1 may have increased statin concentrations and be|
01570|020|P|predisposed to myopathy or rhabdomyolysis.|
01570|021|B||
01570|022|M|PATIENT MANAGEMENT:  Do not exceed a dosage of 20 mg daily of simvastatin in|
01570|023|M|patients receiving concurrent therapy with ranolazine.(1,2,4-6)|
01570|024|M|   Consider a reduction of lovastatin dose with concurrent ranolazine.|
01570|025|B||
01570|026|D|DISCUSSION:  In healthy subjects, ranolazine (1000 mg twice daily) increased|
01570|027|D|plasma levels of simvastatin (80 mg daily) and its active metabolite each by|
01570|028|D|2-fold.(1)|
01570|029|D|   In healthy subjects, simvastatin (20 mg daily) had no effect on|
01570|030|D|ranolazine levels.(1)|
01570|031|D|   In a study in 17 healthy volunteers, simvastatin (80 mg daily) did not|
01570|032|D|have a significant effect on ranolazine sustained release (SR, 1750 mg|
01570|033|D|initial dose followed by 1000 mg twice daily) pharmacokinetics with the mean|
01570|034|D|area under the curve (AUC), maximum concentration (Cmax), and minimum|
01570|035|D|concentration (Cmin) being within 80% to 125%. In contrast, ranolazine SR|
01570|036|D|increased the Cmax of simvastatin lactone, simvastatin acid, and HMG-CoA|
01570|037|D|reductase inhibitor activity by 2-fold with the corresponding AUC increases|
01570|038|D|in the range of 40% to 60%.(2,7)|
01570|039|D|   In a case report, a patient had been maintained on simvastatin for 12|
01570|040|D|years, one of which with concurrent cyclosporine.  Two months after the|
01570|041|D|addition of carvedilol, diltiazem, and ranolazine, the patient developed|
01570|042|D|rhabdomyolysis.(8)|
01570|043|D|   In a case report, a patient had been maintained on a stable dose of|
01570|044|D|simvastatin (80 mg). Ten days after the addition of ranolazine (500 mg|
01570|045|D|extended release) was added to the patient's medication regimen, the patient|
01570|046|D|developed rhabdomyolysis.(9)|
01570|047|B||
01570|048|R|REFERENCES:|
01570|049|B||
01570|050|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
01570|051|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01570|052|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01570|053|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01570|054|R|  February, 2014.|1
01570|055|R|4.USFood and Drug Administration. FDA Drug Safety Communication: New|1
01570|056|R|  restrictions, contraindications, and dose limitations for Zocor|1
01570|057|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
01570|058|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01570|059|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
01570|060|R|  June 8, 2011.|1
01570|061|R|5.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
01570|062|R|  2023.|1
01570|063|R|6.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
01570|064|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
01570|065|R|7.Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to|2
01570|066|R|  investigate the pharmacokinetic interactions between ranolazine and|2
01570|067|R|  ketoconazole, diltiazem, or simvastatin during combined administration in|2
01570|068|R|  healthy subjects. J Clin Pharmacol 2005 Apr;45(4):422-33.|2
01570|069|R|8.Rifkin SI. Multiple drug interactions in a renal transplant patient|3
01570|070|R|  leading to simvastatin-induced rhabdomyolysis: a case report. Medscape J|3
01570|071|R|  Med 2008;10(11):264.|3
01570|072|R|9.Hylton AC, Ezekiel TO. Rhabdomyolysis in a patient receiving ranolazine|3
01570|073|R|  and simvastatin. Am J Health Syst Pharm 2010 Nov 1;67(21):1829-31.|3
01571|001|T|MONOGRAPH TITLE:  Digoxin/Ranolazine|
01571|002|B||
01571|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01571|004|L|take action as needed.|
01571|005|B||
01571|006|A|MECHANISM OF ACTION:  Ranolazine may increase the absorption of digoxin by|
01571|007|A|inhibiting P-glycoprotein.(1,2)|
01571|008|B||
01571|009|E|CLINICAL EFFECTS:  Concurrent ranolazine may result in elevated levels of|
01571|010|E|and toxicity from digoxin.(1,2)  Symptoms of digoxin toxicity can include|
01571|011|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
01571|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
01571|013|E|disturbances, and arrhythmias.|
01571|014|B||
01571|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
01571|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
01571|017|P|risk of digoxin toxicity.|
01571|018|B||
01571|019|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
01571|020|M|digoxin and ranolazine.  The dosage of digoxin may need to be adjusted by|
01571|021|M|30% to 50% or the frequency of administration may need to be reduced.(1-3)|
01571|022|B||
01571|023|D|DISCUSSION:  In healthy subjects, ranolazine (1000 mg twice daily) increased|
01571|024|D|plasma levels of digoxin (0.125 mg daily) by 1.5-fold.(1,2)|
01571|025|D|   In healthy subjects, digoxin (0.125 mg daily) had no effect on ranolazine|
01571|026|D|levels.(1)|
01571|027|D|   Concomitant administration of ranolazine with digoxin increased the|
01571|028|D|digoxin serum concentration 50%.(3)|
01571|029|B||
01571|030|R|REFERENCES:|
01571|031|B||
01571|032|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
01571|033|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01571|034|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01571|035|R|3.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
01571|036|R|  Pharmaceuticals, Inc. August, 2018.|1
01572|001|T|MONOGRAPH TITLE:  Ranolazine/Selected Azole Antifungals (mono deleted|
01572|002|T|01/30/2014)|
01572|003|B||
01572|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01572|005|L|is contraindicated and generally should not be dispensed or administered to|
01572|006|L|the same patient.|
01572|007|B||
01572|008|A|MECHANISM OF ACTION:  Some azole antifungals may inhibit the metabolism of|
01572|009|A|ranolazine by CYP P-450-3A4.(1,2)|
01572|010|B||
01572|011|E|CLINICAL EFFECTS:  Concurrent azole antifungals that are potent inhibitors|
01572|012|E|of CYP P-450-3A4 may result in elevated levels of and clinical effects from|
01572|013|E|ranolazine.  Elevated ranolazine levels may result in QTc prolongation,|
01572|014|E|which may result in life-threatening cardiac arrhythmia, including torsades|
01572|015|E|de pointes.(1,2)|
01572|016|B||
01572|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01572|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
01572|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01572|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01572|021|P|female gender, or advanced age.(4)|
01572|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01572|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01572|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01572|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01572|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01572|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01572|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01572|029|B||
01572|030|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that|
01572|031|M|concurrent use with potent CYP P-450-3A4 inhibitors such as itraconazole and|
01572|032|M|ketoconazole is contraindicated.(1)|
01572|033|M|   The UK manufacturer of ranolazine states that concurrent use with potent|
01572|034|M|CYP P-450-3A4 inhibitors such as itraconazole, ketoconazole, posaconazole,|
01572|035|M|and voriconazole is contraindicated.(1)|
01572|036|B||
01572|037|D|DISCUSSION:  Concurrent use of ketoconazole (200 mg twice daily), increased|
01572|038|D|plasma levels of ranolazine (1000 mg twice daily) by 3.2-fold.(1)|
01572|039|D|   Ranolazine-induced QTc prolongation is dose and concentration-related.(1)|
01572|040|D|   In one study, concomitant administration of either ranolazine sustained|
01572|041|D|release (SR, 375 mg twice daily) or ranolazine SR (1000 mg twice daily) with|
01572|042|D|ketoconazole (200 mg twice daily) resulted in an increase in ranolazine SR|
01572|043|D|minimum concentrations (Cmin), maximum concentration (Cmax), steady-state|
01572|044|D|concentration (Css), and concentration at 12 hours postdose by between 2.5|
01572|045|D|and 4.5-fold.(3)|
01572|046|B||
01572|047|R|REFERENCES:|
01572|048|B||
01572|049|R|1.Ranexa (ranolazine) US prescribing information. CV Therapeutics, Inc.|1
01572|050|R|  July, 2011.|1
01572|051|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01572|052|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01572|053|R|3.Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to|2
01572|054|R|  investigate the pharmacokinetic interactions between ranolazine and|2
01572|055|R|  ketoconazole, diltiazem, or simvastatin during combined administration in|2
01572|056|R|  healthy subjects. J Clin Pharmacol 2005 Apr;45(4):422-33.|2
01572|057|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01572|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01572|059|R|  settings: a scientific statement from the American Heart Association and|6
01572|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01572|061|R|  2;55(9):934-47.|6
01573|001|T|MONOGRAPH TITLE:  Warfarin/Selected Herbals That May Decrease Warfarin|
01573|002|T|Effects|
01573|003|B||
01573|004|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01573|005|L|Assess the risk to the patient and take action as needed.|
01573|006|B||
01573|007|A|MECHANISM OF ACTION:  Some alternative therapy agents may have coagulant|
01573|008|A|properties and antagonize the effects of warfarin.(1)|
01573|009|B||
01573|010|E|CLINICAL EFFECTS:  Concurrent use of warfarin and some alternative therapy|
01573|011|E|agents may result in decreased INR values and effectiveness of warfarin.(1)|
01573|012|B||
01573|013|P|PREDISPOSING FACTORS:  None determined.|
01573|014|B||
01573|015|M|PATIENT MANAGEMENT:  Advise patients against using alternative therapy|
01573|016|M|agents with warfarin and to report the initiation or discontinuation of any|
01573|017|M|alternative therapy agents.  If concurrent therapy is initiated or|
01573|018|M|discontinued, monitor for changes in INR values and clinical effects, as|
01573|019|M|well as signs of bleeding.(1)|
01573|020|B||
01573|021|D|DISCUSSION:  The following alternative therapy agents contain vitamin K and|
01573|022|D|can antagonize the effects of warfarin: broccoli, brussel sprouts, cabbage,|
01573|023|D|cauliflower, kale, parsley, and spinach.(1)|
01573|024|B||
01573|025|R|REFERENCE:|
01573|026|B||
01573|027|R|1.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
01573|028|R|  Squibb Company September, 2016.|1
01574|001|T|MONOGRAPH TITLE:  Warfarin/Agrimony|
01574|002|B||
01574|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01574|004|L|Assess the risk to the patient and take action as needed.|
01574|005|B||
01574|006|A|MECHANISM OF ACTION:  Agrimony contains salicylates and also has coagulant|
01574|007|A|properties.  Concurrent use may result in additive, synergist, or|
01574|008|A|antagonistic effects with warfarin.|
01574|009|B||
01574|010|E|CLINICAL EFFECTS:  Concurrent use of warfarin and agrimony may result in|
01574|011|E|changes in INR values (either increases or decreased) and changes in the|
01574|012|E|clinical effects of warfarin, including an increased risk of bleeding.(1)|
01574|013|B||
01574|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01574|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01574|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
01574|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01574|018|P|risk for bleeding (e.g. NSAIDs).|
01574|019|B||
01574|020|M|PATIENT MANAGEMENT:  Advise patients against using agrimony with warfarin|
01574|021|M|and to report the initiation or discontinuation of agrimony.|
01574|022|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01574|023|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01574|024|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01574|025|M|patients with any symptoms.|
01574|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01574|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01574|028|M|anticoagulation in patients with active pathologic bleeding.|
01574|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01574|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01574|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01574|032|M|and/or swelling.|
01574|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01574|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01574|035|M|initiating, altering the dose or discontinuing either drug.|
01574|036|B||
01574|037|D|DISCUSSION:  Agrimony contains salicylates and has coagulant properties.(1)|
01574|038|B||
01574|039|R|REFERENCE:|
01574|040|B||
01574|041|R|1.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
01574|042|R|  Squibb Company September, 2016.|1
01575|001|T|MONOGRAPH TITLE:  Posaconazole/QT Prolonging Agents|
01575|002|B||
01575|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01575|004|L|take action as needed.|
01575|005|B||
01575|006|A|MECHANISM OF ACTION:  Concurrent use of posaconazole and agents known to|
01575|007|A|prolong the QT interval may result in additive or synergistic effects on the|
01575|008|A|QTc Interval.(1)|
01575|009|B||
01575|010|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01575|011|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01575|012|E|torsades de pointes.|
01575|013|B||
01575|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01575|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01575|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01575|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01575|018|P|gender, or advanced age.(3)|
01575|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01575|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01575|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01575|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01575|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01575|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01575|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01575|026|B||
01575|027|M|PATIENT MANAGEMENT:  The UK manufacturer of posaconazole states that|
01575|028|M|posaconazole should be used with caution when given with other agents known|
01575|029|M|to prolong the QT interval.(1)|
01575|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01575|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01575|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01575|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01575|034|B||
01575|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01575|036|D|degrees of potential to prolong the QTc interval. Agents linked to this|
01575|037|D|monograph have been shown to prolong the QTc interval either through their|
01575|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01575|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01575|040|D|clinical trials and/or postmarketing reports.(2)|
01575|041|B||
01575|042|R|REFERENCES:|
01575|043|B||
01575|044|R|1.Noxafil (posaconazole) UK summary of product characteristics.|1
01575|045|R|  Schering-Plough Ltd. January, 2022.|1
01575|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01575|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01575|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01575|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01575|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01575|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01575|052|R|  settings: a scientific statement from the American Heart Association and|6
01575|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01575|054|R|  2;55(9):934-47.|6
01576|001|T|MONOGRAPH TITLE:  Halofantrine/Posaconazole|
01576|002|B||
01576|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01576|004|L|is contraindicated and generally should not be dispensed or administered to|
01576|005|L|the same patient.|
01576|006|B||
01576|007|A|MECHANISM OF ACTION:  Concurrent use of posaconazole and halofantrine may|
01576|008|A|result in additive or synergistic effects on the QTc interval.  Posaconazole|
01576|009|A|may also inhibit the metabolism of halofantrine by CYP3A4.(1,2)|
01576|010|B||
01576|011|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
01576|012|E|of halofantrine and/or prolongation of the QTc interval, which may result in|
01576|013|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)|
01576|014|B||
01576|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01576|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01576|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01576|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01576|019|P|female gender, or advanced age.(3)|
01576|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01576|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01576|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01576|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01576|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01576|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01576|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01576|027|B||
01576|028|M|PATIENT MANAGEMENT:  The US manufacturer of posaconazole states that the|
01576|029|M|concurrent use of agents that prolong the QTc interval that are metabolized|
01576|030|M|by CYP3A4, such as halofantrine, is contraindicated.(1)  The UK manufacturer|
01576|031|M|of posaconazole state that the concurrent use of halofantrine is|
01576|032|M|contraindicated.(2)|
01576|033|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01576|034|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01576|035|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01576|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01576|037|B||
01576|038|D|DISCUSSION:  Posaconazole has been shown to inhibit CYP3A4.  Elevated levels|
01576|039|D|of halofantrine may prolong the QTc interval.  Other azoles have been|
01576|040|D|associated with QTc prolongation.(1,2)|
01576|041|B||
01576|042|R|REFERENCES:|
01576|043|B||
01576|044|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01576|045|R|  January, 2022.|1
01576|046|R|2.Noxafil (posaconazole) UK summary of product characteristics.|1
01576|047|R|  Schering-Plough Ltd. January, 2022.|1
01576|048|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01576|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01576|050|R|  settings: a scientific statement from the American Heart Association and|6
01576|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01576|052|R|  2;55(9):934-47.|6
01577|001|T|MONOGRAPH TITLE:  Posaconazole/Rifamycins|
01577|002|B||
01577|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01577|004|L|of severe adverse interaction.|
01577|005|B||
01577|006|A|MECHANISM OF ACTION:  Rifamycins may induce the metabolism of posaconazole|
01577|007|A|by CYP3A4.(1,2)  Posaconazole may inhibit the metabolism of rifabutin.(2)|
01577|008|B||
01577|009|E|CLINICAL EFFECTS:  Concurrent use of rifamycins may result in decreased|
01577|010|E|levels and clinical effectiveness of posaconazole.(1,2)|
01577|011|E|   Concurrent use of posaconazole may result in elevated levels of and|
01577|012|E|toxicity from rifabutin, including uveitis and leukopenia.(2)|
01577|013|B||
01577|014|P|PREDISPOSING FACTORS:  None determined.|
01577|015|B||
01577|016|M|PATIENT MANAGEMENT:  The UK manufacturer of posaconazole states that|
01577|017|M|concurrent use of rifamycins should be avoided unless the benefit to the|
01577|018|M|patient outweighs the risk of concurrent therapy.(1)|
01577|019|M|   The US manufacturer of posaconazole states that concurrent use of|
01577|020|M|rifabutin should be avoided unless benefit outweighs the risk.  If|
01577|021|M|concurrent use is warranted, frequent monitoring of full blood counts and|
01577|022|M|for adverse effects such as uveitis and leucopenia should be performed.(2)|
01577|023|B||
01577|024|D|DISCUSSION:  Concurrent rifabutin (300 mg daily) decreased posaconazole|
01577|025|D|area-under-curve (AUC) and maximum concentration (Cmax) by 51% and 57%,|
01577|026|D|respectively.(1)|
01577|027|D|   Concurrent rifabutin (300 mg daily) with posaconazole (200 mg daily)|
01577|028|D|decreased posaconazole AUC and Cmax by 43% and 49%, respectively.  Rifabutin|
01577|029|D|AUC and Cmax increased by 72% and by 31%, respectively.(2)|
01577|030|B||
01577|031|R|REFERENCES:|
01577|032|B||
01577|033|R|1.Noxafil (posaconazole) UK summary of product characteristics.|1
01577|034|R|  Schering-Plough Ltd. January, 2022.|1
01577|035|R|2.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01577|036|R|  January, 2022.|1
01578|001|T|MONOGRAPH TITLE:  Posaconazole/Selected Anticonvulsants|
01578|002|B||
01578|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01578|004|L|of severe adverse interaction.|
01578|005|B||
01578|006|A|MECHANISM OF ACTION:  Posaconazole is primarily metabolized via|
01578|007|A|glucuronidation (UGT).(1)   Carbamazepine, phenobarbital, phenytoin, and|
01578|008|A|primidone induce one or more UGT pathways.(3)|
01578|009|B||
01578|010|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, phenobarbital,|
01578|011|E|primidone,(1) and phenytoin(1,2) may result in decreased levels and clinical|
01578|012|E|effectiveness of posaconazole.|
01578|013|B||
01578|014|P|PREDISPOSING FACTORS:  None determined.|
01578|015|B||
01578|016|M|PATIENT MANAGEMENT:  The US manufacturer of posaconazole states that|
01578|017|M|concurrent use of phenytoin, a UGT inducer, should be avoided unless the|
01578|018|M|benefit to the patient outweighs the risk of concurrent therapy.(1)|
01578|019|M|   The UK manufacturer of posaconazole states that concurrent use of|
01578|020|M|carbamazepine, phenobarbital, primidone, and phenytoin should be avoided|
01578|021|M|unless the benefit to the patient outweighs the risk of concurrent therapy.|
01578|022|M|   If concomitant therapy is required, therapeutic monitoring of|
01578|023|M|posaconazole concentrations should be considered to assure posaconazole|
01578|024|M|levels are sufficient(1) for prevention or treatment of fungal infections.|
01578|025|M|   In a posaconazole interaction study, concurrent low dose phenytoin (200|
01578|026|M|mg daily) decreased posaconazole area-under-curve (AUC) and maximum|
01578|027|M|concentration (Cmax) by 50% and 41%, respectively.(1,2)|
01578|028|M|   When carbamazepine, phenobarbital, primidone, or phenytoin is started in|
01578|029|M|a patient already taking posaconazole, the onset of induction is gradual;|
01578|030|M|maximal induction of posaconazole metabolism may not occur for 1-3 weeks|
01578|031|M|after initiation of the anticonvulsant.(3)|
01578|032|B||
01578|033|D|DISCUSSION:  Posaconazole is primarily metabolized via glucuronidation|
01578|034|D|(UGT).(1)|
01578|035|D|   Selected anticonvulsants, including carbamazepine, phenobarbital,|
01578|036|D|phenytoin, and primidone, induce one or more UGT pathways.(3)|
01578|037|D|   Concurrent low dose phenytoin (200 mg daily) decreased posaconazole|
01578|038|D|area-under-curve (AUC) and maximum concentration (Cmax) by 50% and 41%,|
01578|039|D|respectively.(1,2)|
01578|040|B||
01578|041|R|REFERENCES:|
01578|042|B||
01578|043|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01578|044|R|  January, 2022.|1
01578|045|R|2.Noxafil (posaconazole) UK summary of product characteristics.|1
01578|046|R|  Schering-Plough Ltd. January, 2022.|1
01578|047|R|3.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
01578|048|R|  Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
01578|049|R|4.This information is based on an extract from the Certara Drug Interaction|6
01578|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01579|001|T|MONOGRAPH TITLE:  Amprenavir/Contraceptives (Monograph Deleted) (mono|
01579|002|T|deleted 02/01/2013)|
01579|003|B||
01579|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01579|005|L|is contraindicated and generally should not be dispensed or administered to|
01579|006|L|the same patient.|
01579|007|B||
01579|008|A|MECHANISM OF ACTION:  Contraceptives may induced the metabolism of|
01579|009|A|amprenavir.(1)|
01579|010|B||
01579|011|E|CLINICAL EFFECTS:  Concurrent use of contraceptives may result in decreased|
01579|012|E|levels and effectiveness of amprenavir.(1)|
01579|013|B||
01579|014|P|PREDISPOSING FACTORS:  None determined.|
01579|015|B||
01579|016|M|PATIENT MANAGEMENT:  The US manufacturer of amprenavir states that hormonal|
01579|017|M|contraceptives should not be used in patients taking amprenavir.(1)|
01579|018|B||
01579|019|D|DISCUSSION:  Concurrent administration of amprenavir (1200 mg twice daily)|
01579|020|D|with ethinyl estradiol/norethindrone (0.035 mg/1 mg daily) decreased the|
01579|021|D|amprenavir area-under-curve (AUC) and minimum concentration (Cmin) by 22%|
01579|022|D|and 20%, respectively.  The Cmin of ethinyl estradiol was increased by 32%.|
01579|023|D|The AUC and Cmin of norethindrone were increased by 18% and 45%,|
01579|024|D|respectively.(1)|
01579|025|B||
01579|026|R|REFERENCE:|
01579|027|B||
01579|028|R|1.Agenerase (amprenavir) Oral Solution US prescribing information.|1
01579|029|R|  GlaxoSmithKline May, 2005.|1
01580|001|T|MONOGRAPH TITLE:  Nifedipine; Nimodipine; Nisoldipine/Selected Strong CYP3A4|
01580|002|T|Inducers|
01580|003|B||
01580|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01580|005|L|is contraindicated and generally should not be dispensed or administered to|
01580|006|L|the same patient.|
01580|007|B||
01580|008|A|MECHANISM OF ACTION:  Concurrent use of barbiturates, carbamazepine,|
01580|009|A|phenobarbital, phenytoin, or primidone may induce the CYP3A4 mediated|
01580|010|A|metabolism of nifedipine,(1) and nimodipine,(2,3) and nisoldipine.(4)|
01580|011|A|   Nisoldipine is particularly susceptible to changes in CYP3A4|
01580|012|A|activity.(4,5)|
01580|013|B||
01580|014|E|CLINICAL EFFECTS:  Concurrent use of barbiturates, carbamazepine,|
01580|015|E|phenobarbital, phenytoin, or primidone may result in decreased levels and|
01580|016|E|effectiveness of nifedipine(1), nimodipine or nisoldipine.(6)|
01580|017|B||
01580|018|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01580|019|P|of the inducer for longer than 1-2 weeks.|
01580|020|B||
01580|021|M|PATIENT MANAGEMENT:  Due to the risk for treatment failure, use an|
01580|022|M|alternative agent if possible.|
01580|023|M|   The US manufacturer of nifedipine states that the concurrent use of|
01580|024|M|strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, or|
01580|025|M|primidone is contraindicated because efficacy could be significantly|
01580|026|M|reduced.(1)|
01580|027|M|   The UK manufacturer of nimodipine states that the concurrent use of|
01580|028|M|carbamazepine, phenobarbital, phenytoin, or primidone is contraindicated.(2)|
01580|029|M|   The US manufacturer of nimodipine states that the concurrent use of|
01580|030|M|strong CYP3A4 inducers should generally be avoided due to decreased|
01580|031|M|nimodipine plasma concentrations and significantly reduced efficacy.(6)|
01580|032|M|   The US manufacturer of nisoldipine states it should generally not be|
01580|033|M|coadministered with CYP3A4 inducers.  Concurrent administration of phenytoin|
01580|034|M|with nisoldipine (40 mg) decreased nisoldipine plasma concentrations below|
01580|035|M|detectable levels.(7)|
01580|036|B||
01580|037|D|DISCUSSION:  Coadministration of phenytoin with nifedipine (10 mg capsule|
01580|038|D|and 60 mg extended-release tablet) decreased the area-under-curve (AUC) and|
01580|039|D|maximum concentration (Cmax) of nifedipine by 70%.(1)|
01580|040|D|   A study examined nimodipine pharmacokinetics in three groups: normal|
01580|041|D|drug-free controls (n=8), epileptic patients taking enzyme-inducing|
01580|042|D|anticonvulsants (phenobarbital alone, n=4; phenobarbital with carbamazepine,|
01580|043|D|n=2, carbamazepine with clobazam, n=1, and carbamazepine with phenytoin,|
01580|044|D|n=1), and epileptic patients taking valproic acid (n=8).  In patients taking|
01580|045|D|enzyme-inducing anticonvulsants, nimodipine AUC, Cmax, and half-life (T1/2)|
01580|046|D|were 86.2%, 89.2%, and 68.1%, respectively, lower than in controls.  In|
01580|047|D|patients taking valproic acid, nimodipine AUC was 54.5% higher than in|
01580|048|D|control patients.(3)|
01580|049|D|   Concurrent administration of phenytoin with nisoldipine (40 mg) decreased|
01580|050|D|nisoldipine plasma concentrations below detectable levels.(7)|
01580|051|D|   In a study comparing patients receiving chronic phenytoin therapy to|
01580|052|D|healthy controls, phenytoin decreased the AUC of a single dose of|
01580|053|D|nisoldipine by 89%.(8)|
01580|054|B||
01580|055|R|REFERENCES:|
01580|056|B||
01580|057|R|1.Adalat (nifedipine) US prescribing information. Bayer Healthcare|1
01580|058|R|  Pharmaceuticals Inc. August, 2016.|1
01580|059|R|2.Nimotop (nimodipine) UK  summary of product characteristics. Bayer plc|1
01580|060|R|  April 23, 2008.|1
01580|061|R|3.Tartara A, Galimberti CA, Manni R, Parietti L, Zucca C, Baasch H, Caresia|2
01580|062|R|  L, Muck W, Barzaghi N, Gatti G, et al. Differential effects of valproic|2
01580|063|R|  acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in|2
01580|064|R|  epileptic patients. Br J Clin Pharmacol 1991 Sep;32(3):335-40.|2
01580|065|R|4.This information is based on an extract from the Certara Drug Interaction|6
01580|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01580|067|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
01580|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01580|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01580|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01580|071|R|  11/14/2017.|1
01580|072|R|6.Nymalize (nimodipine) solution US prescribing information. Arbor|1
01580|073|R|  Pharmaceuticals April, 2020.|1
01580|074|R|7.Sular (nisoldipine) US prescribing information. Shionogi, Inc. June, 2017.|1
01580|075|R|8.Michelucci R, Cipolla G, Passarelli D, Gatti G, Ochan M, Heinig R,|2
01580|076|R|  Tassinari CA, Perucca E. Reduced plasma nisoldipine concentrations in|2
01580|077|R|  phenytoin-treated patients with epilepsy. Epilepsia 1996 Nov;|2
01580|078|R|  37(11):1107-10.|2
01581|001|T|MONOGRAPH TITLE:  Drospirenone/ACE Inhibitors; ARBs|
01581|002|B||
01581|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01581|004|L|take action as needed.|
01581|005|B||
01581|006|A|MECHANISM OF ACTION:  Drospirenone has antimineralocorticoid activity and|
01581|007|A|may cause hyperkalemia.  ACE inhibitors and angiotensin II receptor|
01581|008|A|antagonists may also increase potassium levels.(1)|
01581|009|B||
01581|010|E|CLINICAL EFFECTS:  Concurrent use of drospirenone and ACE inhibitors or|
01581|011|E|angiotensin II receptor antagonists may result in hyperkalemia.(1)|
01581|012|B||
01581|013|P|PREDISPOSING FACTORS:  Renal insufficiency, hepatic dysfunction, adrenal|
01581|014|P|insufficiency, and use of potassium supplements, potassium-sparing|
01581|015|P|diuretics, heparin, and NSAIDs may increase potassium levels.(1)|
01581|016|B||
01581|017|M|PATIENT MANAGEMENT:  Patients receiving drospirenone with either an ACE|
01581|018|M|inhibitor or an angiotensin II receptor antagonist should have their serum|
01581|019|M|potassium level checked during the first treatment cycle.(1)|
01581|020|B||
01581|021|D|DISCUSSION:  Drospirenone has antimineralocorticoid activity comparable to|
01581|022|D|25 mg of spironolactone and may result in hyperkalemia.  Concurrent use of|
01581|023|D|ACE inhibitors or angiotensin II receptor antagonists may also increase|
01581|024|D|potassium levels.(1)|
01581|025|D|   In a study in 24 mildly hypertensive postmenopausal women who received|
01581|026|D|concurrent drospirenone/estradiol (3 mg/1 mg) with enalapril (10 mg), mean|
01581|027|D|serum potassium levels were 0.22 mEq/L higher than in the placebo group.  On|
01581|028|D|day 14 of concurrent therapy, the ratios for serum potassium maximum|
01581|029|D|concentration (Cmax) and area-under-curve (AUC) were 0.955 and 1.010,|
01581|030|D|respectively.  No patient developed hyperkalemia.(1)|
01581|031|B||
01581|032|R|REFERENCE:|
01581|033|B||
01581|034|R|1.Yasmin (drospirenone/ethinyl estradiol) US prescribing information. Bayer|1
01581|035|R|  HealthCare Pharmaceuticals Inc. June, 2015.|1
01582|001|T|MONOGRAPH TITLE:  Drospirenone/Potassium Sparing Diuretics|
01582|002|B||
01582|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01582|004|L|take action as needed.|
01582|005|B||
01582|006|A|MECHANISM OF ACTION:  Drospirenone has antimineralocorticoid activity and|
01582|007|A|may cause hyperkalemia.  Potassium sparing diuretics may also increase|
01582|008|A|potassium levels.(1)|
01582|009|B||
01582|010|E|CLINICAL EFFECTS:  Concurrent use of drospirenone and potassium sparing|
01582|011|E|diuretics may result in hyperkalemia.(1)|
01582|012|B||
01582|013|P|PREDISPOSING FACTORS:  Renal insufficiency, hepatic dysfunction, adrenal|
01582|014|P|insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin|
01582|015|P|II receptor antagonists, heparin, and NSAIDs may increase potassium|
01582|016|P|levels.(1)|
01582|017|B||
01582|018|M|PATIENT MANAGEMENT:  Patients receiving drospirenone with a potassium|
01582|019|M|sparing diuretic should have their serum potassium level checked during the|
01582|020|M|first treatment cycle.(1)|
01582|021|B||
01582|022|D|DISCUSSION:  Drospirenone has antimineralocorticoid activity comparable to|
01582|023|D|25 mg of spironolactone and may result in hyperkalemia.  Concurrent use of|
01582|024|D|potassium sparing diuretics may also increase potassium levels.(1)|
01582|025|B||
01582|026|R|REFERENCE:|
01582|027|B||
01582|028|R|1.Yasmin (drospirenone/ethinyl estradiol) US prescribing information. Bayer|1
01582|029|R|  HealthCare Pharmaceuticals Inc. June, 2015.|1
01583|001|T|MONOGRAPH TITLE:  Drospirenone/NSAIDs; Salicylates|
01583|002|B||
01583|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01583|004|L|take action as needed.|
01583|005|B||
01583|006|A|MECHANISM OF ACTION:  Drospirenone has antimineralocorticoid activity and|
01583|007|A|may cause hyperkalemia.  NSAIDs may also increase potassium levels.(1)|
01583|008|B||
01583|009|E|CLINICAL EFFECTS:  Concurrent use of drospirenone and NSAIDs may result in|
01583|010|E|hyperkalemia.(1)|
01583|011|B||
01583|012|P|PREDISPOSING FACTORS:  Renal insufficiency, hepatic dysfunction, adrenal|
01583|013|P|insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin|
01583|014|P|II receptor antagonists, heparin, and potassium-sparing diuretics may|
01583|015|P|increase potassium levels.(1)|
01583|016|B||
01583|017|M|PATIENT MANAGEMENT:  Patients receiving drospirenone with a NSAID should|
01583|018|M|have their serum potassium level checked during the first treatment|
01583|019|M|cycle.(1)|
01583|020|B||
01583|021|D|DISCUSSION:  Drospirenone has antimineralocorticoid activity comparable to|
01583|022|D|25 mg of spironolactone and may result in hyperkalemia.  Concurrent use of|
01583|023|D|NSAIDs may also increase potassium levels.(1)|
01583|024|D|   Occasional or chronic use of NSAIDs was not restricted in clinical trials|
01583|025|D|of drospirenone.(1)|
01583|026|B||
01583|027|R|REFERENCE:|
01583|028|B||
01583|029|R|1.Yasmin (drospirenone/ethinyl estradiol) US prescribing information. Bayer|1
01583|030|R|  HealthCare Pharmaceuticals Inc. June, 2015.|1
01584|001|T|MONOGRAPH TITLE:  Drospirenone/Potassium Supplements|
01584|002|B||
01584|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01584|004|L|take action as needed.|
01584|005|B||
01584|006|A|MECHANISM OF ACTION:  Drospirenone has antimineralocorticoid activity and|
01584|007|A|may cause hyperkalemia.  Potassium supplements also increase potassium|
01584|008|A|levels.(1)|
01584|009|B||
01584|010|E|CLINICAL EFFECTS:  Concurrent use of drospirenone and potassium supplements|
01584|011|E|may result in hyperkalemia.(1)|
01584|012|B||
01584|013|P|PREDISPOSING FACTORS:  Renal insufficiency, hepatic dysfunction, adrenal|
01584|014|P|insufficiency, and use of potassium-sparing diuretics, ACE inhibitors,|
01584|015|P|angiotensin II receptor antagonists, heparin, and NSAIDs may increase|
01584|016|P|potassium levels.(1)|
01584|017|B||
01584|018|M|PATIENT MANAGEMENT:  Patients receiving drospirenone with a potassium|
01584|019|M|supplement should have their serum potassium level checked during the first|
01584|020|M|treatment cycle.(1)|
01584|021|B||
01584|022|D|DISCUSSION:  Drospirenone has antimineralocorticoid activity comparable to|
01584|023|D|25 mg of spironolactone and may result in hyperkalemia.  Concurrent use of|
01584|024|D|potassium-supplements also increase potassium levels.(1)|
01584|025|B||
01584|026|R|REFERENCE:|
01584|027|B||
01584|028|R|1.Yasmin (drospirenone/ethinyl estradiol) US prescribing information. Bayer|1
01584|029|R|  HealthCare Pharmaceuticals Inc. June, 2015.|1
01585|001|T|MONOGRAPH TITLE:  Drospirenone/Heparin|
01585|002|B||
01585|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01585|004|L|take action as needed.|
01585|005|B||
01585|006|A|MECHANISM OF ACTION:  Drospirenone has antimineralocorticoid activity and|
01585|007|A|may cause hyperkalemia.  Heparin may also increase potassium levels.(1)|
01585|008|B||
01585|009|E|CLINICAL EFFECTS:  Concurrent use of drospirenone and heparin may result in|
01585|010|E|hyperkalemia.(1)|
01585|011|B||
01585|012|P|PREDISPOSING FACTORS:  Renal insufficiency, hepatic dysfunction, adrenal|
01585|013|P|insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin|
01585|014|P|II receptor antagonists, NSAIDs, and potassium-sparing diuretics may|
01585|015|P|increase potassium levels.(1)|
01585|016|B||
01585|017|M|PATIENT MANAGEMENT:  Patients receiving drospirenone with heparin should|
01585|018|M|have their serum potassium level checked during the first treatment cycle.|
01585|019|M|(1)|
01585|020|B||
01585|021|D|DISCUSSION:  Drospirenone has antimineralocorticoid activity comparable to|
01585|022|D|25 mg of spironolactone and may result in hyperkalemia.  Concurrent use of|
01585|023|D|heparin may also increase potassium levels.(1)|
01585|024|B||
01585|025|R|REFERENCE:|
01585|026|B||
01585|027|R|1.Yasmin (drospirenone/ethinyl estradiol) US prescribing information. Bayer|1
01585|028|R|  HealthCare Pharmaceuticals Inc. June, 2015.|1
01586|001|T|MONOGRAPH TITLE:  Hydantoins/Fluorouracil & Fluorouracil Prodrugs|
01586|002|B||
01586|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01586|004|L|of severe adverse interaction.|
01586|005|B||
01586|006|A|MECHANISM OF ACTION:  Fluorouracil may inhibit the metabolism of hydantoins|
01586|007|A|by CYP2C9.(1)|
01586|008|B||
01586|009|E|CLINICAL EFFECTS:  Concurrent use of fluorouracil or fluorouracil prodrugs|
01586|010|E|may result in hydantoin toxicity. Phenytoin has a narrow therapeutic range.|
01586|011|E|Early symptoms of phenytoin toxicity may include nystagmus, ataxia,|
01586|012|E|dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision,|
01586|013|E|nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g.|
01586|014|E|coma, irreversible cerebellar dysfunction and atrophy, hypotension,|
01586|015|E|bradycardia, seizures, and cardiac arrest) and may be fatal.(6)|
01586|016|B||
01586|017|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
01586|018|P|hypoalbuminemia.|
01586|019|B||
01586|020|M|PATIENT MANAGEMENT:  Monitor hydantoin levels and for signs of hydantoin|
01586|021|M|toxicity (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia,|
01586|022|M|lethargy, slurred speech, blurred vision, nausea, and vomiting) in patients|
01586|023|M|receiving concurrent fluorouracil or fluorouracil prodrugs.  The dosage of|
01586|024|M|the hydantoin may need to be adjusted if fluorouracil or a fluorouracil|
01586|025|M|prodrug is added to or discontinued from concurrent therapy.|
01586|026|B||
01586|027|D|DISCUSSION:  There have been four reports of elevated phenytoin levels and|
01586|028|D|phenytoin toxicity following fluorouracil therapy in patients who had been|
01586|029|D|stabilized on phenytoin for several years.(1-3)|
01586|030|D|   There is one case report of phenytoin toxicity in a patient previously|
01586|031|D|stabilized on phenytoin following capecitabine therapy.(1)|
01586|032|D|   Elevated phenytoin levels have been reported in patients receiving|
01586|033|D|concurrent tegafur.(4,5)|
01586|034|D|   Fluorouracil prodrugs linked to this monograph include: capecitabine,|
01586|035|D|doxifluridine, and tegafur.|
01586|036|B||
01586|037|R|REFERENCES:|
01586|038|B||
01586|039|R|1.Brickell K, Porter D, Thompson P. Phenytoin toxicity due to|3
01586|040|R|  fluoropyrimidines (5FU/capecitabine): three case reports. Br J Cancer 2003|3
01586|041|R|  Aug 18;89(4):615-6.|3
01586|042|R|2.Rosemergy I, Findlay M. Phenytoin toxicity as a result of 5-fluorouracil|3
01586|043|R|  administration. N Z Med J 2002 Aug 9;115(1159):U124.|3
01586|044|R|3.Gilbar PJ, Brodribb TR. Phenytoin and fluorouracil interaction. Ann|3
01586|045|R|  Pharmacother 2001 Nov;35(11):1367-70.|3
01586|046|R|4.Uftoral (tegafur/uracil) UK summary of product characteristics. Merck|1
01586|047|R|  Pharmaceuticals March 9, 2006.|1
01586|048|R|5.Wakisaka S, Shimauchi M, Kaji Y, Nonaka A, Kinoshita K. Acute phenytoin|3
01586|049|R|  intoxication associated with the antineoplastic agent UFT. Fukuoka Igaku|3
01586|050|R|  Zasshi 1990 Apr;81(4):192-6.|3
01586|051|R|6.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
01586|052|R|  March, 2022.|1
01587|001|T|MONOGRAPH TITLE:  Tenofovir/Selected Nephrotoxic Agents|
01587|002|B||
01587|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01587|004|L|take action as needed.|
01587|005|B||
01587|006|A|MECHANISM OF ACTION:  Tenofovir and other nephrotoxic agents may result in|
01587|007|A|additive or synergistic effects on renal function and increase|
01587|008|A|nephrotoxicity risk.(1)|
01587|009|B||
01587|010|E|CLINICAL EFFECTS:  Concurrent use of tenofovir and other nephrotoxic agents|
01587|011|E|may result in renal toxicity and acute renal failure.(1)  Reports of acute|
01587|012|E|renal failure and Fanconi syndrome have been reported with tenofovir|
01587|013|E|use.(2,3)|
01587|014|E|   However, this has been reported in 3 case reports and the renal failure|
01587|015|E|may have been complicated by other pre-existing conditions.(2)|
01587|016|B||
01587|017|P|PREDISPOSING FACTORS:  Pre-existing renal dysfunction, long duration of use,|
01587|018|P|low body weight, concomitant use of drugs that may increase tenofovir levels|
01587|019|P|may increase the risk of nephrotoxicity.(1)|
01587|020|B||
01587|021|M|PATIENT MANAGEMENT:  The US prescribing information for tenofovir recommends|
01587|022|M|avoiding concurrent or recent use of a nephrotoxic agent.(3)|
01587|023|M|   Evaluate renal function prior to initiation of concurrent therapy and|
01587|024|M|continue renal function monitoring during therapy.  Dose adjustments may be|
01587|025|M|required for impaired renal function.|
01587|026|M|   Tenofovir should be avoided with high-dose or multiple NSAIDs.|
01587|027|M|Alternatives to NSAIDs should be considered in patients at risk for renal|
01587|028|M|dysfunction.(3)  Patients receiving concurrent NSAIDs with tenofovir should|
01587|029|M|be monitored for possible renal toxicity.(1,2)  The dosing interval should|
01587|030|M|be adjusted in patients with a baseline creatinine clearance of less than 50|
01587|031|M|ml/min.(1-3)|
01587|032|B||
01587|033|D|DISCUSSION:  From March 18, 2003 to December 1, 2005, Health Canada received|
01587|034|D|10 reports of nephrotoxic reactions with tenofovir.  Three of these occurred|
01587|035|D|following the addition of a NSAID to tenofovir therapy.  In the first|
01587|036|D|report, a patient maintained on tenofovir for 29 months developed acute|
01587|037|D|renal failure and acute tubular necrosis requiring dialysis 5 days after|
01587|038|D|beginning indomethacin (100 mg rectally twice daily).  In the second report,|
01587|039|D|a patient maintained on tenofovir for 7 months developed acute renal failure|
01587|040|D|and acute tubular necrosis after taking 90 tablets of naproxen (375 mg) over|
01587|041|D|2 months.  The patient died.  In the third report, a patient maintained on|
01587|042|D|tenofovir for over a year developed acute renal failure and nephrotic|
01587|043|D|syndrome after 2 months of valdecoxib (20 mg daily) therapy.  Symptoms|
01587|044|D|subsided following discontinuation of valdecoxib.(1)|
01587|045|B||
01587|046|R|REFERENCES:|
01587|047|B||
01587|048|R|1.McMorran M. Tenofovir (viread) and NSAIDs:  acute renal failure. Canadian|1
01587|049|R|  Adverse Reaction Newsletter 2006;16(2):1-2.|1
01587|050|R|2.Viread (tenofovir disoproxil fumarate) Canadian product information.|1
01587|051|R|  Gilead Sciences, Inc. January 11, 2008.|1
01587|052|R|3.Viread (tenofovir disoproxil fumarate) US prescribing information. Gilead|1
01587|053|R|  Sciences, Inc. December, 2018.|1
01588|001|T|MONOGRAPH TITLE:  Live Vaccines; Live BCG/Selected Immunosuppressive Agents|
01588|002|B||
01588|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01588|004|L|is contraindicated and generally should not be dispensed or administered to|
01588|005|L|the same patient.|
01588|006|B||
01588|007|A|MECHANISM OF ACTION:  A variety of disease modifying agents suppress the|
01588|008|A|immune system. Immunocompromised patients may be at increased risk for|
01588|009|A|uninhibited replication after administration of live, attenuated vaccines or|
01588|010|A|intravesicular BCG.|
01588|011|A|   Immune response to vaccines may be decreased during periods of|
01588|012|A|immunocompromise.(1)|
01588|013|B||
01588|014|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained|
01588|015|E|and/or the vaccine may result in illness.(1)|
01588|016|E|   After instillation of intravesicular BCG, immunosuppression may interfere|
01588|017|E|with local immune response, or increase the severity of mycobacterial|
01588|018|E|infection following inadvertent systemic exposure.(2)|
01588|019|B||
01588|020|P|PREDISPOSING FACTORS:  Immunosuppressive diseases (e.g. hematologic|
01588|021|P|malignancies, HIV disease), treatments (e.g. radiation) and drugs may all|
01588|022|P|increase the magnitude of immunodeficiency.|
01588|023|B||
01588|024|M|PATIENT MANAGEMENT:  The Centers for Disease Control(CDC) Advisory Committee|
01588|025|M|on Immunization Practices (ACIP) states that live-virus and live, attenuated|
01588|026|M|vaccines should not be administered to patients who are immunocompromised.|
01588|027|M|The magnitude of immunocompromise and associated risks should be determined|
01588|028|M|by a physician.(1)|
01588|029|M|   For patients scheduled to receive chemotherapy, vaccination should|
01588|030|M|ideally precede the initiation of chemotherapy by 14 days.  Patients|
01588|031|M|vaccinated while on immunosuppressive therapy or in the 2 weeks prior to|
01588|032|M|starting therapy should be considered unimmunized and should be revaccinated|
01588|033|M|at least 3 months after discontinuation of therapy.(1)|
01588|034|M|   Patients who receive anti-B cell therapies should not receive live|
01588|035|M|vaccines for at least 6 months after such therapies due to a prolonged|
01588|036|M|duration of immunosuppression.  An exception is the Zoster vaccine, which|
01588|037|M|can be given at least 1 month after receipt of anti-B cell therapies.(1)|
01588|038|M|   The US manufacturer of abatacept states live vaccines should not be given|
01588|039|M|during or for up to 3 months after discontinuation of abatacept.(2)|
01588|040|M|   The US manufacturer of live BCG for intravesicular treatment of bladder|
01588|041|M|cancer states use is contraindicated in immunosuppressed patients.(3)|
01588|042|M|   The US manufacturer of daclizumab states live vaccines are not|
01588|043|M|recommended during and for up to 4 months after discontinuation of|
01588|044|M|treatment.(4)|
01588|045|M|   The US manufacturer of guselkumab states that live vaccines should be|
01588|046|M|avoided during treatment with guselkumab.(5)|
01588|047|M|   The US manufacturer of inebilizumab-cdon states that live vaccines are|
01588|048|M|not recommended during treatment and after discontinuation until B-cell|
01588|049|M|repletion.  Administer all live vaccinations at least 4 weeks prior to|
01588|050|M|initiation of inebilizumab-cdon.(6)|
01588|051|M|   The US manufacturer of ocrelizumab states that live vaccines are not|
01588|052|M|recommended during treatment and until B-cell repletion occurs after|
01588|053|M|discontinuation of therapy.  Administer all live vaccines at least 4 weeks|
01588|054|M|prior to initiation of ocrelizumab.(7)|
01588|055|M|   The US manufacturer of ozanimod states that live vaccines should be|
01588|056|M|avoided during and for up to 3 months after discontinuation of ozanimod.(8)|
01588|057|M|   The US manufacturer of siponimod states that live vaccines are not|
01588|058|M|recommended during treatment and for up to 4 weeks after discontinuation of|
01588|059|M|treatment.(9)|
01588|060|M|   The US manufacturer of ustekinumab states BCG vaccines should not be|
01588|061|M|given in the year prior to, during, or the year after ustekinumab|
01588|062|M|therapy.(10)|
01588|063|M|   The US manufacturer of satralizumab-mwge states that live vaccines are|
01588|064|M|not recommended during treatment and should be administered at least four|
01588|065|M|weeks prior to initiation of satralizumab-mwge.(11)|
01588|066|M|   The US manufacturer of ublituximab-xiiy states that live vaccines are not|
01588|067|M|recommended during treatment and until B-cell recovery.  Live vaccines|
01588|068|M|should be administered at least 4 weeks prior to initiation of|
01588|069|M|ublituximab-xiiy.(12)|
01588|070|M|   The US manufacturer of etrasimod states that live vaccines should be|
01588|071|M|avoided during and for 5 weeks after treatment.  Live vaccines should be|
01588|072|M|administered at least 4 weeks prior to initiation of etrasimod.(13)|
01588|073|M|   The US manufacturer of emapalumab-lzsg states that live vaccines should|
01588|074|M|not be administered to patients receiving emapalumab-lzsg and for at least 4|
01588|075|M|weeks after the last dose of emapalumab-lzsg. The safety of immunization|
01588|076|M|with live vaccines during or following emapalumab-lzsg therapy has not been|
01588|077|M|studied.(14)|
01588|078|B||
01588|079|D|DISCUSSION:  Killed or inactivated vaccines do not pose a danger to|
01588|080|D|immunocompromised patients.(1)|
01588|081|D|   Patients with a history of leukemia who are in remission and have not|
01588|082|D|received chemotherapy for at least 3 months are not considered to be|
01588|083|D|immunocompromised.(1)|
01588|084|B||
01588|085|R|REFERENCES:|
01588|086|B||
01588|087|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
01588|088|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
01588|089|R|  Practices (ACIP). MMWR.  Available at:|1
01588|090|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
01588|091|R|  February 17, 2022;60(RR No.2):1-68.|1
01588|092|R|2.Orencia (abatacept) US prescribing information. Bristol-Myers Squibb|1
01588|093|R|  Company December, 2021.|1
01588|094|R|3.TICE BCG (BCG live, for intravesical use) prescribing information. Organon|1
01588|095|R|  USA Inc. October, 2010.|1
01588|096|R|4.Zinbryta (daclizumab) US prescribing information. Biogen Inc. August,|1
01588|097|R|  2017.|1
01588|098|R|5.Tremfya (guselkumab) US prescribing information. Janssen Biotech, Inc.|1
01588|099|R|  July, 2020.|1
01588|100|R|6.Uplizna (inebilizumab-cdon) US prescribing information. Viela Bio June,|1
01588|101|R|  2020.|1
01588|102|R|7.Ocrevus (ocrelizumab) US prescribing information. Genentech November,|1
01588|103|R|  2020.|1
01588|104|R|8.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
01588|105|R|  2024.|1
01588|106|R|9.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
01588|107|R|  Corporation August, 2025.|1
01588|108|R|10.Stelara (ustekinumab) US prescribing information. Janssen Biotech, Inc.|1
01588|109|R|   March, 2024.|1
01588|110|R|11.Enspryng (satralizumab-mwge) US Prescribing Information. Genentech, Inc.|1
01588|111|R|   August 2020.|1
01588|112|R|12.Briumvi (ublituximab-xiiy) US prescribing information. TG Therapeutics|1
01588|113|R|   December, 2022.|1
01588|114|R|13.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
01588|115|R|   2023.|1
01588|116|R|14.Gamifant (emapalumab-lzsg) US prescribing information. Swedish Orphan|1
01588|117|R|   Biovitrum June 2023.|1
01589|001|T|MONOGRAPH TITLE:  Valproic Acid Derivatives/Topiramate|
01589|002|B||
01589|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01589|004|L|take action as needed.|
01589|005|B||
01589|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but a pharmacokinetic|
01589|007|A|interaction does not occur.(1-4)  Topiramate may contribute to increased|
01589|008|A|ammonia levels by inhibiting carbonic anhydrase and cerebral glutamine.(5)|
01589|009|A|Concurrent use may exacerbate or unmask existing metabolism defects.(1-4)|
01589|010|B||
01589|011|E|CLINICAL EFFECTS:  Concurrent use of valproic acid or its derivatives and|
01589|012|E|topiramate may increase the risk of hyperammonemia with or without|
01589|013|E|encephalopathy.  Hyperammonemic encephalopathy may present as changes in|
01589|014|E|state of consciousness and/or cognitive function with lethargy and|
01589|015|E|vomiting.(1-4)  Concurrent use has also resulted in hypothermia.(1)|
01589|016|B||
01589|017|P|PREDISPOSING FACTORS:  The risk of hyperammonemia with or without|
01589|018|P|encephalopathy may be increased in patients with inborn metabolism errors or|
01589|019|P|decreased hepatic mitochondrial activity.(1-4)|
01589|020|B||
01589|021|M|PATIENT MANAGEMENT:  In patients receiving concurrent valproic acid|
01589|022|M|derivatives and topiramate, monitor for unexplained lethargy, vomiting, and/|
01589|023|M|or changes in mental status.  If these symptoms develop, check the patient's|
01589|024|M|ammonia level.(1-4)  The valproic acid derivative and/or topiramate may need|
01589|025|M|to be discontinued if hyperammonemia develops.(1-3)|
01589|026|B||
01589|027|D|DISCUSSION:  There have been several reports of hyperammonemia with and|
01589|028|D|without encephalopathy in patients receiving concurrent valproic acid|
01589|029|D|derivatives and topiramate.(1-12)  In many of these reports, the patients|
01589|030|D|tolerated the valproic acid derivative alone, but developed hyperammonemia|
01589|031|D|with or without encephalopathy following the addition of topiramate.(1-9)|
01589|032|D|  Two clinical trials showed no clinically significant pharmacokinetic|
01589|033|D|interaction between valproic acid and topiramate.(12,13)|
01589|034|B||
01589|035|R|REFERENCES:|
01589|036|B||
01589|037|R|1.Depakote (divalproex sodium) US prescribing information. AbbVie Inc.|1
01589|038|R|  February, 2023.|1
01589|039|R|2.Depacon (valproate sodium) US prescribing information. AbbVie Inc.|1
01589|040|R|  December, 2019.|1
01589|041|R|3.Depakene (valproic acid) US prescribing information. Abbvie Inc. December,|1
01589|042|R|  2019.|1
01589|043|R|4.Topamax (topiramate) US prescribing information. Janssen Pharmaceuticals,|1
01589|044|R|  Inc. May, 2023.|1
01589|045|R|5.Hamer HM, Knake S, Schomburg U, Rosenow F. Valproate-induced|3
01589|046|R|  hyperammonemic encephalopathy in the presence of topiramate. Neurology|3
01589|047|R|  2000 Jan 11;54(1):230-2.|3
01589|048|R|6.Longin E, Teich M, Koelfen W, Konig S. Topiramate enhances the risk of|3
01589|049|R|  valproate-associated side effects in three children. Epilepsia 2002 Apr;|3
01589|050|R|  43(4):451-4.|3
01589|051|R|7.Ortiz-Saenz de Santa Maria MR, Barriuso-Perez E, Soto-Alvarez MI,|3
01589|052|R|  Moche-Loeri JA. Ring chromosome 20, hypersensitivity to valproate and|3
01589|053|R|  hyperammonemic encephalopathy. Rev Neurol 2003 Oct 16-31;37(8):733-5.|3
01589|054|R|8.Cheung E, Wong V, Fung CW. Topiramate-valproate-induced hyperammonemic|3
01589|055|R|  encephalopathy syndrome: case report. J Child Neurol 2005 Feb;|3
01589|056|R|  20(2):157-60.|3
01589|057|R|9.Panda S, Radhakrishnan K. Two cases of valproate-induced hyperammonemic|3
01589|058|R|  encephalopathy without hepatic failure. J Assoc Physicians India 2004 Sep;|3
01589|059|R|  52:746-8.|3
01589|060|R|10.Rath A, Naryanan TJ, Chowdhary GV, Murthy JM. Valproate-induced|3
01589|061|R|   hyperammonemic encephalopathy with normal liver function. Neurol India|3
01589|062|R|   2005 Jun;53(2):226-8.|3
01589|063|R|11.Latour P, Biraben A, Polard E, Bentue-Ferrer D, Beauplet A, Tribut O,|3
01589|064|R|   Allain H. Drug induced encephalopathy in six epileptic patients:|3
01589|065|R|   topiramate? valproate? or both?. Hum Psychopharmacol 2004 Apr;|3
01589|066|R|   19(3):193-203.|3
01589|067|R|12.Solomon GE. Valproate-induced hyperammonemic encephalopathy in the|3
01589|068|R|   presence of topiramate. Neurology 2000 Aug 22;55(4):606.|3
01589|069|R|13.Rosenfeld WE, Liao S, Kramer LD, Anderson G, Palmer M, Levy RH, Nayak RK.|2
01589|070|R|   Comparison of the steady-state pharmacokinetics of topiramate and|2
01589|071|R|   valproate in patients with epilepsy during monotherapy and concomitant|2
01589|072|R|   therapy. Epilepsia 1997 Mar;38(3):324-33.|2
01589|073|R|14.Mimrod D, Specchio LM, Britzi M, Perucca E, Specchio N, La Neve A, Soback|2
01589|074|R|   S, Levy RH, Gatti G, Doose DR, Maryanoff BE, Bialer M. A comparative|2
01589|075|R|   study of the effect of carbamazepine and valproic acid on the|2
01589|076|R|   pharmacokinetics and metabolic profile of topiramate at steady state in|2
01589|077|R|   patients with epilepsy. Epilepsia 2005 Jul;46(7):1046-54.|2
01590|001|T|MONOGRAPH TITLE:  Propranolol/Zileuton|
01590|002|B||
01590|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01590|004|L|take action as needed.|
01590|005|B||
01590|006|A|MECHANISM OF ACTION:  Zileuton may inhibit the metabolism of propranolol by|
01590|007|A|CYP1A2.(1)|
01590|008|B||
01590|009|E|CLINICAL EFFECTS:  Concurrent use of zileuton may result in increased levels|
01590|010|E|of and effects from propranolol.(2)|
01590|011|B||
01590|012|P|PREDISPOSING FACTORS:  None determined.|
01590|013|B||
01590|014|M|PATIENT MANAGEMENT:  Patient receiving concurrent therapy with zileuton and|
01590|015|M|propranolol should be closely monitored for adverse effects.  The dosage of|
01590|016|M|propranolol may need to be adjusted if zileuton is initiated or|
01590|017|M|discontinued.(2)|
01590|018|B||
01590|019|D|DISCUSSION:  In a study in 16 healthy males, pretreatment with zileuton (600|
01590|020|D|mg ever 6 hours for 5 days) increased the maximum concentration (Cmax),|
01590|021|D|area-under-curve (AUC), and half-life (T1/2) of a single dose of propranolol|
01590|022|D|(80 mg) by 52%, 104%, and 25%, respectively.  During concurrent|
01590|023|D|administration, beta-blockade was increased and heart rate was decreased.(2)|
01590|024|D|  A study in human liver microsomes showed that zileuton inhibited the|
01590|025|D|metabolism of propranolol by CYP1A2.(1)|
01590|026|B||
01590|027|R|REFERENCES:|
01590|028|B||
01590|029|R|1.Lu P, Schrag ML, Slaughter DE, Raab CE, Shou M, Rodrigues AD.|5
01590|030|R|  Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2|5
01590|031|R|  by zileuton, a 5-lipoxygenase inhibitor. Drug Metab Dispos 2003 Nov;|5
01590|032|R|  31(11):1352-60.|5
01590|033|R|2.Zyflo (zileuton) US prescribing information. Cornerstone Therapeutics,|1
01590|034|R|  Inc. November, 2011.|1
01591|001|T|MONOGRAPH TITLE:  Darunavir/Selected Strong CYP3A4 Inducers|
01591|002|B||
01591|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01591|004|L|of severe adverse interaction.|
01591|005|B||
01591|006|A|MECHANISM OF ACTION:  Barbiturates, phenobarbital, phenytoin and primidone|
01591|007|A|may induce the metabolism of darunavir by CYP3A4.(1,2)  Darunavir may induce|
01591|008|A|the metabolism of phenobarbital, phenytoin and primidone.(3)|
01591|009|B||
01591|010|E|CLINICAL EFFECTS:  Darunavir and either barbiturates, phenobarbital,|
01591|011|E|phenytoin or primidone may result in decreased levels and effectiveness of|
01591|012|E|these agents.(1-3)|
01591|013|B||
01591|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01591|015|P|of the inducer for longer than 1-2 weeks.|
01591|016|B||
01591|017|M|PATIENT MANAGEMENT:  The Canadian(1) and UK(2) manufacturers of darunavir|
01591|018|M|state that darunavir should not be coadministered with phenobarbital,|
01591|019|M|phenytoin or primidone.|
01591|020|M|   The US manufacturer of darunavir states that phenobarbital, phenytoin and|
01591|021|M|primidone levels should be monitored during concurrent therapy with|
01591|022|M|darunavir.(3)|
01591|023|B||
01591|024|D|DISCUSSION:  Concurrent use may result in significant decreases in|
01591|025|D|darunavir(1,2) or barbiturates, phenobarbital, phenytoin(3) and primidone|
01591|026|D|concentrations and loss of therapeutic effect.|
01591|027|B||
01591|028|R|REFERENCES:|
01591|029|B||
01591|030|R|1.Prezista (darunavir) Canadian prescribing information. Jannsen-Ortho June,|1
01591|031|R|  2008.|1
01591|032|R|2.Prezista (darunavir) UK Summary of product characteristics. Janssen-Cilgat|1
01591|033|R|  LTD August 8, 2008.|1
01591|034|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01591|035|R|  March, 2023.|1
01592|001|T|MONOGRAPH TITLE:  Darunavir/Lopinavir; Saquinavir;|
01592|002|T|Ombitasvir-paritaprevir-ritonavir|
01592|003|B||
01592|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01592|005|L|of severe adverse interaction.|
01592|006|B||
01592|007|A|MECHANISM OF ACTION:  Lopinavir-ritonavir, saquinavir-ritonavir, and|
01592|008|A|ombitasvir-paritaprevir-ritonavir may induce the metabolism of darunavir by|
01592|009|A|CYP3A4.(1,2)|
01592|010|B||
01592|011|E|CLINICAL EFFECTS:  Concurrent use of lopinavir-ritonavir,|
01592|012|E|ombitasvir-paritaprevir-ritonavir or saquinavir-ritonavir may result in|
01592|013|E|decreased levels and effectiveness of darunavir.(1-3)|
01592|014|B||
01592|015|P|PREDISPOSING FACTORS:  None determined.|
01592|016|B||
01592|017|M|PATIENT MANAGEMENT:  The US manufacturer of darunavir states that|
01592|018|M|coadministration of darunavir with either lopinavir/ritonavir with or|
01592|019|M|without an additional low-dose ritonavir, or saquinavir with or without|
01592|020|M|low-dose ritonavir is not recommended.(1)|
01592|021|M|   The FDA and manufacturer of ombitasvir-paritaprevir-ritonavir state that:|
01592|022|M|   - In treatment-naive patients and treatment-experienced patients with no|
01592|023|M|darunavir-associated mutations, darunavir 800 mg daily without ritonavir can|
01592|024|M|be co-administered with ombitasvir-paritaprevir-ritonavir.|
01592|025|M|   - In treatment-experienced patients with at least one|
01592|026|M|darunavir-associated resistance mutation or with no resistance information,|
01592|027|M|coadministration of darunavir is not recommended because lower minimum|
01592|028|M|concentrations (Cmin) of darunavir increase the risk for HIV treatment|
01592|029|M|failure.(2-3)|
01592|030|B||
01592|031|D|DISCUSSION:  In a study in 14 subjects, concurrent darunavir/ritonavir|
01592|032|D|(1200/100 mg twice daily) with lopinavir/ritonavir (400/100 mg twice daily)|
01592|033|D|decreased darunavir maximum concentration (Cmax), area-under-curve (AUC),|
01592|034|D|and minimum concentration (Cmin) by 21%, 38%, and 51%, respectively.|
01592|035|D|Lopinavir AUC and Cmin increased by 9% and 23%, respectively, when compared|
01592|036|D|to the administration of lopinavir/ritonavir (400/100 mg twice daily)|
01592|037|D|administered alone.(1)|
01592|038|D|  In a study in 15 subjects, concurrent darunavir/ritonavir (1200/100 mg|
01592|039|D|twice daily) with lopinavir/ritonavir (533/133.3 mg twice daily) decreased|
01592|040|D|darunavir Cmax, AUC, and Cmin by 21%, 41%, and 55%, respectively.  Lopinavir|
01592|041|D|Cmax, AUC, and Cmin increased by 11%, 9%, and 13%, respectively, when|
01592|042|D|compared to the administration of lopinavir/ritonavir (400/100 mg twice|
01592|043|D|daily) administered alone.(1)|
01592|044|D|   In a study in 14 subjects, concurrent darunavir/ritonavir (400/100 mg|
01592|045|D|twice daily) with saquinavir (1000 mg twice daily) decreased the darunavir|
01592|046|D|Cmax, AUC, and Cmin by 17%, 26%, and 42%, respectively.  Saquinavir Cmax,|
01592|047|D|AUC, and Cmin decreased by 6%, 6%, and 18%, respectively, when compared to|
01592|048|D|saquinavir/ritonavir (1000/100 mg twice daily) administered alone.(1)|
01592|049|D|   In a study in 8 subjects, concurrent darunavir (800 mg once daily) with|
01592|050|D|ombitasvir-paritaprevir-ritonavir-dasabuvir (Viekira Pak) decreased the|
01592|051|D|darunavir Cmax, AUC, and Cmin by 8%, 24%, and 48%, respectively, Darunavir|
01592|052|D|administered with Viekira Pak in the morning was compared to darunavir|
01592|053|D|administered with ritonavir (100 mg) in the morning. In a study in 7|
01592|054|D|subjects, concurrent darunavir (600 mg twice daily) with ritonavir (100 mg|
01592|055|D|once daily in the evening) with Viekira Pak decreased the darunavir Cmax,|
01592|056|D|AUC, and Cmin by 13%, 20%, and 43%, respectively. In a study in 10 subjects,|
01592|057|D|darunavir (800 mg) and ritonavir (100 mg once daily in the evening) with|
01592|058|D|Viekira Pak decreased the darunavir Cmax and Cmin by 21% and 46%.|
01592|059|D|Darunavir's AUC was increased by 34%.(2)|
01592|060|B||
01592|061|R|REFERENCES:|
01592|062|B||
01592|063|R|1.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01592|064|R|  March, 2023.|1
01592|065|R|2.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
01592|066|R|  prescribing information. AbbVie Inc. December, 2019.|1
01592|067|R|3.FDA. CDER Application number: 2066190 Viekira Pak (ombitasvir,|1
01592|068|R|  paritaprevir, ritonavir, dasabuvir) Clinical Pharmacology and|1
01592|069|R|  Biopharmaceutics Review(s). URL:|1
01592|070|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206619Orig1s000Clin|1
01592|071|R|  PharmR.pdf December 19, 2014.|1
01593|001|T|MONOGRAPH TITLE:  Pravastatin/Darunavir|
01593|002|B||
01593|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01593|004|L|take action as needed.|
01593|005|B||
01593|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.(1)|
01593|007|B||
01593|008|E|CLINICAL EFFECTS:  Concurrent use of darunavir may result in elevated levels|
01593|009|E|of and toxicity from pravastatin, including rhabdomyolysis.(1)|
01593|010|B||
01593|011|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01593|012|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01593|013|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01593|014|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01593|015|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01593|016|P|transporter OATP1B1 may have increased statin concentrations and be|
01593|017|P|predisposed to myopathy or rhabdomyolysis.|
01593|018|B||
01593|019|M|PATIENT MANAGEMENT:  Consider the use of fluvastatin in patients receiving|
01593|020|M|darunavir.  If pravastatin is used, use the lowest possible dose of|
01593|021|M|pravastatin with careful monitoring.(1)|
01593|022|B||
01593|023|D|DISCUSSION:  In a study in 14 subjects, concurrent darunavir/ritonavir|
01593|024|D|(400/100 mg twice daily) increased the maximum concentration (Cmax) and|
01593|025|D|area-under-curve (AUC) of a single dose of pravastatin (40 mg) by 63% and|
01593|026|D|81%, respectively.  However, pravastatin AUC increased by up to 5-fold in|
01593|027|D|some subjects.(1)|
01593|028|B||
01593|029|R|REFERENCE:|
01593|030|B||
01593|031|R|1.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01593|032|R|  March, 2023.|1
01594|001|T|MONOGRAPH TITLE:  Dasatinib/QT Prolonging Agents|
01594|002|B||
01594|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01594|004|L|take action as needed.|
01594|005|B||
01594|006|A|MECHANISM OF ACTION:  Concurrent use of dasatinib and agents known to|
01594|007|A|prolong the QT interval may result in additive or synergistic effects on the|
01594|008|A|QTc interval.(1)|
01594|009|B||
01594|010|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01594|011|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01594|012|E|torsades de pointes.|
01594|013|B||
01594|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01594|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01594|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01594|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01594|018|P|gender, or advanced age.(3)|
01594|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01594|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01594|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01594|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01594|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01594|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01594|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01594|026|B||
01594|027|M|PATIENT MANAGEMENT:  The US manufacturer of dasatinib states that dasatinib|
01594|028|M|should be used with caution when given with other agents known to prolong|
01594|029|M|the QT interval.(1)|
01594|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01594|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01594|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01594|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01594|034|B||
01594|035|D|DISCUSSION:  A retrospective review of 618 cancer patients treated with 902|
01594|036|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
01594|037|D|incidence of QTc prolongation.  In patients who received dasatinib, QTc|
01594|038|D|prolongation was identified in 48 (41.7%) with 8 (16.7%) having Grade 1 (QTc|
01594|039|D|450-480 ms) and 15 (31.3%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
01594|040|D|occurred in 8 (16.7%) having QTc greater than or equal to 500 ms and 14|
01594|041|D|(29.2%) having QTc change greater than or equal to 60 ms.  Ventricular|
01594|042|D|tachycardia was seen in 2 (4.2%) of patients and 1 (2.1%) patient|
01594|043|D|experienced TdP.(4)|
01594|044|D|   Agents that are linked to this monograph may have varying degrees of|
01594|045|D|potential to prolong the QTc interval. Agents linked to this monograph have|
01594|046|D|been shown to prolong the QTc interval either through their mechanism of|
01594|047|D|action, through studies on their effects on the QTc interval, or through|
01594|048|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01594|049|D|and/or postmarketing reports.(2)|
01594|050|B||
01594|051|R|REFERENCES:|
01594|052|B||
01594|053|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01594|054|R|  Company February, 2023.|1
01594|055|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01594|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01594|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01594|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01594|059|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01594|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01594|061|R|  settings: a scientific statement from the American Heart Association and|6
01594|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01594|063|R|  2;55(9):934-47.|6
01594|064|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
01594|065|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
01594|066|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
01595|001|T|MONOGRAPH TITLE:  Selected Kinase Inhibitors/Antacids|
01595|002|B||
01595|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01595|004|L|take action as needed.|
01595|005|B||
01595|006|A|MECHANISM OF ACTION:  The solubility of bosutinib,(1) dasatinib,(2)|
01595|007|A|erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and|
01595|008|A|pexidartinib(8) is pH dependent.  Antacid-induced changes in gastric pH may|
01595|009|A|decrease the absorption of these agents.(1-8)|
01595|010|B||
01595|011|E|CLINICAL EFFECTS:  Simultaneous administration of antacids may result in|
01595|012|E|decreased levels and effectiveness of bosutinib,(1) dasatinib,(2)|
01595|013|E|erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and|
01595|014|E|pexidartinib.(8)|
01595|015|B||
01595|016|P|PREDISPOSING FACTORS:  None determined.|
01595|017|B||
01595|018|M|PATIENT MANAGEMENT:  Antacid use should be considered in place of H2|
01595|019|M|blockers or proton pump inhibitors in patients receiving bosutinib,(1)|
01595|020|M|dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6),|
01595|021|M|pazopanib,(7) and pexidartinib;(8) however, separation of administration|
01595|022|M|times is required.|
01595|023|M|   If antacids are used, separate the administration times by several|
01595|024|M|hours(1-8) but at least 2 hours for bosutinib,(1) dasatinib,(2)|
01595|025|M|nilotinib,(6) and pexidartinib(8), 6 hours for gefitinib,(4) and 3 hours for|
01595|026|M|neratinib.(5)|
01595|027|M|   Some vitamin preparations may contain sufficient quantities of calcium|
01595|028|M|and/or magnesium salts with antacid properties to interact as well.|
01595|029|B||
01595|030|D|DISCUSSION:  In a study in 24 healthy subjects, lansoprazole (60 mg)|
01595|031|D|decreased bosutinib (400 mg single dose) area-under-curve (AUC) and maximum|
01595|032|D|concentration (Cmax) by 26% and 46%, respectively.(1)|
01595|033|D|   In a study in 24 healthy subjects, simultaneous administration of|
01595|034|D|dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml)|
01595|035|D|decreased dasatinib AUC and Cmax by 55% and 58%, respectively.  In the same|
01595|036|D|subjects, administration of the antacid 2 hours before dasatinib decreased|
01595|037|D|dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(2)|
01595|038|D|   In a study in 24 healthy subjects, administration of a single dose of|
01595|039|D|dasatinib (50 mg) 10 hours after famotidine decreased dasatinib AUC and Cmax|
01595|040|D|by 61% and 63%, respectively.(2)|
01595|041|D|   In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib|
01595|042|D|by 46% and 61%, respectively.3)|
01595|043|D|   In a study, concurrent esomeprazole decreased the AUC of nilotinib by|
01595|044|D|34%.(6)|
01595|045|D|   In a study in 15 healthy subjects, lansoprazole (30 mg at steady state)|
01595|046|D|decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and|
01595|047|D|65%, respectively.(5)|
01595|048|D|   There were no significant changes in nilotinib pharmacokinetics when|
01595|049|D|famotidine was administered 10 hours before or 2 hours after nilotinib.(6)|
01595|050|D|   There were no significant changes in nilotinib pharmacokinetics when an|
01595|051|D|antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was|
01595|052|D|administered 2 hours before or after nilotinib.(6)|
01595|053|D|   Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by|
01595|054|D|55% and 50%.(8)|
01595|055|B||
01595|056|R|REFERENCES:|
01595|057|B||
01595|058|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
01595|059|R|  2023.|1
01595|060|R|2.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01595|061|R|  Company February, 2023.|1
01595|062|R|3.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
01595|063|R|  2016.|1
01595|064|R|4.Iressa (gefitinib) US prescribing information. AstraZeneca March 6, 2012.|1
01595|065|R|5.Nerlynx (neratinib) US prescribing information. Puma Biotechnology, Inc.|1
01595|066|R|  June, 2021.|1
01595|067|R|6.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01595|068|R|  Corporation September, 2021.|1
01595|069|R|7.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
01595|070|R|  2020.|1
01595|071|R|8.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
01595|072|R|  November, 2023.|1
01596|001|T|MONOGRAPH TITLE:  Selected Kinase Inhibitors/Proton Pump Inhibitors|
01596|002|B||
01596|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01596|004|L|of severe adverse interaction.|
01596|005|B||
01596|006|A|MECHANISM OF ACTION:  The solubility of bosutinib,(1) dacomitinib,(2)|
01596|007|A|dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7)|
01596|008|A|pazopanib(8), and pexidartinib (9) is pH dependent.  Changes in gastric pH|
01596|009|A|from proton pump inhibitors may decrease the absorption of bosutinib,(1)|
01596|010|A|dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6)|
01596|011|A|nilotinib,(7) pazopanib,(8) and pexidartinib.(9)|
01596|012|B||
01596|013|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
01596|014|E|levels and effectiveness of bosutinib,(1) dacomitinib,(2) dasatinib,(3)|
01596|015|E|erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and|
01596|016|E|pexidartinib.(9)|
01596|017|B||
01596|018|P|PREDISPOSING FACTORS:  None determined.|
01596|019|B||
01596|020|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs) in|
01596|021|M|patients receiving treatment with bosutinib,(1) dacomitinib,(2)|
01596|022|M|dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7)|
01596|023|M|pazopanib,(8) and pexidartinib.(9)|
01596|024|M|   Consider the use of short-acting antacids in these patients.(1-9)  If|
01596|025|M|antacids are used, separate the administration times by several hours(1-9)|
01596|026|M|but at least 2 hours for bosutinib,(1) dasatinib,(3) nilotinib,(7) and|
01596|027|M|pexidartinib(9), 6 hours for gefitinib,(5) and 3 hours for neratinib.(6)|
01596|028|M|   If PPIs are required with gefitinib, administer gefitinib 12 hours after|
01596|029|M|the last dose or 12 hours before the next dose of the PPI.  Administer|
01596|030|M|gefitinib 6 hours before or after H2-antagonists or antacids.(5)|
01596|031|M|   If H2 antagonist therapy is used with bosutinib, separate administration|
01596|032|M|by at least 2 hours.(1)|
01596|033|M|   If H2 antagonist therapy is required with dacomitinib, dacomitinib must|
01596|034|M|be given once daily 10 hours after the H2 blocker and 6 hours before the|
01596|035|M|next dose of the H2 blocker.(2)|
01596|036|M|   If H2 antagonist therapy is required with erlotinib, neratinib,|
01596|037|M|nilotinib, or pexidartinib, the kinase inhibitor must be given 10 hours|
01596|038|M|after the H2 blocker and at least 2 hours before the next dose of the H2|
01596|039|M|blocker.(4,6,7,9)|
01596|040|M|   If H2 antagonist therapy is required with gefitinib, gefitinib should be|
01596|041|M|given at least 6 hours before or after the H2 antagonist.(5)|
01596|042|M|   The manufacturer of Phyrago states that it can be administered with|
01596|043|M|gastric acid reducing agents. Administration times should be separated with|
01596|044|M|antacids.|
01596|045|B||
01596|046|D|DISCUSSION:  In a study, concurrent rabeprazole decreased the Cmax and AUC|
01596|047|D|of dacomitinib by 51% and 39%, respectively.(2)|
01596|048|D|   In a study in 24 healthy subjects, administration of a single dose of|
01596|049|D|dasatinib (50 mg) 10 hours after famotidine decreased dasatinib|
01596|050|D|area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%,|
01596|051|D|respectively.(3)|
01596|052|D|   In a study in 14 healthy subjects, administration of a single dose of|
01596|053|D|dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state)|
01596|054|D|decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(3)|
01596|055|D|   In a study in 24 healthy subjects, simultaneous administration of|
01596|056|D|dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml)|
01596|057|D|decreased dasatinib AUC and Cmax by 55% and 58%, respectively.  In the same|
01596|058|D|subjects, administration of the antacid 2 hours before dasatinib decreased|
01596|059|D|dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(3)|
01596|060|D|   In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib|
01596|061|D|by 46% and 61%, respectively.(4)|
01596|062|D|   In a study, administration of erlotinib two hours after a dose of|
01596|063|D|ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%,|
01596|064|D|respectively.  Administration of erlotinib 10 hours after and two hours|
01596|065|D|before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by|
01596|066|D|15% and 17%, respectively.(4)|
01596|067|D|   In a case report, a patient that was given erlotinib (150 mg daily,) with|
01596|068|D|algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before|
01596|069|D|or 2 hours after erlotinib) did not see a significant reduction in serum|
01596|070|D|trough concentrations of erlotinib.  When the patient was switched to|
01596|071|D|intravenous pantoprazole via continuous infusion (8 mg per hour), serum|
01596|072|D|erlotinib levels decreased significantly below minimal trough concentrations|
01596|073|D|for effective tyrosine kinase inhibition.  When the patient was switched to|
01596|074|D|oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib|
01596|075|D|returned to therapeutic levels.(9)|
01596|076|D|   In a study in healthy subjects, high dose ranitidine with sodium|
01596|077|D|carbonate was administered to maintain gastric pH above 5.0 and gefitinib|
01596|078|D|AUC decreased 47%.(5)|
01596|079|D|   In a study in 15 healthy subjects, lansoprazole (30 mg at steady state)|
01596|080|D|decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and|
01596|081|D|65%, respectively.(6)|
01596|082|D|   In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg|
01596|083|D|daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by|
01596|084|D|27% and 34%, respectively.(7,10)  Increasing the dosage of nilotinib or|
01596|085|D|separating the administration time of nilotinib and the proton pump|
01596|086|D|inhibitor is not expected to eliminate the interaction.(7)|
01596|087|D|   There were no significant changes in nilotinib pharmacokinetics when|
01596|088|D|famotidine was administered 10 hours before or 2 hours after nilotinib.(7)|
01596|089|D|   There were no significant changes in nilotinib pharmacokinetics when an|
01596|090|D|antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was|
01596|091|D|administered 2 hours before or after nilotinib.(7)|
01596|092|D|   In a study in 13 patients, esomeprazole (40 mg daily for 5 days)|
01596|093|D|decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%,|
01596|094|D|respectively, when compared to the administration of pazopanib alone.(11)|
01596|095|D|   In an open-label, crossover study in 17 evaluable patients, omeprazole|
01596|096|D|(40 mg daily) had no significant effects on the pharmacokinetics,|
01596|097|D|pharmacodynamics, or safety of bortezomib (1.3 mg/m2).(12)|
01596|098|D|   Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by|
01596|099|D|55% and 50%. (13)|
01596|100|D|   Phyrago is not sensitive to increased gastric pH due to its polymer|
01596|101|D|formulation. No clinically significant dasatinib pharmacokinetic changes|
01596|102|D|were seen with concurrent administration of Phyrago with omeprazole (proton|
01596|103|D|pump inhibitor) or famotidine (H2 receptor antagonist).(14)|
01596|104|B||
01596|105|R|REFERENCES:|
01596|106|B||
01596|107|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
01596|108|R|  2023.|1
01596|109|R|2.Vizimpro (dacomitinib) US prescribing information. Pfizer, Inc. September,|1
01596|110|R|  2018.|1
01596|111|R|3.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01596|112|R|  Company February, 2023.|1
01596|113|R|4.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
01596|114|R|  2016.|1
01596|115|R|5.Iressa (gefitinib) US prescribing information. AstraZeneca March 6, 2012.|1
01596|116|R|6.Nerlynx (neratinib) US prescribing information. Puma Biotechnology, Inc.|1
01596|117|R|  June, 2021.|1
01596|118|R|7.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01596|119|R|  Corporation September, 2021.|1
01596|120|R|8.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
01596|121|R|  2020.|1
01596|122|R|9.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
01596|123|R|  November, 2023.|1
01596|124|R|10.Ter Heine R, Fanggiday JC, Lankheet NA, Beijnen JH, Van Der Westerlaken|3
01596|125|R|   MM, Staaks GH, Malingre MM. Erlotinib and pantoprazole: a relevant|3
01596|126|R|   interaction or not?. Br J Clin Pharmacol 2010 Dec;70(6):908-11.|3
01596|127|R|11.Yin OQ, Gallagher N, Fischer D, Demirhan E, Zhou W, Golor G, Schran H.|2
01596|128|R|   Effect of the Proton Pump Inhibitor Esomeprazole on the Oral Absorption|2
01596|129|R|   and Pharmacokinetics of Nilotinib. J Clin Pharmacol 2010 May 24.|2
01596|130|R|12.Tan AR, Gibbon DG, Stein MN, Lindquist D, Edenfield JW, Martin JC,|2
01596|131|R|   Gregory C, Suttle AB, Tada H, Botbyl J, Stephenson JJ. Effects of|2
01596|132|R|   ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in|2
01596|133|R|   patients with solid tumors. Cancer Chemother Pharmacol 2013 Jun;|2
01596|134|R|   71(6):1635-43.|2
01596|135|R|13.Quinn DI, Nemunaitis J, Fuloria J, Britten CD, Gabrail N, Yee L, Acharya|2
01596|136|R|   M, Chan K, Cohen N, Dudov A. Effect of the cytochrome P450 2C19 inhibitor|2
01596|137|R|   omeprazole on the pharmacokinetics and safety profile of bortezomib in|2
01596|138|R|   patients with advanced solid tumours, non-Hodgkin's lymphoma or multiple|2
01596|139|R|   myeloma. Clin Pharmacokinet 2009;48(3):199-209.|2
01596|140|R|14.Phyrago (dasatinib) US Prescribing Information. Nanocopoeia, LLC December|1
01596|141|R|   2024.|1
01597|001|T|MONOGRAPH TITLE:  Tipranavir/Anticoagulants; Antiplatelets|
01597|002|B||
01597|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01597|004|L|of severe adverse interaction.|
01597|005|B||
01597|006|A|MECHANISM OF ACTION:  Tipranavir has been shown to inhibit platelet|
01597|007|A|aggregation in vitro in human platelets(1-3) and in rodents.(1,2)  The|
01597|008|A|mechanism behind this platelet aggregation is unknown.(1,2)|
01597|009|B||
01597|010|E|CLINICAL EFFECTS:  Concurrent use of tipranavir with anticoagulants and/or|
01597|011|E|antiplatelet agents may result in additive or synergistic effects, including|
01597|012|E|fatal and non-fatal intracranial hemorrhage.(1-3)|
01597|013|B||
01597|014|P|PREDISPOSING FACTORS:  The risk of intracranial hemorrhage may be increased|
01597|015|P|by CNS lesions, head trauma, neurosurgery, coagulopathy, hypertension, or|
01597|016|P|alcohol abuse.(1-3)|
01597|017|P|   The risk for bleeding episodes may also be greater in patients with other|
01597|018|P|disease-associated factors (e.g. thrombocytopenia).|
01597|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
01597|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01597|021|P|risk for bleeding (e.g. NSAIDs).|
01597|022|B||
01597|023|M|PATIENT MANAGEMENT:  Tipranavir should be administered with caution in|
01597|024|M|patients receiving anticoagulants and/or antiplatelet agents.|
01597|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01597|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01597|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01597|028|M|patients with any symptoms.|
01597|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01597|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01597|031|M|anticoagulation in patients with active pathologic bleeding.|
01597|032|M|   Patients should be warned that tipranavir has been associated with fatal|
01597|033|M|and non-fatal intracranial hemorrhage and instructed to report any unusual|
01597|034|M|or unexplained bleeding to their physician.(1-3)  Signs or symptoms of|
01597|035|M|bleeding may include unusual bleeding from the gums or nose; unusual|
01597|036|M|bruising; red or black, tarry stools; red, pink or dark brown urine; acute|
01597|037|M|abdominal or joint pain and/or swelling.|
01597|038|B||
01597|039|D|DISCUSSION:  As of June 7, 2006,(3) the manufacturer of tipranavir has has|
01597|040|D|identified 14 cases of intracranial hemorrhage, including 8 fatalities, in|
01597|041|D|13 out of 6,840 HIV+ subjects in clinical trials.(1,3)  No pattern of|
01597|042|D|abnormal coagulation parameters has been noted in patients receiving|
01597|043|D|tipranavir in general or preceding the development of intracranial|
01597|044|D|hemorrhage.(1-3)|
01597|045|D|   In vitro tests showed that tipranavir inhibits human platelet aggregation|
01597|046|D|at concentrations consistent with normal exposure during therapy.  In|
01597|047|D|rodents, tipranavir resulted in increased prothrombin and activated partial|
01597|048|D|thromboplastin times.  At higher doses and in extreme cases, these changes|
01597|049|D|resulted in bleeding in multiple organs and death.  This effect was not seen|
01597|050|D|in studies in dogs.(1,2)|
01597|051|B||
01597|052|R|REFERENCES:|
01597|053|B||
01597|054|R|1.Dear Healthcare Professional:  Subject:  Important safety information:|1
01597|055|R|  Intracranial hemorrhage in patients receiving Aptivus (tipranavir)|1
01597|056|R|  capsules. Boehringer Ingelheim June 30, 2006.|1
01597|057|R|2.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01597|058|R|  Pharmaceuticals, Inc. April, 2024.|1
01597|059|R|3.Dear Canadian Healthcare Professional:  Subject:  Important safety|1
01597|060|R|  information:  Intracranial hemorrhage in patients receiving Aptivus|1
01597|061|R|  (tipranavir) capsules. Boehringer Ingelheim June 29, 2006.|1
01598|001|T|MONOGRAPH TITLE:  HMG-CoA Reductase Inhibitors/Daptomycin|
01598|002|B||
01598|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01598|004|L|of severe adverse interaction.|
01598|005|B||
01598|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown but may involve|
01598|007|A|additive or synergistic effects on skeletal muscle.|
01598|008|B||
01598|009|E|CLINICAL EFFECTS:  Concurrent use of HMG-CoA reductase inhibitors and|
01598|010|E|daptomycin can result in elevated creatinine phosphokinase (CPK) levels and|
01598|011|E|skeletal muscle effects.(1)|
01598|012|B||
01598|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01598|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01598|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01598|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01598|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01598|018|P|transporter OATP1B1 may have increased statin concentrations and be|
01598|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
01598|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
01598|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
01598|022|P|Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may|
01598|023|P|have increased fluvastatin concentrations and  risk of myopathy.|
01598|024|B||
01598|025|M|PATIENT MANAGEMENT:  The manufacturer of daptomycin recommends considering|
01598|026|M|suspending HMG-CoA reductase inhibitor therapy in patients receiving|
01598|027|M|daptomycin.  CPK levels should be monitored more frequently than the weekly|
01598|028|M|standard frequency in patients who have recently received HMG-CoA reductase|
01598|029|M|therapy or in whom concurrent therapy is warranted.  Closely monitor|
01598|030|M|patients for the development of muscle pain and/or weakness.(1)|
01598|031|B||
01598|032|D|DISCUSSION:  In the Phase 3 Staphylococcus aureus bacteremia/endocarditis|
01598|033|D|trial, 5 of 22 patients who received prior or concurrent HMG Co-A reductase|
01598|034|D|inhibitor therapy developed CPK elevations greater than 500 U/L.  At a dose|
01598|035|D|of 6 mg/kg of daptomycin, a total of 11 patients developed CPK elevations|
01598|036|D|greater than 500 U/L.  Of these, 4 had prior or concurrent HMG Co-A|
01598|037|D|reductase therapy.  Rhabdomyolysis in patients treated concurrently with HMG|
01598|038|D|Co-A reductase inhibitors has been reported in post-marketing experience.(1)|
01598|039|D|   In 20 healthy subjects, concurrent simvastatin (40 mg daily) and|
01598|040|D|daptomycin (4 mg/kg daily) was not associated with a higher incidence of|
01598|041|D|adverse effects when compared to 10 subjects receiving placebo.(1)|
01598|042|B||
01598|043|R|REFERENCE:|
01598|044|B||
01598|045|R|1.Cubicin (daptomycin) US prescribing information. Cubist Pharmaceuticals,|1
01598|046|R|  Inc. August, 2022.|1
01599|001|T|MONOGRAPH TITLE:  Amphotericin B/Corticosteroids; Corticotropin (ACTH)|
01599|002|B||
01599|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01599|004|L|of severe adverse interaction.|
01599|005|B||
01599|006|A|MECHANISM OF ACTION:  Corticosteroids and corticotropin may potentiate|
01599|007|A|potassium excretion and overload salt and water retention.(1)|
01599|008|B||
01599|009|E|CLINICAL EFFECTS:  Concurrent use of amphotericin b with corticosteroids or|
01599|010|E|corticotropin may potentiate amphotericin b-induced hypokalemia, thereby|
01599|011|E|predisposing patients to cardiac dysfunction.(1-2)|
01599|012|B||
01599|013|P|PREDISPOSING FACTORS:  None determined.|
01599|014|B||
01599|015|M|PATIENT MANAGEMENT:  The US manufacturer of amphotericin b states that|
01599|016|M|concurrent use of corticosteroids or corticotropin should be avoided unless|
01599|017|M|absolutely necessary to avoid side effects.  If concurrent use is necessary,|
01599|018|M|serum electrolytes and cardiac function must be monitored closely.(1)|
01599|019|B||
01599|020|D|DISCUSSION:  There are four case reports of cardiac enlargement,|
01599|021|D|hypokalemia, and hypernatremia from concurrent use of amphotericin b and|
01599|022|D|corticosteroids.(2)|
01599|023|B||
01599|024|R|REFERENCES:|
01599|025|B||
01599|026|R|1.Amphotericin B US prescribing information. X-Gen Pharmaceuticals|1
01599|027|R|  September, 2005.|1
01599|028|R|2.Chung DK, Koenig MG. Reversible cardiac enlargement during treatment with|3
01599|029|R|  amphotericin B and hydrocortisone. Report of three cases. Am Rev Respir|3
01599|030|R|  Dis 1971 Jun;103(6):831-41.|3
01600|001|T|MONOGRAPH TITLE:  Colistimethate/Selected Nephrotoxic Agents|
01600|002|B||
01600|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01600|004|L|of severe adverse interaction.|
01600|005|B||
01600|006|A|MECHANISM OF ACTION:  Colistimethate can cause nephrotoxicity.(1,2)|
01600|007|A|Concurrent administration of other nephrotoxic agents may result in an|
01600|008|A|increased risk of nephrotoxicity.(1)|
01600|009|A|   It is suspected that cephalothin interferes with the excretion of|
01600|010|A|colistimethate resulting in enhanced nephrotoxicity.(2,3)|
01600|011|B||
01600|012|E|CLINICAL EFFECTS:  Concurrent use of colistimethate with other nephrotoxic|
01600|013|E|agents may result in additive nephrotoxic effects.|
01600|014|B||
01600|015|P|PREDISPOSING FACTORS:  Factors predisposing to nephrotoxicity include higher|
01600|016|P|cumulative doses of colistimethate, longer treatment duration, hypovolemia,|
01600|017|P|and critical illness.|
01600|018|B||
01600|019|M|PATIENT MANAGEMENT:  Concurrent use of potentially nephrotoxic agents with|
01600|020|M|colistimethate should be avoided.(1,2)  If concurrent use is necessary, it|
01600|021|M|should be undertaken with great caution.(1)|
01600|022|B||
01600|023|D|DISCUSSION:  In a case control study of 42 patients on intravenous|
01600|024|D|colistimethate sodium, NSAIDs were identified as an independent risk factor|
01600|025|D|for nephrotoxicity (OR 40.105, p=0.044).(4)|
01600|026|D|   In 4 case reports, patients developed elevated serum creatinine and blood|
01600|027|D|urea nitrogen following concurrent colistimethate and cephalothin (3|
01600|028|D|patients) or when colistimethate followed cephalothin therapy (1|
01600|029|D|patient).(3)|
01600|030|D|   A literature review found that individual nephrotoxic agents, including|
01600|031|D|aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE|
01600|032|D|inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently|
01600|033|D|associated with additive nephrotoxicity when used with colistimethate.|
01600|034|D|However, when multiple agents (at least 2 additional potential nephrotoxins)|
01600|035|D|were used concurrently, there was a significant correlation to|
01600|036|D|colistimethate nephrotoxicity.(5)|
01600|037|B||
01600|038|R|REFERENCES:|
01600|039|B||
01600|040|R|1.Colomycin (colistimethate) UK Summary of Prescribing Information. Teva UK|1
01600|041|R|  Limited May 27, 2020.|1
01600|042|R|2.Coly-Mycin M (colistimethate) US prescribing information. Par|1
01600|043|R|  Pharmaceutical December, 2018.|1
01600|044|R|3.Adler S, Segel DP. Nonoliguric renal failure secondary to sodium|3
01600|045|R|  colistimethate: a report of four cases. Am J Med Sci 1971 Aug;|3
01600|046|R|  262(2):109-14.|3
01600|047|R|4.Pike M, Saltiel E. Colistin- and polymyxin-induced nephrotoxicity: focus|6
01600|048|R|  on literature utilizing the  RIFLE classification scheme of acute kidney|6
01600|049|R|  injury. J Pharm Pract 2014 Dec;27(6):554-61.|6
01600|050|R|5.Kim J, Lee KH, Yoo S, Pai H. Clinical characteristics and risk factors of|2
01600|051|R|  colistin-induced nephrotoxicity. Int J Antimicrob Agents 2009 Nov;|2
01600|052|R|  34(5):434-8.|2
01601|001|T|MONOGRAPH TITLE:  Dantrolene/Calcium Channel Blockers|
01601|002|B||
01601|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01601|004|L|of severe adverse interaction.|
01601|005|B||
01601|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Dantrolene may|
01601|007|A|decrease the release of calcium from the sarcoplasmic reticulum, resulting|
01601|008|A|in additive or synergistic effects with calcium channel blockers.(1)|
01601|009|B||
01601|010|E|CLINICAL EFFECTS:  Concurrent use of dantrolene and calcium channel blockers|
01601|011|E|may result in cardiogenic shock.(2-4)|
01601|012|B||
01601|013|P|PREDISPOSING FACTORS:  None determined.|
01601|014|B||
01601|015|M|PATIENT MANAGEMENT:  The US, UK, and Australian manufacturers of dantrolene|
01601|016|M|state that concurrent use with calcium channel blockers during the|
01601|017|M|management of malignant hyperthermia crisis is not recommended.(2-4)|
01601|018|M|   The Australian and UK manufacturers of diltiazem state that concurrent|
01601|019|M|use of dantrolene infusion with calcium channel blockers is|
01601|020|M|contraindicated.(5-6)|
01601|021|B||
01601|022|D|DISCUSSION:  Cardiogenic shock in patients treated simultaneously with|
01601|023|D|verapamil and dantrolene is rare but has been reported.(2-4,7)  Concurrent|
01601|024|D|use of dantrolene and verapamil in swine has been reported to result in|
01601|025|D|cardiogenic shock and hyperkalemia.(8)  In dogs, the combination has been|
01601|026|D|reported to cause hyperkalemia.(9)|
01601|027|D|   The combination of diltiazem and dantrolene has been reported to cause|
01601|028|D|adverse cardiovascular effects in swine.(10)|
01601|029|D|   A study in swine showed no adverse effects from the combination of|
01601|030|D|dantrolene and nifedipine(10) and one patient who experience cardiogenic|
01601|031|D|shock with dantrolene and verapamil had no adverse effects with the|
01601|032|D|combination of dantrolene and nifedipine;(7) however, the US manufacturer|
01601|033|D|cannot endorse the safety of the combination.(2)|
01601|034|B||
01601|035|R|REFERENCES:|
01601|036|B||
01601|037|R|1.Goodman-Gilman A. In Gilman AG, Rall TW, Nies AS, Taylor P, editors:|6
01601|038|R|  Goodman and Gilman's The Phamacological Basis of Therapeutics. 8th|6
01601|039|R|  edition. Elmsford, New York: Pergamon Press, Inc. 1990.|6
01601|040|R|2.Dantrium (dantrolene sodium) US prescribing information. JHP|1
01601|041|R|  Pharmaceuticals, LLC. July, 2012.|1
01601|042|R|3.Dantrolene Australian Product Information. Pfizer Australia Pty Ltd|1
01601|043|R|  September, 2020.|1
01601|044|R|4.Agilus (dantrolene) UK Summary of Product Characteristics. Norgine Limited|1
01601|045|R|  July, 2024.|1
01601|046|R|5.Cardizem (diltiazem) Australian Product Information. sanofi-aventis|1
01601|047|R|  australia pty ltd August, 2024.|1
01601|048|R|6.Tildiem LA (diltiazem) UK Summary of Product Characteristics. Sanofi May,|1
01601|049|R|  2024.|1
01601|050|R|7.Rubin AS, Zablocki AD. Hyperkalemia, verapamil, and dantrolene.|3
01601|051|R|  Anesthesiology 1987 Feb;66(2):246-9.|3
01601|052|R|8.Saltzman LS, Kates RA, Corke BC, Norfleet EA, Heath KR. Hyperkalemia and|5
01601|053|R|  cardiovascular collapse after verapamil and dantrolene administration in|5
01601|054|R|  swine. Anesth Analg 1984 May;63(5):473-8.|5
01601|055|R|9.San Juan AC Jr, Wong KC, Port JD. Hyperkalemia after dantrolene and|5
01601|056|R|  verapamil-dantrolene administration in dogs. Anesth Analg 1988 Aug;|5
01601|057|R|  67(8):759-62.|5
01601|058|R|10.Saltzman LS, Kates RA, Norfleet EA, Corke BC, Heath KR. Hemodynamic|5
01601|059|R|   interactions of diltiazem-dantrolene and nifedipine-dantrolene.|5
01601|060|R|   Anesthesiology 1984.|5
01602|001|T|MONOGRAPH TITLE:  Gadoxetate/QT Prolonging Agents (mono deleted 06/14/2018)|
01602|002|B||
01602|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01602|004|L|take action as needed.|
01602|005|B||
01602|006|A|MECHANISM OF ACTION:  Concurrent use of gadoxetate and agents known to|
01602|007|A|prolong the QT interval may result in additive or synergistic effects on the|
01602|008|A|QTc interval.(1,2)|
01602|009|B||
01602|010|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01602|011|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01602|012|E|torsades de pointes.|
01602|013|B||
01602|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01602|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01602|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01602|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01602|018|P|gender, or advanced age.(4)|
01602|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01602|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01602|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01602|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01602|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01602|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01602|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01602|026|B||
01602|027|M|PATIENT MANAGEMENT:  The Australian(1) and UK(2) manufacturers of gadoxetate|
01602|028|M|state that gadoxetate should be used with caution in patients receiving|
01602|029|M|other agents known to prolong the QT interval.  Gadoxetate's affects on the|
01602|030|M|QTc interval may last at least 28 hours after injection.(1)|
01602|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01602|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01602|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01602|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01602|035|B||
01602|036|D|DISCUSSION:  In vitro and clinical studies suggest that gadoxetate can lead|
01602|037|D|to prolongation of the QTc interval, especially at doses higher than|
01602|038|D|recommended.  Transient QT prolongation with no adverse effects was observed|
01602|039|D|in clinical studies.  In 2 Phase III studies, 2 of 468 patients had an|
01602|040|D|increase in QTc greater than 60 ms from baseline to time-points up to 20-28|
01602|041|D|hours after injection.(1)|
01602|042|D|   Agents that are linked to this monograph may have varying degrees of|
01602|043|D|potential to prolong the QTc interval. Agents linked to this monograph have|
01602|044|D|been shown to prolong the QTc interval either through their mechanism of|
01602|045|D|action, through studies on their effects on the QTc interval, or through|
01602|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01602|047|D|and/or postmarketing reports.(3)|
01602|048|B||
01602|049|R|REFERENCES:|
01602|050|B||
01602|051|R|1.Primovist (gadoxetate disodium) Australian prescribing information.|1
01602|052|R|  Schering-Plough Corporation November 1, 2005.|1
01602|053|R|2.Primovist (gadoxetic acid) UK summary of product characteristics. Bayer|1
01602|054|R|  plc May 1, 2008.|1
01602|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01602|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01602|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01602|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01602|059|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01602|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01602|061|R|  settings: a scientific statement from the American Heart Association and|6
01602|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01602|063|R|  2;55(9):934-47.|6
01603|001|T|MONOGRAPH TITLE:  Clarithromycin/NNRTIs|
01603|002|B||
01603|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01603|004|L|take action as needed.|
01603|005|B||
01603|006|A|MECHANISM OF ACTION:  Efavirenz, etravirine, and nevirapine may induce the|
01603|007|A|metabolism of clarithromycin via CYP3A4.  Clarithromycin may inhibit the|
01603|008|A|metabolism of etravirine by CYP3A4.|
01603|009|A|   Also, delavirdine may inhibit the metabolism of clarithromycin by CYP3A4.|
01603|010|B||
01603|011|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin with efavirenz,|
01603|012|E|etravirine, or nevirapine may alter blood levels of clarithromycin and its|
01603|013|E|active metabolite, 14-OH-clarithromycin, resulting in decreased|
01603|014|E|effectiveness and/or toxicity.|
01603|015|E|   Concurrent use of clarithromycin may increase etravirine levels.|
01603|016|E|   Concurrent use of clarithromycin with delavirdine may increase the levels|
01603|017|E|and toxicities of clarithromycin.|
01603|018|B||
01603|019|P|PREDISPOSING FACTORS:  None determined.|
01603|020|B||
01603|021|M|PATIENT MANAGEMENT:  The US manufacturers of efavirenz,(1,2) etravirine,(3)|
01603|022|M|and nevirapine(4) state that concurrent use with clarithromycin is not|
01603|023|M|recommended and that alternative antibiotic agents, such as azithromycin,|
01603|024|M|should be considered. If concurrent therapy is warranted, monitor patients|
01603|025|M|closely for efficacy and adverse effects.  No dosage adjustment of|
01603|026|M|efavirenz(2) or the combination of efavirenz/emtricitabine/tenofovir(3) is|
01603|027|M|recommended.|
01603|028|M|   The US manufacturer of delavirdine recommends that the dose of|
01603|029|M|clarithromycin be reduced by 50% in patients with a CrCl of 30 ml/min to 60|
01603|030|M|ml/min. For patients with a CrCl of less than 30 ml/min, the dose of|
01603|031|M|clarithromycin should be reduced by 75%. No adjustment is necessary in|
01603|032|M|patients with normal renal function.(5)|
01603|033|B||
01603|034|D|DISCUSSION:  In a study in 11 subjects, concurrent efavirenz (400 mg) and|
01603|035|D|clarithromycin (500 mg twice daily) decreased the maximum concentration|
01603|036|D|(Cmax), AUC, and minimum concentration (Cmin) by 26%, 39%, and 53%,|
01603|037|D|respectively.  The Cmax, AUC, and Cmin of 14-OH-clarithromycin increased by|
01603|038|D|49%, 34%, and 26%, respectively.  The Cmax of efavirenz increased by 11%. In|
01603|039|D|uninfected subjects, 46% developed a rash during concurrent therapy.(1,2)|
01603|040|D|   In a study in 15 subjects, concurrent clarithromycin (500 mg twice daily)|
01603|041|D|increased the Cmax, AUC, and Cmin of etravirine (dosage not stated) by 46%,|
01603|042|D|42%, and 46%, respectively.  The Cmax, AUC, and Cmin of clarithromycin|
01603|043|D|decreased by 34%, 39%, and 53%, respectively.  The Cmax, AUC, and Cmin of|
01603|044|D|14-OH-clarithromycin increased by 33%, 21%, and 5%, respectively.(3)|
01603|045|D|   In a study in 15 subjects, concurrent nevirapine (200 mg daily for 14|
01603|046|D|days, then 200 mg twice daily for 14 days) and clarithromycin (500 mg twice|
01603|047|D|daily) decreased the Cmax, AUC, and Cmin of clarithromycin by 23%, 31%, and|
01603|048|D|56%, respectively.  The Cmax and AUC of 14-OH-clarithromycin increased by|
01603|049|D|47% and 42 %, respectively.(4)|
01603|050|D|   Although 14-OH-clarithromycin is an active metabolite, it has reduced|
01603|051|D|activity against Mycobacterium avium-intracellulare complex.(4)|
01603|052|D|   In a study in 6 subjects, concurrent delavirdine (300 mg 3 times daily)|
01603|053|D|with clarithromycin (500 mg 3 times daily) increased the area-under-curve|
01603|054|D|(AUC) of clarithromycin by 100%.  There was no effect on delavirdine|
01603|055|D|levels.(5)|
01603|056|B||
01603|057|R|REFERENCES:|
01603|058|B||
01603|059|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01603|060|R|  Company November, 2023.|1
01603|061|R|2.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01603|062|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01603|063|R|3.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01603|064|R|  August, 2014.|1
01603|065|R|4.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
01603|066|R|  Pharmaceuticals, Inc. June, 2022.|1
01603|067|R|5.Rescriptor (delavirdine mesylate) US prescribing information. Pharmacia &|1
01603|068|R|  Upjohn Company August, 2012.|1
01604|001|T|MONOGRAPH TITLE:  Solid Oral Potassium Tablets/Anticholinergics|
01604|002|B||
01604|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01604|004|L|of severe adverse interaction.|
01604|005|B||
01604|006|A|MECHANISM OF ACTION:  Concentrated potassium may damage the lining of the GI|
01604|007|A|tract. Anticholinergics delay gastric emptying, resulting in the potassium|
01604|008|A|product remaining in the gastrointestinal tract for a longer period of|
01604|009|A|time.(1-16)|
01604|010|B||
01604|011|E|CLINICAL EFFECTS:  Use of solid oral dosage forms of potassium in patients|
01604|012|E|treated with anticholinergics may result in gastrointestinal erosions,|
01604|013|E|ulcers, stenosis and bleeding.(1-16)|
01604|014|B||
01604|015|P|PREDISPOSING FACTORS:  Diseases or conditions which may increase risk for GI|
01604|016|P|damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic|
01604|017|P|gastroparesis, elderly status, or insufficient oral intake to allow dilution|
01604|018|P|of potassium.(1-10,21)|
01604|019|P|   Other drugs which may add to risk for GI damage include: nonsteroidal|
01604|020|P|anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)|
01604|021|B||
01604|022|M|PATIENT MANAGEMENT:  Regulatory agency and manufacturer recommendations|
01604|023|M|regarding this interaction:|
01604|024|M|   - In the US, all solid oral dosage forms (including tablets and extended|
01604|025|M|release capsules) of potassium are contraindicated in patients receiving|
01604|026|M|anticholinergics at sufficient dosages to result in systemic effects.(2-8)|
01604|027|M|Patients receiving such anticholinergic therapy should use a liquid form of|
01604|028|M|potassium chloride.(2)|
01604|029|M|   - In Canada, solid oral potassium is contraindicated in any patient with|
01604|030|M|a  cause for arrest or delay in tablet/capsule passage through the|
01604|031|M|gastrointestinal tract and the manufacturers recommend caution with|
01604|032|M|concurrent anticholinergic medications.(1,9-10)|
01604|033|M|   Evaluate each patient for predisposing factors which may increase risk|
01604|034|M|for GI damage.  In patients with multiple risk factors for harm, consider|
01604|035|M|use of liquid potassium supplements, if tolerated.  For patients receiving|
01604|036|M|concomitant therapy, assure any potassium dose form is taken after meals|
01604|037|M|with a large glass of water or other fluid. To decrease potassium|
01604|038|M|concentration in the GI tract, limit each dose to 20 meq; if more than 20|
01604|039|M|meq daily is required, give in divided doses.(2)|
01604|040|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01604|041|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01604|042|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01604|043|M|patients with any symptoms.|
01604|044|M|   Patients should be instructed to immediately report any difficulty|
01604|045|M|swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal|
01604|046|M|bleeding.|
01604|047|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01604|048|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01604|049|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01604|050|M|and/or swelling.|
01604|051|B||
01604|052|D|DISCUSSION:  In clinical trials, there was a higher incidence of gastric and|
01604|053|D|duodenal lesions in patients receiving a high dose of a wax-matrix|
01604|054|D|controlled-release formulation with a concurrent anticholinergic agent.|
01604|055|D|Some lesions were asymptomatic and not accompanied by bleeding, as shown by|
01604|056|D|a lack of positive Hemoccult tests.(1-17)|
01604|057|D|   Several studies suggest that the incidence of gastric and duodenal|
01604|058|D|lesions may be less with the microencapsulated formulation of potassium|
01604|059|D|chloride.(14-17)|
01604|060|B||
01604|061|R|REFERENCES:|
01604|062|B||
01604|063|R|1.K-Dur (potassium chloride) Canadian prescribing information. Merck Canada|1
01604|064|R|  Inc. March, 2011.|1
01604|065|R|2.K-TAB (potassium chloride) tablet, film coated, extended release, US|1
01604|066|R|  Prescribing Information. Zydus Pharmaceuticals April, 2018.|1
01604|067|R|3.K-Dur (potassium chloride) US prescribing information. Key|1
01604|068|R|  Pharmaceuticals, Inc. April, 2004.|1
01604|069|R|4.Potassium chloride extended-release capsules US Prescribing information.|1
01604|070|R|  Ethex Corporation September, 2003.|1
01604|071|R|5.Klor-Con (potassium chloride) US prescribing information. Upsher-Smith|1
01604|072|R|  Laboratories April, 2018.|1
01604|073|R|6.Urocit-K (potassium citrate) US prescribing information. Mission Pharmacal|1
01604|074|R|  December, 2021.|1
01604|075|R|7.Slow-K (potassium chloride) US prescribing information. Novartis|1
01604|076|R|  Pharmaceuticals Corporation April, 2004.|1
01604|077|R|8.Micro-K (potassium chloride) US prescribing information. KV Pharmaceutical|1
01604|078|R|  October, 2000.|1
01604|079|R|9.Micro-K Extencaps (potassium chloride) Canadian prescribing information.|1
01604|080|R|  Wyeth Pharmaceuticals 2007.|1
01604|081|R|10.Slow-K (potassium chloride) Canadian prescribing information. Novartis|1
01604|082|R|   Pharmaceuticals Canada Inc. 2007.|1
01604|083|R|11.McMahon FG, Ryan JR, Akdamar K, Ertan A. Effect of potassium chloride|2
01604|084|R|   supplements on upper gastrointestinal mucosa. Clin Pharmacol Ther 1984|2
01604|085|R|   Jun;35(6):852-5.|2
01604|086|R|12.Kendall C, Krantz KD, Berger A, Sharp T. Endoscopic evaluation of|2
01604|087|R|   slow-release potassium chloride preparations. Clin Pharmacol Ther 1985|2
01604|088|R|   Jul;38(1):28-30.|2
01604|089|R|13.Gonzalez GB, Pak CY, Adams-Huet B, Taylor R, Bilhartz LE. Effect of|2
01604|090|R|   potassium-magnesium citrate on upper gastrointestinal mucosa. Aliment|2
01604|091|R|   Pharmacol Ther 1998 Jan;12(1):105-10.|2
01604|092|R|14.Sinar DR, Bozymski EM, Blackshear JL. Effects of oral potassium|2
01604|093|R|   supplements on upper gastrointestinal mucosa: multicenter clinical|2
01604|094|R|   comparison of three formulations and placebo. Clin Ther 1986;8(2):157-63.|2
01604|095|R|15.McMahon FG, Ryan JR, Akdamar K, Ertan A. Upper gastrointestinal lesions|2
01604|096|R|   after potassium chloride supplements: a controlled clinical trial. Lancet|2
01604|097|R|   1982 Nov 13;2(8307):1059-61.|2
01604|098|R|16.Barkin JS, Harary AM, Shamblen CE, Lasseter KC. Potassium chloride and|2
01604|099|R|   gastrointestinal injury. Ann Intern Med 1983 Feb;98(2):261-2.|2
01604|100|R|17.Strom BL, Carson JL, Schinnar R, Sim E, Maislin G, Soper K, Morse ML.|2
01604|101|R|   Upper gastrointestinal tract bleeding from oral potassium chloride.|2
01604|102|R|   Comparative risk from microencapsulated vs wax-matrix formulations. Arch|2
01604|103|R|   Intern Med 1987 May;147(5):954-7.|2
01604|104|R|18.Rosenthal T, Adar R, Militianu J, Deutsch V. Esophageal ulceration and|3
01604|105|R|   oral potassium chloride ingestion. Chest 1974 Apr;65(4):463-5.|3
01604|106|R|19.McLoughlin JC. Effects on upper gastrointestinal mucosa of three delivery|2
01604|107|R|   systems of potassium as supplement to frusemide administration. J R Soc|2
01604|108|R|   Med 1985 Jun;78(6):459-62.|2
01604|109|R|20.Farquharson-Roberts MA, Giddings AE, Nunn AJ. Perforation of small bowel|3
01604|110|R|   due to slow release potassium chloride (slow-K). Br Med J 1975 Jul 26;|3
01604|111|R|   3(5977):206.|3
01604|112|R|21.O'Neill JL, Remington TL. Drug-induced esophageal injuries and dysphagia.|6
01604|113|R|   Ann Pharmacother 2003 Nov;37(11):1675-84.|6
01605|001|T|MONOGRAPH TITLE:  Solid Oral Potassium Tablets/Inhaled Anticholinergics|
01605|002|B||
01605|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01605|004|L|take action as needed.|
01605|005|B||
01605|006|A|MECHANISM OF ACTION:  Concentrated potassium may damage the lining of the GI|
01605|007|A|tract.  Anticholinergics delay gastric emptying, resulting in the potassium|
01605|008|A|product remaining in the gastrointestinal tract for a longer period of|
01605|009|A|time.(1-16)|
01605|010|B||
01605|011|E|CLINICAL EFFECTS:  Use of solid oral dosage forms of potassium in patients|
01605|012|E|treated with inhaled anticholinergics could potentially result in|
01605|013|E|gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)|
01605|014|B||
01605|015|P|PREDISPOSING FACTORS:  Diseases or conditions which may increase risk for GI|
01605|016|P|damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic|
01605|017|P|gastroparesis, elderly status, or insufficient oral intake to allow dilution|
01605|018|P|of potassium.(1-10,21)|
01605|019|P|   Other drugs which may add to risk for GI damage include: nonsteroidal|
01605|020|P|anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)|
01605|021|B||
01605|022|M|PATIENT MANAGEMENT:  Regulatory agency and manufacturer recommendations|
01605|023|M|regarding this interaction:|
01605|024|M|   - In the US, all solid oral dosage forms (including tablets and extended|
01605|025|M|release capsules) of potassium are contraindicated in patients receiving|
01605|026|M|anticholinergics at sufficient dosages to result in systemic effects.(2-8)|
01605|027|M|Patients receiving such anticholinergic therapy should use a liquid form of|
01605|028|M|potassium chloride.(2)|
01605|029|M|   - In Canada, solid oral potassium is contraindicated in any patient with|
01605|030|M|a  cause for arrest or delay in tablet/capsule passage through the|
01605|031|M|gastrointestinal tract and the manufacturers recommend caution with|
01605|032|M|concurrent anticholinergic medications.(1,9-10)|
01605|033|M|   Evaluate each patient for predisposing factors which may increase risk|
01605|034|M|for GI damage.  In patients with multiple risk factors for harm, consider|
01605|035|M|use of liquid potassium supplements, if tolerated.  For patients receiving|
01605|036|M|concomitant therapy, assure any potassium dose form is taken after meals|
01605|037|M|with a large glass of water or other fluid. To decrease potassium|
01605|038|M|concentration in the GI tract, limit each dose to 20 meq; if more than 20|
01605|039|M|meq daily is required, give in divided doses.(2)|
01605|040|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01605|041|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01605|042|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01605|043|M|patients with any symptoms.|
01605|044|M|   Patients should be instructed to immediately report any difficulty|
01605|045|M|swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal|
01605|046|M|bleeding.|
01605|047|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01605|048|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01605|049|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01605|050|M|and/or swelling.|
01605|051|B||
01605|052|D|DISCUSSION:  In clinical trials, there was a higher incidence of gastric and|
01605|053|D|duodenal lesions in patients receiving a high dose of a wax-matrix|
01605|054|D|controlled-release formulation with a concurrent anticholinergic agent.|
01605|055|D|Some lesions were asymptomatic and not accompanied by bleeding, as shown by|
01605|056|D|a lack of positive Hemoccult tests.(1-17)|
01605|057|D|   Several studies suggest that the incidence of gastric and duodenal|
01605|058|D|lesions may be less with the microencapsulated formulation of potassium|
01605|059|D|chloride.(14-17)|
01605|060|D|   Constipation has been reported as a side effect of inhaled|
01605|061|D|anticholinergic agents such as ipratropium(22) and tiotropium.(23)|
01605|062|B||
01605|063|R|REFERENCES:|
01605|064|B||
01605|065|R|1.K-Dur (potassium chloride) Canadian prescribing information. Merck Canada|1
01605|066|R|  Inc. March, 2011.|1
01605|067|R|2.K-TAB (potassium chloride) tablet, film coated, extended release, US|1
01605|068|R|  Prescribing Information. Zydus Pharmaceuticals April, 2018.|1
01605|069|R|3.K-Dur (potassium chloride) US prescribing information. Key|1
01605|070|R|  Pharmaceuticals, Inc. April, 2004.|1
01605|071|R|4.Potassium chloride extended-release capsules US Prescribing information.|1
01605|072|R|  Ethex Corporation September, 2003.|1
01605|073|R|5.Klor-Con (potassium chloride) US prescribing information. Upsher-Smith|1
01605|074|R|  Laboratories April, 2018.|1
01605|075|R|6.Urocit-K (potassium citrate) US prescribing information. Mission Pharmacal|1
01605|076|R|  December, 2021.|1
01605|077|R|7.Slow-K (potassium chloride) US prescribing information. Novartis|1
01605|078|R|  Pharmaceuticals Corporation April, 2004.|1
01605|079|R|8.Micro-K (potassium chloride) US prescribing information. KV Pharmaceutical|1
01605|080|R|  October, 2000.|1
01605|081|R|9.Micro-K Extencaps (potassium chloride) Canadian prescribing information.|1
01605|082|R|  Wyeth Pharmaceuticals 2007.|1
01605|083|R|10.Slow-K (potassium chloride) Canadian prescribing information. Novartis|1
01605|084|R|   Pharmaceuticals Canada Inc. 2007.|1
01605|085|R|11.McMahon FG, Ryan JR, Akdamar K, Ertan A. Effect of potassium chloride|2
01605|086|R|   supplements on upper gastrointestinal mucosa. Clin Pharmacol Ther 1984|2
01605|087|R|   Jun;35(6):852-5.|2
01605|088|R|12.Kendall C, Krantz KD, Berger A, Sharp T. Endoscopic evaluation of|2
01605|089|R|   slow-release potassium chloride preparations. Clin Pharmacol Ther 1985|2
01605|090|R|   Jul;38(1):28-30.|2
01605|091|R|13.Gonzalez GB, Pak CY, Adams-Huet B, Taylor R, Bilhartz LE. Effect of|2
01605|092|R|   potassium-magnesium citrate on upper gastrointestinal mucosa. Aliment|2
01605|093|R|   Pharmacol Ther 1998 Jan;12(1):105-10.|2
01605|094|R|14.Sinar DR, Bozymski EM, Blackshear JL. Effects of oral potassium|2
01605|095|R|   supplements on upper gastrointestinal mucosa: multicenter clinical|2
01605|096|R|   comparison of three formulations and placebo. Clin Ther 1986;8(2):157-63.|2
01605|097|R|15.McMahon FG, Ryan JR, Akdamar K, Ertan A. Upper gastrointestinal lesions|2
01605|098|R|   after potassium chloride supplements: a controlled clinical trial. Lancet|2
01605|099|R|   1982 Nov 13;2(8307):1059-61.|2
01605|100|R|16.Barkin JS, Harary AM, Shamblen CE, Lasseter KC. Potassium chloride and|2
01605|101|R|   gastrointestinal injury. Ann Intern Med 1983 Feb;98(2):261-2.|2
01605|102|R|17.Strom BL, Carson JL, Schinnar R, Sim E, Maislin G, Soper K, Morse ML.|2
01605|103|R|   Upper gastrointestinal tract bleeding from oral potassium chloride.|2
01605|104|R|   Comparative risk from microencapsulated vs wax-matrix formulations. Arch|2
01605|105|R|   Intern Med 1987 May;147(5):954-7.|2
01605|106|R|18.Rosenthal T, Adar R, Militianu J, Deutsch V. Esophageal ulceration and|3
01605|107|R|   oral potassium chloride ingestion. Chest 1974 Apr;65(4):463-5.|3
01605|108|R|19.McLoughlin JC. Effects on upper gastrointestinal mucosa of three delivery|2
01605|109|R|   systems of potassium as supplement to frusemide administration. J R Soc|2
01605|110|R|   Med 1985 Jun;78(6):459-62.|2
01605|111|R|20.Farquharson-Roberts MA, Giddings AE, Nunn AJ. Perforation of small bowel|3
01605|112|R|   due to slow release potassium chloride (slow-K). Br Med J 1975 Jul 26;|3
01605|113|R|   3(5977):206.|3
01605|114|R|21.O'Neill JL, Remington TL. Drug-induced esophageal injuries and dysphagia.|6
01605|115|R|   Ann Pharmacother 2003 Nov;37(11):1675-84.|6
01605|116|R|22.Combivent (ipratropium bromide and albuterol sulfate) US prescribing|1
01605|117|R|   information. Boehringer Ingelheim April, 2011.|1
01605|118|R|23.Spiriva (tiotropium bromide) US prescribing information. Boehringer|1
01605|119|R|   Ingelheim February 1, 2018.|1
01606|001|T|MONOGRAPH TITLE:  Ambenonium/Atropine|
01606|002|B||
01606|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01606|004|L|is contraindicated and generally should not be dispensed or administered to|
01606|005|L|the same patient.|
01606|006|B||
01606|007|A|MECHANISM OF ACTION:  Atropine may suppress the parasympathomimetic signs of|
01606|008|A|ambenonium overdose (excessive gastrointestinal stimulation).  This leaves|
01606|009|A|only the serious overdose signs (fasciculation and paralysis of voluntary|
01606|010|A|muscles). (1)|
01606|011|B||
01606|012|E|CLINICAL EFFECTS:  Concurrent use of ambenonium and atropine may result in|
01606|013|E|masking of the initial signs of ambenonium overdose. (1)|
01606|014|B||
01606|015|P|PREDISPOSING FACTORS:  None determined.|
01606|016|B||
01606|017|M|PATIENT MANAGEMENT:  The manufacturer states that routine administration of|
01606|018|M|atropine to patients receiving ambenonium is contraindicated. (1)|
01606|019|B||
01606|020|D|DISCUSSION:  Ambenonium is a cholinesterase inhibitor.  Signs of overdose|
01606|021|D|are minimal.  Early signs include excessive salivation, abdominal cramps,|
01606|022|D|diarrhea, miosis, urinary urgency, sweating, nausea, increase in bronchial|
01606|023|D|and lacrimal secretions, and vomiting.  Use of atropine may mask these|
01606|024|D|signs.  Later signs of overdose include muscle cramps, fasciculation of|
01606|025|D|voluntary muscles, and rarely generalized malaise with anxiety and vertigo.|
01606|026|D|(1)|
01606|027|B||
01606|028|R|REFERENCE:|
01606|029|B||
01606|030|R|1.Mytelase (Ambenonium Chloride) US prescribing information. Sanofi-Aventis|1
01606|031|R|  November, 2011.|1
01607|001|T|MONOGRAPH TITLE:  Ambenonium/Mecamylamine|
01607|002|B||
01607|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01607|004|L|is contraindicated and generally should not be dispensed or administered to|
01607|005|L|the same patient.|
01607|006|B||
01607|007|A|MECHANISM OF ACTION:  Mecamylamine may suppress the parasympathomimetic|
01607|008|A|signs of ambenonium overdose (excessive gastrointestinal stimulation).  This|
01607|009|A|leaves only the serious overdose signs (fasciculation and paralysis of|
01607|010|A|voluntary muscles). (1)|
01607|011|B||
01607|012|E|CLINICAL EFFECTS:  Concurrent use of ambenonium and mecamylamine may result|
01607|013|E|in masking of the initial signs of ambenonium overdose. (1,2)|
01607|014|B||
01607|015|P|PREDISPOSING FACTORS:  None determined.|
01607|016|B||
01607|017|M|PATIENT MANAGEMENT:  The manufacturer states that administration of|
01607|018|M|mecamylamine to patients receiving ambenonium is contraindicated. (1)|
01607|019|B||
01607|020|D|DISCUSSION:  Ambenonium is a cholinesterase inhibitor.  Signs of overdose|
01607|021|D|are minimal.  Early signs include excessive salivation, abdominal cramps,|
01607|022|D|diarrhea, miosis, urinary urgency, sweating, nausea, increase in bronchial|
01607|023|D|and lacrimal secretions, and vomiting.  Use of mecamylamine may mask these|
01607|024|D|signs.  Later signs of overdose include muscle cramps, fasciculation of|
01607|025|D|voluntary muscles, and rarely generalized malaise with anxiety and vertigo.|
01607|026|D|(1)|
01607|027|B||
01607|028|R|REFERENCES:|
01607|029|B||
01607|030|R|1.Mytelase (Ambenonium Chloride) US prescribing information. Sanofi-Aventis|1
01607|031|R|  November, 2011.|1
01607|032|R|2.Inversine (mecamylamine) US Prescribing Information. Targacept Inc. July,|1
01607|033|R|  2002.|1
01608|001|T|MONOGRAPH TITLE:  Oral Contraceptives/Select Cephalosporin (mono deleted|
01608|002|T|02/19/2020)|
01608|003|B||
01608|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01608|005|L|take action as needed.|
01608|006|B||
01608|007|A|MECHANISM OF ACTION:  Estrogens and progesterones are extensively excreted|
01608|008|A|in bile, principally as glycuronide conjugates.  Subsequently, they undergo|
01608|009|A|enterohepatic circulation where bacterial hydrolysis occurs, allowing for|
01608|010|A|reabsorption of the oral contraceptives through the bowel wall and eventual|
01608|011|A|urinary excretion.  Treatment with antibiotics destroys the gut flora and|
01608|012|A|prevents steroid reabsorption, resulting in lower than normal concentrations|
01608|013|A|of the contraceptive and excretion via the feces rather than the urine.|
01608|014|B||
01608|015|E|CLINICAL EFFECTS:  May observe reduced pharmacologic effects of oral|
01608|016|E|contraceptives with resultant breakthrough bleeding and pregnancy.  Reduced|
01608|017|E|effects may be seen for several days after discontinuation of antibiotic|
01608|018|E|therapy.|
01608|019|B||
01608|020|P|PREDISPOSING FACTORS:  None determined.|
01608|021|B||
01608|022|M|PATIENT MANAGEMENT:  Current guidelines suggest that additional precautions|
01608|023|M|are not necessary when non-enzyme inducing antibiotics are used concurrently|
01608|024|M|with hormonal contraceptives; however, some patients may still prefer to use|
01608|025|M|an additional method of contraception.|
01608|026|B||
01608|027|D|DISCUSSION:  Evidence for this interaction is limited and conflicting;|
01608|028|D|however, the CDC and the Faculty of Sexual and Reproductive Healthcare|
01608|029|D|Clinical Effectiveness Unit no longer recommend use of a backup|
01608|030|D|contraceptive method during use of a non-enzyme inducing antibiotic.|
01608|031|D|   The manufacturer states that lower estrogen reabsorption and reduced|
01608|032|D|efficacy may result in women taking oral contraceptives with cefuroxime.|
01608|033|B||
01608|034|R|REFERENCES:|
01608|035|B||
01608|036|R|1.Back DJ, Breckenridge AM, Crawford FE, MacIver M, Orme ML, Rowe PH.|6
01608|037|R|  Interindividual variation and drug interactions with hormonal steroid|6
01608|038|R|  contraceptives. Drugs 1981 Jan;21(1):46-61.|6
01608|039|R|2.DeSano EA Jr, Hurley SC. Possible interactions of antihistamines and|6
01608|040|R|  antibiotics with oral contraceptive effectiveness. Fertil Steril 1982 Jun;|6
01608|041|R|  37(6):853-4.|6
01608|042|R|3.Bainton R. Interaction between antibiotic therapy and contraceptive|3
01608|043|R|  medication. Oral Surg Oral Med Oral Pathol 1986 May;61(5):453-5.|3
01608|044|R|4.Silber TJ. Apparent oral contraceptive failure associated with antibiotic|3
01608|045|R|  administration. J Adolesc Health Care 1983 Dec;4(4):287-9.|3
01608|046|R|5.True RJ. Interactions between antibiotics and oral contraceptives. JAMA|6
01608|047|R|  1982 Mar 12;247(10):1408.|6
01608|048|R|6.Rubin DF. Antibiotics and oral contraceptives. Arch Dermatol 1981 Apr;|6
01608|049|R|  117(4):189.|6
01608|050|R|7.Tikkanen MJ, Adlercreutz H, Pulkkinen MO. Effects of antibiotics on|2
01608|051|R|  oestrogen metabolism. Br Med J 1973 May 12;2(5862):369.|2
01608|052|R|8.Adlercreutz H, Pulkkinen MO, Hamalainen EK, Korpela JT. Studies on the|2
01608|053|R|  role of intestinal bacteria in metabolism of synthetic and natural steroid|2
01608|054|R|  hormones. J Steroid Biochem 1984 Jan;20(1):217-29.|2
01608|055|R|9.Zinacef (cefuroxime) US prescribing information. GlaxoSmithKline February,|1
01608|056|R|  2020.|1
01608|057|R|10.Ceftin (cefuroxime axetil) US prescribing information. GlaxoSmithKline|1
01608|058|R|   January, 2010.|1
01608|059|R|11.Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness|6
01608|060|R|   Unit. Clinical guidance drug interactions with hormonal contraception.|6
01608|061|R|   January, 2011.|6
01608|062|R|12.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
01608|063|R|   Criteria for Contraceptive Use, 2010. MMWR Early Release 2010;59:1-86.|6
01609|001|T|MONOGRAPH TITLE:  Fenofibrate; Gemfibrozil/Bile Acid Sequestrants|
01609|002|B||
01609|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01609|004|L|take action as needed.|
01609|005|B||
01609|006|A|MECHANISM OF ACTION:  Bile acid sequestrants may bind to fenofibrate and|
01609|007|A|gemfibrozil resulting in decreased absorption of fenofibrate and|
01609|008|A|gemfibrozil.(1,2)|
01609|009|B||
01609|010|E|CLINICAL EFFECTS:  Concurrent use of fenofibrate and gemfibrozil with bile|
01609|011|E|acid sequestrants may result in decreased fenofibrate absorption and|
01609|012|E|clinical effects.(1,2)|
01609|013|B||
01609|014|P|PREDISPOSING FACTORS:  None determined.|
01609|015|B||
01609|016|M|PATIENT MANAGEMENT:  The US manufacturer states that fenofibrate should be|
01609|017|M|administered 1 hour before or 4-6 hours after administration of bile acid|
01609|018|M|sequestrants.(1)|
01609|019|M|   The US manufacturer states that gemfibrozil should be administered 2|
01609|020|M|hours apart from bile acid sequestrants.(2)|
01609|021|B||
01609|022|D|DISCUSSION:  Bile acid sequestrants are known to bind to drugs when given|
01609|023|D|concurrently.  Administration with fenofibrate and gemfibrozil may result in|
01609|024|D|decreased systemic absorption.(1,2)|
01609|025|B||
01609|026|R|REFERENCES:|
01609|027|B||
01609|028|R|1.Triglide (fenofibrate) US prescribing information. Sciele Pharma, Inc.|1
01609|029|R|  January, 2013.|1
01609|030|R|2.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
01609|031|R|  Ltd. December, 2020.|1
01610|001|T|MONOGRAPH TITLE:  Amphetamines/H2 Antagonists; Proton Pump Inhibitors|
01610|002|B||
01610|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01610|004|L|take action as needed.|
01610|005|B||
01610|006|A|MECHANISM OF ACTION:  H2 antagonists and proton pump inhibitors (PPIs) may|
01610|007|A|alter the timing of absorption of amphetamines.|
01610|008|B||
01610|009|E|CLINICAL EFFECTS:  Concurrent use of amphetamines and H2 antagonists or PPIs|
01610|010|E|may result in an increased absorption rate and a change in timing of peak|
01610|011|E|amphetamine levels.|
01610|012|B||
01610|013|P|PREDISPOSING FACTORS:  None determined.|
01610|014|B||
01610|015|M|PATIENT MANAGEMENT:  The US manufacturer states that patients receiving|
01610|016|M|concurrent amphetamines and H2 antagonists or PPIs should be monitored for|
01610|017|M|changes in the timing and clinical effects of amphetamines.(1)|
01610|018|M|   Monitor patients receiving concurrent therapy for changes in amphetamine|
01610|019|M|effectiveness and side effects.|
01610|020|M|   The Canadian manufacturer states that concurrent use of proton pump|
01610|021|M|inhibitors and amphetamines should be avoided.(3)|
01610|022|B||
01610|023|D|DISCUSSION:  During concurrent use of a proton pump inhibitor, the median|
01610|024|D|time to maximum concentration (Tmax) of Adderall XR decreased from 5 hours|
01610|025|D|to 2.75 hours.(3)|
01610|026|D|   In a 4-way crossover study in healthy subjects, omeprazole had no effect|
01610|027|D|on the total exposure a single dose of mixed amphetamine salts (20 mg);|
01610|028|D|however median Tmax decreased from 5 hours to 2.75 hours.  Approximately 50%|
01610|029|D|of subjects had a decrease in Tmax of equal to or greater than 1 hour.(4)|
01610|030|B||
01610|031|R|REFERENCES:|
01610|032|B||
01610|033|R|1.Adderall XR (amphetamine) US prescribing information. Shire US Inc. April,|1
01610|034|R|  2015.|1
01610|035|R|2.Adderall (amphetmine) US prescribing information. Barr Laboratories, Inc.|1
01610|036|R|  January, 2017.|1
01610|037|R|3.Adderall XR (amphetamine) Canadian prescribing information. Shire Canada|1
01610|038|R|  Inc. September 30, 2009.|1
01610|039|R|4.Haffey MB, Buckwalter M, Zhang P, Homolka R, Martin P, Lasseter KC, Ermer|2
01610|040|R|  JC. Effects of omeprazole on the pharmacokinetic profiles of|2
01610|041|R|  lisdexamfetamine dimesylate and extended-release mixed amphetamine salts|2
01610|042|R|  in adults. Postgrad Med 2009 Sep;121(5):11-9.|2
01611|001|T|MONOGRAPH TITLE:  Nondepolarizing Muscle Relaxants/Piperacillin|
01611|002|B||
01611|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01611|004|L|take action as needed.|
01611|005|B||
01611|006|A|MECHANISM OF ACTION:  Piperacillin may prolong the neuromuscular blockade of|
01611|007|A|the nondepolarizing muscle relaxants.(1,2)|
01611|008|B||
01611|009|E|CLINICAL EFFECTS:  Concurrent use of nondepolarizing muscle relaxants and|
01611|010|E|piperacillin may result in prolonged neuromuscular blockade including|
01611|011|E|profound sedation, respiratory depression, coma, and/or death.(1)|
01611|012|B||
01611|013|P|PREDISPOSING FACTORS:  None determined.|
01611|014|B||
01611|015|M|PATIENT MANAGEMENT:  Patients should be monitored for increased or|
01611|016|M|unexpected prolongation of neuromuscular blockade when using piperacillin|
01611|017|M|with nondepolarizing muscle relaxants. Assure monitoring protocols are in|
01611|018|M|place for patients receiving neuromuscular blocking agents.|
01611|019|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
01611|020|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
01611|021|M|unresponsiveness.|
01611|022|B||
01611|023|D|DISCUSSION:  Concurrent use of nondepolarizing muscle relaxants and|
01611|024|D|piperacillin may result in increased or prolonged neuromuscular|
01611|025|D|blockage.(1,2)  If these agents are used together, patients should be|
01611|026|D|monitored closely for increased neuromuscular blockage.|
01611|027|B||
01611|028|R|REFERENCES:|
01611|029|B||
01611|030|R|1.Zosyn (piperacillin and tazobactam) US prescribing information. Wyeth|1
01611|031|R|  Pharmaceuticals July, 2021.|1
01611|032|R|2.Vecuronium bromide prescribing information. Pfizer Inc. February, 2011.|1
01612|001|T|MONOGRAPH TITLE:  Tizanidine/Zileuton|
01612|002|B||
01612|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01612|004|L|of severe adverse interaction.|
01612|005|B||
01612|006|A|MECHANISM OF ACTION:  Zileuton may inhibit the metabolism of tizanidine by|
01612|007|A|CYP1A2.(1)|
01612|008|B||
01612|009|E|CLINICAL EFFECTS:  Concurrent use of zileuton may result in elevated levels|
01612|010|E|of and effects from tizanidine, including hypotension, bradycardia,|
01612|011|E|drowsiness, sedation, and decreased psychomotor function.|
01612|012|B||
01612|013|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
01612|014|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
01612|015|P|patients using more than one medicine with anticholinergic properties.(2)|
01612|016|B||
01612|017|M|PATIENT MANAGEMENT:  The US manufacturer of tizanidine states that|
01612|018|M|concurrent use of tizanidine with inhibitors of CYP1A2, such as zileuton,|
01612|019|M|should be avoided.  If concurrent use is warranted, tizanidine should be|
01612|020|M|initiated with 2 mg dose and increased in 2-4 mg steps daily based on|
01612|021|M|patient response to therapy.(1)|
01612|022|M|   If adverse reactions such as hypotension, bradycardia or excessive|
01612|023|M|drowsiness occur, reduce or discontinue tizanidine therapy.(1)|
01612|024|B||
01612|025|D|DISCUSSION:  In a study in 10 healthy subjects, concurrent fluvoxamine,|
01612|026|D|another inhibitor of CYP1A2, increased tizanidine maximum concentration|
01612|027|D|(Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold,|
01612|028|D|and 3-fold, respectively.  Significant decreases in blood pressure and|
01612|029|D|increases in drowsiness and psychomotor impairment occurred.(1)|
01612|030|D|   In a study in 10 healthy subjects, concurrent ciprofloxacin, another|
01612|031|D|inhibitor of CYP1A2, increase tizanidine Cmax and AUC by 7-fold and 10-fold,|
01612|032|D|respectively.  Significant decreases in blood pressure and and increases in|
01612|033|D|drowsiness and psychomotor impairment occurred.(1)|
01612|034|D|   One or more of the drug pairs linked to this monograph have been included|
01612|035|D|in a list of interactions that should be considered "high-priority" for|
01612|036|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01612|037|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01612|038|D|Coordinator (ONC) for Health Information Technology.|
01612|039|B||
01612|040|R|REFERENCES:|
01612|041|B||
01612|042|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
01612|043|R|  Pharma Inc. November 22, 2024.|1
01612|044|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01612|045|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01612|046|R|  Soc 2023 Jul;71(7):2052-2081.|6
01612|047|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01612|048|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01612|049|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01612|050|R|  19(5):735-43.|6
01612|051|R|4.This information is based on an extract from the Certara Drug Interaction|6
01612|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01613|001|T|MONOGRAPH TITLE:  Tizanidine/Selected Antiarrhythmics|
01613|002|B||
01613|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01613|004|L|of severe adverse interaction.|
01613|005|B||
01613|006|A|MECHANISM OF ACTION:  Amiodarone, mexiletine, propafenone, and verapamil may|
01613|007|A|inhibit the metabolism of tizanidine by CYP1A2.(1)|
01613|008|B||
01613|009|E|CLINICAL EFFECTS:  Concurrent use of amiodarone, mexiletine, propafenone, or|
01613|010|E|verapamil may result in elevated levels of and effects from tizanidine,|
01613|011|E|including hypotension, bradycardia, drowsiness, sedation, and decreased|
01613|012|E|psychomotor function.|
01613|013|B||
01613|014|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
01613|015|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
01613|016|P|patients using more than one medicine with anticholinergic properties.(2)|
01613|017|B||
01613|018|M|PATIENT MANAGEMENT:  The US manufacturer of tizanidine states that|
01613|019|M|concurrent use of tizanidine with inhibitors of CYP1A2, such as zileuton,|
01613|020|M|should be avoided.  If concurrent use is warranted, tizanidine should be|
01613|021|M|initiated with a 2 mg dose and increased in 2-4 mg steps daily based on|
01613|022|M|patient response to therapy. If adverse reactions such as hypotension,|
01613|023|M|bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine|
01613|024|M|therapy.(1)|
01613|025|B||
01613|026|D|DISCUSSION:  In a study in 10 healthy subjects, concurrent fluvoxamine,|
01613|027|D|another inhibitor of CYP1A2, increased tizanidine maximum concentration|
01613|028|D|(Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold,|
01613|029|D|and 3-fold, respectively.  Significant decreases in blood pressure and|
01613|030|D|increases in drowsiness and psychomotor impairment occurred.(1)|
01613|031|D|   In a study in 10 healthy subjects, concurrent ciprofloxacin, another|
01613|032|D|inhibitor of CYP1A2, increased tizanidine Cmax and AUC by 7-fold and|
01613|033|D|10-fold, respectively.  Significant decreases in blood pressure and and|
01613|034|D|increases in drowsiness and psychomotor impairment occurred.(1)|
01613|035|D|   In an open label study in 12 healthy subjects, concurrent tizanidine|
01613|036|D|(single 2 mg dose) with mexiletine (50 mg, 3 times a day for one day and|
01613|037|D|then 2 times for one day), increased tizanidine Cmax and AUC by 3.1-fold and|
01613|038|D|3.6-fold, respectively. Subjects were found to have significantly lower|
01613|039|D|systolic and diastolic blood pressure after concurrent administration as|
01613|040|D|well as drowsiness, dry mouth, or dizziness.(3)|
01613|041|D|   One or more of the drug pairs linked to this monograph have been included|
01613|042|D|in a list of interactions that should be considered "high-priority" for|
01613|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01613|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01613|045|D|Coordinator (ONC) for Health Information Technology.|
01613|046|B||
01613|047|R|REFERENCES:|
01613|048|B||
01613|049|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
01613|050|R|  Pharma Inc. November 22, 2024.|1
01613|051|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01613|052|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01613|053|R|  Soc 2023 Jul;71(7):2052-2081.|6
01613|054|R|3.Momo K, Homma M, Osaka Y, Inomata S, Tanaka M, Kohda Y. Effects of|2
01613|055|R|  mexiletine, a CYP1A2 inhibitor, on tizanidine pharmacokinetics and|2
01613|056|R|  pharmacodynamics. J Clin Pharmacol 2010 Mar;50(3):331-7.|2
01613|057|R|4.This information is based on an extract from the Certara Drug Interaction|6
01613|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01613|059|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01613|060|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01613|061|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01613|062|R|  19(5):735-43.|6
01614|001|T|MONOGRAPH TITLE:  Tizanidine/Cimetidine; Famotidine|
01614|002|B||
01614|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01614|004|L|of severe adverse interaction.|
01614|005|B||
01614|006|A|MECHANISM OF ACTION:  Cimetidine and famotidine may inhibit the metabolism|
01614|007|A|of tizanidine by CYP1A2.(1)|
01614|008|B||
01614|009|E|CLINICAL EFFECTS:  Concurrent use of cimetidine or famotidine may result in|
01614|010|E|elevated levels of and effects from tizanidine, including hypotension,|
01614|011|E|bradycardia, drowsiness, sedation, and decreased psychomotor function.|
01614|012|B||
01614|013|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
01614|014|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
01614|015|P|patients using more than one medicine with anticholinergic properties.(2)|
01614|016|B||
01614|017|M|PATIENT MANAGEMENT:  The US manufacturer of tizanidine states that|
01614|018|M|concurrent use of tizanidine with inhibitors of CYP1A2, such as cimetidine|
01614|019|M|or famotidine, should be avoided.  If concurrent use is warranted,|
01614|020|M|tizanidine should be initiated with 2 mg dose and increased in 2-4 mg steps|
01614|021|M|daily based on patient response to therapy.(1)|
01614|022|M|   If adverse reactions such as hypotension, bradycardia, or excessive|
01614|023|M|drowsiness occur, reduce or discontinue tizanidine therapy.(1)|
01614|024|B||
01614|025|D|DISCUSSION:  In a study in 10 healthy subjects, concurrent fluvoxamine,|
01614|026|D|another inhibitor of CYP1A2, increased tizanidine maximum concentration|
01614|027|D|(Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold,|
01614|028|D|and 3-fold, respectively.  Significant decreases in blood pressure and|
01614|029|D|increases in drowsiness and psychomotor impairment occurred.(1)|
01614|030|D|   In a study in 10 healthy subjects, concurrent ciprofloxacin, another|
01614|031|D|inhibitor of CYP1A2, increase tizanidine Cmax and AUC by 7-fold and 10-fold,|
01614|032|D|respectively.  Significant decreases in blood pressure and and increases in|
01614|033|D|drowsiness and psychomotor impairment occurred.(1)|
01614|034|B||
01614|035|R|REFERENCES:|
01614|036|B||
01614|037|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
01614|038|R|  Pharma Inc. November 22, 2024.|1
01614|039|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01614|040|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01614|041|R|  Soc 2023 Jul;71(7):2052-2081.|6
01614|042|R|3.Duexis (ibuprofen, famotidine) US prescribing information. Horizon|1
01614|043|R|  Medicines LLC April, 2021.|1
01614|044|R|4.This information is based on an extract from the Certara Drug Interaction|6
01614|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01615|001|T|MONOGRAPH TITLE:  Tizanidine/Estrogens|
01615|002|B||
01615|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01615|004|L|of severe adverse interaction.|
01615|005|B||
01615|006|A|MECHANISM OF ACTION:  Estrogen containing hormonal contraceptives or hormone|
01615|007|A|replacement therapy may decrease the clearance of tizanidine by inhibiting|
01615|008|A|CYP1A2.(1)|
01615|009|B||
01615|010|E|CLINICAL EFFECTS:  Concurrent use of tizanidine and estrogen containing|
01615|011|E|hormonal contraceptives or hormone replacement therapy may result in|
01615|012|E|elevated levels of and effects from tizanidine, including hypotension,|
01615|013|E|bradycardia, drowsiness, sedation, and decreased psychomotor function.|
01615|014|B||
01615|015|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
01615|016|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
01615|017|P|patients using more than one medicine with anticholinergic properties.(2)|
01615|018|B||
01615|019|M|PATIENT MANAGEMENT:  The manufacturer states that routine administration of|
01615|020|M|tizanidine and estrogen containing hormonal contraceptives or hormone|
01615|021|M|replacement therapy should be avoided.(1)  If concurrent use is necessary,|
01615|022|M|tizanidine should be initiated with a 2 mg dose and increased 2-4 mg daily|
01615|023|M|based on patient response to therapy.(1)|
01615|024|M|   If adverse reactions such as hypotension, bradycardia, or excessive|
01615|025|M|drowsiness occur, reduce or discontinue tizanidine therapy.(1)|
01615|026|B||
01615|027|D|DISCUSSION:  In a retrospective analysis of population pharmacokinetic data,|
01615|028|D|women taking oral contraceptives with tizanidine has a 50% lower clearance|
01615|029|D|compared to women not on oral contraceptives.(1)|
01615|030|D|   In fifteen women using oral contraceptives, tizanidine (4 mg) increased|
01615|031|D|the area-under-curve (AUC) and peak plasma tizanidine concentration,|
01615|032|D|3.9-fold and 3.0-fold respectively, compared to placebo.  In one patient,|
01615|033|D|the AUC of tizanidine exceeded twenty times the AUC of the placebo group.(3)|
01615|034|B||
01615|035|R|REFERENCES:|
01615|036|B||
01615|037|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
01615|038|R|  Pharma Inc. November 22, 2024.|1
01615|039|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01615|040|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01615|041|R|  Soc 2023 Jul;71(7):2052-2081.|6
01615|042|R|3.Granfors MT, Backman JT, Laitila J, Neuvonen PJ. Oral contraceptives|2
01615|043|R|  containing ethinyl estradiol and gestodene markedly increase plasma|2
01615|044|R|  concentrations and effects of tizanidine by inhibiting cytochrome P450|2
01615|045|R|  1A2. Clin Pharmacol Ther 2005 Oct;78(4):400-11.|2
01616|001|T|MONOGRAPH TITLE:  Tizanidine/Acyclovir|
01616|002|B||
01616|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01616|004|L|of severe adverse interaction.|
01616|005|B||
01616|006|A|MECHANISM OF ACTION:  Acyclovir may inhibit the metabolism of tizanidine by|
01616|007|A|CYP1A2.(1)|
01616|008|B||
01616|009|E|CLINICAL EFFECTS:  Concurrent use of acyclovir may result in elevated levels|
01616|010|E|of and effects from tizanidine, including hypotension, bradycardia,|
01616|011|E|drowsiness, sedation, and decreased psychomotor function.|
01616|012|B||
01616|013|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
01616|014|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
01616|015|P|patients using more than one medicine with anticholinergic properties.(2)|
01616|016|B||
01616|017|M|PATIENT MANAGEMENT:  The US manufacturer of tizanidine states that|
01616|018|M|concurrent use of tizanidine with inhibitors of CYP1A2, such as acyclovir,|
01616|019|M|should be avoided.  If concurrent use is warranted, tizanidine should be|
01616|020|M|initiated with a 2 mg dose and increased in 2-4 mg steps daily based on|
01616|021|M|patient response to therapy.(1)|
01616|022|M|   If adverse reactions such as hypotension, bradycardia, or excessive|
01616|023|M|drowsiness occur, reduce or discontinue tizanidine therapy.(1)|
01616|024|B||
01616|025|D|DISCUSSION:  In a study in 10 healthy subjects, concurrent fluvoxamine,|
01616|026|D|another inhibitor of CYP1A2, increased tizanidine maximum concentration|
01616|027|D|(Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold,|
01616|028|D|and 3-fold, respectively.  Significant decreases in blood pressure and|
01616|029|D|increases in drowsiness and psychomotor impairment occurred.(1)|
01616|030|D|   In a study in 10 healthy subjects, concurrent ciprofloxacin, another|
01616|031|D|inhibitor of CYP1A2, increase tizanidine Cmax and AUC by 7-fold and 10-fold,|
01616|032|D|respectively.  Significant decreases in blood pressure and and increases in|
01616|033|D|drowsiness and psychomotor impairment occurred.(1)|
01616|034|B||
01616|035|R|REFERENCES:|
01616|036|B||
01616|037|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
01616|038|R|  Pharma Inc. November 22, 2024.|1
01616|039|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01616|040|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01616|041|R|  Soc 2023 Jul;71(7):2052-2081.|6
01617|001|T|MONOGRAPH TITLE:  Tizanidine/Ticlopidine|
01617|002|B||
01617|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01617|004|L|of severe adverse interaction.|
01617|005|B||
01617|006|A|MECHANISM OF ACTION:  Ticlopidine may inhibit the metabolism of tizanidine|
01617|007|A|by CYP1A2.(1)|
01617|008|B||
01617|009|E|CLINICAL EFFECTS:  Concurrent use of ticlopidine may result in elevated|
01617|010|E|levels of and effects from tizanidine, including hypotension, bradycardia,|
01617|011|E|drowsiness, sedation, and decreased psychomotor function.|
01617|012|B||
01617|013|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
01617|014|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
01617|015|P|patients using more than one medicine with anticholinergic properties.(2)|
01617|016|B||
01617|017|M|PATIENT MANAGEMENT:  The US manufacturer of tizanidine states that|
01617|018|M|concurrent use of tizanidine with inhibitors of CYP1A2, such as ticlopidine,|
01617|019|M|should be avoided.  If concurrent use is warranted, tizanidine therapy|
01617|020|M|should be initiated at 2 mg dose and increased in 2-4 mg steps daily based|
01617|021|M|on patient response to therapy.(1)|
01617|022|M|   If adverse reactions such as hypotension, bradycardia, or excessive|
01617|023|M|drowsiness occur, reduce or discontinue tizanidine therapy.(1)|
01617|024|B||
01617|025|D|DISCUSSION:  In a study in 10 healthy subjects, concurrent fluvoxamine,|
01617|026|D|another inhibitor of CYP1A2, increased tizanidine maximum concentration|
01617|027|D|(Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold,|
01617|028|D|and 3-fold, respectively.  Significant decreases in blood pressure and|
01617|029|D|increases in drowsiness and psychomotor impairment occurred.(1)|
01617|030|D|   In a study in 10 healthy subjects, concurrent ciprofloxacin, another|
01617|031|D|inhibitor of CYP1A2, increase tizanidine Cmax and AUC by 7-fold and 10-fold,|
01617|032|D|respectively.  Significant decreases in blood pressure and and increases in|
01617|033|D|drowsiness and psychomotor impairment occurred.(1)|
01617|034|D|   One or more of the drug pairs linked to this monograph have been included|
01617|035|D|in a list of interactions that should be considered "high-priority" for|
01617|036|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01617|037|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01617|038|D|Coordinator (ONC) for Health Information Technology.|
01617|039|B||
01617|040|R|REFERENCES:|
01617|041|B||
01617|042|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
01617|043|R|  Pharma Inc. November 22, 2024.|1
01617|044|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01617|045|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01617|046|R|  Soc 2023 Jul;71(7):2052-2081.|6
01617|047|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01617|048|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01617|049|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01617|050|R|  19(5):735-43.|6
01618|001|T|MONOGRAPH TITLE:  Irinotecan/Selected Strong CYP3A4 Inducers|
01618|002|B||
01618|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01618|004|L|of severe adverse interaction.|
01618|005|B||
01618|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers including barbiturates,|
01618|007|A|carbamazepine, fosphenytoin, phenytoin, phenobarbital, and primidone may|
01618|008|A|induce the metabolism of irinotecan by CYP3A4.(1-4)|
01618|009|B||
01618|010|E|CLINICAL EFFECTS:  Concurrent use of barbiturates, carbamazepine,|
01618|011|E|fosphenytoin, phenytoin, phenobarbital, or primidone with irinotecan may|
01618|012|E|result in decreased levels of irinotecan, as well as its active metabolites,|
01618|013|E|and decreased clinical effectiveness.|
01618|014|B||
01618|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01618|016|P|of the inducer for longer than 1-2 weeks.|
01618|017|B||
01618|018|M|PATIENT MANAGEMENT:  The manufacturer states do not administer strong CYP3A4|
01618|019|M|inducers with irinotecan unless there are no therapeutic alternatives.|
01618|020|M|Consideration should be given to substituting non-enzyme inducing|
01618|021|M|anticonvulsants at least 2 weeks prior to irinotecan therapy.(1)|
01618|022|M|   Levels of irinotecan and the active metabolites should be monitored in|
01618|023|M|patients receiving concurrent carbamazepine, fosphenytoin, phenytoin,|
01618|024|M|phenobarbital, or primidone.  If these agents are added to or discontinued|
01618|025|M|from concurrent irinotecan the dosage of irinotecan may need to be adjusted|
01618|026|M|to ensure therapeutic effects or prevent toxicity.|
01618|027|B||
01618|028|D|DISCUSSION:  In a clinical trial, irinotecan clearance values were 65.4%|
01618|029|D|higher in patients receiving phenytoin when compared to patients who were|
01618|030|D|not taking enzyme-inducing anticonvulsants.(2)  In another clinical trial,|
01618|031|D|irinotecan clearance was 117% higher in patients receiving anticonvulsants|
01618|032|D|that included phenytoin.(5)  Data from another clinical trial also suggested|
01618|033|D|that phenytoin increases irinotecan clearance.(6)|
01618|034|D|   Case reports have also noted increased irinotecan clearance by 4-fold(3)|
01618|035|D|and by 62.7%(4) in patients receiving concurrent phenytoin.  Levels of|
01618|036|D|irinotecan and its active metabolite, SN-38 were both decreased.|
01618|037|B||
01618|038|R|REFERENCES:|
01618|039|B||
01618|040|R|1.Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia|1
01618|041|R|  & Upjohn Company January, 2020.|1
01618|042|R|2.Kuhn JG. Influence of anticonvulsants on the metabolism and elimination of|2
01618|043|R|  irinotecan. A North American Brain Tumor Consortium preliminary report.|2
01618|044|R|  Oncology (Huntingt) 2002 Aug;16(8 Suppl 7):33-40.|2
01618|045|R|3.Mathijssen RH, Sparreboom A, Dumez H, van Oosterom AT, de Bruijn EA.|3
01618|046|R|  Altered irinotecan metabolism in a patient receiving phenytoin. Anticancer|3
01618|047|R|  Drugs 2002 Feb;13(2):139-40.|3
01618|048|R|4.Murry DJ, Cherrick I, Salama V, Berg S, Bernstein M, Kuttesch N, Blaney|3
01618|049|R|  SM. Influence of phenytoin on the disposition of irinotecan: a case|3
01618|050|R|  report. J Pediatr Hematol Oncol 2002 Feb;24(2):130-3.|3
01618|051|R|5.Gajjar A, Radomski K, Bowers D, Chintagumpala M, Thompson S, Houghton P,|4
01618|052|R|  Stewart C. Pharmacokinetics of Irinotecan (IRN) and metabolites in|4
01618|053|R|  pediatric high-grade giloma patients with and without co-administration of|4
01618|054|R|  enzyme-inducing anticonvulsants. 2000.|4
01618|055|R|6.Reid J, Buckner L, Schaaf L, Cha S, Wright K, Marks R, Wiesenfeld M,|4
01618|056|R|  Pfeifle D, Harfield A, Krook J, Duncan B, Miller L. Anticonvulsants alter|4
01618|057|R|  the pharmacokinetics of Irinotecan (CPT-11) in patients with recurrent|4
01618|058|R|  glioma. 2000.|4
01619|001|T|MONOGRAPH TITLE:  Irinotecan/Selected Strong CYP3A4 Inducers|
01619|002|B||
01619|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01619|004|L|of severe adverse interaction.|
01619|005|B||
01619|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
01619|007|A|irinotecan by CYP3A4.(1)|
01619|008|B||
01619|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
01619|010|E|decreased levels of irinotecan, as well as its active metabolites, and|
01619|011|E|decreased clinical effectiveness.|
01619|012|B||
01619|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01619|014|P|of the inducer for longer than 1-2 weeks.|
01619|015|B||
01619|016|M|PATIENT MANAGEMENT:  The manufacturer states do not administer strong CYP3A4|
01619|017|M|inducers with irinotecan unless there are no therapeutic alternatives.|
01619|018|M|Consideration should be given to substituting non-enzyme inducing therapies|
01619|019|M|at least 2 weeks prior to irinotecan therapy.(1)|
01619|020|M|   Levels of irinotecan and the active metabolites should be monitored in|
01619|021|M|patients receiving concurrent use of strong CYP3A4 inducers.  If strong|
01619|022|M|CYP3A4 inducers are added to or discontinued from concurrent irinotecan, the|
01619|023|M|dosage of irinotecan may need to be adjusted to ensure therapeutic effects|
01619|024|M|or prevent toxicity.|
01619|025|B||
01619|026|D|DISCUSSION:  The manufactures states that irinotecan may interact with|
01619|027|D|strong CYP3A4 inducers which may result in increased irinotecan|
01619|028|D|metabolism.(1)|
01619|029|D|   In a clinical trial, irinotecan clearance values were 65.4% higher in|
01619|030|D|patients receiving phenytoin when compared to patients who were not taking|
01619|031|D|enzyme-inducing anticonvulsants.(2)|
01619|032|D|   In another clinical trial, irinotecan clearance was 117% higher in|
01619|033|D|patients receiving anticonvulsants that included phenytoin.(5)|
01619|034|D|   Data from another clinical trial also suggested that phenytoin increases|
01619|035|D|irinotecan clearance.(6)|
01619|036|D|   Case reports have also noted increased irinotecan clearance by 4-fold(3)|
01619|037|D|and by 62.7%(4) in patients receiving concurrent phenytoin.  Levels of|
01619|038|D|irinotecan and its active metabolite, SN-38 were both decreased.|
01619|039|D|   Selected strong CYP3A4 inducers linked include: apalutamide, encorafenib,|
01619|040|D|enzalutamide, ivosidenib, lumacaftor, mitotane, rifabutin, rifampin, and|
01619|041|D|rifapentine.|
01619|042|B||
01619|043|R|REFERENCES:|
01619|044|B||
01619|045|R|1.Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia|1
01619|046|R|  & Upjohn Company January, 2020.|1
01619|047|R|2.Kuhn JG. Influence of anticonvulsants on the metabolism and elimination of|2
01619|048|R|  irinotecan. A North American Brain Tumor Consortium preliminary report.|2
01619|049|R|  Oncology (Huntingt) 2002 Aug;16(8 Suppl 7):33-40.|2
01619|050|R|3.Mathijssen RH, Sparreboom A, Dumez H, van Oosterom AT, de Bruijn EA.|3
01619|051|R|  Altered irinotecan metabolism in a patient receiving phenytoin. Anticancer|3
01619|052|R|  Drugs 2002 Feb;13(2):139-40.|3
01619|053|R|4.Murry DJ, Cherrick I, Salama V, Berg S, Bernstein M, Kuttesch N, Blaney|3
01619|054|R|  SM. Influence of phenytoin on the disposition of irinotecan: a case|3
01619|055|R|  report. J Pediatr Hematol Oncol 2002 Feb;24(2):130-3.|3
01619|056|R|5.Gajjar A, Radomski K, Bowers D, Chintagumpala M, Thompson S, Houghton P,|4
01619|057|R|  Stewart C. Pharmacokinetics of Irinotecan (IRN) and metabolites in|4
01619|058|R|  pediatric high-grade giloma patients with and without co-administration of|4
01619|059|R|  enzyme-inducing anticonvulsants. 2000.|4
01619|060|R|6.Reid J, Buckner L, Schaaf L, Cha S, Wright K, Marks R, Wiesenfeld M,|4
01619|061|R|  Pfeifle D, Harfield A, Krook J, Duncan B, Miller L. Anticonvulsants alter|4
01619|062|R|  the pharmacokinetics of Irinotecan (CPT-11) in patients with recurrent|4
01619|063|R|  glioma. 2000.|4
01620|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Romidepsin; Vorinostat|
01620|002|B||
01620|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01620|004|L|of severe adverse interaction.|
01620|005|B||
01620|006|A|MECHANISM OF ACTION:  Romidepsin(1) and vorinostat(2) may increase the|
01620|007|A|effects of coumarin anticoagulants when co-administered.|
01620|008|B||
01620|009|E|CLINICAL EFFECTS:  Concurrent use of romidepsin(1) or vorinostat(2) with a|
01620|010|E|coumarin anticoagulants may increase the risk of bleeding.|
01620|011|B||
01620|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01620|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01620|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
01620|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01620|016|P|risk for bleeding (e.g. NSAIDs).|
01620|017|B||
01620|018|M|PATIENT MANAGEMENT:  The manufacturers of romidepsin(1) and vorinostat(2)|
01620|019|M|recommend close monitoring of patients taking these agents with coumarin|
01620|020|M|anticoagulants using an appropriate measure, such as the International|
01620|021|M|Normalized Ratio (INR).|
01620|022|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01620|023|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01620|024|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01620|025|M|patients with any symptoms.|
01620|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01620|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01620|028|M|anticoagulation in patients with active pathologic bleeding.|
01620|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01620|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01620|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01620|032|M|and/or swelling.|
01620|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01620|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01620|035|M|initiating, altering the dose or discontinuing either drug.|
01620|036|B||
01620|037|D|DISCUSSION:  Prolongation of prothrombin time (PT) and INR have been|
01620|038|D|observed in patients taking coumarin anticoagulants with romidepsin(1) and|
01620|039|D|vorinostat.(2)|
01620|040|B||
01620|041|R|REFERENCES:|
01620|042|B||
01620|043|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
01620|044|R|  November, 2018.|1
01620|045|R|2.Zolinza (vorinostat) US prescribing information. Merck & Co., Inc. 2006.|1
01621|001|T|MONOGRAPH TITLE:  Vorinostat/HDAC Inhibitors|
01621|002|B||
01621|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01621|004|L|of severe adverse interaction.|
01621|005|B||
01621|006|A|MECHANISM OF ACTION:  The mechanism of the increased thrombocytopenia and|
01621|007|A|gastrointestinal bleeding with concurrent vorinostat and other HDAC|
01621|008|A|inhibitors is not known.|
01621|009|B||
01621|010|E|CLINICAL EFFECTS:  Concurrent use of vorinostat and another HDAC inhibitor|
01621|011|E|may result in severe thrombocytopenia and gastrointestinal bleeding.|
01621|012|B||
01621|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01621|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01621|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01621|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01621|017|P|risk for bleeding (e.g. NSAIDs).|
01621|018|B||
01621|019|M|PATIENT MANAGEMENT:  The manufacturer recommends close monitoring of|
01621|020|M|patients taking vorinostat with other HDAC inhibitors.  The platelet count|
01621|021|M|should be monitored every 2 weeks for the first 2 months.(1)|
01621|022|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01621|023|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01621|024|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01621|025|M|patients with any symptoms.|
01621|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01621|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01621|028|M|anticoagulation in patients with active pathologic bleeding.|
01621|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01621|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01621|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01621|032|M|and/or swelling.|
01621|033|B||
01621|034|D|DISCUSSION:  Concurrent use of vorinostat and another HDAC inhibitor may|
01621|035|D|result in severe thrombocytopenia and gastrointestinal bleeding.  The|
01621|036|D|manufacturer recommends monitoring the platelet count every 2 weeks for the|
01621|037|D|first 2 months.(1)|
01621|038|D|   HDAC inhibitors include: belinostat, panobinostat, phenylbutyrate,|
01621|039|D|romidepsin, sodium butyrate, and valproic acid.|
01621|040|B||
01621|041|R|REFERENCE:|
01621|042|B||
01621|043|R|1.Zolinza (vorinostat) US prescribing information. Merck & Co., Inc.|1
01621|044|R|  December, 2018.|1
01622|001|T|MONOGRAPH TITLE:  Vorinostat/QT Prolonging Agents (mono deleted 11/19/2009)|
01622|002|B||
01622|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01622|004|L|take action as needed.|
01622|005|B||
01622|006|A|MECHANISM OF ACTION:  Vorinostat has been shown to prolong the QTc interval.|
01622|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01622|008|A|additive effects on the QTc interval.(1)|
01622|009|B||
01622|010|E|CLINICAL EFFECTS:  The concurrent use of vorinostat with other agents that|
01622|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01622|012|E|arrhythmias, including torsades de pointes.(1)|
01622|013|B||
01622|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by|
01622|015|P|cardiovascular disease, hypokalemia, hypomagnesemia, bradycardia.|
01622|016|B||
01622|017|M|PATIENT MANAGEMENT:  The manufacturer of vorinostat states that vorinostat|
01622|018|M|should be used with particular caution with other agents known to prolong|
01622|019|M|the QTc interval.(1)|
01622|020|B||
01622|021|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01622|022|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01622|023|D|monograph have been shown to prolong the QTc interval either through their|
01622|024|D|mechanism of action, through studies on their effects on the QTc interval,|
01622|025|D|or through reports of QTc prolongation and/or torsades de pointes in|
01622|026|D|clinical trials and/or postmarketing reports.(2)|
01622|027|B||
01622|028|R|REFERENCES:|
01622|029|B||
01622|030|R|1.Zolinza (vorinostat) US prescribing information. Merck & Co., Inc. 2006.|1
01622|031|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01622|032|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01622|033|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01622|034|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01623|001|T|MONOGRAPH TITLE:  Posaconazole Suspension/H2 Antagonists; Proton Pump|
01623|002|T|Inhibitors|
01623|003|B||
01623|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01623|005|L|of severe adverse interaction.|
01623|006|B||
01623|007|A|MECHANISM OF ACTION:  H2 antagonists and proton pump inhibitors (PPIs)|
01623|008|A|increase the stomach pH, possibly reducing gastrointestinal absorption of|
01623|009|A|posaconazole suspension.|
01623|010|B||
01623|011|E|CLINICAL EFFECTS:  Concurrent use of H2 antagonists or proton pump|
01623|012|E|inhibitors (PPIs) may result in decreased effectiveness of posaconazole|
01623|013|E|suspension.|
01623|014|B||
01623|015|P|PREDISPOSING FACTORS:  None determined.|
01623|016|B||
01623|017|M|PATIENT MANAGEMENT:  Avoid the concurrent use of posaconazole suspension|
01623|018|M|with H2 antagonists or proton pump inhibitors (PPIs).(1)|
01623|019|M|   If H2 antagonists or PPI therapy is required, use the tablet formulation|
01623|020|M|or powder mix formulation of posaconazole.|
01623|021|B||
01623|022|D|DISCUSSION:  Concurrent cimetidine (400 mg twice daily) decreased both|
01623|023|D|posaconazole (200 mg daily) maximum concentration (Cmax) and|
01623|024|D|area-under-curve (AUC) levels by 39%.(1)|
01623|025|D|   No significant effects with other H2 blockers have been noted.(1)|
01623|026|D|   Esomeprazole (40 mg daily for 3 days) decreased the Cmax and AUC of a|
01623|027|D|single dose of posaconazole suspension (400 mg) by 46% and 32%,|
01623|028|D|respectively.(1)|
01623|029|D|   In a study of posaconazole levels in patients with acute myeloid leukemia|
01623|030|D|or myelodysplastic syndrome, use of pantoprazole was associated with|
01623|031|D|decreased posaconazole levels.(3)|
01623|032|D|   In a cross-over study in 5 healthy subjects, esomeprazole decreased the|
01623|033|D|Cmax and AUC of posaconazole suspension by 37% and 84%, respectively.|
01623|034|D|Simultaneous intake of Coca-Cola did not completely counteract the effects|
01623|035|D|of esomeprazole.(4)|
01623|036|D|   In a study in healthy subjects, esomeprazole decreased the Cmax and AUC|
01623|037|D|of posaconazole suspension by 55% and 49%, respectively.  Simultaneous|
01623|038|D|intake of Coca-Cola did not completely counteract the effects of|
01623|039|D|esomeprazole.(5)|
01623|040|B||
01623|041|R|REFERENCES:|
01623|042|B||
01623|043|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01623|044|R|  January, 2022.|1
01623|045|R|2.Tagamet (cimetidine) US prescribing information. GlaxoSmithKline December,|1
01623|046|R|  2005.|1
01623|047|R|3.Vehreschild JJ, Muller C, Farowski F, Vehreschild MJ, Cornely OA, Fuhr U,|2
01623|048|R|  Kreuzer KA, Hallek M, Kohl V. Factors influencing the pharmacokinetics of|2
01623|049|R|  prophylactic posaconazole oral suspension in patients with acute myeloid|2
01623|050|R|  leukemia or myelodysplastic syndrome. Eur J Clin Pharmacol 2012 Jun;|2
01623|051|R|  68(6):987-95.|2
01623|052|R|4.Walravens J, Brouwers J, Spriet I, Tack J, Annaert P, Augustijns P. Effect|2
01623|053|R|  of pH and comedication on gastrointestinal absorption of posaconazole:|2
01623|054|R|  monitoring of intraluminal and plasma drug concentrations. Clin|2
01623|055|R|  Pharmacokinet 2011 Nov 1;50(11):725-34.|2
01623|056|R|5.Krishna G, Moton A, Ma L, Medlock MM, McLeod J. Pharmacokinetics and|2
01623|057|R|  absorption of posaconazole oral suspension under various gastric|2
01623|058|R|  conditions in healthy volunteers. Antimicrob Agents Chemother 2009 Mar;|2
01623|059|R|  53(3):958-66.|2
01624|001|T|MONOGRAPH TITLE:  Magnesium Hydroxide/Polystyrene Sulfonate (mono deleted|
01624|002|T|12/06/2023)|
01624|003|B||
01624|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01624|005|L|take action as needed.|
01624|006|B||
01624|007|A|MECHANISM OF ACTION:  Polystyrene sulfonate may bind magnesium from the|
01624|008|A|antacid, resulting in increased intestinal absorption of non-neutralized|
01624|009|A|bicarbonate, which may result in systemic alkalosis and decreased potassium|
01624|010|A|binding by polystyrene sulfonate.  Intestinal obstruction may occur because|
01624|011|A|of concretion.|
01624|012|B||
01624|013|E|CLINICAL EFFECTS:  Simultaneous oral use may result in metabolic alkalosis|
01624|014|E|and a decrease in the potassium lowering effect of polystyrene sulfonate.|
01624|015|E|Intestinal obstruction has been reported with concurrent use of another|
01624|016|E|cation-donating antacid and may occur with use of magnesium hydroxide.|
01624|017|B||
01624|018|P|PREDISPOSING FACTORS:  Renal failure.|
01624|019|B||
01624|020|M|PATIENT MANAGEMENT:  Consider the use of alternative agents to|
01624|021|M|cation-donating antacids in patients receiving oral polystyrene sulfonate|
01624|022|M|when possible.  If concurrent use is required, separate the dosing by|
01624|023|M|several hours.(1)|
01624|024|B||
01624|025|D|DISCUSSION:  In a study in 11 patients with decreased renal function, the|
01624|026|D|administration of magnesium hydroxide and sodium polystyrene sulfonate|
01624|027|D|produced moderate to moderately severe metabolic alkalosis.(2)  There are|
01624|028|D|case reports documenting this affect as well.(3-7)  Intestinal obstruction|
01624|029|D|has been reported with aluminum hydroxide and sodium polystyrene sulfonate,|
01624|030|D|another cation donating antacid.(8)|
01624|031|D|   If the polystyrene sulfonate is administered rectally, a clinically|
01624|032|D|significant interaction is not likely to occur.|
01624|033|B||
01624|034|R|REFERENCES:|
01624|035|B||
01624|036|R|1.Kayexalate (sodium polystyrene sulfonate) US prescribing information.|1
01624|037|R|  Concordia Pharmaceuticals Inc. July 31, 2017.|1
01624|038|R|2.Schroeder ET. Alkalosis resulting from combined administration of a|2
01624|039|R|  "nonsystemic" antacid and a cation-exchange resin. Gastroenterology 1969|2
01624|040|R|  May;56(5):868-74.|2
01624|041|R|3.Nassif F, Sinnassamy P, Bensman A. A cause of alkalosis in children under|3
01624|042|R|  hemodialysis: combined administration of  magnesium hydroxide and|3
01624|043|R|  polystyrene sodium sulfonate. Presse Med 1987 May 30;16(20):1003.|3
01624|044|R|4.Madias NE, Levey AS. Metabolic alkalosis due to absorption of|3
01624|045|R|  "nonabsorbable" antacids. Am J Med 1983 Jan;74(1):155-8.|3
01624|046|R|5.Ziessman HA. Alkalosis and seizure due to a cation-exchange resin and|3
01624|047|R|  magnesium hydroxide. South Med J 1976 Apr;69(4):497-9.|3
01624|048|R|6.Fernandez PC, Kovnat PJ. Metabolic acidosis reversed by the combination of|3
01624|049|R|  magnesium hydroxide and a cation-exchange resin. N Engl J Med 1972 Jan 6;|3
01624|050|R|  286(1):23-4.|3
01624|051|R|7.Baluarte HJ, Prebis J, Goldberg M, Gruskin AB. Metabolic alkalosis in an|3
01624|052|R|  anephric child caused by the combined use of Kayexalate and Basaljel. J|3
01624|053|R|  Pediatr 1978 Feb;92(2):237-9.|3
01624|054|R|8.Foresti V. Intestinal obstruction due to kayexalate in a patient|3
01624|055|R|  concurrently treated with aluminum hydroxide and morphine sulfate. Clin|3
01624|056|R|  Nephrol 1994 Apr;41(4):252.|3
01625|001|T|MONOGRAPH TITLE:  Pregabalin/Thiazolidinedione Antidiabetics|
01625|002|B||
01625|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01625|004|L|take action as needed.|
01625|005|B||
01625|006|A|MECHANISM OF ACTION:  Both pregabalin and thiazolidinedione antidiabetics|
01625|007|A|may cause weight gain and/or fluid retention.(1)|
01625|008|B||
01625|009|E|CLINICAL EFFECTS:  Concurrent use of pregabalin and thiazolidinedione|
01625|010|E|antidiabetics may result in weight gain and/or fluid retention, which may|
01625|011|E|increase the risk of heart failure in patients with preexisting cardiac|
01625|012|E|conditions.(1)|
01625|013|B||
01625|014|P|PREDISPOSING FACTORS:  Preexisting cardiac conditions may increase the risk|
01625|015|P|of heart failure.(1)|
01625|016|B||
01625|017|M|PATIENT MANAGEMENT:  Patients should be monitored for weight gain and/or|
01625|018|M|fluid retention when taking pregabalin with the thiazolidinedione|
01625|019|M|antidiabetics agents together.  Congestive heart failure or worsening of|
01625|020|M|existing congestive heart failure may occur.|
01625|021|B||
01625|022|D|DISCUSSION:  In clinical trials, the incidence of peripheral edema was 3% of|
01625|023|D|patients receiving a thiazolidinedione antidiabetic alone, 8% of patients|
01625|024|D|receiving pregabalin alone, and 19% of patients on combination therapy.  The|
01625|025|D|incidence of weight gain was 0% of patients receiving a thiazolidinedione|
01625|026|D|antidiabetic alone, 4% of patients receiving pregabalin alone, and 7.5% of|
01625|027|D|patients on combination therapy.(1)|
01625|028|B||
01625|029|R|REFERENCE:|
01625|030|B||
01625|031|R|1.Lyrica (pregabalin) US prescribing information. Pfizer, Inc. May, 2019.|1
01626|001|T|MONOGRAPH TITLE:  Ophthalmic Sodium sulfacetamide/Ophthalmic Silver|
01626|002|B||
01626|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01626|004|L|is contraindicated and generally should not be dispensed or administered to|
01626|005|L|the same patient.|
01626|006|B||
01626|007|A|MECHANISM OF ACTION:  Ophthalmic sodium sulfacetamide and ophthalmic silver|
01626|008|A|are physically incompatible.(1)|
01626|009|B||
01626|010|E|CLINICAL EFFECTS:  Concurrent application of ophthalmic sodium sulfacetamide|
01626|011|E|and ophthalmic silver preparations may result in decreased clinical|
01626|012|E|effectiveness of the products.(1)|
01626|013|B||
01626|014|P|PREDISPOSING FACTORS:  None determined.|
01626|015|B||
01626|016|M|PATIENT MANAGEMENT:  Avoid using ophthalmic silver preparations in the same|
01626|017|M|eye as ophthalmic sodium sulfacetamide products.(1)|
01626|018|B||
01626|019|D|DISCUSSION:  Ophthalmic sodium sulfacetamide and ophthalmic silver are|
01626|020|D|physically incompatible.(1)|
01626|021|B||
01626|022|R|REFERENCE:|
01626|023|B||
01626|024|R|1.Sulfacetamide Sodium Ophthalmic US prescribing information. E. Fougera &|1
01626|025|R|  Co. March, 1998.|1
01627|001|T|MONOGRAPH TITLE:  Aspirin (for Cardioprotection)/Selected NSAIDs|
01627|002|B||
01627|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01627|004|L|take action as needed.|
01627|005|B||
01627|006|A|MECHANISM OF ACTION:  Some non-steroidal anti-inflammatory agents (NSAIDs)|
01627|007|A|are reversible inhibitors of cyclooxygenase and aspirin is an irreversible|
01627|008|A|inhibitor.  If these NSAIDs are given before aspirin, the aspirin will not|
01627|009|A|be able to bind to the cyclooxygenase site, which will result in a lack of|
01627|010|A|effect.|
01627|011|B||
01627|012|E|CLINICAL EFFECTS:  The antiplatelet and cardioprotective effect of aspirin|
01627|013|E|may be decreased with the concurrent use of some NSAIDs, particularly during|
01627|014|E|the washout period of the NSAID.|
01627|015|B||
01627|016|P|PREDISPOSING FACTORS:  None determined.|
01627|017|B||
01627|018|M|PATIENT MANAGEMENT:  Consideration should be given to use of an NSAID that|
01627|019|M|does not interfere with the antiplatelet effect of aspirin, or a non-NSAID|
01627|020|M|analgesic if appropriate.  If an NSAID must be used, cardioprotective doses|
01627|021|M|of aspirin should be administered before taking any NSAIDs.  Single doses of|
01627|022|M|ibuprofen should be given at least 8 hours before or at least 2 hours after|
01627|023|M|immediate release aspirin.  The administration of other NSAIDs should be|
01627|024|M|separated from aspirin by at least 2 hours.|
01627|025|B||
01627|026|D|DISCUSSION:  The cardioprotective effect from aspirin is based on the|
01627|027|D|antiplatelet effects.  The irreversible inhibition of cyclooxygenase|
01627|028|D|mediates the antiplatelet effects.  Administration of a reversible inhibitor|
01627|029|D|or cyclooxygenase blocks the irreversible effect of aspirin on the|
01627|030|D|platelets.  This effect has been seen with celecoxib, flufenamic acid,|
01627|031|D|ibuprofen, indomethacin, naproxen, nimesulide, oxaprozin, piroxicam, and|
01627|032|D|tiaprofenic acid but not with diclofenac, etoricoxib, ketorolac, meloxicam,|
01627|033|D|or sulindac.|
01627|034|D|   In a study of 80 healthy volunteers, aspirin antiplatelet activity,|
01627|035|D|measured by % thromboxane B2 inhibition (TxB2), was decreased when naproxen|
01627|036|D|220 mg daily was given simultaneously with or 30 minutes before aspirin 81|
01627|037|D|mg daily for 10 days (98.7% aspirin alone vs 93.1% and 87.7% naproxen and|
01627|038|D|aspirin).  The interaction persisted at least 1 day following|
01627|039|D|discontinuation of naproxen but was normalized by the 3rd day.|
01627|040|D|   In a nationwide cohort study, patients were evaluated for thromboembolic|
01627|041|D|cardiovascular and clinically relevant bleeding events with concurrent|
01627|042|D|antithrombotic and ongoing NSAID treatment.  A total of 108,232 patients|
01627|043|D|were followed for a mean of 2.3 +/- 1.8 years after diagnosis of myocardial|
01627|044|D|infarction.  Concomitant NSAID treatment significantly increased the risk|
01627|045|D|for cardiovascular events (hazard ratio (HR) 6.96; 95% CI 6.24 - 6.77;|
01627|046|D|p<0.001) and bleeding events (HR 4.08; 95% CI 3.51 - 4.73; p<0.001) compared|
01627|047|D|to no NSAID treatment.  NSAIDs were further evaluated and revealed the use|
01627|048|D|of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI:|
01627|049|D|2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68|
01627|050|D|to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively)|
01627|051|D|had the lowest risk for cardiovascular and bleeding events, receptively.|
01627|052|B||
01627|053|R|REFERENCES:|
01627|054|B||
01627|055|R|1.US Food and Drug Administration Center for Drug Evaluations and Research -|6
01627|056|R|  FDA Science Paper. Concomitant Use of Ibuprofen and Aspirin Potential for|6
01627|057|R|  Attenuation of the Anti-Platelet Effect of Aspirin. available at:|6
01627|058|R|  http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformat|6
01627|059|R|  ionforPatientsandProviders/UCM161282.pdf September 8, 2006.|6
01627|060|R|2.Cheema AA. Should people on aspirin avoid Ibuprofen? A review of the|6
01627|061|R|  literature. Cardiol Rev 2004 May-Jun;12(3):174-6.|6
01627|062|R|3.Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier|2
01627|063|R|  B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet|2
01627|064|R|  effects of aspirin. N Engl J Med 2001 Dec 20;345(25):1809-17.|2
01627|065|R|4.Cryer B, Berlin RG, Cooper SA, Hsu C, Wason S. Double-blind, randomized,|2
01627|066|R|  parallel, placebo-controlled study of ibuprofen effects on thromboxane B2|2
01627|067|R|  concentrations in aspirin-treated healthy adult volunteers. Clin Ther 2005|2
01627|068|R|  Feb;27(2):185-91.|2
01627|069|R|5.Curtis JP, Wang Y, Portnay EL, Masoudi FA, Havranek EP, Krumholz HM.|2
01627|070|R|  Aspirin, ibuprofen, and mortality after myocardial infarction:|2
01627|071|R|  retrospective cohort study. BMJ 2003 Dec 6;327(7427):1322-3.|2
01627|072|R|6.Patel TN, Goldberg KC. Use of aspirin and ibuprofen compared with aspirin|2
01627|073|R|  alone and the risk of myocardial infarction. Arch Intern Med 2004 Apr 26;|2
01627|074|R|  164(8):852-6.|2
01627|075|R|7.MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of|2
01627|076|R|  aspirin. Lancet 2003 Feb 15;361(9357):573-4.|2
01627|077|R|8.Kurth T, Glynn RJ, Walker AM, Chan KA, Buring JE, Hennekens CH, Gaziano|2
01627|078|R|  JM. Inhibition of clinical benefits of aspirin on first myocardial|2
01627|079|R|  infarction by nonsteroidal antiinflammatory drugs. Circulation 2003 Sep 9;|2
01627|080|R|  108(10):1191-5.|2
01627|081|R|9.Kimmel SE, Berlin JA, Reilly M, Jaskowiak J, Kishel L, Chittams J, Strom|2
01627|082|R|  BL. The effects of nonselective non-aspirin non-steroidal|2
01627|083|R|  anti-inflammatory medications on the risk of nonfatal myocardial|2
01627|084|R|  infarction and their interaction with aspirin. J Am Coll Cardiol 2004 Mar|2
01627|085|R|  17;43(6):985-90.|2
01627|086|R|10.Saxena A, Balaramnavar VM, Hohlfeld T, Saxena AK. Drug/drug interaction|2
01627|087|R|   of common NSAIDs with antiplatelet effect of aspirin in human platelets.|2
01627|088|R|   Eur J Pharmacol 2013 Dec 5;721(1-3):215-24.|2
01627|089|R|11.Meek IL, Vonkeman HE, Kasemier J, Movig KL, van de Laar MA. Interference|2
01627|090|R|   of NSAIDs with the thrombocyte inhibitory effect of aspirin: a|2
01627|091|R|   placebo-controlled, ex vivo, serial placebo-controlled serial crossover|2
01627|092|R|   study. Eur J Clin Pharmacol 2013 Mar;69(3):365-71.|2
01627|093|R|12.Anzellotti P, Capone ML, Jeyam A, Tacconelli S, Bruno A, Tontodonati P,|2
01627|094|R|   Di Francesco L, Grossi L, Renda G, Merciaro G, Di Gregorio P, Price TS,|2
01627|095|R|   Garcia Rodriguez LA, Patrignani P. Low-dose naproxen interferes with the|2
01627|096|R|   antiplatelet effects of aspirin in healthy  subjects: recommendations to|2
01627|097|R|   minimize the functional consequences. Arthritis Rheum 2011 Mar;|2
01627|098|R|   63(3):850-9.|2
01627|099|R|13.Gladding PA, Webster MW, Farrell HB, Zeng IS, Park R, Ruijne N. The|2
01627|100|R|   antiplatelet effect of six non-steroidal anti-inflammatory drugs and|2
01627|101|R|   their pharmacodynamic interaction with aspirin in healthy volunteers. Am|2
01627|102|R|   J Cardiol 2008 Apr 1;101(7):1060-3.|2
01627|103|R|14.Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di|2
01627|104|R|   Gregorio P, Merciaro G, Patrignani P. Pharmacodynamic interaction of|2
01627|105|R|   naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol|2
01627|106|R|   2005 Apr 19;45(8):1295-301.|2
01627|107|R|15.Russo NW, Petrucci G, Rocca B. Aspirin, stroke and drug-drug|6
01627|108|R|   interactions. Vascul Pharmacol 2016 Dec;87:14-22.|6
01627|109|R|16.Naprosyn (naproxen) US prescribing information. Atnahs Pharma May, 2021.|1
01627|110|R|17.Caldolor (ibuprofen) US prescribing information. Cumberland|1
01627|111|R|   Pharmaceuticals Inc. November, 2021.|1
01627|112|R|18.Gurbel PA, Bliden KP, Zhu J, Troullos E, Centofanti R, Jarvis S,|2
01627|113|R|   Venkataraman P, Tantry US. Thromboxane inhibition during concurrent|2
01627|114|R|   therapy with low-dose aspirin and over-the-counter naproxen sodium. J|2
01627|115|R|   Thromb Thrombolysis 2018 Jan;45(1):18-26.|2
01627|116|R|19.Kang DO, An H, Park GU, Yum Y, Park EJ, Park Y, Jang WY, Kim W, Choi JY,|2
01627|117|R|   Roh SY, Na JO, Kim JW, Kim EJ, Rha SW, Park CG, Seo HS, Choi CU.|2
01627|118|R|   Cardiovascular and Bleeding Risks Associated With Nonsteroidal|2
01627|119|R|   Anti-Inflammatory  Drugs After Myocardial Infarction. J Am Coll Cardiol|2
01627|120|R|   2020 Aug 4;76(5):518-529.|2
01628|001|T|MONOGRAPH TITLE:  Topical Tretinoin/Tetracyclines|
01628|002|B||
01628|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01628|004|L|of severe adverse interaction.|
01628|005|B||
01628|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01628|007|B||
01628|008|E|CLINICAL EFFECTS:  Concurrent use of topical tretinoin with tetracyclines|
01628|009|E|may increase the risk of phototoxicity(1) in some patients.(2)|
01628|010|B||
01628|011|P|PREDISPOSING FACTORS:  Patients using topical tretinoin for the treatment of|
01628|012|P|photodamage may be predisposed to photosensitivity.(2)|
01628|013|B||
01628|014|M|PATIENT MANAGEMENT:  Concurrent use of topical tretinoin and tetracycline is|
01628|015|M|standard practice in the treatment of acne.(3)  However, patients taking|
01628|016|M|tetracyclines should not use topical tretinoin (e.g Renova) for the|
01628|017|M|treatment of photodamage.(1,2)|
01628|018|B||
01628|019|D|DISCUSSION:  The concurrent use of topical tretinoin and tetracyclines may|
01628|020|D|result in an increased risk of phototoxicity.(1,2)|
01628|021|B||
01628|022|R|REFERENCES:|
01628|023|B||
01628|024|R|1.Renova (tretinoin cream) US prescribing information. Ortho Dermatological|1
01628|025|R|  August 31, 2000.|1
01628|026|R|2.Hagerty D. Personal communication. OrthoNeutrogena February 22, 2007.|1
01628|027|R|3.Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, Shalita|6
01628|028|R|  AR, Thiboutot D. Management of acne: a report from a Global Alliance to|6
01628|029|R|  Improve Outcomes in Acne. J Am Acad Dermatol 2003 Jul;49(1 Suppl):S1-37.|6
01629|001|T|MONOGRAPH TITLE:  Diltiazem/Guggul|
01629|002|B||
01629|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01629|004|L|Assess the risk to the patient and take action as needed.|
01629|005|B||
01629|006|A|MECHANISM OF ACTION:  Guggul may decrease rate and extent of diltiazem|
01629|007|A|absorption.(1)|
01629|008|B||
01629|009|E|CLINICAL EFFECTS:  Concurrent use of diltiazem and guggul may decrease the|
01629|010|E|area-under-curve (AUC) and maximum plasma concentration (Cmax) of|
01629|011|E|diltiazem.(1)|
01629|012|B||
01629|013|P|PREDISPOSING FACTORS:  None determined.|
01629|014|B||
01629|015|M|PATIENT MANAGEMENT:  Concurrent administration of diltiazem and guggul need|
01629|016|M|not be avoided, however, patients receiving diltiazem therapy who have|
01629|017|M|guggul added to or withdrawn from their regimen may require a diltiazem|
01629|018|M|dosage adjustment.|
01629|019|B||
01629|020|D|DISCUSSION:  In a randomized single dose cross-over study (1), seven healthy|
01629|021|D|volunteers received a single dose diltiazem (60 mg) alone and with a single|
01629|022|D|dose of guggul (1 G).  A seven day washout period separated the phases.|
01629|023|D|Serial blood samples were obtained hourly for up to eight hours. The|
01629|024|D|concurrent administration of diltiazem with guggul resulted in a decrease in|
01629|025|D|the diltiazem maximum plasma concentration by 40.9% and the AUC by 35.1%|
01629|026|D|Diltiazem time to Cmax was not changed.|
01629|027|B||
01629|028|R|REFERENCES:|
01629|029|B||
01629|030|R|1.Dalvi SS, Nayak VK, Pohujani SM, Desai NK, Kshirsagar NA, Gupta KC. Effect|2
01629|031|R|  of gugulipid on bioavailability of diltiazem and propranolol. J Assoc|2
01629|032|R|  Physicians India 1994 Jun;42(6):454-5.|2
01629|033|R|2.Singh RB, Niaz MA, Ghosh S. Hypolipidemic and antioxidant effects of|2
01629|034|R|  Commiphora mukul as an adjunct to dietary therapy in patients with|2
01629|035|R|  hypercholesterolemia. Cardiovasc Drugs Ther 1994 Aug;8(4):659-64.|2
01630|001|T|MONOGRAPH TITLE:  Propranolol/Guggul|
01630|002|B||
01630|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01630|004|L|Assess the risk to the patient and take action as needed.|
01630|005|B||
01630|006|A|MECHANISM OF ACTION:  Guggul may decrease rate and extent of propranolol|
01630|007|A|absorption.(1)|
01630|008|B||
01630|009|E|CLINICAL EFFECTS:  Concurrent use of propranolol and guggul may decrease the|
01630|010|E|area-under-curve (AUC) and maximum plasma concentration (Cmax) of|
01630|011|E|propranolol.(1)|
01630|012|B||
01630|013|P|PREDISPOSING FACTORS:  None determined.|
01630|014|B||
01630|015|M|PATIENT MANAGEMENT:  Concurrent administration of propranolol and guggul|
01630|016|M|need not be avoided, however, patients receiving propranolol therapy who|
01630|017|M|have guggul added to or withdrawn from their regimen may require a|
01630|018|M|propranolol dosage adjustment.|
01630|019|B||
01630|020|D|DISCUSSION:  In a randomized single dose cross-over study (1), ten healthy|
01630|021|D|volunteers received a single dose propranolol (40 mg) alone and with a|
01630|022|D|single dose of guggul (1 G).  A seven day washout period separated the|
01630|023|D|phases.  Serial blood samples were obtained hourly for up to eight hours.|
01630|024|D|The concurrent administration of propranolol with guggul resulted in a|
01630|025|D|decrease in the propranolol maximum plasma concentration by 44% and the AUC|
01630|026|D|by 45%.  Propranolol time to Cmax was not changed.|
01630|027|B||
01630|028|R|REFERENCES:|
01630|029|B||
01630|030|R|1.Dalvi SS, Nayak VK, Pohujani SM, Desai NK, Kshirsagar NA, Gupta KC. Effect|2
01630|031|R|  of gugulipid on bioavailability of diltiazem and propranolol. J Assoc|2
01630|032|R|  Physicians India 1994 Jun;42(6):454-5.|2
01630|033|R|2.Singh RB, Niaz MA, Ghosh S. Hypolipidemic and antioxidant effects of|2
01630|034|R|  Commiphora mukul as an adjunct to dietary therapy in patients with|2
01630|035|R|  hypercholesterolemia. Cardiovasc Drugs Ther 1994 Aug;8(4):659-64.|2
01631|001|T|MONOGRAPH TITLE:  Oseltamivir/Clopidogrel|
01631|002|B||
01631|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01631|004|L|take action as needed.|
01631|005|B||
01631|006|A|MECHANISM OF ACTION:  Clopidogrel inhibits the carboxylesterase HCE1 which|
01631|007|A|hydrolyzes oseltamivir.  This metabolism is necessary for the activation of|
01631|008|A|oseltamivir.(1)|
01631|009|B||
01631|010|E|CLINICAL EFFECTS:  Concurrent use of oseltamivir and clopidogrel may result|
01631|011|E|in decreased activation and clinical effect of oseltamivir.(1)|
01631|012|B||
01631|013|P|PREDISPOSING FACTORS:  None determined.|
01631|014|B||
01631|015|M|PATIENT MANAGEMENT:  Patients receiving this combination should have|
01631|016|M|antiviral response monitored particularly closely.|
01631|017|B||
01631|018|D|DISCUSSION:  Although human clinical trials are needed, preliminary in vitro|
01631|019|D|data suggest that the clinical effects of oseltamivir may be decreased by|
01631|020|D|clopidogrel because of inhibition of the activation of oseltamivir.(1)  The|
01631|021|D|manufacturer of oseltamivir disputes these findings because the|
01631|022|D|concentrations of both drugs used in this study were higher than those found|
01631|023|D|in systemic circulation.(2)  However, the study's authors noted that the|
01631|024|D|concentrations used more closely resemble those seen prior to the first|
01631|025|D|pass-metabolism of both agents in the liver, which is where and when the|
01631|026|D|interaction would likely occur.(3)|
01631|027|B||
01631|028|R|REFERENCES:|
01631|029|B||
01631|030|R|1.Shi D, Yang J, Yang D, Lecluyse EL, Black C, You L, Akhlaghi F, Yan B.|5
01631|031|R|  Anti-influenza prodrug oseltamivir is activated by carboxylesterase human|5
01631|032|R|  carboxylesterase 1, and the activation is inhibited by antiplatelet agent|5
01631|033|R|  clopidogrel. J Pharmacol Exp Ther 2006 Sep 11.|5
01631|034|R|2.Fowler S, Lennon SM, Hoffmann G, Rayner CR. Comments on "Anti-influenza|6
01631|035|R|  prodrug oseltamivir is activated by carboxylesterase human|6
01631|036|R|  carboxylesterase 1, and the activation is inhibited by antiplatelet agent|6
01631|037|R|  clopidogrel". J Pharmacol Exp Ther 2007 Jul;322(1):422-3; author reply|6
01631|038|R|  424-5.|6
01631|039|R|3.Shi D, Yang J, Yang D, LeCluyse EL, Black C, You L, Akhlaghi F, Yan B.|6
01631|040|R|  Response to Comments on "Anti-influenza prodrug oseltamivir is activated|6
01631|041|R|  by carboxylesterase human carboxylesterase 1, and the activation is|6
01631|042|R|  inhibited by antiplatelet agent clopidogrel". J Pharmacol Exp Ther 2007|6
01631|043|R|  Jul;322(1):424-5.|6
01632|001|T|MONOGRAPH TITLE:  Tamoxifen/Selected Weak CYP2D6 Inhibitors|
01632|002|B||
01632|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01632|004|L|take action as needed.|
01632|005|B||
01632|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2D6 may inhibit the conversion of|
01632|007|A|tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2)  The role|
01632|008|A|of endoxifen in tamoxifen's efficacy has been debated and may involve a|
01632|009|A|minimum concentration level.(3-5)|
01632|010|B||
01632|011|E|CLINICAL EFFECTS:  Concurrent use of inhibitors of CYP2D6 may decrease the|
01632|012|E|effectiveness of tamoxifen in preventing breast cancer recurrence.|
01632|013|B||
01632|014|P|PREDISPOSING FACTORS:  Concurrent use of weak CYP2D6 inhibitors in patients|
01632|015|P|who are CYP2D6 intermediate metabolizers should be avoided.  Patients who|
01632|016|P|are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by|
01632|017|P|CYP2D6 inhibition.|
01632|018|B||
01632|019|M|PATIENT MANAGEMENT:  Although data on this interaction are conflicting, it|
01632|020|M|may be prudent to use alternatives to CYP2D6 inhibitors when possible in|
01632|021|M|patients taking tamoxifen.  The US manufacturer of tamoxifen states that the|
01632|022|M|impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain|
01632|023|M|and makes no recommendation regarding coadministration with inhibitors of|
01632|024|M|CYP2D6.(12)  The manufacturer of paroxetine (a strong CYP2D6 inhibitor)|
01632|025|M|states that alternative agents with little or no CYP2D6 inhibition should be|
01632|026|M|considered.(13)|
01632|027|M|   The National Comprehensive Cancer Network's breast cancer guidelines|
01632|028|M|advises caution when coadministering strong CYP2D6 inhibitors with|
01632|029|M|tamoxifen.(14)|
01632|030|M|   If concurrent therapy is warranted, the risks versus benefits should be|
01632|031|M|discussed with the patient.|
01632|032|B||
01632|033|D|DISCUSSION:  Some studies have suggested that administration of fluoxetine,|
01632|034|D|paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer|
01632|035|D|phenotype may result in a decrease in the formation of endoxifen (an active|
01632|036|D|metabolite of tamoxifen) and a shorter time to breast cancer|
01632|037|D|recurrence.(1-2,9)|
01632|038|D|   A retrospective study of 630 breast cancer patients found an increasing|
01632|039|D|risk of breast cancer mortality with increasing durations of|
01632|040|D|coadministration of tamoxifen and paroxetine.  In the adjusted analysis,|
01632|041|D|absolute increases of 25%, 50%, and 75% in the proportion of time of|
01632|042|D|overlapping use of tamoxifen with paroxetine was associated with 24%, 54%,|
01632|043|D|and 91% increase in the risk of death from breast cancer, respectively.(16)|
01632|044|D|   The CYP2D6 genotype of the patient may have a role in the effects of this|
01632|045|D|interaction.  Patients with wild-type CYP2D6 genotype may be affected to a|
01632|046|D|greater extent by this interaction.  Patients with a variant CYP2D6 genotype|
01632|047|D|may have lower baseline levels of endoxifen and may be affected to a lesser|
01632|048|D|extent by this interaction.(6-10)|
01632|049|D|   In a retrospective review, 1,325 patients treated with tamoxifen for|
01632|050|D|breast cancer were classified as being poor 2D6 metabolizers (lacking|
01632|051|D|functional CYP2D6 enzymes), intermediate metabolizers (heterozygous|
01632|052|D|alleles), or extensive metabolizers (possessing 2 functional alleles).|
01632|053|D|After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%,|
01632|054|D|20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and|
01632|055|D|poor metabolizers, respectively.(11)|
01632|056|D|   In October of 2006, the Advisory Committee Pharmaceutical Science,|
01632|057|D|Clinical Pharmacology Subcommittee of the US Food and Drug Administration|
01632|058|D|recommended that the US tamoxifen labeling be updated to include information|
01632|059|D|about the increased risk of breast cancer recurrence in poor CYP2D6|
01632|060|D|metabolizers (either by genotype or drug interaction).(17-18)  The labeling|
01632|061|D|changes were never made due to ongoing uncertainty about the effects of|
01632|062|D|CYP2D6 genotypes on tamoxifen efficacy.|
01632|063|D|   In contrast to the above information, two studies have shown no|
01632|064|D|relationship between CYP2D6 genotype and breast cancer outcome.(19-21)  As|
01632|065|D|well, a number of studies found no association between use of CYP2D6|
01632|066|D|inhibitors and/or antidepressants in patients on tamoxifen and breast cancer|
01632|067|D|recurrence,(22-26) though the studies were limited by problematic selection|
01632|068|D|of CYP2D6 inhibitors and short follow-up.|
01632|069|D|   Weak inhibitors of CYP2D6 include:  alogliptin, artesunate, celecoxib,|
01632|070|D|chloroquine, cimetidine, clobazam, clomipramine,  cobicistat, delavirdine,|
01632|071|D|diltiazem, dimenhydrinate, diphenhydramine, dronabinol, dupilumab,|
01632|072|D|echinacea, enasidenib, fedratinib, felodipine, fluvoxamine, gefitinib,|
01632|073|D|hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat,|
01632|074|D|ranitidine, ritonavir, sertraline, verapamil and viloxazine.(27)|
01632|075|B||
01632|076|R|REFERENCES:|
01632|077|B||
01632|078|R|1.Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes|2
01632|079|R|  DF, Desta Z, Flockhart DA. Active tamoxifen metabolite plasma|2
01632|080|R|  concentrations after coadministration of tamoxifen and the selective|2
01632|081|R|  serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003 Dec 3;|2
01632|082|R|  95(23):1758-64.|2
01632|083|R|2.Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li|2
01632|084|R|  L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S,|2
01632|085|R|  Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype,|2
01632|086|R|  antidepressant use, and tamoxifen metabolism during adjuvant breast cancer|2
01632|087|R|  treatment. J Natl Cancer Inst 2005 Jan 5;97(1):30-9.|2
01632|088|R|3.Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z,|2
01632|089|R|  Flockhart DA, Skaar TC. Pharmacological characterization of|2
01632|090|R|  4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen.|2
01632|091|R|  Breast Cancer Res Treat 2004 May;85(2):151-9.|2
01632|092|R|4.Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of|2
01632|093|R|  tamoxifen sequential biotransformation by the human cytochrome P450 system|2
01632|094|R|  in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004|2
01632|095|R|  Sep;310(3):1062-75.|2
01632|096|R|5.Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen|2
01632|097|R|  (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast|2
01632|098|R|  cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother|2
01632|099|R|  Pharmacol 2005 May;55(5):471-8.|2
01632|100|R|6.Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, Nussler|5
01632|101|R|  A, Neuhaus P, Zanger UM, Eichelbaum M, Murdter TE. The influence of|5
01632|102|R|  CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent|5
01632|103|R|  antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol|5
01632|104|R|  2002 Aug;54(2):157-67.|5
01632|105|R|7.Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6|6
01632|106|R|  as a predictor of drug response. Clin Pharmacol Ther 2008 Jan;83(1):160-6.|6
01632|107|R|8.Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD. CYP2D6 polymorphisms|6
01632|108|R|  and the impact on tamoxifen therapy. J Pharm Sci 2007 Sep;96(9):2224-31.|6
01632|109|R|9.Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW,|2
01632|110|R|  Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM,|2
01632|111|R|  Desta Z, Nguyen A, Flockhart DA. Perez EA, Ingle JN. The impact of|2
01632|112|R|  cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.|2
01632|113|R|  Breast Cancer Res Treat 2007 Jan;101(1):113-21.|2
01632|114|R|10.Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C,|2
01632|115|R|   Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN.|2
01632|116|R|   Pharmacogenetics of tamoxifen biotransformation is associated with|2
01632|117|R|   clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005 Dec 20;|2
01632|118|R|   23(36):9312-8.|2
01632|119|R|11.Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P,|2
01632|120|R|   Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J,|2
01632|121|R|   Strick R, Beckmann MW, Koelbl H. Weinshilboum RM, Ingle JN, Eichelbaum M,|2
01632|122|R|   Schwab M, Brauch H. Association between CYP2D6 polymorphisms and outcomes|2
01632|123|R|   among women with early stage breast cancer treated with tamoxifen. JAMA|2
01632|124|R|   2009 Oct 7;302(13):1429-36.|2
01632|125|R|12.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
01632|126|R|   US Inc. September 25, 2018.|1
01632|127|R|13.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
01632|128|R|   Technologies January, 2017.|1
01632|129|R|14.Gradishar WJ, Anderson BO, Avraham J, etal. NCCN Clinical Practice|6
01632|130|R|   Guidelines in Oncology: Breast Cancer. Available at:|6
01632|131|R|   https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf September|6
01632|132|R|   6, 2019.|6
01632|133|R|15.Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC,|2
01632|134|R|   Paszat LF. Selective serotonin reuptake inhibitors and breast cancer|2
01632|135|R|   mortality in women receiving tamoxifen: a population based cohort study.|2
01632|136|R|   BMJ 2010 Feb 8;340:c693.|2
01632|137|R|16.Phan MT, Venitz J. Summary minutes of the Advisory Committee|1
01632|138|R|   Pharmaceutical Science Clinical Pharmacology Subcommittee. Available at:|1
01632|139|R|   http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4248m1.pdf October|1
01632|140|R|   18-19, 2006.|1
01632|141|R|17.Rahman NA. Personal communication. Division Director, Office of Clinical|1
01632|142|R|   Pharmacology, US Food and Drug Administration March 4, 2008.|1
01632|143|R|18.Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, Salter J,|2
01632|144|R|   Sestak I, Cuzick J, Dowsett M. CYP2D6 and UGT2B7 genotype and risk of|2
01632|145|R|   recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer|2
01632|146|R|   Inst 2012 Mar 21;104(6):452-60.|2
01632|147|R|19.Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R,|2
01632|148|R|   Dell'orto P, Biasi MO, Thurlimann B, Lyng MB, Ditzel HJ, Neven P, Debled|2
01632|149|R|   M, Maibach R, Price KN, Gelber RD, Coates AS. Goldhirsch A, Rae JM, Viale|2
01632|150|R|   G,. CYP2D6 genotype and tamoxifen response in postmenopausal women with|2
01632|151|R|   endocrine-responsive breast cancer: the breast international group 1-98|2
01632|152|R|   trial. J Natl Cancer Inst 2012 Mar 21;104(6):441-51.|2
01632|153|R|20.Kelly CM, Pritchard KI. CYP2D6 genotype as a marker for benefit of|6
01632|154|R|   adjuvant tamoxifen in postmenopausal women: lessons learned. J Natl|6
01632|155|R|   Cancer Inst 2012 Mar 21;104(6):427-8.|6
01632|156|R|21.Donneyong MM, Bykov K, Bosco-Levy P, Dong YH, Levin R, Gagne JJ. Risk of|2
01632|157|R|   mortality with concomitant use of tamoxifen and selective serotonin|2
01632|158|R|   reuptake inhibitors: multi-database cohort study. BMJ 2016 Sep 30;|2
01632|159|R|   354:i5014.|2
01632|160|R|22.Haque R, Shi J, Schottinger JE, Ahmed SA, Cheetham TC, Chung J, Avila C,|2
01632|161|R|   Kleinman K, Habel LA, Fletcher SW, Kwan ML. Tamoxifen and Antidepressant|2
01632|162|R|   Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors. J Natl|2
01632|163|R|   Cancer Inst 2016 Mar;108(3):.|2
01632|164|R|23.Cronin-Fenton DP, Damkier P, Lash TL. Metabolism and transport of|2
01632|165|R|   tamoxifen in relation to its effectiveness: new perspectives on an|2
01632|166|R|   ongoing controversy. Future Oncol 2014 Jan;10(1):107-22.|2
01632|167|R|24.Azoulay L, Dell'Aniello S, Huiart L, du Fort GG, Suissa S. Concurrent use|2
01632|168|R|   of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer|2
01632|169|R|   recurrence. Breast Cancer Res Treat 2011 Apr;126(3):695-703.|2
01632|170|R|25.Dezentje VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel|2
01632|171|R|   MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ. Effect of|2
01632|172|R|   concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer|2
01632|173|R|   recurrence in early-stage breast cancer. J Clin Oncol 2010 May 10;|2
01632|174|R|   28(14):2423-9.|2
01632|175|R|26.This information is based on an extract from the Certara Drug Interaction|6
01632|176|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01632|177|R|27.US Food and Drug Administration (FDA). Drug Development and Drug|1
01632|178|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
01632|179|R|   at:|1
01632|180|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
01632|181|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01632|182|R|   11/14/2017.|1
01632|183|R|28.Goetz MP, Sangkuhl K, Guchelaar HJ, Schwab M, Province M, Whirl-Carrillo|6
01632|184|R|   M, Symmans WF, McLeod HL, Ratain MJ, Zembutsu H, Gaedigk A, van Schaik|6
01632|185|R|   RH, Ingle JN, Caudle KE, Klein TE. Clinical Pharmacogenetics|6
01632|186|R|   Implementation Consortium (CPIC) Guideline for CYP2D6  and Tamoxifen|6
01632|187|R|   Therapy. Clin Pharmacol Ther 2018 May;103(5):770-777.|6
01633|001|T|MONOGRAPH TITLE:  HMG-CoA Reductase Inhibitors/Selected Fibrates|
01633|002|B||
01633|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01633|004|L|take action as needed.|
01633|005|B||
01633|006|A|MECHANISM OF ACTION:  Unknown.|
01633|007|B||
01633|008|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
01633|009|E|and fibric acid derivatives has been associated with severe myopathy,|
01633|010|E|rhabdomyolysis and acute renal failure.|
01633|011|B||
01633|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01633|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01633|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01633|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01633|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01633|017|P|transporter OATP1B1 may have increased statin concentrations and be|
01633|018|P|predisposed to myopathy or rhabdomyolysis.  Patients on fluvastatin who are|
01633|019|P|CYP2C9 intermediate or poor metabolizers may have increased fluvastatin|
01633|020|P|concentrations and risk of myopathy.  Patients on rosuvastatin with ABCG2|
01633|021|P|polymorphisms leading to decreased or poor BCRP transporter function may|
01633|022|P|have increased rosuvastatin concentrations and risk of myopathy.|
01633|023|B||
01633|024|M|PATIENT MANAGEMENT:  When possible, avoid administration of these drugs|
01633|025|M|concomitantly unless patients require aggressive therapy.  Instruct patients|
01633|026|M|to report any unexplained muscle pain, tenderness or weakness.  If muscular|
01633|027|M|symptoms develop, monitor serum creatine kinase levels and renal function.|
01633|028|M|One or both agents may need to be discontinued.|
01633|029|M|   If a fibrate is to be given concomitantly with a statin, fenofibrate is|
01633|030|M|the preferred fibrate to be administered.|
01633|031|M|   The manufacturer of pravastatin states that concurrent therapy should be|
01633|032|M|avoided unless the benefits of combination therapy outweigh the risks.|
01633|033|M|   The Canadian manufacturer of rosuvastatin states that concurrent therapy|
01633|034|M|with other fibrates should be approached with caution.  The Australian and|
01633|035|M|UK manufacturers of rosuvastatin state that rosuvastatin 40 mg is|
01633|036|M|contraindicated with concomitant use of fibrates.  The risks of concurrent|
01633|037|M|use of fibrates should be carefully weighed against the benefits.  Patients|
01633|038|M|taking a fibrate should start rosuvastatin therapy with the 5 mg dose.  The|
01633|039|M|US manufacturer of rosuvastatin states that the risks of concurrent use of|
01633|040|M|fibrates should be carefully weighed against the benefits.|
01633|041|M|   The US manufacturer of simvastatin states that patients receiving|
01633|042|M|concurrent therapy with fibrates other than gemfibrozil should be approached|
01633|043|M|with caution.  The Canadian manufacturer of simvastatin states that the dose|
01633|044|M|of simvastatin should not exceed 10 mg per day in patients on concurrent|
01633|045|M|therapy with fibrates other than gemfibrozil and fenofibrate.|
01633|046|B||
01633|047|D|DISCUSSION:  Concurrent fenofibrate (145 mg) with atorvastatin (20 mg)|
01633|048|D|decreased the atorvastatin area-under-curve (AUC) by 17% (range from 67%|
01633|049|D|decrease to 44% increase).  Atorvastatin maximum concentration (Cmax) and|
01633|050|D|the kinetics of fenofibrate were not significantly affected.|
01633|051|D|   Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of|
01633|052|D|pitavastatin (4 mg daily) by 18% and 11%, respectively.|
01633|053|D|   Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of|
01633|054|D|pitavastatin (4 mg daily) by 45% and 31%, respectively.|
01633|055|D|   Concurrent fenofibrate (145 mg) with pravastatin (40 mg) increased|
01633|056|D|pravastatin Cmax and AUC by 36% (range from 69% decrease to 321% increase)|
01633|057|D|and 28% (range from 54% decrease to 128% increase), respectively, and the|
01633|058|D|3-alpha-hydroxy-iso-pravastatin Cmax and AUC by 55% (range from 32% decrease|
01633|059|D|to 314% increase) and by 39% (range from 24% decrease to 261% increase),|
01633|060|D|respectively.  A single dose of pravastatin had no effect on the kinetics of|
01633|061|D|fenofibrate.|
01633|062|D|   In a study in 24 healthy subjects, concurrent fenofibrate (160 mg daily)|
01633|063|D|increased the average AUC of pravastatin (40 mg daily) by 19-28%; however,|
01633|064|D|individual changes were variable and not statistically significant.|
01633|065|D|   Concurrent fenofibrate and rosuvastatin resulted in no significant|
01633|066|D|changes in rosuvastatin or fenofibrate levels; however, rhabdomyolysis has|
01633|067|D|been reported during concurrent therapy.|
01633|068|D|   Concurrent fenofibrate and simvastatin resulted in no significant changes|
01633|069|D|in simvastatin or fenofibrate levels; however, rhabdomyolysis has been|
01633|070|D|reported during concurrent therapy.  In a study in 29 patients, 4 patients|
01633|071|D|reported myalgia during concurrent simvastatin and fenofibrate, compared|
01633|072|D|with no reports during concurrent simvastatin and cholestyramine.|
01633|073|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
01633|074|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
01633|075|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
01633|076|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
01633|077|D|Veteran's Administration over a 2 year period, there were 149 reports of|
01633|078|D|rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil|
01633|079|D|and statin therapy compared with no reports in 1,830 patients receiving|
01633|080|D|concurrent fenofibrate and statin therapy.|
01633|081|D|   The ACCORD trial was a randomized trial of 5518 patients with type 2|
01633|082|D|diabetes receiving simvastatin (40 mg per day or less) and either|
01633|083|D|fenofibrate (initial dose of 160 mg per day, dose adjusted for renal|
01633|084|D|function) or placebo.  At the mean follow up of 4.7 years, the primary|
01633|085|D|efficacy endpoint of first occurrence of a major cardiovascular event,|
01633|086|D|including nonfatal myocardial infarction, nonfatal stroke, or death from|
01633|087|D|cardiovascular causes, occurred at an annual rate of 2.2% in the fenofibrate|
01633|088|D|group and 2.4 % in the placebo group (p=0.32).|
01633|089|B||
01633|090|R|REFERENCES:|
01633|091|B||
01633|092|R|1.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
01633|093|R|  cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
01633|094|R|  polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
01633|095|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01633|096|R|  February, 2014.|1
01633|097|R|3.McDonald KB, Garber BG, Perreault MM. Pancreatitis associated with|3
01633|098|R|  simvastatin plus fenofibrate. Ann Pharmacother 2002 Feb;36(2):275-9.|3
01633|099|R|4.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of a|3
01633|100|R|  statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
01633|101|R|  2002;101(7):53-6.|3
01633|102|R|5.Crestor (rosuvastatin) UK summary of product characteristics. AstraZeneca|1
01633|103|R|  UK Limited December 23, 2022.|1
01633|104|R|6.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
01633|105|R|  Pharmaceuticals LP July, 2024.|1
01633|106|R|7.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
01633|107|R|  Squibb Company May, 2022.|1
01633|108|R|8.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
01633|109|R|  2023.|1
01633|110|R|9.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
01633|111|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
01633|112|R|10.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
01633|113|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
01633|114|R|   at:|3
01633|115|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
01633|116|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
01633|117|R|11.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
01633|118|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
01633|119|R|   95(1):120-2.|2
01633|120|R|12.Gustavson LE, Schweitzer SM, Koehne-Voss S, Achari R, Chira TO, Esslinger|2
01633|121|R|   HU, Yannicelli HD. The effects of multiple doses of fenofibrate on the|2
01633|122|R|   pharmacokinetics of pravastatin and its 3alpha-hydroxy isomeric|2
01633|123|R|   metabolite. J Clin Pharmacol 2005 Aug;45(8):947-53.|2
01633|124|R|13.Ireland JH, Eggert CH, Arendt CJ, Williams AW. Rhabdomyolysis with|2
01633|125|R|   cardiac involvement and acute renal failure in a patient taking|2
01633|126|R|   rosuvastatin and fenofibrate. Ann Intern Med 2005 Jun 7;142(11):949-50.|2
01633|127|R|14.Jacob SS, Jacob S, Williams C, Deeg MA. Simvastatin, fenofibrate, and|3
01633|128|R|   rhabdomyolysis. Diabetes Care 2005 May;28(5):1258.|3
01633|129|R|15.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
01633|130|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
01633|131|R|16.Bergman AJ, Murphy G, Burke J, Zhao JJ, Valesky R, Liu L, Lasseter KC, He|2
01633|132|R|   W, Prueksaritanont T, Qiu Y, Hartford A, Vega JM, Paolini JF. Simvastatin|2
01633|133|R|   does not have a clinically significant pharmacokinetic interaction with|2
01633|134|R|   fenofibrate in humans. J Clin Pharmacol 2004 Sep;44(9):1054-62.|2
01633|135|R|17.Martin PD, Dane AL, Schneck DW, Warwick MJ. An open-label, randomized,|2
01633|136|R|   three-way crossover trial of the effects of coadministration of|2
01633|137|R|   rosuvastatin and fenofibrate on the pharmacokinetic properties of|2
01633|138|R|   rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther|2
01633|139|R|   2003 Feb;25(2):459-71.|2
01633|140|R|18.Wierzbicki AS, Lumb PJ, Cheung J, Crook MA. Fenofibrate plus simvastatin|2
01633|141|R|   therapy versus simvastatin plus cholestyramine therapy for familial|2
01633|142|R|   hypercholesterolaemia. QJM 1997 Oct;90(10):631-4.|2
01633|143|R|19.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
01633|144|R|   America, Inc. November, 2022.|1
01633|145|R|20.Ginsberg HN, Elam MB, Lovato LC, Crouse JRetal. Effects of combination|2
01633|146|R|   lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010 Apr 29;|2
01633|147|R|   362(17):1563-74.|2
01633|148|R|21.Zocor (simvastatin) Canadian prescribing information. Merck Canada Inc.|1
01633|149|R|   May 24, 2019.|1
01633|150|R|22.Crestor (rosuvastatin calcium) Australian Product Information. A.|1
01633|151|R|   Menarini Australia Pty Ltd July 8, 2024.|1
01634|001|T|MONOGRAPH TITLE:  Paliperidone/QT Prolonging Agents|
01634|002|B||
01634|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01634|004|L|of severe adverse interaction.|
01634|005|B||
01634|006|A|MECHANISM OF ACTION:  Paliperidone has been shown to cause a modest increase|
01634|007|A|in the QTc interval.  Concurrent use with other agents that prolong the QTc|
01634|008|A|interval may result in additive effects on the QTc interval.(1,2)|
01634|009|B||
01634|010|E|CLINICAL EFFECTS:  The concurrent use of paliperidone with other agents that|
01634|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01634|012|E|arrhythmias, including torsades de pointes.(1,2)|
01634|013|B||
01634|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01634|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01634|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01634|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01634|018|P|gender, or advanced age.(4)|
01634|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01634|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01634|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01634|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01634|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01634|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01634|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01634|026|B||
01634|027|M|PATIENT MANAGEMENT:  The US manufacturer of paliperidone states that the use|
01634|028|M|of paliperidone should be avoided with other drugs that are known to prolong|
01634|029|M|the QTc interval, including Class IA and Class III antiarrhythmics,|
01634|030|M|antipsychotics, antibiotics such as gatifloxacin and moxifloxacin, or any|
01634|031|M|other class of medications known to prolong the QTc interval.(1,2)|
01634|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01634|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01634|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01634|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01634|036|B||
01634|037|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01634|038|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01634|039|D|monograph have been shown to prolong the QTc interval either through their|
01634|040|D|mechanism of action, through studies on their effects on the QTc interval,|
01634|041|D|or through reports of QTc prolongation and/or torsades de pointes in|
01634|042|D|clinical trials and/or postmarketing reports.(3)|
01634|043|B||
01634|044|R|REFERENCES:|
01634|045|B||
01634|046|R|1.Invega (paliperidone) US prescribing information. Janssen Pharmaceuticals,|1
01634|047|R|  Inc. February 23, 2017.|1
01634|048|R|2.Invega Sustenna (paliperidone palmitate) US prescribing information.|1
01634|049|R|  Janssen Pharmaceuticals, Inc. December 20, 2017.|1
01634|050|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01634|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01634|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01634|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01634|054|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01634|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01634|056|R|  settings: a scientific statement from the American Heart Association and|6
01634|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01634|058|R|  2;55(9):934-47.|6
01635|001|T|MONOGRAPH TITLE:  Paliperidone/Possible QT Prolonging Agents|
01635|002|B||
01635|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01635|004|L|take action as needed.|
01635|005|B||
01635|006|A|MECHANISM OF ACTION:  Paliperidone has been shown to cause a modest increase|
01635|007|A|in the QTc interval.  Concurrent use with other agents that prolong the QTc|
01635|008|A|interval may result in additive effects on the QTc interval.(1,2)|
01635|009|B||
01635|010|E|CLINICAL EFFECTS:  The concurrent use of paliperidone with other agents that|
01635|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01635|012|E|arrhythmias, including torsades de pointes.(1,2)|
01635|013|B||
01635|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01635|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01635|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01635|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01635|018|P|gender, or advanced age.(4)|
01635|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01635|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01635|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01635|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01635|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01635|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01635|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01635|026|B||
01635|027|M|PATIENT MANAGEMENT:  The US manufacturer of paliperidone states that the use|
01635|028|M|of paliperidone should be avoided with other drugs that are known to prolong|
01635|029|M|the QTc interval, including Class IA and Class III antiarrhythmics,|
01635|030|M|antipsychotics, antibiotics such as gatifloxacin and moxifloxacin, or any|
01635|031|M|other class of medications known to prolong the QTc interval.(1,2)|
01635|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01635|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01635|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01635|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01635|036|B||
01635|037|D|DISCUSSION:  Agents that are linked to this monograph may have been|
01635|038|D|associated with torsades de pointes and/or QT prolongation but at this time|
01635|039|D|lack substantial evidence for causing torsades de pointes.(3)|
01635|040|B||
01635|041|R|REFERENCES:|
01635|042|B||
01635|043|R|1.Invega (paliperidone) US prescribing information. Janssen Pharmaceuticals,|1
01635|044|R|  Inc. February 23, 2017.|1
01635|045|R|2.Invega Sustenna (paliperidone palmitate) US prescribing information.|1
01635|046|R|  Janssen Pharmaceuticals, Inc. December 20, 2017.|1
01635|047|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01635|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01635|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01635|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01635|051|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01635|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01635|053|R|  settings: a scientific statement from the American Heart Association and|6
01635|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01635|055|R|  2;55(9):934-47.|6
01636|001|T|MONOGRAPH TITLE:  Lamotrigine/Carbamazepine|
01636|002|B||
01636|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01636|004|L|take action as needed.|
01636|005|B||
01636|006|A|MECHANISM OF ACTION:  Carbamazepine may induce the metabolism of|
01636|007|A|lamotrigine.(1)|
01636|008|B||
01636|009|E|CLINICAL EFFECTS:  The concurrent use of carbamazepine with lamotrigine|
01636|010|E|without valproate and without dosage adjustments may result in decreased|
01636|011|E|levels and clinical effectiveness of lamotrigine.(1)  Coadministration of|
01636|012|E|lamotrigine and valproic acid with carbamazepine may result in elevated|
01636|013|E|lamotrigine concentrations.(2)|
01636|014|B||
01636|015|P|PREDISPOSING FACTORS:  None determined.|
01636|016|B||
01636|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with lamotrigine|
01636|018|M|and carbamazepine without valproate should be observed for decreased|
01636|019|M|lamotrigine levels and clinical effectiveness.  The dose of lamotrigine may|
01636|020|M|need to be adjusted if carbamazepine is added to or removed from lamotrigine|
01636|021|M|therapy.  Refer to the current lamotrigine prescribing information for|
01636|022|M|information on dosage adjustments.|
01636|023|M|   Lamotrigine levels for patients whose therapeutic regimens include|
01636|024|M|coadministration of lamotrigine with carbamazepine should be monitored for|
01636|025|M|elevation.  The dose of lamotrigine should be adjusted accordingly while the|
01636|026|M|medication is being coadministered with valproic acid and other|
01636|027|M|antiepileptic drugs.|
01636|028|B||
01636|029|D|DISCUSSION:  In 24 epileptic adults taking carbamazepine, phenytoin,|
01636|030|D|phenobarbital, or primidone, the time to maximum concentration (Tmax),|
01636|031|D|half-life, and apparent plasma clearance for a single dose of lamotrigine|
01636|032|D|were 2.3 hours, 14.4 hours, and 1.10 ml/min/kg, respectively.  In 179|
01636|033|D|healthy adults taking no other medications, these values were 2.2 hours,|
01636|034|D|32.8 hours, and 0.44 ml/min/kg, respectively.(1)|
01636|035|D|   In 17 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or|
01636|036|D|primidone, the Tmax, half-life, and apparent plasma clearance of multiple|
01636|037|D|dose lamotrigine were 2.0 hours, 12.6 hours, and 1.21 ml/min/kg.  These|
01636|038|D|values were 1.7 hours, 25.4 hours, and 0.58 ml/min/kg, respectively, in 36|
01636|039|D|healthy adults taking no other medications.(1)|
01636|040|D|   In 10 pediatric patients with epilepsy aged 10 months to 5.3 years who|
01636|041|D|were taking carbamazepine, phenytoin, phenobarbital, or primidone,|
01636|042|D|lamotrigine Tmax, half-life, and apparent plasma clearance were 3.0 hours,|
01636|043|D|7.7 hours, and 3.62 ml/min/kg, respectively.  In 7 patients in the same age|
01636|044|D|range who where not taking other medications known to affect lamotrigine|
01636|045|D|clearance, these values were 5.2 hours, 19.0 hours, and 1.2 ml/min/kg,|
01636|046|D|respectively.(1)|
01636|047|D|   In 527 adult patients with epilepsy, the mean oral clearance of|
01636|048|D|lamotrigine in patients receiving one concomitant enzyme-inducing|
01636|049|D|anti-epileptic agent and not valproic acid was estimated to be 1|
01636|050|D|ml/min/kg.(3)|
01636|051|D|   One study of 302 patients looked at the results of combining lamotrigine|
01636|052|D|with carbamazepine, phenytoin, or phenobarbital with or without valproic|
01636|053|D|acid.  The study found when the lamotrigine combinations contained valproic|
01636|054|D|acid that lamotrigine concentrations were two times higher when compared to|
01636|055|D|patients taking either lamotrigine alone or in combination with one of the|
01636|056|D|other antiepileptic drugs even when the lamotrigine doses were halved.(2)|
01636|057|B||
01636|058|R|REFERENCES:|
01636|059|B||
01636|060|R|1.Lamictal (lamotrigine) US prscribing information. GlaxoSmithKline October,|1
01636|061|R|  2025.|1
01636|062|R|2.May TW, Rambeck B, Jurgens U. Serum concentrations of lamotrigine in|2
01636|063|R|  epileptic patients: the influence of dose and comedication. Ther Drug|2
01636|064|R|  Monit 1996 Oct;18(5):523-31.|2
01636|065|R|3.Grasela TH, Fiedler-Kelly J, Cox E, Womble GP, Risner ME, Chen C.|2
01636|066|R|  Population pharmacokinetics of lamotrigine adjunctive therapy in adults|2
01636|067|R|  with epilepsy. J Clin Pharmacol 1999 Apr;39(4):373-84.|2
01637|001|T|MONOGRAPH TITLE:  Docetaxel/Sorafenib|
01637|002|B||
01637|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01637|004|L|take action as needed.|
01637|005|B||
01637|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01637|007|B||
01637|008|E|CLINICAL EFFECTS:  Concurrent administration of sorafenib may result in|
01637|009|E|elevated levels of and effects (including toxicity) from docetaxel.(1)|
01637|010|B||
01637|011|P|PREDISPOSING FACTORS:  None determined.|
01637|012|B||
01637|013|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with sorafenib|
01637|014|M|and docetaxel should be closely monitored for toxicities.  The dosage of|
01637|015|M|docetaxel may need to be adjusted.|
01637|016|B||
01637|017|D|DISCUSSION:  Concurrent administration of sorafenib (200 mg twice daily or|
01637|018|D|400 mg twice daily on Days 2 through 19 of a 21 day cycle) with docetaxel|
01637|019|D|(75 mg/m2 or 100 mg/m2 every 21 days) increased the area-under-curve (AUC)|
01637|020|D|and maximum concentration (Cmax) of docetaxel by 36%-80% and by 16%-32%,|
01637|021|D|respectively.(1)|
01637|022|B||
01637|023|R|REFERENCE:|
01637|024|B||
01637|025|R|1.Nexavar (sorafenib tosylate) UK summary of product characteristics. Bayer|1
01637|026|R|  Plc February 13, 2007.|1
01638|001|T|MONOGRAPH TITLE:  Alprazolam/Indinavir|
01638|002|B||
01638|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01638|004|L|is contraindicated and generally should not be dispensed or administered to|
01638|005|L|the same patient.|
01638|006|B||
01638|007|A|MECHANISM OF ACTION:  Indinavir may inhibit the metabolism of alprazolam by|
01638|008|A|CYP3A4.(1)|
01638|009|B||
01638|010|E|CLINICAL EFFECTS:  Concurrent administration of indinavir may result in|
01638|011|E|elevated levels of and clinical effects from alprazolam, which may result in|
01638|012|E|profound sedation, respiratory depression, coma, and/or death.(1)|
01638|013|B||
01638|014|P|PREDISPOSING FACTORS:  None determined.|
01638|015|B||
01638|016|M|PATIENT MANAGEMENT:  The concurrent administration of alprazolam with|
01638|017|M|indinavir is contraindicated by the US manufacturer of indinavir.(1)|
01638|018|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
01638|019|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
01638|020|M|unresponsiveness.|
01638|021|B||
01638|022|D|DISCUSSION:  Because of the risk of prolonged or increased sedation or|
01638|023|D|respiratory depression, concurrent administration of alprazolam with|
01638|024|D|indinavir is contraindicated by the US manufacturer of indinavir.(1)|
01638|025|B||
01638|026|R|REFERENCE:|
01638|027|B||
01638|028|R|1.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01638|029|R|  September, 2016.|1
01639|001|T|MONOGRAPH TITLE:  Influenza Virus Vaccine Live/Oseltamivir (mono deleted|
01639|002|T|09/25/2008)|
01639|003|B||
01639|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01639|005|L|is contraindicated and generally should not be dispensed or administered to|
01639|006|L|the same patient.|
01639|007|B||
01639|008|A|MECHANISM OF ACTION:  Oseltamivir may prevent replication of the live|
01639|009|A|vaccine virus.(1)|
01639|010|B||
01639|011|E|CLINICAL EFFECTS:  Administration of the live influenza virus vaccine within|
01639|012|E|2 weeks before or 48 hours after oseltamivir may result in decreased|
01639|013|E|efficacy of the vaccine.(1)|
01639|014|B||
01639|015|P|PREDISPOSING FACTORS:  None determined.|
01639|016|B||
01639|017|M|PATIENT MANAGEMENT:  The US manufacturer of oseltamivir states that the live|
01639|018|M|influenza virus vaccine should not be administered within 2 weeks before or|
01639|019|M|48 hours after oseltamivir.(1)|
01639|020|B||
01639|021|D|DISCUSSION:  Oseltamivir may prevent replication of the live vaccine virus,|
01639|022|D|resulting in the vaccine being ineffective.  Therefore, the US manufacturer|
01639|023|D|of oseltamivir states that the live influenza virus vaccine should not be|
01639|024|D|administered within 2 weeks before or 48 hours after oseltamivir.(1)|
01639|025|B||
01639|026|R|REFERENCE:|
01639|027|B||
01639|028|R|1.Tamiflu (oseltamivir phosphate) US prescribing information. Roche|1
01639|029|R|  Laboratories, Inc. March, 2018.|1
01640|001|T|MONOGRAPH TITLE:  Furosemide/Aliskiren|
01640|002|B||
01640|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01640|004|L|take action as needed.|
01640|005|B||
01640|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01640|007|B||
01640|008|E|CLINICAL EFFECTS:  Concurrent use of aliskiren may decrease levels and|
01640|009|E|effectiveness of furosemide.(1)|
01640|010|B||
01640|011|P|PREDISPOSING FACTORS:  None determined.|
01640|012|B||
01640|013|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent aliskiren and|
01640|014|M|furosemide for decreased furosemide effects.  The dose of furosemide may|
01640|015|M|need to be adjusted if aliskiren is initiated or discontinued, or furosemide|
01640|016|M|may need to be replaced with an alternative diuretic agent.|
01640|017|B||
01640|018|D|DISCUSSION:  Concurrent aliskiren decreased furosemide maximum concentration|
01640|019|D|(Cmax) and area-under-curve (AUC) by 50% and 30%, respectively.  There were|
01640|020|D|no significant effects on aliskiren levels.(1)|
01640|021|D|   Concurrent aliskiren decreased furosemide Cmax and AUC by 27% and 17%,|
01640|022|D|respectively and 24-hour urinary furosemide excretion was reduced by 29%.|
01640|023|D|There were no significant effects on aliskiren levels.(2)|
01640|024|B||
01640|025|R|REFERENCES:|
01640|026|B||
01640|027|R|1.Rasilez (aliskiren hemifumarate) UK summary of product characteristics.|1
01640|028|R|  Novartis Pharmaceuticals UK Ltd. September, 2014.|1
01640|029|R|2.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
01640|030|R|  Corporation November, 2017.|1
01641|001|T|MONOGRAPH TITLE:  Midazolam; Triazolam/Diltiazem; Verapamil|
01641|002|B||
01641|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01641|004|L|of severe adverse interaction.|
01641|005|B||
01641|006|A|MECHANISM OF ACTION:  Diltiazem and verapamil may inhibit the metabolism of|
01641|007|A|midazolam and triazolam by CYP3A4.(1-7)|
01641|008|B||
01641|009|E|CLINICAL EFFECTS:  Concurrent use of diltiazem or verapamil may result in|
01641|010|E|elevated levels of and clinical effects, including profound sedation,|
01641|011|E|respiratory depression, coma, and/or death, from midazolam and|
01641|012|E|triazolam.(1-4)|
01641|013|B||
01641|014|P|PREDISPOSING FACTORS:  None determined.|
01641|015|B||
01641|016|M|PATIENT MANAGEMENT:  Consider the use of alternative agents to midazolam and|
01641|017|M|triazolam in patients maintained on diltiazem or verapamil.  The concurrent|
01641|018|M|use of midazolam or triazolam with diltiazem or verapamil should be|
01641|019|M|approached with caution.  The dose of midazolam or triazolam should be|
01641|020|M|reduced and patients should be observed for increased benzodiazepine effects|
01641|021|M|such as prolonged sedation.(1-4)|
01641|022|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
01641|023|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
01641|024|M|unresponsiveness.|
01641|025|B||
01641|026|D|DISCUSSION:  In a double-blind, randomized, cross-over study in 9 healthy|
01641|027|D|subjects, pretreatment with diltiazem (60 mg 3 times daily for 2 days)|
01641|028|D|increased the area-under-curve (AUC) of a single oral dose of midazolam (15|
01641|029|D|mg) by 2.75-fold.  Midazolam maximum concentration (Cmax) doubled and|
01641|030|D|half-life (T1/2) was prolonged.  These changes were associated with profound|
01641|031|D|and prolonged sedative effects.(1)|
01641|032|D|   In a double-blind, randomized, cross-over study in 9 healthy subjects,|
01641|033|D|pretreatment with verapamil (80 mg 3 times daily for 2 days) increased the|
01641|034|D|AUC of a single oral dose of midazolam (15 mg) by 1.9-fold.  Midazolam Cmax|
01641|035|D|doubled and T1/2 was prolonged.  These changes were associated with profound|
01641|036|D|and prolonged sedative effects.(1)|
01641|037|D|   In a randomized, cross-over study in 7 healthy males, pretreatment with|
01641|038|D|diltiazem (180 mg daily for 3 days) increased the AUC, Cmax, and T1/s of a|
01641|039|D|single oral dose of triazolam (0.25 mg) by 1.275-fold, 71%, and 85%,|
01641|040|D|respectively.  Pharmacodynamic effects of triazolam were significantly|
01641|041|D|increased as measured by peak saccadic velocity of eye movements (PSV),|
01641|042|D|electroencephalogram (EEG), and visual analogue scale (VAS).(2)|
01641|043|D|   In a randomized, double-blind, cross-over study in 10 healthy subjects,|
01641|044|D|pretreatment with diltiazem (60 mg 3 times daily for 2 days) increased the|
01641|045|D|AUC, Cmax, and T1/2 of a single oral dose of triazolam (0.25 mg) by 3-fold,|
01641|046|D|2-fold, and 2-fold, respectively.  These changes were associated with|
01641|047|D|increased and prolonged pharmacodynamic effects.(3)|
01641|048|D|   Studies have shown that diltiazem increases midazolam and triazolam AUC|
01641|049|D|by 3-fold to 4-fold, Cmax by 2-fold, and T1/2 by 1.5-fold to 2.5-fold.(4)|
01641|050|B||
01641|051|R|REFERENCES:|
01641|052|B||
01641|053|R|1.Backman JT, Olkkola KT, Aranko K, Himberg JJ, Neuvonen PJ. Dose of|2
01641|054|R|  midazolam should be reduced during diltiazem and verapamil treatments. Br|2
01641|055|R|  J Clin Pharmacol 1994 Mar;37(3):221-5.|2
01641|056|R|2.Kosuge K, Nishimoto M, Kimura M, Umemura K, Nakashima M, Ohashi K.|2
01641|057|R|  Enhanced effect of triazolam with diltiazem. Br J Clin Pharmacol 1997 Apr;|2
01641|058|R|  43(4):367-72.|2
01641|059|R|3.Varhe A, Olkkola KT, Neuvonen PJ. Diltiazem enhances the effects of|2
01641|060|R|  triazolam by inhibiting its metabolism. Clin Pharmacol Ther 1996 Apr;|2
01641|061|R|  59(4):369-75.|2
01641|062|R|4.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
01641|063|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
01641|064|R|5.Jones DR, Gorski JC, Hamman MA, Mayhew BS, Rider S, Hall SD. Diltiazem|5
01641|065|R|  inhibition of cytochrome P-450 3A activity is due to metabolite|5
01641|066|R|  intermediate complex formation. J Pharmacol Exp Ther 1999 Sep;|5
01641|067|R|  290(3):1116-25.|5
01641|068|R|6.Wang JS, Wen X, Backman JT, Taavitsainen P, Neuvonen PJ, Kivisto KT.|5
01641|069|R|  Midazolam alpha-hydroxylation by human liver microsomes in vitro:|5
01641|070|R|  inhibition by calcium channel blockers, itraconazole and ketoconazole.|5
01641|071|R|  Pharmacol Toxicol 1999 Oct;85(4):157-61.|5
01641|072|R|7.Wang YH, Jones DR, Hall SD. Prediction of cytochrome P450 3A inhibition by|5
01641|073|R|  verapamil enantiomers and their metabolites. Drug Metab Dispos 2004 Feb;|5
01641|074|R|  32(2):259-66.|5
01642|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Polystyrene Sulfonate|
01642|002|B||
01642|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01642|004|L|take action as needed.|
01642|005|B||
01642|006|A|MECHANISM OF ACTION:  Polystyrene sulfonate may bind and delay or prevent|
01642|007|A|the absorption of thyroid preparations from the gastrointestinal tract.(1)|
01642|008|B||
01642|009|E|CLINICAL EFFECTS:  Simultaneous administration of polystyrene sulfonate may|
01642|010|E|result in decreased levels of and effectiveness from thyroid|
01642|011|E|preparations.(1)|
01642|012|B||
01642|013|P|PREDISPOSING FACTORS:  None determined.|
01642|014|B||
01642|015|M|PATIENT MANAGEMENT:  The US manufacturer of levothyroxine states that|
01642|016|M|levothyroxine should be administered at least 4 hours apart from polystyrene|
01642|017|M|sulfonate.(1)|
01642|018|B||
01642|019|D|DISCUSSION:  Because polystyrene sulfonate may bind and delay or prevent the|
01642|020|D|absorption of levothyroxine from the gastrointestinal tract, the US|
01642|021|D|manufacturer of levothyroxine states that levothyroxine should be|
01642|022|D|administered at least 4 hours apart from polystyrene sulfonate.(1)|
01642|023|B||
01642|024|R|REFERENCE:|
01642|025|B||
01642|026|R|1.Synthroid (levothyroxine sodium) US prescribing information. Abbott|1
01642|027|R|  Laboratories February, 2024.|1
01643|001|T|MONOGRAPH TITLE:  Pioglitazone; Rosiglitazone/Rifampin (mono deleted|
01643|002|T|07/23/2014)|
01643|003|B||
01643|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01643|005|L|take action as needed.|
01643|006|B||
01643|007|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of pioglitazone|
01643|008|A|(1,2) and rosiglitazone(3,4) by CYP P-450-2C8.|
01643|009|B||
01643|010|E|CLINICAL EFFECTS:  Concurrent use of rifampin may result in decreased levels|
01643|011|E|of and clinical effects from pioglitazone(1,2) or rosiglitazone.(3,4)|
01643|012|B||
01643|013|P|PREDISPOSING FACTORS:  None determined.|
01643|014|B||
01643|015|M|PATIENT MANAGEMENT:  If concurrent therapy with rifampin is warranted,|
01643|016|M|patients should be closely monitored for decreased response to pioglitazone|
01643|017|M|or rosiglitazone.|
01643|018|M|   The dosage of pioglitazone(1,2) or rosiglitazone(3,4) may need to be|
01643|019|M|adjusted when rifampin is initiated or discontinued.  The maximum|
01643|020|M|recommended dosage of 45 mg daily of pioglitazone should not be exceeded.(2)|
01643|021|B||
01643|022|D|DISCUSSION:  In a randomized cross-over study in 10 healthy subjects,|
01643|023|D|pretreatment with rifampin (600 mg daily for 6 days) decreased the the|
01643|024|D|area-under-curve (AUC) and half-life (T1/2) of a single dose of pioglitazone|
01643|025|D|(30 mg) by 54% and by 53%, respectively.  There were no significant effects|
01643|026|D|on pioglitazone maximum concentration (Cmax) or time to Cmax (Tmax).  The|
01643|027|D|AUC of the M-III and M-IV active metabolites of pioglitazone increased by|
01643|028|D|34% and by 39%, respectively.(1,2)|
01643|029|D|   In a randomized crossover study in 10 subjects, pretreatment with|
01643|030|D|rifampin (600 mg daily for 6 days) decreased the AUC, Cmax, and T1/2 of a|
01643|031|D|single dose of rosiglitazone (4 mg) by 54%, 28%, and 50%, respectively.  The|
01643|032|D|formation of N-desmethylrosiglitazone was increased.(3)|
01643|033|D|   In a randomized, open-label, cross-over study in 10 healthy Korean|
01643|034|D|subjects, pretreatment with rifampin (600 mg daily for 7 days) decreased the|
01643|035|D|AUC, Cmax, and T1/2 of a single dose of rosiglitazone (8 mg) by 65%, 32.6%,|
01643|036|D|and 69%, respectively.  The apparent oral clearance of rosiglitazone|
01643|037|D|increased by about 3-fold.(4)|
01643|038|B||
01643|039|R|REFERENCES:|
01643|040|B||
01643|041|R|1.Jaakkola T, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ. Effect of|2
01643|042|R|  rifampicin on the pharmacokinetics of pioglitazone. Br J Clin Pharmacol|2
01643|043|R|  2006 Jan;61(1):70-8.|2
01643|044|R|2.Actos (pioglitazone hydrochloride) US prescribing information. Takeda|1
01643|045|R|  Pharmaceuticals Inc. November, 2013.|1
01643|046|R|3.Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampin on|2
01643|047|R|  the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone.|2
01643|048|R|  Clin Pharmacol Ther 2004 Sep;76(3):239-49.|2
01643|049|R|4.Park JY, Kim KA, Kang MH, Kim SL, Shin JG. Effect of rifampin on the|2
01643|050|R|  pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther|2
01643|051|R|  2004 Mar;75(3):157-62.|2
01644|001|T|MONOGRAPH TITLE:  Lorazepam; Mexazolam/Valproate|
01644|002|B||
01644|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01644|004|L|take action as needed.|
01644|005|B||
01644|006|A|MECHANISM OF ACTION:  Valproate may inhibit the metabolism of lorazepam by|
01644|007|A|glucuronidation via UDP-glucuronosyltransferases (UGT).(1-4) One of the|
01644|008|A|active metabolites of mexazolam is lorazepam.|
01644|009|B||
01644|010|E|CLINICAL EFFECTS:  Concurrent use of valproate or derivatives may increase|
01644|011|E|levels of or clinical effects from lorazepam, including profound sedation,|
01644|012|E|respiratory depression, and coma.(1-4)|
01644|013|B||
01644|014|P|PREDISPOSING FACTORS:  None determined.|
01644|015|B||
01644|016|M|PATIENT MANAGEMENT:  The US manufacturers of lorazepam state that the dosage|
01644|017|M|of lorazepam should be reduced by 50% in patients receiving valproate.(1,2)|
01644|018|B||
01644|019|D|DISCUSSION:  In a study in 8 healthy males, pretreatment with valproate (250|
01644|020|D|mg twice daily for 3 days) decreased the total clearance of a single dose of|
01644|021|D|lorazepam (2 mg intravenously) by 40% in 6 subjects.  The formation rate of|
01644|022|D|lorazepam glucuronide was decreased by 55% in these subjects.  Lorazepam|
01644|023|D|concentrations were about 2-fold higher for at least 12 hours post-dose|
01644|024|D|during concurrent valproate.(1,3)|
01644|025|D|   In a randomized, double-blind, placebo-controlled study in 16 healthy|
01644|026|D|males, concurrent divalproex (500 mg every 12 hours for 12 days) increased|
01644|027|D|the area-under-curve (AUC), maximum concentration (Cmax), and minimum|
01644|028|D|concentration (Cmin) of lorazepam (1 mg every 12 hours, Days 6-10) by 20%,|
01644|029|D|8%, and 31%, respectively.  Lorazepam clearance was decreased by 31% during|
01644|030|D|concurrent divalproex.(4)|
01644|031|D|   There is one case report of coma following the injection of 6 mg of|
01644|032|D|lorazepam over 24 hours in a patient maintained on valproate (1000 mg).  The|
01644|033|D|patient remained in a coma for between 48 and 72 hours.(5)|
01644|034|B||
01644|035|R|REFERENCES:|
01644|036|B||
01644|037|R|1.Ativan (lorazepam injection) US prescribing information. Biovail|1
01644|038|R|  Laboratories International SRL April 27, 2017.|1
01644|039|R|2.Ativan (lorazepam tablets) US prescribing information. Biovail|1
01644|040|R|  Pharmaceuticals February 5, 2021.|1
01644|041|R|3.Anderson GD, Gidal BE, Kantor ED, Wilensky AJ. Lorazepam-valproate|2
01644|042|R|  interaction: studies in normal subjects and isolated perfused rat liver.|2
01644|043|R|  Epilepsia 1994 Jan-Feb;35(1):221-5.|2
01644|044|R|4.Samara EE, Granneman RG, Witt GF, Cavanaugh JH. Effect of valproate on the|2
01644|045|R|  pharmacokinetics and pharmacodynamics of lorazepam. J Clin Pharmacol 1997|2
01644|046|R|  May;37(5):442-50.|2
01644|047|R|5.von Moltke LL, Manis M, Harmatz JS, Poorman R, Greenblatt DJ. Inhibition|5
01644|048|R|  of acetaminophen and lorazepam glucuronidation in vitro by probenecid.|5
01644|049|R|  Biopharm Drug Dispos 1993 Mar;14(2):119-30.|5
01645|001|T|MONOGRAPH TITLE:  Lorazepam; Mexazolam/UGT Inhibitors|
01645|002|B||
01645|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01645|004|L|take action as needed.|
01645|005|B||
01645|006|A|MECHANISM OF ACTION:  Inhibitors of UDP-glucuronosyltransferases (UGT) may|
01645|007|A|inhibit the metabolism of lorazepam.(1-4)|
01645|008|A|   One of the active metabolites of mexazolam is lorazepam.|
01645|009|B||
01645|010|E|CLINICAL EFFECTS:  Concurrent use of UGT inhibitors may increase levels of|
01645|011|E|and clinical effects from lorazepam, including profound sedation,|
01645|012|E|respiratory depression, and coma.(1-4)|
01645|013|B||
01645|014|P|PREDISPOSING FACTORS:  None determined.|
01645|015|B||
01645|016|M|PATIENT MANAGEMENT:  The US manufacturers of lorazepam state that the dosage|
01645|017|M|of lorazepam should be reduced by 50% in patients receiving UGT|
01645|018|M|inhibitors.(1,2)|
01645|019|B||
01645|020|D|DISCUSSION:  In a study in 9 healthy subjects, pretreatment with probenecid|
01645|021|D|(500 mg every 6 hours) increased the half-life (T1/2) of a single|
01645|022|D|intravenous dose of lorazepam (2 mg) by 130%.  Lorazepam clearance was|
01645|023|D|decreased by 45%.  There was no change in lorazepam apparent volume of|
01645|024|D|distribution.(1,4)|
01645|025|D|   In 7 patients given probenecid 1G orally one hour prior to induction|
01645|026|D|anesthesia with midazolam, there was no significant change in plasma protein|
01645|027|D|binding due to probenecid pretreatment.  The mean free midazolam fractions|
01645|028|D|were 3.31% prior and 3.34% following pretreatment.(5)|
01645|029|D|   UGT inhibitors linked to this monograph include: atazanavir, belumosudil,|
01645|030|D|capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib,|
01645|031|D|mefenamic acid, nilotinib, pazopanib, probenecid, regorafenib, and|
01645|032|D|sorafenib.|
01645|033|B||
01645|034|R|REFERENCES:|
01645|035|B||
01645|036|R|1.Ativan (lorazepam injection) US prescribing information. Biovail|1
01645|037|R|  Laboratories International SRL April 27, 2017.|1
01645|038|R|2.Ativan (lorazepam tablets) US prescribing information. Biovail|1
01645|039|R|  Pharmaceuticals February 5, 2021.|1
01645|040|R|3.von Moltke LL, Manis M, Harmatz JS, Poorman R, Greenblatt DJ. Inhibition|5
01645|041|R|  of acetaminophen and lorazepam glucuronidation in vitro by probenecid.|5
01645|042|R|  Biopharm Drug Dispos 1993 Mar;14(2):119-30.|5
01645|043|R|4.Abernethy DR, Greenblatt DJ, Ameer B, Shader RI. Probenecid impairment of|2
01645|044|R|  acetaminophen and lorazepam clearance: direct inhibition of ether|2
01645|045|R|  glucuronide formation. J Pharmacol Exp Ther 1985 Aug;234(2):345-9.|2
01645|046|R|5.Halliday NJ, Dundee JW, Collier PS, Loughran PG, Harper KW. Influence of|2
01645|047|R|  plasma proteins on the onset of hypnotic action of intravenous midazolam.|2
01645|048|R|  Anaesthesia 1985 Aug;40(8):763-6.|2
01646|001|T|MONOGRAPH TITLE:  Lapatinib/QT Prolonging Agents|
01646|002|B||
01646|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01646|004|L|take action as needed.|
01646|005|B||
01646|006|A|MECHANISM OF ACTION:  Concurrent use of lapatinib and agents known to|
01646|007|A|prolong the QT interval may result in additive or synergistic effects on the|
01646|008|A|QTc interval.(1)|
01646|009|B||
01646|010|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01646|011|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01646|012|E|torsades de pointes.|
01646|013|B||
01646|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01646|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01646|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01646|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01646|018|P|gender, or advanced age.(3)|
01646|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01646|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01646|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01646|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01646|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01646|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01646|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01646|026|B||
01646|027|M|PATIENT MANAGEMENT:  The US manufacturer of lapatinib states that lapatinib|
01646|028|M|should be used with caution when given with other agents known to prolong|
01646|029|M|the QT interval.(1)|
01646|030|M|   If concurrent therapy is warranted, obtain serum calcium, magnesium, and|
01646|031|M|potassium levels and monitor ECG at baseline and at regular intervals.|
01646|032|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
01646|033|M|irregular heartbeat, dizziness, or fainting.|
01646|034|B||
01646|035|D|DISCUSSION:  Lapatinib is associated with concentration-dependent QTc|
01646|036|D|interval prolongation. In a single-blind, placebo-controlled crossover study|
01646|037|D|with lapatinib 2,000 mg every 12 hours for 3 doses, a maximum mean double|
01646|038|D|delta QTcF of 8.75 ms was observed.|
01646|039|D|   Agents that are linked to this monograph may have varying degrees of|
01646|040|D|potential to prolong the QTc interval. Agents linked to this monograph have|
01646|041|D|been shown to prolong the QTc interval either through their mechanism of|
01646|042|D|action, through studies on their effects on the QTc interval, or through|
01646|043|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01646|044|D|and/or postmarketing reports.(2)|
01646|045|B||
01646|046|R|REFERENCES:|
01646|047|B||
01646|048|R|1.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
01646|049|R|  2018.|1
01646|050|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01646|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01646|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01646|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01646|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01646|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01646|056|R|  settings: a scientific statement from the American Heart Association and|6
01646|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01646|058|R|  2;55(9):934-47.|6
01647|001|T|MONOGRAPH TITLE:  Ketorolac/Pentoxifylline|
01647|002|B||
01647|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01647|004|L|is contraindicated and generally should not be dispensed or administered to|
01647|005|L|the same patient.|
01647|006|B||
01647|007|A|MECHANISM OF ACTION:  Ketorolac affects platelet function.(1) Pentoxifylline|
01647|008|A|affects blood viscosity.(2)|
01647|009|B||
01647|010|E|CLINICAL EFFECTS:  Concurrent use of ketorolac and pentoxifylline may result|
01647|011|E|in an increased risk of bleeding.(1-3)|
01647|012|B||
01647|013|P|PREDISPOSING FACTORS:  Concomitant use of other medications known to|
01647|014|P|increase risk of bleeds (anticoagulants, aspirin, other NSAIDs, probenecid,|
01647|015|P|lithium).(1-3)|
01647|016|P|   The risk for bleeding episodes may be greater in patients with|
01647|017|P|disease-associated factors (e.g. thrombocytopenia).|
01647|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
01647|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01647|020|P|risk for bleeding.|
01647|021|B||
01647|022|M|PATIENT MANAGEMENT:  The US manufacturers of ketorolac(1) and|
01647|023|M|pentoxifylline(2) states that concurrent use of these agents is|
01647|024|M|contraindicated.|
01647|025|M|   The Australian manufacturer of ketorolac recommends careful monitoring if|
01647|026|M|ketorolac is administered concomitantly with other medications that affect|
01647|027|M|hemostasis such as pentoxifylline.(3)|
01647|028|M|   If concurrent therapy is deemed medically necessary, monitor patients|
01647|029|M|receiving concurrent therapy for signs of blood loss, including decreased|
01647|030|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
01647|031|M|and promptly evaluate patients with any symptoms.|
01647|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01647|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01647|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01647|035|M|and/or swelling.|
01647|036|B||
01647|037|D|DISCUSSION:  When ketorolac is administered with pentoxifylline, there is an|
01647|038|D|increased tendency to bleeding.(1)|
01647|039|B||
01647|040|R|REFERENCES:|
01647|041|B||
01647|042|R|1.Toradol (ketorolac tromethamine) US prescribing information. Roche|1
01647|043|R|  Pharmaceuticals March, 2013.|1
01647|044|R|2.Trental (pentoxifylline) US prescribing information. Aventis|1
01647|045|R|  Pharmaceuticals, Inc. January, 2016.|1
01647|046|R|3.Toradol (ketorolac trometamol) Australian prescribing information. Roche|1
01647|047|R|  February, 2012.|1
01648|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
01648|002|T|antagonists)/Sitaxsentan|
01648|003|B||
01648|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01648|005|L|take action as needed.|
01648|006|B||
01648|007|A|MECHANISM OF ACTION:  Sitaxsentan may inhibit the metabolism of some|
01648|008|A|anticoagulants by CYP2C9.(1,2)|
01648|009|B||
01648|010|E|CLINICAL EFFECTS:  Concurrent use of sitaxsentan may result in elevated|
01648|011|E|levels of and clinical effects from the anticoagulant, including increased|
01648|012|E|risk for bleeding.(1,2)|
01648|013|B||
01648|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01648|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01648|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
01648|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01648|018|P|risk for bleeding (e.g. NSAIDs).|
01648|019|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
01648|020|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
01648|021|P|are expected to be more susceptible to this interaction.|
01648|022|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
01648|023|P|are expected to be less susceptible to effects from this drug combination,|
01648|024|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
01648|025|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
01648|026|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
01648|027|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to|
01648|028|P|achieve effective and safe anticoagulation than patients without these|
01648|029|P|CYP2C9 variants.|
01648|030|B||
01648|031|M|PATIENT MANAGEMENT:  The Canadian manufacturer of sitaxsentan states that in|
01648|032|M|clinical trials, the dose of warfarin was decreased by 80% when initiating|
01648|033|M|sitaxsentan and then increased by no greater than 0.5 mg/day while titrating|
01648|034|M|to the desired INR.(1)|
01648|035|M|   The UK manufacturer of sitaxsentan recommends that if vitamin-K|
01648|036|M|antagonists are initiated in patients maintained on sitaxsentan, they should|
01648|037|M|be initiated at the lowest possible dose and carefully titrated.  If|
01648|038|M|sitaxsentan is initiated in patients maintained on vitamin-K antagonists,|
01648|039|M|the dosage of the anticoagulant should be reduced.(2)|
01648|040|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01648|041|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01648|042|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01648|043|M|patients with any symptoms.|
01648|044|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01648|045|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01648|046|M|anticoagulation in patients with active pathologic bleeding.|
01648|047|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01648|048|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01648|049|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01648|050|M|and/or swelling.|
01648|051|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01648|052|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01648|053|M|initiating, altering the dose or discontinuing either drug.|
01648|054|B||
01648|055|D|DISCUSSION:  Concurrent sitaxsentan (100 mg daily) increased the|
01648|056|D|area-under-curve (AUC) of S-warfarin following a single dose (25 mg) by 96%.|
01648|057|D|The clearance of S-warfarin decreased by 63%.  Increased effects on PT and|
01648|058|D|INR were observed.  In clinical trials, the dose of warfarin was decreased|
01648|059|D|by 80% when initiating sitaxsentan and then increased by no greater than 0.5|
01648|060|D|mg/day while titrating to the desired INR.  The mean dose of warfarin after|
01648|061|D|18 weeks of concurrent therapy in the STRIDE 2 trial was 2.2 mg/day in|
01648|062|D|patients receiving sitaxsentan compared with 3.6 mg/day for patients|
01648|063|D|receiving placebo.  The need to change the warfarin dosage as a result of|
01648|064|D|changes in INR was similar in both groups.(1)|
01648|065|D|   Concurrent sitaxsentan increased S-warfarin exposure by 2.4-fold.(2)|
01648|066|B||
01648|067|R|REFERENCES:|
01648|068|B||
01648|069|R|1.Gehshan A. Dear Canadian Healthcare Professional letter:  Subject:  Saftey|1
01648|070|R|  information regarding Thelin (sitaxsentan sodium) and the ocurrence of|1
01648|071|R|  liver toxicity, risks to the fetus, and important drug-drug interactions.|1
01648|072|R|  Encysive Pharmaceuticals July 9, 2007.|1
01648|073|R|2.Thelin (sitaxentan sodium) UK summary of product characteristics. Encysive|1
01648|074|R|  (UK) Limited August 10, 2006.|1
01649|001|T|MONOGRAPH TITLE:  Bepridil/Efavirenz (mono deleted 06/12/2014)|
01649|002|B||
01649|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01649|004|L|is contraindicated and generally should not be dispensed or administered to|
01649|005|L|the same patient.|
01649|006|B||
01649|007|A|MECHANISM OF ACTION:  Efavirenz may inhibit the metabolism of bepridil.(1,2)|
01649|008|B||
01649|009|E|CLINICAL EFFECTS:  Concurrent use of efavirenz may result in elevated levels|
01649|010|E|of and clinical effects from bepridil, including potentially|
01649|011|E|life-threatening cardiac arrhythmias.(1,2)|
01649|012|B||
01649|013|P|PREDISPOSING FACTORS:  None determined.|
01649|014|B||
01649|015|M|PATIENT MANAGEMENT:  The US manufacturer of efavirenz states that the|
01649|016|M|concurrent use of bepridil is contraindicated.(1,2)|
01649|017|B||
01649|018|D|DISCUSSION:  Because efavirenz inhibits CYP P-450-3A4, the concurrent use of|
01649|019|D|agents that are highly dependent on CYP P-450-3A4 for clearance and for|
01649|020|D|which elevated plasma concentration are associated with serious and/or|
01649|021|D|life-threatening events, such as bepridil, is contraindicated by the US|
01649|022|D|manufacturer of efavirenz.(1,2)|
01649|023|B||
01649|024|R|REFERENCES:|
01649|025|B||
01649|026|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01649|027|R|  Company August, 2012.|1
01649|028|R|2.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01649|029|R|  prescribing information. Gilead Sciences, Inc. October, 2013.|1
01650|001|T|MONOGRAPH TITLE:  Didanosine/Stavudine|
01650|002|B||
01650|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01650|004|L|is contraindicated and generally should not be dispensed or administered to|
01650|005|L|the same patient.|
01650|006|B||
01650|007|A|MECHANISM OF ACTION:  Lactic acidosis has been reported with didanosine and|
01650|008|A|stavudine alone.  Concurrent use may result in additive or synergistic|
01650|009|A|effects.(1)|
01650|010|B||
01650|011|E|CLINICAL EFFECTS:  Concurrent use of didanosine and stavudine may increase|
01650|012|E|the risk of lactic acidosis, severe hepatomegaly, and/or pancreatitis.|
01650|013|E|Fatalities have been reported.(1)  Concurrent therapy may also increase the|
01650|014|E|risk of neuropathy.(1)|
01650|015|B||
01650|016|P|PREDISPOSING FACTORS:  Female gender, obesity, and prolonged nucleoside|
01650|017|P|exposure may increase the risk of lactic acidosis.  Pregnancy may increase|
01650|018|P|the risk of fatal lactic acidosis.  Pre-existing liver disease may increase|
01650|019|P|the risk of hepatomegaly.  Concurrent therapy with didanosine, hydroxyurea,|
01650|020|P|and stavudine may further increase the risk of hepatotoxicity, pancreatitis,|
01650|021|P|(1) and neuropathy.(2,3)|
01650|022|B||
01650|023|M|PATIENT MANAGEMENT:  Coadministration of stavudine with didanosine is|
01650|024|M|contraindicated due to the potential for serious and life-threatening events|
01650|025|M|(e.g. lactic acidosis, hepatotoxicity, peripheral neuropathy,and|
01650|026|M|pancreatitis.(1)|
01650|027|M|   Suspend treatment if clinical or laboratory findings suggestive of lactic|
01650|028|M|acidosis, pronounced hepatotoxicity, peripheral neuropathy, or pancreatitis|
01650|029|M|occur. Signs of lactic acidosis may include generalized fatigue, digestive|
01650|030|M|symptoms (nausea, vomiting, abdominal pain, unexplained weight loss),|
01650|031|M|respiratory symptoms (tachypnea, dyspnea), and/or neurologic symptoms (motor|
01650|032|M|weakness).(1)|
01650|033|M|   Permanent discontinuation of stavudine should be considered for patients|
01650|034|M|with confirmed lactic acidosis.(1)|
01650|035|B||
01650|036|D|DISCUSSION:  In a retrospective review, 12 cases of lactic acidosis in|
01650|037|D|HIV-positive patients during a 5 year period were identified.  Nine of the|
01650|038|D|12 patients were receiving concurrent therapy with didanosine and stavudine.|
01650|039|D|Four of the nine were also receiving hydroxyurea.  Three of the nine died,|
01650|040|D|none of whom were taking hydroxyurea.(4)|
01650|041|D|   In a randomized trial comparing concurrent didanosine and stavudine with|
01650|042|D|and without hydroxyurea, 35% of patients receiving triple therapy developed|
01650|043|D|neuropathy, compared with only 15% of patients receiving didanosine and|
01650|044|D|stavudine without hydroxyurea.  One case of pancreatitis was reported in a|
01650|045|D|patient receiving didanosine and stavudine without hydroxyurea.(2)|
01650|046|D|   In a retrospective review, neuropathy was reported in 27% (6 of 27) of|
01650|047|D|patients receiving concurrent didanosine, stavudine, and hydroxyurea|
01650|048|D|compared to 10% (6 of 61) of patients receiving didanosine and stavudine|
01650|049|D|without hydroxyurea.(3)|
01650|050|D|   A retrospective review of HIV-positive patients found that the relative|
01650|051|D|risk of neuropathy for combination therapy relative to didanosine alone was|
01650|052|D|1.39 for stavudine alone, 2.35 for didanosine with hydroxyurea, 3.50 for|
01650|053|D|didanosine and stavudine, and 7.80 for didanosine, stavudine, and|
01650|054|D|hydroxyurea.(5)|
01650|055|D|   In a retrospective review of 616 patients receiving concurrent didanosine|
01650|056|D|and stavudine, adverse events were documented in 22.1% (136) patients. There|
01650|057|D|were 118 mild or moderate adverse effects and 18 severe adverse effects.|
01650|058|D|Mean time to the adverse effect was 52 weeks for mild to moderate effects|
01650|059|D|and 72 weeks for severe effects.  Peripheral neuropathy was reported in 4.7%|
01650|060|D|(29) of patients.  Pancreatitis was reported in 1.1% (7) of patients.(6)|
01650|061|D|   In a randomized, prospective study evaluating the safety and efficacy of|
01650|062|D|didanosine and stavudine in 86 HIV-positive subjects, 2 patients developed|
01650|063|D|peripheral neuropathy and two patients developed pancreatitis.  Ten percent|
01650|064|D|of subjects had one or more grades 3-4 abnormalities in liver function tests|
01650|065|D|and 7% had grades 3-4 elevations in lipase.(7)|
01650|066|B||
01650|067|R|REFERENCES:|
01650|068|B||
01650|069|R|1.Zerit (stavudine) US prescribing information. Bristol-Myers Squibb Company|1
01650|070|R|  December 19, 2017.|1
01650|071|R|2.Rutschmann OT, Vernazza PL, Bucher HC, Opravil M, Ledergerber B, Telenti|2
01650|072|R|  A, Malinverni R, Bernasconi E, Fagard C, Leduc D, Perrin L, Hirschel B.|2
01650|073|R|  Long-term hydroxyurea in combination with didanosine and stavudine for the|2
01650|074|R|  treatment of HIV-1 infection. Swiss HIV Cohort Study. AIDS 2000 Sep 29;|2
01650|075|R|  14(14):2145-51.|2
01650|076|R|3.Cepeda JA, Wilks D. Excess peripheral neuropathy in patients treated with|2
01650|077|R|  hydroxyurea plus didanosine and stavudine for HIV infection. AIDS 2000 Feb|2
01650|078|R|  18;14(3):332-3.|2
01650|079|R|4.Coghlan ME, Sommadossi JP, Jhala NC, Many WJ, Saag MS, Johnson VA.|3
01650|080|R|  Symptomatic lactic acidosis in hospitalized antiretroviral-treated|3
01650|081|R|  patients with human immunodeficiency virus infection: a report of 12|3
01650|082|R|  cases. Clin Infect Dis 2001 Dec 1;33(11):1914-21.|3
01650|083|R|5.Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in|2
01650|084|R|  HIV-infected patients on monotherapy versus those on combination therapy|2
01650|085|R|  with didanosine, stavudine and hydroxyurea. AIDS 2000 Feb 18;14(3):273-8.|2
01650|086|R|6.Hernandez B, Moreno S, Perez-Elias MJ, Casado JL, Dronda F, Moreno A,|2
01650|087|R|  Antela A. Severity of the toxicity associated with combinations that|2
01650|088|R|  include didanosine plus stavudine in HIV-infected experienced patients. J|2
01650|089|R|  Acquir Immune Defic Syndr 2006 Dec 15;43(5):556-9.|2
01650|090|R|7.Pollard RB, Peterson D, Hardy D, Pottage J, Murphy RL, Gathe J, Beall G,|2
01650|091|R|  Rutkievicz V, Reynolds L, Cross AP, Dunkle LM. Safety and antiretroviral|2
01650|092|R|  effects of combined didanosine and stavudine therapy in HIV-infected|2
01650|093|R|  individuals with CD4 counts of 200 to 500 cells/mm3. J Acquir Immune Defic|2
01650|094|R|  Syndr 1999 Sep 1;22(1):39-48.|2
01651|001|T|MONOGRAPH TITLE:  Pentosan/Heparins|
01651|002|B||
01651|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01651|004|L|take action as needed.|
01651|005|B||
01651|006|A|MECHANISM OF ACTION:  Pentosan is a weak anticoagulant with 1/15 the|
01651|007|A|activity of heparin.  Concurrent use with heparin may result in additive|
01651|008|A|effects.(1)|
01651|009|B||
01651|010|E|CLINICAL EFFECTS:  Concurrent use of pentosan and heparin may increase the|
01651|011|E|risk of hemorrhage.(1)|
01651|012|B||
01651|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01651|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01651|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01651|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01651|017|P|risk for bleeding (e.g. NSAIDs).|
01651|018|B||
01651|019|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with pentosan and|
01651|020|M|heparin should be evaluated for hemorrhage.(1)|
01651|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01651|022|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01651|023|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01651|024|M|patients with any symptoms.|
01651|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01651|026|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01651|027|M|anticoagulation in patients with active pathologic bleeding.|
01651|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01651|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01651|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01651|031|M|and/or swelling.|
01651|032|B||
01651|033|D|DISCUSSION:  Pentosan is a weak anticoagulant with 1/15 the activity of|
01651|034|D|heparin.(1)|
01651|035|D|   In a study in 41 patients with interstitial cystitis, the concurrent use|
01651|036|D|of pentosan and heparin (5000 units 3 times daily for 2 days, 5000 units 2|
01651|037|D|times daily for 12 days, then 5000 units daily as maintenance) resulted in|
01651|038|D|increased response rates at 3 and 9 months, compared with 17 controls|
01651|039|D|receiving pentosan alone.(2)|
01651|040|B||
01651|041|R|REFERENCES:|
01651|042|B||
01651|043|R|1.Elmiron (pentosan polysulfate sodium) US prescribing information.|1
01651|044|R|  Ortho-McNeil Pharmaceutical, Inc. March, 2021.|1
01651|045|R|2.van Ophoven A, Heinecke A, Hertle L. Safety and efficacy of concurrent|2
01651|046|R|  application of oral pentosan polysulfate and subcutaneous low-dose heparin|2
01651|047|R|  for patients with interstitial cystitis. Urology 2005 Oct;66(4):707-11.|2
01652|001|T|MONOGRAPH TITLE:  Darifenacin/Clarithromycin (mono deleted 01/12/2012)|
01652|002|B||
01652|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01652|004|L|take action as needed.|
01652|005|B||
01652|006|A|MECHANISM OF ACTION:  Clarithromycin may inhibit the metabolism of|
01652|007|A|darifenacin by CYP P-450-3A4.(1)|
01652|008|B||
01652|009|E|CLINICAL EFFECTS:  The concurrent administration of clarithromycin may|
01652|010|E|result in elevated levels of and toxicity from darifenacin.(1)|
01652|011|B||
01652|012|P|PREDISPOSING FACTORS:  None determined.|
01652|013|B||
01652|014|M|PATIENT MANAGEMENT:  The US manufacturer of darifenacin recommends a maximum|
01652|015|M|darifenacin dosage of 7.5 mg daily in patients receiving concurrent|
01652|016|M|concurrent therapy with potent CYP P-450-3A4 inhibitors such as|
01652|017|M|clarithromycin.(1)|
01652|018|B||
01652|019|D|DISCUSSION:  In a study in 10 extensive CYP P-450-2D6 metabolizers and 1|
01652|020|D|poor CYP P-450-2D6 metabolizer, concurrent administration of ketoconazole|
01652|021|D|(400 mg), another potent inhibitor of CYP P-450-3A4, increased the|
01652|022|D|area-under-curve (AUC) and maximum concentration (Cmax) of darifenacin (7.5|
01652|023|D|mg daily) by 3.9-fold and 4.6-fold, respectively, in extensive metabolizers|
01652|024|D|and by 12.9-fold and 12-fold, respectively, in the poor metabolizer,|
01652|025|D|compared to historical controls.  The concurrent administration of|
01652|026|D|ketoconazole (400 mg) and darifenacin (15 mg daily) increased darifenacin|
01652|027|D|AUC and Cmax by 11.5-fold and 10.73-fold, respectively, in extensive|
01652|028|D|metabolizers and by 4.9-fold and 4.9-fold, respectively, in the poor|
01652|029|D|metabolizer, compared to historical controls.(1)|
01652|030|D|   Concurrent administration of darifenacin (30 mg daily) and erythromycin,|
01652|031|D|a moderate CYP P-450-3A4 inhibitor, increased darifenacin AUC and Cmax by|
01652|032|D|95% and 128%, respectively.  No dosage adjustment is recommended during|
01652|033|D|concurrent erythromycin therapy.(1)|
01652|034|B||
01652|035|R|REFERENCE:|
01652|036|B||
01652|037|R|1.Enablex (darifenacin) US prescribing information. Novartis Pharmaceuticals|1
01652|038|R|  Corporation October, 2010.|1
01653|001|T|MONOGRAPH TITLE:  Darifenacin/Nefazodone (mono deleted 01/12/2012)|
01653|002|B||
01653|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01653|004|L|take action as needed.|
01653|005|B||
01653|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of darifenacin|
01653|007|A|by CYP P-450-3A4.(1)|
01653|008|B||
01653|009|E|CLINICAL EFFECTS:  The concurrent administration of nefazodone may result in|
01653|010|E|elevated levels of and toxicity from darifenacin.(1)|
01653|011|B||
01653|012|P|PREDISPOSING FACTORS:  None determined.|
01653|013|B||
01653|014|M|PATIENT MANAGEMENT:  The US manufacturer of darifenacin recommends a maximum|
01653|015|M|darifenacin dosage of 7.5 mg daily in patients receiving concurrent|
01653|016|M|concurrent therapy with potent CYP P-450-3A4 inhibitors such as|
01653|017|M|nefazodone.(1)|
01653|018|B||
01653|019|D|DISCUSSION:  In a study in 10 extensive CYP P-450-2D6 metabolizers and 1|
01653|020|D|poor CYP P-450-2D6 metabolizer, concurrent administration of ketoconazole|
01653|021|D|(400 mg), another potent inhibitor of CYP P-450-3A4, increased the|
01653|022|D|area-under-curve (AUC) and maximum concentration (Cmax) of darifenacin (7.5|
01653|023|D|mg daily) by 3.9-fold and 4.6-fold, respectively, in extensive metabolizers|
01653|024|D|and by 12.9-fold and 12-fold, respectively, in the poor metabolizer,|
01653|025|D|compared to historical controls.  The concurrent administration of|
01653|026|D|ketoconazole (400 mg) and darifenacin (15 mg daily) increased darifenacin|
01653|027|D|AUC and Cmax by 11.5-fold and 10.73-fold, respectively, in extensive|
01653|028|D|metabolizers and by 4.9-fold and 4.9-fold, respectively, in the poor|
01653|029|D|metabolizer, compared to historical controls.(1)|
01653|030|B||
01653|031|R|REFERENCE:|
01653|032|B||
01653|033|R|1.Enablex (darifenacin) US prescribing information. Novartis Pharmaceuticals|1
01653|034|R|  Corporation October, 2010.|1
01654|001|T|MONOGRAPH TITLE:  Darifenacin/Nelfinavir; Ritonavir (mono deleted|
01654|002|T|01/12/2012)|
01654|003|B||
01654|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01654|005|L|take action as needed.|
01654|006|B||
01654|007|A|MECHANISM OF ACTION:  Nelfinavir and ritonavir may inhibit the metabolism of|
01654|008|A|darifenacin by CYP P-450-3A4.(1)|
01654|009|B||
01654|010|E|CLINICAL EFFECTS:  The concurrent administration of nelfinavir or ritonavir|
01654|011|E|may result in elevated levels of and toxicity from darifenacin.(1)|
01654|012|B||
01654|013|P|PREDISPOSING FACTORS:  None determined.|
01654|014|B||
01654|015|M|PATIENT MANAGEMENT:  The US manufacturer of darifenacin recommends a maximum|
01654|016|M|darifenacin dosage of 7.5 mg daily in patients receiving concurrent|
01654|017|M|concurrent therapy with potent CYP P-450-3A4 inhibitors such as nelfinavir|
01654|018|M|or ritonavir.(1)|
01654|019|B||
01654|020|D|DISCUSSION:  In a study in 10 extensive CYP P-450-2D6 metabolizers and 1|
01654|021|D|poor CYP P-450-2D6 metabolizer, concurrent administration of ketoconazole|
01654|022|D|(400 mg), another potent inhibitor of CYP P-450-3A4, increased the|
01654|023|D|area-under-curve (AUC) and maximum concentration (Cmax) of darifenacin (7.5|
01654|024|D|mg daily) by 3.9-fold and 4.6-fold, respectively, in extensive metabolizers|
01654|025|D|and by 12.9-fold and 12-fold, respectively, in the poor metabolizer,|
01654|026|D|compared to historical controls.  The concurrent administration of|
01654|027|D|ketoconazole (400 mg) and darifenacin (15 mg daily) increased darifenacin|
01654|028|D|AUC and Cmax by 11.5-fold and 10.73-fold, respectively, in extensive|
01654|029|D|metabolizers and by 4.9-fold and 4.9-fold, respectively, in the poor|
01654|030|D|metabolizer, compared to historical controls.(1)|
01654|031|B||
01654|032|R|REFERENCE:|
01654|033|B||
01654|034|R|1.Enablex (darifenacin) US prescribing information. Novartis Pharmaceuticals|1
01654|035|R|  Corporation October, 2010.|1
01655|001|T|MONOGRAPH TITLE:  Tizanidine/Selected Fluoroquinolones|
01655|002|B||
01655|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01655|004|L|of severe adverse interaction.|
01655|005|B||
01655|006|A|MECHANISM OF ACTION:  Some fluoroquinolones may inhibit the metabolism of|
01655|007|A|tizanidine by CYP1A2.(1)|
01655|008|B||
01655|009|E|CLINICAL EFFECTS:  Concurrent use of fluoroquinolones may result in elevated|
01655|010|E|levels of and effects from tizanidine, including hypotension, bradycardia,|
01655|011|E|drowsiness, sedation, and decreased psychomotor function.|
01655|012|B||
01655|013|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
01655|014|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
01655|015|P|patients using more than one medicine with anticholinergic properties.(2)|
01655|016|B||
01655|017|M|PATIENT MANAGEMENT:  The US manufacturer of tizanidine states that|
01655|018|M|concurrent use of tizanidine with potent inhibitors of CYP1A2, such as|
01655|019|M|ciprofloxacin, is contraindicated.|
01655|020|M|   If concurrent use of less potent inhibitors of CYP1A2 is warranted,|
01655|021|M|tizanidine therapy should be initiated with 2 mg dose and increased in 2-4|
01655|022|M|mg steps daily based on patient response to therapy.|
01655|023|M|   If adverse reactions such as hypotension, bradycardia, or excessive|
01655|024|M|drowsiness occur, reduce or discontinue tizanidine therapy.(1)|
01655|025|B||
01655|026|D|DISCUSSION:  In a study in 10 healthy subjects, concurrent fluvoxamine,|
01655|027|D|another inhibitor of CYP1A2, increased tizanidine maximum concentration|
01655|028|D|(Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold,|
01655|029|D|and 3-fold, respectively.  Significant decreases in blood pressure and|
01655|030|D|increases in drowsiness and psychomotor impairment occurred.(1)|
01655|031|D|   In a study in 10 healthy subjects, concurrent ciprofloxacin, another|
01655|032|D|inhibitor of CYP1A2, increase tizanidine Cmax and AUC by 7-fold and 10-fold,|
01655|033|D|respectively.  Significant decreases in blood pressure and and increases in|
01655|034|D|drowsiness and psychomotor impairment occurred.(1)|
01655|035|D|   Quinolones that inhibit CYP1A2 include antofloxacin, cinoxacin,|
01655|036|D|clinafloxacin, nadifloxacin, nitroxoline, pefloxacin, pipemidic acid, and|
01655|037|D|tosufloxacin.|
01655|038|B||
01655|039|R|REFERENCES:|
01655|040|B||
01655|041|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
01655|042|R|  Pharma Inc. November 22, 2024.|1
01655|043|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01655|044|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01655|045|R|  Soc 2023 Jul;71(7):2052-2081.|6
01656|001|T|MONOGRAPH TITLE:  Itraconazole; Ketoconazole; Posaconazole/Efavirenz|
01656|002|B||
01656|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01656|004|L|of severe adverse interaction.|
01656|005|B||
01656|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of|
01656|007|A|itraconazole,(1-4) ketoconazole,(1-5) and posaconazole (1,6) via CYP3A4.|
01656|008|B||
01656|009|E|CLINICAL EFFECTS:  Concurrent use of efavirenz may result in decreased|
01656|010|E|levels and effectiveness of itraconazole,(1-4) ketoconazole,(1-5) and|
01656|011|E|posaconazole.(1)|
01656|012|B||
01656|013|P|PREDISPOSING FACTORS:  None determined.|
01656|014|B||
01656|015|M|PATIENT MANAGEMENT:  Consider alternatives to itraconazole,(1-4)|
01656|016|M|ketoconazole,(1-5) and posaconazole,(1,6) such as fluconazole, in patients|
01656|017|M|receiving efavirenz unless the benefits of therapy outweigh the risks.  If|
01656|018|M|concurrent therapy is necessary, monitor patients closely for decreased|
01656|019|M|therapeutic effects.|
01656|020|M|   The US manufacturer of itraconazole states that concurrent use with|
01656|021|M|efavirenz is not recommended two weeks before and during itraconazole|
01656|022|M|treatment.|
01656|023|B||
01656|024|D|DISCUSSION:  In a study in 18 subjects, concurrent efavirenz (600 mg daily)|
01656|025|D|decreased the maximum concentration (Cmax), area-under-curve (AUC), and|
01656|026|D|minimum concentration (Cmin) of itraconazole (200 mg twice daily) by 37%,|
01656|027|D|39%, and 44%, respectively.  The Cmax, AUC, and Cmin of hydroxyitraconazole|
01656|028|D|decreased by 35%, 37%, and 43%, respectively.(1-3)  There were no effects on|
01656|029|D|efavirenz levels.(3,4)|
01656|030|D|   In a study in 12 HIV-positive subjects, efavirenz (600 mg daily)|
01656|031|D|decreased the Cmax, AUC, and half-life (T1/2) of a single dose of|
01656|032|D|ketoconazole (400 mg) by 44%, 72%, and 58%, respectively.(5)|
01656|033|D|   In a study in 11 subjects, efavirenz (400 mg daily) decreased the Cmax|
01656|034|D|and AUC of posaconazole (400 mg twice daily) by 45% and 50%,|
01656|035|D|respectively.(5,6)|
01656|036|D|   In a study in 10 subjects, efavirenz (400 mg daily) had no effect on the|
01656|037|D|pharmacokinetics of fluconazole (200 mg daily).(1-3)  The AUC and Cmin of|
01656|038|D|fluconazole increased by 16% and 22%, respectively.(1)|
01656|039|B||
01656|040|R|REFERENCES:|
01656|041|B||
01656|042|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01656|043|R|  Company November, 2023.|1
01656|044|R|2.Sustiva (efavirenz) Canadian prescribing information. Bristol-Myers Squibb|1
01656|045|R|  January 8, 2007.|1
01656|046|R|3.Sustiva (efavirenz) UK summary of product characteristics. Bristol-Myers|1
01656|047|R|  Squibb Pharmaceuticals Ltd January 26, 2007.|1
01656|048|R|4.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01656|049|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01656|050|R|5.Sriwiriyajan S, Mahatthanatrakul W, Ridtitid W, Jaruratanasirikul S.|2
01656|051|R|  Effect of efavirenz on the pharmacokinetics of ketoconazole in|2
01656|052|R|  HIV-infected patients. Eur J Clin Pharmacol 2007 May;63(5):479-83.|2
01656|053|R|6.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01656|054|R|  January, 2022.|1
01656|055|R|7.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01656|056|R|  Products, L.P. February, 2024.|1
01657|001|T|MONOGRAPH TITLE:  Influenza Virus Vaccine Live/Selected Antiviral Agents|
01657|002|B||
01657|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01657|004|L|is contraindicated and generally should not be dispensed or administered to|
01657|005|L|the same patient.|
01657|006|B||
01657|007|A|MECHANISM OF ACTION:  Amantadine,(1) oseltamivir,(2) rimantadine,(3)|
01657|008|A|zanamivir,(4) and baloxavir,(5) may inactivate the intranasal live influenza|
01657|009|A|virus vaccine, preventing the body from developing an immune response.|
01657|010|B||
01657|011|E|CLINICAL EFFECTS:  Administration of amantadine,(1) oseltamivir,(2)|
01657|012|E|rimantadine,(3) zanamivir,(4) and baloxavir,(5) may render the intranasal|
01657|013|E|live influenza virus vaccine ineffective.|
01657|014|B||
01657|015|P|PREDISPOSING FACTORS:  None determined.|
01657|016|B||
01657|017|M|PATIENT MANAGEMENT:  The US manufacturers of amantadine,(1) oseltamivir,(2)|
01657|018|M|rimantadine,(3) zanamivir(4), baloxavir(5), and the intranasal live|
01657|019|M|influenza virus vaccine(6) state that these agents should not be initiated|
01657|020|M|within 2 weeks of the administration of the intranasal live influenza virus|
01657|021|M|vaccine and that the vaccine should not be administered within 48 hours of|
01657|022|M|the discontinuation of these agents.|
01657|023|M|   Inactivated influenza vaccine may be used at any time.(1)|
01657|024|B||
01657|025|D|DISCUSSION:  Because antiviral drugs such as amantadine,(1) oseltamivir,(2)|
01657|026|D|rimantadine,(3) zanamivir,(4) and baloxavir (5) inhibit the replication of|
01657|027|D|live viruses, these agents may interfere with the efficacy of the intranasal|
01657|028|D|live influenza virus vaccine.|
01657|029|B||
01657|030|R|REFERENCES:|
01657|031|B||
01657|032|R|1.Symmetrel (amantadine hydrochloride) US prescribing information. Endo|1
01657|033|R|  Pharmaceuticals Inc. January, 2009.|1
01657|034|R|2.Tamiflu (oseltamivir phosphate) US prescribing information. Roche|1
01657|035|R|  Laboratories, Inc. March, 2018.|1
01657|036|R|3.Flumadine (rimantadine hydrochloride) US prescribing information. Forest|1
01657|037|R|  Pharmaceuticals, Inc. April, 2010.|1
01657|038|R|4.Relenza (zanamivir) US prescribing information. GlaxoSmithKline October,|1
01657|039|R|  2021.|1
01657|040|R|5.Xofluza (baloxavir) US prescribing information. Genentech USA, Inc.|1
01657|041|R|  November, 2020.|1
01657|042|R|6.FluMist (influenza virus vaccine live, intranasal) US prescribing|1
01657|043|R|  information. MedImmune LLC July, 2010.|1
01658|001|T|MONOGRAPH TITLE:  Sunitinib/Class IA & III Antiarrhythmics|
01658|002|B||
01658|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01658|004|L|take action as needed.|
01658|005|B||
01658|006|A|MECHANISM OF ACTION:  Concurrent use of sunitinib and Class IA or III|
01658|007|A|antiarrhythmics may result in additive effects on the QTc interval.(1)|
01658|008|B||
01658|009|E|CLINICAL EFFECTS:  Concurrent use of sunitinib and Class IA or III|
01658|010|E|antiarrhythmics may result in QTc prolongation and life-threatening cardiac|
01658|011|E|arrhythmias, including torsades de pointes.(1)|
01658|012|B||
01658|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01658|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
01658|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01658|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01658|017|P|female gender, advanced age, use of multiple medications, and/or in patients|
01658|018|P|who are taking strong CYP P-450-3A4 inhibitors.(2)|
01658|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01658|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01658|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01658|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01658|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01658|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01658|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01658|026|B||
01658|027|M|PATIENT MANAGEMENT:  Use sunitinib with caution in patients maintained on|
01658|028|M|Class IA or III antiarrhythmics.(1)|
01658|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01658|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01658|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01658|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01658|033|B||
01658|034|D|DISCUSSION:  Sunitinib has been shown to prolong the QT interval in a dose|
01658|035|D|dependent manner.  Torsade de Pointes has been observed in less than 0.1% of|
01658|036|D|patients receiving sunitinib.(1)|
01658|037|D|   A retrospective review of 618 cancer patients treated with 902|
01658|038|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
01658|039|D|incidence of QTc prolongation.  In patients who received sunitinib, QTc|
01658|040|D|prolongation was identified in 26 (19.4%) with 16 (61.5%) having Grade 1|
01658|041|D|(QTc 450-480 ms) and 6 (23.1%) having Grade 2 (QTc 480-500 ms).  Grade 3|
01658|042|D|events occurred in 1 (3.8%) having QTc greater than or equal to 500 ms and 1|
01658|043|D|(3.8%) having QTc change greater than or equal to 60 ms.  Ventricular|
01658|044|D|tachycardia was seen in 1 (3.8%) of patients and 1 (3.8%) patient|
01658|045|D|experienced sudden cardiac death.(3)|
01658|046|B||
01658|047|R|REFERENCES:|
01658|048|B||
01658|049|R|1.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
01658|050|R|  2021.|1
01658|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01658|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01658|053|R|  settings: a scientific statement from the American Heart Association and|6
01658|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01658|055|R|  2;55(9):934-47.|6
01658|056|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
01658|057|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
01658|058|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
01659|001|T|MONOGRAPH TITLE:  Macitentan/Strong CYP3A4 Inducers|
01659|002|B||
01659|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01659|004|L|of severe adverse interaction.|
01659|005|B||
01659|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
01659|007|A|macitentan.(1)|
01659|008|A|   CYP3A4 is the primary metabolism pathway of macitentan to its less active|
01659|009|A|metabolite.(1,2)|
01659|010|B||
01659|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease|
01659|012|E|systemic levels and effectiveness of macitentan.(1,2)|
01659|013|B||
01659|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01659|015|P|of the inducer for longer than 1-2 weeks.|
01659|016|B||
01659|017|M|PATIENT MANAGEMENT:  The manufacturer of macitentan recommends avoiding|
01659|018|M|concurrent use of macitentan and strong CYP3A4 inducers.(2)  If concurrent|
01659|019|M|therapy is warranted, monitor closely for loss of efficacy and adjust|
01659|020|M|macitentan dose or dosing interval if needed.  Note the onset of induction|
01659|021|M|is gradual;  maximal induction may not occur for 2 or more weeks.|
01659|022|M|   When concurrent treatment with rifampin is stopped, induction will|
01659|023|M|gradually wane and systemic concentrations of macitentan will gradually|
01659|024|M|increase over 2 or more weeks.  Monitor for toxicity and adjust dose as|
01659|025|M|required.|
01659|026|B||
01659|027|D|DISCUSSION:  An interaction study in 10 healthy male subjects evaluated the|
01659|028|D|effect of rifampin on macitentan and active metabolite pharmacokinetics.|
01659|029|D|Although less potent, the active metabolite was evaluated as its longer|
01659|030|D|half-life leads to a 3-fold higher systemic exposure than macitentan.  About|
01659|031|D|40% of macitentan pharmacologic activity is thought due to this|
01659|032|D|metabolite.(2)  Subjects received a 30 mg macitentan loading dose followed|
01659|033|D|by 10 mg daily for four more days.  Beginning on day 6, rifampin 600 mg and|
01659|034|D|macitentan 10 mg were co-administered daily for 7 days.  Macitentan|
01659|035|D|area-under-curve (AUC) and concentration minimum (Cmin) were measured on|
01659|036|D|days 5 and 12.  Co-administration decreased macitentan AUC 79% and trough|
01659|037|D|concentration 93%.  The AUC and Cmin of the macitentan active metabolite was|
01659|038|D|unchanged and decreased 17% respectively.(1)|
01659|039|D|   Strong CYP3A4 inducers linked to this monograph include:  apalutamide,|
01659|040|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
01659|041|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
01659|042|D|rifampin, rifapentine, and St. John's Wort.(3)|
01659|043|B||
01659|044|R|REFERENCES:|
01659|045|B||
01659|046|R|1.Opsumit (macitentan) US prescribing information. Actelion Pharmaceuticals|1
01659|047|R|  US, Inc. October, 2021.|1
01659|048|R|2.Bruderer S, Aanismaa P, Homery MC, Hausler S, Landskroner K, Sidharta PN,|2
01659|049|R|  Treiber A, Dingemanse J. Effect of cyclosporine and rifampin on the|2
01659|050|R|  pharmacokinetics of macitentan, a tissue-targeting dual endothelin|2
01659|051|R|  receptor antagonist. AAPS J 2012 Mar;14(1):68-78.|2
01659|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
01659|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01660|001|T|MONOGRAPH TITLE:  Oral Bisphosphonates/Oral Multivalent Cations|
01660|002|B||
01660|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01660|004|L|take action as needed.|
01660|005|B||
01660|006|A|MECHANISM OF ACTION:  Multivalent cations may bind to and inhibit the|
01660|007|A|absorption of oral bisphosphonates.(1-6)|
01660|008|B||
01660|009|E|CLINICAL EFFECTS:  Simultaneous administration of products containing|
01660|010|E|multivalent cations may result in decreased levels of and clinical effects|
01660|011|E|from oral bisphosphonates.(1-6)|
01660|012|B||
01660|013|P|PREDISPOSING FACTORS:  None determined.|
01660|014|B||
01660|015|M|PATIENT MANAGEMENT:  Instruct patients to separate the administration times|
01660|016|M|of products containing multivalent cations and oral bisphosphonates.|
01660|017|M|   Manufacturer recommendations regarding the separation of administration|
01660|018|M|times of oral bisphosphonates and multivalent cations vary.|
01660|019|M|   Do NOT give multivalent cation-containing products:|
01660|020|M|    - until at least 30 minutes after taking alendronate(1)|
01660|021|M|    - within 2 hours of etidronate(2)|
01660|022|M|    - until at least 1 hour after taking ibandronate(3)|
01660|023|M|    - until at least 30 minutes after taking risedronate(4)|
01660|024|M|    - within 2 hours of tiludronate(5)|
01660|025|B||
01660|026|D|DISCUSSION:  Multivalent cations may bind to and inhibit the absorption of|
01660|027|D|oral bisphosphonates, resulting in decreased levels of and clinical effects|
01660|028|D|from these agents.(1-6)|
01660|029|D|   Administration of aluminum- or magnesium-containing antacids 1 hour|
01660|030|D|before tiludronate decreased the bioavailability of tiludronate by 60%.(5)|
01660|031|B||
01660|032|R|REFERENCES:|
01660|033|B||
01660|034|R|1.Fosamax (alendronate sodium) US prescribing information. Merck & Co., Inc.|1
01660|035|R|  August, 2019.|1
01660|036|R|2.Didronel (etidronate disodium) US prescribing information. Warner Chilcott|1
01660|037|R|  (US), LLC April, 2015.|1
01660|038|R|3.Boniva (ibandronate sodium) tablets US prescribing information. Roche|1
01660|039|R|  Therapeutics, Inc. January, 2022.|1
01660|040|R|4.Actonel (risedronate sodium) US prescribing information. Warner Chilcott|1
01660|041|R|  (US), LLC April, 2015.|1
01660|042|R|5.Skelid (tiludronate disodium) US prescribing information. Sanofi-Aventis|1
01660|043|R|  U.S. LLC March, 2010.|1
01660|044|R|6.Loron (disodium clodronate) UK summary of product characteristics. Roche|1
01660|045|R|  Products Limited October 25, 2006.|1
01661|001|T|MONOGRAPH TITLE:  Tiludronate Disodium/Aspirin (Greater Than 100 mg);|
01661|002|T|Indomethacin|
01661|003|B||
01661|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01661|005|L|take action as needed.|
01661|006|B||
01661|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01661|008|B||
01661|009|E|CLINICAL EFFECTS:  Simultaneous administration of aspirin may decrease|
01661|010|E|levels and effectiveness of tiludronate.  Simultaneous administration of|
01661|011|E|indomethacin may increase levels of and side effects from tiludronate.(1)|
01661|012|B||
01661|013|P|PREDISPOSING FACTORS:  None determined.|
01661|014|B||
01661|015|M|PATIENT MANAGEMENT:  The US manufacturer of tiludronate disodium states that|
01661|016|M|aspirin or indomethacin should not be administered within 2 hours of|
01661|017|M|tiludronate disodium.(1)|
01661|018|B||
01661|019|D|DISCUSSION:  Aspirin may decrease tiludronate disodium bioavailability by|
01661|020|D|50% when taken 2 hours after tiludronate disodium.(1)|
01661|021|D|   Indomethacin may increase the bioavailability of tiludronate disodium by|
01661|022|D|2-fold to 4-fold.  Tiludronate disodium bioavailability is not affected by|
01661|023|D|diclofenac.(1)|
01661|024|B||
01661|025|R|REFERENCE:|
01661|026|B||
01661|027|R|1.Skelid (tiludronate disodium) US prescribing information. Sanofi-Aventis|1
01661|028|R|  U.S. LLC March, 2010.|1
01662|001|T|MONOGRAPH TITLE:  Guanethidine/MAOIs|
01662|002|B||
01662|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01662|004|L|is contraindicated and generally should not be dispensed or administered to|
01662|005|L|the same patient.|
01662|006|B||
01662|007|A|MECHANISM OF ACTION:  In patients treated with MAOIs, guanethidine may|
01662|008|A|result in the release of a large quantity of catecholamines.(1,2)|
01662|009|B||
01662|010|E|CLINICAL EFFECTS:  Use of guanethidine in patients treated with a MAOI may|
01662|011|E|result in hypertensive crisis.(1,2)|
01662|012|B||
01662|013|P|PREDISPOSING FACTORS:  None determined.|
01662|014|B||
01662|015|M|PATIENT MANAGEMENT:  At least 2 weeks should elapse between the|
01662|016|M|discontinuation of an MAOI and the use of guanethidine.(1,2)|
01662|017|B||
01662|018|D|DISCUSSION:  In patients treated with MAOIs, guanethidine may result in the|
01662|019|D|release of a large quantity of catecholamines, which may result in|
01662|020|D|hypertensive crisis.(1,2)|
01662|021|D|   Methylene blue, when administered intravenously, has been shown to reach|
01662|022|D|sufficient concentrations to be a potent inhibitor of MAO-A.(3,4)|
01662|023|D|   Metaxalone is a weak inhibitor of MAO.(5,6)|
01662|024|B||
01662|025|R|REFERENCES:|
01662|026|B||
01662|027|R|1.Ismelin (guanethidine monosulfate) UK summary of product characteristics.|1
01662|028|R|  Amdipharm September 30, 2005.|1
01662|029|R|2.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
01662|030|R|  2007.|1
01662|031|R|3.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
01662|032|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
01662|033|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
01662|034|R|4.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
01662|035|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
01662|036|R|  2000 Jun;56(3):247-50.|2
01662|037|R|5.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
01662|038|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
01662|039|R|  Feb;34(2):346.e5-6.|3
01662|040|R|6.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
01662|041|R|  Pfizer Inc. January, 2024.|1
01663|001|T|MONOGRAPH TITLE:  Selected Anticonvulsants; Barbiturates/Slt Azole|
01663|002|T|Antifungals|
01663|003|B||
01663|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01663|005|L|of severe adverse interaction.|
01663|006|B||
01663|007|A|MECHANISM OF ACTION:  Barbiturates, carbamazepine, phenobarbital and|
01663|008|A|phenytoin induce and are metabolized by various CYP P-450 enzymes.  Azole|
01663|009|A|antifungals inhibit and are also metabolized by various CYP P-450 enzymes.|
01663|010|A|   Details for specific agents(1,2):|
01663|011|A|   - Carbamazepine is metabolized by CYP3A4 and is an inducer of CYP3A4,|
01663|012|A|CYP2C9, and CYP2C19.|
01663|013|A|   - Phenobarbital and phenytoin are both metabolized by CYP2C9 and CYP2C19,|
01663|014|A|and are inducers of CYP3A4, CYP2C9, and 2C19.|
01663|015|A|   - Barbiturates are inducers of CYP3A4.|
01663|016|A|   - Fluconazole is a strong inhibitor of CYP2C19 and is a dose-dependent|
01663|017|A|inhibitor of CYP2C9 and CYP3A4.|
01663|018|A|   - Itraconazole is primarily metabolized by and is a strong inhibitor of|
01663|019|A|CYP3A4.|
01663|020|A|   Fluconazole, itraconazole and ketoconazole may inhibit the metabolism of|
01663|021|A|carbamazepine, phenobarbital and phenytoin by CYP3A4 and CYP2C9.(1-13)|
01663|022|A|   Barbiturates, carbamazepine, phenobarbital and phenytoin, strong inducers|
01663|023|A|of CYP3A4, may increase the metabolism of itraconazole or|
01663|024|A|ketoconazole(5,14-16) leading to lower systemic concentrations.  Fluconazole|
01663|025|A|is renally eliminated and less susceptible to induction.(16)|
01663|026|B||
01663|027|E|CLINICAL EFFECTS:  Concurrent use of fluconazole, itraconazole or|
01663|028|E|ketoconazole may result in elevated levels of and toxicity from|
01663|029|E|carbamazepine, phenobarbital and phenytoin.|
01663|030|E|   Concurrent use of barbiturates, carbamazepine, phenobarbital or phenytoin|
01663|031|E|with itraconazole or ketoconazole(5,14-16) may result in decreased|
01663|032|E|effectiveness or failure of antifungal therapy.|
01663|033|B||
01663|034|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01663|035|P|of the inducer for longer than 1-2 weeks.|
01663|036|B||
01663|037|M|PATIENT MANAGEMENT:  When usual doses of itraconazole or ketoconazole are|
01663|038|M|prescribed for patients maintained on carbamazepine, phenobarbital or|
01663|039|M|phenytoin, suboptimal response or treatment failure of the antifungal agent|
01663|040|M|may occur.  If clinically appropriate consider using another antifungal|
01663|041|M|agent.  If itraconazole or ketoconazole is required, consider therapeutic|
01663|042|M|drug monitoring to optimize antifungal dose-regimen.|
01663|043|M|   The dosage of carbamazepine, phenobarbital or phenytoin may need to be|
01663|044|M|adjusted when initiating or discontinuing fluconazole, itraconazole or|
01663|045|M|ketoconazole.  Monitor carbamazepine or phenytoin levels and patient|
01663|046|M|tolerance and adjust dose accordingly.  Instruct patients to report adverse|
01663|047|M|effects or toxicity.|
01663|048|M|   The US manufacturer of itraconazole states that concurrent administration|
01663|049|M|with carbamazepine is not recommended two weeks before, during, or two weeks|
01663|050|M|after itraconazole treatment.(6)|
01663|051|M|   The US manufacturer of itraconazole states that concomitant|
01663|052|M|administration with phenytoin or phenobarbital is not recommended during or|
01663|053|M|two weeks after itraconazole treatment.(6)|
01663|054|M|   The US manufacturer of ketoconazole states that concomitant|
01663|055|M|administration with carbamazepine is not recommended during and up to one|
01663|056|M|week after discontinuation of treatment with ketoconazole.  If|
01663|057|M|coadministration cannot be avoided, plasma concentrations should be|
01663|058|M|measured.(7)|
01663|059|B||
01663|060|D|DISCUSSION:  There are four case reports of elevated carbamazepine levels|
01663|061|D|(levels ranged from 18 mcg/ml to 24.5 mcg/ml) following the addition of|
01663|062|D|fluconazole (150 mg/day to 400 mg/day).(1-3)  In two of the reports, the|
01663|063|D|patients reported symptoms of carbamazepine toxicity such as blurred vision,|
01663|064|D|dizziness, severe diplopia, oscillopsia, nausea, vomiting, gait instability,|
01663|065|D|nystagmus,(1) lethargy, and lack of response to painful stimuli.(2)  In the|
01663|066|D|third report, the patient had no signs of carbamazepine toxicity.(3) In the|
01663|067|D|fourth report, a patient treated with carbamazepine for bipolar disorder|
01663|068|D|experienced carbamazepine toxicity symptoms of diplopia, dizziness, and|
01663|069|D|nystagmus, but no other neurological effects typically seen in carbamazepine|
01663|070|D|toxicity were noted.|
01663|071|D|   In a study of 8 subjects, concurrent ketoconazole (200 mg/day) increased|
01663|072|D|carbamazepine (range 400 mg/day to 800 mg/day) levels by 25%.  There were no|
01663|073|D|effects on levels of carbamazepine-10-11-epoxide, the active metabolite of|
01663|074|D|carbamazepine.  There were no signs of carbamazepine toxicity or change in|
01663|075|D|seizure frequency.(5)|
01663|076|D|   There are three case reports of undetectable levels and therapeutic|
01663|077|D|failure of itraconazole in patients maintained on carbamazepine.(15,17)|
01663|078|D|   Controlled studies in healthy volunteers have found that concurrent|
01663|079|D|administration of phenytoin and fluconazole increase the area under the|
01663|080|D|concentration-time curve of phenytoin by 75% and increase serum phenytoin|
01663|081|D|concentration.(9-11)|
01663|082|D|   Case reports have documented the occurrence of phenytoin toxicity when|
01663|083|D|fluconazole was added to the treatment of patients receiving|
01663|084|D|phenytoin.(12,13)|
01663|085|D|   A controlled study in healthy volunteers documented that concurrent|
01663|086|D|administration of itraconazole and phenytoin resulted in a decrease in|
01663|087|D|itraconazole area-under-curve (AUC) by 93% and half-life by 83%.|
01663|088|D|Itraconazole increased phenytoin AUC by 10%.(15)|
01663|089|B||
01663|090|R|REFERENCES:|
01663|091|B||
01663|092|R|1.This information is based on an extract from the Certara Drug Interaction|6
01663|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01663|094|R|2.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
01663|095|R|  Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
01663|096|R|3.Ulivelli M, Rubegni P, Nuti D, Bartalini S, Giannini F, Rossi S. Clinical|3
01663|097|R|  evidence of fluconazole-induced carbamazepine toxicity. J Neurol 2004 May;|3
01663|098|R|  251(5):622-3.|3
01663|099|R|4.Nair DR, Morris HH. Potential fluconazole-induced carbamazepine toxicity.|3
01663|100|R|  Ann Pharmacother 1999 Jul-Aug;33(7-8):790-2.|3
01663|101|R|5.Finch CK, Green CA, Self TH. Fluconazole-carbamazepine interaction. South|3
01663|102|R|  Med J 2002 Sep;95(9):1099-100.|3
01663|103|R|6.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01663|104|R|  Products, L.P. February, 2024.|1
01663|105|R|7.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01663|106|R|  Pharmaceuticals February, 2014.|1
01663|107|R|8.Spina E, Arena D, Scordo MG, Fazio A, Pisani F, Perucca E. Elevation of|2
01663|108|R|  plasma carbamazepine concentrations by ketoconazole in patients with|2
01663|109|R|  epilepsy. Ther Drug Monit 1997 Oct;19(5):535-8.|2
01663|110|R|9.Pirmohamed M, Kitteringham NR, Guenthner TM, Breckenridge AM, Park BK. An|5
01663|111|R|  investigation of the formation of cytotoxic, protein-reactive and stable|5
01663|112|R|  metabolites from carbamazepine in vitro. Biochem Pharmacol 1992 Apr 15;|5
01663|113|R|  43(8):1675-82.|5
01663|114|R|10.Pearce RE, Vakkalagadda GR, Leeder JS. Pathways of carbamazepine|5
01663|115|R|   bioactivation in vitro I. Characterization of human cytochromes P450|5
01663|116|R|   responsible for the formation of 2- and 3-hydroxylated metabolites. Drug|5
01663|117|R|   Metab Dispos 2002 Nov;30(11):1170-9.|5
01663|118|R|11.Blum RA, Wilton JH, Hilligoss DM, Gardner MJ, Henry EB, Harrison NJ,|2
01663|119|R|   Schentag JJ. Effect of fluconazole on the disposition of phenytoin. Clin|2
01663|120|R|   Pharmacol Ther 1991 Apr;49(4):420-5.|2
01663|121|R|12.Touchette MA, Chandrasekar PH, Milad MA, Edwards DJ. Contrasting effects|2
01663|122|R|   of fluconazole and ketoconazole on phenytoin and testosterone disposition|2
01663|123|R|   in man. Br J Clin Pharmacol 1992 Jul;34(1):75-8.|2
01663|124|R|13.Ducharme MP, Slaughter RL, Warbasse LH, Chandrasekar PH, Van de Velde V,|2
01663|125|R|   Mannens G, Edwards DJ. Itraconazole and hydroxyitraconazole serum|2
01663|126|R|   concentrations are reduced more than tenfold by phenytoin. Clin Pharmacol|2
01663|127|R|   Ther 1995 Dec;58(6):617-24.|2
01663|128|R|14.Mitchell AS, Holland JT. Fluconazole and phenytoin: a predictable|3
01663|129|R|   interaction. BMJ 1989 May 13;298(6683):1315.|3
01663|130|R|15.Howitt KM, Oziemski MA. Phenytoin toxicity induced by fluconazole. Med J|3
01663|131|R|   Aust 1989 Nov 20;151(10):603-4.|3
01663|132|R|16.Bonay M, Jonville-Bera AP, Diot P, Lemarie E, Lavandier M, Autret E.|3
01663|133|R|   Possible interaction between phenobarbital, carbamazepine and|3
01663|134|R|   itraconazole. Drug Saf 1993 Oct;9(4):309-11.|3
01663|135|R|17.Tucker RM, Denning DW, Hanson LH, Rinaldi MG, Graybill JR, Sharkey PK,|3
01663|136|R|   Pappagianis D, Stevens DA. Interaction of azoles with rifampin,|3
01663|137|R|   phenytoin, and carbamazepine: in vitro and clinical observations. Clin|3
01663|138|R|   Infect Dis 1992 Jan;14(1):165-74.|3
01663|139|R|18.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
01663|140|R|   2024.|1
01663|141|R|19.Tsouli S, Maranis S, Kyritsis AP. Fluconazole-carbamazepine interaction|3
01663|142|R|   in a patient with bipolar disorder. Psychiatry Clin Neurosci 2011 Feb;|3
01663|143|R|   65(1):112.|3
01664|001|T|MONOGRAPH TITLE:  Doripenem; Meropenem/OAT3 Inhibitors|
01664|002|B||
01664|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01664|004|L|of severe adverse interaction.|
01664|005|B||
01664|006|A|MECHANISM OF ACTION:  Inhibitors of organic anion transporter 3 (OAT3) may|
01664|007|A|inhibit the renal excretion of doripenem (1) and meropenem(2) by competing|
01664|008|A|with them for active tubular secretion.|
01664|009|B||
01664|010|E|CLINICAL EFFECTS:  Concurrent use of organic anion transporter 3 (OAT3)|
01664|011|E|inhibitors may result in elevated levels of and toxicity from doripenem(1)|
01664|012|E|or meropenem.(2)|
01664|013|B||
01664|014|P|PREDISPOSING FACTORS:  None determined.|
01664|015|B||
01664|016|M|PATIENT MANAGEMENT:  The US manufacturer of doripenem states that concurrent|
01664|017|M|use of organic anion transporter 3 (OAT3) inhibitors is not recommended.(1)|
01664|018|M|   The US manufacturer of meropenem states that concurrent use of OAT3|
01664|019|M|inhibitors is not recommended.(2)|
01664|020|B||
01664|021|D|DISCUSSION:  Probenecid has been shown to increase doripenem half-life|
01664|022|D|(T1/2) and area-under-curve (AUC) by 53% and 75%, respectively.(1)|
01664|023|D|   In a study in six subjects, concurrent probenecid increased meropenem|
01664|024|D|T1/2 by 33%.(3)  Other studies have shown probenecid to increase the T1/2 of|
01664|025|D|meropenem by 38% and the extent of meropenem systemic exposure by 58%.(2)|
01664|026|D|   OAT3 inhibitors linked to this monograph include:  cabotegravir,|
01664|027|D|leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(4)|
01664|028|B||
01664|029|R|REFERENCES:|
01664|030|B||
01664|031|R|1.Doribax (doripenem) US prescribing information. Shionogi, Inc. August,|1
01664|032|R|  2015.|1
01664|033|R|2.Merrem (meropenem) US prescribing information. AstraZeneca Pharmaceuticals|1
01664|034|R|  LP June, 2018.|1
01664|035|R|3.Bax RP, Bastain W, Featherstone A, Wilkinson DM, Hutchison M, Haworth SJ.|2
01664|036|R|  The pharmacokinetics of meropenem in volunteers. J Antimicrob Chemother|2
01664|037|R|  1989 Sep;24 Suppl A:311-20.|2
01664|038|R|4.This information is based on an extract from the Certara Drug Interaction|6
01664|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01665|001|T|MONOGRAPH TITLE:  Pramlintide/Inhaled Anticholinergics|
01665|002|B||
01665|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01665|004|L|of severe adverse interaction.|
01665|005|B||
01665|006|A|MECHANISM OF ACTION:  Pramlintide slows gastric emptying.  Anticholinergics|
01665|007|A|may result in additive or synergistic effects.(1)|
01665|008|B||
01665|009|E|CLINICAL EFFECTS:  Concurrent use of pramlintide and anticholinergics may|
01665|010|E|result in additive or synergistic effects.(1)|
01665|011|B||
01665|012|P|PREDISPOSING FACTORS:  None determined.|
01665|013|B||
01665|014|M|PATIENT MANAGEMENT:  The manufacturer of pramlintide states that pramlintide|
01665|015|M|therapy should not be considered in patients requiring the use of drugs that|
01665|016|M|stimulate gastrointestinal motility or in patients taking drugs that alter|
01665|017|M|gastrointestinal motility.(1)  Patients receiving inhaled anticholinergics|
01665|018|M|should be evaluated for signs of systemic effects, which may include|
01665|019|M|constipation.|
01665|020|B||
01665|021|D|DISCUSSION:  Patients using drugs that alter gastrointestinal motility have|
01665|022|D|not been studied in clinical trials for pramlintide.(1)|
01665|023|D|   Constipation has been reported as a side effect of inhaled|
01665|024|D|anticholinergic agents such as ipratropium(2) and tiotropium.(3)|
01665|025|B||
01665|026|R|REFERENCES:|
01665|027|B||
01665|028|R|1.Symlin (pramlintide acetate) US prescribing information. Amylin|1
01665|029|R|  Pharmaceuticals Inc. March, 2005.|1
01665|030|R|2.Combivent (ipratropium bromide and albuterol sulfate) US prescribing|1
01665|031|R|  information. Boehringer Ingelheim April, 2011.|1
01665|032|R|3.Spiriva (tiotropium bromide) US prescribing information. Boehringer|1
01665|033|R|  Ingelheim February 1, 2018.|1
01666|001|T|MONOGRAPH TITLE:  Opioids/Buprenorphine; Pentazocine|
01666|002|B||
01666|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01666|004|L|take action as needed.|
01666|005|B||
01666|006|A|MECHANISM OF ACTION:  Buprenorphine is a partial agonist at mu-opiate|
01666|007|A|receptors, exhibiting a ceiling effect at which higher doses produce no|
01666|008|A|further effect.  Pentazocine is a mixed agonist-antagonist at opiate|
01666|009|A|receptors.(1)  Full mu-opioid agonists (e.g., morphine, methadone) continue|
01666|010|A|to have increased effects at higher doses without ceiling effects.(2)|
01666|011|B||
01666|012|E|CLINICAL EFFECTS:  Concurrent use of buprenorphine or pentazocine with other|
01666|013|E|opioids in opioid dependent patients may result in withdrawal symptoms.|
01666|014|E|Concurrent use in other patients may result in additive or decreased|
01666|015|E|analgesia and decreased opioid side effects.|
01666|016|B||
01666|017|P|PREDISPOSING FACTORS:  Patients dependent on opioids or who take higher|
01666|018|P|dosages of opioids may be more likely to experience withdrawal symptoms with|
01666|019|P|concurrent use.|
01666|020|B||
01666|021|M|PATIENT MANAGEMENT:  Use buprenorphine and pentazocine with caution in|
01666|022|M|patients maintained or dependent on other opioids and monitor for signs of|
01666|023|M|withdrawal.  In other patients, also monitor for changes in analgesic|
01666|024|M|effects.|
01666|025|M|   The manufacturer of Sublocade states buprenorphine may precipitate opioid|
01666|026|M|withdrawal in patients who are currently physically dependent on full opioid|
01666|027|M|agonists. The risk of withdrawal may be increased if buprenorphine is given|
01666|028|M|less than 6 hours after short-acting opioids (such as heroin, morphine) and|
01666|029|M|less than 24 hours after long-acting opioids (such as methadone).(3)|
01666|030|B||
01666|031|D|DISCUSSION:  Concurrent use of buprenorphine with other opioids in opioid|
01666|032|D|dependent patients could result in withdrawal symptoms.  Concurrent use in|
01666|033|D|other patients may result in additive or decreased analgesia, decreased|
01666|034|D|opioid side effects, and/or renarcotization.(2)|
01666|035|D|   In clinical trials, administration of buprenorphine injection produced|
01666|036|D|withdrawal symptoms in patients maintained on methadone (30 mg daily) when|
01666|037|D|administered 2 hours post-methadone,(4) but not when administered 20 hours|
01666|038|D|post-methadone.(5)|
01666|039|D|   In another study, sublingual buprenorphine produced withdrawal symptoms|
01666|040|D|in patients maintained on methadone.  Symptoms were more pronounced in|
01666|041|D|patients maintained on 60 mg daily doses than in patients maintained on 30|
01666|042|D|mg daily doses.(6)|
01666|043|D|   In a study of 10 patients maintained on methadone (100 mg daily), only|
01666|044|D|three were able to tolerate escalating sublingual doses of|
01666|045|D|buprenorphine/naloxone up to 32/8 mg.  Split doses produced less withdrawal|
01666|046|D|symptoms than full doses.(7)|
01666|047|D|   In a case report, a heroin-user maintained in a buprenorphine-maintenance|
01666|048|D|program began stockpiling his buprenorphine instead of ingesting it and|
01666|049|D|began using heroin.  He then decided to re-initiate treatment on his own and|
01666|050|D|ingested between 80 and 88 mg of buprenorphine over a two day period and|
01666|051|D|experienced extreme withdrawal symptoms, despite restarting heroin during|
01666|052|D|these symptoms.  Methadone relieved his withdrawal symptoms.(8)|
01666|053|B||
01666|054|R|REFERENCES:|
01666|055|B||
01666|056|R|1.Talwin (pentazocine) US Prescribing Information. Hospira, Inc. Oct 2019.|1
01666|057|R|2.Buprenex (buprenorphine hydrochloride) US prescribing information. Reckitt|1
01666|058|R|  Benckiser Pharmaceuticals, Inc. April, 2005.|1
01666|059|R|3.Sublocade (buprenorphine extended release injection) US prescribing|1
01666|060|R|  information. Indivior Inc. February, 2025.|1
01666|061|R|4.Strain EC, Preston KL, Liebson IA, Bigelow GE. Buprenorphine effects in|2
01666|062|R|  methadone-maintained volunteers: effects at two hours after methadone. J|2
01666|063|R|  Pharmacol Exp Ther 1995 Feb;272(2):628-38.|2
01666|064|R|5.Strain EC, Preston KL, Liebson IA, Bigelow GE. Acute effects of|2
01666|065|R|  buprenorphine, hydromorphone and naloxone in methadone-maintained|2
01666|066|R|  volunteers. J Pharmacol Exp Ther 1992 Jun;261(3):985-93.|2
01666|067|R|6.Walsh SL, June HL, Schuh KJ, Preston KL, Bigelow GE, Stitzer ML. Effects|2
01666|068|R|  of buprenorphine and methadone in methadone-maintained subjects.|2
01666|069|R|  Psychopharmacology (Berl) 1995 Jun;119(3):268-76.|2
01666|070|R|7.Rosado J, Walsh SL, Bigelow GE, Strain EC. Sublingual|2
01666|071|R|  buprenorphine/naloxone precipitated withdrawal in subjects maintained on|2
01666|072|R|  100mg of daily methadone. Drug Alcohol Depend 2007 Oct 8;90(2-3):261-9.|2
01666|073|R|8.Clark NC, Lintzeris N, Muhleisen PJ. Severe opiate withdrawal in a heroin|3
01666|074|R|  user precipitated by a massive buprenorphine dose. Med J Aust 2002 Feb 18;|3
01666|075|R|  176(4):166-7.|3
01667|001|T|MONOGRAPH TITLE:  Gefitinib; Imatinib/Slt Azole Antifungals;|
01667|002|T|Levoketoconazole|
01667|003|B||
01667|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01667|005|L|take action as needed.|
01667|006|B||
01667|007|A|MECHANISM OF ACTION:  Azole antifungals such as itraconazole,(1-3)|
01667|008|A|ketoconazole,(1-2,4,5) and voriconazole(1,3,7) may inhibit the metabolism of|
01667|009|A|gefitinib and imatinib by CYP3A4. Levoketoconazole may inhibit the|
01667|010|A|metabolism of gefitinib and imatinib by CYP3A4.(7)|
01667|011|B||
01667|012|E|CLINICAL EFFECTS:  Concurrent use of itraconazole,(1-3)|
01667|013|E|ketoconazole,(1-2,4,5) voriconazole(2,6), or levoketoconazole(7) may result|
01667|014|E|in elevated levels of and toxicity from gefitinib or imatinib.|
01667|015|B||
01667|016|P|PREDISPOSING FACTORS:  None determined.|
01667|017|B||
01667|018|M|PATIENT MANAGEMENT:  Concurrent use of gefitinib(1) or imatinib(2) with|
01667|019|M|itraconazole, ketoconazole, or voriconazole should be approached with|
01667|020|M|caution.  Patients receiving concurrent therapy with gefitinib or imatinib|
01667|021|M|should be monitored closely for increased levels of and toxicity from these|
01667|022|M|agents if one of these azole antifungals is initiated.  The dosage of|
01667|023|M|gefitinib or imatinib may need to be adjusted if one of these azole|
01667|024|M|antifungals is initiated or discontinued.|
01667|025|M|   The US manufacturer of levoketoconazole states that concurrent|
01667|026|M|administration with sensitive CYP3A4 substrates is not recommended.(7)|
01667|027|B||
01667|028|D|DISCUSSION:  In a study in healthy subjects, itraconazole (200 mg daily for|
01667|029|D|12 days) increased the area-under-curve (AUC) of a single dose of gefitinib|
01667|030|D|(250 mg) by 88%.(1)|
01667|031|D|   In a study in healthy male subjects, itraconazole increased the AUC of|
01667|032|D|250 mg of gefitinib by 78% and the AUC of 500 mg of gefitinib by 61%.(3)|
01667|033|D|   An in vitro study in human liver microsomes found that ketoconazole was a|
01667|034|D|potent inhibitor of gefitinib metabolism.(4)|
01667|035|D|   In a study in 14 healthy subjects, a single oral dose of ketoconazole|
01667|036|D|(400 mg) increased the AUC and maximum concentration (Cmax) of a single oral|
01667|037|D|dose of imatinib (200 mg) by 40% and 26%, respectively.(2,5)|
01667|038|D|   In a case report, a patient developed elevated imatinib levels and a|
01667|039|D|pustular eruption following the addition of voriconazole.(6)|
01667|040|B||
01667|041|R|REFERENCES:|
01667|042|B||
01667|043|R|1.Iressa (gefitinib tablets) US prescribing information. AstraZeneca|1
01667|044|R|  Pharmaceuticals LP April 7, 2004.|1
01667|045|R|2.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
01667|046|R|  Pharmaceuticals Corporation August, 2022.|1
01667|047|R|3.Swaisland HC, Ranson M, Smith RP, Leadbetter J, Laight A, McKillop D, Wild|2
01667|048|R|  MJ. Pharmacokinetic drug interactions of gefitinib with rifampicin,|2
01667|049|R|  itraconazole and metoprolol. Clin Pharmacokinet 2005;44(10):1067-81.|2
01667|050|R|4.McKillop D, McCormick AD, Millar A, Miles GS, Phillips PJ, Hutchison M.|5
01667|051|R|  Cytochrome P450-dependent metabolism of gefitinib. Xenobiotica 2005 Jan;|5
01667|052|R|  35(1):39-50.|5
01667|053|R|5.Dutreix C, Peng B, Mehring G, Hayes M, Capdeville R, Pokorny R, Seiberling|2
01667|054|R|  M. Pharmacokinetic interaction between ketoconazole and imatinib mesylate|2
01667|055|R|  (Glivec) in healthy subjects. Cancer Chemother Pharmacol 2004 Oct;|2
01667|056|R|  54(4):290-4.|2
01667|057|R|6.Gambillara E, Laffitte E, Widmer N, Decosterd LA, Duchosal MA, Kovacsovics|3
01667|058|R|  T, Panizzon RG. Severe pustular eruption associated with imatinib and|3
01667|059|R|  voriconazole in a patient with chronic myeloid leukemia. Dermatology 2005;|3
01667|060|R|  211(4):363-5.|3
01667|061|R|7.Recorlev (levoketoconazole) US prescribing information. Xeris|1
01667|062|R|  Pharmaceuticals, Inc. June, 2023.|1
01668|001|T|MONOGRAPH TITLE:  Slt HMG Co-A Reductase Inhibitors/Efavirenz (mono deleted|
01668|002|T|11/20/2020)|
01668|003|B||
01668|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01668|005|L|take action as needed.|
01668|006|B||
01668|007|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of atorvastatin,|
01668|008|A|pravastatin, and simvastatin by CYP P-450-3A4.(1)|
01668|009|B||
01668|010|E|CLINICAL EFFECTS:  Concurrent efavirenz may result in decreased levels and|
01668|011|E|clinical effectiveness of atorvastatin, pravastatin, or simvastatin.(1-3)|
01668|012|B||
01668|013|P|PREDISPOSING FACTORS:  None determined.|
01668|014|B||
01668|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent efavirenz may require|
01668|016|M|higher than normal dosages of atorvastatin, pravastatin, or simvastatin.|
01668|017|M|Monitor patients for therapeutic response and adjust the dosage of the HMG|
01668|018|M|CoA reductase inhibitor accordingly.  If efavirenz is discontinued, the|
01668|019|M|dosage of the HMG CoA reductase inhibitor may need to be adjusted.|
01668|020|B||
01668|021|D|DISCUSSION:  In an open-label study in 52 healthy, HIV-negative subjects,|
01668|022|D|subjects received atorvastatin (10 mg daily), pravastatin (40 mg daily), or|
01668|023|D|simvastatin (40 mg daily) for 3 days before and on Days 14-16 of 16 days of|
01668|024|D|efavirenz (600 mg daily).  Efavirenz decreased the area-under-curve (AUC) of|
01668|025|D|atorvastatin and total active atorvastatin by 43% and 34%, respectively.|
01668|026|D|Efavirenz decreased pravastatin AUC by 40%.  Efavirenz decreased simvastatin|
01668|027|D|acid AUC by 58% and active HMG CoA reductase inhibitory activity by 60%.|
01668|028|D|Atorvastatin, pravastatin, and simvastatin had no effect on efavirenz|
01668|029|D|pharmacokinetics.(1)|
01668|030|D|   In a study in 14 subjects, concurrent atorvastatin (10 mg daily for 4|
01668|031|D|days) and efavirenz (600 mg daily for 15 days) decreased atorvastatin AUC,|
01668|032|D|maximum concentration (Cmax), and minimum concentration (Cmin) by 43%, 14%,|
01668|033|D|and 69%, respectively.  The AUC, Cmax, and Cmin of the total active|
01668|034|D|atorvastatin decreased by 32%, 15%, and 48%, respectively.  There was no|
01668|035|D|effect on efavirenz levels.(2,3)|
01668|036|D|   In a study in 13 subjects, concurrent pravastatin (40 mg daily for 4|
01668|037|D|days) and efavirenz (600 mg daily for 15 days) decreased pravastatin AUC,|
01668|038|D|Cmax, and Cmin by 44%, 32%, and 19%, respectively.  There was no effect on|
01668|039|D|efavirenz levels.(2,3)|
01668|040|D|   In a study in 14 subjects, concurrent simvastatin (40 mg daily for 4|
01668|041|D|days) and efavirenz (600 mg daily for 15 days) decreased simvastatin AUC,|
01668|042|D|Cmax, and Cmin by 68%, 72%, and 45%, respectively.  The AUC and Cmax of the|
01668|043|D|total active simvastatin decreased by 60% and 68%, respectively.  Efavirenz|
01668|044|D|Cmax and Cmin both decreased by 12%; however, there was no effect on|
01668|045|D|efavirenz AUC.(2,3)|
01668|046|B||
01668|047|R|REFERENCES:|
01668|048|B||
01668|049|R|1.Gerber JG, Rosenkranz SL, Fichtenbaum CJ, Vega JM, Yang A, Alston BL,|2
01668|050|R|  Brobst SW, Segal Y, Aberg JA. Effect of efavirenz on the pharmacokinetics|2
01668|051|R|  of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical|2
01668|052|R|  Trials Group 5108 Study. J Acquir Immune Defic Syndr 2005 Jul 1;|2
01668|053|R|  39(3):307-12.|2
01668|054|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01668|055|R|  Company November, 2023.|1
01668|056|R|3.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01668|057|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01669|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Nefazodone|
01669|002|B||
01669|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01669|004|L|of severe adverse interaction.|
01669|005|B||
01669|006|A|MECHANISM OF ACTION:  Nefazodone increases plasma levels of sirolimus and|
01669|007|A|temsirolimus by inhibition on CYP3A4.(1,2)|
01669|008|B||
01669|009|E|CLINICAL EFFECTS:  Concurrent nefazodone may result in elevated levels of|
01669|010|E|and toxicity from sirolimus and temsirolimus.(1,2)|
01669|011|B||
01669|012|P|PREDISPOSING FACTORS:  None determined.|
01669|013|B||
01669|014|M|PATIENT MANAGEMENT:  The US manufacturer of sirolimus recommends that|
01669|015|M|concurrent therapy with strong CYP3A4 inhibitors such as nefazodone by|
01669|016|M|avoided.  Alternative agents with lesser interaction potential with|
01669|017|M|sirolimus should be considered.(1)|
01669|018|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
01669|019|M|with strong CYP3A4 inhibitors such as nefazodone be avoided.  If concurrent|
01669|020|M|use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should|
01669|021|M|be considered.  If nefazodone is discontinued, a washout period of 1 week|
01669|022|M|should be allowed before adjusting the dosage of temsirolimus to previous|
01669|023|M|levels.(2)|
01669|024|B||
01669|025|D|DISCUSSION:  Multiple-dose ketoconazole, another inhibitor of CYP3A4,|
01669|026|D|administration significantly affected the rate and extent of absorption and|
01669|027|D|sirolimus exposure after administration of sirolimus oral solution, as|
01669|028|D|reflected by increases in sirolimus concentration maximum (Cmax), time|
01669|029|D|maximum (tmax), and area-under-curve (AUC) of 4.3-fold, 38%, and 10.9-fold,|
01669|030|D|respectively.  However, the terminal half-life of sirolimus was not changed.|
01669|031|D|Single-dose sirolimus did not affect steady-state 12-hour plasma|
01669|032|D|ketoconazole concentrations.(1)|
01669|033|D|   Concurrent administration of ketoconazole, another inhibitor of CYP3A4,|
01669|034|D|had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax|
01669|035|D|increased 3.1-fold and 2.2-fold, respectively.  Dosage adjustment of|
01669|036|D|temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is|
01669|037|D|expected to adjust levels to the range observed without inhibitors;|
01669|038|D|however, there are no data available with this dose adjustment.(2)|
01669|039|B||
01669|040|R|REFERENCES:|
01669|041|B||
01669|042|R|1.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
01669|043|R|  Aug, 2022.|1
01669|044|R|2.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01669|045|R|  Inc. March, 2018.|1
01670|001|T|MONOGRAPH TITLE:  Temsirolimus/Dexamethasone|
01670|002|B||
01670|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01670|004|L|of severe adverse interaction.|
01670|005|B||
01670|006|A|MECHANISM OF ACTION:  Dexamethasone may induce the metabolism of|
01670|007|A|temsirolimus by CYP3A4.(1)|
01670|008|B||
01670|009|E|CLINICAL EFFECTS:  Concurrent dexamethasone may result in decreased levels|
01670|010|E|and effectiveness of temsirolimus.(1)|
01670|011|B||
01670|012|P|PREDISPOSING FACTORS:  None determined.|
01670|013|B||
01670|014|M|PATIENT MANAGEMENT:  The US manufacturer of temsirolimus states that|
01670|015|M|concurrent use of strong inducers of CYP3A4, such as dexamethasone, should|
01670|016|M|be avoided.  If concurrent therapy is warranted, consider increasing the|
01670|017|M|dosage of temsirolimus from 25 mg/week to 50 mg/week.  If the inducer is|
01670|018|M|discontinued, the dosage of temsirolimus should be returned to the previous|
01670|019|M|dose.(1)|
01670|020|B||
01670|021|D|DISCUSSION:  Concurrent rifampin, a potent inducer of CYP3A4 and CYP3A5, had|
01670|022|D|no significant effects on the area-under-curve (AUC) or maximum|
01670|023|D|concentration (Cmax) of temsirolimus; however, sirolimus AUC and Cmax|
01670|024|D|decreased by 56% and 65%, respectively.(1)|
01670|025|D|   A dosage adjustment to 50 mg/week of temsirolimus in the presence of|
01670|026|D|strong CYP3A4 inducers is predicted to adjust levels to those seen without|
01670|027|D|inducers; however, there are no clinical data in patients using this|
01670|028|D|dose.(1)|
01670|029|B||
01670|030|R|REFERENCE:|
01670|031|B||
01670|032|R|1.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01670|033|R|  Inc. March, 2018.|1
01671|001|T|MONOGRAPH TITLE:  Temsirolimus/Selected Anticonvulsants (mono deleted|
01671|002|T|10/17/2013)|
01671|003|B||
01671|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01671|005|L|of severe adverse interaction.|
01671|006|B||
01671|007|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital, and phenytoin may induce|
01671|008|A|the metabolism of temsirolimus by CYP P-450-3A4.(1)|
01671|009|B||
01671|010|E|CLINICAL EFFECTS:  Concurrent carbamazepine, phenobarbital, or phenytoin may|
01671|011|E|result in decreased levels and effectiveness of temsirolimus.(1)|
01671|012|B||
01671|013|P|PREDISPOSING FACTORS:  None determined.|
01671|014|B||
01671|015|M|PATIENT MANAGEMENT:  The US manufacturer of temsirolimus states that|
01671|016|M|concurrent use of strong inducers of CYP P-450-3A4, such as carbamazepine,|
01671|017|M|phenobarbital, or phenytoin should be avoided.  If concurrent therapy is|
01671|018|M|warranted, consider increasing the dosage of temsirolimus from 25 mg/week to|
01671|019|M|50 mg/week.  If the inducer is discontinued, the dosage of temsirolimus|
01671|020|M|should be returned to the previous dose.(1)|
01671|021|B||
01671|022|D|DISCUSSION:  Concurrent rifampin, a potent inducer of CYP P-450-3A4 and CYP|
01671|023|D|P-450-3A5, had no significant effects on the area-under-curve (AUC) or|
01671|024|D|maximum concentration (Cmax) of temsirolimus; however, sirolimus AUC and|
01671|025|D|Cmax decreased by 56% and 65%, respectively.(1)|
01671|026|D|   A dosage adjustment to 50 mg/week of temsirolimus in the presence of|
01671|027|D|strong CYP P-450-3A4 inducers is predicted to adjust levels to those seen|
01671|028|D|without inducers; however, there are no clinical data in patients using this|
01671|029|D|dose.(1)|
01671|030|B||
01671|031|R|REFERENCE:|
01671|032|B||
01671|033|R|1.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01671|034|R|  Inc. May, 2012.|1
01672|001|T|MONOGRAPH TITLE:  Intravenous Ceftriaxone/Intravenous Calcium Products|
01672|002|B||
01672|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01672|004|L|of severe adverse interaction.|
01672|005|B||
01672|006|A|MECHANISM OF ACTION:  Intravenous ceftriaxone and intravenous calcium may|
01672|007|A|form an insoluble precipitate if administered too closely together.|
01672|008|B||
01672|009|E|CLINICAL EFFECTS:  Intravenous administration of calcium-containing products|
01672|010|E|with intravenous ceftriaxone may have serious risks in all patients,|
01672|011|E|especially in the neonate population.|
01672|012|E|NEONATES: Intravenous administration of calcium-containing products within|
01672|013|E|48(1-2) to 120(3) hours of intravenous administration of ceftriaxone may|
01672|014|E|result in damage to the lungs and/or kidneys in neonates.  Fatalities in|
01672|015|E|neonates have been reported.(1-7)|
01672|016|E|OLDER CHILDREN and ADULTS: Sequential administration requires proper line|
01672|017|E|flushing.  Use within 48 hours may result in the formation of kidney stones|
01672|018|E|in older children(5) and the formation of "sludge" in the gallbladder.(2)|
01672|019|E|Simultaneous administration in patients older than 28 days may result in the|
01672|020|E|formation of an insoluble ceftriaxone-calcium precipitate.(1-7)|
01672|021|B||
01672|022|P|PREDISPOSING FACTORS:  Neonates, both preterm and term, may be a greatest|
01672|023|P|risk of death from this interaction.(1-4)  Young age may predispose patients|
01672|024|P|to formation of ceftriaxone-calcium precipitates in the kidney.(5)  High|
01672|025|P|doses of ceftriaxone may also increase the risk of precipitates.(6)|
01672|026|B||
01672|027|M|PATIENT MANAGEMENT:  The US manufacturer of ceftriaxone, Health Canada, and|
01672|028|M|the US Food and Drug Administration (FDA) state that the concomitant use of|
01672|029|M|ceftriaxone and intravenous calcium-containing products is contraindicated|
01672|030|M|in neonates less than or equal to 28 days of age.  Ceftriaxone should not be|
01672|031|M|used in neonates less than or equal to 28 days of age if they are receiving|
01672|032|M|or are expected to receive calcium-containing intravenous products.(2,3,7)|
01672|033|M|   The US manufacturer of ceftriaxone, Health Canada, and the US FDA state|
01672|034|M|that in patients older than 28 days of age, ceftriaxone and|
01672|035|M|calcium-containing products may be administered sequentially, provided the|
01672|036|M|infusion lines are thoroughly flushed between infusions with a compatible|
01672|037|M|fluid.(2,3,7)|
01672|038|M|   The US manufacturer of ceftriaxone, Health Canada, and the US FDA state|
01672|039|M|that ceftriaxone must not be administered simultaneously with intravenous|
01672|040|M|calcium-containing solutions via a Y-site in any age group.(2,3,7)|
01672|041|B||
01672|042|D|DISCUSSION:  Isolated reports of neonatal (both term and preterm infants)|
01672|043|D|deaths have been associated with ceftriaxone-calcium precipitates in the|
01672|044|D|lungs and kidneys.  A total of 7 cases have been reported to the FDA,|
01672|045|D|resulting in 5 deaths.  All 5 deaths were in neonates of 3 weeks or less in|
01672|046|D|age.  Six of the 7 patients received calcium gluconate, 1 received calcium|
01672|047|D|via hyperalimentation.(6)  In some cases, ceftriaxone and the calcium|
01672|048|D|product were administered by different routes,(1) lines,(2) and/or at|
01672|049|D|different times.(1,2)|
01672|050|D|   Reports of a ceftriaxone-calcium salt precipitate in the gall-bladder|
01672|051|D|have also been reported.(2)|
01672|052|D|   In in vitro studies in adult and neonatal plasma, ceftriaxone recovery|
01672|053|D|was examined with ceftriaxone concentrations up to 1 mM (in excess of|
01672|054|D|concentrations seen with 2 g ceftriaxone infused over 30 minutes) and|
01672|055|D|calcium concentrations up to 12 mM (48 mg/dL).  Ceftriaxone recovery was|
01672|056|D|reduced with calcium concentrations of 6 mM (24 mg/dL) in adult plasma and 4|
01672|057|D|mM (16 mg/dL) in neonatal plasma.  This may indicate ceftriaxone-calcium|
01672|058|D|precipitation formation.(2,7)|
01672|059|D|   There have been no reports associated with concurrent use of oral calcium|
01672|060|D|products and the US manufacturer of ceftriaxone states that there is no risk|
01672|061|D|with oral calcium products or use of intramuscular ceftriaxone.(4)|
01672|062|B||
01672|063|R|REFERENCES:|
01672|064|B||
01672|065|R|1.Birgerson L. Dear Healthcare Professional letter. Roche Pharmaceuticals|1
01672|066|R|  August, 2007.|1
01672|067|R|2.Rocephin (ceftriaxone) US prescribing information. Roche Pharmaceuticals|1
01672|068|R|  June, 2015.|1
01672|069|R|3.Dear Hospital Chief of Medical Staff:  Subject:  Health Canada issued|1
01672|070|R|  important safety information on ceftriaxone. Health Canada October 15,|1
01672|071|R|  2009.|1
01672|072|R|4.Koserowski S. Personal communication. Roche Pharmaceuticals July 12, 2007.|1
01672|073|R|5.Avci Z, Koktener A, Uras N, Catal F, Karadag A, Tekin O, Degirmencioglu H,|2
01672|074|R|  Baskin E. Nephrolithiasis associated with ceftriaxone therapy: a|2
01672|075|R|  prospective study in 51 children. Arch Dis Child 2004 Nov;89(11):1069-72.|2
01672|076|R|6.Bradley JS, Wassel RT, Lee L, Nambiar S. Intravenous ceftriaxone and|3
01672|077|R|  calcium in the neonate: assessing the risk for cardiopulmonary adverse|3
01672|078|R|  events. Pediatrics 2009 Apr;123(4):e609-13.|3
01672|079|R|7.Anonymous. Information for Healthcare Professionals:  Ceftriaxone|1
01672|080|R|  (marketed as Rocephin and generics). Available at:|1
01672|081|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01672|082|R|  providers/ceftriaxone-marketed-rocephin-information Accessed April 15,|1
01672|083|R|  2009.|1
01673|001|T|MONOGRAPH TITLE:  Chloroquine; Hydroxychloroquine/Di-; Trivalent Cations|
01673|002|B||
01673|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01673|004|L|take action as needed.|
01673|005|B||
01673|006|A|MECHANISM OF ACTION:  Di- and trivalent cations such as aluminum, calcium,|
01673|007|A|lanthanum, and magnesium may adsorb chloroquine and hydroxychloroquine;|
01673|008|A|preventing their absorption.(1-5)  The adsorption may also limit the|
01673|009|A|effectiveness of the di- or trivalent cation.(1)|
01673|010|B||
01673|011|E|CLINICAL EFFECTS:  Simultaneous administration of di- or trivalent cations|
01673|012|E|may result in decreased levels and effectiveness of chloroquine and|
01673|013|E|hydroxychloroquine(2-5) and decreased effectiveness of the di- or trivalent|
01673|014|E|cation.(1)|
01673|015|B||
01673|016|P|PREDISPOSING FACTORS:  None determined.|
01673|017|B||
01673|018|M|PATIENT MANAGEMENT:  Instruct patients to separate the administration times|
01673|019|M|of these medicines by 2 to 4 hours.(2,3)|
01673|020|B||
01673|021|D|DISCUSSION:  Adsorption of chloroquine by magnesium trisilicate was found to|
01673|022|D|decrease hydrochloric acid uptake and decrease the amount of magnesium|
01673|023|D|released in an acidic environment.(1)|
01673|024|D|   In a study, calcium carbonate, kaolin, and magnesium trisilicate were|
01673|025|D|found to decrease the absorption of chloroquine by 52.8%, 46.5%, and 31.3%,|
01673|026|D|respectively.(3)|
01673|027|D|   Magnesium trisilicate and magnesium oxide have been shown to decrease the|
01673|028|D|release of chloroquine from tablets and to adsorb chloroquine after its|
01673|029|D|release.(4)|
01673|030|D|   In a study in 6 subjects, magnesium trisilicate and kaolin decreased the|
01673|031|D|area-under-curve (AUC) of chloroquine by 18.2% and 28.6%, respectively.(5)|
01673|032|B||
01673|033|R|REFERENCES:|
01673|034|B||
01673|035|R|1.Khalil SA. Effect of chloroquine adsorption on acid reactivity of|2
01673|036|R|  magnesium trisilicate. J Pharm Sci 1977 Feb;66(2):289-90.|2
01673|037|R|2.Fosrenol (lanthanum carbonate) Canadian prescribing information. Shire|1
01673|038|R|  BioChem February 19, 2007.|1
01673|039|R|3.McElnay JC, Mukhtar HA, D'Arcy PF, Temple DJ, Collier PS. The effect of|2
01673|040|R|  magnesium trisilicate and kaolin on the in vivo absorption of chloroquine.|2
01673|041|R|  J Trop Med Hyg 1982 Aug;85(4):159-63.|2
01673|042|R|4.Iwuagwu MA, Aloko KS. Adsorption of paracetamol and chloroquine phosphate|5
01673|043|R|  by some antacids. J Pharm Pharmacol 1992 Aug;44(8):655-8.|5
01673|044|R|5.McElnay JC, Mukhtar HA, D'Arcy PF, Temple DJ. In vitro experiments on|5
01673|045|R|  chloroquine and pyrimethamine absorption in the presence of antacid|5
01673|046|R|  constituents or kaolin. J Trop Med Hyg 1982 Aug;85(4):153-8.|5
01674|001|T|MONOGRAPH TITLE:  Acetaminophen/Isoniazid|
01674|002|B||
01674|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01674|004|L|take action as needed.|
01674|005|B||
01674|006|A|MECHANISM OF ACTION:  Isoniazid may induce the metabolism of acetaminophen|
01674|007|A|to its toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite by CYP2E1.(1)|
01674|008|B||
01674|009|E|CLINICAL EFFECTS:  Concurrent isoniazid and acetaminophen may result in|
01674|010|E|hepatotoxicity.(1)  Symptoms can include nausea, vomiting, jaundice, dark|
01674|011|E|urine, abdominal pain, and unexplained fatigue.|
01674|012|B||
01674|013|P|PREDISPOSING FACTORS:  The interaction may be more severe in fast|
01674|014|P|acetylators.|
01674|015|B||
01674|016|M|PATIENT MANAGEMENT:  Concurrent use of acetaminophen in patients treated|
01674|017|M|with isoniazid should be approached with caution.  Consider an alternative|
01674|018|M|analgesic agent.|
01674|019|M|   If concurrent therapy is warranted, advise patients not to exceed the|
01674|020|M|maximum recommended daily dose of acetaminophen and to immediately report|
01674|021|M|any symptoms of hepatotoxicity.|
01674|022|B||
01674|023|D|DISCUSSION:  Isoniazid has been shown to induce, after initially inhibiting,|
01674|024|D|the metabolism of acetaminophen to N-acetyl-p-benzoquinone imine (NAPQI),|
01674|025|D|which is hepatotoxicity.  Normally, NAPQI is rapidly converted to non-toxic|
01674|026|D|metabolites by glutathione; however, high levels of NAPQI can overwhelm this|
01674|027|D|system.(2-4)|
01674|028|D|   In a case report, a patient receiving isoniazid developed severe|
01674|029|D|acetaminophen toxicity following a suicide attempt, despite only having|
01674|030|D|ingested a maximum of 11.5 grams of acetaminophen and having a blood|
01674|031|D|acetaminophen level of 15 mmol/L 13 hours later.  Toxicity is usually seen|
01674|032|D|with levels greater than 26 mmol/L.(5)|
01674|033|D|   In a retrospective review of 20 deaths in patients taking isoniazid alone|
01674|034|D|or with ethambutol during a 13 year period, two deaths involved patients|
01674|035|D|receiving concurrent isoniazid and acetaminophen.(6,7)|
01674|036|B||
01674|037|R|REFERENCES:|
01674|038|B||
01674|039|R|1.Isoniazid US prescribing information. Sandoz Inc. July, 2016.|1
01674|040|R|2.Chien JY, Peter RM, Nolan CM, Wartell C, Slattery JT, Nelson SD, Carithers|2
01674|041|R|  RL Jr, Thummel KE. Influence of polymorphic N-acetyltransferase phenotype|2
01674|042|R|  on the inhibition and induction of acetaminophen bioactivation with|2
01674|043|R|  long-term isoniazid. Clin Pharmacol Ther 1997 Jan;61(1):24-34.|2
01674|044|R|3.Zand R, Nelson SD, Slattery JT, Thummel KE, Kalhorn TF, Adams SP, Wright|2
01674|045|R|  JM. Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by|2
01674|046|R|  isoniazid in humans. Clin Pharmacol Ther 1993 Aug;54(2):142-9.|2
01674|047|R|4.Epstein MM, Nelson SD, Slattery JT, Kalhorn TF, Wall RA, Wright JM.|2
01674|048|R|  Inhibition of the metabolism of paracetamol by isoniazid. Br J Clin|2
01674|049|R|  Pharmacol 1991 Feb;31(2):139-42.|2
01674|050|R|5.Murphy R, Swartz R, Watkins PB. Severe acetaminophen toxicity in a patient|3
01674|051|R|  receiving isoniazid. Ann Intern Med 1990 Nov 15;113(10):799-800.|3
01674|052|R|6.Moulding TS, Redeker AG, Kanel GC. Acetaminophen, isoniazid, and hepatic|3
01674|053|R|  toxicity. Ann Intern Med 1991 Mar 1;114(5):431.|3
01674|054|R|7.Moulding TS, Redeker AG, Kanel GC. Twenty isoniazid-associated deaths in|3
01674|055|R|  one state. Am Rev Respir Dis 1989 Sep;140(3):700-5.|3
01675|001|T|MONOGRAPH TITLE:  Oral Iron Supplements/Antacids and Selected Minerals|
01675|002|B||
01675|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01675|004|L|take action as needed.|
01675|005|B||
01675|006|A|MECHANISM OF ACTION:  Some antacids may bind to iron, preventing its|
01675|007|A|absorption.  Alterations in gastric pH by antacids may also play a role.|
01675|008|A|   Iron may bind to other minerals such as calcium, manganese, tin, and zinc|
01675|009|A|in the GI tract.|
01675|010|B||
01675|011|E|CLINICAL EFFECTS:  Simultaneous administration of an antacid or minerals may|
01675|012|E|decrease the absorption of orally administered iron.|
01675|013|B||
01675|014|P|PREDISPOSING FACTORS:  The interaction with some combinations may be|
01675|015|P|affected by the presence or absence of food.|
01675|016|B||
01675|017|M|PATIENT MANAGEMENT:  Iron supplements should not be taken within 1 hour|
01675|018|M|before or 2 hours after antacids, calcium, manganese, or zinc.(1)|
01675|019|M|   Some vitamin preparations may contain sufficient quantities of calcium|
01675|020|M|and/or magnesium salts with antacid properties to interact as well.|
01675|021|B||
01675|022|D|DISCUSSION:  Magnesium hydroxide has been shown to inhibit the absorption of|
01675|023|D|elemental iron,(2) although other studies have shown conflicting|
01675|024|D|results.(3,4)|
01675|025|D|   Sodium bicarbonate has been shown to decrease the absorption of iron by|
01675|026|D|50%.(3)|
01675|027|D|   In a study in 61 healthy subjects, calcium citrate, calcium carbonate,|
01675|028|D|and calcium phosphate inhibited iron absorption when taken with food.|
01675|029|D|However, in the fasted state, calcium carbonate had no effect on iron|
01675|030|D|absorption.  In the fasted state, calcium citrate and calcium phosphate|
01675|031|D|decreased iron absorption by 49% and 62%, respectively,(6)|
01675|032|D|   In a study in 23 healthy subjects, calcium acetate and calcium carbonate|
01675|033|D|decreased the area-under-curve (AUC) of elemental iron (65 mg) by 27% and|
01675|034|D|19%, respectively.(7)|
01675|035|D|   In a study, manganese decreased iron absorption.  A ratio of 5:1 of|
01675|036|D|zinc:iron decreased iron absorption by 56%.(8)|
01675|037|D|   In a study, inorganic iron decreased zinc absorption.(9)|
01675|038|D|   In another study, ferrous sulfate decreased the absorption of zinc|
01675|039|D|sulfate in a concentration dependent manner; however, heme chloride had no|
01675|040|D|effect on zinc sulfate.(10)|
01675|041|D|   In a study in premature infants, administration of liquid zinc and iron|
01675|042|D|supplements between feedings decreased iron uptake; however, no effect was|
01675|043|D|seen when the supplements were mixed with feedings.(11)|
01675|044|D|   One or more of the drug pairs linked to this monograph have been included|
01675|045|D|in a list of interactions that could be considered for classification as|
01675|046|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
01675|047|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
01675|048|D|Health Information Technology.|
01675|049|B||
01675|050|R|REFERENCES:|
01675|051|B||
01675|052|R|1.Ferrous gluconate US prescribing information. GFR Nutritionals Ltd|1
01675|053|R|  September 29, 2003.|1
01675|054|R|2.Wallace KL, Curry SC, LoVecchio F, Raschke RA. Effect of magnesium|2
01675|055|R|  hydroxide on iron absorption following simulated mild iron overdose in|2
01675|056|R|  human subjects. Acad Emerg Med 1998 Oct;5(10):961-5.|2
01675|057|R|3.O'Neil-Cutting MA, Crosby WH. The effect of antacids on the absorption of|2
01675|058|R|  simultaneously ingested iron. JAMA 1986 Mar 21;255(11):1468-70.|2
01675|059|R|4.Snyder BK, Clark RF. Effect of magnesium hydroxide administration on iron|2
01675|060|R|  absorption after a supratherapeutic dose of ferrous sulfate in human|2
01675|061|R|  volunteers: a randomized controlled trial. Ann Emerg Med 1999 Apr;|2
01675|062|R|  33(4):400-5.|2
01675|063|R|5.Hall GJ, Davis AE. Inhibition of iron absorption by magnesium trisilicate.|2
01675|064|R|  Med J Aust 1969 Jul 12;2(2):95-6.|2
01675|065|R|6.Cook JD, Dassenko SA, Whittaker P. Calcium supplementation: effect on iron|2
01675|066|R|  absorption. Am J Clin Nutr 1991 Jan;53(1):106-11.|2
01675|067|R|7.Pruchnicki MC, Coyle JD, Hoshaw-Woodard S, Bay WH. Effect of phosphate|2
01675|068|R|  binders on supplemental iron absorption in healthy subjects. J Clin|2
01675|069|R|  Pharmacol 2002 Oct;42(10):1171-6.|2
01675|070|R|8.Rossander-Hulten L, Brune M, Sandstrom B, Lonnerdal B, Hallberg L.|2
01675|071|R|  Competitive inhibition of iron absorption by manganese and zinc in humans.|2
01675|072|R|  Am J Clin Nutr 1991 Jul;54(1):152-6.|2
01675|073|R|9.Valberg LS, Flanagan PR, Chamberlain MJ. Effects of iron, tin, and copper|2
01675|074|R|  on zinc absorption in humans. Am J Clin Nutr 1984 Sep;40(3):536-41.|2
01675|075|R|10.Solomons NW, Jacob RA. Studies on the bioavailability of zinc in humans:|2
01675|076|R|   effects of heme and nonheme iron on the absorption of zinc. Am J Clin|2
01675|077|R|   Nutr 1981 Apr;34(4):475-82.|2
01675|078|R|11.Friel JK, Serfass RE, Fennessey PV, Miller LV, Andrews WL, Simmons BS,|2
01675|079|R|   Downton GF, Kwa PG. Elevated intakes of zinc in infant formulas do not|2
01675|080|R|   interfere with iron absorption in premature infants. J Pediatr|2
01675|081|R|   Gastroenterol Nutr 1998 Sep;27(3):312-6.|2
01675|082|R|12.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
01675|083|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
01675|084|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
01675|085|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
01676|001|T|MONOGRAPH TITLE:  Oral Iron Supplements/Selected Minerals (mono deleted|
01676|002|T|05/31/2022)|
01676|003|B||
01676|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01676|005|L|take action as needed.|
01676|006|B||
01676|007|A|MECHANISM OF ACTION:  Iron may bind to other minerals such as calcium,|
01676|008|A|manganese, tin, and zinc in the GI tract.|
01676|009|B||
01676|010|E|CLINICAL EFFECTS:  Simultaneous administration of calcium, manganese, or|
01676|011|E|zinc may decrease the absorption of orally administered iron.  Iron may|
01676|012|E|decrease the absorption of zinc.|
01676|013|B||
01676|014|P|PREDISPOSING FACTORS:  The interaction with some combinations may be|
01676|015|P|affected by the presence or absence of food.|
01676|016|B||
01676|017|M|PATIENT MANAGEMENT:  Iron supplements should not be taken within 1 hour|
01676|018|M|before or 2 hours after calcium, manganese, or zinc.(1-X)|
01676|019|B||
01676|020|D|DISCUSSION:  In a study in 61 healthy subjects, calcium citrate, calcium|
01676|021|D|carbonate, and calcium phosphate inhibited iron absorption when taken with|
01676|022|D|food.  However, in the fasted state, calcium carbonate had no effect on iron|
01676|023|D|absorption.  In the fasted state, calcium citrate and calcium phosphate|
01676|024|D|decreased iron absorption by 49% and 62%, respectively,(2)|
01676|025|D|   In a study in 23 healthy subjects, calcium acetate and calcium carbonate|
01676|026|D|decreased the area-under-curve (AUC) of elemental iron (65 mg) by 27% and|
01676|027|D|19%, respectively.(3)|
01676|028|D|   In a study, manganese decreased iron absorption.  A ratio of 5:1 of|
01676|029|D|zinc:iron decreased iron absorption by 56%.(4)|
01676|030|D|   In a study, inorganic iron decreased zinc absorption.(5)|
01676|031|D|   In another study, ferrous sulfate decreased the absorption of zinc|
01676|032|D|sulfate in a concentration dependent manner; however, heme chloride had no|
01676|033|D|effect on zinc sulfate.(6)|
01676|034|D|   In a study in premature infants, administration of liquid zinc and iron|
01676|035|D|supplements between feedings decreased iron uptake; however, no effect was|
01676|036|D|seen when the supplements were mixed with feedings.(7)|
01676|037|D|   In a study in 680 infants, concurrent zinc and iron was found to decrease|
01676|038|D|the absorption of both agents.(8)|
01676|039|B||
01676|040|R|REFERENCES:|
01676|041|B||
01676|042|R|1.Ferrous gluconate US prescribing information. GFR Nutritionals Ltd|1
01676|043|R|  September 29, 2003.|1
01676|044|R|2.Cook JD, Dassenko SA, Whittaker P. Calcium supplementation: effect on iron|2
01676|045|R|  absorption. Am J Clin Nutr 1991 Jan;53(1):106-11.|2
01676|046|R|3.Pruchnicki MC, Coyle JD, Hoshaw-Woodard S, Bay WH. Effect of phosphate|2
01676|047|R|  binders on supplemental iron absorption in healthy subjects. J Clin|2
01676|048|R|  Pharmacol 2002 Oct;42(10):1171-6.|2
01676|049|R|4.Rossander-Hulten L, Brune M, Sandstrom B, Lonnerdal B, Hallberg L.|2
01676|050|R|  Competitive inhibition of iron absorption by manganese and zinc in humans.|2
01676|051|R|  Am J Clin Nutr 1991 Jul;54(1):152-6.|2
01676|052|R|5.Valberg LS, Flanagan PR, Chamberlain MJ. Effects of iron, tin, and copper|2
01676|053|R|  on zinc absorption in humans. Am J Clin Nutr 1984 Sep;40(3):536-41.|2
01676|054|R|6.Solomons NW, Jacob RA. Studies on the bioavailability of zinc in humans:|2
01676|055|R|  effects of heme and nonheme iron on the absorption of zinc. Am J Clin Nutr|2
01676|056|R|  1981 Apr;34(4):475-82.|2
01676|057|R|7.Friel JK, Serfass RE, Fennessey PV, Miller LV, Andrews WL, Simmons BS,|2
01676|058|R|  Downton GF, Kwa PG. Elevated intakes of zinc in infant formulas do not|2
01676|059|R|  interfere with iron absorption in premature infants. J Pediatr|2
01676|060|R|  Gastroenterol Nutr 1998 Sep;27(3):312-6.|2
01677|001|T|MONOGRAPH TITLE:  Dimercaprol/Iron|
01677|002|B||
01677|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01677|004|L|is contraindicated and generally should not be dispensed or administered to|
01677|005|L|the same patient.|
01677|006|B||
01677|007|A|MECHANISM OF ACTION:  Dimercaprol can complex with iron, forming a chelation|
01677|008|A|compound that is more toxic than iron alone.(1)|
01677|009|B||
01677|010|E|CLINICAL EFFECTS:  Concurrent use of dimercaprol and iron may result in|
01677|011|E|toxicity, especially renal toxicity.(1)|
01677|012|B||
01677|013|P|PREDISPOSING FACTORS:  None determined.|
01677|014|B||
01677|015|M|PATIENT MANAGEMENT:  Medicinal iron should not be administered to patients|
01677|016|M|receiving dimercaprol.(1)|
01677|017|B||
01677|018|D|DISCUSSION:  Because the dimercaprol-iron complex is more toxic than iron|
01677|019|D|alone, especially to the kidneys, medicinal iron should not be administered|
01677|020|D|to patients receiving dimercaprol.(1)|
01677|021|B||
01677|022|R|REFERENCE:|
01677|023|B||
01677|024|R|1.BAL in oil (dimercaprol) US prescribing information. Akorn April, 2007.|1
01678|001|T|MONOGRAPH TITLE:  Buspirone/Diltiazem; Verapamil|
01678|002|B||
01678|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01678|004|L|take action as needed.|
01678|005|B||
01678|006|A|MECHANISM OF ACTION:  Diltiazem and verapamil may inhibit the metabolism of|
01678|007|A|buspirone by CYP3A4.(1)|
01678|008|B||
01678|009|E|CLINICAL EFFECTS:  Concurrent use of diltiazem(1,2) or verapamil(1) may|
01678|010|E|result in increased levels of and effects from buspirone, including|
01678|011|E|lightheadedness, asthenia, dizziness, and somnolence.(3)|
01678|012|B||
01678|013|P|PREDISPOSING FACTORS:  None determined.|
01678|014|B||
01678|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with buspirone|
01678|016|M|and either diltiazem or verapamil should be monitored for adverse effects.|
01678|017|M|The dosage of buspirone may need to be adjusted.(1,2)|
01678|018|B||
01678|019|D|DISCUSSION:  In a randomized, 3-way cross-over study in 9 healthy subjects,|
01678|020|D|concurrent diltiazem (60 mg 3 times daily) and verapamil (80 mg 3 times|
01678|021|D|daily) increased the area-under-curve (AUC) of a single dose of buspirone|
01678|022|D|(10 mg) by 5.5-fold and 3.4-fold, respectively.  Buspirone maximum|
01678|023|D|concentration (Cmax) increased by 4.1-fold and 3.4-fold, respectively.|
01678|024|D|Overall drug effects were increased with concurrent diltiazem and verapamil.|
01678|025|D|(1)|
01678|026|B||
01678|027|R|REFERENCES:|
01678|028|B||
01678|029|R|1.Lamberg TS, Kivisto KT, Neuvonen PJ. Effects of verapamil and diltiazem on|2
01678|030|R|  the pharmacokinetics and pharmacodynamics of buspirone. Clin Pharmacol|2
01678|031|R|  Ther 1998 Jun;63(6):640-5.|2
01678|032|R|2.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
01678|033|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
01678|034|R|3.BuSpar (buspirone hydrochloride) US prescribing information. Bristol Myers|1
01678|035|R|  Squibb Company September, 2007.|1
01679|001|T|MONOGRAPH TITLE:  Saquinavir Mesylate/Tipranavir|
01679|002|B||
01679|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01679|004|L|of severe adverse interaction.|
01679|005|B||
01679|006|A|MECHANISM OF ACTION:  Tipranavir may induce the metabolism of saquinavir|
01679|007|A|mesylate by CYP3A4.(1)|
01679|008|B||
01679|009|E|CLINICAL EFFECTS:  Concurrent use of tipranavir may decrease the levels and|
01679|010|E|effectiveness of saquinavir mesylate.(1)|
01679|011|B||
01679|012|P|PREDISPOSING FACTORS:  None determined.|
01679|013|B||
01679|014|M|PATIENT MANAGEMENT:  The US manufacturers of saquinavir mesylate(1) and|
01679|015|M|tipranavir(2) state that concurrent use is not recommended.|
01679|016|B||
01679|017|D|DISCUSSION:  In a study in 20 HIV-positive patients, concurrent use of|
01679|018|D|tipranavir/ritonavir (500/200 mg twice daily) and saquinavir mesylate/|
01679|019|D|ritonavir (600/100 mg twice daily) decreased the area-under-curve (AUC) and|
01679|020|D|maximum concentration (Cmax) of saquinavir by 76% and 70%, respectively.|
01679|021|D|(1,2)  Saquinavir minimum concentration (Cmin) decreased by 82%.(2)|
01679|022|B||
01679|023|R|REFERENCES:|
01679|024|B||
01679|025|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01679|026|R|  Laboratories, Inc. March, 2019.|1
01679|027|R|2.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01679|028|R|  Pharmaceuticals, Inc. April, 2024.|1
01680|001|T|MONOGRAPH TITLE:  Tretinoin-Mequinol/Selected Photosensitizers|
01680|002|B||
01680|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01680|004|L|is contraindicated and generally should not be dispensed or administered to|
01680|005|L|the same patient.|
01680|006|B||
01680|007|A|MECHANISM OF ACTION:  Tretinoin, anthralin, coal tar and derivatives,|
01680|008|A|fluoroquinolones, griseofulvin, organic staining dyes (such as methylene|
01680|009|A|blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such|
01680|010|A|as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic|
01680|011|A|acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas,|
01680|012|A|tetracyclines, and thiazides are all known photosensitizers.(1)|
01680|013|B||
01680|014|E|CLINICAL EFFECTS:  Concurrent use of tretinoin in patients taking anthralin,|
01680|015|E|coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining|
01680|016|E|dyes (such as methylene blue, rose bengal, or toluidine blue),|
01680|017|E|phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone,|
01680|018|E|naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort,|
01680|019|E|sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the|
01680|020|E|risk of phototoxicity.(1)|
01680|021|B||
01680|022|P|PREDISPOSING FACTORS:  None determined.|
01680|023|B||
01680|024|M|PATIENT MANAGEMENT:  The US manufacturer states that tretinoin-mequinol|
01680|025|M|should not be administered to patients receiving photosensitizers including|
01680|026|M|anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic|
01680|027|M|staining dyes (such as methylene blue, rose bengal, or toluidine blue),|
01680|028|M|phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone,|
01680|029|M|naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort,|
01680|030|M|sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)|
01680|031|B||
01680|032|D|DISCUSSION:  Because of the risk of increased photosensitivity, the US|
01680|033|D|manufacturer states that tretinoin-mequinol should not be administered to|
01680|034|D|patients receiving photosensitizers including anthralin, coal tar and|
01680|035|D|derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as|
01680|036|D|methylene blue, rose bengal, or toluidine blue), methotrexate,|
01680|037|D|phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone,|
01680|038|D|naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides,|
01680|039|D|sulfonylureas, tetracyclines, and thiazides.(1)|
01680|040|B||
01680|041|R|REFERENCE:|
01680|042|B||
01680|043|R|1.Solage (tretinoin-mequinol) US prescribing information. Barrier|1
01680|044|R|  Therapeutics, Inc. April, 2007.|1
01681|001|T|MONOGRAPH TITLE:  Serotonin Reuptake Inhibitors/Linezolid|
01681|002|B||
01681|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01681|004|L|of severe adverse interaction.|
01681|005|B||
01681|006|A|MECHANISM OF ACTION:  Serotonin reuptake inhibitors and linezolid, which|
01681|007|A|inhibits MAO, may act synergistically to increase central nervous system|
01681|008|A|(CNS) serotonin concentrations, leading to toxicity.|
01681|009|B||
01681|010|E|CLINICAL EFFECTS:  Concurrent use or switching between agents without a|
01681|011|E|sufficient washout period may result in serotonin syndrome.  Symptoms of|
01681|012|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
01681|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2)|
01681|014|E|Serotonin syndrome may result in death.|
01681|015|B||
01681|016|P|PREDISPOSING FACTORS:  High doses of serotonin reuptake inhibitors or|
01681|017|P|concurrent use of multiple drugs which increase CNS serotonin levels may|
01681|018|P|increase risk for serotonin syndrome.|
01681|019|B||
01681|020|M|PATIENT MANAGEMENT:  If linezolid is required for urgent or life threatening|
01681|021|M|treatment, the FDA states the interacting serotonergic drug should be|
01681|022|M|stopped.  Although discontinued, serotonin toxicity due to the interaction|
01681|023|M|is still possible. Patients should be monitored for CNS serotonin toxicity|
01681|024|M|for two weeks (five weeks if fluoxetine, 3 weeks if vortioxetine, 7 days if|
01681|025|M|desvenlafaxine or venlafaxine, or 5 days if duloxetine was taken) or until|
01681|026|M|24 hours after the last linezolid dose, whichever comes first.  Therapy with|
01681|027|M|the SSRI may be resumed 24 hours after the last dose of linezolid.(1,3-13)|
01681|028|B||
01681|029|D|DISCUSSION:  Serotonin syndrome has been reported in four patients receiving|
01681|030|D|concurrent citalopram and linezolid, in a patient in whom linezolid was|
01681|031|D|initiated 18 days after fluoxetine discontinuation, in a patient receiving|
01681|032|D|concurrent linezolid and fluoxetine, in a patient in whom linezolid was|
01681|033|D|initiated three days after the discontinuation of paroxetine, in three|
01681|034|D|patients receiving concurrent linezolid and sertraline, and in a patient|
01681|035|D|receiving concurrent linezolid and venlafaxine.|
01681|036|D|   Many authors state that linezolid is a weak MAOI and rarely causes|
01681|037|D|serotonin toxicity.  Cases of serotonin toxicity were rapidly reversible|
01681|038|D|with discontinuation of the offending agent(s) and supportive care.  Some|
01681|039|D|authors suggest that use of serotonergic medications should not preclude the|
01681|040|D|use of linezolid but that the clinical situation should be assessed.  If|
01681|041|D|concurrent use or use of linezolid without a washout is warranted, the|
01681|042|D|patient should be closely monitored.(24-29)|
01681|043|B||
01681|044|R|REFERENCES:|
01681|045|B||
01681|046|R|1.USFood and Drug Administration. FDA Drug Safety Communication: Serious CNS|1
01681|047|R|  reactions possible when linezolid (Zyvox) is given to patients taking|1
01681|048|R|  certain psychiatric medications. available at:|1
01681|049|R|  http://wayback.archive-it.org/7993/20170722185915/https://www.fda.gov/Drug|1
01681|050|R|  s/DrugSafety/ucm265305.htm July 26, 2011.|1
01681|051|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01681|052|R|  352(11):1112-20.|6
01681|053|R|3.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
01681|054|R|  Laboratories Inc. August, 2023.|1
01681|055|R|4.Priligy (dapoxetine hydrochloride) Australian prescribing information.|1
01681|056|R|  Ortho-McNeil Pharmaceutical March 19, 2013.|1
01681|057|R|5.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
01681|058|R|  and Company September, 2021.|1
01681|059|R|6.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
01681|060|R|  Pharmaceuticals Inc. May, 2023.|1
01681|061|R|7.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
01681|062|R|  Pharmaceuticals, Inc. August, 2023.|1
01681|063|R|8.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
01681|064|R|  and Company August, 2023.|1
01681|065|R|9.Serzone (nefazodone hydrochloride) US prescribing information.|1
01681|066|R|  Bristol-Myers Squibb Company January, 2005.|1
01681|067|R|10.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
01681|068|R|   Therapeutics, LLC September, 2021.|1
01681|069|R|11.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
01681|070|R|12.Effexor XR (venlafaxine hydrochloride) US prescribing information.|1
01681|071|R|   Viatris August, 2023.|1
01681|072|R|13.Trintellix (vortioxetine) US prescribing information. Takeda|1
01681|073|R|   Pharmaceuticals America, Inc. November, 2020.|1
01681|074|R|14.Bernard L, Stern R, Lew D, Hoffmeyer P. Serotonin syndrome after|3
01681|075|R|   concomitant treatment with linezolid and citalopram. Clin Infect Dis 2003|3
01681|076|R|   May 1;36(9):1197.|3
01681|077|R|15.Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis|3
01681|078|R|   2002 Jun 15;34(12):1651-2.|3
01681|079|R|16.Hachem RY, Hicks K, Huen A, Raad I. Myelosuppression and serotonin|3
01681|080|R|   syndrome associated with concurrent use of linezolid and selective|3
01681|081|R|   serotonin reuptake inhibitors in bone marrow transplant recipients. Clin|3
01681|082|R|   Infect Dis 2003 Jul 1;37(1):e8-11.|3
01681|083|R|17.Tahir N. Serotonin syndrome as a consequence of drug-resistant|3
01681|084|R|   infections: an interaction between linezolid and citalopram. J Am Med Dir|3
01681|085|R|   Assoc 2004 Mar-Apr;5(2):111-3.|3
01681|086|R|18.Bergeron L, Boule M, Perreault S. Serotonin toxicity associated with|3
01681|087|R|   concomitant use of linezolid. Ann Pharmacother 2005 May;39(5):956-61.|3
01681|088|R|19.Thomas CR, Rosenberg M, Blythe V, Meyer WJ 3rd. Serotonin syndrome and|3
01681|089|R|   linezolid. J Am Acad Child Adolesc Psychiatry 2004 Jul;43(7):790.|3
01681|090|R|20.Morales N, Vermette H. Serotonin syndrome associated with linezolid|3
01681|091|R|   treatment after discontinuation of fluoxetine. Psychosomatics 2005|3
01681|092|R|   May-Jun;46(3):274-5.|3
01681|093|R|21.Lavery S, Ravi H, McDaniel WW, Pushkin YR. Linezolid and serotonin|3
01681|094|R|   syndrome. Psychosomatics 2001 Sep-Oct;42(5):432-4.|3
01681|095|R|22.Jones SL, Athan E, O'Brien D. Serotonin syndrome due to co-administration|3
01681|096|R|   of linezolid and venlafaxine. J Antimicrob Chemother 2004 Jul;|3
01681|097|R|   54(1):289-90.|3
01681|098|R|23.Clark DB, Andrus MR, Byrd DC. Drug interactions between linezolid and|3
01681|099|R|   selective serotonin reuptake inhibitors: case report involving sertraline|3
01681|100|R|   and review of the literature. Pharmacotherapy 2006 Feb;26(2):269-76.|3
01681|101|R|24.Lodise TP, Patel N, Rivera A, Tristani L, Lazariu V, Vandewall H, McNutt|2
01681|102|R|   LA. Comparative evaluation of serotonin toxicity among veterans affairs|2
01681|103|R|   patients  receiving linezolid and vancomycin. Antimicrob Agents Chemother|2
01681|104|R|   2013 Dec;57(12):5901-11.|2
01681|105|R|25.Ramsey TD, Lau TT, Ensom MH. Serotonergic and adrenergic drug|6
01681|106|R|   interactions associated with linezolid: a critical  review and practical|6
01681|107|R|   management approach. Ann Pharmacother 2013 Apr;47(4):543-60.|6
01681|108|R|26.Woytowish MR, Maynor LM. Clinical relevance of linezolid-associated|6
01681|109|R|   serotonin toxicity. Ann Pharmacother 2013 Mar;47(3):388-97.|6
01681|110|R|27.Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, Lodise TP.|2
01681|111|R|   Comparison of serotonin toxicity with concomitant use of either linezolid|2
01681|112|R|   or  comparators and serotonergic agents: an analysis of Phase III and IV|2
01681|113|R|   randomized  clinical trial data. J Antimicrob Chemother 2012 Feb;|2
01681|114|R|   67(2):494-502.|2
01681|115|R|28.Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion|6
01681|116|R|   J Clin Psychiatry 2009;11(6):353-6.|6
01681|117|R|29.Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug|2
01681|118|R|   interactions: a retrospective survey. Clin Infect Dis 2006 Jul 15;|2
01681|119|R|   43(2):180-7.|2
01682|001|T|MONOGRAPH TITLE:  Maraviroc/Selected Protease Inhibitors|
01682|002|B||
01682|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01682|004|L|of severe adverse interaction.|
01682|005|B||
01682|006|A|MECHANISM OF ACTION:  Some protease inhibitors may inhibit the metabolism of|
01682|007|A|maraviroc by CYP3A4.(1)|
01682|008|B||
01682|009|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors without a dosage|
01682|010|E|adjustment of maraviroc may result in elevated levels of and toxicity from|
01682|011|E|maraviroc.(1-3)|
01682|012|B||
01682|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01682|014|P|renal and/or hepatic impairment.(1)|
01682|015|B||
01682|016|M|PATIENT MANAGEMENT:  The US manufacturer of maraviroc states that adult|
01682|017|M|patients receiving concurrent therapy with strong inhibitors of CYP3A4 such|
01682|018|M|as protease inhibitors (except for tipranavir/ritonavir) should receive a|
01682|019|M|dose of 150 mg maraviroc twice daily.  This is the recommended dose in|
01682|020|M|patients receiving strong CYP3A4 inhibitors regardless of whether or not the|
01682|021|M|patient is also receiving a strong inducer of CYP3A4.(1)|
01682|022|M|   In adults, maraviroc should not be used with a potent CYP3A4 inhibitor in|
01682|023|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
01682|024|M|disease.  Patients with hepatic impairment should be closely monitored for|
01682|025|M|maraviroc-related side effects.(1)|
01682|026|M|   In adults, patients receiving tipranavir/ritonavir should receive 300 mg|
01682|027|M|maraviroc twice daily.(1)|
01682|028|M|   In pediatric patients aged 2 years and older weighing at least 10 kg,|
01682|029|M|patients receiving concurrent therapy with strong inhibitors of CYP3A4 such|
01682|030|M|as protease inhibitors (except for tipranavir/ritonavir) regardless of|
01682|031|M|whether or not the patient is also receiving a strong inducer of CYP3A4|
01682|032|M|should receive the following maraviroc dose based on tablet or oral solution|
01682|033|M|(20 mg/ml):|
01682|034|M|- 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily|
01682|035|M|- 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily|
01682|036|M|- 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily|
01682|037|M|- >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily|
01682|038|M|   In pediatric patients aged 2 years and older weighing at least 10 kg, no|
01682|039|M|dose recommendations are available with mild to moderate renal impairment.|
01682|040|M|Maraviroc is contraindicated in pediatric patients with severe renal|
01682|041|M|impairment or end-stage renal disease who are on concurrent therapy with|
01682|042|M|strong CYP3A4 inhibitors.(1)|
01682|043|B||
01682|044|D|DISCUSSION:  In a study in 12 subjects, concurrent atazanavir (400 mg daily)|
01682|045|D|increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by|
01682|046|D|4.19-fold, 3.57-fold, and 2.09-fold, respectively.(1)|
01682|047|D|   In a study in 12 subjects, concurrent atazanavir/ritonavir (300/100 mg|
01682|048|D|twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice|
01682|049|D|daily) by 6.67-fold, 4.88-fold, and 2.67-fold, respectively.(1)|
01682|050|D|   In a study in 12 subjects, concurrent darunavir/ritonavir (600/100 mg|
01682|051|D|twice daily) increased the Cmin, AUC, and Cmax of maraviroc (150 mg twice|
01682|052|D|daily) by 8.00-fold, 4.05-fold, and 2.29-fold, respectively.(1)|
01682|053|D|   In a study in 10 subjects, concurrent darunavir/ritonavir (600/100 mg|
01682|054|D|twice daily) and etravirine (200 mg twice daily) increased the Cmin, AUC,|
01682|055|D|and Cmax of maraviroc (150 mg twice daily) by 5.27-fold, 3.10-fold,|
01682|056|D|1.77-fold, respectively.(1)|
01682|057|D|   In a study in 12 subjects, concurrent ketoconazole (400 mg daily)|
01682|058|D|increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by|
01682|059|D|3.75-fold, 5.00-fold, and 3.38-fold, respectively.(1)|
01682|060|D|   In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg|
01682|061|D|twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice|
01682|062|D|daily) by 9.24-fold, 3.95-fold, and 1.97-fold, respectively.(1)|
01682|063|D|   In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg|
01682|064|D|twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax|
01682|065|D|of maraviroc (300 mg twice daily) by 6.29-fold, 2.53-fold, 1.25-fold,|
01682|066|D|respectively.(1)|
01682|067|D|   In a study in 8 subjects, concurrent ritonavir (100 mg twice daily)|
01682|068|D|increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by|
01682|069|D|4.55-fold, 2.61-fold, and 1.28-fold, respectively.(1)|
01682|070|D|   In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg|
01682|071|D|twice daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice|
01682|072|D|daily) by 11.3-fold, 9.77-fold, 4.78-fold, respectively.(1)|
01682|073|D|   In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg|
01682|074|D|twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax,|
01682|075|D|of maraviroc (100 mg twice daily) by 8.42-fold, 5.00-fold, and 2.26-fold,|
01682|076|D|respectively.(1)|
01682|077|D|   In a study in 12 subjects, concurrent tipranavir/ritonavir (500/200 mg|
01682|078|D|twice daily) increased the Cmin and AUC of maraviroc (150 mg twice daily) by|
01682|079|D|80% and 2%, respectively.  The Cmax of maraviroc decreased by 14%.(1)|
01682|080|D|   Selected protease inhibitors include: amprenavir, atazanavir, darunavir,|
01682|081|D|fosamprenavir, indinavir, lopinavir, nelfinavir, nirmatrelvir/ritonavir,|
01682|082|D|ritonavir, saquinavir, and tipranavir.|
01682|083|B||
01682|084|R|REFERENCES:|
01682|085|B||
01682|086|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. October,|1
01682|087|R|  2020.|1
01682|088|R|2.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01682|089|R|  Laboratories December, 2019.|1
01682|090|R|3.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01682|091|R|  December, 2019.|1
01683|001|T|MONOGRAPH TITLE:  Maraviroc/Strong CYP3A4 Inhibitors|
01683|002|B||
01683|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01683|004|L|of severe adverse interaction.|
01683|005|B||
01683|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
01683|007|A|of maraviroc.(1)|
01683|008|B||
01683|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 without a|
01683|010|E|dosage adjustment of maraviroc may result in elevated levels of and toxicity|
01683|011|E|from maraviroc. (1)|
01683|012|B||
01683|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01683|014|P|renal and/or hepatic impairment.(1)|
01683|015|B||
01683|016|M|PATIENT MANAGEMENT:  The US manufacturer of maraviroc states that adult|
01683|017|M|patients receiving concurrent therapy with strong inhibitors of CYP3A4|
01683|018|M|should receive a dose of 150 mg maraviroc twice daily.  This is the|
01683|019|M|recommended dose in patients receiving strong CYP3A4 inhibitors regardless|
01683|020|M|of whether or not the patient is also receiving a strong inducer of|
01683|021|M|CYP3A4.(1)|
01683|022|M|   In adults, maraviroc should not be used with a strong CYP3A4 inhibitor in|
01683|023|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
01683|024|M|disease.(1)|
01683|025|M|   Adult patients with hepatic impairment should be closely monitored for|
01683|026|M|maraviroc-related side effects.(1)|
01683|027|M|   In pediatric patients aged 2 years and older weighing at least 10 kg,|
01683|028|M|patients receiving concurrent therapy with strong inhibitors of CYP3A4|
01683|029|M|should receive the following maraviroc dose based on tablet or oral solution|
01683|030|M|(20 mg/ml):|
01683|031|M|- 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily|
01683|032|M|- 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily|
01683|033|M|- 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily|
01683|034|M|- >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily|
01683|035|M|   In pediatric patients aged 2 years and older weighing at least 10 kg, no|
01683|036|M|dose recommendations are available with mild to moderate renal impairment.|
01683|037|M|Maraviroc is contraindicated in pediatric patients with severe renal|
01683|038|M|impairment or end-stage renal disease who are on concurrent therapy with|
01683|039|M|strong CYP3A4 inhibitors.(1)|
01683|040|M|   NIH guidelines recommend a dose reduction of 150 mg maraviroc twice daily|
01683|041|M|with itraconazole and posaconazole.  Dose reduction should also be|
01683|042|M|considered with concurrent isavuconazole and voriconazole.(2)|
01683|043|B||
01683|044|D|DISCUSSION:  In a study in 12 subjects, concurrent atazanavir (400 mg daily)|
01683|045|D|increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by|
01683|046|D|4.19-fold, 3.57-fold, and 2.09-fold, respectively.(1)|
01683|047|D|   In a study in 12 subjects, concurrent atazanavir/ritonavir (300/100 mg|
01683|048|D|twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice|
01683|049|D|daily) by 6.67-fold, 4.88-fold, and 2.67-fold, respectively.(1)|
01683|050|D|   In a study in 12 subjects, concurrent darunavir/ritonavir (600/100 mg|
01683|051|D|twice daily) increased the Cmin, AUC, and Cmax of maraviroc (150 mg twice|
01683|052|D|daily) by 8.00-fold, 4.05-fold, and 2.29-fold, respectively.(1)|
01683|053|D|   In a study in 10 subjects, concurrent darunavir/ritonavir (600/100 mg|
01683|054|D|twice daily) and etravirine (200 mg twice daily) increased the Cmin, AUC,|
01683|055|D|and Cmax of maraviroc (150 mg twice daily) by 5.27-fold, 3.10-fold,|
01683|056|D|1.77-fold, respectively.(1)|
01683|057|D|   In a study in 12 subjects, concurrent ketoconazole (400 mg daily)|
01683|058|D|increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by|
01683|059|D|3.75-fold, 5.00-fold, and 3.38-fold, respectively.(1)|
01683|060|D|   In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg|
01683|061|D|twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice|
01683|062|D|daily) by 9.24-fold, 3.95-fold, and 1.97-fold, respectively.(1)|
01683|063|D|   In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg|
01683|064|D|twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax|
01683|065|D|of maraviroc (300 mg twice daily) by 6.29-fold, 2.53-fold, 1.25-fold,|
01683|066|D|respectively.(1)|
01683|067|D|   In a study in 8 subjects, concurrent ritonavir (100 mg twice daily)|
01683|068|D|increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by|
01683|069|D|4.55-fold, 2.61-fold, and 1.28-fold, respectively.(1)|
01683|070|D|   In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg|
01683|071|D|twice daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice|
01683|072|D|daily) by 11.3-fold, 9.77-fold, 4.78-fold, respectively.(1)|
01683|073|D|   In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg|
01683|074|D|twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax,|
01683|075|D|of maraviroc (100 mg twice daily) by 8.42-fold, 5.00-fold, and 2.26-fold,|
01683|076|D|respectively.(1)|
01683|077|D|   In a study in 12 subjects, concurrent tipranavir/ritonavir (500/200 mg|
01683|078|D|twice daily) increased the Cmin and AUC of maraviroc (150 mg twice daily) by|
01683|079|D|80% and 2%, respectively.  The Cmax of maraviroc decreased by 14%.(1)|
01683|080|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
01683|081|D|clarithromycin, cobicistat, delavirdine, idelalisib, isavuconazonium,|
01683|082|D|itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone,|
01683|083|D|nefazodone, ribociclib, posaconazole, telaprevir, telithromycin, tucatinib,|
01683|084|D|and voriconazole.(2)|
01683|085|B||
01683|086|R|REFERENCES:|
01683|087|B||
01683|088|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. October,|1
01683|089|R|  2020.|1
01683|090|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01683|091|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01683|092|R|  HIV. Department of Health and Human Services. Available at|6
01683|093|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
01683|094|R|  new-guidelines June 13, 2021.|6
01684|001|T|MONOGRAPH TITLE:  Maraviroc/Clarithromycin; Telithromycin (mono deleted|
01684|002|T|01/11/2012)|
01684|003|B||
01684|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01684|005|L|of severe adverse interaction.|
01684|006|B||
01684|007|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01684|008|A|metabolism of maraviroc by CYP P-450-3A4.(1)|
01684|009|B||
01684|010|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin or telithromycin without|
01684|011|E|a dosage adjustment of maraviroc may result in elevated levels of and|
01684|012|E|toxicity from maraviroc.(1)|
01684|013|B||
01684|014|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01684|015|P|renal and/or hepatic impairment.(1)|
01684|016|B||
01684|017|M|PATIENT MANAGEMENT:  The US manufacturer of maraviroc states that patients|
01684|018|M|receiving concurrent therapy with strong inhibitors of CYP P-450-3A4 such as|
01684|019|M|clarithromycin or telithromycin should receive a dose of 150 mg maraviroc|
01684|020|M|twice daily.  This is the recommended dose in patients receiving strong CYP|
01684|021|M|P-450-3A4 inhibitors regardless of whether or not the patient is also|
01684|022|M|receiving a strong inducer of CYP P-450-3A4.(1)|
01684|023|M|   Maraviroc should not be used with a potent CYP P-450-3A4 inhibitor in|
01684|024|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
01684|025|M|disease.(1)|
01684|026|M|   Patients with hepatic impairment should be closely monitored for|
01684|027|M|maraviroc-related side effects.(1)|
01684|028|B||
01684|029|D|DISCUSSION:  Studies have shown that atazanavir, ketoconazole, lopinavir,|
01684|030|D|ritonavir and saquinavir, all inhibitors of CYP p-450-3A4 inhibit the    ,|
01684|031|D|metabolism of maraviroc.  Increases in maraviroc area-under-curve (AUC)|
01684|032|D|ranged from 2.53-fold to 9.77-fold.  Clarithromycin and telithromycin are|
01684|033|D|expected to have similar effects.(1)|
01684|034|B||
01684|035|R|REFERENCE:|
01684|036|B||
01684|037|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. May, 2010.|1
01685|001|T|MONOGRAPH TITLE:  Maraviroc/Strong CYP3A4 Inducers|
01685|002|B||
01685|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01685|004|L|of severe adverse interaction.|
01685|005|B||
01685|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolism of|
01685|007|A|maraviroc.(1)|
01685|008|B||
01685|009|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 in the|
01685|010|E|absence of an inhibitor of CYP3A4 and without a dosage adjustment of|
01685|011|E|maraviroc may result in decreased levels and effectiveness of maraviroc.(1)|
01685|012|B||
01685|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01685|014|P|renal impairment.(1)|
01685|015|P|   Induction effects may be more likely with regular use of the inducer for|
01685|016|P|longer than 1-2 weeks.|
01685|017|B||
01685|018|M|PATIENT MANAGEMENT:  The US manufacturer of maraviroc states that adult|
01685|019|M|patients receiving therapy with inducers of CYP3A4 who are not also|
01685|020|M|receiving an inhibitor of CYP3A4 should receive a dose of 600 mg maraviroc|
01685|021|M|twice daily.(1)|
01685|022|M|   The US manufacturer of maraviroc states that adult patients receiving|
01685|023|M|therapy with inducers of CYP3A4 who are also receiving a strong inhibitor of|
01685|024|M|CYP3A4 should receive a dose of 150 mg maraviroc twice daily.(1)|
01685|025|M|   In adults, maraviroc should not be used with a strong CYP3A4 inducer in|
01685|026|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
01685|027|M|disease.(1)|
01685|028|M|   In children aged 2 years and older weighing at least 10 kg, patients|
01685|029|M|receiving therapy with strong CYP3A4 inducers who are not also receiving an|
01685|030|M|inhibitor of CYP3A4 is not recommended.(1)|
01685|031|M|   In children aged 2 years and older weighing at least 10 kg, patients|
01685|032|M|receiving therapy with a strong CYP3A4 inducer and a strong CYP3A4 inhibitor|
01685|033|M|should receive the following maraviroc dose based on tablet or oral solution|
01685|034|M|(20 mg/ml):|
01685|035|M|- 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily|
01685|036|M|- 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily|
01685|037|M|- 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily|
01685|038|M|- >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily|
01685|039|M|   In pediatric patients aged 2 years and older weighing at least 10 kg, no|
01685|040|M|dose recommendations are available with mild to moderate renal impairment.|
01685|041|M|Maraviroc is contraindicated in pediatric patients with severe renal|
01685|042|M|impairment or end-stage renal disease who are on concurrent therapy with|
01685|043|M|strong CYP3A4 inhibitors.(1)|
01685|044|B||
01685|045|D|DISCUSSION:  In a study in 12 subjects, concurrent efavirenz (600 mg daily)|
01685|046|D|decreased the minimum concentration (Cmin), area-under-curve (AUC), and|
01685|047|D|maximum concentration (Cmax) of maraviroc (100 mg twice daily) by 45%,|
01685|048|D|44.8%, and 51.4%, respectively.(1)|
01685|049|D|   In a study in 12 subjects, concurrent efavirenz (600 mg daily) increased|
01685|050|D|the Cmin, AUC, and Cmax of maraviroc (200 mg twice daily) by 9%, 15%, and|
01685|051|D|16%, respectively, when compared to the administration of maraviroc (100 mg|
01685|052|D|twice daily) alone.(1)|
01685|053|D|   In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased|
01685|054|D|the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 78%, 63%, and|
01685|055|D|66%, respectively.(1)|
01685|056|D|   In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased|
01685|057|D|the Cmin and Cmax of maraviroc (200 mg twice daily) by 34% and 4%,|
01685|058|D|respectively, when compared to the administration of maraviroc (100 mg twice|
01685|059|D|daily) alone.  The AUC of maraviroc increased by 3%.(1)|
01685|060|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
01685|061|D|barbiturates, carbamazepine, efavirenz, encorafenib, enzalutamide,|
01685|062|D|fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital,|
01685|063|D|phenytoin, primidone, rifampin, and rifapentine.|
01685|064|B||
01685|065|R|REFERENCE:|
01685|066|B||
01685|067|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. October,|1
01685|068|R|  2020.|1
01686|001|T|MONOGRAPH TITLE:  Maraviroc/Rifampin (mono deleted 01/11/2012)|
01686|002|B||
01686|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01686|004|L|of severe adverse interaction.|
01686|005|B||
01686|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of maraviroc by CYP|
01686|007|A|P-450-3A4.(1)|
01686|008|B||
01686|009|E|CLINICAL EFFECTS:  Concurrent use of rifampin in the absence of an inhibitor|
01686|010|E|of CYP P-450-3A4 and without a dosage adjustment of maraviroc may result in|
01686|011|E|decreased levels and effectiveness of maraviroc.(1)|
01686|012|B||
01686|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01686|014|P|renal impairment.(3)|
01686|015|B||
01686|016|M|PATIENT MANAGEMENT:  The US manufacturer of maraviroc states that patients|
01686|017|M|receiving therapy with inducers of CYP P-450-3A4, such as rifampin, who are|
01686|018|M|not also receiving an inhibitor of CYP P-450-3A4 should receive a dose of|
01686|019|M|600 mg maraviroc twice daily.|
01686|020|M|   The US manufacturer of maraviroc states that patients receiving therapy|
01686|021|M|with inducers of CYP P-450-3A4, such as rifampin, who are also receiving a|
01686|022|M|strong inhibitor of CYP P-450-3A4 such as clarithromycin, delavirdine,|
01686|023|M|itraconazole, ketoconazole, nefazodone, protease inhibitors (except for|
01686|024|M|tipranavir/ritonavir), or telithromycin should receive a dose of 150 mg|
01686|025|M|maraviroc twice daily.(1)|
01686|026|M|   Maraviroc should not be used with a potent CYP P-450-3A4 inducer in|
01686|027|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
01686|028|M|disease.(1)|
01686|029|B||
01686|030|D|DISCUSSION:  In a study in 12 subjects, concurrent rifampin (600 mg daily)|
01686|031|D|decreased the minimum concentration (Cmin), area-under-curve (AUC), and|
01686|032|D|maximum concentration (Cmax) of maraviroc (100 mg twice daily) by 78%,|
01686|033|D|63.2%, and 66.3%, respectively.(1)|
01686|034|D|   In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg|
01686|035|D|twice daily, and inhibitor of CYP P-450-3A4) and efavirenz (600 mg daily, an|
01686|036|D|inducer of CYP P-450-3A4) increased the Cmin, AUC, and Cmax of maraviroc|
01686|037|D|9300 mg twice daily) by 6.39-fold, 2.53-fold, 1.25-fold, respectively.(1)|
01686|038|D|   In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg|
01686|039|D|twice daily, an inhibitor of CYP P-450-3A4) and efavirenz (600 mg daily)|
01686|040|D|increased the Cmin, AUC, and Cmax, of maraviroc (100 mg twice daily) by|
01686|041|D|8.42-fold, 5.00-fold, and 2.26-fold, respectively.(1)|
01686|042|B||
01686|043|R|REFERENCE:|
01686|044|B||
01686|045|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. May, 2010.|1
01687|001|T|MONOGRAPH TITLE:  Maraviroc/Selected Anticonvulsants (mono deleted|
01687|002|T|01/11/2012)|
01687|003|B||
01687|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01687|005|L|of severe adverse interaction.|
01687|006|B||
01687|007|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital, and phenytoin may induce|
01687|008|A|the metabolism of maraviroc by CYP P-450-3A4.(1)|
01687|009|B||
01687|010|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, phenobarbital, or|
01687|011|E|phenytoin in the absence of an inhibitor of CYP P-450-3A4 and without a|
01687|012|E|dosage adjustment of maraviroc may result in decreased levels and|
01687|013|E|effectiveness of maraviroc.(1)|
01687|014|B||
01687|015|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01687|016|P|renal impairment.(1)|
01687|017|B||
01687|018|M|PATIENT MANAGEMENT:  The US manufacturer of maraviroc states that patients|
01687|019|M|receiving therapy with inducers of CYP P-450-3A4, such as carbamazepine,|
01687|020|M|phenobarbital, or phenytoin who are not also receiving an inhibitor of CYP|
01687|021|M|P-450-3A4 should receive a dose of 600 mg maraviroc twice daily.(1)|
01687|022|M|   The US manufacturer of maraviroc states that patients receiving therapy|
01687|023|M|with inducers of CYP P-450-3A4, such as carbamazepine, phenobarbital, or|
01687|024|M|phenytoin who are also receiving a strong inhibitor of CYP P-450-3A4 such as|
01687|025|M|clarithromycin, delavirdine, itraconazole, ketoconazole, nefazodone,|
01687|026|M|protease inhibitors (except for tipranavir/ritonavir), or telithromycin|
01687|027|M|should receive a dose of 150 mg maraviroc twice daily.(1)|
01687|028|M|   Maraviroc should not be used with a potent CYP P-450-3A4 inducer in|
01687|029|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
01687|030|M|disease.(1)|
01687|031|B||
01687|032|D|DISCUSSION:  In a study in 12 subjects, concurrent rifampin (600 mg daily,|
01687|033|D|another inducer of CYP P-450-3A4) decreased the minimum concentration|
01687|034|D|(Cmin), area-under-curve (AUC), and maximum concentration (Cmax) of|
01687|035|D|maraviroc (100 mg twice daily) by 78%, 63.2%, and 66.3%, respectively.(1)|
01687|036|D|   In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg|
01687|037|D|twice daily, and inhibitor of CYP P-450-3A4) and efavirenz (600 mg daily, an|
01687|038|D|inducer of CYP P-450-3A4) increased the Cmin, AUC, and Cmax of maraviroc|
01687|039|D|9300 mg twice daily) by 6.39-fold, 2.53-fold, 1.25-fold, respectively.(1)|
01687|040|D|   In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg|
01687|041|D|twice daily, an inhibitor of CYP P-450-3A4) and efavirenz (600 mg daily)|
01687|042|D|increased the Cmin, AUC, and Cmax, of maraviroc (100 mg twice daily) by|
01687|043|D|8.42-fold, 5.00-fold, and 2.26-fold, respectively.(1)|
01687|044|B||
01687|045|R|REFERENCE:|
01687|046|B||
01687|047|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. May, 2010.|1
01688|001|T|MONOGRAPH TITLE:  Maraviroc/Itraconazole; Ketoconazole (mono deleted|
01688|002|T|01/11/2012)|
01688|003|B||
01688|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01688|005|L|of severe adverse interaction.|
01688|006|B||
01688|007|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
01688|008|A|metabolism of maraviroc by CYP P-450-3A4.(1)|
01688|009|B||
01688|010|E|CLINICAL EFFECTS:  Concurrent use of itraconazole or ketoconazole without a|
01688|011|E|dosage adjustment of maraviroc may result in elevated levels of and toxicity|
01688|012|E|from maraviroc.(1)|
01688|013|B||
01688|014|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01688|015|P|renal and/or hepatic impairment.(1)|
01688|016|B||
01688|017|M|PATIENT MANAGEMENT:  The US manufacturer of maraviroc states that patients|
01688|018|M|receiving concurrent therapy with strong inhibitors of CYP P-450-3A4 such as|
01688|019|M|itraconazole or ketoconazole should receive a dose of 150 mg maraviroc twice|
01688|020|M|daily.  This is the recommended dose in patients receiving strong CYP|
01688|021|M|P-450-3A4 inhibitors regardless of whether or not the patient is also|
01688|022|M|receiving a strong inducer of CYP P-450-3A4.(1)|
01688|023|M|   Maraviroc should not be used with a potent CYP P-450-3A4 inhibitor in|
01688|024|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
01688|025|M|disease.(1)|
01688|026|M|   Patients with hepatic impairment should be closely monitored for|
01688|027|M|maraviroc-related side effects.(1)|
01688|028|B||
01688|029|D|DISCUSSION:  In a study in 12 subjects, concurrent ketoconazole (400 mg|
01688|030|D|daily) increased the minimum concentration (Cmin), area-under-curve (AUC),|
01688|031|D|and maximum concentration (Cmax) of maraviroc (100 mg twice daily) by|
01688|032|D|3.75-fold, 5.00-fold, and 3.38-fold, respectively.(1)|
01688|033|B||
01688|034|R|REFERENCE:|
01688|035|B||
01688|036|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. May, 2010.|1
01689|001|T|MONOGRAPH TITLE:  Maraviroc/St. John's Wort|
01689|002|B||
01689|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01689|004|L|is contraindicated and generally should not be dispensed or administered to|
01689|005|L|the same patient.|
01689|006|B||
01689|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of maraviroc|
01689|008|A|by CYP3A4.(1)|
01689|009|B||
01689|010|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
01689|011|E|levels of, effectiveness of, and resistance to maraviroc.(1)|
01689|012|B||
01689|013|P|PREDISPOSING FACTORS:  None determined.|
01689|014|B||
01689|015|M|PATIENT MANAGEMENT:  The US manufacturer of maraviroc states that patients|
01689|016|M|receiving maraviroc should not use St. John's wort.(1)|
01689|017|B||
01689|018|D|DISCUSSION:  Concurrent use of St. John's wort is expected to substantially|
01689|019|D|decrease maraviroc levels.(1)|
01689|020|B||
01689|021|R|REFERENCE:|
01689|022|B||
01689|023|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. October,|1
01689|024|R|  2020.|1
01690|001|T|MONOGRAPH TITLE:  Maraviroc/Nefazodone (mono deleted 01/11/2012)|
01690|002|B||
01690|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01690|004|L|of severe adverse interaction.|
01690|005|B||
01690|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of maraviroc by|
01690|007|A|CYP P-450-3A4.(1)|
01690|008|B||
01690|009|E|CLINICAL EFFECTS:  Concurrent use of nefazodone without a dosage adjustment|
01690|010|E|of maraviroc may result in elevated levels of and toxicity from maraviroc.|
01690|011|E|(1)|
01690|012|B||
01690|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01690|014|P|renal and/or hepatic impairment.(1)|
01690|015|B||
01690|016|M|PATIENT MANAGEMENT:  The US manufacturer of maraviroc states that patients|
01690|017|M|receiving concurrent therapy with strong inhibitors of CYP P-450-3A4 such as|
01690|018|M|nefazodone should receive a dose of 150 mg maraviroc twice daily.  This is|
01690|019|M|the recommended dose in patients receiving strong CYP P-450-3A4 inhibitors|
01690|020|M|regardless of whether or not the patient is also receiving a strong inducer|
01690|021|M|inducer of CYP P-450-3A4.(1)|
01690|022|M|   Maraviroc should not be used with a potent CYP P-450-3A4 inhibitor in|
01690|023|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
01690|024|M|disease.(1)|
01690|025|M|   Patients with hepatic impairment should be closely monitored for|
01690|026|M|maraviroc-related side effects.(1)|
01690|027|B||
01690|028|D|DISCUSSION:  Studies have shown that atazanavir, ketoconazole, lopinavir,|
01690|029|D|ritonavir and saquinavir, all inhibitors of CYP p-450-3A4 inhibit the|
01690|030|D|metabolism of maraviroc.  Increases in maraviroc area-under-curve (AUC)|
01690|031|D|ranged from 2.53-fold to 9.77-fold.  Nefazodone is expected to have similar|
01690|032|D|effects.(1)|
01690|033|B||
01690|034|R|REFERENCE:|
01690|035|B||
01690|036|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. May, 2010.|1
01691|001|T|MONOGRAPH TITLE:  Live BCG/Selected Antimycobacterials|
01691|002|B||
01691|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01691|004|L|of severe adverse interaction.|
01691|005|B||
01691|006|A|MECHANISM OF ACTION:  Bacillus Calmette-Guerin (BCG) is a live, attenuated|
01691|007|A|strain of Mycobacterium bovis (M.bovis) used to induce a granulomatous|
01691|008|A|response in the treatment of localized bladder cancer and as a vaccine to|
01691|009|A|prevent tuberculosis.(1-2)|
01691|010|A|   Co-treatment with antibacterial agents active against M.bovis may lead to|
01691|011|A|an attenuation of the immune response associated with BCG|
01691|012|A|administration.(1-2)|
01691|013|B||
01691|014|E|CLINICAL EFFECTS:  The effectiveness of chemotherapy may be impaired, or the|
01691|015|E|vaccine may be ineffective.|
01691|016|E|   Agents linked to this monograph may have activity against M.bovis:|
01691|017|E|amikacin, capreomycin, ciprofloxacin, clofazimine, cycloserine, ethambutol,|
01691|018|E|ethionamide, gatifloxacin, isoniazid, kanamycin, levofloxacin, moxifloxacin,|
01691|019|E|ofloxacin, rifabutin, rifampin, rifapentine, and streptomycin.|
01691|020|B||
01691|021|P|PREDISPOSING FACTORS:  None determined.|
01691|022|B||
01691|023|M|PATIENT MANAGEMENT:  Intravesical instillation of BCG should be postponed|
01691|024|M|during treatment with antibacterials which may decrease effectiveness.(2)|
01691|025|M|   Administration of BCG vaccine to patients receiving antibiotic therapy|
01691|026|M|should only be done under close medical supervision.(1)|
01691|027|M|   If a patient develops a systemic BCG infection due to intravesicular or|
01691|028|M|vaccine administration, treatment with multiple antimycobacterial agents may|
01691|029|M|be required.|
01691|030|B||
01691|031|D|DISCUSSION:  Because antibiotic therapy may prevent sufficient|
01691|032|D|vaccine-organism replication to generate an immune response, the|
01691|033|D|manufacturer of BCG vaccine states that administration of BCG vaccine to|
01691|034|D|patients receiving antibiotic therapy should only be done under close|
01691|035|D|medical supervision.(1)|
01691|036|D|   Pyrazinamide is not included in this interaction as BCG is not sensitive|
01691|037|D|to pyrazinamide.(2)|
01691|038|B||
01691|039|R|REFERENCES:|
01691|040|B||
01691|041|R|1.BCG Vaccine US prescribing information. Organon Inc. October, 2006.|1
01691|042|R|2.TICE BCG (BCG live, for intravesical use) prescribing information. Organon|1
01691|043|R|  USA Inc. October, 2010.|1
01692|001|T|MONOGRAPH TITLE:  Rufinamide/Valproate|
01692|002|B||
01692|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01692|004|L|take action as needed.|
01692|005|B||
01692|006|A|MECHANISM OF ACTION:  Valproate decreases the clearance of rufinamide.(1-3)|
01692|007|B||
01692|008|E|CLINICAL EFFECTS:  Concurrent use of valproate may result in elevated levels|
01692|009|E|of and toxicity from rufinamide.(1-3)|
01692|010|B||
01692|011|P|PREDISPOSING FACTORS:  Greater increases in rufinamide concentrations have|
01692|012|P|been observed in patients with body weights less than 30 kg(1,3) and with|
01692|013|P|higher dosages of valproate.(1-3)|
01692|014|B||
01692|015|M|PATIENT MANAGEMENT:  The US manufacturers of rufinamide and valproic acid|
01692|016|M|state that if patients are stabilized on rufinamide, valproate should be|
01692|017|M|initiated at a low dose and titrated to an effective dose.  Patients|
01692|018|M|maintained on valproate should begin rufinamide at a dosage lower than 400|
01692|019|M|mg. Pediatric patients taking valproate should begin rufinamide at a dose|
01692|020|M|lower than 10 mg/kg per day.(2)|
01692|021|M|   The UK manufacturer of rufinamide recommends that in children from 1 year|
01692|022|M|to less than 4 years of age receiving valproate, rufinamide treatment should|
01692|023|M|be initiated at a dose of 10 mg/kg/day and according to clinical response|
01692|024|M|and tolerability, the dose may be increased by up to 10 mg/kg/day every|
01692|025|M|third day to a maximum target dose of 30 mg/kg/day administered in two|
01692|026|M|equally divided doses separated by approximately 12 hours.(1)|
01692|027|M|   The Australian and UK manufacturers of rufinamide recommend that children|
01692|028|M|4 years of age or older and less than 30 kg receiving valproate should|
01692|029|M|initiate rufinamide treatment at a daily dose of 200 mg.  According to|
01692|030|M|clinical response and tolerability, after a minimum of 2 days the dose may|
01692|031|M|be increased by 200 mg/day, to the maximum recommended dose of 600|
01692|032|M|mg/day.(1,3)|
01692|033|M|   The Australian and UK manufacturers of rufinamide recommend that adults,|
01692|034|M|adolescents and children 4 years of age or older and 30 kg or over receiving|
01692|035|M|valproate should initiate rufinamide treatment at a daily dose of 400 mg.|
01692|036|M|According to clinical response and tolerability, the dose may be increased|
01692|037|M|by 400 mg/day increments, as frequently as every other day, up to a maximum|
01692|038|M|recommended dose as defined by weight:|
01692|039|M|   - Weight range: 30.0 to 50.0 kg = maximum recommended dose of 1,200|
01692|040|M|mg/day.|
01692|041|M|   - Weight range: 50.1 to 70.0 kg = maximum recommended dose of 1,600|
01692|042|M|mg/day.|
01692|043|M|   - Weight range: 70.1 kg or greater = maximum recommended dose of 2,200|
01692|044|M|mg/day.(1,3)|
01692|045|M|   The UK manufacturer of rufinamide recommends that in patients established|
01692|046|M|on rufinamide treatment a dosage reduction of rufinamide be considered if|
01692|047|M|valproate is initiated.(1)|
01692|048|B||
01692|049|D|DISCUSSION:  Valproate increases rufinamide by 16% to 70%.  The largest|
01692|050|D|effects were seen in children at high doses/concentration of valproate.(1-3)|
01692|051|D|The largest increases were seen in patients weighing less than 30 kg.(1)|
01692|052|B||
01692|053|R|REFERENCES:|
01692|054|B||
01692|055|R|1.Inovelon (rufinamide) UK summary of product characteristics. Eisai Limited|1
01692|056|R|  January 16, 2007.|1
01692|057|R|2.Banzel (rufinamide) US prescribing information. Eisai Inc. November, 2019.|1
01692|058|R|3.Inovelon (rufinamide) Australian prescribing information. Eisai Australia|1
01692|059|R|  Pty. Ltd. November 2024.|1
01693|001|T|MONOGRAPH TITLE:  Nifedipine/Ginkgo Biloba|
01693|002|B||
01693|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01693|004|L|Assess the risk to the patient and take action as needed.|
01693|005|B||
01693|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.(1)|
01693|007|B||
01693|008|E|CLINICAL EFFECTS:  Concurrent use of nifedipine and ginkgo may result in|
01693|009|E|increased heart rate.(1)|
01693|010|B||
01693|011|P|PREDISPOSING FACTORS:  None determined.|
01693|012|B||
01693|013|M|PATIENT MANAGEMENT:  Patients should be warned about and observed for|
01693|014|M|increased side effects from nifedipine if they use ginkgo concurrently.  The|
01693|015|M|dose of nifedipine may need to be adjusted if ginkgo is added to or|
01693|016|M|discontinued from concurrent therapy.|
01693|017|B||
01693|018|D|DISCUSSION:  In an open-label, random, crossover study, 8 volunteers|
01693|019|D|received nifedipine (10 mg) with either ginkgo biloba (240 mg) or placebo|
01693|020|D|for 2 weeks.  Concurrent ginkgo increased the mean heart rate by 9%.  Ginkgo|
01693|021|D|did not significantly affect any mean nifedipine pharmacokinetic parameters;|
01693|022|D|however, 2 patients experienced a 2-fold increase in nifedipine maximum|
01693|023|D|concentration (Cmax).  These patients also had more severe and longer|
01693|024|D|lasting headaches, dizziness, and hot flashes during combination therapy.(1)|
01693|025|B||
01693|026|R|REFERENCE:|
01693|027|B||
01693|028|R|1.Yoshioka M, Ohnishi N, Koishi T, Obata Y, Nakagawa M, Matsumoto T, Tagagi|2
01693|029|R|  K, Takara K, Ohkuni T, Yokoyama T, Kuroda K. Studies on interactions|2
01693|030|R|  between functional foods or dietary supplements and medicines. IV. Effects|2
01693|031|R|  of ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics|2
01693|032|R|  of nifedipine in healthy volunteers. Biol Pharm Bull 2004 Dec;|2
01693|033|R|  27(12):2006-9.|2
01694|001|T|MONOGRAPH TITLE:  Oral Vancomycin/Bile Acid Sequestrants|
01694|002|B||
01694|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01694|004|L|take action as needed.|
01694|005|B||
01694|006|A|MECHANISM OF ACTION:  Bile acid sequestrants bind to vancomycin when the|
01694|007|A|medications are coadministered.(1,2)|
01694|008|B||
01694|009|E|CLINICAL EFFECTS:  When using both medications concurrently, bile acid|
01694|010|E|sequestrants may bind to oral vancomycin, causing a decrease in its unbound|
01694|011|E|concentration and potentially affecting the antibiotic activity of the|
01694|012|E|medication.(1,2)|
01694|013|B||
01694|014|P|PREDISPOSING FACTORS:  None determined.|
01694|015|B||
01694|016|M|PATIENT MANAGEMENT:  It has been suggested when using both medications that|
01694|017|M|the course of bile acid sequestrants follow the course of oral vancomycin in|
01694|018|M|order to avoid a reduction in vancomycin concentration by preventing the|
01694|019|M|binding of vancomycin to the bile acid sequestrant.(2,3)|
01694|020|B||
01694|021|D|DISCUSSION:  One study found when oral vancomycin and cholestyramine were|
01694|022|D|coadministered that the active concentration of vancomycin decreased by as|
01694|023|D|much as 80%.(2)  Conversely another study suggests when both medications are|
01694|024|D|used concurrently that vancomycin antibacterial activity is unaffected by|
01694|025|D|cholestyramine binding.(1)|
01694|026|D|   Two additional studies looked at the combination of cholestyramine and|
01694|027|D|oral vancomycin for the treatment of C. difficile associated|
01694|028|D|pseudomembranous colitis.  One looked at the results from both in vitro and|
01694|029|D|hamster models(4) while the other recorded results from hamster as well as|
01694|030|D|clinical studies.(3)  Both of the studies had similar results noting a|
01694|031|D|10-fold decrease in therapeutically active vancomycin concentration when|
01694|032|D|used in combination with cholestyramine.  Both studies also found no|
01694|033|D|clinical benefit from coadministration of the medications versus the use of|
01694|034|D|oral vancomycin alone.|
01694|035|D|   Another study found the in vitro combination of cholestyramine and oral|
01694|036|D|vancomycin resulted in substantially decreased vancomycin concentrations|
01694|037|D|potentially hindering its therapeutic activity.(5)|
01694|038|B||
01694|039|R|REFERENCES:|
01694|040|B||
01694|041|R|1.King CY, Barriere SL. Analysis of the in vitro interaction between|5
01694|042|R|  vancomycin and cholestyramine. Antimicrob Agents Chemother 1981 Feb;|5
01694|043|R|  19(2):326-7.|5
01694|044|R|2.Pantosti A, Luzzi I, Cardines R, Gianfrilli P. Comparison of the in vitro|5
01694|045|R|  activities of teicoplanin and vancomycin against Clostridium difficile and|5
01694|046|R|  their interactions with cholestyramine. Antimicrob Agents Chemother 1985|5
01694|047|R|  Dec;28(6):847-8.|5
01694|048|R|3.Bartlett JG. Treatment of antibiotic-associated pseudomembranous colitis.|2
01694|049|R|  Rev Infect Dis 1984 Mar-Apr;6 Suppl 1:S235-41.|2
01694|050|R|4.Taylor NS, Bartlett JG. Binding of Clostridium difficile cytotoxin and|5
01694|051|R|  vancomycin by anion-exchange resins. J Infect Dis 1980 Jan;141(1):92-7.|5
01694|052|R|5.George RH, Youngs DJ, Johnson EM, Burdon DW. Anion-exchange resins in|5
01694|053|R|  pseudomembranous colitis. Lancet 1978 Sep 16;2(8090):624.|5
01695|001|T|MONOGRAPH TITLE:  Palonosetron/QT Prolonging Agents (mono deleted|
01695|002|T|05/01/2014)|
01695|003|B||
01695|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01695|005|L|take action as needed.|
01695|006|B||
01695|007|A|MECHANISM OF ACTION:  Concurrent use of palonosetron and agents known to|
01695|008|A|prolong the QT interval may result in additive or synergistic effects on the|
01695|009|A|QTc interval.(1)|
01695|010|B||
01695|011|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01695|012|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01695|013|E|torsades de pointes.|
01695|014|B||
01695|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01695|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01695|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01695|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01695|019|P|gender, or advanced age.(3)|
01695|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01695|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01695|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01695|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01695|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01695|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01695|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01695|027|B||
01695|028|M|PATIENT MANAGEMENT:  The US manufacturer of palonosetron states that|
01695|029|M|palonosetron should be used with caution when given with anti-arrhythmic|
01695|030|M|agents, other drugs that prolong the QT interval, and cumulative high dose|
01695|031|M|anthracycline therapy.(1)|
01695|032|B||
01695|033|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01695|034|D|degrees of potential to prolong the QTc interval. Agents linked to this|
01695|035|D|monograph have been shown to prolong the QTc interval either through their|
01695|036|D|mechanism of action, through studies on their effects on the QTc interval,|
01695|037|D|or through reports of QTc prolongation and/or torsades de pointes in|
01695|038|D|clinical trials and/or postmarketing reports.(2)|
01695|039|B||
01695|040|R|REFERENCES:|
01695|041|B||
01695|042|R|1.Aloxi  (polonosetron hydrochloride) US prescribing information. MGI Pharma|1
01695|043|R|  September, 2007.|1
01695|044|R|2.Aloxi (palonosetron hydrochloride) UK summary of product characteristics.|1
01695|045|R|  Cambridge Laboratories September 29, 2005.|1
01695|046|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01695|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01695|048|R|  settings: a scientific statement from the American Heart Association and|6
01695|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01695|050|R|  2;55(9):934-47.|6
01696|001|T|MONOGRAPH TITLE:  Ixabepilone/Amprenavir; Delavirdine|
01696|002|B||
01696|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01696|004|L|of severe adverse interaction.|
01696|005|B||
01696|006|A|MECHANISM OF ACTION:  Amprenavir and delavirdine may inhibit the metabolism|
01696|007|A|of ixabepilone by CYP3A4.(1)|
01696|008|B||
01696|009|E|CLINICAL EFFECTS:  Concurrent use of amprenavir or delavirdine without a|
01696|010|E|dosage adjustment of ixabepilone may result in increased levels of and|
01696|011|E|toxicity from ixabepilone.(1)|
01696|012|B||
01696|013|P|PREDISPOSING FACTORS:  None determined.|
01696|014|B||
01696|015|M|PATIENT MANAGEMENT:  The US manufacturer of ixabepilone recommends that|
01696|016|M|concurrent use of amprenavir or delavirdine be avoided during ixabepilone|
01696|017|M|therapy.(1)|
01696|018|M|   If concurrent use is warranted, a dose reduction to 20 mg/m2 of|
01696|019|M|ixabepilone should be considered.  Patients receiving concurrent therapy|
01696|020|M|should be closely monitored for acute toxicities (e.g. frequent monitoring|
01696|021|M|of peripheral blood counts).(1)|
01696|022|M|   If the inhibitor is discontinued, allow a 1 week washout period before|
01696|023|M|adjusting the dose of ixabepilone to recommended amounts.(1)|
01696|024|B||
01696|025|D|DISCUSSION:  Concurrent administration of ketoconazole, a strong inhibitor|
01696|026|D|of CYP3A4, increased the area-under-curve (AUC) of ixabepilone by 79%.(1)|
01696|027|D|   A dose reduction to 20 mg/m2 of ixabepilone during concurrent use of|
01696|028|D|amprenavir or delavirdine is predicted to adjust the ixabepilone AUC to the|
01696|029|D|range observed without a concurrent CYP3A4 inhibitor.(1)|
01696|030|B||
01696|031|R|REFERENCE:|
01696|032|B||
01696|033|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
01696|034|R|  Company October, 2011.|1
01697|001|T|MONOGRAPH TITLE:  Ixabepilone/Clarithromycin; Telithromycin (mono deleted|
01697|002|T|12/29/2011)|
01697|003|B||
01697|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01697|005|L|of severe adverse interaction.|
01697|006|B||
01697|007|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01697|008|A|metabolism of ixabepilone by CYP P-450-3A4.(1)|
01697|009|B||
01697|010|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin or telithromycin without|
01697|011|E|a dosage adjustment of ixabepilone may result in increased levels of and|
01697|012|E|toxicity from ixabepilone.(1)|
01697|013|B||
01697|014|P|PREDISPOSING FACTORS:  None determined.|
01697|015|B||
01697|016|M|PATIENT MANAGEMENT:  The US manufacturer of ixabepilone recommends that|
01697|017|M|concurrent use of strong inhibitor of CYP P-450-3A4 such as clarithromycin|
01697|018|M|or telithromycin be avoided during ixabepilone therapy.(1)|
01697|019|M|   If concurrent use is warranted, a dose reduction to 20 mg/m2 of|
01697|020|M|ixabepilone should be considered.  Patients receiving concurrent therapy|
01697|021|M|should be closely monitored for acute toxicities (e.g. frequent monitoring|
01697|022|M|of peripheral blood counts).(1)|
01697|023|M|   If the inhibitor is discontinued, allow a 1 week washout period before|
01697|024|M|adjusting the dose of ixabepilone to recommended amounts.(1)|
01697|025|B||
01697|026|D|DISCUSSION:  Concurrent administration of ketoconazole, another potent|
01697|027|D|inhibitor of CYP P-450-3A4, increased the area-under-curve (AUC) of|
01697|028|D|ixabepilone by 79%.(1)|
01697|029|D|   A dose reduction to 20 mg/m2 of ixabepilone during concurrent use of a|
01697|030|D|potent CYP P-450-3A4 inhibitor is predicted to adjust the ixabepilone AUC to|
01697|031|D|the range observed without a concurrent CYP P-450-3A4 inhibitor.(1)|
01697|032|B||
01697|033|R|REFERENCE:|
01697|034|B||
01697|035|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
01697|036|R|  Company October, 2011.|1
01698|001|T|MONOGRAPH TITLE:  Ixabepilone/Protease Inhibitors (mono deleted 12/29/2011)|
01698|002|B||
01698|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01698|004|L|of severe adverse interaction.|
01698|005|B||
01698|006|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
01698|007|A|ixabepilone by CYP P-450-3A4.(1)|
01698|008|B||
01698|009|E|CLINICAL EFFECTS:  Concurrent use of a protease inhibitor without a dosage|
01698|010|E|adjustment of ixabepilone may result in increased levels of and toxicity|
01698|011|E|from ixabepilone.(1)|
01698|012|B||
01698|013|P|PREDISPOSING FACTORS:  None determined.|
01698|014|B||
01698|015|M|PATIENT MANAGEMENT:  The US manufacturer of ixabepilone recommends that|
01698|016|M|concurrent use of strong inhibitor of CYP P-450-3A4 such as the protease|
01698|017|M|inhibitors be avoided during ixabepilone therapy.(1)|
01698|018|M|   If concurrent use is warranted, a dose reduction to 20 mg/m2 of|
01698|019|M|ixabepilone should be considered.  Patients receiving concurrent therapy|
01698|020|M|should be closely monitored for acute toxicities (e.g. frequent monitoring|
01698|021|M|of peripheral blood counts).(1)|
01698|022|M|   If the inhibitor is discontinued, allow a 1 week washout period before|
01698|023|M|adjusting the dose of ixabepilone to recommended amounts.(1)|
01698|024|B||
01698|025|D|DISCUSSION:  Concurrent administration of ketoconazole, another potent|
01698|026|D|inhibitor of CYP P-450-3A4, increased the area-under-curve (AUC) of|
01698|027|D|ixabepilone by 79%.(1)|
01698|028|D|   A dose reduction to 20 mg/m2 of ixabepilone during concurrent use of a|
01698|029|D|potent CYP P-450-3A4 inhibitor is predicted to adjust the ixabepilone AUC to|
01698|030|D|the range observed without a concurrent CYP P-450-3A4 inhibitor.(1)|
01698|031|B||
01698|032|R|REFERENCE:|
01698|033|B||
01698|034|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
01698|035|R|  Company October, 2011.|1
01699|001|T|MONOGRAPH TITLE:  Ixabepilone/Nefazodone (mono deleted 12/29/2011)|
01699|002|B||
01699|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01699|004|L|of severe adverse interaction.|
01699|005|B||
01699|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of ixabepilone|
01699|007|A|by CYP P-450-3A4.(1)|
01699|008|B||
01699|009|E|CLINICAL EFFECTS:  Concurrent use of nefazodone without a dosage adjustment|
01699|010|E|of ixabepilone may result in increased levels of and toxicity from|
01699|011|E|ixabepilone.(1)|
01699|012|B||
01699|013|P|PREDISPOSING FACTORS:  None determined.|
01699|014|B||
01699|015|M|PATIENT MANAGEMENT:  The US manufacturer of ixabepilone recommends that|
01699|016|M|concurrent use of strong inhibitor of CYP P-450-3A4 such as nefazodone be|
01699|017|M|avoided during ixabepilone therapy.(1)|
01699|018|M|   If concurrent use is warranted, a dose reduction to 20 mg/m2 of|
01699|019|M|ixabepilone should be considered.  Patients receiving concurrent therapy|
01699|020|M|should be closely monitored for acute toxicities (e.g. frequent monitoring|
01699|021|M|of peripheral blood counts).(1)|
01699|022|M|   If the inhibitor is discontinued, allow a 1 week washout period before|
01699|023|M|adjusting the dose of ixabepilone to recommended amounts.(1)|
01699|024|B||
01699|025|D|DISCUSSION:  Concurrent administration of ketoconazole, another potent|
01699|026|D|inhibitor of CYP P-450-3A4, increased the area-under-curve (AUC) of|
01699|027|D|ixabepilone by 79%.(1)|
01699|028|D|   A dose reduction to 20 mg/m2 of ixabepilone during concurrent use of a|
01699|029|D|potent CYP P-450-3A4 inhibitor is predicted to adjust the ixabepilone AUC to|
01699|030|D|the range observed without a concurrent CYP P-450-3A4 inhibitor.(1)|
01699|031|B||
01699|032|R|REFERENCE:|
01699|033|B||
01699|034|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
01699|035|R|  Company October, 2011.|1
01700|001|T|MONOGRAPH TITLE:  Ixabepilone/Delavirdine (mono deleted 12/29/2011)|
01700|002|B||
01700|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01700|004|L|of severe adverse interaction.|
01700|005|B||
01700|006|A|MECHANISM OF ACTION:  Delavirdine may inhibit the metabolism of ixabepilone|
01700|007|A|by CYP P-450-3A4.(1)|
01700|008|B||
01700|009|E|CLINICAL EFFECTS:  Concurrent use of delavirdine without a dosage adjustment|
01700|010|E|of ixabepilone may result in increased levels of and toxicity from|
01700|011|E|ixabepilone.(1)|
01700|012|B||
01700|013|P|PREDISPOSING FACTORS:  None determined.|
01700|014|B||
01700|015|M|PATIENT MANAGEMENT:  The US manufacturer of ixabepilone recommends that|
01700|016|M|concurrent use of strong inhibitor of CYP P-450-3A4 such as delavirdine be|
01700|017|M|avoided during ixabepilone therapy.(1)|
01700|018|M|   If concurrent use is warranted, a dose reduction to 20 mg/m2 of|
01700|019|M|ixabepilone should be considered.  Patients receiving concurrent therapy|
01700|020|M|should be closely monitored for acute toxicities (e.g. frequent monitoring|
01700|021|M|of peripheral blood counts).(1)|
01700|022|M|   If the inhibitor is discontinued, allow a 1 week washout period before|
01700|023|M|adjusting the dose of ixabepilone to recommended amounts.(1)|
01700|024|B||
01700|025|D|DISCUSSION:  Concurrent administration of ketoconazole, another potent|
01700|026|D|inhibitor of CYP P-450-3A4, increased the area-under-curve (AUC) of|
01700|027|D|ixabepilone by 79%.(1)|
01700|028|D|   A dose reduction to 20 mg/m2 of ixabepilone during concurrent use of a|
01700|029|D|potent CYP P-450-3A4 inhibitor is predicted to adjust the ixabepilone AUC to|
01700|030|D|the range observed without a concurrent CYP P-450-3A4 inhibitor.(1)|
01700|031|B||
01700|032|R|REFERENCE:|
01700|033|B||
01700|034|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
01700|035|R|  Company October, 2011.|1
01701|001|T|MONOGRAPH TITLE:  Ixabepilone/St. John's Wort|
01701|002|B||
01701|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01701|004|L|of severe adverse interaction.|
01701|005|B||
01701|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01701|007|A|ixabepilone by CYP3A4.(1)|
01701|008|B||
01701|009|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
01701|010|E|levels and effectiveness of ixabepilone.(1)|
01701|011|B||
01701|012|P|PREDISPOSING FACTORS:  None determined.|
01701|013|B||
01701|014|M|PATIENT MANAGEMENT:  The US manufacturer of ixabepilone recommends that|
01701|015|M|concurrent use St. John's wort be avoided.(1)|
01701|016|B||
01701|017|D|DISCUSSION:  Concurrent administration of St. John's wort is expected to|
01701|018|D|result in unpredictable decreases in ixabepilone levels.(1)|
01701|019|B||
01701|020|R|REFERENCE:|
01701|021|B||
01701|022|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
01701|023|R|  Company October, 2011.|1
01702|001|T|MONOGRAPH TITLE:  Slt HMG-CoA Reductase Inhibitors/Bosentan (mono deleted|
01702|002|T|11/20/2020)|
01702|003|B||
01702|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01702|005|L|take action as needed.|
01702|006|B||
01702|007|A|MECHANISM OF ACTION:  Bosentan may induce the metabolism of atorvastatin,|
01702|008|A|lovastatin, and simvastatin by CYP P-450-3A4.(1,2)|
01702|009|B||
01702|010|E|CLINICAL EFFECTS:  Concurrent use of bosentan may result in decreased levels|
01702|011|E|and effectiveness of atorvastatin, lovastatin, and simvastatin.(1,2)|
01702|012|B||
01702|013|P|PREDISPOSING FACTORS:  None determined.|
01702|014|B||
01702|015|M|PATIENT MANAGEMENT:  Consider the use of alternative HMG-CoA reductase|
01702|016|M|inhibitors, such as fluvastatin or pravastatin, in patients receiving|
01702|017|M|bosentan.(1)  In patients receiving a HMG-CoA reductase inhibitor that is|
01702|018|M|metabolized by CYP P-450-3A4, monitor cholesterol levels after the|
01702|019|M|initiation of bosentan to determine if the dose of the HMG Co-A reductase|
01702|020|M|inhibitor needs to be adjusted.(2)|
01702|021|B||
01702|022|D|DISCUSSION:  In an open-label, randomized, cross-over study in 9 healthy|
01702|023|D|subjects, concurrent use of bosentan (125 mg twice daily for 5.5 days) and|
01702|024|D|simvastatin (40 mg daily for 6 days) decreased the area-under-curve (AUC) of|
01702|025|D|simvastatin and B-hydroxyacid simvastatin by 34% and 46%, respectively.|
01702|026|D|There were no effects on bosentan levels.(1)|
01702|027|B||
01702|028|R|REFERENCES:|
01702|029|B||
01702|030|R|1.Dingemanse J, Schaarschmidt D, van Giersbergen PL. Investigation of the|2
01702|031|R|  mutual pharmacokinetic interactions between bosentan, a dual endothelin|2
01702|032|R|  receptor antagonist, and simvastatin. Clin Pharmacokinet 2003;|2
01702|033|R|  42(3):293-301.|2
01702|034|R|2.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
01702|035|R|  US, Inc. September 5, 2017.|1
01703|001|T|MONOGRAPH TITLE:  Selected Statins/Carb;Esli:Oxcarbazepine (mono deleted|
01703|002|T|11/20/2020)|
01703|003|B||
01703|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01703|005|L|take action as needed.|
01703|006|B||
01703|007|A|MECHANISM OF ACTION:  Carbamazepine,(1) eslicarbazepine,(2,3) and|
01703|008|A|oxcarbazepine may induce the metabolism of atorvastatin, lovastatin, and|
01703|009|A|simvastatin by CYP3A4. Carbamazepine is a more potent inducer than|
01703|010|A|oxcarbazepine(4) or its active metabolite, eslicarbazepine.(5)|
01703|011|B||
01703|012|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, eslicarbazepine, or|
01703|013|E|oxcarbazepine may result in decreased levels and effectiveness of|
01703|014|E|atorvastatin, lovastatin, and simvastatin.(1-3)|
01703|015|B||
01703|016|P|PREDISPOSING FACTORS:  None determined.|
01703|017|B||
01703|018|M|PATIENT MANAGEMENT:  Consider the use of alternative HMG-CoA reductase|
01703|019|M|inhibitors, such as fluvastatin or pravastatin, in patients receiving|
01703|020|M|carbamazepine, eslicarbazepine, and oxcarbazepine.  Alternatively, a higher|
01703|021|M|dosage of atorvastatin, lovastatin, or simvastatin may be required.(1-3)  If|
01703|022|M|carbamazepine, eslicarbazepine, or oxcarbazepine is discontinued, the dosage|
01703|023|M|of these statins will need to be reduced to prevent toxicity.|
01703|024|M|   Monitor patients receiving concurrent therapy for reduced statin|
01703|025|M|effectiveness.|
01703|026|B||
01703|027|D|DISCUSSION:  In a study in 12 healthy males, pretreatment with carbamazepine|
01703|028|D|(200 mg daily, Days 1-2; 300 mg twice daily Days 3-14) decreased exposure|
01703|029|D|(area-under-curve or AUC) of simvastatin and simvastatin acid from a single|
01703|030|D|dose of simvastatin (80 mg) by 75% and 82%, respectively.  The maximum|
01703|031|D|concentration (Cmax) of simvastatin and simvastatin acid both decreased by|
01703|032|D|68%.(1)|
01703|033|D|   Manufacturer prescribing information describes an interaction study in|
01703|034|D|which eslicarbazepine 800 mg once daily decreased simvastatin exposure by an|
01703|035|D|average of 50%.(3)|
01703|036|B||
01703|037|R|REFERENCES:|
01703|038|B||
01703|039|R|1.Ucar M, Neuvonen M, Luurila H, Dahlqvist R, Neuvonen PJ, Mjorndal T.|2
01703|040|R|  Carbamazepine markedly reduces serum concentrations of simvastatin and|2
01703|041|R|  simvastatin acid. Eur J Clin Pharmacol 2004 Feb;59(12):879-82.|2
01703|042|R|2.Aptiom (eslicarbazepine) US prescribing information. Sunovian|1
01703|043|R|  Pharmaceuticals Inc. September 13, 2017.|1
01703|044|R|3.Zebinix (eslicarbazepine) UK prescribing information. Eisai Ltd. April 29,|1
01703|045|R|  2013.|1
01703|046|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
01703|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01703|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01703|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01703|050|R|  11/14/2017.|1
01703|051|R|5.Bialer M, White HS. Key factors in the discovery and development of new|6
01703|052|R|  antiepileptic drugs. Nat Rev Drug Discov 2010 Jan;9(1):68-82.|6
01704|001|T|MONOGRAPH TITLE:  Selected HMG-CoA Reductase Inhibitors/Digoxin|
01704|002|B||
01704|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01704|004|L|take action as needed.|
01704|005|B||
01704|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
01704|007|A|competitive inhibition of P-glycoproteins.(1)|
01704|008|B||
01704|009|E|CLINICAL EFFECTS:  Concurrent use of digoxin and a HMG-CoA reductase|
01704|010|E|inhibitor may result in rhabdomyolysis.(1)|
01704|011|E|   Concurrent use of atorvastatin(2) or simvastatin(3) may result in|
01704|012|E|increased levels of digoxin.  Symptoms of digoxin toxicity can include|
01704|013|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
01704|014|E|generalized muscle weakness, disorientation, hallucinations, visual|
01704|015|E|disturbances, and arrhythmias.|
01704|016|B||
01704|017|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
01704|018|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
01704|019|P|risk of digoxin toxicity.|
01704|020|P|   The risk for myopathy or rhabdomyolysis may be greater in patients 65|
01704|021|P|years and older, inadequately treated hypothyroidism, renal impairment,|
01704|022|P|carnitine deficiency, malignant hyperthermia, or in patients with a history|
01704|023|P|of myopathy or rhabdomyolysis.  Patients with a SLCO1B1 polymorphism that|
01704|024|P|leads to decreased function of the hepatic uptake transporter OATP1B1 may|
01704|025|P|have increased statin concentrations and be predisposed to myopathy or|
01704|026|P|rhabdomyolysis.  Patients on fluvastatin who are CYP2C9 intermediate or poor|
01704|027|P|metabolizers may have increased fluvastatin concentrations and risk of|
01704|028|P|myopathy.  Patients on rosuvastatin with ABCG2 polymorphisms leading to|
01704|029|P|decreased or poor BCRP transporter function may have increased rosuvastatin|
01704|030|P|concentrations and risk of myopathy.|
01704|031|B||
01704|032|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with digoxin and|
01704|033|M|a HMG-CoA reductase inhibitor should be closely monitored for rhabdomyolysis|
01704|034|M|and instructed to report any symptoms of myopathy.(1)|
01704|035|M|   Patients receiving concurrent atorvastatin(2) or simvastatin(3) should be|
01704|036|M|monitored for elevated digoxin levels and instructed to report any symptoms|
01704|037|M|of digoxin toxicity.  The dosage of digoxin may need to be decreased by|
01704|038|M|15-30% or the frequency of administration may be reduced.(4)|
01704|039|B||
01704|040|D|DISCUSSION:  A retrospective review examined all reports of HMG-CoA|
01704|041|D|reductase inhibitor-induced rhabdomyolysis submitted to the Food and Drug|
01704|042|D|Administration (FDA) between November, 1997 and March, 2000.  There were 601|
01704|043|D|unique cases of rhabdomyolysis, with 26 cases involving concurrent use of|
01704|044|D|digoxin.  There were 5 reports involving concurrent atorvastatin/digoxin, 7|
01704|045|D|reports with cerivastatin/digoxin, 1 report with fluvastatin/digoxin, 2 with|
01704|046|D|lovastatin/digoxin, 2 with pravastatin/digoxin, and 9 with|
01704|047|D|simvastatin/digoxin.(5)|
01704|048|D|   Concurrent use of atorvastatin (80 mg daily for 14 days) with digoxin|
01704|049|D|(0.25mg daily for 20 days) increased digoxin maximum concentration (Cmax)|
01704|050|D|and area-under-curve (AUC) by 20% and 15%, respectively.(2)|
01704|051|D|   In a study in 18 subjects, concurrent fluvastatin had no effect on|
01704|052|D|digoxin AUC but digoxin Cmax increased 11%.(6)|
01704|053|D|   Concurrent use of lovastatin had no effect on digoxin levels.(7)|
01704|054|D|   In a study in 18 subjects, concurrent pravastatin had no effect on|
01704|055|D|digoxin levels.(8)|
01704|056|D|   Concurrent use of rosuvastatin had no effect on digoxin levels.(9)|
01704|057|D|   Concurrent simvastatin slightly increased the concentration of a single|
01704|058|D|dose of digoxin by less than 0.3 ng/ml.(3)|
01704|059|B||
01704|060|R|REFERENCES:|
01704|061|B||
01704|062|R|1.Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical|6
01704|063|R|  pharmacokinetics and drug interactions. Circulation 2004 Jun 15;109(23|6
01704|064|R|  Suppl 1):III50-7.|6
01704|065|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
01704|066|R|  2020.|1
01704|067|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
01704|068|R|  2023.|1
01704|069|R|4.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
01704|070|R|  Pharmaceuticals, Inc. August, 2018.|1
01704|071|R|5.Omar MA, Wilson JP. FDA adverse event reports on statin-associated|3
01704|072|R|  rhabdomyolysis. Ann Pharmacother 2002 Feb;36(2):288-95.|3
01704|073|R|6.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
01704|074|R|  Pharmaceuticals Corporation August, 2017.|1
01704|075|R|7.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
01704|076|R|  February, 2014.|1
01704|077|R|8.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
01704|078|R|  Squibb Company May, 2022.|1
01704|079|R|9.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
01704|080|R|  Pharmaceuticals LP July, 2024.|1
01705|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Mycophenolate|
01705|002|B||
01705|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01705|004|L|of severe adverse interaction.|
01705|005|B||
01705|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01705|007|B||
01705|008|E|CLINICAL EFFECTS:  Concurrent use of mycophenolate may result in decreased|
01705|009|E|levels and effectiveness of hormonal contraceptives.  The use of|
01705|010|E|mycophenolate in pregnancy has been associated with an increased risk for|
01705|011|E|first trimester pregnancy loss and and congenital malformations.(1,2)|
01705|012|B||
01705|013|P|PREDISPOSING FACTORS:  None determined.|
01705|014|B||
01705|015|M|PATIENT MANAGEMENT:  Patients should be informed that mycophenolate may|
01705|016|M|reduce the effectiveness of hormonal contraceptives and that the use of|
01705|017|M|mycophenolate in pregnancy has been associated with an increased risk for|
01705|018|M|first trimester pregnancy loss and congenital malformations.(1,2)|
01705|019|M|   Female patients of childbearing potential should use two forms of|
01705|020|M|contraception four weeks prior to initiating mycophenolate, during therapy,|
01705|021|M|and for six weeks after completing mycophenolate therapy.(1,2)|
01705|022|B||
01705|023|D|DISCUSSION:  In a study in 18 female patients, concurrent mycophenolate|
01705|024|D|mofetil (1 gram twice daily) and oral contraceptives containing ethinyl|
01705|025|D|estradiol (0.02 to 0.04 mg) with levonorgestrel (0.05 mg to 0.20 mg),|
01705|026|D|desogestrel (0.15 mg), or gestodene (0.05 mg to 0.10 mg) decreased the|
01705|027|D|area-under-curve (AUC) of levonorgestrel by 15%.  There was large|
01705|028|D|inter-patient variability in the data, especially for ethinyl estradiol.|
01705|029|D|Mean serum levels of LH, FSH, and progesterone were not significantly|
01705|030|D|affected. (1)|
01705|031|B||
01705|032|R|REFERENCES:|
01705|033|B||
01705|034|R|1.CellCept (mycophenolate mofetil) US prescribing information. Roche|1
01705|035|R|  Pharmaceuticals June, 2022.|1
01705|036|R|2.Birgerson LE. Dear Health Care Professional letter Subject:  Important|1
01705|037|R|  changes in the CellCept (mycophenolate mofetil) prescribing information -|1
01705|038|R|  Use of CellCept is associated with increased pregnancy loss and cogential|1
01705|039|R|  malformations/change from. pregnancy category C to pregnancy category D.|1
01705|040|R|  Roche Pharmaceuticals October, 2007.|1
01706|001|T|MONOGRAPH TITLE:  Nilotinib/QT Prolonging Agents|
01706|002|B||
01706|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01706|004|L|of severe adverse interaction.|
01706|005|B||
01706|006|A|MECHANISM OF ACTION:  Nilotinib prolongs the QTc interval.  Concurrent use|
01706|007|A|with other agents that prolong the QTc interval may result in additive|
01706|008|A|effects on the QTc interval.(1,3)|
01706|009|B||
01706|010|E|CLINICAL EFFECTS:  The concurrent use of nilotinib with other agents that|
01706|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01706|012|E|arrhythmias, including torsades de pointes.(1,3)|
01706|013|B||
01706|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01706|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01706|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01706|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01706|018|P|gender, or advanced age.(4)|
01706|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01706|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01706|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01706|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01706|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01706|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01706|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01706|026|B||
01706|027|M|PATIENT MANAGEMENT:  The US manufacturer of nilotinib states that the use of|
01706|028|M|nilotinib should be avoided with other drugs that are known to prolong the|
01706|029|M|QTc interval.  Should treatment with a QT prolonging agent be required,|
01706|030|M|interruption of nilotinib therapy should be considered.  If concurrent|
01706|031|M|therapy cannot be avoided, monitor patients closely for prolongation of the|
01706|032|M|QT interval and follow recommended nilotinib dosage adjustments for QT|
01706|033|M|prolongation.(1)  Consider obtaining serum calcium, magnesium, and potassium|
01706|034|M|levels and monitoring ECG at baseline and at regular intervals.  Correct any|
01706|035|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01706|036|M|heartbeat, dizziness, or fainting.|
01706|037|M|   The UK manufacturer of nilotinib states that the use of nilotinib should|
01706|038|M|be used with caution with other drugs that are known to prolong the QTc|
01706|039|M|interval.(3)|
01706|040|B||
01706|041|D|DISCUSSION:  A retrospective review of 618 cancer patients treated with 902|
01706|042|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
01706|043|D|incidence of QTc prolongation.  In patients who received nilotinib, QTc|
01706|044|D|prolongation was identified in 29 (38.7%) with 1 (3.5%) having Grade 1 (QTc|
01706|045|D|450-480 ms) and 2 (7%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
01706|046|D|occurred in 9 (31%) having QTc greater than or equal to 500 ms and 17|
01706|047|D|(58.6%) having QTc change greater than or equal to 60 ms.  No patients|
01706|048|D|developed ventricular tachycardia, sudden cardiac death, or TdP.(5)|
01706|049|D|   Agents that are linked to this monograph may have varying degrees of|
01706|050|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
01706|051|D|been shown to prolong the QTc interval either through their mechanism of|
01706|052|D|action, through studies on their effects on the QTc interval, or through|
01706|053|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01706|054|D|and/or postmarketing reports.(2)|
01706|055|B||
01706|056|R|REFERENCES:|
01706|057|B||
01706|058|R|1.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01706|059|R|  Corporation September, 2021.|1
01706|060|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01706|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01706|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01706|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01706|064|R|3.Tasigna (nilotinib) UK prescribing information. Novartis Pharmaceuticals|1
01706|065|R|  Corporation November, 2020.|1
01706|066|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01706|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01706|068|R|  settings: a scientific statement from the American Heart Association and|6
01706|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01706|070|R|  2;55(9):934-47.|6
01706|071|R|5.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
01706|072|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
01706|073|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
01707|001|T|MONOGRAPH TITLE:  Nilotinib/Possible QT Prolonging Agents|
01707|002|B||
01707|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01707|004|L|take action as needed.|
01707|005|B||
01707|006|A|MECHANISM OF ACTION:  Nilotinib prolongs the QTc interval.  Concurrent use|
01707|007|A|with other agents that prolong the QTc interval may result in additive|
01707|008|A|effects on the QTc interval.(1,3)|
01707|009|B||
01707|010|E|CLINICAL EFFECTS:  The concurrent use of nilotinib with other agents that|
01707|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01707|012|E|arrhythmias, including torsades de pointes.(1,3)|
01707|013|B||
01707|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01707|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01707|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01707|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01707|018|P|gender, or advanced age.(4)|
01707|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01707|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01707|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01707|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01707|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01707|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01707|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01707|026|B||
01707|027|M|PATIENT MANAGEMENT:  The US manufacturer of nilotinib states that the use of|
01707|028|M|nilotinib should be avoided with other drugs that are known to prolong the|
01707|029|M|QTc interval.  Should treatment with a QT prolonging agent be required,|
01707|030|M|interruption of nilotinib therapy should be considered.|
01707|031|M|    The UK manufacturer of nilotinib states that the use of nilotinib should|
01707|032|M|be used with caution with other drugs that are known to prolong the QTc|
01707|033|M|interval.(3)|
01707|034|M|    Patient monitoring recommendations:|
01707|035|M|   If concurrent therapy cannot be avoided, monitor patients closely for|
01707|036|M|prolongation of the QT interval and follow recommended nilotinib dosage|
01707|037|M|adjustments for QT prolongation.(1) Consider obtaining serum calcium,|
01707|038|M|magnesium, and potassium levels at baseline and regular intervals. Correct|
01707|039|M|any electrolyte abnormalities.|
01707|040|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
01707|041|M|fainting.|
01707|042|B||
01707|043|D|DISCUSSION:  A retrospective review of 618 cancer patients treated with 902|
01707|044|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
01707|045|D|incidence of QTc prolongation.  In patients who received nilotinib, QTc|
01707|046|D|prolongation was identified in 29 (38.7%) with 1 (3.5%) having Grade 1 (QTc|
01707|047|D|450-480 ms) and 2 (7%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
01707|048|D|occurred in 9 (31%) having QTc greater than or equal to 500 ms and 17|
01707|049|D|(58.6%) having QTc change greater than or equal to 60 ms.  No patients|
01707|050|D|developed ventricular tachycardia, sudden cardiac death, or TdP.(5)|
01707|051|D|   Agents that are linked to this monograph may have been associated with|
01707|052|D|torsades de pointes and/or QT prolongation but at this time lack substantial|
01707|053|D|evidence for causing torsades de pointes.(2)|
01707|054|B||
01707|055|R|REFERENCES:|
01707|056|B||
01707|057|R|1.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01707|058|R|  Corporation September, 2021.|1
01707|059|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01707|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01707|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01707|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01707|063|R|3.Tasigna (nilotinib) UK prescribing information. Novartis Pharmaceuticals|1
01707|064|R|  Corporation November, 2020.|1
01707|065|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01707|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01707|067|R|  settings: a scientific statement from the American Heart Association and|6
01707|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01707|069|R|  2;55(9):934-47.|6
01707|070|R|5.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
01707|071|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
01707|072|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
01708|001|T|MONOGRAPH TITLE:  Saquinavir/Garlic|
01708|002|B||
01708|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01708|004|L|of severe adverse interaction.|
01708|005|B||
01708|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Garlic may induce the|
01708|007|A|metabolism of saquinavir by CYP3A4 and P-glycoproteins (P-gp) may also be|
01708|008|A|involved.(1)|
01708|009|B||
01708|010|E|CLINICAL EFFECTS:  Concurrent use of garlic and saquinavir may result in|
01708|011|E|decreased levels and effectiveness of saquinavir.(2)|
01708|012|B||
01708|013|P|PREDISPOSING FACTORS:  None determined.|
01708|014|B||
01708|015|M|PATIENT MANAGEMENT:  The US manufacturer of saquinavir states that|
01708|016|M|concurrent use of garlic is not recommended.(2)|
01708|017|B||
01708|018|D|DISCUSSION:  A study in nine HIV-negative subjects examined the effects of|
01708|019|D|the concurrent use of a garlic supplement (taken twice daily) on saquinavir|
01708|020|D|(1200 mg twice daily).  Concurrent use resulted in a decrease in saquinavir|
01708|021|D|area-under-curve (AUC), maximum concentration (Cmax), and trough|
01708|022|D|concentration (Cmin) by 51%, 49%, and 54%, respectively, when compared to|
01708|023|D|the administration of saquinavir alone.  Following a garlic washout period,|
01708|024|D|saquinavir levels only returned to 60-70% of baseline.(1)|
01708|025|B||
01708|026|R|REFERENCES:|
01708|027|B||
01708|028|R|1.Piscitelli SC, Burstein AH, Welden N, Gallicano KD, Falloon J. The effect|2
01708|029|R|  of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect|2
01708|030|R|  Dis 2002 Jan 15;34(2):234-8.|2
01708|031|R|2.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01708|032|R|  Laboratories, Inc. March, 2019.|1
01709|001|T|MONOGRAPH TITLE:  Drotrecogin/Anticoagulants; Antiplatelets; Thrombolytics|
01709|002|B||
01709|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01709|004|L|take action as needed.|
01709|005|B||
01709|006|A|MECHANISM OF ACTION:  Drotrecogin, anticoagulants, antiplatelets, and|
01709|007|A|thrombolytics all affect hemostasis.(1)|
01709|008|B||
01709|009|E|CLINICAL EFFECTS:  Concurrent use of drotrecogin with anticoagulants,|
01709|010|E|antiplatelets, or thrombolytics, including heparin and aspirin, may increase|
01709|011|E|the risk of bleeding.(1)|
01709|012|B||
01709|013|P|PREDISPOSING FACTORS:  None determined.|
01709|014|B||
01709|015|M|PATIENT MANAGEMENT:  Drotrecogin should be used with caution with other|
01709|016|M|agents that affect hemostasis, including concurrent heparin for thrombotic|
01709|017|M|or embolic events; recent administration (within 3 days) of thrombolytics;|
01709|018|M|recent administration of oral anticoagulants (within 7 days) or glycoprotein|
01709|019|M|IIb/IIIa inhibitors; or recent administration (within 7 days) of aspirin|
01709|020|M|(greater than 650 mg daily) or other platelet inhibitors.(1)|
01709|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01709|022|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01709|023|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01709|024|M|patients with any symptoms.|
01709|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01709|026|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01709|027|M|anticoagulation in patients with active pathologic bleeding.|
01709|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01709|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01709|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01709|031|M|and/or swelling.|
01709|032|B||
01709|033|D|DISCUSSION:  Because of the increased risk of bleeding, drotrecogin should|
01709|034|D|be used with caution with other agents that affect hemostasis, including|
01709|035|D|concurrent heparin for thrombotic  or embolic events; recent administration|
01709|036|D|(within 3 days) of thrombolytics; recent administration of oral|
01709|037|D|anticoagulants (within 7 days) or glycoprotein IIb/IIIa inhibitors; or|
01709|038|D|recent administration (within 7 days) of aspirin (greater than 650 mg daily)|
01709|039|D|or other platelet inhibitors.(1)|
01709|040|B||
01709|041|R|REFERENCE:|
01709|042|B||
01709|043|R|1.Xigris (drotrecogin alpha activated) US prescribing information. Eli Lilly|1
01709|044|R|  and Company April 27, 2007.|1
01710|001|T|MONOGRAPH TITLE:  Rosiglitazone/Nitrates (mono deleted 03/03/2011)|
01710|002|B||
01710|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01710|004|L|of severe adverse interaction.|
01710|005|B||
01710|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01710|007|B||
01710|008|E|CLINICAL EFFECTS:  Patients receiving concurrent rosiglitazone and nitrates|
01710|009|E|may have a greater risk of myocardial infarction.(1)|
01710|010|B||
01710|011|P|PREDISPOSING FACTORS:  None determined.|
01710|012|B||
01710|013|M|PATIENT MANAGEMENT:  The US manufacturer of rosiglitazone states that|
01710|014|M|concurrent use with nitrates is not recommended.(1)|
01710|015|B||
01710|016|D|DISCUSSION:  In patients receiving rosiglitazone with a nitrate, the odds|
01710|017|D|ratio for a myocardial ischemic event was 2.9, compared to 1.3 for|
01710|018|D|non-nitrate users.  This translated into an extra 12 myocardial ischemic|
01710|019|D|events per 100 patient-years.  Most nitrate users had established coronary|
01710|020|D|heart disease.(1)|
01710|021|B||
01710|022|R|REFERENCE:|
01710|023|B||
01710|024|R|1.Avandia (rosiglitazone maleate) US prescribing information.|1
01710|025|R|  GlaxoSmithKline October, 2008.|1
01711|001|T|MONOGRAPH TITLE:  Rosiglitazone/Insulin|
01711|002|B||
01711|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01711|004|L|of severe adverse interaction.|
01711|005|B||
01711|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may be the result|
01711|007|A|of additive fluid retention.(1,2)|
01711|008|B||
01711|009|E|CLINICAL EFFECTS:  The concurrent use of rosiglitazone and insulin may|
01711|010|E|increase the risk of edema, heart failure, and other cardiovascular effects|
01711|011|E|such as myocardial infarction.(1,2)|
01711|012|B||
01711|013|P|PREDISPOSING FACTORS:  Use in patients with NYHA Class I and II heart|
01711|014|P|failure may increase the risk of other cardiovascular events.(1,2)|
01711|015|B||
01711|016|M|PATIENT MANAGEMENT:  The US manufacturer of rosiglitazone states that|
01711|017|M|concurrent use with insulin is not recommended.(1)  If concurrent therapy is|
01711|018|M|warranted, patients should be monitored for cardiovascular adverse events.|
01711|019|M|If signs and symptoms of congestive heart failure develop, patients should|
01711|020|M|be treated according to current standards of care.  Consideration should be|
01711|021|M|given to lowering the dosage of or discontinuing rosiglitazone.(2)|
01711|022|B||
01711|023|D|DISCUSSION:  In a meta-analysis of 7 controlled, randomized, double-blind|
01711|024|D|clinical trials in which patients were randomized to coadministration of|
01711|025|D|rosiglitazone with insulin or insulin alone, the incidence of congestive|
01711|026|D|heart failure in patients receiving concurrent rosiglitazone was 2.3%,|
01711|027|D|compared with 1.0% in patients receiving insulin alone.  More patients in|
01711|028|D|the concurrent rosiglitazone group experienced myocardial infarctions, MACE|
01711|029|D|(a composite of myocardial infarction, cardiovascular death, or stroke),|
01711|030|D|cardiovascular deaths, and all-cause deaths than in the group receiving|
01711|031|D|insulin alone.(1)|
01711|032|D|   In clinical trials, edema was reported in 14.7% of patients receiving|
01711|033|D|concurrent rosiglitazone and insulin, compared with 5.4% on insulin alone or|
01711|034|D|4.8% on rosiglitazone alone.(1)|
01711|035|D|   In clinical trials, new onset or exacerbation of congestive heart failure|
01711|036|D|occurred at rates of 1%, 2%, and 3%, respectively, in patients treated with|
01711|037|D|insulin alone, insulin with 4 mg of rosiglitazone, and insulin with 8 mg of|
01711|038|D|rosiglitazone.(1)|
01711|039|B||
01711|040|R|REFERENCES:|
01711|041|B||
01711|042|R|1.Avandia (rosiglitazone) US prescribing information. GlaxoSmithKline May,|1
01711|043|R|  2012.|1
01711|044|R|2.Humalog (insulin lispro) US prescribing information. Eli Lilly and Company|1
01711|045|R|  July, 2023.|1
01712|001|T|MONOGRAPH TITLE:  Ritonavir/Rifampin; Rifapentine (mono deleted 07/31/2019)|
01712|002|B||
01712|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01712|004|L|of severe adverse interaction.|
01712|005|B||
01712|006|A|MECHANISM OF ACTION:  Rifampin (1) and rifapentine(2) may increase the|
01712|007|A|metabolism of ritonavir by inducing CYP P-450-3A4.|
01712|008|B||
01712|009|E|CLINICAL EFFECTS:  Concurrent use of either rifampin or rifapentine may|
01712|010|E|result in decreased levels and clinical effectiveness of ritonavir.(1,2)|
01712|011|E|   Rifapentine use may result in rifamycin resistance.(2)|
01712|012|B||
01712|013|P|PREDISPOSING FACTORS:  None determined.|
01712|014|B||
01712|015|M|PATIENT MANAGEMENT:  The manufacturer of ritonavir states that alternative|
01712|016|M|agents to rifampin should be considered.(1)|
01712|017|M|   The manufacturer of rifapentine states that rifapentine should only be|
01712|018|M|used with great caution, if at all, in patients taking protease inhibitors.|
01712|019|M|(2)|
01712|020|M|   The Centers for Disease Control and Prevention (CDC) Division of|
01712|021|M|Tuberculosis Elimination states that the use of rifampin in combination with|
01712|022|M|ritonavir and nucleoside/tide reverse transcriptase inhibitors (NRTI's) is|
01712|023|M|supported.  Alternative, but less supported protease inhibitor combinations|
01712|024|M|with rifampin include:|
01712|025|M|   1) ritonavir (400 mg twice daily) and saquinavir (400 mg twice daily)|
01712|026|M|with NRTI's|
01712|027|M|   2) ritonavir (400 mg twice daily) and lopinavir (400 mg twice daily) with|
01712|028|M|NRTI's (the current coformulated lopinavir/ritonavir combination must be|
01712|029|M|supplemented with additional ritonavir)(3)|
01712|030|B||
01712|031|D|DISCUSSION:  The concurrent administration of ritonavir and rifampin|
01712|032|D|decreased the area-under-curve (AUC), maximum concentration (Cmax), and|
01712|033|D|minimum concentration (Cmin) of ritonavir by 35%, 25%, and 49%,|
01712|034|D|respectively.(1)|
01712|035|D|   One or more of the drug pairs linked to this monograph have been included|
01712|036|D|in a list of interactions that should be considered "high-priority" for|
01712|037|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01712|038|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01712|039|D|Coordinator (ONC) for Health Information Technology.|
01712|040|B||
01712|041|R|REFERENCES:|
01712|042|B||
01712|043|R|1.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01712|044|R|  December, 2019.|1
01712|045|R|2.Priftin (rifapentine) US prescribing information. Sanofi-Aventis U.S. LLC|1
01712|046|R|  July, 2010.|1
01712|047|R|3.Centers for Disease Control and Prevention Division of Tuberculosis|1
01712|048|R|  Elimination. Updated Guidelines for the Use of Rifamycins for the|1
01712|049|R|  Treatment of Tuberculosis Among HIV-Infected Patients Taking Protease|1
01712|050|R|  Inhibitors or Nonnucleoside Reverse Transcriptase Inhibitors. Available at|1
01712|051|R|  http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/PDF/tbhiv.pdf January 20, 2004.|1
01712|052|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01712|053|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01712|054|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01712|055|R|  19(5):735-43.|6
01713|001|T|MONOGRAPH TITLE:  Warfarin/Nilotinib (mono deleted 08/19/2010)|
01713|002|B||
01713|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01713|004|L|take action as needed.|
01713|005|B||
01713|006|A|MECHANISM OF ACTION:  Nilotinib may inhibit the metabolism of warfarin by|
01713|007|A|CYP P-450-2C9 and CYP P-450-3A4.(1,2)|
01713|008|B||
01713|009|E|CLINICAL EFFECTS:  Concurrent use of nilotinib may result in increased|
01713|010|E|levels of and effects from warfarin.(1,2)|
01713|011|B||
01713|012|P|PREDISPOSING FACTORS:  None determined.|
01713|013|B||
01713|014|M|PATIENT MANAGEMENT:  The US(1) and UK(2) manufacturers of nilotinib|
01713|015|M|recommend caution with concurrent use of warfarin.  If concurrent use is|
01713|016|M|warranted, patients should be closely monitored.|
01713|017|B||
01713|018|D|DISCUSSION:  Nilotinib has been shown to inhibit CYP P-450-2C9 and CYP|
01713|019|D|P-450-3A4 in vitro.  In healthy subjects, administration of single doses of|
01713|020|D|nilotinib and midazolam, which is metabolized by CYP P-450-3A4, increased|
01713|021|D|midazolam exposure by 30%.(1)|
01713|022|B||
01713|023|R|REFERENCES:|
01713|024|B||
01713|025|R|1.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
01713|026|R|  Corporation January, 2011.|1
01713|027|R|2.Tasigna (nilotinib) UK prescribing information. Novartis Pharmaceuticals|1
01713|028|R|  Corporation November, 2020.|1
01714|001|T|MONOGRAPH TITLE:  Nebivolol/Fluoxetine|
01714|002|B||
01714|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01714|004|L|take action as needed.|
01714|005|B||
01714|006|A|MECHANISM OF ACTION:  Fluoxetine may inhibit the metabolism of nebivolol by|
01714|007|A|CYP2D6.(1)|
01714|008|B||
01714|009|E|CLINICAL EFFECTS:  Concurrent fluoxetine may result in elevated levels of|
01714|010|E|and increased effects from nebivolol.(1)|
01714|011|B||
01714|012|P|PREDISPOSING FACTORS:  None determined.|
01714|013|B||
01714|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent fluoxetine should be|
01714|015|M|closely monitored and their dosage of nebivolol should be adjusted according|
01714|016|M|to blood pressure response.(1)|
01714|017|B||
01714|018|D|DISCUSSION:  In a study in 10 healthy subjects, pretreatment with fluoxetine|
01714|019|D|(20 mg daily for 21 days) increased the area-under-curve (AUC) and maximum|
01714|020|D|concentration (Cmax) of a single dose of nebivolol (10 mg) by 8-fold and|
01714|021|D|3-fold, respectively.(1)|
01714|022|D|   In a study in 10 healthy extensive metabolizers, pretreatment with|
01714|023|D|fluoxetine (20 mg daily for 21 days) increased the AUC and Cmax of a single|
01714|024|D|dose of nebivolol (10 mg) by 6-fold and 2.3-fold.(3)|
01714|025|D|   One or more of the drug pairs linked to this monograph have been included|
01714|026|D|in a list of interactions that could be considered for classification as|
01714|027|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
01714|028|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
01714|029|D|Health Information Technology.|
01714|030|B||
01714|031|R|REFERENCES:|
01714|032|B||
01714|033|R|1.Bystolic (nebivolol) US prescribing information. Forsest Pharmaceuticals|1
01714|034|R|  Inc. November, 2017.|1
01714|035|R|2.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
01714|036|R|  Middleton B, Bates DW. Drug-drug interactions that should be|6
01714|037|R|  non-interruptive in order to reduce alert fatigue in electronic health|6
01714|038|R|  records. J Am Med Inform Assoc 2012 Sep 25.|6
01714|039|R|3.Lindamood C, Ortiz S, Shaw A, Rackley R, Gorski JC. Effects of commonly|2
01714|040|R|  administered agents and genetics on nebivolol pharmacokinetics: drug-drug|2
01714|041|R|  interaction studies. J Clin Pharmacol 2011 Apr;51(4):575-85.|2
01715|001|T|MONOGRAPH TITLE:  Etravirine/Non-Nucleoside Reverse Transcriptase Inhibitors|
01715|002|T|(NNRTIs) (mono deleted 01/28/2021)|
01715|003|B||
01715|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01715|005|L|is contraindicated and generally should not be dispensed or administered to|
01715|006|L|the same patient.|
01715|007|B||
01715|008|A|MECHANISM OF ACTION:  Delavirdine may inhibit the metabolism of etravirine|
01715|009|A|by CYP3A4.  Efavirenz and nevirapine may induce the metabolism of etravirine|
01715|010|A|via CYP3A4.  Etravirine may decrease levels of rilpivirine.(1)|
01715|011|B||
01715|012|E|CLINICAL EFFECTS:  Concurrent use of delavirdine may increase etravirine|
01715|013|E|levels and toxicity.(1)|
01715|014|E|   Concurrent use of efavirenz and nevirapine may result in decreased|
01715|015|E|etravirine levels and effectiveness.(1)|
01715|016|E|   Concurrent use of etravirine may result in decreased rilpivirine levels|
01715|017|E|and effectiveness.(1)|
01715|018|B||
01715|019|P|PREDISPOSING FACTORS:  None determined.|
01715|020|B||
01715|021|M|PATIENT MANAGEMENT:  The US manufacturer of etravirine states that it should|
01715|022|M|not be use with other NNRTIs.(1)|
01715|023|B||
01715|024|D|DISCUSSION:  Combining two NNRTIs has not been shown to be beneficial.(1)|
01715|025|B||
01715|026|R|REFERENCE:|
01715|027|B||
01715|028|R|1.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01715|029|R|  August, 2014.|1
01716|001|T|MONOGRAPH TITLE:  Fosamprenavir/Etravirine|
01716|002|B||
01716|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01716|004|L|of severe adverse interaction.|
01716|005|B||
01716|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unclear but may|
01716|007|A|involve P-glycoprotein inhibition by etravirine.  Fosamprenavir is a prodrug|
01716|008|A|of amprenavir.(1-2)|
01716|009|B||
01716|010|E|CLINICAL EFFECTS:  Concurrent etravirine and fosamprenavir use with or|
01716|011|E|without low-dose ritonavir may increase amprenavir levels and toxicity.(1)|
01716|012|B||
01716|013|P|PREDISPOSING FACTORS:  None determined.|
01716|014|B||
01716|015|M|PATIENT MANAGEMENT:  The US manufacturer of etravirine states that|
01716|016|M|coadministration with fosamprenavir (with or without ritonavir) is not|
01716|017|M|recommended.(1)|
01716|018|B||
01716|019|D|DISCUSSION:  In a study in 8 subjects, etravirine increased amprenavir|
01716|020|D|maximum concentration (Cmax), area-under-curve (AUC), and trough|
01716|021|D|concentration (Cmin) by 62%, 69%, and 77%, respectively.(1)|
01716|022|B||
01716|023|R|REFERENCES:|
01716|024|B||
01716|025|R|1.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01716|026|R|  August, 2014.|1
01716|027|R|2.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01716|028|R|  March, 2019.|1
01717|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Etravirine|
01717|002|B||
01717|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01717|004|L|of severe adverse interaction.|
01717|005|B||
01717|006|A|MECHANISM OF ACTION:  Etravirine may induce the metabolism of atazanavir and|
01717|007|A|indinavir.(1)|
01717|008|B||
01717|009|E|CLINICAL EFFECTS:  Concurrent atazanavir or indinavir with etravirine may|
01717|010|E|result in decreased levels and effectiveness of atazanavir and indinavir.(1)|
01717|011|B||
01717|012|P|PREDISPOSING FACTORS:  None determined.|
01717|013|B||
01717|014|M|PATIENT MANAGEMENT:  The US manufacturer of etravirine states that|
01717|015|M|etravirine should not be co-administered with atazanavir or indinavir|
01717|016|M|without the use of low-dose ritonavir.  Co-administration of etravirine with|
01717|017|M|cobicistat-boosted atazanavir is not recommended.(1)|
01717|018|B||
01717|019|D|DISCUSSION:  In a study in 14 subjects, concurrent atazanavir (400 mg daily)|
01717|020|D|increased etravirine maximum concentration (Cmax), area-under-curve (AUC),|
01717|021|D|and minimum concentration (Cmin) by 47%, 50%, and 58%, respectively.|
01717|022|D|Atazanavir Cmax, AUC, and Cmin decreased by 3%, 17%, and 47%, respectively.|
01717|023|D|In a study in 14 subjects, concurrent atazanavir/ritonavir (300/100 mg|
01717|024|D|daily) increased etravirine Cmax, AUC, and Cmin by 30%, 30%, and 26%,|
01717|025|D|respectively.  In a study in 13 subjects, atazanavir Cmax, AUC, and Cmin|
01717|026|D|decreased by 3%, 14%, and 38%, respectively.(1)|
01717|027|B||
01717|028|R|REFERENCES:|
01717|029|B||
01717|030|R|1.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01717|031|R|  August, 2014.|1
01717|032|R|2.Kaletra (lopinavir/ritonavir capsules) US prescribing information. Abbott|1
01717|033|R|  Laboratories September, 2016.|1
01718|001|T|MONOGRAPH TITLE:  Etravirine/St. John's Wort|
01718|002|B||
01718|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01718|004|L|is contraindicated and generally should not be dispensed or administered to|
01718|005|L|the same patient.|
01718|006|B||
01718|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01718|008|A|etravirine by CYP3A4.(1)|
01718|009|B||
01718|010|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
01718|011|E|levels and effectiveness of etravirine.(1)|
01718|012|B||
01718|013|P|PREDISPOSING FACTORS:  None determined.|
01718|014|B||
01718|015|M|PATIENT MANAGEMENT:  The US manufacturer of etravirine states that it should|
01718|016|M|not be co-administered with St. John's wort.(1)|
01718|017|B||
01718|018|D|DISCUSSION:  Etravirine has been shown to be metabolized by CYP3A4 and St.|
01718|019|D|John's wort is expected to decreased etravirine levels and effectiveness.(1)|
01718|020|B||
01718|021|R|REFERENCE:|
01718|022|B||
01718|023|R|1.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01718|024|R|  August, 2014.|1
01719|001|T|MONOGRAPH TITLE:  Rifabutin/Etravirine|
01719|002|B||
01719|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01719|004|L|of severe adverse interaction.|
01719|005|B||
01719|006|A|MECHANISM OF ACTION:  Etravirine and rifabutin may induce the metabolism of|
01719|007|A|each other.(1)|
01719|008|B||
01719|009|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
01719|010|E|effectiveness of both etravirine and rifabutin.(1)|
01719|011|B||
01719|012|P|PREDISPOSING FACTORS:  None determined.|
01719|013|B||
01719|014|M|PATIENT MANAGEMENT:  The US manufacturer of etravirine recommends a|
01719|015|M|rifabutin dose of 300 mg daily in patients not receiving concurrent therapy|
01719|016|M|with a protease inhibitor.(1)|
01719|017|M|   The US manufacturer of etravirine recommends that rifabutin not be|
01719|018|M|administered to patients receiving concurrent etravirine with|
01719|019|M|darunavir/ritonavir, lopinavir/ritonavir, or saquinavir/ritonavir.(1)|
01719|020|B||
01719|021|D|DISCUSSION:  In a study in 12 subjects, concurrent rifabutin (300 mg daily)|
01719|022|D|decreased etravirine maximum concentration (Cmax), area-under-curve (AUC),|
01719|023|D|and minimum concentration (Cmin) by 37%, 37%, and 35%.  Rifabutin Cmax, AUC,|
01719|024|D|and Cmin decreased by 10%, 17%, and 24%.  The Cmax, AUC, and Cmin of|
01719|025|D|25-O-desacetylrifabutin decreased by 15%, 17%, and 22%, respectively.(1)|
01719|026|B||
01719|027|R|REFERENCES:|
01719|028|B||
01719|029|R|1.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01719|030|R|  August, 2014.|1
01719|031|R|2.Kakuda TN, Woodfall B, De Marez T, Peeters M, Vandermeulen K, Aharchi F,|2
01719|032|R|  Hoetelmans RM. Pharmacokinetic evaluation of the interaction between|2
01719|033|R|  etravirine and rifabutin or clarithromycin in HIV-negative, healthy|2
01719|034|R|  volunteers: results from two Phase 1 studies. J Antimicrob Chemother 2014|2
01719|035|R|  Mar;69(3):728-34.|2
01720|001|T|MONOGRAPH TITLE:  Selected Anticoagulants/Acetaminophen|
01720|002|B||
01720|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01720|004|L|take action as needed.|
01720|005|B||
01720|006|A|MECHANISM OF ACTION:  Acetaminophen may reduce levels of functional Factor|
01720|007|A|VI, thereby increasing the International Normalized Ratio (INR).(1)  In one|
01720|008|A|trial factors II and VII levels were also reduced, thereby increasing the|
01720|009|A|INR. (2)|
01720|010|B||
01720|011|E|CLINICAL EFFECTS:  Concurrent use of routine acetaminophen, especially at|
01720|012|E|dosages greater than 2 grams/day, and coumarin anticoagulants may result in|
01720|013|E|elevated anticoagulant effects.|
01720|014|B||
01720|015|P|PREDISPOSING FACTORS:  Routine use of acetaminophen at dosages greater than|
01720|016|P|2 grams/day may increase the risk of the interaction.|
01720|017|B||
01720|018|M|PATIENT MANAGEMENT:  Patients receiving routine acetaminophen at dosages|
01720|019|M|greater than 2 grams/day with coumarin anticoagulants should be closely|
01720|020|M|monitored for changes in anticoagulant effects.  The dosage of the|
01720|021|M|anticoagulant may need to be adjusted.|
01720|022|M|   Patients receiving coumarin anticoagulants should be counseled on the use|
01720|023|M|of acetaminophen.|
01720|024|B||
01720|025|D|DISCUSSION:  A large systematic review was performed on 72 warfarin|
01720|026|D|drug-drug interactions studies that reported on bleeding, thromboembolic|
01720|027|D|events, or death.  Most studies were retrospective cohorts.  A meta-analysis|
01720|028|D|of 4 of those studies found a higher rate of clinically significant bleeding|
01720|029|D|in patients on warfarin and non-NSAID analgesics (OR=2.12; 95% CI|
01720|030|D|1.65-2.73).  Increased bleeding risk was also seen in subgroup analyses with|
01720|031|D|acetaminophen (OR=2.32; 95% CI 1.22-4.44).(3)|
01720|032|D|   In a study in 11 patients maintained on warfarin, use of acetaminophen (4|
01720|033|D|grams daily for 14 days) increased INR values by an average of 1.04.(4)|
01720|034|D|   In a study in 36 patients maintained on warfarin, the addition of|
01720|035|D|acetaminophen (2 grams/day or 4 grams/day) increased INR values.(5)|
01720|036|D|   In a study in 20 patients maintained on warfarin, the addition of|
01720|037|D|acetaminophen (4 grams/day for 14 days) increased average INR values by 1.20|
01720|038|D|(from 2.6 to 3.45).(6)|
01720|039|D|   In a study, 12 patients maintained on various anticoagulants|
01720|040|D|(anisindione, dicoumarol, phenprocoumon, and warfarin) who received 4 weeks|
01720|041|D|of acetaminophen (2.6 grams/day) were compared to 50 subjects maintained on|
01720|042|D|various anticoagulants who did not receive acetaminophen.  By the third week|
01720|043|D|of concurrent acetaminophen, prothrombin times increased from 23 seconds to|
01720|044|D|28.4 seconds.  The average warfarin-equivalent dose decreased by 5.8 mg to|
01720|045|D|4.4 mg.  In another phase, 50 subjects maintained on various anticoagulants|
01720|046|D|received acetaminophen (2.6 grams/day for 14 days).  The mean prothrombin|
01720|047|D|increase was 3.6 seconds.(7)|
01720|048|D|   There have been case reports of increased INRs following concurrent|
01720|049|D|acetaminophen in patients maintained on warfarin(8-11) and|
01720|050|D|acenocoumarol.(12)|
01720|051|D|   In contrast to the above reports, other studies have found no effects on|
01720|052|D|acenocoumarol,(14) phenprocoumon,(13-15) or warfarin(16,17) by|
01720|053|D|acetaminophen.|
01720|054|D|   In a study in 45 patients maintained on warfarin, the addition of|
01720|055|D|acetaminophen (2 or 3 grams/day for 10 days) increased average INR by 0.7|
01720|056|D|and 0.67 with 2 grams/day and 3 grams/day, respectively.  This increase was|
01720|057|D|apparent by day 3, and a decrease in factor II and VII was observed.(2)|
01720|058|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
01720|059|D|pairs were reviewed and found 14% of drug pairs were associated with a|
01720|060|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
01720|061|D|of warfarin and acetaminophen resulted in a ratio of rate ratios (95% CI) of|
01720|062|D|1.28 (1.18-1.38).(18)|
01720|063|D|   One or more of the drug pairs linked to this monograph have been included|
01720|064|D|in a list of interactions that could be considered for classification as|
01720|065|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
01720|066|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
01720|067|D|Health Information Technology.|
01720|068|B||
01720|069|R|REFERENCES:|
01720|070|B||
01720|071|R|1.Whyte IM, Buckley NA, Reith DM, Goodhew I, Seldon M, Dawson AH.|2
01720|072|R|  Acetaminophen causes an increased International Normalized Ratio by|2
01720|073|R|  reducing functional factor VII. Ther Drug Monit 2000 Dec;22(6):742-8.|2
01720|074|R|2.Zhang Q, Bal-dit-Sollier C, Drouet L, Simoneau G, Alvarez JC, Pruvot S,|2
01720|075|R|  Aubourg R, Berge N, Bergmann JF, Mouly S, Mahe I. Interaction between|2
01720|076|R|  acetaminophen and warfarin in adults receiving long-term oral|2
01720|077|R|  anticoagulants: a randomized controlled trial. Eur J Clin Pharmacol 2011|2
01720|078|R|  Mar;67(3):309-14.|2
01720|079|R|3.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
01720|080|R|  Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
01720|081|R|  interactions with warfarin: A systematic review and meta-analysis. Br J|6
01720|082|R|  Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
01720|083|R|4.Mahe I, Bertrand N, Drouet L, Simoneau G, Mazoyer E, Bal dit Sollier C,|2
01720|084|R|  Caulin C, Bergmann JF. Paracetamol: a haemorrhagic risk factor in patients|2
01720|085|R|  on warfarin. Br J Clin Pharmacol 2005 Mar;59(3):371-4.|2
01720|086|R|5.Parra D, Beckey NP, Stevens GR. The effect of acetaminophen on the|2
01720|087|R|  international normalized ratio in patients stabilized on warfarin therapy.|2
01720|088|R|  Pharmacotherapy 2007 May;27(5):675-83.|2
01720|089|R|6.Mahe I, Bertrand N, Drouet L, Bal Dit Sollier C, Simoneau G, Mazoyer E,|2
01720|090|R|  Caulin C, Bergmann JF. Interaction between paracetamol and warfarin in|2
01720|091|R|  patients: a double-blind, placebo-controlled, randomized study.|2
01720|092|R|  Haematologica 2006 Dec;91(12):1621-7.|2
01720|093|R|7.Antlitz AM, Mead JA Jr, Tolentino MA. Potentiation of oral anticoagulant|2
01720|094|R|  therapy by acetaminophen. Curr Ther Res Clin Exp 1968 Oct;10(10):501-7.|2
01720|095|R|8.Justice JL, Kline SS. Analgesics and warfarin. A case that brings up|3
01720|096|R|  questions and cautions. Postgrad Med 1988 Apr;83(5):217-8, 220.|3
01720|097|R|9.Thijssen HH, Soute BA, Vervoort LM, Claessens JG. Paracetamol|3
01720|098|R|  (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of|3
01720|099|R|  paracetamol, is an inhibitor of enzymes in the vitamin K cycle. Thromb|3
01720|100|R|  Haemost 2004 Oct;92(4):797-802.|3
01720|101|R|10.Gebauer MG, Nyfort-Hansen K, Henschke PJ, Gallus AS. Warfarin and|3
01720|102|R|   acetaminophen interaction. Pharmacotherapy 2003 Jan;23(1):109-12.|3
01720|103|R|11.Lesho EP, Saullo L, Udvari-Nagy S. A 76-year-old woman with erratic|3
01720|104|R|   anticoagulation. Cleve Clin J Med 2004 Aug;71(8):651-6.|3
01720|105|R|12.Bagheri H, Bernhard NB, Montastruc JL. Potentiation of the acenocoumarol|3
01720|106|R|   anticoagulant effect by acetaminophen. Ann Pharmacother 1999 Apr;|3
01720|107|R|   33(4):506.|3
01720|108|R|13.van den Bemt PM, Geven LM, Kuitert NA, Risselada A, Brouwers JR. The|2
01720|109|R|   potential interaction between oral anticoagulants and acetaminophen in|2
01720|110|R|   everyday practice. Pharm World Sci 2002 Oct;24(5):201-4.|2
01720|111|R|14.Fattinger K, Frisullo R, Masche U, Braunschweig S, Meier PJ, Roos M. No|2
01720|112|R|   clinically relevant drug interaction between paracetamol and|2
01720|113|R|   phenprocoumon based on a pharmacoepidemiological cohort study in medical|2
01720|114|R|   inpatients. Eur J Clin Pharmacol 2002 Feb;57(12):863-7.|2
01720|115|R|15.Gadisseur AP, Van Der Meer FJ, Rosendaal FR. Sustained intake of|2
01720|116|R|   paracetamol (acetaminophen) during oral anticoagulant therapy with|2
01720|117|R|   coumarins does not cause clinically important INR changes: a randomized|2
01720|118|R|   double-blind clinical trial. J Thromb Haemost 2003 Apr;1(4):714-7.|2
01720|119|R|16.Kwan D, Bartle WR, Walker SE. The effects of acetaminophen on|2
01720|120|R|   pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999|2
01720|121|R|   Jan;39(1):68-75.|2
01720|122|R|17.Udall JA. Drug infererence with warfarin therapy. Clin Med 1970;77:20-25.|2
01720|123|R|18.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
01720|124|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
01720|125|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
01720|126|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
01720|127|R|19.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
01720|128|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
01720|129|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
01720|130|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
01721|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Tetracyclines|
01721|002|B||
01721|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01721|004|L|take action as needed.|
01721|005|B||
01721|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Tetracyclines may|
01721|007|A|interfere with vitamin-K producing gut flora.|
01721|008|B||
01721|009|E|CLINICAL EFFECTS:  The addition of a tetracycline to a patient maintained on|
01721|010|E|a coumarin anticoagulant may result in increased anticoagulant effects,|
01721|011|E|including bleeding.|
01721|012|B||
01721|013|P|PREDISPOSING FACTORS:  he risk for bleeding episodes may be greater in|
01721|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01721|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
01721|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01721|017|P|risk for bleeding (e.g. NSAIDs).|
01721|018|B||
01721|019|M|PATIENT MANAGEMENT:  Patients maintained on coumarin anticoagulants should|
01721|020|M|be closely monitored when tetracyclines are initiated and discontinued.  The|
01721|021|M|dosage of the anticoagulant may need to be adjusted.|
01721|022|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01721|023|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01721|024|M|anticoagulation in patients with active pathologic bleeding.|
01721|025|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01721|026|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01721|027|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01721|028|M|and/or swelling.|
01721|029|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01721|030|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01721|031|M|initiating, altering the dose or discontinuing either drug.|
01721|032|B||
01721|033|D|DISCUSSION:  In a retrospective review of patients receiving either|
01721|034|D|acenocoumarol or phenprocoumon, use of doxycycline and tetracycline was|
01721|035|D|associated with relative risk of major bleeding of 3 and 9, respectively.(1)|
01721|036|D|   There are several case reports of bleeding following the addition of|
01721|037|D|doxycycline(2-4) and tetracycline(5,6) to warfarin therapy.|
01721|038|B||
01721|039|R|REFERENCES:|
01721|040|B||
01721|041|R|1.Penning-van Beest FJ, Koerselman J, Herings RM. Risk of major bleeding|2
01721|042|R|  during concomitant use of antibiotic drugs and coumarin anticoagulants. J|2
01721|043|R|  Thromb Haemost 2008 Feb;6(2):284-90.|2
01721|044|R|2.Hasan SA. Interaction of doxycycline and warfarin: an enhanced|3
01721|045|R|  anticoagulant effect. Cornea 2007 Jul;26(6):742-3.|3
01721|046|R|3.Baciewicz AM, Bal BS. Bleeding associated with doxycycline and warfarin|3
01721|047|R|  treatment. Arch Intern Med 2001 May 14;161(9):1231.|3
01721|048|R|4.Caraco Y, Rubinow A. Enhanced anticoagulant effect of coumarin derivatives|3
01721|049|R|  induced by doxycycline coadministration. Ann Pharmacother 1992 Sep;|3
01721|050|R|  26(9):1084-6.|3
01721|051|R|5.Westfall LK, Mintzer DL, Wiser TH. Potentiation of warfarin by|3
01721|052|R|  tetracycline. Am J Hosp Pharm 1980 Dec;37(12):1620, 1625.|3
01721|053|R|6.Danos EA. Apparent potentiation of warfarin activity by tetracycline. Clin|3
01721|054|R|  Pharm 1992 Sep;11(9):806-8.|3
01722|001|T|MONOGRAPH TITLE:  TNF Blockers/Azathioprine; Mercaptopurine|
01722|002|B||
01722|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01722|004|L|of severe adverse interaction.|
01722|005|B||
01722|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
01722|007|A|additive or synergistic effects on the immune system.|
01722|008|B||
01722|009|E|CLINICAL EFFECTS:  Concurrent use of a TNF blocker with either azathioprine|
01722|010|E|or mercaptopurine may increase the risk of hepatosplenic T-cell lymphoma|
01722|011|E|(HSTCL), a rare but usually fatal cancer.(1-3)|
01722|012|B||
01722|013|P|PREDISPOSING FACTORS:  The majority of reports of hepatosplenic T cell|
01722|014|P|lymphoma in patients receiving concurrent TNF blockers with either|
01722|015|P|azathioprine or mercaptopurine have occurred in patients with Crohn's|
01722|016|P|disease or ulcerative colitis; however, there is one report in a psoriasis|
01722|017|P|patient and two reports in rheumatoid arthritis patients.(1)  The majority|
01722|018|P|of patients were adolescent or young males.(2)|
01722|019|B||
01722|020|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with TNF blockers|
01722|021|M|and either azathioprine or mercaptopurine should be counseled on the risk of|
01722|022|M|developing hepatosplenic T-cell lymphoma, a rare but usually fatal cancer.|
01722|023|M|They should be counseled on the signs and symptoms of malignancies such as|
01722|024|M|HSTCL, which may include splenomegaly, hepatomegaly, abdominal pain,|
01722|025|M|persistent fever, night sweats, and weight loss.|
01722|026|B||
01722|027|D|DISCUSSION:  From initiation of TNF marketing to December 31, 2010, the FDA|
01722|028|D|has received 28 reports of hepatosplenic T-cell lymphoma (HSTCL) in patients|
01722|029|D|receiving TNF blockers:  infliximab (20), etanercept (1), adalimumab (2),|
01722|030|D|infliximab/adalimumab (5), certolizumab (0), golimumab (0).  In 22 of these|
01722|031|D|cases, the patients were also receiving azathioprine or mercaptopurine (18|
01722|032|D|with infliximab, 4 with infliximab/adalimumab).(1)|
01722|033|B||
01722|034|R|REFERENCES:|
01722|035|B||
01722|036|R|1.USFood and Drug Administration. FDA Drug Safety Communication: Safety|1
01722|037|R|  Review update on reports of Hepatosplenic T-Cell Lymphoma in adolescents|1
01722|038|R|  and young adults receiving tumor necrosis factor (TNF) blockers,|1
01722|039|R|  azathioprine and/or mercaptopurine. Available at:|1
01722|040|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01722|041|R|  munication-update-tumor-necrosis-factor-tnf-blockers-and-risk-pediatric|1
01722|042|R|  April 14, 2011.|1
01722|043|R|2.Remicade (infliximab) US prescribing information. Janssen Biotech, Inc.|1
01722|044|R|  May, 2020.|1
01722|045|R|3.Humira (adalimumab) US prescribing information. Abbott Laboratories|1
01722|046|R|  December, 2018.|1
01722|047|R|4.Mackey AC, Green L, Liang LC, Dinndorf P, Avigan M. Hepatosplenic T cell|3
01722|048|R|  lymphoma associated with infliximab use in young patients treated for|3
01722|049|R|  inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007 Feb;|3
01722|050|R|  44(2):265-7.|3
01723|001|T|MONOGRAPH TITLE:  Yellow Fever Vaccine/Trabectedin (mono deleted 08/27/2014)|
01723|002|B||
01723|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01723|004|L|is contraindicated and generally should not be dispensed or administered to|
01723|005|L|the same patient.|
01723|006|B||
01723|007|A|MECHANISM OF ACTION:  Trabectedin suppresses the immune system.  In severely|
01723|008|A|immunocompromised patients, virus replication after administration of live,|
01723|009|A|attenuated-virus vaccines can be enhanced and/or the immune response to the|
01723|010|A|the vaccine may be decreased.(1)|
01723|011|B||
01723|012|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained|
01723|013|E|and/or the vaccine may result in illness.(1)|
01723|014|B||
01723|015|P|PREDISPOSING FACTORS:  None determined.|
01723|016|B||
01723|017|M|PATIENT MANAGEMENT:  The UK manufacturer of trabectedin states that|
01723|018|M|combination with the yellow fever vaccine is contraindicated.(2)|
01723|019|B||
01723|020|D|DISCUSSION:  The UK manufacturer of trabectedin states that combination with|
01723|021|D|the yellow fever vaccine is contraindicated.(2)|
01723|022|B||
01723|023|R|REFERENCES:|
01723|024|B||
01723|025|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
01723|026|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
01723|027|R|  Practices (ACIP). MMWR.  Available at:|1
01723|028|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
01723|029|R|  February 17, 2022;60(RR No.2):1-68.|1
01723|030|R|2.Yondelis (trabectedin) UK summary of product characteristics. Pharma Mar,|1
01723|031|R|  S.A. January 7, 2008.|1
01724|001|T|MONOGRAPH TITLE:  Methotrexate (Oncology-Injection)/Iodinated Contrast Media|
01724|002|B||
01724|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01724|004|L|of severe adverse interaction.|
01724|005|B||
01724|006|A|MECHANISM OF ACTION:  One possible mechanism is renal dysfunction caused by|
01724|007|A|the nephrotoxicity of both agents.|
01724|008|B||
01724|009|E|CLINICAL EFFECTS:  Concurrent use of iodinated contrast media may result in|
01724|010|E|methotrexate toxicity, leading to increased risk of severe neurotoxicity,|
01724|011|E|stomatitis, and myelosuppression, including neutropenia.|
01724|012|B||
01724|013|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
01724|014|P|- High-dose oncology regimens|
01724|015|P|- Impaired renal function, ascites, or pleural effusions|
01724|016|B||
01724|017|M|PATIENT MANAGEMENT:  It is recommended that the use of iodinated contrast|
01724|018|M|media in patients receiving high dose methotrexate therapy be avoided until|
01724|019|M|the serum methotrexate level is 0.1 mcmol/L or lower.  With lower dose|
01724|020|M|methotrexate therapy, iodinated contrast media should be used with caution|
01724|021|M|and preventative measures should be considered.(1)|
01724|022|B||
01724|023|D|DISCUSSION:  There are three case reports of patients receiving concurrent|
01724|024|D|iodinated contrast agents and methotrexate therapy developing methotrexate|
01724|025|D|toxicity. One patient received iodinated contrast media the day after|
01724|026|D|receiving a methotrexate infusion while the other two patients received|
01724|027|D|contrast media 30 hours and 4.5 hours after methotrexate therapy.(1,2)|
01724|028|B||
01724|029|R|REFERENCES:|
01724|030|B||
01724|031|R|1.Harned TM, Mascarenhas L. Severe methotrexate toxicity precipitated by|3
01724|032|R|  intravenous radiographic contrast. J Pediatr Hematol Oncol 2007 Jul;|3
01724|033|R|  29(7):496-9.|3
01724|034|R|2.Fong CM, Lee AC. High-dose methotrexate-associated acute renal failure may|3
01724|035|R|  be an avoidable complication. Pediatr Hematol Oncol 2006 Jan-Feb;|3
01724|036|R|  23(1):51-7.|3
01725|001|T|MONOGRAPH TITLE:  Sildenafil/Ciprofloxacin|
01725|002|B||
01725|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01725|004|L|take action as needed.|
01725|005|B||
01725|006|A|MECHANISM OF ACTION:  Ciprofloxacin may increase the absorption and|
01725|007|A|bioavailability of sildenafil.(1,2)|
01725|008|B||
01725|009|E|CLINICAL EFFECTS:  The concurrent use of ciprofloxacin may increase|
01725|010|E|sildenafil levels and effects.|
01725|011|B||
01725|012|P|PREDISPOSING FACTORS:  None determined.|
01725|013|B||
01725|014|M|PATIENT MANAGEMENT:  The dose of sildenafil may need to be adjusted during|
01725|015|M|concurrent therapy with ciprofloxacin.(2)|
01725|016|B||
01725|017|D|DISCUSSION:  In a bioavailability study of 12 male volunteers, concurrent|
01725|018|D|use of sildenafil and ciprofloxacin resulted in an increase in the|
01725|019|D|area-under-curve (AUC) of 112% and maximum concentration (Cmax) by 117%.|
01725|020|D|Sildenafil half-life was prolonged 37.6%.(1)|
01725|021|B||
01725|022|R|REFERENCES:|
01725|023|B||
01725|024|R|1.Hedaya MA, El-Afify DR, El-Maghraby GM. The effect of ciprofloxacin and|2
01725|025|R|  clarithromycin on sildenafil oral bioavailability in human volunteers.|2
01725|026|R|  Biopharm Drug Dispos 2006 Mar;27(2):103-10.|2
01725|027|R|2.Viagra (sildenafil) US prescribing information. Pfizer Inc. December 14,|1
01725|028|R|  2017.|1
01726|001|T|MONOGRAPH TITLE:  Warfarin/Chitosan|
01726|002|B||
01726|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01726|004|L|Assess the risk to the patient and take action as needed.|
01726|005|B||
01726|006|A|MECHANISM OF ACTION:  Chitosan can impair the absorption of vitamin K,|
01726|007|A|thereby potentiating the anticoagulant effects of warfarin.(1)|
01726|008|B||
01726|009|E|CLINICAL EFFECTS:  Concurrent use of chitosan with warfarin may cause|
01726|010|E|increased INR and increased risk of bleeding.|
01726|011|B||
01726|012|P|PREDISPOSING FACTORS:  None determined.|
01726|013|B||
01726|014|M|PATIENT MANAGEMENT:  Patients receiving warfarin should be carefully|
01726|015|M|monitored for increased clinical effect if chitosan is added to concurrent|
01726|016|M|therapy.  The dose of warfarin may need to be adjusted or chitosan may need|
01726|017|M|to be discontinued.|
01726|018|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01726|019|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01726|020|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01726|021|M|patients with any symptoms.|
01726|022|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01726|023|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01726|024|M|anticoagulation in patients with active pathologic bleeding.|
01726|025|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01726|026|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01726|027|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01726|028|M|and/or swelling.|
01726|029|B||
01726|030|D|DISCUSSION:  There has been one case report of an 83 year-old male whose INR|
01726|031|D|was 2 prior to chitosan therapy.  After two months of concurrent chitosan|
01726|032|D|and warfarin therapy his INR increased to 9 with no changes in the patient's|
01726|033|D|diet or medications.(1)|
01726|034|B||
01726|035|R|REFERENCE:|
01726|036|B||
01726|037|R|1.Huang SS, Sung SH, Chiang CE. Chitosan potentiation of warfarin effect.|3
01726|038|R|  Ann Pharmacother 2007 Nov;41(11):1912-4.|3
01727|001|T|MONOGRAPH TITLE:  Tolbutamide/Ginkgo Biloba|
01727|002|B||
01727|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01727|004|L|take action as needed.|
01727|005|B||
01727|006|A|MECHANISM OF ACTION:  Ginkgo biloba may induce the metabolism of|
01727|007|A|tolbutamide.|
01727|008|B||
01727|009|E|CLINICAL EFFECTS:  The concurrent use of ginkgo biloba may result in a|
01727|010|E|decrease in tolbutamide levels and clinical effect.|
01727|011|B||
01727|012|P|PREDISPOSING FACTORS:  None determined.|
01727|013|B||
01727|014|M|PATIENT MANAGEMENT:  Patients should be carefully monitored for changes in|
01727|015|M|tolbutamide levels and clinical effect if ginkgo biloba is added to or|
01727|016|M|discontinued from concurrent therapy. The dose of tolbutamide may need to be|
01727|017|M|adjusted.|
01727|018|B||
01727|019|D|DISCUSSION:  A study involving ten healthy nonsmoking volunteers showed that|
01727|020|D|concurrent use of tolbutamide and a standardized dose of ginkgo biloba|
01727|021|D|resulted in a 16% decrease in tolbutamide area-under curve (AUC) and a 17%|
01727|022|D|decrease in the ratio of AUC for tolbutamide to 4-hydroxytolbutamide. The|
01727|023|D|metabolic ratio for tolbutamide in urine was not altered by concurrent|
01727|024|D|ginkgo biloba administration.(1)|
01727|025|B||
01727|026|R|REFERENCE:|
01727|027|B||
01727|028|R|1.Uchida S, Yamada H, Li XD, Maruyama S, Ohmori Y, Oki T, Watanabe H,|2
01727|029|R|  Umegaki K, Ohashi K, Yamada S. Effects of Ginkgo biloba extract on|2
01727|030|R|  pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in|2
01727|031|R|  healthy volunteers. J Clin Pharmacol 2006 Nov;46(11):1290-8.|2
01728|001|T|MONOGRAPH TITLE:  Irinotecan/Milk Thistle|
01728|002|B||
01728|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01728|004|L|Assess the risk to the patient and take action as needed.|
01728|005|B||
01728|006|A|MECHANISM OF ACTION:  Milk thistle has been shown to increase levels of an|
01728|007|A|irinotecan metabolite, SN-38 through its inhibition of CYP3A4 and UGT1A1.|
01728|008|B||
01728|009|E|CLINICAL EFFECTS:  The concurrent administration of irinotecan and milk|
01728|010|E|thistle may result in a slight decrease in the metabolic conversion of|
01728|011|E|irinotecan.|
01728|012|B||
01728|013|P|PREDISPOSING FACTORS:  None determined.|
01728|014|B||
01728|015|M|PATIENT MANAGEMENT:  At recommended doses, the concurrent administration of|
01728|016|M|milk thistle and irinotecan is not likely to result in a change in the|
01728|017|M|clinical effect of irinotecan.  At higher dosages, this could result in an|
01728|018|M|increase in serum SN-38 levels and should be monitored.|
01728|019|B||
01728|020|D|DISCUSSION:  In one study, six cancer patients were given irinotecan for|
01728|021|D|four consecutive weeks.  Four days prior to the second dose of irinotecan,|
01728|022|D|patients began taking milk thistle seed extract for 14 days.  The only|
01728|023|D|effect of concurrent administration was a decrease in the SN-38 irinotecan|
01728|024|D|metabolite from 2.58% to 2.17% on day 15.  The authors state that this is|
01728|025|D|unlikely to be clinically significant at recommended dosages of milk|
01728|026|D|thistle.(1)|
01728|027|B||
01728|028|R|REFERENCE:|
01728|029|B||
01728|030|R|1.van Erp NP, Baker SD, Zhao M, Rudek MA, Guchelaar HJ, Nortier JW,|2
01728|031|R|  Sparreboom A, Gelderblom H. Effect of milk thistle (Silybum marianum) on|2
01728|032|R|  the pharmacokinetics of irinotecan. Clin Cancer Res 2005 Nov 1;|2
01728|033|R|  11(21):7800-6.|2
01729|001|T|MONOGRAPH TITLE:  Midazolam/Ginkgo Biloba|
01729|002|B||
01729|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01729|004|L|take action as needed.|
01729|005|B||
01729|006|A|MECHANISM OF ACTION:  Ginkgo biloba may inhibit the metabolism of midazolam|
01729|007|A|by CYP3A4.|
01729|008|B||
01729|009|E|CLINICAL EFFECTS:  The concurrent use of midazolam and ginkgo biloba may|
01729|010|E|result in an increase in the midazolam area-under curve (AUC) and clinical|
01729|011|E|effects.|
01729|012|B||
01729|013|P|PREDISPOSING FACTORS:  None determined.|
01729|014|B||
01729|015|M|PATIENT MANAGEMENT:  The concurrent use of midazolam and ginkgo biloba|
01729|016|M|should be approached with caution. The patient should be monitored for a|
01729|017|M|possible change in midazolam clinical effect if ginkgo biloba is added to or|
01729|018|M|removed from concurrent therapy.|
01729|019|B||
01729|020|D|DISCUSSION:  A study involving ten healthy nonsmoking volunteers found that|
01729|021|D|concurrent use of ginkgo biloba and midazolam showed an increase in the|
01729|022|D|midazolam AUC of 25%.(1)|
01729|023|B||
01729|024|R|REFERENCE:|
01729|025|B||
01729|026|R|1.Uchida S, Yamada H, Li XD, Maruyama S, Ohmori Y, Oki T, Watanabe H,|2
01729|027|R|  Umegaki K, Ohashi K, Yamada S. Effects of Ginkgo biloba extract on|2
01729|028|R|  pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in|2
01729|029|R|  healthy volunteers. J Clin Pharmacol 2006 Nov;46(11):1290-8.|2
01731|001|T|MONOGRAPH TITLE:  Azathioprine; Mercaptopurine/Sulfamethoxazole-Trimethoprim|
01731|002|B||
01731|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01731|004|L|take action as needed.|
01731|005|B||
01731|006|A|MECHANISM OF ACTION:  The combination of antimetabolite properties of either|
01731|007|A|azathioprine or mercaptopurine with the inhibition of dihydrofolate|
01731|008|A|reductase by sulfamethoxazole-trimethoprim may result in cytopenias.(1)|
01731|009|B||
01731|010|E|CLINICAL EFFECTS:  Concurrent use of either azathioprine or mercaptopurine|
01731|011|E|with sulfamethoxazole-trimethoprim may result in leucopenia,(2,3)|
01731|012|E|neutropenia, or thrombocytopenia,(1)|
01731|013|B||
01731|014|P|PREDISPOSING FACTORS:  Renal transplant patients(2), especially those within|
01731|015|P|60 days of transplant,(3) may be predisposed to this interaction.|
01731|016|P|   Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or|
01731|017|P|nucleotide diphosphatase (NUDT15) activity are at higher risk of|
01731|018|P|accumulating thiopurine metabolites and severe myelosuppression.|
01731|019|P|Approximately 0.3 % of patients of European, Latino, or African descent have|
01731|020|P|mutations of the TPMT gene resulting in little to no TPMT activity|
01731|021|P|(homozygous deficiency), and approximately 10 % have intermediate TPMT|
01731|022|P|activity (heterozygous deficiency).  NUDT15 deficiency is not seen in|
01731|023|P|patients of African descent and is seen in less than 1 % of patients of|
01731|024|P|European descent.  Approximately 1 % of patients of East Asian descent, 0.5|
01731|025|P|% of patients of central/south Asian descent, and 2 % of patients of Latino|
01731|026|P|descent have homozygous NUDT15 deficiency.  About 17 % of patients of East|
01731|027|P|Asian descent, 13 % of patients of central/south Asian descent, and 8 % of|
01731|028|P|patients of Latino descent have heterozygous NUDT15 deficiency.(4)|
01731|029|B||
01731|030|M|PATIENT MANAGEMENT:  Patients receiving this combination should be closely|
01731|031|M|monitored for cytopenias.|
01731|032|M|   The Australian manufacturer of sulfamethoxazole-trimethoprim states that|
01731|033|M|alternatives to sulfamethoxazole-trimethoprim should be considered for|
01731|034|M|patients receiving azathioprine or mercaptopurine.(6)|
01731|035|B||
01731|036|D|DISCUSSION:  In a retrospective review of 40 renal transplant patients, 25|
01731|037|D|received azathioprine alone, 6 received azathioprine with|
01731|038|D|sulfamethoxazole-trimethoprim prophylaxis, and 9 received|
01731|039|D|sulfamethoxazole-trimethoprim for treatment of a urinary tract infection|
01731|040|D|(UTI).  Patients in the prophylaxis group had an increased incidence and|
01731|041|D|duration of neutropenia and thrombocytopenia compared to patients receiving|
01731|042|D|azathioprine alone.  There were no differences in the incidence or duration|
01731|043|D|of neutropenia or thrombocytopenia between patients receiving azathioprine|
01731|044|D|alone or with concurrent sulfamethoxazole-trimethoprim for UTI treatment.|
01731|045|D|   In a study of renal transplant patients, 4 of 14 patients maintained on|
01731|046|D|azathioprine developed leucopenia following the addition of|
01731|047|D|sulfamethoxazole-trimethoprim for the treatment of UTI.  In 3 patients, the|
01731|048|D|leucopenia developed within 2 days of the initiation of|
01731|049|D|sulfamethoxazole-trimethoprim.(3)|
01731|050|D|   In contrast to these reports, a retrospective review of 94 renal|
01731|051|D|transplant patients found that the incidence of leucopenia with concurrent|
01731|052|D|azathioprine and sulfamethoxazole-trimethoprim was not significantly|
01731|053|D|different than the incidence with concurrent azathioprine and other|
01731|054|D|antibiotics.(5)|
01731|055|B||
01731|056|R|REFERENCES:|
01731|057|B||
01731|058|R|1.Bradley PP, Warden GD, Maxwell JG, Rothstein G. Neutropenia and|2
01731|059|R|  thrombocytopenia in renal allograft recipients treated with|2
01731|060|R|  trimethoprim-sulfamethoxazole. Ann Intern Med 1980 Oct;93(4):560-2.|2
01731|061|R|2.Imuran (azathioprine) US prescribing information. Prometheus Laboratories|1
01731|062|R|  Inc. February, 2014.|1
01731|063|R|3.Hulme B, Reeves DS. Leucopenia associated with|2
01731|064|R|  trimethoprim-sulphamethoxazole after renal transplantation. Br Med J 1971|2
01731|065|R|  Sep 11;3(5775):610-2.|2
01731|066|R|4.Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM,|6
01731|067|R|  Moyer AM, Evans WE, Klein TE, Antillon-Klussmann FG, Caudle KE, Kato M,|6
01731|068|R|  Yeoh AEJ, Schmiegelow K, Yang JJ. Clinical Pharmacogenetics Implementation|6
01731|069|R|  Consortium Guideline for Thiopurine Dosing  Based on TPMT and NUDT15|6
01731|070|R|  Genotypes: 2018 Update. Clin Pharmacol Ther 2019 May;105(5):1095-1105.|6
01731|071|R|5.Hall CL. Co-trimoxazole and azathioprine: a safe combination. Br Med J|2
01731|072|R|  1974 Oct 5;4(5935):15-6.|2
01731|073|R|6.Bactrim DS (sulfamethoxazole and trimethoprim) Australian Product|1
01731|074|R|  Information. Echo Therapeutics Pty Ltd Jan 2024.|1
01732|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Stiripentol|
01732|002|B||
01732|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01732|004|L|of severe adverse interaction.|
01732|005|B||
01732|006|A|MECHANISM OF ACTION:  Stiripentol may inhibit the metabolism of ergot|
01732|007|A|alkaloids by CYP3A4.(1)|
01732|008|B||
01732|009|E|CLINICAL EFFECTS:  Concurrent use of stiripentol may result in elevated|
01732|010|E|levels of ergot alkaloids, which may result in ergotism with the possibility|
01732|011|E|of necrosis of the extremities.(1)|
01732|012|B||
01732|013|P|PREDISPOSING FACTORS:  None determined.|
01732|014|B||
01732|015|M|PATIENT MANAGEMENT:  The UK manufacturer of stiripentol states that|
01732|016|M|concurrent use of ergot alkaloids should be avoided unless strictly|
01732|017|M|necessary.(1)|
01732|018|B||
01732|019|D|DISCUSSION:  Stiripentol has been shown to inhibit CYP3A4.  In a pediatric|
01732|020|D|study, concurrent administration of stiripentol and clobazam (a CYP3A4|
01732|021|D|substrate) increased clobazam plasma levels by approximately 2- to|
01732|022|D|3-fold.(1)|
01732|023|B||
01732|024|R|REFERENCE:|
01732|025|B||
01732|026|R|1.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
01732|027|R|  March, 2007.|1
01733|001|T|MONOGRAPH TITLE:  Cisapride/Stiripentol|
01733|002|B||
01733|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01733|004|L|of severe adverse interaction.|
01733|005|B||
01733|006|A|MECHANISM OF ACTION:  Stiripentol may inhibit the metabolism of cisapride by|
01733|007|A|CYP3A4.(1)|
01733|008|B||
01733|009|E|CLINICAL EFFECTS:  Concurrent use of stiripentol may result in elevated|
01733|010|E|levels of cisapride, which may increase the risk of cardiac arrhythmias|
01733|011|E|including QT prolongation or torsades de pointes/wave burst arrhythmia.(1)|
01733|012|B||
01733|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01733|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
01733|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01733|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01733|017|P|female gender, or advanced age.(2)|
01733|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01733|019|P|higher systemic concentrations of either QT prolonging drug are additional|
01733|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01733|021|P|drug concentrations include rapid infusion of an intravenous dose or|
01733|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01733|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01733|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01733|025|B||
01733|026|M|PATIENT MANAGEMENT:  The UK manufacturer of stiripentol states that|
01733|027|M|concurrent use of cisapride should be avoided unless strictly necessary.(1)|
01733|028|B||
01733|029|D|DISCUSSION:  Stiripentol has been shown to inhibit CYP3A4.(1)|
01733|030|B||
01733|031|R|REFERENCES:|
01733|032|B||
01733|033|R|1.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
01733|034|R|  March, 2007.|1
01733|035|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01733|036|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01733|037|R|  settings: a scientific statement from the American Heart Association and|6
01733|038|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01733|039|R|  2;55(9):934-47.|6
01734|001|T|MONOGRAPH TITLE:  Halofantrine/Stiripentol|
01734|002|B||
01734|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01734|004|L|of severe adverse interaction.|
01734|005|B||
01734|006|A|MECHANISM OF ACTION:  Stiripentol may inhibit the metabolism of halofantrine|
01734|007|A|by CYP3A4.(1)|
01734|008|B||
01734|009|E|CLINICAL EFFECTS:  Concurrent use of stiripentol may result in elevated|
01734|010|E|levels of halofantrine, which may increase the risk of cardiac arrhythmias|
01734|011|E|including QT prolongation or torsades de pointes/wave burst arrhythmia.(1)|
01734|012|B||
01734|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01734|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
01734|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01734|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01734|017|P|female gender, or advanced age.(2)|
01734|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01734|019|P|higher systemic concentrations of either QT prolonging drug are additional|
01734|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01734|021|P|drug concentrations include rapid infusion of an intravenous dose or|
01734|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01734|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01734|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01734|025|B||
01734|026|M|PATIENT MANAGEMENT:  The UK manufacturer of stiripentol states that|
01734|027|M|concurrent use of halofantrine should be avoided unless strictly|
01734|028|M|necessary.(1)|
01734|029|B||
01734|030|D|DISCUSSION:  Stiripentol has been shown to inhibit CYP3A4.(1)|
01734|031|B||
01734|032|R|REFERENCES:|
01734|033|B||
01734|034|R|1.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
01734|035|R|  March, 2007.|1
01734|036|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01734|037|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01734|038|R|  settings: a scientific statement from the American Heart Association and|6
01734|039|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01734|040|R|  2;55(9):934-47.|6
01735|001|T|MONOGRAPH TITLE:  Pimozide/Stiripentol|
01735|002|B||
01735|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01735|004|L|of severe adverse interaction.|
01735|005|B||
01735|006|A|MECHANISM OF ACTION:  Stiripentol may inhibit the metabolism of pimozide by|
01735|007|A|CYP3A4.(1)|
01735|008|B||
01735|009|E|CLINICAL EFFECTS:  Concurrent use of stiripentol may result in elevated|
01735|010|E|levels of pimozide, which may increase the risk of cardiac arrhythmias|
01735|011|E|including QT prolongation or torsades de pointes/wave burst arrhythmia.(1)|
01735|012|B||
01735|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01735|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
01735|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01735|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01735|017|P|female gender, or advanced age.(2)|
01735|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01735|019|P|higher systemic concentrations of either QT prolonging drug are additional|
01735|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01735|021|P|drug concentrations include rapid infusion of an intravenous dose or|
01735|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01735|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01735|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01735|025|P|   The risk of anticholinergic toxicities including cognitive decline,|
01735|026|P|delirium, falls and fractures is increased in geriatric patients using more|
01735|027|P|than one medicine with anticholinergic properties.(3)|
01735|028|B||
01735|029|M|PATIENT MANAGEMENT:  The UK manufacturer of stiripentol states that|
01735|030|M|concurrent use of pimozide should be avoided unless strictly necessary.(1)|
01735|031|B||
01735|032|D|DISCUSSION:  Stiripentol has been shown to inhibit CYP3A4.(1)|
01735|033|B||
01735|034|R|REFERENCES:|
01735|035|B||
01735|036|R|1.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
01735|037|R|  March, 2007.|1
01735|038|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01735|039|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01735|040|R|  settings: a scientific statement from the American Heart Association and|6
01735|041|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01735|042|R|  2;55(9):934-47.|6
01735|043|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01735|044|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01735|045|R|  Soc 2023 Jul;71(7):2052-2081.|6
01736|001|T|MONOGRAPH TITLE:  Bepridil; Quinidine/Stiripentol|
01736|002|B||
01736|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01736|004|L|of severe adverse interaction.|
01736|005|B||
01736|006|A|MECHANISM OF ACTION:  Stiripentol may inhibit the metabolism of bepridil and|
01736|007|A|quinidine by CYP3A4.(1)|
01736|008|B||
01736|009|E|CLINICAL EFFECTS:  Concurrent use of stiripentol may result in elevated|
01736|010|E|levels of bepridil and quinidine, which may increase the risk of cardiac|
01736|011|E|arrhythmias including QT prolongation or torsades de pointes/wave burst|
01736|012|E|arrhythmia.(1)|
01736|013|B||
01736|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01736|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01736|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01736|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01736|018|P|female gender, or advanced age.(2)|
01736|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01736|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01736|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01736|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01736|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01736|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01736|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01736|026|B||
01736|027|M|PATIENT MANAGEMENT:  The UK manufacturer of stiripentol states that|
01736|028|M|concurrent use of bepridil or quinidine should be avoided unless strictly|
01736|029|M|necessary.(1)|
01736|030|B||
01736|031|D|DISCUSSION:  Stiripentol has been shown to inhibit CYP3A4.(1)|
01736|032|B||
01736|033|R|REFERENCES:|
01736|034|B||
01736|035|R|1.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
01736|036|R|  March, 2007.|1
01736|037|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01736|038|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01736|039|R|  settings: a scientific statement from the American Heart Association and|6
01736|040|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01736|041|R|  2;55(9):934-47.|6
01737|001|T|MONOGRAPH TITLE:  Selected HMG-CoA Reductase Inhibitors/Stiripentol|
01737|002|B||
01737|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01737|004|L|of severe adverse interaction.|
01737|005|B||
01737|006|A|MECHANISM OF ACTION:  Stiripentol may inhibit the metabolism of some HMG-CoA|
01737|007|A|reductase inhibitors by CYP3A4.(1)|
01737|008|B||
01737|009|E|CLINICAL EFFECTS:  Concurrent use of stiripentol may result in elevated|
01737|010|E|levels of HMG-CoA reductase inhibitors that are metabolized by CYP3A4, which|
01737|011|E|may result in rhabdomyolysis.(1)|
01737|012|B||
01737|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01737|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01737|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01737|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01737|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01737|018|P|transporter OATP1B1 may have increased statin concentrations and be|
01737|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
01737|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
01737|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
01737|022|B||
01737|023|M|PATIENT MANAGEMENT:  The UK manufacturer of stiripentol states that|
01737|024|M|concurrent use of HMG-CoA reductase inhibitors metabolized by CYP3A4 should|
01737|025|M|d be avoided unless strictly necessary.(1)|
01737|026|B||
01737|027|D|DISCUSSION:  Stiripentol has been shown to inhibit CYP3A4.(1)|
01737|028|B||
01737|029|R|REFERENCE:|
01737|030|B||
01737|031|R|1.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
01737|032|R|  March, 2007.|1
01738|001|T|MONOGRAPH TITLE:  Telbivudine/Interferon Alfa-2a (non-pegylated)|
01738|002|B||
01738|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01738|004|L|of severe adverse interaction.|
01738|005|B||
01738|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01738|007|B||
01738|008|E|CLINICAL EFFECTS:  Concurrent use of telbivudine and interferon alfa-2a may|
01738|009|E|increase the risk of peripheral neuropathy.(1,2))|
01738|010|B||
01738|011|P|PREDISPOSING FACTORS:  None determined.|
01738|012|B||
01738|013|M|PATIENT MANAGEMENT:  The concurrent use of telbivudine and pegylated|
01738|014|M|interferon alfa-2a is contraindicated.(1)|
01738|015|M|   Patients receiving concurrent therapy with telbivudine and other forms of|
01738|016|M|interferon alfa-2a should be closely observed for and instructed to report|
01738|017|M|any symptoms of peripheral neuropathy.  Treatment with telbivudine should be|
01738|018|M|reconsidered if peripheral neuropathy is suspected.(1,2)|
01738|019|B||
01738|020|D|DISCUSSION:  In a small clinical trial, 10% (5/48) of patients receiving|
01738|021|D|concurrent therapy with telbivudine and interferon alfa-2a developed serious|
01738|022|D|peripheral neuropathy.  An additional 3 patients developed non-serious|
01738|023|D|peripheral neuropathy, for a total incidence of 17% (8/48).  Incidence of|
01738|024|D|peripheral neuropathy in clinical trials with telbivudine alone has been|
01738|025|D|reported to be 0.3% and up to 5% with interferon alfa-2a alone.(2)|
01738|026|D|   The time to onset of serious neuropathy during concurrent therapy with|
01738|027|D|telbivudine and interferon alfa-2a was 1 to 6 months.  Symptoms included|
01738|028|D|weakness and paraesthesias and pain in the legs.(2)|
01738|029|B||
01738|030|R|REFERENCES:|
01738|031|B||
01738|032|R|1.Tyzeka (telbivudine) US prescribing information. Novartis Pharmaceuticals|1
01738|033|R|  Corporation December, 2018.|1
01738|034|R|2.Leclerc JM. Dear Health Care Professional letter.  Subject:  Risk of|1
01738|035|R|  peripheral neuropathy in patients treated with telbivudine (SEBIVO) and|1
01738|036|R|  interferon. Novartis Pharmaceuticeuticals Canada, Inc. March 7, 2008.|1
01739|001|T|MONOGRAPH TITLE:  Phenytoin/Aluminum-Magnesium Hydroxide; Oral Calcium|
01739|002|B||
01739|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01739|004|L|take action as needed.|
01739|005|B||
01739|006|A|MECHANISM OF ACTION:  Aluminum hydroxide; magnesium hydroxide, and oral|
01739|007|A|calcium may bind to phenytoin, preventing its absorption.(1-4)|
01739|008|B||
01739|009|E|CLINICAL EFFECTS:  Simultaneous ingestion of aluminum-magnesium hydroxide|
01739|010|E|and/or calcium-containing products may result in decreased levels and|
01739|011|E|effectiveness of phenytoin.(1-4)|
01739|012|B||
01739|013|P|PREDISPOSING FACTORS:  None determined.|
01739|014|B||
01739|015|M|PATIENT MANAGEMENT:  The US manufacturer of phenytoin recommends that|
01739|016|M|administration times of phenytoin and antacids being staggered.(1)|
01739|017|B||
01739|018|D|DISCUSSION:  In a study in 8 healthy subjects, simultaneous administration|
01739|019|D|of phenytoin (600 mg) with calcium carbonate significantly decreased the|
01739|020|D|area-under-curve (AUC) of phenytoin.(2)|
01739|021|D|   In a study in 8 healthy subjects, simultaneous administration of|
01739|022|D|aluminum-magnesium hydroxide or calcium carbonate significantly decreased|
01739|023|D|the AUC of phenytoin.(3)|
01739|024|D|   In a study in 6 patients with epilepsy, concurrent administration of an|
01739|025|D|aluminum-magnesium hydroxide antacid resulted in a small but statistically|
01739|026|D|significant decrease in phenytoin AUC.(4)|
01739|027|B||
01739|028|R|REFERENCES:|
01739|029|B||
01739|030|R|1.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
01739|031|R|  March, 2022.|1
01739|032|R|2.Garnett WR, Carter BL, Pellock JM. Effect of calcium and antacids on|2
01739|033|R|  phenytoin bioavailability. Arch Neurol 1980 Jul;37(7):467.|2
01739|034|R|3.Carter BL, Garnett WR, Pellock JM, Stratton MA, Howell JR. Effect of|2
01739|035|R|  antacids on phenytoin bioavailability. Ther Drug Monit 1981;3(4):333-40.|2
01739|036|R|4.Kulshrestha VK, Thomas M, Wadsworth J, Richens A. Interaction between|2
01739|037|R|  phenytoin and antacids. Br J Clin Pharmacol 1978 Aug;6(2):177-9.|2
01740|001|T|MONOGRAPH TITLE:  Tamoxifen/Selected Strong CYP2D6 Inhibitors|
01740|002|B||
01740|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01740|004|L|of severe adverse interaction.|
01740|005|B||
01740|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2D6 may inhibit the conversion of|
01740|007|A|tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2)  The role|
01740|008|A|of endoxifen in tamoxifen's efficacy has been debated and may involve a|
01740|009|A|minimum concentration level.(3-5)|
01740|010|B||
01740|011|E|CLINICAL EFFECTS:  Concurrent use of inhibitors of CYP2D6 may decrease the|
01740|012|E|effectiveness of tamoxifen in preventing breast cancer recurrence.|
01740|013|B||
01740|014|P|PREDISPOSING FACTORS:  Concurrent use of strong CYP2D6 inhibitors in|
01740|015|P|patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers|
01740|016|P|should be avoided.  Patients who are CYP2D6 poor metabolizers lack CYP2D6|
01740|017|P|function and are not affected by CYP2D6 inhibition.|
01740|018|B||
01740|019|M|PATIENT MANAGEMENT:  Although data on this interaction are conflicting, it|
01740|020|M|may be prudent to use alternatives to CYP2D6 inhibitors when possible in|
01740|021|M|patients taking tamoxifen.  The US manufacturer of tamoxifen states that the|
01740|022|M|impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain|
01740|023|M|and makes no recommendation regarding coadministration with inhibitors of|
01740|024|M|CYP2D6.(12)  The manufacturer of paroxetine (a strong CYP2D6 inhibitor)|
01740|025|M|states that alternative agents with little or no CYP2D6 inhibition should be|
01740|026|M|considered.(13)|
01740|027|M|   The Canadian and UK manufacturers of fluoxetine state that whenever|
01740|028|M|possible co-administration with tamoxifen should be avoided.(14-15)|
01740|029|M|   The National Comprehensive Cancer Network's breast cancer guidelines|
01740|030|M|advises caution when coadministering strong CYP2D6 inhibitors with|
01740|031|M|tamoxifen.(16)|
01740|032|M|   If concurrent therapy is warranted, the risks versus benefits should be|
01740|033|M|discussed with the patient.|
01740|034|B||
01740|035|D|DISCUSSION:  Some studies have suggested that administration of fluoxetine,|
01740|036|D|paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer|
01740|037|D|phenotype may result in a decrease in the formation of endoxifen (an active|
01740|038|D|metabolite of tamoxifen) and a shorter time to breast cancer|
01740|039|D|recurrence.(1-2,9)|
01740|040|D|   A retrospective study of 630 breast cancer patients found an increasing|
01740|041|D|risk of breast cancer mortality with increasing durations of|
01740|042|D|coadministration of tamoxifen and paroxetine.  In the adjusted analysis,|
01740|043|D|absolute increases of 25%, 50%, and 75% in the proportion of time of|
01740|044|D|overlapping use of tamoxifen with paroxetine was associated with 24%, 54%,|
01740|045|D|and 91% increase in the risk of death from breast cancer, respectively.(17)|
01740|046|D|   The CYP2D6 genotype of the patient may have a role in the effects of this|
01740|047|D|interaction.  Patients with wild-type CYP2D6 genotype may be affected to a|
01740|048|D|greater extent by this interaction.  Patients with a variant CYP2D6 genotype|
01740|049|D|may have lower baseline levels of endoxifen and may be affected to a lesser|
01740|050|D|extent by this interaction.(6-10)|
01740|051|D|   In a retrospective review, 1,325 patients treated with tamoxifen for|
01740|052|D|breast cancer were classified as being poor 2D6 metabolizers (lacking|
01740|053|D|functional CYP2D6 enzymes), intermediate metabolizers (heterozygous|
01740|054|D|alleles), or extensive metabolizers (possessing 2 functional alleles).|
01740|055|D|After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%,|
01740|056|D|20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and|
01740|057|D|poor metabolizers, respectively.(11)|
01740|058|D|   In October of 2006, the Advisory Committee Pharmaceutical Science,|
01740|059|D|Clinical Pharmacology Subcommittee of the US Food and Drug Administration|
01740|060|D|recommended that the US tamoxifen labeling be updated to include information|
01740|061|D|about the increased risk of breast cancer recurrence in poor CYP2D6|
01740|062|D|metabolizers (either by genotype or drug interaction).(18-19)  The labeling|
01740|063|D|changes were never made due to ongoing uncertainty about the effects of|
01740|064|D|CYP2D6 genotypes on tamoxifen efficacy.|
01740|065|D|   In contrast to the above information, two studies have shown no|
01740|066|D|relationship between CYP2D6 genotype and breast cancer outcome.(20-22)  As|
01740|067|D|well, a number of studies found no association between use of CYP2D6|
01740|068|D|inhibitors and/or antidepressants in patients on tamoxifen and breast cancer|
01740|069|D|recurrence,(23-27) though the studies were limited by problematic selection|
01740|070|D|of CYP2D6 inhibitors and short follow-up.|
01740|071|D|   Strong inhibitors of CYP2D6 include bupropion, dacomitinib, fluoxetine,|
01740|072|D|paroxetine, peruvian bark extract, and terbinafine.(28-29)|
01740|073|B||
01740|074|R|REFERENCES:|
01740|075|B||
01740|076|R|1.Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes|2
01740|077|R|  DF, Desta Z, Flockhart DA. Active tamoxifen metabolite plasma|2
01740|078|R|  concentrations after coadministration of tamoxifen and the selective|2
01740|079|R|  serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003 Dec 3;|2
01740|080|R|  95(23):1758-64.|2
01740|081|R|2.Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li|2
01740|082|R|  L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S,|2
01740|083|R|  Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype,|2
01740|084|R|  antidepressant use, and tamoxifen metabolism during adjuvant breast cancer|2
01740|085|R|  treatment. J Natl Cancer Inst 2005 Jan 5;97(1):30-9.|2
01740|086|R|3.Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z,|2
01740|087|R|  Flockhart DA, Skaar TC. Pharmacological characterization of|2
01740|088|R|  4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen.|2
01740|089|R|  Breast Cancer Res Treat 2004 May;85(2):151-9.|2
01740|090|R|4.Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of|2
01740|091|R|  tamoxifen sequential biotransformation by the human cytochrome P450 system|2
01740|092|R|  in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004|2
01740|093|R|  Sep;310(3):1062-75.|2
01740|094|R|5.Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen|2
01740|095|R|  (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast|2
01740|096|R|  cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother|2
01740|097|R|  Pharmacol 2005 May;55(5):471-8.|2
01740|098|R|6.Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, Nussler|5
01740|099|R|  A, Neuhaus P, Zanger UM, Eichelbaum M, Murdter TE. The influence of|5
01740|100|R|  CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent|5
01740|101|R|  antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol|5
01740|102|R|  2002 Aug;54(2):157-67.|5
01740|103|R|7.Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6|6
01740|104|R|  as a predictor of drug response. Clin Pharmacol Ther 2008 Jan;83(1):160-6.|6
01740|105|R|8.Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD. CYP2D6 polymorphisms|6
01740|106|R|  and the impact on tamoxifen therapy. J Pharm Sci 2007 Sep;96(9):2224-31.|6
01740|107|R|9.Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW,|2
01740|108|R|  Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM,|2
01740|109|R|  Desta Z, Nguyen A, Flockhart DA. Perez EA, Ingle JN. The impact of|2
01740|110|R|  cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.|2
01740|111|R|  Breast Cancer Res Treat 2007 Jan;101(1):113-21.|2
01740|112|R|10.Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C,|2
01740|113|R|   Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN.|2
01740|114|R|   Pharmacogenetics of tamoxifen biotransformation is associated with|2
01740|115|R|   clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005 Dec 20;|2
01740|116|R|   23(36):9312-8.|2
01740|117|R|11.Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P,|2
01740|118|R|   Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J,|2
01740|119|R|   Strick R, Beckmann MW, Koelbl H. Weinshilboum RM, Ingle JN, Eichelbaum M,|2
01740|120|R|   Schwab M, Brauch H. Association between CYP2D6 polymorphisms and outcomes|2
01740|121|R|   among women with early stage breast cancer treated with tamoxifen. JAMA|2
01740|122|R|   2009 Oct 7;302(13):1429-36.|2
01740|123|R|12.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
01740|124|R|   US Inc. September 25, 2018.|1
01740|125|R|13.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
01740|126|R|   Technologies January, 2017.|1
01740|127|R|14.Prozac (fluoxetine) Canadian Product Information. Eli Lilly Canada Inc.|1
01740|128|R|   Jan 2024.|1
01740|129|R|15.Fluoxetine 20mg hard capsules UK Prescribing Information. Brown & Burk UK|1
01740|130|R|   Ltd June 2024.|1
01740|131|R|16.Gradishar WJ, Anderson BO, Avraham J, etal. NCCN Clinical Practice|6
01740|132|R|   Guidelines in Oncology: Breast Cancer. Available at:|6
01740|133|R|   https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf September|6
01740|134|R|   6, 2019.|6
01740|135|R|17.Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC,|2
01740|136|R|   Paszat LF. Selective serotonin reuptake inhibitors and breast cancer|2
01740|137|R|   mortality in women receiving tamoxifen: a population based cohort study.|2
01740|138|R|   BMJ 2010 Feb 8;340:c693.|2
01740|139|R|18.Phan MT, Venitz J. Summary minutes of the Advisory Committee|1
01740|140|R|   Pharmaceutical Science Clinical Pharmacology Subcommittee. Available at:|1
01740|141|R|   http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4248m1.pdf October|1
01740|142|R|   18-19, 2006.|1
01740|143|R|19.Rahman NA. Personal communication. Division Director, Office of Clinical|1
01740|144|R|   Pharmacology, US Food and Drug Administration March 4, 2008.|1
01740|145|R|20.Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, Salter J,|2
01740|146|R|   Sestak I, Cuzick J, Dowsett M. CYP2D6 and UGT2B7 genotype and risk of|2
01740|147|R|   recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer|2
01740|148|R|   Inst 2012 Mar 21;104(6):452-60.|2
01740|149|R|21.Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R,|2
01740|150|R|   Dell'orto P, Biasi MO, Thurlimann B, Lyng MB, Ditzel HJ, Neven P, Debled|2
01740|151|R|   M, Maibach R, Price KN, Gelber RD, Coates AS. Goldhirsch A, Rae JM, Viale|2
01740|152|R|   G,. CYP2D6 genotype and tamoxifen response in postmenopausal women with|2
01740|153|R|   endocrine-responsive breast cancer: the breast international group 1-98|2
01740|154|R|   trial. J Natl Cancer Inst 2012 Mar 21;104(6):441-51.|2
01740|155|R|22.Kelly CM, Pritchard KI. CYP2D6 genotype as a marker for benefit of|6
01740|156|R|   adjuvant tamoxifen in postmenopausal women: lessons learned. J Natl|6
01740|157|R|   Cancer Inst 2012 Mar 21;104(6):427-8.|6
01740|158|R|23.Donneyong MM, Bykov K, Bosco-Levy P, Dong YH, Levin R, Gagne JJ. Risk of|2
01740|159|R|   mortality with concomitant use of tamoxifen and selective serotonin|2
01740|160|R|   reuptake inhibitors: multi-database cohort study. BMJ 2016 Sep 30;|2
01740|161|R|   354:i5014.|2
01740|162|R|24.Haque R, Shi J, Schottinger JE, Ahmed SA, Cheetham TC, Chung J, Avila C,|2
01740|163|R|   Kleinman K, Habel LA, Fletcher SW, Kwan ML. Tamoxifen and Antidepressant|2
01740|164|R|   Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors. J Natl|2
01740|165|R|   Cancer Inst 2016 Mar;108(3):.|2
01740|166|R|25.Cronin-Fenton DP, Damkier P, Lash TL. Metabolism and transport of|2
01740|167|R|   tamoxifen in relation to its effectiveness: new perspectives on an|2
01740|168|R|   ongoing controversy. Future Oncol 2014 Jan;10(1):107-22.|2
01740|169|R|26.Azoulay L, Dell'Aniello S, Huiart L, du Fort GG, Suissa S. Concurrent use|2
01740|170|R|   of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer|2
01740|171|R|   recurrence. Breast Cancer Res Treat 2011 Apr;126(3):695-703.|2
01740|172|R|27.Dezentje VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel|2
01740|173|R|   MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ. Effect of|2
01740|174|R|   concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer|2
01740|175|R|   recurrence in early-stage breast cancer. J Clin Oncol 2010 May 10;|2
01740|176|R|   28(14):2423-9.|2
01740|177|R|28.This information is based on an extract from the Certara Drug Interaction|6
01740|178|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01740|179|R|29.US Food and Drug Administration (FDA). Drug Development and Drug|1
01740|180|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
01740|181|R|   at:|1
01740|182|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
01740|183|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01740|184|R|   11/14/2017.|1
01740|185|R|30.Dehal SS, Kupfer D. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human|5
01740|186|R|   liver. Cancer Res 1997 Aug 15;57(16):3402-6.|5
01740|187|R|31.Goetz MP, Sangkuhl K, Guchelaar HJ, Schwab M, Province M, Whirl-Carrillo|6
01740|188|R|   M, Symmans WF, McLeod HL, Ratain MJ, Zembutsu H, Gaedigk A, van Schaik|6
01740|189|R|   RH, Ingle JN, Caudle KE, Klein TE. Clinical Pharmacogenetics|6
01740|190|R|   Implementation Consortium (CPIC) Guideline for CYP2D6  and Tamoxifen|6
01740|191|R|   Therapy. Clin Pharmacol Ther 2018 May;103(5):770-777.|6
01741|001|T|MONOGRAPH TITLE:  Aripiprazole; Iloperidone/Clarithromycin; Telithromycin|
01741|002|T|(mono deleted 03/22/2012)|
01741|003|B||
01741|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01741|005|L|take action as needed.|
01741|006|B||
01741|007|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01741|008|A|metabolism of aripiprazole(1) and iloperidone(2) by CYP P-450-3A4.|
01741|009|B||
01741|010|E|CLINICAL EFFECTS:  Concurrent administration of clarithromycin or|
01741|011|E|telithromycin may result in elevated levels of and toxicity from|
01741|012|E|aripiprazole(1) and iloperidone.(2)  Elevated levels of iloperidone may|
01741|013|E|increase the risk of QTc prolongation.(2)|
01741|014|B||
01741|015|P|PREDISPOSING FACTORS:  None determined.|
01741|016|B||
01741|017|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole states that the|
01741|018|M|dose of aripiprazole should be reduced to one-half of its normal dose when|
01741|019|M|strong inhibitors of CYP P-450-3A4 are coadministered, unless aripiprazole|
01741|020|M|is being administered as adjunctive therapy for Major Depressive Disorder.|
01741|021|M|When the strong inhibitor is discontinued, the dose of aripiprazole should|
01741|022|M|be increased.(1)|
01741|023|M|   The US manufacturer of iloperidone states that the dose of iloperidone|
01741|024|M|should be reduced to one-half of its normal dose when strong inhibitors of|
01741|025|M|CYP P-450-3A4 are coadministered.  When the strong inhibitor is|
01741|026|M|discontinued, the dose of iloperidone should be increased.(2)|
01741|027|B||
01741|028|D|DISCUSSION:  The coadministration of ketoconazole (200 mg daily for 14|
01741|029|D|days), another strong CYP P-450-3A4 inhibitor, with a single dose of|
01741|030|D|aripiprazole (15 mg) resulted in increases in the area-under-curve (AUC) of|
01741|031|D|aripiprazole and its active metabolite by 63% and 77%, respectively.(1)|
01741|032|D|   Coadministration of ketoconazole (200 mg twice daily for 4 days)|
01741|033|D|increased the AUC of iloperidone (3 mg single dose) and its P88 and P95|
01741|034|D|metabolites by 57%, 55%, and 35%, respectively.(2)|
01741|035|D|   Coadministration of ketoconazole (200 mg twice daily) and iloperidone (12|
01741|036|D|mg twice daily) was associated with a mean QTcF increase of 19 msec from|
01741|037|D|baseline, compared with an increase of 9 msec with iloperidone alone.(2)|
01741|038|B||
01741|039|R|REFERENCES:|
01741|040|B||
01741|041|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
01741|042|R|  Pharmaceutical, Inc. July, 2014.|1
01741|043|R|2.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
01741|044|R|  Inc April, 2024.|1
01742|001|T|MONOGRAPH TITLE:  Buspirone/Itraconazole; Ketoconazole (mono deleted|
01742|002|T|04/17/2014)|
01742|003|B||
01742|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01742|005|L|take action as needed.|
01742|006|B||
01742|007|A|MECHANISM OF ACTION:  Itraconazole(1-3) and ketoconazole(1,4) may inhibit|
01742|008|A|the metabolism of buspirone by CYP P-450-3A4.|
01742|009|B||
01742|010|E|CLINICAL EFFECTS:  Concurrent use of itraconazole(1,2) or ketoconazole(1)|
01742|011|E|may result in increased levels and side effects from buspirone.|
01742|012|B||
01742|013|P|PREDISPOSING FACTORS:  None determined.|
01742|014|B||
01742|015|M|PATIENT MANAGEMENT:  The US manufacturer of buspirone recommends a low dose|
01742|016|M|of buspirone (2.5 mg daily) be used in patients receiving potent inhibitors|
01742|017|M|of CYP P-450-3A4.(1)|
01742|018|B||
01742|019|D|DISCUSSION:  In a study in 8 healthy subjects, pretreatment with|
01742|020|D|itraconazole (200 mg daily for 4 days) increased the maximum concentration|
01742|021|D|(Cmax) and area-under-curve (AUC) of buspirone by 13-fold and 19-fold,|
01742|022|D|respectively.(1,2)  However, only the Critical Flicker Fusion test showed|
01742|023|D|statistically significant differences when compared to the administration of|
01742|024|D|buspirone alone.(2)|
01742|025|D|   In a study in 6 subjects, pretreatment with itraconazole (200 mg daily|
01742|026|D|for 4 days) increased the Cmax and AUC of buspirone by 10.5-fold and|
01742|027|D|14.5-fold, respectively.  The Cmax and AUC of the piperazine metabolite of|
01742|028|D|buspirone increased by 57% and 50%, respectively.(3)|
01742|029|D|   Ketoconazole has been shown to inhibit the metabolism of buspirone in|
01742|030|D|vitro.(4)|
01742|031|B||
01742|032|R|REFERENCES:|
01742|033|B||
01742|034|R|1.BuSpar (buspirone hydrochloride) US prescribing information. Bristol Myers|1
01742|035|R|  Squibb Company September, 2007.|1
01742|036|R|2.Kivisto KT, Lamberg TS, Kantola T, Neuvonen PJ. Plasma buspirone|2
01742|037|R|  concentrations are greatly increased by erythromycin and itraconazole.|2
01742|038|R|  Clin Pharmacol Ther 1997 Sep;62(3):348-54.|2
01742|039|R|3.Kivisto KT, Lamberg TS, Neuvonen PJ. Interactions of buspirone with|2
01742|040|R|  itraconazole and rifampicin: effects on the pharmacokinetics of the active|2
01742|041|R|  1-(2-pyrimidinyl)-piperazine metabolite of buspirone. Pharmacol Toxicol|2
01742|042|R|  1999 Feb;84(2):94-7.|2
01742|043|R|4.Zhu M, Zhao W, Jimenez H, Zhang D, Yeola S, Dai R, Vachharajani N, Mitroka|5
01742|044|R|  J. Cytochrome P450 3A-mediated metabolism of buspirone in human liver|5
01742|045|R|  microsomes. Drug Metab Dispos 2005 Apr;33(4):500-7.|5
01743|001|T|MONOGRAPH TITLE:  Acitretin/Ethyl Alcohol|
01743|002|B||
01743|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01743|004|L|of severe adverse interaction.|
01743|005|B||
01743|006|A|MECHANISM OF ACTION:  Ethanol trans esterifies acitretin into|
01743|007|A|etretinate,(1-3) which is stored in adipose tissue and slowly eliminated.(1)|
01743|008|B||
01743|009|E|CLINICAL EFFECTS:  Ingestion of ethanol, even sporadically, during acitretin|
01743|010|E|usage and for 2 months after discontinuation of acitretin may result in|
01743|011|E|formation of etretinate.  Etretinate is also highly teratogenic and is|
01743|012|E|slowly eliminated from the body over several years after discontinuation.(4)|
01743|013|B||
01743|014|P|PREDISPOSING FACTORS:  None determined.|
01743|015|B||
01743|016|M|PATIENT MANAGEMENT:  The US manufacturer of acitretin states that use of|
01743|017|M|ethanol during or for 2 months after acitretin therapy in females is|
01743|018|M|contraindicated.(4)|
01743|019|M|   Females on acitretin therapy should be counseled to avoid consumption and|
01743|020|M|use of ethanol containing products during and for two months after acitretin|
01743|021|M|use.(4)|
01743|022|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
01743|023|M|   - The quantity of alcohol in paclitaxel injection formulations|
01743|024|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
01743|025|M|dose contains approximately 13 grams of alcohol.|
01743|026|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
01743|027|M|3-fold depending upon the manufacturer. FDA data on alcohol content (6):|
01743|028|M|   Product                      Manufacturer           Alcohol/200 mg dose|
01743|029|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
01743|030|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
01743|031|M|   Docetaxel Inj.               Accord                  4.0 grams|
01743|032|M|   Taxotere-one vial            Sanofi                  4.0 grams|
01743|033|M|    formulation|
01743|034|M|   Docetaxel Inj.               Hospira                 3.7 grams|
01743|035|M|   Docefrez                     Sun Pharma              2.9 grams|
01743|036|M|   Taxotere-two vial            Sanofi                  2.0 grams|
01743|037|M|    formulation|
01743|038|B||
01743|039|D|DISCUSSION:  In a 2-way cross-over study in 10 subjects, consumption of a|
01743|040|D|single dose of acitretin (100 mg) during ethanol ingestion (1.4 g/kg)|
01743|041|D|resulted in formation of etretinate in all 10 subjects.  The levels of|
01743|042|D|etretinate formed were comparable to a 5 mg dose of etretinate.  There was|
01743|043|D|no detectable etretinate levels in any subject during administration of|
01743|044|D|acitretin without ethanol.(4)|
01743|045|D|   In a study in 10 subjects treated with acitretin (30 mg daily for 3|
01743|046|D|months), 7 patients had detectable etretinate levels, 4 of which were|
01743|047|D|teratogenic.  Consumption of ethanol was linked to the formation of|
01743|048|D|etretinate.(1)|
01743|049|D|   In a study in 86 patients treated with acitretin, 30 patients had|
01743|050|D|detectable levels of etretinate.  No etretinate was found in 20 subjects who|
01743|051|D|reported no ethanol intake.  Etretinate was found in all 16 subjects with an|
01743|052|D|average weekly alcohol consumption of greater than 200 g (approximately 15|
01743|053|D|servings/week).  Etretinate was found in 15 of 50 patients with an average|
01743|054|D|weekly ethanol intake less than 200 g.(5)|
01743|055|D|   The half-life of etretinate has been estimated at 120 days (range 84-168|
01743|056|D|days).  In a study of 47 patients treated with etretinate, 5 had detectable|
01743|057|D|etretinate levels 2.1 years to 2.9 years after discontinuation of therapy.|
01743|058|D|However, one patient who reported sporadic ethanol intake had detectable|
01743|059|D|etretinate levels 52 months after discontinuation of acitretin.(4)|
01743|060|B||
01743|061|R|REFERENCES:|
01743|062|B||
01743|063|R|1.Larsen FG, Jakobsen P, Knudsen J, Weismann K, Kragballe K, Nielsen-Kudsk|2
01743|064|R|  F. Conversion of acitretin to etretinate in psoriatic patients is|2
01743|065|R|  influenced by ethanol. J Invest Dermatol 1993 May;100(5):623-7.|2
01743|066|R|2.Schmitt-Hoffmann AH, Dittrich S, Saulnier E, Schenk P, Chou RC.|5
01743|067|R|  Mechanistic studies on the ethyl-esterification of acitretin by human|5
01743|068|R|  liver preparations in vitro. Life Sci 1995 Nov 17;57(26):PL407-12.|5
01743|069|R|3.Knights KM, Gasser R, Klemisch W. In vitro metabolism of acitretin by|5
01743|070|R|  human liver microsomes: evidence of an acitretinoyl-coenzyme A thioester|5
01743|071|R|  conjugate in the transesterification to etretinate. Biochem Pharmacol 2000|5
01743|072|R|  Aug 15;60(4):507-16.|5
01743|073|R|4.Soriatane (acitretin) US prescribing information. Roche Pharmaceuticals|1
01743|074|R|  February, 2014.|1
01743|075|R|5.Gronhoj Larsen F, Steinkjer B, Jakobsen P, Hjorter A, Brockhoff PB,|2
01743|076|R|  Nielsen-Kudsk F. Acitretin is converted to etretinate only during|2
01743|077|R|  concomitant alcohol intake. Br J Dermatol 2000 Dec;143(6):1164-9.|2
01743|078|R|6.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
01743|079|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
01743|080|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
01743|081|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
01743|082|R|  20, 2014.|1
01744|001|T|MONOGRAPH TITLE:  Contraceptives/Chloramphenicol|
01744|002|B||
01744|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01744|004|L|of severe adverse interaction.|
01744|005|B||
01744|006|A|MECHANISM OF ACTION:  Estrogens and progesterones are extensively excreted|
01744|007|A|in bile, principally as glycuronide conjugates.  Subsequently, they undergo|
01744|008|A|enterohepatic circulation where bacterial hydrolysis occurs, allowing for|
01744|009|A|reabsorption of the oral contraceptives through the bowel wall and eventual|
01744|010|A|urinary excretion.  Treatment with antibiotics destroys the gut flora and|
01744|011|A|prevents steroid reabsorption, resulting in lower than normal concentrations|
01744|012|A|of the contraceptive and excretion via the feces rather than the urine.|
01744|013|A|  Chloramphenicol may also induce hepatic enzymes, resulting in increased|
01744|014|A|metabolism of the contraceptive agent.|
01744|015|B||
01744|016|E|CLINICAL EFFECTS:  May observe reduced pharmacologic effects of oral|
01744|017|E|contraceptives with resultant breakthrough bleeding and pregnancy.  Reduced|
01744|018|E|effects may be seen for several days after discontinuation of antibiotic|
01744|019|E|therapy.|
01744|020|B||
01744|021|P|PREDISPOSING FACTORS:  None determined.|
01744|022|B||
01744|023|M|PATIENT MANAGEMENT:  It is recommended that additional forms of birth|
01744|024|M|control be used during concurrent administration of short courses of|
01744|025|M|chloramphenicol.  For longer courses, use another method of birth control.|
01744|026|M|The patient should be asked to report any spotting or bleeding.|
01744|027|B||
01744|028|D|DISCUSSION:  The manufacturer states that lower estrogen reabsorption and|
01744|029|D|reduced efficacy may result in women taking oral contraceptives and|
01744|030|D|chloramphenicol.|
01744|031|B||
01744|032|R|REFERENCE:|
01744|033|B||
01744|034|R|1.Marvelon (desogestrel-ethinyl estradiol) Canadian prescribing information.|1
01744|035|R|  Organon 2008.|1
01745|001|T|MONOGRAPH TITLE:  Propoxyphene; Tramadol/Rasagiline; Selegiline|
01745|002|B||
01745|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01745|004|L|is contraindicated and generally should not be dispensed or administered to|
01745|005|L|the same patient.|
01745|006|B||
01745|007|A|MECHANISM OF ACTION:  Tramadol and propoxyphene inhibit neural reuptake of|
01745|008|A|serotonin.  MAOIs may increase neuronal serotonin concentrations via|
01745|009|A|inhibition of MAO-A.|
01745|010|B||
01745|011|E|CLINICAL EFFECTS:  The concurrent use of some opioids with MAOIs has|
01745|012|E|resulted in serotonin syndrome.  Symptoms of serotonin syndrome may include|
01745|013|E|tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
01745|014|E|hyperthermia, and muscle rigidity.|
01745|015|B||
01745|016|P|PREDISPOSING FACTORS:  High doses or concurrent use of multiple drugs which|
01745|017|P|increase CNS serotonin levels may increase risk for serotonin syndrome.|
01745|018|B||
01745|019|M|PATIENT MANAGEMENT:  The US manufacturers of both rasagiline and selegiline|
01745|020|M|state that use of propoxyphene or tramadol is contraindicated during therapy|
01745|021|M|with and within 14 days of discontinuation of rasagiline or selegiline due|
01745|022|M|to the risk for serotonin syndrome.|
01745|023|B||
01745|024|D|DISCUSSION:  The US manufacturer of rasagiline reports a case of serotonin|
01745|025|D|syndrome in a patient treated with both tramadol (dose not stated) and|
01745|026|D|rasagiline 4 mg daily, and also warns that cases of serotonin syndrome have|
01745|027|D|been reported with concomitant use of meperidine, methadone, or|
01745|028|D|propoxyphene.|
01745|029|D|   The interaction between meperidine and MAOIs has been well documented.|
01745|030|D|   There are two reports of potential interactions between MAOIs and|
01745|031|D|dextromethorphan.|
01745|032|D|   There is one case report of serotonin syndrome with concurrent meperidine|
01745|033|D|and linezolid.|
01745|034|D|   One or more of the drug pairs linked to this monograph have been included|
01745|035|D|in a list of interactions that should be considered "high-priority" for|
01745|036|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01745|037|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01745|038|D|Coordinator (ONC) for Health Information Technology.|
01745|039|B||
01745|040|R|REFERENCES:|
01745|041|B||
01745|042|R|1.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01745|043|R|  352(11):1112-20.|6
01745|044|R|2.Mitchell RS. Fatal toxic encephalitis occurring during iproniazid therapy|2
01745|045|R|  in pulmonary tuberculosis. Ann Intern Med 1955;42:417-24.|2
01745|046|R|3.Papp C, Benaim S. Toxic effects of iproniazid in a patient with angina. Br|3
01745|047|R|  Med J 1958 Nov 1;2:1070-2.|3
01745|048|R|4.Palmer H. Potentiation of pethidine. Br Med J 1960 Sep 24;2:944.|3
01745|049|R|5.Shee JC. Dangerous potentiation of pethidine by iproniazid, and its|3
01745|050|R|  treatment. Br Med J 1960 Aug 13;2:507-9.|3
01745|051|R|6.London DR, Milne MD. Dangers of monoamine oxidase inhibitors. Br Med J|6
01745|052|R|  1962 Dec 29;2:1752.|6
01745|053|R|7.Brownlee G, Williams GW. Potentiation of amphetamine and pethidine by|5
01745|054|R|  monoamieoxidase inhibitors. Lancet 1963 Mar 23;1:669.|5
01745|055|R|8.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
01745|056|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
01745|057|R|9.VigramnIM. Dangerous potentiation of meperidine hydrochloride by pargyline|3
01745|058|R|  hydrochloride. JAMA 1964 Mar 21;187(12):953-4.|3
01745|059|R|10.Anonymous. Analgesics and monoamine-oxidase inhibitors. Br Med J 1967 Nov|6
01745|060|R|   4;4(574):284.|6
01745|061|R|11.Evans-Prosser CD. The use of pethidine and morphine in the presence of|2
01745|062|R|   monoamine oxidase inhibitors. Br J Anaesth 1968 Apr;40(4):279-82.|2
01745|063|R|12.Jounela AJ, Kivimaki T. Possible sensitivity to meperidine in|3
01745|064|R|   phenylketonuria. N Engl J Med 1973 Jun 28;288(26):1411.|3
01745|065|R|13.Barry BJ. Adverse effects of MAO inhibitors with narcotics reversed with|3
01745|066|R|   naloxone. Anaesth Intensive Care 1979 May;7(2):194.|3
01745|067|R|14.Browne B, Linter S. Monoamine oxidase inhibitors and narcotic analgesics.|6
01745|068|R|   A critical review of the implications for treatment. Br J Psychiatry 1987|6
01745|069|R|   Aug;151:210-2.|6
01745|070|R|15.Zornberg GL, Bodkin JA, Cohen BM. Severe adverse interaction between|3
01745|071|R|   pethidine and selegiline. Lancet 1991 Jan 26;337(8735):246.|3
01745|072|R|16.Rossiter A, Souney PF. Interaction between MAOIs and opioids:|6
01745|073|R|   pharmacologic and clinical considerations. Hosp Formul 1993 Aug;28:692-8.|6
01745|074|R|17.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
01745|075|R|   2007.|1
01745|076|R|18.Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine|3
01745|077|R|   oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988 Dec 22;|3
01745|078|R|   319(25):1671.|3
01745|079|R|19.Rivers N, Horner B. Possible lethal reaction between Nardil and|3
01745|080|R|   dextromethorphan. Can Med Assoc J 1970 Jul;103:85.|3
01745|081|R|20.Das PK, Warkentin DI, Hewko R, Forrest DL. Serotonin syndrome after|3
01745|082|R|   concomitant treatment with linezolid and meperidine. Clin Infect Dis 2008|3
01745|083|R|   Jan 15;46(2):264-5.|3
01745|084|R|21.Diamorphine hydrochloride Australian prescribing information. Auralis|1
01745|085|R|   March 13, 2008.|1
01745|086|R|22.Emsam (selegline) US prescribing information. Somerset July, 2017.|1
01745|087|R|23.Zelapar (selegiline hydrochloride) US prescribing information. Valeant|1
01745|088|R|   Pharmaceuticals North America May, 2007.|1
01745|089|R|24.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
01745|090|R|   June, 2020.|1
01745|091|R|25.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
01745|092|R|   warns about several safety issues with opioid pain medicines; requires|1
01745|093|R|   label changes. available at:|1
01745|094|R|   http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
01745|095|R|26.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01745|096|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01745|097|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01745|098|R|   19(5):735-43.|6
01746|001|T|MONOGRAPH TITLE:  Selected Opioids/Rasagiline; Selegiline|
01746|002|B||
01746|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01746|004|L|of severe adverse interaction.|
01746|005|B||
01746|006|A|MECHANISM OF ACTION:  Selected opioids may inhibit neuronal reuptake of|
01746|007|A|serotonin.  MAOIs increase neuronal serotonin concentration via inhibition|
01746|008|A|of MAO-A.|
01746|009|B||
01746|010|E|CLINICAL EFFECTS:  The concurrent use of some opioids with MAOIs has|
01746|011|E|resulted in serotonin syndrome.  Symptoms of serotonin syndrome may include|
01746|012|E|tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
01746|013|E|hyperthermia, and muscle rigidity.(1-3)|
01746|014|B||
01746|015|P|PREDISPOSING FACTORS:  High doses or concurrent use of multiple drugs which|
01746|016|P|increase CNS serotonin levels may increase risk for serotonin syndrome.|
01746|017|B||
01746|018|M|PATIENT MANAGEMENT:  This combination should be avoided if possible.|
01746|019|M|   If concurrent therapy is warranted, patients should be monitored for|
01746|020|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
01746|021|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
01746|022|M|heart palpitations, restlessness, confusion, agitation, trouble with|
01746|023|M|coordination, or severe diarrhea.|
01746|024|B||
01746|025|D|DISCUSSION:  Although documentation is lacking for some opioids, the FDA|
01746|026|D|recommends health professionals monitor and advise patients to report|
01746|027|D|symptoms of serotonin syndrome in patients receiving analgesic opioids and|
01746|028|D|serotonergic agents.(2)|
01746|029|D|  Selected opioids linked to this monograph include: alfentanil, anileridine|
01746|030|D|(not available in US/CA), diphenoxin, meptazinol (not available in US/CA),|
01746|031|D|pentazocine, phenoperidine (not available in US/CA), propoxyphene (not|
01746|032|D|available in US/CA), remifentanil, and sufentanil.|
01746|033|B||
01746|034|R|REFERENCES:|
01746|035|B||
01746|036|R|1.Carlsson A, Lindqvist M. Central and peripheral monoaminergic|2
01746|037|R|  membrane-pump blockade by some addictive analgesics and antihistamines. J|2
01746|038|R|  Pharm Pharmacol 1969 Jul;21(7):460-4.|2
01746|039|R|2.Emsam (selegline) US prescribing information. Somerset July, 2017.|1
01746|040|R|3.Zelapar (selegiline hydrochloride) US prescribing information. Valeant|1
01746|041|R|  Pharmaceuticals North America May, 2007.|1
01746|042|R|4.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
01746|043|R|  June, 2020.|1
01746|044|R|5.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
01746|045|R|  warns about several safety issues with opioid pain medicines; requires|1
01746|046|R|  label changes. available at:|1
01746|047|R|  http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
01747|001|T|MONOGRAPH TITLE:  Rosuvastatin/Aluminum Hydroxide; Magnesium Hydroxide;|
01747|002|T|Lanthanum|
01747|003|B||
01747|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01747|005|L|take action as needed.|
01747|006|B||
01747|007|A|MECHANISM OF ACTION:  The mechanism of action is not known, but it theorized|
01747|008|A|to be caused by aluminum/magnesium binding to rosuvastatin in the|
01747|009|A|gastrointestinal tract and/or an increase in gastric pH.(1)|
01747|010|B||
01747|011|E|CLINICAL EFFECTS:  Simultaneous administration of aluminum|
01747|012|E|hydroxide/magnesium hydroxide with rosuvastatin may decrease the clinical|
01747|013|E|effects of rosuvastatin.|
01747|014|B||
01747|015|P|PREDISPOSING FACTORS:  None determined.|
01747|016|B||
01747|017|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that|
01747|018|M|patients receiving concurrent aluminum hydroxide/magnesium hydroxide and|
01747|019|M|rosuvastatin should take the antacid at least 2 hours after taking the|
01747|020|M|rosuvastatin.(2)|
01747|021|B||
01747|022|D|DISCUSSION:  In a randomized, open-label, cross-over trial in 14 healthy|
01747|023|D|males, concurrent use of (20 ml) aluminum hydroxide(200 mg/5 ml)/magnesium|
01747|024|D|hydroxide(195 mg/5 ml)and rosuvastatin (40 mg) decreased the|
01747|025|D|area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin by|
01747|026|D|54% and 50%, respectively.  However, the interaction was determined to be|
01747|027|D|clinically insignificant when administration was separated by 2 hours.(1,2)|
01747|028|B||
01747|029|R|REFERENCES:|
01747|030|B||
01747|031|R|1.Martin PD, Schneck DW, Dane AL, Warwick MJ. The effect of a combination|2
01747|032|R|  antacid preparation containing aluminium hydroxide and magnesium hydroxide|2
01747|033|R|  on rosuvastatin pharmacokinetics. Curr Med Res Opin 2008 Apr;24(4):1231-5.|2
01747|034|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
01747|035|R|  Pharmaceuticals LP July, 2024.|1
01748|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Orlistat|
01748|002|B||
01748|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01748|004|L|take action as needed.|
01748|005|B||
01748|006|A|MECHANISM OF ACTION:  Orlistat may bind to the thyroid preparation in the|
01748|007|A|small intestine, decreasing systemic absorption.(1-4)|
01748|008|B||
01748|009|E|CLINICAL EFFECTS:  Concurrent administration of orlistat and thyroid|
01748|010|E|preparations may decrease the clinical effects of the thyroid agent.(1-4)|
01748|011|E|Hypothyroidism has been reported.(3)|
01748|012|B||
01748|013|P|PREDISPOSING FACTORS:  None determined.|
01748|014|B||
01748|015|M|PATIENT MANAGEMENT:  Separate the administration times of orlistat and|
01748|016|M|thyroid preparations by at least 4 hours.  Patients receiving concurrent|
01748|017|M|therapy should be monitored for changes in thyroid function.(1-3)|
01748|018|B||
01748|019|D|DISCUSSION:  In a case report, a post-thyroidectomy patient on a stable dose|
01748|020|D|of levothyroxine (250 mcg daily) started concurrent orlistat therapy.|
01748|021|D|Within two weeks of starting orlistat therapy, she felt experienced cold|
01748|022|D|intolerance and felt lethargic and tired.  She was found be severely|
01748|023|D|hypothyroid and the orlistat was discontinued.  Within two weeks, her|
01748|024|D|symptoms improved and, within 4 weeks, her thyroid levels normalized.(4)|
01748|025|B||
01748|026|R|REFERENCES:|
01748|027|B||
01748|028|R|1.Synthroid (levothyroxine sodium) US prescribing information. Abbott|1
01748|029|R|  Laboratories February, 2024.|1
01748|030|R|2.Tirosint (levothyroxine sodium) US prescribing information. Institut|1
01748|031|R|  Biochimique SA (IBSA) February, 2017.|1
01748|032|R|3.Xenical (orlistat) US prescribing information. Roche Laboratories, Inc.|1
01748|033|R|  November, 2022.|1
01748|034|R|4.Madhava K, Hartley A. Hypothyroidism in thyroid carcinoma follow-up:|3
01748|035|R|  orlistat may inhibit the absorption of thyroxine. Clin Oncol (R Coll|3
01748|036|R|  Radiol) 2005 Sep;17(6):492.|3
01749|001|T|MONOGRAPH TITLE:  Posaconazole/Fosamprenavir|
01749|002|B||
01749|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01749|004|L|take action as needed.|
01749|005|B||
01749|006|A|MECHANISM OF ACTION:  The exact mechanism responsible for decreased|
01749|007|A|posaconazole levels is unknown, but may involve P-glycoprotein (P-gp) or|
01749|008|A|UGT1A4 induction.(1)|
01749|009|B||
01749|010|E|CLINICAL EFFECTS:  Concurrent use of fosamprenavir may result in decreased|
01749|011|E|levels and effectiveness of posaconazole.(1,2)|
01749|012|B||
01749|013|P|PREDISPOSING FACTORS:  None determined.|
01749|014|B||
01749|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with|
01749|016|M|fosamprenavir should be monitored for decreased levels and effectiveness of|
01749|017|M|posaconazole.(1,2)|
01749|018|B||
01749|019|D|DISCUSSION:  In a study in 20 subjects, concurrent fosamprenavir (700 mg BID|
01749|020|D|for 10 days) decreased the maximum concentration (Cmax) and area-under-curve|
01749|021|D|(AUC) of posaconazole (200 mg Day 1, 200 mg BID Day 2, then 400 mg BID for 8|
01749|022|D|days) by 21% and 23%, respectively.(1,2)  During posaconazole|
01749|023|D|administration, amprenavir Cmax and AUC were 36% and 65% lower than during|
01749|024|D|the administration of fosamprenavir/ritonavir (700/100 mg BID), suggesting|
01749|025|D|that posaconazole cannot replace ritonavir as a booster for fosamprenavir.|
01749|026|D|However, amprenavir levels were comparable to historical levels of unboosted|
01749|027|D|fosamprenavir.(1)|
01749|028|B||
01749|029|R|REFERENCES:|
01749|030|B||
01749|031|R|1.Bruggemann RJ, van Luin M, Colbers EP, van den Dungen MW, Pharo C,|2
01749|032|R|  Schouwenberg BJ, Burger DM. Effect of posaconazole on the pharmacokinetics|2
01749|033|R|  of fosamprenavir and vice versa in healthy volunteers. J Antimicrob|2
01749|034|R|  Chemother 2010 Oct;65(10):2188-94.|2
01749|035|R|2.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01749|036|R|  January, 2022.|1
01750|001|T|MONOGRAPH TITLE:  Lopinavir/Tipranavir|
01750|002|B||
01750|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01750|004|L|of severe adverse interaction.|
01750|005|B||
01750|006|A|MECHANISM OF ACTION:  Tipranavir may induce the metabolism of lopinavir by|
01750|007|A|CYP3A4.(1)|
01750|008|B||
01750|009|E|CLINICAL EFFECTS:  Concurrent use of tipranavir-ritonavir may result in|
01750|010|E|decreased levels of, effectiveness of, and resistance to lopinavir.(1)|
01750|011|B||
01750|012|P|PREDISPOSING FACTORS:  None determined.|
01750|013|B||
01750|014|M|PATIENT MANAGEMENT:  The US manufacturer of lopinavir-ritonavir states that|
01750|015|M|coadministration with tipranavir (500 mg twice daily) and ritonavir (200 mg|
01750|016|M|twice daily) is not recommended.(1)|
01750|017|M|   The US manufacturer of tipranavir states that concurrent use is not|
01750|018|M|recommended.(2)|
01750|019|B||
01750|020|D|DISCUSSION:  In 21 subjects, concurrent tipranavir-ritonavir (500/200 mg|
01750|021|D|twice daily) and lopinavir-ritonavir (400/100 mg twice daily) decreased the|
01750|022|D|lopinavir maximum concentration (Cmax), area-under-curve (AUC), and minimum|
01750|023|D|concentration (Cmin) by 47%, 55%, and 70%, respectively.(1,2)|
01750|024|B||
01750|025|R|REFERENCES:|
01750|026|B||
01750|027|R|1.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01750|028|R|  Laboratories December, 2019.|1
01750|029|R|2.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01750|030|R|  Pharmaceuticals, Inc. April, 2024.|1
01752|001|T|MONOGRAPH TITLE:  Nimodipine/Valproic Acid|
01752|002|B||
01752|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01752|004|L|take action as needed.|
01752|005|B||
01752|006|A|MECHANISM OF ACTION:  Valproic acid may inhibit the metabolism of|
01752|007|A|nimodipine.(1)|
01752|008|B||
01752|009|E|CLINICAL EFFECTS:  Concurrent use of valproic acid may result in increased|
01752|010|E|levels of and toxicity from nimodipine.(1)|
01752|011|B||
01752|012|P|PREDISPOSING FACTORS:  None determined.|
01752|013|B||
01752|014|M|PATIENT MANAGEMENT:  Patients taking valproic acid may required reduced|
01752|015|M|dosages of nimodipine.(1)|
01752|016|B||
01752|017|D|DISCUSSION:  A study examined nimodipine pharmacokinetics in three groups:|
01752|018|D|normal drug-free controls (n=8), epileptic patients taking enzyme-inducing|
01752|019|D|anticonvulsants (phenobarbital alone, n=4; phenobarbital with carbamazepine,|
01752|020|D|n=2, carbamazepine with clobazam, n=1, and carbamazepine with phenytoin,|
01752|021|D|n=1), and epileptic patients taking valproic acid (n=8).  In patients taking|
01752|022|D|enzyme-inducing anticonvulsants, nimodipine area-under-curve (AUC), maximum|
01752|023|D|concentration (Cmax), and half-life (T1/2) were 86.2%, 89.2%, and 68.1%,|
01752|024|D|respectively, lower than in controls.  In patients taking valproic acid,|
01752|025|D|nimodipine AUC was 54.5% higher than in control patients.(1)|
01752|026|B||
01752|027|R|REFERENCE:|
01752|028|B||
01752|029|R|1.Tartara A, Galimberti CA, Manni R, Parietti L, Zucca C, Baasch H, Caresia|2
01752|030|R|  L, Muck W, Barzaghi N, Gatti G, et al. Differential effects of valproic|2
01752|031|R|  acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in|2
01752|032|R|  epileptic patients. Br J Clin Pharmacol 1991 Sep;32(3):335-40.|2
01753|001|T|MONOGRAPH TITLE:  Nimodipine/Selected Strong CYP3A4 Inducers|
01753|002|B||
01753|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01753|004|L|is contraindicated and generally should not be dispensed or administered to|
01753|005|L|the same patient.|
01753|006|B||
01753|007|A|MECHANISM OF ACTION:  Concurrent use of strong CYP3A4 inducers may induce|
01753|008|A|the metabolism of nimodipine.(1,2)|
01753|009|B||
01753|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
01753|011|E|decreased levels and effectiveness of nimodipine.(1,2)|
01753|012|B||
01753|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01753|014|P|of the inducer for longer than 1-2 weeks.|
01753|015|B||
01753|016|M|PATIENT MANAGEMENT:  The UK manufacturer of nimodipine states that the|
01753|017|M|concurrent use of strong CYP3A4 inducers is contraindicated.(1)|
01753|018|M|   The US manufacturer of nimodipine states that the concurrent use of|
01753|019|M|strong CYP3A4 inducers should be avoided.(2)|
01753|020|B||
01753|021|D|DISCUSSION:  A study examined nimodipine pharmacokinetics in three groups:|
01753|022|D|normal drug-free controls (n=8), epileptic patients taking enzyme-inducing|
01753|023|D|anticonvulsants (phenobarbital alone, n=4; phenobarbital with carbamazepine,|
01753|024|D|n=2, carbamazepine with clobazam, n=1, and carbamazepine with phenytoin,|
01753|025|D|n=1). In patients taking enzyme-inducing anticonvulsants, nimodipine|
01753|026|D|area-under-curve (AUC), maximum concentration (Cmax), and half-life (T1/2)|
01753|027|D|were 86.2%, 89.2%, and 68.1%, respectively, lower than in controls.(2)|
01753|028|D|   Strong CYP3A4 inducers linked include: apalutamide, encorafenib,|
01753|029|D|enzalutamide, ivosidenib, lumacaftor, mitotane, rifampin, rifapentine, and|
01753|030|D|St. Johns wort.(3)|
01753|031|B||
01753|032|R|REFERENCES:|
01753|033|B||
01753|034|R|1.Nimotop (nimodipine) UK  summary of product characteristics. Bayer plc|1
01753|035|R|  April 23, 2008.|1
01753|036|R|2.Nymalize (nimodipine) solution US prescribing information. Arbor|1
01753|037|R|  Pharmaceuticals April, 2020.|1
01753|038|R|3.Tartara A, Galimberti CA, Manni R, Parietti L, Zucca C, Baasch H, Caresia|2
01753|039|R|  L, Muck W, Barzaghi N, Gatti G, et al. Differential effects of valproic|2
01753|040|R|  acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in|2
01753|041|R|  epileptic patients. Br J Clin Pharmacol 1991 Sep;32(3):335-40.|2
01753|042|R|4.This information is based on an extract from the Certara Drug Interaction|6
01753|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01754|001|T|MONOGRAPH TITLE:  Amiodarone/Dabigatran (mono deleted 02/05/2015)|
01754|002|B||
01754|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01754|004|L|take action as needed.|
01754|005|B||
01754|006|A|MECHANISM OF ACTION:  Amiodarone is an inhibitor of the P-glycoprotein|
01754|007|A|transport and dabigatran is a substrate of this transporter.(1)|
01754|008|B||
01754|009|E|CLINICAL EFFECTS:  May see an increase in the pharmacologic effects of|
01754|010|E|dabigatran due to elevated serum levels of dabigatran.(1)|
01754|011|B||
01754|012|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
01754|013|P|bleeding include renal impairment, concomitant use of P-glycoprotein|
01754|014|P|inhibitors, patient age >74 years, coexisting conditions (e.g. recent|
01754|015|P|trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and|
01754|016|P|patient weight <50 kg. (1-3)|
01754|017|B||
01754|018|M|PATIENT MANAGEMENT:  Monitor patients closely when initiating or|
01754|019|M|discontinuing concurrent dabigatran and amiodarone therapy.|
01754|020|M|   The US manufacturer of dabigatran states that no dosage adjustment is|
01754|021|M|necessary;(2) however, the UK manufacturer of dabigatran recommends that the|
01754|022|M|dose of dabigatran be reduced from 220 mg daily to 150 mg daily.(1)|
01754|023|B||
01754|024|D|DISCUSSION:  When dabigatran was co-administered with amiodarone, the extent|
01754|025|D|and rate of absorption of amiodarone and its active metabolite DEA were|
01754|026|D|essentially unchanged. The dabigatran area-under-curve (AUC) and maximum|
01754|027|D|concentration (Cmax) were increased by about 60% and 50%, respectively;(1,2)|
01754|028|D|however, dabigatran clearance was increased by 65%.(2)|
01754|029|D|   In population pharmacokinetic studies, there were no significant changes|
01754|030|D|in dabigatran trough levels in subjects receiving concurrent amiodarone.(2)|
01754|031|B||
01754|032|R|REFERENCES:|
01754|033|B||
01754|034|R|1.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
01754|035|R|  characteristics. Boehringer Ingelheim Limited August 18, 2011.|1
01754|036|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
01754|037|R|  Boehringer Ingelheim Pharmaceuticals, Inc. September, 2014.|1
01754|038|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
01754|039|R|  Boehringer Ingelheim March, 23 2020.|1
01755|001|T|MONOGRAPH TITLE:  Heparins/Dabigatran|
01755|002|B||
01755|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01755|004|L|is contraindicated and generally should not be dispensed or administered to|
01755|005|L|the same patient.|
01755|006|B||
01755|007|A|MECHANISM OF ACTION:  Heparin inhibits thrombosis by inactivating activated|
01755|008|A|Factor X and inhibiting the conversion of prothrombin to thrombin.|
01755|009|A|Dabigatran is a direct thrombin inhibitor.(1,2)|
01755|010|B||
01755|011|E|CLINICAL EFFECTS:  Concurrent use of anticoagulants with heparin can enhance|
01755|012|E|the effects of heparin and may increase the risk of bleeding.(1,2)|
01755|013|B||
01755|014|P|PREDISPOSING FACTORS:  Factors associated with an increase risk for bleeding|
01755|015|P|include renal impairment, concomitant use of P-glycoprotein inhibitors,|
01755|016|P|patient age >74 years, coexisting conditions (e.g. recent trauma) or use of|
01755|017|P|drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight <50|
01755|018|P|kg.(1-3)|
01755|019|P|   The risk for bleeding episodes may be greater in patients with|
01755|020|P|disease-associated factors (e.g. thrombocytopenia).|
01755|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
01755|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01755|023|P|risk for bleeding (e.g. NSAIDs).|
01755|024|B||
01755|025|M|PATIENT MANAGEMENT:  The long-term use of concurrent therapy with Direct|
01755|026|M|Oral Anticoagulants (DOACs) and other anticoagulants is generally considered|
01755|027|M|contraindicated.  However, overlap may be necessary when switching therapy|
01755|028|M|from one agent to another in order to prevent thrombotic events.|
01755|029|M|Manufacturer recommendations concerning overlap (if any) and timing of|
01755|030|M|discontinuation versus initiation vary depending upon which agent is being|
01755|031|M|discontinued and initiated. Refer to current prescribing information for|
01755|032|M|both agents for additional details.|
01755|033|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
01755|034|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
01755|035|M|blood pressure and promptly evaluate patients with any symptoms.|
01755|036|M|Discontinue dabigatran in patients with active pathological bleeding.(2)|
01755|037|M|   The UK manufacturer states that the use of unfractionated heparin,|
01755|038|M|heparin derivatives, and low molecular weight heparins with concomitant|
01755|039|M|dabigatran therapy is contraindicated unless switching treatment to or from|
01755|040|M|dabigatran or when unfractionated heparin is given at doses appropriate to|
01755|041|M|maintain open central venous or arterial catheter.(1)|
01755|042|M|   When converting from parenteral anticoagulant to dabigatran, administer|
01755|043|M|dabigatran 0-2 hours before the next dose of the parenteral drug is due or|
01755|044|M|at time of discontinuation of a continuously infused anticoagulant.(2)|
01755|045|M|   When converting from dabigatran to a parenteral anticoagulant, begin|
01755|046|M|parenteral anticoagulant:|
01755|047|M|-----12 hours after last dose of dabigatran in patients with CrCl greater|
01755|048|M|than or equal to 30ml/min,|
01755|049|M|-----24 hours after last dose of dabigatran in patients with CrCl less than|
01755|050|M|30 ml/min.(2)|
01755|051|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01755|052|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01755|053|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01755|054|M|patients with any symptoms.|
01755|055|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01755|056|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01755|057|M|anticoagulation in patients with active pathologic bleeding.|
01755|058|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01755|059|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01755|060|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01755|061|M|and/or swelling.|
01755|062|B||
01755|063|D|DISCUSSION:  The use of both agents is likely to increase the frequency and|
01755|064|D|occurrence of unwanted bleeding episodes.  The use of heparin to maintain|
01755|065|D|catheter patency is acceptable with the use of these agents together.(1,2)|
01755|066|B||
01755|067|R|REFERENCES:|
01755|068|B||
01755|069|R|1.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
01755|070|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
01755|071|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
01755|072|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
01755|073|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
01755|074|R|  Boehringer Ingelheim March, 23 2020.|1
01756|001|T|MONOGRAPH TITLE:  Abciximab/Dabigatran|
01756|002|B||
01756|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01756|004|L|take action as needed.|
01756|005|B||
01756|006|A|MECHANISM OF ACTION:  Direct thrombin inhibitors decrease plasma fibrinogen|
01756|007|A|levels.(1) When direct thrombin inhibitors are administered with abciximab,|
01756|008|A|there is enhanced inhibition of platelet aggregation.|
01756|009|B||
01756|010|E|CLINICAL EFFECTS:  Concurrent use of abciximab and dabigatran may result in|
01756|011|E|greater inhibition of platelet aggregation which may lead to an increased|
01756|012|E|risk of bleeding.(2,3)|
01756|013|B||
01756|014|P|PREDISPOSING FACTORS:  Active internal bleed, thrombocytopenia, recent major|
01756|015|P|surgery or trauma, severe uncontrolled hypertension, use of IV dextran|
01756|016|P|before PCI, and history of cerebrovascular accident within two years.(2)|
01756|017|P|   Additional factors associated with an increased risk for bleeding include|
01756|018|P|renal impairment, concomitant use of P-glycoprotein inhibitors, patient age|
01756|019|P|>74 years,  use of other drugs associated with bleeding risk (e.g. NSAIDs),|
01756|020|P|and patient weight <50 kg. (3-5)|
01756|021|B||
01756|022|M|PATIENT MANAGEMENT:  The UK manufacturer states that the use of|
01756|023|M|unfractionated heparin, heparin derivatives, and low molecular weight|
01756|024|M|heparins with concomitant dabigatran therapy is not recommended.(3)|
01756|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01756|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01756|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01756|028|M|patients with any symptoms.|
01756|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01756|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01756|031|M|anticoagulation in patients with active pathologic bleeding.|
01756|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01756|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01756|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01756|035|M|and/or swelling.|
01756|036|B||
01756|037|D|DISCUSSION:  The concurrent use of both agents is likely to increase the|
01756|038|D|frequency and occurrence of unwanted bleeding episodes.(1,2,3)|
01756|039|B||
01756|040|R|REFERENCES:|
01756|041|B||
01756|042|R|1.Streptase (streptokinase) US prescribing information. Aventis Behring|1
01756|043|R|  June, 2002.|1
01756|044|R|2.ReoPro (abciximab) US prescribing information. Eli Lilly and Company|1
01756|045|R|  November 25, 2013.|1
01756|046|R|3.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
01756|047|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
01756|048|R|4.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
01756|049|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
01756|050|R|5.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
01756|051|R|  Boehringer Ingelheim March, 23 2020.|1
01757|001|T|MONOGRAPH TITLE:  Dabigatran/Antiplatelets; Aspirin (Greater Than 100 mg)|
01757|002|B||
01757|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01757|004|L|of severe adverse interaction.|
01757|005|B||
01757|006|A|MECHANISM OF ACTION:  Dabigatran is a direct thrombin inhibitor and when|
01757|007|A|taken with agents that effect platelet aggregation increased bleeding|
01757|008|A|episodes can occur.(1,2)|
01757|009|B||
01757|010|E|CLINICAL EFFECTS:  Concurrent use of dabigatran with antiplatelet agents may|
01757|011|E|result in additive or synergistic effects resulting in unwanted bleeding|
01757|012|E|episodes.(1,2)|
01757|013|B||
01757|014|P|PREDISPOSING FACTORS:  Factors associated with an increase risk for bleeding|
01757|015|P|include renal impairment, concomitant use of P-glycoprotein inhibitors,|
01757|016|P|patient age >74 years, coexisting conditions (e.g. recent trauma) or use of|
01757|017|P|drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight <50|
01757|018|P|kg.(1-3)|
01757|019|P|   The risk for bleeding episodes may be greater in patients with|
01757|020|P|disease-associated factors (e.g. thrombocytopenia).|
01757|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
01757|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01757|023|P|risk for bleeding (e.g. NSAIDs).|
01757|024|B||
01757|025|M|PATIENT MANAGEMENT:  Patients requiring concurrent therapy with dabigatran|
01757|026|M|and an antiplatelet agent should be closely monitored for signs of bleeding.|
01757|027|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01757|028|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01757|029|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01757|030|M|patients with any symptoms.|
01757|031|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01757|032|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01757|033|M|anticoagulation in patients with active pathologic bleeding.|
01757|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01757|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01757|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01757|037|M|and/or swelling.|
01757|038|M|   The time of highest risk for a coumarin-type drug interaction is when the|
01757|039|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
01757|040|M|initiating, altering the dose or discontinuing either drug.|
01757|041|M|   Discontinue dabigatran in patients with active bleeding.|
01757|042|B||
01757|043|D|DISCUSSION:  Dabigatran is a direct thrombin inhibitor and when taken with|
01757|044|D|agents that effect platelet aggregation and/or other clotting factors|
01757|045|D|increased bleeding episodes can occur.(1,2)|
01757|046|D|   In the RE-LY trial, 40% of patients were on aspirin at baseline.(1)|
01757|047|D|   In the RE-MEDY trial, 7.7% of patients were on aspirin at baseline.(1)|
01757|048|D|   In the RE-DUAL PCI trial, patients were randomly assigned to one of three|
01757|049|D|treatments: (A) dual therapy with dabigatran 110 mg twice daily plus either|
01757|050|D|clopidogrel or ticagrelor, (B) dual therapy with dabigatran 150 mg twice|
01757|051|D|daily plus either clopidogrel or ticagrelor, or (C) triple therapy with|
01757|052|D|warfarin (goal INR 2-3) plus aspirin (< or = 100 mg daily) plus either|
01757|053|D|clopidogrel or ticagrelor.  The incidence of the first major or clinically|
01757|054|D|relevant non-major (CRNM) bleeding event was 15.4% in group A compared with|
01757|055|D|26.9% in group C (hazard ratio, 0.52; 95% CI 0.42 to 0.63; p<0.001 for|
01757|056|D|noninferiority; p<0.001 for superiority) and 20.2% in group B compared to|
01757|057|D|25.7% in corresponding group C (hazard ratio, 0.72; 95% CI 0.58 to 0.88;|
01757|058|D|p<0.001 for noninferiority).  For major bleeding as defined by Thrombolysis|
01757|059|D|in Myocardial Infarction (TIMI) criteria, the rate was lower in both|
01757|060|D|dual-therapy groups than in the triple-therapy group: 1.4% in group A|
01757|061|D|compared to 3.8% in group C (hazard ratio, 0.37; 95% CI 0.2 to 0.68;|
01757|062|D|p=0.002) and 2.1% in group B compared to 3.9% in corresponding group C|
01757|063|D|(hazard ratio, 0.51; 95% CI 0.28 to 0.93; p=0.03).  Incidence of composite|
01757|064|D|efficacy end point of thromboembolic events (myocardial infarction, stroke,|
01757|065|D|or systemic embolism), death, or unplanned revascularization was 13.7% in|
01757|066|D|groups A and B compared to 13.4% in group C (hazard ratio, 1.04; 95% CI 0.84|
01757|067|D|to 1.29; p=0.005 for noninferiority).(4)|
01757|068|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
01757|069|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
01757|070|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
01757|071|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
01757|072|D|aspirin, with the highest allowable dose being 165 mg/day.  Compared with|
01757|073|D|DOACs alone, the use of DOACs with antiplatelet agents was associated with|
01757|074|D|an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM|
01757|075|D|bleeding (OR 1.82; 95% CI, 1.50-2.22).  There was no difference between|
01757|076|D|groups in the efficacy outcome of symptomatic recurrent venous|
01757|077|D|thromboembolism (VTE) or VTE-related death.(5)|
01757|078|B||
01757|079|R|REFERENCES:|
01757|080|B||
01757|081|R|1.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
01757|082|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
01757|083|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
01757|084|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
01757|085|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
01757|086|R|  Boehringer Ingelheim March, 23 2020.|1
01757|087|R|4.Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T, Maeng M,|2
01757|088|R|  Merkely B. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial|2
01757|089|R|  Fibrillation. N Engl J Med 2017 Aug 27.|2
01757|090|R|5.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
01757|091|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
01757|092|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
01757|093|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
01758|001|T|MONOGRAPH TITLE:  Dabigatran/Selected P-glycoprotein (P-gp) Inhibitors|
01758|002|B||
01758|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01758|004|L|of severe adverse interaction.|
01758|005|B||
01758|006|A|MECHANISM OF ACTION:  Dabigatran etexilate is a substrate for the|
01758|007|A|P-glycoprotein (P-gp) system.  Inhibition of intestinal P-gp leads to|
01758|008|A|increased absorption of dabigatran.(1-3)|
01758|009|B||
01758|010|E|CLINICAL EFFECTS:  The concurrent use dabigatran with P-gp inhibitors may|
01758|011|E|lead to elevated plasma levels of dabigatran, increasing the risk for|
01758|012|E|bleeding.|
01758|013|B||
01758|014|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
01758|015|P|bleeding include renal impairment, concomitant use of P-gp inhibitors,|
01758|016|P|patient age >74 years, coexisting conditions (e.g. recent trauma) or use of|
01758|017|P|drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50|
01758|018|P|kg.(1-4)|
01758|019|B||
01758|020|M|PATIENT MANAGEMENT:  Assess renal function and evaluate patient for other|
01758|021|M|pre-existing risk factors for bleeding prior to initiating concurrent|
01758|022|M|therapy.  The US manufacturer of dabigatran states that the concurrent use|
01758|023|M|of dabigatran and P-gp inhibitors should be avoided in atrial fibrillation|
01758|024|M|patients with severe renal impairment (CrCl less than 30 ml/min) and in|
01758|025|M|patients with moderate renal impairment (CrCl less than 50 ml/min) being|
01758|026|M|treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or|
01758|027|M|pulmonary embolism (PE).  The interaction with P-gp inhibitors can be|
01758|028|M|minimized by taking dabigatran several hours apart from the P-gp inhibitor|
01758|029|M|dose.(1)|
01758|030|M|   The concomitant use of dabigatran with P-gp inhibitors has not been|
01758|031|M|studied in pediatric patients but may increase exposure to dabigatran.(1)|
01758|032|M|   While the US manufacturer of dabigatran states that no dosage adjustment|
01758|033|M|is necessary in other patients,(1) the Canadian manufacturer of dabigatran|
01758|034|M|states that concomitant use of strong P-gp inhibitors (e.g.,|
01758|035|M|glecaprevir-pibrentasvir) is contraindicated.  When dabigatran is used for|
01758|036|M|the prevention of venous thromboembolism (VTE) after total hip or knee|
01758|037|M|replacement concurrently with amiodarone, quinidine, or verapamil, the dose|
01758|038|M|of dabigatran should be reduced from 110 mg twice daily to 150 mg once|
01758|039|M|daily.  For patients with CrCl less than 50 ml/min on verapamil, a further|
01758|040|M|dabigatran dose reduction to 75 mg once daily should be considered.|
01758|041|M|Verapamil should be given at least 2 hours after dabigatran to minimize the|
01758|042|M|interaction.(2)|
01758|043|M|   The UK manufacturer of dabigatran also states the use of dabigatran with|
01758|044|M|strong P-gp inhibitors (e.g., cyclosporine, glecaprevir-pibrentasvir or|
01758|045|M|itraconazole) is contraindicated.  Concurrent use of ritonavir is not|
01758|046|M|recommended.  When dabigatran is used in atrial fibrillation patients and|
01758|047|M|for treatment of DVT and PE concurrently with verapamil, the UK manufacturer|
01758|048|M|recommends reducing the dose of dabigatran from 150 mg twice daily to 110 mg|
01758|049|M|twice daily, taken simultaneously with verapamil.  When used for VTE|
01758|050|M|prophylaxis after orthopedic surgery concurrently with amiodarone,|
01758|051|M|quinidine, or verapamil, the dabigatran loading dose should be reduced from|
01758|052|M|110 mg to 75 mg, and the maintenance dose should be reduced from 220 mg|
01758|053|M|daily to 150 mg daily, taken simultaneously with the P-gp inhibitor.  For|
01758|054|M|patients with CLcr 30-50 mL/min on concurrent verapamil, consider further|
01758|055|M|lowering the dabigatran dose to 75 mg daily.(3)|
01758|056|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
01758|057|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
01758|058|M|and/or decreased blood pressure and promptly evaluate patients with any|
01758|059|M|symptoms.  Consider regular monitoring of hemoglobin, platelet levels,|
01758|060|M|and/or activated partial thromboplastin time (aPTT) or ecarin clotting time|
01758|061|M|(ECT).|
01758|062|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01758|063|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01758|064|M|anticoagulation in patients with active pathologic bleeding.|
01758|065|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01758|066|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01758|067|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01758|068|M|and/or swelling.|
01758|069|B||
01758|070|D|DISCUSSION:  When dabigatran was co-administered with amiodarone, the extent|
01758|071|D|and rate of absorption of amiodarone and its active metabolite DEA were|
01758|072|D|essentially unchanged. The dabigatran area-under-curve (AUC) and maximum|
01758|073|D|concentration (Cmax) were increased by about 60% and 50%, respectively;(1,2)|
01758|074|D|however, dabigatran clearance was increased by 65%.(1)|
01758|075|D|   Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000|
01758|076|D|mg) increased the AUC and Cmax of dabigatran by 53% and 56%,|
01758|077|D|respectively.(1,2)|
01758|078|D|   Chronic administration of immediate release verapamil one hour prior to|
01758|079|D|dabigatran dose increased dabigatran AUC by 154%.(4)  Administration of|
01758|080|D|dabigatran two hours before verapamil results in a negligible increase in|
01758|081|D|dabigatran AUC.(1)|
01758|082|D|   Administration of sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg|
01758|083|D|daily) increased the Cmax and AUC of a single dose of dabigatran (75 mg) by|
01758|084|D|2.87-fold and 2.61-fold, respectively.(5)|
01758|085|D|   Simultaneous administration of glecaprevir-pibrentasvir (300/120 mg|
01758|086|D|daily) with a single dose of dabigatran (150 mg) increased the Cmax and AUC|
01758|087|D|by 2.05-fold and 2.38-fold, respectively.(6)|
01758|088|D|   A retrospective comparative effectiveness cohort study including data|
01758|089|D|from 9,886 individuals evaluated adverse bleeding rates with standard doses|
01758|090|D|of oral anticoagulants with concurrent verapamil or diltiazem in patients|
01758|091|D|with nonvalvular atrial fibrillation and normal kidney function.  The study|
01758|092|D|compared rates of bleeding following co-administration of either dabigatran,|
01758|093|D|rivaroxaban, or apixaban with verapamil or diltiazem, compared to|
01758|094|D|co-administration with amlodipine or metoprolol.  Results of the study found|
01758|095|D|that concomitant dabigatran use with verapamil or diltiazem was associated|
01758|096|D|with increased overall bleeding (hazard ratio (HR) 1.52; 95% confidence|
01758|097|D|interval (CI), 1.05-2.20, p<0.05) and increased overall GI bleeding (HR|
01758|098|D|2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine.  When compared|
01758|099|D|to metoprolol, concomitant dabigatran use with verapamil or diltiazem was|
01758|100|D|also associated with increased overall bleeding (HR, 1.43; 95% CI,|
01758|101|D|1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI,|
01758|102|D|1.42-3.79, p<0.05).  No association was found between increased bleeding of|
01758|103|D|any kind and concurrent use of rivaroxaban or apixaban with verapamil or|
01758|104|D|diltiazem.(7)|
01758|105|D|   A summary of pharmacokinetic interactions with dabigatran and amiodarone|
01758|106|D|or verapamil concluded that concurrent use is considered safe if CrCl is|
01758|107|D|greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min|
01758|108|D|in VTE and less than 30 ml/min for NVAF.  Concurrent use with diltiazem was|
01758|109|D|considered safe.(9)|
01758|110|D|   P-gp inhibitors include amiodarone, asunaprevir, belumosudil, capmatinib,|
01758|111|D|carvedilol, cimetidine, conivaptan, cyclosporine, daclatasvir, danicopan,|
01758|112|D|daridorexant, diosmin, erythromycin, flibanserin, fostamatinib, ginseng,|
01758|113|D|glecaprevir, imlunestrant, indinavir, itraconazole, ivacaftor, josamycin,|
01758|114|D|lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib,|
01758|115|D|pibrentasvir, propafenone, quinidine, ranolazine, ritonavir, selpercatinib,|
01758|116|D|sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib,|
01758|117|D|valbenazine, velpatasvir, vemurafenib, verapamil, vimseltinib, voclosporin,|
01758|118|D|and voxilaprevir.(1-9)|
01758|119|B||
01758|120|R|REFERENCES:|
01758|121|B||
01758|122|R|1.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
01758|123|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
01758|124|R|2.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
01758|125|R|  Boehringer Ingelheim March, 23 2020.|1
01758|126|R|3.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
01758|127|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
01758|128|R|4.Anonymous. FDA Dabigatran background package for Cardio-Renal Advisory|1
01758|129|R|  Committee. available at|1
01758|130|R|  http://wayback.archive-it.org/7993/20170405212218/https://www.fda.gov/down|1
01758|131|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascularan|1
01758|132|R|  dRenalDrugsAdvisoryCommittee/UCM247244.pdf September 20, 2010.|1
01758|133|R|5.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
01758|134|R|  Gilead Sciences, Inc. September, 2019.|1
01758|135|R|6.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
01758|136|R|  Inc. October, 2023.|1
01758|137|R|7.Pham P, Schmidt S, Lesko L, Lip GYH, Brown JD. Association of Oral|2
01758|138|R|  Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding  Events in|2
01758|139|R|  Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function.|2
01758|140|R|  JAMA Netw Open;3(4)(2574-3805 (Electronic). 2574-3805 (Linking)):.|2
01758|141|R|8.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
01758|142|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
01758|143|R|  of  the Week..|6
01758|144|R|9.This information is based on an extract from the Certara Drug Interaction|6
01758|145|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01759|001|T|MONOGRAPH TITLE:  Fesoterodine/Selected Protease Inhibitors (mono deleted|
01759|002|T|04/05/2012)|
01759|003|B||
01759|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01759|005|L|take action as needed.|
01759|006|B||
01759|007|A|MECHANISM OF ACTION:  Atazanavir, indinavir, nelfinavir, ritonavir, or|
01759|008|A|saquinavir may inhibit the metabolism of fesoterodine by CYP P-450-3A4|
01759|009|A|inhibition.(1,2)|
01759|010|B||
01759|011|E|CLINICAL EFFECTS:  The concurrent administration of atazanavir, indinavir,|
01759|012|E|nelfinavir, ritonavir, or saquinavir may result in elevated levels of and|
01759|013|E|toxicity from fesoterodine.(1,2)|
01759|014|B||
01759|015|P|PREDISPOSING FACTORS:  None determined.|
01759|016|B||
01759|017|M|PATIENT MANAGEMENT:  The US(1) and UK(2) manufacturer of fesoterodine|
01759|018|M|recommends a maximum fesoterodine dosage of 4 mg daily in patients receiving|
01759|019|M|concurrent therapy with potent CYP P-450-3A4 inhibitors such as atazanavir,|
01759|020|M|indinavir, nelfinavir, ritonavir, or saquinavir.|
01759|021|B||
01759|022|D|DISCUSSION:  In a study, co-administration of ketoconazole (200 mg twice a|
01759|023|D|day), another inhibitor of CYP P-450-3A4, increased the Cmax and AUC of the|
01759|024|D|active metabolite of fesoterodine 2.0 and 2.3-fold in CYP P-450-2D6|
01759|025|D|extensive metabolizers and 2.1 and 2.5-fold in CYP P-450-2D6 poor|
01759|026|D|metabolizers, respectively.(1,2)  Fesoterodine Cmax and AUC were 4.5-fold|
01759|027|D|and 5.7-fold higher in subjects who were CYP P-450-2D6 poor metabolizers and|
01759|028|D|taking ketoconazole when compared to extensive CYP P-450-2D6 metabolizers|
01759|029|D|not taking ketoconazole.(1)|
01759|030|D|   In another study, ketoconazole (200 mg daily) increased the Cmax and AUC|
01759|031|D|of the active metabolite of fesoterodine 2.2-fold in CYP P-450-2D6 extensive|
01759|032|D|metabolizers and 1.5-fold and 1.9-fold in CYP P-450-2D6 poor metabolizers,|
01759|033|D|respectively.(1,2)  Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold|
01759|034|D|higher in subjects who were CYP P-450-2D6 poor metabolizers and taking|
01759|035|D|ketoconazole when compared to extensive CYP P-450-2D6 metabolizers not|
01759|036|D|taking ketoconazole.(1)|
01759|037|B||
01759|038|R|REFERENCES:|
01759|039|B||
01759|040|R|1.Toviaz (fesoterodine fumarate) US prescribing information. Pfizer|1
01759|041|R|  February, 2011.|1
01759|042|R|2.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
01759|043|R|  Limited February, 2011.|1
01761|001|T|MONOGRAPH TITLE:  Fesoterodine/Clarithromycin; Telithromycin (mono deleted|
01761|002|T|04/05/2012)|
01761|003|B||
01761|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01761|005|L|take action as needed.|
01761|006|B||
01761|007|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01761|008|A|metabolism of fesoterodine by CYP P-450-3A4.(1,2)|
01761|009|B||
01761|010|E|CLINICAL EFFECTS:  The concurrent administration of clarithromycin and|
01761|011|E|telithromycin may result in elevated levels of and toxicity from|
01761|012|E|fesoterodine.(1,2)|
01761|013|B||
01761|014|P|PREDISPOSING FACTORS:  None determined.|
01761|015|B||
01761|016|M|PATIENT MANAGEMENT:  The US(1) and UK(2) manufacturers of fesoterodine|
01761|017|M|recommend a maximum fesoterodine dosage of 4 mg daily in patients receiving|
01761|018|M|concurrent concurrent therapy with potent CYP P-450-3A4 inhibitors such as|
01761|019|M|clarithromycin or telithromycin.|
01761|020|B||
01761|021|D|DISCUSSION:  In a study, co-administration of ketoconazole (200 mg twice a|
01761|022|D|day), another inhibitor of CYP P-450-3A4, increased the Cmax and AUC of the|
01761|023|D|active metabolite of fesoterodine 2.0 and 2.3-fold in CYP P-450-2D6|
01761|024|D|extensive metabolizers and 2.1 and 2.5-fold in CYP P-450-2D6 poor|
01761|025|D|metabolizers, respectively.(1,2)  Fesoterodine Cmax and AUC were 4.5-fold|
01761|026|D|and 5.7-fold higher in subjects who were CYP P-450-2D6 poor metabolizers and|
01761|027|D|taking ketoconazole when compared to extensive CYP P-450-2D6 metabolizers|
01761|028|D|not taking ketoconazole.(1)|
01761|029|D|   In another study, ketoconazole (200 mg daily) increased the Cmax and AUC|
01761|030|D|of the active metabolite of fesoterodine 2.2-fold in CYP P-450-2D6 extensive|
01761|031|D|metabolizers and 1.5-fold and 1.9-fold in CYP P-450-2D6 poor metabolizers,|
01761|032|D|respectively.(1,2)  Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold|
01761|033|D|higher in subjects who were CYP P-450-2D6 poor metabolizers and taking|
01761|034|D|ketoconazole when compared to extensive CYP P-450-2D6 metabolizers not|
01761|035|D|taking ketoconazole.(1)|
01761|036|B||
01761|037|R|REFERENCES:|
01761|038|B||
01761|039|R|1.Toviaz (fesoterodine fumarate) US prescribing information. Pfizer|1
01761|040|R|  February, 2011.|1
01761|041|R|2.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
01761|042|R|  Limited February, 2011.|1
01762|001|T|MONOGRAPH TITLE:  Fesoterodine/Ketoconazole; Itraconazole (mono deleted|
01762|002|T|04/05/2012)|
01762|003|B||
01762|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01762|005|L|take action as needed.|
01762|006|B||
01762|007|A|MECHANISM OF ACTION:  Ketoconazole and itraconazole may inhibit the|
01762|008|A|metabolism of fesoterodine by CYP P-450-3A4.(1,2)|
01762|009|B||
01762|010|E|CLINICAL EFFECTS:  The concurrent administration of ketoconazole and|
01762|011|E|itraconazole may result in elevated levels of and toxicity from|
01762|012|E|fesoterodine.(1,2)|
01762|013|B||
01762|014|P|PREDISPOSING FACTORS:  None determined.|
01762|015|B||
01762|016|M|PATIENT MANAGEMENT:  The US(1) and UK(2) manufacturers of fesoterodine|
01762|017|M|recommends a maximum fesoterodine dosage of 4 mg daily in patients receiving|
01762|018|M|concurrent therapy with potent CYP P-450-3A4 inhibitors such as ketoconazole|
01762|019|M|or itraconazole.|
01762|020|B||
01762|021|D|DISCUSSION:  In a study, co-administration of ketoconazole (200 mg twice a|
01762|022|D|day) increased the Cmax and AUC of the active metabolite of fesoterodine 2.0|
01762|023|D|and 2.3-fold in CYP P-450-2D6 extensive metabolizers and 2.1 and 2.5-fold in|
01762|024|D|CYP P-450-2D6 poor metabolizers, respectively.(1,2)  Fesoterodine Cmax and|
01762|025|D|AUC were 4.5-fold and 5.7-fold higher in subjects who were CYP P-450-2D6|
01762|026|D|poor metabolizers and taking ketoconazole when compared to extensive CYP|
01762|027|D|P-450-2D6 metabolizers not taking ketoconazole.(1)|
01762|028|D|   In another study, ketoconazole (200 mg daily) increased the Cmax and AUC|
01762|029|D|of the active metabolite of fesoterodine 2.2-fold in CYP P-450-2D6 extensive|
01762|030|D|metabolizers and 1.5-fold and 1.9-fold in CYP P-450-2D6 poor metabolizers,|
01762|031|D|respectively.(1,2)  Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold|
01762|032|D|higher in subjects who were CYP P-450-2D6 poor metabolizers and taking|
01762|033|D|ketoconazole when compared to extensive CYP P-450-2D6 metabolizers not|
01762|034|D|taking ketoconazole.(1)|
01762|035|B||
01762|036|R|REFERENCES:|
01762|037|B||
01762|038|R|1.Toviaz (fesoterodine fumarate) US prescribing information. Pfizer|1
01762|039|R|  February, 2011.|1
01762|040|R|2.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
01762|041|R|  Limited February, 2011.|1
01763|001|T|MONOGRAPH TITLE:  Fesoterodine/Nefazodone (mono deleted 04/05/2012)|
01763|002|B||
01763|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01763|004|L|take action as needed.|
01763|005|B||
01763|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of fesoterodine|
01763|007|A|by CYP P-450-3A4.(1,2)|
01763|008|B||
01763|009|E|CLINICAL EFFECTS:  The concurrent administration of nefazodone may result in|
01763|010|E|elevated levels of and toxicity from fesoterodine.(1,2)|
01763|011|B||
01763|012|P|PREDISPOSING FACTORS:  None determined.|
01763|013|B||
01763|014|M|PATIENT MANAGEMENT:  The US(1) and UK(2) manufacturers of fesoterodine|
01763|015|M|recommends a maximum fesoterodine dosage of 4 mg daily in patients receiving|
01763|016|M|concurrent concurrent therapy with potent CYP P-450-3A4 inhibitors such as|
01763|017|M|nefazodone.|
01763|018|B||
01763|019|D|DISCUSSION:  In a study, co-administration of ketoconazole (200 mg twice a|
01763|020|D|day), another inhibitor of CYP P-450-3A4, increased the Cmax and AUC of the|
01763|021|D|active metabolite of fesoterodine 2.0 and 2.3-fold in CYP P-450-2D6|
01763|022|D|extensive metabolizers and 2.1 and 2.5-fold in CYP P-450-2D6 poor|
01763|023|D|metabolizers, respectively.(1,2)  Fesoterodine Cmax and AUC were 4.5-fold|
01763|024|D|and 5.7-fold higher in subjects who were CYP P-450-2D6 poor metabolizers and|
01763|025|D|taking ketoconazole when compared to extensive CYP P-450-2D6 metabolizers|
01763|026|D|not taking ketoconazole.(1)|
01763|027|D|   In another study, ketoconazole (200 mg daily) increased the Cmax and AUC|
01763|028|D|of the active metabolite of fesoterodine 2.2-fold in CYP P-450-2D6 extensive|
01763|029|D|metabolizers and 1.5-fold and 1.9-fold in CYP P-450-2D6 poor metabolizers,|
01763|030|D|respectively.(1,2)  Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold|
01763|031|D|higher in subjects who were CYP P-450-2D6 poor metabolizers and taking|
01763|032|D|ketoconazole when compared to extensive CYP P-450-2D6 metabolizers not|
01763|033|D|taking ketoconazole.(1)|
01763|034|B||
01763|035|R|REFERENCES:|
01763|036|B||
01763|037|R|1.Toviaz (fesoterodine fumarate) US prescribing information. Pfizer|1
01763|038|R|  February, 2011.|1
01763|039|R|2.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
01763|040|R|  Limited February, 2011.|1
01764|001|T|MONOGRAPH TITLE:  Fesoterodine/Selected Anticonvulsants; Barbiturates|
01764|002|B||
01764|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01764|004|L|of severe adverse interaction.|
01764|005|B||
01764|006|A|MECHANISM OF ACTION:  Barbiturates, carbamazepine, phenobarbital, phenytoin,|
01764|007|A|and primidone may induce the metabolism of fesoterodine by CYP3A4.(1,2)|
01764|008|B||
01764|009|E|CLINICAL EFFECTS:  Concurrent use of barbiturates, carbamazepine,|
01764|010|E|phenobarbital, phenytoin, or primidone with fesoterodine may result in|
01764|011|E|decreased levels of fesoterodine as well as their active metabolites, and|
01764|012|E|decreased clinical effectiveness.|
01764|013|B||
01764|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01764|015|P|of the inducer for longer than 1-2 weeks.|
01764|016|B||
01764|017|M|PATIENT MANAGEMENT:  Concurrent or recent use may lead to subtherapeutic|
01764|018|M|levels of fesoterodine. Monitor patients for decreased effectiveness.|
01764|019|M|   The UK manufacturer of fesoterodine suggests that the concomitant use of|
01764|020|M|these agents is not recommended;(1) however, the US manufacturer states no|
01764|021|M|dosage adjustment is necessary.(2)|
01764|022|B||
01764|023|D|DISCUSSION:  In one clinical study, the induction of CYP3A4 by|
01764|024|D|co-administration of rifampicin (600 mg once a day), another inducer of|
01764|025|D|CYP3A4, maximum concentration (Cmax) and area-under-curve (AUC) of the|
01764|026|D|active metabolite of fesoterodine decreased by 70% and 75%, respectively,|
01764|027|D|following the oral administration of 8 mg of fesoterodine.(1,2)|
01764|028|B||
01764|029|R|REFERENCES:|
01764|030|B||
01764|031|R|1.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
01764|032|R|  Limited February, 2011.|1
01764|033|R|2.Toviaz (fesoterodine fumarate) US prescribing information. Pfizer June,|1
01764|034|R|  2021.|1
01765|001|T|MONOGRAPH TITLE:  Fesoterodine/St. John's Wort|
01765|002|B||
01765|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01765|004|L|of severe adverse interaction.|
01765|005|B||
01765|006|A|MECHANISM OF ACTION:  St. John's Wort may induce the metabolism of|
01765|007|A|fesoterodine by CYP3A4.(1,2)|
01765|008|B||
01765|009|E|CLINICAL EFFECTS:  St. John's Wort with fesoterodine may result in decreased|
01765|010|E|levels of fesoterodine as well as their active metabolites, and decreased|
01765|011|E|clinical effectiveness.|
01765|012|B||
01765|013|P|PREDISPOSING FACTORS:  None determined.|
01765|014|B||
01765|015|M|PATIENT MANAGEMENT:  Concurrent or recent use may lead to subtherapeutic|
01765|016|M|levels of fesoterodine. Monitor patients for decreased effectiveness.|
01765|017|M|   The UK manufacturer of fesoterodine suggests that the concomitant use of|
01765|018|M|these agents is not recommended;(1) however, the US manufacturer states no|
01765|019|M|dosage adjustment is necessary.(2)|
01765|020|B||
01765|021|D|DISCUSSION:  In one clinical study, the induction of CYP3A4 by|
01765|022|D|co-administration of rifampicin (600 mg once a day), another inducer of|
01765|023|D|CYP3A4, Cmax and AUC of the active metabolite of fesoterodine decreased by|
01765|024|D|70% and 75%, respectively, following the oral administration of 8mg of|
01765|025|D|fesoterodine.(1,2)|
01765|026|B||
01765|027|R|REFERENCES:|
01765|028|B||
01765|029|R|1.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
01765|030|R|  Limited February, 2011.|1
01765|031|R|2.Toviaz (fesoterodine fumarate) US prescribing information. Pfizer June,|1
01765|032|R|  2021.|1
01766|001|T|MONOGRAPH TITLE:  Fesoterodine/Rifampin|
01766|002|B||
01766|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01766|004|L|of severe adverse interaction.|
01766|005|B||
01766|006|A|MECHANISM OF ACTION:  Rifampicin may induce the metabolism of fesoterodine|
01766|007|A|by CYP3A4.(1,2)|
01766|008|B||
01766|009|E|CLINICAL EFFECTS:  Administering rifampicin with fesoterodine may result in|
01766|010|E|decreased levels of fesoterodine, as well as its active metabolites, and|
01766|011|E|decreased clinical effectiveness.|
01766|012|B||
01766|013|P|PREDISPOSING FACTORS:  None determined.|
01766|014|B||
01766|015|M|PATIENT MANAGEMENT:  Concurrent or recent use may lead to subtherapeutic|
01766|016|M|levels of fesoterodine. Monitor patients for decreased effectiveness.|
01766|017|M|   The UK manufacturer of fesoterodine suggests that the concomitant use of|
01766|018|M|these agents is not recommended;(1) however, the US manufacturer states no|
01766|019|M|dosage adjustment is necessary.(2)|
01766|020|B||
01766|021|D|DISCUSSION:  In one clinical study, the induction of CYP3A4 by|
01766|022|D|co-administration of rifampicin (600 mg once a day), maximum concentration|
01766|023|D|(Cmax) and area-under-curve (AUC) of the active metabolite of fesoterodine|
01766|024|D|decreased by 70% and 75%, respectively, following the oral administration of|
01766|025|D|8mg of fesoterodine.(1,2)|
01766|026|B||
01766|027|R|REFERENCES:|
01766|028|B||
01766|029|R|1.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
01766|030|R|  Limited February, 2011.|1
01766|031|R|2.Toviaz (fesoterodine fumarate) US prescribing information. Pfizer June,|1
01766|032|R|  2021.|1
01768|001|T|MONOGRAPH TITLE:  Fesoterodine/QT Prolonging Agents (mono deleted|
01768|002|T|05/23/2013)|
01768|003|B||
01768|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01768|005|L|take action as needed.|
01768|006|B||
01768|007|A|MECHANISM OF ACTION:  Concurrent use of fesoterodine and agents known to|
01768|008|A|prolong the QT interval may result in additive or synergistic effects on the|
01768|009|A|QTc interval.(1)|
01768|010|B||
01768|011|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01768|012|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01768|013|E|torsades de pointes.|
01768|014|B||
01768|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01768|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01768|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01768|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01768|019|P|gender, or advanced age.(2)|
01768|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01768|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01768|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01768|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01768|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01768|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01768|026|P|dysfunction).(2)|
01768|027|B||
01768|028|M|PATIENT MANAGEMENT:  The UK manufacturer of fesoterodine states that|
01768|029|M|fesoterodine should be used with caution when given with anti-arrhythmic|
01768|030|M|agents, other drugs that prolong the QT interval.(1)|
01768|031|B||
01768|032|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01768|033|D|degrees of potential to prolong the QTc interval. Agents linked to this|
01768|034|D|monograph have been shown to prolong the QTc interval either through their|
01768|035|D|mechanism of action, through studies on their effects on the QTc interval,|
01768|036|D|or through reports of QTc prolongation and/or torsades de pointes in|
01768|037|D|clinical trials and/or post-marketing reports.(2)|
01768|038|B||
01768|039|R|REFERENCES:|
01768|040|B||
01768|041|R|1.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
01768|042|R|  Limited February, 2011.|1
01768|043|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01768|044|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01768|045|R|  settings: a scientific statement from the American Heart Association and|6
01768|046|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01768|047|R|  2;55(9):934-47.|6
01769|001|T|MONOGRAPH TITLE:  Pegvisomant/Somatostatin Analogues|
01769|002|B||
01769|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01769|004|L|take action as needed.|
01769|005|B||
01769|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01769|007|B||
01769|008|E|CLINICAL EFFECTS:  Concurrent use may result in an increased risk of|
01769|009|E|hepatotoxicity.(1)|
01769|010|B||
01769|011|P|PREDISPOSING FACTORS:  None determined.|
01769|012|B||
01769|013|M|PATIENT MANAGEMENT:  The Canadian manufacturer of pegvisomant states that|
01769|014|M|the concurrent use of pegvisomant and somatostatin analogues may lead to|
01769|015|M|markedly increase hepatic enzymes in patients treated with this|
01769|016|M|combination.(1)|
01769|017|B||
01769|018|D|DISCUSSION:  Based on post marketing studies, there was marked hepatic|
01769|019|D|elevations (greater than 10 times the upper limit of normal (ULN) which was|
01769|020|D|reported in 3 out of 26 patients treated with the combination of pegvisomant|
01769|021|D|and octreotide. The ranges for the elevations for ALT and AST ranged from 13|
01769|022|D|to 45 times the ULN within three months of treatment. All three patients|
01769|023|D|recovered after discontinuation of treatment.(1)|
01769|024|B||
01769|025|R|REFERENCE:|
01769|026|B||
01769|027|R|1.Somavert (pegvisomant) Canadian prescribing information. Pfizer October,|1
01769|028|R|  2005.|1
01770|001|T|MONOGRAPH TITLE:  Aripiprazole/Duloxetine (mono deleted 06/26/2024)|
01770|002|B||
01770|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01770|004|L|take action as needed.|
01770|005|B||
01770|006|A|MECHANISM OF ACTION:  Aripiprazole is primarily metabolized by CYP3A4 and|
01770|007|A|CYP2D6. Duloxetine may inhibit the CYP2D6 mediated metabolism of|
01770|008|A|aripiprazole.(1,2)|
01770|009|B||
01770|010|E|CLINICAL EFFECTS:  Concurrent administration of duloxetine with aripiprazole|
01770|011|E|may result in elevated levels of aripiprazole and signs of toxicity.(1,2)|
01770|012|B||
01770|013|P|PREDISPOSING FACTORS:  Concomitant treatment with a CYP3A4 inhibitor would|
01770|014|P|lead to inhibition of both major metabolic pathways for aripiprazole,|
01770|015|P|further increasing aripiprazole concentrations and risk for toxicities.|
01770|016|B||
01770|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with aripiprazole|
01770|018|M|and duloxetine (a CYP2D6 inhibitor) should be monitored for increased|
01770|019|M|effects of aripiprazole.  Evaluate other medications for inhibition of|
01770|020|M|CYP3A4 to determine if a dosage adjustment is necessary.  The manufacturer|
01770|021|M|of aripiprazole immediate release oral and injection dose forms states that|
01770|022|M|for patients receiving concurrent therapy with drug combinations which lead|
01770|023|M|to inhibition of both CYP2D6 and CYP3A4, the aripiprazole dose may be|
01770|024|M|adjusted to one-quarter (25%) of the usual dose initially, then adjusted|
01770|025|M|based on clinical response.|
01770|026|B||
01770|027|D|DISCUSSION:  The administration of quinidine (166 mg daily for 13 days) with|
01770|028|D|a single dose of aripiprazole (10 mg) resulted in a 112% increase in the|
01770|029|D|area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of|
01770|030|D|dehydro-aripiprazole, the active metabolite of aripiprazole.  Duloxetine is|
01770|031|D|an inhibitor of CYP2D6 and is expected to interact similarly.(1,2)|
01770|032|D|   In a study in 78 patients, concurrent administration of duloxetine with|
01770|033|D|aripiprazole resulted in a 54% increase in plasma concentration. 12.8% of|
01770|034|D|patients exhibited aripiprazole plasma concentrations above the upper limit|
01770|035|D|of the therapeutic reference range.(5)|
01770|036|B||
01770|037|R|REFERENCES:|
01770|038|B||
01770|039|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
01770|040|R|  Pharmaceutical, Inc. August, 2019.|1
01770|041|R|2.Schwartz  T Raza S. Aripiprazole (Abilify) and Tardive Dyskinesia. P&T|3
01770|042|R|  January, 2008;33(1):32-34.|3
01770|043|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01770|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01770|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01770|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01770|047|R|  11/14/2017.|1
01770|048|R|4.Abilify Maintena (aripiprazole ext-rel inj.) prescribing information.|1
01770|049|R|  Otsuka Pharmaceuticals January, 2016.|1
01770|050|R|5.Margraff T, Schoretsanitis G, Neuner I, Haen E, Gaebler AJ, Paulzen M.|2
01770|051|R|  Discovering interactions in augmentation strategies: Impact of duloxetine|2
01770|052|R|  on the  metabolism of aripiprazole. Basic Clin Pharmacol Toxicol 2023 Jul;|2
01770|053|R|  133(1):73-81.|2
01771|001|T|MONOGRAPH TITLE:  Aliskiren/Cyclosporine|
01771|002|B||
01771|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01771|004|L|is contraindicated and generally should not be dispensed or administered to|
01771|005|L|the same patient.|
01771|006|B||
01771|007|A|MECHANISM OF ACTION:  Aliskiren is a substrate for the P-glycoprotein (P-gp)|
01771|008|A|system.  Cyclosporine is a potent inhibitor of P-gp.(1)|
01771|009|B||
01771|010|E|CLINICAL EFFECTS:  The concurrent use of aliskiren and cyclosporine may|
01771|011|E|result in elevated levels of aliskiren.  This may result in increased effect|
01771|012|E|and toxicity of aliskiren such as hypotension.(1,2)|
01771|013|B||
01771|014|P|PREDISPOSING FACTORS:  None determined.|
01771|015|B||
01771|016|M|PATIENT MANAGEMENT:  The US manufacturer of aliskiren states that concurrent|
01771|017|M|use of cyclosporine should be avoided.(1)|
01771|018|M|   The UK manufacturer of aliskiren states that the concurrent use of potent|
01771|019|M|P-gp inhibitors such as cyclosporine is contraindicated.(2)|
01771|020|B||
01771|021|D|DISCUSSION:  In a study in healthy subjects, concurrent cyclosporine (200 mg|
01771|022|D|and 600 mg) increased the maximum concentration (Cmax) and area-under-curve|
01771|023|D|(AUC) of aliskiren (75 mg) by 2.5-fold and 5-fold, respectively.(1,2)|
01771|024|B||
01771|025|R|REFERENCES:|
01771|026|B||
01771|027|R|1.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
01771|028|R|  Corporation November, 2017.|1
01771|029|R|2.Rasilez (aliskiren hemifumarate) UK summary of product characteristics.|1
01771|030|R|  Novartis Pharmaceuticals UK Ltd. September, 2014.|1
01772|001|T|MONOGRAPH TITLE:  Valproic Acid Derivatives/Pivmecillinam|
01772|002|B||
01772|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01772|004|L|of severe adverse interaction.|
01772|005|B||
01772|006|A|MECHANISM OF ACTION:  Pivalic acid is released after hydrolysis from several|
01772|007|A|prodrugs.  In humans, formation and urinary excretion of pivaloylcarnitine|
01772|008|A|generated from pivaloyl-CoA is the major route of pivalate elimination.|
01772|009|B||
01772|010|E|CLINICAL EFFECTS:  Concurrent use of valproic acid or its derivatives and|
01772|011|E|pivmecillinam may increase the risk of low carnitine levels leading to|
01772|012|E|neurologic deficits with or without encephalopathy.  Neurologic deficits may|
01772|013|E|present as changes in state of consciousness and/or cognitive function with|
01772|014|E|lethargy and vomiting.(1-3)|
01772|015|B||
01772|016|P|PREDISPOSING FACTORS:  Patients with low carnitine levels, significant renal|
01772|017|P|impairment, or decreased muscle mass.|
01772|018|B||
01772|019|M|PATIENT MANAGEMENT:  The US and UK manufacturers of pivmecillinam state that|
01772|020|M|the use of pivmecillinam and valproic acid and its derivatives should be|
01772|021|M|avoided.(1,2)|
01772|022|M|   In patients receiving concurrent valproic acid derivatives and|
01772|023|M|pivmecillinam, monitor for unexplained lethargy, vomiting, and/ or changes|
01772|024|M|in mental status.  If these symptoms develop, check the patient's carnitine|
01772|025|M|level and administer exogenous carnitine to increase body stores.(3)|
01772|026|B||
01772|027|D|DISCUSSION:  There are reports of low carnitine levels caused by the long|
01772|028|D|term (> 6 months) use of these agents resulting in neurological deficits|
01772|029|D|caused by the concurrent use of pivalic acid containing products.(3)  The|
01772|030|D|patient improved after carnitine supplementation.|
01772|031|B||
01772|032|R|REFERENCES:|
01772|033|B||
01772|034|R|1.Selexid (pivmecillinam hydrochloride)  UK summary of product|1
01772|035|R|  characteristics. Leo Laboratories Limited January, 2008.|1
01772|036|R|2.Pivmecillinam (Pivya) US prescribing information. UTILITY therapeutics Ltd|1
01772|037|R|  April 2024.|1
01772|038|R|3.Makino Y, Sugiura T, Ito T, Sugiyama N, Koyama N. Carnitine-associated|2
01772|039|R|  encephalopathy caused by long-term treatment with an antibiotic containing|2
01772|040|R|  pivalic acid. Pediatrics 2007 Sep;120(3):e739-41.|2
01773|001|T|MONOGRAPH TITLE:  Dabigatran/Sulfinpyrazone|
01773|002|B||
01773|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01773|004|L|of severe adverse interaction.|
01773|005|B||
01773|006|A|MECHANISM OF ACTION:  Dabigatran is a direct thrombin inhibitor and when|
01773|007|A|taken with agents that effect platelet aggregation and/or other clotting|
01773|008|A|factors increased bleeding episodes can occur.|
01773|009|B||
01773|010|E|CLINICAL EFFECTS:  Concurrent use of dabigatran with sulfinpyrazone may|
01773|011|E|result in additive or synergistic effects resulting in unwanted bleeding|
01773|012|E|episodes.|
01773|013|B||
01773|014|P|PREDISPOSING FACTORS:  Factors associated with an increase risk of bleeding|
01773|015|P|include renal impairment, concomitant use of P-glycoprotein inhibitors,|
01773|016|P|patient age >74 years, coexisting conditions (e.g. recent trauma) or use of|
01773|017|P|drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight <50|
01773|018|P|kg. (1-3)|
01773|019|P|   The risk for bleeding episodes may be greater in patients with|
01773|020|P|disease-associated factors (e.g. thrombocytopenia).|
01773|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
01773|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01773|023|P|risk for bleeding (e.g. NSAIDs).|
01773|024|B||
01773|025|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
01773|026|M|receiving concurrent therapy for signs of blood loss, including decreased|
01773|027|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
01773|028|M|and promptly evaluate patients with any symptoms.|
01773|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01773|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01773|031|M|anticoagulation in patients with active pathologic bleeding.|
01773|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01773|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01773|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01773|035|M|and/or swelling.|
01773|036|M|   The UK manufacturer of dabigatran states the use of dabigatran and|
01773|037|M|sulfinpyrazone is not recommended.(1)|
01773|038|B||
01773|039|D|DISCUSSION:  Dabigatran is a direct thrombin inhibitor and when taken with|
01773|040|D|agents that effect platelet aggregation and/or other clotting factors|
01773|041|D|increased bleeding episodes can occur.(1)|
01773|042|B||
01773|043|R|REFERENCES:|
01773|044|B||
01773|045|R|1.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
01773|046|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
01773|047|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
01773|048|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
01773|049|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
01773|050|R|  Boehringer Ingelheim March, 23 2020.|1
01776|001|T|MONOGRAPH TITLE:  Repaglinide/NPH Insulin|
01776|002|B||
01776|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01776|004|L|of severe adverse interaction.|
01776|005|B||
01776|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown but may be a result of|
01776|007|A|additive serum glucose lowering.(1)|
01776|008|B||
01776|009|E|CLINICAL EFFECTS:  The concurrent use of repaglinide and NPH insulin may|
01776|010|E|increase the risk of hypoglycemia and increase in myocardial ischemia.(1)|
01776|011|B||
01776|012|P|PREDISPOSING FACTORS:  Patients predisposed to hypoglycemia. This may|
01776|013|P|include the elderly, debilitated, or malnourished patients and those with|
01776|014|P|adrenal or pituitary insufficiency.|
01776|015|B||
01776|016|M|PATIENT MANAGEMENT:  The US manufacturer of repaglinide states that the|
01776|017|M|concurrent use with NPH insulin is not recommended.(1)|
01776|018|B||
01776|019|D|DISCUSSION:  The concurrent use of repaglinide and NPH insulin is not|
01776|020|D|recommended due to increase in hypoglycemia and cardiovascular events,|
01776|021|D|especially ischemia. Seven controlled clinical trials included repaglinide|
01776|022|D|combination therapy with NPH-insulin (n=431), insulin formulations alone|
01776|023|D|(n=388) or other combinations (sulfonylurea plus NPH-insulin or plus|
01776|024|D|metformin) (n=120). There were six serious adverse events of myocardial|
01776|025|D|ischemia in patients treated with repaglinide plus NPH-insulin from two|
01776|026|D|studies during clinical trials.(1)|
01776|027|B||
01776|028|R|REFERENCE:|
01776|029|B||
01776|030|R|1.Prandin (repaglinide) US prescribing information. Novo Nordisk|1
01776|031|R|  Pharmaceuticals, Inc. February 8, 2017.|1
01777|001|T|MONOGRAPH TITLE:  Nisoldipine/Hydantoins (mono deleted 06/26/2014)|
01777|002|B||
01777|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01777|004|L|is contraindicated and generally should not be dispensed or administered to|
01777|005|L|the same patient.|
01777|006|B||
01777|007|A|MECHANISM OF ACTION:  Hydantoins may induce the metabolism of nisoldipine.|
01777|008|B||
01777|009|E|CLINICAL EFFECTS:  Concurrent use of hydantoins may result in dramatically|
01777|010|E|reduced levels of nisoldipine, resulting in a lack of antihypertensive|
01777|011|E|effects.(1)|
01777|012|B||
01777|013|P|PREDISPOSING FACTORS:  None determined.|
01777|014|B||
01777|015|M|PATIENT MANAGEMENT:  The US manufacturer of nisoldipine states that|
01777|016|M|concurrent use of phenytoin should be avoided.(1)|
01777|017|B||
01777|018|D|DISCUSSION:  Concurrent administration of phenytoin with nisoldipine (40 mg)|
01777|019|D|decreased nisoldipine plasma concentrations below detectable levels.(1)|
01777|020|D|   In a study comparing patients receiving chronic phenytoin therapy to|
01777|021|D|healthy controls, phenytoin decreased the AUC of a single dose of|
01777|022|D|nisoldipine by 89%.(2)|
01777|023|B||
01777|024|R|REFERENCES:|
01777|025|B||
01777|026|R|1.Sular (nisoldipine) US prescribing information. Shionogi, Inc. December,|1
01777|027|R|  2012.|1
01777|028|R|2.Michelucci R, Cipolla G, Passarelli D, Gatti G, Ochan M, Heinig R,|2
01777|029|R|  Tassinari CA, Perucca E. Reduced plasma nisoldipine concentrations in|2
01777|030|R|  phenytoin-treated patients with epilepsy. Epilepsia 1996 Nov;|2
01777|031|R|  37(11):1107-10.|2
01780|001|T|MONOGRAPH TITLE:  Bevacizumab/Sunitinib|
01780|002|B||
01780|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01780|004|L|of severe adverse interaction.|
01780|005|B||
01780|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is not known at this|
01780|007|A|time.|
01780|008|B||
01780|009|E|CLINICAL EFFECTS:  Concurrent use of sunitinib and bevacizumab may result in|
01780|010|E|the development microangiopathic hemolytic anemia.(1)|
01780|011|B||
01780|012|P|PREDISPOSING FACTORS:  None determined.|
01780|013|B||
01780|014|M|PATIENT MANAGEMENT:  Use sunitinib with bevacizumab may result in|
01780|015|M|microangiopathic hemolytic anemia. Bevacizumab is not approved for use in|
01780|016|M|combination with sunitinib malate and this combination is not|
01780|017|M|recommended.(1)|
01780|018|B||
01780|019|D|DISCUSSION:  Twenty-five patients were enrolled in a Phase I dose-escalation|
01780|020|D|study combining Avastin and sunitinib malate. The study consisted of 3|
01780|021|D|cohorts using a fixed dose of Avastin at 10mg/kg/IV every 2 weeks and|
01780|022|D|escalating doses of sunitinib that included 25, 37.5, and 50 mg orally daily|
01780|023|D|given in a 4 weeks on/ 2 weeks off schedule. Two of these cases were|
01780|024|D|considered severe with evidence of thrombocytopenia, anemia,|
01780|025|D|reticulocytosis, reductions in serum haptoglobin, schistocytes on peripheral|
01780|026|D|smear, modest increases in serum creatinine levels, and severe hypertension,|
01780|027|D|reversible posterior leukoencephalopathy syndrome, and proteinuria. The|
01780|028|D|findings in these two cases were reversible within three weeks upon|
01780|029|D|discontinuation of both drugs without additional interventions. These drugs|
01780|030|D|are not recommended to be administered together.(1)|
01780|031|B||
01780|032|R|REFERENCE:|
01780|033|B||
01780|034|R|1.Dear Healthcare Provider Letter: Subject: Microangiopathic Hemolytic|1
01780|035|R|  Anemia (MAHA) in Patients treated with Avastin (bevacizumab) and sunitinib|1
01780|036|R|  malate. Genetech, Inc. July 11, 2008.|1
01781|001|T|MONOGRAPH TITLE:  Midazolam/Posaconazole (mono deleted 06/25/2009)|
01781|002|B||
01781|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01781|004|L|take action as needed.|
01781|005|B||
01781|006|A|MECHANISM OF ACTION:  Posaconazole may inhibit the metabolism of midazolam|
01781|007|A|via CYP P-450-3A4.(1)|
01781|008|B||
01781|009|E|CLINICAL EFFECTS:  Concurrent use of midazolam and posaconazole may result|
01781|010|E|in increased levels of midazolam, which may lead to increased clinical|
01781|011|E|effects and toxicity.(1)|
01781|012|B||
01781|013|P|PREDISPOSING FACTORS:  None determined.|
01781|014|B||
01781|015|M|PATIENT MANAGEMENT:  The US manufacturer of posaconazole states that|
01781|016|M|patients taking the combination of posaconazole and midazolam, an agent|
01781|017|M|primarily metabolized by CYP P-450-3A4, should be closely and frequently|
01781|018|M|monitored for adverse effects during therapy.|
01781|019|B||
01781|020|D|DISCUSSION:  Posaconazole is an inhibitor of CYP P-450-3A4.  During clinical|
01781|021|D|studies in healthy volunteers and patients (who were administered 200 mg|
01781|022|D|twice a day for 7 days of posaconazole suspension), the Cmax for a single|
01781|023|D|0.4 mg IV dose of midazolam was increased 30% and the AUC was increased|
01781|024|D|362%, respectively. For a single 2 mg oral dose of midazolam, the Cmax was|
01781|025|D|increased 126% and the AUC was increased 362%.|
01781|026|B||
01781|027|R|REFERENCE:|
01781|028|B||
01781|029|R|1.Noxafil (posaconazole) US prescribing information. Schering Corporation|1
01781|030|R|  June, 2012.|1
01782|001|T|MONOGRAPH TITLE:  Atazanavir; Ritonavir/Posaconazole|
01782|002|B||
01782|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01782|004|L|take action as needed.|
01782|005|B||
01782|006|A|MECHANISM OF ACTION:  Posaconazole may inhibit the metabolism of atazanavir|
01782|007|A|and ritonavir via CYP3A4.(1)|
01782|008|B||
01782|009|E|CLINICAL EFFECTS:  Concurrent use of atazanavir and/or ritonavir with|
01782|010|E|posaconazole may result in increased levels of atazanavir and ritonavir,|
01782|011|E|which may lead to increased clinical effects and toxicity.(1)|
01782|012|B||
01782|013|P|PREDISPOSING FACTORS:  None determined.|
01782|014|B||
01782|015|M|PATIENT MANAGEMENT:  The US manufacturer of posaconazole states that|
01782|016|M|patients taking the combination of posaconazole and atazanavir and/or|
01782|017|M|ritonavir should be closely and frequently monitored for adverse effects|
01782|018|M|during therapy.  Dosage adjustments may be required.(1)|
01782|019|B||
01782|020|D|DISCUSSION:  In a clinical study, posaconazole (400 mg twice daily for 7|
01782|021|D|days), increased the maximum concentration (Cmax) and area-under-curve (AUC)|
01782|022|D|of atazanavir (300 mg daily for 14 days) by 155% and 268%, respectively.(1)|
01782|023|D|   In a clinical study, posaconazole (400 mg twice daily for 7 days),|
01782|024|D|increased the Cmax and AUC of atazanavir (atazanavir/ritonavir 300/100 mg|
01782|025|D|daily) for 14 days by 53% and 146%, respectively.(1)|
01782|026|D|   In a clinical study, posaconazole (400 mg twice daily for 7 days),|
01782|027|D|increased the Cmax and AUC of ritonavir (100 mg daily for 14 days) by 49%|
01782|028|D|and 80%, respectively.(1)|
01782|029|B||
01782|030|R|REFERENCE:|
01782|031|B||
01782|032|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01782|033|R|  January, 2022.|1
01783|001|T|MONOGRAPH TITLE:  Typhoid Vaccine Live Attenuated/Mefloquine|
01783|002|B||
01783|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01783|004|L|take action as needed.|
01783|005|B||
01783|006|A|MECHANISM OF ACTION:  Mefloquine may attenuate the immunization response to|
01783|007|A|vaccines with attenuated live bacteria.(1)|
01783|008|B||
01783|009|E|CLINICAL EFFECTS:  Concurrent use may make the vaccine ineffective.(1)|
01783|010|B||
01783|011|P|PREDISPOSING FACTORS:  None determined.|
01783|012|B||
01783|013|M|PATIENT MANAGEMENT:  The manufacturer of mefloquine states that|
01783|014|M|administration of vaccines which contain attenuated live bacteria should be|
01783|015|M|completed three days before the initiation of mefloquine.(1)  To optimize|
01783|016|M|vaccine effectiveness, the Centers for Disease Control(CDC) recommends, when|
01783|017|M|feasible, delay of antibacterial drug therapy for one week after the last|
01783|018|M|dose of oral typhoid vaccine.(2)|
01783|019|M|   The manufacturer of oral typhoid Ty21a vaccine states concomitant|
01783|020|M|treatment with mefloquine does not significantly reduce immune response|
01783|021|M|rate.(3)|
01783|022|B||
01783|023|D|DISCUSSION:  The manufacturer of mefloquine states that attenuation of|
01783|024|D|immunization response to vaccines with attenuated live bacteria cannot be|
01783|025|D|excluded and therefore the manufacturer of mefloquine states that|
01783|026|D|vaccinations with vaccines containing attenuated live bacteria should be|
01783|027|D|completed three days before the initiation of mefloquine.(1)|
01783|028|B||
01783|029|R|REFERENCES:|
01783|030|B||
01783|031|R|1.Lariam (mefloquine hydrochloride) US prescribing information. Roche|1
01783|032|R|  Pharmaceuticals August, 2009.|1
01783|033|R|2.Centers for Disease Control and Prevention. General Recommendations on|1
01783|034|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
01783|035|R|  Practices (ACIP). MMWR.  Available at:|1
01783|036|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
01783|037|R|  February 17, 2022;60(RR No.2):1-68.|1
01783|038|R|3.Vivotif (typhoid vaccine live attenuated) US prescribing information.|1
01783|039|R|  Berna Products August, 2006.|1
01785|001|T|MONOGRAPH TITLE:  Colchicine/HMG-CoA Reductase Inhibitors|
01785|002|B||
01785|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01785|004|L|take action as needed.|
01785|005|B||
01785|006|A|MECHANISM OF ACTION:  Colchicine and HMG-CoA Reductase Inhibitors(statins)|
01785|007|A|each have a risk for myopathy and rhabdomyolysis; these risks may be|
01785|008|A|additive.(1-3)|
01785|009|B||
01785|010|E|CLINICAL EFFECTS:  Concurrent use of the statin drugs and colchicine may|
01785|011|E|increase the risk of myopathy or rhabdomyolysis, which is characterized by|
01785|012|E|progressive muscle weakness and pain in the presence of a normal|
01785|013|E|neurological exam.(1-8)|
01785|014|B||
01785|015|P|PREDISPOSING FACTORS:  Long term use of colchicine, generally from weeks to|
01785|016|P|months in duration of use, may predispose patients to myopathy or|
01785|017|P|rhabdomyolysis.(1)|
01785|018|P|   The risk for myopathy or rhabdomyolysis may also be greater in patients|
01785|019|P|65 years and older, inadequately treated hypothyroidism, renal impairment,|
01785|020|P|carnitine deficiency, malignant hyperthermia, or in patients with a history|
01785|021|P|of myopathy or rhabdomyolysis.  Patients with a SLCO1B1 polymorphism that|
01785|022|P|leads to decreased function of the hepatic uptake transporter OATP1B1 may|
01785|023|P|have increased statin concentrations and be predisposed to myopathy or|
01785|024|P|rhabdomyolysis.  Patients on fluvastatin who are CYP2C9 intermediate or poor|
01785|025|P|metabolizers may have increased fluvastatin concentrations and  risk of|
01785|026|P|myopathy.  Patients on rosuvastatin with ABCG2 polymorphisms leading to|
01785|027|P|decreased or poor BCRP transporter function may have increased rosuvastatin|
01785|028|P|concentrations and risk of myopathy.|
01785|029|B||
01785|030|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with colchicine|
01785|031|M|and HMG-CoA reductase inhibitors should be carefully monitored for myopathy|
01785|032|M|or rhabdomyolysis.|
01785|033|M|   Patients should be instructed to report any symptoms of myopathy such as|
01785|034|M|unexplained muscle aches, tenderness, weakness, or the onset of|
01785|035|M|tingling/numbness in the fingers or toes.(1-6)|
01785|036|B||
01785|037|D|DISCUSSION:  The development of myopathy and clinical rhabdomyolysis have|
01785|038|D|been reported in several case reports with concurrent use of colchicine and|
01785|039|D|atorvastatin,(4) fluvastatin,(5) pravastatin,(6) simvastatin(7,8), and|
01785|040|D|rosuvastatin.(2)  The incidence and frequency appear to increase in patients|
01785|041|D|with mild to moderate renal insufficiency and length of colchicine therapy.|
01785|042|B||
01785|043|R|REFERENCES:|
01785|044|B||
01785|045|R|1.Colcrys (colchicine) tablets, US prescribing information. Takeda|1
01785|046|R|  Pharmaceuticals America Inc. December, 2015.|1
01785|047|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
01785|048|R|  Pharmaceuticals LP July, 2024.|1
01785|049|R|3.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
01785|050|R|  Pharmaceuticals Corporation August, 2017.|1
01785|051|R|4.Tufan A, Dede DS, Cavus S, Altintas ND, Iskit AB, Topeli A. Rhabdomyolysis|3
01785|052|R|  in a patient treated with colchicine and atorvastatin. Ann Pharmacother|3
01785|053|R|  2006 Jul-Aug;40(7-8):1466-9.|3
01785|054|R|5.Atasoyu EM, Evrenkaya TR, Solmazgul E. Possible colchicine rhabdomyolysis|3
01785|055|R|  in a fluvastatin-treated patient. Ann Pharmacother 2005 Jul-Aug;|3
01785|056|R|  39(7-8):1368-9.|3
01785|057|R|6.Alayli G, Cengiz K, Canturk F, Durmus D, Akyol Y, Menekse EB. Acute|3
01785|058|R|  myopathy in a patient with concomitant use of pravastatin and colchicine.|3
01785|059|R|  Ann Pharmacother 2005 Jul-Aug;39(7-8):1358-61.|3
01785|060|R|7.Justiniano M, Dold S, Espinoza LR. Rapid onset of muscle weakness|3
01785|061|R|  (rhabdomyolysis) associated with the combined use of simvastatin and|3
01785|062|R|  colchicine. J Clin Rheumatol 2007 Oct;13(5):266-8.|3
01785|063|R|8.Hsu WC, Chen WH, Chang MT, Chiu HC. Colchicine-induced acute myopathy in a|3
01785|064|R|  patient with concomitant use of simvastatin. Clin Neuropharmacol 2002|3
01785|065|R|  Sep-Oct;25(5):266-8.|3
01786|001|T|MONOGRAPH TITLE:  Atazanavir/Nevirapine|
01786|002|B||
01786|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01786|004|L|is contraindicated and generally should not be dispensed or administered to|
01786|005|L|the same patient.|
01786|006|B||
01786|007|A|MECHANISM OF ACTION:  Nevirapine is a weak inducer of CYP3A and CYP2B6 and|
01786|008|A|atazanavir is a moderate inhibitor of CYP3A and a weak inhibitor of|
01786|009|A|CYP2C8.(1)|
01786|010|B||
01786|011|E|CLINICAL EFFECTS:  Concurrent use of atazanavir and nevirapine may result in|
01786|012|E|decreased atazanavir levels and effectiveness. The possibility exists for|
01786|013|E|increased toxicity to nevirapine based on increase exposure.(1,2)|
01786|014|B||
01786|015|P|PREDISPOSING FACTORS:  None determined.|
01786|016|B||
01786|017|M|PATIENT MANAGEMENT:  The manufacturers of atazanavir(2) and nevirapine(1)|
01786|018|M|state that these agents should not be given together because of the|
01786|019|M|decreased in atazanavir levels and the potential for virologic failure.|
01786|020|M|Increased exposure to nevirapine with concurrent atazanavir use may lead to|
01786|021|M|increased hepatic and skin reactions.|
01786|022|B||
01786|023|D|DISCUSSION:  In a study in 23 subjects, concurrent nevirapine (200 mg twice|
01786|024|D|daily) with atazanavir/ritonavir (300/100 mg daily) decreased atazanavir|
01786|025|D|maximum concentration (Cmax), area-under-curve (AUC), and minimum|
01786|026|D|concentration (Cmin) by 28%, 42%, an 72%, respectively.(1,2)  Nevirapine|
01786|027|D|Cmax, AUC, and Cmin increased 17%, 25%, and 32%, respectively.(2)|
01786|028|D|   In a study in 23 subjects, concurrent nevirapine (200 mg twice daily)|
01786|029|D|with atazanavir/ritonavir (400/100 mg daily) decreased atazanavir AUC and|
01786|030|D|Cmin by 19% and 59%, respectively.(1,2)  Nevirapine Cmax, AUC, and Cmin|
01786|031|D|increased 21%, 26%, and 35%, respectively.(2)|
01786|032|B||
01786|033|R|REFERENCES:|
01786|034|B||
01786|035|R|1.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
01786|036|R|  Pharmaceuticals, Inc. June, 2022.|1
01786|037|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01786|038|R|  Squibb Company December, 2024.|1
01787|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vit K antagonists)/Natisedine|
01787|002|T|(Quinidine and Phenobarbital)|
01787|003|B||
01787|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01787|005|L|of severe adverse interaction.|
01787|006|B||
01787|007|A|MECHANISM OF ACTION:  It is speculated that induction of hepatic microsomal|
01787|008|A|enzymes results in increased metabolism of anticoagulants,(1) resulting in|
01787|009|A|decreased anticoagulant response.(2,3)  Barbiturates or barbiturate|
01787|010|A|containing products may also increase the synthesis of clotting factors by|
01787|011|A|the liver.(4)  The absorption of dicumarol, but not warfarin, from the|
01787|012|A|gastrointestinal may be decreased by barbiturates.(5)|
01787|013|B||
01787|014|E|CLINICAL EFFECTS:  Concurrent use may result in decreased anticoagulant|
01787|015|E|effects.  Increased anticoagulant effects may occur if the barbiturate or|
01787|016|E|barbiturate containing product is withdrawn.  The effect may be dose-related|
01787|017|E|and may continue beyond the discontinuation of the barbiturate.|
01787|018|B||
01787|019|P|PREDISPOSING FACTORS:  None determined.|
01787|020|B||
01787|021|M|PATIENT MANAGEMENT:  If possible, avoid the concurrent use of these agents.|
01787|022|M|If a barbiturate or barbiturate containing product is initiated or|
01787|023|M|discontinued in a patient maintained on anticoagulant therapy, monitor|
01787|024|M|prothrombin times and adjust the dose of the anticoagulant as needed.|
01787|025|M|   For hypnotic indications, benzodiazepines and diphenhydramine may be|
01787|026|M|alternatives to barbiturates in patients stabilized on anticoagulant|
01787|027|M|therapy.|
01787|028|B||
01787|029|D|DISCUSSION:  Phenobarbital,(1) and secobarbital(6) have been shown to|
01787|030|D|interact with coumarin anticoagulants.  Dicumarol,(5) warfarin(1), and|
01787|031|D|phenprocoumon(4) have been reported to interact with the barbiturates.|
01787|032|D|   It would be prudent to assume that all barbiturates and the indanedione|
01787|033|D|derivatives would interact in a similar fashion.|
01787|034|D|   The time of highest risk for a coumarin-type drug interaction is when the|
01787|035|D|precipitant drug is initiated, altered, or discontinued.|
01787|036|B||
01787|037|R|REFERENCES:|
01787|038|B||
01787|039|R|1.Levy G, O'Reilly RA, Aggeler PM, Keech GM. Pharmacokinetic analysis of the|2
01787|040|R|  effect of barbiturate on the anticoagulant action of warfarin in man. Clin|2
01787|041|R|  Pharmacol Ther 1970 May-Jun;11(3):372-7.|2
01787|042|R|2.Goss JE, Dickhaus DW. Increased bishydroxycoumarin requirements in|2
01787|043|R|  patients receiving phenobarbital. N Engl J Med 1965 Nov 11;273(20):1094-5.|2
01787|044|R|3.MacDonald MG, Robinson DS. Clinical observations of possible barbiturate|6
01787|045|R|  interference with anticoagulation. JAMA 1968 Apr 8;204(2):97-100.|6
01787|046|R|4.Lucas ON. Study of the interaction of barbiturates and dicumarol and their|5
01787|047|R|  effect on prothrombin activity, hemorrhage, and sleeping time in rats. Can|5
01787|048|R|  J Physiol Pharmacol 1967 Sep;45(5):905-13.|5
01787|049|R|5.Aggeler PM, O'Reilly RA. Effect of heptabarbital on the response to|2
01787|050|R|  bishydroxycoumarin in man. J Lab Clin Med 1969 Aug;74(2):229-38.|2
01787|051|R|6.Breckenridge A, Orme M. Clinical implications of enzyme induction. Ann N Y|5
01787|052|R|  Acad Sci 1971 Jul 6;179:421-31.|5
01789|001|T|MONOGRAPH TITLE:  Higher Strength Select Tricyclics/Cinacalcet|
01789|002|B||
01789|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01789|004|L|take action as needed.|
01789|005|B||
01789|006|A|MECHANISM OF ACTION:  Cinacalcet may inhibit the CYP2D6 mediated metabolism|
01789|007|A|of amitriptyline, desipramine, nortriptyline, and trimipramine.(1,2)|
01789|008|B||
01789|009|E|CLINICAL EFFECTS:  Concurrent use of cinacalcet and amitriptyline,|
01789|010|E|desipramine, nortriptyline, or trimipramine may result in elevated levels of|
01789|011|E|and toxicity from these tricyclic antidepressants.(1,3)|
01789|012|B||
01789|013|P|PREDISPOSING FACTORS:  Higher doses of either agent are expected to increase|
01789|014|P|the severity of the interaction.|
01789|015|P|  In patients with moderate to severe hepatic impairment, cinacalcet|
01789|016|P|exposure is 2.4 to 4.2-fold higher and the mean half-life increased from 49|
01789|017|P|to 65-84 hours compared with healthy volunteers.(1)|
01789|018|P|   The risk of seizures may be increased in patients with a history of head|
01789|019|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
01789|020|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
01789|021|P|of over-the-counter stimulants and anorectics; diabetics treated with oral|
01789|022|P|hypoglycemics or insulin; or with concomitant medications known to lower|
01789|023|P|seizure threshold (antipsychotics, theophylline, systemic steroids).|
01789|024|P|   The risk of anticholinergic toxicities including cognitive decline,|
01789|025|P|delirium, falls and fractures is increased in geriatric patients using more|
01789|026|P|than one medicine with anticholinergic properties.(4)|
01789|027|B||
01789|028|M|PATIENT MANAGEMENT:  The manufacturer describes cinacalcet as a strong|
01789|029|M|inhibitor of CYP2D6. Dose adjustments may be required for concomitant|
01789|030|M|medications predominantly metabolized by CYP2D6, particularly if they have a|
01789|031|M|narrow therapeutic index.(1)|
01789|032|M|   Cinacalcet has a long elimination half-life of 49 hours so the time to|
01789|033|M|maximal inhibition of a CYP2D6 metabolized drug may not be seen for a week|
01789|034|M|or more after starting or increasing the dose of cinacalcet.|
01789|035|M|   In an interaction study, cinacalcet 90 mg daily increased desipramine|
01789|036|M|exposure (AUC, area-under-curve) 264%.(1)|
01789|037|M|   Instruct patients to report seizures, fainting, irregular heartbeat, new|
01789|038|M|or worsening blurred vision, urinary retention, mental or mood changes,|
01789|039|M|confusion, dry mouth or constipation.|
01789|040|B||
01789|041|D|DISCUSSION:  In an interaction study, fourteen subjects who were extensive|
01789|042|D|metabolizers of CYP2D6 received one dose of desipramine 50 mg, either alone|
01789|043|D|or after 7 days of pretreatment with cinacalcet 90 mg daily. Compared with|
01789|044|D|desipramine alone, cinacalcet administration increased desipramine exposure|
01789|045|D|(AUC, area-under-curve) and maximum concentration (Cmax) 3.6 and 1.8-fold|
01789|046|D|respectively. Desipramine half-life was also longer when it was|
01789|047|D|coadministered with cinacalcet (21.0 versus 43.3 hs). Fewer subjects|
01789|048|D|reported adverse events following treatment with desipramine alone than when|
01789|049|D|receiving desipramine with cinacalcet (33% versus 86%).(2)|
01789|050|D|   In an interaction study, subjects who were extensive metabolizers of|
01789|051|D|CYP2D6 received one dose of amitriptyline 50 mg with a single dose of|
01789|052|D|cinacalcet (25 or 100 mg) resulting in a change in AUC and Cmax for|
01789|053|D|amitriptyline of 21-22% and 13-21%, respectively. The change in AUC and Cmax|
01789|054|D|for nortriptyline was 17-23% and 11-15%, respectively.(1)|
01789|055|B||
01789|056|R|REFERENCES:|
01789|057|B||
01789|058|R|1.Sensipar (cinacalcet hydrochloride) US prescribing information. Amgen Inc.|1
01789|059|R|  March, 2019.|1
01789|060|R|2.This information is based on an extract from the Certara Drug Interaction|6
01789|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01789|062|R|3.Harris RZ, Salfi M, Posvar E, Hoelscher D, Padhi D. Pharmacokinetics of|2
01789|063|R|  desipramine HCl when administered with cinacalcet HCl. Eur J Clin|2
01789|064|R|  Pharmacol 2007 Feb;63(2):159-63.|2
01789|065|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01789|066|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01789|067|R|  Soc 2023 Jul;71(7):2052-2081.|6
01790|001|T|MONOGRAPH TITLE:  Natisedine; Quinidine/Telithromycin|
01790|002|B||
01790|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01790|004|L|of severe adverse interaction.|
01790|005|B||
01790|006|A|MECHANISM OF ACTION:  Telithromycin may prolong the QT interval.(1)|
01790|007|A|Quinidine is a Class IA antiarrhythmic agent and may prolong the QT|
01790|008|A|interval.(3)  Phenobarbital, a component of natisedine, induce the|
01790|009|A|metabolism of telithromycin by CYP3A4.(1,2)|
01790|010|B||
01790|011|E|CLINICAL EFFECTS:  Concurrent administration of telithromycin with a Class|
01790|012|E|IA or III antiarrhythmic may result in prolongation of the QTc interval,|
01790|013|E|which may result in potentially life-threatening arrhythmias.(1,2)|
01790|014|E|   Concurrent phenobarbital may result in decreased levels and effectiveness|
01790|015|E|of telithromycin.(1,2)|
01790|016|B||
01790|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01790|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
01790|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01790|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01790|021|P|female gender, or advanced age.(4)|
01790|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01790|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01790|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01790|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01790|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01790|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01790|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01790|029|B||
01790|030|M|PATIENT MANAGEMENT:  The US manufacturer of telithromycin states that|
01790|031|M|telithromycin should be avoided in patients taking Class IA or III|
01790|032|M|antiarrhythmics.(2)|
01790|033|M|   The UK manufacturer of telithromycin states that treatment with|
01790|034|M|telithromycin should be avoided during and for two weeks after treatment|
01790|035|M|with phenobarbital.(1)|
01790|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01790|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01790|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01790|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01790|040|B||
01790|041|D|DISCUSSION:  Telithromycin may prolong the QT interval. Concurrent|
01790|042|D|administration with a Class IA or III antiarrhythmic may result in|
01790|043|D|prolongation of the QTc interval, which may result in potentially|
01790|044|D|life-threatening arrhythmias, and should be avoided.(2)|
01790|045|D|   Concurrent use of telithromycin with potent CYP3A4 inducers such as|
01790|046|D|phenobarbital could result in major reductions of telithromycin plasma|
01790|047|D|concentrations and decreased telithromycin clinical effectiveness. The|
01790|048|D|induction effect decreases during the two weeks following the|
01790|049|D|discontinuation of the inducer.(1)|
01790|050|B||
01790|051|R|REFERENCES:|
01790|052|B||
01790|053|R|1.Ketek (telithromycin) UK summary of product characteristics.|1
01790|054|R|  Sanofi-Aventis June 2, 2009.|1
01790|055|R|2.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
01790|056|R|  November, 2015.|1
01790|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01790|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01790|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01790|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01790|061|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01790|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01790|063|R|  settings: a scientific statement from the American Heart Association and|6
01790|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01790|065|R|  2;55(9):934-47.|6
01791|001|T|MONOGRAPH TITLE:  Ethacrynic Acid/Furosemide|
01791|002|B||
01791|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01791|004|L|is contraindicated and generally should not be dispensed or administered to|
01791|005|L|the same patient.|
01791|006|B||
01791|007|A|MECHANISM OF ACTION:  The exact mechanism of the interaction is not well|
01791|008|A|understood.|
01791|009|B||
01791|010|E|CLINICAL EFFECTS:  Concurrent use of furosemide and ethacrynic acid may|
01791|011|E|increase the risk of ototoxicity.(1)|
01791|012|B||
01791|013|P|PREDISPOSING FACTORS:  Rapid intravenous injection, severe renal impairment,|
01791|014|P|high doses exceeding the usual recommended dose, concomitant therapy with|
01791|015|P|other drugs known to ototoxic.|
01791|016|B||
01791|017|M|PATIENT MANAGEMENT:  The US manufacturer of furosemide states that|
01791|018|M|furosemide should not be used concurrently with ethacrynic acid.(1)|
01791|019|B||
01791|020|D|DISCUSSION:  Furosemide and ethacrynic acid have the potential to cause|
01791|021|D|ototoxicity.(1,2) Deafness, tinnitus, and vertigo with a sense of fullness|
01791|022|D|have occurred, most frequently in patients with severe renal impairment. The|
01791|023|D|deafness usually has been reported as being transient in nature and of short|
01791|024|D|duration (one to 24 hours) but in some patients the hearing loss has been|
01791|025|D|permanent.(2)|
01791|026|B||
01791|027|R|REFERENCES:|
01791|028|B||
01791|029|R|1.Lasix (furosemide) US prescribing information. Sanofi-Aventis U.S. LLC|1
01791|030|R|  March, 2016.|1
01791|031|R|2.Edecrin (ethacrynic acid) US prescribing information. Merck & Co.|1
01791|032|R|  February, 2005.|1
01792|001|T|MONOGRAPH TITLE:  Zuclopenthixol/QT Prolonging Agents|
01792|002|B||
01792|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01792|004|L|of severe adverse interaction.|
01792|005|B||
01792|006|A|MECHANISM OF ACTION:  Zuclopenthixol prolongs the QTc interval.  Concurrent|
01792|007|A|use with other agents that prolong the QTc interval may result in additive|
01792|008|A|effects on the QTc interval.(1)|
01792|009|A|   Zuclopenthixol is partially metabolized by CYP2D6.  Some QT prolonging|
01792|010|A|agents such as quinidine are also CYP2D6 inhibitors and may inhibit|
01792|011|A|metabolism of zuclopenthixol.|
01792|012|B||
01792|013|E|CLINICAL EFFECTS:  The concurrent use of zuclopenthixol with other agents|
01792|014|E|that prolong the QTc interval may result in potentially life-threatening|
01792|015|E|cardiac arrhythmias, including torsades de pointes.(1)|
01792|016|E|   CYP2D6 inhibitors such as quinidine may increase zuclopenthixol|
01792|017|E|concentrations resulting in zuclopenthixol toxicity.|
01792|018|B||
01792|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01792|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01792|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01792|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01792|023|P|gender, or advanced age.(3)|
01792|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01792|025|P|higher systemic concentrations of either QT prolonging drug are additional|
01792|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01792|027|P|drug concentrations include rapid infusion of an intravenous dose or|
01792|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01792|029|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01792|030|P|dysfunction).(3)|
01792|031|B||
01792|032|M|PATIENT MANAGEMENT:  The UK manufacturer of zuclopenthixol states that the|
01792|033|M|concurrent administration of other drugs that are known to prolong the QTc|
01792|034|M|interval should be avoided.(1)|
01792|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01792|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01792|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01792|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01792|039|B||
01792|040|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01792|041|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01792|042|D|monograph have been shown to prolong the QTc interval either through their|
01792|043|D|mechanism of action, through studies on their effects on the QTc interval,|
01792|044|D|or through reports of QTc prolongation and/or torsades de pointes in|
01792|045|D|clinical trials and/or postmarketing reports.(2)|
01792|046|B||
01792|047|R|REFERENCES:|
01792|048|B||
01792|049|R|1.Clopixol (zuclopenthixol acetate) UK summary of product characteristics.|1
01792|050|R|  Lundbeck Limited October 15, 2020.|1
01792|051|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01792|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01792|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01792|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01792|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01792|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01792|057|R|  settings: a scientific statement from the American Heart Association and|6
01792|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01792|059|R|  2;55(9):934-47.|6
01793|001|T|MONOGRAPH TITLE:  Zuclopenthixol/Possible QT Prolonging Agents|
01793|002|B||
01793|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01793|004|L|take action as needed.|
01793|005|B||
01793|006|A|MECHANISM OF ACTION:  Zuclopenthixol prolongs the QTc interval.  Concurrent|
01793|007|A|use with other agents that prolong the QTc interval may result in additive|
01793|008|A|effects on the QTc interval.(1)|
01793|009|B||
01793|010|E|CLINICAL EFFECTS:  The concurrent use of zuclopenthixol with other agents|
01793|011|E|that prolong the QTc interval may result in potentially life-threatening|
01793|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
01793|013|B||
01793|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01793|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01793|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01793|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01793|018|P|gender, or advanced age.(3)|
01793|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01793|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01793|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01793|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01793|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01793|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01793|025|P|dysfunction).(3)|
01793|026|B||
01793|027|M|PATIENT MANAGEMENT:  The UK manufacturer of zuclopenthixol states that the|
01793|028|M|concurrent administration of other drugs that are known to prolong the QTc|
01793|029|M|interval should be avoided.(1)|
01793|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01793|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01793|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01793|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01793|034|B||
01793|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01793|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01793|037|D|monograph have been shown to prolong the QTc interval either through their|
01793|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01793|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01793|040|D|clinical trials and/or postmarketing reports.(2)|
01793|041|B||
01793|042|R|REFERENCES:|
01793|043|B||
01793|044|R|1.Clopixol (zuclopenthixol acetate) UK summary of product characteristics.|1
01793|045|R|  Lundbeck Limited October 15, 2020.|1
01793|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01793|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01793|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01793|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01793|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01793|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01793|052|R|  settings: a scientific statement from the American Heart Association and|6
01793|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01793|054|R|  2;55(9):934-47.|6
01794|001|T|MONOGRAPH TITLE:  Cyclosporine/Nefazodone|
01794|002|B||
01794|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01794|004|L|take action as needed.|
01794|005|B||
01794|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of cyclosporine|
01794|007|A|by CYP3A4.|
01794|008|B||
01794|009|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in elevated|
01794|010|E|levels of and toxicity from cyclosporine.|
01794|011|B||
01794|012|P|PREDISPOSING FACTORS:  None determined.|
01794|013|B||
01794|014|M|PATIENT MANAGEMENT:  Monitor cyclosporine levels and kidney function in|
01794|015|M|patients in whom nefazodone is initiated, adjusted, or discontinued.  The|
01794|016|M|dosage of cyclosporine may need to be adjusted or nefazodone may need to be|
01794|017|M|discontinued.|
01794|018|B||
01794|019|D|DISCUSSION:  In a case report, cyclosporine (225 mg twice daily) levels|
01794|020|D|increased 70% 3 days following the addition of nefazodone (25 mg twice|
01794|021|D|daily) the regimen of a 23 year-old male kidney transplant patient.(1)|
01794|022|D|   In a case report, cyclosporine (200 mg twice daily) levels increased|
01794|023|D|1.67-fold following the addition of nefazodone (100 mg twice daily) to the|
01794|024|D|regimen of a 50 year-old male kidney transplant patient.  The patient also|
01794|025|D|developed tremors, headaches, and increased blood pressure.  The|
01794|026|D|cyclosporine dose was reduced 50% and levels returned to baseline.(2)|
01794|027|D|   In a case report, cyclosporine (130 mg twice daily) levels increased from|
01794|028|D|the low 100's to 775 ng/ml within 2 weeks of initiating nefazodone (150 mg|
01794|029|D|twice daily) in a 58 year-old female cardiac transplant patient.(3)|
01794|030|B||
01794|031|R|REFERENCES:|
01794|032|B||
01794|033|R|1.Helms-Smith KM, Curtis SL, Hatton RC. Apparent interaction between|3
01794|034|R|  nefazodone and cyclosporine. Ann Intern Med 1996 Sep 1;125(5):424.|3
01794|035|R|2.Vella JP, Sayegh MH. Interactions between cyclosporine and newer|3
01794|036|R|  antidepressant medications. Am J Kidney Dis 1998 Feb;31(2):320-3.|3
01794|037|R|3.Wright DH, Lake KD, Bruhn PS, Emery RW Jr. Nefazodone and cyclosporine|3
01794|038|R|  drug-drug interaction. J Heart Lung Transplant 1999 Sep;18(9):913-5.|3
01795|001|T|MONOGRAPH TITLE:  Varicella Virus Vaccine Live/Salicylates|
01795|002|B||
01795|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01795|004|L|of severe adverse interaction.|
01795|005|B||
01795|006|A|MECHANISM OF ACTION:  Use of salicylates during natural varicella infection|
01795|007|A|has been associated with Reye's Syndrome.(1-4)|
01795|008|B||
01795|009|E|CLINICAL EFFECTS:  Use of the live varicella virus vaccine in patients|
01795|010|E|receiving salicylate therapy or use of salicylates within 6 weeks after|
01795|011|E|vaccination with the live varicella virus vaccine may increase the risk of|
01795|012|E|Reye's Syndrome.(1-4)  Symptoms of Reye's syndrome include drowsiness,|
01795|013|E|confusion, seizures, coma.  In severe cases, Reye's syndrome can result in|
01795|014|E|death.|
01795|015|B||
01795|016|P|PREDISPOSING FACTORS:  None determined.|
01795|017|B||
01795|018|M|PATIENT MANAGEMENT:  The Canadian, UK, and US manufacturers of live|
01795|019|M|varicella virus vaccine indicated for the prevention of chicken pox state|
01795|020|M|that vaccine recipients should avoid the use of salicylates for 6 weeks|
01795|021|M|after vaccination.(1-4)|
01795|022|M|   There is no such restriction in the labeling for live varicella virus|
01795|023|M|vaccine indicated for the prevention of shingles, which is only indicated|
01795|024|M|for patients age 60 and older.(5)|
01795|025|B||
01795|026|D|DISCUSSION:  Because the use of salicylates during natural varicella|
01795|027|D|infection has been associated with Reye's Syndrome, the use of salicylates|
01795|028|D|for 6 weeks following vaccination with live varicella virus vaccine should|
01795|029|D|be avoided.(1-4)|
01795|030|B||
01795|031|R|REFERENCES:|
01795|032|B||
01795|033|R|1.Varilrix (varicella virus vaccine, live, attenuated) Canadian prescribing|1
01795|034|R|  information. GlaxoSmithKline January 10,. 1997.|1
01795|035|R|2.Varivax III (varicella virus vaccine, live, attenuated) Canadian|1
01795|036|R|  prescribing information. Merck Frosst September 21, 1997.|1
01795|037|R|3.Varivax (varicella vaccine, live) UK summary of product characteristics.|1
01795|038|R|  Sanofi Pasteur MSD Limited June, 2008.|1
01795|039|R|4.Varivax (varicella virus vaccine live) US prescribing information. Merck &|1
01795|040|R|  Co., Inc. March, 2008.|1
01795|041|R|5.Zostavax (zoster vaccine live) US prescribing information. Merck & Co.,|1
01795|042|R|  Inc. March, 2018.|1
01796|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/Bicalutamide|
01796|002|B||
01796|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01796|004|L|is contraindicated and generally should not be dispensed or administered to|
01796|005|L|the same patient.|
01796|006|B||
01796|007|A|MECHANISM OF ACTION:  Bicalutamide may inhibit the metabolism of astemizole|
01796|008|A|and terfenadine by CYP3A4.(1)|
01796|009|B||
01796|010|E|CLINICAL EFFECTS:  Concurrent use of bicalutamide and either astemizole or|
01796|011|E|terfenadine may result in elevated levels of astemizole or terfenadine,|
01796|012|E|which may result in cardiac arrhythmias, including QT prolongation or|
01796|013|E|life-threatening torsades de pointes.(1)|
01796|014|B||
01796|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01796|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01796|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01796|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01796|019|P|female gender, or advanced age.(2)|
01796|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01796|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01796|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01796|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01796|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01796|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01796|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01796|027|B||
01796|028|M|PATIENT MANAGEMENT:  The UK manufacturer of bicalutamide states that|
01796|029|M|concurrent use with astemizole or terfenadine is contraindicated.(1)|
01796|030|B||
01796|031|D|DISCUSSION:  R-bicalutamide has been shown to inhibit CYP3A4 in vitro.|
01796|032|D|Concurrent administration of bicalutamide with midazolam, which is also|
01796|033|D|metabolized by CYP3A4, for 28 days increased midazolam area-under-curve|
01796|034|D|(AUC) by 80%.(1)|
01796|035|B||
01796|036|R|REFERENCES:|
01796|037|B||
01796|038|R|1.Casodex (bicalutamide) UK summary of product characteristics. AstraZeneca|1
01796|039|R|  UK Limited November 13, 2007.|1
01796|040|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01796|041|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01796|042|R|  settings: a scientific statement from the American Heart Association and|6
01796|043|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01796|044|R|  2;55(9):934-47.|6
01797|001|T|MONOGRAPH TITLE:  Cisapride/Bicalutamide|
01797|002|B||
01797|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01797|004|L|is contraindicated and generally should not be dispensed or administered to|
01797|005|L|the same patient.|
01797|006|B||
01797|007|A|MECHANISM OF ACTION:  Bicalutamide may inhibit the metabolism of cisapride|
01797|008|A|by CYP3A4.(1)|
01797|009|B||
01797|010|E|CLINICAL EFFECTS:  Concurrent use of bicalutamide and cisapride may result|
01797|011|E|in elevated levels of cisapride, which may result in cardiac arrhythmias,|
01797|012|E|including QT prolongation or life-threatening torsades de pointes.(1)|
01797|013|B||
01797|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01797|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01797|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01797|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01797|018|P|female gender, or advanced age.(2)|
01797|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01797|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01797|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01797|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01797|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01797|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01797|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01797|026|B||
01797|027|M|PATIENT MANAGEMENT:  The UK manufacturer of bicalutamide states that|
01797|028|M|concurrent use with cisapride is contraindicated.(1)|
01797|029|B||
01797|030|D|DISCUSSION:  R-bicalutamide has been shown to inhibit CYP3A4 in vitro.|
01797|031|D|Concurrent administration of bicalutamide with midazolam, which is also|
01797|032|D|metabolized by CYP3A4, for 28 days increased midazolam area-under-curve|
01797|033|D|(AUC) by 80%.(1)|
01797|034|B||
01797|035|R|REFERENCES:|
01797|036|B||
01797|037|R|1.Casodex (bicalutamide) UK summary of product characteristics. AstraZeneca|1
01797|038|R|  UK Limited November 13, 2007.|1
01797|039|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01797|040|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01797|041|R|  settings: a scientific statement from the American Heart Association and|6
01797|042|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01797|043|R|  2;55(9):934-47.|6
01798|001|T|MONOGRAPH TITLE:  Warfarin/St. John's Wort|
01798|002|B||
01798|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01798|004|L|Assess the risk to the patient and take action as needed.|
01798|005|B||
01798|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of the|
01798|007|A|warfarin at CYP3A4 and CYP2C9.(1,2)|
01798|008|B||
01798|009|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort with warfarin may|
01798|010|E|result in decreased levels and clinical effectiveness of warfarin resulting|
01798|011|E|in subtherapeutic INR values.(1-3)|
01798|012|B||
01798|013|P|PREDISPOSING FACTORS:  None determined.|
01798|014|B||
01798|015|M|PATIENT MANAGEMENT:  The concurrent use of warfarin and St. John's wort|
01798|016|M|should be approached with caution.  Consider an alternative agent to St.|
01798|017|M|John's wort, if possible, or consider increasing the dose of warfarin based|
01798|018|M|on the patients response.  Additional PT/INR determinations may be required|
01798|019|M|when initiating or discontinuing St. John's wort.(1-4)|
01798|020|B||
01798|021|D|DISCUSSION:  Several studies have shown that St. John's wort induces CYP3A4|
01798|022|D|and CYP2C9.  CYP2C9 has been shown to be mainly responsible for metabolism|
01798|023|D|of the pharmacologically active S-enantiomer.(2,3)  Difficulty in product|
01798|024|D|standardization make definitive data difficult to analyze.  There was a|
01798|025|D|tendency for increase in INR's in a longitudinal study of patients taking St|
01798|026|D|John's wort although it did not increase the risk of a supratherapeutic INR|
01798|027|D|over the study period.(3)|
01798|028|B||
01798|029|R|REFERENCES:|
01798|030|B||
01798|031|R|1.Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO,|2
01798|032|R|  McLachlan AJ. Effect of St John's wort and ginseng on the pharmacokinetics|2
01798|033|R|  and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol|2
01798|034|R|  2004 May;57(5):592-9.|2
01798|035|R|2.Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P. St John's wort|6
01798|036|R|  (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin|6
01798|037|R|  Pharmacol 2002 Oct;54(4):349-56.|6
01798|038|R|3.Shalansky S, Lynd L, Richardson K, Ingaszewski A, Kerr C. Risk of|6
01798|039|R|  warfarin-related bleeding events and supratherapeutic international|6
01798|040|R|  normalized ratios associated with complementary and alternative medicine:|6
01798|041|R|  a longitudinal analysis. Pharmacotherapy 2007 Sep;27(9):1237-47.|6
01798|042|R|4.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
01798|043|R|  Squibb Company September, 2016.|1
01799|001|T|MONOGRAPH TITLE:  Topotecan/P-glycoprotein (P-gp) Inhibitors|
01799|002|B||
01799|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01799|004|L|of severe adverse interaction.|
01799|005|B||
01799|006|A|MECHANISM OF ACTION:  Inhibitors of P-glycoprotein may increase the|
01799|007|A|absorption of topotecan.(1)|
01799|008|B||
01799|009|E|CLINICAL EFFECTS:  The concurrent administration of topotecan with an|
01799|010|E|inhibitor of P-glycoprotein may result in elevated levels of topotecan and|
01799|011|E|signs of toxicity.  These signs may include but are not limited to anemia,|
01799|012|E|diarrhea, and thrombocytopenia.(1)|
01799|013|B||
01799|014|P|PREDISPOSING FACTORS:  None determined.|
01799|015|B||
01799|016|M|PATIENT MANAGEMENT:  The US manufacturer of topotecan states that the use of|
01799|017|M|topotecan and P-glycoprotein inhibitors should be avoided.  If concurrent|
01799|018|M|use is warranted, carefully monitor patients for adverse effects.(1)|
01799|019|B||
01799|020|D|DISCUSSION:  In clinical studies, the combined use of elacridar (100 mg to|
01799|021|D|1000 mg) increased the area-under-curve (AUC) of topotecan approximately|
01799|022|D|2.5-fold.(1)|
01799|023|D|   Oral cyclosporine (15 mg/kg) increased the AUC of topotecan lactone and|
01799|024|D|total topotecan to 2-fold to 3-fold of the control group, respectively.(1)|
01799|025|D|   P-gp inhibitors linked to this monograph include:  adagrasib, amiodarone,|
01799|026|D|asciminib, asunaprevir, azithromycin, belumosudil, bosutinib, carvedilol,|
01799|027|D|cimetidine, clarithromycin, cobicistat, conivaptan, daridorexant,|
01799|028|D|deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin,|
01799|029|D|ginseng, hydroquinidine, imlunestrant, isavuconazonium, itraconazole,|
01799|030|D|ivacaftor, josamycin, ketoconazole, ledipasvir, lonafarnib, mavorixafor,|
01799|031|D|neratinib, osimertinib, pibrentasvir/glecaprevir, propafenone, quinidine,|
01799|032|D|ranolazine, selpercatinib, sotorasib, tepotinib, tucatinib, valbenazine,|
01799|033|D|velpatasvir, vemurafenib, verapamil, vimseltinib, and voclosporin.(2,3)|
01799|034|B||
01799|035|R|REFERENCES:|
01799|036|B||
01799|037|R|1.Hycamtin Oral (topotecan) US prescribing information. GlaxoSmithKline|1
01799|038|R|  September, 2018.|1
01799|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
01799|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01799|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01799|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01799|043|R|  11/14/2017.|1
01799|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
01799|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01800|001|T|MONOGRAPH TITLE:  Topotecan/Ketoconazole (mono deleted 02/16/2012)|
01800|002|B||
01800|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01800|004|L|of severe adverse interaction.|
01800|005|B||
01800|006|A|MECHANISM OF ACTION:  Ketoconazole may inhibit the metabolism of topotecan|
01800|007|A|by P-glycoprotein and CYP P-450-3A4 inhibition.(1)|
01800|008|B||
01800|009|E|CLINICAL EFFECTS:  The concurrent administration of topotecan with|
01800|010|E|ketoconazole may result in elevated levels of topotecan and signs of|
01800|011|E|toxicity. These signs may include but are not limited to anemia, diarrhea,|
01800|012|E|and thrombocytopenia.(1)|
01800|013|B||
01800|014|P|PREDISPOSING FACTORS:  None determined.|
01800|015|B||
01800|016|M|PATIENT MANAGEMENT:  The manufacturer of topotecan suggests that the use of|
01800|017|M|topotecan and ketoconazole should be avoided.(1)|
01800|018|B||
01800|019|D|DISCUSSION:  The combined use of ketoconazole and topotecan should be|
01800|020|D|avoided due to the potential increase in topotecan concentrations and|
01800|021|D|potential for side effects. (1)|
01800|022|B||
01800|023|R|REFERENCE:|
01800|024|B||
01800|025|R|1.Hycamtin Oral (topotecan) US prescribing information. GlaxoSmithKline|1
01800|026|R|  June, 2010.|1
01801|001|T|MONOGRAPH TITLE:  Topotecan/Ritonavir; Saquinavir (mono deleted 02/16/2012)|
01801|002|B||
01801|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01801|004|L|of severe adverse interaction.|
01801|005|B||
01801|006|A|MECHANISM OF ACTION:  Ritonavir or saquinavir may inhibit the metabolism of|
01801|007|A|topotecan by P-glycoprotein and CYP P-450-3A4 inhibition.(1)|
01801|008|B||
01801|009|E|CLINICAL EFFECTS:  The concurrent administration of topotecan with ritonavir|
01801|010|E|and saquinavir may result in elevated levels of topotecan and signs of|
01801|011|E|toxicity.|
01801|012|E|These signs may include but are not limited to anemia, diarrhea, and|
01801|013|E|thrombocytopenia.(1)|
01801|014|B||
01801|015|P|PREDISPOSING FACTORS:  None determined.|
01801|016|B||
01801|017|M|PATIENT MANAGEMENT:  The manufacturer of topotecan suggests that the use of|
01801|018|M|topotecan and ritonavir and saquinavir should be avoided.(1)|
01801|019|B||
01801|020|D|DISCUSSION:  In clinical studies, the combined use of ritonavir and|
01801|021|D|saquinavir and topotecan should be avoided due to the potential increase in|
01801|022|D|topotecan concentrations and potential for side effects.(1)|
01801|023|B||
01801|024|R|REFERENCE:|
01801|025|B||
01801|026|R|1.Hycamtin Oral (topotecan) US prescribing information. GlaxoSmithKline|1
01801|027|R|  June, 2010.|1
01802|001|T|MONOGRAPH TITLE:  Aliskiren/Quinidine|
01802|002|B||
01802|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01802|004|L|is contraindicated and generally should not be dispensed or administered to|
01802|005|L|the same patient.|
01802|006|B||
01802|007|A|MECHANISM OF ACTION:  Aliskiren is a substrate for the P-glycoprotein (P-gp)|
01802|008|A|system.  Quinidine is a potent inhibitor of P-gp.(1)|
01802|009|B||
01802|010|E|CLINICAL EFFECTS:  The concurrent use of aliskiren and quinidine may result|
01802|011|E|in elevated levels of aliskiren.  This may result in increased effect and|
01802|012|E|toxicity of aliskiren including hypotension.(1)|
01802|013|B||
01802|014|P|PREDISPOSING FACTORS:  None determined.|
01802|015|B||
01802|016|M|PATIENT MANAGEMENT:  The UK manufacturer states the use of aliskiren and|
01802|017|M|potent P-glycoprotein inhibitors are contraindicated.(1)|
01802|018|B||
01802|019|D|DISCUSSION:  In a study in healthy subjects, concurrent cyclosporine (200 mg|
01802|020|D|and 600 mg), another potent inhibitor of P-glycoprotein, increased the|
01802|021|D|maximum concentration (Cmax) and area-under-curve (AUC) of aliskiren (75 mg)|
01802|022|D|by 2.5-fold and 5-fold, respectively.(1)|
01802|023|B||
01802|024|R|REFERENCE:|
01802|025|B||
01802|026|R|1.Rasilez (aliskiren hemifumarate) UK summary of product characteristics.|1
01802|027|R|  Novartis Pharmaceuticals UK Ltd. September, 2014.|1
01803|001|T|MONOGRAPH TITLE:  Aliskiren/Verapamil (mono deleted 11/18/2021)|
01803|002|B||
01803|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01803|004|L|take action as needed.|
01803|005|B||
01803|006|A|MECHANISM OF ACTION:  Verapamil is a moderate to potent inhibitor of|
01803|007|A|P-glycoprotein.(1,2)|
01803|008|B||
01803|009|E|CLINICAL EFFECTS:  The concurrent use of aliskiren and verapamil may result|
01803|010|E|in elevated levels of aliskiren.(1,2) This may result in increased effect|
01803|011|E|and toxicity of aliskiren.(2)|
01803|012|B||
01803|013|P|PREDISPOSING FACTORS:  None determined.|
01803|014|B||
01803|015|M|PATIENT MANAGEMENT:  The US manufacturer states that no dosage adjustment is|
01803|016|M|necessary during concurrent administration.(1) The UK manufacturer|
01803|017|M|recommends caution with concomitant use of aliskiren and verapamil.(2)|
01803|018|B||
01803|019|D|DISCUSSION:  Concurrent administration of verapamil (240 mg) with aliskiren|
01803|020|D|(300 mg) increased the area-under-curve (AUC) and maximum concentration|
01803|021|D|(Cmax) of aliskiren by approximately 2-fold.(1,2)|
01803|022|B||
01803|023|R|REFERENCES:|
01803|024|B||
01803|025|R|1.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
01803|026|R|  Corporation November, 2017.|1
01803|027|R|2.Rasilez (aliskiren hemifumarate) UK summary of product characteristics.|1
01803|028|R|  Novartis Pharmaceuticals UK Ltd. September, 2014.|1
01804|001|T|MONOGRAPH TITLE:  Raltegravir/Rifampin|
01804|002|B||
01804|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01804|004|L|take action as needed.|
01804|005|B||
01804|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of raltegravir by|
01804|007|A|UDP-glucuronosyltransferase 1A1 (UGT-1A1).(1-4)|
01804|008|B||
01804|009|E|CLINICAL EFFECTS:  Concurrent use of rifampin may reduce levels and clinical|
01804|010|E|effectiveness of raltegravir.(1-4)|
01804|011|B||
01804|012|P|PREDISPOSING FACTORS:  None determined.|
01804|013|B||
01804|014|M|PATIENT MANAGEMENT:  The concurrent use of rifampin and raltegravir should|
01804|015|M|be approached with caution.(1,2)  The US manufacturer of raltegravir|
01804|016|M|recommends a dosage of 800 mg raltegravir twice daily with or without food|
01804|017|M|in adult patients receiving concurrent rifampin.(2)  The UK manufacturer|
01804|018|M|recommends considering this dosage adjustment as well if concurrent use of|
01804|019|M|rifampin is unavoidable.(4)|
01804|020|M|   No dosage adjustment recommendation is available for patients younger|
01804|021|M|than 18 years of age.(1)|
01804|022|B||
01804|023|D|DISCUSSION:  Concurrent rifampin (600 mg daily) with raltegravir (400 mg|
01804|024|D|single dose) decreased raltegravir maximum concentration (Cmax),|
01804|025|D|area-under-curve (AUC), and minimum concentration (Cmin) by 38%, 40%, and|
01804|026|D|61%, respectively.(1-4)  When raltegravir was given at a dosage of 800 mg|
01804|027|D|twice daily with rifampin (600 mg daily), the Cmax and AUC of raltegravir|
01804|028|D|were increased 62% and 27%, respectively, and the Cmin was decreased 53%|
01804|029|D|when compared to the administration of raltegravir (400 mg twice daily)|
01804|030|D|alone.(2)|
01804|031|B||
01804|032|R|REFERENCES:|
01804|033|B||
01804|034|R|1.Isentress (raltegravir) Australian prescribing information. Merck Sharp &|1
01804|035|R|  Dohme PTY Limited May 19, 2008.|1
01804|036|R|2.Isentress (raltegravir) US prescribing information. Merck & CO., Inc. May,|1
01804|037|R|  2021.|1
01804|038|R|3.Isentress (raltegravir) Canadian prescribing information. Merck Frosst|1
01804|039|R|  February 18, 2009.|1
01804|040|R|4.Isentress (raltegravir) UK summary of product characteristics. Merck Sharp|1
01804|041|R|  & Dohme Limited August 3, 2013.|1
01805|001|T|MONOGRAPH TITLE:  Adefovir/Tenofovir|
01805|002|B||
01805|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01805|004|L|is contraindicated and generally should not be dispensed or administered to|
01805|005|L|the same patient.|
01805|006|B||
01805|007|A|MECHANISM OF ACTION:  The mechanism involves competition for active tubular|
01805|008|A|secretion sites in the kidney.(1-4)|
01805|009|B||
01805|010|E|CLINICAL EFFECTS:  Concurrent use of adefovir and tenofovir in the treatment|
01805|011|E|of hepatitis B may result in elevated levels of tenofovir or adefovir.|
01805|012|B||
01805|013|P|PREDISPOSING FACTORS:  Renal impairment or use of concurrent renally|
01805|014|P|excreted drugs.|
01805|015|B||
01805|016|M|PATIENT MANAGEMENT:  The US manufacturer of adefovir(1) and the UK(2) and|
01805|017|M|US(3) manufacturers of tenofovir state that adefovir and tenofovir should be|
01805|018|M|not be administered together.|
01805|019|B||
01805|020|D|DISCUSSION:  Tenofovir is eliminated principally by renal tubular secretion|
01805|021|D|and any competitive inhibition of excretion of tenofovir by adefovir|
01805|022|D|increases the likelihood of increased serum concentrations of tenofovir and|
01805|023|D|resultant toxicity.(1-4)|
01805|024|B||
01805|025|R|REFERENCES:|
01805|026|B||
01805|027|R|1.Viread (tenofovir disoproxil fumarate) UK summary of product|1
01805|028|R|  characteristics. Gilead Sciences, Ltd June 4, 2008.|1
01805|029|R|2.Viread (tenofovir disoproxil fumarate) US prescribing information. Gilead|1
01805|030|R|  Sciences, Inc. December, 2018.|1
01805|031|R|3.Hepsera (adefovir dipivoxil) US prescribing information. Gilead Sciences,|1
01805|032|R|  Inc. December, 2018.|1
01805|033|R|4.Viread (tenofovir disoproxil fumarate) Canadian product information.|1
01805|034|R|  Gilead Sciences, Inc. January 11, 2008.|1
01806|001|T|MONOGRAPH TITLE:  Raltegravir/H2 Antagonists; Proton Pump Inhibitors (mono|
01806|002|T|deleted 05/27/2021)|
01806|003|B||
01806|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01806|005|L|take action as needed.|
01806|006|B||
01806|007|A|MECHANISM OF ACTION:  An increase in gastric pH may result in increased|
01806|008|A|absorption of raltegravir(1) because raltegravir is more soluble at a higher|
01806|009|A|pH.(2)|
01806|010|B||
01806|011|E|CLINICAL EFFECTS:  Concurrent use of H2 antagonists or proton pump|
01806|012|E|inhibitors may result in elevated levels of and toxicity from|
01806|013|E|raltegravir.(1)|
01806|014|B||
01806|015|P|PREDISPOSING FACTORS:  None determined.|
01806|016|B||
01806|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy agents that|
01806|018|M|increase gastric pH should be monitored for adverse effects from|
01806|019|M|raltegravir,(3) but routine dosage adjustments should not be required.(1-3)|
01806|020|B||
01806|021|D|DISCUSSION:  US manufacturer information describes a study where a single|
01806|022|D|dose of raltegravir was coadministered with omeprazole 20 mg daily (duration|
01806|023|D|not stated).  Raltegravir maximum concentration (Cmax), area-under-curve|
01806|024|D|(AUC) and minimum concentration (Cmin) ratio with/without concurrent therapy|
01806|025|D|were 4.15, 3.12 and 1.46 respectively.(2)|
01806|026|D|   UK manufacturer information describes a study where raltegravir 400 mg|
01806|027|D|twice daily was given with omeprazole (dose and duration not stated).|
01806|028|D|Raltegravir Cmax and AUC increased 51% and 37% respectively.  Similarly,|
01806|029|D|raltegravir 400 mg twice daily was given with famotidine (dose and duration|
01806|030|D|not stated). Raltegravir Cmax and AUC increased 60% and 44% respectively.(1)|
01806|031|D|   Data from HIV-infected patients shows a smaller effect of gastric|
01806|032|D|pH-altering medications on raltegravir Cmax (21%).(3)|
01806|033|B||
01806|034|R|REFERENCES:|
01806|035|B||
01806|036|R|1.Isentress (raltegravir) UK summary of product characteristics. Merck Sharp|1
01806|037|R|  & Dohme Limited August 3, 2013.|1
01806|038|R|2.Isentress (raltegravir) US prescribing information. Merck & CO., Inc. May,|1
01806|039|R|  2021.|1
01806|040|R|3.Iwamoto M, Wenning LA, Nguyen BY, Teppler H, Moreau AR, Rhodes RR, Hanley|2
01806|041|R|  WD, Jin B, Harvey CM, Breidinger SA, Azrolan N, Farmer Jr HF, Isaacs RD,|2
01806|042|R|  Chodakewitz JA, Stone JA, Wagner JA. Effects of Omeprazole on Plasma|2
01806|043|R|  Levels of Raltegravir. Clin Infect Dis 2009 Jan 1.|2
01807|001|T|MONOGRAPH TITLE:  Maraviroc/Etravirine|
01807|002|B||
01807|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01807|004|L|of severe adverse interaction.|
01807|005|B||
01807|006|A|MECHANISM OF ACTION:  Etravirine may induce the metabolism of maraviroc by|
01807|007|A|CYP3A4.  This effect may be overcome by the concurrent administration of an|
01807|008|A|inhibitor of CYP3A4(1-4)|
01807|009|B||
01807|010|E|CLINICAL EFFECTS:  Concurrent use of etravirine without a strong inhibitor|
01807|011|E|of CYP3A4 may result in decreased levels and effectiveness of maraviroc and|
01807|012|E|the development of resistance.  Concurrent use of etravirine with a strong|
01807|013|E|inhibitor of CYP3A4 may result in increased levels of maraviroc and the|
01807|014|E|development of toxicity.(1-4)|
01807|015|B||
01807|016|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01807|017|P|renal impairment.(3)|
01807|018|B||
01807|019|M|PATIENT MANAGEMENT:  In adults, the recommended dosage of maraviroc in|
01807|020|M|combination with etravirine in the absence of a strong CYP3A4 inhibitor is|
01807|021|M|600 mg twice daily.  The recommended dosage of maraviroc in combination with|
01807|022|M|etravirine and a CYP3A4 inhibitor (except tipranavir/ritonavir) is 150 mg|
01807|023|M|twice daily.(2,3,5)|
01807|024|M|   In adults, maraviroc should not be used with a strong CYP3A4 inducer in|
01807|025|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
01807|026|M|disease.(3)|
01807|027|M|   In children aged 2 years and older weighing at least 10 kg, maraviroc in|
01807|028|M|combination with etravirine is not recommended.(3)|
01807|029|M|   No dosage adjustments are recommended for etravirine.(5)|
01807|030|B||
01807|031|D|DISCUSSION:  In a study in 28 healthy subjects, concurrent use of etravirine|
01807|032|D|(200 mg twice daily) with maraviroc (300 mg twice daily) decreased maraviroc|
01807|033|D|area-under-curve (AUC), maximum concentration (Cmax), and minimum|
01807|034|D|concentration (Cmin) by 53%, 60%, and 39%, respectively, when compared to|
01807|035|D|the use of maraviroc (300 mg twice daily) alone.(1-4)  There were no|
01807|036|D|significant changes in etravirine pharmacokinetics.(5)|
01807|037|D|   The concurrent use of etravirine (200 mg twice daily),|
01807|038|D|darunavir/ritonavir (600/100 mg twice daily), and maraviroc (150 mg twice|
01807|039|D|daily) increased maraviroc AUC, Cmax, and Cmin by 210%, 77%, and 427%,|
01807|040|D|respectively, when compared to the administration of maraviroc (150 mg twice|
01807|041|D|daily) alone.(1-4)  There were no significant changes in etravirine|
01807|042|D|pharmacokinetics.(5)|
01807|043|B||
01807|044|R|REFERENCES:|
01807|045|B||
01807|046|R|1.Intelence (etravirine) UK summary of product characteristics.|1
01807|047|R|  Janssen-Cilag Ltd August 28, 2008.|1
01807|048|R|2.Spillane R. Personal communication. Pfizer U.S. Medical Information May|1
01807|049|R|  23, 2008.|1
01807|050|R|3.Selzentry (maraviroc) US prescribing information. Pfizer Inc. October,|1
01807|051|R|  2020.|1
01807|052|R|4.Davis J, Scholler-Gyure M, Kakuda TN, et al. An open, randomized,|2
01807|053|R|  two-period, crossover study in two cohorts to investigate the effect of|2
01807|054|R|  steady-state TMC125 (etravirine) and the combination of|2
01807|055|R|  TMC125/darunavir/ritonavir on the steady-state pharmacokinetics of oral|2
01807|056|R|  maraviroc in healthy subjects. Presented at the 11th European AIDS|2
01807|057|R|  Conference. Madrid, Spain. October 24-27, 2007.|2
01807|058|R|5.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01807|059|R|  August, 2014.|1
01808|001|T|MONOGRAPH TITLE:  Ranolazine/Strong CYP3A4 Inducers|
01808|002|B||
01808|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01808|004|L|is contraindicated and generally should not be dispensed or administered to|
01808|005|L|the same patient.|
01808|006|B||
01808|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
01808|008|A|ranolazine.(1,2)|
01808|009|B||
01808|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
01808|011|E|in decreased levels and effectiveness of ranolazine.(1,2)|
01808|012|B||
01808|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01808|014|P|of the inducer for longer than 1-2 weeks.|
01808|015|B||
01808|016|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
01808|017|M|concurrent use of CYP3A4 inducers is contraindicated.(1)|
01808|018|M|   The UK manufacturer of ranolazine states that ranolazine should not be|
01808|019|M|used in patients receiving CYP3A4 inducers such as rifampin.(2)|
01808|020|B||
01808|021|D|DISCUSSION:  Concurrent rifampin (600 mg daily), strong inducer of CYP3A4,|
01808|022|D|decreased ranolazine plasma concentrations by 95%.(1,2)|
01808|023|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
01808|024|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
01808|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin,|
01808|026|D|rifampin, rifapentine, and St. John's wort.(1-4)|
01808|027|B||
01808|028|R|REFERENCES:|
01808|029|B||
01808|030|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
01808|031|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01808|032|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01808|033|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01808|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01808|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01808|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01808|037|R|  11/14/2017.|1
01808|038|R|4.This information is based on an extract from the Certara Drug Interaction|6
01808|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01809|001|T|MONOGRAPH TITLE:  Ranolazine/Carbamazepine; Phenobarbital; Phenytoin (mono|
01809|002|T|deleted 01/30/2014)|
01809|003|B||
01809|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01809|005|L|is contraindicated and generally should not be dispensed or administered to|
01809|006|L|the same patient.|
01809|007|B||
01809|008|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital, and phenytoin may induce|
01809|009|A|the metabolism of ranolazine by CYP P-450-3A4.(1,2)|
01809|010|B||
01809|011|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, phenobarbital, or|
01809|012|E|phenytoin may result in decreased levels and effectiveness of|
01809|013|E|ranolazine.(1,2)|
01809|014|B||
01809|015|P|PREDISPOSING FACTORS:  None determined.|
01809|016|B||
01809|017|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
01809|018|M|concurrent use of CYP P-450-3A4 inducers such as carbamazepine,|
01809|019|M|phenobarbital, or phenytoin is contraindicated.(1)|
01809|020|M|   The UK manufacturer of ranolazine states that ranolazine should not be|
01809|021|M|used in patients receiving CYP P-450-3A4 inducers such as carbamazepine,|
01809|022|M|phenobarbital, or phenytoin.(2)|
01809|023|B||
01809|024|D|DISCUSSION:  Concurrent rifampin (600 mg daily), another inducer of CYP|
01809|025|D|P-450-3A4, decreased ranolazine plasma concentrations by 95%.(1,2)|
01809|026|B||
01809|027|R|REFERENCES:|
01809|028|B||
01809|029|R|1.Ranexa (ranolazine) US prescribing information. CV Therapeutics, Inc.|1
01809|030|R|  July, 2011.|1
01809|031|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01809|032|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01810|001|T|MONOGRAPH TITLE:  Ranolazine/St. John's Wort (mono deleted 01/30/2014)|
01810|002|B||
01810|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01810|004|L|is contraindicated and generally should not be dispensed or administered to|
01810|005|L|the same patient.|
01810|006|B||
01810|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01810|008|A|ranolazine by CYP P-450-3A4.(1,2)|
01810|009|B||
01810|010|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
01810|011|E|levels and effectiveness of ranolazine.(1,2)|
01810|012|B||
01810|013|P|PREDISPOSING FACTORS:  None determined.|
01810|014|B||
01810|015|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
01810|016|M|concurrent use of CYP P-450-3A4 inducers such as St. John's wort is|
01810|017|M|contraindicated.(1)|
01810|018|M|   The UK manufacturer of ranolazine states that ranolazine should not be|
01810|019|M|used in patients receiving CYP P-450-3A4 inducers such as St. John's|
01810|020|M|wort.(2)|
01810|021|B||
01810|022|D|DISCUSSION:  Concurrent rifampin (600 mg daily), another inducer of CYP|
01810|023|D|P-450-3A4, decreased ranolazine plasma concentrations by 95%.(1,2)|
01810|024|B||
01810|025|R|REFERENCES:|
01810|026|B||
01810|027|R|1.Ranexa (ranolazine) US prescribing information. CV Therapeutics, Inc.|1
01810|028|R|  July, 2011.|1
01810|029|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01810|030|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01811|001|T|MONOGRAPH TITLE:  Methenamine/Urinary Alkalinizers|
01811|002|B||
01811|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01811|004|L|of severe adverse interaction.|
01811|005|B||
01811|006|A|MECHANISM OF ACTION:  Urinary alkalinizers may elevate urinary ph preventing|
01811|007|A|the conversion of methenamine to formaldehyde and mandelic acid.(1)|
01811|008|B||
01811|009|E|CLINICAL EFFECTS:  Concurrent administration may result in alkalinization of|
01811|010|E|the urine causing methenamine to be less effective.(1)|
01811|011|B||
01811|012|P|PREDISPOSING FACTORS:  None determined.|
01811|013|B||
01811|014|M|PATIENT MANAGEMENT:  The Australian and UK manufacturers of methenamine|
01811|015|M|state that concurrent use with agents that make urine alkaline or urine|
01811|016|M|alkalinizing agents should be avoided.(2,3)|
01811|017|M|   Patients receiving concurrent therapy should be monitored for urinary ph|
01811|018|M|and any worsening symptoms of their infection, including dysuria, flank|
01811|019|M|pain, or fever.(1)|
01811|020|B||
01811|021|D|DISCUSSION:  Administration of urinary alkalinizers may result in|
01811|022|D|alkalinization of the urine resulting in therapeutic failure of methenamine.|
01811|023|D|Formaldehyde is released by acid hydrolysis from methenamine resulting in|
01811|024|D|bactericidal concentrations at urinary ph 5.0 to 5.5. Above urinary ph 6.0|
01811|025|D|there is insufficient quantities of formaldehyde and methenamine released to|
01811|026|D|achieve a therapeutic response.(1)|
01811|027|D|   An in vitro study showed that methenamine efficacy is achieved when the|
01811|028|D|urine pH is less than 5.7 to 5.85.(4)|
01811|029|B||
01811|030|R|REFERENCES:|
01811|031|B||
01811|032|R|1.Visqid A/A (methenamine and sodium acid phosphate monohydrate) US|1
01811|033|R|  prescribing information. January, 2007.|1
01811|034|R|2.Hiprex (methenamine hippurate) Australian Product Information. iNova|1
01811|035|R|  Pharmaceuticals (Australia) Pty Limited April 7, 2025.|1
01811|036|R|3.Hiprex (methenamine hippurate) UK Summary of Product Characteristics.|1
01811|037|R|  Mylan Products Ltd. May 12, 2025.|1
01811|038|R|4.Musher DM, Griffith DP. Generation of formaldehyde from methenamine:|5
01811|039|R|  effect of pH and concentration, and  antibacterial effect. Antimicrob|5
01811|040|R|  Agents Chemother 1974 Dec;6(6):708-11.|5
01813|001|T|MONOGRAPH TITLE:  Rivaroxaban/P-gp and Strong CYP3A4 Inhibitors|
01813|002|B||
01813|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01813|004|L|is contraindicated and generally should not be dispensed or administered to|
01813|005|L|the same patient.|
01813|006|B||
01813|007|A|MECHANISM OF ACTION:  Adagrasib, itraconazole, josamycin, ketoconazole,|
01813|008|A|levoketoconazole, lonafarnib, paritaprevir, posaconazole, telaprevir,|
01813|009|A|telithromycin, and tucatinib may inhibit the metabolism of rivaroxaban by|
01813|010|A|CYP3A4 and by P-glycoprotein.(1-3)|
01813|011|B||
01813|012|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
01813|013|E|P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and|
01813|014|E|clinical effects of rivaroxaban,(1-3) including an increased risk of|
01813|015|E|bleeding.|
01813|016|B||
01813|017|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01813|018|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01813|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
01813|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01813|021|P|risk for bleeding (e.g. NSAIDs).|
01813|022|B||
01813|023|M|PATIENT MANAGEMENT:  The Canadian manufacturer of rivaroxaban states that|
01813|024|M|the concurrent use of agents that are both an inhibitor of P-gp and a strong|
01813|025|M|inhibitor of CYP3A4 with rivaroxaban is contraindicated.(1)  The US|
01813|026|M|manufacturer states that concurrent use of these agents should be|
01813|027|M|avoided.(2)  The UK manufacturer states that concurrent use is not|
01813|028|M|recommended.(3)|
01813|029|M|   The US manufacturer of itraconazole states concurrent use with|
01813|030|M|rivaroxaban is not recommended during and two weeks after itraconazole|
01813|031|M|treatment.(5)|
01813|032|M|   Agents that are not strong inhibitors of both CYP3A4 and P-glycoprotein,|
01813|033|M|including fluconazole, are expected to increase rivaroxaban levels to a|
01813|034|M|lesser extent and can be used with rivaroxaban with caution(3) in patients|
01813|035|M|with normal renal function.(6)|
01813|036|M|   If concurrent therapy is deemed medically necessary, monitor patients|
01813|037|M|receiving concurrent therapy for signs of blood loss, including decreased|
01813|038|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
01813|039|M|and promptly evaluate patients with any symptoms.|
01813|040|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01813|041|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01813|042|M|anticoagulation in patients with active pathologic bleeding.|
01813|043|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01813|044|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01813|045|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01813|046|M|and/or swelling.|
01813|047|B||
01813|048|D|DISCUSSION:  Concurrent use of rivaroxaban with ketoconazole (400 mg daily)|
01813|049|D|increased rivaroxaban AUC and Cmax by 2.6-fold and 1.7-fold, respectively.|
01813|050|D|There were also significant increases in pharmacodynamic effects.(1-3)|
01813|051|D|   Clarithromycin increased the Cmax and AUC of a single dose of rivaroxaban|
01813|052|D|by 40% and 50%, respectively and is not expected to affect bleeding risk.(2)|
01813|053|D|   Agents that are not strong inhibitors of both CYP3A4 and P-glycoprotein,|
01813|054|D|including fluconazole, are expected to increase rivaroxaban levels to a|
01813|055|D|lesser extent and can be used with rivaroxaban with caution(2) in patients|
01813|056|D|with normal renal function.(3)|
01813|057|B||
01813|058|R|REFERENCES:|
01813|059|B||
01813|060|R|1.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
01813|061|R|  2015.|1
01813|062|R|2.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
01813|063|R|  Inc. March, 2020.|1
01813|064|R|3.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
01813|065|R|  August, 2021.|1
01813|066|R|4.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01813|067|R|  December, 2019.|1
01813|068|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01813|069|R|  Products, L.P. February, 2024.|1
01814|001|T|MONOGRAPH TITLE:  Rivaroxaban/HIV Protease Inhibitors; Cobicistat|
01814|002|B||
01814|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01814|004|L|is contraindicated and generally should not be dispensed or administered to|
01814|005|L|the same patient.|
01814|006|B||
01814|007|A|MECHANISM OF ACTION:  Rivaroxaban is metabolized by CYP3A4 and is a|
01814|008|A|substrate of the P-glycoprotein (P-gp) efflux transport protein.(1-3)|
01814|009|A|   HIV protease inhibitors are CYP3A4 and P-gp inhibitors and may increase|
01814|010|A|the absorption and decrease the elimination of rivaroxaban.(1-4)|
01814|011|B||
01814|012|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors may result in|
01814|013|E|elevated levels and clinical effects of rivaroxaban, including an increased|
01814|014|E|risk of bleeding.(1-4)|
01814|015|B||
01814|016|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01814|017|P|patients with disease-associated factors (e.g. thrombocytopenia).|
01814|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
01814|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01814|020|P|risk for bleeding (e.g. NSAIDs).|
01814|021|B||
01814|022|M|PATIENT MANAGEMENT:  Recommendations for concurrent use of rivaroxaban and|
01814|023|M|HIV protease inhibitors vary in different regions.|
01814|024|M|   The Australian(1) and Canadian(2) manufacturers of rivaroxaban state that|
01814|025|M|the concurrent use of strong inhibitors of both P-gp and CYP3A4 with|
01814|026|M|rivaroxaban is contraindicated.  The UK manufacturer of rivaroxaban states|
01814|027|M|that concurrent use of these agents is not recommended.(3)  The US|
01814|028|M|manufacturer of rivaroxaban states that concurrent use should be avoided.(4)|
01814|029|M|   The US manufacturer of atazanavir states that coadministration of|
01814|030|M|atazanavir with ritonavir is not recommended.  Coadministration of|
01814|031|M|atazanavir alone should be monitored closely.(5)|
01814|032|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
01814|033|M|loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
01814|034|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
01814|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01814|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01814|037|M|anticoagulation in patients with active pathologic bleeding.|
01814|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01814|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01814|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01814|041|M|and/or swelling.|
01814|042|B||
01814|043|D|DISCUSSION:  Concurrent use of rivaroxaban with ritonavir (600 mg twice|
01814|044|D|daily) increased rivaroxaban area-under-curve (AUC) and maximum|
01814|045|D|concentration (Cmax) by 2.5-fold and 1.6-fold, respectively.  There were|
01814|046|D|also significant increases in pharmacodynamic effects.(1,2)|
01814|047|D|   HIV protease inhibitors linked to this monograph are: atazanavir,|
01814|048|D|cobicistat, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir,|
01814|049|D|ritonavir, saquinavir, and tipranavir.|
01814|050|B||
01814|051|R|REFERENCES:|
01814|052|B||
01814|053|R|1.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
01814|054|R|  2015.|1
01814|055|R|2.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
01814|056|R|  August, 2021.|1
01814|057|R|3.Xarelto (rivaroxaban) Australian prescribing information. BAYER AUSTRALIA|1
01814|058|R|  LTD December, 2022.|1
01814|059|R|4.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
01814|060|R|  Inc. March, 2020.|1
01814|061|R|5.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01814|062|R|  Squibb Company December, 2024.|1
01815|001|T|MONOGRAPH TITLE:  Selected CYP2D6 Substrates/Terbinafine|
01815|002|B||
01815|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01815|004|L|take action as needed.|
01815|005|B||
01815|006|A|MECHANISM OF ACTION:  Terbinafine is a strong inhibitor of CYP2D6 and may|
01815|007|A|convert patients from the extensive metabolizer to poor metabolizer|
01815|008|A|phenotype for this enzyme.(1)|
01815|009|B||
01815|010|E|CLINICAL EFFECTS:  Concurrent use of terbinafine may result in increased|
01815|011|E|serum levels and adverse effects of drugs primarily metabolized by or|
01815|012|E|sensitive to changes in the activity of the CYP2D6 metabolic pathway.(1,2)|
01815|013|B||
01815|014|P|PREDISPOSING FACTORS:  With paroxetine, the risk of anticholinergic|
01815|015|P|toxicities including cognitive decline, delirium, falls and fractures is|
01815|016|P|increased in geriatric patients using more than one medicine with|
01815|017|P|anticholinergic properties.(3)|
01815|018|B||
01815|019|M|PATIENT MANAGEMENT:  Terbinafine has a serum half-life of approximately 36|
01815|020|M|hours, so the maximal effect of this interaction may be delayed for one to|
01815|021|M|two weeks. Extended monitoring may be necessary.|
01815|022|M|   Patients receiving therapy with agents primarily metabolized by CYP2D6|
01815|023|M|need increased monitoring for adverse effects and may need a dose reduction.|
01815|024|M|Plasma level monitoring should be considered in patients receiving|
01815|025|M|flecainide.(4)|
01815|026|M|   The effect of terbinafine on CYP2D6 substrates may last for up to four|
01815|027|M|weeks after terbinafine discontinuation. Over time, patients previously|
01815|028|M|stabilized on the combination of terbinafine and a selected CYP2D6 substrate|
01815|029|M|may need an increase in the dose of the CYP2D6 metabolized drug.|
01815|030|B||
01815|031|D|DISCUSSION:  In a randomized, placebo-controlled trial in 12 healthy|
01815|032|D|subjects, terbinafine (150 mg daily for 6 days) increased the|
01815|033|D|area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of|
01815|034|D|paroxetine (20 mg) by 2.9-fold and 1.9-fold, respectively.(6)|
01815|035|D|   In a placebo-controlled trial in 12 healthy males, terbinafine (250 mg|
01815|036|D|for 4 days) increased the Cmax and AUC of a single dose of venlafaxine (75|
01815|037|D|mg) by 2.67-fold and 4.9-fold, respectively.(7)|
01815|038|D|   CYP2D6 substrates linked to this monograph are: dapoxetine, flecainide,|
01815|039|D|metoprolol, nebivolol, paroxetine, perphenazine, propafenone, propranolol,|
01815|040|D|venlafaxine and yohimbine.|
01815|041|B||
01815|042|R|REFERENCES:|
01815|043|B||
01815|044|R|1.Lamisil (terbinafine hydrochloride) tablet US prescribing information.|1
01815|045|R|  Novartis Pharmaceuticals Corporation June, 2013.|1
01815|046|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
01815|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01815|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01815|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01815|050|R|  11/14/2017.|1
01815|051|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01815|052|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01815|053|R|  Soc 2023 Jul;71(7):2052-2081.|6
01815|054|R|4.Tambocor (flecainide) US prescribing information. Medicis December, 2011.|1
01815|055|R|5.Yasui-Furukori N, Saito M, Inoue Y, Niioka T, Sato Y, Tsuchimine S, Kaneko|2
01815|056|R|  S. Terbinafine increases the plasma concentration of paroxetine after a|2
01815|057|R|  single oral administration of paroxetine in healthy subjects. Eur J Clin|2
01815|058|R|  Pharmacol 2007 Jan;63(1):51-6.|2
01815|059|R|6.Hynninen VV, Olkkola KT, Bertilsson L, Kurkinen K, Neuvonen PJ, Laine K.|2
01815|060|R|  Effect of terbinafine and voriconazole on the pharmacokinetics of the|2
01815|061|R|  antidepressant venlafaxine. Clin Pharmacol Ther 2008 Feb;83(2):342-8.|2
01815|062|R|7.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
01815|063|R|  Laboratories March, 2013.|1
01816|001|T|MONOGRAPH TITLE:  Antidiabetic Agents/Gatifloxacin|
01816|002|B||
01816|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01816|004|L|of severe adverse interaction.|
01816|005|B||
01816|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01816|007|B||
01816|008|E|CLINICAL EFFECTS:  Concurrent use of gatifloxacin may result in hypoglycemia|
01816|009|E|and/or hyperglycemia.(1-4)  Hypoglycemia is more common during the first|
01816|010|E|three days of concurrent therapy.  Hyperglycemia is more common after the|
01816|011|E|first three days of concurrent therapy.(2)|
01816|012|B||
01816|013|P|PREDISPOSING FACTORS:  Elderly patients, especially those with decreased|
01816|014|P|renal function may be predisposed to this interaction.(2)|
01816|015|B||
01816|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent gatifloxacin should be|
01816|017|M|closely monitored for hypoglycemia during the first three days of concurrent|
01816|018|M|therapy and for hyperglycemia after the first three days of concurrent|
01816|019|M|therapy.  Patients should be instructed to discontinue gatifloxacin if|
01816|020|M|hypoglycemia or hyperglycemia occur.(2)|
01816|021|B||
01816|022|D|DISCUSSION:  Hypoglycemia has been reported with gatifloxacin and|
01816|023|D|glyburide(1,5,6) or glimepiride.(7)|
01816|024|D|   In a study in patients with type 2 diabetes mellitus, concurrent|
01816|025|D|gatifloxacin (400 mg daily for 10 days) had no effect on the|
01816|026|D|pharmacokinetics of glyburide (steady state daily regimen); however,|
01816|027|D|pharmacodynamic interactions have been reported.(2)|
01816|028|D|   Health Canada has received 19 reports of hypoglycemia in patients taking|
01816|029|D|gatifloxacin.  Seventeen of these involved concurrent hypoglycemic agents.|
01816|030|D|Health Canada has received 2 reports of hyperglycemia in patients taking|
01816|031|D|gatifloxacin and hypoglycemic agents.  Health Canada has received 2 reports|
01816|032|D|of patients experiencing hypoglycemia and hyperglycemia during concurrent|
01816|033|D|gatifloxacin and hypoglycemic agents.(3)|
01816|034|D|   In a study, 13 reports of dysglycemia were reported in patients taking|
01816|035|D|gatifloxacin. Ten of these patients had diabetes mellitus and were on|
01816|036|D|concurrent hypoglycemic agents.  Of these ten patients, nine patients|
01816|037|D|experienced hypoglycemia, while one patient experienced hyperglycemia.(8)|
01816|038|B||
01816|039|R|REFERENCES:|
01816|040|B||
01816|041|R|1.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
01816|042|R|  Company January, 2006.|1
01816|043|R|2.Dear Canadian Healthcare Professional letter:  Subject:  Updated safety|1
01816|044|R|  information for TEQUIN (gatifloxacin) and serious hypoglycemia and|1
01816|045|R|  hyperglycemia. Bristol-Myers Squibb Canada May 12, 2006.|1
01816|046|R|3.Letourneau G, Morrison B, McMorran M. Gatifloxacin (Tequin):  hypoglycemia|1
01816|047|R|  and hyperglycemia. Canadian Adverse Reaction Newsletter 2003 Jul;|1
01816|048|R|  13(2):1-2.|1
01816|049|R|4.Lewis-Hall F. Dear Healthcare Provider letter. Bristol-Myers Squibb|1
01816|050|R|  February 15, 2006.|1
01816|051|R|5.LeBlanc M, Belanger C, Cossette P. Severe and resistant hypoglycemia|3
01816|052|R|  associated with concomitant gatifloxacin and glyburide therapy.|3
01816|053|R|  Pharmacotherapy 2004 Jul;24(7):926-31.|3
01816|054|R|6.Bhasin R, Arce FC, Pasmantier R. Hypoglycemia associated with the use of|3
01816|055|R|  gatifloxacin. Am J Med Sci 2005 Nov;330(5):250-3.|3
01816|056|R|7.Kesavadev J, Rasheed SA. Gatifloxacin induced abnormalities in glucose|3
01816|057|R|  homeostasis in a patient on glimepiride. J Assoc Physicians India 2006|3
01816|058|R|  Dec;54:951-2.|3
01816|059|R|8.Zvonar R. Gatifloxacin-induced dysglycemia. Am J Health Syst Pharm 2006|3
01816|060|R|  Nov 1;63(21):2087-92.|3
01817|001|T|MONOGRAPH TITLE:  Tetrabenazine/QT Prolonging Agents (mono deleted|
01817|002|T|12/17/2020)|
01817|003|B||
01817|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01817|005|L|of severe adverse interaction.|
01817|006|B||
01817|007|A|MECHANISM OF ACTION:  Tetrabenazine has been shown to prolong the QTc|
01817|008|A|interval by about 8 msec.  Concurrent use with other agents that prolong the|
01817|009|A|QTc interval may result in additive effects on the QTc interval.(1)|
01817|010|B||
01817|011|E|CLINICAL EFFECTS:  The concurrent use of tetrabenazine with other agents|
01817|012|E|that prolong the QTc interval may result in potentially life-threatening|
01817|013|E|cardiac arrhythmias, including torsades de pointes.(1)|
01817|014|B||
01817|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01817|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01817|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01817|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01817|019|P|gender, or advanced age.(3)|
01817|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01817|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01817|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01817|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01817|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01817|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01817|026|P|dysfunction).(3)|
01817|027|B||
01817|028|M|PATIENT MANAGEMENT:  The US manufacturer of tetrabenazine states that the|
01817|029|M|concurrent administration of other drugs that are known to prolong the QTc|
01817|030|M|interval should be avoided.(1)|
01817|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01817|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01817|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01817|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01817|035|B||
01817|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01817|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01817|038|D|monograph have been shown to prolong the QTc interval either through their|
01817|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01817|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01817|041|D|clinical trials and/or postmarketing reports.(2)|
01817|042|B||
01817|043|R|REFERENCES:|
01817|044|B||
01817|045|R|1.Xenazine (tetrabenazine) US prescribing information. Valeant International|1
01817|046|R|  September, 2017.|1
01817|047|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01817|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01817|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01817|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01817|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01817|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01817|053|R|  settings: a scientific statement from the American Heart Association and|6
01817|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01817|055|R|  2;55(9):934-47.|6
01818|001|T|MONOGRAPH TITLE:  Tetrabenazine/Possible QT Prolonging Agents (mono deleted|
01818|002|T|12/17/2020)|
01818|003|B||
01818|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01818|005|L|take action as needed.|
01818|006|B||
01818|007|A|MECHANISM OF ACTION:  Tetrabenazine has been shown to prolong the QTc|
01818|008|A|interval by about 8 msec.  Concurrent use with other agents that prolong the|
01818|009|A|QTc interval may result in additive effects on the QTc interval.(1)|
01818|010|B||
01818|011|E|CLINICAL EFFECTS:  The concurrent use of tetrabenazine with other agents|
01818|012|E|that prolong the QTc interval may result in potentially life-threatening|
01818|013|E|cardiac arrhythmias, including torsades de pointes.(1)|
01818|014|B||
01818|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01818|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01818|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01818|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01818|019|P|gender, or advanced age.(3)|
01818|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01818|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01818|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01818|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01818|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01818|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01818|026|P|dysfunction).(3)|
01818|027|B||
01818|028|M|PATIENT MANAGEMENT:  The US manufacturer of tetrabenazine states that the|
01818|029|M|concurrent administration of other drugs that are known to prolong the QTc|
01818|030|M|interval should be avoided.(1)|
01818|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01818|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01818|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01818|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01818|035|B||
01818|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01818|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01818|038|D|monograph have been shown to prolong the QTc interval either through their|
01818|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01818|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01818|041|D|clinical trials and/or postmarketing reports.(2)|
01818|042|B||
01818|043|R|REFERENCES:|
01818|044|B||
01818|045|R|1.Xenazine (tetrabenazine) US prescribing information. Valeant International|1
01818|046|R|  September, 2017.|1
01818|047|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01818|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01818|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01818|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01818|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01818|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01818|053|R|  settings: a scientific statement from the American Heart Association and|6
01818|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01818|055|R|  2;55(9):934-47.|6
01819|001|T|MONOGRAPH TITLE:  Deutetrabenazine;Tetrabenazine/Strong CYP2D6 Inhibitors|
01819|002|B||
01819|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01819|004|L|take action as needed.|
01819|005|B||
01819|006|A|MECHANISM OF ACTION:  After ingestion, tetrabenazine is rapidly to converted|
01819|007|A|the active agent, dihydrotetrabenazine (HTBZ, a mixture of alpha-HTBZ and|
01819|008|A|beta-HTBZ).  Both alpha and beta-HTBZ are metabolized by CYP2D6.  Strong|
01819|009|A|inhibitors of CYP2D6 may inhibit the metabolism of tetrabenazine active|
01819|010|A|metabolites.(1)|
01819|011|A|  Deutetrabenazine is a deuterated form of tetrabenazine.(2)|
01819|012|B||
01819|013|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP2D6 inhibitor may result in|
01819|014|E|increased levels of and adverse effects from deutetrabenazine(2) or|
01819|015|E|tetrabenazine.(1)|
01819|016|B||
01819|017|P|PREDISPOSING FACTORS:  None determined.|
01819|018|B||
01819|019|M|PATIENT MANAGEMENT:  The maximum recommended dose of deutetrabenazine when|
01819|020|M|administered with a strong inhibitor of CYP2D6 is 36 mg daily (tablets:|
01819|021|M|given as 18 mg twice daily; or extended-release tablets: given as 36 mg|
01819|022|M|daily).(2,3)|
01819|023|M|   The maximum recommended dose of tetrabenazine when administered with a|
01819|024|M|strong inhibitor of CYP2D6 is 50 mg daily (given as 25 mg twice daily).(1)|
01819|025|M|   Monitor patients receiving concurrent deutetrabenazine or tetrabenazine|
01819|026|M|and a strong CYP2D6 inhibitor for adverse effects, including depression,|
01819|027|M|suicidal thoughts, stiff muscles, trouble swallowing, irritability or|
01819|028|M|agitation, shaking, and restlessness.|
01819|029|M|   If the CYP2D6 inhibitor is discontinued, the dose of deutetrabenazine or|
01819|030|M|tetrabenazine may need adjustment.|
01819|031|B||
01819|032|D|DISCUSSION:  In a study in 24 healthy subjects, following the administration|
01819|033|D|of a single oral dose of deutetrabenazine (22.5 mg) after 8 days of|
01819|034|D|paroxetine (20 mg daily), the maximum concentration (Cmax) of alpha-HTBZ and|
01819|035|D|beta-HTBZ increased by 1.2-fold and 2.2-fold, respectively.  The|
01819|036|D|area-under-curve (AUC) of alpha-HTBZ and beta-HTBZ increased by 1.9-fold and|
01819|037|D|6.5-fold, respectively.(2)|
01819|038|D|   In a study in 25 healthy subjects, following the administration of a|
01819|039|D|single oral dose of tetrabenazine (50 mg) after 10 days of paroxetine (20 mg|
01819|040|D|daily), the Cmax of alpha-HTBZ and beta-HTBZ increased by 30% and 2.4-fold,|
01819|041|D|respectively.  The AUC of alpha-HTBZ and beta-HTBZ increased by 3-fold and|
01819|042|D|9-fold, respectively.(1)|
01819|043|D|   Strong inhibitors of CYP2D6 include:  bupropion, dacomitinib, fluoxetine,|
01819|044|D|paroxetine and terbinafine.(1-4)|
01819|045|B||
01819|046|R|REFERENCES:|
01819|047|B||
01819|048|R|1.Xenazine (tetrabenazine) US prescribing information. Valeant International|1
01819|049|R|  September, 2017.|1
01819|050|R|2.Austedo (deutetrabenazine) US prescribing information. Teva|1
01819|051|R|  Pharmaceutical, Inc. July, 2024.|1
01819|052|R|3.Austedo XR (deutetrabenazine) US prescribing information. Teva|1
01819|053|R|  Pharmaceuticals July, 2024.|1
01819|054|R|4.This information is based on an extract from the Certara Drug Interaction|6
01819|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01820|001|T|MONOGRAPH TITLE:  Deutetrabenazine;Tetrabenazine/Quinidine|
01820|002|B||
01820|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01820|004|L|take action as needed.|
01820|005|B||
01820|006|A|MECHANISM OF ACTION:  After ingestion, tetrabenazine is rapidly converted to|
01820|007|A|the active agent, dihydrotetrabenazine (HTBZ, a mixture of alpha-HTBZ and|
01820|008|A|beta-HTBZ).  Both alpha and beta-HTBZ are metabolized by CYP2D6.  Strong|
01820|009|A|inhibitors of CYP2D6, such as quinidine, may inhibit the metabolism of|
01820|010|A|tetrabenazine active metabolites.(1)|
01820|011|A|   Deutetrabenazine is a deuterated form of tetrabenazine.(2)|
01820|012|B||
01820|013|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP2D6 inhibitor, such as|
01820|014|E|quinidine, may result in increased levels of and adverse effects from|
01820|015|E|deutetrabenazine(2) or tetrabenazine.(1)|
01820|016|B||
01820|017|P|PREDISPOSING FACTORS:  None determined.|
01820|018|B||
01820|019|M|PATIENT MANAGEMENT:  The maximum recommended dose of deutetrabenazine when|
01820|020|M|administered with quinidine is 36 mg daily (given as 18 mg twice daily).(2)|
01820|021|M|   The maximum recommended dose of tetrabenazine when administered with|
01820|022|M|quinidine is 50 mg daily (given as 25 mg twice daily).(1)|
01820|023|M|   Monitor patients receiving concurrent therapy for adverse effects,|
01820|024|M|including depression, suicidal thoughts, stiff muscles, trouble swallowing,|
01820|025|M|irritability or agitation, shaking, and restlessness.|
01820|026|M|   If the CYP2D6 inhibitor is discontinued, the dose of deutetrabenazine or|
01820|027|M|tetrabenazine may need adjustment.|
01820|028|B||
01820|029|D|DISCUSSION:  In a study in 24 healthy subjects, following the administration|
01820|030|D|of a single oral dose of deutetrabenazine (22.5 mg) after 8 days of|
01820|031|D|paroxetine (20 mg daily), the maximum concentration (Cmax) of alpha-HTBZ and|
01820|032|D|beta-HTBZ increased by 1.2-fold and 2.2-fold, respectively.  The|
01820|033|D|area-under-curve (AUC) of alpha-HTBZ and beta-HTBZ increased by 1.9-fold and|
01820|034|D|6.5-fold, respectively.(2)|
01820|035|D|   In a study in 25 healthy subjects, following the administration of a|
01820|036|D|single oral dose of tetrabenazine (50 mg) after 10 days of paroxetine (20 mg|
01820|037|D|daily), the Cmax of alpha-HTBZ and beta-HTBZ increased by 30% and 2.4-fold,|
01820|038|D|respectively.  The AUC of alpha-HTBZ and beta-HTBZ increased by 3-fold and|
01820|039|D|9-fold, respectively.(1)|
01820|040|B||
01820|041|R|REFERENCES:|
01820|042|B||
01820|043|R|1.Xenazine (tetrabenazine) US prescribing information. Valeant International|1
01820|044|R|  September, 2017.|1
01820|045|R|2.Austedo (deutetrabenazine) US prescribing information. Teva|1
01820|046|R|  Pharmaceutical, Inc. July, 2024.|1
01820|047|R|3.This information is based on an extract from the Certara Drug Interaction|6
01820|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01821|001|T|MONOGRAPH TITLE:  Intramuscular Olanzapine/Parenteral Benzodiazepines|
01821|002|B||
01821|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01821|004|L|of severe adverse interaction.|
01821|005|B||
01821|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01821|007|B||
01821|008|E|CLINICAL EFFECTS:  Concurrent use of intramuscular olanzapine with a|
01821|009|E|parenteral benzodiazepine may result in excessive sedation,|
01821|010|E|cardiorespiratory depression, and death.|
01821|011|B||
01821|012|P|PREDISPOSING FACTORS:  None determined.|
01821|013|B||
01821|014|M|PATIENT MANAGEMENT:  The Canadian,(1) UK,(2) and US(3) manufacturers of|
01821|015|M|olanzapine state that simultaneous injection of intramuscular olanzapine and|
01821|016|M|parenteral benzodiazepines is not recommended.|
01821|017|M|   If parenteral benzodiazepine therapy is required in a patient who has|
01821|018|M|received IM olanzapine, wait 1 hour after the administration of IM|
01821|019|M|olanzapine.(2)|
01821|020|M|   IM olanzapine should only be considered in patients who have received|
01821|021|M|parenteral benzodiazepines after careful evaluation and they should be|
01821|022|M|closely monitored for excessive sedation and cardiorespiratory|
01821|023|M|depression.(2)|
01821|024|B||
01821|025|D|DISCUSSION:  In post-marketing reports, temporal association of IM|
01821|026|D|olanzapine with respiratory depression, hypotension, bradycardia, and death|
01821|027|D|have been rarely reported (<0.01%).  Many of the patients also received|
01821|028|D|parenteral benzodiazepines.(2)|
01821|029|D|   In an analysis of 160 spontaneous reports of adverse events during a|
01821|030|D|review of the first 21 months of olanzapine usage, benzodiazepines were used|
01821|031|D|concurrently in 27% of non serious reports (21/77), 44% of serious nonfatal|
01821|032|D|reports (24/54), and in 66% (19/29) fatal reports.(4)|
01821|033|D|   Concurrent use with diazepam has shown to increase orthostatic|
01821|034|D|hypotension.  There was no effect on the pharmacokinetics of diazepam or its|
01821|035|D|active metabolite, N-desmethyldiazepam.(3)|
01821|036|D|   Concurrent use with intramuscular lorazepam did not affect the|
01821|037|D|pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam.|
01821|038|D|Somnolence was increased.(3)|
01821|039|B||
01821|040|R|REFERENCES:|
01821|041|B||
01821|042|R|1.Zyprexa (olanzapine) oral, intramuscular Canadian prescribing information.|1
01821|043|R|  Lilly February, 2013.|1
01821|044|R|2.Zyprexa (olanzapine) powder for solution for injection UK summary of|1
01821|045|R|  product characteristics. Eli Lilly and Company Limited July 28, 2008.|1
01821|046|R|3.Zyprexa Relprevv (olanzapine ext-rel IM susp.) US prescribing information.|1
01821|047|R|  Eli Lilly and Company February, 2017.|1
01821|048|R|4.Sorsaburu S, Hornbuckle K, Blake DS. The first 21 months of safety|3
01821|049|R|  experience with post-marketing use of olanzapine's intramuscular|3
01821|050|R|  formulation. (Abstract NR432). Presented at the 159th Annual Meeting|3
01821|051|R|  American Psychiatry Association. Toronto, Canada, May, 2006..|3
01822|001|T|MONOGRAPH TITLE:  Eltrombopag/Polyvalent Cations|
01822|002|B||
01822|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01822|004|L|take action as needed.|
01822|005|B||
01822|006|A|MECHANISM OF ACTION:  Eltrombopag chelates polyvalent cations such as|
01822|007|A|aluminum, calcium, iron, magnesium, selenium, and zinc.(1)|
01822|008|B||
01822|009|E|CLINICAL EFFECTS:  Simultaneous administration of eltrombopag and polyvalent|
01822|010|E|cations may decrease the absorption and clinical effects of eltrombopag.|
01822|011|B||
01822|012|P|PREDISPOSING FACTORS:  None determined.|
01822|013|B||
01822|014|M|PATIENT MANAGEMENT:  The US manufacturer of eltrombopag states that it|
01822|015|M|should be administered at least 2 hours before or 4 hours after any|
01822|016|M|medications or products containing polyvalent cations such as antacids or|
01822|017|M|mineral supplements.(1)|
01822|018|B||
01822|019|D|DISCUSSION:  In a crossover study in 25 healthy subjects, administration of|
01822|020|D|eltrombopag with an antacid (1524 mg aluminum hydroxide/1425 mg magnesium|
01822|021|D|carbonate/sodium alginate) decreased eltrombopag levels by 70%.(1,2)|
01822|022|B||
01822|023|R|REFERENCES:|
01822|024|B||
01822|025|R|1.Promacta (eltrombopag) US prescribing information. GlaxoSmithKline|1
01822|026|R|  February, 2021.|1
01822|027|R|2.Williams DD, Peng B, Bailey CK, Wire MB, Deng Y, Park JW, Collins DA,|2
01822|028|R|  Kapsi SG, Jenkins JM. Effects of food and antacids on the pharmacokinetics|2
01822|029|R|  of eltrombopag in healthy adult subjects: two single-dose, open-label,|2
01822|030|R|  randomized-sequence, crossover studies. Clin Ther 2009 Apr;31(4):764-76.|2
01823|001|T|MONOGRAPH TITLE:  Eltrombopag/Rosuvastatin|
01823|002|B||
01823|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01823|004|L|take action as needed.|
01823|005|B||
01823|006|A|MECHANISM OF ACTION:  Eltrombopag has been shown to inhibit OATP1B1.|
01823|007|A|Rosuvastatin is a substrate of this transporter.(1,2)|
01823|008|B||
01823|009|E|CLINICAL EFFECTS:  Simultaneous use of eltrombopag may result in increased|
01823|010|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1,2)|
01823|011|B||
01823|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01823|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01823|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01823|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01823|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01823|017|P|transporter OATP1B1 may have increased statin concentrations and be|
01823|018|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
01823|019|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
01823|020|P|may have increased rosuvastatin concentrations and risk of myopathy.|
01823|021|B||
01823|022|M|PATIENT MANAGEMENT:  In clinical trials, a 50% rosuvastatin dosage reduction|
01823|023|M|was recommended during concurrent eltrombopag.(1)|
01823|024|B||
01823|025|D|DISCUSSION:  In a clinical trial in 39 healthy subjects, administration of|
01823|026|D|eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum|
01823|027|D|concentration (Cmax) of a single dose of rosuvastatin (10 mg) by 55% and|
01823|028|D|103%, respectively.(1-3)|
01823|029|B||
01823|030|R|REFERENCES:|
01823|031|B||
01823|032|R|1.Promacta (eltrombopag) US prescribing information. GlaxoSmithKline|1
01823|033|R|  February, 2021.|1
01823|034|R|2.Allred AJ, Bowen CJ, Park JW, Peng B, Williams DD, Wire MB, Lee E.|2
01823|035|R|  Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers.|2
01823|036|R|  Br J Clin Pharmacol 2011 Aug;72(2):321-9.|2
01823|037|R|3.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
01823|038|R|  Pharmaceuticals LP July, 2024.|1
01824|001|T|MONOGRAPH TITLE:  Sugammadex/Fusidic acid|
01824|002|B||
01824|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01824|004|L|take action as needed.|
01824|005|B||
01824|006|A|MECHANISM OF ACTION:  Fusidic acid may displace rocuronium or vecuronium|
01824|007|A|from sugammadex.(1)|
01824|008|B||
01824|009|E|CLINICAL EFFECTS:  Parenteral administration of fusidic acid pre-operatively|
01824|010|E|may result in a delay in the recovery of the T4/T1 ratio to 0.9.(1)|
01824|011|B||
01824|012|P|PREDISPOSING FACTORS:  None determined.|
01824|013|B||
01824|014|M|PATIENT MANAGEMENT:  Closely monitor ventilation, especially during the|
01824|015|M|first 15 minutes after dosing.  If reoccurrence of blockade occurs, stop the|
01824|016|M|infusion of fusidic acid and readminister sugammadex as recommended.(1)|
01824|017|B||
01824|018|D|DISCUSSION:  Parenteral administration of fusidic acid pre-operatively may|
01824|019|D|result in a delay in the recovery of the T4/T1 ratio to 0.9.(1)|
01824|020|B||
01824|021|R|REFERENCE:|
01824|022|B||
01824|023|R|1.Bridion (sugammadex sodium) UK summary of product characteristics. Merck|1
01824|024|R|  Sharp & Dohme Limited August 31, 2016.|1
01825|001|T|MONOGRAPH TITLE:  Sugammadex/Toremifene|
01825|002|B||
01825|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01825|004|L|of severe adverse interaction.|
01825|005|B||
01825|006|A|MECHANISM OF ACTION:  Toremifene may displace rocuronium or vecuronium from|
01825|007|A|sugammadex.(1)|
01825|008|B||
01825|009|E|CLINICAL EFFECTS:  Use of toremifene on the same day as sugammadex may|
01825|010|E|result in a delay in the recovery of the T4/T1 ratio to 0.9.(1)|
01825|011|B||
01825|012|P|PREDISPOSING FACTORS:  None determined.|
01825|013|B||
01825|014|M|PATIENT MANAGEMENT:  Patients who have received toremifene on the same day|
01825|015|M|as sugammadex should be closely observed for delayed recovery from|
01825|016|M|rocuronium or vecuronium.(1)|
01825|017|B||
01825|018|D|DISCUSSION:  Use of toremifene on the same day as sugammadex may result in a|
01825|019|D|delay in the recovery of the T4/T1 ratio to 0.9.(1)|
01825|020|B||
01825|021|R|REFERENCE:|
01825|022|B||
01825|023|R|1.Bridion (sugammadex sodium) UK summary of product characteristics. Merck|1
01825|024|R|  Sharp & Dohme Limited August 31, 2016.|1
01826|001|T|MONOGRAPH TITLE:  Sugammadex/Hormonal Contraceptives|
01826|002|B||
01826|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01826|004|L|of severe adverse interaction.|
01826|005|B||
01826|006|A|MECHANISM OF ACTION:  Sugammadex may bind to hormonal contraceptives.(1,2)|
01826|007|B||
01826|008|E|CLINICAL EFFECTS:  Use of sugammadex may result in decreased levels of|
01826|009|E|hormonal contraceptive similar to those seen with a missed dose of an oral|
01826|010|E|contraceptive, which may result in decreased hormonal contraceptive|
01826|011|E|effectiveness.(1,2)|
01826|012|B||
01826|013|P|PREDISPOSING FACTORS:  None determined.|
01826|014|B||
01826|015|M|PATIENT MANAGEMENT:  The US manufacturer of sugammadex recommends that all|
01826|016|M|patients using hormonal contraceptives use an additional non-hormonal|
01826|017|M|contraceptive method for 7 days following the administration of|
01826|018|M|sugammadex.(1)|
01826|019|M|   The UK manufacturer of sugammadex recommends that patients taking oral|
01826|020|M|hormonal contraceptives should be instructed to follow the missed dose|
01826|021|M|instructions for their oral hormonal contraceptive on the day they receive|
01826|022|M|sugammadex.  Patients taking non-oral hormonal contraceptives should use an|
01826|023|M|additional non-hormonal contraceptive method for 7 days following the|
01826|024|M|administration of sugammadex and should refer to the advice in the package|
01826|025|M|leaflet of their non-oral hormonal contraceptive.(2)|
01826|026|B||
01826|027|D|DISCUSSION:  Use of sugammadex may result in decreased levels of hormonal|
01826|028|D|contraceptive similar to those seen with a missed dose of an oral|
01826|029|D|contraceptive, which may result in decreased hormonal contraceptive|
01826|030|D|effectiveness.(1,2)|
01826|031|B||
01826|032|R|REFERENCES:|
01826|033|B||
01826|034|R|1.Bridion (sugammadex) US prescribing information. Merck Sharp & Dohme LLC|1
01826|035|R|  November, 2022.|1
01826|036|R|2.Bridion (sugammadex sodium) UK summary of product characteristics. Merck|1
01826|037|R|  Sharp & Dohme Limited August 31, 2016.|1
01827|001|T|MONOGRAPH TITLE:  Sodium Phosphate Bowel Cleanser/Diuretics|
01827|002|B||
01827|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01827|004|L|of severe adverse interaction.|
01827|005|B||
01827|006|A|MECHANISM OF ACTION:  Bowel cleansing with sodium phosphate causes|
01827|007|A|dehydration, decreased intravascular volume and hyperphosphatemia, which|
01827|008|A|increases phosphate levels in the renal tubules.  Abnormally high levels of|
01827|009|A|calcium and phosphate in the renal tubules may precipitate out, resulting in|
01827|010|A|renal injury.(1)|
01827|011|B||
01827|012|E|CLINICAL EFFECTS:  Use of sodium phosphate for bowel cleansing in patients|
01827|013|E|maintained on diuretics may increase the risk of acute phosphate|
01827|014|E|nephropathy, which is an acute kidney injury associated with deposits of|
01827|015|E|calcium phosphate crystal in the renal tubules that may result in permanent|
01827|016|E|renal function impairment.  Acute phosphate nephropathy presents as acute|
01827|017|E|kidney injury with minimal proteinuria and a bland urine sediment.(2)|
01827|018|E|   Use of oral sodium phosphate products at laxative doses has not been|
01827|019|E|associated with acute kidney injury.(3)|
01827|020|B||
01827|021|P|PREDISPOSING FACTORS:  Patients who may be at an increased risk of acute|
01827|022|P|phosphate nephropathy include those who are over age 55; are hypovolemic or|
01827|023|P|have decreased intravascular volume; have baseline kidney disease, bowel|
01827|024|P|obstruction, or active colitis; and who are using medications that affect|
01827|025|P|renal perfusion or function (such as diuretics, angiotensin converting|
01827|026|P|enzyme (ACE) inhibitors, angiotension receptor blockers (ARBs) and possibly|
01827|027|P|nonsteroidal anti-inflammatory drugs (NSAIDs).(2)|
01827|028|B||
01827|029|M|PATIENT MANAGEMENT:  If possible, use an alternative agent for bowel|
01827|030|M|cleansing.(1)|
01827|031|M|   Use sodium phosphate products with caution in patients taking medications|
01827|032|M|that affect kidney function or perfusion, such as diuretics.  Obtain|
01827|033|M|baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN,|
01827|034|M|creatinine, and [in smaller, frail individuals] glomerular filtration rate).|
01827|035|M|Instruct patients to drink sufficient quantities of clear fluids before,|
01827|036|M|during, and after bowel cleansing and to avoid other laxatives that contain|
01827|037|M|sodium phosphate.  Consider hospitalization and intravenous hydration during|
01827|038|M|bowel cleansing to support frail patients who may be unable to drink an|
01827|039|M|appropriate volume of fluid or who may be without assistance at home.(2)|
01827|040|M|   Use of an electrolyte solution for rehydration may decrease the risk of|
01827|041|M|acute phosphate nephropathy.(4,5)|
01827|042|B||
01827|043|D|DISCUSSION:  Since May 2006, the FDA has received 20 reports of acute|
01827|044|D|phosphate nephropathy associated with the use of Osmo Prep.  Concomitant|
01827|045|D|medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs|
01827|046|D|(4).(2)|
01827|047|D|   In a retrospective review of colonoscopy patients, simultaneous use of|
01827|048|D|ACE inhibitors or ARBs significantly increased the risk of acute kidney|
01827|049|D|injury from oral sodium phosphate.  Diuretic use was also a risk factor.(6)|
01827|050|D|   In a case series study of 21 cases of acute phosphate nephropathy in|
01827|051|D|patients who had used oral sodium phosphate, 14 patients received an ACE|
01827|052|D|inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7)|
01827|053|D|   Cases have also been reported with rectal products.(8)|
01827|054|B||
01827|055|R|REFERENCES:|
01827|056|B||
01827|057|R|1.Anonymous. Food and Drug Administration Science Background Paper: Acute|1
01827|058|R|  Phosphate Nephropathy and Renal Failure Associated With the Use of Oral|1
01827|059|R|  Sodium Phosphate Bowel Cleansing Products. Available at:|1
01827|060|R|  http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformat|1
01827|061|R|  ionforpatientsandproviders/ucm161579.pdf Downloaded December 15, 2008..|1
01827|062|R|2.Anonymous. Information for Healthcare Professionals:  Oral Sodium|1
01827|063|R|  Phosphate (OSP) Products for Bowel Cleansing (marketed as Visicol and|1
01827|064|R|  OsmoPrep, and oral sodium phosphate products available without a|1
01827|065|R|  prescription). Available at:|1
01827|066|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01827|067|R|  providers/information-oral-sodium-phosphate-osp-products-bowel-cleansing-m|1
01827|068|R|  arketed-visicol-and-osmoprep-and Accessed December 15, 2008..|1
01827|069|R|3.Anonymous. Oral Sodium Phosphate (OSP) Actions. Questions and Answers.|1
01827|070|R|  Available at:|1
01827|071|R|  http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPati|1
01827|072|R|  entsandProviders/ucm103383.htm Accessed December 15, 2008..|1
01827|073|R|4.Barclay RL, Depew WT, Vanner SJ. Carbohydrate-electrolyte rehydration|2
01827|074|R|  protects against intravascular volume contraction during colonic cleansing|2
01827|075|R|  with orally administered sodium phosphate. Gastrointest Endosc 2002 Nov;|2
01827|076|R|  56(5):633-8.|2
01827|077|R|5.Tjandra JJ, Tagkalidis P. Carbohydrate-electrolyte (E-Lyte) solution|2
01827|078|R|  enhances bowel preparation with oral fleet phospho-soda. Dis Colon Rectum|2
01827|079|R|  2004 Jul;47(7):1181-6.|2
01827|080|R|6.Brunelli SM, Lewis JD, Gupta M, Latif SM, Weiner MG, Feldman HI. Risk of|2
01827|081|R|  kidney injury following oral phosphosoda bowel preparations. J Am Soc|2
01827|082|R|  Nephrol 2007 Dec;18(12):3199-205.|2
01827|083|R|7.Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate|3
01827|084|R|  nephropathy following oral sodium phosphate bowel purgative: an|3
01827|085|R|  underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005 Nov;|3
01827|086|R|  16(11):3389-96.|3
01827|087|R|8.USFood and Drug Administration. FDA Drug Safety Communication:   FDA warns|1
01827|088|R|  of possible harm from exceeding recommended dose of over-the-counter|1
01827|089|R|  sodium phosphate products to treat constipation. available at:|1
01827|090|R|  http://www.fda.gov/Drugs/DrugSafety/ucm380757.htm January 8, 2014.|1
01828|001|T|MONOGRAPH TITLE:  Sodium Phosphate Bowel Cleanser/ACE Inhibitors; ARBs|
01828|002|B||
01828|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01828|004|L|of severe adverse interaction.|
01828|005|B||
01828|006|A|MECHANISM OF ACTION:  Bowel cleansing with sodium phosphate causes|
01828|007|A|dehydration, decreased intravascular volume and hyperphosphatemia, which|
01828|008|A|increases phosphate levels in the renal tubules.  Abnormally high levels of|
01828|009|A|calcium and phosphate in the renal tubules may precipitate out, resulting in|
01828|010|A|renal injury.(1)|
01828|011|B||
01828|012|E|CLINICAL EFFECTS:  Use of sodium phosphate for bowel cleansing in patients|
01828|013|E|maintained on angiotensin converting enzyme (ACE) inhibitors, angiotension|
01828|014|E|receptor blockers (ARBs) may increase the risk of acute phosphate|
01828|015|E|nephropathy, which is an acute kidney injury associated with deposits of|
01828|016|E|calcium phosphate crystal in the renal tubules that may result in permanent|
01828|017|E|renal function impairment.  Acute phosphate nephropathy presents as acute|
01828|018|E|kidney injury with minimal proteinuria and a bland urine sediment.(2)|
01828|019|E|   Use of sodium phosphate products at laxative doses has not been|
01828|020|E|associated with acute kidney injury.(3)|
01828|021|B||
01828|022|P|PREDISPOSING FACTORS:  Patients who may be at an increased risk of acute|
01828|023|P|phosphate nephropathy include those who are over age 55; are hypovolemic or|
01828|024|P|have decreased intravascular volume; have baseline kidney disease, bowel|
01828|025|P|obstruction, or active colitis; and who are using medications that affect|
01828|026|P|renal perfusion or function (such as diuretics, ACE inhibitors, ARBs, and|
01828|027|P|possibly nonsteroidal anti-inflammatory drugs (NSAIDs).(2)|
01828|028|B||
01828|029|M|PATIENT MANAGEMENT:  If possible, use an alternative agent for bowel|
01828|030|M|cleansing.(1)|
01828|031|M|   Use sodium phosphate products with caution in patients taking medications|
01828|032|M|that affect kidney function or perfusion, such as ACE inhibitors or ARBs.|
01828|033|M|Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate,|
01828|034|M|BUN, creatinine, and [in smaller, frail individuals] glomerular filtration|
01828|035|M|rate).  Instruct patients to drink sufficient quantities of clear fluids|
01828|036|M|before, during, and after bowel cleansing and to avoid other laxatives that|
01828|037|M|contain sodium phosphate.  Consider hospitalization and intravenous|
01828|038|M|hydration during bowel cleansing to support frail patients who may be unable|
01828|039|M|to drink an appropriate volume of fluid or who may be without assistance at|
01828|040|M|home.(2)|
01828|041|M|   Use of an electrolyte solution for rehydration may decrease the risk of|
01828|042|M|acute phosphate nephropathy.(4,5)|
01828|043|B||
01828|044|D|DISCUSSION:  Since May 2006, the FDA has received 20 reports of acute|
01828|045|D|phosphate nephropathy associated with the use of Osmo Prep.  Concomitant|
01828|046|D|medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs|
01828|047|D|(4).(2)|
01828|048|D|   In a retrospective review of colonoscopy patients, simultaneous use of|
01828|049|D|ACE inhibitors or ARBs significantly increased the risk of acute kidney|
01828|050|D|injury from oral sodium phosphate.  Diuretic use was also a risk factor.(6)|
01828|051|D|   In a case series study of 21 cases of acute phosphate nephropathy in|
01828|052|D|patients who had used oral sodium phosphate, 14 patients received an ACE|
01828|053|D|inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7)|
01828|054|D|   Cases have also been reported with rectal products.(8)|
01828|055|B||
01828|056|R|REFERENCES:|
01828|057|B||
01828|058|R|1.Anonymous. Food and Drug Administration Science Background Paper: Acute|1
01828|059|R|  Phosphate Nephropathy and Renal Failure Associated With the Use of Oral|1
01828|060|R|  Sodium Phosphate Bowel Cleansing Products. Available at:|1
01828|061|R|  http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformat|1
01828|062|R|  ionforpatientsandproviders/ucm161579.pdf Downloaded December 15, 2008..|1
01828|063|R|2.Anonymous. Information for Healthcare Professionals:  Oral Sodium|1
01828|064|R|  Phosphate (OSP) Products for Bowel Cleansing (marketed as Visicol and|1
01828|065|R|  OsmoPrep, and oral sodium phosphate products available without a|1
01828|066|R|  prescription). Available at:|1
01828|067|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01828|068|R|  providers/information-oral-sodium-phosphate-osp-products-bowel-cleansing-m|1
01828|069|R|  arketed-visicol-and-osmoprep-and Accessed December 15, 2008..|1
01828|070|R|3.Anonymous. Oral Sodium Phosphate (OSP) Actions. Questions and Answers.|1
01828|071|R|  Available at:|1
01828|072|R|  http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPati|1
01828|073|R|  entsandProviders/ucm103383.htm Accessed December 15, 2008..|1
01828|074|R|4.Barclay RL, Depew WT, Vanner SJ. Carbohydrate-electrolyte rehydration|2
01828|075|R|  protects against intravascular volume contraction during colonic cleansing|2
01828|076|R|  with orally administered sodium phosphate. Gastrointest Endosc 2002 Nov;|2
01828|077|R|  56(5):633-8.|2
01828|078|R|5.Tjandra JJ, Tagkalidis P. Carbohydrate-electrolyte (E-Lyte) solution|2
01828|079|R|  enhances bowel preparation with oral fleet phospho-soda. Dis Colon Rectum|2
01828|080|R|  2004 Jul;47(7):1181-6.|2
01828|081|R|6.Brunelli SM, Lewis JD, Gupta M, Latif SM, Weiner MG, Feldman HI. Risk of|2
01828|082|R|  kidney injury following oral phosphosoda bowel preparations. J Am Soc|2
01828|083|R|  Nephrol 2007 Dec;18(12):3199-205.|2
01828|084|R|7.Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate|3
01828|085|R|  nephropathy following oral sodium phosphate bowel purgative: an|3
01828|086|R|  underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005 Nov;|3
01828|087|R|  16(11):3389-96.|3
01828|088|R|8.USFood and Drug Administration. FDA Drug Safety Communication:   FDA warns|1
01828|089|R|  of possible harm from exceeding recommended dose of over-the-counter|1
01828|090|R|  sodium phosphate products to treat constipation. available at:|1
01828|091|R|  http://www.fda.gov/Drugs/DrugSafety/ucm380757.htm January 8, 2014.|1
01829|001|T|MONOGRAPH TITLE:  Sodium Phosphate Bowel Cleanser/NSAIDs; Salicylates|
01829|002|B||
01829|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01829|004|L|of severe adverse interaction.|
01829|005|B||
01829|006|A|MECHANISM OF ACTION:  Bowel cleansing with sodium phosphate causes|
01829|007|A|dehydration, decreased intravascular volume and hyperphosphatemia, which|
01829|008|A|increases phosphate levels in the renal tubules.  Abnormally high levels of|
01829|009|A|calcium and phosphate in the renal tubules may precipitate out, resulting in|
01829|010|A|renal injury.(1)|
01829|011|B||
01829|012|E|CLINICAL EFFECTS:  Use of sodium phosphate for bowel cleansing in patients|
01829|013|E|maintained on nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the|
01829|014|E|risk of acute phosphate nephropathy, which is an acute kidney injury|
01829|015|E|associated with deposits of calcium phosphate crystal in the renal tubules|
01829|016|E|that may result in permanent renal function impairment.  Acute phosphate|
01829|017|E|nephropathy presents as acute kidney injury with minimal proteinuria and a|
01829|018|E|bland urine sediment.(2)|
01829|019|E|   Use of oral sodium phosphate products at laxative doses has not been|
01829|020|E|associated with acute kidney injury.(3)|
01829|021|B||
01829|022|P|PREDISPOSING FACTORS:  Patients who may be at an increased risk of acute|
01829|023|P|phosphate nephropathy include those who are over age 55; are hypovolemic or|
01829|024|P|have decreased intravascular volume; have baseline kidney disease, bowel|
01829|025|P|obstruction, or active colitis; and who are using medications that affect|
01829|026|P|renal perfusion or function (such as diuretics, ACE inhibitors, angiotension|
01829|027|P|receptor blockers [ARBs]), and NSAIDs.(2)|
01829|028|B||
01829|029|M|PATIENT MANAGEMENT:  If possible, use an alternative agent for bowel|
01829|030|M|cleansing.(1)|
01829|031|M|   Use sodium phosphate products with caution in patients taking medications|
01829|032|M|that affect kidney function or perfusion, such as ACE inhibitors or ARBs.|
01829|033|M|Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate,|
01829|034|M|BUN, creatinine, and [in smaller, frail individuals] glomerular filtration|
01829|035|M|rate).  Instruct patients to drink sufficient quantities of clear fluids|
01829|036|M|before, during, and after bowel cleansing and to avoid other laxatives that|
01829|037|M|contain sodium phosphate.  Consider hospitalization and intravenous|
01829|038|M|hydration during bowel cleansing to support frail patients who may be unable|
01829|039|M|to drink an appropriate volume of fluid or who may be without assistance at|
01829|040|M|home.(2)|
01829|041|M|   Use of an electrolyte solution for rehydration may decrease the risk of|
01829|042|M|acute phosphate nephropathy.(4,5)|
01829|043|B||
01829|044|D|DISCUSSION:  Since May 2006, the FDA has received 20 reports of acute|
01829|045|D|phosphate nephropathy associated with the use of Osmo Prep.  Concomitant|
01829|046|D|medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs|
01829|047|D|(4).(2)|
01829|048|D|   In a retrospective review of colonoscopy patients, simultaneous use of|
01829|049|D|ACE inhibitors or ARBs significantly increased the risk of acute kidney|
01829|050|D|injury from oral sodium phosphate.  Diuretic use was also a risk factor.(6)|
01829|051|D|   In a case series study of 21 cases of acute phosphate nephropathy in|
01829|052|D|patients who had used oral sodium phosphate, 14 patients received an ACE|
01829|053|D|inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7)|
01829|054|D|   Cases have also been reported with rectal products.(8)|
01829|055|B||
01829|056|R|REFERENCES:|
01829|057|B||
01829|058|R|1.Anonymous. Food and Drug Administration Science Background Paper: Acute|1
01829|059|R|  Phosphate Nephropathy and Renal Failure Associated With the Use of Oral|1
01829|060|R|  Sodium Phosphate Bowel Cleansing Products. Available at:|1
01829|061|R|  http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformat|1
01829|062|R|  ionforpatientsandproviders/ucm161579.pdf Downloaded December 15, 2008..|1
01829|063|R|2.Anonymous. Information for Healthcare Professionals:  Oral Sodium|1
01829|064|R|  Phosphate (OSP) Products for Bowel Cleansing (marketed as Visicol and|1
01829|065|R|  OsmoPrep, and oral sodium phosphate products available without a|1
01829|066|R|  prescription). Available at:|1
01829|067|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01829|068|R|  providers/information-oral-sodium-phosphate-osp-products-bowel-cleansing-m|1
01829|069|R|  arketed-visicol-and-osmoprep-and Accessed December 15, 2008..|1
01829|070|R|3.Anonymous. Oral Sodium Phosphate (OSP) Actions. Questions and Answers.|1
01829|071|R|  Available at:|1
01829|072|R|  http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPati|1
01829|073|R|  entsandProviders/ucm103383.htm Accessed December 15, 2008..|1
01829|074|R|4.Barclay RL, Depew WT, Vanner SJ. Carbohydrate-electrolyte rehydration|2
01829|075|R|  protects against intravascular volume contraction during colonic cleansing|2
01829|076|R|  with orally administered sodium phosphate. Gastrointest Endosc 2002 Nov;|2
01829|077|R|  56(5):633-8.|2
01829|078|R|5.Tjandra JJ, Tagkalidis P. Carbohydrate-electrolyte (E-Lyte) solution|2
01829|079|R|  enhances bowel preparation with oral fleet phospho-soda. Dis Colon Rectum|2
01829|080|R|  2004 Jul;47(7):1181-6.|2
01829|081|R|6.Brunelli SM, Lewis JD, Gupta M, Latif SM, Weiner MG, Feldman HI. Risk of|2
01829|082|R|  kidney injury following oral phosphosoda bowel preparations. J Am Soc|2
01829|083|R|  Nephrol 2007 Dec;18(12):3199-205.|2
01829|084|R|7.Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate|3
01829|085|R|  nephropathy following oral sodium phosphate bowel purgative: an|3
01829|086|R|  underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005 Nov;|3
01829|087|R|  16(11):3389-96.|3
01829|088|R|8.USFood and Drug Administration. FDA Drug Safety Communication:   FDA warns|1
01829|089|R|  of possible harm from exceeding recommended dose of over-the-counter|1
01829|090|R|  sodium phosphate products to treat constipation. available at:|1
01829|091|R|  http://www.fda.gov/Drugs/DrugSafety/ucm380757.htm January 8, 2014.|1
01830|001|T|MONOGRAPH TITLE:  Solid Oral Potassium Capsules/Anticholinergics|
01830|002|B||
01830|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01830|004|L|of severe adverse interaction.|
01830|005|B||
01830|006|A|MECHANISM OF ACTION:  Concentrated potassium may damage the lining of the GI|
01830|007|A|tract. Anticholinergics delay gastric emptying, resulting in the potassium|
01830|008|A|product remaining in the gastrointestinal tract for a longer period of|
01830|009|A|time.(1-16))|
01830|010|B||
01830|011|E|CLINICAL EFFECTS:  Use of solid oral dosage forms of potassium in patients|
01830|012|E|treated with anticholinergics may result in gastrointestinal erosions,|
01830|013|E|ulcers, stenosis and bleeding.(1-16)|
01830|014|B||
01830|015|P|PREDISPOSING FACTORS:  Diseases or conditions which may increase risk for GI|
01830|016|P|damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic|
01830|017|P|gastroparesis, elderly status, or insufficient oral intake to allow dilution|
01830|018|P|of potassium.(1-10,21)|
01830|019|P|   Other drugs which may add to risk for GI damage include: nonsteroidal|
01830|020|P|anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)|
01830|021|B||
01830|022|M|PATIENT MANAGEMENT:  Regulatory agency and manufacturer recommendations|
01830|023|M|regarding this interaction:|
01830|024|M|   - In the US, all solid oral dosage forms (including tablets and extended|
01830|025|M|release capsules) of potassium are contraindicated in patients receiving|
01830|026|M|anticholinergics at sufficient dosages to result in systemic effects.(2-8)|
01830|027|M|Patients receiving such anticholinergic therapy should use a liquid form of|
01830|028|M|potassium chloride.(2)|
01830|029|M|   - In Canada, solid oral potassium is contraindicated in any patient with|
01830|030|M|a  cause for arrest or delay in tablet/capsule passage through the|
01830|031|M|gastrointestinal tract and the manufacturers recommend caution with|
01830|032|M|concurrent anticholinergic medications.(1,9-10)|
01830|033|M|   Evaluate each patient for predisposing factors which may increase risk|
01830|034|M|for GI damage.  In patients with multiple risk factors for harm, consider|
01830|035|M|use of liquid potassium supplements, if tolerated.  For patients receiving|
01830|036|M|concomitant therapy, assure any potassium dose form is taken after meals|
01830|037|M|with a large glass of water or other fluid. To decrease potassium|
01830|038|M|concentration in the GI tract, limit each dose to 20 meq; if more than 20|
01830|039|M|meq daily is required, give in divided doses.(2)|
01830|040|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01830|041|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01830|042|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01830|043|M|patients with any symptoms.|
01830|044|M|   Patients should be instructed to immediately report any difficulty|
01830|045|M|swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal|
01830|046|M|bleeding.|
01830|047|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01830|048|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01830|049|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01830|050|M|and/or swelling.|
01830|051|B||
01830|052|D|DISCUSSION:  In clinical trials, there was a higher incidence of gastric and|
01830|053|D|duodenal lesions in patients receiving a high dose of a wax-matrix|
01830|054|D|controlled-release formulation with a concurrent anticholinergic agent.  The|
01830|055|D|lesions were asymptomatic and not accompanied by bleeding, as shown by a|
01830|056|D|lack of positive Hemoccult tests.(1-17)|
01830|057|D|   Several studies suggest that the incidence of gastric and duodenal|
01830|058|D|lesions may be less with the microencapsulated formulation of potassium|
01830|059|D|chloride.(14-17)|
01830|060|B||
01830|061|R|REFERENCES:|
01830|062|B||
01830|063|R|1.K-Dur (potassium chloride) Canadian prescribing information. Merck Canada|1
01830|064|R|  Inc. March, 2011.|1
01830|065|R|2.K-TAB (potassium chloride) tablet, film coated, extended release, US|1
01830|066|R|  Prescribing Information. Zydus Pharmaceuticals April, 2018.|1
01830|067|R|3.K-Dur (potassium chloride) US prescribing information. Key|1
01830|068|R|  Pharmaceuticals, Inc. April, 2004.|1
01830|069|R|4.Potassium chloride extended-release capsules US Prescribing information.|1
01830|070|R|  Ethex Corporation September, 2003.|1
01830|071|R|5.Klor-Con (potassium chloride) US prescribing information. Upsher-Smith|1
01830|072|R|  Laboratories April, 2018.|1
01830|073|R|6.Urocit-K (potassium citrate) US prescribing information. Mission Pharmacal|1
01830|074|R|  December, 2021.|1
01830|075|R|7.Slow-K (potassium chloride) US prescribing information. Novartis|1
01830|076|R|  Pharmaceuticals Corporation April, 2004.|1
01830|077|R|8.Micro-K (potassium chloride) US prescribing information. KV Pharmaceutical|1
01830|078|R|  October, 2000.|1
01830|079|R|9.Micro-K Extencaps (potassium chloride) Canadian prescribing information.|1
01830|080|R|  Wyeth Pharmaceuticals 2007.|1
01830|081|R|10.Slow-K (potassium chloride) Canadian prescribing information. Novartis|1
01830|082|R|   Pharmaceuticals Canada Inc. 2007.|1
01830|083|R|11.McMahon FG, Ryan JR, Akdamar K, Ertan A. Effect of potassium chloride|2
01830|084|R|   supplements on upper gastrointestinal mucosa. Clin Pharmacol Ther 1984|2
01830|085|R|   Jun;35(6):852-5.|2
01830|086|R|12.Kendall C, Krantz KD, Berger A, Sharp T. Endoscopic evaluation of|2
01830|087|R|   slow-release potassium chloride preparations. Clin Pharmacol Ther 1985|2
01830|088|R|   Jul;38(1):28-30.|2
01830|089|R|13.Gonzalez GB, Pak CY, Adams-Huet B, Taylor R, Bilhartz LE. Effect of|2
01830|090|R|   potassium-magnesium citrate on upper gastrointestinal mucosa. Aliment|2
01830|091|R|   Pharmacol Ther 1998 Jan;12(1):105-10.|2
01830|092|R|14.Sinar DR, Bozymski EM, Blackshear JL. Effects of oral potassium|2
01830|093|R|   supplements on upper gastrointestinal mucosa: multicenter clinical|2
01830|094|R|   comparison of three formulations and placebo. Clin Ther 1986;8(2):157-63.|2
01830|095|R|15.McMahon FG, Ryan JR, Akdamar K, Ertan A. Upper gastrointestinal lesions|2
01830|096|R|   after potassium chloride supplements: a controlled clinical trial. Lancet|2
01830|097|R|   1982 Nov 13;2(8307):1059-61.|2
01830|098|R|16.Barkin JS, Harary AM, Shamblen CE, Lasseter KC. Potassium chloride and|2
01830|099|R|   gastrointestinal injury. Ann Intern Med 1983 Feb;98(2):261-2.|2
01830|100|R|17.Strom BL, Carson JL, Schinnar R, Sim E, Maislin G, Soper K, Morse ML.|2
01830|101|R|   Upper gastrointestinal tract bleeding from oral potassium chloride.|2
01830|102|R|   Comparative risk from microencapsulated vs wax-matrix formulations. Arch|2
01830|103|R|   Intern Med 1987 May;147(5):954-7.|2
01830|104|R|18.Rosenthal T, Adar R, Militianu J, Deutsch V. Esophageal ulceration and|3
01830|105|R|   oral potassium chloride ingestion. Chest 1974 Apr;65(4):463-5.|3
01830|106|R|19.McLoughlin JC. Effects on upper gastrointestinal mucosa of three delivery|2
01830|107|R|   systems of potassium as supplement to frusemide administration. J R Soc|2
01830|108|R|   Med 1985 Jun;78(6):459-62.|2
01830|109|R|20.Farquharson-Roberts MA, Giddings AE, Nunn AJ. Perforation of small bowel|3
01830|110|R|   due to slow release potassium chloride (slow-K). Br Med J 1975 Jul 26;|3
01830|111|R|   3(5977):206.|3
01830|112|R|21.O'Neill JL, Remington TL. Drug-induced esophageal injuries and dysphagia.|6
01830|113|R|   Ann Pharmacother 2003 Nov;37(11):1675-84.|6
01831|001|T|MONOGRAPH TITLE:  Solid Oral Potassium Capsules/Inhaled Anticholinergics|
01831|002|B||
01831|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01831|004|L|take action as needed.|
01831|005|B||
01831|006|A|MECHANISM OF ACTION:  Concentrated potassium may damage the lining of the GI|
01831|007|A|tract.  Anticholinergics delay gastric emptying, resulting in the potassium|
01831|008|A|product remaining in the gastrointestinal tract for a longer period of|
01831|009|A|time.(1-16)|
01831|010|B||
01831|011|E|CLINICAL EFFECTS:  Use of solid oral dosage forms of potassium in patients|
01831|012|E|treated with inhaled anticholinergics could potentially result in|
01831|013|E|gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)|
01831|014|B||
01831|015|P|PREDISPOSING FACTORS:  Diseases or conditions which may increase risk for GI|
01831|016|P|damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic|
01831|017|P|gastroparesis, elderly status, or insufficient oral intake to allow dilution|
01831|018|P|of potassium.(1-10,21)|
01831|019|P|   Other drugs which may add to risk for GI damage include: nonsteroidal|
01831|020|P|anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)|
01831|021|B||
01831|022|M|PATIENT MANAGEMENT:  Regulatory agency and manufacturer recommendations|
01831|023|M|regarding this interaction:|
01831|024|M|   - In the US, all solid oral dosage forms (including tablets and extended|
01831|025|M|release capsules) of potassium are contraindicated in patients receiving|
01831|026|M|anticholinergics at sufficient dosages to result in systemic effects.(2-8)|
01831|027|M|Patients receiving such anticholinergic therapy should use a liquid form of|
01831|028|M|potassium chloride.(2)|
01831|029|M|   - In Canada, solid oral potassium is contraindicated in any patient with|
01831|030|M|a  cause for arrest or delay in tablet/capsule passage through the|
01831|031|M|gastrointestinal tract and the manufacturers recommend caution with|
01831|032|M|concurrent anticholinergic medications.(1,9-10)|
01831|033|M|   Evaluate each patient for predisposing factors which may increase risk|
01831|034|M|for GI damage.  In patients with multiple risk factors for harm, consider|
01831|035|M|use of liquid potassium supplements, if tolerated.  For patients receiving|
01831|036|M|concomitant therapy, assure any potassium dose form is taken after meals|
01831|037|M|with a large glass of water or other fluid. To decrease potassium|
01831|038|M|concentration in the GI tract, limit each dose to 20 meq; if more than 20|
01831|039|M|meq daily is required, give in divided doses.(2)|
01831|040|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01831|041|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01831|042|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01831|043|M|patients with any symptoms.|
01831|044|M|   Patients should be instructed to immediately report any difficulty|
01831|045|M|swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal|
01831|046|M|bleeding.|
01831|047|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01831|048|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01831|049|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01831|050|M|and/or swelling.|
01831|051|B||
01831|052|D|DISCUSSION:  In clinical trials, there was a higher incidence of gastric and|
01831|053|D|duodenal lesions in patients receiving a high dose of a wax-matrix|
01831|054|D|controlled-release formulation with a concurrent anticholinergic agent.|
01831|055|D|Some lesions were asymptomatic and not accompanied by bleeding, as shown by|
01831|056|D|a lack of positive Hemoccult tests.(1-17)|
01831|057|D|   Several studies suggest that the incidence of gastric and duodenal|
01831|058|D|lesions may be less with the microencapsulated formulation of potassium|
01831|059|D|chloride.(14-17)|
01831|060|D|   Constipation has been reported as a side effect of inhaled|
01831|061|D|anticholinergic agents such as ipratropium(22) and tiotropium.(23)|
01831|062|B||
01831|063|R|REFERENCES:|
01831|064|B||
01831|065|R|1.K-Dur (potassium chloride) Canadian prescribing information. Merck Canada|1
01831|066|R|  Inc. March, 2011.|1
01831|067|R|2.K-TAB (potassium chloride) tablet, film coated, extended release, US|1
01831|068|R|  Prescribing Information. Zydus Pharmaceuticals April, 2018.|1
01831|069|R|3.K-Dur (potassium chloride) US prescribing information. Key|1
01831|070|R|  Pharmaceuticals, Inc. April, 2004.|1
01831|071|R|4.Potassium chloride extended-release capsules US Prescribing information.|1
01831|072|R|  Ethex Corporation September, 2003.|1
01831|073|R|5.Klor-Con (potassium chloride) US prescribing information. Upsher-Smith|1
01831|074|R|  Laboratories April, 2018.|1
01831|075|R|6.Urocit-K (potassium citrate) US prescribing information. Mission Pharmacal|1
01831|076|R|  December, 2021.|1
01831|077|R|7.Slow-K (potassium chloride) US prescribing information. Novartis|1
01831|078|R|  Pharmaceuticals Corporation April, 2004.|1
01831|079|R|8.Micro-K (potassium chloride) US prescribing information. KV Pharmaceutical|1
01831|080|R|  October, 2000.|1
01831|081|R|9.Micro-K Extencaps (potassium chloride) Canadian prescribing information.|1
01831|082|R|  Wyeth Pharmaceuticals 2007.|1
01831|083|R|10.Slow-K (potassium chloride) Canadian prescribing information. Novartis|1
01831|084|R|   Pharmaceuticals Canada Inc. 2007.|1
01831|085|R|11.McMahon FG, Ryan JR, Akdamar K, Ertan A. Effect of potassium chloride|2
01831|086|R|   supplements on upper gastrointestinal mucosa. Clin Pharmacol Ther 1984|2
01831|087|R|   Jun;35(6):852-5.|2
01831|088|R|12.Kendall C, Krantz KD, Berger A, Sharp T. Endoscopic evaluation of|2
01831|089|R|   slow-release potassium chloride preparations. Clin Pharmacol Ther 1985|2
01831|090|R|   Jul;38(1):28-30.|2
01831|091|R|13.Gonzalez GB, Pak CY, Adams-Huet B, Taylor R, Bilhartz LE. Effect of|2
01831|092|R|   potassium-magnesium citrate on upper gastrointestinal mucosa. Aliment|2
01831|093|R|   Pharmacol Ther 1998 Jan;12(1):105-10.|2
01831|094|R|14.Sinar DR, Bozymski EM, Blackshear JL. Effects of oral potassium|2
01831|095|R|   supplements on upper gastrointestinal mucosa: multicenter clinical|2
01831|096|R|   comparison of three formulations and placebo. Clin Ther 1986;8(2):157-63.|2
01831|097|R|15.McMahon FG, Ryan JR, Akdamar K, Ertan A. Upper gastrointestinal lesions|2
01831|098|R|   after potassium chloride supplements: a controlled clinical trial. Lancet|2
01831|099|R|   1982 Nov 13;2(8307):1059-61.|2
01831|100|R|16.Barkin JS, Harary AM, Shamblen CE, Lasseter KC. Potassium chloride and|2
01831|101|R|   gastrointestinal injury. Ann Intern Med 1983 Feb;98(2):261-2.|2
01831|102|R|17.Strom BL, Carson JL, Schinnar R, Sim E, Maislin G, Soper K, Morse ML.|2
01831|103|R|   Upper gastrointestinal tract bleeding from oral potassium chloride.|2
01831|104|R|   Comparative risk from microencapsulated vs wax-matrix formulations. Arch|2
01831|105|R|   Intern Med 1987 May;147(5):954-7.|2
01831|106|R|18.Rosenthal T, Adar R, Militianu J, Deutsch V. Esophageal ulceration and|3
01831|107|R|   oral potassium chloride ingestion. Chest 1974 Apr;65(4):463-5.|3
01831|108|R|19.McLoughlin JC. Effects on upper gastrointestinal mucosa of three delivery|2
01831|109|R|   systems of potassium as supplement to frusemide administration. J R Soc|2
01831|110|R|   Med 1985 Jun;78(6):459-62.|2
01831|111|R|20.Farquharson-Roberts MA, Giddings AE, Nunn AJ. Perforation of small bowel|3
01831|112|R|   due to slow release potassium chloride (slow-K). Br Med J 1975 Jul 26;|3
01831|113|R|   3(5977):206.|3
01831|114|R|21.O'Neill JL, Remington TL. Drug-induced esophageal injuries and dysphagia.|6
01831|115|R|   Ann Pharmacother 2003 Nov;37(11):1675-84.|6
01831|116|R|22.Combivent (ipratropium bromide and albuterol sulfate) US prescribing|1
01831|117|R|   information. Boehringer Ingelheim April, 2011.|1
01831|118|R|23.Spiriva (tiotropium bromide) US prescribing information. Boehringer|1
01831|119|R|   Ingelheim February 1, 2018.|1
01832|001|T|MONOGRAPH TITLE:  Vinblastine; Vincristine/Ritonavir (mono deleted|
01832|002|T|07/30/2015)|
01832|003|B||
01832|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01832|005|L|take action as needed.|
01832|006|B||
01832|007|A|MECHANISM OF ACTION:  Ritonavir may inhibit the metabolism of vinblastine|
01832|008|A|and vincristine.(1,2)|
01832|009|B||
01832|010|E|CLINICAL EFFECTS:  Concurrent use of ritonavir-containing regimens may|
01832|011|E|result in elevated levels of and toxicity, including hematologic or|
01832|012|E|gastrointestinal), from vinblastine and vincristine.(1,2)|
01832|013|B||
01832|014|P|PREDISPOSING FACTORS:  None determined.|
01832|015|B||
01832|016|M|PATIENT MANAGEMENT:  Monitor patients receiving ritonavir-containing|
01832|017|M|regimens closely during vinblastine or vincristine therapy.|
01832|018|M|   The US manufacturer of lopinavir-ritonavir(2) and ritonavir(1) state that|
01832|019|M|consideration should be given to temporarily withholding|
01832|020|M|ritonavir-containing antiretroviral regimen in patients receiving|
01832|021|M|vinblastine or vincristine who develop significant hematologic and/or|
01832|022|M|gastrointestinal side effects.  If the antiretroviral regimen must be|
01832|023|M|withheld for a prolonged period, consider initiating a revised|
01832|024|M|antiretroviral regimen that does not include a CYP P-45-3A or p-glycoprotein|
01832|025|M|inhibitor.(1,2)|
01832|026|B||
01832|027|D|DISCUSSION:  There have been 2 case reports of vinblastine hematologic|
01832|028|D|toxicity during concurrent lopinavir-ritonavir therapy.  In both cases,|
01832|029|D|vinblastine was administered without toxicity when lopinavir-ritonavir|
01832|030|D|therapy was suspended.(3,4)|
01832|031|B||
01832|032|R|REFERENCES:|
01832|033|B||
01832|034|R|1.Norvir (ritonavir) US prescribing information. Abbott Laboratories March,|1
01832|035|R|  2015.|1
01832|036|R|2.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01832|037|R|  Laboratories December, 2019.|1
01832|038|R|3.Makinson A, Martelli N, Peyriere H, Turriere C, Le Moing V, Reynes J.|3
01832|039|R|  Profound neutropenia resulting from interaction between antiretroviral|3
01832|040|R|  therapy and vinblastine in a patient with HIV-associated Hodgkin's|3
01832|041|R|  disease. Eur J Haematol 2007 Apr;78(4):358-60.|3
01832|042|R|4.Kotb R, Vincent I, Dulioust A, Peretti D, Taburet AM, Delfraissy JF,|3
01832|043|R|  Goujard C. Life-threatening interaction between antiretroviral therapy and|3
01832|044|R|  vinblastine in HIV-associated multicentric Castleman's disease. Eur J|3
01832|045|R|  Haematol 2006 Mar;76(3):269-71.|3
01833|001|T|MONOGRAPH TITLE:  Barbiturates; Phenobarbital; Phenytoin/Selected Protease|
01833|002|T|Inhibitors|
01833|003|B||
01833|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01833|005|L|of severe adverse interaction.|
01833|006|B||
01833|007|A|MECHANISM OF ACTION:  The anticonvulsants and protease inhibitors may induce|
01833|008|A|the metabolism of each other.(1-3)|
01833|009|A|   Primidone is metabolized to phenobarbital.|
01833|010|B||
01833|011|E|CLINICAL EFFECTS:  Concurrent use of barbiturates, phenobarbital, phenytoin|
01833|012|E|or primidone with fosamprenavir, indinavir, lopinavir, nelfinavir,|
01833|013|E|saquinavir or tipranavir may result in decreased levels and effectiveness of|
01833|014|E|both agents.(1-6)|
01833|015|B||
01833|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01833|017|P|of the inducer for longer than 1-2 weeks.|
01833|018|B||
01833|019|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy closely.|
01833|020|M|The dosage of both agents may need to be adjusted.(1-6)|
01833|021|M|   US labeling states that use of fosamprenavir, indinavir, saquinavir or|
01833|022|M|tipranavir in patients receiving concurrent phenobarbital or phenytoin|
01833|023|M|should done used with caution.(1-2,4-5)|
01833|024|M|   The US manufacturer of lopinavir/ritonavir states that|
01833|025|M|lopinavir/ritonavir should not be administered once daily in patients|
01833|026|M|receiving concurrent phenobarbital or phenytoin.(3)|
01833|027|B||
01833|028|D|DISCUSSION:  In an open-label, randomized clinical trial in 24 subjects, the|
01833|029|D|addition of phenytoin (300 mg daily) to lopinavir/ritonavir (400/100 mg|
01833|030|D|twice daily) decreased lopinavir area-under-curve (AUC) by 30%. The addition|
01833|031|D|of lopinavir/ritonavir (400/100 mg twice daily) to phenytoin (300 mg daily)|
01833|032|D|decreased phenytoin AUC by 23%.(6)|
01833|033|B||
01833|034|R|REFERENCES:|
01833|035|B||
01833|036|R|1.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01833|037|R|  March, 2019.|1
01833|038|R|2.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01833|039|R|  September, 2016.|1
01833|040|R|3.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01833|041|R|  Laboratories December, 2019.|1
01833|042|R|4.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01833|043|R|  Pharmaceuticals, Inc. September, 2016.|1
01833|044|R|5.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01833|045|R|  Pharmaceuticals, Inc. April, 2024.|1
01833|046|R|6.Lim ML, Min SS, Eron JJ, Bertz RJ, Robinson M, Gaedigk A, Kashuba AD.|2
01833|047|R|  Coadministration of lopinavir/ritonavir and phenytoin results in two-way|2
01833|048|R|  drug interaction through cytochrome P-450 induction. J Acquir Immune Defic|2
01833|049|R|  Syndr 2004 Aug 15;36(5):1034-40.|2
01834|001|T|MONOGRAPH TITLE:  Ethambutol/Aluminum hydroxide|
01834|002|B||
01834|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01834|004|L|take action as needed.|
01834|005|B||
01834|006|A|MECHANISM OF ACTION:  Aluminum hydroxide may bind to ethambutol in the|
01834|007|A|gastrointestinal tract, preventing its absorption.|
01834|008|B||
01834|009|E|CLINICAL EFFECTS:  Simultaneous administration of an aluminum|
01834|010|E|hydroxide-containing antacid may decrease levels and effectiveness of|
01834|011|E|ethambutol.(1)|
01834|012|B||
01834|013|P|PREDISPOSING FACTORS:  None determined.|
01834|014|B||
01834|015|M|PATIENT MANAGEMENT:  The US manufacturer of ethambutol recommends that the|
01834|016|M|administration times of ethambutol and aluminum hydroxide-containing|
01834|017|M|antacids be separated by 4 hours.(1)|
01834|018|B||
01834|019|D|DISCUSSION:  In a study in 13 tuberculosis patients, simultaneous|
01834|020|D|administration of ethambutol with aluminum hydroxide decreased the|
01834|021|D|area-under-curve (AUC) and urinary excretion of ethambutol by 20% and 13%,|
01834|022|D|respectively.(1,2)|
01834|023|D|   In a study in 14 healthy subjects, simultaneous administration of|
01834|024|D|ethambutol with an aluminum-magnesium antacid, ethambutol AUC and maximum|
01834|025|D|concentration (Cmax) decreased by 10% and 29%, respectively.(3)|
01834|026|B||
01834|027|R|REFERENCES:|
01834|028|B||
01834|029|R|1.Myambutol (ethambutol hcl) US prescribing information. X-GEN|1
01834|030|R|  Pharmaceuticals, Inc. October, 2008.|1
01834|031|R|2.Mattila MJ, Linnoila M, Seppala T, Koskinen R. Effect of aluminium|2
01834|032|R|  hydroxide and glycopyrrhonium on the absorption of ethambutol and alcohol|2
01834|033|R|  in man. Br J Clin Pharmacol 1978 Feb;5(2):161-6.|2
01834|034|R|3.Peloquin CA, Bulpitt AE, Jaresko GS, Jelliffe RW, Childs JM, Nix DE.|2
01834|035|R|  Pharmacokinetics of ethambutol under fasting conditions, with food, and|2
01834|036|R|  with antacids. Antimicrob Agents Chemother 1999 Mar;43(3):568-72.|2
01835|001|T|MONOGRAPH TITLE:  Clopidogrel/Esomeprazole; Omeprazole; Cimetidine|
01835|002|B||
01835|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01835|004|L|of severe adverse interaction.|
01835|005|B||
01835|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
01835|007|A|active metabolite via a 2 step process.  The first conversion step is|
01835|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
01835|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
01835|010|A|thought to be the more important enzyme involved in formation of the|
01835|011|A|pharmacologically active metabolite.(1)|
01835|012|A|   Proton pump inhibitors (PPIs) may inhibit CYP2C19 mediated conversion to|
01835|013|A|the active metabolite of clopidogrel. The magnitude and clinical|
01835|014|A|significance of CYP2C19 inhibition is highly variable between agents.(1)|
01835|015|B||
01835|016|E|CLINICAL EFFECTS:  Concurrent use of esomeprazole, omeprazole, or cimetidine|
01835|017|E|may result in decreased clopidogrel effectiveness, resulting in increased|
01835|018|E|risk of adverse cardiac events.|
01835|019|B||
01835|020|P|PREDISPOSING FACTORS:  None determined.|
01835|021|B||
01835|022|M|PATIENT MANAGEMENT:  Evaluate patient risk for gastrointestinal(GI)|
01835|023|M|bleeding.  When PPIs are needed, use dexlansoprazole, lansoprazole,|
01835|024|M|pantoprazole or rabeprazole as they have a lower interaction risk.(1,3)|
01835|025|M|Consider the use of H2 blockers (such as famotidine, nizatidine, or|
01835|026|M|ranitidine) in patients with a low bleeding risk and reserve the use of PPIs|
01835|027|M|for patients at higher risk of GI bleeding.|
01835|028|M|   US manufacturers for clopidogrel and omeprazole state concurrent use of|
01835|029|M|clopidogrel esomeprazole and omeprazole should be avoided.(1,4-5)  As|
01835|030|M|esomeprazole and omeprazole are irreversible inhibitors of CYP2C19,|
01835|031|M|separating clopidogrel from esomeprazole or omeprazole administration times|
01835|032|M|does not change the magnitude of this interaction.(1,4,6)|
01835|033|M|   The US manufacturer of clopidogrel states that alternatives to|
01835|034|M|clopidogrel should be considered in patients who are poor metabolizers of|
01835|035|M|CYP2C19.(1)  It would be prudent to assume that patients taking strong|
01835|036|M|inhibitors of CYP2C19 are poor metabolizers of this isoenzyme.  Moderate|
01835|037|M|CYP2C19 inhibitors, such as omeprazole, and weak CYP2C19 inhibitors, such as|
01835|038|M|cimetidine, may also affect this interaction.|
01835|039|M|   Consider alternatives to esomeprazole, omeprazole, and cimetidine in|
01835|040|M|patients stabilized on clopidogrel and alternatives to clopidogrel in|
01835|041|M|patients stabilized on esomeprazole, omeprazole, and cimetidine.  If|
01835|042|M|concurrent therapy is warranted, consider appropriate testing to assure|
01835|043|M|adequate inhibition of platelet reactivity.|
01835|044|B||
01835|045|D|DISCUSSION:  US manufacturer for clopidogrel states omeprazole and|
01835|046|D|esomeprazole have been shown to reduce antiplatelet activity of clopidogrel|
01835|047|D|and recommends against concomitant use.  The antiplatelet effect of|
01835|048|D|clopidogrel is reduced by approximately 40% in patients receiving 80 mg per|
01835|049|D|day of omeprazole.  Dexlansoprazole, lansoprazole and pantoprazole are|
01835|050|D|described as having less effect on clopidogrel antiplatelet activity.(1,3)|
01835|051|D|   In the primary literature, documentation for this interaction is|
01835|052|D|conflicting.  However, both in-vitro and retrospective analyses indicate|
01835|053|D|that omeprazole decreases the effectiveness of clopidogrel.  Although the|
01835|054|D|half-lives of esomeprazole and omeprazole (a racemic mixture of R- and|
01835|055|D|esomeprazole) are short, the effect on CYP2C19 is long lasting because|
01835|056|D|esomeprazole is an irreversible inhibitor of CYP2C19.(6)|
01835|057|D|   In two studies in healthy subjects, concurrent omeprazole decreased the|
01835|058|D|effects of clopidogrel on platelets.(7-8)|
01835|059|D|   Several studies have found coadministration of clopidogrel with|
01835|060|D|omeprazole resulted in increased platelet aggregation compared to|
01835|061|D|clopidogrel with pantoprazole, or no PPI.(9-12)|
01835|062|D|   In a study, use of omeprazole was associated with a decreased risk of|
01835|063|D|upper gastrointestinal bleeding in patients receiving dual antiplatelet|
01835|064|D|therapy with clopidogrel and aspirin.  There was no significant difference|
01835|065|D|between the groups in rate of cardiovascular events.(12)|
01835|066|D|   Three studies found that simultaneous omeprazole with clopidogrel reduced|
01835|067|D|clopidogrel concentrations and effects.(13-15)|
01835|068|D|   In a cross-over trial, healthy subjects received clopidogrel (300 mg|
01835|069|D|loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg oral once|
01835|070|D|daily) co-administered for 30 days.  Exposure to the active metabolite of|
01835|071|D|clopidogrel was reduced by 35% to 40% over this time period.(16)|
01835|072|D|    In a study in 39 healthy subjects, the effects of omeprazole and|
01835|073|D|rabeprazole on clopidogrel in patients with different CYP2C19 genotypes was|
01835|074|D|examined.  In rapid 2C19 metabolizers, simultaneous omeprazole and|
01835|075|D|rabeprazole significantly decreased clopidogrel response.  In decreased 2C19|
01835|076|D|responders, there was wide variation in clopidogrel response and|
01835|077|D|simultaneous omeprazole and rabeprazole had no significant effect on overall|
01835|078|D|clopidogrel effects; however, some subjects became low responders to|
01835|079|D|clopidogrel while on PPI therapy.  Staggered dosing of omeprazole had no|
01835|080|D|effect on clopidogrel response in rapid metabolizers, but decreased|
01835|081|D|clopidogrel response in decreased metabolizers.(17)|
01835|082|D|    Several retrospective studies found that patients who took clopidogrel|
01835|083|D|with a PPI had increased incidence of major cardiovascular events compared|
01835|084|D|to patients who took clopidogrel without a PPI.(18-22)|
01835|085|D|   A retrospective cohort study of 20,596 patients in the Tennessee Medicaid|
01835|086|D|program, evaluated both cardiovascular disease event and GI bleed risk in|
01835|087|D|patients prescribed clopidogrel with or without concurrent PPI use.|
01835|088|D|Pantoprazole was prescribed in 62% of PPI patients.  Concomitant PPI and|
01835|089|D|clopidogrel use decreased the risk of hospitalization from GI bleeding by|
01835|090|D|50%. There was no clear-cut increase risk for serious cardiovascular disease|
01835|091|D|events; however, the 95% CI for this was wide.(23)|
01835|092|D|   A post-hoc analysis of the PRINCIPLE-TIMI 44 trial and the TRITON-TIMI|
01835|093|D|trial examined the effects of PPI use on the pharmacodynamic effects and|
01835|094|D|clinical efficacy of clopidogrel.  The PRINCIPLE-TIMI 44 trial examined 201|
01835|095|D|patients undergoing cardiac catheterization with planned percutaneous|
01835|096|D|coronary intervention, 53 of which were taking a PPI at randomization.|
01835|097|D|Patients receiving a PPI had significantly lower rates of inhibition of|
01835|098|D|platelet aggregation at 0.5 hours, 2 hours, 6 hours, and 18-24 hours|
01835|099|D|post-loading dose of clopidogrel.  After 15 days of maintenance therapy,|
01835|100|D|there were significantly more non-responders in the group receiving PPI (50%|
01835|101|D|versus 7.9%).  The TRITON-TIMI trial examined 13,608 patients who underwent|
01835|102|D|cardiac catheterization with planned percutaneous coronary intervention,|
01835|103|D|4529 of which were taking a PPI at randomization.  Patients received|
01835|104|D|clopidogrel treatment for 6-15 months.  There were no significant|
01835|105|D|differences in occurrence of cardiovascular death, non-fatal MI, or|
01835|106|D|non-fatal stroke between patients taking PPIs at randomization and those|
01835|107|D|not; however, use of PPIs was only assessed at randomization and not during|
01835|108|D|the study.(24)|
01835|109|B||
01835|110|R|REFERENCES:|
01835|111|B||
01835|112|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01835|113|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01835|114|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
01835|115|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
01835|116|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
01835|117|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
01835|118|R|  38(1):92-9.|5
01835|119|R|3.Aciphex (rabeprazole) prescribing information. Eisai Inc. June, 2018.|1
01835|120|R|4.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
01835|121|R|  Pharmaceuticals LP June, 2018.|1
01835|122|R|5.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
01835|123|R|  Pharmaceuticals LP August, 2021.|1
01835|124|R|6.Ogilvie BW, Yerino P, Kazmi F, Buckley DB, Rostami-Hodjegan A, Paris BL,|5
01835|125|R|  Toren P, Parkinson A. The proton pump inhibitor, omeprazole, but not|5
01835|126|R|  lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of|5
01835|127|R|  CYP2C19: implications for coadministration with clopidogrel. Drug Metab|5
01835|128|R|  Dispos 2011 Nov;39(11):2020-33.|5
01835|129|R|7.Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati|2
01835|130|R|  J, Mottier D, Abgrall JF, Boschat J. Influence of omeprazole on the|2
01835|131|R|  antiplatelet action of clopidogrel associated with aspirin: the|2
01835|132|R|  randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am|2
01835|133|R|  Coll Cardiol 2008 Jan 22;51(3):256-60.|2
01835|134|R|8.Yun KH, Rhee SJ, Park HY, Yoo NJ, Kim NH, Oh SK, Jeong JW. Effects of|2
01835|135|R|  omeprazole on the antiplatelet activity of clopidogrel. Int Heart J 2010|2
01835|136|R|  Jan;51(1):13-6.|2
01835|137|R|9.Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, Schomig A,|2
01835|138|R|  Kastrati A, von Beckerath N. Impact of proton pump inhibitors on the|2
01835|139|R|  antiplatelet effects of clopidogrel. Thromb Haemost 2009 Apr;101(4):714-9.|2
01835|140|R|10.Cuisset T, Frere C, Quilici J, Poyet R, Gaborit B, Bali L, Brissy O,|2
01835|141|R|   Morange PE, Alessi MC, Bonnet JL. Comparison of omeprazole and|2
01835|142|R|   pantoprazole influence on a high 150-mg clopidogrel maintenance dose the|2
01835|143|R|   PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective|2
01835|144|R|   randomized study. J Am Coll Cardiol 2009 Sep 22;54(13):1149-53.|2
01835|145|R|11.Zuern CS, Geisler T, Lutilsky N, Winter S, Schwab M, Gawaz M. Effect of|2
01835|146|R|   comedication with proton pump inhibitors (PPIs) on post-interventional|2
01835|147|R|   residual platelet aggregation in patients undergoing coronary stenting|2
01835|148|R|   treated by dual antiplatelet therapy. Thromb Res 2010 Feb;125(2):e51-4.|2
01835|149|R|12.Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL,|2
01835|150|R|   Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP.|2
01835|151|R|   Clopidogrel with or without Omeprazole in Coronary Artery Disease. N Engl|2
01835|152|R|   J Med 2010 Oct 6.|2
01835|153|R|13.Siriswangvat S, Sansanayudh N, Nathisuwan S, Panomvana D. Comparison|2
01835|154|R|   between the effect of omeprazole and rabeprazole on the antiplatelet|2
01835|155|R|   action of clopidogrel. Circ J 2010 Oct;74(10):2187-92.|2
01835|156|R|14.Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L,|2
01835|157|R|   Perrin L, Lacreta FP, Hurbin F, Dubar M. Differential Effects of|2
01835|158|R|   Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics|2
01835|159|R|   of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled,|2
01835|160|R|   Crossover Comparison Studies. Clin Pharmacol Ther 2010 Sep.|2
01835|161|R|15.Ferreiro JL, Ueno M, Capodanno D, Desai B, Dharmashankar K, Darlington A,|2
01835|162|R|   Charlton RK, Bass TA, Angiolillo DJ. Pharmacodynamic effects of|2
01835|163|R|   concomitant versus staggered clopidogrel and omeprazole intake: results|2
01835|164|R|   of a prospective randomized crossover study. Circ Cardiovasc Interv 2010|2
01835|165|R|   Oct 1;3(5):436-41.|2
01835|166|R|16.Vimovo (naproxen and esomeprazole magnesium) US prescribing information.|1
01835|167|R|   Horizon Therapeutics USA, Inc. November 2024.|1
01835|168|R|17.Furuta T, Iwaki T, Umemura K. Influences of different proton pump|2
01835|169|R|   inhibitors on the anti-platelet function of clopidogrel in relation to|2
01835|170|R|   CYP2C19 genotypes. Br J Clin Pharmacol 2010 Sep;70(3):383-92.|2
01835|171|R|18.Kreutz RP, Stanek EJ, Aubert R, Yao J, Breall JA, Desta Z, Skaar TC,|2
01835|172|R|   Teagarden JR, Frueh FW, Epstein RS, Flockhart DA. Impact of proton pump|2
01835|173|R|   inhibitors on the effectiveness of clopidogrel after coronary stent|2
01835|174|R|   placement: the clopidogrel medco outcomes study. Pharmacotherapy 2010|2
01835|175|R|   Aug;30(8):787-96.|2
01835|176|R|19.Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp|2
01835|177|R|   A, Mamdani MM. A population-based study of the drug interaction between|2
01835|178|R|   proton pump inhibitors and clopidogrel.  Available at:|2
01835|179|R|   http://www.cmaj.ca/cgi/rapidpdf/cmaj.082001. CMAJ March 31, 2009;|2
01835|180|R|   180(7):online 1-7.|2
01835|181|R|20.Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS.|2
01835|182|R|   Risk of adverse outcomes associated with concomitant use of clopidogrel|2
01835|183|R|   and proton pump inhibitors following acute coronary syndrome. JAMA 2009|2
01835|184|R|   Mar 4;301(9):937-44.|2
01835|185|R|21.Stockl KM, Le L, Zakharyan A, Harada AS, Solow BK, Addiego JE, Ramsey S.|2
01835|186|R|   Risk of rehospitalization for patients using clopidogrel with a proton|2
01835|187|R|   pump inhibitor. Arch Intern Med 2010 Apr 26;170(8):704-10.|2
01835|188|R|22.Gaglia MA Jr, Torguson R, Hanna N, Gonzalez MA, Collins SD, Syed AI,|2
01835|189|R|   Ben-Dor I, Maluenda G, Delhaye C, Wakabayashi K, Xue Z, Suddath WO, Kent|2
01835|190|R|   KM, Satler LF, Pichard AD, Waksman R. Relation of proton pump inhibitor|2
01835|191|R|   use after percutaneous coronary intervention with drug-eluting stents to|2
01835|192|R|   outcomes. Am J Cardiol 2010 Mar 15;105(6):833-8.|2
01835|193|R|23.Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Daugherty|2
01835|194|R|   JR, Kaltenbach LA, Stein CM. Outcomes with concurrent use of clopidogrel|2
01835|195|R|   and proton-pump inhibitors: a cohort study. Ann Intern Med 2010 Mar 16;|2
01835|196|R|   152(6):337-45.|2
01835|197|R|24.O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y,|2
01835|198|R|   Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL,|2
01835|199|R|   Sabatine MS, Wiviott SD. Pharmacodynamic effect and clinical efficacy of|2
01835|200|R|   clopidogrel and prasugrel with or without a proton-pump inhibitor: an|2
01835|201|R|   analysis of two randomised trials. Lancet 2009 Sep 19;374(9694):989-97.|2
01835|202|R|25.Zairis MN, Tsiaousis GZ, Patsourakos NG, Georgilas AT, Kontos CF,|2
01835|203|R|   Adamopoulou EN, Vogiatzidis K, Argyrakis SK, Fakiolas CN, Foussas SG. The|2
01835|204|R|   impact of treatment with omeprazole on the effectiveness of clopidogrel|2
01835|205|R|   drug therapy during the first year after successful coronary stenting.|2
01835|206|R|   Can J Cardiol 2010 Feb;26(2):e54-7.|2
01835|207|R|26.Aubert RE, Epstein RS, Teagarden JR, Xia F, Yao J, Desta Z, Skaar T,|2
01835|208|R|   Flockhart DA. Abstract 3998:  Proton pump inhibitiors effect on|2
01835|209|R|   clopidogrel effectiveness:  the clopidogrel Medco outcomes study.|2
01835|210|R|   Circulation 2008;118:S815.|2
01835|211|R|27.Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B.|2
01835|212|R|   Effects of pantoprazole and esomeprazole on platelet inhibition by|2
01835|213|R|   clopidogrel. Am Heart J 2009 Jan;157(1):148.e1-5.|2
01835|214|R|28.US Food and Drug Association. Information on Clopidogrel Bisulfate|1
01835|215|R|   (marketed as Plavix). Available at:|1
01835|216|R|   http://wayback.archive-it.org/7993/20170111075953/http:/www.fda.gov/Drugs|1
01835|217|R|   /DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm190|1
01835|218|R|   836.htm October 27, 2010.|1
01836|001|T|MONOGRAPH TITLE:  Voriconazole/Efavirenz-Emtricitabine-Tenofovir|
01836|002|B||
01836|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01836|004|L|is contraindicated and generally should not be dispensed or administered to|
01836|005|L|the same patient.|
01836|006|B||
01836|007|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of voriconazole by|
01836|008|A|CYP3A4.  Voriconazole may inhibit the metabolism of efavirenz by|
01836|009|A|CYP3A4.(1,2)|
01836|010|B||
01836|011|E|CLINICAL EFFECTS:  Concurrent use of efavirenz and voriconazole may result|
01836|012|E|in decreased levels of voriconazole, therapeutic failure of voriconazole,|
01836|013|E|elevated levels of efavirenz, and efavirenz toxicity.(1,2)|
01836|014|B||
01836|015|P|PREDISPOSING FACTORS:  None determined.|
01836|016|B||
01836|017|M|PATIENT MANAGEMENT:  When coadministered, the dose of voriconazole should be|
01836|018|M|increased to 400 mg every 12 hours and the dose of efavirenz should be|
01836|019|M|decreased to 300 mg daily(1,2) using the capsule formulation(1) because|
01836|020|M|efavirenz tablets should not be broken.(1)|
01836|021|M|   Therefore, the UK and US manufacturers of the combination product|
01836|022|M|containing efavirenz/emtricitabine/tenofovir state that this product should|
01836|023|M|not be used with voriconazole because it is a fixed dose of efavirenz that|
01836|024|M|cannot be adjusted.(3,4)|
01836|025|B||
01836|026|D|DISCUSSION:  In a study in healthy subjects, efavirenz (400 mg daily)|
01836|027|D|decreased voriconazole (400 mg twice daily for 1 day, then 200 mg twice|
01836|028|D|daily) maximum concentration (Cmax) and area-under-curve (AUC) by 61% and by|
01836|029|D|77%, respectively.  Efavirenz Cmax and AUC increased by 38% and by 44%,|
01836|030|D|respectively.(1,2)|
01836|031|D|   In a study in healthy males, concurrent administration of voriconazole|
01836|032|D|(300 mg twice daily) with efavirenz (300 mg daily) decreased voriconazole|
01836|033|D|AUC and Cmax by 55% and 36%, when compared to levels achieved with|
01836|034|D|voriconazole 200 mg twice daily.  When compared to levels achieved with|
01836|035|D|efavirenz 600 mg daily, efavirenz AUC was equivalent and Cmax decreased by|
01836|036|D|14%.(1,2)|
01836|037|D|   In a study in healthy males, concurrent administration of voriconazole|
01836|038|D|(400 mg twice daily) with efavirenz (300 mg daily) decreased voriconazole|
01836|039|D|AUC by 7% and increased voriconazole Cmax by 23%, when compared to levels|
01836|040|D|achieved with voriconazole 200 mg twice daily.  When compared to levels|
01836|041|D|achieved with efavirenz 600 mg daily, efavirenz Cmax was equivalent and AUC|
01836|042|D|increased by 17%.(1,2)|
01836|043|B||
01836|044|R|REFERENCES:|
01836|045|B||
01836|046|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01836|047|R|  Company November, 2023.|1
01836|048|R|2.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01836|049|R|3.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) UK summary|1
01836|050|R|  of product characteristics. Gilead  Sciences Ltd July 8, 2020.|1
01836|051|R|4.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01836|052|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01837|001|T|MONOGRAPH TITLE:  Azathioprine; Mercaptopurine/Febuxostat|
01837|002|B||
01837|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01837|004|L|is contraindicated and generally should not be dispensed or administered to|
01837|005|L|the same patient.|
01837|006|B||
01837|007|A|MECHANISM OF ACTION:  Febuxostat may inhibit the metabolism of azathioprine|
01837|008|A|and mercaptopurine by xanthine oxidase.(1)|
01837|009|B||
01837|010|E|CLINICAL EFFECTS:  Concurrent use of febuxostat may result in elevated|
01837|011|E|levels of and toxicity from azathioprine and mercaptopurine.(1)|
01837|012|B||
01837|013|P|PREDISPOSING FACTORS:  Higher doses of the thiopurine would increase the|
01837|014|P|risk for severe toxicity.|
01837|015|P|   Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or|
01837|016|P|nucleotide diphosphatase (NUDT15) activity are at higher risk of|
01837|017|P|accumulating thiopurine metabolites and severe myelosuppression, since two|
01837|018|P|thiopurine metabolism pathways would be blocked.  Approximately 0.3 % of|
01837|019|P|patients of European, Latino, or African descent have mutations of the TPMT|
01837|020|P|gene resulting in little to no TPMT activity (homozygous deficiency), and|
01837|021|P|approximately 10 % have intermediate TPMT activity (heterozygous|
01837|022|P|deficiency).  NUDT15 deficiency is not seen in patients of African descent|
01837|023|P|and is seen in less than 1 % of patients of European descent.  Approximately|
01837|024|P|1 % of patients of East Asian descent, 0.5 % of patients of central/south|
01837|025|P|Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15|
01837|026|P|deficiency.  About 17 % of patients of East Asian descent, 13 % of patients|
01837|027|P|of central/south Asian descent, and 8 % of patients of Latino descent have|
01837|028|P|heterozygous NUDT15 deficiency.(2)|
01837|029|B||
01837|030|M|PATIENT MANAGEMENT:  The US manufacturer of febuxostat states that the|
01837|031|M|concurrent use of azathioprine or mercaptopurine is contraindicated.(1)|
01837|032|B||
01837|033|D|DISCUSSION:  Azathioprine and mercaptopurine are metabolized by xanthine|
01837|034|D|oxidase.  Although no formal interaction studies with febuxostat have been|
01837|035|D|performed, allopurinol, another xanthine oxidase inhibitor, has been shown|
01837|036|D|to increase azathioprine and mercaptopurine levels.  Febuxostat is expected|
01837|037|D|to also increase levels of these agents, which could result in severe|
01837|038|D|toxicity.(1)|
01837|039|D|   A review found 19 case reports of myelosuppressive adverse events with|
01837|040|D|the combination of febuxostat and thiopurines including anemia, leukopenia,|
01837|041|D|pancytopenia, and decreased red blood cells.  Sixteen of the 19 cases|
01837|042|D|resulted in hospitalization, and 17 of the 19 cases required one or more|
01837|043|D|additional treatments including blood products, granulocyte or|
01837|044|D|erythropoietin stimulating agents, antimicrobials, and immune globulin.(3)|
01837|045|D|   One or more of the drug pairs linked to this monograph have been included|
01837|046|D|in a list of interactions that should be considered "high-priority" for|
01837|047|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01837|048|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01837|049|D|Coordinator (ONC) for Health Information Technology.|
01837|050|B||
01837|051|R|REFERENCES:|
01837|052|B||
01837|053|R|1.Uloric (febuxostat) US prescribing information. Takeda Pharmaceuticals|1
01837|054|R|  America, Inc. April, 2023.|1
01837|055|R|2.Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM,|6
01837|056|R|  Moyer AM, Evans WE, Klein TE, Antillon-Klussmann FG, Caudle KE, Kato M,|6
01837|057|R|  Yeoh AEJ, Schmiegelow K, Yang JJ. Clinical Pharmacogenetics Implementation|6
01837|058|R|  Consortium Guideline for Thiopurine Dosing  Based on TPMT and NUDT15|6
01837|059|R|  Genotypes: 2018 Update. Clin Pharmacol Ther 2019 May;105(5):1095-1105.|6
01837|060|R|3.Logan JK, Wickramaratne Senarath Yapa S, Harinstein L, Saluja B, Munoz M,|6
01837|061|R|  Sahajwalla C, Neuner R, Seymour S. Drug Interaction Between Febuxostat and|6
01837|062|R|  Thiopurine Antimetabolites: A Review of the FDA Adverse Event Reporting|6
01837|063|R|  System and Medical Literature. Pharmacotherapy 2020 Feb;40(2):125-132.|6
01837|064|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01837|065|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01837|066|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01837|067|R|  19(5):735-43.|6
01838|001|T|MONOGRAPH TITLE:  Theophylline/Febuxostat|
01838|002|B||
01838|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01838|004|L|take action as needed.|
01838|005|B||
01838|006|A|MECHANISM OF ACTION:  Febuxostat may inhibit the metabolism of theophylline|
01838|007|A|by xanthine oxidase.(1)|
01838|008|B||
01838|009|E|CLINICAL EFFECTS:  Concurrent use of febuxostat may result in elevated|
01838|010|E|levels of and toxicity from theophylline.(1)|
01838|011|B||
01838|012|P|PREDISPOSING FACTORS:  None determined.|
01838|013|B||
01838|014|M|PATIENT MANAGEMENT:  The US manufacturer of febuxostat states that the|
01838|015|M|concurrent use of theophylline should be approached with caution.(1)|
01838|016|B||
01838|017|D|DISCUSSION:  Concurrent febuxostat (80 mg daily) increased the maximum|
01838|018|D|concentration (Cmax) and area-under-curve (AUC) of theophylline by 6% and|
01838|019|D|6.5%, respectively.  The amount of 1-methylxanthine, a major theophylline|
01838|020|D|metabolite, excreted in the urine increased 400-fold.  The safety of|
01838|021|D|long-term exposure to 1-methylxanthine has not been determined.(1)|
01838|022|B||
01838|023|R|REFERENCE:|
01838|024|B||
01838|025|R|1.Uloric (febuxostat) US prescribing information. Takeda Pharmaceuticals|1
01838|026|R|  America, Inc. April, 2023.|1
01839|001|T|MONOGRAPH TITLE:  Ranolazine/Erythromycin (mono deleted 01/30/2014)|
01839|002|B||
01839|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01839|004|L|take action as needed.|
01839|005|B||
01839|006|A|MECHANISM OF ACTION:  Erythromycin may inhibit the metabolism of ranolazine|
01839|007|A|by CYP P-450-3A4.(1,2)|
01839|008|B||
01839|009|E|CLINICAL EFFECTS:  Concurrent erythromycin may result in elevated levels of|
01839|010|E|and clinical effects from ranolazine.  Elevated ranolazine levels may result|
01839|011|E|in QTc prolongation, which may result in life-threatening cardiac|
01839|012|E|arrhythmia, including torsades de pointes.(1,2)|
01839|013|B||
01839|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01839|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01839|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01839|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01839|018|P|female gender, or advanced age.(3)|
01839|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01839|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01839|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01839|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01839|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01839|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01839|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01839|026|B||
01839|027|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
01839|028|M|dosage of ranolazine should be limited to 500 mg twice daily in patients|
01839|029|M|receiving moderately potent CYP P-450-3A4 inhibitors such as|
01839|030|M|erythromycin.(1)|
01839|031|B||
01839|032|D|DISCUSSION:  Concurrent use of diltiazem, another CYP P-450-3A4 inhibitor,|
01839|033|D|at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine|
01839|034|D|(1000 mg twice daily) by 1.5-fold and 2.4-fold, respectively.(2)|
01839|035|D|   Concurrent use of ketoconazole (200 mg twice daily), another CYP|
01839|036|D|P-450-3A4 inhibitor, increased plasma levels of ranolazine (1000 mg twice|
01839|037|D|daily) by 3.2-fold.(1)|
01839|038|D|   Concurrent use of verapamil (120 mg three times daily) increased plasma|
01839|039|D|levels of ranolazine (1000 mg twice daily) by 2.2-fold.(2)|
01839|040|D|   Ranolazine-induced QTc prolongation is dose and|
01839|041|D|concentration-related.(1,2)|
01839|042|B||
01839|043|R|REFERENCES:|
01839|044|B||
01839|045|R|1.Ranexa (ranolazine) US prescribing information. CV Therapeutics, Inc.|1
01839|046|R|  July, 2011.|1
01839|047|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01839|048|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01839|049|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01839|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01839|051|R|  settings: a scientific statement from the American Heart Association and|6
01839|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01839|053|R|  2;55(9):934-47.|6
01840|001|T|MONOGRAPH TITLE:  Ranolazine/Fluconazole (mono deleted 01/30/2014)|
01840|002|B||
01840|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01840|004|L|take action as needed.|
01840|005|B||
01840|006|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of ranolazine|
01840|007|A|by CYP P-450-3A4.(1,2)|
01840|008|B||
01840|009|E|CLINICAL EFFECTS:  Concurrent azole antifungals that are potent inhibitors|
01840|010|E|of CYP P-450-3A4 may result in elevated levels of and clinical effects from|
01840|011|E|ranolazine.  Elevated ranolazine levels may result in QTc prolongation,|
01840|012|E|which may result in life-threatening cardiac arrhythmia, including torsades|
01840|013|E|de pointes.(1,2)|
01840|014|B||
01840|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01840|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01840|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01840|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01840|019|P|female gender, or advanced age.(4)|
01840|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01840|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01840|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01840|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01840|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01840|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01840|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01840|027|B||
01840|028|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
01840|029|M|dosage of ranolazine should be limited to 500 mg twice daily in patients|
01840|030|M|receiving moderately potent CYP P-450-3A4 inhibitors such as fluconazole.(1)|
01840|031|B||
01840|032|D|DISCUSSION:  Concurrent use of ketoconazole (200 mg twice daily) increased|
01840|033|D|plasma levels of ranolazine (1000 mg twice daily) by 3.2-fold.(1)|
01840|034|D|   Ranolazine-induced QTc prolongation is dose and concentration-related.(1)|
01840|035|D|   In one study, concomitant administration of either ranolazine sustained|
01840|036|D|release (SR, 375 mg twice daily) or ranolazine SR (1000 mg twice daily) with|
01840|037|D|ketoconazole (200 mg twice daily) resulted in an increase in ranolazine SR|
01840|038|D|minimum concentrations (Cmin), maximum concentration (Cmax), steady-state|
01840|039|D|concentration (Css), and concentration at 12 hours postdose by between 2.5|
01840|040|D|and 4.5-fold.(3)|
01840|041|B||
01840|042|R|REFERENCES:|
01840|043|B||
01840|044|R|1.Ranexa (ranolazine) US prescribing information. CV Therapeutics, Inc.|1
01840|045|R|  July, 2011.|1
01840|046|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01840|047|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01840|048|R|3.Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to|2
01840|049|R|  investigate the pharmacokinetic interactions between ranolazine and|2
01840|050|R|  ketoconazole, diltiazem, or simvastatin during combined administration in|2
01840|051|R|  healthy subjects. J Clin Pharmacol 2005 Apr;45(4):422-33.|2
01840|052|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01840|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01840|054|R|  settings: a scientific statement from the American Heart Association and|6
01840|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01840|056|R|  2;55(9):934-47.|6
01841|001|T|MONOGRAPH TITLE:  Ranolazine/Aprepitant (mono deleted 01/30/2014)|
01841|002|B||
01841|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01841|004|L|take action as needed.|
01841|005|B||
01841|006|A|MECHANISM OF ACTION:  Aprepitant may inhibit the metabolism of ranolazine by|
01841|007|A|CYP P-450-3A4.(1,2)|
01841|008|B||
01841|009|E|CLINICAL EFFECTS:  Concurrent aprepitant may result in elevated levels of|
01841|010|E|and clinical effects from ranolazine.  Elevated ranolazine levels may result|
01841|011|E|in QTc prolongation, which may result in life-threatening cardiac|
01841|012|E|arrhythmia, including torsades de pointes.(1,2)|
01841|013|B||
01841|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01841|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01841|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01841|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01841|018|P|female gender, or advanced age.(3)|
01841|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01841|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01841|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01841|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01841|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01841|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01841|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01841|026|B||
01841|027|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
01841|028|M|dosage of ranolazine should be limited to 500 mg twice daily in patients|
01841|029|M|receiving moderately potent CYP P-450-3A4 inhibitors such as aprepitant.(1)|
01841|030|B||
01841|031|D|DISCUSSION:  Concurrent use of diltiazem, another moderate inhibitor of CYP|
01841|032|D|P-450-3A4, at daily doses of 180 mg to 360 mg increased plasma levels of|
01841|033|D|ranolazine (1000 mg twice daily) by 1.5-fold and 2.4-fold, respectively.(2)|
01841|034|D|   In healthy subjects, concurrent ranolazine (1000 mg twice daily) had no|
01841|035|D|effects on the pharmacokinetics of diltiazem (60 mg three times daily).(1)|
01841|036|D|   Concurrent use of verapamil ,another moderate inhibitor of CYP P-450-3A4,|
01841|037|D|at 120 mg three times daily increased plasma levels of ranolazine (1000 mg|
01841|038|D|twice daily) by 2-fold.(1)|
01841|039|D|   Ranolazine-induced QTc prolongation is dose and concentration-related.(1)|
01841|040|B||
01841|041|R|REFERENCES:|
01841|042|B||
01841|043|R|1.Ranexa (ranolazine) US prescribing information. CV Therapeutics, Inc.|1
01841|044|R|  July, 2011.|1
01841|045|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01841|046|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01841|047|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01841|048|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01841|049|R|  settings: a scientific statement from the American Heart Association and|6
01841|050|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01841|051|R|  2;55(9):934-47.|6
01842|001|T|MONOGRAPH TITLE:  Ranolazine/Nefazodone (mono deleted 01/30/2014)|
01842|002|B||
01842|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01842|004|L|is contraindicated and generally should not be dispensed or administered to|
01842|005|L|the same patient.|
01842|006|B||
01842|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of ranolazine by|
01842|008|A|CYP P-450-3A4.(1,2)|
01842|009|B||
01842|010|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in elevated|
01842|011|E|levels of and clinical effects from ranolazine.  Elevated ranolazine levels|
01842|012|E|may result in QTc prolongation, which may result in life-threatening cardiac|
01842|013|E|arrhythmia, including torsades de pointes.(1,2)|
01842|014|B||
01842|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01842|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01842|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01842|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01842|019|P|female gender, or advanced age.(3)|
01842|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01842|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01842|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01842|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01842|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01842|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01842|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01842|027|B||
01842|028|M|PATIENT MANAGEMENT:  The US and UK manufacturers of ranolazine state that|
01842|029|M|concurrent use with potent CYP P-450-3A4 inhibitors such as nefazodone is|
01842|030|M|contraindicated.(1,2)|
01842|031|B||
01842|032|D|DISCUSSION:  Concurrent use of diltiazem, another CYP P-450-3A4 inhibitor,|
01842|033|D|at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine|
01842|034|D|(1000 mg twice daily) by 1.5-fold and 2.4-fold, respectively.(2)|
01842|035|D|   Concurrent use of ketoconazole (200 mg twice daily), another CYP|
01842|036|D|P-450-3A4 inhibitor, increased plasma levels of ranolazine (1000 mg twice|
01842|037|D|daily) by 3.2-fold.(1)|
01842|038|D|   Concurrent use of verapamil (120 mg three times daily) increased plasma|
01842|039|D|levels of ranolazine (1000 mg twice daily) by 2.2-fold.(2)|
01842|040|D|   Ranolazine-induced QTc prolongation is dose and|
01842|041|D|concentration-related.(1,2)|
01842|042|B||
01842|043|R|REFERENCES:|
01842|044|B||
01842|045|R|1.Ranexa (ranolazine) US prescribing information. CV Therapeutics, Inc.|1
01842|046|R|  July, 2011.|1
01842|047|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01842|048|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01842|049|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01842|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01842|051|R|  settings: a scientific statement from the American Heart Association and|6
01842|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01842|053|R|  2;55(9):934-47.|6
01843|001|T|MONOGRAPH TITLE:  Ranolazine/Selected Antiarrhythmics|
01843|002|B||
01843|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01843|004|L|take action as needed.|
01843|005|B||
01843|006|A|MECHANISM OF ACTION:  Ranolazine prolongs the QTc interval in a dose-related|
01843|007|A|manner.  Use with other agents that prolong the QTc interval may result in|
01843|008|A|additive effects.(1)|
01843|009|B||
01843|010|E|CLINICAL EFFECTS:  Concurrent use of ranolazine and agents known to prolong|
01843|011|E|the QTc interval may result in prolongation of the QTc interval and|
01843|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
01843|013|B||
01843|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01843|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01843|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01843|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01843|018|P|female gender, advanced age, and/or use of multiple medications.(4)|
01843|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01843|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01843|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01843|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01843|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01843|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01843|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01843|026|B||
01843|027|M|PATIENT MANAGEMENT:  The concurrent use of ranolazine with Class Ia or III|
01843|028|M|antiarrhythmics should be approached with caution.(2)|
01843|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01843|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01843|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01843|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01843|033|B||
01843|034|D|DISCUSSION:  Ranolazine has been shown to prolong the QTc interval in a|
01843|035|D|dose-related manner.(1,2)  Although the UK manufacturer of ranolazine states|
01843|036|D|that concurrent use with Class Ia or III antiarrhythmics other than|
01843|037|D|amiodarone is contraindicated,(1) this warning was removed from the US|
01843|038|D|labeling as a result of analysis of data from the MERLIN-TIMI 36 trial.(3)|
01843|039|B||
01843|040|R|REFERENCES:|
01843|041|B||
01843|042|R|1.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
01843|043|R|  Pharma U.K. S.R.I. October 30, 2008.|1
01843|044|R|2.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
01843|045|R|3.MehtaY. Personal communication. Gilead Sciences, Inc. June 1, 2012.|1
01843|046|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01843|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01843|048|R|  settings: a scientific statement from the American Heart Association and|6
01843|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01843|050|R|  2;55(9):934-47.|6
01844|001|T|MONOGRAPH TITLE:  Alfuzosin; Silodosin; Tamsulosin/Clarithromycin;|
01844|002|T|Telithromycin (mono deleted 01/26/2012)|
01844|003|B||
01844|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01844|005|L|is contraindicated and generally should not be dispensed or administered to|
01844|006|L|the same patient.|
01844|007|B||
01844|008|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01844|009|A|metabolism of alfuzosin,(1) silodosin,(2) and tamsulosin(3) by CYP|
01844|010|A|P-450-3A4.|
01844|011|B||
01844|012|E|CLINICAL EFFECTS:  Co-administration of clarithromycin or telithromycin may|
01844|013|E|result in increased alfuzosin,(1) silodosin,(2) and tamsulosin(3) levels and|
01844|014|E|effects, including severe hypotension.|
01844|015|B||
01844|016|P|PREDISPOSING FACTORS:  In patients receiving tamsulosin, the interaction may|
01844|017|P|be worse in patients who are CYP P-450-2D6 poor metabolizers because|
01844|018|P|tamsulosin also undergoes metabolism by this pathway.(3)|
01844|019|B||
01844|020|M|PATIENT MANAGEMENT:  The US manufacturers of alfuzosin(1) and silodosin(2)|
01844|021|M|state that concurrent use of strong CYP P-450-3A4 inhibitors is|
01844|022|M|contraindicated.|
01844|023|M|   The US manufacturer of tamsulosin states that tamsulosin should not be|
01844|024|M|used with strong CYP P-450-3A4 inhibitors.(3)|
01844|025|B||
01844|026|D|DISCUSSION:  Administration of ketoconazole (400 mg daily), another|
01844|027|D|inhibitor of CYP P-450-3A4, increased the maximum concentration (Cmax) and|
01844|028|D|area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and|
01844|029|D|3.2-fold, respectively.(1)|
01844|030|D|   Administration of ketoconazole (200 mg daily) increased the Cmax and AUC|
01844|031|D|of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold,|
01844|032|D|respectively.(1)|
01844|033|D|   Administration of ketoconazole (200 mg daily for 4 days), increased the|
01844|034|D|Cmax and AUC of a single dose of silodosin (4 mg) by 3.7-fold and 2.9-fold,|
01844|035|D|respectively.(2)|
01844|036|D|   Administration of ketoconazole (400 mg daily for 4 days) increased the|
01844|037|D|Cmax and AUC of a single dose of silodosin (8 mg) by 3.8-fold and 3.2-fold,|
01844|038|D|respectively.(2)|
01844|039|D|   In a study in 24 healthy subjects, administration of ketoconazole (400 mg|
01844|040|D|daily for 5 days) increased the Cmax and AUC of a single dose of tamsulosin|
01844|041|D|(0.4 mg) by 2.2-fold and 2.8-fold, respectively.(3)|
01844|042|B||
01844|043|R|REFERENCES:|
01844|044|B||
01844|045|R|1.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
01844|046|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
01844|047|R|2.Rapaflo (silodosin) US prescribing information. Watson Laboratories, Inc.|1
01844|048|R|  March, 2010.|1
01844|049|R|3.Flomax (tamsulosin hydrochloride) US prescribing information. Boehringer|1
01844|050|R|  Ingelheim Pharmaceuticals, Inc. May, 2012.|1
01845|001|T|MONOGRAPH TITLE:  Terbinafine/Rifampin|
01845|002|B||
01845|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01845|004|L|of severe adverse interaction.|
01845|005|B||
01845|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of terbinafine.(1)|
01845|007|B||
01845|008|E|CLINICAL EFFECTS:  Concurrent use of rifampin may result in decreased levels|
01845|009|E|of and clinical effects from terbinafine.(1)|
01845|010|B||
01845|011|P|PREDISPOSING FACTORS:  None determined.|
01845|012|B||
01845|013|M|PATIENT MANAGEMENT:  Consider the use of alternative agents if possible.  If|
01845|014|M|concurrent therapy is warranted, monitor for decreased levels and|
01845|015|M|effectiveness of terbinafine.  The dosage of terbinafine may need to be|
01845|016|M|adjusted or rifampin may need to be discontinued.|
01845|017|B||
01845|018|D|DISCUSSION:  Rifampin has been shown to increase the clearance of|
01845|019|D|terbinafine by 100%.(1)|
01845|020|B||
01845|021|R|REFERENCE:|
01845|022|B||
01845|023|R|1.Lamisil (terbinafine hydrochloride) tablet US prescribing information.|1
01845|024|R|  Novartis Pharmaceuticals Corporation June, 2013.|1
01846|001|T|MONOGRAPH TITLE:  Milnacipran/Linezolid|
01846|002|B||
01846|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01846|004|L|of severe adverse interaction.|
01846|005|B||
01846|006|A|MECHANISM OF ACTION:  Serotonin reuptake inhibitors and MAOIs may act|
01846|007|A|synergistically to increase blood pressure and evoke behavioral excitation.|
01846|008|B||
01846|009|E|CLINICAL EFFECTS:  Concurrent use or switching between agents without a|
01846|010|E|sufficient washout period may result in serotonin syndrome.(1,2)  Symptoms|
01846|011|E|of serotonin syndrome may include tremor, agitation, diaphoresis,|
01846|012|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3,4)|
01846|013|B||
01846|014|P|PREDISPOSING FACTORS:  None determined.|
01846|015|B||
01846|016|M|PATIENT MANAGEMENT:  The US manufacturers of milnacipran and levomilnacipran|
01846|017|M|state that concurrent administration with a MAOI, including linezolid, is|
01846|018|M|contraindicated.  At least 5 days should elapse between discontinuing|
01846|019|M|milnacipran and initiating linezolid,(1) and at least 7 days should elapse|
01846|020|M|between discontinuing levomilnacipran and initiating linezolid.(2)|
01846|021|M|   In emergency situations in patients maintained on milnacipran or|
01846|022|M|levomilnacipran, weigh the availability and safety of alternatives to|
01846|023|M|linezolid against the risk of serotonin syndrome.  If linezolid therapy is|
01846|024|M|required, the patient's milnacipran or levomilnacipran should be immediately|
01846|025|M|discontinued.  Patients should be monitored for serotonin syndrome for 5|
01846|026|M|days (2 weeks in the case of levomilnacipran) or until 24 hours after the|
01846|027|M|last dose of linezolid, whichever comes first.|
01846|028|M|   Do not initiate milnacipran or levomilnacipran therapy in patients|
01846|029|M|receiving linezolid until 24 hours after the last dose of linezolid.|
01846|030|B||
01846|031|D|DISCUSSION:  Concurrent use or switching between agents without a sufficient|
01846|032|D|washout period may result in serotonin syndrome.  Therefore, the US|
01846|033|D|manufacturers of milnacipran and levomilnacipran state that concurrent|
01846|034|D|administration with a MAOI, including linezolid, is contraindicated.  At|
01846|035|D|least 5 days should elapse between discontinuing milnacipran and initiating|
01846|036|D|linezolid,(1) and at least 7 days should elapse between discontinuing|
01846|037|D|levomilnacipran and initiating linezolid.(2)  Symptoms of serotonin syndrome|
01846|038|D|may include tremor, agitation, diaphoresis, hyperreflexia, clonus,|
01846|039|D|tachycardia, hyperthermia, and muscle rigidity.(3,4)|
01846|040|D|   Many authors state that linezolid is a weak MAOI and rarely causes|
01846|041|D|serotonin toxicity.  Cases of serotonin toxicity were rapidly reversible|
01846|042|D|with discontinuation of the offending agent(s) and supportive care.  Some|
01846|043|D|authors suggest that use of serotonergic medications should not preclude the|
01846|044|D|use of linezolid but that the clinical situation should be assessed.  If|
01846|045|D|concurrent use or use of linezolid without a washout is warranted, the|
01846|046|D|patient should be closely monitored.(5-10)|
01846|047|B||
01846|048|R|REFERENCES:|
01846|049|B||
01846|050|R|1.Savella (milnacipran hydrochloride) US prescribing information. Forest|1
01846|051|R|  Pharmaceuticals, Inc. September, 2021.|1
01846|052|R|2.Fetzima (levomilnacipran) US prescribing information. Forest|1
01846|053|R|  Pharmaceuticals, Inc. October, 2023.|1
01846|054|R|3.Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis 2002|3
01846|055|R|  Jun 15;34(12):1651-2.|3
01846|056|R|4.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01846|057|R|  352(11):1112-20.|6
01846|058|R|5.Lodise TP, Patel N, Rivera A, Tristani L, Lazariu V, Vandewall H, McNutt|2
01846|059|R|  LA. Comparative evaluation of serotonin toxicity among veterans affairs|2
01846|060|R|  patients  receiving linezolid and vancomycin. Antimicrob Agents Chemother|2
01846|061|R|  2013 Dec;57(12):5901-11.|2
01846|062|R|6.Ramsey TD, Lau TT, Ensom MH. Serotonergic and adrenergic drug interactions|6
01846|063|R|  associated with linezolid: a critical  review and practical management|6
01846|064|R|  approach. Ann Pharmacother 2013 Apr;47(4):543-60.|6
01846|065|R|7.Woytowish MR, Maynor LM. Clinical relevance of linezolid-associated|6
01846|066|R|  serotonin toxicity. Ann Pharmacother 2013 Mar;47(3):388-97.|6
01846|067|R|8.Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, Lodise TP.|2
01846|068|R|  Comparison of serotonin toxicity with concomitant use of either linezolid|2
01846|069|R|  or  comparators and serotonergic agents: an analysis of Phase III and IV|2
01846|070|R|  randomized  clinical trial data. J Antimicrob Chemother 2012 Feb;|2
01846|071|R|  67(2):494-502.|2
01846|072|R|9.Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion|6
01846|073|R|  J Clin Psychiatry 2009;11(6):353-6.|6
01846|074|R|10.Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug|2
01846|075|R|   interactions: a retrospective survey. Clin Infect Dis 2006 Jul 15;|2
01846|076|R|   43(2):180-7.|2
01847|001|T|MONOGRAPH TITLE:  Quinine/Possible QT Prolonging Agents|
01847|002|B||
01847|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01847|004|L|take action as needed.|
01847|005|B||
01847|006|A|MECHANISM OF ACTION:  Quinine has been shown to prolong the QTc interval.|
01847|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01847|008|A|additive effects on the QTc interval.(1)|
01847|009|B||
01847|010|E|CLINICAL EFFECTS:  The concurrent use of quinine with other agents that|
01847|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01847|012|E|arrhythmias, including torsades de pointes.(1)|
01847|013|B||
01847|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01847|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01847|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01847|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01847|018|P|gender, or advanced age.(3)|
01847|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01847|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01847|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01847|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01847|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01847|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01847|025|P|dysfunction).(3)|
01847|026|B||
01847|027|M|PATIENT MANAGEMENT:  The US manufacturer of quinine states that concurrent|
01847|028|M|use with agents known to prolong the QT interval should be avoided.(1)|
01847|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01847|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01847|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01847|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01847|033|B||
01847|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01847|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
01847|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
01847|037|D|monograph have been shown to prolong the QTc interval either through their|
01847|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01847|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
01847|040|D|clinical trials and/or post-marketing reports.|
01847|041|B||
01847|042|R|REFERENCES:|
01847|043|B||
01847|044|R|1.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
01847|045|R|  Industries, Inc. August, 2019.|1
01847|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01847|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01847|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01847|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01847|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01847|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01847|052|R|  settings: a scientific statement from the American Heart Association and|6
01847|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01847|054|R|  2;55(9):934-47.|6
01848|001|T|MONOGRAPH TITLE:  Quinidine; Quinine/Selected Macrolides|
01848|002|B||
01848|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01848|004|L|of severe adverse interaction.|
01848|005|B||
01848|006|A|MECHANISM OF ACTION:  Clarithromycin, erythromycin and troleandomycin may|
01848|007|A|inhibit the metabolism of quinidine(1) and quinine(2) by CYP3A4.|
01848|008|A|Azithromycin, clarithromycin and erythromycin have been associated with|
01848|009|A|prolongation of the QT interval.(3,4)|
01848|010|B||
01848|011|E|CLINICAL EFFECTS:  The concurrent use of azithromycin, clarithromycin,|
01848|012|E|erythromycin, or troleandomycin may result in elevated levels and effects|
01848|013|E|from quinidine and quinine, including torsades de pointes.(3,4)|
01848|014|B||
01848|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01848|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01848|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01848|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01848|019|P|gender, or advanced age.(5)|
01848|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01848|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01848|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01848|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01848|024|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
01848|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01848|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
01848|027|B||
01848|028|M|PATIENT MANAGEMENT:  Concurrent use of quinidine with azithromycin,|
01848|029|M|clarithromycin, erythromycin or troleandomycin should be avoided when|
01848|030|M|possible.  If combination therapy is required evaluate patient-specific|
01848|031|M|predisposing risk factors, baseline QTc interval, and monitor as|
01848|032|M|appropriate.  Consider obtaining serum calcium, magnesium, and potassium|
01848|033|M|levels and correct any electrolyte abnormalities.  The dosage of quinidine|
01848|034|M|may need to be adjusted in patients receiving erythromycin or|
01848|035|M|troleandomycin.|
01848|036|M|   The US manufacturer of quinine states that concurrent use of erythromycin|
01848|037|M|or troleandomycin should be avoided.(2)|
01848|038|B||
01848|039|D|DISCUSSION:  In a study in 30 healthy males, pretreatment with erythromycin|
01848|040|D|(250 mg 4 times daily) decreased the total clearance, partial clearance by|
01848|041|D|3-hydroxylation, and partial clearance by N-oxidation of a single oral dose|
01848|042|D|of quinidine (200 mg) by 34%, 50%, and 33%, respectively.  Quinidine maximum|
01848|043|D|concentration (Cmax) increased by 39%.(6)|
01848|044|D|   QT prolongation(7) and quinidine toxicity(8) have been reported following|
01848|045|D|erythromycin administration.|
01848|046|D|   In a cross-over study in 10 healthy subjects, troleandomycin (500 mg|
01848|047|D|every 8 hours) increased the area-under-curve (AUC) of a single oral dose of|
01848|048|D|quinine sulfate (600 mg) by 87%.  Quinine clearance was 45% lower and the|
01848|049|D|formation clearance of 3-hydroxyquinine, quinine's main metabolite,|
01848|050|D|decreased 81%.(2)|
01848|051|D|   One or more of the drug pairs linked to this monograph have been included|
01848|052|D|in a list of interactions that should be considered "high-priority" for|
01848|053|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01848|054|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01848|055|D|Coordinator (ONC) for Health Information Technology.|
01848|056|B||
01848|057|R|REFERENCES:|
01848|058|B||
01848|059|R|1.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
01848|060|R|  Industries, Inc. August, 2019.|1
01848|061|R|2.Zhao XJ, Ishizaki T. A further interaction study of quinine with|5
01848|062|R|  clinically important drugs by human liver microsomes: determinations of|5
01848|063|R|  inhibition constant (Ki) and type of inhibition. Eur J Drug Metab|5
01848|064|R|  Pharmacokinet 1999 Jul-Sep;24(3):272-8.|5
01848|065|R|3.Zithromax (azithromycin oral) US prescribing information. Pifzer Labs|1
01848|066|R|  April, 2019.|1
01848|067|R|4.E.E.S. (erythromycin ethylsuccinate) US prescribing information. Arbor|1
01848|068|R|  Pharmaceuticals, Inc. April, 2018.|1
01848|069|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01848|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01848|071|R|  settings: a scientific statement from the American Heart Association and|6
01848|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01848|073|R|  2;55(9):934-47.|6
01848|074|R|6.Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfiram,|2
01848|075|R|  itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of|2
01848|076|R|  quinidine. Br J Clin Pharmacol 1999 Dec;48(6):829-38.|2
01848|077|R|7.Lin JC, Quasny HA. QT prolongation and development of torsades de pointes|3
01848|078|R|  with the concomitant administration of oral erythromycin base and|3
01848|079|R|  quinidine. Pharmacotherapy 1997 May-Jun;17(3):626-30.|3
01848|080|R|8.Spinler SA, Cheng JW, Kindwall KE, Charland SL. Possible inhibition of|3
01848|081|R|  hepatic metabolism of quinidine by erythromycin. Clin Pharmacol Ther 1995|3
01848|082|R|  Jan;57(1):89-94.|3
01848|083|R|9.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01848|084|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01848|085|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01848|086|R|  19(5):735-43.|6
01849|001|T|MONOGRAPH TITLE:  Atazanavir/Efavirenz|
01849|002|B||
01849|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01849|004|L|of severe adverse interaction.|
01849|005|B||
01849|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of atazanavir via|
01849|007|A|CYP3A4.(1-4)|
01849|008|B||
01849|009|E|CLINICAL EFFECTS:  Concurrent use of atazanavir and efavirenz without|
01849|010|E|concurrent ritonavir may result in decreased levels and effectiveness of|
01849|011|E|atazanavir.(1-4)|
01849|012|B||
01849|013|P|PREDISPOSING FACTORS:  None determined.|
01849|014|B||
01849|015|M|PATIENT MANAGEMENT:  The manufacturers of atazanavir(1,2), cobicistat,(3)|
01849|016|M|and efavirenz(4) state that if atazanavir is to be used concurrently with|
01849|017|M|efavirenz in treatment naive patients, patients should receive 400 mg|
01849|018|M|atazanavir with 100 mg ritonavir or 150 mg cobicistat as a single daily dose|
01849|019|M|with food, and 600 mg of efavirenz should be administered once a day on an|
01849|020|M|empty stomach, preferably at bedtime.(1,3)|
01849|021|M|   Atazanavir should not be administered with efavirenz without ritonavir or|
01849|022|M|cobicistat.(2)|
01849|023|M|   Atazanavir and efavirenz should not be coadministered in|
01849|024|M|treatment-experienced patients.(1-3)|
01849|025|M|   The combination product containing efavirenz/emtricitabine/tenofovir is|
01849|026|M|not recommended for use in patients receiving atazanavir.(5)|
01849|027|B||
01849|028|D|DISCUSSION:  In a study in 27 subjects, the administration of atazanavir and|
01849|029|D|efavirenz without ritonavir decreased the atazanavir area-under-curve (AUC),|
01849|030|D|maximum concentration (Cmax), and minimum concentration (Cmin) by 74%, 59%,|
01849|031|D|and 93% respectively.(1,2)|
01849|032|D|   In a study in 13 subjects, concurrent atazanavir/ritonavir (300/100 mg|
01849|033|D|daily) with efavirenz (600 mg daily) increased atazanavir AUC, Cmax, and|
01849|034|D|Cmin by 39%, 14%, and 48%, when compared to atazanavir 400 mg daily|
01849|035|D|alone.(1,2)|
01849|036|D|   In a study in 14 subjects, concurrent atazanavir/ritonavir (400/100 mg|
01849|037|D|daily) with efavirenz (600 mg daily) increased atazanavir Cmax by 17%.|
01849|038|D|Atazanavir Cmin decreased by 42%.(1)|
01849|039|D|   Because both efavirenz and tenofovir decrease atazanavir concentrations|
01849|040|D|and the effect of taking both on atazanavir pharmacokinetics has not been|
01849|041|D|studied, the use of atazanavir with the combination product|
01849|042|D|efavirenz/emtricitabine/tenofovir is not recommended.(5)|
01849|043|B||
01849|044|R|REFERENCES:|
01849|045|B||
01849|046|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01849|047|R|  Squibb Company December, 2024.|1
01849|048|R|2.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01849|049|R|  Squibb Pharmaceuticals October 25, 2023.|1
01849|050|R|3.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
01849|051|R|  June, 2025.|1
01849|052|R|4.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01849|053|R|  Company November, 2023.|1
01849|054|R|5.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01849|055|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01850|001|T|MONOGRAPH TITLE:  Atazanavir/Efavirenz-Emtricitabine-Tenofovir|
01850|002|B||
01850|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01850|004|L|of severe adverse interaction.|
01850|005|B||
01850|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of atazanavir via|
01850|007|A|CYP3A4.(1-4)  Tenofovir may also decrease atazanavir exposure through an|
01850|008|A|unknown mechanism.(1,2)|
01850|009|A|   Atazanavir may increase exposure to tenofovir.(4,5)|
01850|010|B||
01850|011|E|CLINICAL EFFECTS:  Concurrent use of atazanavir and efavirenz and tenofovir|
01850|012|E|may result in decreased levels and effectiveness of atazanavir(1-4) and|
01850|013|E|increased levels of tenofovir.(4,5)|
01850|014|B||
01850|015|P|PREDISPOSING FACTORS:  None determined.|
01850|016|B||
01850|017|M|PATIENT MANAGEMENT:  The combination product containing|
01850|018|M|efavirenz/emtricitabine/tenofovir is not recommended for use in patients|
01850|019|M|receiving atazanavir.(4)|
01850|020|B||
01850|021|D|DISCUSSION:  In a study in 27 subjects, the administration of atazanavir and|
01850|022|D|efavirenz without ritonavir decreased the atazanavir area-under-curve (AUC),|
01850|023|D|maximum concentration (Cmax), and minimum concentration (Cmin) by 74%, 59%|
01850|024|D|and 93% respectively.(1,2)|
01850|025|D|   In a study in 13 subjects, concurrent atazanavir/ritonavir (300/100 mg|
01850|026|D|daily) with efavirenz (600 mg daily) increased atazanavir AUC, Cmax, and|
01850|027|D|Cmin by 39%, 14%, and 48%, when compared to atazanavir 400 mg daily|
01850|028|D|alone.(1,2)|
01850|029|D|   In a study in 14 subjects, concurrent atazanavir/ritonavir (400/100 mg|
01850|030|D|daily) with efavirenz (600 mg daily) increased atazanavir Cmax by 17%.|
01850|031|D|Atazanavir Cmin decreased by 42%.(1)|
01850|032|D|   In a study in healthy subjects, concurrent atazanavir (400 mg daily) with|
01850|033|D|tenofovir (300 mg daily) decreased atazanavir area-under-curve (AUC),|
01850|034|D|maximum concentration (Cmax), and minimum concentration (Cmin) by 25%, 21%,|
01850|035|D|and 40%, respectively.   The AUC, Cmax, and Cmin of tenofovir increased by|
01850|036|D|24%, 14%, and 22%, respectively.(1)|
01850|037|D|   In another study, atazanavir AUC, Cmax, and Cmin decreased by 25%, 28%,|
01850|038|D|and 23%, respectively, when atazanavir (300 mg daily), ritonavir (100 mg|
01850|039|D|daily), and tenofovir (300 mg daily) were coadministered, when compared to|
01850|040|D|the administration of atazanavir and ritonavir alone. However, these|
01850|041|D|decreased levels were approximately 2.3-fold and 4-fold higher that the|
01850|042|D|respective values for atazanavir (400 mg daily) alone.(1)  Interim data|
01850|043|D|suggests that rate of moderate or severe adverse effects is similar between|
01850|044|D|atazanavir-treated patients and unboosted atazanavir-treated patients.(1)|
01850|045|D|    In a study of 12 subjects, the AUC, Cmax and Cmin of tenofovir (300 mg|
01850|046|D|daily) increased 137%, 134% and 129% respectively, when given with|
01850|047|D|atazanavir (300 mg daily) and ritonavir (100 mg daily).(1)|
01850|048|D|   Because both efavirenz and tenofovir decrease atazanavir concentrations|
01850|049|D|and the effect of taking both on atazanavir pharmacokinetics has not been|
01850|050|D|studied, the use of atazanavir with the combination product|
01850|051|D|efavirenz/emtricitabine/tenofovir is not recommended.(4)|
01850|052|B||
01850|053|R|REFERENCES:|
01850|054|B||
01850|055|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01850|056|R|  Squibb Company December, 2024.|1
01850|057|R|2.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
01850|058|R|  Squibb Pharmaceuticals October 25, 2023.|1
01850|059|R|3.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01850|060|R|  Company November, 2023.|1
01850|061|R|4.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
01850|062|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
01850|063|R|5.Viread (tenofovir disoproxil fumarate) US prescribing information. Gilead|1
01850|064|R|  Sciences, Inc. December, 2018.|1
01851|001|T|MONOGRAPH TITLE:  Digitalis Glycosides/Intravenous Calcium Products|
01851|002|B||
01851|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01851|004|L|of severe adverse interaction.|
01851|005|B||
01851|006|A|MECHANISM OF ACTION:  The mechanism of action of digitalis glycosides|
01851|007|A|involves its ability to cause an increase in excitation-contraction coupling|
01851|008|A|mediated through the effects of calcium.  Excitable tissues in the heart|
01851|009|A|experience inhibition of sodium/potassium ATPase (the membrane "sodium|
01851|010|A|pump") by digitalis glycosides and so attain relatively higher intracellular|
01851|011|A|sodium and lower potassium concentrations.  Higher intracellular sodium|
01851|012|A|concentrations facilitate exchange of extracellular calcium ions and the|
01851|013|A|inward and internal flux of calcium results in modified transmembrane|
01851|014|A|potentials and stronger contractions of cardiac muscle.  Elevated|
01851|015|A|extracellular concentrations of calcium after parenteral calcium salts|
01851|016|A|further facilitate these inward calcium fluxes.|
01851|017|B||
01851|018|E|CLINICAL EFFECTS:  Rapid administration of calcium via the intravenous route|
01851|019|E|may result in digitalis toxicity, including arrhythmias.(1)|
01851|020|B||
01851|021|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
01851|022|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
01851|023|P|risk of digoxin toxicity.|
01851|024|B||
01851|025|M|PATIENT MANAGEMENT:  In patients maintain on a digitalis glycosides,|
01851|026|M|administer intravenous calcium slowly and with caution.  If cardiac toxicity|
01851|027|M|develops, supportive measures without additional antiarrhythmics may be|
01851|028|M|sufficient.|
01851|029|B||
01851|030|D|DISCUSSION:  Effects of digitalis glycosides on the heart are increased by|
01851|031|D|elevated extracellular concentrations of ionic calcium. Intravenous|
01851|032|D|administration of calcium salts during digitalis therapy may result in|
01851|033|D|altered cardiac electrophysiologic activity such as tachycardia or|
01851|034|D|arrhythmias.|
01851|035|D|   Oral calcium carbonate has not been shown to affect the bioavailability|
01851|036|D|of oral digitalis.|
01851|037|B||
01851|038|R|REFERENCES:|
01851|039|B||
01851|040|R|1.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
01851|041|R|  Pharmaceuticals, Inc. August, 2018.|1
01851|042|R|2.Bower JO, Mengle HAK. The additive effect of calcium and digitalis. JAMA|2
01851|043|R|  1936 Apr 4;106(14):1151-53.|2
01851|044|R|3.Nola GT, Pope S, Harrison DC. Assessment of the synergistic relationship|5
01851|045|R|  between serum calcium and digitalis. Am Heart J 1970 Apr;79(4):499-507.|5
01851|046|R|4.Hougen TJ, Smith TW. Inhibition of myocardial monovalent cation active|5
01851|047|R|  transport by subtoxic doses of ouabain in the dog. Circ Res 1978 Jun;|5
01851|048|R|  42(6):856-63.|5
01851|049|R|5.Brown RH Jr, Cohen I, Noble D. The interactions of protons, calcium and|5
01851|050|R|  potassium ions on cardiac Purkinje fibres. J Physiol 1978 Sep;282:345-52.|5
01851|051|R|6.Hansteen V, Jacobsen D, Knudsen K, Reikvam A, Skuterud B. Acute, massive|3
01851|052|R|  poisoning with digitoxin: report of seven cases and discussion of|3
01851|053|R|  treatment. Clin Toxicol 1981 Jun;18(6):679-92.|3
01851|054|R|7.Brown DD, Juhl RP. Altered bioavailability of digoxin produced by|2
01851|055|R|  gastrointestinal medications. Clin Res 1979;27:610A.|2
01852|001|T|MONOGRAPH TITLE:  Everolimus/Dexamethasone (mono deleted 09/15/2011)|
01852|002|B||
01852|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01852|004|L|of severe adverse interaction.|
01852|005|B||
01852|006|A|MECHANISM OF ACTION:  Dexamethasone may induce the metabolism of everolimus|
01852|007|A|by CYP P-450-3A4.(1)|
01852|008|B||
01852|009|E|CLINICAL EFFECTS:  Concurrent use of dexamethasone may result in decreased|
01852|010|E|levels and effectiveness of everolimus.(1)|
01852|011|B||
01852|012|P|PREDISPOSING FACTORS:  None determined.|
01852|013|B||
01852|014|M|PATIENT MANAGEMENT:  The US manufacturer of everolimus states that|
01852|015|M|concurrent use with strong CYP P-450-3A4 inducers such as dexamethasone|
01852|016|M|should be avoided.  If concurrent use is warranted, consider increasing the|
01852|017|M|dose of everolimus from 10 mg daily to 20 mg daily in 5 mg increments.(1)|
01852|018|M|   If the inducer is discontinued, the dosage of everolimus should be|
01852|019|M|returned to the dose use prior to the use of the strong inducer.(1)|
01852|020|B||
01852|021|D|DISCUSSION:  In healthy subjects, concurrent use of rifampin, another strong|
01852|022|D|inhibitor of CYP P-450-3A4, decreased everolimus area-under-curve (AUC) and|
01852|023|D|maximum concentration (Cmax) by 64% and 58%, respectively.(1)|
01852|024|D|   Increasing the dosage of everolimus to 20 mg daily in patients taking a|
01852|025|D|strong inducer of CYP P-450-3A4 is expected to increase the AUC of|
01852|026|D|everolimus to levels seen without a concurrent inducer; however, there are|
01852|027|D|no clinical data available with this dosage in patients receiving strong CYP|
01852|028|D|P-450-3A4 inducers.(1)|
01852|029|B||
01852|030|R|REFERENCE:|
01852|031|B||
01852|032|R|1.Afinitor (everolimus) US prescribing information. Novartis Pharmaceuticals|1
01852|033|R|  Corporation March, 2009.|1
01853|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Strong CYP3A4 Inducers|
01853|002|B||
01853|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01853|004|L|of severe adverse interaction.|
01853|005|B||
01853|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may increase the metabolism|
01853|007|A|of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.(1)|
01853|008|B||
01853|009|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 may result in|
01853|010|E|decreased levels and effectiveness of cyclosporine, everolimus, sirolimus,|
01853|011|E|tacrolimus, and temsirolimus.(1)|
01853|012|B||
01853|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01853|014|P|of the inducer for longer than 1-2 weeks.|
01853|015|B||
01853|016|M|PATIENT MANAGEMENT:  The American Society of Transplantation guidelines|
01853|017|M|state that cyclosporine and tacrolimus should be avoided in combination with|
01853|018|M|rifabutin and rifampin.  Everolimus should be avoided in combination with|
01853|019|M|rifampin and is contraindicated with rifabutin.  Sirolimus is|
01853|020|M|contraindicated with rifabutin and rifampin.  If concurrent therapy of|
01853|021|M|cyclosporine, everolimus, sirolimus, or tacrolimus with rifampin is needed,|
01853|022|M|increase the dose of the immunosuppressant by 2-fold when the combination is|
01853|023|M|initiated and monitor immunosuppressant concentrations frequently with rapid|
01853|024|M|subsequent dose increases as needed.  The reverse is recommended when|
01853|025|M|rifampin is discontinued.(62)|
01853|026|M|   The US manufacturer of everolimus states that concurrent use with strong|
01853|027|M|CYP3A4 inducers should be avoided.  If concurrent use is warranted, consider|
01853|028|M|increasing the dose of everolimus.  In patients with advanced hormone|
01853|029|M|receptor-positive, HER2-negative breast cancer (HR+BC); advanced pancreatic|
01853|030|M|neuroendocrine tumors (PNET); or advanced renal cell carcinoma; or renal|
01853|031|M|angiomyolipoma with TSC, double the daily dose of everolimus using 5 mg|
01853|032|M|increments or less.  If the inducer is discontinued, return the dose to that|
01853|033|M|used prior to inducer therapy once the inducer has been stopped for 5 days.|
01853|034|M|In patients with subependymal giant cell astrocytoma with TSC, double the|
01853|035|M|dose of everolimus using 5 mg increments or less.  Subsequent dosing should|
01853|036|M|be individualized based on therapeutic drug monitoring.  If the inducer is|
01853|037|M|discontinued, return the dose of everolimus to the dose used prior to the|
01853|038|M|inducer once the inducer has been stopped for 5 days, and assess everolimus|
01853|039|M|trough levels 2 weeks later.(1)|
01853|040|M|   St. John's wort may decrease everolimus levels unpredictably and should|
01853|041|M|be avoided entirely.(1)|
01853|042|M|   The US manufacturer of temsirolimus states that concurrent use of strong|
01853|043|M|inducers of CYP3A4, such as carbamazepine, phenobarbital, phenytoin,|
01853|044|M|rifabutin, rifampicin, or rifampin should be avoided.  If concurrent therapy|
01853|045|M|is warranted, consider increasing the dosage of temsirolimus from 25 mg/week|
01853|046|M|to 50 mg/week.  If the inducer is discontinued, the dosage of temsirolimus|
01853|047|M|should be returned to the previous dose.(2)|
01853|048|M|   If possible, consider alternatives to strong CYP3A4 inducers in patients|
01853|049|M|maintained on cyclosporine, sirolimus, and tacrolimus.  If concurrent|
01853|050|M|therapy is warranted, monitor cyclosporine, sirolimus, and tacrolimus serum|
01853|051|M|levels and observe the patient for graft rejection.  The dosage of|
01853|052|M|cyclosporine, sirolimus, and tacrolimus may need to be adjusted following|
01853|053|M|the initiation or discontinuation of these agents.|
01853|054|M|   Strong CYP3A4 inducers linked to this monograph include: allobarbital,|
01853|055|M|amobarbital, apalutamide, aprobarbital, barbexaclone, barbital,|
01853|056|M|brallobarbital, butabarbital, butalbital, butethal, carbamazepine,|
01853|057|M|cyclobarbital, difebarbamate, ethotoin, febarbamate, fosphenytoin,|
01853|058|M|hexobarbital, lumacaftor, mephenytoin, mephobarbital, metharbital, mitotane,|
01853|059|M|natisedine, pentobarbital, phenobarbital, phenytoin, primidone, probarbital,|
01853|060|M|proxibarbal, rifabutin, rifampin, rifapentine, secobarbital, St. John's|
01853|061|M|wort, talbutal, vinbarbital, and vinylbital.|
01853|062|B||
01853|063|D|DISCUSSION:  In a study in 10 lung transplant patients, significantly higher|
01853|064|D|doses of cyclosporine were required during nafcillin therapy to maintain|
01853|065|D|therapeutic trough levels.  Patients also developed higher serum creatinine|
01853|066|D|levels and more renal dysfunction than patients not receiving nafcillin.  In|
01853|067|D|a case report, a patient experienced 70% and 85% drops in cyclosporine|
01853|068|D|levels during two separate courses of nafcillin therapy.|
01853|069|D|   Trough cyclosporine concentrations have been found to decrease within 48|
01853|070|D|hours after starting phenytoin even when the dose of cyclosporine is|
01853|071|D|increased. Conversely, cyclosporine concentrations may increase when the|
01853|072|D|hydantoin is discontinued. The effect of the hydantoin on cyclosporine may|
01853|073|D|reverse over a period of one to three weeks after stopping the hydantoin.|
01853|074|D|   Concurrent administration of cyclosporine and rifampin has been|
01853|075|D|associated with lowering of cyclosporine to undetectable serum levels.|
01853|076|D|Decreases in cyclosporine levels have been observed within 2 days of|
01853|077|D|concomitant therapy but will probably not be maximal for 1 week. The effects|
01853|078|D|of the interaction may persist for up to 3 weeks after rifampin is stopped.|
01853|079|D|   In an open-label study in 11 renal transplant patients, subjects received|
01853|080|D|St. John's wort (600 mg daily) for 14 days in addition to their normal|
01853|081|D|cyclosporine regimen.  After 14 days of St. John's wort, dose-corrected|
01853|082|D|cyclosporine area-under-curve (AUC), maximum concentration (Cmax), and|
01853|083|D|minimum concentration (Cmin) decreased by 46%, 42%, and 41%, respectively.|
01853|084|D|Mean cyclosporine dose increased from 2.7 mg/kg/day at 4.2 mg/kg/day at the|
01853|085|D|end of the study.  Subjects required their first cyclosporine dosage|
01853|086|D|adjustment at Day 3.|
01853|087|D|   There are several  case reports of decreased cyclosporine with concurrent|
01853|088|D|carbamazepine, phenobarbital, and St. John's wort.|
01853|089|D|   In healthy subjects, concurrent use of rifampin, a strong inducer of|
01853|090|D|CYP3A4, decreased everolimus AUC and Cmax by 64% and 58%, respectively.|
01853|091|D|   Increasing the dosage of everolimus to 20 mg daily in patients taking a|
01853|092|D|strong inducer of CYP3A4 is expected to increase the AUC of everolimus to|
01853|093|D|levels seen without a concurrent inducer; however, there are no clinical|
01853|094|D|data available with this dosage in patients receiving strong CYP3A4|
01853|095|D|inducers.|
01853|096|D|  In an open-label clinical trial, 10 male patients received ridaforolimus|
01853|097|D|(40 mg daily, days 1 and 14) and rifampin (600 mg daily, days 1-21).|
01853|098|D|Administration of rifampin resulted in a reduction in the mean whole-blood|
01853|099|D|concentration of ridaforolimus (AUC-GMR 0.57, Cmax- GMR 0.66).  The mean|
01853|100|D|whole-blood concentration of ridaforolimus increased 1.5-fold following|
01853|101|D|ketoconazole administration.|
01853|102|D|   In a study in 14 healthy subjects, pretreatment with rifampin (600 mg|
01853|103|D|daily for 14 days) decreased the AUC and Cmax of a single dose of sirolimus|
01853|104|D|(20 mg) by 82% and 71%, respectively.  The oral clearance of sirolimus|
01853|105|D|increased by 5.5-fold.|
01853|106|D|   There are case report of decreased sirolimus levels with concurrent|
01853|107|D|phenytoin and rifampin.|
01853|108|D|   A study in six healthy subjects examined the effects of rifampin on|
01853|109|D|single doses of oral (0.1 mg/kg) and intravenous (0.025 mg/kg/4 hours)|
01853|110|D|tacrolimus.  Rifampin increased tacrolimus clearance by 47% and decreased|
01853|111|D|tacrolimus bioavailability by 51%.|
01853|112|D|   In a study in 10 healthy subjects, pretreatment with St. John's wort (300|
01853|113|D|mg 3 times daily for 18 days) decreased the AUC of a single dose of|
01853|114|D|tacrolimus (0.1 mg/kg) by 35.3%.  Tacrolimus apparent oral clearance and|
01853|115|D|volume of distribution increased by 68% and 53%, respectively.|
01853|116|D|   In a study in 10 renal transplant patients, concurrent St. John's wort|
01853|117|D|(600 mg daily) for 2 weeks increased tacrolimus dose requirements from a|
01853|118|D|baseline of 4.5 mg/day to 8.0 mg/day.  Dose-correct tacrolimus AUC decreased|
01853|119|D|by 57.8%.|
01853|120|D|   There have been several case reports of decreased tacrolimus levels with|
01853|121|D|concurrent carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's|
01853|122|D|wort.   Phenobarbital and phenytoin have been used successfully to treat|
01853|123|D|tacrolimus overdose.|
01853|124|D|   Concurrent rifampin had no significant effects on the AUC or Cmax of|
01853|125|D|temsirolimus; however, sirolimus AUC and Cmax decreased by 56% and 65%,|
01853|126|D|respectively.  A dosage adjustment to 50 mg/week of temsirolimus in the|
01853|127|D|presence of strong CYP3A4 inducers is predicted to adjust levels to those|
01853|128|D|seen without inducers; however, there are no clinical data in patients using|
01853|129|D|this dose.|
01853|130|D|   There is a case report of decreased temsirolimus effectiveness with|
01853|131|D|concurrent rifampin.|
01853|132|B||
01853|133|R|REFERENCES:|
01853|134|B||
01853|135|R|1.Afinitor (everolimus) US prescribing information. Novartaris|1
01853|136|R|  Pharmaceuticals Corporation February, 2020.|1
01853|137|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
01853|138|R|  Aug, 2022.|1
01853|139|R|3.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
01853|140|R|  Inc. March, 2018.|1
01853|141|R|4.Langhoff E, Madsen S. Rapid metabolism of cyclosporin and prednisone in|3
01853|142|R|  kidney transplant patient receiving tuberculostatic treatment. Lancet 1983|3
01853|143|R|  Oct 29;2(8357):1031.|3
01853|144|R|5.Van Buren D, Wideman CA, Ried M, Gibbons S, Van Buren CT, Jarowenko M,|3
01853|145|R|  Flechner SM, Frazier OH, Cooley DA, Kahan BD. The antagonistic effect of|3
01853|146|R|  rifampin upon cyclosporine bioavailability. Transplant Proc 1984 Dec;|3
01853|147|R|  16(6):1642-5.|3
01853|148|R|6.Daniels NJ, Dover JS, Schachter RK. Interaction between cyclosporin and|3
01853|149|R|  rifampicin. Lancet 1984 Sep 15;2(8403):639.|3
01853|150|R|7.Allen RD, Hunnisett AG, Morris PJ. Cyclosporin and rifampicin in renal|3
01853|151|R|  transplantation. Lancet 1985 Apr 27;1(8435):980.|3
01853|152|R|8.Howard P, Bixler TJ, Gill B. Cyclosporine-rifampin drug interaction. Drug|3
01853|153|R|  Intell Clin Pharm 1985 Oct;19(10):763-4.|3
01853|154|R|9.Anonymous. Cyclosporin and antituberculous therapy. Lancet 1985 Jun 8;|3
01853|155|R|  1(8441):1342-3.|3
01853|156|R|10.Cassidy MJ, Van Zyl-Smit R, Pascoe MD, Swanepoel CR, Jacobson JE. Effect|3
01853|157|R|   of rifampicin on cyclosporin A blood levels in a renal transplant|3
01853|158|R|   recipient. Nephron 1985;41(2):207-8.|3
01853|159|R|11.Offermann G, Keller F, Molzahn M. Low cyclosporin A blood levels and|3
01853|160|R|   acute graft rejection in a renal transplant recipient during rifampin|3
01853|161|R|   treatment. Am J Nephrol 1985;5(5):385-7.|3
01853|162|R|12.al-Sulaiman MH, Dhar JM, al-Khader AA. Successful use of rifampicin in|2
01853|163|R|   the treatment of tuberculosis in renal transplant patients|2
01853|164|R|   immunosuppressed with cyclosporine. Transplantation 1990 Oct;50(4):597-8.|2
01853|165|R|13.Vandevelde C, Chang A, Andrews D, Riggs W, Jewesson P. Rifampin and|3
01853|166|R|   ansamycin interactions with cyclosporine after renal transplantation.|3
01853|167|R|   Pharmacotherapy 1991;11(1):88-9.|3
01853|168|R|14.Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of|2
01853|169|R|   cyclosporine with concomitant rifampin administration is markedly less|2
01853|170|R|   than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992 Nov;|2
01853|171|R|   52(5):453-7.|2
01853|172|R|15.Keown PA, Stiller CR, Laupacis AL, Howson W, Coles R, Stawecki M, Koegler|2
01853|173|R|   J, Carruthers G, McKenzie N, Sinclair NR. The effects and side effects of|2
01853|174|R|   cyclosporine: relationship to drug pharmacokinetics. Transplant Proc 1982|2
01853|175|R|   Dec;14(4):659-61.|2
01853|176|R|16.Freeman DJ, Laupacis A, Keown PA, Stiller CR, Carruthers SG. Evaluation|2
01853|177|R|   of cyclosporin-phenytoin interaction with observations on cyclosporin|2
01853|178|R|   metabolites. Br J Clin Pharmacol 1984 Dec;18(6):887-93.|2
01853|179|R|17.Keown PA, Laupacis A, Carruthers G, Stawecki M, Koegler J, McKenzie FN,|2
01853|180|R|   Wall W, Stiller CR. Interaction between phenytoin and cyclosporine|2
01853|181|R|   following organ transplantation. Transplantation 1984 Sep;38(3):304-6.|2
01853|182|R|18.Rowland M, Gupta SK. Cyclosporin-phenytoin interaction: re-evaluation|2
01853|183|R|   using metabolite data. Br J Clin Pharmacol 1987 Sep;24(3):329-34.|2
01853|184|R|19.Ptachcinski RJ, Venkataramanan R, Rosenthal JT, Burckart GJ, Taylor RJ,|2
01853|185|R|   Hakala TR. Cyclosporine kinetics in renal transplantation. Clin Pharmacol|2
01853|186|R|   Ther 1985 Sep;38(3):296-300.|2
01853|187|R|20.Carstensen H, Jacobsen N, Dieperink H. Interaction between cyclosporin A|3
01853|188|R|   and phenobarbitone. Br J Clin Pharmacol 1986 May;21(5):550-1.|3
01853|189|R|21.Noguchi M, Kiuchi C, Akiyama H, Sakamaki H, Onozawa Y. Interaction|3
01853|190|R|   between cyclosporin A and anticonvulsants. Bone Marrow Transplantation|3
01853|191|R|   Team. Bone Marrow Transplant 1992 May;9(5):391.|3
01853|192|R|22.Schofield OM, Camp RD, Levene GM. Cyclosporin A in psoriasis: interaction|3
01853|193|R|   with carbamazepine. Br J Dermatol 1990 Mar;122(3):425-6.|3
01853|194|R|23.Lele P, Peterson P, Yang S, Jarrell B, Burke JF Jr. Cyclosporine and|4
01853|195|R|   tegretrol -- another drug interaction. Kidney Int 1985;27(1):344.|4
01853|196|R|24.Soto Alvarez J, Sacristan Del Castillo JA, Alsar Ortiz MJ. Effect of|3
01853|197|R|   carbamazepine on cyclosporin blood level. Nephron 1991;58(2):235-6.|3
01853|198|R|25.Cooney GF, Mochon M, Kaiser B, Dunn SP, Goldsmith B. Effects of|2
01853|199|R|   carbamazepine on cyclosporine metabolism in pediatric renal transplant|2
01853|200|R|   recipients. Pharmacotherapy 1995 May-Jun;15(3):353-6.|2
01853|201|R|26.Kovarik JM, Hartmann S, Figueiredo J, Rouilly M, Port A, Rordorf C.|2
01853|202|R|   Effect of rifampin on apparent clearance of everolimus. Ann Pharmacother|2
01853|203|R|   2002 Jun;36(6):981-5.|2
01853|204|R|27.Hebert MF, Fisher RM, Marsh CL, Dressler D, Bekersky I. Effects of|2
01853|205|R|   rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin|2
01853|206|R|   Pharmacol 1999 Jan;39(1):91-6.|2
01853|207|R|28.Kiuchi T, Tanaka K, Inomata Y, Uemoto S, Satomura K, Egawa H, Uyama S,|3
01853|208|R|   Sano K, Okajima H, Yamaoka Y. Experience of tacrolimus-based|3
01853|209|R|   immunosuppression in living-related liver transplantation complicated|3
01853|210|R|   with graft tuberculosis: interaction with rifampicin and side effects.|3
01853|211|R|   Transplant Proc 1996 Dec;28(6):3171-2.|3
01853|212|R|29.Furlan V, Perello L, Jacquemin E, Debray D, Taburet AM. Interactions|3
01853|213|R|   between FK506 and rifampicin or erythromycin in pediatric liver|3
01853|214|R|   recipients. Transplantation 1995 Apr 27;59(8):1217-8.|3
01853|215|R|30.Bhaloo S, Prasad GV. Severe reduction in tacrolimus levels with rifampin|3
01853|216|R|   despite multiple cytochrome P450 inhibitors: a case report. Transplant|3
01853|217|R|   Proc 2003 Nov;35(7):2449-51.|3
01853|218|R|31.Chenhsu RY, Loong CC, Chou MH, Lin MF, Yang WC. Renal allograft|3
01853|219|R|   dysfunction associated with rifampin-tacrolimus interaction. Ann|3
01853|220|R|   Pharmacother 2000 Jan;34(1):27-31.|3
01853|221|R|32.Ngo BT, Pascoe M, Kahn D. Drug interaction between rifampicin and|3
01853|222|R|   sirolimus in transplant patients. Saudi J Kidney Dis Transpl 2011|3
01853|223|R|   Jan-Feb;22(1):112-5.|3
01853|224|R|33.Stroh M, Palcza J, McCrea J, Marsilio S, Breidinger S, Panebianco D,|2
01853|225|R|   Johnson-Levonas A, Kraft WK, Orford K, Murphy G, Agrawal N, Trucksis M,|2
01853|226|R|   Wagner JA, Iwamoto M. The effect of multiple doses of rifampin and|2
01853|227|R|   ketoconazole on the single-dose pharmacokinetics of ridaforolimus. Cancer|2
01853|228|R|   Chemother Pharmacol 2012 May;69(5):1247-53.|2
01853|229|R|34.Lopez-Montes A, Gallego E, Lopez E, Perez J, Lorenzo I, Llamas F, Serrano|3
01853|230|R|   A, Andres E, Illescas L, Gomez C. Treatment of tuberculosis with|3
01853|231|R|   rifabutin in a renal transplant recipient. Am J Kidney Dis 2004 Oct;|3
01853|232|R|   44(4):e59-63.|3
01853|233|R|35.Bauer S, Stormer E, Johne A, Kruger H, Budde K, Neumayer HH, Roots I, Mai|2
01853|234|R|   I. Alterations in cyclosporin A pharmacokinetics and metabolism during|2
01853|235|R|   treatment with St John's wort in renal transplant patients. Br J Clin|2
01853|236|R|   Pharmacol 2003 Feb;55(2):203-11.|2
01853|237|R|36.Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John's|2
01853|238|R|   wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy|2
01853|239|R|   volunteers. J Clin Pharmacol 2004 Jan;44(1):89-94.|2
01853|240|R|37.Mai I, Stormer E, Bauer S, Kruger H, Budde K, Roots I. Impact of St|2
01853|241|R|   John's wort treatment on the pharmacokinetics of tacrolimus and|2
01853|242|R|   mycophenolic acid in renal transplant patients. Nephrol Dial Transplant|2
01853|243|R|   2003 Apr;18(4):819-22.|2
01853|244|R|38.Alscher DM, Klotz U. Drug interaction of herbal tea containing St. John's|3
01853|245|R|   wort with cyclosporine. Transpl Int 2003 Jul;16(7):543-4.|3
01853|246|R|39.Turton-Weeks SM, Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz|3
01853|247|R|   SR. St John's wort: a hidden risk for transplant patients. Prog|3
01853|248|R|   Transplant 2001 Jun;11(2):116-20.|3
01853|249|R|40.Moschella C, Jaber BL. Interaction between cyclosporine and Hypericum|3
01853|250|R|   perforatum (St. John's wort) after organ transplantation. Am J Kidney Dis|3
01853|251|R|   2001 Nov;38(5):1105-7.|3
01853|252|R|41.Beer AM, Ostermann T. St. John's wort: interaction with cyclosporine|3
01853|253|R|   increases risk of rejection for the kidney transplant and raises daily|3
01853|254|R|   cost of medication. Med Klin (Munich) 2001 Aug 15;96(8):480-3.|3
01853|255|R|42.Ahmed SM, Banner NR, Dubrey SW. Low cyclosporin-A level due to|3
01853|256|R|   Saint-John's-wort in heart transplant patients. J Heart Lung Transplant|3
01853|257|R|   2001 Jul;20(7):795.|3
01853|258|R|43.Karliova M, Treichel U, Malago M, Frilling A, Gerken G, Broelsch CE.|3
01853|259|R|   Interaction of Hypericum perforatum (St. John's wort) with cyclosporin A|3
01853|260|R|   metabolism in a patient after liver transplantation. J Hepatol 2000 Nov;|3
01853|261|R|   33(5):853-5.|3
01853|262|R|44.Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. Drug|3
01853|263|R|   interaction between St. John's wort and cyclosporine. Ann Pharmacother|3
01853|264|R|   2000 Sep;34(9):1013-6.|3
01853|265|R|45.Mandelbaum A, Pertzborn F, Martin-Facklam M, Wiesel M. Unexplained|3
01853|266|R|   decrease of cyclosporin trough levels in a compliant renal transplant|3
01853|267|R|   patient. Nephrol Dial Transplant 2000 Sep;15(9):1473-4.|3
01853|268|R|46.Breidenbach T, Kliem V, Burg M, Radermacher J, Hoffmann MW, Klempnauer J.|3
01853|269|R|   Profound drop of cyclosporin A whole blood trough levels caused by St.|3
01853|270|R|   John's wort (Hypericum perforatum). Transplantation 2000 May 27;|3
01853|271|R|   69(10):2229-30.|3
01853|272|R|47.Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G. Acute heart|3
01853|273|R|   transplant rejection due to Saint John's wort. Lancet 2000 Feb 12;|3
01853|274|R|   355(9203):548-9.|3
01853|275|R|48.Bolley R, Zulke C, Kammerl M, Fischereder M, Kramer BK.|3
01853|276|R|   Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4|3
01853|277|R|   system with St John's wort. Transplantation 2002 Mar 27;73(6):1009.|3
01853|278|R|49.Fridell JA, Jain AK, Patel K, Virji M, Rao KN, Fung JJ, Venkataramanan R.|3
01853|279|R|   Phenytoin decreases the blood concentrations of sirolimus in a liver|3
01853|280|R|   transplant recipient: a case report. Ther Drug Monit 2003 Feb;|3
01853|281|R|   25(1):117-9.|3
01853|282|R|50.Wada K, Takada M, Ueda T, Ochi H, Kotake T, Morishita H, Hanatani A,|3
01853|283|R|   Nakatani T. Drug interactions between tacrolimus and phenytoin in|3
01853|284|R|   Japanese heart transplant recipients: 2 case reports. Int J Clin|3
01853|285|R|   Pharmacol Ther 2007 Sep;45(9):524-8.|3
01853|286|R|51.Formea CM, Evans CG, Karlix JL. Altered cytochrome p450 metabolism of|3
01853|287|R|   calcineurin inhibitors: case report and review of the literature.|3
01853|288|R|   Pharmacotherapy 2005 Jul;25(7):1021-9.|3
01853|289|R|52.Karasu Z, Gurakar A, Carlson J, Pennington S, Kerwin B, Wright H, Nour B,|3
01853|290|R|   Sebastian A. Acute tacrolimus overdose and treatment with phenytoin in|3
01853|291|R|   liver transplant recipients. J Okla State Med Assoc 2001 Apr;94(4):121-3.|3
01853|292|R|53.Bates D, Burak KW, Coffin CS, Ying T, Enns EM. Phenytoin-induced|3
01853|293|R|   reduction in sirolimus levels. Can J Hosp Pharm 2011 Jul;64(4):271-4.|3
01853|294|R|54.Siddiqi N, Marfo K. Clinically significant drug-drug interaction between|3
01853|295|R|   tacrolimus and phenobarbital: the price we pay. J Pharm Pract 2010 Dec;|3
01853|296|R|   23(6):585-9.|3
01853|297|R|55.Coriat R, Mir O, Ropert S, Loulergue P, Billemont B, Goldwasser F.|3
01853|298|R|   Reactivation of tuberculosis during temsirolimus therapy. Invest New|3
01853|299|R|   Drugs 2011 Dec;29(6):1494-6.|3
01853|300|R|56.Abdel Halim M, Al-Otaibi T, Gheith O, El-Kholy O, Abdel Tawab K, Said T,|3
01853|301|R|   Nair P, Nampoory MR. Toxic tacrolimus blood levels with rifampin|3
01853|302|R|   administration in a renal transplant  recipient. Ann Transplant 2010|3
01853|303|R|   Jan-Mar;15(1):57-60.|3
01853|304|R|57.Wada K, Takada M, Sakai M, Ochi H, Kotake T, Okada H, Morishita H, Oda N,|3
01853|305|R|   Mano A, Kato TS, Komamura K, Nakatani T. Drug interaction between|3
01853|306|R|   tacrolimus and carbamazepine in a Japanese heart transplant recipient: a|3
01853|307|R|   case report. J Heart Lung Transplant 2009 Apr;28(4):409-11.|3
01853|308|R|58.Quiros-Tejeira RE, Chang IF, Bristow LJ, Karpen SJ, Goss JA. Treatment of|3
01853|309|R|   acute tacrolimus whole-blood elevation with phenobarbital in the|3
01853|310|R|   pediatric liver transplant recipient. Pediatr Transplant 2005 Dec;|3
01853|311|R|   9(6):792-6.|3
01853|312|R|59.McLaughlin GE, Rossique-Gonzalez M, Gelman B, Kato T. Use of|3
01853|313|R|   phenobarbital in the management of acute tacrolimus toxicity: a case|3
01853|314|R|   report. Transplant Proc 2000 May;32(3):665-8.|3
01853|315|R|60.Jahansouz F, Kriett JM, Smith CM, Jamieson SW. Potentiation of|2
01853|316|R|   cyclosporine nephrotoxicity by nafcillin in lung transplant recipients.|2
01853|317|R|   Transplantation 1993 May;55(5):1045-8.|2
01853|318|R|61.Veremis SA, Maddux MS, Pollak R, Mozes MF. Subtherapeutic cyclosporine|3
01853|319|R|   concentrations during nafcillin therapy. Transplantation 1987 Jun;|3
01853|320|R|   43(6):913-5.|3
01853|321|R|62.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
01853|322|R|   immunosuppressants-Guidelines from the American Society of|6
01853|323|R|   Transplantation Infectious Diseases Community of Practice. Clin|6
01853|324|R|   Transplant 2019 Feb 28;e13510.|6
01854|001|T|MONOGRAPH TITLE:  Everolimus/Strong CYP3A4 Inhibitors; Darunavir|
01854|002|B||
01854|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01854|004|L|of severe adverse interaction.|
01854|005|B||
01854|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
01854|007|A|everolimus.(1,2)|
01854|008|B||
01854|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
01854|010|E|elevated levels of and toxicity from everolimus.(1,2)|
01854|011|B||
01854|012|P|PREDISPOSING FACTORS:  None determined.|
01854|013|B||
01854|014|M|PATIENT MANAGEMENT:  The US manufacturer of everolimus states that|
01854|015|M|concurrent use of strong inhibitors of CYP3A4 should be avoided.(1,2)  The|
01854|016|M|Department of Health and Human Services HIV guidelines state that darunavir|
01854|017|M|should not be coadministered with everolimus, and therapeutic drug|
01854|018|M|monitoring is recommended when everolimus is used with other protease|
01854|019|M|inhibitors.(3)  The American Society of Transplantation (AST) guidelines|
01854|020|M|state that clarithromycin, ketoconazole, voriconazole, and HIV protease|
01854|021|M|inhibitors are contraindicated with everolimus.(4)|
01854|022|M|   If the combination of clarithromycin and everolimus must be used, AST|
01854|023|M|guidelines recommend lowering the dose of everolimus by up to 50% upon|
01854|024|M|initiation of the antibiotic and monitoring levels daily.(4)|
01854|025|M|   The US manufacturer of itraconazole states that concurrent use of|
01854|026|M|everolimus is not recommended during and two weeks after itraconazole|
01854|027|M|treatment.(5)  If everolimus is used with itraconazole or ketoconazole, AST|
01854|028|M|guidelines recommend lowering the dose of everolimus by at least 50% and|
01854|029|M|monitoring everolimus levels closely.(4)  Case reports have described the|
01854|030|M|use of voriconazole with everolimus.(6)|
01854|031|B||
01854|032|D|DISCUSSION:  In a study in healthy subjects, concurrent use of ketoconazole,|
01854|033|D|a strong CYP3A4 inhibitor and a Pg-p inhibitor, increased everolimus|
01854|034|D|area-under-curve (AUC) and maximum concentration (Cmax) by 3.9-fold and|
01854|035|D|15.0-fold, respectively.(1)|
01854|036|D|   In a case report, a renal transplant patient on everolimus and started on|
01854|037|D|voriconazole experienced an increase in everolimus trough concentration|
01854|038|D|(Cmin) of 7.5-fold, which was normalized with a lowering of everolimus dose|
01854|039|D|from 1.5 mg twice daily to 0.25 mg twice daily.  Voriconazole was|
01854|040|D|discontinued after one month, and another month later, posaconazole was|
01854|041|D|started.  Cmin increased by 3.8-fold, which led to an adjustment of|
01854|042|D|everolimus dose from 1 mg twice daily to 0.5 mg twice daily.(6)|
01854|043|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
01854|044|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole,|
01854|045|D|ketoconazole, lonafarnib, lopinavir, nefazodone, nirmatrelvir/ritonavir,|
01854|046|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
01854|047|D|tucatinib, and voriconazole.(1,7,8)|
01854|048|D|   Moderate inhibitors of CYP3A4 have been shown to have less of an effect|
01854|049|D|on everolimus pharmacokinetics.  In a study in healthy subjects, concurrent|
01854|050|D|use of erythromycin, a moderate CYP3A4 inhibitor and a P-gp inhibitor,|
01854|051|D|increased everolimus AUC and Cmax by 2.0-fold and 4.4-fold, respectively.(1)|
01854|052|D|In a study in healthy subjects, concurrent use of verapamil, a moderate|
01854|053|D|CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by|
01854|054|D|2.3-fold and 3.5-fold, respectively.(1)|
01854|055|B||
01854|056|R|REFERENCES:|
01854|057|B||
01854|058|R|1.Afinitor (everolimus) US prescribing information. Novartaris|1
01854|059|R|  Pharmaceuticals Corporation February, 2020.|1
01854|060|R|2.Zortress (everolimus) US prescribing information. Novartis Pharmaceuticals|1
01854|061|R|  Corporation Sept, 2023.|1
01854|062|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01854|063|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01854|064|R|  HIV. Department of Health and Human Services. Available at:|6
01854|065|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
01854|066|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
01854|067|R|4.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
01854|068|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
01854|069|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
01854|070|R|  e13510.|6
01854|071|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01854|072|R|  Products, L.P. February, 2024.|1
01854|073|R|6.Billaud EM, Antoine C, Berge M, Abboud I, Lefeuvre S, Benammar M, Glotz D.|3
01854|074|R|  Management of metabolic cytochrome P450 3A4 drug-drug interaction between|3
01854|075|R|  everolimus and azole antifungals in a renal transplant patient. Clin Drug|3
01854|076|R|  Investig 2009;29(7):481-6.|3
01854|077|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
01854|078|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01854|079|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01854|080|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01854|081|R|  11/14/2017.|1
01854|082|R|8.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
01854|083|R|  Indiana University School of Medicine.  Available at:|1
01854|084|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
01855|001|T|MONOGRAPH TITLE:  Everolimus/Dual P-gp and Moderate CYP3A4 Inhibitors|
01855|002|B||
01855|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01855|004|L|take action as needed.|
01855|005|B||
01855|006|A|MECHANISM OF ACTION:  Dual P-glycoprotein (P-gp) and moderate CYP3A4|
01855|007|A|inhibitors may increase absorption and decrease elimination of|
01855|008|A|everolimus.(1-2)|
01855|009|B||
01855|010|E|CLINICAL EFFECTS:  Concurrent use of dual P-gp and moderate CYP3A4|
01855|011|E|inhibitors may result in elevated levels of and toxicity from|
01855|012|E|everolimus.(1-2)|
01855|013|B||
01855|014|P|PREDISPOSING FACTORS:  None determined.|
01855|015|B||
01855|016|M|PATIENT MANAGEMENT:  If concurrent therapy with everolimus and dual P-gp and|
01855|017|M|moderate CYP3A4 inhibitors is warranted, reduce the dosage of everolimus.(1)|
01855|018|M|   In patients with advanced hormone receptor-positive, HER2-negative breast|
01855|019|M|cancer (HR+BC); advanced pancreatic neuroendocrine tumors (PNET); advanced|
01855|020|M|renal cell carcinoma; or renal angiomyolipoma with TSC, decrease the dose of|
01855|021|M|everolimus to 2.5 mg daily.  An increase to 5 mg daily may be considered|
01855|022|M|based on patient tolerance.  If the inhibitor is discontinued, allow an|
01855|023|M|elimination period of 3 days before increasing the dose to that used prior|
01855|024|M|to the inhibitor.(1)|
01855|025|M|   In patients with subependymal giant cell astrocytoma with TSC and|
01855|026|M|TSC-associated partial-onset seizures, reduce the dosage of everolimus by|
01855|027|M|50% to maintain trough concentrations of 5 ng/ml to 15 ng/ml.  If the|
01855|028|M|patient is already receiving 2.5 mg daily, consider a dose of 2.5 mg every|
01855|029|M|other day.  Assess everolimus levels 2 weeks after the addition of the|
01855|030|M|inhibitor.  Resume the everolimus dose used prior to initiation of the|
01855|031|M|inhibitor after the inhibitor has been discontinued for 3 days, and assess|
01855|032|M|everolimus trough levels 2 weeks later.(1)|
01855|033|M|   In patients taking everolimus for prophylaxis of organ rejection, monitor|
01855|034|M|everolimus blood concentration and adjust dose as needed.(2)|
01855|035|M|   Guidelines from the American Society of Transplantation state that|
01855|036|M|protease inhibitors are contraindicated, and recommend avoiding the use of|
01855|037|M|erythromycin with everolimus.  If the combination must be used, lower the|
01855|038|M|dose of everolimus by up to 50% upon initiation of the antibiotic and|
01855|039|M|monitor levels daily.(3)|
01855|040|B||
01855|041|D|DISCUSSION:  In a study in healthy subjects, concurrent use of erythromycin,|
01855|042|D|a moderate CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC|
01855|043|D|and Cmax by 2.0-fold and 4.4-fold, respectively.(1)|
01855|044|D|   In a study in healthy subjects, concurrent use of ketoconazole, a strong|
01855|045|D|CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus area-under-curve|
01855|046|D|(AUC) and maximum concentration (Cmax) by 3.9-fold and 15.0-fold,|
01855|047|D|respectively.(1)|
01855|048|D|   In a study in healthy subjects, concurrent use of verapamil, a moderate|
01855|049|D|CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by|
01855|050|D|2.3-fold and 3.5-fold, respectively.(1)|
01855|051|D|   In a study in 16 healthy subjects, concurrent use of verapamil increased|
01855|052|D|everolimus Cmax and AUC by 130% and 250%, respectively.(4)|
01855|053|D|   Moderate CYP3A4 and/or P-gp inhibitors include: conivaptan, diltiazem,|
01855|054|D|dronedarone, erythromycin, fluvoxamine, isavuconazonium, lenacapavir,|
01855|055|D|rilzabrutinib, and verapamil.(5-7)|
01855|056|B||
01855|057|R|REFERENCES:|
01855|058|B||
01855|059|R|1.Afinitor (everolimus) US prescribing information. Novartaris|1
01855|060|R|  Pharmaceuticals Corporation February, 2020.|1
01855|061|R|2.Zortress (everolimus) US prescribing information. Novartis Pharmaceuticals|1
01855|062|R|  Corporation Sept, 2023.|1
01855|063|R|3.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
01855|064|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
01855|065|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
01855|066|R|  e13510.|6
01855|067|R|4.Covera-HS (verapamil hydrochloride) US prescribing information. G.D.|1
01855|068|R|  Searle LLC September, 2017.|1
01855|069|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
01855|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01855|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01855|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01855|073|R|  11/14/2017.|1
01855|074|R|6.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
01855|075|R|  Indiana University School of Medicine.  Available at:|1
01855|076|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
01855|077|R|7.This information is based on an extract from the Certara Drug Interaction|6
01855|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01856|001|T|MONOGRAPH TITLE:  Everolimus/Aprepitant (mono deleted 09/15/2011)|
01856|002|B||
01856|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01856|004|L|of severe adverse interaction.|
01856|005|B||
01856|006|A|MECHANISM OF ACTION:  Aprepitant may inhibit the metabolism of everolimus by|
01856|007|A|CYP P-450-3A4.(1)|
01856|008|B||
01856|009|E|CLINICAL EFFECTS:  Concurrent use of aprepitant may result in elevated|
01856|010|E|levels of and toxicity from everolimus.(1)|
01856|011|B||
01856|012|P|PREDISPOSING FACTORS:  None determined.|
01856|013|B||
01856|014|M|PATIENT MANAGEMENT:  The US manufacturer of everolimus states that|
01856|015|M|concurrent use of strong or moderate inhibitors of CYP P-450-3A4 such as|
01856|016|M|aprepitant should be avoided.(1)|
01856|017|B||
01856|018|D|DISCUSSION:  In a study in healthy subjects, concurrent use of ketoconazole,|
01856|019|D|a strong CYP P-450-3A4 inhibitor and a PgP inhibitor, increased everolimus|
01856|020|D|area-under-curve (AUC) and maximum concentration (Cmax) by 3.9-fold and|
01856|021|D|15.0-fold, respectively.(1)|
01856|022|D|   In a study in healthy subjects, concurrent use of erythromycin, a|
01856|023|D|moderate CYP P-450-3A4 inhibitor and a PgP inhibitor, increased everolimus|
01856|024|D|AUC and Cmax by 2.0-fold and 4.4-fold, respectively.(1)|
01856|025|D|   In a study in healthy subjects, concurrent use of verapamil, a moderate|
01856|026|D|CYP P-450-3A4 inhibitor and a PgP inhibitor, increased everolimus AUC and|
01856|027|D|Cmax by 2.3-fold and 3.5-fold, respectively.(1)|
01856|028|B||
01856|029|R|REFERENCE:|
01856|030|B||
01856|031|R|1.Afinitor (everolimus) US prescribing information. Novartis Pharmaceuticals|1
01856|032|R|  Corporation March, 2009.|1
01857|001|T|MONOGRAPH TITLE:  Everolimus/Diltiazem (mono deleted 09/15/2011)|
01857|002|B||
01857|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01857|004|L|of severe adverse interaction.|
01857|005|B||
01857|006|A|MECHANISM OF ACTION:  Diltiazem may inhibit the metabolism of everolimus by|
01857|007|A|CYP P-450-3A4.(1)|
01857|008|B||
01857|009|E|CLINICAL EFFECTS:  Concurrent use of diltiazem may result in elevated levels|
01857|010|E|of and toxicity from everolimus.(1)|
01857|011|B||
01857|012|P|PREDISPOSING FACTORS:  None determined.|
01857|013|B||
01857|014|M|PATIENT MANAGEMENT:  The US manufacturer of everolimus states that|
01857|015|M|concurrent use of strong or moderate inhibitors of CYP P-450-3A4 such as|
01857|016|M|diltiazem should be avoided.(1)|
01857|017|B||
01857|018|D|DISCUSSION:  In a study in healthy subjects, concurrent use of ketoconazole,|
01857|019|D|a strong CYP P-450-3A4 inhibitor and a PgP inhibitor, increased everolimus|
01857|020|D|area-under-curve (AUC) and maximum concentration (Cmax) by 3.9-fold and|
01857|021|D|15.0-fold, respectively.(1)|
01857|022|D|   In a study in healthy subjects, concurrent use of erythromycin, a|
01857|023|D|moderate CYP P-450-3A4 inhibitor and a PgP inhibitor, increased everolimus|
01857|024|D|AUC and Cmax by 2.0-fold and 4.4-fold, respectively.(1)|
01857|025|D|   In a study in healthy subjects, concurrent use of verapamil, a moderate|
01857|026|D|CYP P-450-3A4 inhibitor and a PgP inhibitor, increased everolimus AUC and|
01857|027|D|Cmax by 2.3-fold and 3.5-fold, respectively.(1)|
01857|028|B||
01857|029|R|REFERENCE:|
01857|030|B||
01857|031|R|1.Afinitor (everolimus) US prescribing information. Novartis Pharmaceuticals|1
01857|032|R|  Corporation March, 2009.|1
01858|001|T|MONOGRAPH TITLE:  Everolimus/Verapamil (mono deleted 09/15/2011)|
01858|002|B||
01858|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01858|004|L|is contraindicated and generally should not be dispensed or administered to|
01858|005|L|the same patient.|
01858|006|B||
01858|007|A|MECHANISM OF ACTION:  Verapamil may inhibit the metabolism of everolimus by|
01858|008|A|CYP P-450-3A4.(1)|
01858|009|B||
01858|010|E|CLINICAL EFFECTS:  Concurrent use of verapamil may result in elevated levels|
01858|011|E|of and toxicity from everolimus.(1)|
01858|012|B||
01858|013|P|PREDISPOSING FACTORS:  None determined.|
01858|014|B||
01858|015|M|PATIENT MANAGEMENT:  The US manufacturer of everolimus states that strong or|
01858|016|M|moderate inhibitors of CYP P-450-3A4 and PgP such as verapamil should not be|
01858|017|M|used with everolimus.(1)|
01858|018|B||
01858|019|D|DISCUSSION:  In a study in healthy subjects, concurrent use of verapamil, a|
01858|020|D|moderate CYP P-450-3A4 inhibitor and a PgP inhibitor, increased everolimus|
01858|021|D|AUC and Cmax by 2.3-fold and 3.5-fold, respectively.(1)|
01858|022|B||
01858|023|R|REFERENCE:|
01858|024|B||
01858|025|R|1.Afinitor (everolimus) US prescribing information. Novartis Pharmaceuticals|1
01858|026|R|  Corporation March, 2009.|1
01859|001|T|MONOGRAPH TITLE:  Linezolid/MAOIs|
01859|002|B||
01859|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01859|004|L|is contraindicated and generally should not be dispensed or administered to|
01859|005|L|the same patient.|
01859|006|B||
01859|007|A|MECHANISM OF ACTION:  Linezolid is a reversible, nonselective inhibitor of|
01859|008|A|monoamine oxidase (MAO).(1,2)|
01859|009|B||
01859|010|E|CLINICAL EFFECTS:  Concurrent use of linezolid and other MAO inhibitors may|
01859|011|E|result in additive effects and toxicity.(1,2)|
01859|012|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
01859|013|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
01859|014|E|rigidity.|
01859|015|B||
01859|016|P|PREDISPOSING FACTORS:  None determined.|
01859|017|B||
01859|018|M|PATIENT MANAGEMENT:  The US and UK manufacturer of linezolid state that it|
01859|019|M|should not be used within 2 weeks of another product which inhibits|
01859|020|M|monoamine oxidase A or B.(1,2)|
01859|021|M|   In emergency situations in patients maintained on linezolid, weigh the|
01859|022|M|availability and safety of alternatives to linezolid against the risk of|
01859|023|M|serotonin syndrome.  If therapy with linezolid is required, discontinue the|
01859|024|M|MAOI immediately.  Patients should be monitored for serotonin syndrome for 2|
01859|025|M|weeks or until 24 hours after the last dose of linezolid, whichever comes|
01859|026|M|first.(3,4)|
01859|027|M|   In non-emergency situations in patients maintained on MAOIs when|
01859|028|M|linezolid therapy is planned, discontinue the patient's MAOI at least 2|
01859|029|M|weeks in advance of linezolid therapy.  The patient's MAOI therapy may be|
01859|030|M|resumed 24 hours after the last dose of linezolid.(3)|
01859|031|M|   Do not initiate MAOI therapy in patients receiving linezolid until 24|
01859|032|M|hours after the last dose of the linezolid.(3,4)|
01859|033|M|   If concurrent therapy is warranted, patients should be monitored for|
01859|034|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
01859|035|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
01859|036|M|heart palpitations, restlessness, confusion, agitation, trouble with|
01859|037|M|coordination, or severe diarrhea.|
01859|038|B||
01859|039|D|DISCUSSION:  Linezolid is a reversible, nonselective inhibitor MAO.|
01859|040|D|Concurrent use of linezolid and other MAO inhibitors may result in additive|
01859|041|D|effects and toxicity.  The US and UK manufacturer of linezolid state that it|
01859|042|D|should not be used within 2 weeks of another product which inhibits|
01859|043|D|monoamine oxidase A or B.(1,2)|
01859|044|D|   Methylene blue, when administered intravenously, has been shown to reach|
01859|045|D|sufficient concentrations to be a potent inhibitor of MAO-A.(5,6)|
01859|046|D|   Metaxalone is a weak inhibitor of MAO.(7.8)|
01859|047|D|   The FDA AERS contains reports of serotonin syndrome with the concurrent|
01859|048|D|use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram,|
01859|049|D|fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine as well as|
01859|050|D|reports of serotonin syndrome with concurrent injectable methylene blue and|
01859|051|D|citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine,|
01859|052|D|escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and|
01859|053|D|venlafaxine.  The risk of serotonin syndrome with other psychiatric drugs is|
01859|054|D|unclear.(9,10)|
01859|055|B||
01859|056|R|REFERENCES:|
01859|057|B||
01859|058|R|1.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
01859|059|R|2.Zyvox (linezolid) UK summary of product characteristics. Pharmacia Limited|1
01859|060|R|  July 10, 2008.|1
01859|061|R|3.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
01859|062|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
01859|063|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
01859|064|R|4.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
01859|065|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
01859|066|R|  2000 Jun;56(3):247-50.|2
01859|067|R|5.USFood and Drug Administration. FDA Drug Safety Communication: Serious CNS|1
01859|068|R|  reactions possible when linezolid (Zyvox) is given to patients taking|1
01859|069|R|  certain psychiatric medications. available at:|1
01859|070|R|  http://wayback.archive-it.org/7993/20170722185915/https://www.fda.gov/Drug|1
01859|071|R|  s/DrugSafety/ucm265305.htm July 26, 2011.|1
01859|072|R|6.USFood and Drug Administration. FDA Drug Safety Communication: Serious CNS|1
01859|073|R|  reactions possible when methylene blue is given to patients taking certain|1
01859|074|R|  psychiatric medications. available at:|1
01859|075|R|  http://wayback.archive-it.org/7993/20170722185916/https://www.fda.gov/Drug|1
01859|076|R|  s/DrugSafety/ucm263190.htm July 26, 2011.|1
01859|077|R|7.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
01859|078|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
01859|079|R|  Feb;34(2):346.e5-6.|3
01859|080|R|8.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
01859|081|R|  Pfizer Inc. January, 2024.|1
01859|082|R|9.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
01859|083|R|  information about the drug interaction between methylene blue|1
01859|084|R|  (methylthioninium chloride) and serotonergic psychiatric medications.|1
01859|085|R|  available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
01859|086|R|  21, 2011.|1
01859|087|R|10.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
01859|088|R|   information about the drug interaction between linezolid (Zyvox) and|1
01859|089|R|   serotonergic psychiatric medications. available at:|1
01859|090|R|   http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm October 21, 2011.|1
01860|001|T|MONOGRAPH TITLE:  Barbiturates/Phenothiazines|
01860|002|B||
01860|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01860|004|L|take action as needed.|
01860|005|B||
01860|006|A|MECHANISM OF ACTION:  The concurrent administration of phenothiazines and|
01860|007|A|barbiturates may result in additive CNS depressant effects.  Some|
01860|008|A|barbiturates may induce the metabolism of phenothiazines.|
01860|009|A|   Primidone is metabolized to phenobarbital.|
01860|010|B||
01860|011|E|CLINICAL EFFECTS:  Concurrent use of phenothiazines without barbiturate|
01860|012|E|dosage adjustment may result in potentiation of CNS depression, which may|
01860|013|E|result in hypotension, increased sedation, and respiratory depression.|
01860|014|E|   Phenothiazines do not intensify the anti-convulsant effects of|
01860|015|E|barbiturates.|
01860|016|E|   Some barbiturates may reduce the effectiveness of phenothiazines.|
01860|017|B||
01860|018|P|PREDISPOSING FACTORS:  None determined.|
01860|019|B||
01860|020|M|PATIENT MANAGEMENT:  Respiration and blood pressure should be closely|
01860|021|M|monitored in patients receiving concurrent barbiturate and phenothiazine|
01860|022|M|therapy.  The dosage of the barbiturate may need to be adjusted in patients|
01860|023|M|receiving barbiturates for indications other than anticonvulsant use.|
01860|024|M|   One US manufacturer of chlorpromazine recommends a barbiturate dosage|
01860|025|M|reduction of one-fourth to one-half in patients receiving barbiturates for|
01860|026|M|indications other than as an anticonvulsant.  In patients taking|
01860|027|M|barbiturates as an anticonvulsant, start chlorpromazine at a low dose and|
01860|028|M|increase as needed.|
01860|029|M|   One US manufacturer of promethazine recommends a barbiturate dosage|
01860|030|M|reduction by at least one one-half.|
01860|031|B||
01860|032|D|DISCUSSION:  A study in rats found increased sleeping time with concurrent|
01860|033|D|chlorpromazine and pentobarbital.  Another study in rats found an increase|
01860|034|D|in pentobarbital concentrations with concurrent chlorpromazine.|
01860|035|D|   In a study in 10 subjects, the addition of phenobarbital to|
01860|036|D|chlorpromazine therapy increased chlorpromazine excretion by 37%.  In|
01860|037|D|another study, the addition of phenobarbital decreased chlorpromazine|
01860|038|D|levels.  In a case report, the addition of phenobarbital to a patient|
01860|039|D|maintained on chlorpromazine resulted in decreased chlorpromazine levels and|
01860|040|D|effectiveness.|
01860|041|D|   In a study in patients, phenobarbital decreased thioridazine levels.  In|
01860|042|D|contrast, another study found increased thioridazine levels following the|
01860|043|D|addition of phenobarbital and another found no affect on thioridazine levels|
01860|044|D|but decreased mesoridazine levels.|
01860|045|B||
01860|046|R|REFERENCES:|
01860|047|B||
01860|048|R|1.Phenergan (promethazine hydrochloride) US prescribing information. Baxter|1
01860|049|R|  Healthcare Corporation December, 2006.|1
01860|050|R|2.Chlorpromazine hydrochloride US prescribing information. Baxter Healthcare|1
01860|051|R|  Corporation October, 2006.|1
01860|052|R|3.Hatanaka T, Negishi S, Katayama K, Kakemi M, Koizumi T. The|5
01860|053|R|  pharmacodynamic and pharmacokinetic interaction of pentobarbital and|5
01860|054|R|  chlorpromazine in rats. J Pharmacobiodyn 1988 Jan;11(1):47-52.|5
01860|055|R|4.Hatanaka T, Sato S, Endoh M, Katayama K, Kakemi M, Koizumi T. Effect of|5
01860|056|R|  chlorpromazine on the pharmacokinetics and pharmacodynamics of|5
01860|057|R|  pentobarbital in rats. J Pharmacobiodyn 1988 Jan;11(1):18-30.|5
01860|058|R|5.Forrest FM, Forrest IS, Serra MT. Modification of chlorpromazine|2
01860|059|R|  metabolism by some other drugs frequently administered to psychiatric|2
01860|060|R|  patients. Biol Psychiatry 1970 Jan;2(1):53-8.|2
01860|061|R|6.Curry SH, Marshall JH, Davis JM, Janowsky DS. Chlorpromazine plasma levels|3
01860|062|R|  and effects. Arch Gen Psychiatry 1970 Apr;22(4):289-96.|3
01860|063|R|7.Loga S, Curry S, Lader M. Interactions of orphenadrine and phenobarbitone|2
01860|064|R|  with chlorpromazine: plasma concentrations and effects in man. Br J Clin|2
01860|065|R|  Pharmacol 1975 Jun;2(3):197-208.|2
01860|066|R|8.Gay PE, Madsen JA. Interaction between phenobarbital and thioridazine.|2
01860|067|R|  Neurology 1983 Dec;33(12):1631-2.|2
01860|068|R|9.Ellenor GL, Musa MN, Beuthin FC. Phenobarbital--thioridazine interaction|2
01860|069|R|  in man. Res Commun Chem Pathol Pharmacol 1978 Jul;21(1):185-8.|2
01860|070|R|10.Linnoila M, Viukari M, Vaisanen K, Auvinen J. Effect of anticonvulsants|2
01860|071|R|   on plasma haloperidol and thioridazine levels. Am J Psychiatry 1980 Jul;|2
01860|072|R|   137(7):819-21.|2
01861|001|T|MONOGRAPH TITLE:  Artemether-Lumefantrine/QT Prolonging Agents|
01861|002|B||
01861|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01861|004|L|is contraindicated and generally should not be dispensed or administered to|
01861|005|L|the same patient.|
01861|006|B||
01861|007|A|MECHANISM OF ACTION:  Concurrent use of artemether-lumefantrine and agents|
01861|008|A|known to prolong the QT interval may result in additive or synergistic|
01861|009|A|effects on the QTc interval.(1)|
01861|010|B||
01861|011|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01861|012|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01861|013|E|torsades de pointes.|
01861|014|B||
01861|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01861|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01861|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01861|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01861|019|P|gender, or advanced age.(4)|
01861|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01861|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01861|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01861|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01861|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01861|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01861|026|P|dysfunction).(4)|
01861|027|B||
01861|028|M|PATIENT MANAGEMENT:  The UK manufacturer of artemether-lumefantrine states|
01861|029|M|that the use of artemether-lumefantrine in patients taking drugs that are|
01861|030|M|known to prolong the QTc interval is contraindicated.  These agents include|
01861|031|M|class IA and III antiarrhythmics; neuroleptics; antidepressive agents; some|
01861|032|M|macrolides, fluoroquinolones, imidazole and triazole antifungals;|
01861|033|M|terfenadine; astemizole; and cisapride.(1)|
01861|034|M|   The US manufacturer of artemether-lumefantrine states that the use of|
01861|035|M|artemether-lumefantrine should be avoided in patients taking drugs that are|
01861|036|M|known to prolong the QTc interval.  These agents include class IA and III|
01861|037|M|antiarrhythmics; neuroleptics; antidepressive agents; some macrolides,|
01861|038|M|fluoroquinolones, imidazole and triazole antifungals; terfenadine;|
01861|039|M|astemizole; and cisapride.(2)|
01861|040|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01861|041|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01861|042|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01861|043|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01861|044|B||
01861|045|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01861|046|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01861|047|D|monograph have been shown to prolong the QTc interval either through their|
01861|048|D|mechanism of action, through studies on their effects on the QTc interval,|
01861|049|D|or through reports of QTc prolongation and/or torsades de pointes in|
01861|050|D|clinical trials and/or postmarketing reports.(3)|
01861|051|B||
01861|052|R|REFERENCES:|
01861|053|B||
01861|054|R|1.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
01861|055|R|  Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
01861|056|R|2.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01861|057|R|  Pharmaceuticals Corporation August, 2019.|1
01861|058|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01861|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01861|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01861|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01861|062|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01861|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01861|064|R|  settings: a scientific statement from the American Heart Association and|6
01861|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01861|066|R|  2;55(9):934-47.|6
01862|001|T|MONOGRAPH TITLE:  Artemether-Lumefantrine/Possible QT Prolonging Agents|
01862|002|B||
01862|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01862|004|L|of severe adverse interaction.|
01862|005|B||
01862|006|A|MECHANISM OF ACTION:  Concurrent use of artemether-lumefantrine and agents|
01862|007|A|known to prolong the QT interval may result in additive or synergistic|
01862|008|A|effects on the QTc interval.(1)|
01862|009|B||
01862|010|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01862|011|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01862|012|E|torsades de pointes.|
01862|013|B||
01862|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01862|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01862|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01862|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01862|018|P|gender, or advanced age.(4)|
01862|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01862|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01862|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01862|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01862|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01862|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01862|025|P|dysfunction).(4)|
01862|026|B||
01862|027|M|PATIENT MANAGEMENT:  The UK manufacturer of artemether-lumefantrine states|
01862|028|M|that the use of artemether-lumefantrine in patients taking drugs that are|
01862|029|M|known to prolong the QTc interval is contraindicated.  These agents include|
01862|030|M|class IA and III antiarrhythmics; neuroleptics; antidepressive agents; some|
01862|031|M|macrolides, fluoroquinolones, imidazole and triazole antifungals;|
01862|032|M|terfenadine; astemizole; and cisapride.(1)|
01862|033|M|   The US manufacturer of artemether-lumefantrine states that the use of|
01862|034|M|artemether-lumefantrine should be avoided in patients taking drugs that are|
01862|035|M|known to prolong the QTc interval.  These agents include class IA and III|
01862|036|M|antiarrhythmics; neuroleptics; antidepressive agents; some macrolides,|
01862|037|M|fluoroquinolones, imidazole and triazole antifungals; terfenadine;|
01862|038|M|astemizole; and cisapride.(2)|
01862|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01862|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01862|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01862|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01862|043|B||
01862|044|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01862|045|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01862|046|D|monograph have been shown to prolong the QTc interval either through their|
01862|047|D|mechanism of action, through studies on their effects on the QTc interval,|
01862|048|D|or through reports of QTc prolongation and/or torsades de pointes in|
01862|049|D|clinical trials and/or postmarketing reports.(3)|
01862|050|B||
01862|051|R|REFERENCES:|
01862|052|B||
01862|053|R|1.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
01862|054|R|  Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
01862|055|R|2.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
01862|056|R|  Pharmaceuticals Corporation August, 2019.|1
01862|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01862|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01862|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01862|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01862|061|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01862|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01862|063|R|  settings: a scientific statement from the American Heart Association and|6
01862|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01862|065|R|  2;55(9):934-47.|6
01863|001|T|MONOGRAPH TITLE:  Quinidine; Hydroquinidine; Natisedine/Selected QT|
01863|002|T|Prolongers (mono deleted 10/22/2015)|
01863|003|B||
01863|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01863|005|L|take action as needed.|
01863|006|B||
01863|007|A|MECHANISM OF ACTION:  Concurrent use of quinidine, hydroquinidine, or|
01863|008|A|natisedine with agents known to prolong the QTc interval may result in|
01863|009|A|additive effects on the QTc interval.|
01863|010|B||
01863|011|E|CLINICAL EFFECTS:  Concurrent use may result in potentially life-threatening|
01863|012|E|cardiac arrhythmias, including torsades de pointes.(1-48)|
01863|013|B||
01863|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01863|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01863|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01863|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01863|018|P|gender, or advanced age.(1)|
01863|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01863|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01863|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01863|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01863|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01863|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01863|025|P|dysfunction).(1)|
01863|026|B||
01863|027|M|PATIENT MANAGEMENT:  In addition to agent-specific recommendations below, if|
01863|028|M|concurrent therapy is warranted consider obtaining serum calcium, magnesium,|
01863|029|M|and potassium levels at baseline and regular intervals. Correct any|
01863|030|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01863|031|M|heartbeat, dizziness, or fainting.|
01863|032|M|   The manufacturers of alfuzosin,(2) apomorphine,(3) clozapine,(4)|
01863|033|M|dasatinib,(5) dolasetron,(6) domperidone,(7), fesoterodine,(8)|
01863|034|M|formoterol,(9,10) gadoxetate,(11,12) haloperidol,(13-15) lapatinib,(16)|
01863|035|M|methadone,(17) pazopanib,(18) rilpivirine,(19) risperidone,(20) and|
01863|036|M|vorticosa(21) state that these agents should used with caution with other|
01863|037|M|agents known to prolong the QT interval.|
01863|038|M|   The manufacturer of abarelix states that physicians should consider if|
01863|039|M|the risks of QTc prolongation outweigh the benefits of abarelix therapy in|
01863|040|M|patients taking Class IA or III antiarrhythmics.(22)|
01863|041|M|   The manufacturer of arsenic trioxide states that, if possible, drugs that|
01863|042|M|are known to prolong the QT interval should be discontinued prior to therapy|
01863|043|M|and caution is advised during coadministration.  Patients who reach an|
01863|044|M|absolute QT interval value >500 msec should be reassessed and immediate|
01863|045|M|action should be taken to correct concomitant risk factors, if any, and the|
01863|046|M|risk/benefit of continuing therapy should be considered.  If syncope, rapid|
01863|047|M|or irregular heartbeat develops, the patient should be hospitalized for|
01863|048|M|monitoring, serum electrolytes should be assessed.  Arsenic trioxide therapy|
01863|049|M|should be temporarily discontinued until the QTc interval regresses to below|
01863|050|M|460 msec, electrolyte abnormalities are corrected, and the syncope and|
01863|051|M|irregular heartbeat cease.(23)|
01863|052|M|   Bedaquiline should be used with caution in patients receiving therapy|
01863|053|M|with agents that prolong the QT interval.  Patients should receive a|
01863|054|M|baseline electrocardiogram (ECG) and at 2, 12, and 24 weeks of therapy and|
01863|055|M|more closely if receiving concurrent agents that prolong the QT interval.|
01863|056|M|If a patient develops syncope, perform an ECG.  Bedaquiline and other QT|
01863|057|M|prolonging agents should be discontinued if the patient develops a|
01863|058|M|clinically significant ventricular arrhythmia or a QTcF of greater than 500|
01863|059|M|msec confirmed on two ECGs.(24)|
01863|060|M|   Consider periodic electrocardiogram (ECG) and electrolyte monitoring in|
01863|061|M|patients receiving concurrent therapy with ceritinib and another agent that|
01863|062|M|prolongs the QTc interval.  In patients who develop a QTC interval greater|
01863|063|M|than 500 msec on at least 2 occasions, withhold ceritinib until the QTc|
01863|064|M|interval is less than 481 msec or recovery to baseline if baseline QTc was|
01863|065|M|greater than or equal to 481 msec, then resume ceritinib with a 150 mg dose|
01863|066|M|reduction.  If the patient develops QTc interval prolongation in combination|
01863|067|M|with torsades de pointes or polymorphic ventricular tachycardia or|
01863|068|M|signs/symptoms of serious arrhythmia, permanently discontinue ceritinib.(25)|
01863|069|M|   The US manufacturer of ciprofloxacin states that ciprofloxacin should be|
01863|070|M|used with caution with other agents known to prolong the QT interval,|
01863|071|M|especially in the elderly.(26)  The UK manufacturer of ciprofloxacin states|
01863|072|M|that ciprofloxacin should be used with caution in patients at risk for|
01863|073|M|torsades.(27)|
01863|074|M|   Consider periodic electrocardiogram (ECG) and electrolyte monitoring in|
01863|075|M|patients receiving concurrent therapy with crizotinib and another agent that|
01863|076|M|prolongs the QTc interval.  In patients who develop Grade 3 QTc|
01863|077|M|prolongation, withhold crizotinib until recovery to less than or equal to|
01863|078|M|Grade 1, then resume crizotinib at a dosage of 200 mg twice daily.  If the|
01863|079|M|patient re-develops Grade 3 QTc prolongation, withhold crizotinib until|
01863|080|M|recovery to less than or equal to Grade 1, then resume crizotinib at a|
01863|081|M|dosage of 250 mg daily.  If the patient re-develops Grade 3 prolongation|
01863|082|M|again, permanently discontinue crizotinib.  In patients who develop Grade 4|
01863|083|M|QTc prolongation, permanently discontinue|
01863|084|M|crizotinib.(28)|
01863|085|M|   The US manufacturer of eribulin states that patients receiving concurrent|
01863|086|M|therapy with eribulin and other agents known to prolong the QT interval|
01863|087|M|should receive ECG monitoring.(29)|
01863|088|M|   While the US FDA and manufacturer recommend no special precautions when|
01863|089|M|escitalopram is used with QT prolonging agents,(30,31) Health Canada and the|
01863|090|M|Canadian manufacturer of escitalopram discourage the concurrent use of|
01863|091|M|agents known to prolong the QT interval(32,33) and the UK manufacturer|
01863|092|M|states that concurrent use is contraindicated.(4)|
01863|093|M|   The concurrent use of ezogabine with agents known to prolong the QT|
01863|094|M|interval should be approached with caution.  Patients receiving concurrent|
01863|095|M|therapy with other QT prolongers, an electrocardiogram (ECG) should be|
01863|096|M|performed prior to ezogabine initiation.  In those patients|
01863|097|M|with a corrected QT interval greater than 440 msec at baseline, a repeat ECG|
01863|098|M|should be performed after reaching the maintenance dose of ezogabine.(35)|
01863|099|M|   In patients maintained on agents known to prolong the QT interval,|
01863|100|M|consider a baseline ECG prior to administration of gadofosveset|
01863|101|M|to asses the risk/benefit of gadofosveset.  If gadofosveset is used,|
01863|102|M|consider ECG monitoring for 72 hours until the majority of gadofosveset is|
01863|103|M|eliminated.  Counsel patients to report any irregular heartbeat, dizziness,|
01863|104|M|or fainting episodes during this time frame.(36)|
01863|105|M|   Approach the concurrent use of ondansetron and other agents that are|
01863|106|M|known to prolong the QTc interval with caution.  Electrocardiogram (ECG)|
01863|107|M|monitoring should be performed in patients receiving concurrent|
01863|108|M|therapy.(37,38)|
01863|109|M|   Pasireotide should be used with caution in patients receiving therapy|
01863|110|M|with agents that prolong the QT interval.  Patients should|
01863|111|M|receive a baseline electrocardiogram (ECG) and hypokalemia and|
01863|112|M|hypomagnesemia should be corrected before therapy is initiated.  Monitor ECG|
01863|113|M|and potassium and magnesium levels during therapy.(39)|
01863|114|M|   The US manufacturer of quetiapine states that concurrent use with agents|
01863|115|M|known to prolong the QT interval should be approached with caution.(40)|
01863|116|M|   The US manufacturer of romidepsin states that appropriate cardiovascular|
01863|117|M|monitoring, such as monitoring of electrolytes and ECGs at baseline and|
01863|118|M|periodically during treatment should be considered in patients receiving|
01863|119|M|concurrent therapy with agents known to prolong the QT interval.(41)|
01863|120|M|   Patients receiving concurrent therapy with agents known to prolong the|
01863|121|M|QTc interval should be monitored with electrocardiograms during treatment|
01863|122|M|with sorafenib. Electrolytes (calcium, magnesium, and potassium) should also|
01863|123|M|be monitored.(42)|
01863|124|M|   The manufacturer of sotalol states that concurrent use with other agents|
01863|125|M|known to prolong the QT interval is not recommended.(43)|
01863|126|M|   The manufacturer of sunitinib recommends caution with the use of|
01863|127|M|sunitinib in patients maintained on Class IA or III antiarrhythmics.(44)|
01863|128|M|   The US manufacturer of telavancin recommends against the use of|
01863|129|M|telavancin with other drugs known to cause QT prolongation.(45)|
01863|130|M|   Use tolterodine with caution in patients maintained on Class IA or III|
01863|131|M|antiarrhythmics.(46)|
01863|132|M|   The concurrent use of vemurafenib with agents known to prolong the QT|
01863|133|M|interval is not recommended.  Initiation of vemurafenib in patients with a|
01863|134|M|baseline QTc greater than 500 msec is not recommended.  All patients|
01863|135|M|receiving vemurafenib should undergo ECG testing at baseline, after 15 days|
01863|136|M|of treatment, monthly during the first 3 months of treatment, and then every|
01863|137|M|3 months.  If a patient's QTc exceeds 500 msec during treatment, vemurafenib|
01863|138|M|should be discontinued and cardiac risk factors for QT prolongation should|
01863|139|M|be controlled.  Consider discontinuing other medications known to prolong|
01863|140|M|the QT interval at this time.  If the patient's QTc decreases below 500|
01863|141|M|msec, vemurafenib may be introduced at a lower dosage according to the|
01863|142|M|current labeling recommendations.(47)|
01863|143|B||
01863|144|D|DISCUSSION:  Quinidine, also component of natisedine, and hydroquinidine,|
01863|145|D|have been shown to prolong the QTc interval.  Other agents that are linked|
01863|146|D|to this monograph may have varying degrees of potential to prolong the QTc|
01863|147|D|interval.(49)|
01863|148|D|   One or more of the drug pairs linked to this monograph have been included|
01863|149|D|in a list of interactions that should be considered "high-priority" for|
01863|150|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01863|151|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01863|152|D|Coordinator (ONC) for Health Information Technology.|
01863|153|B||
01863|154|R|REFERENCES:|
01863|155|B||
01863|156|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01863|157|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01863|158|R|  settings: a scientific statement from the American Heart Association and|6
01863|159|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01863|160|R|  2;55(9):934-47.|6
01863|161|R|2.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
01863|162|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
01863|163|R|3.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
01863|164|R|  Inc. May, 2019.|1
01863|165|R|4.Clozaril (clozapine tablets) US prescribing information. Novartis|1
01863|166|R|  Pharmaceuticals Corporation April, 2020.|1
01863|167|R|5.Anzemet (dolasetron mesylate) US prescribing information. Sanofi-Aventis|1
01863|168|R|  Us.S. LLC September, 2014.|1
01863|169|R|6.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
01863|170|R|  Company August, 2015.|1
01863|171|R|7.Mathivanan M. Dear Canadian Healthcare Professional:  Subject:|1
01863|172|R|  Association of domperidone maleate with serious ventricular arrhythmias|1
01863|173|R|  and sudden cardiac death. Teva Canada Limited March 2, 2012.|1
01863|174|R|8.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
01863|175|R|  Limited February, 2011.|1
01863|176|R|9.Foradil Aerolizer (formoterol fumarate) US prescribing information.|1
01863|177|R|  Schering Corporation September, 2012.|1
01863|178|R|10.Symbicort Turbuhaler (budesonide-eformoterol fumarate dihydrate)|1
01863|179|R|   Australian prescribing information. AstraZeneca Pty Ltd April 30, 2004.|1
01863|180|R|11.Primovist (gadoxetate disodium) Australian prescribing information.|1
01863|181|R|   Schering-Plough Corporation November 1, 2005.|1
01863|182|R|12.Primovist (gadoxetic acid) UK summary of product characteristics. Bayer|1
01863|183|R|   plc May 1, 2008.|1
01863|184|R|13.Serenace (haloperidol) Australian prescribing information. Sigma|1
01863|185|R|   Pharmaceuticals Pty Ltd. June 5, 2001.|1
01863|186|R|14.Dozic (haloperidol) UK summary of product characteristics. Rosemont|1
01863|187|R|   Pharmaceuticals Limited September 10, 2007.|1
01863|188|R|15.Haldol (haloperidol) US prescribing information. Ortho-McNeil-Janssen|1
01863|189|R|   Pharmaceuticals, Inc. August, 2011.|1
01863|190|R|16.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
01863|191|R|   2018.|1
01863|192|R|17.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
01863|193|R|   Pharmaceuticals Corp. December, 2016.|1
01863|194|R|18.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
01863|195|R|   2020.|1
01863|196|R|19.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
01863|197|R|   January, 2021.|1
01863|198|R|20.Risperidal (risperidone) UK summary of product characteristics.|1
01863|199|R|   Janssen-Cilag, UK Limited May 14, 2004.|1
01863|200|R|21.Zolinza (vorinostat) US prescribing information. Merck & Co., Inc. 2006.|1
01863|201|R|22.Plenaxis (abarelix) US prescribing information. Praecis Pharmaceuticals|1
01863|202|R|   Incorporated November, 2003.|1
01863|203|R|23.Trisenox (arsenic trioxide) US prescribing information. Cell|1
01863|204|R|   Therapeutics, Inc. March, 2001.|1
01863|205|R|24.Sirturo (bedaquiline) US prescribing information. Janssen Therapeutics|1
01863|206|R|   June, 2024.|1
01863|207|R|25.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
01863|208|R|   Corporation November, 2017.|1
01863|209|R|26.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
01863|210|R|   Corporation August, 2013.|1
01863|211|R|27.Ciproxin (ciprofloxacin hydrochloride) UK summary of product|1
01863|212|R|   characteristics. Bayer plc April 13, 2010.|1
01863|213|R|28.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
01863|214|R|   2023.|1
01863|215|R|29.Halaven (eribulin mesylate) US prescribing information. Eisai, Inc.|1
01863|216|R|   August, 2014.|1
01863|217|R|30.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
01863|218|R|   Pharmaceuticals Inc. December, 2012.|1
01863|219|R|31.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
01863|220|R|   recommendations for Celexa (citalopram hydrobromide) related to a|1
01863|221|R|   potential risk of abnormal heart rhythms with high doses. Available at:|1
01863|222|R|   http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
01863|223|R|32.Health Canada. Antidepressant Cipralex (escitalopram): Updated|1
01863|224|R|   information regarding dose-related heart risk. Available at:|1
01863|225|R|   http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/136|1
01863|226|R|   74a-eng.php May 7, 2012.|1
01863|227|R|33.Cipralex (escitalopram oxalate) Canadian prescribing information.|1
01863|228|R|   Lundbeck August 13, 2012.|1
01863|229|R|34.Cipralex (escitalopram oxalate) UK summary of product characteristics.|1
01863|230|R|   Lunbeck Limited June 25, 2020.|1
01863|231|R|35.Trobalt (retigabine) UK summary of product characteristics.|1
01863|232|R|   GlaxoSmithKline UK March 28, 2011.|1
01863|233|R|36.Ablavar (gadofosveset trisodium) US prescribing information. Lantheus|1
01863|234|R|   Medical Imaging, Inc. August, 2013.|1
01863|235|R|37.Zofran (ondansetron) US prescribing information. GlaxoSmithKline October,|1
01863|236|R|   2021.|1
01863|237|R|38.USFood and Drug Administration. FDA Drug Safety Communication: Abnormal|1
01863|238|R|   heart rhythms may be associated with use of Zofran (ondansetron).|1
01863|239|R|   available at:|1
01863|240|R|   https://wayback.archive-it.org/7993/20170722185907/https:/www.fda.gov/Dru|1
01863|241|R|   gs/DrugSafety/ucm271913.htm September 15, 2011.|1
01863|242|R|39.Signifor (pasireotide diasparate) US prescribing information. Novartis|1
01863|243|R|   Pharmaceuticals Corporation January, 2020.|1
01863|244|R|40.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
01863|245|R|   Pharmaceuticals LP July, 2011.|1
01863|246|R|41.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
01863|247|R|   November, 2018.|1
01863|248|R|42.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
01863|249|R|   Corporation July, 2020.|1
01863|250|R|43.Betapace (sotalol hydrochloride) US prescribing information. Bayer|1
01863|251|R|   Healthcare Inc. June, 2021.|1
01863|252|R|44.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01863|253|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01863|254|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01863|255|R|   19(5):735-43.|6
01863|256|R|45.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. April,|1
01863|257|R|   2015.|1
01863|258|R|46.Vibativ (telavancin) US prescribing information. Theravance Biopharma US,|1
01863|259|R|   Inc. February, 2020.|1
01863|260|R|47.Detrol LA (tolterodine tartrate) US prescribing information. Pharmacia &|1
01863|261|R|   Upjohn Company September, 2008.|1
01863|262|R|48.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
01863|263|R|   August, 2015.|1
01863|264|R|49.USDepartment of Health and Human Services Food and Drug Administration.|1
01863|265|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01863|266|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01863|267|R|   https://www.fda.gov/media/71372/download October, 2005.|1
01864|001|T|MONOGRAPH TITLE:  Tacrolimus/Selected Calcium Channel Blockers|
01864|002|B||
01864|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01864|004|L|take action as needed.|
01864|005|B||
01864|006|A|MECHANISM OF ACTION:  Some calcium channel blockers may inhibit the|
01864|007|A|metabolism of tacrolimus by CYP3A4.(1-13)|
01864|008|B||
01864|009|E|CLINICAL EFFECTS:  Concurrent use of calcium channel blockers may result in|
01864|010|E|elevated levels of and side effects from tacrolimus, including|
01864|011|E|nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and|
01864|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1-13)|
01864|013|B||
01864|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01864|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01864|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01864|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01864|018|P|gender, or advanced age.|
01864|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01864|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01864|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01864|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01864|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01864|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01864|025|P|dysfunction).|
01864|026|B||
01864|027|M|PATIENT MANAGEMENT:  Patients maintained on tacrolimus should be closely|
01864|028|M|monitored if calcium channel blockers such as amlodipine, diltiazem,|
01864|029|M|felodipine, nifedipine, or verapamil are initiated or discontinued.  The|
01864|030|M|dosage of tacrolimus may need to be adjusted or the calcium channel blocker|
01864|031|M|may need to be discontinued.|
01864|032|M|   When concurrent therapy of selected calcium channel blockers and|
01864|033|M|tacrolimus is warranted, consider obtaining serum calcium, magnesium, and|
01864|034|M|potassium levels and monitoring ECG at baseline and at regular intervals.|
01864|035|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
01864|036|M|irregular heartbeat, dizziness, or fainting.|
01864|037|B||
01864|038|D|DISCUSSION:  A study of 9 healthy volunteers who are CYP3A5 expressers found|
01864|039|D|that concomitant tacrolimus and amlodipine resulted in increased tacrolimus|
01864|040|D|AUC by 2.44-fold and 4.1-fold in a single-dose and a 7-day multi-dose study,|
01864|041|D|respectively, compared to tacrolimus alone.  No interaction was observed in|
01864|042|D|CYP3A5 non-expressers.(2)  However, a case report of a 4-year-old renal|
01864|043|D|transplant patient who is a CYP3A5 non-expresser on tacrolimus and started|
01864|044|D|on amlodipine described increased tacrolimus trough level and AUC from 3.7|
01864|045|D|to 12.2 ng/mL and 211 to 638 h/ng/mL, respectively.(3)|
01864|046|D|   A non-randomized study in 2 liver and 2 renal transplant recipients|
01864|047|D|examined the effects of diltiazem on tacrolimus.  In the 2 kidney|
01864|048|D|recipients, concurrent diltiazem at a dosage of 20 mg daily increased|
01864|049|D|tacrolimus AUC by 26% and by 67%.  Diltiazem at a dosage of 180 mg increased|
01864|050|D|tacrolimus AUC by 48% and by 177%.  In the 2 liver recipients, no tacrolimus|
01864|051|D|increases were seen until diltiazem dosage reached 60 mg daily.  One subject|
01864|052|D|received 120 mg of diltiazem daily and tacrolimus AUC was increased by 18%.|
01864|053|D|The other subject received 180 mg diltiazem daily and tacrolimus AUC|
01864|054|D|increased 22%.(4)  There is one case report of elevated tacrolimus levels|
01864|055|D|and toxicity in a liver transplant patient 3 days after the addition of|
01864|056|D|diltiazem to his regimen.(5)  There is one case report of elevated|
01864|057|D|tacrolimus levels in a renal transplant patient.(6)  In contrast, a|
01864|058|D|retrospective review of renal transplant patients found no difference in|
01864|059|D|tacrolimus-related side effects or tacrolimus exposure in patients treated|
01864|060|D|with diltiazem versus those not treated with diltiazem.(7)|
01864|061|D|   There is one report of increased tacrolimus levels with concurrent|
01864|062|D|felodipine in a renal transplant patient.(8)|
01864|063|D|   A retrospective review examined the effects of nifedipine on tacrolimus|
01864|064|D|dosing requirements in renal transplant patients.  In patients who received|
01864|065|D|concurrent nifedipine (n=22), tacrolimus daily dosing requirements were 26%,|
01864|066|D|29%, and 38% lower at 3, 6, and 12 months post-transplant when compared to|
01864|067|D|patients not taking nifedipine (n=28).(9)  In a study of liver transplant|
01864|068|D|patients, nifedipine improved kidney function as indicated by lowering of|
01864|069|D|serum creatinine levels at 6 and 12 months.(10)|
01864|070|D|   In vitro studies in human tissue found that tacrolimus metabolism was|
01864|071|D|inhibited by nifedipine and verapamil.(12,13)|
01864|072|B||
01864|073|R|REFERENCES:|
01864|074|B||
01864|075|R|1.Norvasc (amlodipine) US Prescribing Information. Pfizer Labs October,|1
01864|076|R|  2017.|1
01864|077|R|2.Zuo XC, Zhou YN, Zhang BK, Yang GP, Cheng ZN, Yuan H, Ouyang DS, Liu SK,|2
01864|078|R|  Barrett JS, Li PJ, Liu Z, Tan HY, Guo R, Zhou LY, Xie YL, Li ZJ, Li J,|2
01864|079|R|  Wang CJ, Wang JL. Effect of CYP3A5*3 polymorphism on pharmacokinetic drug|2
01864|080|R|  interaction between tacrolimus and amlodipine. Drug Metab Pharmacokinet|2
01864|081|R|  2013 Feb 26.|2
01864|082|R|3.Zhao W, Baudouin V, Fakhoury M, Storme T, Deschenes G, Jacqz-Aigrain E.|3
01864|083|R|  Pharmacokinetic interaction between tacrolimus and amlodipine in a renal|3
01864|084|R|  transplant child. Transplantation 2012 Apr 15;93(7):e29-30.|3
01864|085|R|4.Jones TE, Morris RG. Pharmacokinetic interaction between tacrolimus and|2
01864|086|R|  diltiazem: dose-response relationship in kidney and liver transplant|2
01864|087|R|  recipients. Clin Pharmacokinet 2002;41(5):381-8.|2
01864|088|R|5.Hebert MF, Lam AY. Diltiazem increases tacrolimus concentrations. Ann|3
01864|089|R|  Pharmacother 1999 Jun;33(6):680-2.|3
01864|090|R|6.Hardy G, Stanke-Labesque F, Contamin C, Serre-Debeauvais F, Bayle F, Zaoui|3
01864|091|R|  P, Bessard G. Protease inhibitors and diltiazem increase tacrolimus blood|3
01864|092|R|  concentration in a patient with renal transplantation: a case report. Eur|3
01864|093|R|  J Clin Pharmacol 2004 Oct;60(8):603-5.|3
01864|094|R|7.Kothari J, Nash M, Zaltzman J, Ramesh Prasad GV. Diltiazem use in|2
01864|095|R|  tacrolimus-treated renal transplant recipients. J Clin Pharm Ther 2004|2
01864|096|R|  Oct;29(5):425-30.|2
01864|097|R|8.Butani L, Berg G, Makker SP. Effect of felodipine on tacrolimus|3
01864|098|R|  pharmacokinetics in a renal transplant recipient. Transplantation 2002 Jan|3
01864|099|R|  15;73(1):159-60.|3
01864|100|R|9.Seifeldin R, Marcos-Alvarez A, Lewis WD, Gordon FD, Jenkins RL. Effect of|2
01864|101|R|  nifedipine on renal function in liver transplant recipients receiving|2
01864|102|R|  tacrolimus. Clin Ther 1996 May-Jun;18(3):491-6.|2
01864|103|R|10.Seifeldin RA, Marcos-Alvarez A, Gordon FD, Lewis WD, Jenkins RL.|2
01864|104|R|   Nifedipine interaction with tacrolimus in liver transplant recipients.|2
01864|105|R|   Ann Pharmacother 1997 May;31(5):571-5.|2
01864|106|R|11.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
01864|107|R|   August, 2023.|1
01864|108|R|12.Christians U, Schmidt G, Bader A, Lampen A, Schottmann R, Linck A, Sewing|5
01864|109|R|   KF. Identification of drugs inhibiting the in vitro metabolism of|5
01864|110|R|   tacrolimus by human liver microsomes. Br J Clin Pharmacol 1996 Mar;|5
01864|111|R|   41(3):187-90.|5
01864|112|R|13.Lampen A, Christians U, Guengerich FP, Watkins PB, Kolars JC, Bader A,|5
01864|113|R|   Gonschior AK, Dralle H, Hackbarth I, Sewing KF. Metabolism of the|5
01864|114|R|   immunosuppressant tacrolimus in the small intestine: cytochrome P450,|5
01864|115|R|   drug interactions, and interindividual variability. Drug Metab Dispos|5
01864|116|R|   1995 Dec;23(12):1315-24.|5
01864|117|R|14.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
01864|118|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
01864|119|R|   hospital settings: a scientific statement from the American Heart|6
01864|120|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
01864|121|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
01865|001|T|MONOGRAPH TITLE:  Rosuvastatin/Selected Protease Inhibitors|
01865|002|B||
01865|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01865|004|L|take action as needed.|
01865|005|B||
01865|006|A|MECHANISM OF ACTION:  The mechanism for this interaction is not known but|
01865|007|A|may involve inhibition of the hepatic uptake transporter OATP1B1 and/or|
01865|008|A|efflux transporter BCRP by protease inhibitors.|
01865|009|B||
01865|010|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors may result in|
01865|011|E|elevated levels of rosuvastatin, which could result in rhabdomyolysis.|
01865|012|B||
01865|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01865|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01865|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01865|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01865|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01865|018|P|transporter OATP1B1 may have increased statin concentrations and be|
01865|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
01865|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
01865|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
01865|022|B||
01865|023|M|PATIENT MANAGEMENT:  In patients receiving protease inhibitors, consider the|
01865|024|M|use of fluvastatin.|
01865|025|M|   If rosuvastatin is used with a protease inhibitor, use the lowest|
01865|026|M|rosuvastatin dose possible with careful monitoring.(1-7)|
01865|027|M|   The UK manufacturer of rosuvastatin states that concurrent use with|
01865|028|M|protease inhibitors is not recommended.(9)|
01865|029|M|   The manufacturer of cobicistat states that the rosuvastatin dose should|
01865|030|M|not exceed 20 mg when cobicistat is coadministered with darunavir.(8)|
01865|031|M|   Counsel patients to report unexplained muscle pain, tenderness, weakness,|
01865|032|M|or dark, cola-colored urine.|
01865|033|B||
01865|034|D|DISCUSSION:  In a study, darunavir/ritonavir (600/100 mg twice daily for 7|
01865|035|D|days) increased the Cmax and AUC of a single dose of rosuvastatin (10 mg) by|
01865|036|D|2.4-fold and 1.5-fold, respectively.(1)|
01865|037|D|   In a study, darunavir/cobicistat (800/150 mg once daily) increased the|
01865|038|D|Cmax and AUC of a single dose of rosuvastatin (10mg) by 277% and 93%,|
01865|039|D|respectively.(9)|
01865|040|B||
01865|041|R|REFERENCES:|
01865|042|B||
01865|043|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
01865|044|R|  Pharmaceuticals LP July, 2024.|1
01865|045|R|2.Crestor (rosuvastatin) UK summary of product characteristics. AstraZeneca|1
01865|046|R|  UK Limited December 23, 2022.|1
01865|047|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01865|048|R|  March, 2023.|1
01865|049|R|4.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01865|050|R|  Pharmaceuticals, Inc. September, 2016.|1
01865|051|R|5.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01865|052|R|  December, 2019.|1
01865|053|R|6.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
01865|054|R|  June, 2025.|1
01866|001|T|MONOGRAPH TITLE:  SSRIs;SNRIs/Slt Anticoagulants;Antiplatelets;Thrombolytics|
01866|002|B||
01866|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01866|004|L|take action as needed.|
01866|005|B||
01866|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
01866|007|A|hemostasis.(1,2)  The increased risk of bleeding may be a result of a|
01866|008|A|decrease in serotonin reuptake by platelets.|
01866|009|B||
01866|010|E|CLINICAL EFFECTS:  Concurrent use of a selective serotonin reuptake|
01866|011|E|inhibitor(1-6) or a serotonin-norepinephrine reuptake inhibitor(7-9) and|
01866|012|E|agents that affect coagulation may result in bleeding.|
01866|013|B||
01866|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01866|015|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
01866|016|P|impairment has been associated with an elevated risk of GI bleed in patients|
01866|017|P|on SSRIs.(15)|
01866|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
01866|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01866|020|P|risk for bleeding (e.g. NSAIDs).|
01866|021|B||
01866|022|M|PATIENT MANAGEMENT:  Selective serotonin reuptake inhibitors(1-6) or|
01866|023|M|serotonin-norepinephrine reuptake inhibitors(7-9) and agents that affect|
01866|024|M|coagulation should be used concurrently with caution.|
01866|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01866|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01866|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01866|028|M|patients with any symptoms.|
01866|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01866|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01866|031|M|anticoagulation in patients with active pathologic bleeding.|
01866|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01866|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01866|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01866|035|M|and/or swelling.|
01866|036|B||
01866|037|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
01866|038|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
01866|039|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
01866|040|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
01866|041|D|only based on an observed-expected ration was 4.5 and in a patient using|
01866|042|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
01866|043|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
01866|044|D|bleeding to 12.2 and 5.2, respectively.(10)|
01866|045|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
01866|046|D|in patients receiving concurrent therapy with selective serotonin reuptake|
01866|047|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
01866|048|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
01866|049|D|respectively.(11)|
01866|050|D|   In a case-control study conducted in users of acenocoumarol or|
01866|051|D|phenprocoumon, 1848 patients who had been hospitalized with abnormal|
01866|052|D|bleeding were each matched to 4 control patients.  When patients took both a|
01866|053|D|SSRI and a coumarin, an increased risk of hospitalization due to major|
01866|054|D|non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to|
01866|055|D|gastrointestinal bleeding (adjusted OR 0.8).(12)|
01866|056|D|   A retrospective review examined patients discharged from a hospital with|
01866|057|D|antiplatelet therapy following a myocardial infarction.  When compared to|
01866|058|D|aspirin therapy alone, both aspirin therapy with a SSRI and aspirin,|
01866|059|D|clopidogrel, and SSRI therapy were associated with an increased risk of|
01866|060|D|bleeding (hazard ratios 1.42 and 2.35, respectively.)  Compared with dual|
01866|061|D|antiplatelet therapy (aspirin and clopidogrel), use of aspirin and|
01866|062|D|clopidogrel and a SSRI was also associated with increased risk of bleeding|
01866|063|D|(hazard ratio 1.57).(13)|
01866|064|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
01866|065|D|anticoagulation (hazard ratio 2.63).  Paroxetine was not associated with an|
01866|066|D|increased risk.  There were insufficient numbers of patients taking other|
01866|067|D|SSRIs to assess increased risk.(14)|
01866|068|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
01866|069|D|pairs were reviewed and found 14% of drug pairs were associated with a|
01866|070|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
01866|071|D|of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of|
01866|072|D|1.69 (1.11-2.57).(16)|
01866|073|D|   A systematic review and meta-analysis of 22 cohort and case-controlled|
01866|074|D|studies including over 1 million patients found 1.55-fold higher odds of|
01866|075|D|upper gastrointestinal (GI) bleeding in SSRI users compared with non-SSRI|
01866|076|D|users (95% CI, 1.35-1.78).  In subgroup analyses, the risk was found to be|
01866|077|D|greatest among participants taking SSRIs concurrently with NSAIDs or|
01866|078|D|antiplatelet medications.(17)|
01866|079|B||
01866|080|R|REFERENCES:|
01866|081|B||
01866|082|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
01866|083|R|  Laboratories Inc. August, 2023.|1
01866|084|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
01866|085|R|  Pharmaceuticals Inc. May, 2023.|1
01866|086|R|3.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
01866|087|R|  and Company August, 2023.|1
01866|088|R|4.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
01866|089|R|  Technologies January, 2017.|1
01866|090|R|5.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
01866|091|R|  Therapeutics, LLC September, 2021.|1
01866|092|R|6.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
01866|093|R|7.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
01866|094|R|  Pharmaceuticals, Inc. August, 2023.|1
01866|095|R|8.Effexor XR (venlafaxine hydrochloride) US prescribing information. Viatris|1
01866|096|R|  August, 2023.|1
01866|097|R|9.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
01866|098|R|  and Company September, 2021.|1
01866|099|R|10.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
01866|100|R|   Use of selective serotonin reuptake inhibitors and risk of upper|2
01866|101|R|   gastrointestinal tract bleeding: a population-based cohort study. Arch|2
01866|102|R|   Intern Med 2003 Jan 13;163(1):59-64.|2
01866|103|R|11.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
01866|104|R|   serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
01866|105|R|   population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
01866|106|R|12.Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding|2
01866|107|R|   risk with concurrent use of selective serotonin reuptake inhibitors and|2
01866|108|R|   coumarins. Arch Intern Med 2008 Jan 28;168(2):180-5.|2
01866|109|R|13.Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding|2
01866|110|R|   associated with combined use of selective serotonin reuptake inhibitors|2
01866|111|R|   and antiplatelet therapy following acute myocardial infarction. CMAJ 2011|2
01866|112|R|   Nov 8;183(16):1835-43.|2
01866|113|R|14.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
01866|114|R|   Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
01866|115|R|   antidepressants and the risk of overanticoagulation during acenocoumarol|2
01866|116|R|   maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
01866|117|R|15.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
01866|118|R|   Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
01866|119|R|   by level of kidney function: A population-based cohort study. Br J Clin|2
01866|120|R|   Pharmacol 2018 Sep;84(9):2142-2151.|2
01866|121|R|16.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
01866|122|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
01866|123|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
01866|124|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
01866|125|R|17.Jiang HY, Chen HZ, Hu XJ, Yu ZH, Yang W, Deng M, Zhang YH, Ruan B. Use of|6
01866|126|R|   selective serotonin reuptake inhibitors and risk of upper|6
01866|127|R|   gastrointestinal  bleeding: a systematic review and meta-analysis. Clin|6
01866|128|R|   Gastroenterol Hepatol 2015 Jan;13(1):42-50.e3.|6
01867|001|T|MONOGRAPH TITLE:  Phenobarbital/Felbamate (mono deleted 02/02/2012)|
01867|002|B||
01867|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01867|004|L|take action as needed.|
01867|005|B||
01867|006|A|MECHANISM OF ACTION:  Phenobarbital may induce the metabolism of felbamate.|
01867|007|A|Felbamate may inhibit the metabolism of phenobarbital.|
01867|008|B||
01867|009|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
01867|010|E|toxicity from phenobarbital and decreased levels and effectiveness of|
01867|011|E|felbamate.|
01867|012|B||
01867|013|P|PREDISPOSING FACTORS:  None determined.|
01867|014|B||
01867|015|M|PATIENT MANAGEMENT:  The US manufacturer of felbamate recommends that as|
01867|016|M|felbamate is added to or substituted for phenobarbital, that the dosage of|
01867|017|M|phenobarbital be reduced by 20-33% to minimize side effects.  Refer to the|
01867|018|M|prescribing information for felbamate for specific recommendations for|
01867|019|M|specific patients.(1)|
01867|020|B||
01867|021|D|DISCUSSION:  In a study in 12 healthy males, administration of felbamate|
01867|022|D|(2400 mg daily) increased phenobarbital levels by 25%.(1)|
01867|023|D|   In a study in 24 healthy subjects, administration of felbamate (2400 mg|
01867|024|D|daily) increased phenobarbital (100 mg daily) area-under-curve (AUC) and|
01867|025|D|maximum concentration (Cmax) levels by 22% and 24%, respectively.(2)|
01867|026|D|   In clinical trials, patients receiving concurrent phenobarbital were|
01867|027|D|found to have felbamate concentrations that were 29% lower than patients not|
01867|028|D|receiving concurrent phenobarbital.(1)  In contrast, a retrospective review|
01867|029|D|of felbamate levels found no effect by barbiturates.(3)|
01867|030|D|   In a case report, felbamate was initiated and titrated to 50 mg/kg/day|
01867|031|D|over three weeks.  At this time, the patient's phenobarbital dosage was|
01867|032|D|decreased 13% (from 230 mg/daily to 200 mg/day).  Despite this, the|
01867|033|D|patient's phenobarbital level increased 42% and the patient developed|
01867|034|D|neurotoxicity.  The patient's phenobarbital dosage was further reduced to|
01867|035|D|35% of the original dosage (to 150 mg daily) and the patient's phenobarbital|
01867|036|D|levels returned to therapeutic range.(4)|
01867|037|B||
01867|038|R|REFERENCES:|
01867|039|B||
01867|040|R|1.Felbatrol (felbamate) US prescribing information. MedPoint Pharmaceuticals|1
01867|041|R|  Inc. August 27, 2012.|1
01867|042|R|2.Reidenberg P, Glue P, Banfield CR, Colucci RD, Meehan JW, Radwanski E,|2
01867|043|R|  Mojavarian P, Lin CC, Nezamis J, Guillaume M, et al. Effects of felbamate|2
01867|044|R|  on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995 Sep;|2
01867|045|R|  58(3):279-87.|2
01867|046|R|3.Kelley MT, Walson PD, Cox S, Dusci LJ. Population pharmacokinetics of|2
01867|047|R|  felbamate in children. Ther Drug Monit 1997 Feb;19(1):29-36.|2
01867|048|R|4.Gidal BE, Zupanc ML. Potential pharmacokinetic interaction between|3
01867|049|R|  felbamate and phenobarbital. Ann Pharmacother 1994 Apr;28(4):455-8.|3
01868|001|T|MONOGRAPH TITLE:  Tolvaptan/Itraconazole; Ketoconazole (mono deleted|
01868|002|T|04/12/2012)|
01868|003|B||
01868|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01868|005|L|is contraindicated and generally should not be dispensed or administered to|
01868|006|L|the same patient.|
01868|007|B||
01868|008|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole inhibit the metabolism|
01868|009|A|of tolvaptan by CYP P-450-3A4.(1)|
01868|010|B||
01868|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP P-450-3A4 inhibitors such as|
01868|012|E|itraconazole or ketoconazole may result in elevated levels of and toxicity|
01868|013|E|from tolvaptan.(1)  During initiation of tolvaptan, this may increase the|
01868|014|E|risk of osmotic demyelination syndrome (ODS), which can lead to coma and|
01868|015|E|death.   Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy,|
01868|016|E|affective changes, spastic quadriparesis, seizures, and coma.  During|
01868|017|E|maintenance therapy, it may increase the risk of dehydration.|
01868|018|B||
01868|019|P|PREDISPOSING FACTORS:  None determined.|
01868|020|B||
01868|021|M|PATIENT MANAGEMENT:  The US manufacturer of tolvaptan states that concurrent|
01868|022|M|administration with strong CYP P-450-3A4 inhibitors such as itraconazole or|
01868|023|M|ketoconazole is contraindicated.(1)|
01868|024|B||
01868|025|D|DISCUSSION:  Concurrent administration of ketoconazole (200 mg daily)|
01868|026|D|increased tolvaptan exposure by 5-fold.  Administration of ketoconazole at|
01868|027|D|dosages of 400 mg daily would be expected to produce greater increases, as|
01868|028|D|would concurrent administration with other strong CYP P-450-3A4|
01868|029|D|inhibitors.(1)|
01868|030|B||
01868|031|R|REFERENCE:|
01868|032|B||
01868|033|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01868|034|R|  Ltd. November, 2012.|1
01869|001|T|MONOGRAPH TITLE:  Tolvaptan/Clarithromycin; Troleandomycin (mono deleted|
01869|002|T|04/12/2012)|
01869|003|B||
01869|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01869|005|L|is contraindicated and generally should not be dispensed or administered to|
01869|006|L|the same patient.|
01869|007|B||
01869|008|A|MECHANISM OF ACTION:  Clarithromycin and troleandomycin inhibit the|
01869|009|A|metabolism of tolvaptan by CYP P-450-3A4.(1)|
01869|010|B||
01869|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP P-450-3A4 inhibitors such as|
01869|012|E|clarithromycin or troleandomycin may result in elevated levels of and|
01869|013|E|toxicity from tolvaptan.(1)  During initiation of tolvaptan, this may|
01869|014|E|increase the risk of osmotic demyelination syndrome (ODS), which can lead to|
01869|015|E|coma and death.   Symptoms of ODS include dysarthria, mutism, dysphagia,|
01869|016|E|lethargy, affective changes, spastic quadriparesis, seizures, and coma.|
01869|017|E|During maintenance therapy, it may increase the risk of dehydration.|
01869|018|B||
01869|019|P|PREDISPOSING FACTORS:  None determined.|
01869|020|B||
01869|021|M|PATIENT MANAGEMENT:  The US manufacturer of tolvaptan states that concurrent|
01869|022|M|administration with strong CYP P-450-3A4 inhibitors such as clarithromycin|
01869|023|M|or troleandomycin is contraindicated.(1)|
01869|024|B||
01869|025|D|DISCUSSION:  Concurrent administration of ketoconazole (200 mg daily),|
01869|026|D|another strong inhibitor of CYP P-450-3A4, increased tolvaptan exposure by|
01869|027|D|5-fold.  Administration of ketoconazole at dosages of 400 mg daily or other|
01869|028|D|strong CYP P-450-3A4 inhibitors would be expected to produce greater|
01869|029|D|increases.(1)|
01869|030|B||
01869|031|R|REFERENCE:|
01869|032|B||
01869|033|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01869|034|R|  Ltd. November, 2012.|1
01870|001|T|MONOGRAPH TITLE:  Tolvaptan/Selected Protease Inhibitors (mono deleted|
01870|002|T|04/12/2012)|
01870|003|B||
01870|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01870|005|L|is contraindicated and generally should not be dispensed or administered to|
01870|006|L|the same patient.|
01870|007|B||
01870|008|A|MECHANISM OF ACTION:  Indinavir, nelfinavir, ritonavir, and saquinavir may|
01870|009|A|inhibit the metabolism of tolvaptan by CYP P-450-3A4.(1)|
01870|010|B||
01870|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP P-450-3A4 inhibitors such as|
01870|012|E|indinavir, nelfinavir, ritonavir, or saquinavir may result in elevated|
01870|013|E|levels of and toxicity from tolvaptan.(1)  During initiation of tolvaptan,|
01870|014|E|this may increase the risk of osmotic demyelination syndrome (ODS), which|
01870|015|E|can lead to coma and death.   Symptoms of ODS include dysarthria, mutism,|
01870|016|E|dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and|
01870|017|E|coma.  During maintenance therapy, it may increase the risk of dehydration.|
01870|018|B||
01870|019|P|PREDISPOSING FACTORS:  None determined.|
01870|020|B||
01870|021|M|PATIENT MANAGEMENT:  The US manufacturer of tolvaptan states that concurrent|
01870|022|M|administration with strong CYP P-450-3A4 inhibitors such as indinavir,|
01870|023|M|nelfinavir, ritonavir, or saquinavir is contraindicated.(1)|
01870|024|B||
01870|025|D|DISCUSSION:  Concurrent administration of ketoconazole (200 mg daily),|
01870|026|D|another strong inhibitor of CYP P-450-3A4, increased tolvaptan exposure by|
01870|027|D|5-fold.  Administration of ketoconazole at dosages of 400 mg daily or other|
01870|028|D|strong CYP P-450-3A4 inhibitors would be expected to produce greater|
01870|029|D|increases.(1)|
01870|030|B||
01870|031|R|REFERENCE:|
01870|032|B||
01870|033|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01870|034|R|  Ltd. November, 2012.|1
01871|001|T|MONOGRAPH TITLE:  Tolvaptan/Nefazodone (mono deleted 04/12/2012)|
01871|002|B||
01871|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01871|004|L|is contraindicated and generally should not be dispensed or administered to|
01871|005|L|the same patient.|
01871|006|B||
01871|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of tolvaptan by|
01871|008|A|CYP P-450-3A4.(1)|
01871|009|B||
01871|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP P-450-3A4 inhibitors such as|
01871|011|E|nefazodone may result in elevated levels of and toxicity from tolvaptan.(1)|
01871|012|E|During initiation of tolvaptan, this may increase the risk of osmotic|
01871|013|E|demyelination syndrome (ODS), which can lead to coma and death.   Symptoms|
01871|014|E|of ODS include dysarthria, mutism, dysphagia, lethargy, affective changes,|
01871|015|E|spastic quadriparesis, seizures, and coma.  During maintenance therapy, it|
01871|016|E|may increase the risk of dehydration.|
01871|017|B||
01871|018|P|PREDISPOSING FACTORS:  None determined.|
01871|019|B||
01871|020|M|PATIENT MANAGEMENT:  The US manufacturer of tolvaptan states that concurrent|
01871|021|M|administration with strong CYP P-450-3A4 inhibitors such as nefazodone is|
01871|022|M|contraindicated.(1)|
01871|023|B||
01871|024|D|DISCUSSION:  Concurrent administration of ketoconazole (200 mg daily),|
01871|025|D|another strong inhibitor of CYP P-450-3A4, increased tolvaptan exposure by|
01871|026|D|5-fold.  Administration of ketoconazole at dosages of 400 mg daily or other|
01871|027|D|strong CYP P-450-3A4 inhibitors would be expected to produce greater|
01871|028|D|increases.(1)|
01871|029|B||
01871|030|R|REFERENCE:|
01871|031|B||
01871|032|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01871|033|R|  Ltd. November, 2012.|1
01872|001|T|MONOGRAPH TITLE:  Tolvaptan/Strong CYP3A4 Inducers|
01872|002|B||
01872|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01872|004|L|of severe adverse interaction.|
01872|005|B||
01872|006|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
01872|007|A|tolvaptan.(1)|
01872|008|B||
01872|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
01872|010|E|decreased levels and effectiveness of tolvaptan.(1)|
01872|011|B||
01872|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01872|013|P|of the inducer for longer than 1-2 weeks.|
01872|014|B||
01872|015|M|PATIENT MANAGEMENT:  Concurrent administration with strong CYP3A4 inducers|
01872|016|M|should be avoided.  If concurrent use is required, the dosage of tolvaptan|
01872|017|M|may need to be increased.(1)|
01872|018|B||
01872|019|D|DISCUSSION:  Concurrent administration of rifampin, a strong inducer of|
01872|020|D|CYP3A4, decreased tolvaptan exposure by 85%.(1)|
01872|021|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
01872|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
01872|023|D|lumacaftor, mitotane, phenytoin, primidone, rifabutin, rifampin,|
01872|024|D|rifapentine, and St. John's wort.(1,2)|
01872|025|B||
01872|026|R|REFERENCES:|
01872|027|B||
01872|028|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01872|029|R|  Ltd. April, 2018.|1
01872|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
01872|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01873|001|T|MONOGRAPH TITLE:  Tolvaptan/CBMZ; Phenytoin; Barbiturates (mono deleted|
01873|002|T|04/10/2014)|
01873|003|B||
01873|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01873|005|L|of severe adverse interaction.|
01873|006|B||
01873|007|A|MECHANISM OF ACTION:  Carbamazepine, phenytoin, and barbiturates induce the|
01873|008|A|metabolism of tolvaptan by CYP P-450-3A4.(1)|
01873|009|B||
01873|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP P-450-3A4 inducers such as|
01873|011|E|carbamazepine, phenytoin, or barbiturates may result in decreased levels and|
01873|012|E|effectiveness of tolvaptan.(1)|
01873|013|B||
01873|014|P|PREDISPOSING FACTORS:  None determined.|
01873|015|B||
01873|016|M|PATIENT MANAGEMENT:  The US manufacturer of tolvaptan states that concurrent|
01873|017|M|administration with strong CYP P-450-3A4 inducers such as carbamazepine,|
01873|018|M|phenytoin, or barbiturates should be avoided.  If concurrent use is|
01873|019|M|required, the dosage of tolvaptan may need to be increased.(1)|
01873|020|B||
01873|021|D|DISCUSSION:  Concurrent administration of rifampin, another strong CYP|
01873|022|D|P-450-3A4 inducer, decreased tolvaptan exposure by 85%.(1)|
01873|023|B||
01873|024|R|REFERENCE:|
01873|025|B||
01873|026|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01873|027|R|  Ltd. February, 2014.|1
01874|001|T|MONOGRAPH TITLE:  Tolvaptan/St. John's Wort (mono deleted 04/10/2014)|
01874|002|B||
01874|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01874|004|L|of severe adverse interaction.|
01874|005|B||
01874|006|A|MECHANISM OF ACTION:  St. John's wort induces the metabolism of tolvaptan by|
01874|007|A|CYP P-450-3A4.(1)|
01874|008|B||
01874|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP P-450-3A4 inducers such as|
01874|010|E|St. John's wort may result in decreased levels and effectiveness of|
01874|011|E|tolvaptan.(1)|
01874|012|B||
01874|013|P|PREDISPOSING FACTORS:  None determined.|
01874|014|B||
01874|015|M|PATIENT MANAGEMENT:  The US manufacturer of tolvaptan states that concurrent|
01874|016|M|administration with strong CYP P-450-3A4 inducers such as St. John's wort|
01874|017|M|should be avoided.  If concurrent use is required, the dosage of tolvaptan|
01874|018|M|may need to be increased.(1)|
01874|019|B||
01874|020|D|DISCUSSION:  Concurrent administration of rifampin, another strong CYP|
01874|021|D|P-450-3A4 inducer, decreased tolvaptan exposure by 85%.(1)|
01874|022|B||
01874|023|R|REFERENCE:|
01874|024|B||
01874|025|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01874|026|R|  Ltd. February, 2014.|1
01875|001|T|MONOGRAPH TITLE:  Tolvaptan/Moderate CYP3A4 Inhibitors|
01875|002|B||
01875|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01875|004|L|of severe adverse interaction.|
01875|005|B||
01875|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
01875|007|A|metabolism of tolvaptan.(1)|
01875|008|B||
01875|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
01875|010|E|in elevated levels of and toxicity from tolvaptan.(1)|
01875|011|E|   Elevated levels of tolvaptan may lead to increased clinical effects such|
01875|012|E|as hypotension, hypovolemia, and thirst, as well as toxicity in the form of|
01875|013|E|neurologic sequelae such as osmotic demyelination syndrome (ODS).  ODS can|
01875|014|E|lead to coma and death.  Symptoms of ODS include dysarthria, mutism,|
01875|015|E|dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and|
01875|016|E|coma.(1)|
01875|017|B||
01875|018|P|PREDISPOSING FACTORS:  None determined.|
01875|019|B||
01875|020|M|PATIENT MANAGEMENT:  The US manufacturer of Samsca for the treatment of|
01875|021|M|clinically significant hypervolemic and euvolemic hyponatremia states that|
01875|022|M|concurrent administration with moderate CYP3A4 inhibitors should be|
01875|023|M|avoided.(1)|
01875|024|M|   The US manufacturer of Jynarque for the management to slow kidney|
01875|025|M|function decline in adults at risk of rapidly progressing autosomal dominant|
01875|026|M|polycystic kidney disease states concurrent administration with moderate|
01875|027|M|CYP3A4 inhibitors warrants a dose reduction of Jynarque as follows:|
01875|028|M|- Standard morning and evening dose: 90 mg and 30 mg should be dose adjusted|
01875|029|M|to 45 mg and 15 mg, respectively|
01875|030|M|- Standard morning and evening dose: 60 mg and 30 mg should be dose adjusted|
01875|031|M|to 30 mg and 15 mg, respectively|
01875|032|M|- Standard morning and evening dose: 45 mg and 15 mg should be dose adjusted|
01875|033|M|to 15 mg and 15 mg, respectively|
01875|034|M|   Interrupt Jynarque temporarily for short term therapy with moderate|
01875|035|M|CYP3A4 inhibitors if the recommended reduced doses are not available.(2)|
01875|036|B||
01875|037|D|DISCUSSION:  Fluconazole 400 mg (moderate inhibitor of CYP3A4) given one day|
01875|038|D|prior and 200 mg given concomitantly produced an 80% and 200% increase in|
01875|039|D|tolvaptan maximum concentration (Cmax) and area-under-curve (AUC),|
01875|040|D|respectively.(1)|
01875|041|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
01875|042|D|atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir,|
01875|043|D|diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine,|
01875|044|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin,|
01875|045|D|lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib,|
01875|046|D|schisandra, stiripentol, treosulfan, and verapamil.(1-4)|
01875|047|B||
01875|048|R|REFERENCES:|
01875|049|B||
01875|050|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01875|051|R|  Ltd. April, 2018.|1
01875|052|R|2.Jynarque (tolvaptan) tablets US prescribing information. Otsuka America|1
01875|053|R|  Pharmaceutical, Inc. April, 2018.|1
01875|054|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01875|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01875|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01875|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01875|058|R|  11/14/2017.|1
01875|059|R|4.This information is based on an extract from the Certara Drug Interaction|6
01875|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01876|001|T|MONOGRAPH TITLE:  Tolvaptan/Erythromycin (mono deleted 04/12/2012)|
01876|002|B||
01876|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01876|004|L|of severe adverse interaction.|
01876|005|B||
01876|006|A|MECHANISM OF ACTION:  Erythromycin inhibits the metabolism of tolvaptan by|
01876|007|A|CYP P-450-3A4.(1)|
01876|008|B||
01876|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP P-450-3A4 inhibitors such|
01876|010|E|as erythromycin may result in elevated levels of and toxicity from|
01876|011|E|tolvaptan.(1)  During initiation of tolvaptan, this may increase the risk of|
01876|012|E|osmotic demyelination syndrome (ODS), which can lead to coma and death.|
01876|013|E|Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective|
01876|014|E|changes, spastic quadriparesis, seizures, and coma.  During maintenance|
01876|015|E|therapy, it may increase the risk of dehydration.|
01876|016|B||
01876|017|P|PREDISPOSING FACTORS:  None determined.|
01876|018|B||
01876|019|M|PATIENT MANAGEMENT:  The US manufacturer of tolvaptan states that concurrent|
01876|020|M|administration with moderate CYP P-450-3A4 inhibitors such as erythromycin|
01876|021|M|should be avoided.(1)|
01876|022|B||
01876|023|D|DISCUSSION:  Concurrent administration of ketoconazole (200 mg daily), a|
01876|024|D|reduced dosage of a strong inhibitor of CYP P-450-3A4, increased tolvaptan|
01876|025|D|exposure by 5-fold.  The impact of moderate CYP P-450-3A4 inhibitors has not|
01876|026|D|been assessed, but is expected to produce a substantial increase in|
01876|027|D|tolvaptan exposure.(1)|
01876|028|B||
01876|029|R|REFERENCE:|
01876|030|B||
01876|031|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01876|032|R|  Ltd. November, 2012.|1
01877|001|T|MONOGRAPH TITLE:  Tolvaptan/Diltiazem; Verapamil (mono deleted 04/12/2012)|
01877|002|B||
01877|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01877|004|L|of severe adverse interaction.|
01877|005|B||
01877|006|A|MECHANISM OF ACTION:  Diltiazem and verapamil inhibit the metabolism of|
01877|007|A|tolvaptan by CYP P-450-3A4.(1)|
01877|008|B||
01877|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP P-450-3A4 inhibitors such|
01877|010|E|as diltiazem or verapamil may result in elevated levels of and toxicity from|
01877|011|E|tolvaptan.(1)  During initiation of tolvaptan, this may increase the risk of|
01877|012|E|osmotic demyelination syndrome (ODS), which can lead to coma and death.|
01877|013|E|Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective|
01877|014|E|changes, spastic quadriparesis, seizures, and coma.  During maintenance|
01877|015|E|therapy, it may increase the risk of dehydration.|
01877|016|B||
01877|017|P|PREDISPOSING FACTORS:  None determined.|
01877|018|B||
01877|019|M|PATIENT MANAGEMENT:  The US manufacturer of tolvaptan states that concurrent|
01877|020|M|administration with moderate CYP P-450-3A4 inhibitors such as diltiazem or|
01877|021|M|verapamil should be avoided.(1)|
01877|022|B||
01877|023|D|DISCUSSION:  Concurrent administration of ketoconazole (200 mg daily), a|
01877|024|D|reduced dosage of a strong inhibitor of CYP P-450-3A4, increased tolvaptan|
01877|025|D|exposure by 5-fold.  The impact of moderate CYP P-450-3A4 inhibitors has not|
01877|026|D|been assessed, but is expected to produce a substantial increase in|
01877|027|D|tolvaptan exposure.(1)|
01877|028|B||
01877|029|R|REFERENCE:|
01877|030|B||
01877|031|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01877|032|R|  Ltd. November, 2012.|1
01878|001|T|MONOGRAPH TITLE:  Tolvaptan/Fluconazole (mono deleted 04/12/2012)|
01878|002|B||
01878|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01878|004|L|of severe adverse interaction.|
01878|005|B||
01878|006|A|MECHANISM OF ACTION:  Fluconazole inhibits the metabolism of tolvaptan by|
01878|007|A|CYP P-450-3A4.(1)|
01878|008|B||
01878|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP P-450-3A4 inhibitors such|
01878|010|E|as fluconazole may result in elevated levels of and toxicity from|
01878|011|E|tolvaptan.(1)  During initiation of tolvaptan, this may increase the risk of|
01878|012|E|osmotic demyelination syndrome (ODS), which can lead to coma and death.|
01878|013|E|Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective|
01878|014|E|changes, spastic quadriparesis, seizures, and coma.  During maintenance|
01878|015|E|therapy, it may increase the risk of dehydration.|
01878|016|B||
01878|017|P|PREDISPOSING FACTORS:  None determined.|
01878|018|B||
01878|019|M|PATIENT MANAGEMENT:  The US manufacturer of tolvaptan states that concurrent|
01878|020|M|administration with moderate CYP P-450-3A4 inhibitors such as fluconazole|
01878|021|M|should be avoided.(1)|
01878|022|B||
01878|023|D|DISCUSSION:  Concurrent administration of ketoconazole (200 mg daily), a|
01878|024|D|reduced dosage of a strong inhibitor of CYP P-450-3A4, increased tolvaptan|
01878|025|D|exposure by 5-fold.  The impact of moderate CYP P-450-3A4 inhibitors has not|
01878|026|D|been assessed, but is expected to produce a substantial increase in|
01878|027|D|tolvaptan exposure.(1)|
01878|028|B||
01878|029|R|REFERENCE:|
01878|030|B||
01878|031|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
01878|032|R|  Ltd. November, 2012.|1
01879|001|T|MONOGRAPH TITLE:  Agomelatine/Fluvoxamine|
01879|002|B||
01879|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01879|004|L|is contraindicated and generally should not be dispensed or administered to|
01879|005|L|the same patient.|
01879|006|B||
01879|007|A|MECHANISM OF ACTION:  Fluvoxamine inhibits the metabolism of agomelatine by|
01879|008|A|CYP P-450-1A2 and by CYP P-450-2C9.(1)|
01879|009|B||
01879|010|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine results in dramatic|
01879|011|E|increases in agomelatine levels, which can produce toxicity.(1)|
01879|012|B||
01879|013|P|PREDISPOSING FACTORS:  None determined.|
01879|014|B||
01879|015|M|PATIENT MANAGEMENT:  The UK manufacturer of agomelatine states that|
01879|016|M|concurrent use of fluvoxamine is contraindicated.(1)|
01879|017|B||
01879|018|D|DISCUSSION:  Concurrent use of fluvoxamine increased agomelatine exposure by|
01879|019|D|60-fold (range: 12-fold to 412-fold).(1)|
01879|020|B||
01879|021|R|REFERENCE:|
01879|022|B||
01879|023|R|1.Valdoxan (agomelatine) UK summary of product characteristics. Les|1
01879|024|R|  Laboratoires Servier February 19, 2009.|1
01880|001|T|MONOGRAPH TITLE:  Agomelatine/Ciprofloxacin|
01880|002|B||
01880|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01880|004|L|is contraindicated and generally should not be dispensed or administered to|
01880|005|L|the same patient.|
01880|006|B||
01880|007|A|MECHANISM OF ACTION:  Ciprofloxacin may inhibit the metabolism of|
01880|008|A|agomelatine by CYP1A2.(1)|
01880|009|B||
01880|010|E|CLINICAL EFFECTS:  Concurrent use of ciprofloxacin may result in dramatic|
01880|011|E|increases in agomelatine levels, which can produce toxicity.(1)|
01880|012|B||
01880|013|P|PREDISPOSING FACTORS:  None determined.|
01880|014|B||
01880|015|M|PATIENT MANAGEMENT:  The UK manufacturer of agomelatine states that|
01880|016|M|concurrent use of ciprofloxacin is contraindicated.(1)|
01880|017|B||
01880|018|D|DISCUSSION:  Concurrent use of fluvoxamine, another strong inhibitor of|
01880|019|D|CYP1A2 and a moderate inhibitor of CYP2C9, increased agomelatine exposure by|
01880|020|D|60-fold (range: 12-fold to 412-fold).(1)|
01880|021|B||
01880|022|R|REFERENCE:|
01880|023|B||
01880|024|R|1.Valdoxan (agomelatine) UK summary of product characteristics. Les|1
01880|025|R|  Laboratoires Servier February 19, 2009.|1
01881|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 10 mg)/Atazanavir;|
01881|002|T|Lopinavir; Simeprevir|
01881|003|B||
01881|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01881|005|L|take action as needed.|
01881|006|B||
01881|007|A|MECHANISM OF ACTION:  How atazanavir and lopinavir increase rosuvastatin|
01881|008|A|levels is not known.  Simeprevir may increase the absorption of rosuvastatin|
01881|009|A|by inhibiting OATP1B1.(1,2)|
01881|010|B||
01881|011|E|CLINICAL EFFECTS:  Concurrent use of atazanavir,(3) lopinavir,(4) or|
01881|012|E|simeprevir(2) may result in elevated levels of rosuvastatin, which could|
01881|013|E|result in rhabdomyolysis.|
01881|014|B||
01881|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01881|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01881|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01881|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01881|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01881|020|P|transporter OATP1B1 may have increased statin concentrations and be|
01881|021|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
01881|022|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
01881|023|P|may have increased rosuvastatin concentrations and risk of myopathy.|
01881|024|B||
01881|025|M|PATIENT MANAGEMENT:  In patients receiving protease inhibitors, consider the|
01881|026|M|use of fluvastatin.|
01881|027|M|   If concurrent rosuvastatin is required, limit the dose of rosuvastatin to|
01881|028|M|10 mg daily or less with careful monitoring.(1,2)|
01881|029|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
01881|030|M|should not exceed 5 mg daily when used with atazanavir, lopinavir, or|
01881|031|M|simeprevir.(5)|
01881|032|B||
01881|033|D|DISCUSSION:  In a study in 6 healthy subjects, administration of|
01881|034|D|atazanavir/ritonavir increased the area-under-curve (AUC) and maximum|
01881|035|D|concentration (Cmax) of a single dose of rosuvastatin (10 mg) by 213% and|
01881|036|D|600%, respectively.(6)|
01881|037|D|   In a study of healthy subjects, concurrent use of lopinavir/ritonavir|
01881|038|D|(400 mg-100 mg) and rosuvastatin (20 mg) increased the AUC and Cmax of|
01881|039|D|rosuvastatin 2.1-fold and 4.7-fold, respectively.  There were no effects on|
01881|040|D|lopinavir/ritonavir levels.(3,7)|
01881|041|D|   In an open-label study of 22 HIV-infected patients, concurrent use of|
01881|042|D|lopinavir/ritonavir and rosuvastatin appears to have increased the AUC of|
01881|043|D|rosuvastatin by 1.6-fold when compared to healthy volunteers.  There were no|
01881|044|D|effects on lopinavir/ritonavir levels.(8)|
01881|045|D|   In a study in 16 subjects, simeprevir (150 mg daily for 7 days) increased|
01881|046|D|the Cmax and AUC of rosuvastatin (10 mg single dose) by 3.17-fold and|
01881|047|D|2.81-fold, respectively.(2)|
01881|048|D|   In a study, simeprevir (150 mg daily for 7 days) increased the AUC and|
01881|049|D|Cmax of rosuvastatin (10 mg single dose) by 2.8-fold (1.7-2.6) and 3.2-fold|
01881|050|D|(2.6-3.9), respectively. (1)|
01881|051|B||
01881|052|R|REFERENCES:|
01881|053|B||
01881|054|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
01881|055|R|  Pharmaceuticals LP July, 2024.|1
01881|056|R|2.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
01881|057|R|  November, 2017.|1
01881|058|R|3.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01881|059|R|  Squibb Company December, 2024.|1
01881|060|R|4.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01881|061|R|  Laboratories December, 2019.|1
01881|062|R|5.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
01881|063|R|  Australia Pty Ltd July 8, 2024.|1
01881|064|R|6.Busti AJ, Bain AM, Hall RG 2nd, Bedimo RG, Leff RD, Meek C, Mehvar R.|2
01881|065|R|  Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the|2
01881|066|R|  pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol 2008 Jun;|2
01881|067|R|  51(6):605-10.|2
01881|068|R|7.Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/Drug|2
01881|069|R|  Interaction Between Lopinavir/Ritonavir and Rosuvastatin in Healthy|2
01881|070|R|  Volunteers. J Acquir Immune Defic Syndr 2008 Apr 15;47(5):570-578.|2
01881|071|R|8.van der Lee M, Sankatsing R, Schippers E, Vogel M, Fatkenheuer G, van der|2
01881|072|R|  Ven A, Kroon F, Rockstroh J, Wyen C, Baumer A, de Groot E, Koopmans P,|2
01881|073|R|  Stroes E, Reiss P, Burger D. Pharmacokinetics and pharmacodynamics of|2
01881|074|R|  combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected|2
01881|075|R|  patients. Antivir Ther 2007;12(7):1127-32.|2
01882|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 10 mg)/Atazanavir; Lopinavir;|
01882|002|T|Simeprevir|
01882|003|B||
01882|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01882|005|L|is contraindicated and generally should not be dispensed or administered to|
01882|006|L|the same patient.|
01882|007|B||
01882|008|A|MECHANISM OF ACTION:  How atazanavir and lopinavir increase rosuvastatin|
01882|009|A|levels is not known.  Simeprevir may increase the absorption of rosuvastatin|
01882|010|A|by inhibiting OATP1B1.(1,2)|
01882|011|B||
01882|012|E|CLINICAL EFFECTS:  Concurrent use of atazanavir,(3) lopinavir,(4) or|
01882|013|E|simeprevir(2) may result in elevated levels of rosuvastatin, which could|
01882|014|E|result in rhabdomyolysis.|
01882|015|B||
01882|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
01882|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
01882|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
01882|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
01882|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
01882|021|P|transporter OATP1B1 may have increased statin concentrations and be|
01882|022|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
01882|023|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
01882|024|P|may have increased rosuvastatin concentrations and risk of myopathy.|
01882|025|B||
01882|026|M|PATIENT MANAGEMENT:  In patients receiving protease inhibitors, consider the|
01882|027|M|use of fluvastatin.|
01882|028|M|   If concurrent rosuvastatin is required, limit the dose of rosuvastatin to|
01882|029|M|10 mg daily or less with careful monitoring.(1,2)|
01882|030|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
01882|031|M|of rosuvastatin should not exceed 5 mg daily when used with atazanavir,|
01882|032|M|lopinavir, or simeprevir.(5)|
01882|033|B||
01882|034|D|DISCUSSION:  In a study in 6 healthy subjects, administration of|
01882|035|D|atazanavir/ritonavir increased the area-under-curve (AUC) and maximum|
01882|036|D|concentration (Cmax) of a single dose of rosuvastatin (10 mg) by 213% and|
01882|037|D|600%, respectively.(6)|
01882|038|D|   In a study of healthy subjects, concurrent use of lopinavir/ritonavir|
01882|039|D|(400 mg-100 mg) and rosuvastatin (20 mg) increased the AUC and Cmax of|
01882|040|D|rosuvastatin 2.1-fold and 4.7-fold, respectively.  There were no effects on|
01882|041|D|lopinavir/ritonavir levels.(4,7)|
01882|042|D|   In an open-label study of 22 HIV-infected patients, concurrent use of|
01882|043|D|lopinavir/ritonavir and rosuvastatin appears to have increased the AUC of|
01882|044|D|rosuvastatin by 1.6-fold when compared to healthy volunteers.  There were no|
01882|045|D|effects on lopinavir/ritonavir levels.(8)|
01882|046|D|   In a study in 16 subjects, simeprevir (150 mg daily for 7 days) increased|
01882|047|D|the Cmax and AUC of rosuvastatin (10 mg single dose) by 3.17-fold and|
01882|048|D|2.81-fold, respectively.(2)|
01882|049|D|   In a study, simeprevir (150 mg daily for 7 days) increased the AUC and|
01882|050|D|Cmax of rosuvastatin (10 mg single dose) by 2.8-fold (1.7-2.6) and 3.2-fold|
01882|051|D|(2.6-3.9), respectively. (1)|
01882|052|B||
01882|053|R|REFERENCES:|
01882|054|B||
01882|055|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
01882|056|R|  Pharmaceuticals LP July, 2024.|1
01882|057|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01882|058|R|  Squibb Company December, 2024.|1
01882|059|R|3.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01882|060|R|  Laboratories December, 2019.|1
01882|061|R|4.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
01882|062|R|  November, 2017.|1
01882|063|R|5.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
01882|064|R|  Australia Pty Ltd July 8, 2024.|1
01882|065|R|6.Busti AJ, Bain AM, Hall RG 2nd, Bedimo RG, Leff RD, Meek C, Mehvar R.|2
01882|066|R|  Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the|2
01882|067|R|  pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol 2008 Jun;|2
01882|068|R|  51(6):605-10.|2
01882|069|R|7.Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/Drug|2
01882|070|R|  Interaction Between Lopinavir/Ritonavir and Rosuvastatin in Healthy|2
01882|071|R|  Volunteers. J Acquir Immune Defic Syndr 2008 Apr 15;47(5):570-578.|2
01882|072|R|8.van der Lee M, Sankatsing R, Schippers E, Vogel M, Fatkenheuer G, van der|2
01882|073|R|  Ven A, Kroon F, Rockstroh J, Wyen C, Baumer A, de Groot E, Koopmans P,|2
01882|074|R|  Stroes E, Reiss P, Burger D. Pharmacokinetics and pharmacodynamics of|2
01882|075|R|  combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected|2
01882|076|R|  patients. Antivir Ther 2007;12(7):1127-32.|2
01883|001|T|MONOGRAPH TITLE:  Fosphenytoin/Selected QT Prolongers (mono deleted|
01883|002|T|03/19/2015)|
01883|003|B||
01883|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01883|005|L|take action as needed.|
01883|006|B||
01883|007|A|MECHANISM OF ACTION:  Concurrent use of fosphenytoin with agents known to|
01883|008|A|prolong the QTc interval may result in additive effects on the QTc interval.|
01883|009|B||
01883|010|E|CLINICAL EFFECTS:  Concurrent use may result in potentially life-threatening|
01883|011|E|cardiac arrhythmias, including torsades de pointes.(1-52)|
01883|012|B||
01883|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01883|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01883|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01883|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01883|017|P|gender, or advanced age.(1)|
01883|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01883|019|P|higher systemic concentrations of either QT prolonging drug are additional|
01883|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01883|021|P|drug concentrations include rapid infusion of an intravenous dose or|
01883|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01883|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01883|024|P|dysfunction).(1)|
01883|025|B||
01883|026|M|PATIENT MANAGEMENT:  The manufacturers of alfuzosin,(2) apomorphine,(3)|
01883|027|M|clozapine,(4) dolasetron,(5) domperidone,(6) formoterol,(7,8)|
01883|028|M|gadoxetate,(9,10) gatifloxacin,(11) gemifloxacin,(12) haloperidol,(13-15)|
01883|029|M|lapatinib,(16) levofloxacin,(17) methadone,(18) moxifloxacin,(19) nalidixic|
01883|030|M|acid,(20) norfloxacin,(21) risperidone,(22) sotalol,(23) and vorinostat(24)|
01883|031|M|state that these agents should be used with caution with other agents known|
01883|032|M|to prolong the QTc interval.|
01883|033|M|   The manufacturer of arsenic trioxide states that, if possible, drugs that|
01883|034|M|are known to prolong the QT interval should be discontinued prior to therapy|
01883|035|M|and caution is advised during coadministration.  Patients who reach an|
01883|036|M|absolute QT interval value >500 msec should be reassessed and immediate|
01883|037|M|action should be taken to correct concomitant risk factors, if any, and the|
01883|038|M|risk/benefit of continuing therapy should be considered.  If syncope, rapid|
01883|039|M|or irregular heartbeat develops, the patient should be hospitalized for|
01883|040|M|monitoring, serum electrolytes should be assessed.  Arsenic trioxide therapy|
01883|041|M|should be temporarily discontinued until the QTc interval regresses to below|
01883|042|M|460 msec, electrolyte abnormalities are corrected, and the syncope and|
01883|043|M|irregular heartbeat cease.(25)|
01883|044|M|   Bedaquiline should be used with caution in patients receiving therapy|
01883|045|M|with agents that prolong the QT interval.  Patients should receive a|
01883|046|M|baseline electrocardiogram (ECG) and at 2, 12, and 24 weeks of therapy and|
01883|047|M|more closely if receiving concurrent agents that prolong the QT interval.|
01883|048|M|If a patient develops syncope, perform an ECG.  Bedaquiline and other QT|
01883|049|M|prolonging agents should be discontinued if the patient develops a|
01883|050|M|clinically significant ventricular arrhythmia or a QTcF of greater than 500|
01883|051|M|msec confirmed on two ECGs.(26)|
01883|052|M|   Concurrent use of citalopram with agents known to prolong the QT interval|
01883|053|M|is not recommended.  Consider more frequent ECG monitoring in patients|
01883|054|M|receiving concurrent therapy.  Citalopram should be discontinued in patients|
01883|055|M|with persistent QTc measurements greater than 500 ms.(27)|
01883|056|M|   The US manufacturer of eribulin states that patients receiving concurrent|
01883|057|M|therapy with eribulin and other agents known to prolong the QT interval|
01883|058|M|should receive ECG monitoring.(28)|
01883|059|M|   While the US FDA and manufacturer recommend no special precautions when|
01883|060|M|escitalopram is used with QT prolonging agents,(29,30) Health Canada and the|
01883|061|M|Canadian manufacturer of escitalopram discourage the concurrent use of|
01883|062|M|agents known to prolong the QT interval(31,32) and the UK manufacturer|
01883|063|M|states that concurrent use is contraindicated.(33)|
01883|064|M|   The concurrent use of ezogabine with agents known to prolong the QT|
01883|065|M|interval should be approached with caution.  Patients receiving concurrent|
01883|066|M|therapy with other QT prolongers, an electrocardiogram (ECG) should be|
01883|067|M|performed prior to ezogabine initiation.  In those patients with a corrected|
01883|068|M|QT interval greater than 440 msec at baseline, a repeat ECG should be|
01883|069|M|performed after reaching the maintenance dose of ezogabine.(34)|
01883|070|M|   In patients maintained on agents known to prolong the QT interval,|
01883|071|M|consider a baseline ECG prior to administration of gadofosveset to asses the|
01883|072|M|risk/benefit of gadofosveset.  If gadofosveset is used, consider ECG|
01883|073|M|monitoring for 72 hours until the majority of gadofosveset is eliminated.|
01883|074|M|Counsel patients to report any irregular heartbeat, dizziness, or fainting|
01883|075|M|episodes during this time frame.(35)|
01883|076|M|   Approach the concurrent use of ondansetron and other agents that are|
01883|077|M|known to prolong the QTc interval with caution.  Electrocardiogram (ECG)|
01883|078|M|monitoring should be performed in patients receiving concurrent|
01883|079|M|therapy.(36,37)|
01883|080|M|   Pasireotide should be used with caution in patients receiving therapy|
01883|081|M|with agents that prolong the QT interval.  Patients should receive a|
01883|082|M|baseline electrocardiogram (ECG) and hypokalemia and hypomagnesemia should|
01883|083|M|be corrected before therapy is initiated.  Monitor ECG and potassium and|
01883|084|M|magnesium levels during therapy.(38)|
01883|085|M|   The US manufacturer of saquinavir states that concurrent use of agents|
01883|086|M|known to prolong the QT interval should only be used when there is no|
01883|087|M|alternative therapy and potential benefits outweigh the risks.  Perform an|
01883|088|M|ECG prior to concurrent therapy.  Patients with a QT interval greater than|
01883|089|M|450 msec should not initiate concurrent therapy.  For patients with a|
01883|090|M|baseline QT interval less than 450 msec, a repeat ECG should be performed|
01883|091|M|after 3-4 days of concurrent therapy.  In patients who experience an|
01883|092|M|increase in QT interval to greater than 480 msec or by greater than 20 msec,|
01883|093|M|consideration should be given to discontinuing one or both agents.(39)|
01883|094|M|   Patients receiving concurrent therapy with agents known to prolong the|
01883|095|M|QTc interval should be monitored with electrocardiograms during treatment|
01883|096|M|with sorafenib. Electrolytes (calcium, magnesium, and potassium) should also|
01883|097|M|be monitored.(40)|
01883|098|M|   The US manufacturer of toremifene states that concurrent use should be|
01883|099|M|avoided.  If treatment with an agent known to prolong the QT interval is|
01883|100|M|required, toremifene therapy should be interrupted.  If it is not possible|
01883|101|M|to interrupt toremifene therapy, electrocardiograms (ECGs) should be|
01883|102|M|obtained and patients should be closely monitored for QT prolongation.(41)|
01883|103|M|The UK manufacturer of toremifene states that the use of other drugs that|
01883|104|M|are known to prolong the QTc interval is contraindicated.  These agents|
01883|105|M|include class IA and III antiarrhythmics, astemizole, bepridil, cisapride,|
01883|106|M|diphemanil, erythromycin IV, halofantrine, haloperidol, mizolastine,|
01883|107|M|moxifloxacin, pentamidine, phenothiazines, pimozide, sertindole,|
01883|108|M|terfenadine, and vincamine IV.(42)|
01883|109|M|   The manufacturer of vandetanib states that the use of vandetanib with|
01883|110|M|other agents known to prolong the QT interval should be avoided.  If another|
01883|111|M|drug known to prolong the QT interval must be coadministered with|
01883|112|M|vandetanib, more frequent ECG monitoring is recommended.(43)|
01883|113|M|   Consider obtaining serum calcium, magnesium, and potassium levels at|
01883|114|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01883|115|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01883|116|M|   The concurrent use of vemurafenib with agents known to prolong the QT|
01883|117|M|interval is not recommended.  Initiation of vemurafenib in patients with a|
01883|118|M|baseline QTc greater than 500 msec is not recommended.  All patients|
01883|119|M|receiving vemurafenib should undergo ECG testing at baseline, after 15 days|
01883|120|M|of treatment, monthly during the first 3 months of treatment, and then every|
01883|121|M|3 months.  If a patient's QTc exceeds 500 msec during treatment, vemurafenib|
01883|122|M|should be discontinued and cardiac risk factors for QT prolongation should|
01883|123|M|be controlled.  Consider discontinuing other medications known to prolong|
01883|124|M|the QT interval at this time.  If the patient's QTc decreases below 500|
01883|125|M|msec, vemurafenib may be introduced at a lower dosage according to the|
01883|126|M|current labeling recommendations.(44)|
01883|127|M|   The manufacturers of dofetilide(45), propafenone,(46) sotalol(47) state|
01883|128|M|that concurrent use with other agents known to prolong the QT interval is|
01883|129|M|not recommended.|
01883|130|M|   The US manufacturers of quinine(48) and telavancin(49) recommend against|
01883|131|M|the use of these agents with other drugs known to cause QT prolongation.|
01883|132|M|   The manufacturers of asenapine,(50) iloperidone,(51) ivabradine,(52)|
01883|133|M|mesoridazine,(53) paliperidone,(54) tetrabenazine,(55) trazodone,(56)|
01883|134|M|vinflunine,(57) and zuclopenthixol(58) state that concurrent use of agents|
01883|135|M|known to prolong the QT interval should be avoided.|
01883|136|B||
01883|137|D|DISCUSSION:  Fosphenytoin has been shown to prolong the QTc interval.|
01883|138|D|Agents that are linked to this monograph may have varying degrees of|
01883|139|D|potential to prolong the QTc interval.(59)|
01883|140|B||
01883|141|R|REFERENCES:|
01883|142|B||
01883|143|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01883|144|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01883|145|R|  settings: a scientific statement from the American Heart Association and|6
01883|146|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01883|147|R|  2;55(9):934-47.|6
01883|148|R|2.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
01883|149|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
01883|150|R|3.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
01883|151|R|  Inc. May, 2019.|1
01883|152|R|4.Clozaril (clozapine tablets) US prescribing information. Novartis|1
01883|153|R|  Pharmaceuticals Corporation March, 2013.|1
01883|154|R|5.Anzemet (dolasetron mesylate) US prescribing information. Sanofi-Aventis|1
01883|155|R|  Us.S. LLC September, 2014.|1
01883|156|R|6.Mathivanan M. Dear Canadian Healthcare Professional:  Subject:|1
01883|157|R|  Association of domperidone maleate with serious ventricular arrhythmias|1
01883|158|R|  and sudden cardiac death. Teva Canada Limited March 2, 2012.|1
01883|159|R|7.Foradil Aerolizer (formoterol fumarate) US prescribing information.|1
01883|160|R|  Schering Corporation September, 2012.|1
01883|161|R|8.Symbicort Turbuhaler (budesonide-eformoterol fumarate dihydrate)|1
01883|162|R|  Australian prescribing information. AstraZeneca Pty Ltd April 30, 2004.|1
01883|163|R|9.Primovist (gadoxetate disodium) Australian prescribing information.|1
01883|164|R|  Schering-Plough Corporation November 1, 2005.|1
01883|165|R|10.Primovist (gadoxetic acid) UK summary of product characteristics. Bayer|1
01883|166|R|   plc May 1, 2008.|1
01883|167|R|11.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
01883|168|R|   Company January, 2006.|1
01883|169|R|12.Factive (gemifloxacin mesylate) US prescribing information. Oscient|1
01883|170|R|   Pharmaceuticals August, 2013.|1
01883|171|R|13.Serenace (haloperidol) Australian prescribing information. Sigma|1
01883|172|R|   Pharmaceuticals Pty Ltd. June 5, 2001.|1
01883|173|R|14.Dozic (haloperidol) UK summary of product characteristics. Rosemont|1
01883|174|R|   Pharmaceuticals Limited September 10, 2007.|1
01883|175|R|15.Haldol (haloperidol) US prescribing information. Ortho-McNeil-Janssen|1
01883|176|R|   Pharmaceuticals, Inc. August, 2011.|1
01883|177|R|16.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
01883|178|R|   2018.|1
01883|179|R|17.Levaquin (levofloxacin) US prescribing information. Ortho-McNeil|1
01883|180|R|   Pharmaceutical, Inc. August, 2013.|1
01883|181|R|18.Dolophine (methadone hydrochloride) US prescribing information. Roxane|1
01883|182|R|   Laboratories, Inc. July, 2012.|1
01883|183|R|19.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
01883|184|R|   Pharmaceuticals Corporation August, 2013.|1
01883|185|R|20.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
01883|186|R|   Inc. November, 2012.|1
01883|187|R|21.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc.|1
01883|188|R|   August, 2013.|1
01883|189|R|22.Risperidal (risperidone) UK summary of product characteristics.|1
01883|190|R|   Janssen-Cilag, UK Limited May 14, 2004.|1
01883|191|R|23.Ultane (sevoflurane) US prescribing information. AbbVie, Inc. February,|1
01883|192|R|   2014.|1
01883|193|R|24.Zolinza (vorinostat) US prescribing information. Merck & Co., Inc. 2006.|1
01883|194|R|25.Trisenox (arsenic trioxide) US prescribing information. Cell|1
01883|195|R|   Therapeutics, Inc. March, 2001.|1
01883|196|R|26.Sirturo (bedaquiline) US prescribing information. Janssen Therapeutics|1
01883|197|R|   June, 2024.|1
01883|198|R|27.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
01883|199|R|   recommendations for Celexa (citalopram hydrobromide) related to a|1
01883|200|R|   potential risk of abnormal heart rhythms with high doses. available at:|1
01883|201|R|   http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
01883|202|R|28.Halaven (eribulin mesylate) US prescribing information. Eisai, Inc.|1
01883|203|R|   August, 2014.|1
01883|204|R|29.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
01883|205|R|   Pharmaceuticals Inc. December, 2012.|1
01883|206|R|30.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
01883|207|R|   recommendations for Celexa (citalopram hydrobromide) related to a|1
01883|208|R|   potential risk of abnormal heart rhythms with high doses. Available at:|1
01883|209|R|   http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
01883|210|R|31.Health Canada. Antidepressant Cipralex (escitalopram): Updated|1
01883|211|R|   information regarding dose-related heart risk. Available at:|1
01883|212|R|   http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/136|1
01883|213|R|   74a-eng.php May 7, 2012.|1
01883|214|R|32.Cipralex (escitalopram oxalate) Canadian prescribing information.|1
01883|215|R|   Lundbeck August 13, 2012.|1
01883|216|R|33.Cipralex (escitalopram oxalate) UK summary of product characteristics.|1
01883|217|R|   Lunbeck Limited June 25, 2020.|1
01883|218|R|34.Potiga (ezogabine) US Prescribing Information. Valeant Pharmaceuticals|1
01883|219|R|   May, 2016.|1
01883|220|R|35.Ablavar (gadofosveset trisodium) US prescribing information. Lantheus|1
01883|221|R|   Medical Imaging, Inc. August, 2013.|1
01883|222|R|36.Zofran (ondansetron) US prescribing information. GlaxoSmithKline October,|1
01883|223|R|   2021.|1
01883|224|R|37.USFood and Drug Administration. FDA Drug Safety Communication: Abnormal|1
01883|225|R|   heart rhythms may be associated with use of Zofran (ondansetron).|1
01883|226|R|   available at:|1
01883|227|R|   https://wayback.archive-it.org/7993/20170722185907/https:/www.fda.gov/Dru|1
01883|228|R|   gs/DrugSafety/ucm271913.htm September 15, 2011.|1
01883|229|R|38.Signifor (pasireotide diasparate) US prescribing information. Novartis|1
01883|230|R|   Pharmaceuticals Corporation January, 2020.|1
01883|231|R|39.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01883|232|R|   Laboratories, Inc. February, 2012.|1
01883|233|R|40.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
01883|234|R|   Corporation July, 2020.|1
01883|235|R|41.Fareston (toremifene citrate) US prescribing information. GTx, Inc.|1
01883|236|R|   March, 2011.|1
01883|237|R|42.Fareston (toremifene citrate) UK summary of product characteristics.|1
01883|238|R|   Orion Pharma (UK) Limited January, 2009.|1
01883|239|R|43.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
01883|240|R|   Pharmaceuticals LP October, 2018.|1
01883|241|R|44.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
01883|242|R|   March, 2014.|1
01883|243|R|45.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
01883|244|R|   2013.|1
01883|245|R|46.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
01883|246|R|   Laboratories March, 2013.|1
01883|247|R|47.Betapace (sotalol hydrochloride) US prescribing information. Bayer|1
01883|248|R|   Healthcare Inc. June, 2021.|1
01883|249|R|48.Qualaquin (quinine sulfate) US prescribing information. Sun|1
01883|250|R|   Pharmaceutical Industries, Inc. August, 2019.|1
01883|251|R|49.Vibativ (telavancin) US prescribing information. Theravance Biopharma US,|1
01883|252|R|   Inc. February, 2020.|1
01883|253|R|50.Saphris (asenapine) US prescribing information. Schering Corporation|1
01883|254|R|   October, 2011.|1
01883|255|R|51.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
01883|256|R|   Inc April, 2024.|1
01883|257|R|52.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
01883|258|R|   Les Laboratoires Servier March, 2015.|1
01883|259|R|53.Serentil (mesoridazine besylate) US prescribing information. Novartis|1
01883|260|R|   Pharmaceuticals Corporation August, 2000.|1
01883|261|R|54.Invega (paliperidone) US prescribing information. Janssen|1
01883|262|R|   Pharmaceuticals, Inc. April, 2011.|1
01883|263|R|55.Xenazine (tetrabenazine) US prescribing information. Valeant|1
01883|264|R|   International September, 2012.|1
01883|265|R|56.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
01883|266|R|   Labopharm Inc. November, 2012.|1
01883|267|R|57.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
01883|268|R|   Pierre Fabre Limited September 21, 2009.|1
01883|269|R|58.Clopixol (zuclopenthixol acetate) UK summary of product characteristics.|1
01883|270|R|   Lundbeck Limited October 15, 2020.|1
01883|271|R|59.USDepartment of Health and Human Services Food and Drug Administration.|1
01883|272|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01883|273|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01883|274|R|   https://www.fda.gov/media/71372/download October, 2005.|1
01884|001|T|MONOGRAPH TITLE:  Sirolimus/Posaconazole|
01884|002|B||
01884|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01884|004|L|is contraindicated and generally should not be dispensed or administered to|
01884|005|L|the same patient.|
01884|006|B||
01884|007|A|MECHANISM OF ACTION:  Posaconazole inhibits the metabolism of sirolimus by|
01884|008|A|CYP3A4.(1,2)|
01884|009|B||
01884|010|E|CLINICAL EFFECTS:  Concurrent use of posaconazole may result in elevated|
01884|011|E|levels of and toxicity from sirolimus.(1,2)|
01884|012|B||
01884|013|P|PREDISPOSING FACTORS:  None determined.|
01884|014|B||
01884|015|M|PATIENT MANAGEMENT:  The US manufacturer of posaconazole states that|
01884|016|M|concurrent use with sirolimus is contraindicated.(1)|
01884|017|M|   The UK manufacturer of posaconazole states that concurrent use with|
01884|018|M|sirolimus is not recommended and should be avoided whenever possible.(2)|
01884|019|B||
01884|020|D|DISCUSSION:  In a study in 12 healthy subjects, administration of|
01884|021|D|posaconazole (400 mg twice daily for 16 days) increased the maximum|
01884|022|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
01884|023|D|sirolimus (2 mg) by 6.7-fold and 8.9-fold (range 3.1-fold to 17.5-fold),|
01884|024|D|respectively.(1-3)|
01884|025|B||
01884|026|R|REFERENCES:|
01884|027|B||
01884|028|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01884|029|R|  January, 2022.|1
01884|030|R|2.Noxafil (posaconazole) UK summary of product characteristics.|1
01884|031|R|  Schering-Plough Ltd. January, 2022.|1
01884|032|R|3.Moton A, Ma L, Krishna G, Martinho M, Seiberling M, McLeod J. Effects of|2
01884|033|R|  oral posaconazole on the pharmacokinetics of sirolimus. Curr Med Res Opin|2
01884|034|R|  2009 Feb 2.|2
01885|001|T|MONOGRAPH TITLE:  Selected Calcium Channel Blockers/Selected Strong CYP3A4|
01885|002|T|Inhibitors|
01885|003|B||
01885|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01885|005|L|take action as needed.|
01885|006|B||
01885|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the first-pass|
01885|008|A|and elimination metabolism of calcium channel blockers by CYP3A4.|
01885|009|B||
01885|010|E|CLINICAL EFFECTS:  The concurrent use of strong CYP3A4 inhibitors with|
01885|011|E|calcium channel blockers metabolized by CYP3A4 may result in elevated levels|
01885|012|E|of the calcium channel blocker and risk of adverse effects, including|
01885|013|E|hypotension and bradycardia.|
01885|014|B||
01885|015|P|PREDISPOSING FACTORS:  None determined.|
01885|016|B||
01885|017|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
01885|018|M|calcium channel blockers should be approached with caution.  When these|
01885|019|M|agents are used concurrently, the dose of the calcium channel blocker may|
01885|020|M|need to be adjusted or an alternative agent considered.  Monitor patients|
01885|021|M|for increased calcium channel blocker effects.|
01885|022|M|   If the strong CYP3A4 inhibitor is discontinued, the dose of the calcium|
01885|023|M|channel blocker may need to be increased and patients should be observed for|
01885|024|M|decreased effects.|
01885|025|B||
01885|026|D|DISCUSSION:  A double-blind, randomized, two-phase crossover study in nine|
01885|027|D|subjects examined the effects of itraconazole on felodipine.  The half-life|
01885|028|D|of felodipine increased by 71% during concurrent itraconazole.  In seven of|
01885|029|D|the nine subjects, the maximum concentration (Cmax) of felodipine when|
01885|030|D|administered with placebo was lower than the 32-hour concentration of|
01885|031|D|felodipine when administered with itraconazole.  Concurrent use also|
01885|032|D|resulted in significantly greater effects on both blood pressure and heart|
01885|033|D|rate.(10,11)|
01885|034|D|   A randomized cross-over trial in seven subjects examined the effects of|
01885|035|D|ketoconazole (200 mg daily for 4 days) on nisoldipine (5 mg daily).  The|
01885|036|D|concurrent use of ketoconazole increased the nisoldipine area-under-curve|
01885|037|D|(AUC) and Cmax by 24-fold and 11-fold, respectively.  Increases in the M9|
01885|038|D|nisoldipine metabolite were similar.(7)|
01885|039|D|   PKPB modeling of nifedipine and ritonavir noted a decreased systolic|
01885|040|D|blood pressure > 40 mmHg.(8)|
01885|041|D|   There are several case reports of patients developing increased levels of|
01885|042|D|calcium channel blockers and adverse effects with concurrent strong CYP3A4|
01885|043|D|inhibitors.(9-16)|
01885|044|D|   Strong CYP3A4 inhibitors include: adagrasib, ceritinib, cobicistat,|
01885|045|D|grapefruit, idelalisib, indinavir, itraconazole, ketoconazole,|
01885|046|D|levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone,|
01885|047|D|nelfinavir, posaconazole, ribociclib, saquinavir, tipranavir,|
01885|048|D|troleandomycin, tucatinib, and voriconazole.(17,18)|
01885|049|B||
01885|050|R|REFERENCES:|
01885|051|B||
01885|052|R|1.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
01885|053|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
01885|054|R|2.Plendil (felodipine) US prescribing information. AstraZeneca|1
01885|055|R|  Pharmaceuticals LP November, 2003.|1
01885|056|R|3.Cardene (nicardipine) US prescribing information. EKR Therapeutics, Inc.|1
01885|057|R|  August, 2016.|1
01885|058|R|4.Procardia (nifedipine) US prescribing information. Pfizer Inc. January 9,|1
01885|059|R|  2015.|1
01885|060|R|5.Calan (verapamil hydrochloride) US prescribing information. Pfizer, Inc.|1
01885|061|R|  August, 2016.|1
01885|062|R|6.Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma|2
01885|063|R|  concentrations and effects of felodipine. Clin Pharmacol Ther 1997 Apr;|2
01885|064|R|  61(4):410-5.|2
01885|065|R|7.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
01885|066|R|  January, 2022.|1
01885|067|R|8.Niu W, Li S, Jin S, Lin X, Zhang M, Cai W, Jiao Z, Xiang X. Investigating|5
01885|068|R|  the interaction between nifedipine- and ritonavir-containing  antiviral|5
01885|069|R|  regimens: A physiologically based pharmacokinetic/pharmacodynamic|5
01885|070|R|  analysis. Br J Clin Pharmacol 2021 Jul;87(7):2790-2806.|5
01885|071|R|9.Neuvonen PJ, Suhonen R. Itraconazole interacts with felodipine. J Am Acad|3
01885|072|R|  Dermatol 1995 Jul;33(1):134-5.|3
01885|073|R|10.Kremens B, Brendel E, Bald M, Czyborra P, Michel MC. Loss of blood|3
01885|074|R|   pressure control on withdrawal of fluconazole during nifedipine therapy.|3
01885|075|R|   Br J Clin Pharmacol 1999 Jun;47(6):707-8.|3
01885|076|R|11.Tailor SA, Gupta AK, Walker SE, Shear NH. Peripheral edema due to|3
01885|077|R|   nifedipine-itraconazole interaction: a case report. Arch Dermatol 1996|3
01885|078|R|   Mar;132(3):350-2.|3
01885|079|R|12.Mishima E, Maruyama K, Nakazawa T, Abe T, Ito S. Acute Kidney Injury from|3
01885|080|R|   Excessive Potentiation of Calcium-channel Blocker via  Synergistic CYP3A4|3
01885|081|R|   Inhibition by Clarithromycin Plus Voriconazole. Intern Med 2017;|3
01885|082|R|   56(13):1687-1690.|3
01885|083|R|13.Shah SP, Self TH, Bradsher RW 3rd, Owens RE.|3
01885|084|R|   Clarithromycin-nifedipine-induced acute kidney injury. Nurse Pract 2017|3
01885|085|R|   Sep 21;42(9):49-51.|3
01885|086|R|14.Cook RMD, Garcia-Gayoso AS, Twilla JD. Concomitant Use of Nifedipine and|3
01885|087|R|   Clarithromycin Leading to Pulseless,  Bradycardic Arrest. Am J Ther 2019|3
01885|088|R|   Jul/Aug;26(4):e543-e546.|3
01885|089|R|15.Baeza MT, Merino E, Boix V, Climent E. Nifedipine-lopinavir/ritonavir|3
01885|090|R|   severe interaction: a case report. AIDS 2007 Jan 2;21(1):119-20.|3
01885|091|R|16.Zhao X, Zhang C, Zhu L, Wu B, Han Y, Heung M, Zuo L. Severe secondary|3
01885|092|R|   hyperkalemia and arrhythmia from drug interactions between|3
01885|093|R|   calcium-channel blocker and voriconazole: a case presentation. BMC|3
01885|094|R|   Nephrol 2021 May 10;22(1):172.|3
01885|095|R|17.US Food and Drug Administration (FDA). Drug Development and Drug|1
01885|096|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
01885|097|R|   at:|1
01885|098|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
01885|099|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01885|100|R|   11/14/2017.|1
01885|101|R|18.This information is based on an extract from the Certara Drug Interaction|6
01885|102|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01886|001|T|MONOGRAPH TITLE:  Felodipine; Nisoldipine/Itraconazole; Ketoconazole;|
01886|002|T|Levoketoconazole|
01886|003|B||
01886|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01886|005|L|is contraindicated and generally should not be dispensed or administered to|
01886|006|L|the same patient.|
01886|007|B||
01886|008|A|MECHANISM OF ACTION:  Itraconazole(1), ketoconazole(2), and|
01886|009|A|levoketoconazole(3) may inhibit the metabolism of felodipine by CYP3A4.|
01886|010|A|   Nisoldipine has a low absolute bioavailability of approximately 5% due to|
01886|011|A|intestinal and hepatic first-pass metabolism by CYP3A4.(4)  FDA designates|
01886|012|A|nisoldipine as a CYP3A4 sensitive substrate, i.e. a drug whose plasma|
01886|013|A|area-under-curve (AUC) has been shown to increase 5-fold or more in the|
01886|014|A|presence of a strong inhibitor of CYP3A4.(5)  Both itraconazole(1,5-6) and|
01886|015|A|ketoconazole(2,5-6) are strong inhibitors of CYP3A4.|
01886|016|A|   In addition, itraconazole has been shown to have negative inotropic|
01886|017|A|effects, which may be additive with those of nisoldipine.(1)|
01886|018|B||
01886|019|E|CLINICAL EFFECTS:  The concurrent administration of itraconazole or|
01886|020|E|ketoconazole may result in a 6 to 8 fold increase in felodipine AUC(1) or a|
01886|021|E|10 to 24-fold increase in nisoldipine AUC(1) leading to adverse effects such|
01886|022|E|as severe hypotension or peripheral edema.|
01886|023|B||
01886|024|P|PREDISPOSING FACTORS:  None determined.|
01886|025|B||
01886|026|M|PATIENT MANAGEMENT:  The concurrent use of itraconazole(1,7,8),|
01886|027|M|ketoconazole(2,9), or levoketoconazole(3) with felodipine or nisoldipine is|
01886|028|M|contraindicated.|
01886|029|M|   The US manufacturer of itraconazole states that concurrent administration|
01886|030|M|with felodipine or nisoldipine is contraindicated during and two weeks after|
01886|031|M|itraconazole treatment.(1)|
01886|032|M|   While all dihydropyridine calcium channel blockers are metabolized and|
01886|033|M|could be affected by CYP3A4 inhibitors, nisoldipine and felodipine are|
01886|034|M|particularly sensitive to CYP3A4 inhibition.(6)  If ketoconazole or|
01886|035|M|itraconazole therapy is required, it would be prudent to change to a low|
01886|036|M|dose of a different dihydropyridine with careful monitoring for adverse|
01886|037|M|effects.|
01886|038|B||
01886|039|D|DISCUSSION:  A double-blind, randomized, two-phase crossover study in nine|
01886|040|D|subjects examined the effects of itraconazole on felodipine.  The|
01886|041|D|area-under-curve (AUC) and half-life of felodipine increased by 6-fold and|
01886|042|D|2-fold, respectively, during concurrent itraconazole.  In seven of the nine|
01886|043|D|subjects, the maximum concentration (Cmax) of felodipine when administered|
01886|044|D|with placebo was lower than the 32-hour concentration of felodipine when|
01886|045|D|administered with itraconazole.  Concurrent use also resulted in|
01886|046|D|significantly greater effects on both blood pressure and heart rate.(10)|
01886|047|D|There are two case reports of patients developing edema following the|
01886|048|D|addition of itraconazole to felodipine therapy.  In the second report, the|
01886|049|D|patient was rechallenged with concurrent itraconazole and again developed|
01886|050|D|edema.(11)|
01886|051|D|   Concurrent use of itraconazole produces clinically significant increases|
01886|052|D|in nisoldipine levels that cannot be managed by dosage adjustment.(1)|
01886|053|D|   A randomized cross-over trial in seven subjects examined the effects of|
01886|054|D|ketoconazole (200 mg daily for 4 days) on nisoldipine (5 mg daily).  The|
01886|055|D|concurrent use of ketoconazole increased the nisoldipine AUC and Cmax by|
01886|056|D|24-fold and 11-fold, respectively.  Increases in the M9 nisoldipine|
01886|057|D|metabolite were similar.(12)|
01886|058|D|   A study in 14 healthy volunteers with concurrent administration of|
01886|059|D|levoketoconazole (400 mg once daily) with felodipine increased the|
01886|060|D|felodipine AUC and Cmax by 1007.3% and 937.1%.(3)|
01886|061|B||
01886|062|R|REFERENCES:|
01886|063|B||
01886|064|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01886|065|R|  Products, L.P. February, 2024.|1
01886|066|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
01886|067|R|  Pharmaceuticals February, 2014.|1
01886|068|R|3.Recorlev (levoketoconazole) US prescribing information. Xeris|1
01886|069|R|  Pharmaceuticals, Inc. June, 2023.|1
01886|070|R|4.Sular (nisoldipine) US prescribing information. Shionogi, Inc. June, 2017.|1
01886|071|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
01886|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01886|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01886|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01886|075|R|  11/14/2017.|1
01886|076|R|6.This information is based on an extract from the Certara Drug Interaction|6
01886|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01886|078|R|7.Sporanox (itraconazole) UK summary of product characteristics.|1
01886|079|R|  Janssen-Cilag Ltd April, 2021.|1
01886|080|R|8.Sporanox (itraconazole) Canadian prescribing information. Janssen-Ortho|1
01886|081|R|  December, 2023.|1
01886|082|R|9.Nizoral (ketoconazole) UK summary of product characteristics.|1
01886|083|R|  Janssen-Cilag Ltd October, 2008.|1
01886|084|R|10.Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma|2
01886|085|R|   concentrations and effects of felodipine. Clin Pharmacol Ther 1997 Apr;|2
01886|086|R|   61(4):410-5.|2
01886|087|R|11.Neuvonen PJ, Suhonen R. Itraconazole interacts with felodipine. J Am Acad|3
01886|088|R|   Dermatol 1995 Jul;33(1):134-5.|3
01886|089|R|12.Heinig R, Adelmann HG, Ahr G. The effect of ketoconazole on the|2
01886|090|R|   pharmacokinetics, pharmacodynamics and safety of nisoldipine. Eur J Clin|2
01886|091|R|   Pharmacol 1999 Mar;55(1):57-60.|2
01887|001|T|MONOGRAPH TITLE:  Erlotinib/Anti-Angiogenic Agents|
01887|002|B||
01887|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01887|004|L|take action as needed.|
01887|005|B||
01887|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01887|007|B||
01887|008|E|CLINICAL EFFECTS:  Concurrent use of anti-angiogenic agents may increase the|
01887|009|E|risk of gastrointestinal perforation in patients receiving erlotinib.|
01887|010|E|Fatalities have been reported.(1)|
01887|011|B||
01887|012|P|PREDISPOSING FACTORS:  Patients with a history of peptic ulceration or|
01887|013|P|diverticular disease or who are receiving concomitant corticosteroids,|
01887|014|P|NSAIDs, and/or taxane-based chemotherapy may be an increased risk of|
01887|015|P|gastrointestinal perforation.(1)|
01887|016|B||
01887|017|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
01887|018|M|of gastrointestinal perforation.  Discontinue erlotinib in patients who|
01887|019|M|develop gastrointestinal perforation.(1)|
01887|020|B||
01887|021|D|DISCUSSION:  In a phase II trial of concurrent bevacizumab plus erlotinib, 2|
01887|022|D|of 13 patients suffered fatal gastrointestinal perforations.(2)|
01887|023|D|   In another phase II trial of concurrent bevacizumab with erlotinib, 1 of|
01887|024|D|104 patients died of gastrointestinal perforation.(3)|
01887|025|B||
01887|026|R|REFERENCES:|
01887|027|B||
01887|028|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
01887|029|R|  2016.|1
01887|030|R|2.Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, Salgia R,|2
01887|031|R|  Stadler WM, Vokes EE, Fleming GF. Efficacy and safety of bevacizumab plus|2
01887|032|R|  erlotinib for patients with recurrent ovarian, primary peritoneal, and|2
01887|033|R|  fallopian tube cancer: a trial of the Chicago, PMH, and California Phase|2
01887|034|R|  II Consortia. Gynecol Oncol 2008 Jul;110(1):49-55.|2
01887|035|R|3.Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S,|2
01887|036|R|  Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA,|2
01887|037|R|  McDermott D. Randomized phase II study of erlotinib combined with|2
01887|038|R|  bevacizumab compared with bevacizumab alone in metastatic renal cell|2
01887|039|R|  cancer. J Clin Oncol 2007 Oct 10;25(29):4536-41.|2
01888|001|T|MONOGRAPH TITLE:  Erlotinib/Corticosteroids|
01888|002|B||
01888|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01888|004|L|take action as needed.|
01888|005|B||
01888|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01888|007|B||
01888|008|E|CLINICAL EFFECTS:  Concurrent use of corticosteroids may increase the risk|
01888|009|E|of gastrointestinal perforation in patients receiving erlotinib.  Fatalities|
01888|010|E|have been reported.(1)|
01888|011|B||
01888|012|P|PREDISPOSING FACTORS:  Patients with a history of peptic ulceration or|
01888|013|P|diverticular disease or who are receiving concomitant anti-angiogenic,|
01888|014|P|NSAIDs, and/or taxane-based chemotherapy may be an increased risk of|
01888|015|P|gastrointestinal perforation.(1)|
01888|016|B||
01888|017|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
01888|018|M|of gastrointestinal perforation.  Discontinue erlotinib in patients who|
01888|019|M|develop gastrointestinal perforation.(1)|
01888|020|B||
01888|021|D|DISCUSSION:  In a phase II trial of concurrent bevacizumab plus erlotinib, 2|
01888|022|D|of 13 patients suffered fatal gastrointestinal perforations.(2)|
01888|023|D|   In another phase II trial of concurrent bevacizumab with erlotinib, 1 of|
01888|024|D|104 patients died of gastrointestinal perforation.(3)|
01888|025|D|   Two patients developed gastrointestinal perforations while taking|
01888|026|D|erlotinib, corticosteroids, and ciprofloxacin.(3)|
01888|027|B||
01888|028|R|REFERENCES:|
01888|029|B||
01888|030|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
01888|031|R|  2016.|1
01888|032|R|2.Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, Salgia R,|2
01888|033|R|  Stadler WM, Vokes EE, Fleming GF. Efficacy and safety of bevacizumab plus|2
01888|034|R|  erlotinib for patients with recurrent ovarian, primary peritoneal, and|2
01888|035|R|  fallopian tube cancer: a trial of the Chicago, PMH, and California Phase|2
01888|036|R|  II Consortia. Gynecol Oncol 2008 Jul;110(1):49-55.|2
01888|037|R|3.Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S,|2
01888|038|R|  Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA,|2
01888|039|R|  McDermott D. Randomized phase II study of erlotinib combined with|2
01888|040|R|  bevacizumab compared with bevacizumab alone in metastatic renal cell|2
01888|041|R|  cancer. J Clin Oncol 2007 Oct 10;25(29):4536-41.|2
01888|042|R|4.Gass-Jegu F, Gschwend A, Gairard-Dory AC, Mennecier B, Tebacher-Alt M,|3
01888|043|R|  Gourieux B, Quoix E. Gastrointestinal perforations in patients treated|3
01888|044|R|  with erlotinib: A report of two cases with fatal outcome and literature|3
01888|045|R|  review. Lung Cancer 2016 Sep;99:76-8.|3
01889|001|T|MONOGRAPH TITLE:  Erlotinib/NSAIDs|
01889|002|B||
01889|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01889|004|L|take action as needed.|
01889|005|B||
01889|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01889|007|B||
01889|008|E|CLINICAL EFFECTS:  Concurrent use of NSAIDs may increase the risk of|
01889|009|E|gastrointestinal bleeding and/or perforation in patients receiving|
01889|010|E|erlotinib.  Fatalities have been reported.(1)|
01889|011|B||
01889|012|P|PREDISPOSING FACTORS:  Patients with a history of peptic ulceration or|
01889|013|P|diverticular disease or who are receiving concomitant anti-angiogenic,|
01889|014|P|corticosteroids, and/or taxane-based chemotherapy may be an increased risk|
01889|015|P|of gastrointestinal perforation.(1)|
01889|016|P|   The risk for bleeding episodes may be greater in patients with|
01889|017|P|disease-associated factors (e.g. thrombocytopenia).|
01889|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
01889|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01889|020|P|risk for bleeding.|
01889|021|B||
01889|022|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
01889|023|M|of gastrointestinal bleeding and/or perforation.  Discontinue erlotinib in|
01889|024|M|patients who develop gastrointestinal perforation.(1)|
01889|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01889|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01889|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01889|028|M|patients with any symptoms.|
01889|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01889|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01889|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01889|032|M|and/or swelling.|
01889|033|B||
01889|034|D|DISCUSSION:  Infrequent cases of gastrointestinal bleeding were reported|
01889|035|D|during erlotinib trials.  Some cases were associated with NSAID|
01889|036|D|administration.(1)|
01889|037|D|   In a phase II trial of concurrent bevacizumab plus erlotinib, 2 of 13|
01889|038|D|patients suffered fatal gastrointestinal perforations.(2)|
01889|039|D|   In another phase II trial of concurrent bevacizumab with erlotinib, 1 of|
01889|040|D|104 patients died of gastrointestinal perforation.(3)|
01889|041|B||
01889|042|R|REFERENCES:|
01889|043|B||
01889|044|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
01889|045|R|  2016.|1
01889|046|R|2.Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, Salgia R,|2
01889|047|R|  Stadler WM, Vokes EE, Fleming GF. Efficacy and safety of bevacizumab plus|2
01889|048|R|  erlotinib for patients with recurrent ovarian, primary peritoneal, and|2
01889|049|R|  fallopian tube cancer: a trial of the Chicago, PMH, and California Phase|2
01889|050|R|  II Consortia. Gynecol Oncol 2008 Jul;110(1):49-55.|2
01889|051|R|3.Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S,|2
01889|052|R|  Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA,|2
01889|053|R|  McDermott D. Randomized phase II study of erlotinib combined with|2
01889|054|R|  bevacizumab compared with bevacizumab alone in metastatic renal cell|2
01889|055|R|  cancer. J Clin Oncol 2007 Oct 10;25(29):4536-41.|2
01890|001|T|MONOGRAPH TITLE:  Erlotinib/Docetaxel; Paclitaxel|
01890|002|B||
01890|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01890|004|L|take action as needed.|
01890|005|B||
01890|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
01890|007|B||
01890|008|E|CLINICAL EFFECTS:  Concurrent use of docetaxel or paclitaxel may increase|
01890|009|E|the risk of gastrointestinal perforation in patients receiving erlotinib.|
01890|010|E|Fatalities have been reported.(1)|
01890|011|B||
01890|012|P|PREDISPOSING FACTORS:  Patients with a history of peptic ulceration or|
01890|013|P|diverticular disease or who are receiving concomitant anti-angiogenic,|
01890|014|P|corticosteroids, and/or NSAIDs may be an increased risk of gastrointestinal|
01890|015|P|perforation.(1)|
01890|016|B||
01890|017|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
01890|018|M|of gastrointestinal perforation.  Discontinue erlotinib in patients who|
01890|019|M|develop gastrointestinal perforation.(1)|
01890|020|B||
01890|021|D|DISCUSSION:  In a phase II trial of concurrent bevacizumab plus erlotinib, 2|
01890|022|D|of 13 patients suffered fatal gastrointestinal perforations.(2)|
01890|023|D|   In another phase II trial of concurrent bevacizumab with erlotinib, 1 of|
01890|024|D|104 patients died of gastrointestinal perforation.(3)|
01890|025|D|   Two trials showed no benefit from combination therapy with erlotinib and|
01890|026|D|paclitaxel in first-line patients with locally advanced or metastatic|
01890|027|D|NSCLC.(1)|
01890|028|B||
01890|029|R|REFERENCES:|
01890|030|B||
01890|031|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
01890|032|R|  2016.|1
01890|033|R|2.Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, Salgia R,|2
01890|034|R|  Stadler WM, Vokes EE, Fleming GF. Efficacy and safety of bevacizumab plus|2
01890|035|R|  erlotinib for patients with recurrent ovarian, primary peritoneal, and|2
01890|036|R|  fallopian tube cancer: a trial of the Chicago, PMH, and California Phase|2
01890|037|R|  II Consortia. Gynecol Oncol 2008 Jul;110(1):49-55.|2
01890|038|R|3.Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S,|2
01890|039|R|  Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA,|2
01890|040|R|  McDermott D. Randomized phase II study of erlotinib combined with|2
01890|041|R|  bevacizumab compared with bevacizumab alone in metastatic renal cell|2
01890|042|R|  cancer. J Clin Oncol 2007 Oct 10;25(29):4536-41.|2
01891|001|T|MONOGRAPH TITLE:  Tacrine/Fluvoxamine|
01891|002|B||
01891|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01891|004|L|take action as needed.|
01891|005|B||
01891|006|A|MECHANISM OF ACTION:  Fluvoxamine may inhibit the metabolism of tacrine by|
01891|007|A|CYP P-450-1A2.(1-4)|
01891|008|B||
01891|009|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine may result in elevated|
01891|010|E|levels of and toxicity from tacrine.(1-4)  Nausea, vomiting, sweating, and|
01891|011|E|diarrhea have been reported.(1,2)|
01891|012|B||
01891|013|P|PREDISPOSING FACTORS:  None determined.|
01891|014|B||
01891|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent fluvoxamine should be|
01891|016|M|monitored for adverse tacrine effects, including hepatotoxicity.  The dosage|
01891|017|M|of tacrine may need to be adjusted or fluvoxamine may need to be|
01891|018|M|discontinued.|
01891|019|B||
01891|020|D|DISCUSSION:  In a randomized, double-blind, placebo-controlled, cross-over|
01891|021|D|study in 13 healthy subjects, pretreatment with fluvoxamine (100 mg daily|
01891|022|D|for 6 days) increased the maximum concentration (Cmax) and area-under-curve|
01891|023|D|(AUC) of a single dose of tacrine (40 mg) by 5-fold and 8-fold,|
01891|024|D|respectively.  Five of 13 subjects reported nausea, vomiting, sweating, and|
01891|025|D|diarrhea.(1,2)  The AUC of 1-hydroxytacrine, 2-hydroxytacrine, and|
01891|026|D|4-hydroxytacrine increased 2.8-fold, 2-fold, and 5-fold, respectively.  The|
01891|027|D|Cmax of 4-hydroxytacrine increased 100%.  Concomitant fluvoxamine decreased|
01891|028|D|tacrine apparent oral clearance 8-fold.(2)|
01891|029|D|   In an open-label, randomized, cross-over study in 18 healthy subjects,|
01891|030|D|concurrent administration of fluvoxamine (50 mg or 100 mg daily) decreased|
01891|031|D|tacrine (20 mg single dose) oral clearance by 85%.(3)|
01891|032|D|   Fluvoxamine was shown to inhibit tacrine metabolism in vitro in human|
01891|033|D|liver microsomes.(4)|
01891|034|B||
01891|035|R|REFERENCES:|
01891|036|B||
01891|037|R|1.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
01891|038|R|  Pharmaceuticals, Inc. August, 2023.|1
01891|039|R|2.Becquemont L, Ragueneau I, Le Bot MA, Riche C, Funck-Brentano C, Jaillon|2
01891|040|R|  P. Influence of the CYP1A2 inhibitor fluvoxamine on tacrine|2
01891|041|R|  pharmacokinetics in humans. Clin Pharmacol Ther 1997 Jun;61(6):619-27.|2
01891|042|R|3.Larsen JT, Hansen LL, Spigset O, Brosen K. Fluvoxamine is a potent|2
01891|043|R|  inhibitor of tacrine metabolism in vivo. Eur J Clin Pharmacol 1999 Jul;|2
01891|044|R|  55(5):375-82.|2
01891|045|R|4.Becquemont L, Le Bot MA, Riche C, Beaune P. Influence of fluvoxamine on|5
01891|046|R|  tacrine metabolism in vitro: potential implication for the hepatotoxicity|5
01891|047|R|  in vivo. Fundam Clin Pharmacol 1996;10(2):156-7.|5
01892|001|T|MONOGRAPH TITLE:  Dronedarone/Strong CYP3A4 Inhibitors; Darunavir|
01892|002|B||
01892|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01892|004|L|is contraindicated and generally should not be dispensed or administered to|
01892|005|L|the same patient.|
01892|006|B||
01892|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
01892|008|A|of dronedarone.(1)|
01892|009|B||
01892|010|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
01892|011|E|prolongation of the QTc interval and life-threatening cardiac arrhythmias,|
01892|012|E|including torsades de pointes.(1)|
01892|013|B||
01892|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01892|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01892|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01892|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01892|018|P|gender, or advanced age.(2)|
01892|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01892|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01892|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01892|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01892|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01892|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01892|025|P|dysfunction).(2)|
01892|026|B||
01892|027|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that|
01892|028|M|concurrent administration of strong CYP3A4 inhibitors is contraindicated.(1)|
01892|029|M|The US manufacturer of darunavir states that concurrent use of dronedarone|
01892|030|M|is contraindicated.(3)|
01892|031|M|   The US manufacturer of itraconazole states that concurrent administration|
01892|032|M|of dronedarone is contraindicated during and two weeks after itraconazole|
01892|033|M|treatment.(5)|
01892|034|M|   If alternatives are not available and concurrent therapy is deemed|
01892|035|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
01892|036|M|and monitor ECG at baseline and at regular intervals.  Correct any|
01892|037|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01892|038|M|heartbeat, dizziness, or fainting.|
01892|039|B||
01892|040|D|DISCUSSION:  Concurrent use of ketoconazole and dronedarone (dosages not|
01892|041|D|stated) increased the area-under-curve (AUC) and maximum concentration|
01892|042|D|(Cmax) of dronedarone by 17-fold and 9-fold, respectively.(1)|
01892|043|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
01892|044|D|cobicistat, grapefruit, idelalisib, itraconazole, josamycin, ketoconazole,|
01892|045|D|mibefradil, nefazodone, telaprevir, tucatinib, ritonavir-boosted darunavir,|
01892|046|D|paritaprevir, and tipranavir, ritonavir-boosted or unboosted indinavir, and|
01892|047|D|nelfinavir.  Ritonavir is always used with another protease inhibitor as a|
01892|048|D|pharmacokinetic booster and is captured as part of the protease inhibitor|
01892|049|D|regimen.|
01892|050|D|   One or more of the drug pairs linked to this monograph have been included|
01892|051|D|in a list of interactions that should be considered "high-priority" for|
01892|052|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01892|053|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01892|054|D|Coordinator (ONC) for Health Information Technology.|
01892|055|B||
01892|056|R|REFERENCES:|
01892|057|B||
01892|058|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01892|059|R|  November, 2020.|1
01892|060|R|2.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01892|061|R|  March, 2023.|1
01892|062|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01892|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01892|064|R|  settings: a scientific statement from the American Heart Association and|6
01892|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01892|066|R|  2;55(9):934-47.|6
01892|067|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01892|068|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01892|069|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01892|070|R|  19(5):735-43.|6
01892|071|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01892|072|R|  Products, L.P. February, 2024.|1
01893|001|T|MONOGRAPH TITLE:  Dronedarone/Cyclosporine|
01893|002|B||
01893|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01893|004|L|is contraindicated and generally should not be dispensed or administered to|
01893|005|L|the same patient.|
01893|006|B||
01893|007|A|MECHANISM OF ACTION:  Cyclosporine may inhibit the metabolism of dronedarone|
01893|008|A|by CYP3A4.(1)  Dronedarone may inhibit the metabolism of cyclosporine by|
01893|009|A|CYP3A4.(2)|
01893|010|B||
01893|011|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine with dronedarone may|
01893|012|E|result in elevated levels of and toxicity from dronedarone and cyclosporine,|
01893|013|E|including serious infections, nephrotoxicity, hepatotoxicity, and|
01893|014|E|prolongation of the QTc interval and life-threatening cardiac arrhythmias,|
01893|015|E|which may lead to torsades de pointes.(1)|
01893|016|B||
01893|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01893|018|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01893|019|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01893|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01893|021|P|gender, or advanced age.(3)|
01893|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01893|023|P|higher systemic concentrations of either QT prolonging drug are additional|
01893|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01893|025|P|drug concentrations include rapid infusion of an intravenous dose or|
01893|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01893|027|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01893|028|P|dysfunction).(3)|
01893|029|B||
01893|030|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that|
01893|031|M|concurrent administration of cyclosporine is contraindicated.(1)|
01893|032|M|   If alternatives are not available and concurrent therapy is deemed|
01893|033|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
01893|034|M|and monitor ECG at baseline and at regular intervals.  Correct any|
01893|035|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01893|036|M|heartbeat, dizziness, or fainting.|
01893|037|B||
01893|038|D|DISCUSSION:  Concurrent use of ketoconazole (a strong CYP3A4 inhibitor) with|
01893|039|D|dronedarone increased the area-under-curve (AUC) and maximum concentration|
01893|040|D|(Cmax) of dronedarone by 17-fold and 9-fold, respectively.(1)|
01893|041|B||
01893|042|R|REFERENCES:|
01893|043|B||
01893|044|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01893|045|R|  January, 2011.|1
01893|046|R|2.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
01893|047|R|  Corporation September, 2023.|1
01893|048|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01893|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01893|050|R|  settings: a scientific statement from the American Heart Association and|6
01893|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01893|052|R|  2;55(9):934-47.|6
01894|001|T|MONOGRAPH TITLE:  Dronedarone/Clarithromycin; Telithromycin (mono deleted|
01894|002|T|03/29/2012)|
01894|003|B||
01894|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01894|005|L|is contraindicated and generally should not be dispensed or administered to|
01894|006|L|the same patient.|
01894|007|B||
01894|008|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01894|009|A|metabolism of dronedarone by CYP P-450-3A4.(1)|
01894|010|B||
01894|011|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin or telithromycin may|
01894|012|E|result in elevated levels of and toxicity from dronedarone.(1)|
01894|013|B||
01894|014|P|PREDISPOSING FACTORS:  None determined.|
01894|015|B||
01894|016|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that|
01894|017|M|concurrent administration of clarithromycin or telithromycin is|
01894|018|M|contraindicated.(1)|
01894|019|B||
01894|020|D|DISCUSSION:  Concurrent use of ketoconazole, another potent inhibitor of CYP|
01894|021|D|P-450-3A4 and dronedarone (dosages not stated) increased the|
01894|022|D|area-under-curve (AUC) and maximum concentration (Cmax) of dronedarone by|
01894|023|D|17-fold and 9-fold, respectively.(1)|
01894|024|B||
01894|025|R|REFERENCE:|
01894|026|B||
01894|027|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01894|028|R|  January, 2011.|1
01895|001|T|MONOGRAPH TITLE:  Dronedarone/Nefazodone (mono deleted 03/29/2012)|
01895|002|B||
01895|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01895|004|L|is contraindicated and generally should not be dispensed or administered to|
01895|005|L|the same patient.|
01895|006|B||
01895|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of dronedarone|
01895|008|A|by CYP P-450-3A4.(1)|
01895|009|B||
01895|010|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in elevated|
01895|011|E|levels of and toxicity from dronedarone.(1)|
01895|012|B||
01895|013|P|PREDISPOSING FACTORS:  None determined.|
01895|014|B||
01895|015|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that|
01895|016|M|concurrent administration of nefazodone is contraindicated.(1)|
01895|017|B||
01895|018|D|DISCUSSION:  Concurrent use of ketoconazole, another potent inhibitor of CYP|
01895|019|D|P-450-3A4 and dronedarone (dosages not stated) increased the|
01895|020|D|area-under-curve (AUC) and maximum concentration (Cmax) of dronedarone by|
01895|021|D|17-fold and 9-fold, respectively.(1)|
01895|022|B||
01895|023|R|REFERENCE:|
01895|024|B||
01895|025|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01895|026|R|  January, 2011.|1
01896|001|T|MONOGRAPH TITLE:  Dronedarone/Selected Protease Inhibitors (mono deleted|
01896|002|T|03/29/2012)|
01896|003|B||
01896|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01896|005|L|is contraindicated and generally should not be dispensed or administered to|
01896|006|L|the same patient.|
01896|007|B||
01896|008|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01896|009|A|dronedarone by CYP P-450-3A4.(1)|
01896|010|B||
01896|011|E|CLINICAL EFFECTS:  Concurrent use of a protease inhibitor may result in|
01896|012|E|elevated levels of and toxicity from dronedarone.(1)|
01896|013|B||
01896|014|P|PREDISPOSING FACTORS:  None determined.|
01896|015|B||
01896|016|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that|
01896|017|M|concurrent administration of strong CYP P-450-3A4 inhibitors is|
01896|018|M|contraindicated.(1)|
01896|019|B||
01896|020|D|DISCUSSION:  Concurrent use of ketoconazole, another potent inhibitor of CYP|
01896|021|D|P-450-3A4, and dronedarone (dosages not stated) increased the|
01896|022|D|area-under-curve (AUC) and maximum concentration (Cmax) of dronedarone by|
01896|023|D|17-fold and 9-fold, respectively.(1)|
01896|024|B||
01896|025|R|REFERENCE:|
01896|026|B||
01896|027|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01896|028|R|  January, 2011.|1
01897|001|T|MONOGRAPH TITLE:  Dronedarone/QT Prolonging Agents|
01897|002|B||
01897|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01897|004|L|is contraindicated and generally should not be dispensed or administered to|
01897|005|L|the same patient.|
01897|006|B||
01897|007|A|MECHANISM OF ACTION:  Concurrent use of dronedarone and agents known to|
01897|008|A|prolong the QT interval may result in additive or synergistic effects on the|
01897|009|A|QTc interval.(1)|
01897|010|B||
01897|011|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01897|012|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01897|013|E|torsades de pointes.|
01897|014|B||
01897|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01897|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01897|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01897|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01897|019|P|gender, or advanced age.(3)|
01897|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01897|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01897|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01897|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01897|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01897|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01897|026|P|dysfunction).(3)|
01897|027|B||
01897|028|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that the use|
01897|029|M|of drugs or herbal products that are known to prolong the QTc interval is|
01897|030|M|contraindicated.  These agents include phenothiazine anti-psychotics,|
01897|031|M|tricyclic antidepressants, certain oral macrolide antibiotics, and Class IA|
01897|032|M|and III antiarrhythmics.(1)|
01897|033|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01897|034|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01897|035|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01897|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01897|037|B||
01897|038|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01897|039|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01897|040|D|monograph have been shown to prolong the QTc interval either through their|
01897|041|D|mechanism of action, through studies on their effects on the QTc interval,|
01897|042|D|or through reports of QTc prolongation and/or torsades de pointes in|
01897|043|D|clinical trials and/or postmarketing reports.(2)|
01897|044|D|   One or more of the drug pairs linked to this monograph have been included|
01897|045|D|in a list of interactions that should be considered "high-priority" for|
01897|046|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01897|047|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01897|048|D|Coordinator (ONC) for Health Information Technology.|
01897|049|B||
01897|050|R|REFERENCES:|
01897|051|B||
01897|052|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01897|053|R|  November, 2020.|1
01897|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01897|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01897|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01897|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01897|058|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01897|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01897|060|R|  settings: a scientific statement from the American Heart Association and|6
01897|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01897|062|R|  2;55(9):934-47.|6
01897|063|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01897|064|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01897|065|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01897|066|R|  19(5):735-43.|6
01898|001|T|MONOGRAPH TITLE:  Dronedarone/Possible QT Prolonging Agents|
01898|002|B||
01898|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01898|004|L|of severe adverse interaction.|
01898|005|B||
01898|006|A|MECHANISM OF ACTION:  Concurrent use of dronedarone and agents known to|
01898|007|A|prolong the QT interval may result in additive or synergistic effects on the|
01898|008|A|QTc interval.(1)|
01898|009|B||
01898|010|E|CLINICAL EFFECTS:  Concurrent administration of dronedarone and QT|
01898|011|E|prolonging agents may result in prolongation of the QTc interval and|
01898|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.|
01898|013|B||
01898|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01898|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01898|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01898|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01898|018|P|gender, or advanced age.(3)|
01898|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01898|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01898|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01898|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01898|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01898|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01898|025|P|dysfunction).(3)|
01898|026|B||
01898|027|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that the use|
01898|028|M|of drugs or herbal products that are known to prolong the QTc interval is|
01898|029|M|contraindicated.  These agents include phenothiazine anti-psychotics,|
01898|030|M|tricyclic antidepressants, certain oral macrolide antibiotics, and Class IA|
01898|031|M|and III antiarrhythmics.(1)|
01898|032|M|   When concurrent therapy of dronedarone and possible QT prolonging agents|
01898|033|M|is warranted, consider obtaining serum calcium, magnesium, and potassium|
01898|034|M|levels and monitoring ECG at baseline and at regular intervals.  Correct any|
01898|035|M|electrolyte abnormalities.  Instruct patients to report any irregular|
01898|036|M|heartbeat, dizziness, or fainting.|
01898|037|B||
01898|038|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01898|039|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01898|040|D|monograph have been shown to prolong the QTc interval either through their|
01898|041|D|mechanism of action, through studies on their effects on the QTc interval,|
01898|042|D|or through reports of QTc prolongation and/or torsades de pointes in|
01898|043|D|clinical trials and/or postmarketing reports.(2)|
01898|044|D|   One or more of the drug pairs linked to this monograph have been included|
01898|045|D|in a list of interactions that should be considered "high-priority" for|
01898|046|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01898|047|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01898|048|D|Coordinator (ONC) for Health Information Technology.|
01898|049|B||
01898|050|R|REFERENCES:|
01898|051|B||
01898|052|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01898|053|R|  November, 2020.|1
01898|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01898|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01898|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01898|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01898|058|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01898|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01898|060|R|  settings: a scientific statement from the American Heart Association and|6
01898|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01898|062|R|  2;55(9):934-47.|6
01898|063|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01898|064|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01898|065|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01898|066|R|  19(5):735-43.|6
01899|001|T|MONOGRAPH TITLE:  Amiodarone; Dronedarone/Rifampin; Rifapentine|
01899|002|B||
01899|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01899|004|L|of severe adverse interaction.|
01899|005|B||
01899|006|A|MECHANISM OF ACTION:  Rifampin and rifapentine, strong inducers of CYP3A4,|
01899|007|A|may induce the metabolism of amiodarone(1) and dronedarone.(2)|
01899|008|B||
01899|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifampin or rifapentine may|
01899|010|E|result in decreased levels and effectiveness of amiodarone(1) and|
01899|011|E|dronedarone.(2)|
01899|012|B||
01899|013|P|PREDISPOSING FACTORS:  None determined.|
01899|014|B||
01899|015|M|PATIENT MANAGEMENT:  Avoid the use of rifampin or rifapentine in patients|
01899|016|M|maintained on amiodarone or dronedarone.  If concurrent use is warranted,|
01899|017|M|monitor patients for decreased antiarrythmic response.|
01899|018|B||
01899|019|D|DISCUSSION:  Concurrent rifampin has been shown to decrease levels of|
01899|020|D|amiodarone and desethylamiodarone.(1)  There is a case report of increased|
01899|021|D|palpitations and triggering of an internal defibrillator that occurred five|
01899|022|D|weeks after the addition of rifampin to amiodarone therapy.(3)|
01899|023|D|   Concurrent use of rifampin and dronedarone (exact dosages not stated)|
01899|024|D|decreased dronedarone exposure by 80%.(2)|
01899|025|B||
01899|026|R|REFERENCES:|
01899|027|B||
01899|028|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
01899|029|R|  Pharmaceuticals October, 2018.|1
01899|030|R|2.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01899|031|R|  November, 2020.|1
01899|032|R|3.Zarembski DG, Fischer SA, Santucci PA, Porter MT, Costanzo MR, Trohman RG.|3
01899|033|R|  Impact of rifampin on serum amiodarone concentrations in a patient with|3
01899|034|R|  congenital heart disease. Pharmacotherapy 1999 Feb;19(2):249-51.|3
01900|001|T|MONOGRAPH TITLE:  Amiodarone/Selected Strong CYP3A4 Inducers|
01900|002|B||
01900|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01900|004|L|of severe adverse interaction.|
01900|005|B||
01900|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
01900|007|A|amiodarone by CYP3A4.(1)|
01900|008|A|   Amiodarone may inhibit the metabolism of phenytoin.(1)|
01900|009|B||
01900|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
01900|011|E|decreased levels and effectiveness of amiodarone.(1)|
01900|012|E|   Concurrent use of amiodarone and phenytoin may also result in elevated|
01900|013|E|levels of and toxicity from phenytoin.(1)|
01900|014|B||
01900|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01900|016|P|of the inducer for longer than 1-2 weeks.|
01900|017|B||
01900|018|M|PATIENT MANAGEMENT:  The US manufacturer of amiodarone states concurrent use|
01900|019|M|with CYP3A4 inducers may decrease amiodarone serum concentrations.  Consider|
01900|020|M|monitoring amiodarone serum concentrations during concurrent use.(1)|
01900|021|M|   Monitor phenytoin levels when initiating or discontinuing amiodarone in|
01900|022|M|patients maintained on phenytoin.|
01900|023|B||
01900|024|D|DISCUSSION:  In a study in cardiac patients, amiodarone had no effect on|
01900|025|D|carbamazepine levels.(2)|
01900|026|D|   In a study in 5 healthy subjects, phenytoin (2-4 mg/kg/day) decreased|
01900|027|D|amiodarone levels (200 mg daily) by 32% to 49%.(3)|
01900|028|D|   In a study in 7 healthy subject, amiodarone (200 mg daily for three|
01900|029|D|weeks) increased phenytoin (5 mg/kg) area-under-curve (AUC) by 40%.(6)  In a|
01900|030|D|separate study in 7 healthy subjects, amiodarone (200 mg daily for 6 weeks)|
01900|031|D|increased phenytoin (2-4 mg/kg/day) by 40%.(5)|
01900|032|D|   Concurrent use of rifampin, another potent inducer of CYP3A4, and|
01900|033|D|amiodarone has been shown to decrease levels of amiodarone and|
01900|034|D|desethylamiodarone.(1)|
01900|035|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
01900|036|D|barbiturates, carbamazepine, enzalutamide, lumacaftor, mitotane,|
01900|037|D|phenobarbital, phenytoin and primidone.(6)|
01900|038|B||
01900|039|R|REFERENCES:|
01900|040|B||
01900|041|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
01900|042|R|  Pharmaceuticals October, 2018.|1
01900|043|R|2.Leite SA, Leite PJ, Rocha GA, Routledge PA, Bittencourt PR. Carbamazepine|2
01900|044|R|  kinetics in cardiac patients before and during amiodarone. Arq|2
01900|045|R|  Neuropsiquiatr 1994 Jun;52(2):210-5.|2
01900|046|R|3.Nolan PE Jr, Marcus FI, Karol MD, Hoyer GL, Gear K. Effect of phenytoin on|2
01900|047|R|  the clinical pharmacokinetics of amiodarone. J Clin Pharmacol 1990 Dec;|2
01900|048|R|  30(12):1112-9.|2
01900|049|R|4.Nolan PE Jr, Marcus FI, Hoyer GL, Bliss M, Gear K. Pharmacokinetic|2
01900|050|R|  interaction between intravenous phenytoin and amiodarone in healthy|2
01900|051|R|  volunteers. Clin Pharmacol Ther 1989 Jul;46(1):43-50.|2
01900|052|R|5.Nolan PE Jr, Erstad BL, Hoyer GL, Bliss M, Gear K, Marcus FI. Steady-state|2
01900|053|R|  interaction between amiodarone and phenytoin in normal subjects. Am J|2
01900|054|R|  Cardiol 1990 May 15;65(18):1252-7.|2
01900|055|R|6.This information is based on an extract from the Certara Drug Interaction|6
01900|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01901|001|T|MONOGRAPH TITLE:  Amiodarone; Dronedarone/St. John's Wort|
01901|002|B||
01901|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01901|004|L|of severe adverse interaction.|
01901|005|B||
01901|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01901|007|A|amiodarone(1) and dronedarone(2) by CYP3A4.|
01901|008|B||
01901|009|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
01901|010|E|levels and effectiveness of amiodarone(1) and dronedarone.(2)|
01901|011|B||
01901|012|P|PREDISPOSING FACTORS:  None determined.|
01901|013|B||
01901|014|M|PATIENT MANAGEMENT:  The US manufacturer of amiodarone states the concurrent|
01901|015|M|use of St. John's wort may decrease amiodarone serum concentrations.|
01901|016|M|Consider monitoring amiodarone serum concentrations during concurrent|
01901|017|M|use.(1)|
01901|018|M|   The US manufacturer of dronedarone states that concurrent use of St.|
01901|019|M|John's wort should be avoided.(2)|
01901|020|B||
01901|021|D|DISCUSSION:  Concurrent rifampin, another potent inducer of CYP3A4, has been|
01901|022|D|shown to decrease levels of amiodarone and desethylamiodarone.(1)|
01901|023|D|   Concurrent use of rifampin, another potent inducer of CYP3A4 and|
01901|024|D|dronedarone (exact dosages not stated) decreased dronedarone exposure by|
01901|025|D|80%.(2)|
01901|026|B||
01901|027|R|REFERENCES:|
01901|028|B||
01901|029|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
01901|030|R|  Pharmaceuticals October, 2018.|1
01901|031|R|2.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01901|032|R|  November, 2020.|1
01902|001|T|MONOGRAPH TITLE:  Dronedarone/Diltiazem; Nifedipine; Verapamil|
01902|002|B||
01902|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01902|004|L|take action as needed.|
01902|005|B||
01902|006|A|MECHANISM OF ACTION:  Dronedarone my inhibit the metabolism of diltiazem,|
01902|007|A|nifedipine, and verapamil by CYP3A4.  Diltiazem and verapamil may inhibit|
01902|008|A|the metabolism of dronedarone by CYP3A4.  Calcium channel blockers may|
01902|009|A|potentiate dronedarone conduction effects by depressing the sinus and AV|
01902|010|A|nodes.(1)|
01902|011|B||
01902|012|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels and effects|
01902|013|E|of both dronedarone and the calcium channel blocker.  Calcium channel|
01902|014|E|blockers may also potentiate dronedarone's conduction effects.|
01902|015|B||
01902|016|P|PREDISPOSING FACTORS:  None determined.|
01902|017|B||
01902|018|M|PATIENT MANAGEMENT:  Give low initial doses of the calcium channel blockers.|
01902|019|M|The dosage of the calcium channel blocker should only be increased after|
01902|020|M|ECG verification of good tolerability.(1)|
01902|021|B||
01902|022|D|DISCUSSION:  Concurrent use of diltiazem and verapamil with dronedarone|
01902|023|D|(exact dosages not stated) increased dronedarone exposure by 1.7-fold and|
01902|024|D|1.4-fold, respectively.(1)|
01902|025|D|   Concurrent use of dronedarone with diltiazem, nifedipine, or verapamil|
01902|026|D|(exact dosages not stated) increased  exposure of the calcium channel|
01902|027|D|blocker by 1.4-fold to 1.5-fold.(1)|
01902|028|B||
01902|029|R|REFERENCE:|
01902|030|B||
01902|031|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
01902|032|R|  November, 2020.|1
01903|001|T|MONOGRAPH TITLE:  Metoclopramide/SSRIs; SNRIs (mono deleted 09/16/2025)|
01903|002|B||
01903|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01903|004|L|of severe adverse interaction.|
01903|005|B||
01903|006|A|MECHANISM OF ACTION:  Both metoclopramide and serotonin reuptake inhibitors|
01903|007|A|(SSRIs, SNRIs) may be associated with extrapyramidal side effects|
01903|008|A|(EPS).(1-7) Some SSRIs or SNRIs may also inhibit the metabolism of|
01903|009|A|metoclopramide by CYP2D6, further increasing the risk for EPS.(8)|
01903|010|A|   A few case reports have reported serotonin syndrome with this|
01903|011|A|combination.(9,10)  The mechanism of action is not clear.|
01903|012|B||
01903|013|E|CLINICAL EFFECTS:  Concurrent use may result in extrapyramidal side effects|
01903|014|E|(EPS) such as acute dystonia, Parkinsonism, akathisia, neuroleptic malignant|
01903|015|E|syndrome, or tardive dyskinesia.  Tardive dyskinesia may be permanent.|
01903|016|E|   Serotonin syndrome has been reported infrequently with this combination.|
01903|017|E|Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
01903|018|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
01903|019|E|   Adverse effects may be may be more frequent or severe with SSRIs or SNRIs|
01903|020|E|which inhibit CYP2D6 mediated metabolism of metoclopramide.  CYP2D6|
01903|021|E|inhibitors linked to this monograph and their strength of inhibition(8)|
01903|022|E|(S=strong, M=moderate, W=weak) are: fluoxetine(S), paroxetine(S),|
01903|023|E|duloxetine(M), desvenlafaxine(W), fluvoxamine(W), sertraline(W),|
01903|024|E|escitalopram(W), and venlafaxine(magnitude unclear).|
01903|025|E|   Agents linked to this monograph which are not known to inhibit CYP2D6 are|
01903|026|E|levomilnacipran, milnacipran, and vilazodone.|
01903|027|B||
01903|028|P|PREDISPOSING FACTORS:  Patients with renal and/or hepatic impairment may|
01903|029|P|have an increased risk from this combination. The risk of extrapyramidal|
01903|030|P|symptoms is also increased in patients on metoclopramide for longer than 12|
01903|031|P|weeks.|
01903|032|P|   Elderly patients, especially elderly women, and diabetics are at higher|
01903|033|P|risk of developing tardive dyskinesia.|
01903|034|P|   Other extrapyramidal symptoms, like acute dystonia, have occurred more|
01903|035|P|frequently in patients younger than 30 years old.(1)|
01903|036|B||
01903|037|M|PATIENT MANAGEMENT:  If possible, consider alternatives to metoclopramide in|
01903|038|M|patients receiving SSRI or SNRI therapy.  If concurrent therapy is|
01903|039|M|warranted, monitor patients for signs of extrapyramidal side effects (acute|
01903|040|M|dystonic reaction, Parkinsonian symptoms, akathisia, tardive dyskinesia) and|
01903|041|M|neuroleptic malignant syndrome.  Symptoms unique to serotonin syndrome may|
01903|042|M|include diaphoresis, hyperreflexia, and clonus.(11)  The manufacturer of|
01903|043|M|metoclopramide says to avoid treatment with metoclopramide for longer than|
01903|044|M|12 weeks, and to use the lowest possible dose.(1)|
01903|045|M|   For gastroesophageal reflux, the manufacturer recommends reduction in the|
01903|046|M|dosage of metoclopramide to 5 mg four times daily (thirty minutes before|
01903|047|M|each meal and at bedtime) or 10 mg taken three times daily for a maximum|
01903|048|M|daily dosage of 30 mg in patients taking fluoxetine or paroxetine.(1)|
01903|049|M|   For acute and recurrent diabetic gastroparesis, reduce the dosage of|
01903|050|M|metoclopramide to 5 mg four times daily (30 minutes before each meal and at|
01903|051|M|bedtime) for a maximum daily dosage of 20 mg in patients taking fluoxetine|
01903|052|M|or paroxetine.(1)|
01903|053|B||
01903|054|D|DISCUSSION:  In a study in 20 healthy male subjects, concurrent fluoxetine|
01903|055|D|(60 mg daily for 9 days to simulate steady-state levels of 20 mg daily)|
01903|056|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
01903|057|D|metoclopramide (20 mg single dose) by 42% and 89%, respectively.(2)|
01903|058|D|   There have been case reports of extrapyramidal side effects(EPS) in|
01903|059|D|patients receiving concurrent metoclopramide and fluoxetine,(3)|
01903|060|D|fluvoxamine,(4) sertraline,(5) and venlafaxine.(9)  A review of a review of|
01903|061|D|EPS associated with SSRIs or SNRIs, with or without other precipitating|
01903|062|D|agents has been published.(6)|
01903|063|D|   Case reports have described serotonin syndrome with the combination of|
01903|064|D|sertraline or venlafaxine with metoclopramide.(9,10)|
01903|065|B||
01903|066|R|REFERENCES:|
01903|067|B||
01903|068|R|1.Reglan (metoclopramide) tablets US prescribing information. ANI|1
01903|069|R|  Pharmaceuticals, Inc. August 29, 2017.|1
01903|070|R|2.Vlase L, Leucuta A, Farcau D, Nanulescu M. Pharmacokinetic interaction|2
01903|071|R|  between fluoxetine and metoclopramide in healthy volunteers. Biopharm Drug|2
01903|072|R|  Dispos 2006 Sep;27(6):285-9.|2
01903|073|R|3.Coulter DM, Pillans PI. Fluoxetine and extrapyramidal side effects. Am J|3
01903|074|R|  Psychiatry 1995 Jan;152(1):122-5.|3
01903|075|R|4.Palop V, Jimenez MJ, Catalan C, Martinez-Mir I. Acute dystonia associated|3
01903|076|R|  with fluvoxamine-metoclopramide. Ann Pharmacother 1999 Mar;33(3):382.|3
01903|077|R|5.Christensen RC, Byerly MJ. Mandibular dystonia associated with the|3
01903|078|R|  combination of sertraline and metoclopramide. J Clin Psychiatry 1996 Dec;|3
01903|079|R|  57(12):596.|3
01903|080|R|6.Hawthorne JM, Caley CF. Extrapyramidal Reactions Associated with|6
01903|081|R|  Serotonergic Antidepressants. Ann Pharmacother 2015 Oct;49(10):1136-52.|6
01903|082|R|7.Morelli E, Moore H, Rebello TJ, Gray N, Steele K, Esposito E, Gingrich JA,|5
01903|083|R|  Ansorge MS. Chronic 5-HT transporter blockade reduces DA signaling to|5
01903|084|R|  elicit basal ganglia dysfunction. J Neurosci 2011 Nov 02;31(44):15742-50.|5
01903|085|R|8.This information is based on an extract from the Certara Drug Interaction|6
01903|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01903|087|R|9.Vandemergel X, Beukinga I, Neve P. Serotonin syndrome secondary to the use|3
01903|088|R|  of sertraline and metoclopramide. Rev Med Brux 2000 Jun;21(3):161-3.|3
01903|089|R|10.Fisher AA, Davis MW. Serotonin syndrome caused by selective serotonin|3
01903|090|R|   reuptake-inhibitors-metoclopramide interaction. Ann Pharmacother 2002|3
01903|091|R|   Jan;36(1):67-71.|3
01903|092|R|11.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
01903|093|R|   352(11):1112-20.|6
01904|001|T|MONOGRAPH TITLE:  Amitriptyline; Clomipramine; Nortriptyline/Valproic Acid|
01904|002|B||
01904|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01904|004|L|take action as needed.|
01904|005|B||
01904|006|A|MECHANISM OF ACTION:  Valproic acid may inhibit the metabolism of|
01904|007|A|amitriptyline, clomipramine, and nortriptyline.|
01904|008|B||
01904|009|E|CLINICAL EFFECTS:  Concurrent use of valproic acid may result in elevated|
01904|010|E|levels of and toxicity from amitriptyline, clomipramine, and nortriptyline.|
01904|011|B||
01904|012|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
01904|013|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
01904|014|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
01904|015|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
01904|016|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
01904|017|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
01904|018|P|systemic steroids).|
01904|019|P|   The risk of anticholinergic toxicities including cognitive decline,|
01904|020|P|delirium, falls and fractures is increased in geriatric patients using more|
01904|021|P|than one medicine with anticholinergic properties.(1)|
01904|022|B||
01904|023|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
01904|024|M|monitored for signs of toxicity.  Monitor tricyclic levels carefully during|
01904|025|M|initiation, titration, and discontinuation of valproic acid.  The dosage of|
01904|026|M|the tricyclic antidepressant may need to be adjusted.|
01904|027|B||
01904|028|D|DISCUSSION:  In a study in 15 healthy subjects, pretreatment with divalproex|
01904|029|D|sodium (500 mg every 12 hours for 9 doses) increased the area-under-curve|
01904|030|D|(AUC) and maximum concentration (Cmax) of a single dose of amitriptyline (50|
01904|031|D|mg) by 31% and 17%, respectively.  The AUC and Cmax of nortriptyline|
01904|032|D|increased by 55% and 28%, respectively.  The sum of amitriptyline and|
01904|033|D|nortriptyline AUC and Cmax increased by 42% and 19%, respectively.(2)|
01904|034|D|   In a study in 20 subjects with depression receiving amitriptyline (125 mg|
01904|035|D|daily), 10 subjects received valpromide (600 mg daily).  Amitriptyline and|
01904|036|D|nortriptyline levels increased 50% and 65%, respectively, in subjects|
01904|037|D|receiving concurrent valpromide.(3)|
01904|038|D|   There are case reports of encephalopathy and myoclonus,(4) status|
01904|039|D|epilepticus,(5) and increased clomipramine levels(6) have been reported|
01904|040|D|following concurrent administration of valproic acid and clomipramine.|
01904|041|D|   In a case report, a patient previous maintained on desipramine and|
01904|042|D|valproic acid developed elevated desipramine levels following the|
01904|043|D|discontinuation of valproic acid.(7)|
01904|044|D|   Extrapyramidal symptoms(8) and increased nortriptyline levels(9) have|
01904|045|D|been reported with concurrent nortriptyline and valproic acid.|
01904|046|B||
01904|047|R|REFERENCES:|
01904|048|B||
01904|049|R|1.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
01904|050|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
01904|051|R|  Soc 2023 Jul;71(7):2052-2081.|6
01904|052|R|2.Wong SL, Cavanaugh J, Shi H, Awni WM, Granneman GR. Effects of divalproex|2
01904|053|R|  sodium on amitriptyline and nortriptyline pharmacokinetics. Clin Pharmacol|2
01904|054|R|  Ther 1996 Jul;60(1):48-53.|2
01904|055|R|3.Vandel S, Bertschy G, Jounet JM, Allers G. Valpromide increases the plasma|2
01904|056|R|  concentrations of amitriptyline and its metabolite nortriptyline in|2
01904|057|R|  depressive patients. Ther Drug Monit 1988;10(4):386-9.|2
01904|058|R|4.Reif A, Leonhard C, Mossner R, Lesch KP, Fallgatter AJ. Encephalopathy and|3
01904|059|R|  myoclonus triggered by valproic acid. Prog Neuropsychopharmacol Biol|3
01904|060|R|  Psychiatry 2004 Sep;28(6):1061-3.|3
01904|061|R|5.DeToledo JC, Haddad H, Ramsay RE. Status epilepticus associated with the|3
01904|062|R|  combination of valproic acid and clomipramine. Ther Drug Monit 1997 Feb;|3
01904|063|R|  19(1):71-3.|3
01904|064|R|6.Fehr C, Grunder G, Hiemke C, Dahmen N. Increase in serum clomipramine|3
01904|065|R|  concentrations caused by valproate. J Clin Psychopharmacol 2000 Aug;|3
01904|066|R|  20(4):493-4.|3
01904|067|R|7.Joseph AB, Wroblewski BA. Potentially toxic serum concentrations of|3
01904|068|R|  desipramine after discontinuation of valproic acid. Brain Inj 1993|3
01904|069|R|  Sep-Oct;7(5):463-5.|3
01904|070|R|8.Conforti D, Borgherini G, Fiorellini Bernardis LA, Magni G. Extrapyramidal|3
01904|071|R|  symptoms associated with the adjunct of nortriptyline to a|3
01904|072|R|  venlafaxine-valproic acid combination. Int Clin Psychopharmacol 1999 May;|3
01904|073|R|  14(3):197-8.|3
01904|074|R|9.Fu C, Katzman M, Goldbloom DS. Valproate/nortriptyline interaction. J Clin|3
01904|075|R|  Psychopharmacol 1994 Jun;14(3):205-6.|3
01905|001|T|MONOGRAPH TITLE:  Bosentan/Protease Inhibitors|
01905|002|B||
01905|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01905|004|L|of severe adverse interaction.|
01905|005|B||
01905|006|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01905|007|A|bosentan by CYP3A4 and by inhibiting its uptake into hepatocytes by|
01905|008|A|OATP.(1-11)  Bosentan may induce the metabolism of atazanavir.(2)|
01905|009|B||
01905|010|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors without adjusting|
01905|011|E|the dose of bosentan may result in elevated levels of and toxicity from|
01905|012|E|bosentan.(1)  Administration of bosentan and atazanavir without ritonavir|
01905|013|E|may result in decreased levels of atazanavir.(2)|
01905|014|B||
01905|015|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, a protease inhibitor that|
01905|016|P|is a CYP3A4 inhibitor and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole,|
01905|017|P|oxandrolone, or sulfinpyrazone)(12) could lead to blockade of both major|
01905|018|P|metabolic pathways for bosentan, resulting in large increases in bosentan|
01905|019|P|plasma concentrations.(12)|
01905|020|B||
01905|021|M|PATIENT MANAGEMENT:  In patients who have been receiving a protease|
01905|022|M|inhibitor for at least 10 days, initiate bosentan at a dosage of 62.5 mg|
01905|023|M|once daily or every other day based on tolerability.(1-11)|
01905|024|M|   In patients who have been receiving bosentan, discontinue bosentan for at|
01905|025|M|least 36 hours prior to initiating atazanavir, darunavir, fosamprenavir,|
01905|026|M|lopinavir/ritonavir, nirmatrelvir/ritonavir, ritonavir, saquinavir, or|
01905|027|M|tipranavir.  After 10 days of protease inhibitor therapy, bosentan may be|
01905|028|M|resumed at a dosage of 62.5 mg once daily or every other day based on|
01905|029|M|tolerability.(1-8,11)|
01905|030|M|   In patients who have been receiving bosentan, adjust the dosage of|
01905|031|M|bosentan to 62.5 mg once daily or every other day based on tolerability in|
01905|032|M|patients who have been receiving indinavir or nelfinavir.(9-10)|
01905|033|M|   Review medication list to see if patient is also receiving a CYP2C9|
01905|034|M|inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
01905|035|M|sulfinpyrazone, or phenylbutazone).|
01905|036|M|   Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended|
01905|037|M|by the manufacturer as the combination may lead to large increases in|
01905|038|M|bosentan plasma concentrations.(1)|
01905|039|B||
01905|040|D|DISCUSSION:  In a study in healthy subjects, concurrent lopinavir/ritonavir|
01905|041|D|increased the initial and steady-state minimum concentrations (Cmin) of|
01905|042|D|bosentan by 48-fold and 5-fold, respectively.  There were no significant|
01905|043|D|effects on lopinavir/ritonavir pharmacokinetics.(1)|
01905|044|D|   One or more of the drug pairs linked to this monograph have been included|
01905|045|D|in a list of interactions that should be considered "high-priority" for|
01905|046|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
01905|047|D|vetted by an expert panel commissioned by the U.S. Office of the National|
01905|048|D|Coordinator (ONC) for Health Information Technology.|
01905|049|B||
01905|050|R|REFERENCES:|
01905|051|B||
01905|052|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
01905|053|R|  US, Inc. September 5, 2017.|1
01905|054|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01905|055|R|  Squibb Company December, 2024.|1
01905|056|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01905|057|R|  March, 2023.|1
01905|058|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01905|059|R|  March, 2019.|1
01905|060|R|5.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01905|061|R|  Laboratories December, 2019.|1
01905|062|R|6.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01905|063|R|  December, 2019.|1
01905|064|R|7.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01905|065|R|  Laboratories, Inc. March, 2019.|1
01905|066|R|8.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01905|067|R|  Pharmaceuticals, Inc. April, 2024.|1
01905|068|R|9.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01905|069|R|  September, 2016.|1
01905|070|R|10.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01905|071|R|   Pharmaceuticals, Inc. September, 2016.|1
01905|072|R|11.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01905|073|R|   information. Pfizer Inc. February, 2025.|1
01905|074|R|12.This information is based on an extract from the Certara Drug Interaction|6
01905|075|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01905|076|R|13.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
01905|077|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
01905|078|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
01905|079|R|   19(5):735-43.|6
01906|001|T|MONOGRAPH TITLE:  Sulindac/Dimethyl Sulfoxide (DMSO)|
01906|002|B||
01906|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01906|004|L|is contraindicated and generally should not be dispensed or administered to|
01906|005|L|the same patient.|
01906|006|B||
01906|007|A|MECHANISM OF ACTION:  Dimethyl sulfoxide (DMSO) inhibits the bioactivation|
01906|008|A|of sulindac to its active metabolite.(1,2)|
01906|009|B||
01906|010|E|CLINICAL EFFECTS:  Concurrent use of DMSO may result in decreased|
01906|011|E|effectiveness of sulindac(1,2) and peripheral neuropathy.(1,3,4)|
01906|012|B||
01906|013|P|PREDISPOSING FACTORS:  None determined.|
01906|014|B||
01906|015|M|PATIENT MANAGEMENT:  The US manufacturer of sulindac states that DMSO should|
01906|016|M|not be used with sulindac.(1)|
01906|017|B||
01906|018|D|DISCUSSION:  In a study in 8 healthy male subjects, pretreatment with an|
01906|019|D|oral dose of DMSO (30 ml of a 70% solution) 60 minutes before a single dose|
01906|020|D|of sulindac (400 mg) decreased concentrations of the active sulfide|
01906|021|D|metabolite of sulindac at 1.5, 2, 3, 4, 8, and 12 hours post dose.  The|
01906|022|D|area-under-curve (AUC) of the active sulfide metabolite was 30% lower (range|
01906|023|D|7% to 56%).(2)|
01906|024|D|   There are case reports of peripheral neuropathy during the concurrent use|
01906|025|D|of sulindac and DMSO,(1,3,4) including one report with topical use of|
01906|026|D|DMSO.(3)|
01906|027|B||
01906|028|R|REFERENCES:|
01906|029|B||
01906|030|R|1.Clinoril (sulindac) US prescribing information. Merck & Co., Inc.|1
01906|031|R|  December, 2010.|1
01906|032|R|2.Swanson BN, Boppana VK, Vlasses PH, Rotmensch HH, Ferguson RK. Dimethyl|2
01906|033|R|  sulfoxide inhibits bioactivation of sulindac. J Lab Clin Med 1983 Jul;|2
01906|034|R|  102(1):95-101.|2
01906|035|R|3.Reinstein L, Mahon R Jr, Russo GL. Peripheral neuropathy after concomitant|3
01906|036|R|  dimethyl sulfoxide use and sulindac therapy. Arch Phys Med Rehabil 1982|3
01906|037|R|  Nov;63(11):581-4.|3
01906|038|R|4.Swanson BN, Ferguson RK, Raskin NH, Wolf BA. Peripheral neuropathy after|3
01906|039|R|  concomitant administration of dimethyl sulfoxide and sulindac. Arthritis|3
01906|040|R|  Rheum 1983 Jun;26(6):791-3.|3
01907|001|T|MONOGRAPH TITLE:  Saxagliptin (>2.5 mg)/Strong CYP3A4 Inhibitors;|
01907|002|T|Atazanavir; Darunavir|
01907|003|B||
01907|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01907|005|L|is contraindicated and generally should not be dispensed or administered to|
01907|006|L|the same patient.|
01907|007|B||
01907|008|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
01907|009|A|of saxagliptin.(1,2)|
01907|010|B||
01907|011|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
01907|012|E|in elevated levels and increased effects of saxagliptin.(1,2)|
01907|013|B||
01907|014|P|PREDISPOSING FACTORS:  None determined.|
01907|015|B||
01907|016|M|PATIENT MANAGEMENT:  The US manufacturer of saxagliptin states that the dose|
01907|017|M|of saxagliptin should be limited to 2.5 mg daily in patients taking strong|
01907|018|M|inhibitors of CYP3A4.(1)|
01907|019|B||
01907|020|D|DISCUSSION:  Pretreatment with ketoconazole (200 mg every 12 hours for 9|
01907|021|D|days) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
01907|022|D|of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively.|
01907|023|D|The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and|
01907|024|D|91%, respectively.   The Cmax and AUC of ketoconazole decreased 16% and 13%,|
01907|025|D|respectively.(1,2)|
01907|026|D|   Pretreatment with ketoconazole (200 mg every 12 hours for 7 days)|
01907|027|D|increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by|
01907|028|D|2.4-fold and 3.7-fold, respectively.  The Cmax and AUC of the active|
01907|029|D|metabolite of saxagliptin decreased 96% and 90%, respectively.(1)|
01907|030|D|   Inhibitors of CYP3A4 linked to this monograph include:  adagrasib,|
01907|031|D|atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir,|
01907|032|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib,|
01907|033|D|lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
01907|034|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir,|
01907|035|D|telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)|
01907|036|B||
01907|037|R|REFERENCES:|
01907|038|B||
01907|039|R|1.Onglyza (saxagliptin) US prescribing information. Bristol-Myers Squibb|1
01907|040|R|  Company October, 2024.|1
01907|041|R|2.Patel CG, Li L, Girgis S, Kornhauser DM, Frevert EU, Boulton DW. Two-way|2
01907|042|R|  pharmacokinetic interaction studies between saxagliptin and cytochrome|2
01907|043|R|  P450 substrates or inhibitors: simvastatin, diltiazem extended-release,|2
01907|044|R|  and ketoconazole. Clin Pharmacol 2011;3:13-25.|2
01907|045|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01907|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01907|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01907|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01907|049|R|  11/14/2017.|1
01907|050|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01907|051|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01907|052|R|  HIV. Department of Health and Human Services. Available at|6
01907|053|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
01907|054|R|  new-guidelines June 13, 2021.|6
01908|001|T|MONOGRAPH TITLE:  Saxagliptin(<=2.5 mg)/Strong CYP3A4 Inhibitors;|
01908|002|T|Atazanavir; Darunavir|
01908|003|B||
01908|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01908|005|L|take action as needed.|
01908|006|B||
01908|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
01908|008|A|of saxagliptin.(1,2)|
01908|009|B||
01908|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
01908|011|E|in elevated levels and increased effects of saxagliptin.(1,2)|
01908|012|B||
01908|013|P|PREDISPOSING FACTORS:  None determined.|
01908|014|B||
01908|015|M|PATIENT MANAGEMENT:  The US manufacturer of saxagliptin states that the dose|
01908|016|M|of saxagliptin should be limited to 2.5 mg daily in patients taking strong|
01908|017|M|inhibitors of CYP3A4.(1)|
01908|018|B||
01908|019|D|DISCUSSION:  Pretreatment with ketoconazole (200 mg every 12 hours for 9|
01908|020|D|days) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
01908|021|D|of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively.|
01908|022|D|The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and|
01908|023|D|91%, respectively.   The Cmax and AUC of ketoconazole decreased 16% and 13%,|
01908|024|D|respectively.(1,2)|
01908|025|D|   Pretreatment with ketoconazole (200 mg every 12 hours for 7 days)|
01908|026|D|increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by|
01908|027|D|2.4-fold and 3.7-fold, respectively.  The Cmax and AUC of the active|
01908|028|D|metabolite of saxagliptin decreased 96% and 90%, respectively.(1)|
01908|029|D|   Inhibitors of CYP3A4 linked to this monograph include:  adagrasib,|
01908|030|D|atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir,|
01908|031|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib,|
01908|032|D|lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
01908|033|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir,|
01908|034|D|telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)|
01908|035|B||
01908|036|R|REFERENCES:|
01908|037|B||
01908|038|R|1.Onglyza (saxagliptin) US prescribing information. Bristol-Myers Squibb|1
01908|039|R|  Company October, 2024.|1
01908|040|R|2.Patel CG, Li L, Girgis S, Kornhauser DM, Frevert EU, Boulton DW. Two-way|2
01908|041|R|  pharmacokinetic interaction studies between saxagliptin and cytochrome|2
01908|042|R|  P450 substrates or inhibitors: simvastatin, diltiazem extended-release,|2
01908|043|R|  and ketoconazole. Clin Pharmacol 2011;3:13-25.|2
01908|044|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01908|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01908|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01908|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01908|048|R|  11/14/2017.|1
01908|049|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01908|050|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01908|051|R|  HIV. Department of Health and Human Services. Available at|6
01908|052|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
01908|053|R|  new-guidelines June 13, 2021.|6
01909|001|T|MONOGRAPH TITLE:  Saxagliptin/Clarithromycin; Telithromycin (mono deleted|
01909|002|T|03/29/2012)|
01909|003|B||
01909|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01909|005|L|take action as needed.|
01909|006|B||
01909|007|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01909|008|A|metabolism of saxagliptin by CYP P-450-3A4.(1)|
01909|009|B||
01909|010|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin or telithromycin may|
01909|011|E|result in elevated levels and increased effects of saxagliptin.(1)|
01909|012|B||
01909|013|P|PREDISPOSING FACTORS:  None determined.|
01909|014|B||
01909|015|M|PATIENT MANAGEMENT:  The US manufacturer of saxagliptin states that the dose|
01909|016|M|of saxagliptin should be limited to 2.5 mg daily in patients taking strong|
01909|017|M|inhibitors of CYP P-450-3A4 such as clarithromycin or telithromycin.(1)|
01909|018|B||
01909|019|D|DISCUSSION:  Pretreatment with ketoconazole (200 mg every 12 hours at steady|
01909|020|D|state), another strong inhibitor of CYP P-450-3A4, increased the maximum|
01909|021|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
01909|022|D|saxagliptin (100 mg) by 62% and 2.5-fold, respectively.  The Cmax and AUC of|
01909|023|D|the active metabolite of saxagliptin decreased 95% and 91%, respectively.|
01909|024|D|The Cmax and AUC of ketoconazole decreased 16% and 13%, respectively.(1)|
01909|025|D|   Pretreatment with ketoconazole (200 mg every 12 hours at steady state)|
01909|026|D|increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by|
01909|027|D|2.4-fold and 3.7-fold, respectively.  The Cmax and AUC of the active|
01909|028|D|metabolite of saxagliptin decreased 96% and 90%, respectively.(1)|
01909|029|B||
01909|030|R|REFERENCE:|
01909|031|B||
01909|032|R|1.Onglyza (saxagliptin) US prescribing information. Bristol-Myers Squibb|1
01909|033|R|  Company July, 2009.|1
01910|001|T|MONOGRAPH TITLE:  Saxagliptin/Nefazodone (mono deleted 03/29/2012)|
01910|002|B||
01910|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01910|004|L|take action as needed.|
01910|005|B||
01910|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of saxagliptin|
01910|007|A|by CYP P-450-3A4.(1)|
01910|008|B||
01910|009|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in elevated|
01910|010|E|levels and increased effects of saxagliptin.(1)|
01910|011|B||
01910|012|P|PREDISPOSING FACTORS:  None determined.|
01910|013|B||
01910|014|M|PATIENT MANAGEMENT:  The US manufacturer of saxagliptin states that the dose|
01910|015|M|of saxagliptin should be limited to 2.5 mg daily in patients taking strong|
01910|016|M|inhibitors of CYP P-450-3A4 such as nefazodone.(1)|
01910|017|B||
01910|018|D|DISCUSSION:  Pretreatment with ketoconazole (200 mg every 12 hours at steady|
01910|019|D|state), another strong inhibitor of CYP P-450-3A4, increased the maximum|
01910|020|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
01910|021|D|saxagliptin (100 mg) by 62% and 2.5-fold, respectively.  The Cmax and AUC of|
01910|022|D|the active metabolite of saxagliptin decreased 95% and 91%, respectively.|
01910|023|D|The Cmax and AUC of ketoconazole decreased 16% and 13%, respectively.(1)|
01910|024|D|   Pretreatment with ketoconazole (200 mg every 12 hours at steady state)|
01910|025|D|increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by|
01910|026|D|2.4-fold and 3.7-fold, respectively.  The Cmax and AUC of the active|
01910|027|D|metabolite of saxagliptin decreased 96% and 90%, respectively.(1)|
01910|028|B||
01910|029|R|REFERENCE:|
01910|030|B||
01910|031|R|1.Onglyza (saxagliptin) US prescribing information. Bristol-Myers Squibb|1
01910|032|R|  Company July, 2009.|1
01911|001|T|MONOGRAPH TITLE:  Colchicine/Selected Protease Inhibitors (mono deleted|
01911|002|T|04/26/2012)|
01911|003|B||
01911|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01911|005|L|of severe adverse interaction.|
01911|006|B||
01911|007|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01911|008|A|colchicine by CYP P-450-3A4.(1-11)|
01911|009|B||
01911|010|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors may result in|
01911|011|E|elevated levels of and toxicity from colchicine.(1-11)  Symptoms of|
01911|012|E|colchicine toxicity include muscle weakness or pain; numbness or tingling in|
01911|013|E|the fingers or toes; unusual bleeding or bruising; abdominal pain; nausea;|
01911|014|E|severe diarrhea or vomiting; feeling weak or tired; increased infections;|
01911|015|E|and pale or gray color of the lips, tongue, or palms of hands.(1,2)|
01911|016|B||
01911|017|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01911|018|P|patients with renal and/or hepatic impairment.(1-11)|
01911|019|B||
01911|020|M|PATIENT MANAGEMENT:  The concurrent use of colchicine with strong CYP|
01911|021|M|P450-3A4 inhibitors such as atazanavir, darunavir-ritonavir,|
01911|022|M|fosamprenavir-ritonavir, indinavir, lopinavir/ritonavir, nelfinavir,|
01911|023|M|ritonavir, saquinavir, and tipranavir is contraindicated in patients with|
01911|024|M|renal or hepatic impairment.(1-11)|
01911|025|M|   In patients without renal or hepatic impairment who are currently taking|
01911|026|M|or have taken strong CYP P-450-3A4 inhibitors in the previous 14 days, the|
01911|027|M|dosage of colchicine should be reduced.  For gout flares, the recommended|
01911|028|M|dosage is 0.6 mg (1 tablet) for one dose, then 0.3 mg (half tablet) 1 hour|
01911|029|M|later.  This dose should be repeated no earlier than in 3 days.(1-11)  For|
01911|030|M|gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg|
01911|031|M|daily.  If the original dosage was 0.6 mg daily, use 0.3 mg every other|
01911|032|M|day.(3-11)  For Familial Mediterranean fever (FMF), the recommended maximum|
01911|033|M|daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1-11)|
01911|034|M|   Patients should be instructed to immediately report any signs of|
01911|035|M|colchicine toxicity.|
01911|036|B||
01911|037|D|DISCUSSION:  In a study in 18 subjects, pretreatment with ritonavir (100 mg|
01911|038|D|twice daily for 5 days) increased the maximum concentration (Cmax) and|
01911|039|D|area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 184.4%|
01911|040|D|(range 79.2% to 447.4%) and by 296% (range 53.8% to 924.4%),|
01911|041|D|respectively.(1)|
01911|042|D|   Colchicine toxicity has been reported with concurrent use of other CYP|
01911|043|D|P-450-3A4 inhibitors such as clarithromycin, cyclosporine, diltiazem,|
01911|044|D|erythromycin, and verapamil.(1,2)|
01911|045|B||
01911|046|R|REFERENCES:|
01911|047|B||
01911|048|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01911|049|R|  2011.|1
01911|050|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
01911|051|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01911|052|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01911|053|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01911|054|R|3.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01911|055|R|  Squibb Company June, 2014.|1
01911|056|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01911|057|R|  March, 2023.|1
01911|058|R|5.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01911|059|R|  February, 2013.|1
01911|060|R|6.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01911|061|R|  February, 2011.|1
01911|062|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01911|063|R|  Laboratories December, 2019.|1
01911|064|R|8.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01911|065|R|  Pharmaceuticals, Inc. February, 2011.|1
01911|066|R|9.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01911|067|R|  November, 2012.|1
01911|068|R|10.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01911|069|R|   Laboratories, Inc. November, 2010.|1
01911|070|R|11.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01911|071|R|   Pharmaceuticals, Inc. February, 2012.|1
01912|001|T|MONOGRAPH TITLE:  Colchicine (for Gout & FMF)/Moderate CYP3A4 Inhibitors|
01912|002|B||
01912|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01912|004|L|of severe adverse interaction.|
01912|005|B||
01912|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
01912|007|A|of colchicine(1-3)|
01912|008|B||
01912|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
01912|010|E|in elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
01912|011|E|toxicity include muscle weakness or pain; numbness or tingling in the|
01912|012|E|fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea|
01912|013|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
01912|014|E|color of the lips, tongue, or palms of hands.(1-3)|
01912|015|B||
01912|016|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01912|017|P|patients with renal and/or hepatic impairment.(1-3)|
01912|018|B||
01912|019|M|PATIENT MANAGEMENT:  Avoid use of colchicine concurrently with or within 14|
01912|020|M|days of taking moderate CYP3A4 inhibitors (without ritonavir).  If|
01912|021|M|concurrent use is unavoidable, the dosage of colchicine should be|
01912|022|M|reduced.(1-3)|
01912|023|M|   For gout flares, the recommended dosage is 1.2 mg (2 tablets) for one|
01912|024|M|dose.  This dose should be repeated no earlier than in 3 days.(1-4)|
01912|025|M|   For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use|
01912|026|M|0.3 mg twice daily or 0.6 mg daily.  If the original dosage was 0.6 mg|
01912|027|M|daily, use 0.3 mg daily.(1-4)|
01912|028|M|   For Familial Mediterranean fever (FMF), the recommended maximum daily|
01912|029|M|dose is 1.2 mg (may be given as 0.6 mg twice a day).(1-4)|
01912|030|M|   Patients should be instructed to immediately report any signs of|
01912|031|M|colchicine toxicity, such as muscle weakness/pain, numbness/tingling in|
01912|032|M|fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness,|
01912|033|M|pale/gray color of the lips/tongue/palms of hands, and/or severe|
01912|034|M|diarrhea/vomiting.|
01912|035|B||
01912|036|D|DISCUSSION:  Fluconazole (400 mg loading dose followed by 200 mg daily for 4|
01912|037|D|days) increased the area-under-curve (AUC) of colchicine by 40%.(2)|
01912|038|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant, avacopan,|
01912|039|D|clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole,|
01912|040|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir,|
01912|041|D|lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, sevabertinib,|
01912|042|D|stiripentol, and treosulfan.(1,5,6)|
01912|043|B||
01912|044|R|REFERENCES:|
01912|045|B||
01912|046|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01912|047|R|  2011.|1
01912|048|R|2.Mitigare (colchicine) US prescribing information. Hikma Specialty USA Inc.|1
01912|049|R|  March, 2023.|1
01912|050|R|3.Anonymous. Information for Healthcare Professionals: New Safety|1
01912|051|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01912|052|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01912|053|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01912|054|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01912|055|R|  March, 2019.|1
01912|056|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
01912|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01912|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01912|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01912|060|R|  11/14/2017.|1
01912|061|R|6.This information is based on an extract from the Certara Drug Interaction|6
01912|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01913|001|T|MONOGRAPH TITLE:  Colchicine/Diltiazem; Verapamil (mono deleted 04/26/2012)|
01913|002|B||
01913|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01913|004|L|take action as needed.|
01913|005|B||
01913|006|A|MECHANISM OF ACTION:  Diltiazem and verapamil may inhibit the metabolism of|
01913|007|A|colchicine by CYP P-450-3A4.(1,2)|
01913|008|B||
01913|009|E|CLINICAL EFFECTS:  Concurrent use of diltiazem or verapamil may result in|
01913|010|E|elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
01913|011|E|toxicity include muscle weakness or pain; numbness or tingling in the|
01913|012|E|fingers or toes; unusual bleeding or bruising; abdominal pain; nausea;|
01913|013|E|severe diarrhea or vomiting; feeling weak or tired; increased infections;|
01913|014|E|and pale or gray color of the lips, tongue, or palms of hands.(1,2)|
01913|015|B||
01913|016|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01913|017|P|patients with renal and/or hepatic impairment.(1,2)|
01913|018|B||
01913|019|M|PATIENT MANAGEMENT:  In patients who are currently taking or have taken|
01913|020|M|moderate CYP P-450-3A4 inhibitors in the previous 14 days, the dosage of|
01913|021|M|colchicine should be reduced.  For gout flares, the recommended dosage is|
01913|022|M|1.2 mg (2 tablets) for one dose.  This dose should be repeated no earlier|
01913|023|M|than in 3 days.  For gout prophylaxis, if the original dosage was 0.6 mg|
01913|024|M|twice daily, use 0.3 mg twice daily or 0.6 mg daily.  If the original dosage|
01913|025|M|was 0.6 mg daily, use 0.3 mg daily.  For Familial Mediterranean fever (FMF),|
01913|026|M|the recommended maximum daily dose is 1.2 mg (may be given as 0.6 mg twice a|
01913|027|M|day)(1,2)|
01913|028|M|   Patients should be instructed to immediately report any signs of|
01913|029|M|colchicine toxicity.|
01913|030|B||
01913|031|D|DISCUSSION:  In a study in 20 subjects, pretreatment with diltiazem (240 mg|
01913|032|D|daily for 7 days) increased the maximum concentration (Cmax) and|
01913|033|D|area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2%|
01913|034|D|(range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%),|
01913|035|D|respectively.(1)|
01913|036|D|   In a study in 24 subjects, pretreatment with verapamil (240 mg twice|
01913|037|D|daily for 7 days) increased the Cmax and AUC of a single dose of colchicine|
01913|038|D|(0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to|
01913|039|D|217.2%), respectively.(1)|
01913|040|D|   Colchicine toxicity has been reported with concurrent use of CYP|
01913|041|D|P-450-3A4 inhibitors such as diltiazem and verapamil.(1,2)|
01913|042|B||
01913|043|R|REFERENCES:|
01913|044|B||
01913|045|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01913|046|R|  2011.|1
01913|047|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
01913|048|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01913|049|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01913|050|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01914|001|T|MONOGRAPH TITLE:  Colchicine/Aprepitant (mono deleted 04/26/2012)|
01914|002|B||
01914|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01914|004|L|take action as needed.|
01914|005|B||
01914|006|A|MECHANISM OF ACTION:  Aprepitant may inhibit the metabolism of colchicine by|
01914|007|A|CYP P-450-3A4.(1,2)|
01914|008|B||
01914|009|E|CLINICAL EFFECTS:  Concurrent use of aprepitant may result in elevated|
01914|010|E|levels of and toxicity from colchicine.  Symptoms of colchicine toxicity|
01914|011|E|include muscle weakness or pain; numbness or tingling in the fingers or|
01914|012|E|toes; unusual bleeding or bruising; abdominal pain; nausea; severe diarrhea|
01914|013|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
01914|014|E|color of the lips, tongue, or palms of hands.(1,2)|
01914|015|B||
01914|016|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01914|017|P|patients with renal and/or hepatic impairment.(1,2)|
01914|018|B||
01914|019|M|PATIENT MANAGEMENT:  In patients who are currently taking or have taken|
01914|020|M|moderate CYP P-450-3A4 inhibitors in the previous 14 days, the dosage of|
01914|021|M|colchicine should be reduced.  For gout flares, the recommended dosage is|
01914|022|M|1.2 mg (2 tablets) for one dose.  This dose should be repeated no earlier|
01914|023|M|than in 3 days.  For gout prophylaxis, if the original dosage was 0.6 mg|
01914|024|M|twice daily, use 0.3 mg twice daily or 0.6 mg daily.  If the original dosage|
01914|025|M|was 0.6 mg daily, use 0.3 mg daily.  For Familial Mediterranean fever (FMF),|
01914|026|M|the recommended maximum daily dose is 1.2 mg (may be given as 0.6 mg twice a|
01914|027|M|day)(1,2)|
01914|028|M|   Patients should be instructed to immediately report any signs of|
01914|029|M|colchicine toxicity.|
01914|030|B||
01914|031|D|DISCUSSION:  Colchicine toxicity has been reported with concurrent use of|
01914|032|D|other CYP P-450-3A4 inhibitors such as clarithromycin, cyclosporine,|
01914|033|D|diltiazem, erythromycin, and verapamil.(1,2)|
01914|034|B||
01914|035|R|REFERENCES:|
01914|036|B||
01914|037|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01914|038|R|  2011.|1
01914|039|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
01914|040|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01914|041|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01914|042|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01915|001|T|MONOGRAPH TITLE:  Colchicine/Fluconazole (mono deleted 04/26/2012)|
01915|002|B||
01915|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01915|004|L|take action as needed.|
01915|005|B||
01915|006|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of colchicine|
01915|007|A|by CYP P-450-3A4.(1,2)|
01915|008|B||
01915|009|E|CLINICAL EFFECTS:  Concurrent use of fluconazole may result in elevated|
01915|010|E|levels of and toxicity from colchicine.  Symptoms of colchicine toxicity|
01915|011|E|include muscle weakness or pain; numbness or tingling in the fingers or|
01915|012|E|toes; unusual bleeding or bruising; abdominal pain; nausea; severe diarrhea|
01915|013|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
01915|014|E|color of the lips, tongue, or palms of hands.(1,2)|
01915|015|B||
01915|016|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01915|017|P|patients with renal and/or hepatic impairment.(1,2)|
01915|018|B||
01915|019|M|PATIENT MANAGEMENT:  In patients who are currently taking or have taken|
01915|020|M|moderate CYP P-450-3A4 inhibitors in the previous 14 days, the dosage of|
01915|021|M|colchicine should be reduced.  For gout flares, the recommended dosage is|
01915|022|M|1.2 mg (2 tablets) for one dose.  This dose should be repeated no earlier|
01915|023|M|than in 3 days.  For gout prophylaxis, if the original dosage was 0.6 mg|
01915|024|M|twice daily, use 0.3 mg twice daily or 0.6 mg daily.  If the original dosage|
01915|025|M|was 0.6 mg daily, use 0.3 mg daily.  For Familial Mediterranean fever (FMF),|
01915|026|M|the recommended maximum daily dose is 1.2 mg (may be given as 0.6 mg twice a|
01915|027|M|day)(1,2)|
01915|028|M|   Patients should be instructed to immediately report any signs of|
01915|029|M|colchicine toxicity.|
01915|030|B||
01915|031|D|DISCUSSION:  Colchicine toxicity has been reported with concurrent use of|
01915|032|D|other CYP P-450-3A4 inhibitors such as clarithromycin, cyclosporine,|
01915|033|D|diltiazem, erythromycin, and verapamil.(1,2)|
01915|034|B||
01915|035|R|REFERENCES:|
01915|036|B||
01915|037|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01915|038|R|  2011.|1
01915|039|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
01915|040|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01915|041|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01915|042|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01916|001|T|MONOGRAPH TITLE:  Colchicine/Itraconazole; Ketoconazole (mono deleted|
01916|002|T|04/26/2012)|
01916|003|B||
01916|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01916|005|L|of severe adverse interaction.|
01916|006|B||
01916|007|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
01916|008|A|metabolism of colchicine by CYP P-450-3A4.(1,2)|
01916|009|B||
01916|010|E|CLINICAL EFFECTS:  Concurrent use of itraconazole or ketoconazole may result|
01916|011|E|in elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
01916|012|E|toxicity include muscle weakness or pain; numbness or tingling in the|
01916|013|E|fingers or toes; unusual bleeding or bruising; abdominal pain; nausea;|
01916|014|E|severe diarrhea or vomiting; feeling weak or tired; increased infections;|
01916|015|E|and pale or gray color of the lips, tongue, or palms of hands.(1,2)|
01916|016|B||
01916|017|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01916|018|P|patients with renal and/or hepatic impairment.(1,2)|
01916|019|B||
01916|020|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP P450-3A4 inhibitors|
01916|021|M|such as itraconazole or ketoconazole is contraindicated in patients with|
01916|022|M|renal or hepatic impairment.(1,2)|
01916|023|M|   In patients without renal or hepatic impairment who are currently taking|
01916|024|M|or have taken strong CYP P-450-3A4 inhibitors in the previous 14 days, the|
01916|025|M|dosage of colchicine should be reduced.  For gout flares, the recommended|
01916|026|M|dosage is 0.6 mg (1 tablet) for one dose, then 0.3 mg (half tablet) 1 hour|
01916|027|M|later.  This dose should be repeated no earlier than in 3 days.(1,2)  For|
01916|028|M|gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg|
01916|029|M|daily.  If the original dosage was 0.6 mg daily, use 0.3 mg every other|
01916|030|M|day.(3-11)  For Familial Mediterranean fever (FMF), the recommended maximum|
01916|031|M|daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,2)|
01916|032|M|   Patients should be instructed to immediately report any signs of|
01916|033|M|colchicine toxicity.|
01916|034|B||
01916|035|D|DISCUSSION:  In a study in 24 subjects, pretreatment with ketoconazole (200|
01916|036|D|mg twice daily for 5 days) increased the maximum concentration (Cmax) and|
01916|037|D|area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 101.7%|
01916|038|D|(range 19.6% to 219%) and by 212.2% (range 76.7% to 419.6%),|
01916|039|D|respectively.(1)|
01916|040|D|   Colchicine toxicity has been reported with concurrent use of other CYP|
01916|041|D|P-450-3A4 inhibitors such as clarithromycin, cyclosporine, diltiazem,|
01916|042|D|erythromycin, and verapamil.(1,2)|
01916|043|B||
01916|044|R|REFERENCES:|
01916|045|B||
01916|046|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01916|047|R|  2011.|1
01916|048|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
01916|049|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01916|050|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01916|051|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01917|001|T|MONOGRAPH TITLE:  Colchicine/Nefazodone (mono deleted 04/26/2012)|
01917|002|B||
01917|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01917|004|L|of severe adverse interaction.|
01917|005|B||
01917|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of colchicine by|
01917|007|A|CYP P-450-3A4.(1,2)|
01917|008|B||
01917|009|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in elevated|
01917|010|E|levels of and toxicity from colchicine.  Symptoms of colchicine toxicity|
01917|011|E|include muscle weakness or pain; numbness or tingling in the fingers or|
01917|012|E|toes; unusual bleeding or bruising; abdominal pain; nausea; severe diarrhea|
01917|013|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
01917|014|E|color of the lips, tongue, or palms of hands.(1,2)|
01917|015|B||
01917|016|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01917|017|P|patients with renal and/or hepatic impairment.(1,2)|
01917|018|B||
01917|019|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP P-450-3A4 inhibitors|
01917|020|M|such as nefazodone is contraindicated in patients with renal or hepatic|
01917|021|M|impairment.(1,2)|
01917|022|M|   In patients without renal or hepatic impairment who are currently taking|
01917|023|M|or have taken strong CYP P-450-3A4 inhibitors in the previous 14 days, the|
01917|024|M|dosage of colchicine should be reduced.  For gout flares, the recommended|
01917|025|M|dosage is 0.6 mg (1 tablet) for one dose, then 0.3 mg (half tablet) 1 hour|
01917|026|M|later.  This dose should be repeated no earlier than in 3 days.(1,2)  For|
01917|027|M|gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg|
01917|028|M|daily.  If the original dosage was 0.6 mg daily, use 0.3 mg every other|
01917|029|M|day.(3-11)  For Familial Mediterranean fever (FMF), the recommended maximum|
01917|030|M|daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,2)|
01917|031|M|   Patients should be instructed to immediately report any signs of|
01917|032|M|colchicine toxicity.|
01917|033|B||
01917|034|D|DISCUSSION:  Colchicine toxicity has been reported with concurrent use of|
01917|035|D|other CYP P-450-3A4 inhibitors such as clarithromycin, cyclosporine,|
01917|036|D|diltiazem, erythromycin, and verapamil.(1,2)|
01917|037|B||
01917|038|R|REFERENCES:|
01917|039|B||
01917|040|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01917|041|R|  2011.|1
01917|042|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
01917|043|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01917|044|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01917|045|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01918|001|T|MONOGRAPH TITLE:  Colchicine/Selected Macrolide Antibiotics (mono deleted|
01918|002|T|04/26/2012)|
01918|003|B||
01918|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01918|005|L|take action as needed.|
01918|006|B||
01918|007|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
01918|008|A|colchicine by CYP P-450-3A4 and may interfere with colchicine transport by|
01918|009|A|the P-glycoprotein system.|
01918|010|B||
01918|011|E|CLINICAL EFFECTS:  Concurrent use of a macrolide antibiotic may result in|
01918|012|E|elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
01918|013|E|toxicity include muscle weakness or pain; numbness or tingling in the|
01918|014|E|fingers or toes; unusual bleeding or bruising; abdominal pain; nausea;|
01918|015|E|severe diarrhea or vomiting; feeling weak or tired; increased infections;|
01918|016|E|and pale or gray color of the lips, tongue, or palms of hands.(1,2)|
01918|017|B||
01918|018|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01918|019|P|patients with renal and/or hepatic impairment(1,2) and in patients who|
01918|020|P|receive concurrent therapy.|
01918|021|B||
01918|022|M|PATIENT MANAGEMENT:  In patients who are currently taking or have taken|
01918|023|M|moderate CYP P-450-3A4 inhibitors in the previous 14 days, the dosage of|
01918|024|M|colchicine should be reduced.  For gout flares, the recommended dosage is|
01918|025|M|1.2 mg (2 tablets) for one dose.  This dose should be repeated no earlier|
01918|026|M|than in 3 days.  For gout prophylaxis, if the original dosage was 0.6 mg|
01918|027|M|twice daily, use 0.3 mg twice daily or 0.6 mg daily.  If the original dosage|
01918|028|M|was 0.6 mg daily, use 0.3 mg daily.  For Familial Mediterranean fever (FMF),|
01918|029|M|the recommended maximum daily dose is 1.2 mg (may be given as 0.6 mg twice a|
01918|030|M|day)(1,2)|
01918|031|M|   Patients should be instructed to immediately report any signs of|
01918|032|M|colchicine toxicity.|
01918|033|B||
01918|034|D|DISCUSSION:  There are several reports of colchicine toxicity(1-3) and|
01918|035|D|death(4,5) following the addition of clarithromycin to therapy.  In a|
01918|036|D|retrospective review of 116 patients who received clarithromycin and|
01918|037|D|colchicine during the same hospitalization, 10.2% (9/88) of patients who|
01918|038|D|received simultaneous therapy died, compared to 3.6% (1/28) of patients who|
01918|039|D|received sequential therapy.(6)|
01918|040|D|   An FDA review of 117 colchicine-related deaths that were not attributable|
01918|041|D|to overdose found that 60 deaths (51%) involved concurrent use of|
01918|042|D|clarithromycin.(2)|
01918|043|D|   In a study in 23 subjects, pretreatment with clarithromycin (250 mg twice|
01918|044|D|daily for 7 days) increased the maximum concentration (Cmax) and|
01918|045|D|area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 227.2%|
01918|046|D|(range 65.7% to 591.1%) and by 281.5% (range 88.7% to 851.6%),|
01918|047|D|respectively.(1)|
01918|048|D|   In a study in 21 subjects, pretreatment with azithromycin (500 mg Day 1,|
01918|049|D|then 250 mg daily Days2-5) increased the Cmax and AUC of a single dose of|
01918|050|D|colchicine (0.6 mg) by 21.6% (range -41.7% to 222%) and by 57.1% (range|
01918|051|D|-24.3% to 241.1%), respectively.(1)|
01918|052|D|   There is one case report of colchicine toxicity with concurrent|
01918|053|D|erythromycin.(7)|
01918|054|D|   In a case report of a fatal suicide involving colchicine, it was believed|
01918|055|D|that concurrent ingestion of josamycin further increased colchicine levels|
01918|056|D|and decreased its elimination.(8)|
01918|057|D|   Troleandomycin has been shown to inhibit colchicine metabolism in|
01918|058|D|vitro.(9)|
01918|059|B||
01918|060|R|REFERENCES:|
01918|061|B||
01918|062|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01918|063|R|  2011.|1
01918|064|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
01918|065|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01918|066|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01918|067|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01918|068|R|3.van der Velden W, Huussen J, Ter Laak H, de Sevaux R. Colchicine-induced|3
01918|069|R|  neuromyopathy in a patient with chronic renal failure: the role of|3
01918|070|R|  clarithromycin. Neth J Med 2008 May;66(5):204-6.|3
01918|071|R|4.Akdag I, Ersoy A, Kahvecioglu S, Gullulu M, Dilek K. Acute colchicine|3
01918|072|R|  intoxication during clarithromycin administration in patients with chronic|3
01918|073|R|  renal failure. J Nephrol 2006 Jul-Aug;19(4):515-7.|3
01918|074|R|5.Rollot F, Pajot O, Chauvelot-Moachon L, Nazal EM, Kelaidi C, Blanche P.|3
01918|075|R|  Acute colchicine intoxication during clarithromycin administration. Ann|3
01918|076|R|  Pharmacother 2004 Dec;38(12):2074-7.|3
01918|077|R|6.Cheng VC, Ho PL, Yuen KY. Two probable cases of serious drug interaction|3
01918|078|R|  between clarithromycin and colchicine. South Med J 2005 Aug;98(8):811-3.|3
01918|079|R|7.Dogukan A, Oymak FS, Taskapan H, Guven M, Tokgoz B, Utas C. Acute fatal|3
01918|080|R|  colchicine intoxication in a patient on continuous ambulatory peritoneal|3
01918|081|R|  dialysis (CAPD). Possible role of clarithromycin administration. Clin|3
01918|082|R|  Nephrol 2001 Feb;55(2):181-2.|3
01918|083|R|8.Hung IF, Wu AK, Cheng VC, Tang BS, To KW, Yeung CK, Woo PC, Lau SK, Cheung|2
01918|084|R|  BM, Yuen KY. Fatal interaction between clarithromycin and colchicine in|2
01918|085|R|  patients with renal insufficiency: a retrospective study. Clin Infect Dis|2
01918|086|R|  2005 Aug 1;41(3):291-300.|2
01918|087|R|9.Caraco Y, Putterman C, Rahamimov R, Ben-Chetrit E. Acute colchicine|3
01918|088|R|  intoxication--possible role of erythromycin administration. J Rheumatol|3
01918|089|R|  1992 Mar;19(3):494-6.|3
01918|090|R|10.Borron SW, Scherrmann JM, Baud FJ. Markedly altered colchicine kinetics|6
01918|091|R|   in a fatal intoxication: examination of contributing factors. Hum Exp|6
01918|092|R|   Toxicol 1996 Nov;15(11):885-90.|6
01918|093|R|11.Tateishi T, Soucek P, Caraco Y, Guengerich FP, Wood AJ. Colchicine|6
01918|094|R|   biotransformation by human liver microsomes. Identification of CYP3A4 as|6
01918|095|R|   the major isoform responsible for colchicine demethylation. Biochem|6
01918|096|R|   Pharmacol 1997 Jan 10;53(1):111-6.|6
01919|001|T|MONOGRAPH TITLE:  Colchicine/Ranolazine (mono deleted 04/26/2012)|
01919|002|B||
01919|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01919|004|L|of severe adverse interaction.|
01919|005|B||
01919|006|A|MECHANISM OF ACTION:  Ranolazine may inhibit the transport of colchicine by|
01919|007|A|P-glycoprotein (P-gp).(1,2)|
01919|008|B||
01919|009|E|CLINICAL EFFECTS:  Concurrent use of ranolazine may result in elevated|
01919|010|E|levels of and toxicity from colchicine.  Symptoms of colchicine toxicity|
01919|011|E|include muscle weakness or pain; numbness or tingling in the fingers or|
01919|012|E|toes; unusual bleeding or bruising; abdominal pain; nausea; severe diarrhea|
01919|013|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
01919|014|E|color of the lips, tongue, or palms of hands.(1,2)|
01919|015|B||
01919|016|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
01919|017|P|patients with renal and/or hepatic impairment.(1,2)|
01919|018|B||
01919|019|M|PATIENT MANAGEMENT:  The concurrent use of strong P-gp inhibitors such as|
01919|020|M|ranolazine is contraindicated in patients with renal or hepatic|
01919|021|M|impairment.(1,2)|
01919|022|M|   In patients without renal or hepatic impairment who are currently taking|
01919|023|M|or have taken strong P-gp inhibitors such as ranolazine in the previous 14|
01919|024|M|days, the dosage of colchicine should be reduced.  For gout flares, the|
01919|025|M|recommended dosage is 0.6 mg (1 tablet) for one dose.  This dose should be|
01919|026|M|repeated no earlier than in 3 days.  For gout prophylaxis, if the original|
01919|027|M|dosage was 0.6 mg twice daily, use 0.3 mg daily.  If the original dosage was|
01919|028|M|0.6 mg daily, use 0.3 mg every other day.  For Familial Mediterranean fever|
01919|029|M|(FMF), the recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg|
01919|030|M|twice a day).(1)|
01919|031|M|   Patients should be instructed to immediately report any signs of|
01919|032|M|colchicine toxicity.|
01919|033|B||
01919|034|D|DISCUSSION:  Colchicine toxicity has been reported with concurrent use of|
01919|035|D|other P-gp inhibitors such as cyclosporine.(1,2)|
01919|036|B||
01919|037|R|REFERENCES:|
01919|038|B||
01919|039|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01919|040|R|  2011.|1
01919|041|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
01919|042|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
01919|043|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
01919|044|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
01920|001|T|MONOGRAPH TITLE:  Diltiazem/Resveratrol|
01920|002|B||
01920|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01920|004|L|Assess the risk to the patient and take action as needed.|
01920|005|B||
01920|006|A|MECHANISM OF ACTION:  Resveratrol may increase the bioavailability of|
01920|007|A|diltiazem by inhibiting metabolism by CYP3A4 and the P-glycoprotein (P-gp)|
01920|008|A|pump in the intestine and liver.(1)|
01920|009|B||
01920|010|E|CLINICAL EFFECTS:  Concurrent use of resveratrol may increase levels and|
01920|011|E|effects of diltiazem.(1)|
01920|012|B||
01920|013|P|PREDISPOSING FACTORS:  None determined.|
01920|014|B||
01920|015|M|PATIENT MANAGEMENT:  Monitor patients taking concurrent diltiazem and|
01920|016|M|resveratrol.  The dosage of diltiazem may need to be adjusted.(1)|
01920|017|B||
01920|018|D|DISCUSSION:  In a study in rats, resveratrol at dosages of 2.5 mg/kg and 10|
01920|019|D|mg/kg increased diltiazem bioavailability by 1.48-fold and 1.60-fold,|
01920|020|D|respectively. The area-under-curve (AUC) of desacetyldiltiazem was|
01920|021|D|significantly increased.  There were no affects on diltiazem's absorption|
01920|022|D|rate constant or time to peak concentration.  Resveratrol at a dosage of 0.5|
01920|023|D|mg/kg had no significant affects on diltiazem levels.(1)|
01920|024|B||
01920|025|R|REFERENCE:|
01920|026|B||
01920|027|R|1.Hong SP, Choi DH, Choi JS. Effects of resveratrol on the pharmacokinetics|5
01920|028|R|  of diltiazem and its major metabolite, desacetyldiltiazem, in rats.|5
01920|029|R|  Cardiovasc Ther 2008 Winter;26(4):269-75.|5
01921|001|T|MONOGRAPH TITLE:  Tacrolimus/Caspofungin|
01921|002|B||
01921|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01921|004|L|take action as needed.|
01921|005|B||
01921|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown.|
01921|007|B||
01921|008|E|CLINICAL EFFECTS:  Concurrent use of caspofungin may result in decreased|
01921|009|E|levels and effectiveness of tacrolimus.(1,2)|
01921|010|B||
01921|011|P|PREDISPOSING FACTORS:  None determined.|
01921|012|B||
01921|013|M|PATIENT MANAGEMENT:  Tacrolimus levels should be closely monitored in|
01921|014|M|patients receiving concurrent caspofungin.  The dosage of tacrolimus may|
01921|015|M|need to be adjusted during and after caspofungin.(1,2)|
01921|016|B||
01921|017|D|DISCUSSION:  In a placebo-controlled, randomized, parallel panel study in|
01921|018|D|healthy subjects, caspofungin (70 mg daily for 10 days) decreased the|
01921|019|D|area-under-curve (AUC), maximum concentration, (Cmax) and minimum|
01921|020|D|concentration (Cmin) of tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) by|
01921|021|D|20%, 16%, and 26%, respectively.(1,2)  There were no significant effects on|
01921|022|D|caspofungin levels.(1)|
01921|023|B||
01921|024|R|REFERENCES:|
01921|025|B||
01921|026|R|1.Cancidas (caspofungin acetate) US prescribing information. Merck & Co.,|1
01921|027|R|  Inc. January, 2013.|1
01921|028|R|2.Stone J, Holland S, Wickersham P, Deutsch P, Winchell G, Hesney M, Miller|4
01921|029|R|  R, Freeman A, Dilzer S, Lasseter K. Drug interactions between caspofungin|4
01921|030|R|  and tacrolimus (abstract A-13). Presented at the 41st Interscience|4
01921|031|R|  Conference on Antimicrobial Agents and Chemotherapy. Chicago, Illinois.|4
01921|032|R|  December, 2001.|4
01922|001|T|MONOGRAPH TITLE:  Pioglitazone; Repaglinide; Rosiglitazone/Trimethoprim|
01922|002|B||
01922|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01922|004|L|take action as needed.|
01922|005|B||
01922|006|A|MECHANISM OF ACTION:  Trimethoprim, a weak CYP2C8 inhibitor, may inhibit the|
01922|007|A|metabolism of pioglitazone,(1,2) repaglinide,(3) and rosiglitazone.(4,5)|
01922|008|B||
01922|009|E|CLINICAL EFFECTS:  Concurrent use of trimethoprim may result in increased|
01922|010|E|levels of and effects from pioglitazone,(1,2) repaglinide,(3) and|
01922|011|E|rosiglitazone.(4,5)|
01922|012|B||
01922|013|P|PREDISPOSING FACTORS:  None determined.|
01922|014|B||
01922|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent trimethoprim and|
01922|016|M|pioglitazone, repaglinide, or rosiglitazone should be monitored for signs|
01922|017|M|and symptoms of hypoglycemia.  The dosage of the antidiabetic agent may need|
01922|018|M|to be adjusted during and following trimethoprim therapy.|
01922|019|B||
01922|020|D|DISCUSSION:  In a randomized, cross-over study in 16 healthy subjects,|
01922|021|D|trimethoprim (160 mg twice daily for 6 days) increased the area-under-curve|
01922|022|D|(AUC) of a single dose of pioglitazone (15 mg) by 42%.(1)  Trimethoprim was|
01922|023|D|shown to inhibit pioglitazone metabolism in vitro in human liver|
01922|024|D|microsomes.(1,2)|
01922|025|D|   In a randomized, double-blind, cross-over study in 9 healthy subjects,|
01922|026|D|trimethoprim (160 mg twice daily for 3 days) increased the AUC and maximum|
01922|027|D|concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 61% and|
01922|028|D|41%, respectively.  Trimethoprim also inhibited repaglinide metabolism in|
01922|029|D|vitro in a concentration-dependent manner.(3)|
01922|030|D|   In a randomized, cross-over study in 8 healthy subjects, trimethoprim|
01922|031|D|(200 mg twice daily for 5 days) increased the AUC of a single dose of|
01922|032|D|rosiglitazone (8 mg) by 31%.  An in vitro study in human liver microsomes|
01922|033|D|showed that trimethoprim inhibited troglitazone metabolism.(4)|
01922|034|D|   In a randomized, cross-over study in 10 healthy subjects, trimethoprim|
01922|035|D|(160 mg twice daily for 4 days) increased the AUC of a single dose of|
01922|036|D|troglitazone (4 mg) by 37%.(5)|
01922|037|B||
01922|038|R|REFERENCES:|
01922|039|B||
01922|040|R|1.Tornio A, Niemi M, Neuvonen PJ, Backman JT. Trimethoprim and the CYP2C8*3|2
01922|041|R|  allele have opposite effects on the pharmacokinetics of pioglitazone. Drug|2
01922|042|R|  Metab Dispos 2008 Jan;36(1):73-80.|2
01922|043|R|2.Jaakkola T, Laitila J, Neuvonen PJ, Backman JT. Pioglitazone is|5
01922|044|R|  metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with|5
01922|045|R|  CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol 2006 Jul;99(1):44-51.|5
01922|046|R|3.Niemi M, Kajosaari LI, Neuvonen M, Backman JT, Neuvonen PJ. The CYP2C8|2
01922|047|R|  inhibitor trimethoprim increases the plasma concentrations of repaglinide|2
01922|048|R|  in healthy subjects. Br J Clin Pharmacol 2004 Apr;57(4):441-7.|2
01922|049|R|4.Hruska MW, Amico JA, Langaee TY, Ferrell RE, Fitzgerald SM, Frye RF. The|2
01922|050|R|  effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in|2
01922|051|R|  human liver microsomes and healthy subjects. Br J Clin Pharmacol 2005 Jan;|2
01922|052|R|  59(1):70-9.|2
01922|053|R|5.Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampin on|2
01922|054|R|  the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone.|2
01922|055|R|  Clin Pharmacol Ther 2004 Sep;76(3):239-49.|2
01923|001|T|MONOGRAPH TITLE:  Macrolides/Lincosamides (mono deleted 01/17/2019)|
01923|002|B||
01923|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01923|004|L|take action as needed.|
01923|005|B||
01923|006|A|MECHANISM OF ACTION:  Macrolides and lincosamides may antagonize the action|
01923|007|A|of each other by blocking access to the ribosomal binding site.(1-5)|
01923|008|A|Erythromycin and clarithromycin binding sites on the 50S subunit of|
01923|009|A|bacterial ribosomes overlap with clindamycin binding sites to a large|
01923|010|A|extent.(6)  Azithromycin shares similar overlapping binding sites with|
01923|011|A|erythromycin.(7)|
01923|012|B||
01923|013|E|CLINICAL EFFECTS:  Concurrent use of a macrolide with a lincosamide may|
01923|014|E|result in decreased effectiveness of both agents.(5,8)|
01923|015|B||
01923|016|P|PREDISPOSING FACTORS:  None determined.|
01923|017|B||
01923|018|M|PATIENT MANAGEMENT:  Consider avoiding co-administration of clindamycin or|
01923|019|M|lincomycin with macrolide antibiotics.|
01923|020|B||
01923|021|D|DISCUSSION:  Lincosamides and erythromycin have been shown to be|
01923|022|D|antagonistic.  In an in vitro study of lincomycin and erythromycin on an|
01923|023|D|agar plate containing an erythromycin-resistant but lincomycin-sensitive|
01923|024|D|Staphylococcus, the minimum inhibitory concentration of lincomycin was|
01923|025|D|increased in the presence of erythromycin.(9)  Other double-disk diffusion|
01923|026|D|tests with a lincosamide and erythromycin against Streptococci have also|
01923|027|D|demonstrated antagonism.(10)|
01923|028|B||
01923|029|R|REFERENCES:|
01923|030|B||
01923|031|R|1.Igarashi K, Ishitsuka H, Kaji A. Comparative studies on the mechanism of|6
01923|032|R|  action of lincomycin, streptomycin, and erythromycin. Biochem Biophys Res|6
01923|033|R|  Commun 1969 Oct 22;37(3):499-504.|6
01923|034|R|2.Weinstein L. Modes of action of antibiotics on bacteria and man. N Y State|6
01923|035|R|  J Med 1972 Sep 1;72(17):2166-70.|6
01923|036|R|3.Garrett ER, Heman-Ackah SM, Perry GL. Kinetics and mechanisms of action of|5
01923|037|R|  drugs on microorganisms. XI. Effect of erythromycin and its supposed|5
01923|038|R|  antagonism with lincomycin on the microbial growth of Escherichia coli. J|5
01923|039|R|  Pharm Sci 1970 Oct;59(10):1448-56.|5
01923|040|R|4.Mao JC. The stoichiometry of erythromycin binding to ribosomal particles|5
01923|041|R|  of Staphylococcus aureus. Biochem Pharmacol 1967 Dec;16(12):2441-3.|5
01923|042|R|5.Sivapalasingam S, Steigbigel NH. Macrolides, Clindamycin, and Ketolides.|6
01923|043|R|  2015;358,372.|6
01923|044|R|6.Schlunzen F, Zarivach R, Harms J, Bashan A, Tocilj A, Albrecht R, Yonath|5
01923|045|R|  A, Franceschi F. Structural basis for the interaction of antibiotics with|5
01923|046|R|  the peptidyl transferase centre in eubacteria. Nature 2001 Oct 25;|5
01923|047|R|  413(6858):814-21.|5
01923|048|R|7.Dinos GP, Michelinaki M, Kalpaxis DL. Insights into the mechanism of|5
01923|049|R|  azithromycin interaction with an Escherichia coli  functional ribosomal|5
01923|050|R|  complex. Mol Pharmacol 2001 Jun;59(6):1441-5.|5
01923|051|R|8.E.E.S. (erythromycin ethylsuccinate) US prescribing information. Arbor|1
01923|052|R|  Pharmaceuticals, Inc. April, 2018.|1
01923|053|R|9.GRIFFITH LJ, OSTRANDER WE, MULLINS CG, BESWICK DE. DRUG ANTAGONISM BETWEEN|5
01923|054|R|  LINCOMYCIN AND ERYTHROMYCIN. Science 1965 Feb 12;147(3659):746-7.|5
01923|055|R|10.Leclercq R. Mechanisms of resistance to macrolides and lincosamides:|6
01923|056|R|   nature of the resistance elements and their clinical implications. Clin|6
01923|057|R|   Infect Dis 2002 Feb 15;34(4):482-92.|6
01924|001|T|MONOGRAPH TITLE:  Toremifene/QT Prolonging Agents|
01924|002|B||
01924|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01924|004|L|of severe adverse interaction.|
01924|005|B||
01924|006|A|MECHANISM OF ACTION:  Toremifene has been shown to prolong the QTc interval|
01924|007|A|in a dose-related and concentration-related manner.(1)  Concurrent use of|
01924|008|A|toremifene and agents known to prolong the QT interval may result in|
01924|009|A|additive or synergistic effects on the QTc interval.(1,2)|
01924|010|B||
01924|011|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01924|012|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01924|013|E|torsades de pointes.(1,2)|
01924|014|B||
01924|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01924|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01924|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01924|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01924|019|P|gender, or advanced age.(4)|
01924|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01924|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01924|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01924|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01924|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01924|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01924|026|P|dysfunction).(4)|
01924|027|B||
01924|028|M|PATIENT MANAGEMENT:  The US manufacturer of toremifene states that|
01924|029|M|concurrent use should be avoided.  If treatment with an agent known to|
01924|030|M|prolong the QT interval is required, toremifene therapy should be|
01924|031|M|interrupted.  If it is not possible to interrupt toremifene therapy,|
01924|032|M|patients should be closely monitored. Electrocardiograms (ECGs) should be|
01924|033|M|obtained.(1)  Consider obtaining serum calcium, magnesium, and potassium|
01924|034|M|levels and correct any electrolyte abnormalities.  Instruct patients to|
01924|035|M|report any irregular heartbeat, dizziness, or fainting.|
01924|036|M|   The UK manufacturer of toremifene states that the use of other drugs that|
01924|037|M|are known to prolong the QTc interval is contraindicated.  These agents|
01924|038|M|include class IA and III antiarrhythmics, astemizole, bepridil, cisapride,|
01924|039|M|diphemanil, erythromycin IV, halofantrine, haloperidol, mizolastine,|
01924|040|M|moxifloxacin, pentamidine, phenothiazines, pimozide, sertindole,|
01924|041|M|terfenadine, and vincamine IV.(2)|
01924|042|B||
01924|043|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01924|044|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01924|045|D|monograph have been shown to prolong the QTc interval either through their|
01924|046|D|mechanism of action, through studies on their effects on the QTc interval,|
01924|047|D|or through reports of QTc prolongation and/or torsades de pointes in|
01924|048|D|clinical trials and/or postmarketing reports.(3)|
01924|049|B||
01924|050|R|REFERENCES:|
01924|051|B||
01924|052|R|1.Fareston (toremifene citrate) US prescribing information. GTx, Inc. March,|1
01924|053|R|  2011.|1
01924|054|R|2.Fareston (toremifene citrate) UK summary of product characteristics. Orion|1
01924|055|R|  Pharma (UK) Limited January, 2009.|1
01924|056|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01924|057|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01924|058|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01924|059|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01924|060|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01924|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01924|062|R|  settings: a scientific statement from the American Heart Association and|6
01924|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01924|064|R|  2;55(9):934-47.|6
01925|001|T|MONOGRAPH TITLE:  Toremifene/Possible QT Prolonging Agents|
01925|002|B||
01925|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01925|004|L|take action as needed.|
01925|005|B||
01925|006|A|MECHANISM OF ACTION:  Toremifene has been shown to prolong the QTc interval|
01925|007|A|in a dose-related and concentration-related manner.(1)  Concurrent use of|
01925|008|A|toremifene and agents known to prolong the QT interval may result in|
01925|009|A|additive or synergistic effects on the QTc interval.(1,2)|
01925|010|B||
01925|011|E|CLINICAL EFFECTS:  Concurrent administration may result in prolongation of|
01925|012|E|the QTc interval and life-threatening cardiac arrhythmias, including|
01925|013|E|torsades de pointes.(1,2)|
01925|014|B||
01925|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01925|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01925|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01925|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01925|019|P|gender, or advanced age.(4)|
01925|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01925|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01925|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01925|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01925|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01925|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01925|026|P|dysfunction).(4)|
01925|027|B||
01925|028|M|PATIENT MANAGEMENT:  The US manufacturer of toremifene states that|
01925|029|M|concurrent use should be avoided.  If treatment with an agent known to|
01925|030|M|prolong the QT interval is required, toremifene therapy should be|
01925|031|M|interrupted.  If it is not possible to interrupt toremifene therapy,|
01925|032|M|electrocardiograms (ECGs) should be obtained and patients should be closely|
01925|033|M|monitored for QT prolongation.(1)|
01925|034|M|   Additional monitoring when concurrent therapy is warranted: consider|
01925|035|M|obtaining serum calcium, magnesium, and potassium levels at baseline and|
01925|036|M|regular intervals. Correct any electrolyte abnormalities.|
01925|037|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
01925|038|M|fainting.|
01925|039|M|   The UK manufacturer of toremifene states that the use of other drugs that|
01925|040|M|are known to prolong the QTc interval is contraindicated.  These agents|
01925|041|M|include class IA and III antiarrhythmics, astemizole, bepridil, cisapride,|
01925|042|M|diphemanil, erythromycin IV, halofantrine, haloperidol, mizolastine,|
01925|043|M|moxifloxacin, pentamidine, phenothiazines, pimozide, sertindole,|
01925|044|M|terfenadine, and vincamine IV.(2)|
01925|045|B||
01925|046|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01925|047|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01925|048|D|monograph have been shown to prolong the QTc interval either through their|
01925|049|D|mechanism of action, through studies on their effects on the QTc interval,|
01925|050|D|or through reports of QTc prolongation and/or torsades de pointes in|
01925|051|D|clinical trials and/or postmarketing reports.(3)|
01925|052|B||
01925|053|R|REFERENCES:|
01925|054|B||
01925|055|R|1.Fareston (toremifene citrate) US prescribing information. GTx, Inc. March,|1
01925|056|R|  2011.|1
01925|057|R|2.Fareston (toremifene citrate) UK summary of product characteristics. Orion|1
01925|058|R|  Pharma (UK) Limited January, 2009.|1
01925|059|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01925|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01925|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01925|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01925|063|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01925|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01925|065|R|  settings: a scientific statement from the American Heart Association and|6
01925|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01925|067|R|  2;55(9):934-47.|6
01926|001|T|MONOGRAPH TITLE:  Asenapine/QT Prolonging Agents (mono deleted 09/26/2019)|
01926|002|B||
01926|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01926|004|L|of severe adverse interaction.|
01926|005|B||
01926|006|A|MECHANISM OF ACTION:  Asenapine has been shown to prolong the QTc interval|
01926|007|A|by 2-5 msec.  Concurrent use with other agents that prolong the QTc interval|
01926|008|A|may result in additive effects on the QTc interval.(1)|
01926|009|B||
01926|010|E|CLINICAL EFFECTS:  The concurrent use of asenapine with other agents that|
01926|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01926|012|E|arrhythmias, including torsades de pointes.(1)|
01926|013|B||
01926|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01926|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01926|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01926|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01926|018|P|gender, or advanced age.(3)|
01926|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01926|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01926|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01926|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01926|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01926|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01926|025|P|dysfunction).(3)|
01926|026|B||
01926|027|M|PATIENT MANAGEMENT:  The US manufacturer of asenapine states that the|
01926|028|M|concurrent administration of other drugs that are known to prolong the QTc|
01926|029|M|interval should be avoided.(1)|
01926|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01926|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01926|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01926|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01926|034|B||
01926|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01926|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01926|037|D|monograph have been shown to prolong the QTc interval either through their|
01926|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01926|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
01926|040|D|clinical trials and/or postmarketing reports.(2)|
01926|041|B||
01926|042|R|REFERENCES:|
01926|043|B||
01926|044|R|1.Saphris (asenapine) US prescribing information. Actavis, Inc. February 23,|1
01926|045|R|  2017.|1
01926|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01926|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01926|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01926|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01926|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01926|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01926|052|R|  settings: a scientific statement from the American Heart Association and|6
01926|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01926|054|R|  2;55(9):934-47.|6
01927|001|T|MONOGRAPH TITLE:  Asenapine/Possible QT Prolonging Agents (mono deleted|
01927|002|T|09/26/2019)|
01927|003|B||
01927|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01927|005|L|take action as needed.|
01927|006|B||
01927|007|A|MECHANISM OF ACTION:  Asenapine has been shown to prolong the QTc interval|
01927|008|A|by 2-5 msec.  Concurrent use with other agents that prolong the QTc interval|
01927|009|A|may result in additive effects on the QTc interval.(1)|
01927|010|B||
01927|011|E|CLINICAL EFFECTS:  The concurrent use of asenapine with other agents that|
01927|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01927|013|E|arrhythmias, including torsades de pointes.(1)|
01927|014|B||
01927|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01927|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01927|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01927|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01927|019|P|gender, or advanced age.(3)|
01927|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01927|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01927|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01927|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01927|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01927|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01927|026|P|dysfunction).(3)|
01927|027|B||
01927|028|M|PATIENT MANAGEMENT:  The US manufacturer of asenapine states that the|
01927|029|M|concurrent administration of other drugs that are known to prolong the QTc|
01927|030|M|interval should be avoided.(1)|
01927|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01927|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01927|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01927|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01927|035|B||
01927|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01927|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01927|038|D|monograph have been shown to prolong the QTc interval either through their|
01927|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01927|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01927|041|D|clinical trials and/or postmarketing reports.(2)|
01927|042|B||
01927|043|R|REFERENCES:|
01927|044|B||
01927|045|R|1.Saphris (asenapine) US prescribing information. Actavis, Inc. February 23,|1
01927|046|R|  2017.|1
01927|047|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01927|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01927|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01927|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01927|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01927|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01927|053|R|  settings: a scientific statement from the American Heart Association and|6
01927|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01927|055|R|  2;55(9):934-47.|6
01928|001|T|MONOGRAPH TITLE:  Almotriptan/Select Strong CYP3A4 Inhibitors (mono deleted|
01928|002|T|01/18/2022)|
01928|003|B||
01928|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01928|005|L|take action as needed.|
01928|006|B||
01928|007|A|MECHANISM OF ACTION:  Itraconazole, ketoconazole, and levoketoconazole may|
01928|008|A|inhibit the metabolism of almotriptan by CYP3A4.(1)|
01928|009|B||
01928|010|E|CLINICAL EFFECTS:  Concurrent use of itraconazole, ketoconazole, or|
01928|011|E|levoketoconazole may result in elevated levels of and toxicity from|
01928|012|E|almotriptan.(1)|
01928|013|B||
01928|014|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01928|015|P|renal or hepatic impairment.(1)|
01928|016|B||
01928|017|M|PATIENT MANAGEMENT:  The US manufacturer of almotriptan states that in|
01928|018|M|patients receiving concurrent therapy with potent CYP3A4 inhibitors such as|
01928|019|M|itraconazole or ketoconazole the recommended starting dose is 6.25 mg and|
01928|020|M|the maximum daily dose should not exceed 12.5 mg within a 24-hour period.(1)|
01928|021|B||
01928|022|D|DISCUSSION:  In a cross-over study in 16 healthy subjects, pretreatment with|
01928|023|D|ketoconazole (400 mg daily for 3 days) increased the area-under-curve (AUC)|
01928|024|D|and maximum concentration (Cmax) of a single dose of almotriptan (12.5 mg on|
01928|025|D|Day 2) by 57% and 62%, respectively.(2)|
01928|026|B||
01928|027|R|REFERENCES:|
01928|028|B||
01928|029|R|1.Axert (almotriptan) US prescribing information. Ortho-McNeil Neurologics|1
01928|030|R|  May, 2009.|1
01928|031|R|2.Fleishaker JC, Herman BD, Carel BJ, Azie NE. Interaction between|2
01928|032|R|  ketoconazole and almotriptan in healthy volunteers. J Clin Pharmacol 2003|2
01928|033|R|  Apr;43(4):423-7.|2
01929|001|T|MONOGRAPH TITLE:  Almotriptan/Ritonavir (mono deleted 01/18/2022)|
01929|002|B||
01929|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01929|004|L|take action as needed.|
01929|005|B||
01929|006|A|MECHANISM OF ACTION:  Ritonavir may inhibit the metabolism of almotriptan by|
01929|007|A|CYP3A4.(1)|
01929|008|B||
01929|009|E|CLINICAL EFFECTS:  Concurrent use of ritonavir may result in elevated levels|
01929|010|E|of and toxicity from almotriptan.(1)|
01929|011|B||
01929|012|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01929|013|P|renal or hepatic impairment.(1)|
01929|014|B||
01929|015|M|PATIENT MANAGEMENT:  The US manufacturer of almotriptan states that in|
01929|016|M|patients receiving concurrent therapy with potent CYP3A4 inhibitors such as|
01929|017|M|ritonavir, the recommended starting dose is 6.25 mg and the maximum daily|
01929|018|M|dose should not exceed 12.5 mg within a 24-hour period.(1)|
01929|019|B||
01929|020|D|DISCUSSION:  In a cross-over study in 16 healthy subjects, pretreatment with|
01929|021|D|ketoconazole (400 mg daily for 3 days) increased the area-under-curve (AUC)|
01929|022|D|and maximum concentration (Cmax) of a single dose of almotriptan (12.5 mg on|
01929|023|D|Day 2) by 57% and 62%, respectively.(2)  Other strong CYP P-450-3A4|
01929|024|D|inhibitors such as ritonavir are expected to have similar effects.(1)|
01929|025|B||
01929|026|R|REFERENCES:|
01929|027|B||
01929|028|R|1.Axert (almotriptan) US prescribing information. Ortho-McNeil Neurologics|1
01929|029|R|  May, 2009.|1
01929|030|R|2.Fleishaker JC, Herman BD, Carel BJ, Azie NE. Interaction between|2
01929|031|R|  ketoconazole and almotriptan in healthy volunteers. J Clin Pharmacol 2003|2
01929|032|R|  Apr;43(4):423-7.|2
01930|001|T|MONOGRAPH TITLE:  Almotriptan/Erythromycin (mono deleted 01/18/2022)|
01930|002|B||
01930|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01930|004|L|take action as needed.|
01930|005|B||
01930|006|A|MECHANISM OF ACTION:  Erythromycin may inhibit the metabolism of almotriptan|
01930|007|A|by CYP3A4.(1)|
01930|008|B||
01930|009|E|CLINICAL EFFECTS:  Concurrent use of erythromycin may result in elevated|
01930|010|E|levels of and toxicity from almotriptan.(1)|
01930|011|B||
01930|012|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
01930|013|P|renal or hepatic impairment.(1)|
01930|014|B||
01930|015|M|PATIENT MANAGEMENT:  The US manufacturer of almotriptan states that in|
01930|016|M|patients receiving concurrent therapy with potent CYP3A4 inhibitors such as|
01930|017|M|erythromycin, the recommended starting dose is 6.25 mg and the maximum daily|
01930|018|M|dose should not exceed 12.5 mg within a 24-hour period.(1)|
01930|019|B||
01930|020|D|DISCUSSION:  In a cross-over study in 16 healthy subjects, pretreatment with|
01930|021|D|ketoconazole (400 mg daily for 3 days) increased the area-under-curve (AUC)|
01930|022|D|and maximum concentration (Cmax) of a single dose of almotriptan (12.5 mg on|
01930|023|D|Day 2) by 57% and 62%, respectively.(2)  Other strong CYP P-450-3A4|
01930|024|D|inhibitors such as erythromycin are expected to have similar effects.(1)|
01930|025|D|   In an open-label, randomized, cross-over study in 24 healthy subjects,|
01930|026|D|pretreatment with clarithromycin (500 mg twice daily for 3 days) had no|
01930|027|D|clinically significant effects on the AUC or Cmax of a single dose of|
01930|028|D|sumatriptan (50 mg orally).(3)|
01930|029|B||
01930|030|R|REFERENCES:|
01930|031|B||
01930|032|R|1.Axert (almotriptan) US prescribing information. Ortho-McNeil Neurologics|1
01930|033|R|  May, 2009.|1
01930|034|R|2.Fleishaker JC, Herman BD, Carel BJ, Azie NE. Interaction between|2
01930|035|R|  ketoconazole and almotriptan in healthy volunteers. J Clin Pharmacol 2003|2
01930|036|R|  Apr;43(4):423-7.|2
01930|037|R|3.Moore KH, Leese PT, McNeal S, Gray P, O'Quinn S, Bye C, Sale M. The|2
01930|038|R|  pharmacokinetics of sumatriptan when administered with clarithromycin in|2
01930|039|R|  healthy volunteers. Clin Ther 2002 Apr;24(4):583-94.|2
01931|001|T|MONOGRAPH TITLE:  Ulipristal/Rifamycins|
01931|002|B||
01931|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01931|004|L|of severe adverse interaction.|
01931|005|B||
01931|006|A|MECHANISM OF ACTION:  Rifamycins (rifabutin, rifampin, rifapentine) may|
01931|007|A|induce the metabolism of ulipristal by CYP3A4.(1)|
01931|008|B||
01931|009|E|CLINICAL EFFECTS:  Concurrent use or use of rifamycins within the previous|
01931|010|E|2-3 weeks may result in decreased levels and effectiveness of ulipristal.(1)|
01931|011|B||
01931|012|P|PREDISPOSING FACTORS:  None determined.|
01931|013|B||
01931|014|M|PATIENT MANAGEMENT:  The US and UK manufacturers of ulipristal state that|
01931|015|M|concurrent use with CYP3A4 inducers such as rifampin is not recommended.|
01931|016|M|Decreased effectiveness of ulipristal may occur even 2-3 weeks after|
01931|017|M|discontinuation of rifamycins.(1,2)|
01931|018|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
01931|019|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
01931|020|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
01931|021|M|contraceptive (ie a copper IUD).  Advise the patient to have a pregnancy|
01931|022|M|test to exclude pregnancy after use and to seek medical advice if they do|
01931|023|M|become pregnant.|
01931|024|B||
01931|025|D|DISCUSSION:  CYP3A4 inducers may decrease levels and effectiveness of|
01931|026|D|ulipristal.  Enzyme induction may take 2-3 weeks to wear off.  Plasma levels|
01931|027|D|of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in|
01931|028|D|the previous 2-3 weeks.(1)|
01931|029|D|   Concurrent administration of ulipristal 30 mg and rifampin 600 mg for 9|
01931|030|D|days decreased the maximum concentration (Cmax) and area-under-the-curve|
01931|031|D|(AUC) by 90% and 93%, respectively. The Cmax and AUC of|
01931|032|D|monodemethyl-ulipristal decreased by 84% and 90% respectively.(2)|
01931|033|B||
01931|034|R|REFERENCES:|
01931|035|B||
01931|036|R|1.Ellaone (ulipristal acetate) UK summary of product characteristics. HRA|1
01931|037|R|  Pharma UK Ltd May 15, 2009.|1
01931|038|R|2.Ella (ulipristal acetate) US prescribing information. Afaxys Inc June,|1
01931|039|R|  2021.|1
01932|001|T|MONOGRAPH TITLE:  Ulipristal/Selected Strong CYP3A4 Inducers|
01932|002|B||
01932|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01932|004|L|of severe adverse interaction.|
01932|005|B||
01932|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
01932|007|A|ulipristal by CYP3A4.(1)|
01932|008|B||
01932|009|E|CLINICAL EFFECTS:  Concurrent use or use of strong CYP3A4 inducers within|
01932|010|E|the previous 2-3 weeks may result in decreased levels and effectiveness of|
01932|011|E|ulipristal.(1)|
01932|012|B||
01932|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01932|014|P|of the inducer for longer than 1-2 weeks.|
01932|015|B||
01932|016|M|PATIENT MANAGEMENT:  The US and UK manufacturers of ulipristal states that|
01932|017|M|concurrent use with CYP3A4 inducers such as barbiturates, carbamazepine,|
01932|018|M|phenobarbital, phenytoin or primidone is not recommended.  Decreased|
01932|019|M|effectiveness of ulipristal may occur even 2-3 weeks after discontinuation|
01932|020|M|of these agents.(1,2)|
01932|021|B||
01932|022|D|DISCUSSION:  CYP3A4 inducers may decrease levels and effectiveness of|
01932|023|D|ulipristal.  Enzyme induction may take 2-3 weeks to wear off.  Plasma levels|
01932|024|D|of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in|
01932|025|D|the previous 2-3 weeks.(1)|
01932|026|D|   Concurrent administration of ulipristal 30 mg and rifampin 600 mg,|
01932|027|D|another CYP3A4 inducer, for 9 days decreased the maximum concentration|
01932|028|D|(Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax|
01932|029|D|and AUC of monodemethyl-ulipristal decreased by 84% and 90%,|
01932|030|D|respectively.(2)|
01932|031|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
01932|032|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
01932|033|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and|
01932|034|D|primidone.(3)|
01932|035|B||
01932|036|R|REFERENCES:|
01932|037|B||
01932|038|R|1.Ellaone (ulipristal acetate) UK summary of product characteristics. HRA|1
01932|039|R|  Pharma UK Ltd May 15, 2009.|1
01932|040|R|2.Ella (ulipristal acetate) US prescribing information. Afaxys Inc June,|1
01932|041|R|  2021.|1
01932|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
01932|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01933|001|T|MONOGRAPH TITLE:  Ulipristal/Fosamprenavir; Ritonavir|
01933|002|B||
01933|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01933|004|L|of severe adverse interaction.|
01933|005|B||
01933|006|A|MECHANISM OF ACTION:  Fosamprenavir and ritonavir may initially inhibit (use|
01933|007|A|less than 7 days) then induce (use greater than 7 days) the metabolism of|
01933|008|A|ulipristal by CYP3A4.(1)|
01933|009|A|   With short term use (less than 7 days), fosamprenavir or ritonavir lead|
01933|010|A|to CYP3A4 inhibition. However, with long-term use (greater than 7 days),|
01933|011|A|fosamprenavir or ritonavir lead to CYP3A4 induction.|
01933|012|B||
01933|013|E|CLINICAL EFFECTS:  Concurrent use of fosamprenavir or ritonavir may result|
01933|014|E|in an initial effect of increased ulipristal levels, but continued use over|
01933|015|E|time or use within the previous 2-3 weeks may result decreased levels and|
01933|016|E|effectiveness of ulipristal.(1)|
01933|017|B||
01933|018|P|PREDISPOSING FACTORS:  None determined.|
01933|019|B||
01933|020|M|PATIENT MANAGEMENT:  The UK manufacturer of ulipristal states that|
01933|021|M|concurrent use with ritonavir is not recommended.  Decreased effectiveness|
01933|022|M|of ulipristal may occur even 2-3 weeks after discontinuation of|
01933|023|M|ritonavir.(1)|
01933|024|B||
01933|025|D|DISCUSSION:  CYP3A4 inducers may decrease levels and effectiveness of|
01933|026|D|ulipristal.  Enzyme induction may take 2-3 weeks to wear off.  Plasma levels|
01933|027|D|of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in|
01933|028|D|the previous 2-3 weeks.(1)|
01933|029|B||
01933|030|R|REFERENCE:|
01933|031|B||
01933|032|R|1.Esmya (ulipristal) UK summary of product characteristics. Gedeon Richter|1
01933|033|R|  (UK) Ltd February, 2021.|1
01934|001|T|MONOGRAPH TITLE:  Ulipristal/St. John's Wort|
01934|002|B||
01934|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01934|004|L|of severe adverse interaction.|
01934|005|B||
01934|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01934|007|A|ulipristal by CYP3A4.(1)|
01934|008|B||
01934|009|E|CLINICAL EFFECTS:  Concurrent use or use of St. John's wort within the|
01934|010|E|previous 2-3 weeks may result in decreased levels and effectiveness of|
01934|011|E|ulipristal.(1)|
01934|012|B||
01934|013|P|PREDISPOSING FACTORS:  None determined.|
01934|014|B||
01934|015|M|PATIENT MANAGEMENT:  The US and UK manufacturers of ulipristal state that|
01934|016|M|concurrent use with CYP3A4 inducers such as St. John's wort is not|
01934|017|M|recommended.  Decreased effectiveness of ulipristal may occur even 2-3 weeks|
01934|018|M|after discontinuation of St. John's wort.(1,2)|
01934|019|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
01934|020|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
01934|021|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
01934|022|M|contraceptive (ie a copper IUD).  Advise the patient to have a pregnancy|
01934|023|M|test to exclude pregnancy after use and to seek medical advice if they do|
01934|024|M|become pregnant.|
01934|025|B||
01934|026|D|DISCUSSION:  CYP3A4 inducers may decrease levels and effectiveness of|
01934|027|D|ulipristal.  Enzyme induction may take 2-3 weeks to wear off.  Plasma levels|
01934|028|D|of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in|
01934|029|D|the previous 2-3 weeks.(1)|
01934|030|D|   Concurrent administration of ulipristal 30 mg and rifampin 600 mg,|
01934|031|D|another CYP3A4 inducer, for 9 days decreased the maximum concentration|
01934|032|D|(Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively.  The|
01934|033|D|Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90%|
01934|034|D|respectively.(2)|
01934|035|B||
01934|036|R|REFERENCES:|
01934|037|B||
01934|038|R|1.Ellaone (ulipristal acetate) UK summary of product characteristics. HRA|1
01934|039|R|  Pharma UK Ltd May 15, 2009.|1
01934|040|R|2.Ella (ulipristal acetate) US prescribing information. Afaxys Inc June,|1
01934|041|R|  2021.|1
01935|001|T|MONOGRAPH TITLE:  Ulipristal/Antacids; H2 Antagonists; Proton Pump|
01935|002|T|Inhibitors (mono deleted 05/26/2016)|
01935|003|B||
01935|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01935|005|L|of severe adverse interaction.|
01935|006|B||
01935|007|A|MECHANISM OF ACTION:  Ulipristal's absorption is pH dependent and may be|
01935|008|A|reduced when gastric pH is increased.(1)|
01935|009|B||
01935|010|E|CLINICAL EFFECTS:  Concurrent use of antacids, H2 antagonists, or proton|
01935|011|E|pump inhibitors may reduce the absorption and effectiveness of|
01935|012|E|ulipristal.(1)|
01935|013|B||
01935|014|P|PREDISPOSING FACTORS:  None determined.|
01935|015|B||
01935|016|M|PATIENT MANAGEMENT:  The UK manufacturer of ulipristal states that|
01935|017|M|concurrent use agents that increase gastric pH such as antacids, H2|
01935|018|M|antagonists, and proton pump inhibitors is not recommended.(1)|
01935|019|B||
01935|020|D|DISCUSSION:  Ulipristal's absorption is pH dependent and may be reduced when|
01935|021|D|gastric pH is increased.(1)|
01935|022|B||
01935|023|R|REFERENCE:|
01935|024|B||
01935|025|R|1.Ellaone (ulipristal acetate) UK summary of product characteristics. HRA|1
01935|026|R|  Pharma UK Ltd May 15, 2009.|1
01936|001|T|MONOGRAPH TITLE:  Progestin-Containing Contraceptives/Ulipristal|
01936|002|B||
01936|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01936|004|L|of severe adverse interaction.|
01936|005|B||
01936|006|A|MECHANISM OF ACTION:  Ulipristal is a progesterone receptor modulator and|
01936|007|A|binds to the progesterone receptor with high affinity.(1)(2)|
01936|008|B||
01936|009|E|CLINICAL EFFECTS:  Concurrent use of ulipristal may make hormonal|
01936|010|E|contraception (including combined hormonal products, progestin-only|
01936|011|E|products, and levonorgestrel emergency contraception) ineffective.(1,2)|
01936|012|E|These agents may also make ulipristal ineffective.|
01936|013|B||
01936|014|P|PREDISPOSING FACTORS:  None determined.|
01936|015|B||
01936|016|M|PATIENT MANAGEMENT:  The US and UK manufacturers of ulipristal recommends|
01936|017|M|that patients who have received ulipristal use a reliable barrier method of|
01936|018|M|contraception for subsequent acts of intercourse until the next menstrual|
01936|019|M|cycle begins.(1)(2)|
01936|020|M|   The US manufacturer of ulipristal states that if a woman wishes to start|
01936|021|M|or resume hormonal contraception after taking ulipristal, she should do so|
01936|022|M|no sooner than 5 days afterwards.|
01936|023|M|   The UK manufacturer of ulipristal states that concurrent use with|
01936|024|M|levonorgestrel emergency contraception is not recommended.(1)|
01936|025|B||
01936|026|D|DISCUSSION:  Ulipristal is a progesterone receptor modulator and binds to|
01936|027|D|the progesterone receptor with high affinity, thus it may interfere with the|
01936|028|D|efficacy of hormonal contraception (including combined hormonal products,|
01936|029|D|progestin-only products, and levonorgestrel emergency contraception) and|
01936|030|D|progestin products.(1-2)  These products may also make ulipristal|
01936|031|D|ineffective.|
01936|032|B||
01936|033|R|REFERENCES:|
01936|034|B||
01936|035|R|1.Ellaone (ulipristal acetate) UK summary of product characteristics. HRA|1
01936|036|R|  Pharma UK Ltd May 15, 2009.|1
01936|037|R|2.Ella (ulipristal acetate) US prescribing information. Afaxys Inc June,|1
01936|038|R|  2021.|1
01937|001|T|MONOGRAPH TITLE:  Didanosine Pediatric Powder for|
01937|002|T|Susp/Levomethadone;Methadone|
01937|003|B||
01937|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01937|005|L|is contraindicated and generally should not be dispensed or administered to|
01937|006|L|the same patient.|
01937|007|B||
01937|008|A|MECHANISM OF ACTION:  Methadone may decrease the bioavailability of|
01937|009|A|didanosine.(1-3)|
01937|010|A|   Levomethadone is an enantiomer of methadone.(4)|
01937|011|B||
01937|012|E|CLINICAL EFFECTS:  Concurrent use of methadone may result in decreased|
01937|013|E|levels and effectiveness of didanosine.(1-3)|
01937|014|B||
01937|015|P|PREDISPOSING FACTORS:  None determined.|
01937|016|B||
01937|017|M|PATIENT MANAGEMENT:  Methadone should not be coadministered with the|
01937|018|M|pediatric powder formulation of didanosine.  Instead, use the enteric coated|
01937|019|M|formulation of didanosine and monitor for changes in HIV RNA viral load in|
01937|020|M|patients requiring concurrent therapy.(2,3)|
01937|021|B||
01937|022|D|DISCUSSION:  In a study in healthy subjects, the addition of didanosine to|
01937|023|D|17 patients stabilized on methadone and 10 untreated controls decreased the|
01937|024|D|area-under-curve (AUC) of didanosine by 57%.  The maximum concentration|
01937|025|D|(Cmax) of didanosine decreased by 66%.(1,2)|
01937|026|B||
01937|027|R|REFERENCES:|
01937|028|B||
01937|029|R|1.Rainey PM, Friedland G, McCance-Katz EF, Andrews L, Mitchell SM, Charles|2
01937|030|R|  C, Jatlow P. Interaction of methadone with didanosine and stavudine. J|2
01937|031|R|  Acquir Immune Defic Syndr 2000 Jul 1;24(3):241-8.|2
01937|032|R|2.Videx (didanosine) US prescribing information. Bristol-Myers Squibb|1
01937|033|R|  Company November, 2011.|1
01937|034|R|3.Videx EC (didanosine) US prescribing information. Bristol-Myers Squibb|1
01937|035|R|  Company January 25, 2018.|1
01937|036|R|4.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
01937|037|R|  Pharma AS November 30, 2018.|1
01938|001|T|MONOGRAPH TITLE:  Mycophenolate/Rifampin|
01938|002|B||
01938|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01938|004|L|of severe adverse interaction.|
01938|005|B||
01938|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of|
01938|007|A|mycophenolate.(1-3)|
01938|008|B||
01938|009|E|CLINICAL EFFECTS:  Concurrent use of rifampin may decrease the levels and|
01938|010|E|effectiveness of mycophenolate.(1-3)|
01938|011|B||
01938|012|P|PREDISPOSING FACTORS:  None determined.|
01938|013|B||
01938|014|M|PATIENT MANAGEMENT:  The US manufacturer of mycophenolate mofetil states|
01938|015|M|that concurrent use is not recommended unless the benefit outweighs the|
01938|016|M|risk.(1)|
01938|017|B||
01938|018|D|DISCUSSION:  In a prospective, open-label, nonrandomized, controlled trial|
01938|019|D|in 8 stable renal allograft recipients, rifampin (600 mg daily for 8 days)|
01938|020|D|decreased the 0-12 hour area-under-curve (AUC) of mycophenolic acid by|
01938|021|D|17.5%.(2)|
01938|022|D|   In a single heart-lung transplant patient, concurrent rifampin decreased|
01938|023|D|exposure to mycophenolic acid by 67%.(1,3)|
01938|024|B||
01938|025|R|REFERENCES:|
01938|026|B||
01938|027|R|1.CellCept (mycophenolate mofetil) US prescribing information. Roche|1
01938|028|R|  Pharmaceuticals June, 2022.|1
01938|029|R|2.Naesens M, Kuypers DR, Streit F, Armstrong VW, Oellerich M, Verbeke K,|2
01938|030|R|  Vanrenterghem Y. Rifampin induces alterations in mycophenolic acid|2
01938|031|R|  glucuronidation and elimination: implications for drug exposure in renal|2
01938|032|R|  allograft recipients. Clin Pharmacol Ther 2006 Nov;80(5):509-21.|2
01938|033|R|3.Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction|3
01938|034|R|  between mycophenolate mofetil and rifampin: possible induction of uridine|3
01938|035|R|  diphosphate-glucuronosyltransferase. Clin Pharmacol Ther 2005 Jul;|3
01938|036|R|  78(1):81-8.|3
01939|001|T|MONOGRAPH TITLE:  Voriconazole/Darunavir; Lopinavir (mono deleted|
01939|002|T|04/23/2021)|
01939|003|B||
01939|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01939|005|L|of severe adverse interaction.|
01939|006|B||
01939|007|A|MECHANISM OF ACTION:  Ritonavir,which is taken with darunavir and lopinavir,|
01939|008|A|may induce the metabolism of voriconazole by CYP P-450-3A4.(1-4)|
01939|009|A|Voriconazole may induce the metabolism of low-dose ritonavir.(1)|
01939|010|B||
01939|011|E|CLINICAL EFFECTS:  Concurrent use of darunavir/ritonavir(2) or|
01939|012|E|lopinavir/ritonavir(3) may result in decreased levels of voriconazole and|
01939|013|E|therapeutic failure.  Concurrent use of voriconazole and low-dose ritonavir|
01939|014|E|may result in decreased levels of ritonavir.(2)|
01939|015|B||
01939|016|P|PREDISPOSING FACTORS:  None determined.|
01939|017|B||
01939|018|M|PATIENT MANAGEMENT:  The US manufacturers of darunavir(2) and|
01939|019|M|lopinavir/ritonavir(3) state that voriconazole should not be used with|
01939|020|M|darunavir/ritonavir or lopinavir/ritonavir unless the benefit outweighs the|
01939|021|M|risk.|
01939|022|M|   The US manufacturers of ritonavir(4) and voriconazole(1) state that|
01939|023|M|concurrent use of voriconazole with low-dose ritonavir (100 mg twice daily)|
01939|024|M|should be avoided, unless the potential benefits justifies the risk to the|
01939|025|M|patient.|
01939|026|B||
01939|027|D|DISCUSSION:  In a study in healthy subjects, ritonavir (400 mg twice daily)|
01939|028|D|decreased voriconazole (400 mg twice daily) maximum concentration (Cmax) and|
01939|029|D|area-under-curve (AUC) by 66% and by 82%, respectively.  There were no|
01939|030|D|significant effects on ritonavir Cmax or AUC.(1,4)|
01939|031|D|   In a study in healthy subjects, ritonavir (100 mg twice daily) decreased|
01939|032|D|voriconazole (400 mg twice daily for one day, then 200 mg twice daily) Cmax|
01939|033|D|and AUC by 24% and 39%, respectively.  Ritonavir Cmax and AUC decreased by|
01939|034|D|24% and 14%, respectively.(1)|
01939|035|D|   Conversely, in a study of 20 healthy subjects, ritonavir (300 mg twice|
01939|036|D|daily for 2 days) increased voriconazole (400 mg single dose) Cmax and AUC|
01939|037|D|by 17.5% and 3.5 fold respectively.(5)|
01939|038|D|   In an open-label parallel study in 18 subjects, concurrent voriconazole|
01939|039|D|and indinavir had no effect on the pharmacokinetics of either agent.(6)|
01939|040|B||
01939|041|R|REFERENCES:|
01939|042|B||
01939|043|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
01939|044|R|2.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01939|045|R|  March, 2023.|1
01939|046|R|3.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01939|047|R|  Laboratories December, 2019.|1
01939|048|R|4.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01939|049|R|  December, 2019.|1
01939|050|R|5.Mikus G, Schowel V, Drzewinska M, Rengelshausen J, Ding R, Riedel KD,|2
01939|051|R|  Burhenne J, Weiss J, Thomsen T, Haefeli WE. Potent cytochrome P450 2C19|2
01939|052|R|  genotype-related interaction between voriconazole and the cytochrome P450|2
01939|053|R|  3A4 inhibitor ritonavir. Clin Pharmacol Ther 2006 Aug;80(2):126-35.|2
01939|054|R|6.Purkins L, Wood N, Kleinermans D, Love ER. No clinically significant|2
01939|055|R|  pharmacokinetic interactions between voriconazole and indinavir in healthy|2
01939|056|R|  volunteers. Br J Clin Pharmacol 2003 Dec;56 Suppl 1:62-8.|2
01940|001|T|MONOGRAPH TITLE:  Lopinavir/QT Prolonging Agents|
01940|002|B||
01940|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01940|004|L|of severe adverse interaction.|
01940|005|B||
01940|006|A|MECHANISM OF ACTION:  Lopinavir has been shown to prolong the QTc interval|
01940|007|A|by 5 msec.  Concurrent use with other agents that prolong the QTc interval|
01940|008|A|may result in additive effects on the QTc interval.(1)|
01940|009|B||
01940|010|E|CLINICAL EFFECTS:  The concurrent use of lopinavir with other agents that|
01940|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01940|012|E|arrhythmias, including torsades de pointes.(1)|
01940|013|B||
01940|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01940|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01940|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01940|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01940|018|P|gender, or advanced age.(3)|
01940|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01940|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01940|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01940|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01940|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01940|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01940|025|P|dysfunction).(3)|
01940|026|B||
01940|027|M|PATIENT MANAGEMENT:  The US manufacturer of lopinavir states that the|
01940|028|M|concurrent administration of other drugs that are known to prolong the QTc|
01940|029|M|interval should be avoided.(1)|
01940|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01940|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01940|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01940|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01940|034|B||
01940|035|D|DISCUSSION:  In a randomized, placebo and active controlled crossover study|
01940|036|D|in 39 healthy subjects designed to evaluated QTc intervals,|
01940|037|D|lopinavir/ritonavir increased QTc by 5.3 msec and 15.2 msec for 400/100 mg|
01940|038|D|twice daily and 800/200 mg twice daily, respectively.(1)|
01940|039|D|   Agents that are linked to this monograph may have varying degrees of|
01940|040|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
01940|041|D|been shown to prolong the QTc interval either through their mechanism of|
01940|042|D|action, through studies on their effects on the QTc interval, or through|
01940|043|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01940|044|D|and/or postmarketing reports.(2)|
01940|045|B||
01940|046|R|REFERENCES:|
01940|047|B||
01940|048|R|1.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01940|049|R|  Laboratories December, 2019.|1
01940|050|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01940|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01940|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01940|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01940|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01940|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01940|056|R|  settings: a scientific statement from the American Heart Association and|6
01940|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01940|058|R|  2;55(9):934-47.|6
01941|001|T|MONOGRAPH TITLE:  Lopinavir/Possible QT Prolonging Agents|
01941|002|B||
01941|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01941|004|L|take action as needed.|
01941|005|B||
01941|006|A|MECHANISM OF ACTION:  Lopinavir has been shown to prolong the QTc interval|
01941|007|A|by 5 msec.  Concurrent use with other agents that prolong the QTc interval|
01941|008|A|may result in additive effects on the QTc interval.(1)|
01941|009|B||
01941|010|E|CLINICAL EFFECTS:  The concurrent use of lopinavir with other agents that|
01941|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01941|012|E|arrhythmias, including torsades de pointes.(1)|
01941|013|B||
01941|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01941|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01941|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01941|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01941|018|P|gender, or advanced age.(3)|
01941|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01941|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01941|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01941|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01941|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01941|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01941|025|P|dysfunction).(3)|
01941|026|B||
01941|027|M|PATIENT MANAGEMENT:  The US manufacturer of lopinavir states that the|
01941|028|M|concurrent administration of other drugs that are known to prolong the QTc|
01941|029|M|interval should be avoided.(1)|
01941|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01941|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01941|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01941|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01941|034|B||
01941|035|D|DISCUSSION:  In a randomized, placebo and active controlled crossover study|
01941|036|D|in 39 healthy subjects designed to evaluated QTc intervals,|
01941|037|D|lopinavir/ritonavir increased QTc by 5.3 msec and 15.2 msec for 400/100 mg|
01941|038|D|twice daily and 800/200 mg twice daily, respectively.(1)|
01941|039|D|   Agents that are linked to this monograph may have varying degrees of|
01941|040|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
01941|041|D|been shown to prolong the QTc interval either through their mechanism of|
01941|042|D|action, through studies on their effects on the QTc interval, or through|
01941|043|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01941|044|D|and/or postmarketing reports.(2)|
01941|045|B||
01941|046|R|REFERENCES:|
01941|047|B||
01941|048|R|1.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01941|049|R|  Laboratories December, 2019.|1
01941|050|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01941|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01941|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01941|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01941|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01941|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01941|056|R|  settings: a scientific statement from the American Heart Association and|6
01941|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01941|058|R|  2;55(9):934-47.|6
01942|001|T|MONOGRAPH TITLE:  Everolimus/Ketoconazole (mono deleted 09/15/2011)|
01942|002|B||
01942|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01942|004|L|is contraindicated and generally should not be dispensed or administered to|
01942|005|L|the same patient.|
01942|006|B||
01942|007|A|MECHANISM OF ACTION:  Ketoconazole may inhibit the metabolism of everolimus|
01942|008|A|by CYP P-450-3A4.(1,2)|
01942|009|B||
01942|010|E|CLINICAL EFFECTS:  The concurrent administration of everolimus and|
01942|011|E|ketocconazole may result in elevated levels of everolimus and toxicity.(1,2)|
01942|012|B||
01942|013|P|PREDISPOSING FACTORS:  None determined.|
01942|014|B||
01942|015|M|PATIENT MANAGEMENT:  The Australian manufacturer of ketoconazole states that|
01942|016|M|concurrent use of everolimus is contraindicated.(1)|
01942|017|M|   The Australian(2) and US(3) manufacturers of everolimus state that|
01942|018|M|concurrent use with ketoconazole should be avoided.  The UK manufacturer of|
01942|019|M|everolimus state that concurrent use with ketoconazole is not|
01942|020|M|recommended.(4)|
01942|021|M|   If concurrent therapy is warranted, everolimus levels should be closely|
01942|022|M|monitored.|
01942|023|B||
01942|024|D|DISCUSSION:  In a crossover study in 12 healthy subjects, ketoconazole (200|
01942|025|D|mg twice daily for 8 days) increased the area-under-curve (AUC), maximum|
01942|026|D|concentration (Cmax), and half-life of a single oral dose of everolimus (2|
01942|027|D|mg on day 4) by 15-fold, 3.9-fold, and 1.9-fold, respectively.(5,6)|
01942|028|B||
01942|029|R|REFERENCES:|
01942|030|B||
01942|031|R|1.Nizoral (ketoconazole) Australian prescribing information. Janssen-Cilag|1
01942|032|R|  Pty Ltd June 6, 2008.|1
01942|033|R|2.Afinitor (everolimus) Australian prescribing information. Novartis|1
01942|034|R|  Pharmaceuticals Australia Pty Limited July 29, 2009.|1
01942|035|R|3.Afinitor (everolimus) US prescribing information. Novartis Pharmaceuticals|1
01942|036|R|  Corporation March, 2009.|1
01942|037|R|4.Afinitor (everolimus) UK summary of product characteristics. Novartis|1
01942|038|R|  Pharmaceuticals UK Ltd August 3, 2009.|1
01942|039|R|5.Kovarik JM, Beyer D, Bizot MN, Jiang Q, Shenouda M, Schmouder RL. Blood|2
01942|040|R|  concentrations of everolimus are markedly increased by ketoconazole. J|2
01942|041|R|  Clin Pharmacol 2005 May;45(5):514-8.|2
01942|042|R|6.Kovarik JM, Beyer D, Schmouder RL. Everolimus drug interactions:|2
01942|043|R|  application of a classification system for clinical decision making.|2
01942|044|R|  Biopharm Drug Dispos 2006 Dec;27(9):421-6.|2
01943|001|T|MONOGRAPH TITLE:  Everolimus/Selected Azole Antifungals (mono deleted|
01943|002|T|09/15/2011)|
01943|003|B||
01943|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01943|005|L|of severe adverse interaction.|
01943|006|B||
01943|007|A|MECHANISM OF ACTION:  Azoles may inhibit the metabolism of everolimus by CYP|
01943|008|A|P-450-3A4.(1-3)|
01943|009|B||
01943|010|E|CLINICAL EFFECTS:  The concurrent administration azole antifungals may|
01943|011|E|result in elevated levels of everolimus and toxicity.(1-3)|
01943|012|B||
01943|013|P|PREDISPOSING FACTORS:  None determined.|
01943|014|B||
01943|015|M|PATIENT MANAGEMENT:  The Australian manufacturer of everolimus states that|
01943|016|M|concurrent use with strong CYP P-450-3A4 inhibitors such as itraconazole and|
01943|017|M|voriconazole should be avoided.  Use of moderate CYP P-450-3A4 inhibitors|
01943|018|M|such as fluconazole should be approached with caution.  If concurrent|
01943|019|M|therapy with fluconazole is warranted, decrease the dose of everolimus to 5|
01943|020|M|mg daily.  Further reduction to 5 mg every other day may be required.(1)|
01943|021|M|   The UK manufacturer of everolimus states that concurrent use with strong|
01943|022|M|CYP P-450-3A4 inhibitors such as itraconazole, posaconazole, and|
01943|023|M|voriconazole is not recommended.  If treatment with moderate CYP P-450-3A4|
01943|024|M|inhibitors such as fluconazole cannot be avoided, a dosage reduction to 5 mg|
01943|025|M|daily or every other day may be considered.(2)|
01943|026|M|   The US manufacturer of everolimus states that concurrent use with strong|
01943|027|M|and moderate CYP P-450-3A4 inhibitors such as fluconazole, itraconazole, and|
01943|028|M|voriconazole should be avoided.(3)|
01943|029|B||
01943|030|D|DISCUSSION:  In a crossover study in 12 healthy subjects, ketoconazole (200|
01943|031|D|mg twice daily for 8 days) increased the area-under-curve (AUC), maximum|
01943|032|D|concentration (Cmax), and half-life of a single oral dose of everolimus (2|
01943|033|D|mg on day 4) by 15-fold, 3.9-fold, and 1.9-fold, respectively.(4,5)|
01943|034|D|   In a 54 year-old male renal transplant patient, use of posaconazole and|
01943|035|D|voriconazole increased everolimus minimum concentrations (Cmin) by 3.8-fold|
01943|036|D|and 7.5-fold, respectively.(6)|
01943|037|D|   In a 65 year-old male liver transplant patient, everolimus|
01943|038|D|concentration/dose ratio was markedly lower during fluconazole versus|
01943|039|D|voriconazole therapy (3.49 ng/ml versus 11.05 ng/ml, respectively).(7)|
01943|040|D|   An analysis of everolimus levels in a multicenter efficacy trial found|
01943|041|D|that one patient receiving concurrent itraconazole had a 74% reduction in|
01943|042|D|everolimus clearance.(8)|
01943|043|B||
01943|044|R|REFERENCES:|
01943|045|B||
01943|046|R|1.Afinitor (everolimus) Australian prescribing information. Novartis|1
01943|047|R|  Pharmaceuticals Australia Pty Limited July 29, 2009.|1
01943|048|R|2.Afinitor (everolimus) US prescribing information. Novartis Pharmaceuticals|1
01943|049|R|  Corporation March, 2009.|1
01943|050|R|3.Afinitor (everolimus) UK summary of product characteristics. Novartis|1
01943|051|R|  Pharmaceuticals UK Ltd August 3, 2009.|1
01943|052|R|4.Kovarik JM, Beyer D, Bizot MN, Jiang Q, Shenouda M, Schmouder RL. Blood|2
01943|053|R|  concentrations of everolimus are markedly increased by ketoconazole. J|2
01943|054|R|  Clin Pharmacol 2005 May;45(5):514-8.|2
01943|055|R|5.Kovarik JM, Beyer D, Schmouder RL. Everolimus drug interactions:|2
01943|056|R|  application of a classification system for clinical decision making.|2
01943|057|R|  Biopharm Drug Dispos 2006 Dec;27(9):421-6.|2
01943|058|R|6.Billaud EM, Antoine C, Berge M, Abboud I, Lefeuvre S, Benammar M, Glotz D.|3
01943|059|R|  Management of metabolic cytochrome P450 3A4 drug-drug interaction between|3
01943|060|R|  everolimus and azole antifungals in a renal transplant patient. Clin Drug|3
01943|061|R|  Investig 2009;29(7):481-6.|3
01943|062|R|7.Pea F, Baccarani U, Tavio M, Cojutti P, Adani GL, Londero A, Baraldo M,|3
01943|063|R|  Franceschi L, Furlanut M, Viale P. Pharmacokinetic interaction between|3
01943|064|R|  everolimus and antifungal triazoles in a liver transplant patient. Ann|3
01943|065|R|  Pharmacother 2008 Nov;42(11):1711-6.|3
01943|066|R|8.Kovarik JM, Hsu CH, McMahon L, Berthier S, Rordorf C. Population|3
01943|067|R|  pharmacokinetics of everolimus in de novo renal transplant patients:|3
01943|068|R|  impact of ethnicity and comedications. Clin Pharmacol Ther 2001 Sep;|3
01943|069|R|  70(3):247-54.|3
01944|001|T|MONOGRAPH TITLE:  Telavancin/Possible QT Prolonging Agents|
01944|002|B||
01944|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01944|004|L|take action as needed.|
01944|005|B||
01944|006|A|MECHANISM OF ACTION:  Telavancin has been shown to prolong the QTc interval.|
01944|007|A|Concurrent use with other agents that prolong the QTc interval may result|
01944|008|A|in additive effects on the QTc interval.(1)|
01944|009|B||
01944|010|E|CLINICAL EFFECTS:  The concurrent use of telavancin with other agents that|
01944|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01944|012|E|arrhythmias, including torsades de pointes.(1)|
01944|013|B||
01944|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01944|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01944|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01944|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01944|018|P|female gender, or advanced age.(2)|
01944|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01944|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01944|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01944|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01944|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01944|024|P|an agent which inhibits its metabolism  or elimination, genetic impairment|
01944|025|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01944|026|B||
01944|027|M|PATIENT MANAGEMENT:  The US manufacturer of telavancin recommends against|
01944|028|M|the use of telavancin with other drugs known to cause QT prolongation.(1)|
01944|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01944|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01944|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01944|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01944|033|B||
01944|034|D|DISCUSSION:  In a randomized, double-blind, multiple-dose,|
01944|035|D|positive-controlled, placebo-controlled, parallel study in healthy subjects,|
01944|036|D|the mean maximum baseline-corrected, placebo-corrected QTc prolongation was|
01944|037|D|11.6 msec and 15.1 msec for telavancin at dosages of 7.5 mg/kg and 15 mg/kg,|
01944|038|D|respectively.  The estimated  mean maximum baseline-corrected,|
01944|039|D|placebo-corrected QTc prolongation for a telavancin dosage of 10 mg/kg is|
01944|040|D|12-15 msec.(1)|
01944|041|D|   In studies in patients, 21% of patients receiving telavancin (214 of|
01944|042|D|1029, 10 mg/kg) and 16% of patients receiving vancomycin (164 of 1033)|
01944|043|D|received concurrent QT prolonging agents.  The rate of QTc prolongation|
01944|044|D|greater than 60 msec was 1.5% (15 patients) in the telavancin group and 0.6%|
01944|045|D|(6 patients) in the vancomycin group.  Nine of the 15 telavancin subjects|
01944|046|D|with QTc prolongation received concurrent QT prolongers, compared with 1 of|
01944|047|D|the vancomycin patients.(1)|
01944|048|D|   Agents that are linked to this monograph may have varying degrees of|
01944|049|D|potential to prolong the QTc interval but are generally accepted to have a|
01944|050|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
01944|051|D|been shown to prolong the QTc interval either through their mechanism of|
01944|052|D|action, through studies on their effects on the QTc interval, or through|
01944|053|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
01944|054|D|and/or post-marketing reports.(3)|
01944|055|B||
01944|056|R|REFERENCES:|
01944|057|B||
01944|058|R|1.Vibativ (telavancin) US prescribing information. Theravance Biopharma US,|1
01944|059|R|  Inc. February, 2020.|1
01944|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01944|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01944|062|R|  settings: a scientific statement from the American Heart Association and|6
01944|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01944|064|R|  2;55(9):934-47.|6
01944|065|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
01944|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01944|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01944|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01945|001|T|MONOGRAPH TITLE:  Mefloquine/Ketoconazole; Levoketoconazole|
01945|002|B||
01945|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01945|004|L|is contraindicated and generally should not be dispensed or administered to|
01945|005|L|the same patient.|
01945|006|B||
01945|007|A|MECHANISM OF ACTION:  Ketoconazole and levoketoconazole may inhibit the|
01945|008|A|metabolism of mefloquine by CYP3A4 and the transport of mefloquine by|
01945|009|A|P-glycoprotein.(1,4)|
01945|010|B||
01945|011|E|CLINICAL EFFECTS:  Concurrent use of ketoconazole or levoketoconazole may|
01945|012|E|result in elevated levels of and toxicity from mefloquine, including|
01945|013|E|prolongation of the QTc interval, which may be fatal.(1)|
01945|014|B||
01945|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01945|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
01945|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01945|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01945|019|P|female gender, or advanced age.(3)|
01945|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01945|021|P|higher systemic concentrations of either QT prolonging drug are risk factors|
01945|022|P|for torsades de pointes.  Factors which may increase systemic drug|
01945|023|P|concentrations include rapid infusion of an intravenous dose or impaired|
01945|024|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
01945|025|P|which inhibits its metabolism or elimination, genetic impairment in drug|
01945|026|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01945|027|B||
01945|028|M|PATIENT MANAGEMENT:  The US manufacturer of mefloquine states that|
01945|029|M|ketoconazole should not be administered with mefloquine or within 15 weeks|
01945|030|M|of the last dose of mefloquine.(1)|
01945|031|M|   The manufacture of levoketoconazole states that concurrent use of|
01945|032|M|levoketoconazole with substrates of CYP3A4 and P-gp is not recommended.(4)|
01945|033|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
01945|034|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
01945|035|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
01945|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
01945|037|B||
01945|038|D|DISCUSSION:  In an open-label, cross-over study in 7 healthy subjects,|
01945|039|D|ketoconazole (400 mg daily for 10 days) increased the area-under-curve|
01945|040|D|(AUC), maximum concentration (Cmax), and half-life (T1/2) of a single dose|
01945|041|D|of mefloquine (500 mg) by 79%, 64%, and 39%, respectively.(1,2)|
01945|042|B||
01945|043|R|REFERENCES:|
01945|044|B||
01945|045|R|1.Lariam (mefloquine hydrochloride) US prescribing information. Roche|1
01945|046|R|  Pharmaceuticals August, 2009.|1
01945|047|R|2.Ridtitid W, Wongnawa M, Mahatthanatrakul W, Raungsri N, Sunbhanich M.|2
01945|048|R|  Ketoconazole increases plasma concentrations of antimalarial mefloquine in|2
01945|049|R|  healthy human volunteers. J Clin Pharm Ther 2005 Jun;30(3):285-90.|2
01945|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01945|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01945|052|R|  settings: a scientific statement from the American Heart Association and|6
01945|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01945|054|R|  2;55(9):934-47.|6
01945|055|R|4.Recorlev (levoketoconazole) US prescribing information. Xeris|1
01945|056|R|  Pharmaceuticals, Inc. June, 2023.|1
01946|001|T|MONOGRAPH TITLE:  Repaglinide/Deferasirox|
01946|002|B||
01946|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01946|004|L|take action as needed.|
01946|005|B||
01946|006|A|MECHANISM OF ACTION:  Deferasirox may inhibit the metabolism of repaglinide|
01946|007|A|by CYP2C8.(1)|
01946|008|B||
01946|009|E|CLINICAL EFFECTS:  Concurrent use of deferasirox may result in elevated|
01946|010|E|levels of and increased effects of repaglinide.(1)|
01946|011|B||
01946|012|P|PREDISPOSING FACTORS:  None determined.|
01946|013|B||
01946|014|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
01946|015|M|deferasirox and repaglinide closely.  Consider decreasing the dosage of|
01946|016|M|repaglinide.(1)|
01946|017|B||
01946|018|D|DISCUSSION:  In a study in healthy subjects, administration of deferasirox|
01946|019|D|(30 mg/kg/day for 4 days) increased the area-under-curve (AUC) and maximum|
01946|020|D|concentration (Cmax) of a single dose of repaglinide (0.5 mg) by 2.3-fold|
01946|021|D|and 62%, respectively.(1)|
01946|022|B||
01946|023|R|REFERENCE:|
01946|024|B||
01946|025|R|1.Exjade (deferasirox) US prescribing information. Novartis Pharmaceuticals|1
01946|026|R|  Corporation July, 2019.|1
01947|001|T|MONOGRAPH TITLE:  Deferasirox/Strong UGT Inducers|
01947|002|B||
01947|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01947|004|L|of severe adverse interaction.|
01947|005|B||
01947|006|A|MECHANISM OF ACTION:  Strong inducers of UDP-glucuronosyltransferase (UGT)|
01947|007|A|may induce the metabolism of deferasirox.(1)|
01947|008|B||
01947|009|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, efavirenz, etravirine,|
01947|010|E|fosphenytoin, phenobarbital, phenytoin, primidone, rifampin, or ritonavir|
01947|011|E|may result in decreased levels and effectiveness of deferasirox.(1)|
01947|012|B||
01947|013|P|PREDISPOSING FACTORS:  None determined.|
01947|014|B||
01947|015|M|PATIENT MANAGEMENT:  Avoid the use of strong UGT inducers with deferasirox.|
01947|016|M|If concurrent therapy is warranted, consider increasing the initial dose of|
01947|017|M|deferasirox by 50%.  Further dosage adjustments should be made based upon|
01947|018|M|serum ferritin levels and clinical response.  Doses above 40 mg/kg are not|
01947|019|M|recommended.(1)|
01947|020|B||
01947|021|D|DISCUSSION:  In a study in healthy subjects, administration of rifampin (600|
01947|022|D|mg/day for 9 days) decreased the area-under-curve (AUC) of a single dose of|
01947|023|D|deferasirox (30 mg/kg) by 44%.(1)|
01947|024|D|   Other strong inducers of UGT, such as carbamazepine, efavirenz,|
01947|025|D|etravirine, fosphenytoin, phenobarbital, phenytoin, primidone, and ritonavir|
01947|026|D|are expected to produce similar results.(1)|
01947|027|B||
01947|028|R|REFERENCE:|
01947|029|B||
01947|030|R|1.Exjade (deferasirox) US prescribing information. Novartis Pharmaceuticals|1
01947|031|R|  Corporation July, 2019.|1
01948|001|T|MONOGRAPH TITLE:  Deferasirox/Phenobarbital; Phenytoin (mono deleted|
01948|002|T|12/15/2011)|
01948|003|B||
01948|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01948|005|L|take action as needed.|
01948|006|B||
01948|007|A|MECHANISM OF ACTION:  Phenobarbital and phenytoin may induce the metabolism|
01948|008|A|of deferasirox by UDP-glucuronosyltransferase (UGT).(1)|
01948|009|B||
01948|010|E|CLINICAL EFFECTS:  Concurrent use of phenobarbital or phenytoin may result|
01948|011|E|in decreased levels and effectiveness of deferasirox.(1)|
01948|012|B||
01948|013|P|PREDISPOSING FACTORS:  None determined.|
01948|014|B||
01948|015|M|PATIENT MANAGEMENT:  The US manufacturer of deferasirox recommends a dosage|
01948|016|M|increase for deferasirox in patients receiving a potent UGT inducer, such as|
01948|017|M|phenobarbital or phenytoin. Dosage adjustments should be made in steps of 5|
01948|018|M|mg/kg or 10 mg/kg.  Monitor serum ferritin levels and clinical responses for|
01948|019|M|further dosage modification.  Doses above 40 mg/kg are not recommended.(1)|
01948|020|B||
01948|021|D|DISCUSSION:  In a study in healthy subjects, administration of rifampin|
01948|022|D|(another potent inhibitor of UGT, 600 mg/day for 9 days) decreased the|
01948|023|D|area-under-curve (AUC) of a single dose of deferasirox (30 mg/kg) by 44%.(1)|
01948|024|B||
01948|025|R|REFERENCE:|
01948|026|B||
01948|027|R|1.Exjade (deferasirox) US prescribing information. Novartis Pharmaceuticals|1
01948|028|R|  Corporation October, 2013.|1
01949|001|T|MONOGRAPH TITLE:  Deferasirox/Ritonavir (mono deleted 12/15/2011)|
01949|002|B||
01949|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01949|004|L|take action as needed.|
01949|005|B||
01949|006|A|MECHANISM OF ACTION:  Ritonavir may induce the metabolism of deferasirox by|
01949|007|A|UDP-glucuronosyltransferase (UGT).(1)|
01949|008|B||
01949|009|E|CLINICAL EFFECTS:  Concurrent use of ritonavir may result in decreased|
01949|010|E|levels and effectiveness of deferasirox.(1)|
01949|011|B||
01949|012|P|PREDISPOSING FACTORS:  None determined.|
01949|013|B||
01949|014|M|PATIENT MANAGEMENT:  The US manufacturer of deferasirox recommends a dosage|
01949|015|M|increase for deferasirox in patients receiving a potent UGT inducer, such as|
01949|016|M|ritonavir. Dosage adjustments should be made in steps of 5 mg/kg or 10|
01949|017|M|mg/kg.  Monitor serum ferritin levels and clinical responses for further|
01949|018|M|dosage modification.  Doses above 40 mg/kg are not recommended.(1)|
01949|019|B||
01949|020|D|DISCUSSION:  In a study in healthy subjects, administration of rifampin|
01949|021|D|(another potent inhibitor of UGT, 600 mg/day for 9 days) decreased the|
01949|022|D|area-under-curve (AUC) of a single dose of deferasirox (30 mg/kg) by 44%.(1)|
01949|023|B||
01949|024|R|REFERENCE:|
01949|025|B||
01949|026|R|1.Exjade (deferasirox) US prescribing information. Novartis Pharmaceuticals|1
01949|027|R|  Corporation October, 2013.|1
01950|001|T|MONOGRAPH TITLE:  Valproate/Chitosan|
01950|002|B||
01950|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01950|004|L|Assess the risk to the patient and take action as needed.|
01950|005|B||
01950|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Chitosan may bind to|
01950|007|A|valproate in the gastrointestinal tract, preventing its absorption or|
01950|008|A|chitosan may decrease the enterohepatic recirculation of valproate by|
01950|009|A|decreasing enteric bacteria.(1)|
01950|010|B||
01950|011|E|CLINICAL EFFECTS:  Concurrent use of chitosan may decrease levels and|
01950|012|E|effectiveness of valproate, resulting in an increase in seizures.|
01950|013|B||
01950|014|P|PREDISPOSING FACTORS:  None determined.|
01950|015|B||
01950|016|M|PATIENT MANAGEMENT:  Patients maintained on valproate derivatives should be|
01950|017|M|cautioned that the use of chitosan may increase their risk of seizures.|
01950|018|M|Consider monitoring valproate levels and instruct patients to discontinue|
01950|019|M|chitosan if seizures occur.|
01950|020|B||
01950|021|D|DISCUSSION:  In a case report, a 35 year-old female had been seizure-free|
01950|022|D|for three years on a regimen of valproate (500 mg twice daily, 52 mcg/ml)|
01950|023|D|and phenobarbital.  The patient developed seizures within 5 days of|
01950|024|D|initiating chitosan (500 mg twice daily) on two separate occasions.|
01950|025|D|Seizures remitted following discontinuation of chitosan.  During the second|
01950|026|D|trial of chitosan, valproate levels were undetectable while phenobarbital|
01950|027|D|levels were therapeutic.  Valproate levels returned to baseline 4 days after|
01950|028|D|chitosan discontinuation.(1)|
01950|029|D|   In another case report, a 29 year-old female had been seizure-free for|
01950|030|D|two years on a regimen of valproate (1250 mg/day, 65 mcg/ml).  Following one|
01950|031|D|week of chitosan (500 mg/day), the patient experienced seizures and her|
01950|032|D|valproate levels were undetectable.(1)|
01950|033|B||
01950|034|R|REFERENCE:|
01950|035|B||
01950|036|R|1.Striano P, Zara F, Minetti C, Striano S. Chitosan may decrease serum|3
01950|037|R|  valproate and increase the risk of seizure reappearance. BMJ 2009;|3
01950|038|R|  339:b3751.|3
01951|001|T|MONOGRAPH TITLE:  Pazopanib/Possible QT Prolonging Agents|
01951|002|B||
01951|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01951|004|L|take action as needed.|
01951|005|B||
01951|006|A|MECHANISM OF ACTION:  Pazopanib has been shown to prolong the QTc interval.|
01951|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01951|008|A|additive effects on the QTc interval.(1)|
01951|009|B||
01951|010|E|CLINICAL EFFECTS:  The concurrent use of pazopanib with other agents that|
01951|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01951|012|E|arrhythmias, including torsades de pointes.(1)|
01951|013|B||
01951|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01951|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01951|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01951|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01951|018|P|gender, or advanced age.(3)|
01951|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01951|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01951|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01951|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01951|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01951|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01951|025|P|dysfunction).(3)|
01951|026|B||
01951|027|M|PATIENT MANAGEMENT:  The US manufacturer of pazopanib states that pazopanib|
01951|028|M|should be avoided in patients receiving other drugs known to cause QT|
01951|029|M|prolongation.(1)|
01951|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01951|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01951|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01951|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01951|034|B||
01951|035|D|DISCUSSION:  In clinical studies, 2% (11/558) of patients receiving|
01951|036|D|pazopanib experienced QT prolongation.  Torsades de pointes occurred in less|
01951|037|D|than 1% (2/977) of patients who received pazopanib in monotherapy studies.|
01951|038|D|In a randomized clinical trial, 3 of 290 patients who received pazopanib had|
01951|039|D|post-baseline QTc values between 500 and  549 msec.  None of the patients|
01951|040|D|receiving placebo had post-baseline QTc values greater than or equal to 500|
01951|041|D|msec.(1)|
01951|042|D|   A retrospective review of 618 cancer patients treated with 902|
01951|043|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
01951|044|D|incidence of QTc prolongation.  In patients who received pazopanib, QTc|
01951|045|D|prolongation was identified in 32 (19.4%) with 18 (56.3%) having Grade 1|
01951|046|D|(QTc 450-480 ms) and 4 (12.5%) having Grade 2 (QTc 480-500 ms).  Grade 3|
01951|047|D|events occurred in 3 (9.3%) having QTc greater than or equal to 500 ms and 4|
01951|048|D|(12.5%) having QTc change greater than or equal to 60 ms.  Ventricular|
01951|049|D|tachycardia was seen in 2 (6.3%) of patients and 1 (3.1%) patient|
01951|050|D|experienced sudden cardiac death.(4)|
01951|051|D|   Agents that are linked to this monograph may have varying degrees of|
01951|052|D|potential to prolong the QTc interval but are generally accepted to have a|
01951|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
01951|054|D|been shown to prolong the QTc interval either through their mechanism of|
01951|055|D|action, through studies on their effects on the QTc interval, or through|
01951|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
01951|057|D|and/or post-marketing reports.(2)|
01951|058|B||
01951|059|R|REFERENCES:|
01951|060|B||
01951|061|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
01951|062|R|  2020.|1
01951|063|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01951|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01951|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01951|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01951|067|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01951|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01951|069|R|  settings: a scientific statement from the American Heart Association and|6
01951|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01951|071|R|  2;55(9):934-47.|6
01951|072|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
01951|073|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
01951|074|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
01952|001|T|MONOGRAPH TITLE:  Efavirenz/St. John's Wort|
01952|002|B||
01952|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01952|004|L|is contraindicated and generally should not be dispensed or administered to|
01952|005|L|the same patient.|
01952|006|B||
01952|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of efavirenz|
01952|008|A|via CYP3A4.(1,2)|
01952|009|B||
01952|010|E|CLINICAL EFFECTS:  The concurrent administration of efavirenz and St. John's|
01952|011|E|wort may result in decreased levels and clinical effects of the NNRTI.(1,2)|
01952|012|B||
01952|013|P|PREDISPOSING FACTORS:  None determined.|
01952|014|B||
01952|015|M|PATIENT MANAGEMENT:  Patients taking efavirenz should not use St. John's|
01952|016|M|wort.(1)|
01952|017|M|   Patients receiving both of these medications should be alerted to the the|
01952|018|M|possibility of decreased effects of efavirenz and the development of|
01952|019|M|resistance to NNRTIs.(1)|
01952|020|B||
01952|021|D|DISCUSSION:  St. John's wort is expected to lower concentrations of|
01952|022|D|efavirenz.(1,2)|
01952|023|B||
01952|024|R|REFERENCES:|
01952|025|B||
01952|026|R|1.Sustiva (efavirenz) UK summary of product characteristics. Bristol-Myers|1
01952|027|R|  Squibb Pharmaceuticals Ltd January 26, 2007.|1
01952|028|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01952|029|R|  Company November, 2023.|1
01953|001|T|MONOGRAPH TITLE:  Efavirenz/Carbamazepine|
01953|002|B||
01953|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01953|004|L|of severe adverse interaction.|
01953|005|B||
01953|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of carbamazepine|
01953|007|A|via CYP3A4.  Carbamazepine may induce the metabolism of efavirenz by CYP3A4|
01953|008|A|and CYP2B6.(1)|
01953|009|B||
01953|010|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels of and|
01953|011|E|effectiveness of both carbamazepine and efavirenz.(1)|
01953|012|B||
01953|013|P|PREDISPOSING FACTORS:  None determined.|
01953|014|B||
01953|015|M|PATIENT MANAGEMENT:  The US manufacturer of efavirenz states that|
01953|016|M|alternative agents to carbamazepine should be used in patients receiving|
01953|017|M|efavirenz.(1) If concurrent use is warranted, monitor levels of both|
01953|018|M|efavirenz and carbamazepine.|
01953|019|B||
01953|020|D|DISCUSSION:  In a study in 12 healthy subjects, administration of efavirenz|
01953|021|D|(600 mg daily for 14 days) decreased the maximum concentration (Cmax),|
01953|022|D|area-under-curve (AUC), and minimum concentration (Cmin) of carbamazepine|
01953|023|D|(200 mg daily for 3 days, 200 mg twice daily for 3 days, then 400 mg daily|
01953|024|D|for 29 days) by 20%, 27%, and 35%, respectively.  The Cmin of the epoxide|
01953|025|D|metabolite of carbamazepine decreased by 13%.  The Cmax, AUC, and Cmin of|
01953|026|D|efavirenz decreased by 21%, 36%, and 47%, respectively.(1,2)|
01953|027|B||
01953|028|R|REFERENCES:|
01953|029|B||
01953|030|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
01953|031|R|  Company November, 2023.|1
01953|032|R|2.Ji P, Damle B, Xie J, Unger SE, Grasela DM, Kaul S. Pharmacokinetic|2
01953|033|R|  interaction between efavirenz and carbamazepine after multiple-dose|2
01953|034|R|  administration in healthy subjects. J Clin Pharmacol 2008 Aug;|2
01953|035|R|  48(8):948-56.|2
01954|001|T|MONOGRAPH TITLE:  Polystyrene Sulfonate/Sorbitol|
01954|002|B||
01954|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01954|004|L|of severe adverse interaction.|
01954|005|B||
01954|006|A|MECHANISM OF ACTION:  Sorbitol may damage the intestinal mucosa, trigger|
01954|007|A|vasospasms in the intestinal vasculature, and increase inflammation.(1)|
01954|008|A|Polystyrene sulfonate crystals may deposit in these areas, resulting in|
01954|009|A|further damage.(2,3)|
01954|010|B||
01954|011|E|CLINICAL EFFECTS:  Concurrent use of sorbitol and polystyrene sulfonate|
01954|012|E|(either orally or rectally) may result in colonic necrosis, bleeding,|
01954|013|E|ischemic colitis, and perforation of the gastrointestinal tract.  Fatalities|
01954|014|E|have been reported.(4)|
01954|015|B||
01954|016|P|PREDISPOSING FACTORS:  Predisposing factors may include a history of|
01954|017|P|intestinal disease or surgery, hypovolemia, and/or renal|
01954|018|P|insufficiency/failure.  Premature infants may also be predisposed to the|
01954|019|P|interaction.(4)|
01954|020|B||
01954|021|M|PATIENT MANAGEMENT:  The US manufacturer of sodium polystyrene sulfonate|
01954|022|M|states that concurrent use with sorbitol (either orally or rectally) is not|
01954|023|M|recommended.(4)|
01954|024|M|   In the event that sorbitol is used as a vehicle to administer polystyrene|
01954|025|M|sulfonate rectally as an enema, particular attention should be given to|
01954|026|M|administering a cleansing enema following the completion of the sodium|
01954|027|M|polystyrene sulfonate enema.(4)|
01954|028|M|   Patients who have received concurrent polystyrene sulfonate and sorbitol|
01954|029|M|should be monitored for signs of gastrointestinal complications and|
01954|030|M|instructed to report abdominal pain and/or signs of gastrointestinal|
01954|031|M|bleeding.|
01954|032|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01954|033|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01954|034|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01954|035|M|patients with any symptoms.|
01954|036|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
01954|037|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
01954|038|M|anticoagulation in patients with active pathologic bleeding.|
01954|039|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01954|040|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01954|041|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01954|042|M|and/or swelling.|
01954|043|B||
01954|044|D|DISCUSSION:  There have been numerous case reports of intestinal necrosis|
01954|045|D|following the use of sodium polystyrene sulfonate and sorbitol.(1,5-13)  In|
01954|046|D|the majority of these cases, sorbitol was used as a vehicle for rectal|
01954|047|D|administration of sodium polystyrene sulfonate(5-10); however, there have|
01954|048|D|also been reports with oral administration (1,11,12) and in patients who|
01954|049|D|received both oral and rectal sodium polystyrene with sorbitol.(13,14)|
01954|050|D|Fatalities have been reported.(1,5,6)|
01954|051|B||
01954|052|R|REFERENCES:|
01954|053|B||
01954|054|R|1.McGowan CE, Saha S, Chu G, Resnick MB, Moss SF. Intestinal necrosis due to|3
01954|055|R|  sodium polystyrene sulfonate (Kayexalate) in sorbitol. South Med J 2009|3
01954|056|R|  May;102(5):493-7.|3
01954|057|R|2.Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic|5
01954|058|R|  patients as a result of sodium polystyrene sulfonate (Kayexalate) in|5
01954|059|R|  sorbitol: an underrecognized condition. Am J Surg Pathol 1997 Jan;|5
01954|060|R|  21(1):60-9.|5
01954|061|R|3.Abraham SC, Bhagavan BS, Lee LA, Rashid A, Wu TT. Upper gastrointestinal|5
01954|062|R|  tract injury in patients receiving kayexalate (sodium polystyrene|5
01954|063|R|  sulfonate) in sorbitol: clinical, endoscopic, and histopathologic|5
01954|064|R|  findings. Am J Surg Pathol 2001 May;25(5):637-44.|5
01954|065|R|4.Kayexalate (sodium polystyrene sulfonate) US prescribing information.|1
01954|066|R|  Concordia Pharmaceuticals Inc. July 31, 2017.|1
01954|067|R|5.Milley JR, Jung AL. Hematochezia associated with the use of hypertonic|3
01954|068|R|  sodium polystyrene sulfonate enemas in premature infants. J Perinatol 1995|3
01954|069|R|  Mar-Apr;15(2):139-42.|3
01954|070|R|6.Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams|3
01954|071|R|  GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol|3
01954|072|R|  enemas: clinical and experimental support for the hypothesis. Surgery 1987|3
01954|073|R|  Mar;101(3):267-72.|3
01954|074|R|7.Bennett LN, Myers TF, Lambert GH. Cecal perforation associated with sodium|3
01954|075|R|  polystyrene sulfonate-sorbitol enemas in a 650 gram infant with|3
01954|076|R|  hyperkalemia. Am J Perinatol 1996 Apr;13(3):167-70.|3
01954|077|R|8.Scott TR, Graham SM, Schweitzer EJ, Bartlett ST. Colonic necrosis|3
01954|078|R|  following sodium polystyrene sulfonate (Kayexalate)-sorbitol enema in a|3
01954|079|R|  renal transplant patient. Report of a case and review of the literature.|3
01954|080|R|  Dis Colon Rectum 1993 Jun;36(6):607-9.|3
01954|081|R|9.Wootton FT, Rhodes DF, Lee WM, Fitts CT. Colonic necrosis with|3
01954|082|R|  Kayexalate-sorbitol enemas after renal transplantation. Ann Intern Med|3
01954|083|R|  1989 Dec 1;111(11):947-9.|3
01954|084|R|10.Rogers FB, Li SC. Acute colonic necrosis associated with sodium|3
01954|085|R|   polystyrene sulfonate (Kayexalate) enemas in a critically ill patient:|3
01954|086|R|   case report and review of the literature. J Trauma 2001 Aug;51(2):395-7.|3
01954|087|R|11.Gerstman BB, Kirkman R, Platt R. Intestinal necrosis associated with|3
01954|088|R|   postoperative orally administered sodium polystyrene sulfonate in|3
01954|089|R|   sorbitol. Am J Kidney Dis 1992 Aug;20(2):159-61.|3
01954|090|R|12.Thomas A, James BR, Landsberg D. Colonic necrosis due to oral kayexalate|3
01954|091|R|   in a critically-ill patient. Am J Med Sci 2009 Apr;337(4):305-6.|3
01954|092|R|13.Dardik A, Moesinger RC, Efron G, Barbul A, Harrison MG. Acute abdomen|3
01954|093|R|   with colonic necrosis induced by Kayexalate-sorbitol. South Med J 2000|3
01954|094|R|   May;93(5):511-3.|3
01954|095|R|14.Roy-Chaudhury P, Meisels IS, Freedman S, Steinman TI, Steer M. Combined|3
01954|096|R|   gastric and ileocecal toxicity (serpiginous ulcers) after oral kayexalate|3
01954|097|R|   in sorbital therapy. Am J Kidney Dis 1997 Jul;30(1):120-2.|3
01955|001|T|MONOGRAPH TITLE:  Clopidogrel/Fluconazole; Ketoconazole; Voriconazole|
01955|002|B||
01955|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01955|004|L|of severe adverse interaction.|
01955|005|B||
01955|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
01955|007|A|active metabolite via a 2 step process.  The first conversion step is|
01955|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
01955|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
01955|010|A|thought to be the more important enzyme involved in formation of the|
01955|011|A|pharmacologically active metabolite.(1)|
01955|012|A|   Fluconazole, ketoconazole, and voriconazole may inhibit the metabolism of|
01955|013|A|clopidogrel to its active form by CYP2C19 and CYP3A4.(1)|
01955|014|B||
01955|015|E|CLINICAL EFFECTS:  Concurrent use of fluconazole, ketoconazole, or|
01955|016|E|voriconazole may result in decreased clopidogrel effectiveness, resulting in|
01955|017|E|increased risk of adverse cardiac events.(1)|
01955|018|B||
01955|019|P|PREDISPOSING FACTORS:  None determined.|
01955|020|B||
01955|021|M|PATIENT MANAGEMENT:  The US manufacturer of clopidogrel states that|
01955|022|M|concurrent use of inhibitors of CYP2C19, such as fluconazole, ketoconazole,|
01955|023|M|and voriconazole should be avoided.(1)|
01955|024|M|   The US manufacturer of clopidogrel states that alternatives to|
01955|025|M|clopidogrel should be considered in patients who are poor metabolizers of|
01955|026|M|CYP2C19.(1)  It would be prudent to assume that patients taking strong|
01955|027|M|inhibitors of CYP2C19, such as fluconazole, are poor metabolizers of this|
01955|028|M|isoenzyme.  Voriconazole is a moderate CYP2C19 inhibitor.|
01955|029|M|   Ketoconazole and voriconazole are strong inhibitors of CYP3A4.|
01955|030|M|Fluconazole is a moderate inhibitor of CYP3A4.|
01955|031|M|   Consider alternatives to fluconazole, ketoconazole, and voriconazole in|
01955|032|M|patients stabilized on clopidogrel and alternatives to clopidogrel in|
01955|033|M|patients stabilized on fluconazole, ketoconazole, and voriconazole.  If|
01955|034|M|concurrent therapy is warranted, consider appropriate testing to assure|
01955|035|M|adequate inhibition of platelet reactivity.|
01955|036|B||
01955|037|D|DISCUSSION:  In a randomized, cross-over study in healthy subjects,|
01955|038|D|ketoconazole (400 mg daily) decreased the maximum concentration (Cmax) of|
01955|039|D|the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg|
01955|040|D|daily) by 61%.  The area-under-curve (AUC) of the active metabolite of|
01955|041|D|clopidogrel was decreased by 22% following the loading dose and by 29%|
01955|042|D|during maintenance dosing.  Clopidogrel-induced inhibition of platelet|
01955|043|D|aggregation was decreased by 28% following the loading dose and by 33%|
01955|044|D|during the maintenance dose.(3)|
01955|045|B||
01955|046|R|REFERENCES:|
01955|047|B||
01955|048|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01955|049|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01955|050|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
01955|051|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
01955|052|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
01955|053|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
01955|054|R|  38(1):92-9.|5
01955|055|R|3.Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT,|2
01955|056|R|  Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by|2
01955|057|R|  ketoconazole affects prasugrel and clopidogrel pharmacokinetics and|2
01955|058|R|  pharmacodynamics differently. Clin Pharmacol Ther 2007 May;81(5):735-41.|2
01956|001|T|MONOGRAPH TITLE:  Clopidogrel/Efavirenz; Etravirine|
01956|002|B||
01956|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01956|004|L|of severe adverse interaction.|
01956|005|B||
01956|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
01956|007|A|active metabolite via a 2 step process.  The first conversion step is|
01956|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
01956|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
01956|010|A|thought to be the more important enzyme involved in formation of the|
01956|011|A|pharmacologically active metabolite.(1)|
01956|012|A|   Efavirenz and etravirine may inhibit the metabolism of clopidogrel to its|
01956|013|A|active form by CYP2C19.(1-4)|
01956|014|B||
01956|015|E|CLINICAL EFFECTS:  Concurrent use of efavirenz or etravirine may result in|
01956|016|E|decreased clopidogrel effectiveness, resulting in increased risk of adverse|
01956|017|E|cardiac events.(1-4)|
01956|018|B||
01956|019|P|PREDISPOSING FACTORS:  None determined.|
01956|020|B||
01956|021|M|PATIENT MANAGEMENT:  The US manufacturer of clopidogrel states that|
01956|022|M|concurrent use of inhibitors of CYP2C19, such as efavirenz or etravirine|
01956|023|M|should be avoided.(1)|
01956|024|M|   HIV treatment guidelines from the US Department of Health and Human|
01956|025|M|Services and the University of Liverpool HIV Drug Interactions database|
01956|026|M|recommend not to coadminister clopidogrel with efavirenz or etravirine.|
01956|027|M|Consider alternative antiretroviral or antiplatelet therapy.(4,5)|
01956|028|M|   The US manufacturer of etravirine recommends alternative to clopidogrel|
01956|029|M|in patients maintained on etravirine.(2)|
01956|030|M|   The US manufacturer of clopidogrel states that alternatives to|
01956|031|M|clopidogrel should be considered in patients who are poor metabolizers of|
01956|032|M|CYP2C19.(1)  It would be prudent to assume that patients taking strong|
01956|033|M|inhibitors of CYP2C19 are poor metabolizers of this isoenzyme.  Moderate|
01956|034|M|CYP2C19 inhibitors, such as efavirenz or etravirine, may also affect this|
01956|035|M|interaction.|
01956|036|M|   Consider alternatives to etravirine in patients stabilized on clopidogrel|
01956|037|M|and alternatives to clopidogrel in patients stabilized on etravirine.  If|
01956|038|M|concurrent therapy is warranted, consider appropriate testing to assure|
01956|039|M|adequate inhibition of platelet reactivity.|
01956|040|B||
01956|041|D|DISCUSSION:  In a randomized, cross-over study in healthy subjects,|
01956|042|D|ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the maximum|
01956|043|D|concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading|
01956|044|D|dose, followed by 75 mg daily) by 61%.  The area-under-curve (AUC) of the|
01956|045|D|active metabolite of clopidogrel was decreased by 22% following the loading|
01956|046|D|dose and by 29% during maintenance dosing.  Clopidogrel-induced inhibition|
01956|047|D|of platelet aggregation was decreased by 28% following the loading dose and|
01956|048|D|by 33% during the maintenance dose.(6)|
01956|049|D|   In a cross-over study in 72 healthy subjects, simultaneous administration|
01956|050|D|of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300|
01956|051|D|mg loading dose, followed by 75 mg daily) decreased the AUC of the active|
01956|052|D|metabolite of clopidogrel by 46% following the loading dose and by 42%|
01956|053|D|during maintenance dosing.  Clopidogrel-induced inhibition of platelet|
01956|054|D|aggregation was decreased by 47% following the loading dose and by 30%|
01956|055|D|during the maintenance dose.  In a cross-over study in 72 healthy subjects,|
01956|056|D|administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12|
01956|057|D|hours after clopidogrel (300 mg loading dose, followed by 75 mg daily)|
01956|058|D|produced similar effects.(1)|
01956|059|B||
01956|060|R|REFERENCES:|
01956|061|B||
01956|062|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01956|063|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01956|064|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
01956|065|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
01956|066|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
01956|067|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
01956|068|R|  38(1):92-9.|5
01956|069|R|3.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
01956|070|R|  August, 2014.|1
01956|071|R|4.This information is based on an extract from the Certara Drug Interaction|6
01956|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01956|073|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
01956|074|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
01956|075|R|  HIV. Department of Health and Human Services. Available at:|6
01956|076|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
01956|077|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
01956|078|R|6.Liverpool Drug Interactions Group. HIV Drug Interactions. Available at:|6
01956|079|R|  https://hiv-druginteractions.org/.|6
01956|080|R|7.Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT,|2
01956|081|R|  Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by|2
01956|082|R|  ketoconazole affects prasugrel and clopidogrel pharmacokinetics and|2
01956|083|R|  pharmacodynamics differently. Clin Pharmacol Ther 2007 May;81(5):735-41.|2
01957|001|T|MONOGRAPH TITLE:  Clopidogrel/Felbamate; Stiripentol|
01957|002|B||
01957|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01957|004|L|of severe adverse interaction.|
01957|005|B||
01957|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
01957|007|A|active metabolite via a 2 step process.  The first conversion step is|
01957|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
01957|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
01957|010|A|thought to be the more important enzyme involved in formation of the|
01957|011|A|pharmacologically active metabolite.(1)|
01957|012|A|   Felbamate and stiripentol may inhibit the metabolism of clopidogrel to|
01957|013|A|its active form by CYP2C19.(1,3)|
01957|014|B||
01957|015|E|CLINICAL EFFECTS:  Concurrent use of felbamate or stiripentol may result in|
01957|016|E|decreased clopidogrel effectiveness, resulting in increased risk of adverse|
01957|017|E|cardiac events.(1,3)|
01957|018|B||
01957|019|P|PREDISPOSING FACTORS:  None determined.|
01957|020|B||
01957|021|M|PATIENT MANAGEMENT:  The US manufacturer of clopidogrel states that|
01957|022|M|concurrent use of inhibitors of CYP2C19, such as felbamate and stiripentol,|
01957|023|M|should be avoided.(1)|
01957|024|M|   The US manufacturer of clopidogrel states that alternatives to|
01957|025|M|clopidogrel should be considered in patients who are poor metabolizers of|
01957|026|M|CYP2C19.(1)  It would be prudent to assume that patients taking strong|
01957|027|M|inhibitors of CYP2C19 are poor metabolizers of this isoenzyme.|
01957|028|M|   Consider alternatives to felbamate or stiripentol in patients stabilized|
01957|029|M|on clopidogrel, or alternatives to clopidogrel in patients stabilized on|
01957|030|M|felbamate or stiripentol.  If concurrent therapy is warranted, consider|
01957|031|M|appropriate testing to assure adequate inhibition of platelet reactivity.|
01957|032|B||
01957|033|D|DISCUSSION:  In a randomized, cross-over study in healthy subjects,|
01957|034|D|ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the maximum|
01957|035|D|concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading|
01957|036|D|dose, followed by 75 mg daily) by 61%.  The area-under-curve (AUC) of the|
01957|037|D|active metabolite of clopidogrel was decreased by 22% following the loading|
01957|038|D|dose and by 29% during maintenance dosing.  Clopidogrel-induced inhibition|
01957|039|D|of platelet aggregation was decreased by 28% following the loading dose and|
01957|040|D|by 33% during the maintenance dose.(3)|
01957|041|D|   In a cross-over study in 72 healthy subjects, simultaneous administration|
01957|042|D|of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300|
01957|043|D|mg loading dose, followed by 75 mg daily) decreased the AUC of the active|
01957|044|D|metabolite of clopidogrel by 46% following the loading dose and by 42%|
01957|045|D|during maintenance dosing.  Clopidogrel-induced inhibition of platelet|
01957|046|D|aggregation was decreased by 47% following the loading dose and by 30%|
01957|047|D|during the maintenance dose.  In a cross-over study in 72 healthy subjects,|
01957|048|D|administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12|
01957|049|D|hours after clopidogrel (300 mg loading dose, followed by 75 mg daily)|
01957|050|D|produced similar effects.(1)|
01957|051|B||
01957|052|R|REFERENCES:|
01957|053|B||
01957|054|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01957|055|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01957|056|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
01957|057|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
01957|058|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
01957|059|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
01957|060|R|  38(1):92-9.|5
01957|061|R|3.Diacomit (stiripentol) US prescribing information. Biocodex, Inc. May 15,|1
01957|062|R|  2020.|1
01957|063|R|4.Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT,|2
01957|064|R|  Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by|2
01957|065|R|  ketoconazole affects prasugrel and clopidogrel pharmacokinetics and|2
01957|066|R|  pharmacodynamics differently. Clin Pharmacol Ther 2007 May;81(5):735-41.|2
01958|001|T|MONOGRAPH TITLE:  Clopidogrel/Ticlopidine|
01958|002|B||
01958|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01958|004|L|of severe adverse interaction.|
01958|005|B||
01958|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
01958|007|A|active metabolite via a 2 step process.  The first conversion step is|
01958|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
01958|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
01958|010|A|thought to be the more important enzyme involved in formation of the|
01958|011|A|pharmacologically active metabolite.(1)|
01958|012|A|    Ticlopidine may inhibit the metabolism of clopidogrel to its active form|
01958|013|A|by CYP2C19.(1)|
01958|014|B||
01958|015|E|CLINICAL EFFECTS:  Concurrent use of ticlopidine may result in decreased|
01958|016|E|clopidogrel effectiveness, resulting in increased risk of adverse cardiac|
01958|017|E|events.(1)|
01958|018|B||
01958|019|P|PREDISPOSING FACTORS:  None determined.|
01958|020|B||
01958|021|M|PATIENT MANAGEMENT:  The US manufacturer of clopidogrel states that|
01958|022|M|concurrent use of inhibitors of CYP2C19, such as ticlopidine, should be|
01958|023|M|avoided.(1)|
01958|024|M|   The US manufacturer of clopidogrel states that alternatives to|
01958|025|M|clopidogrel should be considered in patients who are poor metabolizers of|
01958|026|M|CYP2C19.(1)  It would be prudent to assume that patients taking strong|
01958|027|M|inhibitors of CYP2C19, such as ticlopidine, are poor metabolizers of this|
01958|028|M|isoenzyme.|
01958|029|M|   Consider alternatives to ticlopidine in patients stabilized on|
01958|030|M|clopidogrel and alternatives to clopidogrel in patients stabilized on|
01958|031|M|ticlopidine.  If concurrent therapy is warranted, consider appropriate|
01958|032|M|testing to assure adequate inhibition of platelet reactivity.|
01958|033|B||
01958|034|D|DISCUSSION:  In a randomized, cross-over study in healthy subjects,|
01958|035|D|ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the maximum|
01958|036|D|concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading|
01958|037|D|dose, followed by 75 mg daily) by 61%.  The area-under-curve (AUC) of the|
01958|038|D|active metabolite of clopidogrel was decreased by 22% following the loading|
01958|039|D|dose and by 29% during maintenance dosing.  Clopidogrel-induced inhibition|
01958|040|D|of platelet aggregation was decreased by 28% following the loading dose and|
01958|041|D|by 33% during the maintenance dose.(3)|
01958|042|D|   In a cross-over study in 72 healthy subjects, simultaneous administration|
01958|043|D|of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300|
01958|044|D|mg loading dose, followed by 75 mg daily) decreased the AUC of the active|
01958|045|D|metabolite of clopidogrel by 46% following the loading dose and by 42%|
01958|046|D|during maintenance dosing.  Clopidogrel-induced inhibition of platelet|
01958|047|D|aggregation was decreased by 47% following the loading dose and by 30%|
01958|048|D|during the maintenance dose.  In a cross-over study in 72 healthy subjects,|
01958|049|D|administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12|
01958|050|D|hours after clopidogrel (300 mg loading dose, followed by 75 mg daily)|
01958|051|D|produced similar effects.(1)|
01958|052|B||
01958|053|R|REFERENCES:|
01958|054|B||
01958|055|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01958|056|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01958|057|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
01958|058|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
01958|059|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
01958|060|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
01958|061|R|  38(1):92-9.|5
01958|062|R|3.Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT,|2
01958|063|R|  Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by|2
01958|064|R|  ketoconazole affects prasugrel and clopidogrel pharmacokinetics and|2
01958|065|R|  pharmacodynamics differently. Clin Pharmacol Ther 2007 May;81(5):735-41.|2
01959|001|T|MONOGRAPH TITLE:  Selected SSRIs; SNRIs/Clopidogrel|
01959|002|B||
01959|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01959|004|L|take action as needed.|
01959|005|B||
01959|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
01959|007|A|hemostasis.(1,2)  The increased risk of bleeding may be a result of a|
01959|008|A|decrease in serotonin reuptake by platelets.|
01959|009|B||
01959|010|E|CLINICAL EFFECTS:  Concurrent use of a selective serotonin reuptake|
01959|011|E|inhibitor(1-5) or a serotonin-norepinephrine reuptake inhibitor(7-9) and|
01959|012|E|agents that affect coagulation may result in bleeding.(12)|
01959|013|B||
01959|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
01959|015|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
01959|016|P|impairment has been associated with an elevated risk of GI bleed in patients|
01959|017|P|on SSRIs.(13)|
01959|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
01959|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
01959|020|P|risk for bleeding (e.g. NSAIDs).|
01959|021|B||
01959|022|M|PATIENT MANAGEMENT:  Selective serotonin reuptake inhibitors(1-5) or|
01959|023|M|serotonin-norepinephrine reuptake inhibitors(6-8) and agents that affect|
01959|024|M|coagulation should be used concurrently with caution.|
01959|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
01959|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
01959|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
01959|028|M|patients with any symptoms.|
01959|029|M|   Discontinue antiplatelet agents in patients with active pathologic|
01959|030|M|bleeding.|
01959|031|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
01959|032|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
01959|033|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
01959|034|M|and/or swelling.|
01959|035|B||
01959|036|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
01959|037|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
01959|038|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
01959|039|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
01959|040|D|only based on an observed-expected ratio was 4.5 and in a patient using|
01959|041|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
01959|042|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
01959|043|D|bleeding to 12.2 and 5.2, respectively.(9)|
01959|044|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
01959|045|D|in patients receiving concurrent therapy with selective serotonin reuptake|
01959|046|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
01959|047|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
01959|048|D|respectively.(10)|
01959|049|B||
01959|050|R|REFERENCES:|
01959|051|B||
01959|052|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
01959|053|R|  Laboratories Inc. August, 2023.|1
01959|054|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
01959|055|R|  Pharmaceuticals Inc. May, 2023.|1
01959|056|R|3.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
01959|057|R|  Technologies January, 2017.|1
01959|058|R|4.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
01959|059|R|  Therapeutics, LLC September, 2021.|1
01959|060|R|5.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
01959|061|R|6.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
01959|062|R|  Pharmaceuticals, Inc. August, 2023.|1
01959|063|R|7.Effexor XR (venlafaxine hydrochloride) US prescribing information. Viatris|1
01959|064|R|  August, 2023.|1
01959|065|R|8.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
01959|066|R|  and Company September, 2021.|1
01959|067|R|9.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
01959|068|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
01959|069|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
01959|070|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
01959|071|R|10.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
01959|072|R|   serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
01959|073|R|   population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
01959|074|R|11.Trintellix (vortioxetine) US prescribing information. Takeda|1
01959|075|R|   Pharmaceuticals America, Inc. November, 2020.|1
01959|076|R|12.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01959|077|R|   Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01959|078|R|13.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
01959|079|R|   Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
01959|080|R|   by level of kidney function: A population-based cohort study. Br J Clin|2
01959|081|R|   Pharmacol 2018 Sep;84(9):2142-2151.|2
01960|001|T|MONOGRAPH TITLE:  Clopidogrel/Fluoxetine; Fluvoxamine|
01960|002|B||
01960|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01960|004|L|of severe adverse interaction.|
01960|005|B||
01960|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
01960|007|A|active metabolite via a 2 step process.  The first conversion step is|
01960|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
01960|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
01960|010|A|thought to be the more important enzyme involved in formation of the|
01960|011|A|pharmacologically active metabolite.(1)|
01960|012|A|   Fluoxetine and fluvoxamine may inhibit the metabolism of clopidogrel to|
01960|013|A|its active form by CYP2C19.(1)|
01960|014|B||
01960|015|E|CLINICAL EFFECTS:  Concurrent use of fluoxetine and fluvoxamine may result|
01960|016|E|in decreased clopidogrel effectiveness, resulting in increased risk of|
01960|017|E|adverse cardiac events.(1)|
01960|018|B||
01960|019|P|PREDISPOSING FACTORS:  None determined.|
01960|020|B||
01960|021|M|PATIENT MANAGEMENT:  The US manufacturer of clopidogrel states that|
01960|022|M|alternatives to clopidogrel should be considered in patients who are poor|
01960|023|M|metabolizers of CYP2C19.(1)  It would be prudent to assume that patients|
01960|024|M|taking strong inhibitors of CYP2C19, such as fluoxetine and fluvoxamine, are|
01960|025|M|poor metabolizers of this isoenzyme.|
01960|026|M|   Consider alternatives to fluoxetine and fluvoxamine in patients|
01960|027|M|stabilized on clopidogrel and alternatives to clopidogrel in patients|
01960|028|M|stabilized on fluoxetine or fluvoxamine.  If concurrent therapy is|
01960|029|M|warranted, consider appropriate testing to assure adequate inhibition of|
01960|030|M|platelet reactivity.|
01960|031|B||
01960|032|D|DISCUSSION:  In an open-label, cross-over study in 8 health male volunteers,|
01960|033|D|a loading dose of clopidogrel (600 mg) was administered alone and after 5|
01960|034|D|days of fluoxetine (20 mg).  The maximum concentration (Cmax) and|
01960|035|D|area-under-curve (AUC) of the active metabolite of clopidogrel were|
01960|036|D|decreased by 25.3% and 20.6%, respectively.  There was an average decrease|
01960|037|D|of approximately 25% in the antiplatelet effects of clopidogrel when|
01960|038|D|administered with fluoxetine.(2)  However, it is likely that this study|
01960|039|D|significantly underestimates the magnitude of this interaction. Both|
01960|040|D|fluoxetine and its norfluoxetine metabolite inhibit CYP2C19 and have long|
01960|041|D|half-lives of 4 to 9 days and so  and is an irreversible inhibitor of|
01960|042|D|CYP2C19.|
01960|043|D|   In a randomized, cross-over study in healthy subjects, ketoconazole|
01960|044|D|(another CYP2C19 inhibitor, 400 mg daily) decreased the Cmax of the active|
01960|045|D|metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by|
01960|046|D|61%.  The AUC of the active metabolite of clopidogrel was decreased by 22%|
01960|047|D|following the loading dose and by 29% during maintenance dosing.|
01960|048|D|Clopidogrel-induced inhibition of platelet aggregation was decreased by 28%|
01960|049|D|following the loading dose and by 33% during the maintenance dose.(4)|
01960|050|D|   In a cross-over study in 72 healthy subjects, simultaneous administration|
01960|051|D|of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300|
01960|052|D|mg loading dose, followed by 75 mg daily) decreased the AUC of the active|
01960|053|D|metabolite of clopidogrel by 46% following the loading dose and by 42%|
01960|054|D|during maintenance dosing.  Clopidogrel-induced inhibition of platelet|
01960|055|D|aggregation was decreased by 47% following the loading dose and by 30%|
01960|056|D|during the maintenance dose.  In a cross-over study in 72 healthy subjects,|
01960|057|D|administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12|
01960|058|D|hours after clopidogrel (300 mg loading dose, followed by 75 mg daily)|
01960|059|D|produced similar effects.(1)|
01960|060|B||
01960|061|R|REFERENCES:|
01960|062|B||
01960|063|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
01960|064|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
01960|065|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
01960|066|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
01960|067|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
01960|068|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
01960|069|R|  38(1):92-9.|5
01960|070|R|3.Delavenne X, Magnin M, Basset T, Piot M, Mallouk N, Ressnikoff D, Garcin|2
01960|071|R|  A, Laporte S, Garnier P, Mismetti P. Investigation of drug-drug|2
01960|072|R|  interactions between clopidogrel and fluoxetine. Fundam Clin Pharmacol|2
01960|073|R|  2013 Feb 17.|2
01960|074|R|4.Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT,|2
01960|075|R|  Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by|2
01960|076|R|  ketoconazole affects prasugrel and clopidogrel pharmacokinetics and|2
01960|077|R|  pharmacodynamics differently. Clin Pharmacol Ther 2007 May;81(5):735-41.|2
01961|001|T|MONOGRAPH TITLE:  Colchicine/Fibrates|
01961|002|B||
01961|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01961|004|L|take action as needed.|
01961|005|B||
01961|006|A|MECHANISM OF ACTION:  The exact mechanism of action is not clear.|
01961|007|A|Concurrent use of colchicine and fibrates may result in additive or|
01961|008|A|synergistic risk for myopathy or rhabdomyolysis.(1-2)|
01961|009|B||
01961|010|E|CLINICAL EFFECTS:  Concurrent use of colchicine and fibrates have been|
01961|011|E|associated with myopathy and rhabdomyolysis.(1-2)|
01961|012|B||
01961|013|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in the|
01961|014|P|elderly and in patients with renal impairment.(1-3)|
01961|015|B||
01961|016|M|PATIENT MANAGEMENT:  The risks and benefits of colchicine should be|
01961|017|M|carefully weighed in patients who are currently taking fibrates.  Assure|
01961|018|M|that colchicine dosage has been reduced in patients with a creatinine|
01961|019|M|clearance < 30 mL/min.  Patients should be monitored and instructed to|
01961|020|M|report any signs or symptoms of unexpected muscle pain, tenderness or|
01961|021|M|weakness.(1)|
01961|022|B||
01961|023|D|DISCUSSION:  Neuromyopathy was reported in a patient maintained on|
01961|024|D|bezafibrate who received colchicine for recurrent gout.(4)|
01961|025|D|   Rhabdomyolysis was reported in a patient following the addition of|
01961|026|D|gemfibrozil to colchicine therapy.  The patient had pre-existing mild renal|
01961|027|D|failure, hepatitis B-related chronic liver disease, and amyloidosis, which|
01961|028|D|may have contributed.(3)|
01961|029|B||
01961|030|R|REFERENCES:|
01961|031|B||
01961|032|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
01961|033|R|  2011.|1
01961|034|R|2.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
01961|035|R|  Ltd. December, 2020.|1
01961|036|R|3.Atmaca H, Sayarlioglu H, Kulah E, Demircan N, Akpolat T. Rhabdomyolysis|3
01961|037|R|  associated with gemfibrozil-colchicine therapy. Ann Pharmacother 2002 Nov;|3
01961|038|R|  36(11):1719-21.|3
01961|039|R|4.Sugie M, Kuriki A, Arai D, Ichikawa H, Kawamura M. A case report of acute|3
01961|040|R|  neuromyopathy induced by concomitant use of colchicine and bezafibrate. No|3
01961|041|R|  To Shinkei 2005 Sep;57(9):785-90.|3
01962|001|T|MONOGRAPH TITLE:  Alfuzosin; Silodosin; Tamsulosin/Nefazodone (mono deleted|
01962|002|T|01/26/2012)|
01962|003|B||
01962|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01962|005|L|is contraindicated and generally should not be dispensed or administered to|
01962|006|L|the same patient.|
01962|007|B||
01962|008|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of alfuzosin,(1)|
01962|009|A|silodosin,(2) and tamsulosin(3) by CYP P-450-3A4.|
01962|010|B||
01962|011|E|CLINICAL EFFECTS:  Co-administration of nefazodone may result in increased|
01962|012|E|alfuzosin,(1) silodosin,(2) and tamsulosin(3) levels and serious effects|
01962|013|E|such as hypotension.|
01962|014|B||
01962|015|P|PREDISPOSING FACTORS:  In patients receiving tamsulosin, the interaction may|
01962|016|P|be worse in patients who are CYP P-450-2D6 poor metabolizers because|
01962|017|P|tamsulosin also undergoes metabolism by this pathway.(3)|
01962|018|B||
01962|019|M|PATIENT MANAGEMENT:  The US manufacturers of alfuzosin(1) and silodosin(2)|
01962|020|M|state that concurrent use of strong CYP P-450-3A4 inhibitors is|
01962|021|M|contraindicated.|
01962|022|M|   The US manufacturer of tamsulosin states that tamsulosin should not be|
01962|023|M|used with strong CYP P-450-3A4 inhibitors.(3)|
01962|024|B||
01962|025|D|DISCUSSION:  Administration of ketoconazole (400 mg daily), another|
01962|026|D|inhibitor of CYP P-450-3A4, increased the maximum concentration (Cmax) and|
01962|027|D|area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and|
01962|028|D|3.2-fold, respectively.(1)|
01962|029|D|   Administration of ketoconazole (200 mg daily) increased the Cmax and AUC|
01962|030|D|of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold,|
01962|031|D|respectively.(1)|
01962|032|D|   Administration of ketoconazole (200 mg daily for 4 days), increased the|
01962|033|D|Cmax and AUC of a single dose of silodosin (4 mg) by 3.7-fold and 2.9-fold,|
01962|034|D|respectively.(2)|
01962|035|D|   Administration of ketoconazole (400 mg daily for 4 days) increased the|
01962|036|D|Cmax and AUC of a single dose of silodosin (8 mg) by 3.8-fold and 3.2-fold,|
01962|037|D|respectively.(2)|
01962|038|D|   In a study in 24 healthy subjects, administration of ketoconazole (400 mg|
01962|039|D|daily for 5 days) increased the Cmax and AUC of a single dose of tamsulosin|
01962|040|D|(0.4 mg) by 2.2-fold and 2.8-fold, respectively.(3)|
01962|041|B||
01962|042|R|REFERENCES:|
01962|043|B||
01962|044|R|1.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
01962|045|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
01962|046|R|2.Rapaflo (silodosin) US prescribing information. Watson Laboratories, Inc.|1
01962|047|R|  March, 2010.|1
01962|048|R|3.Flomax (tamsulosin hydrochloride) US prescribing information. Boehringer|1
01962|049|R|  Ingelheim Pharmaceuticals, Inc. May, 2012.|1
01963|001|T|MONOGRAPH TITLE:  Cyclosporine/Methotrexate|
01963|002|B||
01963|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01963|004|L|of severe adverse interaction.|
01963|005|B||
01963|006|A|MECHANISM OF ACTION:  Cyclosporine may inhibit the metabolism of|
01963|007|A|methotrexate to its inactive metabolite, increasing its toxicity.(1)|
01963|008|A|Concurrent use may result in excessive immunosuppression.(2)|
01963|009|B||
01963|010|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine and methotrexate may|
01963|011|E|increase the levels of and toxicity from methotrexate, leading to increased|
01963|012|E|risk of severe neurotoxicity, stomatitis, and myelosuppression, including|
01963|013|E|neutropenia.  Concurrent use may also increase the risk of malignancy.(2)|
01963|014|B||
01963|015|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
01963|016|P|- High-dose oncology regimens|
01963|017|P|- Impaired renal function, ascites, or pleural effusions|
01963|018|B||
01963|019|M|PATIENT MANAGEMENT:  The US manufacturer of cyclosporine states that|
01963|020|M|concurrent use of cyclosporine and methotrexate in contraindicated in|
01963|021|M|psoriasis patients because of the possibility of excessive immunosuppression|
01963|022|M|and the subsequent risk of malignancies.(2)|
01963|023|M|   Cyclosporine and methotrexate can be used concurrently in the treatment|
01963|024|M|of rheumatoid arthritis.  CBC and liver function tests should be performed|
01963|025|M|monthly in patients receiving concurrent therapy.(2)|
01963|026|B||
01963|027|D|DISCUSSION:  In a study in 30 subjects with rheumatoid arthritis, concurrent|
01963|028|D|cyclosporine increased methotrexate maximum concentration (Cmax) and|
01963|029|D|area-under-curve (AUC) by 26% and 18%, respectively.  The plasma AUC of the|
01963|030|D|inactive 7-hydroxymethotrexate metabolite decreased by 80%.  In 13 subjects|
01963|031|D|who received a 10 mg dose of methotrexate, the urinary excretion of|
01963|032|D|7-hydroxymethotrexate decreased by 87%.  There were no effects on the|
01963|033|D|pharmacokinetics of cyclosporine or its metabolites.(1)|
01963|034|D|   A study that compared 30 rheumatoid arthritis patients who received|
01963|035|D|concurrent cyclosporine and methotrexate to 30 rheumatoid arthritis patients|
01963|036|D|who received cyclosporine alone found no effects by methotrexate on|
01963|037|D|cyclosporine pharmacokinetics.(3)|
01963|038|D|   Tumors have been reported in 32 (2.2%) of 1439 psoriasis patients treated|
01963|039|D|with cyclosporine in clinical trials.  Tumors have been reported in an|
01963|040|D|additional 7 patients in post-marketing reports.  Sixteen of these reports|
01963|041|D|involved skin malignancies.  Methotrexate was used by 7 of the patients.(2)|
01963|042|B||
01963|043|R|REFERENCES:|
01963|044|B||
01963|045|R|1.Fox RI, Morgan SL, Smith HT, Robbins BA, Choc MG, Baggott JE. Combined|2
01963|046|R|  oral cyclosporin and methotrexate therapy in patients with rheumatoid|2
01963|047|R|  arthritis elevates methotrexate levels and reduces 7-hydroxymethotrexate|2
01963|048|R|  levels when compared with methotrexate alone. Rheumatology (Oxford) 2003|2
01963|049|R|  Aug;42(8):989-94.|2
01963|050|R|2.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
01963|051|R|  Corporation September, 2023.|1
01963|052|R|3.Baraldo M, Ferraccioli G, Pea F, Gremese E, Furlanut M. Cyclosporine A|2
01963|053|R|  pharmacokinetics in rheumatoid arthritis patients after 6 months of|2
01963|054|R|  methotrexate therapy. Pharmacol Res 1999 Dec;40(6):483-6.|2
01964|001|T|MONOGRAPH TITLE:  Cyclosporine/Coal Tar|
01964|002|B||
01964|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01964|004|L|of severe adverse interaction.|
01964|005|B||
01964|006|A|MECHANISM OF ACTION:  Concurrent use of cyclosporine and coal tar may result|
01964|007|A|in excessive immunosuppression.(1)|
01964|008|B||
01964|009|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine and coal tar may increase|
01964|010|E|the risk of skin malignancy.(1)|
01964|011|B||
01964|012|P|PREDISPOSING FACTORS:  None determined.|
01964|013|B||
01964|014|M|PATIENT MANAGEMENT:  The US manufacturer of cyclosporine states that|
01964|015|M|concurrent use of cyclosporine and coal tar is contraindicated in psoriasis|
01964|016|M|patients because of the possibility of increased risk of malignancies.(1)|
01964|017|B||
01964|018|D|DISCUSSION:  Tumors have been reported in 32 (2.2%) of 1439 psoriasis|
01964|019|D|patients treated with cyclosporine in clinical trials.  Tumors have been|
01964|020|D|reported in an additional 7 patients in post-marketing reports.  Sixteen of|
01964|021|D|these reports involved skin malignancies.  Coal tar was used by 3 of the|
01964|022|D|patients.(1)|
01964|023|B||
01964|024|R|REFERENCE:|
01964|025|B||
01964|026|R|1.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
01964|027|R|  Corporation September, 2023.|1
01965|001|T|MONOGRAPH TITLE:  Tramadol/5-HT3 Antagonists|
01965|002|B||
01965|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01965|004|L|take action as needed.|
01965|005|B||
01965|006|A|MECHANISM OF ACTION:  The interaction may involve a reduction in the binding|
01965|007|A|involving 5-HT3 receptors.(1)|
01965|008|B||
01965|009|E|CLINICAL EFFECTS:  Concurrent use of 5-HT3 antagonists may decrease the|
01965|010|E|effectiveness of tramadol, resulting in increased use of tramadol.(1-3)|
01965|011|E|5-HT3 antagonists may not be effective in reducing tramadol-induced|
01965|012|E|nausea.(4)|
01965|013|B||
01965|014|P|PREDISPOSING FACTORS:  None determined.|
01965|015|B||
01965|016|M|PATIENT MANAGEMENT:  Consider the use of alternative anti-emetics in|
01965|017|M|patients receiving tramadol, or the use of other opioids in patients|
01965|018|M|receiving 5-HT3 antagonists.|
01965|019|B||
01965|020|D|DISCUSSION:  In a randomized study in 59 post-surgical patients in recovery,|
01965|021|D|compared to tramadol alone, patients receiving concurrent ondansetron|
01965|022|D|required significantly larger doses of tramadol at four hours (223 mg versus|
01965|023|D|71 mg), at 8 hours (285 mg versus 128 mg), and at 12 hours (406 mg versus|
01965|024|D|190 mg).  Vomiting rates at 4 hours and 8 hours were significantly higher|
01965|025|D|with tramadol and concurrent ondansetron compared to tramadol alone.(1)|
01965|026|D|   In a randomized, double-blind study in 40 surgical patients undergoing|
01965|027|D|lumbar laminectomy, compared to tramadol alone, cumulative tramadol|
01965|028|D|consumption with concurrent ondansetron during the first 24 hours was|
01965|029|D|significantly increased (between 26% and 35%) as well as thereafter (22% to|
01965|030|D|25%).(2)|
01965|031|D|   In another randomized study in 120 post-surgical patients, it was|
01965|032|D|discovered that tramadol consumption was increased in those patients|
01965|033|D|receiving concurrent ondansetron compared to tramadol alone.(3)|
01965|034|D|   In a prospective, randomized, double-blinded study in dental patients,|
01965|035|D|patients received one of four treatments: fentanyl and metoclopramide,|
01965|036|D|tramadol and metoclopramide, fentanyl and ondansetron, or tramadol and|
01965|037|D|ondansetron.  The patients who received tramadol and ondansetron had the|
01965|038|D|highest nausea scores among the treatment groups.  There were no significant|
01965|039|D|differences in the incidences of pain or nausea in the 24 hours following|
01965|040|D|the procedure.(4)|
01965|041|D|   In a randomized, controlled trial in 40 surgical patients undergoing|
01965|042|D|hernioplasty or thyroidectomy, compared to tramadol alone, cumulative|
01965|043|D|tramadol consumption was higher at the 2-hour time point with concurrent|
01965|044|D|ondansetron (0.24 +/- 0.1 vs. 0.17 +/- 0.16; p = 0.01).(5)|
01965|045|D|   A systematic review and meta-analysis of randomized controlled trials in|
01965|046|D|the postoperative setting comparing tramadol alone and in combination with|
01965|047|D|ondansetron were included.  At 4-hours, 8-hours, 12-hours, and 24-hours|
01965|048|D|post-procedure, patients had increased tramadol requirements when|
01965|049|D|administered with concurrent ondansetron compared to tramadol alone.(6)|
01965|050|D|   5-HT3 antagonists linked to this monograph include: alosetron, azasetron,|
01965|051|D|dolasetron, granisetron, ondansetron, palonosetron, ramosetron, and|
01965|052|D|tropisetron.|
01965|053|B||
01965|054|R|REFERENCES:|
01965|055|B||
01965|056|R|1.Arcioni R, della Rocca M, Romano S, Romano R, Pietropaoli P, Gasparetto A.|2
01965|057|R|  Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3)|2
01965|058|R|  spinal receptor involvement in acute pain in humans. Anesth Analg 2002|2
01965|059|R|  Jun;94(6):1553-7, table of contents.|2
01965|060|R|2.De Witte JL, Schoenmaekers B, Sessler DI, Deloof T. The analgesic efficacy|2
01965|061|R|  of tramadol is impaired by concurrent administration of ondansetron.|2
01965|062|R|  Anesth Analg 2001 May;92(5):1319-21.|2
01965|063|R|3.Cubukcu Z, Ozbek H, Gunes Y, Gunduz M, Ozcengiz D, Isik G. Effect of|2
01965|064|R|  ondansetron in lower extremity bone surgery on morphine and tramadol|2
01965|065|R|  consumption using patient controlled analgesia. Agri 2007 Jan;19(1):36-41.|2
01965|066|R|4.Broome IJ, Robb HM, Raj N, Girgis Y, Wardall GJ. The use of tramadol|2
01965|067|R|  following day--case oral surgery. Anaesthesia 1999 Mar;54(3):289-92.|2
01965|068|R|5.Vale C, Oliveira F, Assuncao J, Fontes-Ribeiro C, Pereira F.|2
01965|069|R|  Co-administration of ondansetron decreases the analgesic efficacy of|2
01965|070|R|  tramadol in  humans. Pharmacology 2011;88(3-4):182-7.|2
01965|071|R|6.Stevens AJ, Woodman RJ, Owen H. The effect of ondansetron on the efficacy|6
01965|072|R|  of postoperative tramadol: a systematic review and meta-analysis of a drug|6
01965|073|R|  interaction. Anaesthesia 2015 Feb;70(2):209-18.|6
01966|001|T|MONOGRAPH TITLE:  Aripiprazole; Iloperidone/Selected Protease Inhibitors|
01966|002|T|(mono deleted 03/29/2012)|
01966|003|B||
01966|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01966|005|L|take action as needed.|
01966|006|B||
01966|007|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01966|008|A|aripiprazole(1) and iloperidone(2) by CYP P-450-3A4.|
01966|009|B||
01966|010|E|CLINICAL EFFECTS:  Concurrent administration of a protease inhibitor may|
01966|011|E|result in elevated levels of and toxicity from aripiprazole(1) and|
01966|012|E|iloperidone.(2)  Elevated levels of iloperidone may increase the risk of QTc|
01966|013|E|prolongation.(2)|
01966|014|B||
01966|015|P|PREDISPOSING FACTORS:  None determined.|
01966|016|B||
01966|017|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole states that the|
01966|018|M|dose of aripiprazole should be reduced to one-half of its normal dose when|
01966|019|M|strong inhibitors of CYP P-450-3A4 are coadministered, unless aripiprazole|
01966|020|M|is being administered as adjunctive therapy for Major Depressive Disorder.|
01966|021|M|If the strong inhibitor is discontinued, the dose of aripiprazole should be|
01966|022|M|increased.(1)|
01966|023|M|   The US manufacturer of iloperidone states that the dose of iloperidone|
01966|024|M|should be reduced to one-half of its normal dose when strong inhibitors of|
01966|025|M|CYP P-450-3A4 are coadministered.  If the strong inhibitor is discontinued,|
01966|026|M|the dose of iloperidone should be increased.(2)|
01966|027|B||
01966|028|D|DISCUSSION:  The coadministration of ketoconazole (200 mg daily for 14|
01966|029|D|days), another strong CYP P-450-3A4 inhibitor, with a single dose of|
01966|030|D|aripiprazole (15 mg) resulted in increases in the area-under-curve (AUC) of|
01966|031|D|aripiprazole and its active metabolite by 63% and 77%, respectively.(1)|
01966|032|D|   Coadministration of ketoconazole (200 mg twice daily for 4 days)|
01966|033|D|increased the AUC of iloperidone (3 mg single dose) and its P88 and P95|
01966|034|D|metabolites by 57%, 55%, and 35%, respectively.(2)|
01966|035|D|   Coadministration of ketoconazole (200 mg twice daily) and iloperidone (12|
01966|036|D|mg twice daily) was associated with a mean QTcF increase of 19 msec from|
01966|037|D|baseline, compared with an increase of 9 msec with iloperidone alone.(2)|
01966|038|B||
01966|039|R|REFERENCES:|
01966|040|B||
01966|041|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
01966|042|R|  Pharmaceutical, Inc. July, 2014.|1
01966|043|R|2.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
01966|044|R|  Inc April, 2024.|1
01967|001|T|MONOGRAPH TITLE:  Aripiprazole; Iloperidone/Nefazodone (mono deleted|
01967|002|T|03/29/2012)|
01967|003|B||
01967|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01967|005|L|take action as needed.|
01967|006|B||
01967|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of|
01967|008|A|aripiprazole(1) and iloperidone(2) by CYP P-450-3A4.|
01967|009|B||
01967|010|E|CLINICAL EFFECTS:  Concurrent administration of nefazodone may result in|
01967|011|E|elevated levels of and toxicity from aripiprazole(1) and iloperidone.(2)|
01967|012|E|Elevated levels of iloperidone may increase the risk of QTc prolongation.(2)|
01967|013|B||
01967|014|P|PREDISPOSING FACTORS:  None determined.|
01967|015|B||
01967|016|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole states that the|
01967|017|M|dose of aripiprazole should be reduced to one-half of its normal dose when|
01967|018|M|strong inhibitors of CYP P-450-3A4 are coadministered, unless aripiprazole|
01967|019|M|is being administered as adjunctive therapy for Major Depressive Disorder.|
01967|020|M|If the strong inhibitor is discontinued, the dose of aripiprazole should be|
01967|021|M|increased.(1)|
01967|022|M|   The US manufacturer of iloperidone states that the dose of iloperidone|
01967|023|M|should be reduced to one-half of its normal dose when strong inhibitors of|
01967|024|M|CYP P-450-3A4 are coadministered.  If the strong inhibitor is discontinued,|
01967|025|M|the dose of iloperidone should be increased.(2)|
01967|026|B||
01967|027|D|DISCUSSION:  The coadministration of ketoconazole (200 mg daily for 14|
01967|028|D|days), another strong CYP P-450-3A4 inhibitor, with a single dose of|
01967|029|D|aripiprazole (15 mg) resulted in increases in the area-under-curve (AUC) of|
01967|030|D|aripiprazole and its active metabolite by 63% and 77%, respectively.(1)|
01967|031|D|   Coadministration of ketoconazole (200 mg twice daily for 4 days)|
01967|032|D|increased the AUC of iloperidone (3 mg single dose) and its P88 and P95|
01967|033|D|metabolites by 57%, 55%, and 35%, respectively.(2)|
01967|034|D|   Coadministration of ketoconazole (200 mg twice daily) and iloperidone (12|
01967|035|D|mg twice daily) was associated with a mean QTcF increase of 19 msec from|
01967|036|D|baseline, compared with an increase of 9 msec with iloperidone alone.(2)|
01967|037|B||
01967|038|R|REFERENCES:|
01967|039|B||
01967|040|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
01967|041|R|  Pharmaceutical, Inc. July, 2014.|1
01967|042|R|2.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
01967|043|R|  Inc April, 2024.|1
01968|001|T|MONOGRAPH TITLE:  Iloperidone/QT Prolonging Agents|
01968|002|B||
01968|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01968|004|L|of severe adverse interaction.|
01968|005|B||
01968|006|A|MECHANISM OF ACTION:  Iloperidone has been shown to prolong the QTc interval|
01968|007|A|by 9 msec at dosages of 12 mg twice daily.  Concurrent use with other agents|
01968|008|A|that prolong the QTc interval may result in additive effects on the QTc|
01968|009|A|interval.(1)|
01968|010|B||
01968|011|E|CLINICAL EFFECTS:  The concurrent use of iloperidone with other agents that|
01968|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01968|013|E|arrhythmias, including torsades de pointes.(1)|
01968|014|B||
01968|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased in|
01968|016|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01968|017|P|infarction, history of torsades de pointes), hypokalemia, hypomagnesemia,|
01968|018|P|hypocalcemia, bradycardia, congenital prolongation of the QT interval,|
01968|019|P|female gender, advanced age and with concurrent use of inhibitors of CYP3A4|
01968|020|P|or CYP2D6, which metabolize iloperidone.|
01968|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01968|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01968|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01968|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01968|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01968|026|P|an agent which inhibits its metabolism  or elimination, genetic impairment|
01968|027|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01968|028|B||
01968|029|M|PATIENT MANAGEMENT:  The US manufacturer of iloperidone states that the|
01968|030|M|concurrent administration of other drugs that are known to prolong the QTc|
01968|031|M|interval should be avoided.  Disopyramide and procainamide should not be|
01968|032|M|used to treat iloperidone-overdose-induced arrhythmias.(1)|
01968|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01968|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01968|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01968|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01968|037|B||
01968|038|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01968|039|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01968|040|D|monograph have been shown to prolong the QTc interval either through their|
01968|041|D|mechanism of action, through studies on their effects on the QTc interval,|
01968|042|D|or through reports of QTc prolongation and/or torsades de pointes in|
01968|043|D|clinical trials and/or postmarketing reports.(2)|
01968|044|D|   Coadministration of ketoconazole (200 mg twice daily, an inhibitor of|
01968|045|D|CYP3A4) and iloperidone (12|
01968|046|D|mg twice daily) was associated with a mean QTcF increase of 19 msec from|
01968|047|D|baseline, compared with an increase of 9 msec with iloperidone alone.(1)|
01968|048|D|   Coadministration of paroxetine (20 mg daily, an inhibitor of CYP2D6) and|
01968|049|D|iloperidone (12 mg twice daily) was associated with a mean QTcF increase of|
01968|050|D|19 msec from baseline, compared with an increase of 9 msec with iloperidone|
01968|051|D|alone.(1)|
01968|052|B||
01968|053|R|REFERENCES:|
01968|054|B||
01968|055|R|1.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
01968|056|R|  Inc May, 2016.|1
01968|057|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01968|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01968|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01968|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01968|061|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01968|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01968|063|R|  settings: a scientific statement from the American Heart Association and|6
01968|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01968|065|R|  2;55(9):934-47.|6
01969|001|T|MONOGRAPH TITLE:  Iloperidone/Possible QT Prolonging Agents|
01969|002|B||
01969|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01969|004|L|take action as needed.|
01969|005|B||
01969|006|A|MECHANISM OF ACTION:  Iloperidone has been shown to prolong the QTc interval|
01969|007|A|by 9 msec at dosages of 12 mg twice daily.  Concurrent use with other agents|
01969|008|A|that prolong the QTc interval may result in additive effects on the QTc|
01969|009|A|interval.(1)|
01969|010|B||
01969|011|E|CLINICAL EFFECTS:  The concurrent use of iloperidone with other agents that|
01969|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01969|013|E|arrhythmias, including torsades de pointes.(1)|
01969|014|B||
01969|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased in|
01969|016|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
01969|017|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
01969|018|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender,|
01969|019|P|advanced age or with concurrent use of inhibitors of CYP3A4 or CYP2D6, which|
01969|020|P|metabolize iloperidone.(1,3)|
01969|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01969|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01969|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01969|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01969|025|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
01969|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01969|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
01969|028|B||
01969|029|M|PATIENT MANAGEMENT:  The US manufacturer of iloperidone states that the|
01969|030|M|concurrent administration of other drugs that are known to prolong the QTc|
01969|031|M|interval should be avoided.(1)|
01969|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01969|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01969|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01969|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01969|036|B||
01969|037|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01969|038|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01969|039|D|monograph have been shown to prolong the QTc interval either through their|
01969|040|D|mechanism of action, through studies on their effects on the QTc interval,|
01969|041|D|or through reports of QTc prolongation and/or torsades de pointes in|
01969|042|D|clinical trials and/or postmarketing reports.(2)|
01969|043|D|   Coadministration of ketoconazole (200 mg twice daily, an inhibitor of CYP|
01969|044|D|P-450-3A4) and iloperidone (12|
01969|045|D|mg twice daily) was associated with a mean QTcF increase of 19 msec from|
01969|046|D|baseline, compared with an increase of 9 msec with iloperidone alone.(1)|
01969|047|D|   Coadministration of paroxetine (20 mg daily, an inhibitor of CYP|
01969|048|D|P-450-2D6) and iloperidone (12 mg twice daily) was associated with a mean|
01969|049|D|QTcF increase of 19 msec from baseline, compared with an increase of 9 msec|
01969|050|D|with iloperidone alone.(1)|
01969|051|B||
01969|052|R|REFERENCES:|
01969|053|B||
01969|054|R|1.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
01969|055|R|  Inc May, 2016.|1
01969|056|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01969|057|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01969|058|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01969|059|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01969|060|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01969|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01969|062|R|  settings: a scientific statement from the American Heart Association and|6
01969|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01969|064|R|  2;55(9):934-47.|6
01970|001|T|MONOGRAPH TITLE:  Iloperidone/Strong CYP2D6 Inhibitors that Prolong QT|
01970|002|B||
01970|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01970|004|L|of severe adverse interaction.|
01970|005|B||
01970|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors that prolong QT may inhibit|
01970|007|A|the metabolism of iloperidone by CYP2D6 and may result in additive effects|
01970|008|A|on the QTc interval.(1)|
01970|009|B||
01970|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
01970|011|E|toxicity from iloperidone, including potentially life-threatening cardiac|
01970|012|E|arrhythmias, such as torsades de pointes.(1)|
01970|013|B||
01970|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01970|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01970|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01970|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01970|018|P|female gender, advanced age, or concurrent use of inhibitors of CYP3A4 or|
01970|019|P|CYP2D6, which metabolize iloperidone.(2)|
01970|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01970|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01970|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01970|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01970|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01970|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01970|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
01970|027|B||
01970|028|M|PATIENT MANAGEMENT:  The US manufacturer of iloperidone states that the|
01970|029|M|concurrent administration of other drugs that are known to prolong the QTc|
01970|030|M|interval should be avoided.  Additionally, quinidine should not be used to|
01970|031|M|treat iloperidone-overdose-induced arrhythmias.(1)|
01970|032|M|   If a strong CYP2D6 inhibitor is used concurrently, the dose of|
01970|033|M|iloperidone should be reduced to one-half of its normal dose.  When|
01970|034|M|quinidine is discontinued, the dose of iloperidone should be increased.(1)|
01970|035|M|   Concurrent administration of iloperidone with both a CYP2D6 inhibitor and|
01970|036|M|CYP3A4 inhibitor should be reduced to one-half of its normal dose, and|
01970|037|M|further dose reduction is not required.(1)|
01970|038|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01970|039|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01970|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01970|041|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01970|042|B||
01970|043|D|DISCUSSION:  In a study in patients with schizophrenia, paroxetine (20 mg|
01970|044|D|daily for 5-8 days, a strong inhibitor of CYP2D6) increased the maximum|
01970|045|D|concentration (Cmax) of iloperidone and its P88 metabolite by about|
01970|046|D|1.6-fold.  The Cmax of iloperidone's P95 metabolite decreased by 50%.(1)|
01970|047|D|   Coadministration of paroxetine (20 mg daily) and iloperidone (12 mg twice|
01970|048|D|daily) was associated with a mean QTcF increase of 19 msec from baseline,|
01970|049|D|compared with an increase of 9 msec with iloperidone alone.(1)|
01970|050|D|   In a study in 23 healthy subjects, fluoxetine (20 mg twice daily for 21|
01970|051|D|days, a strong inhibitor of CYP2D6) increased the AUC of iloperidone (3 mg|
01970|052|D|single dose) and its P88 metabolite by 2-3-fold.  The AUC of iloperidone's|
01970|053|D|P95 metabolite decreased by 50%.(2)|
01970|054|D|   Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did|
01970|055|D|not increase the effects on iloperidone compared with either agent alone.(1)|
01970|056|D|   Strong CYP2D6 inhibitors that prolong the QTc interval linked to this|
01970|057|D|monograph include: quinidine.(3,4)|
01970|058|B||
01970|059|R|REFERENCES:|
01970|060|B||
01970|061|R|1.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
01970|062|R|  Inc May, 2016.|1
01970|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01970|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01970|065|R|  settings: a scientific statement from the American Heart Association and|6
01970|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01970|067|R|  2;55(9):934-47.|6
01970|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
01970|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01970|070|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
01970|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01970|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01970|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01970|074|R|  11/14/2017.|1
01971|001|T|MONOGRAPH TITLE:  Salmeterol/Selected Strong CYP3A4 Inhibitors|
01971|002|B||
01971|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01971|004|L|of severe adverse interaction.|
01971|005|B||
01971|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
01971|007|A|the portion of salmeterol that is swallowed, resulting in significant|
01971|008|A|systemic absorption.(1)  An in vitro study showed that ketoconazole|
01971|009|A|completely inhibited the formation of alpha-hydroxysalmeterol by|
01971|010|A|CYP3A4.(1,2)|
01971|011|B||
01971|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
01971|013|E|systemic effects of salmeterol, including QTc prolongation, palpitations,|
01971|014|E|and sinus tachycardia.(1)|
01971|015|B||
01971|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01971|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
01971|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01971|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01971|020|P|female gender, or advanced age.(4)|
01971|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01971|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01971|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01971|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01971|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01971|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01971|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01971|028|B||
01971|029|M|PATIENT MANAGEMENT:  The US manufacturer states that the concurrent use of|
01971|030|M|salmeterol with strong inhibitors of CYP3A4 is not recommended.(1)  The|
01971|031|M|Canadian manufacturer of salmeterol states that concurrent use of|
01971|032|M|itraconazole should be approached with caution.(2)|
01971|033|M|   The US manufacturer of itraconazole states that concurrent administration|
01971|034|M|with salmeterol is not recommended during and two weeks after itraconazole|
01971|035|M|treatment.(5)|
01971|036|M|   Consider the use of alternative agents.  Advise patients to rinse their|
01971|037|M|mouth thoroughly after administering salmeterol to limit the amount of|
01971|038|M|salmeterol that is swallowed.|
01971|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01971|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01971|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01971|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01971|043|B||
01971|044|D|DISCUSSION:  In a study in 20 healthy subjects, concurrent administration of|
01971|045|D|salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily) for 7|
01971|046|D|days increased the plasma area-under-curve (AUC) and maximum concentration|
01971|047|D|(Cmax) of salmeterol 16-fold and 1.4-fold, respectively.  Concurrent use did|
01971|048|D|not result in clinically significant changes in heart rate, mean blood|
01971|049|D|potassium, mean blood glucose or mean QTc; however, concurrent use was|
01971|050|D|associated with more frequent increases in QTc duration.  Three subjects|
01971|051|D|were withdrawn from the study because of systemic salmeterol effects (2 with|
01971|052|D|QTc prolongation and 1 with palpitations and sinus tachycardia).(1)|
01971|053|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
01971|054|D|ceritinib, clarithromycin, idelalisib, itraconazole, josamycin,|
01971|055|D|ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone,|
01971|056|D|posaconazole, ribociclib, telithromycin, troleandomycin, tucatinib, and|
01971|057|D|voriconazole.(6,7)|
01971|058|B||
01971|059|R|REFERENCES:|
01971|060|B||
01971|061|R|1.Serevent Diskus (salmeterol xinafoate) US prescribing information.|1
01971|062|R|  SmithKline Beecham Corporation December, 2010.|1
01971|063|R|2.Manchee GR, Eddershaw PJ, Ranshaw LE, Herriott D, Park GR, Bayliss MK,|5
01971|064|R|  Tarbit MH. The aliphatic oxidation of salmeterol to|5
01971|065|R|  alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A.|5
01971|066|R|  Drug Metab Dispos 1996 May;24(5):555-9.|5
01971|067|R|3.Advair (fluticasone propionate/salmeterol) Canadian prescribing|1
01971|068|R|  information. GlaxoSmithKline May 20, 2011.|1
01971|069|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01971|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01971|071|R|  settings: a scientific statement from the American Heart Association and|6
01971|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01971|073|R|  2;55(9):934-47.|6
01971|074|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
01971|075|R|  Products, L.P. February, 2024.|1
01971|076|R|6.This information is based on an extract from the Certara Drug Interaction|6
01971|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01971|078|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
01971|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01971|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01971|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01971|082|R|  11/14/2017.|1
01972|001|T|MONOGRAPH TITLE:  Salmeterol/Cobicistat; Protease Inhibitors|
01972|002|B||
01972|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01972|004|L|of severe adverse interaction.|
01972|005|B||
01972|006|A|MECHANISM OF ACTION:  Some protease inhibitors may inhibit the metabolism of|
01972|007|A|the portion of salmeterol that is swallowed, resulting in significant|
01972|008|A|systemic absorption.(1-14)|
01972|009|B||
01972|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4, such as|
01972|011|E|atazanavir, boceprevir, cobicistat, darunavir, fosamprenavir, indinavir,|
01972|012|E|lopinavir, nelfinavir, nirmatrelvir, saquinavir, telaprevir and tipranavir|
01972|013|E|may result in systemic effects of salmeterol, including QTc prolongation,|
01972|014|E|palpitations, and sinus tachycardia.(1-14)|
01972|015|B||
01972|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01972|017|P|may be increased in patients with cardiovascular disease (e.g heart failure,|
01972|018|P|myocardial infarction, history of torsades de pointes, congenital long QT|
01972|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01972|020|P|gender, or advanced age.(15)|
01972|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01972|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01972|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01972|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01972|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01972|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01972|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(15)|
01972|028|B||
01972|029|M|PATIENT MANAGEMENT:  The US manufacturers of salmeterol and the protease|
01972|030|M|inhibitors state that the concurrent use of salmeterol with HCV or HIV|
01972|031|M|protease inhibitors is not recommended.(1-14)  The National Institutes of|
01972|032|M|Health COVID-19 treatment guidelines recommend holding salmeterol during and|
01972|033|M|for at least 2-3 days after completion of nirmatrelvir/ritonavir|
01972|034|M|therapy.(16)|
01972|035|M|   The Canadian manufacturer of salmeterol states that concurrent use of|
01972|036|M|atazanavir, indinavir, nelfinavir, ritonavir, and saquinavir is not|
01972|037|M|recommended.(17)  Canadian labeling contraindicates concurrent use of|
01972|038|M|atazanavir/ritonavir, darunavir/cobicistat, and lopinavir/ritonavir with|
01972|039|M|salmeterol.(19-22)|
01972|040|M|   Consider the use of alternative agents.  Advise patients receiving|
01972|041|M|concurrent therapy to rinse their mouth thoroughly after administering|
01972|042|M|salmeterol to limit the amount of salmeterol that is swallowed.|
01972|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01972|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01972|045|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01972|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01972|047|M|   Protease inhibitors linked to this monograph include: amprenavir,|
01972|048|M|atazanavir, boceprevir, cobicistat, darunavir, fosamprenavir, indinavir,|
01972|049|M|lopinavir, nelfinavir, nirmatrelvir, saquinavir, telaprevir, and tipranavir.|
01972|050|B||
01972|051|D|DISCUSSION:  In a study in 20 healthy subjects, concurrent administration of|
01972|052|D|salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily, a|
01972|053|D|strong inhibitor of CYP3A4) for 7 days increased the plasma area-under-curve|
01972|054|D|(AUC) and maximum concentration (Cmax) of salmeterol 16-fold and 1.4-fold,|
01972|055|D|respectively.  Concurrent use did not result in clinically significant|
01972|056|D|changes in heart rate, mean blood potassium, mean blood glucose or mean QTc;|
01972|057|D|however, concurrent use was associated with more frequent increases in QTc|
01972|058|D|duration.  Three subjects were withdrawn from the study because of systemic|
01972|059|D|salmeterol effects (2 with QTc prolongation and 1 with palpitations and|
01972|060|D|sinus tachycardia).(1)|
01972|061|D|   An in vitro study showed that ketoconazole completely inhibited the|
01972|062|D|formation of alpha-hydroxysalmeterol by CYP3A4.(1,23)|
01972|063|B||
01972|064|R|REFERENCES:|
01972|065|B||
01972|066|R|1.Serevent Diskus (salmeterol xinafoate) US prescribing information.|1
01972|067|R|  SmithKline Beecham Corporation December, 2010.|1
01972|068|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01972|069|R|  Squibb Company December, 2024.|1
01972|070|R|3.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
01972|071|R|  January, 2017.|1
01972|072|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01972|073|R|  March, 2023.|1
01972|074|R|5.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01972|075|R|  March, 2019.|1
01972|076|R|6.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01972|077|R|  September, 2016.|1
01972|078|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01972|079|R|  Laboratories December, 2019.|1
01972|080|R|8.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01972|081|R|  Pharmaceuticals, Inc. September, 2016.|1
01972|082|R|9.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01972|083|R|  December, 2019.|1
01972|084|R|10.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01972|085|R|   Laboratories, Inc. March, 2019.|1
01972|086|R|11.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
01972|087|R|   Incorporated October, 2013.|1
01972|088|R|12.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01972|089|R|   Pharmaceuticals, Inc. April, 2024.|1
01972|090|R|13.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
01972|091|R|   June, 2025.|1
01972|092|R|14.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01972|093|R|   information. Pfizer Inc. February, 2025.|1
01972|094|R|15.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
01972|095|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
01972|096|R|   hospital settings: a scientific statement from the American Heart|6
01972|097|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
01972|098|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
01972|099|R|16.National Institutes of Health. COVID-19 Treatment Guidelines Panel.|6
01972|100|R|   Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Available at|6
01972|101|R|   https://www.covid19treatmentguidelines.nih.gov/ Accessed July 5, 2022.|6
01972|102|R|17.Advair (fluticasone propionate/salmeterol) Canadian prescribing|1
01972|103|R|   information. GlaxoSmithKline May 20, 2011.|1
01972|104|R|18.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
01972|105|R|   Monograph. Pfizer Canada ULC October, 2023.|1
01972|106|R|19.Kaletra (lopinavir/ritonavir) Canadian prescribing information. Abbott|1
01972|107|R|   Limited May 22, 2019.|1
01972|108|R|20.Norvir (ritonavir) Canadian prescribing information. Abbott May 29, 2019.|1
01972|109|R|21.Reyataz (atazanavir) Canadian prescribing information. Bristol-Myers|1
01972|110|R|   Squibb Canada August 31, 2023.|1
01972|111|R|22.Prezcobix (darunavir-cobicistat) Canadian prescribing information.|1
01972|112|R|   Janssen Inc. June 18, 2014.|1
01972|113|R|23.Manchee GR, Eddershaw PJ, Ranshaw LE, Herriott D, Park GR, Bayliss MK,|5
01972|114|R|   Tarbit MH. The aliphatic oxidation of salmeterol to|5
01972|115|R|   alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A.|5
01972|116|R|   Drug Metab Dispos 1996 May;24(5):555-9.|5
01973|001|T|MONOGRAPH TITLE:  Salmeterol/Clarithromycin; Telithromycin (mono deleted|
01973|002|T|02/17/2023)|
01973|003|B||
01973|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01973|005|L|of severe adverse interaction.|
01973|006|B||
01973|007|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
01973|008|A|metabolism of the portion of salmeterol that is swallowed, resulting in|
01973|009|A|significant systemic absorption.(1)|
01973|010|B||
01973|011|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4, such as|
01973|012|E|clarithromycin or telithromycin, may result in systemic effects of|
01973|013|E|salmeterol, including QTc prolongation, palpitations, and sinus|
01973|014|E|tachycardia.(1)|
01973|015|B||
01973|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01973|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
01973|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01973|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01973|020|P|female gender, or advanced age.(4)|
01973|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01973|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01973|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01973|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01973|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01973|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01973|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01973|028|B||
01973|029|M|PATIENT MANAGEMENT:  The US manufacturer states that the concurrent use of|
01973|030|M|salmeterol with strong inhibitors of CYP3A4, such as clarithromycin or|
01973|031|M|telithromycin, is not recommended.(1)  The Canadian manufacturer of|
01973|032|M|salmeterol states that concurrent use of clarithromycin and telithromycin|
01973|033|M|should be approached with caution.(2)|
01973|034|M|   Consider the use of alternative agents.  Advise patients to rinse their|
01973|035|M|mouth thoroughly after administering salmeterol to limit the amount of|
01973|036|M|salmeterol that is swallowed.|
01973|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01973|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01973|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01973|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01973|041|B||
01973|042|D|DISCUSSION:  In a study in 20 healthy subjects, concurrent administration of|
01973|043|D|salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily, a|
01973|044|D|strong inhibitor of CYP3A4) for 7 days increased the plasma area-under-curve|
01973|045|D|(AUC) and maximum concentration (Cmax) of salmeterol 16-fold and 1.4-fold,|
01973|046|D|respectively.  Concurrent use did not result in clinically significant|
01973|047|D|changes in heart rate, mean blood potassium, mean blood glucose or mean QTc;|
01973|048|D|however, concurrent use was associated with more frequent increases in QTc|
01973|049|D|duration.  Three subjects were withdrawn from the study because of systemic|
01973|050|D|salmeterol effects (2 with QTc prolongation and 1 with palpitations and|
01973|051|D|sinus tachycardia).(1)|
01973|052|D|   An in vitro study showed that ketoconazole completely inhibited the|
01973|053|D|formation of alpha-hydroxysalmeterol by CYP3A4.(1,3)|
01973|054|B||
01973|055|R|REFERENCES:|
01973|056|B||
01973|057|R|1.Serevent Diskus (salmeterol xinafoate) US prescribing information.|1
01973|058|R|  SmithKline Beecham Corporation December, 2010.|1
01973|059|R|2.Advair (fluticasone propionate/salmeterol) Canadian prescribing|1
01973|060|R|  information. GlaxoSmithKline May 20, 2011.|1
01973|061|R|3.Manchee GR, Eddershaw PJ, Ranshaw LE, Herriott D, Park GR, Bayliss MK,|5
01973|062|R|  Tarbit MH. The aliphatic oxidation of salmeterol to|5
01973|063|R|  alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A.|5
01973|064|R|  Drug Metab Dispos 1996 May;24(5):555-9.|5
01973|065|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01973|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01973|067|R|  settings: a scientific statement from the American Heart Association and|6
01973|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01973|069|R|  2;55(9):934-47.|6
01974|001|T|MONOGRAPH TITLE:  Salmeterol/Nefazodone (mono deleted 02/17/2023)|
01974|002|B||
01974|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01974|004|L|of severe adverse interaction.|
01974|005|B||
01974|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of the portion|
01974|007|A|of salmeterol that is swallowed, resulting in significant systemic|
01974|008|A|absorption.(1)|
01974|009|B||
01974|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4, such as|
01974|011|E|nefazodone, may result in systemic effects of salmeterol, including QTc|
01974|012|E|prolongation, palpitations, and sinus tachycardia.(1)|
01974|013|B||
01974|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
01974|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
01974|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
01974|017|P|long QT syndrome),hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
01974|018|P|female gender, or advanced age.(4)|
01974|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01974|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01974|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
01974|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01974|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01974|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
01974|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
01974|026|B||
01974|027|M|PATIENT MANAGEMENT:  The US manufacturer states that the concurrent use of|
01974|028|M|salmeterol with strong inhibitors of CYP3A4, such as nefazodone, is not|
01974|029|M|recommended.(1)  The Canadian manufacturer of salmeterol states that|
01974|030|M|concurrent use of nefazodone should be approached with caution.(2)|
01974|031|M|   Consider the use of alternative agents.  Advise patients to rinse their|
01974|032|M|mouth thoroughly after administering salmeterol to limit the amount of|
01974|033|M|salmeterol that is swallowed.|
01974|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01974|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01974|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01974|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01974|038|B||
01974|039|D|DISCUSSION:  In a study in 20 healthy subjects, concurrent administration of|
01974|040|D|salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily, a|
01974|041|D|strong inhibitor of CYP3A4) for 7 days increased the plasma area-under-curve|
01974|042|D|(AUC) and maximum concentration (Cmax) of salmeterol 16-fold and 1.4-fold,|
01974|043|D|respectively.  Concurrent use did not result in clinically significant|
01974|044|D|changes in heart rate, mean blood potassium, mean blood glucose or mean QTc;|
01974|045|D|however, concurrent use was associated with more frequent increases in QTc|
01974|046|D|duration.  Three subjects were withdrawn from the study because of systemic|
01974|047|D|salmeterol effects (2 with QTc prolongation and 1 with palpitations and|
01974|048|D|sinus tachycardia).(1)|
01974|049|D|   An in vitro study showed that ketoconazole completely inhibited the|
01974|050|D|formation of alpha-hydroxysalmeterol by CYP3A4.(1,3)|
01974|051|B||
01974|052|R|REFERENCES:|
01974|053|B||
01974|054|R|1.Serevent Diskus (salmeterol xinafoate) US prescribing information.|1
01974|055|R|  SmithKline Beecham Corporation December, 2010.|1
01974|056|R|2.Advair (fluticasone propionate/salmeterol) Canadian prescribing|1
01974|057|R|  information. GlaxoSmithKline May 20, 2011.|1
01974|058|R|3.Manchee GR, Eddershaw PJ, Ranshaw LE, Herriott D, Park GR, Bayliss MK,|5
01974|059|R|  Tarbit MH. The aliphatic oxidation of salmeterol to|5
01974|060|R|  alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A.|5
01974|061|R|  Drug Metab Dispos 1996 May;24(5):555-9.|5
01974|062|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01974|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01974|064|R|  settings: a scientific statement from the American Heart Association and|6
01974|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01974|066|R|  2;55(9):934-47.|6
01975|001|T|MONOGRAPH TITLE:  COMT Inhibitors/Rasagiline; Oral Selegiline|
01975|002|B||
01975|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01975|004|L|take action as needed.|
01975|005|B||
01975|006|A|MECHANISM OF ACTION:  Since MAOIs and COMT are the two major enzymes|
01975|007|A|responsible for the metabolism of catecholamines, the combination of|
01975|008|A|entacapone, tolcapone, or opicapone and a non-selective MAOI may inhibit the|
01975|009|A|majority of catecholamine metabolism pathways.(1-3)|
01975|010|B||
01975|011|E|CLINICAL EFFECTS:  Concurrent administration of entacapone, tolcapone, or|
01975|012|E|opicapone with a non-selective MAOI may result in elevated levels of|
01975|013|E|catecholamines, which may result in elevated heart rate and blood pressure.|
01975|014|B||
01975|015|P|PREDISPOSING FACTORS:  None determined.|
01975|016|B||
01975|017|M|PATIENT MANAGEMENT:  Entacapone(1,4), tolcapone(5), and opicapone(9,10)|
01975|018|M|should not be used with either a non-selective MAOI or the combination of a|
01975|019|M|selective MAO-A inhibitor and a selective MAO-B inhibitor.  Nonselective|
01975|020|M|MAOIs should be discontinued at least 2 weeks prior to initiating COMT|
01975|021|M|inhibitor therapy.|
01975|022|M|   Entacapone, tolcapone, or opicapone may be used with oral selegiline,|
01975|023|M|provided that the daily dose of selegiline does not exceed 10 mg, and with|
01975|024|M|rasagiline, provided that the daily dose of rasagiline does not exceed 1 mg,|
01975|025|M|and that patients are not also receiving a selective MAO-A inhibitor.|
01975|026|B||
01975|027|D|DISCUSSION:  Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)|
01975|028|D|are the two major enzymes systems involved in the metabolism of|
01975|029|D|catecholamines.  Therefore, theoretically, the combination of either|
01975|030|D|entacapone or tolcapone with a non-selective MAO inhibitor will result in|
01975|031|D|inhibition of the majority of catecholamine metabolism pathways.(1,2)|
01975|032|D|   Rasagiline is selective for MAO-B in humans at recommended dosages of 1|
01975|033|D|mg per day or less.(6)  Rasagiline has been used with entacapone in clinical|
01975|034|D|trials with no reports of adverse effects.(6) Concurrent administration of|
01975|035|D|rasagiline and entacapone increased rasagiline oral clearance by 28%.(7)|
01975|036|D|   At daily doses of 10 mg, selegiline is primarily a selective MAO-B|
01975|037|D|inhibitor; however, at higher doses, selegiline is capable of inhibiting|
01975|038|D|MAO-A.(8)|
01975|039|B||
01975|040|R|REFERENCES:|
01975|041|B||
01975|042|R|1.Comtess (entacapone) UK summary of product characteristics. Orion Pharma,|1
01975|043|R|  UK September 16, 1998.|1
01975|044|R|2.Tasmar (tolcapone) US prescribing information. Valeant Pharmaceuticals|1
01975|045|R|  International May, 2013.|1
01975|046|R|3.Comtan (entacapone) US prescribing information. Orion Corporation|1
01975|047|R|  February, 2016.|1
01975|048|R|4.Comtan (entacapone) Canadian prescribing information. Novartis|1
01975|049|R|  Pharmaceuticals Canada Inc. March, 2006.|1
01975|050|R|5.Tasmar (tolcapone) UK summary of product characteristics. Valeant|1
01975|051|R|  Pharmaceuticals Ltd. Januar 11, 2006.|1
01975|052|R|6.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
01975|053|R|  June, 2020.|1
01975|054|R|7.A randomized placebo-controlled trial of rasagiline in levodopa-treated|2
01975|055|R|  patients with Parkinson disease and motor fluctuations: the PRESTO study.|2
01975|056|R|  Arch Neurol 2005 Feb;62(2):241-8.|2
01975|057|R|8.Eldepryl (selegiline) US prescribing information. Somerset Pharmaceuticals|1
01975|058|R|  February, 1997.|1
01975|059|R|9.Ongentys (opicapone) Middle East prescribing information. Bial-Portela and|1
01975|060|R|  Ca, S.A. 2018.|1
01975|061|R|10.Ongentys (opicapone) US prescribing information. Neurocrine Biosciences,|1
01975|062|R|   Inc. April, 2020.|1
01976|001|T|MONOGRAPH TITLE:  Ursodiol/Bile Acid Sequestrants|
01976|002|B||
01976|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01976|004|L|take action as needed.|
01976|005|B||
01976|006|A|MECHANISM OF ACTION:  Bile acid sequestrants may bind to ursodiol in the|
01976|007|A|gastrointestinal tract, preventing its absorption.(1)|
01976|008|B||
01976|009|E|CLINICAL EFFECTS:  Simultaneously administering ursodiol and a bile acid|
01976|010|E|sequestrant may decrease the effectiveness of ursodiol.(1)|
01976|011|B||
01976|012|P|PREDISPOSING FACTORS:  None determined.|
01976|013|B||
01976|014|M|PATIENT MANAGEMENT:  Separate the administration time of ursodiol and bile|
01976|015|M|acid sequestrants by as much time as possible.(2)|
01976|016|B||
01976|017|D|DISCUSSION:  In a study in 5 healthy subjects, simultaneous administration|
01976|018|D|of cholestyramine (4 grams daily) and ursodiol (12.5 mg/kg daily) decreased|
01976|019|D|ursodiol levels by 60%.  Separation of the dosage times by 5 hours decreased|
01976|020|D|this effect.(2)|
01976|021|D|   In a study in 5 healthy subjects, simultaneous administration of|
01976|022|D|colestimide (1.5 grams) and ursodiol (200 mg) decreased ursodiol by more|
01976|023|D|than 50% in 4 of the 5 subjects.(3)|
01976|024|B||
01976|025|R|REFERENCES:|
01976|026|B||
01976|027|R|1.Urso (ursodiol) US prescribing information. Aptalis Pharma US, Inc June,|1
01976|028|R|  2013.|1
01976|029|R|2.Rust C, Sauter GH, Oswald M, Buttner J, Kullak-Ublick GA, Paumgartner G,|2
01976|030|R|  Beuers U. Effect of cholestyramine on bile acid pattern and synthesis|2
01976|031|R|  during administration of ursodeoxycholic acid in man. Eur J Clin Invest|2
01976|032|R|  2000 Feb;30(2):135-9.|2
01976|033|R|3.Takikawa H, Ogasawara T, Sato A, Ohashi M, Hasegawa Y, Hojo M. Effect of|2
01976|034|R|  colestimide on intestinal absorption of ursodeoxycholic acid in men. Int J|2
01976|035|R|  Clin Pharmacol Ther 2001 Dec;39(12):558-60.|2
01977|001|T|MONOGRAPH TITLE:  Certolizumab/Rituximab|
01977|002|B||
01977|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01977|004|L|of severe adverse interaction.|
01977|005|B||
01977|006|A|MECHANISM OF ACTION:  Possibly additive or synergistic effects on the immune|
01977|007|A|system.|
01977|008|B||
01977|009|E|CLINICAL EFFECTS:  Concurrent use of certolizumab and rituximab may increase|
01977|010|E|the risk of severe infection and/or neutropenia without providing any|
01977|011|E|clinical benefit.(1)|
01977|012|B||
01977|013|P|PREDISPOSING FACTORS:  None determined.|
01977|014|B||
01977|015|M|PATIENT MANAGEMENT:  The US manufacturer of certolizumab states that|
01977|016|M|concurrent therapy with rituximab is not recommended.(1)  Patients receiving|
01977|017|M|concurrent therapy should be closely monitored for signs of infection and|
01977|018|M|neutropenia.|
01977|019|B||
01977|020|D|DISCUSSION:  Preliminary data suggest a higher rate of serious infections|
01977|021|D|(7%) in patients treated concurrently with anakinra and etanercept compared|
01977|022|D|to when anakinra is administered alone (2%)(2) or when etanercept is|
01977|023|D|administered alone (0%).(3,4)  The most common infections were bacterial|
01977|024|D|pneumonia (4 cases) and cellulitis (4 cases).  One patient with pulmonary|
01977|025|D|fibrosis and pneumonia died from respiratory failure.(5)  Preliminary data|
01977|026|D|also suggest a higher rate of neutropenia (2-3%) when anakinra is|
01977|027|D|administered with etanercept.(2,3)  Data also suggest that the combination|
01977|028|D|provides no added clinical benefit.(5)|
01977|029|D|   Similar effects are expected with the combination of certolizumab and|
01977|030|D|rituximab.(1)|
01977|031|B||
01977|032|R|REFERENCES:|
01977|033|B||
01977|034|R|1.Cimzia (certolizumab pegol) US prescribing information. UCB, Inc.|1
01977|035|R|  February, 2019.|1
01977|036|R|2.Kineret (anakinra) US prescribing information. Amgen Inc. May, 2016.|1
01977|037|R|3.Simponi (golimumab) US prescribing information. Centocor Ortho Biotech|1
01977|038|R|  Inc. March, 2018.|1
01977|039|R|4.Arcalyst (rilonacept) US prescribing information. Regeneron|1
01977|040|R|  Pharmaceuticals, Inc. March, 2021.|1
01977|041|R|5.Enbrel (etanercept) US prescribing information. Amgen December, 2023.|1
01978|001|T|MONOGRAPH TITLE:  Sildenafil (for PAH)/HIV Protease Inhibitors; Cobicistat|
01978|002|B||
01978|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01978|004|L|is contraindicated and generally should not be dispensed or administered to|
01978|005|L|the same patient.|
01978|006|B||
01978|007|A|MECHANISM OF ACTION:  The metabolism of sildenafil by CYP3A4 may be|
01978|008|A|inhibited by the protease inhibitors and cobicistat.|
01978|009|B||
01978|010|E|CLINICAL EFFECTS:  The concurrent administration of sildenafil with a|
01978|011|E|protease inhibitor or cobicistat may result in elevated levels of|
01978|012|E|sildenafil, which may result in increased adverse effects such as|
01978|013|E|hypotension, syncope, visual changes, and priapism.|
01978|014|B||
01978|015|P|PREDISPOSING FACTORS:  None determined.|
01978|016|B||
01978|017|M|PATIENT MANAGEMENT:  The US manufacturers of atazanavir,(1) darunavir,(2)|
01978|018|M|fosamprenavir,(3) indinavir,(4) lopinavir/ritonavir,(5) nelfinavir,(6)|
01978|019|M|nirmatrelvir/ritonavir,(7) saquinavir,(9) tipranavir,(10) cobicistat(11),|
01978|020|M|and ombitasvir-paritaprevir-ritonavir-dasabuvir(15) state that the|
01978|021|M|concurrent use of sildenafil when used for the treatment of pulmonary|
01978|022|M|arterial hypertension (PAH) is contraindicated.|
01978|023|M|   The US manufacturer of Revatio states that concurrent use is not|
01978|024|M|recommended.(12)|
01978|025|B||
01978|026|D|DISCUSSION:  In a study in 16 subjects, administration of|
01978|027|D|darunavir/ritonavir (400/100 mg twice daily) decreased the area-under-curve|
01978|028|D|(AUC) and maximum concentration (Cmax) of a single dose of sildenafil (25|
01978|029|D|mg) by 38% and 3%, respectively, when compared to the administration of a|
01978|030|D|100 mg single dose of sildenafil given without darunavir.(3)|
01978|031|D|   In a study in 6 HIV-infected males, indinavir (800 mg every 8 hours)|
01978|032|D|increased the AUC and Cmax of indinavir by 11% and 48%, respectively.|
01978|033|D|Sildenafil AUC increased by 340%.(4)|
01978|034|D|   The concurrent administration of ritonavir (400 mg twice daily) at steady|
01978|035|D|state with sildenafil (100 mg single dose) resulted in increases in the|
01978|036|D|sildenafil Cmax and AUC by 300% (4-fold) and 1000% (11-fold),|
01978|037|D|respectively.(7,12-14)  After 24 hours, plasma levels of sildenafil were|
01978|038|D|still approximately 200 ng/ml (normally 5 ng/ml 24 hours post-dose).(14)|
01978|039|D|   In a study in 27 healthy volunteers, the concurrent use of saquinavir|
01978|040|D|(1200 mg 3 times daily for 8 days) increased the AUC and Cmax of a single|
01978|041|D|dose of sildenafil (100 mg) by 210% and 140%, respectively.(9)|
01978|042|D|   Because a safe and effective dosage regimen for the use of sildenafil for|
01978|043|D|PAH with concurrent protease inhibitor therapy has not been determined, the|
01978|044|D|US manufacturer of the protease inhibitors state that concurrent use is|
01978|045|D|contraindicated.(1-10,15)|
01978|046|B||
01978|047|R|REFERENCES:|
01978|048|B||
01978|049|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01978|050|R|  Squibb Company December, 2024.|1
01978|051|R|2.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01978|052|R|  March, 2023.|1
01978|053|R|3.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01978|054|R|  March, 2019.|1
01978|055|R|4.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01978|056|R|  September, 2016.|1
01978|057|R|5.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01978|058|R|  Laboratories December, 2019.|1
01978|059|R|6.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01978|060|R|  Pharmaceuticals, Inc. September, 2016.|1
01978|061|R|7.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01978|062|R|  information. Pfizer Inc. February, 2025.|1
01978|063|R|8.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01978|064|R|  December, 2019.|1
01978|065|R|9.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01978|066|R|  Laboratories, Inc. March, 2019.|1
01978|067|R|10.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01978|068|R|   Pharmaceuticals, Inc. April, 2024.|1
01978|069|R|11.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
01978|070|R|   prescribing information. Gilead Sciences, Inc. September, 2021.|1
01978|071|R|12.Revatio (sildenafil citrate) US prescribing information. Viatris January,|1
01978|072|R|   2023.|1
01978|073|R|13.Back DJ. Re: 'Pharmacokinetic interactions between sildenafil and|2
01978|074|R|   saquinavir/ritonavir'. Br J Clin Pharmacol 2000 Aug;50(2):85.|2
01978|075|R|14.Viagra (sildenafil) US prescribing information. Pfizer Inc. December 14,|1
01978|076|R|   2017.|1
01978|077|R|15.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
01978|078|R|   prescribing information. AbbVie Inc. December, 2019.|1
01979|001|T|MONOGRAPH TITLE:  Sildenafil (ED);Tadalafil (ED)/Slt Protease|
01979|002|T|Inhib;Cobicistat|
01979|003|B||
01979|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01979|005|L|take action as needed.|
01979|006|B||
01979|007|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
01979|008|A|sildenafil and tadalafil.(1-13)|
01979|009|B||
01979|010|E|CLINICAL EFFECTS:  The concurrent administration of a protease inhibitor may|
01979|011|E|result in elevated levels of sildenafil or tadalafil, which may result in|
01979|012|E|increased adverse effects such as hypotension, visual changes, and priapism.|
01979|013|B||
01979|014|P|PREDISPOSING FACTORS:  None determined.|
01979|015|B||
01979|016|M|PATIENT MANAGEMENT:  The US manufacturers of Viagra (sildenafil, 1) and the|
01979|017|M|protease inhibitors (2-11)  state that the recommended dose of sildenafil,|
01979|018|M|when used for erectile dysfunction, is 25 mg of sildenafil in a 48 hour|
01979|019|M|period for patients receiving concurrent therapy.|
01979|020|M|   Patients should be counseled that they are at an increased risk of|
01979|021|M|sildenafil adverse effects, including hypotension, syncope, visual changes,|
01979|022|M|and priapism.  Patients experiencing these effects should report them|
01979|023|M|promptly to their physician.|
01979|024|M|   The US manufacturers of the protease inhibitors state that concurrent use|
01979|025|M|of sildenafil when used for the treatment of pulmonary arterial hypertension|
01979|026|M|(PAH) is contraindicated.(2-11)  The US manufacturer of Revatio (sildenafil)|
01979|027|M|states that concurrent use with ritonavir is not recommended.(12)|
01979|028|M|   The US manufacturers of tadalafil(12) and the protease inhibitors(2-10)|
01979|029|M|state that the recommended dose of as needed tadalafil for the treatment of|
01979|030|M|erectile dysfunction is 10 mg of tadalafil every 72 hours in patients|
01979|031|M|receiving concurrent therapy.|
01979|032|M|   The US manufacturer of tadalafil states that the recommended dose of|
01979|033|M|daily tadalafil for the treatment of erectile dysfunction in patients taking|
01979|034|M|potent inhibitors of CYP3A4 is 2.5 mg.(13)|
01979|035|M|   The US manufacturer of tadalafil chewable tablets (Chewtadzy) states the|
01979|036|M|maximum recommended dose of as needed tadalafil for erectile dysfunction in|
01979|037|M|patients taking strong CYP3A4 inhibitors is 10 mg every 72 hours.  The use|
01979|038|M|of tadalafil chewable tablets (Chewtazdy) for once daily use for erectile|
01979|039|M|dysfunction or benign prostatic hyperplasia (BPH) is not recommended in|
01979|040|M|patients taking strong CYP3A4 inhibitors due to the lack of a 2.5 mg tablet|
01979|041|M|strength.(14)|
01979|042|M|   The US manufacturers of the protease inhibitors state that in patients|
01979|043|M|who have received a protease inhibitor for at least one week, the initial|
01979|044|M|dosage of tadalafil for the treatment of primary pulmonary hypertension|
01979|045|M|should be 20 mg daily.  The dosage may be increased to 40 mg daily based|
01979|046|M|upon tolerability.(2-11)|
01979|047|M|   The US manufacturers of the protease inhibitors state that in patients|
01979|048|M|who have been receiving tadalafil for the treatment of primary pulmonary|
01979|049|M|hypertension, tadalafil should be discontinued for 24 hours before beginning|
01979|050|M|protease inhibitor therapy other than nelfinavir without concurrent|
01979|051|M|ritonavir.  After one week, tadalafil may be resumed at a dosage of 20 mg|
01979|052|M|daily.  The dosage may be increased to 40 mg daily based upon|
01979|053|M|tolerability.(2-9)|
01979|054|M|   In patients who have been receiving tadalafil for the treatment of|
01979|055|M|primary pulmonary hypertension, tadalafil should be adjusted to 20 mg daily|
01979|056|M|prior to beginning therapy with nelfinavir without concurrent ritonavir.|
01979|057|M|The dosage may be increased to 40 mg daily based upon tolerability.(10)|
01979|058|M|   In patients who have been receiving tadalafil for the treatment of|
01979|059|M|primary pulmonary hypertension, maintain tadalafil dose when switching from|
01979|060|M|darunavir/ritonavir to darunavir/cobicistat.(16)|
01979|061|M|   Patients should be counseled that they are at an increased risk of|
01979|062|M|tadalafil adverse effects, including hypotension, syncope, visual changes,|
01979|063|M|and priapism.  Patients experiencing these effects should report them|
01979|064|M|promptly to their physician.|
01979|065|B||
01979|066|D|DISCUSSION:  In a study in 16 subjects, administration of|
01979|067|D|darunavir/ritonavir (400/100 mg twice daily) decreased the area-under-curve|
01979|068|D|(AUC) and maximum concentration (Cmax) of a single dose of sildenafil (25|
01979|069|D|mg) by 38% and 3%, respectively, when compared to the administration of a|
01979|070|D|100 mg single dose of sildenafil given alone.(3)|
01979|071|D|   In a study in 6 HIV-infected males, indinavir (800 mg every 8 hours)|
01979|072|D|increased the AUC and Cmax of indinavir by 11% and 48%, respectively.|
01979|073|D|Sildenafil AUC increased by 340%.(5)|
01979|074|D|   The concurrent administration of ritonavir (400 mg twice daily) at steady|
01979|075|D|state with sildenafil (100 mg single dose) resulted in increases in the|
01979|076|D|sildenafil Cmax and AUC by 300% (4-fold) and 1000% (11-fold),|
01979|077|D|respectively.(1,8)  After 24 hours, plasma levels of sildenafil were still|
01979|078|D|approximately 200 ng/ml (normally 5 ng/ml 24 hours post-dose).(1)|
01979|079|D|   In a study in 27 healthy volunteers, the concurrent use of saquinavir|
01979|080|D|(1200 mg 3 times daily for 8 days) increased the AUC and Cmax of a single|
01979|081|D|dose of sildenafil (100 mg) by 210% and 140%, respectively.(9)|
01979|082|D|   In a study of 28 healthy male volunteers, the effects of sildenafil when|
01979|083|D|coadministered with ritonavir were determined in 14 of these volunteers.|
01979|084|D|Ritonavir showed increases in sildenafil AUC and Cmax of 11-fold and|
01979|085|D|3.9-fold respectively.(15)|
01979|086|D|   Concurrent administration of tipranavir/ritonavir (500/200 mg twice daily|
01979|087|D|for 17 doses) had no significant effects on the AUC of a single dose of|
01979|088|D|tadalafil (10 mg).  Tadalafil Cmax decreased 30%.  Tipranavir Cmax, AUC, and|
01979|089|D|Cmin decreased by 10%, 15%, and 19%, respectively.  Administration of a|
01979|090|D|single dose of tipranavir/ritonavir (500/200 mg) increased the AUC of a|
01979|091|D|single dose of tadalafil (10 mg) by 2.33-fold.  Tadalafil Cmax decreased|
01979|092|D|22%.(9)|
01979|093|D|   Concurrent administration of a single dose of tadalafil (20 mg) with|
01979|094|D|ritonavir (200 mg twice daily) increased tadalafil AUC by 124%.(2,7)|
01979|095|D|Concurrent administration of a single dose of tadalafil (20 mg) with|
01979|096|D|ritonavir (500 mg or 600 mg twice daily) increased tadalafil AUC by 32% and|
01979|097|D|decreased tadalafil Cmax by 30%.(13)|
01979|098|B||
01979|099|R|REFERENCES:|
01979|100|B||
01979|101|R|1.Viagra (sildenafil) US prescribing information. Pfizer Inc. December 14,|1
01979|102|R|  2017.|1
01979|103|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
01979|104|R|  Squibb Company December, 2024.|1
01979|105|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
01979|106|R|  March, 2023.|1
01979|107|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
01979|108|R|  March, 2019.|1
01979|109|R|5.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
01979|110|R|  September, 2016.|1
01979|111|R|6.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
01979|112|R|  Laboratories December, 2019.|1
01979|113|R|7.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
01979|114|R|  Pharmaceuticals, Inc. September, 2016.|1
01979|115|R|8.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
01979|116|R|  December, 2019.|1
01979|117|R|9.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01979|118|R|  Laboratories, Inc. March, 2019.|1
01979|119|R|10.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
01979|120|R|   Pharmaceuticals, Inc. April, 2024.|1
01979|121|R|11.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
01979|122|R|   information. Pfizer Inc. February, 2025.|1
01979|123|R|12.Revatio (sildenafil citrate) US prescribing information. Viatris January,|1
01979|124|R|   2023.|1
01979|125|R|13.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
01979|126|R|   February, 2018.|1
01979|127|R|14.Chewtadzy (tadalafil chewable tablets) US prescribing information. ANI|1
01979|128|R|   Pharmaceuticals, Inc. June, 2024.|1
01979|129|R|15.Back DJ. Re: 'Pharmacokinetic interactions between sildenafil and|2
01979|130|R|   saquinavir/ritonavir'. Br J Clin Pharmacol 2000 Aug;50(2):85.|2
01979|131|R|16.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
01979|132|R|   Pharmaceuticals, Inc. March, 2025.|1
01980|001|T|MONOGRAPH TITLE:  Linezolid/Rifampin|
01980|002|B||
01980|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01980|004|L|take action as needed.|
01980|005|B||
01980|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
01980|007|A|induction of linezolid metabolism by CYP2D6(1) or induction of linezolid|
01980|008|A|excretion by P-glycoprotein.(2,3)|
01980|009|B||
01980|010|E|CLINICAL EFFECTS:  Concurrent or recent use of rifampin may result in|
01980|011|E|decreased levels and effectiveness of linezolid.(1-3)|
01980|012|B||
01980|013|P|PREDISPOSING FACTORS:  None determined.|
01980|014|B||
01980|015|M|PATIENT MANAGEMENT:  Monitor linezolid levels and clinical response in|
01980|016|M|patients who are receiving concurrent rifampin or who have recently|
01980|017|M|discontinued rifampin.  The dosage of linezolid may need to be adjusted.|
01980|018|B||
01980|019|D|DISCUSSION:  In a study in 16 healthy males, pretreatment with oral rifampin|
01980|020|D|(600 mg daily for 8 days) decreased the maximum concentration (Cmax) and|
01980|021|D|area-under-curve (AUC) of a single oral dose of linezolid by 21% and 32%,|
01980|022|D|respectively. when compared to the administration of linezolid alone.(1)|
01980|023|D|   In a study in 8 healthy males, administration of a single intravenous|
01980|024|D|dose of rifampin (600 mg) decreased the plasma levels of a single|
01980|025|D|intravenous dose of linezolid (600 mg) by 10% at 6 hours post-dose, 20% at 9|
01980|026|D|hours post-dose, and by 35% at 12 hours post-dose when compared to the|
01980|027|D|administration of linezolid alone.(2)|
01980|028|D|   In a case report, low linezolid levels and slow clinical response were|
01980|029|D|noted in a 31 year-old female undergoing concurrent treatment with linezolid|
01980|030|D|and rifampin.(3)|
01980|031|B||
01980|032|R|REFERENCES:|
01980|033|B||
01980|034|R|1.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
01980|035|R|2.Egle H, Trittler R, Kummerer K, Lemmen SW. Linezolid and rifampin: Drug|2
01980|036|R|  interaction contrary to expectations?. Clin Pharmacol Ther 2005 May;|2
01980|037|R|  77(5):451-3.|2
01980|038|R|3.Gebhart BC, Barker BC, Markewitz BA. Decreased serum linezolid levels in a|3
01980|039|R|  critically ill patient receiving concomitant linezolid and rifampin.|3
01980|040|R|  Pharmacotherapy 2007 Mar;27(3):476-9.|3
01981|001|T|MONOGRAPH TITLE:  Quinine/QT Prolonging Agents|
01981|002|B||
01981|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01981|004|L|of severe adverse interaction.|
01981|005|B||
01981|006|A|MECHANISM OF ACTION:  Quinine has been shown to prolong the QTc interval.|
01981|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
01981|008|A|additive effects on the QTc interval.(1)|
01981|009|B||
01981|010|E|CLINICAL EFFECTS:  The concurrent use of quinine with other agents that|
01981|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01981|012|E|arrhythmias, including torsades de pointes.(1)|
01981|013|B||
01981|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01981|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01981|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01981|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01981|018|P|gender, or advanced age.(3)|
01981|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01981|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01981|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01981|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01981|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01981|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01981|025|P|dysfunction).(3)|
01981|026|B||
01981|027|M|PATIENT MANAGEMENT:  The US manufacturer of quinine states that concurrent|
01981|028|M|use with agents known to prolong the QT interval should be avoided.(1)|
01981|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01981|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01981|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01981|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01981|033|B||
01981|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01981|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
01981|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
01981|037|D|monograph have been shown to prolong the QTc interval either through their|
01981|038|D|mechanism of action, through studies on their effects on the QTc interval,|
01981|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
01981|040|D|clinical trials and/or post-marketing reports.|
01981|041|B||
01981|042|R|REFERENCES:|
01981|043|B||
01981|044|R|1.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
01981|045|R|  Industries, Inc. August, 2019.|1
01981|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01981|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01981|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01981|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01981|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01981|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01981|052|R|  settings: a scientific statement from the American Heart Association and|6
01981|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01981|054|R|  2;55(9):934-47.|6
01982|001|T|MONOGRAPH TITLE:  Quetiapine/Protease Inhibitors (mono deleted 06/19/2014)|
01982|002|B||
01982|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01982|004|L|take action as needed.|
01982|005|B||
01982|006|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
01982|007|A|quetiapine by CYP P-450-3A4.(1)|
01982|008|B||
01982|009|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors and quetiapine may|
01982|010|E|result in elevated levels of and toxicity from quetiapine.(1)|
01982|011|B||
01982|012|P|PREDISPOSING FACTORS:  None determined.|
01982|013|B||
01982|014|M|PATIENT MANAGEMENT:  The manufacturer of quetiapine states that quetiapine|
01982|015|M|dosage adjustments are required in patients receiving inhibitors of CYP|
01982|016|M|P-450-3A4, such as the protease inhibitors.(1)|
01982|017|B||
01982|018|D|DISCUSSION:  In a study, concurrent use of ketoconazole (another strong|
01982|019|D|inhibitor of CYP P-450-3A4, 200 mg daily for 4 days) and quetiapine resulted|
01982|020|D|in an increase in quetiapine Cmax and AUC by 3.35-fold and 6.2-fold,|
01982|021|D|respectively. Ketoconazole also decreased the mean apparent oral clearance|
01982|022|D|of quetiapine by 84%, and increased quetiapine mean elimination half-life by|
01982|023|D|2.6-fold.(1,2)|
01982|024|B||
01982|025|R|REFERENCES:|
01982|026|B||
01982|027|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
01982|028|R|  Pharmaceuticals LP July, 2011.|1
01982|029|R|2.Grimm SW, Richtand NM, Winter HR, Stams KR, Reele SB. Effects of|2
01982|030|R|  cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine|2
01982|031|R|  pharmacokinetics. Br J Clin Pharmacol 2006 Jan;61(1):58-69.|2
01983|001|T|MONOGRAPH TITLE:  Nelarabine/Pentostatin|
01983|002|B||
01983|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01983|004|L|of severe adverse interaction.|
01983|005|B||
01983|006|A|MECHANISM OF ACTION:  Pentostatin is a strong inhibitor of adenosine|
01983|007|A|deaminase, which is the enzyme that converts nelarabine to its active|
01983|008|A|form.(1)|
01983|009|B||
01983|010|E|CLINICAL EFFECTS:  Concurrent use of pentostatin may result in decreased|
01983|011|E|effectiveness of nelarabine.(1)|
01983|012|B||
01983|013|P|PREDISPOSING FACTORS:  None determined.|
01983|014|B||
01983|015|M|PATIENT MANAGEMENT:  The US manufacturer of nelarabine states that|
01983|016|M|concurrent use of pentostatin is not recommended.(1)|
01983|017|B||
01983|018|D|DISCUSSION:  Pentostatin is a strong inhibitor of adenosine deaminase, which|
01983|019|D|is the enzyme that converts nelarabine to its active form, therefore, the US|
01983|020|D|manufacturer of nelarabine states that concurrent use of pentostatin is not|
01983|021|D|recommended.(1)|
01983|022|B||
01983|023|R|REFERENCE:|
01983|024|B||
01983|025|R|1.Arranon (nelarabine) US prescribing information. GlaxoSmithKline November,|1
01983|026|R|  2018.|1
01984|001|T|MONOGRAPH TITLE:  Vinflunine/Itraconazole; Ketoconazole (mono deleted|
01984|002|T|12/26/2013)|
01984|003|B||
01984|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01984|005|L|of severe adverse interaction.|
01984|006|B||
01984|007|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
01984|008|A|metabolism of vinflunine by CYP P-450-3A4.(1)|
01984|009|B||
01984|010|E|CLINICAL EFFECTS:  Concurrent use of itraconazole and ketoconazole may|
01984|011|E|result in elevated levels of and toxicity from vinflunine and its active|
01984|012|E|metabolite, 4Odeacetyl-vinflunine (DVFL).(1)|
01984|013|B||
01984|014|P|PREDISPOSING FACTORS:  None determined.|
01984|015|B||
01984|016|M|PATIENT MANAGEMENT:  The UK manufacturer of vinflunine states that the|
01984|017|M|concurrent administration of potent CYP P-450-3A4 inhibitors, such as|
01984|018|M|itraconazole and ketoconazole, should be avoided.(1)|
01984|019|B||
01984|020|D|DISCUSSION:  In a phase I study, concurrent use of ketoconazole (400 mg|
01984|021|D|orally daily for 8 days) increased the exposure to vinflunine and DVFL by|
01984|022|D|30% and 50%, respectively.(1)|
01984|023|B||
01984|024|R|REFERENCE:|
01984|025|B||
01984|026|R|1.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
01984|027|R|  Pierre Fabre Limited September 21, 2009.|1
01985|001|T|MONOGRAPH TITLE:  Vinflunine/Ritonavir (mono deleted 07/30/2015)|
01985|002|B||
01985|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01985|004|L|of severe adverse interaction.|
01985|005|B||
01985|006|A|MECHANISM OF ACTION:  Ritonavir may inhibit the metabolism of vinflunine by|
01985|007|A|CYP P-450-3A4.(1)|
01985|008|B||
01985|009|E|CLINICAL EFFECTS:  Concurrent use of ritonavir may result in elevated levels|
01985|010|E|of and toxicity from vinflunine and its active metabolite,|
01985|011|E|4Odeacetyl-vinflunine (DVFL).(1)|
01985|012|B||
01985|013|P|PREDISPOSING FACTORS:  None determined.|
01985|014|B||
01985|015|M|PATIENT MANAGEMENT:  The UK manufacturer of vinflunine states that the|
01985|016|M|concurrent administration of potent CYP P-450-3A4 inhibitors, such as|
01985|017|M|ritonavir, should be avoided.(1)|
01985|018|B||
01985|019|D|DISCUSSION:  In a phase I study, concurrent use of ketoconazole (another|
01985|020|D|potent inhibitor of CYP P-450-3A4, 400 mg orally daily for 8 days) increased|
01985|021|D|the exposure to vinflunine and DVFL by 30% and 50%, respectively.(1)|
01985|022|B||
01985|023|R|REFERENCE:|
01985|024|B||
01985|025|R|1.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
01985|026|R|  Pierre Fabre Limited September 21, 2009.|1
01986|001|T|MONOGRAPH TITLE:  Vinflunine/Strong CYP3A4 Inducers|
01986|002|B||
01986|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01986|004|L|of severe adverse interaction.|
01986|005|B||
01986|006|A|MECHANISM OF ACTION:  Vinflunine is metabolized primarily by CYP3A4 to|
01986|007|A|inactive metabolites.  Strong CYP3A4 inducers may accelerate the metabolism|
01986|008|A|of vinflunine by CYP3A4.(1,2)|
01986|009|B||
01986|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
01986|011|E|decreased levels and effectiveness of vinflunine and its active metabolite,|
01986|012|E|4-O-deacetylvinflunine (DVFL), which is formed by multiple esterases.(1)|
01986|013|B||
01986|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01986|015|P|of the inducer for longer than 1-2 weeks.|
01986|016|B||
01986|017|M|PATIENT MANAGEMENT:  The UK manufacturer of vinflunine states that the|
01986|018|M|concurrent administration of strong CYP3A4 inducers should be avoided.(1)|
01986|019|B||
01986|020|D|DISCUSSION:  In a phase I study, concurrent use of ketoconazole (a potent|
01986|021|D|inhibitor of CYP3A4, 400 mg orally daily for 8 days) increased the exposure|
01986|022|D|to vinflunine by 30%.  Exposure to the active metabolite,|
01986|023|D|4-O-deacetylvinflunine (DVFL), was increased by 50%.  Strong inducers of|
01986|024|D|CYP3A4 are expected to substantially decrease levels of vinflunine and|
01986|025|D|DVFL.(1)|
01986|026|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
01986|027|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
01986|028|D|ivosidenib lumacaftor, mitotane, phenobarbital, phenytoin, primidone, and|
01986|029|D|rifapentine.(3,4)|
01986|030|B||
01986|031|R|REFERENCES:|
01986|032|B||
01986|033|R|1.Javlor (vinflunine) UK summary of product information. Pierre Fabre|1
01986|034|R|  Medicament Production May, 2014.|1
01986|035|R|2.Delord JP, Ravaud A, Bennouna J, Fumoleau P, Favrel S, Pinel MC, Ferre P,|2
01986|036|R|  Saliba F. Phase I and pharmacokinetic study of IV vinflunine in cancer|2
01986|037|R|  patients with liver  dysfunction. Invest New Drugs 2013 Jun;31(3):724-33.|2
01986|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
01986|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
01986|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
01986|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
01986|042|R|  11/14/2017.|1
01986|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
01986|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
01987|001|T|MONOGRAPH TITLE:  Vinflunine/St. John's Wort|
01987|002|B||
01987|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01987|004|L|of severe adverse interaction.|
01987|005|B||
01987|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
01987|007|A|vinflunine by CYP3A4.(1)|
01987|008|B||
01987|009|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
01987|010|E|levels and effectiveness of vinflunine and its active metabolite,|
01987|011|E|4Odeacetyl-vinflunine (DVFL).(1)|
01987|012|B||
01987|013|P|PREDISPOSING FACTORS:  None determined.|
01987|014|B||
01987|015|M|PATIENT MANAGEMENT:  The UK manufacturer of vinflunine states that the|
01987|016|M|concurrent administration of strong CYP3A4 inducers, such as St. John's|
01987|017|M|wort, should be avoided.  Instruct patients not to use products containing|
01987|018|M|St. John's wort during therapy with vinflunine.(1)|
01987|019|B||
01987|020|D|DISCUSSION:  In a phase I study, concurrent use of ketoconazole (a potent|
01987|021|D|inhibitor of CYP3A4, 400 mg orally daily for 8 days) increased the exposure|
01987|022|D|to vinflunine and DVFL by 30% and 50%, respectively.  Strong inducers of|
01987|023|D|CYP3A4 are expected to substantially decreased levels of vinflunine and|
01987|024|D|DVFL.(1)|
01987|025|B||
01987|026|R|REFERENCE:|
01987|027|B||
01987|028|R|1.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
01987|029|R|  Pierre Fabre Limited September 21, 2009.|1
01988|001|T|MONOGRAPH TITLE:  Vinflunine/QT Prolonging Agents (mono deleted 07/23/2020)|
01988|002|B||
01988|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01988|004|L|of severe adverse interaction.|
01988|005|B||
01988|006|A|MECHANISM OF ACTION:  QT prolongation has been reported with vinflunine|
01988|007|A|administration.  Concurrent use with other agents that prolong the QTc|
01988|008|A|interval may result in additive effects on the QTc interval.(1)|
01988|009|B||
01988|010|E|CLINICAL EFFECTS:  The concurrent use of vinflunine with other agents that|
01988|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01988|012|E|arrhythmias, including torsades de pointes.(1)|
01988|013|B||
01988|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01988|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01988|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01988|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01988|018|P|gender, advanced age, or with concurrent use of inhibitors of CYP3A4, which|
01988|019|P|metabolize vinflunine.(1,3)|
01988|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01988|021|P|higher systemic concentrations of either QT prolonging drug are additional|
01988|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01988|023|P|drug concentrations include rapid infusion of an intravenous dose or|
01988|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01988|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01988|026|P|dysfunction).(3)|
01988|027|B||
01988|028|M|PATIENT MANAGEMENT:  The UK manufacturer of vinflunine states that the|
01988|029|M|concurrent administration of other drugs that are known to prolong the QTc|
01988|030|M|interval should be avoided.(1)|
01988|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01988|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01988|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01988|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01988|035|B||
01988|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01988|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01988|038|D|monograph have been shown to prolong the QTc interval either through their|
01988|039|D|mechanism of action, through studies on their effects on the QTc interval,|
01988|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
01988|041|D|clinical trials and/or postmarketing reports.(2)|
01988|042|B||
01988|043|R|REFERENCES:|
01988|044|B||
01988|045|R|1.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
01988|046|R|  Pierre Fabre Limited September 21, 2009.|1
01988|047|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01988|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01988|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01988|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01988|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01988|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01988|053|R|  settings: a scientific statement from the American Heart Association and|6
01988|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01988|055|R|  2;55(9):934-47.|6
01989|001|T|MONOGRAPH TITLE:  Vinflunine/Possible QT Prolonging Agents (mono deleted|
01989|002|T|07/23/2020)|
01989|003|B||
01989|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01989|005|L|take action as needed.|
01989|006|B||
01989|007|A|MECHANISM OF ACTION:  QT prolongation has been reported with vinflunine|
01989|008|A|administration.  Concurrent use with other agents that prolong the QTc|
01989|009|A|interval may result in additive effects on the QTc interval.(1)|
01989|010|B||
01989|011|E|CLINICAL EFFECTS:  The concurrent use of vinflunine with other agents that|
01989|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
01989|013|E|arrhythmias, including torsades de pointes.(1)|
01989|014|B||
01989|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01989|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01989|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01989|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01989|019|P|gender, advanced age, or with concurrent use of inhibitors of CYP3A4, which|
01989|020|P|metabolize vinflunine.(3)|
01989|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01989|022|P|higher systemic concentrations of either QT prolonging drug are additional|
01989|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01989|024|P|drug concentrations include rapid infusion of an intravenous dose or|
01989|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01989|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01989|027|P|dysfunction).(3)|
01989|028|B||
01989|029|M|PATIENT MANAGEMENT:  The UK manufacturer of vinflunine states that the|
01989|030|M|concurrent administration of other drugs that are known to prolong the QTc|
01989|031|M|interval should be avoided.(1)|
01989|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
01989|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
01989|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01989|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01989|036|B||
01989|037|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
01989|038|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
01989|039|D|monograph have been shown to prolong the QTc interval either through their|
01989|040|D|mechanism of action, through studies on their effects on the QTc interval,|
01989|041|D|or through reports of QTc prolongation and/or torsades de pointes in|
01989|042|D|clinical trials and/or postmarketing reports.(2)|
01989|043|B||
01989|044|R|REFERENCES:|
01989|045|B||
01989|046|R|1.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
01989|047|R|  Pierre Fabre Limited September 21, 2009.|1
01989|048|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01989|049|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01989|050|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01989|051|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01989|052|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01989|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01989|054|R|  settings: a scientific statement from the American Heart Association and|6
01989|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01989|056|R|  2;55(9):934-47.|6
01990|001|T|MONOGRAPH TITLE:  Deferasirox/Bile Acid Sequestrants|
01990|002|B||
01990|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01990|004|L|of severe adverse interaction.|
01990|005|B||
01990|006|A|MECHANISM OF ACTION:  Bile acid sequestrants may interfere with the|
01990|007|A|enterohepatic recycling of deferasirox.(1)|
01990|008|B||
01990|009|E|CLINICAL EFFECTS:  Concurrent use of bile acid sequestrants may result in|
01990|010|E|decreased levels and effectiveness of deferasirox, even when the|
01990|011|E|administration times are separated.(1)|
01990|012|B||
01990|013|P|PREDISPOSING FACTORS:  None determined.|
01990|014|B||
01990|015|M|PATIENT MANAGEMENT:  Avoid the use of bile acid sequestrants with|
01990|016|M|deferasirox.  If concurrent therapy is warranted, consider increasing the|
01990|017|M|initial dose of deferasirox by 50%.  Further dosage adjustments should be|
01990|018|M|made based upon serum ferritin levels and clinical response.  Doses above 40|
01990|019|M|mg/kg are not recommended.(1)|
01990|020|B||
01990|021|D|DISCUSSION:  In a study in healthy subjects, administration of|
01990|022|D|cholestyramine (12 g twice daily, 4 and 10 hours after deferasirox)|
01990|023|D|decreased the area-under-curve (AUC) of a single dose of deferasirox (dosage|
01990|024|D|not stated) by 45%.(1)|
01990|025|B||
01990|026|R|REFERENCE:|
01990|027|B||
01990|028|R|1.Exjade (deferasirox) US prescribing information. Novartis Pharmaceuticals|1
01990|029|R|  Corporation July, 2019.|1
01991|001|T|MONOGRAPH TITLE:  Saquinavir/QT Prolonging Agents|
01991|002|B||
01991|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01991|004|L|of severe adverse interaction.|
01991|005|B||
01991|006|A|MECHANISM OF ACTION:  QT prolongation has been reported with|
01991|007|A|ritonavir-boosted saquinavir.  Concurrent use with other agents that prolong|
01991|008|A|the QTc interval may result in additive effects on the QTc interval.(1)|
01991|009|B||
01991|010|E|CLINICAL EFFECTS:  The concurrent use of ritonavir-boosted saquinavir with|
01991|011|E|other agents that prolong the QTc interval may result in potentially|
01991|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
01991|013|B||
01991|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01991|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01991|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01991|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01991|018|P|gender, or advanced age.(3)|
01991|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01991|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01991|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01991|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01991|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01991|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01991|025|P|dysfunction).(3)|
01991|026|B||
01991|027|M|PATIENT MANAGEMENT:  The US manufacturer of saquinavir states that|
01991|028|M|concurrent use of agents known to prolong the QT interval should only be|
01991|029|M|used when there is no alternative therapy and potential benefits outweigh|
01991|030|M|the risks.(1)|
01991|031|M|   Perform an ECG prior to initiation of saquinavir or prior to concurrent|
01991|032|M|therapy with concurrent agents known to prolong the QT interval.|
01991|033|M|   Treatment-naive patients: Patients with a QT interval greater than 450|
01991|034|M|msec should not initiate therapy with saquinavir/ritonavir.  Treatment-naive|
01991|035|M|patients should receive a reduced dose of saquinavir 500 mg twice daily with|
01991|036|M|ritonavir 100 mg twice daily for the first 7 days followed by saquinavir|
01991|037|M|1000 mg twice daily with ritonavir 100 mg twice daily (standard dose).  For|
01991|038|M|patients with a baseline QT interval less than 450 msec, a repeat ECG should|
01991|039|M|be performed after 10 days of therapy.  In patients who experience an|
01991|040|M|increase in QT interval of greater than 20 msec, therapy should|
01991|041|M|discontinued.|
01991|042|M|   Treatment-experienced:  Patients with a QT interval greater than 450 msec|
01991|043|M|should not initiate concurrent therapy.  For patients with a baseline QT|
01991|044|M|interval less than 450 msec, a repeat ECG should be performed after 3-4 days|
01991|045|M|of concurrent therapy.  In patients who experience an increase in QT|
01991|046|M|interval by greater than 20 msec, consideration should be given to|
01991|047|M|discontinuing one or both agents.(1)|
01991|048|M|   In addition, if concurrent therapy is warranted, consider obtaining serum|
01991|049|M|calcium, magnesium, and potassium levels and monitoring ECG at baseline and|
01991|050|M|at regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01991|051|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01991|052|B||
01991|053|D|DISCUSSION:  Ritonavir-boosted saquinavir increases the QT interval in a|
01991|054|D|dose dependent manner.(1)|
01991|055|D|   Agents that are linked to this monograph may have varying degrees of|
01991|056|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
01991|057|D|been shown to prolong the QTc interval either through their mechanism of|
01991|058|D|action, through studies on their effects on the QTc interval, or through|
01991|059|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01991|060|D|and/or postmarketing reports.(2)|
01991|061|B||
01991|062|R|REFERENCES:|
01991|063|B||
01991|064|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01991|065|R|  Laboratories, Inc. March, 2019.|1
01991|066|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01991|067|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01991|068|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01991|069|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01991|070|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01991|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01991|072|R|  settings: a scientific statement from the American Heart Association and|6
01991|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01991|074|R|  2;55(9):934-47.|6
01992|001|T|MONOGRAPH TITLE:  Saquinavir/Possible QT Prolonging Agents|
01992|002|B||
01992|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01992|004|L|take action as needed.|
01992|005|B||
01992|006|A|MECHANISM OF ACTION:  QT prolongation has been reported with|
01992|007|A|ritonavir-boosted saquinavir.  Concurrent use with other agents that prolong|
01992|008|A|the QTc interval may result in additive effects on the QTc interval.(1)|
01992|009|B||
01992|010|E|CLINICAL EFFECTS:  The concurrent use of ritonavir-boosted saquinavir with|
01992|011|E|other agents that prolong the QTc interval may result in potentially|
01992|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
01992|013|B||
01992|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
01992|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
01992|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
01992|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
01992|018|P|gender, or advanced age.(3)|
01992|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
01992|020|P|higher systemic concentrations of either QT prolonging drug are additional|
01992|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
01992|022|P|drug concentrations include rapid infusion of an intravenous dose or|
01992|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
01992|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
01992|025|P|dysfunction).(3)|
01992|026|B||
01992|027|M|PATIENT MANAGEMENT:  The US manufacturer of saquinavir states that|
01992|028|M|concurrent use of agents known to prolong the QT interval should only be|
01992|029|M|used when there is no alternative therapy and potential benefits outweigh|
01992|030|M|the risks.(1)|
01992|031|M|   Perform an ECG prior to initiation of saquinavir or prior to concurrent|
01992|032|M|therapy with concurrent agents known to prolong the QT interval.|
01992|033|M|   Treatment-naive patients: Patients with a QT interval greater than 450|
01992|034|M|msec should not initiate therapy with saquinavir/ritonavir.  Treatment-naive|
01992|035|M|patients should receive a reduced dose of saquinavir 500 mg twice daily with|
01992|036|M|ritonavir 100 mg twice daily for the first 7 days followed by saquinavir|
01992|037|M|1000 mg twice daily with ritonavir 100 mg twice daily (standard dose).  For|
01992|038|M|patients with a baseline QT interval less than 450 msec, a repeat ECG should|
01992|039|M|be performed after 10 days of therapy.  In patients who experience an|
01992|040|M|increase in QT interval of greater than 20 msec, therapy should|
01992|041|M|discontinued.|
01992|042|M|   Treatment-experienced:  Patients with a QT interval greater than 450 msec|
01992|043|M|should not initiate concurrent therapy.  For patients with a baseline QT|
01992|044|M|interval less than 450 msec, a repeat ECG should be performed after 3-4 days|
01992|045|M|of concurrent therapy.  In patients who experience an increase in QT|
01992|046|M|interval by greater than 20 msec, consideration should be given to|
01992|047|M|discontinuing one or both agents.(1)|
01992|048|M|   In addition, if concurrent therapy is warranted, consider obtaining serum|
01992|049|M|calcium, magnesium, and potassium levels and monitoring ECG at baseline and|
01992|050|M|at regular intervals.  Correct any electrolyte abnormalities.  Instruct|
01992|051|M|patients to report any irregular heartbeat, dizziness, or fainting.|
01992|052|B||
01992|053|D|DISCUSSION:  Ritonavir-boosted saquinavir increases the QT interval in a|
01992|054|D|dose dependent manner.(1)|
01992|055|D|   Agents that are linked to this monograph may have varying degrees of|
01992|056|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
01992|057|D|been shown to prolong the QTc interval either through their mechanism of|
01992|058|D|action, through studies on their effects on the QTc interval, or through|
01992|059|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
01992|060|D|and/or postmarketing reports.(2)|
01992|061|B||
01992|062|R|REFERENCES:|
01992|063|B||
01992|064|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
01992|065|R|  Laboratories, Inc. March, 2019.|1
01992|066|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
01992|067|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
01992|068|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
01992|069|R|  https://www.fda.gov/media/71372/download October, 2005.|1
01992|070|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
01992|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
01992|072|R|  settings: a scientific statement from the American Heart Association and|6
01992|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
01992|074|R|  2;55(9):934-47.|6
01993|001|T|MONOGRAPH TITLE:  Live Vaccines/Live Vaccines|
01993|002|B||
01993|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01993|004|L|of severe adverse interaction.|
01993|005|B||
01993|006|A|MECHANISM OF ACTION:  The immune response to an injectable or nasally|
01993|007|A|administered live vaccine may be impaired if it is administered within 28|
01993|008|A|days of another injectable or nasally administered live vaccine.(1)|
01993|009|B||
01993|010|E|CLINICAL EFFECTS:  Non-simultaneous administration (i.e. given on different|
01993|011|E|days) of an injectable or nasally administered live vaccine to an individual|
01993|012|E|who has received another injectable or nasally administered live vaccine in|
01993|013|E|the previous 28 days may result in the second vaccine being ineffective.(1)|
01993|014|B||
01993|015|P|PREDISPOSING FACTORS:  None determined.|
01993|016|B||
01993|017|M|PATIENT MANAGEMENT:  The CDC states that multiple injectable or nasal live|
01993|018|M|vaccines (e.g. MMR and varicella) may be administered on the same day.|
01993|019|M|However, injectable or nasally administered live vaccines not administered|
01993|020|M|on the same day should be administered at least 4 weeks apart whenever|
01993|021|M|possible.|
01993|022|M|   If injectable or nasal live vaccines are administered less than 4 weeks|
01993|023|M|apart and not on the same day, the vaccine administered second should be|
01993|024|M|considered invalid and be repeated at least 4 weeks after the last, invalid|
01993|025|M|dose.(1)|
01993|026|B||
01993|027|D|DISCUSSION:  The immune response to a live vaccine may be impaired if it is|
01993|028|D|administered within 28 days of another live vaccine.  In a study, patients|
01993|029|D|who received varicella vaccine less than 28 days after MMR vaccination had|
01993|030|D|an increased risk for varicella vaccine failure (i.e., varicella disease in|
01993|031|D|a vaccinated person) of 2.5-fold compared with those who received varicella|
01993|032|D|vaccine before or more than 28 days after MMR.(1)|
01993|033|B||
01993|034|R|REFERENCE:|
01993|035|B||
01993|036|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
01993|037|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
01993|038|R|  Practices (ACIP). MMWR.  Available at:|1
01993|039|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
01993|040|R|  February 17, 2022;60(RR No.2):1-68.|1
01994|001|T|MONOGRAPH TITLE:  Zoster Vaccine Live/Pneumococcal Vaccine|
01994|002|B||
01994|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
01994|004|L|take action as needed.|
01994|005|B||
01994|006|A|MECHANISM OF ACTION:  Concurrent administration of pneumococcal and zoster|
01994|007|A|vaccines may decrease the immune response to the zoster vaccine.  The|
01994|008|A|mechanism is not clear.(1,2)|
01994|009|B||
01994|010|E|CLINICAL EFFECTS:  Concurrent administration of pneumococcal vaccine may|
01994|011|E|decrease antibody titers and possibly the effectiveness of the zoster|
01994|012|E|vaccine.(1,2)  The safety profile of the vaccines is unaffected.(3)|
01994|013|B||
01994|014|P|PREDISPOSING FACTORS:  None determined.|
01994|015|B||
01994|016|M|PATIENT MANAGEMENT:  The CDC states that to avoid potential barriers to|
01994|017|M|vaccination posed by separation of vaccine administration, zoster and|
01994|018|M|pneumovax vaccines may be administered during the same visit.(3,4)|
01994|019|M|   A large observational study did not find an increased risk for herpes|
01994|020|M|zoster in patients who received pneumococcal and zoster vaccines on the same|
01994|021|M|day compared with patients who received pneumococcal vaccine 30 to 265 days|
01994|022|M|prior to zoster vaccine administration.(5)|
01994|023|M|   The US manufacturer of zoster vaccine states providers should consider|
01994|024|M|separating administration of pneumococcal and zoster vaccines by 4 weeks.(1)|
01994|025|B||
01994|026|D|DISCUSSION:  In a manufacturer sponsored double-blind controlled trial, 473|
01994|027|D|adults who received concurrent administration of zoster and Pneumovax(r) had|
01994|028|D|significantly lower varicella zoster virus antibody titers compared with|
01994|029|D|individuals who had vaccine administration separated by 4 weeks.  Based upon|
01994|030|D|this trial result the manufacturer recommends consideration of a 4 week|
01994|031|D|separation between zoster and pneumococcal vaccine administration.(1-2)|
01994|032|D|   A retrospective cohort study compared the incidence of herpes zoster in|
01994|033|D|7,187 patients who received pneumococcal and zoster vaccines on the same day|
01994|034|D|with 7,179 patients who received pneumococcal vaccine 30 - 365 days prior to|
01994|035|D|zoster vaccination.  Patients were followed for up to 3.5 years.  The|
01994|036|D|estimated incidence of herpes zoster in the concomitant vaccination cohort|
01994|037|D|was 4.54 per 1000 person-years, and in the nonconcomitant cohort was 4.51|
01994|038|D|per 1000 person-years.  The hazard ratio for concomitant vaccination|
01994|039|D|compared with noncomitant vaccination was 1.19 (95% CI, 0.81 - 1.74), not|
01994|040|D|statistically significant.(5)|
01994|041|B||
01994|042|R|REFERENCES:|
01994|043|B||
01994|044|R|1.Zostavax (zoster vaccine live) US prescribing information. Merck & Co.,|1
01994|045|R|  Inc. March, 2018.|1
01994|046|R|2.MacIntyre CR, Egerton T, McCaughey M, Parrino J, Campbell BV, Su SC,|2
01994|047|R|  Pagnoni MF, Stek JE, Xu J, Annunziato PW, Chan IS, Silber JL. Concomitant|2
01994|048|R|  administration of zoster and pneumococcal vaccines in adults >/=60 years|2
01994|049|R|  old. Hum Vaccin 2010 Nov;6(11):894-902.|2
01994|050|R|3.Centers for Disease Control and Prevention (CDC) National Center for|1
01994|051|R|  Immunization and Respiratory Diseases. Herpes Zoster Vaccination|1
01994|052|R|  Information for Health Care Professionals. available at:|1
01994|053|R|  http://www.cdc.gov/vaccines/vpd/shingles/hcp/recommendations.html October|1
01994|054|R|  19, 2012.|1
01994|055|R|4.Centers for Disease Control and Prevention. General Recommendations on|1
01994|056|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
01994|057|R|  Practices (ACIP). MMWR.  Available at:|1
01994|058|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
01994|059|R|  February 17, 2022;60(RR No.2):1-68.|1
01994|060|R|5.Tseng HF, Smith N, Sy LS, Jacobsen SJ. Evaluation of the incidence of|2
01994|061|R|  herpes zoster after concomitant administration of zoster vaccine and|2
01994|062|R|  polysaccharide pneumococcal vaccine. Vaccine 2011 May 9;29(20):3628-32.|2
01995|001|T|MONOGRAPH TITLE:  Praziquantel/Rifampin; Rifapentine|
01995|002|B||
01995|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01995|004|L|is contraindicated and generally should not be dispensed or administered to|
01995|005|L|the same patient.|
01995|006|B||
01995|007|A|MECHANISM OF ACTION:  Rifampin and rifapentine may induce the metabolism of|
01995|008|A|praziquantel by CYP3A4.(1)|
01995|009|B||
01995|010|E|CLINICAL EFFECTS:  Concurrent or recent use of rifampin or rifapentine may|
01995|011|E|decrease the levels and effectiveness of praziquantel.(1,2)|
01995|012|B||
01995|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
01995|014|P|of the inducer for longer than 1-2 weeks.|
01995|015|B||
01995|016|M|PATIENT MANAGEMENT:  The concurrent use of praziquantel and rifampin or|
01995|017|M|rifapentine is contraindicated.(1)|
01995|018|M|   In patients receiving rifampin or rifapentine who need immediate|
01995|019|M|treatment for schistosomiasis, alternative agents for schistosomiasis should|
01995|020|M|be used.  If praziquantel is required,  increase monitoring for praziquantel|
01995|021|M|efficacy.  If schistosomiasis treatment can be delayed, discontinue rifampin|
01995|022|M|or rifapentine at least 2 to 4 weeks before administration of praziquantel.|
01995|023|M|Rifampin or rifapentine therapy may be resumed 1 day after completion of|
01995|024|M|praziquantel therapy.(1)|
01995|025|B||
01995|026|D|DISCUSSION:  In an open, randomized, cross-over study in 10 healthy Thai|
01995|027|D|males, pretreatment with rifampin (600 mg daily for 5 days) decreased the|
01995|028|D|levels of a single oral dose of praziquantel (40 mg/kg) to undetectable|
01995|029|D|levels in 7 of 10 subjects.  In the 3 subjects with detectable levels, the|
01995|030|D|maximum concentration (Cmax) and area-under-curve (AUC) of praziquantel were|
01995|031|D|decreased by 81% and 85%, respectively.  In the same subjects, pretreatment|
01995|032|D|with rifampin (600 mg daily for 5 days) decreased the levels of praziquantel|
01995|033|D|(3 doses of 40 mg/kg, 8 hours apart) to undetectable levels in 5 of 10|
01995|034|D|subjects.  In the 5 subjects with detectable levels, Cmax and AUC of|
01995|035|D|praziquantel were decreased by 74% and 80%, respectively.(2)|
01995|036|B||
01995|037|R|REFERENCES:|
01995|038|B||
01995|039|R|1.Biltricide (praziquantel) US prescribing information. Bayer HealthCare|1
01995|040|R|  Pharmaceuticals Inc. January, 2019.|1
01995|041|R|2.Ridtitid W, Wongnawa M, Mahatthanatrakul W, Punyo J, Sunbhanich M.|2
01995|042|R|  Rifampin markedly decreases plasma concentrations of praziquantel in|2
01995|043|R|  healthy volunteers. Clin Pharmacol Ther 2002 Nov;72(5):505-13.|2
01996|001|T|MONOGRAPH TITLE:  Cisplatin/Black Cohosh|
01996|002|B||
01996|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
01996|004|L|Assess the risk to the patient and take action as needed.|
01996|005|B||
01996|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.|
01996|007|B||
01996|008|E|CLINICAL EFFECTS:  Concurrent use of black cohosh may decrease the|
01996|009|E|effectiveness of cisplatin.(1)|
01996|010|B||
01996|011|P|PREDISPOSING FACTORS:  None determined.|
01996|012|B||
01996|013|M|PATIENT MANAGEMENT:  Suggest that patients receiving therapy with cisplatin|
01996|014|M|avoid black cohosh.|
01996|015|B||
01996|016|D|DISCUSSION:  An in vitro study in EMT6 mouse mammary tumor cells found that|
01996|017|D|cells treated with black cohosh were slightly more resistant to cisplatin|
01996|018|D|than were cells treated with cisplatin alone or cisplatin with vehicle.  The|
01996|019|D|resistance was small, but statistically significant.  Further studies are|
01996|020|D|needed to determine if these affects are seen in vivo.(1)|
01996|021|B||
01996|022|R|REFERENCE:|
01996|023|B||
01996|024|R|1.Rockwell S, Liu Y, Higgins SA. Alteration of the effects of cancer therapy|5
01996|025|R|  agents on breast cancer cells by the herbal medicine black cohosh. Breast|5
01996|026|R|  Cancer Res Treat 2005 Apr;90(3):233-9.|5
01997|001|T|MONOGRAPH TITLE:  Mifamurtide/Calcineurin Inhibitors|
01997|002|B||
01997|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
01997|004|L|is contraindicated and generally should not be dispensed or administered to|
01997|005|L|the same patient.|
01997|006|B||
01997|007|A|MECHANISM OF ACTION:  Mifamurtide activates macrophages as its mechanism of|
01997|008|A|action.  Calcineurin inhibitors inhibit macrophages and mononuclear|
01997|009|A|phagocytic function.(1)|
01997|010|B||
01997|011|E|CLINICAL EFFECTS:  Concurrent use of calcineurin inhibitors may decrease the|
01997|012|E|effectiveness of mifamurtide.(1)|
01997|013|B||
01997|014|P|PREDISPOSING FACTORS:  None determined.|
01997|015|B||
01997|016|M|PATIENT MANAGEMENT:  The UK manufacturer of mifamurtide states that|
01997|017|M|concurrent use with calcineurin inhibitors is contraindicated.(1)|
01997|018|B||
01997|019|D|DISCUSSION:  Because calcineurin inhibitors are thought to inhibit splenic|
01997|020|D|macrophages and mononuclear phagocytic function, their concurrent use with|
01997|021|D|mifamurtide is contraindicated.(1)|
01997|022|B||
01997|023|R|REFERENCE:|
01997|024|B||
01997|025|R|1.Mepact (mifamurtide) UK summary of product characteristics. Takeda UK Ltd|1
01997|026|R|  January 18, 2010.|1
01998|001|T|MONOGRAPH TITLE:  Mifamurtide/NSAIDs; Aspirin (Greater Than 100 mg);|
01998|002|T|Salicylates|
01998|003|B||
01998|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01998|005|L|of severe adverse interaction.|
01998|006|B||
01998|007|A|MECHANISM OF ACTION:  High-dose NSAIDs or salicylates may block the|
01998|008|A|macrophage activating effect of mifamurtide.(1)|
01998|009|B||
01998|010|E|CLINICAL EFFECTS:  Concurrent use of high-dose NSAIDs or salicylates may|
01998|011|E|decrease the effectiveness of mifamurtide.(1)|
01998|012|B||
01998|013|P|PREDISPOSING FACTORS:  None determined.|
01998|014|B||
01998|015|M|PATIENT MANAGEMENT:  The UK manufacturer of mifamurtide states that|
01998|016|M|concurrent use with high-dose NSAIDs or salicylates is contraindicated.(1)|
01998|017|B||
01998|018|D|DISCUSSION:  In vitro studies have shown that high-dose NSAIDs or|
01998|019|D|salicylates can block the macrophage activating effect of mifamurtide.(1)|
01998|020|B||
01998|021|R|REFERENCE:|
01998|022|B||
01998|023|R|1.Mepact (mifamurtide) UK summary of product characteristics. Takeda UK Ltd|1
01998|024|R|  January 18, 2010.|1
01999|001|T|MONOGRAPH TITLE:  Mifamurtide/Corticosteroids|
01999|002|B||
01999|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
01999|004|L|of severe adverse interaction.|
01999|005|B||
01999|006|A|MECHANISM OF ACTION:  Mifamurtide activates macrophages as its mechanism of|
01999|007|A|action.  Corticosteroids suppress the immune system.(1)|
01999|008|B||
01999|009|E|CLINICAL EFFECTS:  Chronic or routine use of corticosteroids may decrease|
01999|010|E|the effectiveness of mifamurtide.(1)|
01999|011|B||
01999|012|P|PREDISPOSING FACTORS:  None determined.|
01999|013|B||
01999|014|M|PATIENT MANAGEMENT:  The UK manufacturer of mifamurtide states that the|
01999|015|M|chronic or routine use of corticosteroids should be avoided during therapy|
01999|016|M|with mifamurtide.(1)|
01999|017|B||
01999|018|D|DISCUSSION:  Because mifamurtide stimulates the immune system, the chronic|
01999|019|D|or routine use of corticosteroids should be avoided during therapy with|
01999|020|D|mifamurtide.(1)|
01999|021|B||
01999|022|R|REFERENCE:|
01999|023|B||
01999|024|R|1.Mepact (mifamurtide) UK summary of product characteristics. Takeda UK Ltd|1
01999|025|R|  January 18, 2010.|1
02000|001|T|MONOGRAPH TITLE:  Topical Macrolides/Topical Clindamycin (mono deleted|
02000|002|T|01/17/2019)|
02000|003|B||
02000|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02000|005|L|is contraindicated and generally should not be dispensed or administered to|
02000|006|L|the same patient.|
02000|007|B||
02000|008|A|MECHANISM OF ACTION:  Macrolides and clindamycin may antagonize the action|
02000|009|A|of each other by blocking access to the ribosomal binding site.(1-4)|
02000|010|B||
02000|011|E|CLINICAL EFFECTS:  Concurrent use of macrolides with clindamycin may result|
02000|012|E|in decreased effectiveness of both agents.(5,6)|
02000|013|B||
02000|014|P|PREDISPOSING FACTORS:  None determined.|
02000|015|B||
02000|016|M|PATIENT MANAGEMENT:  The US manufacturers of topical clindamycin(5,6) state|
02000|017|M|that these agents should not be used with topical erythromycin.|
02000|018|B||
02000|019|D|DISCUSSION:  Erythromycin has been shown to antagonize clindamycin in|
02000|020|D|vitro.(1-6)|
02000|021|B||
02000|022|R|REFERENCES:|
02000|023|B||
02000|024|R|1.Igarashi K, Ishitsuka H, Kaji A. Comparative studies on the mechanism of|6
02000|025|R|  action of lincomycin, streptomycin, and erythromycin. Biochem Biophys Res|6
02000|026|R|  Commun 1969 Oct 22;37(3):499-504.|6
02000|027|R|2.Weinstein L. Modes of action of antibiotics on bacteria and man. N Y State|6
02000|028|R|  J Med 1972 Sep 1;72(17):2166-70.|6
02000|029|R|3.Garrett ER, Heman-Ackah SM, Perry GL. Kinetics and mechanisms of action of|5
02000|030|R|  drugs on microorganisms. XI. Effect of erythromycin and its supposed|5
02000|031|R|  antagonism with lincomycin on the microbial growth of Escherichia coli. J|5
02000|032|R|  Pharm Sci 1970 Oct;59(10):1448-56.|5
02000|033|R|4.Mao JC. The stoichiometry of erythromycin binding to ribosomal particles|5
02000|034|R|  of Staphylococcus aureus. Biochem Pharmacol 1967 Dec;16(12):2441-3.|5
02000|035|R|5.Acanya (clindamycin phosphate and benzoyl peroxide) kit. Dow|1
02000|036|R|  Pharmaceuticals Sciences June, 2010.|1
02000|037|R|6.Ziana (clindamycin phosphate and tretinoin) US prescribing information.|1
02000|038|R|  Medicis Pharmaceutical Corp October, 2009.|1
02001|001|T|MONOGRAPH TITLE:  Quinidine; Natisedine/Selected QT Prolongers (mono deleted|
02001|002|T|10/22/2015)|
02001|003|B||
02001|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02001|005|L|of severe adverse interaction.|
02001|006|B||
02001|007|A|MECHANISM OF ACTION:  Concurrent use of quinidine or natisedine with agents|
02001|008|A|known to prolong the QTc interval may result in additive effects on the QTc|
02001|009|A|interval.|
02001|010|B||
02001|011|E|CLINICAL EFFECTS:  Concurrent use may result in potentially life-threatening|
02001|012|E|cardiac arrhythmias, including torsades de pointes.|
02001|013|B||
02001|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02001|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02001|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02001|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02001|018|P|gender, or advanced age.(1)|
02001|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02001|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02001|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02001|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02001|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02001|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02001|025|P|dysfunction).(1)|
02001|026|P|   Use of thioridazine in patients with reduced CYP P-450-2D6 activity|
02001|027|P|(either through genetic predisposition or use of drugs that inhibit CYP2D6|
02001|028|P|activity) may increase the risk of torsades de pointes and/or sudden death|
02001|029|P|in patients taking thioridazine.(9)|
02001|030|B||
02001|031|M|PATIENT MANAGEMENT:  The manufacturers of asenapine,(2) delamanid,(3)|
02001|032|M|ivabradine,(4) mesoridazine,(5) nilotinib,(6) paliperidone,(7)|
02001|033|M|quetiapine,(8) quinine,(9) thioridazine,(10) trazodone,(11) vinflunine,(12)|
02001|034|M|and zuclopenthixol(13) state that concurrent use of agents known to prolong|
02001|035|M|the QT interval should be avoided.|
02001|036|M|   Concurrent use of citalopram with agents known to prolong the QT interval|
02001|037|M|is not recommended.  The manufacturer recommends ECG monitoring in patients|
02001|038|M|for whom citalopram is not recommended, including those receiving concurrent|
02001|039|M|therapy with agents known to prolong the QT interval.  Citalopram should be|
02001|040|M|discontinued in patients with persistent QTc measurements greater than 500|
02001|041|M|ms.(14,15)|
02001|042|M|   If treatment with a QT prolonging agent be required, interruption of|
02001|043|M|nilotinib therapy should be considered.  If concurrent therapy cannot be|
02001|044|M|avoided, monitor patients closely for prolongation of the QT interval and|
02001|045|M|follow recommended nilotinib dosage adjustments for QT prolongation.(6)|
02001|046|M|   The manufacturer of vandetanib states that the use of vandetanib with|
02001|047|M|other agents known to prolong the QT interval should be avoided.  If another|
02001|048|M|drug known to prolong the QT interval must be coadministered with|
02001|049|M|vandetanib, more frequent ECG monitoring is recommended.(16)|
02001|050|M|   The manufacturer of Nuedexta (dextromethorphan-quinidine) states that if|
02001|051|M|concurrent use with QT prolonging agents cannot be avoided, ECG monitoring|
02001|052|M|should be done at initiation of concurrent therapy and at 3-4 hours after|
02001|053|M|the first dose.(17)|
02001|054|M|   If concurrent use of delamanid and quinidine is necessary, frequently|
02001|055|M|monitor ECGs (more frequently than the standard recommended monthly ECG|
02001|056|M|during delamanid therapy).  Discontinue delamanid if a QTcF greater than 500|
02001|057|M|msec is observed.  Discontinue delamanid if albumin falls below 2.8 g/DL.(3)|
02001|058|M|   Consider obtaining serum calcium, magnesium, and potassium levels at|
02001|059|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02001|060|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02001|061|B||
02001|062|D|DISCUSSION:  Quinidine, a component of natisedine, has been shown to prolong|
02001|063|D|the QTc interval.  Other agents that are linked to this monograph may have|
02001|064|D|varying degrees of potential to prolong the QTc interval.(18)|
02001|065|D|   One or more of the drug pairs linked to this monograph have been included|
02001|066|D|in a list of interactions that should be considered "high-priority" for|
02001|067|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02001|068|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02001|069|D|Coordinator (ONC) for Health Information Technology.|
02001|070|B||
02001|071|R|REFERENCES:|
02001|072|B||
02001|073|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02001|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02001|075|R|  settings: a scientific statement from the American Heart Association and|6
02001|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02001|077|R|  2;55(9):934-47.|6
02001|078|R|2.Saphris (asenapine) US prescribing information. Actavis, Inc. February 23,|1
02001|079|R|  2017.|1
02001|080|R|3.Deltyba (delamanid) EMA summary of products characteristics. Otsuka Novel|1
02001|081|R|  Products GmbH March, 2023.|1
02001|082|R|4.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
02001|083|R|  Les Laboratoires Servier March, 2015.|1
02001|084|R|5.Serentil (mesoridazine besylate) US prescribing information. Novartis|1
02001|085|R|  Pharmaceuticals Corporation August, 2000.|1
02001|086|R|6.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
02001|087|R|  Corporation September, 2014.|1
02001|088|R|7.Invega (paliperidone) US prescribing information. Janssen Pharmaceuticals,|1
02001|089|R|  Inc. April, 2014.|1
02001|090|R|8.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
02001|091|R|  Pharmaceuticals LP July, 2011.|1
02001|092|R|9.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
02001|093|R|  Industries, Inc. August, 2019.|1
02001|094|R|10.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
02001|095|R|   September, 2014.|1
02001|096|R|11.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
02001|097|R|   Labopharm Inc. November, 2012.|1
02001|098|R|12.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
02001|099|R|   Pierre Fabre Limited September 21, 2009.|1
02001|100|R|13.Clopixol (zuclopenthixol acetate) UK summary of product characteristics.|1
02001|101|R|   Lundbeck Limited October 15, 2020.|1
02001|102|R|14.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
02001|103|R|   Laboratories Inc. December, 2012.|1
02001|104|R|15.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02001|105|R|   recommendations for Celexa (citalopram hydrobromide) related to a|1
02001|106|R|   potential risk of abnormal heart rhythms with high doses. available at:|1
02001|107|R|   http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02001|108|R|16.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
02001|109|R|   Pharmaceuticals LP October, 2018.|1
02001|110|R|17.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
02001|111|R|   prescribing information. Avanir  Pharmaceuticals June, 2019.|1
02001|112|R|18.USDepartment of Health and Human Services Food and Drug Administration.|1
02001|113|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02001|114|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02001|115|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02001|116|R|19.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02001|117|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02001|118|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02001|119|R|   19(5):735-43.|6
02002|001|T|MONOGRAPH TITLE:  Romidepsin/Possible QT Prolonging Agents|
02002|002|B||
02002|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02002|004|L|take action as needed.|
02002|005|B||
02002|006|A|MECHANISM OF ACTION:  Romidepsin has been shown to prolong the QTc interval.|
02002|007|A|Concurrent use with other agents that prolong the QTc interval may result|
02002|008|A|in additive effects on the QTc interval.(1)|
02002|009|B||
02002|010|E|CLINICAL EFFECTS:  The concurrent use of romidepsin with other agents that|
02002|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02002|012|E|arrhythmias, including torsades de pointes.(1)|
02002|013|B||
02002|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02002|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02002|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02002|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02002|018|P|gender, or advanced age.(2)|
02002|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02002|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02002|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02002|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02002|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02002|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02002|025|P|dysfunction).(2)|
02002|026|B||
02002|027|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin states that|
02002|028|M|appropriate cardiovascular monitoring, such as baseline and regular|
02002|029|M|monitoring of ECG and obtaining serum calcium, magnesium, and potassium|
02002|030|M|levels, should be performed if concurrent therapy with agents known to|
02002|031|M|prolong the ECG is warranted.(1)|
02002|032|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02002|033|M|fainting.|
02002|034|B||
02002|035|D|DISCUSSION:  In two clinical trials, discontinuation of romidepsin secondary|
02002|036|D|to QT prolongation occurred in at least 2% of patients.(1)|
02002|037|D|   Agents that are linked to this monograph may have varying degrees of|
02002|038|D|potential to prolong the QTc interval but are generally accepted to have a|
02002|039|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02002|040|D|been shown to prolong the QTc interval either through their mechanism of|
02002|041|D|action, through studies on their effects on the QTc interval, or through|
02002|042|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02002|043|D|and/or post-marketing reports.(3)|
02002|044|B||
02002|045|R|REFERENCES:|
02002|046|B||
02002|047|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
02002|048|R|  November, 2018.|1
02002|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02002|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02002|051|R|  settings: a scientific statement from the American Heart Association and|6
02002|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02002|053|R|  2;55(9):934-47.|6
02002|054|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02002|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02002|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02002|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02003|001|T|MONOGRAPH TITLE:  Panobinostat (Less than or Equal To 10 mg)/Strong CYP3A4|
02003|002|T|Inhibitors|
02003|003|B||
02003|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02003|005|L|take action as needed.|
02003|006|B||
02003|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02003|008|A|panobinostat.(1)|
02003|009|B||
02003|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
02003|011|E|in elevated levels of and toxicity from panobinostat, including increased|
02003|012|E|risk of bleeding and prolongation of the QT interval which may result in|
02003|013|E|life-threatening arrhythmia and death.(1)|
02003|014|B||
02003|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02003|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02003|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02003|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02003|019|P|female gender, or advanced age.(2)|
02003|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02003|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02003|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02003|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02003|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02003|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02003|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02003|027|P|   The risk for bleeding episodes may be greater in patients with|
02003|028|P|disease-associated factors (e.g. thrombocytopenia).|
02003|029|P|   Drug associated risk factors include concurrent use of multiple drugs|
02003|030|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02003|031|P|risk for bleeding (e.g. NSAIDs).|
02003|032|B||
02003|033|M|PATIENT MANAGEMENT:  Reduce the dose of panobinostat to 10 mg when|
02003|034|M|coadministered with strong CYP3A4 inhibitors.  Limit the starting dose of|
02003|035|M|panobinostat to 10 mg in patients taking strong CYP3A4 inhibitors.(1)|
02003|036|M|   If concurrent therapy is warranted, continue standard monitoring of|
02003|037|M|complete blood counts, ECG, and serum electrolytes.  Instruct patients to|
02003|038|M|report any irregular heartbeat, dizziness, or fainting; nausea, vomiting, or|
02003|039|M|diarrhea; unusual tiredness, shortness of breath, paleness; unusual or|
02003|040|M|unexplained bleeding or bruising; signs of infection such as fever, cough,|
02003|041|M|or flu-like symptoms.  If panobinostat toxicity occurs, panobinostat or the|
02003|042|M|CYP3A4 inhibitor may need to be discontinued.(1)|
02003|043|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
02003|044|M|including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
02003|045|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02003|046|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02003|047|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02003|048|M|anticoagulation in patients with active pathologic bleeding.|
02003|049|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02003|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02003|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02003|052|M|and/or swelling.|
02003|053|B||
02003|054|D|DISCUSSION:  In 14 patients with advanced cancer, ketoconazole (a strong|
02003|055|D|CYP3A4 inhibitor, 200 mg twice daily for 14 days) increased the maximum|
02003|056|D|concentration (Cmax) and area-under-curve (AUC) of panobinostat by 62% and|
02003|057|D|73%, respectively.(1)|
02003|058|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, grapefruit,|
02003|059|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
02003|060|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
02003|061|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(3,4)|
02003|062|B||
02003|063|R|REFERENCES:|
02003|064|B||
02003|065|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
02003|066|R|  Pharmaceuticals Corporation June, 2016.|1
02003|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02003|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02003|069|R|  settings: a scientific statement from the American Heart Association and|6
02003|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02003|071|R|  2;55(9):934-47.|6
02003|072|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02003|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02003|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02003|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02003|076|R|  11/14/2017.|1
02003|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
02003|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02004|001|T|MONOGRAPH TITLE:  Romidepsin/Clarithromycin; Telithromycin (mono deleted|
02004|002|T|01/12/2012)|
02004|003|B||
02004|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02004|005|L|of severe adverse interaction.|
02004|006|B||
02004|007|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
02004|008|A|metabolism of romidepsin by CYP P-450-3A4.(1)|
02004|009|B||
02004|010|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin or telithromycin may|
02004|011|E|result in elevated levels of and toxicity from romidepsin.(1)|
02004|012|B||
02004|013|P|PREDISPOSING FACTORS:  None determined.|
02004|014|B||
02004|015|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin recommends avoiding|
02004|016|M|the use of strong inhibitors of P-450-3A4, such as clarithromycin and|
02004|017|M|telithromycin, in patients receiving romidepsin.(1)|
02004|018|B||
02004|019|D|DISCUSSION:  Romidepsin is metabolized by CYP P-450-3A4.  It is expected|
02004|020|D|that strong inhibitors of CYP P-450-3A4 will increase the concentrations of|
02004|021|D|romidepsin.(1)|
02004|022|B||
02004|023|R|REFERENCE:|
02004|024|B||
02004|025|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation June,|1
02004|026|R|  2011.|1
02005|001|T|MONOGRAPH TITLE:  Romidepsin/Protease Inhibitors (mono deleted 01/12/2012)|
02005|002|B||
02005|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02005|004|L|of severe adverse interaction.|
02005|005|B||
02005|006|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
02005|007|A|romidepsin by CYP P-450-3A4.(1)|
02005|008|B||
02005|009|E|CLINICAL EFFECTS:  Concurrent use of a protease inhibitor may result in|
02005|010|E|elevated levels of and toxicity from romidepsin.(1)|
02005|011|B||
02005|012|P|PREDISPOSING FACTORS:  None determined.|
02005|013|B||
02005|014|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin recommends avoiding|
02005|015|M|the use of strong inhibitors of P-450-3A4, such as atazanavir, indinavir,|
02005|016|M|nelfinavir, ritonavir, and saquinavir, in patients receiving romidepsin.(1)|
02005|017|B||
02005|018|D|DISCUSSION:  Romidepsin is metabolized by CYP P-450-3A4.  It is expected|
02005|019|D|that strong inhibitors of CYP P-450-3A4 will increase the concentrations of|
02005|020|D|romidepsin.(1)|
02005|021|B||
02005|022|R|REFERENCE:|
02005|023|B||
02005|024|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation June,|1
02005|025|R|  2011.|1
02006|001|T|MONOGRAPH TITLE:  Romidepsin/Nefazodone (mono deleted 01/12/2012)|
02006|002|B||
02006|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02006|004|L|of severe adverse interaction.|
02006|005|B||
02006|006|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of romidepsin by|
02006|007|A|CYP P-450-3A4.(1)|
02006|008|B||
02006|009|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in elevated|
02006|010|E|levels of and toxicity from romidepsin.(1)|
02006|011|B||
02006|012|P|PREDISPOSING FACTORS:  None determined.|
02006|013|B||
02006|014|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin recommends avoiding|
02006|015|M|the use of strong inhibitors of P-450-3A4, such as nefazodone, in patients|
02006|016|M|receiving romidepsin.(1)|
02006|017|B||
02006|018|D|DISCUSSION:  Romidepsin is metabolized by CYP P-450-3A4.  It is expected|
02006|019|D|that strong inhibitors of CYP P-450-3A4 will increase the concentrations of|
02006|020|D|romidepsin.(1)|
02006|021|B||
02006|022|R|REFERENCE:|
02006|023|B||
02006|024|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation June,|1
02006|025|R|  2011.|1
02007|001|T|MONOGRAPH TITLE:  Romidepsin/Strong CYP3A4 Inducers; Rifabutin|
02007|002|B||
02007|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02007|004|L|of severe adverse interaction.|
02007|005|B||
02007|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 and rifabutin may increase|
02007|007|A|the metabolism of romidepsin.(1,2)|
02007|008|B||
02007|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer or rifabutin|
02007|010|E|may result in decreased levels and effectiveness of romidepsin.(1,2)|
02007|011|B||
02007|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02007|013|P|of the inducer for longer than 1-2 weeks.|
02007|014|B||
02007|015|M|PATIENT MANAGEMENT:  The manufacturer of romidepsin recommends avoiding the|
02007|016|M|use of strong inducers of CYP3A4 in patients receiving romidepsin.(1,2)  The|
02007|017|M|Canadian manufacturer includes rifabutin on its list of CYP3A4 inducers that|
02007|018|M|should be avoided.(2)|
02007|019|B||
02007|020|D|DISCUSSION:  In a study in advanced cancer patients, rifampin, a strong|
02007|021|D|inducer of CYP3A4 and an inhibitor and inducer of other CYP enzymes and|
02007|022|D|transporters, unexpectedly increased the maximum concentration (Cmax) and|
02007|023|D|area-under-curve (AUC) of romidepsin (14 mg/m2) by 60% and 80%,|
02007|024|D|respectively.  Romidepsin clearance and volume of distribution decreased by|
02007|025|D|44% and 52%, respectively.  This is likely due to inhibition of an|
02007|026|D|undetermined hepatic uptake process responsible for the disposition of|
02007|027|D|romidepsin.(1)|
02007|028|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
02007|029|D|carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor,|
02007|030|D|mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifapentine and|
02007|031|D|St. John's wort.(1-3)|
02007|032|B||
02007|033|R|REFERENCES:|
02007|034|B||
02007|035|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
02007|036|R|  November, 2018.|1
02007|037|R|2.Istodax (romidepsin) Canadian prescribing information. Celgene Inc July|1
02007|038|R|  25, 2019.|1
02007|039|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02007|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02007|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02007|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02007|043|R|  11/14/2017.|1
02008|001|T|MONOGRAPH TITLE:  Romidepsin/Carbamazepine; Phenobarbital; Phenytoin (mono|
02008|002|T|deleted 01/12/2012)|
02008|003|B||
02008|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02008|005|L|of severe adverse interaction.|
02008|006|B||
02008|007|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital, and phenytoin may induce|
02008|008|A|the metabolism of romidepsin by CYP P-450-3A4.(1)|
02008|009|B||
02008|010|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, phenobarbital, or|
02008|011|E|phenytoin may result in decreased levels and effectiveness of romidepsin.(1)|
02008|012|B||
02008|013|P|PREDISPOSING FACTORS:  None determined.|
02008|014|B||
02008|015|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin recommends avoiding|
02008|016|M|the use of potent inducers of P-450-3A4, such as carbamazepine,|
02008|017|M|phenobarbital, and phenytoin, in patients receiving romidepsin.(1)|
02008|018|B||
02008|019|D|DISCUSSION:  Romidepsin is metabolized by CYP P-450-3A4.  It is expected|
02008|020|D|that potent inducers of CYP P-450-3A4 will decrease the concentrations of|
02008|021|D|romidepsin.(1)|
02008|022|B||
02008|023|R|REFERENCE:|
02008|024|B||
02008|025|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation June,|1
02008|026|R|  2011.|1
02009|001|T|MONOGRAPH TITLE:  Romidepsin/Rifamycins (mono deleted 01/12/2012)|
02009|002|B||
02009|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02009|004|L|of severe adverse interaction.|
02009|005|B||
02009|006|A|MECHANISM OF ACTION:  Rifabutin, rifampin, and rifapentine may induce the|
02009|007|A|metabolism of romidepsin by CYP P-450-3A4.(1)|
02009|008|B||
02009|009|E|CLINICAL EFFECTS:  Concurrent use of rifabutin, rifampin, or rifapentine may|
02009|010|E|result in decreased levels and effectiveness of romidepsin.(1)|
02009|011|B||
02009|012|P|PREDISPOSING FACTORS:  None determined.|
02009|013|B||
02009|014|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin recommends avoiding|
02009|015|M|the use of potent inducers of P-450-3A4, such as rifabutin, rifampin, and|
02009|016|M|rifapentine, in patients receiving romidepsin.(1)|
02009|017|B||
02009|018|D|DISCUSSION:  Romidepsin is metabolized by CYP P-450-3A4.  It is expected|
02009|019|D|that potent inducers of CYP P-450-3A4 will decrease the concentrations of|
02009|020|D|romidepsin.(1)|
02009|021|B||
02009|022|R|REFERENCE:|
02009|023|B||
02009|024|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation June,|1
02009|025|R|  2011.|1
02010|001|T|MONOGRAPH TITLE:  Romidepsin/St. John's Wort (mono deleted 01/12/2012)|
02010|002|B||
02010|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02010|004|L|of severe adverse interaction.|
02010|005|B||
02010|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
02010|007|A|romidepsin by CYP P-450-3A4.(1)|
02010|008|B||
02010|009|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort may result in decreased|
02010|010|E|levels and effectiveness of romidepsin.(1)|
02010|011|B||
02010|012|P|PREDISPOSING FACTORS:  None determined.|
02010|013|B||
02010|014|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin recommends avoiding|
02010|015|M|the use of potent inducers of P-450-3A4, such as St. John's wort, in|
02010|016|M|patients receiving romidepsin.(1)|
02010|017|B||
02010|018|D|DISCUSSION:  Romidepsin is metabolized by CYP P-450-3A4.  It is expected|
02010|019|D|that potent inducers of CYP P-450-3A4 will decrease the concentrations of|
02010|020|D|romidepsin.(1)|
02010|021|B||
02010|022|R|REFERENCE:|
02010|023|B||
02010|024|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation June,|1
02010|025|R|  2011.|1
02011|001|T|MONOGRAPH TITLE:  Estrogen-Containing Contraceptives/Romidepsin (mono|
02011|002|T|deleted 01/12/2012)|
02011|003|B||
02011|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02011|005|L|of severe adverse interaction.|
02011|006|B||
02011|007|A|MECHANISM OF ACTION:  Romidepsin competes with beta-estradiol for binding to|
02011|008|A|estrogen receptors.(1)|
02011|009|B||
02011|010|E|CLINICAL EFFECTS:  Concurrent use of romidepsin may result in decreased|
02011|011|E|effectiveness of estrogen-containing contraceptives.  Pregnancy may result|
02011|012|E|and romidepsin may result in fetal harm.(1)|
02011|013|B||
02011|014|P|PREDISPOSING FACTORS:  None determined.|
02011|015|B||
02011|016|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin states that women|
02011|017|M|should be advised that romidepsin may decrease the effectiveness of|
02011|018|M|estrogen.(1)  Advise women of child-bearing age to use appropriate back-up|
02011|019|M|methods of birth-control while on romidepsin.|
02011|020|B||
02011|021|D|DISCUSSION:  In vitro studies have shown that romidepsin competes with|
02011|022|D|beta-estradiol for binding to estrogen receptors, thus the effectiveness of|
02011|023|D|estrogen contraceptives may be compromised.  Based on its mechanism of|
02011|024|D|action, it is expected that romidepsin will harm a developing fetus.(1)|
02011|025|B||
02011|026|R|REFERENCE:|
02011|027|B||
02011|028|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation June,|1
02011|029|R|  2011.|1
02012|001|T|MONOGRAPH TITLE:  Atorvastatin; Pitavastatin (Less Than or Equal To 1 mg);|
02012|002|T|Pravastatin/Erythromycin|
02012|003|B||
02012|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02012|005|L|take action as needed.|
02012|006|B||
02012|007|A|MECHANISM OF ACTION:  Erythromycin may inhibit the metabolism of|
02012|008|A|atorvastatin, pitavastatin, and pravastatin by organic anion transporting|
02012|009|A|polypeptide (OATP).  When used concomitantly, erythromycin inhibits hepatic|
02012|010|A|uptake of atorvastatin, pitavastatin, and pravastatin in a concentration|
02012|011|A|dependent manner.(1,2)|
02012|012|B||
02012|013|E|CLINICAL EFFECTS:  Concurrent erythromycin may result in increased levels of|
02012|014|E|atorvastatin, pitavastatin, or pravastatin, which may produce|
02012|015|E|rhabdomyolysis.  Symptoms of rhabdomyolysis include muscle pain, tenderness,|
02012|016|E|weakness, elevated creatine kinase levels, and reddish-brown, heme positive|
02012|017|E|urine.|
02012|018|B||
02012|019|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02012|020|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02012|021|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02012|022|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02012|023|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02012|024|P|transporter OATP1B1 may have increased statin concentrations and be|
02012|025|P|predisposed to myopathy or rhabdomyolysis.|
02012|026|B||
02012|027|M|PATIENT MANAGEMENT:  The US manufacturer of pitavastatin states that a daily|
02012|028|M|dose of 1 mg of pitavastatin should not be exceeded during erythromycin|
02012|029|M|therapy.(1)|
02012|030|M|   If possible, consider suspending statin therapy during macrolide therapy.|
02012|031|M|Monitor patients receiving concurrent therapy for signs of rhabdomyolysis.|
02012|032|B||
02012|033|D|DISCUSSION:  In a study in healthy subjects, azithromycin (500 mg daily for|
02012|034|D|3 days) had no effect on the AUC or Cmax of atorvastatin (10 mg daily).(4)|
02012|035|D|   In a study in 12 healthy subjects, pretreatment with seven days of|
02012|036|D|erythromycin resulted in increases in the Cmax and AUC of a single dose of|
02012|037|D|atorvastatin (10 mg) by 37.7% and 32.5%, respectively.(2,3)|
02012|038|D|   In a study, pretreatment with erythromycin (500 mg 4 times daily for 6|
02012|039|D|days) increased the AUC and Cmax of a single dose of pitavastatin (4 mg on|
02012|040|D|Day 4) by 2.8-fold and 3.6-fold, respectively.(1)|
02012|041|B||
02012|042|R|REFERENCES:|
02012|043|B||
02012|044|R|1.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
02012|045|R|  America, Inc. November, 2022.|1
02012|046|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02012|047|R|  2020.|1
02012|048|R|3.Amsden GW, Kuye O, Wei GC. A study of the interaction potential of|2
02012|049|R|  azithromycin and clarithromycin with atorvastatin in healthy volunteers. J|2
02012|050|R|  Clin Pharmacol 2002 Apr;42(4):444-9.|2
02012|051|R|4.Siedlik PH, Olson SC, Yang BB, Stern RH. Erythromycin coadministration|2
02012|052|R|  increases plasma atorvastatin concentrations. J Clin Pharmacol 1999 May;|2
02012|053|R|  39(5):501-4.|2
02014|001|T|MONOGRAPH TITLE:  Methotrexate(low strength inj, oral)/Proton Pump|
02014|002|T|Inhibitors|
02014|003|B||
02014|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02014|005|L|take action as needed.|
02014|006|B||
02014|007|A|MECHANISM OF ACTION:  Proton pump inhibitors(PPIs) may inhibit the active|
02014|008|A|secretion of methotrexate from the kidney via inhibition of the|
02014|009|A|hydrogen-potassium ATPase(1) and may reduce uptake of methotrexate into|
02014|010|A|breast cancer resistance protein via competitive inhibition.(2,3)|
02014|011|B||
02014|012|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and proton pump|
02014|013|E|inhibitors may result in elevated levels of methotrexate and increased|
02014|014|E|methotrexate-related adverse effects and toxicities, leading to increased|
02014|015|E|risk of severe neurotoxicity, stomatitis, and myelosuppression, including|
02014|016|E|neutropenia.(1-7,9)|
02014|017|B||
02014|018|P|PREDISPOSING FACTORS:  High dose methotrexate therapy appears to increase|
02014|019|P|the risk for and severity of this interaction.(4,9)|
02014|020|B||
02014|021|M|PATIENT MANAGEMENT:  Patients receiving concurrent use of methotrexate and|
02014|022|M|proton pump inhibitors should be monitored closely for elevated methotrexate|
02014|023|M|levels and methotrexate toxicity.  The US manufacturer of omeprazole states|
02014|024|M|that secretory ability returns gradually over three to five days following|
02014|025|M|discontinuation.(4)|
02014|026|M|  This interaction has best described in patients receiving high dose|
02014|027|M|methotrexate for cancer treatment. Therefore, it would seem prudent to|
02014|028|M|discontinue proton pump inhibitors several days prior to high dose|
02014|029|M|methotrexate therapy.|
02014|030|M|  The magnitude and frequency of this interaction in patients receiving less|
02014|031|M|than or equal to 15 mg weekly is less clear.  While a small study suggested|
02014|032|M|lansoprazole was safe in rheumatoid arthritis patients taking 7.5 - 15 mg|
02014|033|M|weekly(8), at least one case report of PPI associated methotrexate toxicity|
02014|034|M|at a low dose (15 mg IM weekly) has been described.(7)|
02014|035|B||
02014|036|D|DISCUSSION:  In a clinical trial in 74 patients on high dose (1-5 G/m2)|
02014|037|D|methotrexate therapy, data was examined to determine if proton pump|
02014|038|D|inhibitor (omeprazole, pantoprazole, rabeprazole) use affects methotrexate|
02014|039|D|elimination.  Delayed elimination was found to be more frequent in those|
02014|040|D|with co-administration of a proton pump inhibitor (31.7% vs. 13.8%),|
02014|041|D|resulting in higher plasma methotrexate concentrations at 24, 48, and 74|
02014|042|D|hours.  The effect was seen with lansoprazole, omeprazole, pantoprazole, and|
02014|043|D|rabeprazole.(2)|
02014|044|D|   There are three case reports(1,5,6) of elevated methotrexate levels or|
02014|045|D|delayed methotrexate elimination resulting from concurrent administration of|
02014|046|D|high dose methotrexate and omeprazole, including one patient(6) that|
02014|047|D|developed severe mucositis.  In each case, omeprazole was discontinued and|
02014|048|D|normal methotrexate kinetics were observed on subsequent cycles with no|
02014|049|D|further adverse effects noted.|
02014|050|D|   In a case report of a 59 year-old male on low dose (15 mg weekly)|
02014|051|D|methotrexate, administration of pantoprazole (20 mg daily) was found to|
02014|052|D|increase the AUC of the metabolite 7-hydroxymethotrexate by 70%.(7)|
02014|053|D|   In a manufacturer sponsored clinical trial, 28 adults with rheumatoid|
02014|054|D|arthritis on low dose (7.5-15 mg weekly) methotrexate were assigned to|
02014|055|D|receive lansoprazole (30 mg daily) and naproxen (500 mg twice daily) on Days|
02014|056|D|1-7 of therapy.  The half life of the metabolite 7-hydroxymethotrexate was|
02014|057|D|prolonged with concurrent administration, but no other statistically|
02014|058|D|significant differences were found in regards to the plasma concentration|
02014|059|D|profiles of methotrexate or 7-hydroxymethotrexate.(8)|
02014|060|B||
02014|061|R|REFERENCES:|
02014|062|B||
02014|063|R|1.Reid T, Yuen A, Catolico M, Carlson RW. Impact of omeprazole on the plasma|3
02014|064|R|  clearance of methotrexate. Cancer Chemother Pharmacol 1993;33(1):82-4.|3
02014|065|R|2.Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, Sawada Y, Kohda Y.|2
02014|066|R|  Co-administration of proton pump inhibitors delays elimination of plasma|2
02014|067|R|  methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol 2009|2
02014|068|R|  Jan;67(1):44-9.|2
02014|069|R|3.Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH,|5
02014|070|R|  Schinkel AH, van Tellingen O, Borst P, Schellens JH. Mechanism of the|5
02014|071|R|  pharmacokinetic interaction between methotrexate and benzimidazoles:|5
02014|072|R|  potential role for breast cancer resistance protein in clinical drug-drug|5
02014|073|R|  interactions. Cancer Res 2004 Aug 15;64(16):5804-11.|5
02014|074|R|4.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
02014|075|R|  Pharmaceuticals LP June, 2018.|1
02014|076|R|5.Beorlegui B, Aldaz A, Ortega A, Aquerreta I, Sierrasesumega L, Giraldez J.|3
02014|077|R|  Potential interaction between methotrexate and omeprazole. Ann|3
02014|078|R|  Pharmacother 2000 Sep;34(9):1024-7.|3
02014|079|R|6.Bauters TG, Verlooy J, Robays H, Laureys G. Interaction between|3
02014|080|R|  methotrexate and omeprazole in an adolescent with leukemia: a case report.|3
02014|081|R|  Pharm World Sci 2008 Aug;30(4):316-8.|3
02014|082|R|7.Troger U, Stotzel B, Martens-Lobenhoffer J, Gollnick H, Meyer FP. Drug|3
02014|083|R|  points: Severe myalgia from an interaction between treatments with|3
02014|084|R|  pantoprazole and methotrexate. BMJ 2002 Jun 22;324(7352):1497.|3
02014|085|R|8.Vakily M, Amer F, Kukulka MJ, Andhivarothai N. Coadministration of|2
02014|086|R|  lansoprazole and naproxen does not affect the pharmacokinetic profile of|2
02014|087|R|  methotrexate in adult patients with rheumatoid arthritis. J Clin Pharmacol|2
02014|088|R|  2005 Oct;45(10):1179-86.|2
02014|089|R|9.Health Canada. New Safety Information: Interaction of Proton Pump|1
02014|090|R|  Inhibitors (PPIs) with Methotrexate. Available at:|1
02014|091|R|  http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/1507|1
02014|092|R|  6a-eng.php October 19, 2012.|1
02015|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Nefazodone|
02015|002|B||
02015|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02015|004|L|is contraindicated and generally should not be dispensed or administered to|
02015|005|L|the same patient.|
02015|006|B||
02015|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of lovastatin(1)|
02015|008|A|and simvastatin(2-5) by CYP3A4.|
02015|009|B||
02015|010|E|CLINICAL EFFECTS:  The concurrent administration of nefazodone may result in|
02015|011|E|elevated levels of lovastatin(1) or simvastatin,(2-5) which may result in|
02015|012|E|rhabdomyolysis.|
02015|013|B||
02015|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02015|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02015|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02015|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02015|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02015|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02015|020|P|predisposed to myopathy or rhabdomyolysis.|
02015|021|B||
02015|022|M|PATIENT MANAGEMENT:  Do not use lovastatin(1) or simvastatin(2-4) with|
02015|023|M|nefazodone.|
02015|024|M|   Fluvastatin and pravastatin, HMG-CoA reductase inhibitors that are not|
02015|025|M|extensively metabolized by CYP3A4, may be alternatives to other HMG-CoA|
02015|026|M|reductase inhibitors in patients taking nefazodone.(4)|
02015|027|B||
02015|028|D|DISCUSSION:  In a single-dose study, the administration of simvastatin (40|
02015|029|D|mg) or atorvastatin (40 mg) following six days of nefazodone (200 mg twice|
02015|030|D|daily) resulted in a 20-fold increase in simvastatin and simvastatin acid|
02015|031|D|levels and 3- to 4-fold increase in atorvastatin and atorvastatin lactone|
02015|032|D|levels.(5)|
02015|033|D|   There are case reports of rhabdomyolysis in patients receiving concurrent|
02015|034|D|nefazodone and lovastatin(9) or simvastatin(5-9) therapy.|
02015|035|D|   One or more of the drug pairs linked to this monograph have been included|
02015|036|D|in a list of interactions that should be considered "high-priority" for|
02015|037|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02015|038|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02015|039|D|Coordinator (ONC) for Health Information Technology.|
02015|040|B||
02015|041|R|REFERENCES:|
02015|042|B||
02015|043|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02015|044|R|  February, 2014.|1
02015|045|R|2.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02015|046|R|  restrictions, contraindications, and dose limitations for Zocor|1
02015|047|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02015|048|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02015|049|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02015|050|R|  June 8, 2011.|1
02015|051|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02015|052|R|  2023.|1
02015|053|R|4.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02015|054|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
02015|055|R|5.Jacobson RH, Wang P, Glueck CJ. Myositis and rhabdomyolysis associated|3
02015|056|R|  with concurrent use of simvastatin and nefazodone. JAMA 1997 Jan 22-29;|3
02015|057|R|  277(4):296-7.|3
02015|058|R|6.Karnik NS, Maldonado JR. Antidepressant and statin interactions: a review|3
02015|059|R|  and case report of simvastatin and nefazodone-induced rhabdomyolysis and|3
02015|060|R|  transaminitis. Psychosomatics 2005 Nov-Dec;46(6):565-8.|3
02015|061|R|7.Skrabal MZ, Stading JA, Monaghan MS. Rhabdomyolysis associated with|3
02015|062|R|  simvastatin-nefazodone therapy. South Med J 2003 Oct;96(10):1034-5.|3
02015|063|R|8.Thompson M, Samuels S. Rhabdomyolysis with simvastatin and nefazodone. Am|3
02015|064|R|  J Psychiatry 2002 Sep;159(9):1607.|3
02015|065|R|9.Serzone (nefazodone hydrochloride) US prescribing information.|1
02015|066|R|  Bristol-Myers Squibb Company January, 2005.|1
02015|067|R|10.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02015|068|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02015|069|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02015|070|R|   19(5):735-43.|6
02016|001|T|MONOGRAPH TITLE:  Simvastatin/Gemfibrozil|
02016|002|B||
02016|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02016|004|L|is contraindicated and generally should not be dispensed or administered to|
02016|005|L|the same patient.|
02016|006|B||
02016|007|A|MECHANISM OF ACTION:  Unknown.|
02016|008|B||
02016|009|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
02016|010|E|and gemfibrozil has been associated with severe myopathy, rhabdomyolysis and|
02016|011|E|acute renal failure.|
02016|012|B||
02016|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02016|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02016|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02016|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02016|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02016|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02016|019|P|predisposed to myopathy or rhabdomyolysis.|
02016|020|B||
02016|021|M|PATIENT MANAGEMENT:  According to the 2018 ACC/AHA Blood Cholesterol|
02016|022|M|Guidelines, gemfibrozil is contraindicated in patients on statin therapy.|
02016|023|M|   According to the 2016 AHA Scientific Statement Recommendations for|
02016|024|M|Management of Clinically Significant Drug-Drug Interactions with Statins and|
02016|025|M|Select Agents Used in Patients with Cardiovascular Disease, simvastatin is|
02016|026|M|contraindicated with gemfibrozil.|
02016|027|M|   The manufacturers of gemfibrozil and simvastatin both contraindicate|
02016|028|M|concurrent use.|
02016|029|M|   When possible, avoid administration of these drugs concomitantly unless|
02016|030|M|patients require aggressive therapy.  If possible, consider the use of|
02016|031|M|fenofibrate over gemfibrozil for concurrent therapy with a statin.  Instruct|
02016|032|M|patients to report any unexplained muscle pain, tenderness or weakness.  If|
02016|033|M|muscular symptoms develop, monitor serum creatine kinase levels and renal|
02016|034|M|function.  One or both agents may need to be discontinued.|
02016|035|B||
02016|036|D|DISCUSSION:  Gemfibrozil has been shown to increase levels of cerivastatin,|
02016|037|D|lovastatin, pravastatin, rosuvastatin, and simvastatin.  Administration of|
02016|038|D|gemfibrozil with cerivastatin, lovastatin, and simvastatin has been|
02016|039|D|associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and|
02016|040|D|weakness).  Although the reaction has been reported with the statins alone,|
02016|041|D|the incidence increases dramatically with concurrent administration of|
02016|042|D|gemfibrozil.|
02016|043|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
02016|044|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
02016|045|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
02016|046|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
02016|047|D|Veteran's Administration over a 2 year period, there were 149 reports of|
02016|048|D|rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil|
02016|049|D|and statin therapy compared with no reports in 1,830 patients receiving|
02016|050|D|concurrent fenofibrate and statin therapy.|
02016|051|D|   In a retrospective cohort study of 252,460 patients, concurrent use of|
02016|052|D|statins and fibrates increased the risk of rhabdomyolysis, especially in|
02016|053|D|patients with diabetes mellitus.  The risk of hospitalization for patients|
02016|054|D|aged 65 or older with diabetes mellitus, treated with a statin and fibrate,|
02016|055|D|increased 48-fold compared to statin monotherapy.|
02016|056|D|   In a retrospective study, of 468 patients with a diagnosis of myopathy,|
02016|057|D|61 received a statin prior to their diagnosis. Forty-one of these patients|
02016|058|D|developed confirmed myopathy, creatinine kinase more than or equal to 1000|
02016|059|D|IU/L.|
02016|060|B||
02016|061|R|REFERENCES:|
02016|062|B||
02016|063|R|1.Thompson GR, Ford J, Jenkinson M, Trayner I. Efficacy of mevinolin as|2
02016|064|R|  adjuvant therapy for refractory familial hypercholesterolaemia. Q J Med|2
02016|065|R|  1986 Aug;60(232):803-11.|2
02016|066|R|2.East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA. Rhabdomyolysis in|3
02016|067|R|  patients receiving lovastatin after cardiac transplantation. N Engl J Med|3
02016|068|R|  1988 Jan 7;318(1):47-8.|3
02016|069|R|3.Marais GE, Larson KK. Rhabdomyolysis and acute renal failure induced by|3
02016|070|R|  combination lovastatin and gemfibrozil therapy. Ann Intern Med 1990 Feb 1;|3
02016|071|R|  112(3):228-30.|3
02016|072|R|4.Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated|3
02016|073|R|  with lovastatin-gemfibrozil combination therapy. JAMA 1990 Jul 4;|3
02016|074|R|  264(1):71-5.|3
02016|075|R|5.Glueck CJ, Speirs J, Tracy T. Safety and efficacy of combined|2
02016|076|R|  gemfibrozil-lovastatin therapy for primary dyslipoproteinemias. J Lab Clin|2
02016|077|R|  Med 1990 May;115(5):603-9.|2
02016|078|R|6.Glueck CJ, Oakes N, Speirs J, Tracy T, Lang J. Gemfibrozil-lovastatin|2
02016|079|R|  therapy for primary hyperlipoproteinemias. Am J Cardiol 1992 Jul 1;|2
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02016|081|R|7.Wirebaugh SR, Shapiro ML, McIntyre TH, Whitney EJ. A retrospective review|2
02016|082|R|  of the use of lipid-lowering agents in combination, specifically,|2
02016|083|R|  gemfibrozil and lovastatin. Pharmacotherapy 1992;12(6):445-50.|2
02016|084|R|8.Wiklund O, Angelin B, Bergman M, Berglund L, Bondjers G, Carlsson A,|2
02016|085|R|  Linden T, Miettinen T, Odman B, Olofsson SO, et al. Pravastatin and|2
02016|086|R|  gemfibrozil alone and in combination for the treatment of|2
02016|087|R|  hypercholesterolemia. Am J Med 1993 Jan;94(1):13-20.|2
02016|088|R|9.Chucrallah A, De Girolami U, Freeman R, Federman M. Lovastatin/gemfibrozil|3
02016|089|R|  myopathy: a clinical, histochemical, and ultrastructural study. Eur Neurol|3
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02016|091|R|10.Knoll RW, Ciafone R, Galen M. Rhabdomyolysis and renal failure secondary|3
02016|092|R|   to combination therapy of hyperlipidemia with lovastatin and gemfibozil.|3
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02016|094|R|11.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
02016|095|R|   cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
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02016|097|R|12.Rosenson RS. Gemfibrozil-lovastatin-associated myalgia. Am J Cardiol 1993|3
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02016|099|R|13.Illingworth DR, Bacon S. Influence of lovastatin plus gemfibrozil on|2
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02016|102|R|14.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
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02016|104|R|15.Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly|2
02016|105|R|   increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 2002|2
02016|106|R|   Dec;72(6):685-91.|2
02016|107|R|16.Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ.|2
02016|108|R|   Plasma concentrations of active lovastatin acid are markedly increased by|2
02016|109|R|   gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 2001 May;|2
02016|110|R|   69(5):340-5.|2
02016|111|R|17.Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases|2
02016|112|R|   plasma pravastatin concentrations and reduces pravastatin renal|2
02016|113|R|   clearance. Clin Pharmacol Ther 2003 Jun;73(6):538-44.|2
02016|114|R|18.Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma|2
02016|115|R|   concentrations of active simvastatin acid are increased by gemfibrozil.|2
02016|116|R|   Clin Pharmacol Ther 2000 Aug;68(2):122-9.|2
02016|117|R|19.Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with|3
02016|118|R|   simvastatin-gemfibrozil therapy. South Med J 1997 May;90(5):546-7.|3
02016|119|R|20.McDonald KB, Garber BG, Perreault MM. Pancreatitis associated with|3
02016|120|R|   simvastatin plus fenofibrate. Ann Pharmacother 2002 Feb;36(2):275-9.|3
02016|121|R|21.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of|3
02016|122|R|   a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
02016|123|R|   2002;101(7):53-6.|3
02016|124|R|22.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02016|125|R|   Pharmaceuticals LP July, 2024.|1
02016|126|R|23.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
02016|127|R|   Squibb Company May, 2022.|1
02016|128|R|24.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02016|129|R|   2023.|1
02016|130|R|25.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02016|131|R|   Merck/Schering-Plough Pharmaceuticals February, 2024.|1
02016|132|R|26.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
02016|133|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
02016|134|R|   at:|3
02016|135|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
02016|136|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
02016|137|R|27.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
02016|138|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
02016|139|R|   95(1):120-2.|2
02016|140|R|28.Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, Liu L, Lin|5
02016|141|R|   JH, Pearson PG, Baillie TA. Mechanistic studies on metabolic interactions|5
02016|142|R|   between gemfibrozil and statins. J Pharmacol Exp Ther 2002 Jun;|5
02016|143|R|   301(3):1042-51.|5
02016|144|R|29.Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly|2
02016|145|R|   decreases and gemfibrozil increases the plasma concentrations of|2
02016|146|R|   atorvastatin and its metabolites. Clin Pharmacol Ther 2005 Aug;|2
02016|147|R|   78(2):154-67.|2
02016|148|R|30.Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J.|5
02016|149|R|   Interaction between fibrates and statins--metabolic interactions with|5
02016|150|R|   gemfibrozil. Drug Metabol Drug Interact 2003;19(3):161-76.|5
02016|151|R|31.Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking|3
02016|152|R|   atorvastatin with gemfibrozil. Am J Cardiol 1998 Feb 1;81(3):368-9.|3
02016|153|R|32.Shanahan RL, Kerzee JA, Sandhoff BG, Carroll NM, Merenich JA. Low|2
02016|154|R|   myopathy rates associated with statins as monotherapy or combination|2
02016|155|R|   therapy with interacting drugs in a group model health maintenance|2
02016|156|R|   organization. Pharmacotherapy 2005 Mar;25(3):345-51.|2
02016|157|R|33.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
02016|158|R|   Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized|2
02016|159|R|   rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004|2
02016|160|R|   Dec 1;292(21):2585-90.|2
02016|161|R|34.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
02016|162|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
02016|163|R|35.Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and|3
02016|164|R|   acute renal failure after changing statin-fibrate combinations.|3
02016|165|R|   Cardiology 2000;94(2):127-8.|3
02016|166|R|36.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02016|167|R|   restrictions, contraindications, and dose limitations for Zocor|1
02016|168|R|   (simvastatin) to reduce the risk of muscle injury. available at:|1
02016|169|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-co|1
02016|170|R|   mmunication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02016|171|R|   June 8, 2011.|1
02016|172|R|37.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun|6
02016|173|R|   LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,|6
02016|174|R|   Heidenreich PA. 2018|6
02016|175|R|   AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the|6
02016|176|R|   Management of Blood Cholesterol: A Report of the American College of|6
02016|177|R|   Cardiology/American Heart Association Task Force on Clinical Practice|6
02016|178|R|   Guidelines. J Am Coll Cardiol 2019 Jun 25;73(24):e285-e350.|6
02017|001|T|MONOGRAPH TITLE:  Fluvastatin (Greater Than 20 mg BID); Pitavastatin;|
02017|002|T|Pravastatin (Greater Than 20 mg); Rosuvastatin (Greater Than 5 mg);|
02017|003|T|Simvastatin/Cyclosporine|
02017|004|B||
02017|005|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02017|006|L|is contraindicated and generally should not be dispensed or administered to|
02017|007|L|the same patient.|
02017|008|B||
02017|009|A|MECHANISM OF ACTION:  Cyclosporine is a CYP3A4, P-glycoprotein, and OATP|
02017|010|A|inhibitor, while statins are CYP3A4, P-glycoprotein, and OATP substrates.|
02017|011|A|(18,30) When a statin is combined with cyclosporine, statin clearance is|
02017|012|A|reduced and elevated statin concentrations remain in the peripheral blood|
02017|013|A|and muscle cells.(31)|
02017|014|B||
02017|015|E|CLINICAL EFFECTS:  Myopathy and muscle aches, tenderness and weakness|
02017|016|E|(rhabdomyolysis) may occur with concurrent administration of HMG-CoA|
02017|017|E|reductase inhibitors and cyclosporine.|
02017|018|B||
02017|019|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02017|020|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02017|021|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02017|022|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02017|023|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02017|024|P|transporter OATP1B1 may have increased statin concentrations and be|
02017|025|P|predisposed to myopathy or rhabdomyolysis.  Patients on fluvastatin who are|
02017|026|P|CYP2C9 intermediate or poor metabolizers may have increased fluvastatin|
02017|027|P|concentrations and  risk of myopathy.  Patients on rosuvastatin with ABCG2|
02017|028|P|polymorphisms leading to decreased or poor BCRP transporter function may|
02017|029|P|have increased rosuvastatin concentrations and risk of myopathy.|
02017|030|B||
02017|031|M|PATIENT MANAGEMENT:  The dosage of fluvastatin should not exceed 20 mg BID|
02017|032|M|in patients receiving cyclosporine.(1)|
02017|033|M|   The concurrent use of pitavastatin with cyclosporine is|
02017|034|M|contraindicated.(2)|
02017|035|M|   The dosage of pravastatin should not exceed 20 mg in patients receiving|
02017|036|M|cyclosporine.(3)|
02017|037|M|   The dosage of rosuvastatin should not exceed 5 mg in patients receiving|
02017|038|M|cyclosporine.(4)|
02017|039|M|   The concurrent use of simvastatin with cyclosporine is|
02017|040|M|contraindicated.(5-7)|
02017|041|M|   Patients receiving concurrent therapy should be instructed to report|
02017|042|M|symptoms of muscle pain/tenderness/weakness, fever, unusual tiredness,|
02017|043|M|and/or a change in the amount of urine.|
02017|044|B||
02017|045|D|DISCUSSION:  Since this reaction may occur with HMG-CoA-reductase inhibitors|
02017|046|D|alone, a causal relationship is difficult to establish.  However, the|
02017|047|D|incidence of myopathy and rhabdomyolysis appears to increase with concurrent|
02017|048|D|administration of cyclosporine.|
02017|049|D|   In a study, administration of a single dose of cyclosporine (2 mg/kg) on|
02017|050|D|Day 6 of pitavastatin (2 mg daily) increased the AUC and Cmax of|
02017|051|D|pitavastatin by 4.6-fold and 6.6-fold, respectively.(2)|
02017|052|D|   In a study, administration of pravastatin in 11 heart transplant patients|
02017|053|D|receiving cyclosporine was compared to 8 control subjects not receiving|
02017|054|D|cyclosporine.  Pravastatin AUC and Cmax were 7-8-fold and 12-fold higher,|
02017|055|D|respectively, in subjects taking cyclosporine.(8)|
02017|056|D|   In a double-blind, randomized, cross-over study in 44 renal transplant|
02017|057|D|patients, neither lovastatin nor pravastatin affected cyclosporine levels.|
02017|058|D|Pravastatin levels after 1 day and after 28 days of concurrent therapy were|
02017|059|D|5-fold higher than historical controls.  Lovastatin levels accumulated over|
02017|060|D|the course of the study and by Day 28 were 20-fold higher than historical|
02017|061|D|controls.(9)|
02017|062|D|   In a study in 31 renal transplant patients, neither pravastatin nor|
02017|063|D|simvastatin affected cyclosporine levels.(10)  In contrast, in a study in 44|
02017|064|D|heart transplant subjects, cyclosporine clearance was increased following|
02017|065|D|the addition of simvastatin.(11)|
02017|066|D|   In a study, a single dose of cyclosporine (5 mg/kg) increased the Cmax|
02017|067|D|and AUC of a single dose of pravastatin (40 mg) by 327% and 282%,|
02017|068|D|respectively.(3)|
02017|069|D|   Several studies have found no effect from fluvastatin on cyclosporine|
02017|070|D|pharmacokinetics.(12-16)  One of these also noted no affects of cyclosporine|
02017|071|D|on fluvastatin levels.(12)  In contrast, a study that compared the|
02017|072|D|administration of fluvastatin in 10 heart transplant to 10 healthy control|
02017|073|D|subjects found that fluvastatin AUC and Cmax were 2.55-fold and 3.10-fold|
02017|074|D|higher than in control subjects.(17)  In another study, stable cyclosporine|
02017|075|D|doses increased the Cmax and AUC of fluvastatin (20 mg daily for 14 weeks)|
02017|076|D|by 30% and 90%, respectively.(1)|
02017|077|D|   In an open-label study in 10 heart transplant patients, concurrent|
02017|078|D|cyclosporine increased rosuvastatin AUC and Cmax by 7.1-fold and 10.6-fold,|
02017|079|D|respectively, when compared to historical controls.  There were no effects|
02017|080|D|on cyclosporine levels.(4,18)|
02017|081|D|   Rhabdomyolysis has been reported with concurrent cyclosporine and|
02017|082|D|lovastatin(19-23) and simvastatin.(24-29)|
02017|083|B||
02017|084|R|REFERENCES:|
02017|085|B||
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02017|089|R|  America, Inc. November, 2022.|1
02017|090|R|3.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
02017|091|R|  Squibb Company May, 2022.|1
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02017|093|R|  Pharmaceuticals LP July, 2024.|1
02017|094|R|5.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02017|095|R|  2023.|1
02017|096|R|6.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02017|097|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
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02017|099|R|  restrictions, contraindications, and dose limitations for Zocor|1
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02017|102|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
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02017|109|R|  pravastatin, in the blood of cyclosporine-treated kidney graft patients|2
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02017|115|R|11.Akhlaghi F, McLachlan AJ, Keogh AM, Brown KF. Effect of simvastatin on|2
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02017|118|R|12.Holdaas H, Hagen E, Asberg A, Lund K, Hartman A, Vaidyanathan S, Prasad|2
02017|119|R|   P, He YL, Yeh CM, Bigler H, Rouilly M, Denouel J. Evaluation of the|2
02017|120|R|   pharmacokinetic interaction between fluvastatin XL and cyclosporine in|2
02017|121|R|   renal transplant recipients. Int J Clin Pharmacol Ther 2006 Apr;|2
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02017|126|R|14.Li PK, Mak TW, Chan TH, Wang A, Lam CW, Lai KN. Effect of fluvastatin on|2
02017|127|R|   lipoprotein profiles in treating renal transplant recipients with|2
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02017|129|R|15.Holdaas H, Hartmann A, Stenstrom J, Dahl KJ, Borge M, Pfister P. Effect|2
02017|130|R|   of fluvastatin for safely lowering atherogenic lipids in renal transplant|2
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02017|133|R|16.Li PK, Mak TW, Wang AY, Lee YT, Leung CB, Lui SF, Lam CW, Lai KN. The|2
02017|134|R|   interaction of fluvastatin and cyclosporin A in renal transplant|2
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02017|136|R|17.Park JW, Siekmeier R, Lattke P, Merz M, Mix C, Schuler S, Jaross W.|2
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02017|138|R|   recipients taking cyclosporine A. J Cardiovasc Pharmacol Ther 2001 Oct;|2
02017|139|R|   6(4):351-61.|2
02017|140|R|18.Simonson SG, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CD, Windass|2
02017|141|R|   AS, Schneck DW. Rosuvastatin pharmacokinetics in heart transplant|2
02017|142|R|   recipients administered an antirejection regimen including cyclosporine.|2
02017|143|R|   Clin Pharmacol Ther 2004 Aug;76(2):167-77.|2
02017|144|R|19.Alejandro DS, Petersen J. Myoglobinuric acute renal failure in a cardiac|3
02017|145|R|   transplant patient taking lovastatin and cyclosporine. J Am Soc Nephrol|3
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02017|147|R|20.Norman DJ, Illingworth DR, Munson J, Hosenpud J. Myolysis and acute renal|3
02017|148|R|   failure in a heart-transplant recipient receiving lovastatin. N Engl J|3
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02017|150|R|21.East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA. Rhabdomyolysis in|3
02017|151|R|   patients receiving lovastatin after cardiac transplantation. N Engl J Med|3
02017|152|R|   1988 Jan 7;318(1):47-8.|3
02017|153|R|22.Tobert JA. Rhabdomyolysis in patients receiving lovastatin after cardiac|3
02017|154|R|   transplantation (reply). N Engl J Med 1988 Jan 7;318(1):48.|3
02017|155|R|23.Corpier CL, Jones PH, Suki WN, Lederer ED, Quinones MA, Schmidt SW, Young|3
02017|156|R|   JB. Rhabdomyolysis and renal injury with lovastatin use. Report of two|3
02017|157|R|   cases in cardiac transplant recipients. JAMA 1988 Jul 8;260(2):239-41.|3
02017|158|R|24.Tong J, Laport G, Lowsky R. Rhabdomyolysis after concomitant use of|3
02017|159|R|   cyclosporine and simvastatin in a patient transplanted for multiple|3
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02017|162|R|   rhabdomyolysis on changing from one statin to another one. Int J Cardiol|3
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02018|001|T|MONOGRAPH TITLE:  Lovastatin (Greater Than 20 mg); Simvastatin/Danazol|
02018|002|B||
02018|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02018|004|L|is contraindicated and generally should not be dispensed or administered to|
02018|005|L|the same patient.|
02018|006|B||
02018|007|A|MECHANISM OF ACTION:  Danazol may inhibit the metabolism of lovastatin(1)|
02018|008|A|and simvastatin(2) by CYP3A4.|
02018|009|B||
02018|010|E|CLINICAL EFFECTS:  Concurrent use of danazol may result in elevated levels|
02018|011|E|of lovastatin(1) and simvastatin(2,3) and toxicity, including|
02018|012|E|rhabdomyolysis. One case report of pancreatitis was possibly caused by the|
02018|013|E|danazol/lovastatin interaction.(7)|
02018|014|B||
02018|015|P|PREDISPOSING FACTORS:  Higher doses of lovastatin(1) or simvastatin(2,3) may|
02018|016|P|increase the risk of myopathy.|
02018|017|P|   The risk for myopathy or rhabdomyolysis may also be greater in patients|
02018|018|P|65 years and older, inadequately treated hypothyroidism, renal impairment,|
02018|019|P|carnitine deficiency, malignant hyperthermia, or in patients with a history|
02018|020|P|of myopathy or rhabdomyolysis.  Patients with a SLCO1B1 polymorphism that|
02018|021|P|leads to decreased function of the hepatic uptake transporter OATP1B1 may|
02018|022|P|have increased statin concentrations and be predisposed to myopathy or|
02018|023|P|rhabdomyolysis.|
02018|024|B||
02018|025|M|PATIENT MANAGEMENT:  The US manufacturer of lovastatin states that in|
02018|026|M|patients receiving danazol, lovastatin should be started at a dose of 10 mg|
02018|027|M|daily and that the dose of lovastatin should not exceed 20 mg daily.  The|
02018|028|M|benefits of concurrent use should be carefully weighed against the risk of|
02018|029|M|the combination.(1)|
02018|030|M|   Do not use simvastatin with danazol.(2-4)|
02018|031|B||
02018|032|D|DISCUSSION:  Concurrent use of danazol with lovastatin(1) or|
02018|033|D|simvastatin(2-4) increases the risk of rhabdomyolysis.|
02018|034|D|   Rhabdomyolysis(5-7) and pancreatitis(5) have been reported with|
02018|035|D|concurrent lovastatin and danazol and with concurrent simvastatin and|
02018|036|D|danazol.(8,9)  One case involved death.(8)|
02018|037|B||
02018|038|R|REFERENCES:|
02018|039|B||
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02018|042|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02018|043|R|  2023.|1
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02018|061|R|  fatal rhabdomyolysis. Clin Ther 2010 May;32(5):909-14.|3
02018|062|R|9.Andreou ER, Ledger S. Potential drug interaction between simvastatin and|3
02018|063|R|  danazol causing rhabdomyolysis. Can J Clin Pharmacol 2003 Winter;|3
02018|064|R|  10(4):172-4.|3
02019|001|T|MONOGRAPH TITLE:  Lovastatin (Greater Than 40 mg); Simvastatin (Greater Than|
02019|002|T|20 mg)/Amiodarone|
02019|003|B||
02019|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02019|005|L|is contraindicated and generally should not be dispensed or administered to|
02019|006|L|the same patient.|
02019|007|B||
02019|008|A|MECHANISM OF ACTION:  Amiodarone may inhibit the metabolism of lovastatin(1)|
02019|009|A|and simvastatin(2-5) by CYP3A4.|
02019|010|B||
02019|011|E|CLINICAL EFFECTS:  Concurrent use of amiodarone(1) with certain HMG CoA|
02019|012|E|reductase inhibitors may increase the risk of rhabdomyolysis.|
02019|013|B||
02019|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02019|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02019|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02019|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02019|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02019|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02019|020|P|predisposed to myopathy or rhabdomyolysis.|
02019|021|B||
02019|022|M|PATIENT MANAGEMENT:  The US manufacturers of lovastatin(1) and amiodarone(6)|
02019|023|M|recommend that the dose of lovastatin not exceed 40 mg daily in patients|
02019|024|M|receiving concurrent amiodarone unless the potential benefit outweighs the|
02019|025|M|increased risk of myopathy.|
02019|026|M|   The US manufacturers of simvastatin(2-5) and amiodarone(6) recommend that|
02019|027|M|the dose of simvastatin not exceed 20 mg daily in patients receiving|
02019|028|M|concurrent amiodarone unless the potential benefit outweighs the increased|
02019|029|M|risk of myopathy.|
02019|030|B||
02019|031|D|DISCUSSION:  Rhabdomyolysis has been reported with concurrent amiodarone and|
02019|032|D|simvastatin.(6)|
02019|033|D|   In a case report, a 63 year-old male developed rhabdomyolysis 4 weeks|
02019|034|D|after starting simvastatin therapy and 2 weeks after starting amiodarone.(7)|
02019|035|D|   In a clinical trial, myopathy was been reported in 6% of patients|
02019|036|D|receiving concurrent simvastatin (80 mg) and amiodarone.(3)|
02019|037|D|   In a randomized, cross-over study in 12 healthy subjects, subjects|
02019|038|D|received amiodarone (400 mg daily) with either simvastatin (40 mg) or|
02019|039|D|pravastatin (40 mg).  Amiodarone increase simvastatin area-under-curve (AUC)|
02019|040|D|by 73%, maximum concentration (Cmax) by 100%, and half-life by 48%.  There|
02019|041|D|were no significant effects on pravastatin pharmacokinetics.(8)|
02019|042|D|   In a case report, a 72 year-old male developed rhabdomyolysis 10 weeks|
02019|043|D|after starting amiodarone (200 mg daily) therapy and 6 weeks after starting|
02019|044|D|simvastatin (80 mg daily).(9)|
02019|045|D|   In a retrospective review of patients receiving amiodarone, the rate of|
02019|046|D|adverse events in combination with a statin was 1.0%, 0.7%, and 0.4% for|
02019|047|D|simvastatin, atorvastatin, and pravastatin, respectively.  The most commonly|
02019|048|D|reported adverse effect was muscle soreness, which was present in 77% of|
02019|049|D|reports and was found more often in older male patients.(10)|
02019|050|D|   One or more of the drug pairs linked to this monograph have been included|
02019|051|D|in a list of interactions that should be considered "high-priority" for|
02019|052|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02019|053|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02019|054|D|Coordinator (ONC) for Health Information Technology.|
02019|055|B||
02019|056|R|REFERENCES:|
02019|057|B||
02019|058|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02019|059|R|  February, 2014.|1
02019|060|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02019|061|R|  2023.|1
02019|062|R|3.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02019|063|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
02019|064|R|4.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02019|065|R|  restrictions, contraindications, and dose limitations for Zocor|1
02019|066|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02019|067|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02019|068|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02019|069|R|  June 8, 2011.|1
02019|070|R|5.Ede M. Dear Canadian Healthcare Professional:  Subject:  ZOCOR|1
02019|071|R|  (simvastatin) - New Safety Recommendations on Dosage Associated with the|1
02019|072|R|  Increased Risk of Myopathy/Rhabdomyolysis. Merck Canada Inc. November 7,|1
02019|073|R|  2012.|1
02019|074|R|6.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
02019|075|R|  Pharmaceuticals October, 2018.|1
02019|076|R|7.Roten L, Schoenenberger RA, Krahenbuhl S, Schlienger RG. Rhabdomyolysis in|3
02019|077|R|  association with simvastatin and amiodarone. Ann Pharmacother 2004 Jun;|3
02019|078|R|  38(6):978-81.|3
02019|079|R|8.Becquemont L, Neuvonen M, Verstuyft C, Jaillon P, Letierce A, Neuvonen PJ,|2
02019|080|R|  Funck-Brentano C. Amiodarone interacts with simvastatin but not with|2
02019|081|R|  pravastatin disposition kinetics. Clin Pharmacol Ther 2007 May;|2
02019|082|R|  81(5):679-84.|2
02019|083|R|9.Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin-amiodarone|3
02019|084|R|  interaction resulting in rhabdomyolysis, azotemia, and possible|3
02019|085|R|  hepatotoxicity. Ann Pharmacother 2006 Apr;40(4):753-7.|3
02019|086|R|10.Alsheikh-Ali AA, Karas RH. Adverse events with concomitant amiodarone and|2
02019|087|R|   statin therapy. Prev Cardiol 2005 Spring;8(2):95-7.|2
02019|088|R|11.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02019|089|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02019|090|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02019|091|R|   19(5):735-43.|6
02020|001|T|MONOGRAPH TITLE:  Atorvastatin; Lovastatin (Less Than or Equal To 20 mg);|
02020|002|T|Simvastatin (Less Than or Equal To 10 mg)/Verapamil|
02020|003|B||
02020|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02020|005|L|take action as needed.|
02020|006|B||
02020|007|A|MECHANISM OF ACTION:  Verapamil may inhibit the metabolism of lovastatin and|
02020|008|A|simvastatin by CYP3A4.(1-6)|
02020|009|A|   Atorvastatin may inhibit the metabolism of verapamil by CYP3A4.(7)|
02020|010|B||
02020|011|E|CLINICAL EFFECTS:  Concurrent verapamil may result in elevated levels of|
02020|012|E|lovastatin or simvastatin, which may result in rhabdomyolysis.(1-6)|
02020|013|E|   Concurrent atorvastatin may result in elevated levels of and clinical|
02020|014|E|effects from verapamil.(7)|
02020|015|B||
02020|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02020|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02020|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02020|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02020|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02020|021|P|transporter OATP1B1 may have increased statin concentrations and be|
02020|022|P|predisposed to myopathy or rhabdomyolysis.|
02020|023|B||
02020|024|M|PATIENT MANAGEMENT:  The manufacturer of lovastatin states that the dose of|
02020|025|M|lovastatin should be started at a dose of 10 mg daily and that the dose of|
02020|026|M|lovastatin should not exceed 20 mg daily in patients receiving concurrent|
02020|027|M|therapy with verapamil.(2)|
02020|028|M|   The manufacturer of simvastatin recommends that the dose of simvastatin|
02020|029|M|not exceed 10 mg daily in patients receiving concurrent therapy with|
02020|030|M|verapamil unless the potential benefit outweighs the increased risk of|
02020|031|M|myopathy.(3-6)|
02020|032|M|   Patients receiving concurrent atorvastatin should be monitored for|
02020|033|M|increased effects of verapamil.|
02020|034|M|   Patients receiving concurrent therapy with verapamil with lovastatin or|
02020|035|M|simvastatin should be monitored closely for adverse effects of the HMG-CoA|
02020|036|M|reductase inhibitor, including rhabdomyolysis.  The dosage of the HMG-CoA|
02020|037|M|reductase inhibitor may need to be reduced or discontinued.|
02020|038|M|   Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not|
02020|039|M|metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and|
02020|040|M|simvastatin in patients receiving verapamil.|
02020|041|B||
02020|042|D|DISCUSSION:  A study in 12 subjects examined the effects of pretreatment|
02020|043|D|with verapamil (240 mg daily) for two days on a single dose of simvastatin|
02020|044|D|(40 mg).  Pretreatment with verapamil resulted in 2.6-fold and 4.6-fold|
02020|045|D|increases in the Cmax and AUC of simvastatin, respectively.  Pretreatment|
02020|046|D|with verapamil also increased the Cmax and AUC of simvastatin acid 3.4-fold|
02020|047|D|and 2.8-fold, respectively.  There were no effects on the half-life or time|
02020|048|D|to maximum concentration (Cmax) of simvastatin.(1)|
02020|049|D|   Administration of multiple doses of low-dose verapamil (10 mg) and|
02020|050|D|simvastatin (80 mg) increased simvastatin exposure by 2.5-fold.(8)|
02020|051|D|   In an analysis of clinical trials involving 25,248 patients treated with|
02020|052|D|simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients|
02020|053|D|receiving verapamil and simvastatin (4/635) than in patients taking|
02020|054|D|simvastatin without a calcium channel blocker (13/21,224).(3,4)|
02020|055|D|   In a study in 12 healthy subjects, concurrent atorvastatin (40 mg)|
02020|056|D|increased the AUC of verapamil (60 mg) by 42.8%.(7)|
02020|057|B||
02020|058|R|REFERENCES:|
02020|059|B||
02020|060|R|1.Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil|2
02020|061|R|  considerably increase serum simvastatin and simvastatin acid|2
02020|062|R|  concentrations. Clin Pharmacol Ther 1998 Aug;64(2):177-82.|2
02020|063|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02020|064|R|  February, 2014.|1
02020|065|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02020|066|R|  2023.|1
02020|067|R|4.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02020|068|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
02020|069|R|5.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02020|070|R|  restrictions, contraindications, and dose limitations for Zocor|1
02020|071|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02020|072|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02020|073|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02020|074|R|  June 8, 2011.|1
02020|075|R|6.Ede M. Dear Canadian Healthcare Professional:  Subject:  ZOCOR|1
02020|076|R|  (simvastatin) - New Safety Recommendations on Dosage Associated with the|1
02020|077|R|  Increased Risk of Myopathy/Rhabdomyolysis. Merck Canada Inc. November 7,|1
02020|078|R|  2012.|1
02020|079|R|7.Choi DH, Shin WG, Choi JS. Drug interaction between oral atorvastatin and|2
02020|080|R|  verapamil in healthy subjects: effects of atorvastatin on the|2
02020|081|R|  pharmacokinetics of verapamil and norverapamil. Eur J Clin Pharmacol 2008|2
02020|082|R|  May;64(5):445-9.|2
02020|083|R|8.Calan (verapamil hydrochloride) US prescribing information. Pfizer, Inc.|1
02020|084|R|  August, 2016.|1
02021|001|T|MONOGRAPH TITLE:  Simvastatin (Greater Than 10 mg); Lovastatin (Greater Than|
02021|002|T|20 mg)/Diltiazem|
02021|003|B||
02021|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02021|005|L|is contraindicated and generally should not be dispensed or administered to|
02021|006|L|the same patient.|
02021|007|B||
02021|008|A|MECHANISM OF ACTION:  Diltiazem may inhibit the metabolism of lovastatin(1)|
02021|009|A|and simvastatin(2-4) by CYP3A4.|
02021|010|B||
02021|011|E|CLINICAL EFFECTS:  Concurrent diltiazem may result in elevated levels of|
02021|012|E|lovastatin(1) or simvastatin,(3) which may result in rhabdomyolysis.|
02021|013|B||
02021|014|P|PREDISPOSING FACTORS:  None determined.|
02021|015|B||
02021|016|M|PATIENT MANAGEMENT:  Do not use more than 20 mg of lovastatin in patients|
02021|017|M|receiving diltiazem.(1)|
02021|018|M|   Do not use more than 10 mg of simvastatin in patients receiving|
02021|019|M|diltiazem.(2-4)|
02021|020|M|   Patients receiving concurrent therapy with diltiazem should be monitored|
02021|021|M|closely for adverse effects of the HMG-CoA reductase inhibitor, including|
02021|022|M|rhabdomyolysis.  The dosage of the HMG-CoA reductase inhibitor may need to|
02021|023|M|be reduced or discontinued.|
02021|024|M|   Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not|
02021|025|M|metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and|
02021|026|M|simvastatin in patients receiving diltiazem.|
02021|027|B||
02021|028|D|DISCUSSION:  In a four-way crossover study in ten subjects, subjects|
02021|029|D|received single doses of lovastatin (20 mg) alone and following two weeks of|
02021|030|D|diltiazem (120 mg twice daily) therapy and single doses of pravastatin (20|
02021|031|D|mg) alone and following two weeks of diltiazem therapy (120 mg twice daily).|
02021|032|D|Concurrent administration of diltiazem increased lovastatin|
02021|033|D|area-under-curve (AUC) and maximum concentration (Cmax) by 2.6-fold and|
02021|034|D|3.3-fold, respectively.  The increase in lovastatin AUC ranged from 51% to|
02021|035|D|906%. There were no changes in lovastatin half-life.  Concurrent|
02021|036|D|administration of diltiazem had no effect on the AUC, Cmax, or half-life of|
02021|037|D|pravastatin.(5,6)|
02021|038|D|   In a study, diltiazem (120 mg twice daily for 10 days) increased the AUC|
02021|039|D|and Cmax of a single dose of simvastatin (80 mg on Day 10) by 3.1-fold and|
02021|040|D|2.88-fold, respectively.  The AUC and Cmax of simvastatin acid increased by|
02021|041|D|2.69-fold and 2.69-fold, respectively.(3)|
02021|042|D|   In a study in Chinese subjects, concurrent diltiazem (60 mg TID) and|
02021|043|D|simvastatin (20 mg daily) enhanced reduction of LDL levels by 1.66% when|
02021|044|D|compared to simvastatin (20 mg alone).(7)|
02021|045|D|   In a study in 11 patients with hypercholesterolemia and hypertension,|
02021|046|D|concurrent administration of diltiazem (90 mg daily) and simvastatin (5 mg|
02021|047|D|daily) increased the Cmax and AUC of simvastatin by 97% and 99.5%,|
02021|048|D|respectively, when compared to administration of simvastatin (5 mg daily)|
02021|049|D|alone.  Diltiazem Cmax and AUC decreased by 21% and 21%, respectively, when|
02021|050|D|compared to the administration of diltiazem (90 mg) alone.  Combination|
02021|051|D|therapy lowered LDL levels by an additional 9% when compared to simvastatin|
02021|052|D|monotherapy.(8)|
02021|053|D|   In a study in 10 healthy subjects, diltiazem (120 mg daily for 2 weeks)|
02021|054|D|increased the Cmax and AUC of a single dose of simvastatin (20 mg) by|
02021|055|D|3.6-fold and 5-fold, respectively.  The Cmax of simvastatin acid increased|
02021|056|D|by 3.7-fold.(2,9)  A daily dose of 480 mg of diltiazem is expected to|
02021|057|D|increase simvastatin levels 8-fold.(2|
02021|058|D|   In a retrospective review, patients who received simvastatin with|
02021|059|D|concurrent diltiazem experienced a 33.3% reduction in cholesterol levels|
02021|060|D|compared with 24.7% in patients receiving simvastatin without concurrent|
02021|061|D|diltiazem.(10)|
02021|062|D|   There are several case reports of myopathy and rhabdomyolysis in patients|
02021|063|D|receiving concurrent simvastatin and diltiazem.(11-16)|
02021|064|D|   One or more of the drug pairs linked to this monograph have been included|
02021|065|D|in a list of interactions that should be considered "high-priority" for|
02021|066|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02021|067|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02021|068|D|Coordinator (ONC) for Health Information Technology.|
02021|069|B||
02021|070|R|REFERENCES:|
02021|071|B||
02021|072|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02021|073|R|  February, 2014.|1
02021|074|R|2.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02021|075|R|  restrictions, contraindications, and dose limitations for Zocor|1
02021|076|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02021|077|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02021|078|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02021|079|R|  June 8, 2011.|1
02021|080|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02021|081|R|  2023.|1
02021|082|R|4.Ede M. Dear Canadian Healthcare Professional:  Subject:  ZOCOR|1
02021|083|R|  (simvastatin) - New Safety Recommendations on Dosage Associated with the|1
02021|084|R|  Increased Risk of Myopathy/Rhabdomyolysis. Merck Canada Inc. November 7,|1
02021|085|R|  2012.|1
02021|086|R|5.Azie NE, Brater DC, Becker PA, Jones DR, Hall SD. The interaction of|2
02021|087|R|  diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998 Oct;|2
02021|088|R|  64(4):369-77.|2
02021|089|R|6.Dilacor (diltiazem hydrochloride) US prescribing information. Watson|1
02021|090|R|  Pharma, Inc. June, 2011.|1
02021|091|R|7.You JH, Chan WK, Chung PF, Hu M, Tomlinson B. Effects of concomitant|2
02021|092|R|  therapy with diltiazem on the lipid responses to simvastatin in Chinese|2
02021|093|R|  subjects. J Clin Pharmacol 2010 Oct;50(10):1151-8.|2
02021|094|R|8.Watanabe H, Kosuge K, Nishio S, Yamada H, Uchida S, Satoh H, Hayashi H,|2
02021|095|R|  Ishizaki T, Ohashi K. Pharmacokinetic and pharmacodynamic interactions|2
02021|096|R|  between simvastatin and diltiazem in patients with hypercholesterolemia|2
02021|097|R|  and hypertension. Life Sci 2004 Dec 3;76(3):281-92.|2
02021|098|R|9.Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with|2
02021|099|R|  simvastatin. Clin Pharmacol Ther 2000 Mar;67(3):267-74.|2
02021|100|R|10.Yeo KR, Yeo WW, Wallis EJ, Ramsay LE. Enhanced cholesterol reduction by|2
02021|101|R|   simvastatin in diltiazem-treated patients. Br J Clin Pharmacol 1999 Oct;|2
02021|102|R|   48(4):610-5.|2
02021|103|R|11.Hu M, Mak VW, Tomlinson B. Simvastatin-induced myopathy, the role of|3
02021|104|R|   interaction with diltiazem and genetic predisposition. J Clin Pharm Ther|3
02021|105|R|   2011 Jun;36(3):419-25.|3
02021|106|R|12.Rifkin SI. Multiple drug interactions in a renal transplant patient|3
02021|107|R|   leading to simvastatin-induced rhabdomyolysis: a case report. Medscape J|3
02021|108|R|   Med 2008;10(11):264.|3
02021|109|R|13.Najafian B, Franklin DB, Fogo AB. Acute renal failure and myalgia in a|3
02021|110|R|   transplant patient. J Am Soc Nephrol 2007 Nov;18(11):2870-4.|3
02021|111|R|14.Bae J, Jarcho JA, Denton MD, Magee CC. Statin specific toxicity in organ|3
02021|112|R|   transplant recipients: case report and review of the literature. J|3
02021|113|R|   Nephrol 2002 May-Jun;15(3):317-9.|3
02021|114|R|15.Kanathur N, Mathai MG, Byrd RP Jr, Fields CL, Roy TM.|3
02021|115|R|   Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and|3
02021|116|R|   hepatitis. Tenn Med 2001 Sep;94(9):339-41.|3
02021|117|R|16.Peces R, Pobes A. Rhabdomyolysis associated with concurrent use of|3
02021|118|R|   simvastatin and diltiazem. Nephron 2001 Sep;89(1):117-8.|3
02021|119|R|17.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02021|120|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02021|121|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02021|122|R|   19(5):735-43.|6
02022|001|T|MONOGRAPH TITLE:  Lovastatin (Greater Than 20 mg); Simvastatin (Greater Than|
02022|002|T|10 mg)/Verapamil|
02022|003|B||
02022|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02022|005|L|is contraindicated and generally should not be dispensed or administered to|
02022|006|L|the same patient.|
02022|007|B||
02022|008|A|MECHANISM OF ACTION:  Verapamil may inhibit the metabolism of lovastatin and|
02022|009|A|simvastatin by CYP3A4.(1-6)|
02022|010|B||
02022|011|E|CLINICAL EFFECTS:  Concurrent verapamil may result in elevated levels of|
02022|012|E|lovastatin or simvastatin, which may result in rhabdomyolysis.(1-6)|
02022|013|B||
02022|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02022|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02022|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02022|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02022|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02022|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02022|020|P|predisposed to myopathy or rhabdomyolysis.|
02022|021|B||
02022|022|M|PATIENT MANAGEMENT:  The manufacturer of lovastatin states that the dose of|
02022|023|M|lovastatin should be started at a dose of 10 mg daily and that the dose of|
02022|024|M|lovastatin should not exceed 20 mg daily in patients receiving concurrent|
02022|025|M|therapy with verapamil.(2)|
02022|026|M|   The manufacturer of simvastatin recommends that the dose of simvastatin|
02022|027|M|not exceed 10 mg daily in patients receiving concurrent therapy with|
02022|028|M|verapamil unless the potential benefit outweighs the increased risk of|
02022|029|M|myopathy.(3-6)|
02022|030|M|   Patients receiving concurrent therapy with verapamil with lovastatin or|
02022|031|M|simvastatin should be monitored closely for adverse effects of the HMG-CoA|
02022|032|M|reductase inhibitor, including rhabdomyolysis.  The dosage of the HMG-CoA|
02022|033|M|reductase inhibitor may need to be further reduced or discontinued.|
02022|034|M|   Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not|
02022|035|M|metabolized by CYP P-450-3A4, may be alternatives to atorvastatin,|
02022|036|M|lovastatin, and simvastatin in patients receiving verapamil.|
02022|037|B||
02022|038|D|DISCUSSION:  A study in 12 subjects examined the effects of pretreatment|
02022|039|D|with verapamil (240 mg daily) for two days on a single dose of simvastatin|
02022|040|D|(40 mg).  Pretreatment with verapamil resulted in 2.6-fold and 4.6-fold|
02022|041|D|increases in the Cmax and AUC of simvastatin, respectively.  Pretreatment|
02022|042|D|with verapamil also increased the Cmax and AUC of simvastatin acid 3.4-fold|
02022|043|D|and 2.8-fold, respectively.  There were no effects on the half-life or time|
02022|044|D|to maximum concentration (Cmax) of simvastatin.(1)|
02022|045|D|   In an analysis of clinical trials involving 25,248 patients treated with|
02022|046|D|simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients|
02022|047|D|receiving verapamil and simvastatin (4/635) than in patients taking|
02022|048|D|simvastatin without a calcium channel blocker (13/21,224).(3,4)|
02022|049|D|   Administration of multiple doses of low-dose verapamil (10 mg) and|
02022|050|D|simvastatin (80 mg) increased simvastatin exposure by 2.5-fold.(7)|
02022|051|D|   One or more of the drug pairs linked to this monograph have been included|
02022|052|D|in a list of interactions that should be considered "high-priority" for|
02022|053|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02022|054|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02022|055|D|Coordinator (ONC) for Health Information Technology.|
02022|056|B||
02022|057|R|REFERENCES:|
02022|058|B||
02022|059|R|1.Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil|2
02022|060|R|  considerably increase serum simvastatin and simvastatin acid|2
02022|061|R|  concentrations. Clin Pharmacol Ther 1998 Aug;64(2):177-82.|2
02022|062|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02022|063|R|  February, 2014.|1
02022|064|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02022|065|R|  2023.|1
02022|066|R|4.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02022|067|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
02022|068|R|5.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02022|069|R|  restrictions, contraindications, and dose limitations for Zocor|1
02022|070|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02022|071|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02022|072|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02022|073|R|  June 8, 2011.|1
02022|074|R|6.Ede M. Dear Canadian Healthcare Professional:  Subject:  ZOCOR|1
02022|075|R|  (simvastatin) - New Safety Recommendations on Dosage Associated with the|1
02022|076|R|  Increased Risk of Myopathy/Rhabdomyolysis. Merck Canada Inc. November 7,|1
02022|077|R|  2012.|1
02022|078|R|7.Calan (verapamil hydrochloride) US prescribing information. Pfizer, Inc.|1
02022|079|R|  August, 2016.|1
02022|080|R|8.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02022|081|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02022|082|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02022|083|R|  19(5):735-43.|6
02023|001|T|MONOGRAPH TITLE:  IOP-Lowering Prostaglandin Analogs/Bimatoprost Topical|
02023|002|B||
02023|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02023|004|L|take action as needed.|
02023|005|B||
02023|006|A|MECHANISM OF ACTION:  When used ophthalmically to lower intraocular|
02023|007|A|pressure, prostaglandin analogs may be at the top of the dose-response|
02023|008|A|curve.  Use of an additional prostaglandin may result in decreased|
02023|009|A|effectiveness.(1)|
02023|010|B||
02023|011|E|CLINICAL EFFECTS:  Concurrent use of topical bimatoprost may result in|
02023|012|E|decreased effectiveness of ophthalmic prostaglandin analogs and an increase|
02023|013|E|in intraocular pressure.(1)|
02023|014|B||
02023|015|P|PREDISPOSING FACTORS:  None determined.|
02023|016|B||
02023|017|M|PATIENT MANAGEMENT:  Patients using ophthalmic prostaglandin analogs to|
02023|018|M|lower intraocular pressure should be monitored for changes in their|
02023|019|M|intraocular pressure.(1)  Use of topical bimatoprost may need to be|
02023|020|M|discontinued in patients who stop responding to their ophthalmic|
02023|021|M|prostaglandin analogue.|
02023|022|B||
02023|023|D|DISCUSSION:  Studies have shown that the ophthalmic administration of|
02023|024|D|bimatoprost twice daily is less effective at lowering intraocular pressure|
02023|025|D|than ophthalmic bimatoprost administered once daily.  Concurrent use of|
02023|026|D|topical bimatoprost may decrease the effectiveness of ophthalmic|
02023|027|D|prostaglandin analogs.(1)|
02023|028|B||
02023|029|R|REFERENCE:|
02023|030|B||
02023|031|R|1.Latisse (bimatoprost) US prescribing information. Allergan, Inc.|1
02023|032|R|  September, 2020.|1
02024|001|T|MONOGRAPH TITLE:  Telithromycin/QT Prolonging Agents|
02024|002|B||
02024|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02024|004|L|take action as needed.|
02024|005|B||
02024|006|A|MECHANISM OF ACTION:  Telithromycin may prolong the QTc interval.|
02024|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02024|008|A|additive effects on the QTc interval.(1)|
02024|009|B||
02024|010|E|CLINICAL EFFECTS:  The concurrent use of telithromycin with other agents|
02024|011|E|that prolong the QTc interval may result in potentially life-threatening|
02024|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02024|013|B||
02024|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02024|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02024|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02024|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02024|018|P|gender, or advanced age.(2)|
02024|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02024|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02024|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02024|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02024|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02024|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02024|025|P|dysfunction).(2)|
02024|026|B||
02024|027|M|PATIENT MANAGEMENT:  The manufacturer of telithromycin states to avoid|
02024|028|M|concurrent use with class IA and III antiarrhythmics.  Caution should be|
02024|029|M|used with other agents that can cause QT prolongation.(1)|
02024|030|M|    Additional monitoring when concurrent therapy is warranted: consider|
02024|031|M|obtaining serum calcium, magnesium, and potassium levels at baseline and|
02024|032|M|regular intervals. Correct any electrolyte abnormalities.|
02024|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02024|034|M|fainting.|
02024|035|B||
02024|036|D|DISCUSSION:  Cases of ventricular arrhythmias have been reported with|
02024|037|D|telithromycin and sometimes occurred within a few hours of the first|
02024|038|D|dose.(1)|
02024|039|D|   In clinical trials, no cardiovascular morbidity or mortality attributed|
02024|040|D|to QTc prolongation occurred with telithromycin.(1)|
02024|041|D|   In vitro electrophysiological studies suggested an inhibition of the|
02024|042|D|rapid activating component of the delayed rectifier potassium current as the|
02024|043|D|underlying mechanism.  However, these effects were observed at|
02024|044|D|concentrations significantly greater than those circulating in clinical|
02024|045|D|use.(1)|
02024|046|D|   Agents that are linked to this monograph may have varying degrees of|
02024|047|D|potential to prolong the QTc interval but are generally accepted to have a|
02024|048|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02024|049|D|been shown to prolong the QTc interval either through their mechanism of|
02024|050|D|action, through studies on their effects on the QTc interval, or through|
02024|051|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02024|052|D|and/or post-marketing reports.|
02024|053|B||
02024|054|R|REFERENCES:|
02024|055|B||
02024|056|R|1.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
02024|057|R|  November, 2015.|1
02024|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02024|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02024|060|R|  settings: a scientific statement from the American Heart Association and|6
02024|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02024|062|R|  2;55(9):934-47.|6
02024|063|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02024|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02024|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02024|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02025|001|T|MONOGRAPH TITLE:  Amifampridine/QT Prolonging Agents (mono deleted|
02025|002|T|05/10/2019)|
02025|003|B||
02025|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02025|005|L|is contraindicated and generally should not be dispensed or administered to|
02025|006|L|the same patient.|
02025|007|B||
02025|008|A|MECHANISM OF ACTION:  Concurrent use of amifampridine with agents that|
02025|009|A|prolong the QTc interval may result in additive effects on the QTc|
02025|010|A|interval.(1)|
02025|011|B||
02025|012|E|CLINICAL EFFECTS:  The concurrent use of amifampridine with agents that|
02025|013|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02025|014|E|arrhythmias, including torsades de pointes.(1)|
02025|015|B||
02025|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02025|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
02025|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02025|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02025|020|P|female gender, or advanced age.(3)|
02025|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02025|022|P|higher systemic concentrations of either QT prolonging drug are additional|
02025|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02025|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02025|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02025|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02025|027|P|dysfunction).(3)|
02025|028|B||
02025|029|M|PATIENT MANAGEMENT:  The UK manufacturer of amifampridine states that the|
02025|030|M|concurrent use of drugs that may prolong the QT interval is|
02025|031|M|contraindicated.(1)|
02025|032|B||
02025|033|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02025|034|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02025|035|D|monograph have been shown to prolong the QTc interval either through their|
02025|036|D|mechanism of action, through studies on their effects on the QTc interval,|
02025|037|D|or through reports of QTc prolongation and/or torsades de pointes in|
02025|038|D|clinical trials and/or postmarketing reports.(2)|
02025|039|B||
02025|040|R|REFERENCES:|
02025|041|B||
02025|042|R|1.Firdapse (amifampridine phosphate) UK summary of product characteristics.|1
02025|043|R|  BioMarin Europe Limited February, 2010.|1
02025|044|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02025|045|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02025|046|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02025|047|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02025|048|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02025|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02025|050|R|  settings: a scientific statement from the American Heart Association and|6
02025|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02025|052|R|  2;55(9):934-47.|6
02026|001|T|MONOGRAPH TITLE:  Amifampridine/Possible QT Prolonging Agents (mono deleted|
02026|002|T|05/10/2019)|
02026|003|B||
02026|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02026|005|L|of severe adverse interaction.|
02026|006|B||
02026|007|A|MECHANISM OF ACTION:  Concurrent use of amifampridine with agents that|
02026|008|A|prolong the QTc interval may result in additive effects on the QTc|
02026|009|A|interval.(1)|
02026|010|B||
02026|011|E|CLINICAL EFFECTS:  The concurrent use of amifampridine with agents that|
02026|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02026|013|E|arrhythmias, including torsades de pointes.(1)|
02026|014|B||
02026|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02026|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02026|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02026|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02026|019|P|gender, or advanced age.(3)|
02026|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02026|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02026|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02026|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02026|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02026|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02026|026|P|dysfunction).(3)|
02026|027|B||
02026|028|M|PATIENT MANAGEMENT:  The UK manufacturer of amifampridine states that the|
02026|029|M|concurrent use of drugs that may prolong the QT interval is|
02026|030|M|contraindicated.(1)|
02026|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02026|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02026|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02026|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02026|035|B||
02026|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02026|037|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02026|038|D|monograph have been shown to prolong the QTc interval either through their|
02026|039|D|mechanism of action, through studies on their effects on the QTc interval,|
02026|040|D|or through reports of QTc prolongation and/or torsades de pointes in|
02026|041|D|clinical trials and/or postmarketing reports.(2)|
02026|042|B||
02026|043|R|REFERENCES:|
02026|044|B||
02026|045|R|1.Firdapse (amifampridine phosphate) UK summary of product characteristics.|1
02026|046|R|  BioMarin Europe Limited February, 2010.|1
02026|047|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02026|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02026|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02026|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02026|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02026|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02026|053|R|  settings: a scientific statement from the American Heart Association and|6
02026|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02026|055|R|  2;55(9):934-47.|6
02027|001|T|MONOGRAPH TITLE:  Nifedipine/Selected CYP3A4 Inducers|
02027|002|B||
02027|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02027|004|L|is contraindicated and generally should not be dispensed or administered to|
02027|005|L|the same patient.|
02027|006|B||
02027|007|A|MECHANISM OF ACTION:  CYP3A4 inducers may induce the hepatic metabolism of|
02027|008|A|nifedipine.(1)|
02027|009|B||
02027|010|E|CLINICAL EFFECTS:  Concurrent use of an inducer of CYP3A4 may decrease|
02027|011|E|levels and effectiveness of nifedipine.(1)|
02027|012|B||
02027|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02027|014|P|of the inducer for longer than 1-2 weeks.|
02027|015|B||
02027|016|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inducers with|
02027|017|M|nifedipine is contraindicated.(1)|
02027|018|B||
02027|019|D|DISCUSSION:  In a study in 12 healthy males, pretreatment with rifampin (600|
02027|020|D|mg daily for 14 days) decreased the maximum concentration (Cmax) and|
02027|021|D|area-under-curve (AUC) of a single dose of nifedipine (20 mg) by 95% and|
02027|022|D|97%, respectively.(1)|
02027|023|D|   In a study of 6 healthy subjects, pretreatment with rifampin (600 mg|
02027|024|D|daily for 7 days) increased the clearance of a single oral dose of|
02027|025|D|nifedipine (20 mg) by 9.28-fold and decrease the nifedipine bioavailability|
02027|026|D|by 87%.  There were no significant effects on a single intravenous dose of|
02027|027|D|nifedipine.(2)|
02027|028|D|   In a study in 6 healthy subjects, pretreatment with a single dose of|
02027|029|D|rifampin (600 mg) 8 hours before a single oral dose of nifedipine decreased|
02027|030|D|nifedipine bioavailability by 64.2%.  Nifedipine half-life decreased by 60%.|
02027|031|D|Nifedipine clearance increased by 1.89-fold.(3)|
02027|032|D|   There have been case reports of decreased effectiveness of nifedipine|
02027|033|D|during concurrent rifampin therapy.(4-6)|
02027|034|D|   Enzalutamide is a strong inducer of CYP3A4.(7)|
02027|035|D|   Selected CYP3A4 inducers linked to this monograph include apalutamide,|
02027|036|D|encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifabutin,|
02027|037|D|rifampin, and rifapentine.|
02027|038|B||
02027|039|R|REFERENCES:|
02027|040|B||
02027|041|R|1.Adalat (nifedipine) US prescribing information. Bayer Healthcare|1
02027|042|R|  Pharmaceuticals Inc. August, 2016.|1
02027|043|R|2.Holtbecker N, Fromm MF, Kroemer HK, Ohnhaus EE, Heidemann H. The|2
02027|044|R|  nifedipine-rifampin interaction. Evidence for induction of gut wall|2
02027|045|R|  metabolism. Drug Metab Dispos 1996 Oct;24(10):1121-3.|2
02027|046|R|3.Ndanusa BU, Mustapha A, Abdu-Aguye I. The effect of single does of|2
02027|047|R|  rifampicin on the pharmacokinetics of oral nifedipine. J Pharm Biomed Anal|2
02027|048|R|  1997 Jun;15(9-10):1571-5.|2
02027|049|R|4.Yoshimoto H, Takahashi M, Saima S. Influence of rifampicin on|3
02027|050|R|  antihypertensive effects of dihydropiridine calcium-channel blockers in|3
02027|051|R|  four elderly patients. Nippon Ronen Igakkai Zasshi 1996 Sep;33(9):692-6.|3
02027|052|R|5.Tada Y, Tsuda Y, Otsuka T, Nagasawa K, Kimura H, Kusaba T, Sakata T. Case|3
02027|053|R|  report: nifedipine-rifampicin interaction attenuates the effect on blood|3
02027|054|R|  pressure in a patient with essential hypertension. Am J Med Sci 1992 Jan;|3
02027|055|R|  303(1):25-7.|3
02027|056|R|6.Tsuchihashi K, Fukami K, Kishimoto H, Sumiyoshi T, Haze K, Saito M,|3
02027|057|R|  Hiramori K. A case of variant angina exacerbated by administration of|3
02027|058|R|  rifampicin. Heart Vessels 1987;3(4):214-7.|3
02027|059|R|7.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
02027|060|R|  September, 2022.|1
02028|001|T|MONOGRAPH TITLE:  Nifedipine/St. John's Wort|
02028|002|B||
02028|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02028|004|L|is contraindicated and generally should not be dispensed or administered to|
02028|005|L|the same patient.|
02028|006|B||
02028|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
02028|008|A|nifedipine by CYP3A4.(1)|
02028|009|B||
02028|010|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort may result in|
02028|011|E|decreased levels and clinical effects of nifedipine.(1)|
02028|012|B||
02028|013|P|PREDISPOSING FACTORS:  None determined.|
02028|014|B||
02028|015|M|PATIENT MANAGEMENT:  The US manufacturer of nifedipine states that|
02028|016|M|concurrent use of strong CYP3A4 inducers such as St. John's wort is|
02028|017|M|contraindicated.(1)|
02028|018|B||
02028|019|D|DISCUSSION:  Coadministration of phenytoin, another inducer of CYP3A4, with|
02028|020|D|nifedipine (10 mg capsule and 60 mg extended-release tablet) decreased the|
02028|021|D|area-under-curve (AUC) and maximum concentration (Cmax) of nifedipine by|
02028|022|D|70%.(1)|
02028|023|D|   In a study in 12 healthy males, pretreatment with rifampin (600 mg daily|
02028|024|D|for 14 days), another inducers of CYP3A4, decreased the Cmax and AUC of a|
02028|025|D|single dose of nifedipine (20 mg) by 95% and 97%, respectively.(1)|
02028|026|B||
02028|027|R|REFERENCE:|
02028|028|B||
02028|029|R|1.Adalat (nifedipine) US prescribing information. Bayer Healthcare|1
02028|030|R|  Pharmaceuticals Inc. August, 2016.|1
02029|001|T|MONOGRAPH TITLE:  Pitavastatin/Lopinavir-Ritonavir (mono deleted 03/01/2012)|
02029|002|B||
02029|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02029|004|L|is contraindicated and generally should not be dispensed or administered to|
02029|005|L|the same patient.|
02029|006|B||
02029|007|A|MECHANISM OF ACTION:  Lopinavir-ritonavir is expected to increase|
02029|008|A|pitavastatin exposure.(1)|
02029|009|B||
02029|010|E|CLINICAL EFFECTS:  Concurrent use of lopinavir-ritonavir may result in|
02029|011|E|elevated levels of and toxicity from pitavastatin, which may include|
02029|012|E|rhabdomyolysis.(1)|
02029|013|B||
02029|014|P|PREDISPOSING FACTORS:  None determined.|
02029|015|B||
02029|016|M|PATIENT MANAGEMENT:  The US manufacturer of pitavastatin states that|
02029|017|M|pitavastatin should not be used with lopinavir-ritonavir.(1)|
02029|018|B||
02029|019|D|DISCUSSION:  Pitavastatin has not been studied with lopinavir-ritonavir;|
02029|020|D|however, use of lopinavir-ritonavir with another HMG CoA reductase inhibitor|
02029|021|D|that is similar to pitavastatin resulted in significant increases in levels|
02029|022|D|of the HMG CoA reductase inhibitor.  Similar results are expected with|
02029|023|D|pitavastatin.(1)|
02029|024|B||
02029|025|R|REFERENCE:|
02029|026|B||
02029|027|R|1.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
02029|028|R|  America, Inc. November, 2022.|1
02030|001|T|MONOGRAPH TITLE:  Pitavastatin (Greater Than 2 mg)/Rifampin|
02030|002|B||
02030|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02030|004|L|is contraindicated and generally should not be dispensed or administered to|
02030|005|L|the same patient.|
02030|006|B||
02030|007|A|MECHANISM OF ACTION:  Rifampin is an organic anion transporting polypeptide|
02030|008|A|(OATP) inhibitor and pitavastatin is an OATP substrate.  When used|
02030|009|A|concomitantly, rifampin inhibits hepatic uptake of pitavastatin in a|
02030|010|A|concentration dependent manner.(2)|
02030|011|B||
02030|012|E|CLINICAL EFFECTS:  Concurrent use of rifampin and pitavastatin may result in|
02030|013|E|elevated levels of and toxicity from pitavastatin, which may include|
02030|014|E|rhabdomyolysis, and a small decrease in rifampin levels.(1)|
02030|015|B||
02030|016|P|PREDISPOSING FACTORS:  None determined.|
02030|017|B||
02030|018|M|PATIENT MANAGEMENT:  The dosage of pitavastatin should not exceed 2 mg daily|
02030|019|M|in patients receiving rifampin.(1)  Monitor patients receiving concurrent|
02030|020|M|therapy with other dosages for signs of myopathy and rifampin efficacy.|
02030|021|B||
02030|022|D|DISCUSSION:  In a study, concurrent use of rifampin (600 mg daily for 5|
02030|023|D|days) and pitavastatin (4 mg daily) increased pitavastatin area-under-curve|
02030|024|D|(AUC) and maximum concentration (Cmax) by 29% and 2-fold, respectively.  The|
02030|025|D|AUC and Cmax of rifampin 15% and 18%, respectively.(1)|
02030|026|D|In an animal study, rifampicin inhibited uptake of pitavastatin into|
02030|027|D|cynomolgus monkey hepatocytes in a manner comparable to human|
02030|028|D|hepatocytes.(2)|
02030|029|B||
02030|030|R|REFERENCES:|
02030|031|B||
02030|032|R|1.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
02030|033|R|  America, Inc. November, 2022.|1
02030|034|R|2.Takahashi T, Ohtsuka T, Yoshikawa T, Tatekawa I, Uno Y, Utoh M, Yamazaki|5
02030|035|R|  H, Kume T. Pitavastatin as an in vivo probe for studying hepatic organic|5
02030|036|R|  anion transporting  polypeptide-mediated drug-drug interactions in|5
02030|037|R|  cynomolgus monkeys. Drug Metab Dispos 2013 Oct;41(10):1875-82.|5
02030|038|R|3.Hirano M, Maeda K, Shitara Y, Sugiyama Y. Drug-drug interaction between|5
02030|039|R|  pitavastatin and various drugs via OATP1B1. Drug Metab Dispos 2006 Jul;|5
02030|040|R|  34(7):1229-36.|5
02031|001|T|MONOGRAPH TITLE:  Pitavastatin (<= 2 mg)/Rifampin|
02031|002|B||
02031|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02031|004|L|take action as needed.|
02031|005|B||
02031|006|A|MECHANISM OF ACTION:  Although the exact mechanisms are not known,(1)|
02031|007|A|pitavastatin is a substrate for the OATP1B1 transporter and rifampin|
02031|008|A|inhibits the activity of this transport protein.(2)|
02031|009|B||
02031|010|E|CLINICAL EFFECTS:  Concurrent use of rifampin and pitavastatin may result in|
02031|011|E|elevated levels of and toxicity from pitavastatin, which may include|
02031|012|E|rhabdomyolysis, and a small decrease in rifampin levels.(1)|
02031|013|B||
02031|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02031|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02031|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02031|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02031|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02031|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02031|020|P|predisposed to myopathy or rhabdomyolysis.|
02031|021|B||
02031|022|M|PATIENT MANAGEMENT:  The dosage of pitavastatin should not exceed 2 mg daily|
02031|023|M|in patients receiving rifampin.(1)  Monitor patients receiving concurrent|
02031|024|M|therapy with other dosages for signs of myopathy and rifampin efficacy.|
02031|025|B||
02031|026|D|DISCUSSION:  In a study, concurrent use of rifampin (600 mg daily for 5|
02031|027|D|days) and pitavastatin (4 mg daily) increased pitavastatin area-under-curve|
02031|028|D|(AUC) and maximum concentration (Cmax) by 29% and 2-fold, respectively.  The|
02031|029|D|AUC and Cmax of rifampin 15% and 18%, respectively.(1)|
02031|030|B||
02031|031|R|REFERENCES:|
02031|032|B||
02031|033|R|1.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
02031|034|R|  America, Inc. November, 2022.|1
02031|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
02031|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02032|001|T|MONOGRAPH TITLE:  Quetiapine/Barbiturates (mono deleted 05/26/2011)|
02032|002|B||
02032|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02032|004|L|take action as needed.|
02032|005|B||
02032|006|A|MECHANISM OF ACTION:  Barbiturates may induce the metabolism of quetiapine|
02032|007|A|by CYP P-450-3A4.(1)|
02032|008|B||
02032|009|E|CLINICAL EFFECTS:  Concurrent use of barbiturates may result in decreased|
02032|010|E|levels of quetiapine and ineffectiveness.(1)|
02032|011|B||
02032|012|P|PREDISPOSING FACTORS:  None determined.|
02032|013|B||
02032|014|M|PATIENT MANAGEMENT:  The US manufacturer of quetiapine states that|
02032|015|M|quetiapine dosage adjustments are required in patients receiving strong|
02032|016|M|inducers of CYP P-450-3A4 such as barbiturates.(1)|
02032|017|B||
02032|018|D|DISCUSSION:  Concurrent use of phenytoin (another strong inducer of CYP|
02032|019|D|P-450-3A4, 100 mg three times daily) and quetiapine increased oral clearance|
02032|020|D|of quetiapine by 5-fold.(1)|
02032|021|B||
02032|022|R|REFERENCE:|
02032|023|B||
02032|024|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
02032|025|R|  Pharmaceuticals LP July, 2011.|1
02033|001|T|MONOGRAPH TITLE:  Quetiapine/Rifampin (mono deleted 05/26/2011)|
02033|002|B||
02033|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02033|004|L|take action as needed.|
02033|005|B||
02033|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of quetiapine by|
02033|007|A|CYP P-450-3A4.(1)|
02033|008|B||
02033|009|E|CLINICAL EFFECTS:  Concurrent use of rifampin may result in decreased levels|
02033|010|E|of quetiapine and ineffectiveness.(1)|
02033|011|B||
02033|012|P|PREDISPOSING FACTORS:  None determined.|
02033|013|B||
02033|014|M|PATIENT MANAGEMENT:  The US manufacturer of quetiapine states that|
02033|015|M|quetiapine dosage adjustments are required in patients receiving strong|
02033|016|M|inducers of CYP P-450-3A4 such as rifampin.(1)|
02033|017|B||
02033|018|D|DISCUSSION:  Concurrent use of phenytoin (another strong inducer of CYP|
02033|019|D|P-450-3A4, 100 mg three times daily) and quetiapine increased oral clearance|
02033|020|D|of quetiapine by 5-fold.(1)|
02033|021|B||
02033|022|R|REFERENCE:|
02033|023|B||
02033|024|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
02033|025|R|  Pharmaceuticals LP July, 2011.|1
02034|001|T|MONOGRAPH TITLE:  Quetiapine/Glucocorticoids (mono deleted 05/26/2011)|
02034|002|B||
02034|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02034|004|L|take action as needed.|
02034|005|B||
02034|006|A|MECHANISM OF ACTION:  Glucocorticoids may induce the metabolism of|
02034|007|A|quetiapine by CYP P-450-3A4.(1)|
02034|008|B||
02034|009|E|CLINICAL EFFECTS:  Concurrent use of glucocorticoids may result in decreased|
02034|010|E|levels of quetiapine and ineffectiveness.(1)|
02034|011|B||
02034|012|P|PREDISPOSING FACTORS:  None determined.|
02034|013|B||
02034|014|M|PATIENT MANAGEMENT:  The US manufacturer of quetiapine states that|
02034|015|M|quetiapine dosage adjustments are required in patients receiving strong|
02034|016|M|inducers of CYP P-450-3A4 such as glucocorticoids.(1)|
02034|017|B||
02034|018|D|DISCUSSION:  Concurrent use of phenytoin (another strong inducer of CYP|
02034|019|D|P-450-3A4, 100 mg three times daily) and quetiapine increased oral clearance|
02034|020|D|of quetiapine by 5-fold.(1)|
02034|021|B||
02034|022|R|REFERENCE:|
02034|023|B||
02034|024|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
02034|025|R|  Pharmaceuticals LP July, 2011.|1
02035|001|T|MONOGRAPH TITLE:  Tapentadol; Tramadol/5-HT1D Agonists (Triptans) (mono|
02035|002|T|deleted 12/17/2019)|
02035|003|B||
02035|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02035|005|L|of severe adverse interaction.|
02035|006|B||
02035|007|A|MECHANISM OF ACTION:  The concurrent administration of tapentadol(1) or|
02035|008|A|tramadol(2) with a 5-HT1D agonist may result in additive blockade of|
02035|009|A|serotonin reuptake, resulting in central serotonergic hyperstimulation.  The|
02035|010|A|combination may also lower the seizure threshold.(2)|
02035|011|B||
02035|012|E|CLINICAL EFFECTS:  The concurrent administration of tapentadol(1) or|
02035|013|E|tramadol with a 5-HT1D agonist may result in serotonin syndrome.  Symptoms|
02035|014|E|of serotonin syndrome may include tremor, agitation, diaphoresis,|
02035|015|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)|
02035|016|E|Serotonin syndrome may result in death.(1,2)  Concurrent administration may|
02035|017|E|also increase the risk of seizures.(2)|
02035|018|B||
02035|019|P|PREDISPOSING FACTORS:  Predisposing factors include a history of seizures or|
02035|020|P|epilepsy, a recognized risk for seizures (head trauma, metabolic disorders,|
02035|021|P|alcohol, drug withdrawal, or infections of the central nervous system).|
02035|022|B||
02035|023|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, patients should be|
02035|024|M|closely monitored for signs and symptoms of serotonin syndrome, especially|
02035|025|M|during treatment initiation and during dosage increases.  One or both agents|
02035|026|M|may need to be discontinued.(1,2)|
02035|027|M|   Instruct patients to seek immediate medical attention if they develop any|
02035|028|M|signs of serotonin syndrome or seizures.(1,2)|
02035|029|B||
02035|030|D|DISCUSSION:  The manufacturer of tapentadol states that the risk of|
02035|031|D|serotonin syndrome is increased in patients receiving concurrent therapy|
02035|032|D|with agents that affect serotonin such as the 5-HT1D agonists.(1)|
02035|033|D|   The manufacturer of tramadol states that the risk of seizure and/or|
02035|034|D|serotonin syndrome is increased in patients receiving concurrent therapy|
02035|035|D|with agents that affect serotonin such as the 5-HT1D agonists.(2)|
02035|036|B||
02035|037|R|REFERENCES:|
02035|038|B||
02035|039|R|1.Nucynta ER (tapentadol) US prescribing information. Janssen|1
02035|040|R|  Pharmaceuticals December, 2023.|1
02035|041|R|2.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
02035|042|R|  October, 2019.|1
02035|043|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02035|044|R|  352(11):1112-20.|6
02036|001|T|MONOGRAPH TITLE:  Tipranavir/Fluconazole (Greater Than or Equal To 200 mg)|
02036|002|B||
02036|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02036|004|L|of severe adverse interaction.|
02036|005|B||
02036|006|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of tipranavir|
02036|007|A|by CYP3A4.  The clinical significance of this interaction is unknown.(1,2)|
02036|008|B||
02036|009|E|CLINICAL EFFECTS:  Concurrent use of fluconazole may result in increased|
02036|010|E|levels of and toxicity from tipranavir.(1,2)|
02036|011|B||
02036|012|P|PREDISPOSING FACTORS:  None determined.|
02036|013|B||
02036|014|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
02036|015|M|of tipranavir toxicity.(1)  Fluconazole doses 200 mg daily or greater are|
02036|016|M|not recommended. Tipranavir dosage adjustment is not required.(1,2)|
02036|017|B||
02036|018|D|DISCUSSION:  In a study in 28 patients, concurrent fluconazole (100 mg daily|
02036|019|D|for 12 doses) and tipranavir/ritonavir (500/200 mg twice daily) increased|
02036|020|D|the maximum concentration (Cmax), area-under-curve (AUC), and minimum|
02036|021|D|concentration (Cmin) of tipranavir by 32%, 50%, and 69%, respectively.|
02036|022|D|However, tipranavir was well tolerated in the healthy volunteers and no|
02036|023|D|unexpected safety issues arose during the study.  It was shown in a prior|
02036|024|D|study at a 45.6% increase in tipranavir exposure did not cause an increase|
02036|025|D|in toxicity.  Therefore, the clinical relevance of this interaction is|
02036|026|D|unknown.(1,2)|
02036|027|D|   In a study in 19 subjects, concurrent administration of fluconazole (200|
02036|028|D|mg Day 1, followed by 100 mg daily for 6 or 12 doses) and|
02036|029|D|tipranavir/ritonavir  (500/200 mg twice daily for 2 or 14 doses) had no|
02036|030|D|effect on fluconazole levels.(1,2)|
02036|031|B||
02036|032|R|REFERENCES:|
02036|033|B||
02036|034|R|1.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
02036|035|R|  Pharmaceuticals, Inc. April, 2024.|1
02036|036|R|2.la Porte CJ, Sabo JP, Elgadi M, Cameron DW. Interaction studies of|2
02036|037|R|  tipranavir-ritonavir with clarithromycin, fluconazole, and rifabutin in|2
02036|038|R|  healthy volunteers. Antimicrob Agents Chemother 2009 Jan;53(1):162-73.|2
02037|001|T|MONOGRAPH TITLE:  Trazodone (Less Than or Equal To 100 mg)/MAOIs|
02037|002|B||
02037|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02037|004|L|take action as needed.|
02037|005|B||
02037|006|A|MECHANISM OF ACTION:  Trazodone is primarily an inhibitor of 5HT2A serotonin|
02037|007|A|receptors, H1 histamine, and alpha-1 receptors.(1)  Inhibition of serotonin|
02037|008|A|reuptake is weak and estimated to be 1/20th of 5HT2A inhibiting activity.|
02037|009|A|Metabolism of trazodone leads to formation of an active metabolite,|
02037|010|A|m-chlorophenylpiperazine (mCPP) which is an agonist at a variety of|
02037|011|A|serotonin receptors.(1)  MCPP is further converted to an inactive metabolite|
02037|012|A|by CYP2D6.(3)|
02037|013|A|   MAO Inhibitors increase serotonin levels via inhibition of its|
02037|014|A|metabolism.|
02037|015|B||
02037|016|E|CLINICAL EFFECTS:  Concurrent administration could increase the risk for|
02037|017|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
02037|018|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
02037|019|E|and muscle rigidity.(2)|
02037|020|B||
02037|021|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
02037|022|P|systemic concentrations of trazodone, mCPP or more potent MAO inhibitors|
02037|023|P|would be predicted to increase risk for serotonin toxicity.(2)|
02037|024|P|   Concomitant therapy with multiple agents which increase brain serotonin|
02037|025|P|concentrations may also increase risk for serotonin syndrome.(2)|
02037|026|P|   Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion,|
02037|027|P|cinacalcet, dacomitinib, fluoxetine, paroxetine, quinidine, or systemic|
02037|028|P|terbinafine)(4) may increase mCPP concentration, increasing the risk for|
02037|029|P|serotonin toxicity.|
02037|030|P|   Patients who are poor metabolizers at CYP2D6 would be expected to have|
02037|031|P|higher mCPP concentrations compared with extensive metabolizers.|
02037|032|B||
02037|033|M|PATIENT MANAGEMENT:  It would be prudent to seek trazodone alternatives in|
02037|034|M|patients who require treatment with a MAOI and a strong inhibitor of CYP2D6|
02037|035|M|(e.g. bupropion, cinacalcet, dacomitinib, fluoxetine, paroxetine, quinidine,|
02037|036|M|systemic terbinafine) or another serotonergic agent.  Assess patient for|
02037|037|M|additional predisposing risk factors then change/adjust medications or|
02037|038|M|monitor accordingly.|
02037|039|M|   To minimize accumulation of mCPP, limit dosage of trazodone to less than|
02037|040|M|or equal to 100 mg daily.|
02037|041|M|   Assure careful monitoring for signs and symptoms of serotonin syndrome|
02037|042|M|when the dose of either agent is increased.|
02037|043|M|   If concurrent therapy is warranted, patients should be monitored for|
02037|044|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02037|045|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02037|046|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02037|047|M|coordination, or severe diarrhea.|
02037|048|B||
02037|049|D|DISCUSSION:  In a case report, a 37 year-old male developed serotonin|
02037|050|D|syndrome following the addition of linezolid to citalopram and trazodone.(5)|
02037|051|D|   In a case report, a patient developed serotonin syndrome with concurrent|
02037|052|D|trazodone, isocarboxazid, and methylphenidate.(6)|
02037|053|D|   In a case report, a patient developed serotonin syndrome following the|
02037|054|D|abrupt replacement of trazodone with moclobemide.(7)|
02037|055|D|   An open study evaluated the efficacy and safety of low dose trazodone for|
02037|056|D|the treatment of MAOI-associated insomnia.  Twenty-one patients successfully|
02037|057|D|treated with a MAOI for unipolar or bipolar depression but with persistent|
02037|058|D|insomnia participated in the study.  Trazodone 25 to 75 mg was given at|
02037|059|D|bedtime. Patients with a fair or good response to trazodone were monitored|
02037|060|D|for a minimum of 4 months to assess efficacy and safety of treatment.|
02037|061|D|Eleven patients had a resolution of insomnia, 9 had a partial response, and|
02037|062|D|one had no benefit. Side effects noted were nausea in 2 patients, persistent|
02037|063|D|morning grogginess in one patient and memory problems in one patient.(8)|
02037|064|D|   A small double-blind placebo controlled study evaluated the efficacy and|
02037|065|D|safety of trazodone 50 mg to treat insomnia due to brofaromine, a MAO-A|
02037|066|D|inhibitor. All seven patients had responded to brofaromine and had been in|
02037|067|D|remission for at least 3 months.  Three patients received trazodone on week|
02037|068|D|1, followed by placebo on week 2, while the other 4 patients received|
02037|069|D|placebo on week 1 and trazodone on week 2.  At the end of the trial 4|
02037|070|D|patients elected to continue trazodone and 3 patients discontinued therapy|
02037|071|D|due to adverse effects (nausea, constipation, vertigo, dry mouth,|
02037|072|D|palpitations, or heartburn). The authors stated no patients had symptoms|
02037|073|D|suggestive of serotonin syndrome.(9)|
02037|074|D|   Metaxalone is a weak inhibitor of MAO.(10,11)|
02037|075|D|   The FDA AERS contains reports of serotonin syndrome with the concurrent|
02037|076|D|use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram,|
02037|077|D|fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine as well as|
02037|078|D|reports of serotonin syndrome with concurrent injectable methylene blue and|
02037|079|D|citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine,|
02037|080|D|escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and|
02037|081|D|venlafaxine.  The risk of serotonin syndrome with other psychiatric drugs is|
02037|082|D|unclear.(12,13)|
02037|083|B||
02037|084|R|REFERENCES:|
02037|085|B||
02037|086|R|1.O'Donnell JM Shelton RC. Chapter 15 - Drug Therapy of Depression and|6
02037|087|R|  Anxiety Disorders. In Bruton L, Chabner B, Knollman B eds. Goodman &|6
02037|088|R|  Gilman's The Pharmacological Basis of Therapeutics. 12th ed. 2011.|6
02037|089|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02037|090|R|  352(11):1112-20.|6
02037|091|R|3.Kovaleva J, Devuyst E, De Paepe P, Verstraete A. Acute|3
02037|092|R|  chlorophenylpiperazine overdose: a case report and review of the|3
02037|093|R|  literature. Ther Drug Monit 2008 Jun;30(3):394-8.|3
02037|094|R|4.This information is based on an extract from the Certara Drug Interaction|6
02037|095|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02037|096|R|5.Bergeron L, Boule M, Perreault S. Serotonin toxicity associated with|3
02037|097|R|  concomitant use of linezolid. Ann Pharmacother 2005 May;39(5):956-61.|3
02037|098|R|6.Bodner RA, Lynch T, Lewis L, Kahn D. Serotonin syndrome. Neurology 1995|3
02037|099|R|  Feb;45(2):219-23.|3
02037|100|R|7.Zivanovic O, Till E. Serotonin syndrome--a case account. Med Pregl 1992;|3
02037|101|R|  45(3-4):116-8.|3
02037|102|R|8.Jacobsen FM. Low-dose trazodone as a hypnotic in patients treated with|2
02037|103|R|  MAOIs and other psychotropics: a pilot study. J Clin Psychiatry 1990 Jul;|2
02037|104|R|  51(7):298-302.|2
02037|105|R|9.Haffmans PM, Vos MS. The effects of trazodone on sleep disturbances|2
02037|106|R|  induced by brofaromine. Eur Psychiatry 1999 Jun;14(3):167-71.|2
02037|107|R|10.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
02037|108|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
02037|109|R|   Feb;34(2):346.e5-6.|3
02037|110|R|11.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
02037|111|R|   Pfizer Inc. January, 2024.|1
02037|112|R|12.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
02037|113|R|   information about the drug interaction between methylene blue|1
02037|114|R|   (methylthioninium chloride) and serotonergic psychiatric medications.|1
02037|115|R|   available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
02037|116|R|   21, 2011.|1
02037|117|R|13.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
02037|118|R|   information about the drug interaction between linezolid (Zyvox) and|1
02037|119|R|   serotonergic psychiatric medications. available at:|1
02037|120|R|   http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm October 21, 2011.|1
02038|001|T|MONOGRAPH TITLE:  MAOIs/Metoclopramide|
02038|002|B||
02038|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02038|004|L|of severe adverse interaction.|
02038|005|B||
02038|006|A|MECHANISM OF ACTION:  In patients treated with MAOIs, metoclopramide may|
02038|007|A|result in the release of a large quantity of catecholamines.(1)|
02038|008|B||
02038|009|E|CLINICAL EFFECTS:  Use of metoclopramide in patients treated with a MAOI may|
02038|010|E|result in hypertensive crisis.(1)|
02038|011|B||
02038|012|P|PREDISPOSING FACTORS:  None determined.|
02038|013|B||
02038|014|M|PATIENT MANAGEMENT:  Avoid the concurrent use of metoclopramide and MAOIs.|
02038|015|M|If concurrent use is warranted, monitor patients closely for hypertensive|
02038|016|M|crisis.(1)|
02038|017|B||
02038|018|D|DISCUSSION:  In patients treated with MAOIs, metoclopramide may result in|
02038|019|D|the release of a large quantity of catecholamines, which may result in|
02038|020|D|hypertensive crisis.(1)|
02038|021|D|   Metaxalone is a weak inhibitor of MAO.(2,3)|
02038|022|B||
02038|023|R|REFERENCES:|
02038|024|B||
02038|025|R|1.Metozolv (metoclopramide hydrochloride) US prescribing information. Salix|1
02038|026|R|  Pharmaceuticals, Inc. February, 2019.|1
02038|027|R|2.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
02038|028|R|  Pfizer Inc. January, 2024.|1
02038|029|R|3.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
02038|030|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
02038|031|R|  Feb;34(2):346.e5-6.|3
02039|001|T|MONOGRAPH TITLE:  Repaglinide/Cyclosporine|
02039|002|B||
02039|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02039|004|L|take action as needed.|
02039|005|B||
02039|006|A|MECHANISM OF ACTION:  Cyclosporine may inhibit the metabolism of repaglinide|
02039|007|A|by CYP3A4 and OATP-mediated hepatic uptake of repaglinide.(1)|
02039|008|B||
02039|009|E|CLINICAL EFFECTS:  Concurrent use with cyclosporine may result in increased|
02039|010|E|levels of and effects from repaglinide, including hypoglycemia.(1,2)|
02039|011|B||
02039|012|P|PREDISPOSING FACTORS:  None determined.|
02039|013|B||
02039|014|M|PATIENT MANAGEMENT:  Use caution when initiating repaglinide in patients|
02039|015|M|maintained on cyclosporine.(1,2)  Lower starting doses and careful titration|
02039|016|M|may be required.(3)  Monitor patients receiving concurrent therapy for signs|
02039|017|M|of hypoglycemia.(1,2)  The dose of repaglinide may need to be adjusted.|
02039|018|M|   The US manufacturer of repaglinide recommends the daily maximum dose|
02039|019|M|should be limited to 6 mg and increased frequency of glucose monitoring may|
02039|020|M|be required with concurrent therapy.(4)|
02039|021|B||
02039|022|D|DISCUSSION:  In a study in 12 healthy males, cyclosporine (100 mg every 12|
02039|023|D|hours for 2 doses) increased the maximum concentration (Cmax) and|
02039|024|D|area-under-curve (AUC) of a single dose of repaglinide (0.25 mg) by 1.8-fold|
02039|025|D|(range 0.6-3.7-fold, p<0.001) and by 2.4-fold (range 1.2-5.3-fold,|
02039|026|D|p<0.001).(1,2)  The amount of unchanged repaglinide, its M2 metabolite, and|
02039|027|D|its M4 metabolite excreted in the urine 2.7-fold, 7.5-fold, 5.0-fold,|
02039|028|D|respectively.  No statistically significant changes in blood glucose|
02039|029|D|response were noted; however, individual responses correlated with the|
02039|030|D|degree of increased repaglinide levels.(1)|
02039|031|B||
02039|032|R|REFERENCES:|
02039|033|B||
02039|034|R|1.Kajosaari LI, Niemi M, Neuvonen M, Laitila J, Neuvonen PJ, Backman JT.|2
02039|035|R|  Cyclosporine markedly raises the plasma concentrations of repaglinide.|2
02039|036|R|  Clin Pharmacol Ther 2005 Oct;78(4):388-99.|2
02039|037|R|2.Sandimmune (cyclosporine) US prescribing information. Novartis|1
02039|038|R|  Pharmaceuticals Corporation September 2023.|1
02039|039|R|3.Turk T, Witzke O. Pharmacological interaction between cyclosporine a and|6
02039|040|R|  repaglinide. Is it clinically relevant?. Am J Transplant 2006 Sep;|6
02039|041|R|  6(9):2223.|6
02039|042|R|4.Prandin (repaglinide) US prescribing information. Novo Nordisk|1
02039|043|R|  Pharmaceuticals, Inc. February 8, 2017.|1
02040|001|T|MONOGRAPH TITLE:  Conivaptan/Nefazodone (mono deleted 04/12/2012)|
02040|002|B||
02040|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02040|004|L|is contraindicated and generally should not be dispensed or administered to|
02040|005|L|the same patient.|
02040|006|B||
02040|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of conivaptan|
02040|008|A|via CYP P-450-3A4.  Toxicity may result from an overly rapid correction of|
02040|009|A|serum sodium.(1)|
02040|010|B||
02040|011|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in increased|
02040|012|E|levels of conivaptan, which may lead to increased clinical effects such as|
02040|013|E|hypotension, hypovolemia, and thirst, as well as toxicity in the form of|
02040|014|E|neurologic sequelae such as osmotic demyelination syndrome.(1)|
02040|015|B||
02040|016|P|PREDISPOSING FACTORS:  None determined.|
02040|017|B||
02040|018|M|PATIENT MANAGEMENT:  The US manufacturer of conivaptan states that the|
02040|019|M|combination of potent CYP P-450-3A4 inhibitors, such as nefazodone, and|
02040|020|M|conivaptan is contraindicated.(1)|
02040|021|B||
02040|022|D|DISCUSSION:  Conivaptan is a sensitive substrate of CYP P-450-3A4.|
02040|023|D|Coadministration of conivaptan and ketoconazole, another CYP P-450-3A4|
02040|024|D|inhibitor, resulted in a 4-fold increase in the area under the curve (AUC)|
02040|025|D|and an 11-fold increase in the maximum concentration (Cmax) of|
02040|026|D|conivaptan.(1)|
02040|027|B||
02040|028|R|REFERENCE:|
02040|029|B||
02040|030|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
02040|031|R|  Pharma US, Inc. February, 2012.|1
02041|001|T|MONOGRAPH TITLE:  Ixabepilone/Rifamycins|
02041|002|B||
02041|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02041|004|L|of severe adverse interaction.|
02041|005|B||
02041|006|A|MECHANISM OF ACTION:  Rifamycins may induce the metabolism of ixabepilone by|
02041|007|A|CYP3A4.(1)|
02041|008|B||
02041|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifamycins may result in|
02041|010|E|decreased levels and effectiveness of ixabepilone.(1)|
02041|011|B||
02041|012|P|PREDISPOSING FACTORS:  None determined.|
02041|013|B||
02041|014|M|PATIENT MANAGEMENT:  The US manufacturer of ixabepilone states that|
02041|015|M|concurrent use of strong inducers of CYP3A4, such as rifampin, rifapentine,|
02041|016|M|and rifabutin, should be avoided.|
02041|017|M|   If concurrent therapy is required, the dose of ixabepilone may be|
02041|018|M|gradually increased from 40 mg/m2 to 60 mg/m2, depending on tolerance.  If|
02041|019|M|the dose is increased, ixabepilone should be given as a 4 hour infusion.|
02041|020|M|Monitor patients closely for toxicity.  If the inducer is discontinued, the|
02041|021|M|dose of ixabepilone should be returned to the dose used prior to concurrent|
02041|022|M|therapy.(1)|
02041|023|B||
02041|024|D|DISCUSSION:  Concurrent use of rifampin increased ixabepilone|
02041|025|D|area-under-curve (AUC) by 43%, compared to treatment with ixabepilone|
02041|026|D|alone.(1)|
02041|027|D|   Adjustment of the ixabepilone dose in the presence of a strong CYP3A4|
02041|028|D|inducer to 60 mg/m2 given over 4 hours is predicted to adjust the|
02041|029|D|ixabepilone AUC to the range observed without inducers; however, there is no|
02041|030|D|clinical data with this dose.(1)|
02041|031|B||
02041|032|R|REFERENCE:|
02041|033|B||
02041|034|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
02041|035|R|  Company October, 2011.|1
02042|001|T|MONOGRAPH TITLE:  Ixabepilone/Selected Strong CYP3A4 Inducers|
02042|002|B||
02042|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02042|004|L|of severe adverse interaction.|
02042|005|B||
02042|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
02042|007|A|ixabepilone by CYP3A4.(1)|
02042|008|B||
02042|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
02042|010|E|result in decreased levels and effectiveness of ixabepilone.(1)|
02042|011|B||
02042|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02042|013|P|of the inducer for longer than 1-2 weeks.|
02042|014|B||
02042|015|M|PATIENT MANAGEMENT:  The US manufacturer of ixabepilone states that|
02042|016|M|concurrent use of strong inducers of CYP3A4 should be avoided.|
02042|017|M|   If concurrent therapy is required, the dose of ixabepilone may be|
02042|018|M|gradually increased from 40 mg/m2 to 60 mg/m2, depending on tolerance.  If|
02042|019|M|the dose is increased, ixabepilone should be given as a 4 hour infusion.|
02042|020|M|Monitor patients closely for toxicity.  If the inducer is discontinued, the|
02042|021|M|dose of ixabepilone should be returned to the dose used prior to concurrent|
02042|022|M|therapy.(1)|
02042|023|B||
02042|024|D|DISCUSSION:  Concurrent use of rifampin, another strong inducer of CYP3A4,|
02042|025|D|increased ixabepilone area-under-curve (AUC) by 43%, compared to treatment|
02042|026|D|with ixabepilone alone.(1)|
02042|027|D|   Adjustment of the ixabepilone dose in the presence of a strong CYP3A4|
02042|028|D|inducer to 60 mg/m2 given over 4 hours is predicted to adjust the|
02042|029|D|ixabepilone AUC to the range observed without inducers; however, there is no|
02042|030|D|clinical data with this dose.(1)|
02042|031|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
02042|032|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02042|033|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and|
02042|034|D|primidone.(2)|
02042|035|B||
02042|036|R|REFERENCES:|
02042|037|B||
02042|038|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
02042|039|R|  Company October, 2011.|1
02042|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
02042|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02043|001|T|MONOGRAPH TITLE:  Ixabepilone/Dexamethasone|
02043|002|B||
02043|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02043|004|L|of severe adverse interaction.|
02043|005|B||
02043|006|A|MECHANISM OF ACTION:  Dexamethasone may induce the metabolism of ixabepilone|
02043|007|A|by CYP3A4.(1)|
02043|008|B||
02043|009|E|CLINICAL EFFECTS:  Concurrent or recent use of dexamethasone may result in|
02043|010|E|decreased levels and effectiveness of ixabepilone.(1)|
02043|011|B||
02043|012|P|PREDISPOSING FACTORS:  None determined.|
02043|013|B||
02043|014|M|PATIENT MANAGEMENT:  The US manufacturer of ixabepilone states that|
02043|015|M|concurrent use of strong inducers of CYP3A4, such as dexamethasone, should|
02043|016|M|be avoided.  Pretreatment with single doses of dexamethasone may be required|
02043|017|M|in patients who have experienced a hypersensitivity reaction to|
02043|018|M|ixabepilone.(1)|
02043|019|M|   If concurrent long-term therapy is required, the dose of ixabepilone may|
02043|020|M|be gradually increased from 40 mg/m2 to 60 mg/m2, depending on tolerance.|
02043|021|M|If the dose is increased, ixabepilone should be given as a 4 hour infusion.|
02043|022|M|Monitor patients closely for toxicity.  If the inducer is discontinued, the|
02043|023|M|dose of ixabepilone should be returned to the dose used prior to concurrent|
02043|024|M|therapy.(1)|
02043|025|B||
02043|026|D|DISCUSSION:  Concurrent use of rifampin, another strong inducer of CYP3A4,|
02043|027|D|increased ixabepilone area-under-curve (AUC) by 43%, compared to treatment|
02043|028|D|with ixabepilone alone.(1)|
02043|029|D|   Adjustment of the ixabepilone dose in the presence of a strong CYP3A4|
02043|030|D|inducer to 60 mg/m2 given over 4 hours is predicted to adjust the|
02043|031|D|ixabepilone AUC to the range observed without inducers; however, there is no|
02043|032|D|clinical data with this dose.(1)|
02043|033|B||
02043|034|R|REFERENCE:|
02043|035|B||
02043|036|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
02043|037|R|  Company October, 2011.|1
02044|001|T|MONOGRAPH TITLE:  Taxanes; Ixabepilone/Strong CYP3A4 Inhibitors (mono|
02044|002|T|deleted 03/05/2015)|
02044|003|B||
02044|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02044|005|L|of severe adverse interaction.|
02044|006|B||
02044|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02044|008|A|cabazitaxel,(1) docetaxel,(2) ixabepilone,(3) and paclitaxel.(4)|
02044|009|B||
02044|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
02044|011|E|in increased levels of and toxicity from cabazitaxel,(1) docetaxel,(2)|
02044|012|E|ixabepilone,(3) and paclitaxel.(4)|
02044|013|B||
02044|014|P|PREDISPOSING FACTORS:  None determined.|
02044|015|B||
02044|016|M|PATIENT MANAGEMENT:  The US manufacturer of cabazitaxel states that the|
02044|017|M|concurrent use of strong inhibitors of CYP3A4 should be avoided.(1)|
02044|018|M|   The US manufacturer of docetaxel states that the concurrent use of strong|
02044|019|M|inhibitors of CYP3A4 should be avoided.  If concurrent therapy is required,|
02044|020|M|consider a 50% reduction in the dose of docetaxel.  Monitor patients|
02044|021|M|receiving concurrent therapy closely for signs of toxicity.(2)|
02044|022|M|   The US manufacturer of ixabepilone recommends that concurrent use of|
02044|023|M|strong inhibitors of CYP3A4 be avoided during ixabepilone therapy.  If|
02044|024|M|concurrent use is warranted, a dose reduction to 20 mg/m2 of ixabepilone|
02044|025|M|should be considered.  Patients receiving concurrent therapy should be|
02044|026|M|closely monitored for acute toxicities (e.g. frequent monitoring of|
02044|027|M|peripheral blood counts).  If the inhibitor is discontinued, allow a 1 week|
02044|028|M|washout period before adjusting the dose of ixabepilone to recommended|
02044|029|M|amounts.(3)|
02044|030|M|   While the manufacturer of paclitaxel only recommends caution with|
02044|031|M|concurrent inhibitors of CYP3A4,(4) it would be prudent to avoid concurrent|
02044|032|M|use is possible.  In patients whom concurrent therapy is required, monitor|
02044|033|M|patients closely for signs of toxicity.|
02044|034|B||
02044|035|D|DISCUSSION:  Cabazitaxel is primarily metabolized by CYP3A4 and strong|
02044|036|D|inhibitors of this isoenzyme are expected to increase cabazitaxel levels.(1)|
02044|037|D|   In a randomized, cross-over study in 7 cancer patients, patients received|
02044|038|D|docetaxel (100 mg/m2 intravenous) alone and docetaxel (10 mg/m2 intravenous)|
02044|039|D|with ketoconazole (200 mg daily for 3 days).  The mean dose-normalized|
02044|040|D|area-under-curve (AUC) of docetaxel increased 2.2-fold and docetaxel|
02044|041|D|clearance decreased 49% when administered with ketoconazole.(2)|
02044|042|D|   In a randomized, cross-over study in 7 subjects, subjects received|
02044|043|D|docetaxel (100 mg/m2) alone and docetaxel (15 mg/m2) with ketoconazole (400|
02044|044|D|mg 3 times daily).  Ketoconazole decreased docetaxel clearance by 50%.|
02044|045|D|There was large inter-patient variability.(5)|
02044|046|D|   In a study in 15 subjects, ketoconazole increased fecal docetaxel|
02044|047|D|excretion by 2-fold but did not affect urinary parent drug excretion.(6)|
02044|048|D|   In a study in 41 patients, concurrent ketoconazole allowed a dose of 70|
02044|049|D|mg docetaxel with similar docetaxel AUC and toxicity compared to the|
02044|050|D|administration of docetaxel (75 mg/m2) alone.(7)|
02044|051|D|   A study in 42 patients examined escalating doses of ketoconazole on|
02044|052|D|docetaxel pharmacokinetics.  Ketoconazole at doses of 1200 mg daily, 800 mg|
02044|053|D|daily, and 600 mg daily increased docetaxel exposed 2.6-fold, 1.6-fold, and|
02044|054|D|1.3-1.5-fold, respectively.(8)|
02044|055|D|   A parallel study in 82 subjects compared docetaxel (75 mg/m2) alone with|
02044|056|D|docetaxel (70 mg) with ketoconazole.  Concurrent ketoconazole decreased|
02044|057|D|docetaxel clearance by 40%.  Similar docetaxel AUC and tumor efficacy were|
02044|058|D|noted, with decreased toxicity during concurrent ketoconazole and|
02044|059|D|reduced-dose docetaxel therapy.(9)|
02044|060|D|   In a study in 12 patients, the administration of ritonavir (100 mg)|
02044|061|D|simultaneously or 60 minutes before docetaxel (100 mg orally) increased the|
02044|062|D|bioavailability of docetaxel by 131% and 161%, respectively.(10)|
02044|063|D|   There are several case reports of docetaxel toxicity in patients treated|
02044|064|D|with concurrent ritonavir.(11,12)|
02044|065|D|   Data from two clinical trials involving patients taking docetaxel|
02044|066|D|concurrently with ritonavir and patients taking docetaxel oral or I.V. alone|
02044|067|D|were analyzed in order to determine the impact of ritonavir's strong|
02044|068|D|inhibition of CYP3A4 on the pharmacokinetics of docetaxel.  Patients from|
02044|069|D|the first trial were randomly assigned to receive either ritonavir 100 mg|
02044|070|D|followed by oral docetaxel 10 mg 60 minutes later on day 1, ritonavir 100 mg|
02044|071|D|and docetaxel 10 mg simultaneously on day 8, and I.V. docetaxel 100 mg on|
02044|072|D|day 22 or an identical regimen with the only difference being that days 1|
02044|073|D|and 8 were reversed.  The second trial was utilized solely for the data on|
02044|074|D|patients being administered oral docetaxel 75 mg/m2 alone or I.V. docetaxel|
02044|075|D|100 mg/m2.  The results of the study showed an increase in the gut|
02044|076|D|bioavailability of docetaxel from 19 to 39% with co-administration of|
02044|077|D|ritonavir as well as a reduction in the clearance of docetaxel by|
02044|078|D|approximately 90%.(13)|
02044|079|D|   Concurrent administration of ketoconazole, a strong inhibitor of CYP3A4,|
02044|080|D|increased the area-under-curve (AUC) of ixabepilone by 79%.  A dose|
02044|081|D|reduction to 20 mg/m2 of ixabepilone during concurrent use of a potent|
02044|082|D|CYP3A4 inhibitor is predicted to adjust the ixabepilone AUC to the range|
02044|083|D|observed without a concurrent CYP3A4 inhibitor.(3)|
02044|084|D|   Strong inhibitors of CYP3A4 include:  atazanavir, boceprevir,|
02044|085|D|clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole,|
02044|086|D|lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole,|
02044|087|D|ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole.(14,15)|
02044|088|B||
02044|089|R|REFERENCES:|
02044|090|B||
02044|091|R|1.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02044|092|R|  November, 2014.|1
02044|093|R|2.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02044|094|R|  December, 2013.|1
02044|095|R|3.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
02044|096|R|  Company October, 2011.|1
02044|097|R|4.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
02044|098|R|  Company August, 2010.|1
02044|099|R|5.Engels FK, Mathot RA, Loos WJ, van Schaik RH, Verweij J. Influence of|2
02044|100|R|  high-dose ketoconazole on the pharmacokinetics of docetaxel. Cancer Biol|2
02044|101|R|  Ther 2006 Jul;5(7):833-9.|2
02044|102|R|6.Engels FK, Loos WJ, Mathot RA, van Schaik RH, Verweij J. Influence of|2
02044|103|R|  ketoconazole on the fecal and urinary disposition of docetaxel. Cancer|2
02044|104|R|  Chemother Pharmacol 2007 Sep;60(4):569-79.|2
02044|105|R|7.Yong WP, Wang LZ, Tham LS, Wong CI, Lee SC, Soo R, Sukri N, Lee HS, Goh|2
02044|106|R|  BC. A phase I study of docetaxel with ketoconazole modulation in patients|2
02044|107|R|  with advanced cancers. Cancer Chemother Pharmacol 2008 Jul;62(2):243-51.|2
02044|108|R|8.Figg WD, Woo S, Zhu W, Chen X, Ajiboye AS, Steinberg SM, Price DK, Wright|2
02044|109|R|  JJ, Parnes HL, Arlen PM, Gulley JL, Dahut WL. A phase I clinical study of|2
02044|110|R|  high dose ketoconazole plus weekly docetaxel for metastatic castration|2
02044|111|R|  resistant prostate cancer. J Urol 2010 Jun;183(6):2219-26.|2
02044|112|R|9.Lim YW, Goh BC, Wang LZ, Tan SH, Chuah BY, Lim SE, Iau P, Buhari SA, Chan|2
02044|113|R|  CW, Sukri NB, Cordero MT, Soo R, Lee SC. Pharmacokinetics and|2
02044|114|R|  pharmacodynamics of docetaxel with or without ketoconazole modulation in|2
02044|115|R|  chemonaive breast cancer patients. Ann Oncol 2010 Apr 29.|2
02044|116|R|10.Oostendorp RL, Huitema A, Rosing H, Jansen RS, Ter Heine R, Keessen M,|2
02044|117|R|   Beijnen JH, Schellens JH. Coadministration of ritonavir strongly enhances|2
02044|118|R|   the apparent oral bioavailability of docetaxel in patients with solid|2
02044|119|R|   tumors. Clin Cancer Res 2009 Jun 15;15(12):4228-33.|2
02044|120|R|11.Mir O, Dessard-Diana B, Louet AL, Loulergue P, Viard JP, Langlois A,|3
02044|121|R|   Durdux C, Le Beller C. Severe toxicity related to a pharmacokinetic|3
02044|122|R|   interaction between docetaxel and ritonavir in HIV-infected patients. Br|3
02044|123|R|   J Clin Pharmacol 2010 Jan;69(1):99-101.|3
02044|124|R|12.Loulergue P, Mir O, Allali J, Viard JP. Possible pharmacokinetic|3
02044|125|R|   interaction involving ritonavir and docetaxel in a patient with Kaposi's|3
02044|126|R|   sarcoma. AIDS 2008 Jun 19;22(10):1237-9.|3
02044|127|R|13.Koolen SL, Oostendorp RL, Beijnen JH, Schellens JH, Huitema AD.|2
02044|128|R|   Population pharmacokinetics of intravenously and orally administered|2
02044|129|R|   docetaxel with or without co-administration of ritonavir in patients with|2
02044|130|R|   advanced cancer. Br J Clin Pharmacol 2010 May;69(5):465-74.|2
02044|131|R|14.US Food and Drug Administration (FDA). Drug Development and Drug|1
02044|132|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
02044|133|R|   at:|1
02044|134|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
02044|135|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02044|136|R|   11/14/2017.|1
02044|137|R|15.This information is based on an extract from the Certara Drug Interaction|6
02044|138|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02045|001|T|MONOGRAPH TITLE:  Cabazitaxel; Docetaxel/Selected Protease Inhibitors (mono|
02045|002|T|deleted 11/07/2013)|
02045|003|B||
02045|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02045|005|L|of severe adverse interaction.|
02045|006|B||
02045|007|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
02045|008|A|cabazitaxel(1) and docetaxel(2) by CYP3A4.|
02045|009|B||
02045|010|E|CLINICAL EFFECTS:  Concurrent use of atazanavir, indinavir, nelfinavir,|
02045|011|E|ritonavir, or saquinavir may result in increased levels of and toxicity from|
02045|012|E|cabazitaxel(1) and docetaxel.(2)|
02045|013|B||
02045|014|P|PREDISPOSING FACTORS:  None determined.|
02045|015|B||
02045|016|M|PATIENT MANAGEMENT:  The US manufacturer of cabazitaxel states that the|
02045|017|M|concurrent use of strong inhibitors of CYP3A4, such as atazanavir,|
02045|018|M|indinavir, nelfinavir, ritonavir, or saquinavir, should be avoided.(1)|
02045|019|M|   The US manufacturer of docetaxel states that the concurrent use of strong|
02045|020|M|inhibitors of CYP3A4, such as atazanavir, indinavir, nelfinavir, ritonavir,|
02045|021|M|or saquinavir, should be avoided.  If concurrent therapy is required,|
02045|022|M|consider a 50% reduction in the dose of docetaxel.  Monitor patients|
02045|023|M|receiving concurrent therapy closely for signs of toxicity.(2)|
02045|024|B||
02045|025|D|DISCUSSION:  Cabazitaxel is primarily metabolized by CYP3A4 and strong|
02045|026|D|inhibitors of this isoenzyme are expected to increase cabazitaxel levels.(1)|
02045|027|D|   The dosage adjustment recommendation for docetaxel is based on an|
02045|028|D|extrapolation from a pharmacokinetic study with ketoconazole in which|
02045|029|D|ketoconazole (another strong inhibitor of CYP3A4) reduced the clearance of|
02045|030|D|docetaxel by 49%.  No clinical data with this dose is available.(2)|
02045|031|D|   In a study in 12 patients, the administration of ritonavir (100 mg)|
02045|032|D|simultaneously or 60 minutes before docetaxel (100 mg orally) increased the|
02045|033|D|bioavailability of docetaxel by 131% and 161%, respectively.(3)|
02045|034|D|   There are several case reports of docetaxel toxicity in patients treated|
02045|035|D|with concurrent ritonavir.(4,5)|
02045|036|D|   Data from two clinical trials involving patients taking docetaxel|
02045|037|D|concurrently with ritonavir and patients taking docetaxel oral or I.V. alone|
02045|038|D|were analyzed in order to determine the impact of ritonavir's strong|
02045|039|D|inhibtion of CYP3A4 on the pharmacokinetics of docetaxel.  Patients from the|
02045|040|D|first trial were randomly assigned to receive either ritonavir 100 mg|
02045|041|D|followed by oral docetaxel 10 mg 60 minutes later on day 1, ritonavir 100 mg|
02045|042|D|and docetaxel 10 mg simultaneously on day 8, and I.V. docetaxel 100 mg on|
02045|043|D|day 22 or an identical regimen with the only difference being that days 1|
02045|044|D|and 8 were reversed.  The second trial was utilized solely for the data on|
02045|045|D|patients being administered oral docetaxel 75 mg/mx2 alone or I.V. docetaxel|
02045|046|D|100 mg/mx2.  The results of the study showed an increase in the gut|
02045|047|D|bioavailability of docetaxel from 19 to 39% with co-administration of|
02045|048|D|ritonavir as well as a reduction in the clearance of docetaxel by|
02045|049|D|approximately 90%.(6)|
02045|050|B||
02045|051|R|REFERENCES:|
02045|052|B||
02045|053|R|1.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02045|054|R|  June, 2010.|1
02045|055|R|2.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02045|056|R|  May, 2010.|1
02045|057|R|3.Oostendorp RL, Huitema A, Rosing H, Jansen RS, Ter Heine R, Keessen M,|2
02045|058|R|  Beijnen JH, Schellens JH. Coadministration of ritonavir strongly enhances|2
02045|059|R|  the apparent oral bioavailability of docetaxel in patients with solid|2
02045|060|R|  tumors. Clin Cancer Res 2009 Jun 15;15(12):4228-33.|2
02045|061|R|4.Mir O, Dessard-Diana B, Louet AL, Loulergue P, Viard JP, Langlois A,|3
02045|062|R|  Durdux C, Le Beller C. Severe toxicity related to a pharmacokinetic|3
02045|063|R|  interaction between docetaxel and ritonavir in HIV-infected patients. Br J|3
02045|064|R|  Clin Pharmacol 2010 Jan;69(1):99-101.|3
02045|065|R|5.Loulergue P, Mir O, Allali J, Viard JP. Possible pharmacokinetic|3
02045|066|R|  interaction involving ritonavir and docetaxel in a patient with Kaposi's|3
02045|067|R|  sarcoma. AIDS 2008 Jun 19;22(10):1237-9.|3
02045|068|R|6.Koolen SL, Oostendorp RL, Beijnen JH, Schellens JH, Huitema AD. Population|2
02045|069|R|  pharmacokinetics of intravenously and orally administered docetaxel with|2
02045|070|R|  or without co-administration of ritonavir in patients with advanced|2
02045|071|R|  cancer. Br J Clin Pharmacol 2010 May;69(5):465-74.|2
02046|001|T|MONOGRAPH TITLE:  Cabazitaxel; Docetaxel/Clarithromycin; Telithromycin (mono|
02046|002|T|deleted 11/07/2013)|
02046|003|B||
02046|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02046|005|L|of severe adverse interaction.|
02046|006|B||
02046|007|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
02046|008|A|metabolism of cabazitaxel(1) and docetaxel by CYP P-450-3A4.(2)|
02046|009|B||
02046|010|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin or telithromycin may|
02046|011|E|result in increased levels of and toxicity from cabazitaxel(1) and|
02046|012|E|docetaxel.(2)|
02046|013|B||
02046|014|P|PREDISPOSING FACTORS:  None determined.|
02046|015|B||
02046|016|M|PATIENT MANAGEMENT:  The US manufacturer of cabazitaxel states that the|
02046|017|M|concurrent use of strong inhibitors of CYP P-450-3A4, such as clarithromycin|
02046|018|M|or telithromycin, should be avoided.(1)|
02046|019|M|   The US manufacturer of docetaxel states that the concurrent use of strong|
02046|020|M|inhibitors of CYP P-450-3A4, such as clarithromycin or telithromycin, should|
02046|021|M|be avoided.  If concurrent therapy is required, consider a 50% reduction in|
02046|022|M|the dose of docetaxel.  Monitor patients receiving concurrent therapy|
02046|023|M|closely for signs of toxicity.(2)|
02046|024|B||
02046|025|D|DISCUSSION:  Cabazitaxel is primarily metabolized by CYP P-450-3A4 and|
02046|026|D|strong inhibitors of this isoenzyme are expected to increase cabazitaxel|
02046|027|D|levels.(1)|
02046|028|D|   The dosage adjustment recommendation for docetaxel is based on an|
02046|029|D|extrapolation from a pharmacokinetic study with ketoconazole in which|
02046|030|D|ketoconazole (another strong inhibitor of CYP P-450-3A4) reduced the|
02046|031|D|clearance of docetaxel by 49%.  No clinical data with this dose is|
02046|032|D|available.(2)|
02046|033|B||
02046|034|R|REFERENCES:|
02046|035|B||
02046|036|R|1.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02046|037|R|  June, 2010.|1
02046|038|R|2.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02046|039|R|  May, 2010.|1
02047|001|T|MONOGRAPH TITLE:  Cabazitaxel; Docetaxel/Nefazodone (mono deleted|
02047|002|T|11/07/2013)|
02047|003|B||
02047|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02047|005|L|of severe adverse interaction.|
02047|006|B||
02047|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of|
02047|008|A|cabazitaxel(1) and docetaxel by CYP P-450-3A4.(2)|
02047|009|B||
02047|010|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in increased|
02047|011|E|levels of and toxicity from cabazitaxel(1) and docetaxel.(2)|
02047|012|B||
02047|013|P|PREDISPOSING FACTORS:  None determined.|
02047|014|B||
02047|015|M|PATIENT MANAGEMENT:  The US manufacturer of cabazitaxel states that the|
02047|016|M|concurrent use of strong inhibitors of CYP P-450-3A4, such as nefazodone,|
02047|017|M|should be avoided.(1)|
02047|018|M|   The US manufacturer of docetaxel states that the concurrent use of strong|
02047|019|M|inhibitors of CYP P-450-3A4, such as nefazodone, should be avoided.  If|
02047|020|M|concurrent therapy is required, consider a 50% reduction in the dose of|
02047|021|M|docetaxel.  Monitor patients receiving concurrent therapy closely for signs|
02047|022|M|of toxicity.(1)|
02047|023|B||
02047|024|D|DISCUSSION:  Cabazitaxel is primarily metabolized by CYP P-450-3A4 and|
02047|025|D|strong inhibitors of this isoenzyme are expected to increase cabazitaxel|
02047|026|D|levels.(1)|
02047|027|D|   The dosage adjustment recommendation for docetaxel is based on an|
02047|028|D|extrapolation from a pharmacokinetic study with ketoconazole in which|
02047|029|D|ketoconazole (another strong inhibitor of CYP P-450-3A4) reduced the|
02047|030|D|clearance of docetaxel by 49%.  No clinical data with this dose is|
02047|031|D|available.(2)|
02047|032|B||
02047|033|R|REFERENCES:|
02047|034|B||
02047|035|R|1.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02047|036|R|  June, 2010.|1
02047|037|R|2.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02047|038|R|  May, 2010.|1
02048|001|T|MONOGRAPH TITLE:  Strontium/Oral Quinolones|
02048|002|B||
02048|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02048|004|L|take action as needed.|
02048|005|B||
02048|006|A|MECHANISM OF ACTION:  Strontium may form a complex with oral quinolones,|
02048|007|A|preventing their absorption.(1,2)|
02048|008|B||
02048|009|E|CLINICAL EFFECTS:  Simultaneous administration of strontium with oral|
02048|010|E|quinolones may result in decreased levels and effectiveness of the oral|
02048|011|E|quinolone.(1,2)|
02048|012|B||
02048|013|P|PREDISPOSING FACTORS:  None determined.|
02048|014|B||
02048|015|M|PATIENT MANAGEMENT:  Separate the administration times of oral quinolones|
02048|016|M|and dietary supplements containing strontium by as much time as possible.|
02048|017|B||
02048|018|D|DISCUSSION:  Divalent cations such as strontium can form complexes with oral|
02048|019|D|quinolones.(1,2)|
02048|020|B||
02048|021|R|REFERENCES:|
02048|022|B||
02048|023|R|1.Protelos (strontium ranelate) UK summary of product characteristics. Les|1
02048|024|R|  Laboratoires Servier September 21, 2004.|1
02048|025|R|2.Bonisara (strontium gluconate) US prescribing information. Zylera|1
02048|026|R|  Pharmaceuticals September, 2006.|1
02049|001|T|MONOGRAPH TITLE:  Leflunomide/Rifampin|
02049|002|B||
02049|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02049|004|L|take action as needed.|
02049|005|B||
02049|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of leflunomide to|
02049|007|A|its active metabolite.(1)|
02049|008|B||
02049|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifampin may result in|
02049|010|E|elevated levels of the active metabolite of leflunomide and toxicity.(1)|
02049|011|B||
02049|012|P|PREDISPOSING FACTORS:  None determined.|
02049|013|B||
02049|014|M|PATIENT MANAGEMENT:  Monitor patients closely who are receiving concurrent|
02049|015|M|therapy with rifampin.(1)|
02049|016|B||
02049|017|D|DISCUSSION:  Multiple doses of rifampin (exact dose/duration not specified)|
02049|018|D|increased the maximum concentration (Cmax) of the active metabolite of|
02049|019|D|leflunomide by 40% following a single dose of leflunomide.  Levels are|
02049|020|D|expected to increase more with multiple dosing.(1)|
02049|021|B||
02049|022|R|REFERENCE:|
02049|023|B||
02049|024|R|1.Arava (leflunomide) US prescribing information. Aventis Pharmaceuticals,|1
02049|025|R|  Inc. November, 2012.|1
02050|001|T|MONOGRAPH TITLE:  Taxanes/Strong 3A4 Inducers (mono deleted 03/05/2015)|
02050|002|B||
02050|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02050|004|L|of severe adverse interaction.|
02050|005|B||
02050|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02050|007|A|cabazitaxel,(1) docetaxel,(2) and paclitaxel.(3)|
02050|008|B||
02050|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inhibitor of CYP3A4|
02050|010|E|may result in decreased levels and effectiveness of cabazitaxel,(1)|
02050|011|E|docetaxel,(2) and paclitaxel.(3)|
02050|012|B||
02050|013|P|PREDISPOSING FACTORS:  None determined.|
02050|014|B||
02050|015|M|PATIENT MANAGEMENT:  The US manufacturer of cabazitaxel states that the|
02050|016|M|concurrent use of strong inducers of CYP3A4 should be avoided.(1)  It would|
02050|017|M|be prudent to avoid strong CYP3A4 inducers with docetaxel and paclitaxel as|
02050|018|M|well.|
02050|019|M|   If concurrent therapy is warranted, monitor patients closely for loss of|
02050|020|M|efficacy.|
02050|021|B||
02050|022|D|DISCUSSION:  Cabazitaxel,(1) docetaxel,(2) and paclitaxel,(3) are|
02050|023|D|metabolized by CYP3A4 and strong inducers of this isoenzyme are expected to|
02050|024|D|decrease levels of these agents.|
02050|025|D|   In a study in 10 cancer patients, St. John's wort decreased the|
02050|026|D|area-under-curve (AUC) of docetaxel by 11.6%.  There were no significant|
02050|027|D|decreases in docetaxel maximum concentration (Cmax) or half-life.|
02050|028|D|Docetaxel-related toxicities were lower during St. John's wort.(4)|
02050|029|D|   In an in vitro study, hyperforin, a constituent of St. John's wort,|
02050|030|D|induced the metabolism of docetaxel in a dose-dependent fashion with|
02050|031|D|induction ranged from 2.6-fold to 7-fold greater than controls.  In this|
02050|032|D|same experiment, rifampin induced docetaxel metabolism 6.8-fold to|
02050|033|D|32-fold.(5)|
02050|034|D|   In a Phase 2 study of paclitaxel, none of the subjects taking phenytoin|
02050|035|D|experienced a partial or complete response to paclitaxel.  Paclitaxel levels|
02050|036|D|were 70% lower in these patients than in patients not receiving|
02050|037|D|phenytoin.(6)|
02050|038|D|   Strong inducers of CYP3A4 include:  carbamazepine, efavirenz,|
02050|039|D|enzalutamide, mitotane, phenobarbital, phenytoin, primidone, rifabutin,|
02050|040|D|rifampin, rifapentine, and St. John's wort.(1-3,7,8)|
02050|041|B||
02050|042|R|REFERENCES:|
02050|043|B||
02050|044|R|1.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02050|045|R|  November, 2014.|1
02050|046|R|2.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02050|047|R|  December, 2013.|1
02050|048|R|3.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
02050|049|R|  Company August, 2010.|1
02050|050|R|4.Goey AK, Meijerman I, Rosing H, Marchetti S, Mergui-Roelvink M, Keessen M,|2
02050|051|R|  Burgers JA, Beijnen JH, Schellens JH. The Effect of St John's Wort on the|2
02050|052|R|  Pharmacokinetics of Docetaxel. Clin Pharmacokinet 2014 Jan;53(1):103-10.|2
02050|053|R|5.Komoroski BJ, Parise RA, Egorin MJ, Strom SC, Venkataramanan R. Effect of|5
02050|054|R|  the St. John's wort constituent hyperforin on docetaxel metabolism by|5
02050|055|R|  human hepatocyte cultures. Clin Cancer Res 2005 Oct 1;11(19 Pt 1):6972-9.|5
02050|056|R|6.Fetell MR, Grossman SA, Fisher JD, Erlanger B, Rowinsky E, Stockel J,|2
02050|057|R|  Piantadosi S. Preirradiation paclitaxel in glioblastoma multiforme:|2
02050|058|R|  efficacy, pharmacology, and drug interactions. New Approaches to Brain|2
02050|059|R|  Tumor Therapy Central Nervous System Consortium. J Clin Oncol 1997 Sep;|2
02050|060|R|  15(9):3121-8.|2
02050|061|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
02050|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02050|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02050|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02050|065|R|  11/14/2017.|1
02050|066|R|8.This information is based on an extract from the Certara Drug Interaction|6
02050|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02051|001|T|MONOGRAPH TITLE:  Cabazitaxel/Rifamycins (mono deleted 02/27/2014)|
02051|002|B||
02051|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02051|004|L|of severe adverse interaction.|
02051|005|B||
02051|006|A|MECHANISM OF ACTION:  Rifamycins may induce the metabolism of cabazitaxel by|
02051|007|A|CYP P-450-3A4.(1)|
02051|008|B||
02051|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifabutin, rifapentine, or|
02051|010|E|rifampin may result in decreased levels and effectiveness of cabazitaxel.(1)|
02051|011|B||
02051|012|P|PREDISPOSING FACTORS:  None determined.|
02051|013|B||
02051|014|M|PATIENT MANAGEMENT:  The US manufacturer of cabazitaxel states that the|
02051|015|M|concurrent use of strong inducers of CYP P-450-3A4, such as rifabutin,|
02051|016|M|rifapentine, or rifampin, should be avoided.(1)|
02051|017|B||
02051|018|D|DISCUSSION:  Cabazitaxel is primarily metabolized by CYP P-450-3A4 and|
02051|019|D|strong inducers of this isoenzyme are expected to decrease cabazitaxel|
02051|020|D|levels.(1)|
02051|021|B||
02051|022|R|REFERENCE:|
02051|023|B||
02051|024|R|1.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02051|025|R|  June, 2010.|1
02052|001|T|MONOGRAPH TITLE:  Cabazitaxel/St. John's Wort (mono deleted 02/27/2014)|
02052|002|B||
02052|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02052|004|L|of severe adverse interaction.|
02052|005|B||
02052|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
02052|007|A|cabazitaxel by CYP P-450-3A4.(1)|
02052|008|B||
02052|009|E|CLINICAL EFFECTS:  Concurrent or recent use of St. John's wort may result in|
02052|010|E|den creased levels and effectiveness of cabazitaxel.(1)|
02052|011|B||
02052|012|P|PREDISPOSING FACTORS:  None determined.|
02052|013|B||
02052|014|M|PATIENT MANAGEMENT:  The US manufacturer of cabazitaxel states that the|
02052|015|M|concurrent use of strong inducers of CYP P-450-3A4, such as St. John's wort,|
02052|016|M|should be avoided.(1)|
02052|017|B||
02052|018|D|DISCUSSION:  Cabazitaxel is primarily metabolized by CYP P-450-3A4 and|
02052|019|D|strong inducers of this isoenzyme are expected to decrease cabazitaxel|
02052|020|D|levels.(1)|
02052|021|B||
02052|022|R|REFERENCE:|
02052|023|B||
02052|024|R|1.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02052|025|R|  June, 2010.|1
02053|001|T|MONOGRAPH TITLE:  ACE Inhibitors; ARBs/Trimethoprim|
02053|002|B||
02053|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02053|004|L|of severe adverse interaction.|
02053|005|B||
02053|006|A|MECHANISM OF ACTION:  ACE Inhibitors, Angiotensin Receptor Blockers (ARBs),|
02053|007|A|and trimethoprim have all been proven to increase serum potassium levels.|
02053|008|A|The increase is achieved by reduction in potassium elimination by|
02053|009|A|trimethoprim(1,2) and a decrease in angiotensin activity by ACE Inhibitors|
02053|010|A|and ARBs.  The use of these medications in combination can have an additive|
02053|011|A|effect on serum potassium resulting in potentially dangerous levels.(1-5)|
02053|012|B||
02053|013|E|CLINICAL EFFECTS:  Concurrent use of trimethoprim and ACE Inhibitors or|
02053|014|E|Angiotensin Receptor Blockers may result in increased serum potassium|
02053|015|E|levels,(1-5) which may be fatal.(2)|
02053|016|B||
02053|017|P|PREDISPOSING FACTORS:  The interaction may be more significant in elderly|
02053|018|P|patients and patients with renal insufficiency.(1)|
02053|019|B||
02053|020|M|PATIENT MANAGEMENT:  Use trimethoprim with caution in patients maintained on|
02053|021|M|ACE Inhibitors or ARBs.  Patients using these medications concurrently|
02053|022|M|should have their serum potassium monitored.  In the elderly or renally|
02053|023|M|impaired, alternative antibiotic therapy should be considered.|
02053|024|B||
02053|025|D|DISCUSSION:  In a retrospective review of patients in Ontario maintained on|
02053|026|D|an ACE inhibitor or ARB who were admitted to a hospital for hyperkalemia|
02053|027|D|within 14 days of receiving a prescription for SMX-TMP, amoxicillin,|
02053|028|D|ciprofloxacin, norfloxacin, or nitrofurantion, 371 patients were identified.|
02053|029|D|More than half of the patients with hyperkalemia had received SMX-TMP.|
02053|030|D|Patients receiving SMX-TMP had a 7-fold increased risk of hyperkalemia|
02053|031|D|compared to patients receiving other antibiotics.  No risk was found with|
02053|032|D|the other antibiotics.(1)|
02053|033|D|   A retrospective review of patients in Ontario maintained on an ACE|
02053|034|D|inhibitor or ARB examined those who died within 7 days of filling an|
02053|035|D|outpatient prescription for amoxicillin, ciprofloxacin, norfloxacin,|
02053|036|D|nitrofurantoin, or SMX-TMP.  Patients receiving SMX-TMP had an increased|
02053|037|D|risk of death (adjusted odds ratio 1.38) compared to amoxicillin.  Risk was|
02053|038|D|slightly higher at 14 days (adjusted odds ration 1.54).  This corresponded|
02053|039|D|to 3 sudden deaths within 14 days per 1000 SMX-TMP prescriptions.(2)|
02053|040|D|   A review of nine case reports of hyperkalemia with SMX-TMP found that 2|
02053|041|D|patients were receiving concurrent ACE inhibitors (enalapril and|
02053|042|D|benazepril).  One of these patients had severe hyperkalemia with a peak|
02053|043|D|potassium level of 7.4 mEq/l.(3)|
02053|044|D|   Hyperkalemia has also been reported with concurrent SMX-TMP and|
02053|045|D|enalapril(4) and with quinapril.(5)|
02053|046|B||
02053|047|R|REFERENCES:|
02053|048|B||
02053|049|R|1.Antoniou T, Gomes T, Juurlink DN, Loutfy MR, Glazier RH, Mamdani MM.|2
02053|050|R|  Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving|2
02053|051|R|  inhibitors of the renin-angiotensin system: a population-based study. Arch|2
02053|052|R|  Intern Med 2010 Jun 28;170(12):1045-9.|2
02053|053|R|2.Fralick M, Macdonald EM, Gomes T, Antoniou T, Hollands S, Mamdani MM,|2
02053|054|R|  Juurlink DN. Co-trimoxazole and sudden death in patients receiving|2
02053|055|R|  inhibitors of renin-angiotensin system: population based study. BMJ 2014;|2
02053|056|R|  349:g6196.|2
02053|057|R|3.Marinella MA. Trimethoprim-induced hyperkalemia: An analysis of reported|6
02053|058|R|  cases. Gerontology 1999 Jul-Aug;45(4):209-12.|6
02053|059|R|4.Bugge JF. Severe hyperkalaemia induced by trimethoprim in combination with|3
02053|060|R|  an angiotensin-converting enzyme inhibitor in a patient with transplanted|3
02053|061|R|  lungs. J Intern Med 1996 Oct;240(4):249-51.|3
02053|062|R|5.Thomas RJ. Severe hyperkalemia with trimethoprim-quinapril. Ann|3
02053|063|R|  Pharmacother 1996 Apr;30(4):413-4.|3
02054|001|T|MONOGRAPH TITLE:  Azathioprine/Ribavirin|
02054|002|B||
02054|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02054|004|L|take action as needed.|
02054|005|B||
02054|006|A|MECHANISM OF ACTION:  Ribavirin inhibits inosine monophosphate dehydrogenase|
02054|007|A|(IMDH), which leads to accumulation of 6-methylthioinosine monophosphate|
02054|008|A|(6-MTITP), a metabolite of azathioprine that is associated with|
02054|009|A|myelotoxicity (neutropenia, thrombocytopenia, and anemia).(1,2)|
02054|010|B||
02054|011|E|CLINICAL EFFECTS:  Concurrent use of ribavirin and azathioprine may increase|
02054|012|E|the risk of severe pancytopenia, bone marrow suppression, and|
02054|013|E|azathioprine-related myelotoxicity.  Pancytopenia and/or bone marrow|
02054|014|E|suppression has typically developed within 3 to 7 weeks after initiation of|
02054|015|E|concurrent therapy and has reversed within 4 to 6 weeks of withdrawing|
02054|016|E|concurrent therapy.(1,2)|
02054|017|B||
02054|018|P|PREDISPOSING FACTORS:  Concurrent use of interferon may make the interaction|
02054|019|P|more severe and/or likely.(1)|
02054|020|P|   Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or|
02054|021|P|nucleotide diphosphatase (NUDT15) activity are at higher risk of|
02054|022|P|accumulating thiopurine metabolites and severe myelosuppression.|
02054|023|P|Approximately 0.3 % of patients of European, Latino, or African descent have|
02054|024|P|mutations of the TPMT gene resulting in little to no TPMT activity|
02054|025|P|(homozygous deficiency), and approximately 10 % have intermediate TPMT|
02054|026|P|activity (heterozygous deficiency).  NUDT15 deficiency is not seen in|
02054|027|P|patients of African descent and is seen in less than 1 % of patients of|
02054|028|P|European descent.  Approximately 1 % of patients of East Asian descent, 0.5|
02054|029|P|% of patients of central/south Asian descent, and 2 % of patients of Latino|
02054|030|P|descent have homozygous NUDT15 deficiency.  About 17 % of patients of East|
02054|031|P|Asian descent, 13 % of patients of central/south Asian descent, and 8 % of|
02054|032|P|patients of Latino descent have heterozygous NUDT15 deficiency.(3)|
02054|033|B||
02054|034|M|PATIENT MANAGEMENT:  Patients receiving concurrent azathioprine and|
02054|035|M|ribavirin should have complete blood counts, including platelet counts,|
02054|036|M|weekly during the first month of therapy, then twice monthly for the second|
02054|037|M|and third months of treatment, then monthly or more frequently if therapy|
02054|038|M|changes are made.(1,2)|
02054|039|M|   If pancytopenia develops, discontinue concurrent therapy and do not|
02054|040|M|reintroduce concurrent therapy.(1)|
02054|041|M|   The UK manufacturer of mercaptopurine states that concomitant|
02054|042|M|administration of ribavirin and mercaptopurine is not advised.(7)|
02054|043|B||
02054|044|D|DISCUSSION:  Pancytopenia, bone marrow suppression, and azathioprine-related|
02054|045|D|myelotoxicity have been reported with concurrent use of azathioprine and|
02054|046|D|ribavirin.(1,2,4-6)  Pancytopenia and/or bone marrow suppression has|
02054|047|D|typically developed within 3 to 7 weeks after initiation of concurrent|
02054|048|D|therapy and has reversed within 4 to 6 weeks of withdrawing concurrent|
02054|049|D|therapy.(1)|
02054|050|B||
02054|051|R|REFERENCES:|
02054|052|B||
02054|053|R|1.Copegus (ribavirin) US prescribing information. Roche Laboratories, Inc.|1
02054|054|R|  August, 2015.|1
02054|055|R|2.Imuran (azathioprine) US prescribing information. Prometheus Laboratories|1
02054|056|R|  Inc. February, 2014.|1
02054|057|R|3.Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM,|6
02054|058|R|  Moyer AM, Evans WE, Klein TE, Antillon-Klussmann FG, Caudle KE, Kato M,|6
02054|059|R|  Yeoh AEJ, Schmiegelow K, Yang JJ. Clinical Pharmacogenetics Implementation|6
02054|060|R|  Consortium Guideline for Thiopurine Dosing  Based on TPMT and NUDT15|6
02054|061|R|  Genotypes: 2018 Update. Clin Pharmacol Ther 2019 May;105(5):1095-1105.|6
02054|062|R|4.Chaparro M, Trapero-Marugan M, Moreno-Otero R, Gisbert JP. Azathioprine|3
02054|063|R|  plus ribavirin treatment and pancytopenia. Aliment Pharmacol Ther 2009 Nov|3
02054|064|R|  1;30(9):962-3.|3
02054|065|R|5.Peyrin-Biroulet L, Cadranel JF, Nousbaum JB, Oussalah A, Seddik M, Canva|2
02054|066|R|  V, Cortot A, Sogni P, Gueant JL, Bigard MA, Roblin X, Bronowicki JP.|2
02054|067|R|  Interaction of ribavirin with azathioprine metabolism potentially induces|2
02054|068|R|  myelosuppression. Aliment Pharmacol Ther 2008 Oct 15;28(8):984-93.|2
02054|069|R|6.Thevenot T, Mathurin P, Moussalli J, Perrin M, Plassart F, Blot C, Opolon|2
02054|070|R|  P, Poynard T. Effects of cirrhosis, interferon and azathioprine on adverse|2
02054|071|R|  events in patients with chronic hepatitis C treated with ribavirin. J|2
02054|072|R|  Viral Hepat 1997 Jul;4(4):243-53.|2
02054|073|R|7.Xaluprine (mercaptopurine) UK product information. Nova Laboratories Ltd|1
02054|074|R|  Feb 20, 2025.|1
02055|001|T|MONOGRAPH TITLE:  Mebendazole/Metronidazole|
02055|002|B||
02055|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02055|004|L|of severe adverse interaction.|
02055|005|B||
02055|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Both mebendazole and|
02055|007|A|metronidazole have been documented to cause Stevens-Johnson syndrome/toxic|
02055|008|A|epidermal necrolysis.  Concurrent use may result in additive or synergistic|
02055|009|A|risk.(1)|
02055|010|B||
02055|011|E|CLINICAL EFFECTS:  Concurrent use of mebendazole and metronidazole may|
02055|012|E|increase the risk of Stevens-Johnson syndrome/toxic epidermal|
02055|013|E|necrolysis.(1,2)|
02055|014|B||
02055|015|P|PREDISPOSING FACTORS:  None determined.|
02055|016|B||
02055|017|M|PATIENT MANAGEMENT:  The Canadian manufacturer of mebendazole states that|
02055|018|M|concurrent use of metronidazole should be avoided.(2)  If concurrent use is|
02055|019|M|warranted, monitor patients closely for signs and symptoms of|
02055|020|M|Stevens-Johnson syndrome/toxic epidermal necrolysis.  Instruct patients to|
02055|021|M|discontinue therapy and seek medical attention for any peeling skin rash or|
02055|022|M|blisters.|
02055|023|B||
02055|024|D|DISCUSSION:  In a retrospective review, 46 cases of Stevens-Johnson|
02055|025|D|syndrome/toxic epidermal necrolysis that were reported to the Taiwan|
02055|026|D|Department of Health for the period between February, 1996 and February,|
02055|027|D|1997 were matched to 2 case controls each.  The odds ratio for developing|
02055|028|D|Stevens-Johnson syndrome/toxic epidermal necrolysis was 9.5 among subjects|
02055|029|D|who had used both metronidazole and mebendazole in the preceding 6 weeks.|
02055|030|D|All 46 workers were Filipino.  Following a change in practice in the|
02055|031|D|Philippines that stopped routine prescription of anthelmintic drugs to|
02055|032|D|workers going abroad, no new cases were reported.(1)|
02055|033|B||
02055|034|R|REFERENCES:|
02055|035|B||
02055|036|R|1.Chen KT, Twu SJ, Chang HJ, Lin RS. Outbreak of Stevens-Johnson|2
02055|037|R|  syndrome/toxic epidermal necrolysis associated with mebendazole and|2
02055|038|R|  metronidazole use among Filipino laborers in Taiwan. Am J Public Health|2
02055|039|R|  2003 Mar;93(3):489-92.|2
02055|040|R|2.Vermox (mebendazole) Canadian prescribing information. Janssen-Ortho July|1
02055|041|R|  23, 2004.|1
02056|001|T|MONOGRAPH TITLE:  Warfarin/Leflunomide|
02056|002|B||
02056|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02056|004|L|take action as needed.|
02056|005|B||
02056|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02056|007|B||
02056|008|E|CLINICAL EFFECTS:  Concurrent use of leflunomide may result in elevated|
02056|009|E|levels and effects of warfarin, which may increase the risk of bleeding.|
02056|010|B||
02056|011|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02056|012|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02056|013|P|   Drug associated risk factors include concurrent use of multiple drugs|
02056|014|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02056|015|P|risk for bleeding (e.g. NSAIDs).|
02056|016|B||
02056|017|M|PATIENT MANAGEMENT:  Monitor INR response closely in patients maintained on|
02056|018|M|warfarin when initiating, titrating, and discontinuing leflunomide.|
02056|019|M|Patients maintained on leflunomide may require lower initial dosages of|
02056|020|M|warfarin.|
02056|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02056|022|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02056|023|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02056|024|M|patients with any symptoms.|
02056|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02056|026|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02056|027|M|anticoagulation in patients with active pathologic bleeding.|
02056|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02056|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02056|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02056|031|M|and/or swelling.|
02056|032|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02056|033|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02056|034|M|initiating, altering the dose or discontinuing either drug.|
02056|035|B||
02056|036|D|DISCUSSION:  In a case report, a 61 year-old female who had stable INRs for|
02056|037|D|4 months on warfarin dosage of 36 mg/week had an elevated INR of 7.3|
02056|038|D|approximately 2 weeks after initiating leflunomide (100 mg daily for 3 days,|
02056|039|D|then 20 mg daily).(1)|
02056|040|D|   In another case report, a 49 year-old male who had stable INR values for|
02056|041|D|1 year developed gross hematuria two days after initiating leflunomide (100|
02056|042|D|mg daily for 3 days, then 20 mg daily).(2)|
02056|043|D|   Four cases of elevated INR during concurrent warfarin and leflunomide|
02056|044|D|have been reported to the UK Committee on Safety of Medicines.(2,3)|
02056|045|B||
02056|046|R|REFERENCES:|
02056|047|B||
02056|048|R|1.Chonlahan J, Halloran MA, Hammonds A. Leflunomide and warfarin|3
02056|049|R|  interaction: case report and review of the literature. Pharmacotherapy|3
02056|050|R|  2006 Jun;26(6):868-71.|3
02056|051|R|2.Lim V, Pande I. Leflunomide can potentiate the anticoagulant effect of|3
02056|052|R|  warfarin. BMJ 2002 Dec 7;325(7376):1333.|3
02056|053|R|3.Lim V, Pande I. Erratum:  Leflunomide can potentiate the anticoagulant|3
02056|054|R|  effect of warfarin. BMJ 2003 Feb 22;326(7386):432.|3
02057|001|T|MONOGRAPH TITLE:  Selected Benzodiazepines/Selected CYP3A4 Inducers|
02057|002|B||
02057|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02057|004|L|take action as needed.|
02057|005|B||
02057|006|A|MECHANISM OF ACTION:  CYP3A4 inducers may induce the metabolism of some|
02057|007|A|benzodiazepines.|
02057|008|B||
02057|009|E|CLINICAL EFFECTS:  Concurrent or recent use of CYP3A4 inducers may result in|
02057|010|E|decreased levels and loss of effectiveness of some benzodiazepines.|
02057|011|B||
02057|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02057|013|P|of the inducer for longer than 1-2 weeks.|
02057|014|B||
02057|015|M|PATIENT MANAGEMENT:  Monitor patients receiving CYP3A4 inducers or who have|
02057|016|M|received these agents in the previous 2 weeks for decreased benzodiazepine|
02057|017|M|effectiveness.  The dose of the benzodiazepine may need to be adjusted or an|
02057|018|M|alternative agent used.|
02057|019|M|   If the CYP3A4 inducer is discontinued, benzodiazepine levels will|
02057|020|M|gradually rise as induction effects diminish.  Monitor for increased|
02057|021|M|benzodiazepine effects and adjust the dose accordingly.|
02057|022|B||
02057|023|D|DISCUSSION:  In a study in 95 healthy subjects, rifampin (450 mg daily for 5|
02057|024|D|days) decreased the plasma concentrations of a single oral dose of|
02057|025|D|alprazolam (1 mg) by 79%.(1)|
02057|026|D|   In another study in 4 healthy subjects, rifampin (given for 4 days)|
02057|027|D|decreased the area-under-curve (AUC) of a single oral dose of alprazolam (1|
02057|028|D|mg) by 88%.(2)|
02057|029|D|   In a double-blind, randomized, cross-over trial in 13 healthy subjects,|
02057|030|D|rifampin (450 mg daily for 7 days) decreased the maximum concentration|
02057|031|D|(Cmax), AUC, and half-life of a single oral dose of brotizolam (0.5 mg) by|
02057|032|D|69%, 90%, and 69%, respectively.  Concurrent rifampin increased scores on|
02057|033|D|the Digit Symbol Substitution Test (DSST) and decreased scores on the|
02057|034|D|Stanford Sleepiness Scale.(3)|
02057|035|D|   In a study in 21 healthy subjects, rifampin (600 mg or 1200 mg daily for|
02057|036|D|7 days) increased total body clearance of diazepam by 300%.(4)|
02057|037|D|   An in vitro study in human hepatocytes found that rifampin increased the|
02057|038|D|biotransformation of diazepam and midazolam by 1.9-fold.(5)|
02057|039|D|   In a study in 24 healthy subjects, rifampin (600 mg daily for 10 days)|
02057|040|D|increased the clearance of a single intravenous dose of lorazepam by|
02057|041|D|140%.(6)|
02057|042|D|   In an open-label cross-over study in 19 healthy subjects, rifampin (600|
02057|043|D|mg daily for 9 days) increased the clearance of a single oral dose of|
02057|044|D|midazolam (0.075 mg/kg) by 7-fold.(7)|
02057|045|D|   In a study in 57 healthy subjects, rifampin increased the systemic and|
02057|046|D|oral clearance of midazolam by 2-fold and 16-fold, respectively.(8)|
02057|047|D|   In a study in 8 healthy subjects, rifampin (given for 6 days)|
02057|048|D|significantly increased the clearance of midazolam.(9)|
02057|049|D|   In a study in 9 healthy subjects, received a single oral dose of|
02057|050|D|midazolam (15 mg) before, one day after the administration of rifampin (600|
02057|051|D|mg daily for 5 days), and 4 days after the last dose of rifampin.  One day|
02057|052|D|after rifampin, the AUC of midazolam was decreased by 97.7% when compared to|
02057|053|D|the administration of midazolam prior to rifampin.  Four days after the|
02057|054|D|completion of rifampin, the AUC of midazolam was decreased by 87% when|
02057|055|D|compared to the administration of midazolam prior to rifampin.(10)|
02057|056|D|   In a double-blind, randomized, cross-over study in 10 healthy subjects,|
02057|057|D|rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of|
02057|058|D|a single oral dose of midazolam (15 mg) by 94%, 96%, and 58%, respectively.|
02057|059|D|The pharmacodynamic effects of midazolam were also significantly decreased|
02057|060|D|during rifampin therapy.(11)|
02057|061|D|   In a study in 16 healthy subjects, rifampin (600 mg daily for 7 days)|
02057|062|D|increased the clearance of nitrazepam by 83%.  There were no significant|
02057|063|D|effects on the pharmacokinetics of temazepam.(12)|
02057|064|D|   In a randomized, double-blind, cross-over study in 10 healthy subjects,|
02057|065|D|rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of|
02057|066|D|a single dose of triazolam (0.5 mg) by 87.6%, 94.9%, and 54%, respectively.|
02057|067|D|The pharmacodynamic effects of triazolam were also significantly decreased|
02057|068|D|during rifampin therapy.(13)|
02057|069|D|   In an open-label, randomized, cross-over study in 27 healthy subjects,|
02057|070|D|rifaximin (200 mg three times daily for 7 days) had no effect on the|
02057|071|D|pharmacokinetics of single doses of oral or intravenous midazolam.(14)|
02057|072|D|   In a study in 98 patients with schizophrenia or bipolar disorder, the|
02057|073|D|expression of CYP3A4 was found to be the major determinant of clonazepam|
02057|074|D|plasma concentrations normalized by the dose and bodyweight (1263 +/- 482.9|
02057|075|D|and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal expressers,|
02057|076|D|respectively, p<0.0001).(18)|
02057|077|D|   Selected CYP3A4 inducers linked to this monograph include:  apalutamide,|
02057|078|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02057|079|D|lumacaftor, mitotane, phenytoin, rifabutin, rifampin, rifapentine, and St.|
02057|080|D|John's wort.|
02057|081|B||
02057|082|R|REFERENCES:|
02057|083|B||
02057|084|R|1.Gashaw I, Kirchheiner J, Goldammer M, Bauer S, Seidemann J, Zoller K,|2
02057|085|R|  Mrozikiewicz PM, Roots I, Brockmoller J. Cytochrome p450 3A4 messenger|2
02057|086|R|  ribonucleic acid induction by rifampin in human peripheral blood|2
02057|087|R|  mononuclear cells: correlation with alprazolam pharmacokinetics. Clin|2
02057|088|R|  Pharmacol Ther 2003 Nov;74(5):448-57.|2
02057|089|R|2.Schmider J, Brockmoller J, Arold G, Bauer S, Roots I. Simultaneous|2
02057|090|R|  assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and|2
02057|091|R|  caffeine. Pharmacogenetics 1999 Dec;9(6):725-34.|2
02057|092|R|3.Ujiie Y, Fukasawa T, Yasui-Furukori N, Suzuki A, Tateishi T, Otani K.|2
02057|093|R|  Rifampicin markedly decreases plasma concentration and hypnotic effect of|2
02057|094|R|  brotizolam. Ther Drug Monit 2006 Jun;28(3):299-302.|2
02057|095|R|4.Ohnhaus EE, Brockmeyer N, Dylewicz P, Habicht H. The effect of antipyrine|2
02057|096|R|  and rifampin on the metabolism of diazepam. Clin Pharmacol Ther 1987 Aug;|2
02057|097|R|  42(2):148-56.|2
02057|098|R|5.Reinach B, de Sousa G, Dostert P, Ings R, Gugenheim J, Rahmani R.|5
02057|099|R|  Comparative effects of rifabutin and rifampicin on cytochromes P450 and|5
02057|100|R|  UDP-glucuronosyl-transferases expression in fresh and cryopreserved human|5
02057|101|R|  hepatocytes. Chem Biol Interact 1999 Jun 1;121(1):37-48.|5
02057|102|R|6.Chung JY, Cho JY, Yu KS, Kim JR, Jung HR, Lim KS, Jang IJ, Shin SG. Effect|2
02057|103|R|  of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and|2
02057|104|R|  drug interactions of intravenous lorazepam in healthy volunteers. Clin|2
02057|105|R|  Pharmacol Ther 2005 Jun;77(6):486-94.|2
02057|106|R|7.Chung E, Nafziger AN, Kazierad DJ, Bertino JS Jr. Comparison of midazolam|2
02057|107|R|  and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther 2006|2
02057|108|R|  Apr;79(4):350-61.|2
02057|109|R|8.Floyd MD, Gervasini G, Masica AL, Mayo G, George AL Jr, Bhat K, Kim RB,|2
02057|110|R|  Wilkinson GR. Genotype-phenotype associations for common CYP3A4 and CYP3A5|2
02057|111|R|  variants in the basal and induced metabolism of midazolam in European- and|2
02057|112|R|  African-American men and women. Pharmacogenetics 2003 Oct;13(10):595-606.|2
02057|113|R|9.Eeckhoudt SL, Desager JP, Robert AR, Leclercq I, Verbeeck RK, Horsmans Y.|2
02057|114|R|  Midazolam and cortisol metabolism before and after CYP3A induction in|2
02057|115|R|  humans. Int J Clin Pharmacol Ther 2001 Jul;39(7):293-9.|2
02057|116|R|10.Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ. The area under the|2
02057|117|R|   plasma concentration-time curve for oral midazolam is 400-fold larger|2
02057|118|R|   during treatment with itraconazole than with rifampicin. Eur J Clin|2
02057|119|R|   Pharmacol 1998 Mar;54(1):53-8.|2
02057|120|R|11.Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma|2
02057|121|R|   concentrations and effects of oral midazolam. Clin Pharmacol Ther 1996|2
02057|122|R|   Jan;59(1):7-13.|2
02057|123|R|12.Brockmeyer NH, Mertins L, Klimek K, Goos M, Ohnhaus EE. Comparative|2
02057|124|R|   effects of rifampin and/or probenecid on the pharmacokinetics of|2
02057|125|R|   temazepam and nitrazepam. Int J Clin Pharmacol Ther Toxicol 1990 Sep;|2
02057|126|R|   28(9):387-93.|2
02057|127|R|13.Villikka K, Kivisto KT, Backman JT, Olkkola KT, Neuvonen PJ. Triazolam is|2
02057|128|R|   ineffective in patients taking rifampin. Clin Pharmacol Ther 1997 Jan;|2
02057|129|R|   61(1):8-14.|2
02057|130|R|14.Pentikis HS, Connolly M, Trapnell CB, Forbes WP, Bettenhausen DK. The|2
02057|131|R|   effect of multiple-dose, oral rifaximin on the pharmacokinetics of|2
02057|132|R|   intravenous and oral midazolam in healthy volunteers. Pharmacotherapy|2
02057|133|R|   2007 Oct;27(10):1361-9.|2
02057|134|R|15.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
02057|135|R|   Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
02057|136|R|16.This information is based on an extract from the Certara Drug Interaction|6
02057|137|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02057|138|R|17.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
02057|139|R|   Pharmaceuticals Inc. August, 2023.|1
02057|140|R|18.Toth K, Csukly G, Sirok D, Belic A, Kiss A, Hafra E, Deri M, Menus A,|2
02057|141|R|   Bitter I, Monostory K. Optimization of Clonazepam Therapy Adjusted to|2
02057|142|R|   Patient's CYP3A Status and NAT2 Genotype. Int J Neuropsychopharmacol 2016|2
02057|143|R|   Dec;19(12):.|2
02058|001|T|MONOGRAPH TITLE:  Tamoxifen/Aminoglutethimide|
02058|002|B||
02058|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02058|004|L|take action as needed.|
02058|005|B||
02058|006|A|MECHANISM OF ACTION:  Aminoglutethimide may induce the metabolism of|
02058|007|A|tamoxifen by CYP3A4.(1)  Concurrent use may result in additive toxicities.|
02058|008|B||
02058|009|E|CLINICAL EFFECTS:  Concurrent use of aminoglutethimide and tamoxifen may|
02058|010|E|result in increased toxicity while not increasing efficacy.|
02058|011|B||
02058|012|P|PREDISPOSING FACTORS:  None determined.|
02058|013|B||
02058|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be closely|
02058|015|M|monitored for toxicity and decreased tamoxifen efficacy.|
02058|016|B||
02058|017|D|DISCUSSION:  In a study in 6 women with breast cancer, concurrent|
02058|018|D|aminoglutethimide (1 gram/day) increased the clearance of tamoxifen (20|
02058|019|D|mg/day to 90 mg/day) by 2.2-fold.  The area-under-curve (AUC) of tamoxifen|
02058|020|D|decreased 73%.  Levels of most tamoxifen metabolites were also decreased.(2)|
02058|021|D|   Several clinical trials examining concurrent use of aminoglutethimide and|
02058|022|D|tamoxifen have documented increased toxicity(3-8) and/or no increase in|
02058|023|D|efficacy.(3-11)|
02058|024|B||
02058|025|R|REFERENCES:|
02058|026|B||
02058|027|R|1.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
02058|028|R|  US Inc. September 25, 2018.|1
02058|029|R|2.Lien EA, Anker G, Lonning PE, Solheim E, Ueland PM. Decreased serum|2
02058|030|R|  concentrations of tamoxifen and its metabolites induced by|2
02058|031|R|  aminoglutethimide. Cancer Res 1990 Sep 15;50(18):5851-7.|2
02058|032|R|3.Schmid M, Jakesz R, Samonigg H, Kubista E, Gnant M, Menzel C, Seifert M,|2
02058|033|R|  Haider K, Taucher S, Mlineritsch B, Steindorfer P, Kwasny W, Stierer M,|2
02058|034|R|  Tausch C, Fridrik M, Wette V, Steger G, Hausmaninger H. Randomized trial|2
02058|035|R|  of tamoxifen versus tamoxifen plus aminoglutethimide as adjuvant treatment|2
02058|036|R|  in postmenopausal breast cancer patients with hormone receptor-positive|2
02058|037|R|  disease: Austrian breast and colorectal cancer study group trial 6. J Clin|2
02058|038|R|  Oncol 2003 Mar 15;21(6):984-90.|2
02058|039|R|4.Rose C, Kamby C, Mouridsen HT, Andersson M, Bastholt L, Moller KA,|2
02058|040|R|  Andersen J, Munkholm P, Dombernowsky P, Christensen IJ. Combined endocrine|2
02058|041|R|  treatment of elderly postmenopausal patients with metastatic breast|2
02058|042|R|  cancer. A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide|2
02058|043|R|  and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years|2
02058|044|R|  of age. Breast Cancer Res Treat 2000 May;61(2):103-10.|2
02058|045|R|5.Alonso-Munoz MC, Ojeda-Gonzalez MB, Beltran-Fabregat M, Dorca-Ribugent J,|2
02058|046|R|  Lopez-Lopez L, Borras-Balada J, Cardenal-Alemany F, Gomez-Batiste X,|2
02058|047|R|  Fabregat-Mayol J, Viladiu-Quemada P. Randomized trial of tamoxifen versus|2
02058|048|R|  aminoglutethimide and versus combined tamoxifen and aminoglutethimide in|2
02058|049|R|  advanced postmenopausal breast cancer. Oncology 1988;45(5):350-3.|2
02058|050|R|6.Ingle JN, Green SJ, Ahmann DL, Long HJ, Edmonson JH, Rubin J, Chang MN,|2
02058|051|R|  Creagan ET. Randomized trial of tamoxifen alone or combined with|2
02058|052|R|  aminoglutethimide and hydrocortisone in women with metastatic breast|2
02058|053|R|  cancer. J Clin Oncol 1986 Jun;4(6):958-64.|2
02058|054|R|7.Rose C, Kamby C, Mouridsen HT, Bastholt L, Brincker H, Skovgaard-Poulsen|2
02058|055|R|  H, Andersen AP, Loft H, Dombernowsky P, Andersen KW. Combined endocrine|2
02058|056|R|  treatment of postmenopausal patients with advanced breast cancer. A|2
02058|057|R|  randomized trial of tamoxifen vs. tamoxifen plus aminoglutethimide and|2
02058|058|R|  hydrocortisone. Breast Cancer Res Treat 1986;7 Suppl:S45-50.|2
02058|059|R|8.Smith IE, Harris AL, Stuart-Harris R, Ford HT, Gazet JC, White H, Harmer|2
02058|060|R|  CL, Carr L, McKinna JA, Morgan M. Combination treatment with tamoxifen and|2
02058|061|R|  aminoglutethimide in advanced breast cancer. Br Med J (Clin Res Ed) 1983|2
02058|062|R|  May 21;286(6378):1615-6.|2
02058|063|R|9.Hisamatsu K, Nomura Y, Tashiro H. Aminoglutethimide and aminoglutethimide|2
02058|064|R|  plus tamoxifen treatment for advanced breast cancer. Gan To Kagaku Ryoho|2
02058|065|R|  1992 Oct;19(12):2017-23.|2
02058|066|R|10.Smith IE, Harris AL, Morgan M, Gazet JC, McKinna JA. Tamoxifen versus|2
02058|067|R|   aminoglutethimide versus combined tamoxifen and aminoglutethimide in the|2
02058|068|R|   treatment of advanced breast carcinoma. Cancer Res 1982 Aug;42(8|2
02058|069|R|   Suppl):3430s-3433s.|2
02058|070|R|11.Dowsett M, Harris AL, Smith IE, Jeffcoate SL. Endocrine and clinical|2
02058|071|R|   consequences of combination tamoxifen-aminoglutethimide in postmenopausal|2
02058|072|R|   breast cancer. Br J Cancer 1984 Sep;50(3):357-61.|2
02059|001|T|MONOGRAPH TITLE:  Ciprofloxacin/QT Prolonging Agents|
02059|002|B||
02059|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02059|004|L|take action as needed.|
02059|005|B||
02059|006|A|MECHANISM OF ACTION:  Ciprofloxacin has been shown to prolong the QTc|
02059|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02059|008|A|may result in additive effects on the QTc interval.(1)|
02059|009|B||
02059|010|E|CLINICAL EFFECTS:  The concurrent use of ciprofloxacin with other agents|
02059|011|E|that prolong the QTc interval may result in potentially life-threatening|
02059|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02059|013|B||
02059|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02059|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02059|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02059|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02059|018|P|gender, or advanced age.(4)|
02059|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02059|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02059|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02059|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02059|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02059|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02059|025|P|dysfunction).(4)|
02059|026|B||
02059|027|M|PATIENT MANAGEMENT:  The US manufacturer of ciprofloxacin states that|
02059|028|M|ciprofloxacin should be used with caution with other agents known to prolong|
02059|029|M|the QT interval, especially in the elderly.(1)  The UK manufacturer of|
02059|030|M|ciprofloxacin states that ciprofloxacin should be used with caution in|
02059|031|M|patients at risk for torsades.(2)|
02059|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02059|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02059|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02059|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02059|036|B||
02059|037|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02059|038|D|degrees of potential to prolong the QTc interval but are generally accepted|
02059|039|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02059|040|D|monograph have been shown to prolong the QTc interval either through their|
02059|041|D|mechanism of action, through studies on their effects on the QTc interval,|
02059|042|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02059|043|D|clinical trials and/or post-marketing reports.(3)|
02059|044|D|   One or more of the drug pairs linked to this monograph have been included|
02059|045|D|in a list of interactions that should be considered "high-priority" for|
02059|046|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02059|047|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02059|048|D|Coordinator (ONC) for Health Information Technology.|
02059|049|B||
02059|050|R|REFERENCES:|
02059|051|B||
02059|052|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
02059|053|R|  Corporation March, 2022.|1
02059|054|R|2.Ciproxin (ciprofloxacin hydrochloride) UK summary of product|1
02059|055|R|  characteristics. Bayer plc April 13, 2010.|1
02059|056|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02059|057|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02059|058|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02059|059|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02059|060|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02059|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02059|062|R|  settings: a scientific statement from the American Heart Association and|6
02059|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02059|064|R|  2;55(9):934-47.|6
02059|065|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02059|066|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02059|067|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02059|068|R|  19(5):735-43.|6
02060|001|T|MONOGRAPH TITLE:  Lamotrigine/Lopinavir; Ritonavir|
02060|002|B||
02060|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02060|004|L|take action as needed.|
02060|005|B||
02060|006|A|MECHANISM OF ACTION:  Lopinavir and ritonavir may induce the glucuronidation|
02060|007|A|of lamotrigine.(1,2)|
02060|008|B||
02060|009|E|CLINICAL EFFECTS:  Concurrent use of ritonavir or lopinavir-ritonavir may|
02060|010|E|result in decreased levels and effectiveness of lamotrigine.(1,2)|
02060|011|B||
02060|012|P|PREDISPOSING FACTORS:  None determined.|
02060|013|B||
02060|014|M|PATIENT MANAGEMENT:  A dosage increase of lamotrigine may be required in|
02060|015|M|patients receiving concurrent ritonavir or lopinavir-ritonavir.  Monitor|
02060|016|M|lamotrigine levels and adjust the dose as necessary.  One set of authors|
02060|017|M|suggested doubling the dose of lamotrigine with concurrent|
02060|018|M|lopinavir-ritonavir.(1)|
02060|019|M|   The American Academy of Neurology (AAN) and International League Against|
02060|020|M|Epilepsy (ILAE) clinical practice guidelines recommend considering a dose|
02060|021|M|increase of lamotrigine of 50% in patients receiving atazanavir-ritonavir or|
02060|022|M|lopinavir-ritonavir.(3,4)|
02060|023|M|   The NIH Covid-19 treatment guidelines state when extended-course (>= 10|
02060|024|M|days of therapy) nirmatrelvir-ritonavir is warranted, lamotrigine levels may|
02060|025|M|decrease.  Closely monitor lamotrigine levels and adjust lamotrigine dosing|
02060|026|M|to maintain therapeutic lamotrigine levels.  Short-course (5 days of|
02060|027|M|therapy) nirmatrelvir-ritonavir is not expected to cause a clinically|
02060|028|M|significant decrease in lamotrigine levels.(5)|
02060|029|B||
02060|030|D|DISCUSSION:  In a study in 24 healthy subjects, administration of|
02060|031|D|lopinavir-ritonavir (400/100 mg twice daily) decreased the minimum|
02060|032|D|concentration (Cmin) of lamotrigine (50 mg daily on Days 1-2, then 100 mg|
02060|033|D|twice daily) by 55.4%.  Increasing the dose of lamotrigine to 200 mg daily|
02060|034|D|with concurrent lopinavir-ritonavir resulted in bioequivalent levels to|
02060|035|D|those seen with lamotrigine alone at a dosage of 100 mg twice daily.(1)|
02060|036|D|   In a study in 21 healthy subjects, atazanavir (400 mg daily) had no|
02060|037|D|effect on the pharmacokinetics of a single dose of lamotrigine (100 mg).|
02060|038|D|Concurrent atazanavir/ritonavir (300/100 mg daily) decreased the|
02060|039|D|area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of|
02060|040|D|lamotrigine (100 mg) by 32% and 6%, respectively.(2)|
02060|041|B||
02060|042|R|REFERENCES:|
02060|043|B||
02060|044|R|1.van der Lee MJ, Dawood L, ter Hofstede HJ, de Graaff-Teulen MJ, van|2
02060|045|R|  Ewijk-Beneken Kolmer EW, Caliskan-Yassen N, Koopmans PP, Burger DM.|2
02060|046|R|  Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy|2
02060|047|R|  subjects. Clin Pharmacol Ther 2006 Aug;80(2):159-68.|2
02060|048|R|2.Burger DM, Huisman A, Van Ewijk N, Neisingh H, Van Uden P, Rongen GA,|2
02060|049|R|  Koopmans P, Bertz RJ. The effect of atazanavir and atazanavir/ritonavir on|2
02060|050|R|  UDP-glucuronosyltransferase using lamotrigine as a phenotypic probe. Clin|2
02060|051|R|  Pharmacol Ther 2008 Dec;84(6):698-703.|2
02060|052|R|3.Birbeck GL, French JA, Perucca E, Simpson DM, Fraimow H, George JM,|6
02060|053|R|  Okulicz JF, Clifford DB, Hachad H, Levy RH. Antiepileptic drug selection|6
02060|054|R|  for people with HIV/AIDS: evidence-based guidelines  from the ILAE and|6
02060|055|R|  AAN. Epilepsia 2012 Jan;53(1):207-14.|6
02060|056|R|4.Birbeck GL, French JA, Perucca E, Simpson DM, Fraimow H, George JM,|6
02060|057|R|  Okulicz JF, Clifford DB, Hachad H, Levy RH. Evidence-based guideline:|6
02060|058|R|  Antiepileptic drug selection for people with HIV/AIDS:  report of the|6
02060|059|R|  Quality Standards Subcommittee of the AAN and the Ad Hoc Task Force of the|6
02060|060|R|  Commission on Therapeutic Strategies of the  ILAE. Neurology 2012 Jan 10;|6
02060|061|R|  78(2):139-45.|6
02060|062|R|5.COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines Panel.|6
02060|063|R|  Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National|6
02060|064|R|  Institutes of Health..|6
02061|001|T|MONOGRAPH TITLE:  HMG-CoA Reductase Inhibitors/Fusidic Acid|
02061|002|B||
02061|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02061|004|L|is contraindicated and generally should not be dispensed or administered to|
02061|005|L|the same patient.|
02061|006|B||
02061|007|A|MECHANISM OF ACTION:  The exact mechanism of this interaction is unknown.|
02061|008|A|Fusidic acid may inhibit the metabolism of some HMG-CoA reductase inhibitors|
02061|009|A|by CYP3A4 or their hepatic uptake by OATP1B1/1B3.(1-5)|
02061|010|B||
02061|011|E|CLINICAL EFFECTS:  Concurrent use of fusidic acid and a HMG-CoA reductase|
02061|012|E|inhibitor may result in elevated levels of the HMG-CoA reductase inhibitor|
02061|013|E|and rhabdomyolysis.(1-3)|
02061|014|B||
02061|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02061|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02061|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02061|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02061|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02061|020|P|transporter OATP1B1 may have increased statin concentrations and be|
02061|021|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02061|022|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02061|023|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02061|024|P|Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may|
02061|025|P|have increased fluvastatin concentrations and  risk of myopathy.|
02061|026|B||
02061|027|M|PATIENT MANAGEMENT:  The concurrent administration of fusidic acid and|
02061|028|M|HMG-CoA reductase inhibitors is contraindicated.(1-3)  Therapy with these|
02061|029|M|agents should be suspended until 7 days after completion of fusidic acid to|
02061|030|M|ensure clearance of residual intracellular fusidic acid.(1-3,5)|
02061|031|M|   In patient requiring long-term therapy with fusidic acid, consider the|
02061|032|M|use of HMG-CoA reductase inhibitors on a case by case basis and under close|
02061|033|M|medical supervision.(1)  Consider statins that are less dependent on CYP3A4|
02061|034|M|metabolism, such as fluvastatin or pravastatin.|
02061|035|M|   If concurrent therapy is warranted, monitor patients closely and instruct|
02061|036|M|them to immediately report unexplained muscle pain, tenderness, weakness, or|
02061|037|M|urine discoloration.|
02061|038|B||
02061|039|D|DISCUSSION:  There have been reports of rhabdomyolysis following the|
02061|040|D|addition of fusidic acid to patients who previously tolerated therapy with|
02061|041|D|simvastatin(6-9) and atorvastatin.(10)|
02061|042|B||
02061|043|R|REFERENCES:|
02061|044|B||
02061|045|R|1.Fucidin (fusidic acid) Australian prescribing information. CSL Limited|1
02061|046|R|  January 9, 2003.|1
02061|047|R|2.Fucidin (fusidic acid) UK summary of product characteristics. Leo|1
02061|048|R|  Laboratories Lmited October 24, 2012.|1
02061|049|R|3.Pravachol (pravastatin) Australian Product Information. Arrotex|1
02061|050|R|  Pharmaceuticals Pty Ltd October, 2024.|1
02061|051|R|4.Gupta A, Harris JJ, Lin J, Bulgarelli JP, Birmingham BK, Grimm SW. Fusidic|5
02061|052|R|  Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause|5
02061|053|R|  of Clinical Drug-Drug Interaction Observed with Statin Coadministration.|5
02061|054|R|  Antimicrob Agents Chemother 2016 Oct;60(10):5986-94.|5
02061|055|R|5.Eng H, Scialis RJ, Rotter CJ, Lin J, Lazzaro S, Varma MV, Di L, Feng B,|5
02061|056|R|  West M, Kalgutkar AS. The Antimicrobial Agent Fusidic Acid Inhibits|5
02061|057|R|  Organic Anion Transporting  Polypeptide-Mediated Hepatic Clearance and May|5
02061|058|R|  Potentiate Statin-Induced  Myopathy. Drug Metab Dispos 2016 May;|5
02061|059|R|  44(5):692-9.|5
02061|060|R|6.EMA. Fusidic acid - Risk of rhabdomyolysis due to interaction with HMG-CoA|1
02061|061|R|  reductase inhibitors. Monthly report - Pharmacovigilance Working Party|1
02061|062|R|  (PhVWP) July 2011 plenary meeting. Available at:|1
02061|063|R|  https://www.ema.europa.eu/en/documents/report/monthly-report-pharmacovigil|1
02061|064|R|  ance-working-party-phvwp-july-2011-plenary-meeting_en.pdf. July 28, 2011;|1
02061|065|R|  1107:.|1
02061|066|R|7.Burtenshaw AJ, Sellors G, Downing R. Presumed interaction of fusidic acid|3
02061|067|R|  with simvastatin. Anaesthesia 2008 Jun;63(6):656-8.|3
02061|068|R|8.Yuen SL, McGarity B. Rhabdomyolysis secondary to interaction of fusidic|3
02061|069|R|  acid and simvastatin. Med J Aust 2003 Aug 4;179(3):172.|3
02061|070|R|9.Kotanko P, Kirisits W, Skrabal F. Rhabdomyolysis and acute renal graft|3
02061|071|R|  impairment in a patient treated with simvastatin, tacrolimus, and fusidic|3
02061|072|R|  acid. Nephron 2002 Feb;90(2):234-5.|3
02061|073|R|10.Dromer C, Vedrenne C, Billey T, Pages M, Fournie B, Fournie A.|3
02061|074|R|   Rhabdomyolysis due to simvastin. Apropos of a case with review of the|3
02061|075|R|   literature. Rev Rhum Mal Osteoartic 1992 Apr;59(4):281-3.|3
02061|076|R|11.Wenisch C, Krause R, Fladerer P, El Menjawi I, Pohanka E. Acute|3
02061|077|R|   rhabdomyolysis after atorvastatin and fusidic acid therapy. Am J Med 2000|3
02061|078|R|   Jul;109(1):78.|3
02062|001|T|MONOGRAPH TITLE:  Select Benzodiazepines;|
02062|002|T|Buspirone/Itraconazole;Ketoconazole|
02062|003|B||
02062|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02062|005|L|take action as needed.|
02062|006|B||
02062|007|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole may inhibit the|
02062|008|A|metabolism of brotizolam, buspirone, diazepam, etizolam, flunitrazepam, and|
02062|009|A|midazolam injection by CYP3A4.(1-23)|
02062|010|B||
02062|011|E|CLINICAL EFFECTS:  Inhibition of benzodiazepine or buspirone metabolism may|
02062|012|E|produce increased levels of these agents, as well as increased clinical|
02062|013|E|effects.  Toxic effects of increased benzodiazepine levels include profound|
02062|014|E|sedation, respiratory depression, coma, and/or death. Increased effects from|
02062|015|E|buspirone may include lightheadedness, asthenia, dizziness, and somnolence.|
02062|016|B||
02062|017|P|PREDISPOSING FACTORS:  None determined.|
02062|018|B||
02062|019|M|PATIENT MANAGEMENT:  The US manufacturer of buspirone recommends a low dose|
02062|020|M|of buspirone (2.5 mg daily) be used in patients receiving potent inhibitors|
02062|021|M|of CYP3A4.(23)|
02062|022|M|   Monitor patients receiving concurrent therapy with itraconazole or|
02062|023|M|ketoconazole and hepatically metabolized benzodiazepines carefully for|
02062|024|M|increased effects including unusual dizziness or lightheadedness, extreme|
02062|025|M|sleepiness, slowed or difficult breathing, or unresponsiveness.|
02062|026|B||
02062|027|D|DISCUSSION:  In a randomized, double-blind, cross-over study in 10 healthy|
02062|028|D|males, itraconazole (200 mg daily for 4 days) increased the area-under-cure|
02062|029|D|(AUC) and half-life of a single dose of brotizolam (0.5 mg) by 142% and|
02062|030|D|410%, respectively.  Brotizolam clearance decreased by 76%.  Brotizolam|
02062|031|D|effects were increased.(6)|
02062|032|D|   Ketoconazole has been shown to inhibit brotizolam metabolism in vitro.(7)|
02062|033|D|   In a randomized, double-blind, cross-over study in 10 healthy males,|
02062|034|D|itraconazole (200 mg daily for 4 days) increased the AUC and half-life of a|
02062|035|D|single dose of diazepam (5 mg); however, there were no significant effects|
02062|036|D|on diazepam pharmacodynamics.(8)|
02062|037|D|   In a randomized, double-blind, cross-over study in 12 healthy males,|
02062|038|D|itraconazole (200 mg daily for 7 days) increased the AUC and half-life of a|
02062|039|D|single dose of etizolam (1 mg) by 53% and 44%, respectively.  There were no|
02062|040|D|significant effects on etizolam pharmacodynamics.(9)|
02062|041|D|   Ketoconazole has been shown to inhibit flunitrazepam metabolism in|
02062|042|D|vitro.(10)|
02062|043|D|   In a study in 9 healthy subjects, itraconazole increased the AUC of oral|
02062|044|D|midazolam by 8-fold.  Increased effects were also noted.(11)  In a|
02062|045|D|double-blind cross-over study in 12 subjects, itraconazole increased the|
02062|046|D|AUC, maximum concentration (Cmax), and half-life of oral midazolam by|
02062|047|D|6-fold, 2.5-fold, and 2-fold, respectively. Increased effects were also|
02062|048|D|noted.(12) In a cross-over study in 12 subjects, one dose of itraconazole|
02062|049|D|increased the AUC and Cmax of oral midazolam by 3.5-fold and by 2-fold,|
02062|050|D|respectively. Six doses of itraconazole increased the AUC of oral midazolam|
02062|051|D|by almost 7-fold. Increased midazolam effects were seen.(13)  In a|
02062|052|D|double-blind, cross-over study, itraconazole increased midazolam AUC by|
02062|053|D|10-fold.  Subjects also experienced significantly increased sedation and|
02062|054|D|amnesiac effects.(14)  Itraconazole has also been shown to inhibit midazolam|
02062|055|D|metabolism in vitro.(15,16)|
02062|056|D|   In a study in healthy subjects, ketoconazole increased the AUC of oral|
02062|057|D|midazolam by 771.9%.(17)  In a double-blind, cross-over study, ketoconazole|
02062|058|D|increased midazolam AUC by 15-fold. Subjects also experienced significantly|
02062|059|D|increased sedation and amnesiac effects.(14)  In a study in 11 healthy|
02062|060|D|subjects, administration of ketoconazole (400 mg daily) for 1 day, 2 days,|
02062|061|D|and 5 days increased the AUC of a single dose of oral midazolam (2 mg) by|
02062|062|D|10.28-fold, 13.14-fold, and 13.96-fold, respectively, and the Cmax by|
02062|063|D|5.01-fold, 5.29-fold, and 5.42-fold, respectively.(18)  In a study in|
02062|064|D|healthy subjects, ketoconazole (200 mg twice daily) reduced the clearance of|
02062|065|D|midazolam 6-fold.(19)  Ketoconazole has also been shown to inhibit the|
02062|066|D|metabolism of midazolam in vitro.(15,16,20-22)|
02062|067|D|   In a study in 8 healthy subjects, pretreatment with itraconazole (200 mg|
02062|068|D|daily for 4 days) increased the maximum concentration (Cmax) and|
02062|069|D|area-under-curve (AUC) of buspirone by 13-fold and 19-fold,|
02062|070|D|respectively.(1,2)  However, only the Critical Flicker Fusion test showed|
02062|071|D|statistically significant differences when compared to the administration of|
02062|072|D|buspirone alone.(2)|
02062|073|D|   In a study in 6 subjects, pretreatment with itraconazole (200 mg daily|
02062|074|D|for 4 days) increased the Cmax and AUC of buspirone by 10.5-fold and|
02062|075|D|14.5-fold, respectively.  The Cmax and AUC of the piperazine metabolite of|
02062|076|D|buspirone increased by 57% and 50%, respectively.(3)|
02062|077|D|   Ketoconazole has been shown to inhibit the metabolism of buspirone in|
02062|078|D|vitro.(4)|
02062|079|B||
02062|080|R|REFERENCES:|
02062|081|B||
02062|082|R|1.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
02062|083|R|  Pharmaceuticals February, 2014.|1
02062|084|R|2.Halcion (triazolam) US prescribing information. Pharmacia & Upjohn Company|1
02062|085|R|  October, 2019.|1
02062|086|R|3.Valium (diazepam) US prescribing information. Roche Products Inc December,|1
02062|087|R|  2016.|1
02062|088|R|4.Midazolam Hydrochloride Syrup US Prescribing Information. Padagis US LLC|1
02062|089|R|  December 11, 2021.|1
02062|090|R|5.Versed Injection (midazolam hydrochloride) US prescribing information.|1
02062|091|R|  Roche Pharmaceuticals June, 2000.|1
02062|092|R|6.Osanai T, Ohkubo T, Yasui N, Kondo T, Kaneko S. Effect of itraconazole on|2
02062|093|R|  the pharmacokinetics and pharmacodynamics of a single oral dose of|2
02062|094|R|  brotizolam. Br J Clin Pharmacol 2004 Nov;58(5):476-81.|2
02062|095|R|7.Senda C, Kishimoto W, Sakai K, Nagakura A, Igarashi T. Identification of|5
02062|096|R|  human cytochrome P450 isoforms involved in the metabolism of brotizolam.|5
02062|097|R|  Xenobiotica 1997 Sep;27(9):913-22.|5
02062|098|R|8.Ahonen J, Olkkola KT, Neuvonen PJ. The effect of the antimycotic|2
02062|099|R|  itraconazole on the pharmacokinetics and pharmacodynamics of diazepam.|2
02062|100|R|  Fundam Clin Pharmacol 1996;10(3):314-8.|2
02062|101|R|9.Araki K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Inoue Y,|2
02062|102|R|  Tateishi T, Otani K. Inhibition of the metabolism of etizolam by|2
02062|103|R|  itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam|2
02062|104|R|  metabolism. Eur J Clin Pharmacol 2004 Aug;60(6):427-30.|2
02062|105|R|10.Kilicarslan T, Haining RL, Rettie AE, Busto U, Tyndale RF, Sellers EM.|5
02062|106|R|   Flunitrazepam metabolism by cytochrome P450S 2C19 and 3A4. Drug Metab|5
02062|107|R|   Dispos 2001 Apr;29(4 Pt 1):460-5.|5
02062|108|R|11.Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ. The area under the|2
02062|109|R|   plasma concentration-time curve for oral midazolam is 400-fold larger|2
02062|110|R|   during treatment with itraconazole than with rifampicin. Eur J Clin|2
02062|111|R|   Pharmacol 1998 Mar;54(1):53-8.|2
02062|112|R|12.Ahonen J, Olkkola KT, Neuvonen PJ. Effect of itraconazole and terbinafine|2
02062|113|R|   on the pharmacokinetics and pharmacodynamics of midazolam in healthy|2
02062|114|R|   volunteers. Br J Clin Pharmacol 1995 Sep;40(3):270-2.|2
02062|115|R|13.Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic|2
02062|116|R|   antimycotics, itraconazole and fluconazole, on the pharmacokinetics and|2
02062|117|R|   pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996|2
02062|118|R|   Mar;82(3):511-6.|2
02062|119|R|14.Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in|2
02062|120|R|   patients receiving the systemic antimycotics ketoconazole or|2
02062|121|R|   itraconazole. Clin Pharmacol Ther 1994 May;55(5):481-5.|2
02062|122|R|15.Wang JS, Wen X, Backman JT, Taavitsainen P, Neuvonen PJ, Kivisto KT.|5
02062|123|R|   Midazolam alpha-hydroxylation by human liver microsomes in vitro:|5
02062|124|R|   inhibition by calcium channel blockers, itraconazole and ketoconazole.|5
02062|125|R|   Pharmacol Toxicol 1999 Oct;85(4):157-61.|5
02062|126|R|16.von Moltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS,|5
02062|127|R|   Shader RI. Midazolam hydroxylation by human liver microsomes in vitro:|5
02062|128|R|   inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents.|5
02062|129|R|   J Clin Pharmacol 1996 Sep;36(9):783-91.|5
02062|130|R|17.Lam YW, Alfaro CL, Ereshefsky L, Miller M. Pharmacokinetic and|2
02062|131|R|   pharmacodynamic interactions of oral midazolam with ketoconazole,|2
02062|132|R|   fluoxetine, fluvoxamine, and nefazodone. J Clin Pharmacol 2003 Nov;|2
02062|133|R|   43(11):1274-82.|2
02062|134|R|18.Stoch SA, Friedman E, Maes A, Yee K, Xu Y, Larson P, Fitzgerald M,|2
02062|135|R|   Chodakewitz J, Wagner JA. Effect of different durations of ketoconazole|2
02062|136|R|   dosing on the single-dose pharmacokinetics of midazolam: shortening the|2
02062|137|R|   paradigm. J Clin Pharmacol 2009 Apr;49(4):398-406.|2
02062|138|R|19.Tham LS, Lee HS, Wang L, Yong WP, Fan L, Ong AB, Sukri N, Soo R, Lee SC,|2
02062|139|R|   Goh BC. Ketoconazole renders poor CYP3A phenotype status with midazolam|2
02062|140|R|   as probe drug. Ther Drug Monit 2006 Apr;28(2):255-61.|2
02062|141|R|20.Patki KC, Von Moltke LL, Greenblatt DJ. In vitro metabolism of midazolam,|5
02062|142|R|   triazolam, nifedipine, and testosterone by human liver microsomes and|5
02062|143|R|   recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab|5
02062|144|R|   Dispos 2003 Jul;31(7):938-44.|5
02062|145|R|21.Takano M, Hasegawa R, Fukuda T, Yumoto R, Nagai J, Murakami T.|5
02062|146|R|   Interaction with P-glycoprotein and transport of erythromycin, midazolam|5
02062|147|R|   and ketoconazole in Caco-2 cells. Eur J Pharmacol 1998 Oct 9;|5
02062|148|R|   358(3):289-94.|5
02062|149|R|22.Wrighton SA, Ring BJ. Inhibition of human CYP3A catalyzed 1'-hydroxy|5
02062|150|R|   midazolam formation by ketoconazole, nifedipine, erythromycin,|5
02062|151|R|   cimetidine, and nizatidine. Pharm Res 1994 Jun;11(6):921-4.|5
02062|152|R|23.BuSpar (buspirone hydrochloride) US prescribing information. Bristol|1
02062|153|R|   Myers Squibb Company September, 2007.|1
02063|001|T|MONOGRAPH TITLE:  Apremilast; Roflumilast/Strong CYP3A4 Inducers|
02063|002|B||
02063|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02063|004|L|of severe adverse interaction.|
02063|005|B||
02063|006|A|MECHANISM OF ACTION:  CYP3A4 inducers may induce the metabolism of|
02063|007|A|apremilast(1) and roflumilast(2,3) by CYP3A4.|
02063|008|B||
02063|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
02063|010|E|reduce the clinical effectiveness of apremilast(1) and roflumilast.(2,3)|
02063|011|B||
02063|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02063|013|P|of the inducer for longer than 1-2 weeks.|
02063|014|B||
02063|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent CYP3A4 inducers|
02063|016|M|for decreased apremilast(1) and roflumilast(2,3) efficacy.  Concurrent use|
02063|017|M|is not recommended.(1,2)|
02063|018|M|  The dosage of roflumilast may need to be adjusted or additional COPD|
02063|019|M|therapy may need to be adjusted during and for up to two weeks after therapy|
02063|020|M|with a CYP3A4 inducer has been completed.|
02063|021|B||
02063|022|D|DISCUSSION:  Pretreatment with rifampin (600 mg daily for 15 days) decreased|
02063|023|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
02063|024|D|of apremilast by 43% and 72%, respectively.(1)|
02063|025|D|   In an open-label study in 16 healthy males, rifampin (600 mg daily)|
02063|026|D|decreased AUC and Cmax of a single dose of roflumilast (500 mcg) by 80% and|
02063|027|D|68%, respectively.  The AUC and Cmax of roflumilast N-oxide decreased by 56%|
02063|028|D|and 30%, respectively.(2)  The total PDE4 inhibitory activity of roflumilast|
02063|029|D|decreased by 60%.(2-4)|
02063|030|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
02063|031|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02063|032|D|ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin,|
02063|033|D|primidone, rifampin, rifapentine and St. John's wort.|
02063|034|B||
02063|035|R|REFERENCES:|
02063|036|B||
02063|037|R|1.Otezla (apremilast) US prescribing information. Celgene Corporation April,|1
02063|038|R|  2020.|1
02063|039|R|2.Daxas (roflumilast) UK summary of product characteristics. Merck Sharp &|1
02063|040|R|  Dohme Limited July, 2010.|1
02063|041|R|3.Daliresp (roflumilast) US prescribing information. AstraZeneca|1
02063|042|R|  Pharmaceuticals LP March, 2020.|1
02063|043|R|4.Nassr N, Huennemeyer A, Herzog R, von Richter O, Hermann R, Koch M, Duffy|2
02063|044|R|  K, Zech K, Lahu G. Effects of rifampicin on the pharmacokinetics of|2
02063|045|R|  roflumilast and roflumilast N-oxide in healthy subjects. Br J Clin|2
02063|046|R|  Pharmacol 2009 Oct;68(4):580-7.|2
02064|001|T|MONOGRAPH TITLE:  Mycophenolate Mofetil/Proton Pump Inhibitors|
02064|002|B||
02064|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02064|004|L|take action as needed.|
02064|005|B||
02064|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  One theory is that|
02064|007|A|proton pump inhibitors may prevent mycophenolate mofetil from being|
02064|008|A|converted to mycophenolic acid in the gastrointestinal tract.(1-5)|
02064|009|B||
02064|010|E|CLINICAL EFFECTS:  Concurrent use of proton pump inhibitors (PPIs) may|
02064|011|E|result in decreased mycophenolic acid levels and effects, including|
02064|012|E|increased risk of transplant rejection.|
02064|013|B||
02064|014|P|PREDISPOSING FACTORS:  Other factors which may affect systemic mycophenolate|
02064|015|P|exposure include renal function, serum albumin, gender, race, the choice of|
02064|016|P|calcineurin inhibitor (CNI), and use of other drugs which inhibit absorption|
02064|017|P|or enterohepatic recirculation of mycophenolate.|
02064|018|B||
02064|019|M|PATIENT MANAGEMENT:  If concurrent treatment of mycophenolate mofetil and a|
02064|020|M|PPI is needed, evaluate predisposing risk factors (e.g. renal function,|
02064|021|M|gender, race, and presence of other interacting drugs) which may increase or|
02064|022|M|decrease mycophenolate exposure.|
02064|023|M|   If a patient is at risk for low mycophenolic acid levels, options may|
02064|024|M|include converting to delayed release mycophenolic acid (mycophenolate|
02064|025|M|sodium) which is not susceptible to this interaction (4,8,9), or monitoring|
02064|026|M|mycophenolic acid levels to assure therapeutic concentrations are attained.|
02064|027|B||
02064|028|D|DISCUSSION:  A study compared 21 heart transplant patients maintained on|
02064|029|D|mycophenolate mofetil and pantoprazole (40 mg daily) to 12 patients|
02064|030|D|maintained on mycophenolate without pantoprazole.  There was no significant|
02064|031|D|difference in mycophenolate dose between the groups.  However, mycophenolic|
02064|032|D|acid levels at 30 minutes, 1 hour, 2 hours, and 12 hours were significantly|
02064|033|D|lower in patients who received pantoprazole (63%, 44%, 34%, 52%,|
02064|034|D|respectively).  Mycophenolic acid area-under-curve (AUC) and maximum|
02064|035|D|concentration (Cmax) were also significantly lower in patients who received|
02064|036|D|pantoprazole (30% and 78%, respectively).  There was a trend for more acute|
02064|037|D|rejection episodes and transplant vasculopathy in patients receiving|
02064|038|D|pantoprazole.(1)|
02064|039|D|   A study compared 23 patients with autoimmune diseases maintained on|
02064|040|D|mycophenolate mofetil and pantoprazole (40 mg daily) to 13 patients|
02064|041|D|maintained on mycophenolate without pantoprazole.  There was no significant|
02064|042|D|difference in mycophenolate dose between the groups.  The AUC and Cmax of|
02064|043|D|mycophenolic acid decreased by 37% and 60%, respectively, in patients|
02064|044|D|treated with pantoprazole.  The activity of mycophenolic acid decreased by|
02064|045|D|42% in patients receiving pantoprazole.(2)|
02064|046|D|   In a study in 22 heart transplant patients receiving mycophenolate|
02064|047|D|mofetil (1000 mg twice daily), mycophenolic acid levels at 30 and 60 minutes|
02064|048|D|post-dose were 55% and 37% lower, respectively, when patients were receiving|
02064|049|D|pantoprazole (40 mg daily).  The AUC and Cmax of mycophenolic acid were both|
02064|050|D|41% when patients were receiving pantoprazole.  The time to reach Cmax|
02064|051|D|(Tmax) was 29% longer.(3)|
02064|052|D|   A study in 12 healthy subjects compared the effects of pantoprazole (40|
02064|053|D|mg twice daily) on single doses of mycophenolate mofetil (1000 mg) and|
02064|054|D|enteric-coated mycophenolate sodium (720 mg).  Pantoprazole decreased the|
02064|055|D|Cmax and AUC of mycophenolic acid following mycophenolate mofetil|
02064|056|D|administration by 57% and 27%, respectively.  There were no effects on|
02064|057|D|mycophenolate acid following mycophenolate sodium administration.(4)|
02064|058|D|   A study in renal transplant patients, patients receiving mycophenolate|
02064|059|D|mofetil and tacrolimus without PPI therapy (n=22) were compared to patients|
02064|060|D|receiving concurrent mycophenolate mofetil, tacrolimus, and lansoprazole (30|
02064|061|D|mg, n=22) and patients receiving concurrent mycophenolate mofetil,|
02064|062|D|tacrolimus, and rabeprazole (10 mg, n=17).  Mycophenolic acid Cmax,|
02064|063|D|dose-adjusted Cmax, and AUC(0-6h) were significantly lower in patients|
02064|064|D|receiving lansoprazole when compared to patients not receiving PPI therapy.|
02064|065|D|There were no significant differences between patients receiving rabeprazole|
02064|066|D|and those not receiving PPI therapy; however, rabeprazole acid lowering|
02064|067|D|effects are lower than lansoprazole.(5)|
02064|068|D|   A cross-sectional, retrospective analysis of renal transplant patients on|
02064|069|D|omeprazole, mycophenolate, and a calcineurin inhibitor found that in the|
02064|070|D|first week post-transplant the mycophenolate active moiety levels were|
02064|071|D|reduced to a point of clinical significance.  However, after that first|
02064|072|D|week, the effect seemed to be less clinically significant.(6)|
02064|073|D|   In a study of heart transplant patients, use of pantoprazole (20 mg to 80|
02064|074|D|mg daily) significantly reduced the AUC of mycophenolic acid produced from a|
02064|075|D|mean daily dose of 2.2+/-0.8 mycophenolate mofetil (p=0.02).  However,|
02064|076|D|mycophenolic acid minimum concentration (Cmin) was not significantly|
02064|077|D|different.(7)|
02064|078|D|   In a study in healthy subjects, the Cmax and AUC of mycophenolic acid|
02064|079|D|were decreased when mycophenolate mofetil was administered with omeprazole|
02064|080|D|(20 mg BID); however, there was no effect on the Cmax or AUC of mycophenolic|
02064|081|D|acid when enteric-coated mycophenolate mofetil was administered with|
02064|082|D|omeprazole.(8)|
02064|083|D|   In a study in heart or lung transplant patients, concurrent pantoprazole|
02064|084|D|had no effect on the Cmax, Tmax, or AUC of mycophenolic acid following|
02064|085|D|administration of enteric-coated mycophenolate sodium.  Additionally no|
02064|086|D|significant difference of inosine 5?-monophosphate dehydrogenase (IMPDH)|
02064|087|D|activity was seen with EC-mycophenolate given alone or with pantoprazole.(9)|
02064|088|D|   In a subanalysis of the CLEAR Study, there were no significant effects of|
02064|089|D|omeprazole or pantoprazole on mycophenolic acid levels in the study group|
02064|090|D|randomized to received intensified dosing with mycophenolate mofetil (1.5 g|
02064|091|D|BID for 5 days, then 1 g BID).(10)|
02064|092|B||
02064|093|R|REFERENCES:|
02064|094|B||
02064|095|R|1.Kofler S, Deutsch MA, Bigdeli AK, Shvets N, Vogeser M, Mueller TH, Meiser|2
02064|096|R|  B, Steinbeck G, Reichart B, Kaczmarek I. Proton pump inhibitor|2
02064|097|R|  co-medication reduces mycophenolate acid drug exposure in heart transplant|2
02064|098|R|  recipients. J Heart Lung Transplant 2009 Jun;28(6):605-11.|2
02064|099|R|2.Schaier M, Scholl C, Scharpf D, Hug F, Bonisch-Schmidt S, Dikow R, Schmitt|2
02064|100|R|  WH, Schwenger V, Zeier M, Sommerer C. Proton pump inhibitors interfere|2
02064|101|R|  with the immunosuppressive potency of mycophenolate mofetil. Rheumatology|2
02064|102|R|  (Oxford) 2010 Jul 29.|2
02064|103|R|3.Kofler S, Shvets N, Bigdeli AK, Konig MA, Kaczmarek P, Deutsch MA, Vogeser|2
02064|104|R|  M, Steinbeck G, Reichart B, Kaczmarek I. Proton pump inhibitors reduce|2
02064|105|R|  mycophenolate exposure in heart transplant recipients-a prospective|2
02064|106|R|  case-controlled study. Am J Transplant 2009 Jul;9(7):1650-6.|2
02064|107|R|4.Rupprecht K, Schmidt C, Raspe A, Schweda F, Shipkova M, Fischer W, Bucher|2
02064|108|R|  M, Kees F, Faerber L. Bioavailability of mycophenolate mofetil and|2
02064|109|R|  enteric-coated mycophenolate sodium is differentially affected by|2
02064|110|R|  pantoprazole in healthy volunteers. J Clin Pharmacol 2009 Oct;|2
02064|111|R|  49(10):1196-201.|2
02064|112|R|5.Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Suzuki T, Habuchi T.|2
02064|113|R|  Influence of lansoprazole and rabeprazole on mycophenolic acid|2
02064|114|R|  pharmacokinetics one year after renal transplantation. Ther Drug Monit|2
02064|115|R|  2008 Feb;30(1):46-51.|2
02064|116|R|6.David-Neto E, Takaki KM, Agena F, Romano P, Sumita NM, Mendes ME, Neri LA,|6
02064|117|R|  Nahas WC. Diminished mycophenolic Acid exposure caused by omeprazole may|6
02064|118|R|  be clinically relevant in the first week posttransplantation. Ther Drug|6
02064|119|R|  Monit 2012 Jun;34(3):331-6.|6
02064|120|R|7.Doesch AO, Mueller S, Konstandin M, Celik S, Erbel C, Kristen A,|2
02064|121|R|  Frankenstein L, Koch A, Ehlermann P, Zugck C, Katus HA. Proton pump|2
02064|122|R|  inhibitor co-medication reduces active drug exposure in heart transplant|2
02064|123|R|  recipients receiving mycophenolate mofetil. Transplant Proc 2010 Dec;|2
02064|124|R|  42(10):4243-6.|2
02064|125|R|8.Kees MG, Steinke T, Moritz S, Rupprecht K, Paulus EM, Kees F, Bucher M,|2
02064|126|R|  Faerber L. Omeprazole Impairs the Absorption of Mycophenolate Mofetil But|2
02064|127|R|  Not of Enteric-Coated Mycophenolate Sodium in Healthy Volunteers. J Clin|2
02064|128|R|  Pharmacol 2011 Sep 8.|2
02064|129|R|9.Kofler S, Wolf C, Shvets N, Sisic Z, Muller T, Behr J, Sohn HY, Vogeser M,|2
02064|130|R|  Shipkova M, Meiser B, Steinbeck G, Reichart B, Kaczmarek I. The proton|2
02064|131|R|  pump inhibitor pantoprazole and its interaction with enteric-coated|2
02064|132|R|  mycophenolate sodium in transplant recipients. J Heart Lung Transplant|2
02064|133|R|  2011 May;30(5):565-71.|2
02064|134|R|10.Kiberd BA, Wrobel M, Dandavino R, Keown P, Gourishankar S. The role of|2
02064|135|R|   proton pump inhibitors on early mycophenolic acid exposure in kidney|2
02064|136|R|   transplantation: evidence from the CLEAR study. Ther Drug Monit 2011 Feb;|2
02064|137|R|   33(1):120-3.|2
02065|001|T|MONOGRAPH TITLE:  Non-Live or Non-Replicating Vaccines/Fingolimod|
02065|002|B||
02065|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02065|004|L|take action as needed.|
02065|005|B||
02065|006|A|MECHANISM OF ACTION:  Fingolimod is an immunosuppressant and may alter the|
02065|007|A|immune system's response to vaccines.(1)|
02065|008|B||
02065|009|E|CLINICAL EFFECTS:  Administration of a vaccine during and for 2 months|
02065|010|E|following fingolimod therapy may result in decreased effectiveness of the|
02065|011|E|vaccine.(1,2)|
02065|012|B||
02065|013|P|PREDISPOSING FACTORS:  None determined.|
02065|014|B||
02065|015|M|PATIENT MANAGEMENT:  Ideally, administer vaccines prior to initiating|
02065|016|M|fingolimod therapy.|
02065|017|M|   The immune response to non-live vaccines should be monitored in patients|
02065|018|M|receiving fingolimod or who have received fingolimod in the previous two|
02065|019|M|months.  Vaccinations given during and for 2 months after stopping|
02065|020|M|fingolimod therapy may need to be repeated.(1,2)|
02065|021|M|   The Centers for Disease Control's (CDC) Advisory Committee on|
02065|022|M|Immunization Practices (ACIP) states that non-live vaccines should be used|
02065|023|M|with caution in patients who are severely immunosuppressed.  Patients who|
02065|024|M|are vaccinated within the 14 days prior to initiating immunosuppressive|
02065|025|M|therapy should be considered unvaccinated and should be revaccinated at|
02065|026|M|least 3 months after immunosuppressive therapy is discontinued when immune|
02065|027|M|competence is restored.(3)|
02065|028|B||
02065|029|D|DISCUSSION:  Vaccinations may be less effective during and for 2 months|
02065|030|D|following fingolimod therapy(1) however they are considered safe to|
02065|031|D|administer.(2)|
02065|032|B||
02065|033|R|REFERENCES:|
02065|034|B||
02065|035|R|1.Gilenya (fingolimod) US prescribing information. Novartis Pharmaceuticals|1
02065|036|R|  Corporation June, 2024.|1
02065|037|R|2.Williamson EM, Chahin S, Berger JR. Vaccines in Multiple Sclerosis. Curr|6
02065|038|R|  Neurol Neurosci Rep 2016 Apr;16(4):36.|6
02065|039|R|3.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
02065|040|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
02065|041|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
02065|042|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
02065|043|R|  recs.pdf February 10, 2023;1-197.|6
02066|001|T|MONOGRAPH TITLE:  Risperidone/Rifampin (mono deleted 01/10/2013)|
02066|002|B||
02066|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02066|004|L|take action as needed.|
02066|005|B||
02066|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of risperidone by|
02066|007|A|CYP P-450-3A4.(1-3)|
02066|008|B||
02066|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifmapin may result in|
02066|010|E|decreased levels and effectiveness of risperidone.(1-3)|
02066|011|B||
02066|012|P|PREDISPOSING FACTORS:  None determined.|
02066|013|B||
02066|014|M|PATIENT MANAGEMENT:  Patients receiving risperidone should be closely|
02066|015|M|monitored if rifampin is initiated or discontinued from concurrent therapy.|
02066|016|M|The dosage of risperidone may need to be adjusted.|
02066|017|M|   The US manufacturer of extended release risperidone microspheres for|
02066|018|M|injection (Risperdal Consta) recommends that patients maintained on this|
02066|019|M|product be closely monitored during the first 4-8 weeks of concurrent|
02066|020|M|therapy if rifampin is initiated.  Patients may need a dosage increase of|
02066|021|M|this product or additional oral risperidone.  If rifampin is discontinued,|
02066|022|M|the manufacturer recommends that patients maintained on the recommended 25|
02066|023|M|mg dose continue to receive this dose, unless clinical judgment necessitates|
02066|024|M|lowering the dose or interrupting therapy.  If a decision is made to lower|
02066|025|M|the dose, the dose may be lowered to 12.5 mg 2 to 4 weeks before the|
02066|026|M|discontinuation of rifmapin although the efficacy of this dose has not been|
02066|027|M|confirmed in clinical trials.(1)|
02066|028|B||
02066|029|D|DISCUSSION:  In an open, randomized cross-over study in 10 healthy males,|
02066|030|D|pretreatment with rifampin (600 mg daily for 5 days) decreased the|
02066|031|D|area-under-curve (AUC) and maximum concentration (Cmax) of a single oral|
02066|032|D|dose of risperidone (4 mg) by 72% and 50%, respectively.(2)|
02066|033|D|   In a study in 10 healthy males, pretreatment with rifampin (600 mg daily|
02066|034|D|for 7 days) decreased the AUC and Cmax of a single oral dose of risperidine|
02066|035|D|(1 mg) by 51% and 38%, respectively.  The AUC of 9-hydroxyrisperidone and|
02066|036|D|the active moieties (risperidone + 9-hydroxyperidone) decreased by 43% and|
02066|037|D|45%, respectively.  The Cmax of 9-hydroxyrisperidone and the active moieties|
02066|038|D|decreased by 46% and 41%, respectively.(3)|
02066|039|B||
02066|040|R|REFERENCES:|
02066|041|B||
02066|042|R|1.Risperdal Consta (risperidone long acting injection) US prescribing|1
02066|043|R|  information. Janssen Pharmaceutical Ltd. September, 2011.|1
02066|044|R|2.Mahatthanatrakul W, Nontaput T, Ridtitid W, Wongnawa M, Sunbhanich M.|2
02066|045|R|  Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of|2
02066|046|R|  antipsychotic risperidone in healthy volunteers. J Clin Pharm Ther 2007|2
02066|047|R|  Apr;32(2):161-7.|2
02066|048|R|3.Kim KA, Park PW, Liu KH, Kim KB, Lee HJ, Shin JG, Park JY. Effect of|2
02066|049|R|  rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics|2
02066|050|R|  of risperidone. J Clin Pharmacol 2008 Jan;48(1):66-72.|2
02067|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Rifapentine (mono deleted|
02067|002|T|12/26/2013)|
02067|003|B||
02067|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02067|005|L|of severe adverse interaction.|
02067|006|B||
02067|007|A|MECHANISM OF ACTION:  Rifapentine may induce the metabolism of the protease|
02067|008|A|inhibitor by CYP P-450-3A4.(1)|
02067|009|B||
02067|010|E|CLINICAL EFFECTS:  Concurrent or recent use of rifapentine may result in|
02067|011|E|decreased levels and effectiveness of the protease inhibitor.(1)|
02067|012|B||
02067|013|P|PREDISPOSING FACTORS:  None determined.|
02067|014|B||
02067|015|M|PATIENT MANAGEMENT:  Consider alternatives to rifapentine in patients|
02067|016|M|receiving protease inhibitors.(1)|
02067|017|B||
02067|018|D|DISCUSSION:  Rifapentine (600 mg twice weekly for 28 days) decreased the|
02067|019|D|area-under-curve (AUC) and maximum concentration (Cmax) of indinavir (800 mg|
02067|020|D|3 times daily on Days 15-28) by 70% and 55%, respectively.  Indinavir|
02067|021|D|clearance increased 3-fold.  There was no affect on indinavir half-life.|
02067|022|D|There were no effects on rifapentine pharmacokinetics.(1)|
02067|023|D|   One or more of the drug pairs linked to this monograph have been included|
02067|024|D|in a list of interactions that should be considered "high-priority" for|
02067|025|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02067|026|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02067|027|D|Coordinator (ONC) for Health Information Technology.|
02067|028|B||
02067|029|R|REFERENCES:|
02067|030|B||
02067|031|R|1.Priftin (rifapentine) US prescribing information. Sanofi-Aventis U.S. LLC|1
02067|032|R|  July, 2010.|1
02067|033|R|2.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02067|034|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02067|035|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02067|036|R|  19(5):735-43.|6
02068|001|T|MONOGRAPH TITLE:  Zoledronic Acid/Diuretics|
02068|002|B||
02068|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02068|004|L|take action as needed.|
02068|005|B||
02068|006|A|MECHANISM OF ACTION:  Concurrent use of zoledronic acid and a diuretic may|
02068|007|A|have adverse effects on the renal system.(1,2)|
02068|008|B||
02068|009|E|CLINICAL EFFECTS:  Concurrent use of zoledronic acid and a diuretic may|
02068|010|E|result in renal dysfunction.  Deterioration in renal function, acute renal|
02068|011|E|failure requiring dialysis, and death have been reported.(1)|
02068|012|B||
02068|013|P|PREDISPOSING FACTORS:  The interaction may be more likely in elderly|
02068|014|P|patients, patients who are taking other drugs that impact renal function,|
02068|015|P|patients with pre-existing renal compromise, and patients who are|
02068|016|P|dehydrated.(1)|
02068|017|B||
02068|018|M|PATIENT MANAGEMENT:  Patients should be adequately hydrated with 500 ml (2|
02068|019|M|glasses of water) before and after zoledronic acid administration.(1)|
02068|020|M|Creatinine clearance should be monitored before and after therapy and|
02068|021|M|zoledronic acid should not be administered in patients with a creatinine|
02068|022|M|clearance less than 35 ml/min.(1,3)|
02068|023|B||
02068|024|D|DISCUSSION:  Zoledronic acid has been associated with renal dysfunction,|
02068|025|D|including deterioration in renal function, acute renal failure requiring|
02068|026|D|dialysis, and death.  Risk factors include advanced age, concomitant|
02068|027|D|nephrotoxic agents, and dehydration.(1)  The FDA has received 16 reports of|
02068|028|D|fatal acute renal failure and 9 reports of renal injury requiring dialysis|
02068|029|D|following the administration of Reclast (zoledronic acid).(3)|
02068|030|B||
02068|031|R|REFERENCES:|
02068|032|B||
02068|033|R|1.Aclasta (zoledronic acid) Canadian prescribing information. Novartis|1
02068|034|R|  Pharmaceuticals Canada Inc. September 11, 2014.|1
02068|035|R|2.Reclast (zoledronic acid) US prescribing information. Novartis April,|1
02068|036|R|  2015.|1
02068|037|R|3.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02068|038|R|  contraindication and updated warning on kidney impairment for Reclast|1
02068|039|R|  (zoledronic acid). available at:|1
02068|040|R|  http://www.fda.gov/Drugs/DrugSafety/ucm270199.htm September 1, 2011.|1
02069|001|T|MONOGRAPH TITLE:  Praziquantel/Selected Strong CYP3A4 Inducers|
02069|002|B||
02069|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02069|004|L|is contraindicated and generally should not be dispensed or administered to|
02069|005|L|the same patient.|
02069|006|B||
02069|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
02069|008|A|praziquantel by CYP3A4.(1)|
02069|009|B||
02069|010|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong CYP3A4 inducer may|
02069|011|E|decrease the levels and effectiveness of praziquantel.|
02069|012|B||
02069|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02069|014|P|of the inducer for longer than 1-2 weeks.|
02069|015|B||
02069|016|M|PATIENT MANAGEMENT:  The concurrent use of praziquantel and strong inducers|
02069|017|M|of CYP3A4 is contraindicated.(1)|
02069|018|M|   In patients receiving strong CYP3A4 inducers who need immediate treatment|
02069|019|M|for schistosomiasis, alternative agents for schistosomiasis should be used.|
02069|020|M|If praziquantel is required, increase monitoring for praziquantel efficacy.|
02069|021|M|If schistosomiasis treatment can be delayed, discontinue strong CYP3A4|
02069|022|M|inducers at least 2 to 4 weeks before administration of praziquantel.  The|
02069|023|M|inducer may be resumed 1 day after completion of praziquantel therapy.(1)|
02069|024|B||
02069|025|D|DISCUSSION:  A study examined praziquantel levels in 10 healthy controls, 10|
02069|026|D|subjects maintained on phenytoin monotherapy, and 10 subjects maintained on|
02069|027|D|carbamazepine monotherapy.  Praziquantel area-under-curve (AUC) and maximum|
02069|028|D|concentration (Cmax) were reduced by 90.3% and by 92.1%, respectively, in|
02069|029|D|carbamazepine-treated subjects when compared to control subjects.|
02069|030|D|Praziquantel AUC and Cmax were reduced by 74% and 76%, respectively, in|
02069|031|D|phenytoin-treated subjects when compared to control subjects.(2)|
02069|032|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
02069|033|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02069|034|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, and|
02069|035|D|St. John's Wort.(3)|
02069|036|B||
02069|037|R|REFERENCES:|
02069|038|B||
02069|039|R|1.Biltricide (praziquantel) US prescribing information. Bayer HealthCare|1
02069|040|R|  Pharmaceuticals Inc. January, 2019.|1
02069|041|R|2.Bittencourt PR, Gracia CM, Martins R, Fernandes AG, Diekmann HW, Jung W.|2
02069|042|R|  Phenytoin and carbamazepine decreased oral bioavailability of|2
02069|043|R|  praziquantel. Neurology 1992 Mar;42(3 Pt 1):492-6.|2
02069|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
02069|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02070|001|T|MONOGRAPH TITLE:  Dabigatran/P-glycoprotein (P-gp) Inducers|
02070|002|B||
02070|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02070|004|L|is contraindicated and generally should not be dispensed or administered to|
02070|005|L|the same patient.|
02070|006|B||
02070|007|A|MECHANISM OF ACTION:  Dabigatran is a substrate of the intestinal efflux|
02070|008|A|transporter P-glycoprotein (P-gp), and has a low oral bioavailability of|
02070|009|A|3-7%.|
02070|010|B||
02070|011|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide, carbamazepine,|
02070|012|E|fosphenytoin, lorlatinib, phenytoin, rifampin, rifapentine, or St. John's|
02070|013|E|wort may result in decreased levels and effectiveness of dabigatran.(1-3)|
02070|014|B||
02070|015|P|PREDISPOSING FACTORS:  None determined.|
02070|016|B||
02070|017|M|PATIENT MANAGEMENT:  Avoid concurrent use of an inducer of P-gp such as|
02070|018|M|apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampin,|
02070|019|M|rifapentine or St. John's wort in patients maintained on dabigatran.(1)|
02070|020|M|Consider alternatives to these agents in patients maintained on dabigatran.|
02070|021|M|If therapy with an inducer of P-gp is required, alternatives to dabigatran|
02070|022|M|may need to be considered.|
02070|023|M|  If a P-gp inducer is discontinued, dabigatran exposure will remain|
02070|024|M|impaired for at least one week after the completion of therapy.(1,2)|
02070|025|B||
02070|026|D|DISCUSSION:  Pretreatment with rifampin (an inducer of P-gp, 600 mg daily|
02070|027|D|for 7 days) decreased the area-under-curve (AUC) and maximum concentration|
02070|028|D|(Cmax) of a single dose of dabigatran by 66% and 67%, respectively.(1-3)|
02070|029|D|One week after rifampin discontinuation, exposure to dabigatran was close to|
02070|030|D|normal.(1,2)|
02070|031|D|   In a case report, a patient taking concomitant dabigatran (150 mg twice a|
02070|032|D|day) and phenytoin (100 mg three times a day) had no detectable serum|
02070|033|D|concentration of dabigatran 10 hours after the morning dabigatran dose.(6)|
02070|034|D|   Other inducers of P-glycoprotein include apalutamide, carbamazepine,|
02070|035|D|fosphenytoin, lorlatinib, phenytoin, rifampin, rifapentine, and St. John's|
02070|036|D|wort.(2-5)|
02070|037|B||
02070|038|R|REFERENCES:|
02070|039|B||
02070|040|R|1.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
02070|041|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
02070|042|R|2.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
02070|043|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
02070|044|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
02070|045|R|  Boehringer Ingelheim March, 23 2020.|1
02070|046|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02070|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02070|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02070|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02070|050|R|  11/14/2017.|1
02070|051|R|5.This information is based on an extract from the Certara Drug Interaction|6
02070|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02070|053|R|6.Wiggins BS, Northup A, Johnson D, Senfield J. Reduced Anticoagulant Effect|3
02070|054|R|  of Dabigatran in a Patient Receiving Concomitant Phenytoin.|3
02070|055|R|  Pharmacotherapy 2016 Feb 5.|3
02071|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Ritonavir|
02071|002|B||
02071|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02071|004|L|take action as needed.|
02071|005|B||
02071|006|A|MECHANISM OF ACTION:  Ritonavir may induce the metabolism of methadone by|
02071|007|A|CYP2B6.(1,2)|
02071|008|A|   Levomethadone is an enantiomer of methadone.(3)|
02071|009|B||
02071|010|E|CLINICAL EFFECTS:  Concurrent use of ritonavir may result in decreased|
02071|011|E|levels of methadone, which may result in withdrawal symptoms in some|
02071|012|E|patients.(1)|
02071|013|B||
02071|014|P|PREDISPOSING FACTORS:  None determined.|
02071|015|B||
02071|016|M|PATIENT MANAGEMENT:  Patients maintained on methadone may need dosage|
02071|017|M|adjustments if ritonavir is added to or discontinued from therapy.  Patients|
02071|018|M|receiving ritonavir may need higher dosages of methadone than expected.|
02071|019|M|Patients should be monitored for signs of methadone withdrawal.(1)|
02071|020|B||
02071|021|D|DISCUSSION:  In a study, an HIV-infected patient maintained on methadone for|
02071|022|D|the treatment of opiate addiction showed a decrease of 44% in steady-state|
02071|023|D|methadone concentration following the addition of ritonavir to his|
02071|024|D|medication regimen.  Another two patients showed a decrease of 50.1% and|
02071|025|D|58.4% in methadone concentrations following the addition of nelfinavir to|
02071|026|D|their regimens.  In this same study, six other patients received indinavir|
02071|027|D|and one other patient received saquinavir with no significant change in|
02071|028|D|methadone steady-state concentrations.(4)|
02071|029|D|   In a study in HIV-negative subjects, acute (3 days) and steady-state|
02071|030|D|ritonavir increased systemic and apparent oral R-methadone and S-methadone|
02071|031|D|clearances by 1.5-fold and 2-fold, respectively.  Methadone renal clearance|
02071|032|D|was increased 40%-50%.  Ritonavir stereoselectively (S > R) increased|
02071|033|D|hepatic methadone N-demethylation by 50%-80%, extraction 2-fold, and|
02071|034|D|clearance 2-fold.(5)|
02071|035|D|   A case report documents a potential opiate withdrawal syndrome in a|
02071|036|D|patient treated with methadone following ritonavir administration.(6)|
02071|037|B||
02071|038|R|REFERENCES:|
02071|039|B||
02071|040|R|1.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
02071|041|R|  December, 2019.|1
02071|042|R|2.Younis IR, Lakota EA, Volpe DA, Patel V, Xu Y, Sahajwalla CG. Drug-Drug|6
02071|043|R|  Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned. J|6
02071|044|R|  Clin Pharmacol 2019 Aug;59(8):1035-1043.|6
02071|045|R|3.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
02071|046|R|  Pharma AS November 30, 2018.|1
02071|047|R|4.Beauverie P, Taburet AM, Dessalles MC, Furlan V, Touzeau D. Therapeutic|2
02071|048|R|  drug monitoring of methadone in HIV-infected patients receiving protease|2
02071|049|R|  inhibitors. AIDS 1998 Dec 24;12(18):2510-1.|2
02071|050|R|5.Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, Hoffer C.|2
02071|051|R|  Mechanism of ritonavir changes in methadone pharmacokinetics and|2
02071|052|R|  pharmacodynamics: I. Evidence against CYP3A mediation of methadone|2
02071|053|R|  clearance. Clin Pharmacol Ther 2008 Oct;84(4):497-505.|2
02071|054|R|6.Jimenez-Lerma JM, Iraurgi I. Potential opiate withdrawal syndrome after|3
02071|055|R|  ritonavir administration in a patient treated with methadone. Rev Clin Esp|3
02071|056|R|  1999 Mar;199(3):188-9.|3
02072|001|T|MONOGRAPH TITLE:  Fentanyl; Oxycodone/Aprepitant (mono deleted 03/15/2012)|
02072|002|B||
02072|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02072|004|L|of severe adverse interaction.|
02072|005|B||
02072|006|A|MECHANISM OF ACTION:  Aprepitant may inhibit the metabolism of fentanyl(1)|
02072|007|A|and oxycodone(2) by CYP P-450-3A4.|
02072|008|B||
02072|009|E|CLINICAL EFFECTS:  Increased or prolonged adverse drug effects of|
02072|010|E|fentanyl(1) and oxycodone(2) with possible potentially fatal respiratory|
02072|011|E|depression.(1,2)|
02072|012|B||
02072|013|P|PREDISPOSING FACTORS:  None determined.|
02072|014|B||
02072|015|M|PATIENT MANAGEMENT:  The US manufacturers of fentanyl(1) and oxycodone(2)|
02072|016|M|recommend that patients receiving potent or moderate CYP P-450-3A4|
02072|017|M|inhibitors such as aprepitant should be carefully monitored for an extended|
02072|018|M|period of time and dosage adjustments should be made if warranted.|
02072|019|B||
02072|020|D|DISCUSSION:  Fentanyl(1) and oxycodone(2) are metabolized by the CYP|
02072|021|D|P-450-3A4 isoenzyme.  Moderate and strong inhibitors of this isoenzyme are|
02072|022|D|expected to increase fentanyl(1) and oxycodone(2) levels.|
02072|023|B||
02072|024|R|REFERENCES:|
02072|025|B||
02072|026|R|1.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
02072|027|R|  Inc. October, 2019.|1
02072|028|R|2.OxyContin (oxycodone hydrochloride) US prescribing information. Perdue|1
02072|029|R|  Pharma L.P. October, 2021.|1
02073|001|T|MONOGRAPH TITLE:  Selected Opioids/Selected Moderate CYP3A4 Inhibitors|
02073|002|B||
02073|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02073|004|L|take action as needed.|
02073|005|B||
02073|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
02073|007|A|alfentanil, benzhydrocodone, fentanyl,(1) hydrocodone, meperidine,(2)|
02073|008|A|oxycodone,(3) and sufentanil.(4)|
02073|009|B||
02073|010|E|CLINICAL EFFECTS:  The concurrent administration of a CYP3A4 inhibitor may|
02073|011|E|result in elevated levels of and toxicity from alfentanil, benzhydrocodone,|
02073|012|E|fentanyl,(1,5) hydrocodone, meperidine,(2) oxycodone(3) and sufentanil(4),|
02073|013|E|including somnolence and potentially fatal respiratory depression.|
02073|014|B||
02073|015|P|PREDISPOSING FACTORS:  Heat.|
02073|016|B||
02073|017|M|PATIENT MANAGEMENT:  Monitor patients receiving moderate CYP3A4 inhibitors|
02073|018|M|for an extended period of time.  Dosage adjustments should be made if|
02073|019|M|warranted.|
02073|020|M|   The manufacturer of sufentanil sublingual tablets states that if|
02073|021|M|concomitant use with CYP3A4 inhibitors is necessary, consider use of an|
02073|022|M|alternate agent that allows dose adjustment.(4)|
02073|023|M|    Respiratory depression can occur at any time during opioid therapy,|
02073|024|M|especially during therapy initiation and following dosage increases.  The|
02073|025|M|risk of opioid-related overdose or overdose-related death is increased with|
02073|026|M|higher opioid doses, and this risk persists over the course of therapy.|
02073|027|M|Consider these risks when using concurrently with other agents that may|
02073|028|M|cause CNS depression.(6)|
02073|029|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02073|030|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02073|031|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02073|032|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02073|033|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02073|034|M|as those taking CNS depressants) and when a patient has household|
02073|035|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02073|036|M|for obtaining an opioid reversal agent (e.g., prescription,|
02073|037|M|over-the-counter, or as part of a community-based program).(7)|
02073|038|M|   Avoid exposing the fentanyl patch application site and surrounding area|
02073|039|M|to direct external heat sources as there have been reports of overdose and|
02073|040|M|death as a result of exposure to heat.(1)|
02073|041|B||
02073|042|D|DISCUSSION:  Fentanyl(1) and oxycodone(3) are metabolized by the CYP3A4|
02073|043|D|isoenzyme.  Moderate and strong inhibitors of this isoenzyme are expected to|
02073|044|D|increase fentanyl(1) and oxycodone(3) levels.|
02073|045|D|   In a single dose study of sufentanil sublingual tablet 15 mcg with a|
02073|046|D|strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC|
02073|047|D|and Cmax values of sufentanil, respectively, compared to its administration|
02073|048|D|alone.(4)|
02073|049|D|   In a randomized study in 30 patients, continuous diltiazem (1 mcg/kg/min)|
02073|050|D|infusion had no effect on epidural fentanyl consumption when compared to|
02073|051|D|placebo.  There were no significant differences in Visual Analogue Scores|
02073|052|D|(VAS), Verbal Rating Scores (VRS), or incidence of side effects, although|
02073|053|D|there was a trend towards increased nausea with concurrent diltiazem.(5)|
02073|054|D|   In a randomized study of coronary artery bypass patients, concurrent|
02073|055|D|diltiazem (60 mg orally 2 hours before induction of anesthesia then 0.1|
02073|056|D|mg/kg/hr infusion) increased the area-under-curve (AUC) and half-life of|
02073|057|D|alfentanil by 40% and 50%, respectively, when compared to placebo.  Patients|
02073|058|D|who received diltiazem were extubated an average of 2.5 hours later than in|
02073|059|D|patients who received placebo.(8)|
02073|060|D|   In a study in 13 patients, administration of a single dose of verapamil|
02073|061|D|(75mcg/kg to 150mcg/kg) had no significant effects on the pharmacodynamic|
02073|062|D|effects of a single dose of fentanyl; however, individual patients had|
02073|063|D|modest decreases in blood pressure.(9)|
02073|064|D|   In a case report, concurrent diltiazem and fentanyl produced|
02073|065|D|delirium.(10)|
02073|066|D|   A study in healthy subjects shown that the application of heat over the|
02073|067|D|fentanyl patch system increased mean overall fentanyl exposure by 120% and|
02073|068|D|average maximum fentanyl level by 61%.(1)|
02073|069|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
02073|070|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir,|
02073|071|D|diltiazem, dronedarone, duvelisib, fedratinib, fosamprenavir, fosnetupitant,|
02073|072|D|imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
02073|073|D|rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(11,12)|
02073|074|B||
02073|075|R|REFERENCES:|
02073|076|B||
02073|077|R|1.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
02073|078|R|  Inc. October, 2019.|1
02073|079|R|2.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
02073|080|R|  Pharmaceuticals LLC. December, 2023.|1
02073|081|R|3.OxyContin (oxycodone hydrochloride) US prescribing information. Perdue|1
02073|082|R|  Pharma L.P. October, 2021.|1
02073|083|R|4.Dsuvia (sufentanil) sublingual tablet US prescribing information. AcelRx|1
02073|084|R|  Pharmaceuticals, Inc. December, 2023.|1
02073|085|R|5.Nitahara K, Matsunaga M, Katori K, Yotsui H, Higuchi H, Higa K. Effect of|2
02073|086|R|  continuous low-dose intravenous diltiazem on epidural fentanyl analgesia|2
02073|087|R|  after lower abdominal surgery. Br J Anaesth 2003 Apr;90(4):507-9.|2
02073|088|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02073|089|R|  prescribing information for all opioid pain medicines to provide|1
02073|090|R|  additional guidance for safe use. Available at:|1
02073|091|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02073|092|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02073|093|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02073|094|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02073|095|R|  recommends health care professionals discuss naloxone with all patients|1
02073|096|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02073|097|R|  disorder. Available at:|1
02073|098|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02073|099|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02073|100|R|  d-pain July 23, 2020.|1
02073|101|R|8.Ahonen J, Olkkola KT, Salmenpera M, Hynynen M, Neuvonen PJ. Effect of|2
02073|102|R|  diltiazem on midazolam and alfentanil disposition in patients undergoing|2
02073|103|R|  coronary artery bypass grafting. Anesthesiology 1996 Dec;85(6):1246-52.|2
02073|104|R|9.Kapur PA, Norel EJ, Dajee H, Cohen G, Flacke W. Haemodynamic effects of|2
02073|105|R|  verapamil administration after large doses of fentanyl in man. Can Anaesth|2
02073|106|R|  Soc J 1986 Mar;33(2):138-44.|2
02073|107|R|10.Levin TT, Bakr MH, Nikolova T. Case report: delirium due to a|3
02073|108|R|   diltiazem-fentanyl CYP3A4 drug interaction. Gen Hosp Psychiatry 2010|3
02073|109|R|   Nov-Dec;32(6):648.e9-648.e10.|3
02073|110|R|11.US Food and Drug Administration (FDA). Drug Development and Drug|1
02073|111|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
02073|112|R|   at:|1
02073|113|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
02073|114|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02073|115|R|   11/14/2017.|1
02073|116|R|12.This information is based on an extract from the Certara Drug Interaction|6
02073|117|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02074|001|T|MONOGRAPH TITLE:  Ketorolac (Injectable)/NSAIDs; Aspirin (Greater Than 300|
02074|002|T|mg); Salicylates|
02074|003|B||
02074|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02074|005|L|is contraindicated and generally should not be dispensed or administered to|
02074|006|L|the same patient.|
02074|007|B||
02074|008|A|MECHANISM OF ACTION:  Possible additive or synergistic side effects.(1)|
02074|009|B||
02074|010|E|CLINICAL EFFECTS:  Concurrent use of multiple doses of ketorolac with other|
02074|011|E|non-steroidal anti-inflammatory agents (NSAIDs), salicylates or aspirin may|
02074|012|E|result in an increase in NSAID-related side effects such as bleeding or|
02074|013|E|renal impairment.(1-3)|
02074|014|B||
02074|015|P|PREDISPOSING FACTORS:  Patients with pre-existing renal impairment may be at|
02074|016|P|an increased risk of adverse effects from this interaction.|
02074|017|P|   The risk for bleeding episodes may be greater in patients with multiple|
02074|018|P|disease-associated factors (e.g. thrombocytopenia, advanced liver disease).|
02074|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
02074|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02074|021|P|risk for bleeding (e.g., anticoagulants, antiplatelets, corticosteroids,|
02074|022|P|selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine|
02074|023|P|reuptake inhibitors (SNRIs).|
02074|024|P|   Risk of GI bleed may be increased in patients who are of older age, in|
02074|025|P|poor health status, or who use alcohol or smoke. Risk may also be increased|
02074|026|P|with longer duration of NSAID use and prior history of peptic ulcer disease|
02074|027|P|and/or GI bleeding.|
02074|028|B||
02074|029|M|PATIENT MANAGEMENT:  The manufacturer of ketorolac states that concurrent|
02074|030|M|use of ketorolac with either other NSAIDs, salicylates or aspirin is|
02074|031|M|contraindicated.(1)|
02074|032|M|   If concurrent therapy is deemed medically necessary, monitor patients|
02074|033|M|receiving concurrent therapy for signs of blood loss, including decreased|
02074|034|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
02074|035|M|and promptly evaluate patients with any symptoms.|
02074|036|M|    When applicable, perform agent-specific laboratory tests (e.g. INR,|
02074|037|M|aPTT) to monitor efficacy and safety of anticoagulation. Discontinue|
02074|038|M|anticoagulation in patients with active pathologic bleeding.|
02074|039|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02074|040|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02074|041|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02074|042|M|and/or swelling.|
02074|043|B||
02074|044|D|DISCUSSION:  Manufacturers of ketorolac state that concurrent use of|
02074|045|D|ketorolac with either other NSAIDs, salicylates or aspirin is|
02074|046|D|contraindicated.(1,2)|
02074|047|D|   If concurrent therapy is deemed medically necessary, monitor patients|
02074|048|D|receiving concurrent therapy for signs of blood loss, including decreased|
02074|049|D|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
02074|050|D|and promptly evaluate patients with any symptoms.|
02074|051|D|   Conduct periodic monitoring of renal function, especially in patients|
02074|052|D|with renal impairment.|
02074|053|B||
02074|054|R|REFERENCE:|
02074|055|B||
02074|056|R|1.Toradol (ketorolac tromethamine) US prescribing information. Roche|1
02074|057|R|  Pharmaceuticals March, 2013.|1
02075|001|T|MONOGRAPH TITLE:  Eribulin/Possible QT Prolonging Agents|
02075|002|B||
02075|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02075|004|L|take action as needed.|
02075|005|B||
02075|006|A|MECHANISM OF ACTION:  Eribulin has been shown to prolong the QTc interval.|
02075|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02075|008|A|additive effects on the QTc interval.(1)|
02075|009|B||
02075|010|E|CLINICAL EFFECTS:  The concurrent use of eribulin with other agents that|
02075|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02075|012|E|arrhythmias, including torsades de pointes.(1)|
02075|013|B||
02075|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02075|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02075|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02075|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02075|018|P|gender, or advanced age.(2)|
02075|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02075|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02075|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02075|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02075|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02075|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02075|025|P|dysfunction).(2)|
02075|026|B||
02075|027|M|PATIENT MANAGEMENT:  The US manufacturer of eribulin states that patients|
02075|028|M|receiving concurrent therapy with eribulin and other agents known to prolong|
02075|029|M|the QT interval should receive ECG monitoring.(1)|
02075|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02075|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02075|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02075|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02075|034|B||
02075|035|D|DISCUSSION:  QT prolongation, independent of eribulin concentration, was|
02075|036|D|observed on Day 8 of therapy but not on Day 1 in  an uncontrolled open-label|
02075|037|D|ECG study in 26 patients.(1)|
02075|038|D|   Agents that are linked to this monograph may have varying degrees of|
02075|039|D|potential to prolong the QTc interval but are generally accepted to have a|
02075|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02075|041|D|been shown to prolong the QTc interval either through their mechanism of|
02075|042|D|action, through studies on their effects on the QTc interval, or through|
02075|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02075|044|D|and/or post-marketing reports.(3)|
02075|045|B||
02075|046|R|REFERENCES:|
02075|047|B||
02075|048|R|1.Halaven (eribulin mesylate) US prescribing information. Eisai, Inc.|1
02075|049|R|  January, 2016.|1
02075|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02075|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02075|052|R|  settings: a scientific statement from the American Heart Association and|6
02075|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02075|054|R|  2;55(9):934-47.|6
02075|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02075|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02075|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02075|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02076|001|T|MONOGRAPH TITLE:  Selected Oral Quinolones/Selected Oral Cations|
02076|002|B||
02076|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02076|004|L|take action as needed.|
02076|005|B||
02076|006|A|MECHANISM OF ACTION:  Aluminum, calcium, iron, lanthanum, magnesium, and|
02076|007|A|zinc may form chelation compounds with the quinolones.(1-40)|
02076|008|B||
02076|009|E|CLINICAL EFFECTS:  Simultaneous administration or administration of products|
02076|010|E|containing aluminum, calcium, iron, lanthanum, magnesium, and/or zinc close|
02076|011|E|to the administration time of an oral quinolone may result in decreased|
02076|012|E|absorption and clinical effectiveness of the quinolone.|
02076|013|B||
02076|014|P|PREDISPOSING FACTORS:  None determined.|
02076|015|B||
02076|016|M|PATIENT MANAGEMENT:  If possible, avoid concurrent therapy with quinolones|
02076|017|M|and cation-containing products.  If it is necessary to administer these|
02076|018|M|agents concurrently, follow the manufacturers' recommendations regarding|
02076|019|M|timing of administration of the quinolone and cation-containing products.|
02076|020|M|   Manufacturer recommendations regarding the separation of administration|
02076|021|M|times of quinolones and products containing aluminum, calcium, iron,|
02076|022|M|lanthanum, magnesium, and/or zinc vary:|
02076|023|M|---Do not give ciprofloxacin for at least 2 hours before or 6 hours after|
02076|024|M|oral cations.(1)|
02076|025|M|---Do not give delafloxacin for at least 2 hours before or 6 hours after|
02076|026|M|oral cations.(2)|
02076|027|M|---Do not give enoxacin for at least 2 hours before or 8 hours after oral|
02076|028|M|cations.(3)|
02076|029|M|---Do not give levofloxacin for at least 2 hours before or 2 hours after|
02076|030|M|oral cations.(4)|
02076|031|M|---Do not give nalidixic acid for at least 2 hours before or 2 hours after|
02076|032|M|oral cations.(5)|
02076|033|M|---Do not give norfloxacin for at least 2 hours before or 2 hours after oral|
02076|034|M|cations.(6)|
02076|035|M|---Do not give ofloxacin for at least 2 hours before or 2 hours after oral|
02076|036|M|cations.(7)|
02076|037|M|---Do not give sparfloxacin for at least 4 hours before oral cations.(8)|
02076|038|M|---Do not give sitafloxacin for at least 2 hours before or 2 hours after|
02076|039|M|oral cations.(9)|
02076|040|M|   The US manufacturer of lanthanum recommends that quinolones be taken at|
02076|041|M|least 1 hour before or 4 hours after lanthanum;(10) however, it would be|
02076|042|M|prudent to follow the specific quinolone manufacturers' recommendations|
02076|043|M|regarding concurrent administration of cations.|
02076|044|M|   For quinolones not listed above, separate their administration from oral|
02076|045|M|cations by as much time as feasible.|
02076|046|B||
02076|047|D|DISCUSSION:  Aluminum, calcium, iron, magnesium, and zinc products have been|
02076|048|D|shown to form chelation compounds with quinolone antibiotics, resulting in|
02076|049|D|decreased absorption of the quinolone.(1-40)  Treatment failures have been|
02076|050|D|reported.(11-12)|
02076|051|D|   In a study in 12 healthy subjects, simultaneous administration of|
02076|052|D|didanosine chewable tablets, which contain aluminum and magnesium, decreased|
02076|053|D|ciprofloxacin area-under-curve (AUC) and maximum concentration (Cmax) by 92%|
02076|054|D|and 98%, respectively.(14)  The administration of ciprofloxacin 2 hours|
02076|055|D|prior to Videx chewable/dispersible tablets decreased ciprofloxacin|
02076|056|D|concentrations by 26%.(15,16)|
02076|057|D|   In a study in healthy subjects, pretreatment with an antacid containing|
02076|058|D|aluminum-magnesium hydroxide at 5-10 minutes, 2 hours, and 4 hours before a|
02076|059|D|single dose of ciprofloxacin decreased ciprofloxacin AUC by 84.9%, 76.8%,|
02076|060|D|and 30%, respectively.  There was no effect when the antacid was|
02076|061|D|administered 6 hours before or 2 hours after.(17)|
02076|062|D|   In a study in 12 healthy subjects, aluminum hydroxide decreased|
02076|063|D|ciprofloxacin AUC by 85%.(18)|
02076|064|D|   In a study in patients on continuous ambulatory peritoneal dialysis, peak|
02076|065|D|levels of ciprofloxacin were decreased by 67% to 92% in patients receiving|
02076|066|D|aluminum-containing antacids.(19)|
02076|067|D|   In a study in 15 healthy subjects, simultaneous administration of calcium|
02076|068|D|acetate decreased the bioavailability of ciprofloxacin by 51%.(20)|
02076|069|D|   In a study in 6 healthy males, simultaneous administration of calcium|
02076|070|D|carbonate decreased ciprofloxacin Cmax and AUC by 40% and 43%,|
02076|071|D|respectively.(21)|
02076|072|D|   In a study in 12 healthy subjects, calcium carbonate decreased|
02076|073|D|ciprofloxacin AUC by 40%.(18)|
02076|074|D|   In a study in 13 healthy males, calcium carbonate had no effect on|
02076|075|D|ciprofloxacin bioavailability when administered 2 hours prior to the|
02076|076|D|antibiotic.(22,23)|
02076|077|D|   In a study in healthy males, simultaneous administration of calcium|
02076|078|D|polycarbophil decreased ciprofloxacin AUC by 50%.(24)|
02076|079|D|   In a study in 8 healthy males, simultaneous administration of ferrous|
02076|080|D|fumarate (200 mg) decreased ciprofloxacin AUC by 70%.(25)|
02076|081|D|   In a study in healthy subjects, ferrous gluconate decreased ciprofloxacin|
02076|082|D|bioavailability by 50%; however, no significant effects were seen with|
02076|083|D|iron-ovotransferrin.(26)|
02076|084|D|   In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and|
02076|085|D|AUC of simultaneously administered ciprofloxacin by 54% and 57%,|
02076|086|D|respectively.(27)|
02076|087|D|   In a study in 8 healthy subjects, administration of ferrous sulfate|
02076|088|D|decreased the Cmax and AUC of ciprofloxacin by 33% and 46%, respectively.|
02076|089|D|Administration of ferrous gluconate decreased the Cmax and AUC of|
02076|090|D|ciprofloxacin by 57% and 67%, respectively.  Administration of a|
02076|091|D|multivitamin product containing calcium, copper, iron, magnesium, manganese,|
02076|092|D|and zinc decreased the Cmax and AUC of ciprofloxacin by 53% and 56%,|
02076|093|D|respectively.(28)|
02076|094|D|   In a study in 12 healthy males, ferrous sulfate decreased ciprofloxacin|
02076|095|D|AUC by 63%.(29)|
02076|096|D|   In a study in 12 healthy subjects, lanthanum carbonate decreased the|
02076|097|D|area-under-curve (AUC) and maximum concentration (Cmax) of concurrently|
02076|098|D|administered ciprofloxacin by 54% and 56%, respectively.(30)|
02076|099|D|   In a study in 12 healthy males, a multivitamin containing zinc decreased|
02076|100|D|ciprofloxacin AUC by 22%.(29)|
02076|101|D|   In a study in 12 healthy subjects, an antacid containing|
02076|102|D|aluminum-magnesium hydroxide had no effect on the pharmacokinetics of|
02076|103|D|intravenous enoxacin.(31)|
02076|104|D|   In a study in 10 healthy subjects, administration of an|
02076|105|D|aluminum-magnesium hydroxide antacid 0.5 hours or 2 hours before oral|
02076|106|D|enoxacin (400 mg single dose) decreased the AUC of enoxacin by 73% and 43%,|
02076|107|D|respectively.  There were no significant effects on enoxacin AUC when the|
02076|108|D|antacid was administered 8 hours before or 2 hours after enoxacin.(32)|
02076|109|D|   In a study in 9 healthy subjects, colloidal aluminum phosphate had no|
02076|110|D|effect on the amount of enoxacin absorbed; however, ferrous sulfate (1050|
02076|111|D|mg) decreased the amount of enoxacin absorption by 10%.(33)|
02076|112|D|   In a study in 5 healthy subjects and 5 patients with cystic fibrosis,|
02076|113|D|separation of levofloxacin (750 mg) and calcium carbonate (500 mg 3 times|
02076|114|D|daily with meals) by 2 hours resulted in no interaction in healthy subjects;|
02076|115|D|however, levofloxacin levels were not bioequivalent in patients with cystic|
02076|116|D|fibrosis.(34)|
02076|117|D|   Concurrent magnesium-aluminum hydroxide or calcium have been shown to|
02076|118|D|decrease the bioavailability of norfloxacin by 91.0% and 63.5%,|
02076|119|D|respectively.(35)  Concurrent zinc has been shown to decrease the|
02076|120|D|bioavailability of norfloxacin.(36)|
02076|121|D|   In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and|
02076|122|D|AUC of simultaneously administered norfloxacin by 75% and 73%,|
02076|123|D|respectively.(27)|
02076|124|D|   Simultaneous aluminum phosphate was found to decrease the rate, but not|
02076|125|D|the extent, of absorption of ofloxacin.(37)|
02076|126|D|   In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and|
02076|127|D|AUC of simultaneously administered norfloxacin by 36% and 25%,|
02076|128|D|respectively.(27)|
02076|129|D|   In an in vitro study, ferrous sulfate, aluminum hydroxide, and calcium|
02076|130|D|carbonate decreased ofloxacin availability by 32.6%, 30.7%, and 26.2%,|
02076|131|D|respectively.  However, in vivo tests showed a significant effect with only|
02076|132|D|aluminum hydroxide.(38)|
02076|133|D|   In a study in 9 healthy subjects, simultaneous administration colloidal|
02076|134|D|aluminum phosphate had no effect on ofloxacin (200 mg) absorption; however,|
02076|135|D|ferrous sulfate (1050 mg) decreased the ofloxacin fraction of dose absorbed|
02076|136|D|by 10.85%.(33)|
02076|137|D|   In a study in 16 subjects, administration of either aluminum-magnesium|
02076|138|D|hydroxide or calcium carbonate at least 2 hours before or after ofloxacin|
02076|139|D|administration had no significant effects on ofloxacin levels.(39)|
02076|140|D|   The administration of an antacid containing aluminum hydroxide and|
02076|141|D|magnesium hydroxide 2 hours before, 2 hours after, and 4 hours after|
02076|142|D|sparfloxacin decreased sparfloxacin levels by 23%, 17%, and 5%,|
02076|143|D|respectively.(40)|
02076|144|D|   One or more of the drug pairs linked to this monograph have been included|
02076|145|D|in a list of interactions that could be considered for classification as|
02076|146|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
02076|147|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
02076|148|D|Health Information Technology.|
02076|149|B||
02076|150|R|REFERENCES:|
02076|151|B||
02076|152|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
02076|153|R|  Corporation March, 2022.|1
02076|154|R|2.Baxdela (delafloxacin) US prescribing information. Melinta Therapeutics,|1
02076|155|R|  Inc. June 19, 2017.|1
02076|156|R|3.Penetrex (enoxacin) US prescribing information. Aventis Pharmaceuticals,|1
02076|157|R|  Inc. July, 1998.|1
02076|158|R|4.Levaquin (levofloxacin) US prescribing information. Janssen|1
02076|159|R|  Pharmaceuticals, Inc. October 18, 2018.|1
02076|160|R|5.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
02076|161|R|  Inc. November, 2012.|1
02076|162|R|6.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
02076|163|R|  2016.|1
02076|164|R|7.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
02076|165|R|  Pharmaceutical, Inc. February, 2011.|1
02076|166|R|8.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
02076|167|R|  Inc. February, 2003.|1
02076|168|R|9.Gracevit (sitafloxacin) Japanese prescribing information. Daiichi-Sankyo|1
02076|169|R|  Co., Ltd March 2025.|1
02076|170|R|10.Fosrenol (lanthanum carbonate) US prescribing information. Shire US Inc.|1
02076|171|R|   May, 2020.|1
02076|172|R|11.LePennec MP, Kitzis MD, Terdjman M, Foubard S, Garbarz E, Hanania G.|3
02076|173|R|   Possible interaction of ciprofloxacin with ferrous sulphate. J Antimicrob|3
02076|174|R|   Chemother 1990 Jan;25(1):184-5.|3
02076|175|R|12.Spivey JM, Cummings DM, Pierson NR. Failure of prostatitis treatment|3
02076|176|R|   secondary to probable ciprofloxacin-sucralfate drug interaction.|3
02076|177|R|   Pharmacotherapy 1996 Mar-Apr;16(2):314-6.|3
02076|178|R|13.Noyes M, Polk RE. Norfloxacin and absorption of magnesium-aluminum. Ann|3
02076|179|R|   Intern Med 1988 Jul 15;109(2):168-9.|3
02076|180|R|14.Sahai J, Gallicano K, Oliveras L, Khaliq S, Hawley-Foss N, Garber G.|2
02076|181|R|   Cations in the didanosine tablet reduce ciprofloxacin bioavailability.|2
02076|182|R|   Clin Pharmacol Ther 1993 Mar;53(3):292-7.|2
02076|183|R|15.Videx (didanosine) US prescribing information. Bristol-Myers Squibb|1
02076|184|R|   Company November, 2011.|1
02076|185|R|16.Knupp CA, Barbhaiya RH. A multiple-dose pharmacokinetic interaction study|2
02076|186|R|   between didanosine (Videx) and ciprofloxacin (Cipro) in male subjects|2
02076|187|R|   seropositive for HIV but asymptomatic. Biopharm Drug Dispos 1997 Jan;|2
02076|188|R|   18(1):65-77.|2
02076|189|R|17.Nix DE, Watson WA, Lener ME, Frost RW, Krol G, Goldstein H, Lettieri J,|2
02076|190|R|   Schentag JJ. Effects of aluminum and magnesium antacids and ranitidine on|2
02076|191|R|   the absorption of ciprofloxacin. Clin Pharmacol Ther 1989 Dec;|2
02076|192|R|   46(6):700-5.|2
02076|193|R|18.Frost RW, Lasseter KC, Noe AJ, Shamblen EC, Lettieri JT. Effects of|2
02076|194|R|   aluminum hydroxide and calcium carbonate antacids on the bioavailability|2
02076|195|R|   of ciprofloxacin. Antimicrob Agents Chemother 1992 Apr;36(4):830-2.|2
02076|196|R|19.Golper TA, Hartstein AI, Morthland VH, Christensen JM. Effects of|2
02076|197|R|   antacids and dialysate dwell times on multiple-dose pharmacokinetics of|2
02076|198|R|   oral ciprofloxacin in patients on continuous ambulatory peritoneal|2
02076|199|R|   dialysis. Antimicrob Agents Chemother 1987 Nov;31(11):1787-90.|2
02076|200|R|20.Kays MB, Overholser BR, Mueller BA, Moe SM, Sowinski KM. Effects of|2
02076|201|R|   sevelamer hydrochloride and calcium acetate on the oral bioavailability|2
02076|202|R|   of ciprofloxacin. Am J Kidney Dis 2003 Dec;42(6):1253-9.|2
02076|203|R|21.Sahai J, Healy DP, Stotka J, Polk RE. The influence of chronic|2
02076|204|R|   administration of calcium carbonate on the bioavailability of oral|2
02076|205|R|   ciprofloxacin. Br J Clin Pharmacol 1993 Mar;35(3):302-4.|2
02076|206|R|22.Lomaestro BM, Bailie GR. Effect of multiple staggered doses of calcium on|2
02076|207|R|   the bioavailability of ciprofloxacin. Ann Pharmacother 1993 Nov;|2
02076|208|R|   27(11):1325-8.|2
02076|209|R|23.Lomaestro BM, Bailie GR. Effect of staggered dose of calcium on the|2
02076|210|R|   bioavailability of ciprofloxacin. Antimicrob Agents Chemother 1991 May;|2
02076|211|R|   35(5):1004-7.|2
02076|212|R|24.Kato R, Ueno K, Imano H, Kawai M, Kuwahara S, Tsuchishita Y, Yonezawa E,|2
02076|213|R|   Tanaka K. Impairment of ciprofloxacin absorption by calcium|2
02076|214|R|   polycarbophil. J Clin Pharmacol 2002 Jul;42(7):806-11.|2
02076|215|R|25.Brouwers JR, Van der Kam HJ, Sijtsma J, Proost JH. Decreased|2
02076|216|R|   ciprofloxacin absorption with concomitant administration of ferrous|2
02076|217|R|   fumarate. Pharm Weekbl Sci 1990 Oct 19;12(5):182-3.|2
02076|218|R|26.Pazzucconi F, Barbi S, Baldassarre D, Colombo N, Dorigotti F, Sirtori CR.|2
02076|219|R|   Iron-ovotransferrin preparation does not interfere with ciprofloxacin|2
02076|220|R|   absorption. Clin Pharmacol Ther 1996 Apr;59(4):418-22.|2
02076|221|R|27.Lehto P, Kivisto KT, Neuvonen PJ. The effect of ferrous sulphate on the|2
02076|222|R|   absorption of norfloxacin, ciprofloxacin and ofloxacin. Br J Clin|2
02076|223|R|   Pharmacol 1994 Jan;37(1):82-5.|2
02076|224|R|28.Kara M, Hasinoff BB, McKay DW, Campbell NR. Clinical and chemical|2
02076|225|R|   interactions between iron preparations and ciprofloxacin. Br J Clin|2
02076|226|R|   Pharmacol 1991 Mar;31(3):257-61.|2
02076|227|R|29.Polk RE, Healy DP, Sahai J, Drwal L, Racht E. Effect of ferrous sulfate|2
02076|228|R|   and multivitamins with zinc on absorption of ciprofloxacin in normal|2
02076|229|R|   volunteers. Antimicrob Agents Chemother 1989 Nov;33(11):1841-4.|2
02076|230|R|30.How PP, Fischer JH, Arruda JA, Lau AH. Effects of lanthanum carbonate on|2
02076|231|R|   the absorption and oral bioavailability of ciprofloxacin. Clin J Am Soc|2
02076|232|R|   Nephrol 2007 Nov;2(6):1235-40.|2
02076|233|R|31.Nix DE, Lebsack ME, Chapelsky M, Sedman AJ, Busch J, Norman A. Effect of|2
02076|234|R|   oral antacids on disposition of intravenous enoxacin. Antimicrob Agents|2
02076|235|R|   Chemother 1993 Apr;37(4):775-7.|2
02076|236|R|32.Grasela TH Jr, Schentag JJ, Sedman AJ, Wilton JH, Thomas DJ, Schultz RW,|2
02076|237|R|   Lebsack ME, Kinkel AW. Inhibition of enoxacin absorption by antacids or|2
02076|238|R|   ranitidine. Antimicrob Agents Chemother 1989 May;33(5):615-7.|2
02076|239|R|33.Martinez Cabarga M, Sanchez Navarro A, Colino Gandarillas CI,|2
02076|240|R|   Dominguez-Gil A. Effects of two cations on gastrointestinal absorption of|2
02076|241|R|   ofloxacin. Antimicrob Agents Chemother 1991 Oct;35(10):2102-5.|2
02076|242|R|34.Pai MP, Allen SE, Amsden GW. Altered steady state pharmacokinetics of|2
02076|243|R|   levofloxacin in adult cystic fibrosis patients receiving calcium|2
02076|244|R|   carbonate. J Cyst Fibros 2006 Aug;5(3):153-7.|2
02076|245|R|35.Nix DE, Wilton JH, Ronald B, Distlerath L, Williams VC, Norman A.|2
02076|246|R|   Inhibition of norfloxacin absorption by antacids. Antimicrob Agents|2
02076|247|R|   Chemother 1990 Mar;34(3):432-5.|2
02076|248|R|36.Campbell NR, Kara M, Hasinoff BB, Haddara WM, McKay DW. Norfloxacin|2
02076|249|R|   interaction with antacids and minerals. Br J Clin Pharmacol 1992 Jan;|2
02076|250|R|   33(1):115-6.|2
02076|251|R|37.Sanchez Navarro A, Martinez Cabarga M, Dominguez-Gil Hurle A. Oral|2
02076|252|R|   absorption of ofloxacin administered together with aluminum. Antimicrob|2
02076|253|R|   Agents Chemother 1994 Oct;38(10):2510-2.|2
02076|254|R|38.Akerele JO, Okhamafe AO. Influence of oral co-administered metallic drugs|2
02076|255|R|   on ofloxacin pharmacokinetics. J Antimicrob Chemother 1991 Jul;|2
02076|256|R|   28(1):87-94.|2
02076|257|R|39.Flor S, Guay DR, Opsahl JA, Tack K, Matzke GR. Effects of|2
02076|258|R|   magnesium-aluminum hydroxide and calcium carbonate antacids on|2
02076|259|R|   bioavailability of ofloxacin. Antimicrob Agents Chemother 1990 Dec;|2
02076|260|R|   34(12):2436-8.|2
02076|261|R|40.Johnson RD, Dorr MB, Talbot GH, Caille G. Effect of Maalox on the oral|2
02076|262|R|   absorption of sparfloxacin. Clin Ther 1998 Nov-Dec;20(6):1149-58.|2
02076|263|R|41.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
02076|264|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
02076|265|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
02076|266|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
02077|001|T|MONOGRAPH TITLE:  Oral Itraconazole; Ketoconazole/Hyoscyamine|
02077|002|B||
02077|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02077|004|L|take action as needed.|
02077|005|B||
02077|006|A|MECHANISM OF ACTION:  Hyoscyamine delays gastric emptying and may increase|
02077|007|A|gastric pH, thereby decreasing the absorption of orally administered|
02077|008|A|itraconazole and ketoconazole.(1)|
02077|009|B||
02077|010|E|CLINICAL EFFECTS:  Simultaneous administration of hyoscyamine may result in|
02077|011|E|decreased levels and effectiveness of oral itraconazole and ketoconazole.(1)|
02077|012|B||
02077|013|P|PREDISPOSING FACTORS:  None determined.|
02077|014|B||
02077|015|M|PATIENT MANAGEMENT:  Oral itraconazole and ketoconazole should be|
02077|016|M|administered at least 2 hours after hyoscyamine.(1)|
02077|017|B||
02077|018|D|DISCUSSION:  Hyoscyamine delays gastric emptying and may increase gastric|
02077|019|D|pH, decreasing the amount of azole antifungal absorption.(1)|
02077|020|B||
02077|021|R|REFERENCE:|
02077|022|B||
02077|023|R|1.Darcalma (hyoscyamine sulfate, methenamine, phenyl salicylate, sodium|1
02077|024|R|  phosphate, monobasic and methylene blue) US prescribing information.|1
02077|025|R|  River's Edge Pharmaceuticals, LLC December, 2008.|1
02078|001|T|MONOGRAPH TITLE:  Sirolimus; Tacrolimus/Phenytoin (mono deleted 11/01/2012)|
02078|002|B||
02078|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02078|004|L|take action as needed.|
02078|005|B||
02078|006|A|MECHANISM OF ACTION:  Phenytoin may induce the metabolism of sirolimus and|
02078|007|A|tacrolimus by CYP P-450-3A4.(1-11)|
02078|008|B||
02078|009|E|CLINICAL EFFECTS:  Concurrent use of phenytoin may result in decreased|
02078|010|E|levels and effectiveness of sirolimus or tacrolimus.(1-11)|
02078|011|B||
02078|012|P|PREDISPOSING FACTORS:  None determined.|
02078|013|B||
02078|014|M|PATIENT MANAGEMENT:  Patients maintained on sirolimus or tacrolimus should|
02078|015|M|be closely monitored if phenytoin is initiated or discontinued.  The dosage|
02078|016|M|of sirolimus or tacrolimus may need to be adjusted or phenytoin may need to|
02078|017|M|be discontinued.|
02078|018|B||
02078|019|D|DISCUSSION:  There are four case reports of decreased sirolimus(1) and|
02078|020|D|tacrolimus(2,3) levels in patients taking phenytoin.  In two of these|
02078|021|D|reports, patients required 2-fold and 3-fold increases in tacrolimus dosage|
02078|022|D|to maintain required blood levels.(2)|
02078|023|D|   Phenytoin has been used successfully to treat tacrolimus overdose.(4)|
02078|024|B||
02078|025|R|REFERENCES:|
02078|026|B||
02078|027|R|1.Fridell JA, Jain AK, Patel K, Virji M, Rao KN, Fung JJ, Venkataramanan R.|3
02078|028|R|  Phenytoin decreases the blood concentrations of sirolimus in a liver|3
02078|029|R|  transplant recipient: a case report. Ther Drug Monit 2003 Feb;25(1):117-9.|3
02078|030|R|2.Wada K, Takada M, Ueda T, Ochi H, Kotake T, Morishita H, Hanatani A,|3
02078|031|R|  Nakatani T. Drug interactions between tacrolimus and phenytoin in Japanese|3
02078|032|R|  heart transplant recipients: 2 case reports. Int J Clin Pharmacol Ther|3
02078|033|R|  2007 Sep;45(9):524-8.|3
02078|034|R|3.Formea CM, Evans CG, Karlix JL. Altered cytochrome p450 metabolism of|3
02078|035|R|  calcineurin inhibitors: case report and review of the literature.|3
02078|036|R|  Pharmacotherapy 2005 Jul;25(7):1021-9.|3
02078|037|R|4.Karasu Z, Gurakar A, Carlson J, Pennington S, Kerwin B, Wright H, Nour B,|3
02078|038|R|  Sebastian A. Acute tacrolimus overdose and treatment with phenytoin in|3
02078|039|R|  liver transplant recipients. J Okla State Med Assoc 2001 Apr;94(4):121-3.|3
02079|001|T|MONOGRAPH TITLE:  Dolasetron/Flecainide; Quinidine; Verapamil|
02079|002|B||
02079|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02079|004|L|of severe adverse interaction.|
02079|005|B||
02079|006|A|MECHANISM OF ACTION:  Dolasetron has been shown to cause dose-dependent PR,|
02079|007|A|QRS and QTc interval prolongation.(1,2) Concurrent use with other agents|
02079|008|A|that prolong the PR, QRS and/or QTc intervals may result in additive effects|
02079|009|A|on heart rhythm.(1,2)|
02079|010|B||
02079|011|E|CLINICAL EFFECTS:  The concurrent use of dolasetron with other agents that|
02079|012|E|prolong the PR, QRS or QTc interval may result in potentially|
02079|013|E|life-threatening cardiac arrhythmias.(1,2)|
02079|014|B||
02079|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02079|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02079|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02079|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02079|019|P|female gender, advanced age, use of diuretics with potential for inducing|
02079|020|P|electrolyte abnormalities, or cumulative high dose anthracycline|
02079|021|P|therapy.(1,2,3)|
02079|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02079|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02079|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02079|025|P|drug concentrations include rapid infusion of an intravenous dose or|
02079|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02079|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02079|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02079|029|B||
02079|030|M|PATIENT MANAGEMENT:  Concurrent use of dolasetron with agents that prolong|
02079|031|M|the PR interval such as verapamil, or agents that prolong the QRS or QTc|
02079|032|M|intervals like flecainide and quinidine should be avoided.(1,2,4)  If the|
02079|033|M|combination must be used, address electrolyte disorders and other modifiable|
02079|034|M|predisposing risk factors prior to administration.  Monitor the ECG prior to|
02079|035|M|and during concomitant treatment.(1)|
02079|036|M|   Single or repeat doses of intravenous dolasetron are contraindicated in|
02079|037|M|all patients receiving emetogenic cancer chemotherapy due to the risk for QT|
02079|038|M|prolongation.(1)|
02079|039|B||
02079|040|D|DISCUSSION:  Dolasetron can cause dose-dependent PR, QRS and QTc|
02079|041|D|prolongation. A QT crossover study evaluated QTc interval effects of|
02079|042|D|dolasetron 100 mg or 300 mg IV once daily vs. placebo or active|
02079|043|D|control(moxifloxacin 400 mg once daily) in 80 healthy adults.  The mean|
02079|044|D|increase in the upper bound of the 95% confidence interval for QTc|
02079|045|D|prolongation was 16.1 ms and 38.6 ms for 100 mg and 300 mg(supratherapeutic)|
02079|046|D|doses respectively.  In this QT study, the mean increase in the upper bound|
02079|047|D|of the 95% confidence interval for PR prolongation was 11.6 and 34.9 ms for|
02079|048|D|100 mg and 300 mg doses respectively.   The mean increase in the upper bound|
02079|049|D|of the 95% confidence interval for QRS prolongation was 4.5 ms and 14.5 ms|
02079|050|D|for 100 mg and 300 mg doses respectively.(1)|
02079|051|B||
02079|052|R|REFERENCES:|
02079|053|B||
02079|054|R|1.Anzemet (dolasetron mesylate) US prescribing information. Sanofi-Aventis|1
02079|055|R|  Us.S. LLC September, 2014.|1
02079|056|R|2.USFood and Drug Administration. FDA Drug Safety Communication: Abnormal|1
02079|057|R|  heart rhythms associated with use of Anzemet (dolasetron mesylate).|1
02079|058|R|  Available at: http://www.fda.gov/Drugs/DrugSafety/ucm237081.htm December|1
02079|059|R|  17, 2010.|1
02079|060|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02079|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02079|062|R|  settings: a scientific statement from the American Heart Association and|6
02079|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02079|064|R|  2;55(9):934-47.|6
02079|065|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
02079|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02079|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02079|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02080|001|T|MONOGRAPH TITLE:  Tacrolimus/Selected Proton Pump Inhibitors|
02080|002|B||
02080|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02080|004|L|take action as needed.|
02080|005|B||
02080|006|A|MECHANISM OF ACTION:  Some proton-pump inhibitors (PPIs) may inhibit the|
02080|007|A|metabolism of tacrolimus by CYP3A4 and intestinal CYP3A5.|
02080|008|B||
02080|009|E|CLINICAL EFFECTS:  Concurrent use may increase tacrolimus levels in some|
02080|010|E|patients and result in toxic effects, including nephrotoxicity,|
02080|011|E|neurotoxicity, and prolongation of the QTc interval and life-threatening|
02080|012|E|cardiac arrhythmias, including torsades de pointes.|
02080|013|B||
02080|014|P|PREDISPOSING FACTORS:  This interaction may be is more severe in patients|
02080|015|P|who are poor metabolizers of CYP2C19.|
02080|016|P|   The risk of QT prolongation or torsade de pointes may be increased in|
02080|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02080|018|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
02080|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02080|020|P|advanced age.(17)|
02080|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02080|022|P|higher systemic concentrations of either QT prolonging drug are additional|
02080|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02080|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02080|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02080|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02080|027|P|dysfunction).(17)|
02080|028|B||
02080|029|M|PATIENT MANAGEMENT:  Consider monitoring tacrolimus levels when initiating|
02080|030|M|or discontinuing a PPI other than pantoprazole in patients who are poor|
02080|031|M|metabolizers of CYP2C19 or whose genotype is unknown.  The dosage of|
02080|032|M|tacrolimus may need to be adjusted.  Pantoprazole may be an alternative to|
02080|033|M|other PPIs in patients maintained on tacrolimus.|
02080|034|M|   When concurrent therapy of selected proton pump inhibitors and tacrolimus|
02080|035|M|is warranted, consider obtaining serum calcium, magnesium, and potassium|
02080|036|M|levels and monitoring ECG at baseline and at regular intervals.  Correct any|
02080|037|M|electrolyte abnormalities.  Instruct patients to report any irregular|
02080|038|M|heartbeat, dizziness, or fainting.|
02080|039|B||
02080|040|D|DISCUSSION:  In vitro studies have shown that omeprazole inhibits the|
02080|041|D|metabolism of tacrolimus.(1,2)  In a case report, tacrolimus levels|
02080|042|D|increased 1.8-fold in a pediatric live-transplant patient following the|
02080|043|D|initiation of omeprazole.(3)  In another report, the tacrolimus|
02080|044|D|concentration/dose ratio was higher during omeprazole therapy when compared|
02080|045|D|to rabeprazole therapy.(4)  In a study in 48 renal transplant patients, the|
02080|046|D|dose/weight normalized trough levels of tacrolimus decreased 15% following|
02080|047|D|the switch of cimetidine to omeprazole.(5)  In contrast, in a study in 51|
02080|048|D|renal transplant patients found no difference in tacrolimus level/dose ratio|
02080|049|D|following the discontinuation of omeprazole.(6)  In a study in 12 renal|
02080|050|D|transplant patients who were CYP3A5-nonexpressors, there was no effect by|
02080|051|D|omeprazole on tacrolimus pharmacokinetics.(7)  A study in 89 liver|
02080|052|D|transplant patients showed that the interaction between omeprazole and|
02080|053|D|tacrolimus was more severe in patients that are either poor or intermediate|
02080|054|D|metabolizers of CYP2C19.(8)|
02080|055|D|   There are three reports of elevated tacrolimus levels during the use of|
02080|056|D|lansoprazole.(9,10,11,12)  In a study in 73 renal transplant patients,|
02080|057|D|lansoprazole and rabeprazole had significant effects on tacrolimus levels|
02080|058|D|only in patients who were poor or intermediate metabolizers of CYP2C19.(13)|
02080|059|D|In a study in 19 healthy subjects, lansoprazole increased tacrolimus levels|
02080|060|D|in extensive and poor CYP2C19 metabolizers by 81% and 20%, respectively.(14)|
02080|061|D|In contrast, a study in 55 liver-transplant patients, rabeprazole had no|
02080|062|D|effect on tacrolimus concentrations regardless of CYP3A5 or CYP2C19|
02080|063|D|genotype.(15)|
02080|064|D|   In a study in 12 transplant recipients, pantoprazole had no effect on|
02080|065|D|tacrolimus levels.(16)|
02080|066|B||
02080|067|R|REFERENCES:|
02080|068|B||
02080|069|R|1.Lampen A, Christians U, Guengerich FP, Watkins PB, Kolars JC, Bader A,|5
02080|070|R|  Gonschior AK, Dralle H, Hackbarth I, Sewing KF. Metabolism of the|5
02080|071|R|  immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug|5
02080|072|R|  interactions, and interindividual variability. Drug Metab Dispos 1995 Dec;|5
02080|073|R|  23(12):1315-24.|5
02080|074|R|2.Christians U, Schmidt G, Bader A, Lampen A, Schottmann R, Linck A, Sewing|5
02080|075|R|  KF. Identification of drugs inhibiting the in vitro metabolism of|5
02080|076|R|  tacrolimus by human liver microsomes. Br J Clin Pharmacol 1996 Mar;|5
02080|077|R|  41(3):187-90.|5
02080|078|R|3.Moreau C, Debray D, Loriot MA, Taburet AM, Furlan V. Interaction between|3
02080|079|R|  tacrolimus and omeprazole in a pediatric liver transplant recipient.|3
02080|080|R|  Transplantation 2006 Feb 15;81(3):487-8.|3
02080|081|R|4.Takahashi K, Yano I, Fukuhara Y, Katsura T, Takahashi T, Ito N, Yamamoto|3
02080|082|R|  S, Ogawa O, Inui K. Distinct effects of omeprazole and rabeprazole on the|3
02080|083|R|  tacrolimus blood concentration in a kidney transplant recipient. Drug|3
02080|084|R|  Metab Pharmacokinet 2007 Dec;22(6):441-4.|3
02080|085|R|5.Lemahieu WP, Maes BD, Verbeke K, Vanrenterghem Y. Impact of gastric acid|2
02080|086|R|  suppressants on cytochrome P450 3A4 and P-glycoprotein: consequences for|2
02080|087|R|  FK506 assimilation. Kidney Int 2005 Mar;67(3):1152-60.|2
02080|088|R|6.Pascual J, Marcen R, Orea OE, Navarro M, Alarcon MC, Ocana J, Villafruela|2
02080|089|R|  JJ, Burgos FJ, Ortuno J. Interaction between omeprazole and tacrolimus in|2
02080|090|R|  renal allograft recipients: a clinical-analytical study. Transplant Proc|2
02080|091|R|  2005 Nov;37(9):3752-3.|2
02080|092|R|7.Katsakiori PF, Papapetrou EP, Goumenos DS, Nikiforidis GC, Flordellis CS.|2
02080|093|R|  Investigation of clinical interaction between omeprazole and tacrolimus in|2
02080|094|R|  CYP3A5 non-expressors, renal transplant recipients. Ther Clin Risk Manag|2
02080|095|R|  2010;6:265-9.|2
02080|096|R|8.Hosohata K, Masuda S, Katsura T, Takada Y, Kaido T, Ogura Y, Oike F, Egawa|2
02080|097|R|  H, Uemoto S, Inui K. Impact of intestinal CYP2C19 genotypes on the|2
02080|098|R|  interaction between tacrolimus and omeprazole, but not lansoprazole, in|2
02080|099|R|  adult living-donor liver transplant patients. Drug Metab Dispos 2009 Apr;|2
02080|100|R|  37(4):821-6.|2
02080|101|R|9.Itagaki F, Homma M, Yuzawa K, Fukao K, Kohda Y. Drug interaction of|2
02080|102|R|  tacrolimus and proton pump inhibitors in renal transplant recipients with|2
02080|103|R|  CYP2C19 gene mutation. Transplant Proc 2002 Nov;34(7):2777-8.|2
02080|104|R|10.Takahashi K, Motohashi H, Yonezawa A, Okuda M, Ito N, Yamamoto S, Ogawa|3
02080|105|R|   O, Inui K. Lansoprazole-tacrolimus interaction in Japanese transplant|3
02080|106|R|   recipient with CYP2C19 polymorphism. Ann Pharmacother 2004 May;|3
02080|107|R|   38(5):791-4.|3
02080|108|R|11.Homma M, Itagaki F, Yuzawa K, Fukao K, Kohda Y. Effects of lansoprazole|3
02080|109|R|   and rabeprazole on tacrolimus blood concentration: case of a renal|3
02080|110|R|   transplant recipient with CYP2C19 gene mutation. Transplantation 2002 Jan|3
02080|111|R|   27;73(2):303-4.|3
02080|112|R|12.Hosohata K, Masuda S, Ogura Y, Oike F, Takada Y, Katsura T, Uemoto S,|2
02080|113|R|   Inui K. Interaction between tacrolimus and lansoprazole, but not|2
02080|114|R|   rabeprazole in living-donor liver transplant patients with defects of|2
02080|115|R|   CYP2C19 and CYP3A5. Drug Metab Pharmacokinet 2008;23(2):134-8.|2
02080|116|R|13.Miura M, Inoue K, Kagaya H, Satoh S, Tada H, Sagae Y, Habuchi T, Suzuki|2
02080|117|R|   T. Influence of rabeprazole and lansoprazole on the pharmacokinetics of|2
02080|118|R|   tacrolimus in relation to CYP2C19, CYP3A5 and MDR1 polymorphisms in renal|2
02080|119|R|   transplant recipients. Biopharm Drug Dispos 2007 May;28(4):167-75.|2
02080|120|R|14.Itagaki F, Homma M, Yuzawa K, Nishimura M, Naito S, Ueda N, Ohkohchi N,|2
02080|121|R|   Kohda Y. Effect of lansoprazole and rabeprazole on tacrolimus|2
02080|122|R|   pharmacokinetics in healthy volunteers with CYP2C19 mutations. J Pharm|2
02080|123|R|   Pharmacol 2004 Aug;56(8):1055-9.|2
02080|124|R|15.Hosohata K, Masuda S, Yonezawa A, Sugimoto M, Takada Y, Kaido T, Ogura Y,|2
02080|125|R|   Oike F, Uemoto S, Inui K. Absence of influence of concomitant|2
02080|126|R|   administration of rabeprazole on the pharmacokinetics of tacrolimus in|2
02080|127|R|   adult living-donor liver transplant patients: a case-control study. Drug|2
02080|128|R|   Metab Pharmacokinet 2009;24(5):458-63.|2
02080|129|R|16.Lorf T, Ramadori G, Ringe B, Schworer H. The effect of pantoprazole on|2
02080|130|R|   tacrolimus and cyclosporin A blood concentration in transplant|2
02080|131|R|   recipients. Eur J Clin Pharmacol 2000 Aug;56(5):439-40.|2
02080|132|R|17.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
02080|133|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
02080|134|R|   hospital settings: a scientific statement from the American Heart|6
02080|135|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
02080|136|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
02081|001|T|MONOGRAPH TITLE:  Lurasidone/Selected Azole Antifungal Agents|
02081|002|B||
02081|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02081|004|L|is contraindicated and generally should not be dispensed or administered to|
02081|005|L|the same patient.|
02081|006|B||
02081|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors such as itraconazole,|
02081|008|A|ketoconazole,(1) posaconazole, and voriconazole may inhibit the metabolism|
02081|009|A|of lurasidone.(2)|
02081|010|B||
02081|011|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with strong inhibitors of|
02081|012|E|CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia,|
02081|013|E|Parkinsonism or other lurasidone toxicities.(2)|
02081|014|B||
02081|015|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02081|016|P|of falls, swallowing disorders, Parkinson Disease, Lewy Body Disease, or|
02081|017|P|other dementias are more sensitive to antipsychotics and have a greater risk|
02081|018|P|for adverse effects.(2)|
02081|019|B||
02081|020|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors, such as|
02081|021|M|itraconazole, ketoconazole,(1) posaconazole, and voriconazole, with|
02081|022|M|lurasidone, is contraindicated.(2)|
02081|023|M|   The US manufacturer of itraconazole states that concomitant|
02081|024|M|administration of lurasidone is contraindicated during and two weeks after|
02081|025|M|itraconazole treatment.(4)|
02081|026|B||
02081|027|D|DISCUSSION:  Pretreatment with ketoconazole (400 mg daily for 5 days)|
02081|028|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02081|029|D|single dose of lurasidone (10 mg) by 6.9-fold, and 9.0-fold,|
02081|030|D|respectively.(2)|
02081|031|B||
02081|032|R|REFERENCES:|
02081|033|B||
02081|034|R|1.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
02081|035|R|  Pharmaceuticals February, 2014.|1
02081|036|R|2.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02081|037|R|  Pharamceuticals, Inc. December, 2019.|1
02081|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02081|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02081|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02081|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02081|042|R|  11/14/2017.|1
02081|043|R|4.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02081|044|R|  Products, L.P. February, 2024.|1
02082|001|T|MONOGRAPH TITLE:  Lurasidone/Protease Inhibitors; Cobicistat|
02082|002|B||
02082|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02082|004|L|is contraindicated and generally should not be dispensed or administered to|
02082|005|L|the same patient.|
02082|006|B||
02082|007|A|MECHANISM OF ACTION:  Lurasidone is a sensitive substrate for CYP3A4.(1)|
02082|008|A|Sensitive substrates will have at least a 5-fold increase in|
02082|009|A|area-under-curve (AUC) when given with a strong inhibitor of the enzyme.(2)|
02082|010|A|Protease inhibitors and cobicistat are strong and moderate inhibitors of|
02082|011|A|CYP3A4 and may inhibit the metabolism of lurasidone.(1,3-5)|
02082|012|B||
02082|013|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02082|014|E|may lead to orthostatic hypotension, akathisia, acute dystonia,|
02082|015|E|Parkinsonism, confusion, postural instability or other lurasidone|
02082|016|E|toxicities.(1)|
02082|017|B||
02082|018|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02082|019|P|of falls, swallowing disorders, Parkinson Disease, Lewy Body Disease, or|
02082|020|P|other dementias are more sensitive to antipsychotics and have a greater risk|
02082|021|P|for adverse effects.(1)|
02082|022|B||
02082|023|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that|
02082|024|M|concurrent use of a strong CYP3A4 inhibitor is contraindicated.(1)  The US|
02082|025|M|Department of Health and Human Services HIV guidelines state that all|
02082|026|M|protease inhibitors boosted with ritonavir or cobicistat are|
02082|027|M|contraindicated.(5)|
02082|028|M|   If a patient maintained on lurasidone requires a protease inhibitor for|
02082|029|M|treatment of HIV or hepatitis C, then the patient should be converted to|
02082|030|M|another antipsychotic prior to initiation of protease inhibitor therapy.|
02082|031|M|   If a patient is currently on lurasidone and addition of unboosted|
02082|032|M|atazanavir is necessary, the dose of lurasidone should be decreased by 50%|
02082|033|M|of the original dose.(5)  If a patient is currently on unboosted atazanavir|
02082|034|M|and lurasidone is added to therapy, the recommended starting dose of|
02082|035|M|lurasidone is 20 mg per day, and the maximum dose is 80 mg daily.(5)|
02082|036|B||
02082|037|D|DISCUSSION:  Pretreatment with ketoconazole (400 mg daily for 5 days), a|
02082|038|D|strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02082|039|D|area-under-curve (AUC) of a single dose of lurasidone (10 mg) by 6.9-fold,|
02082|040|D|and 9.0-fold, respectively.(1)|
02082|041|D|   Pretreatment with diltiazem (240 mg daily for 5 days), a moderate|
02082|042|D|inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of|
02082|043|D|lurasidone (20 mg) by 2.1-fold, and 2.2-fold, respectively.(1)|
02082|044|D|   Agents linked to this monograph are atazanavir, boceprevir, cobicistat,|
02082|045|D|darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, nirmatrelvir,|
02082|046|D|paritaprevir, saquinavir, telaprevir, and tipranavir.|
02082|047|B||
02082|048|R|REFERENCES:|
02082|049|B||
02082|050|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02082|051|R|  Pharamceuticals, Inc. December, 2019.|1
02082|052|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02082|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02082|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02082|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02082|056|R|  11/14/2017.|1
02082|057|R|3.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02082|058|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02082|059|R|4.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
02082|060|R|  information. Pfizer Inc. February, 2025.|1
02082|061|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02082|062|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02082|063|R|  HIV. Department of Health and Human Services. Available at:|6
02082|064|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
02082|065|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
02083|001|T|MONOGRAPH TITLE:  Lurasidone/Clarithromycin; Telithromycin|
02083|002|B||
02083|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02083|004|L|is contraindicated and generally should not be dispensed or administered to|
02083|005|L|the same patient.|
02083|006|B||
02083|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors such as clarithromycin and|
02083|008|A|telithromycin may inhibit the metabolism of lurasidone.(1)|
02083|009|B||
02083|010|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with strong inhibitors of|
02083|011|E|CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia,|
02083|012|E|Parkinsonism or other lurasidone toxicities.(1)|
02083|013|B||
02083|014|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02083|015|P|of falls, swallowing disorders, Parkinson Disease, Lewy Body Disease, or|
02083|016|P|other dementias are more sensitive to antipsychotics and have a greater risk|
02083|017|P|for adverse effects.(1)|
02083|018|B||
02083|019|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that|
02083|020|M|concurrent use of strong CYP3A4 inhibitors, such as clarithromycin or|
02083|021|M|telithromycin, are contraindicated.(1)|
02083|022|B||
02083|023|D|DISCUSSION:  Pretreatment with ketoconazole (400 mg daily for 5 days),|
02083|024|D|another strong inhibitor of CYP3A4, increased the maximum concentration|
02083|025|D|(Cmax) and area-under-curve (AUC) of a single dose of lurasidone (10 mg) by|
02083|026|D|6.9-fold and 9.0-fold, respectively.(1)|
02083|027|B||
02083|028|R|REFERENCE:|
02083|029|B||
02083|030|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02083|031|R|  Pharamceuticals, Inc. December, 2019.|1
02084|001|T|MONOGRAPH TITLE:  Lurasidone/Selected Strong CYP3A4 Inhibitors|
02084|002|B||
02084|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02084|004|L|is contraindicated and generally should not be dispensed or administered to|
02084|005|L|the same patient.|
02084|006|B||
02084|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02084|008|A|lurasidone.(1)  Sensitive substrates will have at least a 5-fold increase in|
02084|009|A|area-under-curve (AUC) when given with a strong inhibitor of the enzyme.(2)|
02084|010|B||
02084|011|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with strong inhibitors of|
02084|012|E|CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia,|
02084|013|E|Parkinsonism, confusion, postural instability or other lurasidone|
02084|014|E|toxicities.(1)|
02084|015|B||
02084|016|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02084|017|P|of falls, swallowing disorders, Parkinson Disease, Lewy Body Disease, or|
02084|018|P|other dementias are more sensitive to antipsychotics and have a greater risk|
02084|019|P|for adverse effects.(1)|
02084|020|B||
02084|021|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that|
02084|022|M|concurrent use of strong CYP3A4 inhibitors is contraindicated.(1)|
02084|023|M|   If a patient is maintained on lurasidone and requires a strong CYP3A4|
02084|024|M|inhibitor for treatment, then the patient should be converted to another|
02084|025|M|antipsychotic prior to initiation of the strong CYP3A4 inhibitor therapy.|
02084|026|B||
02084|027|D|DISCUSSION:  Pretreatment with ketoconazole (400 mg daily for 5 days), a|
02084|028|D|strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02084|029|D|area-under-curve (AUC) of a single dose of lurasidone (10 mg) by 6.9-fold|
02084|030|D|and 9.0-fold, respectively.(1)|
02084|031|D|   Agents linked to this monograph include adagrasib, ceritinib, idelalisib,|
02084|032|D|josamycin, levoketoconazole, lonafarnib, mibefradil, mifepristone,|
02084|033|D|nefazodone, troleandomycin, and tucatinib.(2)|
02084|034|B||
02084|035|R|REFERENCES:|
02084|036|B||
02084|037|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02084|038|R|  Pharamceuticals, Inc. December, 2019.|1
02084|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
02084|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02085|001|T|MONOGRAPH TITLE:  Lurasidone (Less Than or Equal To 80 mg)/Diltiazem;|
02085|002|T|Verapamil|
02085|003|B||
02085|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02085|005|L|take action as needed.|
02085|006|B||
02085|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as diltiazem or|
02085|008|A|verapamil may inhibit the metabolism of lurasidone.(1)|
02085|009|B||
02085|010|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02085|011|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02085|012|E|or other lurasidone toxicities.(1)|
02085|013|B||
02085|014|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02085|015|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02085|016|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02085|017|P|have a greater risk for adverse effects.(1)|
02085|018|B||
02085|019|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02085|020|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02085|021|M|CYP3A4 inhibitors, such as diltiazem or verapamil.(1)|
02085|022|M|   If a patient is currently on lurasidone and either diltiazem or verapamil|
02085|023|M|is added to therapy, the dose of lurasidone should be decreased by 50% of|
02085|024|M|the original dose.(1)|
02085|025|M|   If a patient is currently on diltiazem or verapamil and lurasidone is|
02085|026|M|added to therapy, the recommended starting dose of lurasidone is 20 mg per|
02085|027|M|day.(1)|
02085|028|B||
02085|029|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days) increased|
02085|030|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
02085|031|D|of lurasidone (20 mg) by 2.1-fold, and 2.2-fold, respectively.(1)|
02085|032|B||
02085|033|R|REFERENCES:|
02085|034|B||
02085|035|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02085|036|R|  Pharamceuticals, Inc. December, 2019.|1
02085|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02085|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02085|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02085|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02085|041|R|  11/14/2017.|1
02086|001|T|MONOGRAPH TITLE:  Lurasidone/Strong CYP3A4 Inducers|
02086|002|B||
02086|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02086|004|L|is contraindicated and generally should not be dispensed or administered to|
02086|005|L|the same patient.|
02086|006|B||
02086|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02086|008|A|lurasidone.(1)|
02086|009|B||
02086|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong inducers of CYP3A4 may|
02086|011|E|result in decreased levels and efficacy of lurasidone.(1)|
02086|012|B||
02086|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02086|014|P|of the inducer for longer than 1-2 weeks.|
02086|015|B||
02086|016|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that|
02086|017|M|concurrent use of strong CYP3A4 inducers is contraindicated.(1)|
02086|018|B||
02086|019|D|DISCUSSION:  Pretreatment with rifampin (600 mg daily for 8 days) decreased|
02086|020|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
02086|021|D|of lurasidone (40 mg) by 86%, and 80%, respectively.(1)|
02086|022|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02086|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02086|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02086|025|D|rifapentine and St. John's wort.(2)|
02086|026|B||
02086|027|R|REFERENCES:|
02086|028|B||
02086|029|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02086|030|R|  Pharamceuticals, Inc. December, 2019.|1
02086|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02086|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02086|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02086|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02086|035|R|  11/14/2017.|1
02087|001|T|MONOGRAPH TITLE:  Lurasidone (Greater Than 80 mg)/Diltiazem; Verapamil|
02087|002|B||
02087|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02087|004|L|is contraindicated and generally should not be dispensed or administered to|
02087|005|L|the same patient.|
02087|006|B||
02087|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as diltiazem and|
02087|008|A|verapamil may inhibit the metabolism of lurasidone.(1)|
02087|009|B||
02087|010|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02087|011|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02087|012|E|or other lurasidone toxicities.(1)|
02087|013|B||
02087|014|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02087|015|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02087|016|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02087|017|P|have a greater risk for adverse effects.(1)|
02087|018|B||
02087|019|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02087|020|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02087|021|M|CYP3A4 inhibitors, such as diltiazem or verapamil.(1)|
02087|022|M|   If a patient is currently on lurasidone and either diltiazem or verapamil|
02087|023|M|is added to therapy, the dose of lurasidone should be decreased by 50% of|
02087|024|M|the original dose.(1)|
02087|025|M|   If a patient is currently on diltiazem or verapamil and lurasidone is|
02087|026|M|added to therapy, the recommended starting dose of lurasidone is 20 mg per|
02087|027|M|day.(1)|
02087|028|B||
02087|029|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days) increased|
02087|030|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
02087|031|D|of lurasidone (20 mg) by 2.1-fold, and 2.2-fold, respectively.(1)|
02087|032|B||
02087|033|R|REFERENCES:|
02087|034|B||
02087|035|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02087|036|R|  Pharamceuticals, Inc. December, 2019.|1
02087|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02087|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02087|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02087|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02087|041|R|  11/14/2017.|1
02088|001|T|MONOGRAPH TITLE:  Lurasidone (Greater Than 80 mg)/Selected Protease|
02088|002|T|Inhibitors (mono deleted 12/22/2023)|
02088|003|B||
02088|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02088|005|L|is contraindicated and generally should not be dispensed or administered to|
02088|006|L|the same patient.|
02088|007|B||
02088|008|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as amprenavir,|
02088|009|A|atazanavir, darunavir, and fosamprenavir may inhibit the metabolism of|
02088|010|A|lurasidone.(1)|
02088|011|B||
02088|012|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02088|013|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02088|014|E|or other lurasidone toxicities.(1)|
02088|015|B||
02088|016|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02088|017|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02088|018|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02088|019|P|have a greater risk for adverse effects.(1)|
02088|020|B||
02088|021|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02088|022|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02088|023|M|CYP3A4 inhibitors, such as amprenavir, atazanavir, darunavir, or|
02088|024|M|fosamprenavir.(1)|
02088|025|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor,|
02088|026|M|such as amprenavir, atazanavir, darunavir, or fosamprenavir, is added to|
02088|027|M|therapy, the dose of lurasidone should be decreased by 50% of the original|
02088|028|M|dose.(1)|
02088|029|M|   If a patient is currently on a moderate CYP3A4 inhibitor, such as|
02088|030|M|amprenavir, atazanavir, darunavir, or fosamprenavir, and lurasidone is added|
02088|031|M|to therapy, the recommended starting dose of lurasidone is 20 mg per day.(1)|
02088|032|B||
02088|033|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
02088|034|D|moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02088|035|D|area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold,|
02088|036|D|and 2.2-fold, respectively.(1)|
02088|037|B||
02088|038|R|REFERENCES:|
02088|039|B||
02088|040|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02088|041|R|  Pharamceuticals, Inc. December, 2019.|1
02088|042|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02088|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02088|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02088|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02088|046|R|  11/14/2017.|1
02089|001|T|MONOGRAPH TITLE:  Lurasidone (Less Than or Equal To 80 mg)/Selected Protease|
02089|002|T|Inhibitors (mono deleted 12/22/2023)|
02089|003|B||
02089|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02089|005|L|take action as needed.|
02089|006|B||
02089|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as amprenavir,|
02089|008|A|atazanavir, darunavir, and fosamprenavir may inhibit the metabolism of|
02089|009|A|lurasidone.(1)|
02089|010|B||
02089|011|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02089|012|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02089|013|E|or other lurasidone toxicities.(1)|
02089|014|B||
02089|015|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02089|016|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02089|017|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02089|018|P|have a greater risk for adverse effects.(1)|
02089|019|B||
02089|020|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02089|021|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02089|022|M|CYP3A4 inhibitors, such as amprenavir, atazanavir, darunavir, or|
02089|023|M|fosamprenavir.(1)|
02089|024|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor,|
02089|025|M|such as amprenavir, atazanavir, darunavir, or fosamprenavir, is added to|
02089|026|M|therapy, the dose of lurasidone should be decreased by 50% of the original|
02089|027|M|dose.(1)|
02089|028|M|   If a patient is currently on a moderate CYP3A4 inhibitor, such as|
02089|029|M|amprenavir, atazanavir, darunavir, or fosamprenavir, and lurasidone is added|
02089|030|M|to therapy, the recommended starting dose of lurasidone is 20 mg per day.(1)|
02089|031|B||
02089|032|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
02089|033|D|moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02089|034|D|area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold,|
02089|035|D|and 2.2-fold, respectively.(1)|
02089|036|B||
02089|037|R|REFERENCES:|
02089|038|B||
02089|039|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02089|040|R|  Pharamceuticals, Inc. December, 2019.|1
02089|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02089|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02089|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02089|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02089|045|R|  11/14/2017.|1
02090|001|T|MONOGRAPH TITLE:  Lurasidone (Greater Than 80 mg)/Aprepitant; Netupitant|
02090|002|B||
02090|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02090|004|L|is contraindicated and generally should not be dispensed or administered to|
02090|005|L|the same patient.|
02090|006|B||
02090|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as aprepitant or|
02090|008|A|netupitant may inhibit the metabolism of lurasidone.(1)|
02090|009|B||
02090|010|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02090|011|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02090|012|E|or other lurasidone toxicities.(1)|
02090|013|B||
02090|014|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02090|015|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02090|016|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02090|017|P|have a greater risk for adverse effects.(1)|
02090|018|B||
02090|019|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02090|020|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02090|021|M|CYP3A4 inhibitors, such as aprepitant or netupitant.(1)|
02090|022|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor,|
02090|023|M|such as aprepitant or netupitant, is added to therapy, the dose of|
02090|024|M|lurasidone should be decreased by 50% of the original dose.(1)|
02090|025|M|   If a patient is currently on a moderate CYP3A4 inhibitor, such as|
02090|026|M|aprepitant or netupitant, and lurasidone is added to therapy, the|
02090|027|M|recommended starting dose of lurasidone is 20 mg per day.(1)|
02090|028|B||
02090|029|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
02090|030|D|moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02090|031|D|area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold,|
02090|032|D|and 2.2-fold, respectively.(1)|
02090|033|B||
02090|034|R|REFERENCES:|
02090|035|B||
02090|036|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02090|037|R|  Pharamceuticals, Inc. December, 2019.|1
02090|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02090|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02090|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02090|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02090|042|R|  11/14/2017.|1
02091|001|T|MONOGRAPH TITLE:  Lurasidone (Less Than or Equal To 80 mg)/Aprepitant;|
02091|002|T|Netupitant|
02091|003|B||
02091|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02091|005|L|take action as needed.|
02091|006|B||
02091|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as aprepitant or|
02091|008|A|netupitant may inhibit the metabolism of lurasidone.(1)|
02091|009|B||
02091|010|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02091|011|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02091|012|E|or other lurasidone toxicities.(1)|
02091|013|B||
02091|014|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02091|015|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02091|016|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02091|017|P|have a greater risk for adverse effects.(1)|
02091|018|B||
02091|019|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02091|020|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02091|021|M|CYP3A4 inhibitors, such as aprepitant or netupitant.(1)|
02091|022|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor,|
02091|023|M|such as aprepitant or netupitant, is added to therapy, the dose of|
02091|024|M|lurasidone should be decreased by 50% of the original dose.(1)|
02091|025|M|   If a patient is currently on a moderate CYP3A4 inhibitor, such as|
02091|026|M|aprepitant or netupitant, and lurasidone is added to therapy, the|
02091|027|M|recommended starting dose of lurasidone is 20 mg per day.(1)|
02091|028|B||
02091|029|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
02091|030|D|moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02091|031|D|area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold,|
02091|032|D|and 2.2-fold, respectively.(1)|
02091|033|B||
02091|034|R|REFERENCES:|
02091|035|B||
02091|036|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02091|037|R|  Pharamceuticals, Inc. December, 2019.|1
02091|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02091|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02091|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02091|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02091|042|R|  11/14/2017.|1
02092|001|T|MONOGRAPH TITLE:  Lurasidone (Less Than or Equal To 80 mg)/Erythromycin|
02092|002|B||
02092|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02092|004|L|take action as needed.|
02092|005|B||
02092|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as erythromycin may|
02092|007|A|inhibit the metabolism of lurasidone.(1)|
02092|008|B||
02092|009|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02092|010|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02092|011|E|or other lurasidone toxicities.(1)|
02092|012|B||
02092|013|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02092|014|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02092|015|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02092|016|P|have a greater risk for adverse effects.(1)|
02092|017|B||
02092|018|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02092|019|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02092|020|M|CYP3A4 inhibitors, such as erythromycin.(1)|
02092|021|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor,|
02092|022|M|such as erythromycin, is added to therapy, the dose of lurasidone should be|
02092|023|M|decreased by 50% of the original dose.(1)|
02092|024|M|   If a patient is currently on a moderate CYP3A4 inhibitor, such as|
02092|025|M|erythromycin, and lurasidone is added to therapy, the recommended starting|
02092|026|M|dose of lurasidone is 20 mg per day.(1)|
02092|027|B||
02092|028|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
02092|029|D|moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02092|030|D|area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold,|
02092|031|D|and 2.2-fold, respectively.(1)|
02092|032|B||
02092|033|R|REFERENCES:|
02092|034|B||
02092|035|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02092|036|R|  Pharamceuticals, Inc. December, 2019.|1
02092|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02092|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02092|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02092|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02092|041|R|  11/14/2017.|1
02093|001|T|MONOGRAPH TITLE:  Lurasidone (Greater Than 80 mg)/Erythromycin|
02093|002|B||
02093|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02093|004|L|is contraindicated and generally should not be dispensed or administered to|
02093|005|L|the same patient.|
02093|006|B||
02093|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as erythromycin may|
02093|008|A|inhibit the metabolism of lurasidone.(1)|
02093|009|B||
02093|010|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02093|011|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02093|012|E|or other lurasidone toxicities.(1)|
02093|013|B||
02093|014|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02093|015|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02093|016|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02093|017|P|have a greater risk for adverse effects.(1)|
02093|018|B||
02093|019|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02093|020|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02093|021|M|CYP3A4 inhibitors, such as erythromycin.(1)|
02093|022|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor,|
02093|023|M|such as erythromycin, is added to therapy, the dose of lurasidone should be|
02093|024|M|decreased by 50% of the original dose.(1)|
02093|025|M|   If a patient is currently on a moderate CYP3A4 inhibitor, such as|
02093|026|M|erythromycin, and lurasidone is added to therapy, the recommended starting|
02093|027|M|dose of lurasidone is 20 mg per day.(1)|
02093|028|B||
02093|029|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
02093|030|D|moderate inhibitor of CYP P-450-3A4, increased the maximum concentration|
02093|031|D|(Cmax) and area-under-curve (AUC) of a single dose of lurasidone (20 mg) by|
02093|032|D|2.1-fold, and 2.2-fold, respectively.(1)|
02093|033|B||
02093|034|R|REFERENCES:|
02093|035|B||
02093|036|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02093|037|R|  Pharamceuticals, Inc. December, 2019.|1
02093|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02093|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02093|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02093|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02093|042|R|  11/14/2017.|1
02094|001|T|MONOGRAPH TITLE:  Lurasidone (Greater Than 80 mg)/Fluconazole|
02094|002|B||
02094|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02094|004|L|is contraindicated and generally should not be dispensed or administered to|
02094|005|L|the same patient.|
02094|006|B||
02094|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as fluconazole may|
02094|008|A|inhibit the metabolism of lurasidone.(1)|
02094|009|B||
02094|010|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02094|011|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02094|012|E|or other lurasidone toxicities.(1)|
02094|013|B||
02094|014|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02094|015|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02094|016|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02094|017|P|have a greater risk for adverse effects.(1)|
02094|018|B||
02094|019|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02094|020|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02094|021|M|CYP3A4 inhibitors, such as fluconazole.(1)|
02094|022|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor,|
02094|023|M|such as fluconazole, is added to therapy, the dose of lurasidone should be|
02094|024|M|decreased by 50% of the original dose.(1)|
02094|025|M|   If a patient is currently on a moderate CYP3A4 inhibitor, such as|
02094|026|M|fluconazole, and lurasidone is added to therapy, the recommended starting|
02094|027|M|dose of lurasidone is 20 mg per day.(1)|
02094|028|B||
02094|029|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
02094|030|D|moderate inhibitor of CYP P-450-3A4, increased the maximum concentration|
02094|031|D|(Cmax) and area-under-curve (AUC) of a single dose of lurasidone (20 mg) by|
02094|032|D|2.1-fold, and 2.2-fold, respectively.(1)|
02094|033|B||
02094|034|R|REFERENCES:|
02094|035|B||
02094|036|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02094|037|R|  Pharamceuticals, Inc. December, 2019.|1
02094|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02094|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02094|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02094|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02094|042|R|  11/14/2017.|1
02095|001|T|MONOGRAPH TITLE:  Lurasidone (Less Than or Equal To 80 mg)/Fluconazole|
02095|002|B||
02095|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02095|004|L|take action as needed.|
02095|005|B||
02095|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as fluconazole may|
02095|007|A|inhibit the metabolism of lurasidone.(1)|
02095|008|B||
02095|009|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
02095|010|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
02095|011|E|or other lurasidone toxicities.(1)|
02095|012|B||
02095|013|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02095|014|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02095|015|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02095|016|P|have a greater risk for adverse effects.(1)|
02095|017|B||
02095|018|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
02095|019|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
02095|020|M|CYP3A4 inhibitors, such as fluconazole.(1)|
02095|021|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor,|
02095|022|M|such as fluconazole, is added to therapy, the dose of lurasidone should be|
02095|023|M|decreased by 50% of the original dose.(1)|
02095|024|M|   If a patient is currently on a moderate CYP3A4 inhibitor, such as|
02095|025|M|fluconazole, and lurasidone is added to therapy, the recommended starting|
02095|026|M|dose of lurasidone is 20 mg per day.(1)|
02095|027|B||
02095|028|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
02095|029|D|moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02095|030|D|area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold,|
02095|031|D|and 2.2-fold, respectively.(1)|
02095|032|B||
02095|033|R|REFERENCES:|
02095|034|B||
02095|035|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02095|036|R|  Pharamceuticals, Inc. December, 2019.|1
02095|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02095|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02095|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02095|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02095|041|R|  11/14/2017.|1
02096|001|T|MONOGRAPH TITLE:  Mixed & Indirect Sympathomimetics; Oral|
02096|002|T|Phenylephrine/Selected MAOIs|
02096|003|B||
02096|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02096|005|L|of severe adverse interaction.|
02096|006|B||
02096|007|A|MECHANISM OF ACTION:  Catecholamine stores increased by MAOIs can be|
02096|008|A|released by indirect acting sympathomimetics such as ephedrine and|
02096|009|A|amphetamine. MAO inhibitors also interfere with gut and liver metabolism of|
02096|010|A|direct acting sympathomimetics (e.g oral phenylephrine).|
02096|011|B||
02096|012|E|CLINICAL EFFECTS:  Concurrent use of MAOIs may result in potentiation of|
02096|013|E|sympathomimetic effects, which may result in headaches, hypertensive crisis,|
02096|014|E|toxic neurological effects, and malignant hyperpyrexia.  Fatalities have|
02096|015|E|occurred with combinations of sympathomimetics and MAO-A inhibitors.|
02096|016|B||
02096|017|P|PREDISPOSING FACTORS:  None determined.|
02096|018|B||
02096|019|M|PATIENT MANAGEMENT:  Concurrent use of MAO-A inhibitors and sympathomimetics|
02096|020|M|is contraindicated.  The manufacturers of sympathomimetic agents recommend|
02096|021|M|waiting 14 days after discontinuation of MAO inhibitors before initiating|
02096|022|M|the sympathomimetic.|
02096|023|M|   Patients receiving indirect acting sympathomimetics should not receive|
02096|024|M|linezolid unless they are monitored for potential increases in blood|
02096|025|M|pressure.  Initial dosages of dopamine should be reduced.|
02096|026|M|   At recommended dosages, oral selegiline and transdermal selegiline up to|
02096|027|M|6mg/day are selective for MAO-B; however, at higher dosages they have been|
02096|028|M|shown to lose their selectivity.  Patients receiving higher dosages of|
02096|029|M|selegiline should be considered susceptive to this interaction.|
02096|030|B||
02096|031|D|DISCUSSION:  Indirect acting sympathomimetic amines may cause abrupt|
02096|032|D|elevation of blood pressure when administered to patients taking monoamine|
02096|033|D|oxidase inhibitors, resulting in a potentially fatal hypertensive crisis.|
02096|034|D|   Mixed (direct and indirect) acting sympathomimetics have also been shown|
02096|035|D|to interact with monoamine oxidase inhibitors depending on their degree of|
02096|036|D|indirect action.  The direct-acting sympathomimetics have not been reported|
02096|037|D|to interact.  Dopamine is metabolized by monoamine oxidase, and its pressor|
02096|038|D|effect is enhanced by monoamine oxidase inhibitors.|
02096|039|D|   Furazolidone, an antibacterial with monoamine oxidase inhibitor action,|
02096|040|D|has also been shown to interact with indirect acting sympathomimetics.|
02096|041|D|   Foods containing large amounts of tyramine have also been implicated in|
02096|042|D|this interaction.  A significant pressor response was observed in normal|
02096|043|D|subjects receiving linezolid and tyramine doses of more than 100 mg.|
02096|044|D|   Administration of linezolid (600 mg BID for 3 days) with pseudoephedrine|
02096|045|D|(60 mg q 4 hours for 2 doses) increased blood pressure by 32 mmHg.|
02096|046|D|Administration of linezolid (600 mg BID for 3 days) with phenylpropanolamine|
02096|047|D|(25 mg q 4 hours for 2 doses) increased blood pressure by 38 mmHg.|
02096|048|D|   One or more of the drug pairs linked to this monograph have been included|
02096|049|D|in a list of interactions that should be considered "high-priority" for|
02096|050|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02096|051|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02096|052|D|Coordinator (ONC) for Health Information Technology.|
02096|053|B||
02096|054|R|REFERENCES:|
02096|055|B||
02096|056|R|1.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
02096|057|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
02096|058|R|2.Pettinger WA, Soyangco FG, Oates JA. Inhibition of monoamine oxidase in|2
02096|059|R|  man by furazolidone. Clin Pharmacol Ther 1968 Jul-Aug;9(4):442-7.|2
02096|060|R|3.Adderall XR (amphetamine) US prescribing information. Shire US Inc. April,|1
02096|061|R|  2015.|1
02096|062|R|4.Ritalin LA (methylphenidate hydrochloride) US prescribing information.|1
02096|063|R|  Novartis Pharmaceuticals Corporation June, 2021.|1
02096|064|R|5.Focalin (dexmethylphenidate hydrochloride) US prescribing information.|1
02096|065|R|  Novartis Pharmaceuticals Corporation June, 2021.|1
02096|066|R|6.Parnate (tranylcypromine sulfate) US prescribing information.|1
02096|067|R|  GlaxoSmithKline January 4, 2018.|1
02096|068|R|7.Cuthbert MF, Greenberg MP, Morley SW. Cough and cold remedies: a potential|2
02096|069|R|  danger to patients on monoamine oxidase inhibitors. Br Med J 1969 Feb 15;|2
02096|070|R|  1(5641):404-6.|2
02096|071|R|8.Smookler S, Bermudez AJ. Hypertensive crisis resulting from an MAO|3
02096|072|R|  inhibitor and an over-the-counter appetite suppressant. Ann Emerg Med 1982|3
02096|073|R|  Sep;11(9):482-4U.|3
02096|074|R|9.Mason AM, Buckle RM. "Cold" cures and monoamine-oxidase inhibitors. Br Med|3
02096|075|R|  J 1969 Mar 29;1(5647):845-6.|3
02096|076|R|10.LLOYD JT, WALKER DR. DEATH AFTER COMBINED DEXAMPHETAMINE AND PHENELZINE.|3
02096|077|R|   Br Med J 1965 Jul 17;2(5454):168-9.|3
02096|078|R|11.Krisko I, Lewis E, Johnson JE 3rd. Severe hyperpyrexia due to|3
02096|079|R|   tranylcypromine-amphetamine toxicity. Ann Intern Med 1969 Mar;|3
02096|080|R|   70(3):559-64.|3
02096|081|R|12.Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN.|2
02096|082|R|   Interactions between sympathomimetic amines and antidepressant agents in|2
02096|083|R|   man. Br Med J 1973 Feb 10;1(5849):311-5.|2
02096|084|R|13.Elis J, Laurence DR, Mattie H, Prichard BN. Modification by monoamine|2
02096|085|R|   oxidase inhibitors of the effect of some sympathomimetics on blood|2
02096|086|R|   pressure. Br Med J 1967 Apr 8;2(5544):75-8.|2
02096|087|R|14.HORWITZ D, GOLDBERG LI, SJOERDSMA A. Increased blood pressure responses|2
02096|088|R|   to dopamine and norepinephrine produced by monoamine oxidase inhibitors|2
02096|089|R|   in man. J Lab Clin Med 1960 Nov;56:747-53.|2
02096|090|R|15.Cuthbert MF, Vere DW. Potentiation of the cardiovascular effects of some|2
02096|091|R|   catecholamines by a monoamine oxidase inhibitor. Br J Pharmacol 1971 Oct;|2
02096|092|R|   43(2):471P-472P.|2
02096|093|R|16.Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function.|5
02096|094|R|   Pharmacol Rev 1966 Jun;18(2):925-64.|5
02096|095|R|17.GOLDBERG LI. MONOAMINE OXIDASE INHIBITORS. ADVERSE REACTIONS AND POSSIBLE|6
02096|096|R|   MECHANISMS. JAMA 1964 Nov 2;190:456-62.|6
02096|097|R|18.Kopin IJ. Biochemical aspects of release of norepinephrine and other|5
02096|098|R|   amines from sympathetic nerve endings. Pharmacol Rev 1966 Mar;|5
02096|099|R|   18(1):513-23.|5
02096|100|R|19.BETHUNE HC, BURRELL RH, CULPAN RH, OGG GJ. VASCULAR CRISES ASSOCIATED|6
02096|101|R|   WITH MONOAMINE-OXIDASE INHIBITORS. Am J Psychiatry 1964 Sep;121:245-8.|6
02096|102|R|20.O'Dea K, Rand MJ. Interaction between amphetamine and monoamine oxidase|5
02096|103|R|   inhibitors. Eur J Pharmacol 1969 May;6(2):115-20.|5
02096|104|R|21.Eldepryl (selegiline) US prescribing information. Somerset|1
02096|105|R|   Pharmaceuticals February, 1997.|1
02096|106|R|22.Emsam (selegline) US prescribing information. Somerset July, 2017.|1
02096|107|R|23.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
02096|108|R|24.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02096|109|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02096|110|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02096|111|R|   19(5):735-43.|6
02097|001|T|MONOGRAPH TITLE:  Ticagrelor/Strong CYP3A4 Inhibitors; Protease Inhibitors|
02097|002|B||
02097|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02097|004|L|is contraindicated and generally should not be dispensed or administered to|
02097|005|L|the same patient.|
02097|006|B||
02097|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
02097|008|A|of ticagrelor.(1,2)|
02097|009|B||
02097|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02097|011|E|in a substantial increase in exposure to and effects from ticagrelor,|
02097|012|E|including increased risk of bleeding.(1,2)|
02097|013|B||
02097|014|P|PREDISPOSING FACTORS:  None determined.|
02097|015|B||
02097|016|M|PATIENT MANAGEMENT:  The UK manufacturer of ticagrelor states that|
02097|017|M|concurrent use of strong CYP3A4 inhibitors is contraindicated.(1)|
02097|018|M|   The US manufacturer of ticagrelor states that concurrent use of strong|
02097|019|M|CYP3A4 inhibitors should be avoided.(2)|
02097|020|M|   The US manufacturer of itraconazole states that concurrent use of|
02097|021|M|ticagrelor is contraindicated during and two weeks after itraconazole|
02097|022|M|treatment.(3)|
02097|023|B||
02097|024|D|DISCUSSION:  Concurrent ketoconazole increased ticagrelor maximum|
02097|025|D|concentration (Cmax) and area-under-curve (AUC) by 2.4-fold and 7.3-fold,|
02097|026|D|respectively.  The Cmax and AUC of the active ticagrelor metabolite|
02097|027|D|decreased by 89% and 56%, respectively.(1)|
02097|028|D|   Strong CYP3A4 inhibitors linked include:  adagrasib, atazanavir,|
02097|029|D|boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, fosamprenavir,|
02097|030|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib,|
02097|031|D|lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
02097|032|D|nirmatrelvir/ritonavir, paritaprevir/ritonavir, posaconazole, ribociclib,|
02097|033|D|saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(4,5)|
02097|034|B||
02097|035|R|REFERENCES:|
02097|036|B||
02097|037|R|1.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02097|038|R|  UK Limited October 24, 2012.|1
02097|039|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP November,|1
02097|040|R|  2024.|1
02097|041|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02097|042|R|  Products, L.P. February, 2024.|1
02097|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
02097|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02097|045|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02097|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02097|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02097|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02097|049|R|  11/14/2017.|1
02098|001|T|MONOGRAPH TITLE:  Ticagrelor/Clarithromycin; Telithromycin (mono deleted|
02098|002|T|02/21/2013)|
02098|003|B||
02098|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02098|005|L|is contraindicated and generally should not be dispensed or administered to|
02098|006|L|the same patient.|
02098|007|B||
02098|008|A|MECHANISM OF ACTION:  Clarithromycin and telithromycin may inhibit the|
02098|009|A|metabolism of ticagrelor by CYP P-450-3A4.(1,2)|
02098|010|B||
02098|011|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin and telithromycin may|
02098|012|E|result in a substantial increase in exposure to and effects from|
02098|013|E|ticagrelor.(1,2)|
02098|014|B||
02098|015|P|PREDISPOSING FACTORS:  None determined.|
02098|016|B||
02098|017|M|PATIENT MANAGEMENT:  The UK manufacturer of ticagrelor states that|
02098|018|M|concurrent use of strong CYP P-450-3A4 inhibitors, such as clarithromycin|
02098|019|M|and telithromycin, is contraindicated.(1)|
02098|020|M|   The US manufacturer of ticagrelor states that concurrent use of strong|
02098|021|M|CYP P-450-3A4 inhibitors, such as clarithromycin and telithromycin, should|
02098|022|M|be avoided.(2)|
02098|023|B||
02098|024|D|DISCUSSION:  Concurrent ketoconazole, another strong inhibitor of CYP|
02098|025|D|P-450-3A4, increased ticagrelor maximum concentration (Cmax) and|
02098|026|D|area-under-curve (AUC) by 2.4-fold and 7.3-fold, respectively.  The Cmax and|
02098|027|D|AUC of the active ticagrelor metabolite decreased by 89% and 56%,|
02098|028|D|respectively.  Other strong inhibitors of CYP P-450-3A4 are expected to have|
02098|029|D|similar effects.(1)|
02098|030|B||
02098|031|R|REFERENCES:|
02098|032|B||
02098|033|R|1.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02098|034|R|  UK Limited October 24, 2012.|1
02098|035|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP July 20,|1
02098|036|R|  2011.|1
02099|001|T|MONOGRAPH TITLE:  Ticagrelor/Nefazodone (mono deleted 02/21/2013)|
02099|002|B||
02099|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02099|004|L|is contraindicated and generally should not be dispensed or administered to|
02099|005|L|the same patient.|
02099|006|B||
02099|007|A|MECHANISM OF ACTION:  Nefazodone may inhibit the metabolism of ticagrelor by|
02099|008|A|CYP P-450-3A4.(1,2)|
02099|009|B||
02099|010|E|CLINICAL EFFECTS:  Concurrent use of nefazodone may result in a substantial|
02099|011|E|increase in exposure to and effects from ticagrelor.(1,2)|
02099|012|B||
02099|013|P|PREDISPOSING FACTORS:  None determined.|
02099|014|B||
02099|015|M|PATIENT MANAGEMENT:  The UK manufacturer of ticagrelor states that|
02099|016|M|concurrent use of strong CYP P-450-3A4 inhibitors, such as nefazodone, is|
02099|017|M|contraindicated.(1)|
02099|018|M|   The US manufacturer of ticagrelor states that concurrent use of strong|
02099|019|M|CYP P-450-3A4 inhibitors, such as nefazodone, should be avoided.(2)|
02099|020|B||
02099|021|D|DISCUSSION:  Concurrent ketoconazole, another strong inhibitor of CYP|
02099|022|D|P-450-3A4, increased ticagrelor maximum concentration (Cmax) and|
02099|023|D|area-under-curve (AUC) by 2.4-fold and 7.3-fold, respectively.  The Cmax and|
02099|024|D|AUC of the active ticagrelor metabolite decreased by 89% and 56%,|
02099|025|D|respectively.  Other strong inhibitors of CYP P-450-3A4 are expected to have|
02099|026|D|similar effects.(1)|
02099|027|B||
02099|028|R|REFERENCES:|
02099|029|B||
02099|030|R|1.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02099|031|R|  UK Limited October 24, 2012.|1
02099|032|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP July 20,|1
02099|033|R|  2011.|1
02100|001|T|MONOGRAPH TITLE:  Ticagrelor/Selected Protease Inhibitors (mono deleted|
02100|002|T|02/21/2013)|
02100|003|B||
02100|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02100|005|L|is contraindicated and generally should not be dispensed or administered to|
02100|006|L|the same patient.|
02100|007|B||
02100|008|A|MECHANISM OF ACTION:  Some protease inhibitors may inhibit the metabolism of|
02100|009|A|ticagrelor by CYP P-450-3A4.(1,2)|
02100|010|B||
02100|011|E|CLINICAL EFFECTS:  Concurrent use of some protease inhibitors may result in|
02100|012|E|a substantial increase in exposure to and effects from ticagrelor.(1,2)|
02100|013|B||
02100|014|P|PREDISPOSING FACTORS:  None determined.|
02100|015|B||
02100|016|M|PATIENT MANAGEMENT:  The UK manufacturer of ticagrelor states that|
02100|017|M|concurrent use of strong CYP P-450-3A4 inhibitors, such as atazanavir,|
02100|018|M|indinavir, nelfinavir, ritonavir, or saquinavir, is contraindicated.(1)|
02100|019|M|   The US manufacturer of ticagrelor states that concurrent use of strong|
02100|020|M|CYP P-450-3A4 inhibitors, such as atazanavir, indinavir, nelfinavir,|
02100|021|M|ritonavir, or saquinavir, should be avoided.(2)|
02100|022|B||
02100|023|D|DISCUSSION:  Concurrent ketoconazole, another strong inhibitor of CYP|
02100|024|D|P-450-3A4, increased ticagrelor maximum concentration (Cmax) and|
02100|025|D|area-under-curve (AUC) by 2.4-fold and 7.3-fold, respectively.  The Cmax and|
02100|026|D|AUC of the active ticagrelor metabolite decreased by 89% and 56%,|
02100|027|D|respectively.  Other strong inhibitors of CYP P-450-3A4 are expected to have|
02100|028|D|similar effects.(1)|
02100|029|B||
02100|030|R|REFERENCES:|
02100|031|B||
02100|032|R|1.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02100|033|R|  UK Limited October 24, 2012.|1
02100|034|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP July 20,|1
02100|035|R|  2011.|1
02101|001|T|MONOGRAPH TITLE:  Ticagrelor; Vorapaxar/Strong CYP3A4 Inducers|
02101|002|B||
02101|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02101|004|L|is contraindicated and generally should not be dispensed or administered to|
02101|005|L|the same patient.|
02101|006|B||
02101|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02101|008|A|ticagrelor(1,2) and vorapaxar.(3)|
02101|009|B||
02101|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
02101|011|E|result in decreased levels and loss of efficacy of ticagrelor(1,2) and|
02101|012|E|vorapaxar.(3)|
02101|013|B||
02101|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02101|015|P|of the inducer for longer than 1-2 weeks.|
02101|016|B||
02101|017|M|PATIENT MANAGEMENT:  The manufacturers of ticagrelor and vorapaxar state|
02101|018|M|concurrent use with strong CYP3A4 inducers should be avoided due to the|
02101|019|M|substantially reduced levels which may result in loss of ticagrelor and|
02101|020|M|vorapaxar efficacy.(1,3)|
02101|021|M|   If therapy with a strong CYP3A4 inducer is needed, it would be prudent to|
02101|022|M|select an alternative antiplatelet agent.|
02101|023|M|   If concurrent therapy cannot be avoided, consider performing platelet|
02101|024|M|reactivity measurements to determine patient-specific risk for treatment|
02101|025|M|failure.  Monitor patients receiving concurrent therapy for signs of heart|
02101|026|M|attack, stroke, or blood clots.|
02101|027|B||
02101|028|D|DISCUSSION:  Concurrent use of rifampin (600 mg once daily) decreased the|
02101|029|D|maximum concentration (Cmax) and area-under-curve (AUC) of ticagrelor by 73%|
02101|030|D|and 86%, respectively.  The AUC of ticagrelor's active metabolite decreased|
02101|031|D|46%.(1,4)|
02101|032|D|   A retrospective study of CArdiovascular Percutaneous Intervention TriAL|
02101|033|D|(CAPITAL) registry participants was performed to determine the effects of|
02101|034|D|antiepileptic (AED) CYP3A4 inducers on ticagrelor efficacy.  Platelet|
02101|035|D|reactivity in 8 patients receiving one or more AED CYP3A4 inducers were|
02101|036|D|compared with 49 patients on identical doses of aspirin and ticagrelor who|
02101|037|D|were not receiving CYP3A4 inducers.  The mean P2Y12 reaction units (PRU) in|
02101|038|D|AED patients was 194.6(+ or - 29.9) vs 26.3(+ or - 29.8) in control|
02101|039|D|patients.  Three of 8 AED patients had PRU = or > 208, the cut off for high|
02101|040|D|platelet reactivity.  One ticagrelor AED patient was changed to clopidogrel.|
02101|041|D|PRU on ticagrelor was 220, and after conversion to clopidogrel was reduced|
02101|042|D|to 110.(5)|
02101|043|D|   In a study in 12 healthy subjects, rifampin (600 mg daily for 28 days)|
02101|044|D|decreased the exposure of vorapaxar (20 mg on Day 7, 2.5 mg on Days 8-28) by|
02101|045|D|50%.(6)|
02101|046|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02101|047|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02101|048|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02101|049|D|rifapentine and St. John's wort.(7,8)|
02101|050|B||
02101|051|R|REFERENCES:|
02101|052|B||
02101|053|R|1.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP November,|1
02101|054|R|  2024.|1
02101|055|R|2.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02101|056|R|  UK Limited October 24, 2012.|1
02101|057|R|3.Zontivity (vorapaxar) US prescribing information. Merck & Co., Inc.|1
02101|058|R|  November, 2019.|1
02101|059|R|4.Teng R, Mitchell P, Butler K. Effect of rifampicin on the pharmacokinetics|2
02101|060|R|  and pharmacodynamics of ticagrelor in  healthy subjects. Eur J Clin|2
02101|061|R|  Pharmacol 2013 Apr;69(4):877-83.|2
02101|062|R|5.Pourdjabbar A, Hibbert B, Chong AY, Abunassar J, Malhotra N, Whitten TA,|2
02101|063|R|  Le May MR, So DY. A pharmacodynamic analysis for the co-administration of|2
02101|064|R|  inducers of CYP3A with ticagrelor: A cautionary tale in managing patients|2
02101|065|R|  with acute coronary syndromes. Int J Cardiol 2016 Mar 24;214:423-425.|2
02101|066|R|6.Kosoglou T, Statkevich P, Kumar B, Xuan F, Schiller JE, Johnson-Levonas|2
02101|067|R|  AO, Young S, Cutler DL. The effect of multiple doses of ketoconazole or|2
02101|068|R|  rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar. J|2
02101|069|R|  Clin Pharmacol 2013 May;53(5):540-9.|2
02101|070|R|7.This information is based on an extract from the Certara Drug Interaction|6
02101|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02101|072|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
02101|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02101|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02101|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02101|076|R|  11/14/2017.|1
02102|001|T|MONOGRAPH TITLE:  Ticagrelor/Carbamazepine; Phenobarbital; Phenytoin (mono|
02102|002|T|deleted 02/21/2013)|
02102|003|B||
02102|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02102|005|L|of severe adverse interaction.|
02102|006|B||
02102|007|A|MECHANISM OF ACTION:  Carbamazepine, phenobarbital, and phenytoin may induce|
02102|008|A|the metabolism of ticagrelor by CYP P-450-3A4.(1,2)|
02102|009|B||
02102|010|E|CLINICAL EFFECTS:  Concurrent or recent use of carbamazepine, phenobarbital,|
02102|011|E|or phenytoin may result in decreased levels and effectiveness of|
02102|012|E|ticagrelor.(1,2)|
02102|013|B||
02102|014|P|PREDISPOSING FACTORS:  None determined.|
02102|015|B||
02102|016|M|PATIENT MANAGEMENT:  If possible, consider alternatives to strong CYP|
02102|017|M|P-450-3A4 inducers, such as carbamazepine, phenobarbital, or phenytoin, in|
02102|018|M|patients maintained on ticagrelor(1) and avoid concurrent therapy.(2)  If|
02102|019|M|therapy with a strong CYP P-450-3A4 inducer is required, an alternative|
02102|020|M|antiplatelet agent may be required.|
02102|021|B||
02102|022|D|DISCUSSION:  Concurrent rifampin decreased the maximum concentration (Cmax)|
02102|023|D|and area-under-curve (AUC) of ticagrelor by 73% and 86%, respectively.  The|
02102|024|D|AUC of ticagrelor's active metabolite decreased 46%.  Other strong CYP|
02102|025|D|P-450-3A4 inducers such as carbamazepine, phenobarbital, and phenytoin are|
02102|026|D|expected to have similar effects.(1)|
02102|027|B||
02102|028|R|REFERENCES:|
02102|029|B||
02102|030|R|1.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02102|031|R|  UK Limited October 24, 2012.|1
02102|032|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP July 20,|1
02102|033|R|  2011.|1
02103|001|T|MONOGRAPH TITLE:  Ticagrelor/Dexamethasone (mono deleted 02/21/2013)|
02103|002|B||
02103|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02103|004|L|of severe adverse interaction.|
02103|005|B||
02103|006|A|MECHANISM OF ACTION:  Dexamethasone may induce the metabolism of ticagrelor|
02103|007|A|by CYP P-450-3A4.(1)|
02103|008|B||
02103|009|E|CLINICAL EFFECTS:  Concurrent or recent use of dexamethasone may result in|
02103|010|E|decreased levels and effectiveness of ticagrelor.(1)|
02103|011|B||
02103|012|P|PREDISPOSING FACTORS:  None determined.|
02103|013|B||
02103|014|M|PATIENT MANAGEMENT:  If possible, consider alternatives to strong CYP|
02103|015|M|P-450-3A4 inducers, such as dexamethasone, in patients maintained on|
02103|016|M|ticagrelor(1) and avoid concurrent therapy.(2)  If therapy with a strong CYP|
02103|017|M|P-450-3A4 inducer is required, an alternative antiplatelet agent may be|
02103|018|M|required.|
02103|019|B||
02103|020|D|DISCUSSION:  Concurrent rifampin decreased the maximum concentration (Cmax)|
02103|021|D|and area-under-curve (AUC) of ticagrelor by 73% and 86%, respectively.  The|
02103|022|D|AUC of ticagrelor's active metabolite decreased 46%.  Other strong CYP|
02103|023|D|P-450-3A4 inducers such as dexamethasone are expected to have similar|
02103|024|D|effects.(1)|
02103|025|B||
02103|026|R|REFERENCES:|
02103|027|B||
02103|028|R|1.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02103|029|R|  UK Limited October 24, 2012.|1
02103|030|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP July 20,|1
02103|031|R|  2011.|1
02104|001|T|MONOGRAPH TITLE:  Ticagrelor/High-Dose Aspirin|
02104|002|B||
02104|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02104|004|L|of severe adverse interaction.|
02104|005|B||
02104|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02104|007|B||
02104|008|E|CLINICAL EFFECTS:  Chronic use of high-dose aspirin may decrease the|
02104|009|E|efficacy of ticagrelor.(1,2)|
02104|010|B||
02104|011|P|PREDISPOSING FACTORS:  None determined.|
02104|012|B||
02104|013|M|PATIENT MANAGEMENT:  After an initial loading dose, low dose aspirin is|
02104|014|M|indicated with concurrent ticagrelor for the prevention of thrombotic|
02104|015|M|events.  Specific dosage recommendations vary between countries, however all|
02104|016|M|agree that the maintenance aspirin dose should be < or = 150 mg per day.|
02104|017|M|   US prescribing information recommends the following based on indication:|
02104|018|M|   -For Acute Coronary Syndrome or Myocardial Infarction - Initiate|
02104|019|M|ticagrelor with a maintenance dose of aspirin 75 mg to 100 mg.|
02104|020|M|   -For Coronary Artery Disease but No Prior Stroke or Myocardial Infarction|
02104|021|M|- Use ticagrelor with a daily maintenance dose of aspirin of 75 mg to 100|
02104|022|M|mg.|
02104|023|M|   -For Acute Ischemic Stroke or Transient Ischemic Attack - Use ticagrelor|
02104|024|M|with a loading dose of aspirin (300 mg to 325 mg) and a daily maintenance|
02104|025|M|dose of 75 mg to 100 mg.(1)|
02104|026|M|   Canada and UK prescribing information recommends a maintenance aspirin|
02104|027|M|dose of 75 mg to 150 mg daily.(2,3)|
02104|028|M|   For use other than platelet aggregation, it would be prudent to recommend|
02104|029|M|an alternative product that does not contain aspirin for patients maintained|
02104|030|M|on ticagrelor.|
02104|031|B||
02104|032|D|DISCUSSION:  Ticagrelor is indicated with concurrent aspirin for the|
02104|033|D|prevention of thrombotic events. In the PLATO trial, there was a|
02104|034|D|relationship between the maintenance dose of aspirin and efficacy of|
02104|035|D|ticagrelor.  At increased aspirin dosages, ticagrelor was less|
02104|036|D|effective.(1-3)|
02104|037|B||
02104|038|R|REFERENCES:|
02104|039|B||
02104|040|R|1.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP November,|1
02104|041|R|  2024.|1
02104|042|R|2.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02104|043|R|  UK Limited October 24, 2012.|1
02104|044|R|3.Brilinta (ticagrelor) Canada prescribing information. AstraZeneca Canada|1
02104|045|R|  May 26, 2011.|1
02105|001|T|MONOGRAPH TITLE:  Rasagiline (Less Than or Equal To 0.5 mg)/Selected CYP1A2|
02105|002|T|Inhibitors|
02105|003|B||
02105|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02105|005|L|take action as needed.|
02105|006|B||
02105|007|A|MECHANISM OF ACTION:  Inhibitors of CYP1A2 may inhibit the metabolism of|
02105|008|A|rasagiline.(1)|
02105|009|B||
02105|010|E|CLINICAL EFFECTS:  Concurrent use of a CYP1A2 inhibitor may increase levels|
02105|011|E|of and adverse effects from rasagiline.(1)|
02105|012|B||
02105|013|P|PREDISPOSING FACTORS:  None determined.|
02105|014|B||
02105|015|M|PATIENT MANAGEMENT:  The US manufacturer of rasagiline states that patients|
02105|016|M|receiving concurrent therapy with an inhibitor of CYP1A2 should receive no|
02105|017|M|more than 0.5 mg of rasagiline daily.(1)|
02105|018|M|   Concurrent therapy with vemurafenib may require extended monitoring for|
02105|019|M|interaction onset and severity because steady-state levels of vemurafenib|
02105|020|M|are not attained for approximately 15 days.(2)|
02105|021|B||
02105|022|D|DISCUSSION:  In a study in 12 healthy subjects, ciprofloxacin (500 mg twice|
02105|023|D|daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily)|
02105|024|D|by 83%.(1)|
02105|025|D|   Strong CYP1A2 inhibitors linked to this monograph include: angelica root,|
02105|026|D|ciprofloxacin, enasidenib, enoxacin, and rofecoxib.|
02105|027|D|   Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib,|
02105|028|D|dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen,|
02105|029|D|mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib,|
02105|030|D|troleandomycin, and vemurafenib.(3-5)|
02105|031|B||
02105|032|R|REFERENCES:|
02105|033|B||
02105|034|R|1.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
02105|035|R|  June, 2020.|1
02105|036|R|2.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02105|037|R|  November, 2017.|1
02105|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02105|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02105|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02105|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02105|042|R|  11/14/2017.|1
02105|043|R|4.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
02105|044|R|  Indiana University School of Medicine.  Available at:|1
02105|045|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
02105|046|R|5.This information is based on an extract from the Certara Drug Interaction|6
02105|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02106|001|T|MONOGRAPH TITLE:  Quinidine; Hydroquinidine/Selected QT Prolongers (mono|
02106|002|T|deleted 10/22/2015)|
02106|003|B||
02106|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02106|005|L|is contraindicated and generally should not be dispensed or administered to|
02106|006|L|the same patient.|
02106|007|B||
02106|008|A|MECHANISM OF ACTION:  Concurrent use of quinidine or hydroquinidine with|
02106|009|A|agents that prolong the QTc interval may result in additive effects on the|
02106|010|A|QTc interval.|
02106|011|B||
02106|012|E|CLINICAL EFFECTS:  The concurrent use of quinidine or hydroquinidine with|
02106|013|E|agents that prolong the QTc interval may result in potentially|
02106|014|E|life-threatening cardiac arrhythmias, including torsades de pointes.|
02106|015|B||
02106|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02106|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02106|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02106|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02106|020|P|gender, or advanced age.(1)|
02106|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02106|022|P|higher systemic concentrations of either QT prolonging drug are additional|
02106|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02106|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02106|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02106|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02106|027|P|dysfunction).(10)|
02106|028|B||
02106|029|M|PATIENT MANAGEMENT:  The UK manufacturers of amifampridine,(2)|
02106|030|M|artemether-lumefantrine,(3) and toremifene(4) state that the concurrent use|
02106|031|M|of drugs that may prolong the QT interval is contraindicated.|
02106|032|M|   The US manufacturers of bepridil,(5) dronedarone,(6) and levomethadyl(7)|
02106|033|M|state that concurrent use of agents known to prolong the QT interval is|
02106|034|M|contraindicated.|
02106|035|M|   The US manufacturers of anagrelide(8) and droperidol(9) state that drugs|
02106|036|M|known to have the potential to prolong the QT interval should not be used|
02106|037|M|with droperidol.|
02106|038|M|   The US manufacturer of artemether-lumefantrine states that the use of|
02106|039|M|artemether-lumefantrine should be avoided in patients taking drugs that are|
02106|040|M|known to prolong the QTc interval.(10)|
02106|041|M|   If alternatives are not available and concurrent therapy is deemed|
02106|042|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
02106|043|M|and monitor ECG at baseline and at regular intervals.  Correct any|
02106|044|M|electrolyte abnormalities.  Instruct patients to report any irregular|
02106|045|M|heartbeat, dizziness, or fainting.|
02106|046|B||
02106|047|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02106|048|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02106|049|D|monograph have been shown to prolong the QTc interval either through their|
02106|050|D|mechanism of action, through studies on their effects on the QTc interval,|
02106|051|D|or through reports of QTc prolongation and/or torsades de pointes in|
02106|052|D|clinical trials and/or postmarketing reports.(11)|
02106|053|D|   One or more of the drug pairs linked to this monograph have been included|
02106|054|D|in a list of interactions that should be considered "high-priority" for|
02106|055|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02106|056|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02106|057|D|Coordinator (ONC) for Health Information Technology.|
02106|058|B||
02106|059|R|REFERENCES:|
02106|060|B||
02106|061|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02106|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02106|063|R|  settings: a scientific statement from the American Heart Association and|6
02106|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02106|065|R|  2;55(9):934-47.|6
02106|066|R|2.Firdapse (amifampridine phosphate) UK summary of product characteristics.|1
02106|067|R|  BioMarin Europe Limited February, 2010.|1
02106|068|R|3.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
02106|069|R|  Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
02106|070|R|4.Fareston (toremifene citrate) UK summary of product characteristics. Orion|1
02106|071|R|  Pharma (UK) Limited January, 2009.|1
02106|072|R|5.Vascor (bepridil hydrochloride) US prescribing information. Ortho-McNeil|1
02106|073|R|  Pharmaceutical, Inc. March, 2000.|1
02106|074|R|6.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
02106|075|R|  November, 2020.|1
02106|076|R|7.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
02106|077|R|  Roxane Laboratories, Inc. May, 2001.|1
02106|078|R|8.Agrylin (anagrelide hydrochloride) US prescribing information. Shire US|1
02106|079|R|  Inc. October, 2021.|1
02106|080|R|9.Inapsine (droperidol) US prescribing information. Akorn, Inc. November,|1
02106|081|R|  2001.|1
02106|082|R|10.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
02106|083|R|   Pharmaceuticals Corporation March, 2015.|1
02106|084|R|11.USDepartment of Health and Human Services Food and Drug Administration.|1
02106|085|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02106|086|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02106|087|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02106|088|R|12.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02106|089|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02106|090|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02106|091|R|   19(5):735-43.|6
02107|001|T|MONOGRAPH TITLE:  Trazodone/Clarithromycin; Erythromycin; Telithromycin|
02107|002|T|(mono deleted 12/01/2011)|
02107|003|B||
02107|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02107|005|L|of severe adverse interaction.|
02107|006|B||
02107|007|A|MECHANISM OF ACTION:  Some macrolides may inhibit the metabolism of|
02107|008|A|trazodone by CYP P-450-3A4.(1,2)  Trazodone has been shown to prolong the|
02107|009|A|QTc interval.(2)|
02107|010|B||
02107|011|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin, erythromycin, or|
02107|012|E|telithromycin may result in elevated levels of and effects from trazodone,|
02107|013|E|including the potential for life-threatening cardiac arrhythmias.(1,2)|
02107|014|B||
02107|015|P|PREDISPOSING FACTORS:  This interaction may be more severe with larger|
02107|016|P|and/or routine doses of trazodone.|
02107|017|B||
02107|018|M|PATIENT MANAGEMENT:  A lower dose of trazodone should be considered in|
02107|019|M|patients receiving CYP P-450-3A4 inhibitors(2) such as clarithromycin,|
02107|020|M|erythromycin, and telithromycin.  Instruct patients to report any irregular|
02107|021|M|heartbeat or fainting episodes.|
02107|022|B||
02107|023|D|DISCUSSION:  In a cross-over study in 10 healthy subjects, pretreatment with|
02107|024|D|clarithromycin (500 mg, 4 doses given over 32 hours) increased the maximum|
02107|025|D|concentration, (Cmax) half-life, and area-under-curve (AUC) of a single dose|
02107|026|D|of trazodone (50 mg) by 35% (p<0.005), 96% (p<0.02), and 99% (p<0.001),|
02107|027|D|respectively.  Trazodone oral clearance decreased by 46% (p<0.001).|
02107|028|D|Pharmacodynamic effects of trazodone were also increased, as shown by|
02107|029|D|changes in self-rated sedation, observer-rated sedation, digit-symbol|
02107|030|D|substitution test (DSST) scores.(1)|
02107|031|B||
02107|032|R|REFERENCES:|
02107|033|B||
02107|034|R|1.Farkas D, Volak LP, Harmatz JS, von Moltke LL, Court MH, Greenblatt DJ.|2
02107|035|R|  Short-term clarithromycin administration impairs clearance and enhances|2
02107|036|R|  pharmacodynamic effects of trazodone but not of zolpidem. Clin Pharmacol|2
02107|037|R|  Ther 2009 Jun;85(6):644-50.|2
02107|038|R|2.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
02107|039|R|  Labopharm Inc. November, 2012.|1
02109|001|T|MONOGRAPH TITLE:  Metoprolol/Selected CYP2D6 Inhibitors|
02109|002|B||
02109|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02109|004|L|take action as needed.|
02109|005|B||
02109|006|A|MECHANISM OF ACTION:  CYP2D6 inhibitors may inhibit the metabolism of|
02109|007|A|metoprolol.(1,2)|
02109|008|B||
02109|009|E|CLINICAL EFFECTS:  Concurrent use of CYP2D6 inhibitors may result in|
02109|010|E|elevated levels of and toxicity from metoprolol.(1,2)|
02109|011|B||
02109|012|P|PREDISPOSING FACTORS:  The interaction may be more severe in patients who|
02109|013|P|are ultrarapid metabolizers of CYP2D6.(1,2)|
02109|014|B||
02109|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
02109|016|M|metoprolol and inhibitors of CYP2D6.  The dosage of metoprolol may need to|
02109|017|M|be adjusted.(1,2)|
02109|018|B||
02109|019|D|DISCUSSION:  In an open-label, randomized, cross-over study in 12 healthy|
02109|020|D|males, celecoxib (200 mg BID) increased the AUC of metoprolol (50 mg) by|
02109|021|D|64%.  One subject experienced a 200% increase.(3)|
02109|022|D|   In a randomized, double-blind, cross-over study in 7 healthy subjects,|
02109|023|D|hydroxychloroquine (400 mg) increased the AUC of a single dose of metoprolol|
02109|024|D|by 65%.(4)|
02109|025|D|   In a study in 20 Chinese patients with chronic myelogenous leukemia,|
02109|026|D|imatinib (400 mg BID) increased the AUC of metoprolol (100 mg single dose)|
02109|027|D|by 23%. (5)|
02109|028|D|   In healthy subjects, ranolazine (750 mg twice daily) increased plasma|
02109|029|D|levels of a single dose of metoprolol (100 mg) by 1.8-fold.(6)|
02109|030|D|   CYP2D6 inhibitors include:  abiraterone, asunaprevir, berotralstat,|
02109|031|D|bupropion, capivasertib, celecoxib, chloroquine, cinacalcet, citalopram,|
02109|032|D|clomipramine, dacomitinib, diphenhydramine, dronabinol, duloxetine,|
02109|033|D|eliglustat, escitalopram, fedratinib, fluoxetine, hydroxychloroquine,|
02109|034|D|imatinib, lorcaserin, moclobemide, osilodrostat, paroxetine, quinine,|
02109|035|D|ranitidine, ranolazine, rolapitant, and sertraline.|
02109|036|B||
02109|037|R|REFERENCES:|
02109|038|B||
02109|039|R|1.Lopressor (metoprolol tartrate) US prescribing information. Validus|1
02109|040|R|  Pharmaceuticals. LLC July, 2023.|1
02109|041|R|2.Toprol-XL (metoprolol succinate) US prescribing information. AstraZeneca|1
02109|042|R|  LP January, 2022.|1
02109|043|R|3.Werner U, Werner D, Rau T, Fromm MF, Hinz B, Brune K. Celecoxib inhibits|2
02109|044|R|  metabolism of cytochrome P450 2D6 substrate metoprolol in humans. Clin|2
02109|045|R|  Pharmacol Ther 2003 Aug;74(2):130-7.|2
02109|046|R|4.Somer M, Kallio J, Pesonen U, Pyykko K, Huupponen R, Scheinin M. Influence|2
02109|047|R|  of hydroxychloroquine on the bioavailability of oral metoprolol. Br J Clin|2
02109|048|R|  Pharmacol 2000 Jun;49(6):549-54.|2
02109|049|R|5.Wang Y, Zhou L, Dutreix C, Leroy E, Yin Q, Sethuraman V, Riviere GJ, Yin|2
02109|050|R|  OQ, Schran H, Shen ZX. Effects of imatinib (Glivec) on the|2
02109|051|R|  pharmacokinetics of metoprolol, a CYP2D6 substrate, in Chinese patients|2
02109|052|R|  with chronic myelogenous leukaemia. Br J Clin Pharmacol 2008 Jun;|2
02109|053|R|  65(6):885-92.|2
02109|054|R|6.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
02110|001|T|MONOGRAPH TITLE:  Propafenone/QT Prolonging Agents|
02110|002|B||
02110|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02110|004|L|of severe adverse interaction.|
02110|005|B||
02110|006|A|MECHANISM OF ACTION:  Propafenone has been shown to prolong the QTc|
02110|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02110|008|A|may result in additive effects on the QTc interval.(1)|
02110|009|B||
02110|010|E|CLINICAL EFFECTS:  The concurrent use of propafenone with other agents that|
02110|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02110|012|E|arrhythmias, including torsades de pointes.(1)|
02110|013|B||
02110|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02110|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02110|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02110|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02110|018|P|gender, or advanced age.(3)|
02110|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02110|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02110|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02110|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02110|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02110|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02110|025|P|dysfunction).(3)|
02110|026|B||
02110|027|M|PATIENT MANAGEMENT:  The manufacturer of propafenone states that the use of|
02110|028|M|propafenone with other agents known to prolong the QT interval should be|
02110|029|M|avoided.(1)|
02110|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02110|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02110|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02110|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02110|034|B||
02110|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02110|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02110|037|D|monograph have been shown to prolong the QTc interval either through their|
02110|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02110|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
02110|040|D|clinical trials and/or postmarketing reports.(2)|
02110|041|B||
02110|042|R|REFERENCES:|
02110|043|B||
02110|044|R|1.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
02110|045|R|  Laboratories March, 2013.|1
02110|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02110|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02110|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02110|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02110|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02110|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02110|052|R|  settings: a scientific statement from the American Heart Association and|6
02110|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02110|054|R|  2;55(9):934-47.|6
02111|001|T|MONOGRAPH TITLE:  Trazodone/Saquinavir|
02111|002|B||
02111|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02111|004|L|is contraindicated and generally should not be dispensed or administered to|
02111|005|L|the same patient.|
02111|006|B||
02111|007|A|MECHANISM OF ACTION:  Saquinavir may inhibit the metabolism of trazodone by|
02111|008|A|CYP3A4.(1,2)  Trazodone has been shown to prolong the QT interval.(1)|
02111|009|B||
02111|010|E|CLINICAL EFFECTS:  Concurrent use of saquinavir may result in elevated|
02111|011|E|levels of and adverse effects from trazodone,(1,2) including nausea,|
02111|012|E|dizziness, hypotension, syncope, and cardiac arrhythmias such as QT|
02111|013|E|prolongation or torsades de pointes, which may be life-threatening.(1)|
02111|014|B||
02111|015|P|PREDISPOSING FACTORS:  This interaction may be more severe with larger|
02111|016|P|and/or routine doses of trazodone.|
02111|017|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02111|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02111|019|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02111|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02111|021|P|advanced age.(4)|
02111|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02111|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02111|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02111|025|P|drug concentrations include rapid infusion of an intravenous dose or|
02111|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02111|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02111|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02111|029|B||
02111|030|M|PATIENT MANAGEMENT:  The US manufacturer of saquinavir states that|
02111|031|M|concurrent use of trazodone is contraindicated.(1)  One US manufacturer of|
02111|032|M|trazodone recommends consideration of a lower dose of trazodone in patients|
02111|033|M|receiving potent CYP3A4 inhibitors such as a protease inhibitor.(2)|
02111|034|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02111|035|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02111|036|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02111|037|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02111|038|B||
02111|039|D|DISCUSSION:  In a study in 10 healthy subjects, short-term ritonavir (four|
02111|040|D|doses of 200 mg twice daily) increased the area-under-curve (AUC) and|
02111|041|D|half-life of a single dose of trazodone (50 mg) by 2.4-fold and 2.2-fold,|
02111|042|D|respectively.  The maximum concentration (Cmax) of trazodone increased 34%|
02111|043|D|and its clearance decreased 52%.  Three subjects experienced nausea,|
02111|044|D|dizziness, or hypotension and one of these subjects also experienced syncope|
02111|045|D|during concurrent administration.(2,3)|
02111|046|B||
02111|047|R|REFERENCES:|
02111|048|B||
02111|049|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
02111|050|R|  Laboratories, Inc. March, 2019.|1
02111|051|R|2.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
02111|052|R|  Labopharm Inc. November, 2012.|1
02111|053|R|3.Greenblatt DJ, von Moltke LL, Harmatz JS, Fogelman SM, Chen G, Graf JA,|2
02111|054|R|  Mertzanis P, Byron S, Culm KE, Granda BW, Daily JP, Shader RI. Short-term|2
02111|055|R|  exposure to low-dose ritonavir impairs clearance and enhances adverse|2
02111|056|R|  effects of trazodone. J Clin Pharmacol 2003 Apr;43(4):414-22.|2
02111|057|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02111|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02111|059|R|  settings: a scientific statement from the American Heart Association and|6
02111|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02111|061|R|  2;55(9):934-47.|6
02111|062|R|5.Zalma A, von Moltke LL, Granda BW, Harmatz JS, Shader RI, Greenblatt DJ.|5
02111|063|R|  In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and|5
02111|064|R|  human immunodeficiency viral protease inhibitors. Biol Psychiatry 2000 Apr|5
02111|065|R|  1;47(7):655-61.|5
02112|001|T|MONOGRAPH TITLE:  Dabigatran/NSAIDs; Salicylates|
02112|002|B||
02112|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02112|004|L|of severe adverse interaction.|
02112|005|B||
02112|006|A|MECHANISM OF ACTION:  Dabigatran is a direct thrombin inhibitor and when|
02112|007|A|taken with agents that effect platelet aggregation and/or other clotting|
02112|008|A|factors increased bleeding episodes can occur.(1,2)|
02112|009|B||
02112|010|E|CLINICAL EFFECTS:  Concurrent use of dabigatran with NSAIDs or salicylates|
02112|011|E|may result in additive or synergistic effects resulting in unwanted bleeding|
02112|012|E|episodes.(1)|
02112|013|B||
02112|014|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
02112|015|P|bleeding include renal impairment, concomitant use of P-glycoprotein|
02112|016|P|inhibitors, patient older than 74 years, coexisting conditions (e.g. recent|
02112|017|P|trauma, thrombocytopenia, advanced liver disease), use of drugs associated|
02112|018|P|with bleeding risk (e.g. other anticoagulants, antiplatelets,|
02112|019|P|corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or|
02112|020|P|serotonin-norepinephrine  reuptake inhibitors (SNRIs)), and patient weight|
02112|021|P|less than 50 kg. (1-3)|
02112|022|P|   Risk of GI bleed may be increased in patients who are of older age, in|
02112|023|P|poor health status, who use alcohol or smoke, with longer duration of NSAID|
02112|024|P|use, and with prior history of peptic ulcer disease and/or GI bleeding.|
02112|025|B||
02112|026|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
02112|027|M|of blood loss and promptly evaluate patients with any symptoms.  Discontinue|
02112|028|M|dabigatran in patients with active pathological bleeding.(1)|
02112|029|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02112|030|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02112|031|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02112|032|M|patients with any symptoms.|
02112|033|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02112|034|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02112|035|M|anticoagulation in patients with active pathologic bleeding.|
02112|036|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02112|037|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02112|038|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02112|039|M|and/or swelling.|
02112|040|B||
02112|041|D|DISCUSSION:  Dabigatran is a direct thrombin inhibitor and when taken with|
02112|042|D|agents that effect platelet aggregation and/or other clotting factors|
02112|043|D|increased bleeding episodes can occur.(1,2)|
02112|044|D|   A post hoc analysis of nonselective NSAIDs in the RE-LY study (compared|
02112|045|D|dabigatran 150 and 110 mg twice daily with warfarin in atrial fibrillation)|
02112|046|D|assessed clinical outcomes by comparing nonselective NSAID use (at least|
02112|047|D|once during trial) with no NSAID use in 2279 patients. The use of NSAIDs was|
02112|048|D|associated an increased risk of major bleeding (hazard ratio (HR) 1.68),|
02112|049|D|gastrointestinal major bleeding (HR 1.81), stroke or systemic embolism (HR|
02112|050|D|1.50), and hospitalization (HR 1.64).(22)|
02112|051|B||
02112|052|R|REFERENCES:|
02112|053|B||
02112|054|R|1.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
02112|055|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
02112|056|R|2.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
02112|057|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
02112|058|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
02112|059|R|  Boehringer Ingelheim March, 23 2020.|1
02112|060|R|4.Kent AP, Brueckmann M, Fraessdorf M, Connolly SJ, Yusuf S, Eikelboom JW,|2
02112|061|R|  Oldgren J, Reilly PA, Wallentin L, Ezekowitz MD. Concomitant Oral|2
02112|062|R|  Anticoagulant and Nonsteroidal Anti-Inflammatory Drug Therapy in Patients|2
02112|063|R|  With Atrial Fibrillation. J Am Coll Cardiol 2018 Jul 17;72(3):255-267.|2
02113|001|T|MONOGRAPH TITLE:  Voriconazole/Fluconazole|
02113|002|B||
02113|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02113|004|L|of severe adverse interaction.|
02113|005|B||
02113|006|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of voriconazole|
02113|007|A|by CYP2C9, 2C19, and 3A4.(1)|
02113|008|B||
02113|009|E|CLINICAL EFFECTS:  Concurrent use of fluconazole or use of voriconazole|
02113|010|E|following fluconazole therapy may result in elevated levels of and toxicity|
02113|011|E|from voriconazole.(1)|
02113|012|B||
02113|013|P|PREDISPOSING FACTORS:  None determined.|
02113|014|B||
02113|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of voriconazole and|
02113|016|M|fluconazole.  Patients switching from fluconazole to voriconazole should be|
02113|017|M|closely monitored, especially within 24 hours of the last dose of|
02113|018|M|fluconazole.(1)|
02113|019|B||
02113|020|D|DISCUSSION:  In a study in 6 healthy males, concurrent fluconazole (400 mg|
02113|021|D|Day 1, then 200 mg daily for 4 days) increased the maximum concentration|
02113|022|D|(Cmax) and area-under-curve (AUC) of voriconazole (400 mg BID Day 1, then|
02113|023|D|200 mg BID for 2.5 days) by 57% and 79%, respectively.  In a follow-up study|
02113|024|D|in 8 healthy males, reduced dosages and/or frequency of fluconazole and|
02113|025|D|voriconazole did not reduce the effects of the interaction.(1)|
02113|026|B||
02113|027|R|REFERENCE:|
02113|028|B||
02113|029|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
02114|001|T|MONOGRAPH TITLE:  Ambrisentan (Less than or Equal To 5 mg)/Cyclosporine|
02114|002|B||
02114|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02114|004|L|take action as needed.|
02114|005|B||
02114|006|A|MECHANISM OF ACTION:  Cyclosporine may inhibit the metabolism/transport of|
02114|007|A|ambrisentan by CYP3A4, OATP, and P-gp.(1,2)|
02114|008|B||
02114|009|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine may result in elevated|
02114|010|E|levels of and toxicity from ambrisentan.(1,2)|
02114|011|B||
02114|012|P|PREDISPOSING FACTORS:  None determined.|
02114|013|B||
02114|014|M|PATIENT MANAGEMENT:  Patients maintained on cyclosporine should receive a|
02114|015|M|maximum daily dose of 5 mg of ambrisentan.(1,2)|
02114|016|B||
02114|017|D|DISCUSSION:  In an open-label, parallel-treatment study, 28 healthy subjects|
02114|018|D|had ambrisentan (5 mg daily) added to steady-state cyclosporine (100-150 mg|
02114|019|D|BID) and 24 subjects had cyclosporine (100-150 mg BID) added to steady-state|
02114|020|D|ambrisentan (5 mg daily).  All drug levels were evaluated at steady-state.|
02114|021|D|Ambrisentan maximum concentration (Cmax) and area-under-curve (AUC)|
02114|022|D|increased 1.5-fold and 2-fold, respectively, in the presence of|
02114|023|D|cyclosporine.  There were no significant effects on cyclosporine levels.|
02114|024|D|The addition of ambrisentan to cyclosporine was less tolerable than the|
02114|025|D|addition of cyclosporine to ambrisentan therapy.(1,2)|
02114|026|B||
02114|027|R|REFERENCES:|
02114|028|B||
02114|029|R|1.Letairis (ambrisentran) US prescribing information. Gilead Sciences, Inc.|1
02114|030|R|  August, 2019.|1
02114|031|R|2.Spence R, Mandagere A, Richards DB, Magee MH, Dufton C, Boinpally R.|2
02114|032|R|  Potential for pharmacokinetic interactions between ambrisentan and|2
02114|033|R|  cyclosporine. Clin Pharmacol Ther 2010 Oct;88(4):513-20.|2
02115|001|T|MONOGRAPH TITLE:  Deferoxamine/Ascorbic Acid (Vitamin C)|
02115|002|B||
02115|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02115|004|L|take action as needed.|
02115|005|B||
02115|006|A|MECHANISM OF ACTION:  It is believed that ascorbic acid increases the iron|
02115|007|A|available for chelation from an labile intracellular iron pool.  Ascorbic|
02115|008|A|acid may then facilitate iron-induced oxidative tissue damage.(1)|
02115|009|B||
02115|010|E|CLINICAL EFFECTS:  Dietary ascorbic acid may increase the absorption of|
02115|011|E|dietary iron.  Supplemental ascorbic acid therapy given during chelation|
02115|012|E|therapy may improve iron output;(1-9) however, excessive dosages may result|
02115|013|E|in cardiac toxicity from iron-induced oxidative tissue damage.(1,2,11-13)|
02115|014|B||
02115|015|P|PREDISPOSING FACTORS:  None determined.|
02115|016|B||
02115|017|M|PATIENT MANAGEMENT:  Ascorbic acid intake is often restricted in patients|
02115|018|M|with iron overload; however, it has been used in conjunction with|
02115|019|M|deferoxamine to increase iron excretion.(2)|
02115|020|M|   Supplemental ascorbic acid therapy should only be initiated after one|
02115|021|M|month of deferoxamine therapy.  Ascorbic acid therapy should only be given|
02115|022|M|in patients receiving deferoxamine regularly and the dose should be given|
02115|023|M|after the infusion has started.  The dosage of ascorbic acid should be|
02115|024|M|limited to 50 mg daily in children under 10 years of age; 100 mg daily in|
02115|025|M|older children; and 200 mg daily, in divided doses, in adults.(2)|
02115|026|M|   Cardiac function should be monitored in patients receiving concurrent|
02115|027|M|therapy.  Discontinue ascorbic acid therapy in patients who develop cardiac|
02115|028|M|dysfunction.(2)|
02115|029|B||
02115|030|D|DISCUSSION:  Supplemental ascorbic acid therapy given during chelation|
02115|031|D|therapy has been shown to improve iron output,(1-9) possibly by increasing|
02115|032|D|iron available for chelation from an labile intracellular iron pool.(1)|
02115|033|D|However, dosages in excess of 500 mg daily have been associated with cardiac|
02115|034|D|dysfunction.(1,2,11-13)|
02115|035|B||
02115|036|R|REFERENCES:|
02115|037|B||
02115|038|R|1.Roeser HP. The role of ascorbic acid in the turnover of storage iron.|6
02115|039|R|  Semin Hematol 1983 Apr;20(2):91-100.|6
02115|040|R|2.Desferal (deferoxamine mesylate) US prescribing information. Novartis|1
02115|041|R|  Pharmaceuticals Corporation December, 2011.|1
02115|042|R|3.Nienhuis AW, Delea C, Aamodt R, Bartter F, Anderson WF. Evaluation of|2
02115|043|R|  desferrioxamine and ascorbic acid for the treatment of chronic iron|2
02115|044|R|  overload. Birth Defects Orig Artic Ser 1976;12(8):177-85.|2
02115|045|R|4.O'Brien RT. Ascorbic acid enhancement of desferrioxamine-induced urinary|2
02115|046|R|  iron excretion in thalassemia major. Ann N Y Acad Sci 1974;232(0):221-5.|2
02115|047|R|5.Hussain MA, Green N, Flynn DM, Hoffbrand AV. Effect of dose, time, and|2
02115|048|R|  ascorbate on iron excretion after subcutaneous desferrioxamine. Lancet|2
02115|049|R|  1977 May 7;1(8019):977-9.|2
02115|050|R|6.Conte D, Brunelli L, Ferrario L, Mandelli C, Quatrini M, Velio P, Bianchi|2
02115|051|R|  PA. Effect of ascorbic acid on desferrioxamine-induced urinary iron|2
02115|052|R|  excretion in idiopathic hemochromatosis. Acta Haematol 1984;72(2):117-20.|2
02115|053|R|7.Ambruso DR, Mahony BS, Githens JH, Rhoades ED. Effect of subcutaneous|2
02115|054|R|  deferoxamine and oral vitamin C on iron excretion in congenital|2
02115|055|R|  hypoplastic anemia and refractory anemia associated with the 5q-syndrome.|2
02115|056|R|  Am J Pediatr Hematol Oncol 1982 Summer;4(2):115-23.|2
02115|057|R|8.Wapnick AA, Lynch SR, Charlton RW, Seftel HC, Bothwell TH. The effect of|2
02115|058|R|  ascorbic acid deficiency on desferrioxamine-induced urinary iron|2
02115|059|R|  excretion. Br J Haematol 1969 Dec;17(6):563-8.|2
02115|060|R|9.Cohen A, Schwartz E. Iron chelation therapy with deferoxamine in Cooley|2
02115|061|R|  anemia. J Pediatr 1978 Apr;92(4):643-7.|2
02115|062|R|10.Thalassemia major: molecular and clinical aspects. NIH Conference. Ann|4
02115|063|R|   Intern Med 1979 Dec;91(6):883-97.|4
02115|064|R|11.McLaran CJ, Bett JH, Nye JA, Halliday JW. Congestive cardiomyopathy and|3
02115|065|R|   haemochromatosis--rapid progression possibly accelerated by excessive|3
02115|066|R|   ingestion of ascorbic acid. Aust N Z J Med 1982 Apr;12(2):187-8.|3
02115|067|R|12.Rowbotham B, Roeser HP. Iron overload associated with congenital pyruvate|3
02115|068|R|   kinase deficiency and high dose ascorbic acid ingestion. Aust N Z J Med|3
02115|069|R|   1984 Oct;14(5):667-9.|3
02115|070|R|13.Schafer AI, Rabinowe S, Le Boff MS, Bridges K, Cheron RG, Dluhy R.|2
02115|071|R|   Long-term efficacy of deferoxamine iron chelation therapy in adults with|2
02115|072|R|   acquired transfusional iron overload. Arch Intern Med 1985 Jul;|2
02115|073|R|   145(7):1217-21.|2
02116|001|T|MONOGRAPH TITLE:  Gadofosveset/Possible QT Prolonging Agents|
02116|002|B||
02116|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02116|004|L|take action as needed.|
02116|005|B||
02116|006|A|MECHANISM OF ACTION:  QT prolongation has been reported following|
02116|007|A|gadofosveset administration.  Concurrent use with other agents that prolong|
02116|008|A|the QTc interval may result in additive effects on the QTc interval.(1)|
02116|009|B||
02116|010|E|CLINICAL EFFECTS:  The use of gadofosveset in patients maintained on agents|
02116|011|E|that prolong the QTc interval may result in potentially life-threatening|
02116|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02116|013|B||
02116|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02116|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02116|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02116|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02116|018|P|gender, or advanced age.(2)|
02116|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02116|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02116|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02116|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02116|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02116|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02116|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02116|026|B||
02116|027|M|PATIENT MANAGEMENT:  In patients maintained on agents known to prolong the|
02116|028|M|QT interval, consider a baseline ECG prior to administration of gadofosveset|
02116|029|M|to asses the risk/benefit of gadofosveset.  If gadofosveset is used,|
02116|030|M|consider ECG monitoring for 72 hours until the majority of gadofosveset is|
02116|031|M|eliminated.  Consider obtaining serum calcium, magnesium, and potassium|
02116|032|M|levels and correct any electrolyte abnormalities.  Counsel patients to|
02116|033|M|report any irregular heartbeat, dizziness, or fainting episodes during this|
02116|034|M|time frame.(1)|
02116|035|B||
02116|036|D|DISCUSSION:  In clinical trials, 6% of patients experienced an increase in|
02116|037|D|QTc of 30 msec to 60 msec 45 minutes after the administration of|
02116|038|D|gadofosveset and 0.4% of patients experienced a QTc increase of greater than|
02116|039|D|60 msec at 45 minutes post-administration.(1)|
02116|040|D|   Agents that are linked to this monograph may have varying degrees of|
02116|041|D|potential to prolong the QTc interval but are generally accepted to have a|
02116|042|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02116|043|D|been shown to prolong the QTc interval either through their mechanism of|
02116|044|D|action, through studies on their effects on the QTc interval, or through|
02116|045|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02116|046|D|and/or post-marketing reports.(3)|
02116|047|B||
02116|048|R|REFERENCES:|
02116|049|B||
02116|050|R|1.Ablavar (gadofosveset trisodium) US prescribing information. Lantheus|1
02116|051|R|  Medical Imaging, Inc. August, 2013.|1
02116|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02116|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02116|054|R|  settings: a scientific statement from the American Heart Association and|6
02116|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02116|056|R|  2;55(9):934-47.|6
02116|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02116|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02116|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02116|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02117|001|T|MONOGRAPH TITLE:  Gabapentinoids/Opioids (IR & ER)|
02117|002|B||
02117|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02117|004|L|take action as needed.|
02117|005|B||
02117|006|A|MECHANISM OF ACTION:  Opioid-induced reduction in GI motility may increase|
02117|007|A|the absorption of gabapentin and pregabalin.(1)  Gabapentin and pregabalin|
02117|008|A|may reverse opioid-induced tolerance of respiratory depression.(2)|
02117|009|A|Concurrent use may result in profound sedation, respiratory depression,|
02117|010|A|coma, and/or death.(3)|
02117|011|B||
02117|012|E|CLINICAL EFFECTS:  Concurrent use of opioids may result in elevated levels|
02117|013|E|of and toxicity from gabapentin and pregabalin, including profound sedation,|
02117|014|E|respiratory depression, coma, and/or death.(1-7)|
02117|015|B||
02117|016|P|PREDISPOSING FACTORS:  Patients who are elderly, are taking other CNS|
02117|017|P|depressants, have decreased renal function, and/or have conditions that|
02117|018|P|reduce lung function (e.g. Chronic Obstructive Pulmonary Disease [COPD]) may|
02117|019|P|be at a higher risk of this interaction.|
02117|020|B||
02117|021|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics and gabapentinoids|
02117|022|M|to patients for whom alternatives are ineffective, not tolerated, or would|
02117|023|M|be otherwise inadequate to provide sufficient management of pain.(1)|
02117|024|M|   If concurrent use is necessary, limit the dosages and duration of each|
02117|025|M|drug to the minimum possible while achieving the desired clinical effect.|
02117|026|M|If starting a gabapentinoid with an opioid analgesic, prescribe a lower|
02117|027|M|initial dose of the gabapentinoid than indicated in the absence of an opioid|
02117|028|M|and titrate based upon clinical response.  If an opioid analgesic is|
02117|029|M|indicated in a patient already taking a gabapentinoid, prescribe a lower|
02117|030|M|dose of the opioid and titrate based upon clinical response.(1)|
02117|031|M|   Respiratory depression can occur at any time during opioid therapy,|
02117|032|M|especially during therapy initiation and following dosage increases.  The|
02117|033|M|risk of opioid-related overdose or overdose-related death is increased with|
02117|034|M|higher opioid doses, and this risk persists over the course of therapy.|
02117|035|M|Consider these risks when using concurrently with other agents that may|
02117|036|M|cause CNS depression.(8)|
02117|037|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02117|038|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02117|039|M|unresponsiveness.(1)|
02117|040|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02117|041|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02117|042|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02117|043|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02117|044|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02117|045|M|as those taking CNS depressants) and when a patient has household|
02117|046|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02117|047|M|for obtaining an opioid reversal agent (e.g., prescription,|
02117|048|M|over-the-counter, or as part of a community-based program).(9)|
02117|049|B||
02117|050|D|DISCUSSION:  In a study in 12 healthy males, administration of a single dose|
02117|051|D|of morphine (60 mg sustained release) increased the area-under-curve (AUC)|
02117|052|D|of a single dose of gabapentin (600 mg) by 44%.(1,3,4)  There were no|
02117|053|D|affects on the pharmacokinetics of morphine.(1,3,4)  The combination of|
02117|054|D|gabapentin plus morphine increased pain tolerance over the combination of|
02117|055|D|morphine plus placebo.  Side effects were not significantly different|
02117|056|D|between morphine plus placebo and morphine plus gabapentin.(1)|
02117|057|D|   A retrospective, case-control study of opioid users in Ontario, Canada|
02117|058|D|between August 1, 1997 and December 31, 2013 who died of an opioid-related|
02117|059|D|cause matched cases to up to 4 controls who also used opioids.  Use of|
02117|060|D|gabapentin in the 120 days prior to death resulted in a significant increase|
02117|061|D|in odds of opioid-related death (OR 1.99, CI=1.61-2.47, p<0.001), compared|
02117|062|D|to opioid use alone.  Use of moderate dose (900 mg to 1,799 mg daily) or|
02117|063|D|high dose (>= 1,800 mg daily) gabapentin increased the odds of|
02117|064|D|opioid-related death 60% compared to opioid use without gabapentin.  Review|
02117|065|D|of gabapentin prescriptions from calendar year 2013 found that 46% of|
02117|066|D|gabapentin users received at least 1 opioid prescription.(3)|
02117|067|D|   Among 49 case reports submitted to FDA over a 5 year period (2012-2017),|
02117|068|D|12 people died from respiratory depression with gabapentinoids. Two|
02117|069|D|randomized, double-blind, placebo-controlled clinical trials in healthy|
02117|070|D|people, three observational studies, and several studies in animals were|
02117|071|D|reviewed. A trial showed that using pregabalin alone and using it with an|
02117|072|D|opioid pain reliever can depress breathing function. Three observational|
02117|073|D|studies showed a relationship between gabapentinoids given before surgery|
02117|074|D|and respiratory depression occurring after surgery. Several animal studies|
02117|075|D|also showed that pregabalin plus opioids can depress respiratory|
02117|076|D|function.(7)|
02117|077|D|   A retrospective cohort study evaluated the risk of mortality among|
02117|078|D|Medicare beneficiaries aged 65 and older who were taking gabapentin with or|
02117|079|D|without concurrent use of opioids.  All-cause mortality in gabapentin users|
02117|080|D|compared to duloxetine users was 12.16 per 1,000 person years vs. 9.94 per|
02117|081|D|1,000 person years, respectively.  Adjusted for covariates, the risk of|
02117|082|D|all-cause mortality among gabapentin users on high-dose opioids was more|
02117|083|D|than double the control group (hazard ratio (HR) 2.03, CI=1.19-3.46).(10)|
02117|084|B||
02117|085|R|REFERENCES:|
02117|086|B||
02117|087|R|1.Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin|2
02117|088|R|  enhances the analgesic effect of morphine in healthy volunteers. Anesth|2
02117|089|R|  Analg 2000 Jul;91(1):185-91.|2
02117|090|R|2.FDA (US Food and Drug Administration). FDA MedWatch Safety Alert: FDA|6
02117|091|R|  warns about serious breathing problems with seizure and nerve pain|6
02117|092|R|  medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin|6
02117|093|R|  (Lyrica). Available at:|6
02117|094|R|  https://www.fda.gov/drugs/drug-safety-and-availability Dec19, 2019.|6
02117|095|R|3.Hill R, Dewey WL, Kelly E, Henderson G. Oxycodone-induced tolerance to|5
02117|096|R|  respiratory depression: reversal by ethanol,  pregabalin and protein|5
02117|097|R|  kinase C inhibition. Br J Pharmacol 2018 Jun;175(12):2492-2503.|5
02117|098|R|4.Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink|2
02117|099|R|  W. Gabapentin, opioids, and the risk of opioid-related death: A|2
02117|100|R|  population-based nested case-control study. PLoS Med 2017 Oct;|2
02117|101|R|  14(10):e1002396.|2
02117|102|R|5.Neurontin (gabapentin) US prescribing information. Pfizer, Inc. December,|1
02117|103|R|  2020.|1
02117|104|R|6.Gralise (gabapentin) US prescribing information. Abbott Laboratories|1
02117|105|R|  August, 2012.|1
02117|106|R|7.Health Canada. Health Canada MedEffect e-Notice: Health Canada advises|6
02117|107|R|  Canadians to exercise caution when taking gabapentin or pregabalin with|6
02117|108|R|  opioids. available at:|6
02117|109|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/71003a-e|6
02117|110|R|  ng.php Sept 17, 2019.|6
02117|111|R|8.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02117|112|R|  prescribing information for all opioid pain medicines to provide|1
02117|113|R|  additional guidance for safe use. Available at:|1
02117|114|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02117|115|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02117|116|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02117|117|R|9.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02117|118|R|  recommends health care professionals discuss naloxone with all patients|1
02117|119|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02117|120|R|  disorder. Available at:|1
02117|121|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02117|122|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02117|123|R|  d-pain July 23, 2020.|1
02117|124|R|10.Corriere MA, Daniel LL, Dickson AL, Nepal P, Hall K, Plummer WD, Dupont|2
02117|125|R|   WD, Murray KT, Stein CM, Ray WA, Chung CP. Concurrent Gabapentin and|2
02117|126|R|   Opioid Use and Risk of Mortality in Medicare Recipients  with Non-Cancer|2
02117|127|R|   Pain. Clin Pharmacol Ther 2023 Aug 7.|2
02118|001|T|MONOGRAPH TITLE:  Selected Live Viral Vaccines/Rho Immunoglobulin|
02118|002|B||
02118|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02118|004|L|is contraindicated and generally should not be dispensed or administered to|
02118|005|L|the same patient.|
02118|006|B||
02118|007|A|MECHANISM OF ACTION:  Immune globulin products may prevent the immune system|
02118|008|A|from properly responding to the vaccine.(1-6)|
02118|009|B||
02118|010|E|CLINICAL EFFECTS:  Administration of a live viral vaccine after|
02118|011|E|immunoglobulins may impair the efficacy of the vaccine.(1-6)|
02118|012|E|   Administration of immunoglobulins within 2-4 weeks after a live viral|
02118|013|E|vaccine impair the efficacy of the vaccine.(1-6)|
02118|014|B||
02118|015|P|PREDISPOSING FACTORS:  None determined.|
02118|016|B||
02118|017|M|PATIENT MANAGEMENT:  Administration of a live viral vaccine should be|
02118|018|M|postponed for three months in patients who have received immunoglobulin|
02118|019|M|therapy, including Rho immunoglobulin.(1-6)|
02118|020|M|   If a live viral vaccine is given within two to four weeks of rho|
02118|021|M|immunoglobulin, then repeat vaccination three months after the completion of|
02118|022|M|immunoglobulin should be considered.(2-4)|
02118|023|B||
02118|024|D|DISCUSSION:  Administration of a live viral vaccine after|
02118|025|D|immunoglobulins(1-6) or administration of immunoglobulins after a live|
02118|026|D|vaccine(3) may impair the efficacy of the vaccine.|
02118|027|B||
02118|028|R|REFERENCES:|
02118|029|B||
02118|030|R|1.WinRho SDF (anti-D (Rho) immunoglobulin (human)) Australian prescribing|1
02118|031|R|  information. CSL August 30, 2002.|1
02118|032|R|2.Rhophylac (human immunoglobulin anti-D (Rh)) UK prescribing information.|1
02118|033|R|  ZLB Bioplasma UK Limited December 19, 2003.|1
02118|034|R|3.Rhophylac (Rho human immune globlin) US prescribing information. ZLB|1
02118|035|R|  Bioplasma Inc. January, 2004.|1
02118|036|R|4.Bayrho-D (immune globulin, Rho(D) human) Canadian prescribing information.|1
02118|037|R|  Bayer 2004.|1
02118|038|R|5.WinRho SDF (Rho(D) immune globulin intravenous (human)) US prescribing|1
02118|039|R|  information. Baxter Healthcare Corporation December, 2005.|1
02118|040|R|6.RhoGAM (Rho immune globulin human) US prescribing information.|1
02118|041|R|  Ortho-Clinical Diagnostics, Inc. November, 2012.|1
02119|001|T|MONOGRAPH TITLE:  Rubella Vaccine/Rho Immunoglobulin|
02119|002|B||
02119|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02119|004|L|take action as needed.|
02119|005|B||
02119|006|A|MECHANISM OF ACTION:  Immune globulin products may prevent the immune system|
02119|007|A|from properly responding to the vaccine.(1-6)|
02119|008|B||
02119|009|E|CLINICAL EFFECTS:  Administration of live rubella vaccine after|
02119|010|E|immunoglobulins may impair the efficacy of the vaccine.(1-6)|
02119|011|E|   Administration of immunoglobulins within 2-4 weeks after a live viral|
02119|012|E|vaccine impair the efficacy of the vaccine.(1-6)|
02119|013|B||
02119|014|P|PREDISPOSING FACTORS:  The amount of antigen-specific antibody present in|
02119|015|P|the administered immunoglobulin product determines the duration of the|
02119|016|P|interaction.(7)|
02119|017|B||
02119|018|M|PATIENT MANAGEMENT:  Due to the importance of rubella immunity in women of|
02119|019|M|child-bearing age, and the low dose of anti-Rho immunoglobulin administered,|
02119|020|M|postpartum vaccination of rubella-susceptible women with rubella or MMR|
02119|021|M|should not be delayed.(7) CDC recommendations state the low dose of anti-Rho|
02119|022|M|globulin administered to postpartum women has not been demonstrated to|
02119|023|M|reduce the response to the RA27/3 strain of rubella vaccine.(7)  Vaccination|
02119|024|M|should be performed immediately after delivery.  If possible, test for|
02119|025|M|immune response to rubella and measles three or more months after|
02119|026|M|vaccination and repeat the vaccine if necessary.(6,7)|
02119|027|M|   Administration of live rubella vaccine should be postponed for 3 to 11|
02119|028|M|months in patients who have received other types of immunoglobulin|
02119|029|M|therapy.(1-7)|
02119|030|M|   If live rubella vaccine is given and administration of an immune globulin|
02119|031|M|becomes necessary within 14 days, vaccination should be repeated unless|
02119|032|M|serologic testing indicates a protective antibody response.(7)|
02119|033|B||
02119|034|D|DISCUSSION:  CDC Immunization Recommendations(7) provide discussions,|
02119|035|D|charts, and further details regarding appropriate use and timing of vaccine|
02119|036|D|therapy.|
02119|037|B||
02119|038|R|REFERENCES:|
02119|039|B||
02119|040|R|1.WinRho SDF (anti-D (Rho) immunoglobulin (human)) Australian prescribing|1
02119|041|R|  information. CSL August 30, 2002.|1
02119|042|R|2.Rhophylac (human immunoglobulin anti-D (Rh)) UK prescribing information.|1
02119|043|R|  ZLB Bioplasma UK Limited December 19, 2003.|1
02119|044|R|3.Rhophylac (Rho human immune globlin) US prescribing information. ZLB|1
02119|045|R|  Bioplasma Inc. January, 2004.|1
02119|046|R|4.Bayrho-D (immune globulin, Rho(D) human) Canadian prescribing information.|1
02119|047|R|  Bayer 2004.|1
02119|048|R|5.WinRho SDF (Rho(D) immune globulin intravenous (human)) US prescribing|1
02119|049|R|  information. Baxter Healthcare Corporation December, 2005.|1
02119|050|R|6.RhoGAM (Rho immune globulin human) US prescribing information.|1
02119|051|R|  Ortho-Clinical Diagnostics, Inc. November, 2012.|1
02119|052|R|7.Centers for Disease Control and Prevention. General Recommendations on|1
02119|053|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
02119|054|R|  Practices (ACIP). MMWR.  Available at:|1
02119|055|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
02119|056|R|  February 17, 2022;60(RR No.2):1-68.|1
02120|001|T|MONOGRAPH TITLE:  Moxifloxacin/QT Prolonging Agents|
02120|002|B||
02120|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02120|004|L|of severe adverse interaction.|
02120|005|B||
02120|006|A|MECHANISM OF ACTION:  Moxifloxacin has been shown to prolong the QTc|
02120|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02120|008|A|may result in additive effects on the QTc interval.(1)|
02120|009|B||
02120|010|E|CLINICAL EFFECTS:  The concurrent use of moxifloxacin with other agents that|
02120|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02120|012|E|arrhythmias, including torsades de pointes.(1)|
02120|013|B||
02120|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02120|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02120|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02120|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02120|018|P|gender, or advanced age.(3)|
02120|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02120|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02120|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02120|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02120|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02120|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02120|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02120|026|B||
02120|027|M|PATIENT MANAGEMENT:  The manufacturer of moxifloxacin states that|
02120|028|M|moxifloxacin should avoided in patients receiving agents known to prolong|
02120|029|M|the QT interval.(1)|
02120|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02120|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02120|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02120|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02120|034|B||
02120|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02120|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02120|037|D|monograph have been shown to prolong the QTc interval either through their|
02120|038|D|mechanism of action, through studies on their effects on the QTC interval,|
02120|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
02120|040|D|clinical trials and/or postmarketing reports.(2)|
02120|041|D|   One or more of the drug pairs linked to this monograph have been included|
02120|042|D|in a list of interactions that should be considered "high-priority" for|
02120|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02120|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02120|045|D|Coordinator (ONC) for Health Information Technology.|
02120|046|B||
02120|047|R|REFERENCES:|
02120|048|B||
02120|049|R|1.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
02120|050|R|  Pharmaceuticals Corporation October 18, 2018.|1
02120|051|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02120|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02120|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02120|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02120|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02120|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02120|057|R|  settings: a scientific statement from the American Heart Association and|6
02120|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02120|059|R|  2;55(9):934-47.|6
02120|060|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02120|061|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02120|062|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02120|063|R|  19(5):735-43.|6
02121|001|T|MONOGRAPH TITLE:  Ketorolac (Injectable)/NSAID;Aspirin (Injectable)|
02121|002|B||
02121|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02121|004|L|is contraindicated and generally should not be dispensed or administered to|
02121|005|L|the same patient.|
02121|006|B||
02121|007|A|MECHANISM OF ACTION:  Possible additive or synergistic side effects.(1)|
02121|008|B||
02121|009|E|CLINICAL EFFECTS:  Concurrent use of multiple dose of ketorolac with other|
02121|010|E|non-steroidal anti-inflammatory agents (NSAIDs) or aspirin may result in an|
02121|011|E|increase in NSAID-related side effects.(1)|
02121|012|B||
02121|013|P|PREDISPOSING FACTORS:  Patients with pre-existing renal impairment may be at|
02121|014|P|an increased risk of adverse effects from this interaction.|
02121|015|P|The risk for bleeding episodes may be greater in patients with multiple|
02121|016|P|disease-associated factors (e.g. thrombocytopenia, advanced liver disease).|
02121|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
02121|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02121|019|P|risk for bleeding (e.g., anticoagulants, antiplatelets, corticosteroids,|
02121|020|P|selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine|
02121|021|P|reuptake inhibitors (SNRIs).|
02121|022|P|   Risk of GI bleed may be increased in patients who are of older age, in|
02121|023|P|poor health status, or who use alcohol or smoke. Risk may also be increased|
02121|024|P|with longer duration of NSAID use and prior history of peptic ulcer disease|
02121|025|P|and/or GI bleeding.|
02121|026|B||
02121|027|M|PATIENT MANAGEMENT:  The manufacturer of ketorolac states that concurrent|
02121|028|M|use of ketorolac with either other NSAIDs or aspirin is contraindicated.(1)|
02121|029|B||
02121|030|D|DISCUSSION:  There is no clinical documentation to support this interaction.|
02121|031|D|The manufacturer of ketorolac states that as a result of the cumulative|
02121|032|D|risks of inducing serious NSAID-related adverse events, the concurrent|
02121|033|D|administration of ketorolac with other NSAIDs or aspirin is|
02121|034|D|contraindicated.(1)|
02121|035|B||
02121|036|R|REFERENCE:|
02121|037|B||
02121|038|R|1.Toradol (ketorolac tromethamine) US prescribing information. Roche|1
02121|039|R|  Pharmaceuticals March, 2013.|1
02122|001|T|MONOGRAPH TITLE:  Vandetanib/QT Prolonging Agents|
02122|002|B||
02122|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02122|004|L|of severe adverse interaction.|
02122|005|B||
02122|006|A|MECHANISM OF ACTION:  Vandetanib has been shown to prolong the QTc interval.|
02122|007|A|Concurrent use with other agents that prolong the QTc interval may result|
02122|008|A|in additive effects on the QTc interval.(1)|
02122|009|B||
02122|010|E|CLINICAL EFFECTS:  The concurrent use of vandetanib with other agents that|
02122|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02122|012|E|arrhythmias, including torsades de pointes.(1)|
02122|013|B||
02122|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02122|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02122|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02122|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02122|018|P|gender, or advanced age.(3)|
02122|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02122|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02122|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02122|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02122|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02122|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02122|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02122|026|B||
02122|027|M|PATIENT MANAGEMENT:  The manufacturer of vandetanib states that the use of|
02122|028|M|vandetanib with other agents known to prolong the QT interval should be|
02122|029|M|avoided.(1)|
02122|030|M|   The manufacturer of vandetanib states therapy should be interrupted if|
02122|031|M|Corrected QT interval, Frederica (QTcF) is greater than 500 ms; resume at a|
02122|032|M|reduced dose when the QTcF returns to less than 450 ms.  Consult current|
02122|033|M|prescribing information for further details.(1)|
02122|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02122|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02122|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02122|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02122|038|B||
02122|039|D|DISCUSSION:  Vandetanib has been shown to prolong the QTc interval in a|
02122|040|D|dose-dependent manner.  Vandetanib has a long half-life (19 days) and|
02122|041|D|effects on the QTc interval may not resolve quickly following vandetanib|
02122|042|D|discontinuation.(1)|
02122|043|D|   A retrospective review of 618 cancer patients treated with 902|
02122|044|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02122|045|D|incidence of QTc prolongation.  In patients who received vandetanib, QTc|
02122|046|D|prolongation was identified in 4 (80%) with 0 (0%) having Grade 1 (QTc|
02122|047|D|450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
02122|048|D|occurred in 1 (25%) having QTc greater than or equal to 500 ms and 2 (50%)|
02122|049|D|having QTc change greater than or equal to 60 ms.  No patients had|
02122|050|D|ventricular tachycardia, sudden cardiac death, or TdP.(4)|
02122|051|D|   Agents that are linked to this monograph may have varying degrees of|
02122|052|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02122|053|D|been shown to prolong the QTc interval either through their mechanism of|
02122|054|D|action, through studies on their effects on the QTc interval, or through|
02122|055|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02122|056|D|and/or postmarketing reports.(2)|
02122|057|D|   One or more of the drug pairs linked to this monograph have been included|
02122|058|D|in a list of interactions that should be considered "high-priority" for|
02122|059|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02122|060|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02122|061|D|Coordinator (ONC) for Health Information Technology.|
02122|062|B||
02122|063|R|REFERENCES:|
02122|064|B||
02122|065|R|1.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
02122|066|R|  Pharmaceuticals LP October, 2018.|1
02122|067|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02122|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02122|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02122|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02122|071|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02122|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02122|073|R|  settings: a scientific statement from the American Heart Association and|6
02122|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02122|075|R|  2;55(9):934-47.|6
02122|076|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02122|077|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02122|078|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02122|079|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02122|080|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02122|081|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02122|082|R|  19(5):735-43.|6
02123|001|T|MONOGRAPH TITLE:  Vandetanib/Possible QT Prolonging Agents|
02123|002|B||
02123|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02123|004|L|take action as needed.|
02123|005|B||
02123|006|A|MECHANISM OF ACTION:  Vandetanib has been shown to prolong the QTc interval.|
02123|007|A|Concurrent use with other agents that prolong the QTc interval may result|
02123|008|A|in additive effects on the QTc interval.(1)|
02123|009|B||
02123|010|E|CLINICAL EFFECTS:  The concurrent use of vandetanib with other agents that|
02123|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02123|012|E|arrhythmias, including torsades de pointes.(1)|
02123|013|B||
02123|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02123|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02123|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02123|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02123|018|P|gender, or advanced age.(3)|
02123|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02123|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02123|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02123|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02123|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02123|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02123|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02123|026|B||
02123|027|M|PATIENT MANAGEMENT:  The manufacturer of vandetanib states that the use of|
02123|028|M|vandetanib with other agents known to prolong the QT interval should be|
02123|029|M|avoided.(1)|
02123|030|M|   The manufacturer of vandetanib states therapy should be interrupted if|
02123|031|M|Corrected QT interval, Frederica (QTcF) is greater than 500 ms; resume at a|
02123|032|M|reduced dose when the QTcF returns to less than 450 ms.  Consult current|
02123|033|M|prescribing information for further details.(1)|
02123|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02123|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02123|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02123|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02123|038|B||
02123|039|D|DISCUSSION:  Vandetanib has been shown to prolong the QTc interval in a|
02123|040|D|dose-dependent manner.  Vandetanib has a long half-life (19 days) and|
02123|041|D|effects on the QTc interval may not resolve quickly following vandetanib|
02123|042|D|discontinuation.(1)|
02123|043|D|   A retrospective review of 618 cancer patients treated with 902|
02123|044|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02123|045|D|incidence of QTc prolongation.  In patients who received vandetanib, QTc|
02123|046|D|prolongation was identified in 4 (80%) with 0 (0%) having Grade 1 (QTc|
02123|047|D|450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
02123|048|D|occurred in 1 (25%) having QTc greater than or equal to 500 ms and 2 (50%)|
02123|049|D|having QTc change greater than or equal to 60 ms.  No patients had|
02123|050|D|ventricular tachycardia, sudden cardiac death, or TdP.(4)|
02123|051|D|   Agents that are linked to this monograph may have varying degrees of|
02123|052|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02123|053|D|been shown to prolong the QTc interval either through their mechanism of|
02123|054|D|action, through studies on their effects on the QTc interval, or through|
02123|055|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02123|056|D|and/or postmarketing reports.(2)|
02123|057|D|   One or more of the drug pairs linked to this monograph have been included|
02123|058|D|in a list of interactions that should be considered "high-priority" for|
02123|059|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02123|060|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02123|061|D|Coordinator (ONC) for Health Information Technology.|
02123|062|B||
02123|063|R|REFERENCES:|
02123|064|B||
02123|065|R|1.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
02123|066|R|  Pharmaceuticals LP October, 2018.|1
02123|067|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02123|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02123|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02123|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02123|071|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02123|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02123|073|R|  settings: a scientific statement from the American Heart Association and|6
02123|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02123|075|R|  2;55(9):934-47.|6
02123|076|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02123|077|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02123|078|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02123|079|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02123|080|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02123|081|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02123|082|R|  19(5):735-43.|6
02124|001|T|MONOGRAPH TITLE:  Thioridazine/Abiraterone|
02124|002|B||
02124|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02124|004|L|of severe adverse interaction.|
02124|005|B||
02124|006|A|MECHANISM OF ACTION:  Abiraterone may inhibit the metabolism of thioridazine|
02124|007|A|by CYP2D6.(1)|
02124|008|B||
02124|009|E|CLINICAL EFFECTS:  Concurrent use of abiraterone may result in elevated|
02124|010|E|levels of and toxicity from thioridazine, including potentially|
02124|011|E|life-threatening cardiac arrhythmias such as torsades de pointes.(1)|
02124|012|B||
02124|013|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers may|
02124|014|P|be affected to a greater extent by CYP2D6 inhibitors.  Patients who are|
02124|015|P|CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6|
02124|016|P|inhibition.|
02124|017|P|   The risk of QT prolongation or torsade de pointes may be increased in|
02124|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02124|019|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02124|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02124|021|P|advanced age.(2)|
02124|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02124|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02124|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02124|025|P|drug concentrations include rapid infusion of an intravenous dose or|
02124|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02124|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02124|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02124|029|P|   The risk of anticholinergic toxicities including cognitive decline,|
02124|030|P|delirium, falls and fractures is increased in geriatric patients using more|
02124|031|P|than one medicine with anticholinergic properties.(3)|
02124|032|B||
02124|033|M|PATIENT MANAGEMENT:  The US manufacturer of abiraterone states that|
02124|034|M|concurrent use of CYP2D6 substrates with narrow therapeutic indexes such as|
02124|035|M|thioridazine should be avoided.  If concurrent use is warranted, consider|
02124|036|M|decreasing the dose of thioridazine.(1)  Additionally, consider obtaining|
02124|037|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02124|038|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02124|039|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02124|040|M|fainting.|
02124|041|B||
02124|042|D|DISCUSSION:  Concurrent abiraterone increased the area-under-curve (AUC) and|
02124|043|D|maximum concentration (Cmax) of dextromethorphan (another CYP2D6 substrate)|
02124|044|D|by 2.9-fold and 2.8-fold, respectively.(1)|
02124|045|B||
02124|046|R|REFERENCES:|
02124|047|B||
02124|048|R|1.Zytiga (abiraterone acetate) US prescribing information. Centocor Ortho|1
02124|049|R|  Biotech, Inc. October, 2020.|1
02124|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02124|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02124|052|R|  settings: a scientific statement from the American Heart Association and|6
02124|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02124|054|R|  2;55(9):934-47.|6
02124|055|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02124|056|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02124|057|R|  Soc 2023 Jul;71(7):2052-2081.|6
02125|001|T|MONOGRAPH TITLE:  Linagliptin/Strong P-gp or CYP3A4 Inducer|
02125|002|B||
02125|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02125|004|L|of severe adverse interaction.|
02125|005|B||
02125|006|A|MECHANISM OF ACTION:  Strong P-gp or CYP3A4 inducers may increase the|
02125|007|A|metabolism of linagliptin.(1)|
02125|008|B||
02125|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong P-gp or CYP3A4|
02125|010|E|inducers may result in decreased levels and effectiveness of linagliptin.(1)|
02125|011|B||
02125|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02125|013|P|of the inducer for longer than 1-2 weeks.|
02125|014|B||
02125|015|M|PATIENT MANAGEMENT:  If possible, use an alternative agent to strong P-gp or|
02125|016|M|CYP3A4 inducers in patients maintained on linagliptin.  If concurrent|
02125|017|M|therapy is required, patients may need adjustment to their diabetes therapy,|
02125|018|M|including replacement of linagliptin.(1)|
02125|019|B||
02125|020|D|DISCUSSION:  Concurrent rifampin (600 mg daily) decreased the|
02125|021|D|area-under-curve (AUC) and maximum concentration (Cmax) of linagliptin (5 mg|
02125|022|D|daily) by 40% and 44%, respectively.(1)|
02125|023|D|   Strong P-gp or CYP3A4 inducers linked to this monograph include:|
02125|024|D|apalutamide, barbiturates, carbamazepine, efavirenz, encorafenib,|
02125|025|D|enzalutamide, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mitotane,|
02125|026|D|phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and|
02125|027|D|St. John's wort.(2)|
02125|028|B||
02125|029|R|REFERENCES:|
02125|030|B||
02125|031|R|1.Tradjenta (linagliptin) US prescribing information. Boehringer Ingelheim|1
02125|032|R|  International GmbH April, 2022.|1
02125|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
02125|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02126|001|T|MONOGRAPH TITLE:  Metoclopramide/Antipsychotics; Phenothiazines;|
02126|002|T|Rivastigmine|
02126|003|B||
02126|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02126|005|L|of severe adverse interaction.|
02126|006|B||
02126|007|A|MECHANISM OF ACTION:  These agents block dopamine (D2) receptors. D2|
02126|008|A|blockade can cause extrapyramidal reactions, such acute dystonic reactions,|
02126|009|A|pseudoparkinsonian tremors, akathisia, or tardive dyskinesia. Neuroleptic|
02126|010|A|malignant syndrome may also occur in patients receiving D2 blockers.  The|
02126|011|A|risk of these adverse effects may be increased by concurrent use.(1-3)|
02126|012|B||
02126|013|E|CLINICAL EFFECTS:  Concurrent use may increase the risk of extrapyramidal|
02126|014|E|reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors,|
02126|015|E|akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome.|
02126|016|E|Tardive dyskinesia, which may be permanent, typically affects the facial|
02126|017|E|muscles and may result in uncontrollable lip smacking, chewing, puckering of|
02126|018|E|the mouth, frowning or scowling, sticking out the tongue, blinking and|
02126|019|E|moving the eyes, and shaking of the arms and/or legs.(1-3)|
02126|020|E|   Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle|
02126|021|E|rigidity, altered mental status, an autonomic instability (irregular pulse|
02126|022|E|or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias),|
02126|023|E|elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute|
02126|024|E|renal failure.(1)|
02126|025|B||
02126|026|P|PREDISPOSING FACTORS:  Patients with Parkinson's or Lewy Body Disease may be|
02126|027|P|more likely to have extrapyramidal reactions or unmasking of their primary|
02126|028|P|disease symptoms. The risk of extrapyramidal symptoms is also increased in|
02126|029|P|patients on metoclopramide for longer than 12 weeks.|
02126|030|P|   Elderly patients, especially elderly women, and diabetics are at higher|
02126|031|P|risk of developing tardive dyskinesia.|
02126|032|P|   Other extrapyramidal symptoms, like acute dystonia, have occurred more|
02126|033|P|frequently in patients younger than 30 years old.(1)|
02126|034|B||
02126|035|M|PATIENT MANAGEMENT:  The concurrent use of metoclopramide and agents likely|
02126|036|M|to cause extrapyramidal reactions should be avoided.(1)|
02126|037|M|   If concurrent use is warranted, monitor patients closely for|
02126|038|M|extrapyramidal reactions and neuroleptic malignant syndrome.  The|
02126|039|M|manufacturer of metoclopramide says to avoid treatment with metoclopramide|
02126|040|M|for longer than 12 weeks, and to use the lowest possible dose.(1)|
02126|041|M|Discontinue therapy if symptoms occur.  Instruct patients to seek immediate|
02126|042|M|medical attention if symptoms develop.|
02126|043|M|   Symptoms of extrapyramidal reactions, including tardive dyskinesia,|
02126|044|M|include involuntary movements of limbs and facial grimacing, torticollis,|
02126|045|M|oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech,|
02126|046|M|trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.(3)|
02126|047|B||
02126|048|D|DISCUSSION:  Both metoclopramide and phenothiazines can cause extrapyramidal|
02126|049|D|reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome.|
02126|050|D|The risk may be increased by concurrent use.(1,2)|
02126|051|D|   Extrapyramidal symptoms have been reported with concurrent metoclopramide|
02126|052|D|and neuroleptics, prochlorperazine, and chlorpromazine.(4-6)|
02126|053|B||
02126|054|R|REFERENCES:|
02126|055|B||
02126|056|R|1.Reglan (metoclopramide) tablets US prescribing information. ANI|1
02126|057|R|  Pharmaceuticals, Inc. August 29, 2017.|1
02126|058|R|2.Reglan (metoclopramide) injection US prescribing information. Baxter|1
02126|059|R|  Healthcare Corporation November, 2010.|1
02126|060|R|3.Exelon (rivastigmine tartrate) US prescribing information. Novartis|1
02126|061|R|  Pharmaceuticals Corporation December, 2018.|1
02126|062|R|4.Krahenbuhl S, Raisin J, Herren T. Malignant neuroleptic syndrome under|3
02126|063|R|  metoclopramide and neuroleptics in anuria. Schweiz Med Wochenschr 1993 Jul|3
02126|064|R|  3;123(26):1359-62.|3
02126|065|R|5.Factor SA, Matthews MK. Persistent extrapyramidal syndrome with dystonia|3
02126|066|R|  and rigidity caused by combined metoclopramide and prochlorperazine|3
02126|067|R|  therapy. South Med J 1991 May;84(5):626-8.|3
02126|068|R|6.Schou H, Kongstad LL. Acute dystonia with fatal outcome. A possible|3
02126|069|R|  adverse drug reaction in the simultaneous administration of chlorpromazine|3
02126|070|R|  (Prozil) and metoclopramide (Primperan). Ugeskr Laeger 1986 Sep 8;|3
02126|071|R|  148(37):2357-8.|3
02127|001|T|MONOGRAPH TITLE:  Ioflupane I 123/Dopamine Transporter Binders|
02127|002|B||
02127|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02127|004|L|of severe adverse interaction.|
02127|005|B||
02127|006|A|MECHANISM OF ACTION:  Ioflupane binds to the dopamine transporter.  Agents|
02127|007|A|that also bind to this transporter may affect the results of single photon|
02127|008|A|emission computed tomography (SPECT) brain imaging using ioflupane.(1)|
02127|009|B||
02127|010|E|CLINICAL EFFECTS:  SPECT imaging using ioflupane may not be accurate in|
02127|011|E|patients taking other drugs that bind to the dopamine transporter|
02127|012|E|binders.(1)|
02127|013|B||
02127|014|P|PREDISPOSING FACTORS:  None determined.|
02127|015|B||
02127|016|M|PATIENT MANAGEMENT:  It is unknown if discontinuing other agents that bind|
02127|017|M|to the dopamine transporter prior to a scan with ioflupane will decrease|
02127|018|M|interference with the scan.(1)  Make sure the radiologist interpreting the|
02127|019|M|scan knows the patient is taking another agent that binds to the dopamine|
02127|020|M|transporter.  Alternative diagnostic tools may need to be considered.|
02127|021|B||
02127|022|D|DISCUSSION:  Ioflupane binds to the dopamine transporter.  Agents that also|
02127|023|D|bind to this transporter may affect the results of the scan.  These agents|
02127|024|D|include amoxapine, amphetamine, armodafinil, benztropine, bupropion,|
02127|025|D|buspirone, citalopram, cocaine, dexmethylphenidate, escitalopram,|
02127|026|D|fluoxetine, fluvoxamine, mazindol, methamphetamine, methylphenidate,|
02127|027|D|modafinil, norephedrine, paroxetine, phentermine, phenylpropanolamine,|
02127|028|D|selegiline, and sertraline.(1)|
02127|029|B||
02127|030|R|REFERENCE:|
02127|031|B||
02127|032|R|1.DaTscan (Ioflupane I 123) US prescribing information. GE Healthcare|1
02127|033|R|  November, 2022.|1
02128|001|T|MONOGRAPH TITLE:  Aliskiren/Selected P-glycoprotein (P-gp) Inhibitors|
02128|002|B||
02128|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02128|004|L|of severe adverse interaction.|
02128|005|B||
02128|006|A|MECHANISM OF ACTION:  Aliskiren is a substrate for the P-glycoprotein (P-gp)|
02128|007|A|system. Inhibitors of P-gp may increase the absorption of aliskiren.(1-3)|
02128|008|B||
02128|009|E|CLINICAL EFFECTS:  The concurrent use of aliskiren and P-gp inhibitors may|
02128|010|E|result in elevated levels of aliskiren.  This may result in increased effect|
02128|011|E|and toxicity of aliskiren including hypotension.(1-3)|
02128|012|B||
02128|013|P|PREDISPOSING FACTORS:  None determined.|
02128|014|B||
02128|015|M|PATIENT MANAGEMENT:  The US manufacturer of aliskiren states that concurrent|
02128|016|M|use of itraconazole should be avoided.(1)|
02128|017|M|   The UK manufacturer of aliskiren states that the concurrent use of P-gp|
02128|018|M|inhibitors such as itraconazole is contraindicated.(2)|
02128|019|M|   The US manufacturer of itraconazole states that concurrent administration|
02128|020|M|of aliskiren is not recommended during and two weeks after itraconazole|
02128|021|M|treatment.(4)|
02128|022|B||
02128|023|D|DISCUSSION:  In a study in healthy subjects, concurrent itraconazole (100|
02128|024|D|mg) increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02128|025|D|aliskiren (150 mg) by 5.8-fold and 6.5-fold, respectively.(2,3)|
02128|026|D|   Selected P-gp inhibitors linked to this monograph include:  azithromycin,|
02128|027|D|belumosudil, clarithromycin, danicopan, daridorexant, fostamatinib,|
02128|028|D|indinavir, itraconazole, lopinavir/ritonavir, mavorixafor,|
02128|029|D|nirmatrelvir/ritonavir, pirtobrutinib, rifampin and vimseltinib.(4,5)|
02128|030|B||
02128|031|R|REFERENCES:|
02128|032|B||
02128|033|R|1.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
02128|034|R|  Corporation November, 2017.|1
02128|035|R|2.Rasilez (aliskiren hemifumarate) UK summary of product characteristics.|1
02128|036|R|  Novartis Pharmaceuticals UK Ltd. September, 2014.|1
02128|037|R|3.Tapaninen T, Backman JT, Kurkinen KJ, Neuvonen PJ, Niemi M. Itraconazole,|2
02128|038|R|  a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma|2
02128|039|R|  concentrations and enhances the renin-inhibiting effect of aliskiren. J|2
02128|040|R|  Clin Pharmacol 2011 Mar;51(3):359-67.|2
02128|041|R|4.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02128|042|R|  Products, L.P. February, 2024.|1
02128|043|R|5.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
02128|044|R|  information. Pfizer Inc. February, 2025.|1
02128|045|R|6.This information is based on an extract from the Certara Drug Interaction|6
02128|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02129|001|T|MONOGRAPH TITLE:  Vilazodone/Strong CYP3A4 Inhibitors (mono deleted|
02129|002|T|11/20/2014)|
02129|003|B||
02129|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02129|005|L|take action as needed.|
02129|006|B||
02129|007|A|MECHANISM OF ACTION:  CYP P-450-3A4 inhibitors may inhibit the metabolism of|
02129|008|A|vilazodone.(1)|
02129|009|B||
02129|010|E|CLINICAL EFFECTS:  Concurrent use of a CYP P-450-3A4 inhibitor may result in|
02129|011|E|elevated levels of and toxicity from vilazodone.(1)|
02129|012|B||
02129|013|P|PREDISPOSING FACTORS:  None determined.|
02129|014|B||
02129|015|M|PATIENT MANAGEMENT:  The US manufacturer recommends reducing the dose of|
02129|016|M|vilazodone to 20 mg daily when coadministered with strong inhibitors of CYP|
02129|017|M|P-450-3A4.(1)|
02129|018|B||
02129|019|D|DISCUSSION:  Ketoconazole, a strong inhibitor of CYP P-450-3A4, increased|
02129|020|D|vilazodone concentrations by 50%.(1)|
02129|021|D|   Strong inhibitors of CYP P-450-3A4 include atazanavir, boceprevir,|
02129|022|D|clarithromycin, cobicistat, conivaptan, indinavir, itraconazole,|
02129|023|D|ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,|
02129|024|D|telaprevir, telithromycin and voriconazole.(2)|
02129|025|B||
02129|026|R|REFERENCES:|
02129|027|B||
02129|028|R|1.Viibryd (vilazodone hydrochloride) US prescribing information. Forest|1
02129|029|R|  Laboratories Inc. October, 2023.|1
02129|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02129|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02129|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02129|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02129|034|R|  11/14/2017.|1
02130|001|T|MONOGRAPH TITLE:  Toremifene/Strong CYP3A4 Inducers|
02130|002|B||
02130|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02130|004|L|of severe adverse interaction.|
02130|005|B||
02130|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02130|007|A|toremifene.(1)|
02130|008|A|   Toremifene may inhibit the metabolism of phenytoin.(1)|
02130|009|B||
02130|010|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide, barbiturates,|
02130|011|E|carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor,|
02130|012|E|mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin,|
02130|013|E|rifapentine, and St. John's wort may result in decreased levels and|
02130|014|E|effectiveness of toremifene.(1)|
02130|015|E|   Concurrent use of toremifene may decrease phenytoin levels.(1)|
02130|016|B||
02130|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02130|018|P|of the inducer for longer than 1-2 weeks.|
02130|019|B||
02130|020|M|PATIENT MANAGEMENT:  Avoid the use of strong inducers of CYP3A4 in patients|
02130|021|M|receiving toremifene.|
02130|022|M|   If concurrent toremifene and phenytoin are required, monitor phenytoin|
02130|023|M|levels.  The dosage of phenytoin may need to be adjusted.(1)|
02130|024|B||
02130|025|D|DISCUSSION:  In clinical trials, ten patients on anticonvulsants which|
02130|026|D|included carbamazepine, phenobarbital, and phenytoin experienced a 2-fold|
02130|027|D|increase in clearance and a decrease in the elimination half-life of|
02130|028|D|toremifene.(1,2)  The area-under-curve (AUC) and half-life of|
02130|029|D|N-demethyltoremifene, an active metabolite of toremifene, decreased by 61%|
02130|030|D|and 78%, respectively.(2)|
02130|031|D|   In a study in healthy males, rifampin (600 mg daily for 5 days) decreased|
02130|032|D|maximum concentration (Cmax) and AUC of a single dose of toremifene (120 mg)|
02130|033|D|by 55% and 87%, respectively.  The Cmax of N-demethyltoremifene increased|
02130|034|D|48% and the AUC of N-demethyltoremifene decreased by 80%.(3)|
02130|035|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02130|036|D|carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor,|
02130|037|D|mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin,|
02130|038|D|rifapentine, and St. John's wort.(4,5)|
02130|039|B||
02130|040|R|REFERENCES:|
02130|041|B||
02130|042|R|1.Fareston (toremifene citrate) US prescribing information. GTx, Inc. March,|1
02130|043|R|  2011.|1
02130|044|R|2.Anttila M, Laakso S, Nylanden P, Sotaniemi EA. Pharmacokinetics of the|2
02130|045|R|  novel antiestrogenic agent toremifene in subjects with altered liver and|2
02130|046|R|  kidney function. Clin Pharmacol Ther 1995 Jun;57(6):628-35.|2
02130|047|R|3.Kivisto KT, Villikka K, Nyman L, Anttila M, Neuvonen PJ. Tamoxifen and|2
02130|048|R|  toremifene concentrations in plasma are greatly decreased by rifampin.|2
02130|049|R|  Clin Pharmacol Ther 1998 Dec;64(6):648-54.|2
02130|050|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02130|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02130|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02130|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02130|054|R|  11/14/2017.|1
02130|055|R|5.This information is based on an extract from the Certara Drug Interaction|6
02130|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02131|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors; Cobicistat/CYP3A4 Inducers|
02131|002|B||
02131|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02131|004|L|is contraindicated and generally should not be dispensed or administered to|
02131|005|L|the same patient.|
02131|006|B||
02131|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 are expected to increase the|
02131|008|A|metabolism of boceprevir,(1) cobicistat,(2,3) and telaprevir.(4)|
02131|009|A|   Inhibitors of CYP3A4 may inhibit the metabolism of carbamazepine.(5,6)|
02131|010|A|Boceprevir, cobicistat, nirmatrelvir, and telaprevir are CYP3A4|
02131|011|A|inhibitors.(7,8)|
02131|012|B||
02131|013|E|CLINICAL EFFECTS:  Concurrent or recent use of strong inducers of CYP3A4 may|
02131|014|E|result in decreased levels and effectiveness of boceprevir,(1)|
02131|015|E|cobicistat,(2,3) and telaprevir.(4)|
02131|016|E|   Increased serum carbamazepine levels with subsequent increases in the|
02131|017|E|pharmacological and toxic effects of carbamazepine, including dizziness,|
02131|018|E|ataxia, blurred vision, or SIADH.(5)|
02131|019|B||
02131|020|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02131|021|P|of the inducer for longer than 1-2 weeks.|
02131|022|B||
02131|023|M|PATIENT MANAGEMENT:  Concurrent administration of strong inducers of CYP3A4|
02131|024|M|with boceprevir,(1) cobicistat,(2,3) and telaprevir(4) is contraindicated.|
02131|025|B||
02131|026|D|DISCUSSION:  Boceprevir is metabolized by CYP3A4.  Strong inducers of CYP3A4|
02131|027|D|are expected to reduce boceprevir levels, which may lead to loss of|
02131|028|D|response.(1)|
02131|029|D|   In a study in 16 subjects, rifampin (600 mg daily for 8 days), a strong|
02131|030|D|inducer of CYP3A4, decreased the maximum concentration (Cmax) and|
02131|031|D|area-under-curve (AUC) of a single dose of telaprevir (750 mg) by 86% and|
02131|032|D|92%, respectively.(4)|
02131|033|D|   Carbamazepine is almost completely metabolized to|
02131|034|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
02131|035|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
02131|036|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
02131|037|D|CYP3A5.(5,6)|
02131|038|D|   In a study of 12 healthy volunteers, carbamazepine was titrated to 300 mg|
02131|039|D|every 12 hours and then coadministered with nirmatrelvir/ritonavir 300|
02131|040|D|mg/100 mg on day 15 of carbamazepine.  Carbamazepine decreased nirmatrelvir|
02131|041|D|AUC and Cmax by 55% and 43%, respectively, and decreased ritonavir AUC and|
02131|042|D|Cmax both by about 74%.(7)|
02131|043|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02131|044|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02131|045|D|lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone,|
02131|046|D|rifampin, and St. John's wort.(8,9)|
02131|047|B||
02131|048|R|REFERENCES:|
02131|049|B||
02131|050|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02131|051|R|  January, 2017.|1
02131|052|R|2.Tybost (cobicistat) EMA summary of product characteristics. Gilead|1
02131|053|R|  Sciences Limited May, 2014.|1
02131|054|R|3.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02131|055|R|  June, 2025.|1
02131|056|R|4.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02131|057|R|  Incorporated October, 2013.|1
02131|058|R|5.Tegretol (carbamazepine) US prescribing information. Novartis|1
02131|059|R|  Pharmaceuticals Corporation September, 2023.|1
02131|060|R|6.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
02131|061|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
02131|062|R|  Dec;21(12):906-10.|6
02131|063|R|7.Cox DS, Van Eyck L, Pawlak S, Beckerman B, Linn C, Ginman K, Cha YT,|2
02131|064|R|  LaBadie RR, Shi H, Damle B. Effects of itraconazole and carbamazepine on|2
02131|065|R|  the pharmacokinetics of  nirmatrelvir/ritonavir in healthy adults. Br J|2
02131|066|R|  Clin Pharmacol 2023 May 15.|2
02131|067|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
02131|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02131|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02131|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02131|071|R|  11/14/2017.|1
02131|072|R|9.This information is based on an extract from the Certara Drug Interaction|6
02131|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02132|001|T|MONOGRAPH TITLE:  Alfuzosin/Boceprevir; Telaprevir (mono deleted 02/20/2014)|
02132|002|B||
02132|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02132|004|L|is contraindicated and generally should not be dispensed or administered to|
02132|005|L|the same patient.|
02132|006|B||
02132|007|A|MECHANISM OF ACTION:  Boceprevir(1) and telaprevir(2) may inhibit the|
02132|008|A|metabolism of alfuzosin by CYP P-450-3A4.|
02132|009|B||
02132|010|E|CLINICAL EFFECTS:  Concurrent use of boceprevir(1) or telaprevir(2) may|
02132|011|E|result in elevated levels of and effects from alfuzosin, including severe|
02132|012|E|hypotension.|
02132|013|B||
02132|014|P|PREDISPOSING FACTORS:  None determined.|
02132|015|B||
02132|016|M|PATIENT MANAGEMENT:  The US manufacturers of boceprevir(1) and telaprevir(2)|
02132|017|M|state that concurrent use of alfuzosin is contraindicated.|
02132|018|B||
02132|019|D|DISCUSSION:  Boceprevir has been shown to be a strong inhibitor of CYP|
02132|020|D|P-450-3A4.(1)  Telaprevir has also been shown to inhibit CYP P-450-3A4.(2)|
02132|021|D|Therefore, concurrent use of boceprevir(1) or telaprevir(2) with agents that|
02132|022|D|are highly dependent on CYP P-450-3A4 for clearance and for which elevated|
02132|023|D|plasma levels are associated with serious and/or life-threatening events is|
02132|024|D|contraindicated.|
02132|025|B||
02132|026|R|REFERENCES:|
02132|027|B||
02132|028|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02132|029|R|  May, 2011.|1
02132|030|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02132|031|R|  Incorporated October, 2013.|1
02133|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Boceprevir; Telaprevir|
02133|002|B||
02133|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02133|004|L|is contraindicated and generally should not be dispensed or administered to|
02133|005|L|the same patient.|
02133|006|B||
02133|007|A|MECHANISM OF ACTION:  Boceprevir(1) and telaprevir(2) may inhibit the|
02133|008|A|metabolism of ergot alkaloids by CYP3A4.|
02133|009|B||
02133|010|E|CLINICAL EFFECTS:  Concurrent use of boceprevir(1) or telaprevir(2) may|
02133|011|E|result in elevated levels of and effects from ergot alkaloids, including|
02133|012|E|peripheral vasospasm and ischemia.|
02133|013|B||
02133|014|P|PREDISPOSING FACTORS:  None determined.|
02133|015|B||
02133|016|M|PATIENT MANAGEMENT:  The US manufacturers of boceprevir(1) and telaprevir(2)|
02133|017|M|state that concurrent use of ergot alkaloids, including dihydroergotamine,|
02133|018|M|ergonovine, ergotamine, and methylergonovine, is contraindicated.|
02133|019|B||
02133|020|D|DISCUSSION:  Boceprevir has been shown to be a strong inhibitor of|
02133|021|D|CYP3A4.(1)  Telaprevir has also been shown to inhibit CYP3A4.(2)  Therefore,|
02133|022|D|concurrent use of boceprevir(1) or telaprevir(2) with agents that are highly|
02133|023|D|dependent on CYP3A4 for clearance and for which elevated plasma levels are|
02133|024|D|associated with serious and/or life-threatening events is contraindicated.|
02133|025|B||
02133|026|R|REFERENCES:|
02133|027|B||
02133|028|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02133|029|R|  January, 2017.|1
02133|030|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02133|031|R|  Incorporated October, 2013.|1
02134|001|T|MONOGRAPH TITLE:  Cisapride/Simeprevir|
02134|002|B||
02134|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02134|004|L|is contraindicated and generally should not be dispensed or administered to|
02134|005|L|the same patient.|
02134|006|B||
02134|007|A|MECHANISM OF ACTION:  Simeprevir may increase the absorption of|
02134|008|A|cisapride.(3)|
02134|009|B||
02134|010|E|CLINICAL EFFECTS:  Concurrent use of simeprevir may result in elevated|
02134|011|E|levels of and effects from cisapride, including life-threatening cardiac|
02134|012|E|arrhythmias such as QT prolongation or torsades de pointes.(1)|
02134|013|B||
02134|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsades|
02134|015|P|de pointes may be increased in patients with cardiovascular disease (e.g.|
02134|016|P|heart failure, myocardial infarction, history of torsades de pointes,|
02134|017|P|congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
02134|018|P|bradycardia, female gender, or advanced age.(2)|
02134|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02134|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02134|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02134|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02134|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02134|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02134|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02134|026|B||
02134|027|M|PATIENT MANAGEMENT:  The US manufacturer of simeprevir states that|
02134|028|M|concurrent use of cisapride is not recommended.(1)|
02134|029|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02134|030|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02134|031|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02134|032|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02134|033|B||
02134|034|D|DISCUSSION:  Simeprevir has been shown to inhibit CYP3A4 in the intestine|
02134|035|D|and may result in increased cisapride absorption.(1)|
02134|036|B||
02134|037|R|REFERENCES:|
02134|038|B||
02134|039|R|1.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
02134|040|R|  November, 2017.|1
02134|041|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02134|042|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02134|043|R|  settings: a scientific statement from the American Heart Association and|6
02134|044|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02134|045|R|  2;55(9):934-47.|6
02135|001|T|MONOGRAPH TITLE:  Atorvastatin (Greater Than 40 mg); Lovastatin;|
02135|002|T|Simvastatin/Boceprevir|
02135|003|B||
02135|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02135|005|L|is contraindicated and generally should not be dispensed or administered to|
02135|006|L|the same patient.|
02135|007|B||
02135|008|A|MECHANISM OF ACTION:  Boceprevir may inhibit the metabolism of|
02135|009|A|atorvastatin,(1,2) lovastatin,(1,3) and simvastatin(1,4) by CYP3A4.|
02135|010|B||
02135|011|E|CLINICAL EFFECTS:  Concurrent use of boceprevir may result in elevated|
02135|012|E|levels of and effects from atorvastatin,(1,2) lovastatin(1,2) and|
02135|013|E|simvastatin,(1,4) including myopathy and rhabdomyolysis.|
02135|014|B||
02135|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02135|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02135|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02135|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02135|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02135|020|P|transporter OATP1B1 may have increased statin concentrations and be|
02135|021|P|predisposed to myopathy or rhabdomyolysis.|
02135|022|B||
02135|023|M|PATIENT MANAGEMENT:  Concurrent use of lovastatin(1,3) or simvastatin(1,4)|
02135|024|M|with boceprevir is contraindicated.  Dosages of atorvastatin should not|
02135|025|M|exceed 40 mg daily with concurrent boceprevir.(1,2)|
02135|026|B||
02135|027|D|DISCUSSION:  Boceprevir (800 mg TID for 7 days) increased the maximum|
02135|028|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
02135|029|D|atorvastatin (40 mg) by 2.66-fold and 2.30-fold, respectively.(1-3)  There|
02135|030|D|were no significant effects on boceprevir pharmacokinetics.(1)|
02135|031|B||
02135|032|R|REFERENCES:|
02135|033|B||
02135|034|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02135|035|R|  January, 2017.|1
02135|036|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02135|037|R|  February, 2014.|1
02135|038|R|3.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02135|039|R|  2020.|1
02135|040|R|4.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02135|041|R|  2023.|1
02136|001|T|MONOGRAPH TITLE:  Drospirenone/Boceprevir|
02136|002|B||
02136|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02136|004|L|is contraindicated and generally should not be dispensed or administered to|
02136|005|L|the same patient.|
02136|006|B||
02136|007|A|MECHANISM OF ACTION:  Boceprevir is both and inducer and inhibitor of CYP3A4|
02136|008|A|and may inhibit the metabolism of drospirenone and induce the metabolism of|
02136|009|A|estrogens via this pathway.|
02136|010|B||
02136|011|E|CLINICAL EFFECTS:  Concurrent use of boceprevir may result in elevated|
02136|012|E|levels of and effects from drospirenone, including hyperkalemia.(1)|
02136|013|E|  Concurrent use of boceprevir and hormonal contraceptive agents may|
02136|014|E|decrease the effectiveness of the hormonal contraceptive agent, which may|
02136|015|E|result in contraceptive failure.  Boceprevir is only indicated for use with|
02136|016|E|ribavirin, a known teratogen.(1)|
02136|017|B||
02136|018|P|PREDISPOSING FACTORS:  None determined.|
02136|019|B||
02136|020|M|PATIENT MANAGEMENT:  The US manufacturer of boceprevir states that|
02136|021|M|concurrent use of drospirenone is contraindicated.(1)|
02136|022|M|   Women receiving boceprevir therapy should not rely on hormonal|
02136|023|M|contraceptive agents (including oral, implantable, injectable, or|
02136|024|M|transdermal agents) because they may not be effective.  Two alternative|
02136|025|M|effective methods of contraception (e.g. intrauterine devices and/or barrier|
02136|026|M|methods) should be used during combination treatment with ribavirin and for|
02136|027|M|six months after completing therapy.(1)|
02136|028|B||
02136|029|D|DISCUSSION:  Concurrent use of boceprevir (800 mg three times daily for 7|
02136|030|D|days) decreased the area-under-curve (AUC) of ethinyl estradiol|
02136|031|D|(administered as drospirenone/ethinyl estradiol 3/0.02 mg daily for 14 days)|
02136|032|D|by 24%.  Drospirenone maximum concentration (Cmax) and AUC increased by|
02136|033|D|1.57-fold and 1.99-fold, respectively.(1)|
02136|034|B||
02136|035|R|REFERENCES:|
02136|036|B||
02136|037|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02136|038|R|  January, 2017.|1
02136|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
02136|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02137|001|T|MONOGRAPH TITLE:  Pimozide/Boceprevir; Telaprevir|
02137|002|B||
02137|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02137|004|L|is contraindicated and generally should not be dispensed or administered to|
02137|005|L|the same patient.|
02137|006|B||
02137|007|A|MECHANISM OF ACTION:  Boceprevir(1) and telaprevir(2) may inhibit the|
02137|008|A|metabolism of pimozide by CYP3A4.|
02137|009|B||
02137|010|E|CLINICAL EFFECTS:  Concurrent use of boceprevir(1) or telaprevir(2) may|
02137|011|E|result in elevated levels of and effects from pimozide, including|
02137|012|E|life-threatening cardiac arrhythmias.|
02137|013|B||
02137|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02137|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02137|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02137|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02137|018|P|female gender, or advanced age.(3)|
02137|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02137|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02137|021|P|risk factors for torsades de pointes.  Factors which may increased systemic|
02137|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02137|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02137|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02137|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02137|026|P|   The risk of anticholinergic toxicities including cognitive decline,|
02137|027|P|delirium, falls and fractures is increased in geriatric patients using more|
02137|028|P|than one medicine with anticholinergic properties.(4)|
02137|029|B||
02137|030|M|PATIENT MANAGEMENT:  The US manufacturers of boceprevir(1) and telaprevir(2)|
02137|031|M|state that concurrent use of pimozide is contraindicated.|
02137|032|M|   The manufacturer of pimozide states that concomitant treatment with|
02137|033|M|strong CYP3A4 inhibitors is contraindicated and treatment with less potent|
02137|034|M|inhibitors of CYP3A4 should also be avoided.(1)|
02137|035|M|   If concurrent use cannot be avoided, then correct or minimize QT|
02137|036|M|prolonging risk factors, use the lowest effective dose of pimozide, and|
02137|037|M|discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if|
02137|038|M|possible.|
02137|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02137|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02137|041|M|regular intervals.  Correct any electrolyte abnormalities.(1,3)  Instruct|
02137|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02137|043|B||
02137|044|D|DISCUSSION:  Boceprevir has been shown to be a strong inhibitor of|
02137|045|D|CYP3A4.(1)  Telaprevir has also been shown to inhibit CYP3A4.(2)  Therefore,|
02137|046|D|concurrent use of boceprevir(1) or telaprevir(2) with agents that are highly|
02137|047|D|dependent on CYP3A4 for clearance and for which elevated plasma levels are|
02137|048|D|associated with serious and/or life-threatening events is contraindicated.|
02137|049|B||
02137|050|R|REFERENCES:|
02137|051|B||
02137|052|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02137|053|R|  January, 2017.|1
02137|054|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02137|055|R|  Incorporated October, 2013.|1
02137|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02137|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02137|058|R|  settings: a scientific statement from the American Heart Association and|6
02137|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02137|060|R|  2;55(9):934-47.|6
02137|061|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02137|062|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02137|063|R|  Soc 2023 Jul;71(7):2052-2081.|6
02138|001|T|MONOGRAPH TITLE:  Sildenafil; Tadalafil (for PAH)/Boceprevir;Telaprevir|
02138|002|B||
02138|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02138|004|L|is contraindicated and generally should not be dispensed or administered to|
02138|005|L|the same patient.|
02138|006|B||
02138|007|A|MECHANISM OF ACTION:  The metabolism of sildenafil and tadalafil by CYP3A4|
02138|008|A|may be inhibited by boceprevir(1) and telaprevir.(2)|
02138|009|B||
02138|010|E|CLINICAL EFFECTS:  The concurrent administration of boceprevir(1) or|
02138|011|E|telaprevir(2) may result in elevated levels of sildenafil or tadalafil,|
02138|012|E|which may result in increased adverse effects such as hypotension, visual|
02138|013|E|changes, and priapism.|
02138|014|B||
02138|015|P|PREDISPOSING FACTORS:  None determined.|
02138|016|B||
02138|017|M|PATIENT MANAGEMENT:  The US manufacturers of boceprevir(1) and telaprevir(2)|
02138|018|M|state that concurrent use of sildenafil or tadalafil when used for the|
02138|019|M|treatment of pulmonary arterial hypertension (PAH) is contraindicated.|
02138|020|B||
02138|021|D|DISCUSSION:  Boceprevir has been shown to be a strong inhibitor of|
02138|022|D|CYP3A4.(1)  Telaprevir has also been shown to inhibit CYP3A4.(1)  Therefore,|
02138|023|D|concurrent use of boceprevir(1) or telaprevir(2) with agents that are highly|
02138|024|D|dependent on CYP3A4 for clearance and for which elevated plasma levels are|
02138|025|D|associated with serious and/or life-threatening events is contraindicated.|
02138|026|B||
02138|027|R|REFERENCES:|
02138|028|B||
02138|029|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02138|030|R|  January, 2017.|1
02138|031|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02138|032|R|  Incorporated October, 2013.|1
02139|001|T|MONOGRAPH TITLE:  Sildenafil; Tadalafil; Vardenafil|
02139|002|T|(ED)/Boceprevir;Telaprevir|
02139|003|B||
02139|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02139|005|L|take action as needed.|
02139|006|B||
02139|007|A|MECHANISM OF ACTION:  The metabolism of sildenafil, tadalafil, and|
02139|008|A|vardenafil by CYP3A4 may be inhibited by boceprevir(1) and telaprevir.(2)|
02139|009|B||
02139|010|E|CLINICAL EFFECTS:  The concurrent administration of boceprevir(1) or|
02139|011|E|telaprevir(2) may result in elevated levels of sildenafil, tadalafil, or|
02139|012|E|vardenafil, which may result in increased adverse effects such as|
02139|013|E|hypotension, visual changes, or priapism.|
02139|014|B||
02139|015|P|PREDISPOSING FACTORS:  None determined.|
02139|016|B||
02139|017|M|PATIENT MANAGEMENT:  In patients receiving boceprevir, the dosage of CGMP|
02139|018|M|PDE Type-5 Inhibitors used for the treatment of erectile dysfunction should|
02139|019|M|be limited to 25 mg of sildenafil every 48 hours, 10 mg of tadalafil every|
02139|020|M|72 hours, and 2.5 mg of vardenafil every 24 hours.(1)|
02139|021|M|   In patients receiving telaprevir, the dosage of CGMP PDE Type-5|
02139|022|M|Inhibitors used for the treatment of erectile dysfunction should be limited|
02139|023|M|to 25 mg of sildenafil every 48 hours, 10 mg of tadalafil every 72 hours,|
02139|024|M|and 2.5 mg of vardenafil every 72 hours.(2)|
02139|025|M|   The US manufacturer of tadalafil chewable tablets (Chewtadzy) states the|
02139|026|M|maximum recommended dose of as needed tadalafil for erectile dysfunction in|
02139|027|M|patients taking strong CYP3A4 inhibitors is 10 mg every 72 hours.  The use|
02139|028|M|of tadalafil chewable tablets (Chewtazdy) for once daily use for erectile|
02139|029|M|dysfunction or benign prostatic hyperplasia (BPH) is not recommended in|
02139|030|M|patients taking strong CYP3A4 inhibitors due to the lack of a 2.5 mg tablet|
02139|031|M|strength.(3)|
02139|032|M|   Patients should be counseled that they are at an increased risk of|
02139|033|M|adverse effects, including hypotension, syncope, visual changes, and|
02139|034|M|priapism.  Patients experiencing these effects should report them promptly|
02139|035|M|to their physician.|
02139|036|M|   The US manufacturers of boceprevir(1) and telaprevir(2) state that|
02139|037|M|concurrent use of sildenafil or tadalafil when used for the treatment of|
02139|038|M|pulmonary arterial hypertension (PAH) is contraindicated.|
02139|039|B||
02139|040|D|DISCUSSION:  Boceprevir has been shown to be a strong inhibitor of|
02139|041|D|CYP3A4.(1)  Telaprevir has also been shown to inhibit CYP3A4.(2)|
02139|042|B||
02139|043|R|REFERENCES:|
02139|044|B||
02139|045|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02139|046|R|  January, 2017.|1
02139|047|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02139|048|R|  Incorporated October, 2013.|1
02139|049|R|3.Chewtadzy (tadalafil chewable tablets) US prescribing information. ANI|1
02139|050|R|  Pharmaceuticals, Inc. June, 2024.|1
02140|001|T|MONOGRAPH TITLE:  Oral Midazolam/Selected CYP3A4 Inhibitors|
02140|002|B||
02140|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02140|004|L|is contraindicated and generally should not be dispensed or administered to|
02140|005|L|the same patient.|
02140|006|B||
02140|007|A|MECHANISM OF ACTION:  The metabolism of midazolam by CYP3A4 may be inhibited|
02140|008|A|by boceprevir,(1) cobicistat,(2) idelalisib,(3) and telaprevir.(4)|
02140|009|B||
02140|010|E|CLINICAL EFFECTS:  The concurrent administration of boceprevir,(1)|
02140|011|E|cobicistat,(2) idelalisib,(3) or telaprevir(4) may result in elevated levels|
02140|012|E|of triazolam or midazolam, which may result in increased adverse effects|
02140|013|E|including profound sedation, respiratory depression, coma, and/or death.|
02140|014|B||
02140|015|P|PREDISPOSING FACTORS:  None determined.|
02140|016|B||
02140|017|M|PATIENT MANAGEMENT:  The US manufacturers of boceprevir,(1) cobicistat,(2)|
02140|018|M|idelalisib,(3) and telaprevir(4) state that concurrent use of oral midazolam|
02140|019|M|is contraindicated.(1)|
02140|020|M|   Patients receiving intravenous midazolam should be closely monitored.|
02140|021|M|Consideration should be given to lowering the dose of intravenous midazolam|
02140|022|M|in patients maintained on boceprevir,(1) cobicistat,(2) idelalisib,(3) and|
02140|023|M|telaprevir.(4)|
02140|024|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
02140|025|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02140|026|M|unresponsiveness.|
02140|027|B||
02140|028|D|DISCUSSION:  Boceprevir (800 mg 3 times daily for 6 days) increased the|
02140|029|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single oral|
02140|030|D|dose of midazolam (4mg) by 2.77-fold and 5.30-fold, respectively.(1)|
02140|031|D|   Coadministration of idelalisib with midazolam increased the Cmax and AUC|
02140|032|D|of midazolam by 2.4-fold and 5.4-fold, respectively.(3)|
02140|033|D|   In a study in 21 subjects, telaprevir (750mg every 8 hours for 11 days)|
02140|034|D|increased the Cmax and AUC of a single oral dose of midazolam (2 mg) by|
02140|035|D|2.86-fold and 8.96-fold, respectively.(4)|
02140|036|D|   In a study in 22 subjects, telaprevir (750mg every 8 hours for 9 days)|
02140|037|D|increased the Cmax and AUC of a single intravenous dose of midazolam (0.5|
02140|038|D|mg) by 2% and 3.40-fold, respectively.(4,5)|
02140|039|B||
02140|040|R|REFERENCES:|
02140|041|B||
02140|042|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02140|043|R|  January, 2017.|1
02140|044|R|2.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02140|045|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02140|046|R|3.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
02140|047|R|  October, 2020.|1
02140|048|R|4.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02140|049|R|  Incorporated October, 2013.|1
02140|050|R|5.Garg V, Chandorkar G, Farmer HF, Smith F, Alves K, van Heeswijk RP. Effect|2
02140|051|R|  of Telaprevir on the Pharmacokinetics of Midazolam and Digoxin. J Clin|2
02140|052|R|  Pharmacol 2012 Jan 26.|2
02141|001|T|MONOGRAPH TITLE:  Colchicine/Boceprevir; Telaprevir (mono deleted|
02141|002|T|04/26/2012)|
02141|003|B||
02141|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02141|005|L|of severe adverse interaction.|
02141|006|B||
02141|007|A|MECHANISM OF ACTION:  Boceprevir(1) and telaprevir(2) may inhibit the|
02141|008|A|metabolism of colchicine by CYP P-450-3A4.|
02141|009|B||
02141|010|E|CLINICAL EFFECTS:  Concurrent use of boceprevir(1) and telaprevir(2) may|
02141|011|E|result in elevated levels of and toxicity from colchicine.(1)  Symptoms of|
02141|012|E|colchicine toxicity include muscle weakness or pain; numbness or tingling in|
02141|013|E|the fingers or toes; unusual bleeding or bruising; abdominal pain; nausea;|
02141|014|E|severe diarrhea or vomiting; feeling weak or tired; increased infections;|
02141|015|E|and pale or gray color of the lips, tongue, or palms of hands.(3,4)|
02141|016|B||
02141|017|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
02141|018|P|patients with renal and/or hepatic impairment.(1-4)|
02141|019|B||
02141|020|M|PATIENT MANAGEMENT:  The concurrent use of colchicine with strong CYP|
02141|021|M|P450-3A4 inhibitors such as boceprevir or telaprevir is contraindicated in|
02141|022|M|patients with renal or hepatic impairment.(2,3)|
02141|023|M|   In patients without renal or hepatic impairment who are currently taking|
02141|024|M|or have taken strong CYP P-450-3A4 inhibitors in the previous 14 days, the|
02141|025|M|dosage of colchicine should be reduced.  For gout flares, the recommended|
02141|026|M|dosage is 0.6 mg (1 tablet) for one dose, then 0.3 mg (half tablet) 1 hour|
02141|027|M|later.  This dose should be repeated no earlier than in 3 days.(1-4)  For|
02141|028|M|gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg|
02141|029|M|daily.  If the original dosage was 0.6 mg daily, use 0.3 mg every other|
02141|030|M|day.(1-4)  For Familial Mediterranean fever (FMF), the recommended maximum|
02141|031|M|daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1-4)|
02141|032|M|   Patients should be instructed to immediately report any signs of|
02141|033|M|colchicine toxicity.|
02141|034|B||
02141|035|D|DISCUSSION:  In a study in 18 subjects, pretreatment with ritonavir (100 mg|
02141|036|D|twice daily for 5 days) increased the maximum concentration (Cmax) and|
02141|037|D|area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 184.4%|
02141|038|D|(range 79.2% to 447.4%) and by 296% (range 53.8% to 924.4%),|
02141|039|D|respectively.(3)|
02141|040|D|   Colchicine toxicity has been reported with concurrent use of other CYP|
02141|041|D|P-450-3A4 inhibitors such as clarithromycin, cyclosporine, diltiazem,|
02141|042|D|erythromycin, and verapamil.(3,4)|
02141|043|D|   Boceprevir has been shown to be a strong inhibitor of CYP P-450-3A4.(1)|
02141|044|D|Telaprevir has also been shown to inhibit CYP P-450-3A4.(2)|
02141|045|B||
02141|046|R|REFERENCES:|
02141|047|B||
02141|048|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02141|049|R|  May, 2011.|1
02141|050|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02141|051|R|  Incorporated April, 2013.|1
02141|052|R|3.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
02141|053|R|  2011.|1
02141|054|R|4.Anonymous. Information for Healthcare Professionals: New Safety|1
02141|055|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
02141|056|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
02141|057|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
02142|001|T|MONOGRAPH TITLE:  Hormonal Contraceptive Agents/Boceprevir|
02142|002|B||
02142|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02142|004|L|of severe adverse interaction.|
02142|005|B||
02142|006|A|MECHANISM OF ACTION:  Boceprevir may induce the metabolism of hormonal|
02142|007|A|contraceptives by CYP3A4.|
02142|008|B||
02142|009|E|CLINICAL EFFECTS:  Concurrent use of boceprevir and hormonal contraceptive|
02142|010|E|agents may decrease the effectiveness of the hormonal contraceptive agent,|
02142|011|E|which may result in contraceptive failure.  Boceprevir is only indicated for|
02142|012|E|use with ribavirin, a known teratogen.(1)|
02142|013|B||
02142|014|P|PREDISPOSING FACTORS:  None determined.|
02142|015|B||
02142|016|M|PATIENT MANAGEMENT:  Women receiving boceprevir therapy should not rely on|
02142|017|M|hormonal contraceptive agents (including oral, implantable, injectable, or|
02142|018|M|transdermal agents) because they may not be effective.  Two alternative|
02142|019|M|effective methods of contraception (e.g. intrauterine devices and/or barrier|
02142|020|M|methods) should be used during combination treatment with ribavirin and for|
02142|021|M|six months after completing therapy.(1)|
02142|022|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
02142|023|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
02142|024|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
02142|025|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
02142|026|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
02142|027|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
02142|028|M|and to seek medical advice if they do become pregnant.(2)|
02142|029|B||
02142|030|D|DISCUSSION:  Concurrent use of boceprevir (800 mg three times daily for 7|
02142|031|D|days) decreased the area-under-curve (AUC) of ethinyl estradiol|
02142|032|D|(administered as drospirenone/ethinyl estradiol 3/0.02 mg daily for 14 days)|
02142|033|D|by 24%.(1)|
02142|034|D|   Concurrent use of boceprevir (800 mg three times daily for 21 days)|
02142|035|D|decreased the AUC and maximum concentration (Cmax) of ethinyl estradiol|
02142|036|D|(administered as norethindrone/ethinyl estradiol 1/0.035 mg daily for 21|
02142|037|D|days) by 26% and 21%, respectively.  The AUC and Cmax of norethindrone|
02142|038|D|decreased by 4% and 17%, respectively.(1)|
02142|039|B||
02142|040|R|REFERENCES:|
02142|041|B||
02142|042|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02142|043|R|  January, 2017.|1
02142|044|R|2.Medicines and Healthcare products Regulatory Agency.|1
02142|045|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
02142|046|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
02142|047|R|  available at:|1
02142|048|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
02142|049|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
02142|050|R|  -and-contraceptive-efficacy September 15, 2016..|1
02143|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 40 mg)/Boceprevir|
02143|002|B||
02143|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02143|004|L|take action as needed.|
02143|005|B||
02143|006|A|MECHANISM OF ACTION:  Boceprevir may inhibit the metabolism of atorvastatin|
02143|007|A|by CYP3A4.(1,2)|
02143|008|B||
02143|009|E|CLINICAL EFFECTS:  Concurrent use of boceprevir may result in elevated|
02143|010|E|levels of and effects from atorvastatin, including myopathy and|
02143|011|E|rhabdomyolysis.(1,2)|
02143|012|B||
02143|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02143|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02143|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02143|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02143|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02143|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02143|019|P|predisposed to myopathy or rhabdomyolysis.|
02143|020|B||
02143|021|M|PATIENT MANAGEMENT:  Dosages of atorvastatin should not exceed 40 mg daily|
02143|022|M|with concurrent boceprevir.(1,2)  Patients receiving concurrent therapy|
02143|023|M|should be monitored closely for signs and symptoms of myopathy.|
02143|024|B||
02143|025|D|DISCUSSION:  Boceprevir (800 mg TID for 7 days) increased the maximum|
02143|026|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
02143|027|D|atorvastatin (40 mg) by 2.66-fold and 2.30-fold, respectively.(1,2)  There|
02143|028|D|were no significant effects on boceprevir pharmacokinetics.(1)|
02143|029|B||
02143|030|R|REFERENCES:|
02143|031|B||
02143|032|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02143|033|R|  January, 2017.|1
02143|034|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02143|035|R|  2020.|1
02144|001|T|MONOGRAPH TITLE:  Selected Azole Antifungals/Boceprevir; Telaprevir|
02144|002|B||
02144|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02144|004|L|take action as needed.|
02144|005|B||
02144|006|A|MECHANISM OF ACTION:  Boceprevir(1) and telaprevir(2) may inhibit the|
02144|007|A|metabolism of itraconazole, ketoconazole, posaconazole, and voriconazole by|
02144|008|A|CYP3A4.  The azole antifungals may inhibit the metabolism of boceprevir(1)|
02144|009|A|and telaprevir.(1)|
02144|010|B||
02144|011|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
02144|012|E|effects from boceprevir, itraconazole, ketoconazole, posaconazole, and|
02144|013|E|voriconazole.(1,2)|
02144|014|B||
02144|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02144|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02144|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02144|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02144|019|P|female gender, or advanced age.(3)|
02144|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02144|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02144|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02144|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02144|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02144|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02144|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02144|027|B||
02144|028|M|PATIENT MANAGEMENT:  The US manufacturers of boceprevir(1) and telaprevir(2)|
02144|029|M|state that dosages of itraconazole and ketoconazole should not exceed 200 mg|
02144|030|M|daily with concurrent boceprevir.  Patients receiving concurrent therapy|
02144|031|M|should be monitored closely for signs and symptoms of toxicity, including QT|
02144|032|M|prolongation.|
02144|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02144|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02144|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02144|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02144|037|B||
02144|038|D|DISCUSSION:  In a study, concurrent ketoconazole (400 mg twice daily for 6|
02144|039|D|days), increased the maximum concentration (Cmax) and area-under-curve (AUC)|
02144|040|D|of a single dose of boceprevir (400 mg) by 1.41-fold and 2.31-fold,|
02144|041|D|respectively.(1)|
02144|042|D|   Boceprevir has been shown to be a strong inhibitor of CYP3A4 and is|
02144|043|D|expected to increase levels of the azole antifungals.(1)|
02144|044|D|   In a study in 17 subjects, a single dose of ketoconazole (400 mg)|
02144|045|D|increased the Cmax and AUC of a single dose of telaprevir (750 mg) by 24%|
02144|046|D|and 62%, respectively.(2)|
02144|047|D|   In a study in 81 subjects, telaprevir (1250 mg every 8 hours for 4 doses)|
02144|048|D|increased the Cmax and AUC of a single dose of ketoconazole (400 mg) by 23%|
02144|049|D|and 46%, respectively.(2)|
02144|050|D|   In a study in 28 subjects, telaprevir (1250 mg every 8 hours for 4 doses)|
02144|051|D|increased the Cmax and AUC of a single dose of ketoconazole (200 mg) by 75%|
02144|052|D|and 2.25-fold, respectively.(2)|
02144|053|B||
02144|054|R|REFERENCES:|
02144|055|B||
02144|056|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02144|057|R|  January, 2017.|1
02144|058|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02144|059|R|  Incorporated October, 2013.|1
02144|060|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02144|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02144|062|R|  settings: a scientific statement from the American Heart Association and|6
02144|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02144|064|R|  2;55(9):934-47.|6
02145|001|T|MONOGRAPH TITLE:  Rilpivirine/Selected Strong CYP3A4 Inducers|
02145|002|B||
02145|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02145|004|L|is contraindicated and generally should not be dispensed or administered to|
02145|005|L|the same patient.|
02145|006|B||
02145|007|A|MECHANISM OF ACTION:  Apalutamide, barbiturates, carbamazepine,|
02145|008|A|dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib,|
02145|009|A|lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone,|
02145|010|A|oxcarbazepine, rifampin, rifapentine, and St. John's wort may induce the|
02145|011|A|metabolism of rilpivirine by CYP3A4.(1)|
02145|012|B||
02145|013|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide, barbiturates,|
02145|014|E|carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin,|
02145|015|E|ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin,|
02145|016|E|primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort may|
02145|017|E|result in decreased levels and effectiveness of rilpivirine, as well as the|
02145|018|E|development of resistance.(1)|
02145|019|B||
02145|020|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02145|021|P|of the inducer for longer than 1-2 weeks.|
02145|022|B||
02145|023|M|PATIENT MANAGEMENT:  The US manufacturer of rilpivirine states that|
02145|024|M|concurrent use of CYP3A4 inducers such as apalutamide, barbiturates,|
02145|025|M|carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin,|
02145|026|M|ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin,|
02145|027|M|primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort is|
02145|028|M|contraindicated.(1)  It may take several weeks after the discontinuation of|
02145|029|M|an enzyme inducer for enzyme activity to return to normal.(1)|
02145|030|B||
02145|031|D|DISCUSSION:  In a study in 16 subjects, rifampin (600 mg daily) decreased|
02145|032|D|the Cmax, AUC, and Cmin of rilpivirine (150 mg daily) by 69%, 80%, and 89%,|
02145|033|D|respectively.  There were no significant effects on the Cmax or AUC of|
02145|034|D|rifampin or 25-desacetylrifampin.(1)|
02145|035|D|   Strong CYP3A4 inducers linked include: apalutamide, barbiturates,|
02145|036|D|carbamazepine, dexamethasone, encorafenib, enzalutamide, fosphenytoin,|
02145|037|D|ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin,|
02145|038|D|primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort.|
02145|039|B||
02145|040|R|REFERENCES:|
02145|041|B||
02145|042|R|1.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
02145|043|R|  March, 2024.|1
02145|044|R|2.This information is based on an extract from the Certara Drug Interaction|6
02145|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02146|001|T|MONOGRAPH TITLE:  Rilpivirine/Proton Pump Inhibitors|
02146|002|B||
02146|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02146|004|L|is contraindicated and generally should not be dispensed or administered to|
02146|005|L|the same patient.|
02146|006|B||
02146|007|A|MECHANISM OF ACTION:  Rilpivirine requires an acidic medium for absorption.|
02146|008|A|The proton pump inhibitor induced decrease in gastric pH may result in a|
02146|009|A|decrease in rilpivirine absorption.(1)|
02146|010|B||
02146|011|E|CLINICAL EFFECTS:  Concurrent use of a proton pump inhibitor may result in|
02146|012|E|decreased levels and effectiveness of rilpivirine, as well as the|
02146|013|E|development of resistance.(1)|
02146|014|B||
02146|015|P|PREDISPOSING FACTORS:  None determined.|
02146|016|B||
02146|017|M|PATIENT MANAGEMENT:  The US manufacturer of rilpivirine states that|
02146|018|M|concurrent use of proton pump inhibitors is contraindicated.(1)|
02146|019|M|   When substituting antacids for proton pump inhibitors in patients|
02146|020|M|maintained on rilpivirine, administer the antacid at least 2 hours before or|
02146|021|M|4 hours after rilpivirine.(1)|
02146|022|M|   When substituting H2 antagonists for proton pump inhibitors in patients|
02146|023|M|maintained on rilpivirine, administer the H2 antagonist at least 12 hours|
02146|024|M|before or 4 hours after rilpivirine.(1)|
02146|025|B||
02146|026|D|DISCUSSION:  In a study in 16 subjects, omeprazole (20 mg daily) decreased|
02146|027|D|the maximum concentration (Cmax), area-under-curve (AUC), and minimum|
02146|028|D|concentration (Cmin) of rilpivirine (150 mg daily) by 40%, 40%, and 33%,|
02146|029|D|respectively.  The Cmax and AUC of omeprazole decreased by 14% and 14%,|
02146|030|D|respectively.(1)|
02146|031|D|   In a study in 24 subjects, famotidine (40 mg single dose) administered 12|
02146|032|D|hours before a single dose of rilpivirine (150 mg) had no significant effect|
02146|033|D|on rilpivirine Cmax or AUC.(1)|
02146|034|D|   In a study in 23 subjects, famotidine (40 mg single dose) administered 2|
02146|035|D|hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine|
02146|036|D|Cmax and AUC by 85% and 76%, respectively.(1)|
02146|037|D|   In a study in 24 subjects, famotidine (40 mg single dose) administered 4|
02146|038|D|hours after a single dose of rilpivirine (150 mg) increased the rilpivirine|
02146|039|D|Cmax and AUC by 21% and 13%, respectively.(1)|
02146|040|B||
02146|041|R|REFERENCE:|
02146|042|B||
02146|043|R|1.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
02146|044|R|  March, 2024.|1
02147|001|T|MONOGRAPH TITLE:  Rilpivirine/Antacids; H2 Antagonists|
02147|002|B||
02147|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02147|004|L|take action as needed.|
02147|005|B||
02147|006|A|MECHANISM OF ACTION:  Rilpivirine requires an acidic medium for absorption.|
02147|007|A|Antacid or H2 antagonist induced decrease in gastric pH may result in a|
02147|008|A|decrease in rilpivirine absorption.(1)|
02147|009|B||
02147|010|E|CLINICAL EFFECTS:  Simultaneous administration of an antacid or a H2|
02147|011|E|antagonist may result in decreased levels and effectiveness of rilpivirine,|
02147|012|E|as well as the development of resistance.(1)|
02147|013|B||
02147|014|P|PREDISPOSING FACTORS:  None determined.|
02147|015|B||
02147|016|M|PATIENT MANAGEMENT:  In patients maintained on rilpivirine, administer|
02147|017|M|antacids at least 2 hours before or 4 hours after rilpivirine.(1)|
02147|018|M|   In patients maintained on rilpivirine, administer H2 antagonists at least|
02147|019|M|12 hours before or 4 hours after rilpivirine.(1)|
02147|020|M|   Concurrent use of proton pump inhibitors with rilpivirine is|
02147|021|M|contraindicated.(1)|
02147|022|M|   Some vitamin preparations may contain sufficient quantities of calcium|
02147|023|M|and/or magnesium salts with antacid properties to interact as well.|
02147|024|B||
02147|025|D|DISCUSSION:  In a study in 16 subjects, omeprazole (20 mg daily) decreased|
02147|026|D|the maximum concentration (Cmax), area-under-curve (AUC), and minimum|
02147|027|D|concentration (Cmin) of rilpivirine (150 mg daily) by 40%, 40%, and 33%,|
02147|028|D|respectively.  The Cmax and AUC of omeprazole decreased by 14% and 14%,|
02147|029|D|respectively.(1)|
02147|030|D|   In a study in 24 subjects, famotidine (40 mg single dose) administered 12|
02147|031|D|hours before a single dose of rilpivirine (150 mg) had no significant effect|
02147|032|D|on rilpivirine Cmax or AUC.(1)|
02147|033|D|   In a study in 23 subjects, famotidine (40 mg single dose) administered 2|
02147|034|D|hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine|
02147|035|D|Cmax and AUC by 85% and 76%, respectively.(1)|
02147|036|D|   In a study in 24 subjects, famotidine (40 mg single dose) administered 4|
02147|037|D|hours after a single dose of rilpivirine (150 mg) increased the rilpivirine|
02147|038|D|Cmax and AUC by 21% and 13%, respectively.(1)|
02147|039|B||
02147|040|R|REFERENCE:|
02147|041|B||
02147|042|R|1.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
02147|043|R|  March, 2024.|1
02148|001|T|MONOGRAPH TITLE:  Rilpivirine/QT Prolonging Agents (mono deleted 04/15/2021)|
02148|002|B||
02148|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02148|004|L|take action as needed.|
02148|005|B||
02148|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02148|007|A|interval may result in additive effects on the QTc interval.(1)|
02148|008|B||
02148|009|E|CLINICAL EFFECTS:  The use of rilpivirine in patients maintained on agents|
02148|010|E|that prolong the QTc interval may result in potentially life-threatening|
02148|011|E|cardiac arrhythmias, including torsades de pointes.(1)|
02148|012|B||
02148|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02148|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02148|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02148|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02148|017|P|gender, advanced age or when receiving concomitant treatment with an|
02148|018|P|inhibitor of CYP3A4.(1,3)|
02148|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02148|020|P|higher systemic concentrations or either QT prolonging drug are additional|
02148|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02148|022|P|drug concentrations include rapid infusion or an intravenous dose or|
02148|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02148|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02148|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02148|026|B||
02148|027|M|PATIENT MANAGEMENT:  The concurrent use of rilpivirine with agents known to|
02148|028|M|prolong the QT interval should be approached with caution.(1)|
02148|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02148|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02148|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02148|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02148|033|B||
02148|034|D|DISCUSSION:  In a clinical trial in healthy adults, rilpivirine at|
02148|035|D|recommended dosages (25 mg daily) had no significant effects on the QTc|
02148|036|D|interval.  However, supratherapeutic dosages (75 mg daily and 300 mg daily)|
02148|037|D|increased the QTc interval by 10.7 msec and 23.3 msec, respectively.|
02148|038|D|Rilpivirine dosages of 75 mg daily and 300 mg daily resulted in rilpivirine|
02148|039|D|maximum concentration (Cmax) levels of 2.6-fold and 6.7-respectively.(1)|
02148|040|D|Increases of rilpivirine AUC of 2.3-fold were noted in combination with|
02148|041|D|darunavir/ritonavir(1) and may be seen with other commonly co-administered|
02148|042|D|HIV therapies.|
02148|043|D|   Agents that are linked to this monograph may have varying degrees of|
02148|044|D|potential to prolong the QTc interval but are generally accepted to have a|
02148|045|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02148|046|D|been shown to prolong the QTc interval either through their mechanism of|
02148|047|D|action, through studies on their effects on the QTc interval, or through|
02148|048|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02148|049|D|and/or post-marketing reports.(2)|
02148|050|B||
02148|051|R|REFERENCES:|
02148|052|B||
02148|053|R|1.Ciprofloxacin Australian prescribing information. Aspen Pharmacare Ltd 23|1
02148|054|R|  June 2022.|1
02148|055|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02148|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02148|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02148|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02148|059|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02148|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02148|061|R|  settings: a scientific statement from the American Heart Association and|6
02148|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02148|063|R|  2;55(9):934-47.|6
02149|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Telaprevir|
02149|002|B||
02149|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02149|004|L|is contraindicated and generally should not be dispensed or administered to|
02149|005|L|the same patient.|
02149|006|B||
02149|007|A|MECHANISM OF ACTION:  Telaprevir, a strong inhibitor of CYP3A4, may inhibit|
02149|008|A|the metabolism of lovastatin, and simvastatin.(1-3)|
02149|009|B||
02149|010|E|CLINICAL EFFECTS:  Concurrent use of telaprevir may result in elevated|
02149|011|E|levels of and effects from lovastatin and simvastatin, including myopathy|
02149|012|E|and rhabdomyolysis.(1-3)|
02149|013|B||
02149|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02149|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02149|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02149|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02149|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02149|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02149|020|P|predisposed to myopathy or rhabdomyolysis.|
02149|021|B||
02149|022|M|PATIENT MANAGEMENT:  The concurrent use of lovastatin,(1,2) or|
02149|023|M|simvastatin(1,3) with telaprevir is contraindicated.|
02149|024|M|   Based upon US manufacturer information, fluvastatin, pitavastatin,|
02149|025|M|pravastatin and rosuvastatin appear to be less susceptible to CYP3A4|
02149|026|M|inhibition.(4-7)|
02149|027|B||
02149|028|D|DISCUSSION:  In a study in 19 subjects, telaprevir (750 mg every 8 hours for|
02149|029|D|7 days) increased the maximum concentration (Cmax) and area-under-curve|
02149|030|D|(AUC) of a single dose of atorvastatin (20 mg) by 10.60-fold and 7.88-fold,|
02149|031|D|respectively.(1)  There were no significant effects on telaprevir|
02149|032|D|pharmacokinetics.(8)|
02149|033|B||
02149|034|R|REFERENCES:|
02149|035|B||
02149|036|R|1.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02149|037|R|  Incorporated October, 2013.|1
02149|038|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02149|039|R|  February, 2014.|1
02149|040|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02149|041|R|  2023.|1
02149|042|R|4.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
02149|043|R|  Pharmaceuticals Corporation August, 2017.|1
02149|044|R|5.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
02149|045|R|  Squibb Company May, 2022.|1
02149|046|R|6.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
02149|047|R|  America, Inc. November, 2022.|1
02149|048|R|7.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02149|049|R|  Pharmaceuticals LP July, 2024.|1
02149|050|R|8.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02149|051|R|  2020.|1
02150|001|T|MONOGRAPH TITLE:  Telaprevir/Selected CYP 3A4-PgP Inducers (mono deleted|
02150|002|T|01/09/2014)|
02150|003|B||
02150|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02150|005|L|is contraindicated and generally should not be dispensed or administered to|
02150|006|L|the same patient.|
02150|007|B||
02150|008|A|MECHANISM OF ACTION:  Rifampin and St. John's wort may induce the metabolism|
02150|009|A|of telaprevir by CYP P-450-3A4 and/or P-glycoprotein.(1)|
02150|010|B||
02150|011|E|CLINICAL EFFECTS:  Concurrent or recent use of rifampin or St. John's wort|
02150|012|E|may result in decreased levels and effectiveness of telaprevir.(1)|
02150|013|B||
02150|014|P|PREDISPOSING FACTORS:  None determined.|
02150|015|B||
02150|016|M|PATIENT MANAGEMENT:  The US manufacturer of telaprevir states that|
02150|017|M|concurrent administration of strong inducers of CYP P-450-3A4 such as|
02150|018|M|rifampin or St. John's wort is contraindicated.(1)|
02150|019|B||
02150|020|D|DISCUSSION:  In a study in 16 subjects, rifampin (600 mg daily for 8 days)|
02150|021|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02150|022|D|single dose of telaprevir (750 mg) by 86% and 92%, respectively.(1)|
02150|023|B||
02150|024|R|REFERENCE:|
02150|025|B||
02150|026|R|1.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02150|027|R|  Incorporated April, 2013.|1
02151|001|T|MONOGRAPH TITLE:  Hormonal Contraceptive Agents/Telaprevir|
02151|002|B||
02151|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02151|004|L|of severe adverse interaction.|
02151|005|B||
02151|006|A|MECHANISM OF ACTION:  Telaprevir may induce the metabolism of hormonal|
02151|007|A|contraceptives by CYP3A4.|
02151|008|B||
02151|009|E|CLINICAL EFFECTS:  Concurrent use of telaprevir and hormonal contraceptive|
02151|010|E|agents may decrease the effectiveness of the hormonal contraceptive agent,|
02151|011|E|which may result in contraceptive failure.  Telaprevir is only indicated for|
02151|012|E|use with ribavirin, a known teratogen.(1)|
02151|013|B||
02151|014|P|PREDISPOSING FACTORS:  None determined.|
02151|015|B||
02151|016|M|PATIENT MANAGEMENT:  Women receiving telaprevir therapy should not rely on|
02151|017|M|hormonal contraceptive agents (including oral, implantable, injectable, or|
02151|018|M|transdermal agents) because they may not be effective during and for two|
02151|019|M|weeks after completing telaprevir therapy.  Two alternative effective|
02151|020|M|methods of contraception (e.g. intrauterine devices and/or barrier methods)|
02151|021|M|should be used during combination treatment with ribavirin and for six|
02151|022|M|months after completing therapy.(1)|
02151|023|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
02151|024|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
02151|025|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
02151|026|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
02151|027|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
02151|028|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
02151|029|M|and to seek medical advice if they do become pregnant.(2)|
02151|030|B||
02151|031|D|DISCUSSION:  In a study in 24 subjects, concurrent use of telaprevir (750 mg|
02151|032|D|every 8 hours for 21 days) decreased the maximum concentration (Cmax),|
02151|033|D|area-under-curve (AUC), and minimum concentration (Cmin) of ethinyl|
02151|034|D|estradiol (administered as ethinyl estradiol/norethindrone 0.035/0.5 mg|
02151|035|D|daily for 21 days) by 26%, 28%, and 33% respectively.  The Cmax, AUC, and|
02151|036|D|Cmin of norethindrone decreased by 15%, 11%, and 6%, respectively.  There|
02151|037|D|were no significant effects on telaprevir levels.(1,2)|
02151|038|B||
02151|039|R|REFERENCES:|
02151|040|B||
02151|041|R|1.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02151|042|R|  Incorporated October, 2013.|1
02151|043|R|2.Garg V, van Heeswijk R, Yang Y, Kauffman R, Smith F, Adda N. The|2
02151|044|R|  Pharmacokinetic Interaction Between an Oral Contraceptive Containing|2
02151|045|R|  Ethinyl  Estradiol and Norethindrone and the HCV Protease Inhibitor|2
02151|046|R|  Telaprevir. J Clin Pharmacol 2011 Oct 30.|2
02151|047|R|3.Medicines and Healthcare products Regulatory Agency.|1
02151|048|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
02151|049|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
02151|050|R|  available at:|1
02151|051|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
02151|052|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
02151|053|R|  -and-contraceptive-efficacy September 15, 2016..|1
02152|001|T|MONOGRAPH TITLE:  Opioids/Butorphanol|
02152|002|B||
02152|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02152|004|L|take action as needed.|
02152|005|B||
02152|006|A|MECHANISM OF ACTION:  Butorphanol antagonize mu-opiate receptors. Other|
02152|007|A|opioids agonize mu-opiate receptors.(1)|
02152|008|B||
02152|009|E|CLINICAL EFFECTS:  Concurrent use of butorphanol with other opioids in|
02152|010|E|opioid dependent patients may result in withdrawal symptoms.  Concurrent use|
02152|011|E|in other patients may result in additive or decreased analgesia and|
02152|012|E|decreased opioid side effects.|
02152|013|B||
02152|014|P|PREDISPOSING FACTORS:  Patients dependent on opioids may be more likely to|
02152|015|P|experience withdrawal symptoms with concurrent use.  Patients using higher|
02152|016|P|doses of opioids may also be at a higher risk.|
02152|017|B||
02152|018|M|PATIENT MANAGEMENT:  Use butorphanol with caution in patients maintained or|
02152|019|M|dependent on other opioids and monitor for signs of withdrawal.  In other|
02152|020|M|patients, also monitor for changes in analgesic effects.|
02152|021|B||
02152|022|D|DISCUSSION:  Because butorphanol antagonizes mu-opiate receptors and other|
02152|023|D|opioids agonize mu-opiate receptors, concurrent use of buprenorphine with|
02152|024|D|other opioids in opioid dependent patients may result in withdrawal|
02152|025|D|symptoms.  Concurrent use in other patients may result in additive or|
02152|026|D|decreased analgesia and decreased opioid side effects.(1)|
02152|027|D|   In a study in patients maintained on methadone, butorphanol produced|
02152|028|D|withdrawal symptoms comparable to naloxone.(2)|
02152|029|D|   In a case report, the use of remifentanil for conscious sedation in a|
02152|030|D|patient maintained on butorphanol produced severe withdrawal symptoms.(3)|
02152|031|B||
02152|032|R|REFERENCES:|
02152|033|B||
02152|034|R|1.Stadol (butorphanol tartrate) US prescribing information. Bristol-Myers|1
02152|035|R|  Squibb April, 2002.|1
02152|036|R|2.Preston KL, Bigelow GE, Liebson IA. Butorphanol-precipitated withdrawal in|2
02152|037|R|  opioid-dependent human volunteers. J Pharmacol Exp Ther 1988 Aug;|2
02152|038|R|  246(2):441-8.|2
02152|039|R|3.Igarashi A, Amagasa S, Yokoo N, Sato M. Acute withdrawal syndrome in a|3
02152|040|R|  butorphanol-treated patient: an adverse combination of opioids. Br J|3
02152|041|R|  Anaesth 2008 Jul;101(1):127-8.|3
02153|001|T|MONOGRAPH TITLE:  Opioids/Nalbuphine|
02153|002|B||
02153|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02153|004|L|take action as needed.|
02153|005|B||
02153|006|A|MECHANISM OF ACTION:  Nalbuphine(1) antagonizes mu-opiate receptors.  Other|
02153|007|A|opioids agonize mu-opiate receptors.|
02153|008|B||
02153|009|E|CLINICAL EFFECTS:  Concurrent use of nalbuphine with other opioids in opioid|
02153|010|E|dependent patients may result in withdrawal symptoms.  Concurrent use in|
02153|011|E|other patients may result in additive or decreased analgesia, decreased|
02153|012|E|opioid side effects, and/or renarcotization.|
02153|013|B||
02153|014|P|PREDISPOSING FACTORS:  Patients dependent on opioids may be more likely to|
02153|015|P|experience withdrawal symptoms with concurrent use.  In opioid naive|
02153|016|P|patients, higher doses of nalbuphine may result in decreased analgesic|
02153|017|P|effects.|
02153|018|B||
02153|019|M|PATIENT MANAGEMENT:  Use nalbuphine with caution in patients maintained or|
02153|020|M|dependent on other opioids and monitor for signs of withdrawal.  In other|
02153|021|M|patients, also monitor for changes in analgesic effects.  If nalbuphine is|
02153|022|M|used to reverse opioid anesthesia, monitor patients for renarcotization.|
02153|023|B||
02153|024|D|DISCUSSION:  Nalbuphine has been successfully used as an adjunct to morphine|
02153|025|D|without decreasing analgesic effects.(2,3)  However, other studies reported|
02153|026|D|increased morphine requirements in patients who had initially received|
02153|027|D|nalbuphine.(4,5)|
02153|028|D|   Nalbuphine has been used to reverse fentanyl anesthesia;(8-13) however,|
02153|029|D|patients often required additional pain medication(5-7) and some studies|
02153|030|D|reported renarcotization after the effects of nalbuphine wore off.(9,10)|
02153|031|D|Nalbuphine has also been used to prevent epidural fentanyl,(13)|
02153|032|D|morphine(14-16), and hydromorphone induced pruritus;(17-18) however, one|
02153|033|D|study reported shortening of the duration of analgesia(16) and another|
02153|034|D|reported increased PCA demands.(17)|
02153|035|D|   In methadone-dependent subjects, administration of nalbuphine produced|
02153|036|D|withdrawal symptoms similar to naloxone.(19,20)  Administration of|
02153|037|D|nalbuphine to patients maintained on controlled-release morphine resulted in|
02153|038|D|withdrawal symptoms.(20,21)|
02153|039|B||
02153|040|R|REFERENCES:|
02153|041|B||
02153|042|R|1.Nubain (nalbuphine hydrochloride) US prescribing information. Endo|1
02153|043|R|  Pharmaceuticals Inc. October, 2019.|1
02153|044|R|2.Wang JJ, Ho ST, Hu OY. Comparison of intravenous nalbuphine infusion|2
02153|045|R|  versus saline as an adjuvant for epidural morphine. Reg Anesth 1996|2
02153|046|R|  May-Jun;21(3):214-8.|2
02153|047|R|3.Wang JJ, Ho ST, Tzeng JI. Comparison of intravenous nalbuphine infusion|2
02153|048|R|  versus naloxone in the prevention of epidural morphine-related side|2
02153|049|R|  effects. Reg Anesth Pain Med 1998 Sep-Oct;23(5):479-84.|2
02153|050|R|4.Houlihan KP, Mitchell RG, Flapan AD, Steedman DJ. Excessive morphine|2
02153|051|R|  requirements after pre-hospital nalbuphine analgesia. J Accid Emerg Med|2
02153|052|R|  1999 Jan;16(1):29-31.|2
02153|053|R|5.Robinson N, Burrows N. Excessive morphine requirements after pre-hospital|2
02153|054|R|  nalbuphine analgesia. J Accid Emerg Med 1999 Sep;16(5):392.|2
02153|055|R|6.Jaffe RS, Moldenhauer CC, Hug CC Jr, Finlayson DC, Tobia V, Kopel ME.|2
02153|056|R|  Nalbuphine antagonism of fentanyl-induced ventilatory depression: a|2
02153|057|R|  randomized trial. Anesthesiology 1988 Feb;68(2):254-60.|2
02153|058|R|7.Ramsay JG, Higgs BD, Wynands JE, Robbins R, Townsend GE. Early extubation|2
02153|059|R|  after high-dose fentanyl anaesthesia for aortocoronary bypass surgery:|2
02153|060|R|  reversal of respiratory depression with low-dose nalbuphine. Can Anaesth|2
02153|061|R|  Soc J 1985 Nov;32(6):597-606.|2
02153|062|R|8.Blaise GA, Nugent M, McMichan JC, Durant PA. Side effects of nalbuphine|2
02153|063|R|  while reversing opioid-induced respiratory depression: report of four|2
02153|064|R|  cases. Can J Anaesth 1990 Oct;37(7):794-7.|2
02153|065|R|9.Moldenhauer CC, Roach GW, Finlayson DC, Hug CC Jr, Kopel ME, Tobia V,|2
02153|066|R|  Kelly S. Nalbuphine antagonism of ventilatory depression following|2
02153|067|R|  high-dose fentanyl anesthesia. Anesthesiology 1985 May;62(5):647-50.|2
02153|068|R|10.Bailey PL, Clark NJ, Pace NL, Stanley TH, East KA, van Vreeswijk H, van|2
02153|069|R|   de Pol P, Clissold MA, Rozendaal W. Antagonism of postoperative|2
02153|070|R|   opioid-induced respiratory depression: nalbuphine versus naloxone. Anesth|2
02153|071|R|   Analg 1987 Nov;66(11):1109-14.|2
02153|072|R|11.Latasch L, Teichmuller T, Dudziak R, Probst S. Antagonisation of|2
02153|073|R|   fentanyl-induced respiratory depression by nalbuphine. Acta Anaesthesiol|2
02153|074|R|   Belg 1989;40(1):35-40.|2
02153|075|R|12.Zsigmond EK, Durrani Z, Barabas E, Wang XY, Tran L. Endocrine and|2
02153|076|R|   hemodynamic effects of antagonism of fentanyl-induced respiratory|2
02153|077|R|   depression by nalbuphine. Anesth Analg 1987 May;66(5):421-6.|2
02153|078|R|13.Davies GG, From R. A blinded study using nalbuphine for prevention of|2
02153|079|R|   pruritus induced by epidural fentanyl. Anesthesiology 1988 Nov;|2
02153|080|R|   69(5):763-5.|2
02153|081|R|14.Kendrick WD, Woods AM, Daly MY, Birch RF, DiFazio C. Naloxone versus|2
02153|082|R|   nalbuphine infusion for prophylaxis of epidural morphine-induced|2
02153|083|R|   pruritus. Anesth Analg 1996 Mar;82(3):641-7.|2
02153|084|R|15.Cohen SE, Ratner EF, Kreitzman TR, Archer JH, Mignano LR. Nalbuphine is|2
02153|085|R|   better than naloxone for treatment of side effects after epidural|2
02153|086|R|   morphine. Anesth Analg 1992 Nov;75(5):747-52.|2
02153|087|R|16.Alhashemi JA, Crosby ET, Grodecki W, Duffy PJ, Hull KA, Gallant C.|2
02153|088|R|   Treatment of intrathecal morphine-induced pruritus following caesarean|2
02153|089|R|   section. Can J Anaesth 1997 Oct;44(10):1060-5.|2
02153|090|R|17.Parker RK, Holtmann B, White PF. Patient-controlled epidural analgesia:|2
02153|091|R|   interactions between nalbuphine and hydromorphone. Anesth Analg 1997 Apr;|2
02153|092|R|   84(4):757-63.|2
02153|093|R|18.Henderson SK, Cohen H. Nalbuphine augmentation of analgesia and reversal|3
02153|094|R|   of side effects following epidural hydromorphone. Anesthesiology 1986|3
02153|095|R|   Aug;65(2):216-8.|3
02153|096|R|19.Preston KL, Bigelow GE, Liebson IA. Antagonist effects of nalbuphine in|2
02153|097|R|   opioid-dependent human volunteers. J Pharmacol Exp Ther 1989 Mar;|2
02153|098|R|   248(3):929-37.|2
02153|099|R|20.Hartree C. Caution with nalbuphine in patients on long-term opioids.|3
02153|100|R|   Palliat Med 2005 Mar;19(2):168.|3
02153|101|R|21.Smith J, Guly H. Nalbuphine and slow release morphine. BMJ 2004 Jun 12;|3
02153|102|R|   328(7453):1426.|3
02154|001|T|MONOGRAPH TITLE:  Toremifene/Strong CYP 3A4 Inhibitors (mono deleted|
02154|002|T|03/05/2015)|
02154|003|B||
02154|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02154|005|L|of severe adverse interaction.|
02154|006|B||
02154|007|A|MECHANISM OF ACTION:  Toremifene has been shown to prolong the QTc interval|
02154|008|A|in a dose-related and concentration-related manner.  Strong CYP P-450-3A4|
02154|009|A|inhibitors may inhibit the metabolism of toremifene.(1)  Strong inhibitors|
02154|010|A|of CYP P-450-3A4 include atazanavir, clarithromycin, indinavir,|
02154|011|A|itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,|
02154|012|A|telithromycin, and voriconazole.(1,2)|
02154|013|B||
02154|014|E|CLINICAL EFFECTS:  Concurrent use of atazanavir, clarithromycin, indinavir,|
02154|015|E|itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,|
02154|016|E|telithromycin, or voriconazole may result in increased levels of and side|
02154|017|E|effects from toremifene, including potentially life-threatening cardiac|
02154|018|E|arrhythmias.(1)|
02154|019|B||
02154|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02154|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
02154|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02154|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02154|024|P|female gender, or advanced age.(3)|
02154|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02154|026|P|higher systemic concentrations of either QT prolonging drug are additional|
02154|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02154|028|P|drug concentrations include rapid infusion of an intravenous dose or|
02154|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02154|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02154|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02154|032|B||
02154|033|M|PATIENT MANAGEMENT:  The US manufacturer of toremifene recommends avoiding|
02154|034|M|concurrent use of strong inhibitor of CYP P-450-3A4 such as atazanavir,|
02154|035|M|clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone,|
02154|036|M|nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole.(1)|
02154|037|M|   If treatment with a strong CYP P-450-3A4 inhibitor is required,|
02154|038|M|toremifene therapy should be interrupted.  If it is not possible to|
02154|039|M|interrupt toremifene therapy, electrocardiograms (ECGs) should be obtained|
02154|040|M|and patients should be closely monitored for QT prolongation.(1)|
02154|041|B||
02154|042|D|DISCUSSION:  In a study in 18 subjects, ketoconazole (200 mg daily)|
02154|043|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02154|044|D|toremifene (80 mg daily) by 1.4-fold and 2.9-fold, respectively.|
02154|045|D|N-demethyltoremifene Cmax and AUC decreased by 56% and 20%, respectively.(1)|
02154|046|D|  Atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole,|
02154|047|D|nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and|
02154|048|D|voriconazole have been shown to be strong inhibitors of CYP P-450-3A4.(1,2)|
02154|049|B||
02154|050|R|REFERENCES:|
02154|051|B||
02154|052|R|1.Fareston (toremifene citrate) US prescribing information. GTx, Inc. March,|1
02154|053|R|  2011.|1
02154|054|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02154|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02154|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02154|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02154|058|R|  11/14/2017.|1
02154|059|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02154|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02154|061|R|  settings: a scientific statement from the American Heart Association and|6
02154|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02154|063|R|  2;55(9):934-47.|6
02155|001|T|MONOGRAPH TITLE:  Ezogabine/Possible QT Prolonging Agents|
02155|002|B||
02155|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02155|004|L|take action as needed.|
02155|005|B||
02155|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02155|007|A|interval may result in additive effects on the QTc interval.(1)|
02155|008|B||
02155|009|E|CLINICAL EFFECTS:  The use of ezogabine in patients maintained on agents|
02155|010|E|that prolong the QTc interval may result in potentially life-threatening|
02155|011|E|cardiac arrhythmias, including torsade de pointes.(1)|
02155|012|B||
02155|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02155|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02155|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02155|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02155|017|P|gender, or advanced age.(2)|
02155|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02155|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02155|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02155|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02155|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02155|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02155|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02155|025|B||
02155|026|M|PATIENT MANAGEMENT:  The concurrent use of ezogabine with agents known to|
02155|027|M|prolong the QT interval should be approached with caution.  Patients|
02155|028|M|receiving concurrent therapy with other QT prolongers, an electrocardiogram|
02155|029|M|(ECG) should be performed prior to ezogabine initiation.  In those patients|
02155|030|M|with a corrected QT interval greater than 440 msec at baseline, a repeat ECG|
02155|031|M|should be performed after reaching the maintenance dose of ezogabine.(1)|
02155|032|M|   Consider obtaining serum calcium, magnesium, and potassium levels at|
02155|033|M|baseline and regular intervals. Correct any electrolyte abnormalities.|
02155|034|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02155|035|M|fainting.|
02155|036|B||
02155|037|D|DISCUSSION:  In a study in healthy subjects, ezogabine titrated to 1200|
02155|038|D|mg/day increased the mean QTc interval by 6.7 msec (upper bound of 95% CI|
02155|039|D|was 12.6 msec) within three hours of dosing.(1)|
02155|040|B||
02155|041|R|REFERENCES:|
02155|042|B||
02155|043|R|1.Potiga (ezogabine) US Prescribing Information. Valeant Pharmaceuticals|1
02155|044|R|  May, 2016.|1
02155|045|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02155|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02155|047|R|  settings: a scientific statement from the American Heart Association and|6
02155|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02155|049|R|  2;55(9):934-47.|6
02155|050|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02155|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02155|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02155|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02156|001|T|MONOGRAPH TITLE:  Simvastatin (Greater Than 20 mg)/Ranolazine|
02156|002|B||
02156|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02156|004|L|is contraindicated and generally should not be dispensed or administered to|
02156|005|L|the same patient.|
02156|006|B||
02156|007|A|MECHANISM OF ACTION:  Ranolazine may inhibit the metabolism of simvastatin|
02156|008|A|by CYP3A4.(1-5)|
02156|009|B||
02156|010|E|CLINICAL EFFECTS:  Concurrent ranolazine may result in elevated levels of|
02156|011|E|simvastatin,(1-5) which may result in myopathy and rhabdomyolysis.|
02156|012|B||
02156|013|P|PREDISPOSING FACTORS:  None determined.|
02156|014|B||
02156|015|M|PATIENT MANAGEMENT:  Do not exceed a dosage of 20 mg daily of simvastatin in|
02156|016|M|patients receiving concurrent therapy with ranolazine.(1-3)|
02156|017|B||
02156|018|D|DISCUSSION:  In healthy subjects, ranolazine (1000 mg twice daily) increased|
02156|019|D|plasma levels of simvastatin (80 mg daily) and its active metabolite each by|
02156|020|D|2-fold.(4)|
02156|021|D|   In healthy subjects, simvastatin (20 mg daily) had no effect on|
02156|022|D|ranolazine levels.(4)|
02156|023|D|   In a study in 17 healthy volunteers, simvastatin (80 mg daily) did not|
02156|024|D|have a significant effect on ranolazine sustained release (SR, 1750 mg|
02156|025|D|initial dose followed by 1000 mg twice daily) pharmacokinetics with the mean|
02156|026|D|area under the curve (AUC), maximum concentration (Cmax), and minimum|
02156|027|D|concentration (Cmin) being within 80% to 125%. In contrast, ranolazine SR|
02156|028|D|increased the Cmax of simvastatin lactone, simvastatin acid, and HMG-CoA|
02156|029|D|reductase inhibitor activity by 2-fold with the corresponding AUC increases|
02156|030|D|in the range of 40% to 60%.(5,6)|
02156|031|D|   In a case report, a patient had been maintained on simvastatin for 12|
02156|032|D|years, one of which with concurrent cyclosporine.  Two months after the|
02156|033|D|addition of carvedilol, diltiazem, and ranolazine, the patient developed|
02156|034|D|rhabdomyolysis.(7)|
02156|035|D|   In a case report, a patient had been maintained on a stable dose of|
02156|036|D|simvastatin (80 mg).  Ten days after the addition of ranolazine (500 mg|
02156|037|D|extended release) was added to the patient's medication regimen, the patient|
02156|038|D|developed rhabdomyolysis.(9)|
02156|039|B||
02156|040|R|REFERENCES:|
02156|041|B||
02156|042|R|1.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02156|043|R|  restrictions, contraindications, and dose limitations for Zocor|1
02156|044|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02156|045|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02156|046|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02156|047|R|  June 8, 2011.|1
02156|048|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02156|049|R|  2023.|1
02156|050|R|3.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02156|051|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
02156|052|R|4.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
02156|053|R|5.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
02156|054|R|  Pharma U.K. S.R.I. October 30, 2008.|1
02156|055|R|6.Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to|2
02156|056|R|  investigate the pharmacokinetic interactions between ranolazine and|2
02156|057|R|  ketoconazole, diltiazem, or simvastatin during combined administration in|2
02156|058|R|  healthy subjects. J Clin Pharmacol 2005 Apr;45(4):422-33.|2
02156|059|R|7.Rifkin SI. Multiple drug interactions in a renal transplant patient|3
02156|060|R|  leading to simvastatin-induced rhabdomyolysis: a case report. Medscape J|3
02156|061|R|  Med 2008;10(11):264.|3
02156|062|R|8.Hylton AC, Ezekiel TO. Rhabdomyolysis in a patient receiving ranolazine|3
02156|063|R|  and simvastatin. Am J Health Syst Pharm 2010 Nov 1;67(21):1829-31.|3
02157|001|T|MONOGRAPH TITLE:  Simvastatin (Greater Than 20 mg)/Amlodipine|
02157|002|B||
02157|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02157|004|L|is contraindicated and generally should not be dispensed or administered to|
02157|005|L|the same patient.|
02157|006|B||
02157|007|A|MECHANISM OF ACTION:  Amlodipine may inhibit the metabolism of simvastatin|
02157|008|A|by CYP3A4.(1-7)|
02157|009|A|   Levamlodipine is the active isomer of amlodipine.(8)|
02157|010|B||
02157|011|E|CLINICAL EFFECTS:  Concurrent amlodipine may result in elevated levels of|
02157|012|E|simvastatin,(1-7) which may result in myopathy and rhabdomyolysis.|
02157|013|B||
02157|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02157|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02157|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02157|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02157|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02157|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02157|020|P|predisposed to myopathy or rhabdomyolysis.|
02157|021|B||
02157|022|M|PATIENT MANAGEMENT:  Do not exceed a dosage of 20 mg daily of simvastatin in|
02157|023|M|patients receiving concurrent therapy with amlodipine.(1-4)  Consider|
02157|024|M|separating the administration times of amlodipine and simvastatin in|
02157|025|M|patients receiving concurrent therapy with amlodipine and simvastatin doses|
02157|026|M|of 20 mg or less.(5)|
02157|027|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
02157|028|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
02157|029|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
02157|030|M|urine, and/or discolored urine.|
02157|031|B||
02157|032|D|DISCUSSION:  In a study in 8 patients with hypercholesterolemia and|
02157|033|D|hypertension, 4 weeks of concurrent administration of amlodipine (5 mg|
02157|034|D|daily) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
02157|035|D|of simvastatin (5 mg daily) by 43% and 28%, respectively.  There were no|
02157|036|D|changes in the lipid-lowering affects of simvastatin.(6)|
02157|037|D|   In a study in 17 subjects, administration of amlodipine (5 mg daily) 4|
02157|038|D|hours after simvastatin (5 mg daily) resulted in Cmax and AUC values of|
02157|039|D|simvastatin that were 63.2% and 66.0%, respectively, of values obtained with|
02157|040|D|simultaneous dosing.(5)|
02157|041|D|   Acute renal failure and rhabdomyolysis was reported in patient maintained|
02157|042|D|on amlodipine and alprazolam two days after beginning the maximal dose of|
02157|043|D|simvastatin.(7)|
02157|044|B||
02157|045|R|REFERENCES:|
02157|046|B||
02157|047|R|1.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02157|048|R|  restrictions, contraindications, and dose limitations for Zocor|1
02157|049|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02157|050|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02157|051|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02157|052|R|  June 8, 2011.|1
02157|053|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02157|054|R|  2023.|1
02157|055|R|3.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02157|056|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
02157|057|R|4.Ede M. Dear Canadian Healthcare Professional:  Subject:  ZOCOR|1
02157|058|R|  (simvastatin) - New Safety Recommendations on Dosage Associated with the|1
02157|059|R|  Increased Risk of Myopathy/Rhabdomyolysis. Merck Canada Inc. November 7,|1
02157|060|R|  2012.|1
02157|061|R|5.Park CG, Lee H, Choi JW, Lee SJ, Kim SH, Lim HE. Non-concurrent dosing|2
02157|062|R|  attenuates the pharmacokinetic interaction between amlodipine and|2
02157|063|R|  simvastatin. Int J Clin Pharmacol Ther 2010 Aug;48(8):497-503.|2
02157|064|R|6.Nishio S, Watanabe H, Kosuge K, Uchida S, Hayashi H, Ohashi K. Interaction|2
02157|065|R|  between amlodipine and simvastatin in patients with hypercholesterolemia|2
02157|066|R|  and hypertension. Hypertens Res 2005 Mar;28(3):223-7.|2
02157|067|R|7.Deme D, Al-Hadad A, Varga T, Szanto E, Sandor K, Rakonczai E. Maximal|3
02157|068|R|  initial dose of simvastatin causing acute renal failure through|3
02157|069|R|  rhabdomyolysis: risk factors, pathomechanism and therapy related to a|3
02157|070|R|  case. Orv Hetil 2009 Feb 8;150(6):265-9.|3
02157|071|R|8.Conjupri (levamlodipine) US prescribing information. CSPC Ouyi|1
02157|072|R|  Pharmaceutical Co., Ltd. December, 2019.|1
02157|073|R|9.This information is based on an extract from the Certara Drug Interaction|6
02157|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02158|001|T|MONOGRAPH TITLE:  Simvastatin (Less than or Equal To 20 mg)/Amlodipine|
02158|002|B||
02158|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02158|004|L|take action as needed.|
02158|005|B||
02158|006|A|MECHANISM OF ACTION:  Amlodipine may inhibit the metabolism of simvastatin|
02158|007|A|by CYP3A4.(1-7)|
02158|008|A|   Levamlodipine is the active isomer of amlodipine.(8)|
02158|009|B||
02158|010|E|CLINICAL EFFECTS:  Concurrent amlodipine may result in elevated levels of|
02158|011|E|simvastatin,(1-7) which may result in myopathy and rhabdomyolysis.|
02158|012|B||
02158|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02158|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02158|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02158|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02158|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02158|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02158|019|P|predisposed to myopathy or rhabdomyolysis.|
02158|020|B||
02158|021|M|PATIENT MANAGEMENT:  Do not exceed a dosage of 20 mg daily of simvastatin in|
02158|022|M|patients receiving concurrent therapy with amlodipine.(1-4)  Consider|
02158|023|M|separating the administration times of amlodipine and simvastatin in|
02158|024|M|patients receiving concurrent therapy with amlodipine and simvastatin doses|
02158|025|M|of 20 mg or less.(5)|
02158|026|B||
02158|027|D|DISCUSSION:  In a study in 8 patients with hypercholesterolemia and|
02158|028|D|hypertension, 4 weeks of concurrent administration of amlodipine (5 mg|
02158|029|D|daily) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
02158|030|D|of simvastatin (5 mg daily) by 43% and 28%, respectively.  There were no|
02158|031|D|changes in the lipid-lowering affects of simvastatin.(6)|
02158|032|D|   In a study in 17 subjects, administration of amlodipine (5 mg daily) 4|
02158|033|D|hours after simvastatin (5 mg daily) resulted in Cmax and AUC values of|
02158|034|D|simvastatin that were 63.2% and 66.0%, respectively, of values obtained with|
02158|035|D|simultaneous dosing.(5)|
02158|036|D|   Acute renal failure and rhabdomyolysis was reported in patient maintained|
02158|037|D|on amlodipine and alprazolam two days after beginning the maximal dose of|
02158|038|D|simvastatin.(7)|
02158|039|B||
02158|040|R|REFERENCES:|
02158|041|B||
02158|042|R|1.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02158|043|R|  restrictions, contraindications, and dose limitations for Zocor|1
02158|044|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02158|045|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02158|046|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02158|047|R|  June 8, 2011.|1
02158|048|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02158|049|R|  2023.|1
02158|050|R|3.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02158|051|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
02158|052|R|4.Ede M. Dear Canadian Healthcare Professional:  Subject:  ZOCOR|1
02158|053|R|  (simvastatin) - New Safety Recommendations on Dosage Associated with the|1
02158|054|R|  Increased Risk of Myopathy/Rhabdomyolysis. Merck Canada Inc. November 7,|1
02158|055|R|  2012.|1
02158|056|R|5.Park CG, Lee H, Choi JW, Lee SJ, Kim SH, Lim HE. Non-concurrent dosing|2
02158|057|R|  attenuates the pharmacokinetic interaction between amlodipine and|2
02158|058|R|  simvastatin. Int J Clin Pharmacol Ther 2010 Aug;48(8):497-503.|2
02158|059|R|6.Nishio S, Watanabe H, Kosuge K, Uchida S, Hayashi H, Ohashi K. Interaction|2
02158|060|R|  between amlodipine and simvastatin in patients with hypercholesterolemia|2
02158|061|R|  and hypertension. Hypertens Res 2005 Mar;28(3):223-7.|2
02158|062|R|7.Deme D, Al-Hadad A, Varga T, Szanto E, Sandor K, Rakonczai E. Maximal|3
02158|063|R|  initial dose of simvastatin causing acute renal failure through|3
02158|064|R|  rhabdomyolysis: risk factors, pathomechanism and therapy related to a|3
02158|065|R|  case. Orv Hetil 2009 Feb 8;150(6):265-9.|3
02158|066|R|8.Conjupri (levamlodipine) US prescribing information. CSPC Ouyi|1
02158|067|R|  Pharmaceutical Co., Ltd. December, 2019.|1
02159|001|T|MONOGRAPH TITLE:  Astemizole; Terfenadine/Selected QT Prolongers|
02159|002|B||
02159|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02159|004|L|take action as needed.|
02159|005|B||
02159|006|A|MECHANISM OF ACTION:  Concurrent use of astemizole or terfenadine with|
02159|007|A|agents known to prolong the QTc interval may result in additive effects on|
02159|008|A|the QTc interval.|
02159|009|B||
02159|010|E|CLINICAL EFFECTS:  Concurrent use may result in potentially life-threatening|
02159|011|E|cardiac arrhythmias, including torsade de pointes.(1)|
02159|012|B||
02159|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02159|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02159|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02159|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02159|017|P|female gender, or advanced age.(1)|
02159|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02159|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02159|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02159|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02159|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02159|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02159|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02159|025|B||
02159|026|M|PATIENT MANAGEMENT:  The manufacturers of apomorphine,(2) dasatinib,(3)|
02159|027|M|dolasetron,(4) fesoterodine,(5) formoterol,(6,7) gadoxetate,(8,9)|
02159|028|M|gatifloxacin,(10) gemifloxacin,(11) haloperidol,(12-14) lapatinib,(15)|
02159|029|M|levofloxacin,(16) methadone,(17) nalidixic acid,(18) norfloxacin,(19) and|
02159|030|M|risperidone(20) state that these agents should be used with caution with|
02159|031|M|other agents known to prolong the QTc interval.|
02159|032|M|   The manufacturer of arsenic trioxide states that, if possible, drugs that|
02159|033|M|are known to prolong the QT interval should be discontinued prior to therapy|
02159|034|M|and caution is advised during coadministration.  In patients who reach a QTc|
02159|035|M|interval value > 450 msec in men or >460 msec in women, withhold arsenic and|
02159|036|M|any other QT prolonging agents.  Monitor electrolytes and correct|
02159|037|M|abnormalities.  After the QTc normalizes, follow manufacturer instructions|
02159|038|M|concerning restarting arsenic and escalation of dosing.(21)|
02159|039|M|   The US manufacturer of ciprofloxacin states that ciprofloxacin should be|
02159|040|M|used with caution with other agents known to prolong the QT interval,|
02159|041|M|especially in the elderly.(23)  The UK manufacturer of ciprofloxacin states|
02159|042|M|that ciprofloxacin should be used with caution in patients at risk for|
02159|043|M|torsades.(23)|
02159|044|M|   The US manufacturer of eribulin states that patients receiving concurrent|
02159|045|M|therapy with eribulin and other agents known to prolong the QT interval|
02159|046|M|should receive ECG monitoring.(24)|
02159|047|M|   The concurrent use of ezogabine with agents known to prolong the QT|
02159|048|M|interval should be approached with caution.  Patients receiving concurrent|
02159|049|M|therapy with other QT prolongers, an electrocardiogram (ECG) should be|
02159|050|M|performed prior to ezogabine initiation.  In those patients with a corrected|
02159|051|M|QT interval greater than 440 msec at baseline, a repeat ECG should be|
02159|052|M|performed after reaching the maintenance dose of ezogabine.(25)|
02159|053|M|   In patients maintained on agents known to prolong the QT interval,|
02159|054|M|consider a baseline ECG prior to administration of gadofosveset to asses the|
02159|055|M|risk/benefit of gadofosveset.  If gadofosveset is used, consider ECG|
02159|056|M|monitoring for 72 hours until the majority of gadofosveset is eliminated.|
02159|057|M|Counsel patients to report any irregular heartbeat, dizziness, or fainting|
02159|058|M|episodes during this time frame.(26)|
02159|059|M|   The UK manufacturer of ranolazine states that concurrent use with agents|
02159|060|M|known to prolong the QT interval should be approached with caution.(28)|
02159|061|M|Patients should be instructed to inform their physician if they are|
02159|062|M|receiving any drugs that prolong the QTc interval.(28)|
02159|063|M|   The US manufacturer of romidepsin states that appropriate cardiovascular|
02159|064|M|monitoring, such as monitoring of electrolytes and ECGs at baseline and|
02159|065|M|periodically during treatment should be considered in patients receiving|
02159|066|M|concurrent therapy with agents known to prolong the QT interval.(29)|
02159|067|M|   The manufacturers of dofetilide(31) and sotalol(32) state that concurrent|
02159|068|M|use with other agents known to prolong the QT interval is not recommended.|
02159|069|M|   The manufacturer of telavancin recommends against the use of telavancin|
02159|070|M|with other drugs known to cause QT prolongation.(32)|
02159|071|M|   Additional monitoring when concurrent therapy is warranted: consider|
02159|072|M|obtaining serum calcium, magnesium, and potassium levels at baseline and|
02159|073|M|regular intervals. Correct any electrolyte abnormalities.|
02159|074|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02159|075|M|fainting.|
02159|076|B||
02159|077|D|DISCUSSION:  Astemizole and terfenadine have been shown to prolong the QTc|
02159|078|D|interval.  Other agents that are linked to this monograph may have varying|
02159|079|D|degrees of potential to prolong the QTc interval.(33)|
02159|080|D|   One or more of the drug pairs linked to this monograph have been included|
02159|081|D|in a list of interactions that should be considered "high-priority" for|
02159|082|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02159|083|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02159|084|D|Coordinator (ONC) for Health Information Technology.|
02159|085|B||
02159|086|R|REFERENCES:|
02159|087|B||
02159|088|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02159|089|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02159|090|R|  settings: a scientific statement from the American Heart Association and|6
02159|091|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02159|092|R|  2;55(9):934-47.|6
02159|093|R|2.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
02159|094|R|  Inc. May, 2019.|1
02159|095|R|3.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
02159|096|R|  Company February, 2023.|1
02159|097|R|4.Anzemet (dolasetron mesylate) US prescribing information. Sanofi-Aventis|1
02159|098|R|  Us.S. LLC September, 2014.|1
02159|099|R|5.Toviaz (fesoterodine) UK summary of product characteristics. Pfizer|1
02159|100|R|  Limited February, 2011.|1
02159|101|R|6.Foradil Aerolizer (formoterol fumarate) US prescribing information.|1
02159|102|R|  Schering Corporation September, 2012.|1
02159|103|R|7.Symbicort Turbuhaler (budesonide-eformoterol fumarate dihydrate)|1
02159|104|R|  Australian prescribing information. AstraZeneca Pty Ltd April 30, 2004.|1
02159|105|R|8.Primovist (gadoxetate disodium) Australian prescribing information.|1
02159|106|R|  Schering-Plough Corporation November 1, 2005.|1
02159|107|R|9.Primovist (gadoxetic acid) UK summary of product characteristics. Bayer|1
02159|108|R|  plc May 1, 2008.|1
02159|109|R|10.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
02159|110|R|   Company January, 2006.|1
02159|111|R|11.Factive (gemifloxacin mesylate) US prescribing information. Merus Labs|1
02159|112|R|   International, Inc. October, 2018.|1
02159|113|R|12.Serenace (haloperidol) Australian prescribing information. Sigma|1
02159|114|R|   Pharmaceuticals Pty Ltd. June 5, 2001.|1
02159|115|R|13.Dozic (haloperidol) UK summary of product characteristics. Rosemont|1
02159|116|R|   Pharmaceuticals Limited September 10, 2007.|1
02159|117|R|14.Haldol injection (haloperidol) US prescribing information. Janssen|1
02159|118|R|   Pharmaceuticals, Inc. October, 2025.|1
02159|119|R|15.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
02159|120|R|   2018.|1
02159|121|R|16.Levaquin (levofloxacin) US prescribing information. Janssen|1
02159|122|R|   Pharmaceuticals, Inc. October 18, 2018.|1
02159|123|R|17.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
02159|124|R|   Pharmaceuticals Corp. June, 2021.|1
02159|125|R|18.NegGram (nalidixic acid) US prescribing information. Sanofi-Synthelabo,|1
02159|126|R|   Inc. November, 2012.|1
02159|127|R|19.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
02159|128|R|   2016.|1
02159|129|R|20.Risperidal (risperidone) UK summary of product characteristics.|1
02159|130|R|   Janssen-Cilag, UK Limited May 14, 2004.|1
02159|131|R|21.Trisenox (arsenic trioxide) US Prescribing information. Teva|1
02159|132|R|   Pharmaceuticals USA, Inc. October, 2020.|1
02159|133|R|22.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
02159|134|R|   Corporation March, 2022.|1
02159|135|R|23.Ciproxin (ciprofloxacin hydrochloride) UK summary of product|1
02159|136|R|   characteristics. Bayer plc April 13, 2010.|1
02159|137|R|24.Halaven (eribulin mesylate) US prescribing information. Eisai, Inc.|1
02159|138|R|   January, 2016.|1
02159|139|R|25.Trobalt (retigabine) UK summary of product characteristics.|1
02159|140|R|   GlaxoSmithKline UK March 28, 2011.|1
02159|141|R|26.Ablavar (gadofosveset trisodium) US prescribing information. Lantheus|1
02159|142|R|   Medical Imaging, Inc. August, 2013.|1
02159|143|R|27.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
02159|144|R|   Pharma U.K. S.R.I. October 30, 2008.|1
02159|145|R|28.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
02159|146|R|29.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
02159|147|R|   November, 2018.|1
02159|148|R|30.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
02159|149|R|   2013.|1
02159|150|R|31.Betapace (sotalol hydrochloride) US prescribing information. Bayer|1
02159|151|R|   Healthcare Inc. June, 2021.|1
02159|152|R|32.Vibativ (telavancin) US prescribing information. Theravance Biopharma US,|1
02159|153|R|   Inc. February, 2020.|1
02159|154|R|33.USDepartment of Health and Human Services Food and Drug Administration.|1
02159|155|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02159|156|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02159|157|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02159|158|R|34.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02159|159|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02159|160|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02159|161|R|   19(5):735-43.|6
02160|001|T|MONOGRAPH TITLE:  Live Vaccines/Belatacept (mono deleted 04/26/2012)|
02160|002|B||
02160|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02160|004|L|of severe adverse interaction.|
02160|005|B||
02160|006|A|MECHANISM OF ACTION:  Belatacept may interfere with the normal immune|
02160|007|A|response to new antigens.(1)|
02160|008|B||
02160|009|E|CLINICAL EFFECTS:  Live vaccines may not be effective in patients treated|
02160|010|E|with belatacept.(1)|
02160|011|B||
02160|012|P|PREDISPOSING FACTORS:  None determined.|
02160|013|B||
02160|014|M|PATIENT MANAGEMENT:  The manufacturer of belatacept states that live|
02160|015|M|vaccines should be avoided in patients treated with belatacept.(1)|
02160|016|B||
02160|017|D|DISCUSSION:  Because belatacept interferes with the normal immune response,|
02160|018|D|vaccination may not be effective.  Therefore, the manufacturer of belatacept|
02160|019|D|states that live vaccines should be avoided.(1)|
02160|020|B||
02160|021|R|REFERENCE:|
02160|022|B||
02160|023|R|1.Nulojix (belatacept) US prescribing information. Bristol-Myers Squibb|1
02160|024|R|  Company July, 2021.|1
02161|001|T|MONOGRAPH TITLE:  Dexmethylphenidate; Methylphenidate/St. John's Wort|
02161|002|B||
02161|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
02161|004|L|Assess the risk to the patient and take action as needed.|
02161|005|B||
02161|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
02161|007|A|methylphenidate by CYP3A4.(1)|
02161|008|A|   Dexmethylphenidate is an enantiomer of methylphenidate.(2)|
02161|009|B||
02161|010|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort with|
02161|011|E|dexmethylphenidate or methylphenidate may result in decreased levels and|
02161|012|E|clinical effectiveness of dexmethylphenidate and methylphenidate.(1)|
02161|013|B||
02161|014|P|PREDISPOSING FACTORS:  None determined.|
02161|015|B||
02161|016|M|PATIENT MANAGEMENT:  The concurrent use of dexmethylphenidate or|
02161|017|M|methylphenidate and St. John's wort should be approached with caution.|
02161|018|M|Monitor patients for decreased response to methylphenidate.|
02161|019|B||
02161|020|D|DISCUSSION:  In a case report, the addition of St. John's wort (600 mg|
02161|021|D|daily) to the therapy of an ADHD patient maintained on methylphenidate|
02161|022|D|resulted in decreased methylphenidate effects.  Over the four-month course|
02161|023|D|of St. John's wort, the patient became more disattentive, as shown by the|
02161|024|D|Conner's score.  Three weeks after discontinuing St. John's wort, the|
02161|025|D|patient's Conner's score decreased again.(1)|
02161|026|B||
02161|027|R|REFERENCES:|
02161|028|B||
02161|029|R|1.Niederhofer H. St. John's wort may diminish methylphenidate's efficacy in|3
02161|030|R|  treating patients suffering from attention deficit hyperactivity disorder.|3
02161|031|R|  Med Hypotheses 2007;68(5):1189.|3
02161|032|R|2.Focalin (dexmethylphenidate hydrochloride) US prescribing information.|1
02161|033|R|  Novartis Pharmaceuticals Corporation June, 2021.|1
02162|001|T|MONOGRAPH TITLE:  Buspirone/St. John's Wort (mono deleted 07/30/2020)|
02162|002|B||
02162|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
02162|004|L|Assess the risk to the patient and take action as needed.|
02162|005|B||
02162|006|A|MECHANISM OF ACTION:  Both buspirone and St. John's wort may affect|
02162|007|A|serotonin levels.(1)|
02162|008|B||
02162|009|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort and buspirone may|
02162|010|E|result in serotonin syndrome.(1)  Symptoms of serotonin syndrome may include|
02162|011|E|tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
02162|012|E|hyperthermia, and muscle rigidity.(2)|
02162|013|B||
02162|014|P|PREDISPOSING FACTORS:  None determined.|
02162|015|B||
02162|016|M|PATIENT MANAGEMENT:  Consider a 14 day washout period for patients who have|
02162|017|M|taken St. John's wort before initiating buspirone.  Patients on buspirone|
02162|018|M|should be cautioned about and observed for serotonin syndrome if they add|
02162|019|M|St. John's wort to their regimen.|
02162|020|M|   If concurrent therapy is warranted, patients should be monitored for|
02162|021|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02162|022|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02162|023|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02162|024|M|coordination, or severe diarrhea.|
02162|025|B||
02162|026|D|DISCUSSION:  In a case report, a 27 year-old female developed serotonin|
02162|027|D|syndrome two months after adding St. John's wort (2000 mg three times daily)|
02162|028|D|to her buspirone (30 mg daily) therapy.(1)|
02162|029|B||
02162|030|R|REFERENCES:|
02162|031|B||
02162|032|R|1.Dannawi M. Possible serotonin syndrome after combination of buspirone and|3
02162|033|R|  St John's Wort. J Psychopharmacol 2002 Dec;16(4):401.|3
02162|034|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02162|035|R|  352(11):1112-20.|6
02163|001|T|MONOGRAPH TITLE:  Bupropion/St. John's Wort|
02163|002|B||
02163|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
02163|004|L|Assess the risk to the patient and take action as needed.|
02163|005|B||
02163|006|A|MECHANISM OF ACTION:  Both bupropion and St. John's wort may affect|
02163|007|A|serotonin levels.(1)  In addition, St. John's wort may induce the metabolism|
02163|008|A|of bupropion.(2)|
02163|009|B||
02163|010|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort and bupropion may|
02163|011|E|result in serotonin syndrome(1) or decreased levels and efficacy of|
02163|012|E|bupropion.(2)  Symptoms of serotonin syndrome may include tremor, agitation,|
02163|013|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02163|014|E|rigidity.(3)|
02163|015|B||
02163|016|P|PREDISPOSING FACTORS:  None determined.|
02163|017|B||
02163|018|M|PATIENT MANAGEMENT:  Consider a 14 day washout period for patients who have|
02163|019|M|taken St. John's wort before initiating bupropion.  Patients on bupropion|
02163|020|M|should be cautioned about and observed for serotonin syndrome and decreased|
02163|021|M|bupropion efficacy if they add St. John's wort to their regimen.|
02163|022|M|   If concurrent therapy is warranted, patients should be monitored for|
02163|023|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02163|024|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02163|025|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02163|026|M|coordination, or severe diarrhea.|
02163|027|B||
02163|028|D|DISCUSSION:  In a case report, a 58 year-old female developed dystonic|
02163|029|D|movements of the right side of her face, neck, and arms 4 days after the|
02163|030|D|addition of bupropion (150 mg daily) to St. John's wort (300 mg once|
02163|031|D|daily).(1)|
02163|032|D|   In a study in 18 healthy Chinese males, St. John's wort (325 mg three|
02163|033|D|times daily) decreased the area-under-curve (AUC) of a single dose of|
02163|034|D|bupropion by 14%.  Bupropion clearance increased 20%.(2)|
02163|035|D|   St. John's wort with low hyperforin content (< 1 mg) is not expected to|
02163|036|D|induce CYP3A4.(4)|
02163|037|B||
02163|038|R|REFERENCES:|
02163|039|B||
02163|040|R|1.Milton JC, Abdulla A. Prolonged oro-facial dystonia in a 58 year old|3
02163|041|R|  female following therapy with bupropion and St John's Wort. Br J Clin|3
02163|042|R|  Pharmacol 2007 Nov;64(5):717-8.|3
02163|043|R|2.Lei HP, Yu XY, Xie HT, Li HH, Fan L, Dai LL, Chen Y, Zhou HH. Effect of|2
02163|044|R|  St. John's wort supplementation on the pharmacokinetics of bupropion in|2
02163|045|R|  healthy male Chinese volunteers. Xenobiotica 2010 Apr;40(4):275-81.|2
02163|046|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02163|047|R|  352(11):1112-20.|6
02163|048|R|4.Remotiv (St. John's wort) Israeli Prescribing Information. Max Zeller|1
02163|049|R|  Sohne AG September, 2024.|1
02164|001|T|MONOGRAPH TITLE:  Vardenafil (Less Than or Equal To 5 mg)/Selected CYP3A4|
02164|002|T|Inhibitors|
02164|003|B||
02164|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02164|005|L|take action as needed.|
02164|006|B||
02164|007|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
02164|008|A|vardenafil by CYP3A4.(1-4)|
02164|009|B||
02164|010|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
02164|011|E|increased levels of and adverse effects from vardenafil, including|
02164|012|E|hypotension, visual changes, and sustained erections.(1-4)|
02164|013|B||
02164|014|P|PREDISPOSING FACTORS:  The interaction may be more severe in men older than|
02164|015|P|75 years.(4)|
02164|016|B||
02164|017|M|PATIENT MANAGEMENT:  The US manufacturer of vardenafil states that a maximum|
02164|018|M|dose of 2.5 mg of vardenafil every 24 hours should not be exceeded in|
02164|019|M|patients taking 400 mg of itraconazole or ketoconazole and that a maximum|
02164|020|M|dose of 5 mg of vardenafil every 24 hours should not be exceeded in patients|
02164|021|M|taking 200 mg of itraconazole or ketoconazole.(1)|
02164|022|M|  For moderate CYP3A4 inhibitors, do not exceed a maximum dose of 5 mg of|
02164|023|M|vardenafil every 24 hours.(1)|
02164|024|M|  Patients receiving concurrent therapy should be monitored for increased|
02164|025|M|vardenafil effects.|
02164|026|M|  Note that other countries have stricter warnings.  The Australian|
02164|027|M|manufacturer of vardenafil states that vardenafil must not be taken with|
02164|028|M|dosages of itraconazole or ketoconazole greater than 200 mg.  A maximum dose|
02164|029|M|of 5 mg of vardenafil should not be exceeded if used with lower dosages of|
02164|030|M|itraconazole and ketoconazole.(2)  The Canadian manufacturer of vardenafil|
02164|031|M|states that the concurrent use of vardenafil with itraconazole or|
02164|032|M|ketoconazole is contraindicated and that the dosage should not exceed 5 mg|
02164|033|M|in patients taking erythromycin.(3)  The UK manufacturer of vardenafil|
02164|034|M|states that the concurrent use of vardenafil with either oral itraconazole|
02164|035|M|or oral ketoconazole is contraindicated in men older than 75 years and|
02164|036|M|should be avoided in all patients.  The dosage of vardenafil should not|
02164|037|M|exceed 5 mg in patients taking erythromycin.(4))|
02164|038|B||
02164|039|D|DISCUSSION:  Concurrent use of ketoconazole (200 mg) with vardenafil (5 mg)|
02164|040|D|increased the vardenafil area-under-curve (AUC) and maximum concentration|
02164|041|D|(Cmax) by 10-fold and 4-fold, respectively.(1-4)|
02164|042|D|   Concurrent administration of erythromycin (500 mg three times daily) with|
02164|043|D|vardenafil (5 mg) increased the AUC and Cmax of vardenafil by 4-fold and|
02164|044|D|3-fold, respectively.(1-4)|
02164|045|B||
02164|046|R|REFERENCES:|
02164|047|B||
02164|048|R|1.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
02164|049|R|  Pharmaceuticals Corporation March, 2023.|1
02164|050|R|2.Levitra (vardenafil hydrochloride trihydrate) Australian prescribing|1
02164|051|R|  information. Bayer Australia Limited November 2, 2006.|1
02164|052|R|3.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
02164|053|R|  Bayer, Inc. October 24, 2006.|1
02164|054|R|4.Levitra (vardenafil hydrochloride trihydrate) UK summary of product|1
02164|055|R|  characteristics. Bayer plc December 20, 2006.|1
02165|001|T|MONOGRAPH TITLE:  Vardenafil (Less Than or Equal To 2.5 mg)/Strong CYP3A4|
02165|002|T|Inhibitors|
02165|003|B||
02165|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02165|005|L|take action as needed.|
02165|006|B||
02165|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02165|008|A|vardenafil.(1-3)|
02165|009|B||
02165|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
02165|011|E|increased levels, clinical effects, and side effects of vardenafil,|
02165|012|E|including hypotension, visual changes, and sustained erections.(1-3)|
02165|013|B||
02165|014|P|PREDISPOSING FACTORS:  None determined.|
02165|015|B||
02165|016|M|PATIENT MANAGEMENT:  The US manufacturer of vardenafil states that a maximum|
02165|017|M|dose of 2.5 mg of vardenafil every 24 hours should not be exceeded in|
02165|018|M|patients taking strong CYP3A4 inhibitors.(1)|
02165|019|M|   Note that other countries have different warnings.  The Canadian(3) and|
02165|020|M|UK(3) manufacturer of vardenafil state that vardenafil should not exceed 5|
02165|021|M|mg in patients taking clarithromycin.  The UK manufacturer of vardenafil|
02165|022|M|states that the concurrent use of vardenafil with strong CYP3A4 inhibitors|
02165|023|M|should be avoided.(3)|
02165|024|M|   The US manufacturer of cobicistat states that a maximum dose of 2.5 mg of|
02165|025|M|vardenafil every 72 hours should not be exceeded in patients taking|
02165|026|M|cobicistat.(4)|
02165|027|B||
02165|028|D|DISCUSSION:  Concurrent use of ketoconazole (200 mg, a strong inhibitor of|
02165|029|D|CYP3A4) with vardenafil (5 mg) increased the vardenafil area-under-curve|
02165|030|D|(AUC) and maximum concentration (Cmax) by 10-fold and 4-fold,|
02165|031|D|respectively.(1-3)|
02165|032|D|   Concurrent administration of erythromycin (500 mg three times daily, a|
02165|033|D|moderate inhibitor of CYP3A4) with vardenafil (5 mg) increased the AUC and|
02165|034|D|Cmax of vardenafil by 4-fold and 3-fold, respectively.(1-3)|
02165|035|B||
02165|036|R|REFERENCES:|
02165|037|B||
02165|038|R|1.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
02165|039|R|  Pharmaceuticals Corporation March, 2023.|1
02165|040|R|2.Levitra (vardenafil hydrochloride) Canadian prescribing information.|1
02165|041|R|  Bayer, Inc. October 24, 2006.|1
02165|042|R|3.Levitra (vardenafil hydrochloride trihydrate) UK summary of product|1
02165|043|R|  characteristics. Bayer plc December 20, 2006.|1
02165|044|R|4.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02165|045|R|  June, 2025.|1
02166|001|T|MONOGRAPH TITLE:  Apixaban;Rivaroxaban/P-gp & Strong 3A4|
02166|002|T|Inducers;Efavirenz;PB|
02166|003|B||
02166|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02166|005|L|is contraindicated and generally should not be dispensed or administered to|
02166|006|L|the same patient.|
02166|007|B||
02166|008|A|MECHANISM OF ACTION:  Apalutamide, carbamazepine, efavirenz, fosphenytoin,|
02166|009|A|phenytoin, rifampin, rifapentine, and St. John's wort may induce the|
02166|010|A|metabolism of apixaban(1-4) and rivaroxaban(5) by both P-gp and CYP3A4.|
02166|011|A|Phenobarbital and primidone may also induce the metabolism of apixaban and|
02166|012|A|rivaroxaban.(1-5)|
02166|013|B||
02166|014|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide, carbamazepine,|
02166|015|E|efavirenz, fosphenytoin, phenobarbital, phenytoin, primidone, rifapentine,|
02166|016|E|rifampin, or St. John's wort may result in decreased levels and|
02166|017|E|effectiveness of apixaban(1-4) or rivaroxaban.(5)|
02166|018|B||
02166|019|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02166|020|P|of the inducer for longer than 1-2 weeks.|
02166|021|B||
02166|022|M|PATIENT MANAGEMENT:  The manufacturer of apixaban and rivaroxaban states to|
02166|023|M|avoid the concurrent use of agents that are combined P-gp and strong CYP3A4|
02166|024|M|inducers (such as apalutamide, carbamazepine, efavirenz, fosphenytoin,|
02166|025|M|phenytoin, rifampin, rifapentine, and St. John's wort), phenobarbital, and|
02166|026|M|primidone in patients receiving apixaban or rivaroxaban.|
02166|027|B||
02166|028|D|DISCUSSION:  Concurrent rifampin decreased the area-under-curve (AUC) and|
02166|029|D|maximum concentration (Cmax) of apixaban by 54% and 42%, respectively.(1-4)|
02166|030|D|   In a clinical trial, rifampin (600 mg daily) decreased the AUC and Cmax|
02166|031|D|of a single dose of rivaroxaban (20 mg with food) by 50% and|
02166|032|D|22%,respectively.  Similar decreases in pharmacodynamic effects were|
02166|033|D|seen.(5)|
02166|034|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
02166|035|D|pairs were reviewed and found 14% of drug pairs were associated with a|
02166|036|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
02166|037|D|of rivaroxaban and phenytoin resulted in a ratio of rate ratios (95% CI) of|
02166|038|D|2.39 (1.33-3.29).(6)|
02166|039|B||
02166|040|R|REFERENCES:|
02166|041|B||
02166|042|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
02166|043|R|  Squibb Australia Pty. Ltd. January, 2024.|1
02166|044|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
02166|045|R|  Squibb-Pfizer January, 2025.|1
02166|046|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
02166|047|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
02166|048|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
02166|049|R|  Company April, 2025.|1
02166|050|R|5.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
02166|051|R|  Inc. March, 2020.|1
02166|052|R|6.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
02166|053|R|  Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
02166|054|R|  Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
02166|055|R|  Pharmacol Ther 2020 Aug;108(2):377-386.|2
02167|001|T|MONOGRAPH TITLE:  Rivaroxaban/Selected P-gp and Weak CYP3A4 Inhibitors|
02167|002|B||
02167|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02167|004|L|take action as needed.|
02167|005|B||
02167|006|A|MECHANISM OF ACTION:  Amiodarone, azithromycin, brodalumab, chloramphenicol,|
02167|007|A|cimetidine, cyclosporine, felodipine, fluvoxamine, fostamatinib,|
02167|008|A|glecaprevir/pibrentasvir, hydroquinidine, ivacaftor, nilotinib, piperine,|
02167|009|A|pirtobrutinib, quinidine, ranolazine, simeprevir, ticagrelor and tolvaptan|
02167|010|A|may inhibit the metabolism of rivaroxaban by CYP3A4 and by|
02167|011|A|P-glycoprotein.(1,2)|
02167|012|B||
02167|013|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
02167|014|E|P-gp and a weak inhibitor of CYP3A4 may result in elevated levels of and|
02167|015|E|clinical effects of rivaroxaban, including an increased risk of bleeding, in|
02167|016|E|patients with decreased renal function.(1,2)|
02167|017|B||
02167|018|P|PREDISPOSING FACTORS:  Patients with decreased renal function (CrCL of 15|
02167|019|P|ml/min to 80 ml/min) may be predisposed to this interaction.(1)|
02167|020|P|   The risk for bleeding episodes may be greater in patients with|
02167|021|P|disease-associated factors (e.g. thrombocytopenia).|
02167|022|P|   Drug associated risk factors include concurrent use of multiple drugs|
02167|023|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02167|024|P|risk for bleeding (e.g. NSAIDs).|
02167|025|B||
02167|026|M|PATIENT MANAGEMENT:  The US manufacturer states no precautions are necessary|
02167|027|M|with the concurrent use of these agents and rivaroxaban in patients with|
02167|028|M|normal renal function.(1)  It would be prudent to closely monitor concurrent|
02167|029|M|use in patients with reduced renal function (CrCL of 15 ml/min to 80|
02167|030|M|ml/min).|
02167|031|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02167|032|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02167|033|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02167|034|M|patients with any symptoms.|
02167|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02167|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02167|037|M|anticoagulation in patients with active pathologic bleeding.|
02167|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02167|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02167|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02167|041|M|and/or swelling.|
02167|042|B||
02167|043|D|DISCUSSION:  Clarithromycin (500 mg twice daily) increased the|
02167|044|D|area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of|
02167|045|D|rivaroxaban by 50% and 40%, respectively.(1,2)|
02167|046|D|   Erythromycin (500 mg three times daily) increased the AUC and Cmax of a|
02167|047|D|single dose of rivaroxaban by 30% and 30%, respectively.(1-3)  In patients|
02167|048|D|with mild renal impairment (CrCl of 50 ml/min to 79 ml/min) who were|
02167|049|D|receiving erythromycin, rivaroxaban levels were increased 76% when compared|
02167|050|D|to administration of rivaroxaban in patients with normal renal function|
02167|051|D|receiving rivaroxaban alone.  In patients with moderate renal impairment|
02167|052|D|(CrCl of 30 ml/min to 49 ml/min) who were receiving erythromycin,|
02167|053|D|rivaroxaban levels were increased 99% when compared to administration of|
02167|054|D|rivaroxaban in patients with normal renal function receiving rivaroxaban|
02167|055|D|alone.(1)|
02167|056|D|   Fluconazole increased the AUC and Cmax of a single dose of rivaroxaban by|
02167|057|D|40%% and 30%, respectively.(1)|
02167|058|D|   These changes are not expected to be clinically significant in patients|
02167|059|D|with normal renal function.(1,2)|
02167|060|D|   In a case report, an 88-year-old woman with renal impairment on|
02167|061|D|rivaroxaban presented with an elevated INR of 2.5 and a rivaroxaban peak|
02167|062|D|plasma concentration above the upper limit of detection at >800 mcg/L|
02167|063|D|(therapeutic range 58-211 mcg/L).  Nothing in her medical history suggested|
02167|064|D|a reason for supratherapeutic rivaroxaban levels except for a 7-week|
02167|065|D|amiodarone regimen that was discontinued 3 weeks prior.  This suggests the|
02167|066|D|potential for amiodarone to persist in the body weeks after its use and|
02167|067|D|precipitate drug-drug interactions.(4)|
02167|068|D|   A retrospective cohort study examined 24,943 patients aged 66 years and|
02167|069|D|older with concurrent therapy of an anticoagulant, either rivaroxaban|
02167|070|D|(40.0%), apixaban (31.9%), or dabigatran (28.1%), with either azithromycin|
02167|071|D|or clarithromycin.  The primary outcome of hospital admission with major|
02167|072|D|hemorrhage within 30 days on concurrent therapy was higher in patients on|
02167|073|D|clarithromycin (0.77%) compared to azithromycin (0.43%) with an adjusted|
02167|074|D|hazard ratio of 1.71 (95% CI, 1.20-2.45).  In a self-controlled case series,|
02167|075|D|744 major hemorrhage events were identified among 647 unique individuals|
02167|076|D|taking anticoagulants who were exposed to clarithromycin.  The rate of|
02167|077|D|events that occurred during clarithromycin use had a significant rate ratio|
02167|078|D|of 1.44 (95% CI, 1.08-1.92).(5)|
02167|079|D|   A propensity matched cohort evaluated the concurrent use of combined P-gp|
02167|080|D|and moderate CYP3A4 inhibitors with apixaban or rivaroxaban.  Combined|
02167|081|D|inhibitors included amiodarone, diltiazem, erythromycin, dronedarone, and|
02167|082|D|verapamil.  Bleeding occurred in 26.4% of patients in the inhibitor group|
02167|083|D|compared to 18.4% in the control group (hazard ratio 1.8; 95% CI 1.19-2.73;|
02167|084|D|p=0.006).  Although not statistically significant, patients in the inhibitor|
02167|085|D|group also had a higher rate of major bleeding (15% vs 10.3%) and minor|
02167|086|D|bleeding (8.9% vs 5.2%), respectively.(6)|
02167|087|D|   A summary of pharmacokinetic interactions with rivaroxaban and amiodarone|
02167|088|D|concluded that concurrent use should be avoided if CrCl < 80 ml/min.(7)|
02167|089|D|   A prospective cohort study of 174 patients evaluated the concurrent use|
02167|090|D|of rivaroxaban and amiodarone.  The combination of rivaroxaban and|
02167|091|D|amiodarone was associated with a higher incidence of bleeding events|
02167|092|D|(p=0.041; HR=2.83, 95% CI 1.05-7.66) and clinically relevant non-major|
02167|093|D|bleeding (p=0.021; HR=3.65, 95% CI 1.21-10.94).  Concurrent use of|
02167|094|D|amiodarone and rivaroxaban in non-valvular atrial fibrillation patients was|
02167|095|D|an independent risk factor for increased risk of bleeding (p=0.044; OR|
02167|096|D|2.871, 95% CI 1.028-8.023).(8)|
02167|097|D|   P-gp and weak CYP3A4 inhibitors linked to this monograph are:|
02167|098|D|amiodarone, azithromycin, belumosudil, brodalumab, chloramphenicol,|
02167|099|D|cimetidine, cyclosporine, daridorexant, diosmin, flibanserin, fostamatinib,|
02167|100|D|glecaprevir/pibrentasvir, hydroquinidine, istradefylline, ivacaftor,|
02167|101|D|mavorixafor, nilotinib, piperine, pirtobrutinib, quinidine, ranolazine,|
02167|102|D|selpercatinib, simeprevir and tolvaptan.(9,10)|
02167|103|B||
02167|104|R|REFERENCES:|
02167|105|B||
02167|106|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
02167|107|R|  Inc. March, 2020.|1
02167|108|R|2.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
02167|109|R|  August, 2021.|1
02167|110|R|3.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
02167|111|R|  2015.|1
02167|112|R|4.Skov K, Falskov B, Jensen EA, Dorff MH. Supratheraputic rivaroxaban|3
02167|113|R|  levels: A persistent drug-drug interaction after  discontinuation of|3
02167|114|R|  amiodarone. Basic Clin Pharmacol Toxicol 2020 Apr 26.|3
02167|115|R|5.Hill K, Sucha E, Rhodes E, Carrier M, Garg AX, Harel Z, Hundemer GL, Clark|2
02167|116|R|  EG, Knoll G, McArthur E, Sood MM. Risk of Hospitalization With Hemorrhage|2
02167|117|R|  Among Older Adults Taking Clarithromycin vs  Azithromycin and Direct Oral|2
02167|118|R|  Anticoagulants..|2
02167|119|R|6.Hanigan S, Das J, Pogue K, Barnes GD, Dorsch MP. The real world use of|2
02167|120|R|  combined P-glycoprotein and moderate CYP3A4 inhibitors with  rivaroxaban|2
02167|121|R|  or apixaban increases bleeding..|2
02167|122|R|7.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
02167|123|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
02167|124|R|  of  the Week..|6
02167|125|R|8.Ding H, Wang Z, Wang J, Yao Y, Zhang C, Lin H, Zhou Y, Gu Z, Lv Q, Li X.|2
02167|126|R|  Co-Administration of Amiodarone Increases Bleeding by Affecting|2
02167|127|R|  Rivaroxaban Pharmacokinetics in Patients with Atrial Fibrillation.|2
02167|128|R|  Pharmaceutics 30/07/2024;16(1006):1-11.|2
02167|129|R|9.US Food and Drug Administration (FDA). Drug Development and Drug|1
02167|130|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02167|131|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02167|132|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02167|133|R|  11/14/2017.|1
02167|134|R|10.This information is based on an extract from the Certara Drug Interaction|6
02167|135|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02168|001|T|MONOGRAPH TITLE:  Rivaroxaban/Selected Antiplatelets; Aspirin (Greater Than|
02168|002|T|100 mg)|
02168|003|B||
02168|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02168|005|L|of severe adverse interaction.|
02168|006|B||
02168|007|A|MECHANISM OF ACTION:  Additive effects on hemostasis.(1)|
02168|008|B||
02168|009|E|CLINICAL EFFECTS:  Concurrent use of rivaroxaban with anticoagulants,|
02168|010|E|antiplatelets, or thrombolytics may increase the risk of bleeding.(1)|
02168|011|B||
02168|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02168|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02168|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
02168|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02168|016|P|risk for bleeding (e.g. NSAIDs).|
02168|017|B||
02168|018|M|PATIENT MANAGEMENT:  Avoid concurrent use of rivaroxaban and higher doses of|
02168|019|M|aspirin unless the benefit is expected to outweigh the increased risk of|
02168|020|M|bleeding.  In the ROCKET AF trial, concomitant use of low dose aspirin|
02168|021|M|(almost exclusively at less than or equal to 100 mg daily) was identified as|
02168|022|M|an independent risk factor for bleeding.(1)|
02168|023|M|   If the benefit of concurrent use of rivaroxaban with other antiplatelets|
02168|024|M|is expected to outweigh the increased risk of bleeding, closely monitor|
02168|025|M|patients for signs or symptoms of bleeding.(1)|
02168|026|M|   The UK manufacturer of rivaroxaban states that rivaroxaban 2.5 mg twice|
02168|027|M|daily is indicated with aspirin 75 - 100 mg with or without clopidogrel 75|
02168|028|M|mg or standard dose ticlopidine for post-acute coronary syndrome and in|
02168|029|M|patients with CAD and PAD, weighing the risk for ischemic events against the|
02168|030|M|bleeding risks.  Long-term dual antiplatelet therapy should be avoided.|
02168|031|M|Clinical monitoring is recommended throughout treatment.(2)|
02168|032|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02168|033|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
02168|034|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
02168|035|M|evaluate patients with any symptoms.|
02168|036|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02168|037|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02168|038|M|anticoagulation in patients with active pathologic bleeding.|
02168|039|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02168|040|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02168|041|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02168|042|M|and/or swelling.|
02168|043|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02168|044|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02168|045|M|initiating, altering the dose or discontinuing either drug.|
02168|046|B||
02168|047|D|DISCUSSION:  In two clinical trials in healthy subjects, concurrent|
02168|048|D|clopidogrel (300 mg loading dose, then 75 mg daily) and rivaroxaban (15 mg|
02168|049|D|single dose) increased bleeding time to 45 minutes in 45% and 30%|
02168|050|D|of subjects.  This was twice the maximum increase in bleeding time seen with|
02168|051|D|either agent alone.(1)|
02168|052|D|   In the ROCKET AF trial, concomitant aspirin use (almost exclusively at <|
02168|053|D|or = to 100 mg daily) was identified as an independent risk factor for|
02168|054|D|bleeding.(1)|
02168|055|D|   In a study, concurrent enoxaparin (40 mg) and rivaroxaban (10 mg)|
02168|056|D|resulted in additive effects on anti-factor Xa activity with no effects on|
02168|057|D|the pharmacokinetics of rivaroxaban.(1)|
02168|058|D|   In a study, concurrent warfarin (15 mg) and rivaroxaban (5 mg) resulted|
02168|059|D|in additive effects on factor Xa inhibition and PT with no effects on the|
02168|060|D|pharmacokinetics of rivaroxaban.(1)|
02168|061|D|   In a single dose study, there were no pharmacokinetic or pharmacodynamic|
02168|062|D|interactions between rivaroxaban and aspirin.(1)|
02168|063|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
02168|064|D|pairs were reviewed and found 14% of drug pairs were associated with a|
02168|065|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
02168|066|D|of rivaroxaban and dipyridamole resulted in a ratio of rate ratios (95% CI)|
02168|067|D|of 3.49 (1.08-6.64); and rivaroxaban and aspirin ratio of rate ratios 2.19|
02168|068|D|(1.21-2.95).(3)|
02168|069|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
02168|070|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
02168|071|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
02168|072|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
02168|073|D|aspirin, with the highest allowable dose being 165 mg/day.  The use of DOACs|
02168|074|D|with antiplatelet agents was associated with an increased risk of major|
02168|075|D|bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major|
02168|076|D|bleeding (OR 1.82; 95% CI, 1.50-2.22).  There was no difference between|
02168|077|D|groups in the efficacy outcome of symptomatic recurrent venous|
02168|078|D|thromboembolism (VTE) or VTE-related death.(4)|
02168|079|B||
02168|080|R|REFERENCES:|
02168|081|B||
02168|082|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
02168|083|R|  Inc. March, 2020.|1
02168|084|R|2.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
02168|085|R|  August, 2021.|1
02168|086|R|3.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
02168|087|R|  Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
02168|088|R|  Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
02168|089|R|  Pharmacol Ther 2020 Aug;108(2):377-386.|2
02168|090|R|4.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
02168|091|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
02168|092|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
02168|093|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
02169|001|T|MONOGRAPH TITLE:  Apixaban; Betrixaban; Edoxaban; Rivaroxaban/NSAIDs;|
02169|002|T|Salicylates|
02169|003|B||
02169|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02169|005|L|of severe adverse interaction.|
02169|006|B||
02169|007|A|MECHANISM OF ACTION:  Concurrent use of apixaban(1-4), betrixaban(7),|
02169|008|A|edoxaban(5), or rivaroxaban(6) and nonsteroidal antiinflammatory agents|
02169|009|A|(NSAIDs) or salicylates may result in additive increased risk of bleeding.|
02169|010|B||
02169|011|E|CLINICAL EFFECTS:  Concurrent use of apixaban(1), betrixaban(7),|
02169|012|E|edoxaban(5), or rivaroxaban(2) with NSAIDs or salicylates may result in|
02169|013|E|unwanted bleeding episodes.|
02169|014|B||
02169|015|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with renal|
02169|016|P|impairment and in patients older than 75 years.|
02169|017|P|   The risk for bleeding episodes may be greater in patients with multiple|
02169|018|P|disease-associated factors (e.g. thrombocytopenia, advanced liver disease).|
02169|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
02169|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02169|021|P|risk for bleeding (e.g., other anticoagulants, antiplatelets,|
02169|022|P|corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or|
02169|023|P|serotonin-norepinephrine  reuptake inhibitors (SNRIs).|
02169|024|P|   Risk of GI bleed may be increased in patients who are of older age, in|
02169|025|P|poor health status, or who use alcohol or smoke.  Risk may also be increased|
02169|026|P|with longer duration of NSAID use and prior history of peptic ulcer disease|
02169|027|P|and/or GI bleeding.|
02169|028|B||
02169|029|M|PATIENT MANAGEMENT:  Approach concurrent therapy with apixaban(1-4),|
02169|030|M|betrixaban(7), edoxaban(5), or rivaroxaban(6) with caution.  Monitor|
02169|031|M|patients receiving concurrent therapy for signs of blood loss, including|
02169|032|M|decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood|
02169|033|M|pressure and promptly evaluate patients with any symptoms.|
02169|034|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02169|035|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02169|036|M|anticoagulation in patients with active pathologic bleeding.|
02169|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02169|038|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02169|039|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02169|040|M|and/or swelling.|
02169|041|B||
02169|042|D|DISCUSSION:  In a study, naproxen (500 mg) increased apixaban (10 mg)|
02169|043|D|area-under-curve (AUC) and maximum concentration (Cmax) by 1.5-fold an|
02169|044|D|1.6-fold, respectively, with corresponding increases in clotting tests.|
02169|045|D|There were no changes in the effect of naproxen on arachidonic acid-induced|
02169|046|D|platelet aggregation, no clinically relevant changes in bleeding times, or|
02169|047|D|naproxen pharmacokinetics.(1)|
02169|048|D|   In a single dose study, there were no pharmacokinetic or pharmacodynamic|
02169|049|D|interactions between rivaroxaban and naproxen.(6)|
02169|050|D|   Although effects seen in the above studies were limited, NSAIDs are known|
02169|051|D|to increase bleeding and may further increase the risk of bleeding with|
02169|052|D|these agents.(1-6)  In edoxaban clinical studies, concomitant use of|
02169|053|D|low-dose aspirin (less than or equal to 100 mg/day) or thienopyridines, and|
02169|054|D|NSAIDs was permitted and resulted in increased rates of clinically relevant|
02169|055|D|bleeding.(5)    In a study of 34 healthy subjects administered edoxaban 60|
02169|056|D|mg daily and naproxen 500 mg daily, bleeding time increased by 2.08-fold|
02169|057|D|from baseline on the combination, compared to a 1.23-fold increase with|
02169|058|D|naproxen alone and 1.7-fold increase on edoxaban alone.(8)|
02169|059|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
02169|060|D|pairs were reviewed and found 14% of drug pairs were associated with a|
02169|061|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
02169|062|D|of apixaban and ibuprofen resulted in a ratio of rate ratios (RR) (95% CI)|
02169|063|D|of 5.16 (3.0-8.85); apixaban and celecoxib ratio of RR 1.8 (1.06-3.06);|
02169|064|D|rivaroxaban and etodolac ratio of RR 2.47 (1.18-4.22); rivaroxaban and|
02169|065|D|naproxen ratio of RR 1.89 (1.12-1.43); and rivaroxaban and ibuprofen ratio|
02169|066|D|of RR 1.68 (1.29-4.44).(9)|
02169|067|B||
02169|068|R|REFERENCES:|
02169|069|B||
02169|070|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
02169|071|R|  Squibb Australia Pty. Ltd. January, 2024.|1
02169|072|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
02169|073|R|  Squibb-Pfizer January, 2025.|1
02169|074|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
02169|075|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
02169|076|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
02169|077|R|  Company April, 2025.|1
02169|078|R|5.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02169|079|R|  2019.|1
02169|080|R|6.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
02169|081|R|  Inc. March, 2020.|1
02169|082|R|7.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
02169|083|R|  Inc. July, 2019.|1
02169|084|R|8.Mendell J, Lee F, Chen S, Worland V, Shi M, Samama MM. The effects of the|2
02169|085|R|  antiplatelet agents, aspirin and naproxen, on pharmacokinetics and|2
02169|086|R|  pharmacodynamics of the anticoagulant edoxaban, a direct factor Xa|2
02169|087|R|  inhibitor. J Cardiovasc Pharmacol 2013 Aug;62(2):212-21.|2
02169|088|R|9.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
02169|089|R|  Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
02169|090|R|  Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
02169|091|R|  Pharmacol Ther 2020 Aug;108(2):377-386.|2
02170|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Glucosamine and-or Chondroitin|
02170|002|B||
02170|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02170|004|L|take action as needed.|
02170|005|B||
02170|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may be the result|
02170|007|A|of additive or synergistic effects on coagulation.  Glucosamine is a|
02170|008|A|component of heparin(1) and chondroitin is a component of danaparoid.(2)|
02170|009|A|Glucosamine has been shown not to inhibit CYP2C9,(3) thus inhibition of|
02170|010|A|warfarin metabolism is thought to be unlikely.|
02170|011|B||
02170|012|E|CLINICAL EFFECTS:  Concurrent use of glucosamine-chondroitin may result in|
02170|013|E|increased effects on coagulation, including elevated International|
02170|014|E|Normalized Ratio (INR) and bleeding.|
02170|015|B||
02170|016|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02170|017|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02170|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
02170|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02170|020|P|risk for bleeding (e.g. NSAIDs).|
02170|021|B||
02170|022|M|PATIENT MANAGEMENT:  Use caution with adding or discontinuing|
02170|023|M|glucosamine-chondroitin to warfarin therapy.  Monitor patients receiving|
02170|024|M|concurrent therapy closely for elevated INR and signs of bleeding.  Patients|
02170|025|M|who discontinue glucosamine-chondroitin may need their warfarin dosage|
02170|026|M|adjusted to maintain therapeutic INRs.|
02170|027|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02170|028|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02170|029|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02170|030|M|patients with any symptoms.|
02170|031|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02170|032|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02170|033|M|anticoagulation in patients with active pathologic bleeding.|
02170|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02170|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02170|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02170|037|M|and/or swelling.|
02170|038|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02170|039|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02170|040|M|initiating, altering the dose or discontinuing either drug.|
02170|041|B||
02170|042|D|DISCUSSION:  There have been numerous reports of increased INR following the|
02170|043|D|addition of glucosamine, glucosamine-chondroitin, or chondroitin alone to|
02170|044|D|warfarin therapy, including 20 from the United States Food Drug|
02170|045|D|Administration (US FDA), 22 from the World Health Organization (WHO), 3 from|
02170|046|D|the Australian Therapeutic Goods Association (TGA), and 2 published reports.|
02170|047|D|INR values typically increased between two and 20 days after the addition|
02170|048|D|of glucosamine and/or chondroitin to warfarin therapy.  In most cases,|
02170|049|D|patients were asymptomatic; however, there were at least two reports of|
02170|050|D|bleeding.(4-8)|
02170|051|D|   There has also been one report involving glucosamine and|
02170|052|D|acenocoumarol.(9)|
02170|053|B||
02170|054|R|REFERENCES:|
02170|055|B||
02170|056|R|1.Weimann G, Lubenow N, Selleng K, Eichler P, Albrecht D, Greinacher A.|2
02170|057|R|  Glucosamine sulfate does not crossreact with the antibodies of patients|2
02170|058|R|  with heparin-induced thrombocytopenia. Eur J Haematol 2001 Mar;|2
02170|059|R|  66(3):195-9.|2
02170|060|R|2.Wilde MI, Markham A. Danaparoid. A review of its pharmacology and clinical|6
02170|061|R|  use in the management of heparin-induced thrombocytopenia. Drugs 1997 Dec;|6
02170|062|R|  54(6):903-24.|6
02170|063|R|3.Rosenborg S, Stenberg M, Otto S, Ostervall J, Masquelier M, Yue QY,|2
02170|064|R|  Bertilsson L, Eliasson E. Clinically significant CYP2C inhibition by|2
02170|065|R|  noscapine but not by glucosamine. Clin Pharmacol Ther 2010 Sep;|2
02170|066|R|  88(3):343-6.|2
02170|067|R|4.Rozenfeld V, Crain JL, Callahan AK. Possible augmentation of warfarin|3
02170|068|R|  effect by glucosamine-chondroitin. Am J Health Syst Pharm 2004 Feb 1;|3
02170|069|R|  61(3):306-7.|3
02170|070|R|5.Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting|3
02170|071|R|  in increased international normalized ratio: case report and review of the|3
02170|072|R|  literature and MedWatch database. Pharmacotherapy 2008 Apr;28(4):540-8.|3
02170|073|R|6.Therapeutic Goods Administration. Interaction between glucosamine and|3
02170|074|R|  warfarin. Australian Adverse Drug Reactions Bulletin February, 2009;|3
02170|075|R|  27(1):3.|3
02170|076|R|7.Committee on Safety of Medicines and the Medicines and the Healthcare|3
02170|077|R|  products Regulatory Agency. Glucosamine adverse reactions and|3
02170|078|R|  interactions. Current Problems in Pharmacovigilance May, 2006;31:8.|3
02170|079|R|8.Yue QY, Strandell J, Myrberg O. Concomitant use of glucosamine potentiates|3
02170|080|R|  the effect of warfarin (abstract). Drug Saf 2006;29(10):911.|3
02170|081|R|9.Garrote Garcia M, Iglesias Pineiro MJ, Martin Alvarez R, Perez Gonzalez J.|3
02170|082|R|  Pharmacological interaction of glucosamine sulphate and acenocoumarol.|3
02170|083|R|  Aten Primaria 2004 Feb 28;33(3):162-3.|3
02171|001|T|MONOGRAPH TITLE:  Apixaban/Antiplatelets; Aspirin (Greater Than 100 mg)|
02171|002|B||
02171|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02171|004|L|of severe adverse interaction.|
02171|005|B||
02171|006|A|MECHANISM OF ACTION:  Additive effects on hemostasis.(1-4)|
02171|007|B||
02171|008|E|CLINICAL EFFECTS:  Concurrent use of apixaban with antiplatelets may|
02171|009|E|increase the risk of bleeding.(1-4)|
02171|010|B||
02171|011|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02171|012|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02171|013|P|   Drug associated risk factors include concurrent use of multiple drugs|
02171|014|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02171|015|P|risk for bleeding (e.g. NSAIDs).|
02171|016|B||
02171|017|M|PATIENT MANAGEMENT:  Patients requiring concurrent therapy with apixaban and|
02171|018|M|an antiplatelet agent should be closely monitored for signs of bleeding.|
02171|019|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
02171|020|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
02171|021|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02171|022|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02171|023|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02171|024|M|anticoagulation in patients with active pathologic bleeding.|
02171|025|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02171|026|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02171|027|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02171|028|M|and/or swelling.|
02171|029|M|   Discontinue apixaban in patients with active bleeding.|
02171|030|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02171|031|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02171|032|M|initiating, altering the dose or discontinuing either drug.|
02171|033|B||
02171|034|D|DISCUSSION:  Concurrent administration of enoxaparin (40 mg single dose) and|
02171|035|D|apixaban (5 mg single dose) resulted in additive effects on anti-Factor Xa|
02171|036|D|activity.(1)|
02171|037|D|   Concurrent apixaban and aspirin (325 mg daily) resulted in no|
02171|038|D|pharmacokinetic or pharmacodynamic interactions.(1)|
02171|039|D|   Concurrent apixaban with clopidogrel (75 mg daily) or with combination|
02171|040|D|clopidogrel (75 mg daily) and aspirin (162 mg daily) produced no relevant|
02171|041|D|increases in bleeding time, platelet aggregation, or clotting tests (PI,|
02171|042|D|INR, and aPTT) compared either clopidogrel alone or clopidogrel with aspirin|
02171|043|D|without apixaban.(1)|
02171|044|D|   Significant bleeding risk was reported with the combination of apixaban,|
02171|045|D|aspirin, and clopidogrel in patients with acute coronary syndrome.(1)|
02171|046|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
02171|047|D|pairs were reviewed and found 14% of drug pairs were associated with a|
02171|048|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
02171|049|D|of apixaban and clopidogrel resulted in a ratio of rate ratios (95% CI) of|
02171|050|D|1.96 (1.53-2.51).(5)|
02171|051|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
02171|052|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
02171|053|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
02171|054|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
02171|055|D|aspirin, with the highest allowable dose being 165 mg/day.  The use of DOACs|
02171|056|D|with antiplatelet agents was associated with an increased risk of major|
02171|057|D|bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major|
02171|058|D|bleeding (OR 1.82; 95% CI, 1.50-2.22).  There was no difference between|
02171|059|D|groups in the efficacy outcome of symptomatic recurrent venous|
02171|060|D|thromboembolism (VTE) or VTE-related death.(3)|
02171|061|B||
02171|062|R|REFERENCES:|
02171|063|B||
02171|064|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
02171|065|R|  Squibb Australia Pty. Ltd. January, 2024.|1
02171|066|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
02171|067|R|  Squibb-Pfizer January, 2025.|1
02171|068|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
02171|069|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
02171|070|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
02171|071|R|  Company April, 2025.|1
02171|072|R|5.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
02171|073|R|  Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
02171|074|R|  Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
02171|075|R|  Pharmacol Ther 2020 Aug;108(2):377-386.|2
02171|076|R|6.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
02171|077|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
02171|078|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
02171|079|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
02172|001|T|MONOGRAPH TITLE:  Methylene Blue Injection/MAOIs|
02172|002|B||
02172|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02172|004|L|is contraindicated and generally should not be dispensed or administered to|
02172|005|L|the same patient.|
02172|006|B||
02172|007|A|MECHANISM OF ACTION:  Methylene blue, when administered intravenously, has|
02172|008|A|been shown to reach sufficient concentrations to be a potent inhibitor of|
02172|009|A|MAO-A.(1,2)  Taking multiple MAOIs may result in serotonin syndrome.(3)|
02172|010|B||
02172|011|E|CLINICAL EFFECTS:  Concurrent use of methylene blue and other MAO inhibitors|
02172|012|E|or use of methylene blue without a sufficient MAOI washout period may result|
02172|013|E|in serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
02172|014|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
02172|015|E|and muscle rigidity.(4)  Serotonin syndrome may result in death.(3)|
02172|016|B||
02172|017|P|PREDISPOSING FACTORS:  High doses of serotonin reuptake inhibitors or|
02172|018|P|concurrent use of multiple drugs which increase CNS serotonin levels may|
02172|019|P|increase risk for serotonin syndrome.|
02172|020|B||
02172|021|M|PATIENT MANAGEMENT:  In emergency situations in patients maintained on|
02172|022|M|MAOIs, weigh the availability and safety of alternative agents against the|
02172|023|M|risk of serotonin syndrome.  If methylene blue therapy is required, the|
02172|024|M|patient's MAOI should be immediately discontinued.  Patients should be|
02172|025|M|monitored for serotonin syndrome for 2 weeks or until 24 hours after the|
02172|026|M|last dose of methylene blue, which ever comes first.(3)|
02172|027|M|   In non-emergency situations in patients maintained on MAOIs when|
02172|028|M|methylene blue therapy is planned, discontinue the patient's MAOI at least 2|
02172|029|M|weeks in advance of methylene blue therapy.  The patient's MAOI therapy may|
02172|030|M|be resumed 24 hours after the last dose of methylene blue.(3)|
02172|031|M|   Do not initiate MAOI therapy in patients receiving methylene blue until|
02172|032|M|24 hours after the last dose of methylene blue.(3)|
02172|033|M|   If concurrent therapy is warranted, patients should be monitored for|
02172|034|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02172|035|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02172|036|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02172|037|M|coordination, or severe diarrhea.|
02172|038|B||
02172|039|D|DISCUSSION:  Methylene blue, when administered intravenously, has been shown|
02172|040|D|to reach sufficient concentrations to be a potent inhibitor of MAO-A.(1,2)|
02172|041|D|The FDA has received reports of CNS toxicity following the use of injectable|
02172|042|D|methylene blue in patients maintained on psychiatric medications.(3)|
02172|043|D|   Metaxalone is a weak inhibitor of MAO.(5,6)|
02172|044|D|   The FDA AERS contains reports of serotonin syndrome with the concurrent|
02172|045|D|use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram,|
02172|046|D|fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine as well as|
02172|047|D|reports of serotonin syndrome with concurrent injectable methylene blue and|
02172|048|D|citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine,|
02172|049|D|escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and|
02172|050|D|venlafaxine.  The risk of serotonin syndrome with other psychiatric drugs is|
02172|051|D|unclear.(7,8)|
02172|052|B||
02172|053|R|REFERENCES:|
02172|054|B||
02172|055|R|1.USFood and Drug Administration. FDA Drug Safety Communication: Serious CNS|1
02172|056|R|  reactions possible when methylene blue is given to patients taking certain|1
02172|057|R|  psychiatric medications. available at:|1
02172|058|R|  http://wayback.archive-it.org/7993/20170722185916/https://www.fda.gov/Drug|1
02172|059|R|  s/DrugSafety/ucm263190.htm July 26, 2011.|1
02172|060|R|2.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
02172|061|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
02172|062|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
02172|063|R|3.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
02172|064|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
02172|065|R|  2000 Jun;56(3):247-50.|2
02172|066|R|4.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02172|067|R|  352(11):1112-20.|6
02172|068|R|5.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
02172|069|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
02172|070|R|  Feb;34(2):346.e5-6.|3
02172|071|R|6.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
02172|072|R|  Pfizer Inc. January, 2024.|1
02172|073|R|7.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
02172|074|R|  information about the drug interaction between methylene blue|1
02172|075|R|  (methylthioninium chloride) and serotonergic psychiatric medications.|1
02172|076|R|  available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
02172|077|R|  21, 2011.|1
02172|078|R|8.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
02172|079|R|  information about the drug interaction between linezolid (Zyvox) and|1
02172|080|R|  serotonergic psychiatric medications. available at:|1
02172|081|R|  http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm October 21, 2011.|1
02174|001|T|MONOGRAPH TITLE:  Tranexamic Acid (Oral)/Estrogenic Agents|
02174|002|B||
02174|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02174|004|L|is contraindicated and generally should not be dispensed or administered to|
02174|005|L|the same patient.|
02174|006|B||
02174|007|A|MECHANISM OF ACTION:  Tranexamic acid is an antifibrinolytic and|
02174|008|A|estrogen-containing hormonal contraceptives are known to increase the risk|
02174|009|A|of venous thromboembolism and arterial thromboses, including stroke and|
02174|010|A|myocardial infarction.  Concurrent use may increase the risk of these|
02174|011|A|events.(1)|
02174|012|B||
02174|013|E|CLINICAL EFFECTS:  Concurrent use of tranexamic acid in patients taking|
02174|014|E|estrogen-containing agents or hormonal contraceptives may increase the risk|
02174|015|E|of embolisms.(1)|
02174|016|B||
02174|017|P|PREDISPOSING FACTORS:  The risk of thrombosis may be even greater in women|
02174|018|P|who are obese or smoke, especially smokers over age 35.(1)|
02174|019|B||
02174|020|M|PATIENT MANAGEMENT:  The concurrent use of oral tranexamic and and|
02174|021|M|estrogen-containing hormonal contraception is contraindicated.(1)  It would|
02174|022|M|be prudent to follow this restriction with estrogen-replacement therapy as|
02174|023|M|well.|
02174|024|B||
02174|025|D|DISCUSSION:  There are no clinical trial data on the risk of concurrent|
02174|026|D|therapy with tranexamic acid and hormonal contraceptives.  There have been|
02174|027|D|postmarketing reports of venous and arterial thrombotic events in women|
02174|028|D|receiving combination therapy.(1)|
02174|029|D|   Women taking hormonal contraception were excluded from safety and|
02174|030|D|efficacy trials of tranexamic acid.(1)|
02174|031|B||
02174|032|R|REFERENCE:|
02174|033|B||
02174|034|R|1.Lysteda (tranexamic acid) US prescribing information. Ferring|1
02174|035|R|  Pharmaceuticals, Inc. October, 2013.|1
02175|001|T|MONOGRAPH TITLE:  Selected CYP1A2 Substrates/Vemurafenib|
02175|002|B||
02175|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02175|004|L|of severe adverse interaction.|
02175|005|B||
02175|006|A|MECHANISM OF ACTION:  Vemurafenib is a moderate inhibitor of CYP1A2. The FDA|
02175|007|A|defines moderate inhibition as an increase in drug area-under-curve (AUC)|
02175|008|A|greater than two fold, but less than 5 fold.|
02175|009|B||
02175|010|E|CLINICAL EFFECTS:  Concurrent use of vemurafenib with drugs primarily|
02175|011|E|metabolized by CYP1A2 may lead to elevated drug levels and increased side|
02175|012|E|effects.|
02175|013|B||
02175|014|P|PREDISPOSING FACTORS:  Greater risk for adverse events would be expected for|
02175|015|P|drugs with a narrow therapeutic window, or for drugs especially sensitive to|
02175|016|P|CYP1A2 inhibition.|
02175|017|P|   With tizanidine, the risk of anticholinergic toxicities including|
02175|018|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
02175|019|P|patients using more than one medicine with anticholinergic properties.(5)|
02175|020|B||
02175|021|M|PATIENT MANAGEMENT:  Drugs linked to this monograph have a narrow|
02175|022|M|therapeutic window or are sensitive to CYP1A2 inhibition.  If|
02175|023|M|coadministration cannot be avoided, the manufacturer of vemurafenib|
02175|024|M|recommends close monitoring and possible dose reduction of the affected|
02175|025|M|drug.  Steady-state levels of vemurafenib are not attained for approximately|
02175|026|M|15 days and so extended monitoring for interaction onset and severity may be|
02175|027|M|required.|
02175|028|M|   The US manufacturer of tizanidine states that if concurrent therapy is|
02175|029|M|necessary, tizanidine should be initiated at 2 mg dose and increased in 2-4|
02175|030|M|mg steps daily based on patient response to therapy. If adverse reactions|
02175|031|M|such as hypotension, bradycardia, or excessive drowsiness occur, reduce of|
02175|032|M|discontinue tizanidine therapy.(4)|
02175|033|B||
02175|034|D|DISCUSSION:  An interaction study was performed in cancer patients treated|
02175|035|D|with vemurafenib 960 mg twice daily for 15 days. The AUC of caffeine, a|
02175|036|D|sensitive substrate for CYP1A2, was increased 2.6-fold.|
02175|037|D|   Coadministration with tizanidine (2mg, a sensitive CYP1A2 substrate) on|
02175|038|D|day 21 with vemurafenib (960 mg twice daily for 21 days) increased|
02175|039|D|tizanidine AUC and Cmax by 4.7-fold and 2.2-fold in 16 cancer patients. (1)|
02175|040|B||
02175|041|R|REFERENCES:|
02175|042|B||
02175|043|R|1.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02175|044|R|  November, 2017.|1
02175|045|R|2.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
02175|046|R|  June, 2020.|1
02175|047|R|3.Valdoxan (agomelatine) UK summary of product characteristics. Les|1
02175|048|R|  Laboratoires Servier February 19, 2009.|1
02175|049|R|4.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
02175|050|R|  Pharma Inc. November 22, 2024.|1
02175|051|R|5.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02175|052|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02175|053|R|  Soc 2023 Jul;71(7):2052-2081.|6
02176|001|T|MONOGRAPH TITLE:  Vemurafenib/Possible QT Prolonging Agents|
02176|002|B||
02176|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02176|004|L|take action as needed.|
02176|005|B||
02176|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02176|007|A|interval may result in additive effects on the QTc interval.(1)|
02176|008|B||
02176|009|E|CLINICAL EFFECTS:  The use of vemurafenib in patients maintained on agents|
02176|010|E|that prolong the QTc interval may result in potentially life-threatening|
02176|011|E|cardiac arrhythmias, including torsades de pointes.(1)|
02176|012|B||
02176|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02176|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02176|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02176|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02176|017|P|female gender, or advanced age.(2)|
02176|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02176|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02176|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02176|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02176|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02176|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02176|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02176|025|B||
02176|026|M|PATIENT MANAGEMENT:  Vemurafenib should not be initiated in patients taking|
02176|027|M|medications known to prolong the QT interval, patients with a baseline QTc|
02176|028|M|greater than 500 msec, uncorrectable electrolyte abnormalities, or known|
02176|029|M|long QT syndrome is not recommended.(1)|
02176|030|M|   All patients receiving vemurafenib should undergo ECG testing at|
02176|031|M|baseline, after 15 days of treatment, monthly during the first 3 months of|
02176|032|M|treatment, and then every 3 months.  If a patient's QTc exceeds 500 msec|
02176|033|M|during treatment, vemurafenib should be discontinued and cardiac risk|
02176|034|M|factors for QT prolongation should be controlled.  Consider discontinuing|
02176|035|M|other medications known to prolong the QT interval at this time.  If the|
02176|036|M|patient's QTc decreases below 500 msec, vemurafenib may be introduced at a|
02176|037|M|lower dosage according to the current labeling recommendations.  If the|
02176|038|M|patient's QTc remains greater than 500 msec and increased >60 msec from|
02176|039|M|pre-treatment values after controlling cardiac risk factors for|
02176|040|M|prolongation, permanently discontinue vemurafenib.(1)|
02176|041|M|   Consider obtaining serum calcium, magnesium, and potassium levels at|
02176|042|M|baseline and regular intervals. Correct any electrolyte abnormalities.|
02176|043|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02176|044|M|fainting.|
02176|045|B||
02176|046|D|DISCUSSION:  Vemurafenib is associated with concentration-dependent QTc|
02176|047|D|interval prolongation.  In the first month of treatment, the largest mean|
02176|048|D|QTc change was 12.8 msec (upper boundary of 90% CI:  14.9 msec).  In the|
02176|049|D|first 6 months of treatment, the largest mean QTc change was 15.1 msec|
02176|050|D|(upper boundary of 90% CI:  17.7 msec).(1)|
02176|051|D|   Agents that are linked to this monograph may have varying degrees of|
02176|052|D|potential to prolong the QTc interval but are generally accepted to have a|
02176|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02176|054|D|been shown to prolong the QTc interval either through their mechanism of|
02176|055|D|action, through studies on their effects on the QTc interval, or through|
02176|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02176|057|D|and/or post-marketing reports.(3)|
02176|058|B||
02176|059|R|REFERENCES:|
02176|060|B||
02176|061|R|1.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02176|062|R|  November, 2017.|1
02176|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02176|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02176|065|R|  settings: a scientific statement from the American Heart Association and|6
02176|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02176|067|R|  2;55(9):934-47.|6
02176|068|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02176|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02176|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02176|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02177|001|T|MONOGRAPH TITLE:  Citalopram (Greater Than 20 mg)/Select CYP2C19 Inhibitors|
02177|002|B||
02177|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02177|004|L|of severe adverse interaction.|
02177|005|B||
02177|006|A|MECHANISM OF ACTION:  Citalopram is primarily metabolized by the CYP2C19|
02177|007|A|isoenzyme.(1)|
02177|008|B||
02177|009|E|CLINICAL EFFECTS:  Concurrent use of an agent that inhibits CYP2C19 may|
02177|010|E|result in elevated levels of and toxicity from citalopram, including|
02177|011|E|including risks for serotonin syndrome or prolongation of the QTc|
02177|012|E|interval.(1-5)|
02177|013|E|   Prolongation of the QT interval may result in life-threatening|
02177|014|E|arrhythmias, including torsades de pointes.(2)|
02177|015|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
02177|016|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02177|017|E|rigidity.(5)|
02177|018|B||
02177|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02177|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
02177|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02177|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02177|023|P|female gender, advanced age, poor metabolizer status at CYP2C19, or higher|
02177|024|P|blood concentrations of citalopram.(2)|
02177|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02177|026|P|higher systemic concentrations of either QT prolonging drug are additional|
02177|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02177|028|P|drug concentrations include rapid infusion of an intravenous dose or|
02177|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02177|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02177|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02177|032|P|   Predisposing factors for serotonin-related adverse effects include use in|
02177|033|P|the elderly, in patients with hepatic impairment, and in patients receiving|
02177|034|P|multiple agents which increase central serotonin levels.(1,5)|
02177|035|P|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02177|036|P|magnesium, and potassium levels and monitoring ECG at baseline and at|
02177|037|P|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02177|038|P|patients to report any irregular heartbeat, dizziness, or fainting.|
02177|039|B||
02177|040|M|PATIENT MANAGEMENT:  The dose of citalopram should be limited to 20 mg in|
02177|041|M|patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4)|
02177|042|M|Evaluate the patient for other drugs, diseases and conditions which increase|
02177|043|M|risk for QT prolongation and correct risk factors (e.g. correct hypokalemia,|
02177|044|M|discontinue other QT prolonging drugs) when possible.(1,2)  Weigh the|
02177|045|M|specific benefits versus risks for each patient.  The US manufacturer|
02177|046|M|recommends ECG monitoring for citalopram patients with congestive heart|
02177|047|M|failure, bradyarrhythmias, taking concomitant QT prolonging medications or|
02177|048|M|receiving concurrent therapy.(4)  Citalopram should be discontinued in|
02177|049|M|patients with persistent QTc measurements greater than 500 ms.(2)|
02177|050|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02177|051|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02177|052|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02177|053|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02177|054|M|   If concurrent therapy is warranted, patients should be monitored for|
02177|055|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02177|056|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02177|057|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02177|058|M|coordination, or severe diarrhea.|
02177|059|B||
02177|060|D|DISCUSSION:  Concurrent use of citalopram (40 mg daily) and cimetidine (400|
02177|061|D|mg twice daily) for 8 days increased the maximum concentration (Cmax) and|
02177|062|D|area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1)|
02177|063|D|   Inhibitors of CYP2C19 include:  abrocitinib, allicin (garlic derivative),|
02177|064|D|berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200|
02177|065|D|mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib,|
02177|066|D|felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide,|
02177|067|D|modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol,|
02177|068|D|and tecovirimat.(7,8)|
02177|069|B||
02177|070|R|REFERENCES:|
02177|071|B||
02177|072|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
02177|073|R|  Laboratories Inc. August, 2023.|1
02177|074|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02177|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02177|076|R|  settings: a scientific statement from the American Heart Association and|6
02177|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02177|078|R|  2;55(9):934-47.|6
02177|079|R|3.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
02177|080|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
02177|081|R|  and antidepressant use: a cross sectional study of electronic health|2
02177|082|R|  records. BMJ 2013;346:f288.|2
02177|083|R|4.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
02177|084|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
02177|085|R|  Lundbeck Canada January 25, 2012.|1
02177|086|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02177|087|R|  352(11):1112-20.|6
02177|088|R|6.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02177|089|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
02177|090|R|  potential risk of abnormal heart rhythms with high doses. available at:|1
02177|091|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02177|092|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
02177|093|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02177|094|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02177|095|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02177|096|R|  11/14/2017.|1
02177|097|R|8.This information is based on an extract from the Certara Drug Interaction|6
02177|098|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02178|001|T|MONOGRAPH TITLE:  Citalopram/Possible QT Prolonging Agents|
02178|002|B||
02178|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02178|004|L|take action as needed.|
02178|005|B||
02178|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02178|007|A|interval may result in additive effects on the QTc interval.(1-3)|
02178|008|B||
02178|009|E|CLINICAL EFFECTS:  The use of citalopram in patients maintained on agents|
02178|010|E|that prolong the QTc interval may result in potentially life-threatening|
02178|011|E|cardiac arrhythmias, including torsades de pointes.(1-3)|
02178|012|B||
02178|013|P|PREDISPOSING FACTORS:  Higher doses of citalopram, especially doses greater|
02178|014|P|than 40 mg, may increase the risk of QT prolongation.|
02178|015|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02178|016|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02178|017|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02178|018|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02178|019|P|advanced age.(4)|
02178|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02178|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02178|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02178|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02178|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02178|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02178|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02178|027|B||
02178|028|M|PATIENT MANAGEMENT:  Concurrent use of citalopram with agents known to|
02178|029|M|prolong the QT interval should be avoided.|
02178|030|M|   Due to the risk of QT prolongation, citalopram doses greater than 40 mg|
02178|031|M|once daily are not recommended.  Citalopram doses should be limited to 20 mg|
02178|032|M|once daily in patients who are CYP2C19 poor metabolizers or patients|
02178|033|M|receiving CYP2C19 inhibitors.|
02178|034|M|   If patients have a persistent QTc measurement > 500 ms, discontinue|
02178|035|M|citalopram.  If a patient develops symptoms including dizziness,|
02178|036|M|palpitations, or syncope, further evaluation is warranted included cardiac|
02178|037|M|monitoring.|
02178|038|M|   The manufacturer recommends ECG monitoring in patients for whom|
02178|039|M|citalopram is not recommended, including those receiving concurrent therapy|
02178|040|M|with agents known to prolong the QT interval.  Citalopram should be|
02178|041|M|discontinued in patients with persistent QTc measurements greater than 500|
02178|042|M|ms.(1-2)  Consider obtaining serum calcium, magnesium, and potassium levels|
02178|043|M|at regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02178|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02178|045|B||
02178|046|D|DISCUSSION:  Citalopram has been associated with dose-depended increases in|
02178|047|D|the QTc interval.  In healthy subjects, the maximum mean difference in QTc|
02178|048|D|interval seen with 20 mg of citalopram and 60 mg of citalopram were 8.5 msec|
02178|049|D|(90% CI = 6.2-10.8 msec) and 18.5 msec (90% CI = 16.0-21.0 msec),|
02178|050|D|respectively.  Based on extrapolation, a 40 mg dose of citalopram is|
02178|051|D|expected to produce a mean increase in the QTc interval of 12.6 msec (90% CI|
02178|052|D|= 10.9-14.3 msec).(1)|
02178|053|D|   In a clinical trial of use of citalopram for agitation in Alzheimer's|
02178|054|D|disease, citalopram (30 mg daily) was associated with a mean increase in QTc|
02178|055|D|of 18.1 msec.(5)|
02178|056|D|   Agents that are linked to this monograph may have varying degrees of|
02178|057|D|potential to prolong the QTc interval but are generally accepted to have a|
02178|058|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02178|059|D|been shown to prolong the QTc interval either through their mechanism of|
02178|060|D|action, through studies on their effects on the QTc interval, or through|
02178|061|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02178|062|D|and/or post-marketing reports.(6)|
02178|063|B||
02178|064|R|REFERENCES:|
02178|065|B||
02178|066|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
02178|067|R|  Laboratories Inc. August, 2023.|1
02178|068|R|2.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
02178|069|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
02178|070|R|  Lundbeck Canada January 25, 2012.|1
02178|071|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02178|072|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
02178|073|R|  potential risk of abnormal heart rhythms with high doses. available at:|1
02178|074|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02178|075|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02178|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02178|077|R|  settings: a scientific statement from the American Heart Association and|6
02178|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02178|079|R|  2;55(9):934-47.|6
02178|080|R|5.Drye LT, et al. Changes in QTc interval in the citalopram for agitation in|2
02178|081|R|  Alzheimer's disease (CitAD) randomized trial. PLoS One 2014;9(6):e98426.|2
02178|082|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
02178|083|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02178|084|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02178|085|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02179|001|T|MONOGRAPH TITLE:  Citalopram (Less than or Equal To 20 mg)/Selected CYP2C19|
02179|002|T|Inhibitors|
02179|003|B||
02179|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02179|005|L|take action as needed.|
02179|006|B||
02179|007|A|MECHANISM OF ACTION:  Citalopram is primarily metabolized by the CYP2C19|
02179|008|A|isoenzyme.(1)|
02179|009|B||
02179|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that inhibits CYP2C19 may|
02179|011|E|result in elevated levels of and toxicity from citalopram, including|
02179|012|E|including risks for serotonin syndrome or prolongation of the QTc|
02179|013|E|interval.(1-5)|
02179|014|E|   Prolongation of the QT interval may result in life-threatening|
02179|015|E|arrhythmias, including torsades de pointes.(2)|
02179|016|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
02179|017|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02179|018|E|rigidity.(5)|
02179|019|B||
02179|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02179|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
02179|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02179|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02179|024|P|female gender, advanced age, poor metabolizer status at CYP2C19, or higher|
02179|025|P|blood concentrations of citalopram.(2)|
02179|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02179|027|P|higher systemic concentrations of either QT prolonging drug are additional|
02179|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02179|029|P|drug concentrations include rapid infusion of an intravenous dose or|
02179|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02179|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02179|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02179|033|P|   Predisposing factors for serotonin-related adverse effects include use in|
02179|034|P|the elderly, in patients with hepatic impairment, and in patients receiving|
02179|035|P|multiple agents which increase central serotonin levels.(1,5)|
02179|036|P|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02179|037|P|magnesium, and potassium levels and monitoring ECG at baseline and at|
02179|038|P|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02179|039|P|patients to report any irregular heartbeat, dizziness, or fainting.|
02179|040|B||
02179|041|M|PATIENT MANAGEMENT:  The dose of citalopram should be limited to 20 mg in|
02179|042|M|patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4)|
02179|043|M|Evaluate the patient for other drugs, diseases and conditions which increase|
02179|044|M|risk for QT prolongation and correct risk factors (e.g. correct hypokalemia,|
02179|045|M|hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when|
02179|046|M|possible.(1,2)  Weigh the specific benefits versus risks for each patient.|
02179|047|M|The US manufacturer recommends ECG monitoring for citalopram patients with|
02179|048|M|congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging|
02179|049|M|medications or receiving concurrent therapy.(4)  Citalopram should be|
02179|050|M|discontinued in patients with persistent QTc measurements greater than 500|
02179|051|M|ms.(2)|
02179|052|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02179|053|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02179|054|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02179|055|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02179|056|M|   If concurrent therapy is warranted, patients should be monitored for|
02179|057|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02179|058|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02179|059|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02179|060|M|coordination, or severe diarrhea.|
02179|061|B||
02179|062|D|DISCUSSION:  Concurrent use of citalopram (40 mg daily) and cimetidine (400|
02179|063|D|mg twice daily) for 8 days increased the maximum concentration (Cmax) and|
02179|064|D|area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1)|
02179|065|D|   Inhibitors of CYP2C19 include:  abrocitinib, allicin (garlic derivative),|
02179|066|D|berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200|
02179|067|D|mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib,|
02179|068|D|felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide,|
02179|069|D|modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol,|
02179|070|D|and tecovirimat.(7,8)|
02179|071|B||
02179|072|R|REFERENCES:|
02179|073|B||
02179|074|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
02179|075|R|  Laboratories Inc. August, 2023.|1
02179|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02179|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02179|078|R|  settings: a scientific statement from the American Heart Association and|6
02179|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02179|080|R|  2;55(9):934-47.|6
02179|081|R|3.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
02179|082|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
02179|083|R|  and antidepressant use: a cross sectional study of electronic health|2
02179|084|R|  records. BMJ 2013;346:f288.|2
02179|085|R|4.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
02179|086|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
02179|087|R|  Lundbeck Canada January 25, 2012.|1
02179|088|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02179|089|R|  352(11):1112-20.|6
02179|090|R|6.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02179|091|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
02179|092|R|  potential risk of abnormal heart rhythms with high doses. available at:|1
02179|093|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02179|094|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
02179|095|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02179|096|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02179|097|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02179|098|R|  11/14/2017.|1
02179|099|R|8.This information is based on an extract from the Certara Drug Interaction|6
02179|100|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02180|001|T|MONOGRAPH TITLE:  Bezafibrate; Fenofibrate/Rosiglitazone|
02180|002|B||
02180|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02180|004|L|of severe adverse interaction.|
02180|005|B||
02180|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02180|007|B||
02180|008|E|CLINICAL EFFECTS:  Concurrent use of rosiglitazone with bezafibrate or|
02180|009|E|fenofibrate may result in severe paradoxical decreases in high-density|
02180|010|E|lipoprotein (HDL) in some patients.|
02180|011|B||
02180|012|P|PREDISPOSING FACTORS:  None determined.|
02180|013|B||
02180|014|M|PATIENT MANAGEMENT:  Monitor HDL levels in patients receiving combination|
02180|015|M|therapy with rosiglitazone with bezafibrate or fenofibrate.  One or both|
02180|016|M|agents may need to be discontinued.|
02180|017|B||
02180|018|D|DISCUSSION:  There have been numerous reports of severe paradoxical|
02180|019|D|decreases in HDL levels (defined as <0.52 mmol/L or 20 mg/dL) with|
02180|020|D|concurrent pioglitazone or rosiglitazone with bezafibrate or|
02180|021|D|fenofibrate.(1-10)  In some patients, discontinuation of the antidiabetic|
02180|022|D|agent alone increased HDL levels.  In others, both agents were discontinued.|
02180|023|B||
02180|024|R|REFERENCES:|
02180|025|B||
02180|026|R|1.Tremblay P. Rosiglitazone-fenofibrate interaction: severe paradoxical|1
02180|027|R|  decreased high-density lipoprotein cholesterol levels. Canadian Adverse|1
02180|028|R|  Reaction Newsletter 2011 Apr;21(2):2-3.|1
02180|029|R|2.Shetty C, Balasubramani M, Capps N, Milles J, Ramachandran S. Paradoxical|3
02180|030|R|  HDL-C reduction during rosiglitazone and fibrate treatment. Diabet Med|3
02180|031|R|  2007 Jan;24(1):94-7.|3
02180|032|R|3.Keidar S, Guttmann H, Stam T, Fishman I, Shapira C. High incidence of|3
02180|033|R|  reduced plasma HDL cholesterol in diabetic patients treated with|3
02180|034|R|  rosiglitazone and fibrate. Pharmacoepidemiol Drug Saf 2007 Nov;|3
02180|035|R|  16(11):1192-4.|3
02180|036|R|4.Magee G, Sharpe PC. Paradoxical decreases in high-density lipoprotein|3
02180|037|R|  cholesterol with fenofibrate: a quite common phenomenon. J Clin Pathol|3
02180|038|R|  2009 Mar;62(3):250-3.|3
02180|039|R|5.Mymin D, Dembinski T, Friesen MH. Iatrogenic severe depression of|3
02180|040|R|  high-density lipoprotein cholesterol. J Clin Pharmacol 2009 Jul;|3
02180|041|R|  49(7):865-71.|3
02180|042|R|6.Gutschi LM, Malcolm JC, Favreau CM, Ooi TC. Paradoxically decreased|3
02180|043|R|  HDL-cholesterol levels associated with rosiglitazone therapy. Ann|3
02180|044|R|  Pharmacother 2006 Sep;40(9):1672-6.|3
02180|045|R|7.Goldberg RB, Mendez AJ. Severe acquired (secondary) high-density|3
02180|046|R|  lipoprotein deficiency. J Clin Lipidol 2007 Mar;1(1):41-56.|3
02180|047|R|8.Im M, Kim M, Lee JK, Chang YH, Lee DY, Hong SI, Lee YY, Hong YJ. HDL|3
02180|048|R|  cholesterol reduction during rosiglitazone and fenofibrate treatment in a|3
02180|049|R|  type 2 diabetes mellitus patient with dyslipidemia. Korean J Lab Med 2010|3
02180|050|R|  Feb;30(1):17-9.|3
02180|051|R|9.Schwing W, Hustak L, Taylor HC. Paradoxical severe decrease in|3
02180|052|R|  high-density lipoprotein cholesterol due to rosiglitazone-fenofibrate|3
02180|053|R|  interaction. Endocr Pract 2010 May-Jun;16(3):382-8.|3
02180|054|R|10.Venero CV, Thompson PD, Fernandez AB. Reduced high-density lipoprotein|3
02180|055|R|   cholesterol in patients receiving rosiglitazone and fenofibrate. Am J Med|3
02180|056|R|   2008 Oct;121(10):e3-4.|3
02180|057|R|11.Normen L, Frohlich J, Montaner J, Harris M, Elliott T, Bondy G.|3
02180|058|R|   Combination therapy with fenofibrate and rosiglitazone paradoxically|3
02180|059|R|   lowers serum HDL cholesterol. Diabetes Care 2004 Sep;27(9):2241-2.|3
02181|001|T|MONOGRAPH TITLE:  Crizotinib/Possible QT Prolonging Agents|
02181|002|B||
02181|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02181|004|L|take action as needed.|
02181|005|B||
02181|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02181|007|A|interval may result in additive effects on the QTc interval.(1)|
02181|008|B||
02181|009|E|CLINICAL EFFECTS:  The use of crizotinib in patients maintained on agents|
02181|010|E|that prolong the QTc interval may result in potentially life-threatening|
02181|011|E|cardiac arrhythmias, including torsades de pointes.(1)|
02181|012|B||
02181|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02181|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02181|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02181|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02181|017|P|female gender, or advanced age.(2)|
02181|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02181|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02181|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02181|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02181|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02181|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02181|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02181|025|B||
02181|026|M|PATIENT MANAGEMENT:  Consider periodic electrocardiogram (ECG) and|
02181|027|M|electrolyte monitoring (calcium, magnesium, and potassium levels at baseline|
02181|028|M|and regular intervals) in patients receiving concurrent therapy with|
02181|029|M|crizotinib and another agent that prolongs the QTc interval.(1)|
02181|030|M|   In patients who develop a QTc greater than 500 ms on at least 2 separate|
02181|031|M|ECGs, withhold crizotinib until recovery to baseline or to a QTc less than|
02181|032|M|481 ms, then resume crizotinib at reduced dose.(1)|
02181|033|M|   In patients who develop a QTc greater than 500 ms or greater than or|
02181|034|M|equal to 60 ms change from baseline with Torsade de pointes or polymorphic|
02181|035|M|ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently|
02181|036|M|discontinue crizotinib.(1)|
02181|037|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02181|038|M|fainting.|
02181|039|B||
02181|040|D|DISCUSSION:  Crizotinib is associated with concentration-dependent QTc|
02181|041|D|interval prolongation.  In a clinical trial 2.1% of patients were found to|
02181|042|D|have a QTcF greater than or equal to 500 msec and 5% of patients had an|
02181|043|D|increase in QTcF by greater than or equal to 60 msec.(1)|
02181|044|D|   A retrospective review of 618 cancer patients treated with 902|
02181|045|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02181|046|D|incidence of QTc prolongation.  In patients who received crizotinib, QTc|
02181|047|D|prolongation was identified in 1 (50%) with 1 (100%) having Grade 1 (QTc|
02181|048|D|450-480 ms).  No patients had a QTc change greater than or equal to 60 ms,|
02181|049|D|ventricular tachycardia, sudden cardiac death, or TdP.(3)|
02181|050|D|   Agents that are linked to this monograph may have varying degrees of|
02181|051|D|potential to prolong the QTc interval but are generally accepted to have a|
02181|052|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02181|053|D|been shown to prolong the QTc interval either through their mechanism of|
02181|054|D|action, through studies on their effects on the QTc interval, or through|
02181|055|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02181|056|D|and/or post-marketing reports.(4)|
02181|057|B||
02181|058|R|REFERENCES:|
02181|059|B||
02181|060|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
02181|061|R|  2023.|1
02181|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02181|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02181|064|R|  settings: a scientific statement from the American Heart Association and|6
02181|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02181|066|R|  2;55(9):934-47.|6
02181|067|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02181|068|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02181|069|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02181|070|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
02181|071|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02181|072|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02181|073|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02182|001|T|MONOGRAPH TITLE:  Tranexamic Acid; Aminocaproic Acid; Aprotinin/Tretinoin,|
02182|002|T|Oral|
02182|003|B||
02182|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02182|005|L|of severe adverse interaction.|
02182|006|B||
02182|007|A|MECHANISM OF ACTION:  Tranexamic acid, aminocaproic acid, or aprotinin may|
02182|008|A|increase the procoagulant effect of all-trans retinoic acid (tretinoin).(1)|
02182|009|B||
02182|010|E|CLINICAL EFFECTS:  Concurrent use of tranexamic acid, aminocaproic acid, or|
02182|011|E|aprotinin in patients taking tretinoin may increase the risk of|
02182|012|E|embolisms.(1)|
02182|013|B||
02182|014|P|PREDISPOSING FACTORS:  None determined.|
02182|015|B||
02182|016|M|PATIENT MANAGEMENT:  Tranexamic acid, aminocaproic acid, and aprotinin|
02182|017|M|should be used with caution in patients taking oral tretinoin for acute|
02182|018|M|promyelocytic leukemia.(1)|
02182|019|B||
02182|020|D|DISCUSSION:  In a small study of 28 patients with acute promyelocytic|
02182|021|D|leukemia, patients were administered oral tretinoin with intravenous|
02182|022|D|tranexamic acid, oral tretinoin with chemotherapy, or oral tretinoin with|
02182|023|D|intravenous tranexamic acid and chemotherapy.  All four patients who|
02182|024|D|received oral tretinoin with tranexamic acid died.  Three of these deaths|
02182|025|D|involved thrombotic complications.(1)|
02182|026|D|   There is a case report of fatal thromboembolism in a patient with acute|
02182|027|D|promyelocytic leukemia who was administered oral tretinoin and tranexamic|
02182|028|D|acid concurrently.(2)|
02182|029|D|   There are two case reports of thrombosis in patients with acute|
02182|030|D|promyelocytic leukemia who were administered oral tretinoin and aprotinin|
02182|031|D|concurrently.(2-4) Ones of the cases resulted in fatal thromboembolism.(4)|
02182|032|B||
02182|033|R|REFERENCES:|
02182|034|B||
02182|035|R|1.Lysteda (tranexamic acid) US prescribing information. Ferring|1
02182|036|R|  Pharmaceuticals, Inc. October, 2013.|1
02182|037|R|2.Hashimoto S, Koike T, Tatewaki W, Seki Y, Sato N, Azegami T, Tsukada N,|3
02182|038|R|  Takahashi H, Kimura H, Ueno M, et al. Fatal thromboembolism in acute|3
02182|039|R|  promyelocytic leukemia during all-trans retinoic acid therapy combined|3
02182|040|R|  with antifibrinolytic therapy for prophylaxis of hemorrhage. Leukemia 1994|3
02182|041|R|  Jul;8(7):1113-5.|3
02182|042|R|3.Kocak U, Gursel T, Ozturk G, Kantarci S. Thrombosis during|3
02182|043|R|  all-trans-retinoic acid therapy in a child with acute promyelocytic|3
02182|044|R|  leukemia and factor VQ 506 mutation. Pediatr Hematol Oncol 2000 Mar;|3
02182|045|R|  17(2):177-80.|3
02182|046|R|4.Mahendra P, Keeling DM, Hood IM, Baglin TP, Marcus RE. Fatal|3
02182|047|R|  thromboembolism in acute promyelocytic leukaemia treated with a|3
02182|048|R|  combination of all-trans retinoic acid and aprotonin. Clin Lab Haematol|3
02182|049|R|  1996 Mar;18(1):51-2.|3
02183|001|T|MONOGRAPH TITLE:  Quinine/Selected Protease Inhibitors|
02183|002|B||
02183|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02183|004|L|of severe adverse interaction.|
02183|005|B||
02183|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is not completely|
02183|007|A|known and is likely multifactorial.  Quinine is a substrate of CYP3A4, P-gp,|
02183|008|A|and UGT.(1-3)  Protease inhibitors primarily inhibit CYP3A4 but may also|
02183|009|A|inhibit or induce other hepatic metabolic processes.  In particular,|
02183|010|A|ritonavir may induce P-glycoprotein (P-gp) and|
02183|011|A|uridine-5'-diphospho-glucuronosyltransferase (UGT).(2-4)  Nelfinavir and|
02183|012|A|tipranavir are known to induce UGT while atazanavir and indinavir inhibit|
02183|013|A|UGT.|
02183|014|B||
02183|015|E|CLINICAL EFFECTS:  Concurrent ritonavir has been reported to result in|
02183|016|E|elevated levels of and toxicity from quinine.  Quinine toxicity includes|
02183|017|E|symptoms of cinchonism (headache, vasodilation/sweating,|
02183|018|E|nausea/vomiting/diarrhea, tinnitus, hearing impairment, vertigo/dizziness,|
02183|019|E|blurred vision/disturbance in color perception/blindness, abdominal pain,|
02183|020|E|deafness) as well as QTc prolongation and life-threatening cardiac|
02183|021|E|arrhythmias, including torsades de pointes.(1,5)|
02183|022|E|   On the other hand, concurrent lopinavir-ritonavir (fixed dose|
02183|023|E|combination) has been reported to result in decreased levels of quinine.|
02183|024|E|Whether this finding translates into reduced anti-malarial efficacy is|
02183|025|E|unknown.  One of the studies examining the use of lopinavir-ritonavir with|
02183|026|E|quinine found that free, unbound levels of quinine was decreased, whereas|
02183|027|E|the other found an increase in free quinine levels.(2,3)|
02183|028|B||
02183|029|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02183|030|P|may be increased in patients with cardiovascular disease (e.g. heart|
02183|031|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02183|032|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02183|033|P|female gender, or advanced age.(6)|
02183|034|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02183|035|P|higher systemic concentrations of either QT prolonging drug are additional|
02183|036|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02183|037|P|drug concentrations include rapid infusion of an intravenous dose or|
02183|038|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02183|039|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02183|040|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
02183|041|B||
02183|042|M|PATIENT MANAGEMENT:  The US manufacturers of quinine and ritonavir recommend|
02183|043|M|avoiding the use of quinine in patients maintained on ritonavir.(1,4)  If|
02183|044|M|concurrent therapy is required, consider reducing the dose of|
02183|045|M|quinine.(1,4,5)|
02183|046|M|   There is no FDA or guideline recommendation for the concurrent use of|
02183|047|M|other protease inhibitors with quinine.  A physiologically based|
02183|048|M|pharmacokinetic model suggests that quinine dosage may need to be increased|
02183|049|M|when used with lopinavir-ritonavir, based on decreased quinine|
02183|050|M|concentrations when used with lopinavir-ritonavir.(7)|
02183|051|M|   Patients receiving concurrent therapy should be monitored with|
02183|052|M|electrocardiograms during treatment with quinine.  Electrolytes (calcium,|
02183|053|M|magnesium, and potassium) should also be monitored.(1)|
02183|054|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02183|055|M|fainting.|
02183|056|B||
02183|057|D|DISCUSSION:  In 10 healthy subjects, ritonavir (200 mg every 12 hours for 9|
02183|058|D|days) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
02183|059|D|of a single dose of quinine (600 mg) by 4-fold each.  The clearance of|
02183|060|D|quinine decreased 4.5-fold.  There were no significant effects on the|
02183|061|D|pharmacokinetics of ritonavir.(1,5)|
02183|062|D|   A pharmacokinetic study of 12 healthy volunteers who were coadministered|
02183|063|D|quinine and lopinavir-ritonavir found that lopinavir-ritonavir led to a|
02183|064|D|decrease in the Cmax and AUC of total quinine by 48% and 50%, respectively,|
02183|065|D|and of free quinine by 33% and 36%, respectively.  The AUC and Cmax of total|
02183|066|D|3-hydroxyquinine, the major active metabolite of quinine, both decreased by|
02183|067|D|69%, and of free 3-hydroxyquinine decreased by 65% and 39%, respectively.|
02183|068|D|The mechanism of interaction was attributed to ritonavir induction of UGT|
02183|069|D|enzymes and of the P-gp transporter.(2)  The effects of other|
02183|070|D|ritonavir-boosted protease inhibitor regimens on quinine has not been|
02183|071|D|studied.  Nelfinavir and tipranavir are known to induce UGT while atazanavir|
02183|072|D|and indinavir inhibit UGT.|
02183|073|D|   In another pharmacokinetic study of 19 healthy subjects, quinine Cmax and|
02183|074|D|AUC decreased by 49% and 58%, respectively, when administered concurrently|
02183|075|D|with lopinavir-ritonavir, compared to when administered alone.  The Cmax and|
02183|076|D|AUC of 3-hydroxyquinine decreased by 85% and 98%, respectively, when given|
02183|077|D|with lopinavir-ritonavir.  A significant increase (236%) in free quinine|
02183|078|D|Cmax was observed.  The clinical significance of these changes is|
02183|079|D|unclear.(3)|
02183|080|D|   A physiologically based pharmacokinetic model predicted that|
02183|081|D|lopinavir-ritonavir decreases the AUC of unbound quinine by about 70%,|
02183|082|D|compared to quinine alone.  The authors suggested increasing the dose of|
02183|083|D|quinine from 600 mg three times daily to 1,800 mg three times daily.(7)|
02183|084|B||
02183|085|R|REFERENCES:|
02183|086|B||
02183|087|R|1.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
02183|088|R|  Industries, Inc. August, 2019.|1
02183|089|R|2.Nyunt MM, Lu Y, El-Gasim M, Parsons TL, Petty BG, Hendrix CW. Effects of|2
02183|090|R|  ritonavir-boosted lopinavir on the pharmacokinetics of quinine. Clin|2
02183|091|R|  Pharmacol Ther 2012 May;91(5):889-95.|2
02183|092|R|3.Rattanapunya S, Cressey TR, Rueangweerayut R, Tawon Y, Kongjam P,|2
02183|093|R|  Na-Bangchang K. Pharmacokinetic Interactions Between Quinine and|2
02183|094|R|  Lopinavir/Ritonavir in Healthy Thai  Adults. Am J Trop Med Hyg 2015 Dec;|2
02183|095|R|  93(6):1383-90.|2
02183|096|R|4.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
02183|097|R|  December, 2019.|1
02183|098|R|5.Soyinka JO, Onyeji CO, Omoruyi SI, Owolabi AR, Sarma PV, Cook JM.|2
02183|099|R|  Pharmacokinetic interactions between ritonavir and quinine in healthy|2
02183|100|R|  volunteers following concurrent administration. Br J Clin Pharmacol 2010|2
02183|101|R|  Mar;69(3):262-70.|2
02183|102|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02183|103|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02183|104|R|  settings: a scientific statement from the American Heart Association and|6
02183|105|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02183|106|R|  2;55(9):934-47.|6
02183|107|R|7.Saeheng T, Na-Bangchang K, Siccardi M, Rajoli RKR, Karbwang J.|2
02183|108|R|  Physiologically-Based Pharmacokinetic Modeling for Optimal Dosage|2
02183|109|R|  Prediction of  Quinine Coadministered With Ritonavir-Boosted Lopinavir.|2
02183|110|R|  Clin Pharmacol Ther 2020 May;107(5):1209-1220.|2
02183|111|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
02183|112|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02183|113|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02183|114|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02184|001|T|MONOGRAPH TITLE:  Quetiapine/Possible QT Prolonging Agents|
02184|002|B||
02184|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02184|004|L|take action as needed.|
02184|005|B||
02184|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02184|007|A|interval may result in additive effects on the QTc interval.(1)|
02184|008|B||
02184|009|E|CLINICAL EFFECTS:  The use of quetiapine in patients maintained on agents|
02184|010|E|that prolong the QTc interval may result in potentially life-threatening|
02184|011|E|cardiac arrhythmias, including torsades de pointes.(1)|
02184|012|B||
02184|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02184|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02184|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02184|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02184|017|P|female gender, or advanced age.(3)|
02184|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02184|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02184|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02184|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02184|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02184|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02184|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02184|025|B||
02184|026|M|PATIENT MANAGEMENT:  The US manufacturer of quetiapine states that|
02184|027|M|concurrent use with agents known to prolong the QT interval should be|
02184|028|M|avoided.(1)|
02184|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02184|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02184|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02184|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02184|033|B||
02184|034|D|DISCUSSION:  Although quetiapine was not associated with QT or QTc changes|
02184|035|D|in clinical trials, QT prolongation has been reported in post-marketing|
02184|036|D|reports in conjunction with the use of other agents known to prolong the QT|
02184|037|D|interval.(1)|
02184|038|D|   Agents that are linked to this monograph may have varying degrees of|
02184|039|D|potential to prolong the QTc interval but are generally accepted to have a|
02184|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02184|041|D|been shown to prolong the QTc interval either through their mechanism of|
02184|042|D|action, through studies on their effects on the QTc interval, or through|
02184|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02184|044|D|and/or post-marketing reports.(2)|
02184|045|B||
02184|046|R|REFERENCES:|
02184|047|B||
02184|048|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
02184|049|R|  Pharmaceuticals LP July, 2011.|1
02184|050|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02184|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02184|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02184|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02184|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02184|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02184|056|R|  settings: a scientific statement from the American Heart Association and|6
02184|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02184|058|R|  2;55(9):934-47.|6
02185|001|T|MONOGRAPH TITLE:  Lovastatin (Greater Than 40 mg); Simvastatin (Greater Than|
02185|002|T|40 mg)/Ticagrelor|
02185|003|B||
02185|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02185|005|L|of severe adverse interaction.|
02185|006|B||
02185|007|A|MECHANISM OF ACTION:  Ticagrelor may inhibit the metabolism of lovastatin|
02185|008|A|and simvastatin by CYP3A4.(1,2)|
02185|009|B||
02185|010|E|CLINICAL EFFECTS:  Concurrent use of ticagrelor may result in elevated|
02185|011|E|levels of and toxicity from lovastatin and simvastatin, including|
02185|012|E|rhabdomyolysis.(1,2)|
02185|013|B||
02185|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02185|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02185|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02185|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02185|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02185|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02185|020|P|predisposed to myopathy or rhabdomyolysis.|
02185|021|B||
02185|022|M|PATIENT MANAGEMENT:  Avoid the use of doses of lovastatin and simvastatin|
02185|023|M|greater than 40 mg in patients receiving ticagrelor.(1,2)  Monitor patients|
02185|024|M|receiving concurrent therapy for signs and symptoms of myopathy.|
02185|025|B||
02185|026|D|DISCUSSION:  Concurrent ticagrelor increased the maximum concentration|
02185|027|D|(Cmax) and area-under-curve (AUC) of simvastatin by 81% and 56%,|
02185|028|D|respectively.  The Cmax and AUC of simvastatin acid increased 64% and 52%,|
02185|029|D|respectively, with some individual increases equal to 2-fold to 3-fold.(1)|
02185|030|B||
02185|031|R|REFERENCES:|
02185|032|B||
02185|033|R|1.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02185|034|R|  UK Limited October 24, 2012.|1
02185|035|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP November,|1
02185|036|R|  2024.|1
02186|001|T|MONOGRAPH TITLE:  Tramadol/Selected Moderate to Strong CYP2D6 Inhibitors|
02186|002|B||
02186|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02186|004|L|take action as needed.|
02186|005|B||
02186|006|A|MECHANISM OF ACTION:  Abiraterone, asunaprevir, berotralstat, bupropion,|
02186|007|A|cinacalcet, dacomitinib, dronedarone, duloxetine, eliglustat, fluoxetine,|
02186|008|A|hydroquinidine, levomethadone, lorcaserin, mirabegron, paroxetine,|
02186|009|A|quinidine, rolapitant, oral terbinafine, and tipranavir are moderate or|
02186|010|A|strong inhibitors of CYP2D6 and may decrease conversion of tramadol to its|
02186|011|A|more active O-demethylated metabolite (M1).(1-6)  M1 is up to 6 times more|
02186|012|A|potent than tramadol in producing analgesia.(1)|
02186|013|B||
02186|014|E|CLINICAL EFFECTS:  Tramadol analgesic efficacy may be decreased due to lower|
02186|015|E|mu-opioid receptor mediated analgesia.(1,9,10)|
02186|016|E|   Higher concentrations of tramadol may be associated with increased|
02186|017|E|inhibition of norepinephrine and serotonin reuptake, increasing risk for|
02186|018|E|seizures and serotonin syndrome.(1)|
02186|019|E|  Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
02186|020|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(7)|
02186|021|B||
02186|022|P|PREDISPOSING FACTORS:  Risk for seizure may be increased with tramadol doses|
02186|023|P|above the recommended range, in patients with metabolic disorders, alcohol|
02186|024|P|or drug withdrawal, infection of the central nervous system, or with a|
02186|025|P|history of seizures or head trauma.(1)|
02186|026|P|  Treatment with multiple medications which increase serotonin levels, or|
02186|027|P|with medications which inhibit the metabolism of serotonin increasing drugs|
02186|028|P|are risk factors for serotonin syndrome.(1,7)|
02186|029|P|   Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer|
02186|030|P|phenotypes may be affected to a greater extent by CYP2D6 inhibitors.  For|
02186|031|P|patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6|
02186|032|P|poor metabolizer.(14)|
02186|033|P|   Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are|
02186|034|P|not affected by CYP2D6 inhibition.(14)|
02186|035|B||
02186|036|M|PATIENT MANAGEMENT:  If a CYP2D6 inhibitor is started in a patient|
02186|037|M|stabilized on long term tramadol therapy, monitor for loss of analgesic|
02186|038|M|efficacy. When initiating tramadol in a patient stabilized on a moderate or|
02186|039|M|strong CYP2D6 inhibitor, anticipate lower analgesic efficacy. Hospitalized|
02186|040|M|patients may need added doses of rescue analgesics to achieve adequate pain|
02186|041|M|control.(9,10)|
02186|042|M|   To decrease risk for serotonin syndrome, consider change to an|
02186|043|M|alternative analgesic for patients taking other serotonin increasing drugs|
02186|044|M|in addition to concomitant tramadol and a CYP2D6 inhibitor.|
02186|045|M|   If a CYP2D6 inhibitor is discontinued, consider lowering the dose of|
02186|046|M|tramadol until patient achieves stable drug effects.|
02186|047|M|   The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are|
02186|048|M|expected to last at least 28 days after administration.(12)|
02186|049|B||
02186|050|D|DISCUSSION:  Tramadol and its M1 metabolite both contribute to analgesic|
02186|051|D|efficacy.  Tramadol inhibits the reuptake of norepinephrine and serotonin|
02186|052|D|with minimal opioid receptor binding.  The M1 metabolite has 200 times|
02186|053|D|greater binding affinity for the mu-opioid receptor than tramadol and is 6|
02186|054|D|times more potent in producing analgesia.(1)  CYP2D6 converts tramadol to|
02186|055|D|M1.(1,8)|
02186|056|D|   A prospective study evaluated the impact of 2D6 genotype on tramadol|
02186|057|D|analgesia after abdominal surgery. Rescue doses of opioids were required in|
02186|058|D|47% of poor metabolizers (PM) versus 22% of extensive metabolizers (EM) of|
02186|059|D|2D6.(9)  A follow-up study included 2D6 EM patients who received concomitant|
02186|060|D|treatment with 2D6 inhibitors.  Levels of the M1 metabolite were decreased|
02186|061|D|by 80-90% compared with EM patients not taking 2D6 inhibitors.  The authors|
02186|062|D|noted some EM patients were converted to the PM phenotype.(10)  In both|
02186|063|D|studies, higher M1 levels were associated with greater analgesic efficacy|
02186|064|D|and decreased need for rescue opioid treatment.(9,10)|
02186|065|D|   A study in 12 healthy volunteers found that a single dose of tramadol (50|
02186|066|D|mg) given to patients on terbinafine (a strong CYP2D6 inhibitor) resulted in|
02186|067|D|tramadol AUC and Cmax that were 2.1-fold and 1.5-fold higher, respectively,|
02186|068|D|than tramadol given alone.  The AUC and Cmax of M1 were decreased by 64 %|
02186|069|D|and 78 %, respectively.(13)|
02186|070|D|   A single dose of rolapitant increased dextromethorphan, a CYP2D6|
02186|071|D|substrate, about 3-fold on days 8 and day 22 following administration.|
02186|072|D|Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single|
02186|073|D|dose rolapitant.  The inhibitory effects of rolapitant on CYP2D6 are|
02186|074|D|expected to persist beyond 28 days.(12)|
02186|075|B||
02186|076|R|REFERENCES:|
02186|077|B||
02186|078|R|1.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
02186|079|R|  October, 2019.|1
02186|080|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02186|081|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02186|082|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02186|083|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02186|084|R|  11/14/2017.|1
02186|085|R|3.Lamisil (terbinafine hydrochloride) tablet US prescribing information.|1
02186|086|R|  Novartis Pharmaceuticals Corporation June, 2013.|1
02186|087|R|4.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
02186|088|R|  GlaxoSmithKline November, 2019.|1
02186|089|R|5.Sensipar (cinacalcet hydrochloride) US prescribing information. Amgen Inc.|1
02186|090|R|  March, 2019.|1
02186|091|R|6.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
02186|092|R|  prescribing information. Avanir  Pharmaceuticals June, 2019.|1
02186|093|R|7.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02186|094|R|  352(11):1112-20.|6
02186|095|R|8.Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP,|5
02186|096|R|  Lake BG. Identification of cytochrome P-450 isoforms responsible for|5
02186|097|R|  cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001|5
02186|098|R|  Aug;29(8):1146-55.|5
02186|099|R|9.Stamer UM, Lehnen K, Hothker F, Bayerer B, Wolf S, Hoeft A, Stuber F.|2
02186|100|R|  Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 2003|2
02186|101|R|  Sep;105(1-2):231-8.|2
02186|102|R|10.Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F.|2
02186|103|R|   Concentrations of tramadol and O-desmethyltramadol enantiomers in|2
02186|104|R|   different CYP2D6 genotypes. Clin Pharmacol Ther 2007 Jul;82(1):41-7.|2
02186|105|R|11.Myrbetriq (mirabegron) US prescribing information. Astellas Pharma|1
02186|106|R|   Technologies, Inc. March 25, 2021.|1
02186|107|R|12.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
02186|108|R|13.Saarikoski T, Saari TI, Hagelberg NM, Backman JT, Neuvonen PJ, Scheinin|2
02186|109|R|   M, Olkkola KT, Laine K. Effects of terbinafine and itraconazole on the|2
02186|110|R|   pharmacokinetics of orally administered tramadol. Eur J Clin Pharmacol|2
02186|111|R|   2015 Mar;71(3):321-7.|2
02186|112|R|14.Crews KR, Monte AA, Huddart R, Caudle KE, Kharasch ED. Clinical|6
02186|113|R|   Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1,|6
02186|114|R|   and COMT Genotypes and Select Opioid Therapy. Clin Pharmacol Ther 2021|6
02186|115|R|   Oct;110(4):888-896.|6
02187|001|T|MONOGRAPH TITLE:  Ondansetron/Possible QT Prolonging Agents|
02187|002|B||
02187|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02187|004|L|take action as needed.|
02187|005|B||
02187|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02187|007|A|interval may result in additive effects on the QTc interval.(1-3)|
02187|008|B||
02187|009|E|CLINICAL EFFECTS:  The use of ondansetron in patients maintained on agents|
02187|010|E|that prolong the QTc interval may result in potentially life-threatening|
02187|011|E|cardiac arrhythmias, including torsades de pointes.(1-3)|
02187|012|B||
02187|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02187|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02187|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02187|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02187|017|P|female gender, or in the elderly (> or = 75 years of age).(4)|
02187|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02187|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02187|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02187|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02187|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02187|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02187|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02187|025|B||
02187|026|M|PATIENT MANAGEMENT:  The risk for QT prolongation due to ondansetron is dose|
02187|027|M|and route related.  Intravenous (IV) doses lead to higher peak|
02187|028|M|concentrations and systemic exposure and so have a greater risk for QT|
02187|029|M|prolongation compared with the same dose given orally.  Faster rates of IV|
02187|030|M|infusion are also associated with a greater risk for QT prolongation.(5)  If|
02187|031|M|concomitant therapy is needed, correct electrolyte abnormalities prior to|
02187|032|M|starting therapy.  Monitor closely, particularly in patients with|
02187|033|M|predisposing risk factors for QT prolongation (e.g. cardiac disease, female,|
02187|034|M|elderly). Electrocardiogram (ECG) monitoring should be performed in patients|
02187|035|M|receiving concurrent therapy.(1-3)|
02187|036|M|   The Canadian manufacturer of Zofran injection has specific|
02187|037|M|recommendations for use of IV ondansetron in oncology patients greater than|
02187|038|M|or equal to 75 years of age (5):|
02187|039|M|   - all IV doses must be diluted in 50 - 100 mL of compatible fluid and|
02187|040|M|infused over at least 15 minutes|
02187|041|M|   - initial and repeat IV doses must not exceed 8 mg.|
02187|042|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02187|043|M|fainting.|
02187|044|B||
02187|045|D|DISCUSSION:  In a double-blind, randomized, placebo and positive controlled|
02187|046|D|cross-over study, an ondansetron intravenous (IV) dose of 32 mg increased|
02187|047|D|the maximum mean QTcF by 19.6 msec (upper limit of 90% CI:  21.5).  A dose|
02187|048|D|of 8mg increased the QTcF by a maximum mean of 5.8 (upper limit of 90% CI:|
02187|049|D|7.8).  A dose of 16 mg was predicted to have a mean increase in QTcF of 9.1|
02187|050|D|msec (upper limit of 90% CI:  11.2).(1)|
02187|051|D|   QT prolongation and torsades de pointes have been reported in|
02187|052|D|post-marketing reports in patients receiving ondansetron.(2-3)|
02187|053|D|   In a review of published reports of QT prolongation associated with|
02187|054|D|ondansetron administration, 67% of patients were also receiving another|
02187|055|D|medication known to prolong the QT interval.(6)|
02187|056|D|   In a prospective, observational study, administration of a single|
02187|057|D|ondansetron IV dose of 4 mg in the emergency department increased the mean|
02187|058|D|and median QTc interval by 16.2 msec (95% CI 4.2-28.2 msec; p=0.01) and 12|
02187|059|D|msec (IQR 5.5-18 msec; p<0.01), respectively.  Three patients had extreme|
02187|060|D|QTc prolongation.  With exclusion of those 3 patients, the median QTc|
02187|061|D|prolongation was 10 msec (IQR 5-15 msec; p<0.01).(7)|
02187|062|D|   Agents that are linked to this monograph may have varying degrees of|
02187|063|D|potential to prolong the QTc interval but are generally accepted to have a|
02187|064|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02187|065|D|been shown to prolong the QTc interval either through their mechanism of|
02187|066|D|action, through studies on their effects on the QTc interval, or through|
02187|067|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02187|068|D|and/or post-marketing reports.(8)|
02187|069|B||
02187|070|R|REFERENCES:|
02187|071|B||
02187|072|R|1.Kon P. Dear UK Healthcare Professional:   Direct Healthcare Professional|1
02187|073|R|  Communication on ondansetron (Zofran and generics) and dose-dependent QT|1
02187|074|R|  interval prolongation - new dose restriction for intravenous (IV) use.|1
02187|075|R|  GlaxoSmithKline UK Ltd August 5, 2012.|1
02187|076|R|2.Zofran (ondansetron) US prescribing information. GlaxoSmithKline October,|1
02187|077|R|  2021.|1
02187|078|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Abnormal|1
02187|079|R|  heart rhythms may be associated with use of Zofran (ondansetron).|1
02187|080|R|  available at:|1
02187|081|R|  https://wayback.archive-it.org/7993/20170722185907/https:/www.fda.gov/Drug|1
02187|082|R|  s/DrugSafety/ucm271913.htm September 15, 2011.|1
02187|083|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02187|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02187|085|R|  settings: a scientific statement from the American Heart Association and|6
02187|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02187|087|R|  2;55(9):934-47.|6
02187|088|R|5.Health Canada. Zofran (ondansetron) - Dosage and Administration of|1
02187|089|R|  Intravenous Ondansetron in Geriatrics (>65 years of age). available at:|1
02187|090|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/39943a-e|1
02187|091|R|  ng.php June 12, 2014.|1
02187|092|R|6.Freedman SB, Uleryk E, Rumantir M, Finkelstein Y. Ondansetron and the risk|6
02187|093|R|  of cardiac arrhythmias: a systematic review and postmarketing analysis.|6
02187|094|R|  Ann Emerg Med 2014 Jul;64(1):19-25.e6.|6
02187|095|R|7.Li K, Vo K, Lee BK, Addo N, Coralic Z. Effect of a single dose of i.v.|2
02187|096|R|  ondansetron on QTc interval in emergency department patients. Am J Health|2
02187|097|R|  Syst Pharm 2018 Mar 1;75(5):276-282.|2
02187|098|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
02187|099|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02187|100|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02187|101|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02188|001|T|MONOGRAPH TITLE:  Tramadol/Mirtazapine (mono deleted 01/08/2021)|
02188|002|B||
02188|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02188|004|L|take action as needed.|
02188|005|B||
02188|006|A|MECHANISM OF ACTION:  Both tramadol and mirtazapine increase neuronal|
02188|007|A|serotonin activity.(1,2)|
02188|008|B||
02188|009|E|CLINICAL EFFECTS:  Concurrent use of tramadol and mirtazapine may increase|
02188|010|E|the risk for serotonin syndrome.(1,2)  Symptoms of serotonin syndrome may|
02188|011|E|include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
02188|012|E|hyperthermia, and muscle rigidity.(3)|
02188|013|B||
02188|014|P|PREDISPOSING FACTORS:  Treatment with multiple medications which increase|
02188|015|P|serotonin levels, or treatment with medications which inhibit the metabolism|
02188|016|P|of serotonin increasing drugs are risk factors for serotonin|
02188|017|P|syndrome.(1,2,3)|
02188|018|P|   Strong inhibitors of CYP3A4 (e.g. nefazodone, azole antifungals) may|
02188|019|P|inhibit tramadol or mirtazapine metabolism. Strong inhibitors of CYP2D6|
02188|020|P|(e.g. bupropion, quinidine) may inhibit tramadol metabolism.(1,2,4)|
02188|021|B||
02188|022|M|PATIENT MANAGEMENT:  Monitor patient for symptoms of serotonin syndrome,|
02188|023|M|especially if a medication dose is increased or if a CYP3A4 or 2D6 inhibitor|
02188|024|M|is added to concurrent therapy.(1,2)|
02188|025|M|   If concurrent therapy is warranted, patients should be monitored for|
02188|026|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02188|027|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02188|028|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02188|029|M|coordination, or severe diarrhea.|
02188|030|B||
02188|031|D|DISCUSSION:  Tramadol has been associated with many reports of serotonin|
02188|032|D|syndrome, particularly when combined with serotonin reuptake inhibitors|
02188|033|D|(SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or agents|
02188|034|D|which inhibit tramadol metabolism via CYP2D6.(1)  In contrast, US|
02188|035|D|prescribing information describes reports of serotonin syndrome associated|
02188|036|D|with mirtazapine treatment as rare.(2) This is consistent with the|
02188|037|D|pharmacology of mirtazapine; unlike SSRIs and SNRIs, mirtazapine is a potent|
02188|038|D|blocker of the serotonin 5HT2A receptor. Thus agonist effects at the 5HT2A|
02188|039|D|receptor, thought to mediate many of the severe toxicities associated with|
02188|040|D|serotonin syndrome(3), would not be expected in patients receiving|
02188|041|D|mirtazapine.|
02188|042|D|   Patients described in published case reports of serotonin syndrome|
02188|043|D|attributed to mirtazapine are generally elderly or receiving multiple|
02188|044|D|serotonergic agents. In some of these cases, the description was|
02188|045|D|insufficient to verify the diagnosis of serotonin syndrome.(6-9)|
02188|046|D|   A  poison center performed a retrospective chart review of 33 patients|
02188|047|D|with isolated mirtazapine ingestions (mean 343 mg).  Reported symptoms were|
02188|048|D|lethargy in 10 patients, drowsiness in 8 patients, agitation in one patient,|
02188|049|D|tachycardia in 3 patients, bradycardia and hypotension in one patient, no|
02188|050|D|abnormal neurologic findings in 14 patients; no patients died.(5)|
02188|051|B||
02188|052|R|REFERENCES:|
02188|053|B||
02188|054|R|1.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
02188|055|R|  October, 2019.|1
02188|056|R|2.Remeron (mirtazapine) US prescribing information. Organon Inc. November,|1
02188|057|R|  2021.|1
02188|058|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02188|059|R|  352(11):1112-20.|6
02188|060|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02188|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02188|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02188|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02188|064|R|  11/14/2017.|1
02188|065|R|5.LoVecchio F, Riley B, Pizon A, Brown M. Outcomes after isolated|3
02188|066|R|  mirtazapine (Remeron) supratherapeutic ingestions. J Emerg Med 2008 Jan;|3
02188|067|R|  34(1):77-8.|3
02188|068|R|6.Ubogu EE, Katirji B. Mirtazapine-induced serotonin syndrome. Clin|3
02188|069|R|  Neuropharmacol 2003 Mar-Apr;26(2):54-7.|3
02188|070|R|7.Isbister GK, Whyte IM. Adverse reactions to mirtazapine are unlikely to be|3
02188|071|R|  serotonin toxicity. Clin Neuropharmacol 2003 Nov-Dec;26(6):287-8; author|3
02188|072|R|  reply 289-90.|3
02188|073|R|8.Duggal HS, Fetchko J. Serotonin syndrome and atypical antipsychotics. Am J|3
02188|074|R|  Psychiatry 2002 Apr;159(4):672-3.|3
02188|075|R|9.Hernandez JL, Ramos FJ, Infante J, Rebollo M, Gonzalez-Macias J. Severe|3
02188|076|R|  serotonin syndrome induced by mirtazapine monotherapy. Ann Pharmacother|3
02188|077|R|  2002 Apr;36(4):641-3.|3
02189|001|T|MONOGRAPH TITLE:  Simvastatin (Less Than or Equal To 10 mg); Lovastatin|
02189|002|T|(Less Than or Equal To 20 mg)/Diltiazem (Less than or Equal To 240 mg)|
02189|003|B||
02189|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02189|005|L|take action as needed.|
02189|006|B||
02189|007|A|MECHANISM OF ACTION:  Diltiazem may inhibit the metabolism of|
02189|008|A|lovastatin(1,2) and simvastatin(2-6) by CYP3A4.|
02189|009|B||
02189|010|E|CLINICAL EFFECTS:  Concurrent diltiazem may result in elevated levels of|
02189|011|E|lovastatin(1,2) or simvastatin,(2-6) which may result in rhabdomyolysis.|
02189|012|B||
02189|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02189|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02189|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02189|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02189|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02189|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02189|019|P|predisposed to myopathy or rhabdomyolysis.|
02189|020|B||
02189|021|M|PATIENT MANAGEMENT:  Do not use more than 20 mg of lovastatin(1) or more|
02189|022|M|than 240 mg of diltiazem(2) in patients receiving concurrent therapy with|
02189|023|M|these agents.|
02189|024|M|   Do not use more than 10 mg of simvastatin(2-6) or more than 240 mg of|
02189|025|M|diltiazem(2) in patients receiving concurrent therapy with these agents.|
02189|026|M|   Patients receiving concurrent therapy with diltiazem should be monitored|
02189|027|M|closely for adverse effects of the HMG-CoA reductase inhibitor, including|
02189|028|M|rhabdomyolysis.  The dosage of the HMG-CoA reductase inhibitor may need to|
02189|029|M|be reduced or discontinued.|
02189|030|M|   Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not|
02189|031|M|metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and|
02189|032|M|simvastatin in patients receiving diltiazem.|
02189|033|B||
02189|034|D|DISCUSSION:  In a four-way crossover study in ten subjects, subjects|
02189|035|D|received single doses of lovastatin (20 mg) alone and following two weeks of|
02189|036|D|diltiazem (120 mg twice daily) therapy and single doses of pravastatin (20|
02189|037|D|mg) alone and following two weeks of diltiazem therapy (120 mg twice daily).|
02189|038|D|Concurrent administration of diltiazem increased lovastatin|
02189|039|D|area-under-curve (AUC) and maximum concentration (Cmax) by 2.6-fold and|
02189|040|D|3.3-fold, respectively.  The increase in lovastatin AUC ranged from 51% to|
02189|041|D|906%. There were no changes in lovastatin half-life.  Concurrent|
02189|042|D|administration of diltiazem had no effect on the AUC, Cmax, or half-life of|
02189|043|D|pravastatin.(5,6)|
02189|044|D|   In a study, diltiazem (120 mg twice daily for 10 days) increased the AUC|
02189|045|D|and Cmax of a single dose of simvastatin (80 mg on Day 10) by 3.1-fold and|
02189|046|D|2.88-fold, respectively.  The AUC and Cmax of simvastatin acid increased by|
02189|047|D|2.69-fold and 2.69-fold, respectively.(3)|
02189|048|D|   In a study in Chinese subjects, concurrent diltiazem (60 mg TID) and|
02189|049|D|simvastatin (20 mg daily) enhanced reduction of LDL levels by 1.66% when|
02189|050|D|compared to simvastatin (20 mg alone).(7)|
02189|051|D|   In a study in 11 patients with hypercholesterolemia and hypertension,|
02189|052|D|concurrent administration of diltiazem (90 mg daily) and simvastatin (5 mg|
02189|053|D|daily) increased the Cmax and AUC of simvastatin by 97% and 99.5%,|
02189|054|D|respectively, when compared to administration of simvastatin (5 mg daily)|
02189|055|D|alone.  Diltiazem Cmax and AUC decreased by 21% and 21%, respectively, when|
02189|056|D|compared to the administration of diltiazem (90 mg) alone.  Combination|
02189|057|D|therapy lowered LDL levels by an additional 9% when compared to simvastatin|
02189|058|D|monotherapy.(8)|
02189|059|D|   In a study in 10 healthy subjects, diltiazem (120 mg daily for 2 weeks)|
02189|060|D|increased the Cmax and AUC of a single dose of simvastatin (20 mg) by|
02189|061|D|3.6-fold and 5-fold, respectively.  The Cmax of simvastatin acid increased|
02189|062|D|by 3.7-fold.(2,9)  A daily dose of 480 mg of diltiazem is expected to|
02189|063|D|increase simvastatin levels 8-fold.(2|
02189|064|D|   In a retrospective review, patients who received simvastatin with|
02189|065|D|concurrent diltiazem experienced a 33.3% reduction in cholesterol levels|
02189|066|D|compared with 24.7% in patients receiving simvastatin without concurrent|
02189|067|D|diltiazem.(10)|
02189|068|D|   There are several case reports of myopathy and rhabdomyolysis in patients|
02189|069|D|receiving concurrent simvastatin and diltiazem.(11-16)|
02189|070|B||
02189|071|R|REFERENCES:|
02189|072|B||
02189|073|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02189|074|R|  February, 2014.|1
02189|075|R|2.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02189|076|R|  restrictions, contraindications, and dose limitations for Zocor|1
02189|077|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02189|078|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02189|079|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02189|080|R|  June 8, 2011.|1
02189|081|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02189|082|R|  2023.|1
02189|083|R|4.Ede M. Dear Canadian Healthcare Professional:  Subject:  ZOCOR|1
02189|084|R|  (simvastatin) - New Safety Recommendations on Dosage Associated with the|1
02189|085|R|  Increased Risk of Myopathy/Rhabdomyolysis. Merck Canada Inc. November 7,|1
02189|086|R|  2012.|1
02189|087|R|5.Azie NE, Brater DC, Becker PA, Jones DR, Hall SD. The interaction of|2
02189|088|R|  diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998 Oct;|2
02189|089|R|  64(4):369-77.|2
02189|090|R|6.Dilacor (diltiazem hydrochloride) US prescribing information. Watson|1
02189|091|R|  Pharma, Inc. June, 2011.|1
02189|092|R|7.You JH, Chan WK, Chung PF, Hu M, Tomlinson B. Effects of concomitant|2
02189|093|R|  therapy with diltiazem on the lipid responses to simvastatin in Chinese|2
02189|094|R|  subjects. J Clin Pharmacol 2010 Oct;50(10):1151-8.|2
02189|095|R|8.Watanabe H, Kosuge K, Nishio S, Yamada H, Uchida S, Satoh H, Hayashi H,|2
02189|096|R|  Ishizaki T, Ohashi K. Pharmacokinetic and pharmacodynamic interactions|2
02189|097|R|  between simvastatin and diltiazem in patients with hypercholesterolemia|2
02189|098|R|  and hypertension. Life Sci 2004 Dec 3;76(3):281-92.|2
02189|099|R|9.Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with|2
02189|100|R|  simvastatin. Clin Pharmacol Ther 2000 Mar;67(3):267-74.|2
02189|101|R|10.Yeo KR, Yeo WW, Wallis EJ, Ramsay LE. Enhanced cholesterol reduction by|2
02189|102|R|   simvastatin in diltiazem-treated patients. Br J Clin Pharmacol 1999 Oct;|2
02189|103|R|   48(4):610-5.|2
02189|104|R|11.Hu M, Mak VW, Tomlinson B. Simvastatin-induced myopathy, the role of|3
02189|105|R|   interaction with diltiazem and genetic predisposition. J Clin Pharm Ther|3
02189|106|R|   2011 Jun;36(3):419-25.|3
02189|107|R|12.Rifkin SI. Multiple drug interactions in a renal transplant patient|3
02189|108|R|   leading to simvastatin-induced rhabdomyolysis: a case report. Medscape J|3
02189|109|R|   Med 2008;10(11):264.|3
02189|110|R|13.Najafian B, Franklin DB, Fogo AB. Acute renal failure and myalgia in a|3
02189|111|R|   transplant patient. J Am Soc Nephrol 2007 Nov;18(11):2870-4.|3
02189|112|R|14.Bae J, Jarcho JA, Denton MD, Magee CC. Statin specific toxicity in organ|3
02189|113|R|   transplant recipients: case report and review of the literature. J|3
02189|114|R|   Nephrol 2002 May-Jun;15(3):317-9.|3
02189|115|R|15.Kanathur N, Mathai MG, Byrd RP Jr, Fields CL, Roy TM.|3
02189|116|R|   Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and|3
02189|117|R|   hepatitis. Tenn Med 2001 Sep;94(9):339-41.|3
02189|118|R|16.Peces R, Pobes A. Rhabdomyolysis associated with concurrent use of|3
02189|119|R|   simvastatin and diltiazem. Nephron 2001 Sep;89(1):117-8.|3
02190|001|T|MONOGRAPH TITLE:  Simvastatin (Less than or Equal To 10 mg); Lovastatin|
02190|002|T|(Less than or Equal To 20 mg)/Diltiazem (Greater Than 240 mg)|
02190|003|B||
02190|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02190|005|L|is contraindicated and generally should not be dispensed or administered to|
02190|006|L|the same patient.|
02190|007|B||
02190|008|A|MECHANISM OF ACTION:  Diltiazem may inhibit the metabolism of|
02190|009|A|lovastatin(1,2) and simvastatin(2-6) by CYP3A4.|
02190|010|B||
02190|011|E|CLINICAL EFFECTS:  Concurrent diltiazem may result in elevated levels of|
02190|012|E|lovastatin(1,2) or simvastatin,(2-6) which may result in rhabdomyolysis.|
02190|013|B||
02190|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02190|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02190|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02190|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02190|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02190|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02190|020|P|predisposed to myopathy or rhabdomyolysis.|
02190|021|B||
02190|022|M|PATIENT MANAGEMENT:  Do not use more than 20 mg of lovastatin(1) or more|
02190|023|M|than 240 mg of diltiazem(2) in patients receiving concurrent therapy with|
02190|024|M|these agents.|
02190|025|M|   Do not use more than 10 mg of simvastatin(2-6) or more than 240 mg of|
02190|026|M|diltiazem(2) in patients receiving concurrent therapy with these agents.|
02190|027|M|   Patients receiving concurrent therapy with diltiazem should be monitored|
02190|028|M|closely for adverse effects of the HMG-CoA reductase inhibitor, including|
02190|029|M|rhabdomyolysis.  The dosage of the HMG-CoA reductase inhibitor may need to|
02190|030|M|be reduced or discontinued.|
02190|031|M|   Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not|
02190|032|M|metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and|
02190|033|M|simvastatin in patients receiving diltiazem.|
02190|034|B||
02190|035|D|DISCUSSION:  In a four-way crossover study in ten subjects, subjects|
02190|036|D|received single doses of lovastatin (20 mg) alone and following two weeks of|
02190|037|D|diltiazem (120 mg twice daily) therapy and single doses of pravastatin (20|
02190|038|D|mg) alone and following two weeks of diltiazem therapy (120 mg twice daily).|
02190|039|D|Concurrent administration of diltiazem increased lovastatin|
02190|040|D|area-under-curve (AUC) and maximum concentration (Cmax) by 2.6-fold and|
02190|041|D|3.3-fold, respectively.  The increase in lovastatin AUC ranged from 51% to|
02190|042|D|906%. There were no changes in lovastatin half-life.  Concurrent|
02190|043|D|administration of diltiazem had no effect on the AUC, Cmax, or half-life of|
02190|044|D|pravastatin.(5,6)|
02190|045|D|   In a study, diltiazem (120 mg twice daily for 10 days) increased the AUC|
02190|046|D|and Cmax of a single dose of simvastatin (80 mg on Day 10) by 3.1-fold and|
02190|047|D|2.88-fold, respectively.  The AUC and Cmax of simvastatin acid increased by|
02190|048|D|2.69-fold and 2.69-fold, respectively.(3)|
02190|049|D|   In a study in Chinese subjects, concurrent diltiazem (60 mg TID) and|
02190|050|D|simvastatin (20 mg daily) enhanced reduction of LDL levels by 1.66% when|
02190|051|D|compared to simvastatin (20 mg alone).(7)|
02190|052|D|   In a study in 11 patients with hypercholesterolemia and hypertension,|
02190|053|D|concurrent administration of diltiazem (90 mg daily) and simvastatin (5 mg|
02190|054|D|daily) increased the Cmax and AUC of simvastatin by 97% and 99.5%,|
02190|055|D|respectively, when compared to administration of simvastatin (5 mg daily)|
02190|056|D|alone.  Diltiazem Cmax and AUC decreased by 21% and 21%, respectively, when|
02190|057|D|compared to the administration of diltiazem (90 mg) alone.  Combination|
02190|058|D|therapy lowered LDL levels by an additional 9% when compared to simvastatin|
02190|059|D|monotherapy.(8)|
02190|060|D|   In a study in 10 healthy subjects, diltiazem (120 mg daily for 2 weeks)|
02190|061|D|increased the Cmax and AUC of a single dose of simvastatin (20 mg) by|
02190|062|D|3.6-fold and 5-fold, respectively.  The Cmax of simvastatin acid increased|
02190|063|D|by 3.7-fold.(2,9)  A daily dose of 480 mg of diltiazem is expected to|
02190|064|D|increase simvastatin levels 8-fold.(2|
02190|065|D|   In a retrospective review, patients who received simvastatin with|
02190|066|D|concurrent diltiazem experienced a 33.3% reduction in cholesterol levels|
02190|067|D|compared with 24.7% in patients receiving simvastatin without concurrent|
02190|068|D|diltiazem.(10)|
02190|069|D|   There are several case reports of myopathy and rhabdomyolysis in patients|
02190|070|D|receiving concurrent simvastatin and diltiazem.(11-16)|
02190|071|D|   One or more of the drug pairs linked to this monograph have been included|
02190|072|D|in a list of interactions that should be considered "high-priority" for|
02190|073|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02190|074|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02190|075|D|Coordinator (ONC) for Health Information Technology.|
02190|076|B||
02190|077|R|REFERENCES:|
02190|078|B||
02190|079|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02190|080|R|  February, 2014.|1
02190|081|R|2.USFood and Drug Administration. FDA Drug Safety Communication: New|1
02190|082|R|  restrictions, contraindications, and dose limitations for Zocor|1
02190|083|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
02190|084|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02190|085|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
02190|086|R|  June 8, 2011.|1
02190|087|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02190|088|R|  2023.|1
02190|089|R|4.Ede M. Dear Canadian Healthcare Professional:  Subject:  ZOCOR|1
02190|090|R|  (simvastatin) - New Safety Recommendations on Dosage Associated with the|1
02190|091|R|  Increased Risk of Myopathy/Rhabdomyolysis. Merck Canada Inc. November 7,|1
02190|092|R|  2012.|1
02190|093|R|5.Azie NE, Brater DC, Becker PA, Jones DR, Hall SD. The interaction of|2
02190|094|R|  diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998 Oct;|2
02190|095|R|  64(4):369-77.|2
02190|096|R|6.Dilacor (diltiazem hydrochloride) US prescribing information. Watson|1
02190|097|R|  Pharma, Inc. June, 2011.|1
02190|098|R|7.You JH, Chan WK, Chung PF, Hu M, Tomlinson B. Effects of concomitant|2
02190|099|R|  therapy with diltiazem on the lipid responses to simvastatin in Chinese|2
02190|100|R|  subjects. J Clin Pharmacol 2010 Oct;50(10):1151-8.|2
02190|101|R|8.Watanabe H, Kosuge K, Nishio S, Yamada H, Uchida S, Satoh H, Hayashi H,|2
02190|102|R|  Ishizaki T, Ohashi K. Pharmacokinetic and pharmacodynamic interactions|2
02190|103|R|  between simvastatin and diltiazem in patients with hypercholesterolemia|2
02190|104|R|  and hypertension. Life Sci 2004 Dec 3;76(3):281-92.|2
02190|105|R|9.Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with|2
02190|106|R|  simvastatin. Clin Pharmacol Ther 2000 Mar;67(3):267-74.|2
02190|107|R|10.Yeo KR, Yeo WW, Wallis EJ, Ramsay LE. Enhanced cholesterol reduction by|2
02190|108|R|   simvastatin in diltiazem-treated patients. Br J Clin Pharmacol 1999 Oct;|2
02190|109|R|   48(4):610-5.|2
02190|110|R|11.Hu M, Mak VW, Tomlinson B. Simvastatin-induced myopathy, the role of|3
02190|111|R|   interaction with diltiazem and genetic predisposition. J Clin Pharm Ther|3
02190|112|R|   2011 Jun;36(3):419-25.|3
02190|113|R|12.Rifkin SI. Multiple drug interactions in a renal transplant patient|3
02190|114|R|   leading to simvastatin-induced rhabdomyolysis: a case report. Medscape J|3
02190|115|R|   Med 2008;10(11):264.|3
02190|116|R|13.Najafian B, Franklin DB, Fogo AB. Acute renal failure and myalgia in a|3
02190|117|R|   transplant patient. J Am Soc Nephrol 2007 Nov;18(11):2870-4.|3
02190|118|R|14.Bae J, Jarcho JA, Denton MD, Magee CC. Statin specific toxicity in organ|3
02190|119|R|   transplant recipients: case report and review of the literature. J|3
02190|120|R|   Nephrol 2002 May-Jun;15(3):317-9.|3
02190|121|R|15.Kanathur N, Mathai MG, Byrd RP Jr, Fields CL, Roy TM.|3
02190|122|R|   Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and|3
02190|123|R|   hepatitis. Tenn Med 2001 Sep;94(9):339-41.|3
02190|124|R|16.Peces R, Pobes A. Rhabdomyolysis associated with concurrent use of|3
02190|125|R|   simvastatin and diltiazem. Nephron 2001 Sep;89(1):117-8.|3
02190|126|R|17.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02190|127|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02190|128|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02190|129|R|   19(5):735-43.|6
02191|001|T|MONOGRAPH TITLE:  Quetiapine/QT Prolonging Agents|
02191|002|B||
02191|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02191|004|L|of severe adverse interaction.|
02191|005|B||
02191|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02191|007|A|interval may result in additive effects on the QTc interval.(1)|
02191|008|B||
02191|009|E|CLINICAL EFFECTS:  The use of quetiapine in patients maintained on agents|
02191|010|E|that prolong the QTc interval may result in potentially life-threatening|
02191|011|E|cardiac arrhythmias, including torsades de pointes.(1)|
02191|012|B||
02191|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02191|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02191|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02191|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02191|017|P|female gender, or advanced age.(3)|
02191|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02191|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02191|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02191|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02191|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02191|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02191|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02191|025|B||
02191|026|M|PATIENT MANAGEMENT:  The US manufacturer of quetiapine states that|
02191|027|M|concurrent use with agents known to prolong the QT interval should be|
02191|028|M|avoided.(1)|
02191|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02191|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02191|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02191|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02191|033|B||
02191|034|D|DISCUSSION:  Although quetiapine was not associated with QT or QTc changes|
02191|035|D|in clinical trials, QT prolongation has been reported in post-marketing|
02191|036|D|reports in conjunction with the use of other agents known to prolong the QT|
02191|037|D|interval.(1)|
02191|038|D|   Agents that are linked to this monograph may have varying degrees of|
02191|039|D|potential to prolong the QTc interval but are generally accepted to have a|
02191|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02191|041|D|been shown to prolong the QTc interval either through their mechanism of|
02191|042|D|action, through studies on their effects on the QTc interval, or through|
02191|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02191|044|D|and/or post-marketing reports.(2)|
02191|045|B||
02191|046|R|REFERENCES:|
02191|047|B||
02191|048|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
02191|049|R|  Pharmaceuticals LP July, 2011.|1
02191|050|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02191|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02191|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02191|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02191|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02191|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02191|056|R|  settings: a scientific statement from the American Heart Association and|6
02191|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02191|058|R|  2;55(9):934-47.|6
02192|001|T|MONOGRAPH TITLE:  Dabigatran/Verapamil (mono deleted 02/05/2015)|
02192|002|B||
02192|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02192|004|L|take action as needed.|
02192|005|B||
02192|006|A|MECHANISM OF ACTION:  Oral verapamil is an inhibitor of intestinal|
02192|007|A|P-glycoprotein and dabigatran is a substrate for this system.(1-3)|
02192|008|B||
02192|009|E|CLINICAL EFFECTS:  The concurrent use of dabigatran with verapamil may|
02192|010|E|result in elevated plasma levels of dabigatran, increasing the risk for|
02192|011|E|bleeding.  The magnitude of this interaction is determined by the verapamil|
02192|012|E|route, dose form and timing of administration.|
02192|013|B||
02192|014|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
02192|015|P|bleeding include renal impairment, concomitant use of P-glycoprotein|
02192|016|P|inhibitors, patient age >74 years, coexisting conditions (e.g. recent|
02192|017|P|trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and|
02192|018|P|patient weight <50 kg. (1-3)|
02192|019|B||
02192|020|M|PATIENT MANAGEMENT:  Monitor patients closely when initiating or|
02192|021|M|discontinuing concurrent dabigatran and verapamil therapy.|
02192|022|M|   The US manufacturer of dabigatran states that no dosage adjustment is|
02192|023|M|necessary.(2)  However, the UK manufacturer of dabigatran recommends|
02192|024|M|reducing the dabigatran dose from 150 mg two times a day, to 110 mg two|
02192|025|M|times a day. If the dose is reduced, dabigatran and verapamil should be|
02192|026|M|given concurrently.|
02192|027|B||
02192|028|D|DISCUSSION:  Chronic administration of immediate release verapamil one hour|
02192|029|D|prior to dabigatran dose increased dabigatran area-under-curve (AUC)154%.(4)|
02192|030|D|The magnitude of this interaction is lower when dabigatran is given 2 hours|
02192|031|D|before verapamil dose.|
02192|032|B||
02192|033|R|REFERENCES:|
02192|034|B||
02192|035|R|1.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
02192|036|R|  characteristics. Boehringer Ingelheim Limited August 18, 2011.|1
02192|037|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
02192|038|R|  Boehringer Ingelheim Pharmaceuticals, Inc. September, 2014.|1
02192|039|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
02192|040|R|  Boehringer Ingelheim March, 23 2020.|1
02192|041|R|4.Anonymous. FDA Dabigatran background package for Cardio-Renal Advisory|1
02192|042|R|  Committee. available at|1
02192|043|R|  http://wayback.archive-it.org/7993/20170405212218/https://www.fda.gov/down|1
02192|044|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascularan|1
02192|045|R|  dRenalDrugsAdvisoryCommittee/UCM247244.pdf September 20, 2010.|1
02193|001|T|MONOGRAPH TITLE:  Dabigatran/Dronedarone, Ketoconazole|
02193|002|B||
02193|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02193|004|L|of severe adverse interaction.|
02193|005|B||
02193|006|A|MECHANISM OF ACTION:  Oral dronedarone and ketoconazole are inhibitors of|
02193|007|A|intestinal P-glycoprotein (P-gp) and dabigatran etexilate is a substrate for|
02193|008|A|this system.(1-3)  Inhibition of intestinal P-glycoprotein leads to|
02193|009|A|increased absorption of dabigatran.|
02193|010|B||
02193|011|E|CLINICAL EFFECTS:  The concurrent use of dabigatran with dronedarone or|
02193|012|E|systemic ketoconazole may result in elevated plasma levels of dabigatran,|
02193|013|E|increasing the risk for bleeding. Dronedarone or systemic ketoconazole|
02193|014|E|increases exposure to dabigatran by 1.7 - 2 fold, or 2.5 fold|
02193|015|E|respectively.(2,4)|
02193|016|B||
02193|017|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
02193|018|P|bleeding include renal impairment, concomitant use of P-glycoprotein|
02193|019|P|inhibitors, patient age >74 years, coexisting conditions (e.g. recent|
02193|020|P|trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and|
02193|021|P|patient weight < 50 kg.(1,3,4)|
02193|022|P|   The risk for bleeding episodes may be greater in patients with|
02193|023|P|disease-associated factors (e.g. thrombocytopenia).|
02193|024|P|   Drug associated risk factors include concurrent use of multiple drugs|
02193|025|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02193|026|P|risk for bleeding (e.g. NSAIDs).|
02193|027|B||
02193|028|M|PATIENT MANAGEMENT:  Evaluate renal function as this is the primary route of|
02193|029|M|dabigatran elimination.(1-3)|
02193|030|M|   US manufacturer dosage recommendations for dabigatran patients also|
02193|031|M|receiving dronedarone or oral ketoconazole are indication specific.(2)|
02193|032|M|   Non-valvular atrial fibrillation - stroke and systemic embolism risk|
02193|033|M|reduction:|
02193|034|M|     - If creatinine clearance (CrCl) is 30 to 50 mL/min, then consider|
02193|035|M|reducing dabigatran dose to 75 mg twice daily during concomitant therapy|
02193|036|M|with oral ketoconazole or dronedarone.|
02193|037|M|     - If estimated CrCl is less than 30 mL/min, then treatment with oral|
02193|038|M|ketoconazole or dronedarone should be avoided due to the additive risk for|
02193|039|M|bleeding.|
02193|040|M|   Deep vein thrombosis (DVT) or Pulmonary embolism (PE)- treatment or|
02193|041|M|secondary prophylaxis:|
02193|042|M|     - No dose reduction is needed for concomitant therapy if CrCl is|
02193|043|M|greater than or equal to 50 mL/min.|
02193|044|M|     - If CrCl is less than 50 mL/min, then concomitant treatment with oral|
02193|045|M|ketoconazole or dronedarone should be avoided due to the additive risk for|
02193|046|M|bleeding.|
02193|047|M|   Hip replacement surgery - DVT and PE prophylaxis:|
02193|048|M|     - No dose reduction for concomitant therapy is needed if CrCl is|
02193|049|M|greater than or equal to 50 mL/min.|
02193|050|M|     - If CrCl is less than 50 mL/min, then concomitant treatment with oral|
02193|051|M|ketoconazole or dronedarone should be avoided due to the additive risk for|
02193|052|M|bleeding.|
02193|053|M|   In patients receiving concomitant therapy with dabigatran and|
02193|054|M|dronedarone, stagger dosing if possible.  Patients who took dronedarone 2|
02193|055|M|hours after dabigatran dose had approximately 30% lower excess exposure to|
02193|056|M|dabigatran than patients who took dabigatran and dronedarone|
02193|057|M|concurrently.(2)|
02193|058|M|   If dabigatran is to be discontinued, then consider coverage with another|
02193|059|M|anticoagulant.  The FDA boxed warning for dabigatran states discontinuing|
02193|060|M|dabigatran in patients without adequate continuous anticoagulation increases|
02193|061|M|the risk for stroke.(2)|
02193|062|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02193|063|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02193|064|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02193|065|M|patients with any symptoms.|
02193|066|M|   When applicable, perform agent-specific laboratory test (e.g. aPTT) to|
02193|067|M|monitor efficacy and safety of anticoagulation.  Discontinue anticoagulation|
02193|068|M|in patients with active pathologic bleeding.|
02193|069|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02193|070|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02193|071|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02193|072|M|and/or swelling.|
02193|073|M|   When concurrent treatment of dabigatran with dronedarone or ketoconazole|
02193|074|M|is discontinued, dabigatran dose may need to be increased based upon|
02193|075|M|reevaluation of patient risk factors and existing dabigatran dosage.|
02193|076|M|   Canadian and United Kingdom prescribing information state the use of|
02193|077|M|systemic ketoconazole with dabigatran is contraindicated.(1,3)|
02193|078|M|   United Kingdom prescribing information states the use of dabigatran with|
02193|079|M|dronedarone is contraindicated.(1,5)|
02193|080|B||
02193|081|D|DISCUSSION:  Simultaneous administration of dronedarone increased dabigatran|
02193|082|D|exposure by 70% and 140% when dronedarone was administered one or twice|
02193|083|D|daily, respectively.  This exposure is 30% to 60% higher compared to|
02193|084|D|administration of dabigatran alone when dronedarone is administered 2 hours|
02193|085|D|after dabigatran.(2)|
02193|086|D|   A single dose of ketoconazole increased dabigatran maximum concentration|
02193|087|D|(Cmax) and area-under-curve (AUC) by 135% and 138%, respectively.(2)|
02193|088|D|   Multiple daily doses of ketoconazole increased dabigatran Cmax and AUC|
02193|089|D|149% and 153%, respectively.(2)|
02193|090|D|   Simultaneous administration of dabigatran 150 mg once daily with|
02193|091|D|dronedarone 400 mg twice daily increased the dabigatran AUC and Cmax by 100%|
02193|092|D|and 70%, respectively.(5)|
02193|093|D|   A summary of pharmacokinetic interactions with dabigatran and dronedarone|
02193|094|D|concluded that if concurrent therapy is warranted, dabigatran should be|
02193|095|D|given 2 hours before dronedarone.  In patients with CrCl 30-50 ml/min,|
02193|096|D|reduce does to 75 mg twice daily and avoid use if CrCl < 30 ml/min.(6)|
02193|097|B||
02193|098|R|REFERENCES:|
02193|099|B||
02193|100|R|1.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
02193|101|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
02193|102|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
02193|103|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
02193|104|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
02193|105|R|  Boehringer Ingelheim March, 23 2020.|1
02193|106|R|4.Anonymous. FDA Dabigatran background package for Cardio-Renal Advisory|1
02193|107|R|  Committee. available at|1
02193|108|R|  http://wayback.archive-it.org/7993/20170405212218/https://www.fda.gov/down|1
02193|109|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascularan|1
02193|110|R|  dRenalDrugsAdvisoryCommittee/UCM247244.pdf September 20, 2010.|1
02193|111|R|5.Multaq (dronedarone hydrochoride) UK summary of product characteristics.|1
02193|112|R|  Sanofi June 17, 2020.|1
02193|113|R|6.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
02193|114|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
02193|115|R|  of  the Week..|6
02194|001|T|MONOGRAPH TITLE:  Aldosterone Receptor Antagonists/Trimethoprim|
02194|002|B||
02194|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02194|004|L|of severe adverse interaction.|
02194|005|B||
02194|006|A|MECHANISM OF ACTION:  Eplerenone, finerenone, spironolactone, and|
02194|007|A|trimethoprim have all been proven to increase serum potassium levels.(1-7)|
02194|008|A|The increase is achieved by reduction in potassium elimination by|
02194|009|A|trimethoprim(4,5) and inhibition of aldosterone by eplerenone, finerenone,|
02194|010|A|and spironolactone.(2,3,8)  The use of these medications in combination can|
02194|011|A|have an additive effect on serum potassium resulting in potentially|
02194|012|A|dangerous levels.(9)|
02194|013|B||
02194|014|E|CLINICAL EFFECTS:  Concurrent use of trimethoprim and aldosterone|
02194|015|E|antagonists may result in increased serum potassium levels(9) and risk of|
02194|016|E|sudden death.(10)|
02194|017|B||
02194|018|P|PREDISPOSING FACTORS:  Interaction risk appears to be greater in patients|
02194|019|P|with renal insufficiency, heart failure, when receiving other drugs|
02194|020|P|associated with hyperkalemia risk (e.g. ACE Inhibitors, non-steroidal|
02194|021|P|antiinflammatory agents(NSAIDs), angiotensin II receptor antagonists),|
02194|022|P|and/or in older patients.(1,2,3,6,9,10)|
02194|023|B||
02194|024|M|PATIENT MANAGEMENT:  Alternative antibiotic therapy should be considered for|
02194|025|M|patients who have renal impairment, heart failure, or take other meds|
02194|026|M|associated with hyperkalemia risk.(1,2,9,10)   Patients using trimethoprim|
02194|027|M|and an aldosterone antagonist concurrently should have their serum potassium|
02194|028|M|monitored at baseline and during treatment.  Peak potassium increase is|
02194|029|M|delayed and generally occurs after 4 or more days of therapy.(6)|
02194|030|B||
02194|031|D|DISCUSSION:  A nested case-control study of elderly patients chronically|
02194|032|D|treated with spironolactone evaluated hospital admissions due to|
02194|033|D|hyperkalemia within 14 days of receiving a prescription for SMX-TMP,|
02194|034|D|amoxicillin, norfloxacin, or nitrofurantion. 248 patients were identified.|
02194|035|D|Two thirds of the patients with hyperkalemia on admission had received|
02194|036|D|SMX-TMP, a 12-fold increased risk compared to patients receiving amoxicillin|
02194|037|D|or norfloxacin.(9)|
02194|038|D|   A nested case-control study of elderly patients chronically treated with|
02194|039|D|spironolactone evaluated sudden death within 14 days of receiving a|
02194|040|D|prescription for SMX-TMP, amoxicillin, ciprofloxacin, norfloxacin, or|
02194|041|D|nitrofurantion.  328 patients were identified and matched to up to 4 case|
02194|042|D|controls.  Compared with amoxicillin, use of SMX-TMP was associated with a|
02194|043|D|more than 2-fold (2.46 adjusted OR) increased risk of death.(10)|
02194|044|B||
02194|045|R|REFERENCES:|
02194|046|B||
02194|047|R|1.Bactrim Inj. (sulfamethoxazole and trimethoprim) US prescribing|1
02194|048|R|  information. Mutual Pharmaceutical Company, Inc. May, 2021.|1
02194|049|R|2.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
02194|050|R|3.Aldactone (spironolactone) US prescribing information. Pfizer November,|1
02194|051|R|  2025.|1
02194|052|R|4.Marinella MA. Trimethoprim-induced hyperkalemia: An analysis of reported|6
02194|053|R|  cases. Gerontology 1999 Jul-Aug;45(4):209-12.|6
02194|054|R|5.Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of|2
02194|055|R|  trimethoprim-induced hyperkalemia. Ann Intern Med 1993 Aug 15;|2
02194|056|R|  119(4):296-301.|2
02194|057|R|6.Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients|2
02194|058|R|  treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996 Feb 1;|2
02194|059|R|  124(3):316-20.|2
02194|060|R|7.Lam N, Weir MA, Juurlink DN, Gunraj N, Gomes T, Mamdani M, Hackam DG, Jain|2
02194|061|R|  AK, Garg AX. Hospital admissions for hyperkalemia with|2
02194|062|R|  trimethoprim-sulfamethoxazole: a cohort study using health care database|2
02194|063|R|  codes for 393,039 older women with urinary tract infections. Am J Kidney|2
02194|064|R|  Dis 2011 Mar;57(3):521-3.|2
02194|065|R|8.KERENDIA (finerenone) US prescribing information. Bayer HealthCare|1
02194|066|R|  Pharmaceuticals Inc. July, 2025.|1
02194|067|R|9.Antoniou T, Gomes T, Mamdani MM, Yao Z, Hellings C, Garg AX, Weir MA,|2
02194|068|R|  Juurlink DN. Trimethoprim-sulfamethoxazole induced hyperkalaemia in|2
02194|069|R|  elderly patients receiving spironolactone: nested case-control study. BMJ|2
02194|070|R|  2011;343:d5228.|2
02194|071|R|10.Antoniou T, Hollands S, Macdonald EM, Gomes T, Mamdani MM, Juurlink DN.|2
02194|072|R|   Trimethoprim-sulfamethoxazole and risk of sudden death among patients|2
02194|073|R|   taking spironolactone. CMAJ 2015 Mar 3;187(4):E138-43.|2
02195|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/Ceritinib|
02195|002|B||
02195|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02195|004|L|of severe adverse interaction.|
02195|005|B||
02195|006|A|MECHANISM OF ACTION:  Ceritinib inhibits CYP3A4, and thus may inhibit the|
02195|007|A|metabolism of agents processed by this isoenzyme.(1)|
02195|008|B||
02195|009|E|CLINICAL EFFECTS:  Concurrent use of ceritinib with drugs primarily|
02195|010|E|metabolized by CYP3A4 may lead to elevated drug levels and increased side|
02195|011|E|effects of these agents.  Drugs with a narrow therapeutic window that are|
02195|012|E|metabolized by this isoenzyme include:  cyclosporine, felodipine,|
02195|013|E|hydroquinidine, midazolam, nisoldipine, quinidine, and sirolimus.(1,2)|
02195|014|B||
02195|015|P|PREDISPOSING FACTORS:  Greater risk for adverse events would be expected for|
02195|016|P|drugs with a narrow therapeutic window, or for drugs especially sensitive to|
02195|017|P|CYP3A4 inhibition.|
02195|018|P|   With pimozide, the risk of anticholinergic toxicities including cognitive|
02195|019|P|decline, delirium, falls and fractures is increased in geriatric patients|
02195|020|P|using more than one medicine with anticholinergic properties.(4)|
02195|021|B||
02195|022|M|PATIENT MANAGEMENT:  Avoid coadministration of sensitive CYP3A4 substrates|
02195|023|M|with a narrow therapeutic index.  If concomitant use is unavoidable, dosage|
02195|024|M|adjustment of the CYP3A4 substrate should be considered when initiating or|
02195|025|M|discontinuing ceritinib.(1)  Patients maintained on ceritinib may need lower|
02195|026|M|initial doses of the CYP3A4 substrate.  Monitor patients receiving|
02195|027|M|concurrent therapy for adverse effects.|
02195|028|B||
02195|029|D|DISCUSSION:  In a study, ceritinib (750 mg daily for 3 weeks) increased the|
02195|030|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a|
02195|031|D|CYP3A4 substrate) by 5.4-fold and 1.8-fold, respectively, compared to|
02195|032|D|midazolam alone.(1)|
02195|033|D|   Thus, ceritinib is expected to increase levels of cyclosporine,|
02195|034|D|felodipine, hydroquinidine, midazolam, nisoldipine, quinidine, and|
02195|035|D|sirolimus.|
02195|036|B||
02195|037|R|REFERENCES:|
02195|038|B||
02195|039|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
02195|040|R|  Corporation August, 2021.|1
02195|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02195|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02195|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02195|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02195|045|R|  11/14/2017.|1
02195|046|R|3.FDA. CDER Application number: 205755 Zykadia (ceritinib) CLINICAL|1
02195|047|R|  PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S). available at:|1
02195|048|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205755Orig1s000Clin|1
02195|049|R|  PharmR.pdf March 25, 2014.|1
02195|050|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02195|051|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02195|052|R|  Soc 2023 Jul;71(7):2052-2081.|6
02196|001|T|MONOGRAPH TITLE:  Deferiprone/Aluminum, Iron, Zinc|
02196|002|B||
02196|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02196|004|L|take action as needed.|
02196|005|B||
02196|006|A|MECHANISM OF ACTION:  Deferiprone chelates polyvalent cations such as|
02196|007|A|aluminum, iron, and zinc.(1)|
02196|008|B||
02196|009|E|CLINICAL EFFECTS:  Deferiprone chelation with oral aluminum, iron or zinc|
02196|010|E|containing products in the gastrointestinal tract may decrease the amount of|
02196|011|E|free deferiprone available for systemic iron chelation.|
02196|012|E|   Zinc supplements prescribed to counteract deferiprone-induced zinc|
02196|013|E|deficiency may not be effective if taken near time of deferiprone|
02196|014|E|administration.|
02196|015|B||
02196|016|P|PREDISPOSING FACTORS:  None determined.|
02196|017|B||
02196|018|M|PATIENT MANAGEMENT:  The US manufacturer recommends at least a four hour|
02196|019|M|interval between deferiprone dose and administration of aluminum, iron or|
02196|020|M|zinc containing medications or supplements.(1)  Avoid use of iron-containing|
02196|021|M|vitamins or nutritional supplements in patients who require chelation|
02196|022|M|therapy for iron overload.|
02196|023|B||
02196|024|D|DISCUSSION:  The US manufacturer has not studied this interaction.  The|
02196|025|D|recommendation to separate deferiprone and polyvalent cation doses by at|
02196|026|D|least four hours is based upon the deferiprone mechanism of action.(1)|
02196|027|B||
02196|028|R|REFERENCE:|
02196|029|B||
02196|030|R|1.Ferriprox (deferiprone) US prescribing information. ApoPharma February,|1
02196|031|R|  2020.|1
02197|001|T|MONOGRAPH TITLE:  Deferiprone/Selected Myelosuppressive Agents|
02197|002|B||
02197|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02197|004|L|of severe adverse interaction.|
02197|005|B||
02197|006|A|MECHANISM OF ACTION:  Concurrent use of deferiprone with other drugs known|
02197|007|A|to be associated with neutropenia or agranulocytosis may increase the|
02197|008|A|frequency or risk for severe toxicity.(1)|
02197|009|B||
02197|010|E|CLINICAL EFFECTS:  Concurrent use of deferiprone and myelosuppressive agents|
02197|011|E|may result in severe neutropenia or agranulocytosis, which may be fatal.|
02197|012|B||
02197|013|P|PREDISPOSING FACTORS:  Agranulocytosis may be less common in patients|
02197|014|P|receiving deferiprone for thalassemia, and more common in patients treated|
02197|015|P|for other systemic iron overload conditions (e.g. myelodysplastic syndromes,|
02197|016|P|sickle cell disease).(2,3)|
02197|017|P|   Inadequate monitoring appears to increase the risk for severe outcomes.|
02197|018|P|Manufacturer post market surveillance found that in all fatal cases of|
02197|019|P|agranulocytosis reported between 1999 and 2005, data on weekly white blood|
02197|020|P|count (WBC) monitoring was missing.  In three fatal cases, deferiprone was|
02197|021|P|continued for two to seven days after the detection of neutropenia or|
02197|022|P|agranulocytosis.(2)|
02197|023|B||
02197|024|M|PATIENT MANAGEMENT:  If possible, discontinue one of the drugs associated|
02197|025|M|with risk for neutropenia or agranulocytosis.  If alternative therapy is not|
02197|026|M|available, documentation and adherence to the deferiprone monitoring|
02197|027|M|protocol is essential.|
02197|028|M|   Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior|
02197|029|M|to starting deferiprone.  Monitor ANC weekly during therapy.  If infection|
02197|030|M|develops, interrupt deferiprone therapy and monitor ANC more frequently.|
02197|031|M|If ANC is less than 1,500/uL but greater than 500/uL, discontinue|
02197|032|M|deferiprone and any other drugs possibly associated with neutropenia.|
02197|033|M|Initiate ANC and platelet counts daily until recovery (i.e. ANC at least|
02197|034|M|1,500/uL).  If ANC is less than 500/uL, discontinue deferiprone, evaluate|
02197|035|M|patient and hospitalize if appropriate.  Do not resume deferiprone unless|
02197|036|M|potential benefits outweigh potential risks.(1)|
02197|037|B||
02197|038|D|DISCUSSION:  Drugs linked to this monograph have an FDA Boxed Warning for|
02197|039|D|risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for|
02197|040|D|neutropenia and/or warnings describing risk for myelosuppression in|
02197|041|D|manufacturer prescribing information.(1-25)|
02197|042|D|  In pooled clinical studies submitted to the FDA, 6.1% of deferiprone|
02197|043|D|patients met criteria for neutropenia and 1.7% of patients developed|
02197|044|D|agranulocytosis.(1)  The time to onset of agranulocytosis was highly|
02197|045|D|variable with a range of 65 days to 9.2 years (median, 161 days).(3)|
02197|046|B||
02197|047|R|REFERENCES:|
02197|048|B||
02197|049|R|1.Ferriprox (deferiprone) US prescribing information. ApoPharma February,|1
02197|050|R|  2020.|1
02197|051|R|2.Dear Health Care Professional letter "Important Safety Information: Risks|1
02197|052|R|  of Fatal Agranulocytosis and Neurological Disorders with the Use of|1
02197|053|R|  Ferriprox (deferiprone)" UK Medicines Healthcare product Registry Agency|1
02197|054|R|  (MHRA). ApoPharma Inc. September 6, 2006.|1
02197|055|R|3.US Food and Drug Administration. Ferriprox (deferiprone) FDA Briefing|1
02197|056|R|  Document for The Oncologic Drugs Advisory Committee. available at|1
02197|057|R|  http://wayback.archive-it.org/7993/20170405223704/https://www.fda.gov/down|1
02197|058|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAd|1
02197|059|R|  visoryCommittee/UCM271538.pdf September 14, 2011.|1
02197|060|R|4.Campath (alemtuzumab) US prescribing information. Genzyme Corporation|1
02197|061|R|  November 2, 2020.|1
02197|062|R|5.Tegretol (carbamazepine) US prescribing information. Novartis|1
02197|063|R|  Pharmaceuticals Corporation September, 2023.|1
02197|064|R|6.Vistide (cidofovir) US prescribing information. Gilead Sciences, Inc.|1
02197|065|R|  September, 2000.|1
02197|066|R|7.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02197|067|R|  May, 2010.|1
02197|068|R|8.Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia|1
02197|069|R|  & Upjohn Company January, 2020.|1
02197|070|R|9.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
02197|071|R|  Company August, 2010.|1
02197|072|R|10.Hycamtin Injection (topotecan hydrochloride) US prescribing information.|1
02197|073|R|   GlaxoSmithKline June, 2015.|1
02197|074|R|11.Hycamtin Oral (topotecan) US prescribing information. GlaxoSmithKline|1
02197|075|R|   September, 2018.|1
02197|076|R|12.Retrovir (zidovudine) US prescribing information. GlaxoSmithKline|1
02197|077|R|   September, 2018.|1
02197|078|R|13.Carbplatin Inj. US prescribing information. Teva October, 2011.|1
02197|079|R|14.Ridaura (auranofin) US prescribing information. Prometheus Laboratories|1
02197|080|R|   August, 2007.|1
02197|081|R|15.Leukeran (Chlorambucil) US prescribing information. GlaxoSmithKline|1
02197|082|R|   October, 2011.|1
02197|083|R|16.Cytovene IV (ganciclovir) US prescribing information. Genentech Inc.|1
02197|084|R|   August, 2018.|1
02197|085|R|17.Zevalin (ibritumomab) US prescribing information. Spectrum|1
02197|086|R|   Pharmaceuticals September, 2013.|1
02197|087|R|18.Revlimid (lenalidomide) US prescribing information. Celgene Corp.|1
02197|088|R|   January, 2019.|1
02197|089|R|19.Mitoxantrone Inj. US prescribing information. APP Pharmaceuticals July,|1
02197|090|R|   2010.|1
02197|091|R|20.Vumon (teniposide) US prescribing information. E.R. Squibb & Sons|1
02197|092|R|   October, 2011.|1
02197|093|R|21.Bexxar (tositumomab) US prescribing information. GlaxoSmithKline October,|1
02197|094|R|   2005.|1
02197|095|R|22.Valcyte (valganciclovir) US prescribing information. Genentech June,|1
02197|096|R|   2017.|1
02197|097|R|23.Lonsurf (trifluridine-tipiracil) US prescribing information. Taiho|1
02197|098|R|   Oncology Inc. March 30, 2017.|1
02197|099|R|24.Tagrisso (osimertinib) US prescribing information. AstraZeneca|1
02197|100|R|   Pharmaceuticals September, 2024.|1
02197|101|R|25.Aliqopa (copanlisib) US prescribing information. Bayer October, 2019.|1
02198|001|T|MONOGRAPH TITLE:  Ruxolitinib;Tofacitinib/Strong 3A4 Inhibitors (mono|
02198|002|T|deleted 08/26/2014)|
02198|003|B||
02198|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02198|005|L|of severe adverse interaction.|
02198|006|B||
02198|007|A|MECHANISM OF ACTION:  Boceprevir, clarithromycin, conivaptan, indinavir,|
02198|008|A|itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone,|
02198|009|A|nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin,|
02198|010|A|and voriconazole are strong inhibitors of CYP3A4 and may inhibit the|
02198|011|A|metabolism of ruxolitinib(1) and tofacitinib.(2)|
02198|012|B||
02198|013|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors such as|
02198|014|E|boceprevir, clarithromycin, conivaptan, indinavir, itraconazole,|
02198|015|E|ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,|
02198|016|E|posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or|
02198|017|E|voriconazole may result in elevated levels of and toxicity from|
02198|018|E|ruxolitinib(1) and tofacitinib.(2)|
02198|019|B||
02198|020|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
02198|021|P|a low platelet count and taking ruxolitinib.(1)|
02198|022|B||
02198|023|M|PATIENT MANAGEMENT:  In patients with a platelet count greater than or equal|
02198|024|M|to 100 X 10x9/L who are receiving a strong inhibitor of CYP3A4 (such as|
02198|025|M|boceprevir, clarithromycin, conivaptan, indinavir, itraconazole,|
02198|026|M|ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,|
02198|027|M|posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or|
02198|028|M|voriconazole), the recommended starting dose of ruxolitinib is 10 mg twice|
02198|029|M|daily.  The dose should be adjusted based on monitoring of safety and|
02198|030|M|efficacy.(1)|
02198|031|M|   Avoid the use of ruxolitinib in patients with a platelet count less than|
02198|032|M|100 X 10x9/L who are receiving a strong inhibitor of CYP3A4.(1)|
02198|033|M|   In patients taking a strong CYP3A4 inhibitor, the starting dose of|
02198|034|M|tofacitinib should be reduced to 5 mg daily.(2)|
02198|035|B||
02198|036|D|DISCUSSION:  In healthy subjects, ketoconazole (a strong inhibitor of|
02198|037|D|CYP3A4, 200 mg twice daily for 4 days) increased the maximum concentration|
02198|038|D|(Cmax), area-under-curve (AUC), and half-life of a single dose of|
02198|039|D|ruxolitinib (10 mg) by 33%, 91%, and 62%, respectively.  There was also a|
02198|040|D|corresponding increase in pSTAT3 inhibition, a pharmacodynamic marker for|
02198|041|D|ruxolitinib.(1)|
02198|042|D|   In healthy subjects, erythromycin (a moderate inhibitor of CYP3A4, 500 mg|
02198|043|D|twice daily for 4 days) increased the Cmax and AUC of a single dose of|
02198|044|D|ruxolitinib (10 mg) by 8% and 27%, respectively.  Therefore, no dosage|
02198|045|D|adjustment is recommended with moderate or mild inhibitors of CYP3A4.(1)|
02198|046|D|   In a study, administration of ketoconazole, a strong inhibitor of CYP3A4,|
02198|047|D|increased the area-under-curve (AUC) of tofacitinib by more than 2-fold.(2)|
02198|048|B||
02198|049|R|REFERENCES:|
02198|050|B||
02198|051|R|1.Jakafi (ruxolitinib) US prescribing information. Incyte Corporation|1
02198|052|R|  November, 2013.|1
02198|053|R|2.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. November,|1
02198|054|R|  2012.|1
02199|001|T|MONOGRAPH TITLE:  Deferiprone/Milk Thistle|
02199|002|B||
02199|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
02199|004|L|Assess the risk to the patient and take action as needed.|
02199|005|B||
02199|006|A|MECHANISM OF ACTION:  Deferiprone is metabolized via UDP|
02199|007|A|glucuronosyltransferase (UGT) 1A6. Milk thistle is an inhibitor of UGT1A6.|
02199|008|B||
02199|009|E|CLINICAL EFFECTS:  Systemic exposure to deferiprone may be increased.|
02199|010|B||
02199|011|P|PREDISPOSING FACTORS:  None determined.|
02199|012|B||
02199|013|M|PATIENT MANAGEMENT:  The manufacturer of deferiprone recommends avoiding the|
02199|014|M|use of milk thistle with deferiprone.(1)|
02199|015|B||
02199|016|D|DISCUSSION:  The combination of deferiprone and milk thistle has not been|
02199|017|D|evaluated in a clinical study. In vitro data has shown that phenylbutazone|
02199|018|D|(a UGT1A6 inhibitor) can decrease the glucuronidation of deferiprone by up|
02199|019|D|to 78%.(1,2)|
02199|020|B||
02199|021|R|REFERENCES:|
02199|022|B||
02199|023|R|1.Ferriprox (deferiprone) US prescribing information. ApoPharma February,|1
02199|024|R|  2020.|1
02199|025|R|2.Sridar C, Goosen TC, Kent UM, Williams JA, Hollenberg PF. Silybin|5
02199|026|R|  inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic|5
02199|027|R|  glucuronosyltransferases. Drug Metab Dispos 2004 Jun;32(6):587-94.|5
02200|001|T|MONOGRAPH TITLE:  Telaprevir/Selected Protease Inhibitors|
02200|002|B||
02200|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02200|004|L|of severe adverse interaction.|
02200|005|B||
02200|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02200|007|B||
02200|008|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
02200|009|E|effectiveness of darunavir, fosamprenavir, lopinavir, and telaprevir.(1)|
02200|010|B||
02200|011|P|PREDISPOSING FACTORS:  None determined.|
02200|012|B||
02200|013|M|PATIENT MANAGEMENT:  Concurrent use of telaprevir with darunavir/ritonavir,|
02200|014|M|fosamprenavir/ritonavir, or lopinavir/ritonavir is not recommended.  Monitor|
02200|015|M|patients receiving concurrent telaprevir and atazanavir/ritonavir for|
02200|016|M|atazanavir related side effects.(1)|
02200|017|B||
02200|018|D|DISCUSSION:  In a study in 14 subjects, concurrent atazanavir/ritonavir|
02200|019|D|(300/100 mg daily for 20 days) with teleprevir (750 mg q8h for 10 days)|
02200|020|D|decreased the maximum concentration (Cmax), area-under-curve (AUC), and|
02200|021|D|minimum concentration (Cmin) of telaprevir by 21%, 20%, and 15%,|
02200|022|D|respectively.  The Cmax of atazanavir decreased by 15%, while the AUC and|
02200|023|D|Cmin of atazanavir increased by 17% and 85%, respectively.(1)|
02200|024|D|   In a study in 11 subjects, concurrent darunavir/ritonavir (600/100 mg|
02200|025|D|daily for 20 days) with telaprevir (750 mg q8h for 10 days) decreased the|
02200|026|D|Cmax, AUC, Cmin of telaprevir by 36%, 35%, and 32%, respectively.  The Cmax,|
02200|027|D|AUC, and Cmin of darunavir decreased 40%, 40%, and 42%, respectively.  In a|
02200|028|D|study in 15 subjects, concurrent telaprevir (1125 mg q12h for 4 days)|
02200|029|D|decreased the Cmax, AUC, and Cmin of darunavir (600/100 mg bid for 24 days)|
02200|030|D|by 47%, 51%, and 58%, respectively.(1)|
02200|031|D|   In a study in 18 subjects, concurrent fosamprenavir/ritonavir (700/100 mg|
02200|032|D|bid for 20 days) and telaprevir (750 mg q8h for 10 days) decreased the|
02200|033|D|telaprevir Cmax, AUC, and Cmin by 33%, 32%, and 30%, respectively.  The|
02200|034|D|Cmax, AUC, and Cmin of fosamprenavir decreased by 35%, 47%, and 56%,|
02200|035|D|respectively.  In a study in 17 subjects, concurrent telaprevir (1125 mg|
02200|036|D|q12h for 4 days) decreased the Cmax, AUC, and Cmin of fosamprenavir (700/100|
02200|037|D|mg bid for 24 days) by 40%, 49%, and 58%, respectively.(1)|
02200|038|D|   In a study in 12 subjects, concurrent lopinavir/ritonavir (400/100 mg bid|
02200|039|D|for 20 days) and telaprevir (750 mg q8h for 10 days) decreased the|
02200|040|D|telaprevir Cmax, AUC, and Cmin by 53%, 54%, and 52%, respectively.  There|
02200|041|D|were no significant changes in lopinavir pharmacokinetics.(1)|
02200|042|D|   In a study in 14 subjects, a single dose of ritonavir (100 mg) increased|
02200|043|D|the Cmax and AUC of a single dose of telaprevir (750 mg) 1.30-fold and|
02200|044|D|2.00-fold, respectively.(1)|
02200|045|D|   In a study in 5 subjects, concurrent ritonavir (100 mg bid for 14 days)|
02200|046|D|and telaprevir (750 mg q8h for 14 days) decreased the telaprevir Cmax, AUC,|
02200|047|D|and Cmin by 15%, 24%, and 32%, respectively.(1)|
02200|048|B||
02200|049|R|REFERENCE:|
02200|050|B||
02200|051|R|1.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02200|052|R|  Incorporated October, 2013.|1
02201|001|T|MONOGRAPH TITLE:  Pimozide/Strong CYP2D6 Inhibitors|
02201|002|B||
02201|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02201|004|L|is contraindicated and generally should not be dispensed or administered to|
02201|005|L|the same patient.|
02201|006|B||
02201|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
02201|008|A|pimozide at CYP2D6.(1-6)|
02201|009|B||
02201|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2D6 inhibitors that prolong|
02201|011|E|QT may increase the levels and effects of pimozide including additive QTc|
02201|012|E|prolongation and potentially life-threatening cardiac arrhythmias like|
02201|013|E|torsades de pointes.|
02201|014|E|   Concurrent use may also result in extrapyramidal symptoms such as|
02201|015|E|akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and|
02201|016|E|oculogyric crisis.(8)|
02201|017|B||
02201|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02201|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
02201|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02201|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02201|022|P|female gender, or advanced age.(7)|
02201|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02201|024|P|higher systemic concentrations of either QT prolonging drug are additional|
02201|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02201|026|P|drug concentrations include rapid infusion of an intravenous dose or|
02201|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02201|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02201|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)|
02201|030|P|   The risk of anticholinergic toxicities including cognitive decline,|
02201|031|P|delirium, falls and fractures is increased in geriatric patients using more|
02201|032|P|than one medicine with anticholinergic properties.(8)|
02201|033|B||
02201|034|M|PATIENT MANAGEMENT:  The concurrent use of pimozide with strong inhibitors|
02201|035|M|of CYP2D6 is contraindicated.(1)|
02201|036|M|   If concurrent use cannot be avoided, then correct or minimize QT|
02201|037|M|prolonging risk factors, use the lowest effective dose of pimozide, and|
02201|038|M|discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if|
02201|039|M|possible.|
02201|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02201|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02201|042|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
02201|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02201|044|B||
02201|045|D|DISCUSSION:  In a controlled study in healthy subjects, steady-state|
02201|046|D|paroxetine (60 mg daily, a strong inhibitor of CYP2D6) increased the AUC and|
02201|047|D|Cmax of a single dose of pimozide (2 mg) by 151% and 62%, respectively.(2-4)|
02201|048|D|   Strong CYP2D6 inhibitors include: dacomitinib, fluoxetine, paroxetine,|
02201|049|D|and terbinafine.(1,9)|
02201|050|D|   One or more of the drug pairs linked to this monograph have been included|
02201|051|D|in a list of interactions that should be considered "high-priority" for|
02201|052|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02201|053|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02201|054|D|Coordinator (ONC) for Health Information Technology.|
02201|055|B||
02201|056|R|REFERENCES:|
02201|057|B||
02201|058|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
02201|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02201|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02201|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02201|062|R|  11/14/2017.|1
02201|063|R|2.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
02201|064|R|  2011.|1
02201|065|R|3.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
02201|066|R|  Technologies January, 2017.|1
02201|067|R|4.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
02201|068|R|  Therapeutics, LLC September, 2021.|1
02201|069|R|5.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
02201|070|R|  and Company August, 2023.|1
02201|071|R|6.Sarafem (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
02201|072|R|  and Company September, 2021.|1
02201|073|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02201|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02201|075|R|  settings: a scientific statement from the American Heart Association and|6
02201|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02201|077|R|  2;55(9):934-47.|6
02201|078|R|8.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02201|079|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02201|080|R|  Soc 2023 Jul;71(7):2052-2081.|6
02201|081|R|9.This information is based on an extract from the Certara Drug Interaction|6
02201|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02201|083|R|10.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02201|084|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02201|085|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02201|086|R|   19(5):735-43.|6
02202|001|T|MONOGRAPH TITLE:  Selected Oral Quinolones/Selected Oral Cations|
02202|002|B||
02202|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02202|004|L|take action as needed.|
02202|005|B||
02202|006|A|MECHANISM OF ACTION:  Aluminum, iron, lanthanum, magnesium, and zinc may|
02202|007|A|form chelation compounds with the quinolones.(1-23)|
02202|008|B||
02202|009|E|CLINICAL EFFECTS:  Simultaneous administration or administration of products|
02202|010|E|containing aluminum, iron, lanthanum, magnesium, and/or zinc close to the|
02202|011|E|administration time of an oral quinolone may result in decreased absorption|
02202|012|E|and clinical effectiveness of the quinolone|
02202|013|B||
02202|014|P|PREDISPOSING FACTORS:  None determined.|
02202|015|B||
02202|016|M|PATIENT MANAGEMENT:  If possible, avoid concurrent therapy with quinolones|
02202|017|M|and cation-containing products.  If it is necessary to administer these|
02202|018|M|agents concurrently, follow the manufacturers' recommendations regarding|
02202|019|M|timing of administration of the quinolone and cation-containing products.|
02202|020|M|   Manufacturer recommendations regarding the separation of administration|
02202|021|M|times of quinolones and products containing aluminum, iron, lanthanum,|
02202|022|M|magnesium, and/or zinc vary:|
02202|023|M|---Do not give gatifloxacin for at least 4 hours before oral cations(1)|
02202|024|M|---Do not give gemifloxacin for at least 2 hours before or 3 hours after|
02202|025|M|oral cations.(2)|
02202|026|M|---Do not give lomefloxacin for at least 2 hours before or 4 hours after|
02202|027|M|oral cations.(3)|
02202|028|M|---Do not give moxifloxacin for at least 4 hours before or 8 hours after|
02202|029|M|oral cations.(4)|
02202|030|M|---Do not give trovafloxacin for at least 2 hours before or after oral|
02202|031|M|cations.(5)|
02202|032|M|---Do not give prulifloxacin for at least 2 hours before or 4 hours after|
02202|033|M|oral cations.(23)|
02202|034|M|   The US manufacturer of lanthanum recommends that quinolones be taken at|
02202|035|M|least 1 hour before or 4 hours after lanthanum;(6) however, it would be|
02202|036|M|prudent to follow the specific quinolone manufacturers' recommendations|
02202|037|M|regarding concurrent administration of cations.|
02202|038|M|   For quinolones not listed above, separate their administration from oral|
02202|039|M|cations by as much time as feasible.|
02202|040|B||
02202|041|D|DISCUSSION:  Magnesium and aluminum compounds have been shown to form|
02202|042|D|chelation compounds with quinolone antibiotics, resulting in decreased|
02202|043|D|absorption of the quinolone.(1-22)  Treatment failures during concurrent use|
02202|044|D|of cations and gatifloxacin(7) and pefloxacin(8) have been reported.|
02202|045|D|   In a study in 24 healthy subjects, administration of an|
02202|046|D|aluminum-magnesium hydroxide antacid simultaneously, 2 hours before, or 2|
02202|047|D|hours after decreased the area-under-curve (AUC) of a single dose of|
02202|048|D|gatifloxacin (400 mg) by 42%, 64%, or 18%, respectively.  There were no|
02202|049|D|affects on gatifloxacin AUC when the antacid was administered 4 hours after|
02202|050|D|gatifloxacin.(9)|
02202|051|D|   In a study in 16 healthy males, administration of an aluminum-magnesium|
02202|052|D|hydroxide antacid 10 minutes before or 3 hours after a single dose of|
02202|053|D|gemifloxacin (320 mg) decreased the gemifloxacin AUC by 85% and 15%,|
02202|054|D|respectively.  There was no affect when the antacid was administered 2 hours|
02202|055|D|after gemifloxacin.(10)|
02202|056|D|   In a study in 16 subjects, simultaneous administration of calcium|
02202|057|D|carbonate decreased the maximum concentration (Cmax) and AUC of a single|
02202|058|D|dose of gemifloxacin (320 mg) by 17% and 21%, respectively.  There was no|
02202|059|D|effect of calcium carbonate when administered either 2 hours before or after|
02202|060|D|gemifloxacin.(11)|
02202|061|D|   In a study in 27 healthy males, the administration of ferrous sulfate|
02202|062|D|(325 mg) 3 hours before a single dose of gemifloxacin (320 mg) decreased the|
02202|063|D|Cmax and AUC of gemifloxacin by 20% and 11%, respectively.  There were no|
02202|064|D|effects when ferrous sulfate was administered 2 hours after|
02202|065|D|gemifloxacin.(12)|
02202|066|D|   In a study in 8 healthy subjects, ferrous sulfate (100 mg elemental iron)|
02202|067|D|decreased the Cmax and AUC of a single dose of lomefloxacin by 26% and 13%,|
02202|068|D|respectively.  There were no effects with concurrent calcium carbonate (500|
02202|069|D|mg calcium).(13)|
02202|070|D|   Magnesium- and aluminum-containing antacids have been shown to decrease|
02202|071|D|the bioavailability of lomefloxacin by 40%.(14)|
02202|072|D|   Administration of moxifloxacin 2 hours before, simultaneously, or 4 hours|
02202|073|D|after a magnesium- and aluminum-containing antacid decreased moxifloxacin|
02202|074|D|AUC by 26%, 60%, and 23%, respectively.(15)|
02202|075|D|   Simultaneous administration of moxifloxacin and ferrous sulfate (100 mg)|
02202|076|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
02202|077|D|moxifloxacin by 39% and 59%, respectively.(16)|
02202|078|D|   Concurrent administration of calcium had no affect on moxifloxacin|
02202|079|D|pharmacokinetics.(17)|
02202|080|D|   In a study in 10 healthy subjects, an aluminum-magnesium hydroxide|
02202|081|D|antacid decreased the bioavailability of pefloxacin (400 mg) by 44.4%.(18)|
02202|082|D|   The administration of an antacid containing aluminum hydroxide and|
02202|083|D|magnesium hydroxide 5 minutes before rufloxacin decreased rufloxacin levels|
02202|084|D|by 36%.  Administration of the antacid 4 hours after rufloxacin decreased|
02202|085|D|rufloxacin levels by 13%.(19)|
02202|086|D|   Magnesium- and aluminum-containing antacids have been shown to decrease|
02202|087|D|the bioavailability of temafloxacin by 40%.(20)|
02202|088|D|   Aluminum hydroxide has been shown to decrease the bioavailability of|
02202|089|D|tosufloxacin by 31.6%.(21)|
02202|090|D|   Administration of an antacid containing aluminum hydroxide and magnesium|
02202|091|D|hydroxide 30 minutes before trovafloxacin decreased trovafloxacin levels by|
02202|092|D|66%.(22)|
02202|093|D|   One or more of the drug pairs linked to this monograph have been included|
02202|094|D|in a list of interactions that could be considered for classification as|
02202|095|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
02202|096|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
02202|097|D|Health Information Technology.|
02202|098|B||
02202|099|R|REFERENCES:|
02202|100|B||
02202|101|R|1.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
02202|102|R|  Company January, 2006.|1
02202|103|R|2.Factive (gemifloxacin mesylate) US prescribing information. Merus Labs|1
02202|104|R|  International, Inc. October, 2018.|1
02202|105|R|3.Maxaquin (lomefloxacin hydrochloride) US prescribing information. Pfizer|1
02202|106|R|  Inc. January, 2005.|1
02202|107|R|4.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
02202|108|R|  Pharmaceuticals Corporation October 18, 2018.|1
02202|109|R|5.Trovan (trovafloxacin mesylate) US prescribing information. Roerig April,|1
02202|110|R|  2000.|1
02202|111|R|6.Fosrenol (lanthanum carbonate) US prescribing information. Shire US Inc.|1
02202|112|R|  May, 2020.|1
02202|113|R|7.Mallet L, Huang A. Coadministration of gatifloxacin and multivitamin|3
02202|114|R|  preparation containing minerals: potential treatment failure in an elderly|3
02202|115|R|  patient. Ann Pharmacother 2005 Jan;39(1):150-2.|3
02202|116|R|8.Vinceneux P, Weber P, Gaudin H, Boussougant Y. Decreased absorption of|3
02202|117|R|  pefloxacin by gastric antacids. Preliminary study. Presse Med 1986 Oct 18;|3
02202|118|R|  15(36):1826.|3
02202|119|R|9.Lober S, Ziege S, Rau M, Schreiber G, Mignot A, Koeppe P, Lode H.|2
02202|120|R|  Pharmacokinetics of gatifloxacin and interaction with an antacid|2
02202|121|R|  containing aluminum and magnesium. Antimicrob Agents Chemother 1999 May;|2
02202|122|R|  43(5):1067-71.|2
02202|123|R|10.Allen A, Vousden M, Porter A, Lewis A. Effect of Maalox on the|2
02202|124|R|   bioavailability of oral gemifloxacin in healthy volunteers. Chemotherapy|2
02202|125|R|   1999 Nov-Dec;45(6):504-11.|2
02202|126|R|11.Pletz MW, Petzold P, Allen A, Burkhardt O, Lode H. Effect of calcium|2
02202|127|R|   carbonate on bioavailability of orally administered gemifloxacin.|2
02202|128|R|   Antimicrob Agents Chemother 2003 Jul;47(7):2158-60.|2
02202|129|R|12.Allen A, Bygate E, Faessel H, Isaac L, Lewis A. The effect of ferrous|2
02202|130|R|   sulphate and sucralfate on the bioavailability of oral gemifloxacin in|2
02202|131|R|   healthy volunteers. Int J Antimicrob Agents 2000 Aug;15(4):283-9.|2
02202|132|R|13.Lehto P, Kivisto KT. Different effects of products containing metal ions|2
02202|133|R|   on the absorption of lomefloxacin. Clin Pharmacol Ther 1994 Nov;|2
02202|134|R|   56(5):477-82.|2
02202|135|R|14.Shimada J, Shiba K, Oguma T, Miwa H, Yoshimura Y, Nishikawa T, Okabayashi|2
02202|136|R|   Y, Kitagawa T, Yamamoto S. Effect of antacid on absorption of the|2
02202|137|R|   quinolone lomefloxacin. Antimicrob Agents Chemother 1992 Jun;|2
02202|138|R|   36(6):1219-24.|2
02202|139|R|15.Stass H, Bottcher MF, Ochmann K. Evaluation of the influence of antacids|2
02202|140|R|   and H2 antagonists on the absorption of moxifloxacin after oral|2
02202|141|R|   administration of a 400mg dose to healthy volunteers. Clin Pharmacokinet|2
02202|142|R|   2001;40 Suppl 1:39-48.|2
02202|143|R|16.Stass H, Kubitza D. Effects of iron supplements on the oral|2
02202|144|R|   bioavailability of moxifloxacin, a novel 8-methoxyfluoroquinolone, in|2
02202|145|R|   humans. Clin Pharmacokinet 2001;40 Suppl 1:57-62.|2
02202|146|R|17.Stass H, Wandel C, Delesen H, Moller JG. Effect of calcium supplements on|2
02202|147|R|   the oral bioavailability of moxifloxacin in healthy male volunteers. Clin|2
02202|148|R|   Pharmacokinet 2001;40 Suppl 1:27-32.|2
02202|149|R|18.Jaehde U, Sorgel F, Stephan U, Schunack W. Effect of an antacid|2
02202|150|R|   containing magnesium and aluminum on absorption, metabolism, and|2
02202|151|R|   mechanism of renal elimination of pefloxacin in humans. Antimicrob Agents|2
02202|152|R|   Chemother 1994 May;38(5):1129-33.|2
02202|153|R|19.Lazzaroni M, Imbimbo BP, Bargiggia S, Sangaletti O, Dal Bo L, Broccali G,|2
02202|154|R|   Porro GB. Effects of magnesium-aluminum hydroxide antacid on absorption|2
02202|155|R|   of rufloxacin. Antimicrob Agents Chemother 1993 Oct;37(10):2212-6.|2
02202|156|R|20.Granneman GR, Stephan U, Birner B, Sorgel F, Mukherjee D. Effect of|2
02202|157|R|   antacid medication on the pharmacokinetics of temafloxacin. Clin|2
02202|158|R|   Pharmacokinet 1992;22 Suppl 1:83-9.|2
02202|159|R|21.Minami R, Nakamura C, Inotsume N, Nakano M. Effects of aluminum hydroxide|2
02202|160|R|   and famotidine on bioavailability of tosufloxacin in healthy volunteers.|2
02202|161|R|   Antimicrob Agents Chemother 1998 Feb;42(2):453-5.|2
02202|162|R|22.Teng R, Dogolo LC, Willavize SA, Friedman HL, Vincent J. Effect of Maalox|2
02202|163|R|   and omeprazole on the bioavailability of trovafloxacin. J Antimicrob|2
02202|164|R|   Chemother 1997 Jun;39 Suppl B:93-7.|2
02202|165|R|23.Unidrox (prulifloxacin) HK prescribing information. Lee's Pharmaceutical|1
02202|166|R|   (HK) Limited.|1
02202|167|R|24.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
02202|168|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
02202|169|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
02202|170|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
02203|001|T|MONOGRAPH TITLE:  Hormonal Contraceptive Agents/Clobazam|
02203|002|B||
02203|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02203|004|L|of severe adverse interaction.|
02203|005|B||
02203|006|A|MECHANISM OF ACTION:  Clobazam may induce the metabolism of hormonal|
02203|007|A|contraceptive agents by CYP3A4.(1)|
02203|008|B||
02203|009|E|CLINICAL EFFECTS:  Concurrent use of clobazam and hormonal contraceptive|
02203|010|E|agents may decrease the effectiveness of the hormonal contraceptive agent,|
02203|011|E|which may result in contraceptive failure.  While there are no adequate|
02203|012|E|studies in pregnant women, animal data suggests that clobazam use in|
02203|013|E|pregnancy may result in development toxicity and fetal abnormalities.(1)|
02203|014|B||
02203|015|P|PREDISPOSING FACTORS:  None determined.|
02203|016|B||
02203|017|M|PATIENT MANAGEMENT:  Women receiving clobazam therapy should not rely on|
02203|018|M|hormonal contraceptive agents (including oral, implantable, injectable, or|
02203|019|M|transdermal agents) because they may not be effective.  Women taking|
02203|020|M|clobazam should use additional, non-hormonal forms of contraception during|
02203|021|M|and for 28 days after discontinuing clobazam.(1)|
02203|022|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
02203|023|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
02203|024|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
02203|025|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
02203|026|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
02203|027|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
02203|028|M|and to seek medical advice if they do become pregnant.(2)|
02203|029|B||
02203|030|D|DISCUSSION:  Clobazam decreased the maximum concentration (Cmax) and|
02203|031|D|area-under-curve (AUC) of midazolam, a CYP3A4 substrate by 24% and 27%,|
02203|032|D|respectively.  Because some hormonal contraceptives are metabolized by|
02203|033|D|CYP3A4, clobazam use may decrease their effectiveness.(1)|
02203|034|B||
02203|035|R|REFERENCES:|
02203|036|B||
02203|037|R|1.Onfi (clobazam) US prescribing information. Lundbeck, Inc. February, 2021.|1
02203|038|R|2.Medicines and Healthcare products Regulatory Agency.|1
02203|039|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
02203|040|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
02203|041|R|  available at:|1
02203|042|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
02203|043|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
02203|044|R|  -and-contraceptive-efficacy September 15, 2016..|1
02204|001|T|MONOGRAPH TITLE:  Clobazam/Selected Moderate CYP2C19 Inhibitors|
02204|002|B||
02204|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02204|004|L|take action as needed.|
02204|005|B||
02204|006|A|MECHANISM OF ACTION:  Clobazam's active metabolite, N-desmethylclobazam, is|
02204|007|A|metabolized by the CYP2C19 isoenzyme.(1)|
02204|008|B||
02204|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP2C19 may|
02204|010|E|result in elevated levels of and toxicity from the active metabolite of|
02204|011|E|clobazam, including profound sedation, respiratory depression, coma, and/or|
02204|012|E|death.(1)|
02204|013|B||
02204|014|P|PREDISPOSING FACTORS:  None determined.|
02204|015|B||
02204|016|M|PATIENT MANAGEMENT:  The dosage of clobazam may need to be adjusted when|
02204|017|M|initiating or discontinuing a moderate inhibitor of CYP2C19.(1)|
02204|018|M|   When initiating clobazam in a patient maintained on a moderate inhibitor|
02204|019|M|of CYP2C19, it would be prudent to follow the manufacturer's recommendations|
02204|020|M|for dosage adjustments in patients who are CYP2C19 poor metabolizers.  In|
02204|021|M|these patients, consider a starting dose of 5 mg/day and reduce weekly|
02204|022|M|dosage adjustments to half the normal increase.  Based on clinical response,|
02204|023|M|the dosage may be titrated to normal dosage levels based on weight group at|
02204|024|M|Day 21.(1)|
02204|025|M|   When initiating a moderate inhibitor of CYP2C19 in a patient maintained|
02204|026|M|on clobazam monitor for increased effects from clobazam until inhibitor|
02204|027|M|concentration reaches steady-state and adjust dose accordingly.(1-4)|
02204|028|B||
02204|029|D|DISCUSSION:  The active metabolite of clobazam, N-desmethylclobazam, is|
02204|030|D|metabolized by CYP2C19.  Levels of N-desmethylclobazam are 3-5 times higher|
02204|031|D|in poor metabolizers of CYP2C19 and 2 times higher in intermediate|
02204|032|D|metabolizers of CYP2C19.  Thus, moderate inhibitors of CYP2C19 are expected|
02204|033|D|to result in a 2-fold or higher increase in levels of N-desmethylclobazam as|
02204|034|D|well.(1)|
02204|035|D|   Selected moderate inhibitors of CYP2C19 include: abrocitinib,|
02204|036|D|cannabidiol, cenobamate, fluoxetine, moclobemide, and voriconazole.(5)|
02204|037|D|   One or more of the drug pairs linked to this monograph have been included|
02204|038|D|in a list of interactions that could be considered for classification as|
02204|039|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
02204|040|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
02204|041|D|Health Information Technology.|
02204|042|B||
02204|043|R|REFERENCES:|
02204|044|B||
02204|045|R|1.Onfi (clobazam) US prescribing information. Lundbeck, Inc. February, 2021.|1
02204|046|R|2.Carreno M, Gil-Nagel A, Serratosa JM, Toledo M, Rodriguez-Uranga JJ,|6
02204|047|R|  Villanueva V. Spanish consensus on the management of concomitant|6
02204|048|R|  antiseizure medications when using cenobamate in adults with|6
02204|049|R|  drug-resistant focal seizures. Epilepsia Open 24 March 2024;9:1051 - 1058.|6
02204|050|R|3.Villani F, Cianci V, Di Bonaventura C, Di Gennaro G, Galimberti CA,|6
02204|051|R|  Guerrini R, La Neve A, Mecarelli O, Pietrafusa N, Specchio N, Vigevano F,|6
02204|052|R|  Perucca E. Use of cenobamate for the treatment of focal epilepsy: an|6
02204|053|R|  Italian expert opinion paper. Expert Rev Neurother 24 Jan 2023;|6
02204|054|R|  22(11-12):935-940.|6
02204|055|R|4.Smith MC, Klein P, Krauss GL, Rashid S, Seiden LG, Stern JM, Rosenfeld WE.|6
02204|056|R|  Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate|6
02204|057|R|  Treatment: Expert Opinion Consensus Recommendations. Neurol Ther 3|6
02204|058|R|  September 2022;11:1705-1720.|6
02204|059|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02204|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02204|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02204|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02204|063|R|  11/14/2017.|1
02204|064|R|6.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
02204|065|R|  Middleton B, Bates DW. Drug-drug interactions that should be|6
02204|066|R|  non-interruptive in order to reduce alert fatigue in electronic health|6
02204|067|R|  records. J Am Med Inform Assoc 2012 Sep 25.|6
02205|001|T|MONOGRAPH TITLE:  Digoxin/Lapatinib|
02205|002|B||
02205|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02205|004|L|take action as needed.|
02205|005|B||
02205|006|A|MECHANISM OF ACTION:  Lapatinib may increase the absorption of digoxin by|
02205|007|A|inhibiting P-glycoprotein (P-gp).(1)|
02205|008|B||
02205|009|E|CLINICAL EFFECTS:  Concurrent use of lapatinib may result in elevated levels|
02205|010|E|of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can include|
02205|011|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
02205|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
02205|013|E|disturbances, and arrhythmias.|
02205|014|B||
02205|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02205|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02205|017|P|risk of digoxin toxicity.|
02205|018|B||
02205|019|M|PATIENT MANAGEMENT:  Monitor digoxin concentrations before and during the|
02205|020|M|administration of lapatinib.  If digoxin serum concentration is greater than|
02205|021|M|1.2 ng/ml, reduce the dosage of digoxin by one-half during concurrent|
02205|022|M|therapy.(1)|
02205|023|M|   The manufacturer of digoxin recommends decreasing the dose of digoxin by|
02205|024|M|approximately 30-50% or by modifying the dosing frequency to reduce digoxin|
02205|025|M|concentrations.(2)|
02205|026|B||
02205|027|D|DISCUSSION:  Concurrent lapatinib increased the area-under-curve (AUC) of|
02205|028|D|oral digoxin by 2.8-fold.(1)|
02205|029|D|   Concurrent lapatinib administration increased digoxin AUC 180%. (2)|
02205|030|B||
02205|031|R|REFERENCES:|
02205|032|B||
02205|033|R|1.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
02205|034|R|  2018.|1
02205|035|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
02205|036|R|  Pharmaceuticals, Inc. August, 2018.|1
02206|001|T|MONOGRAPH TITLE:  Aliskiren/ACE Inhibitors; ARBs|
02206|002|B||
02206|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02206|004|L|of severe adverse interaction.|
02206|005|B||
02206|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02206|007|B||
02206|008|E|CLINICAL EFFECTS:  In the ALTITUDE study, concurrent use of aliskiren for|
02206|009|E|18-24 months in patients maintained on either an ACE inhibitor or an ARB|
02206|010|E|resulted in an increase in non-fatal stroke, renal complications,|
02206|011|E|hyperkalemia, and hypotension.(1,2)|
02206|012|B||
02206|013|P|PREDISPOSING FACTORS:  Patients with Type II diabetes and/or renal|
02206|014|P|impairment may be at a higher risk from this combination.(1)|
02206|015|B||
02206|016|M|PATIENT MANAGEMENT:  Novartis no longer recommends the concurrent use of|
02206|017|M|aliskiren with either an ACE inhibitor or an ARB.(1,3)  Hypertension|
02206|018|M|regimens of patients receiving concurrent therapy should be re-evaluated.(1)|
02206|019|M|   Concurrent use of aliskiren in diabetic patients receiving either an ACE|
02206|020|M|inhibitor or an ARB is contraindicated.(2,4)  Avoid the combination in|
02206|021|M|patients with CrCl less than 60 ml/min.(5)|
02206|022|B||
02206|023|D|DISCUSSION:  ALTITUDE was a multinational study designed to evaluate the use|
02206|024|D|of aliskiren for more than 1 year in patients with Type II diabetes and|
02206|025|D|renal impairment, who are known to have a high risk for cardiovascular and|
02206|026|D|renal events.  Aliskiren was given with optimal cardiovascular treatment,|
02206|027|D|including an ACE inhibitor or ARB. After 18-24 months of concurrent therapy|
02206|028|D|with aliskiren and either an ACE inhibitor or an ARB, there was an increase|
02206|029|D|in non-fatal stroke, renal complications, hyperkalemia, and|
02206|030|D|hypotension.(1,2)|
02206|031|B||
02206|032|R|REFERENCES:|
02206|033|B||
02206|034|R|1.Anonymous. Novartis announces termination of ALTITUDE study with|1
02206|035|R|  Rasilez/Tekturna in high-risk patients with diabetes and renal impairment.|1
02206|036|R|  available at:|1
02206|037|R|  https://www.fiercepharma.com/pharma/novartis-announces-termination-of-alti|1
02206|038|R|  tude-study-rasilez%C2%AE-tekturna%C2%AE-high-risk-patients December, 20,|1
02206|039|R|  2011.|1
02206|040|R|2.USFood and Drug Administration. FDA Drug Safety Communication: New Warning|1
02206|041|R|  and Contraindication for blood pressure medicines containing aliskiren|1
02206|042|R|  (Tekturna). available at:|1
02206|043|R|  http://www.fda.gov/Drugs/DrugSafety/ucm300889.htm April 20, 2012.|1
02206|044|R|3.Health Canada. Rasilez (aliskiren): Health Canada reviewing safety of|1
02206|045|R|  blood-pressure drug. available at:|1
02206|046|R|  http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2011/1357|1
02206|047|R|  2a-eng.php December 22, 2011.|1
02206|048|R|4.Leclerc JM. Dear Canadian Healthcare Professional letter:  Subject:|1
02206|049|R|  Potential risks of cardiovascular and renal adverse events in patients|1
02206|050|R|  with type 2 diabetes treated with aliskiren (RASILEZ) or|1
02206|051|R|  aliskiren/hydrochlorothiazide (RASILEZ HCT). Novartis January 18, 2012.|1
02206|052|R|5.Zestril (lisinopril) US prescribing information. AstraZeneca|1
02206|053|R|  Pharmaceuticals LP July 21, 2017.|1
02207|001|T|MONOGRAPH TITLE:  Clopidogrel/Selected Proton Pump Inhibitors (mono deleted|
02207|002|T|12/30/2015)|
02207|003|B||
02207|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02207|005|L|take action as needed.|
02207|006|B||
02207|007|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
02207|008|A|active metabolite via a 2 step process. The first conversion step is|
02207|009|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
02207|010|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  As CYP2C19 contributes to both steps, it|
02207|011|A|is thought to be the more important enzyme involved in formation of the|
02207|012|A|pharmacologically active metabolite.  In pharmacogenomic studies and|
02207|013|A|clinical trials, CYP2C19 poor metabolizers have decreased active metabolite|
02207|014|A|exposure, diminished antiplatelet effects and a higher rate of|
02207|015|A|cardiovascular events compared with extensive metabolizers.(1-6,18)|
02207|016|A|   Proton pump inhibitors(PPIs) may inhibit CYP2C19 mediated conversion to|
02207|017|A|the active metabolite of clopidogrel. The magnitude and clinical|
02207|018|A|significance of CYP2C19 inhibition is highly variable between|
02207|019|A|agents.(1,2,7-10,15)|
02207|020|B||
02207|021|E|CLINICAL EFFECTS:  Concurrent use of proton pump inhibitors (PPIs) may|
02207|022|E|result in decreased clopidogrel effectiveness, resulting in increased risk|
02207|023|E|of adverse cardiac events.  Dexlansoprazole, lansoprazole, pantoprazole and|
02207|024|E|rabeprazole appear to have a lower interaction risk than esomeprazole and|
02207|025|E|omeprazole.(2,7-10,24)|
02207|026|B||
02207|027|P|PREDISPOSING FACTORS:  Patients with CYP2C19 poor metabolizer genotype would|
02207|028|P|not be susceptible to this interaction.  However, as noted in the FDA boxed|
02207|029|P|warning, poor metabolizers have an inherently a higher risk for clopidogrel|
02207|030|P|treatment failure than patients with extensive metabolizer status.(2,16)|
02207|031|B||
02207|032|M|PATIENT MANAGEMENT:  Evaluate patient risk for gastrointestinal(GI)|
02207|033|M|bleeding.  Consider the use of H2 blockers (such as famotidine, nizatidine,|
02207|034|M|or ranitidine) in patients with a low bleeding risk and reserve the use of|
02207|035|M|PPIs for patients at higher risk of GI bleeding.  Dexlansoprazole,|
02207|036|M|lansoprazole, pantoprazole and rabeprazole have lower interaction risk and|
02207|037|M|are preferred when PPIs are needed.(2,7-10,24)|
02207|038|B||
02207|039|D|DISCUSSION:  US manufacturer product information (PI) for clopidogrel states|
02207|040|D|omeprazole and esomeprazole have been shown to reduce antiplatelet activity|
02207|041|D|of clopidogrel and recommends against concomitant use.  Dexlansoprazole,|
02207|042|D|lansoprazole and pantoprazole are described as having less effect on|
02207|043|D|clopidogrel antiplatelet activity.(2)|
02207|044|D|   The US manufacturer for both dexlansoprazole and lansoprazole performed a|
02207|045|D|study of healthy subjects who received either clopidogrel 75mg alone, with|
02207|046|D|concomitant lansoprazole 30mg, or with dexlansoprazole 60mg, for nine days.|
02207|047|D|The mean area under the curve (AUC) for the active metabolite of clopidogrel|
02207|048|D|was reduced 14% (90% confidence interval of 8 to 20%) in the lansoprazole|
02207|049|D|group and 9% (90% confidence interval of 3 to 14%) in the dexlansoprazole|
02207|050|D|group when compared with clopidogrel alone.  Measured changes in platelet|
02207|051|D|aggregation were related to changes in exposure to clopidogrel active|
02207|052|D|metabolite.  PIs for each drug state that adjustment of the clopidogrel dose|
02207|053|D|is not necessary when FDA approved doses of dexlansoprazole or lansoprazole|
02207|054|D|are used.(9,10)|
02207|055|D|   In the primary literature, documentation for this interaction is|
02207|056|D|conflicting. Both in-vitro and retrospective analyses indicate that|
02207|057|D|omeprazole decreases the effectiveness of clopidogrel.  While in-vitro|
02207|058|D|studies may indicate that other proton-pump inhibitors (PPIs) do not inhibit|
02207|059|D|clopidogrel antiplatelet effects, retrospective outcomes reviews have|
02207|060|D|indicated an increase risk of myocardial infarction and/or coronary stent|
02207|061|D|replacement with concurrent use of clopidogrel and these agents.  However,|
02207|062|D|in many retrospective studies, the baseline severity of illness was greater|
02207|063|D|in patients receiving PPIs than patients receiving clopidogrel alone.|
02207|064|D|Statistical adjustment for disease severity may not be adequate to correct|
02207|065|D|for this potential confounder.|
02207|066|D|   In a study in patients with coronary artery disease, esomeprazole and|
02207|067|D|pantoprazole had no effects on platelet response to clopidogrel.(11)|
02207|068|D|   In a study of 1000 patients scheduled for angioplasty, platelet|
02207|069|D|aggregation was significantly higher in patients receiving omeprazole than|
02207|070|D|in patients not receiving a PPI.  Platelet aggregation was similar in|
02207|071|D|patients receiving esomeprazole, pantoprazole, or no PPI.(12)|
02207|072|D|   In a prospective, randomized study of 104 patients undergoing PCI,|
02207|073|D|testing one month after the procedure found better platelet response in|
02207|074|D|patients receiving concurrent clopidogrel and pantoprazole compared with|
02207|075|D|patients receiving concurrent clopidogrel and omeprazole.(13)|
02207|076|D|   In a study of 1425 patients undergoing coronary stent placement who|
02207|077|D|received clopidogrel, residual platelet aggregation was significantly higher|
02207|078|D|in patients receiving PPIs.  There was no significant difference between|
02207|079|D|PPIs (esomeprazole, n=108; omeprazole, n=36; pantoprazole, n=280).(14)|
02207|080|D|   Four randomized, placebo-controlled studies in 282 healthy subjects|
02207|081|D|examined the effects of simultaneous omeprazole (80 mg) on clopidogrel (300|
02207|082|D|mg loading dose, 75 mg daily), omeprazole (80 mg) 12 hours apart from|
02207|083|D|clopidogrel(300 mg loading dose, 75 mg daily), omeprazole (80 mg) with|
02207|084|D|clopidogrel (600 mg loading dose, 150 mg daily), and pantoprazole (80 mg) on|
02207|085|D|clopidogrel (300 mg loading dose, 75 mg daily).  Compared with|
02207|086|D|administration of clopidogrel without PPI, the AUC of the active clopidogrel|
02207|087|D|metabolite was reduced by 40%, 47%, 41%, and 14%, respectively, by the|
02207|088|D|different therapy combinations.(15)|
02207|089|D|   A retrospective review of post-stent patients compared patients who took|
02207|090|D|clopidogrel with a PPI (n=4521, exact agent not specified) to patients who|
02207|091|D|took clopidogrel without a PPI.  Stent patients without a preceding|
02207|092|D|cardiovascular event who took a PPI had a 32.5% incidence of a major|
02207|093|D|cardiovascular event within one year of stent placement compared to a 21.2%|
02207|094|D|incidence in patients not receiving a PPI.  Stent patients with a preceding|
02207|095|D|cardiovascular event who took a PPI had a 39.8% incidence of a major|
02207|096|D|cardiovascular event within one year of stent placement compared to a 26.2%|
02207|097|D|incidence in patients not receiving a PPI.(19)  In an expansion of this|
02207|098|D|study, 6828 patients who received clopidogrel with a PPI were compared to|
02207|099|D|the 9862 patients who took clopidogrel without a PPI.  In the clopidogrel|
02207|100|D|without a PPI group, 17.9% experienced a cardiovascular event compared with|
02207|101|D|25.0% who received a PPI (adjusted odds ratio 1.51).  Similar effects were|
02207|102|D|noted with each PPI: esomeprazole, lansoprazole, omeprazole, and|
02207|103|D|pantoprazole.(18)|
02207|104|D|   In a retrospective cohort study of 13,636 patients who received|
02207|105|D|clopidogrel following an acute myocardial infarction, concurrent use of a|
02207|106|D|PPI other than pantoprazole (exact PPI not specified) was associated with an|
02207|107|D|increased risk of reinfarction.(19)|
02207|108|D|   A retrospective review of claims data matched 1033 patients receiving|
02207|109|D|clopidogrel with a PPI (esomeprazole, n=46; lansoprazole, n=83; omeprazole,|
02207|110|D|n=86; pantoprazole, n=659; rabeprazole, n=159) with 1033 patients receiving|
02207|111|D|clopidogrel without a PPI.  Patients receiving a PPI had a higher risk of|
02207|112|D|rehospitalization for a myocardial infarction (adjusted hazard ratio 1.93,|
02207|113|D|p=0.03) and a higher risk of rehospitalization for a myocardial infarction|
02207|114|D|or a coronary stent procedure (adjusted hazard ratio 1.64, p=0.005).  In a|
02207|115|D|subanalysis of patients receiving pantoprazole, patients receiving|
02207|116|D|pantoprazole had a higher risk of rehospitalization for myocardial|
02207|117|D|infarction or coronary stent placement (adjusted hazard ratio 1.91,|
02207|118|D|p=0.008).(20)|
02207|119|D|   In a retrospective review of patients who had undergone PCI, patients who|
02207|120|D|received clopidogrel with a PPI (total n=318; esomeprazole, n=185;|
02207|121|D|lansoprazole, n=41; omeprazole, n=41; pantoprazole, n=35; rabeprazole, n=16)|
02207|122|D|had a higher risk of major adverse cardiac event (p=0.007), target vessel|
02207|123|D|revascularization (p=0.08), and death (p=0.02) compared to match controls|
02207|124|D|who received clopidogrel without a PPI.  There were no significant|
02207|125|D|differences between PPIs.(21)|
02207|126|D|   A retrospective study of 20,596 patients in the Tennessee Medicaid|
02207|127|D|program, evaluated both cardiovascular disease event and GI bleed risk in|
02207|128|D|patients prescribed clopidogrel with or without concurrent PPI use.|
02207|129|D|Pantoprazole was prescribed in 62% of PPI patients. Concomitant PPI and|
02207|130|D|clopidogrel use decreased the risk of hospitalization from GI bleeding by|
02207|131|D|50%. There was no clear-cut increase risk for serious cardiovascular disease|
02207|132|D|events; however, the 95% CI for this was wide.(22)|
02207|133|D|   A post-hoc analysis of the PRINCIPLE-TIMI 44 trial and the TRITON-TIMI|
02207|134|D|trial examined the effects of PPI use on the pharmacodynamic effects and|
02207|135|D|clinical efficacy of clopidogrel.  The PRINCIPLE-TIMI 44 trial examined 201|
02207|136|D|patients undergoing cardiac catheterization with planned percutaneous|
02207|137|D|coronary intervention, 53 of which were taking a PPI at randomization.|
02207|138|D|Patients receiving a PPI had significantly lower rates of inhibition of|
02207|139|D|platelet aggregation at 0.5 hours, 2 hours, 6 hours, and 18-24 hours|
02207|140|D|post-loading dose of clopidogrel.  After 15 days of maintenance therapy,|
02207|141|D|there were significantly more non-responders in the group receiving PPI (50%|
02207|142|D|versus 7.9%).  The TRITON-TIMI trial examined 13,608 patients who underwent|
02207|143|D|cardiac catheterization with planned percutaneous coronary intervention,|
02207|144|D|4529 of which were taking a PPI at randomization.  Records indicated 1844|
02207|145|D|were on pantoprazole, 1675 on omeprazole, 613 on lansoprazole and 66 on|
02207|146|D|rabeprazole.    Patients received clopidogrel treatment for 6-15 months.|
02207|147|D|There were no significant differences in occurrence of cardiovascular death,|
02207|148|D|non-fatal MI, or non-fatal stroke between patients taking PPIs at|
02207|149|D|randomization and those not; however, use of PPIs was only assessed at|
02207|150|D|randomization and not during the study.(23)|
02207|151|B||
02207|152|R|REFERENCES:|
02207|153|B||
02207|154|R|1.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
02207|155|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
02207|156|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
02207|157|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
02207|158|R|  38(1):92-9.|5
02207|159|R|2.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
02207|160|R|  Squibb/Sanofi Pharmaceuticals Partnership March, 2015.|1
02207|161|R|3.US Food and Drug Association. Information on Clopidogrel Bisulfate|1
02207|162|R|  (marketed as Plavix). Available at:|1
02207|163|R|  http://wayback.archive-it.org/7993/20170111075953/http:/www.fda.gov/Drugs/|1
02207|164|R|  DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm19083|1
02207|165|R|  6.htm October 27, 2010.|1
02207|166|R|4.Luria X. Public Statement:  Interaction between clopidogrel and|1
02207|167|R|  proton-pump inhibitors. CHMP updates warning for clopidogrel-containing|1
02207|168|R|  medicines. European Medicines Agency.  Available at:|1
02207|169|R|  http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2010|1
02207|170|R|  /03/WC500076346.pdf March 17, 2010.|1
02207|171|R|5.Jacobs LD, Shulman HM. Dear Canadian Healthcare Professional:  Subject:|1
02207|172|R|  Potential interaction of Proton Pump Inhibitors (PPIs) with Plavix|1
02207|173|R|  (clopidogrel). Sanofi-Aventis Canada Inc. and Bristol Myers Squibb Canada|1
02207|174|R|  Co. August 14, 2009.|1
02207|175|R|6.Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP,|2
02207|176|R|  Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot|2
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02207|178|R|  MS. Reduced-function CYP2C19 genotype and risk of adverse clinical|2
02207|179|R|  outcomes among patients treated with clopidogrel predominantly for PCI: a|2
02207|180|R|  meta-analysis. JAMA 2010 Oct 27;304(16):1821-30.|2
02207|181|R|7.Ogilvie BW, Yerino P, Kazmi F, Buckley DB, Rostami-Hodjegan A, Paris BL,|5
02207|182|R|  Toren P, Parkinson A. The proton pump inhibitor, omeprazole, but not|5
02207|183|R|  lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of|5
02207|184|R|  CYP2C19: implications for coadministration with clopidogrel. Drug Metab|5
02207|185|R|  Dispos 2011 Nov;39(11):2020-33.|5
02207|186|R|8.Protonix (pantoprazole sodium) US prescribing information. Wyeth|1
02207|187|R|  Pharmaceuticals, Inc. August, 2024.|1
02207|188|R|9.Prevacid (lansoprazole) US prescribing information. Takeda Pharmaceuticals|1
02207|189|R|  America, Inc. December, 2014.|1
02207|190|R|10.Dexilant (dexlansoprazole) US prescribing information. Takeda|1
02207|191|R|   Pharmaceuticals North America, Inc. September, 2012.|1
02207|192|R|11.Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B.|2
02207|193|R|   Effects of pantoprazole and esomeprazole on platelet inhibition by|2
02207|194|R|   clopidogrel. Am Heart J 2009 Jan;157(1):148.e1-5.|2
02207|195|R|12.Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, Schomig|2
02207|196|R|   A, Kastrati A, von Beckerath N. Impact of proton pump inhibitors on the|2
02207|197|R|   antiplatelet effects of clopidogrel. Thromb Haemost 2009 Apr;|2
02207|198|R|   101(4):714-9.|2
02207|199|R|13.Cuisset T, Frere C, Quilici J, Poyet R, Gaborit B, Bali L, Brissy O,|2
02207|200|R|   Morange PE, Alessi MC, Bonnet JL. Comparison of omeprazole and|2
02207|201|R|   pantoprazole influence on a high 150-mg clopidogrel maintenance dose the|2
02207|202|R|   PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective|2
02207|203|R|   randomized study. J Am Coll Cardiol 2009 Sep 22;54(13):1149-53.|2
02207|204|R|14.Zuern CS, Geisler T, Lutilsky N, Winter S, Schwab M, Gawaz M. Effect of|2
02207|205|R|   comedication with proton pump inhibitors (PPIs) on post-interventional|2
02207|206|R|   residual platelet aggregation in patients undergoing coronary stenting|2
02207|207|R|   treated by dual antiplatelet therapy. Thromb Res 2010 Feb;125(2):e51-4.|2
02207|208|R|15.Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L,|2
02207|209|R|   Perrin L, Lacreta FP, Hurbin F, Dubar M. Differential Effects of|2
02207|210|R|   Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics|2
02207|211|R|   of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled,|2
02207|212|R|   Crossover Comparison Studies. Clin Pharmacol Ther 2010 Sep.|2
02207|213|R|16.Furuta T, Iwaki T, Umemura K. Influences of different proton pump|2
02207|214|R|   inhibitors on the anti-platelet function of clopidogrel in relation to|2
02207|215|R|   CYP2C19 genotypes. Br J Clin Pharmacol 2010 Sep;70(3):383-92.|2
02207|216|R|17.Aubert RE, Epstein RS, Teagarden JR, Xia F, Yao J, Desta Z, Skaar T,|2
02207|217|R|   Flockhart DA. Abstract 3998:  Proton pump inhibitiors effect on|2
02207|218|R|   clopidogrel effectiveness:  the clopidogrel Medco outcomes study.|2
02207|219|R|   Circulation 2008;118:S815.|2
02207|220|R|18.Kreutz RP, Stanek EJ, Aubert R, Yao J, Breall JA, Desta Z, Skaar TC,|2
02207|221|R|   Teagarden JR, Frueh FW, Epstein RS, Flockhart DA. Impact of proton pump|2
02207|222|R|   inhibitors on the effectiveness of clopidogrel after coronary stent|2
02207|223|R|   placement: the clopidogrel medco outcomes study. Pharmacotherapy 2010|2
02207|224|R|   Aug;30(8):787-96.|2
02207|225|R|19.Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp|2
02207|226|R|   A, Mamdani MM. A population-based study of the drug interaction between|2
02207|227|R|   proton pump inhibitors and clopidogrel.  Available at:|2
02207|228|R|   http://www.cmaj.ca/cgi/rapidpdf/cmaj.082001. CMAJ March 31, 2009;|2
02207|229|R|   180(7):online 1-7.|2
02207|230|R|20.Stockl KM, Le L, Zakharyan A, Harada AS, Solow BK, Addiego JE, Ramsey S.|2
02207|231|R|   Risk of rehospitalization for patients using clopidogrel with a proton|2
02207|232|R|   pump inhibitor. Arch Intern Med 2010 Apr 26;170(8):704-10.|2
02207|233|R|21.Gaglia MA Jr, Torguson R, Hanna N, Gonzalez MA, Collins SD, Syed AI,|2
02207|234|R|   Ben-Dor I, Maluenda G, Delhaye C, Wakabayashi K, Xue Z, Suddath WO, Kent|2
02207|235|R|   KM, Satler LF, Pichard AD, Waksman R. Relation of proton pump inhibitor|2
02207|236|R|   use after percutaneous coronary intervention with drug-eluting stents to|2
02207|237|R|   outcomes. Am J Cardiol 2010 Mar 15;105(6):833-8.|2
02207|238|R|22.Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Daugherty|2
02207|239|R|   JR, Kaltenbach LA, Stein CM. Outcomes with concurrent use of clopidogrel|2
02207|240|R|   and proton-pump inhibitors: a cohort study. Ann Intern Med 2010 Mar 16;|2
02207|241|R|   152(6):337-45.|2
02207|242|R|23.O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y,|2
02207|243|R|   Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL,|2
02207|244|R|   Sabatine MS, Wiviott SD. Pharmacodynamic effect and clinical efficacy of|2
02207|245|R|   clopidogrel and prasugrel with or without a proton-pump inhibitor: an|2
02207|246|R|   analysis of two randomised trials. Lancet 2009 Sep 19;374(9694):989-97.|2
02207|247|R|24.Aciphex (rabeprazole) prescribing information. Eisai Inc. July, 2017.|1
02208|001|T|MONOGRAPH TITLE:  Bleomycin/Brentuximab|
02208|002|B||
02208|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02208|004|L|is contraindicated and generally should not be dispensed or administered to|
02208|005|L|the same patient.|
02208|006|B||
02208|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02208|008|B||
02208|009|E|CLINICAL EFFECTS:  Concurrent use of brentuximab with bleomycin-based|
02208|010|E|chemotherapy regimens may result in non-infectious pulmonary toxicity.(1,2)|
02208|011|B||
02208|012|P|PREDISPOSING FACTORS:  None determined.|
02208|013|B||
02208|014|M|PATIENT MANAGEMENT:  Concurrent use of brentuximab with bleomycin-based|
02208|015|M|chemotherapy regimens is contraindicated.(1,2)|
02208|016|M|   In patients who have received concurrent therapy, monitor for signs of|
02208|017|M|pulmonary toxicity, including cough and dyspnea.  Patients with symptoms of|
02208|018|M|pulmonary toxicity may respond to corticosteroid therapy.(1,2)|
02208|019|B||
02208|020|D|DISCUSSION:  In a clinical trial that compared the use of brentuximab with|
02208|021|D|Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD) to|
02208|022|D|the use of brentuximab with Adriamycin (doxorubicin), vinblastine, and|
02208|023|D|dacarbazine (AVD), 40% of patients receiving brentuximab with ABVD|
02208|024|D|experienced pulmonary toxicity.  No patients receiving brentuximab with AVD|
02208|025|D|have experienced pulmonary toxicity to date.  Historical controls suggest a|
02208|026|D|frequency of pulmonary toxicity of 10-25% in bleomycin-based regimens.(1)|
02208|027|B||
02208|028|R|REFERENCES:|
02208|029|B||
02208|030|R|1.USFood and Drug Administration. FDA Drug Safety Communication: New Boxed|1
02208|031|R|  Warning and Contraindication for Adcetris (brentuximab vedotin). available|1
02208|032|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm287668.htm January 13, 2012.|1
02208|033|R|2.Adcetris (brentuximab) US prescribing information. Seattle Genetics, Inc.|1
02208|034|R|  November, 2018.|1
02209|001|T|MONOGRAPH TITLE:  Buspirone/Rifampin (mono deleted 08/20/2015)|
02209|002|B||
02209|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02209|004|L|take action as needed.|
02209|005|B||
02209|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of buspirone by|
02209|007|A|CYP3A4.(1,2)|
02209|008|B||
02209|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifampin may result in|
02209|010|E|decreased buspirone effectiveness.(1)|
02209|011|B||
02209|012|P|PREDISPOSING FACTORS:  None determined.|
02209|013|B||
02209|014|M|PATIENT MANAGEMENT:  Monitor response to buspirone in patients taking|
02209|015|M|concurrent rifampin.  The dosage of buspirone may need to be increased|
02209|016|M|during and for 2 weeks following the conclusion of rifampin therapy.|
02209|017|B||
02209|018|D|DISCUSSION:  In a randomized, placebo-controlled, cross-over study in 10|
02209|019|D|subjects, rifampin (600 mg daily) decreased buspirone (30 mg single dose)|
02209|020|D|maximum concentration (Cmax), area-under-curve (AUC), and half-life by|
02209|021|D|89.6%, 83.7%, and 54%, respectively.  During the placebo phase, all subjects|
02209|022|D|had measurable plasma buspirone concentrations at 10 hours after|
02209|023|D|administration; however, no subject had measurable plasma buspirone|
02209|024|D|concentrations at 6 hours after administration during the rifampin phase.(1)|
02209|025|D|The Cmax of the buspirone piperazine metabolite increased by 35%.(2)  There|
02209|026|D|were significant decreases in the effects of buspirone in the postural sway|
02209|027|D|test with eyes closed, the visual analogue scale (VAS) test for subjective|
02209|028|D|drowsiness, and the VAS test for overall drug effect during concurrent|
02209|029|D|rifampin.  Buspirone side effects were reported more often during the|
02209|030|D|placebo phase.(1)|
02209|031|B||
02209|032|R|REFERENCES:|
02209|033|B||
02209|034|R|1.Lamberg TS, Kivisto KT, Neuvonen PJ. Concentrations and effects of|2
02209|035|R|  buspirone are considerably reduced by rifampicin. Br J Clin Pharmacol 1998|2
02209|036|R|  Apr;45(4):381-5.|2
02209|037|R|2.Kivisto KT, Lamberg TS, Neuvonen PJ. Interactions of buspirone with|2
02209|038|R|  itraconazole and rifampicin: effects on the pharmacokinetics of the active|2
02209|039|R|  1-(2-pyrimidinyl)-piperazine metabolite of buspirone. Pharmacol Toxicol|2
02209|040|R|  1999 Feb;84(2):94-7.|2
02210|001|T|MONOGRAPH TITLE:  Bupropion/Moderate CYP2B6 Inducers|
02210|002|B||
02210|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02210|004|L|take action as needed.|
02210|005|B||
02210|006|A|MECHANISM OF ACTION:  Moderate CYP2B6 inducers may induce the metabolism of|
02210|007|A|bupropion.(1)|
02210|008|B||
02210|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP2B6 inducers may decrease|
02210|010|E|the effectiveness of bupropion.(1)|
02210|011|B||
02210|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02210|013|P|of the inducer for longer than 1-2 weeks.|
02210|014|B||
02210|015|M|PATIENT MANAGEMENT:  Consider the use of alternative agents in patients|
02210|016|M|maintained on bupropion for psychiatric indications and inform patients that|
02210|017|M|bupropion may not be effective for smoking cessation during concurrent|
02210|018|M|moderate CYP2B6 inducers.|
02210|019|M|   If concurrent use is warranted, monitor patients for decreased levels and|
02210|020|M|effectiveness if moderate CYP2B6 inducers are initiated.  The dosage of|
02210|021|M|bupropion may need to be increased; however, the maximum recommended dose of|
02210|022|M|bupropion should not be exceed.(2)|
02210|023|B||
02210|024|D|DISCUSSION:  In a study in 16 healthy subjects, rifampin (600 mg/day, a|
02210|025|D|moderate CYP2B6 inducer) increased bupropion (150 mg single dose) apparent|
02210|026|D|clearance 2-fold and decreased the bupropion half-life by 48%.  In addition,|
02210|027|D|concurrent rifampin increased the maximum concentration (Cmax) of|
02210|028|D|hydroxybupropion by 43% and decreased the hydroxybupropion area-under-curve|
02210|029|D|(AUC) by 38%.(2)|
02210|030|D|   In a study with 34 subjects, the effects of 150 mg of bupropion alone and|
02210|031|D|150 mg of bupropion with carbamazepine (a strong CYP2B6 inducer) were|
02210|032|D|compared. Carbamazepine decreased bupropion AUC by 90% and peak Cmax by 87%.|
02210|033|D|In addition, hydroxybupropion peak concentration Cmax by 71% and AUC by|
02210|034|D|50%.(3)|
02210|035|D|   Moderate CYP2B6 inducers linked include: dipyrone, efavirenz, rifampin,|
02210|036|D|and ritonavir.(4,5)|
02210|037|B||
02210|038|R|REFERENCES:|
02210|039|B||
02210|040|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
02210|041|R|  GlaxoSmithKline November, 2019.|1
02210|042|R|2.Loboz KK, Gross AS, Williams KM, Liauw WS, Day RO, Blievernicht JK, Zanger|2
02210|043|R|  UM, McLachlan AJ. Cytochrome P450 2B6 activity as measured by bupropion|2
02210|044|R|  hydroxylation: effect of induction by rifampin and ethnicity. Clin|2
02210|045|R|  Pharmacol Ther 2006 Jul;80(1):75-84.|2
02210|046|R|3.Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George|2
02210|047|R|  MS, Callahan AM, Hinton ML, Chao J, Post RM. Carbamazepine but not|2
02210|048|R|  valproate induces bupropion metabolism. J Clin Psychopharmacol 1995 Oct;|2
02210|049|R|  15(5):327-33.|2
02210|050|R|4.This information is based on an extract from the Certara Drug Interaction|6
02210|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02210|052|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02210|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02210|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02210|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02210|056|R|  11/14/2017.|1
02211|001|T|MONOGRAPH TITLE:  Cobimetinib/Strong & Moderate CYP3A4 Inducers|
02211|002|B||
02211|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02211|004|L|of severe adverse interaction.|
02211|005|B||
02211|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
02211|007|A|metabolism of cobimetinib.(1)|
02211|008|B||
02211|009|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
02211|010|E|decrease the levels and effectiveness of cobimetinib.(1)|
02211|011|B||
02211|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02211|013|P|of the inducer for longer than 1-2 weeks.|
02211|014|B||
02211|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong or moderate CYP3A4|
02211|016|M|inducers in patients receiving therapy with cobimetinib.(1)  Consider the|
02211|017|M|use of alternatives with little to no induction potential.|
02211|018|B||
02211|019|D|DISCUSSION:  Based upon simulations, coadministration of cobimetinib with a|
02211|020|D|strong CYP3A4 inducer may decrease cobimetinib exposure by 83%, with a|
02211|021|D|moderate CYP3A4 inducer by 73%, leading to a reduction in efficacy.(1)|
02211|022|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
02211|023|D|carbamazepine, cenobamate, encorafenib, enzalutamide, ivosidenib,|
02211|024|D|lorlatinib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
02211|025|D|rifabutin, rifampin, rifapentine, and St. John's wort.|
02211|026|D|   Moderate inducers of CYP3A4 include: bosentan, dabrafenib, efavirenz,|
02211|027|D|elagolix, etravirine, lesinurad, mavacamten, mitapivat, modafinil,|
02211|028|D|nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat|
02211|029|D|ethyl, thioridazine, and tovorafenib.(1-3)|
02211|030|B||
02211|031|R|REFERENCES:|
02211|032|B||
02211|033|R|1.Cotellic (cobimetinib) US prescribing information. Genentech, Inc.|1
02211|034|R|  October, 2022.|1
02211|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02211|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02211|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02211|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02211|039|R|  11/14/2017.|1
02211|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
02211|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02212|001|T|MONOGRAPH TITLE:  Levoleucovorin; Leucovorin/Glucarpidase|
02212|002|B||
02212|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02212|004|L|take action as needed.|
02212|005|B||
02212|006|A|MECHANISM OF ACTION:  Glucarpidase hydrolyzes the carboxyl-terminal|
02212|007|A|glutamate residue from folates such as leucovorin, rendering them|
02212|008|A|inactive.(1)|
02212|009|B||
02212|010|E|CLINICAL EFFECTS:  A leucovorin dose given near the time of glucarpidase|
02212|011|E|administration may not be effective.|
02212|012|B||
02212|013|P|PREDISPOSING FACTORS:  Leucovorin dose given within two hours of|
02212|014|P|glucarpidase administration.|
02212|015|B||
02212|016|M|PATIENT MANAGEMENT:  The combination of glucarpidase and leucovorin are used|
02212|017|M|to treat toxic concentrations of methotrexate. Patients with potentially|
02212|018|M|life threatening methotrexate serum levels or toxicity must receive both|
02212|019|M|drugs.  However, in addition to inactivating methotrexate, glucarpidase also|
02212|020|M|inactivates leucovorin.|
02212|021|M|   To help decrease leucovorin inactivation, stagger leucovorin|
02212|022|M|administration so it is not given within two hours of glucarpidase dose.|
02212|023|M|Continue leucovorin treatment based upon pre-glucarpidase methotrexate blood|
02212|024|M|levels.(1)|
02212|025|M|   Note that depending upon the laboratory assay used, glucarpidase|
02212|026|M|administration may cause erroneous methotrexate measurements for 48 hours|
02212|027|M|post dose.(1)|
02212|028|B||
02212|029|D|DISCUSSION:  In a study of cancer patients treated with a high dose|
02212|030|D|methotrexate and leucovorin rescue regimen, glucarpidase given two hours|
02212|031|D|before leucovorin reduced the area-under-curve (AUC) of the active|
02212|032|D|leucovorin metabolite, 5-methyltetrahydrofolate, by 92 per cent.(1)|
02212|033|B||
02212|034|R|REFERENCE:|
02212|035|B||
02212|036|R|1.Voraxaze (glucarpidase) US prescribing information. BTG International Inc.|1
02212|037|R|  August, 2019.|1
02213|001|T|MONOGRAPH TITLE:  Ivacaftor/Strong and Moderate CYP3A4 Inhibitors|
02213|002|B||
02213|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02213|004|L|of severe adverse interaction.|
02213|005|B||
02213|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may inhibit|
02213|007|A|the metabolism of ivacaftor.(1)|
02213|008|B||
02213|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inhibitor of|
02213|010|E|CYP3A4 may result in elevated levels of and toxicity from ivacaftor.(1)|
02213|011|B||
02213|012|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
02213|013|P|hepatic impairment.(1)|
02213|014|B||
02213|015|M|PATIENT MANAGEMENT:  In patients receiving concurrent strong CYP3A4|
02213|016|M|inhibitors such as boceprevir, ceritinib, clarithromycin, cobicistat,|
02213|017|M|conivaptan, idelalisib, indinavir, itraconazole, ketoconazole,|
02213|018|M|lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,|
02213|019|M|nirmatrelvir/ritonavir, posaconazole, ritonavir, saquinavir, telaprevir,|
02213|020|M|telithromycin, troleandomycin, tucatinib, or voriconazole, the dose of|
02213|021|M|ivacaftor should be reduced to one 150 mg tablet or one packet (25 mg if|
02213|022|M|body weight 5 kg to < 7 kg, 50 mg if body weight < 14 kg, 75 mg if weight|
02213|023|M|equal or > 14 kg) two times a week.(1)|
02213|024|M|   In patients receiving concurrent moderate CYP3A4 inhibitors such as|
02213|025|M|amprenavir, aprepitant, atazanavir, berotralstat, crizotinib, cyclosporine,|
02213|026|M|darunavir/ritonavir, diltiazem, dronedarone, erythromycin, fluconazole,|
02213|027|M|fosamprenavir, fosaprepitant, imatinib, isavuconazonium, ledipasvir,|
02213|028|M|netupitant, schisandra or verapamil, the dose of ivacaftor should be reduced|
02213|029|M|to one 150 mg tablet or one packet (25 mg if body weight 5 kg to < 7 kg, 50|
02213|030|M|mg if body weight < 14 kg, 75 mg if weight equal or > 14 kg) daily.(1)|
02213|031|M|   In patients who are less than 6 months of age, concurrent use of|
02213|032|M|ivacaftor with strong or moderate CYP3A4 inhibitors is not recommended.(1)|
02213|033|B||
02213|034|D|DISCUSSION:  Concurrent administration with ketoconazole (a strong inhibitor|
02213|035|D|of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1)|
02213|036|D|   Concurrent administration with fluconazole (a moderate inhibitor of|
02213|037|D|CYP3A4) increased ivacaftor area-under-curve (AUC) by 3-fold.(1)|
02213|038|D|   A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with|
02213|039|D|ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B),|
02213|040|D|and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4|
02213|041|D|of ivacaftor administration (study C).  In study A, B, and C, ivacaftor AUC|
02213|042|D|increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively,|
02213|043|D|with the addition of ritonavir.  Ivacaftor concentration maximum (Cmax) was|
02213|044|D|0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(2)|
02213|045|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02213|046|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
02213|047|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone,|
02213|048|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
02213|049|D|saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and|
02213|050|D|voriconazole.(3-5)|
02213|051|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
02213|052|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
02213|053|D|darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin,|
02213|054|D|fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
02213|055|D|imatinib, isavuconazonium, lenacapavir, letermovir, ledipasvir, netupitant,|
02213|056|D|nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan|
02213|057|D|and verapamil.(3-5)|
02213|058|B||
02213|059|R|REFERENCES:|
02213|060|B||
02213|061|R|1.Kalydeco (ivacaftor) US prescribing information. Vertex Pharmaceuticals|1
02213|062|R|  Incorporated May, 2023.|1
02213|063|R|2.Liddy AM, McLaughlin G, Schmitz S, D'Arcy DM, Barry MG. The|2
02213|064|R|  Pharmacokinetic Interaction between Ivacaftor and Ritonavir in Healthy|2
02213|065|R|  Volunteers. Br J Clin Pharmacol 2017 May 06.|2
02213|066|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02213|067|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02213|068|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02213|069|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02213|070|R|  11/14/2017.|1
02213|071|R|4.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
02213|072|R|  Indiana University School of Medicine.  Available at:|1
02213|073|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
02213|074|R|5.This information is based on an extract from the Certara Drug Interaction|6
02213|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02214|001|T|MONOGRAPH TITLE:  Ivacaftor/Strong CYP3A4 Inducers|
02214|002|B||
02214|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02214|004|L|of severe adverse interaction.|
02214|005|B||
02214|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02214|007|A|elexacaftor, tezacaftor, and ivacaftor.(1-3)|
02214|008|B||
02214|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
02214|010|E|may result in decreased levels and effectiveness of elexacaftor, tezacaftor,|
02214|011|E|and ivacaftor.(1-3)|
02214|012|B||
02214|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02214|014|P|of the inducer for longer than 1-2 weeks.|
02214|015|B||
02214|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inducers in patients|
02214|017|M|maintained on ivacaftor or the combination of|
02214|018|M|elexacaftor-tezacaftor-ivacaftor, tezacaftor-ivacaftor.(1-3)  Enzyme|
02214|019|M|induction may last for several weeks after discontinuation a CYP3A4 inducer.|
02214|020|B||
02214|021|D|DISCUSSION:  Concurrent administration with rifampin (a strong inducer of|
02214|022|D|CYP3A4) decreased ivacaftor area-under-curve (AUC) by 9-fold.(1)|
02214|023|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
02214|024|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02214|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02214|026|D|rifapentine and St. John's wort.(1-4)|
02214|027|B||
02214|028|R|REFERENCES:|
02214|029|B||
02214|030|R|1.Kalydeco (ivacaftor) US prescribing information. Vertex Pharmaceuticals|1
02214|031|R|  Incorporated May, 2023.|1
02214|032|R|2.Symdeko (tezacaftor/ivacaftor) US prescribing information. Vertex|1
02214|033|R|  Pharmaceuticals Incorporated December, 2019.|1
02214|034|R|3.Trikafta (elexacaftor, tezacaftor and ivacaftor tablets; ivacaftor|1
02214|035|R|  tablets) US prescribing information. Vertex Pharmaceuticals Incorporated|1
02214|036|R|  December, 2024.|1
02214|037|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02214|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02214|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02214|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02214|041|R|  11/14/2017.|1
02215|001|T|MONOGRAPH TITLE:  Chronic Opioids/Nalbuphine|
02215|002|B||
02215|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02215|004|L|of severe adverse interaction.|
02215|005|B||
02215|006|A|MECHANISM OF ACTION:  Nalbuphine antagonizes mu-opiate receptors.(1)  Other|
02215|007|A|opioids agonize mu-opiate receptors.|
02215|008|B||
02215|009|E|CLINICAL EFFECTS:  Concurrent use of nalbuphine with other opioids in opioid|
02215|010|E|dependent patients may result in withdrawal symptoms.  Concurrent use in|
02215|011|E|other patients may result in additive or decreased analgesia, decreased|
02215|012|E|opioid side effects, and/or renarcotization.|
02215|013|B||
02215|014|P|PREDISPOSING FACTORS:  Patients dependent on opioids or taking higher doses|
02215|015|P|of opioids may be more likely to experience withdrawal symptoms with|
02215|016|P|concurrent use.  In opioid naive patients, higher doses of nalbuphine may|
02215|017|P|result in decreased analgesic effects.|
02215|018|B||
02215|019|M|PATIENT MANAGEMENT:  Use nalbuphine with caution in patients maintained or|
02215|020|M|dependent on other opioids and monitor for signs of withdrawal.  In other|
02215|021|M|patients, also monitor for changes in analgesic effects.  If nalbuphine is|
02215|022|M|used to reverse opioid anesthesia, monitor patients for renarcotization.|
02215|023|B||
02215|024|D|DISCUSSION:  Nalbuphine has been successfully used as an adjunct to morphine|
02215|025|D|without decreasing analgesic effects.(2,3)  However, other studies reported|
02215|026|D|increased morphine requirements in patients who had initially received|
02215|027|D|nalbuphine.(4,5)|
02215|028|D|   Nalbuphine has been used to reverse fentanyl anesthesia;(8-13) however,|
02215|029|D|patients often required additional pain medication(5-7) and some studies|
02215|030|D|reported renarcotization after the effects of nalbuphine wore off.(9,10)|
02215|031|D|Nalbuphine has also been used to prevent epidural fentanyl,(13)|
02215|032|D|morphine(14-16), and hydromorphone induced pruritus;(17,18) however, one|
02215|033|D|study reported shortening of the duration of analgesia(16) and another|
02215|034|D|reported increased PCA demands.(17)|
02215|035|D|   In methadone-dependent subjects, administration of nalbuphine produced|
02215|036|D|withdrawal symptoms similar to naloxone.(19,20)  Administration of|
02215|037|D|nalbuphine to patients maintained on controlled-release morphine resulted in|
02215|038|D|withdrawal symptoms.(20,21)|
02215|039|B||
02215|040|R|REFERENCES:|
02215|041|B||
02215|042|R|1.Nubain (nalbuphine hydrochloride) US prescribing information. Endo|1
02215|043|R|  Pharmaceuticals Inc. October, 2019.|1
02215|044|R|2.Wang JJ, Ho ST, Hu OY. Comparison of intravenous nalbuphine infusion|2
02215|045|R|  versus saline as an adjuvant for epidural morphine. Reg Anesth 1996|2
02215|046|R|  May-Jun;21(3):214-8.|2
02215|047|R|3.Wang JJ, Ho ST, Tzeng JI. Comparison of intravenous nalbuphine infusion|2
02215|048|R|  versus naloxone in the prevention of epidural morphine-related side|2
02215|049|R|  effects. Reg Anesth Pain Med 1998 Sep-Oct;23(5):479-84.|2
02215|050|R|4.Houlihan KP, Mitchell RG, Flapan AD, Steedman DJ. Excessive morphine|2
02215|051|R|  requirements after pre-hospital nalbuphine analgesia. J Accid Emerg Med|2
02215|052|R|  1999 Jan;16(1):29-31.|2
02215|053|R|5.Robinson N, Burrows N. Excessive morphine requirements after pre-hospital|2
02215|054|R|  nalbuphine analgesia. J Accid Emerg Med 1999 Sep;16(5):392.|2
02215|055|R|6.Jaffe RS, Moldenhauer CC, Hug CC Jr, Finlayson DC, Tobia V, Kopel ME.|2
02215|056|R|  Nalbuphine antagonism of fentanyl-induced ventilatory depression: a|2
02215|057|R|  randomized trial. Anesthesiology 1988 Feb;68(2):254-60.|2
02215|058|R|7.Ramsay JG, Higgs BD, Wynands JE, Robbins R, Townsend GE. Early extubation|2
02215|059|R|  after high-dose fentanyl anaesthesia for aortocoronary bypass surgery:|2
02215|060|R|  reversal of respiratory depression with low-dose nalbuphine. Can Anaesth|2
02215|061|R|  Soc J 1985 Nov;32(6):597-606.|2
02215|062|R|8.Blaise GA, Nugent M, McMichan JC, Durant PA. Side effects of nalbuphine|2
02215|063|R|  while reversing opioid-induced respiratory depression: report of four|2
02215|064|R|  cases. Can J Anaesth 1990 Oct;37(7):794-7.|2
02215|065|R|9.Moldenhauer CC, Roach GW, Finlayson DC, Hug CC Jr, Kopel ME, Tobia V,|2
02215|066|R|  Kelly S. Nalbuphine antagonism of ventilatory depression following|2
02215|067|R|  high-dose fentanyl anesthesia. Anesthesiology 1985 May;62(5):647-50.|2
02215|068|R|10.Bailey PL, Clark NJ, Pace NL, Stanley TH, East KA, van Vreeswijk H, van|2
02215|069|R|   de Pol P, Clissold MA, Rozendaal W. Antagonism of postoperative|2
02215|070|R|   opioid-induced respiratory depression: nalbuphine versus naloxone. Anesth|2
02215|071|R|   Analg 1987 Nov;66(11):1109-14.|2
02215|072|R|11.Latasch L, Teichmuller T, Dudziak R, Probst S. Antagonisation of|2
02215|073|R|   fentanyl-induced respiratory depression by nalbuphine. Acta Anaesthesiol|2
02215|074|R|   Belg 1989;40(1):35-40.|2
02215|075|R|12.Zsigmond EK, Durrani Z, Barabas E, Wang XY, Tran L. Endocrine and|2
02215|076|R|   hemodynamic effects of antagonism of fentanyl-induced respiratory|2
02215|077|R|   depression by nalbuphine. Anesth Analg 1987 May;66(5):421-6.|2
02215|078|R|13.Davies GG, From R. A blinded study using nalbuphine for prevention of|2
02215|079|R|   pruritus induced by epidural fentanyl. Anesthesiology 1988 Nov;|2
02215|080|R|   69(5):763-5.|2
02215|081|R|14.Kendrick WD, Woods AM, Daly MY, Birch RF, DiFazio C. Naloxone versus|2
02215|082|R|   nalbuphine infusion for prophylaxis of epidural morphine-induced|2
02215|083|R|   pruritus. Anesth Analg 1996 Mar;82(3):641-7.|2
02215|084|R|15.Cohen SE, Ratner EF, Kreitzman TR, Archer JH, Mignano LR. Nalbuphine is|2
02215|085|R|   better than naloxone for treatment of side effects after epidural|2
02215|086|R|   morphine. Anesth Analg 1992 Nov;75(5):747-52.|2
02215|087|R|16.Alhashemi JA, Crosby ET, Grodecki W, Duffy PJ, Hull KA, Gallant C.|2
02215|088|R|   Treatment of intrathecal morphine-induced pruritus following caesarean|2
02215|089|R|   section. Can J Anaesth 1997 Oct;44(10):1060-5.|2
02215|090|R|17.Parker RK, Holtmann B, White PF. Patient-controlled epidural analgesia:|2
02215|091|R|   interactions between nalbuphine and hydromorphone. Anesth Analg 1997 Apr;|2
02215|092|R|   84(4):757-63.|2
02215|093|R|18.Henderson SK, Cohen H. Nalbuphine augmentation of analgesia and reversal|3
02215|094|R|   of side effects following epidural hydromorphone. Anesthesiology 1986|3
02215|095|R|   Aug;65(2):216-8.|3
02215|096|R|19.Preston KL, Bigelow GE, Liebson IA. Antagonist effects of nalbuphine in|2
02215|097|R|   opioid-dependent human volunteers. J Pharmacol Exp Ther 1989 Mar;|2
02215|098|R|   248(3):929-37.|2
02215|099|R|20.Hartree C. Caution with nalbuphine in patients on long-term opioids.|3
02215|100|R|   Palliat Med 2005 Mar;19(2):168.|3
02215|101|R|21.Smith J, Guly H. Nalbuphine and slow release morphine. BMJ 2004 Jun 12;|3
02215|102|R|   328(7453):1426.|3
02216|001|T|MONOGRAPH TITLE:  Ritonavir & Ritonavir-Boosted Protease|
02216|002|T|Inhibitors/Boceprevir|
02216|003|B||
02216|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02216|005|L|of severe adverse interaction.|
02216|006|B||
02216|007|A|MECHANISM OF ACTION:  Boceprevir may induce the metabolism of the protease|
02216|008|A|inhibitors.  Darunavir/ritonavir and lopinavir/ritonavir may also induce the|
02216|009|A|metabolism of boceprevir.(1-2)|
02216|010|B||
02216|011|E|CLINICAL EFFECTS:  Concurrent use of boceprevir may result in decreased|
02216|012|E|levels and effectiveness of the protease inhibitor.  Concurrent use of|
02216|013|E|darunavir/ritonavir or lopinavir/ritonavir may result in decreased levels|
02216|014|E|and effectiveness of boceprevir.(1,2)|
02216|015|B||
02216|016|P|PREDISPOSING FACTORS:  None determined.|
02216|017|B||
02216|018|M|PATIENT MANAGEMENT:  The concurrent use of boceprevir with ritonavir-boosted|
02216|019|M|protease inhibitors is not recommended.(1,3,4)  Monitor patients receiving|
02216|020|M|concurrent boceprevir and ritonavir without other protease inhibitors for|
02216|021|M|response.(4)|
02216|022|M|   Patients who have already begun concurrent therapy should be monitored|
02216|023|M|for HCV-treatment response and for potential HCV and HIV virologic rebound.|
02216|024|M|Discuss the risk/benefit of continued concurrent therapy with the|
02216|025|M|patient.(2)|
02216|026|B||
02216|027|D|DISCUSSION:  Concurrent use of boceprevir (800 mg TID for 6 days) with|
02216|028|D|atazanavir/ritonavir (300/100 mg daily for 22 days)) decreased atazanavir|
02216|029|D|maximum concentration (Cmax), area-under-curve (AUC), and trough|
02216|030|D|concentrations (Cmin) by 25%, 35%, and 49%, respectively.  There were no|
02216|031|D|significant effect on boceprevir levels.(4)|
02216|032|D|   Concurrent use of boceprevir (800 mg TID for 6 days) with|
02216|033|D|darunavir/ritonavir (600/100 mg BID for 22 days) decreased darunavir Cmax,|
02216|034|D|AUC, and Cmin by 36%, 44%, and 59%, respectively.  Boceprevir Cmax, AUC, and|
02216|035|D|Cmin decreased by 25%, 32%, and 35%, respectively.(4)|
02216|036|D|   Concurrent use of boceprevir (800 mg TID for 6 days with|
02216|037|D|lopinavir/ritonavir (400/100 mg BID for 22 days) decreased lopinavir Cmax,|
02216|038|D|AUC, and Cmin by 30%, 34%, and 43%, respectively.  Boceprevir Cmax, AUC, and|
02216|039|D|Cmin decreased by 50%, 45%, and 57%, respectively.(4)|
02216|040|D|   Concurrent ritonavir (100 mg daily for 12 days) decreased the Cmax and|
02216|041|D|AUC of boceprevir (400 mg TID for 15 days) by 27% and 19%, respectively.|
02216|042|D|The minimum concentration (Cmin) of boceprevir increased by 4%.(4)|
02216|043|B||
02216|044|R|REFERENCES:|
02216|045|B||
02216|046|R|1.Reddy SSK. Dear US Healthcare Professional: SUBJECT: Results of|1
02216|047|R|  Pharmacokinetic Study in Healthy Volunteers Given VICTRELIS (boceprevir)|1
02216|048|R|  and Ritonavir-Boosted HIV Protease Inhibitors May Indicate Clinically|1
02216|049|R|  Significant Drug Interactions for. Patients Coinfected with Chronic|1
02216|050|R|  Hepatitis C and HIV. Merck & Co., Inc. February 6, 2012.|1
02216|051|R|2.US Food and Drug Administration. FDA Drug Safety Communication: Important|1
02216|052|R|  drug interactions between Victrelis (boceprevir) and ritonavir-boosted|1
02216|053|R|  human immunodeficiency virus (HIV) protease inhibitor drugs. Available|1
02216|054|R|  at:http://wayback.archive-it.org/7993/20161022203820/http://www.fda.gov/Dr|1
02216|055|R|  ugs/DrugSafety/ucm291119.htm February 8, 2012.|1
02216|056|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
02216|057|R|  information on drug interactions between Victrelis (boceprevir) and|1
02216|058|R|  certain boosted HIV protease inhibitor drugs. available at:|1
02216|059|R|  http://www.fda.gov/Drugs/DrugSafety/ucm301616.htm April 26, 2012.|1
02216|060|R|4.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02216|061|R|  January, 2017.|1
02217|001|T|MONOGRAPH TITLE:  Clozapine/QT Prolonging Agents|
02217|002|B||
02217|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02217|004|L|take action as needed.|
02217|005|B||
02217|006|A|MECHANISM OF ACTION:  Concurrent use of clozapine with other agents that|
02217|007|A|prolong the QTc interval may result in additive effects on the QTc|
02217|008|A|interval.(1)|
02217|009|B||
02217|010|E|CLINICAL EFFECTS:  The use of clozapine in patients maintained on agents|
02217|011|E|that prolong the QTc interval may result in potentially life-threatening|
02217|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02217|013|B||
02217|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02217|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02217|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02217|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02217|018|P|female gender, or advanced age.(2)|
02217|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02217|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02217|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02217|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02217|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02217|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02217|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02217|026|B||
02217|027|M|PATIENT MANAGEMENT:  Approach the concurrent use of clozapine and other|
02217|028|M|agents that are known to prolong the QTc interval with caution.(1)|
02217|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02217|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02217|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02217|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02217|033|B||
02217|034|D|DISCUSSION:  Treatment with clozapine has been associated with QT|
02217|035|D|prolongation as well as ventricular arrhythmia, Torsades de Pointes, cardiac|
02217|036|D|arrest, and sudden death.(1)|
02217|037|D|   Agents that are linked to this monograph may have varying degrees of|
02217|038|D|potential to prolong the QTc interval but are generally accepted to have a|
02217|039|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02217|040|D|been shown to prolong the QTc interval either through their mechanism of|
02217|041|D|action, through studies on their effects on the QTc interval, or through|
02217|042|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02217|043|D|and/or post-marketing reports.(3)|
02217|044|B||
02217|045|R|REFERENCES:|
02217|046|B||
02217|047|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
02217|048|R|  Pharmaceuticals Corporation April, 2020.|1
02217|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02217|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02217|051|R|  settings: a scientific statement from the American Heart Association and|6
02217|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02217|053|R|  2;55(9):934-47.|6
02217|054|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02217|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02217|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02217|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02218|001|T|MONOGRAPH TITLE:  Efavirenz/Rifampin (mono deleted 09/10/2015)|
02218|002|B||
02218|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02218|004|L|take action as needed.|
02218|005|B||
02218|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of efavirenz.(1)|
02218|007|B||
02218|008|E|CLINICAL EFFECTS:  Concurrent or recent use of rifampin may decrease levels|
02218|009|E|and the effectiveness of efavirenz.(1)|
02218|010|B||
02218|011|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
02218|012|P|patients weighing 50 kg or more.(1)|
02218|013|B||
02218|014|M|PATIENT MANAGEMENT:  In patients weighing 50 kg or more who are receiving|
02218|015|M|concurrent rifampin, consider increasing the dose of efavirenz to 800 mg|
02218|016|M|daily.(1)|
02218|017|B||
02218|018|D|DISCUSSION:  In a study in 12 subjects, concurrent rifampin (600 mg daily|
02218|019|D|for 7 days) decreased the maximum concentration (Cmax), area-under-curve|
02218|020|D|(AUC), and minimum concentration (Cmin) of efavirenz (600 mg daily for 7|
02218|021|D|days) by 20%, 26%, and 32%, respectively.(1)|
02218|022|B||
02218|023|R|REFERENCE:|
02218|024|B||
02218|025|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
02218|026|R|  Company November, 2023.|1
02219|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/Mifepristone|
02219|002|B||
02219|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02219|004|L|is contraindicated and generally should not be dispensed or administered to|
02219|005|L|the same patient.|
02219|006|B||
02219|007|A|MECHANISM OF ACTION:  Mifepristone is an inhibitor of CYP3A4 and may|
02219|008|A|increase levels and effects of drugs metabolized by this enzyme.(1)|
02219|009|B||
02219|010|E|CLINICAL EFFECTS:  Lovastatin, simvastatin and CYP3A4 substrates with a|
02219|011|E|narrow therapeutic window such as alprazolam, cyclosporine,|
02219|012|E|dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and|
02219|013|E|tacrolimus or CYP3A4 substrates with a high first pass effect such as oral|
02219|014|E|midazolam, sildenafil, and triazolam are particularly susceptible to|
02219|015|E|significant toxicity.(1,2)|
02219|016|B||
02219|017|P|PREDISPOSING FACTORS:  Due to the need for continuous therapy and|
02219|018|P|mifepristone's long half-life of 85 hours(1) which leads to accumulation,|
02219|019|P|patients with endogenous Cushing's syndrome may be at an increased risk for|
02219|020|P|toxicity.|
02219|021|P|   With pimozide, the risk of anticholinergic toxicities including cognitive|
02219|022|P|decline, delirium, falls and fractures is increased in geriatric patients|
02219|023|P|using more than one medicine with anticholinergic properties.(3)|
02219|024|B||
02219|025|M|PATIENT MANAGEMENT:  The US manufacturer of mifepristone for|
02219|026|M|hypercortisolism due to endogenous Cushing's syndrome states use with|
02219|027|M|lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range,|
02219|028|M|or CYP3A4 substrates with a high first pass effect is contraindicated.(1)|
02219|029|B||
02219|030|D|DISCUSSION:  Administration of mifepristone 1200 mg daily for 10 days|
02219|031|D|followed by a single dose of simvastatin 80 mg led to an increase of|
02219|032|D|simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC)|
02219|033|D|of 10.4-fold and 15.7-fold, respectively.|
02219|034|B||
02219|035|R|REFERENCES:|
02219|036|B||
02219|037|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
02219|038|R|  November, 2019.|1
02219|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02219|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02219|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02219|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02219|043|R|  11/14/2017.|1
02219|044|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02219|045|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02219|046|R|  Soc 2023 Jul;71(7):2052-2081.|6
02220|001|T|MONOGRAPH TITLE:  Digoxin/Boceprevir; Ritonavir; Telaprevir|
02220|002|B||
02220|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02220|004|L|take action as needed.|
02220|005|B||
02220|006|A|MECHANISM OF ACTION:  Boceprevir(1), ritonavir, and telaprevir(2) inhibit|
02220|007|A|the P-glycoprotein (P-gp) system, which may increase digoxin levels.|
02220|008|B||
02220|009|E|CLINICAL EFFECTS:  Concurrent use of boceprevir, ritonavir, or telaprevir|
02220|010|E|may result in elevated levels and toxicity from digoxin.  Symptoms of|
02220|011|E|digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue,|
02220|012|E|malaise, drowsiness, generalized muscle weakness, disorientation,|
02220|013|E|hallucinations, visual disturbances, and arrhythmias.|
02220|014|B||
02220|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02220|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02220|017|P|risk of digoxin toxicity.|
02220|018|B||
02220|019|M|PATIENT MANAGEMENT:  When initiating digoxin in patients maintained on|
02220|020|M|boceprevir, ritonavir, or telaprevir, use the lowest dose possible.(1,2)|
02220|021|M|   Monitor patients receiving concurrent therapy for elevated digoxin levels|
02220|022|M|and adjust the dose accordingly.(1,2)|
02220|023|M|   The manufacturer of digoxin states to reduce digoxin concentrations by|
02220|024|M|decreasing dose by approximately 30-50% or by modifying the dosing|
02220|025|M|frequency.(3)|
02220|026|B||
02220|027|D|DISCUSSION:  In a study in healthy subjects, boceprevir (800 mg TID for 61|
02220|028|D|days) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
02220|029|D|of a single dose of digoxin (0.25 mg) by 18% and 19%, respectively.(1)|
02220|030|D|   In a study of 12 healthy subjects, ritonavir (200 mg twice daily for 14|
02220|031|D|days) increased the AUC of digoxin (0.4 mg orally) by 29%.(4)  In another|
02220|032|D|study of 12 healthy subjects, ritonavir (300 mg twice daily for 11 days)|
02220|033|D|increased the AUC of digoxin (0.5 mg IV) by 86%.(3-5)|
02220|034|D|   In a study in healthy subjects, telaprevir (750 mg every 8 hours for 11|
02220|035|D|days) increased the Cmax and AUC of a single dose of digoxin (2 mg) by 50%|
02220|036|D|and 85%, respectively.(2,6)|
02220|037|B||
02220|038|R|REFERENCES:|
02220|039|B||
02220|040|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02220|041|R|  January, 2017.|1
02220|042|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02220|043|R|  Incorporated October, 2013.|1
02220|044|R|3.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
02220|045|R|  Pharmaceuticals, Inc. August, 2018.|1
02220|046|R|4.Ding R, Tayrouz Y, Riedel KD, Burhenne J, Weiss J, Mikus G, Haefeli WE.|2
02220|047|R|  Substantial pharmacokinetic interaction between digoxin and ritonavir in|2
02220|048|R|  healthy  volunteers. Clin Pharmacol Ther 2004 Jul;76(1):73-84.|2
02220|049|R|5.Penzak SR, Shen JM, Alfaro RM, Remaley AT, Natarajan V, Falloon J.|2
02220|050|R|  Ritonavir decreases the nonrenal clearance of digoxin in healthy|2
02220|051|R|  volunteers with  known MDR1 genotypes. Ther Drug Monit 2004 Jun;|2
02220|052|R|  26(3):322-30.|2
02220|053|R|6.Garg V, Chandorkar G, Farmer HF, Smith F, Alves K, van Heeswijk RP. Effect|2
02220|054|R|  of Telaprevir on the Pharmacokinetics of Midazolam and Digoxin. J Clin|2
02220|055|R|  Pharmacol 2012 Jan 26.|2
02221|001|T|MONOGRAPH TITLE:  Escitalopram/Boceprevir; Telaprevir|
02221|002|B||
02221|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02221|004|L|take action as needed.|
02221|005|B||
02221|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02221|007|B||
02221|008|E|CLINICAL EFFECTS:  Concurrent use of boceprevir or telaprevir may result in|
02221|009|E|decreased levels and efficacy of escitalopram.|
02221|010|B||
02221|011|P|PREDISPOSING FACTORS:  None determined.|
02221|012|B||
02221|013|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
02221|014|M|either boceprevir or telaprevir with escitalopram for therapeutic|
02221|015|M|effectiveness of escitalopram.  The dosage of escitalopram may need to be|
02221|016|M|adjusted or an alternative agent considered.(1,2)|
02221|017|B||
02221|018|D|DISCUSSION:  Boceprevir (800 mg TID for 11 days) decreased the maximum|
02221|019|D|concentration (Cmax) and area-under-curve (AUC) of escitalopram (10 mg|
02221|020|D|single dose) by 19% and 21%, respectively.  There were no significant|
02221|021|D|effects on boceprevir levels.(1)|
02221|022|D|   In a study in 13 healthy subjects, telaprevir (750 mg every 8 hours for|
02221|023|D|14 days) decreased the Cmax, AUC, and minimum concentration (Cmin) of|
02221|024|D|escitalopram (10 mg daily for 7 days) by 30%, 35%, and 42%, respectively.|
02221|025|D|There were no significant effects on telaprevir levels.(2)|
02221|026|B||
02221|027|R|REFERENCES:|
02221|028|B||
02221|029|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02221|030|R|  January, 2017.|1
02221|031|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02221|032|R|  Incorporated October, 2013.|1
02222|001|T|MONOGRAPH TITLE:  Zolpidem/Boceprevir; Telaprevir (mono deleted 04/20/2022)|
02222|002|B||
02222|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02222|004|L|take action as needed.|
02222|005|B||
02222|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02222|007|B||
02222|008|E|CLINICAL EFFECTS:  Concurrent use of boceprevir or telaprevir may result in|
02222|009|E|decreased levels and efficacy of zolpidem.|
02222|010|B||
02222|011|P|PREDISPOSING FACTORS:  None determined.|
02222|012|B||
02222|013|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
02222|014|M|either boceprevir or telaprevir with zolpidem for therapeutic effectiveness|
02222|015|M|of zolpidem.  The dosage of zolpidem may need to be adjusted or an|
02222|016|M|alternative agent considered.(1,2)|
02222|017|B||
02222|018|D|DISCUSSION:  In a study in 19 healthy subjects, telaprevir (750 mg every 8|
02222|019|D|hours for 10 days) decreased the maximum concentration (Cmax) and|
02222|020|D|area-under-curve (AUC) of zolpidem (5 mg single dose) by 42% and 47%,|
02222|021|D|respectively.(2)|
02222|022|B||
02222|023|R|REFERENCES:|
02222|024|B||
02222|025|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02222|026|R|  January, 2017.|1
02222|027|R|2.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02222|028|R|  Incorporated October, 2013.|1
02223|001|T|MONOGRAPH TITLE:  Calcium Channel Blockers/Selected Hepatitis C Agents|
02223|002|B||
02223|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02223|004|L|take action as needed.|
02223|005|B||
02223|006|A|MECHANISM OF ACTION:  Boceprevir(1), ombitasvir-paritaprevir-ritonavir,(2)|
02223|007|A|or telaprevir(3) may inhibit the metabolism of calcium channel blockers by|
02223|008|A|CYP3A4.|
02223|009|B||
02223|010|E|CLINICAL EFFECTS:  Concurrent use of boceprevir,|
02223|011|E|ombitasvir-paritaprevir-ritonavir, or telaprevir may result in elevated|
02223|012|E|levels of and toxicity from calcium channel blockers.|
02223|013|B||
02223|014|P|PREDISPOSING FACTORS:  None determined.|
02223|015|B||
02223|016|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
02223|017|M|either boceprevir, ombitasvir-paritaprevir-ritonavir, or telaprevir and|
02223|018|M|amlodipine for increased calcium channel blocker effects.  The dosage of the|
02223|019|M|calcium channel blocker may need to be adjusted(1,3) or an alternative agent|
02223|020|M|considered.(1,3)|
02223|021|M|  The US manufacturer of ombitasvir-paritaprevir-ritonavir states that when|
02223|022|M|administered concomitantly with amlodipine the dose of amlodipine should be|
02223|023|M|decreased by at least 50%. Monitor patients for edema and/or signs and|
02223|024|M|symptoms of hypotension. If these events occur, consider further dose|
02223|025|M|reduction of amlodipine or switching to an alternative calcium channel|
02223|026|M|blocker.|
02223|027|B||
02223|028|D|DISCUSSION:  In a study in 19 healthy subjects, telaprevir (750 mg every 8|
02223|029|D|hours for 7 days) increased the maximum concentration (Cmax) and|
02223|030|D|area-under-curve (AUC) of a single dose of amlodipine (5mg) by 1.27-fold and|
02223|031|D|2.79-fold, respectively.(3,4)|
02223|032|D|   In an interaction study, 26 healthy subjects were given|
02223|033|D|ombitasvir-paritaprevir-ritonavir and dasabuvir for 24 days. A single dose|
02223|034|D|of amlodipine 5 mg was given on day 1 and 14 of therapy.  Amlodipine AUC|
02223|035|D|increased 2.1-fold and the half-life increased from 42 (+ or - 6.7) hours to|
02223|036|D|104 (+ or - 18) hours.(5)|
02223|037|B||
02223|038|R|REFERENCES:|
02223|039|B||
02223|040|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02223|041|R|  January, 2017.|1
02223|042|R|2.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02223|043|R|  prescribing information. AbbVie Inc. December, 2019.|1
02223|044|R|3.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02223|045|R|  Incorporated October, 2013.|1
02223|046|R|4.Lee JE, van Heeswijk R, Alves K, Smith F, Garg V. Effect of the hepatitis|2
02223|047|R|  C virus protease inhibitor telaprevir on the pharmacokinetics of|2
02223|048|R|  amlodipine and atorvastatin. Antimicrob Agents Chemother 2011 Oct;|2
02223|049|R|  55(10):4569-74.|2
02223|050|R|5.FDA. CDER Application number: 2066190 Viekira Pak (ombitasvir,|1
02223|051|R|  paritaprevir, ritonavir, dasabuvir) Clinical Pharmacology and|1
02223|052|R|  Biopharmaceutics Review(s). URL:|1
02223|053|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206619Orig1s000Clin|1
02223|054|R|  PharmR.pdf December 19, 2014.|1
02224|001|T|MONOGRAPH TITLE:  Buprenorphine; Methadone/Boceprevir (mono deleted|
02224|002|T|05/04/2017)|
02224|003|B||
02224|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02224|005|L|take action as needed.|
02224|006|B||
02224|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02224|008|B||
02224|009|E|CLINICAL EFFECTS:  Concurrent use of boceprevir may result in increased|
02224|010|E|plasma levels of buprenorphine and decreased levels of methadone.(1)|
02224|011|B||
02224|012|P|PREDISPOSING FACTORS:  None determined.|
02224|013|B||
02224|014|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
02224|015|M|boceprevir and either buprenorphine or methadone for altered response to|
02224|016|M|these agents.  The dosage of buprenorphine or methadone may need to be|
02224|017|M|adjusted in some patients; however, routine adjustments are not|
02224|018|M|recommended.(1)|
02224|019|B||
02224|020|D|DISCUSSION:  In a study, concurrent boceprevir (800 mg TID for 6 days)|
02224|021|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02224|022|D|buprenorphine (administered as buprenorphine/naloxone 8-24 mg plus 2-6 mg|
02224|023|D|daily for 6 days) by 18% and 19%, respectively.  The AUC of naloxone|
02224|024|D|increased by 33%.  Boceprevir Cmax and AUC decreased by 18% and 12%,|
02224|025|D|respectively.(1)|
02224|026|D|   In a study, concurrent boceprevir (800 mg TID for 6 days) and methadone|
02224|027|D|(20-150 mg daily for 6 days) decreased the Cmax and AUC of R-methadone by|
02224|028|D|10% and 15%, respectively.  The Cmax and AUC of S-methadone decreased by 17%|
02224|029|D|and 22%, respectively.  Boceprevir Cmax and AUC decreased by 38% and 20%,|
02224|030|D|respectively.(1)|
02224|031|B||
02224|032|R|REFERENCE:|
02224|033|B||
02224|034|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02224|035|R|  January, 2017.|1
02225|001|T|MONOGRAPH TITLE:  Methotrexate (Oncology-Injection )/Proton Pump Inhibitors|
02225|002|B||
02225|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02225|004|L|of severe adverse interaction.|
02225|005|B||
02225|006|A|MECHANISM OF ACTION:  Proton pump inhibitors may inhibit the active|
02225|007|A|secretion of methotrexate from the kidney via inhibition of the|
02225|008|A|hydrogen-potassium ATPase(1) and may reduce uptake of methotrexate into|
02225|009|A|breast cancer resistance protein via competitive inhibition.(2,3)|
02225|010|B||
02225|011|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and proton pump|
02225|012|E|inhibitors may result in elevated levels of methotrexate and increased|
02225|013|E|methotrexate-related adverse effects and toxicities, leading to increased|
02225|014|E|risk of severe neurotoxicity, stomatitis, and myelosuppression, including|
02225|015|E|neutropenia.|
02225|016|B||
02225|017|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
02225|018|P|- High-dose oncology regimens|
02225|019|P|- Impaired renal function, ascites, or pleural effusions|
02225|020|B||
02225|021|M|PATIENT MANAGEMENT:  For patients receiving high dose methotrexate with|
02225|022|M|leucovorin rescue, consider discontinuation of proton pump inhibitors for|
02225|023|M|the duration of therapy.  Patients receiving concurrent use of methotrexate|
02225|024|M|and proton pump inhibitors should be monitored closely for elevated|
02225|025|M|methotrexate levels and methotrexate toxicity. The US manufacturer of|
02225|026|M|omeprazole states that secretory ability returns gradually over three to|
02225|027|M|five days following discontinuation.(4)  Therefore, it would seem prudent to|
02225|028|M|discontinue proton pump inhibitors several days prior to methotrexate|
02225|029|M|therapy.|
02225|030|B||
02225|031|D|DISCUSSION:  In a clinical trial in 74 patients on high dose (1-5 G/m2)|
02225|032|D|methotrexate therapy, data was examined to determine if proton pump|
02225|033|D|inhibitor (omeprazole, pantoprazole, rabeprazole) use affects methotrexate|
02225|034|D|elimination.  Delayed elimination was found to be more frequent in those|
02225|035|D|with co-administration of a proton pump inhibitor (31.7% vs. 13.8%),|
02225|036|D|resulting in higher plasma methotrexate concentrations at 24, 48, and 74|
02225|037|D|hours.  The effect was seen with lansoprazole, omeprazole, pantoprazole, and|
02225|038|D|rabeprazole.(2)|
02225|039|D|   There are three case reports(1,5,6) of elevated methotrexate levels or|
02225|040|D|delayed methotrexate elimination resulting from concurrent administration of|
02225|041|D|high dose methotrexate and omeprazole, including one patient(6) that|
02225|042|D|developed severe mucositis.  In each case, omeprazole was discontinued and|
02225|043|D|normal methotrexate kinetics were observed on subsequent cycles with no|
02225|044|D|further adverse effects noted.|
02225|045|D|   In a case report of a 59 year-old male on low dose (15 mg weekly)|
02225|046|D|methotrexate, administration of pantoprazole (20 mg daily) was found to|
02225|047|D|increase the AUC of the metabolite 7-hydroxymethotrexate by 70%.(7)|
02225|048|D|   In a clinical trial, 28 adults with rheumatoid arthritis on low dose|
02225|049|D|(7.5-15 mg weekly) methotrexate were assigned to receive lansoprazole (30 mg|
02225|050|D|daily) and naproxen (500 mg twice daily) on Days 1-7 of therapy.  The half|
02225|051|D|life of the metabolite 7-hydroxymethotrexate was prolonged with concurrent|
02225|052|D|administration, but no other statistically significant differences were|
02225|053|D|found in regards to the plasma concentration profiles of methotrexate or|
02225|054|D|7-hydroxymethotrexate.(8)|
02225|055|B||
02225|056|R|REFERENCES:|
02225|057|B||
02225|058|R|1.Reid T, Yuen A, Catolico M, Carlson RW. Impact of omeprazole on the plasma|3
02225|059|R|  clearance of methotrexate. Cancer Chemother Pharmacol 1993;33(1):82-4.|3
02225|060|R|2.Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, Sawada Y, Kohda Y.|2
02225|061|R|  Co-administration of proton pump inhibitors delays elimination of plasma|2
02225|062|R|  methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol 2009|2
02225|063|R|  Jan;67(1):44-9.|2
02225|064|R|3.Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH,|5
02225|065|R|  Schinkel AH, van Tellingen O, Borst P, Schellens JH. Mechanism of the|5
02225|066|R|  pharmacokinetic interaction between methotrexate and benzimidazoles:|5
02225|067|R|  potential role for breast cancer resistance protein in clinical drug-drug|5
02225|068|R|  interactions. Cancer Res 2004 Aug 15;64(16):5804-11.|5
02225|069|R|4.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
02225|070|R|  Pharmaceuticals LP June, 2018.|1
02225|071|R|5.Beorlegui B, Aldaz A, Ortega A, Aquerreta I, Sierrasesumega L, Giraldez J.|3
02225|072|R|  Potential interaction between methotrexate and omeprazole. Ann|3
02225|073|R|  Pharmacother 2000 Sep;34(9):1024-7.|3
02225|074|R|6.Bauters TG, Verlooy J, Robays H, Laureys G. Interaction between|3
02225|075|R|  methotrexate and omeprazole in an adolescent with leukemia: a case report.|3
02225|076|R|  Pharm World Sci 2008 Aug;30(4):316-8.|3
02225|077|R|7.Troger U, Stotzel B, Martens-Lobenhoffer J, Gollnick H, Meyer FP. Drug|3
02225|078|R|  points: Severe myalgia from an interaction between treatments with|3
02225|079|R|  pantoprazole and methotrexate. BMJ 2002 Jun 22;324(7352):1497.|3
02225|080|R|8.Vakily M, Amer F, Kukulka MJ, Andhivarothai N. Coadministration of|2
02225|081|R|  lansoprazole and naproxen does not affect the pharmacokinetic profile of|2
02225|082|R|  methotrexate in adult patients with rheumatoid arthritis. J Clin Pharmacol|2
02225|083|R|  2005 Oct;45(10):1179-86.|2
02226|001|T|MONOGRAPH TITLE:  Tenofovir/Telaprevir|
02226|002|B||
02226|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02226|004|L|take action as needed.|
02226|005|B||
02226|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02226|007|B||
02226|008|E|CLINICAL EFFECTS:  Concurrent use of telaprevir may result in elevated|
02226|009|E|levels of and toxicity from tenofovir.(1)|
02226|010|B||
02226|011|P|PREDISPOSING FACTORS:  None determined.|
02226|012|B||
02226|013|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
02226|014|M|telaprevir and tenofovir without efavirenz for increased tenofovir effects.|
02226|015|M|Discontinue tenofovir in patients who develop tenofovir-associated|
02226|016|M|toxicities.(1)|
02226|017|B||
02226|018|D|DISCUSSION:  In a study in 16 healthy subjects, telaprevir (750 mg every 8|
02226|019|D|hours for 7 days) increased the maximum concentration (Cmax),|
02226|020|D|area-under-curve (AUC), and minimum concentration (Cmin) of tenofovir (300|
02226|021|D|mg daily for 7 days) by 30%, 30%, and 41%, respectively.  There were no|
02226|022|D|significant effects on telaprevir pharmacokinetics.(1)|
02226|023|D|   In a study in 15 subjects, concurrent telaprevir (1125 mg every 8 hours|
02226|024|D|for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg|
02226|025|D|daily for 7 days) increased tenofovir Cmax, AUC, and Cmin by 22%, 10%, and|
02226|026|D|17%, respectively.(1)|
02226|027|D|   In a study in 16 subjects, concurrent telaprevir (1500 mg every 8 hours|
02226|028|D|for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg|
02226|029|D|daily for 7 days) increased tenofovir Cmax, AUC, and Cmin by 24%, 10%, and|
02226|030|D|6%, respectively.(1)|
02226|031|B||
02226|032|R|REFERENCE:|
02226|033|B||
02226|034|R|1.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02226|035|R|  Incorporated October, 2013.|1
02227|001|T|MONOGRAPH TITLE:  Selected Hepatitis C Agents/Efavirenz;|
02227|002|T|Etravirine;Nevirapine|
02227|003|B||
02227|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02227|005|L|of severe adverse interaction.|
02227|006|B||
02227|007|A|MECHANISM OF ACTION:  Efavirenz, etravirine, and nevirapine may induce the|
02227|008|A|metabolism of boceprevir,(1,2) telaprevir,(2,3) simeprevir,(4)|
02227|009|A|velpatasvir(5,6) voxilaprevir, glecaprevir(7), and pibrentasvir(7) via|
02227|010|A|CYP3A4.  Efavirenz may also decrease absorption of these agents through the|
02227|011|A|P-glycoprotein (P-gp) transporter.|
02227|012|B||
02227|013|E|CLINICAL EFFECTS:  Concurrent use of efavirenz, etravirine, or|
02227|014|E|nevirapine(1,2) may result in decreased levels and effectiveness of|
02227|015|E|boceprevir,(3,4) telaprevir,(4,5) simeprevir,(6) velpatasvir,(6,7)|
02227|016|E|voxilaprevir,(8) glecaprevir,(9) and pibrentasvir(9).|
02227|017|B||
02227|018|P|PREDISPOSING FACTORS:  None determined.|
02227|019|B||
02227|020|M|PATIENT MANAGEMENT:  Avoid the concurrent use of boceprevir and|
02227|021|M|efavirenz.(3,4)  The concurrent use of efavirenz, etravirine, or|
02227|022|M|nevirapine(1,2) with simeprevir,(6) velpatasvir,(6,7) voxilaprevir,(8)|
02227|023|M|glecaprevir,(9) and pibrentasvir(9) is not recommended.|
02227|024|M|   If concurrent therapy is warranted, monitor patients for decreased|
02227|025|M|response to boceprevir,(3,4) telaprevir,(4,5) simeprevir,(6)|
02227|026|M|velpatasvir,(6,7) voxilaprevir,(8) glecaprevir,(9) and pibrentasvir(9).|
02227|027|M|   The Swedish manufacturer of telaprevir recommends that the dose of|
02227|028|M|telaprevir be increased to 1125 mg every 8 hours when used concurrently with|
02227|029|M|efavirenz.(10)|
02227|030|B||
02227|031|D|DISCUSSION:  In a study, concurrent efavirenz (600 mg daily for 16 days)|
02227|032|D|decreased the the maximum concentration (Cmax), area-under-curve (AUC), and|
02227|033|D|minimum concentration (Cmin) of boceprevir (800 mg 3 times daily for 6 days)|
02227|034|D|by 8%, 19%, and 44%, respectively.  Efavirenz Cmax and AUC increased by 11%|
02227|035|D|and 20%, respectively.(3,4)|
02227|036|D|   In a study in 21 subjects, efavirenz (600 mg daily for 20 days) decreased|
02227|037|D|the Cmax, AUC, and Cmin of telaprevir (750 mg every 8 hours for 10 days) by|
02227|038|D|9%, 26%, and 47%, respectively.  The Cmax, AUC, and Cmin of efavirenz|
02227|039|D|decreased by 16%, 7%, and 2%, respectively.(4,5)|
02227|040|D|   In a study in 15 subjects, concurrent telaprevir (1125 mg every 8 hours|
02227|041|D|for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg|
02227|042|D|daily for 7 days) decreased telaprevir Cmax, AUC, and Cmin by 14%, 18%, and|
02227|043|D|25%, respectively.  Efavirenz Cmax, AUC, and Cmin decreased by 24%, 18%, and|
02227|044|D|10%, respectively.(5)|
02227|045|D|   In a study in 16 subjects, concurrent telaprevir (1500 mg every 8 hours|
02227|046|D|for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg|
02227|047|D|daily for 7 days) decreased telaprevir Cmax, AUC, and Cmin by 3%, 20%, and|
02227|048|D|48%, respectively.  Efavirenz Cmax, AUC, and Cmin decreased by 20%, 15%, and|
02227|049|D|11%, respectively.(5)|
02227|050|D|   In a study in 23 subjects, efavirenz (600 mg daily for 14 days) decreased|
02227|051|D|the Cmax, AUC, and Cmin of simeprevir (150 mg daily for 14 days) by 51%,|
02227|052|D|71%, and 91%, respectively.(4,6)|
02227|053|D|   In a study in 23 subjects, simeprevir (150 mg daily for 14 days)|
02227|054|D|decreased the AUC and Cmin of efavirenz (600 mg daily for 14 days) by 10%|
02227|055|D|and 13%, respectively.(4)|
02227|056|D|   In an interaction study, efavirenz 600 mg daily (in combination with|
02227|057|D|emtricitabine-tenofovir DF) decreased velpatasvir Cmax, AUC, and Cmin 47%,|
02227|058|D|53% and 57% respectively.(7,8)|
02227|059|B||
02227|060|R|REFERENCES:|
02227|061|B||
02227|062|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02227|063|R|  January, 2017.|1
02227|064|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
02227|065|R|  Company November, 2023.|1
02227|066|R|3.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02227|067|R|  Incorporated October, 2013.|1
02227|068|R|4.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
02227|069|R|  November, 2017.|1
02227|070|R|5.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
02227|071|R|  Sciences, Inc. April, 2022.|1
02227|072|R|6.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02227|073|R|  Gilead Sciences, Inc. September, 2019.|1
02227|074|R|7.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02227|075|R|  Inc. October, 2023.|1
02227|076|R|8.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02227|077|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02227|078|R|  HIV. Department of Health and Human Services. Available at|6
02227|079|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
02227|080|R|  new-guidelines June 13, 2021.|6
02227|081|R|9.Liverpool Drug Interactions Group. HIV Drug Interactions. Available at:|6
02227|082|R|  https://hiv-druginteractions.org/.|6
02227|083|R|10.Efavirenz-Emtricitabine-Tenefovir disoproxil Teva Sweden prescribing|1
02227|084|R|   information. Teva Sweden AB October 20, 2017.|1
02228|001|T|MONOGRAPH TITLE:  Boceprevir/Ritonavir (mono deleted 01/09/2014)|
02228|002|B||
02228|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02228|004|L|take action as needed.|
02228|005|B||
02228|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02228|007|B||
02228|008|E|CLINICAL EFFECTS:  Concurrent use of ritonavir may result in decreased|
02228|009|E|levels and effectiveness of boceprevir.(1)|
02228|010|E|   The effects of ritonavir-boosted protease inhibitor therapy on boceprevir|
02228|011|E|concentrations is unknown.  The effect of boceprevir on protease inhibitor|
02228|012|E|concentrations is also unknown.(1)|
02228|013|B||
02228|014|P|PREDISPOSING FACTORS:  None determined.|
02228|015|B||
02228|016|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for|
02228|017|M|response.(1)|
02228|018|B||
02228|019|D|DISCUSSION:  In a study, concurrent ritonavir (100 mg daily for 12 days)|
02228|020|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02228|021|D|boceprevir by 27% and 19%, respectively.  The minimum concentration (Cmin)|
02228|022|D|of boceprevir increased by 4%.(1)|
02228|023|B||
02228|024|R|REFERENCE:|
02228|025|B||
02228|026|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02228|027|R|  January, 2017.|1
02229|001|T|MONOGRAPH TITLE:  Fingolimod/Beta-Blockers; AV Node Blockers|
02229|002|B||
02229|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02229|004|L|of severe adverse interaction.|
02229|005|B||
02229|006|A|MECHANISM OF ACTION:  Initiation of fingolimod has a negative chronotropic|
02229|007|A|effect leading to a mean decrease in heart rate of 13 beats per minute (bpm)|
02229|008|A|after the first dose.  The first dose has also been associated with heart|
02229|009|A|block.  Beta-blockers or agents which slow AV node conduction further|
02229|010|A|increase the risk for symptomatic bradycardia or heart block.|
02229|011|B||
02229|012|E|CLINICAL EFFECTS:  The heart rate lowering effect of fingolimod is biphasic|
02229|013|E|with an initial decrease usually within 6 hours, followed by a second|
02229|014|E|decrease 12 to 24 hours after the first dose.  Symptomatic bradycardia and|
02229|015|E|heart block have been observed.  Bradycardia may be associated with an|
02229|016|E|increase in the QTc interval, increasing the risk for torsade de pointes.|
02229|017|E|The cause of death in a patient who died within 24 hour after taking the|
02229|018|E|first dose of fingolimod was not conclusive; however a link to fingolimod or|
02229|019|E|a drug interaction with fingolimod could not be ruled out.|
02229|020|E|   Beta-Blockers linked to this monograph are: atenolol, betaxolol,|
02229|021|E|bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol,|
02229|022|E|nebivolol, propranolol and timolol.  AV Node Blocking agents are:digoxin,|
02229|023|E|diltiazem, flecainide, ivabradine, propafenone and verapamil.|
02229|024|B||
02229|025|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular disease (e.g. heart|
02229|026|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
02229|027|P|history of torsades de pointes, or heart block), severe untreated sleep|
02229|028|P|apnea, a prolonged QTc interval prior to fingolimod initiation, or factors|
02229|029|P|associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia,|
02229|030|P|bradycardia, female gender, or advanced age) may increase risk for|
02229|031|P|cardiovascular toxicity due to fingolimod.|
02229|032|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02229|033|P|higher systemic concentrations of either QT prolonging drug are additional|
02229|034|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02229|035|P|drug concentrations include rapid infusion of an intravenous dose or|
02229|036|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02229|037|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02229|038|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
02229|039|B||
02229|040|M|PATIENT MANAGEMENT:  Fingolimod is contraindicated in patients with Class|
02229|041|M|III/IV heart failure or in patients who have experienced myocardial|
02229|042|M|infarction, unstable angina, stroke, transient ischemic attack (TIA) or|
02229|043|M|decompensated heart failure within the past six months.(1)  Patients with|
02229|044|M|pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure,|
02229|045|M|ischemic heart disease, history of myocardial infarction, stroke, or heart|
02229|046|M|block), severe untreated sleep apnea, or a prolonged QTc interval prior to|
02229|047|M|fingolimod initiation should receive cardiologist consultation to evaluate|
02229|048|M|the risks of fingolimod therapy.|
02229|049|M|   Patients receiving agents linked to this monograph should have their|
02229|050|M|physician evaluate the possibility of a switch to agents which do not slow|
02229|051|M|heart rate or cardiac conduction.  If fingolimod is initiated, the patient|
02229|052|M|should stay overnight in a medical facility with continuous ECG monitoring|
02229|053|M|after the first dose.  Correct hypokalemia or hypomagnesemia prior to|
02229|054|M|starting fingolimod.|
02229|055|M|   US monitoring recommendations in addition to continuous ECG with|
02229|056|M|overnight monitoring:|
02229|057|M|   Check blood pressure hourly.|
02229|058|M|   If heart rate (HR) is < 45 beats per minute (BPM) or if the ECG shows new|
02229|059|M|onset of second degree or higher AV block at the end of the monitoring|
02229|060|M|period, then monitoring should continue until the finding has resolved.|
02229|061|M|   If patient requires treatment for symptomatic bradycardia, the first dose|
02229|062|M|monitoring strategy should be repeated for the second dose of fingolimod.|
02229|063|M|   If, within the first two weeks of treatment one or more fingolimod doses|
02229|064|M|is missed, then first dose procedures are recommended upon resumption.|
02229|065|M|   If during weeks 3 and 4 of fingolimod treatment dose is interrupted more|
02229|066|M|than 7 days, then first dose procedures are recommended upon resumption.|
02229|067|M|   United Kingdom recommendations(3):|
02229|068|M|   Obtain a 12-lead ECG prior to initiating fingolimod therapy.  Consult a|
02229|069|M|cardiologist for pretreatment risk-benefit assessment if patient has a|
02229|070|M|resting heart rate less than 55 bpm, history of syncope, second degree or|
02229|071|M|greater AV block, sick-sinus syndrome, concurrent therapy with|
02229|072|M|beta-blockers, Class Ia, or Class III antiarrhythmics, heart failure or|
02229|073|M|other significant cardiovascular disease.  Perform continuous ECG|
02229|074|M|monitoring, measure blood pressure and heart rate every hour, and perform a|
02229|075|M|12-lead ECG 6 hours after the first dose.  Monitoring should be extended|
02229|076|M|beyond 6 hours if symptomatic bradycardia or new onset of second degree AV|
02229|077|M|block, Mobitz Type II or third degree AV block has occurred at any time|
02229|078|M|during the monitoring period.  If heart rate 6 hours after the first dose is|
02229|079|M|less than 40 bpm, has decreased more than 20 bpm compared with baseline, or|
02229|080|M|if a new onset second degree AV block, Mobitz Type I (Wenckebach) persists,|
02229|081|M|then monitoring should also be continued.|
02229|082|M|   If fingolimod treatment is discontinued for more than two weeks, the|
02229|083|M|effects on heart rate and conduction could recur.  Thus, first dose|
02229|084|M|monitoring precautions should be followed upon reintroduction of fingolimod.|
02229|085|B||
02229|086|D|DISCUSSION:  After the first dose of fingolimod, heart rate decrease may|
02229|087|D|begin within an hour. Decline is usually maximal at approximately 6 hours|
02229|088|D|followed by a second decrease 12 to 24 hours after the first dose.  The|
02229|089|D|second dose may further decrease heart rate, but the magnitude of change is|
02229|090|D|smaller than the first dose. With continued, chronic dosing, heart rate|
02229|091|D|gradually returns to baseline in about one month.(1,2)  Diurnal variation in|
02229|092|D|heart rate and response to exercise are not affected by fingolimod|
02229|093|D|treatment.(2)|
02229|094|D|   In a manufacturer sponsored study, fingolimod and atenolol 50 mg daily|
02229|095|D|lowered heart rate 15% more than fingolimod alone. However, additional heart|
02229|096|D|rate lowering was not seen with the combination of extended release|
02229|097|D|diltiazem and fingolimod compared with fingolimod alone.(1)|
02229|098|B||
02229|099|R|REFERENCES:|
02229|100|B||
02229|101|R|1.Gilenya (fingolimod) US prescribing information. Novartis Pharmaceuticals|1
02229|102|R|  Corporation June, 2024.|1
02229|103|R|2.Gilenya (fingolimod) Health Canada prescribing information. Novartis|1
02229|104|R|  Pharmaceuticals September 23, 2011.|1
02229|105|R|3.MHRA United Kingdom. Fingolimod (Gilenya): transient bradycardias and|1
02229|106|R|  heart block after first dose - strengthened cardiovascular monitoring.|1
02229|107|R|  Drug Safety Update Feb 2012;5(7):A1.|1
02229|108|R|4.Godin J. Dear Canadian Healthcare Professional:  Subject:  GILENYA|1
02229|109|R|  (fingolimod) - Stronger recommendations regarding first-dose|1
02229|110|R|  cardiovascular monitoring and use in patients with preexisting|1
02229|111|R|  cardiovascular conditions. Novartis Pharmaceuticals Canada Inc. August 21,|1
02229|112|R|  2012.|1
02229|113|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02229|114|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02229|115|R|  settings: a scientific statement from the American Heart Association and|6
02229|116|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02229|117|R|  2;55(9):934-47.|6
02230|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Mifepristone|
02230|002|B||
02230|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02230|004|L|of severe adverse interaction.|
02230|005|B||
02230|006|A|MECHANISM OF ACTION:  Mifepristone is a progesterone-receptor antagonist,|
02230|007|A|which will interfere mechanism of action of hormonal contraceptives|
02230|008|A|(including oral, implantable, injectable, or transdermal agents).(1)|
02230|009|B||
02230|010|E|CLINICAL EFFECTS:  Concurrent use of mifepristone may decrease the|
02230|011|E|effectiveness of hormonal contraceptives.  Mifepristone will result in the|
02230|012|E|loss of any pregnancy that results from decreased hormonal contraceptive|
02230|013|E|efficacy.(1)|
02230|014|B||
02230|015|P|PREDISPOSING FACTORS:  None determined.|
02230|016|B||
02230|017|M|PATIENT MANAGEMENT:  Females of reproductive age maintained on mifepristone|
02230|018|M|for hyperglycemia secondary to hypercortisolism should use a non-hormonal|
02230|019|M|form of contraception during and for 1 month after mifepristone therapy|
02230|020|M|unless they have been surgically sterilized.(1)|
02230|021|B||
02230|022|D|DISCUSSION:  Mifepristone is a progesterone-receptor antagonist, which will|
02230|023|D|interfere mechanism of action of hormonal contraceptives.  Mifepristone will|
02230|024|D|result in the loss of any pregnancy that results from decreased hormonal|
02230|025|D|contraceptive efficacy.  Therefore, females of reproductive age maintained|
02230|026|D|on mifepristone for hyperglycemia secondary to hypercortisolism should use a|
02230|027|D|non-hormonal form of contraception during and for 1 month after mifepristone|
02230|028|D|therapy unless they have been surgically sterilized.(1)|
02230|029|B||
02230|030|R|REFERENCE:|
02230|031|B||
02230|032|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
02230|033|R|  November, 2019.|1
02231|001|T|MONOGRAPH TITLE:  Fingolimod/Ketoconazole|
02231|002|B||
02231|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02231|004|L|take action as needed.|
02231|005|B||
02231|006|A|MECHANISM OF ACTION:  Systemic ketoconazole may inhibit the metabolism of|
02231|007|A|fingolimod via CYP4F2.|
02231|008|B||
02231|009|E|CLINICAL EFFECTS:  Coadministered fingolimod and ketoconazole increases|
02231|010|E|blood levels of fingolimod and its active metabolite fingolimod-phosphate|
02231|011|E|1.7-fold, increasing the risk for adverse reactions.|
02231|012|B||
02231|013|P|PREDISPOSING FACTORS:  None determined.|
02231|014|B||
02231|015|M|PATIENT MANAGEMENT:  The manufacturer of fingolimod recommends close|
02231|016|M|monitoring in patients on concomitant therapy due to the greater risk for|
02231|017|M|adverse effects.(1,2)|
02231|018|B||
02231|019|D|DISCUSSION:  The primary metabolic pathway of fingolimod is CYP4F2 with|
02231|020|D|minor contributions by CYP3A4, CYP2E1 and other CYP P-450 enzymes.  As|
02231|021|D|ketoconazole is a potent inhibitor or CYP4F2 and CYP3A4, a drug interaction|
02231|022|D|study was performed.  In a 2-period crossover study, healthy subjects|
02231|023|D|received ketoconazole 200mg twice daily for 9 days, followed by a single|
02231|024|D|dose of fingolimod 5 mg (i.e. 10 times recommended dose).  The|
02231|025|D|area-under-curve (AUC) for both fingolimod and the active metabolite|
02231|026|D|fingolimod-phosphate, increased 1.7 fold.(1,2)|
02231|027|B||
02231|028|R|REFERENCES:|
02231|029|B||
02231|030|R|1.Gilenya (fingolimod) US prescribing information. Novartis Pharmaceuticals|1
02231|031|R|  Corporation June, 2024.|1
02231|032|R|2.Gilenya (fingolimod) Health Canada prescribing information. Novartis|1
02231|033|R|  Pharmaceuticals September 23, 2011.|1
02232|001|T|MONOGRAPH TITLE:  Mifepristone/Strong CYP3A4 Inhibitors;|
02232|002|T|Amprenavir;Atazanavir|
02232|003|B||
02232|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02232|005|L|of severe adverse interaction.|
02232|006|B||
02232|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
02232|008|A|of mifepristone.|
02232|009|B||
02232|010|E|CLINICAL EFFECTS:  Concurrent use of mifepristone with a strong inhibitor of|
02232|011|E|CYP3A4 may result in a 5-fold increase in area-under-curve (AUC) or 80 per|
02232|012|E|cent decrease in mifepristone clearance, leading to toxicity such as adrenal|
02232|013|E|insufficiency and hypokalemia.|
02232|014|B||
02232|015|P|PREDISPOSING FACTORS:  None determined.|
02232|016|B||
02232|017|M|PATIENT MANAGEMENT:  The manufacturer of mifepristone for use in patients|
02232|018|M|with endogenous Cushing's syndrome states the benefit of the CYP3A4|
02232|019|M|inhibitor must be carefully weighed against the potential risks and|
02232|020|M|concurrent use should only occur when necessary.(1)|
02232|021|M|   If starting mifepristone in a patient already taking a strong CYP3A4|
02232|022|M|inhibitor, initiate mifepristone at 300 mg and titrate if clinically|
02232|023|M|indicated to a maximum dose of 900 mg.(1)|
02232|024|M|   If a strong CYP3A4 inhibitor is started in a patient already taking|
02232|025|M|mifepristone, the following dose adjustments are recommended:|
02232|026|M| - If current mifepristone dose is 300 mg, no dose change warranted;|
02232|027|M| - If current mifepristone dose is 600 mg, reduce dose to 300 mg and titrate|
02232|028|M|if clinically indicated to a maximum dose of 600 mg;|
02232|029|M| - If current mifepristone dose is 900 mg, reduce dose to 600 mg and titrate|
02232|030|M|if clinically indicated to a maximum dose of 900 mg; and|
02232|031|M| - If current mifepristone dose if 1200 mg, reduce dose to 900 mg.(1)|
02232|032|B||
02232|033|D|DISCUSSION:  A drug interaction study examined mifepristone 600 mg daily|
02232|034|D|with concurrent ketoconazole 200 mg twice daily on days 13-17.  Concurrent|
02232|035|D|administration increased mifepristone area-under-curve (AUC) and maximum|
02232|036|D|concentration (Cmax) by 1.38-fold and 1.28-fold, respectively.(1)|
02232|037|D|   A drug interaction study of 33 healthy subjects on itraconazole 200 mg|
02232|038|D|daily coadministered with mifepristone 900 mg daily for 14 days found that|
02232|039|D|itraconazole increased the Cmax and AUC of mifepristone by 1.1-fold and|
02232|040|D|1.2-fold, respectively.(1)|
02232|041|D|   Strong inhibitors of CYP3A4 include: adagrasib, amprenavir, atazanavir,|
02232|042|D|boceprevir, clarithromycin, cobicistat, fosamprenavir, indinavir,|
02232|043|D|itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil,|
02232|044|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
02232|045|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
02232|046|D|tucatinib, and voriconazole.(1,2)|
02232|047|B||
02232|048|R|REFERENCES:|
02232|049|B||
02232|050|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
02232|051|R|  November, 2019.|1
02232|052|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02232|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02232|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02232|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02232|056|R|  11/14/2017.|1
02233|001|T|MONOGRAPH TITLE:  Lovastatin (Greater Than 20 mg); Simvastatin (Greater Than|
02233|002|T|10 mg)/Dronedarone|
02233|003|B||
02233|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02233|005|L|is contraindicated and generally should not be dispensed or administered to|
02233|006|L|the same patient.|
02233|007|B||
02233|008|A|MECHANISM OF ACTION:  Dronedarone may inhibit the metabolism of HMG CoA|
02233|009|A|reductase inhibitors by CYP3A4 and P-glycoprotein.(1)|
02233|010|B||
02233|011|E|CLINICAL EFFECTS:  Concurrent use of dronedarone with certain HMG CoA|
02233|012|E|reductase inhibitors may increase the risk of rhabdomyolysis.(1)|
02233|013|B||
02233|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02233|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02233|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02233|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02233|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02233|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02233|020|P|predisposed to myopathy or rhabdomyolysis.|
02233|021|B||
02233|022|M|PATIENT MANAGEMENT:  When initiating lovastatin in a patient maintained on|
02233|023|M|dronedarone, the starting dose of lovastatin should not exceed 10 mg.  The|
02233|024|M|dose of lovastatin not exceed 20 mg daily in patients receiving concurrent|
02233|025|M|dronedarone unless the potential benefit outweighs the increased risk of|
02233|026|M|myopathy.(2)|
02233|027|M|   Do not exceed 10 mg of simvastatin daily during concurrent therapy with|
02233|028|M|dronedarone.(1,3)|
02233|029|M|   For other statins, the US manufacturer of dronedarone recommends|
02233|030|M|following recommendations from the statin manufacturer regarding concurrent|
02233|031|M|use of 3A4 inhibitors.(1)|
02233|032|B||
02233|033|D|DISCUSSION:  Concurrent dronedarone (400 mg BID for 14 days) and simvastatin|
02233|034|D|(40 mg daily for 14 days) increased simvastatin maximum concentration (Cmax)|
02233|035|D|and area-under-curve (AUC) and simvastatin acid by 3.75-fold and 3.9-fold,|
02233|036|D|respectively.  The Cmax and AUC of simvastatin acid increased by 2.14-fold|
02233|037|D|and 1.96-fold, respectively.(1,3)|
02233|038|B||
02233|039|R|REFERENCES:|
02233|040|B||
02233|041|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
02233|042|R|  November, 2020.|1
02233|043|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02233|044|R|  February, 2014.|1
02233|045|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02233|046|R|  2023.|1
02234|001|T|MONOGRAPH TITLE:  Atorvastatin; Lovastatin (Less than or Equal To 20 mg);|
02234|002|T|Simvastatin (Less than or Equal To 10 mg)/Dronedarone|
02234|003|B||
02234|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02234|005|L|take action as needed.|
02234|006|B||
02234|007|A|MECHANISM OF ACTION:  Dronedarone may inhibit the metabolism of HMG CoA|
02234|008|A|reductase inhibitors by CYP3A4 and P-glycoprotein.(1)|
02234|009|B||
02234|010|E|CLINICAL EFFECTS:  Concurrent use of dronedarone with certain HMG CoA|
02234|011|E|reductase inhibitors may increase the risk of rhabdomyolysis.(1)|
02234|012|B||
02234|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02234|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02234|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02234|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02234|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02234|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02234|019|P|predisposed to myopathy or rhabdomyolysis.|
02234|020|B||
02234|021|M|PATIENT MANAGEMENT:  When initiating lovastatin in a patient maintained on|
02234|022|M|dronedarone, the starting dose of lovastatin should not exceed 10 mg.  The|
02234|023|M|dose of lovastatin not exceed 20 mg daily in patients receiving concurrent|
02234|024|M|dronedarone unless the potential benefit outweighs the increased risk of|
02234|025|M|myopathy.(2)|
02234|026|M|   Do not exceed 10 mg of simvastatin daily during concurrent therapy with|
02234|027|M|dronedarone.(1,3)|
02234|028|M|   For other statins, the US manufacturer of dronedarone recommends|
02234|029|M|following recommendations from the statin manufacturer regarding concurrent|
02234|030|M|use of 3A4 inhibitors and states no dosage adjustment is needed with dosages|
02234|031|M|of atorvastatin 40 mg daily or less.(1)|
02234|032|M|   Monitor patients receiving concurrent therapy for signs and symptoms of|
02234|033|M|rhabdomyolysis.|
02234|034|B||
02234|035|D|DISCUSSION:  Concurrent dronedarone (400 mg BID for 14 days) and simvastatin|
02234|036|D|(40 mg daily for 14 days) increased simvastatin maximum concentration (Cmax)|
02234|037|D|and area-under-curve (AUC) and simvastatin acid by 3.75-fold and 3.9-fold,|
02234|038|D|respectively.  The Cmax and AUC of simvastatin acid increased by 2.14-fold|
02234|039|D|and 1.96-fold, respectively.(1,3)|
02234|040|B||
02234|041|R|REFERENCES:|
02234|042|B||
02234|043|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
02234|044|R|  November, 2020.|1
02234|045|R|2.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02234|046|R|  February, 2014.|1
02234|047|R|3.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02234|048|R|  2023.|1
02235|001|T|MONOGRAPH TITLE:  Atorvastatin (>20 mg)/Selected Protease Inhibitors|
02235|002|B||
02235|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02235|004|L|is contraindicated and generally should not be dispensed or administered to|
02235|005|L|the same patient.|
02235|006|B||
02235|007|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
02235|008|A|atorvastatin by CYP3A4.(1-5)|
02235|009|B||
02235|010|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors may result in|
02235|011|E|elevated levels of atorvastatin, which could result in rhabdomyolysis.(1-5)|
02235|012|B||
02235|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02235|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02235|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02235|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02235|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02235|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02235|019|P|predisposed to myopathy or rhabdomyolysis.|
02235|020|B||
02235|021|M|PATIENT MANAGEMENT:  In patients receiving protease inhibitors, consider the|
02235|022|M|use of fluvastatin.|
02235|023|M|   If atorvastatin is used with concurrent darunavir, fosamprenavir,|
02235|024|M|lopinavir, or saquinavir, limit the dose of atorvastatin to 20 mg daily with|
02235|025|M|careful monitoring.(1-5)|
02235|026|B||
02235|027|D|DISCUSSION:  A study in 15 subjects found that darunavir/ritonavir (300/100|
02235|028|D|mg twice daily) decreased the maximum concentration (Cmax) and area-under|
02235|029|D|curve (AUC) of atorvastatin (10 mg daily) by 44% and 15%, when compared to|
02235|030|D|atorvastatin (40 mg daily) administered alone.  Atorvastatin minimum|
02235|031|D|concentration (Cmin) increased by 81% during concurrent therapy.(2)|
02235|032|D|   In a study in 16 subjects, concurrent atorvastatin (10 mg daily for 4|
02235|033|D|days) and fosamprenavir (1400 mg twice daily for 2 weeks) increased|
02235|034|D|atorvastatin Cmax and AUC by 304% and 130%, respectively.  Atorvastatin Cmin|
02235|035|D|decreased by 10%.(3)  The Cmax, AUC, and Cmin of amprenavir decreased by by|
02235|036|D|18%, 27%, and 12%, respectively.(3)|
02235|037|D|   In a study in 16 subjects, the administration of atorvastatin (10 mg|
02235|038|D|daily for 4 days) and fosamprenavir (700 mg twice daily for 2 weeks) with|
02235|039|D|ritonavir (100 mg twice daily for 2 weeks) increased the atorvastatin Cmax,|
02235|040|D|AUC, and Cmin by 184%, 153%, and 73%, respectively.(1,4)  There were no|
02235|041|D|changes in amprenavir Cmax, AUC, or Cmin.(3)|
02235|042|D|   A randomized, controlled trial in healthy subjects examined the effects|
02235|043|D|of a combination of ritonavir and saquinavir on the pharmacokinetics of|
02235|044|D|atorvastatin, pravastatin, and simvastatin and the effects of pravastatin on|
02235|045|D|nelfinavir pharmacokinetics.  The combination of ritonavir and saquinavir|
02235|046|D|decreased pravastatin levels by 50% and increased atorvastatin and|
02235|047|D|simvastatin levels by 79% and 3059%, respectively.  Pravastatin had no|
02235|048|D|statistically significant effect on nelfinavir pharmacokinetics.(6)|
02235|049|D|   Concurrent administration of atorvastatin (40 mg for 4 days) with|
02235|050|D|ritonavir-saquinavir (400 mg twice daily) increased atorvastatin AUC and|
02235|051|D|Cmax by 3.9-fold and 4.3-fold, respectively.(1)|
02235|052|D|   Concurrent administration of atorvastatin (20 mg) with|
02235|053|D|lopinavir-ritonavir (400-100 mg twice daily) increased atorvastatin by|
02235|054|D|5.9-fold.(1)|
02235|055|B||
02235|056|R|REFERENCES:|
02235|057|B||
02235|058|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02235|059|R|  2020.|1
02235|060|R|2.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
02235|061|R|  March, 2023.|1
02235|062|R|3.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
02235|063|R|  March, 2019.|1
02235|064|R|4.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
02235|065|R|  Laboratories December, 2019.|1
02235|066|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02235|067|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02235|068|R|  HIV. Department of Health and Human Services. Available at:|6
02235|069|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
02235|070|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
02235|071|R|6.Fichtenbaum CJ, Gerber JG, Rosenkranz SL, Segal Y, Aberg JA, Blaschke T,|2
02235|072|R|  Alston B, Fang F, Kosel B, Aweeka F. Pharmacokinetic interactions between|2
02235|073|R|  protease inhibitors and statins in HIV seronegative volunteers: ACTG Study|2
02235|074|R|  A5047. AIDS 2002 Mar 8;16(4):569-77.|2
02236|001|T|MONOGRAPH TITLE:  Atorvastatin (<= 20 mg)/Selected Protease Inhibitors|
02236|002|B||
02236|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02236|004|L|take action as needed.|
02236|005|B||
02236|006|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
02236|007|A|atorvastatin by CYP3A4.(1-5)|
02236|008|B||
02236|009|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors may result in|
02236|010|E|elevated levels of atorvastatin, which could result in rhabdomyolysis.(1-5)|
02236|011|B||
02236|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02236|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02236|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02236|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02236|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02236|017|P|transporter OATP1B1 may have increased statin concentrations and be|
02236|018|P|predisposed to myopathy or rhabdomyolysis.|
02236|019|B||
02236|020|M|PATIENT MANAGEMENT:  In patients receiving protease inhibitors, consider the|
02236|021|M|use of fluvastatin.|
02236|022|M|   If atorvastatin is used with concurrent darunavir, fosamprenavir,|
02236|023|M|lopinavir, or saquinavir, limit the dose of atorvastatin to 20 mg daily with|
02236|024|M|careful monitoring.(1-5)|
02236|025|M|   Monitor for signs and symptoms of myopathy (e.g. muscle weakness, muscle|
02236|026|M|pain, rising creatine kinase).|
02236|027|B||
02236|028|D|DISCUSSION:  A study in 15 subjects found that darunavir/ritonavir (300/100|
02236|029|D|mg twice daily) decreased the maximum concentration (Cmax) and area-under|
02236|030|D|curve (AUC) of atorvastatin (10 mg daily) by 64% and 15%, when compared to|
02236|031|D|atorvastatin (40 mg daily) administered alone.  Atorvastatin minimum|
02236|032|D|concentration (Cmin) increased by 81% during concurrent therapy.(2)|
02236|033|D|   In a study in 16 subjects, concurrent atorvastatin (10 mg daily for 4|
02236|034|D|days) and fosamprenavir (1400 mg twice daily for 2 weeks) increased|
02236|035|D|atorvastatin Cmax and AUC by 304% and 130%, respectively.  Atorvastatin Cmin|
02236|036|D|decreased by 10%.(3)  The Cmax, AUC, and Cmin of amprenavir decreased by by|
02236|037|D|18%, 27%, and 12%, respectively.(3)|
02236|038|D|   In a study in 16 subjects, the administration of atorvastatin (10 mg|
02236|039|D|daily for 4 days) and fosamprenavir (700 mg twice daily for 2 weeks) with|
02236|040|D|ritonavir (100 mg twice daily for 2 weeks) increased the atorvastatin Cmax,|
02236|041|D|AUC, and Cmin by 184%, 153%, and 73%, respectively.(1,4)  There were no|
02236|042|D|changes in amprenavir Cmax, AUC, or Cmin.(3)|
02236|043|D|   A randomized, controlled trial in healthy subjects examined the effects|
02236|044|D|of a combination of ritonavir and saquinavir on the pharmacokinetics of|
02236|045|D|atorvastatin, pravastatin, and simvastatin and the effects of pravastatin on|
02236|046|D|nelfinavir pharmacokinetics.  The combination of ritonavir and saquinavir|
02236|047|D|decreased pravastatin levels by 50% and increased atorvastatin and|
02236|048|D|simvastatin levels by 79% and 3059%, respectively.  Pravastatin had no|
02236|049|D|statistically significant effect on nelfinavir pharmacokinetics.(6)|
02236|050|D|   Concurrent administration of atorvastatin (40 mg) with|
02236|051|D|ritonavir-saquinavir (400 mg twice daily) increased atorvastatin AUC and|
02236|052|D|Cmax by 3.9-fold and 4.3-fold, respectively.(1)|
02236|053|D|   Concurrent administration of atorvastatin (20 mg) with|
02236|054|D|lopinavir-ritonavir (400-100 mg twice daily) increased atorvastatin by|
02236|055|D|5.9-fold.(1)|
02236|056|B||
02236|057|R|REFERENCES:|
02236|058|B||
02236|059|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02236|060|R|  2020.|1
02236|061|R|2.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
02236|062|R|  March, 2023.|1
02236|063|R|3.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
02236|064|R|  March, 2019.|1
02236|065|R|4.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
02236|066|R|  Laboratories December, 2019.|1
02236|067|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02236|068|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02236|069|R|  HIV. Department of Health and Human Services. Available at:|6
02236|070|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
02236|071|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
02236|072|R|6.Fichtenbaum CJ, Gerber JG, Rosenkranz SL, Segal Y, Aberg JA, Blaschke T,|2
02236|073|R|  Alston B, Fang F, Kosel B, Aweeka F. Pharmacokinetic interactions between|2
02236|074|R|  protease inhibitors and statins in HIV seronegative volunteers: ACTG Study|2
02236|075|R|  A5047. AIDS 2002 Mar 8;16(4):569-77.|2
02237|001|T|MONOGRAPH TITLE:  Atorvastatin (Greater Than 40 mg)/Nelfinavir; Simeprevir|
02237|002|B||
02237|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02237|004|L|is contraindicated and generally should not be dispensed or administered to|
02237|005|L|the same patient.|
02237|006|B||
02237|007|A|MECHANISM OF ACTION:  Nelfinavir may inhibit the metabolism of atorvastatin|
02237|008|A|by CYP3A4.(1-3)  Simeprevir may increase the absorption of atorvastatin by|
02237|009|A|inhibiting OATP1B1 and CYP3A4.(4)|
02237|010|B||
02237|011|E|CLINICAL EFFECTS:  Concurrent use of nelfinavir(1-3) or simeprevir(4) may|
02237|012|E|result in elevated levels of atorvastatin, which could result in|
02237|013|E|rhabdomyolysis.|
02237|014|B||
02237|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02237|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02237|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02237|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02237|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02237|020|P|transporter OATP1B1 may have increased statin concentrations and be|
02237|021|P|predisposed to myopathy or rhabdomyolysis.|
02237|022|B||
02237|023|M|PATIENT MANAGEMENT:  In patients receiving protease inhibitors, consider the|
02237|024|M|use of fluvastatin.|
02237|025|M|   If atorvastatin is used with concurrent nelfinavir(1-3) or simeprevir,(4)|
02237|026|M|limit the dose of atorvastatin to 40 mg daily with careful monitoring.|
02237|027|B||
02237|028|D|DISCUSSION:  In a study, nelfinavir (1250 mg twice a day for 14 days)|
02237|029|D|increased the AUC and Cmax of atorvastatin (10 mg daily for 28 days) 74% and|
02237|030|D|2.2-fold, respectively.(1)|
02237|031|D|   An open-label study in healthy subjects examined the effects of|
02237|032|D|nelfinavir on atorvastatin and simvastatin pharmacokinetics.  Nelfinavir|
02237|033|D|increased the atorvastatin AUC, Cmax, and Cmin by 74%, 122%, and 39%,|
02237|034|D|respectively. Nelfinavir increased simvastatin AUC and Cmax by 505% and|
02237|035|D|517%, respectively.  There was no effect on nelfinavir pharmacokinetics when|
02237|036|D|compared to historical controls.(2,3)|
02237|037|D|   In a study in 18 subjects, simeprevir (150 mg daily for 10 days)|
02237|038|D|increased the Cmax and AUC of a single dose of atorvastatin (40 mg) by|
02237|039|D|1.70-fold and 2.12-fold, respectively.  The Cmax and AUC of|
02237|040|D|2-hydroxy-atorvastatin increased by 1.98-fold and 2.29-fold,|
02237|041|D|respectively.(4)|
02237|042|B||
02237|043|R|REFERENCES:|
02237|044|B||
02237|045|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02237|046|R|  2020.|1
02237|047|R|2.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
02237|048|R|  Pharmaceuticals, Inc. September, 2016.|1
02237|049|R|3.Hsyu PH, Schultz-Smith MD, Lillibridge JH, Lewis RH, Kerr BM.|2
02237|050|R|  Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-|2
02237|051|R|  methylglutaryl coenzyme A reductase inhibitors atorvastatin and|2
02237|052|R|  simvastatin. Antimicrob Agents Chemother 2001 Dec;45(12):3445-50.|2
02237|053|R|4.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
02237|054|R|  November, 2017.|1
02238|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 40 mg)/Nelfinavir;|
02238|002|T|Simeprevir|
02238|003|B||
02238|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02238|005|L|take action as needed.|
02238|006|B||
02238|007|A|MECHANISM OF ACTION:  Nelfinavir may inhibit the metabolism of atorvastatin|
02238|008|A|by CYP3A4.(1-3)  Simeprevir may increase the absorption of atorvastatin by|
02238|009|A|inhibiting OATP1B1 and CYP3A4.(4)|
02238|010|B||
02238|011|E|CLINICAL EFFECTS:  Concurrent use of nelfinavir(1-3) or simeprevir(4) may|
02238|012|E|result in elevated levels of atorvastatin, which could result in|
02238|013|E|rhabdomyolysis.|
02238|014|B||
02238|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02238|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02238|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02238|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02238|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02238|020|P|transporter OATP1B1 may have increased statin concentrations and be|
02238|021|P|predisposed to myopathy or rhabdomyolysis.|
02238|022|B||
02238|023|M|PATIENT MANAGEMENT:  In patients receiving protease inhibitors, consider the|
02238|024|M|use of fluvastatin.|
02238|025|M|   If atorvastatin is used with concurrent nelfinavir(1-3) or simeprevir,(4)|
02238|026|M|limit the dose of atorvastatin to 40 mg daily with careful monitoring.|
02238|027|B||
02238|028|D|DISCUSSION:  In a study, nelfinavir (1250 mg twice a day for 14 days)|
02238|029|D|increased the AUC and Cmax of atorvastatin (10 mg daily for 28 days) 74% and|
02238|030|D|2.2-fold, respectively.(1)|
02238|031|D|   An open-label study in healthy subjects examined the effects of|
02238|032|D|nelfinavir on atorvastatin and simvastatin pharmacokinetics.  Nelfinavir|
02238|033|D|increased the atorvastatin AUC, Cmax, and Cmin by 74%, 122%, and 39%,|
02238|034|D|respectively. Nelfinavir increased simvastatin AUC and Cmax by 505% and|
02238|035|D|517%, respectively.  There was no effect on nelfinavir pharmacokinetics when|
02238|036|D|compared to historical controls.(2,3)|
02238|037|D|   In a study in 18 subjects, simeprevir (150 mg daily for 10 days)|
02238|038|D|increased the Cmax and AUC of a single dose of atorvastatin (40 mg) by|
02238|039|D|1.70-fold and 2.12-fold, respectively.  The Cmax and AUC of|
02238|040|D|2-hydroxy-atorvastatin increased by 1.98-fold and 2.29-fold,|
02238|041|D|respectively.(4)|
02238|042|B||
02238|043|R|REFERENCES:|
02238|044|B||
02238|045|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02238|046|R|  2020.|1
02238|047|R|2.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
02238|048|R|  Pharmaceuticals, Inc. September, 2016.|1
02238|049|R|3.Hsyu PH, Schultz-Smith MD, Lillibridge JH, Lewis RH, Kerr BM.|2
02238|050|R|  Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-|2
02238|051|R|  methylglutaryl coenzyme A reductase inhibitors atorvastatin and|2
02238|052|R|  simvastatin. Antimicrob Agents Chemother 2001 Dec;45(12):3445-50.|2
02238|053|R|4.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
02238|054|R|  November, 2017.|1
02239|001|T|MONOGRAPH TITLE:  Atorvastatin (Greater Than 10 mg)/Tipranavir|
02239|002|B||
02239|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02239|004|L|is contraindicated and generally should not be dispensed or administered to|
02239|005|L|the same patient.|
02239|006|B||
02239|007|A|MECHANISM OF ACTION:  Tipranavir may inhibit the metabolism of atorvastatin|
02239|008|A|by CYP3A4.(1-6)|
02239|009|B||
02239|010|E|CLINICAL EFFECTS:  Concurrent use of tipranavir may result in elevated|
02239|011|E|levels of atorvastatin, which could result in rhabdomyolysis.(1-6)|
02239|012|B||
02239|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02239|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02239|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02239|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02239|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02239|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02239|019|P|predisposed to myopathy or rhabdomyolysis.|
02239|020|B||
02239|021|M|PATIENT MANAGEMENT:  The manufacturers of atorvastatin and tipranavir say to|
02239|022|M|avoid the use of atorvastatin in patients taking tipranavir.(1-6)  If|
02239|023|M|atorvastatin is used with tipranavir, use the lowest dose possible of|
02239|024|M|atorvastatin with careful monitoring.  The UK manufacturer of atorvastatin|
02239|025|M|and the Canadian and UK manufacturers of tipranavir further state that if|
02239|026|M|concurrent administration is required, do not exceed an atorvastatin dose of|
02239|027|M|10 mg daily.(4-6)|
02239|028|M|   Consider the use of fluvastatin in patients maintained on tipranavir.|
02239|029|B||
02239|030|D|DISCUSSION:  In a study in 22 subjects, pretreatment with|
02239|031|D|tipranavir/ritonavir (500/200 mg twice daily) increased the Cmax, AUC, and|
02239|032|D|Cmin of a single dose of atorvastatin (10 mg) by 8.61-fold, 9.36-fold, and|
02239|033|D|5.19-fold, respectively.  The Cmax, AUC, and Cmin of|
02239|034|D|orthohydroxy-atorvastatin decreased by 98%, 89%, and 93%, respectively.  The|
02239|035|D|AUC and Cmin of parahydroxy-atorvastatin decreased by 82% and 66%,|
02239|036|D|respectively.  There were no significant effects on tipranavir levels.(3)|
02239|037|B||
02239|038|R|REFERENCES:|
02239|039|B||
02239|040|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02239|041|R|  2020.|1
02239|042|R|2.Lipitor (atorvastatin) Canadian product information. Pfizer Canada Inc.|1
02239|043|R|  May 31, 2019.|1
02239|044|R|3.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
02239|045|R|  Pharmaceuticals, Inc. April, 2024.|1
02239|046|R|4.Lipitor (atorvastatin calcium trihydrate) UK summary of product|1
02239|047|R|  characteristics. Pfizer Limited April 1, 2019.|1
02239|048|R|5.Aptivus (tipranavir) Canadian prescribing information. Boehringer|1
02239|049|R|  Ingelheim March 5, 2014.|1
02239|050|R|6.Aptivus (tipranavir) UK Summary of product characteristics. Boehringer|1
02239|051|R|  Ingelheim Limited October 3, 2018.|1
02240|001|T|MONOGRAPH TITLE:  Domperidone/QT Prolonging Agents|
02240|002|B||
02240|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02240|004|L|is contraindicated and generally should not be dispensed or administered to|
02240|005|L|the same patient.|
02240|006|B||
02240|007|A|MECHANISM OF ACTION:  Concurrent use of domperidone with other agents that|
02240|008|A|prolong the QTc interval may result in additive effects on the QTc|
02240|009|A|interval.(1)|
02240|010|B||
02240|011|E|CLINICAL EFFECTS:  The use of domperidone patients maintained on agents that|
02240|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02240|013|E|arrhythmias, including torsades de pointes.(1)|
02240|014|B||
02240|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02240|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02240|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02240|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02240|019|P|or female gender.(2)  The elderly and patients taking dosages of domperidone|
02240|020|P|greater than 30 mg may also be at increased risk.|
02240|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02240|022|P|higher systemic concentrations of either QT prolonging drug are additional|
02240|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02240|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02240|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02240|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02240|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02240|028|B||
02240|029|M|PATIENT MANAGEMENT:  The concurrent use of domperidone and agents known to|
02240|030|M|prolong the QT interval is contraindicated.(1)|
02240|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02240|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02240|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02240|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02240|035|B||
02240|036|D|DISCUSSION:  Treatment with domperidone has been associated with increased|
02240|037|D|risk of sudden cardiac death.(1)|
02240|038|D|   Agents that are linked to this monograph may have varying degrees of|
02240|039|D|potential to prolong the QTc interval but are generally accepted to have a|
02240|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02240|041|D|been shown to prolong the QTc interval either through their mechanism of|
02240|042|D|action, through studies on their effects on the QTc interval, or through|
02240|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02240|044|D|and/or post-marketing reports.(2)|
02240|045|D|   One or more of the drug pairs linked to this monograph have been included|
02240|046|D|in a list of interactions that should be considered "high-priority" for|
02240|047|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02240|048|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02240|049|D|Coordinator (ONC) for Health Information Technology.|
02240|050|B||
02240|051|R|REFERENCES:|
02240|052|B||
02240|053|R|1.Teva-Domperidone (Domperidone) Canadian product monograph. Teva Canada|1
02240|054|R|  Limited March 6, 2015.|1
02240|055|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02240|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02240|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02240|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02240|059|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02240|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02240|061|R|  settings: a scientific statement from the American Heart Association and|6
02240|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02240|063|R|  2;55(9):934-47.|6
02240|064|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02240|065|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02240|066|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02240|067|R|  19(5):735-43.|6
02241|001|T|MONOGRAPH TITLE:  Select CYP2C8; 2C9 Substrates/Mifepristone (Chronic|
02241|002|T|therapy)|
02241|003|B||
02241|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02241|005|L|of severe adverse interaction.|
02241|006|B||
02241|007|A|MECHANISM OF ACTION:  Mifepristone is a moderate inhibitor of CYP2C8 and|
02241|008|A|CYP2C9.(1)|
02241|009|B||
02241|010|E|CLINICAL EFFECTS:  Decreased clearance may increase systemic concentrations|
02241|011|E|of drugs primarily metabolized by CYP2C8 or CYP2C9, leading to toxicity.(1)|
02241|012|B||
02241|013|P|PREDISPOSING FACTORS:  None determined.|
02241|014|B||
02241|015|M|PATIENT MANAGEMENT:  Closely monitor patients stable on CYP2C8/2C9|
02241|016|M|substrates for increased therapeutic effect or toxicity when chronic|
02241|017|M|mifepristone therapy is started or adjusted.  Adjust dosage of the 2C8/2C9|
02241|018|M|substrate drug accordingly.  Because of the long half-life of mifepristone,|
02241|019|M|the effect of changes in mifepristone therapy may not be seen for 2 weeks.|
02241|020|M|   For patients on chronic mifepristone and newly started on a CYP2C8/2C9|
02241|021|M|substrate, the smallest recommended dose of the CYP2C8/2C9 substrate is|
02241|022|M|suggested by the manufacturer of mifepristone.(1)|
02241|023|M|   If chronic mifepristone therapy is discontinued, the manufacturer of|
02241|024|M|mifepristone recommends waiting at least 2 weeks before increasing the dose|
02241|025|M|of a concomitant interacting medication.(1)|
02241|026|B||
02241|027|D|DISCUSSION:  Mifepristone 1200 mg was given daily for 7 days, followed by a|
02241|028|D|single dose of fluvastatin (40 mg), a CYP 2C8/2C9 substrate.  The|
02241|029|D|area-under-curve (AUC) of fluvastatin was increased 3.57 fold. The|
02241|030|D|manufacturer notes this result could be representative of other oral drugs|
02241|031|D|with CYP2C8/2C9 metabolism.(1)|
02241|032|D|   Mifepristone has a long elimination half-life of approximately 85 hours|
02241|033|D|and so full effects of a mifepristone dose change on CYP2C8/2C9 substrates|
02241|034|D|may not be seen for two weeks.  Extended monitoring for this interaction may|
02241|035|D|be required when mifepristone is started, stopped or if dose is changed.(1)|
02241|036|D|   Medications linked to this interaction are celecoxib, dasabuvir,|
02241|037|D|fluvastatin, and repaglinide.  These drugs have a narrow therapeutic range|
02241|038|D|or are designated as CYP2C8 or CYP2C9 Sensitive Substrates(2,3), i.e.|
02241|039|D|moderate CYP2C8 or 2C9 inhibitors are expected to increase exposure (AUC) to|
02241|040|D|these agents by 2-fold to 5-fold.|
02241|041|B||
02241|042|R|REFERENCES:|
02241|043|B||
02241|044|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
02241|045|R|  November, 2019.|1
02241|046|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02241|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02241|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02241|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02241|050|R|  11/14/2017.|1
02241|051|R|3.This information is based on an extract from the Certara Drug Interaction|6
02241|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02242|001|T|MONOGRAPH TITLE:  Itraconazole/Atorvastatin (<=20mg)|
02242|002|B||
02242|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02242|004|L|take action as needed.|
02242|005|B||
02242|006|A|MECHANISM OF ACTION:  Itraconazole may inhibit the metabolism of|
02242|007|A|atorvastatin by CYP3A4.|
02242|008|B||
02242|009|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
02242|010|E|of atorvastatin, which may result in an increased risk of rhabdomyolysis.|
02242|011|B||
02242|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02242|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02242|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02242|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02242|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02242|017|P|transporter OATP1B1 may have increased statin concentrations and be|
02242|018|P|predisposed to myopathy or rhabdomyolysis.|
02242|019|B||
02242|020|M|PATIENT MANAGEMENT:  The manufacturer of atorvastatin states the dose of|
02242|021|M|atorvastatin should be limited to 20 mg in patients receiving|
02242|022|M|itraconazole.(1)  The manufacturer of itraconazole(2) states that concurrent|
02242|023|M|use of atorvastatin should be carefully monitored.  Monitor patients|
02242|024|M|receiving concurrent therapy for signs and symptoms of rhabdomyolysis if|
02242|025|M|concurrent therapy is warranted.|
02242|026|B||
02242|027|D|DISCUSSION:  In a randomized, double-blind, cross-over study, administration|
02242|028|D|of atorvastatin (40 mg single dose) on day 4 of itraconazole (200 mg daily|
02242|029|D|for 5 days) increased atorvastatin area-under-curve (AUC) and half-life|
02242|030|D|(T1/2) 3-fold.  There were no significant change in atorvastatin maximum|
02242|031|D|concentration (Cmax).  Atorvastatin lactone AUC, Cmax, and T1/2 increased|
02242|032|D|4-fold, 2-fold, and 2-fold respectively.  The AUC of active and total|
02242|033|D|HMG-CoA reductase inhibitors increased 1.6-fold and 1.7-fold,|
02242|034|D|respectively.(1,3)|
02242|035|D|   In healthy subjects, itraconazole increased atorvastatin T1/2, AUC, and|
02242|036|D|Cmax by 60%, 2.4-fold, and 47%, respectively.  Itraconazole had no effect on|
02242|037|D|pravastatin pharmacokinetics.(4)|
02242|038|D|   In a study in 18 healthy subjects, itraconazole (400 mg) increased the|
02242|039|D|Cmax, AUC, and half-life of a single dose of atorvastatin (20 mg) by 38%,|
02242|040|D|150%, 30%, respectively.(5)|
02242|041|B||
02242|042|R|REFERENCES:|
02242|043|B||
02242|044|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02242|045|R|  2020.|1
02242|046|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02242|047|R|  Products, L.P. February, 2024.|1
02242|048|R|3.Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the|2
02242|049|R|  pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998 Jul;|2
02242|050|R|  64(1):58-65.|2
02242|051|R|4.Jacobson TA. Comparative pharmacokinetic interaction profiles of|2
02242|052|R|  pravastatin, simvastatin, and atorvastatin when coadministered with|2
02242|053|R|  cytochrome P450 inhibitors. Am J Cardiol 2004 Nov 1;94(9):1140-6.|2
02242|054|R|5.Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P.|2
02242|055|R|  Itraconazole alters the pharmacokinetics of atorvastatin to a greater|2
02242|056|R|  extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000|2
02242|057|R|  Oct;68(4):391-400.|2
02243|001|T|MONOGRAPH TITLE:  Selected HMG Co-A Reductase Inhibitors/Fluconazole|
02243|002|B||
02243|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02243|004|L|take action as needed.|
02243|005|B||
02243|006|A|MECHANISM OF ACTION:  Fluconazole(1-2) may inhibit the metabolism of|
02243|007|A|atorvastatin, lovastatin, and simvastatin by CYP3A4. Fluconazole may inhibit|
02243|008|A|the metabolism of fluvastatin by CYP2C9.(3)|
02243|009|B||
02243|010|E|CLINICAL EFFECTS:  Concurrent use of fluconazole(1,2,4-6) or voriconazole(3)|
02243|011|E|may result in elevated levels of atorvastatin, fluvastatin, lovastatin, and|
02243|012|E|simvastatin and rhabdomyolysis.|
02243|013|B||
02243|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02243|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02243|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02243|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02243|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02243|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02243|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on fluvastatin who are|
02243|021|P|CYP2C9 intermediate or poor metabolizers may have increased fluvastatin|
02243|022|P|concentrations and  risk of myopathy.|
02243|023|B||
02243|024|M|PATIENT MANAGEMENT:  Do not use fluvastatin in doses greater than 20 mg|
02243|025|M|twice daily in patients receiving fluconazole.(6)|
02243|026|M|   Concurrent use of fluconazole with atorvastatin, fluvastatin, lovastatin,|
02243|027|M|or simvastatin should be approached with caution.  Patients should be|
02243|028|M|carefully monitored for and instructed to report any signs of myopathy.|
02243|029|M|Adjustment of the statin dose may be required.|
02243|030|B||
02243|031|D|DISCUSSION:  In a study in 12 healthy subjects, pretreatment with|
02243|032|D|fluconazole (400 mg Day 1, 200 mg/day on Days 2-4) increased fluvastatin|
02243|033|D|area-under-curve (AUC) and maximum concentration (Cmax) by 84% and 44%,|
02243|034|D|respectively.(3,5)  Fluvastatin half-life increased by 80%.(3)|
02243|035|D|   There are four case reports of rhabdomyolysis following the addition of|
02243|036|D|fluconazole to patients previously stabilized on simvastatin|
02243|037|D|therapy(1,4,8,9) and one case report of rhabdomyolysis during concurrent|
02243|038|D|fluconazole and atorvastatin.(6)|
02243|039|D|   In a randomized, double-blind, cross-over study in 14 healthy males,|
02243|040|D|pretreatment with fluconazole (200 mg daily for 11 days) increased the AUC|
02243|041|D|and Cmax of a single dose of rosuvastatin (80 mg on Day 8) by 14% and 9%,|
02243|042|D|respectively.  These changes were not considered clinically significant.(7)|
02243|043|D|   In a PKPB model, concurrent use of atorvastatin (40 mg daily) with|
02243|044|D|fluconazole (400 mg daily for 5 days) increased the simulated Cmax ratio and|
02243|045|D|AUC ratio of atorvastatin by 1.42 and 2.17, respectively, and increased the|
02243|046|D|simulated Cmax ratio and AUC ratio of atorvastatin lactone by 2.94 and 3.82,|
02243|047|D|respectively.(10)|
02243|048|D|   One or more of the drug pairs linked to this monograph have been included|
02243|049|D|in a list of interactions that should be considered "high-priority" for|
02243|050|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02243|051|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02243|052|D|Coordinator (ONC) for Health Information Technology.|
02243|053|B||
02243|054|R|REFERENCES:|
02243|055|B||
02243|056|R|1.Shaukat A, Benekli M, Vladutiu GD, Slack JL, Wetzler M, Baer MR.|3
02243|057|R|  Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharmacother 2003|3
02243|058|R|  Jul-Aug;37(7-8):1032-5.|3
02243|059|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02243|060|R|  2020.|1
02243|061|R|3.Kantola T, Backman JT, Niemi M, Kivisto KT, Neuvonen PJ. Effect of|2
02243|062|R|  fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J|2
02243|063|R|  Clin Pharmacol 2000 Jun;56(3):225-9.|2
02243|064|R|4.Moro H, Tsukada H, Tanuma A, Shirasaki A, Iino N, Nishibori T, Nishi S,|3
02243|065|R|  Gejyo F. Rhabdomyolysis after simvastatin therapy in an HIV-infected|3
02243|066|R|  patient with chronic renal failure. AIDS Patient Care STDS 2004 Dec;|3
02243|067|R|  18(12):687-90.|3
02243|068|R|5.Kahri J, Valkonen M, Backlund T, Vuoristo M, Kivisto KT. Rhabdomyolysis in|3
02243|069|R|  a patient receiving atorvastatin and fluconazole. Eur J Clin Pharmacol|3
02243|070|R|  2005 Feb;60(12):905-7.|3
02243|071|R|6.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
02243|072|R|  Pharmaceuticals Corporation August, 2017.|1
02243|073|R|7.Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. The|2
02243|074|R|  effect of fluconazole on the pharmacokinetics of rosuvastatin. Eur J Clin|2
02243|075|R|  Pharmacol 2002 Nov;58(8):527-31.|2
02243|076|R|8.Findling O, Meier N, Sellner J, Nedeltchev K, Arnold M. Clinical|3
02243|077|R|  reasoning: rhabdomyolysis after combined treatment with simvastatin and|3
02243|078|R|  fluconazole. Neurology 2008 Oct 7;71(15):e34-7.|3
02243|079|R|9.Hazin R, Abuzetun JY, Suker M, Porter J. Rhabdomyolysis induced by|3
02243|080|R|  simvastatin-fluconazole combination. J Natl Med Assoc 2008 Apr;|3
02243|081|R|  100(4):444-6.|3
02243|082|R|10.Li S, Yu Y, Jin Z, Dai Y, Lin H, Jiao Z, Ma G, Cai W, Han B, Xiang X.|2
02243|083|R|   Prediction of pharmacokinetic drug-drug interactions causing|2
02243|084|R|   atorvastatin-induced rhabdomyolysis using physiologically based|2
02243|085|R|   pharmacokinetic modelling. Biomed Pharmacother 2019 Sep 10;119:109416.|2
02243|086|R|11.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02243|087|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02243|088|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02243|089|R|   19(5):735-43.|6
02244|001|T|MONOGRAPH TITLE:  Fluvastatin (Greater Than 20 mg BID)/Fluconazole|
02244|002|B||
02244|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02244|004|L|is contraindicated and generally should not be dispensed or administered to|
02244|005|L|the same patient.|
02244|006|B||
02244|007|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of fluvastatin|
02244|008|A|by CYP2C9.(1)|
02244|009|B||
02244|010|E|CLINICAL EFFECTS:  Concurrent use of fluconazole may result in elevated|
02244|011|E|levels of fluvastatin and rhabdomyolysis.|
02244|012|B||
02244|013|P|PREDISPOSING FACTORS:  Patients with a SLCO1B1 polymorphism that leads to|
02244|014|P|decreased or poor function of the hepatic uptake transporter OATP1B1 may|
02244|015|P|have increased statin concentrations and be predisposed to myopathy or|
02244|016|P|rhabdomyolysis.  Patients on fluvastatin who are CYP2C9 intermediate or poor|
02244|017|P|metabolizers may have increased fluvastatin concentrations and  risk of|
02244|018|P|myopathy.|
02244|019|B||
02244|020|M|PATIENT MANAGEMENT:  Do not use fluvastatin in doses greater than 20 mg|
02244|021|M|twice daily in patients receiving fluconazole.|
02244|022|B||
02244|023|D|DISCUSSION:  In a study in 12 healthy subjects, pretreatment with|
02244|024|D|fluconazole (400 mg Day 1, 200 mg/day on Days 2-4) increased fluvastatin|
02244|025|D|area-under-curve (AUC) and maximum concentration (Cmax) by 84% and 44%,|
02244|026|D|respectively.(1,2)  Fluvastatin half-life increased by 80%.(2)|
02244|027|B||
02244|028|R|REFERENCES:|
02244|029|B||
02244|030|R|1.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
02244|031|R|  Pharmaceuticals Corporation August, 2017.|1
02244|032|R|2.Kantola T, Backman JT, Niemi M, Kivisto KT, Neuvonen PJ. Effect of|2
02244|033|R|  fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J|2
02244|034|R|  Clin Pharmacol 2000 Jun;56(3):225-9.|2
02245|001|T|MONOGRAPH TITLE:  Domperidone/Selected Strong and Moderate CYP3A4 Inhibitors|
02245|002|B||
02245|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02245|004|L|is contraindicated and generally should not be dispensed or administered to|
02245|005|L|the same patient.|
02245|006|B||
02245|007|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inhibitors impair the|
02245|008|A|CYP3A4 mediated metabolism of domperidone.(1)|
02245|009|B||
02245|010|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inhibitors|
02245|011|E|may result in elevated levels of and toxicity from domperidone, including|
02245|012|E|life-threatening cardiac arrhythmias such as torsades de pointes.(1-2)|
02245|013|B||
02245|014|P|PREDISPOSING FACTORS:  In epidemiologic studies and post-market safety data,|
02245|015|P|domperidone was associated with an increased risk for serious ventricular|
02245|016|P|arrhythmias in patients > 60 years of age, using more than 30 mg of|
02245|017|P|domperidone daily, and having other risk factors for QT prolongation.(1)|
02245|018|P|   In general, the risk of QT prolongation or torsades de pointes may be|
02245|019|P|increased in patients with cardiovascular disease (e.g. heart failure,|
02245|020|P|myocardial infarction, history of torsades de pointes, congenital long QT|
02245|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02245|022|P|gender, or advanced age.(2)|
02245|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02245|024|P|higher systemic concentrations of either QT prolonging drug are additional|
02245|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02245|026|P|drug concentrations include rapid infusion of an intravenous dose or|
02245|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02245|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02245|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02245|030|B||
02245|031|M|PATIENT MANAGEMENT:  Concurrent use of strong or moderate CYP3A4 inhibitors|
02245|032|M|with domperidone is contraindicated.  Use alternative antiemetics, or an|
02245|033|M|alternative to the strong or moderate CYP3A4 inhibitor, whichever is more|
02245|034|M|clinically appropriate.|
02245|035|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02245|036|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02245|037|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02245|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02245|039|B||
02245|040|D|DISCUSSION:  In a study in 24 healthy subjects, ketoconazole (200 mg twice|
02245|041|D|daily) tripled plasma levels of domperidone (10 mg four times daily).  In|
02245|042|D|male subjects, the combination significantly increased QTc interval greater|
02245|043|D|than either agent alone.  In females, there were no significant changes in|
02245|044|D|QTc intervals, but QTc intervals were correlated with domperidone levels.(3)|
02245|045|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
02245|046|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir,|
02245|047|D|itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib,|
02245|048|D|lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir,|
02245|049|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
02245|050|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.|
02245|051|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  amprenavir,|
02245|052|D|atazanavir, clofazimine, darunavir, dronedarone, erythromycin, fluconazole,|
02245|053|D|and fosamprenavir.|
02245|054|D|   One or more of the drug pairs linked to this monograph have been included|
02245|055|D|in a list of interactions that should be considered "high-priority" for|
02245|056|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02245|057|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02245|058|D|Coordinator (ONC) for Health Information Technology.|
02245|059|B||
02245|060|R|REFERENCES:|
02245|061|B||
02245|062|R|1.Health Canada. Domperidone Maleate - Association with Serious Abnormal|1
02245|063|R|  Heart Rhythms and Sudden Death (Cardiac Arrest). available at:|1
02245|064|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/43423a-e|1
02245|065|R|  ng.php January 20, 2015.|1
02245|066|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02245|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02245|068|R|  settings: a scientific statement from the American Heart Association and|6
02245|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02245|070|R|  2;55(9):934-47.|6
02245|071|R|3.Boyce MJ, Baisley KJ, Warrington SJ. Pharmacokinetic interaction between|2
02245|072|R|  domperidone and ketoconazole leads to QT prolongation in healthy|2
02245|073|R|  volunteers: a randomized, placebo-controlled, double-blind, crossover|2
02245|074|R|  study. Br J Clin Pharmacol 2012 Mar;73(3):411-21.|2
02245|075|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02245|076|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02245|077|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02245|078|R|  19(5):735-43.|6
02246|001|T|MONOGRAPH TITLE:  Anagrelide/Aspirin|
02246|002|B||
02246|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02246|004|L|of severe adverse interaction.|
02246|005|B||
02246|006|A|MECHANISM OF ACTION:  Anagrelide may affect platelet function in a way that|
02246|007|A|synergizes with low-dose aspirin.(1)|
02246|008|B||
02246|009|E|CLINICAL EFFECTS:  Concurrent use of anagrelide and aspirin may increase the|
02246|010|E|risk of hemorrhage.(1,2)|
02246|011|B||
02246|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02246|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02246|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
02246|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02246|016|P|risk for bleeding (e.g. NSAIDs).|
02246|017|B||
02246|018|M|PATIENT MANAGEMENT:  The concurrent use of anagrelide and aspirin should be|
02246|019|M|approached with caution, especially in patients with a high risk profile for|
02246|020|M|hemorrhage.(2)|
02246|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02246|022|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02246|023|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02246|024|M|patients with any symptoms.|
02246|025|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02246|026|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02246|027|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02246|028|M|and/or swelling.|
02246|029|B||
02246|030|D|DISCUSSION:  In healthy subjects, the administration of of single dose|
02246|031|D|anagrelide (1 mg) and aspirin (900 mg) or multiple dose anagrelide (1 mg|
02246|032|D|daily) and aspirin (75 mg daily) resulted in greater anti-platelet|
02246|033|D|aggregation effects than aspirin alone.  Concurrent single doses of both|
02246|034|D|anagrelide and aspirin had no effects on bleeding time, prothrombin time, or|
02246|035|D|activated partial thromboplastin time.(2)|
02246|036|D|   A study in 809 patients with essential thrombocythemia compared the|
02246|037|D|combination of low-dose aspirin with hydroxyurea to the combination of|
02246|038|D|low-dose aspirin with anagrelide.  While patients receiving low-dose aspirin|
02246|039|D|with anagrelide had lower rates of venous thromboembolism, the combination|
02246|040|D|was associated with increased rates of arterial myelofibrosis, serious|
02246|041|D|hemorrhage, and transformation to myelofibrosis.(1)|
02246|042|B||
02246|043|R|REFERENCES:|
02246|044|B||
02246|045|R|1.Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins|2
02246|046|R|  BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR.|2
02246|047|R|  Hydroxyurea compared with anagrelide in high-risk essential|2
02246|048|R|  thrombocythemia. N Engl J Med 2005 Jul 7;353(1):33-45.|2
02246|049|R|2.Agrylin (anagrelide hydrochloride) US prescribing information. Shire US|1
02246|050|R|  Inc. October, 2021.|1
02247|001|T|MONOGRAPH TITLE:  Selected Dopamine Agonists/Selected Antipsychotics|
02247|002|B||
02247|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02247|004|L|of severe adverse interaction.|
02247|005|B||
02247|006|A|MECHANISM OF ACTION:  Selected dopamine agonists are used to treat|
02247|007|A|neurologic conditions such as Parkinson Disease (PD)or restless legs|
02247|008|A|syndrome, and endocrine disorders such as hyperprolactinemia by directly or|
02247|009|A|indirectly increasing dopamine concentrations at D2 receptors in the central|
02247|010|A|nervous system (CNS).  Antipsychotic agents counteract this effect by|
02247|011|A|blocking dopamine activity at CNS D2 receptors.(1-5)|
02247|012|B||
02247|013|E|CLINICAL EFFECTS:  The efficacy of either agent may be decreased, leading to|
02247|014|E|exacerbation of the disease being treated.|
02247|015|E|   In patients with Parkinson disease motor symptoms may worsen, increasing|
02247|016|E|the risk for falls, dysphagia or aspiration.(4,7)  Compared with Parkinson|
02247|017|E|patients not receiving antipsychotic therapy, Parkinson patients receiving|
02247|018|E|antipsychotics appear to have an increased mortality risk.(6)|
02247|019|E|   Patients with other conditions such as restless legs syndrome or a|
02247|020|E|psychotic disorder may also experience symptom exacerbation due to this|
02247|021|E|combination.|
02247|022|B||
02247|023|P|PREDISPOSING FACTORS:  Patients with Parkinson or Diffuse Lewy Body (DLB)|
02247|024|P|disease are particularly susceptible to adverse effects of dopamine blockade|
02247|025|P|by antipsychotics.|
02247|026|B||
02247|027|M|PATIENT MANAGEMENT:  Reassess the need for antipsychotic therapy.  If|
02247|028|M|psychosis or hallucinations are due to an antiparkinson agent, when possible|
02247|029|M|consider reducing the dose or changing the antiparkinson agent before|
02247|030|M|initiating antipsychotic therapy.  In patients with PD and dementia,|
02247|031|M|addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve|
02247|032|M|psychosis.  If an antipsychotic is required, then an atypical antipsychotic|
02247|033|M|should be used.(6,7)|
02247|034|M|   In patients with major psychotic disorders, consider reducing the dose,|
02247|035|M|changing or stopping the dopamine agonist.  The US manufacturer of|
02247|036|M|ropinirole recommends treatment with dopamine agonists only if potential|
02247|037|M|benefits outweigh risks.(1)  The US manufacturer of entacapone states it|
02247|038|M|should not ordinarily be used in patients with major psychotic disorders as|
02247|039|M|entacapone may lead to an exacerbation of psychosis.(4)|
02247|040|B||
02247|041|D|DISCUSSION:  An epidemiologic study evaluated 21,043 elderly patients with|
02247|042|D|Parkinson disease to determine if recent initiation of a typical or atypical|
02247|043|D|antipsychotic was associated with increased mortality.  They found an|
02247|044|D|adjusted odds ratio of 2.0 for death associated with atypical antipsychotics|
02247|045|D|versus no antipsychotic  They found an adjusted odds ratio of 2.4 for death|
02247|046|D|associated with typical versus atypical antipsychotics. The authors noted|
02247|047|D|the increased mortality found with typical antipsychotics supports current|
02247|048|D|treatment recommendations to use atypical antipsychotic agents in patients|
02247|049|D|with Parkinson disease.(6,7)|
02247|050|B||
02247|051|R|REFERENCES:|
02247|052|B||
02247|053|R|1.Requip (ropinirole hydrochloride) US prescribing information.|1
02247|054|R|  GlaxoSmithKline July, 2021.|1
02247|055|R|2.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
02247|056|R|  February, 2011.|1
02247|057|R|3.Stalveo (carbidopa; entacapone; levodopa) US Prescribing Information.|1
02247|058|R|  Orion/Novartis December, 2019.|1
02247|059|R|4.Comtan (entacapone) US prescribing information. Orion Corporation|1
02247|060|R|  February, 2016.|1
02247|061|R|5.Neupro (rotigotine transdermal system) US prescribing information. UCB|1
02247|062|R|  Inc. November, 2018.|1
02247|063|R|6.Marras C, Gruneir A, Wang X, Fischer H, Gill SS, Herrmann N, Anderson GM,|2
02247|064|R|  Hyson C, Rochon PA. Antipsychotics and mortality in Parkinsonism. Am J|2
02247|065|R|  Geriatr Psychiatry 2012 Feb;20(2):149-58.|2
02247|066|R|7.Oertel WH Berardelli A Bloem Br etal. Chapter 15 - Late (complicated)|6
02247|067|R|  Parkinson's disease in European Handbook of Neurological Management. 2011;|6
02247|068|R|  Volume 1, 2nd Edition:237 - 267.|6
02248|001|T|MONOGRAPH TITLE:  Telbivudine/Pegylated Interferon Alfa-2a|
02248|002|B||
02248|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02248|004|L|is contraindicated and generally should not be dispensed or administered to|
02248|005|L|the same patient.|
02248|006|B||
02248|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02248|008|B||
02248|009|E|CLINICAL EFFECTS:  Concurrent use of telbivudine and interferon alfa-2a may|
02248|010|E|increase the risk of peripheral neuropathy.(1,2))|
02248|011|B||
02248|012|P|PREDISPOSING FACTORS:  None determined.|
02248|013|B||
02248|014|M|PATIENT MANAGEMENT:  The concurrent use of telbivudine and pegylated|
02248|015|M|interferon alfa-2a is contraindicated.(1)|
02248|016|M|   Patients receiving concurrent therapy with telbivudine and other forms of|
02248|017|M|interferon alfa-2a should be closely observed for and instructed to report|
02248|018|M|any symptoms of peripheral neuropathy.  Treatment with telbivudine should be|
02248|019|M|reconsidered if peripheral neuropathy is suspected.(1,2)|
02248|020|B||
02248|021|D|DISCUSSION:  In a small clinical trial, 10% (5/48) of patients receiving|
02248|022|D|concurrent therapy with telbivudine and interferon alfa-2a developed serious|
02248|023|D|peripheral neuropathy.  An additional 3 patients developed non-serious|
02248|024|D|peripheral neuropathy, for a total incidence of 17% (8/48).  Incidence of|
02248|025|D|peripheral neuropathy in clinical trials with telbivudine alone has been|
02248|026|D|reported to be 0.3% and up to 5% with interferon alfa-2a alone.(2)|
02248|027|D|   The time to onset of serious neuropathy during concurrent therapy with|
02248|028|D|telbivudine and interferon alfa-2a was 1 to 6 months.  Symptoms included|
02248|029|D|weakness and paraesthesias and pain in the legs.(2)|
02248|030|B||
02248|031|R|REFERENCES:|
02248|032|B||
02248|033|R|1.Tyzeka (telbivudine) US prescribing information. Novartis Pharmaceuticals|1
02248|034|R|  Corporation December, 2018.|1
02248|035|R|2.Leclerc JM. Dear Health Care Professional letter.  Subject:  Risk of|1
02248|036|R|  peripheral neuropathy in patients treated with telbivudine (SEBIVO) and|1
02248|037|R|  interferon. Novartis Pharmaceuticeuticals Canada, Inc. March 7, 2008.|1
02249|001|T|MONOGRAPH TITLE:  Selected Dopamine Agonists/Select Atypical Antipsychotics|
02249|002|B||
02249|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02249|004|L|take action as needed.|
02249|005|B||
02249|006|A|MECHANISM OF ACTION:  Selected dopamine agonists are used to treat|
02249|007|A|neurologic conditions such as Parkinson Disease (PD) or restless legs|
02249|008|A|syndrome, and endocrine disorders such as hyperprolactinemia by directly or|
02249|009|A|indirectly increasing dopamine concentrations at D2 receptors in the central|
02249|010|A|nervous system (CNS).  Antipsychotic agents counteract this effect by|
02249|011|A|blocking dopamine activity at CNS D2 receptors.(1-5)|
02249|012|B||
02249|013|E|CLINICAL EFFECTS:  The efficacy of either agent may be decreased, leading to|
02249|014|E|exacerbation of the disease being treated, e.g. Parkinson disease or a|
02249|015|E|psychotic disorder.|
02249|016|E|   Dopamine agonists linked to this monograph are: bromocriptine,|
02249|017|E|entacapone, levodopa, pergolide, pramipexole, ropinirole and rotigotine.|
02249|018|E|   Atypical antipsychotics linked to this monograph are:  aripiprazole,|
02249|019|E|asenapine, iloperidone, lumateperone, lurasidone, paliperidone, quetiapine,|
02249|020|E|risperidone, ziprasidone and zotepine.|
02249|021|B||
02249|022|P|PREDISPOSING FACTORS:  Patients with Parkinson or Diffuse Lewy Body (DLB)|
02249|023|P|disease are particularly susceptible to adverse effects of dopamine blockade|
02249|024|P|by antipsychotics.|
02249|025|B||
02249|026|M|PATIENT MANAGEMENT:  Reassess the need for antipsychotic therapy. If|
02249|027|M|psychosis or hallucinations are due to an antiparkinson agent, when possible|
02249|028|M|consider reducing the dose or changing the antiparkinson agent before|
02249|029|M|initiating antipsychotic therapy.  In patients with PD and dementia,|
02249|030|M|addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve|
02249|031|M|psychosis.  If an antipsychotic is required, then an atypical antipsychotic|
02249|032|M|should be used.(6,7)|
02249|033|M|   In patients with major psychotic disorders, consider reducing the dose,|
02249|034|M|changing, or stopping the dopamine agonist.  The US manufacturer of|
02249|035|M|ropinirole recommends treatment with dopamine agonists only if potential|
02249|036|M|benefits outweigh risks.(1)  The US manufacturer of entacapone states it|
02249|037|M|should not ordinarily be used in patients with major psychotic disorders as|
02249|038|M|entacapone may lead to an exacerbation of psychosis.(4)|
02249|039|B||
02249|040|D|DISCUSSION:  An epidemiologic study evaluated 21,043 elderly patients with|
02249|041|D|Parkinson disease to determine if recent initiation of a typical or atypical|
02249|042|D|antipsychotic was associated with increased mortality.  They found an|
02249|043|D|adjusted odds ratio of 2.0 for death associated with atypical antipsychotics|
02249|044|D|versus no antipsychotic. They found an adjusted odds ratio of 2.4 for death|
02249|045|D|associated with typical versus atypical antipsychotics. The authors noted|
02249|046|D|the increased mortality found with typical antipsychotics supports current|
02249|047|D|treatment recommendations to use atypical antipsychotic agents in patients|
02249|048|D|with Parkinson disease.(6,7)|
02249|049|D|   Two clozapine trials showed significant improvement in psychosis without|
02249|050|D|worsening of motor symptoms. In contrast, two olanzapine trials were|
02249|051|D|associated with unacceptable worsening of motor symptoms.  Risperidone has|
02249|052|D|also been associated with motor worsening in case reports.  Quetiapine|
02249|053|D|evaluations have been conflicting with several small studies showing|
02249|054|D|improvement in psychotic symptoms while a more rigorous trial showed no|
02249|055|D|improvement.(6)|
02249|056|B||
02249|057|R|REFERENCES:|
02249|058|B||
02249|059|R|1.Requip (ropinirole hydrochloride) US prescribing information.|1
02249|060|R|  GlaxoSmithKline July, 2021.|1
02249|061|R|2.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
02249|062|R|  February, 2011.|1
02249|063|R|3.Stalveo (carbidopa; entacapone; levodopa) US Prescribing Information.|1
02249|064|R|  Orion/Novartis December, 2019.|1
02249|065|R|4.Comtan (entacapone) US prescribing information. Orion Corporation|1
02249|066|R|  February, 2016.|1
02249|067|R|5.Neupro (rotigotine transdermal system) US prescribing information. UCB|1
02249|068|R|  Inc. November, 2018.|1
02249|069|R|6.Marras C, Gruneir A, Wang X, Fischer H, Gill SS, Herrmann N, Anderson GM,|2
02249|070|R|  Hyson C, Rochon PA. Antipsychotics and mortality in Parkinsonism. Am J|2
02249|071|R|  Geriatr Psychiatry 2012 Feb;20(2):149-58.|2
02249|072|R|7.Oertel WH Berardelli A Bloem Br etal. Chapter 15 - Late (complicated)|6
02249|073|R|  Parkinson's disease in European Handbook of Neurological Management. 2011;|6
02249|074|R|  Volume 1, 2nd Edition:237 - 267.|6
02250|001|T|MONOGRAPH TITLE:  Amitriptyline; Nortriptyline/Fluconazole|
02250|002|B||
02250|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02250|004|L|take action as needed.|
02250|005|B||
02250|006|A|MECHANISM OF ACTION:  Amitriptyline and nortriptyline are primarily|
02250|007|A|metabolized via CYP2C19 and CYP2D6. Fluconazole is a strong inhibitor of|
02250|008|A|CYP2C19 and inhibits the metabolism of amitriptyline and nortriptyline via|
02250|009|A|this route.|
02250|010|B||
02250|011|E|CLINICAL EFFECTS:  Syncopal episodes, tachycardia, prolonged QT, and|
02250|012|E|delirium have been noted in case reports.(1-3) One patient died due to|
02250|013|E|complications after cardiac arrest.(1)|
02250|014|B||
02250|015|P|PREDISPOSING FACTORS:  Higher amitriptyline or nortriptyline or fluconazole|
02250|016|P|doses would be expected to increase the risk for a clinically significant|
02250|017|P|interaction.|
02250|018|P|   Concomitant prescribing of agents (e.g. bupropion, paroxetine) which|
02250|019|P|inhibit CYP2D6, the other major amitriptyline and nortriptyline metabolic|
02250|020|P|pathway, would further increase amitriptyline and nortriptyline levels and|
02250|021|P|risk for toxicity.|
02250|022|P|   The risk of seizures may be increased in patients with a history of head|
02250|023|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
02250|024|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
02250|025|P|of over-the-counter stimulants and anorectics; diabetics treated with oral|
02250|026|P|hypoglycemics or insulin; or with concomitant medications known to lower|
02250|027|P|seizure threshold (antipsychotics, theophylline, systemic steroids).|
02250|028|P|   The risk of anticholinergic toxicities including cognitive decline,|
02250|029|P|delirium, falls and fractures is increased in geriatric patients using more|
02250|030|P|than one medicine with anticholinergic properties.(6)|
02250|031|B||
02250|032|M|PATIENT MANAGEMENT:  For patients already on amitriptyline or nortriptyline|
02250|033|M|when fluconazole is started, consider monitoring amitriptyline and/or|
02250|034|M|nortriptyline blood levels, especially for patients with risks for toxicity|
02250|035|M|including renal impairment or who are taking moderate to higher doses of|
02250|036|M|either agent.  5-Nortriptyline and/or S-amitriptyline metabolite levels may|
02250|037|M|be measured at initiation of combination therapy with fluconazole and|
02250|038|M|repeated after 1 week.  The dosage of the tricyclic should be adjusted, if|
02250|039|M|necessary.(5)|
02250|040|M|   Monitor for adverse effects of tricyclics such as drowsiness, dizziness|
02250|041|M|or anticholinergic effects.  Consider lowering the dose in patients with|
02250|042|M|troublesome adverse effects prior to addition of fluconazole or if patient|
02250|043|M|is a fall risk.|
02250|044|M|   If patient is already on fluconazole when amitriptyline or nortriptyline|
02250|045|M|is started, begin with a lower than usual dose for the patient's indication,|
02250|046|M|then gradually increase dose if tolerated.|
02250|047|B||
02250|048|D|DISCUSSION:  Five amitriptyline-fluconazole cases are described in the|
02250|049|D|attached citations.|
02250|050|D|   In one case report(2) a patient receiving amitriptyline 75 mg twice daily|
02250|051|D|and bupropion 75 mg twice daily was started on fluconazole 200 mg daily.|
02250|052|D|Four days later the patient began having a series of syncopal episodes|
02250|053|D|accompanied by heart rates of 115 to 253 beats/minute.  Symptoms persisted|
02250|054|D|for the duration of concomitant therapy.  Discontinuation of fluconazole led|
02250|055|D|to resolution of symptoms.  Subsequently, while still on amitriptyline,|
02250|056|D|fluconazole was again added to the treatment regimen, leading to a return of|
02250|057|D|syncopal symptoms.|
02250|058|B||
02250|059|R|REFERENCES:|
02250|060|B||
02250|061|R|1.Newberry DL, Bass SN, Mbanefo CO. A fluconazole/amitriptyline drug|3
02250|062|R|  interaction in three male adults. Clin Infect Dis 1997 Feb;24(2):270-1.|3
02250|063|R|2.Robinson RF, Nahata MC, Olshefski RS. Syncope associated with concurrent|3
02250|064|R|  amitriptyline and fluconazole therapy. Ann Pharmacother 2000 Dec;|3
02250|065|R|  34(12):1406-9.|3
02250|066|R|3.Dorsey ST, Biblo LA. Prolonged QT interval and torsades de pointes caused|3
02250|067|R|  by the combination of fluconazole and amitriptyline. Am J Emerg Med 2000|3
02250|068|R|  Mar;18(2):227-9.|3
02250|069|R|4.Jiang ZP, Shu Y, Chen XP, Huang SL, Zhu RH, Wang W, He N, Zhou HH. The|2
02250|070|R|  role of CYP2C19 in amitriptyline N-demethylation in Chinese subjects. Eur|2
02250|071|R|  J Clin Pharmacol 2002 May;58(2):109-13.|2
02250|072|R|5.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
02250|073|R|  2024.|1
02250|074|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02250|075|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02250|076|R|  Soc 2023 Jul;71(7):2052-2081.|6
02251|001|T|MONOGRAPH TITLE:  Slt High Strength Antimuscarinics/Strong CYP3A4 Inhibitors|
02251|002|B||
02251|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02251|004|L|is contraindicated and generally should not be dispensed or administered to|
02251|005|L|the same patient.|
02251|006|B||
02251|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02251|008|A|darifenacin,(1) fesoterodine,(2) and solifenacin.(3,4,5)|
02251|009|B||
02251|010|E|CLINICAL EFFECTS:  The concurrent administration of a strong inhibitor of|
02251|011|E|CYP3A4 may result in elevated levels of and signs of toxicity from|
02251|012|E|darifenacin,(1) fesoterodine,(2) and solifenacin.(3,4,5)|
02251|013|B||
02251|014|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
02251|015|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
02251|016|P|patients using more than one medicine with anticholinergic properties.(6)|
02251|017|B||
02251|018|M|PATIENT MANAGEMENT:  The US manufacturer of darifenacin states that the|
02251|019|M|daily dose of darifenacin should not exceed 7.5 mg in patients receiving|
02251|020|M|potent CYP3A4 inhibitors.(1)|
02251|021|M|   The US manufacturer of fesoterodine states that the daily dose of|
02251|022|M|fesoterodine should not exceed 4 mg in adult patients receiving potent|
02251|023|M|CYP3A4 inhibitors.  In pediatric patients, the daily dose of fesoterodine in|
02251|024|M|patients taking strong CYP3A4 inhibitors should be reduced to 4 mg in|
02251|025|M|patients weighing greater than 35 kilograms. Use of fesoterodine in|
02251|026|M|pediatric patients weighing greater than 25 kilograms and up to 35 kilograms|
02251|027|M|is not recommended.(2)|
02251|028|M|   The US and Swedish manufacturers of solifenacin state the daily dose|
02251|029|M|should be limited to 5 mg in adults and should not exceed the starting dose|
02251|030|M|in children and adolescents when administered with strong CYP3A4 inhibitors.|
02251|031|M|The starting dose of solifenacin is 2 mg for patients weighing up to 15 kg,|
02251|032|M|3 mg for patients over 15 kg to 45 kg, 4 mg for patients over 45 kg to 60|
02251|033|M|kg, and 5 mg for patients over 60 kg.(3,4)  The Swedish manufacturer of the|
02251|034|M|combination product of tamsulosin-solifenacin states that the daily dose of|
02251|035|M|solifenacin should not exceed 6 mg in patients receiving potent CYP3A4|
02251|036|M|inhibitors.(5)|
02251|037|M|   The US manufacturer of itraconazole states that concurrent use with|
02251|038|M|fesoterodine or solifenacin is contraindicated in patients with severe renal|
02251|039|M|or hepatic impairment during and two weeks after itraconazole treatment.(7)|
02251|040|B||
02251|041|D|DISCUSSION:  In a study in 10 extensive CYP2D6 metabolizers and 1 poor|
02251|042|D|CYP2D6 metabolizer, concurrent administration of ketoconazole (400 mg)|
02251|043|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
02251|044|D|darifenacin (7.5 mg daily) by 3.9-fold and 4.6-fold, respectively, in|
02251|045|D|extensive metabolizers and by 12.9-fold and 12-fold, respectively, in the|
02251|046|D|poor metabolizer, compared to historical controls.  The concurrent|
02251|047|D|administration of ketoconazole (400 mg) and darifenacin (15 mg daily)|
02251|048|D|increased darifenacin AUC and Cmax by 11.5-fold and 10.73-fold,|
02251|049|D|respectively, in extensive metabolizers and by 4.9-fold and 4.9-fold,|
02251|050|D|respectively, in the poor metabolizer, compared to historical controls.(1)|
02251|051|D|   Concurrent administration of darifenacin (30 mg daily) and erythromycin,|
02251|052|D|a moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 128% and|
02251|053|D|95%, respectively.  Administration of darifenacin (30 mg daily) and|
02251|054|D|fluconazole, another moderate CYP3A4 inhibitor, increased darifenacin AUC|
02251|055|D|and Cmax by 84% and 88%, respectively.  No dosage adjustment is recommended|
02251|056|D|during concurrent therapy with moderate inhibitors of CYP3A4.(1)|
02251|057|D|   In a study, co-administration of ketoconazole (200 mg twice a day)|
02251|058|D|increased the Cmax and AUC of the active metabolite of fesoterodine 2.0 and|
02251|059|D|2.3-fold in CYP2D6 extensive metabolizers and 2.1 and 2.5-fold in CYP2D6|
02251|060|D|poor metabolizers, respectively.  Fesoterodine Cmax and AUC were 4.5-fold|
02251|061|D|and 5.7-fold higher in subjects who were CYP2D6 poor metabolizers and taking|
02251|062|D|ketoconazole when compared to extensive CYP2D6 metabolizers not taking|
02251|063|D|ketoconazole.(2)|
02251|064|D|   In another study, ketoconazole (200 mg daily) increased the Cmax and AUC|
02251|065|D|of the active metabolite of fesoterodine 2.2-fold in CYP2D6 extensive|
02251|066|D|metabolizers and 1.5-fold and 1.9-fold in CYP P-450-2D6 poor metabolizers,|
02251|067|D|respectively.(1,2)  Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold|
02251|068|D|higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole|
02251|069|D|when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2)|
02251|070|D|   Concurrent use of ketoconazole (400 mg daily for 21 days) increased the|
02251|071|D|Cmax and AUC of solifenacin (10 mg) by 1.5-fold and|
02251|072|D|2.7-fold,respectively.(3)|
02251|073|D|   Based on a controlled randomized study in 28 healthy adults, oral|
02251|074|D|fluconazole (200 mg daily) taken with oral fesoterodine (8 mg daily)  was|
02251|075|D|generally well tolerated in patients.  A slightly non-clinically significant|
02251|076|D|rise in plasma fesoterodine levels did occur.  No clinically significant|
02251|077|D|side effects were reported.  The most common side effects reported by|
02251|078|D|patients include: dizziness, blurred vision and abdominal distension when|
02251|079|D|fluconazole was taken with fesoterodine.(8)|
02251|080|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02251|081|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
02251|082|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
02251|083|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
02251|084|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib,|
02251|085|D|and voriconazole.(9)|
02251|086|B||
02251|087|R|REFERENCES:|
02251|088|B||
02251|089|R|1.Enablex (darifenacin) US prescribing information. Warner Chilcott (US),|1
02251|090|R|  LLC July, 2021.|1
02251|091|R|2.Toviaz (fesoterodine fumarate) US prescribing information. Pfizer June,|1
02251|092|R|  2021.|1
02251|093|R|3.Vesicare (solifenacin succinate) US prescribing information. Astella|1
02251|094|R|  Pharma US, Inc. May, 2020.|1
02251|095|R|4.Vesicare (solifenacin) Swedish prescribing information. Astellas Pharma|1
02251|096|R|  March 2018.|1
02251|097|R|5.Urizia (tamsulosin-solifenacin) Swedish prescribing information. Astellas|1
02251|098|R|  Pharma December 5, 2013.|1
02251|099|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02251|100|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02251|101|R|  Soc 2023 Jul;71(7):2052-2081.|6
02251|102|R|7.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02251|103|R|  Products, L.P. February, 2024.|1
02251|104|R|8.Malhotra B, Dickins M, Alvey C, Jumadilova Z, Li X, Duczynski G, Gandelman|2
02251|105|R|  K. Effects of the Moderate CYP3A4 Inhibitor, Fluconazole, on the|2
02251|106|R|  Pharmacokinetics of Fesoterodine in Healthy Subjects. Br J Clin Pharmacol|2
02251|107|R|  2011 May 5.|2
02251|108|R|9.US Food and Drug Administration (FDA). Drug Development and Drug|1
02251|109|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02251|110|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02251|111|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02251|112|R|  11/14/2017.|1
02252|001|T|MONOGRAPH TITLE:  Tolterodine (Greater Than 1 mg IR or Greater Than 2 mg|
02252|002|T|ER)/Selected CYP3A4 Inhibitors|
02252|003|B||
02252|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02252|005|L|of severe adverse interaction.|
02252|006|B||
02252|007|A|MECHANISM OF ACTION:  Cyclosporine, erythromycin, miconazole, and|
02252|008|A|vinblastine may inhibit the metabolism of tolterodine by CYP3A4.(1,2)|
02252|009|B||
02252|010|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with|
02252|011|E|cyclosporine, erythromycin, miconazole, or vinblastine may result in|
02252|012|E|elevated levels of tolterodine and signs of toxicity.(1,2)|
02252|013|B||
02252|014|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers may be at|
02252|015|P|increased risk.(1,2)|
02252|016|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02252|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02252|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02252|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02252|020|P|advanced age.(3)|
02252|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02252|022|P|higher systemic concentrations of either QT prolonging drug are additional|
02252|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02252|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02252|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02252|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02252|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02252|028|P|   The risk of anticholinergic toxicities including cognitive decline,|
02252|029|P|delirium, falls and fractures is increased in geriatric patients using more|
02252|030|P|than one medicine with anticholinergic properties.(4)|
02252|031|B||
02252|032|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
02252|033|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
02252|034|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
02252|035|M|used in patients receiving concurrent therapy with cyclosporine,|
02252|036|M|erythromycin, miconazole, or vinblastine.|
02252|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02252|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02252|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02252|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02252|041|B||
02252|042|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP2D6, the|
02252|043|D|concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg|
02252|044|D|once daily for four days), another inhibitor of CYP3A4, resulted in a 60%|
02252|045|D|decrease in tolterodine clearance.(5)  Tolterodine AUC and Cmax increased|
02252|046|D|2.5-fold and 2-fold, respectively.(2)|
02252|047|D|   In a study of the effect of tolterodine immediate release tablets, the|
02252|048|D|effect on the QT interval appeared greater for 8 mg/day (two times the|
02252|049|D|therapeutic dose) compared to 4 mg/day.  Tolterodine 2 mg BID and|
02252|050|D|tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and|
02252|051|D|11.84 msec (7.11-16.58 msec), respectively.  The change in QT interval was|
02252|052|D|more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers|
02252|053|D|(EMs).(1,2)|
02252|054|B||
02252|055|R|REFERENCES:|
02252|056|B||
02252|057|R|1.Detrol (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
02252|058|R|  August, 2012.|1
02252|059|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
02252|060|R|  July, 2018.|1
02252|061|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02252|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02252|063|R|  settings: a scientific statement from the American Heart Association and|6
02252|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02252|065|R|  2;55(9):934-47.|6
02252|066|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02252|067|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02252|068|R|  Soc 2023 Jul;71(7):2052-2081.|6
02252|069|R|5.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
02252|070|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
02252|071|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
02253|001|T|MONOGRAPH TITLE:  Ambrisentan (Greater Than 5 mg)/Cyclosporine|
02253|002|B||
02253|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02253|004|L|is contraindicated and generally should not be dispensed or administered to|
02253|005|L|the same patient.|
02253|006|B||
02253|007|A|MECHANISM OF ACTION:  Cyclosporine may inhibit the metabolism/transport of|
02253|008|A|ambrisentan by CYP3A4, OATP, and P-gp.(1,2)|
02253|009|B||
02253|010|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine may result in elevated|
02253|011|E|levels of and toxicity from ambrisentan.(1,2)|
02253|012|B||
02253|013|P|PREDISPOSING FACTORS:  None determined.|
02253|014|B||
02253|015|M|PATIENT MANAGEMENT:  Patients maintained on cyclosporine should receive a|
02253|016|M|maximum daily dose of 5 mg of ambrisentan.(1,2)|
02253|017|B||
02253|018|D|DISCUSSION:  In an open-label, parallel-treatment study, 28 healthy subjects|
02253|019|D|had ambrisentan (5 mg daily) added to steady-state cyclosporine (100-150 mg|
02253|020|D|BID) and 24 subjects had cyclosporine (100-150 mg BID) added to steady-state|
02253|021|D|ambrisentan (5 mg daily).  All drug levels were evaluated at steady-state.|
02253|022|D|Ambrisentan maximum concentration (Cmax) and area-under-curve (AUC)|
02253|023|D|increased 1.5-fold and 2-fold, respectively, in the presence of|
02253|024|D|cyclosporine.  There were no significant effects on cyclosporine levels.|
02253|025|D|The addition of ambrisentan to cyclosporine was less tolerable than the|
02253|026|D|addition of cyclosporine to ambrisentan therapy.(1,2)|
02253|027|B||
02253|028|R|REFERENCES:|
02253|029|B||
02253|030|R|1.Letairis (ambrisentran) US prescribing information. Gilead Sciences, Inc.|1
02253|031|R|  August, 2019.|1
02253|032|R|2.Spence R, Mandagere A, Richards DB, Magee MH, Dufton C, Boinpally R.|2
02253|033|R|  Potential for pharmacokinetic interactions between ambrisentan and|2
02253|034|R|  cyclosporine. Clin Pharmacol Ther 2010 Oct;88(4):513-20.|2
02254|001|T|MONOGRAPH TITLE:  Digoxin/Ezogabine|
02254|002|B||
02254|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02254|004|L|take action as needed.|
02254|005|B||
02254|006|A|MECHANISM OF ACTION:  The N-acetyl metabolite of ezogabine (NAMR) is a|
02254|007|A|P-glycoprotein (P-gp) inhibitor and may inhibit P-gp mediated renal|
02254|008|A|elimination of digoxin.(1)|
02254|009|B||
02254|010|E|CLINICAL EFFECTS:  Concurrent use of ezogabine may lead to elevated digoxin|
02254|011|E|levels and risk for toxicity.  Symptoms of digoxin toxicity can include|
02254|012|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
02254|013|E|generalized muscle weakness, disorientation, hallucinations, visual|
02254|014|E|disturbances, and arrhythmias.(2)|
02254|015|B||
02254|016|P|PREDISPOSING FACTORS:  Based upon in vitro studies (1), risk for clinically|
02254|017|P|significant inhibition of digoxin is greater at ezogabine total daily doses|
02254|018|P|greater than or equal to 900 mg per day.|
02254|019|P|   Low body weight, advanced age, impaired renal function, hypokalemia,|
02254|020|P|hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin|
02254|021|P|toxicity.|
02254|022|B||
02254|023|M|PATIENT MANAGEMENT:  For digoxin patients newly started on ezogabine,|
02254|024|M|evaluate prior digoxin measurements then monitor and adjust dose|
02254|025|M|accordingly.(3) As low ezogabine doses may have less effect on digoxin|
02254|026|M|levels, monitoring should continue until a stable ezogabine maintenance dose|
02254|027|M|has been achieved.(1)|
02254|028|M|   When initiating digoxin in patients maintained on ezogabine, lower than|
02254|029|M|expected digoxin doses may be required. Monitor digoxin levels as|
02254|030|M|recommended.(2)|
02254|031|B||
02254|032|D|DISCUSSION:  Based upon manufacturer sponsored in vitro testing, NAMR may|
02254|033|D|reduce P-gp mediated transport activity for digoxin by approximately 30 to|
02254|034|D|50 %.(1)|
02254|035|B||
02254|036|R|REFERENCES:|
02254|037|B||
02254|038|R|1.FDA. Ezogabine CDER Drug Approval Package, Application: 022345, Approval|1
02254|039|R|  Date:06/10/2011. Available at:|1
02254|040|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022345Orig1s000TOC.|1
02254|041|R|  cfm June 10, 2011.|1
02254|042|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
02254|043|R|  Pharmaceuticals, Inc. August, 2018.|1
02254|044|R|3.Potiga (ezogabine) US Prescribing Information. Valeant Pharmaceuticals|1
02254|045|R|  May, 2016.|1
02255|001|T|MONOGRAPH TITLE:  Selected CYP1A2 Substrates/Deferasirox|
02255|002|B||
02255|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02255|004|L|of severe adverse interaction.|
02255|005|B||
02255|006|A|MECHANISM OF ACTION:  Deferasirox is a weak inhibitor of CYP1A2.  The FDA|
02255|007|A|defines weak inhibition as an increase in drug area-under-curve (AUC)|
02255|008|A|greater than 1.25 fold, but less than 2 fold.(1-3)|
02255|009|B||
02255|010|E|CLINICAL EFFECTS:  Concurrent use of deferasirox may lead to increased|
02255|011|E|levels and effects of drugs primarily metabolized by CYP1A2.(1)|
02255|012|B||
02255|013|P|PREDISPOSING FACTORS:  Greater risk for adverse events would be expected for|
02255|014|P|drugs with a narrow therapeutic window, or for drugs especially sensitive to|
02255|015|P|CYP1A2 inhibition.|
02255|016|P|   With tizanidine, the risk of anticholinergic toxicities including|
02255|017|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
02255|018|P|patients using more than one medicine with anticholinergic properties.(4)|
02255|019|B||
02255|020|M|PATIENT MANAGEMENT:  The US manufacturer of deferasirox recommends avoiding|
02255|021|M|concomitant therapy with theophylline or CYP1A2 narrow therapeutic range|
02255|022|M|substrates such as tizanidine.(1)  The Australian and UK manufacturers of|
02255|023|M|deferasirox state that concomitant use with theophylline or other substances|
02255|024|M|predominantly metabolized by CYP1A2 and with a narrow therapeutic index|
02255|025|M|(e.g., clozapine, tizanidine) is not recommended.(5,6)|
02255|026|M|   If concomitant use is necessary in patients already receiving CYP1A2|
02255|027|M|substrates such as clozapine, theophylline, or tizanidine, the dose of the|
02255|028|M|CYP1A2 substrate may need to be reduced when deferasirox is started.|
02255|029|M|Theophylline AUC and elimination half-life may double. Monitor theophylline|
02255|030|M|concentrations and adjust dose accordingly.(1)|
02255|031|M|   Patients already receiving deferasirox when a CYP1A2 substrate is started|
02255|032|M|may be more susceptible to adverse effects.  A lower than usual dose of the|
02255|033|M|CYP1A2 substrate may be needed.|
02255|034|M|   The US manufacturer of tizanidine recommends avoiding concomitant therapy|
02255|035|M|with CYP1A2 inhibitors.  If concurrent therapy is necessary, tizanidine|
02255|036|M|should be initiated at 2 mg dose and increased in 2-4 mg steps daily based|
02255|037|M|on patient response to therapy.  If adverse reactions such as hypotension,|
02255|038|M|bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine|
02255|039|M|therapy.(7)|
02255|040|M|   The US manufacturer of clozapine recommends monitoring patients closely|
02255|041|M|when clozapine is coadministered with moderate or weak CYP1A2 inhibitors.|
02255|042|M|Consider reducing the clozapine dosage if necessary.(8)|
02255|043|B||
02255|044|D|DISCUSSION:  In a study with healthy volunteers, deferasirox dosage of|
02255|045|D|30mg/kg/day (duration not stated) and a single dose of theophylline 120 mg|
02255|046|D|led to an approximate doubling of the theophylline area-under-curve (AUC)|
02255|047|D|and elimination half-life.(1)|
02255|048|D|    Although interactions between deferasirox and clozapine or tizanidine|
02255|049|D|have not been specifically studied, clozapine and tizanidine are considered|
02255|050|D|CYP1A2 narrow therapeutic range substrates.|
02255|051|B||
02255|052|R|REFERENCES:|
02255|053|B||
02255|054|R|1.Exjade (deferasirox) US prescribing information. Novartis Pharmaceuticals|1
02255|055|R|  Corporation July, 2019.|1
02255|056|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02255|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02255|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02255|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02255|060|R|  11/14/2017.|1
02255|061|R|3.This information is based on an extract from the Certara Drug Interaction|6
02255|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02255|063|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02255|064|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02255|065|R|  Soc 2023 Jul;71(7):2052-2081.|6
02255|066|R|5.Jadenu (deferasirox) Australian product information. Novartis|1
02255|067|R|  Pharmaceuticals Australia Pty Ltd November, 2019.|1
02255|068|R|6.Exjade (deferasirox) UK summary of product characteristics. Novartis|1
02255|069|R|  Pharmaceuticals UK Limited May, 2023.|1
02255|070|R|7.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
02255|071|R|  Pharma Inc. November 22, 2024.|1
02255|072|R|8.Clozaril (clozapine tablets) US prescribing information. Novartis|1
02255|073|R|  Pharmaceuticals Corporation April, 2020.|1
02256|001|T|MONOGRAPH TITLE:  Warfarin/Noscapine; Oxolamine|
02256|002|B||
02256|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02256|004|L|take action as needed.|
02256|005|B||
02256|006|A|MECHANISM OF ACTION:  Noscapine may inhibit the metabolism of warfarin by|
02256|007|A|CYP2C9.(1,2)  The mechanism for the interaction between oxolamine and|
02256|008|A|warfarin is unknown.(3)|
02256|009|B||
02256|010|E|CLINICAL EFFECTS:  Concurrent use of noscapine(1,2) or oxolamine(3) may|
02256|011|E|result in increased warfarin effects.|
02256|012|B||
02256|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02256|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02256|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
02256|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02256|017|P|risk for bleeding (e.g. NSAIDs).|
02256|018|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
02256|019|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
02256|020|P|are expected to be more susceptible to this interaction.|
02256|021|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
02256|022|P|are expected to be less susceptible to effects from this drug combination,|
02256|023|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
02256|024|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
02256|025|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
02256|026|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
02256|027|P|and safe anticoagulation than patients without these CYP2C9 variants.|
02256|028|B||
02256|029|M|PATIENT MANAGEMENT:  Monitor patients maintained on warfarin if noscapine or|
02256|030|M|oxolamine is initiated or discontinued.  Consider decreasing the dosage of|
02256|031|M|warfarin by 50% in patients during oxolamine therapy.(1)|
02256|032|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02256|033|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
02256|034|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
02256|035|M|evaluate patients with any symptoms.|
02256|036|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02256|037|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02256|038|M|anticoagulation in patients with active pathologic bleeding.|
02256|039|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02256|040|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02256|041|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02256|042|M|and/or swelling.|
02256|043|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02256|044|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02256|045|M|initiating, altering the dose or discontinuing either drug.|
02256|046|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
02256|047|B||
02256|048|D|DISCUSSION:  Eight cases of increased warfarin effects, 7 involving|
02256|049|D|increased INR and one involving bleeding have been reported to the Swedish|
02256|050|D|Adverse Drug Interactions Register (SWEDIS).(1)  There are another four|
02256|051|D|cases reported elsewhere in the medical literature.(2)|
02256|052|D|   A retrospective review examined 11 patients maintained on warfarin who|
02256|053|D|received concurrent oxolamine.  In the six patients who did not receive a|
02256|054|D|warfarin dosage adjustment at the start of oxolamine therapy, INR increased|
02256|055|D|by 70% to 190%.  Two patients developed hematoma and were treated with|
02256|056|D|phytonadione.  In the 5 subjects whose warfarin dose was decreased by|
02256|057|D|30%-40% at the initiation of oxolamine, 4 had increased INR values up to|
02256|058|D|36%.(3)|
02256|059|D|   In a prospective follow-up to this review, 6 female patients maintained|
02256|060|D|on warfarin with stable INR values were given oxolamine (range 100-600 mg|
02256|061|D|daily for an average of 6.2 days).  At the initiation of oxolamine, warfarin|
02256|062|D|dosages were reduced by 50% and returned to previous dosages at the|
02256|063|D|discontinuation of oxolamine.  At the completion of oxolamine therapy, all|
02256|064|D|patients had INR levels in or slightly below the target range and no patient|
02256|065|D|required any further adjustments.  INRs remained in the target range 1-8|
02256|066|D|weeks after the completion of oxolamine therapy in all but 1 subject who|
02256|067|D|began prednisolone therapy at the end of oxolamine therapy.(3)|
02256|068|B||
02256|069|R|REFERENCES:|
02256|070|B||
02256|071|R|1.Ohlsson S, Holm L, Myrberg O, Sundstrom A, Yue QY. Noscapine may increase|3
02256|072|R|  the effect of warfarin. Br J Clin Pharmacol 2008 Feb;65(2):277-8.|3
02256|073|R|2.Scordo MG, Melhus H, Stjernberg E, Edvardsson AM, Wadelius M.|3
02256|074|R|  Warfarin-noscapine interaction: a series of four case reports. Ann|3
02256|075|R|  Pharmacother 2008 Mar;42(3):448-50.|3
02256|076|R|3.Min KA, Zhu X, Oh JM, Shin WG. Effect of oxolamine on anticoagulant effect|2
02256|077|R|  of warfarin. Am J Health Syst Pharm 2006 Jan 15;63(2):153-6.|2
02257|001|T|MONOGRAPH TITLE:  Voriconazole/QT Prolonging Agents|
02257|002|B||
02257|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02257|004|L|take action as needed.|
02257|005|B||
02257|006|A|MECHANISM OF ACTION:  Concurrent use of voriconazole with agents known to|
02257|007|A|prolong the QTc interval may result in additive effects on the QTc|
02257|008|A|interval.(1)|
02257|009|B||
02257|010|E|CLINICAL EFFECTS:  Concurrent use may result in potentially life-threatening|
02257|011|E|cardiac arrhythmias, including torsades de pointes.|
02257|012|B||
02257|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02257|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02257|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02257|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02257|017|P|female gender, or advanced age.(2)|
02257|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02257|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02257|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02257|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02257|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02257|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02257|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02257|025|B||
02257|026|M|PATIENT MANAGEMENT:  The manufacturer of voriconazole states concurrent use|
02257|027|M|with agents known to prolong the QT interval should be administered with|
02257|028|M|caution.(1)|
02257|029|M|   In patients maintained on voriconazole and other agents known to prolong|
02257|030|M|the QT interval, consider a baseline ECG prior to administration to assess|
02257|031|M|the risk/benefit of therapy.|
02257|032|M|   Consider obtaining serum calcium, magnesium, and potassium levels at|
02257|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities|
02257|034|M|prior to initiation of therapy.  Instruct patients to report any irregular|
02257|035|M|heartbeat, dizziness, or fainting.|
02257|036|B||
02257|037|D|DISCUSSION:  A placebo-controlled, randomized, crossover study to evaluate|
02257|038|D|the effect on the QT interval of healthy male and female subjects was|
02257|039|D|conducted with three single oral doses of voriconazole and ketoconazole.|
02257|040|D|The placebo-adjusted mean maximum increases in QTc from baseline after 800|
02257|041|D|mg, 1200 mg, and 1600 mg of voriconazole and after ketoconazole 800 mg were|
02257|042|D|all <10 msec.  No subject experienced an interval exceeding the potentially|
02257|043|D|clinically relevant threshold of 500 msec.(1)|
02257|044|D|   In a retrospective study of 2,735 patients with a prolonged QTc interval,|
02257|045|D|voriconazole use was associated with an increased risk of torsades de|
02257|046|D|pointes.(4)|
02257|047|B||
02257|048|R|REFERENCES:|
02257|049|B||
02257|050|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
02257|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02257|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02257|053|R|  settings: a scientific statement from the American Heart Association and|6
02257|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02257|055|R|  2;55(9):934-47.|6
02257|056|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02257|057|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02257|058|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02257|059|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02257|060|R|4.Romero J, Baldinger SH, Goodman-Meza D, Engstrom K, Valencia CR, Golive A,|6
02257|061|R|  Medrano F, Rangasamy S, Makkiya M, Fisher JD, Gross J, Krumerman A, Kim S,|6
02257|062|R|  Garcia MJ, Di Biase L, Ferrick KJ. Drug-induced torsades de pointes in an|6
02257|063|R|  underserved urban population. Methadone: is  there therapeutic equipoise?.|6
02257|064|R|  J Interv Card Electrophysiol 2016 Jan;45(1):37-45.|6
02258|001|T|MONOGRAPH TITLE:  Azithromycin; Clarithromycin; Erythromycin/Selected QT|
02258|002|T|Prolonging Agents (mono deleted 11/05/2015)|
02258|003|B||
02258|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02258|005|L|of severe adverse interaction.|
02258|006|B||
02258|007|A|MECHANISM OF ACTION:  Azithromycin, clarithromycin, and erythromycin have|
02258|008|A|been shown to prolong the QTc interval.(1-4)  Concurrent use with other|
02258|009|A|agents that prolong the QTc interval may result in additive effects on the|
02258|010|A|QTc interval.(1-11)|
02258|011|B||
02258|012|E|CLINICAL EFFECTS:  The concurrent use of azithromycin, clarithromycin, or|
02258|013|E|erythromycin with other agents that prolong the QTc interval may result in|
02258|014|E|potentially life-threatening cardiac arrhythmias, including torsades de|
02258|015|E|pointes.(1-11)|
02258|016|B||
02258|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02258|018|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02258|019|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02258|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02258|021|P|gender, or advanced age.(12)|
02258|022|P|    Concurrent use of more than one drug known to cause QT prolongation or|
02258|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02258|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02258|025|P|drug concentrations include: rapid infusion of an intravenous dose or|
02258|026|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
02258|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02258|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(11)|
02258|029|B||
02258|030|M|PATIENT MANAGEMENT:  The manufacturers of asenapine,(5) ivabradine,(6)|
02258|031|M|lopinavir,(7) propafenone,(8) vinflunine,(9) and zuclopenthixol(10) state|
02258|032|M|that concurrent use of agents known to prolong the QT interval should be|
02258|033|M|avoided.|
02258|034|M|   Concurrent use of citalopram with agents known to prolong the QT interval|
02258|035|M|is not recommended.  The manufacturer recommends ECG monitoring in patients|
02258|036|M|for whom citalopram is not recommended, including those receiving concurrent|
02258|037|M|therapy with agents known to prolong the QT interval.  Citalopram should be|
02258|038|M|discontinued in patients with persistent QTc measurements greater than 500|
02258|039|M|ms.(13,14)|
02258|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02258|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02258|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02258|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02258|044|B||
02258|045|D|DISCUSSION:  The manufacturer of azithromycin performed a QT prolongation|
02258|046|D|study in 116 healthy subjects who received either chloroquine 1000 mg alone|
02258|047|D|or combined with azithromycin (500 mg, 1000 mg or 1500 mg once daily).  In|
02258|048|D|comparison with chloroquine alone, co-administration with azithromycin led|
02258|049|D|to mean increases(95% upper confidence bound) in QTcF of 5(10) ms, 7(12) ms,|
02258|050|D|and 9(14) ms for the 500 mg, 1000 mg and 1500 mg respectively.(1)  FDA|
02258|051|D|considers a 10 ms increase in the 95% upper confidence bound as the|
02258|052|D|threshold for regulatory concern.|
02258|053|D|   Agents linked to this monograph may have varying degrees of potential to|
02258|054|D|prolong the QTc interval but are generally accepted to have a risk of|
02258|055|D|causing Torsades de Pointes.  Agents linked to this monograph have been|
02258|056|D|shown to prolong the QTc interval either through their mechanism of action,|
02258|057|D|through studies on their effects on the QTc interval, or through reports of|
02258|058|D|QTc prolongation and/or Torsades de Pointes in clinical trials and/or|
02258|059|D|post-marketing reports.(13)|
02258|060|B||
02258|061|R|REFERENCES:|
02258|062|B||
02258|063|R|1.Zithromax (azithromycin oral) US prescribing information. Pifzer Labs|1
02258|064|R|  April, 2019.|1
02258|065|R|2.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
02258|066|R|  September, 2019.|1
02258|067|R|3.E.E.S. (erythromycin ethylsuccinate) US prescribing information. Arbor|1
02258|068|R|  Pharmaceuticals, Inc. April, 2018.|1
02258|069|R|4.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
02258|070|R|  December, 2010.|1
02258|071|R|5.Saphris (asenapine) US prescribing information. Actavis, Inc. February 23,|1
02258|072|R|  2017.|1
02258|073|R|6.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
02258|074|R|  Les Laboratoires Servier March, 2015.|1
02258|075|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
02258|076|R|  Laboratories December, 2019.|1
02258|077|R|8.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
02258|078|R|  Laboratories March, 2013.|1
02258|079|R|9.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
02258|080|R|  Pierre Fabre Limited September 21, 2009.|1
02258|081|R|10.Clopixol (zuclopenthixol acetate) UK summary of product characteristics.|1
02258|082|R|   Lundbeck Limited October 15, 2020.|1
02258|083|R|11.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
02258|084|R|   Laboratories Inc. December, 2012.|1
02258|085|R|12.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02258|086|R|   recommendations for Celexa (citalopram hydrobromide) related to a|1
02258|087|R|   potential risk of abnormal heart rhythms with high doses. available at:|1
02258|088|R|   http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02258|089|R|13.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
02258|090|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
02258|091|R|   hospital settings: a scientific statement from the American Heart|6
02258|092|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
02258|093|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
02258|094|R|14.USDepartment of Health and Human Services Food and Drug Administration.|1
02258|095|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02258|096|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02258|097|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02259|001|T|MONOGRAPH TITLE:  Fingolimod/Class IA and III Antiarrhythmic Agents|
02259|002|B||
02259|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02259|004|L|is contraindicated and generally should not be dispensed or administered to|
02259|005|L|the same patient.|
02259|006|B||
02259|007|A|MECHANISM OF ACTION:  Initiation of fingolimod has a negative chronotropic|
02259|008|A|effect leading to a mean decrease in heart rate of 13 beats per minute (bpm)|
02259|009|A|after the first dose. The first dose has also been associated with heart|
02259|010|A|block.(1-4)|
02259|011|B||
02259|012|E|CLINICAL EFFECTS:  The heart rate lowering effect of fingolimod is biphasic|
02259|013|E|with an initial decrease usually within 6 hours, followed by a second|
02259|014|E|decrease 12 to 24 hours after the first dose.  Symptomatic bradycardia and|
02259|015|E|heart block, including third degree block, have been observed. Bradycardia|
02259|016|E|may be associated with an increase in the QTc interval, increasing the risk|
02259|017|E|for torsades de pointes.  The cause of death in a patient who died within 24|
02259|018|E|hour after taking the first dose of fingolimod was not conclusive, however a|
02259|019|E|link to fingolimod could not be ruled out.|
02259|020|B||
02259|021|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
02259|022|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
02259|023|P|infarction, history of torsades de pointes, congenital long QT syndrome,|
02259|024|P|stroke, or heart block), severe untreated sleep apnea, a prolonged QTc|
02259|025|P|interval prior to fingolimod initiation, factors associated with QTc|
02259|026|P|prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender,|
02259|027|P|advanced age), or concomitant treatment with Class IA or III agents may|
02259|028|P|increase risk for cardiovascular toxicity due to fingolimod.|
02259|029|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02259|030|P|higher systemic concentrations of either QT prolonging drug are additional|
02259|031|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02259|032|P|drug concentrations include rapid infusion of an intravenous dose or|
02259|033|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02259|034|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02259|035|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
02259|036|B||
02259|037|M|PATIENT MANAGEMENT:  US, Canada and UK manufacturer information states Class|
02259|038|M|Ia or Class III antiarrhythmics are contraindicated and should not be|
02259|039|M|co-administered with fingolimod.(1-4)|
02259|040|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02259|041|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02259|042|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02259|043|M|   After the first dose of fingolimod, heart rate decrease may begin within|
02259|044|M|an hour. Decline is usually maximal at approximately 6 hours followed by a|
02259|045|M|second decrease 12 to 24 hours after the first dose.  The second dose may|
02259|046|M|further decrease heart rate, but the magnitude of change is smaller than the|
02259|047|M|first dose. With continued, chronic dosing, heart rate gradually returns to|
02259|048|M|baseline in about one month.(1,2)|
02259|049|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02259|050|M|fainting.|
02259|051|B||
02259|052|D|DISCUSSION:  After the first dose of fingolimod, heart rate decrease may|
02259|053|D|begin within an hour. Decline is usually maximal at approximately 6 hours|
02259|054|D|followed by a second decrease 12 to 24 hours after the first dose.  The|
02259|055|D|second dose may further decrease heart rate, but the magnitude of change is|
02259|056|D|smaller than the first dose. With continued, chronic dosing, heart rate|
02259|057|D|gradually returns to baseline in about one month.(1,2)|
02259|058|D|   Antiarrhythmic agents linked to this monograph are disopyramide,|
02259|059|D|procainamide, quinidine, amiodarone, dofetilide, dronedarone, ibutilide and|
02259|060|D|sotalol.|
02259|061|B||
02259|062|R|REFERENCES:|
02259|063|B||
02259|064|R|1.Gilenya (fingolimod) US prescribing information. Novartis Pharmaceuticals|1
02259|065|R|  Corporation June, 2024.|1
02259|066|R|2.Gilenya (fingolimod) Health Canada prescribing information. Novartis|1
02259|067|R|  Pharmaceuticals September 23, 2011.|1
02259|068|R|3.Godin J. Dear Canadian Healthcare Professional:  Subject:  GILENYA|1
02259|069|R|  (fingolimod) - Stronger recommendations regarding first-dose|1
02259|070|R|  cardiovascular monitoring and use in patients with preexisting|1
02259|071|R|  cardiovascular conditions. Novartis Pharmaceuticals Canada Inc. August 21,|1
02259|072|R|  2012.|1
02259|073|R|4.MHRA United Kingdom. Fingolimod (Gilenya): transient bradycardias and|1
02259|074|R|  heart block after first dose - strengthened cardiovascular monitoring.|1
02259|075|R|  Drug Safety Update Feb 2012;5(7):A1.|1
02259|076|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02259|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02259|078|R|  settings: a scientific statement from the American Heart Association and|6
02259|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02259|080|R|  2;55(9):934-47.|6
02260|001|T|MONOGRAPH TITLE:  Clozapine/Strong CYP1A2 Inhibitors|
02260|002|B||
02260|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02260|004|L|of severe adverse interaction.|
02260|005|B||
02260|006|A|MECHANISM OF ACTION:  The metabolism of clozapine may be inhibited by CYP1A2|
02260|007|A|inhibitors.(1)|
02260|008|B||
02260|009|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with strong|
02260|010|E|CYP1A2 inhibitors may result in elevated levels of clozapine and an increase|
02260|011|E|in clozapine related side effects such as orthostatic hypotension, syncope,|
02260|012|E|QT prolongation, profound sedation and seizures.  This interaction may be|
02260|013|E|noted with even low doses of CYP1A2 inhibitors and the onset of this|
02260|014|E|interaction may be rapid.(1-7)|
02260|015|B||
02260|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02260|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
02260|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02260|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02260|020|P|female gender, or advanced age.(8)|
02260|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02260|022|P|higher systemic concentrations of either QT prolonging drug are additional|
02260|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02260|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02260|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02260|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02260|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(8)|
02260|028|P|   The risk of anticholinergic toxicities including cognitive decline,|
02260|029|P|delirium, falls and fractures is increased in geriatric patients using more|
02260|030|P|than one medicine with anticholinergic properties.(9)|
02260|031|B||
02260|032|M|PATIENT MANAGEMENT:  The manufacturer recommends reducing the clozapine dose|
02260|033|M|to one-third the original dose with concurrent strong CYP1A2 inhibitors.|
02260|034|M|Close monitoring is required to prevent clozapine toxicity.  Clozapine|
02260|035|M|levels should be monitored in patients receiving concurrent therapy with|
02260|036|M|strong CYP1A2 inhibitors.  Patients should be monitored for adverse|
02260|037|M|clozapine effects and QT prolongation.(1)|
02260|038|M|   If concurrent therapy is warranted in patients receiving clozapine,|
02260|039|M|consider obtaining serum calcium, magnesium, and potassium levels and|
02260|040|M|monitoring ECG at baseline and at regular intervals.  Correct any|
02260|041|M|electrolyte abnormalities.  Instruct patients to report any irregular|
02260|042|M|heartbeat, dizziness, or fainting.|
02260|043|M|   When the strong CYP1A2 inhibitor is discontinued, the clozapine dose|
02260|044|M|should be increased based on clinical response.  Serum clozapine|
02260|045|M|measurements may be useful.|
02260|046|B||
02260|047|D|DISCUSSION:  Several case reports have documented increased levels of|
02260|048|D|clozapine when fluvoxamine was added to therapy.(2-5)  The increases in|
02260|049|D|clozapine levels ranged from 231% to 780%.|
02260|050|D|   Several case reports describe increased clozapine-related side effects|
02260|051|D|following the addition of fluvoxamine to clozapine therapy.(3,6-7)|
02260|052|D|   In a study in 16 subjects(1,10), the addition of fluvoxamine to patients|
02260|053|D|receiving clozapine resulted in 3-fold increases in clozapine,|
02260|054|D|N-desmethylclozapine, and clozapine N-oxide.  The half-life of clozapine|
02260|055|D|increased from 17 hours to 50 hours.  Another study (11) compared patients|
02260|056|D|receiving clozapine monotherapy to patients receiving concurrent therapy|
02260|057|D|with clozapine and fluvoxamine and found that the dose-normalized clozapine|
02260|058|D|concentration increased by a factor of 5-10 when fluvoxamine was added.|
02260|059|D|   Strong CYP1A2 inhibitors linked include:  enasidenib and fluvoxamine.(13)|
02260|060|B||
02260|061|R|REFERENCES:|
02260|062|B||
02260|063|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
02260|064|R|  Pharmaceuticals Corporation April, 2020.|1
02260|065|R|2.Markowitz JS, Gill HS, Lavia M, Brewerton TD, DeVane CL.|3
02260|066|R|  Fluvoxamine-clozapine dose-dependent interaction. Can J Psychiatry 1996|3
02260|067|R|  Dec;41(10):670-1.|3
02260|068|R|3.Dequardo JR, Roberts M. Elevated clozapine levels after fluvoxamine|3
02260|069|R|  initiation. Am J Psychiatry 1996 Jun;153(6):840-1.|3
02260|070|R|4.DuMortier G, Lochu A, Colen de Melo P, Ghribi O, Roche-Rabreau D,|3
02260|071|R|  DeGrassat K, Desce JM. Elevated clozapine plasma concentrations after|3
02260|072|R|  fluvoxamine initiation. Am J Psychiatry 1996 May;153(5):738-9.|3
02260|073|R|5.Hiemke C, Weigmann H, Hartter S, Dahmen N, Wetzel H, Muller H. Elevated|3
02260|074|R|  levels of clozapine in serum after addition of fluvoxamine. J Clin|3
02260|075|R|  Psychopharmacol 1994 Aug;14(4):279-81.|3
02260|076|R|6.Szegedi A, Wiesner J, Hiemke C. Improved efficacy and fewer side effects|3
02260|077|R|  under clozapine treatment after addition of fluvoxamine. J Clin|3
02260|078|R|  Psychopharmacol 1995 Apr;15(2):141-3.|3
02260|079|R|7.Silver H, Kaplan A, Jahjah N. Fluvoxamine augmentation for|3
02260|080|R|  clozapine-resistant schizophrenia. Am J Psychiatry 1995 Jul;152(7):1098.|3
02260|081|R|8.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02260|082|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02260|083|R|  settings: a scientific statement from the American Heart Association and|6
02260|084|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02260|085|R|  2;55(9):934-47.|6
02260|086|R|9.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02260|087|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02260|088|R|  Soc 2023 Jul;71(7):2052-2081.|6
02260|089|R|10.Wetzel H, Anghelescu I, Szegedi A, Wiesner J, Weigmann H, Harter S,|2
02260|090|R|   Hiemke C. Pharmacokinetic interactions of clozapine with selective|2
02260|091|R|   serotonin reuptake inhibitors: differential effects of fluvoxamine and|2
02260|092|R|   paroxetine in a prospective study. J Clin Psychopharmacol 1998 Feb;|2
02260|093|R|   18(1):2-9.|2
02260|094|R|11.Jerling M, Lindstrom L, Bondesson U, Bertilsson L. Fluvoxamine inhibition|2
02260|095|R|   and carbamazepine induction of the metabolism of clozapine: evidence from|2
02260|096|R|   a therapeutic drug monitoring service. Ther Drug Monit 1994 Aug;|2
02260|097|R|   16(4):368-74.|2
02260|098|R|12.Bess AL, Cunningham SR. Dear Healthcare Provider:  Important drug warning|1
02260|099|R|   and new information about Clozaril. Novartis Pharmaceuticals Corporation|1
02260|100|R|   December, 2005.|1
02260|101|R|13.This information is based on an extract from the Certara Drug Interaction|6
02260|102|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02261|001|T|MONOGRAPH TITLE:  Fingolimod/QT Prolonging Agents|
02261|002|B||
02261|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02261|004|L|take action as needed.|
02261|005|B||
02261|006|A|MECHANISM OF ACTION:  Fingolimod is a sphingosine 1-phosphate (S1P) receptor|
02261|007|A|modulator.  Initiation of fingolimod has a negative chronotropic effect|
02261|008|A|leading to a mean decrease in heart rate of 13 beats per minute (bpm) after|
02261|009|A|the first dose.  The first dose has also been associated with heart|
02261|010|A|block.(1-3)|
02261|011|A|   Fingolimod blocks the capacity of lymphocytes to egress from lymph nodes,|
02261|012|A|reducing the number of lymphocytes in peripheral blood.  The mechanism by|
02261|013|A|which fingolimod exerts therapeutic effects in multiple sclerosis is unknown|
02261|014|A|but may involve the reduction of lymphocyte migration into the central|
02261|015|A|nervous system.(1-3)|
02261|016|B||
02261|017|E|CLINICAL EFFECTS:  The heart rate lowering effect of fingolimod is biphasic|
02261|018|E|with an initial decrease usually within 6 hours, followed by a second|
02261|019|E|decrease 12 to 24 hours after the first dose.  Symptomatic bradycardia and|
02261|020|E|heart block, including third degree block, have been observed.  Bradycardia|
02261|021|E|may be associated with an increase in the QTc interval, increasing the risk|
02261|022|E|for torsades de pointes.  There is no consistent signal of increased|
02261|023|E|incidence of QTc outliers, either absolute or change from baseline,|
02261|024|E|associated with fingolimod treatment.(1-3)|
02261|025|B||
02261|026|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
02261|027|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
02261|028|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
02261|029|P|prolonged QTc interval prior to fingolimod initiation, factors associated|
02261|030|P|with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant|
02261|031|P|treatment with QT prolonging agents may increase risk for cardiovascular|
02261|032|P|toxicity due to fingolimod.|
02261|033|P|   The risk of QT prolongation or torsades de pointes may also be increased|
02261|034|P|in patients with a history of torsades de pointes, hypocalcemia,|
02261|035|P|bradycardia, female gender, or advanced age.(4)|
02261|036|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02261|037|P|higher systemic concentrations of the QT prolonging drug are additional risk|
02261|038|P|factors for torsades de pointes.  Factors which may increase systemic drug|
02261|039|P|concentrations include rapid infusion of an intravenous dose or impaired|
02261|040|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
02261|041|P|which inhibits its metabolism or elimination, genetic impairment in drug|
02261|042|P|metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02261|043|B||
02261|044|M|PATIENT MANAGEMENT:  Patients with a baseline QTc interval greater than or|
02261|045|M|equal to 500 milliseconds should not be started on fingolimod.  Patients|
02261|046|M|with pre-existing cardiovascular or cerebrovascular disease (e.g. heart|
02261|047|M|failure, ischemic heart disease, history of myocardial infarction, stroke,|
02261|048|M|or heart block), severe untreated sleep apnea, or a prolonged QTc interval|
02261|049|M|prior to fingolimod initiation should receive cardiologist consultation to|
02261|050|M|evaluate the risks of fingolimod therapy.|
02261|051|M|   In all patients, first dose monitoring is recommended to monitor for|
02261|052|M|bradycardia for the first 6 hours.  Check blood pressure and pulse hourly.|
02261|053|M|ECG monitoring is recommended prior to dosing and at the end of the|
02261|054|M|observation period.|
02261|055|M|   US monitoring recommendations include additional monitoring for the|
02261|056|M|following patients:(1)|
02261|057|M|   If heart rate (HR) is less than 45 beats per minute (bpm), the heart rate|
02261|058|M|6 hours postdose is at the lowest value postdose, or if the ECG shows new|
02261|059|M|onset of second degree or higher AV block at the end of the monitoring|
02261|060|M|period, then monitoring should continue until the finding has resolved.|
02261|061|M|   Continuous overnight ECG monitoring is recommended in patients requiring|
02261|062|M|pharmacologic intervention for symptomatic bradycardia, some preexisting|
02261|063|M|heart and cerebrovascular conditions, prolonged QTc before dosing or during|
02261|064|M|6 hours observation, concurrent therapy with QT prolonging drugs, or|
02261|065|M|concurrent therapy with drugs that slow heart rate or AV conduction.|
02261|066|M|   Consult the prescribing information for full monitoring recommendations.|
02261|067|M|   United Kingdom recommendations:(3)|
02261|068|M|   Obtain a 12-lead ECG prior to initiating fingolimod therapy.  Consult a|
02261|069|M|cardiologist for pretreatment risk-benefit assessment if patient has a|
02261|070|M|resting heart rate less than 55 bpm, history of syncope, second degree or|
02261|071|M|greater AV block, sick-sinus syndrome, concurrent therapy with|
02261|072|M|beta-blockers, Class Ia, or Class III antiarrhythmics, heart failure or|
02261|073|M|other significant cardiovascular disease.  Perform continuous ECG|
02261|074|M|monitoring, measure blood pressure and heart rate every hour, and perform a|
02261|075|M|12-lead ECG 6 hours after the first dose.  Monitoring should be extended|
02261|076|M|beyond 6 hours if symptomatic bradycardia or new onset of second degree AV|
02261|077|M|block, Mobitz Type II or third degree AV block has occurred at any time|
02261|078|M|during the monitoring period.  If heart rate 6 hours after the first dose is|
02261|079|M|less than 40 bpm, has decreased more than 20 bpm compared with baseline, or|
02261|080|M|if a new onset second degree AV block, Mobitz Type I (Wenckebach) persists,|
02261|081|M|then monitoring should also be continued.|
02261|082|M|   If fingolimod treatment is discontinued for more than two weeks, the|
02261|083|M|effects on heart rate and conduction could recur.  Thus, first dose|
02261|084|M|monitoring precautions should be followed upon reintroduction of fingolimod.|
02261|085|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02261|086|M|fainting.|
02261|087|B||
02261|088|D|DISCUSSION:  After the first dose of fingolimod, heart rate decrease may|
02261|089|D|begin within an hour.  Decline is usually maximal at approximately 6 hours|
02261|090|D|followed by a second decrease 12 to 24 hours after the first dose.  The|
02261|091|D|second dose may further decrease heart rate, but the magnitude of change is|
02261|092|D|smaller than the first dose. With continued, chronic dosing, heart rate|
02261|093|D|gradually returns to baseline in about one month.(1,2)|
02261|094|D|   In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at|
02261|095|D|steady-state, when a negative chronotropic effect of fingolimod was still|
02261|096|D|present, fingolimod treatment resulted in a prolongation of QTc, with the|
02261|097|D|upper boundary of the 90% confidence interval (CI) of 14.0 msec.  The cause|
02261|098|D|of death in a patient who died within 24 hour after taking the first dose of|
02261|099|D|fingolimod was not conclusive; however a link to fingolimod or a drug|
02261|100|D|interaction with fingolimod could not be ruled out.(1)|
02261|101|B||
02261|102|R|REFERENCES:|
02261|103|B||
02261|104|R|1.Gilenya (fingolimod) US prescribing information. Novartis Pharmaceuticals|1
02261|105|R|  Corporation June, 2024.|1
02261|106|R|2.Gilenya (fingolimod) Health Canada prescribing information. Novartis|1
02261|107|R|  Pharmaceuticals September 23, 2011.|1
02261|108|R|3.MHRA United Kingdom. Fingolimod (Gilenya): transient bradycardias and|1
02261|109|R|  heart block after first dose - strengthened cardiovascular monitoring.|1
02261|110|R|  Drug Safety Update Feb 2012;5(7):A1.|1
02261|111|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02261|112|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02261|113|R|  settings: a scientific statement from the American Heart Association and|6
02261|114|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02261|115|R|  2;55(9):934-47.|6
02262|001|T|MONOGRAPH TITLE:  Sirolimus/Amiodarone; Dronedarone|
02262|002|B||
02262|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02262|004|L|take action as needed.|
02262|005|B||
02262|006|A|MECHANISM OF ACTION:  Amiodarone and dronedarone may inhibit the metabolism|
02262|007|A|of sirolimus by CYP3A4.|
02262|008|B||
02262|009|E|CLINICAL EFFECTS:  Concurrent use of amiodarone or dronedarone may result in|
02262|010|E|elevated levels of and toxicity from sirolimus.|
02262|011|B||
02262|012|P|PREDISPOSING FACTORS:  None determined.|
02262|013|B||
02262|014|M|PATIENT MANAGEMENT:  Monitor sirolimus levels and renal function in patients|
02262|015|M|receiving concurrent therapy, especially at the initiation of amiodarone or|
02262|016|M|dronedarone.  The dosage of sirolimus may need adjusting.  If concurrent|
02262|017|M|amiodarone or dronedarone is discontinued, the dosage of sirolimus may need|
02262|018|M|adjusting.|
02262|019|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
02262|020|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
02262|021|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
02262|022|M|inhibitors should be avoided.(3)|
02262|023|B||
02262|024|D|DISCUSSION:  There are case reports of sirolimus toxicity with both|
02262|025|D|amiodarone(1) and dronedarone(2).  Dronedarone is a moderate inhibitor of|
02262|026|D|CYP3A4 and would be expected to increase sirolimus levels.(4)|
02262|027|B||
02262|028|R|REFERENCES:|
02262|029|B||
02262|030|R|1.Nalli N, Stewart-Teixeira L, Dipchand AI. Amiodarone-sirolimus/tacrolimus|3
02262|031|R|  interaction in a pediatric heart transplant patient. Pediatr Transplant|3
02262|032|R|  2006 Sep;10(6):736-9.|3
02262|033|R|2.Tichy EM, Medwid AJ, Mills EA, Formica RN, Kulkarni S. Significant|3
02262|034|R|  sirolimus and dronedarone interaction in a kidney transplant recipient.|3
02262|035|R|  Ann Pharmacother 2010 Jul-Aug;44(7-8):1338-41.|3
02262|036|R|3.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
02262|037|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
02262|038|R|4.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
02262|039|R|  November, 2020.|1
02263|001|T|MONOGRAPH TITLE:  Bivalirudin; Desirudin/GPIs; Heparin; Thrombolytics;|
02263|002|T|Warfarin|
02263|003|B||
02263|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02263|005|L|of severe adverse interaction.|
02263|006|B||
02263|007|A|MECHANISM OF ACTION:  Concurrent use may result in additive effects on|
02263|008|A|hemostasis.(1,2)|
02263|009|B||
02263|010|E|CLINICAL EFFECTS:  Concurrent use of bivalirudin with GPIs, heparin, or|
02263|011|E|warfarin may increase the risk of bleeding.(1,2)|
02263|012|B||
02263|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02263|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02263|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
02263|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02263|017|P|risk for bleeding (e.g. NSAIDs).|
02263|018|B||
02263|019|M|PATIENT MANAGEMENT:  Concurrent use of bivalirudin and GPIs, heparin, or|
02263|020|M|warfarin should be avoided.(1)|
02263|021|M|   Discontinue agents that may increase the risk of hemorrhage prior to|
02263|022|M|initiation of desirudin.(2)|
02263|023|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02263|024|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02263|025|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02263|026|M|patients with any symptoms.|
02263|027|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02263|028|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02263|029|M|anticoagulation in patients with active pathologic bleeding.|
02263|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02263|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02263|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02263|033|M|and/or swelling.|
02263|034|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02263|035|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02263|036|M|initiating, altering the dose or discontinuing either drug.|
02263|037|B||
02263|038|D|DISCUSSION:  In clinical trials, concurrent use of bivalirudin with GPIs,|
02263|039|D|heparin, or warfarin was associated with increased risks of major bleeding|
02263|040|D|events compared to patients not receiving concurrent therapy.(1)|
02263|041|D|   Concurrent administration of warfarin did not affect the pharmacokinetics|
02263|042|D|of desirudin; however, greater inhibition of hemostasis was observed as seen|
02263|043|D|by aPPT, PT and INR measurements.(2)|
02263|044|B||
02263|045|R|REFERENCES:|
02263|046|B||
02263|047|R|1.Angiomax (bivalirudin) US prescribing information. The Medicines Company|1
02263|048|R|  June, 2010.|1
02263|049|R|2.Iprivask (desirudin) US prescribing information). Marathon|1
02263|050|R|  Pharmaceuticals, LLC November, 2014.|1
02264|001|T|MONOGRAPH TITLE:  Selected Cephalosporins/Antacids|
02264|002|B||
02264|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02264|004|L|take action as needed.|
02264|005|B||
02264|006|A|MECHANISM OF ACTION:  Absorption of oral cefuroxime may be reduced in|
02264|007|A|patients receiving concomitant treatment with acid reducing agents.(1,2)|
02264|008|B||
02264|009|E|CLINICAL EFFECTS:  Antibiotic efficacy against organisms with a high minimum|
02264|010|E|inhibitory concentration (MIC) to cefuroxime could be decreased.|
02264|011|B||
02264|012|P|PREDISPOSING FACTORS:  Taking cefuroxime on an empty stomach magnifies this|
02264|013|P|effect.|
02264|014|B||
02264|015|M|PATIENT MANAGEMENT:  Separate the administration of cefuroxime by at least|
02264|016|M|1-2 hours after administration of antacids.  Some vitamin preparations may|
02264|017|M|contain sufficient quantities of calcium and/or magnesium salts with antacid|
02264|018|M|properties to interact as well.|
02264|019|M|   Since concurrent use of H2 antagonists and proton pump inhibitors (PPIs)|
02264|020|M|in patients taking cefuroxime should be avoided, these would not be|
02264|021|M|alternatives to antacids in these patients.|
02264|022|B||
02264|023|D|DISCUSSION:  In a study performed prior to the introduction of PPIs,|
02264|024|D|administration of ranitidine 300 mg and sodium bicarbonate followed by|
02264|025|D|cefuroxime taken on a empty stomach lowered both Cmax and AUC of cefuroxime|
02264|026|D|by approximately 40 per cent compared with administration of cefuroxime|
02264|027|D|alone on an empty stomach.  Postprandial administration of cefuroxime in|
02264|028|D|subjects taking ranitidine was similar to that of subjects taking cefuroxime|
02264|029|D|on an empty stomach.(2)|
02264|030|B||
02264|031|R|REFERENCES:|
02264|032|B||
02264|033|R|1.Ceftin (cefuroxime axetil) US prescribing information. GlaxoSmithKline|1
02264|034|R|  January, 2010.|1
02264|035|R|2.Sommers DK, van Wyk M, Moncrieff J, Schoeman HS. Influence of food and|2
02264|036|R|  reduced gastric acidity on the bioavailability of bacampicillin and|2
02264|037|R|  cefuroxime axetil. Br J Clin Pharmacol 1984 Oct;18(4):535-9.|2
02265|001|T|MONOGRAPH TITLE:  Selected Calcium Channel Blockers/Itraconazole (mono|
02265|002|T|deleted 08/27/2015)|
02265|003|B||
02265|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02265|005|L|take action as needed.|
02265|006|B||
02265|007|A|MECHANISM OF ACTION:  Itraconazole(1-3) and ketoconazole(4) may inhibit the|
02265|008|A|first-pass and elimination metabolism of calcium channel blockers by CYP|
02265|009|A|P-450-3A4.  In addition, itraconazole has been shown to have negative|
02265|010|A|inotropic effects, which may be additive with those of the calcium channel|
02265|011|A|blockers.(1)|
02265|012|B||
02265|013|E|CLINICAL EFFECTS:  The concurrent administration of itraconazole or|
02265|014|E|ketoconazole with calcium channel blockers metabolized by CYP P-450-3A4 may|
02265|015|E|result in elevated levels of the calcium channel blocker and adverse|
02265|016|E|effects, including edema.|
02265|017|B||
02265|018|P|PREDISPOSING FACTORS:  None determined.|
02265|019|B||
02265|020|M|PATIENT MANAGEMENT:  The concurrent use of itraconazole or ketoconazole with|
02265|021|M|calcium channel blockers should be approached with caution.  When these|
02265|022|M|agents are used concurrently, the dose of the calcium channel blocker may|
02265|023|M|need to be decreased and patients should be observed for increased effects.|
02265|024|M|If the antifungal is discontinued, the dose of the calcium channel blocker|
02265|025|M|may need to be increased and patients should be observed for decreased|
02265|026|M|effects.|
02265|027|B||
02265|028|D|DISCUSSION:  A double-blind, randomized, two-phase crossover study in nine|
02265|029|D|subjects examined the effects of itraconazole on felodipine.  The half-life|
02265|030|D|of felodipine increased by 71% during concurrent itraconazole.  In seven of|
02265|031|D|the nine subjects, the maximum concentration (Cmax) of felodipine when|
02265|032|D|administered with placebo was lower than the 32-hour concentration of|
02265|033|D|felodipine when administered with itraconazole.  Concurrent use also|
02265|034|D|resulted in significantly greater effects on both blood pressure and heart|
02265|035|D|rate.(5,6) There are two case reports of patients developing edema following|
02265|036|D|the addition of itraconazole to felodipine therapy.  In the second report,|
02265|037|D|the patient was rechallenged with concurrent itraconazole and again|
02265|038|D|developed edema.(7)|
02265|039|D|   In another report, a patient developed edema following the addition of|
02265|040|D|itraconazole to nifedipine therapy.(8)|
02265|041|B||
02265|042|R|REFERENCES:|
02265|043|B||
02265|044|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02265|045|R|  Products, L.P. February, 2024.|1
02265|046|R|2.Sporanox (itraconazole) UK summary of product characteristics.|1
02265|047|R|  Janssen-Cilag Ltd April, 2021.|1
02265|048|R|3.Sporanox (itraconazole) Canadian prescribing information. Janssen-Ortho|1
02265|049|R|  December, 2023.|1
02265|050|R|4.Nizoral (ketoconazole) UK summary of product characteristics.|1
02265|051|R|  Janssen-Cilag Ltd October, 2008.|1
02265|052|R|5.Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma|2
02265|053|R|  concentrations and effects of felodipine. Clin Pharmacol Ther 1997 Apr;|2
02265|054|R|  61(4):410-5.|2
02265|055|R|6.Plendil (felodipine) US prescribing information. AstraZeneca|1
02265|056|R|  Pharmaceuticals LP November, 2003.|1
02265|057|R|7.Neuvonen PJ, Suhonen R. Itraconazole interacts with felodipine. J Am Acad|3
02265|058|R|  Dermatol 1995 Jul;33(1):134-5.|3
02265|059|R|8.Tailor SA, Gupta AK, Walker SE, Shear NH. Peripheral edema due to|3
02265|060|R|  nifedipine-itraconazole interaction: a case report. Arch Dermatol 1996|3
02265|061|R|  Mar;132(3):350-2.|3
02266|001|T|MONOGRAPH TITLE:  Felodipine/Itraconazole (mono deleted 04/10/2014)|
02266|002|B||
02266|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02266|004|L|is contraindicated and generally should not be dispensed or administered to|
02266|005|L|the same patient.|
02266|006|B||
02266|007|A|MECHANISM OF ACTION:  Itraconazole) may inhibit the first-pass and|
02266|008|A|elimination metabolism of felodipine by CYP3A4.(1-3)  In addition,|
02266|009|A|itraconazole has been shown to have negative inotropic effects, which may be|
02266|010|A|additive with those of felodipine.(1)|
02266|011|B||
02266|012|E|CLINICAL EFFECTS:  The concurrent administration of itraconazole may result|
02266|013|E|in elevated levels of and adverse effects, including edema, from felodipine.|
02266|014|B||
02266|015|P|PREDISPOSING FACTORS:  None determined.|
02266|016|B||
02266|017|M|PATIENT MANAGEMENT:  The concurrent use of itraconazole with felodipine is|
02266|018|M|contraindicated.(1,)|
02266|019|B||
02266|020|D|DISCUSSION:  A double-blind, randomized, two-phase crossover study in nine|
02266|021|D|subjects examined the effects of itraconazole on felodipine.  The half-life|
02266|022|D|of felodipine increased by 71% during concurrent itraconazole.  In seven of|
02266|023|D|the nine subjects, the maximum concentration (Cmax) of felodipine when|
02266|024|D|administered with placebo was lower than the 32-hour concentration of|
02266|025|D|felodipine when administered with itraconazole.  Concurrent use also|
02266|026|D|resulted in significantly greater effects on both blood pressure and heart|
02266|027|D|rate.(4,5) There are two case reports of patients developing edema following|
02266|028|D|the addition of itraconazole to felodipine therapy.  In the second report,|
02266|029|D|the patient was rechallenged with concurrent itraconazole and again|
02266|030|D|developed edema.(6)|
02266|031|B||
02266|032|R|REFERENCES:|
02266|033|B||
02266|034|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02266|035|R|  Products, L.P. February, 2024.|1
02266|036|R|2.Sporanox (itraconazole) UK summary of product characteristics.|1
02266|037|R|  Janssen-Cilag Ltd April, 2021.|1
02266|038|R|3.Sporanox (itraconazole) Canadian prescribing information. Janssen-Ortho|1
02266|039|R|  December, 2023.|1
02266|040|R|4.Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma|2
02266|041|R|  concentrations and effects of felodipine. Clin Pharmacol Ther 1997 Apr;|2
02266|042|R|  61(4):410-5.|2
02266|043|R|5.Plendil (felodipine) US prescribing information. AstraZeneca|1
02266|044|R|  Pharmaceuticals LP November, 2003.|1
02266|045|R|6.Neuvonen PJ, Suhonen R. Itraconazole interacts with felodipine. J Am Acad|3
02266|046|R|  Dermatol 1995 Jul;33(1):134-5.|3
02267|001|T|MONOGRAPH TITLE:  Atorvastatin (Greater Than 20 mg); Pravastatin (Greater|
02267|002|T|Than 40 mg)/Clarithromycin|
02267|003|B||
02267|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02267|005|L|is contraindicated and generally should not be dispensed or administered to|
02267|006|L|the same patient.|
02267|007|B||
02267|008|A|MECHANISM OF ACTION:  Clarithromycin may inhibit the metabolism of|
02267|009|A|atorvastatin and pravastatin by CYP3A4.|
02267|010|B||
02267|011|E|CLINICAL EFFECTS:  Concurrent clarithromycin may result in increased levels|
02267|012|E|of atorvastatin and pravastatin, which may produce rhabdomyolysis.  Symptoms|
02267|013|E|of rhabdomyolysis include muscle pain, tenderness, weakness, elevated|
02267|014|E|creatine kinase levels, and reddish-brown, heme positive urine.|
02267|015|B||
02267|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02267|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02267|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02267|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02267|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02267|021|P|transporter OATP1B1 may have increased statin concentrations and be|
02267|022|P|predisposed to myopathy or rhabdomyolysis.|
02267|023|B||
02267|024|M|PATIENT MANAGEMENT:  Do not exceed a dosage of 20 mg daily of|
02267|025|M|atorvastatin(1) or 40 mg daily of pravastatin(2) in patients receiving|
02267|026|M|clarithromycin.(1)|
02267|027|M|   If possible, consider suspending statin therapy during macrolide therapy.|
02267|028|M|Monitor patients receiving concurrent therapy for signs of rhabdomyolysis.|
02267|029|B||
02267|030|D|DISCUSSION:  In a study in healthy subjects, clarithromycin increased the|
02267|031|D|area-under-curve (AUC) of simvastatin, atorvastatin, and pravastatin by|
02267|032|D|10-fold, greater than 4-fold, and almost 2-fold, respectively.(3)|
02267|033|D|   In a study, concurrent clarithromycin (500 mg BID for 9 days) increased|
02267|034|D|the AUC and maximum concentration (Cmax) of atorvastatin (80 mg daily for 8|
02267|035|D|days) by 4.4-fold and 5.4-fold, respectively.(1)|
02267|036|D|   In a study concurrent clarithromycin (500 mg BID for 9 days) increased|
02267|037|D|the AUC and Cmax of pravastatin (40 mg daily for 8 days) by 110% and 128%,|
02267|038|D|respectively.(2)|
02267|039|B||
02267|040|R|REFERENCES:|
02267|041|B||
02267|042|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02267|043|R|  2020.|1
02267|044|R|2.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
02267|045|R|  Squibb Company May, 2022.|1
02267|046|R|3.Jacobson TA. Comparative pharmacokinetic interaction profiles of|2
02267|047|R|  pravastatin, simvastatin, and atorvastatin when coadministered with|2
02267|048|R|  cytochrome P450 inhibitors. Am J Cardiol 2004 Nov 1;94(9):1140-6.|2
02268|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 20 mg); Pitavastatin;|
02268|002|T|Pravastatin (Less Than or Equal To 40 mg)/Clarithromycin|
02268|003|B||
02268|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02268|005|L|take action as needed.|
02268|006|B||
02268|007|A|MECHANISM OF ACTION:  Clarithromycin may inhibit the metabolism of|
02268|008|A|atorvastatin and pravastatin by CYP3A4.|
02268|009|B||
02268|010|E|CLINICAL EFFECTS:  Concurrent clarithromycin may result in increased levels|
02268|011|E|of atorvastatin and pravastatin, which may produce rhabdomyolysis.  Symptoms|
02268|012|E|of rhabdomyolysis include muscle pain, tenderness, weakness, elevated|
02268|013|E|creatine kinase levels, and reddish-brown, heme positive urine.|
02268|014|B||
02268|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02268|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02268|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02268|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02268|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02268|020|P|transporter OATP1B1 may have increased statin concentrations and be|
02268|021|P|predisposed to myopathy or rhabdomyolysis.|
02268|022|B||
02268|023|M|PATIENT MANAGEMENT:  Do not exceed a dosage of 20 mg daily of|
02268|024|M|atorvastatin(1) or 40 mg daily of pravastatin(2) in patients receiving|
02268|025|M|clarithromycin.(1)|
02268|026|M|   If possible, consider suspending statin therapy during macrolide therapy.|
02268|027|M|Monitor patients receiving concurrent therapy for signs of rhabdomyolysis.|
02268|028|B||
02268|029|D|DISCUSSION:  In a study in healthy subjects, clarithromycin increased the|
02268|030|D|area-under-curve (AUC) of simvastatin, atorvastatin, and pravastatin by|
02268|031|D|10-fold, greater than 4-fold, and almost 2-fold, respectively.(3)|
02268|032|D|   In a study, concurrent clarithromycin (500 mg BID for 9 days) increased|
02268|033|D|the AUC and maximum concentration (Cmax) of atorvastatin (80 mg daily for 8|
02268|034|D|days) by 4.4-fold and 5.4-fold, respectively.(1)|
02268|035|D|   In a study concurrent clarithromycin (500 mg BID for 9 days) increased|
02268|036|D|the AUC and Cmax of pravastatin (40 mg daily for 8 days) by 110% and 128%,|
02268|037|D|respectively.(2)|
02268|038|D|   In a study, pretreatment with erythromycin (500 mg 4 times daily for 6|
02268|039|D|days) increased the area-under-curve (AUC) and maximum concentration (Cmax)|
02268|040|D|of a single dose of pitavastatin (4 mg on Day 4) by 2.8-fold and 3.6-fold,|
02268|041|D|respectively.(4)|
02268|042|B||
02268|043|R|REFERENCES:|
02268|044|B||
02268|045|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02268|046|R|  2020.|1
02268|047|R|2.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
02268|048|R|  Squibb Company May, 2022.|1
02268|049|R|3.Jacobson TA. Comparative pharmacokinetic interaction profiles of|2
02268|050|R|  pravastatin, simvastatin, and atorvastatin when coadministered with|2
02268|051|R|  cytochrome P450 inhibitors. Am J Cardiol 2004 Nov 1;94(9):1140-6.|2
02268|052|R|4.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
02268|053|R|  America, Inc. November, 2022.|1
02269|001|T|MONOGRAPH TITLE:  Pitavastatin (Greater Than 1 mg)/Erythromycin|
02269|002|B||
02269|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02269|004|L|is contraindicated and generally should not be dispensed or administered to|
02269|005|L|the same patient.|
02269|006|B||
02269|007|A|MECHANISM OF ACTION:  Erythromycin may inhibit the metabolism of|
02269|008|A|pitavastatin by organic anion transporting polypeptide (OATP).  When used|
02269|009|A|concomitantly, erythromycin inhibits hepatic uptake of pitavastatin in a|
02269|010|A|concentration dependent manner.(1)|
02269|011|B||
02269|012|E|CLINICAL EFFECTS:  Concurrent erythromycin may result in increased levels of|
02269|013|E|pitavastatin, which may produce rhabdomyolysis.  Symptoms of rhabdomyolysis|
02269|014|E|include muscle pain, tenderness, weakness, elevated creatine kinase levels,|
02269|015|E|and reddish-brown, heme positive urine.|
02269|016|B||
02269|017|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02269|018|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02269|019|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02269|020|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02269|021|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02269|022|P|transporter OATP1B1 may have increased statin concentrations and be|
02269|023|P|predisposed to myopathy or rhabdomyolysis.|
02269|024|B||
02269|025|M|PATIENT MANAGEMENT:  Do not exceed a dosage of 1 mg daily of pitavastatin|
02269|026|M|when used with erythromycin.(1)|
02269|027|M|   If possible, consider suspending statin therapy during macrolide therapy.|
02269|028|M|Monitor patients receiving concurrent therapy for signs of rhabdomyolysis.|
02269|029|B||
02269|030|D|DISCUSSION:  In a study, pretreatment with erythromycin (500 mg 4 times|
02269|031|D|daily for 6 days) increased the area-under-curve (AUC) and maximum|
02269|032|D|concentration (Cmax) of a single dose of pitavastatin (4 mg on Day 4) by|
02269|033|D|2.8-fold and 3.6-fold, respectively.(1)|
02269|034|B||
02269|035|R|REFERENCE:|
02269|036|B||
02269|037|R|1.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
02269|038|R|  America, Inc. November, 2022.|1
02271|001|T|MONOGRAPH TITLE:  Potassium Supplements/Potassium Binders|
02271|002|B||
02271|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02271|004|L|of severe adverse interaction.|
02271|005|B||
02271|006|A|MECHANISM OF ACTION:  Patiromer, sodium polystyrene sulfonate and sodium|
02271|007|A|zirconium cyclosilicate bind to potassium.(1-3)|
02271|008|B||
02271|009|E|CLINICAL EFFECTS:  Concurrent use of potassium supplements and patiromer,|
02271|010|E|sodium polystyrene sulfonate or sodium zirconium cyclosilicate may decrease|
02271|011|E|the effectiveness of both agents.|
02271|012|B||
02271|013|P|PREDISPOSING FACTORS:  None determined.|
02271|014|B||
02271|015|M|PATIENT MANAGEMENT:  Patients should normally not receive potassium|
02271|016|M|supplements and patiromer, sodium polystyrene sulfonate or sodium zirconium|
02271|017|M|cyclosilicate concurrently.(1-3)|
02271|018|M|   Patiromer, sodium polystyrene sulfonate or sodium zirconium cyclosilicate|
02271|019|M|are indicated for management of hyperkalemia.  Consider discontinuing or|
02271|020|M|holding potassium supplements in patients who develop hyperkalemia requiring|
02271|021|M|treatment.|
02271|022|B||
02271|023|D|DISCUSSION:  Patiromer, sodium polystyrene sulfonate and sodium zirconium|
02271|024|D|cyclosilicate are indicated for hyperkalemia.  Consider discontinuing or|
02271|025|D|holding potassium supplements in patients receiving sodium polystyrene|
02271|026|D|sulfonate or sodium zirconium cyclosilicate.|
02271|027|B||
02271|028|R|REFERENCES:|
02271|029|B||
02271|030|R|1.Veltassa (patiromer) US prescribing information. Relypasa, Inc. October,|1
02271|031|R|  2023.|1
02271|032|R|2.Sodium Polystyrene Sulfonate US prescribing information. Roxane|1
02271|033|R|  Laboratories, Inc. September, 2005.|1
02271|034|R|3.Lokelma (sodium zirconium cyclosilicate) US prescribing information.|1
02271|035|R|  AstraZeneca Pharmaceuticals Inc. September, 2022.|1
02272|001|T|MONOGRAPH TITLE:  Haloperidol/Fluoxetine; Fluvoxamine|
02272|002|B||
02272|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02272|004|L|take action as needed.|
02272|005|B||
02272|006|A|MECHANISM OF ACTION:  Haloperidol is metabolized via many metabolic|
02272|007|A|pathways. The contributions of CYP2D6, CYP3A4 and possibly CYP1A2 pathways|
02272|008|A|are most clearly defined.  Concomitant use of haloperidol with inhibitors of|
02272|009|A|one or more of these pathways may lead to clinically significant increases|
02272|010|A|in haloperidol levels. Fluoxetine is a strong CYP2D6 inhibitor and a weak|
02272|011|A|CYP3A4 inhibitor. Fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19|
02272|012|A|and is a weak inhibitor of CYP2C8, CYP2C9, and CYP3A4.|
02272|013|B||
02272|014|E|CLINICAL EFFECTS:  The concurrent administration of fluoxetine or|
02272|015|E|fluvoxamine may result in elevated levels of haloperidol and lead to|
02272|016|E|toxicities such as orthostatic hypotension, akathisia, acute dystonia, or|
02272|017|E|Parkinsonism.|
02272|018|B||
02272|019|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02272|020|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
02272|021|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
02272|022|P|have a greater risk for adverse effects.|
02272|023|P|   Younger patients, patients on low doses of haloperidol, or on a dose|
02272|024|P|targeted to lower-therapeutic serum levels, have a lower interaction risk.|
02272|025|B||
02272|026|M|PATIENT MANAGEMENT:  Monitor patient for extrapyramidal side effects and|
02272|027|M|orthostatic hypotension if fluoxetine or fluvoxamine is added to haloperidol|
02272|028|M|therapy and lower haloperidol dose if needed. The onset and peak effects of|
02272|029|M|an interaction with fluoxetine may be delayed 1 to 2 weeks due to its long 3|
02272|030|M|to 7 day half-life.|
02272|031|B||
02272|032|D|DISCUSSION:  Although it is an older agent, the complex pharmacokinetics of|
02272|033|D|haloperidol are not yet fully understood.|
02272|034|B||
02272|035|R|REFERENCES:|
02272|036|B||
02272|037|R|1.Haldol injection (haloperidol) US prescribing information. Janssen|1
02272|038|R|  Pharmaceuticals, Inc. October, 2025.|1
02272|039|R|2.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
02272|040|R|  and Company August, 2023.|1
02272|041|R|3.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
02272|042|R|  Pharmaceuticals, Inc. August, 2023.|1
02273|001|T|MONOGRAPH TITLE:  Select Serotonergic Agents/Fentanyl|
02273|002|B||
02273|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02273|004|L|take action as needed.|
02273|005|B||
02273|006|A|MECHANISM OF ACTION:  Although the exact mechanism is not known, fentanyl is|
02273|007|A|thought to have mild serotonergic effects.(1,7)  Concurrent administration|
02273|008|A|with one or more potent serotonergic agents may increase serotonin effects,|
02273|009|A|leading to toxicity.|
02273|010|B||
02273|011|E|CLINICAL EFFECTS:  Concurrent use of serotonergic agents and fentanyl may|
02273|012|E|result in serotonin syndrome.  Symptoms of serotonin syndrome may include|
02273|013|E|tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
02273|014|E|hyperthermia, and muscle rigidity.(1)|
02273|015|B||
02273|016|P|PREDISPOSING FACTORS:  Based upon case reports, high fentanyl doses in the|
02273|017|P|perioperative period, concomitant use of multiple serotonergic agents, or a|
02273|018|P|recent increase in dosage of either agent may be risk factors for this|
02273|019|P|interaction.(2-6)|
02273|020|B||
02273|021|M|PATIENT MANAGEMENT:  Most patients tolerate the combination of fentanyl with|
02273|022|M|serotonin-increasing agents.  Serotonin syndrome constitutes a range of|
02273|023|M|toxicities from mild to life threatening.(1)  Monitor patients on multiple|
02273|024|M|serotonergic agents for symptoms of serotonin toxicity.|
02273|025|M|   If concurrent therapy is warranted, patients should be monitored for|
02273|026|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02273|027|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02273|028|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02273|029|M|coordination, or severe diarrhea.|
02273|030|M|   Patients in whom serotonin syndrome is suspected should receive immediate|
02273|031|M|medical attention.|
02273|032|B||
02273|033|D|DISCUSSION:  Health Canada recently reported 5 cases of serotonin syndrome|
02273|034|D|associated with patients receiving fentanyl and at least one other|
02273|035|D|serotonergic agent.(2) Additional cases have been reported in the medical|
02273|036|D|literature.(3-6)|
02273|037|D|   Serotonin increasing agents linked to this monograph are: citalopram,|
02273|038|D|clomipramine, desvenlafaxine, duloxetine, fluoxetine, imipramine,|
02273|039|D|levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine,|
02273|040|D|vilazodone and vortioxetine.|
02273|041|B||
02273|042|R|REFERENCES:|
02273|043|B||
02273|044|R|1.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02273|045|R|  352(11):1112-20.|6
02273|046|R|2.Health Canada. Canadian Adverse Reaction Newsletter, Vol. 22 Issue 2|1
02273|047|R|  "Fentanyl and Serotonin Syndrome".|1
02273|048|R|  http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/medeff/bulletin/carn-bcei_v|1
02273|049|R|  22n2-eng.pdf April, 2012.|1
02273|050|R|3.Alkhatib AA, Peterson KA, Tuteja AK. Serotonin syndrome as a complication|3
02273|051|R|  of fentanyl sedation during esophagogastroduodenoscopy. Dig Dis Sci 2010|3
02273|052|R|  Jan;55(1):215-6.|3
02273|053|R|4.Rastogi R, Swarm RA, Patel TA. Case scenario: opioid association with|3
02273|054|R|  serotonin syndrome: implications to the practitioners. Anesthesiology 2011|3
02273|055|R|  Dec;115(6):1291-8.|3
02273|056|R|5.Rang ST, Field J, Irving C. Serotonin toxicity caused by an interaction|3
02273|057|R|  between fentanyl and paroxetine. Can J Anaesth 2008 Aug;55(8):521-5.|3
02273|058|R|6.Ailawadhi S, Sung KW, Carlson LA, Baer MR. Serotonin syndrome caused by|3
02273|059|R|  interaction between citalopram and fentanyl. J Clin Pharm Ther 2007 Apr;|3
02273|060|R|  32(2):199-202.|3
02273|061|R|7.Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin|6
02273|062|R|  toxicity. Br J Anaesth 2005 Oct;95(4):434-41.|6
02274|001|T|MONOGRAPH TITLE:  Cyclosporine/Colesevelam|
02274|002|B||
02274|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02274|004|L|take action as needed.|
02274|005|B||
02274|006|A|MECHANISM OF ACTION:  Colesevelam may bind to cyclosporine in the|
02274|007|A|gastrointestinal track, preventing its absorption.(1)|
02274|008|B||
02274|009|E|CLINICAL EFFECTS:  Simultaneous administration of colesevelam may result in|
02274|010|E|decreased levels and effectiveness of cyclosporine.(1)|
02274|011|B||
02274|012|P|PREDISPOSING FACTORS:  None determined.|
02274|013|B||
02274|014|M|PATIENT MANAGEMENT:  Cyclosporine should be administered four hours before|
02274|015|M|colesevelam.  Monitor cyclosporine levels in patients receiving concurrent|
02274|016|M|therapy and adjust as necessary.(1)|
02274|017|B||
02274|018|D|DISCUSSION:  When administered with colesevelam (3.75 g), the|
02274|019|D|area-under-curve (AUC) and maximum concentration (Cmax) of cyclosporine (200|
02274|020|D|mg) decreased by 34% and by 44%, respectively.(1)|
02274|021|B||
02274|022|R|REFERENCE:|
02274|023|B||
02274|024|R|1.Welchol (colesevelam hydrochloride) US prescribing information. Daiichi|1
02274|025|R|  Sankyo, Inc. October, 2021.|1
02275|001|T|MONOGRAPH TITLE:  Glimepiride; Glipizide; Glyburide/Colesevelam|
02275|002|B||
02275|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02275|004|L|take action as needed.|
02275|005|B||
02275|006|A|MECHANISM OF ACTION:  Colesevelam may bind to glimepiride, glipizide, and|
02275|007|A|glyburide in the gastrointestinal track, preventing their absorption.(1,2)|
02275|008|B||
02275|009|E|CLINICAL EFFECTS:  Simultaneous administration of colesevelam may result in|
02275|010|E|decreased levels and effectiveness of glimepiride,(1) glipizide,(1) or|
02275|011|E|glyburide.(1,2)|
02275|012|B||
02275|013|P|PREDISPOSING FACTORS:  None determined.|
02275|014|B||
02275|015|M|PATIENT MANAGEMENT:  Glyburide,(1) glipizide,(3) and glimepiride(4) should|
02275|016|M|be administered four hours before colesevelam.|
02275|017|B||
02275|018|D|DISCUSSION:  When administered with colesevelam (3.75 g), the|
02275|019|D|area-under-curve (AUC) and maximum concentration (Cmax) of glimepiride (4|
02275|020|D|mg) decreased by 18% and by 8%, respectively.  When administered 4 hours|
02275|021|D|prior to colesevelam, the AUC of glimepiride decreased by 6% and the Cmax|
02275|022|D|increased 3%.(1)|
02275|023|D|   When administered with colesevelam (3.75 g), the AUC and Cmax of|
02275|024|D|glipizide (20 mg) decreased by 12% and by 13%, respectively.  When|
02275|025|D|administered 4 hours prior to colesevelam, the AUC of glipizide decreased by|
02275|026|D|4%.  There was no effect on glipizide Cmax when glipizide and colesevelam|
02275|027|D|were separated by 4 hours.(1)|
02275|028|D|   When administered with colesevelam (3.75 g), AUC and Cmax of glyburide (3|
02275|029|D|mg) decreased by 32% and by 47%, respectively.  When administered 1 hour|
02275|030|D|prior to colesevelam, the AUC and Cmax of glyburide decreased by 20% and|
02275|031|D|15%, respectively.  When administered 4 hours prior to colesevelam, the AUC|
02275|032|D|and Cmax of glyburide decreased by 7% and 4%, respectively.(1,2)|
02275|033|B||
02275|034|R|REFERENCES:|
02275|035|B||
02275|036|R|1.Welchol (colesevelam hydrochloride) US prescribing information. Daiichi|1
02275|037|R|  Sankyo, Inc. October, 2021.|1
02275|038|R|2.Brown KS, Armstrong IC, Wang A, Walker JR, Noveck RJ, Swearingen D,|2
02275|039|R|  Allison M, Kissling JC, Kisicki J, Salazar DE. Effect of the bile acid|2
02275|040|R|  sequestrant colesevelam on the pharmacokinetics of pioglitazone,|2
02275|041|R|  repaglinide, estrogen estradiol, norethindrone, levothyroxine, and|2
02275|042|R|  glyburide. J Clin Pharmacol 2010 May;50(5):554-65.|2
02275|043|R|3.Diabeta (glyburide) US prescribing information. Sanofi-Aventis U.S. LLC|1
02275|044|R|  October, 2013.|1
02275|045|R|4.Amaryl (glimepiride) US prescribing information. Sanofi-Aventis U.S. LLC|1
02275|046|R|  October, 2013.|1
02276|001|T|MONOGRAPH TITLE:  Oral Contraceptives/Colesevelam|
02276|002|B||
02276|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02276|004|L|take action as needed.|
02276|005|B||
02276|006|A|MECHANISM OF ACTION:  Colesevelam may bind to oral contraceptives in the|
02276|007|A|gastrointestinal track, preventing their absorption.(1,2)|
02276|008|B||
02276|009|E|CLINICAL EFFECTS:  Simultaneous administration of colesevelam may result in|
02276|010|E|decreased levels and effectiveness of oral contraceptives.(1,2)|
02276|011|B||
02276|012|P|PREDISPOSING FACTORS:  None determined.|
02276|013|B||
02276|014|M|PATIENT MANAGEMENT:  Oral contraceptives should be administered four hours|
02276|015|M|before colesevelam.(1)|
02276|016|B||
02276|017|D|DISCUSSION:  When administered with colesevelam (3.75 g), the|
02276|018|D|area-under-curve (AUC) and maximum concentration (Cmax) of ethinyl estradiol|
02276|019|D|(0.035 mg) decreased by 24% and by 24%, respectively, and the AUC and Cmax|
02276|020|D|of norethindrone (1 mg) decreased by 1% and 20%, respectively.  When|
02276|021|D|administered 1 hour prior to colesevelam, the AUC and Cmax of ethinyl|
02276|022|D|estradiol decreased by 18% and 1%, respectively, the AUC of norethindrone|
02276|023|D|increased by 5%, and the Cmax of norethindrone decreased by 3%.  When|
02276|024|D|administered 4 hours prior to colesevelam, the AUC of ethinyl decreased  by|
02276|025|D|12% and the AUC and Cmax of norethindrone increased by 6% and 7%,|
02276|026|D|respectively.(1,2)|
02276|027|B||
02276|028|R|REFERENCES:|
02276|029|B||
02276|030|R|1.Welchol (colesevelam hydrochloride) US prescribing information. Daiichi|1
02276|031|R|  Sankyo, Inc. October, 2021.|1
02276|032|R|2.Brown KS, Armstrong IC, Wang A, Walker JR, Noveck RJ, Swearingen D,|2
02276|033|R|  Allison M, Kissling JC, Kisicki J, Salazar DE. Effect of the bile acid|2
02276|034|R|  sequestrant colesevelam on the pharmacokinetics of pioglitazone,|2
02276|035|R|  repaglinide, estrogen estradiol, norethindrone, levothyroxine, and|2
02276|036|R|  glyburide. J Clin Pharmacol 2010 May;50(5):554-65.|2
02277|001|T|MONOGRAPH TITLE:  Phenytoin/Colesevelam|
02277|002|B||
02277|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02277|004|L|take action as needed.|
02277|005|B||
02277|006|A|MECHANISM OF ACTION:  Colesevelam may bind to phenytoin in the|
02277|007|A|gastrointestinal track, preventing its absorption.(1)|
02277|008|B||
02277|009|E|CLINICAL EFFECTS:  Simultaneous administration of colesevelam may result in|
02277|010|E|decreased levels and effectiveness of phenytoin.  Increased seizure activity|
02277|011|E|has been reported.(1)|
02277|012|B||
02277|013|P|PREDISPOSING FACTORS:  None determined.|
02277|014|B||
02277|015|M|PATIENT MANAGEMENT:  Phenytoin should be administered four hours before|
02277|016|M|colesevelam.(1)|
02277|017|B||
02277|018|D|DISCUSSION:  Decreased phenytoin levels and increased seizure activity have|
02277|019|D|been observed in post-marketing reports involving colesevelam.(1)|
02277|020|B||
02277|021|R|REFERENCE:|
02277|022|B||
02277|023|R|1.Welchol (colesevelam hydrochloride) US prescribing information. Daiichi|1
02277|024|R|  Sankyo, Inc. October, 2021.|1
02278|001|T|MONOGRAPH TITLE:  Radioactive Iodide/Agents that Affect Iodide|
02278|002|B||
02278|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02278|004|L|of severe adverse interaction.|
02278|005|B||
02278|006|A|MECHANISM OF ACTION:  Many compounds can affect iodide protein binding and|
02278|007|A|alter iodide pharmacokinetics and pharmacodynamics.(1)|
02278|008|B||
02278|009|E|CLINICAL EFFECTS:  Compounds that affect iodide pharmacokinetics and|
02278|010|E|pharmacodynamics may impact the effectiveness of radioactive iodide.(1)|
02278|011|B||
02278|012|P|PREDISPOSING FACTORS:  Compounds that affect iodide pharmacokinetics and|
02278|013|P|pharmacodynamics are expected to have the most impact during therapy using|
02278|014|P|radioactive iodide.  Diagnostic procedures would be expected to be impacted|
02278|015|P|less.|
02278|016|B||
02278|017|M|PATIENT MANAGEMENT:  Discuss the use of agents that affect iodide|
02278|018|M|pharmacokinetics and pharmacodynamics with the patient's oncologist.(1)|
02278|019|M|   Because indocyanine green contains sodium iodide, the iodine-binding|
02278|020|M|capacity of thyroid tissue may be reduced for at least one week following|
02278|021|M|administration.  Do not perform radioactive iodine uptake studies for at|
02278|022|M|least one week following administration of indocyanine green.(2)|
02278|023|M|   The manufacturer of iopamidol states administration may interfere with|
02278|024|M|thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic|
02278|025|M|efficacy.  Avoid thyroid therapy or testing for up to 6 weeks post|
02278|026|M|administration of iopamidol.(3)|
02278|027|B||
02278|028|D|DISCUSSION:  Many agents interact with radioactive iodine.  The average|
02278|029|D|duration of effect is:|
02278|030|D|   anticoagulants - 1 week|
02278|031|D|   antihistamines - 1 week|
02278|032|D|   anti-thyroid drugs, e.g:|
02278|033|D|      carbimazole, methimazole, propylthiouracil - 3-5 days|
02278|034|D|   corticosteroids - 1 week|
02278|035|D|   iodide-containing medications, e.g:|
02278|036|D|      amiodarone - 1-6 months|
02278|037|D|      expectorants - 2 weeks|
02278|038|D|      Lugol solution - 3 weeks|
02278|039|D|      saturated solution of potassium iodine - 3 weeks|
02278|040|D|      vitamins - 10-14 days|
02278|041|D|   iodide-containing X-ray contrast agents - up to 1 year|
02278|042|D|   lithium - 4 weeks|
02278|043|D|   phenylbutazone - 1-2 weeks|
02278|044|D|   sulfonamides - 1 week|
02278|045|D|   thyroid hormones (natural or synthetic), e.g.:|
02278|046|D|      thyroxine - 4 weeks|
02278|047|D|      tri-iodothyronine - 2 weeks|
02278|048|D|   tolbutamide - 1 week|
02278|049|D|   topical iodide - 1-9 months (1)|
02278|050|B||
02278|051|R|REFERENCES:|
02278|052|B||
02278|053|R|1.Sodium Iodide I 131 Solution Therapeutic US prescribing information.|1
02278|054|R|  Mallinckrodt Inc. March, 2014.|1
02278|055|R|2.IC-GREEN (Indocyanine green for injection) US prescribing information.|1
02278|056|R|  Diagnostic Green LLC December 2024.|1
02278|057|R|3.ISOVUE (iopamidol) US Prescribing Information. Bracco Diagnostic Inc.|1
02278|058|R|  December 2024.|1
02279|001|T|MONOGRAPH TITLE:  Lithium/Aldosterone Receptor Antagonists|
02279|002|B||
02279|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02279|004|L|take action as needed.|
02279|005|B||
02279|006|A|MECHANISM OF ACTION:  Aldosterone receptor antagonists, including|
02279|007|A|eplerenone, finerenone and spironolactone, bind to mineralocorticoid|
02279|008|A|receptors, blocking the action of aldosterone.  The subsequent increase in|
02279|009|A|sodium and water excretion may lead to reduced renal clearance of|
02279|010|A|lithium.(1-3)|
02279|011|B||
02279|012|E|CLINICAL EFFECTS:  Lithium has a narrow therapeutic range. Unintended|
02279|013|E|increases in lithium concentrations may lead to lithium toxicity.  Early|
02279|014|E|symptoms of lithium toxicity may include: lethargy, muscle weakness or|
02279|015|E|stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea,|
02279|016|E|confusion, ataxia, blurred vision, tinnitus and nystagmus. Severe toxicity|
02279|017|E|may produce multiple organ dysfunction (e.g. seizures, coma, renal failure,|
02279|018|E|cardiac arrhythmias, cardiovascular collapse) and may be fatal.(4)|
02279|019|B||
02279|020|P|PREDISPOSING FACTORS:  Risk factors for lithium toxicity include: renal|
02279|021|P|impairment or worsening of existing renal disease, dehydration, low sodium|
02279|022|P|diet, and concomitant use of multiple medications which may impair renal|
02279|023|P|elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics).(4)|
02279|024|P|Patients who require higher therapeutic lithium levels to maintain symptom|
02279|025|P|control are particularly susceptible to these factors.|
02279|026|B||
02279|027|M|PATIENT MANAGEMENT:  Evaluate renal function and most recent lithium levels.|
02279|028|M|If renal function is not stable or if the lithium level is in the high|
02279|029|M|therapeutic range, then consider lowering the lithium dose when an|
02279|030|M|aldosterone antagonist is started, or consider withholding the aldosterone|
02279|031|M|antagonist until renal function is stable. If renal function is stable and|
02279|032|M|baseline lithium concentrations are in the therapeutic range, recheck|
02279|033|M|lithium levels 5 to 7 days after initiation of eplerenone, finerenone, or|
02279|034|M|spironolactone.  Adjust the lithium dose as necessary based on lithium serum|
02279|035|M|levels and patient response.|
02279|036|M|   If an interacting drug is discontinued, the lithium level may fall.|
02279|037|M|Monitor lithium concentration and adjust dose if needed.(4)|
02279|038|M|   Counsel patient to assure they know signs and symptoms of lithium|
02279|039|M|toxicity and understand the importance of follow-up laboratory testing.|
02279|040|B||
02279|041|D|DISCUSSION:  Although the magnitude and frequency of this specific diuretic|
02279|042|D|interaction is not clear, manufacturer product information for|
02279|043|D|spironolactone and lithium state that lithium patients should generally not|
02279|044|D|receive diuretics.(2,3)  The manufacturer of eplerenone recommends frequent|
02279|045|D|monitoring of lithium levels in patients who receive concomitant therapy.(1)|
02279|046|B||
02279|047|R|REFERENCES:|
02279|048|B||
02279|049|R|1.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
02279|050|R|2.Aldactone (spironolactone) US prescribing information. Pfizer November,|1
02279|051|R|  2025.|1
02279|052|R|3.KERENDIA (finerenone) US prescribing information. Bayer HealthCare|1
02279|053|R|  Pharmaceuticals Inc. July, 2025.|1
02279|054|R|4.Lithobid (lithium carbonate) US prescribing information. ANI|1
02279|055|R|  Pharmaceuticals, Inc. May, 2018.|1
02280|001|T|MONOGRAPH TITLE:  Selected Tricyclic Antidepressants/Quinidine; Thioridazine|
02280|002|B||
02280|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02280|004|L|of severe adverse interaction.|
02280|005|B||
02280|006|A|MECHANISM OF ACTION:  Quinidine and thioridazine are strong inhibitors of|
02280|007|A|CYP2D6.(1)  Doses as low as 50 mg to 100 mg of thioridazine or 30 mg of|
02280|008|A|quinidine will convert most individuals with a CYP2D6 extensive metabolizer|
02280|009|A|(EM) genotype to a poor metabolizer (PM) phenotype.(2,3,7)|
02280|010|A|   CYP2D6 is the primary metabolic pathway for desipramine and|
02280|011|A|nortriptyline; amitriptyline, clomipramine, doxepin, and imipramine are|
02280|012|A|metabolized by both CYP2D6 and CYP2C19 pathways.|
02280|013|B||
02280|014|E|CLINICAL EFFECTS:  Concurrent use of quinidine or thioridazine and selected|
02280|015|E|tricyclic antidepressants (TCAs) may increase levels of the TCA and the risk|
02280|016|E|for toxicities from either or both drugs. Risks include seizures,|
02280|017|E|anticholinergic, sedative, and alpha-blocking effects.(1,3,4)|
02280|018|B||
02280|019|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
02280|020|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
02280|021|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
02280|022|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
02280|023|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
02280|024|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
02280|025|P|systemic steroids).|
02280|026|P|   The risk of anticholinergic toxicities including cognitive decline,|
02280|027|P|delirium, falls and fractures is increased in geriatric patients using more|
02280|028|P|than one medicine with anticholinergic properties.(8)|
02280|029|B||
02280|030|M|PATIENT MANAGEMENT:  Alternative antipsychotics or antidepressants are|
02280|031|M|available and should be used whenever possible due to the potential|
02280|032|M|morbidity associated with this combination.|
02280|033|M|   If concomitant treatment is necessary, begin with a lower than usual TCA|
02280|034|M|starting dose and closely monitor serum levels of the tricyclic|
02280|035|M|antidepressant.(3,5)  Dosages of desipramine above 40 mg daily with Nuedexta|
02280|036|M|(dextromethorphan-quinidine) are not recommended.(6)|
02280|037|M|   If concurrent use with doxepin is warranted, monitor doxepin plasma|
02280|038|M|concentrations and reduce the doxepin dose based on doxepin plasma|
02280|039|M|concentrations.(9)|
02280|040|B||
02280|041|D|DISCUSSION:  TCAs vary in their sensitivity to CYP2D6 inhibition:|
02280|042|D|   Paroxetine, another strong CYP2D6 inhibitor, increases the plasma|
02280|043|D|concentration of amitriptyline by 60 percent. However, paroxetine is a more|
02280|044|D|potent inhibitor for nortriptyline (active metabolite of amitriptyline)|
02280|045|D|yielding a nortriptyline AUC ratio of 4.8.|
02280|046|D|   Desipramine is described as sensitive substrate at CYP2D6. Other strong|
02280|047|D|CYP2D6 inhibitors, fluoxetine and paroxetine, increase desipramine AUC ratio|
02280|048|D|by 7.8 and 5.4 respectively.  Use of a combination product containing|
02280|049|D|dextromethorphan-quinidine (30 mg/30 mg) increased steady state levels of|
02280|050|D|desipramine (25 mg) by 8-fold.(6)|
02280|051|B||
02280|052|R|REFERENCES:|
02280|053|B||
02280|054|R|1.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
02280|055|R|  September, 2014.|1
02280|056|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02280|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02280|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02280|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02280|060|R|  11/14/2017.|1
02280|061|R|3.LLerena A, Berecz R, de la Rubia A, Fernandez-Salguero P, Dorado P. Effect|2
02280|062|R|  of thioridazine dosage on the debrisoquine hydroxylation phenotype in|2
02280|063|R|  psychiatric patients with different CYP2D6 genotypes. Ther Drug Monit 2001|2
02280|064|R|  Dec;23(6):616-20.|2
02280|065|R|4.Amitriptyline hydrochloride, US prescribing information. Sandoz Inc.|1
02280|066|R|  January, 2010.|1
02280|067|R|5.Pamelor (nortriptyline hydrochloride) US prescribing information.|1
02280|068|R|  Mallinckrodt Inc. October, 2012.|1
02280|069|R|6.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
02280|070|R|  prescribing information. Avanir  Pharmaceuticals June, 2019.|1
02280|071|R|7.FDA Drug Approval Package application: 021879. Nuedexta (dextromethorphan|1
02280|072|R|  hydrobromide and quinidine sulfate), Clinical Pharmacology and|1
02280|073|R|  Biopharmaceutics Reviews. URL:|1
02280|074|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/021879Orig1s000Clin|1
02280|075|R|  PharmR.pdf 10/29/2010.|1
02280|076|R|8.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02280|077|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02280|078|R|  Soc 2023 Jul;71(7):2052-2081.|6
02280|079|R|9.Sinequan (doxepin) US prescribing information. Pfizer July, 2025.|1
02281|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Fluconazole; Voriconazole|
02281|002|B||
02281|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02281|004|L|of severe adverse interaction.|
02281|005|B||
02281|006|A|MECHANISM OF ACTION:  Fluconazole and voriconazole may inhibit CYP3A4|
02281|007|A|mediated metabolism of methadone, resulting in elevated methadone|
02281|008|A|levels.(1,2)  Methadone, fluconazole and voriconazole have been associated|
02281|009|A|with prolongation the QTc interval.(1-3)|
02281|010|A|   Levomethadone is an enantiomer of methadone.(4)|
02281|011|B||
02281|012|E|CLINICAL EFFECTS:  Increased methadone levels may be associated with|
02281|013|E|profound sedation, respiratory depression, coma, and/or death or other|
02281|014|E|opioid toxicities, and with an increased risk for QT prolongation.(5)|
02281|015|E|   Concurrent use of multiple agents that prolong the QTc interval may|
02281|016|E|result in potentially life-threatening cardiac arrhythmias, including|
02281|017|E|torsades de pointes.|
02281|018|E|   Methadone has been associated with serotonin syndrome.  Symptoms of|
02281|019|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
02281|020|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
02281|021|B||
02281|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02281|023|P|may be increased in patients with cardiovascular disease (e.g. heart|
02281|024|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02281|025|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02281|026|P|female gender, advanced age, or high daily doses of methadone.(5)|
02281|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02281|028|P|higher systemic concentrations of either QT prolonging drug are additional|
02281|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02281|030|P|drug concentrations include rapid infusion of an intravenous dose or|
02281|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02281|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02281|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
02281|034|B||
02281|035|M|PATIENT MANAGEMENT:  Patients receiving concurrent methadone and fluconazole|
02281|036|M|or voriconazole should be closely monitored for adverse effects.|
02281|037|M|   Respiratory depression can occur at any time during opioid therapy,|
02281|038|M|especially during therapy initiation and following dosage increases.  The|
02281|039|M|risk of opioid-related overdose or overdose-related death is increased with|
02281|040|M|higher opioid doses, and this risk persists over the course of therapy.|
02281|041|M|Consider these risks when using concurrently with agents that may increase|
02281|042|M|opioid drug levels.(6)|
02281|043|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
02281|044|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02281|045|M|unresponsiveness.  The dosage of methadone may need to be lowered.(1,2)|
02281|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02281|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02281|048|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02281|049|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02281|050|M|   If concurrent therapy is warranted, patients should be monitored for|
02281|051|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02281|052|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02281|053|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02281|054|M|coordination, or severe diarrhea.|
02281|055|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02281|056|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02281|057|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02281|058|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02281|059|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02281|060|M|as those taking CNS depressants) and when a patient has household|
02281|061|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02281|062|M|for obtaining an opioid reversal agent (e.g., prescription,|
02281|063|M|over-the-counter, or as part of a community-based program).(7)|
02281|064|B||
02281|065|D|DISCUSSION:  Voriconazole (400 mg twice daily Day 1, 200 mg twice daily Days|
02281|066|D|2-5) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
02281|067|D|of R-methadone by 31% and 47%, respectively, and the Cmax and AUC of|
02281|068|D|S-methadone by 65% and 103%, respectively, in patients receiving maintenance|
02281|069|D|doses (30-100 mg daily) of methadone.(1)|
02281|070|D|   One or more of the drug pairs linked to this monograph have been included|
02281|071|D|in a list of interactions that should be considered "high-priority" for|
02281|072|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02281|073|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02281|074|D|Coordinator (ONC) for Health Information Technology.|
02281|075|B||
02281|076|R|REFERENCES:|
02281|077|B||
02281|078|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
02281|079|R|2.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
02281|080|R|  2024.|1
02281|081|R|3.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
02281|082|R|  Pharmaceuticals Corp. June, 2021.|1
02281|083|R|4.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
02281|084|R|  Pharma AS November 30, 2018.|1
02281|085|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02281|086|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02281|087|R|  settings: a scientific statement from the American Heart Association and|6
02281|088|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02281|089|R|  2;55(9):934-47.|6
02281|090|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02281|091|R|  prescribing information for all opioid pain medicines to provide|1
02281|092|R|  additional guidance for safe use. Available at:|1
02281|093|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02281|094|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02281|095|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02281|096|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02281|097|R|  recommends health care professionals discuss naloxone with all patients|1
02281|098|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02281|099|R|  disorder. Available at:|1
02281|100|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02281|101|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02281|102|R|  d-pain July 23, 2020.|1
02281|103|R|8.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02281|104|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02281|105|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02281|106|R|  19(5):735-43.|6
02282|001|T|MONOGRAPH TITLE:  Pioglitazone (Greater Than 15 mg)/Strong CYP2C8 Inhibitors|
02282|002|B||
02282|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02282|004|L|is contraindicated and generally should not be dispensed or administered to|
02282|005|L|the same patient.|
02282|006|B||
02282|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2C8 may inhibit the metabolism|
02282|008|A|of pioglitazone.(1-5)|
02282|009|B||
02282|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2C8 inhibitors may result in|
02282|011|E|elevated levels of and clinical effects, including severe hypoglycemia, from|
02282|012|E|pioglitazone.(1-5)|
02282|013|B||
02282|014|P|PREDISPOSING FACTORS:  None determined.|
02282|015|B||
02282|016|M|PATIENT MANAGEMENT:  The maximum recommended dosage of pioglitazone is 15 mg|
02282|017|M|daily when used concurrently with strong CYP2C8 inhibitors.(2)|
02282|018|B||
02282|019|D|DISCUSSION:  In a randomized, cross-over study in 10 healthy subjects,|
02282|020|D|pretreatment with gemfibrozil (600 mg daily for 3 days) increased the the|
02282|021|D|area-under-curve (AUC) of a single dose of pioglitazone (30 mg) by 3.4-fold.|
02282|022|D|The AUC of the ratios of the M-III metabolite/pioglitazone and M-IV|
02282|023|D|metabolite/pioglitazone were reduced by 71% and by 65%, respectively. (1,2)|
02282|024|D|   In a randomized, double-blind, cross-over study in 12 healthy subjects,|
02282|025|D|pretreatment with gemfibrozil (600 mg daily for 3 days) increased the AUC|
02282|026|D|and half-life (T1/2) of a single dose of pioglitazone (15 mg) by 3.2-fold|
02282|027|D|(range 2.3-fold to 6.5-fold) and by 1.7-fold, respectively.  There was no|
02282|028|D|significant effect on pioglitazone maximum concentration (Cmax).  The 0-48|
02282|029|D|hour AUC of the M-III and M-IV metabolites were decreased by 42% and by 45%,|
02282|030|D|respectively; however, there was no significant effect on their 0-infinity|
02282|031|D|AUC.(3)|
02282|032|D|   In a randomized, cross-over study, gemfibrozil (600 mg twice daily for 4|
02282|033|D|days) increased the AUC of a single dose of pioglitazone (15 mg) by|
02282|034|D|4.3-fold.  The increase was variable between CYP2C8 genotypes.  Individuals|
02282|035|D|who were CYP2C8*3 carriers had a 5.2-fold increase in pioglitazone, while|
02282|036|D|CYP2C8*1 homozygotes had a 3.3-fold increase in pioglitazone.(5)|
02282|037|D|   Strong inhibitors of CYP2C8 include: gemfibrozil.(8,9)|
02282|038|B||
02282|039|R|REFERENCES:|
02282|040|B||
02282|041|R|1.Deng LJ, Wang F, Li HD. Effect of gemfibrozil on the pharmacokinetics of|2
02282|042|R|  pioglitazone. Eur J Clin Pharmacol 2005 Dec;61(11):831-6.|2
02282|043|R|2.Actos (pioglitazone hydrochloride) US prescribing information. Takeda|1
02282|044|R|  Pharmaceuticals Inc. November, 2013.|1
02282|045|R|3.Jaakkola T, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil,|2
02282|046|R|  itraconazole, and their combination on the pharmacokinetics of|2
02282|047|R|  pioglitazone. Clin Pharmacol Ther 2005 May;77(5):404-14.|2
02282|048|R|4.Jaakkola T, Laitila J, Neuvonen PJ, Backman JT. Pioglitazone is|5
02282|049|R|  metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with|5
02282|050|R|  CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol 2006 Jul;99(1):44-51.|5
02282|051|R|5.Aquilante CL, Kosmiski LA, Bourne DW, Bushman L, Daily EB, Hammond KP,|2
02282|052|R|  Hopley CW, Kadam RS, Kanack AT, Kompella UB, Le M, Predhomme JA, Rower JE,|2
02282|053|R|  Sidhom MS. Impact of the CYP2C8*3 polymorphism on the drug-drug|2
02282|054|R|  interaction between gemfibrozil and pioglitazone. Br J Clin Pharmacol 2012|2
02282|055|R|  May 25.|2
02282|056|R|6.Niemi M, Backman JT, Granfors M, Laitila J, Neuvonen M, Neuvonen PJ.|2
02282|057|R|  Gemfibrozil considerably increases the plasma concentrations of|2
02282|058|R|  rosiglitazone. Diabetologia 2003 Oct;46(10):1319-23.|2
02282|059|R|7.Avandia (rosiglitazone) US prescribing information. GlaxoSmithKline May,|1
02282|060|R|  2012.|1
02282|061|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
02282|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02282|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02282|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02282|065|R|  11/14/2017.|1
02282|066|R|9.This information is based on an extract from the Certara Drug Interaction|6
02282|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02283|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Selected Strong CYP3A4 Inhibitors|
02283|002|B||
02283|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02283|004|L|is contraindicated and generally should not be dispensed or administered to|
02283|005|L|the same patient.|
02283|006|B||
02283|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the hepatic|
02283|008|A|metabolism of ergot alkaloids.(1-4)|
02283|009|B||
02283|010|E|CLINICAL EFFECTS:  Concurrent use may result in increased levels of ergot|
02283|011|E|alkaloids, which may result in clinical signs of ergotism, including|
02283|012|E|vasospasm, dysesthesia, renal ischemia, and peripheral ischemia.|
02283|013|B||
02283|014|P|PREDISPOSING FACTORS:  None determined.|
02283|015|B||
02283|016|M|PATIENT MANAGEMENT:  The concurrent use of dihydroergotamine,(1,2)|
02283|017|M|ergotamine,(2,3) or methylergonovine(2,4) and strong inhibitors of CYP3A4 is|
02283|018|M|contraindicated.|
02283|019|M|   It would be prudent to avoid the concurrent use of all ergot alkaloids|
02283|020|M|and strong inhibitors of CYP3A4.  Patients receiving concurrent therapy|
02283|021|M|should be monitored for clinical signs of ergotism.  One or both agents may|
02283|022|M|need to be discontinued.  Patients should be treated symptomatically for|
02283|023|M|ergotism.|
02283|024|B||
02283|025|D|DISCUSSION:  Case reports have documented clinical signs of ergotism|
02283|026|D|following concomitant therapy with various ergot alkaloids and strong|
02283|027|D|inhibitors of CYP3A4 such as clarithromycin, erythromycin, indinavir,|
02283|028|D|nelfinavir, ritonavir, and troleandomycin.|
02283|029|D|   Selected strong CYP3A4 inhibitors linked include:  adagrasib, ceritinib,|
02283|030|D|cobicistat, grapefruit, idelalisib, josamycin, levoketoconazole, lonafarnib,|
02283|031|D|mibefradil, nefazodone, ribociclib, and tucatinib.|
02283|032|B||
02283|033|R|REFERENCES:|
02283|034|B||
02283|035|R|1.D. H. E. 45 (dihydroergotamine mesylate) US prescribing information.|1
02283|036|R|  Valeant Pharmaceuticals North America November 6, 2017.|1
02283|037|R|2.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02283|038|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02283|039|R|3.Cafergot (ergotamine tartrate and caffeine) tablets US prescribing|1
02283|040|R|  information. Sandoz Inc May 14, 2012.|1
02283|041|R|4.Methergine (methylergonovine maleate) US prescribing information. Novartis|1
02283|042|R|  Pharmaceuticals Corporation June, 2012.|1
02284|001|T|MONOGRAPH TITLE:  Atorvastatin/Telaprevir|
02284|002|B||
02284|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02284|004|L|of severe adverse interaction.|
02284|005|B||
02284|006|A|MECHANISM OF ACTION:  Telaprevir, a strong inhibitor of CYP3A4, may inhibit|
02284|007|A|the metabolism of atorvastatin.(1)|
02284|008|B||
02284|009|E|CLINICAL EFFECTS:  Concurrent use of telaprevir may result in elevated|
02284|010|E|levels of and effects from atorvastatin, including myopathy and|
02284|011|E|rhabdomyolysis.(1)|
02284|012|B||
02284|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02284|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02284|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02284|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02284|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02284|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02284|019|P|predisposed to myopathy or rhabdomyolysis.|
02284|020|B||
02284|021|M|PATIENT MANAGEMENT:  The concurrent use of atorvastatin with telaprevir|
02284|022|M|should be avoided.(1,2)|
02284|023|M|   Based upon US manufacturer information, fluvastatin, pitavastatin,|
02284|024|M|pravastatin and rosuvastatin appear to be less susceptible to CYP3A4|
02284|025|M|inhibition.(3-7)|
02284|026|B||
02284|027|D|DISCUSSION:  In a study in 19 subjects, telaprevir (750 mg every 8 hours for|
02284|028|D|7 days) increased the maximum concentration (Cmax) and area-under-curve|
02284|029|D|(AUC) of a single dose of atorvastatin (20 mg) by 10.60-fold and 7.88-fold,|
02284|030|D|respectively.(1)  There were no significant effects on telaprevir|
02284|031|D|pharmacokinetics.(2)|
02284|032|B||
02284|033|R|REFERENCES:|
02284|034|B||
02284|035|R|1.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02284|036|R|  Incorporated October, 2013.|1
02284|037|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02284|038|R|  2020.|1
02284|039|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02284|040|R|  February, 2014.|1
02284|041|R|4.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
02284|042|R|  Pharmaceuticals Corporation August, 2017.|1
02284|043|R|5.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
02284|044|R|  Squibb Company May, 2022.|1
02284|045|R|6.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
02284|046|R|  America, Inc. November, 2022.|1
02284|047|R|7.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02284|048|R|  Pharmaceuticals LP July, 2024.|1
02285|001|T|MONOGRAPH TITLE:  Buprenorphine/Benzodiazepines|
02285|002|B||
02285|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02285|004|L|take action as needed.|
02285|005|B||
02285|006|A|MECHANISM OF ACTION:  Buprenorphine is a partial agonist at mu-opioid|
02285|007|A|receptors leading to ceiling effects which limit agonist activity, including|
02285|008|A|respiratory depression, at high doses.  However, concomitant benzodiazepine|
02285|009|A|use (e.g. taken shortly after buprenorphine dose) or high doses of|
02285|010|A|benzodiazepines may lead to potentiation of respiratory depression,|
02285|011|A|counteracting the ceiling effect.(1,2)|
02285|012|A|   Concurrent use of buprenorphine and benzodiazepines may result in|
02285|013|A|additive CNS depression.(3)|
02285|014|B||
02285|015|E|CLINICAL EFFECTS:  Concurrent use may result in profound sedation,|
02285|016|E|respiratory depression, coma, and/or death.  Fatal respiratory depression|
02285|017|E|has occurred with the combination of buprenorphine and a|
02285|018|E|benzodiazepine.(1-2,4-7)  High benzodiazepine levels have been identified in|
02285|019|E|80% or more of buprenorphine fatalities.(6)|
02285|020|B||
02285|021|P|PREDISPOSING FACTORS:  Patients with a history of alcohol or benzodiazepine|
02285|022|P|abuse may be at risk for relapse and overuse or abuse of prescribed|
02285|023|P|benzodiazepines.(1,2,4,6)|
02285|024|P|   Individuals with significant obstructive pulmonary disease (COPD), sleep|
02285|025|P|apnea, the elderly, and debilitated patients are at greater risk for|
02285|026|P|respiratory depression from either agent.(1,2,8)|
02285|027|B||
02285|028|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
02285|029|M|depressants such as benzodiazepines to patients for whom alternatives are|
02285|030|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
02285|031|M|sufficient management.(3)|
02285|032|M|   Medication assisted therapy (MAT) with buprenorphine is not|
02285|033|M|contraindicated in patients taking CNS depressants; however discontinuation|
02285|034|M|of CNS depressants is preferred in most cases. In some cases, monitoring at|
02285|035|M|a higher level of care for tapering may be appropriate. In others gradual|
02285|036|M|tapering or decreasing to the lowest effective dose of the CNS depressant is|
02285|037|M|appropriate.|
02285|038|M|   For buprenorphine patients newly starting a benzodiazepine, consider|
02285|039|M|beginning the benzodiazepine at a lower than usual dose, especially if|
02285|040|M|predisposing factors (e.g. COPD, sleep apnea, debilitation, elderly) are|
02285|041|M|present.  High doses of benzodiazepines are associated with a greater risk|
02285|042|M|for respiratory depression.  Use the lowest effective dose and monitor for|
02285|043|M|excessive sedation or respiratory depression, particularly in patients with|
02285|044|M|predisposing risk factors for respiratory compromise.(1,2)|
02285|045|M|   Buprenorphine-naloxone combination products are used for maintenance|
02285|046|M|treatment of opioid dependence.  Patients with comorbid benzodiazepine|
02285|047|M|dependence, on high doses of benzodiazepines, or a history of benzodiazepine|
02285|048|M|abuse may require benzodiazepine detoxification prior to initiation of|
02285|049|M|office-based buprenorphine treatment.(3)  For patients receiving opioid|
02285|050|M|maintenance treatment, it would be prudent to assure all controlled|
02285|051|M|substance prescriptions are approved or written by the|
02285|052|M|buprenorphine-naloxone provider.(5)|
02285|053|M|   Respiratory depression can occur at any time during opioid therapy,|
02285|054|M|especially during therapy initiation and following dosage increases.  The|
02285|055|M|risk of opioid-related overdose or overdose-related death is increased with|
02285|056|M|higher opioid doses, and this risk persists over the course of therapy.|
02285|057|M|Consider these risks when using concurrently with other agents that may|
02285|058|M|cause CNS depression.(9)|
02285|059|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02285|060|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02285|061|M|unresponsiveness.(3)|
02285|062|M|   Discuss opioid reversal agents (e.g., naloxone or nalmefene) with all|
02285|063|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02285|064|M|treat opioid use disorder (OUD).  Consider prescribing opioid reversal|
02285|065|M|agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02285|066|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02285|067|M|as those taking CNS depressants) and when a patient has household|
02285|068|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02285|069|M|for obtaining an opioid reversal agent (e.g., prescription,|
02285|070|M|over-the-counter, or as part of a community-based program).(10)|
02285|071|B||
02285|072|D|DISCUSSION:  Buprenorphine is a partial agonist at mu-opioid receptors|
02285|073|D|leading to ceiling effects which limits agonist activity, including|
02285|074|D|respiratory depression, at high doses. However, concomitant benzodiazepine|
02285|075|D|use (e.g. taking shortly after buprenorphine dose) or high doses of|
02285|076|D|benzodiazepines may counteract the ceiling effect leading to potentiation of|
02285|077|D|respiratory depression or sedative effects. High benzodiazepine levels have|
02285|078|D|identified in 80% or more of buprenorphine fatalities.(6)|
02285|079|D|   Between 2002 and 2014, the number of patients receiving an opioid|
02285|080|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
02285|081|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
02285|082|D|to 30 million patients.  During this time, the proportion of patients|
02285|083|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
02285|084|D|patients.(11)|
02285|085|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02285|086|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02285|087|D|per 100,000 and drug overdose deaths involving both opioids and|
02285|088|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02285|089|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02285|090|D|increased from 18% to 31% during this time.(12)|
02285|091|D|   A prospective observational cohort study in North Carolina found that the|
02285|092|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02285|093|D|benzodiazepines were 10 times higher than patients receiving opioid|
02285|094|D|analgesics alone.(13)|
02285|095|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02285|096|D|death from overdose increased with concomitant opioid analgesics and|
02285|097|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02285|098|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02285|099|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02285|100|D|increased risk of fatal overdose.(14)|
02285|101|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02285|102|D|which benzodiazepines were determined to be a cause of death and that|
02285|103|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02285|104|D|determined to be a cause of death.  This study also found that other CNS|
02285|105|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02285|106|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02285|107|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02285|108|D|where opioid analgesics were also implicated.(15)|
02285|109|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02285|110|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02285|111|D|deaths.(16)|
02285|112|D|   A study of 315,428 privately insured patients who filled at least one|
02285|113|D|prescription for an opioid from 2001 to 2013 were enrolled in a|
02285|114|D|retrospective study.  Concurrent use of a benzodiazepine was recorded as|
02285|115|D|having at least one day of overlap in a given calendar year.  Baseline|
02285|116|D|characteristics among opioid users with concurrent use of a benzodiazepine|
02285|117|D|were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%,|
02285|118|D|p<0.001), and had a higher prevalence rate of every comorbidity examined|
02285|119|D|(p<0.001).  The proportion of opioid users with concurrent benzodiazepine|
02285|120|D|use nearly doubled from 9% in 2001 to 17% in 2013.  The primary outcome was|
02285|121|D|an emergency room visit or inpatient admission for opioid overdose within a|
02285|122|D|calendar year.  Among all opioid users, the annual adjusted incidence for|
02285|123|D|the primary outcome was 1.16% without concurrent benzodiazepine use compared|
02285|124|D|to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24;|
02285|125|D|p<0.001).  Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI|
02285|126|D|1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95%|
02285|127|D|CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the|
02285|128|D|primary outcome with concurrent benzodiazepine use compared to without|
02285|129|D|concurrent benzodiazepine use, respectively.(17)|
02285|130|B||
02285|131|R|REFERENCES:|
02285|132|B||
02285|133|R|1.Suboxone sublingual tablet (buprenorphine and naloxone) prescribing|1
02285|134|R|  information. Reckitt Benckiser Pharmaceuticals Inc. October, 2019.|1
02285|135|R|2.Butrans (buprenorphine) US prescribing information. Purdue Pharm L.P.|1
02285|136|R|  September, 2018.|1
02285|137|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02285|138|R|  warns about serious risks and death when combining opioid pain or cough|1
02285|139|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02285|140|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02285|141|R|4.Center for Substance Abuse Treatment. Clinical Guidelines for the Use of|6
02285|142|R|  Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement|6
02285|143|R|  Protocol (TIP) Series 40. Substance Abuse and Mental Health Services|6
02285|144|R|  Administration (US) 2004.|6
02285|145|R|5.Center for Substance Abuse Treatment. Medication-Assisted Treatment for|6
02285|146|R|  Opioid Addiction in Opioid Treatment Programs (TIP 43). Substance Abuse|6
02285|147|R|  and Mental Health Services Administration (US) 2012.|6
02285|148|R|6.Lintzeris N, Nielsen S. Benzodiazepines, methadone and buprenorphine:|6
02285|149|R|  interactions and clinical management. Am J Addict 2010 Jan-Feb;|6
02285|150|R|  19(1):59-72.|6
02285|151|R|7.McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical|6
02285|152|R|  importance among the opioids, methadone and buprenorphine, and other|6
02285|153|R|  frequently prescribed medications: a review. Am J Addict 2010 Jan-Feb;|6
02285|154|R|  19(1):4-16.|6
02285|155|R|8.Valium (diazepam) US prescribing information. Roche Products Inc December,|1
02285|156|R|  2016.|1
02285|157|R|9.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02285|158|R|  prescribing information for all opioid pain medicines to provide|1
02285|159|R|  additional guidance for safe use. Available at:|1
02285|160|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02285|161|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02285|162|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02285|163|R|10.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02285|164|R|   recommends health care professionals discuss naloxone with all patients|1
02285|165|R|   when prescribing opioid pain relievers or medicines to treat opioid use|1
02285|166|R|   disorder. Available at:|1
02285|167|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-hea|1
02285|168|R|   lth-care-professionals-discuss-naloxone-all-patients-when-prescribing-opi|1
02285|169|R|   oid-pain July 23, 2020.|1
02285|170|R|11.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02285|171|R|   in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02285|172|R|   Am J Prev Med 2016 Aug;51(2):151-60.|2
02285|173|R|12.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02285|174|R|   From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015|2
02285|175|R|   Oct;49(4):493-501.|2
02285|176|R|13.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02285|177|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02285|178|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02285|179|R|14.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02285|180|R|   prescribing patterns and deaths from drug overdose among US veterans|2
02285|181|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
02285|182|R|   350:h2698.|2
02285|183|R|15.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02285|184|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02285|185|R|16.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02285|186|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02285|187|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02285|188|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02285|189|R|17.Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association|2
02285|190|R|   between concurrent use of prescription opioids and benzodiazepines and|2
02285|191|R|   overdose: retrospective analysis. BMJ 2017 Mar 14;356:j760.|2
02286|001|T|MONOGRAPH TITLE:  Adenosine/Carbamazepine|
02286|002|B||
02286|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02286|004|L|of severe adverse interaction.|
02286|005|B||
02286|006|A|MECHANISM OF ACTION:  Both drugs may slow conduction through the AV|
02286|007|A|node.(1-3)|
02286|008|B||
02286|009|E|CLINICAL EFFECTS:  When adenosine is used to slow conduction in the AV node|
02286|010|E|or accessory pathways, the presence of carbamazepine may lead to prolonged|
02286|011|E|or higher degrees of heart block.(1)|
02286|012|E|   When adenosine is used during diagnostic imaging studies, carbamazepine|
02286|013|E|may increase the risk for symptomatic AV block.(3)|
02286|014|B||
02286|015|P|PREDISPOSING FACTORS:  History of an underlying cardiac conduction disorder|
02286|016|P|is a risk factor for carbamazepine-induced AV block.(2)|
02286|017|B||
02286|018|M|PATIENT MANAGEMENT:  When used for supraventricular tachycardias, Advanced|
02286|019|M|Cardiac Life Support (ACLS) Guidelines recommend lowering initial adenosine|
02286|020|M|dose to 3 mg.(4)|
02286|021|M|   Unless a functioning pacemaker is in place, when adenosine is used for|
02286|022|M|myocardial imaging studies, the provider should weigh the risks versus|
02286|023|M|benefits of adenosine administration in patients receiving chronic|
02286|024|M|carbamazepine therapy.(3)|
02286|025|B||
02286|026|D|DISCUSSION:  Carbamazepine has a tricyclic structure which may be partly|
02286|027|D|responsible for its effects on neuronal and cardiac conduction.  Numerous|
02286|028|D|case reports have documented the potential AV node blocking capabilities of|
02286|029|D|carbamazepine.  In most cases patients had underlying heart disease; however|
02286|030|D|cases without known risk factors have been reported.(5,6)|
02286|031|D|   Although this specific interaction has not been documented, the|
02286|032|D|interaction is plausible based upon the pharmacology of both agents.|
02286|033|B||
02286|034|R|REFERENCES:|
02286|035|B||
02286|036|R|1.Adenocard IV (adenosine inj.) prescribing information. Astellas Pharma US,|1
02286|037|R|  Inc. February 23, 2011.|1
02286|038|R|2.Tegretol (carbamazepine) US prescribing information. Novartis|1
02286|039|R|  Pharmaceuticals Corporation September, 2023.|1
02286|040|R|3.Adenoscan (adenosine) US prescribing information. Astellas Pharma US, Inc.|1
02286|041|R|  August, 2014.|1
02286|042|R|4.Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, Kudenchuk|6
02286|043|R|  PJ, Ornato JP, McNally B, Silvers SM, Passman RS, White RD, Hess EP, Tang|6
02286|044|R|  W, Davis D, Sinz E, Morrison LJ. Part 8: adult advanced cardiovascular|6
02286|045|R|  life support: 2010 American Heart Association Guidelines for|6
02286|046|R|  Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.|6
02286|047|R|  Circulation 2010 Nov 2;122(18 Suppl 3):S729-67.|6
02286|048|R|5.Ide A, Kamijo Y. Intermittent complete atrioventricular block after long|3
02286|049|R|  term low-dose carbamazepine therapy with a serum concentration less than|3
02286|050|R|  the therapeutic level. Intern Med 2007;46(9):627-9.|3
02286|051|R|6.Labrecque J, Cote MA, Vincent P. Carbamazepine-induced atrioventricular|3
02286|052|R|  block. Am J Psychiatry 1992 Apr;149(4):572-3.|3
02287|001|T|MONOGRAPH TITLE:  Bortezomib/Selected Strong CYP3A4 Inducers|
02287|002|B||
02287|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02287|004|L|of severe adverse interaction.|
02287|005|B||
02287|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
02287|007|A|metabolism of antineoplastic systemic enzyme inhibitors, including|
02287|008|A|bortezomib(1).|
02287|009|B||
02287|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
02287|011|E|levels and effectiveness of bortezomib.|
02287|012|B||
02287|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02287|014|P|of the inducer for longer than 1-2 weeks.|
02287|015|B||
02287|016|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
02287|017|M|patients receiving bortezomib therapy.  Consider the use of alternative|
02287|018|M|agents with less enzyme induction potential.(1-2)|
02287|019|B||
02287|020|D|DISCUSSION:  Rifampin (600 mg daily), a CYP3A4 inducer, decreased bortezomib|
02287|021|D|area-under-curve (AUC) by 45%.(1,2)|
02287|022|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02287|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02287|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
02287|025|D|rifapentine.(1,3)|
02287|026|B||
02287|027|R|REFERENCES:|
02287|028|B||
02287|029|R|1.Velcade (bortezomib) US prescribing information. Mellennium|1
02287|030|R|  Pharmaceuticals, Inc. October, 2021.|1
02287|031|R|2.Hellmann A, Rule S, Walewski J, Shpilberg O, Feng H, van de Velde H, Patel|2
02287|032|R|  H, Skee DM, Girgis S, Louw VJ. Effect of cytochrome P450 3A4 inducers on|2
02287|033|R|  the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in|2
02287|034|R|  patients with multiple myeloma or non-Hodgkin's lymphoma. Clin|2
02287|035|R|  Pharmacokinet 2011 Dec 1;50(12):781-91.|2
02287|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02287|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02287|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02287|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02287|040|R|  11/14/2017.|1
02288|001|T|MONOGRAPH TITLE:  Alfuzosin/QT Prolonging Agents|
02288|002|B||
02288|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02288|004|L|take action as needed.|
02288|005|B||
02288|006|A|MECHANISM OF ACTION:  Concurrent use of alfuzosin with other agents that|
02288|007|A|prolong the QTc interval may result in additive effects on the QTc|
02288|008|A|interval.(1)|
02288|009|B||
02288|010|E|CLINICAL EFFECTS:  The use of alfuzosin in patients maintained on agents|
02288|011|E|that prolong the QTc interval may result in potentially life-threatening|
02288|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02288|013|B||
02288|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02288|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02288|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02288|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02288|018|P|gender, or advanced age.(3)|
02288|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02288|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02288|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02288|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02288|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02288|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02288|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02288|026|B||
02288|027|M|PATIENT MANAGEMENT:  Approach the concurrent use of alfuzosin and other|
02288|028|M|agents that are known to prolong the QTc interval with caution.(1)|
02288|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02288|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02288|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02288|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02288|033|B||
02288|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02288|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02288|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02288|037|D|monograph have been shown to prolong the QTc interval either through their|
02288|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02288|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02288|040|D|clinical trials and/or post-marketing reports.(2)|
02288|041|B||
02288|042|R|REFERENCES:|
02288|043|B||
02288|044|R|1.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
02288|045|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
02288|046|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02288|047|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02288|048|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02288|049|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02288|050|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02288|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02288|052|R|  settings: a scientific statement from the American Heart Association and|6
02288|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02288|054|R|  2;55(9):934-47.|6
02289|001|T|MONOGRAPH TITLE:  Selected CYP2D6 Substrates/Mirabegron|
02289|002|B||
02289|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02289|004|L|of severe adverse interaction.|
02289|005|B||
02289|006|A|MECHANISM OF ACTION:  Mirabegron is considered a moderate inhibitor of|
02289|007|A|CYP2D6. FDA defines a moderate inhibitor as a drug which increases the|
02289|008|A|area-under-curve (AUC) of a sensitive substrate 2 to 5 fold.(1,2)|
02289|009|B||
02289|010|E|CLINICAL EFFECTS:  Drugs linked to this monograph are primarily metabolized|
02289|011|E|by CYP2D6, have a narrow therapeutic window, and are antiarrhythmic or QT|
02289|012|E|prolonging agents: flecainide, propafenone and thioridazine.  The use of|
02289|013|E|mirabegron in patients maintained on agents that prolong the QTc interval|
02289|014|E|may result in potentially life-threatening cardiac arrhythmias, including|
02289|015|E|torsades de pointes.|
02289|016|B||
02289|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02289|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
02289|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02289|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02289|021|P|female gender, or advanced age.(3)|
02289|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02289|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02289|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02289|025|P|drug concentrations include rapid infusion of an intravenous dose or|
02289|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02289|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02289|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02289|029|B||
02289|030|M|PATIENT MANAGEMENT:  Carefully weigh the risks versus benefit of mirabegron|
02289|031|M|treatment for overactive bladder symptoms in patients receiving flecainide,|
02289|032|M|propafenone and thioridazine.  The manufacturer of mirabegron recommends|
02289|033|M|appropriate monitoring and dose adjustment if necessary for drugs with a|
02289|034|M|narrow therapeutic index.(1)  Mirabegron has a long half-life of|
02289|035|M|approximately 50 hours so extended monitoring over 10 to 13 days may be|
02289|036|M|required to evaluate the full effect of this interaction.|
02289|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02289|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02289|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02289|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02289|041|B||
02289|042|D|DISCUSSION:  The manufacturer of mirabegron conducted interaction studies|
02289|043|D|with two sensitive substrates of CYP2D6: desipramine and metoprolol.(1)|
02289|044|D|   Mirabegron 160 mg daily for 5 days increased the AUC of a single dose of|
02289|045|D|metoprolol 100mg by 229%.|
02289|046|D|   Mirabegron 100 mg daily for 18 days increased the AUC of a single dose of|
02289|047|D|desipramine by 241%.|
02289|048|B||
02289|049|R|REFERENCES:|
02289|050|B||
02289|051|R|1.Myrbetriq (mirabegron) US prescribing information. Astellas Pharma|1
02289|052|R|  Technologies, Inc. March 25, 2021.|1
02289|053|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02289|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02289|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02289|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02289|057|R|  11/14/2017.|1
02289|058|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02289|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02289|060|R|  settings: a scientific statement from the American Heart Association and|6
02289|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02289|062|R|  2;55(9):934-47.|6
02290|001|T|MONOGRAPH TITLE:  Cobicistat-Elvitegravir/NNRTIs|
02290|002|B||
02290|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02290|004|L|is contraindicated and generally should not be dispensed or administered to|
02290|005|L|the same patient.|
02290|006|B||
02290|007|A|MECHANISM OF ACTION:  Cobicistat inhibits CYP2D6, CYP3A4, BCRP, OATP1B1 and|
02290|008|A|OATP1B3.  Elvitegravir induces CYP2C9.|
02290|009|A|   Efavirenz may induce the metabolism of cobicistat via CYP3A4.(1)|
02290|010|B||
02290|011|E|CLINICAL EFFECTS:  Concurrent use of cobicistat-elvitegravir with|
02290|012|E|non-nucleoside reverse transcriptase inhibitors (NNRTIs) may result in|
02290|013|E|altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir,|
02290|014|E|and/or the NNRTI.(1)|
02290|015|B||
02290|016|P|PREDISPOSING FACTORS:  None determined.|
02290|017|B||
02290|018|M|PATIENT MANAGEMENT:  The combination product containing|
02290|019|M|cobicistat-elvitegravir-emtricitabine-tenofovir should not be used with|
02290|020|M|non-nucleoside reverse transcriptase inhibitors.(1)|
02290|021|B||
02290|022|D|DISCUSSION:  Concurrent use of cobicistat-elvitegravir with non-nucleoside|
02290|023|D|reverse transcriptase inhibitors may result in altered and/or suboptimal|
02290|024|D|pharmacokinetics of cobicistat, elvitegravir, and/or the NNRTI.(1)|
02290|025|B||
02290|026|R|REFERENCE:|
02290|027|B||
02290|028|R|1.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02290|029|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02291|001|T|MONOGRAPH TITLE:  Elvitegravir/Selected Oral Cations|
02291|002|B||
02291|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02291|004|L|take action as needed.|
02291|005|B||
02291|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but aluminum, calcium,|
02291|007|A|iron, magnesium, sucralfate, and zinc may bind to elvitegravir in GI tract.|
02291|008|B||
02291|009|E|CLINICAL EFFECTS:  Simultaneous administration or administration of products|
02291|010|E|containing aluminum, calcium, iron, magnesium, and/or sucralfate may result|
02291|011|E|in decreased levels and effectiveness of elvitegravir, as well as the|
02291|012|E|development of resistance.(1)|
02291|013|B||
02291|014|P|PREDISPOSING FACTORS:  None determined.|
02291|015|B||
02291|016|M|PATIENT MANAGEMENT:  Separate the administration of elvitegravir and|
02291|017|M|products containing aluminum, calcium, iron, magnesium, and/or sucralfate by|
02291|018|M|at least 2 hours.(1)|
02291|019|M|   Some vitamin preparations may contain sufficient quantities of calcium|
02291|020|M|and/or magnesium salts with antacid properties to interact as well.|
02291|021|B||
02291|022|D|DISCUSSION:  Administration of an antacid (exact formulation not stated) 2|
02291|023|D|hours before elvitegravir (50 mg) decreased the maximum concentration|
02291|024|D|(Cmax), area-under-curve (AUC), or minimum concentration (Cmin) of|
02291|025|D|elvitegravir by 18%, 15%, and 10%, respectively.(1)|
02291|026|D|   Administration of an antacid 2 hours after elvitegravir (50 mg) decreased|
02291|027|D|the Cmax, AUC, or Cmin of elvitegravir by 21%, 20%, and 20%,|
02291|028|D|respectively.(1)|
02291|029|D|   Administration of an antacid 4 hours before elvitegravir (50 mg)|
02291|030|D|decreased the Cmax and AUC of elvitegravir by 5%, and 4%, respectively.(1)|
02291|031|D|   Administration of an antacid 4 hours before elvitegravir (50 mg)|
02291|032|D|decreased both the Cmax and AUC of elvitegravir by 2%.(1)|
02291|033|B||
02291|034|R|REFERENCE:|
02291|035|B||
02291|036|R|1.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02291|037|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02292|001|T|MONOGRAPH TITLE:  Clarithromycin/Cobicistat (mono deleted 12/26/2013)|
02292|002|B||
02292|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02292|004|L|take action as needed.|
02292|005|B||
02292|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02292|007|B||
02292|008|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
02292|009|E|of clarithromycin and cobicistat(1) and reduced levels of|
02292|010|E|14-OH-clarithromycin.|
02292|011|B||
02292|012|P|PREDISPOSING FACTORS:  Patients with decreased renal function (as shown by a|
02292|013|P|creatinine clearance (CrCL) of 60 ml/min or less are more susceptible to|
02292|014|P|effects of the interaction.|
02292|015|B||
02292|016|M|PATIENT MANAGEMENT:  No adjustment is necessary in patients with a CrCl|
02292|017|M|greater than or equal to 60 ml/min.  In patients with a CrCl of 50 ml/min to|
02292|018|M|60 ml/min, the dose of clarithromycin should be reduced by 50%.(1)|
02292|019|B||
02292|020|D|DISCUSSION:  Concentrations of clarithromycin and/or cobicistat are expected|
02292|021|D|to be altered during concurrent administration.(1)|
02292|022|B||
02292|023|R|REFERENCE:|
02292|024|B||
02292|025|R|1.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) prescribing|1
02292|026|R|  information. Gilead Sciences, Inc. December, 2014.|1
02293|001|T|MONOGRAPH TITLE:  Bosentan/Cobicistat|
02293|002|B||
02293|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02293|004|L|of severe adverse interaction.|
02293|005|B||
02293|006|A|MECHANISM OF ACTION:  Cobicistat may inhibit the metabolism of bosentan by|
02293|007|A|CYP3A4 and by inhibiting its uptake into hepatocytes by OATP.(1)|
02293|008|B||
02293|009|E|CLINICAL EFFECTS:  Concurrent use of cobicistat without adjusting the dose|
02293|010|E|of bosentan may result in elevated levels of and toxicity from bosentan.(1)|
02293|011|B||
02293|012|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, a CYP3A4 inhibitor and a|
02293|013|P|CYP2C9 inhibitor (e.g. amiodarone, fluconazole, oxandrolone, or|
02293|014|P|sulfinpyrazone)(3) could lead to blockade of both major metabolic pathways|
02293|015|P|for bosentan, resulting in large increases in bosentan plasma|
02293|016|P|concentrations.(3)|
02293|017|B||
02293|018|M|PATIENT MANAGEMENT:  Review medication list to see if patient is also|
02293|019|M|receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole,|
02293|020|M|oxandrolone, sulfinpyrazone, or phenylbutazone).|
02293|021|M|   Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended|
02293|022|M|by the manufacturer as the combination may lead to large increases in|
02293|023|M|bosentan plasma concentrations.(1)|
02293|024|M|   For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated,|
02293|025|M|monitor tolerance to concomitant therapy and adjust bosentan dose if needed.|
02293|026|M|   In patients who have been receiving a strong CYP3A4 inhibitor for at|
02293|027|M|least 10 days, start bosentan at 62.5 mg once daily or every other day based|
02293|028|M|upon individual tolerability.|
02293|029|M|   Discontinue use of bosentan at least 36 hours prior to initiation of a|
02293|030|M|strong CYP3A4 inhibitor.|
02293|031|M|   After at least 10 days following the initiation of a strong CYP3A4|
02293|032|M|inhibitor, resume bosentan at 62.5 mg once daily or every other day based|
02293|033|M|upon individual tolerability.)|
02293|034|B||
02293|035|D|DISCUSSION:  In a study in healthy subjects, concurrent lopinavir/ritonavir|
02293|036|D|increased the initial and steady-state minimum concentrations (Cmin) of|
02293|037|D|bosentan by 48-fold and 5-fold, respectively.  There were no significant|
02293|038|D|effects on lopinavir/ritonavir pharmacokinetics.(2)  Cobicistat inhibits|
02293|039|D|CYP3A4 to a similar extent that ritonavir does.(1)|
02293|040|B||
02293|041|R|REFERENCES:|
02293|042|B||
02293|043|R|1.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02293|044|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02293|045|R|2.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
02293|046|R|  US, Inc. September 5, 2017.|1
02293|047|R|3.This information is based on an extract from the Certara Drug Interaction|6
02293|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02294|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Elvitegravir-Cobicistat|
02294|002|B||
02294|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02294|004|L|of severe adverse interaction.|
02294|005|B||
02294|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02294|007|B||
02294|008|E|CLINICAL EFFECTS:  Concurrent administration may result in increased effects|
02294|009|E|from the progestin (insulin resistance, dyslipidemia, acne, and venous|
02294|010|E|thrombosis) and decreased effects of the estrogen component.(1,2)|
02294|011|E|   Concurrent use of cobicistat-containing products may result in elevated|
02294|012|E|levels of and adverse effects from drospirenone, including hyperkalemia.|
02294|013|B||
02294|014|P|PREDISPOSING FACTORS:  None determined.|
02294|015|B||
02294|016|M|PATIENT MANAGEMENT:  The manufacturer of|
02294|017|M|cobicistat-elvitegravir-emtricitabine-tenofovir recommends the use of|
02294|018|M|non-hormonal methods of contraception.(1)|
02294|019|M|   The manufacturer of cobicistat-elvitegravir-emtricitabine-tenofovir|
02294|020|M|alafenamide recommends clinical monitoring due to the potential for|
02294|021|M|hyperkalemia when administered concurrently with drospirenone-ethinyl|
02294|022|M|estradiol.(2)|
02294|023|B||
02294|024|D|DISCUSSION:  Concurrent administration of|
02294|025|D|cobicistat-elvitegravir-emtricitabine-tenofovir increased Cmax, AUC, and|
02294|026|D|minimum concentration (Cmin) of norgestimate by 2.08-fold, 2.26-fold, and|
02294|027|D|2.67-fold, respectively.  The Cmax, AUC, and Cmin of ethinyl estradiol|
02294|028|D|decreased by 6%, 25%, and 44%, respectively.(1)|
02294|029|D|   Drospirenone has anti-mineralocorticoid activity comparable to a 25mg|
02294|030|D|dose of spironolactone.|
02294|031|B||
02294|032|R|REFERENCES:|
02294|033|B||
02294|034|R|1.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02294|035|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02294|036|R|2.Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02294|037|R|  prescribing information. Gilead Sciences, Inc September, 2021.|1
02295|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP2D6 Substrates/Mirabegron|
02295|002|B||
02295|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02295|004|L|take action as needed.|
02295|005|B||
02295|006|A|MECHANISM OF ACTION:  Mirabegron is considered a moderate inhibitor of|
02295|007|A|CYP2D6.  FDA defines a moderate inhibitor as a drug which increases the|
02295|008|A|area-under-curve (AUC) of a sensitive substrate 2 to 5 fold.(1,2)|
02295|009|B||
02295|010|E|CLINICAL EFFECTS:  Concurrent use of mirabegron may lead to increased serum|
02295|011|E|levels and adverse effects of drugs sensitive to inhibition of the CYP2D6|
02295|012|E|pathway.(1)  Agents linked to this monograph are: atomoxetine, clomipramine,|
02295|013|E|desipramine, duloxetine, imipramine, metoprolol, nebivolol, nortriptyline|
02295|014|E|and yohimbine.|
02295|015|B||
02295|016|P|PREDISPOSING FACTORS:  With desipramine, clomipramine, imipramine and|
02295|017|P|nortriptyline, the risk of seizures may be increased in patients with a|
02295|018|P|history of head trauma or prior seizure; CNS tumor; severe hepatic|
02295|019|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
02295|020|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
02295|021|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
02295|022|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
02295|023|P|systemic steroids).|
02295|024|P|   The risk of anticholinergic toxicities including cognitive decline,|
02295|025|P|delirium, falls and fractures is increased in geriatric patients using more|
02295|026|P|than one medicine with anticholinergic properties.(3)|
02295|027|B||
02295|028|M|PATIENT MANAGEMENT:  Mirabegron has a long half-life of approximately 50|
02295|029|M|hours so extended monitoring over 10 to 13 days may be required to evaluate|
02295|030|M|the full effect of this interaction.  The manufacturer of mirabegron|
02295|031|M|recommends appropriate monitoring and dose adjustment if necessary for drugs|
02295|032|M|with a narrow therapeutic index.(1)  Weigh the risks versus benefits of|
02295|033|M|mirabegron treatment for overactive bladder symptoms based upon the|
02295|034|M|interacting medication and patient specific characteristics.|
02295|035|B||
02295|036|D|DISCUSSION:  The manufacturer of mirabegron conducted interaction studies|
02295|037|D|with two sensitive substrates of CYP2D6: desipramine and metoprolol.(1)|
02295|038|D|   Mirabegron 160 mg daily for 5 days increased the AUC of a single dose of|
02295|039|D|metoprolol 100mg by 229%.|
02295|040|D|   Mirabegron 100 mg daily for 18 days increased the AUC of a single dose of|
02295|041|D|desipramine by 241%.|
02295|042|B||
02295|043|R|REFERENCES:|
02295|044|B||
02295|045|R|1.Myrbetriq (mirabegron) US prescribing information. Astellas Pharma|1
02295|046|R|  Technologies, Inc. March 25, 2021.|1
02295|047|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02295|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02295|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02295|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02295|051|R|  11/14/2017.|1
02295|052|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02295|053|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02295|054|R|  Soc 2023 Jul;71(7):2052-2081.|6
02296|001|T|MONOGRAPH TITLE:  Cobicistat-Elvitegravir/Selected CYP3A4 Inducers|
02296|002|B||
02296|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02296|004|L|of severe adverse interaction.|
02296|005|B||
02296|006|A|MECHANISM OF ACTION:  Cobicistat may inhibit rifabutin and rifapentine|
02296|007|A|metabolism by CYP3A4.  Apalutamide, encorafenib, enzalutamide, lumacaftor,|
02296|008|A|mitotane, oxcarbazepine, rifabutin, and rifapentine may induce the|
02296|009|A|metabolism of cobicistat and elvitegravir.(1)|
02296|010|B||
02296|011|E|CLINICAL EFFECTS:  Concurrent use of cobicistat-elvitegravir with|
02296|012|E|apalutamide, encorafenib, enzalutamide, lumacaftor, mitotane, oxcarbazepine,|
02296|013|E|rifabutin, or rifapentine may result decreased levels of elvitegravir and|
02296|014|E|development of resistance.(1)|
02296|015|E|   Concurrent use of cobicistat-elvitegravir may result in elevated levels|
02296|016|E|of apalutamide, oxcarbazepine, rifabutin, or rifapentine, as well as|
02296|017|E|ivacaftor (which is coformulated with lumacaftor).(1)|
02296|018|B||
02296|019|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02296|020|P|of the inducer for longer than 1-2 weeks.|
02296|021|B||
02296|022|M|PATIENT MANAGEMENT:  Concurrent use of combination product containing|
02296|023|M|cobicistat-elvitegravir-emtricitabine-tenofovir and rifabutin or rifapentine|
02296|024|M|is not recommended.(1)  Consider the use of alternative anticonvulsants to|
02296|025|M|oxcarbazepine.(1)  Concurrent use with carbamazepine, phenobarbital, or|
02296|026|M|phenytoin is contraindicated.(1)|
02296|027|B||
02296|028|D|DISCUSSION:  Concurrent cobicistat-elvitegravir (150 mg each daily)|
02296|029|D|increased the maximum concentration (Cmax) of rifabutin (150 mg every other|
02296|030|D|day) by 1.09-fold.  The area-under-curve (AUC) and minimum concentration|
02296|031|D|(Cmin) of rifabutin decreased by 8% and 6%, respectively, when compared to|
02296|032|D|the administration of 300 mg daily of rifabutin.  The Cmax, AUC, and Cmin of|
02296|033|D|25-O-desacetyl-rifabutin increased by 4.84-fold, 6.25-fold, and 4.94-fold,|
02296|034|D|respectively, when compared to the administration of 300 mg daily of|
02296|035|D|rifabutin.  The Cmax, AUC, and Cmin of elvitegravir decreased by 9%, 21%,|
02296|036|D|and 67%, respectively.(1)|
02296|037|D|   Concurrent cobicistat-elvitegravir (150 mg each daily) with carbamazepine|
02296|038|D|(200 mg twice daily) decreased the Cmax, AUC, and Cmin of elvitegravir by|
02296|039|D|45%, 69%, and 97%, respectively. Concurrent cobicistat-elvitegravir (150 mg|
02296|040|D|each daily) with carbamazepine (200 mg twice daily) increased the Cmax, AUC,|
02296|041|D|and Cmin of carbamazepine by 40%, 43%, and 51%, respectively. The Cmax, AUC,|
02296|042|D|and Cmin was decreased for carbamazepine-10,11-epoxide by 29%, 35%, and 41%,|
02296|043|D|respectively. (2)|
02296|044|B||
02296|045|R|REFERENCES:|
02296|046|B||
02296|047|R|1.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02296|048|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02296|049|R|2.Vitekta (elvitegravir) US prescribing information. Gilead Sciences Inc.|1
02296|050|R|  July, 2015.|1
02297|001|T|MONOGRAPH TITLE:  Atovaquone/Tetracycline|
02297|002|B||
02297|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02297|004|L|of severe adverse interaction.|
02297|005|B||
02297|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02297|007|B||
02297|008|E|CLINICAL EFFECTS:  The concurrent administration of tetracycline may result|
02297|009|E|in decreased levels and effectiveness of atovaquone.(1,2)|
02297|010|B||
02297|011|P|PREDISPOSING FACTORS:  None determined.|
02297|012|B||
02297|013|M|PATIENT MANAGEMENT:  The CDC states that tetracycline should not be|
02297|014|M|administered with atovaquone.(1)  If concurrent use of tetracycline and|
02297|015|M|atovaquone is warranted, parasitemia should be closely monitored.(2)|
02297|016|B||
02297|017|D|DISCUSSION:  Concurrent tetracycline has been associated with a 40% decrease|
02297|018|D|in atovaquone plasma concentrations.(1)|
02297|019|B||
02297|020|R|REFERENCES:|
02297|021|B||
02297|022|R|1.Malarone (atovaquone and proguanil hydrochloride) US prescribing|1
02297|023|R|  information. GlaxoSmithKline March, 2010.|1
02297|024|R|2.Youngster I, Barnett ED. Interactions among Travel Vaccines & Drugs. CDC|1
02297|025|R|  Health Information for International Travel 2018 (The Yellow Book)|1
02297|026|R|  available at:|1
02297|027|R|  https://wwwnc.cdc.gov/travel/yellowbook/2018/the-pre-travel-consultation/i|1
02297|028|R|  nteractions-among-travel-vaccines-and-drugs May 31, 2017.|1
02298|001|T|MONOGRAPH TITLE:  Enzalutamide/Strong CYP2C8 Inhibitors|
02298|002|B||
02298|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02298|004|L|of severe adverse interaction.|
02298|005|B||
02298|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2C8 may inhibit the metabolism|
02298|007|A|of enzalutamide.(1)|
02298|008|B||
02298|009|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP2C8 may result|
02298|010|E|in elevated levels of and toxicity from enzalutamide.(1)|
02298|011|B||
02298|012|P|PREDISPOSING FACTORS:  None determined.|
02298|013|B||
02298|014|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inhibitors of CYP2C8|
02298|015|M|with enzalutamide.  If concurrent use is required, reduce the dosage of|
02298|016|M|enzalutamide to 80 mg once daily.  If the strong CYP2C8 inhibitor is|
02298|017|M|discontinued, return the dosage of enzalutamide to the dosage used prior to|
02298|018|M|initiation of the strong CYP2C8 inhibitor.(1)|
02298|019|B||
02298|020|D|DISCUSSION:  In a clinical trial in healthy subjects, administration of|
02298|021|D|gemfibrozil (a strong inhibitor of CYP2C8, 600 mg BID) increased the|
02298|022|D|area-under-curve (AUC of enzalutamide by 2.2-fold.  There was no significant|
02298|023|D|effect on enzalutamide maximum concentration (Cmax).(1)|
02298|024|D|   Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)|
02298|025|B||
02298|026|R|REFERENCES:|
02298|027|B||
02298|028|R|1.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
02298|029|R|  September, 2022.|1
02298|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02298|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02298|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02298|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02298|034|R|  11/14/2017.|1
02298|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
02298|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02299|001|T|MONOGRAPH TITLE:  Enzalutamide/Strong CYP3A4 Inducers|
02299|002|B||
02299|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02299|004|L|of severe adverse interaction.|
02299|005|B||
02299|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may increase the metabolism|
02299|007|A|of enzalutamide.(1)|
02299|008|B||
02299|009|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 may result in|
02299|010|E|decreased levels and effectiveness of enzalutamide.(1)|
02299|011|B||
02299|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02299|013|P|of the inducer for longer than 1-2 weeks.|
02299|014|B||
02299|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
02299|016|M|enzalutamide.  Consider the use of agents with no or minimal induction|
02299|017|M|potential if possible.(1)|
02299|018|M|   If concurrent therapy with a strong CYP3A4 inducer is necessary, increase|
02299|019|M|the enzalutamide dose from 160 mg to 240 mg once daily.  If concurrent|
02299|020|M|therapy with a strong CYP3A4 inducer is discontinued, the enzalutamide dose|
02299|021|M|should be returned to the dose used prior to initiation of the strong CYP3A4|
02299|022|M|inducer.(1)|
02299|023|B||
02299|024|D|DISCUSSION:  Enzalutamide is primarily metabolized by CYP2C8 and CYP3A4.|
02299|025|D|CYP2C8 is responsible for metabolism of enzalutamide to the active|
02299|026|D|metabolite.(1)|
02299|027|D|   Coadministration of rifampin (strong CYP3A4 inducer and moderate CYP2C8|
02299|028|D|inducer) decreased the composite area-under-curve (AUC) of enzalutamide and|
02299|029|D|its active metabolite by 37% with no effect on concentration maximum|
02299|030|D|(Cmax).(1)|
02299|031|D|   Strong CYP3A4 inducers linked to this monograph include: barbiturates,|
02299|032|D|carbamazepine, lumacaftor, mitotane, phenobarbital, primidone, rifampin,|
02299|033|D|rifapentine, and St. John's wort.(2)|
02299|034|B||
02299|035|R|REFERENCES:|
02299|036|B||
02299|037|R|1.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
02299|038|R|  September, 2022.|1
02299|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
02299|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02300|001|T|MONOGRAPH TITLE:  Sensitive CYP3A4; CYP2C9; CYP2C19 Substrates/Enzalutamide|
02300|002|B||
02300|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02300|004|L|of severe adverse interaction.|
02300|005|B||
02300|006|A|MECHANISM OF ACTION:  Enzalutamide may induce the metabolism of agents|
02300|007|A|metabolized by CYP3A4, CYP2C9, and CYP2C19.(1)|
02300|008|B||
02300|009|E|CLINICAL EFFECTS:  Concurrent use of enzalutamide with agents metabolized by|
02300|010|E|CYP3A4, CYP2C9, and CYP2C19 may result in decreased levels and effectiveness|
02300|011|E|of these agents.(1)|
02300|012|B||
02300|013|P|PREDISPOSING FACTORS:  None determined.|
02300|014|B||
02300|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of agents metabolized by CYP3A4,|
02300|016|M|CYP2C9, or CYP2C19 that have a narrow therapeutic index with enzalutamide.|
02300|017|M|If concurrent use is required, consider increased monitoring of the affected|
02300|018|M|agent.(1)  Dosage adjustments may be required.|
02300|019|B||
02300|020|D|DISCUSSION:  In a clinical trial in healthy subjects, enzalutamide was shown|
02300|021|D|to reduce the area-under-curve (AUC) of midazolam (a sensitive CYP3A4|
02300|022|D|substrate), warfarin (a sensitive CYP2C9 substrate), and omeprazole (a|
02300|023|D|sensitive CYP2C19 substrate.(1)|
02300|024|D|   A case report in a 77-year-old Caucasian male was initiated on 160 mg of|
02300|025|D|enzalutamide after being stable on warfarin with an INR of 3.5.  The INR|
02300|026|D|dropped to 1.4 after approximately 20 days on enzalutamide therapy.  Due to|
02300|027|D|the drop in INR, the warfarin dose was increased by 50% which lead to a|
02300|028|D|therapeutic INR.  When enzalutamide was discontinued, the warfarin dose was|
02300|029|D|decreased by 33% to remain at a therapeutic level.  Upon reinitiation, the|
02300|030|D|warfarin dose was increased once by 50% to achieve a therapeutic INR.(2)|
02300|031|D|   Sensitive CYP3A4 substrates with narrow therapeutic indexes include:|
02300|032|D|abemaciclib, astemizole, cisapride, clarithromycin, cyclosporine,|
02300|033|D|dihydroergotamine, ergonovine, ergotamine, hydroquinidine, pimozide,|
02300|034|D|sirolimus, tacrolimus, temsirolimus, and terfenadine.(1,3,4)|
02300|035|D|   Sensitive CYP2C9 substrates with narrow therapeutic indexes include:|
02300|036|D|warfarin.(1,3)|
02300|037|D|   Sensitive CYP2C19 substrates with narrow therapeutic indexes include:|
02300|038|D|S-mephenytoin.(1,3)|
02300|039|B||
02300|040|R|REFERENCES:|
02300|041|B||
02300|042|R|1.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
02300|043|R|  September, 2022.|1
02300|044|R|2.Parrett JL, Reaves AB, Self TH, Owens RE. Enzalutamide-warfarin|3
02300|045|R|  interaction necessitating warfarin dosage adjustment: A case report of|3
02300|046|R|  successful clinical management. J Clin Pharm Ther 2018 Apr;43(2):276-279.|3
02300|047|R|3.This information is based on an extract from the Certara Drug Interaction|6
02300|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02300|049|R|4.Xtandi (enzalutamide) Canadian prescribing information. Astellas May 28,|1
02300|050|R|  2013.|1
02301|001|T|MONOGRAPH TITLE:  Bosutinib/Moderate CYP3A4 Inhibitors|
02301|002|B||
02301|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02301|004|L|of severe adverse interaction.|
02301|005|B||
02301|006|A|MECHANISM OF ACTION:  Agents that inhibit CYP3A4 may inhibit the metabolism|
02301|007|A|of bosutinib.(1)|
02301|008|B||
02301|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
02301|010|E|levels of and effects from bosutinib.(1)|
02301|011|E|    Elevated levels of bosutinib may result in QTc prolongation, which may|
02301|012|E|result in potentially life-threatening cardiac arrhythmias, including|
02301|013|E|torsades de pointes (TdP).  Other toxicities include nausea, vomiting,|
02301|014|E|diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity,|
02301|015|E|and cardiac failure.(1)|
02301|016|B||
02301|017|P|PREDISPOSING FACTORS:  None determined.|
02301|018|B||
02301|019|M|PATIENT MANAGEMENT:  Avoid the use of moderate CYP3A4 inhibitors in patients|
02301|020|M|undergoing therapy with bosutinib.(1)|
02301|021|B||
02301|022|D|DISCUSSION:  In a study in 24 healthy subjects, ketoconazole (400 mg daily|
02301|023|D|for 5 days) increased the maximum concentration (Cmax) and area-under-curve|
02301|024|D|(AUC) of bosutinib (100 mg) by 5.2-fold and 8.6-fold, respectively.(1)|
02301|025|D|   In a cross-over study in 18 healthy subjects, aprepitant (125 mg)|
02301|026|D|increased the Cmax and AUC of bosutinib (single dose 500 mg) by 1.5-fold and|
02301|027|D|2.0-fold, respectively.(1)|
02301|028|D|   A study using PKPB modeling found concurrent use of bosutinib and|
02301|029|D|schisandra would result in an increase in bosutinib exposure with an|
02301|030|D|increased AUC by 3.0-fold.(2)|
02301|031|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
02301|032|D|avacopan, berotralstat, boceprevir, clofazimine, conivaptan, crizotinib,|
02301|033|D|darunavir, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole,|
02301|034|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
02301|035|D|ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
02301|036|D|rilzabrutinib, schisandra, sevabertinib, stiripentol, treosulfan, and|
02301|037|D|verapamil.(3-4)|
02301|038|B||
02301|039|R|REFERENCES:|
02301|040|B||
02301|041|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
02301|042|R|  2023.|1
02301|043|R|2.Adiwidjaja J, Boddy AV, McLachlan AJ. Potential for pharmacokinetic|5
02301|044|R|  interactions between Schisandra sphenanthera and  bosutinib, but not|5
02301|045|R|  imatinib: in vitro metabolism study combined with a  physiologically-based|5
02301|046|R|  pharmacokinetic modelling approach. BJCP 6 April 2020.|5
02301|047|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02301|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02301|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02301|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02301|051|R|  11/14/2017.|1
02301|052|R|4.This information is based on an extract from the Certara Drug Interaction|6
02301|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02302|001|T|MONOGRAPH TITLE:  Warfarin/Teriflunomide|
02302|002|B||
02302|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02302|004|L|take action as needed.|
02302|005|B||
02302|006|A|MECHANISM OF ACTION:  Teriflunomide may induce the metabolism of R-warfarin|
02302|007|A|by CYP1A2.(1,2)|
02302|008|B||
02302|009|E|CLINICAL EFFECTS:  Concurrent use of teriflunomide may result in decreased|
02302|010|E|levels and effectiveness of warfarin, which may increase the risk of|
02302|011|E|clotting.(1)|
02302|012|B||
02302|013|P|PREDISPOSING FACTORS:  None determined.|
02302|014|B||
02302|015|M|PATIENT MANAGEMENT:  Monitor INR response closely in patients maintained on|
02302|016|M|warfarin when initiating, titrating, and discontinuing teriflunomide.|
02302|017|M|Patients maintained on teriflunomide may require higher dosages of warfarin.|
02302|018|B||
02302|019|D|DISCUSSION:  Concurrent teriflunomide and warfarin resulted in a 25%|
02302|020|D|decrease in peak INR values.  Teriflunomide was found to have no effect on|
02302|021|D|the pharmacokinetics of S-warfarin, a CYP2C9 substrates.  However, it is a|
02302|022|D|weak inducer of CYP1A2.(1)  R-warfarin is a substrate of CYP1A2.(2)|
02302|023|B||
02302|024|R|REFERENCES:|
02302|025|B||
02302|026|R|1.Aubagio (teriflunomide) US prescribing information. Genzyme Corporation|1
02302|027|R|  November, 2020.|1
02302|028|R|2.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
02302|029|R|  Indiana University School of Medicine.  Available at:|1
02302|030|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
02303|001|T|MONOGRAPH TITLE:  Selected CYP2C8 Substrates/Leflunomide; Teriflunomide|
02303|002|B||
02303|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02303|004|L|take action as needed.|
02303|005|B||
02303|006|A|MECHANISM OF ACTION:  Teriflunomide may inhibit the metabolism of agents|
02303|007|A|metabolized by CYP2C8.  Leflunomide is metabolized to teriflunomide and|
02303|008|A|recommended dosages of both products produce similar levels of|
02303|009|A|teriflunomide.(1)|
02303|010|B||
02303|011|E|CLINICAL EFFECTS:  Concurrent use of leflunomide or teriflunomide may result|
02303|012|E|in elevated levels of and toxicity from agents metabolized by CYP2C8, such|
02303|013|E|as pioglitazone, repaglinide, or rosiglitazone.(1)|
02303|014|B||
02303|015|P|PREDISPOSING FACTORS:  None determined.|
02303|016|B||
02303|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with leflunomide|
02303|018|M|or teriflunomide and an agent metabolized by CYP2C8 should be closely|
02303|019|M|monitored.  The dosage of the CYP2C8 substrate may need to be adjusted if|
02303|020|M|leflunomide or teriflunomide are initiated.(1)|
02303|021|M|   Because of teriflunomide's slow elimination, the effects of teriflunomide|
02303|022|M|on these CYP2C8 substrates may persist for some time without the use of|
02303|023|M|cholestyramine or activated charcoal to increase teriflunomide|
02303|024|M|elimination.(1)|
02303|025|B||
02303|026|D|DISCUSSION:  Concurrent teriflunomide increased the maximum concentration|
02303|027|D|(Cmax) and area-under-curve (AUC) of repaglinide (0.25 mg single dose) by|
02303|028|D|1.7-fold and 2.4-fold, respectively.(1)|
02303|029|D|   Leflunomide is metabolized to teriflunomide and recommended dosages of|
02303|030|D|both products produce similar levels of teriflunomide.(1)|
02303|031|D|   CYP2C8 substrates include pioglitazone, repaglinide, or|
02303|032|D|rosiglitazone.(1,2)|
02303|033|B||
02303|034|R|REFERENCES:|
02303|035|B||
02303|036|R|1.Aubagio (teriflunomide) US prescribing information. Genzyme Corporation|1
02303|037|R|  November, 2020.|1
02303|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02303|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02303|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02303|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02303|042|R|  11/14/2017.|1
02304|001|T|MONOGRAPH TITLE:  Anthracyclines/Trastuzumab|
02304|002|B||
02304|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02304|004|L|of severe adverse interaction.|
02304|005|B||
02304|006|A|MECHANISM OF ACTION:  Trastuzumab and anthracyclines are independently|
02304|007|A|associated with a risk for cardiotoxicities such as heart failure and|
02304|008|A|cardiomyopathy.  Prescribing information for each agent includes an FDA|
02304|009|A|Boxed Warning describing these risks.  Concurrent or sequential use of an|
02304|010|A|anthracycline and trastuzumab further increases the risk for|
02304|011|A|cardiotoxicity.(1-8)|
02304|012|B||
02304|013|E|CLINICAL EFFECTS:  Cardiotoxicity may manifest as asymptomatic or|
02304|014|E|symptomatic left ventricular dysfunction (LVD), arrhythmias, hypertension,|
02304|015|E|heart failure or cardiomyopathy.(1,2)  Early signs of LVD are often|
02304|016|E|asymptomatic; diagnosis may be delayed in the absence routine measurement of|
02304|017|E|left ventricular ejection fraction (LVEF).(3)  Cardiac dysfunction from this|
02304|018|E|combination may be irreversible.|
02304|019|B||
02304|020|P|PREDISPOSING FACTORS:  The elderly, patients with a history of prior|
02304|021|P|anthracycline or mediastinal radiation therapy, with underlying cardiac|
02304|022|P|disease, or with elevated cardiac biomarkers (e.g. troponin, BNP) during or|
02304|023|P|after therapy appear to be at higher risk for cardiotoxicity.(1,3,8)|
02304|024|B||
02304|025|M|PATIENT MANAGEMENT:  If possible, avoid anthracycline-based therapy for up|
02304|026|M|to 7 months after stopping trastuzumab. (1,9)|
02304|027|M|   When both trastuzumab and an anthracycline are included in a|
02304|028|M|chemotherapeutic regimen close monitoring is needed to minimize the risk for|
02304|029|M|permanent heart damage.|
02304|030|M|   Monitoring recommendations from the manufacturer of trastuzumab(1):|
02304|031|M|   - Prior to treatment conduct thorough cardiac assessment, including|
02304|032|M|history, physical examination, and determination of left ventricular|
02304|033|M|ejection fraction (LVEF).|
02304|034|M|   - Measure LVEF every 3 months during trastuzumab therapy.|
02304|035|M|   - Withhold trastuzumab dose at least 4 weeks for reduction of LVEF >= 16%|
02304|036|M|from pre-treatment values, or if LVEF is below institutional limits of|
02304|037|M|normal and LVEF is reduced >= 10% from pre-treatment baseline values.|
02304|038|M|Trastuzumab may be resumed if LVEF improves to above threshold hold|
02304|039|M|parameters within 4 to 8 weeks and the absolute decrease from baseline is <=|
02304|040|M|15%.  If a dose is held for left ventricular dysfunction repeat LVEF|
02304|041|M|measurements at 4 week intervals.|
02304|042|M|   - Discontinue trastuzumab for persistent LVEF decline for > 8 weeks, or|
02304|043|M|if dose has been held on more than 3 occasions for cardiomyopathy.|
02304|044|M|   - Repeat LVEF evaluation upon trastuzumab completion and then every 6|
02304|045|M|months for a minimum of 2 years after treatment.|
02304|046|M|   American Heart Association(AHA)/American College of Cardiology(ACC) and|
02304|047|M|European Society of Medical Oncology(ESMO) treatment guidelines recommend|
02304|048|M|use of ACE Inhibitors or ARBs and beta blockers in asymptomatic patients|
02304|049|M|with reduced LVEF.  Patients who develop overt heart failure should receive|
02304|050|M|standard heart failure therapies.(3,4)|
02304|051|B||
02304|052|D|DISCUSSION:  While treatment with both anthracyclines and trastuzumab may be|
02304|053|D|optimal cancer treatment, there is growing awareness of an increased risk|
02304|054|D|for heart failure or cardiomyopathy in this population.  To decrease risk|
02304|055|D|for symptomatic heart failure consider cardiology consultation, particularly|
02304|056|D|in patients with predisposing risk factors, to assure appropriate assessment|
02304|057|D|and preventative treatment.|
02304|058|D|   A retrospective study of oncology patients treated with an anthracycline|
02304|059|D|and/or trastuzumab examined treatments provided for symptomatic or|
02304|060|D|asymptomatic decreases in LVEF.  All 88 patients received at least one pre|
02304|061|D|and one post chemotherapy echocardiogram. Thirty-five patients (40%) had|
02304|062|D|decreased LVEF after receiving chemotherapy; 26 patients were asymptomatic|
02304|063|D|while 9 were symptomatic. All 9 symptomatic patients received recommended|
02304|064|D|beta blocker therapy and 6 also received an ACEI or ARB.  Only 9 of 26|
02304|065|D|asymptomatic patients received recommended beta blockers; 8 of 26 received|
02304|066|D|recommended ACEI/ARB therapy.  Based upon chart review, none of the|
02304|067|D|asymptomatic patients had contraindications to either therapy.  This|
02304|068|D|treatment rate for decreased LVEF is significantly lower than the 98%|
02304|069|D|background treatment compliance rate at this institution.(5)|
02304|070|D|    A large retrospective cohort study examined heart failure risk after|
02304|071|D|anthracycline and /or trastuzumab therapy. The cohort included 12,500 women|
02304|072|D|diagnosed with invasive breast cancer; 442 women received trastuzumab and an|
02304|073|D|anthracycline. The cumulative incidence of heart failure or cardiomyopathy|
02304|074|D|on the combination was 6.2 % at one year, increasing to 20.1 % at five years|
02304|075|D|with a hazard ratio(HR) of 7.19 (CI = 5.00 to 10.35) for anthracycline plus|
02304|076|D|trastuzumab compared with no chemotherapy.(6)|
02304|077|D|    A large epidemiologic study evaluated Medicare data to determine the|
02304|078|D|risk for heart failure or cardiomyopathy in 45,537 older women (mean age|
02304|079|D|76.2 years) diagnosed with early stage breast cancer. Over a 3 year period|
02304|080|D|the cumulative incidence of heart failure or cardiomyopathy in women who|
02304|081|D|received no chemotherapy, an anthracycline, trastuzumab, or anthracycline|
02304|082|D|and trastuzumab therapy was 18.1%, 20.2%, 32.1% and 41.9% respectively.(8)|
02304|083|B||
02304|084|R|REFERENCES:|
02304|085|B||
02304|086|R|1.Herceptin (trastuzumab) US prescribing information. Genentech Inc. June,|1
02304|087|R|  2024.|1
02304|088|R|2.Ellence (epirubicin hydrochloride) US prescribing information. Pharmacia|1
02304|089|R|  Corporation July, 2019.|1
02304|090|R|3.Curigliano G Cardinale D Suter T etal. Cardiovascular toxicity induced by|6
02304|091|R|  chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice|6
02304|092|R|  Guidelines. Annals of Oncology October, 2012;23(Supplement 7):155-166.|6
02304|093|R|4.Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, . 2009|6
02304|094|R|  Focused update incorporated into the ACC/AHA 2005 Guidelines for the|6
02304|095|R|  Diagnosis and Management of Heart Failure in Adults. J Am Coll Cardiol|6
02304|096|R|  2009 Apr 14;53(15):e1-e90.|6
02304|097|R|5.Yoon GJ, Telli ML, Kao DP, Matsuda KY, Carlson RW, Witteles RM. Left|2
02304|098|R|  ventricular dysfunction in patients receiving cardiotoxic cancer therapies|2
02304|099|R|  are clinicians responding optimally?. J Am Coll Cardiol 2010 Nov 9;|2
02304|100|R|  56(20):1644-50.|2
02304|101|R|6.Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Wagner EH,|2
02304|102|R|  Pharmacovigilance Study  Team. Risk of heart failure in breast cancer|2
02304|103|R|  patients after anthracycline and trastuzumab treatment: a retrospective|2
02304|104|R|  cohort study. J Natl Cancer Inst 2012 Sep 5;104(17):1293-305.|2
02304|105|R|7.Carlson RW, Allred DC, Anderson BO, Burstein HJ, etal. Metastatic breast|6
02304|106|R|  cancer, version 1.2012: featured updates to the NCCN guidelines. J Natl|6
02304|107|R|  Compr Canc Netw 2012 Jul 1;10(7):821-9.|6
02304|108|R|8.Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP. Incidence of|2
02304|109|R|  Heart Failure or Cardiomyopathy After Adjuvant Trastuzumab Therapy for|2
02304|110|R|  Breast Cancer. J Am Coll Cardiol 2012 Nov 2.|2
02304|111|R|9.Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) US prescribing|1
02304|112|R|  information. Genentech, Inc. June, 2024.|1
02305|001|T|MONOGRAPH TITLE:  Buprenorphine/Class IA & III Antiarrhythmics (mono deleted|
02305|002|T|06/05/2023)|
02305|003|B||
02305|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02305|005|L|of severe adverse interaction.|
02305|006|B||
02305|007|A|MECHANISM OF ACTION:  Concurrent use may result in additive effects on the|
02305|008|A|QT interval.|
02305|009|B||
02305|010|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in potentially|
02305|011|E|life-threatening arrhythmias such as torsades de pointes.|
02305|012|B||
02305|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02305|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02305|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02305|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02305|017|P|female gender, or advanced age.(2)|
02305|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02305|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02305|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02305|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02305|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02305|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02305|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02305|025|B||
02305|026|M|PATIENT MANAGEMENT:  The manufacturer of buprenorphine states that the|
02305|027|M|concurrent use of Class IA and III antiarrhythmic agents should be|
02305|028|M|avoided.(1)|
02305|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02305|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02305|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02305|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02305|033|B||
02305|034|D|DISCUSSION:  In a randomized, double-blinded, placebo and active-controlled|
02305|035|D|thorough QT study, a dose of buprenorphine of 10 mcg/hour had no significant|
02305|036|D|effects on the QT interval.  A dose of buprenorphine of 40 mcg/hour|
02305|037|D|prolonged the QTc by a maximum of 9.2 msec (90% CI:  5.2-13.3 msec).(1)|
02305|038|B||
02305|039|R|REFERENCES:|
02305|040|B||
02305|041|R|1.Butrans (buprenorphine) US prescribing information. Purdue Pharm L.P.|1
02305|042|R|  September, 2018.|1
02305|043|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02305|044|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02305|045|R|  settings: a scientific statement from the American Heart Association and|6
02305|046|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02305|047|R|  2;55(9):934-47.|6
02306|001|T|MONOGRAPH TITLE:  Sorafenib/Possible QT Prolonging Agents|
02306|002|B||
02306|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02306|004|L|take action as needed.|
02306|005|B||
02306|006|A|MECHANISM OF ACTION:  Concurrent use of sorafenib with other agents that|
02306|007|A|prolong the QTc interval may result in additive effects on the QTc|
02306|008|A|interval.(1)|
02306|009|B||
02306|010|E|CLINICAL EFFECTS:  The use of sorafenib in patients maintained on agents|
02306|011|E|that prolong the QTc interval may result in potentially life-threatening|
02306|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02306|013|B||
02306|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02306|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02306|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02306|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02306|018|P|female gender, or advanced age.(2)|
02306|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02306|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02306|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02306|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02306|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02306|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02306|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02306|026|B||
02306|027|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with agents known|
02306|028|M|to prolong the QTc interval should be monitored with electrocardiograms|
02306|029|M|during treatment with sorafenib. Electrolytes (calcium, magnesium, and|
02306|030|M|potassium) should also be monitored.(1)|
02306|031|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02306|032|M|fainting.|
02306|033|B||
02306|034|D|DISCUSSION:  In a non-randomized trial in 53 patients, sorafenib resulted in|
02306|035|D|a mean change in QTc of 8.5 msec (upper bound of 90% CI:  13.3 msec).(1)|
02306|036|D|   A retrospective review of 618 cancer patients treated with 902|
02306|037|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02306|038|D|incidence of QTc prolongation.  In patients who received sorafenib, QTc|
02306|039|D|prolongation was identified in 13 (31.7%) with 5 (38.5%) having Grade 1 (QTc|
02306|040|D|450-480 ms) and 4 (30.7%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
02306|041|D|occurred in 2 (15.4%) having QTc greater than or equal to 500 ms and 2|
02306|042|D|(15.4%) having QTc change greater than or equal to 60 ms.  No patients|
02306|043|D|developed ventricular tachycardia, sudden cardiac death, or TdP.(3)|
02306|044|D|   Agents that are linked to this monograph may have varying degrees of|
02306|045|D|potential to prolong the QTc interval but are generally accepted to have a|
02306|046|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02306|047|D|been shown to prolong the QTc interval either through their mechanism of|
02306|048|D|action, through studies on their effects on the QTc interval, or through|
02306|049|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02306|050|D|and/or post-marketing reports.(4)|
02306|051|B||
02306|052|R|REFERENCES:|
02306|053|B||
02306|054|R|1.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
02306|055|R|  Corporation July, 2020.|1
02306|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02306|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02306|058|R|  settings: a scientific statement from the American Heart Association and|6
02306|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02306|060|R|  2;55(9):934-47.|6
02306|061|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02306|062|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02306|063|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02306|064|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
02306|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02306|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02306|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02307|001|T|MONOGRAPH TITLE:  Artemether; Lumefantrine/Strong CYP3A4 Inducers|
02307|002|B||
02307|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02307|004|L|is contraindicated and generally should not be dispensed or administered to|
02307|005|L|the same patient.|
02307|006|B||
02307|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02307|008|A|artemether and lumefantrine.(1)|
02307|009|B||
02307|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers with artemether|
02307|011|E|and lumefantrine may result in decreased levels and effectiveness of the|
02307|012|E|antimalarial agents and treatment failure.(1)|
02307|013|B||
02307|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02307|015|P|of the inducer for longer than 1-2 weeks.|
02307|016|B||
02307|017|M|PATIENT MANAGEMENT:  The manufacturer of artemether-lumefantrine states that|
02307|018|M|the concurrent use of artemether-lumefantrine with strong CYP3A4 inducers is|
02307|019|M|contraindicated.(1)|
02307|020|B||
02307|021|D|DISCUSSION:  In a study in 6 subjects, administration of rifampin (600 mg|
02307|022|D|daily, a strong inducer of CYP3A4) with artemether-lumefantrine (6 dose|
02307|023|D|regimen over 3 days) decreased the area-under-curve (AUC) of artemether,|
02307|024|D|dihydroartemisinin (DHA), and lumefantrine by 89%, 85%, and 68%,|
02307|025|D|respectively.(1)|
02307|026|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
02307|027|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
02307|028|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
02307|029|D|St. John's wort.(2)|
02307|030|B||
02307|031|R|REFERENCES:|
02307|032|B||
02307|033|R|1.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
02307|034|R|  Pharmaceuticals Corporation August, 2019.|1
02307|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
02307|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02308|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Artemether|
02308|002|B||
02308|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02308|004|L|of severe adverse interaction.|
02308|005|B||
02308|006|A|MECHANISM OF ACTION:  Artemether may increase the metabolism of hormonal|
02308|007|A|contraceptives.|
02308|008|B||
02308|009|E|CLINICAL EFFECTS:  Concurrent use of artemether may result in reduced levels|
02308|010|E|and clinical effectiveness of hormonal contraceptives.  In the case of|
02308|011|E|contraceptives, breakthrough bleeding and pregnancy may result.|
02308|012|B||
02308|013|P|PREDISPOSING FACTORS:  None determined.|
02308|014|B||
02308|015|M|PATIENT MANAGEMENT:  Patients receiving artemether should be alerted to the|
02308|016|M|possibility of decreased effectiveness of their hormonal contraceptive.|
02308|017|M|   It is recommended that alternative or additional non-hormonal|
02308|018|M|contraceptive methods be used during artemether therapy(1) and for 28 days|
02308|019|M|after completing therapy.(2)  The patient should be asked to report any|
02308|020|M|spotting or bleeding.|
02308|021|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
02308|022|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
02308|023|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
02308|024|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
02308|025|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
02308|026|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
02308|027|M|and to seek medical advice if they do become pregnant.|
02308|028|B||
02308|029|D|DISCUSSION:  Artemether has been shown to weakly induce CYP2C19, CYP2B6, and|
02308|030|D|CYP3A and may reduce the efficacy of hormonal contraceptives.(1)|
02308|031|B||
02308|032|R|REFERENCES:|
02308|033|B||
02308|034|R|1.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
02308|035|R|  Pharmaceuticals Corporation August, 2019.|1
02308|036|R|2.Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit.|6
02308|037|R|  Clinical guidance drug interactions with hormonal contraception. January,|6
02308|038|R|  2011.|6
02308|039|R|3.Medicines and Healthcare products Regulatory Agency.|1
02308|040|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
02308|041|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
02308|042|R|  available at:|1
02308|043|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
02308|044|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
02308|045|R|  -and-contraceptive-efficacy September 15, 2016..|1
02309|001|T|MONOGRAPH TITLE:  Trimethoprim-Sulfamethoxazole/Leucovorin|
02309|002|B||
02309|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02309|004|L|take action as needed.|
02309|005|B||
02309|006|A|MECHANISM OF ACTION:  Leucovorin may protect Pneumocystis jirovecii from the|
02309|007|A|effects of trimethoprim-sulfamethoxazole by providing a source of|
02309|008|A|folate.(1,2)|
02309|009|B||
02309|010|E|CLINICAL EFFECTS:  Concurrent use of leucovorin in patients undergoing|
02309|011|E|prophylaxis against or being treated for Pneumocystis jiroveci pneumonia|
02309|012|E|(formerly called Pneumocystic carinii) with trimethoprim-sulfamethoxazole|
02309|013|E|has been associated with treatment failure and increased mortality.(1-4)|
02309|014|B||
02309|015|P|PREDISPOSING FACTORS:  None determined.|
02309|016|B||
02309|017|M|PATIENT MANAGEMENT:  The concurrent use of leucovorin and|
02309|018|M|trimethoprim-sulfamethoxazole should be avoided in patients undergoing|
02309|019|M|prophylaxis against or being treated for Pneumocystis jiroveci (formerly|
02309|020|M|carinii) pneumonia.(1-4)|
02309|021|M|   The Australian manufacturer of leucovorin states simultaneous|
02309|022|M|administration of folinic acid and folic acid antagonists (e.g.|
02309|023|M|trimethoprim-sulfamethoxazole, pyrimethamine) is contraindicated because the|
02309|024|M|folinic acid can completely negate the effect of the folic acid|
02309|025|M|antagonist.(5)|
02309|026|M|   Leucovorin is an effective treatment for trimethoprim-sulfamethoxazole|
02309|027|M|induced bone marrow suppression.(3)|
02309|028|B||
02309|029|D|DISCUSSION:  In a prospective, double-blind study in 92 AIDS patients with|
02309|030|D|Pneumocystis jiroveci (formerly carinii) pneumonia, concurrent use of|
02309|031|D|leucovorin with trimethoprim-sulfamethoxazole resulted in an increase in|
02309|032|D|treatment failure (15% versus 0) and death (11% versus 0).  Leucovorin was|
02309|033|D|also associated with a shorter time to therapeutic failure.  Patients|
02309|034|D|receiving leucovorin did have a lower incidence of neutropenia; however,|
02309|035|D|there was no difference in the time to occurrence of neutropenia.(4)|
02309|036|D|   In a study in 12 AIDS/ARC patients, leucovorin had no effect on|
02309|037|D|trimethoprim-sulfamethoxazole induced cytopenia.(6)|
02309|038|D|   In a study in HIV patients with no history of Pneumocystis jiroveci|
02309|039|D|pneumonia, administration of leucovorin had no effect on patient tolerance|
02309|040|D|to trimethoprim-sulfamethoxazole.(7)|
02309|041|D|   In a case report, two renal transplant patients with Pneumocystis|
02309|042|D|jiroveci pneumonia failed to respond to treatment with|
02309|043|D|trimethoprim-sulfamethoxazole until concurrent leucovorin was|
02309|044|D|discontinued.(1)|
02309|045|D|   In a case report, an AIDS patient developed Pneumocystis jiroveci|
02309|046|D|pneumonia despite a regimen of concurrent trimethoprim-sulfamethoxazole and|
02309|047|D|leucovorin.(2)|
02309|048|B||
02309|049|R|REFERENCES:|
02309|050|B||
02309|051|R|1.Nunn PP, Allistone JC. Resistance to trimethoprim-sulfamethoxazole in the|3
02309|052|R|  treatment of Pneumocystis carinii pneumonia. Implication of folinic acid.|3
02309|053|R|  Chest 1984 Jul;86(1):149-50.|3
02309|054|R|2.Razavi B, Lund B, Allen BL, Schlesinger L. Failure of|3
02309|055|R|  trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii|3
02309|056|R|  pneumonia with concurrent leucovorin use. Infection 2002 Jan;30(1):41-2.|3
02309|057|R|3.Bactrim Inj. (sulfamethoxazole and trimethoprim) US prescribing|1
02309|058|R|  information. Mutual Pharmaceutical Company, Inc. May, 2021.|1
02309|059|R|4.Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with|2
02309|060|R|  trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS|2
02309|061|R|  patients is associated with an increased risk of therapeutic failure and|2
02309|062|R|  death. J Infect Dis 1994 Oct;170(4):912-7.|2
02309|063|R|5.Rescuvolin (folinic acid) Australian prescribing information. Teva Pharma|1
02309|064|R|  Belgium NV 05/2018.|1
02309|065|R|6.Bygbjerg IC, Lund JT, Hording M. Effect of folic and folinic acid on|2
02309|066|R|  cytopenia occurring during co-trimoxazole treatment of Pneumocystis|2
02309|067|R|  carinii pneumonia. Scand J Infect Dis 1988;20(6):685-6.|2
02309|068|R|7.Bozzette SA, Forthal D, Sattler FR, Kemper C, Richman DD, Tilles JG,|2
02309|069|R|  Leedom J, McCutchan JA. The tolerance for zidovudine plus thrice weekly or|2
02309|070|R|  daily trimethoprim-sulfamethoxazole with and without leucovorin for|2
02309|071|R|  primary prophylaxis in advanced HIV disease. California Collaborative|2
02309|072|R|  Treatment Group. Am J Med 1995 Feb;98(2):177-82.|2
02310|001|T|MONOGRAPH TITLE:  Zolmitriptan (Greater Than 2.5 mg)/Cimetidine|
02310|002|B||
02310|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02310|004|L|is contraindicated and generally should not be dispensed or administered to|
02310|005|L|the same patient.|
02310|006|B||
02310|007|A|MECHANISM OF ACTION:  Cimetidine inhibits the CYP1A2 mediated metabolism of|
02310|008|A|zolmitriptan and its active N-desmethyl metabolite.(1,2)|
02310|009|B||
02310|010|E|CLINICAL EFFECTS:  Increased concentrations of zolmitriptan and its active|
02310|011|E|N-desmethyl metabolite may increase the risk for adverse effects such as|
02310|012|E|paresthesia, dizziness, or sensation of heaviness or tightness in the|
02310|013|E|neck/throat/jaw, or chest.(1)|
02310|014|B||
02310|015|P|PREDISPOSING FACTORS:  Due to the extended half-life associated with|
02310|016|P|concurrent cimetidine use, multiple doses of zolmitriptan within a 24-hour|
02310|017|P|period may lead to accumulation, increasing the risk for adverse|
02310|018|P|effects.(1,2)|
02310|019|B||
02310|020|M|PATIENT MANAGEMENT:  The manufacturer of zolmitriptan recommends the maximum|
02310|021|M|single dose be reduced to 2.5 mg, not to exceed 5 mg in any 24-hour|
02310|022|M|period.(1)|
02310|023|M|   When possible, consider use of an alternative acid reducing agent.|
02310|024|B||
02310|025|D|DISCUSSION:  Zolmitriptan is converted to several metabolites, but only the|
02310|026|D|N-desmethyl metabolite is active.  Although plasma concentrations are about|
02310|027|D|2/3 of the parent drug, the N-desmethyl metabolite is 2 to 6 times more|
02310|028|D|potent at 5-HT1B/1D receptors than zolmitriptan and may contribute|
02310|029|D|substantially to its pharmacologic effect.(1)|
02310|030|D|   Zolmitriptan added to therapeutic doses of cimetidine 400 mg three times|
02310|031|D|a day increased the area-under-curve(AUC) for zolmitriptan and its active|
02310|032|D|N-desmethyl metabolite of approximately 1.5 fold and 2 fold|
02310|033|D|respectively.(1,2)|
02310|034|D|   An open 2 period crossover study in 16 volunteer subjects evaluated the|
02310|035|D|pharmacokinetics of zolmitriptan and the N-desmethyl metabolite with or|
02310|036|D|without cimetidine 400mg every 8 hours for 2 days.  After cimetidine|
02310|037|D|treatment, the AUC of zolmitriptan and the N-desmethyl metabolite increased|
02310|038|D|1.48 and 2.05 fold respectively.  The half-life of zolmitriptan increased|
02310|039|D|from 4.99 to 7.19 hours, while the active metabolite half-life increased|
02310|040|D|from 3.81 to 8.00 hours after treatment with cimetidine.(2)|
02310|041|B||
02310|042|R|REFERENCES:|
02310|043|B||
02310|044|R|1.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
02310|045|R|  Pharmaceuticals LP September, 2012.|1
02310|046|R|2.Dixon R, French S, Kemp J, Sellers M, Yates R. The metabolism of|2
02310|047|R|  zolmitriptan: effects of an inducer and an inhibitor of cytochrome p450 on|2
02310|048|R|  its pharmacokinetics in healthy volunteers. Clin Drug Investig 1998;|2
02310|049|R|  15(6):515-22.|2
02311|001|T|MONOGRAPH TITLE:  Atovaquone/Metoclopramide|
02311|002|B||
02311|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02311|004|L|of severe adverse interaction.|
02311|005|B||
02311|006|A|MECHANISM OF ACTION:  Metoclopramide decreases the absorption of|
02311|007|A|atovaquone.(1-3)|
02311|008|B||
02311|009|E|CLINICAL EFFECTS:  The concurrent use of metoclopramide may result in|
02311|010|E|decreased levels and effectiveness of atovaquone.(1-3)|
02311|011|B||
02311|012|P|PREDISPOSING FACTORS:  None determined.|
02311|013|B||
02311|014|M|PATIENT MANAGEMENT:  Metoclopramide should only be used in patients|
02311|015|M|receiving atovaquone if no other antiemetic is available.(1-3)|
02311|016|B||
02311|017|D|DISCUSSION:  Concurrent metoclopramide has been associated with a 50%|
02311|018|D|decrease in atovaquone plasma concentrations.(1)|
02311|019|B||
02311|020|R|REFERENCES:|
02311|021|B||
02311|022|R|1.Malarone (atovaquone-proguanil) UK summary of product characteristics.|1
02311|023|R|  GlaxoSmithKline UK August 6, 2012.|1
02311|024|R|2.Malarone (atovaquone and proguanil hydrochloride) US prescribing|1
02311|025|R|  information. GlaxoSmithKline March, 2010.|1
02311|026|R|3.Youngster I, Barnett ED. Interactions among Travel Vaccines & Drugs. CDC|1
02311|027|R|  Health Information for International Travel 2018 (The Yellow Book)|1
02311|028|R|  available at:|1
02311|029|R|  https://wwwnc.cdc.gov/travel/yellowbook/2018/the-pre-travel-consultation/i|1
02311|030|R|  nteractions-among-travel-vaccines-and-drugs May 31, 2017.|1
02312|001|T|MONOGRAPH TITLE:  Selected 5-HT1D Agonists/MAOIs (mono deleted 02/19/2025)|
02312|002|B||
02312|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02312|004|L|take action as needed.|
02312|005|B||
02312|006|A|MECHANISM OF ACTION:  Concurrent use may result in additive effects on|
02312|007|A|serotonin.|
02312|008|B||
02312|009|E|CLINICAL EFFECTS:  Concurrent use may result in serotonin syndrome. Symptoms|
02312|010|E|of serotonin syndrome may include tremor, agitation, diaphoresis,|
02312|011|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
02312|012|B||
02312|013|P|PREDISPOSING FACTORS:  None determined.|
02312|014|B||
02312|015|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
02312|016|M|closely, especially during treatment initiation, during dosage increases, or|
02312|017|M|if another serotonergic agent is added to the patient's regimen.(1)|
02312|018|M|   If concurrent therapy is warranted, patients should be monitored for|
02312|019|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02312|020|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02312|021|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02312|022|M|coordination, or severe diarrhea.|
02312|023|B||
02312|024|D|DISCUSSION:  Concurrent moclobemide (150 mg BID for 8 days) decreased the|
02312|025|D|clearance of almotriptan by 27%.  The maximum concentration (Cmax) of|
02312|026|D|almotriptan increased 6%.(2)|
02312|027|D|   Metaxalone is a weak inhibitor of MAO.(3,4)|
02312|028|B||
02312|029|R|REFERENCES:|
02312|030|B||
02312|031|R|1.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
02312|032|R|2.Axert (almotriptan) US prescribing information. Ortho-McNeil Neurologics|1
02312|033|R|  May, 2009.|1
02312|034|R|3.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
02312|035|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
02312|036|R|  Feb;34(2):346.e5-6.|3
02312|037|R|4.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
02312|038|R|  Pfizer Inc. January, 2024.|1
02313|001|T|MONOGRAPH TITLE:  Mercaptopurine/Azathioprine|
02313|002|B||
02313|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02313|004|L|is contraindicated and generally should not be dispensed or administered to|
02313|005|L|the same patient.|
02313|006|B||
02313|007|A|MECHANISM OF ACTION:  Azathioprine is a pro-drug of mercaptopurine.(1)|
02313|008|B||
02313|009|E|CLINICAL EFFECTS:  Concurrent use of azathioprine and mercaptopurine is a|
02313|010|E|duplication of therapy.|
02313|011|B||
02313|012|P|PREDISPOSING FACTORS:  None determined.|
02313|013|B||
02313|014|M|PATIENT MANAGEMENT:  Azathioprine and mercaptopurine should not be used|
02313|015|M|concurrently.(2)|
02313|016|B||
02313|017|D|DISCUSSION:  A Crohn's disease pt. was given azathioprine (150mg/day).|
02313|018|D|Another physician prescribed mercaptopurine (100mg/day). The patient took|
02313|019|D|both medications and developed profound myelosuppression, severe sepsis, and|
02313|020|D|later died.(2)|
02313|021|B||
02313|022|R|REFERENCES:|
02313|023|B||
02313|024|R|1.Imuran (azathioprine) US prescribing information. Prometheus Laboratories|1
02313|025|R|  Inc. February, 2014.|1
02313|026|R|2.ISMP. Duplication with azathioprine and mercaptopurine. Medication Safety|3
02313|027|R|  Alert June 29, 2006.|3
02314|001|T|MONOGRAPH TITLE:  Regorafenib/Strong CYP3A4 Inhibitors|
02314|002|B||
02314|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02314|004|L|of severe adverse interaction.|
02314|005|B||
02314|006|A|MECHANISM OF ACTION:  Regorafenib and active M2 and M5 metabolites|
02314|007|A|contribute to anticancer activity. Although interpatient variability is|
02314|008|A|high, with repeated dosing the systemic exposure to each component|
02314|009|A|(regorafenib, M2 and M5) is similar. CYP3A4 converts regorafenib to the|
02314|010|A|active M2 metabolite.  M2 is subsequently converted, via an unknown pathway,|
02314|011|A|to the active M5 metabolite.(1)  Thus, inhibition of CYP3A4 leads to|
02314|012|A|increased serum levels of regorafenib, but decreased levels of both M2 and|
02314|013|A|M5.(1,2)|
02314|014|B||
02314|015|E|CLINICAL EFFECTS:  In an interaction study of regorafenib with a strong|
02314|016|E|CYP3A4 inhibitor, a 33% increase in exposure to regorafenib did not|
02314|017|E|compensate for a 93% decrease in exposure to M2 and M5. Overall, mean|
02314|018|E|exposure to the combination of regorafenib, M2 and M5 decreased by|
02314|019|E|approximately 50 per cent.(1)|
02314|020|B||
02314|021|P|PREDISPOSING FACTORS:  None determined.|
02314|022|B||
02314|023|M|PATIENT MANAGEMENT:  The manufacturer of regorafenib states concomitant use|
02314|024|M|with strong inhibitors of CYP3A4 should be avoided.  Whenever possible, to|
02314|025|M|assure maximal efficacy of regorafenib it would be prudent to use an|
02314|026|M|alternative agent in place of the strong CYP3A4 inhibitor.(2)|
02314|027|M|   The US manufacturer of itraconazole states that concurrent use of|
02314|028|M|regorafenib is not recommended during and two weeks after itraconazole|
02314|029|M|treatment.(4)|
02314|030|B||
02314|031|D|DISCUSSION:  Regorafenib was approved for use prior to completion of an|
02314|032|D|exposure-response analysis or a population pharmacokinetic study.(1)  The|
02314|033|D|outcomes of these studies will increase understanding and improve prediction|
02314|034|D|of regorafenib interaction risks.|
02314|035|D|   Strong CYP3A4 inhibitors linked to this monograph are:  adagrasib,|
02314|036|D|boceprevir, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole,|
02314|037|D|josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone,|
02314|038|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib,|
02314|039|D|ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, and|
02314|040|D|voriconazole.(3)|
02314|041|B||
02314|042|R|REFERENCES:|
02314|043|B||
02314|044|R|1.FDA. Drug Approval Package: Stivarga (regorafenib) Tablets,|1
02314|045|R|  Application:203085, Clinical Pharmacology Review. accessed at:|1
02314|046|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203085Orig1s000Clin|1
02314|047|R|  PharmR.pdf approval 09/27/2012.|1
02314|048|R|2.Stivarga (regorafenib) US prescribing information. Bayer HealthCare|1
02314|049|R|  Pharmaceuticals, Inc. February, 2020.|1
02314|050|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02314|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02314|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02314|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02314|054|R|  11/14/2017.|1
02314|055|R|4.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02314|056|R|  Products, L.P. February, 2024.|1
02315|001|T|MONOGRAPH TITLE:  Ponatinib/Strong CYP3A4 Inducers; Rifabutin|
02315|002|B||
02315|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02315|004|L|of severe adverse interaction.|
02315|005|B||
02315|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 and rifabutin may induce the|
02315|007|A|metabolism of ponatinib via this pathway.(1-3)|
02315|008|B||
02315|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers or|
02315|010|E|rifabutin may reduce the clinical effectiveness of ponatinib.(1-3)|
02315|011|B||
02315|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02315|013|P|of the inducer for longer than 1-2 weeks.|
02315|014|B||
02315|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ponatinib with strong|
02315|016|M|CYP3A4 inducers.(1-3)  The Canadian and UK manufacturers of ponatinib|
02315|017|M|include rifabutin in their list of CYP3A4 inducers that should be|
02315|018|M|avoided.(2-3)  When possible, select alternative agents in place of the|
02315|019|M|strong CYP3A4 inducer.  Monitor patients receiving concurrent therapy for|
02315|020|M|reduced efficacy.|
02315|021|B||
02315|022|D|DISCUSSION:  Coadministration of a single ponatinib 45 mg dose with rifampin|
02315|023|D|600 mg daily in 19 healthy volunteers resulted in a decrease in ponatinib|
02315|024|D|area-under-the-curve (AUC) and maximum concentration (Cmax) by 62% and 42%,|
02315|025|D|respectively. (1)|
02315|026|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
02315|027|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02315|028|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
02315|029|D|rifabutin, rifampin, rifapentine and St John's Wort.(4,5)|
02315|030|B||
02315|031|R|REFERENCES:|
02315|032|B||
02315|033|R|1.Iclusig (ponatinib) US prescribing information. ARIAD Pharmaceuticals Inc.|1
02315|034|R|  December, 2020.|1
02315|035|R|2.Iclusig (ponatinib) Canadian prescribing information. ARIAD|1
02315|036|R|  Pharmaceuticals, Inc. August 9, 2019.|1
02315|037|R|3.Iclusig (ponatinib) UK Summary of Product Characteristics. Incyte|1
02315|038|R|  Biosciences UK Ltd August 2, 2021.|1
02315|039|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02315|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02315|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02315|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02315|043|R|  11/14/2017.|1
02315|044|R|5.This information is based on an extract from the Certara Drug Interaction|6
02315|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02316|001|T|MONOGRAPH TITLE:  Tofacitinib/Selected Inhibitors of Both CYP3A4 and CYP2C19|
02316|002|B||
02316|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02316|004|L|take action as needed.|
02316|005|B||
02316|006|A|MECHANISM OF ACTION:  Agents that are both strong inhibitors of CYP2C19 and|
02316|007|A|moderate inhibitors of CYP3A4 may inhibit the metabolism of tofacitinib.(1)|
02316|008|B||
02316|009|E|CLINICAL EFFECTS:  Concurrent use of agents that are both strong inhibitors|
02316|010|E|of CYP2C19 and moderate inhibitors of CYP3A4 may result in elevated levels|
02316|011|E|of and toxicity from tofacitinib.(1)|
02316|012|B||
02316|013|P|PREDISPOSING FACTORS:  None determined.|
02316|014|B||
02316|015|M|PATIENT MANAGEMENT:  In patients taking agents that are both strong CYP2C19|
02316|016|M|inhibitors and moderate inhibitors of CYP3A4, such as fluconazole, the|
02316|017|M|starting dose of tofacitinib should be reduced as follows:|
02316|018|M|- Xeljanz for rheumatoid arthritis, psoriatic arthritis, and ankylosing|
02316|019|M|spondylitis: reduce to 5 mg once daily.|
02316|020|M|- Xeljanz XR for rheumatoid arthritis, psoriatic arthritis, and ankylosing|
02316|021|M|spondylitis: switch to Xeljanz 5 mg once daily.|
02316|022|M|- Xeljanz for ulcerative colitis:|
02316|023|M|   - Induction: 5 mg twice daily for 8 weeks. If needed continue for maximum|
02316|024|M|of 16 weeks.|
02316|025|M|   - Maintenance: 5 mg once daily. May consider 5 mg twice daily if loss of|
02316|026|M|response.|
02316|027|M|- Xeljanz XR for ulcerative colitis:|
02316|028|M|   - Induction: 11 mg once daily for 8 weeks. If needed continue for maximum|
02316|029|M|of 16 weeks.|
02316|030|M|   - Maintenance: Not recommended. Switch to Xeljanz and follow strong|
02316|031|M|CYP3A4 inhibitor recommendation.|
02316|032|M|- Xeljanz oral solution for polyarticular course juvenile idiopathic|
02316|033|M|arthritis (pcJIA) or psoriatic arthritis (patients 2 years or older):|
02316|034|M|   - >= 10 kg to <20 kg: 3.2 mg once daily|
02316|035|M|   - >= 20 kg to <40 kg: 4 mg once daily|
02316|036|M|   - >= 40 kg: 5 mg once daily  (1)|
02316|037|B||
02316|038|D|DISCUSSION:  In a study, administration of fluconazole, a strong inhibitor|
02316|039|D|of CYP2C19 and a moderate inhibitor of CYP3A4 increased the area-under-curve|
02316|040|D|(AUC) of tofacitinib by more than 1.75-fold.(1)|
02316|041|B||
02316|042|R|REFERENCE:|
02316|043|B||
02316|044|R|1.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. October,|1
02316|045|R|  2025.|1
02317|001|T|MONOGRAPH TITLE:  Tofacitinib/Immunosuppressives; Immunomodulators|
02317|002|B||
02317|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02317|004|L|of severe adverse interaction.|
02317|005|B||
02317|006|A|MECHANISM OF ACTION:  Concurrent use of tofacitinib and azathioprine, other|
02317|007|A|biologic disease-modifying antirheumatic drugs (DMARDs), or potent|
02317|008|A|immunosuppressants may result in additive or synergistic effects on the|
02317|009|A|immune system.(1)|
02317|010|B||
02317|011|E|CLINICAL EFFECTS:  Concurrent use of tofacitinib and azathioprine, other|
02317|012|E|biologic DMARDs, or potent immunosuppressants use may increase the risk of|
02317|013|E|serious infections.(1)|
02317|014|B||
02317|015|P|PREDISPOSING FACTORS:  None determined.|
02317|016|B||
02317|017|M|PATIENT MANAGEMENT:  Tofacitinib should not be used concurrently with|
02317|018|M|azathioprine, other biologic DMARDs, or cyclosporine.(1)|
02317|019|M|   Patient should be monitored for decreases in lymphocytes and neutrophils.|
02317|020|M|Therapy should be adjusted based on the indication.|
02317|021|M|- For all indications: If absolute neutrophil count (ANC) or lymphocyte|
02317|022|M|count is less than 500 cells/mm3, discontinue tofacitinib.|
02317|023|M|- For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil|
02317|024|M|count (ANC) 500 to 1000 cells/mm3: interrupt dosing.  When ANC is greater|
02317|025|M|than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg|
02317|026|M|once daily.|
02317|027|M|- For ulcerative colitis and ANC 500 to 1000 cells/mm3:|
02317|028|M|   -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily.  When|
02317|029|M|ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on|
02317|030|M|clinical response.|
02317|031|M|   -If taking Xeljanz 5 mg twice daily, interrupt dosing.  When ANC is|
02317|032|M|greater than 1000 cells/mm3, resume 5 mg twice daily.|
02317|033|M|   -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily.|
02317|034|M|When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based|
02317|035|M|on clinical response.|
02317|036|M|   -If taking Xeljanz XR 11 mg once daily, interrupt dosing.  When ANC is|
02317|037|M|greater than 1000 cells/mm3, resume 11 mg once daily.|
02317|038|M|- For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500|
02317|039|M|to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000|
02317|040|M|cells/mm3.(1)|
02317|041|B||
02317|042|D|DISCUSSION:  Concurrent use of tofacitinib and azathioprine, other biologic|
02317|043|D|DMARDs, or potent immunosuppressants may increase the risk of infection.(1)|
02317|044|D|   Serious infections due to bacterial, mycobacterial, invasive fungal,|
02317|045|D|viral, or other opportunistic pathogens have been reported in patients|
02317|046|D|receiving tofacitinib. Some patients presented with disseminated disease and|
02317|047|D|were often taking concomitant immunomodulating agents. In the ulcerative|
02317|048|D|colitis population, a greater risk of serious infections was seen with a|
02317|049|D|higher tofacitinib dose. In 7 placebo-controlled rheumatoid arthritis trials|
02317|050|D|(0-3 months exposure), the overall frequency of infections was 20% in the|
02317|051|D|tofacitinib 5 mg twice daily group and 22% in the tofacitinib 10 mg twice|
02317|052|D|daily group compared to 18% in the placebo group. Serious infections were|
02317|053|D|reported in 11 patients (1.7 events per 100 patient-years) with a rate|
02317|054|D|difference between treatment groups of 1.1 (-0.4, 2.5) events per 100|
02317|055|D|patient-years for both tofacitinib 5 mg twice daily and 10 mg twice daily.|
02317|056|D|During 0-12 months exposure, serious infections were reported in 34 patients|
02317|057|D|(2.7 events per 100 patient years) in the tofacitinib 5 mg twice daily group|
02317|058|D|and 33 patients (2.7 events per 100 patient years) in the tofacitinib 10 mg|
02317|059|D|twice daily group.(1)|
02317|060|B||
02317|061|R|REFERENCE:|
02317|062|B||
02317|063|R|1.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. October,|1
02317|064|R|  2025.|1
02318|001|T|MONOGRAPH TITLE:  Tofacitinib/Strong CYP3A4 Inhibitors (mono deleted|
02318|002|T|04/10/2014)|
02318|003|B||
02318|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02318|005|L|of severe adverse interaction.|
02318|006|B||
02318|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
02318|008|A|of tofacitinib.(1)|
02318|009|B||
02318|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors such as|
02318|011|E|boceprevir, clarithromycin, conivaptan, indinavir, itraconazole,|
02318|012|E|ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,|
02318|013|E|posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or|
02318|014|E|voriconazole may result in elevated levels of and toxicity from|
02318|015|E|tofacitinib.(1)|
02318|016|B||
02318|017|P|PREDISPOSING FACTORS:  None determined.|
02318|018|B||
02318|019|M|PATIENT MANAGEMENT:  In patients taking a strong CYP3A4 inhibitor, the|
02318|020|M|starting dose of tofacitinib should be reduced to 5 mg daily.(1)|
02318|021|B||
02318|022|D|DISCUSSION:  In a study, administration of ketoconazole, a strong inhibitor|
02318|023|D|of CYP3A4, increased the area-under-curve (AUC) of tofacitinib by more than|
02318|024|D|2-fold.(1)|
02318|025|D|   Strong inhibitors of CYP3A4 include:  boceprevir, clarithromycin,|
02318|026|D|conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir,|
02318|027|D|mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,|
02318|028|D|telaprevir, telithromycin, or voriconazole may result in elevated levels of|
02318|029|D|and toxicity from tofacitinib.(2)|
02318|030|B||
02318|031|R|REFERENCES:|
02318|032|B||
02318|033|R|1.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. November,|1
02318|034|R|  2012.|1
02318|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02318|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02318|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02318|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02318|039|R|  11/14/2017.|1
02319|001|T|MONOGRAPH TITLE:  Vernakalant/Class I & Class III Antiarrhythmics|
02319|002|B||
02319|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02319|004|L|of severe adverse interaction.|
02319|005|B||
02319|006|A|MECHANISM OF ACTION:  Concurrent administration of vernakalant and Class I|
02319|007|A|or Class III antiarrhythmics may result in additive effects.|
02319|008|B||
02319|009|E|CLINICAL EFFECTS:  The concurrent administration of vernakalant with Class I|
02319|010|E|or Class III antiarrhythmics may result in additive effects on the heart.|
02319|011|E|Concurrent use of Class I antiarrhythmics may increase the risk of atrial|
02319|012|E|flutter.(1)|
02319|013|B||
02319|014|P|PREDISPOSING FACTORS:  None determined.|
02319|015|B||
02319|016|M|PATIENT MANAGEMENT:  The manufacturer of vernakalant states that intravenous|
02319|017|M|Class I or Class III antiarrhythmic agents should not be used within 4 hours|
02319|018|M|before or after vernakalant administration.  Use of vernakalant in patients|
02319|019|M|who have received intravenous Class I or Class III antiarrhythmic agents in|
02319|020|M|the previous 4-24 hours cannot be recommended.(1)|
02319|021|M|   The manufacturer of vernakalant states that the use of vernakalant in|
02319|022|M|patients receiving oral Class I or Class III antiarrhythmic agents should be|
02319|023|M|approached with caution.  Resumption or initiation of oral Class I or Class|
02319|024|M|III antiarrhythmic agents may be considered 2 hours after completion of|
02319|025|M|vernakalant administration.(1)|
02319|026|B||
02319|027|D|DISCUSSION:  Because of the risk of adverse effects, the manufacturer of|
02319|028|D|vernakalant states that intravenous Class I or Class III antiarrhythmic|
02319|029|D|agents should not be used within 4 hours before or after vernakalant|
02319|030|D|administration.  Resumption or initiation of oral Class I or Class III|
02319|031|D|antiarrhythmic agents may be considered 2 hours after completion of|
02319|032|D|vernakalant administration.(1)|
02319|033|B||
02319|034|R|REFERENCE:|
02319|035|B||
02319|036|R|1.Brinavess (vernakalant hydrochloride) EMA summary of product|1
02319|037|R|  characteristics. Merck Sharp & Dohme Ltd. July 23, 2012.|1
02320|001|T|MONOGRAPH TITLE:  Clopidogrel/Selected CYP2C19 Inhibitors|
02320|002|B||
02320|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02320|004|L|of severe adverse interaction.|
02320|005|B||
02320|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
02320|007|A|active metabolite via a 2 step process.  The first conversion step is|
02320|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
02320|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
02320|010|A|thought to be the more important enzyme involved in formation of the|
02320|011|A|pharmacologically active metabolite.(1)|
02320|012|A|   Inhibitors of CYP2C19 may decrease the conversion of clopidogrel to its|
02320|013|A|active metabolite.(1)|
02320|014|B||
02320|015|E|CLINICAL EFFECTS:  Concurrent use of CYP2C19 inhibitors may result in|
02320|016|E|decreased clopidogrel effectiveness, resulting in increased risk of adverse|
02320|017|E|cardiac events.|
02320|018|B||
02320|019|P|PREDISPOSING FACTORS:  None determined.|
02320|020|B||
02320|021|M|PATIENT MANAGEMENT:  Evaluate medication list or interaction alerts to|
02320|022|M|determine if patient is receiving additional drugs which may also inhibit|
02320|023|M|clopidogrel active metabolite formation.|
02320|024|M|   The US manufacturer of clopidogrel states that alternatives to|
02320|025|M|clopidogrel should be considered in patients who are poor metabolizers of|
02320|026|M|CYP2C19.(1)  It would be prudent to assume that patients taking strong|
02320|027|M|inhibitors of CYP2C19 are poor metabolizers of this isoenzyme.  Moderate or|
02320|028|M|weak inhibitors of CYP2C19 may have less of an effect on this interaction.|
02320|029|M|   Consider alternatives to CYP2C19 inhibitors in patients stabilized on|
02320|030|M|clopidogrel and alternatives to clopidogrel in patients stabilized on|
02320|031|M|CYP2C19 inhibitors.  If concurrent therapy is warranted, consider|
02320|032|M|appropriate testing to assure adequate inhibition of platelet reactivity.|
02320|033|B||
02320|034|D|DISCUSSION:  Clopidogrel is a prodrug and requires conversion to the active|
02320|035|D|metabolite by CYP2C19.|
02320|036|D|   Clopidogrel is not a sensitive substrate for CYP2C19 as CYP3A4, CYP2B6|
02320|037|D|and CYP1A2 also participate in active metabolite formation.  Studies have|
02320|038|D|not evaluated this specific drug combination; the actual magnitude of this|
02320|039|D|interaction is not known.  Given the possible consequences of clopidogrel|
02320|040|D|treatment failure, it would be prudent to avoid concomitant use of|
02320|041|D|clopidogrel and CYP2C19 inhibitors when possible.|
02320|042|D|   Selected CYP2C19 inhibitors include: armodafinil, asciminib,|
02320|043|D|berotralstat, cenobamate, elagolix, enasidenib, eslicarbazepine, fedratinib,|
02320|044|D|fexinidazole, givosiran, lonafarnib, moclobemide, modafinil, obeticholic|
02320|045|D|acid, osilodrostat, piperine, pirtobrutinib, rolapitant, rucaparib,|
02320|046|D|tecovirimat, treosulfan, and triclabendazole.(4,5)|
02320|047|B||
02320|048|R|REFERENCES:|
02320|049|B||
02320|050|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
02320|051|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
02320|052|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
02320|053|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
02320|054|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
02320|055|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
02320|056|R|  38(1):92-9.|5
02320|057|R|3.US Food and Drug Association. Information on Clopidogrel Bisulfate|1
02320|058|R|  (marketed as Plavix). Available at:|1
02320|059|R|  http://wayback.archive-it.org/7993/20170111075953/http:/www.fda.gov/Drugs/|1
02320|060|R|  DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm19083|1
02320|061|R|  6.htm October 27, 2010.|1
02320|062|R|4.This information is based on an extract from the Certara Drug Interaction|6
02320|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02320|064|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02320|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02320|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02320|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02320|068|R|  11/14/2017.|1
02322|001|T|MONOGRAPH TITLE:  Flecainide/Sertraline|
02322|002|B||
02322|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02322|004|L|take action as needed.|
02322|005|B||
02322|006|A|MECHANISM OF ACTION:  Sertraline is a weak inhibitor of CYP2D6.(1,2)  Higher|
02322|007|A|sertraline doses are more likely to be associated clinically significant 2D6|
02322|008|A|inhibition.  A substantial portion of flecainide elimination is via CYP 2D6|
02322|009|A|and flecainide has a narrow therapeutic range. Higher serum flecainide|
02322|010|A|concentrations are associated with a greater risk for proarrhythmic|
02322|011|A|effects.(3)|
02322|012|B||
02322|013|E|CLINICAL EFFECTS:  Concurrent use of sertraline may result in increased|
02322|014|E|serum levels of flecainide and risk for potentially fatal ventricular|
02322|015|E|arrhythmias.(2,3)|
02322|016|B||
02322|017|P|PREDISPOSING FACTORS:  Pre-existing medical conditions which increase the|
02322|018|P|risk for a proarrhythmic event due to flecainide include history of|
02322|019|P|myocardial infarction, chronic atrial fibrillation, chronic heart failure,|
02322|020|P|hypokalemia and hyperkalemia.(3)|
02322|021|P|   Patients with severe renal or hepatic disease may have impaired|
02322|022|P|elimination of flecainide.(3) Women appear to have a slower flecainide|
02322|023|P|elimination rate than men.|
02322|024|B||
02322|025|M|PATIENT MANAGEMENT:  If predisposing medical conditions exist, avoid the use|
02322|026|M|of sertraline or other CYP2D6 inhibitors.|
02322|027|M|   If sertraline is required, use the lowest effective antidepressant dose.|
02322|028|M|Consider plasma level monitoring of flecainide and reduce dose if needed.|
02322|029|M|   Many other antidepressants also inhibit CYP2D6 and would not be safer|
02322|030|M|alternatives.  Antidepressants which are strong inhibitors of CYP2D6 include|
02322|031|M|bupropion, fluoxetine and paroxetine.  Moderate inhibitors include|
02322|032|M|duloxetine and moclobemide (not available in the US).  Additional|
02322|033|M|antidepressants associated with weak inhibition of CYP2D6 include|
02322|034|M|desvenlafaxine/venlafaxine and escitalopram/citalopram.(1)|
02322|035|M|   Counsel patients to seek medical attention if they experience dizziness,|
02322|036|M|shortness of breath, fainting, weakness, or fast/irregular heartbeat.|
02322|037|B||
02322|038|D|DISCUSSION:  Although sertraline is a weak inhibitor of CYP2D6, higher doses|
02322|039|D|(e.g. 150 mg per day) have been associated with clinically meaningful|
02322|040|D|inhibition of this enzyme.|
02322|041|D|   The manufacturer of flecainide states that the majority of patients|
02322|042|D|successfully treated were found to have trough plasma levels between 0.2 and|
02322|043|D|1 microgram/mL. The probability of adverse effects, especially cardiac, may|
02322|044|D|increase when trough levels exceed 1 microgram/mL.(3)|
02322|045|B||
02322|046|R|REFERENCES:|
02322|047|B||
02322|048|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
02322|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02322|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02322|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02322|052|R|  11/14/2017.|1
02322|053|R|2.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
02322|054|R|3.Tambocor (flecainide) US prescribing information. Medicis December, 2011.|1
02323|001|T|MONOGRAPH TITLE:  Procarbazine/Selected MAOIs|
02323|002|B||
02323|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02323|004|L|is contraindicated and generally should not be dispensed or administered to|
02323|005|L|the same patient.|
02323|006|B||
02323|007|A|MECHANISM OF ACTION:  Procarbazine, although used therapeutically as an|
02323|008|A|antineoplastic agent, is an inhibitor of monoamine oxidase (MAO).(1)|
02323|009|B||
02323|010|E|CLINICAL EFFECTS:  Concurrent use of procarbazine and other MAO inhibitors|
02323|011|E|may result in additive effects and toxicity.(1)|
02323|012|B||
02323|013|P|PREDISPOSING FACTORS:  None determined.|
02323|014|B||
02323|015|M|PATIENT MANAGEMENT:  While the Canadian manufacturer of procarbazine states|
02323|016|M|that concurrent use of monoamine oxidase inhibitors should be avoided,(1)|
02323|017|M|other monoamine oxidase inhibitors state that concurrent therapy is|
02323|018|M|contraindicated.(2)|
02323|019|B||
02323|020|D|DISCUSSION:  Procarbazine, although used therapeutically as an|
02323|021|D|antineoplastic agent, is an inhibitor of monoamine oxidase (MAO).(1)|
02323|022|D|   Metaxalone is a weak inhibitor of MAO.(3,4)|
02323|023|D|   One or more of the drug pairs linked to this monograph have been included|
02323|024|D|in a list of interactions that should be considered "high-priority" for|
02323|025|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02323|026|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02323|027|D|Coordinator (ONC) for Health Information Technology.|
02323|028|B||
02323|029|R|REFERENCES:|
02323|030|B||
02323|031|R|1.Matulane (procarbazine) US prescribing information. Sigma-Tua April 15,|1
02323|032|R|  2008.|1
02323|033|R|2.Parnate (tranylcypromine sulfate) US prescribing information.|1
02323|034|R|  GlaxoSmithKline January 4, 2018.|1
02323|035|R|3.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
02323|036|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
02323|037|R|  Feb;34(2):346.e5-6.|3
02323|038|R|4.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
02323|039|R|  Pfizer Inc. January, 2024.|1
02323|040|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02323|041|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02323|042|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02323|043|R|  19(5):735-43.|6
02324|001|T|MONOGRAPH TITLE:  Atorvastatin; Fluvastatin/Voriconazole|
02324|002|B||
02324|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02324|004|L|take action as needed.|
02324|005|B||
02324|006|A|MECHANISM OF ACTION:  Voriconazole may inhibit the metabolism of|
02324|007|A|atorvastatin by CYP3A4.(1)  Voriconazole may inhibit the metabolism of|
02324|008|A|fluvastatin by CYP2C9.(1)|
02324|009|B||
02324|010|E|CLINICAL EFFECTS:  Concurrent use of voriconazole(1) may result in elevated|
02324|011|E|levels of atorvastatin and fluvastatin and increase the risk of|
02324|012|E|rhabdomyolysis.|
02324|013|B||
02324|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02324|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02324|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02324|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02324|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02324|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02324|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on fluvastatin who are|
02324|021|P|CYP2C9 intermediate or poor metabolizers may have increased fluvastatin|
02324|022|P|concentrations and  risk of myopathy.|
02324|023|B||
02324|024|M|PATIENT MANAGEMENT:  Concurrent use of voriconazole with atorvastatin or|
02324|025|M|fluvastatin should be approached with caution.  Consider adjusting the dose|
02324|026|M|of the statin to use the lowest dose possible(2,3) or possibly suspending|
02324|027|M|therapy during antifungal treatment.  Patients should be carefully monitored|
02324|028|M|for and instructed to report any signs of myopathy.|
02324|029|B||
02324|030|D|DISCUSSION:  Voriconazole has been shown to inhibit the metabolism of|
02324|031|D|lovastatin in human liver microsomes in vitro.  Voriconazole has also been|
02324|032|D|shown to inhibit CYP2C9 metabolism.(1)|
02324|033|B||
02324|034|R|REFERENCES:|
02324|035|B||
02324|036|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
02324|037|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02324|038|R|  2020.|1
02325|001|T|MONOGRAPH TITLE:  Cyclosporine/Everolimus|
02325|002|B||
02325|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02325|004|L|of severe adverse interaction.|
02325|005|B||
02325|006|A|MECHANISM OF ACTION:  Cyclosporine may inhibit the metabolism of everolimus|
02325|007|A|by CYP3A4 and P-glycoprotein (P-gp).(1)  Concurrent use may also increase|
02325|008|A|the risk of nephrotoxicity.(1)|
02325|009|B||
02325|010|E|CLINICAL EFFECTS:  Simultaneous use may result in nephrotoxicity and|
02325|011|E|elevated levels of everolimus, as well as increase the risk of thrombotic|
02325|012|E|microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic|
02325|013|E|syndrome (TMA/TTP/HUS).(1)|
02325|014|B||
02325|015|P|PREDISPOSING FACTORS:  None determined.|
02325|016|B||
02325|017|M|PATIENT MANAGEMENT:  Reduced dosages of cyclosporine are required during|
02325|018|M|concurrent therapy.  The dosage of everolimus will need to be adjusted if|
02325|019|M|cyclosporine is initiated, modified, or discontinued.  Serum levels of both|
02325|020|M|cyclosporine and everolimus should be monitored during concurrent therapy|
02325|021|M|and whenever dosage adjustments of either agent are made.  Patients|
02325|022|M|receiving concurrent therapy should also be monitored for proteinuria.|
02325|023|M|Renal function and hematologic parameters should be monitored as well.(1)|
02325|024|M|   Everolimus and cyclosporine should be administered at the same time.(1)|
02325|025|B||
02325|026|D|DISCUSSION:  In a single dose study in healthy subjects, cyclosporine|
02325|027|D|(Neoral, 175 mg) increased everolimus (2 mg) area-under-curve (AUC) by 168%|
02325|028|D|(range:  46% to 365%) and maximum concentration (Cmax) by 82% (range:  25%|
02325|029|D|to 158%).(1,2)  Administration of another formulation of cyclosporine|
02325|030|D|(Sandimmune, 300 mg) had no affect on everolimus Cmax, but increased|
02325|031|D|everolimus AUC by 74%.(2)|
02325|032|D|   In clinical trials, the combination of everolimus and standard doses of|
02325|033|D|cyclosporine resulted in frequent elevations of serum creatinine and higher|
02325|034|D|mean and median serum creatinine levels.(1)|
02325|035|D|   In a study in renal allograft recipients, administration of everolimus|
02325|036|D|(0.75 mg/day to 10 mg/day) had no significant effects on cyclosporine|
02325|037|D|levels.(3)|
02325|038|B||
02325|039|R|REFERENCES:|
02325|040|B||
02325|041|R|1.Zortress (everolimus) US prescribing information. Novartis Pharmaceuticals|1
02325|042|R|  Corporation Sept, 2023.|1
02325|043|R|2.Kovarik JM, Kalbag J, Figueiredo J, Rouilly M, Frazier OL, Rordorf C.|2
02325|044|R|  Differential influence of two cyclosporine formulations on everolimus|2
02325|045|R|  pharmacokinetics: a clinically relevant pharmacokinetic interaction. J|2
02325|046|R|  Clin Pharmacol 2002 Jan;42(1):95-9.|2
02325|047|R|3.Budde K, Lehne G, Winkler M, Renders L, Lison A, Fritsche L, Soulillou JP,|2
02325|048|R|  Fauchald P, Neumayer HH, Dantal J. Influence of everolimus on steady-state|2
02325|049|R|  pharmacokinetics of cyclosporine in maintenance renal transplant patients.|2
02325|050|R|  J Clin Pharmacol 2005 Jul;45(7):781-91.|2
02326|001|T|MONOGRAPH TITLE:  Ponatinib/Strong CYP3A4 Inhibitors (mono deleted|
02326|002|T|10/17/2013)|
02326|003|B||
02326|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02326|005|L|of severe adverse interaction.|
02326|006|B||
02326|007|A|MECHANISM OF ACTION:  Ponatinib is metabolized by CYP3A4 and to a lesser|
02326|008|A|extent by CYP2C8, CYP2D6, and CYP3A5. Boceprevir, clarithromycin,|
02326|009|A|conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir,|
02326|010|A|mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,|
02326|011|A|telaprevir, telithromycin, and voriconazole are strong CYP3A4 inhibitors and|
02326|012|A|may inhibit the metabolism of ponatinib via this pathway.(1)|
02326|013|B||
02326|014|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors(2) such as|
02326|015|E|boceprevir, clarithromycin, conivaptan, indinavir, itraconazole,|
02326|016|E|ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,|
02326|017|E|posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or|
02326|018|E|voriconazole may result in elevated levels of and toxicity from|
02326|019|E|ponatinib.(1)|
02326|020|B||
02326|021|P|PREDISPOSING FACTORS:  None determined.|
02326|022|B||
02326|023|M|PATIENT MANAGEMENT:  The manufacturer of ponatinib states the recommended|
02326|024|M|dose should be reduced to 30 mg once daily during concomitant treatment with|
02326|025|M|strong CYP3A4 inhibitors.  Even with the dose reduction, patients receiving|
02326|026|M|concomitant therapy may be at increased risk for adverse reactions.(1)|
02326|027|M|Assure recommended monitoring (e.g. complete blood counts, liver function,|
02326|028|M|lipase, blood pressure measurement) is scheduled.|
02326|029|M|   If the ponatinib dose has been reduced due to coadministration of a|
02326|030|M|CYP3A4 inhibitor, and the inhibitor is subsequently discontinued, reevaluate|
02326|031|M|ponatinib efficacy and safety to determine if a dose increase is|
02326|032|M|appropriate.|
02326|033|B||
02326|034|D|DISCUSSION:  In 22 healthy volunteers, ketoconazole (a strong inhibitor of|
02326|035|D|CYP3A4, given 400 mg once daily) increased the maximum concentration (Cmax)|
02326|036|D|and area-under-curve (AUC) of a single 15 mg dose of ponatinib by 47% and|
02326|037|D|78%, respectively.(1)|
02326|038|B||
02326|039|R|REFERENCES:|
02326|040|B||
02326|041|R|1.Iclusig (ponatinib) US prescribing information. ARIAD Pharmaceuticals Inc.|1
02326|042|R|  June, 2020.|1
02326|043|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02326|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02326|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02326|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02326|047|R|  11/14/2017.|1
02327|001|T|MONOGRAPH TITLE:  Ponatinib/Antacids; H2 Antagonists; Proton Pump Inhibitors|
02327|002|T|(mono deleted 01/28/2016)|
02327|003|B||
02327|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02327|005|L|take action as needed.|
02327|006|B||
02327|007|A|MECHANISM OF ACTION:  The aqueous solubility of ponatinib is pH dependent.|
02327|008|A|Higher gastric pH leads to lower solubility which may reduce ponatinib|
02327|009|A|absorption.(1)|
02327|010|B||
02327|011|E|CLINICAL EFFECTS:  Coadministration of a proton pump inhibitor (PPI), an H2|
02327|012|E|antagonist, or an antacid may reduce the bioavailability of ponatinib,|
02327|013|E|leading to decreased systemic levels and effectiveness.(1)|
02327|014|B||
02327|015|P|PREDISPOSING FACTORS:  None determined.|
02327|016|B||
02327|017|M|PATIENT MANAGEMENT:  The manufacturer of ponatinib recommends avoiding use|
02327|018|M|of drugs which may increase gastric pH unless the benefit outweighs the risk|
02327|019|M|of possible ponatinib underexposure.(1)|
02327|020|B||
02327|021|D|DISCUSSION:  Coadministration of ponatinib with drugs which elevate pH has|
02327|022|D|not been evaluated in a clinical trial.  This recommendation is based upon|
02327|023|D|the chemical properties of ponatinib.(1)|
02327|024|B||
02327|025|R|REFERENCE:|
02327|026|B||
02327|027|R|1.Iclusig (ponatinib) US prescribing information. ARIAD Pharmaceuticals Inc.|1
02327|028|R|  June, 2020.|1
02328|001|T|MONOGRAPH TITLE:  Ponatinib/Strong CYP3A4 Inducers (mono deleted 03/27/2014)|
02328|002|B||
02328|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02328|004|L|take action as needed.|
02328|005|B||
02328|006|A|MECHANISM OF ACTION:  Carbamazepine, mitotane, phenobarbital, phenytoin,|
02328|007|A|rifabutin, rifampin and St. John's Wort are strong inducers of CYP3A4 and|
02328|008|A|may induce the metabolism of ponatinib via this pathway.(1,2)|
02328|009|B||
02328|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
02328|011|E|reduce the clinical effectiveness of ponatinib.(1)|
02328|012|E|  Strong CYP3A4 inducers linked to this monograph are carbamazepine,|
02328|013|E|mitotane, phenobarbital, phenytoin, rifabutin, rifampin and St. John's|
02328|014|E|Wort.(2)|
02328|015|B||
02328|016|P|PREDISPOSING FACTORS:  None determined.|
02328|017|B||
02328|018|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent ponatinib and|
02328|019|M|CYP3A4 inducer therapy for signs of reduced efficacy.(1)|
02328|020|M|   The US manufacturer of ponatinib states that concurrent use of CYP3A4|
02328|021|M|inducers is not recommended.(1)  After discontinuation, CYP3A4 induction|
02328|022|M|will gradually wane and ponatinib systemic concentrations will gradually|
02328|023|M|increase over approximately 2-4 weeks depending upon which inducer was|
02328|024|M|prescribed.|
02328|025|B||
02328|026|D|DISCUSSION:  This interaction has not been evaluated in vitro or in a|
02328|027|D|clinical trial.  Based upon mechanistic model simulations, the manufacturer|
02328|028|D|of ponatinib believes concomitant use of CYP3A inducers is likely to reduce|
02328|029|D|ponatinib exposure.(1)|
02328|030|B||
02328|031|R|REFERENCES:|
02328|032|B||
02328|033|R|1.Iclusig (ponatinib) US prescribing information. ARIAD Pharmaceuticals Inc.|1
02328|034|R|  June, 2020.|1
02328|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02328|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02328|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02328|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02328|039|R|  11/14/2017.|1
02329|001|T|MONOGRAPH TITLE:  Sodium Oxybate/Agents that May Cause Respiratory|
02329|002|T|Depression|
02329|003|B||
02329|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02329|005|L|of severe adverse interaction.|
02329|006|B||
02329|007|A|MECHANISM OF ACTION:  Oxybate by itself may be associated with severe|
02329|008|A|somnolence or respiratory depression.  Concurrent use with other CNS|
02329|009|A|depressants may further increase the risk for respiratory depression or loss|
02329|010|A|of consciousness.(1-3)|
02329|011|B||
02329|012|E|CLINICAL EFFECTS:  Concurrent use of sodium oxybate and sedative hypnotics|
02329|013|E|or alcohol may further increase the risk for profound sedation, respiratory|
02329|014|E|depression, coma, and/or death.(1,2)  Fatalities have been reported.(3)|
02329|015|B||
02329|016|P|PREDISPOSING FACTORS:  Based upon FDA evaluation of deaths in patients|
02329|017|P|taking sodium oxybate, risk factors may include: use of multiple drugs which|
02329|018|P|depress the CNS, more rapid than recommended oxybate dose titration,|
02329|019|P|exceeding the maximum recommended oxybate dose, and prescribing for|
02329|020|P|unapproved uses such as fibromyalgia, insomnia or migraine.  Note that in|
02329|021|P|oxybate clinical trials for narcolepsy 78% - 85% of patients were also|
02329|022|P|receiving concomitant CNS stimulants.(1-3)|
02329|023|B||
02329|024|M|PATIENT MANAGEMENT:  Avoid use of concomitant opioids, benzodiazepines,|
02329|025|M|sedating antidepressants, sedating antipsychotics, general anesthetics, or|
02329|026|M|muscle relaxants, particularly when predisposing risk factors are present.|
02329|027|M|If combination use is required, dose reduction or discontinuation of one or|
02329|028|M|more CNS depressants should be considered.  If short term use of an opioid|
02329|029|M|or general anesthetic is required, consider interruption of sodium oxybate|
02329|030|M|treatment.(1,2)|
02329|031|M|   Respiratory depression can occur at any time during opioid therapy,|
02329|032|M|especially during therapy initiation and following dosage increases.  The|
02329|033|M|risk of opioid-related overdose or overdose-related death is increased with|
02329|034|M|higher opioid doses, and this risk persists over the course of therapy.|
02329|035|M|Consider these risks when using concurrently with other agents that may|
02329|036|M|cause CNS depression.(4)|
02329|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02329|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02329|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02329|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02329|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02329|042|M|as those taking CNS depressants) and when a patient has household|
02329|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02329|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
02329|045|M|over-the-counter, or as part of a community-based program).(5)|
02329|046|B||
02329|047|D|DISCUSSION:  The FDA evaluated sodium oxybate postmarket fatal adverse event|
02329|048|D|reports from the FDA Adverse Event Reporting System(AERS)and from the|
02329|049|D|manufacturer.  Although report documentation was not always optimal or|
02329|050|D|complete, useful information was obtained.|
02329|051|D|   Factors which may have contributed to fatal outcome: concomitant use of|
02329|052|D|one or more drugs which depress the CNS, more rapid than recommended oxybate|
02329|053|D|dose titration, exceeding the maximum recommended oxybate dose, and|
02329|054|D|prescribing for unapproved uses such as fibromyalgia, insomnia or migraine.|
02329|055|D|   Many deaths occurred in patients with serious psychiatric disorders such|
02329|056|D|as depression and substance abuse. Other concomitant diseases may have also|
02329|057|D|contributed to respiratory and CNS depressant effects of oxybate.(3)|
02329|058|B||
02329|059|R|REFERENCES:|
02329|060|B||
02329|061|R|1.Xyrem (sodium oxybate) US prescribing information. Jazz Pharmaceuticals,|1
02329|062|R|  Inc. April, 2023.|1
02329|063|R|2.Lumryz (sodium oxybate extended-release oral suspension) US prescribing|1
02329|064|R|  information. Avadel CNS Pharmaceuticals, LLC May, 2023.|1
02329|065|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Warning|1
02329|066|R|  against use of Xyrem (sodium oxybate) with alcohol or drugs causing|1
02329|067|R|  respiratory depression. available at:|1
02329|068|R|  http://www.fda.gov/Drugs/DrugSafety/ucm332029.htm December 17, 2012.|1
02329|069|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02329|070|R|  prescribing information for all opioid pain medicines to provide|1
02329|071|R|  additional guidance for safe use. Available at:|1
02329|072|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02329|073|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02329|074|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02329|075|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02329|076|R|  recommends health care professionals discuss naloxone with all patients|1
02329|077|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02329|078|R|  disorder. Available at:|1
02329|079|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02329|080|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02329|081|R|  d-pain July 23, 2020.|1
02330|001|T|MONOGRAPH TITLE:  Pasireotide/QT Prolonging Agents|
02330|002|B||
02330|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02330|004|L|take action as needed.|
02330|005|B||
02330|006|A|MECHANISM OF ACTION:  Concurrent use of pasireotide with other agents that|
02330|007|A|prolong the QTc interval may result in additive effects on the QTc|
02330|008|A|interval.(1)|
02330|009|B||
02330|010|E|CLINICAL EFFECTS:  The use of pasireotide patients maintained on agents that|
02330|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02330|012|E|arrhythmias, including torsades de pointes.(1)|
02330|013|B||
02330|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02330|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02330|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02330|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02330|018|P|female gender, or advanced age.(3)|
02330|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02330|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02330|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02330|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02330|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02330|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02330|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02330|026|B||
02330|027|M|PATIENT MANAGEMENT:  Pasireotide should be used with caution in patients|
02330|028|M|receiving therapy with agents that prolong the QT interval.|
02330|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02330|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02330|031|M|regular intervals.(1)  Correct any electrolyte abnormalities.  Instruct|
02330|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02330|033|B||
02330|034|D|DISCUSSION:  In randomized, blinded, crossover study in healthy subjects,|
02330|035|D|pasireotide (0.6 mg BID) increased the placebo-subtracted QTcI by 12.7 msec|
02330|036|D|(95 upper CI:  14.7 msec).  Supra-therapeutic doses of 1.95 mg BID increased|
02330|037|D|the placebo-subtracted QTcI by 16.6 msec (95 upper CI:  18.6 msec).(1)|
02330|038|D|   Agents that are linked to this monograph may have varying degrees of|
02330|039|D|potential to prolong the QTc interval but are generally accepted to have a|
02330|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02330|041|D|been shown to prolong the QTc interval either through their mechanism of|
02330|042|D|action, through studies on their effects on the QTc interval, or through|
02330|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02330|044|D|and/or post-marketing reports.(2)|
02330|045|B||
02330|046|R|REFERENCES:|
02330|047|B||
02330|048|R|1.Signifor (pasireotide diasparate) US prescribing information. Novartis|1
02330|049|R|  Pharmaceuticals Corporation January, 2020.|1
02330|050|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02330|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02330|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02330|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02330|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02330|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02330|056|R|  settings: a scientific statement from the American Heart Association and|6
02330|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02330|058|R|  2;55(9):934-47.|6
02331|001|T|MONOGRAPH TITLE:  Dofetilide/QT Prolonging Agents|
02331|002|B||
02331|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02331|004|L|of severe adverse interaction.|
02331|005|B||
02331|006|A|MECHANISM OF ACTION:  Dofetilide has been shown to prolong the QTc interval|
02331|007|A|in a dose-dependent fashion.  Concurrent use with other agents that prolong|
02331|008|A|the QTc interval may result in additive effects on the QTc interval.(1)|
02331|009|B||
02331|010|E|CLINICAL EFFECTS:  The concurrent use of dofetilide with other agents that|
02331|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02331|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02331|013|E|   Agents linked to this monograph are: chloroquine, chlorpromazine,|
02331|014|E|dolasetron, domperidone, haloperidol, pentamidine, probucol, and|
02331|015|E|propoxyphene.|
02331|016|B||
02331|017|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
02331|018|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
02331|019|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
02331|020|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
02331|021|P|   Risk factors for QT prolongation include: cardiovascular disease (e.g.|
02331|022|P|heart failure, recent myocardial infarction, history of torsades de pointes,|
02331|023|P|congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia,|
02331|024|P|hypocalcemia, bradycardia, advanced age, and concurrent use of agents known|
02331|025|P|to cause QT prolongation.(2)|
02331|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02331|027|P|higher systemic concentrations of either QT prolonging drug are additional|
02331|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02331|029|P|drug concentrations include rapid infusion of an intravenous dose or|
02331|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02331|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02331|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02331|033|B||
02331|034|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that the use of|
02331|035|M|dofetilide with other agents known to prolong the QTc interval is not|
02331|036|M|recommended.(1) Use available alternative agents whenever possible.|
02331|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02331|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02331|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02331|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02331|041|M|   If dofetilide dose is increased or if dofetilide therapy is reinitiated|
02331|042|M|after an interruption, the patient should be hospitalized for continuous ECG|
02331|043|M|monitoring.(1)|
02331|044|B||
02331|045|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02331|046|D|degrees of potential to prolong the QTc interval but are generally accepted|
02331|047|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02331|048|D|monograph have been shown to prolong the QTc interval either through their|
02331|049|D|mechanism of action, through studies on their effects on the QTc interval,|
02331|050|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02331|051|D|clinical trials and/or post-marketing reports.(3)|
02331|052|D|   One or more of the drug pairs linked to this monograph have been included|
02331|053|D|in a list of interactions that should be considered "high-priority" for|
02331|054|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02331|055|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02331|056|D|Coordinator (ONC) for Health Information Technology.|
02331|057|B||
02331|058|R|REFERENCES:|
02331|059|B||
02331|060|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
02331|061|R|  2013.|1
02331|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02331|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02331|064|R|  settings: a scientific statement from the American Heart Association and|6
02331|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02331|066|R|  2;55(9):934-47.|6
02331|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02331|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02331|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02331|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02331|071|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02331|072|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02331|073|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02331|074|R|  19(5):735-43.|6
02332|001|T|MONOGRAPH TITLE:  Flibanserin/Strong or Moderate CYP3A4 Inhibitors|
02332|002|B||
02332|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02332|004|L|is contraindicated and generally should not be dispensed or administered to|
02332|005|L|the same patient.|
02332|006|B||
02332|007|A|MECHANISM OF ACTION:  Flibanserin is primarily metabolized by CYP3A4, though|
02332|008|A|CYP2C19 also plays a role in metabolism.(1)|
02332|009|B||
02332|010|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inhibitor of|
02332|011|E|CYP3A4 may result in high to very high levels of and toxicity from|
02332|012|E|flibanserin, including severe hypotension or syncope.(1)|
02332|013|B||
02332|014|P|PREDISPOSING FACTORS:  Patients with any degree of hepatic impairment, who|
02332|015|P|are poor CYP2C19 metabolizers, or who also receive concomitant therapy with|
02332|016|P|strong CYP2C19 inhibitors are expected to have increased systemic|
02332|017|P|concentrations of flibanserin, adding to the risk for hypotension or|
02332|018|P|syncopal episodes.(1)|
02332|019|P|   Hypotensive or syncopal episodes are more common when flibanserin is|
02332|020|P|taken during waking hours.(1)|
02332|021|B||
02332|022|M|PATIENT MANAGEMENT:  The concomitant use of flibanserin with moderate or|
02332|023|M|strong CYP3A4 inhibitors significantly increases flibanserin concentrations|
02332|024|M|which may lead to hypotension and syncope.  The manufacturer of flibanserin|
02332|025|M|states moderate or strong CYP3A4 inhibitors are contraindicated.(1)|
02332|026|M|   If the benefit of initiating a CYP3A4 inhibitor within 2 days of stopping|
02332|027|M|flibanserin clearly outweighs the risk flibanserin-associated hypotension or|
02332|028|M|syncope, monitor and counsel the patient regarding symptoms of hypotension|
02332|029|M|or syncope.  Discontinue moderate or strong CYP3A4 inhibitors for 2 weeks|
02332|030|M|before initiating or restarting flibanserin therapy.(1)|
02332|031|B||
02332|032|D|DISCUSSION:  In a drug interaction study with 15 healthy subjects, the|
02332|033|D|combination of flibanserin (100 mg on day 6) and fluconazole (a moderate|
02332|034|D|CYP3A4 and strong CYP2C19 inhibitor, 400 mg once then 200 mg daily for 5|
02332|035|D|days) resulted in an increased flibanserin exposure of 7-fold.  Hypotension|
02332|036|D|or syncope requiring supine placement with leg elevation occurred in 3|
02332|037|D|subjects (20%).  One patient became unresponsive with a blood pressure of|
02332|038|D|64/41 mm Hg and required emergency room treatment where she required|
02332|039|D|intravenous saline.(1)  Though the combination has not been studied, a|
02332|040|D|similar result is plausible with voriconazole, a strong CYP3A4 inhibitor and|
02332|041|D|moderate CYP2C19 inhibitor.(1)|
02332|042|D|   In a drug interaction study with flibanserin 50 mg (one-half of the|
02332|043|D|recommended dose) and ketoconazole 400 mg, flibanserin exposure increased|
02332|044|D|4.5-fold. One of 24 patients(4%) developed syncope.(1)|
02332|045|D|   A study of 12 healthy men and women on itraconazole (400 mg once then 200|
02332|046|D|mg daily for 4 days) with flibanserin 50 mg given 2 hours after itraconazole|
02332|047|D|found that flibanserin exposure was increased 2.6-fold.(1)|
02332|048|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02332|049|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
02332|050|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
02332|051|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
02332|052|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
02332|053|D|troleandomycin, tucatinib, and voriconazole.(1-3)|
02332|054|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
02332|055|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
02332|056|D|darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin,|
02332|057|D|fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine,|
02332|058|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir,|
02332|059|D|letermovir, ledipasvir, netupitant, nilotinib, rilzabrutinib, schisandra,|
02332|060|D|stiripentol, treosulfan, and verapamil.(1-3)|
02332|061|B||
02332|062|R|REFERENCES:|
02332|063|B||
02332|064|R|1.Addyi (flibanserin) US prescribing information. Sprout Pharmaceuticals|1
02332|065|R|  September, 2021.|1
02332|066|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02332|067|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02332|068|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02332|069|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02332|070|R|  11/14/2017.|1
02332|071|R|3.This information is based on an extract from the Certara Drug Interaction|6
02332|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02333|001|T|MONOGRAPH TITLE:  Meperidine/Clomipramine; Imipramine; SSRIs; SNRIs;|
02333|002|B||
02333|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02333|004|L|of severe adverse interaction.|
02333|005|B||
02333|006|A|MECHANISM OF ACTION:  The concurrent administration of meperidine with a|
02333|007|A|selective serotonin reuptake inhibitor or a serotonin/norepinephrine|
02333|008|A|reuptake inhibitor (SNRI) may result in additive blockade of serotonin|
02333|009|A|reuptake, resulting in central serotonergic hyperstimulation.(1,2)  The|
02333|010|A|combination of meperidine and selective serotonin reuptake inhibitors or|
02333|011|A|SNRIs may also lower the seizure threshold.|
02333|012|B||
02333|013|E|CLINICAL EFFECTS:  Concurrent administration may result in serotonin|
02333|014|E|syndrome.  Symptoms of serotonin syndrome may include tremor, agitation,|
02333|015|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02333|016|E|rigidity.(2)|
02333|017|B||
02333|018|P|PREDISPOSING FACTORS:  Predisposing factors include renal dysfunction and|
02333|019|P|use of multiple agents which increase central serotonin levels.  Chronic use|
02333|020|P|of meperidine or high doses of SSRIs or SNRIs would also be expected to|
02333|021|P|increase the risk for serotonin toxicity.|
02333|022|B||
02333|023|M|PATIENT MANAGEMENT:  Use an alternative analgesic whenever possible,|
02333|024|M|particularly in patients with renal impairment.|
02333|025|M|   If concurrent therapy is warranted, patients should be monitored for|
02333|026|M|signs and symptoms of serotonin syndrome, seizure activity.  Instruct|
02333|027|M|patients to report muscle twitching, tremors, shivering and stiffness,|
02333|028|M|fever, heavy sweating, heart palpitations, restlessness, confusion,|
02333|029|M|agitation, trouble with coordination, or severe diarrhea.|
02333|030|B||
02333|031|D|DISCUSSION:  Case reports describe the interaction between meperidine and|
02333|032|D|serotonin-increasing agents.(3-5)|
02333|033|D|   Meperidine has long been associated with the risk for serotonin syndrome,|
02333|034|D|particularly when used with monoamine oxidase inhibitors (MAOIs).(6)|
02333|035|D|   In addition to SSRIs and SNRIs, clomipramine, a tricyclic|
02333|036|D|antidepressant(TCA) with strong serotonin effects and imipramine, a TCA with|
02333|037|D|more moderate serotonin effects are also included in this monograph.(7)|
02333|038|B||
02333|039|R|REFERENCES:|
02333|040|B||
02333|041|R|1.Personal communication:  Cymbalta (duloxetine HCl) concomitant opoid|1
02333|042|R|  analgesic use. Eli Lilly and Company June, 2006.|1
02333|043|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02333|044|R|  352(11):1112-20.|6
02333|045|R|3.Tissot TA. Probable meperidine-induced serotonin syndrome in a patient|3
02333|046|R|  with a history of fluoxetine use. Anesthesiology 2003 Jun;98(6):1511-2.|3
02333|047|R|4.Altman EM, Manos GH. Serotonin syndrome associated with citalopram and|3
02333|048|R|  meperidine. Psychosomatics 2007 Jul-Aug;48(4):361-3.|3
02333|049|R|5.Dougherty JA, Young H, Shafi T. Serotonin syndrome induced by|3
02333|050|R|  amitriptyline, meperidine, and venlafaxine. Ann Pharmacother 2002 Oct;|3
02333|051|R|  36(10):1647-8.|3
02333|052|R|6.Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin|6
02333|053|R|  toxicity. Br J Anaesth 2005 Oct;95(4):434-41.|6
02333|054|R|7.O'Donnell JM Shelton RC. Chapter 15 - Drug Therapy of Depression and|6
02333|055|R|  Anxiety Disorders. In Bruton L, Chabner B, Knollman B eds. Goodman &|6
02333|056|R|  Gilman's The Pharmacological Basis of Therapeutics. 12th ed. 2011.|6
02334|001|T|MONOGRAPH TITLE:  Lomitapide (Less Than or Equal To 30 mg)/Weak CYP3A4|
02334|002|T|Inhibitors|
02334|003|B||
02334|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02334|005|L|of severe adverse interaction.|
02334|006|B||
02334|007|A|MECHANISM OF ACTION:  Weak inhibitors of CYP3A4 may inhibit the metabolism|
02334|008|A|of lomitapide.(1)|
02334|009|A|   Lomitapide is very susceptible to CYP3A4 inhibition.  For example, in an|
02334|010|A|interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide|
02334|011|A|exposure was increased 27-fold.(2)  Thus even weak CYP3A4 inhibitors may|
02334|012|A|affect lomitapide exposure (AUC, area-under-curve).|
02334|013|B||
02334|014|E|CLINICAL EFFECTS:  Concurrent use of a weak inhibitor of CYP3A4 may result|
02334|015|E|in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)|
02334|016|B||
02334|017|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
02334|018|P|hepatic impairment or with end-stage renal disease.(1)|
02334|019|B||
02334|020|M|PATIENT MANAGEMENT:  The maximum lomitapide dose should be 30 mg daily for|
02334|021|M|patients taking concomitant weak CYP3A4 inhibitors.  Due to lomitapide's|
02334|022|M|long half-life, it may take 1 to 2 weeks to see the full effect of this|
02334|023|M|interaction.|
02334|024|M|   When initiating a weak CYP3A4 inhibitor in patients taking lomitapide 10|
02334|025|M|mg daily or more, decrease the dose of lomitapide by 50%.  In patients|
02334|026|M|taking lomitapide 5 mg daily, continue current dose.|
02334|027|B||
02334|028|D|DISCUSSION:  Lomitapide is very susceptible to CYP3A4 inhibition.  For|
02334|029|D|example, in an interaction study with a strong CYP3A4 inhibitor|
02334|030|D|(ketoconazole) lomitapide exposure was increased 27-fold.(2)  Based upon|
02334|031|D|interactions with stronger inhibitors, weak inhibitors of CYP3A4 are|
02334|032|D|predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1)|
02334|033|D|   Weak CYP3A4 inhibitors linked to this interaction include alprazolam,|
02334|034|D|amiodarone, amlodipine, anamorelin, asciminib, atorvastatin, azithromycin,|
02334|035|D|Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab,|
02334|036|D|cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin,|
02334|037|D|chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant,|
02334|038|D|delavirdine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant,|
02334|039|D|fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir,|
02334|040|D|goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor,|
02334|041|D|larotrectinib, lacidipine, lapatinib, lazertinib, leflunomide,|
02334|042|D|levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib,|
02334|043|D|osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine,|
02334|044|D|propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin,|
02334|045|D|rucaparib, selpercatinib, sitaxsentan, skullcap, teriflunomide, ticagrelor,|
02334|046|D|tolvaptan, trofinetide, viloxazine, vonoprazan, ziftomenib, and|
02334|047|D|zileuton.(1-3)|
02334|048|B||
02334|049|R|REFERENCES:|
02334|050|B||
02334|051|R|1.Juxtapid (lomitapide) US prescribing information. Aegerion|1
02334|052|R|  Pharmaceuticals, Inc. May, 2016.|1
02334|053|R|2.This information is based on an extract from the Certara Drug Interaction|6
02334|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02334|055|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02334|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02334|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02334|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02334|059|R|  11/14/2017.|1
02335|001|T|MONOGRAPH TITLE:  Simvastatin (Greater Than 40 mg)/Lomitapide|
02335|002|B||
02335|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02335|004|L|is contraindicated and generally should not be dispensed or administered to|
02335|005|L|the same patient.|
02335|006|B||
02335|007|A|MECHANISM OF ACTION:  Lomitapide inhibits the metabolism of simvastatin via|
02335|008|A|CYP3A4.(1)|
02335|009|B||
02335|010|E|CLINICAL EFFECTS:  Concurrent use of lomitapide may result in elevated|
02335|011|E|levels of simvastatin and an increased risk of myopathy, including|
02335|012|E|rhabdomyolysis.(1)|
02335|013|B||
02335|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02335|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02335|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02335|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02335|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02335|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02335|020|P|predisposed to myopathy or rhabdomyolysis.|
02335|021|B||
02335|022|M|PATIENT MANAGEMENT:  The dose of simvastatin should be reduced 50% when used|
02335|023|M|concurrently with lomitapide.  The dosage of simvastatin should be limited|
02335|024|M|to 20 mg daily in most patients.  A dosage of 40 mg may be used in patients|
02335|025|M|who previously tolerated a daily dose of simvastatin of 80 mg for at least|
02335|026|M|one year.(1,2)|
02335|027|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
02335|028|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
02335|029|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
02335|030|M|urine, and/or discolored urine.|
02335|031|B||
02335|032|D|DISCUSSION:  Administration of lomitapide (60 mg daily for 7 days) increased|
02335|033|D|the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose|
02335|034|D|of simvastatin (40 mg) by 99% and 102%, respectively.  The AUC and Cmax of|
02335|035|D|simvastatin acid increased by 71% and 57%, respectively.(1,2)|
02335|036|D|   Administration of lomitapide (10 mg daily for 7 days) increased the AUC|
02335|037|D|and Cmax of a single dose of simvastatin (20 mg) by 62% and 65%,|
02335|038|D|respectively.  The AUC and Cmax of simvastatin acid increased by 39% and|
02335|039|D|35%, respectively.(1,2)|
02335|040|B||
02335|041|R|REFERENCES:|
02335|042|B||
02335|043|R|1.Juxtapid (lomitapide) US prescribing information. Aegerion|1
02335|044|R|  Pharmaceuticals, Inc. May, 2016.|1
02335|045|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02335|046|R|  2023.|1
02336|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin (Less than or Equal To 40|
02336|002|T|mg)/Lomitapide|
02336|003|B||
02336|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02336|005|L|take action as needed.|
02336|006|B||
02336|007|A|MECHANISM OF ACTION:  Lomitapide inhibits the metabolism of lovastatin and|
02336|008|A|simvastatin via CYP3A4.(1)|
02336|009|B||
02336|010|E|CLINICAL EFFECTS:  Concurrent use of lomitapide may result in elevated|
02336|011|E|levels of lovastatin or simvastatin and an increased risk of myopathy,|
02336|012|E|including rhabdomyolysis.(1)|
02336|013|B||
02336|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02336|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02336|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02336|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02336|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02336|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02336|020|P|predisposed to myopathy or rhabdomyolysis.|
02336|021|B||
02336|022|M|PATIENT MANAGEMENT:  The dose of simvastatin should be reduced 50% when used|
02336|023|M|concurrently with lomitapide.  The dosage of simvastatin should be limited|
02336|024|M|to 20 mg daily in most patients.  A dosage of 40 mg may be used in patients|
02336|025|M|who previously tolerated a daily dose of simvastatin of 80 mg for at least|
02336|026|M|one year.(1,2)|
02336|027|M|   Similar reductions should be considered for lovastatin.(1)|
02336|028|B||
02336|029|D|DISCUSSION:  Administration of lomitapide (60 mg daily for 7 days) increased|
02336|030|D|the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose|
02336|031|D|of simvastatin (40 mg) by 99% and 102%, respectively.  The AUC and Cmax of|
02336|032|D|simvastatin acid increased by 71% and 57%, respectively.(1,2)|
02336|033|D|   Administration of lomitapide (10 mg daily for 7 days) increased the AUC|
02336|034|D|and Cmax of a single dose of simvastatin (20 mg) by 62% and 65%,|
02336|035|D|respectively.  The AUC and Cmax of simvastatin acid increased by 39% and|
02336|036|D|35%, respectively.(1,2)|
02336|037|B||
02336|038|R|REFERENCES:|
02336|039|B||
02336|040|R|1.Juxtapid (lomitapide) US prescribing information. Aegerion|1
02336|041|R|  Pharmaceuticals, Inc. May, 2016.|1
02336|042|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02336|043|R|  2023.|1
02337|001|T|MONOGRAPH TITLE:  Warfarin/Lomitapide|
02337|002|B||
02337|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02337|004|L|take action as needed.|
02337|005|B||
02337|006|A|MECHANISM OF ACTION:  Lomitapide is a weak CYP2C9 inhibitor and a weak CYP3A|
02337|007|A|inhibitor which may decrease the metabolism of both the S-enantiomer and|
02337|008|A|R-enantiomer of warfarin, respectively.(2-4)|
02337|009|B||
02337|010|E|CLINICAL EFFECTS:  Concurrent use of lomitapide may result in elevated|
02337|011|E|levels of warfarin and INR.(1)|
02337|012|E|   Concurrent use of warfarin and lomitapide may increase the risk for|
02337|013|E|bleeding.|
02337|014|B||
02337|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02337|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02337|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
02337|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02337|019|P|risk for bleeding (e.g. NSAIDs).|
02337|020|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
02337|021|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
02337|022|P|are expected to be more susceptible to this interaction.|
02337|023|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
02337|024|P|are expected to be less susceptible to effects from this drug combination,|
02337|025|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
02337|026|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
02337|027|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
02337|028|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
02337|029|P|and safe anticoagulation than patients without these CYP2C9 variants.|
02337|030|B||
02337|031|M|PATIENT MANAGEMENT:  Monitor INRs frequently until stable in patients who|
02337|032|M|start lomitapide therapy, or have the lomitapide dose adjusted.(1)|
02337|033|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02337|034|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
02337|035|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
02337|036|M|evaluate patients with any symptoms.|
02337|037|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02337|038|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02337|039|M|anticoagulation in patients with active pathologic bleeding.|
02337|040|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02337|041|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02337|042|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02337|043|M|and/or swelling.|
02337|044|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02337|045|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02337|046|M|initiating, altering the dose or discontinuing either drug.|
02337|047|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
02337|048|B||
02337|049|D|DISCUSSION:  Administration of lomitapide (60 mg daily for 7 days) increased|
02337|050|D|the area-under-curve (AUC) and maximum concentration (Cmax) of a R-warfarin|
02337|051|D|by 28% and 14%, respectively, following the administration of a single dose|
02337|052|D|of warfarin (10 mg).  The AUC and Cmax of S-warfarin increased by 30% and|
02337|053|D|15%, respectively.  INR values increased by 22%.(1)|
02337|054|D|   In clinical trials for lomitapide, one of five patients receiving|
02337|055|D|concurrent warfarin had to withdraw from the trial as a result of difficulty|
02337|056|D|in controlling INR values.(1)|
02337|057|B||
02337|058|R|REFERENCES:|
02337|059|B||
02337|060|R|1.Juxtapid (lomitapide) US prescribing information. Aegerion|1
02337|061|R|  Pharmaceuticals, Inc. May, 2016.|1
02337|062|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
02337|063|R|  Squibb Company September, 2016.|1
02337|064|R|3.This information is based on an extract from the Certara Drug Interaction|6
02337|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02337|066|R|4.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
02337|067|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
02337|068|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
02337|069|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
02337|070|R|  Oct;90(4):625-9.|6
02338|001|T|MONOGRAPH TITLE:  Bedaquiline/Strong & Moderate CYP3A4 Inducers|
02338|002|B||
02338|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02338|004|L|of severe adverse interaction.|
02338|005|B||
02338|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may induce the|
02338|007|A|metabolism of bedaquiline.(1)|
02338|008|B||
02338|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong or moderate CYP3A4|
02338|010|E|inducers may result in decreased levels and effectiveness of bedaquiline.(1)|
02338|011|B||
02338|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02338|013|P|of the inducer for longer than 1-2 weeks.|
02338|014|B||
02338|015|M|PATIENT MANAGEMENT:  The concurrent administration of strong or moderate|
02338|016|M|CYP3A4 inducers and bedaquiline should be avoided.(1)|
02338|017|B||
02338|018|D|DISCUSSION:  In a study in healthy subjects, concurrent administration of|
02338|019|D|rifampin (600 mg daily) and bedaquiline (300 mg daily) for 21 days decreased|
02338|020|D|the area-under-curve (AUC) of bedaquiline by 52%.(1)|
02338|021|D|   In a study in healthy subjects, pretreatment with efavirenz (600 mg daily|
02338|022|D|for 27 days) decreased the AUC of a single dose of bedaquiline by 20%.|
02338|023|D|There was no effect on bedaquiline Cmax.  The AUC and Cmax of the primary|
02338|024|D|metabolite of bedaquiline increased by 70% and 80%, respectively.(1)|
02338|025|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
02338|026|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
02338|027|D|phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and|
02338|028|D|St. John's wort.(1-3)|
02338|029|D|   Moderate inducers of CYP3A4 include:  belzutifan, bosentan, cenobamate,|
02338|030|D|dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten,|
02338|031|D|mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, sotorasib,|
02338|032|D|telotristat and tovorafenib.(1-3)|
02338|033|B||
02338|034|R|REFERENCES:|
02338|035|B||
02338|036|R|1.Sirturo (bedaquiline) US prescribing information. Janssen Therapeutics|1
02338|037|R|  June, 2024.|1
02338|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02338|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02338|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02338|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02338|042|R|  11/14/2017.|1
02338|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
02338|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02339|001|T|MONOGRAPH TITLE:  Bedaquiline/Strong CYP3A4 Inhibitors (mono deleted|
02339|002|T|07/09/2015)|
02339|003|B||
02339|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02339|005|L|of severe adverse interaction.|
02339|006|B||
02339|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02339|008|A|bedaquiline.(1)|
02339|009|B||
02339|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
02339|011|E|increased levels of and toxicity from bedaquiline, including QT prolongation|
02339|012|E|and liver toxicity.(1)|
02339|013|B||
02339|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02339|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02339|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02339|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02339|018|P|female gender, or advanced age.(2)|
02339|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02339|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02339|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02339|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02339|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02339|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02339|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02339|026|B||
02339|027|M|PATIENT MANAGEMENT:  The concurrent administration of strong CYP3A4|
02339|028|M|inhibitors and bedaquiline for more than 2 weeks should be avoided unless|
02339|029|M|the benefit of concurrent therapy outweighs the risks of concurrent|
02339|030|M|therapy.(1)|
02339|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02339|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02339|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02339|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02339|035|B||
02339|036|D|DISCUSSION:  In a study in healthy subjects, the concurrent administration|
02339|037|D|of bedaquiline (400 mg daily for 14 days) and ketoconazole (400 mg daily for|
02339|038|D|4 days), the area-under-curve (AUC), maximum concentration (Cmax), and|
02339|039|D|minimum concentration (Cmin) of bedaquiline increased by 22%, 9%, and 33%,|
02339|040|D|respectively.  A greater effect on the QTc interval was observed during|
02339|041|D|concurrent therapy than with either drug alone.(1)|
02339|042|B||
02339|043|R|REFERENCES:|
02339|044|B||
02339|045|R|1.Sirturo (bedaquiline) US prescribing information. Janssen Therapeutics|1
02339|046|R|  June, 2024.|1
02339|047|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02339|048|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02339|049|R|  settings: a scientific statement from the American Heart Association and|6
02339|050|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02339|051|R|  2;55(9):934-47.|6
02340|001|T|MONOGRAPH TITLE:  Bedaquiline/QT Prolonging Agents|
02340|002|B||
02340|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02340|004|L|take action as needed.|
02340|005|B||
02340|006|A|MECHANISM OF ACTION:  Concurrent use of bedaquiline with other agents that|
02340|007|A|prolong the QTc interval may result in additive effects on the QTc|
02340|008|A|interval.(1)|
02340|009|B||
02340|010|E|CLINICAL EFFECTS:  The use of bedaquiline patients maintained on agents that|
02340|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02340|012|E|arrhythmias, including torsades de pointes.(1)|
02340|013|B||
02340|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02340|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02340|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02340|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02340|018|P|female gender, or advanced age.(2)|
02340|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02340|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02340|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02340|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02340|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02340|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02340|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02340|026|B||
02340|027|M|PATIENT MANAGEMENT:  Bedaquiline should be used with caution in patients|
02340|028|M|receiving therapy with agents that prolong the QT interval.  Patients should|
02340|029|M|receive a baseline electrocardiogram (ECG) before initiation, 2 weeks after|
02340|030|M|initiation, during treatment as clinically indicated, and at the expected|
02340|031|M|time of maximum increase of the QT interval when receiving concurrent agents|
02340|032|M|that prolong the QT interval.|
02340|033|M|   Bedaquiline and other QT prolonging agents should be discontinued if the|
02340|034|M|patient develops a clinically significant ventricular arrhythmia or a QTcF|
02340|035|M|of greater than 500 msec confirmed by repeat ECGs.  If a patient develops|
02340|036|M|syncope, perform an ECG.(1)|
02340|037|M|   Also consider obtaining serum calcium, magnesium, and potassium levels at|
02340|038|M|baseline and regular intervals.  Correct any electrolyte abnormalities.|
02340|039|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02340|040|M|fainting.|
02340|041|B||
02340|042|D|DISCUSSION:  In a clinical trial, mean increases in QTc were greater in|
02340|043|D|patients treated with bedaquiline than with placebo.  At Week 1, bedaquiline|
02340|044|D|increased QTc by an average of 9.9 msec, compared with 2.5 msec for placebo.|
02340|045|D|At Week 24, bedaquiline increased QTc by an average of 15.7 msec, compared|
02340|046|D|with 6.2 msec for placebo.  In another clinical trial in which patients|
02340|047|D|received bedaquiline with other QT prolonging agents, QT prolongation was|
02340|048|D|additive and proportional to the number of QT prolonging drugs used.|
02340|049|D|Patients receiving bedaquiline alone averaged a QTc increase of 23.7 msec|
02340|050|D|over baseline, while patients receiving bedaquiline with at least one other|
02340|051|D|QT prolonging agent averaged a QTc increase of 30.7 msec.(1)|
02340|052|D|   In a study, bedaquiline was coadministered with QTc prolonging agents|
02340|053|D|clofazimine and levofloxacin.  In the study, 5% of patients had a QTc >= 500|
02340|054|D|ms and 43% of patients had an increase in QTc >= 60 ms from baseline.(1)|
02340|055|D|   Agents that are linked to this monograph may have varying degrees of|
02340|056|D|potential to prolong the QTc interval but are generally accepted to have a|
02340|057|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02340|058|D|been shown to prolong the QTc interval either through their mechanism of|
02340|059|D|action, through studies on their effects on the QTc interval, or through|
02340|060|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02340|061|D|and/or post-marketing reports.(3)|
02340|062|B||
02340|063|R|REFERENCES:|
02340|064|B||
02340|065|R|1.Sirturo (bedaquiline) US prescribing information. Janssen Therapeutics|1
02340|066|R|  June, 2024.|1
02340|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02340|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02340|069|R|  settings: a scientific statement from the American Heart Association and|6
02340|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02340|071|R|  2;55(9):934-47.|6
02340|072|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02340|073|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02340|074|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02340|075|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02341|001|T|MONOGRAPH TITLE:  Atazanavir/Selected QT Prolonging Agents (mono deleted|
02341|002|T|04/28/2016)|
02341|003|B||
02341|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02341|005|L|take action as needed.|
02341|006|B||
02341|007|A|MECHANISM OF ACTION:  Atazanavir may prolong the QT interval.  Concurrent|
02341|008|A|use with other agents that prolong the QT interval may result in additive|
02341|009|A|effects on the QT interval.|
02341|010|B||
02341|011|E|CLINICAL EFFECTS:  The concurrent use of atazanavir with other agents that|
02341|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02341|013|E|arrhythmias, including torsades de pointes.|
02341|014|B||
02341|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02341|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02341|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02341|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02341|019|P|female gender, or advanced age.(1)|
02341|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02341|021|P|higher systemic concentrations or either QT prolonging drug are additional|
02341|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02341|023|P|drug concentrations include rapid infusion or an intravenous dose or|
02341|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02341|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02341|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02341|027|B||
02341|028|M|PATIENT MANAGEMENT:  General monitoring if concurrent therapy is warranted:|
02341|029|M|consider obtaining serum calcium, magnesium, and potassium levels and|
02341|030|M|monitoring ECG at baseline and at regular intervals.  Correct any|
02341|031|M|electrolyte abnormalities.|
02341|032|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02341|033|M|fainting.|
02341|034|M|   Management recommendations for specific agents:|
02341|035|M|   The concurrent administration of asenapine with other drugs that are|
02341|036|M|known to prolong the QTc interval should be avoided.(2)|
02341|037|M|   Ciprofloxacin should be used with caution with other agents known to|
02341|038|M|prolong the QT interval, especially in the elderly,(3) and in patients at|
02341|039|M|risk for torsades.(4)|
02341|040|M|   Concurrent use of citalopram with agents known to prolong the QT interval|
02341|041|M|is not recommended.  Consider more frequent ECG monitoring in patients|
02341|042|M|receiving concurrent therapy.  Citalopram should be discontinued in patients|
02341|043|M|with persistent QTc measurements greater than 500 ms.(5)|
02341|044|M|   Approach the concurrent use of clozapine and other agents that are known|
02341|045|M|to prolong the QTc interval with caution.(6)|
02341|046|M|   Consider periodic electrocardiogram (ECG) and electrolyte monitoring in|
02341|047|M|patients receiving concurrent therapy with crizotinib and another agent that|
02341|048|M|prolongs the QTc interval.  In patients who develop Grade 3 QTc|
02341|049|M|prolongation, withhold crizotinib until recovery to less than or equal to|
02341|050|M|Grade 1, then resume crizotinib at a dosage of 200 mg twice daily.  If the|
02341|051|M|patient re-develops Grade 3 QTc prolongation, withhold crizotinib until|
02341|052|M|recovery to less than or equal to Grade 1, then resume crizotinib at a|
02341|053|M|dosage of 250 mg daily.  If the patient re-develops Grade 3 prolongation|
02341|054|M|again, permanently discontinue crizotinib.  In patients who develop Grade 4|
02341|055|M|QTc prolongation, permanently discontinue crizotinib.(7)|
02341|056|M|   Approach the concurrent use of domperidone and other agents that are|
02341|057|M|known to prolong the QTc interval with caution.(8)|
02341|058|M|   Patients receiving concurrent therapy with eribulin and other agents|
02341|059|M|known to prolong the QT interval should receive ECG monitoring.(9)|
02341|060|M|   The concurrent use of ezogabine with agents known to prolong the QT|
02341|061|M|interval should be approached with caution.  Patients receiving concurrent|
02341|062|M|therapy with other QT prolongers, an electrocardiogram (ECG) should be|
02341|063|M|performed prior to ezogabine initiation.  In those patients with a corrected|
02341|064|M|QT interval greater than 440 msec at baseline, a repeat ECG should be|
02341|065|M|performed after reaching the maintenance dose of ezogabine.(10)|
02341|066|M|   Concurrent use of formoterol with other agents known to prolong the QT|
02341|067|M|interval should be approached with extreme caution.(11,12)|
02341|068|M|   In patients maintained on agents known to prolong the QT interval,|
02341|069|M|consider a baseline ECG prior to administration of gadofosveset to asses the|
02341|070|M|risk/benefit of gadofosveset.  If gadofosveset is used, consider ECG|
02341|071|M|monitoring for 72 hours until the majority of gadofosveset is eliminated.|
02341|072|M|Counsel patients to report any irregular heartbeat, dizziness, or fainting|
02341|073|M|episodes during this time frame.(13)|
02341|074|M|   Gadoxetate should be used with caution in patients receiving other agents|
02341|075|M|agents known to prolong the QT interval.(14,15)  Gadoxetate's affects on the|
02341|076|M|QTc interval may last at least 28 hours after injection.(14)|
02341|077|M|   Concurrent use of ivabradine with cardiovascular and non-cardiovascular|
02341|078|M|QT prolonging agents should be avoided.  If the combination is required,|
02341|079|M|close cardiac monitoring is needed.(16)|
02341|080|M|   The use of mesoridazine should be avoided in combination with other drugs|
02341|081|M|that are known to prolong the QTc interval.(17)|
02341|082|M|   Approach the concurrent use of ondansetron and other agents that are|
02341|083|M|known to prolong the QTc interval with caution.  Electrocardiogram (ECG)|
02341|084|M|monitoring should be performed in patients receiving concurrent|
02341|085|M|therapy.(18-20)|
02341|086|M|   The use of paliperidone should be avoided with other drugs that are known|
02341|087|M|to prolong the QTc interval, including Class IA and Class III|
02341|088|M|antiarrhythmics, antipsychotics, antibiotics such as gatifloxacin and|
02341|089|M|moxifloxacin, or any other class of medications known to prolong the QTc|
02341|090|M|interval.(21,22)|
02341|091|M|   Pasireotide should be used with caution in patients receiving therapy|
02341|092|M|with agents that prolong the QT interval.  Patients should receive a|
02341|093|M|baseline electrocardiogram (ECG) and hypokalemia and hypomagnesemia should|
02341|094|M|be corrected before therapy is initiated.  Monitor ECG and potassium and|
02341|095|M|magnesium levels during therapy.(23)|
02341|096|M|   Concurrent use of quinine with agents known to prolong the QT interval|
02341|097|M|should be avoided.(24)|
02341|098|M|   The concurrent use of rilpivirine with agents known to prolong the QT|
02341|099|M|interval should be approached with caution.(25)|
02341|100|M|   Concurrent use of saquinavir with agents known to prolong the QT interval|
02341|101|M|should only be used when there is no alternative therapy and potential|
02341|102|M|benefits outweigh the risks.  Perform an ECG prior to concurrent therapy.|
02341|103|M|Patients with a QT interval greater than 450 msec should not initiate|
02341|104|M|concurrent therapy.  For patients with a baseline QT interval less than 450|
02341|105|M|msec, a repeat ECG should be performed after 3-4 days of concurrent therapy.|
02341|106|M|In patients who experience an increase in QT interval to greater than 480|
02341|107|M|msec or by greater than 20 msec, consideration should be given to|
02341|108|M|discontinuing one or both agents.(26)|
02341|109|M|   Patients receiving concurrent therapy with agents known to prolong the|
02341|110|M|QTc interval should be monitored with electrocardiograms during treatment|
02341|111|M|with sorafenib. Electrolytes (calcium, magnesium, and potassium) should also|
02341|112|M|be monitored.(27)|
02341|113|M|   The use of telavancin with other drugs known to cause QT prolongation is|
02341|114|M|not recommended.(28)|
02341|115|M|   The concurrent administration of tetrabenazine with other drugs that are|
02341|116|M|known to prolong the QTc interval should be avoided.(29)|
02341|117|M|   The use of vandetanib with other agents known to prolong the QT interval|
02341|118|M|should be avoided.  If another drug known to prolong the QT interval must be|
02341|119|M|coadministered with vandetanib, more frequent ECG monitoring is|
02341|120|M|recommended.(30)|
02341|121|M|   The concurrent use of vemurafenib with agents known to prolong the QT|
02341|122|M|interval is not recommended.  Initiation of vemurafenib in patients with a|
02341|123|M|baseline QTc greater than 500 msec is not recommended.  All patients|
02341|124|M|receiving vemurafenib should undergo ECG testing at baseline, after 15 days|
02341|125|M|of treatment, monthly during the first 3 months of treatment, and then every|
02341|126|M|3 months.  If a patient's QTc exceeds 500 msec during treatment, vemurafenib|
02341|127|M|should be discontinued and cardiac risk factors for QT prolongation should|
02341|128|M|be controlled.  Consider discontinuing other medications known to prolong|
02341|129|M|the QT interval at this time.  If the patient's QTc decreases below 500|
02341|130|M|msec, vemurafenib may be introduced at a lower dosage according to the|
02341|131|M|current labeling recommendations.(31)|
02341|132|M|   The concurrent administration of vinflunine with other drugs that are|
02341|133|M|known to prolong the QTc interval should be avoided.(32)|
02341|134|M|   The concurrent administration of zuclopenthixol with other drugs that are|
02341|135|M|known to prolong the QTc interval should be avoided.(33)|
02341|136|B||
02341|137|D|DISCUSSION:  Citalopram has been associated with dose-depended increases in|
02341|138|D|the QTc interval.  In healthy subjects, the maximum mean difference in QTc|
02341|139|D|interval seen with 20 mg of citalopram and 60 mg of citalopram were 8.5 msec|
02341|140|D|and 18.5 msec, respectively.  Based on extrapolation, a 40 mg dose of|
02341|141|D|citalopram is expected to produce a mean increase in the QTc interval of|
02341|142|D|12.6 msec.(4)|
02341|143|D|   Treatment with clozapine has been associated with QT prolongation as well|
02341|144|D|as ventricular arrhythmia, Torsades de Pointes, cardiac arrest, and sudden|
02341|145|D|death.(5)|
02341|146|D|   Crizotinib is associated with concentration-dependent QTc interval|
02341|147|D|prolongation.  In a clinical trial 1.3% of patients were found to have a|
02341|148|D|QTcF greater than or equal to 500 msec and 3.5% of patients had an increase|
02341|149|D|in QTcF by greater than or equal to 60 msec.(6)|
02341|150|D|   Treatment with domperidone has been associated with increased risk of|
02341|151|D|sudden cardiac death.(7)|
02341|152|D|   QT prolongation, independent of eribulin concentration, was observed on|
02341|153|D|Day 8 of therapy but not on Day 1 in  an uncontrolled open-label ECG study|
02341|154|D|in 26 patients.(8)|
02341|155|D|   In a study in healthy subjects, ezogabine titrated to 1200 mg/day|
02341|156|D|increased the mean QTc interval by 6.7 msec (upper bound of 95% CI was 12.6|
02341|157|D|msec) within three hours of dosing.(9)|
02341|158|D|   In clinical trials, 6% of patients experienced an increase in QTc of 30|
02341|159|D|msec to 60 msec 45 minutes after the administration of gadofosveset and 0.4%|
02341|160|D|of patients experienced a QTc increase of greater than 60 msec at 45 minutes|
02341|161|D|post-administration.(12)0|
02341|162|D|   In vitro and clinical studies suggest that gadoxetate can lead to|
02341|163|D|prolongation of the QTc interval, especially at doses higher than|
02341|164|D|recommended.  Transient QT prolongation with no adverse effects was observed|
02341|165|D|in clinical studies.  In 2 Phase III studies, 2 of 468 patients had an|
02341|166|D|increase in QTc greater than 60 ms from baseline to time-points up to 20-28|
02341|167|D|hours after injection.(13)|
02341|168|D|   In a double-blind, randomized, placebo and positive controlled cross-over|
02341|169|D|study, an ondansetron dose of 32 mg increased the maximum mean QTcF by 19.6|
02341|170|D|msec (upper limit of 90% CI:  21.5).  A dose of 8mg increased the QTcF by a|
02341|171|D|maximum mean of 5.8 (upper limit of 90% CI:  7.8).  A dose of 16 mg was|
02341|172|D|predicted to have a mean increase in QTcF of 9.1 msec (upper limit of 90%|
02341|173|D|CI:  11.2).(17)|
02341|174|D|   In randomized, blinded, crossover study in healthy subjects, pasireotide|
02341|175|D|(0.6 mg BID) increased the placebo-subtracted QTcI by 12.7 msec (95 upper|
02341|176|D|CI:  14.7 msec).  Supra-therapeutic doses of 1.95 mg BID increased the|
02341|177|D|placebo-subtracted QTcI by 16.6 msec (95 upper CI:  18.6 msec).(23)|
02341|178|D|   In a clinical trial in healthy adults, rilpivirine at recommended dosages|
02341|179|D|(25 mg daily) had no significant effects on the QTc interval.  However,|
02341|180|D|supratherapeutic dosages (75 mg daily and 300 mg daily) increased the QTc|
02341|181|D|interval by 10.7 msec and 23.3 msec, respectively.  Rilpivirine dosages of|
02341|182|D|75 mg daily and 300 mg daily resulted in rilpivirine maximum concentration|
02341|183|D|(Cmax) levels of 2.6-fold and 6.7-respectively.  Increases of rilpivirine|
02341|184|D|AUC of 2.3-fold were noted in combination with darunavir/ritonavir(1) and|
02341|185|D|may be seen with other commonly co-administered HIV therapies.(24)|
02341|186|D|   Ritonavir-boosted saquinavir increases the QT interval in a dose|
02341|187|D|dependent manner.(26)|
02341|188|D|   In a randomized, double-blind, multiple-dose, positive-controlled,|
02341|189|D|placebo-controlled, parallel study in healthy subjects, the mean maximum|
02341|190|D|baseline-corrected, placebo-corrected QTc prolongation was 11.6 msec and|
02341|191|D|15.1 msec for telavancin at dosages of 7.5 mg/kg and 15 mg/kg, respectively.|
02341|192|D|The estimated  mean maximum baseline-corrected, placebo-corrected QTc|
02341|193|D|prolongation for a telavancin dosage of 10 mg/kg is 12-15 msec.  In studies|
02341|194|D|in patients, 21% of patients receiving telavancin (214 of 1029, 10 mg/kg)|
02341|195|D|and 16% of patients receiving vancomycin (164 of 1033) received concurrent|
02341|196|D|QT prolonging agents.  The rate of QTc prolongation greater than 60 msec was|
02341|197|D|1.5% (15 patients) in the telavancin group and 0.6% (6 patients) in the|
02341|198|D|vancomycin group.  Nine of the 15 telavancin subjects with QTc prolongation|
02341|199|D|received concurrent QT prolongers, compared with 1 of the vancomycin|
02341|200|D|patients.(28)|
02341|201|D|   In a non-randomized trial in 53 patients, sorafenib resulted in a mean|
02341|202|D|change in QTc of 8.5 msec (upper bound of 90% CI:  13.3 msec).(27)|
02341|203|D|   Vandetanib has been shown to prolong the QTc interval in a dose-dependent|
02341|204|D|manner.  Vandetanib has a long half-life (19 days) and effects on the QTc|
02341|205|D|interval may not resolve quickly following vandetanib discontinuation.(30)|
02341|206|D|   Vemurafenib is associated with concentration-dependent QTc interval|
02341|207|D|prolongation.  In the first month of treatment, the largest mean QTc change|
02341|208|D|was 12.8 msec (upper boundary of 90% CI:  14.9 msec).  In the first 6 months|
02341|209|D|of treatment, the largest mean QTc change was 15.1 msec (upper boundary of|
02341|210|D|90% CI:  17.7 msec).(31)|
02341|211|B||
02341|212|R|REFERENCES:|
02341|213|B||
02341|214|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02341|215|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02341|216|R|  settings: a scientific statement from the American Heart Association and|6
02341|217|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02341|218|R|  2;55(9):934-47.|6
02341|219|R|2.Saphris (asenapine) US prescribing information. Actavis, Inc. February 23,|1
02341|220|R|  2017.|1
02341|221|R|3.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
02341|222|R|  Corporation August, 2013.|1
02341|223|R|4.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
02341|224|R|  Laboratories Inc. December, 2012.|1
02341|225|R|5.Clozaril (clozapine tablets) US prescribing information. Novartis|1
02341|226|R|  Pharmaceuticals Corporation April, 2020.|1
02341|227|R|6.Ciproxin (ciprofloxacin hydrochloride) UK summary of product|1
02341|228|R|  characteristics. Bayer plc April 13, 2010.|1
02341|229|R|7.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
02341|230|R|  2023.|1
02341|231|R|8.Mathivanan M. Dear Canadian Healthcare Professional:  Subject:|1
02341|232|R|  Association of domperidone maleate with serious ventricular arrhythmias|1
02341|233|R|  and sudden cardiac death. Teva Canada Limited March 2, 2012.|1
02341|234|R|9.Halaven (eribulin mesylate) US prescribing information. Eisai, Inc.|1
02341|235|R|  January, 2016.|1
02341|236|R|10.Potiga (ezogabine) US Prescribing Information. Valeant Pharmaceuticals|1
02341|237|R|   May, 2016.|1
02341|238|R|11.Foradil Aerolizer (formoterol fumarate) US prescribing information.|1
02341|239|R|   Schering Corporation September, 2012.|1
02341|240|R|12.Symbicort Turbuhaler (budesonide-eformoterol fumarate dihydrate)|1
02341|241|R|   Australian prescribing information. AstraZeneca Pty Ltd April 30, 2004.|1
02341|242|R|13.Ablavar (gadofosveset trisodium) US prescribing information. Lantheus|1
02341|243|R|   Medical Imaging, Inc. August, 2013.|1
02341|244|R|14.Primovist (gadoxetate disodium) Australian prescribing information.|1
02341|245|R|   Schering-Plough Corporation November 1, 2005.|1
02341|246|R|15.Primovist (gadoxetic acid) UK summary of product characteristics. Bayer|1
02341|247|R|   plc May 1, 2008.|1
02341|248|R|16.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
02341|249|R|   Les Laboratoires Servier March, 2015.|1
02341|250|R|17.Serentil (mesoridazine besylate) US prescribing information. Novartis|1
02341|251|R|   Pharmaceuticals Corporation August, 2000.|1
02341|252|R|18.Kon P. Dear UK Healthcare Professional:   Direct Healthcare Professional|1
02341|253|R|   Communication on ondansetron (Zofran and generics) and dose-dependent QT|1
02341|254|R|   interval prolongation - new dose restriction for intravenous (IV) use.|1
02341|255|R|   GlaxoSmithKline UK Ltd August 5, 2012.|1
02341|256|R|19.Zofran (ondansetron) US prescribing information. GlaxoSmithKline October,|1
02341|257|R|   2021.|1
02341|258|R|20.USFood and Drug Administration. FDA Drug Safety Communication: Abnormal|1
02341|259|R|   heart rhythms may be associated with use of Zofran (ondansetron).|1
02341|260|R|   available at:|1
02341|261|R|   https://wayback.archive-it.org/7993/20170722185907/https:/www.fda.gov/Dru|1
02341|262|R|   gs/DrugSafety/ucm271913.htm September 15, 2011.|1
02341|263|R|21.Invega (paliperidone) US prescribing information. Janssen|1
02341|264|R|   Pharmaceuticals, Inc. April, 2014.|1
02341|265|R|22.Invega Sustenna (paliperidone palmitate) US prescribing information.|1
02341|266|R|   Janssen Pharmaceuticals, Inc. August, 2012.|1
02341|267|R|23.Signifor (pasireotide diasparate) US prescribing information. Novartis|1
02341|268|R|   Pharmaceuticals Corporation January, 2020.|1
02341|269|R|24.Qualaquin (quinine sulfate) US prescribing information. Sun|1
02341|270|R|   Pharmaceutical Industries, Inc. August, 2019.|1
02341|271|R|25.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
02341|272|R|   January, 2021.|1
02341|273|R|26.Invirase (saquinavir mesylate) US prescribing information. Roche|1
02341|274|R|   Laboratories, Inc. March, 2019.|1
02341|275|R|27.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
02341|276|R|   Corporation July, 2020.|1
02341|277|R|28.Vibativ (telavancin) US prescribing information. Theravance Biopharma US,|1
02341|278|R|   Inc. February, 2020.|1
02341|279|R|29.Xenazine (tetrabenazine) US prescribing information. Valeant|1
02341|280|R|   International September, 2017.|1
02341|281|R|30.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
02341|282|R|   Pharmaceuticals LP October, 2018.|1
02341|283|R|31.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02341|284|R|   August, 2015.|1
02341|285|R|32.Javlor (vinflunine ditartrate) UK Summary of Product Characteristics.|1
02341|286|R|   Pierre Fabre Limited September 21, 2009.|1
02341|287|R|33.Clopixol (zuclopenthixol acetate) UK summary of product characteristics.|1
02341|288|R|   Lundbeck Limited October 15, 2020.|1
02342|001|T|MONOGRAPH TITLE:  Azithro; Clarithro; Erythromycin/Slt QT Prolonging Agents|
02342|002|T|(mono deleted 11/05/2015)|
02342|003|B||
02342|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02342|005|L|is contraindicated and generally should not be dispensed or administered to|
02342|006|L|the same patient.|
02342|007|B||
02342|008|A|MECHANISM OF ACTION:  Concurrent use of multiple agents that prolong the QTc|
02342|009|A|interval may result in additive effects on the QTc interval.(1)|
02342|010|B||
02342|011|E|CLINICAL EFFECTS:  The concurrent use of multiple agents that prolong the|
02342|012|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
02342|013|E|including torsades de pointes.(1)|
02342|014|B||
02342|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02342|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02342|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02342|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02342|019|P|gender, or advanced age.(1)|
02342|020|P|    Concurrent use of more than one drug known to cause QT prolongation or|
02342|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02342|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02342|023|P|drug concentrations include: rapid infusion of an intravenous dose or|
02342|024|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
02342|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02342|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02342|027|B||
02342|028|M|PATIENT MANAGEMENT:  The concurrent use of amifampridine with drugs that may|
02342|029|M|prolong the QT interval is contraindicated.(2)|
02342|030|M|   The Australian(3) and UK(4) manufacturers of amiodarone state that|
02342|031|M|concurrent use of agents known to cause torsades de pointes is|
02342|032|M|contraindicated.  The US manufacturer of amiodarone states that the need to|
02342|033|M|co-administer amiodarone with any other drug known to prolong the QTc|
02342|034|M|interval must be based on a careful assessment of the potential risks and|
02342|035|M|benefits of doing so for each patient.(5)|
02342|036|M|   The US manufacturer of anagrelide states that anagrelide should not be|
02342|037|M|used in patients taking medications known to prolong the QT interval.(6)|
02342|038|M|   Bepridil is contraindicated in patients taking other drugs that prolong|
02342|039|M|the QT interval.(7)|
02342|040|M|   The Australian manufacturer of disopyramide states that concurrent use|
02342|041|M|with agents liable to produce torsades de pointes, including tricyclic or|
02342|042|M|tetracyclic antidepressants, erythromycin, vincamine, and sultopride, is|
02342|043|M|contraindicated.(8)|
02342|044|M|   Drugs known to have the potential to prolong the QT interval should not|
02342|045|M|be used together with droperidol.(9)|
02342|046|M|   The manufacturer of halofantrine states in a black box warning that|
02342|047|M|halofantrine is not recommended for use in combination with drugs known to|
02342|048|M|prolong the QTc interval.  Under precautions, drug interactions, the|
02342|049|M|manufacturer states that halofantrine should not be administered with drugs|
02342|050|M|known to prolong the QTc interval.(10)|
02342|051|M|   Levomethadyl is contraindicated in patients being treated concomitantly|
02342|052|M|with other drug products known to prolong the QT interval.(11)|
02342|053|M|   Sertindole is contraindicated in patients receiving drugs known to|
02342|054|M|prolong the QT interval.(12)|
02342|055|M|   Sparfloxacin is contraindicated in patients being treated concomitantly|
02342|056|M|with medications known to produce an increase in the QTc interval and/or|
02342|057|M|torsade de pointes.(13)|
02342|058|M|    The manufacturer of azithromycin recommends providers consider the risks|
02342|059|M|and benefits of azithromycin use in patients with predisposing factors for|
02342|060|M|QT prolongation, including patients receiving Class IA or Class III|
02342|061|M|antiarrhythmic agents.(14)|
02342|062|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02342|063|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02342|064|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02342|065|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02342|066|B||
02342|067|D|DISCUSSION:  QTc prolongation has been reported during concurrent amiodarone|
02342|068|D|and azole antifungals, fluoroquinolones, and macrolide antibiotics.(4)|
02342|069|D|    The manufacturer of azithromycin performed a QT prolongation|
02342|070|D|study in 116 healthy subjects who received either chloroquine 1000 mg alone|
02342|071|D|or combined with azithromycin (500 mg, 1000 mg or 1500 mg once daily).  In|
02342|072|D|comparison with chloroquine alone, co-administration with azithromycin led|
02342|073|D|to mean increases(95% upper confidence bound) in QTcF of 5(10) ms, 7(12) ms,|
02342|074|D|and 9(14) ms for the 500 mg, 1000 mg and 1500 mg respectively.(14)  FDA|
02342|075|D|considers a 10 ms increase in the 95% upper confidence bound as the|
02342|076|D|threshold for regulatory concern.|
02342|077|D|   Agents that are linked to this monograph may have varying degrees of|
02342|078|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02342|079|D|been shown to prolong the QTc interval either through their mechanism of|
02342|080|D|action, through studies on their effects on the QTc interval, or through|
02342|081|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02342|082|D|and/or postmarketing reports.(15)|
02342|083|D|   One or more of the drug pairs linked to this monograph have been included|
02342|084|D|in a list of interactions that should be considered "high-priority" for|
02342|085|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02342|086|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02342|087|D|Coordinator (ONC) for Health Information Technology.|
02342|088|B||
02342|089|R|REFERENCES:|
02342|090|B||
02342|091|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02342|092|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02342|093|R|  settings: a scientific statement from the American Heart Association and|6
02342|094|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02342|095|R|  2;55(9):934-47.|6
02342|096|R|2.Firdapse (amifampridine phosphate) UK summary of product characteristics.|1
02342|097|R|  BioMarin Europe Limited February, 2010.|1
02342|098|R|3.Cordarone X (amiodarone hydrochloride) Australian prescribing information.|1
02342|099|R|  Sanofi-Synthelabo Australia Pty Limited Augsut 15, 2007.|1
02342|100|R|4.Cordarone X (amiodarone hydrochloride) UK summary of product|1
02342|101|R|  characteristics. Sanofi-Aventis July 6, 2010.|1
02342|102|R|5.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
02342|103|R|  Pharmaceuticals April, 2016.|1
02342|104|R|6.Agrylin (anagrelide hydrochloride) US prescribing information. Shire US|1
02342|105|R|  Inc. October, 2021.|1
02342|106|R|7.Vascor (bepridil hydrochloride) US prescribing information. Ortho-McNeil|1
02342|107|R|  Pharmaceutical, Inc. March, 2000.|1
02342|108|R|8.Rythmodan (disopyramide) Australian prescribing information. Aventis|1
02342|109|R|  Pharma Pty Ltd. September 22, 2000.|1
02342|110|R|9.Inapsine (droperidol) US prescribing information. Akorn, Inc. November,|1
02342|111|R|  2001.|1
02342|112|R|10.Halfan (halofantrine hydrochloride) US prescribing information.|1
02342|113|R|   SmithKline Beecham Pharmaceuticals October, 2001.|1
02342|114|R|11.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
02342|115|R|   Roxane Laboratories, Inc. May, 2001.|1
02342|116|R|12.Serdolect (sertindole) UK summary of product characteristics. Lundbeck|1
02342|117|R|   Limited October 25, 1996.|1
02342|118|R|13.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
02342|119|R|   Inc. February, 2003.|1
02342|120|R|14.Zithromax (azithromycin oral) US prescribing information. Pifzer Labs|1
02342|121|R|   April, 2019.|1
02342|122|R|15.USDepartment of Health and Human Services Food and Drug Administration.|1
02342|123|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02342|124|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02342|125|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02342|126|R|16.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02342|127|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02342|128|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02342|129|R|   19(5):735-43.|6
02343|001|T|MONOGRAPH TITLE:  Fosphenytoin/Selected QT Prolonging Agents (mono deleted|
02343|002|T|03/19/2015)|
02343|003|B||
02343|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02343|005|L|of severe adverse interaction.|
02343|006|B||
02343|007|A|MECHANISM OF ACTION:  Concurrent use of fosphenytoin with agents that|
02343|008|A|prolong the QTc interval may result in additive effects on the QTc|
02343|009|A|interval.(1-12)|
02343|010|B||
02343|011|E|CLINICAL EFFECTS:  The concurrent use of fosphenytoin with agents that|
02343|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02343|013|E|arrhythmias, including torsades de pointes.(1-12)|
02343|014|B||
02343|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02343|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02343|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02343|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02343|019|P|female gender, or advanced age.(13)|
02343|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02343|021|P|higher systemic concentrations or either QT prolonging drug are additional|
02343|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02343|023|P|drug concentrations include rapid infusion or an intravenous dose or|
02343|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02343|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02343|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(13)|
02343|027|B||
02343|028|M|PATIENT MANAGEMENT:  The concurrent use of amifampridine with drugs that may|
02343|029|M|prolong the QT interval is contraindicated.(1)|
02343|030|M|   The US manufacturer of anagrelide states that anagrelide should not be|
02343|031|M|used in patients taking medications known to prolong the QT interval.(2)|
02343|032|M|   Bepridil is contraindicated in patients taking other drugs that prolong|
02343|033|M|the QT interval.(3)|
02343|034|M|   The concurrent use of agents known to prolong the QTc interval with|
02343|035|M|cisapride is contraindicated.(4)|
02343|036|M|   Drugs known to have the potential to prolong the QT interval should not|
02343|037|M|be used together with droperidol.(5)|
02343|038|M|   Halofantrine should not be administered with drugs known to prolong the|
02343|039|M|QTc interval.(6)|
02343|040|M|   Levomethadyl is contraindicated in patients being treated concomitantly|
02343|041|M|with other drug products known to prolong the QT interval.(7)|
02343|042|M|   The use of pimozide is contraindicated in patients taking other drugs|
02343|043|M|which prolong the QT interval.(8)|
02343|044|M|   Sertindole is contraindicated in patients receiving drugs known to|
02343|045|M|prolong the QT interval.(9)|
02343|046|M|   Sparfloxacin is contraindicated in patients being treated concomitantly|
02343|047|M|with medications known to produce an increase in the QTc interval and/or|
02343|048|M|torsades de pointes.(10)|
02343|049|M|   The use of thioridazine should be avoided in combination with other drugs|
02343|050|M|that are known to prolong the QTc interval.(11)|
02343|051|M|   Ziprasidone should not be used with other drugs that prolong the QT|
02343|052|M|interval such as dofetilide, sotalol, quinidine, other Class Ia and III|
02343|053|M|anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol,|
02343|054|M|pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine,|
02343|055|M|mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron|
02343|056|M|mesylate, probucol or tacrolimus.(12)  It would be prudent to avoid the use|
02343|057|M|of ziprasidone with medicines suspected of prolonging the QT interval.|
02343|058|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02343|059|M|magnesium, and potassium levels at baseline and at regular intervals.|
02343|060|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
02343|061|M|irregular heartbeat, dizziness, or fainting.|
02343|062|B||
02343|063|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02343|064|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02343|065|D|monograph have been shown to prolong the QTc interval either through their|
02343|066|D|mechanism of action, through studies on their effects on the QTc interval,|
02343|067|D|or through reports of QTc prolongation and/or torsades de pointes in|
02343|068|D|clinical trials and/or postmarketing reports.(14)|
02343|069|B||
02343|070|R|REFERENCES:|
02343|071|B||
02343|072|R|1.Firdapse (amifampridine phosphate) UK summary of product characteristics.|1
02343|073|R|  BioMarin Europe Limited February, 2010.|1
02343|074|R|2.Agrylin (anagrelide hydrochloride) US prescribing information. Shire US|1
02343|075|R|  Inc. February, 2014.|1
02343|076|R|3.Vascor (bepridil hydrochloride) US prescribing information. Ortho-McNeil|1
02343|077|R|  Pharmaceutical, Inc. March, 2000.|1
02343|078|R|4.Prepulsid (cisapride) Australian prescribing information. Janssen-Cilag|1
02343|079|R|  Pty Limited January 25, 2003.|1
02343|080|R|5.Inapsine (droperidol) US prescribing information. Akorn, Inc. November,|1
02343|081|R|  2001.|1
02343|082|R|6.Halfan (halofantrine hydrochloride) US prescribing information. SmithKline|1
02343|083|R|  Beecham Pharmaceuticals October, 2001.|1
02343|084|R|7.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
02343|085|R|  2011.|1
02343|086|R|8.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
02343|087|R|  Roxane Laboratories, Inc. May, 2001.|1
02343|088|R|9.Serdolect (sertindole) UK summary of product characteristics. Lundbeck|1
02343|089|R|  Limited October 25, 1996.|1
02343|090|R|10.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
02343|091|R|   Inc. February, 2003.|1
02343|092|R|11.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
02343|093|R|   September, 2014.|1
02343|094|R|12.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer|1
02343|095|R|   Inc. December, 2010.|1
02343|096|R|13.USDepartment of Health and Human Services Food and Drug Administration.|1
02343|097|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02343|098|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02343|099|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02343|100|R|14.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
02343|101|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
02343|102|R|   hospital settings: a scientific statement from the American Heart|6
02343|103|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
02343|104|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
02344|001|T|MONOGRAPH TITLE:  Lomitapide/Bile Acid Sequestrants; Sevelamer|
02344|002|B||
02344|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02344|004|L|take action as needed.|
02344|005|B||
02344|006|A|MECHANISM OF ACTION:  Bile acid sequestrants and sevelamer may decrease the|
02344|007|A|gastrointestinal absorption of lomitapide.|
02344|008|B||
02344|009|E|CLINICAL EFFECTS:  Simultaneous administration of a bile acid sequestrant or|
02344|010|E|sevelamer may result in decreased absorption and effectiveness of|
02344|011|E|lomitapide.(1)|
02344|012|B||
02344|013|P|PREDISPOSING FACTORS:  None determined.|
02344|014|B||
02344|015|M|PATIENT MANAGEMENT:  For maximal bioavailability, the manufacturer of|
02344|016|M|lomitapide states lomitapide and bile acid sequestrant administration should|
02344|017|M|be separated by at least 4 hours.(1)|
02344|018|M|    Although used for hyperphosphatemia, sevelamer is linked to this|
02344|019|M|monograph due to its structural and pharmacologic similarities to|
02344|020|M|colesevelam. Both agents are non-absorbed cross linked polymers with a high|
02344|021|M|affinity for bile acids.(2)|
02344|022|B||
02344|023|D|DISCUSSION:  Lomitapide maximal systemic concentrations occur approximately|
02344|024|D|6 hours after administration.  Although an interaction study has not been|
02344|025|D|performed, the manufacturer of lomitapide recommends separating bile acid|
02344|026|D|sequestrant administration for a minimum of 4 hours before or after|
02344|027|D|lomitapide dose.(1)|
02344|028|B||
02344|029|R|REFERENCES:|
02344|030|B||
02344|031|R|1.Juxtapid (lomitapide) US prescribing information. Aegerion|1
02344|032|R|  Pharmaceuticals, Inc. May, 2016.|1
02344|033|R|2.Renagel (sevelamer hydrochloride) US prescribing information. Genzyme|1
02344|034|R|  Corporation March 9, 2016.|1
02346|001|T|MONOGRAPH TITLE:  Olmesartan/Colesevelam|
02346|002|B||
02346|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02346|004|L|take action as needed.|
02346|005|B||
02346|006|A|MECHANISM OF ACTION:  Colesevelam may decrease the gastrointestinal|
02346|007|A|absorption of olmesartan by binding to olmesartan in the intestines.(1,2)|
02346|008|B||
02346|009|E|CLINICAL EFFECTS:  Coadministration of colesevelam may result in decreased|
02346|010|E|absorption and effectiveness of olmesartan.(1,2)|
02346|011|B||
02346|012|P|PREDISPOSING FACTORS:  None determined.|
02346|013|B||
02346|014|M|PATIENT MANAGEMENT:  For maximal bioavailability, olmesartan should be taken|
02346|015|M|at least 4 hours prior to colesevelam.(1,2)|
02346|016|B||
02346|017|D|DISCUSSION:  A clinical study described by the manufacturer of olmesartan|
02346|018|D|demonstrated a 39% and 28% mean reduction of olmesartan area-under-curve|
02346|019|D|(AUC) and maximum concentration (Cmax), respectively, when olmesartan and|
02346|020|D|colesevelam were coadministered.  Additionally, the study demonstrated a|
02346|021|D|-15% and -4% mean reduction of olmesartan AUC and Cmax, respectively, when|
02346|022|D|olmesartan was administered 4 hours before colesevelam was|
02346|023|D|administered.(1,2)|
02346|024|B||
02346|025|R|REFERENCES:|
02346|026|B||
02346|027|R|1.Benicar (olmesartan medoxomil) US prescribing information. Daiichi Sankyo,|1
02346|028|R|  Inc. October, 2019.|1
02346|029|R|2.Welchol (colesevelam hydrochloride) US prescribing information. Daiichi|1
02346|030|R|  Sankyo, Inc. October, 2021.|1
02347|001|T|MONOGRAPH TITLE:  Escitalopram (Greater Than 15 mg)/Selected CYP2C19|
02347|002|T|Inhibitors|
02347|003|B||
02347|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02347|005|L|take action as needed.|
02347|006|B||
02347|007|A|MECHANISM OF ACTION:  At lower systemic concentrations, escitalopram is|
02347|008|A|primarily metabolized by CYP2C19; at higher concentrations is also|
02347|009|A|metabolized by CYP3A4.(1)|
02347|010|B||
02347|011|E|CLINICAL EFFECTS:  Concurrent use of an agent which significantly inhibits|
02347|012|E|CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated|
02347|013|E|concentrations and toxicity from escitalopram, including risks for serotonin|
02347|014|E|syndrome or prolongation of the QTc interval.(1,5)  Prolongation of the QT|
02347|015|E|interval may result in life-threatening arrhythmias, including torsades de|
02347|016|E|pointes.(2)  Symptoms of serotonin syndrome may include tremor, agitation,|
02347|017|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02347|018|E|rigidity.(3)|
02347|019|B||
02347|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased in|
02347|021|P|patients with congenital long QT syndrome, cardiovascular disease (e.g.|
02347|022|P|heart failure, myocardial infarction), hypokalemia, hypomagnesemia,|
02347|023|P|hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status|
02347|024|P|at CYP2C19, concurrent use of more than one agent known to cause QT|
02347|025|P|prolongation, or with higher blood concentrations of escitalopram.(2)|
02347|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02347|027|P|higher systemic concentrations of either QT prolonging drug are additional|
02347|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02347|029|P|drug concentrations include rapid infusion of an intravenous dose or|
02347|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02347|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02347|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02347|033|P|   Predisposing factors for serotonin-related adverse effects include use in|
02347|034|P|the elderly, in patients with hepatic impairment, and in patients receiving|
02347|035|P|multiple agents which increase central serotonin levels.(1,3)|
02347|036|P|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02347|037|P|magnesium, and potassium levels and monitoring ECG at baseline and at|
02347|038|P|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02347|039|P|patients to report any irregular heartbeat, dizziness, or fainting.|
02347|040|B||
02347|041|M|PATIENT MANAGEMENT:  Evaluate patient for other drugs, diseases and|
02347|042|M|conditions which may further increase risk for QT prolongation and correct|
02347|043|M|risk factors (e.g. correct hypokalemia, discontinue other QT prolonging|
02347|044|M|drugs) when possible.(2,3)  It would be prudent to limit the escitalopram|
02347|045|M|dose to 10 mg daily in patients with QT prolonging risk factors who also|
02347|046|M|receive concurrent therapy with selected CYP2C19 inhibitors.(5)  Weigh the|
02347|047|M|specific benefits versus risks for each patient.|
02347|048|M|   If concurrent therapy is warranted, patients should be monitored for|
02347|049|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02347|050|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02347|051|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02347|052|M|coordination, or severe diarrhea.|
02347|053|B||
02347|054|D|DISCUSSION:  A thorough QT study evaluating escitalopram 10 mg or 30 mg once|
02347|055|D|daily was conducted; a change of 10 msec for upper bound of the 95%|
02347|056|D|confidence level is the threshold for regulatory concern.  In this study,|
02347|057|D|changes to the upper bound of the 95% confidence interval were 6.4 msec and|
02347|058|D|12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The|
02347|059|D|Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended|
02347|060|D|escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar|
02347|061|D|to expected steady state concentrations in 2C19 poor metabolizers following|
02347|062|D|a 20 mg escitalopram dose.(1)|
02347|063|D|  In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of|
02347|064|D|CYP2C19 was administered daily for 6 days. On day 5 a single dose of|
02347|065|D|escitalopram 20 mg was also administered; the area-under-curve (AUC) of|
02347|066|D|escitalopram was increased by 50%. Manufacturer prescribing information|
02347|067|D|recommends a maximum citalopram dose of 20mg daily in patients receiving|
02347|068|D|CYP2C19 inhibitors.(1)|
02347|069|D|   Inhibitors of CYP2C19 include:  abrocitinib, allicin (garlic derivative),|
02347|070|D|berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200|
02347|071|D|mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib,|
02347|072|D|felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide,|
02347|073|D|modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol,|
02347|074|D|tecovirimat, and tipranavir.(4)|
02347|075|B||
02347|076|R|REFERENCES:|
02347|077|B||
02347|078|R|1.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
02347|079|R|  Pharmaceuticals Inc. May, 2023.|1
02347|080|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02347|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02347|082|R|  settings: a scientific statement from the American Heart Association and|6
02347|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02347|084|R|  2;55(9):934-47.|6
02347|085|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02347|086|R|  352(11):1112-20.|6
02347|087|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02347|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02347|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02347|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02347|091|R|  11/14/2017.|1
02347|092|R|5.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
02347|093|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
02347|094|R|  and antidepressant use: a cross sectional study of electronic health|2
02347|095|R|  records. BMJ 2013;346:f288.|2
02348|001|T|MONOGRAPH TITLE:  Doxorubicin/Paclitaxel|
02348|002|B||
02348|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02348|004|L|take action as needed.|
02348|005|B||
02348|006|A|MECHANISM OF ACTION:  Paclitaxel and Cremophor, a vehicle of paclitaxel, may|
02348|007|A|interfere with the pharmacokinetics of doxorubicin, which may cause an|
02348|008|A|increase in the exposure of doxorubicin and its metabolites.(2)(3)|
02348|009|B||
02348|010|E|CLINICAL EFFECTS:  Concurrent use of doxorubicin and paclitaxel may increase|
02348|011|E|the doxorubicin exposure.  This may increase the risk of doxorubicin|
02348|012|E|associated adverse effects.(1)|
02348|013|B||
02348|014|P|PREDISPOSING FACTORS:  None determined.|
02348|015|B||
02348|016|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
02348|017|M|of cardiotoxicity, heart failure, or other adverse effects associated with|
02348|018|M|doxorubicin.(1)  Avoid coadministration within a short interval.(2)|
02348|019|B||
02348|020|D|DISCUSSION:  An open-label drug interaction study, as part of two parallel|
02348|021|D|clinical phase I trials, studied 19 oncology patients receiving doxorubicin|
02348|022|D|combined with either paclitaxel or docetaxel.  When administered with|
02348|023|D|paclitaxel the mean increase in doxorubicin area-under-curve(AUC) was 80%|
02348|024|D|(p=0.002, 95%CI:  23%-136%) and the mean doxorubicin clearance was decreased|
02348|025|D|by 71% (p=0/013, 95%CI:  8%-133%).(1)|
02348|026|D|   In a study of 28 female breast cancer patients receiving concurrent|
02348|027|D|administration of doxorubicin and paclitaxel, the mean AUC0-24 ratio was|
02348|028|D|1.59 (p <0.0001) when doxorubicin was administered 30 minutes before|
02348|029|D|paclitaxel versus 24 hours before paclitaxel. Even when paclitaxel was given|
02348|030|D|24 hours after doxorubicin, there was a rebound 240% increase in the plasma|
02348|031|D|concentration of doxorubicinol.(2)|
02348|032|D|   Cremophor, a vehicle of paclitaxel, has been demonstrated to inhibit|
02348|033|D|p-glycoprotein (P-gp) in a noncompetitive manner.(3)  Paclitaxel is a|
02348|034|D|substrate of P-gp and therefore metabolism may be inhibited if Cremophor is|
02348|035|D|co-administered.(2)|
02348|036|B||
02348|037|R|REFERENCES:|
02348|038|B||
02348|039|R|1.Briasoulis E, Karavasilis V, Tzamakou E, Rammou D, Soulti K, Piperidou C,|2
02348|040|R|  Pavlidis N. Interaction pharmacokinetics of pegylated liposomal|2
02348|041|R|  doxorubicin (Caelyx) on coadministration with paclitaxel or docetaxel.|2
02348|042|R|  Cancer Chemother Pharmacol 2004 May;53(5):452-7.|2
02348|043|R|2.Moreira A, Lobato R, Morais J, Silva S, Ribeiro J, Figueira A, Vale D,|2
02348|044|R|  Sousa C, Araujo F, Fernandes A, Oliveira J, Passos-Coelho JL. Influence of|2
02348|045|R|  the interval between the administration of doxorubicin and paclitaxel on|2
02348|046|R|  the pharmacokinetics of these drugs in patients with locally advanced|2
02348|047|R|  breast cancer. Cancer Chemother Pharmacol 2001 Oct;48(4):333-7.|2
02348|048|R|3.Shono Y, Nishihara H, Matsuda Y, Furukawa S, Okada N, Fujita T, Yamamoto|5
02348|049|R|  A. Modulation of intestinal P-glycoprotein function by cremophor EL and|5
02348|050|R|  other surfactants by an in vitro diffusion chamber method using the|5
02348|051|R|  isolated rat intestinal membranes. J Pharm Sci 2004 Apr;93(4):877-85.|5
02349|001|T|MONOGRAPH TITLE:  Methotrexate (Oncology-Injection )/Ciprofloxacin|
02349|002|B||
02349|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02349|004|L|of severe adverse interaction.|
02349|005|B||
02349|006|A|MECHANISM OF ACTION:  Ciprofloxacin inhibits renal tubular elimination of|
02349|007|A|methotrexate.(1,2)|
02349|008|B||
02349|009|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and ciprofloxacin may|
02349|010|E|result in elevated levels of methotrexate and increased methotrexate-related|
02349|011|E|adverse effects and toxicities, leading to increased risk of severe|
02349|012|E|neurotoxicity, stomatitis, and myelosuppression.|
02349|013|B||
02349|014|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
02349|015|P|- High-dose oncology regimens|
02349|016|P|- Impaired renal function, ascites, or pleural effusions|
02349|017|B||
02349|018|M|PATIENT MANAGEMENT:  For patients receiving high dose methotrexate, consider|
02349|019|M|an alternative antibiotic or discontinuation of ciprofloxacin for the|
02349|020|M|duration of therapy.(3)  Manufacturers recommend patients receiving|
02349|021|M|concomitant ciprofloxacin and methotrexate therapy should be closely|
02349|022|M|monitored for elevated methotrexate levels and methotrexate toxicity.(1,2)|
02349|023|B||
02349|024|D|DISCUSSION:  Two patients undergoing high dose methotrexate therapy had|
02349|025|D|normal methotrexate elimination on other courses of chemotherapy, but|
02349|026|D|delayed elimination with concomitant ciprofloxacin treatment leading to|
02349|027|D|elevated methotrexate concentrations and toxicity.(3)|
02349|028|D|   - A 15 year old boy with recurrent osteosarcoma had a history of normal|
02349|029|D|methotrexate elimination after all of 17 previous courses of high-dose|
02349|030|D|methotrexate therapy over a 4 year period.  At the time of osteosarcoma|
02349|031|D|recurrence he received ciprofloxacin, prednisolone, and fenoxazoline|
02349|032|D|(decongestant nasal drops) for a sinus infection.  On the sixth day of|
02349|033|D|antibiotic therapy he received high-dose methotrexate per protocol.|
02349|034|D|Methotrexate serum concentration at 24 hours was 300 micromoles/L leading to|
02349|035|D|grade 3 skin toxicity, neutropenia, renal failure, and elevated liver|
02349|036|D|function tests.  All drugs were discontinued and leucovorin rescue doses|
02349|037|D|were increased per protocol leading to normalization of methotrexate|
02349|038|D|concentrations after 10 days.|
02349|039|D|   - A 12 year old girl was started on ciprofloxacin as the sole antibiotic|
02349|040|D|treatment for a Pseudomonas aeruginosa skin infection at the site of a|
02349|041|D|telangiectatic osteosarcoma.  Two days later she was started on high-dose|
02349|042|D|methotrexate at 12 gm/meter-squared. Methotrexate elimination was delayed:|
02349|043|D|serum concentrations were 25, 5.3 and 2.84 micromoles/L at 24, 48 and 72|
02349|044|D|hours respectively.  Leucovorin rescue doses were increased per protocol,|
02349|045|D|but ciprofloxacin was continued.  The patient developed grade 2 skin|
02349|046|D|toxicity and moderate renal impairment.  Methotrexate serum concentrations|
02349|047|D|normalized after 7 days. On 6 subsequent courses of high-dose methotrexate|
02349|048|D|therapy methotrexate elimination was normal.|
02349|049|D|   In a case report, a 28-year-old woman with B-cell non-Hodgkin's lymphoma|
02349|050|D|was started on ciprofloxacin 500 mg twice daily for fever of unknown origin|
02349|051|D|20 hours after receiving high-dose methotrexate (3 gram/m2).  She had|
02349|052|D|tolerated her first cycle with methotrexate well, but after concurrent|
02349|053|D|treatment with ciprofloxacin, she developed febrile pancytopenia, mucositis,|
02349|054|D|diarrhea, and necrotic skin lesions.  Eleven days after her methotrexate|
02349|055|D|infusion, methotrexate level was 0.1 micromol/L.  Despite hydration,|
02349|056|D|leucovorin, and non-detectable methotrexate level on day 16, she went to|
02349|057|D|require an autologous stem cell transplant due to persistent aplasia.(4)|
02349|058|D|   A 17-year-old male with acute lymphoblastic leukemia on ciprofloxacin 200|
02349|059|D|mg daily for pleuropneumopathy started high-dose methotrexate (5 grams/m2).|
02349|060|D|Methotrexate elimination was delayed with serum methotrexate level at 36|
02349|061|D|hours of 24 micromol/L, and remaining above 0.2 micromol/L for 9 days.  The|
02349|062|D|patient developed vomiting and renal impairment, which resolved with|
02349|063|D|intensification of leucovorin therapy.  A second course of high-dose|
02349|064|D|methotrexate 4 months later without ciprofloxacin was tolerated with normal|
02349|065|D|methotrexate levels.(5)|
02349|066|B||
02349|067|R|REFERENCES:|
02349|068|B||
02349|069|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
02349|070|R|  Corporation March, 2022.|1
02349|071|R|2.Methotrexate (tablets, injection) Canada prescribing information. Pfizer|1
02349|072|R|  Canada Inc. July 8, 2019.|1
02349|073|R|3.Dalle JH, Auvrignon A, Vassal G, Leverger G. Interaction between|3
02349|074|R|  methotrexate and ciprofloxacin. J Pediatr Hematol Oncol 2002 May;|3
02349|075|R|  24(4):321-2.|3
02349|076|R|4.Jarfaut A, Santucci R, Leveque D, Herbrecht R. Severe methotrexate|3
02349|077|R|  toxicity due to a concomitant administration of ciprofloxacin. Med Mal|3
02349|078|R|  Infect 2013 Jan;43(1):39-41.|3
02349|079|R|5.Aouinti I, Gaies E, Trabelsi S, Salouage I, Jebabli N, Charfi R, Lakhal M,|3
02349|080|R|  Klouz A. Delayed elimination of methotrexate in a patient receiving|3
02349|081|R|  ciprofloxacin. Therapie 2013 May-Jun;68(3):175-7.|3
02350|001|T|MONOGRAPH TITLE:  Pomalidomide/Strong CYP1A2 Inhibitors|
02350|002|B||
02350|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02350|004|L|of severe adverse interaction.|
02350|005|B||
02350|006|A|MECHANISM OF ACTION:  Pomalidomide is primarily metabolized by CYP1A2, which|
02350|007|A|accounts for approximately 50% of pomalidomide hepatic clearance|
02350|008|A|respectively.(1)|
02350|009|B||
02350|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP1A2 inhibitors may result in|
02350|011|E|elevated levels of and toxicity from pomalidomide.(1)|
02350|012|B||
02350|013|P|PREDISPOSING FACTORS:  None determined.|
02350|014|B||
02350|015|M|PATIENT MANAGEMENT:  The manufacturer of pomalidomide states strong|
02350|016|M|inhibitors of CYP1A2 should be avoided. Reduce the dose of pomalidomide to 2|
02350|017|M|mg if a strong CYP1A2 inhibitor must be administered concomitantly with|
02350|018|M|pomalidomide.  Closely monitor patients for hematologic and other toxicities|
02350|019|M|and adjust pomalidomide dose accordingly.(2)|
02350|020|B||
02350|021|D|DISCUSSION:  In a study in healthy volunteers, coadministration of|
02350|022|D|fluvoxamine and pomalidomide resulted in an increase in pomalidomide's|
02350|023|D|maximum concentration (Cmax) and area-under-the-curve (AUC) by 24% and 125%|
02350|024|D|respectively.(2)|
02350|025|D|   In a study in healthy volunteers, coadministration of ketoconazole and|
02350|026|D|fluvoxamine with pomalidomide resulted in an increase in pomalidomide's AUC|
02350|027|D|by 146%.(2)|
02350|028|D|   Strong CYP1A2 inhibitors include angelica root, enasidenib, enoxacin,|
02350|029|D|fluvoxamine, and rofecoxib.(3,4)|
02350|030|B||
02350|031|R|REFERENCES:|
02350|032|B||
02350|033|R|1.Hoffmann M, Kasserra C, Reyes J, Schafer P, Kosek J, Capone L, Parton A,|2
02350|034|R|  Kim-Kang H, Surapaneni S, Kumar G. Absorption, metabolism and excretion of|2
02350|035|R|  pomalidomide in humans following oral administration. Cancer Chemother|2
02350|036|R|  Pharmacol 2013 Feb;71(2):489-501.|2
02350|037|R|2.Pomalyst (pomalidomide) US prescribing information. Celgene Corporation|1
02350|038|R|  November, 2020.|1
02350|039|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02350|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02350|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02350|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02350|043|R|  11/14/2017.|1
02350|044|R|4.This information is based on an extract from the Certara Drug Interaction|6
02350|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02351|001|T|MONOGRAPH TITLE:  Pomalidomide/Selected CYP1A2 or CYP3A4 Inducers (mono|
02351|002|T|deleted 12/15/2020)|
02351|003|B||
02351|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02351|005|L|of severe adverse interaction.|
02351|006|B||
02351|007|A|MECHANISM OF ACTION:  Pomalidomide is primarily metabolized by CYP1A2 and|
02351|008|A|CYP3A4.  These enzymes account for approximately 50 and 30% of pomalidomide|
02351|009|A|hepatic clearance respectively.(1)|
02351|010|B||
02351|011|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP1A2 or CYP3A4|
02351|012|E|inducers may lead to decreased levels and effectiveness of pomalidomide.(2)|
02351|013|B||
02351|014|P|PREDISPOSING FACTORS:  Cigarette smoking induces CYP1A2 and may further|
02351|015|P|lower systemic exposure to pomalidomide.(2)|
02351|016|B||
02351|017|M|PATIENT MANAGEMENT:  When possible, avoid the concurrent use of strong|
02351|018|M|inducers of CYP3A4 or CYP1A2.  The manufacturer of pomalidomide has not|
02351|019|M|provided dosing recommendations for patients who may require concurrent|
02351|020|M|therapy with agents which induce its metabolism.(2)|
02351|021|B||
02351|022|D|DISCUSSION:  In a study in 16 healthy subjects, coadministration of|
02351|023|D|carbamazepine decreased pomalidomide's area-under-the-curve by 20%.(2)|
02351|024|D|   Co-administration of pomalidomide and dexamethasone, a weak inducer of|
02351|025|D|CYP3A4, had no effect on the pharmacokinetics of pomalidomide.(2)|
02351|026|D|   Strong inducers of CYP3A4 linked to this monograph are: apalutamide,|
02351|027|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, marijuana, mitotane,|
02351|028|D|phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and|
02351|029|D|St. John's wort.  Carbamazepine, fosphenytoin, phenytoin, and phenobarbital|
02351|030|D|are also inducers of CYP1A2.(3,4)|
02351|031|D|   Nafcillin, although only a moderate CYP3A4 inducer,is also a CYP1A2|
02351|032|D|inducer and so is linked to this monograph.(3,4)|
02351|033|B||
02351|034|R|REFERENCES:|
02351|035|B||
02351|036|R|1.Hoffmann M, Kasserra C, Reyes J, Schafer P, Kosek J, Capone L, Parton A,|2
02351|037|R|  Kim-Kang H, Surapaneni S, Kumar G. Absorption, metabolism and excretion of|2
02351|038|R|  pomalidomide in humans following oral administration. Cancer Chemother|2
02351|039|R|  Pharmacol 2013 Feb;71(2):489-501.|2
02351|040|R|2.Pomalyst (pomalidomide) US prescribing information. Celgene Corporation|1
02351|041|R|  November, 2020.|1
02351|042|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
02351|043|R|  Indiana University School of Medicine.  Available at:|1
02351|044|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
02351|045|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02351|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02351|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02351|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02351|049|R|  11/14/2017.|1
02352|001|T|MONOGRAPH TITLE:  Hydantoins/Fluvoxamine|
02352|002|B||
02352|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02352|004|L|of severe adverse interaction.|
02352|005|B||
02352|006|A|MECHANISM OF ACTION:  Phenytoin is metabolized by CYP2C9 and CYP2C19.|
02352|007|A|Fluvoxamine inhibits both of these metabolic pathways.(1-3)|
02352|008|B||
02352|009|E|CLINICAL EFFECTS:  The pharmacological and toxic effects of hydantoins may|
02352|010|E|be increased when fluvoxamine is initiated. If fluvoxamine is stopped after|
02352|011|E|long-term concomitant treatment seizure risk may be increased due to|
02352|012|E|decreased hydantoin serum concentrations.|
02352|013|E|   Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin|
02352|014|E|toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia,|
02352|015|E|lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe|
02352|016|E|toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar|
02352|017|E|dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac|
02352|018|E|arrest) and may be fatal.(1)|
02352|019|B||
02352|020|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
02352|021|P|hypoalbuminemia.|
02352|022|B||
02352|023|M|PATIENT MANAGEMENT:  Serum hydantoin concentrations should be monitored and|
02352|024|M|the patient should be observed for changes in seizure control if therapy|
02352|025|M|with fluvoxamine is started, stopped or altered.|
02352|026|M|   Monitor patients for hydantoin toxicity if fluvoxamine treatment is|
02352|027|M|started or if dose is increased (e.g. nystagmus, ataxia, dysarthria, tremor,|
02352|028|M|hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and|
02352|029|M|vomiting).  Adjust the hydantoin dose as indicated.|
02352|030|M|   If long term fluvoxamine therapy is discontinued, the hydantoin|
02352|031|M|concentration may decrease.(1)|
02352|032|B||
02352|033|D|DISCUSSION:  In one case report, a patient stabilized on phenytoin developed|
02352|034|D|phenytoin intoxication after initiation of fluvoxamine.  Phenytoin|
02352|035|D|concentrations increased from 16.6 to 49.1 mcg/mL with symptoms of|
02352|036|D|ataxia.(4)|
02352|037|D|   In another case report, a patient stabilized on phenytoin for two months|
02352|038|D|developed elevated phenytoin serum concentrations (133% increase) as well as|
02352|039|D|signs and symptoms of phenytoin toxicity within 5 days of starting|
02352|040|D|fluoxetine (another CYP2C19 inhibitor).(5)|
02352|041|D|   In another case report, a patient stabilized on phenytoin for one year|
02352|042|D|had a 309% increase in plasma phenytoin concentration and signs of phenytoin|
02352|043|D|toxicity 10 days after initiation of treatment with fluoxetine. Similar|
02352|044|D|cases have been reported to the FDA through the Spontaneous Reporting|
02352|045|D|System.(6)|
02352|046|B||
02352|047|R|REFERENCES:|
02352|048|B||
02352|049|R|1.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
02352|050|R|  March, 2022.|1
02352|051|R|2.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
02352|052|R|  Pharmaceuticals, Inc. August, 2023.|1
02352|053|R|3.This information is based on an extract from the Certara Drug Interaction|6
02352|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02352|055|R|4.Mamiya K, Kojima K, Yukawa E, Higuchi S, Ieiri I, Ninomiya H, Tashiro N.|3
02352|056|R|  Phenytoin intoxication induced by fluvoxamine..|3
02352|057|R|5.Jalil P. Toxic reaction following the combined administration of|3
02352|058|R|  fluoxetine and phenytoin: two case reports. J Neurol Neurosurg Psychiatry|3
02352|059|R|  1992 May;55(5):412-3.|3
02352|060|R|6.Woods DJ, Coulter DM, Pillans P. Interaction of phenytoin and fluoxetine.|3
02352|061|R|  N Z Med J 1994 Jan 26;107(970):19.|3
02353|001|T|MONOGRAPH TITLE:  Phenytoin/Fluvastatin|
02353|002|B||
02353|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02353|004|L|take action as needed.|
02353|005|B||
02353|006|A|MECHANISM OF ACTION:  Fluvastatin may inhibit the metabolism of phenytoin by|
02353|007|A|CYP2C19.(1)|
02353|008|B||
02353|009|E|CLINICAL EFFECTS:  Concurrent use of fluvastatin may result in elevated|
02353|010|E|levels of and toxicity from phenytoin.(2) Phenytoin has a narrow therapeutic|
02353|011|E|range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia,|
02353|012|E|dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision,|
02353|013|E|nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g.|
02353|014|E|coma, irreversible cerebellar dysfunction and atrophy, hypotension,|
02353|015|E|bradycardia, seizures, and cardiac arrest) and may be fatal.(3)|
02353|016|B||
02353|017|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
02353|018|P|hypoalbuminemia.|
02353|019|B||
02353|020|M|PATIENT MANAGEMENT:  Phenytoin levels should be monitored if fluvastatin is|
02353|021|M|initiated or discontinued or if fluvastatin dosage adjustments are made.|
02353|022|M|The dosage of phenytoin may need to be adjusted.|
02353|023|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
02353|024|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
02353|025|M|vision, nausea, and vomiting).|
02353|026|B||
02353|027|D|DISCUSSION:  In a study, fluvastatin (40 mg daily for 5 days) increased the|
02353|028|D|maximum concentration (Cmax) and area-under-curve (AUC) of phenytoin (300 mg|
02353|029|D|daily) by 5% and 20%, respectively.(2)|
02353|030|D|   In a study, phenytoin (300 mg daily) increased the Cmax and AUC of|
02353|031|D|fluvastatin (40 mg BID) by 27% and 40%, respectively; however, this was not|
02353|032|D|viewed as clinically significant.(2)|
02353|033|B||
02353|034|R|REFERENCES:|
02353|035|B||
02353|036|R|1.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
02353|037|R|  Pharmaceuticals Corporation August, 2017.|1
02353|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02353|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02353|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02353|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02353|042|R|  11/14/2017.|1
02353|043|R|3.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
02353|044|R|  March, 2022.|1
02354|001|T|MONOGRAPH TITLE:  Ado-trastuzumab Emtansine/Strong CYP3A4 Inhibitors (mono|
02354|002|T|deleted 03/05/2015)|
02354|003|B||
02354|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02354|005|L|of severe adverse interaction.|
02354|006|B||
02354|007|A|MECHANISM OF ACTION:  Ado-trastuzumab emtansine is a conjugate of|
02354|008|A|trastuzumab and emtansine, a complex of MCC-DM1.  DM1 is a microtubule|
02354|009|A|inhibitor and is metabolized by CYP3A4.  Strong inhibitors of CYP3A4 are|
02354|010|A|expected to inhibit the metabolism of DM1.(1)|
02354|011|B||
02354|012|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 are|
02354|013|E|expected to increase exposure to and toxicity from DM1.(1)|
02354|014|B||
02354|015|P|PREDISPOSING FACTORS:  None determined.|
02354|016|B||
02354|017|M|PATIENT MANAGEMENT:  Concurrent use of strong inhibitors of CYP3A4 and|
02354|018|M|ado-trastuzumab emtansine should be avoided.  When possible, use an|
02354|019|M|alternative to the strong CYP3A4 inhibitor.  If concurrent use is|
02354|020|M|unavoidable, consider delaying ado-trastuzumab emtansine treatment until the|
02354|021|M|strong CYP3A4 inhibitor has cleared from circulation (approximately 3|
02354|022|M|half-lives of the inhibitor.)  If strong CYP3A4 inhibitors are used|
02354|023|M|concurrently with ado-trastuzumab emtansine, patients should be closely|
02354|024|M|monitored for toxicity.(1)|
02354|025|B||
02354|026|D|DISCUSSION:  Ado-trastuzumab emtansine is a conjugate of trastuzumab and|
02354|027|D|emtansine, a complex of MCC-DM1.  DM1 is a microtubule inhibitor.  In vitro|
02354|028|D|studies in human liver microsomes indicate that DM1 is metabolized by CYP3A4|
02354|029|D|and inhibition of this isoenzyme is expected to result in elevated levels of|
02354|030|D|and toxicity from DM1.(1)|
02354|031|D|   Strong inhibitors of CYP3A4 include:  boceprevir, clarithromycin,|
02354|032|D|conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir,|
02354|033|D|mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,|
02354|034|D|telaprevir, telithromycin, or voriconazole.(2)|
02354|035|B||
02354|036|R|REFERENCES:|
02354|037|B||
02354|038|R|1.Kadcyla (ado-trastuzumab emtansine) US prescribing information. Genentech,|1
02354|039|R|  Inc. July, 2014.|1
02354|040|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02354|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02354|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02354|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02354|044|R|  11/14/2017.|1
02355|001|T|MONOGRAPH TITLE:  Trazodone (Greater Than 50 mg)/Meperidine; Tramadol|
02355|002|B||
02355|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02355|004|L|take action as needed.|
02355|005|B||
02355|006|A|MECHANISM OF ACTION:  Tramadol inhibits the reuptake of serotonin.(1,2)|
02355|007|A|Metabolism of trazodone leads to formation of a common active metabolite,|
02355|008|A|m-chlorophenylpiperazine (mCPP) which is an agonist at a variety of|
02355|009|A|serotonin receptors.(3-5)|
02355|010|A|   Both tramadol and mCPP are metabolized by CYP2D6.(1,3-5)|
02355|011|B||
02355|012|E|CLINICAL EFFECTS:  Concurrent administration could increase the risk for|
02355|013|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
02355|014|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
02355|015|E|and muscle rigidity.(6)|
02355|016|B||
02355|017|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
02355|018|P|systemic concentrations of meperidine, tramadol or mCPP would be predicted|
02355|019|P|to increase risk for serotonin toxicity.  Concomitant therapy with other|
02355|020|P|agents which increase brain serotonin concentrations may also increase|
02355|021|P|risk.(1-3,6)|
02355|022|P|   Renal dysfunction and chronic use of meperidine would be expected to|
02355|023|P|increase the risk for serotonin toxicity due to meperidine.|
02355|024|P|   Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion,|
02355|025|P|cinacalcet, duloxetine, fluoxetine, paroxetine, quinidine, or systemic|
02355|026|P|terbinafine) may also increase mCPP and tramadol concentrations, increasing|
02355|027|P|risk for serotonin toxicity.|
02355|028|P|   Patients who are poor metabolizers at CYP2D6 would be expected to have|
02355|029|P|higher tramadol and mCPP concentrations compared with extensive|
02355|030|P|metabolizers.(1,3)|
02355|031|B||
02355|032|M|PATIENT MANAGEMENT:  Assess patient for predisposing risk factors and|
02355|033|M|monitor accordingly.  Manufacturers of meperidine, tramadol and trazodone|
02355|034|M|recommend careful monitoring for signs and symptoms of serotonin syndrome|
02355|035|M|when a metabolic inhibitor or another serotoninergic agent is started, or|
02355|036|M|when the dose of either agent is increased.(1-3)|
02355|037|B||
02355|038|D|DISCUSSION:  Meperidine, tramadol, and trazodone have each been associated|
02355|039|D|with serotonin syndrome when given concurrently with one or more|
02355|040|D|serotoninergic agents.(1-3)|
02355|041|D|   MCPP has been associated with serotonin syndrome when used as a probe of|
02355|042|D|central serotonin function in human investigational studies.(7)|
02355|043|D|   CYP3A4 converts trazodone to mCPP which is then converted to an inactive|
02355|044|D|metabolite via CYP2D6.(3-4)|
02355|045|B||
02355|046|R|REFERENCES:|
02355|047|B||
02355|048|R|1.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
02355|049|R|  October, 2019.|1
02355|050|R|2.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
02355|051|R|  Pharmaceuticals LLC. December, 2023.|1
02355|052|R|3.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
02355|053|R|  Labopharm Inc. November, 2012.|1
02355|054|R|4.Wen B, Ma L, Rodrigues AD, Zhu M. Detection of novel reactive metabolites|5
02355|055|R|  of trazodone: evidence for CYP2D6-mediated bioactivation of|5
02355|056|R|  m-chlorophenylpiperazine. Drug Metab Dispos 2008 May;36(5):841-50.|5
02355|057|R|5.Kast RE. Trazodone generates m-CPP: in 2008 risks from m-CPP might|6
02355|058|R|  outweigh benefits of trazodone. World J Biol Psychiatry 2009;10(4 Pt|6
02355|059|R|  2):682-5.|6
02355|060|R|6.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02355|061|R|  352(11):1112-20.|6
02355|062|R|7.Kovaleva J, Devuyst E, De Paepe P, Verstraete A. Acute|3
02355|063|R|  chlorophenylpiperazine overdose: a case report and review of the|3
02355|064|R|  literature. Ther Drug Monit 2008 Jun;30(3):394-8.|3
02356|001|T|MONOGRAPH TITLE:  Saquinavir/Proton Pump Inhibitors|
02356|002|B||
02356|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02356|004|L|take action as needed.|
02356|005|B||
02356|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is not clear.|
02356|007|A|Saquinavir is a poorly soluble drug with a low bioavailability.  It is|
02356|008|A|possible that proton pump inhibitors (PPIs) induced elevation of gastric pH|
02356|009|A|increases systemic absorption of saquinavir.(1)|
02356|010|B||
02356|011|E|CLINICAL EFFECTS:  Concurrent use of proton pump inhibitors may lead to|
02356|012|E|elevated saquinavir concentrations and an increased risk for toxicities|
02356|013|E|including gastrointestinal symptoms, hypertriglyceridemia, deep vein|
02356|014|E|thrombosis (DVT) and QT prolongation.(1)|
02356|015|B||
02356|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased in|
02356|017|P|patients with congenital long QT syndrome, cardiovascular disease (e.g.|
02356|018|P|heart failure, myocardial infarction), hypokalemia, hypomagnesemia,|
02356|019|P|hypocalcemia, bradycardia, female sex, advanced age, concurrent use of more|
02356|020|P|than one agent known to cause QT prolongation, and with higher blood|
02356|021|P|concentrations of saquinavir.(2)|
02356|022|B||
02356|023|M|PATIENT MANAGEMENT:  The manufacturer of saquinavir recommends monitoring|
02356|024|M|for saquinavir toxicities including gastrointestinal symptoms,|
02356|025|M|hypertriglyceridemia, DVT and QT prolongation in patients receiving|
02356|026|M|saquinavir and a PPI.  No specific saquinavir dose adjustments are|
02356|027|M|recommended.(1)|
02356|028|M|   If a PPI is newly added to existing saquinavir therapy it would be|
02356|029|M|prudent to assure the patient has been evaluated for QT prolongation risk|
02356|030|M|factors and that laboratory tests (e.g. potassium, magnesium, calcium) are|
02356|031|M|normal.|
02356|032|B||
02356|033|D|DISCUSSION:  A study performed in 19 subjects of concurrent omeprazole 40 mg|
02356|034|D|daily with saquinavir/ritonavir (1000/100 mg twice daily) increased|
02356|035|D|area-under-curve (AUC) and maximum-concentration (Cmax) by 82% and 75%,|
02356|036|D|respectively.(1)|
02356|037|D|   Concurrent use of omeprazole 40 mg with saquinavir/ritonavir increased|
02356|038|D|saquinavir AUC, minimum concentration (Cmin), and Cmax by 54%, 73%, and 55%,|
02356|039|D|respectively.  Staggered administration of omeprazole 40 mg with|
02356|040|D|saquinavir/ritonavir by 2 hours increased AUC, Cmin, and Cmax by 67%, 97%,|
02356|041|D|and 65%, respectively.(3)|
02356|042|B||
02356|043|R|REFERENCES:|
02356|044|B||
02356|045|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
02356|046|R|  Laboratories, Inc. March, 2019.|1
02356|047|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02356|048|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02356|049|R|  settings: a scientific statement from the American Heart Association and|6
02356|050|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02356|051|R|  2;55(9):934-47.|6
02356|052|R|3.Singh K, Dickinson L, Chaikan A, Back D, Fletcher C, Pozniak A, Moyle G,|2
02356|053|R|  Nelson M, Gazzard B, Herath D, Boffito M. Pharmacokinetics and safety of|2
02356|054|R|  saquinavir/ritonavir and omeprazole in HIV-infected subjects. Clin|2
02356|055|R|  Pharmacol Ther 2008 Jun;83(6):867-72.|2
02357|001|T|MONOGRAPH TITLE:  Clobazam/Strong; Selected Moderate CYP2C19 Inhibitors|
02357|002|B||
02357|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02357|004|L|of severe adverse interaction.|
02357|005|B||
02357|006|A|MECHANISM OF ACTION:  Clobazam's active metabolite, N-desmethylclobazam, is|
02357|007|A|metabolized by the CYP2C19 isoenzyme.(1) The FDA categorizes|
02357|008|A|N-desmethylclobazam as a sensitive substrate for CYP2C19. Sensitive|
02357|009|A|substrates are drugs whose plasma area-under-curve (AUC) have been shown to|
02357|010|A|increase 5-fold or higher when co-administered  with a strong inhibitor of|
02357|011|A|the enzyme.(2)|
02357|012|B||
02357|013|E|CLINICAL EFFECTS:  Concurrent use of a strong or selected moderate inhibitor|
02357|014|E|of CYP2C19 may result in elevated levels of and toxicity from the active|
02357|015|E|metabolite of clobazam, including profound sedation, respiratory depression,|
02357|016|E|coma, and/or death.(1)|
02357|017|B||
02357|018|P|PREDISPOSING FACTORS:  None determined.|
02357|019|B||
02357|020|M|PATIENT MANAGEMENT:  The dosage of clobazam may need to be adjusted when|
02357|021|M|initiating or discontinuing a strong or selected moderate inhibitor of|
02357|022|M|CYP2C19.(1)|
02357|023|M|   When initiating a strong or selected moderate inhibitor of CYP2C19 in a|
02357|024|M|patient maintained on clobazam, monitor closely for increased effects from|
02357|025|M|clobazam and adjust dose accordingly.(1)  If possible, use an alternative|
02357|026|M|treatment which does not inhibit CYP2C19.|
02357|027|M|   When initiating clobazam in a patient maintained on a strong or moderate|
02357|028|M|inhibitor of CYP2C19, it would be prudent to follow the manufacturer's|
02357|029|M|recommendations for dosage adjustments in patients who are CYP2C19 poor|
02357|030|M|metabolizers.  In these patients, consider a starting dose of 5 mg/day and|
02357|031|M|reduce weekly dosage adjustments to half the normal increase.  Based on|
02357|032|M|clinical response, the dosage may be titrated to normal dosage levels based|
02357|033|M|on weight group at Day 21.(1)|
02357|034|B||
02357|035|D|DISCUSSION:  The active metabolite of clobazam, N-desmethylclobazam, is|
02357|036|D|metabolized by CYP2C19.  Levels of N-desmethylclobazam are 3-5 times higher|
02357|037|D|in poor metabolizers of CYP2C19 and 2 times higher in intermediate|
02357|038|D|metabolizers of CYP2C19.  Thus, strong and moderate inhibitors of CYP2C19|
02357|039|D|are expected to result in a 3 to 5-fold increase in levels of|
02357|040|D|N-desmethylclobazam as well.(1)|
02357|041|D|   Strong and selected moderate inhibitors of CYP2C19 include: esomeprazole,|
02357|042|D|fluconazole, fluvoxamine, omeprazole, stiripentol, and ticlopidine.(2)|
02357|043|D|   Esomeprazole and omeprazole are irreversible inhibitors of CYP2C19.|
02357|044|D|Although intermittent use may lead to moderate CYP2C19 inhibition, routine|
02357|045|D|use may lead to inactivation of all available CYP2C19, converting patient to|
02357|046|D|the CYP2C19 poor metabolizer phenotype.(3)|
02357|047|D|   One or more of the drug pairs linked to this monograph have been included|
02357|048|D|in a list of interactions that could be considered for classification as|
02357|049|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
02357|050|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
02357|051|D|Health Information Technology.|
02357|052|B||
02357|053|R|REFERENCES:|
02357|054|B||
02357|055|R|1.Onfi (clobazam) US prescribing information. Lundbeck, Inc. February, 2021.|1
02357|056|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02357|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02357|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02357|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02357|060|R|  11/14/2017.|1
02357|061|R|3.Ogilvie BW, Yerino P, Kazmi F, Buckley DB, Rostami-Hodjegan A, Paris BL,|5
02357|062|R|  Toren P, Parkinson A. The proton pump inhibitor, omeprazole, but not|5
02357|063|R|  lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of|5
02357|064|R|  CYP2C19: implications for coadministration with clopidogrel. Drug Metab|5
02357|065|R|  Dispos 2011 Nov;39(11):2020-33.|5
02357|066|R|4.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
02357|067|R|  Middleton B, Bates DW. Drug-drug interactions that should be|6
02357|068|R|  non-interruptive in order to reduce alert fatigue in electronic health|6
02357|069|R|  records. J Am Med Inform Assoc 2012 Sep 25.|6
02358|001|T|MONOGRAPH TITLE:  Canagliflozin/UGT Inducers|
02358|002|B||
02358|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02358|004|L|of severe adverse interaction.|
02358|005|B||
02358|006|A|MECHANISM OF ACTION:  UGT inducers may induce the metabolism of|
02358|007|A|canagliflozin, which is glucuronidated by UGT1A9 and UGT2B4.(1)|
02358|008|B||
02358|009|E|CLINICAL EFFECTS:  Concurrent use of an inducer of UGT may result in|
02358|010|E|decreased levels and effectiveness of canagliflozin.(1)|
02358|011|B||
02358|012|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
02358|013|P|have a eGFR of less than 60 ml/min/1.73m2.(1)|
02358|014|B||
02358|015|M|PATIENT MANAGEMENT:  In patients with a eGFR of 60 ml/min/1.73m2 or more who|
02358|016|M|are currently tolerating canagliflozin 100 mg daily and require therapy with|
02358|017|M|an inducer of UGT, the manufacturer of canagliflozin recommends increasing|
02358|018|M|the dose of canagliflozin to 200 mg daily.  Patients currently tolerating|
02358|019|M|canagliflozin 200 mg daily and require additional glycemic control may have|
02358|020|M|their dose increased to 300 mg daily.(1)|
02358|021|M|   In patients with a eGFR of less than 60 ml/min/1.73m2 who are currently|
02358|022|M|tolerating canagliflozin 100 mg daily and receiving therapy with a UGT|
02358|023|M|inducer, increase the dose of canagliflozin to 200 mg daily. Consider other|
02358|024|M|antihyperglycemic agents in patients who require additional glycemic|
02358|025|M|control.(1)|
02358|026|B||
02358|027|D|DISCUSSION:  Pretreatment with rifampin (600 mg daily for 8 days) decreased|
02358|028|D|the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose|
02358|029|D|of canagliflozin (300 mg) by 51% and 28%, respectively.(1)|
02358|030|D|   Inducers of UGT include:  carbamazepine, efavirenz, etravirine,|
02358|031|D|fosphenytoin, lorlatinib, phenobarbital, phenytoin, primidone, rifampin, and|
02358|032|D|ritonavir.(1)|
02358|033|B||
02358|034|R|REFERENCE:|
02358|035|B||
02358|036|R|1.Invokana (canagliflozin) US prescribing information. Janssen|1
02358|037|R|  Pharmaceuticals, Inc. October, 2022.|1
02359|001|T|MONOGRAPH TITLE:  Bosutinib/Moderate CYP3A4 Inducers (mono deleted|
02359|002|T|11/01/2023)|
02359|003|B||
02359|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02359|005|L|of severe adverse interaction.|
02359|006|B||
02359|007|A|MECHANISM OF ACTION:  Agents that induce CYP3A4 may increase the metabolism|
02359|008|A|of bosutinib.(1)|
02359|009|B||
02359|010|E|CLINICAL EFFECTS:  Concurrent use of moderate inducers of CYP3A4 may|
02359|011|E|decrease levels of and effects from bosutinib.(1)|
02359|012|B||
02359|013|P|PREDISPOSING FACTORS:  None determined.|
02359|014|B||
02359|015|M|PATIENT MANAGEMENT:  Avoid the use of moderate CYP3A4 inducers in patients|
02359|016|M|undergoing therapy with bosutinib.(1)|
02359|017|B||
02359|018|D|DISCUSSION:  In a study in 24 healthy subjects, rifampin decreased bosutinib|
02359|019|D|area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%.(1)|
02359|020|D|   Moderate CYP3A4 inducers include:  belzutifan, bosentan, cenobamate,|
02359|021|D|dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib,|
02359|022|D|mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin,|
02359|023|D|sotorasib, and telotristat.(1,2)|
02359|024|B||
02359|025|R|REFERENCES:|
02359|026|B||
02359|027|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
02359|028|R|  2023.|1
02359|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02359|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02359|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02359|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02359|033|R|  11/14/2017.|1
02360|001|T|MONOGRAPH TITLE:  Ospemifene/Selected CYP2C and CYP3A4 Inducers|
02360|002|B||
02360|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02360|004|L|take action as needed.|
02360|005|B||
02360|006|A|MECHANISM OF ACTION:  Ospemifene is metabolized by CYP3A4, CYP2C9 and|
02360|007|A|CYP2C19.(1) Agents linked to this monograph are strong inducers of CYP3A4,|
02360|008|A|and moderate inducers of CYP2C9 and/or CYP2C19.|
02360|009|B||
02360|010|E|CLINICAL EFFECTS:  Concurrent or recent use of ospemifene with agents which|
02360|011|E|induce both CYP3A4 and CYP2C enzyme pathways may lead to decreased levels|
02360|012|E|and effectiveness of ospemifene.(1)|
02360|013|B||
02360|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02360|015|P|of the inducer for longer than 1-2 weeks.|
02360|016|B||
02360|017|M|PATIENT MANAGEMENT:  Systemic levels of ospemifene are expected to decrease|
02360|018|M|after starting an inducer, then stabilize at a new lower systemic|
02360|019|M|concentration over approximately 2 to 4 weeks depending upon the dose and|
02360|020|M|half-life of the inducing agent. The manufacturer of ospemifene notes that|
02360|021|M|decreased systemic exposure may lead to a decrease in clinical|
02360|022|M|effectiveness, but does not make recommendations for a dosage adjustment.(1)|
02360|023|M|   Instruct patient to contact their prescriber for a significant decrease|
02360|024|M|in ospemifene effectiveness.|
02360|025|M|   To ensure maximal absorption, counsel patient to take ospemifene with a|
02360|026|M|meal as food increases bioavailability 2-3 fold.(1)|
02360|027|B||
02360|028|D|DISCUSSION:  An interaction study included 12 postmenopausal women who|
02360|029|D|received rifampin 600 mg daily for 5 days. On the 6th day, ospemifene 60mg|
02360|030|D|was administered with food. Rifampin reduced maximum concentrations (Cmax)|
02360|031|D|and area-under-curve (AUC) of ospemifene by 51% and 58% respectively.(1)|
02360|032|D|   Agents linked to this monograph are apalutamide, carbamazepine,|
02360|033|D|dabrafenib, enzalutamide and rifampin.|
02360|034|B||
02360|035|R|REFERENCE:|
02360|036|B||
02360|037|R|1.Osphena (ospemifene) US prescribing information. Shionogi Incorporated|1
02360|038|R|  January, 2019.|1
02361|001|T|MONOGRAPH TITLE:  Ospemifene/Fluconazole; Voriconazole|
02361|002|B||
02361|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02361|004|L|of severe adverse interaction.|
02361|005|B||
02361|006|A|MECHANISM OF ACTION:  Ospemifene is primarily metabolized by CYP3A4, CYP2C9|
02361|007|A|and CYP2C19.(1)  Fluconazole and voriconazole each inhibit all three of|
02361|008|A|these metabolic pathways.|
02361|009|A|   Ospemifene is an estrogen agonist/antagonist which has dose-dependent|
02361|010|A|agonist effects on the endometrium.(2)|
02361|011|B||
02361|012|E|CLINICAL EFFECTS:  Inhibition of major metabolic pathways increases systemic|
02361|013|E|exposure to ospemifene and may increase risk for adverse reactions or|
02361|014|E|toxicity, including increased risk for endometrial hyperplasia which may be|
02361|015|E|a precursor to endometrial cancer.(1)|
02361|016|B||
02361|017|P|PREDISPOSING FACTORS:  Patients taking progestin therapy or without an|
02361|018|P|intact uterus have a lower or no risk respectively for endometrial cancer.|
02361|019|B||
02361|020|M|PATIENT MANAGEMENT:  In women at risk for endometrial cancer, discontinue|
02361|021|M|ospemifene when fluconazole or voriconazole treatment is started.  If|
02361|022|M|patient is already receiving fluconazole or voriconazole when ospemifene is|
02361|023|M|prescribed, delay initiation of ospemifene until fluconazole or voriconazole|
02361|024|M|treatment has been completed.|
02361|025|M|   The manufacturer of ospemifene states fluconazole should not be used in|
02361|026|M|patients receiving ospemifene.(1)|
02361|027|M|   Counsel patients to report genital bleeding to their physician. The Boxed|
02361|028|M|Warning for ospemifene states postmenopausal women with undiagnosed|
02361|029|M|persistent or recurring abnormal genital bleeding should be seen for|
02361|030|M|diagnostic testing to rule out endometrial hyperplasia or endometrial|
02361|031|M|cancer.(1)|
02361|032|B||
02361|033|D|DISCUSSION:  Fluconazole is a moderate CYP3A4/strong CYP2C9/moderate CYP2C19|
02361|034|D|inhibitor.  In a drug interaction study fluconazole 400 mg given on day one|
02361|035|D|followed by 200 mg on days 2 through 8 increased the area-under-curve (AUC)|
02361|036|D|for ospemifene 2.7-fold.(2)|
02361|037|D|   Voriconazole, a strong CYP3A4/weak CYP2C9/moderate CYP2C19 inhibitor(3)|
02361|038|D|has not been studied but may have similar effects.|
02361|039|B||
02361|040|R|REFERENCES:|
02361|041|B||
02361|042|R|1.Osphena (ospemifene) US prescribing information. Shionogi Incorporated|1
02361|043|R|  January, 2019.|1
02361|044|R|2.FDA. CDER Application number: 203505 Osphena (ospemifene), Clinical|1
02361|045|R|  Pharmacology and Biopharmaceutics Review. URL:|1
02361|046|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203505Orig1s000Clin|1
02361|047|R|  PharmR.pdf February 26, 2013.|1
02361|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02361|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02361|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02361|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02361|052|R|  11/14/2017.|1
02362|001|T|MONOGRAPH TITLE:  Pirfenidone/Strong CYP1A2 Inhibitors|
02362|002|B||
02362|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02362|004|L|of severe adverse interaction.|
02362|005|B||
02362|006|A|MECHANISM OF ACTION:  Pirfenidone is primarily metabolized by CYP1A2 which|
02362|007|A|is responsible for about 50% of its conversion to inactive drug.  CYP2C9,|
02362|008|A|2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone|
02362|009|A|metabolism.(1,2)|
02362|010|A|   Strong inhibitors of CYP1A2 may inhibit the metabolism of|
02362|011|A|pirfenidone.(1,2)|
02362|012|A|   Fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19, and a weak|
02362|013|A|inhibitor of CYP2C9 and so inhibits both primary and secondary pirfenidone|
02362|014|A|metabolic pathways.(3,4)|
02362|015|B||
02362|016|E|CLINICAL EFFECTS:  Concurrent pirfenidone use with strong inhibitors of|
02362|017|E|CYP1A2 may lead to increased systemic concentrations and toxicity from|
02362|018|E|pirfenidone, including serious liver injury.(1,2)|
02362|019|B||
02362|020|P|PREDISPOSING FACTORS:  A greater risk of adverse events may result from|
02362|021|P|concomitant treatment with fluvoxamine, which also inhibits CYP2C19, or with|
02362|022|P|strong or moderate inhibitors of one or more other CYP isoenzymes involved|
02362|023|P|in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone,|
02362|024|P|fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6|
02362|025|P|(e.g. fluoxetine, paroxetine).|
02362|026|P|   The magnitude of this interaction may be reduced in cigarette smokers.|
02362|027|P|Cigarette smoking induces production of CYP1A2 and, in the absence of a|
02362|028|P|CYP1A2 inhibitor, leads to decreased systemic concentrations of|
02362|029|P|pirfenidone.(1)|
02362|030|B||
02362|031|M|PATIENT MANAGEMENT:  The US manufacturer of pirfenidone states that|
02362|032|M|concurrent use with strong inhibitors of CYP1A2 is not recommended.  Use of|
02362|033|M|strong CYP1A2 inhibitors should be discontinued prior to administration of|
02362|034|M|pirfenidone and avoided during treatment with pirfenidone.  Combinations of|
02362|035|M|strong or moderate CYP1A2 inhibitors with strong or moderate CYP2C9,|
02362|036|M|CYP2C19, and/or CYP2D6 inhibitors should also be discontinued prior to and|
02362|037|M|avoided during pirfenidone treatment.  If concurrent therapy of pirfenidone|
02362|038|M|and strong CYP1A2 inhibitors cannot be avoided, reduce pirfenidone to|
02362|039|M|one-267 mg capsule three times a day (total daily dose of 801 mg/day).(2)|
02362|040|M|   The Canadian(1) and Indian(5) manufacturers of pirfenidone states that|
02362|041|M|fluvoxamine is contraindicated with pirfenidone and fluvoxamine should be|
02362|042|M|discontinued prior to initiation of pirfenidone therapy.  The concurrent use|
02362|043|M|of pirfenidone and other strong or moderate CYP1A2 inhibitors should be used|
02362|044|M|with caution.|
02362|045|B||
02362|046|D|DISCUSSION:  Pirfenidone is converted to inactive metabolites prior to|
02362|047|D|elimination.  CYP1A2 is responsible for approximately half of this|
02362|048|D|metabolism.  In an interaction study conducted in non-smokers and smokers,|
02362|049|D|coadministration of pirfenidone with fluvoxamine (a strong CYP1A2|
02362|050|D|inhibitor), an agent which inhibits multiple pirfenidone elimination|
02362|051|D|pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and|
02362|052|D|7-fold, respectively, increase in pirfenidone exposure.(2)|
02362|053|D|   Strong CYP1A2 inhibitors include: angelica root (angelica dahurica|
02362|054|D|radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(4)|
02362|055|B||
02362|056|R|REFERENCES:|
02362|057|B||
02362|058|R|1.Esbriet (pirfenidone) Canada prescribing information. InterMune Canada,|1
02362|059|R|  Inc. April, 2016.|1
02362|060|R|2.Esbriet (pirfenidone) US prescribing information. InterMune, Inc. October,|1
02362|061|R|  2014.|1
02362|062|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02362|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02362|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02362|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02362|066|R|  11/14/2017.|1
02362|067|R|4.This information is based on an extract from the Certara Drug Interaction|6
02362|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02362|069|R|5.Pirfenex (pirfenidone) Indian prescribing information. Cipla Med, Ltd.|1
02362|070|R|  July, 2015.|1
02363|001|T|MONOGRAPH TITLE:  Sarilumab; Tocilizumab/Biologic DMARDs|
02363|002|B||
02363|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02363|004|L|of severe adverse interaction.|
02363|005|B||
02363|006|A|MECHANISM OF ACTION:  Concurrent use of sarilumab(1) or tocilizumab(2) with|
02363|007|A|other biologic DMARDs may result in additive or synergistic effects on the|
02363|008|A|immune system.|
02363|009|B||
02363|010|E|CLINICAL EFFECTS:  Concurrent use of sarilumab(1) or tocilizumab(2) with|
02363|011|E|other biologic DMARDs may increase the risk of serious infections.|
02363|012|B||
02363|013|P|PREDISPOSING FACTORS:  None determined.|
02363|014|B||
02363|015|M|PATIENT MANAGEMENT:  The concurrent use of sarilumab(1) or tocilizumab(2)|
02363|016|M|with other biologic DMARDs should be avoided.|
02363|017|B||
02363|018|D|DISCUSSION:  Concurrent use of sarilumab(1) or tocilizumab(2) and other|
02363|019|D|biologic DMARDs may increase the risk of infection.|
02363|020|B||
02363|021|R|REFERENCES:|
02363|022|B||
02363|023|R|1.Kevzara (sarilumab) Canadian product monograph. Sanofi-aventis Canada Inc.|1
02363|024|R|  January 12, 2017.|1
02363|025|R|2.Actemra (tocilizumab) US prescribing information. Genentech, Inc. June,|1
02363|026|R|  2019.|1
02364|001|T|MONOGRAPH TITLE:  Live Vaccines/Methotrexate (low strength injection, oral)|
02364|002|B||
02364|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02364|004|L|of severe adverse interaction.|
02364|005|B||
02364|006|A|MECHANISM OF ACTION:  A variety of disease modifying agents such as|
02364|007|A|methotrexate suppress the immune system. Immunocompromised patients may be|
02364|008|A|at increased risk for uninhibited replication after administration of live,|
02364|009|A|attenuated vaccines. Immune response to vaccines may be decreased during|
02364|010|A|periods of immunocompromise.(1)|
02364|011|B||
02364|012|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained|
02364|013|E|and/or the vaccine may result in illness.(1)|
02364|014|B||
02364|015|P|PREDISPOSING FACTORS:  Immunosuppressive diseases (e.g. hematologic|
02364|016|P|malignancies, HIV disease), treatments (e.g. radiation) and drugs may all|
02364|017|P|increase the magnitude of immunodeficiency.|
02364|018|B||
02364|019|M|PATIENT MANAGEMENT:  The Centers for Disease Control(CDC) Advisory Committee|
02364|020|M|on Immunization Practices (ACIP) states that live-virus and live, attenuated|
02364|021|M|vaccines should not be administered to patients who are immunocompromised.|
02364|022|M|The magnitude of immunocompromise and associated risks should be determined|
02364|023|M|by a physician.(1)|
02364|024|M|   CDC recommendations for zoster vaccine state it may be administered to|
02364|025|M|patients receiving methotrexate if the dose is < or = to 0.4 mg/kg/week for|
02364|026|M|treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease or|
02364|027|M|other conditions.(1)|
02364|028|M|   For patients scheduled to receive chemotherapy, vaccination should|
02364|029|M|ideally precede the initiation of chemotherapy by 14 days.  Patients|
02364|030|M|vaccinated while on immunosuppressive therapy or in the 2 weeks prior to|
02364|031|M|starting therapy should be considered unimmunized and should be revaccinated|
02364|032|M|at least 3 months after discontinuation of therapy.(1)|
02364|033|B||
02364|034|D|DISCUSSION:  Killed or inactivated vaccines do not pose a danger to|
02364|035|D|immunocompromised patients.(1)|
02364|036|D|   Patients with a history of leukemia who are in remission and have not|
02364|037|D|received chemotherapy for at least 3 months are not considered to be|
02364|038|D|immunocompromised.(1)|
02364|039|B||
02364|040|R|REFERENCE:|
02364|041|B||
02364|042|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
02364|043|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
02364|044|R|  Practices (ACIP). MMWR.  Available at:|1
02364|045|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
02364|046|R|  February 17, 2022;60(RR No.2):1-68.|1
02365|001|T|MONOGRAPH TITLE:  Varicella; Zoster Live Vaccine/Acyclovir; Famciclovir;|
02365|002|T|Valacyclovir|
02365|003|B||
02365|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02365|005|L|is contraindicated and generally should not be dispensed or administered to|
02365|006|L|the same patient.|
02365|007|B||
02365|008|A|MECHANISM OF ACTION:  Acyclovir, famciclovir, and valacyclovir inhibit|
02365|009|A|varicella zoster virus activity and may prevent the body from developing an|
02365|010|A|immune response to the live vaccine.|
02365|011|B||
02365|012|E|CLINICAL EFFECTS:  Administration of antiviral agents active against|
02365|013|E|varicella zoster virus may decrease the efficacy of live, attenuated|
02365|014|E|varicella or zoster vaccines.(1)|
02365|015|B||
02365|016|P|PREDISPOSING FACTORS:  None determined.|
02365|017|B||
02365|018|M|PATIENT MANAGEMENT:  CDC immunization guidelines recommend acyclovir,|
02365|019|M|famciclovir or valacyclovir discontinuation at least 24 hours prior to|
02365|020|M|administration of varicella or zoster vaccines, if possible. Delay use or|
02365|021|M|resumption of antiviral therapy for 14 days after vaccination.(1)|
02365|022|B||
02365|023|D|DISCUSSION:  Acyclovir, famciclovir, valacyclovir inhibit varicella zoster|
02365|024|D|virus activity and may prevent the body from developing an immune response|
02365|025|D|to the live vaccine, decreasing the efficacy of efficacy of live, attenuated|
02365|026|D|varicella or zoster vaccines.(1)|
02365|027|B||
02365|028|R|REFERENCE:|
02365|029|B||
02365|030|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
02365|031|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
02365|032|R|  Practices (ACIP). MMWR.  Available at:|1
02365|033|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
02365|034|R|  February 17, 2022;60(RR No.2):1-68.|1
02366|001|T|MONOGRAPH TITLE:  Delayed-Release Cysteamine Bitartrate/Bicarbonate|
02366|002|B||
02366|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02366|004|L|of severe adverse interaction.|
02366|005|B||
02366|006|A|MECHANISM OF ACTION:  Bicarbonate increases gastric pH.  As gastric pH|
02366|007|A|increases, the solubility of delayed-release cysteamine bitartrate may|
02366|008|A|increase.(1)  The exact mechanism behind the interaction between|
02366|009|A|delayed-release cysteamine bitartrate and bicarbonate is unknown.|
02366|010|B||
02366|011|E|CLINICAL EFFECTS:  Simultaneous administration of delayed-release cysteamine|
02366|012|E|bitartrate and bicarbonate may result in an early release of cysteamine|
02366|013|E|bitartrate and decreased effectiveness of cysteamine bitartrate.(1)|
02366|014|B||
02366|015|P|PREDISPOSING FACTORS:  None determined.|
02366|016|B||
02366|017|M|PATIENT MANAGEMENT:  The manufacturer of delayed-release cysteamine|
02366|018|M|bitartrate states that delayed-release cysteamine bitartrate should be|
02366|019|M|administered at least 1 hour before or 1 hour after administration of|
02366|020|M|bicarbonate.(3)|
02366|021|B||
02366|022|D|DISCUSSION:  Interactions between delayed-release cysteamine bitartrate and|
02366|023|D|other acid reducing agents including H2-receptor antagonists and proton pump|
02366|024|D|inhibitors were not noted in the clinical trials.(1,2)  The interaction was|
02366|025|D|only documented with co-administration of delayed-release cysteamine|
02366|026|D|bitartrate and bicarbonate.(2,3)|
02366|027|B||
02366|028|R|REFERENCES:|
02366|029|B||
02366|030|R|1.Navarrete T. Personal Communication - Procysbi and bicarbonate. Raptor|1
02366|031|R|  Pharmaceuticals Inc. May 9, 2013.|1
02366|032|R|2.Langman CB, Greenbaum LA, Sarwal M, Grimm P, Niaudet P, Deschenes G,|2
02366|033|R|  Cornelissen E, Morin D, Cochat P, Matossian D, Gaillard S, Bagger MJ,|2
02366|034|R|  Rioux P. A randomized controlled crossover trial with delayed-release|2
02366|035|R|  cysteamine bitartrate in nephropathic cystinosis: effectiveness on white|2
02366|036|R|  blood cell cystine  levels and comparison of safety. Clin J Am Soc Nephrol|2
02366|037|R|  2012 Jul;7(7):1112-20.|2
02366|038|R|3.Procsybi (cysteamine bitratrate) US prescribing information. Horizon|1
02366|039|R|  Therapeutics USA, Inc. February, 2022.|1
02367|001|T|MONOGRAPH TITLE:  Duloxetine/Fluoxetine; Paroxetine|
02367|002|B||
02367|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02367|004|L|take action as needed.|
02367|005|B||
02367|006|A|MECHANISM OF ACTION:  Fluoxetine and paroxetine inhibit CYP2D6 mediated|
02367|007|A|metabolism of duloxetine.(1-3)  In addition, duloxetine, fluoxetine and|
02367|008|A|paroxetine are serotonin reuptake inhibitors.|
02367|009|B||
02367|010|E|CLINICAL EFFECTS:  Higher duloxetine concentrations and concomitant use of|
02367|011|E|two agents which inhibit serotonin reuptake may increase the risk for|
02367|012|E|serotonin syndrome.(1-4)  Symptoms of serotonin syndrome may include tremor,|
02367|013|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
02367|014|E|and muscle rigidity.(4)|
02367|015|B||
02367|016|P|PREDISPOSING FACTORS:  Concurrent use of a CYP1A2 inhibitor (e.g.|
02367|017|P|ciprofloxacin, fluvoxamine, vemurafenib, zileuton) would block duloxetine's|
02367|018|P|other important metabolic pathway further increasing systemic concentrations|
02367|019|P|and risk for toxicities.(1)|
02367|020|P|   High doses of serotonin reuptake inhibitors or concurrent use of multiple|
02367|021|P|drugs which increase CNS serotonin levels may increase risk for serotonin|
02367|022|P|syndrome.(4)|
02367|023|B||
02367|024|M|PATIENT MANAGEMENT:  The prescriber may intend short-term use of this|
02367|025|M|combination when transitioning the patient from one serotonergic agent to|
02367|026|M|another.  However, if fluoxetine or paroxetine is  used to treat a|
02367|027|M|psychiatric disorder (e.g. depression, PTSD, OCD) and duloxetine is used to|
02367|028|M|treat neuropathic pain, concomitant use may be long term.  If the|
02367|029|M|interacting agents are prescribed by different providers, it would be|
02367|030|M|prudent to assure that they are aware of concomitant therapy and monitoring|
02367|031|M|the patient for serotonin toxicities.|
02367|032|M|   If concurrent therapy is warranted, patients should be monitored for|
02367|033|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02367|034|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating|
02367|035|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02367|036|M|coordination, or severe diarrhea.|
02367|037|M|   Patients in whom serotonin syndrome is suspected should receive immediate|
02367|038|M|medical attention.|
02367|039|B||
02367|040|D|DISCUSSION:  An interaction study evaluated concomitant use of duloxetine 40|
02367|041|D|mg once daily with paroxetine 20 mg daily. Paroxetine increased duloxetine|
02367|042|D|AUC 60%. The US manufacturer for duloxetine notes that greater inhibition|
02367|043|D|would be expected with higher doses of paroxetine.(1)|
02367|044|D|   Serotonin syndrome constitutes a range of toxicities from mild to life|
02367|045|D|threatening.(4)  Monitor patients on multiple serotonergic agents for|
02367|046|D|symptoms of serotonin toxicity.|
02367|047|D|   Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis,|
02367|048|D|intermittent tremor or myoclonus.|
02367|049|D|   Moderate serotonin symptoms may include: tachycardia, hypertension,|
02367|050|D|hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds,|
02367|051|D|hyperreflexia and clonus.|
02367|052|D|   Severe serotonin symptoms may include: severe hypertension and|
02367|053|D|tachycardia, shock, agitated delirium, muscular rigidity and hypertonicity.|
02367|054|B||
02367|055|R|REFERENCES:|
02367|056|B||
02367|057|R|1.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
02367|058|R|  and Company September, 2021.|1
02367|059|R|2.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
02367|060|R|  Technologies January, 2017.|1
02367|061|R|3.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
02367|062|R|  and Company August, 2023.|1
02367|063|R|4.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02367|064|R|  352(11):1112-20.|6
02368|001|T|MONOGRAPH TITLE:  Warfarin/Valproic acid|
02368|002|B||
02368|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02368|004|L|take action as needed.|
02368|005|B||
02368|006|A|MECHANISM OF ACTION:  The more active S-isomer of warfarin is primarily|
02368|007|A|metabolized by CYP2C9(1) and valproic acid is an inhibitor of CYP2C9.(2-4)|
02368|008|A|In addition, both drugs are highly protein bound and may compete for albumin|
02368|009|A|binding sites.(4-6)|
02368|010|B||
02368|011|E|CLINICAL EFFECTS:  Valproic acid may increase warfarin concentrations|
02368|012|E|leading to an increase in INR and risk for bleeding.|
02368|013|B||
02368|014|P|PREDISPOSING FACTORS:  Patients with normal serum albumin and valproic acid|
02368|015|P|concentrations at the higher end of the therapeutic range, or patients with|
02368|016|P|low serum albumin at any valproic acid concentration are at greater risk for|
02368|017|P|a clinically significant interaction.|
02368|018|P|   The risk for bleeding episodes may be greater in patients with|
02368|019|P|disease-associated factors (e.g. thrombocytopenia).|
02368|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
02368|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02368|022|P|risk for bleeding (e.g. NSAIDs).|
02368|023|B||
02368|024|M|PATIENT MANAGEMENT:  Monitor INR response closely in patient maintained on|
02368|025|M|warfarin when initiating, increasing or discontinuing valproic acid.|
02368|026|M|Patients maintained on valproic acid may require lower initial doses of|
02368|027|M|warfarin.|
02368|028|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02368|029|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02368|030|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02368|031|M|patients with any symptoms.|
02368|032|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02368|033|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02368|034|M|anticoagulation in patients with active pathologic bleeding.|
02368|035|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02368|036|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02368|037|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02368|038|M|and/or swelling.|
02368|039|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02368|040|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02368|041|M|initiating, altering the dose or discontinuing either drug.|
02368|042|B||
02368|043|D|DISCUSSION:  Valproic acid is highly protein bound. At usual therapeutic|
02368|044|D|doses valproic acid is present in high molar concentrations and may saturate|
02368|045|D|albumin binding sites.(4)  Further increases in valproic acid dosage lead to|
02368|046|D|a disproportionate increase in free (unbound) valproic acid concentration,|
02368|047|D|increasing the risk for inhibition of CYP2C9 mediated metabolism of warfarin|
02368|048|D|and displacement of warfarin from albumin binding sites.  One manufacturer|
02368|049|D|describes an in vitro study in which valproate increased the free fraction|
02368|050|D|of warfarin by up to 32.6%.(5)|
02368|051|D|   In a case report, a 71 year-old female patient with glioblastoma|
02368|052|D|multiforme had been maintained on warfarin (5 mg/day on Saturday and Sunday|
02368|053|D|and 2.5 mg/day the other days of the week) with an INR target range of 2-3.|
02368|054|D|Other medications included oral pravastatin 20 mg/day and dexamethasone 2|
02368|055|D|mg/day. The patient was admitted for complex partial seizures.  During|
02368|056|D|transport, she was given intravenous levetiracetam (dose not stated),|
02368|057|D|midazolam 3 mg, and dexamethasone 4 mg. Upon arrival she was given|
02368|058|D|additional 1 gram of intravenous(IV) levetiracetam. Warfarin 2.5mg was|
02368|059|D|administered on the night of admission. Her INR on Day 2 was 3.4 and the|
02368|060|D|warfarin dose was reduced to 0.75 mg due to bleeding concerns. The dose of|
02368|061|D|levetiracetam was increased to 2.5 grams IV twice daily. An IV loading dose|
02368|062|D|of valproic acid of 20 mg/kg (1,100 mg) was administered followed by a|
02368|063|D|maintenance dose of 500 mg IV twice daily (later changed to 250mg every six|
02368|064|D|hours per nasogastric tube). On Day 3, the total valproic acid level was 108|
02368|065|D|ug/mL (target range: 50-100 ug/mL), free valproic acid level was 20 ug/mL|
02368|066|D|(target range: 4-15 ug/mL), and the INR had increased to 5.5. Eight hours|
02368|067|D|later, the INR had further increased to 7.6. No other hemodynamic or|
02368|068|D|metabolic changes were noted. Valproic acid was stopped, oral vitamin K|
02368|069|D|(dose not stated) was given, and warfarin was held for the following two|
02368|070|D|days. Warfarin was resumed when the INR had decreased to 2.5.(7)|
02368|071|D|   In a case report, a 42 year-old female patient was maintained on a|
02368|072|D|regimen of divalproex sodium (1,000 mg/day) and lamotrigine (150 mg/day).|
02368|073|D|She underwent surgery for cardiac valve replacement. Her INR on post-surgery|
02368|074|D|Day 1 was 1.11 and she received warfarin (2.5 mg). On Day 4 her INR had|
02368|075|D|increased to 6.54. Warfarin was held and she was given two units of fresh|
02368|076|D|frozen plasma. Her INR decreased to 3.23. On Day 5, her INR increased to|
02368|077|D|5.42 without any additional doses of warfarin. Her serum valproate level was|
02368|078|D|91.7 ug/mL. (therapeutic range: 50-100 ug/mL). Divalproex sodium was held.|
02368|079|D|On Day 6, the INR decreased to 3.27. The divalproex sodium was restarted|
02368|080|D|(250 mg twice daily) on Day 7 and the serum valproate level on Day 8 was|
02368|081|D|30.2 ug/mL. The patient was discharged on Day 15 with an INR of 1.73, but|
02368|082|D|had INR levels as high as 8.2 associated with epistaxis. Divalproex sodium|
02368|083|D|was discontinued and replaced with another agent two months after|
02368|084|D|surgery.(8)|
02368|085|B||
02368|086|R|REFERENCES:|
02368|087|B||
02368|088|R|1.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
02368|089|R|  Squibb Company September, 2016.|1
02368|090|R|2.Gunes A, Bilir E, Zengil H, Babaoglu MO, Bozkurt A, Yasar U. Inhibitory|2
02368|091|R|  effect of valproic acid on cytochrome P450 2C9 activity in epilepsy|2
02368|092|R|  patients. Basic Clin Pharmacol Toxicol 2007 Jun;100(6):383-6.|2
02368|093|R|3.Wen X, Wang JS, Kivisto KT, Neuvonen PJ, Backman JT. In vitro evaluation|5
02368|094|R|  of valproic acid as an inhibitor of human cytochrome P450 isoforms:|5
02368|095|R|  preferential inhibition of cytochrome P450 2C9 (CYP2C9). Br J Clin|5
02368|096|R|  Pharmacol 2001 Nov;52(5):547-53.|5
02368|097|R|4.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
02368|098|R|  Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
02368|099|R|5.Depakote (divalproex sodium) US prescribing information. AbbVie Inc.|1
02368|100|R|  February, 2023.|1
02368|101|R|6.Panjehshahin MR, Bowmer CJ, Yates MS. Effect of valproic acid, its|5
02368|102|R|  unsaturated metabolites and some structurally related fatty acids on the|5
02368|103|R|  binding of warfarin and dansylsarcosine to human albumin. Biochem|5
02368|104|R|  Pharmacol 1991 Apr 15;41(8):1227-33.|5
02368|105|R|7.Yoon HW, Giraldo EA, Wijdicks EF. Valproic acid and warfarin: an|3
02368|106|R|  underrecognized drug interaction. Neurocrit Care 2011 Aug;15(1):182-5.|3
02368|107|R|8.Nadkarni A, Oldham M, Howard M, Lazar HL, Berenbaum I. Detrimental effects|3
02368|108|R|  of divalproex on warfarin therapy following mechanical valve  replacement.|3
02368|109|R|  J Card Surg 2011 Sep;26(5):492-4.|3
02369|001|T|MONOGRAPH TITLE:  Slt Anticoagulants (Vit K antagonists)/Slt Cephalosporins|
02369|002|B||
02369|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02369|004|L|take action as needed.|
02369|005|B||
02369|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve a|
02369|007|A|combination of cephalosporin induced platelet inhibition and alteration of|
02369|008|A|gut flora.|
02369|009|B||
02369|010|E|CLINICAL EFFECTS:  Concurrent use of some cephalosporins may increase the|
02369|011|E|hypoprothrombinemic effect of the anticoagulant with possible bleeding.|
02369|012|B||
02369|013|P|PREDISPOSING FACTORS:  High doses, hepatic and/or renal impairment, and poor|
02369|014|P|nutrition may increase the risk of bleeding.|
02369|015|P|   The risk for bleeding episodes may be greater in patients with|
02369|016|P|disease-associated factors (e.g. thrombocytopenia).|
02369|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
02369|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02369|019|P|risk for bleeding (e.g. NSAIDs).|
02369|020|B||
02369|021|M|PATIENT MANAGEMENT:  Monitor prothrombin activity and adjust the|
02369|022|M|anticoagulant dosage accordingly.  Consider using an alternative antibiotic.|
02369|023|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02369|024|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02369|025|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02369|026|M|patients with any symptoms.|
02369|027|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02369|028|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02369|029|M|anticoagulation in patients with active pathologic bleeding.|
02369|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02369|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02369|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02369|033|M|and/or swelling.|
02369|034|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02369|035|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02369|036|M|initiating, altering the dose or discontinuing either drug.|
02369|037|B||
02369|038|D|DISCUSSION:  Although the majority of cephalosporins that have been|
02369|039|D|documented to interact with anticoagulants have a NMTT side chain, there are|
02369|040|D|reports of interactions with cefazolin, cefoxitin, ceftaroline, and|
02369|041|D|ceftriaxone as well.|
02369|042|D|   The time of highest risk for a coumarin-type drug interaction is when the|
02369|043|D|precipitant drug is initiated or discontinued.|
02369|044|D|   A large systematic review was performed on 72 warfarin drug-drug|
02369|045|D|interactions studies that reported on bleeding, thromboembolic events, or|
02369|046|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 11 of|
02369|047|D|those studies found a higher rate of clinically significant bleeding in|
02369|048|D|patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83).|
02369|049|D|Increased bleeding risk was also seen in subgroup analyses with|
02369|050|D|cephalosporins (OR=1.50; 95% CI 1.21-1.86).|
02369|051|B||
02369|052|R|REFERENCES:|
02369|053|B||
02369|054|R|1.Custer GM, Briggs BR, Smith RE. Effect of cefamandole nafate on blood|5
02369|055|R|  coagulation and platelet function. Antimicrob Agents Chemother 1979 Dec;|5
02369|056|R|  16(6):869-72.|5
02369|057|R|2.Rymer W, Greenlaw CL. Hypoprothrombinemia associated with cefamandole.|3
02369|058|R|  Drug Intell Clin Pharm 1980 Nov;14:780-3.|3
02369|059|R|3.Fainstein V, Bodey GP, McCredie KB, Keating MJ, Estey EH, Bolivar R,|2
02369|060|R|  Elting L. Coagulation abnormalities induced by beta-lactam antibiotics in|2
02369|061|R|  cancer patients. J Infect Dis 1983 Oct;148(4):745-50.|2
02369|062|R|4.Weitekamp MR, Aber RC. Prolonged bleeding times and bleeding diathesis|3
02369|063|R|  associated with moxalactam administration. JAMA 1983 Jan 7;249(1):69-71.|3
02369|064|R|5.Parker SW, Baxter J, Beam TR Jr. Cefoperazone-induced coagulopathy. Lancet|3
02369|065|R|  1984 May 5;1(8384):1016.|3
02369|066|R|6.Cristiano P. Hypoprothrombinemia associated with cefoperazone treatment.|3
02369|067|R|  Drug Intell Clin Pharm 1984 Apr;18(4):314-6.|3
02369|068|R|7.Angaran DM, Dias VC, Arom KV, Northrup WF, Kersten TE, Lindsay WG,|2
02369|069|R|  Nicoloff DM. The influence of prophylactic antibiotics on the warfarin|2
02369|070|R|  anticoagulation response in the postoperative prosthetic cardiac valve|2
02369|071|R|  patient. Cefamandole versus vancomycin. Ann Surg 1984 Jan;199(1):107-11.|2
02369|072|R|8.Angaran DM, Dias VC, Arom KV, Northrup WF, Kersten TG, Lindsay WG,|2
02369|073|R|  Nicoloff DM. The comparative influence of prophylactic antibiotics on the|2
02369|074|R|  prothrombin response to warfarin in the postoperative prosthetic cardiac|2
02369|075|R|  valve patient. Cefamandole, cefazolin, vancomycin. Ann Surg 1987 Aug;|2
02369|076|R|  206(2):155-61.|2
02369|077|R|9.Reddy J, Bailey RR. Vitamin K deficiency developing in patients with renal|3
02369|078|R|  failure treated with cephalosporin antibiotics. N Z Med J 1980 Nov 26;|3
02369|079|R|  92(672):378-9.|3
02369|080|R|10.Bang NU, Tessler SS, Heidenreich RO, Marks CA, Mattler LE. Effects of|2
02369|081|R|   moxalactam on blood coagulation and platelet function. Rev Infect Dis|2
02369|082|R|   1982 Nov-Dec;4 Suppl:S546-54.|2
02369|083|R|11.Joehl RJ, Rasbach DA, Ballard JO, Weitekamp MR, Sattler FR. Moxalactam.|3
02369|084|R|   Evaluation of clinical bleeding in patients with abdominal infection.|3
02369|085|R|   Arch Surg 1983 Nov;118(11):1259-61.|3
02369|086|R|12.Lipsky JJ. N-methyl-thio-tetrazole inhibition of the gamma carboxylation|5
02369|087|R|   of glutamic acid: possible mechanism for antibiotic-associated|5
02369|088|R|   hypoprothrombinaemia. Lancet 1983 Jul 23;2(8343):192-3.|5
02369|089|R|13.Meisel S. Severe bleeding diathesis associated with moxalactam|3
02369|090|R|   administration. Drug Intell Clin Pharm 1984 Sep;18(9):721-2.|3
02369|091|R|14.Osborne JC. Hypoprothrombinemia and bleeding due to cefoperazone. Ann|3
02369|092|R|   Intern Med 1985 May;102(5):721-2.|3
02369|093|R|15.Shearer MJ, Bechtold H, Andrassy K, Koderisch J, McCarthy PT, Trenk D,|2
02369|094|R|   Jahnchen E, Ritz E. Mechanism of cephalosporin-induced|2
02369|095|R|   hypoprothrombinemia: relation to cephalosporin side chain, vitamin K|2
02369|096|R|   metabolism, and vitamin K status. J Clin Pharmacol 1988 Jan;28(1):88-95.|2
02369|097|R|16.Decroix MO, Zini R, Chaumeil JC, Tillement JP. Cefazolin serum protein|5
02369|098|R|   binding and its inhibition by bilirubin, fatty acids and other drugs.|5
02369|099|R|   Biochem Pharmacol 1988 Jul 15;37(14):2807-14.|5
02369|100|R|17.Kim KY, Frey RJ, Epplen K, Foruhari F. Interaction between warfarin and|3
02369|101|R|   nafcillin: case report and review of the literature. Pharmacotherapy 2007|3
02369|102|R|   Oct;27(10):1467-70.|3
02369|103|R|18.Clark TR, Burns S. Elevated International Normalized Ratio values|3
02369|104|R|   associated with concomitant use of warfarin and ceftriaxone. Am J Health|3
02369|105|R|   Syst Pharm 2011 Sep 1;68(17):1603-5.|3
02369|106|R|19.Farhat NM, Hutchinson LS, Peters M. Elevated International Normalized|3
02369|107|R|   Ratio values in a patient receiving warfarin and  ceftaroline. Am J|3
02369|108|R|   Health Syst Pharm 2016 Jan 15;73(2):56-9.|3
02369|109|R|20.Bohm NM, Crosby B. Hemarthrosis in a patient on warfarin receiving|3
02369|110|R|   ceftaroline: a case report and brief  review of cephalosporin|3
02369|111|R|   interactions with warfarin. Ann Pharmacother 2012 Jul-Aug;46(7-8):e19.|3
02369|112|R|21.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
02369|113|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
02369|114|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
02369|115|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
02370|001|T|MONOGRAPH TITLE:  Hormonal Contraceptive Agents/Dabrafenib|
02370|002|B||
02370|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02370|004|L|of severe adverse interaction.|
02370|005|B||
02370|006|A|MECHANISM OF ACTION:  Dabrafenib may induce the metabolism of hormonal|
02370|007|A|contraceptive agents by CYP3A4.(1)|
02370|008|B||
02370|009|E|CLINICAL EFFECTS:  Concurrent use of dabrafenib and hormonal contraceptive|
02370|010|E|agents may decrease the effectiveness of the hormonal contraceptive agent,|
02370|011|E|which may result in contraceptive failure.  Dabrafenib may cause birth|
02370|012|E|defects and/or miscarriage if used by pregnant women.(1)|
02370|013|B||
02370|014|P|PREDISPOSING FACTORS:  None determined.|
02370|015|B||
02370|016|M|PATIENT MANAGEMENT:  Women receiving dabrafenib therapy should not rely|
02370|017|M|solely on hormonal contraceptive agents (including oral, implantable,|
02370|018|M|injectable, or transdermal agents) because they may not be effective.  Women|
02370|019|M|should be advised to use a highly effective non-hormonal method of|
02370|020|M|contraception during and for 2 weeks after dabrafenib mono-therapy.(1-3)|
02370|021|M|The Canadian and UK manufacturers of dabrafenib also state that an effective|
02370|022|M|method of contraception should be continued for 16 weeks after the last dose|
02370|023|M|of trametinib when given in combination dabrafenib.(2-3)|
02370|024|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
02370|025|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
02370|026|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
02370|027|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
02370|028|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
02370|029|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
02370|030|M|and to seek medical advice if they do become pregnant.(4)|
02370|031|B||
02370|032|D|DISCUSSION:  Dabrafenib is a moderate inducer of CYP3A4.  In a clinical|
02370|033|D|trial in 12 subjects, dabrafenib decreased the maximum concentration (Cmax)|
02370|034|D|and area-under-curve (AUC) of a single dose of midazolam, a sensitive CYP3A4|
02370|035|D|substrate) by 61% and 74%, respectively.  Hormonal contraceptives are also|
02370|036|D|metabolized by CYP3A4, therefore, hormonal contraceptive agents may not be|
02370|037|D|reliable in patients taking dabrafenib.(1)|
02370|038|B||
02370|039|R|REFERENCES:|
02370|040|B||
02370|041|R|1.Tafinlar (dabrafenib) US prescribing information. Novartis Pharmaceuticals|1
02370|042|R|  Corporation May, 2023.|1
02370|043|R|2.Tafinlar (dabrafenib) Canadian prescribing information. Novartis|1
02370|044|R|  Pharmaceuticals Canada Inc. January. 2024.|1
02370|045|R|3.Tafinlar (dabrafenib) UK summary of product characteristics. Novartis|1
02370|046|R|  Pharmaceuticals UK Ltd January 11, 2021.|1
02370|047|R|4.Medicines and Healthcare products Regulatory Agency.|1
02370|048|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
02370|049|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
02370|050|R|  available at:|1
02370|051|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
02370|052|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
02370|053|R|  -and-contraceptive-efficacy September 15, 2016..|1
02371|001|T|MONOGRAPH TITLE:  Dabrafenib/Strong CYP2C8 Inhibitors|
02371|002|B||
02371|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02371|004|L|of severe adverse interaction.|
02371|005|B||
02371|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2C8 may inhibit the metabolism|
02371|007|A|of dabrafenib.(1)|
02371|008|B||
02371|009|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP2C8 may result|
02371|010|E|in elevated levels of and toxicity from dabrafenib.(1)|
02371|011|B||
02371|012|P|PREDISPOSING FACTORS:  None determined.|
02371|013|B||
02371|014|M|PATIENT MANAGEMENT:  Concurrent use of strong inhibitors of CYP2C8 with|
02371|015|M|dabrafenib is not recommended.  If possible, choose an alternative agent.|
02371|016|M|If concurrent use is required, monitor patients closely for toxicity.(1)|
02371|017|B||
02371|018|D|DISCUSSION:  Concurrent use of gemfibrozil (600 mg BID for 4 days), a strong|
02371|019|D|inhibitor of CYP2C8, increased dabrafenib (75 mg BID) area-under-curve (AUC)|
02371|020|D|by 47%.(1)|
02371|021|D|   Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)|
02371|022|B||
02371|023|R|REFERENCES:|
02371|024|B||
02371|025|R|1.Tafinlar (dabrafenib) US prescribing information. Novartis Pharmaceuticals|1
02371|026|R|  Corporation May, 2023.|1
02371|027|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02371|028|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02371|029|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02371|030|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02371|031|R|  11/14/2017.|1
02371|032|R|3.This information is based on an extract from the Certara Drug Interaction|6
02371|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02372|001|T|MONOGRAPH TITLE:  Dapoxetine/Strong CYP3A4 Inhibitors (mono deleted|
02372|002|T|01/29/2015)|
02372|003|B||
02372|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02372|005|L|is contraindicated and generally should not be dispensed or administered to|
02372|006|L|the same patient.|
02372|007|B||
02372|008|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may decrease the|
02372|009|A|metabolism of dapoxetine.(1)|
02372|010|B||
02372|011|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02372|012|E|in elevated levels of and toxicity from dapoxetine.  Symptoms may include|
02372|013|E|somnolence, nausea/vomiting, tachycardia, tremors, agitation, and/or|
02372|014|E|dizziness.(1)|
02372|015|B||
02372|016|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
02372|017|P|are poor metabolizers of CYP2D6.(1)|
02372|018|B||
02372|019|M|PATIENT MANAGEMENT:  The concurrent use of dapoxetine and a strong inhibitor|
02372|020|M|of CYP3A4 is contraindicated.(1)|
02372|021|B||
02372|022|D|DISCUSSION:  Ketoconazole (200 mg twice daily for 7 days), a strong|
02372|023|D|inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02372|024|D|area-under-curve (AUC) of a single dose of dapoxetine (30 mg) by 35% and|
02372|025|D|99%, respectively.  The Cmax and AUC of the active fraction are expected to|
02372|026|D|increase by 25% and 2-fold, respectively, with strong inhibitors of|
02372|027|D|CYP3A4.(1)|
02372|028|D|  Strong inhibitors of CYP3A4 include:  boceprevir, clarithromycin,|
02372|029|D|conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir,|
02372|030|D|mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,|
02372|031|D|telaprevir, telithromycin, and voriconazole.(2)|
02372|032|B||
02372|033|R|REFERENCES:|
02372|034|B||
02372|035|R|1.Priligy (dapoxetine hydrochloride) Australian prescribing information.|1
02372|036|R|  Ortho-McNeil Pharmaceutical March 19, 2013.|1
02372|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02372|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02372|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02372|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02372|041|R|  11/14/2017.|1
02373|001|T|MONOGRAPH TITLE:  Dapoxetine/Serotoninergic Agents|
02373|002|B||
02373|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02373|004|L|is contraindicated and generally should not be dispensed or administered to|
02373|005|L|the same patient.|
02373|006|B||
02373|007|A|MECHANISM OF ACTION:  Concurrent administration of dapoxetine with other|
02373|008|A|serotonergic agents may result in additive effects on serotonin, resulting|
02373|009|A|in serotonin syndrome.(1,2)|
02373|010|B||
02373|011|E|CLINICAL EFFECTS:  Concurrent use of dapoxetine with other serotonergic|
02373|012|E|agents may result in serotonin syndrome, a potentially life-threatening|
02373|013|E|syndrome which may include one or more of the following symptoms: tremor,|
02373|014|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
02373|015|E|and muscle rigidity.(3)|
02373|016|B||
02373|017|P|PREDISPOSING FACTORS:  Use of multiple drugs which increase serotonin levels|
02373|018|P|is associated with an increased risk for this toxidrome.|
02373|019|B||
02373|020|M|PATIENT MANAGEMENT:  Dapoxetine should not be administered with other|
02373|021|M|serotonergic agents such as the selective serotonin reuptake inhibitors|
02373|022|M|(SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic|
02373|023|M|antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or|
02373|024|M|St. John's Wort.(1,2)|
02373|025|M|   Dapoxetine should not be initiated within 14 days of receiving other|
02373|026|M|serotonergic agents.  Other serotonergics should not be initiated within 7|
02373|027|M|days of receiving dapoxetine.(2)|
02373|028|B||
02373|029|D|DISCUSSION:  This interaction is based on class labeling for these agents.|
02373|030|D|Although there is no clinical documentation for an interaction between|
02373|031|D|dapoxetine and either the elective serotonin reuptake inhibitors (SSRIs),|
02373|032|D|serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic|
02373|033|D|antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or|
02373|034|D|St. John's Wort, caution is still warranted.  This syndrome has been|
02373|035|D|reported with the selective serotonin reuptake inhibitors and other|
02373|036|D|serotonergic agents, including sumatriptan and dihydroergotamine.|
02373|037|B||
02373|038|R|REFERENCES:|
02373|039|B||
02373|040|R|1.Priligy (dapoxetine hydrochloride) Australian prescribing information.|1
02373|041|R|  Ortho-McNeil Pharmaceutical March 19, 2013.|1
02373|042|R|2.Priligy (dapoxetine hydrochloride) UK summary of product characteristics.|1
02373|043|R|  A. Menarini Farmaceutica Internazionale SRL April 15, 2014.|1
02373|044|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02373|045|R|  352(11):1112-20.|6
02374|001|T|MONOGRAPH TITLE:  Vasopressin Antagonists/Hypertonic Saline|
02374|002|B||
02374|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02374|004|L|of severe adverse interaction.|
02374|005|B||
02374|006|A|MECHANISM OF ACTION:  Concurrent administration of vasopressin antagonists|
02374|007|A|and hypertonic saline may result in overly rapid correction of serum sodium|
02374|008|A|levels.(1,2)|
02374|009|B||
02374|010|E|CLINICAL EFFECTS:  Overly rapid correction of serum sodium levels may result|
02374|011|E|in osmotic demyelination.  Symptoms of osmotic demyelination include|
02374|012|E|dysarthria, mutism, dysphagia, lethargy, affective changes, spastic|
02374|013|E|quadriparesis, seizures, coma and/or death.(1,2)|
02374|014|B||
02374|015|P|PREDISPOSING FACTORS:  Patients who are malnourished, have a history of|
02374|016|P|alcoholism, and/or advanced liver disease may be more susceptible to adverse|
02374|017|P|effects of overly rapid hyponatremia correction.(1,2)|
02374|018|B||
02374|019|M|PATIENT MANAGEMENT:  Avoid the concurrent use of vasopressin antagonists and|
02374|020|M|hypertonic saline.  In patients who are malnourished, have a history of|
02374|021|M|alcoholism, and/or advanced liver disease, use slower rates of sodium|
02374|022|M|correction.(1,2)|
02374|023|B||
02374|024|D|DISCUSSION:  Overly rapid correction of serum sodium levels may result in|
02374|025|D|osmotic demyelination.  Symptoms of osmotic demyelination include|
02374|026|D|dysarthria, mutism, dysphagia, lethargy, affective changes, spastic|
02374|027|D|quadriparesis, seizures, coma and/or death.  Patients who are malnourished,|
02374|028|D|have a history of alcoholism, and/or advanced liver disease may be more|
02374|029|D|susceptible to adverse effects of overly rapid hyponatremia correction.|
02374|030|D|Avoid the concurrent use of vasopressin antagonists and hypertonic saline.|
02374|031|D|In patients who are malnourished, have a history of alcoholism, and/or|
02374|032|D|advanced liver disease, use slower rates of sodium correction.(1,2)|
02374|033|B||
02374|034|R|REFERENCES:|
02374|035|B||
02374|036|R|1.Samsca (tolvaptan) US prescribing information. Otsuka Pharmaceutical Co.,|1
02374|037|R|  Ltd. April, 2018.|1
02374|038|R|2.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
02374|039|R|  Pharma US, Inc. October, 2016.|1
02375|001|T|MONOGRAPH TITLE:  Selected Human Immunoglobulins/Estrogens|
02375|002|B||
02375|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02375|004|L|take action as needed.|
02375|005|B||
02375|006|A|MECHANISM OF ACTION:  Concurrent use of human immunoglobulin with estrogens|
02375|007|A|may have additive effects on clotting mechanisms.(1)|
02375|008|B||
02375|009|E|CLINICAL EFFECTS:  Concurrent use of human immunoglobulin with estrogens may|
02375|010|E|increase the risk of thrombosis.  Thrombosis may occur regardless of the|
02375|011|E|route of administration of the immunoglobulin.(1)|
02375|012|B||
02375|013|P|PREDISPOSING FACTORS:  Additional risk factors include advanced age,|
02375|014|P|prolonged immobilization, hypercoagulable states, history of arterial or|
02375|015|P|venous thrombosis, indwelling central vascular catheter, hyperviscosity and|
02375|016|P|cardiovascular risk factors (e.g. coronary artery disease, hypertension,|
02375|017|P|diabetes).(1)|
02375|018|B||
02375|019|M|PATIENT MANAGEMENT:  For patients at risk of thrombosis, administer the|
02375|020|M|minimum concentration of immunoglobulin available at the minimum rate of|
02375|021|M|infusion practicable.  Ensure that patients are adequately hydrated before|
02375|022|M|immunoglobulin is infused.  Patients should be monitored for signs and|
02375|023|M|symptoms of thrombosis.  Assess blood viscosity in patients at risk for|
02375|024|M|hyperviscosity.  Counsel patients on the risk of thrombosis and its signs|
02375|025|M|and symptoms.  Instruct patients to promptly report any symptoms of|
02375|026|M|thrombosis.(1)|
02375|027|B||
02375|028|D|DISCUSSION:  Thrombosis has been associated with the use of human|
02375|029|D|immunoglobulin and may occur without the presence of risk factors and|
02375|030|D|regardless of the route of administration of the immunoglobulin.  Risk|
02375|031|D|factors known to increase the risk of thrombosis include the use of|
02375|032|D|estrogens, advanced age, prolonged immobilization, hypercoagulable states,|
02375|033|D|history of arterial or venous thrombosis, indwelling central vascular|
02375|034|D|catheter, hyperviscosity and cardiovascular risk factors (e.g. coronary|
02375|035|D|artery disease, hypertension, diabetes).  For patients at risk of|
02375|036|D|thrombosis, administer the minimum concentration of immunoglobulin available|
02375|037|D|at the minimum rate of infusion practicable.  Ensure that patients are|
02375|038|D|adequately hydrated before immunoglobulin is infused.  Patients should be|
02375|039|D|monitored for signs and symptoms of thrombosis.  Assess blood viscosity in|
02375|040|D|patients at risk for hyperviscosity.  Counsel patients on the risk of|
02375|041|D|thrombosis and its signs and symptoms.  Instruct patients to promptly report|
02375|042|D|any symptoms of thrombosis.(1)|
02375|043|B||
02375|044|R|REFERENCE:|
02375|045|B||
02375|046|R|1.USFood and Drug Administration. FDA Safety Communication: New boxed|1
02375|047|R|  warning for thrombosis related to human immune globulin products.|1
02375|048|R|  Available at:|1
02375|049|R|  https://primaryimmune.org/fda-safety-communication-new-boxed-warning-for-t|1
02375|050|R|  hrombosis-related-to-human-immune-globulin-products November 14, 2013.|1
02376|001|T|MONOGRAPH TITLE:  Olanzapine Extended Release IM/Ciprofloxacin; Fluvoxamine|
02376|002|B||
02376|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02376|004|L|of severe adverse interaction.|
02376|005|B||
02376|006|A|MECHANISM OF ACTION:  Inhibitors of CYP1A2 may inhibit the metabolism of|
02376|007|A|olanzapine by this pathway.(1-5)|
02376|008|A|   Ciprofloxacin is a moderate CYP1A2 inhibitor and fluvoxamine is a strong|
02376|009|A|CYP1A2 inhibitor.(6,7)|
02376|010|B||
02376|011|E|CLINICAL EFFECTS:  Concurrent use of ciprofloxacin or fluvoxamine may result|
02376|012|E|in elevated levels of and toxicity from olanzapine.  This may be|
02376|013|E|particularly problematic in patients receiving the intramuscular(IM)|
02376|014|E|extended release suspension as this dose form as been associated with|
02376|015|E|post-injection delirium sedation syndrome. Patients with this syndrome have|
02376|016|E|unexpectedly high olanzapine concentrations after a therapeutic dose.|
02376|017|E|Symptoms usually begin within 3 hours of an injection and if not managed may|
02376|018|E|be fatal.  Although the cause has not been identified, very high olanzapine|
02376|019|E|blood levels were also found in two patients who died 3-4 days after a|
02376|020|E|therapeutic dose of extended release olanzapine injection.(8)|
02376|021|B||
02376|022|P|PREDISPOSING FACTORS:  None determined.|
02376|023|B||
02376|024|M|PATIENT MANAGEMENT:  Whenever possible, it would be prudent to use an|
02376|025|M|alternative antibiotic or serotonin reuptake inhibitor.|
02376|026|M|   If concurrent therapy cannot be avoided, the dose of olanzapine may need|
02376|027|M|to be adjusted when ciprofloxacin or fluvoxamine is initiated or|
02376|028|M|discontinued.  Concurrent therapy should be closely monitored for olanzapine|
02376|029|M|side effects as described in the REMS for this product.  Assure that patient|
02376|030|M|has received, read and understood possible serious side effects described in|
02376|031|M|the Medication Guide for olanzapine extended release injection.|
02376|032|B||
02376|033|D|DISCUSSION:  In a study in 10 male smokers with schizophrenia, pretreatment|
02376|034|D|with fluvoxamine (100 mg daily for 10 days) increased olanzapine|
02376|035|D|area-under-curve (AUC), maximum concentration (Cmax), and half-life by|
02376|036|D|30-50%, 12-64%, and by 25-32%, respectively.  Olanzapine volume of|
02376|037|D|distribution and clearance were decreased by 4-26% and 26-38%,|
02376|038|D|respectively.(1)|
02376|039|D|   In a study in 8 schizophrenic patients, the addition of fluvoxamine (100|
02376|040|D|mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from|
02376|041|D|12-112%.  N-desmethylolanzapine levels were not significantly affected.(2)|
02376|042|D|   In a retrospective review, 10 patients receiving concurrent fluvoxamine|
02376|043|D|and olanzapine were compared to 134 patients receiving olanzapine alone. The|
02376|044|D|ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients|
02376|045|D|receiving concurrent fluvoxamine.(3)|
02376|046|D|   Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and|
02376|047|D|by 52%, respectively, in female nonsmokers.  Fluvoxamine has been shown to|
02376|048|D|increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male|
02376|049|D|smokers.(4,5)|
02376|050|B||
02376|051|R|REFERENCES:|
02376|052|B||
02376|053|R|1.Chiu CC, Lane HY, Huang MC, Liu HC, Jann MW, Hon YY, Chang WH, Lu ML.|2
02376|054|R|  Dose-dependent alternations in the pharmacokinetics of olanzapine during|2
02376|055|R|  coadministration of fluvoxamine in patients with schizophrenia. J Clin|2
02376|056|R|  Pharmacol 2004 Dec;44(12):1385-90.|2
02376|057|R|2.Hiemke C, Peled A, Jabarin M, Hadjez J, Weigmann H, Hartter S, Modai I,|2
02376|058|R|  Ritsner M, Silver H. Fluvoxamine augmentation of olanzapine in chronic|2
02376|059|R|  schizophrenia: pharmacokinetic interactions and clinical effects. J Clin|2
02376|060|R|  Psychopharmacol 2002 Oct;22(5):502-6.|2
02376|061|R|3.Weigmann H, Gerek S, Zeisig A, Muller M, Hartter S, Hiemke C. Fluvoxamine|2
02376|062|R|  but not sertraline inhibits the metabolism of olanzapine: evidence from a|2
02376|063|R|  therapeutic drug monitoring service. Ther Drug Monit 2001 Aug;23(4):410-3.|2
02376|064|R|4.Zyprexa (olanzapine) Australian prescribing information. Eli Lilly Pty Ltd|1
02376|065|R|  November 30, 2006.|1
02376|066|R|5.Zyprexa Relprevv (olanzapine ext-rel IM susp.) US prescribing information.|1
02376|067|R|  Eli Lilly and Company February, 2017.|1
02376|068|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
02376|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02376|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02376|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02376|072|R|  11/14/2017.|1
02376|073|R|7.This information is based on an extract from the Certara Drug Interaction|6
02376|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02376|075|R|8.USFood and Drug Administration. FDA Drug Safety Communication: FDA is|1
02376|076|R|  investigating two deaths following injection of long-acting antipsychotic|1
02376|077|R|  Zyprexa Relprevv (olanzapine pamoate) Available at :|1
02376|078|R|  http://www.fda.gov/Drugs/DrugSafety/ucm356971.htm. June 18, 2013.|1
02377|001|T|MONOGRAPH TITLE:  Apixaban/P-gp and Strong CYP3A4 Inhibitors|
02377|002|B||
02377|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02377|004|L|of severe adverse interaction.|
02377|005|B||
02377|006|A|MECHANISM OF ACTION:  Adagrasib, itraconazole, josamycin, ketoconazole,|
02377|007|A|levoketoconazole, lonafarnib, paritaprevir, posaconazole, telaprevir,|
02377|008|A|tucatinib, and telithromycin may inhibit the metabolism of apixaban by|
02377|009|A|CYP3A4 and by P-glycoprotein (P-gp).(1-4)|
02377|010|B||
02377|011|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
02377|012|E|P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and|
02377|013|E|clinical effects of apixaban, including an increased risk of bleeding.(1-4)|
02377|014|B||
02377|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02377|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02377|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
02377|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02377|019|P|risk for bleeding (e.g. NSAIDs).|
02377|020|B||
02377|021|M|PATIENT MANAGEMENT:  The Australian(1) and Canadian(2) manufacturers of|
02377|022|M|apixaban states that the concurrent use of agents that are strong inhibitors|
02377|023|M|of both P-gp and CYP3A4 with apixaban is contraindicated.  The UK|
02377|024|M|manufacturer of apixaban states that concurrent use of these agents is not|
02377|025|M|recommended.(3)  The US manufacturer of apixaban states that if concurrent|
02377|026|M|use cannot be avoided, the dosage of apixaban should be reduced by 50%.  In|
02377|027|M|patients already receiving apixaban 2.5 mg twice daily, avoid the concurrent|
02377|028|M|use of strong inhibitors of both P-gp and CYP3A4.(4)|
02377|029|M|   The US manufacturer of itraconazole states that apixaban is not|
02377|030|M|recommended during and two weeks after itraconazole treatment.(5)|
02377|031|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02377|032|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02377|033|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02377|034|M|patients with any symptoms.|
02377|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02377|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02377|037|M|anticoagulation in patients with active pathologic bleeding.|
02377|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02377|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02377|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02377|041|M|and/or swelling.|
02377|042|B||
02377|043|D|DISCUSSION:  Concurrent ketoconazole (400 mg daily) increased the|
02377|044|D|area-under-curve (AUC) and maximum concentration (Cmax)  of apixaban by|
02377|045|D|2-fold and 1.6-fold, respectively.(1)|
02377|046|D|   P-gp and strong CYP3A4 inhibitors linked to this monograph are:|
02377|047|D|adagrasib, itraconazole, josamycin, ketoconazole, levoketoconazole,|
02377|048|D|lonafarnib, paritaprevir, posaconazole, telaprevir, tucatinib and|
02377|049|D|telithromycin.|
02377|050|B||
02377|051|R|REFERENCES:|
02377|052|B||
02377|053|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
02377|054|R|  Squibb Australia Pty. Ltd. January, 2024.|1
02377|055|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
02377|056|R|  Squibb-Pfizer January, 2025.|1
02377|057|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
02377|058|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
02377|059|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
02377|060|R|  Company April, 2025.|1
02377|061|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02377|062|R|  Products, L.P. February, 2024.|1
02378|001|T|MONOGRAPH TITLE:  Clozapine/Selected Myelosuppressive Agents|
02378|002|B||
02378|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02378|004|L|of severe adverse interaction.|
02378|005|B||
02378|006|A|MECHANISM OF ACTION:  Clozapine and other myelosuppressive agents may be|
02378|007|A|associated with neutropenia or agranulocytosis.(2)|
02378|008|B||
02378|009|E|CLINICAL EFFECTS:  Moderate neutropenia, even if due to combination therapy,|
02378|010|E|may require abrupt discontinuation of clozapine resulting in decompensation|
02378|011|E|of the patient's psychiatric disorder (e.g. schizophrenia).  The disease|
02378|012|E|treated by the myelosuppressive agent may be compromised if myelosuppression|
02378|013|E|requires dose reduction, delay, or discontinuation of the myelosuppressive|
02378|014|E|agent.  Undetected severe neutropenia or agranulocytosis may be fatal.|
02378|015|B||
02378|016|P|PREDISPOSING FACTORS:  Low white blood counts prior to initiation of the|
02378|017|P|myelosuppressive agent may increase risk for clinically significant|
02378|018|P|neutropenia.|
02378|019|B||
02378|020|M|PATIENT MANAGEMENT:  If a patient stabilized on clozapine therapy requires|
02378|021|M|treatment with a myelosuppressive agent, the clozapine prescriber should|
02378|022|M|consult with prescriber of the myelosuppressive agent (e.g. oncologist) to|
02378|023|M|discuss treatment and monitoring options.(2)  More frequent ANC monitoring|
02378|024|M|or treatment alternatives secondary to neutropenic episodes may need to be|
02378|025|M|considered.|
02378|026|M|   Clozapine is only available through a restricted  distribution system|
02378|027|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
02378|028|M|dispensing.(1-2)  For most clozapine patients, clozapine treatment must be|
02378|029|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
02378|030|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
02378|031|M|interrupted for suspected clozapine-induced neutropenia < 500|
02378|032|M|cells/microliter.(2)|
02378|033|B||
02378|034|D|DISCUSSION:  Clozapine is only available through a restricted  distribution|
02378|035|D|system which requires documentation of the ANC prior to dispensing.(1)|
02378|036|D|   Agents linked to this interaction generally have > 5% risk for|
02378|037|D|neutropenia and/or warnings describing risk for myelosuppression in|
02378|038|D|manufacturer prescribing information.(3-26)|
02378|039|B||
02378|040|R|REFERENCES:|
02378|041|B||
02378|042|R|1.FDA (US Food and Drug Administration). Clozapine: Drug Safety|1
02378|043|R|  Communication - FDA Modifies Monitoring for Neutropenia; Approves New|1
02378|044|R|  Shared REMS Program. accessed at:|1
02378|045|R|  http://www.fda.gov/drugs/drugsafety/ucm461853.htm September 15, 2015.|1
02378|046|R|2.Clozaril (clozapine tablets) US prescribing information. Novartis|1
02378|047|R|  Pharmaceuticals Corporation April, 2020.|1
02378|048|R|3.Campath (alemtuzumab) US prescribing information. Genzyme Corporation|1
02378|049|R|  November 2, 2020.|1
02378|050|R|4.Tegretol (carbamazepine) US prescribing information. Novartis|1
02378|051|R|  Pharmaceuticals Corporation September, 2023.|1
02378|052|R|5.Vistide (cidofovir) US prescribing information. Gilead Sciences, Inc.|1
02378|053|R|  September, 2000.|1
02378|054|R|6.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
02378|055|R|  May, 2010.|1
02378|056|R|7.Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia|1
02378|057|R|  & Upjohn Company January, 2020.|1
02378|058|R|8.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
02378|059|R|  Company August, 2010.|1
02378|060|R|9.Hycamtin Injection (topotecan hydrochloride) US prescribing information.|1
02378|061|R|  GlaxoSmithKline June, 2015.|1
02378|062|R|10.Hycamtin Oral (topotecan) US prescribing information. GlaxoSmithKline|1
02378|063|R|   September, 2018.|1
02378|064|R|11.Retrovir (zidovudine) US prescribing information. GlaxoSmithKline|1
02378|065|R|   September, 2018.|1
02378|066|R|12.Carbplatin Inj. US prescribing information. Teva October, 2011.|1
02378|067|R|13.Ridaura (auranofin) US prescribing information. Prometheus Laboratories|1
02378|068|R|   August, 2007.|1
02378|069|R|14.Leukeran (Chlorambucil) US prescribing information. GlaxoSmithKline|1
02378|070|R|   October, 2011.|1
02378|071|R|15.Cytovene IV (ganciclovir) US prescribing information. Genentech Inc.|1
02378|072|R|   August, 2018.|1
02378|073|R|16.Zevalin (ibritumomab) US prescribing information. Spectrum|1
02378|074|R|   Pharmaceuticals September, 2013.|1
02378|075|R|17.Revlimid (lenalidomide) US prescribing information. Celgene Corp.|1
02378|076|R|   January, 2019.|1
02378|077|R|18.Mitoxantrone Inj. US prescribing information. APP Pharmaceuticals July,|1
02378|078|R|   2010.|1
02378|079|R|19.Vumon (teniposide) US prescribing information. E.R. Squibb & Sons|1
02378|080|R|   October, 2011.|1
02378|081|R|20.Bexxar (tositumomab) US prescribing information. GlaxoSmithKline October,|1
02378|082|R|   2005.|1
02378|083|R|21.Valcyte (valganciclovir) US prescribing information. Genentech June,|1
02378|084|R|   2017.|1
02378|085|R|22.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02378|086|R|   Corporation September, 2024.|1
02378|087|R|23.Lartruvo (olaratumab) US prescribing information. Eli Lilly and Company|1
02378|088|R|   February, 2017.|1
02378|089|R|24.Bavencio (avelumab) US prescribing information. EMD Serono November,|1
02378|090|R|   2020.|1
02378|091|R|25.Zejula (niraparib) US prescribing information. Tesaro July, 2021.|1
02378|092|R|26.Aliqopa (copanlisib) US prescribing information. Bayer October, 2019.|1
02379|001|T|MONOGRAPH TITLE:  Afatinib/P-glycoprotein (P-gp) Inhibitors|
02379|002|B||
02379|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02379|004|L|take action as needed.|
02379|005|B||
02379|006|A|MECHANISM OF ACTION:  Inhibitors of P-glycoprotein (P-gp) may increase the|
02379|007|A|absorption of afatinib.(1)|
02379|008|B||
02379|009|E|CLINICAL EFFECTS:  The concurrent administration of afatinib with an|
02379|010|E|inhibitor of P-glycoprotein may result in elevated levels of afatinib and|
02379|011|E|signs of toxicity.  These signs may include but are not limited to worsening|
02379|012|E|diarrhea, stomatitis, skin rash/exfoliation/bullae or paronychia.(1)|
02379|013|B||
02379|014|P|PREDISPOSING FACTORS:  None determined.|
02379|015|B||
02379|016|M|PATIENT MANAGEMENT:  The US manufacturer of afatinib states the afatinib|
02379|017|M|dose should be reduced by 10 mg if the addition of a P-glycoprotein|
02379|018|M|inhibitor is not tolerated.(1)|
02379|019|M|   If afatinib dose was reduced due to addition of a P-gp inhibitor, resume|
02379|020|M|the previous dose after the P-gp inhibitor is discontinued.(1)|
02379|021|M|   The manufacturer of vimseltinib states concurrent use with P-gp|
02379|022|M|substrates should be avoided.  If concurrent use cannot be avoided, take|
02379|023|M|vimseltinib at least 4 hours prior to afatinib.(2)|
02379|024|B||
02379|025|D|DISCUSSION:  A drug interaction study evaluated the effects of ritonavir 200|
02379|026|D|mg twice daily on afatinib exposure.  Administration of ritonavir 1 hour|
02379|027|D|before afatinib administration increased systemic exposure by 48%.  Afatinib|
02379|028|D|exposure was not changed when ritonavir was administered simultaneously with|
02379|029|D|or 6 hours after afatinib dose.(1)|
02379|030|D|   P-glycoprotein inhibitors linked to this monograph are: amiodarone,|
02379|031|D|asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine,|
02379|032|D|clarithromycin, cobicistat, cyclosporine, danicopan, daridorexant,|
02379|033|D|deutivacaftor, diosmin, dronedarone, erythromycin, flibanserin,|
02379|034|D|fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine,|
02379|035|D|imlunestrant, isavuconazonium, itraconazole, ivacaftor, josamycin,|
02379|036|D|ketoconazole, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib,|
02379|037|D|osimertinib, propafenone, quinidine, ranolazine, ritonavir, saquinavir,|
02379|038|D|selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, telaprevir,|
02379|039|D|tepotinib, tucatinib, valbenazine, vemurafenib, verapamil, vimseltinib and|
02379|040|D|voclosporin.(1-3)|
02379|041|B||
02379|042|R|REFERENCES:|
02379|043|B||
02379|044|R|1.Gilotrif (afatinib) prescribing information. Boehringer Ingelheim|1
02379|045|R|  Pharmaceuticals, Inc. October, 2019.|1
02379|046|R|2.Romvimza (vimseltinib) US prescribing information. Deciphera|1
02379|047|R|  Pharmaceuticals, LLC February, 2025.|1
02379|048|R|3.This information is based on an extract from the Certara Drug Interaction|6
02379|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02380|001|T|MONOGRAPH TITLE:  Afatinib/P-glycoprotein (P-gp) Inducers; Phenobarbital|
02380|002|B||
02380|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02380|004|L|take action as needed.|
02380|005|B||
02380|006|A|MECHANISM OF ACTION:  Afatinib is a substrate of the intestinal efflux|
02380|007|A|transporter P-glycoprotein (P-gp).  Apalutamide, carbamazepine, efavirenz,|
02380|008|A|lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort|
02380|009|A|induce production of P-gp which may lead to decreased exposure to|
02380|010|A|afatinib.(1,2)  Phenobarbital may also induce the metabolism of afatinib.(1)|
02380|011|A|Primidone is metabolized to phenobarbital.|
02380|012|B||
02380|013|E|CLINICAL EFFECTS:  Concurrent or recent use of P-glycoprotein inducers|
02380|014|E|(apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin,|
02380|015|E|rifampin, rifapentine, or St. John's wort), phenobarbital, or primidone may|
02380|016|E|result in decreased levels and effectiveness of afatinib.|
02380|017|B||
02380|018|P|PREDISPOSING FACTORS:  None determined.|
02380|019|B||
02380|020|M|PATIENT MANAGEMENT:  The manufacturer of afatinib recommends an increase of|
02380|021|M|afatinib dose by 10 mg per day as tolerated in patients receiving chronic|
02380|022|M|therapy with a P-gp inducer or phenobarbital.(1) Onset of induction is|
02380|023|M|gradual and maximal induction may be delayed for many days or longer,|
02380|024|M|depending upon the inducing agent and dose.|
02380|025|M|   If the P-gp inducer, phenobarbital, or primidone is stopped, the|
02380|026|M|manufacturer of afatinib recommends resumption of previous afatinib dose 2|
02380|027|M|to 3 days after discontinuation of the inducing agent.(1)|
02380|028|B||
02380|029|D|DISCUSSION:  In a drug interaction study, co-administration of rifampin 600|
02380|030|D|mg once daily for 7 days decreased afatinib exposure 34%.(1)  P-gp inducers|
02380|031|D|include apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin,|
02380|032|D|rifabutin, rifampin, rifapentine, and St. John's wort.(1,2)  Based on 2 case|
02380|033|D|reports(3,4) and in vitro studies,(5,6) the manufacturer of afatinib also|
02380|034|D|includes phenobarbital as a P-gp inducer.(1)|
02380|035|B||
02380|036|R|REFERENCES:|
02380|037|B||
02380|038|R|1.Gilotrif (afatinib) prescribing information. Boehringer Ingelheim|1
02380|039|R|  Pharmaceuticals, Inc. October, 2019.|1
02380|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
02380|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02380|042|R|3.Dagan G, Perlman A, Hochberg-Klein S, Kalish Y, Muszkat M. Managing Direct|3
02380|043|R|  Oral Anticoagulants in Patients With Antiepileptic Medication. Can J|3
02380|044|R|  Cardiol 2018 Nov;34(11):1534.e1-1534.e3.|3
02380|045|R|4.King PK, Stump TA, Walkama AM, Ash BM, Bowling SM. Management of|3
02380|046|R|  Phenobarbital and Apixaban Interaction in Recurrent Cardioembolic  Stroke.|3
02380|047|R|  Ann Pharmacother 2018 Jun;52(6):605-606.|3
02380|048|R|5.Wen T, Liu YC, Yang HW, Liu HY, Liu XD, Wang GJ, Xie L. Effect of 21-day|5
02380|049|R|  exposure of phenobarbital, carbamazepine and phenytoin on  P-glycoprotein|5
02380|050|R|  expression and activity in the rat brain. J Neurol Sci 2008 Jul 15;|5
02380|051|R|  270(1-2):99-106.|5
02380|052|R|6.Yang HW, Liu HY, Liu X, Zhang DM, Liu YC, Liu XD, Wang GJ, Xie L.|5
02380|053|R|  Increased P-glycoprotein function and level after long-term exposure of|5
02380|054|R|  four  antiepileptic drugs to rat brain microvascular endothelial cells in|5
02380|055|R|  vitro. Neurosci Lett 2008 Apr 4;434(3):299-303.|5
02381|001|T|MONOGRAPH TITLE:  Digoxin, Oral/Acarbose|
02381|002|B||
02381|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02381|004|L|take action as needed.|
02381|005|B||
02381|006|A|MECHANISM OF ACTION:  Acarbose may alter the absorption of digoxin.(1)|
02381|007|B||
02381|008|E|CLINICAL EFFECTS:  Concurrent use of acarbose with digoxin may result in|
02381|009|E|decreased levels and effectiveness of digoxin.(1-2)|
02381|010|B||
02381|011|P|PREDISPOSING FACTORS:  None determined.|
02381|012|B||
02381|013|M|PATIENT MANAGEMENT:  Monitor digoxin levels if acarbose is initiated or|
02381|014|M|discontinued.  The dosage of digoxin may need to be increased by 20% to|
02381|015|M|40%.(2)|
02381|016|B||
02381|017|D|DISCUSSION:  In a randomized cross-over study in healthy subjects, the|
02381|018|D|area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of|
02381|019|D|digoxin (0.5 mg) was significantly lower when digoxin was administered 30|
02381|020|D|minutes after a single dose of acarbose (200 mg) or 30 minutes after the|
02381|021|D|tenth dose of acarbose (100 mg TID) when compared to the administration of|
02381|022|D|digoxin alone.(1)|
02381|023|D|   In a randomized cross-over study in healthy subjects, there were no|
02381|024|D|effects on digoxin AUC when a single dose of digoxin (0.75 mg) was|
02381|025|D|administered 60 minutes after acarbose (50 mg TID for 8 days).  Digoxin Cmax|
02381|026|D|increased 28%.(3)|
02381|027|D|   There are several case reports of digoxin levels decreasing to|
02381|028|D|subtherapeutic levels following the addition of acarbose to therapy.(4-6)|
02381|029|B||
02381|030|R|REFERENCES:|
02381|031|B||
02381|032|R|1.Miura T, Ueno K, Tanaka K, Sugiura Y, Mizutani M, Takatsu F, Takano Y,|2
02381|033|R|  Shibakawa M. Impairment of absorption of digoxin by acarbose. J Clin|2
02381|034|R|  Pharmacol 1998 Jul;38(7):654-7.|2
02381|035|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
02381|036|R|  Pharmaceuticals, Inc. August, 2018.|1
02381|037|R|3.Cohen E, Almog S, Staruvin D, Garty M. Do therapeutic doses of acarbose|2
02381|038|R|  alter the pharmacokinetics of digoxin?. Isr Med Assoc J 2002 Oct;|2
02381|039|R|  4(10):772-5.|2
02381|040|R|4.Nagai Y, Hayakawa T, Abe T, Nomura G. Are there different effects of|3
02381|041|R|  acarbose and voglibose on serum levels of digoxin  in a diabetic patient|3
02381|042|R|  with congestive heart failure?. Diabetes Care 2000 Nov;23(11):1703.|3
02381|043|R|5.Ben-Ami H, Krivoy N, Nagachandran P, Roguin A, Edoute Y. An interaction|3
02381|044|R|  between digoxin and acarbose. Diabetes Care 1999 May;22(5):860-1.|3
02381|045|R|6.Serrano JS, Jimenez CM, Serrano MI, Balboa B. A possible interaction of|3
02381|046|R|  potential clinical interest between digoxin and acarbose. Clin Pharmacol|3
02381|047|R|  Ther 1996 Nov;60(5):589-92.|3
02382|001|T|MONOGRAPH TITLE:  Bosentan/Strong and Moderate CYP3A4 Inhibitors|
02382|002|B||
02382|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02382|004|L|of severe adverse interaction.|
02382|005|B||
02382|006|A|MECHANISM OF ACTION:  Bosentan is metabolized by CYP2C9 and CYP3A4.  It is|
02382|007|A|also an inducer of these enzymes.  With regular dosing bosentan auto-induces|
02382|008|A|its own metabolism.(1)  Strong and moderate CYP3A4 inhibitors may inhibit|
02382|009|A|the CYP3A4 mediated metabolism of bosentan.(1,2)|
02382|010|B||
02382|011|E|CLINICAL EFFECTS:  Concurrent use of bosentan with an inhibitor of CYP3A4|
02382|012|E|may result in elevated levels of and toxicity from bosentan.(1)|
02382|013|B||
02382|014|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, a CYP3A4 inhibitor and a|
02382|015|P|CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
02382|016|P|sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major|
02382|017|P|metabolic pathways for bosentan, resulting in large increases in bosentan|
02382|018|P|plasma concentrations.(1,3)|
02382|019|B||
02382|020|M|PATIENT MANAGEMENT:  Review medication list to see if patient is also|
02382|021|M|receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole,|
02382|022|M|oxandrolone, sulfinpyrazone, or phenylbutazone).|
02382|023|M|   Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended|
02382|024|M|by the manufacturer as the combination may lead to large increases in|
02382|025|M|bosentan plasma concentrations.(1)|
02382|026|M|   For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated,|
02382|027|M|monitor tolerance to concomitant therapy and adjust bosentan dose if needed.|
02382|028|M|   In patients who have been receiving a strong CYP3A4 inhibitor for at|
02382|029|M|least 10 days, start bosentan at 62.5 mg once daily or every other day based|
02382|030|M|upon individual tolerability.|
02382|031|M|   Discontinue use of bosentan at least 36 hours prior to initiation of a|
02382|032|M|strong CYP3A4 inhibitor.|
02382|033|M|   After at least 10 days following the initiation of a strong CYP3A4|
02382|034|M|inhibitor, resume bosentan at 62.5 mg once daily or every other day based|
02382|035|M|upon individual tolerability.|
02382|036|B||
02382|037|D|DISCUSSION:  In a study in healthy subjects, concurrent bosentan and|
02382|038|D|ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan|
02382|039|D|steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by|
02382|040|D|2.1-fold and 2.3-fold, respectively.(2)|
02382|041|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
02382|042|D|boceprevir, ceritinib, clarithromycin, itraconazole, josamycin,|
02382|043|D|ketoconazole, levoketoconazole, mibefradil, mifepristone, nefazodone,|
02382|044|D|posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin,|
02382|045|D|tucatinib, and voriconazole.(3)|
02382|046|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  aprepitant,|
02382|047|D|berotralstat, clofazimine, conivaptan, diltiazem, dronedarone, erythromycin,|
02382|048|D|fluvoxamine, fosnetupitant, imatinib, isavuconazonium, letermovir,|
02382|049|D|netupitant, nilotinib, schisandra, stiripentol, treosulfan, and|
02382|050|D|verapamil.(3)|
02382|051|B||
02382|052|R|REFERENCES:|
02382|053|B||
02382|054|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
02382|055|R|  US, Inc. September 5, 2017.|1
02382|056|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
02382|057|R|  Pharmaceuticals February, 2014.|1
02382|058|R|3.This information is based on an extract from the Certara Drug Interaction|6
02382|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02383|001|T|MONOGRAPH TITLE:  Pravastatin/Paroxetine|
02383|002|B||
02383|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02383|004|L|take action as needed.|
02383|005|B||
02383|006|A|MECHANISM OF ACTION:  The specific combination of pravastatin and paroxetine|
02383|007|A|increases the risk for hyperglycemia. The mechanism of action is not clear.|
02383|008|B||
02383|009|E|CLINICAL EFFECTS:  Use of pravastatin or paroxetine separately has been|
02383|010|E|associated with minor or no elevations in random glucose measurements.|
02383|011|E|Concurrent use of pravastatin and paroxetine has been associated with a mean|
02383|012|E|glucose increase of 18.5 mg/dl in non-diabetic subjects and 48.1 mg/dl in|
02383|013|E|diabetic subjects.(1)|
02383|014|B||
02383|015|P|PREDISPOSING FACTORS:  None determined.|
02383|016|B||
02383|017|M|PATIENT MANAGEMENT:  Monitor diabetic patients newly started on this|
02383|018|M|combination for elevated glucose measurements. Consider changing to a|
02383|019|M|different statin or SSRI if needed to maintain control of diabetes.|
02383|020|M|   For non-diabetic patients with elevated random glucose measurements, test|
02383|021|M|fasting glucose concentration. If significantly elevated, change to a|
02383|022|M|different statin or SSRI.|
02383|023|B||
02383|024|D|DISCUSSION:  Study authors evaluated the FDA Adverse Event Reporting System|
02383|025|D|(FAERS) for potential drug-drug interaction signals and found a potential|
02383|026|D|signal for a pravastatin - paroxetine interaction. To follow up on this|
02383|027|D|finding, they performed data mining of electronic medical records (EMRs) at|
02383|028|D|3 academic medical centers. Pre and post treatment random blood glucose|
02383|029|D|levels were evaluated for patients started on paroxetine only, pravastatin|
02383|030|D|only, or on the combination of paroxetine and pravastatin.(1)|
02383|031|D|   In the combined site analysis:|
02383|032|D|    - use of paroxetine only, or pravastatin only was not associated with an|
02383|033|D|increase in glucose levels.|
02383|034|D|    - in non-diabetic subjects taking both paroxetine and pravastatin, post|
02383|035|D|treatment increase in random glucose levels was 18.5 mg/dl (CI: 9.2,27.8)|
02383|036|D|    - in diabetic subjects receiving the combination, post treatment|
02383|037|D|increase in random glucose levels was 48.1 mg/dl (CI: 35.1,61.1)(1)|
02383|038|D|   A further evaluation of 324 patients who received any SSRI (except|
02383|039|D|paroxetine) and any statin (other than pravastatin) found an increase in|
02383|040|D|glucose levels of 1.7 mg/dl. Analysis of 115 patients on paroxetine and any|
02383|041|D|other statin found no significant effect on glucose levels. However,|
02383|042|D|analysis of 38 pravastatin patients on any other SSRI found an increase in|
02383|043|D|random glucose levels of 9.5 mg/dl (P = 0.008).(1)|
02383|044|D|   A pharmacovigilance study of web searches looked for signals of this|
02383|045|D|interaction prior to the 2011 study cited above. They found that people who|
02383|046|D|performed both paroxetine and pravastatin searches during the study period|
02383|047|D|were about twice as likely to also search for hyperglycemia-related search|
02383|048|D|terms compared with users who performed only  paroxetine or pravastatin|
02383|049|D|searches.(2)|
02383|050|B||
02383|051|R|REFERENCES:|
02383|052|B||
02383|053|R|1.Tatonetti NP, Denny JC, Murphy SN, Fernald GH, Krishnan G, Castro V, Yue|2
02383|054|R|  P, Tsao PS, Kohane I, Roden DM, Altman RB. Detecting drug interactions|2
02383|055|R|  from adverse-event reports: interaction between paroxetine and pravastatin|2
02383|056|R|  increases blood glucose levels. Clin Pharmacol Ther 2011 Jul;90(1):133-42.|2
02383|057|R|2.White RW, Tatonetti NP, Shah NH, Altman RB, Horvitz E. Web-scale|2
02383|058|R|  pharmacovigilance: listening to signals from the crowd. J Am Med Inform|2
02383|059|R|  Assoc 2013 May 1;20(3):404-8.|2
02384|001|T|MONOGRAPH TITLE:  Dolutegravir/Selected Oral Cations|
02384|002|B||
02384|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02384|004|L|take action as needed.|
02384|005|B||
02384|006|A|MECHANISM OF ACTION:  Aluminum, calcium, iron, lanthanum, magnesium,|
02384|007|A|sucralfate, and zinc may form chelation compounds with dolutegravir.(1)|
02384|008|B||
02384|009|E|CLINICAL EFFECTS:  Simultaneous administration or administration of products|
02384|010|E|containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate|
02384|011|E|close to the administration time of dolutegravir may result in decreased|
02384|012|E|absorption and clinical effectiveness of dolutegravir.(1)|
02384|013|B||
02384|014|P|PREDISPOSING FACTORS:  None determined.|
02384|015|B||
02384|016|M|PATIENT MANAGEMENT:  If possible, avoid concurrent therapy with dolutegravir|
02384|017|M|and cation-containing products.  If it is necessary to use these agents|
02384|018|M|concurrently, dolutegravir should be administered 2 hours before or 6 hours|
02384|019|M|after taking these medications.(1)|
02384|020|M|   Alternatively, dolutegravir and supplements containing calcium or iron|
02384|021|M|can be taken together with food.(1)|
02384|022|B||
02384|023|D|DISCUSSION:  In a study in 16 subjects, the administration of an antacid|
02384|024|D|(Maalox - aluminum and magnesium hydroxide) simultaneously with dolutegravir|
02384|025|D|(50 mg single dose) decreased the maximum concentration (Cmax),|
02384|026|D|area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by|
02384|027|D|72%, 74%, and 74%, respectively.(1)|
02384|028|D|   In a study in 16 subjects, the administration of an antacid (Maalox -|
02384|029|D|aluminum and magnesium hydroxide) 2 hours after dolutegravir (50 mg single|
02384|030|D|dose) decreased dolutegravir Cmax, AUC, and Cmin by 18%, 26%, and 30%,|
02384|031|D|respectively.(1)|
02384|032|D|   In a study in 16 subjects, the administration of a multiple vitamin|
02384|033|D|(One-A-Day) simultaneously with dolutegravir (50 mg single dose) decreased|
02384|034|D|dolutegravir Cmax, AUC, and Cmin by 35%, 33%, and 32%, respectively.(1)|
02384|035|B||
02384|036|R|REFERENCE:|
02384|037|B||
02384|038|R|1.Tivicay (dolutegravir) US prescribing information. GlaxoSmithKline|1
02384|039|R|  October, 2022.|1
02385|001|T|MONOGRAPH TITLE:  Dolutegravir/Etravirine; Efavirenz; Nevirapine|
02385|002|B||
02385|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02385|004|L|of severe adverse interaction.|
02385|005|B||
02385|006|A|MECHANISM OF ACTION:  Etravirine, efavirenz, and nevirapine may induce the|
02385|007|A|metabolism of dolutegravir via CYP3A4.(1,2)   Efavirenz may also induce|
02385|008|A|dolutegravir metabolism via UGT enzymes.|
02385|009|B||
02385|010|E|CLINICAL EFFECTS:  Concurrent use of etravirine, efavirenz, or nevirapine|
02385|011|E|and dolutegravir may result in decreased levels of and clinical|
02385|012|E|effectiveness of dolutegravir.(1,2)|
02385|013|B||
02385|014|P|PREDISPOSING FACTORS:  None determined.|
02385|015|B||
02385|016|M|PATIENT MANAGEMENT:  The US manufacturer of dolutegravir states that|
02385|017|M|dolutegravir should not be used with etravirine without atazanavir/ritonavir|
02385|018|M|(ATVr), darunavir/ritonavir (DRVr), or lopinavir/ritonavir (LPVr).(1)  The|
02385|019|M|Canadian(3) and UK(4) manufacturers of dolutegravir state that INSTI-naive|
02385|020|M|patients may use etravirine concurrently with dolutegravir at an increased|
02385|021|M|dose of 50 mg twice daily.  In pediatric patients, the weight-based once|
02385|022|M|daily dose should be given twice daily.  No dose adjustment for dolutegravir|
02385|023|M|is needed when used with etravirine along with concurrent ATVr, DRVr, or|
02385|024|M|LPVr.(1,3-5)|
02385|025|M|   When used with efavirenz, the dosage of dolutegravir should be 50 mg|
02385|026|M|twice daily.(1,2)  When using the combination|
02385|027|M|abacavir-dolutegravir-lamivudine product, an additional 50 mg dolutegravir|
02385|028|M|table should be taken 12 hours apart from the combination product.(2)|
02385|029|M|Alternative combinations that do not induce metabolic inducers should be|
02385|030|M|considered when possible for INSTI-experience patients with certain|
02385|031|M|INSTI-associated resistance substitutions or clinically suspected INSTI|
02385|032|M|resistance.  In pediatric patients, increase the weight-based dose to twice|
02385|033|M|daily.  Refer to the current labeling for the specific dosing|
02385|034|M|recommendation.(1)|
02385|035|M|   Although the US(1) and Canadian(3) manufacturers of dolutegravir|
02385|036|M|recommend avoiding concurrent use of nevirapine, the US Department of Health|
02385|037|M|and Human Services HIV guidelines recommend standard doses of dolutegravir|
02385|038|M|when administered concurrently with nevirapine.(5)  The UK manufacturer of|
02385|039|M|dolutegravir recommends increasing the dose of dolutegravir to 50 mg twice|
02385|040|M|daily when used concurrently with nevirapine.(4)|
02385|041|B||
02385|042|D|DISCUSSION:  In a study in 12 subjects, the administration of efavirenz with|
02385|043|D|dolutegravir (50 mg daily) decreased the maximum concentration (Cmax),|
02385|044|D|area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by|
02385|045|D|39%, 57%, and 75%, respectively.(1)|
02385|046|D|   In a study in 16 subjects, the administration of etravirine with|
02385|047|D|dolutegravir (50 mg daily) decreased the Cmax, AUC, and Cmin of dolutegravir|
02385|048|D|by 52%, 71%, and 88%, respectively.(1)|
02385|049|D|   In a study in 9 subjects, the administration of etravirine and|
02385|050|D|darunavir/ritonavir (200 mg and 600/100 mg BID) with dolutegravir (50 mg|
02385|051|D|daily) decreased the Cmax, AUC, and Cmin of dolutegravir by 12%, 25%, and|
02385|052|D|37%, respectively.(1)|
02385|053|D|   In a study in 8 subjects, the administration of efavirenz and|
02385|054|D|lopinavir/ritonavir (200 mg and 400/100 mg BID) with dolutegravir (50 mg|
02385|055|D|daily) increased the Cmax, AUC, and Cmin of dolutegravir by 7%, 11%, and|
02385|056|D|28%, respectively.(1)|
02385|057|B||
02385|058|R|REFERENCES:|
02385|059|B||
02385|060|R|1.Tivicay (dolutegravir) US prescribing information. GlaxoSmithKline|1
02385|061|R|  October, 2022.|1
02385|062|R|2.Triumeq (abacavir-dolutegravir-lamivudine) US prescribing information.|1
02385|063|R|  Viiv Healthcare June, 2023.|1
02385|064|R|3.Tivicay (dolutegravir sodium) UK summary of product characteristics. ViiV|1
02385|065|R|  Healthcare UK Ltd January, 2021.|1
02385|066|R|4.Tivicay (dolutegravir) Canadian prescribing information. ViiV Healthcare|1
02385|067|R|  ULC August, 2018.|1
02385|068|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02385|069|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02385|070|R|  HIV. Department of Health and Human Services. Available at|6
02385|071|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
02385|072|R|  new-guidelines June 13, 2021.|6
02386|001|T|MONOGRAPH TITLE:  Dolutegravir/Selected UGT1A & CYP3A4 Inducers|
02386|002|B||
02386|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02386|004|L|of severe adverse interaction.|
02386|005|B||
02386|006|A|MECHANISM OF ACTION:  Dolutegravir is metabolized by UGT1A1 and to a smaller|
02386|007|A|extent by CYP3A4.  Inducers of UGT1A1 and CYP3A4 may induce the metabolism|
02386|008|A|of dolutegravir.(1-6)|
02386|009|B||
02386|010|E|CLINICAL EFFECTS:  Concurrent use of UGT1A1 and CYP3A4 inducers may result|
02386|011|E|in decreased levels of and clinical effectiveness of dolutegravir.(1-6)|
02386|012|B||
02386|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02386|014|P|of the inducer for longer than 1-2 weeks.|
02386|015|B||
02386|016|M|PATIENT MANAGEMENT:  When used with carbamazepine, fosamprenavir/ritonavir,|
02386|017|M|rifampin, or tipranavir/ritonavir, the dosage of dolutegravir should be 50|
02386|018|M|mg twice daily.  When using the combination abacavir-dolutegravir-lamivudine|
02386|019|M|or dolutegravir-lamivudine product, an additional 50 mg dolutegravir table|
02386|020|M|should be taken 12 hours apart from the combination product.  In pediatric|
02386|021|M|patients, increase the weight-based dose to twice daily. Refer to the|
02386|022|M|current labeling for the specific dosing recommendation. Alternative|
02386|023|M|combinations that do not induce metabolic inducers should be considered when|
02386|024|M|possible for INSTI-experience patients with certain INSTI-associated|
02386|025|M|resistance substitutions or clinically suspected INSTI resistance.(1,4-6)|
02386|026|M|   Recommendations for other UGT1A1 and CYP3A4 inducers differ by region.|
02386|027|M|The US manufacturer of dolutegravir states that concurrent use should be|
02386|028|M|avoided due to insufficient data to make dosing recommendations for|
02386|029|M|concomitant use.(1,4)  The Canadian and UK manufacturers of dolutegravir|
02386|030|M|state that the dosage of dolutegravir should be 50 mg twice daily when used|
02386|031|M|concurrently with other UGT1A1 and CYP3A4 inducers.  When using the|
02386|032|M|combination abacavir-dolutegravir-lamivudine product, an additional 50 mg|
02386|033|M|dolutegravir table should be taken 12 hours apart from the combination|
02386|034|M|product.  In pediatric patients, increase the weight-based dose to twice|
02386|035|M|daily. Refer to the current labeling for the specific dosing recommendation.|
02386|036|M|Alternative combinations that do not induce metabolic inducers should be|
02386|037|M|considered when possible for patients with certain INSTI-associated|
02386|038|M|resistance substitutions or clinically suspected INSTI resistance.(5,6)|
02386|039|B||
02386|040|D|DISCUSSION:  In a study in 12 subjects, the administration of|
02386|041|D|fosamprenavir/ritonavir (700/100 mg BID) with dolutegravir (50 mg daily)|
02386|042|D|decreased the maximum concentration (Cmax), area-under-curve (AUC), and|
02386|043|D|minimum concentration (Cmin) of dolutegravir by 24%, 35%, and 49%,|
02386|044|D|respectively.(1)|
02386|045|D|   In a study in 11 subjects, the administration of rifampin (600 mg daily)|
02386|046|D|with dolutegravir (50 mg BID) decreased the Cmax, AUC, and Cmin of|
02386|047|D|dolutegravir by 43%, 54%, and 32%, respectively, when compared to the|
02386|048|D|administration of dolutegravir (50 mg BID) alone.(1)|
02386|049|D|   In a study in 11 subjects, the administration of rifampin (600 mg daily)|
02386|050|D|with dolutegravir (50 mg BID) increased the Cmax, AUC, and Cmin of|
02386|051|D|dolutegravir by 18%, 33%, and 22%, respectively, when compared to the|
02386|052|D|administration of dolutegravir (50 mg daily) alone.(1)|
02386|053|D|   In a study in 14 subjects, the administration of tipranavir/ritonavir|
02386|054|D|(500/200 mg BID) with dolutegravir (50 mg daily) decreased the Cmax, AUC,|
02386|055|D|and Cmin of dolutegravir by 46%, 59%, and 76%, respectively.(1)|
02386|056|D|   In a study in 16 subjects, the administration of carbamazepine (300 mg|
02386|057|D|twice daily) with dolutegravir (50 mg daily) decreased the Cmax, AUC, and|
02386|058|D|Cmin of dolutegravir by 33%, 49%, and 73%, respectively. (1)|
02386|059|D|   UGT1A1 and CYP3A4 inducers linked to this monograph include: apalutamide,|
02386|060|D|barbiturates, carbamazepine, encorafenib, enzalutamide,|
02386|061|D|fosamprenavir/ritonavir, fosphenytoin, ivosidenib, lorlatinib, lumacaftor,|
02386|062|D|mitotane, oxcarbazepine, phenobarbital, phenytoin, primidone, rifampin,|
02386|063|D|rifapentine, and tipranavir/ritonavir.(1,7)|
02386|064|B||
02386|065|R|REFERENCES:|
02386|066|B||
02386|067|R|1.Tivicay (dolutegravir) US prescribing information. GlaxoSmithKline|1
02386|068|R|  October, 2022.|1
02386|069|R|2.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
02386|070|R|  Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
02386|071|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02386|072|R|  for the use of antiretroviral agents in HIV-1-infected adults and|6
02386|073|R|  adolescents. Department of Health and Human Services. Available at|6
02386|074|R|  http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf|6
02386|075|R|  . Accessed March 31, 2016..|6
02386|076|R|4.Triumeq (abacavir-dolutegravir-lamivudine) US prescribing information.|1
02386|077|R|  Viiv Healthcare June, 2023.|1
02386|078|R|5.Triumeq (dolutegravir, abacavir, and lamivudine) Canadian product|1
02386|079|R|  monograph. ViiV Healthcare ULC August 27, 2018.|1
02386|080|R|6.Tivicay (dolutegravir sodium) UK summary of product characteristics. ViiV|1
02386|081|R|  Healthcare UK Ltd January, 2021.|1
02386|082|R|7.This information is based on an extract from the Certara Drug Interaction|6
02386|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02387|001|T|MONOGRAPH TITLE:  Dofetilide/Dolutegravir|
02387|002|B||
02387|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02387|004|L|is contraindicated and generally should not be dispensed or administered to|
02387|005|L|the same patient.|
02387|006|B||
02387|007|A|MECHANISM OF ACTION:  Dolutegravir may inhibit the elimination of dofetilide|
02387|008|A|by the renal organic cation transporter (OCT2).(1)|
02387|009|B||
02387|010|E|CLINICAL EFFECTS:  Concurrent use of dolutegravir may result in elevated|
02387|011|E|levels of dofetilide.(1)  Dofetilide has been shown to prolong the QTc|
02387|012|E|interval in a dose-dependent fashion.  Concurrent use with other agents that|
02387|013|E|prolong the QTc interval may result in additive effects on the QTc interval|
02387|014|E|which may result in potentially life-threatening cardiac arrhythmias,|
02387|015|E|including torsades de pointes(TdP).(2)|
02387|016|B||
02387|017|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
02387|018|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
02387|019|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
02387|020|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
02387|021|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02387|022|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02387|023|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02387|024|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02387|025|P|advanced age.(3)|
02387|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02387|027|P|higher systemic concentrations of either QT prolonging drug are additional|
02387|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02387|029|P|drug concentrations include rapid infusion of an intravenous dose or|
02387|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02387|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02387|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02387|033|B||
02387|034|M|PATIENT MANAGEMENT:  Concurrent use of dofetilide and dolutegravir is|
02387|035|M|contraindicated.  If dofetilide is to be discontinued, a washout of at least|
02387|036|M|2 days is recommended prior to starting dolutegravir.(1,2)|
02387|037|M|   If concurrent therapy is deemed medically necessary, obtain serum|
02387|038|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
02387|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02387|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02387|041|B||
02387|042|D|DISCUSSION:  Dolutegravir has been shown to inhibit OCT2 in vitro and in|
02387|043|D|vivo and is expected to inhibit the excretion of dofetilide.(1)|
02387|044|B||
02387|045|R|REFERENCES:|
02387|046|B||
02387|047|R|1.Tivicay (dolutegravir) US prescribing information. GlaxoSmithKline|1
02387|048|R|  October, 2022.|1
02387|049|R|2.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
02387|050|R|  2013.|1
02387|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02387|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02387|053|R|  settings: a scientific statement from the American Heart Association and|6
02387|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02387|055|R|  2;55(9):934-47.|6
02388|001|T|MONOGRAPH TITLE:  Valproic Acid/Rifampin|
02388|002|B||
02388|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02388|004|L|of severe adverse interaction.|
02388|005|B||
02388|006|A|MECHANISM OF ACTION:  Rifampin induces the metabolism of valproic acid.(1)|
02388|007|B||
02388|008|E|CLINICAL EFFECTS:  Lower valproic acid concentrations may lead to diminished|
02388|009|E|efficacy, e.g. loss of seizure control, increased frequency of migraine|
02388|010|E|headaches, or new onset/more difficult to control manic episodes.|
02388|011|B||
02388|012|P|PREDISPOSING FACTORS:  None determined.|
02388|013|B||
02388|014|M|PATIENT MANAGEMENT:  Initiation of rifampin in a patient already stabilized|
02388|015|M|on valproic acid therapy will lead to a lowering of valproic acid|
02388|016|M|concentrations.  While induction onset may begin within 3 to 7 days, maximal|
02388|017|M|effects may not be seen for 2 to 3 weeks.  Monitor valproate levels and|
02388|018|M|adjust the dose as needed to maintain therapeutic efficacy.|
02388|019|M|   When rifampin therapy is discontinued, systemic valproic acid|
02388|020|M|concentrations will increase over a 1 to 3 week period as enzyme induction|
02388|021|M|wanes.  Valproic acid dosage may need to be lowered.|
02388|022|B||
02388|023|D|DISCUSSION:  Valproate metabolites are formed via three major pathways:|
02388|024|D|mitochondrial beta-oxidation (40%), glucuronidation (30-50%), and CYP P-450|
02388|025|D|(10%).  Rifampin induces several glucuronidation and CYP P-450 pathways, but|
02388|026|D|not mitochondrial pathways.|
02388|027|D|   A study described in manufacturer prescribing information reports a 40%|
02388|028|D|increase in valproate clearance when rifampin 600 mg daily for 5 days was|
02388|029|D|followed by a single dose of valproate 7 mg/kg.|
02388|030|B||
02388|031|R|REFERENCE:|
02388|032|B||
02388|033|R|1.Depakote (divalproex sodium) US prescribing information. AbbVie Inc.|1
02388|034|R|  February, 2023.|1
02389|001|T|MONOGRAPH TITLE:  Phosphate Supplements;Urine pH Modifiers/Phosphate|
02389|002|T|Reducers|
02389|003|B||
02389|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02389|005|L|of severe adverse interaction.|
02389|006|B||
02389|007|A|MECHANISM OF ACTION:  Lanthanum and sevelamer bind to phosphate.(1-2)|
02389|008|A|Tenapanor is a sodium/hydrogen exchanger 3 (NHE3) inhibitor.(3)  All three|
02389|009|A|agents are used to lower phosphate absorption in the body.(1-3)|
02389|010|B||
02389|011|E|CLINICAL EFFECTS:  Concurrent use of phosphate supplements or urinary pH|
02389|012|E|modifiers high in phosphate with agents that reduce serum phosphorus may|
02389|013|E|decrease the effectiveness of both agents.|
02389|014|B||
02389|015|P|PREDISPOSING FACTORS:  None determined.|
02389|016|B||
02389|017|M|PATIENT MANAGEMENT:  Patients should normally not receive phosphate|
02389|018|M|supplements or urinary pH modifiers high in phosphate concurrently with|
02389|019|M|agents that reduce serum phosphorus.|
02389|020|B||
02389|021|D|DISCUSSION:  Lanthanum, sevelamer, and tenapanor are indicated to control|
02389|022|D|phosphorus levels.  Consider discontinuing or holding phosphate supplements|
02389|023|D|and urinary pH modifiers high in phosphate in patients receiving these|
02389|024|D|agents.|
02389|025|B||
02389|026|R|REFERENCES:|
02389|027|B||
02389|028|R|1.Renagel (sevelamer hydrochloride) US prescribing information. Genzyme|1
02389|029|R|  Corporation March 9, 2016.|1
02389|030|R|2.Fosrenol (lanthanum carbonate) US prescribing information. Shire US Inc.|1
02389|031|R|  May, 2020.|1
02389|032|R|3.Xphozah (tenapanor) US prescribing information. Ardelyx, Inc. October|1
02389|033|R|  2023.|1
02390|001|T|MONOGRAPH TITLE:  Agents Contraindicated With QT Agents/QT Prolonging Agents|
02390|002|T|(mono deleted 09/16/2013)|
02390|003|B||
02390|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02390|005|L|is contraindicated and generally should not be dispensed or administered to|
02390|006|L|the same patient.|
02390|007|B||
02390|008|A|MECHANISM OF ACTION:  Concurrent use of multiple agents that prolong the QTc|
02390|009|A|interval may result in additive effects on the QTc interval.(1)|
02390|010|B||
02390|011|E|CLINICAL EFFECTS:  The concurrent use of multiple agents that prolong the|
02390|012|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
02390|013|E|including torsades de pointes.(1)|
02390|014|B||
02390|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02390|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02390|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02390|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02390|019|P|gender, or advanced age.(1)|
02390|020|P|    Concurrent use of more than one drug known to cause QT prolongation or|
02390|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02390|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02390|023|P|drug concentrations include: rapid infusion of an intravenous dose or|
02390|024|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
02390|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02390|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02390|027|B||
02390|028|M|PATIENT MANAGEMENT:  The concurrent use of these agents which are known to|
02390|029|M|prolong the QT interval is generally considered contraindicated.  When|
02390|030|M|evaluating the risk/benefit of concurrent therapy, consider the need for ECG|
02390|031|M|evaluations and electrolyte monitoring, concurrent|
02390|032|M|diseases/conditions/medications which increase the risk of QT prolongation,|
02390|033|M|the patient's history of QT prolongation with agents/combinations involved,|
02390|034|M|and the availability of alternative therapy.|
02390|035|B||
02390|036|D|DISCUSSION:  The concurrent use of bepridil,(2) dronedarone,(3)|
02390|037|D|levomethadyl,(4) pimozide,(5) piperaquine-dihydroartemisinin,(6)|
02390|038|D|sertindole,(7) sparfloxacin,(8) or ziprasidone,(9) and QT prolonging agents|
02390|039|D|is contraindicated.|
02390|040|D|   Cisapride,(10) droperidol,(11) and halofantrine(12) should not be used|
02390|041|D|with QT prolonging agents.|
02390|042|D|   The Australian(13) and UK(14) manufacturers of amiodarone state that|
02390|043|D|concurrent use of QT prolonging agents is contraindicated.  The US|
02390|044|D|manufacturer of amiodarone states that concurrent use must be based on a|
02390|045|D|careful assessment of the potential risks and benefits of doing so for each|
02390|046|D|patient.(15)|
02390|047|D|   The UK manufacturer of artemether-lumefantrine states that concurrent use|
02390|048|D|of QT prolonging agents is contraindicated.(16)  The US manufacturer of|
02390|049|D|artemether-lumefantrine states that concurrent use should be avoided.(17)|
02390|050|D|   The Australian manufacturer of disopyramide states that concurrent use|
02390|051|D|with agents liable to produce torsades de pointes is contraindicated.(18)|
02390|052|D|   The manufacturer of dofetilide states that the use of dofetilide with|
02390|053|D|other agents known to prolong the QTc interval is not recommended.(19)|
02390|054|D|   Vemurafenib should not be initiated in patients taking QT prolonging|
02390|055|D|agents.(21)|
02390|056|D|   Agents that are linked to the "QT Prolonging Agents" side of this|
02390|057|D|monograph may have varying degrees of potential to prolong the QTc interval.|
02390|058|D|Agents linked to this monograph have been shown to prolong the QTc interval|
02390|059|D|either through their mechanism of action, through studies on their effects|
02390|060|D|on the QTc interval, or through reports of QTc prolongation and/or torsades|
02390|061|D|de pointes in clinical trials and/or postmarketing reports.(22)|
02390|062|D|   QTc prolongation has been reported during concurrent amiodarone and azole|
02390|063|D|antifungals, fluoroquinolones, and macrolide antibiotics.(5)|
02390|064|D|   One or more of the drug pairs linked to this monograph have been included|
02390|065|D|in a list of interactions that should be considered "high-priority" for|
02390|066|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02390|067|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02390|068|D|Coordinator (ONC) for Health Information Technology.|
02390|069|B||
02390|070|R|REFERENCES:|
02390|071|B||
02390|072|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02390|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02390|074|R|  settings: a scientific statement from the American Heart Association and|6
02390|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02390|076|R|  2;55(9):934-47.|6
02390|077|R|2.Vascor (bepridil hydrochloride) US prescribing information. Ortho-McNeil|1
02390|078|R|  Pharmaceutical, Inc. March, 2000.|1
02390|079|R|3.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
02390|080|R|  March, 2013.|1
02390|081|R|4.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
02390|082|R|  Roxane Laboratories, Inc. May, 2001.|1
02390|083|R|5.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
02390|084|R|  2011.|1
02390|085|R|6.Eurartesim (piperaquine tetraphosphate-dihydroartemisinin) UK summary of|1
02390|086|R|  product characteristics. Sigma-tau Pharma Limited UK October 27. 2011.|1
02390|087|R|7.Serdolect (sertindole) UK summary of product characteristics. Lundbeck|1
02390|088|R|  Limited October 25, 1996.|1
02390|089|R|8.Zagam (sparfloxacin) US prescribing information. Bertek Pharmaceuticals,|1
02390|090|R|  Inc. February, 2003.|1
02390|091|R|9.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
02390|092|R|  December, 2010.|1
02390|093|R|10.Propulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
02390|094|R|   January, 2000.|1
02390|095|R|11.Inapsine (droperidol) US prescribing information. Akorn, Inc. November,|1
02390|096|R|   2001.|1
02390|097|R|12.Halfan (halofantrine hydrochloride) US prescribing information.|1
02390|098|R|   SmithKline Beecham Pharmaceuticals October, 2001.|1
02390|099|R|13.Cordarone X (amiodarone hydrochloride) Australian prescribing|1
02390|100|R|   information. Sanofi-Synthelabo Australia Pty Limited Augsut 15, 2007.|1
02390|101|R|14.Cordarone X (amiodarone hydrochloride) UK summary of product|1
02390|102|R|   characteristics. Sanofi-Aventis July 6, 2010.|1
02390|103|R|15.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
02390|104|R|   Pharmaceuticals January, 2014.|1
02390|105|R|16.Riamet (artemether/lumefantrine) UK summary of product characteristics.|1
02390|106|R|   Novartis Pharmaceuticals UK Ltd. June 27, 2001.|1
02390|107|R|17.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
02390|108|R|   Pharmaceuticals Corporation April, 2013.|1
02390|109|R|18.Rythmodan (disopyramide) Australian prescribing information. Aventis|1
02390|110|R|   Pharma Pty Ltd. September 22, 2000.|1
02390|111|R|19.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. February,|1
02390|112|R|   2011.|1
02390|113|R|20.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
02390|114|R|   prescribing information. Avanir  Pharmaceuticals June, 2019.|1
02390|115|R|21.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02390|116|R|   March, 2014.|1
02390|117|R|22.USDepartment of Health and Human Services Food and Drug Administration.|1
02390|118|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02390|119|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02390|120|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02390|121|R|23.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02390|122|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02390|123|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02390|124|R|   19(5):735-43.|6
02391|001|T|MONOGRAPH TITLE:  Agents to Avoid-Require Special Precautions With/QT Agents|
02391|002|T|(mono deleted 09/16/2013)|
02391|003|B||
02391|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02391|005|L|of severe adverse interaction.|
02391|006|B||
02391|007|A|MECHANISM OF ACTION:  Concurrent use of multiple agents that prolong the QTc|
02391|008|A|interval may result in additive effects on the QTc interval.(1)|
02391|009|B||
02391|010|E|CLINICAL EFFECTS:  The concurrent use of multiple agents that prolong the|
02391|011|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
02391|012|E|including torsades de pointes.(1)|
02391|013|B||
02391|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02391|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02391|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02391|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02391|018|P|gender, or advanced age.(1)|
02391|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02391|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02391|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02391|022|P|drug concentrations include: rapid infusion of an intravenous dose or|
02391|023|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
02391|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02391|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02391|026|B||
02391|027|M|PATIENT MANAGEMENT:  The concurrent use of these agents which are known to|
02391|028|M|prolong the QT interval should be avoided when possible.  When evaluating|
02391|029|M|the risk/benefit of concurrent therapy, consider the need for ECG|
02391|030|M|evaluations and electrolyte monitoring, concurrent|
02391|031|M|diseases/conditions/medications which increase the risk of QT prolongation,|
02391|032|M|the patient's history of QT prolongation with agents/combinations involved,|
02391|033|M|and the availability of alternative therapy.  If concurrent therapy is|
02391|034|M|warranted, patients should be closely monitored.  Additional actions may be|
02391|035|M|required for specific agents.|
02391|036|M|   The manufacturers of azithromycin,(2) iloperidone,(3) mesoridazine,(4)|
02391|037|M|moxifloxacin,(5) nilotinib,(6) paliperidone,(7) quinine,(8)|
02391|038|M|tetrabenazine,(9) thioridazine,(10) state that concurrent use of QT|
02391|039|M|prolonging agents should be avoided.|
02391|040|M|   If possible, discontinue QT prolongers prior to arsenic trioxide therapy|
02391|041|M|and use caution during coadministration. Patients who reach an absolute QT|
02391|042|M|interval value >500 msec should be reassessed and immediate action should be|
02391|043|M|taken to correct concomitant risk factors, if any, and the risk/benefit of|
02391|044|M|continuing therapy should be considered.  If syncope, rapid or irregular|
02391|045|M|heartbeat develops, the patient should be hospitalized for monitoring, serum|
02391|046|M|electrolytes should be assessed.  Arsenic trioxide therapy should be|
02391|047|M|temporarily discontinued until the QTc interval regresses to below 460 msec,|
02391|048|M|electrolyte abnormalities are corrected, and the syncope and irregular|
02391|049|M|heartbeat cease.(11)|
02391|050|M|   Bedaquiline should be used with caution with QT prolongers.  Patients|
02391|051|M|should receive a baseline electrocardiogram (ECG) and at 2, 12, and 24 weeks|
02391|052|M|of therapy and more closely if receiving concurrent agents that prolong the|
02391|053|M|QT interval.  If a patient develops syncope, perform an ECG.  Bedaquiline|
02391|054|M|and other QT prolongers should be discontinued if the patient develops a|
02391|055|M|clinically significant ventricular arrhythmia or a QTcF of greater than 500|
02391|056|M|msec confirmed on two ECGs.(12)|
02391|057|M|   Concurrent use of citalopram with QT prolongers is not recommended.|
02391|058|M|Consider more frequent ECG monitoring in patients receiving concurrent|
02391|059|M|therapy.  Discontinue citalopram in patients with persistent QTc|
02391|060|M|measurements greater than 500 ms.(13)|
02391|061|M|   Consider periodic ECG and electrolyte monitoring in patients receiving|
02391|062|M|concurrent therapy with crizotinib and QT prolongers.  In patients who|
02391|063|M|develop Grade 3 QTc prolongation, withhold crizotinib until recovery to less|
02391|064|M|than or equal to Grade 1, then resume crizotinib at a dosage of 200 mg twice|
02391|065|M|daily.  If the patient re-develops Grade 3 QTc prolongation, withhold|
02391|066|M|crizotinib until recovery to less than or equal to Grade 1, then resume|
02391|067|M|crizotinib at a dosage of 250 mg daily.  If the patient re-develops Grade 3|
02391|068|M|prolongation again, permanently discontinue crizotinib.  In patients who|
02391|069|M|develop Grade 4 QTc prolongation, permanently discontinue crizotinib.(14)|
02391|070|M|   Patients receiving concurrent therapy with eribulin and QT prolongers|
02391|071|M|should receive ECG monitoring.(15)|
02391|072|M|   The concurrent use of ezogabine with QT prolongers should be approached|
02391|073|M|with caution.  In patients receiving concurrent therapy, an ECG should be|
02391|074|M|performed prior to ezogabine initiation.  In those patients with a corrected|
02391|075|M|QT interval greater than 440 msec at baseline, a repeat ECG should be|
02391|076|M|performed after reaching the maintenance dose of ezogabine.(16)|
02391|077|M|   Patients with a baseline QTc interval > or = 500 milliseconds should not|
02391|078|M|be started on fingolimod.  Patients with pre-existing cardiovascular or|
02391|079|M|cerebrovascular disease (e.g. heart failure, ischemic heart disease, history|
02391|080|M|of myocardial infarction, stroke, or heart block), severe untreated sleep|
02391|081|M|apnea, or a prolonged QTc interval prior to fingolimod initiation should|
02391|082|M|receive cardiologist consultation to evaluate the risks of fingolimod|
02391|083|M|therapy.  Patients receiving concurrent treatment with a QT prolonging agent|
02391|084|M|at the time fingolimod is initiated or resumed should be monitored overnight|
02391|085|M|with continuous ECG monitoring in a medical facility.  Correct hypokalemia|
02391|086|M|or hypomagnesemia prior to starting fingolimod.  US monitoring|
02391|087|M|recommendations in addition to continuous ECG with overnight monitoring:|
02391|088|M|Check blood pressure hourly.  If heart rate (HR) is < 45 beats per minute|
02391|089|M|(BPM) or if the ECG shows new onset of second degree or higher AV block at|
02391|090|M|the end of the monitoring period, then monitoring should continue until the|
02391|091|M|finding has resolved.  If patient requires treatment for symptomatic|
02391|092|M|bradycardia, the first dose monitoring strategy should be repeated for the|
02391|093|M|second dose of fingolimod.  If, within the first two weeks of treatment one|
02391|094|M|or more fingolimod doses is missed, then first dose procedures are|
02391|095|M|recommended upon resumption. If during weeks 3 and 4 of fingolimod treatment|
02391|096|M|dose is interrupted more than 7 days, then first dose procedures are|
02391|097|M|recommended upon resumption.(17)  United Kingdom recommendations:  Obtain a|
02391|098|M|12-lead ECG prior to initiating fingolimod therapy.  Consult a cardiologist|
02391|099|M|for pretreatment risk-benefit assessment if patient has a resting heart rate|
02391|100|M|less than 55 bpm, history of syncope, second degree or greater AV block,|
02391|101|M|sick-sinus syndrome, concurrent therapy with beta-blockers, Class Ia, or|
02391|102|M|Class III antiarrhythmics, heart failure or other significant cardiovascular|
02391|103|M|disease.  Perform continuous ECG monitoring, measure blood pressure and|
02391|104|M|heart rate every hour, and perform a 12-lead ECG 6 hours after the first|
02391|105|M|dose.  Monitoring should be extended beyond 6 hours if symptomatic|
02391|106|M|bradycardia or new onset of second degree AV block, Mobitz Type II or third|
02391|107|M|degree AV block has occurred at any time during the monitoring period.  If|
02391|108|M|heart rate 6 hours after the first dose is less than 40 bpm, has decreased|
02391|109|M|more than 20 bpm compared with baseline, or if a new onset second degree AV|
02391|110|M|block, Mobitz Type I (Wenckebach) persists, then monitoring should also be|
02391|111|M|continued.(18)  If fingolimod treatment is discontinued for more than two|
02391|112|M|weeks, the effects on heart rate and conduction could recur.  Thus, first|
02391|113|M|dose monitoring precautions should be followed upon reintroduction of|
02391|114|M|fingolimod.(17)|
02391|115|M|   In patients maintained on QT prolongers, consider a baseline ECG prior to|
02391|116|M|administration of gadofosveset to asses the risk/benefit of gadofosveset.|
02391|117|M|If gadofosveset is used, consider ECG monitoring for 72 hours until the|
02391|118|M|majority of gadofosveset is eliminated.  Counsel patients to report any|
02391|119|M|irregular heartbeat, dizziness, or fainting episodes during this time|
02391|120|M|frame.(19)|
02391|121|M|   Approach the concurrent use of ondansetron and QT prolongers with|
02391|122|M|caution.  ECG monitoring should be performed in patients receiving|
02391|123|M|concurrent therapy.(20-22)|
02391|124|M|   The manufacturer of Nuedexta (dextromethorphan-quinidine) states that if|
02391|125|M|concurrent use with QT prolonging agents cannot be avoided, ECG monitoring|
02391|126|M|should be done at initiation of concurrent therapy and at 3-4 hours after|
02391|127|M|the first dose.(23)|
02391|128|M|   Concurrent use of saquinavir and QT prolongers should only be used when|
02391|129|M|there is no alternative therapy and potential benefits outweigh the risks.|
02391|130|M|Perform an ECG prior to concurrent therapy.  Patients with a QT interval|
02391|131|M|greater than 450 msec should not initiate concurrent therapy.  For patients|
02391|132|M|with a baseline QT interval less than 450 msec, a repeat ECG should be|
02391|133|M|performed after 3-4 days of concurrent therapy.  In patients who experience|
02391|134|M|an increase in QT interval to greater than 480 msec or by greater than 20|
02391|135|M|msec, consideration should be given to discontinuing one or both agents.(24)|
02391|136|M|   The US manufacturer of toremifene states that concurrent use should be|
02391|137|M|avoided.  If treatment with a QT prolonger is required, toremifene therapy|
02391|138|M|should be interrupted.  If it is not possible to interrupt toremifene|
02391|139|M|therapy, ECGs should be obtained and patients should be closely monitored|
02391|140|M|for QT prolongation.(25)  The UK manufacturer of toremifene states that the|
02391|141|M|use of QT prolongers is contraindicated.(26)|
02391|142|M|   The use of vandetanib with QT prolongers should be avoided.  If|
02391|143|M|concurrent therapy is required, more frequent ECG monitoring is|
02391|144|M|recommended.(27)|
02391|145|B||
02391|146|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02391|147|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02391|148|D|monograph have been shown to prolong the QTc interval either through their|
02391|149|D|mechanism of action, through studies on their effects on the QTc interval,|
02391|150|D|or through reports of QTc prolongation and/or torsades de pointes in|
02391|151|D|clinical trials and/or postmarketing reports.(28)|
02391|152|D|   One or more of the drug pairs linked to this monograph have been included|
02391|153|D|in a list of interactions that should be considered "high-priority" for|
02391|154|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02391|155|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02391|156|D|Coordinator (ONC) for Health Information Technology.|
02391|157|B||
02391|158|R|REFERENCES:|
02391|159|B||
02391|160|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02391|161|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02391|162|R|  settings: a scientific statement from the American Heart Association and|6
02391|163|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02391|164|R|  2;55(9):934-47.|6
02391|165|R|2.Zmax (azithromycin) US prescribing information. Pifzer Inc May, 2016.|1
02391|166|R|3.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
02391|167|R|  Inc April, 2024.|1
02391|168|R|4.Serentil (mesoridazine besylate) US prescribing information. Novartis|1
02391|169|R|  Pharmaceuticals Corporation August, 2000.|1
02391|170|R|5.Avelox (moxifloxacin hydrochloride) US prescribing information. Bayer|1
02391|171|R|  Pharmaceuticals Corporation August, 2012.|1
02391|172|R|6.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
02391|173|R|  Corporation December, 2012.|1
02391|174|R|7.Invega (paliperidone) US prescribing information. Janssen Pharmaceuticals,|1
02391|175|R|  Inc. April, 2014.|1
02391|176|R|8.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
02391|177|R|  Industries, Inc. August, 2019.|1
02391|178|R|9.Xenazine (tetrabenazine) US prescribing information. Valeant International|1
02391|179|R|  September, 2012.|1
02391|180|R|10.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
02391|181|R|   September, 2014.|1
02391|182|R|11.Trisenox (arsenic trioxide) US prescribing information. Cell|1
02391|183|R|   Therapeutics, Inc. March, 2001.|1
02391|184|R|12.Sirturo (bedaquiline) US prescribing information. Janssen Therapeutics|1
02391|185|R|   December, 2012.|1
02391|186|R|13.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02391|187|R|   recommendations for Celexa (citalopram hydrobromide) related to a|1
02391|188|R|   potential risk of abnormal heart rhythms with high doses. available at:|1
02391|189|R|   http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02391|190|R|14.Xalkori (crizotinib) US prescribing information. Pfizer Inc. January,|1
02391|191|R|   2012.|1
02391|192|R|15.Halaven (eribulin mesylate) US prescribing information. Eisai, Inc.|1
02391|193|R|   November, 2010.|1
02391|194|R|16.Potiga (ezogabine) US Prescribing Information. Valeant Pharmaceuticals|1
02391|195|R|   May, 2016.|1
02391|196|R|17.Gilenya (fingolimod) US prescribing information. Novartis Pharmaceuticals|1
02391|197|R|   Corporation May, 2012.|1
02391|198|R|18.MHRA United Kingdom. Fingolimod (Gilenya): transient bradycardias and|1
02391|199|R|   heart block after first dose - strengthened cardiovascular monitoring.|1
02391|200|R|   Drug Safety Update Feb 2012;5(7):A1.|1
02391|201|R|19.Ablavar (gadofosveset trisodium) US prescribing information. Lantheus|1
02391|202|R|   Medical Imaging, Inc. December, 2010.|1
02391|203|R|20.Kon P. Dear UK Healthcare Professional:   Direct Healthcare Professional|1
02391|204|R|   Communication on ondansetron (Zofran and generics) and dose-dependent QT|1
02391|205|R|   interval prolongation - new dose restriction for intravenous (IV) use.|1
02391|206|R|   GlaxoSmithKline UK Ltd August 5, 2012.|1
02391|207|R|21.Zofran (ondansetron) US prescribing information. GlaxoSmithKline|1
02391|208|R|   November, 2012.|1
02391|209|R|22.USFood and Drug Administration. FDA Drug Safety Communication: Abnormal|1
02391|210|R|   heart rhythms may be associated with use of Zofran (ondansetron).|1
02391|211|R|   available at:|1
02391|212|R|   https://wayback.archive-it.org/7993/20170722185907/https:/www.fda.gov/Dru|1
02391|213|R|   gs/DrugSafety/ucm271913.htm September 15, 2011.|1
02391|214|R|23.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
02391|215|R|   prescribing information. Avanir  Pharmaceuticals June, 2019.|1
02391|216|R|24.Invirase (saquinavir mesylate) US prescribing information. Roche|1
02391|217|R|   Laboratories, Inc. February, 2012.|1
02391|218|R|25.Fareston (toremifene citrate) US prescribing information. GTx, Inc.|1
02391|219|R|   March, 2011.|1
02391|220|R|26.Fareston (toremifene citrate) UK summary of product characteristics.|1
02391|221|R|   Orion Pharma (UK) Limited January, 2009.|1
02391|222|R|27.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
02391|223|R|   Pharmaceuticals LP October, 2018.|1
02391|224|R|28.USDepartment of Health and Human Services Food and Drug Administration.|1
02391|225|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02391|226|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02391|227|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02391|228|R|29.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02391|229|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02391|230|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02391|231|R|   19(5):735-43.|6
02392|001|T|MONOGRAPH TITLE:  Agents to Be Used with Caution with QT Agents/QT Agents|
02392|002|T|(mono deleted 09/16/2013)|
02392|003|B||
02392|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02392|005|L|take action as needed.|
02392|006|B||
02392|007|A|MECHANISM OF ACTION:  Concurrent use of multiple agents that prolong the QTc|
02392|008|A|interval may result in additive effects on the QTc interval.(1)|
02392|009|B||
02392|010|E|CLINICAL EFFECTS:  The concurrent use of multiple agents that prolong the|
02392|011|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
02392|012|E|including torsades de pointes.(1)|
02392|013|B||
02392|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02392|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02392|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02392|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02392|018|P|gender, or advanced age.(1)|
02392|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02392|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02392|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02392|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02392|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02392|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02392|025|P|dysfunction).(1)|
02392|026|B||
02392|027|M|PATIENT MANAGEMENT:  The concurrent use of these agents should be approached|
02392|028|M|with caution.  When evaluating the risk/benefit of concurrent therapy,|
02392|029|M|consider the need for ECG evaluations and electrolyte monitoring, concurrent|
02392|030|M|diseases/conditions/medications which increase the risk of QT prolongation,|
02392|031|M|the patient's history of QT prolongation with agents/combinations involved,|
02392|032|M|and the availability of alternative therapy.  .  If concurrent therapy is|
02392|033|M|warranted, patients should be closely monitored.  More frequent ECG|
02392|034|M|monitoring may be required for specific agents.|
02392|035|M|   The manufacturers of clozapine,(2) dasatinib,(3) dolasetron,(4)|
02392|036|M|domperidone,(5) haloperidol,(6-8) lapatinib,(9) levofloxacin,(10)|
02392|037|M|methadone,(11) risperidone,(12) and sevoflurane(13) state that these agents|
02392|038|M|should used with caution with other agents known to prolong the QT interval.|
02392|039|M|   While the US FDA and manufacturer recommend no special precautions when|
02392|040|M|escitalopram is used with QT prolonging agents,(14,15) the Health Canada and|
02392|041|M|the Canadian manufacturer of escitalopram discourage the concurrent use of|
02392|042|M|agents known to prolong the QT interval(16,17) and the UK manufacturer|
02392|043|M|states that concurrent use is contraindicated.(18)|
02392|044|M|   Pasireotide should be used with caution in patients receiving therapy|
02392|045|M|with agents that prolong the QT interval.  Patients should receive a|
02392|046|M|baseline electrocardiogram (ECG) and hypokalemia and hypomagnesemia should|
02392|047|M|be corrected before therapy is initiated.  Monitor ECG and potassium and|
02392|048|M|magnesium levels during therapy.(19)|
02392|049|M|   Patients receiving concurrent therapy with sorafenib and agents known to|
02392|050|M|prolong the QTc interval should be monitored with electrocardiograms during|
02392|051|M|treatment with sorafenib. Electrolytes (calcium, magnesium, and potassium)|
02392|052|M|should also be monitored.(20)|
02392|053|M|   The manufacturer of sotalol states that concurrent use with other agents|
02392|054|M|known to prolong the QT interval is not recommended.(21)|
02392|055|M|   The US manufacturer of telavancin recommends against the use of|
02392|056|M|telavancin with other drugs known to cause QT prolongation.(22)|
02392|057|B||
02392|058|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02392|059|D|degrees of potential to prolong the QTc interval but are generally accepted|
02392|060|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02392|061|D|monograph have been shown to prolong the QTc interval either through their|
02392|062|D|mechanism of action, through studies on their effects on the QTc interval,|
02392|063|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02392|064|D|clinical trials and/or post-marketing reports.(23)|
02392|065|B||
02392|066|R|REFERENCES:|
02392|067|B||
02392|068|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02392|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02392|070|R|  settings: a scientific statement from the American Heart Association and|6
02392|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02392|072|R|  2;55(9):934-47.|6
02392|073|R|2.Clozaril (clozapine tablets) US prescribing information. Novartis|1
02392|074|R|  Pharmaceuticals Corporation March, 2013.|1
02392|075|R|3.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
02392|076|R|  Company June 2013.|1
02392|077|R|4.Anzemet (dolasetron mesylate) US prescribing information. Sanofi-Aventis|1
02392|078|R|  Us.S. LLC September, 2011.|1
02392|079|R|5.Mathivanan M. Dear Canadian Healthcare Professional:  Subject:|1
02392|080|R|  Association of domperidone maleate with serious ventricular arrhythmias|1
02392|081|R|  and sudden cardiac death. Teva Canada Limited March 2, 2012.|1
02392|082|R|6.Serenace (haloperidol) Australian prescribing information. Sigma|1
02392|083|R|  Pharmaceuticals Pty Ltd. June 5, 2001.|1
02392|084|R|7.Dozic (haloperidol) UK summary of product characteristics. Rosemont|1
02392|085|R|  Pharmaceuticals Limited September 10, 2007.|1
02392|086|R|8.Haldol (haloperidol) US prescribing information. Ortho-McNeil-Janssen|1
02392|087|R|  Pharmaceuticals, Inc. August, 2011.|1
02392|088|R|9.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
02392|089|R|  2018.|1
02392|090|R|10.Levaquin (levofloxacin) US prescribing information. Ortho-McNeil|1
02392|091|R|   Pharmaceutical, Inc. February, 2011.|1
02392|092|R|11.Dolophine (methadone hydrochloride) US prescribing information. Roxane|1
02392|093|R|   Laboratories, Inc. July, 2012.|1
02392|094|R|12.Risperidal (risperidone) UK summary of product characteristics.|1
02392|095|R|   Janssen-Cilag, UK Limited May 14, 2004.|1
02392|096|R|13.Ultane (sevoflurane) US prescribing information. AbbVie, Inc. February,|1
02392|097|R|   2014.|1
02392|098|R|14.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02392|099|R|   recommendations for Celexa (citalopram hydrobromide) related to a|1
02392|100|R|   potential risk of abnormal heart rhythms with high doses. Available at:|1
02392|101|R|   http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02392|102|R|15.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
02392|103|R|   Pharmaceuticals Inc. December, 2012.|1
02392|104|R|16.Health Canada. Antidepressant Cipralex (escitalopram): Updated|1
02392|105|R|   information regarding dose-related heart risk. Available at:|1
02392|106|R|   http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/136|1
02392|107|R|   74a-eng.php May 7, 2012.|1
02392|108|R|17.Cipralex (escitalopram oxalate) Canadian prescribing information.|1
02392|109|R|   Lundbeck August 13, 2012.|1
02392|110|R|18.Cipralex (escitalopram oxalate) UK summary of product characteristics.|1
02392|111|R|   Lunbeck Limited June 25, 2020.|1
02392|112|R|19.Signifor (pasireotide diasparate) US prescribing information. Novartis|1
02392|113|R|   Pharmaceuticals Corporation January, 2020.|1
02392|114|R|20.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
02392|115|R|   Corporation August, 2012.|1
02392|116|R|21.Betapace (sotalol hydrochloride) US prescribing information. Bayer|1
02392|117|R|   Healthcare Inc. June, 2021.|1
02392|118|R|22.Vibativ (telavancin) US prescribing information. Astellas Pharma US, Inc.|1
02392|119|R|   September, 2009.|1
02392|120|R|23.USDepartment of Health and Human Services Food and Drug Administration.|1
02392|121|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02392|122|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02392|123|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02393|001|T|MONOGRAPH TITLE:  Quetiapine/Strong CYP3A4 Inhibitors|
02393|002|B||
02393|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02393|004|L|of severe adverse interaction.|
02393|005|B||
02393|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02393|007|A|quetiapine.  Quetiapine is a sensitive substrate for CYP3A4 and so an|
02393|008|A|approximately 5-fold or higher increase in exposure (AUC, area-under-curve)|
02393|009|A|can be anticipated when it is given with a strong CYP3A4 inhibitor.(1-4)|
02393|010|B||
02393|011|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
02393|012|E|elevated levels of and toxicity from quetiapine, including potentially|
02393|013|E|life-threatening cardiac arrhythmias, such as torsades de pointes.(2-4)|
02393|014|B||
02393|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02393|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02393|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02393|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02393|019|P|female gender, or advanced age.(5)|
02393|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02393|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02393|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02393|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02393|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02393|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02393|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
02393|027|B||
02393|028|M|PATIENT MANAGEMENT:  If possible, avoid the use of strong CYP3A4 inhibitors|
02393|029|M|with quetiapine.(2-4)|
02393|030|M|   If addition of concomitant therapy with a strong CYP3A4 inhibitor is|
02393|031|M|required, US manufacturers state the quetiapine dose should be reduced to|
02393|032|M|1/6th of the original dose.  When the inhibitor is discontinued, return to|
02393|033|M|the original quetiapine dose.(2,4)|
02393|034|M|   The UK manufacturer states the concurrent use of quetiapine with strong|
02393|035|M|CYP3A4 inhibitors is contraindicated.(4)|
02393|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02393|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02393|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02393|039|M|patients to report any irregular heartbeat, dizziness, fainting, excessive|
02393|040|M|drowsiness, rapid pulse/hypotension, weakness, fatigue, dizziness, or muscle|
02393|041|M|stiffness/tremors (EPS).  Monitor patients when strong inhibitors of CYP3A4|
02393|042|M|are co-prescribed with quetiapine as the magnitude of the interaction is|
02393|043|M|highly variable between patients.  Use of higher doses of either the CYP3A4|
02393|044|M|inhibitor or quetiapine are other factors which may affect the magnitude of|
02393|045|M|this interaction.  Decrease the quetiapine dose if needed.|
02393|046|B||
02393|047|D|DISCUSSION:  In a study, concurrent use of ketoconazole (200 mg daily for 4|
02393|048|D|days, a strong inhibitor of CYP3A4) and quetiapine resulted in an increase|
02393|049|D|in quetiapine Cmax and AUC by 3.35-fold and 6.2-fold, respectively.|
02393|050|D|Ketoconazole also decreased the mean apparent oral clearance of quetiapine|
02393|051|D|by 84%, and increased quetiapine mean elimination half-life by|
02393|052|D|2.6-fold.(2,6)|
02393|053|D|   Although quetiapine was not associated with QT or QTc changes in clinical|
02393|054|D|trials, QT prolongation has been reported in post-marketing reports in|
02393|055|D|conjunction with the use of other agents known to prolong the QT|
02393|056|D|interval.(2)|
02393|057|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
02393|058|D|itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone,|
02393|059|D|telaprevir, troleandomycin, and tucatinib.(7)|
02393|060|B||
02393|061|R|REFERENCES:|
02393|062|B||
02393|063|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
02393|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02393|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02393|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02393|067|R|  11/14/2017.|1
02393|068|R|2.Seroquel (quetiapine) US prescribing information. AstraZeneca|1
02393|069|R|  Pharmaceuticals LP September, 2020.|1
02393|070|R|3.Seroquel (quetiapine) Canada prescribing information. AstraZeneca Canada|1
02393|071|R|  Inc. May 15,2013.|1
02393|072|R|4.Seroquel (quetiapine) UK summary of product characteristics. Luye Pharma|1
02393|073|R|  Limited June, 2020.|1
02393|074|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02393|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02393|076|R|  settings: a scientific statement from the American Heart Association and|6
02393|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02393|078|R|  2;55(9):934-47.|6
02393|079|R|6.Grimm SW, Richtand NM, Winter HR, Stams KR, Reele SB. Effects of|2
02393|080|R|  cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine|2
02393|081|R|  pharmacokinetics. Br J Clin Pharmacol 2006 Jan;61(1):58-69.|2
02393|082|R|7.This information is based on an extract from the Certara Drug Interaction|6
02393|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02396|001|T|MONOGRAPH TITLE:  Doxorubicin; Etoposide/Ketoconazole (mono deleted|
02396|002|T|10/29/2020)|
02396|003|B||
02396|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02396|005|L|of severe adverse interaction.|
02396|006|B||
02396|007|A|MECHANISM OF ACTION:  Ketoconazole, a P-glycoprotein (Pgp) inhibitor and|
02396|008|A|strong CYP3A4 inhibitor,(1) may inhibit the CYP3A4 metabolism and Pgp|
02396|009|A|mediated elimination of doxorubicin and etoposide.(2)|
02396|010|B||
02396|011|E|CLINICAL EFFECTS:  Concurrent use of ketoconazole may result in elevated|
02396|012|E|levels and toxicity of doxorubicin or etoposide, including myelosuppression.|
02396|013|B||
02396|014|P|PREDISPOSING FACTORS:  The interaction may be more severe in etoposide|
02396|015|P|patients with impaired renal function or in doxorubicin patients with|
02396|016|P|impaired hepatic function.|
02396|017|B||
02396|018|M|PATIENT MANAGEMENT:  Avoid use of ketoconazole if possible.|
02396|019|M|   If concomitant therapy is prescribed anticipate an increased risk for|
02396|020|M|myelosuppression.  Closely monitor doxorubicin patients due to increased|
02396|021|M|risk for cardiotoxicity.  Adjust dosages as required.|
02396|022|B||
02396|023|D|DISCUSSION:  In a study with cyclosporine, another CYP3A4 and Pg inhibitor,|
02396|024|D|the co-administration with etoposide increased etoposide area-under-curve|
02396|025|D|(AUC) by 59% and half-life by 73%.  Etoposide renal clearance was decreased|
02396|026|D|by 38% and nonrenal clearance was decreased by 52%.  White blood cell count|
02396|027|D|nadir was significantly lower during concurrent therapy with cyclosporine|
02396|028|D|and etoposide (1200 mm3) when compared to etoposide alone (2500 mm3). There|
02396|029|D|was also a trend for higher dosages of cyclosporine to exert increased|
02396|030|D|effects on etoposide, although this difference did not reach statistical|
02396|031|D|significance.(3)|
02396|032|B||
02396|033|R|REFERENCES:|
02396|034|B||
02396|035|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
02396|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02396|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02396|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02396|039|R|  11/14/2017.|1
02396|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
02396|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02396|042|R|3.Lum BL, Kaubisch S, Yahanda AM, Adler KM, Jew L, Ehsan MN, Brophy NA,|2
02396|043|R|  Halsey J, Gosland MP, Sikic BI. Alteration of etoposide pharmacokinetics|2
02396|044|R|  and pharmacodynamics by cyclosporine in a phase I trial to modulate|2
02396|045|R|  multidrug resistance. J Clin Oncol 1992 Oct;10(10):1635-42.|2
02397|001|T|MONOGRAPH TITLE:  Riociguat/Nitrates & Nitric Oxide Donors|
02397|002|B||
02397|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02397|004|L|is contraindicated and generally should not be dispensed or administered to|
02397|005|L|the same patient.|
02397|006|B||
02397|007|A|MECHANISM OF ACTION:  Nitrates activate guanyl cyclase, an enzyme that|
02397|008|A|increases levels of cyclic guanosine monophosphate (cGMP), which produces|
02397|009|A|smooth muscle relaxation.  Riociguat stimulates the nitric oxide-soluble|
02397|010|A|guanylate cyclase-cGMP pathway and also increases cGMP. Concurrent use of|
02397|011|A|nitrates with riociguat results in potentiation of the effect of both|
02397|012|A|agents.(1)|
02397|013|B||
02397|014|E|CLINICAL EFFECTS:  The concurrent use riociguat and nitrates potentiates the|
02397|015|E|hypotensive effects of both agents, which may result in dizziness, syncope,|
02397|016|E|heart attack, or stroke.(1)|
02397|017|B||
02397|018|P|PREDISPOSING FACTORS:  None determined.|
02397|019|B||
02397|020|M|PATIENT MANAGEMENT:  The administration of riociguat to patients receiving|
02397|021|M|nitrates, or nitric oxide donors, in any form is contraindicated.(1)|
02397|022|B||
02397|023|D|DISCUSSION:  Riociguat (2.5 mg) potentiated the blood pressure lowering|
02397|024|D|effect of sublingual nitroglycerin (0.4 mg) when taken 4 hour and 8 hours|
02397|025|D|after riociguat.  Syncope was reported in some patients.(1)|
02397|026|B||
02397|027|R|REFERENCES:|
02397|028|B||
02397|029|R|1.Adempas (riociguat) US prescribing information. Bayer HealthCare|1
02397|030|R|  Pharmaceuticals, Inc. September, 2021.|1
02397|031|R|2.Nitrostat (nitroglycerin) US prescribing information. Pfizer January 24,|1
02397|032|R|  2018.|1
02398|001|T|MONOGRAPH TITLE:  Riociguat/PDE Inhibitors|
02398|002|B||
02398|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02398|004|L|is contraindicated and generally should not be dispensed or administered to|
02398|005|L|the same patient.|
02398|006|B||
02398|007|A|MECHANISM OF ACTION:  Riociguat stimulates the nitric oxide-soluble|
02398|008|A|guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway and also|
02398|009|A|increases cGMP.(1)  Aminophylline, avanafil, dipyridamole, sildenafil,|
02398|010|A|tadalafil, theophylline, and vardenafil inhibit phosphodiesterase (PDE),|
02398|011|A|which is responsible for the breakdown of cGMP.(1)|
02398|012|B||
02398|013|E|CLINICAL EFFECTS:  The concurrent use of PDE inhibitors and riociguat|
02398|014|E|potentiates the hypotensive effects of both agents, which may result in|
02398|015|E|dizziness, syncope, heart attack, or stroke.(1)|
02398|016|B||
02398|017|P|PREDISPOSING FACTORS:  Plasma levels of the PDE type-5 inhibitors may be|
02398|018|P|higher in the following patients:  those older than 65, with hepatic|
02398|019|P|impairment, with severe renal impairment, or using concomitant CYP3A4|
02398|020|P|inhibitors.  This may increase the severity of the interaction.|
02398|021|B||
02398|022|M|PATIENT MANAGEMENT:  The administration of riociguat to patients receiving|
02398|023|M|PDE inhibitors, including specific PDE-5 inhibitors (avanafil (5),|
02398|024|M|sildenafil (2), tadalafil (3,6), or vardenafil (4)) and nonspecific PDE|
02398|025|M|inhibitors (aminophylline, dipyridamole, theophylline) is|
02398|026|M|contraindicated.(1)|
02398|027|M|   If transitioning from sildenafil to riociguat, discontinue sildenafil at|
02398|028|M|least 24 hours prior to administering riociguat.(1)|
02398|029|M|   If transitioning from tadalafil to riociguat, discontinue tadalafil at|
02398|030|M|least 48 hours prior to administering riociguat.  Consider starting|
02398|031|M|riociguat at 0.5 mg in patients at risk for hypotension.(1)|
02398|032|M|   If transitioning from riociguat to a PDE inhibitor, discontinue riociguat|
02398|033|M|at least 24 hours prior to administering a PDE inhibitor.(1)|
02398|034|B||
02398|035|D|DISCUSSION:  In a study of 7 PAH patients maintained on sildenafil (20 mg|
02398|036|D|TID), single doses of riociguat (0.5 mg and 1 mg, sequentially) showed|
02398|037|D|additive hemodynamic effects.(1)|
02398|038|D|   In clinical trials, there was a high rate of discontinuation for|
02398|039|D|hypotension among patients receiving sildenafil (20 mg TID) and riociguat (1|
02398|040|D|mg to 2.5 mg TID) and one death.(1)|
02398|041|B||
02398|042|R|REFERENCES:|
02398|043|B||
02398|044|R|1.Adempas (riociguat) US prescribing information. Bayer HealthCare|1
02398|045|R|  Pharmaceuticals, Inc. September, 2021.|1
02398|046|R|2.Revatio (sildenafil citrate) US prescribing information. Viatris January,|1
02398|047|R|  2023.|1
02398|048|R|3.Adcirca (tadalafil) US prescribing information. Eli Lilly and Company|1
02398|049|R|  September, 2020.|1
02398|050|R|4.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
02398|051|R|  Pharmaceuticals Corporation March, 2023.|1
02398|052|R|5.Stendra (avanafil) US prescribing information. Vivus, Inc. October, 2022.|1
02398|053|R|6.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
02398|054|R|  February, 2018.|1
02400|001|T|MONOGRAPH TITLE:  Riociguat/Dual Strong CYP3A4 Inhibitor & P-gp Inhibitors|
02400|002|B||
02400|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02400|004|L|of severe adverse interaction.|
02400|005|B||
02400|006|A|MECHANISM OF ACTION:  Riociguat is primarily metabolized by CYP1A1 and to a|
02400|007|A|lesser extent by CYP3A4/3A5, CYP2C8, and CYP2J2.(1)  P-glycoprotein (P-gp)|
02400|008|A|and BCRP (breast cancer resistance protein) transport proteins participate|
02400|009|A|in the biliary/fecal elimination of riociguat.(2)|
02400|010|A|   Dual inhibitors of CYP3A4 and P-gp may inhibit metabolic and|
02400|011|A|transporter-based elimination of riociguat.(2)|
02400|012|B||
02400|013|E|CLINICAL EFFECTS:  Concurrent use with dual inhibitors of CYP3A4 and P-gp|
02400|014|E|may result in elevated systemic levels and toxicity (e.g. hypotension) from|
02400|015|E|riociguat.(1)|
02400|016|B||
02400|017|P|PREDISPOSING FACTORS:  The risk for riociguat-associated hypotension is|
02400|018|P|higher in patients with a systolic blood pressure (SBP) < or = 110 prior to|
02400|019|P|treatment initiation or dose increase.|
02400|020|P|   Patient specific factors such as renal or hepatic impairment, or age > 65|
02400|021|P|years are associated with higher systemic exposure(1) to riociguat and may|
02400|022|P|increase interaction risk or severity.|
02400|023|B||
02400|024|M|PATIENT MANAGEMENT:  The manufacturer recommends a lower riociguat starting|
02400|025|M|dose of 0.5 mg three times daily in patients receiving concomitant treatment|
02400|026|M|with dual strong CYP and P-gp inhibitors.(1)|
02400|027|M|   The US manufacturer of itraconazole states that concurrent use with|
02400|028|M|riociguat is not recommended during and two weeks after itraconazole|
02400|029|M|treatment.(3)|
02400|030|M|   Patients stabilized on riociguat when a dual strong CYP and P-gp|
02400|031|M|inhibitor is initiated may need to have their riociguat dose lowered for the|
02400|032|M|duration of concurrent therapy.  Monitor blood pressure and counsel patient|
02400|033|M|to report low blood pressure, lightheadedness or chest pain.|
02400|034|M|   Patients stabilized on concomitant therapy may need to have their|
02400|035|M|riociguat dose retitrated upward after discontinuation of the dual strong|
02400|036|M|CYP and P-gp inhibitors.|
02400|037|B||
02400|038|D|DISCUSSION:  In an interaction study, ketoconazole (an inhibitor of CYP1A1,|
02400|039|D|CYP3A4, and P-gp) given 400 mg once daily increased the mean maximum|
02400|040|D|concentration (Cmax) and area-under-curve (AUC) of riociguat by 46% and|
02400|041|D|150%, respectively.(2)|
02400|042|D|  The frequency or magnitude of this interaction is difficult to predict in|
02400|043|D|a specific patient due to significant interpatient variability in drug|
02400|044|D|kinetics. For example, between patient variability in systemic|
02400|045|D|exposure(AUC)relative to dose is 90%.  The amount of riociguat metabolized|
02400|046|D|may be as low as 27% or as high as 72%.  Cigarette smoking induces the|
02400|047|D|CYP1A1 mediated metabolism of riociguat leading to about a 50% decrease in|
02400|048|D|systemic exposure compared with non-smoking patients.|
02400|049|B||
02400|050|R|REFERENCES:|
02400|051|B||
02400|052|R|1.Adempas (riociguat) US prescribing information. Bayer HealthCare|1
02400|053|R|  Pharmaceuticals, Inc. September, 2021.|1
02400|054|R|2.Bayer Healthcare Pharmaceuticals Inc. Briefing Document for Cardiovascular|1
02400|055|R|  and Renal Drugs Advisory Committee Riociguat (BAY 63-2521). URL:|1
02400|056|R|  http://wayback.archive-it.org/7993/20170405211652/https://www.fda.gov/down|1
02400|057|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascularan|1
02400|058|R|  dRenalDrugsAdvisoryCommittee/UCM363543.pdf 6 August, 2013.|1
02400|059|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02400|060|R|  Products, L.P. February, 2024.|1
02401|001|T|MONOGRAPH TITLE:  Dapoxetine; Levomilnacipran (Greater Than 80 mg);|
02401|002|T|Vilazodone (Greater Than 20 mg)/Strong CYP3A4 Inhibitors|
02401|003|B||
02401|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02401|005|L|is contraindicated and generally should not be dispensed or administered to|
02401|006|L|the same patient.|
02401|007|B||
02401|008|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
02401|009|A|of dapoxetine(1-3) levomilnacipran(4) and vilazodone.(5)|
02401|010|B||
02401|011|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02401|012|E|in elevated levels and increased effects of dapoxetine(1-3)|
02401|013|E|levomilnacipran(4) and vilazodone.(5)|
02401|014|B||
02401|015|P|PREDISPOSING FACTORS:  If the patient is a CYP2D6 poor metabolizer,|
02401|016|P|dapoxetine metabolism can be further inhibited.(1-3)|
02401|017|B||
02401|018|M|PATIENT MANAGEMENT:  Concurrent use of dapoxetine at any dose is|
02401|019|M|contraindicated in patients taking strong inhibitors of CYP3A4.(1-3)|
02401|020|M|   The dose of levomilnacipran should not exceed 80 mg daily in patients|
02401|021|M|taking strong inhibitors of CYP3A4.(4)|
02401|022|M|   The dose of vilazodone should be reduced to 20 mg daily when|
02401|023|M|coadministered with strong inhibitors of CYP3A4.(5)|
02401|024|M|   Monitor patients receiving concurrent therapy for agitation,|
02401|025|M|hallucinations, muscle twitching/stiffness/tightness, rapid heartbeat, high|
02401|026|M|or low blood pressure, sweating or fever, nausea or vomiting, diarrhea,|
02401|027|M|abnormal bleeding or bruising, difficulty urinating or the inability to|
02401|028|M|urinate, seizures or convulsions, signs of mania (greatly increased energy,|
02401|029|M|trouble sleeping, racing thoughts, reckless behavior, unusually grand ideas,|
02401|030|M|excessive happiness or irritability, talking more or faster than usual).|
02401|031|B||
02401|032|D|DISCUSSION:  Ketoconazole (200 mg twice daily for 7 days), a strong|
02401|033|D|inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
02401|034|D|area-under-curve (AUC) of a single dose of dapoxetine (30 mg) by 35% and|
02401|035|D|99%, respectively.  The Cmax and AUC of the active fraction are expected to|
02401|036|D|increase by 25% and 2-fold, respectively, with strong inhibitors of|
02401|037|D|CYP3A4.(1-3)|
02401|038|D|   Pretreatment with ketoconazole, a strong inhibitor of CYP3A4, increased|
02401|039|D|the Cmax and AUC of levomilnacipran between 1.25 and 1.50-fold and between|
02401|040|D|1.50 and 1.75-fold, respectively.(4)|
02401|041|D|   Ketoconazole increased vilazodone concentrations by 50%.(5)|
02401|042|D|   Strong inhibitors of CYP3A4 include:  atazanavir, boceprevir,|
02401|043|D|clarithromycin, cobicistat, indinavir, itraconazole, josamycin,|
02401|044|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
02401|045|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
02401|046|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
02401|047|D|tucatinib, and voriconazole.(1-7)|
02401|048|B||
02401|049|R|REFERENCES:|
02401|050|B||
02401|051|R|1.Priligy (dapoxetine hydrochloride) Australian prescribing information.|1
02401|052|R|  Ortho-McNeil Pharmaceutical March 19, 2013.|1
02401|053|R|2.Priligy (dapoxetine hydrochloride) UK summary of product characteristics.|1
02401|054|R|  A. Menarini Farmaceutica Internazionale SRL April 15, 2014.|1
02401|055|R|3.Evoka (dapoxetine hydrochloride) Middle East prescribing information.|1
02401|056|R|  Middle East Pharmaceutical Industries Co. Ltd (Avalon-Pharma) April, 2024.|1
02401|057|R|4.Fetzima (levomilnacipran) US prescribing information. Forest|1
02401|058|R|  Pharmaceuticals, Inc. October, 2023.|1
02401|059|R|5.Viibryd (vilazodone hydrochloride) US prescribing information. Forest|1
02401|060|R|  Laboratories Inc. October, 2023.|1
02401|061|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
02401|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02401|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02401|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02401|065|R|  11/14/2017.|1
02401|066|R|7.This information is based on an extract from the Certara Drug Interaction|6
02401|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02402|001|T|MONOGRAPH TITLE:  Levomilnacipran (Less Than or Equal To 80 mg);|
02402|002|T|Vilazodone(Less Than or Equal To 20 mg)/Strong CYP3A4 Inhibitors|
02402|003|B||
02402|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02402|005|L|take action as needed.|
02402|006|B||
02402|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
02402|008|A|of levomilnacipran(1) and vilazodone.(2)|
02402|009|B||
02402|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02402|011|E|in elevated levels and increased effects of levomilnacipran(1) and|
02402|012|E|vilazodone.(2)|
02402|013|B||
02402|014|P|PREDISPOSING FACTORS:  None determined.|
02402|015|B||
02402|016|M|PATIENT MANAGEMENT:  The dose of levomilnacipran should not exceed 80 mg|
02402|017|M|daily in patients taking strong inhibitors of CYP3A4.(1)|
02402|018|M|   The dose of vilazodone should be reduced to 20 mg daily when|
02402|019|M|coadministered with strong inhibitors of CYP3A4.(2)|
02402|020|B||
02402|021|D|DISCUSSION:  Pretreatment with ketoconazole, a strong inhibitor of CYP3A4,|
02402|022|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02402|023|D|levomilnacipran between 1.25 and 1.50-fold and between 1.50 and 1.75-fold,|
02402|024|D|respectively.(1)|
02402|025|D|   Ketoconazole increased vilazodone concentrations by 50%.(2)|
02402|026|D|   Strong inhibitors of CYP3A4 include:  adagrasib, atazanavir, boceprevir,|
02402|027|D|clarithromycin, cobicistat, grapefruit, indinavir, itraconazole, josamycin,|
02402|028|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
02402|029|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
02402|030|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, and|
02402|031|D|voriconazole.(1-4)|
02402|032|B||
02402|033|R|REFERENCES:|
02402|034|B||
02402|035|R|1.Fetzima (levomilnacipran) US prescribing information. Forest|1
02402|036|R|  Pharmaceuticals, Inc. October, 2023.|1
02402|037|R|2.Viibryd (vilazodone hydrochloride) US prescribing information. Forest|1
02402|038|R|  Laboratories Inc. October, 2023.|1
02402|039|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02402|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02402|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02402|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02402|043|R|  11/14/2017.|1
02402|044|R|4.This information is based on an extract from the Certara Drug Interaction|6
02402|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02403|001|T|MONOGRAPH TITLE:  Riociguat/Antacids|
02403|002|B||
02403|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02403|004|L|take action as needed.|
02403|005|B||
02403|006|A|MECHANISM OF ACTION:  The mechanism of interaction is not clear. Increased|
02403|007|A|gastric pH is thought to decrease riociguat solubility and absorption.(1)|
02403|008|B||
02403|009|E|CLINICAL EFFECTS:  Simultaneous administration of riociguat with an antacid|
02403|010|E|may result in decreased levels and effectiveness of riociguat.(1-2)|
02403|011|B||
02403|012|P|PREDISPOSING FACTORS:  None determined.|
02403|013|B||
02403|014|M|PATIENT MANAGEMENT:  Separate the administration of antacids and riociguat|
02403|015|M|by at least 1 hour.(1)|
02403|016|M|   Some vitamin preparations may contain sufficient quantities of calcium|
02403|017|M|and/or magnesium salts with antacid properties to interact as well.|
02403|018|B||
02403|019|D|DISCUSSION:  Administration of 10 mL of an aluminum hydroxide-magnesium|
02403|020|D|hydroxide containing antacid decreased the area-under-curve (AUC)and maximum|
02403|021|D|concentration (Cmax)of riociguat by 34% and 56% respectively.(1)|
02403|022|B||
02403|023|R|REFERENCES:|
02403|024|B||
02403|025|R|1.Bayer Healthcare Pharmaceuticals Inc. Briefing Document for Cardiovascular|1
02403|026|R|  and Renal Drugs Advisory Committee Riociguat (BAY 63-2521). URL:|1
02403|027|R|  http://wayback.archive-it.org/7993/20170405211652/https://www.fda.gov/down|1
02403|028|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascularan|1
02403|029|R|  dRenalDrugsAdvisoryCommittee/UCM363543.pdf 6 August, 2013.|1
02403|030|R|2.Adempas (riociguat) US prescribing information. Bayer HealthCare|1
02403|031|R|  Pharmaceuticals, Inc. September, 2021.|1
02404|001|T|MONOGRAPH TITLE:  Macitentan/Strong CYP3A4 Inhibitors|
02404|002|B||
02404|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02404|004|L|of severe adverse interaction.|
02404|005|B||
02404|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
02404|007|A|of macitentan.(1)|
02404|008|B||
02404|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02404|010|E|in elevated levels and increased effects of macitentan.(1)|
02404|011|B||
02404|012|P|PREDISPOSING FACTORS:  None determined.|
02404|013|B||
02404|014|M|PATIENT MANAGEMENT:  The manufacturer of macitentan states that use of|
02404|015|M|strong inhibitors of CYP3A4 should be avoided.  When strong CYP3A4|
02404|016|M|inhibitors are required (e.g. protease inhibitors in the treatment of HIV),|
02404|017|M|use other treatment options for pulmonary arterial hypertension.(1)|
02404|018|M|   The Journal of American College of Cardiology (JACC) states concurrent|
02404|019|M|use of macitentan and nirmatrelvir-ritonavir is not advised.  JACC|
02404|020|M|recommends discontinuing macitentan for at least 36 hours before initiation|
02404|021|M|of nirmatrelvir-ritonavir.(2)|
02404|022|B||
02404|023|D|DISCUSSION:  Pretreatment with ketoconazole increased the area-under-curve|
02404|024|D|(AUC) and  maximum concentration (Cmax) of macitentan approximately 2.3 and|
02404|025|D|1.3-fold  respectively.(1)|
02404|026|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02404|027|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
02404|028|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
02404|029|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
02404|030|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
02404|031|D|troleandomycin, tucatinib, and voriconazole.(3)|
02404|032|B||
02404|033|R|REFERENCES:|
02404|034|B||
02404|035|R|1.Opsumit (macitentan) US prescribing information. Actelion Pharmaceuticals|1
02404|036|R|  US, Inc. October, 2021.|1
02404|037|R|2.Abraham S Nohria A Neilan TG Asnani A Saji AM Shah J Lech T Grossman J|6
02404|038|R|  Abraham GM McQuillen DP Martin DT Sax PE Dani SS Ganatra S. Cardiovascular|6
02404|039|R|  Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19:|6
02404|040|R|  JACC Review Topic of the Week. J Am Coll Cardiol 2022 Oct 6.|6
02404|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
02404|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02405|001|T|MONOGRAPH TITLE:  Romidepsin/Rifampin|
02405|002|B||
02405|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02405|004|L|of severe adverse interaction.|
02405|005|B||
02405|006|A|MECHANISM OF ACTION:  Rifampin may inhibit the hepatic uptake of romidepsin|
02405|007|A|through an unknown mechanism.(1)|
02405|008|B||
02405|009|E|CLINICAL EFFECTS:  Concurrent use of rifampin may result in increased levels|
02405|010|E|of and toxicity from romidepsin.(1)|
02405|011|B||
02405|012|P|PREDISPOSING FACTORS:  None determined.|
02405|013|B||
02405|014|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin recommends avoiding|
02405|015|M|the use of rifampin in patients receiving romidepsin.(1)|
02405|016|M|   If concurrent therapy is warranted, monitor for romidepsin toxicity and|
02405|017|M|follow recommended dose modifications for toxicity, if necessary.|
02405|018|B||
02405|019|D|DISCUSSION:  In a study in advanced cancer patients, rifampin, a strong|
02405|020|D|inducer of CYP3A4 and an inhibitor and inducer of other CYP enzymes and|
02405|021|D|transporters, unexpectedly increased the maximum concentration (Cmax) and|
02405|022|D|area-under-curve (AUC) of romidepsin (14 mg/m2) by 60% and 80%,|
02405|023|D|respectively.  Romidepsin clearance and volume of distribution decreased by|
02405|024|D|44% and 52%, respectively.  This is likely due to inhibition of an|
02405|025|D|undetermined hepatic uptake process responsible for the disposition of|
02405|026|D|romidepsin.(1)|
02405|027|B||
02405|028|R|REFERENCES:|
02405|029|B||
02405|030|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
02405|031|R|  November, 2018.|1
02405|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02405|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02405|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02405|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02405|036|R|  11/14/2017.|1
02406|001|T|MONOGRAPH TITLE:  5-Fluorouracil/Leucovorin|
02406|002|B||
02406|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02406|004|L|take action as needed.|
02406|005|B||
02406|006|A|MECHANISM OF ACTION:  Leucovorin has been shown to enhance both the|
02406|007|A|therapeutic and toxic effects of fluoropyrimidines, such as|
02406|008|A|5-fluorouracil(5-FU).(1)|
02406|009|B||
02406|010|E|CLINICAL EFFECTS:  Leucovorin, when used concurrently with 5-FU, has been|
02406|011|E|shown to increase side effects of 5-FU.(1)|
02406|012|B||
02406|013|P|PREDISPOSING FACTORS:  Patients who are intermediate or poor|
02406|014|P|dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no|
02406|015|P|DPYD function.  Since DPYD is the rate-limiting enzyme involved in|
02406|016|P|fluoropyrimidine metabolism, these patients may be more susceptible to the|
02406|017|P|effects of this interaction.(3)|
02406|018|B||
02406|019|M|PATIENT MANAGEMENT:  When leucovorin is added to 5-FU therapy, the dose of|
02406|020|M|5-FU must be reduced from that of the normally administered dose. Patients|
02406|021|M|should be closely monitored for appearance and severity of side effects to|
02406|022|M|determine whether it is appropriate to alter the dose of 5-FU.(1)|
02406|023|B||
02406|024|D|DISCUSSION:  A retrospective study reviewed all patients over the age of 18|
02406|025|D|years treated with combination fluorouracil and leucovorin either as|
02406|026|D|adjuvant or palliative treatment. A total of 122 patients (60% male) were|
02406|027|D|included in the study. Ninety-four patients received fluorouracil (425|
02406|028|D|mg/m2, IV) and leucovorin (20 mg/m2, IV) daily for five days and repeated|
02406|029|D|every four weeks. Twenty-eight patients received fluorouracil (400 mg/m2,|
02406|030|D|IV) and leucovorin (80 mg/m2, IV) once per week for six weeks of an eight|
02406|031|D|week course. All patients were treated for up to six months. Forty-eight|
02406|032|D|patients (39%) experienced toxicity including fatigue (21%), mucositis|
02406|033|D|(17%), diarrhea (11%), and nausea (11%).(2)|
02406|034|D|   A study involving 35 patients evaluated a combination of cisplatin (20|
02406|035|D|mg/m2) on Day 1 through Day 3, leucovorin (200 mg/m2) on Day 1 through Day|
02406|036|D|5, and 5-fluorouracil (500 mg/m2) on Day 1 through Day 5. If patients|
02406|037|D|tolerated the low dose of 5-fluorouracil, the dose was increased to a|
02406|038|D|maximum of 750 mg/m2/day during the remaining courses. Grade I mucositis|
02406|039|D|occurred in three patients, Grade II in 16 patients, and Grade III in 13|
02406|040|D|patients. The dose of 5-fluorouracil was decreased in patients with Grade II|
02406|041|D|and Grade III mucositis, which helped to decrease symptoms.(3)|
02406|042|D|   A randomized trial in advanced colorectal carcinoma patients compared|
02406|043|D|fluorouracil (500 mg/m2 on Days 1-5) every four weeks with escalation as|
02406|044|D|tolerated with high-dose leucovorin (500mg/m2) with fluorouracil (600 mg/m2)|
02406|045|D|given weekly for six weeks with a two-week rest period and with low-dose|
02406|046|D|leucovorin (25 mg/m2) with fluorouracil (600 mg/m2) given weekly for six|
02406|047|D|weeks with a two-week rest period. Severe or worse diarrhea was reported in|
02406|048|D|25% and 13% of patients receiving high-dose leucovorin and low-dose|
02406|049|D|leucovorin with fluorouracil, respectively. Nine elderly patients|
02406|050|D|experienced fatal toxicity during the initial treatment cycle with|
02406|051|D|combination therapy.(4)|
02406|052|D|   A study in five patients with metastatic colorectal carcinoma examined|
02406|053|D|the effects of high dose leucovorin (500 mg/m2) on fluorouracil|
02406|054|D|pharmacokinetics. Subjects received a single dose of fluorouracil (600|
02406|055|D|mg/m2) with leucovorin and, one week later, without leucovorin. With|
02406|056|D|concurrent leucovorin, the time of distribution of fluorouracil increased|
02406|057|D|44% (p<0.0005) and fluorouracil volume of distribution increased 84%|
02406|058|D|(p<0.03). There were no changes in fluorouracil plasma clearance or AUC.|
02406|059|D|Although fluorouracil anabolite levels were lower at two minutes and five|
02406|060|D|minutes post-dose when administered following leucovorin, levels were|
02406|061|D|similar thereafter.(5)|
02406|062|B||
02406|063|R|REFERENCES:|
02406|064|B||
02406|065|R|1.Leucovorin calcium US prescribing information. Bedford Laboratories|1
02406|066|R|  September, 2008.|1
02406|067|R|2.Jansman FG, Jansen AJ, Coenen JL, de Graaf JC, Smit WM, Sleijfer DT,|6
02406|068|R|  Brouwers JR. Assessing the clinical significance of drug interactions with|6
02406|069|R|  fluorouracil in patients with colorectal cancer. Am J Health Syst Pharm|6
02406|070|R|  2005 Sep 1;62(17):1788-93.|6
02406|071|R|3.Figoli F, Chiarion Sileni V, Gulisano M, Maggian P, Fosser V. Leucovorin|2
02406|072|R|  calcium enhancement of mucositis after continuous infusion fluorouracil|2
02406|073|R|  and short infusion cisplatin. J Clin Oncol 1989 May;7(5):680-1.|2
02406|074|R|4.Grem JL, Shoemaker DD, Petrelli NJ, Douglass HO Jr. Severe and fatal toxic|2
02406|075|R|  effects observed in treatment with high- and low-dose leucovorin plus|2
02406|076|R|  5-fluorouracil for colorectal carcinoma. Cancer Treat Rep 1987 Nov;|2
02406|077|R|  71(11):1122.|2
02406|078|R|5.Stein TA, Burns GP, Bailey B, Citron ML. 5-Fluorouracil pharmacokinetics|2
02406|079|R|  in patients with metastatic colorectal carcinoma  after high-dose|2
02406|080|R|  leucovorin. Cancer Invest 1994;12(4):375-8.|2
02407|001|T|MONOGRAPH TITLE:  Dextromethorphan and Quinidine/Fluoxetine; Paroxetine|
02407|002|B||
02407|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02407|004|L|of severe adverse interaction.|
02407|005|B||
02407|006|A|MECHANISM OF ACTION:  Each product may affect the pharmacokinetics of the|
02407|007|A|other.|
02407|008|A|   The combination of dextromethorphan 20 mg and quinidine 10 mg is given|
02407|009|A|twice daily for treatment of pseudobulbar affect.(1)  Due to the presence of|
02407|010|A|quinidine, dextromethorphan exposure in this formulation is about 20-fold|
02407|011|A|higher than expected with dextromethorphan alone.(1)  Fluoxetine and|
02407|012|A|paroxetine, strong inhibitors of CYP2D6, may also inhibit CYP2D6 mediated|
02407|013|A|metabolism of dextromethorphan, further increasing dextromethorphan systemic|
02407|014|A|concentration.(1-4)|
02407|015|A|   Fluoxetine(4) and paroxetine(3) are primarily metabolized by CYP2D6 and|
02407|016|A|so quinidine may inhibit their metabolism as well, resulting in higher|
02407|017|A|systemic concentrations of these SSRIs.(1,2,4)|
02407|018|B||
02407|019|E|CLINICAL EFFECTS:  Patients may experience increased adverse effects of|
02407|020|E|dextromethorphan and fluoxetine or paroxetine due to elevated systemic|
02407|021|E|concentrations.|
02407|022|E|   Concomitant use of two or more serotonergic agents increases the risk for|
02407|023|E|serotonin syndrome.  Serotonin syndrome constitutes a range of toxicities|
02407|024|E|from mild to life threatening.(5)|
02407|025|E|   Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis,|
02407|026|E|intermittent tremor, and/or myoclonus.(5)|
02407|027|E|   Moderate serotonin symptoms may include: tachycardia, hypertension,|
02407|028|E|hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds,|
02407|029|E|hyperreflexia, and/OR clonus.(5)|
02407|030|E|   Severe serotonin symptoms may include: severe hypertension and|
02407|031|E|tachycardia, shock, agitated delirium, muscular rigidity, and/or|
02407|032|E|hypertonicity.(5)|
02407|033|B||
02407|034|P|PREDISPOSING FACTORS:  Concurrent use of additional drugs which increase CNS|
02407|035|P|serotonin levels would be expected to further increase risk for serotonin|
02407|036|P|syndrome.(5)|
02407|037|P|   With paroxetine, the risk of anticholinergic toxicities including|
02407|038|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
02407|039|P|patients using more than one medicine with anticholinergic properties.(6)|
02407|040|B||
02407|041|M|PATIENT MANAGEMENT:  In patients currently stabilized on|
02407|042|M|dextromethorphan-quinidine who require an SSRI, consider use of an agent|
02407|043|M|which is not primarily metabolized by nor a strong inhibitor of CYP2D6 (e.g.|
02407|044|M|sertraline) if clinically appropriate.  When both agents are necessary use|
02407|045|M|the lowest effective dose of each medication and closely monitor for|
02407|046|M|serotonin toxicity and other adverse effects.|
02407|047|M|   Patients stabilized on fluoxetine or paroxetine and newly starting|
02407|048|M|dextromethorphan-quinidine may require lower than the usual recommended|
02407|049|M|dextromethorphan-quinidine maintenance dose.  It may also be necessary to|
02407|050|M|lower the fluoxetine or paroxetine dose.|
02407|051|M|   The manufacturer of dextromethorphan-quinidine recommends limiting|
02407|052|M|paroxetine dosage to less than or equal to 35 mg daily.(1)|
02407|053|M|   If the interacting agents are prescribed by different providers, it would|
02407|054|M|be prudent to assure that both are aware of concomitant therapy and|
02407|055|M|monitoring the patient for serotonin toxicities.|
02407|056|M|   If concurrent therapy is warranted, patients should be monitored for|
02407|057|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02407|058|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02407|059|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02407|060|M|coordination, or severe diarrhea.|
02407|061|M|   Patients in whom serotonin syndrome is suspected should receive immediate|
02407|062|M|medical attention.|
02407|063|B||
02407|064|D|DISCUSSION:  An open label parallel group trial evaluated the interaction|
02407|065|D|between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed|
02407|066|D|strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with|
02407|067|D|a mean age of 33.6 years.  Subjects were randomly divided into 2 groups:|
02407|068|D|  - Group 1 received paroxetine 20 mg once daily for 12 days, followed by|
02407|069|D|the addition of dextromethorphan-quinidine twice daily for 8 days.|
02407|070|D|  - Group 2 received dextromethorphan-quinidine twice daily for 8 days,|
02407|071|D|followed by paroxetine 20 mg daily for 12 days.|
02407|072|D|Results: overall, adverse effects were reported in 19 of 26 subjects who|
02407|073|D|received combination therapy (73%) and 15 of 27 subjects who received|
02407|074|D|monotherapy (56%). Adverse effects from the combination differed somewhat|
02407|075|D|between groups and were more closely associated with the second drug product|
02407|076|D|administered. Group 1 reported dizziness, headache, somnolence, euphoria,|
02407|077|D|nausea, and vomiting after the addition of dextromethorphan-quinidine to|
02407|078|D|paroxetine.  Group 2 adverse events were dizziness, headache, nausea,|
02407|079|D|vomiting, insomnia, anxiety, and hyperhidrosis after the addition of|
02407|080|D|paroxetine to dextromethorphan.(2)|
02407|081|D|   Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of|
02407|082|D|dextromethorphan (without quinidine) by 27-fold.(7)|
02407|083|D|   Serotonin syndrome has been reported in patients following the addition|
02407|084|D|of dextromethorphan containing cough syrups to fluoxetine(7,8) and|
02407|085|D|paroxetine.(10)|
02407|086|B||
02407|087|R|REFERENCES:|
02407|088|B||
02407|089|R|1.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
02407|090|R|  prescribing information. Avanir  Pharmaceuticals June, 2019.|1
02407|091|R|2.Schoedel KA, Pope LE, Sellers EM. Randomized open-label drug-drug|2
02407|092|R|  interaction trial of dextromethorphan/quinidine and paroxetine in healthy|2
02407|093|R|  volunteers. Clin Drug Investig 2012 Mar 1;32(3):157-69.|2
02407|094|R|3.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
02407|095|R|  Technologies January, 2017.|1
02407|096|R|4.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
02407|097|R|  and Company August, 2023.|1
02407|098|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02407|099|R|  352(11):1112-20.|6
02407|100|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02407|101|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02407|102|R|  Soc 2023 Jul;71(7):2052-2081.|6
02407|103|R|7.Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. Fluoxetine-|2
02407|104|R|  and norfluoxetine-mediated complex drug-drug interactions: in vitro to in|2
02407|105|R|  vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol|2
02407|106|R|  Ther 2014 Jun;95(6):653-62.|2
02407|107|R|8.Navarro A, Perry C, Bobo WV. A case of serotonin syndrome precipitated by|3
02407|108|R|  abuse of the anticough remedy dextromethorphan in a bipolar patient|3
02407|109|R|  treated with fluoxetine and lithium. Gen Hosp Psychiatry 2006 Jan-Feb;|3
02407|110|R|  28(1):78-80.|3
02407|111|R|9.Achamallah NS. Visual hallucinations after combining fluoxetine and|3
02407|112|R|  dextromethorphan. Am J Psychiatry 1992 Oct;149(10):1406.|3
02407|113|R|10.Skop BP, Finkelstein JA, Mareth TR, Magoon MR, Brown TM. The serotonin|3
02407|114|R|   syndrome associated with paroxetine, an over-the-counter cold remedy, and|3
02407|115|R|   vascular disease. Am J Emerg Med 1994 Nov;12(6):642-4.|3
02408|001|T|MONOGRAPH TITLE:  Ibrutinib/Moderate CYP3A4 Inhibitors|
02408|002|B||
02408|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02408|004|L|take action as needed.|
02408|005|B||
02408|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
02408|007|A|the metabolism of ibrutinib.(1)|
02408|008|B||
02408|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
02408|010|E|levels of and effects from ibrutinib.(1)|
02408|011|B||
02408|012|P|PREDISPOSING FACTORS:  None determined.|
02408|013|B||
02408|014|M|PATIENT MANAGEMENT:  Concurrent use of moderate CYP3A4 inhibitors in|
02408|015|M|patients undergoing therapy with ibrutinib requires a dose adjustment.(1)|
02408|016|M|   If a moderate CYP3A4 inhibitor is required for B-cell malignancies|
02408|017|M|treatment, reduce the dose of ibrutinib to 280 mg daily.(1)|
02408|018|M|   If a moderate CYP3A4 inhibitor is required for chronic graft versus host|
02408|019|M|disease treatment, reduce the dose of ibrutinib in patients 12 years and|
02408|020|M|older to 420 mg once daily, and in patients 1 year to 12 years old to 240|
02408|021|M|mg/m2 once daily.(1)|
02408|022|M|   After discontinuation of a CYP3A4 inhibitor, resume previous dose of|
02408|023|M|ibrutinib.(1)|
02408|024|B||
02408|025|D|DISCUSSION:  The coadministration of multiple doses of erythromycin|
02408|026|D|(moderate CYP3A inhibitor) increased ibrutinib's concentration maximum|
02408|027|D|(Cmax) and area-under-curve (AUC) by 3.4-fold and 3-fold.(1)|
02408|028|D|   In a case report, concomitant administration of ibrutinib and|
02408|029|D|verapamil/trandolapril resulted in ibrutinib toxicity consisting of nausea,|
02408|030|D|dizziness, malaise, and severe diarrhea.(2)|
02408|031|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
02408|032|D|avacopan, berotralstat, casopitant, clofazimine, clotrimazole, conivaptan,|
02408|033|D|crizotinib, darunavir, dronedarone, duvelisib, erythromycin, fedratinib,|
02408|034|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice,|
02408|035|D|imatinib, isavuconazonium, ledipasvir, oral lefamulin, lenacapavir,|
02408|036|D|letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra,|
02408|037|D|stiripentol, tofisopam, treosulfan, and verapamil.(1,3,4)|
02408|038|B||
02408|039|R|REFERENCES:|
02408|040|B||
02408|041|R|1.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
02408|042|R|  August, 2022.|1
02408|043|R|2.Lambert Kuhn E, Leveque D, Lioure B, Gourieux B, Bilbault P. Adverse event|3
02408|044|R|  potentially due to an interaction between ibrutinib and verapamil:  a case|3
02408|045|R|  report. J Clin Pharm Ther 2016 Feb;41(1):104-5.|3
02408|046|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02408|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02408|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02408|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02408|050|R|  11/14/2017.|1
02408|051|R|4.This information is based on an extract from the Certara Drug Interaction|6
02408|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02409|001|T|MONOGRAPH TITLE:  Tacrolimus/Ertapenem|
02409|002|B||
02409|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02409|004|L|take action as needed.|
02409|005|B||
02409|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.(1)|
02409|007|B||
02409|008|E|CLINICAL EFFECTS:  Concurrent use of ertapenem may result in elevated levels|
02409|009|E|of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity,|
02409|010|E|and prolongation of the QTc interval and life-threatening cardiac|
02409|011|E|arrhythmias, including torsades de pointes.(1)|
02409|012|B||
02409|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02409|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02409|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02409|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02409|017|P|gender, or advanced age.(2)|
02409|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02409|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02409|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02409|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02409|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02409|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02409|024|P|dysfunction).(2)|
02409|025|B||
02409|026|M|PATIENT MANAGEMENT:  Monitor tacrolimus levels in patients receiving|
02409|027|M|concurrent ertapenem.  The dosage of tacrolimus may need to be adjusted if|
02409|028|M|ertapenem is initiated or discontinued.(1)|
02409|029|M|   When concurrent therapy of ertapenem and tacrolimus is warranted,|
02409|030|M|consider obtaining serum calcium, magnesium, and potassium levels and|
02409|031|M|monitoring ECG at baseline and at regular intervals.  Correct any|
02409|032|M|electrolyte abnormalities.  Instruct patients to report any irregular|
02409|033|M|heartbeat, dizziness, or fainting.|
02409|034|B||
02409|035|D|DISCUSSION:  A retrospective review of 13 renal transplant patients found|
02409|036|D|that the addition of ertapenem to tacrolimus therapy decreased the mean dose|
02409|037|D|of tacrolimus required to achieve desired therapeutic concentrations by 46%.|
02409|038|D|Decreased tacrolimus requirements were noted 2 days after initiation of|
02409|039|D|ertapenem.  There was no change in serum creatinine during ertapenem|
02409|040|D|therapy, indicating that a change in renal function was not responsible for|
02409|041|D|the elevated tacrolimus levels.(1)|
02409|042|B||
02409|043|R|REFERENCES:|
02409|044|B||
02409|045|R|1.Bora F, Aliosmanoglu I, Kocak H, Dinckan A, Uslu HB, Gunseren F,|2
02409|046|R|  Suleymanlar G. Drug interaction between tacrolimus and ertapenem in renal|2
02409|047|R|  transplantation recipients. Transplant Proc 2012 Dec;44(10):3029-32.|2
02409|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02409|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02409|050|R|  settings: a scientific statement from the American Heart Association and|6
02409|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02409|052|R|  2;55(9):934-47.|6
02410|001|T|MONOGRAPH TITLE:  Memantine; Amantadine/Urinary Alkalinizers|
02410|002|B||
02410|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02410|004|L|take action as needed.|
02410|005|B||
02410|006|A|MECHANISM OF ACTION:  Memantine and amantadine elimination is impaired by|
02410|007|A|urinary alkalinization.(1,2)|
02410|008|B||
02410|009|E|CLINICAL EFFECTS:  Potentiation of memantine or amantadine effects may be|
02410|010|E|observed.|
02410|011|B||
02410|012|P|PREDISPOSING FACTORS:  None determined.|
02410|013|B||
02410|014|M|PATIENT MANAGEMENT:  Monitor patient for adverse reactions such as|
02410|015|M|dizziness, headache, or confusion if a urinary alkalinizer is required.  The|
02410|016|M|memantine or amantadine dose may need to be adjusted when a urinary|
02410|017|M|alkalinizer is started or stopped.(1,2)|
02410|018|B||
02410|019|D|DISCUSSION:  The clearance of memantine was reduced by about 80% under|
02410|020|D|alkaline urine conditions at pH 8.  Urine alkalinization may lead to an|
02410|021|D|accumulation of memantine with a possible increase in adverse effects.|
02410|022|D|Urine pH is also altered by diet and clinical state of the patient (e.g.,|
02410|023|D|renal tubular acidosis or severe infections of the urinary tract).  Hence,|
02410|024|D|memantine should be used with caution under these conditions.(1)|
02410|025|D|   A study in rats showed that concomitant administration of sodium|
02410|026|D|bicarbonate with amantadine caused a decrease in amantadine renal clearance|
02410|027|D|(1.16 vs. 0.76). Amantadine's area-under-the-curve (AUC) was increased|
02410|028|D|approximately 78%.(3)|
02410|029|D|   A study in 12 healthy subjects showed that plasma concentrations of|
02410|030|D|memantine are dependent on urine pH. Alkaline urine pH caused a 79%|
02410|031|D|reduction in renal clearance.(4)|
02410|032|B||
02410|033|R|REFERENCES:|
02410|034|B||
02410|035|R|1.Namenda (memantine hydrochloride) US prescribing information. Forest|1
02410|036|R|  Pharmaceuticals Inc. July, 2014.|1
02410|037|R|2.Gocovri (amantadine) US Prescribing Information. Adamas Pharma, LLC|1
02410|038|R|  February, 2021.|1
02410|039|R|3.Goralski KB, Smyth DD, Sitar DS. In vivo analysis of amantadine renal|5
02410|040|R|  clearance in the uninephrectomized rat: functional significance of in|5
02410|041|R|  vitro bicarbonate-dependent amantadine renal tubule transport. J Pharmacol|5
02410|042|R|  Exp Ther 1999 Aug;290(2):496-504.|5
02410|043|R|4.Freudenthaler S, Meineke I, Schreeb KH, Boakye E, Gundert-Remy U, Gleiter|2
02410|044|R|  CH. Influence of urine pH and urinary flow on the renal excretion of|2
02410|045|R|  memantine. Br J Clin Pharmacol 1998 Dec;46(6):541-6.|2
02411|001|T|MONOGRAPH TITLE:  Simeprevir/Strong or Moderate CYP3A4 Inducers|
02411|002|B||
02411|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02411|004|L|of severe adverse interaction.|
02411|005|B||
02411|006|A|MECHANISM OF ACTION:  Strong or moderate inducers of CYP3A4 may induce the|
02411|007|A|metabolism of simeprevir.(1)|
02411|008|B||
02411|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong or moderate CYP3A4|
02411|010|E|inducers may lower simeprevir minimum concentrations (Cmin) leading to a|
02411|011|E|loss of virologic response to simeprevir.(1)|
02411|012|B||
02411|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02411|014|P|of the inducer for longer than 1-2 weeks.|
02411|015|B||
02411|016|M|PATIENT MANAGEMENT:  The US manufacturer of simeprevir states that|
02411|017|M|concurrent administration of strong or moderate inducers of CYP3A4 is not|
02411|018|M|recommended due risk for simeprevir treatment failure.(1)|
02411|019|B||
02411|020|D|DISCUSSION:  In a study in 18 subjects, rifampin (600 mg daily for 7 days)|
02411|021|D|decreased the area-under-curve (AUC) and Cmin of simeprevir (200 mg daily|
02411|022|D|for 7 days) by 48% and 92%, respectively.  The simeprevir maximum|
02411|023|D|concentration (Cmax) increased 1.31-fold.(1)|
02411|024|D|   Strong and moderate inducers of CYP3A4 linked to this monograph include|
02411|025|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
02411|026|D|dabrafenib, dexamethasone, elagolix, encorafenib, enzalutamide,|
02411|027|D|fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten,|
02411|028|D|mitapivat, mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib,|
02411|029|D|pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifampin,|
02411|030|D|rifabutin, rifapentine, St. John's wort, sotorasib, telotristat, and|
02411|031|D|tovorafenib.(1-3)|
02411|032|B||
02411|033|R|REFERENCES:|
02411|034|B||
02411|035|R|1.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
02411|036|R|  November, 2017.|1
02411|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02411|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02411|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02411|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02411|041|R|  11/14/2017.|1
02411|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
02411|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02412|001|T|MONOGRAPH TITLE:  Simeprevir/Strong or Moderate CYP3A4 Inhibitors|
02412|002|B||
02412|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02412|004|L|of severe adverse interaction.|
02412|005|B||
02412|006|A|MECHANISM OF ACTION:  Strong or moderate inhibitors of CYP3A4 may slow down|
02412|007|A|the metabolism of simeprevir.(1)  Simeprevir may inhibit the metabolism of|
02412|008|A|darunavir, diltiazem, erythromycin, and verapamil.(1)|
02412|009|B||
02412|010|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inhibitors|
02412|011|E|may result in elevated levels of and toxicity from simeprevir.(1)|
02412|012|E|Simeprevir may increase levels and toxicity of darunavir, diltiazem,|
02412|013|E|erythromycin, and verapamil.(1)|
02412|014|B||
02412|015|P|PREDISPOSING FACTORS:  None determined.|
02412|016|B||
02412|017|M|PATIENT MANAGEMENT:  The US manufacturer of simeprevir states that|
02412|018|M|concurrent administration of strong or moderate inhibitors of CYP3A4 is not|
02412|019|M|recommended due to risk of toxicity.(1)|
02412|020|M|   The American Society of Transplantation guidelines state that the|
02412|021|M|combination of cyclosporine and simeprevir is contraindicated.(7)|
02412|022|M|   The US manufacturer of itraconazole states that concurrent administration|
02412|023|M|with simeprevir is not recommended during and two weeks after itraconazole|
02412|024|M|treatment (6).|
02412|025|B||
02412|026|D|DISCUSSION:  In a study in 24 subjects, erythromycin (500 mg TID for 7 days)|
02412|027|D|increased the maximum concentration (Cmax), area-under-curve (AUC) and Cmin|
02412|028|D|of simeprevir (150 mg daily for 7 days) by 4.53-fold, 7.47-fold, and|
02412|029|D|12.74-fold, respectively.  The Cmax and AUC of erythromycin increased by|
02412|030|D|1.59-fold and 1.39-fold, respectively.(1)|
02412|031|D|   In a study in 9 subjects, an individualized dose of cyclosporine|
02412|032|D|increased the Cmax and AUC of simeprevir (150 mg daily for 14 days) by 4.74|
02412|033|D|fold and 5.81-fold.(1)|
02412|034|D|   In a study in 25 subjects, simeprevir (50 mg once daily) increased the|
02412|035|D|Cmax, AUC, and Cmin of darunavir (800 mg once daily) by 4%, 18%, and 31%.(4)|
02412|036|D|   In a study in 25 subjects, darunavir-ritonavir (800 mg-100 mg once daily)|
02412|037|D|increased the Cmax, AUC, and Cmin of simeprevir (50 mg once daily) by|
02412|038|D|1.79-fold, 2.59-fold, and 4.58-fold.(4)|
02412|039|D|   In a study in 12 subjects, ritonavir (100 mg twice daily, 15 days)|
02412|040|D|increased the AUC, Cmax, and Cmin of simeprevir (200 mg daily, 7 days) by|
02412|041|D|618% (463-815%), 370% (284-476%), and 1335% (929-1901%).(5)|
02412|042|D|   Strong and moderate inhibitors of CYP3A4 linked to this monograph include|
02412|043|D|adagrasib, amprenavir, aprepitant, atazanavir, avacopan, berotralstat,|
02412|044|D|boceprevir, ceritinib, clarithromycin, clofazimine, cobicistat, conivaptan,|
02412|045|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
02412|046|D|fedratinib, fosamprenavir, fluconazole, fluvoxamine, fosnetupitant,|
02412|047|D|idelalisib, imatinib, indinavir, isavuconazonium, itraconazole, josamycin,|
02412|048|D|ketoconazole, lefamulin, lenacapavir, lonafarnib, lopinavir, mibefradil,|
02412|049|D|mifepristone, milk thistle, nefazodone, nelfinavir, netupitant, nilotinib,|
02412|050|D|nirmatrelvir/ritonavir, nirogacestat, posaconazole, ribociclib,|
02412|051|D|rilzabrutinib, ritonavir, saquinavir, schisandra, silibinin, stiripentol,|
02412|052|D|telaprevir, telithromycin, tipranavir, treosulfan, troleandomycin,|
02412|053|D|tucatinib, verapamil, and voriconazole.(1-3)|
02412|054|B||
02412|055|R|REFERENCES:|
02412|056|B||
02412|057|R|1.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
02412|058|R|  November, 2017.|1
02412|059|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02412|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02412|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02412|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02412|063|R|  11/14/2017.|1
02412|064|R|3.This information is based on an extract from the Certara Drug Interaction|6
02412|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02412|066|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
02412|067|R|  March, 2023.|1
02412|068|R|5.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
02412|069|R|  December, 2019.|1
02412|070|R|6.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02412|071|R|  Products, L.P. February, 2024.|1
02412|072|R|7.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
02412|073|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
02412|074|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
02412|075|R|  e13510.|6
02413|001|T|MONOGRAPH TITLE:  Atorvastatin (> 40mg); Lovastatin;|
02413|002|T|Simvastatin/Ciprofloxacin|
02413|003|B||
02413|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02413|005|L|of severe adverse interaction.|
02413|006|B||
02413|007|A|MECHANISM OF ACTION:  Ciprofloxacin may inhibit the metabolism of|
02413|008|A|atorvastatin, lovastatin, and simvastatin by CYP3A4.(1)|
02413|009|B||
02413|010|E|CLINICAL EFFECTS:  Concurrent use of ciprofloxacin may result in elevated|
02413|011|E|levels of atorvastatin, lovastatin, and simvastatin which could result in|
02413|012|E|rhabdomyolysis.|
02413|013|B||
02413|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02413|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02413|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02413|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02413|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02413|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02413|020|P|predisposed to myopathy or rhabdomyolysis.|
02413|021|B||
02413|022|M|PATIENT MANAGEMENT:  For patients receiving atorvastatin (especially high|
02413|023|M|doses), lovastatin, or simvastatin, consider holding statin therapy for the|
02413|024|M|duration of ciprofloxacin therapy.|
02413|025|M|   If atorvastatin is used with ciprofloxacin, consider limiting the dose of|
02413|026|M|atorvastatin to less than or equal to 40 mg daily for the duration of|
02413|027|M|ciprofloxacin therapy.  Monitor patient for statin-associated myopathy.|
02413|028|B||
02413|029|D|DISCUSSION:  A specific interaction study between atorvastatin and|
02413|030|D|ciprofloxacin has not been performed.|
02413|031|D|   Rhabdomyolysis has been reported with concurrent ciprofloxacin and|
02413|032|D|simvastatin.(3-5)|
02413|033|B||
02413|034|R|REFERENCES:|
02413|035|B||
02413|036|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
02413|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02413|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02413|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02413|040|R|  11/14/2017.|1
02413|041|R|2.This information is based on an extract from the Certara Drug Interaction|6
02413|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02413|043|R|3.Goldie FC, Brogan A, Boyle JG. Ciprofloxacin and statin interaction: a|3
02413|044|R|  cautionary tale of rhabdomyolysis. BMJ Case Rep 2016 Jul 28;2016:.|3
02413|045|R|4.De Schryver N, Wittebole X, Van den Bergh P, Haufroid V, Goffin E, Hantson|3
02413|046|R|  P. Severe rhabdomyolysis associated with simvastatin and role of|3
02413|047|R|  ciprofloxacin and amlodipine coadministration. Case Rep Nephrol 2015;|3
02413|048|R|  2015:761393.|3
02413|049|R|5.Sawant RD. Rhabdomyolysis due to an uncommon interaction of ciprofloxacin|3
02413|050|R|  with simvastatin. Can J Clin Pharmacol 2009 Winter;16(1):e78-9.|3
02415|001|T|MONOGRAPH TITLE:  Selected Hepatitis C Agents/P-gp Inducers; Phenobarbital|
02415|002|B||
02415|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02415|004|L|is contraindicated and generally should not be dispensed or administered to|
02415|005|L|the same patient.|
02415|006|B||
02415|007|A|MECHANISM OF ACTION:  Inducers of P-glycoprotein (P-gp) may decrease the|
02415|008|A|absorption of ledipasvir,(1) sofosbuvir,(1-4) velpatasvir,(3,4) and|
02415|009|A|voxilaprevir.(4)|
02415|010|B||
02415|011|E|CLINICAL EFFECTS:  Concurrent or recent use of a P-gp inducer may result in|
02415|012|E|decreased levels and effectiveness of ledipasvir,(1) sofosbuvir,(1-4)|
02415|013|E|velpatasvir,(3,4) and voxilaprevir.(4)|
02415|014|B||
02415|015|P|PREDISPOSING FACTORS:  None determined.|
02415|016|B||
02415|017|M|PATIENT MANAGEMENT:  The US manufacturers of ledipasvir-sofosbuvir,(1)|
02415|018|M|sofosbuvir,(2) sofosbuvir/velpatasvir,(3) and|
02415|019|M|sofosbuvir-velpatasvir-voxilaprevir,(4) do not recommend coadministration|
02415|020|M|with inducers of P-gp.|
02415|021|B||
02415|022|D|DISCUSSION:  A study of 24 healthy subjects found that carbamazepine (300 mg|
02415|023|D|twice daily) decreased the maximum concentration (Cmax) and exposure (AUC,|
02415|024|D|area-under-curve) of sofosbuvir both by 48%.(3)|
02415|025|D|   In a study in 31 subjects, rifampin (600 mg daily) decreased the Cmax and|
02415|026|D|AUC of ledipasvir by 35% and 59%, respectively.(1)|
02415|027|D|   In a study in 17 subjects, rifampin (600 mg daily) decreased the Cmax and|
02415|028|D|AUC of sofosbuvir by 77% and 72%, respectively.(2-4)|
02415|029|D|   In a study in 12 subjects, rifampin (600 mg daily) decreased the Cmax and|
02415|030|D|AUC of velpatasvir by 71% and 82%, respectively.(3-4)|
02415|031|D|   In a study in 24 subjects, rifampin (600 mg daily) decreased the Cmax and|
02415|032|D|AUC of voxilaprevir by 9% and 73%, respectively.(4)|
02415|033|D|   Agents linked to this monograph include apalutamide, carbamazepine,|
02415|034|D|fosphenytoin, lorlatinib, phenobarbital, phenytoin, primidone, rifampin,|
02415|035|D|rifapentine, St. John's wort, and tipranavir.(1-6)|
02415|036|B||
02415|037|R|REFERENCES:|
02415|038|B||
02415|039|R|1.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
02415|040|R|  Sciences November, 2019.|1
02415|041|R|2.Sovaldi (sofosbuvir) US prescribing information. Gilead Sciences, Inc.|1
02415|042|R|  September, 2019.|1
02415|043|R|3.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
02415|044|R|  Sciences, Inc. April, 2022.|1
02415|045|R|4.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02415|046|R|  Gilead Sciences, Inc. September, 2019.|1
02415|047|R|5.This information is based on an extract from the Certara Drug Interaction|6
02415|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02415|049|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
02415|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02415|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02415|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02415|053|R|  11/14/2017.|1
02416|001|T|MONOGRAPH TITLE:  Avanafil/Strong CYP3A4 Inhibitors; Atazanavir; Darunavir|
02416|002|B||
02416|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02416|004|L|is contraindicated and generally should not be dispensed or administered to|
02416|005|L|the same patient.|
02416|006|B||
02416|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
02416|008|A|avanafil.(1-2)|
02416|009|B||
02416|010|E|CLINICAL EFFECTS:  The concurrent administration of a CYP3A4 inhibitor may|
02416|011|E|result in elevated levels of avanafil, which may result in increased adverse|
02416|012|E|effects such as hypotension, visual changes, and priapism.(1-2)|
02416|013|B||
02416|014|P|PREDISPOSING FACTORS:  None determined.|
02416|015|B||
02416|016|M|PATIENT MANAGEMENT:  The US manufacturer of avanafil states that the|
02416|017|M|concurrent use of strong inhibitors of CYP3A4 is contraindicated.(1)|
02416|018|M|   The US Department of Health and Human Services HIV guidelines state that|
02416|019|M|boosted atazanavir or darunavir should not be coadministered with avanafil.|
02416|020|M|Unboosted atazanavir may be coadministered with avanafil doses not exceeding|
02416|021|M|50 mg every 24 hours.(2)|
02416|022|M|   The US manufacturer of itraconazole states that concurrent use of|
02416|023|M|avanafil is contraindicated during and two weeks after itraconazole|
02416|024|M|treatment.(3)|
02416|025|B||
02416|026|D|DISCUSSION:  Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4,|
02416|027|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02416|028|D|single dose of avanafil (50 mg) by 3-fold and 13-fold, respectively.  The|
02416|029|D|half-life of avanafil increased from 5 hours to 9 hours.(1)|
02416|030|D|   Ritonavir (600 mg BID), a strong inhibitor of CYP3A4 and an inhibitor of|
02416|031|D|CYP2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by|
02416|032|D|2.4-fold and 13-fold, respectively.  The half-life of avanafil increased|
02416|033|D|from 5 hours to 9 hours.(1)|
02416|034|D|   Erythromycin (500 mg BID), a moderate inhibitor of CYP3A4, increased the|
02416|035|D|Cmax and AUC of a single dose of avanafil (200 mg) by 2-fold and 3-fold,|
02416|036|D|respectively.  The half-life of avanafil increased from 5 hours to 8|
02416|037|D|hours.(1)|
02416|038|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
02416|039|D|clarithromycin, cobicistat, elvitegravir, idelalisib, indinavir,|
02416|040|D|itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir,|
02416|041|D|mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
02416|042|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
02416|043|D|troleandomycin, tucatinib, and voriconazole.(4-5)|
02416|044|B||
02416|045|R|REFERENCES:|
02416|046|B||
02416|047|R|1.Stendra (avanafil) US prescribing information. Vivus, Inc. October, 2022.|1
02416|048|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02416|049|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02416|050|R|  HIV. Department of Health and Human Services. Available at:|6
02416|051|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
02416|052|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
02416|053|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02416|054|R|  Products, L.P. February, 2024.|1
02416|055|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02416|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02416|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02416|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02416|059|R|  11/14/2017.|1
02416|060|R|5.This information is based on an extract from the Certara Drug Interaction|6
02416|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02417|001|T|MONOGRAPH TITLE:  Avanafil (Greater Than 50 mg)/Moderate CYP3A4 Inhibitors|
02417|002|B||
02417|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02417|004|L|is contraindicated and generally should not be dispensed or administered to|
02417|005|L|the same patient.|
02417|006|B||
02417|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
02417|008|A|metabolism of avanafil.(1)|
02417|009|B||
02417|010|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
02417|011|E|inhibitor may result in elevated levels of avanafil, which may result in|
02417|012|E|increased adverse effects such as hypotension, visual changes, and priapism.|
02417|013|B||
02417|014|P|PREDISPOSING FACTORS:  None determined.|
02417|015|B||
02417|016|M|PATIENT MANAGEMENT:  The US manufacturer of avanafil states that in patients|
02417|017|M|receiving moderate inhibitors of CYP3A4, the dose of avanafil should be|
02417|018|M|limited to 50 mg in 24 hours.(1)|
02417|019|B||
02417|020|D|DISCUSSION:  Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4,|
02417|021|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02417|022|D|single dose of avanafil (50 mg) by 3-fold and 13-fold, respectively.  The|
02417|023|D|half-life of avanafil increased from 5 hours to 9 hours.(1)|
02417|024|D|   Ritonavir (600 mg BID), a strong inhibitor of CYP3A4 and an inhibitor of|
02417|025|D|2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by|
02417|026|D|2-fold and 13-fold, respectively.  The half-life of avanafil increased from|
02417|027|D|5 hours to 9 hours.(1)|
02417|028|D|   Erythromycin (500 mg BID), a moderate inhibitor of CYP3A4, increased the|
02417|029|D|Cmax and AUC of a single dose of avanafil (200 mg) by 2-fold and 3-fold,|
02417|030|D|respectively.  The half-life of avanafil increased from 5 hours to 8|
02417|031|D|hours.(1)|
02417|032|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, avacopan,|
02417|033|D|berotralstat, clofazimine, conivaptan,  crizotinib, diltiazem, dronedarone,|
02417|034|D|duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine,|
02417|035|D|fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium,|
02417|036|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
02417|037|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and|
02417|038|D|verapamil.(1-3)|
02417|039|B||
02417|040|R|REFERENCES:|
02417|041|B||
02417|042|R|1.Stendra (avanafil) US prescribing information. Vivus, Inc. October, 2022.|1
02417|043|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02417|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02417|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02417|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02417|047|R|  11/14/2017.|1
02417|048|R|3.This information is based on an extract from the Certara Drug Interaction|6
02417|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02418|001|T|MONOGRAPH TITLE:  Avanafil (Less Than or Equal To 50 mg)/Moderate CYP3A4|
02418|002|T|Inhibitors|
02418|003|B||
02418|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02418|005|L|take action as needed.|
02418|006|B||
02418|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
02418|008|A|metabolism of avanafil.(1)|
02418|009|B||
02418|010|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
02418|011|E|inhibitor may result in elevated levels of avanafil, which may result in|
02418|012|E|increased adverse effects such as hypotension, visual changes, and priapism.|
02418|013|B||
02418|014|P|PREDISPOSING FACTORS:  None determined.|
02418|015|B||
02418|016|M|PATIENT MANAGEMENT:  The US manufacturer of avanafil states that in patients|
02418|017|M|receiving moderate inhibitors of CYP3A4, the dose of avanafil should be|
02418|018|M|limited to 50 mg in 24 hours.(1)|
02418|019|B||
02418|020|D|DISCUSSION:  Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4,|
02418|021|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02418|022|D|single dose of avanafil (50 mg) by 3-fold and 13-fold, respectively.  The|
02418|023|D|half-life of avanafil increased from 5 hours to 9 hours.(1)|
02418|024|D|   Ritonavir (600 mg BID), a strong inhibitor of CYP3A4 and an inhibitor of|
02418|025|D|2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by|
02418|026|D|2-fold and 13-fold, respectively.  The half-life of avanafil increased from|
02418|027|D|5 hours to 9 hours.(1)|
02418|028|D|   Erythromycin (500 mg BID), a moderate inhibitor of CYP3A4, increased the|
02418|029|D|Cmax and AUC of a single dose of avanafil (200 mg) by 2-fold and 3-fold,|
02418|030|D|respectively.  The half-life of avanafil increased from 5 hours to 8|
02418|031|D|hours.(1)|
02418|032|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant, avacopan,|
02418|033|D|berotralstat, clofazimine, conivaptan,  crizotinib, diltiazem, dronedarone,|
02418|034|D|duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine,|
02418|035|D|fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium,|
02418|036|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
02418|037|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and|
02418|038|D|verapamil.(1-3)|
02418|039|B||
02418|040|R|REFERENCES:|
02418|041|B||
02418|042|R|1.Stendra (avanafil) US prescribing information. Vivus, Inc. October, 2022.|1
02418|043|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02418|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02418|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02418|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02418|047|R|  11/14/2017.|1
02418|048|R|3.This information is based on an extract from the Certara Drug Interaction|6
02418|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02419|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Posaconazole|
02419|002|B||
02419|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02419|004|L|of severe adverse interaction.|
02419|005|B||
02419|006|A|MECHANISM OF ACTION:  The metabolism of cyclosporine and temsirolimus by|
02419|007|A|CYP3A4 may be inhibited by posaconazole.(1-3)|
02419|008|B||
02419|009|E|CLINICAL EFFECTS:  Concurrent administration of posaconazole may result in|
02419|010|E|elevated levels of and toxicity from cyclosporine or temsirolimus.(1-3)|
02419|011|B||
02419|012|P|PREDISPOSING FACTORS:  None determined.|
02419|013|B||
02419|014|M|PATIENT MANAGEMENT:  Cyclosporine or temsirolimus levels and renal function|
02419|015|M|should be monitored if posaconazole is initiated or discontinued from|
02419|016|M|concurrent therapy.(1-3)|
02419|017|M|   The US manufacturer of posaconazole recommends that the dose of|
02419|018|M|cyclosporine be reduced by 25% to an amount that is approximately 75% of the|
02419|019|M|original dosage when posaconazole is initiated.  Cyclosporine levels should|
02419|020|M|be closely monitored during concurrent azole therapy.  The dosage of|
02419|021|M|cyclosporine may need adjusting when azole therapy has been completed.(1-2)|
02419|022|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
02419|023|M|with strong CYP3A4 inhibitors be avoided.  If concurrent use is warranted, a|
02419|024|M|dosage reduction to 12.5 mg/week of temsirolimus should be considered.  If|
02419|025|M|the azole is discontinued, a washout period of 1 week should be allowed|
02419|026|M|before adjusting the dosage of temsirolimus to previous levels.(3)|
02419|027|M|   Posaconazole tablets have improved bioavailability and higher|
02419|028|M|concentrations per dose than posaconazole suspension.  A greater dose|
02419|029|M|reduction of the immunosuppressant may be necessary when posaconazole|
02419|030|M|tablets are used.(4-6)|
02419|031|B||
02419|032|D|DISCUSSION:  Concurrent use of posaconazole in heart transplant patients|
02419|033|D|resulted in increased cyclosporine levels requiring dosage adjustments.  In|
02419|034|D|clinical trials, increased cyclosporine levels resulting in serious adverse|
02419|035|D|events including nephrotoxicity, leukoencephalopathy, and death were|
02419|036|D|reported.|
02419|037|D|   One study looked at the effects of posaconazole on the metabolism of|
02419|038|D|cyclosporine when administered concurrently in heart transplant recipients.|
02419|039|D|The study found when both medications were used concomitantly that|
02419|040|D|cyclosporine exposure increased.  The increased exposure required dosage|
02419|041|D|adjustments of 14-29% in three out of four patients.(7)|
02419|042|B||
02419|043|R|REFERENCES:|
02419|044|B||
02419|045|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
02419|046|R|  January, 2022.|1
02419|047|R|2.Noxafil (posaconazole) UK summary of product characteristics.|1
02419|048|R|  Schering-Plough Ltd. January, 2022.|1
02419|049|R|3.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
02419|050|R|  Inc. March, 2018.|1
02419|051|R|4.Stelzer D, Weber A, Ihle F, Matthes S, Ceelen F, Zimmermann G, Kneidinger|2
02419|052|R|  N, Schramm R, Winter H, Zoller M, Vogeser M, Behr J, Neurohr C.|2
02419|053|R|  Posaconazole liquid vs tablet formulation in lung transplant recipients.|2
02419|054|R|  Mycoses 2018 Mar;61(3):186-194.|2
02419|055|R|5.Chanoine S, Gautier-Veyret E, Pluchart H, Tonini J, Fonrose X, Claustre J,|2
02419|056|R|  Bedouch P, Stanke-Labesque F. Tablets or oral suspension for posaconazole|2
02419|057|R|  in lung transplant recipients?  Consequences for trough concentrations of|2
02419|058|R|  tacrolimus and everolimus. Br J Clin Pharmacol 2020 May 29.|2
02419|059|R|6.Launay M, Roux A, Beaumont L, Douvry B, Lecuyer L, Douez E, Picard C,|2
02419|060|R|  Grenet D, Jullien V, Boussaud V, Guillemain R, Billaud EM. Posaconazole|2
02419|061|R|  Tablets in Real-Life Lung Transplantation: Impact on Exposure,  Drug-Drug|2
02419|062|R|  Interactions, and Drug Management in Lung Transplant Patients, Including|2
02419|063|R|  Those with Cystic Fibrosis. Antimicrob Agents Chemother 2018 Mar;62(3):.|2
02419|064|R|7.Sansone-Parsons A, Krishna G, Martinho M, Kantesaria B, Gelone S, Mant TG.|2
02419|065|R|  Effect of oral posaconazole on the pharmacokinetics of cyclosporine and|2
02419|066|R|  tacrolimus. Pharmacotherapy 2007 Jun;27(6):825-34.|2
02420|001|T|MONOGRAPH TITLE:  Select Antineoplastic Systemic Enzyme|
02420|002|T|Inhibitors/Fluconazole|
02420|003|B||
02420|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02420|005|L|of severe adverse interaction.|
02420|006|B||
02420|007|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of|
02420|008|A|crizotinib,(1) dasatinib,(2) lapatinib,(3) nilotinib,(4-5) pazopanib,(6) and|
02420|009|A|sunitinib.(7)|
02420|010|B||
02420|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
02420|012|E|levels of and effects from crizotinib,(1) dasatinib,(2) lapatinib,(3)|
02420|013|E|nilotinib,(4-5) pazopanib,(6) and sunitinib.(7)  In addition, elevated|
02420|014|E|levels of these agents may result in prolongation of the QTc interval, which|
02420|015|E|may result in potentially life-threatening cardiac arrhythmias, including|
02420|016|E|torsades de pointes.|
02420|017|B||
02420|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02420|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
02420|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02420|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02420|022|P|female gender, or advanced age.(2)|
02420|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02420|024|P|higher systemic concentrations of either QT prolonging drug are additional|
02420|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02420|026|P|drug concentrations include rapid infusion of an intravenous dose or|
02420|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02420|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02420|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(8)|
02420|030|B||
02420|031|M|PATIENT MANAGEMENT:  The manufacturer of fluconazole states that it is|
02420|032|M|contraindicated with agents that prolong the QT interval and are metabolized|
02420|033|M|by CYP3A4;(9) however, the manufacturers of the antineoplastic enzyme|
02420|034|M|inhibitors recommend avoiding concurrent use of strong CYP3A4|
02420|035|M|inhibitors.(1-7)  Given that fluconazole is a moderate inhibitor of|
02420|036|M|CYP3A4,(10) it may be prudent to consider the manufacturer recommendations|
02420|037|M|for concurrent use of strong inhibitors and monitor patients receiving|
02420|038|M|concurrent therapy for QTc prolongation.  If concurrent therapy is|
02420|039|M|warranted, consider obtaining serum calcium, magnesium, and potassium levels|
02420|040|M|and monitoring ECG at baseline and at regular intervals.  Correct any|
02420|041|M|electrolyte abnormalities.|
02420|042|M|Specific recommendations:|
02420|043|M|   In Adults: If concurrent use of crizotinib for metastatic non-small cell|
02420|044|M|lung cancer or inflammatory myofibroblastic tumor in adults and a strong|
02420|045|M|CYP3A4 inhibitor is unavoidable, a dose reduction of crizotinib to 250 mg|
02420|046|M|daily is recommended.|
02420|047|M|   In Pediatrics or Young Adults: If concurrent use of crizotinib for|
02420|048|M|systemic anaplastic large cell lymphoma (in pediatrics), inflammatory|
02420|049|M|myofibroblastic tumor (in pediatrics) or systemic anaplastic large cell|
02420|050|M|lymphoma (in young adults) and a strong CYP3A4 inhibitor is unavoidable,|
02420|051|M|dose reductions of crizotinib based on body surface area (BSA) are|
02420|052|M|recommended for both capsule and pellet formulations.  See prescribing|
02420|053|M|information for dose reductions.|
02420|054|M|   If the strong CYP3A4 inhibitor is discontinued and not replaced with|
02420|055|M|another strong CYP3A4 inhibitor, resume the dose of crizotinib that was|
02420|056|M|taken prior to initiating the inhibitor.(1)|
02420|057|M|   If concurrent use of dasatinib and a strong inhibitor of CYP3A4 is|
02420|058|M|warranted, consider decreasing the dose of dasatinib to 20 mg daily in|
02420|059|M|patients taking dasatinib 70 mg daily or 100 mg daily, and to 40 mg daily in|
02420|060|M|patients taking dasatinib 140 mg daily.  If this dose is not tolerated,|
02420|061|M|either the strong CYP3A4 inhibitor must be discontinued or dasatinib should|
02420|062|M|be stopped until therapy with the 3A4 inhibitor has been completed.  When|
02420|063|M|the 3A4 inhibitor has been discontinued, a one-week elimination period|
02420|064|M|should be allowed before the dosage of dasatinib is increased.(2)|
02420|065|M|   If concurrent use of lapatinib and a strong inhibitor of CYP3A4 is|
02420|066|M|warranted, a dose reduction to 500 mg/day should be considered.  If the|
02420|067|M|CYP3A4 inhibitor is discontinued, at least 1 week should elapse before the|
02420|068|M|lapatinib dose is adjusted upward.(3)|
02420|069|M|   Consider interrupting nilotinib therapy if a strong CYP3A4 inhibitor is|
02420|070|M|needed.  If concurrent use is warranted with nilotinib hydrochloride, a dose|
02420|071|M|reduction to 300 mg once daily in patients with resistant or intolerant|
02420|072|M|Ph+CML or to 200 mg once daily in patients with newly diagnosed Ph+CML-CP|
02420|073|M|should be considered.(4)|
02420|074|M|   If concurrent use is warranted with nilotinib tartrate, a dose reduction|
02420|075|M|to 142 mg once daily in patients with resistant or intolerant Ph+CML or to|
02420|076|M|95 mg once daily in patients with newly diagnosed Ph+CML-CP should be|
02420|077|M|considered.(5)|
02420|078|M|   If the CYP3A4 inhibitor is discontinued, an elimination period should|
02420|079|M|occur before the nilotinib dose is adjusted upward.(4-5)|
02420|080|M|   If concurrent administration of pazopanib and a strong CYP3A4 inhibitor|
02420|081|M|is warranted, the dosage of pazopanib should be reduced to 400 mg.|
02420|082|M|Additional dosage reductions may be required if adverse events occur.(6)|
02420|083|M|   If concurrent therapy with sunitinib and a strong CYP3A4 inhibitor is|
02420|084|M|warranted, a dosage reduction of sunitinib to a minimum of 37.5 mg daily in|
02420|085|M|patients with gastrointestinal stromal tumors (GIST) or advanced renal cell|
02420|086|M|carcinoma (RCC) or to a minimum of 25 mg in patients with pancreatic|
02420|087|M|neuroendocrine tumors (pNET) should be considered.  Monitor the QT interval|
02420|088|M|more frequently.(7)|
02420|089|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02420|090|M|fainting.|
02420|091|B||
02420|092|D|DISCUSSION:  Ketoconazole, a strong inhibitor of CYP3A4, (200 mg twice|
02420|093|D|daily) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
02420|094|D|of a single dose of crizotinib (150 mg) by 44% and 216%, respectively.|
02420|095|D|Itraconazole, another strong inhibitor of CYP3A, (200 mg twice daily)|
02420|096|D|increased the Cmax and AUC of crizotinib (250 mg daily) by 33% and 57%,|
02420|097|D|respectively.(1)|
02420|098|D|   In a study in healthy subjects, concurrent ketoconazole (200 mg twice|
02420|099|D|daily) with dasatinib (20 mg) increased dasatinib Cmax and AUC by 4-fold and|
02420|100|D|5-fold, respectively.  Recommended dosage adjustments are expected to adjust|
02420|101|D|the dasatinib AUC to ranges observed without CYP3A4 inhibitors; however,|
02420|102|D|there are no clinical data available.(2)|
02420|103|D|   In a study in healthy subjects, ketoconazole (200 mg twice daily for 7|
02420|104|D|days) increased lapatinib AUC and half-life (T1/2) by 3.6-fold and 1.7-fold,|
02420|105|D|respectively.  The dosage adjustment to 500 mg/day is based on|
02420|106|D|pharmacokinetic studies and is predicted to adjust lapatinib AUC to the|
02420|107|D|range observed without inhibitors; however, there are no clinical data with|
02420|108|D|this dosage adjustment in patients receiving strong CYP3A4 inhibitors.(3)|
02420|109|D|   In a study in healthy subjects, concurrent ketoconazole (400 mg daily)|
02420|110|D|increased nilotinib AUC 3-fold.(4-5)|
02420|111|D|   Administration of multiple doses of oral pazopanib (400 mg) with multiple|
02420|112|D|doses of oral ketoconazole (400 mg) increased the AUC and Cmax of pazopanib|
02420|113|D|by 1.7-fold and 1.5-fold, respectively.  Administration of a single dose of|
02420|114|D|pazopanib ophthalmic drops and ketoconazole, an inhibitor of CYP3A4 and Pgp,|
02420|115|D|increase the AUC and Cmax of pazopanib by 220% and 150%, respectively.|
02420|116|D|Administration of lapatinib (1500 mg), a weak inhibitor of CYP3A4, Pgp, and|
02420|117|D|BCRP, increased the AUC and Cmax of pazopanib (800 mg) by 50% and 60%,|
02420|118|D|respectively.  Decreasing the dosage of pazopanib to 400 mg in patients|
02420|119|D|receiving strong CYP P3A4 inhibitors is expected to adjust the AUC of|
02420|120|D|pazopanib to the normal range; however, there are no clinical data available|
02420|121|D|to support this.(6)|
02420|122|D|   In a study in healthy subjects, concurrent ketoconazole increased the|
02420|123|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 49% and|
02420|124|D|51%, respectively, of a single dose of sunitinib.(7)|
02420|125|B||
02420|126|R|REFERENCES:|
02420|127|B||
02420|128|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
02420|129|R|  2023.|1
02420|130|R|2.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
02420|131|R|  Company February, 2023.|1
02420|132|R|3.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
02420|133|R|  2018.|1
02420|134|R|4.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
02420|135|R|  Corporation September, 2021.|1
02420|136|R|5.Danziten (nilotinib tartrate) US prescribing information. Novartis|1
02420|137|R|  Pharmaceuticals November 2024.|1
02420|138|R|6.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
02420|139|R|  2020.|1
02420|140|R|7.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
02420|141|R|  2021.|1
02420|142|R|8.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02420|143|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02420|144|R|  settings: a scientific statement from the American Heart Association and|6
02420|145|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02420|146|R|  2;55(9):934-47.|6
02420|147|R|9.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
02420|148|R|  2024.|1
02420|149|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
02420|150|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
02420|151|R|   at:|1
02420|152|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
02420|153|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02420|154|R|   11/14/2017.|1
02421|001|T|MONOGRAPH TITLE:  Guanfacine/Strong & Moderate CYP3A4 Inhibitors|
02421|002|B||
02421|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02421|004|L|of severe adverse interaction.|
02421|005|B||
02421|006|A|MECHANISM OF ACTION:  Strong or moderate inhibitors of CYP3A4 may inhibit|
02421|007|A|the metabolism of guanfacine.(1)|
02421|008|B||
02421|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong or moderate|
02421|010|E|CYP3A4 inhibitor may result in elevated levels of guanfacine, which may|
02421|011|E|result in increased adverse effects such as hypotension, bradycardia, loss|
02421|012|E|of consciousness, and drowsiness.(1)|
02421|013|B||
02421|014|P|PREDISPOSING FACTORS:  None determined.|
02421|015|B||
02421|016|M|PATIENT MANAGEMENT:  Patients maintained on guanfacine may need dosage|
02421|017|M|adjustments if strong or moderate inhibitors of CYP3A4 are initiated or|
02421|018|M|discontinued.|
02421|019|M|   The manufacturer of extended-release guanfacine recommends a starting|
02421|020|M|dose of extended-release guanfacine initiated at half the recommended level|
02421|021|M|of the weight based dosing in patients receiving strong or moderate|
02421|022|M|inhibitors of CYP3A4.|
02421|023|M|   If a patient has been maintained on extended-release guanfacine and is|
02421|024|M|started on a strong or moderate CYP3A4 inhibitor, the dose of|
02421|025|M|extended-release guanfacine should be decreased to half the recommended|
02421|026|M|weight based dose.|
02421|027|M|   If a patient has been maintained on extended-release guanfacine and a|
02421|028|M|strong or moderate CYP3A4 inhibitor and the strong or moderate CYP3A4|
02421|029|M|inhibitor is discontinued, the dose of extended-release guanfacine may need|
02421|030|M|to be increased to the recommended weight based dose based upon patient|
02421|031|M|response.|
02421|032|M|   Extended-release guanfacine target dose range for attention deficit|
02421|033|M|hyperactivity disorder is 0.05-0.12 mg/kg/day.  Doses above 4 mg/day have|
02421|034|M|not been evaluated in children ages 6-12 years and doses above 7 mg/day have|
02421|035|M|not been evaluated in adolescents ages 13-17 years.(1)|
02421|036|B||
02421|037|D|DISCUSSION:  Ketoconazole (dosage not stated), a strong inhibitor of CYP3A4,|
02421|038|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02421|039|D|guanfacine (dosage not stated) by approximately 1.75-fold and 3-fold,|
02421|040|D|respectively.(1)|
02421|041|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02421|042|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
02421|043|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
02421|044|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole,|
02421|045|D|ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir,|
02421|046|D|troleandomycin, tucatinib, and voriconazole.(1-3)|
02421|047|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
02421|048|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
02421|049|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
02421|050|D|fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium,|
02421|051|D|lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra,|
02421|052|D|stiripentol, tofisopam, treosulfan and verapamil.(1-3)|
02421|053|B||
02421|054|R|REFERENCES:|
02421|055|B||
02421|056|R|1.Intuniv (guafacine) US prescribing information. Shire LLC July, 2016.|1
02421|057|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02421|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02421|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02421|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02421|061|R|  11/14/2017.|1
02421|062|R|3.This information is based on an extract from the Certara Drug Interaction|6
02421|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02422|001|T|MONOGRAPH TITLE:  Guanfacine/Strong & Moderate CYP3A4 Inducers|
02422|002|B||
02422|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02422|004|L|of severe adverse interaction.|
02422|005|B||
02422|006|A|MECHANISM OF ACTION:  Strong or moderate inducers of CYP3A4 may induce the|
02422|007|A|metabolism of guanfacine.(1)|
02422|008|B||
02422|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong or moderate|
02422|010|E|CYP3A4 inducer may result in decreased levels and effectiveness of|
02422|011|E|guanfacine.(1)|
02422|012|B||
02422|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02422|014|P|of the inducer for longer than 1-2 weeks.|
02422|015|B||
02422|016|M|PATIENT MANAGEMENT:  Patients maintained on guanfacine may need dosage|
02422|017|M|adjustments if strong or moderate inducers of CYP3A4 are initiated or|
02422|018|M|discontinued.|
02422|019|M|   The manufacturer of extended-release guanfacine recommends a starting|
02422|020|M|dose of extended-release guanfacine initiated at up to double the|
02422|021|M|recommended level of the weight based dosing in patients receiving strong or|
02422|022|M|moderate inducers of CYP3A4.|
02422|023|M|   If a patient has been maintained on extended-release guanfacine and is|
02422|024|M|started on a strong or moderate CYP3A4 inducer, the dose of extended-release|
02422|025|M|guanfacine should be increased up to double the recommended weight based|
02422|026|M|dose over 1 to 2 weeks.|
02422|027|M|   If a patient has been maintained on extended-release guanfacine and a|
02422|028|M|strong or moderate CYP3A4 inducer, and the strong or moderate CYP3A4 inducer|
02422|029|M|is discontinued, the dose of extended-release guanfacine may need to be|
02422|030|M|decreased to the recommended weight based dose over 1 to 2 weeks.|
02422|031|M|  Extended-release guanfacine target dose range for attention deficit|
02422|032|M|hyperactivity disorder is 0.05-0.12 mg/kg/day.  Doses above 4 mg/day have|
02422|033|M|not been evaluated in children ages 6-12 years and doses above 7 mg/day have|
02422|034|M|not been evaluated in adolescents ages 13-17 years.(1)|
02422|035|B||
02422|036|D|DISCUSSION:  Rifampin (dosage not stated), a strong inducer of CYP3A4,|
02422|037|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02422|038|D|guanfacine (dosage not stated) by approximately 50%.(1)|
02422|039|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
02422|040|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02422|041|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin,|
02422|042|D|rifampin, rifapentine, and St. John's wort.(1-3)|
02422|043|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
02422|044|D|dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib,|
02422|045|D|mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib,|
02422|046|D|repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(1-3)|
02422|047|B||
02422|048|R|REFERENCES:|
02422|049|B||
02422|050|R|1.Intuniv (guafacine) US prescribing information. Shire LLC July, 2016.|1
02422|051|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02422|052|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02422|053|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02422|054|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02422|055|R|  11/14/2017.|1
02422|056|R|3.This information is based on an extract from the Certara Drug Interaction|6
02422|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02423|001|T|MONOGRAPH TITLE:  Selected Progestin-only Contraceptives/Lamotrigine|
02423|002|B||
02423|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02423|004|L|take action as needed.|
02423|005|B||
02423|006|A|MECHANISM OF ACTION:  Lamotrigine may induce the metabolism of|
02423|007|A|levonorgestrel and norethindrone.(1-4)|
02423|008|B||
02423|009|E|CLINICAL EFFECTS:  Concurrent use of lamotrigine and levonorgestrel or|
02423|010|E|norethindrone-only contraceptives may result in decreased levels and|
02423|011|E|effectiveness of the contraceptive.|
02423|012|E|   Agents linked to this monograph contain only levonorgestrel or|
02423|013|E|norethindrone.|
02423|014|B||
02423|015|P|PREDISPOSING FACTORS:  None determined.|
02423|016|B||
02423|017|M|PATIENT MANAGEMENT:  Lamotrigine may decrease progestin concentration by|
02423|018|M|approximately 20%.  While this modest decrease does not appear to affect the|
02423|019|M|efficacy of estrogen-progestin contraceptive combinations, it may be|
02423|020|M|important in progestin-only oral or implanted contraceptives.  Thus,|
02423|021|M|contraceptive efficacy may be lower than described in prescribing|
02423|022|M|information.|
02423|023|M|   Patients receiving lamotrigine may have a progestin-only contraceptive|
02423|024|M|prescribed to avoid the effects of estrogens on lamotrigine concentrations.|
02423|025|M|Although studies have not been performed to evaluate this interaction, it|
02423|026|M|would be prudent to counsel patients on the importance of not missing doses|
02423|027|M|of oral contraceptives.  Theoretically, the efficacy of implanted progestins|
02423|028|M|may be lower than expected at the end of the dosing interval as progestin|
02423|029|M|concentrations wane.|
02423|030|B||
02423|031|D|DISCUSSION:  Lamotrigine induces glucuronidation pathways including UGT1A4,|
02423|032|D|a pathway associated with progestin metabolism.(3,4)|
02423|033|D|  In a study, 16 females took lamotrigine titrated up to 300 mg/d for a|
02423|034|D|period of 130 days and either combined it with an estrogen-progestin oral|
02423|035|D|contraceptive or took lamotrigine monotherapy.  Levonorgestrel and|
02423|036|D|lamotrigine serum levels were drawn in the presence or absence of combined|
02423|037|D|therapy. Levonorgestrel AUC and Cmax decreased by 19% and 12%,|
02423|038|D|respectively.(1,2)|
02423|039|B||
02423|040|R|REFERENCES:|
02423|041|B||
02423|042|R|1.Lamictal (lamotrigine) US prscribing information. GlaxoSmithKline October,|1
02423|043|R|  2025.|1
02423|044|R|2.Sidhu J, Job S, Singh S, Philipson R. The pharmacokinetic and|2
02423|045|R|  pharmacodynamic consequences of the co-administration of lamotrigine and a|2
02423|046|R|  combined oral contraceptive in healthy female subjects. Br J Clin|2
02423|047|R|  Pharmacol 2006 Feb;61(2):191-9.|2
02423|048|R|3.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
02423|049|R|  Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
02423|050|R|4.Levy RH Thummel KE Trager WF. Metabolic Drug Interactions (textbook).|6
02423|051|R|  Metabolic Drug Interactions 2000.|6
02424|001|T|MONOGRAPH TITLE:  Trazodone (Greater Than 100 mg)/MAOIs|
02424|002|B||
02424|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02424|004|L|of severe adverse interaction.|
02424|005|B||
02424|006|A|MECHANISM OF ACTION:  Trazodone is primarily an inhibitor of 5HT2A serotonin|
02424|007|A|receptors, H1 histamine, and alpha-1 receptors.(1)  At low doses, inhibition|
02424|008|A|of serotonin reuptake is weak and estimated to be 1/20th of 5HT2A inhibiting|
02424|009|A|activity.  At high trazodone doses receptor specificity may be diminished|
02424|010|A|and serotonin reuptake inhibition could be clinically important.|
02424|011|A|   In addition, one route of trazodone metabolism leads to formation of an|
02424|012|A|active metabolite, m-chlorophenylpiperazine (mCPP) which is|
02424|013|A|pharmacologically distinct from trazodone in that it is an agonist at a|
02424|014|A|variety of serotonin receptors.(1) MCPP concentrations may be clinically|
02424|015|A|important at antidepressant doses of trazodone.  MCPP is converted to an|
02424|016|A|inactive metabolite by CYP2D6.(3)|
02424|017|A|   MAO Inhibitors increase serotonin levels via inhibition of its|
02424|018|A|metabolism.|
02424|019|B||
02424|020|E|CLINICAL EFFECTS:  Concurrent administration could increase the risk for|
02424|021|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
02424|022|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
02424|023|E|and muscle rigidity.(2)|
02424|024|B||
02424|025|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
02424|026|P|systemic concentrations of trazodone, mCPP or more potent MAO inhibitors|
02424|027|P|would be predicted to increase risk for serotonin toxicity.(2)|
02424|028|P|   Concomitant therapy with multiple agents which increase brain serotonin|
02424|029|P|concentrations may also increase risk for serotonin syndrome.(2)|
02424|030|P|   Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion,|
02424|031|P|cinacalcet, dacomitinib, fluoxetine, paroxetine, quinidine, or systemic|
02424|032|P|terbinafine)(4) may increase mCPP concentration, increasing the risk for|
02424|033|P|serotonin toxicity.|
02424|034|P|   Patients who are poor metabolizers at CYP2D6 would be expected to have|
02424|035|P|higher mCPP concentrations compared with extensive metabolizers.|
02424|036|B||
02424|037|M|PATIENT MANAGEMENT:  Trazodone doses greater than 100 mg should not be|
02424|038|M|prescribed in patients who require treatment with any MAOI and a strong|
02424|039|M|inhibitor of CYP2D6 (e.g. bupropion, cinacalcet, dacomitinib, fluoxetine,|
02424|040|M|paroxetine, quinidine, systemic terbinafine) or any other agent with|
02424|041|M|serotonin-increasing effects (e.g. tramadol, meperidine, most|
02424|042|M|antidepressants).|
02424|043|M|   Patients known to be poor metabolizers of CYP2D6 should not receive|
02424|044|M|greater than 100 mg of trazodone per day if they require treatment with a|
02424|045|M|MAOI.|
02424|046|M|   To minimize serotonin reuptake inhibition and accumulation of mCPP, limit|
02424|047|M|dosage of trazodone to less than or equal to 100 mg daily in patients|
02424|048|M|receiving MAO inhibitors. If the benefit of higher dose trazodone is judged|
02424|049|M|to be greater than the risk for serotonin toxicities, assure that the|
02424|050|M|patient and health care team are aware of and monitor for signs and symptoms|
02424|051|M|of serotonin syndrome.|
02424|052|M|   If concurrent therapy is warranted, patients should be monitored for|
02424|053|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02424|054|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02424|055|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02424|056|M|coordination, or severe diarrhea.|
02424|057|B||
02424|058|D|DISCUSSION:  In a case report, a 37 year-old male developed serotonin|
02424|059|D|syndrome following the addition of linezolid to citalopram and trazodone.(5)|
02424|060|D|   In a case report, a patient developed serotonin syndrome with concurrent|
02424|061|D|trazodone, isocarboxazid, and methylphenidate.(6)|
02424|062|D|   In a case report, a patient developed serotonin syndrome following the|
02424|063|D|abrupt replacement of trazodone with moclobemide.(7)|
02424|064|D|   An open study evaluated the efficacy and safety of low dose trazodone for|
02424|065|D|the treatment of MAOI-associated insomnia.  Twenty-one patients successfully|
02424|066|D|treated with a MAOI for unipolar or bipolar depression but with persistent|
02424|067|D|insomnia participated in the study.  Trazodone 25 to 75 mg was given at|
02424|068|D|bedtime. Patients with a fair or good response to trazodone were monitored|
02424|069|D|for a minimum of 4 months to assess efficacy and safety of treatment.|
02424|070|D|Eleven patients had a resolution of insomnia, 9 had a partial response, and|
02424|071|D|one had no benefit. Side effects noted were nausea in 2 patients, persistent|
02424|072|D|morning grogginess in one patient and memory problems in one patient.(8)|
02424|073|D|   A small double-blind placebo controlled study evaluated the efficacy and|
02424|074|D|safety of trazodone 50 mg to treat insomnia due to brofaromine, a MAO-A|
02424|075|D|inhibitor. All seven patients had responded to brofaromine and had been in|
02424|076|D|remission for at least 3 months.  Three patients received trazodone on week|
02424|077|D|1, followed by placebo on week 2, while the other 4 patients received|
02424|078|D|placebo on week 1 and trazodone on week 2.  At the end of the trial 4|
02424|079|D|patients elected to continue trazodone and 3 patients discontinued therapy|
02424|080|D|due to adverse effects (nausea, constipation, vertigo, dry mouth,|
02424|081|D|palpitations, or heartburn). The authors stated no patients had symptoms|
02424|082|D|suggestive of serotonin syndrome.(9)|
02424|083|D|   Metaxalone is a weak inhibitor of MAO.(10,11)|
02424|084|D|   The FDA AERS contains reports of serotonin syndrome with the concurrent|
02424|085|D|use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram,|
02424|086|D|fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine as well as|
02424|087|D|reports of serotonin syndrome with concurrent injectable methylene blue and|
02424|088|D|citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine,|
02424|089|D|escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and|
02424|090|D|venlafaxine.  The risk of serotonin syndrome with linezolid and other|
02424|091|D|psychiatric drugs is unclear.(12,13)|
02424|092|B||
02424|093|R|REFERENCES:|
02424|094|B||
02424|095|R|1.O'Donnell JM Shelton RC. Chapter 15 - Drug Therapy of Depression and|6
02424|096|R|  Anxiety Disorders. In Bruton L, Chabner B, Knollman B eds. Goodman &|6
02424|097|R|  Gilman's The Pharmacological Basis of Therapeutics. 12th ed. 2011.|6
02424|098|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02424|099|R|  352(11):1112-20.|6
02424|100|R|3.Kovaleva J, Devuyst E, De Paepe P, Verstraete A. Acute|3
02424|101|R|  chlorophenylpiperazine overdose: a case report and review of the|3
02424|102|R|  literature. Ther Drug Monit 2008 Jun;30(3):394-8.|3
02424|103|R|4.This information is based on an extract from the Certara Drug Interaction|6
02424|104|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02424|105|R|5.Bergeron L, Boule M, Perreault S. Serotonin toxicity associated with|3
02424|106|R|  concomitant use of linezolid. Ann Pharmacother 2005 May;39(5):956-61.|3
02424|107|R|6.Bodner RA, Lynch T, Lewis L, Kahn D. Serotonin syndrome. Neurology 1995|3
02424|108|R|  Feb;45(2):219-23.|3
02424|109|R|7.Zivanovic O, Till E. Serotonin syndrome--a case account. Med Pregl 1992;|3
02424|110|R|  45(3-4):116-8.|3
02424|111|R|8.Jacobsen FM. Low-dose trazodone as a hypnotic in patients treated with|2
02424|112|R|  MAOIs and other psychotropics: a pilot study. J Clin Psychiatry 1990 Jul;|2
02424|113|R|  51(7):298-302.|2
02424|114|R|9.Haffmans PM, Vos MS. The effects of trazodone on sleep disturbances|2
02424|115|R|  induced by brofaromine. Eur Psychiatry 1999 Jun;14(3):167-71.|2
02424|116|R|10.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
02424|117|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
02424|118|R|   Feb;34(2):346.e5-6.|3
02424|119|R|11.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
02424|120|R|   Pfizer Inc. January, 2024.|1
02424|121|R|12.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
02424|122|R|   information about the drug interaction between methylene blue|1
02424|123|R|   (methylthioninium chloride) and serotonergic psychiatric medications.|1
02424|124|R|   available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
02424|125|R|   21, 2011.|1
02424|126|R|13.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
02424|127|R|   information about the drug interaction between linezolid (Zyvox) and|1
02424|128|R|   serotonergic psychiatric medications. available at:|1
02424|129|R|   http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm October 21, 2011.|1
02426|001|T|MONOGRAPH TITLE:  Raltegravir/Aluminum & Magnesium Antacids & Magnesium|
02426|002|T|Supplements|
02426|003|B||
02426|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02426|005|L|of severe adverse interaction.|
02426|006|B||
02426|007|A|MECHANISM OF ACTION:  Aluminum and/or magnesium containing antacids may|
02426|008|A|alter raltegravir absorption by altering gastric pH.  Magnesium antacids and|
02426|009|A|supplements may bind to raltegravir in the GI tract, preventing its|
02426|010|A|absorption.(1)|
02426|011|B||
02426|012|E|CLINICAL EFFECTS:  Aluminum and/or magnesium containing antacids and|
02426|013|E|magnesium supplements may reduce levels and clinical effectiveness of|
02426|014|E|raltegravir.(1)|
02426|015|B||
02426|016|P|PREDISPOSING FACTORS:  None determined.|
02426|017|B||
02426|018|M|PATIENT MANAGEMENT:  Concurrent use of any formulation of raltegravir and|
02426|019|M|aluminum and/or magnesium antacids is not recommended.  Instruct patients|
02426|020|M|not to use aluminum and/or magnesium containing antacids or magnesium|
02426|021|M|supplements.|
02426|022|M|   Calcium carbonate may be used in place of aluminum and/or magnesium|
02426|023|M|containing antacids in patients receiving raltegravir chewable tablets, oral|
02426|024|M|suspension, or 400 mg tablets.  Calcium carbonate is not recommended for|
02426|025|M|patients receiving one daily raltegravir (600 mg tablets).(1)|
02426|026|B||
02426|027|D|DISCUSSION:  Simultaneous administration of aluminum and magnesium hydroxide|
02426|028|D|(20 ml) with raltegravir (400 mg BID) decreased raltegravir maximum|
02426|029|D|concentration (Cmax), area-under-curve (AUC), and minimum concentration|
02426|030|D|(Cmin) by 44%, 49%, and 63%, respectively.(1)|
02426|031|D|   Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before|
02426|032|D|raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 51%,|
02426|033|D|51%, and 56%, respectively.(1)|
02426|034|D|   Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after|
02426|035|D|raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 22%,|
02426|036|D|30%, and 57%, respectively.(1)|
02426|037|D|   Administration of aluminum and magnesium hydroxide (20 ml) 4 hours before|
02426|038|D|after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by|
02426|039|D|22%, 19%, and 60%, respectively.(1)|
02426|040|D|   Administration of aluminum and magnesium hydroxide (20 ml) 4 hours after|
02426|041|D|after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by|
02426|042|D|30%, 32%, and 62%, respectively.(1)|
02426|043|D|   Administration of aluminum and magnesium hydroxide (20 ml) 6 hours before|
02426|044|D|after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by|
02426|045|D|10%, 13%, and 50%, respectively.(1)|
02426|046|D|   Administration of aluminum and magnesium hydroxide (20 ml) 6 hours after|
02426|047|D|after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by|
02426|048|D|10%, 11%, and 49%, respectively.(1)|
02426|049|D|   Administration of aluminum and magnesium hydroxide (20 ml) 12 hours after|
02426|050|D|after raltegravir (1200 mg single dose) decreased raltegravir Cmax, AUC, and|
02426|051|D|Cmin by 14%, 14%, and 58%, respectively.(1,2)|
02426|052|D|   Data from in vitro(3) and in vivo simulations(4) suggest that magnesium's|
02426|053|D|effect on raltegravir may involve chelation as well as changes in pH.|
02426|054|B||
02426|055|R|REFERENCES:|
02426|056|B||
02426|057|R|1.Isentress (raltegravir) US prescribing information. Merck & CO., Inc. May,|1
02426|058|R|  2021.|1
02426|059|R|2.Krishna R, East L, Larson P, Valiathan C, Butterfield K, Teng Y,|2
02426|060|R|  Hernandez-Illas M. Effect of metal-cation antacids on the pharmacokinetics|2
02426|061|R|  of 1200 mg raltegravir. J Pharm Pharmacol 2016 Nov;68(11):1359-1365.|2
02426|062|R|3.Moss DM, Siccardi M, Back DJ, Owen A. Predicting intestinal absorption of|5
02426|063|R|  raltegravir using a population-based ADME simulation. J Antimicrob|5
02426|064|R|  Chemother 2013 Jul;68(7):1627-34.|5
02426|065|R|4.Moss DM, Siccardi M, Murphy M, Piperakis MM, Khoo SH, Back DJ, Owen A.|5
02426|066|R|  Divalent metals and pH alter raltegravir disposition in vitro. Antimicrob|5
02426|067|R|  Agents Chemother 2012 Jun;56(6):3020-6.|5
02427|001|T|MONOGRAPH TITLE:  Quetiapine (Greater Than 150 mg)/Strong CYP3A4 Inducers|
02427|002|B||
02427|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02427|004|L|of severe adverse interaction.|
02427|005|B||
02427|006|A|MECHANISM OF ACTION:  Quetiapine and its active metabolite are metabolized|
02427|007|A|by CYP3A4.(1) In addition, FDA describes quetiapine as a sensitive CYP3A4|
02427|008|A|substrate: a drug which can have large changes in systemic exposure due to|
02427|009|A|induction (or inhibition) of the CYP3A4 pathway.(2)|
02427|010|B||
02427|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers and quetiapine|
02427|012|E|will result in decreased systemic concentrations of quetiapine and may lead|
02427|013|E|to therapeutic failure.(1)|
02427|014|B||
02427|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02427|016|P|of the inducer for longer than 1-2 weeks.|
02427|017|B||
02427|018|M|PATIENT MANAGEMENT:  In patients on quetiapine receiving chronic treatment|
02427|019|M|(i.e., greater than 7-14 days) of inducers of CYP3A4, titrate the dose of|
02427|020|M|quetiapine based on the patient's clinical response and tolerance, up to|
02427|021|M|5-fold of the original dose.  The onset of induction is gradual but may|
02427|022|M|begin within one week for potent agents (e.g. rifampin). The time to maximal|
02427|023|M|induction may be 2 or more weeks depending upon the half-life and dose of|
02427|024|M|the inducer.|
02427|025|M|   If the CYP3A4 inducer is discontinued, the dose of quetiapine should be|
02427|026|M|reduced to the original level within 7-14 days.(1)|
02427|027|B||
02427|028|D|DISCUSSION:  In an interaction study, 18 stable patients with schizophrenia,|
02427|029|D|schizoaffective or bipolar disorder started treatment with quetiapine,|
02427|030|D|achieving the target dose of 300 mg twice daily on day five.  On day 9|
02427|031|D|carbamazepine  was started, gradually increasing to the target dose of 200|
02427|032|D|mg three times a day on day 13.  Patients continued on the combination|
02427|033|D|through day 33 to assure maximal enzyme induction was achieved.|
02427|034|D|Carbamazepine decreased quetiapine AUC 87%, decreased steady-state maximum|
02427|035|D|concentration (Cmax) by 80%, and increased clearance approximately|
02427|036|D|7-fold.(3)|
02427|037|D|   In a review of 2111 quetiapine levels from 1179 patients, quetiapine|
02427|038|D|levels were 86% lower in patients receiving concurrent carbamazepine.(4)|
02427|039|D|   In a review of 62 psychiatric patients, patients receiving carbamazepine|
02427|040|D|had significantly lower quetiapine concentration-to-dose ratios.(5)|
02427|041|D|   A case report described a newly hospitalized patient admitted on|
02427|042|D|carbamazepine 600 mg daily and risperidone 8 mg daily for schizoaffective|
02427|043|D|disorder. She was then converted from risperidone to quetiapine. After 7|
02427|044|D|days of treatment at the target quetiapine dose of 700 mg daily, serum|
02427|045|D|quetiapine concentrations were undetectable.  A repeat level 7 days later|
02427|046|D|was also undetectable. The decision was then made to discontinue|
02427|047|D|carbamazepine and continue quetiapine without dose adjustment.  Quetiapine|
02427|048|D|concentrations increased over the following days to weeks and were|
02427|049|D|accompanied by clinical improvement sufficient for discharge.  The authors|
02427|050|D|also briefly described 2 additional patients, each receiving carbamazepine|
02427|051|D|for a seizure disorder who were subsequently treated with quetiapine 600 mg|
02427|052|D|or 700 mg daily for more than two weeks.  As with the first case, quetiapine|
02427|053|D|serum concentrations with concurrent carbamazepine therapy were below the|
02427|054|D|limit of detection for each patient (lower limit of detection was 25|
02427|055|D|mcg/mL).(6)|
02427|056|D|   Concurrent use of phenytoin (100 mg three times daily), a strong CYP3A4|
02427|057|D|inducer, and quetiapine increased oral clearance of quetiapine by 5-fold.(7)|
02427|058|D|      FDA defines strong CYP inducers as agents which cause at least an 80%|
02427|059|D|decrease in systemic exposure (area-under-curve or AUC) of a drug|
02427|060|D|metabolized by a specific CYP enzyme.(2)  Strong CYP3A4 inducers linked to|
02427|061|D|this monograph include: apalutamide, barbiturates, carbamazepine,|
02427|062|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin,|
02427|063|D|primidone, rifampin, rifapentine and St. John's Wort.(8)|
02427|064|B||
02427|065|R|REFERENCES:|
02427|066|B||
02427|067|R|1.Seroquel (quetiapine) US prescribing information. AstraZeneca|1
02427|068|R|  Pharmaceuticals LP September, 2020.|1
02427|069|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02427|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02427|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02427|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02427|073|R|  11/14/2017.|1
02427|074|R|3.Grimm SW, Richtand NM, Winter HR, Stams KR, Reele SB. Effects of|2
02427|075|R|  cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine|2
02427|076|R|  pharmacokinetics. Br J Clin Pharmacol 2006 Jan;61(1):58-69.|2
02427|077|R|4.Castberg I, Skogvoll E, Spigset O. Quetiapine and drug interactions:|2
02427|078|R|  evidence from a routine therapeutic drug monitoring service. J Clin|2
02427|079|R|  Psychiatry 2007 Oct;68(10):1540-5.|2
02427|080|R|5.Hasselstrom J, Linnet K. Quetiapine serum concentrations in psychiatric|2
02427|081|R|  patients: the influence of comedication. Ther Drug Monit 2004 Oct;|2
02427|082|R|  26(5):486-91.|2
02427|083|R|6.Nickl-Jockschat T, Paulzen M, Schneider F, Grozinger M. Drug interaction|3
02427|084|R|  can lead to undetectable serum concentrations of quetiapine in the|3
02427|085|R|  presence of carbamazepine. Clin Neuropharmacol 2009 Jan-Feb;32(1):55.|3
02427|086|R|7.Wong YW, Yeh C, Thyrum PT. The effects of concomitant phenytoin|2
02427|087|R|  administration on the steady-state pharmacokinetics of quetiapine. J Clin|2
02427|088|R|  Psychopharmacol 2001 Feb;21(1):89-93.|2
02427|089|R|8.This information is based on an extract from the Certara Drug Interaction|6
02427|090|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02428|001|T|MONOGRAPH TITLE:  Treprostinil/Strong CYP2C8 Inhibitors|
02428|002|B||
02428|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02428|004|L|take action as needed.|
02428|005|B||
02428|006|A|MECHANISM OF ACTION:  Strong CYP2C8 inhibitors may inhibit the metabolism of|
02428|007|A|treprostinil.(1)|
02428|008|B||
02428|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP2C8 inhibitor may increase|
02428|010|E|levels and effects of treprostinil, including severe headache, nausea,|
02428|011|E|diarrhea, and hypotension.(1)|
02428|012|B||
02428|013|P|PREDISPOSING FACTORS:  None determined.|
02428|014|B||
02428|015|M|PATIENT MANAGEMENT:  When initiating oral treprostinil in patient maintained|
02428|016|M|on a strong CYP2C8 inhibitor, the initial dose should be 0.125 mg twice|
02428|017|M|daily, with dosage increases limited to 0.125 mg twice daily every 3 to 4|
02428|018|M|days.(1)|
02428|019|M|   When initiating a strong CYP2C8 inhibitor in patients maintained on oral|
02428|020|M|treprostinil, consider halving the dose of oral treprostinil.(1)|
02428|021|M|   Since it is unknown how strong CYP2C8 inhibitors will affect treprostinil|
02428|022|M|administered intravenously or via inhalation, it would be prudent to|
02428|023|M|initiate and titrate treprostinil doses cautiously in patients maintained on|
02428|024|M|CYP2C8 inhibitors and monitor patients maintained on treprostinil in whom|
02428|025|M|CYP2C8 inhibitors are discontinued.|
02428|026|B||
02428|027|D|DISCUSSION:  Concurrent use of a strong CYP2C8 inhibitor (gemfibrozil, 600|
02428|028|D|mg twice daily for 4 days) doubled the maximum concentration (Cmax) and|
02428|029|D|area-under-curve (AUC) of treprostinil (1 mg).(1)|
02428|030|D|   The extent to which intravenous(2) and inhaled treprostinil(3) would be|
02428|031|D|affected by a CYP2C8 inhibitor is unknown.|
02428|032|D|   Strong inhibitors of CYP2C8 includes gemfibrozil.(4,5)|
02428|033|B||
02428|034|R|REFERENCES:|
02428|035|B||
02428|036|R|1.Orenitram (treprostinil) US prescribing information. United Therapeutics|1
02428|037|R|  Corp. January, 2016.|1
02428|038|R|2.Remodulin (treporstinil) US prescribing information. United Therapeutics|1
02428|039|R|  Corp. July, 2018.|1
02428|040|R|3.Tyvaso (treprostinil) US prescribing information. United Therapeutics Corp|1
02428|041|R|  June, 2016.|1
02428|042|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02428|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02428|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02428|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02428|046|R|  11/14/2017.|1
02428|047|R|5.This information is based on an extract from the Certara Drug Interaction|6
02428|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02429|001|T|MONOGRAPH TITLE:  Escitalopram/QT Prolonging Agents|
02429|002|B||
02429|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02429|004|L|take action as needed.|
02429|005|B||
02429|006|A|MECHANISM OF ACTION:  Concurrent use of multiple agents that prolong the QTc|
02429|007|A|interval may result in additive effects on the QTc interval.(1)|
02429|008|B||
02429|009|E|CLINICAL EFFECTS:  The concurrent use of multiple agents that prolong the|
02429|010|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
02429|011|E|including torsades de pointes.(1)|
02429|012|B||
02429|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02429|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02429|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02429|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02429|017|P|gender, or advanced age.(1)|
02429|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02429|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02429|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02429|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02429|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02429|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02429|024|P|dysfunction).(1)|
02429|025|B||
02429|026|M|PATIENT MANAGEMENT:  While the US FDA and manufacturer recommend no special|
02429|027|M|precautions when escitalopram is used with QT prolonging agents,(2,3) Health|
02429|028|M|Canada and the Canadian manufacturer of escitalopram discourage the|
02429|029|M|concurrent use of agents known to prolong the QT interval(4,5) and the UK|
02429|030|M|manufacturer states that concurrent use is contraindicated.(6)|
02429|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02429|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02429|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02429|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02429|035|B||
02429|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02429|037|D|degrees of potential to prolong the QTc interval but are generally accepted|
02429|038|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02429|039|D|monograph have been shown to prolong the QTc interval either through their|
02429|040|D|mechanism of action, through studies on their effects on the QTc interval,|
02429|041|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02429|042|D|clinical trials and/or post-marketing reports.(7)|
02429|043|D|   One or more of the drug pairs linked to this monograph have been included|
02429|044|D|in a list of interactions that should be considered "high-priority" for|
02429|045|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02429|046|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02429|047|D|Coordinator (ONC) for Health Information Technology.|
02429|048|B||
02429|049|R|REFERENCES:|
02429|050|B||
02429|051|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02429|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02429|053|R|  settings: a scientific statement from the American Heart Association and|6
02429|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02429|055|R|  2;55(9):934-47.|6
02429|056|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
02429|057|R|  Pharmaceuticals Inc. May, 2023.|1
02429|058|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02429|059|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
02429|060|R|  potential risk of abnormal heart rhythms with high doses. Available at:|1
02429|061|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02429|062|R|4.Health Canada. Antidepressant Cipralex (escitalopram): Updated information|1
02429|063|R|  regarding dose-related heart risk. Available at:|1
02429|064|R|  http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/1367|1
02429|065|R|  4a-eng.php May 7, 2012.|1
02429|066|R|5.Cipralex (escitalopram oxalate) Canadian prescribing information. Lundbeck|1
02429|067|R|  August 13, 2012.|1
02429|068|R|6.Cipralex (escitalopram oxalate) UK summary of product characteristics.|1
02429|069|R|  Lunbeck Limited June 25, 2020.|1
02429|070|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
02429|071|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02429|072|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02429|073|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02429|074|R|8.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02429|075|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02429|076|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02429|077|R|  19(5):735-43.|6
02430|001|T|MONOGRAPH TITLE:  Pimozide/Selected Moderate CYP3A4 Inhibitors|
02430|002|B||
02430|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02430|004|L|of severe adverse interaction.|
02430|005|B||
02430|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
02430|007|A|metabolism of pimozide.(1)|
02430|008|B||
02430|009|E|CLINICAL EFFECTS:  Concurrent administration of a moderate inhibitor of|
02430|010|E|CYP3A4 may result in elevated levels of pimozide, which may result in|
02430|011|E|prolongation of the QTc interval and potentially life-threatening|
02430|012|E|ventricular arrhythmias.(1)|
02430|013|B||
02430|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02430|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02430|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02430|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02430|018|P|female gender, or advanced age.(2)|
02430|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02430|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02430|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02430|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02430|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02430|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02430|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02430|026|P|   The risk of anticholinergic toxicities including cognitive decline,|
02430|027|P|delirium, falls and fractures is increased in geriatric patients using more|
02430|028|P|than one medicine with anticholinergic properties.(3)|
02430|029|B||
02430|030|M|PATIENT MANAGEMENT:  Avoid concurrent use, especially when other risk|
02430|031|M|factors for QT prolongation are present.  The manufacturer of pimozide|
02430|032|M|states that concomitant treatment with strong CYP3A4 inhibitors is|
02430|033|M|contraindicated and treatment with less potent inhibitors of CYP3A4 should|
02430|034|M|also be avoided.(1)|
02430|035|M|   If concurrent use cannot be avoided, then correct or minimize QT|
02430|036|M|prolonging risk factors, e.g. correct electrolyte disturbances, use the|
02430|037|M|lowest effective dose of pimozide, and discontinue other concurrent QT|
02430|038|M|prolonging agents or CYP3A4 inhibitors if possible.  Consider ECG to|
02430|039|M|evaluate baseline and/or concurrent QT prolongation risk. Monitor patients|
02430|040|M|on the combination and counsel patients accordingly.|
02430|041|B||
02430|042|D|DISCUSSION:  Pimozide is metabolized at CYP3A.(1,4)  Elevated levels of|
02430|043|D|pimozide may prolong the QTc interval resulting in life-threatening|
02430|044|D|ventricular arrhythmias.(1)|
02430|045|D|   Moderate inhibitors of CYP3A4 include:  avacopan, berotralstat,|
02430|046|D|conivaptan, diltiazem, duvelisib, fedratinib, fosnetupitant, imatinib,|
02430|047|D|isavuconazonium, lenacapavir, netupitant, rilzabrutinib, schisandra,|
02430|048|D|sevabertinib, tofisopam, treosulfan and verapamil.(5,6)|
02430|049|B||
02430|050|R|REFERENCES:|
02430|051|B||
02430|052|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
02430|053|R|  2011.|1
02430|054|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02430|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02430|056|R|  settings: a scientific statement from the American Heart Association and|6
02430|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02430|058|R|  2;55(9):934-47.|6
02430|059|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02430|060|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02430|061|R|  Soc 2023 Jul;71(7):2052-2081.|6
02430|062|R|4.Desta Z, Kerbusch T, Soukhova N, Richard E, Ko JW, Flockhart DA.|5
02430|063|R|  Identification and characterization of human cytochrome P450 isoforms|5
02430|064|R|  interacting with pimozide. J Pharmacol Exp Ther 1998 May;285(2):428-37.|5
02430|065|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02430|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02430|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02430|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02430|069|R|  11/14/2017.|1
02430|070|R|6.This information is based on an extract from the Certara Drug Interaction|6
02430|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02431|001|T|MONOGRAPH TITLE:  Ranolazine (Greater Than 500 mg BID)/Moderate CYP3A4|
02431|002|T|Inhibitors|
02431|003|B||
02431|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02431|005|L|is contraindicated and generally should not be dispensed or administered to|
02431|006|L|the same patient.|
02431|007|B||
02431|008|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
02431|009|A|metabolism of ranolazine.  Verapamil may also increase the absorption of|
02431|010|A|ranolazine by inhibiting P-glycoprotein.(1)|
02431|011|B||
02431|012|E|CLINICAL EFFECTS:  Concurrent use of moderate inhibitors of CYP3A4 may|
02431|013|E|result in elevated levels of and clinical effects from ranolazine.  Elevated|
02431|014|E|ranolazine levels may result in QTc prolongation, which may result in|
02431|015|E|life-threatening cardiac arrhythmia, including torsades de pointes.(1)|
02431|016|B||
02431|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02431|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
02431|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02431|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02431|021|P|female gender, or advanced age.(2)|
02431|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02431|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02431|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02431|025|P|drug concentrations include rapid infusion of an intravenous dose or|
02431|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02431|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02431|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02431|029|B||
02431|030|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
02431|031|M|dosage of ranolazine should be limited to 500 mg twice daily in patients|
02431|032|M|receiving moderate inhibitors of CYP3A4.(1)|
02431|033|M|   If concurrent therapy is deemed medically necessary, obtain serum|
02431|034|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
02431|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02431|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02431|037|B||
02431|038|D|DISCUSSION:  Concurrent use of diltiazem, a moderate inhibitor of CYP3A4, at|
02431|039|D|daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000|
02431|040|D|mg twice daily) by 50% and 130%, respectively.(1,4)  In healthy subjects,|
02431|041|D|concurrent ranolazine (1000 mg twice daily) had no effects on the|
02431|042|D|pharmacokinetics of diltiazem (60 mg three times daily).(1)|
02431|043|D|   Concurrent use of verapamil (120 mg three times daily) increased plasma|
02431|044|D|levels of ranolazine (750 mg twice daily) by 100%.(1)|
02431|045|D|   In a study in 12 healthy males, ranolazine immediate release (IR, 240 mg|
02431|046|D|three times daily) had no effect on diltiazem (60 mg three times daily)|
02431|047|D|pharmacokinetics. However, at ranolazine IR steady state, diltiazem|
02431|048|D|increased ranolazine IR area under the curve (AUC) by 85%, on average, and|
02431|049|D|increased maximum concentration (Cmax) by 1.9-fold and minimum concentration|
02431|050|D|(Cmin) by 2.1-fold.(4)|
02431|051|D|   In a study in 12 subjects, ranolazine sustained release (SR, 500 mg twice|
02431|052|D|daily) had no effect on diltiazem (60 mg three times daily)|
02431|053|D|pharmacokinetics. However, at ranolazine steady state, diltiazem increased|
02431|054|D|ranolazine SR Cmax, concentration minimum (Cmin), AUC by 80%, 216%, and 90%,|
02431|055|D|on average, respectively.(4)|
02431|056|D|   In a study in 8 healthy males, diltiazem modified release (MR, 180 mg, or|
02431|057|D|240 mg, or 360 mg, once daily) increased ranolazine sustained release (SR,|
02431|058|D|1000 mg twice daily) AUC by 52%, 93%, and 139%, respectively. Ranolazine|
02431|059|D|half-lives did not show any consistent trend of changes with increasing|
02431|060|D|doses of diltiazem.(4)|
02431|061|D|   In a study of patients with severe chronic angina, the addition of|
02431|062|D|ranolazine 750 mg twice daily or 1,000 mg twice daily along with their|
02431|063|D|standard dose of diltiazem (180 mg once daily) provided additional|
02431|064|D|antianginal relief, without evident adverse, long-term survival consequences|
02431|065|D|over 1 to 2 years of therapy.(5)|
02431|066|D|   Ranolazine-induced QTc prolongation is dose and concentration-related.(1)|
02431|067|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant, avacopan,|
02431|068|D|berotralstat, clofazimine, conivaptan, crizotinib, diltiazem,  dronedarone,|
02431|069|D|duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine,|
02431|070|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir,|
02431|071|D|lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra,|
02431|072|D|stiripentol, treosulfan and verapamil.(1,3,6,7)|
02431|073|B||
02431|074|R|REFERENCES:|
02431|075|B||
02431|076|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
02431|077|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02431|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02431|079|R|  settings: a scientific statement from the American Heart Association and|6
02431|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02431|081|R|  2;55(9):934-47.|6
02431|082|R|3.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
02431|083|R|  Pharma U.K. S.R.I. October 30, 2008.|1
02431|084|R|4.Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to|2
02431|085|R|  investigate the pharmacokinetic interactions between ranolazine and|2
02431|086|R|  ketoconazole, diltiazem, or simvastatin during combined administration in|2
02431|087|R|  healthy subjects. J Clin Pharmacol 2005 Apr;45(4):422-33.|2
02431|088|R|5.Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W,|2
02431|089|R|  Skettino SL, Wolff AA. Effects of ranolazine with atenolol, amlodipine, or|2
02431|090|R|  diltiazem on exercise tolerance and angina frequency in patients with|2
02431|091|R|  severe chronic angina: a randomized controlled trial. JAMA 2004 Jan 21;|2
02431|092|R|  291(3):309-16.|2
02431|093|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
02431|094|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02431|095|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02431|096|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02431|097|R|  11/14/2017.|1
02431|098|R|7.This information is based on an extract from the Certara Drug Interaction|6
02431|099|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02432|001|T|MONOGRAPH TITLE:  Metformin/Ranolazine|
02432|002|B||
02432|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02432|004|L|take action as needed.|
02432|005|B||
02432|006|A|MECHANISM OF ACTION:  Ranolazine may decrease renal elimination of metformin|
02432|007|A|by inhibiting OCT-2.(1)|
02432|008|B||
02432|009|E|CLINICAL EFFECTS:  Concurrent ranolazine may result in elevated levels of|
02432|010|E|and toxicity from metformin.(1)|
02432|011|B||
02432|012|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
02432|013|P|include renal impairment, sepsis, dehydration, excessive alcohol intake,|
02432|014|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
02432|015|P|failure, metformin plasma levels > 5 micrograms/mL, and conditions which may|
02432|016|P|lead to tissue hypoxia.  Geriatric patients may also be at higher risk due|
02432|017|P|to slower metformin clearance and increased half-life in this population.|
02432|018|B||
02432|019|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
02432|020|M|metformin and ranolazine.  In patients receiving 1000 mg ranolazine twice|
02432|021|M|daily, limit the dose of metformin to 1700 mg daily.(1)|
02432|022|B||
02432|023|D|DISCUSSION:  In healthy subjects, ranolazine (1000 mg twice daily) increased|
02432|024|D|exposure of metformin by 80%.  Ranolazine (500 mg BID) increased metformin|
02432|025|D|exposure by 40%.(1)|
02432|026|B||
02432|027|R|REFERENCE:|
02432|028|B||
02432|029|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
02433|001|T|MONOGRAPH TITLE:  Doxazosin/Boceprevir|
02433|002|B||
02433|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02433|004|L|is contraindicated and generally should not be dispensed or administered to|
02433|005|L|the same patient.|
02433|006|B||
02433|007|A|MECHANISM OF ACTION:  Boceprevir may inhibit the metabolism of doxazosin by|
02433|008|A|CYP3A4.(1)|
02433|009|B||
02433|010|E|CLINICAL EFFECTS:  Concurrent use of boceprevir may result in elevated|
02433|011|E|levels of and effects from doxazosin, including severe hypotension and|
02433|012|E|priapism.(1)|
02433|013|B||
02433|014|P|PREDISPOSING FACTORS:  None determined.|
02433|015|B||
02433|016|M|PATIENT MANAGEMENT:  The US manufacturers of boceprevir states that|
02433|017|M|concurrent use of doxazosin is contraindicated.(1)|
02433|018|B||
02433|019|D|DISCUSSION:  Boceprevir has been shown to be a strong inhibitor of CYP3A4.|
02433|020|D|Therefore, concurrent use of boceprevir with agents that are highly|
02433|021|D|dependent on CYP3A4 for clearance and for which elevated plasma levels are|
02433|022|D|associated with serious and/or life-threatening events is|
02433|023|D|contraindicated.(1)|
02433|024|B||
02433|025|R|REFERENCE:|
02433|026|B||
02433|027|R|1.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02433|028|R|  January, 2017.|1
02434|001|T|MONOGRAPH TITLE:  Nadolol/Green Tea|
02434|002|B||
02434|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02434|004|L|take action as needed.|
02434|005|B||
02434|006|A|MECHANISM OF ACTION:  Nadolol is a substrate of OATP1A2, an influx|
02434|007|A|transporter found in intestinal epithelium.  Green tea catechins inhibit|
02434|008|A|several drug transporters, including OATP1A2, leading to decreased|
02434|009|A|absorption of nadolol.  P-glycoprotein may also be involved, however no|
02434|010|A|studies have confirmed its role.|
02434|011|B||
02434|012|E|CLINICAL EFFECTS:  Concomitant use of nadolol with green tea or green tea|
02434|013|E|catechins may decrease the effectiveness of nadolol.(1)|
02434|014|B||
02434|015|P|PREDISPOSING FACTORS:  None determined.|
02434|016|B||
02434|017|M|PATIENT MANAGEMENT:  Advise patients maintained on nadolol to avoid green|
02434|018|M|tea and green tea supplements.|
02434|019|B||
02434|020|D|DISCUSSION:  In a randomized crossover study in 10 healthy subjects,|
02434|021|D|concurrent use of nadolol (30 mg daily) and green tea (700 mL/day),|
02434|022|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02434|023|D|nadolol by 85.3% and 85%, respectively.  Pharmacodynamic parameters assessed|
02434|024|D|included pulse rate, systolic blood pressure, and diastolic blood pressure.|
02434|025|D|Although all parameters were affected slightly, nadolol's systolic blood|
02434|026|D|pressure lowering effect was significantly suppressed (p = 0.042).(1)|
02434|027|B||
02434|028|R|REFERENCE:|
02434|029|B||
02434|030|R|1.Misaka S, Yatabe J, Muller F, Takano K, Kawabe K, Glaeser H, Yatabe M,|2
02434|031|R|  Onoue S, Werba J, Watanabe H, Yamada S, Fromm M, Kimura J. Green tea|2
02434|032|R|  ingestion greatly reduces plasma concentrations of nadolol in healthy|2
02434|033|R|  subjects. Clin Pharmacol Ther 2014 Jan 13.|2
02435|001|T|MONOGRAPH TITLE:  Oral Methyldopa/Oral Iron|
02435|002|B||
02435|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02435|004|L|take action as needed.|
02435|005|B||
02435|006|A|MECHANISM OF ACTION:  Iron, in several forms, binds strongly to methyldopa,|
02435|007|A|producing iron complexes thereby reducing methyldopa absorption.|
02435|008|B||
02435|009|E|CLINICAL EFFECTS:  Concomitant use of methyldopa with iron supplementation|
02435|010|E|may decrease the clinical efficacy of methyldopa.|
02435|011|B||
02435|012|P|PREDISPOSING FACTORS:  None determined.|
02435|013|B||
02435|014|M|PATIENT MANAGEMENT:  Patients requiring iron supplementation should be|
02435|015|M|advised to take methyldopa two hours prior to any iron products.|
02435|016|B||
02435|017|D|DISCUSSION:  In a randomized crossover trial with 12 subjects, concurrent|
02435|018|D|use of methyldopa (500 mg daily) and ferrous sulfate (325 mg daily) showed a|
02435|019|D|28.4% decrease in the proportion of "free" methyldopa (p<0.01), a 28%|
02435|020|D|increase in the proportion excreted as methyldopa sulfate (p<0.01), and a|
02435|021|D|21.2% decrease in total absorbed methyldopa (p<0.01). Similar results were|
02435|022|D|found when administering ferrous gluconate (600 mg daily). Antihypertensive|
02435|023|D|effects of methyldopa while taking ferrous sulfate were also assessed in|
02435|024|D|five patients chronically taking methyldopa. All participants showed an|
02435|025|D|increase in systolic blood pressure (p=0.03) after two weeks of ferrous|
02435|026|D|sulfate administration. Diastolic blood pressure increased in four patients|
02435|027|D|(p>0.05). After 14 days, three patients had an increase in systolic pressure|
02435|028|D|greater than 15 mm Hg and two patients had an increase of greater than 10 mm|
02435|029|D|Hg in diastolic blood pressures. Both systolic and diastolic pressures|
02435|030|D|decreased after ferrous sulfate was discontinued.(2)|
02435|031|B||
02435|032|R|REFERENCES:|
02435|033|B||
02435|034|R|1.Methyldopa US prescribing information. Mylan Pharmaceuticals Inc. October,|1
02435|035|R|  2012.|1
02435|036|R|2.Campbell N, Paddock V, Sundaram R. Alteration of methyldopa absorption,|2
02435|037|R|  metabolism, and blood pressure control caused by ferrous sulfate and|2
02435|038|R|  ferrous gluconate. Clin Pharmacol Ther 1988 Apr;43(4):381-6.|2
02436|001|T|MONOGRAPH TITLE:  Dofetilide/Saquinavir|
02436|002|B||
02436|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02436|004|L|is contraindicated and generally should not be dispensed or administered to|
02436|005|L|the same patient.|
02436|006|B||
02436|007|A|MECHANISM OF ACTION:  Although dofetilide is primarily eliminated unchanged|
02436|008|A|in the urine, a portion is metabolized via CYP3A4.(1)  Saquinavir is a|
02436|009|A|strong inhibitor of CYP3A4 and may inhibit the metabolism of|
02436|010|A|dofetilide.(2,3)|
02436|011|A|   Concurrent use may also result in additive effects on the QTc|
02436|012|A|interval.(1-3)|
02436|013|B||
02436|014|E|CLINICAL EFFECTS:  Concurrent use of saquinavir with dofetilide may result|
02436|015|E|in elevated levels of and adverse events from dofetilide, including|
02436|016|E|life-threatening reactions such as QT prolongation or torsades de|
02436|017|E|pointes.(1-3)|
02436|018|B||
02436|019|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
02436|020|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
02436|021|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
02436|022|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
02436|023|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02436|024|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02436|025|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02436|026|P|hypokalemia, hypomagnesemia, Hypocalcemia, bradycardia, female gender, or|
02436|027|P|advanced age.(4)|
02436|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02436|029|P|higher systemic concentrations of either QT prolonging drug are additional|
02436|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02436|031|P|drug concentrations include rapid infusion of an intravenous dose or|
02436|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02436|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02436|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02436|035|B||
02436|036|M|PATIENT MANAGEMENT:  The manufacturer of saquinavir mesylate(2) states that|
02436|037|M|the antiarrhythmic dofetilide, is contraindicated in patients receiving|
02436|038|M|saquinavir.  If dofetilide is to be discontinued, a washout of at least 2|
02436|039|M|days is recommended prior to starting saquinavir.(1)|
02436|040|M|   If concurrent therapy is deemed medically necessary, obtain serum|
02436|041|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
02436|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02436|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02436|044|B||
02436|045|D|DISCUSSION:  Because of the risk of serious and potentially life-threatening|
02436|046|D|reactions, the manufacturer of saquinavir mesylate(1) states that the|
02436|047|D|antiarrhythmics dofetilide is contraindicated in patients receiving|
02436|048|D|saquinavir.|
02436|049|B||
02436|050|R|REFERENCES:|
02436|051|B||
02436|052|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
02436|053|R|  2013.|1
02436|054|R|2.Invirase (saquinavir mesylate) US prescribing information. Roche|1
02436|055|R|  Laboratories, Inc. March, 2019.|1
02436|056|R|3.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
02436|057|R|  Inc. December, 2004.|1
02436|058|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02436|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02436|060|R|  settings: a scientific statement from the American Heart Association and|6
02436|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02436|062|R|  2;55(9):934-47.|6
02437|001|T|MONOGRAPH TITLE:  Eslicarbazepine; Oxcarbazepine/Phenobarbital; Primidone|
02437|002|T|(mono deleted 04/17/2014)|
02437|003|B||
02437|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02437|005|L|take action as needed.|
02437|006|B||
02437|007|A|MECHANISM OF ACTION:  Phenobarbital and primidone may induce the metabolism|
02437|008|A|of eslicarbazepine and oxcarbazepine.(1,2)  Eslicarbazepine is the active|
02437|009|A|metabolite of oxcarbazepine.|
02437|010|B||
02437|011|E|CLINICAL EFFECTS:  Concurrent use of eslicarbazepine or oxcarbazepine and|
02437|012|E|phenobarbital or primidone may result in decreased levels of eslicarbazepine|
02437|013|E|and oxcarbazepine.(1,2)|
02437|014|B||
02437|015|P|PREDISPOSING FACTORS:  None determined.|
02437|016|B||
02437|017|M|PATIENT MANAGEMENT:  If phenobarbital or primidone is added to a patient|
02437|018|M|stabilized on eslicarbazepine or oxcarbazepine, the eslicarbazepine or|
02437|019|M|oxcarbazepine dose may need to be increased. The onset of induction is|
02437|020|M|gradual and may not be maximal for days or weeks.|
02437|021|M|   If eslicarbazepine or oxcarbazepine is added to a patient stabilized on|
02437|022|M|phenobarbital or primidone, a higher than expected dose of eslicarbazepine|
02437|023|M|or oxcarbazepine dose may be needed to achieve seizure control.|
02437|024|M|   After discontinuation of phenobarbital or primidone in patients|
02437|025|M|stabilized on concurrent therapy, eslicarbazepine or oxcarbazepine will|
02437|026|M|gradually increase over a number of weeks.  Monitor patients for toxicity|
02437|027|M|and adjust dose accordingly.|
02437|028|B||
02437|029|D|DISCUSSION:  In an interaction study, phenobarbital decreased|
02437|030|D|eslicarbazepine concentrations approximately 20-25%(3).|
02437|031|B||
02437|032|R|REFERENCES:|
02437|033|B||
02437|034|R|1.Trileptal (oxcarbazepine) US prescribing information. Novartis|1
02437|035|R|  Pharmaceuticals Corporation November, 2017.|1
02437|036|R|2.Aptiom (eslicarbazepine) US prescribing information. Sunovian|1
02437|037|R|  Pharmaceuticals Inc. August 27, 2015.|1
02438|001|T|MONOGRAPH TITLE:  Deferoxamine/Prochlorperazine|
02438|002|B||
02438|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02438|004|L|take action as needed.|
02438|005|B||
02438|006|A|MECHANISM OF ACTION:  Although the exact mechanism is unclear, the|
02438|007|A|combination of deferoxamine and prochlorperazine appears to have additive or|
02438|008|A|synergistic  pharmacodynamic effects on central nervous system(CNS) dopamine|
02438|009|A|activity.(1)|
02438|010|A|   Iron is required for normal dopamine cycling in central nervous system|
02438|011|A|(CNS) neurons; iron deficiency has been associated with dopamine-mediated|
02438|012|A|neuropsychiatric disease.(2-5) Deferoxamine chelation of iron in dopamine|
02438|013|A|neurons may lead to diminished neural activity(1) while prochlorperazine may|
02438|014|A|further decrease dopamine activity via blockade of dopamine binding|
02438|015|A|sites.(6)|
02438|016|B||
02438|017|E|CLINICAL EFFECTS:  Concurrent treatment with therapeutic doses of|
02438|018|E|deferoxamine and prochlorperazine has resulted in loss of|
02438|019|E|consciousness.(7,8)|
02438|020|B||
02438|021|P|PREDISPOSING FACTORS:  Patients with normal or low iron stores may have an|
02438|022|P|increased risk for toxicity.(7)  The elderly are more susceptible to adverse|
02438|023|P|effects from prochlorperazine.(6)|
02438|024|B||
02438|025|M|PATIENT MANAGEMENT:  Although the incidence of this interaction is unknown,|
02438|026|M|given the potential severity of the interaction it would be prudent,|
02438|027|M|particularly in patients with normal or low iron stores, to use alternative|
02438|028|M|antiemetics (e.g. ondansetron or other 5-HT3 receptor antagonists) in|
02438|029|M|patients receiving deferoxamine.|
02438|030|M|   The Australian manufacturer of prochlorperazine states that simultaneous|
02438|031|M|administration of deferoxamine and prochlorperazine is contraindicated.(9)|
02438|032|B||
02438|033|D|DISCUSSION:  In a pilot study,(7) deferoxamine was prescribed for patients|
02438|034|D|with progressive rheumatologic disease based upon proposed antiinflammatory|
02438|035|D|effects.  Deferoxamine was administered subcutaneously over 8-12 hours, 5|
02438|036|D|days per week, for a maximum of 3 weeks. Two patients who experienced nausea|
02438|037|D|received prochlorperazine resulting in a loss of consciousness. Case|
02438|038|D|details:|
02438|039|D|   - A 75 year old woman with symmetrical synovitis had pretreatment tests|
02438|040|D|which included C-reactive protein (CRP) 155 mg/L, ferritin 88 mcg/L,|
02438|041|D|hemoglobin (Hb) 9.2 g/dL. She received 42 grams of deferoxamine over three|
02438|042|D|weeks. During the last day of treatment she complained of nausea and took 5|
02438|043|D|doses of 5 mg oral prochlorperazine over 29 hours. Twelve hours after the|
02438|044|D|last dose she became drowsy, progressing to a significant impairment of|
02438|045|D|consciousness; at times she was only partially responsive to painful|
02438|046|D|stimuli. Electrolyte, liver function, blood glucose tests and CT of the|
02438|047|D|brain were normal during this time.  The patient recovered after 3 days|
02438|048|D|without apparent long term sequelae.|
02438|049|D|   - A 58 year old, 67kg man with severe peripheral polyarthritis had|
02438|050|D|pretreatment tests which included CRP 10 mg/L, ferritin 78 mcg/L and Hb 15|
02438|051|D|g/dL. He received twelve 3 gram deferoxamine infusions during the study|
02438|052|D|period.  On the last day of treatment he complained of nausea during the|
02438|053|D|infusion and received 2 doses of prochlorperazine 12.5mg IM in a 13 hour|
02438|054|D|period. The deferoxamine was stopped early due to mental status changes. He|
02438|055|D|gradually lost consciousness over a 6 hour period and was only minimally|
02438|056|D|responsive to painful stimuli for 2 days. During this time brisk reflexes,|
02438|057|D|spontaneous limb movement and clonus were observed.  Electrolyte, liver|
02438|058|D|function and blood glucose tests, lumbar puncture, and CT of the brain were|
02438|059|D|normal during this time. Subsequently he gradually returned to normal over a|
02438|060|D|4 day period.|
02438|061|D|   These cases of unexpected toxicity prompted an interaction study with|
02438|062|D|iron-deficient and iron-replete rats who were given intraperitoneal|
02438|063|D|deferoxamine and prochlorperazine. Given individually, neither drug impaired|
02438|064|D|consciousness, but the combination led to either movement only in response|
02438|065|D|to stimuli, or  total loss of consciousness. Consciousness was regained by|
02438|066|D|36 hours in the iron-deficient group and 12 hours in the iron-replete|
02438|067|D|group.(7)|
02438|068|B||
02438|069|R|REFERENCES:|
02438|070|B||
02438|071|R|1.Smythies J. Does the O'Brien cycle occur in vivo as a key component in|6
02438|072|R|  H(2)O(2) production and redox signalling?. Med Hypotheses 2011 Feb;|6
02438|073|R|  76(2):299-301.|6
02438|074|R|2.Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, Chen TJ, Bai YM.|2
02438|075|R|  Association between psychiatric disorders and iron deficiency anemia among|2
02438|076|R|  children and adolescents: a nationwide population-based study. BMC|2
02438|077|R|  Psychiatry 2013;13:161.|2
02438|078|R|3.Picchietti DL, Wang VC, Picchietti MA. Intravenous iron given prior to|2
02438|079|R|  pregnancy for restless legs syndrome is associated with remission of|2
02438|080|R|  symptoms. J Clin Sleep Med 2012 Oct 15;8(5):585-6.|2
02438|081|R|4.Earley CJ. Clinical practice. Restless legs syndrome. N Engl J Med 2003|6
02438|082|R|  May 22;348(21):2103-9.|6
02438|083|R|5.Hegde NV, Jensen GL, Unger EL. Iron chelation down-regulates dopamine|5
02438|084|R|  transporter expression by decreasing mRNA  stability and increasing|5
02438|085|R|  endocytosis in N2a cells. Exp Cell Res 2011 Feb 15;317(4):405-12.|5
02438|086|R|6.Prochlorperazine maleate US prescribing information. Sandoz Inc.|1
02438|087|R|  September, 2010.|1
02438|088|R|7.Blake DR, Winyard P, Lunec J, Williams A, Good PA, Crewes SJ, Gutteridge|3
02438|089|R|  JM, Rowley D, Halliwell B, Cornish A, et al. Cerebral and ocular toxicity|3
02438|090|R|  induced by desferrioxamine. Q J Med 1985 Jul;56(219):345-55.|3
02438|091|R|8.Desferal (deferoxamine mesylate) US prescribing information. Novartis|1
02438|092|R|  Pharmaceuticals Corporation December, 2011.|1
02438|093|R|9.Stemetil (prochlorperazine) Australian product information. Atnahs Pharma|1
02438|094|R|  Australia Pty Ltd Jan 31, 2025.|1
02439|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Selected Antiarrhythmics|
02439|002|B||
02439|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02439|004|L|of severe adverse interaction.|
02439|005|B||
02439|006|A|MECHANISM OF ACTION:  Methadone has been shown to prolong the QTc|
02439|007|A|interval.(1-4) Concurrent use with other agents that prolong the QTc|
02439|008|A|interval may result in additive effects on the QTc interval.(1-3)|
02439|009|A|   Levomethadone is an enantiomer of methadone.(5)|
02439|010|B||
02439|011|E|CLINICAL EFFECTS:  The concurrent use of methadone with other agents that|
02439|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02439|013|E|arrhythmias, including torsades de pointes.(1-3)|
02439|014|E|   Antiarrhythmic agents linked to this monograph are: dofetilide,|
02439|015|E|flecainide, ibutilide, procainamide, and sotalol.|
02439|016|B||
02439|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02439|018|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02439|019|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02439|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02439|021|P|gender, or advanced age.(3)|
02439|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02439|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02439|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02439|025|P|drug concentrations include rapid infusion of an intravenous dose or|
02439|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02439|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02439|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02439|029|B||
02439|030|M|PATIENT MANAGEMENT:  Evaluate patient for diseases and other predisposing|
02439|031|M|factors which increase the risk for QT prolongation and carefully weigh|
02439|032|M|risks and benefits of concomitant therapy.  Whenever possible, avoid|
02439|033|M|concomitant use of methadone and drugs with known risk for proarrhythmia,|
02439|034|M|including dofetilide, flecainide, ibutilide, procainamide, and sotalol.|
02439|035|M|   If concurrent therapy is warranted, obtain serum calcium, magnesium, and|
02439|036|M|potassium levels, and monitor ECG at baseline and at regular intervals.|
02439|037|M|Correct any electrolyte abnormalities prior to initiating concurrent|
02439|038|M|therapy.|
02439|039|M|   The greatest risk for methadone-induced QT prolongation is associated|
02439|040|M|with, but not limited to, higher dose treatment (greater than or equal to|
02439|041|M|120 mg daily).(4)|
02439|042|M|   Counsel patients to report irregular heartbeat, palpitations, dizziness|
02439|043|M|or syncopal episodes.(1)|
02439|044|B||
02439|045|D|DISCUSSION:  Agents linked to this monograph have been associated with a|
02439|046|D|risk of torsades de pointes.(3)|
02439|047|D|   One or more of the drug pairs linked to this monograph have been included|
02439|048|D|in a list of interactions that should be considered "high-priority" for|
02439|049|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02439|050|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02439|051|D|Coordinator (ONC) for Health Information Technology.|
02439|052|B||
02439|053|R|REFERENCES:|
02439|054|B||
02439|055|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
02439|056|R|  Pharmaceuticals Corp. June, 2021.|1
02439|057|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02439|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02439|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02439|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02439|061|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02439|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02439|063|R|  settings: a scientific statement from the American Heart Association and|6
02439|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02439|065|R|  2;55(9):934-47.|6
02439|066|R|4.Florian J, Garnett CE, Nallani SC, Rappaport BA, Throckmorton DC. A|2
02439|067|R|  modeling and simulation approach to characterize methadone QT prolongation|2
02439|068|R|  using pooled data from five clinical trials in MMT patients. Clin|2
02439|069|R|  Pharmacol Ther 2012 Apr;91(4):666-72.|2
02439|070|R|5.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
02439|071|R|  Pharma AS November 30, 2018.|1
02439|072|R|6.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02439|073|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02439|074|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02439|075|R|  19(5):735-43.|6
02440|001|T|MONOGRAPH TITLE:  Tasimelteon/Strong CYP1A2 Inhibitors|
02440|002|B||
02440|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02440|004|L|of severe adverse interaction.|
02440|005|B||
02440|006|A|MECHANISM OF ACTION:  Strong CYP1A2 inhibitors may inhibit the metabolism of|
02440|007|A|tasimelteon.(1)|
02440|008|B||
02440|009|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP1A2 may result|
02440|010|E|in elevated levels of and toxicity from tasimelteon.(1)|
02440|011|B||
02440|012|P|PREDISPOSING FACTORS:  None determined.|
02440|013|B||
02440|014|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP1A2 inhibitors|
02440|015|M|and tasimelteon.(1)|
02440|016|B||
02440|017|D|DISCUSSION:  Fluvoxamine (50 mg daily for 6 days) increased the maximum|
02440|018|D|concentration (Cmax) and area-under-curve (AUC) of tasimelteon by 2-fold and|
02440|019|D|7-fold, respectively.(1)|
02440|020|D|   Strong inhibitors of CYP1A2 include angelica root (angelica dahurica|
02440|021|D|radix), ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and|
02440|022|D|rofecoxib.(2,3)|
02440|023|B||
02440|024|R|REFERENCES:|
02440|025|B||
02440|026|R|1.Hetlioz (tasimelteon) US prescribing information. Vanda Pharmaceuticals|1
02440|027|R|  Inc. December, 2020.|1
02440|028|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02440|029|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02440|030|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02440|031|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02440|032|R|  11/14/2017.|1
02440|033|R|3.This information is based on an extract from the Certara Drug Interaction|6
02440|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02441|001|T|MONOGRAPH TITLE:  Tasimelteon/Strong CYP3A4 Inducers (mono deleted|
02441|002|T|10/23/2014)|
02441|003|B||
02441|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02441|005|L|of severe adverse interaction.|
02441|006|B||
02441|007|A|MECHANISM OF ACTION:  Strong CYP3a4 inducers may induce the metabolism of|
02441|008|A|tasimelteon.(1)|
02441|009|B||
02441|010|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 may result in|
02441|011|E|decreased levels and efficacy of tasimelteon.(1)|
02441|012|B||
02441|013|P|PREDISPOSING FACTORS:  None determined.|
02441|014|B||
02441|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers and|
02441|016|M|tasimelteon.(1)|
02441|017|B||
02441|018|D|DISCUSSION:  Rifampin (600 mg daily for 11 days) decreased the exposure of|
02441|019|D|tasimelteon by 90%.(1)|
02441|020|D|   Strong inducers of CYP3A4 include carbamazepine, enzalutamide, mitotane,|
02441|021|D|phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(2,3)|
02441|022|B||
02441|023|R|REFERENCES:|
02441|024|B||
02441|025|R|1.Hetlioz (tasimelteon) US prescribing information. Vanda Pharmaceuticals|1
02441|026|R|  Inc. December, 2020.|1
02441|027|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02441|028|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02441|029|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02441|030|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02441|031|R|  11/14/2017.|1
02441|032|R|3.This information is based on an extract from the Certara Drug Interaction|6
02441|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02442|001|T|MONOGRAPH TITLE:  Voriconazole/Natisedine (combo of Quinidine &|
02442|002|T|Phenobarbital)|
02442|003|B||
02442|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02442|005|L|is contraindicated and generally should not be dispensed or administered to|
02442|006|L|the same patient.|
02442|007|B||
02442|008|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 such as phenobarbital may|
02442|009|A|induce the metabolism of voriconazole.(1)  Voriconazole may inhibit the|
02442|010|A|metabolism of quinidine.(1)|
02442|011|B||
02442|012|E|CLINICAL EFFECTS:  The concurrent use of phenobarbital and voriconazole may|
02442|013|E|result in severely reduced levels of voriconazole and therapeutic|
02442|014|E|failure.(1)  The concurrent use of voriconazole with quinidine may result in|
02442|015|E|elevated plasma levels of quinidine, which may result in potentially serious|
02442|016|E|or life-threatening adverse effects, including QT prolongation.(1)|
02442|017|B||
02442|018|P|PREDISPOSING FACTORS:  None determined.|
02442|019|B||
02442|020|M|PATIENT MANAGEMENT:  The concurrent use of voriconazole with phenobarbital|
02442|021|M|or quinidine is contraindicated.(1)|
02442|022|B||
02442|023|D|DISCUSSION:  The concurrent use of rifampin (600 mg once daily, a strong|
02442|024|D|inhibitor of CYP3A4) with voriconazole (200 mg every 12 hours for 7 days)|
02442|025|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02442|026|D|voriconazole by 93% and 96%, respectively.  Doubling the dose of|
02442|027|D|voriconazole did not restore adequate exposure to voriconazole during|
02442|028|D|rifampin.(1)|
02442|029|D|   The concurrent use of rifabutin (300 mg once daily) with voriconazole|
02442|030|D|(200 mg twice daily) decreased the Cmax and AUC of voriconazole by 67% and|
02442|031|D|79%, respectively.  The concurrent use of rifabutin (300 mg once daily) with|
02442|032|D|voriconazole (400 mg twice daily) increased the Cmax and AUC of voriconazole|
02442|033|D|to twice that seen with voriconazole alone at 200 mg twice daily.  However,|
02442|034|D|the Cmax and AUC of rifabutin were 3-fold and 4-fold higher, respectively,|
02442|035|D|when given with voriconazole at 400 mg twice daily.(1)|
02442|036|D|   Therapeutic failures have been reported with voriconazole in patients|
02442|037|D|treated concurrently with phenobarbital.(2|
02442|038|D|   Voriconazole has been shown to increase levels of sirolimus, which is|
02442|039|D|metabolized by the same isoenzyme that quinidine is.  Therefore, the|
02442|040|D|manufacturer of voriconazole states that the concurrent use of voriconazole|
02442|041|D|and quinidine is contraindicated.(1)|
02442|042|B||
02442|043|R|REFERENCES:|
02442|044|B||
02442|045|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
02442|046|R|2.Muldrew KM, Maples HD, Stowe CD, Jacobs RF. Intravenous voriconazole|3
02442|047|R|  therapy in a preterm infant. Pharmacotherapy 2005 Jun;25(6):893-8.|3
02443|001|T|MONOGRAPH TITLE:  Tamsulosin/Diltiazem;Dronedarone;Verapamil|
02443|002|B||
02443|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02443|004|L|take action as needed.|
02443|005|B||
02443|006|A|MECHANISM OF ACTION:  Tamsulosin is primarily metabolized by CYP3A4 and|
02443|007|A|CYP2D6. Diltiazem, dronedarone, and verapamil are both moderate inhibitors|
02443|008|A|of CYP3A4 and weak inhibitors of CYP2D6(1,2) and so may delay tamsulosin|
02443|009|A|metabolism via both major pathways.|
02443|010|A|   The pharmacodynamic effects of diltiazem and verapamil on blood pressure|
02443|011|A|may further increase the risk for hypotension from tamsulosin.|
02443|012|B||
02443|013|E|CLINICAL EFFECTS:  Co-administration of diltiazem, dronedarone, or verapamil|
02443|014|E|may cause an increase in tamsulosin levels and effects, including|
02443|015|E|symptomatic hypotension.|
02443|016|B||
02443|017|P|PREDISPOSING FACTORS:  The interaction may be more severe in poor|
02443|018|P|metabolizers of CYP2D6 or in patients receiving additional agents which|
02443|019|P|inhibit CYP3A4 or CYP2D6.|
02443|020|B||
02443|021|M|PATIENT MANAGEMENT:  The manufacturer of tamsulosin states there is a|
02443|022|M|potential for a significant increase in exposure when tamsulosin is|
02443|023|M|co-administered with both CYP3A4 and CYP2D6 inhibitors.(3)  The risk for|
02443|024|M|hypotension from tamsulosin is more likely after starting or increasing the|
02443|025|M|dose of either drug.(3) Monitor for orthostatic hypotension prior to a dose|
02443|026|M|increase and delay dose adjustment if needed. Monitor patients after a dose|
02443|027|M|increase, particularly those with a history of hypotension, orthostasis or|
02443|028|M|falls.|
02443|029|M|   Instruct patient to report episodes of dizziness, lightheadedness or|
02443|030|M|feeling faint.(3)|
02443|031|B||
02443|032|D|DISCUSSION:  An open label, multicenter, prospective trial evaluated the|
02443|033|D|safety of tamsulosin 0.4 mg daily over 24 weeks in 1784 patients.  The most|
02443|034|D|commonly reported adverse effects were dizziness, headache, abnormal|
02443|035|D|ejaculation  and hypotension.  Patients receiving verapamil had an|
02443|036|D|approximately 3-fold (odds ratio 3.166, 95% confidence interval 1.513, 6.58)|
02443|037|D|increase in the risk for adverse events.(4)|
02443|038|B||
02443|039|R|REFERENCES:|
02443|040|B||
02443|041|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
02443|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02443|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02443|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02443|045|R|  11/14/2017.|1
02443|046|R|2.This information is based on an extract from the Certara Drug Interaction|6
02443|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02443|048|R|3.Flomax (tamsulosin hydrochloride) US prescribing information. Boehringer|1
02443|049|R|  Ingelheim Pharmaceuticals, Inc. October 20. 2014.|1
02443|050|R|4.Michel MC, Bressel HU, Goepel M, Rubben H. A 6-month large-scale study|1
02443|051|R|  into the safety of tamsulosin. Br J Clin Pharmacol 2001 Jun;51(6):609-14.|1
02444|001|T|MONOGRAPH TITLE:  Bortezomib/Ascorbic Acid (Vitamin C)|
02444|002|B||
02444|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02444|004|L|of severe adverse interaction.|
02444|005|B||
02444|006|A|MECHANISM OF ACTION:  Vitamin C can form a complex with the boronic acid|
02444|007|A|moiety of the bortezomib molecule, preventing its absorption into|
02444|008|A|cells.(1-4)  This may protect normal tissue in the body, which may have|
02444|009|A|higher levels of Vitamin C.(5)|
02444|010|B||
02444|011|E|CLINICAL EFFECTS:  Concurrent administration of Vitamin C may result in|
02444|012|E|decreased bortezomib activity.(1-4)|
02444|013|B||
02444|014|P|PREDISPOSING FACTORS:  None determined.|
02444|015|B||
02444|016|M|PATIENT MANAGEMENT:  Instruct patients receiving bortezomib therapy not to|
02444|017|M|begin taking vitamin C supplements without consulting their oncologist|
02444|018|M|first.  Patients who are instructed to take vitamin C should follow their|
02444|019|M|oncologist's instructions on how to separate dosages and should be carefully|
02444|020|M|monitored for bortezomib efficacy.|
02444|021|B||
02444|022|D|DISCUSSION:  An in vitro study with human plasma and multiple myeloma cells|
02444|023|D|found that high levels of vitamin C (following 1 gram/day of ascorbic acid|
02444|024|D|for 4 days) decreased bortezomib effectiveness by 26%.  An in vivo study in|
02444|025|D|mice found that vitamin C administration with bortezomib completely blocked|
02444|026|D|the response of bortezomib.(6)|
02444|027|D|   An in vitro study in rat Schwann cells and myeloma cells(4) and an in|
02444|028|D|vivo study in mice(7) found that delayed administration of vitamin C had no|
02444|029|D|effect on bortezomib effects.|
02444|030|D|   In an in vivo study in multiple myeloma patients, concurrent ascorbic|
02444|031|D|acid, arsenic trioxide, bortezomib, and high-dose melphalan in which|
02444|032|D|ascorbic acid was administered close to bortezomib, the combination was safe|
02444|033|D|and well tolerated, but produced no changes in response rates.(8)|
02444|034|D|   In another in vivo study in multiple myeloma patients, a regimen of|
02444|035|D|ascorbic acid, bortezomib, and melphalan in which bortezomib was|
02444|036|D|administered in the morning and ascorbic acid in the evening was found to be|
02444|037|D|safe and efficacious, with 74% of patients responding to therapy.(9)|
02444|038|B||
02444|039|R|REFERENCES:|
02444|040|B||
02444|041|R|1.Zou W, Yue P, Lin N, He M, Zhou Z, Lonial S, Khuri FR, Wang B, Sun SY.|5
02444|042|R|  Vitamin C inactivates the proteasome inhibitor PS-341 in human cancer|5
02444|043|R|  cells. Clin Cancer Res 2006 Jan 1;12(1):273-80.|5
02444|044|R|2.Llobet D, Eritja N, Encinas M, Sorolla A, Yeramian A, Schoenenberger JA,|5
02444|045|R|  Llombart-Cussac A, Marti RM, Matias-Guiu X, Dolcet X. Antioxidants block|5
02444|046|R|  proteasome inhibitor function in endometrial carcinoma cells. Anticancer|5
02444|047|R|  Drugs 2008 Feb;19(2):115-24.|5
02444|048|R|3.Fernandez Y, Miller TP, Denoyelle C, Esteban JA, Tang WH, Bengston AL,|5
02444|049|R|  Soengas MS. Chemical blockage of the proteasome inhibitory function of|5
02444|050|R|  bortezomib: impact on  tumor cell death. J Biol Chem 2006 Jan 13;|5
02444|051|R|  281(2):1107-18.|5
02444|052|R|4.Bannerman B, Xu L, Jones M, Tsu C, Yu J, Hales P, Monbaliu J, Fleming P,|5
02444|053|R|  Dick L, Manfredi M, Claiborne C, Bolen J, Kupperman E, Berger A.|5
02444|054|R|  Preclinical evaluation of the antitumor activity of bortezomib in|5
02444|055|R|  combination with vitamin C or with epigallocatechin gallate, a component|5
02444|056|R|  of green tea. Cancer Chemother Pharmacol 2011 Nov;68(5):1145-54.|5
02444|057|R|5.Catley L, Anderson KC. Velcade and vitamin C: too much of a good thing?.|6
02444|058|R|  Clin Cancer Res 2006 Jan 1;12(1):3-4.|6
02444|059|R|6.Perrone G, Hideshima T, Ikeda H, Okawa Y, Calabrese E, Gorgun G, Santo L,|5
02444|060|R|  Cirstea D, Raje N, Chauhan D, Baccarani M, Cavo M, Anderson KC. Ascorbic|5
02444|061|R|  acid inhibits antitumor activity of bortezomib in vivo. Leukemia 2009 Sep;|5
02444|062|R|  23(9):1679-86.|5
02444|063|R|7.Nakano A, Abe M, Oda A, Amou H, Hiasa M, Nakamura S, Miki H, Harada T,|5
02444|064|R|  Fujii S, Kagawa K, Takeuchi K, Watanabe T, Ozaki S, Matsumoto T. Delayed|5
02444|065|R|  treatment with vitamin C and N-acetyl-L-cysteine protects Schwann cells|5
02444|066|R|  without compromising the anti-myeloma activity of bortezomib. Int J|5
02444|067|R|  Hematol 2011 Jun;93(6):727-35.|5
02444|068|R|8.Sharma M, Khan H, Thall PF, Orlowski RZ, Bassett RL Jr, Shah N, Bashir Q,|2
02444|069|R|  Parmar S, Wang M, Shah JJ, Hosing CM, Popat UR, Giralt SA, Champlin RE,|2
02444|070|R|  Qazilbash MH. A randomized phase 2 trial of a preparative regimen of|2
02444|071|R|  bortezomib, high-dose melphalan, arsenic trioxide, and ascorbic acid.|2
02444|072|R|  Cancer 2012 May 1;118(9):2507-15.|2
02444|073|R|9.Berenson JR, Yellin O, Woytowitz D, Flam MS, Cartmell A, Patel R, Duvivier|2
02444|074|R|  H, Nassir Y, Eades B, Abaya CD, Hilger J, Swift RA. Bortezomib, ascorbic|2
02444|075|R|  acid and melphalan (BAM) therapy for patients with newly diagnosed|2
02444|076|R|  multiple myeloma: an effective and well-tolerated frontline regimen. Eur J|2
02444|077|R|  Haematol 2009 Jun;82(6):433-9.|2
02445|001|T|MONOGRAPH TITLE:  Selected Nephrotoxic Agents/Adefovir|
02445|002|B||
02445|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02445|004|L|take action as needed.|
02445|005|B||
02445|006|A|MECHANISM OF ACTION:  Recommended doses of adefovir have been associated|
02445|007|A|with delayed nephrotoxicity.(1-4) Concurrent administration of other|
02445|008|A|nephrotoxic agents may result in additive or synergistic effects on renal|
02445|009|A|function.(1)|
02445|010|B||
02445|011|E|CLINICAL EFFECTS:  Concurrent use of adefovir with nephrotoxic agents such|
02445|012|E|as intravenous aminoglycosides, amphotericin B, cyclosporine,|
02445|013|E|tacrolimus,tenofovir, vancomycin, voclosporin and non-steroidal|
02445|014|E|anti-inflammatory agents may result in renal toxicity.(1)  Other nephrotoxic|
02445|015|E|agents include capreomycin, cisplatin, gallium nitrate, high-dose|
02445|016|E|methotrexate, intravenous pentamidine, and streptozocin.|
02445|017|B||
02445|018|P|PREDISPOSING FACTORS:  Patients with pre-existing renal impairment(1,2) or|
02445|019|P|receiving multiple nephrotoxic agents appear to be at greater risk for|
02445|020|P|nephrotoxicity.|
02445|021|B||
02445|022|M|PATIENT MANAGEMENT:  Evaluate renal function prior to initiation of|
02445|023|M|concurrent therapy and continue renal function monitoring during therapy.|
02445|024|M|Dose adjustments may be required for impaired renal function. Weigh the|
02445|025|M|risks and benefits of concurrent therapy in patients with treatment-emergent|
02445|026|M|nephrotoxicity.|
02445|027|B||
02445|028|D|DISCUSSION:  Because of the known risks for adefovir nephrotoxicity,|
02445|029|D|particularly at higher than recommended doses, the safety of adefovir has|
02445|030|D|not been studied in patients receiving other known potentially nephrotoxic|
02445|031|D|agents.|
02445|032|B||
02445|033|R|REFERENCES:|
02445|034|B||
02445|035|R|1.Hepsera (adefovir dipivoxil) US prescribing information. Gilead Sciences,|1
02445|036|R|  Inc. December, 2018.|1
02445|037|R|2.Hartono JL, Aung MO, Dan YY, Gowans M, Lim K, Lee YM, Lee GH, Low HC, Tan|2
02445|038|R|  PS, Thwin MA, Soon C, Chiu LL, Khoo MJ, Koay E, Lim SG. Resolution of|2
02445|039|R|  adefovir-related nephrotoxicity by adefovir dose-reduction in patients|2
02445|040|R|  with chronic hepatitis B. Aliment Pharmacol Ther 2013 Apr;37(7):710-9.|2
02445|041|R|3.Jung YK, Yeon JE, Choi JH, Kim CH, Jung ES, Kim JH, Park JJ, Kim JS, Bak|3
02445|042|R|  YT, Byun KS. Fanconi's Syndrome Associated with Prolonged Adefovir|3
02445|043|R|  Dipivoxil Therapy in a Hepatitis B Virus Patient. Gut Liver 2010 Sep;|3
02445|044|R|  4(3):389-93.|3
02445|045|R|4.Law ST, Li KK, Ho YY. Nephrotoxicity, including acquired Fanconi's|3
02445|046|R|  syndrome, caused by adefovir dipivoxil - is there a safe dose?. J Clin|3
02445|047|R|  Pharm Ther 2012 Apr;37(2):128-31.|3
02446|001|T|MONOGRAPH TITLE:  Linezolid/Tryptophan|
02446|002|B||
02446|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02446|004|L|of severe adverse interaction.|
02446|005|B||
02446|006|A|MECHANISM OF ACTION:  Concurrent use may result in additive effects on|
02446|007|A|serotonin levels.  MAOIs may potentiate the effects of tryptophan.(1)|
02446|008|B||
02446|009|E|CLINICAL EFFECTS:  Concurrent administration of tryptophan with a MAO|
02446|010|E|Inhibitor may result in serotonin syndrome and/or hypertensive crisis.(1)|
02446|011|E|Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
02446|012|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2)|
02446|013|E|In addition to these effects, disorientation, delirium, agitation,|
02446|014|E|hypomania, shivering, ocular oscillation, and Babinski signs have been|
02446|015|E|reported with concurrent tryptophan and phenelzine.(1)|
02446|016|B||
02446|017|P|PREDISPOSING FACTORS:  None determined.|
02446|018|B||
02446|019|M|PATIENT MANAGEMENT:  Patients receiving linezolid should not be administered|
02446|020|M|tryptophan unless they can be closely monitored for serotonin syndrome.|
02446|021|M|   If concurrent therapy is warranted, patients should be monitored for|
02446|022|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02446|023|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02446|024|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02446|025|M|coordination, or severe diarrhea.|
02446|026|B||
02446|027|D|DISCUSSION:  In a case report, a patient receiving metoclopramide and a TPN|
02446|028|D|containing tryptophan developed serotonin syndrome following the addition of|
02446|029|D|linezolid to therapy.(3)|
02446|030|D|   In a study in nine subjects, the administration of a single intravenous|
02446|031|D|dose of tryptophan with tranylcypromine significantly increased the normal|
02446|032|D|prolactin response to tryptophan.  Four of the nine subjects developed a|
02446|033|D|distinctive neuromotor syndrome characterized by hyperreflexia, ankle|
02446|034|D|clonus, nystagmus, incoordination, tremor, myoclonic jerks, and nausea.(4)|
02446|035|D|Another set of authors reported eight cases of delirium, ranging from mild|
02446|036|D|to severe, in patients who received concurrent tranylcypromine and|
02446|037|D|tryptophan. Symptoms developed within two days to 4 weeks of beginning|
02446|038|D|concurrent therapy.(5)  In a case report, the addition of tryptophan to a|
02446|039|D|tranylcypromine regimen resulted in hypomania.(6)  In another report, a|
02446|040|D|patient developed hyperventilation, shivering, hyperthermia, increased|
02446|041|D|muscle tone, and hyperreflexia when tryptophan was added to tranylcypromine|
02446|042|D|therapy.(7)  There are two reports of fatalities following the concurrent|
02446|043|D|administration of tryptophan and tranylcypromine.  In the first report, a a|
02446|044|D|patient had been receiving chlorpromazine, lithium, and tryptophan when|
02446|045|D|phenelzine was initiated.  Four weeks later, the patient developed|
02446|046|D|neuroleptic malignant syndrome and expired despite resuscitation efforts.(8)|
02446|047|D|In the second report, a patient had been receiving fluoxetine,|
02446|048|D|levothyroxine, propranolol, quinidine, and hydroxyzine.  Fluoxetine was|
02446|049|D|discontinued and tranylcypromine, thioridazine, and tryptophan were|
02446|050|D|initiated.  The patient developed neuroleptic malignant syndrome two and|
02446|051|D|one-half hours after the first tryptophan dose and expired 24 hours later.|
02446|052|D|(9)|
02446|053|D|  In a case report, the addition of tryptophan to a regimen that included|
02446|054|D|phenelzine resulted in an acute behavioral and neurologic syndrome.  The|
02446|055|D|patient's symptoms resolved 24 hours after the discontinuation of both|
02446|056|D|agents.(10)  In another report, a patient developed hypomania following the|
02446|057|D|addition of tryptophan to phenelzine therapy.(6)  Another report describes|
02446|058|D|the development of delirium following the addition of tryptophan to|
02446|059|D|phenelzine.(11)  One set of authors reported three cases of myoclonus,|
02446|060|D|hyperreflexia, and diaphoresis following the addition of tryptophan to|
02446|061|D|phenelzine therapy.(12)|
02446|062|D|   Some studies have shown that the addition of tryptophan to MAO Inhibitor|
02446|063|D|therapy may have beneficial results, including greater improvement in|
02446|064|D|depression and faster onset of effects.(13,14)|
02446|065|B||
02446|066|R|REFERENCES:|
02446|067|B||
02446|068|R|1.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
02446|069|R|  2007.|1
02446|070|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02446|071|R|  352(11):1112-20.|6
02446|072|R|3.Colomar Ferra A, Ventayol Bosch P, Raurich JM. Serotonin syndrome due to|3
02446|073|R|  interaction between linezolid, tryptophan, and metoclopramide. Med|3
02446|074|R|  Intensiva 2009 Oct;33(7):360-1.|3
02446|075|R|4.Price LH, Charney DS, Heninger GR. Effects of tranylcypromine treatment on|2
02446|076|R|  neuroendocrine, behavioral, and autonomic responses to tryptophan in|2
02446|077|R|  depressed patients. Life Sci 1985 Sep 2;37(9):809-18.|2
02446|078|R|5.Pope HG Jr, Jonas JM, Hudson JI, Kafka MP. Toxic reactions to the|3
02446|079|R|  combination of monoamine oxidase inhibitors and tryptophan. Am J|3
02446|080|R|  Psychiatry 1985 Apr;142(4):491-2.|3
02446|081|R|6.Goff DC. Two cases of hypomania following the addition of L-tryptophan to|3
02446|082|R|  a monoamine oxidase inhibitor. Am J Psychiatry 1985 Dec;142(12):1487-8.|3
02446|083|R|7.Price WA, Zimmer B, Kucas P. Serotonin syndrome: a case report. J Clin|3
02446|084|R|  Pharmacol 1986 Jan;26(1):77-8.|3
02446|085|R|8.Staufenberg EF, Tantam D. Malignant hyperpyrexia syndrome in combined|3
02446|086|R|  treatment. Br J Psychiatry 1989 Apr;154:577-8.|3
02446|087|R|9.Kline SS, Mauro LS, Scala-Barnett DM, Zick D. Serotonin syndrome versus|3
02446|088|R|  neuroleptic malignant syndrome as a cause of death. Clin Pharm 1989 Jul;|3
02446|089|R|  8(7):510-4.|3
02446|090|R|10.Thomas JM, Rubin EH. Case report of a toxic reaction from a combination|3
02446|091|R|   of tryptophan and phenelzine. Am J Psychiatry 1984 Feb;141(2):281-3.|3
02446|092|R|11.Alvine G, Black DW, Tsuang D. Case of delirium secondary to|3
02446|093|R|   phenelzine/L-tryptophan combination. J Clin Psychiatry 1990 Jul;|3
02446|094|R|   51(7):311.|3
02446|095|R|12.Levy AB, Bucher P, Votolato N. Myoclonus, hyperreflexia and diaphoresis|3
02446|096|R|   in patients on phenelzine- tryptophan combination treatment. Can J|3
02446|097|R|   Psychiatry 1985 Oct;30(6):434-6.|3
02446|098|R|13.Ayuso Gutierrez JL, Alino JJ. Tryptophan and an MAOI (nialamide) in the|2
02446|099|R|   treatment of depression. A double-blind study. Int Pharmacopsychiatry|2
02446|100|R|   1971;6(2):92-7.|2
02446|101|R|14.Glassman AH, Platman SR. Potentiation of a monoamine oxidase inhibitor by|2
02446|102|R|   tryptophan. J Psychiatr Res 1969 Dec;7(2):83-8.|2
02447|001|T|MONOGRAPH TITLE:  Meperidine Injection/Doxepin (Greater Than 25 mg)|
02447|002|B||
02447|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02447|004|L|take action as needed.|
02447|005|B||
02447|006|A|MECHANISM OF ACTION:  The concurrent administration of meperidine with other|
02447|007|A|serotonergic agents may result in additive serotonin effects, resulting in|
02447|008|A|central serotonergic hyperstimulation.(1)|
02447|009|A|   Meperidine, its nor-meperidine metabolite, and antidepressants may also|
02447|010|A|lower the seizure threshold.|
02447|011|B||
02447|012|E|CLINICAL EFFECTS:  Concurrent administration of meperidine and higher dose|
02447|013|E|doxepin may result in serotonin syndrome or seizures.  Symptoms of serotonin|
02447|014|E|syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus,|
02447|015|E|tachycardia, hyperthermia, and muscle rigidity.(1)|
02447|016|B||
02447|017|P|PREDISPOSING FACTORS:  Renal dysfunction may increase seizure risk due to|
02447|018|P|elevated nor-meperidine (toxic metabolite) concentrations.(2,3) Use of|
02447|019|P|multiple serotonergic agents increases the risk for serotonin toxicity.(1)|
02447|020|B||
02447|021|M|PATIENT MANAGEMENT:  Meperidine injection patients with renal impairment who|
02447|022|M|also receive concomitant therapy with higher dose doxepin should be|
02447|023|M|monitored for signs and symptoms of serotonin syndrome or seizure activity.|
02447|024|M|Meperidine may need to be discontinued.|
02447|025|M|   If concurrent therapy is warranted, patients should be monitored for|
02447|026|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02447|027|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02447|028|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02447|029|M|coordination, or severe diarrhea.|
02447|030|B||
02447|031|D|DISCUSSION:  Although this interaction is theoretically possible, no case|
02447|032|D|reports describing this interaction have been found.|
02447|033|B||
02447|034|R|REFERENCES:|
02447|035|B||
02447|036|R|1.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02447|037|R|  352(11):1112-20.|6
02447|038|R|2.Geller RJ. Meperidine in patient-controlled analgesia: a near-fatal|3
02447|039|R|  mishap. Anesth Analg 1993 Mar;76(3):655-7.|3
02447|040|R|3.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
02447|041|R|  Pharmaceuticals LLC. December, 2023.|1
02448|001|T|MONOGRAPH TITLE:  Selected Extended-Release CNS Stimulants/Alcohol|
02448|002|B||
02448|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02448|004|L|of severe adverse interaction.|
02448|005|B||
02448|006|A|MECHANISM OF ACTION:  Concomitant use of alcohol with selected extended or|
02448|007|A|delayed release amphetamine, dextroamphetamine, and methylphenidate products|
02448|008|A|may impair the integrity of the extended-release dose form resulting in|
02448|009|A|accelerated medication release over a short period of time.(1-8)|
02448|010|B||
02448|011|E|CLINICAL EFFECTS:  Rapid release of amphetamine, dextroamphetamine, or|
02448|012|E|methylphenidate may result in increased systemic concentrations and|
02448|013|E|toxicities.|
02448|014|B||
02448|015|P|PREDISPOSING FACTORS:  The increased rate of release may be alcohol|
02448|016|P|concentration-dependent.|
02448|017|B||
02448|018|M|PATIENT MANAGEMENT:  Patients are advised to avoid alcohol while taking|
02448|019|M|these extended-release products.(1-8)  Avoid the use of elixirs containing a|
02448|020|M|high-percentage of alcohol in patients taking these products.|
02448|021|B||
02448|022|D|DISCUSSION:  Some, but not all manufacturers have evaluated the effects of|
02448|023|D|alcohol on the kinetics of their extended release dose forms.|
02448|024|D|   An in vitro study explored the effect of alcohol on the release|
02448|025|D|characteristics of amphetamine from Adzenys XR-OPD.  There was a substantial|
02448|026|D|increase in amphetamine release with 40% alcohol, but not 5%, 10%, or 20%|
02448|027|D|alcohol.(1)|
02448|028|D|   An in vitro study explored the effect of alcohol on the release|
02448|029|D|characteristics of amphetamine from Dyanavel XR.  There was a substantial|
02448|030|D|increase in amphetamine release with 40% alcohol, but not 5%, 10%, or 20%|
02448|031|D|alcohol.(2)|
02448|032|D|   An in vitro study explored the effect of alcohol on the release|
02448|033|D|characteristics of amphetamine from Mydayis.  There was an increase in|
02448|034|D|amphetamine release with 20% alcohol and a larger increase with 40%|
02448|035|D|alcohol.(3)|
02448|036|D|   An in vitro study explored the effect of alcohol on the release|
02448|037|D|characteristics of methylphenidate from Adhansia XR.  At an alcohol|
02448|038|D|concentration of 40%, 71% and 61% of a 70 mg and 100 mg dose, respectively,|
02448|039|D|was released at 2 hours.  A study in healthy adults found that 40% alcohol|
02448|040|D|combined with Adhansia XR resulted in a 1.4-fold increase in peak plasma|
02448|041|D|concentration and 1.3-fold increase in absorption.(4)|
02448|042|D|   An in vitro study explored the effect of alcohol on the release|
02448|043|D|characteristics of methylphenidate for Concerta.  At an alcohol|
02448|044|D|concentration up to 40% there was no increased release of methylphenidate in|
02448|045|D|the first hour.(5)|
02448|046|D|   An in vitro study explored the effect of alcohol on the release|
02448|047|D|characteristics of methylphenidate from Cotempla XR-ODT.  There was an|
02448|048|D|increase in methylphenidate release with 40% alcohol, but not with lower|
02448|049|D|alcohol concentration.(6)|
02448|050|D|   An in vitro study explored the effect of alcohol on the release|
02448|051|D|characteristics of methylphenidate from Metadate CD.  At an alcohol|
02448|052|D|concentration of 40%, 84% of methylphenidate was released in the first|
02448|053|D|hour.(7)|
02448|054|D|   An in vitro study explored the effect of alcohol on the release|
02448|055|D|characteristics of methylphenidate from Ritalin LA.  At an alcohol|
02448|056|D|concentration of 40%, 98% of methylphenidate was released in the first|
02448|057|D|hour.(8)|
02448|058|B||
02448|059|R|REFERENCES:|
02448|060|B||
02448|061|R|1.Adzenys XR-ODT (amphetamine extended release, orally disintegrating|1
02448|062|R|  tablet) US prescribing information. Neos Therapeutics, LP October 18,|1
02448|063|R|  2016.|1
02448|064|R|2.Dyanavel XR (amphetamine suspension, sustained release) US prescribing|1
02448|065|R|  information. Tris Pharma Inc May 18, 2017.|1
02448|066|R|3.Mydayis ER (amphetamine) US prescribing information. Shire LLC June, 2017.|1
02448|067|R|4.Adhansia XR (methylphenidate hydrochloride) US prescribing information.|1
02448|068|R|  Purdue Pharma L.P. June, 2021.|1
02448|069|R|5.Concerta (methylphenidate) Extended-Release prescribing information.|1
02448|070|R|  Janssen Pharmaceuticals October, 2023.|1
02448|071|R|6.Cotempla XR-ODT (methylphenidate extended-release orally disintegrating|1
02448|072|R|  tablets) US prescribing information. Neo Therapeutics, Inc. July, 2021.|1
02448|073|R|7.Metadate CD (methylphenidate) Extended-Release Capsules prescribing|1
02448|074|R|  information. UCB Inc. June, 2021.|1
02448|075|R|8.Ritalin LA (methylphenidate hydrochloride) US prescribing information.|1
02448|076|R|  Novartis Pharmaceuticals Corporation June, 2021.|1
02449|001|T|MONOGRAPH TITLE:  Disopyramide/Itraconazole; Ketoconazole (mono deleted|
02449|002|T|08/21/2014)|
02449|003|B||
02449|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02449|005|L|is contraindicated and generally should not be dispensed or administered to|
02449|006|L|the same patient.|
02449|007|B||
02449|008|A|MECHANISM OF ACTION:  Itraconazole(1) and ketoconazole(2) may inhibit the|
02449|009|A|metabolism of disopyramide by CYP3A4.|
02449|010|B||
02449|011|E|CLINICAL EFFECTS:  The concurrent administration of disopyramide with|
02449|012|E|itraconazole(1) or ketoconazole(2) may result in elevated levels and|
02449|013|E|increased effects of disopyramide, including prolongation of the QT interval|
02449|014|E|and torsades de pointes.|
02449|015|B||
02449|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02449|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
02449|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02449|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02449|020|P|female gender, or advanced age.(2)|
02449|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02449|022|P|higher systemic concentrations or either QT prolonging drug are additional|
02449|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02449|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02449|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02449|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02449|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02449|028|B||
02449|029|M|PATIENT MANAGEMENT:  The concurrent use of disopyramide with itraconazole(1)|
02449|030|M|or ketoconazole(2) is contraindicated.|
02449|031|B||
02449|032|D|DISCUSSION:  The concurrent administration of disopyramide with|
02449|033|D|itraconazole(1) or ketoconazole(2) is expected to increase concentrations of|
02449|034|D|disopyramide, which may lead to arrhythmias.|
02449|035|B||
02449|036|R|REFERENCES:|
02449|037|B||
02449|038|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02449|039|R|  Products, L.P. February, 2024.|1
02449|040|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
02449|041|R|  Pharmaceuticals February, 2014.|1
02449|042|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02449|043|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02449|044|R|  settings: a scientific statement from the American Heart Association and|6
02449|045|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02449|046|R|  2;55(9):934-47.|6
02450|001|T|MONOGRAPH TITLE:  Vilazodone/Strong CYP3A4 Inducers|
02450|002|B||
02450|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02450|004|L|take action as needed.|
02450|005|B||
02450|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02450|007|A|vilazodone.(1)|
02450|008|B||
02450|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
02450|010|E|may result in decreased levels and effectiveness of vilazodone.(1)|
02450|011|B||
02450|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02450|013|P|of the inducer for longer than 1-2 weeks.|
02450|014|B||
02450|015|M|PATIENT MANAGEMENT:  The manufacturer of vilazodone states that the|
02450|016|M|vilazodone dosage may need to be increased 2-fold, up to a maximum of 80 mg|
02450|017|M|daily in patients receiving strong inducers of CYP3A4 for 14 days or more.|
02450|018|M|(1)|
02450|019|M|   If a patient has been maintained on concomitant treatment with vilazodone|
02450|020|M|and a strong CYP3A4 inducer and the strong CYP3A4 inducer is subsequently|
02450|021|M|discontinued, the dose of vilazodone should be decreased by 50% over 1-2|
02450|022|M|weeks based upon patient response.(1)|
02450|023|B||
02450|024|D|DISCUSSION:  Carbamazepine (dosage not stated), a strong inducer of CYP3A4,|
02450|025|D|decreased vilazodone exposure approximately 45%.(1)|
02450|026|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
02450|027|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02450|028|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02450|029|D|rifapentine, and St. John's wort.(2-3)|
02450|030|B||
02450|031|R|REFERENCES:|
02450|032|B||
02450|033|R|1.Viibryd (vilazodone hydrochloride) US prescribing information. Forest|1
02450|034|R|  Laboratories Inc. October, 2023.|1
02450|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02450|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02450|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02450|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02450|039|R|  11/14/2017.|1
02450|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
02450|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02451|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Ciprofloxacin|
02451|002|B||
02451|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02451|004|L|take action as needed.|
02451|005|B||
02451|006|A|MECHANISM OF ACTION:  Ciprofloxacin may inhibit organic anion transporting|
02451|007|A|polypeptide (OATP) 1A2 in the intestines, either through competitive or|
02451|008|A|direct inhibition.(1)|
02451|009|B||
02451|010|E|CLINICAL EFFECTS:  The simultaneous administration of thyroid preparations|
02451|011|E|and ciprofloxacin may result in decreased levels and clinical effects of|
02451|012|E|thyroid hormones.(1)|
02451|013|B||
02451|014|P|PREDISPOSING FACTORS:  This interaction may be more significant in patients|
02451|015|P|receiving long term courses of ciprofloxacin.|
02451|016|B||
02451|017|M|PATIENT MANAGEMENT:  Patients taking thyroid preparations and ciprofloxacin|
02451|018|M|should be monitored for changes in thyroid function.  Separating the|
02451|019|M|administration times of the thyroid preparation and ciprofloxacin by 6|
02451|020|M|hours, may decrease the effects of the interaction.(1,2)|
02451|021|B||
02451|022|D|DISCUSSION:  In a study, 8 healthy individuals received single doses of|
02451|023|D|levothyroxine (100 mcg) combined with placebo or ciprofloxacin (750 mg).|
02451|024|D|The simultaneous administration of ciprofloxacin significantly decreased the|
02451|025|D|T4 AUC by 39% (p=0.035).  The reduction in T4 AUC after coadministration of|
02451|026|D|ciprofloxacin with levothyroxine is consistent with inhibition of an|
02451|027|D|intestinal T4 uptake transport.(1)|
02451|028|D|   In a case report, two patients with hypothyroidism and receiving|
02451|029|D|levothyroxine developed decreased T4 levels after taking ciprofloxacin for|
02451|030|D|3-4 weeks.(2)|
02451|031|B||
02451|032|R|REFERENCES:|
02451|033|B||
02451|034|R|1.Goldberg AS, Tirona RG, Asher LJ, Kim RB, Van Uum SH. Ciprofloxacin and|2
02451|035|R|  rifampin have opposite effects on levothyroxine absorption. Thyroid 2013|2
02451|036|R|  Nov;23(11):1374-8.|2
02451|037|R|2.Cooper JG, Harboe K, Frost SK, Skadberg O. Ciprofloxacin interacts with|3
02451|038|R|  thyroid replacement therapy. BMJ 2005 Apr 30;330(7498):1002.|3
02452|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Imatinib;Sunitinib|
02452|002|B||
02452|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02452|004|L|take action as needed.|
02452|005|B||
02452|006|A|MECHANISM OF ACTION:  The suspected mechanism responsible for this|
02452|007|A|phenomenon is an induction of non-deiodination clearance.  The induction of|
02452|008|A|uridine diphosphate-glucuronyl transferases (UGTs) by imatinib and sunitinib|
02452|009|A|decreases levels of the thyroid preparations.(1)|
02452|010|B||
02452|011|E|CLINICAL EFFECTS:  The coadministration of thyroid preparations and imatinib|
02452|012|E|and sunitinib may result in decreased levels and clinical effects of thyroid|
02452|013|E|hormones.(1-3)|
02452|014|B||
02452|015|P|PREDISPOSING FACTORS:  None determined.|
02452|016|B||
02452|017|M|PATIENT MANAGEMENT:  Patients taking thyroid preparations and imatinib or|
02452|018|M|sunitinib should be monitored for changes in thyroid function.  The dosage|
02452|019|M|of the thyroid preparation may need to be increased.(1-3)|
02452|020|B||
02452|021|D|DISCUSSION:  In a case report, 8 patients had undergone thyroidectomy and|
02452|022|D|used levothyroxine and imatinib. These patients had an increase need for|
02452|023|D|levothyroxine levels and were monitored for elevations in thyrotropin|
02452|024|D|indicating worsening hypothyroidism.(2)|
02452|025|D|   A case report of a 73 year old man who was treated with imatinib and|
02452|026|D|levothyroxine developed worsening hypothyroidism.  An increase in|
02452|027|D|levothyroxine dosage was needed.(3)|
02452|028|D|   In a case report, a 59 year old woman was taking levothyroxine therapy|
02452|029|D|for hypothyroidism secondary to subtotal thyroidectomy and was recently|
02452|030|D|started on imatinib for chronic myeloid leukemia.  The patient developed|
02452|031|D|clinical signs of hypothyroidism and required an increased dose of|
02452|032|D|levothyroxine.(4)|
02452|033|D|   In a case report, a 73 year old woman was taking levothyroxine and|
02452|034|D|developed  fatigue, nausea, cold-intolerance, hair-loss, brittle nails,|
02452|035|D|progressive weakness, and impressive facial oedema 6 months after starting|
02452|036|D|imatinib.  The patient levothyroxine was increased and she remained|
02452|037|D|euthyroid, but the imatinib was discontinued due to extreme fatigue and|
02452|038|D|periorbital oedema.  Five months later the patient was stared on sunitinib|
02452|039|D|and her levothyroxine dose was increased.  The patient developed similar|
02452|040|D|symptoms to imatinib reaction.(5)|
02452|041|D|   In a case report, a patient receiving sunitinib for metastatic papillary|
02452|042|D|renal cell cancer developed high thyroid stimulating hormone levels and|
02452|043|D|severe symptoms despite receiving L-thyroxine.(6)|
02452|044|B||
02452|045|R|REFERENCES:|
02452|046|B||
02452|047|R|1.Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA.|6
02452|048|R|  Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib,|6
02452|049|R|  and nilotinib. Blood 2011 Feb 24;117(8):e75-87.|6
02452|050|R|2.de Groot JW, Zonnenberg BA, Plukker JT, van Der Graaf WT, Links TP.|3
02452|051|R|  Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin|3
02452|052|R|  Pharmacol Ther 2005 Oct;78(4):433-8.|3
02452|053|R|3.Cholongitas E, Pipili C, Katsogridakis K, Relos K, Dasenaki M. Dermatitis|3
02452|054|R|  after suspected imatinib-levothyroxine interaction in a patient with|3
02452|055|R|  gastrointestinal stromal tumor. Cancer Chemother Pharmacol 2008 May;|3
02452|056|R|  61(6):1083-4.|3
02452|057|R|4.de Diego Garcia P, Trincado Aznar P, Playan Uson J, Albero Gamboa R.|3
02452|058|R|  Levothyroxine therapy and imatinib. Endocrinol Nutr 2008 Aug;55(7):304-7.|3
02452|059|R|5.de Groot JW, Links TP, van der Graaf WT. Tyrosine kinase inhibitors|3
02452|060|R|  causing hypothyroidism in a patient on levothyroxine. Ann Oncol 2006 Nov;|3
02452|061|R|  17(11):1719-20.|3
02452|062|R|6.Del Fabbro E, Dev R, Cabanillas ME, Busaidy NL, Rodriguez EC, Bruera E.|3
02452|063|R|  Extreme hypothyroidism associated with sunitinib treatment for metastatic|3
02452|064|R|  renal cancer. J Chemother 2012 Aug;24(4):221-5.|3
02454|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Rifampin|
02454|002|B||
02454|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02454|004|L|take action as needed.|
02454|005|B||
02454|006|A|MECHANISM OF ACTION:  Rifampin is an organic anion transporting polypeptide|
02454|007|A|(OATP) inhibitor and has been found to decrease measured free T4 when taking|
02454|008|A|thyroid replacements.  The mechanism for the rifampin effect may be due to|
02454|009|A|induction of hepatic metabolic and biliary clearance.  It is also possible|
02454|010|A|that rifampin may have increased net intestinal absorption of L-T4 through|
02454|011|A|inhibition of P-glycoprotein, an intestinal efflux transporter.|
02454|012|B||
02454|013|E|CLINICAL EFFECTS:  The concurrent or recent use of rifampin may result in|
02454|014|E|altered levels and clinical effects of thyroid hormones.  Some patients may|
02454|015|E|experience increased thyroid hormone effects, while others may experience|
02454|016|E|decreased effects.(1)|
02454|017|B||
02454|018|P|PREDISPOSING FACTORS:  None determined.|
02454|019|B||
02454|020|M|PATIENT MANAGEMENT:  Patients taking thyroid preparations and rifampin|
02454|021|M|should be monitored for changes in thyroid function. Symptoms of|
02454|022|M|hyperthyroidism  include weight loss, rapid heartbeat, nervousness,|
02454|023|M|sweating, tremor, fatigue, and difficulty sleeping.  Symptoms of|
02454|024|M|hypothyroidism include fatigue, sluggishness, constipation, stiffness,|
02454|025|M|muscle cramps, loss of appetite, excessive weight gain, or dry skin.  The|
02454|026|M|dosage of levothyroxine may need to be adjusted accordingly.|
02454|027|B||
02454|028|D|DISCUSSION:  In a study, 8 healthy individuals received 100 mcg of|
02454|029|D|levothyroxine combined with placebo or rifampin 600 mg.  The|
02454|030|D|coadministration of rifampin significantly increased the 4 AUC by 25%|
02454|031|D|(p=0.003). Levothyroxine absorptions with rifampin was 125% compared to|
02454|032|D|controls.(1)|
02454|033|D|   In contrast to this study, two case reports exist documenting decreased|
02454|034|D|effects of levothyroxine during concurrent rifampin.  In a case report, a 31|
02454|035|D|year old woman had a total thyroidectomy and was receiving levothyroxine and|
02454|036|D|was recently started on rifampin. The patient did not develop symptoms of|
02454|037|D|hypothyroidism, but had a decrease in serum thyroxine levels and free|
02454|038|D|thyroxine index during rifampin therapy and an increase in serum thyrotropin|
02454|039|D|levels.(2)  In a case report of a 50 year old male, stable on levothyroxine,|
02454|040|D|who exhibited significantly elevated TSH levels during therapy with|
02454|041|D|rifampin.  The patient's TSH levels returned to baseline 9 days after|
02454|042|D|discontinuing rifampin.(3)|
02454|043|B||
02454|044|R|REFERENCES:|
02454|045|B||
02454|046|R|1.Goldberg AS, Tirona RG, Asher LJ, Kim RB, Van Uum SH. Ciprofloxacin and|2
02454|047|R|  rifampin have opposite effects on levothyroxine absorption. Thyroid 2013|2
02454|048|R|  Nov;23(11):1374-8.|2
02454|049|R|2.Isley WL. Effect of rifampin therapy on thyroid function tests in a|3
02454|050|R|  hypothyroid patient on  replacement L-thyroxine. Ann Intern Med 1987 Oct;|3
02454|051|R|  107(4):517-8.|3
02454|052|R|3.Nolan SR, Self TH, Norwood JM. Interaction between rifampin and|3
02454|053|R|  levothyroxine. South Med J 1999 May;92(5):529-31.|3
02455|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Soybean Infant Formula; Nutritional|
02455|002|T|Therapy|
02455|003|B||
02455|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02455|005|L|take action as needed.|
02455|006|B||
02455|007|A|MECHANISM OF ACTION:  Soy-based formula and nutritional therapy may bind to|
02455|008|A|thyroid preparations, decreasing their absorption.(1-3)  Also, many products|
02455|009|A|may contain iron, which may also bind to thyroid preparations.(1)|
02455|010|B||
02455|011|E|CLINICAL EFFECTS:  Concurrent use of soy-based formula or nutritional|
02455|012|E|therapy may result in increased TSH levels.(1-3)|
02455|013|B||
02455|014|P|PREDISPOSING FACTORS:  None determined.|
02455|015|B||
02455|016|M|PATIENT MANAGEMENT:  Patients receiving soy-based formula or nutritional|
02455|017|M|therapy should be closely monitored for elevated TSH levels.  The dosage of|
02455|018|M|the thyroid preparation may need to increase during the use of soy-based|
02455|019|M|products.(1-3)|
02455|020|B||
02455|021|D|DISCUSSION:  In a retrospective comparison of 78 infants with congenital|
02455|022|D|hypothyroidism, 8 infants fed a soy-based formula had prolonged increase of|
02455|023|D|TSH and time to TSH normalization, higher first TSH on treatment, and there|
02455|024|D|was a larger percentage with increased TSH at 4 months of age when compared|
02455|025|D|to 70 infants on a non-soy diet.(2)|
02455|026|D|   In a case report of 3 infants with congenital hypothyroidism, infants|
02455|027|D|required 18-25% higher dosages of levothyroxine while receiving soy-based|
02455|028|D|formulas.(3)|
02455|029|D|   In a case report, the administration of levothyroxine concurrently with a|
02455|030|D|soy protein dietary supplement resulted in decreased absorption of|
02455|031|D|levothyroxine and the need for higher oral doses of levothyroxine to attain|
02455|032|D|therapeutic serum thyroid hormone levels.(4)|
02455|033|B||
02455|034|R|REFERENCES:|
02455|035|B||
02455|036|R|1.Synthroid (levothyroxine sodium) US prescribing information. Abbott|1
02455|037|R|  Laboratories February, 2024.|1
02455|038|R|2.Conrad SC, Chiu H, Silverman BL. Soy formula complicates management of|2
02455|039|R|  congenital hypothyroidism. Arch Dis Child 2004 Jan;89(1):37-40.|2
02455|040|R|3.Jabbar MA, Larrea J, Shaw RA. Abnormal thyroid function tests in infants|3
02455|041|R|  with congenital hypothyroidism: the influence of soy-based formula. J Am|3
02455|042|R|  Coll Nutr 1997 Jun;16(3):280-2.|3
02455|043|R|4.Bell DS, Ovalle F. Use of soy protein supplement and resultant need for|3
02455|044|R|  increased dose of levothyroxine. Endocr Pract 2001 May-Jun;7(3):193-4.|3
02456|001|T|MONOGRAPH TITLE:  Anagrelide/QT Prolonging Agents|
02456|002|B||
02456|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02456|004|L|is contraindicated and generally should not be dispensed or administered to|
02456|005|L|the same patient.|
02456|006|B||
02456|007|A|MECHANISM OF ACTION:  Concurrent use of anagrelide with agents that prolong|
02456|008|A|the QTc interval may result in additive effects on the QTc interval.(1-4)|
02456|009|B||
02456|010|E|CLINICAL EFFECTS:  The concurrent use of anagrelide with agents that prolong|
02456|011|E|the QTc interval may result in potentially life-threatening cardiac|
02456|012|E|arrhythmias, including torsades de pointes.(1-4)|
02456|013|B||
02456|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02456|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02456|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02456|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02456|018|P|female gender, or advanced age.(5)|
02456|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02456|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02456|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02456|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02456|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02456|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02456|025|P|dysfunction).(5)|
02456|026|B||
02456|027|M|PATIENT MANAGEMENT:  The US manufacturer of anagrelide states that|
02456|028|M|anagrelide should not be used in patients taking medications known to|
02456|029|M|prolong the QT interval.(1)|
02456|030|M|   The Australian, Canadian, and UK manufacturers of anagrelide state use of|
02456|031|M|anagrelide should be approached with caution in patients taking medications|
02456|032|M|that can prolong the QTc interval.(2-4)|
02456|033|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02456|034|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02456|035|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02456|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02456|037|B||
02456|038|D|DISCUSSION:  In a thorough QT study, dose-related QT changes were observed|
02456|039|D|with anagrelide.  The maximum mean change in QTcI (95% CI) in comparison to|
02456|040|D|placebo was 7.0 (9.8) ms and 13.0 (15.7) msec following doses of 0.5 mg and|
02456|041|D|2.5mg, respectively.(1)|
02456|042|D|   Agents that are linked to this monograph may have varying degrees of|
02456|043|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02456|044|D|been shown to prolong the QTc interval either through their mechanism of|
02456|045|D|action, through studies on their effects on the QTc interval, or through|
02456|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02456|047|D|and/or postmarketing reports.(6)|
02456|048|D|   One or more of the drug pairs linked to this monograph have been included|
02456|049|D|in a list of interactions that should be considered "high-priority" for|
02456|050|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02456|051|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02456|052|D|Coordinator (ONC) for Health Information Technology.|
02456|053|B||
02456|054|R|REFERENCES:|
02456|055|B||
02456|056|R|1.Agrylin (anagrelide hydrochloride) US prescribing information. Shire US|1
02456|057|R|  Inc. October, 2021.|1
02456|058|R|2.Agrylin (anagrelide) Australian Product Information. Takeda|1
02456|059|R|  Pharmaceuticals Australia Ptg Ltd. September, 2022.|1
02456|060|R|3.Agrylin (anagrelide) Canadian Product Monograph. Takeda Canada Inc.|1
02456|061|R|  February, 2023.|1
02456|062|R|4.Anagrelide UK summary of product characteristics. Kent Pharmaceuticals|1
02456|063|R|  Limited November, 2024.|1
02456|064|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02456|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02456|066|R|  settings: a scientific statement from the American Heart Association and|6
02456|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02456|068|R|  2;55(9):934-47.|6
02456|069|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
02456|070|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02456|071|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02456|072|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02456|073|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02456|074|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02456|075|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02456|076|R|  19(5):735-43.|6
02457|001|T|MONOGRAPH TITLE:  Anagrelide/Possible QT Prolonging Agents|
02457|002|B||
02457|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02457|004|L|of severe adverse interaction.|
02457|005|B||
02457|006|A|MECHANISM OF ACTION:  Concurrent use of anagrelide with agents that prolong|
02457|007|A|the QTc interval may result in additive effects on the QTc interval.(1-4)|
02457|008|B||
02457|009|E|CLINICAL EFFECTS:  The concurrent use of anagrelide with agents that prolong|
02457|010|E|the QTc interval may result in potentially life-threatening cardiac|
02457|011|E|arrhythmias, including torsades de pointes.(1-4)|
02457|012|B||
02457|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02457|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02457|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02457|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02457|017|P|female gender, or advanced age.(5)|
02457|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02457|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02457|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02457|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02457|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02457|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02457|024|P|dysfunction).(5)|
02457|025|B||
02457|026|M|PATIENT MANAGEMENT:  The US manufacturer of anagrelide states that|
02457|027|M|anagrelide should not be used in patients taking medications known to|
02457|028|M|prolong the QT interval.(1)|
02457|029|M|   The Australian, Canadian, and UK manufacturers of anagrelide state use of|
02457|030|M|anagrelide should be approached with caution in patients taking medications|
02457|031|M|that can prolong the QTc interval.(2-4)|
02457|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02457|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02457|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02457|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02457|036|B||
02457|037|D|DISCUSSION:  In a thorough QT study, dose-related QT changes were observed|
02457|038|D|with anagrelide.  The maximum mean change in QTcI (95% CI) in comparison to|
02457|039|D|placebo was 7.0 (9.8) ms and 13.0 (15.7) msec following doses of 0.5 mg and|
02457|040|D|2.5mg, respectively.(1)|
02457|041|D|   Agents that are linked to this monograph may have varying degrees of|
02457|042|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02457|043|D|been shown to prolong the QTc interval either through their mechanism of|
02457|044|D|action, through studies on their effects on the QTc interval, or through|
02457|045|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02457|046|D|and/or postmarketing reports.(6)|
02457|047|D|   One or more of the drug pairs linked to this monograph have been included|
02457|048|D|in a list of interactions that should be considered "high-priority" for|
02457|049|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02457|050|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02457|051|D|Coordinator (ONC) for Health Information Technology.|
02457|052|B||
02457|053|R|REFERENCES:|
02457|054|B||
02457|055|R|1.Agrylin (anagrelide hydrochloride) US prescribing information. Shire US|1
02457|056|R|  Inc. October, 2021.|1
02457|057|R|2.Agrylin (anagrelide) Australian Product Information. Takeda|1
02457|058|R|  Pharmaceuticals Australia Ptg Ltd. September, 2022.|1
02457|059|R|3.Agrylin (anagrelide) Canadian Product Monograph. Takeda Canada Inc.|1
02457|060|R|  February, 2023.|1
02457|061|R|4.Anagrelide UK summary of product characteristics. Kent Pharmaceuticals|1
02457|062|R|  Limited November, 2024.|1
02457|063|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02457|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02457|065|R|  settings: a scientific statement from the American Heart Association and|6
02457|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02457|067|R|  2;55(9):934-47.|6
02457|068|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
02457|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02457|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02457|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02457|072|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02457|073|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02457|074|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02457|075|R|  19(5):735-43.|6
02458|001|T|MONOGRAPH TITLE:  Trazodone (Greater Than or Equal To 100 mg)/QT Prolonging|
02458|002|T|Agents|
02458|003|B||
02458|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02458|005|L|of severe adverse interaction.|
02458|006|B||
02458|007|A|MECHANISM OF ACTION:  Concurrent use of trazodone with other agents that|
02458|008|A|prolong the QTc interval may result in additive effects on the QTc|
02458|009|A|interval.(1,2)|
02458|010|B||
02458|011|E|CLINICAL EFFECTS:  The use of trazodone in patients maintained on agents|
02458|012|E|that prolong the QTc interval may result in potentially life-threatening|
02458|013|E|cardiac arrhythmias, including torsades de pointes.(1,2)|
02458|014|B||
02458|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02458|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02458|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02458|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02458|019|P|female gender, or advanced age.(2)|
02458|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02458|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02458|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02458|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02458|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02458|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02458|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02458|027|B||
02458|028|M|PATIENT MANAGEMENT:  The US manufacturer of trazodone states that concurrent|
02458|029|M|use with agents known to prolong the QT interval should be avoided.(1)|
02458|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02458|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02458|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02458|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02458|034|B||
02458|035|D|DISCUSSION:  Trazodone has been reported to prolong the QT interval.(1)|
02458|036|D|   A thorough QT study in 20 subjects evaluated the effects of trazodone at|
02458|037|D|doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation|
02458|038|D|at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI|
02458|039|D|3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that|
02458|040|D|exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval|
02458|041|D|by more than 5 ms. The study found a dose-dependent effect on QTc|
02458|042|D|prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI|
02458|043|D|11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of|
02458|044|D|19.8 ms (95% CI 17.6-22.1).(3)|
02458|045|D|   Agents that are linked to this monograph may have varying degrees of|
02458|046|D|potential to prolong the QTc interval but are generally accepted to have a|
02458|047|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02458|048|D|been shown to prolong the QTc interval either through their mechanism of|
02458|049|D|action, through studies on their effects on the QTc interval, or through|
02458|050|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02458|051|D|and/or post-marketing reports.(4)|
02458|052|B||
02458|053|R|REFERENCES:|
02458|054|B||
02458|055|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
02458|056|R|  Labopharm Inc. November, 2012.|1
02458|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02458|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02458|059|R|  settings: a scientific statement from the American Heart Association and|6
02458|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02458|061|R|  2;55(9):934-47.|6
02458|062|R|3.Tellone V, Rosignoli MT, Picollo R, Dragone P, Del Vecchio A, Comandini A,|2
02458|063|R|  Radicioni M, Leuratti C, Calisti F. Effect of 3 Single Doses of Trazodone|2
02458|064|R|  on QTc Interval in Healthy Subjects..|2
02458|065|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
02458|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02458|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02458|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02459|001|T|MONOGRAPH TITLE:  Trazodone (Greater Than or Equal To 100 mg)/Possible QT|
02459|002|T|Prolonging Agents|
02459|003|B||
02459|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02459|005|L|take action as needed.|
02459|006|B||
02459|007|A|MECHANISM OF ACTION:  Concurrent use of trazodone with other agents that|
02459|008|A|prolong the QTc interval may result in additive effects on the QTc|
02459|009|A|interval.(1,2)|
02459|010|B||
02459|011|E|CLINICAL EFFECTS:  The use of trazodone in patients maintained on agents|
02459|012|E|that prolong the QTc interval may result in potentially life-threatening|
02459|013|E|cardiac arrhythmias, including torsades de pointes.(1,2)|
02459|014|B||
02459|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02459|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02459|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02459|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02459|019|P|female gender, or advanced age.(2)|
02459|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02459|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02459|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02459|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02459|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02459|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02459|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02459|027|B||
02459|028|M|PATIENT MANAGEMENT:  The US manufacturer of trazodone states that concurrent|
02459|029|M|use with agents known to prolong the QT interval should be avoided.(1)|
02459|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02459|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02459|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02459|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02459|034|B||
02459|035|D|DISCUSSION:  Trazodone has been reported to prolong the QT interval.(1)|
02459|036|D|   A thorough QT study in 20 subjects evaluated the effects of trazodone at|
02459|037|D|doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation|
02459|038|D|at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI|
02459|039|D|3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that|
02459|040|D|exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval|
02459|041|D|by more than 5 ms. The study found a dose-dependent effect on QTc|
02459|042|D|prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI|
02459|043|D|11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of|
02459|044|D|19.8 ms (95% CI 17.6-22.1).(3)|
02459|045|D|   Agents that are linked to this monograph may have varying degrees of|
02459|046|D|potential to prolong the QTc interval but are generally accepted to have a|
02459|047|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02459|048|D|been shown to prolong the QTc interval either through their mechanism of|
02459|049|D|action, through studies on their effects on the QTc interval, or through|
02459|050|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02459|051|D|and/or post-marketing reports.(4)|
02459|052|B||
02459|053|R|REFERENCES:|
02459|054|B||
02459|055|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
02459|056|R|  Labopharm Inc. November, 2012.|1
02459|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02459|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02459|059|R|  settings: a scientific statement from the American Heart Association and|6
02459|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02459|061|R|  2;55(9):934-47.|6
02459|062|R|3.Tellone V, Rosignoli MT, Picollo R, Dragone P, Del Vecchio A, Comandini A,|2
02459|063|R|  Radicioni M, Leuratti C, Calisti F. Effect of 3 Single Doses of Trazodone|2
02459|064|R|  on QTc Interval in Healthy Subjects..|2
02459|065|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
02459|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02459|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02459|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02460|001|T|MONOGRAPH TITLE:  Sevoflurane/QT Prolonging Agents|
02460|002|B||
02460|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02460|004|L|take action as needed.|
02460|005|B||
02460|006|A|MECHANISM OF ACTION:  Concurrent use of multiple agents that prolong the QTc|
02460|007|A|interval may result in additive effects on the QTc interval.(1)|
02460|008|B||
02460|009|E|CLINICAL EFFECTS:  The concurrent use of multiple agents that prolong the|
02460|010|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
02460|011|E|including torsades de pointes.(1)|
02460|012|B||
02460|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02460|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02460|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02460|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02460|017|P|gender, or advanced age.(1)|
02460|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02460|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02460|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02460|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02460|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02460|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02460|024|P|dysfunction).(1)|
02460|025|B||
02460|026|M|PATIENT MANAGEMENT:  Sevoflurane should be used with caution in patients|
02460|027|M|taking agents known to prolong the QT interval.(2)|
02460|028|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02460|029|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02460|030|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02460|031|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02460|032|B||
02460|033|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02460|034|D|degrees of potential to prolong the QTc interval but are generally accepted|
02460|035|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02460|036|D|monograph have been shown to prolong the QTc interval either through their|
02460|037|D|mechanism of action, through studies on their effects on the QTc interval,|
02460|038|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02460|039|D|clinical trials and/or post-marketing reports.(3)|
02460|040|D|   One or more of the drug pairs linked to this monograph have been included|
02460|041|D|in a list of interactions that should be considered "high-priority" for|
02460|042|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02460|043|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02460|044|D|Coordinator (ONC) for Health Information Technology.|
02460|045|B||
02460|046|R|REFERENCES:|
02460|047|B||
02460|048|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02460|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02460|050|R|  settings: a scientific statement from the American Heart Association and|6
02460|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02460|052|R|  2;55(9):934-47.|6
02460|053|R|2.Ultane (sevoflurane) US prescribing information. AbbVie, Inc. February,|1
02460|054|R|  2014.|1
02460|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02460|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02460|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02460|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02460|059|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02460|060|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02460|061|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02460|062|R|  19(5):735-43.|6
02461|001|T|MONOGRAPH TITLE:  Ceritinib/Possible QT Prolonging Agents|
02461|002|B||
02461|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02461|004|L|take action as needed.|
02461|005|B||
02461|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02461|007|A|interval may result in additive effects on the QTc interval.(1)|
02461|008|B||
02461|009|E|CLINICAL EFFECTS:  The use of ceritinib in patients maintained on agents|
02461|010|E|that prolong the QTc interval may result in potentially life-threatening|
02461|011|E|cardiac arrhythmias, including torsades de pointes.(1)|
02461|012|B||
02461|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02461|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02461|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02461|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02461|017|P|female gender, or advanced age.(2)|
02461|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02461|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02461|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02461|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02461|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02461|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02461|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02461|025|P|   Patients with severe hepatic impairment (Child-Pugh C) may be at|
02461|026|P|increased risk of this interaction.  Ceritinib dose reduction may be|
02461|027|P|warranted in severe hepatic impairment.  See prescribing information for|
02461|028|P|recommendations.(1)|
02461|029|B||
02461|030|M|PATIENT MANAGEMENT:  When possible, avoid coadministration of ceritinib with|
02461|031|M|other QT prolonging agents.  Consider obtaining electrocardiogram (ECG) and|
02461|032|M|serum calcium, magnesium, and potassium levels at baseline and regular|
02461|033|M|intervals in patients receiving concurrent therapy with ceritinib and|
02461|034|M|another agent that may prolong the QTc interval.(1)|
02461|035|M|   In patients who develop a QTc interval greater than 500 msec on at least|
02461|036|M|2 occasions, withhold ceritinib until the QTc interval is less than 481 msec|
02461|037|M|or recovery to baseline if baseline QTc was greater than or equal to 481|
02461|038|M|msec, then resume ceritinib with a 150 mg dose reduction.  If the patient|
02461|039|M|develops QTc interval prolongation in combination with torsades de pointes|
02461|040|M|or polymorphic ventricular tachycardia or signs/symptoms of serious|
02461|041|M|arrhythmia, permanently discontinue ceritinib.(1)|
02461|042|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02461|043|M|fainting.|
02461|044|B||
02461|045|D|DISCUSSION:  In a clinical trial 3% of patients experienced a QTc interval|
02461|046|D|increase over baseline greater than 60 msec.  Less than 1% of patients (1 of|
02461|047|D|304) treated with ceritinib was found to have a QTc greater than 500 msec.|
02461|048|D|The upper limit of the 90% confidence interval for mean QTC increase was 16|
02461|049|D|msec at ceritinib 750 mg.   Data suggested that ceritinib produces|
02461|050|D|concentration-dependent QTc interval prolongation.(1)|
02461|051|D|   Agents that are linked to this monograph may have varying degrees of|
02461|052|D|potential to prolong the QTc interval but are generally accepted to have a|
02461|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02461|054|D|been shown to prolong the QTc interval either through their mechanism of|
02461|055|D|action, through studies on their effects on the QTc interval, or through|
02461|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02461|057|D|and/or post-marketing reports.(3)|
02461|058|B||
02461|059|R|REFERENCES:|
02461|060|B||
02461|061|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
02461|062|R|  Corporation August, 2021.|1
02461|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02461|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02461|065|R|  settings: a scientific statement from the American Heart Association and|6
02461|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02461|067|R|  2;55(9):934-47.|6
02461|068|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02461|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02461|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02461|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02462|001|T|MONOGRAPH TITLE:  Vorapaxar/Strong CYP3A4 Inducers (mono deleted 01/29/2015)|
02462|002|B||
02462|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02462|004|L|of severe adverse interaction.|
02462|005|B||
02462|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
02462|007|A|vorapaxar.(1)|
02462|008|B||
02462|009|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 may result in|
02462|010|E|decreased levels and efficacy of vorapaxar.(1)|
02462|011|B||
02462|012|P|PREDISPOSING FACTORS:  None determined.|
02462|013|B||
02462|014|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers and|
02462|015|M|vorapaxar.(1)|
02462|016|B||
02462|017|D|DISCUSSION:  In a study in 12 healthy subjects, rifampin (600 mg daily for|
02462|018|D|28 days) decreased the exposure of vorapaxar (20 mg on Day 7, 2.5 mg on Days|
02462|019|D|8-28) by 50%.(1,2)|
02462|020|D|   Strong inducers of CYP3A4 include carbamazepine, enzalutamide, mitotane,|
02462|021|D|phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(3,4)|
02462|022|B||
02462|023|R|REFERENCES:|
02462|024|B||
02462|025|R|1.Zontivity (vorapaxar) US prescribing information. Merck & Co., Inc.|1
02462|026|R|  November, 2019.|1
02462|027|R|2.This information is based on an extract from the Certara Drug Interaction|6
02462|028|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02462|029|R|3.Kosoglou T, Statkevich P, Kumar B, Xuan F, Schiller JE, Johnson-Levonas|2
02462|030|R|  AO, Young S, Cutler DL. The effect of multiple doses of ketoconazole or|2
02462|031|R|  rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar. J|2
02462|032|R|  Clin Pharmacol 2013 May;53(5):540-9.|2
02462|033|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02462|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02462|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02462|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02462|037|R|  11/14/2017.|1
02463|001|T|MONOGRAPH TITLE:  Vorapaxar/Strong CYP3A4 Inhibitors; Protease Inhibitors|
02463|002|B||
02463|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02463|004|L|of severe adverse interaction.|
02463|005|B||
02463|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
02463|007|A|vorapaxar.(1-3)|
02463|008|B||
02463|009|E|CLINICAL EFFECTS:  Concurrent use of an agent that is a strong inhibitor of|
02463|010|E|CYP3A4 or a protease inhibitor may result in elevated levels of and clinical|
02463|011|E|effects of vorapaxar,(1) including an increased risk of bleeding.|
02463|012|B||
02463|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02463|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02463|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
02463|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02463|017|P|risk for bleeding (e.g. NSAIDs).|
02463|018|B||
02463|019|M|PATIENT MANAGEMENT:  The US manufacturer of vorapaxar states that concurrent|
02463|020|M|use with strong inhibitors of CYP3A4 should be avoided.(1)|
02463|021|M|   The US Department of Health and Human Services HIV guidelines state that|
02463|022|M|protease inhibitors should not be coadministered with vorapaxar.(4)|
02463|023|M|   The US manufacturer of itraconazole states that concurrent use with|
02463|024|M|vorapaxar is not recommended during and two weeks after itraconazole|
02463|025|M|treatment.(5)|
02463|026|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02463|027|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02463|028|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02463|029|M|patients with any symptoms.|
02463|030|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02463|031|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02463|032|M|anticoagulation in patients with active pathologic bleeding.|
02463|033|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02463|034|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02463|035|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02463|036|M|and/or swelling.|
02463|037|B||
02463|038|D|DISCUSSION:  In a study in 12 healthy subjects, ketoconazole (400 mg daily|
02463|039|D|for 28 days) increased exposure to vorapaxar (20 mg on Day 7, 2.5 mg on Days|
02463|040|D|8-28) by 2-fold.(1,2)|
02463|041|D|   Strong inhibitors of CYP3A4 and protease inhibitor linked to this|
02463|042|D|monograph include:  adagrasib, atazanavir, ceritinib, clarithromycin,|
02463|043|D|cobicistat, darunavir, fosamprenavir, idelalisib, indinavir, itraconazole,|
02463|044|D|josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
02463|045|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
02463|046|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib,|
02463|047|D|and voriconazole.(6)|
02463|048|B||
02463|049|R|REFERENCES:|
02463|050|B||
02463|051|R|1.Zontivity (vorapaxar) US prescribing information. Merck & Co., Inc.|1
02463|052|R|  November, 2019.|1
02463|053|R|2.Kosoglou T, Statkevich P, Kumar B, Xuan F, Schiller JE, Johnson-Levonas|2
02463|054|R|  AO, Young S, Cutler DL. The effect of multiple doses of ketoconazole or|2
02463|055|R|  rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar. J|2
02463|056|R|  Clin Pharmacol 2013 May;53(5):540-9.|2
02463|057|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02463|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02463|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02463|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02463|061|R|  11/14/2017.|1
02463|062|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02463|063|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02463|064|R|  HIV. Department of Health and Human Services. Available at:|6
02463|065|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
02463|066|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
02463|067|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02463|068|R|  Products, L.P. February, 2024.|1
02463|069|R|6.This information is based on an extract from the Certara Drug Interaction|6
02463|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02464|001|T|MONOGRAPH TITLE:  Vedolizumab/Tumor Necrosis Factor (TNF) Inhibitors|
02464|002|B||
02464|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02464|004|L|of severe adverse interaction.|
02464|005|B||
02464|006|A|MECHANISM OF ACTION:  Possibly additive or synergistic effects on the immune|
02464|007|A|system.|
02464|008|B||
02464|009|E|CLINICAL EFFECTS:  Concurrent use of vedolizumab and a tumor necrosis factor|
02464|010|E|(TNF) inhibitor may increase the risk of severe infections.(1)|
02464|011|B||
02464|012|P|PREDISPOSING FACTORS:  None determined.|
02464|013|B||
02464|014|M|PATIENT MANAGEMENT:  The US manufacturer of vedolizumab states that|
02464|015|M|concurrent use of vedolizumab with tumor necrosis factor (TNF) blocking|
02464|016|M|agents should be avoided.(1)|
02464|017|B||
02464|018|D|DISCUSSION:  Patients receiving or who had received a TNF inhibitor in the|
02464|019|D|past 60 days were excluded from clinical trials for vedolizumab.(1)|
02464|020|B||
02464|021|R|REFERENCE:|
02464|022|B||
02464|023|R|1.Entyvio (vedolizumab) US prescribing information. Takeda Pharmaceuticals|1
02464|024|R|  America, Inc. March, 2024.|1
02465|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Moderate CYP3A4 Inhibitors|
02465|002|B||
02465|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02465|004|L|of severe adverse interaction.|
02465|005|B||
02465|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
02465|007|A|of ergot alkaloids.|
02465|008|B||
02465|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
02465|010|E|in increased levels of the ergot alkaloid, which may result in clinical|
02465|011|E|signs of ergotism, including vasospasm, dysesthesia, renal ischemia, and|
02465|012|E|peripheral ischemia.|
02465|013|B||
02465|014|P|PREDISPOSING FACTORS:  Patients receiving the maximum recommended (or higher|
02465|015|P|than recommended) dosages of ergot alkaloids may be at a higher risk of|
02465|016|P|adverse effects from this combination.|
02465|017|B||
02465|018|M|PATIENT MANAGEMENT:  When possible, avoid the concurrent use of moderate|
02465|019|M|CYP3A4 inhibitors in patients taking ergot alkaloids.  If concurrent use is|
02465|020|M|warranted, consider reducing the dose of the ergot alkaloid during|
02465|021|M|concurrent therapy.  Patients receiving concurrent therapy should be|
02465|022|M|monitored for and instructed to report any signs of ergotism.|
02465|023|B||
02465|024|D|DISCUSSION:  Coadministration of dihydroergotamine and ergotamine with|
02465|025|D|potent inhibitors of CYP3A4 such as clarithromycin, erythromycin, indinavir,|
02465|026|D|nelfinavir, ritonavir, and troleandomycin has resulted in ergotism,|
02465|027|D|characterized by vasospasm and ischemia of the extremities.|
02465|028|D|   Inhibition of ergot alkaloid metabolism by moderate inhibitors would also|
02465|029|D|be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to|
02465|030|D|this monograph are aprepitant, avacopan, berotralstat, clofazimine,|
02465|031|D|conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib,|
02465|032|D|fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium,|
02465|033|D|lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra,|
02465|034|D|sevabertinib, tofisopam, treosulfan and verapamil.|
02465|035|B||
02465|036|R|REFERENCES:|
02465|037|B||
02465|038|R|1.Francis H, Tyndall A, Webb J. Severe vascular spasm due to|3
02465|039|R|  erythromycin-ergotamine interaction. Clin Rheumatol 1984 Jun;3(2):243-6.|3
02465|040|R|2.Collet AM, Moncharmont D, San Marco JL, Eissinger F, Pinot JJ, Laselve L.|3
02465|041|R|  Iatrogenic ergotism. Responsibility of an ergotamine tartrate-|3
02465|042|R|  erythromycine propionate association (author's transl). Sem Hop 1982 Jul|3
02465|043|R|  1;58(26-27):1624-6.|3
02465|044|R|3.Ghali R, De Lean J, Douville Y, Noel HP, Labbe R. Erythromycin-associated|3
02465|045|R|  ergotamine intoxication: arteriographic and electrophysiologic analysis of|3
02465|046|R|  a rare cause of severe ischemia of the lower extremities and associated|3
02465|047|R|  ischemic neuropathy. Ann Vasc Surg 1993 May;7(3):291-6.|3
02465|048|R|4.Chignier E, Riou R, Descotes J, Meunier P, Courpron P, Vignon G. Acute|3
02465|049|R|  iatrogenic ergotism by drug association. Diagnosis through non- invasive|3
02465|050|R|  exploration (Doppler velocimetry (author's transl). Nouv Presse Med 1978|3
02465|051|R|  Aug 26-Sep 2;7(28):2478.|3
02465|052|R|5.Matthews NT, Havill JH. Ergotism with therapeutic doses of ergotamine|3
02465|053|R|  tartrate. N Z Med J 1979 Jun 27;89(638):476-7.|3
02465|054|R|6.Hayton AC. Precipitation of acute ergotism by triacetyloleandomycin. N Z|3
02465|055|R|  Med J 1969 Jan;69(440):42.|3
02465|056|R|7.Bigorie B, Aimez P, Soria RJ, Samama F, di Maria G, Guy-Grand B, Bour H.|3
02465|057|R|  Is triacetyl oleandomycin-ergotamine tartrate combination dangerous?. Nouv|3
02465|058|R|  Presse Med 1975 Nov 8;4(38):2723-5.|3
02465|059|R|8.Monsarrat M, Lefebvre D, Parraguette J, Vaysse C, Bastide G. Acute|3
02465|060|R|  ergotism caused by an ergotamine-oleandomycin combination. Nouv Presse Med|3
02465|061|R|  1982 Feb 20;11(8):603.|3
02465|062|R|9.Horowitz RS, Dart RC, Gomez HF. Clinical ergotism with lingual ischemia|3
02465|063|R|  induced by clarithromycin- ergotamine interaction. Arch Intern Med 1996|3
02465|064|R|  Feb 26;156(4):456-8.|3
02465|065|R|10.Leroy F, Asseman P, Pruvost P, Adnet P, Lacroix D, Thery C.|3
02465|066|R|   Dihydroergotamine-erythromycin-induced ergotism. Ann Intern Med 1988 Aug|3
02465|067|R|   1;109(3):249.|3
02465|068|R|11.Franco A, Bourlard P, Massot C, Lecoeur J, Guidicelli H, Bessard G. Acute|3
02465|069|R|   ergotism caused by dihydroergotamine-triacetyloleandomycin association.|3
02465|070|R|   Nouv Presse Med 1978 Jan 21;7(3):205.|3
02465|071|R|12.Vayssairat M, Fiessinger JN, Bequemin MH, Housset E. Dihydroergotamine|3
02465|072|R|   and triacetyloleandomycin combination. Its role in iatrogenic necrosis of|3
02465|073|R|   the fingers. Nouv Presse Med 1978 Jun 10;7(23):2077.|3
02465|074|R|13.Boucharlat J, Franco A, Carpentier P, Charignon Y, Denis B, Hommel M.|3
02465|075|R|   Ergotism in a psychiatric setting caused by combined dihydroergotamine-|3
02465|076|R|   erythromycin propionate. Apropos of a case. Ann Med Psychol (Paris) 1980|3
02465|077|R|   Mar;138(3):292-6.|3
02465|078|R|14.Neveux E, Lesgourgues B, Luton JP, Guilhaume B, Bertagna, Picard J. Acute|3
02465|079|R|   ergotism caused by the interaction of erythromycin propionate and|3
02465|080|R|   dihydroergotamine. Nouv Presse Med 1981 Sep 26;10(34):2830.|3
02465|081|R|15.Couet W, Mathieu HP, Fourtillan JB. Effect of ponsinomycin on the|2
02465|082|R|   pharmacokinetics of dihydroergotamine administered orally. Fundam Clin|2
02465|083|R|   Pharmacol 1991;5(1):47-52.|2
02465|084|R|16.Rosenthal E, Sala F, Chichmanian RM, Batt M, Cassuto JP. Ergotism related|3
02465|085|R|   to concurrent administration of ergotamine tartrate and indinavir. JAMA|3
02465|086|R|   1999 Mar 17;281(11):987.|3
02465|087|R|17.Mortier E, Pouchot J, Vinceneux P, Lalande M. Ergotism related to|3
02465|088|R|   interaction between nelfinavir and ergotamine. Am J Med 2001 May;|3
02465|089|R|   110(7):594.|3
02465|090|R|18.Montero A, Giovannoni AG, Tvrde PL. Leg ischemia in a patient receiving|3
02465|091|R|   ritonavir and ergotamine. Ann Intern Med 1999 Feb 16;130(4 Pt 1):329-30.|3
02465|092|R|19.Caballero-Granado FJ, Viciana P, Cordero E, Gomez-Vera MJ, del Nozal M,|3
02465|093|R|   Lopez-Cortes LF. Ergotism related to concurrent administration of|3
02465|094|R|   ergotamine tartrate and ritonavir in an AIDS patient. Antimicrob Agents|3
02465|095|R|   Chemother 1997 May;41(5):1207.|3
02465|096|R|20.Blanche P, Rigolet A, Gombert B, Ginsburg C, Salmon D, Sicard D. Ergotism|3
02465|097|R|   related to a single dose of ergotamine tartrate in an AIDS patient|3
02465|098|R|   treated with ritonavir. Postgrad Med J 1999 Sep;75(887):546-7.|3
02465|099|R|21.Liaudet L, Buclin T, Jaccard C, Eckert P. Drug points: severe ergotism|3
02465|100|R|   associated with interaction between ritonavir and ergotamine. BMJ 1999|3
02465|101|R|   Mar 20;318(7186):771.|3
02465|102|R|22.Pardo Rey C, Yebra M, Borrallo M, Vega A, Ramos A, Montero MC.|3
02465|103|R|   Irreversible coma, ergotamine, and ritonavir. Clin Infect Dis 2003 Sep 1;|3
02465|104|R|   37(5):e72-3.|3
02465|105|R|23.Spiegel M, Schmidauer C, Kampfl A, Sarcletti M, Poewe W. Cerebral|3
02465|106|R|   ergotism under treatment with ergotamine and ritonavir. Neurology 2001|3
02465|107|R|   Aug 28;57(4):743-4.|3
02465|108|R|24.Vila A, Mykietiuk A, Bonvehi P, Temporiti E, Uruena A, Herrera F.|3
02465|109|R|   Clinical ergotism induced by ritonavir. Scand J Infect Dis 2001;|3
02465|110|R|   33(10):788-9.|3
02465|111|R|25.Gallo C, de la Fuente B, Garcia-Alcalde ML, Antuna A. Ergotism in a|3
02465|112|R|   patient treated with ritonavir and ergotamine. Med Clin (Barc) 2002 Oct|3
02465|113|R|   26;119(14):558-9.|3
02466|001|T|MONOGRAPH TITLE:  Selected Opioids/Barbiturates; Phenobarbital; Primidone|
02466|002|B||
02466|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02466|004|L|take action as needed.|
02466|005|B||
02466|006|A|MECHANISM OF ACTION:  There are two mechanisms involved in this interaction.|
02466|007|A|   Pharmacokinetic: alfentanil, benzhydrocodone, buprenorphine, fentanyl,|
02466|008|A|hydrocodone, meperidine, oxycodone, and sufentanil are primarily metabolized|
02466|009|A|by CYP3A4/5 and glucuronidation pathways.(1-8)  Phenobarbital is an inducer|
02466|010|A|of these pathways.|
02466|011|A|   Pharmacodynamic: both opioids and barbiturates are associated with|
02466|012|A|respiratory depression; these effects may be additive.(1,3,9)|
02466|013|A|   Benzhydrocodone is a prodrug of hydrocodone.(2)|
02466|014|A|   Primidone is metabolized to phenobarbital.|
02466|015|B||
02466|016|E|CLINICAL EFFECTS:  Short term or intermittent use of phenobarbital and|
02466|017|E|opioids metabolized by CYP3A4 may be associated with respiratory suppression|
02466|018|E|or other CNS depression.|
02466|019|E|   Continuous, longer term use of phenobarbital may result in decreased|
02466|020|E|levels and effectiveness of the opioid.|
02466|021|E|   Induction of meperidine metabolism may result in an increase in levels of|
02466|022|E|normeperidine, the toxic metabolite of meperidine, resulting in a higher|
02466|023|E|risk of excitatory effects, including hallucinations, tremors, and|
02466|024|E|seizures.(6,10)|
02466|025|B||
02466|026|P|PREDISPOSING FACTORS:  Patients with a history of alcohol or sedative abuse|
02466|027|P|may be at risk for relapse and overuse or abuse of prescribed|
02466|028|P|phenobarbital.(1,3,5,11)|
02466|029|P|   Individuals with significant obstructive pulmonary disease, the elderly,|
02466|030|P|and debilitated patients are at greater risk for respiratory depression from|
02466|031|P|either agent.(1,3)|
02466|032|P|   Induction effects may be more likely with regular use of the inducer for|
02466|033|P|longer than 1-2 weeks.|
02466|034|B||
02466|035|M|PATIENT MANAGEMENT:  Patients on chronic therapy with phenobarbital who are|
02466|036|M|newly starting opioids metabolized by CYP3A4 may need higher than usual|
02466|037|M|doses of the opioid for analgesia or opioid maintenance.(1,3,12)|
02466|038|M|   Opioid-treated patients newly started on phenobarbital should be|
02466|039|M|monitored initially for additive CNS sedation or respiratory depression,|
02466|040|M|particularly when predisposing factors (e.g. COPD, sleep apnea,|
02466|041|M|debilitation, elderly) are present.  Continued use of phenobarbital leads to|
02466|042|M|induction of the opioids' metabolism.  The onset is gradual and may not peak|
02466|043|M|for several weeks.  Monitor patient for possible loss of efficacy or opioid|
02466|044|M|withdrawal.|
02466|045|M|   If a patient has been maintained on concurrent treatment with an opioid|
02466|046|M|metabolized by CYP3A4 and phenobarbital, and the phenobarbital is|
02466|047|M|discontinued, opioid levels will gradually rise as induction effects|
02466|048|M|diminish.  Monitor for increased opioid effects and adjust the dose|
02466|049|M|accordingly.(1,3,12)|
02466|050|M|   Respiratory depression can occur at any time during opioid therapy,|
02466|051|M|especially during therapy initiation and following dosage increases.  The|
02466|052|M|risk of opioid-related overdose or overdose-related death is increased with|
02466|053|M|higher opioid doses, and this risk persists over the course of therapy.|
02466|054|M|Consider these risks when using concurrently with other agents that may|
02466|055|M|cause CNS depression.(13)|
02466|056|M|   For patients receiving opioid maintenance treatment, it would be prudent|
02466|057|M|to assure all controlled substance prescriptions are approved or written by|
02466|058|M|the opioid provider.|
02466|059|M|    Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02466|060|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02466|061|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02466|062|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02466|063|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02466|064|M|as those taking CNS depressants) and when a patient has household|
02466|065|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02466|066|M|for obtaining an opioid reversal agent (e.g., prescription,|
02466|067|M|over-the-counter, or as part of a community-based program).(14)|
02466|068|B||
02466|069|D|DISCUSSION:  Alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine,|
02466|070|D|oxycodone, and sufentanil are metabolized by CYP3A4, and barbiturates,|
02466|071|D|phenobarbital, and primidone would be expected to induce their|
02466|072|D|metabolism.(1,2,4-6)|
02466|073|D|   Newer metabolites and minor metabolic pathways for buprenorphine have|
02466|074|D|been recently described.  Phenobarbital, an inducer of multiple enzyme|
02466|075|D|pathways (e.g. CYP2B, CYP2C, CYP3A and UGT) could potentially lower systemic|
02466|076|D|buprenorphine levels via major and minor pathways.(12)|
02466|077|B||
02466|078|R|REFERENCES:|
02466|079|B||
02466|080|R|1.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
02466|081|R|  Inc. October, 2019.|1
02466|082|R|2.Apadaz (benzhydrocodone and acetaminophen) US prescribing information.|1
02466|083|R|  KemPharm, Inc.. December, 2023.|1
02466|084|R|3.Suboxone sublingual tablet (buprenorphine and naloxone) prescribing|1
02466|085|R|  information. Reckitt Benckiser Pharmaceuticals Inc. October, 2019.|1
02466|086|R|4.Butrans (buprenorphine) US prescribing information. Purdue Pharm L.P.|1
02466|087|R|  September, 2018.|1
02466|088|R|5.Zohydro ER (hydrocodone bitarate) US prescribing information. Zogenix Inc.|1
02466|089|R|  October, 2019.|1
02466|090|R|6.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
02466|091|R|  Pharmaceuticals LLC. December, 2023.|1
02466|092|R|7.OxyContin (oxycodone hydrochloride) US prescribing information. Perdue|1
02466|093|R|  Pharma L.P. October, 2021.|1
02466|094|R|8.Dsuvia (sufentanil) sublingual tablet US prescribing information. AcelRx|1
02466|095|R|  Pharmaceuticals, Inc. December, 2023.|1
02466|096|R|9.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
02466|097|R|  Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
02466|098|R|10.Pond SM, Kretschzmar KM. Effect of phenytoin on meperidine clearance and|2
02466|099|R|   normeperidine formation. Clin Pharmacol Ther 1981 Nov;30(5):680-6.|2
02466|100|R|11.Center for Substance Abuse Treatment. Clinical Guidelines for the Use of|6
02466|101|R|   Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement|6
02466|102|R|   Protocol (TIP) Series 40. Substance Abuse and Mental Health Services|6
02466|103|R|   Administration (US) 2004.|6
02466|104|R|12.McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical|6
02466|105|R|   importance among the opioids, methadone and buprenorphine, and other|6
02466|106|R|   frequently prescribed medications: a review. Am J Addict 2010 Jan-Feb;|6
02466|107|R|   19(1):4-16.|6
02466|108|R|13.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02466|109|R|   updates prescribing information for all opioid pain medicines to provide|1
02466|110|R|   additional guidance for safe use. Available at:|1
02466|111|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescr|1
02466|112|R|   ibing-information-all-opioid-pain-medicines-provide-additional-guidance-s|1
02466|113|R|   afe-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02466|114|R|14.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02466|115|R|   recommends health care professionals discuss naloxone with all patients|1
02466|116|R|   when prescribing opioid pain relievers or medicines to treat opioid use|1
02466|117|R|   disorder. Available at:|1
02466|118|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-hea|1
02466|119|R|   lth-care-professionals-discuss-naloxone-all-patients-when-prescribing-opi|1
02466|120|R|   oid-pain July 23, 2020.|1
02467|001|T|MONOGRAPH TITLE:  Theophylline/Marijuana Smoke|
02467|002|B||
02467|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02467|004|L|take action as needed.|
02467|005|B||
02467|006|A|MECHANISM OF ACTION:  Theophylline is primarily metabolized by CYP1A2 with|
02467|007|A|CYP3A4 playing a lesser role in theophylline clearance.(1)  Marijuana, when|
02467|008|A|consumed by smoking, has been shown to induce CYP1A2.(2)|
02467|009|B||
02467|010|E|CLINICAL EFFECTS:  Smoking marijuana may lower serum theophylline|
02467|011|E|concentrations resulting in reduced pharmacologic effects.|
02467|012|B||
02467|013|P|PREDISPOSING FACTORS:  Patients who smoke both marijuana and tobacco may|
02467|014|P|have larger increases in theophylline clearance.(3)|
02467|015|B||
02467|016|M|PATIENT MANAGEMENT:  Monitor serum theophylline concentrations and observe|
02467|017|M|the patient for a change in the therapeutic effects of theophylline if the|
02467|018|M|patient starts, alters, or discontinues marijuana use.|
02467|019|B||
02467|020|D|DISCUSSION:  In a study in chronic marijuana users, users of both marijuana|
02467|021|D|and tobacco, and control subjects, theophylline clearance was 42% higher in|
02467|022|D|marijuana users.  Theophylline clearance was increased 79% in subjects who|
02467|023|D|smoked both marijuana and tobacco.(3)|
02467|024|B||
02467|025|R|REFERENCES:|
02467|026|B||
02467|027|R|1.Levy RH Thummel KE Trager WF. Metabolic Drug Interactions (textbook).|6
02467|028|R|  Metabolic Drug Interactions 2000.|6
02467|029|R|2.Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and|6
02467|030|R|  inducers of human drug metabolizing enzymes: a systematic review. Drug|6
02467|031|R|  Metab Rev 2014 Feb;46(1):86-95.|6
02467|032|R|3.Jusko WJ, Schentag JJ, Clark JH, Gardner M, Yurchak AM. Enhanced|2
02467|033|R|  biotransformation of theophylline in marihuana and tobacco smokers. Clin|2
02467|034|R|  Pharmacol Ther 1978 Oct;24(4):405-10.|2
02468|001|T|MONOGRAPH TITLE:  Belinostat/UGT1A1 Inhibitors|
02468|002|B||
02468|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02468|004|L|of severe adverse interaction.|
02468|005|B||
02468|006|A|MECHANISM OF ACTION:  Inhibitors of UGT1A1 may inhibit the metabolism of|
02468|007|A|belinostat.(1)|
02468|008|B||
02468|009|E|CLINICAL EFFECTS:  Concurrent use of UGT1A1 inhibitor may result in|
02468|010|E|increased exposure to and toxicity from belinostat.  Toxicities from|
02468|011|E|belinostat include thrombocytopenia, neutropenia, anemia, infections,|
02468|012|E|hepatotoxicity, and gastrointestinal toxicity.(1)|
02468|013|B||
02468|014|P|PREDISPOSING FACTORS:  None determined.|
02468|015|B||
02468|016|M|PATIENT MANAGEMENT:  Avoid the use of UGT1A1 inhibitors in patients|
02468|017|M|receiving belinostat.  If concurrent use cannot be avoided, a dose reduction|
02468|018|M|by 25% is recommended as follows:|
02468|019|M|   -If starting dose is 1,000 mg/m2 - reduce dose to 750 mg/m2|
02468|020|M|   -If starting dose is 750 mg/m2 - reduce dose to 562.5 mg/m2|
02468|021|M|   -If starting dose is 500 mg/m2 - interrupt belinostat treatment for the|
02468|022|M|duration of the UGT1A1 inhibitor.  After discontinuation of the UGT1A1|
02468|023|M|inhibitor for 5 half-lives, resume belinostat at the dosage that was taken|
02468|024|M|prior to the UGT1A1 inhibitor.(1)|
02468|025|M|   If concurrent use is required, the dose of belinostat may need to be|
02468|026|M|reduced in response to dose-limiting toxicities.  The manufacturer of|
02468|027|M|belinostat recommends a 25% dose reduction (to 750 mg/m2) in patients who|
02468|028|M|are homozygous for the UGT1A1*28 allele.(1)|
02468|029|B||
02468|030|D|DISCUSSION:  Belinostat is primarily metabolized by UGT1A1 and inhibitors of|
02468|031|D|UGT1A1 are expected to increase belinostat levels and dose limiting|
02468|032|D|toxicities.(1)|
02468|033|D|   In a PKPB model, belinostat half-life increased by 1.5-fold,|
02468|034|D|area-under-curve (AUC) increased by 1.4-fold, concentration maximum (Cmax)|
02468|035|D|decreased by 33%, and renal excretion increased by 2.5-fold following|
02468|036|D|administration with atazanavir (UGT1A1 inhibitor).(1)|
02468|037|D|   UGT1A1 inhibitors linked include: atazanavir, belumosudil, capivasertib,|
02468|038|D|erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, nilotinib,|
02468|039|D|pazopanib, probenecid, regorafenib, and sorafenib.|
02468|040|B||
02468|041|R|REFERENCE:|
02468|042|B||
02468|043|R|1.Beleodaq (belinostat) US prescribing information. Acrotech Biopharma Inc.|1
02468|044|R|  November, 2024.|1
02469|001|T|MONOGRAPH TITLE:  Abiraterone; Panobinostat/Strong CYP3A4 Inducers (mono|
02469|002|T|deleted 03/05/2015)|
02469|003|B||
02469|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02469|005|L|of severe adverse interaction.|
02469|006|B||
02469|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may increase the metabolism|
02469|008|A|of abiraterone(1) and panobinostat.(2)|
02469|009|B||
02469|010|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 may result in|
02469|011|E|decreased levels and effectiveness of abiraterone(1) and panobinostat.(2)|
02469|012|B||
02469|013|P|PREDISPOSING FACTORS:  None determined.|
02469|014|B||
02469|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
02469|016|M|abiraterone(1) or panobinostat.(2)  Consider the use of agents with no or|
02469|017|M|minimal induction potential if possible.  Monitor patients for decreased|
02469|018|M|response to therapy.|
02469|019|M|   If concurrent administration of abiraterone and a strong CYP3A4 inducers|
02469|020|M|is required, increase the dosing frequency of abiraterone from once daily to|
02469|021|M|twice daily during the co-administration period.  If the strong inducer is|
02469|022|M|discontinued, reduce the dose of abiraterone back to the previous dose and|
02469|023|M|frequency.(1)|
02469|024|B||
02469|025|D|DISCUSSION:  In a drug interaction trial, concurrent administration of|
02469|026|D|rifampin, a strong CYP3A4 inducer, decreased abiraterone levels by 55%.(1)|
02469|027|D|   Physiologically-based pharmacokinetic (PBPK) models predict a 70%|
02469|028|D|decrease in exposure of panobinostat with strong inducers of CYP3A4.(2)|
02469|029|D|   CYP3A4 inducers include avasimibe, carbamazepine, enzalutamide, mitotane,|
02469|030|D|phenobarbital, primidone, phenytoin, rifabutin, and rifampin.(1-4)|
02469|031|B||
02469|032|R|REFERENCES:|
02469|033|B||
02469|034|R|1.Zytiga (abiraterone acetate) US prescribing information. Centocor Ortho|1
02469|035|R|  Biotech, Inc. October, 2020.|1
02469|036|R|2.Farydak (panobinostat) US prescribing information. Novartis|1
02469|037|R|  Pharmaceuticals Corporation June, 2016.|1
02469|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02469|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02469|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02469|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02469|042|R|  11/14/2017.|1
02469|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
02469|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02470|001|T|MONOGRAPH TITLE:  Canagliflozin/ACE Inhibitors; ARBs (mono deleted|
02470|002|T|03/08/2023)|
02470|003|B||
02470|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02470|005|L|take action as needed.|
02470|006|B||
02470|007|A|MECHANISM OF ACTION:  Canagliflozin produces intravascular volume|
02470|008|A|contraction through osmotic diuresis, which can result in hypotension in|
02470|009|A|patients who are volume depleted from ACE inhibitor or ARB use.|
02470|010|A|Canagliflozin, ACE inhibitors, and ARBs can all produce hyperkalemia.(1-3)|
02470|011|B||
02470|012|E|CLINICAL EFFECTS:  Concurrent use of canagliflozin with an ACE inhibitor or|
02470|013|E|ARB may result in dehydration, hypotension and/or hyperkalemia.(1-3)|
02470|014|B||
02470|015|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
02470|016|P|have a eGFR of less than 60 ml/min/1.73m2, are also taking diuretics and/or|
02470|017|P|NSAIDs, are on a low salt diet, have low systolic blood pressure prior to|
02470|018|P|initiating canagliflozin, and/or are 65 years of age or older.(1,2)|
02470|019|B||
02470|020|M|PATIENT MANAGEMENT:  Before initiating canagliflozin in patients maintained|
02470|021|M|on ACE inhibitors or ARBs, assess volume status and correct if needed and|
02470|022|M|assess renal function.  Patients receiving concurrent therapy should be|
02470|023|M|monitored for hypotension, renal failure, and hyperkalemia.(1-3)|
02470|024|B||
02470|025|D|DISCUSSION:  In clinical trials of canagliflozin, increases in serum|
02470|026|D|potassium were more commonly seen in patients using ACE inhibitors and ARBs.|
02470|027|D|In a pool of eight Phase 3 clinical trials that examined patients with|
02470|028|D|post-baseline serum potassium levels, 6.8% of patients taking canagliflozin|
02470|029|D|and either an ACE inhibitor or ARB had serum potassium levels outside|
02470|030|D|pre-defined study limits, compared with 5.2% of patients not taking an ACE|
02470|031|D|inhibitor or ARB.  In this same pool of patients, 3.5% of patients taking|
02470|032|D|canagliflozin with either an ACE inhibitor or ARB experienced volume|
02470|033|D|depletion-related adverse events, compared with 1.4% of patients not taking|
02470|034|D|an ACE inhibitor or ARB.(1)|
02470|035|D|   Cases of acute renal failure, most requiring hospitalization, have been|
02470|036|D|reported in patients receiving canagliflozin and dapagliflozin.  Fifty-one|
02470|037|D|of 101 cases involved concurrent use of ACE inhibitors.(2)|
02470|038|B||
02470|039|R|REFERENCES:|
02470|040|B||
02470|041|R|1.Wolf MS. Personal communication:  Invokana - Concomitant use with|1
02470|042|R|  ACE/ARBs. Janssen Scientific Affairs, LLC June 9, 2014.|1
02470|043|R|2.USFood and Drug Administration. FDA Drug Safety Communication:  FDA|1
02470|044|R|  strengthens kidney warnings for diabetes medicines canagliflozin|1
02470|045|R|  (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). available|1
02470|046|R|  at:  http://www.fda.gov/downloads/Drugs/DrugSafety/UCM506772.pdf June 14,|1
02470|047|R|  2016.|1
02470|048|R|3.Invokana (canagliflozin) US prescribing information. Janssen|1
02470|049|R|  Pharmaceuticals, Inc. October, 2022.|1
02471|001|T|MONOGRAPH TITLE:  SGLT2 Inhibitors/Loop Diuretics|
02471|002|B||
02471|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02471|004|L|take action as needed.|
02471|005|B||
02471|006|A|MECHANISM OF ACTION:  SGLT2 inhibitors cause intravascular volume|
02471|007|A|contraction through osmotic diuresis, which can result in hypotension in|
02471|008|A|patients who are volume depleted from loop diuretic use.(1-7)|
02471|009|B||
02471|010|E|CLINICAL EFFECTS:  Concurrent use of SGLT2 inhibitors with loop diuretics|
02471|011|E|may result in dehydration, hypotension, and acute renal failure.(1-8)|
02471|012|B||
02471|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
02471|014|P|have a eGFR of less than 60 ml/min/1.73m2, are also taking ACE inhibitors or|
02471|015|P|ARBs and/or NSAIDs, are on a low sodium diet, have low systolic blood|
02471|016|P|pressure prior to initiating SGLT2 inhibitors, and/or are 65 years of age or|
02471|017|P|older.(1-7)|
02471|018|B||
02471|019|M|PATIENT MANAGEMENT:  Before initiating SGLT2 inhibitors in patients|
02471|020|M|maintained on loop diuretics, assess volume status and correct if needed and|
02471|021|M|also assess renal function.  Patients receiving concurrent therapy should be|
02471|022|M|monitored for hypotension and acute renal failure.(1-8)|
02471|023|B||
02471|024|D|DISCUSSION:  In clinical trials of canagliflozin, volume depletion-related|
02471|025|D|adverse effects were associated with the use of loop diuretics, moderate|
02471|026|D|renal impairment (eGFR 30 ml/min/1.73m2 to less than 60 ml/min/1.73m2), and|
02471|027|D|age 75 years and older.  In a pool of eight Phase 3 clinical trials, 2.3% of|
02471|028|D|all patients taking 100 mg of canagliflozin experienced at least one volume|
02471|029|D|depletion-related event, compared to 3.2% of patients taking 100 mg of|
02471|030|D|canagliflozin with a loop diuretic.  3.4% of all patients taking 300 mg of|
02471|031|D|canagliflozin experienced at least one volume depletion-related event,|
02471|032|D|compared to 8.8% of patients taking 300 mg of canagliflozin with a loop|
02471|033|D|diuretic.(1,2)|
02471|034|D|   Cases of acute renal failure, most requiring hospitalization, have been|
02471|035|D|reported in patients receiving canagliflozin and dapagliflozin.  Twenty-six|
02471|036|D|of 101 cases involved concurrent use of diuretics.(7)|
02471|037|D|   In a post-hoc analysis of the EMPEROR-Preserve trial, the combination of|
02471|038|D|empagliflozin and diuretics was associated with a higher incidence of volume|
02471|039|D|depletion events (HR 1.34; 95% CI, 1.13-1.59).  The most commonly reported|
02471|040|D|events were hypotension, syncope, and dehydration.  Coadministration of|
02471|041|D|diuretics and empagliflozin did not result in a difference in the incidence|
02471|042|D|of acute renal failure, hyperkalemia, or adverse events leading to trial|
02471|043|D|discontinuation (including fatal events) compared to empagliflozin alone.|
02471|044|D|There was also no change in the benefit of empagliflozin for the primary end|
02471|045|D|point of first hospitalization for heart failure or cardiovascular death.(8)|
02471|046|B||
02471|047|R|REFERENCES:|
02471|048|B||
02471|049|R|1.Wolf MS. Personal communication:  Invokana - Concomitant use with|1
02471|050|R|  diuretics. Janssen Scientific Affairs, LLC June 9, 2014.|1
02471|051|R|2.Invokana (canagliflozin) US prescribing information. Janssen|1
02471|052|R|  Pharmaceuticals, Inc. October, 2022.|1
02471|053|R|3.Farxiga (dapagliflozin) US prescribing information. AstraZeneca|1
02471|054|R|  Pharmaceuticals LP June, 2024.|1
02471|055|R|4.Steglatro (ertugliflozin) US prescribing information. Merck & Co. October|1
02471|056|R|  2022.|1
02471|057|R|5.Brenzavvy (bexagliflozin) US prescribing information. TheracosBio, LLC|1
02471|058|R|  January, 2023.|1
02471|059|R|6.Jardiance (empagliflozin) US prescribing information. Boehringer Ingelheim|1
02471|060|R|  Pharmaceuticals, Inc. June, 2023.|1
02471|061|R|7.USFood and Drug Administration. FDA Drug Safety Communication:  FDA|1
02471|062|R|  strengthens kidney warnings for diabetes medicines canagliflozin|1
02471|063|R|  (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). available|1
02471|064|R|  at:  http://www.fda.gov/downloads/Drugs/DrugSafety/UCM506772.pdf June 14,|1
02471|065|R|  2016.|1
02471|066|R|8.Butler J, Usman MS, Filippatos G, Ferreira JP, Bohm M, Brueckmann M,|2
02471|067|R|  Januzzi JL, Kaul S, Pina IL, Ponikowski P, Senni M, Sumin M, Verma S,|2
02471|068|R|  Zaremba-Pechmann L, Pocock SJ, Packer M, Anker S. Safety and Efficacy of|2
02471|069|R|  Empagliflozin and Diuretic Use in Patients with Heart  Failure and|2
02471|070|R|  Preserved Ejection Fraction: A Post Hoc Analysis of the  EMPEROR-Preserved|2
02471|071|R|  Trial. JAMA Cardiol 2023 May 24.|2
02472|001|T|MONOGRAPH TITLE:  Canagliflozin/Potassium-Sparing Diuretics (mono deleted|
02472|002|T|03/08/2023)|
02472|003|B||
02472|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02472|005|L|take action as needed.|
02472|006|B||
02472|007|A|MECHANISM OF ACTION:  Canagliflozin and potassium-sparing diuretics all|
02472|008|A|produce hyperkalemia.  Canagliflozin produces intravascular volume|
02472|009|A|contraction through osmotic diuresis, which can result in hypotension in|
02472|010|A|patients who are volume depleted from diuretic use.  Concurrent use may also|
02472|011|A|result in acute kidney injury.(1-3)|
02472|012|B||
02472|013|E|CLINICAL EFFECTS:  Concurrent use of canagliflozin with a potassium-sparing|
02472|014|E|diuretic may result in hyperkalemia, dehydration and hypotension, and/or|
02472|015|E|acute renal failure.(1-3)|
02472|016|B||
02472|017|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
02472|018|P|have a eGFR of less than 60 ml/min/1.73m2, are also taking ACE inhibitors or|
02472|019|P|ARBs and/or NSAIDs, are on a low salt diet, have low systolic blood pressure|
02472|020|P|prior to initiating canagliflozin, and/or are 65 years of age or older.(1-3)|
02472|021|B||
02472|022|M|PATIENT MANAGEMENT:  Before initiating canagliflozin in patients maintained|
02472|023|M|on potassium-sparing diuretics, assess volume status and correct if needed|
02472|024|M|and also assess renal function.  Patients receiving concurrent therapy|
02472|025|M|should be monitored for hyperkalemia, hypotension, and acute renal|
02472|026|M|failure.(1-3)|
02472|027|B||
02472|028|D|DISCUSSION:  In clinical trials of canagliflozin, patients with moderate|
02472|029|D|renal impairment were more likely to develop increases in potassium if they|
02472|030|D|were taking a medication that reduces potassium excretion, such as a|
02472|031|D|potassium-sparing diuretic.(1)|
02472|032|D|   Cases of acute renal failure, most requiring hospitalization, have been|
02472|033|D|reported in patients receiving canagliflozin and dapagliflozin.  Twenty-six|
02472|034|D|of 101 cases involved concurrent use of diuretics.(3)|
02472|035|B||
02472|036|R|REFERENCES:|
02472|037|B||
02472|038|R|1.Wolf MS. Personal communication:  Invokana - Concomitant use with|1
02472|039|R|  diuretics. Janssen Scientific Affairs, LLC June 9, 2014.|1
02472|040|R|2.Invokana (canagliflozin) US prescribing information. Janssen|1
02472|041|R|  Pharmaceuticals, Inc. October, 2022.|1
02472|042|R|3.USFood and Drug Administration. FDA Drug Safety Communication:  FDA|1
02472|043|R|  strengthens kidney warnings for diabetes medicines canagliflozin|1
02472|044|R|  (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). available|1
02472|045|R|  at:  http://www.fda.gov/downloads/Drugs/DrugSafety/UCM506772.pdf June 14,|1
02472|046|R|  2016.|1
02473|001|T|MONOGRAPH TITLE:  Exemestane/Selected Moderate-Weak CYP3A4 Inducers|
02473|002|B||
02473|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02473|004|L|take action as needed.|
02473|005|B||
02473|006|A|MECHANISM OF ACTION:  CYP3A4 inducers may induce the metabolism of|
02473|007|A|exemestane.(1)|
02473|008|B||
02473|009|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inducer may result in|
02473|010|E|decreased levels and effectiveness of exemestane.(1)|
02473|011|B||
02473|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02473|013|P|of the inducer for longer than 1-2 weeks.|
02473|014|B||
02473|015|M|PATIENT MANAGEMENT:  The US manufacturer of exemestane recommends that|
02473|016|M|patients receiving concurrent therapy with a strong CYP3A4 inducer receive|
02473|017|M|50 mg of exemestane daily after a meal.(1)  It may be prudent to consider a|
02473|018|M|dosage increase for patients receiving weaker CYP3A4 inducers.|
02473|019|B||
02473|020|D|DISCUSSION:  In a study in 10 healthy postmenopausal subjects, pretreatment|
02473|021|D|with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased|
02473|022|D|the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose|
02473|023|D|of exemestane (25 mg) by 54% and 41%, respectively.(1)|
02473|024|D|   Strong inducers of CYP3A4 would be expected to decrease the AUC of a|
02473|025|D|sensitive 3A4 substrate by 80% or more and include:  carbamazepine,|
02473|026|D|enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and|
02473|027|D|St. John's wort.(1-3)|
02473|028|D|   Moderate inducers of CYP3A4 would be expected to decrease the AUC of a|
02473|029|D|sensitive 3A4 substrate by 50-80% and include:  belzutifan, bosentan,|
02473|030|D|cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
02473|031|D|lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
02473|032|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
02473|033|D|thioridazine, and tovorafenib.(2,3)|
02473|034|D|   Weak inducers of CYP3A4 would be expected to decrease the AUC of a|
02473|035|D|sensitive 3A4 substrate by 20-50% and include:  armodafinil, bexarotene,|
02473|036|D|brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone,|
02473|037|D|dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine,|
02473|038|D|floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib,|
02473|039|D|meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone,|
02473|040|D|oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix,|
02473|041|D|rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine,|
02473|042|D|tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate,|
02473|043|D|troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)|
02473|044|B||
02473|045|R|REFERENCES:|
02473|046|B||
02473|047|R|1.Aromasin (exemestane) US prescribing information. Pharmacia & Upjohn|1
02473|048|R|  Company July, 2016.|1
02473|049|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02473|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02473|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02473|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02473|053|R|  11/14/2017.|1
02473|054|R|3.This information is based on an extract from the Certara Drug Interaction|6
02473|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02474|001|T|MONOGRAPH TITLE:  Dextromethorphan/Selected SSRIs that Inhibit CYP2D6|
02474|002|B||
02474|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02474|004|L|take action as needed.|
02474|005|B||
02474|006|A|MECHANISM OF ACTION:  Fluoxetine and paroxetine, strong inhibitors of|
02474|007|A|CYP2D6, may inhibit the metabolism of dextromethorphan.(1-4)|
02474|008|B||
02474|009|E|CLINICAL EFFECTS:  Patients may experience increased adverse effects of|
02474|010|E|dextromethorphan due to elevated systemic concentrations.|
02474|011|E|   Concomitant use of two or more serotonergic agents increases the risk for|
02474|012|E|serotonin syndrome.  Serotonin syndrome constitutes a range of toxicities|
02474|013|E|from mild to life threatening.(5)|
02474|014|E|   Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis,|
02474|015|E|intermittent tremor, and/or myoclonus.(5)|
02474|016|E|   Moderate serotonin symptoms may include: tachycardia, hypertension,|
02474|017|E|hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds,|
02474|018|E|hyperreflexia, and/OR clonus.(5)|
02474|019|E|   Severe serotonin symptoms may include: severe hypertension and|
02474|020|E|tachycardia, shock, agitated delirium, muscular rigidity, and/or|
02474|021|E|hypertonicity.(5)|
02474|022|B||
02474|023|P|PREDISPOSING FACTORS:  Concurrent use of additional drugs which increase CNS|
02474|024|P|serotonin levels would be expected to further increase risk for serotonin|
02474|025|P|syndrome.(5)|
02474|026|B||
02474|027|M|PATIENT MANAGEMENT:  Monitor patients on multiple serotonergic agents for|
02474|028|M|symptoms of serotonin toxicity.  Patients in whom serotonin syndrome is|
02474|029|M|suspected should receive immediate medical attention.  If the interacting|
02474|030|M|agents are prescribed by different providers, it would be prudent to assure|
02474|031|M|that both are aware of concomitant therapy and monitoring the patient for|
02474|032|M|serotonin toxicities.  Advise patients not to exceed recommended dosages of|
02474|033|M|dextromethorphan.|
02474|034|M|   If concurrent therapy is warranted, patients should be monitored for|
02474|035|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02474|036|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02474|037|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02474|038|M|coordination, or severe diarrhea.|
02474|039|B||
02474|040|D|DISCUSSION:  An open label parallel group trial evaluated the interaction|
02474|041|D|between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed|
02474|042|D|strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with|
02474|043|D|a mean age of 33.6 years.  Subjects were randomly divided into 2 groups:|
02474|044|D|  - Group 1 received paroxetine 20 mg once daily for 12 days, followed by|
02474|045|D|the addition of dextromethorphan-quinidine twice daily for 8 days.|
02474|046|D|  - Group 2 received dextromethorphan-quinidine twice daily for 8 days,|
02474|047|D|followed by paroxetine 20 mg daily for 12 days.|
02474|048|D|Results: overall, adverse effects were reported in 19 of 26 subjects who|
02474|049|D|received combination therapy (73%) and 15 of 27 subjects who received|
02474|050|D|monotherapy (56%). Adverse effects from the combination differed somewhat|
02474|051|D|between groups and were more closely associated with the second drug product|
02474|052|D|administered. Group 1 reported dizziness, headache, somnolence, euphoria,|
02474|053|D|nausea, and vomiting after the addition of dextromethorphan-quinidine to|
02474|054|D|paroxetine.  Group 2 adverse events were dizziness, headache, nausea,|
02474|055|D|vomiting, insomnia, anxiety, and hyperhidrosis after the addition of|
02474|056|D|paroxetine to dextromethorphan.(1)|
02474|057|D|   Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of|
02474|058|D|dextromethorphan by 27-fold.(4)|
02474|059|D|   Serotonin syndrome has been reported in patients following the addition|
02474|060|D|of dextromethorphan containing cough syrups to fluoxetine(6,7) and|
02474|061|D|paroxetine.(8)|
02474|062|B||
02474|063|R|REFERENCES:|
02474|064|B||
02474|065|R|1.Schoedel KA, Pope LE, Sellers EM. Randomized open-label drug-drug|2
02474|066|R|  interaction trial of dextromethorphan/quinidine and paroxetine in healthy|2
02474|067|R|  volunteers. Clin Drug Investig 2012 Mar 1;32(3):157-69.|2
02474|068|R|2.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
02474|069|R|  Technologies January, 2017.|1
02474|070|R|3.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
02474|071|R|  and Company August, 2023.|1
02474|072|R|4.Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. Fluoxetine-|2
02474|073|R|  and norfluoxetine-mediated complex drug-drug interactions: in vitro to in|2
02474|074|R|  vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol|2
02474|075|R|  Ther 2014 Jun;95(6):653-62.|2
02474|076|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02474|077|R|  352(11):1112-20.|6
02474|078|R|6.Navarro A, Perry C, Bobo WV. A case of serotonin syndrome precipitated by|3
02474|079|R|  abuse of the anticough remedy dextromethorphan in a bipolar patient|3
02474|080|R|  treated with fluoxetine and lithium. Gen Hosp Psychiatry 2006 Jan-Feb;|3
02474|081|R|  28(1):78-80.|3
02474|082|R|7.Achamallah NS. Visual hallucinations after combining fluoxetine and|3
02474|083|R|  dextromethorphan. Am J Psychiatry 1992 Oct;149(10):1406.|3
02474|084|R|8.Skop BP, Finkelstein JA, Mareth TR, Magoon MR, Brown TM. The serotonin|3
02474|085|R|  syndrome associated with paroxetine, an over-the-counter cold remedy, and|3
02474|086|R|  vascular disease. Am J Emerg Med 1994 Nov;12(6):642-4.|3
02475|001|T|MONOGRAPH TITLE:  Apixaban/Aspirin (Less Than or Equal To 100 mg)|
02475|002|B||
02475|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02475|004|L|take action as needed.|
02475|005|B||
02475|006|A|MECHANISM OF ACTION:  Additive effects on hemostasis.(1-4)|
02475|007|B||
02475|008|E|CLINICAL EFFECTS:  Concurrent use of apixaban with aspirin may increase the|
02475|009|E|risk of bleeding.(1-4)|
02475|010|B||
02475|011|P|PREDISPOSING FACTORS:  Factors associated with an increase risk for bleeding|
02475|012|P|may include renal impairment, concomitant use of P-glycoprotein inhibitors,|
02475|013|P|patient age greater than 74 years, coexisting conditions (e.g. recent|
02475|014|P|trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and|
02475|015|P|patient weight less than 50 kg.(5-7)|
02475|016|P|   The risk for bleeding episodes may be greater in patients with|
02475|017|P|disease-associated factors (e.g. thrombocytopenia).|
02475|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
02475|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02475|020|P|risk for bleeding (e.g. NSAIDs).|
02475|021|B||
02475|022|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
02475|023|M|of blood loss, including decreased hemoglobin, hematocrit, fecal occult|
02475|024|M|blood, and/or blood pressure and promptly evaluate patients with any|
02475|025|M|symptoms.|
02475|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02475|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02475|028|M|anticoagulation in patients with active pathologic bleeding.|
02475|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02475|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02475|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02475|032|M|and/or swelling.|
02475|033|B||
02475|034|D|DISCUSSION:  Concurrent apixaban and aspirin (325 mg daily) resulted in no|
02475|035|D|pharmacokinetic or pharmacodynamic interactions.(1)|
02475|036|D|   In a clinical trial examining the use of apixaban in atrial fibrillation,|
02475|037|D|concurrent use of aspirin increased risk of major bleeding with apixaban|
02475|038|D|from 1.8% per year to 3.4% per year and increased the bleeding risk with|
02475|039|D|warfarin from 2.7% per year to 4.6% per year. Concomitant dual antiplatelet|
02475|040|D|therapy was used in 2.1% of patients.(3,4)|
02475|041|D|   In a clinical trial examining the use of apixaban in high-risk post acute|
02475|042|D|coronary syndrome patients with multiple cardiac and non-cardiac|
02475|043|D|comorbidities, who received ASA or the combination of ASA and clopidogrel,|
02475|044|D|the risk of major bleeding (defined by ISTH -International Society on|
02475|045|D|Thrombosis and Haemostasis criteria) was increased for apixaban (5.13% per|
02475|046|D|year) compared to placebo (2.04% per year).(3,4)|
02475|047|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
02475|048|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
02475|049|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
02475|050|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
02475|051|D|aspirin, with the highest allowable dose being 165 mg/day.  The use of DOACs|
02475|052|D|with antiplatelet agents was associated with an increased risk of major|
02475|053|D|bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major|
02475|054|D|bleeding (OR 1.82; 95% CI, 1.50-2.22).  There was no difference between|
02475|055|D|groups in the efficacy outcome of symptomatic recurrent venous|
02475|056|D|thromboembolism (VTE) or VTE-related death.(8)|
02475|057|B||
02475|058|R|REFERENCES:|
02475|059|B||
02475|060|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
02475|061|R|  Squibb Australia Pty. Ltd. January, 2024.|1
02475|062|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
02475|063|R|  Squibb-Pfizer January, 2025.|1
02475|064|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
02475|065|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
02475|066|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
02475|067|R|  Company April, 2025.|1
02475|068|R|5.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
02475|069|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
02475|070|R|6.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
02475|071|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
02475|072|R|7.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
02475|073|R|  Boehringer Ingelheim March, 23 2020.|1
02475|074|R|8.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
02475|075|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
02475|076|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
02475|077|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
02476|001|T|MONOGRAPH TITLE:  Erythromycin/Fluconazole|
02476|002|B||
02476|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02476|004|L|is contraindicated and generally should not be dispensed or administered to|
02476|005|L|the same patient.|
02476|006|B||
02476|007|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of erythromycin|
02476|008|A|by CYP3A4.(1,2)  Both erythromycin and fluconazole have been shown to|
02476|009|A|prolong the QTc interval and result in torsades de pointes.(1,2)|
02476|010|B||
02476|011|E|CLINICAL EFFECTS:  Concurrent use of erythromycin with potent inhibitors of|
02476|012|E|CYP3A4 such as fluconazole may result in elevated levels of erythromycin, QT|
02476|013|E|prolongation, and risk of sudden death from cardiac causes.(1,2)|
02476|014|B||
02476|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02476|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02476|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02476|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02476|019|P|female gender, or advanced age.(3)|
02476|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02476|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02476|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02476|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02476|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02476|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02476|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02476|027|B||
02476|028|M|PATIENT MANAGEMENT:  The concurrent use of fluconazole and erythromycin is|
02476|029|M|contraindicated.(1)|
02476|030|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02476|031|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02476|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02476|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02476|034|B||
02476|035|D|DISCUSSION:  A retrospective review examined sudden cardiac death in|
02476|036|D|Tennessee Medicaid patients.  Erythromycin use increased the risk of sudden|
02476|037|D|cardiac death by 1.79-fold.  Concurrent use of erythromycin with a potent|
02476|038|D|inhibitor of CYP3A4 (diltiazem, fluconazole, itraconazole, ketoconazole,|
02476|039|D|troleandomycin, or verapamil) increased the risk of sudden cardiac death by|
02476|040|D|5.35-fold when compared to patients receiving no antibiotic therapy.  There|
02476|041|D|was one death in 106 person-years among concurrent users of diltiazem and|
02476|042|D|erythromycin.  There were two deaths in 78 person-years among concurrent|
02476|043|D|users of verapamil and erythromycin.  There were no sudden cardiac deaths|
02476|044|D|among concurrent users of erythromycin and other calcium channel blockers|
02476|045|D|that do not inhibit CYP3A4.(2)|
02476|046|D|   One or more of the drug pairs linked to this monograph have been included|
02476|047|D|in a list of interactions that should be considered "high-priority" for|
02476|048|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02476|049|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02476|050|D|Coordinator (ONC) for Health Information Technology.|
02476|051|B||
02476|052|R|REFERENCES:|
02476|053|B||
02476|054|R|1.Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral|2
02476|055|R|  erythromycin and the risk of sudden death from cardiac causes. N Engl J|2
02476|056|R|  Med 2004 Sep 9;351(11):1089-96.|2
02476|057|R|2.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
02476|058|R|  2024.|1
02476|059|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02476|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02476|061|R|  settings: a scientific statement from the American Heart Association and|6
02476|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02476|063|R|  2;55(9):934-47.|6
02476|064|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02476|065|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02476|066|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02476|067|R|  19(5):735-43.|6
02477|001|T|MONOGRAPH TITLE:  Dabigatran/Aspirin (Less Than or Equal To 100 mg)|
02477|002|B||
02477|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02477|004|L|take action as needed.|
02477|005|B||
02477|006|A|MECHANISM OF ACTION:  Additive effects on hemostasis.(1-3)|
02477|007|B||
02477|008|E|CLINICAL EFFECTS:  Concurrent use of dabigatran with aspirin may increase|
02477|009|E|the risk of bleeding.(1-3)|
02477|010|B||
02477|011|P|PREDISPOSING FACTORS:  Factors associated with an increase risk for bleeding|
02477|012|P|may include renal impairment, concomitant use of P-glycoprotein inhibitors,|
02477|013|P|patient age greater than 74 years, coexisting conditions (e.g. recent|
02477|014|P|trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and|
02477|015|P|patient weight less than 50 kg.(1-3)|
02477|016|P|   The risk for bleeding episodes may be greater in patients with|
02477|017|P|disease-associated factors (e.g. thrombocytopenia).|
02477|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
02477|019|P|which inhibit anticoagulants/antiplatelet metabolism and/or have an inherent|
02477|020|P|risk for bleeding (e.g. NSAIDs).|
02477|021|B||
02477|022|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
02477|023|M|of blood loss, including decreased hemoglobin, hematocrit, fecal occult|
02477|024|M|blood, and/or blood pressure and promptly evaluate patients with any|
02477|025|M|symptoms.|
02477|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02477|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02477|028|M|anticoagulation in patients with active pathologic bleeding.|
02477|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02477|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02477|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02477|032|M|and/or swelling.|
02477|033|B||
02477|034|D|DISCUSSION:  A Phase II study in patients with atrial fibrillation examined|
02477|035|D|the effects of dabigatran and concurrent aspirin on the risk of major|
02477|036|D|bleeds.  Concurrent use of aspirin and dabigatran etexilate (150 mg twice|
02477|037|D|daily) increased the risk for any bleeding from 12 % to 18 % and 24 % with|
02477|038|D|81 mg and 325 mg ASA, respectively, when compared to dabigatran alone.(3)|
02477|039|D|   In the RE-DUAL PCI trial, patients were randomly assigned to one of three|
02477|040|D|treatments: (A) dual therapy with dabigatran 110 mg twice daily plus either|
02477|041|D|clopidogrel or ticagrelor, (B) dual therapy with dabigatran 150 mg twice|
02477|042|D|daily plus either clopidogrel or ticagrelor, or (C) triple therapy with|
02477|043|D|warfarin (goal INR 2-3) plus aspirin (less than or equal to 100 mg daily)|
02477|044|D|plus either clopidogrel or ticagrelor.  The incidence of the first major or|
02477|045|D|clinically relevant non-major (CRNM) bleeding event was 15.4% in group A|
02477|046|D|compared with 26.9% in group C (hazard ratio, 0.52; 95% CI 0.42 to 0.63;|
02477|047|D|p<0.001 for noninferiority; p<0.001 for superiority) and 20.2% in group B|
02477|048|D|compared to 25.7% in corresponding group C (hazard ratio, 0.72; 95% CI 0.58|
02477|049|D|to 0.88; p<0.001 for noninferiority).  Major bleeding as defined by|
02477|050|D|Thrombolysis in Myocardial Infarction (TIMI) criteria, the rate was lower in|
02477|051|D|both dual-therapy groups than in the triple-therapy group: 1.4% in group A|
02477|052|D|compared to 3.8% in group C (hazard ratio, 0.37; 95% CI 0.2 to 0.68;|
02477|053|D|p=0.002) and 2.1% in group B compared to 3.9% in corresponding group C|
02477|054|D|(hazard ratio, 0.51; 95% CI 0.28 to 0.93; p=0.03).  Incidence of composite|
02477|055|D|efficacy end point of thromboembolic events (myocardial infarction, stroke,|
02477|056|D|or systemic embolism), death, or unplanned revascularization was 13.7% in|
02477|057|D|groups A and B compared to 13.4% in group C (hazard ratio, 1.04; 95% CI 0.84|
02477|058|D|to 1.29; p=0.005 for noninferiority).(4)|
02477|059|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
02477|060|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
02477|061|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
02477|062|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
02477|063|D|aspirin, with the highest allowable dose being 165 mg/day.  Compared with|
02477|064|D|DOACs alone, the use of DOACs with antiplatelet agents was associated with|
02477|065|D|an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM|
02477|066|D|bleeding (OR 1.82; 95% CI, 1.50-2.22).  There was no difference between|
02477|067|D|groups in the efficacy outcome of symptomatic recurrent venous|
02477|068|D|thromboembolism (VTE) or VTE-related death.(5)|
02477|069|B||
02477|070|R|REFERENCES:|
02477|071|B||
02477|072|R|1.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
02477|073|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
02477|074|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
02477|075|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
02477|076|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
02477|077|R|  Boehringer Ingelheim March, 23 2020.|1
02477|078|R|4.Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T, Maeng M,|2
02477|079|R|  Merkely B. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial|2
02477|080|R|  Fibrillation. N Engl J Med 2017 Aug 27.|2
02477|081|R|5.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
02477|082|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
02477|083|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
02477|084|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
02478|001|T|MONOGRAPH TITLE:  Empagliflozin/Diuretics (mono deleted 03/08/2023)|
02478|002|B||
02478|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02478|004|L|take action as needed.|
02478|005|B||
02478|006|A|MECHANISM OF ACTION:  Empagliflozin produces intravascular volume|
02478|007|A|contraction through osmotic diuresis, which can result in hypotension in|
02478|008|A|patients who are volume depleted from diuretic use.(1)|
02478|009|B||
02478|010|E|CLINICAL EFFECTS:  Concurrent use of empagliflozin with a diuretic may|
02478|011|E|result in dehydration and hypotension.(1)|
02478|012|B||
02478|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
02478|014|P|have renal impairment, are on a low-sodium diet, have low systolic blood|
02478|015|P|pressure prior to initiating empagliflozin, and/or are 65 years of age or|
02478|016|P|older.(1)|
02478|017|B||
02478|018|M|PATIENT MANAGEMENT:  Before initiating empagliflozin in patients maintained|
02478|019|M|on diuretics, assess volume status and correct if needed.  Patients|
02478|020|M|receiving concurrent therapy should be monitored for hypotension.(1)|
02478|021|B||
02478|022|D|DISCUSSION:  In clinical trials of empagliflozin, diuretic use increased|
02478|023|D|urine volume and frequency of voids.(1)|
02478|024|B||
02478|025|R|REFERENCE:|
02478|026|B||
02478|027|R|1.Jardiance (empagliflozin) US prescribing information. Boehringer Ingelheim|1
02478|028|R|  Pharmaceuticals, Inc. June, 2023.|1
02479|001|T|MONOGRAPH TITLE:  Metformin/Carbonic Anhydrase Inhibitors|
02479|002|B||
02479|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02479|004|L|take action as needed.|
02479|005|B||
02479|006|A|MECHANISM OF ACTION:  Carbonic anhydrase inhibitors increase bicarbonate|
02479|007|A|excretion which may cause metabolic acidosis.(1)  High systemic|
02479|008|A|concentrations of metformin may result in lactic acidosis.(2,3)|
02479|009|A|   Topiramate, a mild carbonic anhydrase inhibitor, may also increase|
02479|010|A|systemic exposure to metformin.(1)|
02479|011|B||
02479|012|E|CLINICAL EFFECTS:  Carbonic anhydrase inhibitors may increase the risk for|
02479|013|E|metformin associated lactic acidosis.(1-3) Untreated lactic acidosis may be|
02479|014|E|fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory|
02479|015|E|distress, low blood pH, increased anion gap and elevated blood lactate.(2)|
02479|016|E|   Carbonic anhydrase inhibitors linked to this monograph are acetazolamide,|
02479|017|E|dichlorphenamide, methazolamide, sulthiame, topiramate, and zonisamide.|
02479|018|B||
02479|019|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
02479|020|P|include renal impairment,sepsis, dehydration, excessive alcohol intake,|
02479|021|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
02479|022|P|failure, metformin plasma levels > 5 micrograms/mL, and conditions which may|
02479|023|P|lead to tissue hypoxia.  Geriatric patients may also be at higher risk due|
02479|024|P|to slower metformin clearance and increased half-life in this population.|
02479|025|P|   The risk for metabolic acidosis is higher with increased doses of either|
02479|026|P|agent.|
02479|027|B||
02479|028|M|PATIENT MANAGEMENT:  For patients receiving concurrent therapy, monitor|
02479|029|M|renal function and assure that patient does not have risk factors for|
02479|030|M|metformin associated lactic acidosis. Discontinue metformin when risk|
02479|031|M|factors are present.|
02479|032|M|   If both drugs are given, monitor renal function and for signs and|
02479|033|M|symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias,|
02479|034|M|respiratory distress, increasing somnolence, and respiratory distress.|
02479|035|M|Laboratory results which may signal lactic acidosis include: low pH, an|
02479|036|M|increased anion gap, and increased lactate to pyruvate ratio.|
02479|037|M|   Manufacturer recommendations: the manufacturer of metformin recommends|
02479|038|M|caution with concomitant use of carbonic anhydrase inhibitors due to an|
02479|039|M|increased risk for metformin associated lactic acidosis.(2) The manufacturer|
02479|040|M|of topiramate notes that topiramate can frequently cause metabolic acidosis|
02479|041|M|and that metformin should not be used in patients with metabolic|
02479|042|M|acidosis.(1)|
02479|043|B||
02479|044|D|DISCUSSION:  A literature search for lactic acidosis due solely to the|
02479|045|D|combination of metformin and carbonic anhydrase inhibitors or topiramate did|
02479|046|D|not reveal any case reports of symptomatic metabolic acidosis due to this|
02479|047|D|combination. Never-the-less, since carbonic anhydrase inhibitors act by|
02479|048|D|inhibiting the reabsorption of bicarbonate in the renal tubule, some|
02479|049|D|lowering of systemic bicarbonate and pH is common and supports the|
02479|050|D|plausibility of this interaction.|
02479|051|D|   In addition, a pharmacokinetic interaction has been described with|
02479|052|D|topiramate.  A study in healthy volunteers evaluated the effect of|
02479|053|D|topiramate 100 mg every 12 hours on the kinetics of metformin 500 mg every|
02479|054|D|12 hours.  Mean metformin exposure (area-under-curve or AUC) was increased|
02479|055|D|25%.(1)|
02479|056|B||
02479|057|R|REFERENCES:|
02479|058|B||
02479|059|R|1.Topamax (topiramate) US prescribing information. Janssen Pharmaceuticals,|1
02479|060|R|  Inc. May, 2023.|1
02479|061|R|2.Glucophage (metformin hydrochloride) US prescribing information.|1
02479|062|R|  Bristol-Myers Squibb Company May, 2018.|1
02479|063|R|3.Xigduo XR (dapagliflozin and metformin) US prescribing information.|1
02479|064|R|  AstraZeneca Pharmaceuticals LP October, 2022.|1
02480|001|T|MONOGRAPH TITLE:  Sodium Oxybate/Valproic Acid|
02480|002|B||
02480|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02480|004|L|take action as needed.|
02480|005|B||
02480|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.(1)|
02480|007|B||
02480|008|E|CLINICAL EFFECTS:  Concurrent use of sodium oxybate and valproic acid may|
02480|009|E|result in elevated levels of and increased clinical effects of sodium|
02480|010|E|oxybate, including significant respiratory depression.(1)|
02480|011|B||
02480|012|P|PREDISPOSING FACTORS:  None determined.|
02480|013|B||
02480|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent valproic acid may require|
02480|015|M|lower dosages of sodium oxybate.  In patients maintained on sodium oxybate,|
02480|016|M|reduce the dosage of sodium oxybate by 20% if valproic acid is initiated.|
02480|017|M|For patients already taking valproic acid, consider a lower starting dose of|
02480|018|M|sodium oxybate.  If valproic acid is discontinued, monitor patient response|
02480|019|M|to sodium oxybate.(1)|
02480|020|B||
02480|021|D|DISCUSSION:  Administration of valproic acid (1250 mg daily) increased the|
02480|022|D|area-under-curve (AUC) of sodium oxybate (6 g per day dosed as 3 grams given|
02480|023|D|4 hours apart) by 25%.  There was no significant change in sodium oxybate|
02480|024|D|maximum concentration (Cmax).(1)|
02480|025|B||
02480|026|R|REFERENCE:|
02480|027|B||
02480|028|R|1.Xyrem (sodium oxybate) US prescribing information. Jazz Pharmaceuticals,|1
02480|029|R|  Inc. April, 2023.|1
02481|001|T|MONOGRAPH TITLE:  Ramelteon; Suvorexant; Tasimelteon/Strong CYP3A4 Inducers|
02481|002|B||
02481|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02481|004|L|of severe adverse interaction.|
02481|005|B||
02481|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
02481|007|A|ramelteon, suvorexant or tasimelteon.(1-3)|
02481|008|B||
02481|009|E|CLINICAL EFFECTS:  Concurrent use with strong inducers of CYP3A4 may result|
02481|010|E|in substantially lower systemic concentrations and decreased efficacy of|
02481|011|E|ramelteon, suvorexant or tasimelteon.(1-3)|
02481|012|B||
02481|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02481|014|P|of the inducer for longer than 1-2 weeks.|
02481|015|B||
02481|016|M|PATIENT MANAGEMENT:  Ramelteon:|
02481|017|M|   The manufacturer notes that ramelteon efficacy may be reduced when used|
02481|018|M|in combination with a strong CYP3A4 inducer.(1)|
02481|019|M|Suvorexant:|
02481|020|M|   If possible, use alternatives to strong CYP3A4 inducers in patients who|
02481|021|M|require suvorexant therapy.  Patients requiring concurrent therapy may need|
02481|022|M|larger doses of suvorexant; however, the maximum daily dose of 20 mg should|
02481|023|M|not be exceeded.(2)|
02481|024|M|Tasimelteon:|
02481|025|M|   The manufacturer of tasimelteon recommends avoiding concurrent use with|
02481|026|M|strong CYP3A4 inducers due to the potentially large decrease in tasimelteon|
02481|027|M|exposure and reduced efficacy.(3)|
02481|028|B||
02481|029|D|DISCUSSION:  Rifampin (600 mg daily for 11 days) decreased both maximum|
02481|030|D|concentration (Cmax) and total exposure (area-under-curve or AUC) to|
02481|031|D|ramelteon by 80%.(1)|
02481|032|D|   In an interaction study, rifampin substantially decreased levels of|
02481|033|D|suvorexant.  Suvorexant AUC and Cmax decreased by approximately 90% and 70%,|
02481|034|D|respectively.(2)|
02481|035|D|   Rifampin (600 mg daily for 11 days) decreased exposure to tasimelteon by|
02481|036|D|90%.(3)|
02481|037|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02481|038|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02481|039|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02481|040|D|rifapentine and St. John's wort.(4-5)|
02481|041|B||
02481|042|R|REFERENCES:|
02481|043|B||
02481|044|R|1.Rozerem (ramelteon) US prescribing information. Takeda Pharmaceuticals|1
02481|045|R|  America Inc. November, 2010.|1
02481|046|R|2.Belsomra (suvorexant) US prescribing information. Merck & Co., Inc. March,|1
02481|047|R|  2021.|1
02481|048|R|3.Hetlioz (tasimelteon) US prescribing information. Vanda Pharmaceuticals|1
02481|049|R|  Inc. December, 2020.|1
02481|050|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02481|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02481|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02481|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02481|054|R|  11/14/2017.|1
02481|055|R|5.This information is based on an extract from the Certara Drug Interaction|6
02481|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02482|001|T|MONOGRAPH TITLE:  Suvorexant/Strong CYP3A4 Inhibitors (mono deleted|
02482|002|T|02/05/2015)|
02482|003|B||
02482|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02482|005|L|of severe adverse interaction.|
02482|006|B||
02482|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
02482|008|A|of suvorexant.(1)|
02482|009|B||
02482|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that is a strong inhibitor of|
02482|011|E|CYP3A4 may result in elevated levels of and clinical effects of|
02482|012|E|suvorexant.(1)|
02482|013|B||
02482|014|P|PREDISPOSING FACTORS:  None determined.|
02482|015|B||
02482|016|M|PATIENT MANAGEMENT:  The US manufacturer of suvorexant states that|
02482|017|M|concurrent use with strong inhibitors of CYP3A4 is not recommended.(1)|
02482|018|M|Consider alternative agents with less CYP3A4 inhibition when possible.|
02482|019|M|Patients requiring concurrent therapy will need a substantially lower doses|
02482|020|M|of suvorexant.  With moderate inhibitors of CYP3A4, the manufacturer|
02482|021|M|recommends a starting dose of 5 mg daily and a maximum dose of 10 mg|
02482|022|M|daily.(1)|
02482|023|B||
02482|024|D|DISCUSSION:  Ketoconazole, a strong inhibitor of CYP3A4, increased|
02482|025|D|suvorexant area-under-curve (AUC) and maximum concentration (Cmax) by|
02482|026|D|approximately 2.75-fold and 1.25-fold, respectively.(1)|
02482|027|D|   Diltiazem, a moderate inhibitor of CYP3A4, increased suvorexant AUC and|
02482|028|D|Cmax by approximately 2-fold and 1.25-fold, respectively.(1)|
02482|029|D|   Strong inhibitors of CYP3A4 include: boceprevir, clarithromycin,|
02482|030|D|cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole,|
02482|031|D|lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole,|
02482|032|D|ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, and|
02482|033|D|voriconazole.(1-3)|
02482|034|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
02482|035|D|atazanavir, casopitant, cimetidine, ciprofloxacin, crizotinib, cyclosporine,|
02482|036|D|darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir,|
02482|037|D|imatinib, lomitapide, tofisopam, and verapamil.(1-3)|
02482|038|B||
02482|039|R|REFERENCES:|
02482|040|B||
02482|041|R|1.Belsomra (suvorexant) US prescribing information. Merck Sharp & Dohme Corp|1
02482|042|R|  August, 2014.|1
02482|043|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02482|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02482|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02482|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02482|047|R|  11/14/2017.|1
02482|048|R|3.This information is based on an extract from the Certara Drug Interaction|6
02482|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02483|001|T|MONOGRAPH TITLE:  Suvorexant (Greater Than 10 mg)/Moderate CYP3A4 Inhibitors|
02483|002|B||
02483|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02483|004|L|of severe adverse interaction.|
02483|005|B||
02483|006|A|MECHANISM OF ACTION:  Moderate and strong inhibitors of CYP3A4 may inhibit|
02483|007|A|the metabolism of suvorexant.(1)|
02483|008|B||
02483|009|E|CLINICAL EFFECTS:  Concurrent use of an agent that is a moderate or strong|
02483|010|E|inhibitor of CYP3A4 may result in elevated levels of and clinical effects of|
02483|011|E|suvorexant.(1)|
02483|012|B||
02483|013|P|PREDISPOSING FACTORS:  None determined.|
02483|014|B||
02483|015|M|PATIENT MANAGEMENT:  The US manufacturer of suvorexant recommends a starting|
02483|016|M|dose of 5 mg daily and a maximum dose of 10 mg daily in patients receiving|
02483|017|M|concomitant therapy with a moderate inhibitor of CYP3A4.(1)|
02483|018|M|   Concurrent use with strong inhibitors of CYP3A4 is not recommended.(1)|
02483|019|B||
02483|020|D|DISCUSSION:  Diltiazem, a moderate inhibitor of CYP3A4, increased suvorexant|
02483|021|D|AUC and Cmax by approximately 2-fold and 1.25-fold, respectively.(1)|
02483|022|D|   Ketoconazole, a strong inhibitor of CYP3A4, increased suvorexant|
02483|023|D|area-under-curve (AUC) and maximum concentration (Cmax) by approximately|
02483|024|D|2.75-fold and 1.25-fold, respectively.(1)|
02483|025|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant, avacopan,|
02483|026|D|berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone,|
02483|027|D|duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine,|
02483|028|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir,|
02483|029|D|letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol,|
02483|030|D|tofisopam, treosulfan and verapamil.(1-3)|
02483|031|B||
02483|032|R|REFERENCES:|
02483|033|B||
02483|034|R|1.Belsomra (suvorexant) US prescribing information. Merck & Co., Inc. March,|1
02483|035|R|  2021.|1
02483|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02483|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02483|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02483|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02483|040|R|  11/14/2017.|1
02483|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
02483|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02484|001|T|MONOGRAPH TITLE:  Suvorexant (Less Than or Equal To 10 mg)/Moderate CYP3A4|
02484|002|T|Inhibitors|
02484|003|B||
02484|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02484|005|L|take action as needed.|
02484|006|B||
02484|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
02484|008|A|metabolism of suvorexant.(1)|
02484|009|B||
02484|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that is a moderate inhibitor|
02484|011|E|of CYP3A4 may result in elevated levels of and clinical effects of|
02484|012|E|suvorexant.(1)|
02484|013|B||
02484|014|P|PREDISPOSING FACTORS:  None determined.|
02484|015|B||
02484|016|M|PATIENT MANAGEMENT:  The US manufacturer of suvorexant recommends a starting|
02484|017|M|dose of 5 mg daily and a maximum dose of 10 mg daily in patients receiving|
02484|018|M|concurrent therapy with a moderate CYP3A4 inhibitor.(1)|
02484|019|B||
02484|020|D|DISCUSSION:  Diltiazem, a moderate inhibitor of CYP3A4, increased suvorexant|
02484|021|D|AUC and Cmax by approximately 2-fold and 1.25-fold, respectively.(1)|
02484|022|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant, avacopan,|
02484|023|D|berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone,|
02484|024|D|erythromycin, duvelisib, fedratinib, fluconazole, fluvoxamine,|
02484|025|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir,|
02484|026|D|lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra,|
02484|027|D|stiripentol, tofisopam, treosulfan and verapamil.(1-3)|
02484|028|B||
02484|029|R|REFERENCES:|
02484|030|B||
02484|031|R|1.Belsomra (suvorexant) US prescribing information. Merck & Co., Inc. March,|1
02484|032|R|  2021.|1
02484|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02484|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02484|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02484|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02484|037|R|  11/14/2017.|1
02484|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
02484|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02485|001|T|MONOGRAPH TITLE:  Eliglustat/Strong & Moderate CYP3A4 Inhibitors|
02485|002|B||
02485|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02485|004|L|of severe adverse interaction.|
02485|005|B||
02485|006|A|MECHANISM OF ACTION:  Strong or moderate inhibitors of CYP3A4 may inhibit|
02485|007|A|the metabolism of eliglustat.  If the patient is also taking an inhibitor of|
02485|008|A|CYP2D6, eliglustat metabolism can be further inhibited.(1)|
02485|009|B||
02485|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that is a strong or moderate|
02485|011|E|inhibitor of CYP3A4 may result in elevated levels of and clinical effects of|
02485|012|E|eliglustat, including prolongation of the PR, QTc, and/or QRS intervals,|
02485|013|E|which may result in life-threatening cardiac arrhythmias.(1)|
02485|014|B||
02485|015|P|PREDISPOSING FACTORS:  If the patient has liver disease, is also taking an|
02485|016|P|inhibitor of CYP2D6 and/or is an intermediate or poor metabolizer of CYP2D6,|
02485|017|P|eliglustat metabolism can be further inhibited.(1)|
02485|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02485|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02485|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02485|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02485|022|P|advanced age.(2)|
02485|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02485|024|P|higher systemic concentrations of either QT prolonging drug are additional|
02485|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02485|026|P|drug concentrations include rapid infusion of an intravenous dose or|
02485|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02485|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02485|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02485|030|B||
02485|031|M|PATIENT MANAGEMENT:  The concurrent use of eliglustat with strong or|
02485|032|M|moderate inhibitors of CYP3A4 concomitantly with strong or moderate|
02485|033|M|inhibitors of CYP2D6 in both extensive and intermediate metabolizers of|
02485|034|M|CYP2D6 is contraindicated.(1)|
02485|035|M|   The concurrent use of eliglustat with strong inhibitors of CYP3A4 in|
02485|036|M|intermediate and poor metabolizers of CYP2D6 is contraindicated.(1)|
02485|037|M|   The concurrent use of eliglustat with moderate inhibitors of CYP3A4 in|
02485|038|M|intermediate and poor metabolizers of CYP2D6 should be avoided.(1)|
02485|039|M|   The dosage of eliglustat with strong or moderate inhibitors of CYP3A4 in|
02485|040|M|extensive metabolizers of CYP2D6 should be limited to 84 mg daily.(1)|
02485|041|M|   The concurrent use of eliglustat with strong inhibitors of CYP3A4|
02485|042|M|concomitantly with strong or moderate inhibitors of CYP2D6 is|
02485|043|M|contraindicated.(1)|
02485|044|M|   The concurrent use of eliglustat with moderate inhibitors of CYP3A4|
02485|045|M|concomitantly with strong or moderate inhibitors of CYP2D6 in poor|
02485|046|M|metabolizers of CYP2D6 should be avoided and is contraindicated in extensive|
02485|047|M|and intermediate metabolizers of CYP2D6.(1)|
02485|048|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02485|049|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02485|050|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02485|051|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02485|052|B||
02485|053|D|DISCUSSION:  Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4,|
02485|054|D|increased eliglustat (84 mg BID) maximum concentration (Cmax) and|
02485|055|D|area-under-curve (AUC) by  4-fold and 4.4-fold, respectively, in extensive|
02485|056|D|metabolizers.  Physiologically-based pharmacokinetic (PKPB) models suggested|
02485|057|D|ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and|
02485|058|D|5.4-fold, respectively, in intermediate metabolizers.  PKPB models suggested|
02485|059|D|ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily)  by|
02485|060|D|4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1)|
02485|061|D|   PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would|
02485|062|D|increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in|
02485|063|D|extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in|
02485|064|D|intermediate metabolizers.|
02485|065|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a|
02485|066|D|strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax|
02485|067|D|and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers.|
02485|068|D|In intermediate metabolizers, eliglustat Cmax and AUC would be expected to|
02485|069|D|increase 7.5-fold and 9.8-fold, respectively.(1)|
02485|070|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine|
02485|071|D|(a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat|
02485|072|D|Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive|
02485|073|D|metabolizers.  In intermediate metabolizers, eliglustat Cmax and AUC would|
02485|074|D|be expected to increase 4.2-fold and 5-fold, respectively.(1)|
02485|075|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02485|076|D|clarithromycin, indinavir, itraconazole, josamycin, ketoconazole,|
02485|077|D|levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone,|
02485|078|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
02485|079|D|ribociclib, saquinavir, telaprevir, telithromycin, tucatinib, and|
02485|080|D|voriconazole.(1,3,4)|
02485|081|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
02485|082|D|atazanavir, avacopan, casopitant, clofazimine, conivaptan, crizotinib,|
02485|083|D|darunavir, duvelisib, erythromycin, fluconazole, fosamprenavir,|
02485|084|D|fosnetupitant, isavuconazonium, lenacapavir, letermovir, netupitant,|
02485|085|D|nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and|
02485|086|D|treosulfan.(1,3,4)|
02485|087|B||
02485|088|R|REFERENCES:|
02485|089|B||
02485|090|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
02485|091|R|  August, 2018.|1
02485|092|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02485|093|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02485|094|R|  settings: a scientific statement from the American Heart Association and|6
02485|095|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02485|096|R|  2;55(9):934-47.|6
02485|097|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02485|098|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02485|099|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02485|100|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02485|101|R|  11/14/2017.|1
02485|102|R|4.This information is based on an extract from the Certara Drug Interaction|6
02485|103|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02486|001|T|MONOGRAPH TITLE:  Citalopram/QT Prolonging Agents|
02486|002|B||
02486|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02486|004|L|of severe adverse interaction.|
02486|005|B||
02486|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02486|007|A|interval may result in additive effects on the QTc interval.(1-3)|
02486|008|B||
02486|009|E|CLINICAL EFFECTS:  The use of citalopram in patients maintained on agents|
02486|010|E|that prolong the QTc interval may result in potentially life-threatening|
02486|011|E|cardiac arrhythmias, including torsades de pointes.(1-3)|
02486|012|B||
02486|013|P|PREDISPOSING FACTORS:  Higher doses of citalopram, especially doses greater|
02486|014|P|than 40 mg, may increase the risk of QT prolongation.|
02486|015|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02486|016|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02486|017|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02486|018|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02486|019|P|advanced age.(4)|
02486|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02486|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02486|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02486|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02486|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02486|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02486|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02486|027|B||
02486|028|M|PATIENT MANAGEMENT:  Concurrent use of citalopram with agents known to|
02486|029|M|prolong the QT interval should be avoided.|
02486|030|M|   Due to the risk of QT prolongation, citalopram doses greater than 40 mg|
02486|031|M|once daily are not recommended.  Citalopram doses should be limited to 20 mg|
02486|032|M|once daily in patients who are CYP2C19 poor metabolizers or patients|
02486|033|M|receiving CYP2C19 inhibitors.|
02486|034|M|   If patients have a persistent QTc measurement > 500 ms, discontinue|
02486|035|M|citalopram.  If a patient develops symptoms including dizziness,|
02486|036|M|palpitations, or syncope, further evaluation is warranted included cardiac|
02486|037|M|monitoring.|
02486|038|M|   The manufacturer recommends ECG monitoring in patients for whom|
02486|039|M|citalopram is not recommended, including those receiving concurrent therapy|
02486|040|M|with agents known to prolong the QT interval.  Citalopram should be|
02486|041|M|discontinued in patients with persistent QTc measurements greater than 500|
02486|042|M|ms.(1-2)  Consider obtaining serum calcium, magnesium, and potassium levels|
02486|043|M|at regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02486|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02486|045|B||
02486|046|D|DISCUSSION:  Citalopram has been associated with dose-depended increases in|
02486|047|D|the QTc interval.  In healthy subjects, the maximum mean difference in QTc|
02486|048|D|interval seen with 20 mg of citalopram and 60 mg of citalopram were 8.5 msec|
02486|049|D|(90% CI = 6.2-10.8 msec) and 18.5 msec (90% CI = 16.0-21.0 msec),|
02486|050|D|respectively.  Based on extrapolation, a 40 mg dose of citalopram is|
02486|051|D|expected to produce a mean increase in the QTc interval of 12.6 msec (90% CI|
02486|052|D|= 10.9-14.3 msec).(1)|
02486|053|D|   In a clinical trial of use of citalopram for agitation in Alzheimer's|
02486|054|D|disease, citalopram (30 mg daily) was associated with a mean increase in QTc|
02486|055|D|of 18.1 msec.(5)|
02486|056|D|   Agents that are linked to this monograph may have varying degrees of|
02486|057|D|potential to prolong the QTc interval but are generally accepted to have a|
02486|058|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02486|059|D|been shown to prolong the QTc interval either through their mechanism of|
02486|060|D|action, through studies on their effects on the QTc interval, or through|
02486|061|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02486|062|D|and/or post-marketing reports.(6)|
02486|063|D|   One or more of the drug pairs linked to this monograph have been included|
02486|064|D|in a list of interactions that should be considered "high-priority" for|
02486|065|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02486|066|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02486|067|D|Coordinator (ONC) for Health Information Technology.|
02486|068|B||
02486|069|R|REFERENCES:|
02486|070|B||
02486|071|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
02486|072|R|  Laboratories Inc. August, 2023.|1
02486|073|R|2.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
02486|074|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
02486|075|R|  Lundbeck Canada January 25, 2012.|1
02486|076|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02486|077|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
02486|078|R|  potential risk of abnormal heart rhythms with high doses. available at:|1
02486|079|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02486|080|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02486|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02486|082|R|  settings: a scientific statement from the American Heart Association and|6
02486|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02486|084|R|  2;55(9):934-47.|6
02486|085|R|5.Drye LT, et al. Changes in QTc interval in the citalopram for agitation in|2
02486|086|R|  Alzheimer's disease (CitAD) randomized trial. PLoS One 2014;9(6):e98426.|2
02486|087|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
02486|088|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02486|089|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02486|090|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02486|091|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02486|092|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02486|093|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02486|094|R|  19(5):735-43.|6
02487|001|T|MONOGRAPH TITLE:  Higher Strength Tricyclics;Trazodone/Fluoxetine;|
02487|002|T|Paroxetine|
02487|003|B||
02487|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02487|005|L|of severe adverse interaction.|
02487|006|B||
02487|007|A|MECHANISM OF ACTION:  Depending upon the interacting combination,|
02487|008|A|pharmacokinetic and/or pharmacodynamic interactions are possible.|
02487|009|A|   Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of|
02487|010|A|CYP2D6.(1)  Paroxetine is a strong inhibitor of CYP2D6.(1,2)|
02487|011|A|   Amitriptyline, clomipramine, doxepin, imipramine and trimipramine are|
02487|012|A|metabolized by CYP2C19 and CYP2D6.(1)  Desipramine and nortriptyline are|
02487|013|A|metabolized by CYP2D6.(1)|
02487|014|A|   Trazodone is metabolized by CYP3A4 and its metabolite, mCPP, is|
02487|015|A|pharmacologically active. MCPP is metabolized by CYP2D6 and when it|
02487|016|A|accumulates may be associated with adverse effects.|
02487|017|A|   Fluoxetine, paroxetine, clomipramine, and imipramine significantly|
02487|018|A|increase neuronal serotonin levels.|
02487|019|B||
02487|020|E|CLINICAL EFFECTS:  Concurrent administration of fluoxetine or paroxetine|
02487|021|E|with selected cyclic agents which are metabolized by CYP2D6 or CYP2C19 may|
02487|022|E|result in an increase in serum levels, toxicities (e.g. risk for seizures,|
02487|023|E|severe anticholinergic effects), and/or clinical effects of the tricyclic|
02487|024|E|agent or trazodone.|
02487|025|E|   Elevated levels of tricyclics and trazodone may increase the risk of QT|
02487|026|E|prolongation and the risk for torsades de pointes.|
02487|027|E|   Concurrent administration of fluoxetine or paroxetine with clomipramine,|
02487|028|E|and perhaps with imipramine, high dose amitriptyline, or trazodone may|
02487|029|E|increase the risk for serotonin syndrome.|
02487|030|B||
02487|031|P|PREDISPOSING FACTORS:  Higher doses or higher systemic concentrations of|
02487|032|P|fluoxetine or paroxetine may increase the magnitude of this interaction.|
02487|033|P|   Concurrent use of multiple drugs which increase CNS serotonin levels|
02487|034|P|would be expected to further increase risk for serotonin syndrome.(21)|
02487|035|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02487|036|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02487|037|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02487|038|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02487|039|P|advanced age.(20)|
02487|040|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02487|041|P|higher systemic concentrations of either QT prolonging drug are additional|
02487|042|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02487|043|P|drug concentrations include rapid infusion of an intravenous dose or|
02487|044|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02487|045|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
02487|046|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(20)|
02487|047|P|   The risk of seizures may be increased in patients with a history of head|
02487|048|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
02487|049|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
02487|050|P|of over-the-counter stimulants and anorectics; diabetics treated with oral|
02487|051|P|hypoglycemics or insulin; or with concomitant medications known to lower|
02487|052|P|seizure threshold (antipsychotics, theophylline, systemic steroids).|
02487|053|P|   The risk of anticholinergic toxicities including cognitive decline,|
02487|054|P|delirium, falls and fractures is increased in geriatric patients using more|
02487|055|P|than one medicine with anticholinergic properties.(22)|
02487|056|B||
02487|057|M|PATIENT MANAGEMENT:  Patients should be observed for increased adverse|
02487|058|M|effects and clinical effects of tricyclic compounds or trazodone at the|
02487|059|M|initiation of concurrent therapy with fluoxetine or paroxetine.  Plasma|
02487|060|M|concentrations of the tricyclic compound (e.g. doxepin,|
02487|061|M|imipramine/desipramine, amitriptyline/nortriptyline) should be monitored and|
02487|062|M|the dosage adjusted accordingly.|
02487|063|M|   If fluoxetine or paroxetine is discontinued in a patient receiving a|
02487|064|M|cyclic antidepressant, the dosage may need to be adjusted upward as the|
02487|065|M|effects of enzyme inhibition wane.|
02487|066|M|   The effects of fluoxetine on hepatic metabolism may last for up to 5|
02487|067|M|weeks after fluoxetine discontinuation.  A cyclic antidepressant started|
02487|068|M|after the discontinuation of fluoxetine should be started at a lower initial|
02487|069|M|dosage.|
02487|070|M|   Patients receiving fluoxetine or paroxetine and clomipramine, imipramine,|
02487|071|M|or higher dose amitriptyline should be monitored for serotonin syndrome.|
02487|072|M|Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis,|
02487|073|M|intermittent tremor, and/or myoclonus.  Moderate serotonin symptoms may|
02487|074|M|include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis,|
02487|075|M|hyperactive bowel sounds, hyperreflexia, and/OR clonus.  Severe serotonin|
02487|076|M|symptoms may include: severe hypertension and tachycardia, shock, agitated|
02487|077|M|delirium, muscular rigidity, and/or hypertonicity.|
02487|078|M|   When concurrent therapy may be associated with QT prolongation, consider|
02487|079|M|obtaining serum calcium, magnesium, and potassium levels and monitoring ECG|
02487|080|M|at baseline and at regular intervals.  Correct any electrolyte|
02487|081|M|abnormalities.  Instruct patients to report any irregular heartbeat,|
02487|082|M|dizziness, and fainting.|
02487|083|B||
02487|084|D|DISCUSSION:  Case reports have shown that the addition of fluoxetine to a|
02487|085|D|tricyclic compound therapy can result in an increase of 100-300% in the|
02487|086|D|tricyclic compound plasma concentration as well as an increase in adverse|
02487|087|D|effects, including seizures and delirium. In an 83 year-old patient, the|
02487|088|D|combination of clomipramine and fluoxetine resulted in high clomipramine|
02487|089|D|concentrations and cardiac side effects. In a 70 year old patient, the use|
02487|090|D|of venlafaxine, fluoxetine, and nortriptyline was associated with severe|
02487|091|D|anticholinergic side effects. This interaction was thought to be due to|
02487|092|D|increased nortriptyline levels.|
02487|093|D|    There is one case report of serotonin syndrome during concurrent therapy|
02487|094|D|with paroxetine and trazodone.(23) There have also been case reports of|
02487|095|D|serotonin syndrome  with trazodone and fluoxetine,(25) trazodone and|
02487|096|D|amitriptyline with lithium, and cyclobenzaprine(structurally related to the|
02487|097|D|TCAs) with duloxetine. In a 24 year-old patient, the use of fluoxetine and|
02487|098|D|trazodone resulted in severe irritability, anger, anxiety, and anorexia.(24)|
02487|099|D|  In a study in 11 patients, concurrent administration of trazodone 100|
02487|100|D|mg/day and fluoxetine 20 mg/day increased the concentrations of trazodone|
02487|101|D|and its active metabolite mCPP by 65% and 231%.(25)|
02487|102|D|   QTc prolongation also exists with some antidepressants. In a case report,|
02487|103|D|the combination of levofloxacin, imipramine, and fluoxetine was associated|
02487|104|D|with a QTc of 509msec. The authors concluded that this interaction was due|
02487|105|D|to the pharmacodynamic additive effect among fluoxetine, imipramine, and|
02487|106|D|levofloxacin.|
02487|107|D|   Cyclic antidepressants included in this monograph are amitriptyline (> 40|
02487|108|D|mg), clomipramine (> 25 mg), desipramine (all strengths), doxepin (> 25 mg),|
02487|109|D|imipramine (> 10 mg), nortriptyline (> 30 mg), trazodone (> 75 mg), and|
02487|110|D|trimipramine (> 25 mg).|
02487|111|B||
02487|112|R|REFERENCES:|
02487|113|B||
02487|114|R|1.This information is based on an extract from the Certara Drug Interaction|6
02487|115|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02487|116|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02487|117|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02487|118|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02487|119|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02487|120|R|  11/14/2017.|1
02487|121|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02487|122|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02487|123|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02487|124|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02487|125|R|4.Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of|3
02487|126|R|  combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990|3
02487|127|R|  Apr;147(4):532.|3
02487|128|R|5.Kahn DG. Increased plasma nortriptyline concentration in a patient|3
02487|129|R|  cotreated with fluoxetine. J Clin Psychiatry 1990 Jan;51(1):36.|3
02487|130|R|6.Ciraulo DA, Shader RI. Fluoxetine drug-drug interactions: I.|6
02487|131|R|  Antidepressants and antipsychotics. J Clin Psychopharmacol 1990 Feb;|6
02487|132|R|  10(1):48-50.|6
02487|133|R|7.Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J|3
02487|134|R|  Psychiatry 1988 Nov;145(11):1478.|3
02487|135|R|8.Bell IR, Cole JO. Fluoxetine induces elevation of desipramine level and|3
02487|136|R|  exacerbation of geriatric nonpsychotic depression. J Clin Psychopharmacol|3
02487|137|R|  1988 Dec;8(6):447-8.|3
02487|138|R|9.Aranow AB, Hudson JI, Pope HG Jr, Grady TA, Laage TA, Bell IR, Cole JO.|3
02487|139|R|  Elevated antidepressant plasma levels after addition of fluoxetine. Am J|3
02487|140|R|  Psychiatry 1989 Jul;146(7):911-3.|3
02487|141|R|10.Goodnick PJ. Influence of fluoxetine on plasma levels of desipramine. Am|3
02487|142|R|   J Psychiatry 1989 Apr;146(4):552.|3
02487|143|R|11.Schraml F, Benedetti G, Hoyle K, Clayton A. Fluoxetine and nortriptyline|3
02487|144|R|   combination therapy. Am J Psychiatry 1989 Dec;146(12):1636-7.|3
02487|145|R|12.Downs JM, Downs AD, Rosenthal TL, Deal N, Akiskal HS. Increased plasma|3
02487|146|R|   tricyclic antidepressant concentrations in two patients concurrently|3
02487|147|R|   treated with fluoxetine. J Clin Psychiatry 1989 Jun;50(6):226-7.|3
02487|148|R|13.Downs JM, Dahmer SK. Fluoxetine and elevated plasma levels of tricyclic|3
02487|149|R|   antidepressants. Am J Psychiatry 1990 Sep;147(9):1251.|3
02487|150|R|14.Westermeyer J. Fluoxetine-induced tricyclic toxicity: extent and|3
02487|151|R|   duration. J Clin Pharmacol 1991 Apr;31(4):388-92.|3
02487|152|R|15.Rosenstein DL, Takeshita J, Nelson JC. Fluoxetine-induced elevation and|3
02487|153|R|   prolongation of tricyclic levels in overdose. Am J Psychiatry 1991 Jun;|3
02487|154|R|   148(6):807.|3
02487|155|R|16.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
02487|156|R|   fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
02487|157|R|   1992 Mar;51(3):239-48.|2
02487|158|R|17.Skjelbo E, Brosen K. Inhibitors of imipramine metabolism by human liver|5
02487|159|R|   microsomes. Br J Clin Pharmacol 1992 Sep;34(3):256-61.|5
02487|160|R|18.Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, Harris S.|2
02487|161|R|   Pharmacokinetics of desipramine coadministered with sertraline or|2
02487|162|R|   fluoxetine. J Clin Psychopharmacol 1994 Apr;14(2):90-8.|2
02487|163|R|19.Balant-Gorgia AE, Ries C, Balant LP. Metabolic interaction between|3
02487|164|R|   fluoxetine and clomipramine: a case report. Pharmacopsychiatry 1996 Jan;|3
02487|165|R|   29(1):38-41.|3
02487|166|R|20.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
02487|167|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
02487|168|R|   hospital settings: a scientific statement from the American Heart|6
02487|169|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
02487|170|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
02487|171|R|21.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02487|172|R|   352(11):1112-20.|6
02487|173|R|22.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02487|174|R|   potentially  inappropriate medication use in older adults. J Am Geriatr|6
02487|175|R|   Soc 2023 Jul;71(7):2052-2081.|6
02487|176|R|23.Reeves RR, Bullen JA. Serotonin syndrome produced by paroxetine and|3
02487|177|R|   low-dose trazodone. Psychosomatics 1995 Mar-Apr;36(2):159-60.|3
02487|178|R|24.Amin R. Fluoxetine and Trazodone Combination Pharmacotherapy Resulting in|3
02487|179|R|   Severe Irritability, Anger, Anxiety, and Anorexia: Probable Adverse Drug|3
02487|180|R|   Interaction. Prim Care Companion CNS Disord 2016 Aug 11;18(4):.|3
02487|181|R|25.Maes M, Westenberg H, Vandoolaeghe E, Demedts P, Wauters A, Neels H,|2
02487|182|R|   Meltzer HY. Effects of trazodone and fluoxetine in the treatment of major|2
02487|183|R|   depression: therapeutic pharmacokinetic and pharmacodynamic interactions|2
02487|184|R|   through formation of meta-chlorophenylpiperazine. J Clin Psychopharmacol|2
02487|185|R|   1997 Oct;17(5):358-64.|2
02487|186|R|26.George TP, Godleski LS. Possible serotonin syndrome with trazodone|3
02487|187|R|   addition to fluoxetine. Biol Psychiatry 1996 Mar 1;39(5):384-5.|3
02488|001|T|MONOGRAPH TITLE:  Eliglustat/Strong & Moderate CYP2D6 Inhibitors|
02488|002|B||
02488|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02488|004|L|of severe adverse interaction.|
02488|005|B||
02488|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2D6 may inhibit the metabolism|
02488|007|A|of eliglustat.  If the patient is also taking an inhibitor of CYP3A4,|
02488|008|A|eliglustat metabolism can be further inhibited.(1)|
02488|009|B||
02488|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that is a strong or moderate|
02488|011|E|inhibitor of CYP2D6 may result in elevated levels of and clinical effects of|
02488|012|E|eliglustat, including prolongation of the PR, QTc, and/or QRS intervals,|
02488|013|E|which may result in life-threatening cardiac arrhythmias.(1)|
02488|014|B||
02488|015|P|PREDISPOSING FACTORS:  If the patient has hepatic impairment, is also taking|
02488|016|P|an inhibitor of CYP3A4 and/or is an extensive or intermediate metabolizer of|
02488|017|P|CYP2D6, eliglustat metabolism can be further inhibited.(1)|
02488|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02488|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02488|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02488|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02488|022|P|advanced age.(2)|
02488|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02488|024|P|higher systemic concentrations of either QT prolonging drug are additional|
02488|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02488|026|P|drug concentrations include rapid infusion of an intravenous dose or|
02488|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02488|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02488|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02488|030|B||
02488|031|M|PATIENT MANAGEMENT:  The dosage of eliglustat with strong or moderate|
02488|032|M|inhibitors of CYP2D6 in both extensive and intermediate CYP2D6 metabolizers|
02488|033|M|should be limited to 84 mg daily.(1)|
02488|034|M|   The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in|
02488|035|M|poor CYP2D6 metabolizers should be continued at 84 mg once daily.(1)|
02488|036|M|   The concurrent use of eliglustat with strong inhibitors of CYP3A4|
02488|037|M|concomitantly with strong or moderate inhibitors of CYP2D6 is|
02488|038|M|contraindicated.(1)|
02488|039|M|   The concurrent use of eliglustat with moderate inhibitors of CYP3A4|
02488|040|M|concomitantly with strong or moderate inhibitors of CYP2D6 in poor|
02488|041|M|metabolizers of CYP2D6 should be avoided and is contraindicated in extensive|
02488|042|M|and intermediate metabolizers of CYP2D6.(1)|
02488|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02488|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02488|045|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02488|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02488|047|M|   Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected|
02488|048|M|to last at least 28 days after administration.(5)|
02488|049|B||
02488|050|D|DISCUSSION:  Paroxetine (30 mg daily), a strong inhibitor of CYP2D6,|
02488|051|D|increased eliglustat (84 mg BID) maximum concentration (Cmax) and|
02488|052|D|area-under-curve (AUC) by  7-fold and 8.4-fold, respectively, in extensive|
02488|053|D|metabolizers.  Physiologically-based pharmacokinetic (PKPB) models suggested|
02488|054|D|paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold,|
02488|055|D|respectively, in intermediate metabolizers.  PKPB models suggested|
02488|056|D|ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily)  by|
02488|057|D|4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1)|
02488|058|D|   PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would|
02488|059|D|increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in|
02488|060|D|extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in|
02488|061|D|intermediate metabolizers.|
02488|062|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a|
02488|063|D|strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax|
02488|064|D|and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers.|
02488|065|D|In intermediate metabolizers, eliglustat Cmax and AUC would be expected to|
02488|066|D|increase 7.5-fold and 9.8-fold, respectively.(1)|
02488|067|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine|
02488|068|D|(a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat|
02488|069|D|Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive|
02488|070|D|metabolizers.  In intermediate metabolizers, eliglustat Cmax and AUC would|
02488|071|D|be expected to increase 4.2-fold and 5-fold, respectively.(1)|
02488|072|D|   A single dose of rolapitant increased dextromethorphan, a CYP2D6|
02488|073|D|substrate, about 3-fold on days 8 and day 22 following administration.|
02488|074|D|Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single|
02488|075|D|dose rolapitant.  The inhibitory effects of rolapitant on CYP2D6 are|
02488|076|D|expected to persist beyond 28 days.(5)|
02488|077|D|   Strong inhibitors of CYP2D6 include:  bupropion, dacomitinib, fluoxetine,|
02488|078|D|hydroquinidine, paroxetine, quinidine, and terbinafine.(1,3,4)|
02488|079|D|   Moderate inhibitors of CYP2D6 include:  abiraterone, asunaprevir,|
02488|080|D|capivasertib, cinacalcet, duloxetine, escitalopram, levomethadone,|
02488|081|D|mirabegron, moclobemide, and rolapitant.(1,3,4)|
02488|082|B||
02488|083|R|REFERENCES:|
02488|084|B||
02488|085|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
02488|086|R|  August, 2018.|1
02488|087|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02488|088|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02488|089|R|  settings: a scientific statement from the American Heart Association and|6
02488|090|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02488|091|R|  2;55(9):934-47.|6
02488|092|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02488|093|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02488|094|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02488|095|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02488|096|R|  11/14/2017.|1
02488|097|R|4.This information is based on an extract from the Certara Drug Interaction|6
02488|098|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02488|099|R|5.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
02489|001|T|MONOGRAPH TITLE:  Lower Strength Tricyclics; Trazodone/Fluoxetine;|
02489|002|T|Paroxetine|
02489|003|B||
02489|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02489|005|L|take action as needed.|
02489|006|B||
02489|007|A|MECHANISM OF ACTION:  Depending upon the interacting combination,|
02489|008|A|pharmacokinetic and/or pharmacodynamic interactions are possible.|
02489|009|A|   Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of|
02489|010|A|CYP2D6.(1)  Paroxetine is a strong inhibitor of CYP2D6.(1,2)|
02489|011|A|   Amitriptyline, clomipramine, doxepin, imipramine and trimipramine are|
02489|012|A|metabolized by CYP2C19 and CYP2D6.(1)  Desipramine, nortriptyline,|
02489|013|A|amoxapine, and protriptyline are metabolized by CYP2D6.(1)|
02489|014|A|   Trazodone is metabolized to mCPP, an active metabolite with potential|
02489|015|A|adverse effects, by CYP2D6. Cyclobenzaprine is metabolized by CYP1A2 and|
02489|016|A|CYP3A4 and so a pharmacokinetic interaction is not expected.|
02489|017|A|   Fluoxetine, paroxetine, and clomipramine significantly increase neuronal|
02489|018|A|serotonin levels.|
02489|019|B||
02489|020|E|CLINICAL EFFECTS:  Concurrent administration of fluoxetine or paroxetine|
02489|021|E|with tricyclics metabolized by CYP2D6 or CYP2C19 may result in an increase|
02489|022|E|in serum levels, toxicities (e.g. risk for seizures, severe anticholinergic|
02489|023|E|effects), and/or clinical effects of the tricyclic or trazodone.|
02489|024|E|   Elevated levels of tricyclics and trazodone may increase the risk of QT|
02489|025|E|prolongation and the risk for torsades de pointes.|
02489|026|E|   Concurrent administration of fluoxetine or paroxetine with clomipramine|
02489|027|E|and perhaps with imipramine, cyclobenzaprine, high dose amitriptyline, or|
02489|028|E|trazodone may increase the risk for serotonin syndrome.|
02489|029|B||
02489|030|P|PREDISPOSING FACTORS:  Higher doses or higher systemic concentrations of|
02489|031|P|fluoxetine or paroxetine may increase the magnitude of this interaction.|
02489|032|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02489|033|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02489|034|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02489|035|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02489|036|P|advanced age.(19)|
02489|037|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02489|038|P|higher systemic concentrations of either QT prolonging drug are additional|
02489|039|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02489|040|P|drug concentrations include rapid infusion of an intravenous dose or|
02489|041|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02489|042|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
02489|043|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(19)|
02489|044|P|   Concurrent use of multiple drugs which increase CNS serotonin levels|
02489|045|P|would be expected to further increase risk for serotonin syndrome.(20)|
02489|046|P|   The risk of seizures may be increased in patients with a history of head|
02489|047|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
02489|048|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
02489|049|P|of over-the-counter stimulants and anorectics; diabetics treated with oral|
02489|050|P|hypoglycemics or insulin; or with concomitant medications known to lower|
02489|051|P|seizure threshold (antipsychotics, theophylline, systemic steroids).|
02489|052|P|   The risk of anticholinergic toxicities including cognitive decline,|
02489|053|P|delirium, falls and fractures is increased in geriatric patients using more|
02489|054|P|than one medicine with anticholinergic properties.(21)|
02489|055|B||
02489|056|M|PATIENT MANAGEMENT:  Patients should be observed for increased adverse|
02489|057|M|effects and clinical effects of tricyclic compounds or trazodone when|
02489|058|M|concurrent therapy with fluoxetine or paroxetine is started or if the dosage|
02489|059|M|of either agent is increased.  Plasma concentrations of the tricyclic|
02489|060|M|compound (e.g. doxepin, amitriptyline/nortriptyline, imipramine/desipramine)|
02489|061|M|should be monitored and the dosage adjusted accordingly.|
02489|062|M|   If the fluoxetine or paroxetine is discontinued in a patient receiving a|
02489|063|M|trazodone or tricyclic compound other than cyclobenzaprine, the dosage may|
02489|064|M|need to be adjusted upward as the effects of enzyme inhibition wane.|
02489|065|M|   The effects of fluoxetine on hepatic metabolism may last for 3-5 weeks|
02489|066|M|after fluoxetine discontinuation.  A cyclic compound (other than|
02489|067|M|cyclobenzaprine) started after the discontinuation of fluoxetine should be|
02489|068|M|started at a lower initial dosage.|
02489|069|M|   Patients receiving fluoxetine or paroxetine and clomipramine, imipramine,|
02489|070|M|and perhaps cyclobenzaprine, higher dose amitriptyline, or trazodone should|
02489|071|M|be monitored for serotonin syndrome.  Mild serotonin symptoms may include:|
02489|072|M|shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.|
02489|073|M|Moderate serotonin symptoms may include: tachycardia, hypertension,|
02489|074|M|hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds,|
02489|075|M|hyperreflexia, and/OR clonus.  Severe serotonin symptoms may include: severe|
02489|076|M|hypertension and tachycardia, shock, agitated delirium, muscular rigidity,|
02489|077|M|and/or hypertonicity.(20)|
02489|078|M|   When concurrent therapy may be associated with QT prolongation, consider|
02489|079|M|obtaining serum calcium, magnesium, and potassium levels and monitoring ECG|
02489|080|M|at baseline and at regular intervals.  Correct any electrolyte|
02489|081|M|abnormalities.  Instruct patients to report any irregular heartbeat,|
02489|082|M|dizziness, or fainting.|
02489|083|B||
02489|084|D|DISCUSSION:  Case reports have shown that the addition of fluoxetine to a|
02489|085|D|tricyclic compound therapy can result in an increase of 100-300% in the|
02489|086|D|tricyclic compound plasma concentration as well as an increase in adverse|
02489|087|D|effects, including seizures and delirium. In a 83 year-old patient, the|
02489|088|D|combination of clomipramine and fluoxetine resulted in high clomipramine|
02489|089|D|concentrations and cardiac side effects. In a 70 year old patient, the use|
02489|090|D|of venlafaxine, fluoxetine, and nortriptyline was associated with severe|
02489|091|D|anticholinergic side effects. This interaction was thought to be due to|
02489|092|D|increased nortriptyline levels.|
02489|093|D|    There is one case report of serotonin syndrome during concurrent therapy|
02489|094|D|with paroxetine and trazodone.(24) There have also been case reports of|
02489|095|D|serotonin syndrome  with trazodone and fluoxetine,(28) and trazodone and|
02489|096|D|amitriptyline with lithium. In a 24 year-old patient, the use of fluoxetine|
02489|097|D|and trazodone resulted in severe irritability, anger, anxiety, and|
02489|098|D|anorexia.(25)|
02489|099|D|   In a study in 11 patients, concurrent administration of trazodone 100|
02489|100|D|mg/day and fluoxetine 20 mg/day increased the concentrations of trazodone|
02489|101|D|and its active metabolite mCPP by 65% and 231%.(27)|
02489|102|D|   In a 50 year-old patient, the use of protriptyline and fluoxetine|
02489|103|D|resulted in anticholinergic delirium.(26)|
02489|104|D|   The manufacturer of cyclobenzaprine reports that serotonin syndrome has|
02489|105|D|been reported when combined with other serotonergic agents.(23)|
02489|106|D|   QTc prolongation also exists with some antidepressants. In a case report,|
02489|107|D|the combination of levofloxacin, imipramine, and fluoxetine was associated|
02489|108|D|with a QTc of 509msec. The authors concluded that this interaction was due|
02489|109|D|to the pharmacodynamic additive effect among fluoxetine, imipramine, and|
02489|110|D|levofloxacin.|
02489|111|D|   Cyclic agents included in this monograph are amitriptyline (<=40mg),|
02489|112|D|amoxapine, clomipramine (<=25mg), cyclobenzaprine (structurally similar to|
02489|113|D|amitriptyline), doxepin (<=25mg), imipramine (<=10mg), melitracen,|
02489|114|D|nortriptyline (<=30mg), protriptyline, trazodone (<=75mg), and trimipramine|
02489|115|D|(<=25mg).|
02489|116|B||
02489|117|R|REFERENCES:|
02489|118|B||
02489|119|R|1.This information is based on an extract from the Certara Drug Interaction|6
02489|120|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02489|121|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02489|122|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02489|123|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02489|124|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02489|125|R|  11/14/2017.|1
02489|126|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02489|127|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02489|128|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02489|129|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02489|130|R|4.Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of|3
02489|131|R|  combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990|3
02489|132|R|  Apr;147(4):532.|3
02489|133|R|5.Kahn DG. Increased plasma nortriptyline concentration in a patient|3
02489|134|R|  cotreated with fluoxetine. J Clin Psychiatry 1990 Jan;51(1):36.|3
02489|135|R|6.Ciraulo DA, Shader RI. Fluoxetine drug-drug interactions: I.|6
02489|136|R|  Antidepressants and antipsychotics. J Clin Psychopharmacol 1990 Feb;|6
02489|137|R|  10(1):48-50.|6
02489|138|R|7.Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J|3
02489|139|R|  Psychiatry 1988 Nov;145(11):1478.|3
02489|140|R|8.Bell IR, Cole JO. Fluoxetine induces elevation of desipramine level and|3
02489|141|R|  exacerbation of geriatric nonpsychotic depression. J Clin Psychopharmacol|3
02489|142|R|  1988 Dec;8(6):447-8.|3
02489|143|R|9.Aranow AB, Hudson JI, Pope HG Jr, Grady TA, Laage TA, Bell IR, Cole JO.|3
02489|144|R|  Elevated antidepressant plasma levels after addition of fluoxetine. Am J|3
02489|145|R|  Psychiatry 1989 Jul;146(7):911-3.|3
02489|146|R|10.Goodnick PJ. Influence of fluoxetine on plasma levels of desipramine. Am|3
02489|147|R|   J Psychiatry 1989 Apr;146(4):552.|3
02489|148|R|11.Schraml F, Benedetti G, Hoyle K, Clayton A. Fluoxetine and nortriptyline|3
02489|149|R|   combination therapy. Am J Psychiatry 1989 Dec;146(12):1636-7.|3
02489|150|R|12.Downs JM, Downs AD, Rosenthal TL, Deal N, Akiskal HS. Increased plasma|3
02489|151|R|   tricyclic antidepressant concentrations in two patients concurrently|3
02489|152|R|   treated with fluoxetine. J Clin Psychiatry 1989 Jun;50(6):226-7.|3
02489|153|R|13.Downs JM, Dahmer SK. Fluoxetine and elevated plasma levels of tricyclic|3
02489|154|R|   antidepressants. Am J Psychiatry 1990 Sep;147(9):1251.|3
02489|155|R|14.Westermeyer J. Fluoxetine-induced tricyclic toxicity: extent and|3
02489|156|R|   duration. J Clin Pharmacol 1991 Apr;31(4):388-92.|3
02489|157|R|15.Rosenstein DL, Takeshita J, Nelson JC. Fluoxetine-induced elevation and|3
02489|158|R|   prolongation of tricyclic levels in overdose. Am J Psychiatry 1991 Jun;|3
02489|159|R|   148(6):807.|3
02489|160|R|16.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
02489|161|R|   fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
02489|162|R|   1992 Mar;51(3):239-48.|2
02489|163|R|17.Skjelbo E, Brosen K. Inhibitors of imipramine metabolism by human liver|5
02489|164|R|   microsomes. Br J Clin Pharmacol 1992 Sep;34(3):256-61.|5
02489|165|R|18.Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, Harris S.|2
02489|166|R|   Pharmacokinetics of desipramine coadministered with sertraline or|2
02489|167|R|   fluoxetine. J Clin Psychopharmacol 1994 Apr;14(2):90-8.|2
02489|168|R|19.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
02489|169|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
02489|170|R|   hospital settings: a scientific statement from the American Heart|6
02489|171|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
02489|172|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
02489|173|R|20.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02489|174|R|   352(11):1112-20.|6
02489|175|R|21.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02489|176|R|   potentially  inappropriate medication use in older adults. J Am Geriatr|6
02489|177|R|   Soc 2023 Jul;71(7):2052-2081.|6
02489|178|R|22.Balant-Gorgia AE, Ries C, Balant LP. Metabolic interaction between|3
02489|179|R|   fluoxetine and clomipramine: a case report. Pharmacopsychiatry 1996 Jan;|3
02489|180|R|   29(1):38-41.|3
02489|181|R|23.Amrix (cyclobenzaprine extended release) US prescribing information. Teva|1
02489|182|R|   Pharmaceuticals Ltd. May, 2016.|1
02489|183|R|24.Reeves RR, Bullen JA. Serotonin syndrome produced by paroxetine and|3
02489|184|R|   low-dose trazodone. Psychosomatics 1995 Mar-Apr;36(2):159-60.|3
02489|185|R|25.Amin R. Fluoxetine and Trazodone Combination Pharmacotherapy Resulting in|3
02489|186|R|   Severe Irritability, Anger, Anxiety, and Anorexia: Probable Adverse Drug|3
02489|187|R|   Interaction. Prim Care Companion CNS Disord 2016 Aug 11;18(4):.|3
02489|188|R|26.Paul KL, Bhatara VS. Anticholinergic delirium possibly associated with|3
02489|189|R|   protriptyline and fluoxetine. Ann Pharmacother 1997 Oct;31(10):1260-1.|3
02489|190|R|27.Maes M, Westenberg H, Vandoolaeghe E, Demedts P, Wauters A, Neels H,|2
02489|191|R|   Meltzer HY. Effects of trazodone and fluoxetine in the treatment of major|2
02489|192|R|   depression: therapeutic pharmacokinetic and pharmacodynamic interactions|2
02489|193|R|   through formation of meta-chlorophenylpiperazine. J Clin Psychopharmacol|2
02489|194|R|   1997 Oct;17(5):358-64.|2
02489|195|R|28.George TP, Godleski LS. Possible serotonin syndrome with trazodone|3
02489|196|R|   addition to fluoxetine. Biol Psychiatry 1996 Mar 1;39(5):384-5.|3
02490|001|T|MONOGRAPH TITLE:  Eliglustat/Class IA & III Antiarrhythmics|
02490|002|B||
02490|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02490|004|L|of severe adverse interaction.|
02490|005|B||
02490|006|A|MECHANISM OF ACTION:  Concurrent use of eliglustat and Class IA or III|
02490|007|A|antiarrhythmics may result in additive effects on the PR, QRS and QTc|
02490|008|A|interval.(1)|
02490|009|B||
02490|010|E|CLINICAL EFFECTS:  Concurrent use of eliglustat and Class IA or III|
02490|011|E|antiarrhythmics may result in QTc prolongation and life-threatening cardiac|
02490|012|E|arrhythmias, including torsades de pointes.(1)|
02490|013|B||
02490|014|P|PREDISPOSING FACTORS:  If the patient has hepatic impairment, eliglustat|
02490|015|P|metabolism can be inhibited and result in increased levels and increased|
02490|016|P|risk of QT prolongation.|
02490|017|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02490|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02490|019|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02490|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender,|
02490|021|P|advanced age, use of multiple medications, and/or in patients who are taking|
02490|022|P|strong CYP3A4 inhibitors.(2)|
02490|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02490|024|P|higher systemic concentrations of either QT prolonging drug are additional|
02490|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02490|026|P|drug concentrations include rapid infusion of an intravenous dose or|
02490|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02490|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02490|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02490|030|B||
02490|031|M|PATIENT MANAGEMENT:  Systemic exposure to eliglustat is highly variable|
02490|032|M|depending upon use of concurrent CYP2D6 and/or CYP3A4 inhibitors and the|
02490|033|M|patient's CYP2D6 metabolizer status. For example,|
02490|034|M|   - Eliglustat maximum concentration (Cmax) and area-under-curve (AUC)|
02490|035|M|increased 7.0-fold and 8.4-fold respectively in CYP2D6 extensive|
02490|036|M|metabolizers (EM) treated with paroxetine 30 mg daily.|
02490|037|M|   - In simulated models, concomitant use of both a strong CYP3A4 inhibitor|
02490|038|M|(e.g. ketoconazole) and a strong CYP2D6 inhibitor (e.g. paroxetine) may|
02490|039|M|increase eliglustat Cmax and AUC 16.7-fold and 24-fold respectively in|
02490|040|M|CYP2D6 EMs.|
02490|041|M|   Because high systemic concentrations of eliglustat prolong PR, QRS and|
02490|042|M|QTc intervals and because systemic exposure to eliglustat in a particular|
02490|043|M|individual may be very high, the use of eliglustat is not recommended in|
02490|044|M|patients maintained on Class IA or III antiarrhythmics.(1)|
02490|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02490|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02490|047|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02490|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02490|049|B||
02490|050|D|DISCUSSION:  Eliglustat has been shown to prolong the PR, QRS and QTc|
02490|051|D|interval in a dose dependent manner.(1)|
02490|052|B||
02490|053|R|REFERENCES:|
02490|054|B||
02490|055|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
02490|056|R|  August, 2018.|1
02490|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02490|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02490|059|R|  settings: a scientific statement from the American Heart Association and|6
02490|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02490|061|R|  2;55(9):934-47.|6
02491|001|T|MONOGRAPH TITLE:  Eliglustat/Strong CYP3A4 Inducers|
02491|002|B||
02491|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02491|004|L|of severe adverse interaction.|
02491|005|B||
02491|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may significantly increase|
02491|007|A|the metabolism of eliglustat.(1)|
02491|008|B||
02491|009|E|CLINICAL EFFECTS:  Coadministration of eliglustat with a strong CYP3A4|
02491|010|E|inducer may increase the risk for treatment failure.|
02491|011|B||
02491|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02491|013|P|of the inducer for longer than 1-2 weeks.|
02491|014|B||
02491|015|M|PATIENT MANAGEMENT:  The concurrent use of eliglustat with strong CYP3A4|
02491|016|M|inducers should be avoided.(1)|
02491|017|M|   Due to the risk for treatment failure, if treatment with a strong CYP3A4|
02491|018|M|inducer is required consider conversion to an alternate treatment for|
02491|019|M|Gaucher disease.|
02491|020|B||
02491|021|D|DISCUSSION:  In CYP2D6 extensive metabolizers (EMs) and intermediate|
02491|022|D|metabolizers (IMs) the concurrent use of eliglustat 127 mg twice daily|
02491|023|D|(higher than approved dose) with rifampin 600mg PO daily decreased|
02491|024|D|eliglustat maximum concentration (Cmax) and area-under-curve (AUC) by|
02491|025|D|approximately 90%.(1)|
02491|026|D|   In CYP2D6 poor metabolizers (PMs), concurrent use of eliglustat 84 mg|
02491|027|D|twice daily (twice the recommended dose for CYP2D6 PMs) with rifampin 600 mg|
02491|028|D|PO daily decreased systemic eliglustat exposures approximately 95%.(1)|
02491|029|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
02491|030|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02491|031|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
02491|032|D|rifampin, rifapentine and St. John's wort.(2,3)|
02491|033|B||
02491|034|R|REFERENCES:|
02491|035|B||
02491|036|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
02491|037|R|  August, 2018.|1
02491|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02491|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02491|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02491|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02491|042|R|  11/14/2017.|1
02491|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
02491|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02492|001|T|MONOGRAPH TITLE:  Digoxin/Eliglustat|
02492|002|B||
02492|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02492|004|L|take action as needed.|
02492|005|B||
02492|006|A|MECHANISM OF ACTION:  Digoxin is a substrate for P-glycoprotein (P-gp).|
02492|007|A|P-gp in the gastrointestinal tract limits systemic absorption of digoxin.|
02492|008|A|Eliglustat inhibition of P-gp may lead to increased absorption of|
02492|009|A|digoxin.(1)|
02492|010|B||
02492|011|E|CLINICAL EFFECTS:  Concurrent eliglustat may result in elevated levels of|
02492|012|E|and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can include|
02492|013|E|anorexia, nausea, vomiting, heart block (first, second or third-degree) or|
02492|014|E|other arrhythmias, visual disturbances, confusion, weakness, malaise,|
02492|015|E|headache, anxiety, depression, delirium, disorientation or|
02492|016|E|hallucinations.(2)|
02492|017|B||
02492|018|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02492|019|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02492|020|P|risk of digoxin toxicity.(2)|
02492|021|B||
02492|022|M|PATIENT MANAGEMENT:  Measure serum digoxin concentrations before starting|
02492|023|M|eliglustat.  Reduce digoxin dose by 30% and continue monitoring.(1)|
02492|024|M|   Counsel patients to assure they are aware of signs or symptoms of digoxin|
02492|025|M|toxicity such as nausea, vomiting, persistent diarrhea, confusion, weakness,|
02492|026|M|or visual disturbances as these could be signs that the digoxin dose may|
02492|027|M|need to be lowered.|
02492|028|B||
02492|029|D|DISCUSSION:  Multiple doses of eliglustat at higher than presently|
02492|030|D|recommended doses - 127 mg twice daily in CYP2D6 extensive or intermediate|
02492|031|D|metabolizers, or 84 mg twice daily in CYP2D6 poor metabolizers, increased|
02492|032|D|systemic exposure to digoxin.  The mean digoxin maximum concentration (Cmax)|
02492|033|D|increased 1.7 fold and area-under-curve (AUC) increased 1.5 fold.(1)|
02492|034|B||
02492|035|R|REFERENCES:|
02492|036|B||
02492|037|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
02492|038|R|  August, 2018.|1
02492|039|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
02492|040|R|  Pharmaceuticals, Inc. August, 2018.|1
02493|001|T|MONOGRAPH TITLE:  Ruxolitinib/Fluconazole|
02493|002|B||
02493|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02493|004|L|of severe adverse interaction.|
02493|005|B||
02493|006|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of ruxolitinib|
02493|007|A|by CYP3A4 and CYP2C9.(1)|
02493|008|B||
02493|009|E|CLINICAL EFFECTS:  Concurrent use of fluconazole may increase levels of and|
02493|010|E|effects from ruxolitinib, including thrombocytopenia, anemia, neutropenia,|
02493|011|E|increased serious infection risk or lipid level elevations.(1)|
02493|012|B||
02493|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
02493|014|P|a low platelet count.(1)|
02493|015|B||
02493|016|M|PATIENT MANAGEMENT:  For patients with acute graft-versus-host disease|
02493|017|M|(GVHD), no dose adjustment of ruxolitinib or fluconazole is needed.(1)|
02493|018|M|   For patients undergoing therapy with ruxolitinib for other indications,|
02493|019|M|avoid the use of fluconazole at doses greater than 200 mg daily.(1)|
02493|020|M|   Starting doses of ruxolitinib therapy in patients with a diagnosis of|
02493|021|M|myelofibrosis and concurrently taking less than or equal to 200 mg of|
02493|022|M|fluconazole, should be made based on platelet count. In patients with a|
02493|023|M|platelet count greater than or equal to 100 X 10x9/L who are receiving|
02493|024|M|fluconazole at doses less than or equal to 200 mg, the recommended starting|
02493|025|M|dose of ruxolitinib is 10 mg twice daily.  In patients with a platelet count|
02493|026|M|greater than 50 X 10x9/L to less than 100 X 10x9/L who are receiving|
02493|027|M|fluconazole at doses less than or equal to 200 mg, the recommended starting|
02493|028|M|dose of ruxolitinib is 5 mg once daily.(1)|
02493|029|M|   The starting dose of ruxolitinib in patients with a diagnosis of|
02493|030|M|polycythemia vera and concurrently taking less than or equal to 200 mg of|
02493|031|M|fluconazole is 5 mg twice daily.(1)|
02493|032|M|   In patients stabilized on ruxolitinib, doses of 10 mg twice daily or more|
02493|033|M|in whom fluconazole at doses less than or equal to 200 mg are initiated,|
02493|034|M|reduce the dose of ruxolitinib by 50% (rounded up to the closest available|
02493|035|M|tablet strength).(1)|
02493|036|M|   In patients stabilized on ruxolitinib doses of 5 mg twice daily in whom|
02493|037|M|fluconazole at doses less than or equal to 200 mg is initiated, reduce the|
02493|038|M|dose of ruxolitinib to 5 mg once daily.|
02493|039|M|   In patients stabilized on ruxolitinib doses of 5 mg once daily, avoid the|
02493|040|M|use of fluconazole even at doses less than or equal to 200 mg or interrupt|
02493|041|M|ruxolitinib therapy for the duration of the CYP3A4 inhibitor treatment.(1)|
02493|042|M|   The dose should be adjusted based on monitoring of safety and|
02493|043|M|efficacy.(1)|
02493|044|B||
02493|045|D|DISCUSSION:  Simulations in physiologically-based pharmacokinetic (PBPK)|
02493|046|D|models predict that fluconazole doses of 100 mg daily will increase the|
02493|047|D|area-under-curve (AUC) of ruxolitinib (10 mg twice daily) by 100%.  PBPK|
02493|048|D|models predict that fluconazole doses of 400 mg daily will increase the AUC|
02493|049|D|of ruxolitinib (10 mg twice daily) by 300%.(1)|
02493|050|B||
02493|051|R|REFERENCE:|
02493|052|B||
02493|053|R|1.Jakafi (ruxolitinib) US prescribing information. Incyte Corporation|1
02493|054|R|  September, 2021.|1
02494|001|T|MONOGRAPH TITLE:  Trazodone/Fluconazole (Less Than or Equal To 150 mg)|
02494|002|B||
02494|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02494|004|L|take action as needed.|
02494|005|B||
02494|006|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of trazodone by|
02494|007|A|CYP3A4.(1,2)  Trazodone has been shown to prolong the QT interval.(1)|
02494|008|B||
02494|009|E|CLINICAL EFFECTS:  Concurrent use of fluconazole may result in elevated|
02494|010|E|levels of and adverse effects from trazodone,(1,2) including nausea,|
02494|011|E|dizziness, hypotension, syncope, serotonin syndrome, and cardiac arrhythmias|
02494|012|E|such as QT prolongation or torsades de pointes, which may be|
02494|013|E|life-threatening.(1)|
02494|014|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
02494|015|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02494|016|E|rigidity.|
02494|017|B||
02494|018|P|PREDISPOSING FACTORS:  This interaction may be more severe with larger|
02494|019|P|and/or routine doses of trazodone.|
02494|020|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02494|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02494|022|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02494|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02494|024|P|advanced age.(3)|
02494|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02494|026|P|higher systemic concentrations of either QT prolonging drug are additional|
02494|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02494|028|P|drug concentrations include rapid infusion of an intravenous dose or|
02494|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02494|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02494|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02494|032|B||
02494|033|M|PATIENT MANAGEMENT:  A lower dose of trazodone should be considered in|
02494|034|M|patients receiving CYP3A4 inhibitors such as fluconazole (especially at|
02494|035|M|dosages greater than 150 mg).(1,2)|
02494|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02494|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02494|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02494|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02494|040|M|   In addition to QT prolongation, patients should be monitored for signs|
02494|041|M|and symptoms of serotonin syndrome.  Instruct patients to report muscle|
02494|042|M|twitching, tremors, shivering and stiffness, fever, heavy sweating, heart|
02494|043|M|palpitations, restlessness, confusion, agitation, trouble with coordination,|
02494|044|M|or severe diarrhea.|
02494|045|B||
02494|046|D|DISCUSSION:  Trazodone has been shown to be metabolized by CYP3A4.(1)|
02494|047|D|Fluconazole's inhibition of CYP3A4 is dose dependent, with dosages greater|
02494|048|D|than 150 mg having the highest potential to inhibit CYP3A4.(4)|
02494|049|B||
02494|050|R|REFERENCES:|
02494|051|B||
02494|052|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
02494|053|R|  Labopharm Inc. November, 2012.|1
02494|054|R|2.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
02494|055|R|  2024.|1
02494|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02494|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02494|058|R|  settings: a scientific statement from the American Heart Association and|6
02494|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02494|060|R|  2;55(9):934-47.|6
02494|061|R|4.Kharasch ED, Walker A, Hoffer C, Sheffels P. Sensitivity of intravenous|5
02494|062|R|  and oral alfentanil and pupillary miosis as minimally  invasive and|5
02494|063|R|  noninvasive probes for hepatic and first-pass CYP3A activity. J Clin|5
02494|064|R|  Pharmacol 2005 Oct;45(10):1187-97.|5
02495|001|T|MONOGRAPH TITLE:  Intravenous Citicoline/Meclofenoxate|
02495|002|B||
02495|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02495|004|L|is contraindicated and generally should not be dispensed or administered to|
02495|005|L|the same patient.|
02495|006|B||
02495|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
02495|008|A|antagonism of citicoline effects by meclofenoxate.|
02495|009|B||
02495|010|E|CLINICAL EFFECTS:  Concurrent administration may result in decreased effects|
02495|011|E|of citicoline.|
02495|012|B||
02495|013|P|PREDISPOSING FACTORS:  None determined.|
02495|014|B||
02495|015|M|PATIENT MANAGEMENT:  Citicoline should not be coadministered with|
02495|016|M|meclofenoxate (centrophenoxine).(1)|
02495|017|B||
02495|018|D|DISCUSSION:  The manufacturer of citicoline states that it should not be|
02495|019|D|administered with meclofenoxate.(1)|
02495|020|B||
02495|021|R|REFERENCE:|
02495|022|B||
02495|023|R|1.Somazine (citicoline sodium) prescribing information. Ferrer Internacional|1
02495|024|R|  January, 2006.|1
02496|001|T|MONOGRAPH TITLE:  Efavirenz/Ginkgo Biloba|
02496|002|B||
02496|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
02496|004|L|Assess the risk to the patient and take action as needed.|
02496|005|B||
02496|006|A|MECHANISM OF ACTION:  The exact mechanism in unknown, but may involve|
02496|007|A|induction of CYP3A4 or P-glycoprotein (P-gp) by ginkgo biloba.(1)|
02496|008|B||
02496|009|E|CLINICAL EFFECTS:  Concurrent use of ginkgo biloba may result in decreased|
02496|010|E|effectiveness of efavirenz and virological failure.(1-3)|
02496|011|B||
02496|012|P|PREDISPOSING FACTORS:  None determined.|
02496|013|B||
02496|014|M|PATIENT MANAGEMENT:  Advise patients taking efavirenz-containing regimens to|
02496|015|M|avoid using ginkgo biloba.  If patients insist on using ginkgo biloba,|
02496|016|M|consider increased monitoring of efavirenz plasma concentrations and viral|
02496|017|M|load.(1-3)|
02496|018|B||
02496|019|D|DISCUSSION:  In a case report, a 41 year-old, HIV-positive male had been|
02496|020|D|successfully maintained on antiretroviral therapy including efavirenz,|
02496|021|D|lamivudine, and zidovudine for 10 years with documented viral loads of < 50|
02496|022|D|copies/ml.  Two months after beginning the use of an herbal product|
02496|023|D|containing ginkgo biloba, the patient's viral load was found to be 1350|
02496|024|D|copies/ml.  Two months after the discontinuation of ginkgo, the patient's|
02496|025|D|viral load had returned to baseline with no change in antiviral|
02496|026|D|therapy.(2,3)|
02496|027|D|   In a case report, a 47 year-old HIV-positive male had been receiving|
02496|028|D|efavirenz, emtricitabine, and tenofovir for 2 years.  Several months after|
02496|029|D|beginning ginkgo biloba use, the patient developed virologic failure.|
02496|030|D|Analysis of stored samples revealed a decrease in efavirenz plasma|
02496|031|D|concentration and increases in viral load associated with the use of|
02496|032|D|ginkgo.(1)|
02496|033|B||
02496|034|R|REFERENCES:|
02496|035|B||
02496|036|R|1.Wiegman DJ, Brinkman K, Franssen EJ. Interaction of Ginkgo biloba with|3
02496|037|R|  efavirenz. AIDS 2009 Jun 1;23(9):1184-5.|3
02496|038|R|2.Naccarato M, Yoong D, Gough K. A potential drug-herbal interaction between|3
02496|039|R|  Ginkgo biloba and efavirenz. J Int Assoc Physicians AIDS Care (Chic) 2012|3
02496|040|R|  Mar-Apr;11(2):98-100.|3
02496|041|R|3.Carruthers-Czyzewski P, Scott C, Cousins J, Ly H, Al-Khalili E, Ungureanu|6
02496|042|R|  NH. Suspected interaction between ginkgo biloba and efavirenz. Canadian|6
02496|043|R|  Adverse Reaction Newsletter 2014 July;24(3):4.|6
02498|001|T|MONOGRAPH TITLE:  Theophylline Derivatives/Selected CYP1A2 Inhibitors|
02498|002|B||
02498|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02498|004|L|take action as needed.|
02498|005|B||
02498|006|A|MECHANISM OF ACTION:  CYP1A2 inhibitors may reduce the elimination rate of|
02498|007|A|theophylline derivatives.|
02498|008|B||
02498|009|E|CLINICAL EFFECTS:  The concurrent administration of selected CYP1A2|
02498|010|E|inhibitors and theophylline or their derivatives may result in increased|
02498|011|E|levels and toxicity of theophylline.(1-19)|
02498|012|B||
02498|013|P|PREDISPOSING FACTORS:  Concomitant therapy with inhibitors of CYP3A4 (e.g.|
02498|014|P|clarithromycin, itraconazole, ritonavir) which block a secondary metabolic|
02498|015|P|pathway for theophylline, may increase the magnitude of this interaction.|
02498|016|B||
02498|017|M|PATIENT MANAGEMENT:  Theophylline levels should be closely monitored in|
02498|018|M|patients receiving concurrent therapy.  The dosage of theophylline may need|
02498|019|M|to be decreased after a CYP1A2 inhibitor is initiated.|
02498|020|M|   If the CYP1A2 inhibitor is discontinued in a patient stabilized on the|
02498|021|M|combination, the theophylline level may fall. Monitor theophylline levels|
02498|022|M|and adjust dose accordingly.|
02498|023|B||
02498|024|D|DISCUSSION:  A study in 5 patients with active hepatitis B and 4 healthy|
02498|025|D|subjects examined the effects of a single dose of interferon alpha (9|
02498|026|D|million units in 8 subjects, 18 million units in 1 subject).  There was no|
02498|027|D|effect on theophylline in 1 subject.  In the other 8 subjects, interferon|
02498|028|D|increased theophylline half-life by 70% and decreased theophylline clearance|
02498|029|D|by 49% (range 33% to 81%).(1)|
02498|030|D|   A study in 11 healthy subjects examined the effects of interferon alpha|
02498|031|D|(3 million International Units daily for 3 days) on a single aminophylline|
02498|032|D|(4 mg/kg) infusion.  Interferon increased the half-life, area-under-curve|
02498|033|D|(AUC), and mean residence time by 13.7%, 17.9%, and 16.3%, respectively.|
02498|034|D|Theophylline clearance decreased by 9.1%.(2)|
02498|035|D|   In a study in healthy males, peginterferon alfa-2a (180 mcg once weekly|
02498|036|D|for 4 weeks) increased theophylline AUC by 25%.(3,4)|
02498|037|D|   Concurrent interferon alfa has been shown to increase theophylline levels|
02498|038|D|by 100%.(5)|
02498|039|D|   A study in 7 patients with chronic hepatitis C examined the effects of|
02498|040|D|interferon beta (3 million to 9 million International Units daily for 8|
02498|041|D|weeks) on theophylline ethylenediamine (single 250 mg infusion).  Interferon|
02498|042|D|decreased theophylline clearance by 26.3% and increased theophylline|
02498|043|D|half-life by 39.3%.  There was no correlation between interferon dose and|
02498|044|D|effect. The greatest effect was seen in a patient who received 3 million|
02498|045|D|International Units daily, while no effect was seen in a patient who|
02498|046|D|received 9 million International Units daily.(6)|
02498|047|D|   Increased serum theophylline levels with signs and symptoms of|
02498|048|D|theophylline toxicity have been reported in patients following the addition|
02498|049|D|of mexiletine to their treatment.(7-15)|
02498|050|D|   In a study evaluated the combination of disulfiram and theophylline in 20|
02498|051|D|recovering alcoholics.  Patients received a single IV dose of theophylline|
02498|052|D|while being given either 250 mg or 500 mg of disulfiram daily. Both dosages|
02498|053|D|of disulfiram decreased the clearance of theophylline.  However, the effect|
02498|054|D|was greatest in patients receiving disulfiram 500 mg daily.(16)|
02498|055|D|   Increases in serum theophylline concentration and half-life have been|
02498|056|D|reported during concurrent administration of theophylline and|
02498|057|D|ticlopidine.(17)|
02498|058|D|   In healthy subjects, rofecoxib (12.5 mg/day, 25 mg/day, or 50 mg/day for|
02498|059|D|seven days) increased the area-under-curve (AUC) of a single dose of|
02498|060|D|theophylline (300 mg) by 38% to 60%.  Therefore, the manufacturer of|
02498|061|D|rofecoxib recommends that theophylline levels be monitored if rofecoxib is|
02498|062|D|initiated or changed in patients receiving theophylline.(18)|
02498|063|D|   Selected CYP1A2 inhibitors linked to this monograph include: Angelica|
02498|064|D|dahurica, artemisinin, cannabidiol, curcumin, danshen, dipyrone, disulfiram,|
02498|065|D|echinacea, enasidenib, fexinidazole, genistein, ginseng, interferons,|
02498|066|D|methoxsalen, mexiletine, parsley, phenylpropanolamine, pipemidic acid,|
02498|067|D|piperine, propafenone, ribociclib, rofecoxib, rucaparib, simeprevir,|
02498|068|D|ticlopidine, triclabendazole, verapamil.(19)|
02498|069|B||
02498|070|R|REFERENCES:|
02498|071|B||
02498|072|R|1.Williams SJ, Baird-Lambert JA, Farrell GC. Inhibition of theophylline|2
02498|073|R|  metabolism by interferon. Lancet 1987 Oct 24;2(8565):939-41.|2
02498|074|R|2.Jonkman JH, Nicholson KG, Farrow PR, Eckert M, Grasmeijer G, Oosterhuis B,|2
02498|075|R|  De Noord OE, Guentert TW. Effects of alpha-interferon on theophylline|2
02498|076|R|  pharmacokinetics and metabolism. Br J Clin Pharmacol 1989 Jun;|2
02498|077|R|  27(6):795-802.|2
02498|078|R|3.Pegasys 135 PFS (interferon alfa-2a) UK summary of product|1
02498|079|R|  characteristics. Roche Products Limited June 20, 2002.|1
02498|080|R|4.Pegasys (peginterferon alfa-2a) US prescribing information. Genentech USA,|1
02498|081|R|  Inc. March, 2015.|1
02498|082|R|5.Intron A (interferon alfa-2b) US prescribing information. Schering|1
02498|083|R|  Corporation May, 2018.|1
02498|084|R|6.Okuno H, Takasu M, Kano H, Seki T, Shiozaki Y, Inoue K. Depression of|2
02498|085|R|  drug-metabolizing activity in the human liver by interferon-beta.|2
02498|086|R|  Hepatology 1993 Jan;17(1):65-9.|2
02498|087|R|7.Katz A, Buskila D, Sukenik S. Oral mexiletine-theophylline interaction.|3
02498|088|R|  Int J Cardiol 1987 Nov;17(2):227-8.|3
02498|089|R|8.Stanley R, Comer T, Taylor JL, Saliba D. Mexiletine-theophylline|3
02498|090|R|  interaction. Am J Med 1989 Jun;86(6 Pt 1):733-4.|3
02498|091|R|9.Kessler KM, Interian A Jr, Cox M, Topaz O, De Marchena EJ, Myerburg RJ.|3
02498|092|R|  Proarrhythmia related to a kinetic and dynamic interaction of mexiletine|3
02498|093|R|  and theophylline. Am Heart J 1989 Apr;117(4):964-6.|3
02498|094|R|10.Loi CM, Vestal RE. Effect of mexiletine on theophylline metabolism. Clin|4
02498|095|R|   Pharmacol Ther 1990 Feb;47(2):130.|4
02498|096|R|11.Ueno K, Miyai K, Seki T, Kawaguchi Y. Interaction between theophylline|3
02498|097|R|   and mexiletine. DICP 1990 May;24(5):471-2.|3
02498|098|R|12.Stoysich AM, Mohiuddin SM, Destache CJ, Nipper HC, Hilleman DE. Influence|2
02498|099|R|   of mexiletine on the pharmacokinetics of theophylline in healthy|2
02498|100|R|   volunteers. J Clin Pharmacol 1991 Apr;31(4):354-7.|2
02498|101|R|13.Loi CM, Wei XX, Vestal RE. Inhibition of theophylline metabolism by|2
02498|102|R|   mexiletine in young male and female nonsmokers. Clin Pharmacol Ther 1991|2
02498|103|R|   May;49(5):571-80.|2
02498|104|R|14.Hurwitz A, Vacek JL, Botteron GW, Sztern MI, Hughes EM, Jayaraj A.|2
02498|105|R|   Mexiletine effects on theophylline disposition. Clin Pharmacol Ther 1991|2
02498|106|R|   Sep;50(3):299-307.|2
02498|107|R|15.Ueno K, Miyai K, Kato M, Kawaguchi Y, Suzuki T. Mechanism of interaction|2
02498|108|R|   between theophylline and mexiletine. DICP 1991 Jul-Aug;25(7-8):727-30.|2
02498|109|R|16.Loi CM, Day JD, Jue SG, Bush ED, Costello P, Dewey LV, Vestal RE.|2
02498|110|R|   Dose-dependent inhibition of theophylline metabolism by disulfiram in|2
02498|111|R|   recovering alcoholics. Clin Pharmacol Ther 1989 May;45(5):476-86.|2
02498|112|R|17.Colli A, Buccino G, Cocciolo M, Parravicini R, Elli GM, Scaltrini G.|2
02498|113|R|   Ticlopidine-theophylline interaction. Clin Pharmacol Ther 1987 Mar;|2
02498|114|R|   41(3):358-62.|2
02498|115|R|18.Vioxx (rofecoxib) US prescribing information. Merck & Co., Inc. May,|1
02498|116|R|   2016.|1
02498|117|R|19.This information is based on an extract from the Certara Drug Interaction|6
02498|118|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02499|001|T|MONOGRAPH TITLE:  Daclatasvir/Strong CYP3A4 Inducers|
02499|002|B||
02499|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02499|004|L|is contraindicated and generally should not be dispensed or administered to|
02499|005|L|the same patient.|
02499|006|B||
02499|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02499|008|A|daclatasvir.(1)|
02499|009|B||
02499|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 is expected|
02499|011|E|to reduce levels and effectiveness of daclatasvir.(1)|
02499|012|B||
02499|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02499|014|P|of the inducer for longer than 1-2 weeks.|
02499|015|B||
02499|016|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 with daclatasvir|
02499|017|M|are contraindicated.(1)|
02499|018|B||
02499|019|D|DISCUSSION:  Rifampin (600 mg daily) decreased the maximum concentration|
02499|020|D|(Cmax) and area-under-curve (AUC) of a single dose of daclatasvir (60 mg) by|
02499|021|D|56% and 79%, respectively.(1)|
02499|022|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02499|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02499|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02499|025|D|rifapentine, and St John's wort.(1-3)|
02499|026|B||
02499|027|R|REFERENCES:|
02499|028|B||
02499|029|R|1.Daklinza (daclatasvir dihydrochloride) UK summary of product|1
02499|030|R|  characteristics. Bristol-Myers Squibb Pharmaceutical Limited August 29,|1
02499|031|R|  2014.|1
02499|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02499|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02499|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02499|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02499|036|R|  11/14/2017.|1
02499|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
02499|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02499|039|R|4.Daklinza (daclatasvir) US prescribing information. Bristol-Myers Squibb|1
02499|040|R|  October, 2019.|1
02500|001|T|MONOGRAPH TITLE:  Daclatasvir/Moderate CYP3A4 Inducers|
02500|002|B||
02500|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02500|004|L|take action as needed.|
02500|005|B||
02500|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
02500|007|A|of daclatasvir.(1)|
02500|008|B||
02500|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 without a|
02500|010|E|dosage adjustment of daclatasvir is expected to reduce levels and|
02500|011|E|effectiveness of daclatasvir.(1)|
02500|012|B||
02500|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02500|014|P|of the inducer for longer than 1-2 weeks.|
02500|015|B||
02500|016|M|PATIENT MANAGEMENT:  The dose of daclatasvir should be increased to 90 mg|
02500|017|M|once daily in patients receiving moderate inducers of CYP3A4.(1)|
02500|018|B||
02500|019|D|DISCUSSION:  Efavirenz (600 mg daily) decreased the maximum concentration|
02500|020|D|(Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of|
02500|021|D|daclatasvir by 17%, 32%, and 59%, respectively.(1)|
02500|022|D|   Moderate inducers of CYP3A4 include belzutifan, bosentan, cenobamate,|
02500|023|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
02500|024|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
02500|025|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
02500|026|D|thioridazine, and tovorafenib.(1-3)|
02500|027|B||
02500|028|R|REFERENCES:|
02500|029|B||
02500|030|R|1.Daklinza (daclatasvir dihydrochloride) UK summary of product|1
02500|031|R|  characteristics. Bristol-Myers Squibb Pharmaceutical Limited August 29,|1
02500|032|R|  2014.|1
02500|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02500|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02500|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02500|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02500|037|R|  11/14/2017.|1
02500|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
02500|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02500|040|R|4.Daklinza (daclatasvir) US prescribing information. Bristol-Myers Squibb|1
02500|041|R|  October, 2019.|1
02501|001|T|MONOGRAPH TITLE:  Daclatasvir/Strong CYP3A4 Inhibitors|
02501|002|B||
02501|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02501|004|L|of severe adverse interaction.|
02501|005|B||
02501|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
02501|007|A|of daclatasvir.(1)|
02501|008|B||
02501|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 is|
02501|010|E|expected to increase levels of and side effects from daclatasvir.(1)|
02501|011|B||
02501|012|P|PREDISPOSING FACTORS:  None determined.|
02501|013|B||
02501|014|M|PATIENT MANAGEMENT:  The dose of daclatasvir should be reduced to 30 mg in|
02501|015|M|patients taking strong inhibitors of CYP3A4.(1)|
02501|016|M|   Concurrent therapy with the following regimens warrants a dose reduction|
02501|017|M|of daclatasvir to 30 mg daily: atazanavir/cobicistat, atazanavir/ritonavir,|
02501|018|M|indinavir/ritonavir, nelfinavir, and saquinavir/ritonavir.(1,2)|
02501|019|M|   No dosage adjustment for daclatasvir is necessary with unboosted|
02501|020|M|atazanavir, darunavir/cobicistat, darunavir/ritonavir, unboosted indinavir,|
02501|021|M|or lopinavir/ritonavir.(1,2)|
02501|022|B||
02501|023|D|DISCUSSION:  Atazanavir/ritonavir (300/100 mg daily) increased the maximum|
02501|024|D|concentration (Cmax), area-under-curve (AUC), and minimum concentration|
02501|025|D|(Cmin) of daclatasvir by 1.35-fold, 2.10-fold, and 3.65-fold,|
02501|026|D|respectively.(1)|
02501|027|D|   Ketoconazole (400 mg daily) increased the Cmax and AUC of daclatasvir by|
02501|028|D|1.57-fold and 3.00-fold, respectively.(1)|
02501|029|D|   Telaprevir (500 mg q12h) increased the Cmax and AUC of daclatasvir by|
02501|030|D|1.46-fold and 2.32-fold, respectively.  There were no significant changes in|
02501|031|D|telaprevir concentrations.(1)|
02501|032|D|   Telaprevir (750 mg q8h) increased the Cmax and AUC of daclatasvir by|
02501|033|D|1.22-fold and 2.15-fold, respectively.  There were no significant changes in|
02501|034|D|telaprevir concentrations.(1)|
02501|035|D|   In a study, concomitant administration of daclatasvir (30 mg once daily)|
02501|036|D|with lopinavir/ritonavir (400 mg/100 mg twice daily) did not result in any|
02501|037|D|clinically relevant changes of exposure.|
02501|038|D|   Strong inhibitors of CYP3A4 include:  adagrasib, atazanavir (when|
02501|039|D|coadministered with ritonavir or cobicistat), boceprevir, ceritinib,|
02501|040|D|clarithromycin, cobicistat, indinavir (when coadministered with ritonavir),|
02501|041|D|itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone,|
02501|042|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir/ritonavir,|
02501|043|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
02501|044|D|tucatinib, and voriconazole.(1-4)|
02501|045|B||
02501|046|R|REFERENCES:|
02501|047|B||
02501|048|R|1.Daklinza (daclatasvir) Australia prescribing information. Bristol-Myers|1
02501|049|R|  Squibb Australia Pty Ltd April 1, 2019.|1
02501|050|R|2.Liverpool Drug Interactions Group. HIV Drug Interactions. Available at:|6
02501|051|R|  https://hiv-druginteractions.org/.|6
02501|052|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02501|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02501|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02501|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02501|056|R|  11/14/2017.|1
02501|057|R|4.This information is based on an extract from the Certara Drug Interaction|6
02501|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02504|001|T|MONOGRAPH TITLE:  Clarithromycin/QT Prolonging Agents|
02504|002|B||
02504|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02504|004|L|take action as needed.|
02504|005|B||
02504|006|A|MECHANISM OF ACTION:  Clarithromycin may prolong the QTc interval.|
02504|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02504|008|A|additive effects on the QTc interval.(1-15)|
02504|009|B||
02504|010|E|CLINICAL EFFECTS:  The concurrent use of clarithromycin with other agents|
02504|011|E|that prolong the QTc interval may result in potentially life-threatening|
02504|012|E|cardiac arrhythmias, including torsades de pointes.(1-15)|
02504|013|B||
02504|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02504|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02504|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02504|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02504|018|P|gender, or advanced age.(1)|
02504|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02504|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02504|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02504|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02504|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02504|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02504|025|P|dysfunction).(1)|
02504|026|B||
02504|027|M|PATIENT MANAGEMENT:  General monitoring when concurrent therapy is|
02504|028|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
02504|029|M|at baseline and regular intervals. Correct any electrolyte abnormalities.|
02504|030|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02504|031|M|fainting.|
02504|032|M|   Agent specific recommendations:|
02504|033|M|   The manufacturers of apomorphine,(2) clarithromycin,(3) gatifloxacin,(4)|
02504|034|M|gemifloxacin,(5) norfloxacin,(6) and sevoflurane(7) state that these agents|
02504|035|M|should used with caution with other agents known to prolong the QT interval.|
02504|036|M|   While the US FDA and manufacturer recommend no special precautions when|
02504|037|M|escitalopram is used with QT prolonging agents,(8,9) Health Canada and the|
02504|038|M|Canadian manufacturer of escitalopram discourage the concurrent use of|
02504|039|M|agents known to prolong the QT interval(10,11) and the UK manufacturer|
02504|040|M|states that concurrent use is contraindicated.(12)|
02504|041|M|   The US manufacturer of ciprofloxacin states that ciprofloxacin should be|
02504|042|M|used with caution with other agents known to prolong the QT interval,|
02504|043|M|especially in the elderly.(13)  The UK manufacturer of ciprofloxacin states|
02504|044|M|that ciprofloxacin should be used with caution in patients at risk for|
02504|045|M|torsades.(14)|
02504|046|B||
02504|047|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02504|048|D|degrees of potential to prolong the QTc interval but are generally accepted|
02504|049|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02504|050|D|monograph have been shown to prolong the QTc interval either through their|
02504|051|D|mechanism of action, through studies on their effects on the QTc interval,|
02504|052|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02504|053|D|clinical trials and/or post-marketing reports.(15)|
02504|054|D|   One or more of the drug pairs linked to this monograph have been included|
02504|055|D|in a list of interactions that should be considered "high-priority" for|
02504|056|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02504|057|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02504|058|D|Coordinator (ONC) for Health Information Technology.|
02504|059|B||
02504|060|R|REFERENCES:|
02504|061|B||
02504|062|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02504|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02504|064|R|  settings: a scientific statement from the American Heart Association and|6
02504|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02504|066|R|  2;55(9):934-47.|6
02504|067|R|2.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
02504|068|R|  Inc. May, 2019.|1
02504|069|R|3.Biaxin (clarithromycin) Canadian prescribing information. Abbott|1
02504|070|R|  Laboratories, Limited October 25, 2021.|1
02504|071|R|4.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
02504|072|R|  Company January, 2006.|1
02504|073|R|5.Factive (gemifloxacin mesylate) US prescribing information. Merus Labs|1
02504|074|R|  International, Inc. October, 2018.|1
02504|075|R|6.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
02504|076|R|  2016.|1
02504|077|R|7.Ultane (sevoflurane) US prescribing information. AbbVie, Inc. February,|1
02504|078|R|  2014.|1
02504|079|R|8.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
02504|080|R|  Pharmaceuticals Inc. May, 2023.|1
02504|081|R|9.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
02504|082|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
02504|083|R|  potential risk of abnormal heart rhythms with high doses. Available at:|1
02504|084|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
02504|085|R|10.Health Canada. Antidepressant Cipralex (escitalopram): Updated|1
02504|086|R|   information regarding dose-related heart risk. Available at:|1
02504|087|R|   http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/136|1
02504|088|R|   74a-eng.php May 7, 2012.|1
02504|089|R|11.Cipralex (escitalopram oxalate) Canadian prescribing information.|1
02504|090|R|   Lundbeck August 13, 2012.|1
02504|091|R|12.Cipralex (escitalopram oxalate) UK summary of product characteristics.|1
02504|092|R|   Lunbeck Limited June 25, 2020.|1
02504|093|R|13.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
02504|094|R|   Corporation March, 2022.|1
02504|095|R|14.Ciproxin (ciprofloxacin hydrochloride) UK summary of product|1
02504|096|R|   characteristics. Bayer plc April 13, 2010.|1
02504|097|R|15.USDepartment of Health and Human Services Food and Drug Administration.|1
02504|098|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02504|099|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02504|100|R|   https://www.fda.gov/media/71372/download October, 2005.|1
02504|101|R|16.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02504|102|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02504|103|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02504|104|R|   19(5):735-43.|6
02505|001|T|MONOGRAPH TITLE:  Atorvastatin (Greater Than 10 mg)/Cyclosporine|
02505|002|B||
02505|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02505|004|L|is contraindicated and generally should not be dispensed or administered to|
02505|005|L|the same patient.|
02505|006|B||
02505|007|A|MECHANISM OF ACTION:  Unknown.|
02505|008|B||
02505|009|E|CLINICAL EFFECTS:  Myopathy and muscle aches, tenderness and weakness|
02505|010|E|(rhabdomyolysis) may occur with concurrent administration of HMG-CoA|
02505|011|E|reductase inhibitors and cyclosporine.|
02505|012|B||
02505|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02505|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02505|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02505|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02505|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02505|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02505|019|P|predisposed to myopathy or rhabdomyolysis.|
02505|020|B||
02505|021|M|PATIENT MANAGEMENT:  Avoid the concurrent use of atorvastatin(1) with|
02505|022|M|cyclosporine.  If concurrent use is necessary, the dose of atorvastatin|
02505|023|M|should be limited to 10 mg or less.(2)|
02505|024|M|   When possible use alternative therapy, such as fluvastatin at dosages of|
02505|025|M|20 mg BID or less,(3) pravastatin at dosages of 20 mg daily or less,(4) or|
02505|026|M|rosuvastatin at dosages of 5 mg daily or less.(5)|
02505|027|M|   Patients receiving concurrent therapy should be instructed to report|
02505|028|M|symptoms of muscle pain, tenderness, or weakness.|
02505|029|B||
02505|030|D|DISCUSSION:  Since this reaction may occur with HMG-CoA-reductase inhibitors|
02505|031|D|alone, a causal relationship is difficult to establish.  However, the|
02505|032|D|incidence of myopathy and rhabdomyolysis appears to increase with concurrent|
02505|033|D|administration of cyclosporine.|
02505|034|D|   In a study in 18 renal transplant patients, atorvastatin had no effect on|
02505|035|D|the pharmacokinetics of cyclosporine.(6)  In a study in six liver transplant|
02505|036|D|patients, atorvastatin increased the area-under-curve (AUC) of cyclosporine|
02505|037|D|by 10%, which was not considered clinically significant.(7)|
02505|038|D|   In a study in 21 renal transplant patients, cyclosporine increased|
02505|039|D|atorvastatin levels by 6.4-fold when compared to historical controls.  The|
02505|040|D|AUC of cyclosporine decreased by 9.5%.(8)|
02505|041|D|   Concurrent administration of atorvastatin (10 mg) and cyclosporine (5.2|
02505|042|D|mg/kg/day) increased atorvastatin AUC and Cmax by 8.7-fold and 10.7-fold.(1)|
02505|043|D|   In a study in 33 renal patients, subjects were randomized to receive|
02505|044|D|either atorvastatin or cerivastatin.  In the cerivastatin group, there were|
02505|045|D|no significant effects on cyclosporine levels.  In the atorvastatin group, 4|
02505|046|D|of 10 subjects had changes in cyclosporine trough levels of 25% or more.(9)|
02505|047|D|   In a study, administration of pravastatin in 11 heart transplant patients|
02505|048|D|receiving cyclosporine was compared to 8 control subjects not receiving|
02505|049|D|cyclosporine.  Pravastatin AUC and Cmax were 7-8-fold and 12-fold higher,|
02505|050|D|respectively, in subjects taking cyclosporine.(10)|
02505|051|D|   In a double-blind, randomized, cross-over study in 44 renal transplant|
02505|052|D|patients, neither lovastatin nor pravastatin affected cyclosporine levels.|
02505|053|D|Pravastatin levels after 1 day and after 28 days of concurrent therapy were|
02505|054|D|5-fold higher than historical controls.  Lovastatin levels accumulated over|
02505|055|D|the course of the study and by Day 28 were 20-fold higher than historical|
02505|056|D|controls.(11)|
02505|057|D|   In a study in 31 renal transplant patients, neither pravastatin nor|
02505|058|D|simvastatin affected cyclosporine levels.(12)  In contrast, in a study in 44|
02505|059|D|heart transplant subjects, cyclosporine clearance was increased following|
02505|060|D|the addition of simvastatin.(13)|
02505|061|D|   Several studies have found no effect from fluvastatin on cyclosporine|
02505|062|D|pharmacokinetics.(14-18)  One of these also noted no affects of cyclosporine|
02505|063|D|on fluvastatin levels.(13)  In contrast, a study that compared the|
02505|064|D|administration of fluvastatin in 10 heart transplant to 10 healthy control|
02505|065|D|subjects found that fluvastatin AUC and Cmax were 2.55-fold and 3.10-fold|
02505|066|D|higher than in control subjects.(19)|
02505|067|D|   In an open-label study in 10 heart transplant patients, concurrent|
02505|068|D|cyclosporine increased rosuvastatin AUC and Cmax by 7.1-fold and 10.6-fold,|
02505|069|D|respectively, when compared to historical controls.  There were no effects|
02505|070|D|on cyclosporine levels.(20)|
02505|071|D|   Rhabdomyolysis has been reported with concurrent cyclosporine and|
02505|072|D|atorvastatin.(21,22)|
02505|073|D|   In a PKPB model, concurrent use of atorvastatin (10 mg daily) with|
02505|074|D|cyclosporine (125 mg daily for 2 months) increased the simulated Cmax ratio|
02505|075|D|and AUC ratio of atorvastatin by 6.85 and 3.92, respectively.(23)|
02505|076|B||
02505|077|R|REFERENCES:|
02505|078|B||
02505|079|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02505|080|R|  2020.|1
02505|081|R|2.Lipitor (atorvastatin calcium trihydrate) UK summary of product|1
02505|082|R|  characteristics. Pfizer Limited April 1, 2019.|1
02505|083|R|3.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
02505|084|R|  Pharmaceuticals Corporation August, 2017.|1
02505|085|R|4.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
02505|086|R|  Squibb Company May, 2022.|1
02505|087|R|5.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02505|088|R|  Pharmaceuticals LP July, 2024.|1
02505|089|R|6.Hermann M, Asberg A, Christensen H, Reubsaet JL, Holdaas H, Hartmann A.|2
02505|090|R|  Atorvastatin does not affect the pharmacokinetics of cyclosporine in renal|2
02505|091|R|  transplant recipients. Eur J Clin Pharmacol 2005 Mar;61(1):59-62.|2
02505|092|R|7.Taylor PJ, Kubler PA, Lynch SV, Allen J, Butler M, Pillans PI. Effect of|2
02505|093|R|  atorvastatin on cyclosporine pharmacokinetics in liver transplant|2
02505|094|R|  recipients. Ann Pharmacother 2004 Feb;38(2):205-8.|2
02505|095|R|8.Asberg A, Hartmann A, Fjeldsa E, Bergan S, Holdaas H. Bilateral|2
02505|096|R|  pharmacokinetic interaction between cyclosporine A and atorvastatin in|2
02505|097|R|  renal transplant recipients. Am J Transplant 2001 Nov;1(4):382-6.|2
02505|098|R|9.Renders L, Mayer-Kadner I, Koch C, Scharffe S, Burkhardt K, Veelken R,|2
02505|099|R|  Schmieder RE, Hauser IA. Efficacy and drug interactions of the new HMG-CoA|2
02505|100|R|  reductase inhibitors cerivastatin and atorvastatin in CsA-treated renal|2
02505|101|R|  transplant recipients. Nephrol Dial Transplant 2001 Jan;16(1):141-6.|2
02505|102|R|10.Park JW, Siekmeier R, Merz M, Krell B, Harder S, Marz W, Seidel D,|2
02505|103|R|   Schuler S, Gross W. Pharmacokinetics of pravastatin in heart-transplant|2
02505|104|R|   patients taking cyclosporin A. Int J Clin Pharmacol Ther 2002 Oct;|2
02505|105|R|   40(10):439-50.|2
02505|106|R|11.Olbricht C, Wanner C, Eisenhauer T, Kliem V, Doll R, Boddaert M, O'Grady|2
02505|107|R|   P, Krekler M, Mangold B, Christians U. Accumulation of lovastatin, but|2
02505|108|R|   not pravastatin, in the blood of cyclosporine-treated kidney graft|2
02505|109|R|   patients after multiple doses. Clin Pharmacol Ther 1997 Sep;62(3):311-21.|2
02505|110|R|12.Capone D, Stanziale P, Gentile A, Imperatore P, Pellegrino T, Basile V.|2
02505|111|R|   Effects of simvastatin and pravastatin on hyperlipidemia and cyclosporin|2
02505|112|R|   blood levels in renal transplant recipients. Am J Nephrol 1999;|2
02505|113|R|   19(3):411-5.|2
02505|114|R|13.Akhlaghi F, McLachlan AJ, Keogh AM, Brown KF. Effect of simvastatin on|2
02505|115|R|   cyclosporine unbound fraction and apparent blood clearance in heart|2
02505|116|R|   transplant recipients. Br J Clin Pharmacol 1997 Dec;44(6):537-42.|2
02505|117|R|14.Holdaas H, Hagen E, Asberg A, Lund K, Hartman A, Vaidyanathan S, Prasad|2
02505|118|R|   P, He YL, Yeh CM, Bigler H, Rouilly M, Denouel J. Evaluation of the|2
02505|119|R|   pharmacokinetic interaction between fluvastatin XL and cyclosporine in|2
02505|120|R|   renal transplant recipients. Int J Clin Pharmacol Ther 2006 Apr;|2
02505|121|R|   44(4):163-71.|2
02505|122|R|15.Locsey L, Asztalos L, Kincses Z, Balazs G. Fluvastatin (Lescol) treatment|2
02505|123|R|   of hyperlipidaemia in patients with renal transplants. Int Urol Nephrol|2
02505|124|R|   1997;29(1):95-106.|2
02505|125|R|16.Li PK, Mak TW, Chan TH, Wang A, Lam CW, Lai KN. Effect of fluvastatin on|2
02505|126|R|   lipoprotein profiles in treating renal transplant recipients with|2
02505|127|R|   dyslipoproteinemia. Transplantation 1995 Oct 15;60(7):652-6.|2
02505|128|R|17.Holdaas H, Hartmann A, Stenstrom J, Dahl KJ, Borge M, Pfister P. Effect|2
02505|129|R|   of fluvastatin for safely lowering atherogenic lipids in renal transplant|2
02505|130|R|   patients receiving cyclosporine. Am J Cardiol 1995 Jul 13;|2
02505|131|R|   76(2):102A-106A.|2
02505|132|R|18.Li PK, Mak TW, Wang AY, Lee YT, Leung CB, Lui SF, Lam CW, Lai KN. The|2
02505|133|R|   interaction of fluvastatin and cyclosporin A in renal transplant|2
02505|134|R|   patients. Int J Clin Pharmacol Ther 1995 Apr;33(4):246-8.|2
02505|135|R|19.Park JW, Siekmeier R, Lattke P, Merz M, Mix C, Schuler S, Jaross W.|2
02505|136|R|   Pharmacokinetics and pharmacodynamics of fluvastatin in heart transplant|2
02505|137|R|   recipients taking cyclosporine A. J Cardiovasc Pharmacol Ther 2001 Oct;|2
02505|138|R|   6(4):351-61.|2
02505|139|R|20.Simonson SG, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CD, Windass|2
02505|140|R|   AS, Schneck DW. Rosuvastatin pharmacokinetics in heart transplant|2
02505|141|R|   recipients administered an antirejection regimen including cyclosporine.|2
02505|142|R|   Clin Pharmacol Ther 2004 Aug;76(2):167-77.|2
02505|143|R|21.Maltz HC, Balog DL, Cheigh JS. Rhabdomyolysis associated with concomitant|3
02505|144|R|   use of atorvastatin and cyclosporine. Ann Pharmacother 1999 Nov;|3
02505|145|R|   33(11):1176-9.|3
02505|146|R|22.Wong WM, Wai-Hung Shek T, Chan KH, Chau E, Lai KC. Rhabdomyolysis|3
02505|147|R|   triggered by cytomegalovirus infection in a heart transplant patient on|3
02505|148|R|   concomitant cyclosporine and atorvastatin therapy. J Gastroenterol|3
02505|149|R|   Hepatol 2004 Aug;19(8):952-3.|3
02505|150|R|23.Li S, Yu Y, Jin Z, Dai Y, Lin H, Jiao Z, Ma G, Cai W, Han B, Xiang X.|2
02505|151|R|   Prediction of pharmacokinetic drug-drug interactions causing|2
02505|152|R|   atorvastatin-induced rhabdomyolysis using physiologically based|2
02505|153|R|   pharmacokinetic modelling. Biomed Pharmacother 2019 Sep 10;119:109416.|2
02506|001|T|MONOGRAPH TITLE:  Ledipasvir; Velpatasvir/Antacids; H2 Antagonists|
02506|002|B||
02506|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02506|004|L|take action as needed.|
02506|005|B||
02506|006|A|MECHANISM OF ACTION:  The aqueous solubility of ledipasvir and velpatasvir|
02506|007|A|is pH dependent.  Higher gastric pH leads to lower solubility which may|
02506|008|A|reduce ledipasvir and velpatasvir's absorption.(1-3)|
02506|009|B||
02506|010|E|CLINICAL EFFECTS:  Administration of antacids and H2 antagonists may reduce|
02506|011|E|the bioavailability of ledipasvir and velpatasvir, leading to decreased|
02506|012|E|systemic levels and effectiveness.(1-3)|
02506|013|B||
02506|014|P|PREDISPOSING FACTORS:  None determined.|
02506|015|B||
02506|016|M|PATIENT MANAGEMENT:  In order to assure systemic absorption and maximal|
02506|017|M|effectiveness from use of this Hepatitis C treatment, counsel patient to|
02506|018|M|separate products containing ledipasvir or velpatasvir from antacid|
02506|019|M|administration by 4 hours.(1-3)|
02506|020|M|   H2 antagonists may be administered simultaneously or 12 hours apart from|
02506|021|M|products containing ledipasvir or velpatasvir at a dose that does not exceed|
02506|022|M|doses comparable to famotidine 40 mg twice daily (or a total daily dose|
02506|023|M|comparable to famotidine 80 mg).(1-3)|
02506|024|M|   Some vitamin preparations may contain sufficient quantities of calcium|
02506|025|M|and/or magnesium salts with antacid properties to interact as well.|
02506|026|B||
02506|027|D|DISCUSSION:  In an interaction study, famotidine 40 mg, given with or 12|
02506|028|D|hours after a ledipasvir-sofosbuvir dose did not have significant effects on|
02506|029|D|ledipasvir-sofosbuvir exposure.(1)|
02506|030|D|   In an interaction study, famotidine 40 mg, given with or 12 hours prior|
02506|031|D|to a velpatasvir-sofosbuvir dose did not have a significant effect on|
02506|032|D|velpatasvir-sofosbuvir exposure.(2)|
02506|033|D|      In an interaction study, famotidine (dosage not stated) did not have a|
02506|034|D|significant effect on the pharmacokinetic of sofosbuvir, velpatasvir, or|
02506|035|D|voxilaprevir.(3)|
02506|036|B||
02506|037|R|REFERENCES:|
02506|038|B||
02506|039|R|1.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
02506|040|R|  Sciences November, 2019.|1
02506|041|R|2.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
02506|042|R|  Sciences, Inc. April, 2022.|1
02506|043|R|3.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02506|044|R|  Gilead Sciences, Inc. September, 2019.|1
02507|001|T|MONOGRAPH TITLE:  Nintedanib/Dual CYP3A4 & P-gp Inhibitors|
02507|002|B||
02507|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02507|004|L|take action as needed.|
02507|005|B||
02507|006|A|MECHANISM OF ACTION:  Nintedanib is a substrate for the P-glycoprotein|
02507|007|A|(P-gp) transporter and is metabolized to a minor extent by CYP3A4.|
02507|008|B||
02507|009|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
02507|010|E|P-gp and CYP3A4 may result in elevated levels of and clinical effects of|
02507|011|E|nintedanib.|
02507|012|B||
02507|013|P|PREDISPOSING FACTORS:  None determined.|
02507|014|B||
02507|015|M|PATIENT MANAGEMENT:  The manufacturer of nintedanib recommends close|
02507|016|M|monitoring for nintedanib patients receiving drugs which are both P-gp and|
02507|017|M|CYP3A4 inhibitors.  In an interaction study ketoconazole increased exposure|
02507|018|M|to nintedanib by 60%. Nintedanib therapy may need to be interrupted or the|
02507|019|M|dose may need to be reduced.(1)|
02507|020|B||
02507|021|D|DISCUSSION:  In an interaction study coadministration with ketoconazole, a|
02507|022|D|P-gp and CYP3A4 inhibitor, increased nintedanib exposure (area-under-curve,|
02507|023|D|AUC) and maximum concentration (Cmax) by 1.61-fold and 1.83 fold|
02507|024|D|respectively.(1)|
02507|025|D|   Strong CYP3A4 & P-gp inhibitors include: adagrasib, boceprevir,|
02507|026|D|clarithromycin, cobicistat, grapefruit, indinavir, itraconazole, josamycin,|
02507|027|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
02507|028|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
02507|029|D|posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir,|
02507|030|D|and tucatinib.|
02507|031|D|   Moderate CYP3A4 & P-gp inhibitors include: conivaptan, diltiazem,|
02507|032|D|dronedarone, erythromycin, fluvoxamine, isavuconazonium, schisandra, and|
02507|033|D|verapamil.|
02507|034|D|   Weak CYP3A4 & P-gp inhibitors include: amiodarone, azithromycin,|
02507|035|D|cimetidine, cyclosporine, daclatasvir, daridorexant, diosmin, flibanserin,|
02507|036|D|fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, ivacaftor, lapatinib,|
02507|037|D|mavorixafor, and ranolazine.(2)|
02507|038|B||
02507|039|R|REFERENCES:|
02507|040|B||
02507|041|R|1.Ofev (nintedanib) US prescribing information. Boehringer Ingelheim|1
02507|042|R|  Pharmaceuticals Inc. September, 2019.|1
02507|043|R|2.This information is based on an extract from the Certara Drug Interaction|6
02507|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02508|001|T|MONOGRAPH TITLE:  Nintedanib/P-gp and Strong CYP3A4 Inducers|
02508|002|B||
02508|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02508|004|L|of severe adverse interaction.|
02508|005|B||
02508|006|A|MECHANISM OF ACTION:  Strong P-gp or CYP3A4 inducers may decrease|
02508|007|A|absorption, increase elimination rate, or increase the metabolism of|
02508|008|A|nintedanib.(1)|
02508|009|B||
02508|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong P-gp or CYP3A4|
02508|011|E|inducers may result in decreased levels and effectiveness of nintedanib.(1)|
02508|012|B||
02508|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02508|014|P|of the inducer for longer than 1-2 weeks.|
02508|015|B||
02508|016|M|PATIENT MANAGEMENT:  The manufacturer recommends avoiding concomitant use of|
02508|017|M|nintedanib with agents which are inducers of both P-gp and CYP3A4 as|
02508|018|M|coadministration may decrease nintedanib exposure by 50%.(1)|
02508|019|B||
02508|020|D|DISCUSSION:  In an interaction study, concurrent rifampin decreased the|
02508|021|D|area-under-curve (AUC) and maximum concentration (Cmax) of nintedanib by|
02508|022|D|50.3% and 60.3%, respectively.(1)|
02508|023|D|   Inducers of both P-gp and CYP3A4 linked to this monograph are|
02508|024|D|apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine,|
02508|025|D|and St. John's wort.|
02508|026|B||
02508|027|R|REFERENCE:|
02508|028|B||
02508|029|R|1.Ofev (nintedanib) US prescribing information. Boehringer Ingelheim|1
02508|030|R|  Pharmaceuticals Inc. September, 2019.|1
02509|001|T|MONOGRAPH TITLE:  Selected Antiarrhythmics/Elvitegravir-Cobicistat|
02509|002|B||
02509|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02509|004|L|of severe adverse interaction.|
02509|005|B||
02509|006|A|MECHANISM OF ACTION:  Cobicistat may inhibit the metabolism of amiodarone,|
02509|007|A|disopyramide, flecainide, propafenone, and quinidine.(1,2)|
02509|008|B||
02509|009|E|CLINICAL EFFECTS:  Concurrent use of cobicistat and amiodarone,|
02509|010|E|disopyramide, flecainide, propafenone, or quinidine may result in elevated|
02509|011|E|levels of these antiarrhythmics and serious and/or life-threatening effects|
02509|012|E|including QT prolongation or torsades de pointes.(1,2)|
02509|013|B||
02509|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02509|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02509|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02509|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02509|018|P|female gender, or advanced age.(3)|
02509|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02509|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02509|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02509|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02509|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02509|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02509|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02509|026|B||
02509|027|M|PATIENT MANAGEMENT:  The concurrent use of cobicistat and amiodarone,|
02509|028|M|disopyramide, flecainide, propafenone, or quinidine should be used with|
02509|029|M|caution and clinical monitoring is recommended with concomitant use.(1,2)|
02509|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02509|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02509|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02509|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02509|034|B||
02509|035|D|DISCUSSION:  Cobicistat may inhibit the metabolism and increase levels of|
02509|036|D|amiodarone, disopyramide, flecainide, propafenone, or quinidine.(1,2)|
02509|037|D|   Selected antiarrhythmics linked to this monograph include: ajmaline,|
02509|038|D|amiodarone, bepridil, disopyramide, flecainide, propafenone, and quinidine.|
02509|039|B||
02509|040|R|REFERENCES:|
02509|041|B||
02509|042|R|1.Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02509|043|R|  prescribing information. Gilead Sciences, Inc September, 2021.|1
02509|044|R|2.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02509|045|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02509|046|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02509|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02509|048|R|  settings: a scientific statement from the American Heart Association and|6
02509|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02509|050|R|  2;55(9):934-47.|6
02511|001|T|MONOGRAPH TITLE:  Eszopiclone > 2 mg; Zopiclone > 5 mg/Strong 3A4 Inhibitors|
02511|002|B||
02511|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02511|004|L|of severe adverse interaction.|
02511|005|B||
02511|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 impair the metabolism of|
02511|007|A|eszopiclone(1) and zopiclone.(2,3)|
02511|008|B||
02511|009|E|CLINICAL EFFECTS:  Concurrent use of eszopiclone(1) or zopiclone(2,3) with a|
02511|010|E|strong CYP3A4 inhibitor may result in an increase in hypnotic levels and|
02511|011|E|clinical adverse effects such as confusion, memory loss, sleep-walking or|
02511|012|E|sleep-driving behaviors, thought or behavioral changes, or excessive daytime|
02511|013|E|drowsiness, as well as toxic effects such as profound sedation, respiratory|
02511|014|E|depression, coma, and/or death.|
02511|015|B||
02511|016|P|PREDISPOSING FACTORS:  Systemic exposure may also be increased in patients|
02511|017|P|with severe hepatic impairment.|
02511|018|P|   Elderly and debilitated patients are more likely to have impaired motor|
02511|019|P|or cognitive performance when treated with hypnotics.|
02511|020|B||
02511|021|M|PATIENT MANAGEMENT:  The US manufacturer of eszopiclone states the total|
02511|022|M|dose should not exceed 2 mg in patients taking strong CYP3A4 inhibitors.(1)|
02511|023|M|   The Canadian manufacturer of zopiclone states the prescribed dose should|
02511|024|M|not exceed 5 mg in patients treated with strong CYP3A4 inhibitors.(2)|
02511|025|M|   Patients should be counseled that concurrent use of a strong CYP3A4|
02511|026|M|inhibitor with eszopiclone or zopiclone may result in an increase in side|
02511|027|M|effects such as confusion, memory loss, sleep-walking or sleep-driving|
02511|028|M|behaviors, or daytime drowsiness.|
02511|029|B||
02511|030|D|DISCUSSION:  Concurrent administration of ketoconazole (400 mg daily for 5|
02511|031|D|days) increased the area-under-curve (AUC) of eszopiclone by 2.2-fold.|
02511|032|D|Eszopiclone maximum concentration (Cmax) and half-life were increased|
02511|033|D|1.4-fold and 1.3-fold, respectively.(1)|
02511|034|D|   An in vitro study in human liver microsomes found that ketoconazole|
02511|035|D|inhibited the metabolism of zopiclone.(2)|
02511|036|D|   In a study in 10 subjects, itraconazole (200 mg daily for 4 days)|
02511|037|D|increased the AUC, Cmax, and half-life of zopiclone by 73%, 29%, and 40%,|
02511|038|D|respectively.  However, there were no significant differences in clinical|
02511|039|D|effects when compared to placebo.(4)|
02511|040|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02511|041|D|clarithromycin, cobicistat, elvitegravir, idelalisib, indinavir,|
02511|042|D|itraconazole, josamycin, ketoconazole, levoketoconazole,|
02511|043|D|lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
02511|044|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, ritonavir,|
02511|045|D|saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and|
02511|046|D|voriconazole.(5,6)|
02511|047|B||
02511|048|R|REFERENCES:|
02511|049|B||
02511|050|R|1.Lunesta (eszopiclone) US prescribing information. Sunovion Pharmaceuticals|1
02511|051|R|  Inc. August, 2019.|1
02511|052|R|2.Imovane (zopiclone) Canada prescribing information. Sanofi-Aventis Canada|1
02511|053|R|  Inc. October 20, 2014.|1
02511|054|R|3.Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Brentano C, Jaillon|5
02511|055|R|  P. Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism. Drug|5
02511|056|R|  Metab Dispos 1999 Sep;27(9):1068-73.|5
02511|057|R|4.Jalava KM, Olkkola KT, Neuvonen PJ. Effect of itraconazole on the|2
02511|058|R|  pharmacokinetics and pharmacodynamics of zopiclone. Eur J Clin Pharmacol|2
02511|059|R|  1996;51(3-4):331-4.|2
02511|060|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02511|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02511|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02511|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02511|064|R|  11/14/2017.|1
02511|065|R|6.This information is based on an extract from the Certara Drug Interaction|6
02511|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02512|001|T|MONOGRAPH TITLE:  Digoxin/Selected Hepatitis C Agents|
02512|002|B||
02512|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02512|004|L|take action as needed.|
02512|005|B||
02512|006|A|MECHANISM OF ACTION:  Ledipasvir,(1) ombitasvir-paritaprevir-ritonavir,(2,3)|
02512|007|A|velpatasvir(4,5), and glecaprevir-pibrentasvir (8) inhibit intestinal|
02512|008|A|P-glycoprotein (P-gp) transport, which may increase digoxin bioavailability.|
02512|009|A|Glecaprevir-pibrentasvir also inhibits OATP1B3.|
02512|010|B||
02512|011|E|CLINICAL EFFECTS:  Concurrent use of ledipasvir,(1) or|
02512|012|E|ombitasvir-paritaprevir-ritonavir,(2,3) or velpatasvir,(4,5) or|
02512|013|E|glecaprevir-pibrentasvir may result in elevated levels and toxicity from|
02512|014|E|digoxin.  Symptoms of digoxin toxicity can include anorexia, nausea,|
02512|015|E|vomiting, headache, fatigue, malaise, drowsiness, generalized muscle|
02512|016|E|weakness, disorientation, hallucinations, visual disturbances, and|
02512|017|E|arrhythmias.|
02512|018|B||
02512|019|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02512|020|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02512|021|P|risk of digoxin toxicity.|
02512|022|B||
02512|023|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
02512|024|M|ledipasvir for elevated digoxin levels and adjust the dose accordingly.(1)|
02512|025|M|   The manufacturer of ombitasvir-paritaprevir-ritonavir recommends a|
02512|026|M|digoxin dose reduction of 30-50% with follow-up digoxin monitoring in|
02512|027|M|patients not also receiving concomitant dasabuvir therapy.(2)  In contrast,|
02512|028|M|monitoring but no automatic dose adjustment is recommended in patients|
02512|029|M|receiving ombitasvir-paritaprevir-ritonavir with dasabuvir.(2,3)|
02512|030|M|   During concomitant therapy, the manufacturer of sofosbuvir-velpatasvir|
02512|031|M|recommends digoxin therapeutic concentration monitoring and digoxin dose|
02512|032|M|adjustment based upon digoxin prescribing information modifications for|
02512|033|M|concentration increases less than 50%.(4)|
02512|034|M|   During concomitant therapy, the manufacturer of|
02512|035|M|sofosbuvir-velpatasvir-voxilaprevir recommends digoxin therapeutic|
02512|036|M|concentration monitoring and digoxin dose adjustment based upon digoxin|
02512|037|M|prescribing information modifications for concentration increases with|
02512|038|M|unclear magnitude.(5)|
02512|039|M|   The manufacture of glecaprevir-pibrentasvir recommends a digoxin dose|
02512|040|M|reduction of 50% or modification of the dosing frequency with follow-up|
02512|041|M|digoxin monitoring in patients.(8)|
02512|042|B||
02512|043|D|DISCUSSION:  In an interaction study, the combination of|
02512|044|D|ombitasvir-paritaprevir-ritonavir increased exposure (area-under-curve, AUC)|
02512|045|D|to a single dose of digoxin by 36% (range: 21 - 54%).(2)  In a second|
02512|046|D|evaluation, the combination of ombitasvir-paritaprevir-ritonavir and|
02512|047|D|dasabuvir with digoxin increased digoxin 16% (range: 9 - 23%).(6)|
02512|048|D|   In an interaction study in 21 subjects, velpatasvir (100 mg) increased|
02512|049|D|the Cmax and AUC of digoxin (0.25 mg single dose) by 88% and 34%,|
02512|050|D|respectively.(4,5)|
02512|051|D|   Concomitant administration of ritonavir and digoxin increased the digoxin|
02512|052|D|AUC 86%.(7)|
02512|053|D|   In an interaction study in 12 subjects, glecaprevir-pibrentasvir (400/120|
02512|054|D|mg daily) increased the Cmax and AUC of digoxin (0.5 mg single dose) by 72%|
02512|055|D|and 48%, respectively.(8)|
02512|056|B||
02512|057|R|REFERENCES:|
02512|058|B||
02512|059|R|1.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
02512|060|R|  Sciences November, 2019.|1
02512|061|R|2.Viekirax (ombitasvir, paritaprevir, ritonavir) UK summary of product|1
02512|062|R|  characteristics. AbbVie Limited January 16, 2019.|1
02512|063|R|3.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02512|064|R|  prescribing information. AbbVie Inc. December, 2019.|1
02512|065|R|4.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
02512|066|R|  Sciences, Inc. April, 2022.|1
02512|067|R|5.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02512|068|R|  Gilead Sciences, Inc. September, 2019.|1
02512|069|R|6.Davis B and Pimentel J. Personal Communications: Harvoni. Gilead Sciences|1
02512|070|R|  November 14 and 18, 2014.|1
02512|071|R|7.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
02512|072|R|  Pharmaceuticals, Inc. August, 2018.|1
02512|073|R|8.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02512|074|R|  Inc. October, 2023.|1
02513|001|T|MONOGRAPH TITLE:  Rosuvastatin/Ledipasvir|
02513|002|B||
02513|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02513|004|L|of severe adverse interaction.|
02513|005|B||
02513|006|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate for breast cancer|
02513|007|A|resistance protein (BCRP). Ledipasvir inhibits intestinal BCRP leading to|
02513|008|A|increased systemic absorption of rosuvastatin.(1)|
02513|009|B||
02513|010|E|CLINICAL EFFECTS:  High systemic concentrations of rosuvastatin increase the|
02513|011|E|risk for statin-induced myopathy or rhabdomyolysis.|
02513|012|B||
02513|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02513|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02513|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02513|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02513|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02513|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02513|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02513|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02513|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02513|022|B||
02513|023|M|PATIENT MANAGEMENT:  Concurrent use of rosuvastatin and ledipasvir is not|
02513|024|M|recommended.(2)  Use an alternative statin during ledipasvir treatment for|
02513|025|M|hepatitis C.|
02513|026|M|   In an interaction study, ledipasvir combined with two investigational|
02513|027|M|hepatitis C agents, increased rosuvastatin exposure (area-under-curve, AUC)|
02513|028|M|699%. The manufacturer primarily attributes elevated rosuvastatin levels to|
02513|029|M|BCRP inhibition by ledipasvir.(3)|
02513|030|B||
02513|031|D|DISCUSSION:  In a randomized cross-over interaction study, healthy subjects|
02513|032|D|received ledipasvir, vedroprevir, tegobuvir (the latter two are|
02513|033|D|investigational hepatitis C agents) for 9 days followed by either one dose|
02513|034|D|of either rosuvastatin or pravastatin on day ten, and then by one dose of|
02513|035|D|the other statin on day 14.  After a 9 day washout, another identical|
02513|036|D|treatment period was started except that the order of statin administration|
02513|037|D|was reversed.  This combination of 3 hepatitis C agents increased|
02513|038|D|rosuvastatin AUC 699%.  The manufacturer attributes this large increase in|
02513|039|D|exposure primarily to BCRP inhibition by ledipasvir.(3)|
02513|040|B||
02513|041|R|REFERENCES:|
02513|042|B||
02513|043|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02513|044|R|  Pharmaceuticals LP July, 2024.|1
02513|045|R|2.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
02513|046|R|  Sciences November, 2019.|1
02513|047|R|3.Davis B and Pimentel J. Personal Communications: Harvoni. Gilead Sciences|1
02513|048|R|  November 14 and 18, 2014.|1
02514|001|T|MONOGRAPH TITLE:  Simeprevir/Ledipasvir|
02514|002|B||
02514|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02514|004|L|of severe adverse interaction.|
02514|005|B||
02514|006|A|MECHANISM OF ACTION:  Ledipasvir may increase systemic absorption of|
02514|007|A|simeprevir via inhibition of intestinal P-glycoprotein (P-gp).(1)|
02514|008|B||
02514|009|E|CLINICAL EFFECTS:  Simeprevir systemic concentrations may be increased.|
02514|010|E|Higher simeprevir exposure is associated with a higher incidence of rash|
02514|011|E|which may be severe.(1,3)|
02514|012|B||
02514|013|P|PREDISPOSING FACTORS:  None determined.|
02514|014|B||
02514|015|M|PATIENT MANAGEMENT:  The US manufacturer of ledipasvir states that|
02514|016|M|concurrent administration with simeprevir is not recommended.(2)|
02514|017|M|   During the approval process, FDA reviewers evaluating ledipasvir|
02514|018|M|interaction studies noted the approximate 2.4-fold increase in simeprevir|
02514|019|M|exposure with this combination.  Given the already large degree of|
02514|020|M|interindividual variability in simeprevir pharmacokinetics and the higher|
02514|021|M|risk for rash with increased exposure to simeprevir, they determined that|
02514|022|M|safety concerns preclude concomitant use of this combination.|
02514|023|B||
02514|024|D|DISCUSSION:  An interaction study in 22 healthy volunteers evaluated the|
02514|025|D|combination of simeprevir (150 mg daily with food for 10 days) and|
02514|026|D|ledipasvir (30 mg daily with food for 10 days; FDA reviewers believe the|
02514|027|D|interaction magnitude would be similar at the approved ledipasvir dose of 90|
02514|028|D|mg). Simeprevir area-under-curve (AUC) and maximum concentration (Cmax) were|
02514|029|D|increased 2.69-fold and 2.61-fold respectively.  Given the already large|
02514|030|D|degree of interindividual variability in simeprevir pharmacokinetics and the|
02514|031|D|higher risk for rash with increased exposure to simeprevir, FDA reviewers|
02514|032|D|determined that safety concerns preclude concomitant use of this|
02514|033|D|combination.(1)|
02514|034|D|   In this interaction study, ledipasvir concentrations were also|
02514|035|D|increased.(1,2) Based upon ledipasvir's safety profile, FDA determined the|
02514|036|D|increased ledipasvir concentration does not present safety concerns.(1)|
02514|037|B||
02514|038|R|REFERENCES:|
02514|039|B||
02514|040|R|1.US Food and Drug Administration (FDA). Drug Approval Package Harvoni|1
02514|041|R|  (ledipasvir and sofosbuvir) Application No.:205834. Accessed at:|1
02514|042|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205834Orig1s000TOC.|1
02514|043|R|  cfm November 3, 2014.|1
02514|044|R|2.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
02514|045|R|  Sciences November, 2019.|1
02514|046|R|3.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
02514|047|R|  November, 2017.|1
02515|001|T|MONOGRAPH TITLE:  Rivaroxaban/Selected P-gp and Moderate CYP3A4 Inhibitors|
02515|002|B||
02515|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02515|004|L|of severe adverse interaction.|
02515|005|B||
02515|006|A|MECHANISM OF ACTION:  Diltiazem, dronedarone, and isavuconazonium may|
02515|007|A|inhibit the metabolism of rivaroxaban by CYP3A4 and by P-glycoprotein.(1-5)|
02515|008|B||
02515|009|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
02515|010|E|P-gp and a moderate inhibitor of CYP3A4 may result in elevated levels of and|
02515|011|E|clinical effects of rivaroxaban, including an increased risk of bleeding, in|
02515|012|E|patients with decreased renal function.(1,2)|
02515|013|B||
02515|014|P|PREDISPOSING FACTORS:  It is expected that this interaction will only be|
02515|015|P|clinically significant in patients with decreased renal function.(1)|
02515|016|P|   The risk for bleeding episodes may be greater in patients with|
02515|017|P|disease-associated factors (e.g. thrombocytopenia).|
02515|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
02515|019|P|which inhibit CYP3A4,(6) inhibit anticoagulant/antiplatelet metabolism|
02515|020|P|and/or have an inherent risk for bleeding (NSAIDs).|
02515|021|B||
02515|022|M|PATIENT MANAGEMENT:  The US manufacturer states no precautions are necessary|
02515|023|M|with the concurrent use of agents that are combined moderate inhibitors of|
02515|024|M|CYP3A4 and P-gp inhibitors with rivaroxaban in patients with normal renal|
02515|025|M|function; however, in patients with decreased renal function (CrCL of 15|
02515|026|M|ml/min to 80 ml/min) these agents should only be used if the benefits of|
02515|027|M|concurrent therapy outweigh the increased risk of bleeding.(1)  The Canadian|
02515|028|M|manufacturer states that if such use must be undertaken, caution is|
02515|029|M|required.(3)  The UK manufacturer states that concomitant use is not|
02515|030|M|recommended.(7)|
02515|031|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02515|032|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02515|033|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02515|034|M|patients with any symptoms.|
02515|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02515|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02515|037|M|anticoagulation in patients with active pathologic bleeding.|
02515|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02515|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02515|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02515|041|M|and/or swelling.|
02515|042|B||
02515|043|D|DISCUSSION:  Clarithromycin (500 mg twice daily) increased the|
02515|044|D|area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of|
02515|045|D|rivaroxaban by 54% and 40%, respectively.(1,2)  In a study in 60 healthy|
02515|046|D|males, clarithromycin (500 mg twice daily) increased the AUC and Cmax of a|
02515|047|D|single dose of rivaroxaban (40 mg) by 94% and 92%, respectively.(8)  In a|
02515|048|D|case report, a 65 year-old male developed hemoptysis, epistaxis, and|
02515|049|D|intracranial hemorrhage 3 days after the addition of clarithromycin (500 mg|
02515|050|D|twice daily) to rivaroxaban (20 mg daily).(9)|
02515|051|D|   A study of 12 healthy volunteers found that cyclosporine increased|
02515|052|D|rivaroxaban AUC and Cmax by 47% and 104%, respectively, compared to|
02515|053|D|rivaroxaban alone.  The combination of fluconazole and cyclosporine|
02515|054|D|administered with rivaroxaban increased rivaroxaban AUC and Cmax by 86% and|
02515|055|D|115%, respectively, compared to rivaroxaban alone.(6)|
02515|056|D|   In a review of 9 liver transplant patients, mean rivaroxaban levels were|
02515|057|D|significantly higher in patients treated with cyclosporine than with|
02515|058|D|tacrolimus (131.7 ng/ml versus 20.3 ng/ml).(10)|
02515|059|D|   In a review of 23 patients who received concurrent rivaroxaban and|
02515|060|D|dronedarone for an average of 9.1+/-6.7 months, there were no thromboembolic|
02515|061|D|or major bleeding events.  One fourth of the patients received a reduced|
02515|062|D|dose of rivaroxaban (15 mg daily), despite having normal renal function.(11)|
02515|063|D|   Erythromycin (500 mg three times daily) increased the AUC and Cmax of a|
02515|064|D|single dose of rivaroxaban by 30% and 30%, respectively.(1-3)  In patients|
02515|065|D|with mild renal impairment (CrCl of 50 ml/min to 79 ml/min) who were|
02515|066|D|receiving erythromycin, rivaroxaban AUC and Cmax were increased 76% and 56%|
02515|067|D|when compared to administration of rivaroxaban in patients with normal renal|
02515|068|D|function receiving rivaroxaban alone.  In patients with moderate renal|
02515|069|D|impairment (CrCl of 30 ml/min to 49 ml/min) who were receiving erythromycin,|
02515|070|D|rivaroxaban AUC and Cmax were increased 99% and 64% when compared to|
02515|071|D|administration of rivaroxaban in patients with normal renal function|
02515|072|D|receiving rivaroxaban alone.(1,12)|
02515|073|D|   In a post hoc analysis of the ROCKET-AF trial, concomitant use of|
02515|074|D|non-dihydropyridine calcium channel blockers and rivaroxaban was associated|
02515|075|D|with an increased risk of major bleeding and intracranial hemorrhage. There|
02515|076|D|was no difference in efficacy or safety of rivaroxaban versus warfarin and|
02515|077|D|concomitant use of CCB across renal function subgroups.(13)|
02515|078|D|   In a study in subjects who were taking verapamil, the combination of|
02515|079|D|verapamil and mild renal insufficiency produced additive effects on the AUC|
02515|080|D|of a single dose of rivaroxaban (20 mg).(14)|
02515|081|D|   A propensity matched cohort evaluated the concurrent use of combined P-gp|
02515|082|D|and moderate CYP3A4 inhibitors with apixaban or rivaroxaban.  Combined|
02515|083|D|inhibitors included amiodarone, diltiazem, erythromycin, dronedarone, and|
02515|084|D|verapamil.  Bleeding occurred in 26.4% of patients in the inhibitor group|
02515|085|D|compared to 18.4% in the control group (hazard ratio 1.8; 95% CI 1.19-2.73;|
02515|086|D|p=0.006).  Although not statistically significant, patients in the inhibitor|
02515|087|D|group also had a higher rate of major bleeding (15% vs 10.3%) and minor|
02515|088|D|bleeding (8.9% vs 5.2%), respectively.(15)|
02515|089|D|   A summary of pharmacokinetic interactions with rivaroxaban and|
02515|090|D|dronedarone concluded that concurrent use should be avoided if CrCl < 80|
02515|091|D|ml/min.(16)|
02515|092|D|   These changes are not expected to be clinically significant in patients|
02515|093|D|with normal renal function.(1-3)|
02515|094|B||
02515|095|R|REFERENCES:|
02515|096|B||
02515|097|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
02515|098|R|  Inc. March, 2020.|1
02515|099|R|2.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
02515|100|R|  August, 2021.|1
02515|101|R|3.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
02515|102|R|  2015.|1
02515|103|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02515|104|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02515|105|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02515|106|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02515|107|R|  11/14/2017.|1
02515|108|R|5.This information is based on an extract from the Certara Drug Interaction|6
02515|109|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02515|110|R|6.Brings A, Lehmann ML, Foerster KI, Burhenne J, Weiss J, Haefeli WE, Czock|2
02515|111|R|  D. Perpetrator effects of ciclosporin (P-glycoprotein inhibitor) and its|2
02515|112|R|  combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of|2
02515|113|R|  rivaroxaban in healthy volunteers. Br J Clin Pharmacol 2019 Jul;|2
02515|114|R|  85(7):1528-1537.|2
02515|115|R|7.Multaq (dronedarone hydrochoride) UK summary of product characteristics.|1
02515|116|R|  Sanofi June 17, 2020.|1
02515|117|R|8.Gouin-Thibault I, Delavenne X, Blanchard A, Siguret V, Salem JE, Narjoz C,|2
02515|118|R|  Gaussem P, Beaune P, Funck-Brentano C, Azizi M, Mismetti P, Loriot MA.|2
02515|119|R|  Interindividual variability in dabigatran and rivaroxaban exposure:|2
02515|120|R|  contribution  of ABCB1 genetic polymorphisms and interaction with|2
02515|121|R|  clarithromycin. J Thromb Haemost 2017 Feb;15(2):273-283.|2
02515|122|R|9.Fralick M, Juurlink DN, Marras T. Bleeding associated with|3
02515|123|R|  coadministration of rivaroxaban and clarithromycin. CMAJ 2016 Jun 14;|3
02515|124|R|  188(9):669-72.|3
02515|125|R|10.Wannhoff A, Weiss KH, Schemmer P, Stremmel W, Gotthardt DN. Increased|2
02515|126|R|   levels of rivaroxaban in patients after liver transplantation treated|2
02515|127|R|   with cyclosporine A. Transplantation 2014 Jul 27;98(2):e12-3.|2
02515|128|R|11.Escobar C, Arceluz M, Montes de Oca R, Mori R, Lopez-Sendon JL, Merino|2
02515|129|R|   JL. Concomitant Rivaroxaban and Dronedarone Administration in Patients|2
02515|130|R|   With Nonvalvular Atrial Fibrillation. Rev Esp Cardiol (Engl Ed) 2017 Feb;|2
02515|131|R|   70(2):121-122.|2
02515|132|R|12.Moore KT, Vaidyanathan S, Natarajan J, Ariyawansa J, Haskell L, Turner|2
02515|133|R|   KC. An open-label study to estimate the effect of steady-state|2
02515|134|R|   erythromycin on the pharmacokinetics, pharmacodynamics, and safety of a|2
02515|135|R|   single dose of rivaroxaban in subjects with renal impairment and normal|2
02515|136|R|   renal function. J Clin Pharmacol 2014 Dec;54(12):1407-20.|2
02515|137|R|13.Washam JB, Hellkamp AS, Lokhnygina Y, Piccini JP, Berkowitz SD, Nessel|2
02515|138|R|   CC, Becker RC, Breithardt G, Fox KAA, Halperin JL, Hankey GJ, Mahaffey|2
02515|139|R|   KW, Singer DE, Patel MR. Efficacy and Safety of Rivaroxaban Versus|2
02515|140|R|   Warfarin in Patients Taking Nondihydropyridine Calcium Channel Blockers|2
02515|141|R|   for Atrial Fibrillation (from the ROCKET AF Trial). Am J Cardiol 2017 Aug|2
02515|142|R|   15;120(4):588-594.|2
02515|143|R|14.Greenblatt DJ, Patel M, Harmatz JS, Nicholson WT, Rubino CM, Chow CR.|2
02515|144|R|   Impaired Rivaroxaban Clearance in Mild Renal Insufficiency With Verapamil|2
02515|145|R|   Coadministration: Potential Implications for Bleeding Risk and Dose|2
02515|146|R|   Selection. J Clin Pharmacol 2018 Apr;58(4):533-540.|2
02515|147|R|15.Hanigan S, Das J, Pogue K, Barnes GD, Dorsch MP. The real world use of|2
02515|148|R|   combined P-glycoprotein and moderate CYP3A4 inhibitors with  rivaroxaban|2
02515|149|R|   or apixaban increases bleeding..|2
02515|150|R|16.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
02515|151|R|   Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
02515|152|R|   of  the Week..|6
02516|001|T|MONOGRAPH TITLE:  Estramustine, Oral/Clodronate|
02516|002|B||
02516|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02516|004|L|of severe adverse interaction.|
02516|005|B||
02516|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve an|
02516|007|A|increase in the bioavailability of estramustine.(1-3)|
02516|008|B||
02516|009|E|CLINICAL EFFECTS:  The concurrent use of clodronate may result in elevated|
02516|010|E|levels of and toxicity from estramustine,(1-3) including infection, edema,|
02516|011|E|blood clots, and altered liver enzymes.(4)|
02516|012|B||
02516|013|P|PREDISPOSING FACTORS:  None determined.|
02516|014|B||
02516|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of clodronate and|
02516|016|M|estramustine.(1)  If concurrent use is warranted, monitor estramustine|
02516|017|M|levels and liver enzymes.  Instruct patients to report symptoms of edema,|
02516|018|M|infection, or blood clots.|
02516|019|B||
02516|020|D|DISCUSSION:  In a study in 12 subjects with prostate cancer and bone|
02516|021|D|metastases, the concurrent use of clodronate (800 mg orally four times|
02516|022|D|daily) and estramustine (280 mg twice daily) increased the serum|
02516|023|D|concentrations of estramustine by 80%.(2)|
02516|024|B||
02516|025|R|REFERENCES:|
02516|026|B||
02516|027|R|1.Clodronate. BC Cancer Agency Cancer Drug Manual June 1, 2013.|1
02516|028|R|2.Kylmala T, Castren-Kortekangas P, Seppanen J, Ylitalo P, Tammela TL.|2
02516|029|R|  Effect of concomitant administration of clodronate and estramustine|2
02516|030|R|  phosphate on  their bioavailability in patients with metastasized prostate|2
02516|031|R|  cancer. Pharmacol Toxicol 1996 Sep;79(3):157-60.|2
02516|032|R|3.Bonefos (clodronate disodium) Canadian prescribing information. Bayer Inc.|1
02516|033|R|  September 22, 2011.|1
02516|034|R|4.Emcyt (estramustine sodium phosphate) Canadian prescribing information.|1
02516|035|R|  Pfizer Canada Inc July 14, 2008.|1
02517|001|T|MONOGRAPH TITLE:  Fosfomycin, Oral/Metoclopramide|
02517|002|B||
02517|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02517|004|L|is contraindicated and generally should not be dispensed or administered to|
02517|005|L|the same patient.|
02517|006|B||
02517|007|A|MECHANISM OF ACTION:  Metoclopramide may decrease the amount of fosfomycin|
02517|008|A|absorbed.(1)|
02517|009|B||
02517|010|E|CLINICAL EFFECTS:  The concurrent use of metoclopramide may result in|
02517|011|E|reduced levels of fosfomycin and treatment failure.(1)|
02517|012|B||
02517|013|P|PREDISPOSING FACTORS:  None determined.|
02517|014|B||
02517|015|M|PATIENT MANAGEMENT:  Fosfomycin should not be used in patients receiving|
02517|016|M|metoclopramide.(1)|
02517|017|M|   Consider the use of alternative urinary tract anti-infectives in patients|
02517|018|M|maintained on metoclopramide.  If concurrent use is warranted, monitor|
02517|019|M|patients for fosfomycin treatment failure.|
02517|020|B||
02517|021|D|DISCUSSION:  Metoclopramide has been shown to reduce fosfomycin levels.|
02517|022|D|Urinary levels of fosfomycin may not exceed required bactericidal levels for|
02517|023|D|a long enough period of time to result in microbiological cure.(1)|
02517|024|B||
02517|025|R|REFERENCE:|
02517|026|B||
02517|027|R|1.Monurol (fosfomycin) Canadian Prescribing Information. Paladin Labs, Inc.|1
02517|028|R|  October 6, 2014.|1
02518|001|T|MONOGRAPH TITLE:  Fosfomycin/Probenecid (mono deleted 03/28/2019)|
02518|002|B||
02518|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02518|004|L|is contraindicated and generally should not be dispensed or administered to|
02518|005|L|the same patient.|
02518|006|B||
02518|007|A|MECHANISM OF ACTION:  Probenecid may inhibit the tubular secretion of|
02518|008|A|fosfomycin.(1)|
02518|009|B||
02518|010|E|CLINICAL EFFECTS:  The concurrent use of probenecid may result in reduced|
02518|011|E|urinary tract levels of fosfomycin and treatment failure.(1)|
02518|012|B||
02518|013|P|PREDISPOSING FACTORS:  None determined.|
02518|014|B||
02518|015|M|PATIENT MANAGEMENT:  Fosfomycin should not be used in patients receiving|
02518|016|M|probenecid.(1)|
02518|017|M|   Consider the use of alternative urinary tract anti-infectives in patients|
02518|018|M|taking probenecid.  If concurrent use is warranted, monitor patients for|
02518|019|M|fosfomycin treatment failure.|
02518|020|B||
02518|021|D|DISCUSSION:  In five healthy subjects, probenecid decreased the urinary|
02518|022|D|excretion of fosfomycin infusion.(1,2)  Urinary levels of fosfomycin may not|
02518|023|D|exceed required bactericidal levels for a long enough period of time to|
02518|024|D|result in microbiological cure.(1)|
02518|025|B||
02518|026|R|REFERENCES:|
02518|027|B||
02518|028|R|1.Monurol (fosfomycin) Canadian Prescribing Information. Paladin Labs, Inc.|1
02518|029|R|  October 6, 2014.|1
02518|030|R|2.Potel G, Meignier M, Baron D, Reynaud A, Touze MD, Courtieu AL.|2
02518|031|R|  Pharmacokinetics of fosfomycin in normal and burn patients. Effect of|2
02518|032|R|  probenecid. Drugs Exp Clin Res 1989;15(4):177-84.|2
02519|001|T|MONOGRAPH TITLE:  Zoster Vaccine Live/Methotrexate (lower dosage or|
02519|002|T|strength)|
02519|003|B||
02519|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02519|005|L|of severe adverse interaction.|
02519|006|B||
02519|007|A|MECHANISM OF ACTION:  A variety of disease modifying agents such as|
02519|008|A|methotrexate suppress the immune system. Immunocompromised patients may be|
02519|009|A|at increased risk for uninhibited replication after administration of live,|
02519|010|A|attenuated vaccines. Immune response to vaccines may be decreased during|
02519|011|A|periods of immunocompromise.(1)|
02519|012|B||
02519|013|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained|
02519|014|E|and/or the vaccine may result in illness.(1)|
02519|015|B||
02519|016|P|PREDISPOSING FACTORS:  Immunosuppressive diseases (e.g. hematologic|
02519|017|P|malignancies, HIV disease), treatments (e.g. radiation) and drugs may all|
02519|018|P|increase the magnitude of immunodeficiency.|
02519|019|B||
02519|020|M|PATIENT MANAGEMENT:  CDC recommendations for zoster vaccine state it may be|
02519|021|M|administered to patients receiving methotrexate if the dose is < or = to 0.4|
02519|022|M|mg/kg/week for treatment of rheumatoid arthritis, psoriasis, inflammatory|
02519|023|M|bowel disease or other conditions.(1)|
02519|024|M|   For patients receiving > 0.4mg/kg/week, Centers for Disease Control(CDC)|
02519|025|M|Advisory Committee on Immunization Practices (ACIP) states that live-virus|
02519|026|M|and live, attenuated vaccines should not be administered to patients who are|
02519|027|M|immunocompromised. The magnitude of immunocompromise and associated risks|
02519|028|M|should be determined by a physician.(1)|
02519|029|M|   For patients scheduled to receive chemotherapy, vaccination should|
02519|030|M|ideally precede the initiation of chemotherapy by 14 days.  Patients|
02519|031|M|vaccinated while on immunosuppressive therapy or in the 2 weeks prior to|
02519|032|M|starting therapy should be considered unimmunized and should be revaccinated|
02519|033|M|at least 3 months after discontinuation of therapy.(1)|
02519|034|B||
02519|035|D|DISCUSSION:  Killed or inactivated vaccines do not pose a danger to|
02519|036|D|immunocompromised patients.(1)|
02519|037|D|   Patients with a history of leukemia who are in remission and have not|
02519|038|D|received chemotherapy for at least 3 months are not considered to be|
02519|039|D|immunocompromised.(1)|
02519|040|B||
02519|041|R|REFERENCE:|
02519|042|B||
02519|043|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
02519|044|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
02519|045|R|  Practices (ACIP). MMWR.  Available at:|1
02519|046|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
02519|047|R|  February 17, 2022;60(RR No.2):1-68.|1
02520|001|T|MONOGRAPH TITLE:  Zoster Vaccine Live/Methotrexate (lowest dose)|
02520|002|B||
02520|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02520|004|L|take action as needed.|
02520|005|B||
02520|006|A|MECHANISM OF ACTION:  A variety of disease modifying agents such as|
02520|007|A|methotrexate suppress the immune system. Immunocompromised patients may be|
02520|008|A|at increased risk for uninhibited replication after administration of live,|
02520|009|A|attenuated vaccines. Immune response to vaccines may be decreased during|
02520|010|A|periods of immunocompromise.(1)|
02520|011|B||
02520|012|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained|
02520|013|E|and/or the vaccine may result in illness.(1)|
02520|014|B||
02520|015|P|PREDISPOSING FACTORS:  Immunosuppressive diseases (e.g. hematologic|
02520|016|P|malignancies, HIV disease), treatments (e.g. radiation) and drugs may all|
02520|017|P|increase the magnitude of immunodeficiency.|
02520|018|B||
02520|019|M|PATIENT MANAGEMENT:  CDC recommendations for zoster vaccine state it may be|
02520|020|M|administered to patients receiving methotrexate if the dose is < or = to 0.4|
02520|021|M|mg/kg/week for treatment of rheumatoid arthritis, psoriasis, inflammatory|
02520|022|M|bowel disease or other conditions.(1)|
02520|023|M|   For patients receiving > 0.4mg/kg/week, Centers for Disease Control(CDC)|
02520|024|M|Advisory Committee on Immunization Practices (ACIP) states that live-virus|
02520|025|M|and live, attenuated vaccines should not be administered to patients who are|
02520|026|M|immunocompromised. The magnitude of immunocompromise and associated risks|
02520|027|M|should be determined by a physician.(1)|
02520|028|M|   For patients scheduled to receive chemotherapy, vaccination should|
02520|029|M|ideally precede the initiation of chemotherapy by 14 days.  Patients|
02520|030|M|vaccinated while on immunosuppressive therapy or in the 2 weeks prior to|
02520|031|M|starting therapy should be considered unimmunized and should be revaccinated|
02520|032|M|at least 3 months after discontinuation of therapy.(1)|
02520|033|B||
02520|034|D|DISCUSSION:  Killed or inactivated vaccines do not pose a danger to|
02520|035|D|immunocompromised patients.(1)|
02520|036|D|   Patients with a history of leukemia who are in remission and have not|
02520|037|D|received chemotherapy for at least 3 months are not considered to be|
02520|038|D|immunocompromised.(1)|
02520|039|B||
02520|040|R|REFERENCE:|
02520|041|B||
02520|042|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
02520|043|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
02520|044|R|  Practices (ACIP). MMWR.  Available at:|1
02520|045|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
02520|046|R|  February 17, 2022;60(RR No.2):1-68.|1
02521|001|T|MONOGRAPH TITLE:  Pirfenidone/Moderate CYP1A2 Inhibitors|
02521|002|B||
02521|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02521|004|L|take action as needed.|
02521|005|B||
02521|006|A|MECHANISM OF ACTION:  Pirfenidone is primarily metabolized by CYP1A2 which|
02521|007|A|is responsible for about 50% of its conversion to inactive drug.  CYP2C9,|
02521|008|A|2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone|
02521|009|A|metabolism.(1)|
02521|010|A|   Inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1)|
02521|011|B||
02521|012|E|CLINICAL EFFECTS:  Concurrent pirfenidone use with moderate inhibitors of|
02521|013|E|CYP1A2 may lead to increased systemic concentrations and toxicity from|
02521|014|E|pirfenidone, including serious liver injury.(1)|
02521|015|B||
02521|016|P|PREDISPOSING FACTORS:  A greater risk of adverse events may result from|
02521|017|P|concomitant treatment with strong or moderate inhibitors of one or more|
02521|018|P|other CYP isoenzymes involved in the metabolism of pirfenidone such as|
02521|019|P|CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole,|
02521|020|P|fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine).(1)|
02521|021|P|   The magnitude of this interaction may be reduced in cigarette smokers.|
02521|022|P|Cigarette smoking induces production of CYP1A2 and, in the absence of a|
02521|023|P|CYP1A2 inhibitor, leads to decreased systemic concentrations of|
02521|024|P|pirfenidone.(1)|
02521|025|B||
02521|026|M|PATIENT MANAGEMENT:  The manufacturer of pirfenidone states that for|
02521|027|M|concurrent use with moderate inhibitors of CYP1A2, dose reduction is|
02521|028|M|recommended.  Reduce the dose of pirfenidone to two-267 mg capsules three|
02521|029|M|times a day (total daily dose of 1602 mg/day).(1)|
02521|030|M|   Combinations of strong or moderate CYP1A2 inhibitors with strong or|
02521|031|M|moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should be discontinued|
02521|032|M|prior to and avoided during pirfenidone treatment.(1)|
02521|033|B||
02521|034|D|DISCUSSION:  Pirfenidone is converted to inactive metabolites prior to|
02521|035|D|elimination.  CYP1A2 is responsible for approximately half of this|
02521|036|D|metabolism.  In an interaction study conducted in non-smokers and smokers,|
02521|037|D|coadministration of pirfenidone with fluvoxamine (a strong CYP1A2|
02521|038|D|inhibitor), an agent which inhibits multiple pirfenidone elimination|
02521|039|D|pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and|
02521|040|D|7-fold, respectively, increase in pirfenidone exposure.(1)|
02521|041|D|   In a single-dose study in 27 healthy subjects, coadministration of 801 mg|
02521|042|D|of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed|
02521|043|D|at 750 mg twice daily from Day 2 to Day 7) increased the exposure to|
02521|044|D|pirfenidone by 81%.(1)|
02521|045|D|   Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib,|
02521|046|D|dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen,|
02521|047|D|mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib,|
02521|048|D|troleandomycin, vemurafenib, and viloxazine.(2)|
02521|049|B||
02521|050|R|REFERENCES:|
02521|051|B||
02521|052|R|1.Esbriet (pirfenidone) US prescribing information. InterMune, Inc. October,|1
02521|053|R|  2014.|1
02521|054|R|2.This information is based on an extract from the Certara Drug Interaction|6
02521|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02521|056|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02521|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02521|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02521|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02521|060|R|  11/14/2017.|1
02522|001|T|MONOGRAPH TITLE:  Cobimetinib; Olaparib; Sonidegib/Moderate CYP3A4|
02522|002|T|Inhibitors|
02522|003|B||
02522|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02522|005|L|of severe adverse interaction.|
02522|006|B||
02522|007|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
02522|008|A|metabolism of cobimetinib, olaparib, and sonidegib.(1-4)|
02522|009|B||
02522|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
02522|011|E|systemic exposure and the risk for adverse effects from cobimetinib,|
02522|012|E|olaparib, or sonidegib.(1-4)|
02522|013|B||
02522|014|P|PREDISPOSING FACTORS:  None determined.|
02522|015|B||
02522|016|M|PATIENT MANAGEMENT:  When possible, avoid the use of moderate CYP3A4|
02522|017|M|inhibitors in patients receiving cobimetinib, olaparib, or sonidegib.(1-4)|
02522|018|M|   For patients taking cobimetinib 60 mg daily, if concurrent short term use|
02522|019|M|(14 days or less) of a moderate CYP3A4 inhibitor cannot be avoided, reduce|
02522|020|M|cobimetinib dose to 20 mg daily.  After discontinuation of the moderate|
02522|021|M|CYP3A4 inhibitor resume the previous 60 mg dose.  Patients who are taking|
02522|022|M|cobimetinib 40 mg or 20 mg daily should not receive a moderate or strong|
02522|023|M|CYP3A4 inhibitor.(1)|
02522|024|M|   If concomitant use with olaparib cannot be avoided, reduce the olaparib|
02522|025|M|dose.  Dosage adjustments are specific to the formulation of olaparib.(2,3)|
02522|026|M|Reduce the dosage of the CAPsule formulation to 200 mg (four 50 mg CAPsules)|
02522|027|M|taken twice daily.(2)  Reduce the dosage of the TABlet formulation to 150 mg|
02522|028|M|(one 150 mg TABlet) twice daily).  If the CYP3A4 inhibitor is discontinued,|
02522|029|M|resume the dose of olaparib taken prior to initiation of the CYP3A4|
02522|030|M|inhibitor after 3 to 5 half-lives.(3)|
02522|031|M|   If sonidegib and a moderate CYP3A4 inhibitor must be used, administer the|
02522|032|M|moderate CYP3A4 inhibitor for less than 14 days and monitor closely for|
02522|033|M|adverse effects, particularly musculoskeletal adverse reactions.(4)|
02522|034|B||
02522|035|D|DISCUSSION:  In an interaction study, itraconazole (a strong CYP3A4|
02522|036|D|inhibitor) given 200 mg once daily for 14 days followed by a single dose of|
02522|037|D|cobimetinib 10 mg increased mean cobimetinib AUC 6.7-fold (90% CI 5.6, 8.0).|
02522|038|D|Subsequent simulations showed that predicted steady-state concentrations of|
02522|039|D|cobimetinib at a reduced daily dose of 20 mg given with short term use of a|
02522|040|D|moderate CYP3A4 inhibitor were similar to observed steady-state|
02522|041|D|concentrations at the 60 mg dose without an inhibitor.(1)|
02522|042|D|   In simulations using physiologically-based pharmacokinetic (PBPK) models,|
02522|043|D|concurrent use of fluconazole, a moderate CYP3A4 inhibitor, may increase the|
02522|044|D|area-under-curve (AUC) of olaparib by 2.2-fold.(2,3)|
02522|045|D|   Based upon PBPK simulations, sonidegib mean steady-state AUC would|
02522|046|D|increase 1.8-fold if administered with a moderate CYP3A4 inhibitor for 14|
02522|047|D|days and would further increase to 2.8-fold if the moderate CYP3A4 inhibitor|
02522|048|D|is coadministered with sonidegib for 4 months.(4)|
02522|049|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  aprepitant,|
02522|050|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem,|
02522|051|D|dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine,|
02522|052|D|fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir,|
02522|053|D|letermovir, netupitant, nilotinib, schisandra, rilzabrutinib, stiripentol,|
02522|054|D|tofisopam, treosulfan, and verapamil.(5)|
02522|055|B||
02522|056|R|REFERENCES:|
02522|057|B||
02522|058|R|1.Cotellic (cobimetinib) US prescribing information. Genentech, Inc.|1
02522|059|R|  October, 2022.|1
02522|060|R|2.Lynparza (olaparib) capsules US prescribing information. AstraZenica|1
02522|061|R|  Pharmaceuticals October 23, 2017.|1
02522|062|R|3.Lynparza (olaparib) tablets US prescribing information. AstraZenica|1
02522|063|R|  Pharmaceuticals March, 2021.|1
02522|064|R|4.Odomzo (sonidegib) US prescribing information. Novartis Pharmaceuticals|1
02522|065|R|  May, 2019.|1
02522|066|R|5.This information is based on an extract from the Certara Drug Interaction|6
02522|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02523|001|T|MONOGRAPH TITLE:  Dasabuvir/Strong CYP2C8 Inhibitors|
02523|002|B||
02523|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02523|004|L|is contraindicated and generally should not be dispensed or administered to|
02523|005|L|the same patient.|
02523|006|B||
02523|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2C8 may impair the CYP2C8|
02523|008|A|mediated metabolism of dasabuvir.(1)|
02523|009|B||
02523|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP2C8 may result|
02523|011|E|in elevated levels of and clinical effects of dasabuvir, including the risk|
02523|012|E|for QT prolongation.|
02523|013|B||
02523|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02523|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02523|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02523|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02523|018|P|gender, or advanced age.(2)|
02523|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02523|020|P|higher systemic concentrations of a QT prolonging drug are additional risk|
02523|021|P|factors for torsade de pointes.  Factors which may increase systemic drug|
02523|022|P|concentrations include rapid infusion of an intravenous dose or impaired|
02523|023|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
02523|024|P|which inhibits its metabolism  or elimination, and/or renal/hepatic|
02523|025|P|dysfunction).(2)|
02523|026|B||
02523|027|M|PATIENT MANAGEMENT:  The manufacturer of Viekira Pak (ombitasvir,|
02523|028|M|paritaprevir, ritonavir, dasabuvir sodium) states that concurrent use of|
02523|029|M|strong CYP2C8 inhibitors is contraindicated due to an increased risk for|
02523|030|M|dasabuvir associated QT prolongation.(1)|
02523|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02523|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02523|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02523|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02523|035|B||
02523|036|D|DISCUSSION:  In an interaction study with 11 subjects, gemfibrozil 600 mg|
02523|037|D|twice daily increased the area-under-curve (AUC) and maximum concentration|
02523|038|D|(Cmax) of dasabuvir 11.25-fold and 2.01-fold respectively.(1)|
02523|039|D|   Strong inhibitors of CYP2C8 include gemfibrozil.(3,4)|
02523|040|B||
02523|041|R|REFERENCES:|
02523|042|B||
02523|043|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02523|044|R|  prescribing information. AbbVie Inc. December, 2019.|1
02523|045|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02523|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02523|047|R|  settings: a scientific statement from the American Heart Association and|6
02523|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02523|049|R|  2;55(9):934-47.|6
02523|050|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02523|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02523|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02523|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02523|054|R|  11/14/2017.|1
02523|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
02523|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02524|001|T|MONOGRAPH TITLE:  Slt Hepatitis C Agents/Slt Moderate-Strong CYP3A4 Inducers|
02524|002|B||
02524|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02524|004|L|is contraindicated and generally should not be dispensed or administered to|
02524|005|L|the same patient.|
02524|006|B||
02524|007|A|MECHANISM OF ACTION:  Strong or moderate inducers of CYP3A4 may induce the|
02524|008|A|metabolism of asunaprevir or ombitasvir-paritaprevir-ritonavir treatment for|
02524|009|A|hepatitis C.(1-3)|
02524|010|A|   Asunaprevir is also a substrate for the OATP1B1 transporter. OATP1B1|
02524|011|A|facilitated transport into the liver is thought to be associated with|
02524|012|A|asunaprevir efficacy.  While rifampin a strong CYP3A4 inducer, is also an|
02524|013|A|OATP1B1 inhibitor and so may further decrease asunaprevir efficacy by|
02524|014|A|inhibiting its transport into the liver.|
02524|015|B||
02524|016|E|CLINICAL EFFECTS:  The combination of asunaprevir or|
02524|017|E|ombitasvir-paritaprevir-ritonavir, with or without dasabuvir, may not be|
02524|018|E|effective for the treatment of hepatitis C.(1-3)|
02524|019|B||
02524|020|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02524|021|P|of the inducer for longer than 1-2 weeks.|
02524|022|B||
02524|023|M|PATIENT MANAGEMENT:  Because of the risk for treatment failure, the|
02524|024|M|manufacturers of asunaprevir, and ombitasvir-paritaprevir-ritonavir state|
02524|025|M|that concomitant use with strong or moderate CYP3A4 inducers is|
02524|026|M|contraindicated.(1-3)|
02524|027|B||
02524|028|D|DISCUSSION:  In an interaction study with 12 subjects, carbamazepine 200 mg|
02524|029|D|once daily followed by 200 mg twice daily decreased antiviral exposure|
02524|030|D|(area-under-curve or AUC) of ombitasvir by 31%, paritaprevir by 70%,|
02524|031|D|ritonavir by 87%, and dasabuvir by 55%.(1)|
02524|032|D|   Strong and moderate CYP3A4 inducers linked to this monograph are:|
02524|033|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
02524|034|D|dabrafenib, encorafenib, enzalutamide, etravirine, fosphenytoin, ivosidenib,|
02524|035|D|lesinurad, lorlatinib, lumacaftor, mitapivat, mitotane, modafinil,|
02524|036|D|nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone,|
02524|037|D|repotrectinib, rifabutin, rifapentine, sotorasib, telotristat, and|
02524|038|D|tovorafenib.|
02524|039|B||
02524|040|R|REFERENCES:|
02524|041|B||
02524|042|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02524|043|R|  prescribing information. AbbVie Inc. December, 2019.|1
02524|044|R|2.Viekirax (ombitasvir, paritaprevir, ritonavir) UK summary of product|1
02524|045|R|  characteristics. AbbVie Limited January 16, 2019.|1
02524|046|R|3.Sunvepra (asunaprevir) Australia Prescribing Information. Bristol-Myers|1
02524|047|R|  Squibb Australia Pty Ltd April 5, 2019.|1
02524|048|R|4.This information is based on an extract from the Certara Drug Interaction|6
02524|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02525|001|T|MONOGRAPH TITLE:  Ombitasvir-paritaprevir-ritonavir-dasabuvir/Rifampin|
02525|002|B||
02525|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02525|004|L|is contraindicated and generally should not be dispensed or administered to|
02525|005|L|the same patient.|
02525|006|B||
02525|007|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of each of the|
02525|008|A|agents in this combination treatment for hepatitis C.(1)|
02525|009|B||
02525|010|E|CLINICAL EFFECTS:  The combination of|
02525|011|E|ombitasvir-paritaprevir-ritonavir-dasabuvir may not be effective for the|
02525|012|E|treatment of hepatitis C.(1)|
02525|013|B||
02525|014|P|PREDISPOSING FACTORS:  None determined.|
02525|015|B||
02525|016|M|PATIENT MANAGEMENT:  Because of the risk for treatment failure, the|
02525|017|M|manufacturer of ombitasvir-paritaprevir-ritonavir-dasabuvir states that|
02525|018|M|concomitant use with rifampin is contraindicated.(1)|
02525|019|B||
02525|020|D|DISCUSSION:  In an interaction study with 12 subjects carbamazepine, another|
02525|021|D|multi-enzyme inducer, at a dose of 200 mg once daily followed by 200 mg|
02525|022|D|twice daily decreased antiviral exposure (area-under-curve or AUC) of|
02525|023|D|ombitasvir by 31%, of paritaprevir by 70%, ritonavir by 87%, and dasabuvir|
02525|024|D|by 70%.(1)|
02525|025|B||
02525|026|R|REFERENCE:|
02525|027|B||
02525|028|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02525|029|R|  prescribing information. AbbVie Inc. December, 2019.|1
02526|001|T|MONOGRAPH TITLE:  Paritaprevir-ritonavir/Efavirenz|
02526|002|B||
02526|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02526|004|L|is contraindicated and generally should not be dispensed or administered to|
02526|005|L|the same patient.|
02526|006|B||
02526|007|A|MECHANISM OF ACTION:  The mechanism of this interaction has not been|
02526|008|A|described.|
02526|009|B||
02526|010|E|CLINICAL EFFECTS:  Co-administration of efavirenz based regimens with|
02526|011|E|paritaprevir-ritonavir was poorly tolerated and resulted in elevations of|
02526|012|E|liver enzymes.(1)|
02526|013|B||
02526|014|P|PREDISPOSING FACTORS:  None determined.|
02526|015|B||
02526|016|M|PATIENT MANAGEMENT:  The manufacturer of Viekira|
02526|017|M|(ombitasvir-paritaprevir-ritonavir-dasabuvir) states that co-administration|
02526|018|M|with efavirenz is contraindicated.(1)|
02526|019|B||
02526|020|D|DISCUSSION:  Co-administration of efavirenz based regimens with|
02526|021|D|dasabuvir-paritaprevir-ritonavir was poorly tolerated and resulted in|
02526|022|D|elevations of liver enzymes.(1)|
02526|023|D|   In efavirenz HIV trials, 20% of hepatitis B or C coinfected patients who|
02526|024|D|received efavirenz had ALT elevations > 5 times the upper limit of normal|
02526|025|D|versus 7% of patients in the control arm.(2)|
02526|026|B||
02526|027|R|REFERENCES:|
02526|028|B||
02526|029|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02526|030|R|  prescribing information. AbbVie Inc. December, 2019.|1
02526|031|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
02526|032|R|  Company November, 2023.|1
02527|001|T|MONOGRAPH TITLE:  Ethinyl|
02527|002|T|Estradiol;Estetrol/Ombitasvir-paritaprevir-ritonavir|
02527|003|B||
02527|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02527|005|L|is contraindicated and generally should not be dispensed or administered to|
02527|006|L|the same patient.|
02527|007|B||
02527|008|A|MECHANISM OF ACTION:  The mechanism of action has not been described.|
02527|009|B||
02527|010|E|CLINICAL EFFECTS:  In clinical trials, subjects receiving concomitant|
02527|011|E|ethinyl estradiol-containing combinations had a significantly higher risk|
02527|012|E|for ALT elevations > 5 times the upper limit of normal (ULN) than subjects|
02527|013|E|receiving ombitasvir-paritaprevir-ritonavir with or without dasabuvir.(1,2)|
02527|014|B||
02527|015|P|PREDISPOSING FACTORS:  None determined.|
02527|016|B||
02527|017|M|PATIENT MANAGEMENT:  Due to the added risk for ALT elevations, the|
02527|018|M|manufacturer of ombitasvir-paritaprevir-ritonavir states that medications|
02527|019|M|which contain ethinyl estradiol such as oral contraceptives, contraceptive|
02527|020|M|patches, or contraceptive vaginal rings must be discontinued prior to|
02527|021|M|starting therapy with ombitasvir-paritaprevir-ritonavir.  In clinical|
02527|022|M|trials, 25% (4/16) women taking ethinyl estradiol containing medications had|
02527|023|M|ALT elevations > 5 times the upper limit of normal (ULN).(1,2)|
02527|024|M|   Alternative methods of contraception, such as progestin only or|
02527|025|M|non-hormonal methods are recommended during|
02527|026|M|ombitasvir-paritaprevir-ritonavir therapy.  Ethinyl estradiol and estetrol|
02527|027|M|containing medications may be restarted 2 weeks after completion of|
02527|028|M|ombitasvir-paritaprevir-ritonavir treatment.(1,2)|
02527|029|M|   Women taking estrogens other than ethinyl estradiol (e.g. estradiol or|
02527|030|M|conjugated estrogens) had a 3% rate of ALT levels > 5 times ULN (2/59|
02527|031|M|subjects).  The risk for similar ALT elevations in subjects not receiving|
02527|032|M|estrogens was 1%.  The manufacturer of ombitasvir-paritaprevir-ritonavir|
02527|033|M|describes these rates as similar.(1,2)|
02527|034|B||
02527|035|D|DISCUSSION:  During clinical trials, approximately 1% of subjects taking|
02527|036|D|ombitasvir-paritaprevir-ritonavir had ALT elevations > 5 times the upper|
02527|037|D|limit of normal.  Women taking estrogens other than ethinyl estradiol (e.g.|
02527|038|D|estradiol or conjugated estrogens) had a 3% rate of ALT levels > 5 times ULN|
02527|039|D|(2/59 subjects).  The manufacturer of ombitasvir-paritaprevir-ritonavir|
02527|040|D|describes these rates as similar.(1,2)|
02527|041|D|   Although the number of exposed subjects was small, 4 of 16 women (25%)|
02527|042|D|receiving ethinyl estradiol containing medications had ALT levels > 5 times|
02527|043|D|ULN.(1,2)|
02527|044|B||
02527|045|R|REFERENCES:|
02527|046|B||
02527|047|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02527|048|R|  prescribing information. AbbVie Inc. December, 2019.|1
02527|049|R|2.Technivie (ombitasvir-paritaprevir-ritonavir) US prescribing information.|1
02527|050|R|  Abbvie Inc. December, 2019.|1
02528|001|T|MONOGRAPH TITLE:  Pravastatin (Greater Than 40 mg); Rosuvastatin (Greater|
02528|002|T|Than 5 mg)/Dasabuvir-Paritaprevir-Ritonavir|
02528|003|B||
02528|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02528|005|L|is contraindicated and generally should not be dispensed or administered to|
02528|006|L|the same patient.|
02528|007|B||
02528|008|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate for a number of|
02528|009|A|transporters including breast cancer resistance protein (BCRP), OATP1B1, and|
02528|010|A|OATP1B3.(1,2)  Pravastatin is a substrate for OATP1B1 transport.|
02528|011|A|   Paritaprevir is an inhibitor of OATP1B1 and OATP1B3, while dasabuvir,|
02528|012|A|paritaprevir, and ritonavir are inhibitors of BCRP.(1)|
02528|013|A|   Depending upon the specific transporter and site of activity, transport|
02528|014|A|inhibition may lead to increased systemic absorption, decreased hepatic|
02528|015|A|concentrations, or decreased hepatic elimination.|
02528|016|B||
02528|017|E|CLINICAL EFFECTS:  Transport inhibition may lead to higher systemic|
02528|018|E|concentrations of pravastatin or rosuvastatin, increasing the risk for|
02528|019|E|statin-induced myopathy or rhabdomyolysis.|
02528|020|B||
02528|021|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02528|022|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02528|023|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02528|024|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02528|025|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02528|026|P|transporter OATP1B1 may have increased statin concentrations and be|
02528|027|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02528|028|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02528|029|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02528|030|B||
02528|031|M|PATIENT MANAGEMENT:  Recommendations for the dosing of pravastatin and|
02528|032|M|rosuvastatin when used concomitantly with|
02528|033|M|ombitasvir/paritaprevir/ritonavir/dasabuvir differ in different regions.|
02528|034|M|   The UK manufacturer of ombitasvir-paritaprevir-ritonavir (Viekirax)|
02528|035|M|states that rosuvastatin doses should not exceed 5 mg per day in patients|
02528|036|M|receiving concurrent Viekirax with dasabuvir.  The dose of pravastatin|
02528|037|M|should be reduced by 50 % in patients receiving concurrent Viekirax with or|
02528|038|M|without dasabuvir.(2)|
02528|039|M|   The US manufacturer of dasabuvir-paritaprevir-ritonavir-ombitasvir|
02528|040|M|(Viekira Pak) states that rosuvastatin doses should not exceed 10 mg per day|
02528|041|M|and pravastatin doses should not exceed 40 mg per day in patients receiving|
02528|042|M|concurrent therapy.(1)|
02528|043|B||
02528|044|D|DISCUSSION:  In a drug interaction study with 11 subjects,|
02528|045|D|dasabuvir-paritaprevir-ritonavir-ombitasvir co-administered with|
02528|046|D|rosuvastatin 5 mg daily (duration not described) increased the maximum|
02528|047|D|concentration (Cmax) and area-under-curve (AUC) of rosuvastatin by 7.13-fold|
02528|048|D|and 2.59-fold respectively.(1)|
02528|049|D|   In a drug interaction study with 12 subjects,|
02528|050|D|dasabuvir-paritaprevir-ritonavir-ombitasvir co-administered with pravastatin|
02528|051|D|10 mg daily (duration not described) increased the Cmax and AUC of|
02528|052|D|pravastatin by 1.37-fold and 1.82-fold respectively.(1)|
02528|053|D|   In interaction trials, dasabuvir-paritaprevir-ritonavir-ombitasvir|
02528|054|D|increased rosuvastatin or pravastatin exposure by 2.59-fold or 1.82-fold|
02528|055|D|respectively.(1)|
02528|056|B||
02528|057|R|REFERENCES:|
02528|058|B||
02528|059|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02528|060|R|  prescribing information. AbbVie Inc. December, 2019.|1
02528|061|R|2.Viekirax (ombitasvir, paritaprevir, ritonavir) EMA summary of product|1
02528|062|R|  characteristics. AbbVie Deutschland GmbH & Co. KG November 14, 2019.|1
02529|001|T|MONOGRAPH TITLE:  Pravastatin (Less Than or Equal To 40 mg); Rosuvastatin|
02529|002|T|(Less Than or Equal To 5 mg)/Dasabuvir-paritaprevir-ritonavir|
02529|003|B||
02529|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02529|005|L|take action as needed.|
02529|006|B||
02529|007|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate for a number of|
02529|008|A|transporters including breast cancer resistance protein (BCRP), OATP1B1, and|
02529|009|A|OATP1B3.(1,2)  Pravastatin is a substrate for OATP1B1 transport.|
02529|010|A|   Paritaprevir is an inhibitor of OATP1B1 and OATP1B3, while dasabuvir,|
02529|011|A|paritaprevir, and ritonavir are inhibitors of BCRP.(1)|
02529|012|A|   Depending upon the specific transporter and site of activity, transport|
02529|013|A|inhibition may lead to increased systemic absorption, decreased hepatic|
02529|014|A|concentrations, or decreased hepatic elimination.|
02529|015|B||
02529|016|E|CLINICAL EFFECTS:  Transport inhibition may lead to higher systemic|
02529|017|E|concentrations of pravastatin or rosuvastatin, increasing the risk for|
02529|018|E|statin-induced myopathy or rhabdomyolysis.|
02529|019|B||
02529|020|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02529|021|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02529|022|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02529|023|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02529|024|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02529|025|P|transporter OATP1B1 may have increased statin concentrations and be|
02529|026|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02529|027|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02529|028|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02529|029|B||
02529|030|M|PATIENT MANAGEMENT:  Recommendations for the dosing of pravastatin and|
02529|031|M|rosuvastatin when used concomitantly with|
02529|032|M|ombitasvir/paritaprevir/ritonavir/dasabuvir differ in different regions.|
02529|033|M|   The UK manufacturer of ombitasvir-paritaprevir-ritonavir (Viekirax)|
02529|034|M|states that rosuvastatin doses should not exceed 5 mg per day in patients|
02529|035|M|receiving concurrent Viekirax with dasabuvir.  The dose of pravastatin|
02529|036|M|should be reduced by 50 % in patients receiving concurrent Viekirax with or|
02529|037|M|without dasabuvir.(2)|
02529|038|M|   The US manufacturer of dasabuvir-paritaprevir-ritonavir-ombitasvir|
02529|039|M|(Viekira Pak) states that rosuvastatin doses should not exceed 10 mg per day|
02529|040|M|and pravastatin doses should not exceed 40 mg per day in patients receiving|
02529|041|M|concurrent therapy.(1)|
02529|042|B||
02529|043|D|DISCUSSION:  In a drug interaction study with 11 subjects,|
02529|044|D|dasabuvir-paritaprevir-ritonavir-ombitasvir co-administered with|
02529|045|D|rosuvastatin 5 mg daily (duration not described) increased the maximum|
02529|046|D|concentration (Cmax) and area-under-curve (AUC) of rosuvastatin by 7.13-fold|
02529|047|D|and 2.59-fold respectively.(1)|
02529|048|D|   In a drug interaction study with 12 subjects,|
02529|049|D|dasabuvir-paritaprevir-ritonavir-ombitasvir co-administered with pravastatin|
02529|050|D|10 mg daily (duration not described) increased the Cmax and AUC of|
02529|051|D|pravastatin by 1.37-fold and 1.82-fold respectively.(1)|
02529|052|D|   In interaction trials, dasabuvir-paritaprevir-ritonavir-ombitasvir|
02529|053|D|increased rosuvastatin or pravastatin exposure by 2.59-fold or 1.82-fold|
02529|054|D|respectively.(1)|
02529|055|B||
02529|056|R|REFERENCES:|
02529|057|B||
02529|058|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02529|059|R|  prescribing information. AbbVie Inc. December, 2019.|1
02529|060|R|2.Viekirax (ombitasvir, paritaprevir, ritonavir) EMA summary of product|1
02529|061|R|  characteristics. AbbVie Deutschland GmbH & Co. KG November 14, 2019.|1
02530|001|T|MONOGRAPH TITLE:  Delamanid/Strong CYP3A4 Inducers|
02530|002|B||
02530|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02530|004|L|is contraindicated and generally should not be dispensed or administered to|
02530|005|L|the same patient.|
02530|006|B||
02530|007|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
02530|008|A|delamanid.(1)|
02530|009|B||
02530|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02530|011|E|in decreased levels and effectiveness of delamanid.(1)|
02530|012|B||
02530|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02530|014|P|of the inducer for longer than 1-2 weeks.|
02530|015|B||
02530|016|M|PATIENT MANAGEMENT:  Concurrent use of delamanid and strong CYP3A4 inducers|
02530|017|M|is contraindicated.(1)|
02530|018|M|   If concurrent use is warranted, monitor the patient for potential|
02530|019|M|treatment failure and decreased delamanid levels.|
02530|020|B||
02530|021|D|DISCUSSION:  In a study in healthy subjects, administration of rifampin (300|
02530|022|D|mg daily) with delamanid (200 mg daily) for 15 days decreased the the|
02530|023|D|exposure to delamanid by 45%.  There was no significant effect on rifampin|
02530|024|D|levels.(1)|
02530|025|D|   In a study in healthy subjects, there were no clinically significant|
02530|026|D|effects on delamanid levels during concurrent use of efavirenz (600 mg|
02530|027|D|daily), a weak CYP3A4 inducer, with delamanid (100 mg twice daily) for 10|
02530|028|D|days.(1)|
02530|029|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02530|030|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02530|031|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02530|032|D|rifapentine and St. John's wort.(2,3)|
02530|033|B||
02530|034|R|REFERENCES:|
02530|035|B||
02530|036|R|1.Deltyba (delamanid) EMA summary of products characteristics. Otsuka Novel|1
02530|037|R|  Products GmbH March, 2023.|1
02530|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02530|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02530|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02530|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02530|042|R|  11/14/2017.|1
02530|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
02530|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02531|001|T|MONOGRAPH TITLE:  Delamanid/Strong CYP3A4 Inhibitors (mono deleted|
02531|002|T|07/09/2015)|
02531|003|B||
02531|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02531|005|L|of severe adverse interaction.|
02531|006|B||
02531|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
02531|008|A|delamanid.(1)|
02531|009|B||
02531|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02531|011|E|in increased levels of and toxicity from delamanid, including QT|
02531|012|E|prolongation.  QT prolongation may result in potentially life-threatening|
02531|013|E|cardiac arrhythmias, including torsades de pointes.(1)|
02531|014|B||
02531|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02531|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02531|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02531|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
02531|019|P|hypoalbuminemia, bradycardia, female gender, or advanced age.(1,2)|
02531|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02531|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02531|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02531|023|P|drug concentrations include rapid infusion or an intravenous dose or|
02531|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02531|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02531|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02531|027|B||
02531|028|M|PATIENT MANAGEMENT:  If possible, avoid concurrent use of delamanid and|
02531|029|M|strong CYP3A4 inhibitors.  If concurrent use is necessary, frequently|
02531|030|M|monitor ECGs (more frequently than the standard recommended monthly ECG|
02531|031|M|during delamanid therapy).  Discontinue delamanid if a QTcF greater than 500|
02531|032|M|msec is observed.(1)  Serum albumin, calcium, magnesium, and potassium|
02531|033|M|levels should be obtained at baseline and at regular intervals.  Correct any|
02531|034|M|electrolyte abnormalities.  Discontinue delamanid if albumin falls below 2.8|
02531|035|M|g/DL.  Instruct patients to report any irregular heartbeat, dizziness, or|
02531|036|M|fainting.|
02531|037|B||
02531|038|D|DISCUSSION:  In a study in healthy subjects, lopinavir/ritonavir (400/100 mg|
02531|039|D|daily) administered with delamanid (100 mg twice daily) increased exposure|
02531|040|D|to delamanid exposed by 30%.  There was no effect on delamanid levels.(1)|
02531|041|D|   QT prolongation has been observed with delamanid and increases over the|
02531|042|D|first 6-10 weeks of therapy.  In a placebo controlled study in healthy|
02531|043|D|subjects, the mean increase in QTcF from baseline during delamanid therapy|
02531|044|D|was 7/6 msec at 1 month and 12.1 msec at 2 months.  Three percent of|
02531|045|D|patients experienced an increase of 60 msec or greater at some point during|
02531|046|D|therapy.  One patient had a QTcF greater than 500 msec.  All patients with a|
02531|047|D|QTcF greater than 60 msec were also taking a fluoroquinolone.(1)|
02531|048|D|   Strong inhibitors of CYP3A4 include: boceprevir, clarithromycin,|
02531|049|D|cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole,|
02531|050|D|lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole,|
02531|051|D|ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, and|
02531|052|D|voriconazole.(1,4,5)|
02531|053|B||
02531|054|R|REFERENCES:|
02531|055|B||
02531|056|R|1.Deltyba (delamanid) EMA summary of products characteristics. Otsuka Novel|1
02531|057|R|  Products GmbH March, 2023.|1
02531|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02531|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02531|060|R|  settings: a scientific statement from the American Heart Association and|6
02531|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02531|062|R|  2;55(9):934-47.|6
02531|063|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02531|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02531|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02531|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02531|067|R|  11/14/2017.|1
02531|068|R|4.This information is based on an extract from the Certara Drug Interaction|6
02531|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02532|001|T|MONOGRAPH TITLE:  Delamanid/QT Prolonging Agents|
02532|002|B||
02532|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02532|004|L|of severe adverse interaction.|
02532|005|B||
02532|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02532|007|A|interval may result in additive effects on the QTc interval.(1)|
02532|008|B||
02532|009|E|CLINICAL EFFECTS:  Concurrent use of delamanid in patients taking other|
02532|010|E|medications that prolong the QT interval may result in additive QT|
02532|011|E|prolongation.  QT prolongation may result in potentially life-threatening|
02532|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02532|013|B||
02532|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02532|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02532|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02532|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
02532|018|P|hypoalbuminemia, bradycardia, female gender, or advanced age.(1,2)|
02532|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02532|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02532|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02532|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02532|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02532|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02532|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02532|026|B||
02532|027|M|PATIENT MANAGEMENT:  If possible, avoid concurrent use of delamanid and|
02532|028|M|other agents that prolong the QT interval.  If concurrent use is necessary,|
02532|029|M|frequently monitor ECGs (more frequently than the standard recommended|
02532|030|M|monthly ECG during delamanid therapy).  Discontinue delamanid if a QTcF|
02532|031|M|greater than 500 msec is observed.(1)  Serum albumin, calcium, magnesium,|
02532|032|M|and potassium levels should be obtained at baseline and at regular|
02532|033|M|intervals.  Correct any electrolyte abnormalities.  Discontinue delamanid if|
02532|034|M|albumin falls below 2.8 g/DL.  Instruct patients to report any irregular|
02532|035|M|heartbeat, dizziness, or fainting.|
02532|036|B||
02532|037|D|DISCUSSION:  QT prolongation has been observed with delamanid and increases|
02532|038|D|over the first 6-10 weeks of therapy.  In a placebo controlled study in|
02532|039|D|healthy subjects, the mean increase in QTcF from baseline during delamanid|
02532|040|D|therapy was 7/6 msec at 1 month and 12.1 msec at 2 months.  Three percent of|
02532|041|D|patients experienced an increase of 60 msec or greater at some point during|
02532|042|D|therapy.  One patient had a QTcF greater than 500 msec.  All patients with a|
02532|043|D|QTcF greater than 60 msec were also taking a fluoroquinolone.(1)|
02532|044|B||
02532|045|R|REFERENCES:|
02532|046|B||
02532|047|R|1.Deltyba (delamanid) EMA summary of products characteristics. Otsuka Novel|1
02532|048|R|  Products GmbH March, 2023.|1
02532|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02532|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02532|051|R|  settings: a scientific statement from the American Heart Association and|6
02532|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02532|053|R|  2;55(9):934-47.|6
02533|001|T|MONOGRAPH TITLE:  Delamanid/Possible QT Prolonging Agents|
02533|002|B||
02533|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02533|004|L|take action as needed.|
02533|005|B||
02533|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02533|007|A|interval may result in additive effects on the QTc interval.(1)|
02533|008|B||
02533|009|E|CLINICAL EFFECTS:  Concurrent use of delamanid in patients taking other|
02533|010|E|medications that prolong the QT interval may result in additive QT|
02533|011|E|prolongation.  QT prolongation may result in potentially life-threatening|
02533|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02533|013|B||
02533|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02533|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02533|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02533|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
02533|018|P|hypoalbuminemia, bradycardia, female gender, or advanced age.(1,2)|
02533|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02533|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02533|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02533|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02533|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02533|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02533|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02533|026|B||
02533|027|M|PATIENT MANAGEMENT:  If possible, avoid concurrent use of delamanid and|
02533|028|M|other agents that prolong the QT interval.  If concurrent use is necessary,|
02533|029|M|frequently monitor ECGs (more frequently than the standard recommended|
02533|030|M|monthly ECG during delamanid therapy).  Discontinue delamanid if a QTcF|
02533|031|M|greater than 500 msec is observed.(1)  Serum albumin, calcium, magnesium,|
02533|032|M|and potassium levels should be obtained at baseline and at regular|
02533|033|M|intervals.  Correct any electrolyte abnormalities.  Discontinue delamanid if|
02533|034|M|albumin falls below 2.8 g/DL.  Instruct patients to report any irregular|
02533|035|M|heartbeat, dizziness, or fainting.|
02533|036|B||
02533|037|D|DISCUSSION:  QT prolongation has been observed with delamanid and increases|
02533|038|D|over the first 6-10 weeks of therapy.  In a placebo controlled study in|
02533|039|D|healthy subjects, the mean increase in QTcF from baseline during delamanid|
02533|040|D|therapy was 7/6 msec at 1 month and 12.1 msec at 2 months.  Three percent of|
02533|041|D|patients experienced an increase of 60 msec or greater at some point during|
02533|042|D|therapy.  One patient had a QTcF greater than 500 msec.  All patients with a|
02533|043|D|QTcF greater than 60 msec were also taking a fluoroquinolone.(1)|
02533|044|B||
02533|045|R|REFERENCES:|
02533|046|B||
02533|047|R|1.Deltyba (delamanid) EMA summary of products characteristics. Otsuka Novel|1
02533|048|R|  Products GmbH March, 2023.|1
02533|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02533|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02533|051|R|  settings: a scientific statement from the American Heart Association and|6
02533|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02533|053|R|  2;55(9):934-47.|6
02534|001|T|MONOGRAPH TITLE:  Naloxegol/Strong CYP3A4 Inhibitors|
02534|002|B||
02534|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02534|004|L|is contraindicated and generally should not be dispensed or administered to|
02534|005|L|the same patient.|
02534|006|B||
02534|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
02534|008|A|naloxegol.(1)|
02534|009|B||
02534|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02534|011|E|in increased levels of naloxegol, which may precipitate opioid withdrawal|
02534|012|E|symptoms.(1)|
02534|013|B||
02534|014|P|PREDISPOSING FACTORS:  Patients taking methadone may be more likely to|
02534|015|P|experience gastrointestinal side effects such as abdominal pain and diarrhea|
02534|016|P|as a result of opioid withdrawal.(1)|
02534|017|B||
02534|018|M|PATIENT MANAGEMENT:  The concurrent use of naloxegol and strong CYP3A4|
02534|019|M|inhibitors is contraindicated.(1)|
02534|020|M|   The US manufacturer of itraconazole states that concurrent administration|
02534|021|M|with naloxegol is contraindicated during and two weeks after itraconazole|
02534|022|M|treatment.(5)|
02534|023|M|   If concurrent use is deemed medically necessary, monitor patients for|
02534|024|M|signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain,|
02534|025|M|anxiety, irritability, yawning, restlessness, muscle/joint aches, increased|
02534|026|M|lacrimation, running nose, and piloerection.  Monitor patients taking|
02534|027|M|methadone for abdominal pain and diarrhea as well.(1)|
02534|028|B||
02534|029|D|DISCUSSION:  Ketoconazole (400 mg daily for 5 days), a strong inhibitor of|
02534|030|D|CYP3A4, increased the maximum concentration (Cmax) and area-under-curve|
02534|031|D|(AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold,|
02534|032|D|respectively.(2)|
02534|033|D|   Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased|
02534|034|D|the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41,|
02534|035|D|respectively.(2)|
02534|036|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02534|037|D|clarithromycin, cobicistat, indinavir, itraconazole, josamycin,|
02534|038|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
02534|039|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
02534|040|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib,|
02534|041|D|and voriconazole.(1,3,4)|
02534|042|B||
02534|043|R|REFERENCES:|
02534|044|B||
02534|045|R|1.Movantik (naloxegol) US prescribing information. AstraZeneca|1
02534|046|R|  Pharmaceuticals LP April, 2020.|1
02534|047|R|2.US FDA Center for Drug Evaluation and Research. Naloxegol Clinical|1
02534|048|R|  Pharmacology and Biopharmaceutics Review.  Application number|1
02534|049|R|  204760Orig1s000. available at:|1
02534|050|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204760Orig1s000Clin|1
02534|051|R|  Pharm.pdf July 25, 2014.|1
02534|052|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02534|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02534|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02534|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02534|056|R|  11/14/2017.|1
02534|057|R|4.This information is based on an extract from the Certara Drug Interaction|6
02534|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02534|059|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02534|060|R|  Products, L.P. February, 2024.|1
02535|001|T|MONOGRAPH TITLE:  Naloxegol (Greater Than 12.5 mg)/Moderate CYP3A4|
02535|002|T|Inhibitors|
02535|003|B||
02535|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02535|005|L|is contraindicated and generally should not be dispensed or administered to|
02535|006|L|the same patient.|
02535|007|B||
02535|008|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
02535|009|A|naloxegol.(1)|
02535|010|B||
02535|011|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 without|
02535|012|E|a dosage adjustment of naloxegol may result in increased levels of|
02535|013|E|naloxegol, which may precipitate opioid withdrawal symptoms.(1)|
02535|014|B||
02535|015|P|PREDISPOSING FACTORS:  Patients taking methadone may be more likely to|
02535|016|P|experience gastrointestinal side effects such as abdominal pain and diarrhea|
02535|017|P|as a result of opioid withdrawal.(1)|
02535|018|B||
02535|019|M|PATIENT MANAGEMENT:  The daily dose of naloxegol should be limited to 12.5|
02535|020|M|mg daily in patients taking moderate inhibitors of CYP3A4.(1)|
02535|021|M|   If concurrent use is deemed medically necessary, monitor patients for|
02535|022|M|signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain,|
02535|023|M|anxiety, irritability, yawning, restlessness, muscle/joint aches, increased|
02535|024|M|lacrimation, running nose, and piloerection.  Monitor patients taking|
02535|025|M|methadone for abdominal pain and diarrhea as well.(1)|
02535|026|B||
02535|027|D|DISCUSSION:  Ketoconazole (400 mg daily for 5 days), a strong inhibitor of|
02535|028|D|CYP3A4, increased the maximum concentration (Cmax) and area-under-curve|
02535|029|D|(AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold,|
02535|030|D|respectively.(2)|
02535|031|D|   Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased|
02535|032|D|the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41,|
02535|033|D|respectively.(2)|
02535|034|D|   According to Physiologically-based-Pharmacokinetic (PBPK) models,|
02535|035|D|erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is|
02535|036|D|expected to increase the Cmax and AUC of naloxegol by 2.77-fold and|
02535|037|D|3.47-fold, respectively.(2)|
02535|038|D|   According to PBPK models, erythromycin at a dose of 400 mg QID is|
02535|039|D|expected to increase the Cmax and AUC of naloxegol by 3.42-fold and|
02535|040|D|4.63-fold, respectively.(2)|
02535|041|D|   According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at|
02535|042|D|a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol|
02535|043|D|by 2.4-fold and 2.81-fold, respectively.(2)|
02535|044|D|   According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a|
02535|045|D|dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol|
02535|046|D|by 1.97-fold and 2.21-fold, respectively.(2)|
02535|047|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
02535|048|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
02535|049|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
02535|050|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
02535|051|D|isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib,|
02535|052|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan|
02535|053|D|and verapamil.(1,3,4)|
02535|054|B||
02535|055|R|REFERENCES:|
02535|056|B||
02535|057|R|1.Movantik (naloxegol) US prescribing information. AstraZeneca|1
02535|058|R|  Pharmaceuticals LP April, 2020.|1
02535|059|R|2.US FDA Center for Drug Evaluation and Research. Naloxegol Clinical|1
02535|060|R|  Pharmacology and Biopharmaceutics Review.  Application number|1
02535|061|R|  204760Orig1s000. available at:|1
02535|062|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204760Orig1s000Clin|1
02535|063|R|  Pharm.pdf July 25, 2014.|1
02535|064|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02535|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02535|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02535|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02535|068|R|  11/14/2017.|1
02535|069|R|4.This information is based on an extract from the Certara Drug Interaction|6
02535|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02536|001|T|MONOGRAPH TITLE:  Naloxegol (Less Than or Equal To 12.5 mg)/Moderate CYP3A4|
02536|002|T|Inhibitors|
02536|003|B||
02536|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02536|005|L|of severe adverse interaction.|
02536|006|B||
02536|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
02536|008|A|naloxegol.(1)|
02536|009|B||
02536|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 without|
02536|011|E|a dosage adjustment of naloxegol may result in increased levels of|
02536|012|E|naloxegol, which may precipitate opioid withdrawal symptoms.(1)|
02536|013|B||
02536|014|P|PREDISPOSING FACTORS:  Patients taking methadone may be more likely to|
02536|015|P|experience gastrointestinal side effects such as abdominal pain and diarrhea|
02536|016|P|as a result of opioid withdrawal.(1)|
02536|017|B||
02536|018|M|PATIENT MANAGEMENT:  Avoid the use of moderate inhibitors of CYP3A4 in|
02536|019|M|patients who require therapy with naloxegol.  If concurrent use cannot be|
02536|020|M|avoided, the daily dose of naloxegol should be limited to 12.5 mg daily in|
02536|021|M|patients taking moderate inhibitors of CYP3A4.(1)|
02536|022|M|   Monitor patients for signs of opioid withdrawal such as sweating, chills,|
02536|023|M|diarrhea, stomach pain, anxiety, irritability, yawning, restlessness,|
02536|024|M|muscle/joint aches, increased lacrimation, running nose, and piloerection.|
02536|025|M|Monitor patients taking methadone for abdominal pain and diarrhea as|
02536|026|M|well.(1)|
02536|027|B||
02536|028|D|DISCUSSION:  Ketoconazole (400 mg daily for 5 days), a strong inhibitor of|
02536|029|D|CYP3A4, increased the maximum concentration (Cmax) and area-under-curve|
02536|030|D|(AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold,|
02536|031|D|respectively.(2)|
02536|032|D|   Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased|
02536|033|D|the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41,|
02536|034|D|respectively.(2)|
02536|035|D|   According to Physiologically-based-Pharmacokinetic (PBPK) models,|
02536|036|D|erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is|
02536|037|D|expected to increase the Cmax and AUC of naloxegol by 2.77-fold and|
02536|038|D|3.47-fold, respectively.(2)|
02536|039|D|   According to PBPK models, erythromycin at a dose of 400 mg QID is|
02536|040|D|expected to increase the Cmax and AUC of naloxegol by 3.42-fold and|
02536|041|D|4.63-fold, respectively.(2)|
02536|042|D|   According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at|
02536|043|D|a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol|
02536|044|D|by 2.4-fold and 2.81-fold, respectively.(2)|
02536|045|D|   According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a|
02536|046|D|dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol|
02536|047|D|by 1.97-fold and 2.21-fold, respectively.(2)|
02536|048|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
02536|049|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
02536|050|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
02536|051|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
02536|052|D|isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib,|
02536|053|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan|
02536|054|D|and verapamil.(1,3,4)|
02536|055|B||
02536|056|R|REFERENCES:|
02536|057|B||
02536|058|R|1.Movantik (naloxegol) US prescribing information. AstraZeneca|1
02536|059|R|  Pharmaceuticals LP April, 2020.|1
02536|060|R|2.US FDA Center for Drug Evaluation and Research. Naloxegol Clinical|1
02536|061|R|  Pharmacology and Biopharmaceutics Review.  Application number|1
02536|062|R|  204760Orig1s000. available at:|1
02536|063|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204760Orig1s000Clin|1
02536|064|R|  Pharm.pdf July 25, 2014.|1
02536|065|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02536|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02536|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02536|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02536|069|R|  11/14/2017.|1
02536|070|R|4.This information is based on an extract from the Certara Drug Interaction|6
02536|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02537|001|T|MONOGRAPH TITLE:  Naloxegol/Strong CYP3A4 Inducers|
02537|002|B||
02537|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02537|004|L|of severe adverse interaction.|
02537|005|B||
02537|006|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
02537|007|A|naloxegol.(1)|
02537|008|B||
02537|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducers of CYP3A4 may result|
02537|010|E|in decreased levels and effectiveness of naloxegol.(1)|
02537|011|B||
02537|012|P|PREDISPOSING FACTORS:  Patients taking methadone may be more likely to|
02537|013|P|experience gastrointestinal side effects such as abdominal pain and diarrhea|
02537|014|P|as a result of opioid withdrawal.(1)|
02537|015|P|   Induction effects may be more likely with regular use of the inducer for|
02537|016|P|longer than 1-2 weeks.|
02537|017|B||
02537|018|M|PATIENT MANAGEMENT:  Concurrent use of a strong inducer of CYP3A4 with|
02537|019|M|naloxegol is not recommended.(1)|
02537|020|M|   If concurrent use is warranted, monitor patients for signs of decreased|
02537|021|M|naloxegol effectiveness, such as constipation.  Patients may require|
02537|022|M|additional laxative therapy.|
02537|023|B||
02537|024|D|DISCUSSION:  Rifampin (600 mg daily for 13 days), a strong inducer of|
02537|025|D|CYP3A4, decreased the maximum concentration (Cmax) and area-under-curve|
02537|026|D|(AUC) of a single dose of naloxegol by 75% and 89%, respectively.(2)|
02537|027|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02537|028|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02537|029|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02537|030|D|rifapentine, and St. John's wort.(1,3,4)|
02537|031|B||
02537|032|R|REFERENCES:|
02537|033|B||
02537|034|R|1.Movantik (naloxegol) US prescribing information. AstraZeneca|1
02537|035|R|  Pharmaceuticals LP April, 2020.|1
02537|036|R|2.US FDA Center for Drug Evaluation and Research. Naloxegol Clinical|1
02537|037|R|  Pharmacology and Biopharmaceutics Review.  Application number|1
02537|038|R|  204760Orig1s000. available at:|1
02537|039|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204760Orig1s000Clin|1
02537|040|R|  Pharm.pdf July 25, 2014.|1
02537|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02537|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02537|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02537|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02537|045|R|  11/14/2017.|1
02537|046|R|4.This information is based on an extract from the Certara Drug Interaction|6
02537|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02538|001|T|MONOGRAPH TITLE:  Edoxaban/Antiplatelets; Aspirin (Greater Than 100 mg)|
02538|002|B||
02538|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02538|004|L|of severe adverse interaction.|
02538|005|B||
02538|006|A|MECHANISM OF ACTION:  Anticoagulants and antiplatelet agents have additive|
02538|007|A|effects on hemostasis.(1)  In addition, aspirin doses greater than or equal|
02538|008|A|to 325 mg daily increase edoxaban exposure.(1)|
02538|009|B||
02538|010|E|CLINICAL EFFECTS:  Concurrent use of edoxaban with antiplatelets may|
02538|011|E|increase the risk of bleeding.(1)|
02538|012|B||
02538|013|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with renal|
02538|014|P|impairment and in patients > 75 years of age.(1)  Use of multiple agents|
02538|015|P|which affect hemostasis increases the risk for bleeding.|
02538|016|P|   The risk for bleeding episodes may be greater in patient with|
02538|017|P|disease-associated factors (e.g. thrombocytopenia).|
02538|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
02538|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02538|020|P|risk for bleeding (e.g. NSAIDs).|
02538|021|B||
02538|022|M|PATIENT MANAGEMENT:  Patients requiring concurrent therapy with edoxaban and|
02538|023|M|an antiplatelet agent should be closely monitored for signs of bleeding.|
02538|024|M|Edoxaban and aspirin at dosages of 100 mg or less may be|
02538|025|M|coadministered.(2,3)|
02538|026|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
02538|027|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
02538|028|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02538|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02538|030|M|to monitor efficacy and safety of anticoagulation.|
02538|031|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02538|032|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02538|033|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02538|034|M|and/or swelling.|
02538|035|M|   Discontinue edoxaban in patients with active bleeding.|
02538|036|B||
02538|037|D|DISCUSSION:  Concomitant use of edoxaban and antiplatelet agents may|
02538|038|D|increase the risk of bleeding.|
02538|039|D|   In edoxaban clinical trials concomitant use of low dose aspirin (< or =|
02538|040|D|100 mg daily), thienopyridines, and NSAIDs was permitted and resulted in|
02538|041|D|increased rates of clinically relevant bleeding. The rates of major bleeding|
02538|042|D|on edoxaban and warfarin were generally consistent among subgroups. Bleeding|
02538|043|D|rates appeared higher in both treatment arms (edoxaban and warfarin) in|
02538|044|D|patients taking aspirin.  Co-administration of aspirin (100 mg or 325 mg)|
02538|045|D|and edoxaban increased bleeding time relative to that seen with either drug|
02538|046|D|alone.(1)|
02538|047|D|   About 30% of the population in ENGAGE-AF received concomitant therapy|
02538|048|D|with aspirin because of co-morbid conditions. While aspirin is known to|
02538|049|D|increase risk for bleeds and the annualized event rate for major bleeds was|
02538|050|D|higher than that in patients not receiving aspirin (3.87% vs. 2.13%), the|
02538|051|D|risk for bleeds in patients receiving edoxaban 60 mg on a background of|
02538|052|D|aspirin was lower than that for warfarin on a background of aspirin (HR 0.78|
02538|053|D|(95%CI 0.65,0.94). Based on these data no dose adjustments/contraindications|
02538|054|D|are required.(4)|
02538|055|D|   Edoxaban and aspirin at dosages of 100 mg or less may be|
02538|056|D|coadministered.(2,3)|
02538|057|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
02538|058|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
02538|059|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
02538|060|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
02538|061|D|aspirin, with the highest allowable dose being 165 mg/day.  The use of DOACs|
02538|062|D|with antiplatelet agents was associated with an increased risk of major|
02538|063|D|bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major|
02538|064|D|bleeding (OR 1.82; 95% CI, 1.50-2.22).  There was no difference between|
02538|065|D|groups in the efficacy outcome of symptomatic recurrent venous|
02538|066|D|thromboembolism (VTE) or VTE-related death.(5)|
02538|067|B||
02538|068|R|REFERENCES:|
02538|069|B||
02538|070|R|1.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02538|071|R|  2019.|1
02538|072|R|2.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
02538|073|R|  Sankyo UK Limited July 2, 2015.|1
02538|074|R|3.Lixiana (edoxaban) Canadian product monograph. Servier Canada Inc.|1
02538|075|R|  February, 2023.|1
02538|076|R|4.FDA Center for Drug Evaluation and Research (CDER). Application number|1
02538|077|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
02538|078|R|  Biopharmaceutics Review. available at:|1
02538|079|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
02538|080|R|  0ClinPharmR.pdf January 8, 2015.|1
02538|081|R|5.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
02538|082|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
02538|083|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
02538|084|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
02539|001|T|MONOGRAPH TITLE:  Praziquantel/Chloroquine|
02539|002|B||
02539|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02539|004|L|of severe adverse interaction.|
02539|005|B||
02539|006|A|MECHANISM OF ACTION:  How chloroquine decreases praziquantel levels is|
02539|007|A|unknown.(1)|
02539|008|B||
02539|009|E|CLINICAL EFFECTS:  Concurrent use of chloroquine may result in decreased|
02539|010|E|levels and effectiveness of praziquantel.(1,2)|
02539|011|B||
02539|012|P|PREDISPOSING FACTORS:  None determined.|
02539|013|B||
02539|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with chloroquine|
02539|015|M|may need higher doses of praziquantel.(2)  Monitor patients for praziquantel|
02539|016|M|therapy failure.|
02539|017|B||
02539|018|D|DISCUSSION:  In a study in 8 healthy male subjects, administration of|
02539|019|D|chloroquine (600 mg) with praziquantel (40 mg/kg) decreased the maximum|
02539|020|D|concentration (Cmax) and area-under-curve (AUC) of praziquantel by 58.7% and|
02539|021|D|64.5%, respectively, when compared to the administration of praziquantel|
02539|022|D|alone in the same subjects.  There was large inter-patient variability and|
02539|023|D|one patient did not have any change in praziquantel levels.(2)|
02539|024|B||
02539|025|R|REFERENCES:|
02539|026|B||
02539|027|R|1.Biltricide (praziquantel) US prescribing information. Bayer HealthCare|1
02539|028|R|  Pharmaceuticals Inc. January, 2019.|1
02539|029|R|2.Masimirembwa CM, Naik YS, Hasler JA. The effect of chloroquine on the|2
02539|030|R|  pharmacokinetics and metabolism of praziquantel  in rats and in humans.|2
02539|031|R|  Biopharm Drug Dispos 1994 Jan;15(1):33-43.|2
02540|001|T|MONOGRAPH TITLE:  Apixaban/P-gp and Moderate CYP3A4 Inhibitors|
02540|002|B||
02540|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02540|004|L|take action as needed.|
02540|005|B||
02540|006|A|MECHANISM OF ACTION:  Cimetidine, diltiazem, dronedarone, erythromycin,|
02540|007|A|isavuconazonium and verapamil may inhibit the metabolism of apixaban by|
02540|008|A|CYP3A4 and by P-glycoprotein.(1,2)|
02540|009|B||
02540|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
02540|011|E|P-gp and a moderate inhibitor of CYP3A4 may result in elevated levels of and|
02540|012|E|clinical effects of apixaban, including an increased risk of bleeding.(1,2)|
02540|013|B||
02540|014|P|PREDISPOSING FACTORS:  This interaction may be more clinically significant|
02540|015|P|in patients with decreased renal function.(1)|
02540|016|P|   The risk for bleeding episodes may be greater in patients with|
02540|017|P|disease-associated factors (e.g. thrombocytopenia).|
02540|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
02540|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02540|020|P|risk for bleeding (e.g. NSAIDs).|
02540|021|B||
02540|022|M|PATIENT MANAGEMENT:  The Australian(1), Canadian(2), UK(3), and US(4)|
02540|023|M|manufacturers state concurrent use of agents that are P-gp and moderate|
02540|024|M|CYP3A4 inhibitors are expected to increase apixaban levels to a lesser|
02540|025|M|extent than agents that are P-gp and strong CYP3A4 inhibitors.  No dose|
02540|026|M|adjustment of apixaban is necessary.  Use caution when administering|
02540|027|M|apixaban with moderate inhibitors of CYP3A4.|
02540|028|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02540|029|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02540|030|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02540|031|M|patients with any symptoms.|
02540|032|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02540|033|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02540|034|M|anticoagulation in patients with active pathologic bleeding.|
02540|035|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02540|036|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02540|037|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02540|038|M|and/or swelling.|
02540|039|B||
02540|040|D|DISCUSSION:  Concurrent ketoconazole (400 mg daily, a strong inhibitor of|
02540|041|D|CYP3A4) increased the area-under-curve (AUC) and maximum concentration|
02540|042|D|(Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1)|
02540|043|D|   A propensity matched cohort evaluated the concurrent use of combined P-gp|
02540|044|D|and moderate CYP3A4 inhibitors with apixaban or rivaroxaban.  Combined|
02540|045|D|inhibitors included amiodarone, diltiazem, erythromycin, dronedarone, and|
02540|046|D|verapamil.  Bleeding occurred in 26.4% of patients in the inhibitor group|
02540|047|D|compared to 18.4% in the control group (hazard ratio 1.8; 95% CI 1.19-2.73;|
02540|048|D|p=0.006).  Although not statistically significant, patients in the inhibitor|
02540|049|D|group also had a higher rate of major bleeding (15% vs 10.3%) and minor|
02540|050|D|bleeding (8.9% vs 5.2%), respectively.(6)|
02540|051|D|   A summary of pharmacokinetic interactions with apixaban and|
02540|052|D|calcium-channel blockers, including diltiazem and verapamil, concluded that|
02540|053|D|concurrent use is considered safe based on a lesser increase in apixaban|
02540|054|D|exposure with moderate CYP3A4 inhibitors.(7)|
02540|055|D|   A population cohort study of 48,422 patients evaluated overall and|
02540|056|D|gastrointestinal major, moderate or minor bleeding in patients on concurrent|
02540|057|D|therapy with apixaban and diltiazem or verapamil.  Concurrent therapy was|
02540|058|D|not associated with increased bleeding rates compared to patients receiving|
02540|059|D|amlodipine or metoprolol.(8)|
02540|060|D|   A retrospective study of two propensity matched cohorts of 1681 patients|
02540|061|D|each found a bleeding rate of 1.31 and 2.14 per 100 years at risk with|
02540|062|D|apixaban and warfarin, respectively, when used concurrently with dronedarone|
02540|063|D|in patients with atrial fibrillation.  The hazard ratio with apixaban and|
02540|064|D|dronedarone was 0.66 compared to warfarin and dronedarone.(9)|
02540|065|D|   An observational study of 29 patients evaluated concurrent administration|
02540|066|D|of apixaban (5 mg) with diltiazem or diltiazem with atorvastatin or|
02540|067|D|rosuvastatin. Administration of apixaban with diltiazem and rosuvastatin|
02540|068|D|resulted in a greater than 1.5-fold increate in apixaban concentrations.|
02540|069|D|Concurrent administration of apixaban with diltiazem alone or diltiazem with|
02540|070|D|atorvastatin did not result in a statistically significant increase in|
02540|071|D|apixaban concentration.(11)|
02540|072|D|   P-gp and moderate CYP3A4 inhibitors linked to this monograph are:|
02540|073|D|conivaptan, diltiazem, dronedarone, erythromycin, isavuconazonium and|
02540|074|D|verapamil.(10)|
02540|075|B||
02540|076|R|REFERENCES:|
02540|077|B||
02540|078|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
02540|079|R|  Squibb Australia Pty. Ltd. January, 2024.|1
02540|080|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
02540|081|R|  Squibb-Pfizer January, 2025.|1
02540|082|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
02540|083|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
02540|084|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
02540|085|R|  Company April, 2025.|1
02540|086|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02540|087|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02540|088|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02540|089|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02540|090|R|  11/14/2017.|1
02540|091|R|6.Hanigan S, Das J, Pogue K, Barnes GD, Dorsch MP. The real world use of|2
02540|092|R|  combined P-glycoprotein and moderate CYP3A4 inhibitors with  rivaroxaban|2
02540|093|R|  or apixaban increases bleeding..|2
02540|094|R|7.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
02540|095|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
02540|096|R|  of  the Week..|6
02540|097|R|8.Pham P, Schmidt S, Lesko L, Lip GYH, Brown JD. Association of Oral|2
02540|098|R|  Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding  Events in|2
02540|099|R|  Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function.|2
02540|100|R|  JAMA Netw Open;3(4)(2574-3805 (Electronic). 2574-3805 (Linking)):.|2
02540|101|R|9.Friberg L. Safety of apixaban in combination with dronedarone in patients|2
02540|102|R|  with atrial  fibrillation. Int J Cardiol;264(1874-1754 (Electronic).|2
02540|103|R|  0167-5273 (Linking)):.|2
02540|104|R|10.This information is based on an extract from the Certara Drug Interaction|6
02540|105|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02540|106|R|11.Milner E, Ainsworth M, Gleaton M, Bookstaver D. Assessment of Anti-Xa|2
02540|107|R|   activity in patients receiving concomitant apixaban with strong|2
02540|108|R|   p-glycoprotein inhibitors and statins. J Clin Pharm Ther 2022 Jan 15.|2
02541|001|T|MONOGRAPH TITLE:  Thioridazine/Selected Strong & Moderate CYP2D6 Inhibitors|
02541|002|T|that Prolong QT|
02541|003|B||
02541|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02541|005|L|is contraindicated and generally should not be dispensed or administered to|
02541|006|L|the same patient.|
02541|007|B||
02541|008|A|MECHANISM OF ACTION:  Dronedarone, escitalopram and quinidine may inhibit|
02541|009|A|the metabolism of thioridazine by CYP2D6.  Dronedarone, escitalopram, and|
02541|010|A|quinidine may also result in additive effects on the QTc interval.(1,2)|
02541|011|B||
02541|012|E|CLINICAL EFFECTS:  Concurrent use of dronedarone, escitalopram, or quinidine|
02541|013|E|may result in thioridazine toxicity, including potentially life-threatening|
02541|014|E|cardiac arrhythmias, including torsades de pointes.(1,2)|
02541|015|B||
02541|016|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers may|
02541|017|P|be affected to a greater extent by CYP2D6 inhibitors.  Patients who are|
02541|018|P|CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6|
02541|019|P|inhibition.|
02541|020|P|   The risk of QT prolongation or torsade de pointes may be increased in|
02541|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02541|022|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
02541|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02541|024|P|advanced age.(3)|
02541|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02541|026|P|higher systemic concentrations of either QT prolonging drug are additional|
02541|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02541|028|P|drug concentrations include rapid infusion of an intravenous dose or|
02541|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02541|030|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02541|031|P|dysfunction).(3)|
02541|032|P|   The risk of anticholinergic toxicities including cognitive decline,|
02541|033|P|delirium, falls and fractures is increased in geriatric patients using more|
02541|034|P|than one medicine with anticholinergic properties.(4)|
02541|035|B||
02541|036|M|PATIENT MANAGEMENT:  The concurrent use of thioridazine and strong or|
02541|037|M|moderate CYP2D6 inhibitors such as dronedarone, escitalopram, or quinidine|
02541|038|M|is contraindicated.(1,2)  Consider the use of alternative antipsychotics|
02541|039|M|with less QT prolongation potential, or an alternative to dronedarone,|
02541|040|M|escitalopram, or quinidine containing products.|
02541|041|M|   If concurrent use is deemed medically necessary, consider obtaining serum|
02541|042|M|calcium, magnesium, and potassium levels at baseline and at regular|
02541|043|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
02541|044|M|report any irregular  heartbeat, dizziness, or fainting.|
02541|045|M|   The manufacturer of Nuedexta states that if concurrent use with QT|
02541|046|M|prolonging agents cannot be avoided, ECG monitoring should be done at|
02541|047|M|initiation of concurrent therapy and at 3-4 hours after the first dose.(2)|
02541|048|B||
02541|049|D|DISCUSSION:  Quinidine is a strong CYP2D6 inhibitor and would be expected to|
02541|050|D|increase thioridazine levels by more than 5-fold.  Dronedarone and|
02541|051|D|escitalopram are moderate CYP2D6 inhibitors and would be excepted to|
02541|052|D|increase thioridazine by 2-fold to 5-fold.(2,5-6)|
02541|053|D|   One or more of the drug pairs linked to this monograph have been included|
02541|054|D|in a list of interactions that should be considered "high-priority" for|
02541|055|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02541|056|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02541|057|D|Coordinator (ONC) for Health Information Technology.|
02541|058|B||
02541|059|R|REFERENCES:|
02541|060|B||
02541|061|R|1.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
02541|062|R|  prescribing information. Avanir  Pharmaceuticals June, 2019.|1
02541|063|R|2.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
02541|064|R|  September, 2014.|1
02541|065|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02541|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02541|067|R|  settings: a scientific statement from the American Heart Association and|6
02541|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02541|069|R|  2;55(9):934-47.|6
02541|070|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02541|071|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02541|072|R|  Soc 2023 Jul;71(7):2052-2081.|6
02541|073|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02541|074|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02541|075|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02541|076|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02541|077|R|  11/14/2017.|1
02541|078|R|6.This information is based on an extract from the Certara Drug Interaction|6
02541|079|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02541|080|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02541|081|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02541|082|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02541|083|R|  19(5):735-43.|6
02542|001|T|MONOGRAPH TITLE:  Sotalol/Selected Class I & Class III Antiarrhythmic Agents|
02542|002|B||
02542|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02542|004|L|is contraindicated and generally should not be dispensed or administered to|
02542|005|L|the same patient.|
02542|006|B||
02542|007|A|MECHANISM OF ACTION:  Sotalol has been shown to prolong the QTc interval.|
02542|008|A|Concurrent use with other agents that prolong the QTc interval may result in|
02542|009|A|additive effects on the QTc interval.(1-2)|
02542|010|B||
02542|011|E|CLINICAL EFFECTS:  The concurrent use of sotalol with other agents that|
02542|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02542|013|E|arrhythmias, including torsades de pointes.(1-2)|
02542|014|B||
02542|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by|
02542|016|P|reduced creatinine clearance, female gender, larger doses of sotalol, and a|
02542|017|P|history of cardiomegaly or congestive heart failure.(1-2)  Risk may also be|
02542|018|P|increased in patients with cardiovascular disease (e.g. myocardial|
02542|019|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02542|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, or advanced age.(4)|
02542|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02542|022|P|higher systemic concentrations of either QT prolonging drug are additional|
02542|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02542|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02542|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02542|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02542|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02542|028|B||
02542|029|M|PATIENT MANAGEMENT:  The manufacturers of sotalol state Class I or Class III|
02542|030|M|antiarrhythmic agents which have the potential to prolong refractoriness may|
02542|031|M|cause prolongation of the QT interval and so are not recommended.(1-2)|
02542|032|M|These agents should be withheld for at least 3 half-lives prior to|
02542|033|M|initiation of sotalol.(2)|
02542|034|M|   Selected Class I or Class III antiarrhythmic agents linked to this|
02542|035|M|monograph are: ajmaline, amiodarone, bretylium, dronedarone, encainide,|
02542|036|M|flecainide, hydroquinidine, indecainide, moricizine, procainamide and|
02542|037|M|quinidine.|
02542|038|M|   If concurrent therapy is deemed medically necessary, obtain serum|
02542|039|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
02542|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02542|041|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02542|042|B||
02542|043|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02542|044|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02542|045|D|monograph have been shown to prolong the QTc interval either through their|
02542|046|D|mechanism of action, through studies on their effects on the QTc interval,|
02542|047|D|or through reports of QTc prolongation and/or torsades de pointes in|
02542|048|D|clinical trials and/or postmarketing reports.(3)|
02542|049|D|   One or more of the drug pairs linked to this monograph have been included|
02542|050|D|in a list of interactions that should be considered "high-priority" for|
02542|051|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02542|052|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02542|053|D|Coordinator (ONC) for Health Information Technology.|
02542|054|B||
02542|055|R|REFERENCES:|
02542|056|B||
02542|057|R|1.Betapace (sotalol hydrochloride) US prescribing information. Bayer|1
02542|058|R|  Healthcare Inc. June, 2021.|1
02542|059|R|2.Sotylize (sotalol) oral solution, US prescribing information. Azurity|1
02542|060|R|  Pharmaceuticals, Inc. January, 2024.|1
02542|061|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02542|062|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02542|063|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02542|064|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02542|065|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02542|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02542|067|R|  settings: a scientific statement from the American Heart Association and|6
02542|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02542|069|R|  2;55(9):934-47.|6
02542|070|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02542|071|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02542|072|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02542|073|R|  19(5):735-43.|6
02543|001|T|MONOGRAPH TITLE:  Lenvatinib/Possible QT Prolonging Agents|
02543|002|B||
02543|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02543|004|L|take action as needed.|
02543|005|B||
02543|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02543|007|A|interval may result in additive effects on the QTc interval.(1)|
02543|008|B||
02543|009|E|CLINICAL EFFECTS:  Concurrent use of lenvatinib in patients taking other|
02543|010|E|medications that prolong the QT interval may result in additive QT|
02543|011|E|prolongation.  QT prolongation may result in potentially life-threatening|
02543|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02543|013|B||
02543|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02543|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02543|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02543|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
02543|018|P|hypoalbuminemia, bradycardia, female gender, or advanced age.(1,2)|
02543|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02543|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02543|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02543|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02543|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02543|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02543|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02543|026|B||
02543|027|M|PATIENT MANAGEMENT:  Monitor electrocardiograms during concurrent therapy|
02543|028|M|with lenvatinib and agents that prolong the QT interval.  In a clinical|
02543|029|M|trial of patients with refractory, progressive thyroid cancer, QT|
02543|030|M|prolongation was reported in 9% of lenvatinib patients.  Monitor and correct|
02543|031|M|electrolyte abnormalities in all patients.(1)  This is particularly|
02543|032|M|important in lenvatinib patients as diarrhea, nausea, vomiting, and|
02543|033|M|decreased appetite are common side effects which may increase the risk for|
02543|034|M|electrolyte disturbances.|
02543|035|M|   Monitor ECG at baseline and at regular intervals.  Lenvatinib dose must|
02543|036|M|be withheld if the QTc exceeds 500 msec until QTc resolves to less than 480|
02543|037|M|msec or baseline.  Lenvatinib must be resumed at reduced dose when QTc|
02543|038|M|prolongation resolves to less than 480 msec or to baseline.  Dose|
02543|039|M|adjustments below are indication specific and are for patients with normal|
02543|040|M|hepatic and renal function:(1)|
02543|041|M|   Dose Modifications in Differentiated Thyroid Cancer(DTC):|
02543|042|M| - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02543|043|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|044|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|045|M|dose to 20 mg once daily|
02543|046|M| - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade|
02543|047|M|3 Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|048|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|049|M|dose to 14 mg once daily|
02543|050|M| - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02543|051|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|052|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|053|M|dose 10 mg once daily|
02543|054|M|   Dose Modifications in Renal Cell Cancer (RCC):|
02543|055|M| - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02543|056|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|057|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|058|M|dose to 14 mg once daily|
02543|059|M| - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade|
02543|060|M|3 Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|061|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|062|M|dose to 10 mg once daily|
02543|063|M| - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02543|064|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|065|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|066|M|dose 8 mg once daily|
02543|067|M|   Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight 60|
02543|068|M|kg or greater:|
02543|069|M| - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02543|070|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|071|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|072|M|dose to 8 mg once daily|
02543|073|M| - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade|
02543|074|M|3 Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|075|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|076|M|dose to 4 mg once daily|
02543|077|M| - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02543|078|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|079|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|080|M|dose 4 mg every other day|
02543|081|M|   Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight|
02543|082|M|less than 60 kg:|
02543|083|M| - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02543|084|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|085|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|086|M|dose to 4 mg once daily|
02543|087|M| - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade|
02543|088|M|3 Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|089|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02543|090|M|dose to 4 mg every other day|
02543|091|M| - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02543|092|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02543|093|M|   Interrupt therapy until resolved to Grade 0-1 or baseline and discontinue|
02543|094|M|lenvatinib (1)|
02543|095|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02543|096|B||
02543|097|D|DISCUSSION:  In a clinical trial of patients with refractory, progressive|
02543|098|D|thyroid cancer, QT prolongation was reported in 9% of lenvatinib patients|
02543|099|D|and 2% of placebo patients.  The incidence of Grade 3 QT prolongation of >|
02543|100|D|500 msec was reported in 2% of lenvatinib patients compared with no reports|
02543|101|D|in placebo patients.(1)|
02543|102|D|   In contrast, a single lenvatinib dose of 32 mg (1.3 times the recommended|
02543|103|D|daily dose) did not prolong the QT/QTc interval in a thorough QT study|
02543|104|D|performed in healthy subjects.(1)|
02543|105|D|   A retrospective review of 618 cancer patients treated with 902|
02543|106|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02543|107|D|incidence of QTc prolongation.  In patients who received lenvatinib, QTc|
02543|108|D|prolongation was identified in 9 (42.9%) with 4 (44.4%) having Grade 1 (QTc|
02543|109|D|450-480 ms) and 3 (33.3%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
02543|110|D|occurred in 0 (0%) having QTc greater than or equal to 500 ms and 1 (11.1%)|
02543|111|D|having QTc change greater than or equal to 60 ms.  Ventricular tachycardia|
02543|112|D|was seen in 1 (11.1%) patient.(3)|
02543|113|B||
02543|114|R|REFERENCES:|
02543|115|B||
02543|116|R|1.Lenvima (lenvatinib) US prescribing information. Eisai Inc. December,|1
02543|117|R|  2021.|1
02543|118|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02543|119|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02543|120|R|  settings: a scientific statement from the American Heart Association and|6
02543|121|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02543|122|R|  2;55(9):934-47.|6
02543|123|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02543|124|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02543|125|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02544|001|T|MONOGRAPH TITLE:  Rilpivirine/Ombitasvir-paritaprevir-ritonavir|
02544|002|B||
02544|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02544|004|L|take action as needed.|
02544|005|B||
02544|006|A|MECHANISM OF ACTION:  Ombitasvir-paritaprevir-ritonavir may inhibit the|
02544|007|A|CYP3A4 mediated metabolism of rilpivirine leading to increased systemic|
02544|008|A|exposure (area-under-curve, AUC).(1)|
02544|009|B||
02544|010|E|CLINICAL EFFECTS:  Increased exposure to rilpivirine may result in toxicity,|
02544|011|E|including potentially life-threatening cardiac arrhythmias, such as torsades|
02544|012|E|de pointes.(1)|
02544|013|B||
02544|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02544|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02544|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02544|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02544|018|P|gender, advanced age or when receiving concomitant treatment with additional|
02544|019|P|inhibitors of CYP3A4.(2)|
02544|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02544|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02544|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02544|023|P|drug concentrations include rapid infusion of an intravenous dose, or|
02544|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02544|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02544|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02544|027|B||
02544|028|M|PATIENT MANAGEMENT:  The concurrent use of rilpivirine with|
02544|029|M|ombitasvir-paritaprevir-ritonavir is not recommended due to the potential|
02544|030|M|risk for QT prolongation.(1)|
02544|031|M|   Rilpivirine does not prolong the QT interval at the recommended dose of|
02544|032|M|25 mg daily.  In interaction studies the combination of|
02544|033|M|ombitasvir-paritaprevir-ritonavir and dasabuvir with rilpivirine (25 mg|
02544|034|M|daily) increased rilpivirine exposure (AUC) approximately 3-fold (range:|
02544|035|M|2.80-3.77), similar to the exposure associated with a rilpivirine dose of 75|
02544|036|M|mg daily.(3) In rilpivirine QT studies, a 75 mg daily dose increased the QTc|
02544|037|M|interval by 10.7 msec, just above the 10 msec threshold for regulatory|
02544|038|M|concern.(3,4)|
02544|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02544|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02544|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02544|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02544|043|B||
02544|044|D|DISCUSSION:  In a clinical trial in healthy adults, rilpivirine at|
02544|045|D|recommended dosages (25 mg daily) had no significant effects on the QTc|
02544|046|D|interval.  However, supratherapeutic dosages (75 mg daily and 300 mg daily)|
02544|047|D|increased the QTc interval by 10.7 msec and 23.3 msec, respectively.|
02544|048|D|Rilpivirine dosages of 75 mg daily and 300 mg daily resulted in rilpivirine|
02544|049|D|maximum concentration (Cmax) levels of 2.6-fold and 6.7-respectively.(4)|
02544|050|B||
02544|051|R|REFERENCES:|
02544|052|B||
02544|053|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02544|054|R|  prescribing information. AbbVie Inc. December, 2019.|1
02544|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02544|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02544|057|R|  settings: a scientific statement from the American Heart Association and|6
02544|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02544|059|R|  2;55(9):934-47.|6
02544|060|R|3.FDA. CDER Application number: 2066190 Viekira Pak (ombitasvir,|1
02544|061|R|  paritaprevir, ritonavir, dasabuvir) Clinical Pharmacology and|1
02544|062|R|  Biopharmaceutics Review(s). URL:|1
02544|063|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206619Orig1s000Clin|1
02544|064|R|  PharmR.pdf December 19, 2014.|1
02544|065|R|4.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
02544|066|R|  March, 2024.|1
02545|001|T|MONOGRAPH TITLE:  Beta-2 Agonists/Non-Cardioselective Beta-Blockers|
02545|002|B||
02545|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02545|004|L|of severe adverse interaction.|
02545|005|B||
02545|006|A|MECHANISM OF ACTION:  Non-cardioselective beta-blockers and beta-2 agonists|
02545|007|A|may antagonize the effects of each other.|
02545|008|B||
02545|009|E|CLINICAL EFFECTS:  Diminished response to either the beta-agonist,|
02545|010|E|beta-blocker, or both may occur.  Beta-blockers may also induce|
02545|011|E|bronchospasm.|
02545|012|B||
02545|013|P|PREDISPOSING FACTORS:  Patients receiving beta-2 agonists for the treatment|
02545|014|P|of asthma may be more at risk for bronchospasm.|
02545|015|B||
02545|016|M|PATIENT MANAGEMENT:  If possible, avoid beta-blocker therapy in asthmatic|
02545|017|M|patients requiring beta-2 agonist therapy.  If beta-blocker therapy is|
02545|018|M|required, use a cardio-selective beta-blocker.|
02545|019|M|   For timolol ophthalmic drops, counsel patients to apply pressure to the|
02545|020|M|inner corner of the eye after administration to prevent systemic absorption.|
02545|021|M|   Monitor patients for decreased effects of either agent, such as increased|
02545|022|M|need for/use of beta-2 agonists or increased heart rate or blood pressure.|
02545|023|B||
02545|024|D|DISCUSSION:  Many patients with asymptomatic or mild reactive airways|
02545|025|D|disease tolerate beta-blockers well.  Most patients with COPD do not have|
02545|026|D|bronchospastic component to their illness and may be given beta-blockers.|
02545|027|D|Heart failure treatment guidelines recommend beta-blockers in the presence|
02545|028|D|of COPD.|
02545|029|D|   Non-selective beta-blockers have been shown to have a negative effect on|
02545|030|D|lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with|
02545|031|D|asthma and COPD.(1)|
02545|032|D|   An open-label study using the nonselective beta blocker nadolol showed no|
02545|033|D|effect on salbutamol in 10 patients with mild asthma not on controller|
02545|034|D|therapy.(2)|
02545|035|D|   A study in 8 healthy men showed that long acting propranolol (160 mg)|
02545|036|D|only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg|
02545|037|D|and 1600 mcg dose were unaffected. However, penbutolol prevented any|
02545|038|D|significant airway dilation with all doses of salbutamol.(3)|
02545|039|D|   In a double blind, three-way, crossover study, 44% (7/16 patients) of|
02545|040|D|patients taking metoprolol showed a greater than 20% decrease in FEV1|
02545|041|D|compared to 19% (3 patients) after dilevalol and 6% (1 patient) after|
02545|042|D|placebo. Dilevalol and metoprolol significantly inhibited isoproterenol|
02545|043|D|response compared to placebo.(4)|
02545|044|D|   A double-blind, randomized, crossover study in 10 asthmatic patients|
02545|045|D|showed that intravenous propranolol produced marked symptomatic|
02545|046|D|bronchoconstriction. Only a slight but significant inhibition of|
02545|047|D|bronchomotor sensitivity to isoproterenol was noted during esmolol|
02545|048|D|infusion.(5)|
02545|049|D|   In 18 patients with reversible bronchial asthma, labetalol caused a|
02545|050|D|significant increase in FEV1 and metoprolol caused a significant decrease in|
02545|051|D|FEV1. Concurrent administration of isoproterenol and labetalol caused a|
02545|052|D|further increase in FEV1. The effect of isoproterenol was decreased by|
02545|053|D|metoprolol (100, 200mg).(6)|
02545|054|D|   In one study propranolol (0.06mg/kg IV) was shown to almost completely|
02545|055|D|block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV)|
02545|056|D|did not affect isoproterenol.(7)|
02545|057|D|   Studies have shown that cardioselective beta-blockers are safe for|
02545|058|D|patients with asthma and COPD.(8,9,10)|
02545|059|D|   Nebivolol and celiprolol significantly decreased FEV1. Inhalation of|
02545|060|D|albuterol (up to 800mcg) significantly improved FEV1, but the values after|
02545|061|D|nebivolol and celiprolol administration were lower than the initial|
02545|062|D|values.(11)|
02545|063|D|   Administration of metoprolol did not cause any respiratory problems in 9|
02545|064|D|asthmatic patients. There was no significant difference between the|
02545|065|D|metoprolol and placebo groups in the respiratory response to an|
02545|066|D|isoproterenol aerosol in 24 asthmatic patients.(12)|
02545|067|D|   Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg|
02545|068|D|bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused|
02545|069|D|bronchoconstriction measured by a significant fall in PEFR (peak expiratory|
02545|070|D|flow rate).  Terbutaline was able to reverse bronchoconstriction in all|
02545|071|D|patients.(13)|
02545|072|D|   A double blind, placebo-controlled study analyzed the use of atenolol|
02545|073|D|100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before|
02545|074|D|and after exercise. All three drugs reduced significantly FEV1 and PEFR.|
02545|075|D|Administration of terbutaline improved all respiratory indices.(14)|
02545|076|D|   A double-blind crossover trial in 10 asthmatic patients showed that a|
02545|077|D|single IV dose of atenolol 3mg caused slight impairment of ventilatory|
02545|078|D|function.  A dose of salbutamol by inhalation was able to reverse the|
02545|079|D|bronchial effect of atenolol.(15)|
02545|080|D|   Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and|
02545|081|D|celiprolol 200mg/day were given to 10 asthmatic patients in a randomized,|
02545|082|D|crossover design with a two week washout period between each drug.  The|
02545|083|D|non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a|
02545|084|D|significant reduction in FEV1 and inhibited the bronchodilator response to|
02545|085|D|inhaled salbutamol.  Atenolol and celiprolol (beta1 selective beta blockers)|
02545|086|D|did not significantly affect respiratory function or antagonize salbutamol|
02545|087|D|effects.(16)|
02545|088|D|   A double blind, randomized, within patient, placebo-controlled study|
02545|089|D|compared the cardioselective beta-blocker atenolol to the non-selective|
02545|090|D|propranolol. Atenolol caused a significantly less drop in FEV1 compared to|
02545|091|D|propranolol. The effect of isoprenaline plus the beta blockers were also|
02545|092|D|studied. Both atenolol and propranolol effected isoprenaline FEV1 dose|
02545|093|D|response curves but the greatest displacement was seen with propranolol.(17)|
02545|094|D|   The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol|
02545|095|D|40mg, atenolol 100 mg were evaluated in 34 asthmatic patients.  Propranolol|
02545|096|D|and atenolol caused significant reductions in pulmonary function.|
02545|097|D|Propranolol pretreatment caused a significant reduction in the effect of the|
02545|098|D|bronchodilator. Celiprolol did not antagonize the bronchodilators.(18)|
02545|099|D|   A double-blind, placebo controlled, randomized, crossover design study|
02545|100|D|studied the effects of propranolol 80mg or celiprolol 200 or 400mg on|
02545|101|D|pulmonary function.  Propranolol produced a significant decrease in FEV1 and|
02545|102|D|FVC. Celiprolol and placebo had similar results. The effect of aerosolized|
02545|103|D|terbutaline was also measured.  Even at supratherapeutic doses, terbutaline|
02545|104|D|was unable to restore pulmonary function parameters to baseline levels after|
02545|105|D|treatment with propranolol.  Terbutaline caused further bronchodilation|
02545|106|D|after administration of celiprolol.(19)|
02545|107|D|   Eleven asthmatic patients showed significant bronchoconstriction in small|
02545|108|D|airways after propranolol 40mg and pindolol 2.5mg in a double blind,|
02545|109|D|randomized trial. Large airways only showed bronchoconstriction with|
02545|110|D|propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment|
02545|111|D|with propranolol and pindolol. The bronchodilator effect of terbutaline on|
02545|112|D|large airways was diminished after both propranolol and timolol.(20)|
02545|113|B||
02545|114|R|REFERENCES:|
02545|115|B||
02545|116|R|1.van der Woude HJ, Zaagsma J, Postma DS, Winter TH, van Hulst M, Aalbers R.|6
02545|117|R|  Detrimental effects of beta-blockers in COPD: a concern for nonselective|6
02545|118|R|  beta-blockers. Chest 2005 Mar;127(3):818-24.|6
02545|119|R|2.Hanania NA, Mannava B, Franklin AE, Lipworth BJ, Williamson PA, Garner WJ,|2
02545|120|R|  Dickey BF, Bond RA. Response to salbutamol in patients with mild asthma|2
02545|121|R|  treated with nadolol. Eur Respir J 2010 Oct;36(4):963-5.|2
02545|122|R|3.Warren JB, Monaghan AT, Clark TJ. Effect of penbutolol and propranolol on|2
02545|123|R|  normal airway response to salbutamol. Clin Pharmacol Ther 1984 Jul;|2
02545|124|R|  36(1):47-50.|2
02545|125|R|4.Chodosh S, Tuck J, Blasucci DJ. The effects of dilevalol, metoprolol, and|2
02545|126|R|  placebo on ventilatory function in asthmatics. J Cardiovasc Pharmacol|2
02545|127|R|  1988;11 Suppl 2:S18-24.|2
02545|128|R|5.Sheppard D, DiStefano S, Byrd RC, Eschenbacher WL, Bell V, Steck J, Laddu|2
02545|129|R|  A. Effects of esmolol on airway function in patients with asthma. J Clin|2
02545|130|R|  Pharmacol 1986 Mar;26(3):169-74.|2
02545|131|R|6.Falliers CJ, Vincent ME, Medakovic M. Effect of single doses of labetalol,|2
02545|132|R|  metoprolol, and placebo on ventilatory function in patients with bronchial|2
02545|133|R|  asthma: interaction with isoproterenol. J Asthma 1986;23(5):251-60.|2
02545|134|R|7.Johnsson G, Svedmyr N, Thiringer G. Effects of intravenous propranolol and|2
02545|135|R|  metoprolol and their interaction with isoprenaline on pulmonary function,|2
02545|136|R|  heart rate and blood pressure in asthmatics. Eur J Clin Pharmacol 1975 Apr|2
02545|137|R|  4;8(3-4):175-80.|2
02545|138|R|8.Tafreshi MJ, Weinacker AB. Beta-adrenergic-blocking agents in|6
02545|139|R|  bronchospastic diseases: a therapeutic dilemma. Pharmacotherapy 1999 Aug;|6
02545|140|R|  19(8):974-8.|6
02545|141|R|9.Chafin CC, Soberman JE, Demirkan K, Self T. Beta-blockers after myocardial|6
02545|142|R|  infarction: do benefits ever outweigh risks in asthma?. Cardiology 1999;|6
02545|143|R|  92(2):99-105.|6
02545|144|R|10.Salpeter SR, Ormiston TM, Salpeter EE, Poole PJ, Cates CJ.|6
02545|145|R|   Cardioselective beta-blockers for chronic obstructive pulmonary disease:|6
02545|146|R|   a meta-analysis. Respir Med 2003 Oct;97(10):1094-101.|6
02545|147|R|11.Cazzola M, Noschese P, D'Amato M, D'Amato G. Comparison of the effects of|2
02545|148|R|   single oral doses of nebivolol and celiprolol on airways in patients with|2
02545|149|R|   mild asthma. Chest 2000 Nov;118(5):1322-6.|2
02545|150|R|12.Mue S, Sasaki T, Shibahara S, Takahashi M, Ohmi T, Yamauchi K, Suzuki S,|2
02545|151|R|   Hida W, Takishima T. Influence of metoprolol on hemodynamics and|2
02545|152|R|   respiratory function in asthmatic patients. Int J Clin Pharmacol Biopharm|2
02545|153|R|   1979 Aug;17(8):346-50.|2
02545|154|R|13.Lammers JW, Folgering HT, van Herwaarden CL. Respiratory tolerance of|2
02545|155|R|   bisoprolol and metoprolol in asthmatic patients. J Cardiovasc Pharmacol|2
02545|156|R|   1986;8 Suppl 11:S69-73.|2
02545|157|R|14.Greefhorst AP, van Herwaarden CL. Comparative study of the ventilatory|2
02545|158|R|   effects of three beta 1-selective blocking agents in asthmatic patients.|2
02545|159|R|   Eur J Clin Pharmacol 1981;20(6):417-21.|2
02545|160|R|15.Boye NP, Vale JR. Effect in bronchial asthma of a new beta-adrenergic|2
02545|161|R|   blocking drug atenolol (ICI 66, 082). Eur J Clin Pharmacol 1977;|2
02545|162|R|   11(1):11-4.|2
02545|163|R|16.Fogari R, Zoppi A, Tettamanti F, Poletti L, Rizzardi G, Fiocchi G.|2
02545|164|R|   Comparative effects of celiprolol, propranolol, oxprenolol, and atenolol|2
02545|165|R|   on respiratory function in hypertensive patients with chronic obstructive|2
02545|166|R|   lung disease. Cardiovasc Drugs Ther 1990 Aug;4(4):1145-9.|2
02545|167|R|17.Ellis ME, Sahay JN, Chatterjee SS, Cruickshank JM, Ellis SH.|2
02545|168|R|   Cardioselectivity of atenolol in asthmatic patients. Eur J Clin Pharmacol|2
02545|169|R|   1981;21(3):173-6.|2
02545|170|R|18.Doshan HD, Rosenthal RR, Brown R, Slutsky A, Applin WJ, Caruso FS.|2
02545|171|R|   Celiprolol, atenolol and propranolol: a comparison of pulmonary effects|2
02545|172|R|   in asthmatic patients. J Cardiovasc Pharmacol 1986;8 Suppl 4:S105-8.|2
02545|173|R|19.Matthys H, Doshan HD, Ruhle KH, Braig H, Pohl M, Applin WJ, Caruso FS,|2
02545|174|R|   Neiss ES. The bronchosparing effect of celiprolol, a new beta 1- alpha|2
02545|175|R|   2-receptor antagonist on pulmonary function of propranolol-sensitive|2
02545|176|R|   asthmatics. J Clin Pharmacol 1985 Jul-Aug;25(5):354-9.|2
02545|177|R|20.Brooks TW, Creekmore FM, Young DC, Asche CV, Oberg B, Samuelson WM. Rates|2
02545|178|R|   of hospitalizations and emergency department visits in patients with|2
02545|179|R|   asthma and chronic obstructive pulmonary disease taking beta-blockers.|2
02545|180|R|   Pharmacotherapy 2007 May;27(5):684-90.|2
02545|181|R|21.Boskabady MH, Snashall PD. Bronchial responsiveness to beta-adrenergic|2
02545|182|R|   stimulation and enhanced beta-blockade in asthma. Respirology 2000 Jun;|2
02545|183|R|   5(2):111-8.|2
02545|184|R|22.Patakas D, Argiropoulou V, Louridas G, Tsara V. Beta-blockers in|2
02545|185|R|   bronchial asthma: effect of propranolol and pindolol on large and small|2
02545|186|R|   airways. Thorax 1983 Feb;38(2):108-12.|2
02546|001|T|MONOGRAPH TITLE:  Disopyramide/Ombitasvir-paritaprevir-ritonavir|
02546|002|B||
02546|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02546|004|L|of severe adverse interaction.|
02546|005|B||
02546|006|A|MECHANISM OF ACTION:  Ombitasvir-paritaprevir-ritonavir may inhibit the|
02546|007|A|metabolism of disopyramide at CYP3A4.(1-3)|
02546|008|B||
02546|009|E|CLINICAL EFFECTS:  Serum disopyramide concentrations may be increased,|
02546|010|E|leading to cardiac arrhythmias including QT prolongation or torsades de|
02546|011|E|pointes.|
02546|012|B||
02546|013|P|PREDISPOSING FACTORS:  Renal and hepatic impairment may increase risk for|
02546|014|P|excessive QTc prolongation as disopyramide is eliminated renally and|
02546|015|P|hepatically. To prevent increased serum levels and risk for ventricular|
02546|016|P|arrhythmias, disopyramide must be dose adjusted in renal and hepatic|
02546|017|P|insufficiency.(3)|
02546|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02546|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02546|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02546|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02546|022|P|advanced age.(4)|
02546|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02546|024|P|higher systemic concentrations of either QT prolonging drug are additional|
02546|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02546|026|P|drug concentrations include rapid infusion of an intravenous dose or|
02546|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02546|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02546|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02546|030|B||
02546|031|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with disopyramide|
02546|032|M|and ombitasvir-paritaprevir-ritonavir should be monitored for changes in|
02546|033|M|cardiac status. The dosage of disopyramide may need to be adjusted.|
02546|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02546|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02546|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02546|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02546|038|B||
02546|039|D|DISCUSSION:  There have been case reports of life-threatening cardiac|
02546|040|D|arrhythmias when other CYP3A4 inhibitors, clarithromycin and erythromycin,|
02546|041|D|were added to disopyramide.(3)|
02546|042|B||
02546|043|R|REFERENCES:|
02546|044|B||
02546|045|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02546|046|R|  prescribing information. AbbVie Inc. December, 2019.|1
02546|047|R|2.Echizen H, Tanizaki M, Tatsuno J, Chiba K, Berwick T, Tani M, Gonzalez FJ,|5
02546|048|R|  Ishizaki T. Identification of CYP3A4 as the enzyme involved in the|5
02546|049|R|  mono-N-dealkylation of disopyramide enantiomers in humans. Drug Metab|5
02546|050|R|  Dispos 2000 Aug;28(8):937-44.|5
02546|051|R|3.Norpace (disopyramide phosphate) US prescribing information. Pfizer Inc.|1
02546|052|R|  December, 2020.|1
02546|053|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02546|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02546|055|R|  settings: a scientific statement from the American Heart Association and|6
02546|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02546|057|R|  2;55(9):934-47.|6
02547|001|T|MONOGRAPH TITLE:  Ledipasvir; Velpatasvir/Proton Pump Inhibitors|
02547|002|B||
02547|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02547|004|L|of severe adverse interaction.|
02547|005|B||
02547|006|A|MECHANISM OF ACTION:  The aqueous solubility of ledipasvir and velpatasvir|
02547|007|A|is pH dependent.  Higher gastric pH leads to lower solubility which may|
02547|008|A|reduce ledipasvir and velpatasvir absorption.(1-3)|
02547|009|B||
02547|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) may|
02547|011|E|reduce the bioavailability of ledipasvir and velpatasvir, leading to|
02547|012|E|decreased systemic levels and effectiveness.(1-3)|
02547|013|B||
02547|014|P|PREDISPOSING FACTORS:  None determined.|
02547|015|B||
02547|016|M|PATIENT MANAGEMENT:  Omeprazole 20 mg daily, or comparable doses of other|
02547|017|M|PPIs, may be administered simultaneously with ledipasvir-sofosbuvir under|
02547|018|M|fasting conditions.(1)|
02547|019|M|   Coadministration of proton pump inhibitors is not recommended with|
02547|020|M|sofosbuvir-velpatasvir. When concomitant proton pump inhibitor use is|
02547|021|M|necessary in patients receiving sofosbuvir-velpatasvir,|
02547|022|M|velpatasvir-sofosbuvir should be administered with food and taken 4 hours|
02547|023|M|before omeprazole 20 mg. Use with other proton pump inhibitors has not been|
02547|024|M|studied.(2)|
02547|025|M|   Omeprazole 20 mg daily may be administered with|
02547|026|M|sofosbuvir-velpatasvir-voxilaprevir. Use with other proton pump inhibitors|
02547|027|M|has not been studied.(3)|
02547|028|M|   When clinically appropriate, consider use of H2 blockers or|
02547|029|M|antacids.(1-3)|
02547|030|B||
02547|031|D|DISCUSSION:  In an interaction study, omeprazole 20 mg given once daily|
02547|032|D|simultaneously with ledipasvir-sofosbuvir, decreased ledipasvir exposure|
02547|033|D|(AUC) by 4%. When omeprazole 20 mg once daily was given 2 hours prior to|
02547|034|D|ledipasvir-sofosbuvir dose, ledipasvir exposure (AUC) decreased|
02547|035|D|approximately 50%.(1)|
02547|036|D|   In an interaction study, omeprazole 20 mg given once daily simultaneously|
02547|037|D|with sofosbuvir-velpatasvir decreased velpatasvir exposure (AUC) by 37%.|
02547|038|D|When omeprazole 20 mg once daily was given 12 hours prior to|
02547|039|D|sofosbuvir-velpatasvir dose, velpatasvir exposure (AUC) decreased 57%. When|
02547|040|D|omeprazole 20 mg once daily was given 2 hours prior to|
02547|041|D|sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 48%. When omeprazole|
02547|042|D|20 mg once daily was given 4 hours after sofosbuvir-velpatasvir dose,|
02547|043|D|velpatasvir AUC decreased 33%. When omeprazole 40 mg once daily was given 4|
02547|044|D|hours after sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 56%.(2)|
02547|045|D|   In an interaction study, when omeprazole 20 mg once daily was given 2|
02547|046|D|hours prior to the sofosbuvir-velpatasvir-voxilaprevir dose, sofosbuvir AUC,|
02547|047|D|velpatasvir AUC, and voxilaprevir AUC decreased 27%, 54%, and 20%,|
02547|048|D|respectively.  When omeprazole 20 mg once daily was given 4 hours after the|
02547|049|D|sofosbuvir-velpatasvir-voxilaprevir dose, sofosbuvir AUC, velpatasvir AUC,|
02547|050|D|and voxilaprevir AUC decreased 18%, 51%, and 5%, respectively %.(3)|
02547|051|D|   Proton pump inhibitors linked to this monograph are: dexlansoprazole,|
02547|052|D|esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole.|
02547|053|B||
02547|054|R|REFERENCES:|
02547|055|B||
02547|056|R|1.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
02547|057|R|  Sciences November, 2019.|1
02547|058|R|2.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
02547|059|R|  Sciences, Inc. April, 2022.|1
02547|060|R|3.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02547|061|R|  Gilead Sciences, Inc. September, 2019.|1
02548|001|T|MONOGRAPH TITLE:  Vecuronium/Dexamethasone; Methylprednisolone|
02548|002|B||
02548|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02548|004|L|take action as needed.|
02548|005|B||
02548|006|A|MECHANISM OF ACTION:  The mechanism of action is not clear.|
02548|007|B||
02548|008|E|CLINICAL EFFECTS:  Concurrent use may increase the risk for critical illness|
02548|009|E|polyneuromyopathy (CIPM).|
02548|010|B||
02548|011|P|PREDISPOSING FACTORS:  Possible risk factors include: extended (> 48 hour)|
02548|012|P|duration of continuous paralysis, high dose corticosteroids, and use in|
02548|013|P|patients with septic shock.|
02548|014|B||
02548|015|M|PATIENT MANAGEMENT:  For patients receiving combination therapy, it would be|
02548|016|M|prudent to limit use of high-dose corticosteroids to conditions where the|
02548|017|M|benefit is clear, and to use vecuronium for the shortest duration possible,|
02548|018|M|preferably < 48 hours.|
02548|019|M|   When possible, avoid concomitant use of vecuronium and high-dose|
02548|020|M|corticosteroids in patients with septic shock.|
02548|021|M|   Closely monitor magnitude and duration of paralysis as per institutional|
02548|022|M|protocol.|
02548|023|B||
02548|024|D|DISCUSSION:  Although the pathophysiology of CIPM is incompletely|
02548|025|D|understood, authors generally agree that concurrent use of vecuronium and|
02548|026|D|high dose corticosteroids is associated with additive or synergistic risk|
02548|027|D|for CIPM.|
02548|028|B||
02548|029|R|REFERENCE:|
02548|030|B||
02548|031|R|1.Vecuronium bromide prescribing information. Pfizer Inc. February, 2011.|1
02549|001|T|MONOGRAPH TITLE:  Panobinostat (Greater Than 10 mg)/Strong CYP3A4 Inhibitors|
02549|002|B||
02549|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02549|004|L|is contraindicated and generally should not be dispensed or administered to|
02549|005|L|the same patient.|
02549|006|B||
02549|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02549|008|A|panobinostat.|
02549|009|B||
02549|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
02549|011|E|in elevated levels of and toxicity from panobinostat,(1) including increased|
02549|012|E|risk of bleeding and prolongation of the QT interval which may result in|
02549|013|E|life-threatening arrhythmia and death.|
02549|014|B||
02549|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02549|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02549|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02549|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02549|019|P|female gender, or advanced age.(2)|
02549|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02549|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02549|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02549|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02549|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02549|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02549|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02549|027|P|   The risk for bleeding episodes may be greater in patients with|
02549|028|P|disease-associated factors (e.g. thrombocytopenia).|
02549|029|P|   Drug associated risk factors include concurrent use of multiple drugs|
02549|030|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02549|031|P|risk for bleeding (e.g. NSAIDs).|
02549|032|B||
02549|033|M|PATIENT MANAGEMENT:  Reduce the dose of panobinostat to 10 mg when|
02549|034|M|coadministered with strong CYP3A4 inhibitors.  Limit the starting dose of|
02549|035|M|panobinostat to 10 mg in patients taking strong CYP3A4 inhibitors.(1)|
02549|036|M|   If concurrent therapy is warranted, continue standard monitoring of|
02549|037|M|complete blood counts, ECG, and serum electrolytes.  Instruct patients to|
02549|038|M|report any irregular heartbeat, dizziness, or fainting; nausea, vomiting, or|
02549|039|M|diarrhea; unusual tiredness, shortness of breath, paleness; unusual or|
02549|040|M|unexplained bleeding or bruising; signs of infection such as fever, cough,|
02549|041|M|or flu-like symptoms.  If panobinostat toxicity occurs, panobinostat or the|
02549|042|M|CYP3A4 inhibitor may need to be discontinued.(1)|
02549|043|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
02549|044|M|including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
02549|045|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02549|046|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02549|047|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02549|048|M|anticoagulation in patients with active pathologic bleeding.|
02549|049|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02549|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02549|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02549|052|M|and/or swelling.|
02549|053|B||
02549|054|D|DISCUSSION:  In 14 patients with advanced cancer, ketoconazole (a strong|
02549|055|D|CYP3A4 inhibitor, 200 mg twice daily for 14 days) increased the maximum|
02549|056|D|concentration (Cmax) and area-under-curve (AUC) of panobinostat by 62% and|
02549|057|D|73%, respectively.(1)|
02549|058|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, grapefruit,|
02549|059|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
02549|060|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
02549|061|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(1,3-4)|
02549|062|B||
02549|063|R|REFERENCES:|
02549|064|B||
02549|065|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
02549|066|R|  Pharmaceuticals Corporation June, 2016.|1
02549|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02549|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02549|069|R|  settings: a scientific statement from the American Heart Association and|6
02549|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02549|071|R|  2;55(9):934-47.|6
02549|072|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02549|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02549|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02549|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02549|076|R|  11/14/2017.|1
02549|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
02549|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02550|001|T|MONOGRAPH TITLE:  Selected CYP2D6 Substrates that Prolong QT/Panobinostat|
02550|002|B||
02550|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02550|004|L|of severe adverse interaction.|
02550|005|B||
02550|006|A|MECHANISM OF ACTION:  Panobinostat is an inhibitor of CYP2D6 and is expected|
02550|007|A|to inhibit the metabolism of agents through this pathway.(1)|
02550|008|B||
02550|009|E|CLINICAL EFFECTS:  Concurrent use of panobinostat may result in elevated|
02550|010|E|levels of and toxicity from agents metabolized by CYP2D6.(1)|
02550|011|E|  Higher systemic concentrations of QT prolonging drugs which are|
02550|012|E|metabolized by CYP2D6 may increase the risk for Torsades de Pointes.|
02550|013|B||
02550|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02550|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02550|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02550|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02550|018|P|gender, or advanced age.(3)|
02550|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02550|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02550|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02550|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02550|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02550|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02550|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02550|026|P|   With pimozide, thioridazine and tolterodine, the risk of anticholinergic|
02550|027|P|toxicities including cognitive decline, delirium, falls and fractures is|
02550|028|P|increased in geriatric patients using more than one medicine with|
02550|029|P|anticholinergic properties.(4)|
02550|030|B||
02550|031|M|PATIENT MANAGEMENT:  Avoid the concurrent use of panobinostat with agents|
02550|032|M|that are sensitive substrates of CYP2D6 (atomoxetine, deutetrabenazine,|
02550|033|M|perphenazine, prajmaline, propafenone, tetrabenazine, or tolterodine) or|
02550|034|M|CYP2D6 substrates with a narrow therapeutic index (pimozide and|
02550|035|M|thioridazine).  If concurrent use is warranted, monitor patients for|
02550|036|M|toxicity.|
02550|037|M|   If concurrent therapy with panobinostat and a CYP2D6 substrate which may|
02550|038|M|prolong the QT interval (atomoxetine, deutetrabenazine, perphenazine,|
02550|039|M|pimozide, prajmaline, thioridazine, or tolterodine) is warranted, consider|
02550|040|M|obtaining serum calcium, magnesium, and potassium levels and monitoring ECG|
02550|041|M|at baseline and at regular intervals.  Correct any electrolyte|
02550|042|M|abnormalities.  Instruct patients to report any irregular heartbeat,|
02550|043|M|dizziness, or fainting.|
02550|044|B||
02550|045|D|DISCUSSION:  In a study in 14 subjects with advanced cancer, panobinostat|
02550|046|D|(20 mg daily on Days 3, 5, and 8) increased the maximum concentration (Cmax)|
02550|047|D|and area-under-curve (AUC) of a single dose of dextromethorphan (60 mg) by|
02550|048|D|20-200% and 20-130%, respectively.  Dextromethorphan exposures were|
02550|049|D|extremely variable.(1)|
02550|050|D|   CYP2D6 substrates that are QT prolonging drugs linked to this monograph|
02550|051|D|include:  perhexiline, pimozide, prajmaline, propafenone, thioridazine, and|
02550|052|D|tolterodine.(2)|
02550|053|B||
02550|054|R|REFERENCES:|
02550|055|B||
02550|056|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
02550|057|R|  Pharmaceuticals Corporation June, 2016.|1
02550|058|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02550|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02550|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02550|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02550|062|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02550|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02550|064|R|  settings: a scientific statement from the American Heart Association and|6
02550|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02550|066|R|  2;55(9):934-47.|6
02550|067|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02550|068|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02550|069|R|  Soc 2023 Jul;71(7):2052-2081.|6
02550|070|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02550|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02550|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02550|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02550|074|R|  11/14/2017.|1
02551|001|T|MONOGRAPH TITLE:  Edoxaban/Anticoagulants; Thrombolytics|
02551|002|B||
02551|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02551|004|L|is contraindicated and generally should not be dispensed or administered to|
02551|005|L|the same patient.|
02551|006|B||
02551|007|A|MECHANISM OF ACTION:  Additive effects on hemostasis.|
02551|008|B||
02551|009|E|CLINICAL EFFECTS:  Concurrent use of edoxaban with anticoagulants or|
02551|010|E|thrombolytics may increase the risk of bleeding.|
02551|011|B||
02551|012|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with renal|
02551|013|P|impairment and in patients > 75 years of age.  Use of multiple agents which|
02551|014|P|affect hemostasis increases the risk for bleeding.|
02551|015|B||
02551|016|M|PATIENT MANAGEMENT:  The long-term use of concurrent therapy with direct|
02551|017|M|oral anticoagulants (DOACs) and other anticoagulants is generally considered|
02551|018|M|contraindicated.  However, overlap may be necessary when switching therapy|
02551|019|M|from one agent to another in order to prevent thrombotic events.|
02551|020|M|Manufacturer recommendations concerning overlap (if any) and timing of|
02551|021|M|discontinuation versus initiation vary depending upon which agent is being|
02551|022|M|discontinued and initiated.  Refer to current prescribing information for|
02551|023|M|both agents for additional details.|
02551|024|M|   Specific recommendations for converting between anticoagulants:|
02551|025|M|   - When converting from other (non-vitamin K antagonist) oral|
02551|026|M|anticoagulants to edoxaban, discontinue current oral anticoagulant and start|
02551|027|M|edoxaban at the time of the next scheduled dose of the old oral|
02551|028|M|anticoagulant.|
02551|029|M|   - When converting from a low molecular weight heparin (LMWH) to edoxaban,|
02551|030|M|start edoxaban at the time of the next scheduled administration of LMWH.|
02551|031|M|   - When converting from unfractionated heparin to edoxaban, discontinue|
02551|032|M|the infusion and start edoxaban 4 hours later.|
02551|033|M|   - When converting from edoxaban to another DOAC, discontinue edoxaban and|
02551|034|M|begin the new oral anticoagulant at the time of the next scheduled dose of|
02551|035|M|edoxaban.|
02551|036|M|   - When converting from edoxaban to parenteral anticoagulation, start the|
02551|037|M|parenteral anticoagulant at the time of the next dose of edoxaban.|
02551|038|M|   - When converting from warfarin to edoxaban, discontinue warfarin and|
02551|039|M|start edoxaban when the INR is < or = to 2.5.|
02551|040|M|   - When converting from edoxaban to warfarin, for patients taking 60 mg of|
02551|041|M|edoxaban, reduce the dose to 30 mg and begin warfarin concomitantly.  For|
02551|042|M|patients receiving 30 mg of edoxaban, reduce the dose to 15 mg and begin|
02551|043|M|warfarin concomitantly.  INR must be measured at least weekly and just prior|
02551|044|M|to the daily dose of edoxaban to minimize the effects of edoxaban on INR|
02551|045|M|measurement.  Once a stable INR = or > 2.0 is achieved, edoxaban should be|
02551|046|M|discontinued and the warfarin continued.|
02551|047|M|   - A second edoxaban to warfarin conversion option:  Discontinue edoxaban|
02551|048|M|and administer a parenteral anticoagulant and warfarin at the time of the|
02551|049|M|next scheduled edoxaban dose. Once a stable INR = or > 2.0 is achieved, the|
02551|050|M|parenteral anticoagulant should be discontinued and the warfarin continued.|
02551|051|M|   The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and|
02551|052|M|thrombolytics is generally considered contraindicated.|
02551|053|M|   The manufacturer of alteplase states that the use of alteplase for an|
02551|054|M|indication of acute ischemic stroke is contraindicated in patients receiving|
02551|055|M|anticoagulants.  Concurrent use of alteplase and anticoagulants is dependent|
02551|056|M|on the therapeutic indication.|
02551|057|M|   In Acute Ischemic Stroke:|
02551|058|M|   - Clinical practice guidelines for acute ischemic stroke state the use of|
02551|059|M|thrombolytic therapy for an indication of acute ischemic stroke is|
02551|060|M|contraindicated in patients who have received thrombin inhibitors or factor|
02551|061|M|Xa inhibitors in the previous 48 hours (in normal renal function) and have|
02551|062|M|abnormal laboratory tests such as activated partial thromboplastin time|
02551|063|M|(aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or|
02551|064|M|direct factor Xa assays at presentation.|
02551|065|M|   In Acute Myocardial Infarction:|
02551|066|M|   - Patients who are receiving thrombolytics for an indication of acute|
02551|067|M|myocardial infarction should be carefully monitored for signs of bleeding,|
02551|068|M|especially at arterial puncture sites, if edoxaban is used concurrently.|
02551|069|M|   - The use of thrombolytics in patients with acute myocardial infarction|
02551|070|M|should follow standard management of myocardial infarction, including|
02551|071|M|minimizing arterial and venous puncture; avoid noncompressible arterial|
02551|072|M|puncture; and minimize internal jugular and subclavian venous punctures to|
02551|073|M|decrease bleeding from the noncompressible sites.|
02551|074|M|   For all indications:|
02551|075|M|   - In the event of serious bleeding, anticoagulants should be discontinued|
02551|076|M|immediately.|
02551|077|M|   - If concurrent therapy is warranted, monitor patients receiving|
02551|078|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
02551|079|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
02551|080|M|evaluate patients with any symptoms.|
02551|081|M|   - When applicable, perform agent-specific laboratory test (e.g. INR,|
02551|082|M|aPTT) to monitor efficacy and safety of anticoagulation.  Discontinue|
02551|083|M|anticoagulation in patients with active pathologic bleeding.|
02551|084|M|   - Instruct patients to report any signs and symptoms of bleeding, such as|
02551|085|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02551|086|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02551|087|M|and/or swelling.|
02551|088|B||
02551|089|D|DISCUSSION:  Limited overlap of DOACs with other anticoagulants may be|
02551|090|D|required when initiating or discontinuing DOACs in order to prevent|
02551|091|D|thrombotic events.  However, long-term concomitant treatment is not|
02551|092|D|recommended because of increased risk of bleeding.|
02551|093|D|   Patients who are receiving thrombolytics should be carefully monitored|
02551|094|D|for signs of bleeding if anticoagulants are being used concurrently or have|
02551|095|D|recently been used.|
02551|096|B||
02551|097|R|REFERENCES:|
02551|098|B||
02551|099|R|1.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02551|100|R|  2019.|1
02551|101|R|2.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
02551|102|R|  Sankyo UK Limited July 2, 2015.|1
02551|103|R|3.Lixiana (edoxaban) Canadian product monograph. Servier Canada Inc.|1
02551|104|R|  February, 2023.|1
02551|105|R|4.Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC. Guidelines|6
02551|106|R|  for the Early Management of Patients With Acute Ischemic Stroke: 2019|6
02551|107|R|  Update to the 2018 Guidelines for the Early Management of Acute Ischemic|6
02551|108|R|  Stroke:  A Guideline for Healthcare Professionals From the AHA/ASA. Stroke|6
02551|109|R|  2019 Dec;50(12):e344-e418.|6
02552|001|T|MONOGRAPH TITLE:  Apixaban/Anticoagulants; Thrombolytics|
02552|002|B||
02552|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02552|004|L|is contraindicated and generally should not be dispensed or administered to|
02552|005|L|the same patient.|
02552|006|B||
02552|007|A|MECHANISM OF ACTION:  Additive effects on hemostasis.|
02552|008|B||
02552|009|E|CLINICAL EFFECTS:  Concurrent use of apixaban with anticoagulants or|
02552|010|E|thrombolytics may increase the risk of bleeding.|
02552|011|B||
02552|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02552|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02552|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
02552|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02552|016|P|risk for bleeding (e.g. NSAIDs).|
02552|017|B||
02552|018|M|PATIENT MANAGEMENT:  The long-term use of concurrent therapy with direct|
02552|019|M|oral anticoagulants (DOACs) and other anticoagulants is generally considered|
02552|020|M|contraindicated.  However, overlap may be necessary when switching therapy|
02552|021|M|from one agent to another in order to prevent thrombotic events.|
02552|022|M|Manufacturer recommendations concerning overlap (if any) and timing of|
02552|023|M|discontinuation versus initiation vary depending upon which agent is being|
02552|024|M|discontinued and initiated.  Refer to current prescribing information for|
02552|025|M|both agents for additional details.|
02552|026|M|   Specific recommendations for converting between anticoagulants:|
02552|027|M|   - When converting between apixaban and anticoagulants other than|
02552|028|M|warfarin, discontinue the current anticoagulant and begin the new one when|
02552|029|M|next dose is due.|
02552|030|M|   - When converting from warfarin to apixaban, discontinue warfarin and|
02552|031|M|begin apixaban when the international normalized ratio (INR) is below 2.0.|
02552|032|M|   - Apixaban affects INR.  Therefore concurrent administration with|
02552|033|M|warfarin when converting from apixaban to warfarin is not useful in|
02552|034|M|determining target warfarin dose.  If continuous anticoagulation is|
02552|035|M|warranted, discontinue apixaban and begin both warfarin and a parenteral|
02552|036|M|anticoagulant when next dose of apixaban is due.  Once INR is within range,|
02552|037|M|discontinue the parenteral anticoagulant.|
02552|038|M|   The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and|
02552|039|M|thrombolytics is generally considered contraindicated.|
02552|040|M|   The manufacturer of alteplase states that the use of alteplase for an|
02552|041|M|indication of acute ischemic stroke is contraindicated in patients receiving|
02552|042|M|anticoagulants.  Concurrent use of alteplase and anticoagulants is dependent|
02552|043|M|on the therapeutic indication.|
02552|044|M|   In Acute Ischemic Stroke:|
02552|045|M|   - Clinical practice guidelines for acute ischemic stroke state the use of|
02552|046|M|thrombolytic therapy for an indication of acute ischemic stroke is|
02552|047|M|contraindicated in patients who have received thrombin inhibitors or factor|
02552|048|M|Xa inhibitors in the previous 48 hours (in normal renal function) and have|
02552|049|M|abnormal laboratory tests such as activated partial thromboplastin time|
02552|050|M|(aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or|
02552|051|M|direct factor Xa assays at presentation.|
02552|052|M|   In Acute Myocardial Infarction:|
02552|053|M|   - Patients who are receiving thrombolytics for an indication of acute|
02552|054|M|myocardial infarction should be carefully monitored for signs of bleeding,|
02552|055|M|especially at arterial puncture sites, if apixaban is used concurrently.|
02552|056|M|   - The use of thrombolytics in patients with acute myocardial infarction|
02552|057|M|should follow standard management of myocardial infarction, including|
02552|058|M|minimizing arterial and venous puncture; avoid noncompressible arterial|
02552|059|M|puncture; and minimize internal jugular and subclavian venous punctures to|
02552|060|M|decrease bleeding from the noncompressible sites.|
02552|061|M|   For all indications:|
02552|062|M|   - In the event of serious bleeding, anticoagulants should be discontinued|
02552|063|M|immediately.|
02552|064|M|   - If concurrent therapy is warranted, monitor patients receiving|
02552|065|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
02552|066|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
02552|067|M|evaluate patients with any symptoms.|
02552|068|M|   - When applicable, perform agent-specific laboratory test (e.g. INR,|
02552|069|M|aPTT) to monitor efficacy and safety of anticoagulation.  Discontinue|
02552|070|M|anticoagulation in patients with active pathologic bleeding.|
02552|071|M|   - Instruct patients to report any signs and symptoms of bleeding, such as|
02552|072|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02552|073|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02552|074|M|and/or swelling.|
02552|075|B||
02552|076|D|DISCUSSION:  Limited overlap of DOACs with other anticoagulants may be|
02552|077|D|required when initiating or discontinuing DOACs in order to prevent|
02552|078|D|thrombotic events.  However, long-term concomitant treatment is not|
02552|079|D|recommended because of increased risk of bleeding.|
02552|080|D|   Patients who are receiving thrombolytics should be carefully monitored|
02552|081|D|for signs of bleeding if anticoagulants are being used concurrently or have|
02552|082|D|recently been used.|
02552|083|B||
02552|084|R|REFERENCES:|
02552|085|B||
02552|086|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
02552|087|R|  Squibb Australia Pty. Ltd. January, 2024.|1
02552|088|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
02552|089|R|  Squibb-Pfizer January, 2025.|1
02552|090|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
02552|091|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
02552|092|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
02552|093|R|  Company April, 2025.|1
02552|094|R|5.Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC. Guidelines|6
02552|095|R|  for the Early Management of Patients With Acute Ischemic Stroke: 2019|6
02552|096|R|  Update to the 2018 Guidelines for the Early Management of Acute Ischemic|6
02552|097|R|  Stroke:  A Guideline for Healthcare Professionals From the AHA/ASA. Stroke|6
02552|098|R|  2019 Dec;50(12):e344-e418.|6
02553|001|T|MONOGRAPH TITLE:  Dabigatran/Anticoagulants; Thrombolytics|
02553|002|B||
02553|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02553|004|L|is contraindicated and generally should not be dispensed or administered to|
02553|005|L|the same patient.|
02553|006|B||
02553|007|A|MECHANISM OF ACTION:  Dabigatran is a direct thrombin inhibitor.  When taken|
02553|008|A|with agents that affect clotting factors, increased bleeding episodes can|
02553|009|A|occur.|
02553|010|B||
02553|011|E|CLINICAL EFFECTS:  Concurrent use of dabigatran with anticoagulants or|
02553|012|E|thrombolytics may result in additive or synergistic effects resulting in|
02553|013|E|unwanted bleeding episodes.|
02553|014|B||
02553|015|P|PREDISPOSING FACTORS:  Factors associated with an increase risk for bleeding|
02553|016|P|include renal impairment, concomitant use of P-glycoprotein inhibitors,|
02553|017|P|patient age >74 years, coexisting conditions (e.g. recent trauma) or use of|
02553|018|P|drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight <50|
02553|019|P|kg.(1-3)|
02553|020|P|   The risk for bleeding episodes may be greater in patients with|
02553|021|P|disease-associated factors (e.g. thrombocytopenia).|
02553|022|P|   Drug associated risk factors include concurrent use of multiple drugs|
02553|023|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02553|024|P|risk for bleeding (e.g. NSAIDs).|
02553|025|B||
02553|026|M|PATIENT MANAGEMENT:  The long-term use of concurrent therapy with direct|
02553|027|M|oral anticoagulants (DOACs) and other anticoagulants is generally considered|
02553|028|M|contraindicated.  However, overlap may be necessary when switching therapy|
02553|029|M|from one agent to another in order to prevent thrombotic events.|
02553|030|M|Manufacturer recommendations concerning overlap (if any) and timing of|
02553|031|M|discontinuation versus initiation vary depending upon which agent is being|
02553|032|M|discontinued and initiated.  Refer to current prescribing information for|
02553|033|M|both agents for additional details.|
02553|034|M|   Specific recommendations for converting between anticoagulants:|
02553|035|M|   - When converting from parenteral anticoagulants to dabigatran,|
02553|036|M|administer dabigatran 0-2 hours before the next dose of the parenteral drug|
02553|037|M|is due.|
02553|038|M|   - When converting from dabigatran to a parenteral anticoagulant in|
02553|039|M|adults, begin parenteral anticoagulant:|
02553|040|M|   --12 hours after last dose of dabigatran in patients with CrCl greater|
02553|041|M|than or equal to 30 ml/min,|
02553|042|M|   --24 hours after last dose of dabigatran in patients with CrCl less than|
02553|043|M|30 ml/min.|
02553|044|M|   - When converting from dabigatran to a parenteral anticoagulant in|
02553|045|M|pedatrics, begin the parenteral anticoagulant 12 hours after the last dose|
02553|046|M|of dabigatran.|
02553|047|M|   - When converting from warfarin to dabigatran, discontinue warfarin and|
02553|048|M|begin dabigatran when the patient's INR is below 2.0.|
02553|049|M|   - When converting from dabigatran to warfarin in adults, start warfarin:|
02553|050|M|   --3 days before discontinuing dabigatran in patients with CrCl greater|
02553|051|M|than 50 ml/min,|
02553|052|M|   --2 days before discontinuing dabigatran in patients with CrCl of 30|
02553|053|M|ml/min to 50 ml/min,|
02553|054|M|   --1 day before discontinuing dabigatran in patients with CrCl of 15|
02553|055|M|ml/min to 30 ml/min.|
02553|056|M|   --There is no recommendation available for converting dabigatran to|
02553|057|M|warfarin in patients with CrCl less than 15 ml/min.|
02553|058|M|   - When converting from dabigatran to warfarin in pediatrics, start|
02553|059|M|warfarin:|
02553|060|M|   --3 days before discontinuing dabigatran in patient with eGFR >= 50|
02553|061|M|ml/min/1.73 m2.|
02553|062|M|   --There is no data on using dabigatran in pediatric patients with eGFR <|
02553|063|M|50 ml/min/1.73 m2.|
02553|064|M|   - Dabigatran affects INR.  Therefore the INR will better reflect|
02553|065|M|warfarin's effect only after stopping dabigatran for at least 2 days.|
02553|066|M|   The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and|
02553|067|M|thrombolytics is generally considered contraindicated.|
02553|068|M|   The manufacturer of alteplase states that the use of alteplase for an|
02553|069|M|indication of acute ischemic stroke is contraindicated in patients receiving|
02553|070|M|anticoagulants.  Concurrent use of alteplase and anticoagulants is dependent|
02553|071|M|on the therapeutic indication.|
02553|072|M|   In Acute Ischemic Stroke:|
02553|073|M|   - Clinical practice guidelines for acute ischemic stroke state the use of|
02553|074|M|thrombolytic therapy for an indication of acute ischemic stroke is|
02553|075|M|contraindicated in patients who have received thrombin inhibitors or factor|
02553|076|M|Xa inhibitors in the previous 48 hours (in normal renal function) and have|
02553|077|M|abnormal laboratory tests such as activated partial thromboplastin time|
02553|078|M|(aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or|
02553|079|M|direct factor Xa assays at presentation.|
02553|080|M|   In Acute Myocardial Infarction:|
02553|081|M|   - Patients who are receiving thrombolytics for an indication of acute|
02553|082|M|myocardial infarction should be carefully monitored for signs of bleeding,|
02553|083|M|especially at arterial puncture sites, if dabigatran is used concurrently.|
02553|084|M|   - The use of thrombolytics in patients with acute myocardial infarction|
02553|085|M|should follow standard management of myocardial infarction, including|
02553|086|M|minimizing arterial and venous puncture; avoid noncompressible arterial|
02553|087|M|puncture; and minimize internal jugular and subclavian venous punctures to|
02553|088|M|decrease bleeding from the noncompressible sites.|
02553|089|M|   For all indications:|
02553|090|M|   - In the event of serious bleeding, anticoagulants should be discontinued|
02553|091|M|immediately.|
02553|092|M|   - If concurrent therapy is warranted, monitor patients receiving|
02553|093|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
02553|094|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
02553|095|M|evaluate patients with any symptoms.|
02553|096|M|   - When applicable, perform agent-specific laboratory test (e.g. INR,|
02553|097|M|aPTT) to monitor efficacy and safety of anticoagulation.  Discontinue|
02553|098|M|anticoagulation in patients with active pathologic bleeding.|
02553|099|M|   - Instruct patients to report any signs and symptoms of bleeding, such as|
02553|100|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02553|101|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02553|102|M|and/or swelling.|
02553|103|B||
02553|104|D|DISCUSSION:  Patients who are receiving thrombolytics should be carefully|
02553|105|D|monitored for signs of bleeding if anticoagulants are being used|
02553|106|D|concurrently or have recently been used.|
02553|107|B||
02553|108|R|REFERENCES:|
02553|109|B||
02553|110|R|1.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
02553|111|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
02553|112|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
02553|113|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
02553|114|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
02553|115|R|  Boehringer Ingelheim March, 23 2020.|1
02553|116|R|4.Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC. Guidelines|6
02553|117|R|  for the Early Management of Patients With Acute Ischemic Stroke: 2019|6
02553|118|R|  Update to the 2018 Guidelines for the Early Management of Acute Ischemic|6
02553|119|R|  Stroke:  A Guideline for Healthcare Professionals From the AHA/ASA. Stroke|6
02553|120|R|  2019 Dec;50(12):e344-e418.|6
02554|001|T|MONOGRAPH TITLE:  Rivaroxaban/Anticoagulants; Thrombolytics|
02554|002|B||
02554|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02554|004|L|is contraindicated and generally should not be dispensed or administered to|
02554|005|L|the same patient.|
02554|006|B||
02554|007|A|MECHANISM OF ACTION:  Additive effects on hemostasis.|
02554|008|B||
02554|009|E|CLINICAL EFFECTS:  Concurrent use of rivaroxaban with anticoagulants or|
02554|010|E|thrombolytics may increase the risk of bleeding.|
02554|011|B||
02554|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02554|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02554|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
02554|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02554|016|P|risk for bleeding (e.g. NSAIDs).|
02554|017|B||
02554|018|M|PATIENT MANAGEMENT:  The long-term use of concurrent therapy with direct|
02554|019|M|oral anticoagulants (DOACs) and other anticoagulants is generally considered|
02554|020|M|contraindicated.  However, overlap may be necessary when switching therapy|
02554|021|M|from one agent to another in order to prevent thrombotic events.|
02554|022|M|Manufacturer recommendations concerning overlap (if any) and timing of|
02554|023|M|discontinuation versus initiation vary depending upon which agent is being|
02554|024|M|discontinued and initiated.  Refer to current prescribing information for|
02554|025|M|both agents for additional details.|
02554|026|M|   Specific recommendations for converting between anticoagulants:|
02554|027|M|   - When converting from rivaroxaban to anticoagulants other than warfarin|
02554|028|M|and switching to an anticoagulant with rapid onset, discontinue rivaroxaban|
02554|029|M|and begin new anticoagulant when next dose of rivaroxaban is due.|
02554|030|M|   - When converting from anticoagulants other than warfarin to rivaroxaban,|
02554|031|M|discontinue current anticoagulant and begin rivaroxaban between 0-2 hours|
02554|032|M|before next evening dose of the drug is due. For patients receiving|
02554|033|M|continuous infusion of unfractionated heparin, simultaneously stop the|
02554|034|M|infusion and administer rivaroxaban.|
02554|035|M|   - When converting from warfarin to rivaroxaban, discontinue warfarin and|
02554|036|M|begin rivaroxaban once international normalized ratio (INR) is below 3.0 in|
02554|037|M|adults and below 2.5 in pediatric patients.|
02554|038|M|   - When converting from rivaroxaban to warfarin in adults, rivaroxaban|
02554|039|M|affects INR.  Therefore concurrent administration with warfarin is not|
02554|040|M|useful in determining target warfarin dose.  If continuous anticoagulation|
02554|041|M|is warranted, discontinue rivaroxaban and begin both warfarin and a|
02554|042|M|parenteral anticoagulant when the next dose of rivaroxaban is due.  Once INR|
02554|043|M|is within range, discontinue the parenteral anticoagulant.|
02554|044|M|   - When converting from rivaroxaban to warfarin in pediatrics, continue|
02554|045|M|rivaroxaban for at least 2 days after the first dose of warfarin.  After two|
02554|046|M|days, INR should be measured just prior to the next scheduled dose of|
02554|047|M|rivaroxaban.  Once a stable INR = or > 2.0 is achieved, rivaroxaban should|
02554|048|M|be discontinued and warfarin continued.|
02554|049|M|   The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and|
02554|050|M|thrombolytics is generally considered contraindicated.|
02554|051|M|   The manufacturer of alteplase states that the use of alteplase for an|
02554|052|M|indication of acute ischemic stroke is contraindicated in patients receiving|
02554|053|M|anticoagulants.  Concurrent use of alteplase and anticoagulants is dependent|
02554|054|M|on the therapeutic indication.|
02554|055|M|   In Acute Ischemic Stroke:|
02554|056|M|   - Clinical practice guidelines for acute ischemic stroke state the use of|
02554|057|M|thrombolytic therapy for an indication of acute ischemic stroke is|
02554|058|M|contraindicated in patients who have received thrombin inhibitors or factor|
02554|059|M|Xa inhibitors in the previous 48 hours (in normal renal function) and have|
02554|060|M|abnormal laboratory tests such as activated partial thromboplastin time|
02554|061|M|(aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or|
02554|062|M|direct factor Xa assays at presentation.|
02554|063|M|   In Acute Myocardial Infarction:|
02554|064|M|   - Patients who are receiving thrombolytics for an indication of acute|
02554|065|M|myocardial infarction should be carefully monitored for signs of bleeding,|
02554|066|M|especially at arterial puncture sites, if rivaroxaban is used concurrently.|
02554|067|M|   - The use of thrombolytics in patients with acute myocardial infarction|
02554|068|M|should follow standard management of myocardial infarction, including|
02554|069|M|minimizing arterial and venous puncture; avoid noncompressible arterial|
02554|070|M|puncture; and minimize internal jugular and subclavian venous punctures to|
02554|071|M|decrease bleeding from the noncompressible sites.|
02554|072|M|   For all indications:|
02554|073|M|   - In the event of serious bleeding, anticoagulants should be discontinued|
02554|074|M|immediately.|
02554|075|M|   - If concurrent therapy is warranted, monitor patients receiving|
02554|076|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
02554|077|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
02554|078|M|evaluate patients with any symptoms.|
02554|079|M|   - When applicable, perform agent-specific laboratory test (e.g. INR,|
02554|080|M|aPTT) to monitor efficacy and safety of anticoagulation.  Discontinue|
02554|081|M|anticoagulation in patients with active pathologic bleeding.|
02554|082|M|   - Instruct patients to report any signs and symptoms of bleeding, such as|
02554|083|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02554|084|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02554|085|M|and/or swelling.|
02554|086|B||
02554|087|D|DISCUSSION:  Patients who are receiving thrombolytics should be carefully|
02554|088|D|monitored for signs of bleeding if anticoagulants are being used|
02554|089|D|concurrently or have recently been used.|
02554|090|B||
02554|091|R|REFERENCES:|
02554|092|B||
02554|093|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
02554|094|R|  Inc. March, 2020.|1
02554|095|R|2.Xarelto (rivaroxaban) Australian prescribing information. BAYER AUSTRALIA|1
02554|096|R|  LTD December, 2022.|1
02554|097|R|3.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
02554|098|R|  2015.|1
02554|099|R|4.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
02554|100|R|  August, 2021.|1
02554|101|R|5.Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC. Guidelines|6
02554|102|R|  for the Early Management of Patients With Acute Ischemic Stroke: 2019|6
02554|103|R|  Update to the 2018 Guidelines for the Early Management of Acute Ischemic|6
02554|104|R|  Stroke:  A Guideline for Healthcare Professionals From the AHA/ASA. Stroke|6
02554|105|R|  2019 Dec;50(12):e344-e418.|6
02556|001|T|MONOGRAPH TITLE:  Abiraterone/Strong CYP3A4 Inducers|
02556|002|B||
02556|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02556|004|L|of severe adverse interaction.|
02556|005|B||
02556|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02556|007|A|abiraterone.(1)|
02556|008|B||
02556|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
02556|010|E|may result in decreased levels and effectiveness of abiraterone.(1)|
02556|011|B||
02556|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02556|013|P|of the inducer for longer than 1-2 weeks.|
02556|014|B||
02556|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
02556|016|M|abiraterone.(1)  Consider the use of agents with no or minimal induction|
02556|017|M|potential if possible.  Monitor patients for decreased response to therapy.|
02556|018|M|   If concurrent administration of abiraterone and a strong CYP3A4 inducers|
02556|019|M|is required, increase the dosing frequency of abiraterone from once daily to|
02556|020|M|twice daily during the co-administration period.  If the strong inducer is|
02556|021|M|discontinued, reduce the dose of abiraterone back to the previous dose and|
02556|022|M|frequency.(1)|
02556|023|B||
02556|024|D|DISCUSSION:  In a drug interaction trial, concurrent administration of|
02556|025|D|rifampin, a strong CYP3A4 inducer, decreased abiraterone levels by 55%.(1)|
02556|026|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
02556|027|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02556|028|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02556|029|D|rifapentine, and St. John's wort.(2,3)|
02556|030|B||
02556|031|R|REFERENCES:|
02556|032|B||
02556|033|R|1.Zytiga (abiraterone acetate) US prescribing information. Centocor Ortho|1
02556|034|R|  Biotech, Inc. October, 2020.|1
02556|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02556|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02556|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02556|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02556|039|R|  11/14/2017.|1
02556|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
02556|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02557|001|T|MONOGRAPH TITLE:  Trastuzumab Emtansine/Strong CYP3A4 Inhibitors|
02557|002|B||
02557|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02557|004|L|of severe adverse interaction.|
02557|005|B||
02557|006|A|MECHANISM OF ACTION:  Trastuzumab emtansine is a conjugate of trastuzumab|
02557|007|A|and emtansine, a complex of MCC-DM1.  DM1 is a microtubule inhibitor and is|
02557|008|A|metabolized by CYP3A4.  Strong inhibitors of CYP3A4 are expected to inhibit|
02557|009|A|the metabolism of DM1.(1-4)|
02557|010|B||
02557|011|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 are|
02557|012|E|expected to increase exposure to and toxicity from DM1, an active metabolite|
02557|013|E|of trastuzumab emtansine, including hepatotoxicity, pneumonitis, hemorrhage,|
02557|014|E|thrombocytopenia, or neurotoxicity.(1-4)|
02557|015|B||
02557|016|P|PREDISPOSING FACTORS:  None determined.|
02557|017|B||
02557|018|M|PATIENT MANAGEMENT:  The US, UK, and Canadian manufacturers recommend|
02557|019|M|avoiding the use of strong CYP3A4 inhibitors in patients undergoing therapy|
02557|020|M|with trastuzumab emtansine.  Consider alternatives with no or minimal enzyme|
02557|021|M|inhibition.(1-4)|
02557|022|M|   If concurrent use with trastuzumab emtansine is unavoidable, consider|
02557|023|M|delaying trastuzumab emtansine treatment until the strong CYP3A4 inhibitor|
02557|024|M|has cleared from circulation (approximately 3 half-lives of the inhibitor).|
02557|025|M|If strong CYP3A4 inhibitors are used concurrently with trastuzumab|
02557|026|M|emtansine, patients should be closely monitored for toxicity.(1-3)|
02557|027|M|   The Australian manufacturer recommends patients receiving strong CYP3A4|
02557|028|M|inhibitors concomitantly with trastuzumab emtansine should be closely|
02557|029|M|monitored for adverse reactions.(4)|
02557|030|B||
02557|031|D|DISCUSSION:  Trastuzumab emtansine is a conjugate of trastuzumab and|
02557|032|D|emtansine, a complex of MCC-DM1.  DM1 is a microtubule inhibitor.  In vitro|
02557|033|D|studies in human liver microsomes indicate that DM1 is metabolized by CYP3A4|
02557|034|D|and inhibition of this isoenzyme is expected to result in elevated levels of|
02557|035|D|and toxicity from DM1.(1-4)|
02557|036|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02557|037|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
02557|038|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
02557|039|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
02557|040|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
02557|041|D|tucatinib, and voriconazole.(5,6)|
02557|042|B||
02557|043|R|REFERENCES:|
02557|044|B||
02557|045|R|1.Kadcyla (ado-trastuzumab emtansine) US prescribing information. Genentech,|1
02557|046|R|  Inc. September, 2020.|1
02557|047|R|2.Kadcyla (trastuzumab emtansine) UK prescribing information. Roche Products|1
02557|048|R|  Limited. May 2025.|1
02557|049|R|3.Kadcyla (trastuzumab emtansine) Canadian prescribing information.|1
02557|050|R|  Hoffmann-La Roche Limited. October 2022.|1
02557|051|R|4.Kadcyla (trastuzumab emtansine) AU prescribing information. Roche Products|1
02557|052|R|  Pty Limited. July 2022.|1
02557|053|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02557|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02557|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02557|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02557|057|R|  11/14/2017.|1
02557|058|R|6.This information is based on an extract from the Certara Drug Interaction|6
02557|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02559|001|T|MONOGRAPH TITLE:  Ethyl Alcohol/Varenicline|
02559|002|B||
02559|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02559|004|L|take action as needed.|
02559|005|B||
02559|006|A|MECHANISM OF ACTION:  The mechanism of this interaction has not been|
02559|007|A|described.|
02559|008|B||
02559|009|E|CLINICAL EFFECTS:  Concurrent use of varenicline and alcohol-containing|
02559|010|E|products may result in increased intoxicating effects of alcohol, aggressive|
02559|011|E|behavior and/or amnesia.(1)|
02559|012|B||
02559|013|P|PREDISPOSING FACTORS:  None determined.|
02559|014|B||
02559|015|M|PATIENT MANAGEMENT:  Patients should be advised that varenicline can change|
02559|016|M|the way they react to alcohol.  Case reports have described decreased|
02559|017|M|alcohol tolerance, sometimes associated with aggressive behavior and/or|
02559|018|M|amnesia with alcohol consumption which was previously tolerated.|
02559|019|M|   Patients and providers should be aware of unsuspected sources of alcohol|
02559|020|M|such as medications.  Reduce the use of non-essential alcohol containing|
02559|021|M|drugs (e.g. cough and cold products) when possible.|
02559|022|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
02559|023|M|   - The quantity of alcohol in paclitaxel injection formulations|
02559|024|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
02559|025|M|dose contains approximately 13 grams of alcohol.|
02559|026|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
02559|027|M|3-fold depending upon the manufacturer. FDA data on alcohol content (2):|
02559|028|M|   Product                      Manufacturer           Alcohol/200 mg dose|
02559|029|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
02559|030|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
02559|031|M|   Docetaxel Inj.               Accord                  4.0 grams|
02559|032|M|   Taxotere-one vial            Sanofi                  4.0 grams|
02559|033|M|    formulation|
02559|034|M|   Docetaxel Inj.               Hospira                 3.7 grams|
02559|035|M|   Docefrez                     Sun Pharma              2.9 grams|
02559|036|M|   Taxotere-two vial            Sanofi                  2.0 grams|
02559|037|M|    formulation|
02559|038|M|   - For comparison, the US National Institute on Alcohol Abuse and|
02559|039|M|Alcoholism definition of a Standard Drink (e.g. 12oz of 5% beer, 5oz of 12%|
02559|040|M|wine) contains 14 grams of alcohol.|
02559|041|B||
02559|042|D|DISCUSSION:  A search of the FDA Adverse Event Reporting System (FAERS)|
02559|043|D|identified 48 cases of adverse events due to the combination of varenicline|
02559|044|D|and alcohol.(1)|
02559|045|D|   Aggressive behavior was described in 37 cases. In these cases, the amount|
02559|046|D|of alcohol consumed was insufficient to explain the event. More than half of|
02559|047|D|the patients involved described their behavior as a significant change from|
02559|048|D|their behavior prior to varenicline treatment. In 16 of the 37 cases,|
02559|049|D|patients reported no or impaired memory of the event; most of these cases|
02559|050|D|were also associated with physical harm to a person and/or property.|
02559|051|D|   Decreased alcohol tolerance was observed in 11 cases in patients who|
02559|052|D|consumed quantities of alcohol which previously did not cause adverse|
02559|053|D|effects.  Outcomes included an automobile accident leading to arrest and a|
02559|054|D|significant facial injury.  Most of the patients in these cases described|
02559|055|D|poor memory of their experience.|
02559|056|B||
02559|057|R|REFERENCES:|
02559|058|B||
02559|059|R|1.US Food and Drug Administration (FDA). FDA updates label for stop smoking|1
02559|060|R|  drug Chantix (varenicline) to include potential alcohol interaction, rare|1
02559|061|R|  risk of seizures, and studies of side effects on mood, behavior, or|1
02559|062|R|  thinking. available at:|1
02559|063|R|  http://www.fda.gov/Drugs/DrugSafety/ucm436494.htm?source=govdelivery&utm_m|1
02559|064|R|  edium=email&utm_source=govdelivery March 9, 2015.|1
02559|065|R|2.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
02559|066|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
02559|067|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02559|068|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
02559|069|R|  20, 2014.|1
02560|001|T|MONOGRAPH TITLE:  Selected Quinolones/Selected Class IA & III|
02560|002|T|Antiarrhythmics|
02560|003|B||
02560|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02560|005|L|of severe adverse interaction.|
02560|006|B||
02560|007|A|MECHANISM OF ACTION:  Unknown.  Possibly additive or synergistic effects on|
02560|008|A|the QTc interval.(1-7)  Proposed mechanisms for this interaction may stem|
02560|009|A|from quinolone inhibition of hepatic cytochromes and/or competitive|
02560|010|A|inhibition of renal elimination via active tubular secretion.(2-7)|
02560|011|A|Norfloxacin is a moderate CYP3A4 inhibitor. Amiodarone, disopyramide, and|
02560|012|A|dronedarone are CYP3A4 substrates.|
02560|013|B||
02560|014|E|CLINICAL EFFECTS:  Increased QTc intervals which may result in potentially|
02560|015|E|life-threatening arrhythmias such as torsades de pointes.|
02560|016|B||
02560|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02560|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
02560|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02560|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02560|021|P|female gender, or advanced age.(1)|
02560|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02560|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02560|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02560|025|P|drug concentrations include rapid infusion of an intravenous dose or|
02560|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02560|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02560|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02560|029|B||
02560|030|M|PATIENT MANAGEMENT:  The manufacturers of gatifloxacin,(2) gemifloxacin,(3)|
02560|031|M|lomefloxacin,(4), norfloxacin(5) and ofloxacin(6) state that these agents|
02560|032|M|should be avoided in patients receiving Class IA and III antiarrhythmic|
02560|033|M|agents.|
02560|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02560|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02560|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02560|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02560|038|B||
02560|039|D|DISCUSSION:  Gatifloxacin,(2) gemifloxacin,(3) lomefloxacin,(4),|
02560|040|D|norfloxacin(5) and ofloxacin(6) have the potential to prolong the QTc|
02560|041|D|interval.|
02560|042|D|   Torsades de pointes has been reported during post-marketing surveillance|
02560|043|D|in patients receiving lomefloxacin.(4)|
02560|044|D|   A pharmacokinetic and pharmacodynamic study evaluated the interaction|
02560|045|D|between ofloxacin and procainamide.  Nine healthy volunteers randomly|
02560|046|D|received one dose of procainamide 1 G, including or excluding pretreatment|
02560|047|D|with ofloxacin (400 mg b.i.d. for 5 doses).  A 12-point EKG monitored for|
02560|048|D|any pharmacodynamic abnormalities and blood urine samples evaluated for|
02560|049|D|pharmacokinetic variations.  The AUC and Cmax for procainamide were|
02560|050|D|increased by 27% and 21% with clearance diminished by 22%.(7)|
02560|051|B||
02560|052|R|REFERENCES:|
02560|053|B||
02560|054|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02560|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02560|056|R|  settings: a scientific statement from the American Heart Association and|6
02560|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02560|058|R|  2;55(9):934-47.|6
02560|059|R|2.Tequin (gatifloxacin) US prescribing information. Bristol-Myers Squibb|1
02560|060|R|  Company January, 2006.|1
02560|061|R|3.Factive (gemifloxacin mesylate) US prescribing information. Merus Labs|1
02560|062|R|  International, Inc. October, 2018.|1
02560|063|R|4.Maxaquin (lomefloxacin hydrochloride) US prescribing information. Pfizer|1
02560|064|R|  Inc. January, 2005.|1
02560|065|R|5.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
02560|066|R|  2016.|1
02560|067|R|6.Floxin (ofloxacin) US prescribing information. Ortho-McNeil|1
02560|068|R|  Pharmaceutical, Inc. February, 2011.|1
02560|069|R|7.Martin DE, Shen J, Griener J, Raasch R, Patterson JH, Cascio W. Effects of|2
02560|070|R|  ofloxacin on the pharmacokinetics and pharmacodynamics of procainamide. J|2
02560|071|R|  Clin Pharmacol 1996 Jan;36(1):85-91.|2
02561|001|T|MONOGRAPH TITLE:  Lidocaine (IV)/Selected Protease Inhibitors (mono deleted|
02561|002|T|09/02/2015)|
02561|003|B||
02561|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02561|005|L|take action as needed.|
02561|006|B||
02561|007|A|MECHANISM OF ACTION:  Lidocaine is primarily metabolized by CYP1A2, but|
02561|008|A|CYP3A4 also plays a role. Darunavir, lopinavir-ritonavir, and|
02561|009|A|ombitasvir-paritaprevir-ritonavir may inhibit the CYP3A4 mediated metabolism|
02561|010|A|of lidocaine.(1)|
02561|011|B||
02561|012|E|CLINICAL EFFECTS:  Concurrent use of darunavir, lopinavir-ritonavir, or|
02561|013|E|ombitasvir-paritaprevir-ritonavir with antiarrhythmic doses of lidocaine may|
02561|014|E|result in elevated levels and toxicity from lidocaine.|
02561|015|B||
02561|016|P|PREDISPOSING FACTORS:  Lidocaine clearance is significantly impaired in|
02561|017|P|patients with moderate or severe hepatic impairment.|
02561|018|B||
02561|019|M|PATIENT MANAGEMENT:  The US manufacturers of darunavir, lopinavir-ritonavir,|
02561|020|M|and ombitasvir-paritaprevir-ritonavir recommends caution and therapeutic|
02561|021|M|concentration monitoring when lidocaine is administered concurrently as an|
02561|022|M|antiarrhythmic.(2-4)|
02561|023|B||
02561|024|D|DISCUSSION:  Darunavir, lopinavir-ritonavir,|
02561|025|D|ombitasvir-paritaprevir-ritonavir have been shown to inhibit CYP3A4, one of|
02561|026|D|the metabolic pathways for lidocaine elimination.(2-4)|
02561|027|B||
02561|028|R|REFERENCES:|
02561|029|B||
02561|030|R|1.Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P.|2
02561|031|R|  Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in|2
02561|032|R|  vivo: effects of liver function. Clin Pharmacol Ther 2004 Jan;75(1):80-8.|2
02561|033|R|2.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
02561|034|R|  March, 2023.|1
02561|035|R|3.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
02561|036|R|  Laboratories December, 2019.|1
02561|037|R|4.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02561|038|R|  prescribing information. AbbVie Inc. July, 2015.|1
02562|001|T|MONOGRAPH TITLE:  Esomeprazole; Omeprazole/Select CYP2C19 and CYP3A4 Inducer|
02562|002|B||
02562|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02562|004|L|of severe adverse interaction.|
02562|005|B||
02562|006|A|MECHANISM OF ACTION:  Proton pump inhibitors are primarily metabolized by|
02562|007|A|CYP2C19, while CYP3A4 also plays a role in metabolism.(1,2)|
02562|008|A|   Enzalutamide, rifampin, and St. John's wort are moderate inducers of|
02562|009|A|CYP2C19 and strong inducers of CYP3A4.(3,4)|
02562|010|A|   Apalutamide is a strong inducer of CYP2C19 and CYP3A4.(5)|
02562|011|A|   Efavirenz and pacritinib are moderate inducers of CYP2C19 and|
02562|012|A|CYP3A4.(3,6)|
02562|013|B||
02562|014|E|CLINICAL EFFECTS:  Concurrent use of agents which induce both CYP2C19 and|
02562|015|E|CYP3A4 decrease systemic exposure and may result in decreased effectiveness|
02562|016|E|of proton pump inhibitors.(1-7)|
02562|017|B||
02562|018|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02562|019|P|of the inducer for longer than 1-2 weeks.|
02562|020|B||
02562|021|M|PATIENT MANAGEMENT:  Avoid concurrent use of esomeprazole or omeprazole with|
02562|022|M|CYP2C19 or CYP3A4 inducers.(1,2)  Monitor patients receiving concurrent|
02562|023|M|therapy for reduced proton pump inhibitor (PPI) effectiveness.|
02562|024|M|   Although specific dosing recommendations are not available, a higher dose|
02562|025|M|of the proton pump inhibitor may be considered to maintain PPI efficacy.|
02562|026|B||
02562|027|D|DISCUSSION:  In an interaction study, subjects with prostate cancer received|
02562|028|D|omeprazole before and after enzalutamide 160 mg daily for at least 55 days.|
02562|029|D|Enzalutamide decreased omeprazole area-under-curve (AUC) by 70.5%.(3,4)|
02562|030|D|   In an interaction study, rifampin 600 mg daily for 7 days decreased|
02562|031|D|omeprazole AUC by 89.5%.(3,7)|
02562|032|D|   In an interaction study, pacritinib 200 mg twice daily at steady state|
02562|033|D|decreased the maximum concentration (Cmax) and AUC of a single dose of|
02562|034|D|omeprazole (20 mg) by 27% and 51%, respectively.|
02562|035|D|   In an interaction study, St. John's wort decreased the maximum|
02562|036|D|concentration (Cmax) and AUC of omeprazole by 37.5% and 49.6%, respectively.|
02562|037|D|The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3%|
02562|038|D|and 136.6%, respectively.  The Cmax and AUC of 5-hydroxyomeprazole (via|
02562|039|D|CYP3A4) increased by 38.1% and 37.2%, respectively.(8,9)|
02562|040|B||
02562|041|R|REFERENCES:|
02562|042|B||
02562|043|R|1.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
02562|044|R|  Pharmaceuticals LP August, 2021.|1
02562|045|R|2.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
02562|046|R|  Pharmaceuticals LP June, 2018.|1
02562|047|R|3.This information is based on an extract from the Certara Drug Interaction|6
02562|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02562|049|R|4.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
02562|050|R|  September, 2022.|1
02562|051|R|5.Erleada (apalutamide) US prescribing information. Janssen Biotech, Inc.|1
02562|052|R|  July, 2021.|1
02562|053|R|6.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
02562|054|R|  2024.|1
02562|055|R|7.Bosilkovska M, Samer CF, Deglon J, Rebsamen M, Staub C, Dayer P, Walder B,|2
02562|056|R|  Desmeules JA, Daali Y. Geneva cocktail for cytochrome p450 and|2
02562|057|R|  P-glycoprotein activity assessment using  dried blood spots. Clin|2
02562|058|R|  Pharmacol Ther 2014 Sep;96(3):349-59.|2
02562|059|R|8.Wang LS, Zhou G, Zhu B, Wu J, Wang JG, Abd El-Aty AM, Li T, Liu J, Yang|2
02562|060|R|  TL, Wang D, Zhong XY, Zhou HH. St John's wort induces both cytochrome P450|2
02562|061|R|  3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of|2
02562|062|R|  omeprazole. Clin Pharmacol Ther 2004 Mar;75(3):191-7.|2
02562|063|R|9.Xie HG. Additional discussions regarding the altered metabolism and|2
02562|064|R|  transport of omeprazole after long-term use of St John's wort. Clin|2
02562|065|R|  Pharmacol Ther 2005 Oct;78(4):440-1.|2
02563|001|T|MONOGRAPH TITLE:  Fluconazole/Selected QT Prolonging Agents|
02563|002|B||
02563|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02563|004|L|take action as needed.|
02563|005|B||
02563|006|A|MECHANISM OF ACTION:  Concurrent use of fluconazole with other agents that|
02563|007|A|prolong the QTc interval may result in additive effects on the QTc interval.|
02563|008|B||
02563|009|E|CLINICAL EFFECTS:  The use of fluconazole patients maintained on agents that|
02563|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02563|011|E|arrhythmias, including torsades de pointes.|
02563|012|B||
02563|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02563|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02563|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02563|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02563|017|P|gender, or advanced age.(1)|
02563|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02563|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02563|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02563|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02563|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02563|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02563|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02563|025|B||
02563|026|M|PATIENT MANAGEMENT:  When concurrent therapy is warranted, approach the use|
02563|027|M|of alfuzosin,(2) apomorphine,(3) clozapine,(4) dolasetron,(5)|
02563|028|M|gemifloxacin,(6) maprotiline, norfloxacin,(7) and pasireotide(8) with other|
02563|029|M|agents that are known to prolong the QTc interval with caution.|
02563|030|M|   For patients receiving concurrent therapy, consider monitoring calcium,|
02563|031|M|magnesium, and potassium levels and monitoring electrocardiogram (ECG) at|
02563|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02563|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02563|034|B||
02563|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02563|036|D|degrees of potential to prolong the QTc interval but are generally accepted|
02563|037|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02563|038|D|monograph have been shown to prolong the QTc interval either through their|
02563|039|D|mechanism of action, through studies on their effects on the QTc interval,|
02563|040|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02563|041|D|clinical trials and/or post-marketing reports.|
02563|042|B||
02563|043|R|REFERENCES:|
02563|044|B||
02563|045|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02563|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02563|047|R|  settings: a scientific statement from the American Heart Association and|6
02563|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02563|049|R|  2;55(9):934-47.|6
02563|050|R|2.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
02563|051|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
02563|052|R|3.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
02563|053|R|  Inc. May, 2019.|1
02563|054|R|4.Clozaril (clozapine tablets) US prescribing information. Novartis|1
02563|055|R|  Pharmaceuticals Corporation April, 2020.|1
02563|056|R|5.Anzemet (dolasetron mesylate) US prescribing information. Sanofi-Aventis|1
02563|057|R|  Us.S. LLC September, 2014.|1
02563|058|R|6.Factive (gemifloxacin mesylate) US prescribing information. Merus Labs|1
02563|059|R|  International, Inc. October, 2018.|1
02563|060|R|7.Noroxin (norfloxacin) US prescribing information. Merck & Co., Inc. July,|1
02563|061|R|  2016.|1
02563|062|R|8.Signifor (pasireotide diasparate) US prescribing information. Novartis|1
02563|063|R|  Pharmaceuticals Corporation January, 2020.|1
02563|064|R|9.USDepartment of Health and Human Services Food and Drug Administration.|1
02563|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02563|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02563|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02564|001|T|MONOGRAPH TITLE:  Amiodarone/Sofosbuvir + Selected Direct Acting Antivirals|
02564|002|B||
02564|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02564|004|L|of severe adverse interaction.|
02564|005|B||
02564|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.(1-7)|
02564|007|B||
02564|008|E|CLINICAL EFFECTS:  Concurrent or recent use of amiodarone with sofosbuvir|
02564|009|E|plus another direct acting antiviral may result in symptomatic bradycardia,|
02564|010|E|which can be life-threatening, and cardiac arrest.(1-7)|
02564|011|B||
02564|012|P|PREDISPOSING FACTORS:  Patients who are also receiving a beta-blocker or who|
02564|013|P|have underlying cardiac comorbidities and/or advanced liver disease may be|
02564|014|P|at a higher risk of developing symptomatic bradycardia.(1-7)|
02564|015|B||
02564|016|M|PATIENT MANAGEMENT:  Concurrent use is potentially life-threatening.  The|
02564|017|M|FDA advises that sofosbuvir/ledipasvir or sofosbuvir combined with another|
02564|018|M|direct acting antiviral should not be combined with amiodarone(1) and the|
02564|019|M|manufacturer states concurrent therapy should only be used when other|
02564|020|M|alternative antiarrhythmic treatments are not tolerated or|
02564|021|M|contraindicated.(2-7)|
02564|022|M|   The AASLD/IDSA hepatitis C guidelines state patients being treated with|
02564|023|M|amiodarone should not receive sofosbuvir-based regimens due to risk of|
02564|024|M|life-threatening arrhythmias.  Due to the long half-life of amiodarone, the|
02564|025|M|guidelines advise that persons should be off amiodarone for at least 6|
02564|026|M|months before initiating sofosbuvir.  If alternatives are deemed not to be|
02564|027|M|clinically appropriate and the decision is made to start sofosbuvir in this|
02564|028|M|setting, continued vigilance for bradycardia should be exercised.(8)|
02564|029|M|   If alternative treatment options are unavailable, or if sofosbuvir is|
02564|030|M|initiated in a patient in whom amiodarone was discontinued in the previous|
02564|031|M|three months, counsel patients about the risk of serious symptomatic|
02564|032|M|bradycardia.  Patients should undergo cardiac monitoring in an in-patient|
02564|033|M|setting for the first 48 hours of coadministration and should then|
02564|034|M|self-monitor their heart rate (or be monitored in a doctor's office) on a|
02564|035|M|daily basis for at least the first two-weeks of treatment.(1-7)|
02564|036|M|   Instruct patients receiving concurrent therapy (and patients in whom|
02564|037|M|amiodarone was recently discontinued) to seek medical attention immediately|
02564|038|M|if they develop signs of symptomatic bradycardia, which may include:|
02564|039|M|near-fainting or fainting, dizziness or lightheadedness, malaise, weakness,|
02564|040|M|excessive tiredness, shortness of breath, chest pains, and/or confusion or|
02564|041|M|memory problems.(1-7)|
02564|042|B||
02564|043|D|DISCUSSION:  Nine cases of symptomatic bradycardia have been reported with|
02564|044|D|sofosbuvir in combination with ledipasvir (n=3), simeprevir (n=1), or|
02564|045|D|daclatasvir (n=5; marketed internationally, investigational agent in US).|
02564|046|D|Seven patients were also receiving a beta-blocker.  Six cases occurred|
02564|047|D|within the first 24 hours of concurrent therapy, while the other cases|
02564|048|D|occurred within 2-12 days of initiation of concurrent therapy.  One case|
02564|049|D|involved a fatal cardiac arrest and 3 required pacemaker insertion.  In 3|
02564|050|D|cases, symptomatic bradycardia recurred following rechallenge with|
02564|051|D|sofosbuvir.  In one case, amiodarone was discontinued and sofosbuvir was|
02564|052|D|re-initiated 8 weeks later with no reoccurrence of bradycardia.(1,2)|
02564|053|B||
02564|054|R|REFERENCES:|
02564|055|B||
02564|056|R|1.USFood and Drug Administration. FDA Drug Safety Communication: FDA warns|1
02564|057|R|  of serious slowing of the heart rate when antiarrhythmic drug amiodarone|1
02564|058|R|  is used with hepatitis C treatments containing sofosbuvir (Harvoni or|1
02564|059|R|  Sovaldi) in combination with another Direct Acting Antiviral drug.|1
02564|060|R|  available at: https://www.fda.gov/Drugs/DrugSafety/ucm439484.htm March 24,|1
02564|061|R|  2015.|1
02564|062|R|2.McHutchison J. Dear Health Care Provider:  Subject: Serious and|1
02564|063|R|  Life-Threatening Cases of Symptomatic Bradycardia as well as One Case of|1
02564|064|R|  Fatal Cardiac Arrest Reported with Coadministration of Amiodarone With|1
02564|065|R|  Either Harvoni (ledipasvir and sofosbuvir. fixed-dose combination)or With|1
02564|066|R|  Sovaldi (sofosbuvir) in Combination with Another Direct Acting Antiviral.|1
02564|067|R|  Gilead Sciences, Inc. March 20, 2015.|1
02564|068|R|3.McHutchison J. Dear Canadian Healthcare Professional Letter:  Amiodarone -|1
02564|069|R|  Slow Heart Rate in Patients Taking Amiodarone Together with Harvoni or|1
02564|070|R|  Sovaldi and a Direct Acting Antiviral. April 2, 2015.|1
02564|071|R|4.Sovaldi (sofosbuvir) US prescribing information. Gilead Sciences, Inc.|1
02564|072|R|  September, 2019.|1
02564|073|R|5.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
02564|074|R|  Sciences November, 2019.|1
02564|075|R|6.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
02564|076|R|  Sciences, Inc. April, 2022.|1
02564|077|R|7.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02564|078|R|  Gilead Sciences, Inc. September, 2019.|1
02564|079|R|8.AASLD-IDSA. HCV Guidance: Recommendations for Testing, Managing, and|6
02564|080|R|  Treating Hepatitis C. http://www.hcvguidelines.org. Accessed April 9,|6
02564|081|R|  2021..|6
02565|001|T|MONOGRAPH TITLE:  Cholic Acid/Aluminum-Based Antacids; Bile Acid|
02565|002|T|Sequestrants|
02565|003|B||
02565|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02565|005|L|take action as needed.|
02565|006|B||
02565|007|A|MECHANISM OF ACTION:  Aluminum-based antacids and bile acid sequestrants may|
02565|008|A|decrease the gastrointestinal absorption of cholic acid.(1)|
02565|009|B||
02565|010|E|CLINICAL EFFECTS:  Simultaneous administration of an aluminum-based antacid|
02565|011|E|or a bile acid sequestrant may result in decreased absorption and|
02565|012|E|effectiveness of cholic acid.(1)|
02565|013|B||
02565|014|P|PREDISPOSING FACTORS:  None determined.|
02565|015|B||
02565|016|M|PATIENT MANAGEMENT:  For maximal bioavailability in patients receiving both|
02565|017|M|medications, administer cholic acid at least 1 hour before or 4-6 hours|
02565|018|M|after (or as great an interval as possible) a bile acid sequestrant or|
02565|019|M|aluminum-based antacid.(1)|
02565|020|B||
02565|021|D|DISCUSSION:  Aluminum-based antacids have been shown to adsorb cholic acid|
02565|022|D|in vitro.  Bile acid sequestrants reduce bile acid absorption.(1)|
02565|023|B||
02565|024|R|REFERENCE:|
02565|025|B||
02565|026|R|1.Cholbam (cholic acid) US prescribing information. Manchester|1
02565|027|R|  Pharmaceuticals, Inc. November 2, 2020.|1
02566|001|T|MONOGRAPH TITLE:  Cholic Acid/Bile Salt Efflux Pump (BSEP) Inhibitors|
02566|002|B||
02566|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02566|004|L|of severe adverse interaction.|
02566|005|B||
02566|006|A|MECHANISM OF ACTION:  BSEP inhibitors, such as cyclosporine, decrease the|
02566|007|A|amount of conjugated cholic acid secreted into the bile.(1)|
02566|008|B||
02566|009|E|CLINICAL EFFECTS:  Concurrent use of a BSEP inhibitor may increase the|
02566|010|E|accumulation of conjugated bile salts in the liver, resulting in|
02566|011|E|exacerbation of liver impairment.(1)|
02566|012|B||
02566|013|P|PREDISPOSING FACTORS:  None determined.|
02566|014|B||
02566|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of cholic acid with BSEP|
02566|016|M|inhibitors such as cyclosporine.  If concurrent use is warranted, monitor|
02566|017|M|serum transaminases and bilirubin.  Instruct patients to report any signs of|
02566|018|M|worsening liver impairment, such as yellowing of the whites of the eyes or|
02566|019|M|skin, dark or brown (tea-colored) urine, pain on the right side of the|
02566|020|M|stomach, bleeding or bruising that occurs more easily than normal, or|
02566|021|M|increased lethargy.(1)|
02566|022|B||
02566|023|D|DISCUSSION:  BSEP inhibitors, such as cyclosporine, decrease the amount of|
02566|024|D|conjugated cholic acid secreted into the bile.  Concurrent use of these|
02566|025|D|agents with cholic acid  may increase the accumulation of conjugated bile|
02566|026|D|salts in the liver, resulting in exacerbation of liver impairment.(1)|
02566|027|B||
02566|028|R|REFERENCE:|
02566|029|B||
02566|030|R|1.Cholbam (cholic acid) US prescribing information. Manchester|1
02566|031|R|  Pharmaceuticals, Inc. November 2, 2020.|1
02567|001|T|MONOGRAPH TITLE:  Isavuconazonium/Phenytoin|
02567|002|B||
02567|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02567|004|L|is contraindicated and generally should not be dispensed or administered to|
02567|005|L|the same patient.|
02567|006|B||
02567|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 such as phenytoin may induce|
02567|008|A|the metabolism of isavuconazonium.(1)|
02567|009|B||
02567|010|E|CLINICAL EFFECTS:  The concurrent use of strong inducers of CYP3A4 such as|
02567|011|E|phenytoin and isavuconazonium may result in severely reduced levels of the|
02567|012|E|azole antibiotic and therapeutic failure.(1)|
02567|013|B||
02567|014|P|PREDISPOSING FACTORS:  None determined.|
02567|015|B||
02567|016|M|PATIENT MANAGEMENT:  The concurrent use of isavuconazonium with strong|
02567|017|M|inducers of CYP3A4 such as phenytoin is contraindicated.(1)|
02567|018|B||
02567|019|D|DISCUSSION:  The concurrent use of rifampin (600 mg) with isavuconazonium|
02567|020|D|(multiple doses) decreased the maximum concentration (Cmax) and|
02567|021|D|area-under-curve (AUC) of voriconazole by 75% and 97%, respectively.(1)|
02567|022|B||
02567|023|R|REFERENCE:|
02567|024|B||
02567|025|R|1.Cresemba (isavuconazonium sulfate) US prescribing information. Astellas|1
02567|026|R|  Pharma US, Inc. May, 2021.|1
02568|001|T|MONOGRAPH TITLE:  Isavuconazonium/Selected Strong CYP3A4 Inhibitors|
02568|002|B||
02568|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02568|004|L|is contraindicated and generally should not be dispensed or administered to|
02568|005|L|the same patient.|
02568|006|B||
02568|007|A|MECHANISM OF ACTION:  Concurrent use of strong CYP3A4 inhibitors may inhibit|
02568|008|A|the metabolism of isavuconazonium.(1)|
02568|009|B||
02568|010|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
02568|011|E|elevated levels and toxicity from isavuconazonium, leading to antifungal|
02568|012|E|discontinuation.  Adverse reactions may include headache, dizziness,|
02568|013|E|paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth,|
02568|014|E|diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness,|
02568|015|E|palpitations, tachycardia, photophobia and arthralgia.(1)|
02568|016|B||
02568|017|P|PREDISPOSING FACTORS:  Patients with familial short QT syndrome may be at|
02568|018|P|increased risk of heart arrhythmias.(1)|
02568|019|B||
02568|020|M|PATIENT MANAGEMENT:  The concurrent use of isavuconazonium with strong|
02568|021|M|inhibitors of CYP3A4 is contraindicated.(1)|
02568|022|M|   The US manufacturer of itraconazole states that administration of|
02568|023|M|isavuconazonium is contraindicated during and two weeks after itraconazole|
02568|024|M|treatment.|
02568|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
02568|026|M|isavuconazonium toxicity, including headache, dizziness, paresthesia,|
02568|027|M|somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral|
02568|028|M|hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations,|
02568|029|M|tachycardia, photophobia and arthralgia.  Isavuconazonium or the CYP3A4|
02568|030|M|inhibitor may need to be discontinued.|
02568|031|B||
02568|032|D|DISCUSSION:  Ketoconazole (200 mg BID) increased the maximum concentration|
02568|033|D|(Cmax) and area-under-curve (AUC) of isavuconazole (from a single dose of|
02568|034|D|isavuconazonium equivalent to 200 mg isavuconazole) by 9% and 422%,|
02568|035|D|respectively.(1)|
02568|036|D|   Lopinavir/ritonavir (400 mg/100 mg BID) increased the Cmax and AUC of|
02568|037|D|isavuconazole by 74% and 96%, respectively.(1)|
02568|038|D|   Supratherapeutic doses of isavuconazonium (three times the recommended|
02568|039|D|dosage) used in a study resulted in 17.9% of patients discontinuing|
02568|040|D|isavuconazonium therapy.(1)|
02568|041|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
02568|042|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir,|
02568|043|D|itraconazole, josamycin, ketoconazole, levoketoconazole, mibefradil,|
02568|044|D|mifepristone, nefazodone, nelfinavir, posaconazole, ribociclib, saquinavir,|
02568|045|D|telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.|
02568|046|B||
02568|047|R|REFERENCES:|
02568|048|B||
02568|049|R|1.Cresemba (isavuconazonium sulfate) US prescribing information. Astellas|1
02568|050|R|  Pharma US, Inc. May, 2021.|1
02568|051|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02568|052|R|  Products, L.P. February, 2024.|1
02569|001|T|MONOGRAPH TITLE:  Isavuconazonium/Ritonavir|
02569|002|B||
02569|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02569|004|L|of severe adverse interaction.|
02569|005|B||
02569|006|A|MECHANISM OF ACTION:  Concurrent use of strong CYP3A4 inhibitors may inhibit|
02569|007|A|the metabolism of isavuconazonium.(1)|
02569|008|B||
02569|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
02569|010|E|elevated levels and toxicity from isavuconazonium, leading to antifungal|
02569|011|E|discontinuation.  Adverse reactions may include headache, dizziness,|
02569|012|E|paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth,|
02569|013|E|diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness,|
02569|014|E|palpitations, tachycardia, photophobia and arthralgia.(1)|
02569|015|B||
02569|016|P|PREDISPOSING FACTORS:  Patients with familial short QT syndrome may be at|
02569|017|P|increased risk of heart arrhythmias.(1)|
02569|018|B||
02569|019|M|PATIENT MANAGEMENT:  The concurrent use of isavuconazonium with high-dose|
02569|020|M|ritonavir (400 mg BID) is contraindicated.  The use of low-dose ritonavir or|
02569|021|M|lopinavir/ritonavir should be approached with caution.(1)|
02569|022|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
02569|023|M|isavuconazonium toxicity, including headache, dizziness, paresthesia,|
02569|024|M|somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral|
02569|025|M|hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations,|
02569|026|M|tachycardia, photophobia and arthralgia.  Isavuconazonium or ritonavir may|
02569|027|M|need to be discontinued.|
02569|028|B||
02569|029|D|DISCUSSION:  Ketoconazole (200 mg BID) increased the maximum concentration|
02569|030|D|(Cmax) and area-under-curve (AUC) of isavuconazole (from a single dose of|
02569|031|D|isavuconazonium equivalent to 200 mg isavuconazole) by 9% and 422%,|
02569|032|D|respectively.(1)|
02569|033|D|   Lopinavir/ritonavir (400 mg/100 mg BID) increased the Cmax and AUC of|
02569|034|D|isavuconazole by 74% and 96%, respectively.(1)|
02569|035|D|   Supratherapeutic doses of isavuconazonium (three times the recommended|
02569|036|D|dosage) used in a study resulted in 17.9% of patients discontinuing|
02569|037|D|isavuconazonium therapy.(1)|
02569|038|B||
02569|039|R|REFERENCE:|
02569|040|B||
02569|041|R|1.Cresemba (isavuconazonium sulfate) US prescribing information. Astellas|1
02569|042|R|  Pharma US, Inc. May, 2021.|1
02570|001|T|MONOGRAPH TITLE:  Digoxin/Isavuconazonium|
02570|002|B||
02570|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02570|004|L|take action as needed.|
02570|005|B||
02570|006|A|MECHANISM OF ACTION:  Isavuconazonium inhibits the P-glycoprotein (P-gp)|
02570|007|A|system, which may increase digoxin levels.(1)|
02570|008|B||
02570|009|E|CLINICAL EFFECTS:  Concurrent use of isavuconazonium may result in elevated|
02570|010|E|levels and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can|
02570|011|E|include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
02570|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
02570|013|E|disturbances, and arrhythmias.|
02570|014|B||
02570|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02570|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02570|017|P|risk of digoxin toxicity.|
02570|018|B||
02570|019|M|PATIENT MANAGEMENT:  Monitor digoxin levels when initiating and|
02570|020|M|discontinuing isavuconazonium.  The dosage of digoxin may need to be|
02570|021|M|adjusted.(1)  Instruct patients to report symptoms of digoxin toxicity such|
02570|022|M|as anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
02570|023|M|generalized muscle weakness, disorientation, hallucinations, visual|
02570|024|M|disturbances, and arrhythmias.|
02570|025|B||
02570|026|D|DISCUSSION:  Isavuconazonium increased the maximum concentration (Cmax) and|
02570|027|D|area-under-curve (AUC) of digoxin (0.5 mg) by approximately 1.25-fold.(1)|
02570|028|B||
02570|029|R|REFERENCE:|
02570|030|B||
02570|031|R|1.Cresemba (isavuconazonium sulfate) US prescribing information. Astellas|1
02570|032|R|  Pharma US, Inc. May, 2021.|1
02571|001|T|MONOGRAPH TITLE:  Aminoglycosides/Ataluren|
02571|002|B||
02571|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02571|004|L|is contraindicated and generally should not be dispensed or administered to|
02571|005|L|the same patient.|
02571|006|B||
02571|007|A|MECHANISM OF ACTION:  The mechanism of this interaction is not known.|
02571|008|B||
02571|009|E|CLINICAL EFFECTS:  The combination of an aminoglycoside and ataluren may|
02571|010|E|increase risk for serious nephrotoxicity.(1)|
02571|011|B||
02571|012|P|PREDISPOSING FACTORS:  Preexisting renal impairment, dehydration, extended|
02571|013|P|duration of aminoglycoside therapy, greater than one aminoglycoside dose per|
02571|014|P|day, or concomitant use of additional nephrotoxic agents such as iodinated|
02571|015|P|contrast media or vancomycin appear to increase the risk for|
02571|016|P|nephrotoxicity.(1-5).|
02571|017|B||
02571|018|M|PATIENT MANAGEMENT:  The manufacturer states that ataluren should not be|
02571|019|M|co-administered with intravenous aminoglycosides based upon cases of|
02571|020|M|decreased renal function observed in a clinical trial with cystic fibrosis|
02571|021|M|patients.|
02571|022|M|   If aminoglycoside therapy is required, stop ataluren and resume therapy 2|
02571|023|M|days after aminoglycoside therapy has ended.(1)|
02571|024|B||
02571|025|D|DISCUSSION:  In a clinical trial with cystic fibrosis patients, 18 of 118|
02571|026|D|(15%) patients in the ataluren group developed increased creatinine|
02571|027|D|concentrations compared with one of 120 patients in the placebo group.(2)|
02571|028|B||
02571|029|R|REFERENCES:|
02571|030|B||
02571|031|R|1.Translarna (ataluren) EU SPC. PTC Therapeutics International Limited July|1
02571|032|R|  31, 2014.|1
02571|033|R|2.Gentamicin Sulfate in 0.9% Sodium Chloride Injection. Baxter Healthcare|1
02571|034|R|  Corporation June 2011.|1
02571|035|R|3.Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani|2
02571|036|R|  R. Experience with a once-daily aminoglycoside program administered to|2
02571|037|R|  2,184 adult patients. Antimicrob Agents Chemother 1995 Mar;39(3):650-5.|2
02571|038|R|4.Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL.|2
02571|039|R|  Prospective evaluation of the effect of an aminoglycoside dosing regimen|2
02571|040|R|  on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents|2
02571|041|R|  Chemother 1999 Jul;43(7):1549-55.|2
02571|042|R|5.Gerlach AT, Stawicki SP, Cook CH, Murphy C. Risk factors for|2
02571|043|R|  aminoglycoside-associated nephrotoxicity in surgical intensive care unit|2
02571|044|R|  patients. Int J Crit Illn Inj Sci 2011 Jan;1(1):17-21.|2
02571|045|R|6.Kerem E, Konstan MW, De Boeck K, et al. Ataluren for the treatment of|2
02571|046|R|  nonsense-mutation cystic fibrosis: a randomised, double-blind,|2
02571|047|R|  placebo-controlled phase 3 trial. Lancet Respir Med 2014 Jul;2(7):539-47.|2
02572|001|T|MONOGRAPH TITLE:  Azathioprine; Mercaptopurine/Aminosalicylate Derivatives|
02572|002|B||
02572|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02572|004|L|take action as needed.|
02572|005|B||
02572|006|A|MECHANISM OF ACTION:  The exact mechanism is not known.|
02572|007|A|   Aminosalicylic acid and its derivatives (balsalazide, mesalamine,|
02572|008|A|olsalazine, sulfasalazine) may inhibit azathioprine or mercaptopurine|
02572|009|A|inactivation via the thiopurine methyltransferase (TPMT) pathway.|
02572|010|A|   Aminosalicylates, azathioprine and mercaptopurine are all associated risk|
02572|011|A|for neutropenia, thrombocytopenia, and anemia and so these risks could be|
02572|012|A|additive.|
02572|013|B||
02572|014|E|CLINICAL EFFECTS:  Concurrent use of azathioprine or mercaptopurine with|
02572|015|E|aminosalicylates may increase the risk for anemia, neutropenia, or|
02572|016|E|thrombocytopenia.|
02572|017|B||
02572|018|P|PREDISPOSING FACTORS:  Patients with reduced or absent thiopurine|
02572|019|P|S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are|
02572|020|P|at higher risk of accumulating thiopurine metabolites and severe|
02572|021|P|myelosuppression.  Approximately 0.3 % of patients of European, Latino, or|
02572|022|P|African descent have mutations of the TPMT gene resulting in little to no|
02572|023|P|TPMT activity (homozygous deficiency), and approximately 10 % have|
02572|024|P|intermediate TPMT activity (heterozygous deficiency).  NUDT15 deficiency is|
02572|025|P|not seen in patients of African descent and is seen in less than 1 % of|
02572|026|P|patients of European descent.  Approximately 1 % of patients of East Asian|
02572|027|P|descent, 0.5 % of patients of central/south Asian descent, and 2 % of|
02572|028|P|patients of Latino descent have homozygous NUDT15 deficiency.  About 17 % of|
02572|029|P|patients of East Asian descent, 13 % of patients of central/south Asian|
02572|030|P|descent, and 8 % of patients of Latino descent have heterozygous NUDT15|
02572|031|P|deficiency.|
02572|032|P|   Added risk for myelosuppression would be expected in patients who also|
02572|033|P|receive allopurinol or other agents which block xanthine oxidase (XO), the|
02572|034|P|other major inactivation pathway for azathioprine and mercaptopurine.|
02572|035|B||
02572|036|M|PATIENT MANAGEMENT:  Use the lowest possible dose of each drug and monitor|
02572|037|M|closely for myelosuppression.|
02572|038|B||
02572|039|D|DISCUSSION:  Manufacturer prescribing information states that concurrent use|
02572|040|D|of aminosalicylates with azathioprine or mercaptopurine has been reported to|
02572|041|D|cause bone marrow suppression.|
02572|042|D|   In a prospective study, 22 inflammatory bowel disease (IBD) patients on|
02572|043|D|concurrent 5-aminosalicylate with (2 g daily and later increased to 4 g|
02572|044|D|daily) with azathioprine had increased levels of 6-thioguanine (6-TGN)|
02572|045|D|metabolites. One patient had signs of myelosuppression.(3)|
02572|046|D|   A prospective study in 183 IBD patients on concurrent 5-aminosalicylic|
02572|047|D|acid and thiopurines found no significant interaction between thiopurines|
02572|048|D|and 5-aminosalicylic acid.(4)|
02572|049|D|   A retrospective study in 199 IBD patients reported an increased rate of|
02572|050|D|adverse events in the dual 5-aminosalicylates and azathioprine dual therapy|
02572|051|D|group compared (48%) to the monotherapy azathioprine group (30%)(chi = 6.4,|
02572|052|D|p = 0.05). Discontinuation of azathioprine because of adverse events was|
02572|053|D|higher in the dual therapy group (52% vs. 24%).(5)|
02572|054|D|   In a prospective study, 16 Crohn's disease patients on a stable dose of|
02572|055|D|azathioprine with sulfasalazine or mesalamine discontinued the|
02572|056|D|aminosalicylate after 3 months, which resulted in an average decrease 0f 10%|
02572|057|D|in 6-TGN levels. Myelosuppression may be related to increased levels of|
02572|058|D|6-TGN.(6)|
02572|059|D|   In a 8 week non-randomized parallel group drug interaction study, 34|
02572|060|D|patients with Crohn's disease receiving azathioprine or 6-mercaptopurine|
02572|061|D|with mesalamine (4 g/day), or sulfasalazine (4 g/day), or balsalazide (6.75|
02572|062|D|g/day) had a high frequency of leukopenia (20-55%) and significant increases|
02572|063|D|in whole blood 6-TGN levels.(7)|
02572|064|D|   A 16 year-old Crohn's disease patient on concurrent 6-mercaptopurine (75|
02572|065|D|mg) and olsalazine (1000 mg) developed leukopenia (WBC count 1.7 x 10*9/L,|
02572|066|D|ANC 1.309 x 10*9/L, hemoglobulin 113 gm/L, platelet count 550 x 10*9/L) and|
02572|067|D|required a dose reduction for 6-mercaptopurine. Another episode occurred|
02572|068|D|later on after increasing her dose of olsalazine and 6-mercaptopurine which|
02572|069|D|resulted in discontinuation of olsalazine.(8)|
02572|070|D|   An in vitro study showed that sulfasalazine and other aminosalicylate|
02572|071|D|derivatives were able to inhibit recombinant human TPMT.(9)|
02572|072|D|   In a prospective study, 17 IBD patients on stable mercaptopurine and|
02572|073|D|mesalamine therapy had a 23% reduction in 6-TGN levels after discontinuing|
02572|074|D|mercaptopurine.(10)|
02572|075|B||
02572|076|R|REFERENCES:|
02572|077|B||
02572|078|R|1.Imuran (azathioprine) US prescribing information. Prometheus Laboratories|1
02572|079|R|  Inc. February, 2014.|1
02572|080|R|2.Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM,|6
02572|081|R|  Moyer AM, Evans WE, Klein TE, Antillon-Klussmann FG, Caudle KE, Kato M,|6
02572|082|R|  Yeoh AEJ, Schmiegelow K, Yang JJ. Clinical Pharmacogenetics Implementation|6
02572|083|R|  Consortium Guideline for Thiopurine Dosing  Based on TPMT and NUDT15|6
02572|084|R|  Genotypes: 2018 Update. Clin Pharmacol Ther 2019 May;105(5):1095-1105.|6
02572|085|R|3.de Graaf P, de Boer NK, Wong DR, Karner S, Jharap B, Hooymans PM, Veldkamp|2
02572|086|R|  AI, Mulder CJ, van Bodegraven AA, Schwab M. Influence of 5-aminosalicylic|2
02572|087|R|  acid on 6-thioguanosine phosphate metabolite levels: a prospective study|2
02572|088|R|  in patients under steady thiopurine therapy. Br J Pharmacol 2010 Jul;|2
02572|089|R|  160(5):1083-91.|2
02572|090|R|4.Daperno M, Sostegni R, Canaparo R, Serpe L, Lavagna A, Crocella L,|2
02572|091|R|  Castagno F, Vernetto A, Rigazio C, Ercole E, D'Antico S, Pera A, Zara G,|2
02572|092|R|  Rocca R. Prospective study of the effects of concomitant medications on|2
02572|093|R|  thiopurine metabolism in inflammatory bowel disease. Aliment Pharmacol|2
02572|094|R|  Ther 2009 Oct 15;30(8):843-53.|2
02572|095|R|5.Shah JA, Edwards CM, Probert CS. Should azathioprine and|2
02572|096|R|  5-aminosalicylates be coprescribed in inflammatory bowel  disease?: an|2
02572|097|R|  audit of adverse events and outcome. Eur J Gastroenterol Hepatol 2008 Mar;|2
02572|098|R|  20(3):169-73.|2
02572|099|R|6.Dewit O, Vanheuverzwyn R, Desager JP, Horsmans Y. Interaction between|2
02572|100|R|  azathioprine and aminosalicylates: an in vivo study in patients with|2
02572|101|R|  Crohn's disease. Aliment Pharmacol Ther 2002 Jan;16(1):79-85.|2
02572|102|R|7.Lowry PW, Franklin CL, Weaver AL, Szumlanski CL, Mays DC, Loftus EV,|2
02572|103|R|  Tremaine WJ, Lipsky JJ, Weinshilboum RM, Sandborn WJ. Leucopenia resulting|2
02572|104|R|  from a drug interaction between azathioprine or 6-mercaptopurine and|2
02572|105|R|  mesalamine, sulphasalazine, or balsalazide. Gut 2001 Nov;49(5):656-64.|2
02572|106|R|8.Lewis LD, Benin A, Szumlanski CL, Otterness DM, Lennard L, Weinshilboum|3
02572|107|R|  RM, Nierenberg DW. Olsalazine and 6-mercaptopurine-related bone marrow|3
02572|108|R|  suppression: a possible drug-drug interaction. Clin Pharmacol Ther 1997|3
02572|109|R|  Oct;62(4):464-75.|3
02572|110|R|9.Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine|5
02572|111|R|  methyltransferase: possible mechanism for interaction with|5
02572|112|R|  6-mercaptopurine and azathioprine. Br J Clin Pharmac 1995;39:456-9.|5
02572|113|R|10.Gilissen LP, Bierau J, Derijks LJ, Bos LP, Hooymans PM, van Gennip A,|2
02572|114|R|   Stockbrugger RW, Engels LG. The pharmacokinetic effect of discontinuation|2
02572|115|R|   of mesalazine on mercaptopurine metabolite levels in inflammatory bowel|2
02572|116|R|   disease patients. Aliment Pharmacol Ther 2005 Oct 1;22(7):605-11.|2
02573|001|T|MONOGRAPH TITLE:  Iloperidone/Selected Strong CYP2D6 Inhibitors|
02573|002|B||
02573|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02573|004|L|take action as needed.|
02573|005|B||
02573|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors(1) such as dacomitinib,|
02573|007|A|fluoxetine, paroxetine, and terbinafine may inhibit the metabolism of|
02573|008|A|iloperidone.(2)|
02573|009|B||
02573|010|E|CLINICAL EFFECTS:  Concurrent administration of iloperidone with|
02573|011|E|dacomitinib, fluoxetine, paroxetine, or terbinafine may result in elevated|
02573|012|E|iloperidone levels and toxicities, including the risk for QTc|
02573|013|E|prolongation.(2)|
02573|014|B||
02573|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02573|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02573|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02573|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02573|019|P|female gender, or advanced age.(3)|
02573|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02573|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02573|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02573|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02573|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02573|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02573|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02573|027|B||
02573|028|M|PATIENT MANAGEMENT:  The US manufacturer of iloperidone states that the dose|
02573|029|M|of iloperidone should be reduced to one-half of its normal dose when strong|
02573|030|M|CYP2D6 inhibitors such as dacomitinib, fluoxetine or paroxetine are|
02573|031|M|coadministered.(2)|
02573|032|M|   Due to its long half-life it may take 2 or more weeks to see the full|
02573|033|M|effects of fluoxetine CYP2D6 inhibition on iloperidone exposure and|
02573|034|M|tolerance.  Maximal CYP2D6 inhibitory effects due to paroxetine|
02573|035|M|coadministration are generally expected within one week after initiation or|
02573|036|M|increase in the paroxetine dosage.|
02573|037|M|   When the inhibitor is discontinued iloperidone exposure will wane and the|
02573|038|M|dose of iloperidone should be increased.(2)|
02573|039|M|   Concurrent administration of iloperidone with both a CYP2D6 inhibitor and|
02573|040|M|CYP3A4 inhibitor does not have additive inhibitory effects compared to|
02573|041|M|either inhibitor alone.  The dose of iloperidone should be reduced to|
02573|042|M|one-half of its normal dose, and further dose reduction is not required.(2)|
02573|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02573|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02573|045|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02573|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02573|047|B||
02573|048|D|DISCUSSION:  In a study in 23 healthy subjects, fluoxetine (20 mg twice|
02573|049|D|daily for 21 days) increased the AUC of iloperidone (3 mg single dose) and|
02573|050|D|its P88 metabolite by 2-3-fold.  The AUC of iloperidone's P95 metabolite|
02573|051|D|decreased by 50%.(2)|
02573|052|D|   In a study in patients with schizophrenia, paroxetine (20 mg daily for|
02573|053|D|5-8 days) increased the maximum concentration (Cmax) of iloperidone and its|
02573|054|D|P88 metabolite by about 1.6-fold.  The Cmax of iloperidone's P95 metabolite|
02573|055|D|decreased by 50%.(2)|
02573|056|D|   Coadministration of paroxetine (20 mg daily) and iloperidone (12 mg twice|
02573|057|D|daily) was associated with a mean QTcF increase of 19 msec from baseline,|
02573|058|D|compared with an increase of 9 msec with iloperidone alone.(2)|
02573|059|D|   Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did|
02573|060|D|not increase the effects on iloperidone compared with either agent alone.(2)|
02573|061|B||
02573|062|R|REFERENCES:|
02573|063|B||
02573|064|R|1.This information is based on an extract from the Certara Drug Interaction|6
02573|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02573|066|R|2.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
02573|067|R|  Inc May, 2016.|1
02573|068|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02573|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02573|070|R|  settings: a scientific statement from the American Heart Association and|6
02573|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02573|072|R|  2;55(9):934-47.|6
02574|001|T|MONOGRAPH TITLE:  Methotrexate (Oncology-Injection)/Selected Salicylates|
02574|002|B||
02574|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02574|004|L|of severe adverse interaction.|
02574|005|B||
02574|006|A|MECHANISM OF ACTION:  Salicylates may inhibit the renal tubular excretion of|
02574|007|A|methotrexate.|
02574|008|B||
02574|009|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and salicylates may|
02574|010|E|result in an increase in the therapeutic and toxic effects of methotrexate,|
02574|011|E|leading to increased risk of severe neurotoxicity, stomatitis, and|
02574|012|E|myelosuppression, including neutropenia.|
02574|013|B||
02574|014|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
02574|015|P|- High-dose oncology regimens|
02574|016|P|- Anti-inflammatory doses of aspirin/salicylates|
02574|017|P|- Impaired renal function, ascites, or pleural effusions|
02574|018|B||
02574|019|M|PATIENT MANAGEMENT:  US manufacturer prescribing information for|
02574|020|M|methotrexate states nonsteroidal anti-inflammatory drugs should not be|
02574|021|M|administered prior to or concomitantly with high doses of methotrexate. If|
02574|022|M|concurrent therapy is warranted, methotrexate plasma levels should be|
02574|023|M|monitored and patients should be observed for methotrexate toxicity.  The|
02574|024|M|dosage of methotrexate may need to be adjusted.|
02574|025|M|   Use caution when administering higher doses of salicylates with lower|
02574|026|M|doses of methotrexate.  Salicylate doses > or = 2 grams per day have been|
02574|027|M|associated with hepatic impairment or impaired renal elimination of|
02574|028|M|methotrexate.  It would be prudent to avoid high-dose aspirin, especially in|
02574|029|M|patients with renal impairment or near the time of methotrexate dosage (in|
02574|030|M|patients receiving weekly therapy).|
02574|031|M|   The Australian prescribing information for aspirin DL-lysine states|
02574|032|M|coadministration with methotrexate at doses of 15 mg/week or greater is|
02574|033|M|contraindicated.|
02574|034|B||
02574|035|D|DISCUSSION:  Several studies and case reports have reported increased and|
02574|036|D|prolonged methotrexate levels in patients receiving concurrent aspirin. One|
02574|037|D|study noted an effect with average weekly doses of methotrexate of 16.6 mg,|
02574|038|D|but not weekly doses of 7.5 mg. Decreased renal function has also been|
02574|039|D|reported with the combination.|
02574|040|D|   Single ingredient aspirin or buffered aspirin products with strengths <|
02574|041|D|or = to 325 mg or formulations which are associated with once daily use for|
02574|042|D|cardiovascular protection are not linked to this interaction.  Other|
02574|043|D|lower-strength aspirin formulations (e.g. headache, cough & cold, opioid|
02574|044|D|combinations) which could be consumed multiple times a day remain linked to|
02574|045|D|this interaction.|
02574|046|B||
02574|047|R|REFERENCES:|
02574|048|B||
02574|049|R|1.Liegler DG, Henderson ES, Hahn MA, Oliverio VT. The effect of organic|2
02574|050|R|  acids on renal clearance of methotrexate in man. Clin Pharmacol Ther 1969|2
02574|051|R|  Nov-Dec;10(6):849-57.|2
02574|052|R|2.Baker H. Intermittent high dose oral methotrexate therapy in psoriasis. Br|3
02574|053|R|  J Dermatol 1970 Jan;82(1):65-9.|3
02574|054|R|3.Mandel MA. The synergistic effect of salicylates on methotrexate toxicity.|2
02574|055|R|  Plast Reconstr Surg 1976 Jun;57(6):733-7.|2
02574|056|R|4.Taylor JR, Halprin KM. Effect of sodium salicylate and indomethacin on|5
02574|057|R|  methotrexate-serum albumin binding. Arch Dermatol 1977 May;113(5):588-91.|5
02574|058|R|5.Tracy TS, Krohn K, Jones DR, Bradley JD, Hall SD, Brater DC. The effects|2
02574|059|R|  of a salicylate, ibuprofen, and naproxen on the disposition of|2
02574|060|R|  methotrexate in patients with rheumatoid arthritis. Eur J Clin Pharmacol|2
02574|061|R|  1992;42(2):121-5.|2
02574|062|R|6.Harrison PV. Methotrexate-induced epidermal necrosis. Br J Dermatol 1987|3
02574|063|R|  Jun;116(6):867-9.|3
02574|064|R|7.Fries JF, Singh G, Lenert L, Furst DE. Aspirin, hydroxychloroquine, and|2
02574|065|R|  hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis.|2
02574|066|R|  Arthritis Rheum 1990 Nov;33(11):1611-9.|2
02574|067|R|8.Furst DE, Herman RA, Koehnke R, Ericksen N, Hash L, Riggs CE, Porras A,|2
02574|068|R|  Veng-Pedersen P. Effect of aspirin and sulindac on methotrexate clearance.|2
02574|069|R|  J Pharm Sci 1990 Sep;79(9):782-6.|2
02574|070|R|9.Stewart CF, Fleming RA, Germain BF, Seleznick MJ, Evans WE. Aspirin alters|2
02574|071|R|  methotrexate disposition in rheumatoid arthritis patients. Arthritis Rheum|2
02574|072|R|  1991 Dec;34(12):1514-20.|2
02574|073|R|10.Seideman P, Muller-Suur R. Renal effects of aspirin and low dose|2
02574|074|R|   methotrexate in rheumatoid arthritis. Ann Rheum Dis 1993 Aug;52(8):613-5.|2
02574|075|R|11.Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory|2
02574|076|R|   drugs on methotrexate (MTX) pharmacokinetics: impairment of renal|2
02574|077|R|   clearance of MTX at weekly maintenance doses but not at 7.5 mg. J|2
02574|078|R|   Rheumatol 1995 Nov;22(11):2072-7.|2
02574|079|R|12.Rheumatrex (methotrexate, oral) US prescribing information. Dava|1
02574|080|R|   Pharmaceuticals, Inc. February, 2013.|1
02574|081|R|13.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
02574|082|R|   Inc. March, 2018.|1
02574|083|R|14.Aspirin IV German Prescribing Information. Bayer Vital GmbH July 2019.|1
02575|001|T|MONOGRAPH TITLE:  Methotrexate (Oncology-Injection)/Aspirin (<=330 mg)|
02575|002|B||
02575|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02575|004|L|take action as needed.|
02575|005|B||
02575|006|A|MECHANISM OF ACTION:  Salicylates may inhibit the renal tubular excretion of|
02575|007|A|methotrexate.|
02575|008|B||
02575|009|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and salicylates may|
02575|010|E|result in an increase in the therapeutic and toxic effects of methotrexate,|
02575|011|E|leading to increased risk of severe neurotoxicity, stomatitis, and|
02575|012|E|myelosuppression, including neutropenia.|
02575|013|B||
02575|014|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
02575|015|P|- High-dose oncology regimens|
02575|016|P|- Anti-inflammatory doses of aspirin/salicylates|
02575|017|P|- Impaired renal function, ascites, or pleural effusions|
02575|018|B||
02575|019|M|PATIENT MANAGEMENT:  US manufacturer prescribing information for|
02575|020|M|methotrexate states nonsteroidal anti-inflammatory drugs including aspirin|
02575|021|M|should not be administered prior to or concomitantly with high doses of|
02575|022|M|methotrexate. If concurrent therapy is warranted, methotrexate plasma levels|
02575|023|M|should be monitored and patients should be observed for methotrexate|
02575|024|M|toxicity.  The dosage of methotrexate may need to be adjusted.|
02575|025|M|   Use caution when administering higher doses of salicylates with lower|
02575|026|M|doses of methotrexate.  Salicylate doses > or = 2 grams per day have been|
02575|027|M|associated with hepatic impairment or impaired renal elimination of|
02575|028|M|methotrexate.  It would be prudent to avoid high-dose aspirin, especially|
02575|029|M|near the time of methotrexate dosage in patients receiving intermittent|
02575|030|M|methotrexate therapy, and in patients with renal impairment.|
02575|031|B||
02575|032|D|DISCUSSION:  Several studies and case reports have reported increased and|
02575|033|D|prolonged methotrexate levels in patients receiving concurrent aspirin. One|
02575|034|D|study noted an effect with average weekly doses of methotrexate of 16.6 mg,|
02575|035|D|but not weekly doses of 7.5 mg. Decreased renal function has also been|
02575|036|D|reported with the combination.|
02575|037|D|   Single ingredient aspirin or buffered aspirin products with strengths <|
02575|038|D|or = to 325 mg or formulations which are associated with once daily use for|
02575|039|D|cardiovascular protection are included in this interaction.  Other aspirin|
02575|040|D|and salicylate products are linked to higher severity level interactions.|
02575|041|B||
02575|042|R|REFERENCES:|
02575|043|B||
02575|044|R|1.Liegler DG, Henderson ES, Hahn MA, Oliverio VT. The effect of organic|2
02575|045|R|  acids on renal clearance of methotrexate in man. Clin Pharmacol Ther 1969|2
02575|046|R|  Nov-Dec;10(6):849-57.|2
02575|047|R|2.Baker H. Intermittent high dose oral methotrexate therapy in psoriasis. Br|3
02575|048|R|  J Dermatol 1970 Jan;82(1):65-9.|3
02575|049|R|3.Mandel MA. The synergistic effect of salicylates on methotrexate toxicity.|2
02575|050|R|  Plast Reconstr Surg 1976 Jun;57(6):733-7.|2
02575|051|R|4.Taylor JR, Halprin KM. Effect of sodium salicylate and indomethacin on|5
02575|052|R|  methotrexate-serum albumin binding. Arch Dermatol 1977 May;113(5):588-91.|5
02575|053|R|5.Tracy TS, Krohn K, Jones DR, Bradley JD, Hall SD, Brater DC. The effects|2
02575|054|R|  of a salicylate, ibuprofen, and naproxen on the disposition of|2
02575|055|R|  methotrexate in patients with rheumatoid arthritis. Eur J Clin Pharmacol|2
02575|056|R|  1992;42(2):121-5.|2
02575|057|R|6.Harrison PV. Methotrexate-induced epidermal necrosis. Br J Dermatol 1987|3
02575|058|R|  Jun;116(6):867-9.|3
02575|059|R|7.Fries JF, Singh G, Lenert L, Furst DE. Aspirin, hydroxychloroquine, and|2
02575|060|R|  hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis.|2
02575|061|R|  Arthritis Rheum 1990 Nov;33(11):1611-9.|2
02575|062|R|8.Furst DE, Herman RA, Koehnke R, Ericksen N, Hash L, Riggs CE, Porras A,|2
02575|063|R|  Veng-Pedersen P. Effect of aspirin and sulindac on methotrexate clearance.|2
02575|064|R|  J Pharm Sci 1990 Sep;79(9):782-6.|2
02575|065|R|9.Stewart CF, Fleming RA, Germain BF, Seleznick MJ, Evans WE. Aspirin alters|2
02575|066|R|  methotrexate disposition in rheumatoid arthritis patients. Arthritis Rheum|2
02575|067|R|  1991 Dec;34(12):1514-20.|2
02575|068|R|10.Seideman P, Muller-Suur R. Renal effects of aspirin and low dose|2
02575|069|R|   methotrexate in rheumatoid arthritis. Ann Rheum Dis 1993 Aug;52(8):613-5.|2
02575|070|R|11.Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory|2
02575|071|R|   drugs on methotrexate (MTX) pharmacokinetics: impairment of renal|2
02575|072|R|   clearance of MTX at weekly maintenance doses but not at 7.5 mg. J|2
02575|073|R|   Rheumatol 1995 Nov;22(11):2072-7.|2
02575|074|R|12.Rheumatrex (methotrexate, oral) US prescribing information. Dava|1
02575|075|R|   Pharmaceuticals, Inc. February, 2013.|1
02575|076|R|13.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
02575|077|R|   Inc. March, 2018.|1
02576|001|T|MONOGRAPH TITLE:  Busulfan/Acetaminophen|
02576|002|B||
02576|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02576|004|L|take action as needed.|
02576|005|B||
02576|006|A|MECHANISM OF ACTION:  Busulfan is eliminated from the body via glutathione|
02576|007|A|conjugation.  Acetaminophen reduces glutathione levels in the blood and|
02576|008|A|tissues and therefore could decrease the elimination rate of busulfan.(1,2)|
02576|009|B||
02576|010|E|CLINICAL EFFECTS:  Concurrent use of acetaminophen may result in elevated|
02576|011|E|levels of, prolonged exposure to, and toxicity from busulfan, including|
02576|012|E|myelosuppression, granulocytopenia, thrombocytopenia, anemia, seizures,|
02576|013|E|hepatic veno-occlusive disease, cardiac tamponade, bronchopulmonary|
02576|014|E|dysplasia, or cellular dysplasia.(1,2)|
02576|015|B||
02576|016|P|PREDISPOSING FACTORS:  None determined.|
02576|017|B||
02576|018|M|PATIENT MANAGEMENT:  Use acetaminophen concurrent with busulfan with|
02576|019|M|caution.(1)  Consider withholding acetaminophen for 72 hours before and|
02576|020|M|during busulfan therapy.|
02576|021|M|   If concurrent use cannot be avoided, monitor patients for busulfan|
02576|022|M|toxicity.|
02576|023|B||
02576|024|D|DISCUSSION:  Although a small population study in adult patients found no|
02576|025|D|effect of acetaminophen on busulfan clearance,(3) caution is still|
02576|026|D|warranted.(1)|
02576|027|B||
02576|028|R|REFERENCES:|
02576|029|B||
02576|030|R|1.Busilvex (busulfan) UK summary of product characteristics. Pierre Fabre|1
02576|031|R|  Medicament August, 2014.|1
02576|032|R|2.Busulfex (busulfan) US prescribing information. Otsuka America|1
02576|033|R|  Pharmaceutical, Inc. November, 2022.|1
02576|034|R|3.Nguyen L, Leger F, Lennon S, Puozzo C. Intravenous busulfan in adults|2
02576|035|R|  prior to haematopoietic stem cell transplantation: a population|2
02576|036|R|  pharmacokinetic study. Cancer Chemother Pharmacol 2006 Jan;57(2):191-8.|2
02577|001|T|MONOGRAPH TITLE:  Alipogene|
02577|002|T|Tiparvovec/Anticoagulant;Antiplatelet;Thrombolytic|
02577|003|B||
02577|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02577|005|L|is contraindicated and generally should not be dispensed or administered to|
02577|006|L|the same patient.|
02577|007|B||
02577|008|A|MECHANISM OF ACTION:  Alipogene tiparvovec is given as a one-time series of|
02577|009|A|intramuscular (IM)injections. Depending upon patient weight 27 to 60|
02577|010|A|injections are given, each at a different site.|
02577|011|B||
02577|012|E|CLINICAL EFFECTS:  Concurrent use of anticoagulant, antiplatelet, or|
02577|013|E|thrombolytic agents increase bleeding risk at IM injection sites.|
02577|014|B||
02577|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02577|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02577|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
02577|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02577|019|P|risk for bleeding (e.g. NSAIDs).|
02577|020|B||
02577|021|M|PATIENT MANAGEMENT:  Antiplatelet or other anticoagulant agents must not be|
02577|022|M|taken for at least one week prior to alipogene tiparvovec therapy. Assure|
02577|023|M|that abnormal bleeding parameters have been corrected prior to|
02577|024|M|administration.|
02577|025|M|   Antiplatelet or anticoagulant therapy may be resumed one day after|
02577|026|M|alipogene tiparvovec administration.|
02577|027|M|   If concurrent therapy is deemed medically necessary, monitor patients|
02577|028|M|receiving concurrent therapy for signs of blood loss, including decreased|
02577|029|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
02577|030|M|and promptly evaluate patients with any symptoms.|
02577|031|M|    When applicable, perform agent-specific laboratory tests (e.g. INR,|
02577|032|M|aPTT) to monitor efficacy and safety of anticoagulation. Discontinue|
02577|033|M|anticoagulation in patients with active pathologic bleeding.|
02577|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02577|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02577|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02577|037|M|and/or swelling.|
02577|038|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02577|039|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02577|040|M|initiating, altering the dose or discontinuing either drug.|
02577|041|B||
02577|042|D|DISCUSSION:  Alipogene tiparvovec is given as a one-time series of|
02577|043|D|intramuscular (IM)injections for the treatment of familial lipoprotein|
02577|044|D|lipase deficiency.  Depending upon patient weight 27 to 60 injections are|
02577|045|D|given, each at a different site.  Concurrent use of anticoagulant,|
02577|046|D|antiplatelet, or thrombolytic agents increase bleeding risk at IM injection|
02577|047|D|sites.|
02577|048|B||
02577|049|R|REFERENCE:|
02577|050|B||
02577|051|R|1.Glybera (alipogene tiparvovec) Europe Medicines Agency SPC. uniQure|1
02577|052|R|  biopharma B.V. June 26, 2015.|1
02578|001|T|MONOGRAPH TITLE:  Azathioprine; Mercaptopurine/Methotrexate|
02578|002|B||
02578|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02578|004|L|of severe adverse interaction.|
02578|005|B||
02578|006|A|MECHANISM OF ACTION:  The mechanism of this interaction has not been fully|
02578|007|A|characterized.  It has been suggested that methotrexate may inhibit the|
02578|008|A|metabolism of mercaptopurine by xanthine oxidase.(1-3)|
02578|009|B||
02578|010|E|CLINICAL EFFECTS:  Concurrent use of methotrexate with azathioprine or|
02578|011|E|mercaptopurine may increase the risk for elevated levels of and toxicity|
02578|012|E|from mercaptopurine, including bone marrow suppression, neutropenia and|
02578|013|E|hepatotoxicity.(1-3)|
02578|014|B||
02578|015|P|PREDISPOSING FACTORS:  Larger doses of methotrexate may produce larger|
02578|016|P|increases in mercaptopurine levels.(1-3)|
02578|017|P|   Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or|
02578|018|P|nucleotide diphosphatase (NUDT15) activity are at higher risk of|
02578|019|P|accumulating thiopurine metabolites and severe myelosuppression.|
02578|020|P|Approximately 0.3 % of patients of European, Latino, or African descent have|
02578|021|P|mutations of the TPMT gene resulting in little to no TPMT activity|
02578|022|P|(homozygous deficiency), and approximately 10 % have intermediate TPMT|
02578|023|P|activity (heterozygous deficiency).  NUDT15 deficiency is not seen in|
02578|024|P|patients of African descent and is seen in less than 1 % of patients of|
02578|025|P|European descent.  Approximately 1 % of patients of East Asian descent, 0.5|
02578|026|P|% of patients of central/south Asian descent, and 2 % of patients of Latino|
02578|027|P|descent have homozygous NUDT15 deficiency.  About 17 % of patients of East|
02578|028|P|Asian descent, 13 % of patients of central/south Asian descent, and 8 % of|
02578|029|P|patients of Latino descent have heterozygous NUDT15 deficiency.(5)|
02578|030|B||
02578|031|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy closely|
02578|032|M|for myelosuppression and hepatotoxicity.  The dose of azathioprine or|
02578|033|M|mercaptopurine may need to be adjusted when administered concomitantly with|
02578|034|M|high-dose methotrexate.(1-4)|
02578|035|B||
02578|036|D|DISCUSSION:  In a study in 14 pediatric patients with leukemia, methotrexate|
02578|037|D|(20 mg/m2) increased the maximum concentration (Cmax) and area-under-curve|
02578|038|D|(AUC) of mercaptopurine by 26% and 31%, respectively.(1,3)|
02578|039|D|   In a study in 10 pediatric patients with acute lymphoblastic leukemia, 2|
02578|040|D|g/m2 of methotrexate increased the Cmax and AUC of mercaptopurine (25 mg/m2)|
02578|041|D|by 108% and 69%, respectively.  Administration of 5 g/m2 of methotrexate|
02578|042|D|increased the Cmax and AUC of mercaptopurine (25 mg/m2) by 121% and 93%,|
02578|043|D|respectively.(2-3)|
02578|044|B||
02578|045|R|REFERENCES:|
02578|046|B||
02578|047|R|1.Balis FM, Holcenberg JS, Zimm S, Tubergen D, Collins JM, Murphy RF,|2
02578|048|R|  Gilchrist GS, Hammond D, Poplack DG. The effect of methotrexate on the|2
02578|049|R|  bioavailability of oral 6-mercaptopurine. Clin Pharmacol Ther 1987 Apr;|2
02578|050|R|  41(4):384-7.|2
02578|051|R|2.Innocenti F, Danesi R, Di Paolo A, Loru B, Favre C, Nardi M, Bocci G,|2
02578|052|R|  Nardini D, Macchia P, Del Tacca M. Clinical and experimental|2
02578|053|R|  pharmacokinetic interaction between 6-mercaptopurine and methotrexate.|2
02578|054|R|  Cancer Chemother Pharmacol 1996;37(5):409-14.|2
02578|055|R|3.Purixan (mercaptopurine) US prescribing information. Nova Laboratories Ltd|1
02578|056|R|  October, 2024.|1
02578|057|R|4.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
02578|058|R|  Inc. March, 2018.|1
02578|059|R|5.Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM,|6
02578|060|R|  Moyer AM, Evans WE, Klein TE, Antillon-Klussmann FG, Caudle KE, Kato M,|6
02578|061|R|  Yeoh AEJ, Schmiegelow K, Yang JJ. Clinical Pharmacogenetics Implementation|6
02578|062|R|  Consortium Guideline for Thiopurine Dosing  Based on TPMT and NUDT15|6
02578|063|R|  Genotypes: 2018 Update. Clin Pharmacol Ther 2019 May;105(5):1095-1105.|6
02579|001|T|MONOGRAPH TITLE:  Topiramate/Hydrochlorothiazide|
02579|002|B||
02579|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02579|004|L|take action as needed.|
02579|005|B||
02579|006|A|MECHANISM OF ACTION:  Hydrochlorothiazide may increase levels of topiramate.|
02579|007|A|Also, both agents may decrease potassium levels.(1,2)|
02579|008|B||
02579|009|E|CLINICAL EFFECTS:  Concurrent use of hydrochlorothiazide may result in|
02579|010|E|elevated levels of topiramate and hypokalemia.(1,2)|
02579|011|B||
02579|012|P|PREDISPOSING FACTORS:  None determined.|
02579|013|B||
02579|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and topiramate in patients|
02579|015|M|receiving concurrent therapy.  The dosage of topiramate may need to be|
02579|016|M|adjusted, an alternative diuretic or potassium supplement may be needed.|
02579|017|B||
02579|018|D|DISCUSSION:  In a study in 23 healthy subjects, concurrent|
02579|019|D|hydrochlorothiazide (25 mg daily) increased the maximum concentration (Cmax)|
02579|020|D|and area-under-curve (AUC) of topiramate (96 mg BID) by 27% and 29%,|
02579|021|D|respectively.  During concurrent therapy, 61% of patients had a serum|
02579|022|D|potassium level less than 3.5 mEq/L, compared with 27% with topiramate alone|
02579|023|D|and 25% with hydrochlorothiazide alone.  During concurrent therapy, the mean|
02579|024|D|decrease in serum potassium levels was -0.60 mEq/L, compared with -0.25|
02579|025|D|mEq/L with topiramate alone and -0.12 mEq/L with hydrochlorothiazide|
02579|026|D|alone.(1)|
02579|027|B||
02579|028|R|REFERENCES:|
02579|029|B||
02579|030|R|1.Topamax (topiramate) Canadian prescribing information. Janssen, Inc. April|1
02579|031|R|  28, 2014.|1
02579|032|R|2.Topamax (topiramate) US prescribing information. Janssen Pharmaceuticals,|1
02579|033|R|  Inc. May, 2023.|1
02580|001|T|MONOGRAPH TITLE:  Clopidogrel; Prasugrel/Cangrelor|
02580|002|B||
02580|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02580|004|L|take action as needed.|
02580|005|B||
02580|006|A|MECHANISM OF ACTION:  Cangrelor blocks the active metabolite of clopidogrel|
02580|007|A|or prasugrel from binding to the platelet P2Y12 receptor when cangrelor|
02580|008|A|occupies the receptor.(1-4)|
02580|009|B||
02580|010|E|CLINICAL EFFECTS:  Doses of clopidogrel and prasugrel administered during|
02580|011|E|cangrelor infusion will not be effective.(1)|
02580|012|B||
02580|013|P|PREDISPOSING FACTORS:  None determined.|
02580|014|B||
02580|015|M|PATIENT MANAGEMENT:  Clopidogrel and prasugrel should not be administered|
02580|016|M|during the cangrelor infusion.  When transitioning to clopidogrel or|
02580|017|M|prasugrel, administer these agents immediately after the discontinuation of|
02580|018|M|cangrelor infusion.(1)|
02580|019|B||
02580|020|D|DISCUSSION:  The expected effects of loading doses of clopidogrel (600 mg)|
02580|021|D|and prasugrel (60 mg) were blocked when these agents were administered|
02580|022|D|during infusion of cangrelor.(1)  There was no effect on loading doses of|
02580|023|D|ticagrelor.(1)|
02580|024|D|   The active metabolite of clopidogrel or prasugrel is blocked from binding|
02580|025|D|to the platelet P2Y12 receptor when cangrelor occupies the receptor.(2-4)|
02580|026|D|   Cangrelor is a direct, selective, and reversible P2Y12 platelet receptor|
02580|027|D|inhibitor.  Clopidogrel and prasugrel are irreversible P2Y12 platelet|
02580|028|D|inhibitors.(1-4)|
02580|029|B||
02580|030|R|REFERENCES:|
02580|031|B||
02580|032|R|1.Kengreal (cangrelor) US prescribing information. The Medicines Company|1
02580|033|R|  October, 2019.|1
02580|034|R|2.Judge HM, Buckland RJ, Jakubowski JA, Storey RF. Cangrelor inhibits the|5
02580|035|R|  binding of the active metabolites of clopidogrel and prasugrel to P2Y12|5
02580|036|R|  receptors in vitro. Platelets 2016;27(3):191-5.|5
02580|037|R|3.Schneider DJ, Agarwal Z, Seecheran N, Gogo P. Pharmacodynamic Effects When|2
02580|038|R|  Clopidogrel is Given Before Cangrelor Discontinuation. J Interv Cardiol|2
02580|039|R|  2015 Oct;28(5):415-9.|2
02580|040|R|4.Schneider DJ. Transition strategies from cangrelor to oral platelet P2Y12|2
02580|041|R|  receptor antagonists. Coron Artery Dis 2016 Jan;27(1):65-9.|2
02581|001|T|MONOGRAPH TITLE:  Lumacaftor-ivacaftor/Slt Strong CYP3A4 Inhibitor &|
02581|002|T|Substrate|
02581|003|B||
02581|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02581|005|L|of severe adverse interaction.|
02581|006|B||
02581|007|A|MECHANISM OF ACTION:  Adagrasib, ceritinib, clarithromycin, idelalisib,|
02581|008|A|indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole,|
02581|009|A|lopinavir/ritonavir, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
02581|010|A|posaconazole, ribociclib, ritonavir, telithromycin, and tucatinib are both|
02581|011|A|strong inhibitors and substrates of CYP3A4.(1,2)|
02581|012|A|   Strong inhibitors of CYP3A4 may inhibit the CYP3A4-mediated metabolism of|
02581|013|A|ivacaftor.|
02581|014|A|   Lumacaftor is a strong inducer of CYP3A4.  Over time, lumacaftor|
02581|015|A|induction moderates the CYP3A4 inhibitor effect on ivacaftor.  In addition,|
02581|016|A|lumacaftor may increase the metabolism of agents that are metabolized by|
02581|017|A|CYP3A4.(3)|
02581|018|B||
02581|019|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02581|020|E|in elevated levels of and toxicity from ivacaftor.(3)|
02581|021|E|   Concurrent use of lumacaftor with agents that are CYP3A4 substrates may|
02581|022|E|result in decreased levels and effectiveness of the substrate.(3)|
02581|023|B||
02581|024|P|PREDISPOSING FACTORS:  The interaction severity may be increased in patients|
02581|025|P|with hepatic impairment.(3)|
02581|026|B||
02581|027|M|PATIENT MANAGEMENT:  The US manufacturer of lumacaftor-ivacaftor states that|
02581|028|M|concurrent use of sensitive CYP3A4 substrates and those with a narrow|
02581|029|M|therapeutic index are not recommended.  An alternative to macrolide|
02581|030|M|antibiotics (e.g. clarithromycin, telithromycin) should be considered, such|
02581|031|M|as ciprofloxacin, azithromycin, and levofloxacin.  Azole antifungals are not|
02581|032|M|recommended.  Consider an alternative such as fluconazole.(3)|
02581|033|M|   The US manufacturer of itraconazole states that concurrent use with|
02581|034|M|lumacaftor-ivacaftor is not recommended two weeks before, during, and two|
02581|035|M|weeks after itraconazole treatment.(5)|
02581|036|M|   If concurrent use is necessary, recommended adjustments depend upon|
02581|037|M|whether lumacaftor-ivacaftor or the strong CYP3A4 inhibitor was started|
02581|038|M|first.|
02581|039|M|   - If the patient has been stabilized on lumacaftor-ivacaftor therapy when|
02581|040|M|the CYP3A4 inhibitor is started, no dose adjustments are necessary.|
02581|041|M|   - If lumacaftor-ivacaftor tablets are started in a patient currently|
02581|042|M|receiving a strong CYP3A4 inhibitor, then begin with one tablet daily for|
02581|043|M|the first week of treatment. Following this period, continue with the|
02581|044|M|recommended daily dose.|
02581|045|M|   - If lumacaftor-ivacaftor granules are started in a patient currently|
02581|046|M|receiving a strong CYP3A4 inhibitor, then begin with one packet of oral|
02581|047|M|granules every other day for the first week of treatment. Following this|
02581|048|M|period, continue with the recommended daily dose.|
02581|049|M|   If lumacaftor-ivacaftor tablet therapy is stopped for more than one week|
02581|050|M|while taking a strong CYP3A4 inhibitor, when re-initiated the|
02581|051|M|lumacaftor-ivacaftor tablets the dose should be one tablet daily for the|
02581|052|M|first week.  Following this period, continue with the recommended daily|
02581|053|M|dose.|
02581|054|M|   If lumacaftor-ivacaftor granules therapy is stopped for more than one|
02581|055|M|week while taking a strong CYP3A4 inhibitor, when re-initiated the|
02581|056|M|lumacaftor-ivacaftor granules the dose should be one packet of oral granules|
02581|057|M|every other day for the first week.  Following this period, continue with|
02581|058|M|the recommended daily dose.|
02581|059|B||
02581|060|D|DISCUSSION:  In an interaction study lumacaftor reduced exposure to|
02581|061|D|ivacaftor, a CYP3A4 sensitive substrate, by 80%.(3)|
02581|062|D|   Concurrent administration with itraconazole (a strong inhibitor of|
02581|063|D|CYP3A4) increased ivacaftor area-under-curve (AUC) by 4.3-fold.(3)|
02581|064|D|   A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with|
02581|065|D|ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B),|
02581|066|D|and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4|
02581|067|D|of ivacaftor administration (study C).  In study A, B, and C, ivacaftor AUC|
02581|068|D|increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively,|
02581|069|D|with the addition of ritonavir.  Ivacaftor concentration maximum (Cmax) was|
02581|070|D|0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(4)|
02581|071|D|   Agents that are both strong inhibitors and substrates of CYP3A4 linked to|
02581|072|D|this monograph include: adagrasib, ceritinib, clarithromycin, idelalisib,|
02581|073|D|indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole,|
02581|074|D|lopinavir/ritonavir, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
02581|075|D|posaconazole, ribociclib, ritonavir, telithromycin, and tucatinib.(1-2)|
02581|076|B||
02581|077|R|REFERENCES:|
02581|078|B||
02581|079|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
02581|080|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02581|081|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02581|082|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02581|083|R|  11/14/2017.|1
02581|084|R|2.This information is based on an extract from the Certara Drug Interaction|6
02581|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02581|086|R|3.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
02581|087|R|  Pharmaceuticals Inc. August, 2023.|1
02581|088|R|4.Liddy AM, McLaughlin G, Schmitz S, D'Arcy DM, Barry MG. The|2
02581|089|R|  Pharmacokinetic Interaction between Ivacaftor and Ritonavir in Healthy|2
02581|090|R|  Volunteers. Br J Clin Pharmacol 2017 May 06.|2
02581|091|R|5.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02581|092|R|  Products, L.P. February, 2024.|1
02582|001|T|MONOGRAPH TITLE:  Hormonal Contraceptive Agents/Lumacaftor|
02582|002|B||
02582|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02582|004|L|of severe adverse interaction.|
02582|005|B||
02582|006|A|MECHANISM OF ACTION:  Lumacaftor, a strong inducer of CYP3A4, may induce the|
02582|007|A|metabolism of hormonal contraceptive agents.(1)|
02582|008|B||
02582|009|E|CLINICAL EFFECTS:  Concurrent use of lumacaftor and hormonal contraceptive|
02582|010|E|agents may decrease the effectiveness of the hormonal contraceptive agent,|
02582|011|E|which may result in contraceptive failure.|
02582|012|E|   In addition, menstrual related adverse effects such as such as|
02582|013|E|amenorrhea, dysmenorrhea, menorrhagia and irregular menses are common.(1)|
02582|014|B||
02582|015|P|PREDISPOSING FACTORS:  None determined.|
02582|016|B||
02582|017|M|PATIENT MANAGEMENT:  Women receiving lumacaftor therapy should not rely|
02582|018|M|solely on hormonal contraceptive agents (including oral, implantable,|
02582|019|M|injectable, or transdermal agents) because they may not be effective.  The|
02582|020|M|manufacturer recommends avoiding concomitant use unless the benefit|
02582|021|M|outweighs the risk.(1)|
02582|022|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
02582|023|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
02582|024|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
02582|025|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
02582|026|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
02582|027|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
02582|028|M|and to seek medical advice if they do become pregnant.(2)|
02582|029|B||
02582|030|D|DISCUSSION:  Lumacaftor is a strong inducer of CYP3A4.  Hormonal|
02582|031|D|contraceptives are metabolized by CYP3A4, therefore, hormonal contraceptive|
02582|032|D|agents may not be reliable in patients taking lumacaftor.(1)|
02582|033|D|   Menstrual irregularities, e.g. amenorrhea, dysmenorrhea, menorrhagia and|
02582|034|D|irregular menses were reported in 27% of lumacaftor patients also taking|
02582|035|D|hormonal contraceptives vs. 3% of female patients not using hormonal|
02582|036|D|contraceptives.(1)|
02582|037|B||
02582|038|R|REFERENCES:|
02582|039|B||
02582|040|R|1.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
02582|041|R|  Pharmaceuticals Inc. August, 2023.|1
02582|042|R|2.Medicines and Healthcare products Regulatory Agency.|1
02582|043|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
02582|044|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
02582|045|R|  available at:|1
02582|046|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
02582|047|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
02582|048|R|  -and-contraceptive-efficacy September 15, 2016..|1
02583|001|T|MONOGRAPH TITLE:  Delamanid/Strong CYP3A4 Inhibitors; Atazanavir; Darunavir|
02583|002|B||
02583|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02583|004|L|take action as needed.|
02583|005|B||
02583|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02583|007|A|delamanid.(1)|
02583|008|B||
02583|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
02583|010|E|increased levels of and toxicity from delamanid,(1) including QT|
02583|011|E|prolongation.  QT prolongation may result in potentially life-threatening|
02583|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02583|013|B||
02583|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02583|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02583|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02583|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02583|018|P|female gender, or advanced age.(2)|
02583|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02583|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02583|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02583|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02583|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02583|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02583|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02583|026|B||
02583|027|M|PATIENT MANAGEMENT:  Concurrent use of delamanid and strong CYP3A4|
02583|028|M|inhibitors should be approached with caution.  If concurrent use is|
02583|029|M|necessary, frequently monitor ECGs (more frequently than the standard|
02583|030|M|recommended monthly ECG during delamanid therapy) throughout the full|
02583|031|M|delamanid treatment period.  Discontinue delamanid if a QTcF greater than|
02583|032|M|500 msec is observed.  Discontinue delamanid if albumin falls below 2.8|
02583|033|M|g/DL.(1)|
02583|034|M|   If concurrent therapy with either delamanid and a strong CYP3A4 inhibitor|
02583|035|M|that prolongs the QTc interval is warranted, consider obtaining serum|
02583|036|M|calcium, magnesium, and potassium levels and monitoring ECG at baseline and|
02583|037|M|at regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02583|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02583|039|B||
02583|040|D|DISCUSSION:  In a study in healthy subjects, lopinavir/ritonavir (400/100 mg|
02583|041|D|daily) administered with delamanid (100 mg twice daily) increased exposure|
02583|042|D|to delamanid exposed by 30%.  There was no effect on delamanid levels.(1)|
02583|043|D|   QT prolongation has been observed with delamanid and increases over the|
02583|044|D|first 6-10 weeks of therapy.  In a placebo controlled study in healthy|
02583|045|D|subjects, the mean increase in QTcF from baseline during delamanid therapy|
02583|046|D|was 7/6 msec at 1 month and 12.1 msec at 2 months.  Three percent of|
02583|047|D|patients experienced an increase of 60 msec or greater at some point during|
02583|048|D|therapy.  One patient had a QTcF greater than 500 msec.  All patients with a|
02583|049|D|QTcF greater than 60 msec were also taking a fluoroquinolone.(1)|
02583|050|D|   Strong inhibitors of CYP3A4 include: atazanavir, boceprevir, cobicistat,|
02583|051|D|darunavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
02583|052|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
02583|053|D|paritaprevir, telaprevir, tipranavir, and tucatinib.(3,4)|
02583|054|B||
02583|055|R|REFERENCES:|
02583|056|B||
02583|057|R|1.Deltyba (delamanid) EMA summary of products characteristics. Otsuka Novel|1
02583|058|R|  Products GmbH March, 2023.|1
02583|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02583|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02583|061|R|  settings: a scientific statement from the American Heart Association and|6
02583|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02583|063|R|  2;55(9):934-47.|6
02583|064|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02583|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02583|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02583|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02583|068|R|  11/14/2017.|1
02583|069|R|4.This information is based on an extract from the Certara Drug Interaction|6
02583|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02584|001|T|MONOGRAPH TITLE:  Brexpiprazole/Moderate CYP3A4 Inhibitors|
02584|002|B||
02584|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02584|004|L|take action as needed.|
02584|005|B||
02584|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02584|007|A|brexpiprazole.(1)|
02584|008|B||
02584|009|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
02584|010|E|may result in elevated levels of and toxicity from brexpiprazole.(1)|
02584|011|B||
02584|012|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
02584|013|P|patients who are CYP2D6 poor metabolizers, or who receive concomitant|
02584|014|P|treatment with a strong or moderate CYP2D6 inhibitor (e.g. bupropion,|
02584|015|P|fluoxetine, paroxetine, quinidine) in addition to treatment with a moderate|
02584|016|P|CYP3A4 inhibitor.|
02584|017|B||
02584|018|M|PATIENT MANAGEMENT:  The US manufacturer of brexpiprazole recommends the|
02584|019|M|following dose adjustments for patients who are receiving a moderate CYP3A4|
02584|020|M|inhibitor:|
02584|021|M|   - in patients taking a moderate CYP3A4 inhibitor who are poor CYP2D6|
02584|022|M|metabolizers or are receiving a strong or moderate inhibitor of CYP2D6,|
02584|023|M|decrease the dose to one-fourth the usual dose.  The dose of brexpiprazole|
02584|024|M|should be adjusted to its original level if the CYP3A4 inhibitor is|
02584|025|M|discontinued.(1)|
02584|026|M|   No empiric dosage adjustment is recommended in other patients.|
02584|027|B||
02584|028|D|DISCUSSION:  Coadministration of ketoconazole, a strong inhibitor of CYP3A4,|
02584|029|D|increased the area-under-curve (AUC) of brexpiprazole approximately|
02584|030|D|2-fold.(1)|
02584|031|D|   Moderate CYP3A4 inhibitors linked to this monograph include aprepitant,|
02584|032|D|avacopan, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone,|
02584|033|D|duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine,|
02584|034|D|fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir,|
02584|035|D|letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol,|
02584|036|D|tofisopam, treosulfan and verapamil.|
02584|037|B||
02584|038|R|REFERENCE:|
02584|039|B||
02584|040|R|1.Rexulti (brexpiprazole) US prescribing information. Otsuka Pharmaceutical|1
02584|041|R|  Co., Ltd. June, 2020.|1
02585|001|T|MONOGRAPH TITLE:  Brexpiprazole/Strong CYP2D6 Inhibitors|
02585|002|B||
02585|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02585|004|L|take action as needed.|
02585|005|B||
02585|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
02585|007|A|brexpiprazole.(1)|
02585|008|B||
02585|009|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
02585|010|E|may result in elevated levels of and toxicity from brexpiprazole.(1)|
02585|011|B||
02585|012|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
02585|013|P|patients who are receiving concomitant treatment with a strong or moderate|
02585|014|P|CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor.|
02585|015|P|Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to|
02585|016|P|increase brexpiprazole levels 5.1-fold in extensive metabolizers of|
02585|017|P|CYP2D6.(1)|
02585|018|B||
02585|019|M|PATIENT MANAGEMENT:  The US manufacturer of brexpiprazole recommends the|
02585|020|M|following dose adjustments for patients who are receiving a strong CYP2D6|
02585|021|M|inhibitor:|
02585|022|M|   - in patients with major depressive disorder who are taking a strong|
02585|023|M|CYP2D6 inhibitor WITHOUT a strong or moderate CYP3A4 inhibitor, no dosage|
02585|024|M|adjustment is required.|
02585|025|M|   - in patients with major depressive disorder who are taking a strong|
02585|026|M|CYP2D6 inhibitor AND who are receiving a strong or moderate inhibitor of|
02585|027|M|CYP3A4, decrease the dose to one-fourth the usual dose.|
02585|028|M|   - in patients with schizophrenia who are taking a strong CYP2D6 inhibitor|
02585|029|M|WITHOUT a strong or moderate CYP3A4 inhibitor, administer half the usual|
02585|030|M|dosage of brexpiprazole.|
02585|031|M|   - in patients with schizophrenia who are taking a strong CYP2D6 inhibitor|
02585|032|M|AND who are receiving a strong or moderate inhibitor of CYP3A4, decrease the|
02585|033|M|dose to one-fourth the usual dose.|
02585|034|M|   The dose of brexpiprazole should be adjusted to its original level if the|
02585|035|M|CYP2D6 inhibitor is discontinued.(1)|
02585|036|B||
02585|037|D|DISCUSSION:  Coadministration of quinidine, a strong inhibitor of CYP2D6,|
02585|038|D|increased the area-under-curve (AUC) of brexpiprazole approximately|
02585|039|D|2-fold.(1)|
02585|040|D|   Strong CYP2D6 inhibitors include: dacomitinib, fluoxetine,|
02585|041|D|hydroquinidine, paroxetine, quinidine, and terbinafine.(2,3)|
02585|042|B||
02585|043|R|REFERENCES:|
02585|044|B||
02585|045|R|1.Rexulti (brexpiprazole) US prescribing information. Otsuka Pharmaceutical|1
02585|046|R|  Co., Ltd. June, 2020.|1
02585|047|R|2.This information is based on an extract from the Certara Drug Interaction|6
02585|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02585|049|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02585|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02585|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02585|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02585|053|R|  11/14/2017.|1
02586|001|T|MONOGRAPH TITLE:  Brexpiprazole/Moderate CYP2D6 Inhibitors|
02586|002|B||
02586|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02586|004|L|take action as needed.|
02586|005|B||
02586|006|A|MECHANISM OF ACTION:  CYP2D6 inhibitors may inhibit the metabolism of|
02586|007|A|brexpiprazole.(1)|
02586|008|B||
02586|009|E|CLINICAL EFFECTS:  Concurrent administration of a moderate CYP2D6 inhibitor|
02586|010|E|may result in elevated levels of and toxicity from brexpiprazole.(1)|
02586|011|B||
02586|012|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
02586|013|P|patients who are receiving concomitant treatment with a strong or moderate|
02586|014|P|CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor.|
02586|015|P|Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to|
02586|016|P|increase brexpiprazole levels 5.1-fold in extensive metabolizers of|
02586|017|P|CYP2D6.(1)|
02586|018|B||
02586|019|M|PATIENT MANAGEMENT:  The US manufacturer of brexpiprazole recommends the|
02586|020|M|following dose adjustments for patients who are receiving a moderate CYP2D6|
02586|021|M|inhibitor:|
02586|022|M|   - in patients with schizophrenia or major depressive disorder who are|
02586|023|M|taking a moderate CYP2D6 inhibitor AND who are receiving a strong or|
02586|024|M|moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual|
02586|025|M|dose.|
02586|026|M|   - no empiric dosage adjustment is recommended for patients receiving|
02586|027|M|moderate CYP2D6 inhibitors without a strong or moderate inhibitor of CYP3A4.|
02586|028|M|   The dose of brexpiprazole should be adjusted to its original level if the|
02586|029|M|CYP2D6 inhibitor is discontinued.(1)|
02586|030|M|   Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected|
02586|031|M|to last at least 28 days after administration.(2)|
02586|032|B||
02586|033|D|DISCUSSION:  Coadministration of quinidine, a strong inhibitor of CYP2D6,|
02586|034|D|increased the area-under-curve (AUC) of brexpiprazole approximately|
02586|035|D|2-fold.(1)|
02586|036|D|   A single dose of rolapitant increased dextromethorphan, a CYP2D6|
02586|037|D|substrate, about 3-fold on days 8 and day 22 following administration.|
02586|038|D|Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single|
02586|039|D|dose rolapitant.  The inhibitory effects of rolapitant on CYP2D6 are|
02586|040|D|expected to persist beyond 28 days.(2)|
02586|041|D|   Moderate CYP2D6 inhibitors linked to this monograph include: abiraterone,|
02586|042|D|asunaprevir, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram,|
02586|043|D|mirabegron, moclobemide, and rolapitant.|
02586|044|B||
02586|045|R|REFERENCES:|
02586|046|B||
02586|047|R|1.Rexulti (brexpiprazole) US prescribing information. Otsuka Pharmaceutical|1
02586|048|R|  Co., Ltd. June, 2020.|1
02586|049|R|2.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
02587|001|T|MONOGRAPH TITLE:  Felodipine/Lumacaftor|
02587|002|B||
02587|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02587|004|L|of severe adverse interaction.|
02587|005|B||
02587|006|A|MECHANISM OF ACTION:  Lumacaftor, a strong inducer of CYP3A4, may induce the|
02587|007|A|metabolism of felodipine.(1)|
02587|008|A|   Felodipine is designated as a sensitive CYP3A4 substrate; strong inducers|
02587|009|A|may decrease exposure (area-under-curve, AUC) by > or = 80%.(2)|
02587|010|B||
02587|011|E|CLINICAL EFFECTS:  Serum levels and bioavailability of felodipine may be|
02587|012|E|decreased resulting in a decrease or loss of antihypertensive or antianginal|
02587|013|E|effects.|
02587|014|B||
02587|015|P|PREDISPOSING FACTORS:  None determined.|
02587|016|B||
02587|017|M|PATIENT MANAGEMENT:  The manufacturer of lumacaftor states concurrent use|
02587|018|M|with sensitive CYP3A4 substrates is not recommended.(1)  Consider use of|
02587|019|M|other antihypertensive agents (except nisoldipine, also a sensitive CYP3A4|
02587|020|M|substrate) when possible.|
02587|021|M|   In patients already receiving felodipine when lumacaftor is started, the|
02587|022|M|onset of this interaction may be delayed, and maximal induction effects may|
02587|023|M|not be seen for 2 or more weeks.  Monitor antihypertensive response and|
02587|024|M|adjust the dose of felodipine as needed.|
02587|025|M|   In patients stabilized on lumacaftor therapy, the addition of felodipine|
02587|026|M|may not be effective for treatment of hypertension or angina.|
02587|027|B||
02587|028|D|DISCUSSION:  In an interaction study lumacaftor reduced exposure to|
02587|029|D|ivacaftor, another CYP3A4 sensitive substrate, by 80%.(1)|
02587|030|D|    A study in healthy subjects compared felodipine exposure in patients|
02587|031|D|receiving felodipine alone or with another strong CYP3A4 inducer|
02587|032|D|(phenytoin). Combination therapy reduced felodipine exposure|
02587|033|D|(area-under-curve) by 94%.(3)|
02587|034|B||
02587|035|R|REFERENCES:|
02587|036|B||
02587|037|R|1.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
02587|038|R|  Pharmaceuticals Inc. August, 2023.|1
02587|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02587|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02587|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02587|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02587|043|R|  11/14/2017.|1
02587|044|R|3.Capewell S, Freestone S, Critchley JA, Pottage A, Prescott LF. Reduced|2
02587|045|R|  felodipine bioavailability in patients taking anticonvulsants. Lancet 1988|2
02587|046|R|  Aug 27;2(8609):480-2.|2
02588|001|T|MONOGRAPH TITLE:  Live Vaccines/Bevacizumab|
02588|002|B||
02588|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02588|004|L|is contraindicated and generally should not be dispensed or administered to|
02588|005|L|the same patient.|
02588|006|B||
02588|007|A|MECHANISM OF ACTION:  Systemic bevacizumab suppresses the immune system.|
02588|008|A|Immunocompromised patients may be at increased risk for uninhibited|
02588|009|A|replication after administration of live, attenuated vaccines. Immune|
02588|010|A|response to vaccines may be decreased during periods of immunocompromise.(1)|
02588|011|B||
02588|012|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained|
02588|013|E|and/or the vaccine may result in illness.(1)|
02588|014|B||
02588|015|P|PREDISPOSING FACTORS:  Immunosuppressive diseases (e.g. hematologic|
02588|016|P|malignancies, HIV disease), treatments (e.g. radiation) and drugs may all|
02588|017|P|increase the magnitude of immunodeficiency.|
02588|018|P|   Intravitreal injections of small doses of bevacizumab for macular|
02588|019|P|degeneration or macular edema are not expected to suppress immune function.|
02588|020|B||
02588|021|M|PATIENT MANAGEMENT:  The Centers for Disease Control(CDC) Advisory Committee|
02588|022|M|on Immunization Practices (ACIP) states that live-virus and live, attenuated|
02588|023|M|vaccines should not be administered to patients who are immunocompromised.|
02588|024|M|The magnitude of immunocompromise and associated risks should be determined|
02588|025|M|by a physician.(1)  Intravitreal injections of small doses of bevacizumab|
02588|026|M|for macular degeneration or macular edema are not expected to suppress|
02588|027|M|immune function.|
02588|028|M|   For patients scheduled to receive chemotherapy, vaccination should|
02588|029|M|ideally precede the initiation of chemotherapy by 14 days.  Patients|
02588|030|M|vaccinated while on immunosuppressive therapy or in the 2 weeks prior to|
02588|031|M|starting therapy should be considered unimmunized and should be revaccinated|
02588|032|M|at least 3 months after discontinuation of therapy.(1)|
02588|033|B||
02588|034|D|DISCUSSION:  Killed or inactivated vaccines do not pose a danger to|
02588|035|D|immunocompromised patients.(1)|
02588|036|D|   Patients with a history of leukemia who are in remission and have not|
02588|037|D|received chemotherapy for at least 3 months are not considered to be|
02588|038|D|immunocompromised.(1)|
02588|039|B||
02588|040|R|REFERENCE:|
02588|041|B||
02588|042|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
02588|043|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
02588|044|R|  Practices (ACIP). MMWR.  Available at:|1
02588|045|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
02588|046|R|  February 17, 2022;60(RR No.2):1-68.|1
02589|001|T|MONOGRAPH TITLE:  Metoclopramide/Prochlorperazine|
02589|002|B||
02589|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02589|004|L|of severe adverse interaction.|
02589|005|B||
02589|006|A|MECHANISM OF ACTION:  Both metoclopramide and prochlorperazine block|
02589|007|A|dopamine (D2) receptors. D2 blockade can cause extrapyramidal reactions,|
02589|008|A|such acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or|
02589|009|A|tardive dyskinesia. Neuroleptic malignant syndrome may also occur in|
02589|010|A|patients receiving D2 blockers.  The risk of these adverse effects may be|
02589|011|A|increased by concurrent use.(1-3)|
02589|012|B||
02589|013|E|CLINICAL EFFECTS:  Concurrent use may increase the risk of extrapyramidal|
02589|014|E|reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors,|
02589|015|E|akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome.|
02589|016|E|Tardive dyskinesia, which may be permanent, typically affects the facial|
02589|017|E|muscles and may result in uncontrollable lip smacking, chewing, puckering of|
02589|018|E|the mouth, frowning or scowling, sticking out the tongue, blinking and|
02589|019|E|moving the eyes, and shaking of the arms and/or legs.(1-3)|
02589|020|E|   Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle|
02589|021|E|rigidity, altered mental status, an autonomic instability (irregular pulse|
02589|022|E|or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias),|
02589|023|E|elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute|
02589|024|E|renal failure.(1)|
02589|025|B||
02589|026|P|PREDISPOSING FACTORS:  Patients with Parkinson's or Lewy Body Disease may be|
02589|027|P|more likely to have extrapyramidal reactions or unmasking of their primary|
02589|028|P|disease symptoms.  The risk of extrapyramidal symptoms is also increased in|
02589|029|P|patients on metoclopramide for longer than 12 weeks.|
02589|030|P|   Elderly patients, especially elderly women, and diabetics are at higher|
02589|031|P|risk of developing tardive dyskinesia.|
02589|032|P|   Other extrapyramidal symptoms, like acute dystonia, have occurred more|
02589|033|P|frequently in patients younger than 30 years old.(1)|
02589|034|B||
02589|035|M|PATIENT MANAGEMENT:  The concurrent use of metoclopramide and agents likely|
02589|036|M|to cause extrapyramidal reactions should be avoided.(1)|
02589|037|M|   If concurrent use is warranted, monitor patients closely for|
02589|038|M|extrapyramidal reactions and neuroleptic malignant syndrome.  The|
02589|039|M|manufacturer of metoclopramide says to avoid treatment with metoclopramide|
02589|040|M|for longer than 12 weeks, and to use the lowest possible dose.(1)|
02589|041|M|Discontinue therapy if symptoms occur.  Instruct patients to seek immediate|
02589|042|M|medical attention if symptoms develop.|
02589|043|M|   Symptoms of extrapyramidal reactions, including tardive dyskinesia,|
02589|044|M|include involuntary movements of limbs and facial grimacing, torticollis,|
02589|045|M|oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech,|
02589|046|M|trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.|
02589|047|B||
02589|048|D|DISCUSSION:  Both metoclopramide and phenothiazines can cause extrapyramidal|
02589|049|D|reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome.|
02589|050|D|The risk may be increased by concurrent use.(1,2)|
02589|051|D|   Extrapyramidal symptoms have been reported with concurrent metoclopramide|
02589|052|D|and neuroleptics, prochlorperazine, and chlorpromazine.(3-6)|
02589|053|B||
02589|054|R|REFERENCES:|
02589|055|B||
02589|056|R|1.Reglan (metoclopramide) tablets US prescribing information. ANI|1
02589|057|R|  Pharmaceuticals, Inc. August 29, 2017.|1
02589|058|R|2.Reglan (metoclopramide) injection US prescribing information. Baxter|1
02589|059|R|  Healthcare Corporation November, 2010.|1
02589|060|R|3.Krahenbuhl S, Raisin J, Herren T. Malignant neuroleptic syndrome under|3
02589|061|R|  metoclopramide and neuroleptics in anuria. Schweiz Med Wochenschr 1993 Jul|3
02589|062|R|  3;123(26):1359-62.|3
02589|063|R|4.Factor SA, Matthews MK. Persistent extrapyramidal syndrome with dystonia|3
02589|064|R|  and rigidity caused by combined metoclopramide and prochlorperazine|3
02589|065|R|  therapy. South Med J 1991 May;84(5):626-8.|3
02589|066|R|5.Schou H, Kongstad LL. Acute dystonia with fatal outcome. A possible|3
02589|067|R|  adverse drug reaction in the simultaneous administration of chlorpromazine|3
02589|068|R|  (Prozil) and metoclopramide (Primperan). Ugeskr Laeger 1986 Sep 8;|3
02589|069|R|  148(37):2357-8.|3
02590|001|T|MONOGRAPH TITLE:  Metoclopramide/Promethazine|
02590|002|B||
02590|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02590|004|L|of severe adverse interaction.|
02590|005|B||
02590|006|A|MECHANISM OF ACTION:  Both metoclopramide and promethazine block dopamine|
02590|007|A|(D2) receptors. D2 blockade can cause extrapyramidal reactions, such acute|
02590|008|A|dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive|
02590|009|A|dyskinesia. Neuroleptic malignant syndrome may also occur in patients|
02590|010|A|receiving D2 blockers.  The risk of these adverse effects may be increased|
02590|011|A|by concurrent use.(1-3)|
02590|012|B||
02590|013|E|CLINICAL EFFECTS:  Concurrent use may increase the risk of extrapyramidal|
02590|014|E|reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors,|
02590|015|E|akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome.|
02590|016|E|Tardive dyskinesia, which may be permanent, typically affects the facial|
02590|017|E|muscles and may result in uncontrollable lip smacking, chewing, puckering of|
02590|018|E|the mouth, frowning or scowling, sticking out the tongue, blinking and|
02590|019|E|moving the eyes, and shaking of the arms and/or legs.(1-3)|
02590|020|E|   Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle|
02590|021|E|rigidity, altered mental status, an autonomic instability (irregular pulse|
02590|022|E|or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias),|
02590|023|E|elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute|
02590|024|E|renal failure.(1)|
02590|025|B||
02590|026|P|PREDISPOSING FACTORS:  Patients with Parkinson's or Lewy Body Disease may be|
02590|027|P|more likely to have extrapyramidal reactions or unmasking of their primary|
02590|028|P|disease symptoms.  The risk of extrapyramidal symptoms is also increased in|
02590|029|P|patients on metoclopramide for longer than 12 weeks.|
02590|030|P|   Elderly patients, especially elderly women, and diabetics are at higher|
02590|031|P|risk of developing tardive dyskinesia.|
02590|032|P|   Other extrapyramidal symptoms, like acute dystonia, have occurred more|
02590|033|P|frequently in patients younger than 30 years old.(1)|
02590|034|B||
02590|035|M|PATIENT MANAGEMENT:  The concurrent use of metoclopramide and agents likely|
02590|036|M|to cause extrapyramidal reactions should be avoided.(1)|
02590|037|M|   If concurrent use is warranted, monitor patients closely for|
02590|038|M|extrapyramidal reactions and neuroleptic malignant syndrome.  The|
02590|039|M|manufacturer of metoclopramide says to avoid treatment with metoclopramide|
02590|040|M|for longer than 12 weeks, and to use the lowest possible dose.(1)|
02590|041|M|Discontinue therapy if symptoms occur.  Instruct patients to seek immediate|
02590|042|M|medical attention if symptoms develop.|
02590|043|M|   Symptoms of extrapyramidal reactions, including tardive dyskinesia,|
02590|044|M|include involuntary movements of limbs and facial grimacing, torticollis,|
02590|045|M|oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech,|
02590|046|M|trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.|
02590|047|B||
02590|048|D|DISCUSSION:  Both metoclopramide and phenothiazines can cause extrapyramidal|
02590|049|D|reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome.|
02590|050|D|The risk may be increased by concurrent use.(1,2)|
02590|051|D|   Extrapyramidal symptoms have been reported with concurrent metoclopramide|
02590|052|D|and neuroleptics, prochlorperazine, and chlorpromazine.(3-5)|
02590|053|B||
02590|054|R|REFERENCES:|
02590|055|B||
02590|056|R|1.Reglan (metoclopramide) tablets US prescribing information. ANI|1
02590|057|R|  Pharmaceuticals, Inc. August 29, 2017.|1
02590|058|R|2.Reglan (metoclopramide) injection US prescribing information. Baxter|1
02590|059|R|  Healthcare Corporation November, 2010.|1
02590|060|R|3.Reglan (metoclopramide) injection US medication guide. Baxter Healthcare|1
02590|061|R|  Corporation June, 2009.|1
02590|062|R|4.Krahenbuhl S, Raisin J, Herren T. Malignant neuroleptic syndrome under|3
02590|063|R|  metoclopramide and neuroleptics in anuria. Schweiz Med Wochenschr 1993 Jul|3
02590|064|R|  3;123(26):1359-62.|3
02590|065|R|5.Factor SA, Matthews MK. Persistent extrapyramidal syndrome with dystonia|3
02590|066|R|  and rigidity caused by combined metoclopramide and prochlorperazine|3
02590|067|R|  therapy. South Med J 1991 May;84(5):626-8.|3
02590|068|R|6.Schou H, Kongstad LL. Acute dystonia with fatal outcome. A possible|3
02590|069|R|  adverse drug reaction in the simultaneous administration of chlorpromazine|3
02590|070|R|  (Prozil) and metoclopramide (Primperan). Ugeskr Laeger 1986 Sep 8;|3
02590|071|R|  148(37):2357-8.|3
02591|001|T|MONOGRAPH TITLE:  Selected Opioids; Dextromethorphan-Quinidine/Linezolid|
02591|002|B||
02591|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02591|004|L|of severe adverse interaction.|
02591|005|B||
02591|006|A|MECHANISM OF ACTION:  Selected opioids inhibit neural reuptake of serotonin.|
02591|007|A|Linezolid may increase neuronal serotonin concentrations via inhibition of|
02591|008|A|MAO-A.(22)|
02591|009|B||
02591|010|E|CLINICAL EFFECTS:  The concurrent use of some opioids with MAOIs has|
02591|011|E|resulted in serotonin syndrome.  Severe cases of serotonin syndrome may be|
02591|012|E|fatal.|
02591|013|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
02591|014|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02591|015|E|rigidity.(22)|
02591|016|B||
02591|017|P|PREDISPOSING FACTORS:  Higher opioid concentrations (e.g., due to inhibition|
02591|018|P|of opioid clearance, patient specific genomic factors such as poor|
02591|019|P|metabolizer status for a cytochrome P450 enzyme, or high opioid dosage) may|
02591|020|P|increase the risk for a severe interaction.|
02591|021|B||
02591|022|M|PATIENT MANAGEMENT:  Diamorphine, meperidine, and tapentadol should not be|
02591|023|M|used in patients taking linezolid.  Use alternative agents for cough or|
02591|024|M|pain.|
02591|025|B||
02591|026|D|DISCUSSION:  The interaction between meperidine and MAOIs has been well|
02591|027|D|documented.|
02591|028|D|   There is one case report of serotonin syndrome with concurrent meperidine|
02591|029|D|and linezolid.|
02591|030|D|   Many authors state that linezolid is a weak MAOI and rarely causes|
02591|031|D|serotonin toxicity.  Cases of serotonin toxicity were rapidly reversible|
02591|032|D|with discontinuation of the offending agent(s) and supportive care.  Some|
02591|033|D|authors suggest that use of serotonergic medications should not preclude the|
02591|034|D|use of linezolid but that the clinical situation should be assessed.  If|
02591|035|D|concurrent use or use of linezolid without a washout is warranted, the|
02591|036|D|patient should be closely monitored.(21-26)|
02591|037|B||
02591|038|R|REFERENCES:|
02591|039|B||
02591|040|R|1.Mitchell RS. Fatal toxic encephalitis occurring during iproniazid therapy|2
02591|041|R|  in pulmonary tuberculosis. Ann Intern Med 1955;42:417-24.|2
02591|042|R|2.Papp C, Benaim S. Toxic effects of iproniazid in a patient with angina. Br|3
02591|043|R|  Med J 1958 Nov 1;2:1070-2.|3
02591|044|R|3.Palmer H. Potentiation of pethidine. Br Med J 1960 Sep 24;2:944.|3
02591|045|R|4.Shee JC. Dangerous potentiation of pethidine by iproniazid, and its|3
02591|046|R|  treatment. Br Med J 1960 Aug 13;2:507-9.|3
02591|047|R|5.London DR, Milne MD. Dangers of monoamine oxidase inhibitors. Br Med J|6
02591|048|R|  1962 Dec 29;2:1752.|6
02591|049|R|6.Brownlee G, Williams GW. Potentiation of amphetamine and pethidine by|5
02591|050|R|  monoamieoxidase inhibitors. Lancet 1963 Mar 23;1:669.|5
02591|051|R|7.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
02591|052|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
02591|053|R|8.Anonymous. Analgesics and monoamine-oxidase inhibitors. Br Med J 1967 Nov|6
02591|054|R|  4;4(574):284.|6
02591|055|R|9.Evans-Prosser CD. The use of pethidine and morphine in the presence of|2
02591|056|R|  monoamine oxidase inhibitors. Br J Anaesth 1968 Apr;40(4):279-82.|2
02591|057|R|10.Jounela AJ, Kivimaki T. Possible sensitivity to meperidine in|3
02591|058|R|   phenylketonuria. N Engl J Med 1973 Jun 28;288(26):1411.|3
02591|059|R|11.Barry BJ. Adverse effects of MAO inhibitors with narcotics reversed with|3
02591|060|R|   naloxone. Anaesth Intensive Care 1979 May;7(2):194.|3
02591|061|R|12.Browne B, Linter S. Monoamine oxidase inhibitors and narcotic analgesics.|6
02591|062|R|   A critical review of the implications for treatment. Br J Psychiatry 1987|6
02591|063|R|   Aug;151:210-2.|6
02591|064|R|13.Zornberg GL, Bodkin JA, Cohen BM. Severe adverse interaction between|3
02591|065|R|   pethidine and selegiline. Lancet 1991 Jan 26;337(8735):246.|3
02591|066|R|14.Rossiter A, Souney PF. Interaction between MAOIs and opioids:|6
02591|067|R|   pharmacologic and clinical considerations. Hosp Formul 1993 Aug;28:692-8.|6
02591|068|R|15.Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine|3
02591|069|R|   oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988 Dec 22;|3
02591|070|R|   319(25):1671.|3
02591|071|R|16.Rivers N, Horner B. Possible lethal reaction between Nardil and|3
02591|072|R|   dextromethorphan. Can Med Assoc J 1970 Jul;103:85.|3
02591|073|R|17.Diamorphine hydrochloride Australian prescribing information. Auralis|1
02591|074|R|   March 13, 2008.|1
02591|075|R|18.Nucynta ER (tapentadol) US prescribing information. Janssen|1
02591|076|R|   Pharmaceuticals December, 2023.|1
02591|077|R|19.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02591|078|R|   352(11):1112-20.|6
02591|079|R|20.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
02591|080|R|   prescribing information. Avanir  Pharmaceuticals June, 2019.|1
02591|081|R|21.Lodise TP, Patel N, Rivera A, Tristani L, Lazariu V, Vandewall H, McNutt|2
02591|082|R|   LA. Comparative evaluation of serotonin toxicity among veterans affairs|2
02591|083|R|   patients  receiving linezolid and vancomycin. Antimicrob Agents Chemother|2
02591|084|R|   2013 Dec;57(12):5901-11.|2
02591|085|R|22.Ramsey TD, Lau TT, Ensom MH. Serotonergic and adrenergic drug|6
02591|086|R|   interactions associated with linezolid: a critical  review and practical|6
02591|087|R|   management approach. Ann Pharmacother 2013 Apr;47(4):543-60.|6
02591|088|R|23.Woytowish MR, Maynor LM. Clinical relevance of linezolid-associated|6
02591|089|R|   serotonin toxicity. Ann Pharmacother 2013 Mar;47(3):388-97.|6
02591|090|R|24.Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, Lodise TP.|2
02591|091|R|   Comparison of serotonin toxicity with concomitant use of either linezolid|2
02591|092|R|   or  comparators and serotonergic agents: an analysis of Phase III and IV|2
02591|093|R|   randomized  clinical trial data. J Antimicrob Chemother 2012 Feb;|2
02591|094|R|   67(2):494-502.|2
02591|095|R|25.Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion|6
02591|096|R|   J Clin Psychiatry 2009;11(6):353-6.|6
02591|097|R|26.Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug|2
02591|098|R|   interactions: a retrospective survey. Clin Infect Dis 2006 Jul 15;|2
02591|099|R|   43(2):180-7.|2
02592|001|T|MONOGRAPH TITLE:  Warfarin Derivatives/Lopinavir; Nelfinavir; Nevirapine;|
02592|002|T|Ritonavir|
02592|003|B||
02592|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02592|005|L|take action as needed.|
02592|006|B||
02592|007|A|MECHANISM OF ACTION:  Lopinavir, nelfinavir, nevirapine, and ritonavir may|
02592|008|A|induce the metabolism of acenocoumarol and warfarin.|
02592|009|A|   The more potent S-enantiomer of warfarin is metabolized by CYP2C9 while|
02592|010|A|the weaker R-enantiomer of warfarin is metabolized by CYP3A4 and CYP1A2.|
02592|011|A|   Although protease inhibitors can induce or inhibit multiple CYP450|
02592|012|A|pathways depending upon the drug and time course of therapy, all antiviral|
02592|013|A|agents linked to this monograph are inducers of CYP2C9.|
02592|014|B||
02592|015|E|CLINICAL EFFECTS:  Concurrent use warfarin derivatives and lopinavir,|
02592|016|E|nelfinavir, nevirapine, and/or ritonavir may result in decreased levels and|
02592|017|E|effectiveness of the anticoagulant, which may increase the risk of clotting.|
02592|018|B||
02592|019|P|PREDISPOSING FACTORS:  None determined.|
02592|020|B||
02592|021|M|PATIENT MANAGEMENT:  Monitor INR response closely in patients maintained on|
02592|022|M|acenocoumarol or warfarin when initiating or titrating lopinavir,|
02592|023|M|nelfinavir, nevirapine, or ritonavir.  Patients maintained on these agents|
02592|024|M|may require higher dosages of the anticoagulant beginning approximately 1-2|
02592|025|M|weeks after starting the antiviral.|
02592|026|M|   If the antiviral is discontinued, enzyme induction will gradually|
02592|027|M|decrease and the anticoagulant concentration is expected to increase over|
02592|028|M|time.  Monitor the INR as the anticoagulant dose may need to be lowered.|
02592|029|M|   Also monitor INR closely when initiating warfarin in patients on current|
02592|030|M|therapy or titrating doses of lopinavir, nelfinavir, nevirapine, and|
02592|031|M|ritonavir.|
02592|032|B||
02592|033|D|DISCUSSION:  In a study in 12 subjects, ritonavir (400mg every 12 hours for|
02592|034|D|12 days) increased the area-under-curve (AUC) of S-warfarin by 9% and|
02592|035|D|decreased the AUC of R-warfarin by 33%, from a single dose of warfarin (5|
02592|036|D|mg).  The maximum concentration (Cmax) of S-warfarin was decreased 9% and|
02592|037|D|unchanged for R-warfarin.|
02592|038|D|   In a case-control study, use of ritonavir (200 mg daily) was associated|
02592|039|D|with an increased warfarin maintenance dose of 3.9 mg.|
02592|040|D|   There have been case reports of increased acenocoumarol and warfarin|
02592|041|D|requirements in patients taking lopinavir-ritonavir, nelfinavir, nevirapine,|
02592|042|D|and/or ritonavir.|
02592|043|D|   In a retrospective study in 29 patients, INR levels were evaluated with|
02592|044|D|concurrent use of nirmatrelvir-ritonavir and warfarin.  In patients treated|
02592|045|D|with nirmatrelvir-ritonavir, the first posttreatment INR was lower than|
02592|046|D|baseline (median INR decrease of 0.40).  Following completion of the 5-day|
02592|047|D|course of nirmatrelvir-ritonavir, the measured INR was lower than the|
02592|048|D|pretreatment nirmatrelvir-ritonavir INR (median INR decrease of 0.50).  No|
02592|049|D|thrombotic events occurred during the study period after|
02592|050|D|nirmatrelvir-ritonavir use.|
02592|051|B||
02592|052|R|REFERENCES:|
02592|053|B||
02592|054|R|1.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
02592|055|R|  December, 2019.|1
02592|056|R|2.Esterly JS, Darin KM, Gerzenshtein L, Othman F, Postelnick MJ, Scarsi KK.|3
02592|057|R|  Clinical implications of antiretroviral drug interactions with warfarin: a|3
02592|058|R|  case-control study. J Antimicrob Chemother 2013 Jun;68(6):1360-3.|3
02592|059|R|3.Fulco PP, Zingone MM, Higginson RT. Possible antiretroviral|3
02592|060|R|  therapy-warfarin drug interaction. Pharmacotherapy 2008 Jul;28(7):945-9.|3
02592|061|R|4.Bonora S, Lanzafame M, D'Avolio A, Trentini L, Lattuada E, Concia E, Di|3
02592|062|R|  Perri G. Drug interactions between warfarin and efavirenz or|3
02592|063|R|  lopinavir-ritonavir in clinical treatment. Clin Infect Dis 2008 Jan 1;|3
02592|064|R|  46(1):146-7.|3
02592|065|R|5.Hughes CA, Freitas A, Miedzinski LJ. Interaction between|3
02592|066|R|  lopinavir/ritonavir and warfarin. CMAJ 2007 Aug 14;177(4):357-9.|3
02592|067|R|6.Griffon C, Gaertner S, Mirea C, Welsch M, Stephan D. Inefficacy of vitamin|3
02592|068|R|  K antagonists in an human immunodeficiency virus seropositive patient|3
02592|069|R|  taking nevirapine. Presse Med 2009 Nov;38(11):1696-8.|3
02592|070|R|7.Dionisio D, Mininni S, Bartolozzi D, Esperti F, Vivarelli A, Leoncini F.|3
02592|071|R|  Need for increased dose of warfarin in HIV patients taking nevirapine.|3
02592|072|R|  AIDS 2001 Jan 26;15(2):277-8.|3
02592|073|R|8.Llibre JM, Romeu J, Lopez E, Sirera G. Severe interaction between|3
02592|074|R|  ritonavir and acenocoumarol. Ann Pharmacother 2002 Apr;36(4):621-3.|3
02592|075|R|9.Knoell KR, Young TM, Cousins ES. Potential interaction involving warfarin|3
02592|076|R|  and ritonavir. Ann Pharmacother 1998 Dec;32(12):1299-302.|3
02592|077|R|10.Newshan G, Tsang P. Ritonavir and warfarin interaction. AIDS 1999 Sep 10;|3
02592|078|R|   13(13):1788-9.|3
02592|079|R|11.Gatti G, Alessandrini A, Camera M, Di Biagio A, Bassetti M, Rizzo F.|3
02592|080|R|   Influence of indinavir and ritonavir on warfarin anticoagulant activity.|3
02592|081|R|   AIDS 1998 May 7;12(7):825-6.|3
02592|082|R|12.Liedtke MD, Rathbun RC. Warfarin-antiretroviral interactions. Ann|6
02592|083|R|   Pharmacother 2009 Feb;43(2):322-8.|6
02592|084|R|13.This information is based on an extract from the Certara Drug Interaction|6
02592|085|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02592|086|R|14.Muse O, Patell R, Lee M, Lech T, Guirguis M, Dodge L, Zwicker JI. Impact|3
02592|087|R|   of Paxlovid on international normalized ratio among patients on chronic|3
02592|088|R|   warfarin therapy. Blood 2022 Dec 22;140(25):2757-2759.|3
02593|001|T|MONOGRAPH TITLE:  Warfarin/Mitotane|
02593|002|B||
02593|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02593|004|L|of severe adverse interaction.|
02593|005|B||
02593|006|A|MECHANISM OF ACTION:  Mitotane may induce the metabolism of warfarin by|
02593|007|A|CYP3A4.(1)|
02593|008|B||
02593|009|E|CLINICAL EFFECTS:  Concurrent or recent use of mitotane may result in|
02593|010|E|decreased levels and effectiveness of warfarin, which may increase the risk|
02593|011|E|of clotting.(1)|
02593|012|B||
02593|013|P|PREDISPOSING FACTORS:  None determined.|
02593|014|B||
02593|015|M|PATIENT MANAGEMENT:  The manufacturer of mitotane states that concomitant|
02593|016|M|use of warfarin should be avoided.  If concomitant use cannot be avoided,|
02593|017|M|monitor INR response more closely when initiating, titrating, and|
02593|018|M|discontinuing mitotane and for several months after mitotane is|
02593|019|M|discontinued.  Patients maintained on mitotane or who discontinued mitotane|
02593|020|M|in the previous six months may require higher dosages of warfarin.(1)|
02593|021|B||
02593|022|D|DISCUSSION:  Mitotane use has been shown to result in elevate warfarin|
02593|023|D|requirements.(1,2)|
02593|024|B||
02593|025|R|REFERENCES:|
02593|026|B||
02593|027|R|1.Lysodren (mitotane) US prescribing information. E.R. Squibb & Sons, L.L.C.|1
02593|028|R|  October, 2024.|1
02593|029|R|2.Cuddy PG, Loftus LS. Influence of mitotane on the hypoprothrombinemic|3
02593|030|R|  effect of warfarin. South Med J 1986 Mar;79(3):387-8.|3
02594|001|T|MONOGRAPH TITLE:  Repaglinide/Clopidogrel|
02594|002|B||
02594|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02594|004|L|is contraindicated and generally should not be dispensed or administered to|
02594|005|L|the same patient.|
02594|006|B||
02594|007|A|MECHANISM OF ACTION:  Repaglinide is primarily metabolized by CYP2C8, and|
02594|008|A|its elimination is facilitated by OATP1B1 transport.  A clopidogrel|
02594|009|A|metabolite inhibits both of these pathways.(1)|
02594|010|B||
02594|011|E|CLINICAL EFFECTS:  Concurrent use of clopidogrel and repaglinide is expected|
02594|012|E|to increase systemic exposure (AUC, area-under-curve) to repaglinide and may|
02594|013|E|result in hypoglycemia.|
02594|014|B||
02594|015|P|PREDISPOSING FACTORS:  Patients who achieve tight control of blood sugars,|
02594|016|P|or have a history of multiple hypoglycemic episodes may be at greater risk|
02594|017|P|for hypoglycemia with this combination.|
02594|018|B||
02594|019|M|PATIENT MANAGEMENT:  Based upon results of a published clinical trial,|
02594|020|M|Health Canada and the Canadian manufacturer of repaglinide state that|
02594|021|M|concurrent use of clopidogrel and repaglinide is contraindicated due to the|
02594|022|M|risk for hypoglycemia from unanticipated lowering of serum glucose|
02594|023|M|concentrations.(2)   Alternative antiplatelet agents (e.g. prasugrel,|
02594|024|M|ticagrelor) and antidiabetic agents are not known to inhibit CYP2C8 or|
02594|025|M|OATP1B1.(3)|
02594|026|M|   The manufacturer of clopidogrel states that when concomitant use is|
02594|027|M|required in a patient maintained on clopidogrel, initiate repaglinide at 0.5|
02594|028|M|mg with each meal and titrate based on blood glucose levels. Do not exceed a|
02594|029|M|total daily dose of 4 mg. If concomitant use of clopidogrel is required in a|
02594|030|M|patient stabilized on repaglinide, down titrate the dose of repaglinide|
02594|031|M|based on blood glucose levels to not exceed a total daily dose of 4 mg.(4)|
02594|032|M|   If concomitant use is deemed medically necessary:|
02594|033|M|   - Hypoglycemic risk is greatest when clopidogrel is added to existing|
02594|034|M|repaglinide therapy.  Frequent monitoring of serum/blood glucose is needed|
02594|035|M|to monitor patient response as the magnitude of glucose lowering varies|
02594|036|M|between patients.|
02594|037|M|   - In patients stabilized on clopidogrel when repaglinide is initiated,|
02594|038|M|increased sensitivity to the hypoglycemic effect of repaglinide would be|
02594|039|M|expected. In addition, because repaglinide half-life is prolonged in the|
02594|040|M|presence of clopidogrel, maximal effects of repaglinide may be delayed -|
02594|041|M|slower than usual dose titration would be prudent.|
02594|042|M|   Separating the timing of drug administration would not be expected to|
02594|043|M|decrease interaction risk as the clopidogrel metabolite (clopidogrel|
02594|044|M|acyl-beta-D-glucuronide) is an irreversible inhibitor of CYP2C8.(1)|
02594|045|B||
02594|046|D|DISCUSSION:  In a drug interaction trial conducted in healthy non-diabetic|
02594|047|D|adults, a clopidogrel 300 mg loading dose increased repaglinide exposure|
02594|048|D|5.1-fold and a 75 mg maintenance dose increased repaglinide exposure|
02594|049|D|3.9-fold.|
02594|050|D|   Corresponding serum glucose changes:|
02594|051|D|   - Clopidogrel 300 mg plus repaglinide decreased minimum glucose|
02594|052|D|concentrations an average of 20 mg/dL (1.1 mmol/L) more than repaglinide|
02594|053|D|alone.|
02594|054|D|   - Clopidogrel 300mg X1 dose, followed by 75 mg daily dosing for two days|
02594|055|D|with daily repaglinide resulted in an average decrease in minimum glucose|
02594|056|D|concentrations of 9 mg/dL lower than patients on repaglinide alone.(1)|
02594|057|B||
02594|058|R|REFERENCES:|
02594|059|B||
02594|060|R|1.Tornio A, Filppula AM, Kailari O, Neuvonen M, Nyronen TH, Tapaninen T,|2
02594|061|R|  Neuvonen PJ, Niemi M, Backman JT. Glucuronidation converts clopidogrel to|2
02594|062|R|  a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a|2
02594|063|R|  perpetrator of drug-drug interactions. Clin Pharmacol Ther 2014 Oct;|2
02594|064|R|  96(4):498-507.|2
02594|065|R|2.Health Canada. Gluconorm (repaglinide) - New Contraindication for|1
02594|066|R|  Concomitant Use with Clopidogrel. accessed at:|1
02594|067|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/54454a-e|1
02594|068|R|  ng.php July 31, 2015.|1
02594|069|R|3.This information is based on an extract from the Certara Drug Interaction|6
02594|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02594|071|R|4.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
02594|072|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
02595|001|T|MONOGRAPH TITLE:  Metformin/Dolutegravir|
02595|002|B||
02595|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02595|004|L|take action as needed.|
02595|005|B||
02595|006|A|MECHANISM OF ACTION:  Dolutegravir may inhibit the renal organic cation|
02595|007|A|transporter, OCT2, responsible for the elimination of metformin.(1)|
02595|008|B||
02595|009|E|CLINICAL EFFECTS:  Concurrent use may result in increased plasma levels of|
02595|010|E|metformin and toxicity such as lactic acidosis.  Untreated lactic acidosis|
02595|011|E|may be fatal. Symptoms of lactic acidosis include malaise, myalgias,|
02595|012|E|respiratory distress, low pH, increased anion gap and elevated blood|
02595|013|E|lactate.|
02595|014|B||
02595|015|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
02595|016|P|include renal impairment,sepsis, dehydration, excessive alcohol intake,|
02595|017|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
02595|018|P|failure, metformin plasma levels > 5 micrograms/mL, and conditions which may|
02595|019|P|lead to tissue hypoxia.  Geriatric patients may also be at higher risk due|
02595|020|P|to slower metformin clearance and increased half-life in this population.|
02595|021|B||
02595|022|M|PATIENT MANAGEMENT:  With concomitant use, assess the benefit and risk of|
02595|023|M|metformin in patients on dolutegravir.  When starting or stopping|
02595|024|M|dolutegravir, the metformin dose may require an adjustment.  Monitor blood|
02595|025|M|glucose when initiating concomitant use and after stopping dolutegravir.(1)|
02595|026|M|   Monitor patient's renal function and for signs and symptoms of metformin|
02595|027|M|toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress,|
02595|028|M|increasing somnolence, and respiratory distress. Laboratory results which|
02595|029|M|may signal lactic acidosis include: low pH, an increased anion gap, and|
02595|030|M|increased lactate to pyruvate ratio.(1)|
02595|031|B||
02595|032|D|DISCUSSION:  Dolutegravir has been shown to inhibit OCT2 in vitro and in|
02595|033|D|vivo and is expected to inhibit the excretion of metformin.(1)|
02595|034|D|   In a study in 15 subjects, concomitant metformin (500 mg twice daily)|
02595|035|D|with dolutegravir (50 mg daily) increased the concentration maximum (Cmax)|
02595|036|D|and area-under-curve (AUC) of metformin by 66% and 79%, respectively. In a|
02595|037|D|study in 15 subjects, concomitant metformin (500 mg twice daily) with|
02595|038|D|dolutegravir (50 mg twice daily) increased the Cmax and AUC of metformin by|
02595|039|D|111% and 145%, respectively.(1)|
02595|040|B||
02595|041|R|REFERENCE:|
02595|042|B||
02595|043|R|1.Tivicay (dolutegravir) US prescribing information. GlaxoSmithKline|1
02595|044|R|  October, 2022.|1
02596|001|T|MONOGRAPH TITLE:  Thioridazine/Asunaprevir|
02596|002|B||
02596|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02596|004|L|is contraindicated and generally should not be dispensed or administered to|
02596|005|L|the same patient.|
02596|006|B||
02596|007|A|MECHANISM OF ACTION:  Asunaprevir may inhibit the metabolism of thioridazine|
02596|008|A|by CYP2D6.(1)  Thioridazine is a moderate inducer of CYP3A4 and may increase|
02596|009|A|the metabolism of asunaprevir.(1,2)|
02596|010|B||
02596|011|E|CLINICAL EFFECTS:  The concurrent administration of asunaprevir with|
02596|012|E|thioridazine may result in elevated levels of thioridazine.  Elevated levels|
02596|013|E|of thioridazine may augment thioridazine-induced prolongation of the QTc|
02596|014|E|interval, increasing the risk of serious, potentially fatal, cardiac|
02596|015|E|arrhythmias such as torsades de pointes.(1,3,4)|
02596|016|E|   In addition, thioridazine may decrease the levels and efficacy of|
02596|017|E|asunaprevir.(1,2)|
02596|018|B||
02596|019|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers may|
02596|020|P|be affected to a greater extent by CYP2D6 inhibitors.  Patients who are|
02596|021|P|CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6|
02596|022|P|inhibition.|
02596|023|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02596|024|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02596|025|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02596|026|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02596|027|P|advanced age.(5)|
02596|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02596|029|P|higher systemic concentrations of either QT prolonging drug are additional|
02596|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02596|031|P|drug concentrations include rapid infusion of an intravenous dose or|
02596|032|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
02596|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02596|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
02596|035|B||
02596|036|M|PATIENT MANAGEMENT:  Use an alternative antipsychotic agent.  The concurrent|
02596|037|M|use of thioridazine with asunaprevir is contraindicated.(1)|
02596|038|M|   If thioridazine cannot be discontinued, use an alternative agent for the|
02596|039|M|treatment of hepatitis C and evaluate the patient for predisposing risk|
02596|040|M|factors which increase the risk for QT prolongation. Correct modifiable risk|
02596|041|M|factors (e.g. electrolyte disorders) and monitor for QT prolongation as|
02596|042|M|appropriate throughout treatment with thioridazine.|
02596|043|M|   Thioridazine should not be initiated in patients with a QTc interval|
02596|044|M|greater than 450 msec and should be discontinued in patients found to have a|
02596|045|M|corrected QTc greater than 500 msec.(4)|
02596|046|B||
02596|047|D|DISCUSSION:  A study in six slow and 13 rapid metabolizers of debrisoquin, a|
02596|048|D|marker of CYP2D6 activity, showed that slow metabolizers of debrisoquin had|
02596|049|D|2.4-fold and 4.5-fold higher thioridazine maximum concentration (Cmax) and|
02596|050|D|AUC, respectively, than rapid metabolizers.(6)|
02596|051|D|   A study in 9 healthy male subjects showed a thioridazine dose-related|
02596|052|D|prolongation of the QTc interval.  One subtherapeutic thioridazine 10 mg|
02596|053|D|dose increased QTc 9 msec (range -1 to 19 msec), and a single|
02596|054|D|low-therapeutic thioridazine dose of 50 mg increased QTc 22 msec (range 11|
02596|055|D|to 33 msec).(7)|
02596|056|B||
02596|057|R|REFERENCES:|
02596|058|B||
02596|059|R|1.Sunvepra (asunaprevir) Australia Prescribing Information. Bristol-Myers|1
02596|060|R|  Squibb Australia Pty Ltd April 5, 2019.|1
02596|061|R|2.This information is based on an extract from the Certara Drug Interaction|6
02596|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02596|063|R|3.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
02596|064|R|  September, 2014.|1
02596|065|R|4.Dear Doctor Letter. Re:  Important drug warning about Mellarill. Novartis|1
02596|066|R|  Pharmaceuticals Corporation July 7, 2000.|1
02596|067|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02596|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02596|069|R|  settings: a scientific statement from the American Heart Association and|6
02596|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02596|071|R|  2;55(9):934-47.|6
02596|072|R|6.von Bahr C, Movin G, Nordin C, Liden A, Hammarlund-Udenaes M, Hedberg A,|2
02596|073|R|  Ring H, Sjoqvist F. Plasma levels of thioridazine and metabolites are|2
02596|074|R|  influenced by the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther|2
02596|075|R|  1991 Mar;49(3):234-40.|2
02596|076|R|7.Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH.|2
02596|077|R|  Concentration-related pharmacodynamic effects of thioridazine and its|2
02596|078|R|  metabolites in humans. Clin Pharmacol Ther 1996 Nov;60(5):543-53.|2
02597|001|T|MONOGRAPH TITLE:  Digoxin/Vemurafenib|
02597|002|B||
02597|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02597|004|L|of severe adverse interaction.|
02597|005|B||
02597|006|A|MECHANISM OF ACTION:  Vemurafenib may increase the absorption of digoxin by|
02597|007|A|inhibiting P-glycoprotein.(1)|
02597|008|B||
02597|009|E|CLINICAL EFFECTS:  Concurrent vemurafenib may result in elevated levels of|
02597|010|E|and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can include|
02597|011|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
02597|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
02597|013|E|disturbances, and arrhythmias.|
02597|014|B||
02597|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02597|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02597|017|P|risk of digoxin toxicity.|
02597|018|B||
02597|019|M|PATIENT MANAGEMENT:  Avoid concurrent use of vemurafenib with digoxin.  If|
02597|020|M|concurrent use is unavoidable, consider dose reduction of digoxin.  Monitor|
02597|021|M|patients receiving concurrent therapy with digoxin and vemurafenib(1) for|
02597|022|M|symptoms of toxicity, including anorexia, nausea, vomiting, headache,|
02597|023|M|fatigue, malaise, drowsiness, generalized muscle weakness, disorientation,|
02597|024|M|hallucinations, visual disturbances, and arrhythmias.|
02597|025|B||
02597|026|D|DISCUSSION:  In vitro studies suggest that vemurafenib is a substrate and an|
02597|027|D|inhibitor of P-glycoprotein. (1)|
02597|028|D|   In a study in 26 cancer patients, administration of vemurafenib (960 mg|
02597|029|D|twice daily) for 22 days increased digoxin AUC by 1.8 fold (90%CI:1.6, 2.0)|
02597|030|D|and Cmax by 1.5-fold (90%CI:1.3, 1.7) after concomitant administration of a|
02597|031|D|single dose of digoxin (0.25 mg).|
02597|032|B||
02597|033|R|REFERENCE:|
02597|034|B||
02597|035|R|1.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02597|036|R|  November, 2017.|1
02598|001|T|MONOGRAPH TITLE:  Edoxaban (Greater Than 30 mg)/Selected P-gp Inhibitors|
02598|002|B||
02598|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02598|004|L|of severe adverse interaction.|
02598|005|B||
02598|006|A|MECHANISM OF ACTION:  Edoxaban is a substrate for P-glycoprotein (P-gp).|
02598|007|A|Inhibitors of P-gp may increase intestinal absorption and decrease renal|
02598|008|A|tubular elimination of edoxaban.(1,2)|
02598|009|B||
02598|010|E|CLINICAL EFFECTS:  Concurrent use with selected P-gp inhibitors may result|
02598|011|E|in higher systemic concentrations of edoxaban which may increase the risk|
02598|012|E|for bleeding.(1-5)  P-gp inhibitors linked to this interaction are:|
02598|013|E|cyclosporine, dronedarone, erythromycin, and ketoconazole.|
02598|014|B||
02598|015|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with|
02598|016|P|creatinine clearance 15mL - 50 mL per minute(1) or weight < or = 60 kg.(2)|
02598|017|P|   Use of multiple agents which increase edoxaban exposure or affect|
02598|018|P|hemostasis would be expected to increase the risk for bleeding.|
02598|019|P|   The risk for bleeding episodes may be greater in patients with|
02598|020|P|disease-associated factors (thrombocytopenia).|
02598|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
02598|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02598|023|P|risk for bleeding (e.g. NSAIDs).|
02598|024|B||
02598|025|M|PATIENT MANAGEMENT:  Management recommendations vary depending upon the|
02598|026|M|approving regulatory agency (FDA or European Medicines Agency, EMA).|
02598|027|M|   US FDA recommendations are based upon the edoxaban indication:|
02598|028|M|   - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE),|
02598|029|M|the edoxaban dose should be reduced to 30 mg daily when used concomitantly|
02598|030|M|with erythromycin or oral ketoconazole.(3)|
02598|031|M|   - For prevention of stroke or embolic events due to nonvalvular atrial|
02598|032|M|fibrillation, no edoxaban dose adjustments are recommended during|
02598|033|M|concomitant therapy with P-glycoprotein inhibitors.(1,3)|
02598|034|M|   - Concurrent use of cyclosporine was not allowed in edoxaban clinical|
02598|035|M|trials (atrial fibrillation or DVT/PE).  US prescribing information does not|
02598|036|M|provide specific management information for concurrent use of cyclosporine|
02598|037|M|with edoxaban.(3)|
02598|038|M|   EMA dosage adjustments are the same, regardless of indication:|
02598|039|M|   - Reduce edoxaban dose to 30 mg daily in patients receiving concomitant|
02598|040|M|treatment with cyclosporine, dronedarone, erythromycin or oral|
02598|041|M|ketoconazole.(4)|
02598|042|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
02598|043|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
02598|044|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02598|045|M|   When applicable, perform agent-specific laboratory test (e.g. anti Factor|
02598|046|M|Xa inhibition) to monitor efficacy and safety of anticoagulation.|
02598|047|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
02598|048|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02598|049|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02598|050|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02598|051|M|and/or swelling.|
02598|052|M|   Discontinue edoxaban in patients with active bleeding.|
02598|053|B||
02598|054|D|DISCUSSION:  Edoxaban in vivo interaction studies have been performed for|
02598|055|D|P-gp inhibitors linked to this monograph:|
02598|056|D|   In an interaction study, the effect of single oral dose of cyclosporine|
02598|057|D|500 mg on a single oral dose of edoxaban 60 mg was evaluated in healthy|
02598|058|D|subjects.  Total and peak systemic exposure to edoxaban increased 1.73-fold|
02598|059|D|and 1.74-fold, respectively. Total and peak systemic exposure to the active|
02598|060|D|M4 metabolite increased 6.87-fold and 8.71-fold respectively, likely due to|
02598|061|D|cyclosporine inhibition of OATP1B1.(1)  In the absence of OATP1B1|
02598|062|D|inhibition, M4 concentrations are generally < or = 10% of edoxaban|
02598|063|D|exposure,(1) but the approximately 7-fold increase in active metabolite|
02598|064|D|exposure may result in clinically meaningful concentrations of M4.|
02598|065|D|   In an interaction study, the effect of repeat administration of|
02598|066|D|dronedarone (400 mg bid) on a single oral dose of edoxaban 60 mg was|
02598|067|D|evaluated in healthy subjects. Total and peak systemic exposure to edoxaban|
02598|068|D|increased 1.84-fold and 1.45-fold, respectively.  Plasma edoxaban|
02598|069|D|concentrations 24 hours post dose (Ctrough) following coadministration|
02598|070|D|edoxaban and dronedarone were 2.6-fold higher compared with administration|
02598|071|D|of edoxaban alone.(1)|
02598|072|D|   In an interaction study, the effect of repeat administration of|
02598|073|D|erythromycin (oral dose of 500 mg four times daily for 8 days) on a single|
02598|074|D|oral dose of edoxaban 60 mg on on study day 7 was evaluated in healthy|
02598|075|D|subjects.  Total and peak systemic exposure to edoxaban increased 1.85-fold|
02598|076|D|and 1.68-fold, respectively.  Total and peak systemic exposure to the M4|
02598|077|D|metabolite increased 1.78-fold and 1.75-fold, respectively.(1)|
02598|078|D|   In an interaction study, the effect of repeat administration of|
02598|079|D|ketoconazole (oral dose of 400 mg QD for 7 days) on a single oral dose of|
02598|080|D|edoxaban (60 mg) was evaluated in healthy subjects. Total and peak systemic|
02598|081|D|exposure to edoxaban increased 1.87-fold and 1.89-fold, respectively.  Total|
02598|082|D|and peak systemic exposure to the M4 metabolite increased 1.46-fold and|
02598|083|D|1.56-fold, respectively.(1)|
02598|084|D|   A summary of pharmacokinetic interactions with edoxaban and dronedarone|
02598|085|D|concluded that if concurrent use is warranted, the edoxaban dose should be|
02598|086|D|reduced by 50%.(6)|
02598|087|B||
02598|088|R|REFERENCES:|
02598|089|B||
02598|090|R|1.FDA Center for Drug Evaluation and Research (CDER). Application number|1
02598|091|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
02598|092|R|  Biopharmaceutics Review. available at:|1
02598|093|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
02598|094|R|  0ClinPharmR.pdf January 8, 2015.|1
02598|095|R|2.Lixiana European Medicines Agency (EMA) Assessment report. Committee for|1
02598|096|R|  Medicinal Products for Human Use (CHMP) 23 April 2015.|1
02598|097|R|3.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02598|098|R|  2019.|1
02598|099|R|4.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
02598|100|R|  Sankyo UK Limited July 2, 2015.|1
02598|101|R|5.FDA Center for Drug Evaluation and Research (CDER). Application no. 206316|1
02598|102|R|  Summary Review Savaysa (edoxaban tosylate). available at:|1
02598|103|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
02598|104|R|  0SumR.pdf January 8, 2015.|1
02598|105|R|6.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
02598|106|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
02598|107|R|  of  the Week..|6
02599|001|T|MONOGRAPH TITLE:  Paroxetine/Asenapine|
02599|002|B||
02599|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02599|004|L|take action as needed.|
02599|005|B||
02599|006|A|MECHANISM OF ACTION:  Asenapine is a weak inhibitor of CYP2D6 and may|
02599|007|A|convert patients from the extensive metabolizer to poor metabolizer|
02599|008|A|phenotype for this enzyme. Asenapine may enhance the inhibitory effects of|
02599|009|A|paroxetine on its own metabolism by CYP2D6.(1)|
02599|010|B||
02599|011|E|CLINICAL EFFECTS:  Concurrent use of asenapine may result in increased serum|
02599|012|E|levels and adverse effects of paroxetine.|
02599|013|B||
02599|014|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
02599|015|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
02599|016|P|patients using more than one medicine with anticholinergic properties.(2)|
02599|017|B||
02599|018|M|PATIENT MANAGEMENT:  The US manufacturer of asenapine recommends that the|
02599|019|M|paroxetine dose be reduced by half when it is used in combination with|
02599|020|M|asenapine. (1)|
02599|021|B||
02599|022|D|DISCUSSION:  Concomitant use of paroxetine with asenapine increased the|
02599|023|D|paroxetine systemic exposure and maximum plasma concentration (Cmax) by|
02599|024|D|2-fold as compared to use of paroxetine alone. (1)|
02599|025|B||
02599|026|R|REFERENCES:|
02599|027|B||
02599|028|R|1.Saphris (asenapine) US prescribing information. Actavis, Inc. February 23,|1
02599|029|R|  2017.|1
02599|030|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02599|031|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02599|032|R|  Soc 2023 Jul;71(7):2052-2081.|6
02600|001|T|MONOGRAPH TITLE:  Lorcaserin/Potent 5-HT2B Receptor Agonists|
02600|002|B||
02600|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02600|004|L|is contraindicated and generally should not be dispensed or administered to|
02600|005|L|the same patient.|
02600|006|B||
02600|007|A|MECHANISM OF ACTION:  5-HT2B receptor agonists may increase the risk of|
02600|008|A|cardiac valvulopathy.(1)|
02600|009|B||
02600|010|E|CLINICAL EFFECTS:  Concurrent use of lorcaserin and potent 5-HT2B receptor|
02600|011|E|agonists may increase the risk of cardiac valvulopathy.(1)|
02600|012|B||
02600|013|P|PREDISPOSING FACTORS:  None determined.|
02600|014|B||
02600|015|M|PATIENT MANAGEMENT:  Lorcaserin should not be used with potent 5-HT2B|
02600|016|M|receptor agonists.(1)|
02600|017|M|   If concurrent use is deemed medically necessary, monitor patients for|
02600|018|M|signs and symptoms of valvular heart disease, including dyspnea, dependent|
02600|019|M|edema, congestive heart failure, and/or cardiac murmur.(1)|
02600|020|B||
02600|021|D|DISCUSSION:  Valvular heart disease has been linked to use of drugs with|
02600|022|D|5-HT2B receptor agonist activity.  At therapeutic dosages, lorcaserin is|
02600|023|D|selective for 5-HT2C receptors; however, in pooled clinical trials,|
02600|024|D|valvulopathy was reported in 2.4% of patients who received lorcaserin|
02600|025|D|compared to placebo, with a pooled relative risk of valvulopathy of 1.16.(1)|
02600|026|B||
02600|027|R|REFERENCE:|
02600|028|B||
02600|029|R|1.Belviq (lorcaserin hydrochloride) US prescribing information. Eisai Inc.|1
02600|030|R|  May 23, 2017.|1
02601|001|T|MONOGRAPH TITLE:  Edoxaban (Greater Than 30 mg)/Select P-gp Inhibitors|
02601|002|B||
02601|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02601|004|L|take action as needed.|
02601|005|B||
02601|006|A|MECHANISM OF ACTION:  Edoxaban is a substrate for P-glycoprotein (P-gp).|
02601|007|A|Inhibitors of P-gp may increase intestinal absorption and decrease renal|
02601|008|A|tubular elimination of edoxaban.(1,2)|
02601|009|B||
02601|010|E|CLINICAL EFFECTS:  Concurrent use with selected P-gp inhibitors may result|
02601|011|E|in higher systemic concentrations of edoxaban which may increase the risk|
02601|012|E|for bleeding.(1,2)|
02601|013|B||
02601|014|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with|
02601|015|P|creatinine clearance below 50 mL per minute(1-4).|
02601|016|P|   Use of multiple agents which increase edoxaban exposure or affect|
02601|017|P|hemostasis would be expected to increase the risk for bleeding.|
02601|018|P|   The risk for bleeding episodes may be greater in patients with|
02601|019|P|disease-associated factors (e.g. thrombocytopenia).|
02601|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
02601|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02601|022|P|risk for bleeding (e.g. NSAIDs).|
02601|023|B||
02601|024|M|PATIENT MANAGEMENT:  Management recommendations between approving regulatory|
02601|025|M|agencies (FDA or European Medicines Agency, EMA) are conflicting.|
02601|026|M|   EMA approved prescribing information specifically states that dosage|
02601|027|M|adjustments are not required solely for concomitant use with amiodarone,|
02601|028|M|quinidine, or verapamil regardless of indication.(3,4) Potential|
02601|029|M|interactions with azithromycin, clarithromycin, or oral itraconazole are not|
02601|030|M|described.(3)|
02601|031|M|   FDA approved prescribing recommendations for edoxaban are indication|
02601|032|M|specific:(2)|
02601|033|M|   - For prevention of stroke or embolic events due to nonvalvular atrial|
02601|034|M|fibrillation, no edoxaban dose adjustments are recommended during|
02601|035|M|concomitant therapy with P-glycoprotein inhibitors.|
02601|036|M|   - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE),|
02601|037|M|the edoxaban dose should be reduced to 30 mg daily during concomitant use|
02601|038|M|with azithromycin, clarithromycin, oral itraconazole, quinidine or|
02601|039|M|verapamil.|
02601|040|M|   The manufacturer of vimseltinib states concurrent use with P-gp|
02601|041|M|substrates should be avoided. If concurrent use cannot be avoided, take|
02601|042|M|vimseltinib at least 4 hours prior to edoxaban.(6)|
02601|043|M|   Monitor patients receiving anticoagulant therapy for signs of blood loss,|
02601|044|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
02601|045|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02601|046|M|   When applicable, perform agent-specific laboratory test (e.g. anti Factor|
02601|047|M|Xa inhibition) to monitor efficacy and safety of anticoagulation.|
02601|048|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
02601|049|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02601|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02601|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02601|052|M|and/or swelling.|
02601|053|M|   Discontinue edoxaban in patients with active bleeding.|
02601|054|B||
02601|055|D|DISCUSSION:  Edoxaban in vivo interaction studies have been performed for|
02601|056|D|quinidine and verapamil.  In vivo interaction studies have not been|
02601|057|D|conducted for the remaining P-gp inhibitors linked to this monograph.(1,4)|
02601|058|D|   In an interaction study, the effect of repeat administration of quinidine|
02601|059|D|(300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in|
02601|060|D|healthy subjects.  Both peak (Cmax) and total systemic exposure (AUC) to|
02601|061|D|edoxaban and to the active M4 metabolite increased approximately|
02601|062|D|1.75-fold.(1)|
02601|063|D|   In an interaction study, the effect of repeat administration of verapamil|
02601|064|D|(240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral|
02601|065|D|dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy|
02601|066|D|subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold|
02601|067|D|and 1.53-fold, respectively. Total and peak systemic exposure to the active|
02601|068|D|M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1)|
02601|069|D|   Based upon the above results, patients in the DVT/PE trial had a 50% dose|
02601|070|D|reduction (from 60 mg to 30 mg) during concomitant therapy with|
02601|071|D|P-glycoprotein inhibitors.  Approximately 0.5% of these patients required a|
02601|072|D|dose reduction solely due to P-gp inhibitor use.  This low rate of|
02601|073|D|concurrent therapy was too small to allow for detailed statistical|
02601|074|D|evaluation.  Almost all of these patients were receiving quinidine or|
02601|075|D|verapamil.  In these patients, both trough edoxaban concentrations (Ctrough)|
02601|076|D|used to evaluate bleeding risk, and total edoxaban exposure (AUC or|
02601|077|D|area-under-curve) used to evaluate treatment efficacy, were lower than|
02601|078|D|patients who did not require any edoxaban dose adjustment.  In this DVT/PE|
02601|079|D|comparator trial, subgroup analysis revealed that warfarin had numerically|
02601|080|D|better efficacy than edoxaban in patients receiving P-gp inhibitors.  Based|
02601|081|D|upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects,|
02601|082|D|both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the|
02601|083|D|edoxaban 50% dose reduction overcorrected for the difference in|
02601|084|D|exposure.(1,4)  Consequently, EMA recommended no edoxaban dose adjustments|
02601|085|D|for patients receiving concomitant therapy with quinidine or verapamil.(3,4)|
02601|086|D|   A summary of pharmacokinetic interactions with edoxaban and verapamil|
02601|087|D|concluded that if concurrent use is considered safe.(7)|
02601|088|D|   P-gp inhibitors linked to this interaction are:  amiodarone, asunaprevir,|
02601|089|D|azithromycin, belumosudil, capmatinib, carvedilol, cimetidine,|
02601|090|D|clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan,|
02601|091|D|daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng,|
02601|092|D|glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, indinavir, oral|
02601|093|D|itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, neratinib,|
02601|094|D|osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine,|
02601|095|D|selpercatinib, sotorasib, telaprevir, telithromycin, tezacaftor, tepotinib,|
02601|096|D|tucatinib, valbenazine, velpatasvir, vemurafenib, verapamil, vimseltinib,|
02601|097|D|and voclosporin.(8)|
02601|098|B||
02601|099|R|REFERENCES:|
02601|100|B||
02601|101|R|1.FDA Center for Drug Evaluation and Research (CDER). Application number|1
02601|102|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
02601|103|R|  Biopharmaceutics Review. available at:|1
02601|104|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
02601|105|R|  0ClinPharmR.pdf January 8, 2015.|1
02601|106|R|2.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02601|107|R|  2019.|1
02601|108|R|3.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
02601|109|R|  Sankyo UK Limited July 2, 2015.|1
02601|110|R|4.Lixiana European Medicines Agency (EMA) Assessment report. Committee for|1
02601|111|R|  Medicinal Products for Human Use (CHMP) 23 April 2015.|1
02601|112|R|5.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02601|113|R|  June, 2025.|1
02601|114|R|6.Romvimza (vimseltinib) US prescribing information. Deciphera|1
02601|115|R|  Pharmaceuticals, LLC February, 2025.|1
02601|116|R|7.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
02601|117|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
02601|118|R|  of  the Week..|6
02601|119|R|8.This information is based on an extract from the Certara Drug Interaction|6
02601|120|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02602|001|T|MONOGRAPH TITLE:  Edoxaban/Rifampin|
02602|002|B||
02602|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02602|004|L|is contraindicated and generally should not be dispensed or administered to|
02602|005|L|the same patient.|
02602|006|B||
02602|007|A|MECHANISM OF ACTION:  Edoxaban is a P-glycoprotein (P-gp) substrate.|
02602|008|A|Rifampin induces production of P-gp which may reduce systemic absorption of|
02602|009|A|edoxaban.(1)|
02602|010|B||
02602|011|E|CLINICAL EFFECTS:  Concurrent or recent use of rifampin may result in|
02602|012|E|decreased levels and effectiveness of edoxaban.(1)|
02602|013|B||
02602|014|P|PREDISPOSING FACTORS:  None determined.|
02602|015|B||
02602|016|M|PATIENT MANAGEMENT:  Avoid concurrent use of an inducer of P-gp such as|
02602|017|M|rifampin in patients maintained on edoxaban.(1)  When possible use an|
02602|018|M|alternative to rifampin in patients maintained on edoxaban.  If therapy with|
02602|019|M|rifampin is required an alternative to edoxaban may need to be considered.|
02602|020|M|  If rifampin is discontinued, edoxaban exposure will remain impaired for at|
02602|021|M|least one week after the completion of therapy.(1)|
02602|022|B||
02602|023|D|DISCUSSION:  Co-administration of rifampin (600 mg QD for 7 days) and|
02602|024|D|edoxaban (60 mg single dose on Day 7) decreased total systemic exposure to|
02602|025|D|edoxaban by 40% without having an apparent effect on peak exposure.  Total|
02602|026|D|and peak systemic exposure to the active M4 metabolite increased 2.86-fold|
02602|027|D|and 5.06-fold, respectively. Metabolite to parent ratios increased|
02602|028|D|approximately 4.5-fold from approximately 9 to 40% for area-under-curve|
02602|029|D|(AUC) and from approximately 10 to 45% for maximum concentration (Cmax).|
02602|030|D|While an increase in systemic exposure to its equipotent active M4|
02602|031|D|metabolite makes up for this loss in total systemic exposure, it is driven|
02602|032|D|by an increase in peak systemic exposure (Cmax) to M4.  At trough (end of|
02602|033|D|inter-dosing interval), there still exists a approximately 80% reduction in|
02602|034|D|exposure to both edoxaban and the active metabolite combined.(2)|
02602|035|B||
02602|036|R|REFERENCES:|
02602|037|B||
02602|038|R|1.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02602|039|R|  2019.|1
02602|040|R|2.FDA Center for Drug Evaluation and Research (CDER). Application number|1
02602|041|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
02602|042|R|  Biopharmaceutics Review. available at:|1
02602|043|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
02602|044|R|  0ClinPharmR.pdf January 8, 2015.|1
02603|001|T|MONOGRAPH TITLE:  Edoxaban/Selected P-glycoprotein (P-gp) Inducers|
02603|002|B||
02603|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02603|004|L|of severe adverse interaction.|
02603|005|B||
02603|006|A|MECHANISM OF ACTION:  Edoxaban is a P-glycoprotein (P-gp) substrate.  P-gp|
02603|007|A|induction may reduce systemic exposure to edoxaban.(1)|
02603|008|B||
02603|009|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide, carbamazepine,|
02603|010|E|efavirenz, fosphenytoin, lorlatinib, phenytoin, rifapentine, or St. John's|
02603|011|E|wort may result in decreased effectiveness of edoxaban.(1-3)|
02603|012|B||
02603|013|P|PREDISPOSING FACTORS:  None determined.|
02603|014|B||
02603|015|M|PATIENT MANAGEMENT:  The US manufacturer of edoxaban states that concomitant|
02603|016|M|use of rifampin should be avoided.  Although there are no recommendations|
02603|017|M|for other P-gp inducers, a similar precaution is reasonable.(4)|
02603|018|M|   The UK manufacturer of edoxaban recommends caution with co-administration|
02603|019|M|of P-gp inducers such as carbamazepine, phenytoin, or St. John's wort.(1,3)|
02603|020|M|Consider alternatives to the P-gp inducing agent.  If therapy with an|
02603|021|M|inducer of P-gp is required, alternatives to  edoxaban may need to be|
02603|022|M|considered.|
02603|023|M|   If a P-gp inducer is discontinued, edoxaban exposure will remain impaired|
02603|024|M|for at least one week after the completion of therapy.|
02603|025|B||
02603|026|D|DISCUSSION:  Co-administration of another P-gp inducer, rifampin 600 mg QD|
02603|027|D|for 7 days with a single dose of edoxaban 60 mg on Day 7, decreased total|
02603|028|D|systemic exposure to edoxaban by 40% without having an apparent effect on|
02603|029|D|peak exposure.(5)|
02603|030|D|   A 76-year-old male on apixaban for atrial fibrillation s/p pulmonary|
02603|031|D|embolism 1 month prior was started on rifabutin 300 mg daily for|
02603|032|D|tuberculosis.  Apixaban was switched to edoxaban due to a drug interaction|
02603|033|D|with rifabutin.  At 1 month, rifabutin was increased to 450 mg daily.  After|
02603|034|D|another 8 weeks, the patient suffered a DVT that was thought to be a result|
02603|035|D|of a drug-drug interaction with rifabutin.(6)|
02603|036|D|   Other inducers of P-glycoprotein linked to this monograph include|
02603|037|D|apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifabutin,|
02603|038|D|rifapentine, and St. John's wort.(2,3)|
02603|039|B||
02603|040|R|REFERENCES:|
02603|041|B||
02603|042|R|1.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
02603|043|R|  Sankyo UK Limited July 2, 2015.|1
02603|044|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02603|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02603|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02603|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02603|048|R|  11/14/2017.|1
02603|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
02603|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02603|051|R|4.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02603|052|R|  2019.|1
02603|053|R|5.FDA Center for Drug Evaluation and Research (CDER). Application number|1
02603|054|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
02603|055|R|  Biopharmaceutics Review. available at:|1
02603|056|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
02603|057|R|  0ClinPharmR.pdf January 8, 2015.|1
02603|058|R|6.Lanier C, Fuller M, Reece BA. Novel Drug-Drug Interaction of Potential|3
02603|059|R|  Rifabutin-Induced Edoxaban Failure: A  Case Report. J Pharm Pract 2023 Nov|3
02603|060|R|  6;8971900231213702.|3
02604|001|T|MONOGRAPH TITLE:  Edoxaban (Greater Than 30 mg)/Lapatinib; Ritonavir|
02604|002|B||
02604|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02604|004|L|take action as needed.|
02604|005|B||
02604|006|A|MECHANISM OF ACTION:  Edoxaban is a substrate for P-glycoprotein (P-gp).|
02604|007|A|Inhibitors of P-gp may increase intestinal absorption and decrease renal|
02604|008|A|tubular elimination of edoxaban.(1,2)|
02604|009|B||
02604|010|E|CLINICAL EFFECTS:  Concurrent use with P-gp inhibitors may result in higher|
02604|011|E|systemic concentrations of edoxaban which may increase the risk for|
02604|012|E|bleeding.(1,2)|
02604|013|E|   P-gp inhibitors linked to this interaction are: lapatinib,|
02604|014|E|lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir,|
02604|015|E|ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir.|
02604|016|B||
02604|017|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with|
02604|018|P|creatinine clearance below 50 mL per minute(1-2).|
02604|019|P|   Use of multiple agents which increase edoxaban exposure or affect|
02604|020|P|hemostasis would be expected to increase the risk for bleeding.|
02604|021|P|   The risk for bleeding episodes may be greater in patients with|
02604|022|P|disease-associated factors (e.g. thrombocytopenia).|
02604|023|P|   Drug associated risk factors include concurrent use of multiple drugs|
02604|024|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02604|025|P|risk for bleeding (e.g. NSAIDs).|
02604|026|B||
02604|027|M|PATIENT MANAGEMENT:  Interaction studies between edoxaban and lapatinib,|
02604|028|M|lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir,|
02604|029|M|ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir have not been|
02604|030|M|performed.  Concurrent use of these agents were not allowed in edoxaban|
02604|031|M|clinical trials.|
02604|032|M|   FDA approved prescribing recommendations for edoxaban are indication|
02604|033|M|specific:(2)|
02604|034|M|   - For prevention of stroke or embolic events due to nonvalvular atrial|
02604|035|M|fibrillation, no edoxaban dose adjustments are recommended during|
02604|036|M|concomitant therapy with P-glycoprotein inhibitors.|
02604|037|M|   - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE),|
02604|038|M|the edoxaban dose should be reduced to 30 mg daily during concomitant use|
02604|039|M|with azithromycin, clarithromycin, oral itraconazole, quinidine or|
02604|040|M|verapamil. No recommendations were made regarding concomitant lapatinib,|
02604|041|M|ritonavir or lopinavir-ritonavir therapy.|
02604|042|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
02604|043|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
02604|044|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02604|045|M|   When applicable, perform agent-specific laboratory test (e.g. anti Factor|
02604|046|M|Xa inhibition) to monitor efficacy and safety of anticoagulation.|
02604|047|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
02604|048|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02604|049|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02604|050|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02604|051|M|and/or swelling.|
02604|052|M|   Discontinue edoxaban in patients with active bleeding.|
02604|053|B||
02604|054|D|DISCUSSION:  Edoxaban interaction studies have not been performed for|
02604|055|D|lapatinib, lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir,|
02604|056|D|ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir(1) and so the|
02604|057|D|magnitude of any interaction with these agents is not known.|
02604|058|B||
02604|059|R|REFERENCES:|
02604|060|B||
02604|061|R|1.FDA Center for Drug Evaluation and Research (CDER). Application number|1
02604|062|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
02604|063|R|  Biopharmaceutics Review. available at:|1
02604|064|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
02604|065|R|  0ClinPharmR.pdf January 8, 2015.|1
02604|066|R|2.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02604|067|R|  2019.|1
02604|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
02604|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02605|001|T|MONOGRAPH TITLE:  Ibrutinib/Selected Anticoagulants; Antiplatelets|
02605|002|B||
02605|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02605|004|L|take action as needed.|
02605|005|B||
02605|006|A|MECHANISM OF ACTION:  Ibrutinib administration lowers platelet count in the|
02605|007|A|majority of patients.(1,2) In addition, ibrutinib has been shown to inhibit|
02605|008|A|collagen-mediated platelet aggregation.(3-4)|
02605|009|A|   Bleeding has been reported with the use of ibrutinib,(1-4)|
02605|010|A|anticoagulants, or antiplatelets alone.|
02605|011|B||
02605|012|E|CLINICAL EFFECTS:  Concurrent use of ibrutinib with either anticoagulants or|
02605|013|E|antiplatelets may increase the risk of hemorrhage.|
02605|014|B||
02605|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02605|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02605|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
02605|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02605|019|P|risk for bleeding (e.g. NSAIDs).|
02605|020|B||
02605|021|M|PATIENT MANAGEMENT:  The Canadian product monograph for ibrutinib recommends|
02605|022|M|concurrent use with anticoagulants or antiplatelets should be approached|
02605|023|M|with caution.  If therapeutic anticoagulation is required, consider|
02605|024|M|temporarily withholding ibrutinib therapy until stable anticoagulation in|
02605|025|M|achieved.(2)|
02605|026|M|   The US prescribing information for ibrutinib states patients receiving|
02605|027|M|concurrent therapy with ibrutinib and anticoagulants and/or antiplatelets|
02605|028|M|should be closely monitored for changes in platelet count or in|
02605|029|M|International Normalized Ratio (INR).  Carefully weigh the risks vs.|
02605|030|M|benefits of concurrent therapy in patients with significant|
02605|031|M|thrombocytopenia.  If a bleeding event occurs, follow manufacturer|
02605|032|M|instructions for ibrutinib dose adjustment.(1)|
02605|033|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02605|034|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02605|035|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02605|036|M|patients with any symptoms.|
02605|037|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
02605|038|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02605|039|M|anticoagulation in patients with active pathologic bleeding.|
02605|040|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02605|041|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02605|042|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02605|043|M|and/or swelling.|
02605|044|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02605|045|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
02605|046|M|before initiating, altering the dose or discontinuing either drug.|
02605|047|B||
02605|048|D|DISCUSSION:  Bleeding has been reported with ibrutinib alone.(1-3)  Across|
02605|049|D|27 clinical trials, grade 3 or higher bleeding events, e.g. subdural|
02605|050|D|hematoma, gastrointestinal bleeding or hematuria, have occurred in up to 4%|
02605|051|D|of patients, with 0.4% fatality.  Grade 3 or 4 thrombocytopenia occurred in|
02605|052|D|5-19% of patients.  Bleeding events of any grade occurred in 39% of patients|
02605|053|D|treated with ibrutinib.(1)|
02605|054|D|   Concurrent use of anticoagulants or antiplatelets has been reported to|
02605|055|D|increase the risk for major bleeding.  In clinical trials, major bleeding|
02605|056|D|occurred in 3.1% of patients taking ibrutinib without concurrent|
02605|057|D|anticoagulants or antiplatelets, 4.4% of patients on concurrent|
02605|058|D|antiplatelets with or without anticoagulants, and 6.1% of patients on|
02605|059|D|concurrent anticoagulants with or without antiplatelets.(1)|
02605|060|D|   In an open-label, phase 2 trial of patients with relapsed/refractory|
02605|061|D|mantle cell lymphoma on ibrutinib, 61 patients (55%) on concurrent|
02605|062|D|anticoagulants or antiplatelets had a higher rate of bleeding (69% any|
02605|063|D|grade, 8% grade 3-4) than patients not on anticoagulants or antiplatelets|
02605|064|D|(28% any grade, 4% grade 3-4).(5)|
02605|065|D|   A retrospective trial found a hazard ratio of 20 (95% CI, 2.1-200) for|
02605|066|D|patients on ibrutinib with concurrent anticoagulants and antiplatelets.|
02605|067|D|There was a trend towards an increased bleeding risk in patients on either|
02605|068|D|anticoagulants or antiplatelets, but this was not statistically significant|
02605|069|D|on multivariate analysis.(6)|
02605|070|D|   A case report of 2 patients with chronic lymphocytic leukemia (CLL) on|
02605|071|D|ibrutinib and dabigatran demonstrated no stroke nor bleeding events during|
02605|072|D|the mean 11.5 month follow-up.(7)|
02605|073|D|   A case report of 4 patients with lymphoproliferative disease on|
02605|074|D|concurrent dabigatran and ibrutinib demonstrated no stroke nor major|
02605|075|D|bleeding events. 1 patient experienced grade 2 conjunctival hemorrhage|
02605|076|D|whilst on both ibrutinib and dabigatran. The anticoagulant was withheld and|
02605|077|D|successfully re-initiated at a lower dose with no further bleeding|
02605|078|D|events.(8)|
02605|079|B||
02605|080|R|REFERENCES:|
02605|081|B||
02605|082|R|1.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
02605|083|R|  August, 2022.|1
02605|084|R|2.Imbruvica (ibrutinib) Canadian prescribing information. Janssen Inc.|1
02605|085|R|  August, 2023.|1
02605|086|R|3.Kamel S, Horton L, Ysebaert L, Levade M, Burbury K, Tan S, Cole-Sinclair|2
02605|087|R|  M, Reynolds J, Filshie R, Schischka S, Khot A, Sandhu S, Keating MJ,|2
02605|088|R|  Nandurkar H, Tam CS. Ibrutinib inhibits collagen-mediated but not|2
02605|089|R|  ADP-mediated platelet aggregation. Leukemia 2015 Apr;29(4):783-7.|2
02605|090|R|4.Levade M, David E, Garcia C, Laurent PA, Cadot S, Michallet AS, Bordet JC,|2
02605|091|R|  Tam C, Sie P, Ysebaert L, Payrastre B. Ibrutinib treatment affects|2
02605|092|R|  collagen and von Willebrand factor-dependent platelet functions. Blood|2
02605|093|R|  2014 Dec 18;124(26):3991-5.|2
02605|094|R|5.Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH,|1
02605|095|R|  Romaguera JE, Williams ME. Long-term follow-up of MCL patients treated|1
02605|096|R|  with single-agent ibrutinib: updated  safety and efficacy results. Blood|1
02605|097|R|  2015 Aug 6;126(6):739-45.|1
02605|098|R|6.Mock J, Kunk PR, Palkimas S, Sen JM, Devitt M, Horton B, Portell CA,|1
02605|099|R|  Williams ME, Maitland H. Risk of Major Bleeding with Ibrutinib. Clin|1
02605|100|R|  Lymphoma Myeloma Leuk 2018 Nov;18(11):755-761.|1
02605|101|R|7.Lewicka E, Daniluk P, Lasocka Z, Zarzycka E, Dabrowska-Kugacka A,|3
02605|102|R|  Nabialek-Trojanowska I, Zaucha JM. Assessment of dabigatran plasma|3
02605|103|R|  concentration may improve the safety of anticoagulation in patients|3
02605|104|R|  treated with ibrutinib with concomitant atrial fibrillation. KARDIOLOGIA|3
02605|105|R|  POLSKA March 2020;78(5):454 - 457.|3
02605|106|R|8.Visentin A, Campello E, Scomazzon E, Spiezia L, Imbergamo S, Pravato S,|3
02605|107|R|  Piazza F, Semenzato G, Simioni P, Trentin L, . Dabigatran in|3
02605|108|R|  ibrutinib-treated patients with atrial fibrillation and|3
02605|109|R|  lymphoproliferative disease: Experience of 4 cases. Hematological Oncology|3
02605|110|R|  August 2018.|3
02606|001|T|MONOGRAPH TITLE:  Thioridazine/Rolapitant|
02606|002|B||
02606|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02606|004|L|is contraindicated and generally should not be dispensed or administered to|
02606|005|L|the same patient.|
02606|006|B||
02606|007|A|MECHANISM OF ACTION:  Rolapitant may inhibit the metabolism of thioridazine|
02606|008|A|by CYP2D6.(1)  Thioridazine may induce the metabolism and clearance of|
02606|009|A|rolapitant via CYP3A4.(2)|
02606|010|B||
02606|011|E|CLINICAL EFFECTS:  The concurrent or recent administration of rolapitant|
02606|012|E|with thioridazine may result in elevated levels of thioridazine.  Elevated|
02606|013|E|levels of thioridazine may augment thioridazine-induced prolongation of the|
02606|014|E|QTc interval, increasing the risk of serious, potentially fatal, cardiac|
02606|015|E|arrhythmias such as torsades de pointes.(1,3,4)|
02606|016|E|   Concurrent thioridazine may result in significantly decreased levels and|
02606|017|E|effectiveness of rolapitant.(2)|
02606|018|B||
02606|019|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers may|
02606|020|P|be affected to a greater extent by CYP2D6 inhibitors.  Patients who are|
02606|021|P|CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6|
02606|022|P|inhibition.|
02606|023|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02606|024|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02606|025|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02606|026|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02606|027|P|advanced age.(5)|
02606|028|P|     Concurrent use of more than one drug known to cause QT prolongation or|
02606|029|P|higher systemic concentrations of either QT prolonging drug are additional|
02606|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02606|031|P|drug concentrations include rapid infusion of an intravenous dose or|
02606|032|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
02606|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02606|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
02606|035|P|   The risk of anticholinergic toxicities including cognitive decline,|
02606|036|P|delirium, falls and fractures is increased in geriatric patients using more|
02606|037|P|than one medicine with anticholinergic properties.(6)|
02606|038|B||
02606|039|M|PATIENT MANAGEMENT:  Use an alternative antipsychotic or antinausea agent.|
02606|040|M|The concurrent use of thioridazine with rolapitant is contraindicated.|
02606|041|M|Effects of rolapitant on thioridazine are expected to last for at least 28|
02606|042|M|days after administration.(1)|
02606|043|M|   If thioridazine cannot be discontinued, use an alternative agent for the|
02606|044|M|treatment of nausea and vomiting and evaluate the patient for predisposing|
02606|045|M|risk factors which increase the risk for QT prolongation.  Correct|
02606|046|M|modifiable risk factors (e.g. electrolyte disorders) and monitor for QT|
02606|047|M|prolongation as appropriate throughout treatment with thioridazine.|
02606|048|M|   If alternative treatments are not possible for either agent and|
02606|049|M|concurrent therapy is deemed medically necessary, strongly consider|
02606|050|M|obtaining serum calcium, magnesium, and potassium levels and monitoring ECG|
02606|051|M|at baseline and at regular intervals.  Correct any electrolyte|
02606|052|M|abnormalities.  Instruct patients to report any irregular heartbeat,|
02606|053|M|dizziness, or fainting.  Monitor patients for decreased rolapitant|
02606|054|M|effectiveness.|
02606|055|M|   Thioridazine should not be initiated in patients with a QTc interval|
02606|056|M|greater than 450 msec and should be discontinued in patients found to have a|
02606|057|M|corrected QTc greater than 500 msec.(4)|
02606|058|B||
02606|059|D|DISCUSSION:  Seven days after administration, a single dose of rolapitant|
02606|060|D|was found to increase exposure to dextromethorphan, a CYP2D6 substrate, by|
02606|061|D|3-fold.(1)|
02606|062|D|   A single dose of rolapitant increased dextromethorphan about 3-fold on|
02606|063|D|days 8 and day 22 following administration.  Dextromethorphan levels|
02606|064|D|remained elevated by 2.3-fold on day 28 after single dose rolapitant.  The|
02606|065|D|inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28|
02606|066|D|days.(1)|
02606|067|D|   A study in six slow and 13 rapid metabolizers of debrisoquin, a marker of|
02606|068|D|CYP2D6 activity, showed that slow metabolizers of debrisoquin had 2.4-fold|
02606|069|D|and 4.5-fold higher thioridazine maximum concentration (Cmax) and AUC,|
02606|070|D|respectively, than rapid metabolizers.(7)|
02606|071|D|   A study in 9 healthy male subjects showed a thioridazine dose-related|
02606|072|D|prolongation of the QTc interval.  One subtherapeutic thioridazine 10 mg|
02606|073|D|dose increased QTc 9 msec (range -1 to 19 msec), and a single|
02606|074|D|low-therapeutic thioridazine dose of 50 mg increased QTc 22 msec (range 11|
02606|075|D|to 33 msec).(8)|
02606|076|D|   Rifampin (600 mg daily for 14 days), a strong CYP3A4 inducer, decreased|
02606|077|D|the Cmax and AUC of a single dose of rolapitant (180 mg on Day 7) by 30% and|
02606|078|D|85%, respectively.  The half-life of rolapitant decreased from 176 hours to|
02606|079|D|41 hours.(2)|
02606|080|B||
02606|081|R|REFERENCES:|
02606|082|B||
02606|083|R|1.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
02606|084|R|2.Varuby (rolapitant) UK Summary of Product Characteristics. Tesaro UK|1
02606|085|R|  Limited March 15, 2019.|1
02606|086|R|3.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
02606|087|R|  September, 2014.|1
02606|088|R|4.Dear Doctor Letter. Re:  Important drug warning about Mellarill. Novartis|1
02606|089|R|  Pharmaceuticals Corporation July 7, 2000.|1
02606|090|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02606|091|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02606|092|R|  settings: a scientific statement from the American Heart Association and|6
02606|093|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02606|094|R|  2;55(9):934-47.|6
02606|095|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02606|096|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02606|097|R|  Soc 2023 Jul;71(7):2052-2081.|6
02606|098|R|7.von Bahr C, Movin G, Nordin C, Liden A, Hammarlund-Udenaes M, Hedberg A,|2
02606|099|R|  Ring H, Sjoqvist F. Plasma levels of thioridazine and metabolites are|2
02606|100|R|  influenced by the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther|2
02606|101|R|  1991 Mar;49(3):234-40.|2
02606|102|R|8.Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH.|2
02606|103|R|  Concentration-related pharmacodynamic effects of thioridazine and its|2
02606|104|R|  metabolites in humans. Clin Pharmacol Ther 1996 Nov;60(5):543-53.|2
02607|001|T|MONOGRAPH TITLE:  Flibanserin/Alcohol|
02607|002|B||
02607|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02607|004|L|of severe adverse interaction.|
02607|005|B||
02607|006|A|MECHANISM OF ACTION:  Flibanserin may be associated with hypotension or|
02607|007|A|syncopal episodes.(1)|
02607|008|B||
02607|009|E|CLINICAL EFFECTS:  Concurrent use of alcohol in patients taking flibanserin|
02607|010|E|may substantially increase the risk for hypotension or syncope.(1)|
02607|011|B||
02607|012|P|PREDISPOSING FACTORS:  Patients with any degree of hepatic impairment, who|
02607|013|P|are CYP2C19 poor metabolizers, or who also receive concomitant therapy with|
02607|014|P|moderate or strong CYP3A4 inhibitors are expected to have increased systemic|
02607|015|P|concentrations of flibanserin, adding to the risk for hypotension or|
02607|016|P|syncopal episodes.(1)|
02607|017|P|   Hypotensive or syncopal episodes are more common when flibanserin is|
02607|018|P|taken during waking hours.(1)|
02607|019|B||
02607|020|M|PATIENT MANAGEMENT:  To decrease the risk for hypotension or syncope,|
02607|021|M|counsel patients to take flibanserin at bedtime.|
02607|022|M|   Advise patients to wait at least two hours after consuming one or two|
02607|023|M|standard alcoholic drinks before taking flibanserin at bedtime.  If three or|
02607|024|M|more standard alcoholic drinks are consumed, skip the dose of flibanserin|
02607|025|M|that evening.  After taking flibanserin at bedtime, patients should not use|
02607|026|M|alcohol until the following day.(1)|
02607|027|M|   One standard alcoholic drink contains 14 grams of pure alcohol and is|
02607|028|M|equivalent to one 12-ounce regular beer (5% alcohol), 5-ounces wine (12%|
02607|029|M|alcohol), or 1.5 ounces of distilled spirits/shot (40% alcohol).|
02607|030|M|   Advise patients to lie down and call for medical help for persistent|
02607|031|M|pre-syncope or lightheadedness.(1)|
02607|032|M|   Significant quantities of alcohol may be present in medicinal products.|
02607|033|M|Alcohol is is used to improve docetaxel and paclitaxel solubility.|
02607|034|M|   - The quantity of alcohol in paclitaxel injection formulations|
02607|035|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
02607|036|M|dose contains approximately 13 grams of alcohol.|
02607|037|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
02607|038|M|3-fold depending upon the manufacturer. FDA data on alcohol content (2):|
02607|039|M|   Product                      Manufacturer         Alcohol/200 mg dose|
02607|040|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
02607|041|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
02607|042|M|   Docetaxel Inj.               Accord                  4.0 grams|
02607|043|M|   Taxotere-one vial            Sanofi                  4.0 grams|
02607|044|M|    formulation|
02607|045|M|   Docetaxel Inj.               Hospira                 3.7 grams|
02607|046|M|   Docefrez                     Sun Pharma              2.9 grams|
02607|047|M|   Taxotere-two vial            Sanofi                  2.0 grams|
02607|048|M|    formulation|
02607|049|B||
02607|050|D|DISCUSSION:  A dedicated alcohol interaction study included 23 men and 2|
02607|051|D|women.  Subjects took flibanserin or alcohol alone, or flibanserin and|
02607|052|D|either 0.4 gram/kg or 0.8 gram/kg of alcohol.  The alcohol dose was consumed|
02607|053|D|over 10 minutes.(1)|
02607|054|D|   Co-administration of flibanserin and 0.4 gram/kg alcohol (approximately|
02607|055|D|equal to 2 glasses of wine or 2 cans of beer) led to hypotension or syncope|
02607|056|D|requiring therapeutic intervention in 4 of 23 subjects (17%).  The magnitude|
02607|057|D|of systolic blood pressure reductions ranged from 28 to 54 mmHg and|
02607|058|D|diastolic blood pressure reductions ranged from 24 to 46 mmHg.  In the|
02607|059|D|flibanserin and alcohol 0.8 gram/kg group, 6 of the 24 subjects experienced|
02607|060|D|orthostatic hypotension when moving from a sitting to standing position.|
02607|061|D|The magnitude of systolic blood pressure reduction ranged from 22 to 48 mmHg|
02607|062|D|and diastolic reductions ranged from 0 to 27 mmHg.  One of the subjects|
02607|063|D|required therapeutic intervention. In contrast, there were no events|
02607|064|D|requiring therapeutic intervention when flibanserin or alcohol were|
02607|065|D|administered alone.(1)|
02607|066|D|   In a study, 96 pre-menopausal women were given flibanserin or alcohol|
02607|067|D|alone, or flibanserin with 0.2 gram/kg, 0.4 gram/kg, or 0.6 gram/kg alcohol|
02607|068|D|in the morning.  Although no subjects had syncope or hypotension requiring|
02607|069|D|therapeutic intervention, subjects were not allowed to stand for|
02607|070|D|orthostatics if they were hypotensive (blood pressure <90/60 mmHg) or dizzy|
02607|071|D|while semi-recumbent.  More subjects who received the combination of|
02607|072|D|flibanserin and alcohol than those who received flibanserin or alcohol alone|
02607|073|D|had missing or delayed orthostatic measurements due to hypotension or|
02607|074|D|dizziness.(1)|
02607|075|D|   A study of 64 pre-menopausal women who drank 0.4 g/kg of alcohol two,|
02607|076|D|four, or six hours before taking a dose of flibanserin 100 mg or placebo|
02607|077|D|found that there was no difference in the incidence of orthostatic|
02607|078|D|hypotension or hypotension at all time points between subjects who received|
02607|079|D|alcohol alone, flibanserin alone, or both.(1)|
02607|080|D|   A study of 24 pre-menopausal women compared flibanserin or alcohol alone,|
02607|081|D|or flibanserin given 2.5 hours or 4 hours after consumption of 0.4 gram/kg|
02607|082|D|alcohol.  There were no cases of syncope, dizziness, or somnolence in any|
02607|083|D|group.(1)|
02607|084|B||
02607|085|R|REFERENCES:|
02607|086|B||
02607|087|R|1.Addyi (flibanserin) US prescribing information. Sprout Pharmaceuticals|1
02607|088|R|  September, 2021.|1
02607|089|R|2.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
02607|090|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
02607|091|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02607|092|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
02607|093|R|  20, 2014.|1
02607|094|R|3.FDA (US Food and Drug Administration). FDA MedWatch Safety Alert: Addyi|1
02607|095|R|  (flibanserin): Safety Labeling Change - Orders Important Safety Labeling|1
02607|096|R|  Changes. Available at:|1
02607|097|R|  https://www.accessdata.fda.gov/drugsatfda_docs/appletter/SLC/2019/022526_S|1
02607|098|R|  LC%20OrderLtr.pdf April 11, 2019.|1
02608|001|T|MONOGRAPH TITLE:  Eluxadoline/OATP1B1 Inhibitors|
02608|002|B||
02608|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02608|004|L|of severe adverse interaction.|
02608|005|B||
02608|006|A|MECHANISM OF ACTION:  OATP1B1 inhibitors may decrease the hepatic uptake of|
02608|007|A|eluxadoline.(1)|
02608|008|B||
02608|009|E|CLINICAL EFFECTS:  Concurrent use of OATP1B1 inhibitors may result in|
02608|010|E|elevated levels of and side effects from eluxadoline, including|
02608|011|E|constipation, nausea, abdominal pain, and impaired mental and physical|
02608|012|E|abilities.(1)|
02608|013|B||
02608|014|P|PREDISPOSING FACTORS:  None determined.|
02608|015|B||
02608|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent OATP1B1 inhibitors should|
02608|017|M|receive a dose of eluxadoline of 75 mg twice daily.  Monitor patients for|
02608|018|M|impaired mental or physical abilities, abdominal pain, nausea, and|
02608|019|M|constipation.(1)|
02608|020|B||
02608|021|D|DISCUSSION:  Concurrent administration of a single dose (600 mg) of|
02608|022|D|cyclosporine, an OATP1B1 inhibitor, increased the maximum concentration|
02608|023|D|(Cmax) and area-under-curve (AUC) of a single dose of eluxadoline (100 mg)|
02608|024|D|by 4.4-fold and 6.2-fold, respectively.(1)|
02608|025|D|   OATP1B1 inhibitors include: atazanavir, belumosudil, boceprevir,|
02608|026|D|cyclosporine, darunavir, encorafenib, eltrombopag, erythromycin,|
02608|027|D|gemfibrozil, leflunomide, leniolisib, letermovir, lopinavir, paritaprevir,|
02608|028|D|resmetirom, rifampin, ritonavir, roxadustat, saquinavir, simeprevir,|
02608|029|D|telaprevir, teriflunomide, tipranavir, vadadustat, and voclosporin.(1,2)|
02608|030|B||
02608|031|R|REFERENCES:|
02608|032|B||
02608|033|R|1.Viberzi (eluxadoline) US prescribing information. Allergan USA, Inc. June,|1
02608|034|R|  2020.|1
02608|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
02608|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02609|001|T|MONOGRAPH TITLE:  Pimozide/Rolapitant|
02609|002|B||
02609|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02609|004|L|is contraindicated and generally should not be dispensed or administered to|
02609|005|L|the same patient.|
02609|006|B||
02609|007|A|MECHANISM OF ACTION:  Rolapitant may inhibit the metabolism of pimozide by|
02609|008|A|CYP2D6.(1)|
02609|009|B||
02609|010|E|CLINICAL EFFECTS:  Concurrent or recent administration of rolapitant may|
02609|011|E|result in elevated levels of pimozide, which may result in prolongation of|
02609|012|E|the QTc interval and potentially life-threatening ventricular|
02609|013|E|arrhythmias.(1)|
02609|014|B||
02609|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02609|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
02609|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02609|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02609|019|P|female gender, or advanced age.(2)|
02609|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02609|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02609|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02609|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02609|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02609|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02609|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02609|027|P|   The risk of anticholinergic toxicities including cognitive decline,|
02609|028|P|delirium, falls and fractures is increased in geriatric patients using more|
02609|029|P|than one medicine with anticholinergic properties.(3)|
02609|030|B||
02609|031|M|PATIENT MANAGEMENT:  The manufacturer of rolapitant states concurrent use|
02609|032|M|with pimozide is contraindicated.  If patients require either rolapitant or|
02609|033|M|pimozide, use an alternative antiemetic to rolapitant or an alternative to|
02609|034|M|pimozide.(1)|
02609|035|M|   Avoid concurrent use, especially when other risk factors for QT|
02609|036|M|prolongation are present.  Rolapitant effects on CYP2D6 are expected to last|
02609|037|M|at least 28 days after administration.(1)|
02609|038|M|   If concurrent use cannot be avoided, then correct or minimize QT|
02609|039|M|prolonging risk factors, e.g. correct electrolyte disturbances, use the|
02609|040|M|lowest effective dose of pimozide, and discontinue other concurrent QT|
02609|041|M|prolonging agents or CYP3A4 inhibitors if possible.  Consider ECG to|
02609|042|M|evaluate baseline and/or concurrent QT prolongation risk. Monitor patients|
02609|043|M|on the combination and counsel patients accordingly.|
02609|044|B||
02609|045|D|DISCUSSION:  Seven days after administration, a single dose of rolapitant|
02609|046|D|was found to increase exposure to dextromethorphan, a CYP2D6 substrate, by|
02609|047|D|3-fold.(1)|
02609|048|D|   A single dose of rolapitant increased dextromethorphan about 3-fold on|
02609|049|D|days 8 and day 22 following administration.  Dextromethorphan levels|
02609|050|D|remained elevated by 2.3-fold on day 28 after single dose rolapitant.  The|
02609|051|D|inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28|
02609|052|D|days.(1)|
02609|053|B||
02609|054|R|REFERENCES:|
02609|055|B||
02609|056|R|1.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
02609|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02609|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02609|059|R|  settings: a scientific statement from the American Heart Association and|6
02609|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02609|061|R|  2;55(9):934-47.|6
02609|062|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02609|063|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02609|064|R|  Soc 2023 Jul;71(7):2052-2081.|6
02609|065|R|4.Desta Z, Kerbusch T, Soukhova N, Richard E, Ko JW, Flockhart DA.|5
02609|066|R|  Identification and characterization of human cytochrome P450 isoforms|5
02609|067|R|  interacting with pimozide. J Pharmacol Exp Ther 1998 May;285(2):428-37.|5
02609|068|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02609|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02609|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02609|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02609|072|R|  11/14/2017.|1
02609|073|R|6.This information is based on an extract from the Certara Drug Interaction|6
02609|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02610|001|T|MONOGRAPH TITLE:  Selected Oral BCRP Substrates/Oral Rolapitant|
02610|002|B||
02610|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02610|004|L|of severe adverse interaction.|
02610|005|B||
02610|006|A|MECHANISM OF ACTION:  Oral rolapitant may inhibit transport of irinotecan,|
02610|007|A|methotrexate, and topotecan by BCRP, leading to increased levels of these|
02610|008|A|agents.(1)|
02610|009|B||
02610|010|E|CLINICAL EFFECTS:  Concurrent use of oral rolapitant may result in elevated|
02610|011|E|levels of and toxicity from irinotecan, methotrexate, and topotecan.(1)|
02610|012|B||
02610|013|P|PREDISPOSING FACTORS:  None determined.|
02610|014|B||
02610|015|M|PATIENT MANAGEMENT:  Avoid concurrent use if possible.  If concurrent use|
02610|016|M|cannot be avoided, monitor patients for increased effects of irinotecan,|
02610|017|M|methotrexate, and topotecan.(1)|
02610|018|B||
02610|019|D|DISCUSSION:  A single dose of oral rolapitant (180 mg on day 1) was found to|
02610|020|D|increase the maximum concentration (Cmax) and area-under-curve (AUC) of|
02610|021|D|sulfasalazine (500 mg single dose), a substrate of BCRP, by 140% and 130%,|
02610|022|D|respectively.(1)|
02610|023|D|   A single dose of intravenous rolapitant (166.5 mg on day 1) was found to|
02610|024|D|have no effect on Cmax and AUC of sulfasalazine (500 mg single dose).(1)|
02610|025|B||
02610|026|R|REFERENCE:|
02610|027|B||
02610|028|R|1.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
02611|001|T|MONOGRAPH TITLE:  Oral Digoxin/Oral Rolapitant|
02611|002|B||
02611|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02611|004|L|of severe adverse interaction.|
02611|005|B||
02611|006|A|MECHANISM OF ACTION:  Rolapitant may increase the absorption of digoxin by|
02611|007|A|inhibiting P-glycoprotein.(1)|
02611|008|B||
02611|009|E|CLINICAL EFFECTS:  Concurrent us of rolapitant may result in elevated levels|
02611|010|E|of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can include|
02611|011|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
02611|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
02611|013|E|disturbances, and arrhythmias.|
02611|014|B||
02611|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02611|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02611|017|P|risk of digoxin toxicity.|
02611|018|B||
02611|019|M|PATIENT MANAGEMENT:  Avoid concurrent use if possible.  If concurrent use|
02611|020|M|cannot be avoided, monitor patients for increased digoxin levels.(1)|
02611|021|M|Monitor patients receiving concurrent therapy for symptoms of digoxin|
02611|022|M|toxicity, including anorexia, nausea, vomiting, headache, fatigue, malaise,|
02611|023|M|drowsiness, generalized muscle weakness, disorientation, hallucinations,|
02611|024|M|visual disturbances, and arrhythmias.|
02611|025|B||
02611|026|D|DISCUSSION:  A single dose of rolapitant was found to increase the maximum|
02611|027|D|concentration (Cmax) and area-under-curve (AUC) of digoxin (0.5 mg single|
02611|028|D|dose) by 70% and 30%, respectively.(1)|
02611|029|B||
02611|030|R|REFERENCE:|
02611|031|B||
02611|032|R|1.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
02612|001|T|MONOGRAPH TITLE:  Thioridazine/Selected Moderate CYP2D6 Inhibitors|
02612|002|B||
02612|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02612|004|L|is contraindicated and generally should not be dispensed or administered to|
02612|005|L|the same patient.|
02612|006|B||
02612|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP2D6 may inhibit the|
02612|008|A|metabolism of thioridazine.(1-4)|
02612|009|B||
02612|010|E|CLINICAL EFFECTS:  The concurrent administration of moderate CYP2D6|
02612|011|E|inhibitors with thioridazine may result in elevated levels of|
02612|012|E|thioridazine.(1-4)  Elevated levels of thioridazine may augment|
02612|013|E|thioridazine-induced prolongation of the QTc interval, increasing the risk|
02612|014|E|of serious, potentially fatal, cardiac arrhythmias such as torsades de|
02612|015|E|pointes.(1)|
02612|016|B||
02612|017|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers may|
02612|018|P|be affected to a greater extent by CYP2D6 inhibitors.  Patients who are|
02612|019|P|CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6|
02612|020|P|inhibition.|
02612|021|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02612|022|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02612|023|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02612|024|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02612|025|P|advanced age.(5)|
02612|026|P|     Concurrent use of more than one drug known to cause QT prolongation or|
02612|027|P|higher systemic concentrations of either QT prolonging drug are additional|
02612|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02612|029|P|drug concentrations include rapid infusion of an intravenous dose or|
02612|030|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
02612|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02612|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
02612|033|P|   The risk of anticholinergic toxicities including cognitive decline,|
02612|034|P|delirium, falls and fractures is increased in geriatric patients using more|
02612|035|P|than one medicine with anticholinergic properties.(6)|
02612|036|B||
02612|037|M|PATIENT MANAGEMENT:  The concurrent use of thioridazine with CYP2D6|
02612|038|M|inhibitors is contraindicated.(1)   Use an alternative agent, or change to|
02612|039|M|another antipsychotic agent.|
02612|040|M|   If the patient is on oral terbinafine for the treatment of onychomycosis,|
02612|041|M|use a terbinafine formulation with a non-systemic route.|
02612|042|M|   If alternative treatments are not possible for either agent and|
02612|043|M|concurrent therapy is deemed medically necessary, strongly consider|
02612|044|M|obtaining serum calcium, magnesium, and potassium levels and monitoring ECG|
02612|045|M|at baseline and at regular intervals.  Correct any electrolyte|
02612|046|M|abnormalities.  Instruct patients to report any irregular heartbeat,|
02612|047|M|dizziness, or fainting.|
02612|048|M|   Thioridazine should not be initiated in patients with a QTc interval|
02612|049|M|greater than 450 msec and should be discontinued in patients found to have a|
02612|050|M|corrected QTc greater than 500 msec.(3)|
02612|051|B||
02612|052|D|DISCUSSION:  A study in six slow and 13 rapid metabolizers of debrisoquin, a|
02612|053|D|marker of CYP2D6 activity, showed that slow metabolizers of debrisoquin had|
02612|054|D|2.4-fold and 4.5-fold higher thioridazine maximum concentration (Cmax) and|
02612|055|D|area-under-curve (AUC), respectively, than rapid metabolizers.(4)|
02612|056|D|   A study in 9 healthy male subjects showed a thioridazine dose-related|
02612|057|D|prolongation of the QTc interval.  One subtherapeutic thioridazine 10 mg|
02612|058|D|dose increased QTc 9 msec (range -1 to 19 msec), and a single|
02612|059|D|low-therapeutic thioridazine dose of 50 mg increased QTc 22 msec (range 11|
02612|060|D|to 33 msec).(7)|
02612|061|D|   Coadministration of cinacalcet (90 mg once daily) and desipramine (50|
02612|062|D|mg), a CYP2D6 substrate, resulted in an approximate 3.6-fold increase in the|
02612|063|D|exposure of desipramine in healthy subjects who were CYP2D6 extensive|
02612|064|D|metabolizers.(8)|
02612|065|D|   In another study, cinacalcet (50 mg daily) increased AUC of single-dose|
02612|066|D|dextromethorphan (30 mg), a CYP2D6 substrate, by 4.93-fold in 2D6 extensive|
02612|067|D|metabolizers.(9)|
02612|068|B||
02612|069|R|REFERENCES:|
02612|070|B||
02612|071|R|1.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
02612|072|R|  September, 2014.|1
02612|073|R|2.Lamisil (terbinafine hydrochloride) tablet US prescribing information.|1
02612|074|R|  Novartis Pharmaceuticals Corporation June, 2013.|1
02612|075|R|3.This information is based on an extract from the Certara Drug Interaction|6
02612|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02612|077|R|4.von Bahr C, Movin G, Nordin C, Liden A, Hammarlund-Udenaes M, Hedberg A,|2
02612|078|R|  Ring H, Sjoqvist F. Plasma levels of thioridazine and metabolites are|2
02612|079|R|  influenced by the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther|2
02612|080|R|  1991 Mar;49(3):234-40.|2
02612|081|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02612|082|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02612|083|R|  settings: a scientific statement from the American Heart Association and|6
02612|084|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02612|085|R|  2;55(9):934-47.|6
02612|086|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02612|087|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02612|088|R|  Soc 2023 Jul;71(7):2052-2081.|6
02612|089|R|7.Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH.|2
02612|090|R|  Concentration-related pharmacodynamic effects of thioridazine and its|2
02612|091|R|  metabolites in humans. Clin Pharmacol Ther 1996 Nov;60(5):543-53.|2
02612|092|R|8.Sensipar (cinacalcet hydrochloride) US prescribing information. Amgen Inc.|1
02612|093|R|  March, 2019.|1
02612|094|R|9.Nakashima D, Takama H, Ogasawara Y, Kawakami T, Nishitoba T, Hoshi S,|2
02612|095|R|  Uchida E, Tanaka H. Effect of cinacalcet hydrochloride, a new calcimimetic|2
02612|096|R|  agent, on the  pharmacokinetics of dextromethorphan: in vitro and clinical|2
02612|097|R|  studies. J Clin Pharmacol 2007 Oct;47(10):1311-9.|2
02613|001|T|MONOGRAPH TITLE:  Sodium Oxybate/Codeine; Tramadol|
02613|002|B||
02613|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02613|004|L|of severe adverse interaction.|
02613|005|B||
02613|006|A|MECHANISM OF ACTION:  Oxybate by itself may be associated with severe|
02613|007|A|somnolence or respiratory depression.  Concurrent use with other CNS|
02613|008|A|depressants may further increase the risk for respiratory depression or loss|
02613|009|A|of consciousness.(1-3)|
02613|010|A|   Codeine and tramadol are converted to their more active opioid|
02613|011|A|metabolites (morphine and O-desmethyltramadol respectively) by CYP2D6.|
02613|012|B||
02613|013|E|CLINICAL EFFECTS:  Concurrent use of sodium oxybate and opioids such as|
02613|014|E|tramadol, or alcohol may further increase the risk for respiratory|
02613|015|E|depression and profound sedation, syncope or coma.(1,2)  Fatalities have|
02613|016|E|been reported.(3)|
02613|017|B||
02613|018|P|PREDISPOSING FACTORS:  Based upon FDA evaluation of deaths in patients|
02613|019|P|taking sodium oxybate, risk factors may include: use of multiple drugs which|
02613|020|P|depress the CNS, more rapid than recommended oxybate dose titration,|
02613|021|P|exceeding the maximum recommended oxybate dose, and prescribing for|
02613|022|P|unapproved uses such as fibromyalgia, insomnia or migraine.  Note that in|
02613|023|P|oxybate clinical trials for narcolepsy 78% - 85% of patients were also|
02613|024|P|receiving concomitant CNS stimulants.(1-3)|
02613|025|P|   In patients receiving codeine or tramadol, ultrarapid metabolizers of|
02613|026|P|CYP2D6 are more likely to have higher than normal systemic concentrations of|
02613|027|P|the active opioid.(4)|
02613|028|P|   Other patients at high risk from this interaction include:  adolescents|
02613|029|P|between 12 and 18 years who are obese or have conditions such as obstructive|
02613|030|P|sleep apnea or severe lung disease, which may increase the risk of|
02613|031|P|respiratory depression; and breastfeeding women (due to the risk of serious|
02613|032|P|adverse reactions in breastfed infants).(5)|
02613|033|B||
02613|034|M|PATIENT MANAGEMENT:  Avoid use of oxybate when concomitant opioids,|
02613|035|M|benzodiazepines, sedating antidepressants, sedating antipsychotics, general|
02613|036|M|anesthetics, or muscle relaxants, particularly when predisposing risk|
02613|037|M|factors are present.  If combination use is required, dose reduction or|
02613|038|M|discontinuation of one or more CNS depressants should be considered.  If|
02613|039|M|short term use of an opioid or general anesthetic is required, consider|
02613|040|M|interruption of sodium oxybate treatment.(1,2)|
02613|041|M|   Codeine and tramadol are converted to their active opioid metabolites by|
02613|042|M|CYP2D6.  Ultrarapid metabolizers of CYP2D6 more rapidly convert codeine or|
02613|043|M|tramadol to their active metabolites (morphine and o-desmethyltramadol|
02613|044|M|respectively) and so are more likely to have higher than normal systemic|
02613|045|M|concentrations of the active opioid.|
02613|046|M|   Respiratory depression can occur at any time during opioid therapy,|
02613|047|M|especially during therapy initiation and following dosage increases.  The|
02613|048|M|risk of opioid-related overdose or overdose-related death is increased with|
02613|049|M|higher opioid doses, and this risk persists over the course of therapy.|
02613|050|M|Consider these risks when using concurrently with other agents that may|
02613|051|M|cause CNS depression.(6)|
02613|052|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02613|053|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02613|054|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02613|055|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02613|056|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02613|057|M|as those taking CNS depressants) and when a patient has household|
02613|058|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02613|059|M|for obtaining an opioid reversal agent (e.g., prescription,|
02613|060|M|over-the-counter, or as part of a community-based program).(7)|
02613|061|B||
02613|062|D|DISCUSSION:  The FDA evaluated sodium oxybate postmarket fatal adverse event|
02613|063|D|reports from the FDA Adverse Event Reporting System(AERS) and from the|
02613|064|D|manufacturer.  Although report documentation was not always optimal or|
02613|065|D|complete, useful information was obtained.|
02613|066|D|   Factors which may have contributed to fatal outcome: concomitant use of|
02613|067|D|one or more drugs which depress the CNS, more rapid than recommended oxybate|
02613|068|D|dose titration, exceeding the maximum recommended oxybate dose, and|
02613|069|D|prescribing for unapproved uses such as fibromyalgia, insomnia or migraine.|
02613|070|D|   FDA reported the case of a 5-year-old patient who received one dose of|
02613|071|D|tramadol following a tonsillectomy and experienced slow, difficult breathing|
02613|072|D|requiring emergency intervention and hospitalization.  The child was|
02613|073|D|subsequently found to be an ultrarapid metabolizer of CYP2D6.(4)|
02613|074|D|   Many deaths occurred in patients with serious psychiatric disorders such|
02613|075|D|as depression and substance abuse. Other concomitant diseases may have also|
02613|076|D|contributed to respiratory and CNS depressant effects of oxybate.(3)|
02613|077|B||
02613|078|R|REFERENCES:|
02613|079|B||
02613|080|R|1.Xyrem (sodium oxybate) US prescribing information. Jazz Pharmaceuticals,|1
02613|081|R|  Inc. April, 2023.|1
02613|082|R|2.Lumryz (sodium oxybate extended-release oral suspension) US prescribing|1
02613|083|R|  information. Avadel CNS Pharmaceuticals, LLC May, 2023.|1
02613|084|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Warning|1
02613|085|R|  against use of Xyrem (sodium oxybate) with alcohol or drugs causing|1
02613|086|R|  respiratory depression. available at:|1
02613|087|R|  http://www.fda.gov/Drugs/DrugSafety/ucm332029.htm December 17, 2012.|1
02613|088|R|4.FDA (US Food and Drug Administration). FDA evaluating the risks of using|1
02613|089|R|  the pain medicine tramadol in children aged 17 and younger. available at:|1
02613|090|R|  http://www.fda.gov/downloads/Drugs/DrugSafety/UCM463471.pdf September 21,|1
02613|091|R|  2015.|1
02613|092|R|5.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02613|093|R|  restricts use of prescription codeine pain and cough medicines and|1
02613|094|R|  tramadol pain medicines in children; recommends against use in|1
02613|095|R|  breastfeeding women. Available at:|1
02613|096|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
02613|097|R|  munication-fda-restricts-use-prescription-codeine-pain-and-cough-medicines|1
02613|098|R|  -and April 20, 2017.|1
02613|099|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02613|100|R|  prescribing information for all opioid pain medicines to provide|1
02613|101|R|  additional guidance for safe use. Available at:|1
02613|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02613|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02613|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02613|105|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02613|106|R|  recommends health care professionals discuss naloxone with all patients|1
02613|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02613|108|R|  disorder. Available at:|1
02613|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02613|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02613|111|R|  d-pain July 23, 2020.|1
02614|001|T|MONOGRAPH TITLE:  Flibanserin/Selected Strong CYP2C19 Inhibitors|
02614|002|B||
02614|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02614|004|L|take action as needed.|
02614|005|B||
02614|006|A|MECHANISM OF ACTION:  Flibanserin is partially metabolized by the CYP2C19|
02614|007|A|isoenzyme.(1)|
02614|008|B||
02614|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP2C19 may|
02614|010|E|result in elevated levels of and toxicity from flibanserin.(1)|
02614|011|B||
02614|012|P|PREDISPOSING FACTORS:  Patients with any degree of hepatic impairment are|
02614|013|P|expected to have increased systemic concentrations of flibanserin, adding to|
02614|014|P|the risk for hypotension or syncopal episodes.(1)|
02614|015|P|   Hypotensive or syncopal episodes are more common when flibanserin is|
02614|016|P|taken during waking hours.(1)|
02614|017|B||
02614|018|M|PATIENT MANAGEMENT:  Increase monitoring for adverse reactions, e.g.|
02614|019|M|hypotension or syncope, in patients who receive concurrent therapy with a|
02614|020|M|strong CYP2C19 inhibitor.(1)|
02614|021|M|   Advise patients who experience pre-syncope or lightheadedness to lie down|
02614|022|M|and to call for help if symptoms persist.  Prompt medical attention should|
02614|023|M|be obtained for patients who experience syncope.(1)|
02614|024|B||
02614|025|D|DISCUSSION:  In a drug interaction study with 15 healthy subjects, the|
02614|026|D|combination of flibanserin (100 mg on day 6) and fluconazole (a moderate|
02614|027|D|CYP3A4 and strong CYP2C19 inhibitor, 400 mg once then 200 mg daily for 5|
02614|028|D|days) resulted in an increased flibanserin exposure of 7-fold.  Hypotension|
02614|029|D|or syncope requiring supine placement with leg elevation occurred in 3|
02614|030|D|subjects (20%).  One patient became unresponsive with a blood pressure of|
02614|031|D|64/41 mm Hg and required emergency room treatment where she required|
02614|032|D|intravenous saline.(1)|
02614|033|D|   In clinical trials, syncope occurred in one subject who was a CYP2C19|
02614|034|D|poor metabolizer.(1)|
02614|035|D|   Selected strong inhibitors of CYP2C19 include: ticlopidine.(2)|
02614|036|B||
02614|037|R|REFERENCES:|
02614|038|B||
02614|039|R|1.Addyi (flibanserin) US prescribing information. Sprout Pharmaceuticals|1
02614|040|R|  September, 2021.|1
02614|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02614|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02614|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02614|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02614|045|R|  11/14/2017.|1
02615|001|T|MONOGRAPH TITLE:  Digoxin/Flibanserin|
02615|002|B||
02615|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02615|004|L|take action as needed.|
02615|005|B||
02615|006|A|MECHANISM OF ACTION:  Flibanserin may increase the absorption of digoxin by|
02615|007|A|inhibiting P-glycoprotein.(1)|
02615|008|B||
02615|009|E|CLINICAL EFFECTS:  Concurrent flibanserin may result in elevated levels of|
02615|010|E|and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can include|
02615|011|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
02615|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
02615|013|E|disturbances, and arrhythmias.|
02615|014|B||
02615|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02615|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02615|017|P|risk of digoxin toxicity.|
02615|018|B||
02615|019|M|PATIENT MANAGEMENT:  Closely monitor digoxin concentration and adjust dose|
02615|020|M|as required to assure levels are in the therapeutic range.(1)|
02615|021|M|   Counsel patients receiving concurrent therapy to assure they get digoxin|
02615|022|M|levels checked and are aware of symptoms of digoxin toxicity, including|
02615|023|M|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
02615|024|M|generalized muscle weakness, disorientation, hallucinations, visual|
02615|025|M|disturbances, and arrhythmias.|
02615|026|B||
02615|027|D|DISCUSSION:  In a study in 24 healthy men and women, administration of|
02615|028|D|flibanserin 100 mg daily for 5 days followed by a single dose of digoxin,|
02615|029|D|increased digoxin AUC by 2.0-fold and Cmax by 1.5-fold compared to digoxin|
02615|030|D|alone.(1)|
02615|031|B||
02615|032|R|REFERENCE:|
02615|033|B||
02615|034|R|1.Addyi (flibanserin) US prescribing information. Sprout Pharmaceuticals|1
02615|035|R|  September, 2021.|1
02616|001|T|MONOGRAPH TITLE:  Selected Multiple Sclerosis Agents/Immunosuppressants;|
02616|002|T|Immunomodulators|
02616|003|B||
02616|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02616|005|L|of severe adverse interaction.|
02616|006|B||
02616|007|A|MECHANISM OF ACTION:  Ocrelizumab or ofatumumab in combination with|
02616|008|A|immunosuppressives and immune-modulators all suppress the immune|
02616|009|A|system.(1,2)|
02616|010|B||
02616|011|E|CLINICAL EFFECTS:  Concurrent use of ocrelizumab or ofatumumab with|
02616|012|E|immunosuppressive or immune-modulating agents may result in an increased|
02616|013|E|risk of serious infections, such as disseminated herpetic infection or|
02616|014|E|progressive multifocal leukoencephalopathy (PML), an opportunistic infection|
02616|015|E|caused by the JC virus (JCV).(1,2)|
02616|016|B||
02616|017|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
02616|018|P|immunosuppressive or immune-modulating medications.|
02616|019|B||
02616|020|M|PATIENT MANAGEMENT:  The ocrelizumab US prescribing information states:|
02616|021|M|   - Ocrelizumab and other immune-modulating or immunosuppressive therapies,|
02616|022|M|(including immunosuppressant doses of corticosteroids) are expected to|
02616|023|M|increase the risk of immunosuppression, and the risk of additive immune|
02616|024|M|system effects must be considered if these therapies are coadministered with|
02616|025|M|ocrelizumab.  When switching from drugs with prolonged immune effects, such|
02616|026|M|as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, the|
02616|027|M|duration and mode of action of these drugs must be considered to avoid|
02616|028|M|unintended additive immunosuppressive effects when initiating|
02616|029|M|ocrelizumab.(1)|
02616|030|M|   The ofatumumab US prescribing information states:|
02616|031|M|   - Ofatumumab and other immunosuppressive therapies (including systemic|
02616|032|M|corticosteroids) may have the potential for increased immunosuppressive|
02616|033|M|effects and increase the risk of infection.  When switching between|
02616|034|M|therapies, the duration and mechanism of action of each therapy should be|
02616|035|M|considered due to the potential for additive immunosuppressive effects.|
02616|036|M|Ofatumumab for MS therapy has not been studied in combination with other MS|
02616|037|M|agents that suppress the immune system.(2)|
02616|038|B||
02616|039|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections|
02616|040|D|and cases of progressive multifocal leukoencephalopathy (PML) have been|
02616|041|D|reported in patients who previously received immunomodulators or|
02616|042|D|immunosuppressants.(1,2)|
02616|043|D|   In a retrospective cohort study of multiple sclerosis patients newly|
02616|044|D|initiated on a disease-modifying therapy, use of high-efficacy agents|
02616|045|D|(alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of|
02616|046|D|overall infections as moderate-efficacy agents, but there was an elevated|
02616|047|D|risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95%|
02616|048|D|confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI =|
02616|049|D|1.14-1.30).(3)|
02616|050|B||
02616|051|R|REFERENCES:|
02616|052|B||
02616|053|R|1.Ocrevus (ocrelizumab) US prescribing information. Genentech November,|1
02616|054|R|  2020.|1
02616|055|R|2.Kesimpta (ofatumumab) US prescribing information. Novartis Pharmaceuticals|1
02616|056|R|  Corporation August, 2020.|1
02616|057|R|3.Li J, Hutton GJ, Varisco TJ, Lin Y, Essien EJ, Aparasu RR. Infection Risk|2
02616|058|R|  Associated with High-Efficacy Disease-Modifying Agents in Multiple|2
02616|059|R|  Sclerosis: A Retrospective Cohort Study. Clin Pharmacol Ther 2024 Nov 15.|2
02617|001|T|MONOGRAPH TITLE:  Cariprazine/Strong CYP3A4 Inhibitors; Protease Inhibitors|
02617|002|B||
02617|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02617|004|L|of severe adverse interaction.|
02617|005|B||
02617|006|A|MECHANISM OF ACTION:  Cariprazine and its major active metabolite DDCAR are|
02617|007|A|metabolized by CYP3A4.|
02617|008|B||
02617|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor or protease|
02617|010|E|inhibitor may result in elevated levels of and toxicity from|
02617|011|E|cariprazine.(1-4)|
02617|012|B||
02617|013|P|PREDISPOSING FACTORS:  None determined.|
02617|014|B||
02617|015|M|PATIENT MANAGEMENT:  When possible, avoid the use of strong CYP3A4|
02617|016|M|inhibitors and protease inhibitors with cariprazine.|
02617|017|M|   The US manufacturer of cariprazine states that concurrent use of strong|
02617|018|M|CYP3A4 inhibitors requires a dose adjustment.  If a strong CYP3A4 inhibitor|
02617|019|M|is initiated in a patient on a stable dose of cariprazine, the following|
02617|020|M|dose adjustments are recommended:|
02617|021|M|   -If current cariprazine dose is 1.5 or 3 mg daily - Decrease cariprazine|
02617|022|M|dose to 1.5 mg every 3 days.|
02617|023|M|   -If current cariprazine dose is 4.5 or 6 mg daily - Decrease cariprazine|
02617|024|M|dose to 1.5 mg every other day.|
02617|025|M|   Cariprazine has two active metabolites, DCAR and DDCAR which have similar|
02617|026|M|in vitro activity and potency.  However, DDCAR has a longer half-life (1-3|
02617|027|M|weeks) than cariprazine (2-4 days), resulting in systemic DDCAR|
02617|028|M|concentrations that are about 4-fold higher than cariprazine.  Thus although|
02617|029|M|interaction onset may begin within a few days, the full effect of inhibition|
02617|030|M|may not be seen for 4 or more weeks.|
02617|031|M|   If a patient is already on a strong CYP3A4 inhibitor when cariprazine is|
02617|032|M|started, the following dose adjustments are recommended:|
02617|033|M|   -For schizophrenia or bipolar mania - Start cariprazine dose at 1.5 mg|
02617|034|M|every 3 days; Increase to 1.5 mg every other day, if needed.|
02617|035|M|   -For bipolar depression or adjunctive therapy for treatment of Major|
02617|036|M|Depressive Disorder (MDD) - Start cariprazine dose at 1.5 mg every 3|
02617|037|M|days.(1)|
02617|038|M|   When the inhibitor is discontinued, cariprazine, DCAR and DDCAR will|
02617|039|M|begin to fall and the dosage may need be increased. Monitor for decreased|
02617|040|M|effectiveness for 4 or more weeks.|
02617|041|M|   The Australian, Canadian, and UK manufacturers of cariprazine state that|
02617|042|M|concurrent use of strong CYP3A4 inhibitors is contraindicated.(2-4)|
02617|043|M|   The Canadian manufacturer of cariprazine states that concurrent use of|
02617|044|M|strong CYP3A4 inhibitors is also contraindicated for at least 2 weeks after|
02617|045|M|cariprazine discontinuation.(3)|
02617|046|B||
02617|047|D|DISCUSSION:  In an interaction study, coadministration of ketoconazole 400|
02617|048|D|mg/day with cariprazine 0.5 mg/day increased cariprazine exposure (AUC,|
02617|049|D|area-under-curve) 4-fold and increased DDCAR AUC about 1.5-fold.(1)|
02617|050|D|   In a PKPB model, coadministration of ketoconazole 400 mg/day with|
02617|051|D|cariprazine 0.5 mg/day is predicted to increase cariprazine concentration|
02617|052|D|maximum (Cmax) and AUC by 5.5-fold and 6-fold, respectively.|
02617|053|D|Coadministration of fluconazole 200 mg/day with cariprazine 0.5 mg/day is|
02617|054|D|predicted to increased cariprazine Cmax and AUC by up to 3-fold.(1)|
02617|055|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
02617|056|D|atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir,|
02617|057|D|grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
02617|058|D|levoketoconazole, lonafarnib, lopinavir-ritonavir, mibefradil, mifepristone,|
02617|059|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
02617|060|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
02617|061|D|troleandomycin, tucatinib, and voriconazole.(6,7)|
02617|062|B||
02617|063|R|REFERENCES:|
02617|064|B||
02617|065|R|1.Vraylar (cariprazine) US prescribing information. Forest Laboratories LLC|1
02617|066|R|  November, 2024.|1
02617|067|R|2.Reagila (capriprazine) Australian Product Information. Gedeon Richter|1
02617|068|R|  Australia Pty Ltd January, 2024.|1
02617|069|R|3.Vraylar (cariprazine) Canadian Product Monograph. AbbVie Corporation March|1
02617|070|R|  6, 2024.|1
02617|071|R|4.Reagila (cariprazine) UK Summary of Product Characteristics. Recordati|1
02617|072|R|  Pharmaceuticals Limited March, 2024.|1
02617|073|R|5.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02617|074|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02617|075|R|  HIV. Department of Health and Human Services. Available at:|6
02617|076|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
02617|077|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
02617|078|R|6.This information is based on an extract from the Certara Drug Interaction|6
02617|079|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02617|080|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
02617|081|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02617|082|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02617|083|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02617|084|R|  11/14/2017.|1
02618|001|T|MONOGRAPH TITLE:  Flibanserin/Strong CYP3A4 Inducers|
02618|002|B||
02618|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02618|004|L|of severe adverse interaction.|
02618|005|B||
02618|006|A|MECHANISM OF ACTION:  Flibanserin is primarily metabolized by CYP3A4.(1)|
02618|007|B||
02618|008|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers and flibanserin|
02618|009|E|will result in decreased systemic concentrations of flibanserin and may lead|
02618|010|E|to therapeutic failure.(1,6)|
02618|011|B||
02618|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02618|013|P|of the inducer for longer than 1-2 weeks.|
02618|014|B||
02618|015|M|PATIENT MANAGEMENT:  The manufacturer of flibanserin states that concomitant|
02618|016|M|use with CYP3A4 inducers is not recommended.  In an interaction study,|
02618|017|M|rifampin decreased flibanserin exposure(AUC) 95%.(1)|
02618|018|M|   The onset of induction is gradual but may begin within one week for|
02618|019|M|potent agents (e.g. rifampin). The time to maximal induction may be 2 or|
02618|020|M|more weeks depending upon the half-life and dose of the inducer.|
02618|021|B||
02618|022|D|DISCUSSION:  In an interaction study described in prescribing information,|
02618|023|D|rifampin decreased flibanserin exposure (AUC) 95%.(1)|
02618|024|D|    FDA defines strong CYP inducers as agents which cause a > or = to 80%|
02618|025|D|decrease in systemic exposure (area-under-curve or AUC) of a drug|
02618|026|D|metabolized by a specific CYP enzyme.(2)  Strong CYP3A4 inducers linked to|
02618|027|D|this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib,|
02618|028|D|enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine,|
02618|029|D|phenytoin, primidone, rifabutin, rifampin, rifapentine and St. John's|
02618|030|D|Wort.(3)|
02618|031|B||
02618|032|R|REFERENCES:|
02618|033|B||
02618|034|R|1.Addyi (flibanserin) US prescribing information. Sprout Pharmaceuticals|1
02618|035|R|  September, 2021.|1
02618|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02618|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02618|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02618|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02618|040|R|  11/14/2017.|1
02618|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
02618|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02619|001|T|MONOGRAPH TITLE:  Flecainide/QT Prolonging Agents|
02619|002|B||
02619|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02619|004|L|of severe adverse interaction.|
02619|005|B||
02619|006|A|MECHANISM OF ACTION:  Flecainide has been shown to prolong the QTc interval.|
02619|007|A|Concurrent use with other agents that prolong the QTc interval may result|
02619|008|A|in additive effects on the QTc interval.(1)|
02619|009|B||
02619|010|E|CLINICAL EFFECTS:  The concurrent use of flecainide with other agents that|
02619|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02619|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02619|013|B||
02619|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02619|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02619|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02619|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02619|018|P|female gender, or advanced age.(1)|
02619|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02619|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02619|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02619|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02619|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02619|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02619|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02619|026|B||
02619|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of flecainide with other|
02619|028|M|agents known to prolong the QT interval.|
02619|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02619|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02619|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02619|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02619|033|B||
02619|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02619|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02619|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02619|037|D|monograph have been shown to prolong the QTc interval either through their|
02619|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02619|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02619|040|D|clinical trials and/or post-marketing reports.(2)|
02619|041|D|   One or more of the drug pairs linked to this monograph have been included|
02619|042|D|in a list of interactions that should be considered "high-priority" for|
02619|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02619|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02619|045|D|Coordinator (ONC) for Health Information Technology.|
02619|046|B||
02619|047|R|REFERENCES:|
02619|048|B||
02619|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02619|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02619|051|R|  settings: a scientific statement from the American Heart Association and|6
02619|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02619|053|R|  2;55(9):934-47.|6
02619|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02619|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02619|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02619|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02619|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02619|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02619|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02619|061|R|  19(5):735-43.|6
02620|001|T|MONOGRAPH TITLE:  Flecainide/Possible QT Prolonging Agents|
02620|002|B||
02620|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02620|004|L|take action as needed.|
02620|005|B||
02620|006|A|MECHANISM OF ACTION:  Flecainide has been shown to prolong the QTc interval.|
02620|007|A|Concurrent use with other agents that prolong the QTc interval may result|
02620|008|A|in additive effects on the QTc interval.(1)|
02620|009|B||
02620|010|E|CLINICAL EFFECTS:  The concurrent use of flecainide with other agents that|
02620|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02620|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02620|013|B||
02620|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02620|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02620|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02620|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02620|018|P|female gender, or advanced age.(1)|
02620|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02620|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02620|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02620|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02620|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02620|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02620|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02620|026|B||
02620|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of flecainide with other|
02620|028|M|agents known to prolong the QT interval.|
02620|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02620|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02620|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02620|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02620|033|B||
02620|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02620|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02620|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02620|037|D|monograph have been shown to prolong the QTc interval either through their|
02620|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02620|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02620|040|D|clinical trials and/or post-marketing reports.(2)|
02620|041|B||
02620|042|R|REFERENCES:|
02620|043|B||
02620|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02620|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02620|046|R|  settings: a scientific statement from the American Heart Association and|6
02620|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02620|048|R|  2;55(9):934-47.|6
02620|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02620|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02620|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02620|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02621|001|T|MONOGRAPH TITLE:  Hydroquinidine; Quinidine/QT Prolonging Agents|
02621|002|B||
02621|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02621|004|L|of severe adverse interaction.|
02621|005|B||
02621|006|A|MECHANISM OF ACTION:  Hydroquinidine and quinidine have been shown to|
02621|007|A|prolong the QTc interval.  Concurrent use with other agents that prolong the|
02621|008|A|QTc interval may result in additive effects on the QTc interval.(1)|
02621|009|B||
02621|010|E|CLINICAL EFFECTS:  The concurrent use of hydroquinidine or quinidine with|
02621|011|E|other agents that prolong the QTc interval may result in potentially|
02621|012|E|life-threatening cardiac arrhythmias, including torsades de pointes(TdP).(1)|
02621|013|B||
02621|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02621|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02621|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02621|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02621|018|P|female gender, or advanced age.(1)|
02621|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02621|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02621|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02621|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02621|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02621|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02621|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02621|026|B||
02621|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of hydroquinidine or|
02621|028|M|quinidine with other agents known to prolong the QT interval.|
02621|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02621|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02621|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02621|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02621|033|B||
02621|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02621|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02621|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02621|037|D|monograph have been shown to prolong the QTc interval either through their|
02621|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02621|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02621|040|D|clinical trials and/or post-marketing reports.(2)|
02621|041|D|   One or more of the drug pairs linked to this monograph have been included|
02621|042|D|in a list of interactions that should be considered "high-priority" for|
02621|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02621|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02621|045|D|Coordinator (ONC) for Health Information Technology.|
02621|046|B||
02621|047|R|REFERENCES:|
02621|048|B||
02621|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02621|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02621|051|R|  settings: a scientific statement from the American Heart Association and|6
02621|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02621|053|R|  2;55(9):934-47.|6
02621|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02621|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02621|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02621|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02621|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02621|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02621|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02621|061|R|  19(5):735-43.|6
02622|001|T|MONOGRAPH TITLE:  Hydroquinidine; Quinidine/Possible QT Prolonging Agents|
02622|002|B||
02622|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02622|004|L|take action as needed.|
02622|005|B||
02622|006|A|MECHANISM OF ACTION:  Hydroquinidine and quinidine have been shown to|
02622|007|A|prolong the QTc interval.  Concurrent use with other agents that prolong the|
02622|008|A|QTc interval may result in additive effects on the QTc interval.(1)|
02622|009|B||
02622|010|E|CLINICAL EFFECTS:  The concurrent use of hydroquinidine or quinidine with|
02622|011|E|other agents that prolong the QTc interval may result in potentially|
02622|012|E|life-threatening cardiac arrhythmias, including torsades de pointes(TdP).(1)|
02622|013|B||
02622|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02622|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02622|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02622|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02622|018|P|female gender, or advanced age.(1)|
02622|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02622|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02622|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02622|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02622|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02622|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02622|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02622|026|B||
02622|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of hydroquinidine or|
02622|028|M|quinidine with other agents known to prolong the QT interval.|
02622|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02622|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02622|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02622|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02622|033|B||
02622|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02622|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02622|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02622|037|D|monograph have been shown to prolong the QTc interval either through their|
02622|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02622|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02622|040|D|clinical trials and/or post-marketing reports.(2)|
02622|041|B||
02622|042|R|REFERENCES:|
02622|043|B||
02622|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02622|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02622|046|R|  settings: a scientific statement from the American Heart Association and|6
02622|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02622|048|R|  2;55(9):934-47.|6
02622|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02622|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02622|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02622|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02623|001|T|MONOGRAPH TITLE:  Ibutilide/QT Prolonging Agents|
02623|002|B||
02623|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02623|004|L|of severe adverse interaction.|
02623|005|B||
02623|006|A|MECHANISM OF ACTION:  Ibutilide has been shown to prolong the QTc|
02623|007|A|interval.(1)  Concurrent use with other agents that prolong the QTc interval|
02623|008|A|may result in additive effects on the QTc interval.(2)|
02623|009|B||
02623|010|E|CLINICAL EFFECTS:  The concurrent use of ibutilide with other agents that|
02623|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02623|012|E|arrhythmias, including torsades de pointes(TdP).(1,2)|
02623|013|B||
02623|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02623|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02623|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02623|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02623|018|P|female gender, or advanced age.(2)|
02623|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02623|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02623|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02623|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02623|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02623|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02623|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02623|026|B||
02623|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of ibutilide with other|
02623|028|M|agents known to prolong the QT interval.(1)|
02623|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02623|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02623|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02623|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02623|033|B||
02623|034|D|DISCUSSION:  In a study in healthy volunteers, intravenous infusions of|
02623|035|D|ibutilide resulted in prolongation of the QT interval that was directly|
02623|036|D|correlated with ibutilide plasma concentration during and after 10-minute|
02623|037|D|and 8-hour infusions.(1)|
02623|038|D|   Agents that are linked to this monograph may have varying degrees of|
02623|039|D|potential to prolong the QTc interval but are generally accepted to have a|
02623|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02623|041|D|been shown to prolong the QTc interval either through their mechanism of|
02623|042|D|action, through studies on their effects on the QTc interval, or through|
02623|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02623|044|D|and/or post-marketing reports.(3)|
02623|045|D|   One or more of the drug pairs linked to this monograph have been included|
02623|046|D|in a list of interactions that should be considered "high-priority" for|
02623|047|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02623|048|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02623|049|D|Coordinator (ONC) for Health Information Technology.|
02623|050|B||
02623|051|R|REFERENCES:|
02623|052|B||
02623|053|R|1.Corvert (ibutilide fumarate) US prescribing information. Pharmacia &|1
02623|054|R|  Upjohn Company July, 2002.|1
02623|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02623|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02623|057|R|  settings: a scientific statement from the American Heart Association and|6
02623|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02623|059|R|  2;55(9):934-47.|6
02623|060|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02623|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02623|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02623|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02623|064|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02623|065|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02623|066|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02623|067|R|  19(5):735-43.|6
02624|001|T|MONOGRAPH TITLE:  Ibutilide/Possible QT Prolonging Agents|
02624|002|B||
02624|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02624|004|L|take action as needed.|
02624|005|B||
02624|006|A|MECHANISM OF ACTION:  Ibutilide has been shown to prolong the QTc|
02624|007|A|interval.(1)  Concurrent use with other agents that prolong the QTc interval|
02624|008|A|may result in additive effects on the QTc interval.(2)|
02624|009|B||
02624|010|E|CLINICAL EFFECTS:  The concurrent use of ibutilide with other agents that|
02624|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02624|012|E|arrhythmias, including torsades de pointes(TdP).(1,2)|
02624|013|B||
02624|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02624|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02624|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02624|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02624|018|P|female gender, or advanced age.(2)|
02624|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02624|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02624|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02624|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02624|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02624|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02624|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02624|026|B||
02624|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of ibutilide with other|
02624|028|M|agents known to prolong the QT interval.(1)|
02624|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02624|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02624|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02624|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02624|033|B||
02624|034|D|DISCUSSION:  In a study in healthy volunteers, intravenous infusions of|
02624|035|D|ibutilide resulted in prolongation of the QT interval that was directly|
02624|036|D|correlated with ibutilide plasma concentration during and after 10-minute|
02624|037|D|and 8-hour infusions.(1)|
02624|038|D|   Agents that are linked to this monograph may have varying degrees of|
02624|039|D|potential to prolong the QTc interval but are generally accepted to have a|
02624|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02624|041|D|been shown to prolong the QTc interval either through their mechanism of|
02624|042|D|action, through studies on their effects on the QTc interval, or through|
02624|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02624|044|D|and/or post-marketing reports.(2)|
02624|045|B||
02624|046|R|REFERENCES:|
02624|047|B||
02624|048|R|1.Corvert (ibutilide fumarate) US prescribing information. Pharmacia &|1
02624|049|R|  Upjohn Company July, 2002.|1
02624|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02624|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02624|052|R|  settings: a scientific statement from the American Heart Association and|6
02624|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02624|054|R|  2;55(9):934-47.|6
02624|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02624|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02624|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02624|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02625|001|T|MONOGRAPH TITLE:  Procainamide/QT Prolonging Agents|
02625|002|B||
02625|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02625|004|L|of severe adverse interaction.|
02625|005|B||
02625|006|A|MECHANISM OF ACTION:  Procainamide has been shown to prolong the QTc|
02625|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02625|008|A|may result in additive effects on the QTc interval.(1)|
02625|009|B||
02625|010|E|CLINICAL EFFECTS:  The concurrent use of procainamide with other agents that|
02625|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02625|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02625|013|B||
02625|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02625|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02625|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02625|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02625|018|P|female gender, or advanced age.(1)|
02625|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02625|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02625|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02625|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02625|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02625|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02625|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02625|026|B||
02625|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of procainamide with other|
02625|028|M|agents known to prolong the QT interval.|
02625|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02625|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02625|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02625|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02625|033|B||
02625|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02625|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02625|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02625|037|D|monograph have been shown to prolong the QTc interval either through their|
02625|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02625|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02625|040|D|clinical trials and/or post-marketing reports.(2)|
02625|041|D|   One or more of the drug pairs linked to this monograph have been included|
02625|042|D|in a list of interactions that should be considered "high-priority" for|
02625|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02625|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02625|045|D|Coordinator (ONC) for Health Information Technology.|
02625|046|B||
02625|047|R|REFERENCES:|
02625|048|B||
02625|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02625|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02625|051|R|  settings: a scientific statement from the American Heart Association and|6
02625|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02625|053|R|  2;55(9):934-47.|6
02625|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02625|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02625|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02625|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02625|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02625|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02625|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02625|061|R|  19(5):735-43.|6
02626|001|T|MONOGRAPH TITLE:  Procainamide/Possible QT Prolonging Agents|
02626|002|B||
02626|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02626|004|L|take action as needed.|
02626|005|B||
02626|006|A|MECHANISM OF ACTION:  Procainamide has been shown to prolong the QTc|
02626|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02626|008|A|may result in additive effects on the QTc interval.(1)|
02626|009|B||
02626|010|E|CLINICAL EFFECTS:  The concurrent use of procainamide with other agents that|
02626|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02626|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02626|013|B||
02626|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02626|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02626|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02626|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02626|018|P|female gender, or advanced age.(1)|
02626|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02626|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02626|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02626|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02626|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02626|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02626|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02626|026|B||
02626|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of procainamide with other|
02626|028|M|agents known to prolong the QT interval.|
02626|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02626|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02626|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02626|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02626|033|B||
02626|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02626|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02626|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02626|037|D|monograph have been shown to prolong the QTc interval either through their|
02626|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02626|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02626|040|D|clinical trials and/or post-marketing reports.(2)|
02626|041|B||
02626|042|R|REFERENCES:|
02626|043|B||
02626|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02626|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02626|046|R|  settings: a scientific statement from the American Heart Association and|6
02626|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02626|048|R|  2;55(9):934-47.|6
02626|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02626|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02626|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02626|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02627|001|T|MONOGRAPH TITLE:  Sotalol/QT Prolonging Agents|
02627|002|B||
02627|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02627|004|L|of severe adverse interaction.|
02627|005|B||
02627|006|A|MECHANISM OF ACTION:  Sotalol has been shown to prolong the QTc interval.|
02627|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02627|008|A|additive effects on the QTc interval.(1)|
02627|009|B||
02627|010|E|CLINICAL EFFECTS:  The concurrent use of sotalol with other agents that|
02627|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02627|012|E|arrhythmias, including torsades de pointes.(1)|
02627|013|B||
02627|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by|
02627|015|P|reduced creatinine clearance, female gender, larger doses of sotalol, and a|
02627|016|P|history of cardiomegaly or congestive heart failure.(1)  Risk may also be|
02627|017|P|increased in patients with cardiovascular disease (e.g. myocardial|
02627|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02627|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, or advanced age.(3)|
02627|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02627|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02627|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02627|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02627|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02627|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02627|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02627|027|B||
02627|028|M|PATIENT MANAGEMENT:  The manufacturer of sotalol states that concurrent use|
02627|029|M|with other agents known to prolong the QT interval is not recommended.(1)|
02627|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02627|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02627|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02627|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02627|034|B||
02627|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02627|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02627|037|D|monograph have been shown to prolong the QTc interval either through their|
02627|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02627|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
02627|040|D|clinical trials and/or postmarketing reports.(2)|
02627|041|D|   One or more of the drug pairs linked to this monograph have been included|
02627|042|D|in a list of interactions that should be considered "high-priority" for|
02627|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02627|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02627|045|D|Coordinator (ONC) for Health Information Technology.|
02627|046|B||
02627|047|R|REFERENCES:|
02627|048|B||
02627|049|R|1.Betapace (sotalol hydrochloride) US prescribing information. Bayer|1
02627|050|R|  Healthcare Inc. June, 2021.|1
02627|051|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02627|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02627|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02627|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02627|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02627|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02627|057|R|  settings: a scientific statement from the American Heart Association and|6
02627|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02627|059|R|  2;55(9):934-47.|6
02627|060|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02627|061|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02627|062|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02627|063|R|  19(5):735-43.|6
02628|001|T|MONOGRAPH TITLE:  Azithromycin/QT Prolonging Agents|
02628|002|B||
02628|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02628|004|L|of severe adverse interaction.|
02628|005|B||
02628|006|A|MECHANISM OF ACTION:  Azithromycin has been shown to prolong the QTc|
02628|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02628|008|A|may result in additive effects on the QTc interval.(1,2)|
02628|009|B||
02628|010|E|CLINICAL EFFECTS:  The concurrent use of azithromycin with other agents that|
02628|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02628|012|E|arrhythmias, including torsades de pointes(TdP).(1,2)|
02628|013|B||
02628|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02628|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02628|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02628|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02628|018|P|female gender, or advanced age.(2)|
02628|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02628|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02628|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02628|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02628|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02628|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02628|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02628|026|B||
02628|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of azithromycin with other|
02628|028|M|agents known to prolong the QT interval.|
02628|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02628|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02628|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02628|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02628|033|B||
02628|034|D|DISCUSSION:  In a randomized, placebo-controlled parallel trial 116 healthy|
02628|035|D|subjects received either chloroquine (1000 mg) alone or in combination with|
02628|036|D|oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily).|
02628|037|D|Co-administration of azithromycin increased the QTc interval in a dose- and|
02628|038|D|concentration- dependent manner.  In comparison to chloroquine alone, the|
02628|039|D|maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms,|
02628|040|D|7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and|
02628|041|D|1500 mg azithromycin, respectively.(1)|
02628|042|D|   Agents that are linked to this monograph may have varying degrees of|
02628|043|D|potential to prolong the QTc interval but are generally accepted to have a|
02628|044|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02628|045|D|been shown to prolong the QTc interval either through their mechanism of|
02628|046|D|action, through studies on their effects on the QTc interval, or through|
02628|047|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02628|048|D|and/or post-marketing reports.(3)|
02628|049|D|   One or more of the drug pairs linked to this monograph have been included|
02628|050|D|in a list of interactions that should be considered "high-priority" for|
02628|051|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02628|052|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02628|053|D|Coordinator (ONC) for Health Information Technology.|
02628|054|B||
02628|055|R|REFERENCES:|
02628|056|B||
02628|057|R|1.Zithromax (azithromycin oral) US prescribing information. Pifzer Labs|1
02628|058|R|  April, 2019.|1
02628|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02628|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02628|061|R|  settings: a scientific statement from the American Heart Association and|6
02628|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02628|063|R|  2;55(9):934-47.|6
02628|064|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02628|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02628|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02628|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02628|068|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02628|069|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02628|070|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02628|071|R|  19(5):735-43.|6
02629|001|T|MONOGRAPH TITLE:  Azithromycin/Possible QT Prolonging Agents|
02629|002|B||
02629|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02629|004|L|take action as needed.|
02629|005|B||
02629|006|A|MECHANISM OF ACTION:  Azithromycin has been shown to prolong the QTc|
02629|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02629|008|A|may result in additive effects on the QTc interval.(1)|
02629|009|B||
02629|010|E|CLINICAL EFFECTS:  The concurrent use of azithromycin with other agents that|
02629|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02629|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02629|013|B||
02629|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02629|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02629|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02629|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02629|018|P|female gender, or advanced age.(1)|
02629|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02629|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02629|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02629|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02629|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02629|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02629|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02629|026|B||
02629|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of azithromycin with other|
02629|028|M|agents known to prolong the QT interval.|
02629|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02629|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02629|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02629|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02629|033|B||
02629|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02629|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02629|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02629|037|D|monograph have been shown to prolong the QTc interval either through their|
02629|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02629|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02629|040|D|clinical trials and/or post-marketing reports.(2)|
02629|041|B||
02629|042|R|REFERENCES:|
02629|043|B||
02629|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02629|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02629|046|R|  settings: a scientific statement from the American Heart Association and|6
02629|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02629|048|R|  2;55(9):934-47.|6
02629|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02629|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02629|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02629|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02630|001|T|MONOGRAPH TITLE:  Chloroquine/QT Prolonging Agents|
02630|002|B||
02630|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02630|004|L|of severe adverse interaction.|
02630|005|B||
02630|006|A|MECHANISM OF ACTION:  Chloroquine has been shown to prolong the QTc|
02630|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02630|008|A|may result in additive effects on the QTc interval.(1)|
02630|009|B||
02630|010|E|CLINICAL EFFECTS:  The concurrent use of chloroquine with other agents that|
02630|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02630|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02630|013|B||
02630|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02630|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02630|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02630|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02630|018|P|female gender, or advanced age.(1)|
02630|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02630|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02630|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02630|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02630|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02630|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02630|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02630|026|B||
02630|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of chloroquine with other|
02630|028|M|agents known to prolong the QT interval.|
02630|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02630|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02630|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02630|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02630|033|B||
02630|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02630|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02630|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02630|037|D|monograph have been shown to prolong the QTc interval either through their|
02630|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02630|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02630|040|D|clinical trials and/or post-marketing reports.(2)|
02630|041|D|   One or more of the drug pairs linked to this monograph have been included|
02630|042|D|in a list of interactions that should be considered "high-priority" for|
02630|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02630|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02630|045|D|Coordinator (ONC) for Health Information Technology.|
02630|046|B||
02630|047|R|REFERENCES:|
02630|048|B||
02630|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02630|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02630|051|R|  settings: a scientific statement from the American Heart Association and|6
02630|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02630|053|R|  2;55(9):934-47.|6
02630|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02630|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02630|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02630|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02630|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02630|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02630|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02630|061|R|  19(5):735-43.|6
02631|001|T|MONOGRAPH TITLE:  Chloroquine/Possible QT Prolonging Agents|
02631|002|B||
02631|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02631|004|L|take action as needed.|
02631|005|B||
02631|006|A|MECHANISM OF ACTION:  Chloroquine has been shown to prolong the QTc|
02631|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02631|008|A|may result in additive effects on the QTc interval.(1)|
02631|009|B||
02631|010|E|CLINICAL EFFECTS:  The concurrent use of chloroquine with other agents that|
02631|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02631|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02631|013|B||
02631|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02631|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02631|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02631|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02631|018|P|female gender, or advanced age.(1)|
02631|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02631|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02631|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02631|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02631|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02631|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02631|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02631|026|B||
02631|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of chloroquine with other|
02631|028|M|agents known to prolong the QT interval.|
02631|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02631|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02631|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02631|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02631|033|B||
02631|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02631|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02631|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02631|037|D|monograph have been shown to prolong the QTc interval either through their|
02631|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02631|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02631|040|D|clinical trials and/or post-marketing reports.(2)|
02631|041|B||
02631|042|R|REFERENCES:|
02631|043|B||
02631|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02631|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02631|046|R|  settings: a scientific statement from the American Heart Association and|6
02631|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02631|048|R|  2;55(9):934-47.|6
02631|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02631|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02631|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02631|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02632|001|T|MONOGRAPH TITLE:  Chlorpromazine/QT Prolonging Agents|
02632|002|B||
02632|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02632|004|L|of severe adverse interaction.|
02632|005|B||
02632|006|A|MECHANISM OF ACTION:  Chlorpromazine has been shown to prolong the QTc|
02632|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02632|008|A|may result in additive effects on the QTc interval.(1)|
02632|009|B||
02632|010|E|CLINICAL EFFECTS:  The concurrent use of chlorpromazine with other agents|
02632|011|E|that prolong the QTc interval may result in potentially life-threatening|
02632|012|E|cardiac arrhythmias, including torsades de pointes(TdP).(1)|
02632|013|B||
02632|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02632|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02632|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02632|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02632|018|P|female gender, or advanced age.(1)|
02632|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02632|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02632|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02632|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02632|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02632|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02632|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02632|026|B||
02632|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of chlorpromazine with other|
02632|028|M|agents known to prolong the QT interval.|
02632|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02632|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02632|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02632|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02632|033|B||
02632|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02632|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02632|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02632|037|D|monograph have been shown to prolong the QTc interval either through their|
02632|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02632|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02632|040|D|clinical trials and/or post-marketing reports.(2)|
02632|041|D|   One or more of the drug pairs linked to this monograph have been included|
02632|042|D|in a list of interactions that should be considered "high-priority" for|
02632|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02632|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02632|045|D|Coordinator (ONC) for Health Information Technology.|
02632|046|B||
02632|047|R|REFERENCES:|
02632|048|B||
02632|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02632|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02632|051|R|  settings: a scientific statement from the American Heart Association and|6
02632|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02632|053|R|  2;55(9):934-47.|6
02632|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02632|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02632|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02632|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02632|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02632|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02632|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02632|061|R|  19(5):735-43.|6
02633|001|T|MONOGRAPH TITLE:  Chlorpromazine/Possible QT Prolonging Agents|
02633|002|B||
02633|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02633|004|L|take action as needed.|
02633|005|B||
02633|006|A|MECHANISM OF ACTION:  Chlorpromazine has been shown to prolong the QTc|
02633|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02633|008|A|may result in additive effects on the QTc interval.(1)|
02633|009|B||
02633|010|E|CLINICAL EFFECTS:  The concurrent use of chlorpromazine with other agents|
02633|011|E|that prolong the QTc interval may result in potentially life-threatening|
02633|012|E|cardiac arrhythmias, including torsades de pointes(TdP).(1)|
02633|013|B||
02633|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02633|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02633|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02633|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02633|018|P|female gender, or advanced age.(1)|
02633|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02633|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02633|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02633|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02633|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02633|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02633|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02633|026|B||
02633|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of chlorpromazine with other|
02633|028|M|agents known to prolong the QT interval.|
02633|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02633|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02633|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02633|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02633|033|B||
02633|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02633|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02633|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02633|037|D|monograph have been shown to prolong the QTc interval either through their|
02633|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02633|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02633|040|D|clinical trials and/or post-marketing reports.(2)|
02633|041|B||
02633|042|R|REFERENCES:|
02633|043|B||
02633|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02633|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02633|046|R|  settings: a scientific statement from the American Heart Association and|6
02633|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02633|048|R|  2;55(9):934-47.|6
02633|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02633|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02633|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02633|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02634|001|T|MONOGRAPH TITLE:  Cilostazol/QT Prolonging Agents|
02634|002|B||
02634|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02634|004|L|of severe adverse interaction.|
02634|005|B||
02634|006|A|MECHANISM OF ACTION:  Cilostazol has been shown to prolong the QTc interval.|
02634|007|A|Concurrent use with other agents that prolong the QTc interval may result|
02634|008|A|in additive effects on the QTc interval.(1)|
02634|009|B||
02634|010|E|CLINICAL EFFECTS:  The concurrent use of cilostazol with other agents that|
02634|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02634|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02634|013|B||
02634|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02634|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02634|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02634|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02634|018|P|female gender, or advanced age.(1)|
02634|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02634|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02634|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02634|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02634|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02634|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02634|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02634|026|B||
02634|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of cilostazol with other|
02634|028|M|agents known to prolong the QT interval.|
02634|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02634|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02634|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02634|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02634|033|B||
02634|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02634|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02634|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02634|037|D|monograph have been shown to prolong the QTc interval either through their|
02634|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02634|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02634|040|D|clinical trials and/or post-marketing reports.(2)|
02634|041|D|   One or more of the drug pairs linked to this monograph have been included|
02634|042|D|in a list of interactions that should be considered "high-priority" for|
02634|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02634|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02634|045|D|Coordinator (ONC) for Health Information Technology.|
02634|046|B||
02634|047|R|REFERENCES:|
02634|048|B||
02634|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02634|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02634|051|R|  settings: a scientific statement from the American Heart Association and|6
02634|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02634|053|R|  2;55(9):934-47.|6
02634|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02634|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02634|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02634|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02634|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02634|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02634|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02634|061|R|  19(5):735-43.|6
02635|001|T|MONOGRAPH TITLE:  Cilostazol/Possible QT Prolonging Agents|
02635|002|B||
02635|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02635|004|L|take action as needed.|
02635|005|B||
02635|006|A|MECHANISM OF ACTION:  Cilostazol has been shown to prolong the QTc interval.|
02635|007|A|Concurrent use with other agents that prolong the QTc interval may result|
02635|008|A|in additive effects on the QTc interval.(1)|
02635|009|B||
02635|010|E|CLINICAL EFFECTS:  The concurrent use of cilostazol with other agents that|
02635|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02635|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02635|013|B||
02635|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02635|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02635|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02635|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02635|018|P|female gender, or advanced age.(1)|
02635|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02635|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02635|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02635|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02635|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02635|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02635|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02635|026|B||
02635|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of cilostazol with other|
02635|028|M|agents known to prolong the QT interval.|
02635|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02635|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02635|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02635|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02635|033|B||
02635|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02635|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02635|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02635|037|D|monograph have been shown to prolong the QTc interval either through their|
02635|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02635|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02635|040|D|clinical trials and/or post-marketing reports.(2)|
02635|041|B||
02635|042|R|REFERENCES:|
02635|043|B||
02635|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02635|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02635|046|R|  settings: a scientific statement from the American Heart Association and|6
02635|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02635|048|R|  2;55(9):934-47.|6
02635|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02635|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02635|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02635|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02636|001|T|MONOGRAPH TITLE:  Donepezil/QT Prolonging Agents|
02636|002|B||
02636|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02636|004|L|of severe adverse interaction.|
02636|005|B||
02636|006|A|MECHANISM OF ACTION:  Donepezil has been shown to prolong the QTc interval.|
02636|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02636|008|A|additive effects on the QTc interval.(1)|
02636|009|B||
02636|010|E|CLINICAL EFFECTS:  The concurrent use of donepezil with other agents that|
02636|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02636|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02636|013|B||
02636|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02636|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02636|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02636|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02636|018|P|female gender, or advanced age.(1)|
02636|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02636|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02636|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02636|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02636|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02636|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02636|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02636|026|B||
02636|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of donepezil with other|
02636|028|M|agents known to prolong the QT interval.|
02636|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02636|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02636|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02636|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02636|033|B||
02636|034|D|DISCUSSION:  A pharmacovigilance study based on the FDA Adverse Event|
02636|035|D|Reporting System (FAERS) database found that, of a total of 33,626 cases of|
02636|036|D|TdP/QT prolongation reported between January 2004 and September 2022, 430|
02636|037|D|cases occurred in patients on donepezil.  The disproportionality analysis|
02636|038|D|found a ROR = 8.98, 95% CI (8.16, 9.89) and a PRR = 8.88, chi-square =|
02636|039|D|2944.95.(2)|
02636|040|D|   Agents that are linked to this monograph may have varying degrees of|
02636|041|D|potential to prolong the QTc interval but are generally accepted to have a|
02636|042|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02636|043|D|been shown to prolong the QTc interval either through their mechanism of|
02636|044|D|action, through studies on their effects on the QTc interval, or through|
02636|045|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02636|046|D|and/or post-marketing reports.(3)|
02636|047|D|   One or more of the drug pairs linked to this monograph have been included|
02636|048|D|in a list of interactions that should be considered "high-priority" for|
02636|049|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02636|050|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02636|051|D|Coordinator (ONC) for Health Information Technology.|
02636|052|B||
02636|053|R|REFERENCES:|
02636|054|B||
02636|055|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02636|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02636|057|R|  settings: a scientific statement from the American Heart Association and|6
02636|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02636|059|R|  2;55(9):934-47.|6
02636|060|R|2.Zhang N, Gan L, Xiang G, Xu J, Jiang T, Li Y, Wu Y, Ni R, Liu Y.|6
02636|061|R|  Cholinesterase inhibitors-associated torsade de pointes/QT prolongation: a|6
02636|062|R|  real-world pharmacovigilance study. Front Pharmacol 2023;14:1343650.|6
02636|063|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02636|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02636|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02636|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02636|067|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02636|068|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02636|069|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02636|070|R|  19(5):735-43.|6
02637|001|T|MONOGRAPH TITLE:  Donepezil/Possible QT Prolonging Agents|
02637|002|B||
02637|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02637|004|L|take action as needed.|
02637|005|B||
02637|006|A|MECHANISM OF ACTION:  Donepezil has been shown to prolong the QTc interval.|
02637|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02637|008|A|additive effects on the QTc interval.(1)|
02637|009|B||
02637|010|E|CLINICAL EFFECTS:  The concurrent use of donepezil with other agents that|
02637|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02637|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02637|013|B||
02637|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02637|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02637|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02637|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02637|018|P|female gender, or advanced age.(1)|
02637|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02637|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02637|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02637|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02637|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02637|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02637|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02637|026|B||
02637|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of donepezil with other|
02637|028|M|agents known to prolong the QT interval.|
02637|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02637|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02637|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02637|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02637|033|B||
02637|034|D|DISCUSSION:  A pharmacovigilance study based on the FDA Adverse Event|
02637|035|D|Reporting System (FAERS) database found that, of a total of 33,626 cases of|
02637|036|D|TdP/QT prolongation reported between January 2004 and September 2022, 430|
02637|037|D|cases occurred in patients on donepezil.  The disproportionality analysis|
02637|038|D|found a ROR = 8.98, 95% CI (8.16, 9.89) and a PRR = 8.88, chi-square =|
02637|039|D|2944.95.(2)|
02637|040|D|   Agents that are linked to this monograph may have varying degrees of|
02637|041|D|potential to prolong the QTc interval but are generally accepted to have a|
02637|042|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02637|043|D|been shown to prolong the QTc interval either through their mechanism of|
02637|044|D|action, through studies on their effects on the QTc interval, or through|
02637|045|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02637|046|D|and/or post-marketing reports.(3)|
02637|047|B||
02637|048|R|REFERENCES:|
02637|049|B||
02637|050|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02637|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02637|052|R|  settings: a scientific statement from the American Heart Association and|6
02637|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02637|054|R|  2;55(9):934-47.|6
02637|055|R|2.Zhang N, Gan L, Xiang G, Xu J, Jiang T, Li Y, Wu Y, Ni R, Liu Y.|6
02637|056|R|  Cholinesterase inhibitors-associated torsade de pointes/QT prolongation: a|6
02637|057|R|  real-world pharmacovigilance study. Front Pharmacol 2023;14:1343650.|6
02637|058|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02637|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02637|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02637|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02638|001|T|MONOGRAPH TITLE:  Erythromycin/QT Prolonging Agents|
02638|002|B||
02638|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02638|004|L|of severe adverse interaction.|
02638|005|B||
02638|006|A|MECHANISM OF ACTION:  Erythromycin has been shown to prolong the QTc|
02638|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02638|008|A|may result in additive effects on the QTc interval.(1)|
02638|009|B||
02638|010|E|CLINICAL EFFECTS:  The concurrent use of erythromycin with other agents that|
02638|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02638|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02638|013|B||
02638|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02638|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02638|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02638|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02638|018|P|female gender, or advanced age.(1)|
02638|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02638|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02638|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02638|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02638|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02638|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02638|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02638|026|B||
02638|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of erythromycin with other|
02638|028|M|agents known to prolong the QT interval.|
02638|029|M|   The Australian manufacturer of erythromycin states that concurrent use|
02638|030|M|with agents known to prolong the QT interval is contraindicated.(4)|
02638|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02638|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02638|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02638|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02638|035|B||
02638|036|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02638|037|D|degrees of potential to prolong the QTc interval but are generally accepted|
02638|038|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02638|039|D|monograph have been shown to prolong the QTc interval either through their|
02638|040|D|mechanism of action, through studies on their effects on the QTc interval,|
02638|041|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02638|042|D|clinical trials and/or post-marketing reports.(2)|
02638|043|D|   One or more of the drug pairs linked to this monograph have been included|
02638|044|D|in a list of interactions that should be considered "high-priority" for|
02638|045|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02638|046|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02638|047|D|Coordinator (ONC) for Health Information Technology.|
02638|048|B||
02638|049|R|REFERENCES:|
02638|050|B||
02638|051|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02638|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02638|053|R|  settings: a scientific statement from the American Heart Association and|6
02638|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02638|055|R|  2;55(9):934-47.|6
02638|056|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02638|057|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02638|058|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02638|059|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02638|060|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02638|061|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02638|062|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02638|063|R|  19(5):735-43.|6
02638|064|R|4.Eryc (erythromycin) Australian prescribing information. Mayne Pharma|1
02638|065|R|  International Pty Ltd. August 2023.|1
02639|001|T|MONOGRAPH TITLE:  Erythromycin/Possible QT Prolonging Agents|
02639|002|B||
02639|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02639|004|L|take action as needed.|
02639|005|B||
02639|006|A|MECHANISM OF ACTION:  Erythromycin has been shown to prolong the QTc|
02639|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02639|008|A|may result in additive effects on the QTc interval.(1)|
02639|009|B||
02639|010|E|CLINICAL EFFECTS:  The concurrent use of erythromycin with other agents that|
02639|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02639|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02639|013|B||
02639|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02639|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02639|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02639|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02639|018|P|female gender, or advanced age.(1)|
02639|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02639|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02639|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02639|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02639|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02639|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02639|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02639|026|B||
02639|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of erythromycin with other|
02639|028|M|agents known to prolong the QT interval.|
02639|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02639|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02639|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02639|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02639|033|B||
02639|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02639|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02639|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02639|037|D|monograph have been shown to prolong the QTc interval either through their|
02639|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02639|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02639|040|D|clinical trials and/or post-marketing reports.(2)|
02639|041|B||
02639|042|R|REFERENCES:|
02639|043|B||
02639|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02639|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02639|046|R|  settings: a scientific statement from the American Heart Association and|6
02639|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02639|048|R|  2;55(9):934-47.|6
02639|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02639|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02639|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02639|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02640|001|T|MONOGRAPH TITLE:  Fluconazole/QT Prolonging Agents|
02640|002|B||
02640|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02640|004|L|of severe adverse interaction.|
02640|005|B||
02640|006|A|MECHANISM OF ACTION:  Fluconazole has been shown to prolong the QTc|
02640|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02640|008|A|may result in additive effects on the QTc interval.(1)|
02640|009|B||
02640|010|E|CLINICAL EFFECTS:  The concurrent use of fluconazole with other agents that|
02640|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02640|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02640|013|B||
02640|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02640|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02640|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02640|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02640|018|P|female gender, or advanced age.(1)|
02640|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02640|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02640|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02640|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02640|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02640|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02640|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02640|026|B||
02640|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of fluconazole with other|
02640|028|M|agents known to prolong the QT interval.|
02640|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02640|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02640|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02640|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02640|033|B||
02640|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02640|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02640|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02640|037|D|monograph have been shown to prolong the QTc interval either through their|
02640|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02640|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02640|040|D|clinical trials and/or post-marketing reports.(2)|
02640|041|D|   One or more of the drug pairs linked to this monograph have been included|
02640|042|D|in a list of interactions that should be considered "high-priority" for|
02640|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02640|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02640|045|D|Coordinator (ONC) for Health Information Technology.|
02640|046|B||
02640|047|R|REFERENCES:|
02640|048|B||
02640|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02640|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02640|051|R|  settings: a scientific statement from the American Heart Association and|6
02640|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02640|053|R|  2;55(9):934-47.|6
02640|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02640|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02640|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02640|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02640|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02640|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02640|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02640|061|R|  19(5):735-43.|6
02641|001|T|MONOGRAPH TITLE:  Fluconazole/Possible QT Prolonging Agents|
02641|002|B||
02641|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02641|004|L|take action as needed.|
02641|005|B||
02641|006|A|MECHANISM OF ACTION:  Fluconazole has been shown to prolong the QTc|
02641|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02641|008|A|may result in additive effects on the QTc interval.(1)|
02641|009|B||
02641|010|E|CLINICAL EFFECTS:  The concurrent use of fluconazole with other agents that|
02641|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02641|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02641|013|B||
02641|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02641|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02641|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02641|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02641|018|P|female gender, or advanced age.(1)|
02641|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02641|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02641|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02641|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02641|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02641|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02641|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02641|026|B||
02641|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of fluconazole with other|
02641|028|M|agents known to prolong the QT interval.|
02641|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02641|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02641|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02641|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02641|033|B||
02641|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02641|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02641|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02641|037|D|monograph have been shown to prolong the QTc interval either through their|
02641|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02641|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02641|040|D|clinical trials and/or post-marketing reports.(2)|
02641|041|B||
02641|042|R|REFERENCES:|
02641|043|B||
02641|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02641|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02641|046|R|  settings: a scientific statement from the American Heart Association and|6
02641|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02641|048|R|  2;55(9):934-47.|6
02641|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02641|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02641|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02641|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02642|001|T|MONOGRAPH TITLE:  Pentamidine/QT Prolonging Agents|
02642|002|B||
02642|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02642|004|L|of severe adverse interaction.|
02642|005|B||
02642|006|A|MECHANISM OF ACTION:  Pentamidine has been shown to prolong the QTc|
02642|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02642|008|A|may result in additive effects on the QTc interval.(1)|
02642|009|B||
02642|010|E|CLINICAL EFFECTS:  The concurrent use of pentamidine with other agents that|
02642|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02642|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02642|013|B||
02642|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02642|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02642|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02642|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02642|018|P|female gender, or advanced age.(1)|
02642|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02642|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02642|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02642|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02642|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02642|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02642|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02642|026|B||
02642|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of pentamidine with other|
02642|028|M|agents known to prolong the QT interval.|
02642|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02642|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02642|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02642|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02642|033|B||
02642|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02642|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02642|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02642|037|D|monograph have been shown to prolong the QTc interval either through their|
02642|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02642|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02642|040|D|clinical trials and/or post-marketing reports.(2)|
02642|041|D|   One or more of the drug pairs linked to this monograph have been included|
02642|042|D|in a list of interactions that should be considered "high-priority" for|
02642|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02642|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02642|045|D|Coordinator (ONC) for Health Information Technology.|
02642|046|B||
02642|047|R|REFERENCES:|
02642|048|B||
02642|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02642|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02642|051|R|  settings: a scientific statement from the American Heart Association and|6
02642|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02642|053|R|  2;55(9):934-47.|6
02642|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02642|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02642|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02642|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02642|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02642|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02642|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02642|061|R|  19(5):735-43.|6
02643|001|T|MONOGRAPH TITLE:  Pentamidine/Possible QT Prolonging Agents|
02643|002|B||
02643|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02643|004|L|take action as needed.|
02643|005|B||
02643|006|A|MECHANISM OF ACTION:  Pentamidine has been shown to prolong the QTc|
02643|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02643|008|A|may result in additive effects on the QTc interval.(1)|
02643|009|B||
02643|010|E|CLINICAL EFFECTS:  The concurrent use of pentamidine with other agents that|
02643|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02643|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02643|013|B||
02643|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02643|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02643|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02643|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02643|018|P|female gender, or advanced age.(1)|
02643|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02643|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02643|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02643|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02643|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02643|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02643|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02643|026|B||
02643|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of pentamidine with other|
02643|028|M|agents known to prolong the QT interval.|
02643|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02643|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02643|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02643|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02643|033|B||
02643|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02643|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02643|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02643|037|D|monograph have been shown to prolong the QTc interval either through their|
02643|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02643|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02643|040|D|clinical trials and/or post-marketing reports.(2)|
02643|041|B||
02643|042|R|REFERENCES:|
02643|043|B||
02643|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02643|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02643|046|R|  settings: a scientific statement from the American Heart Association and|6
02643|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02643|048|R|  2;55(9):934-47.|6
02643|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02643|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02643|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02643|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02644|001|T|MONOGRAPH TITLE:  Propofol/QT Prolonging Agents|
02644|002|B||
02644|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02644|004|L|of severe adverse interaction.|
02644|005|B||
02644|006|A|MECHANISM OF ACTION:  Propofol has been shown to prolong the QTc interval.|
02644|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02644|008|A|additive effects on the QTc interval.(1)|
02644|009|B||
02644|010|E|CLINICAL EFFECTS:  The concurrent use of propofol with other agents that|
02644|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02644|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02644|013|B||
02644|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02644|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02644|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02644|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02644|018|P|female gender, or advanced age.(1)|
02644|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02644|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02644|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02644|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02644|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02644|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02644|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02644|026|B||
02644|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of propofol with other|
02644|028|M|agents known to prolong the QT interval.|
02644|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02644|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02644|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02644|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02644|033|B||
02644|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02644|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02644|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02644|037|D|monograph have been shown to prolong the QTc interval either through their|
02644|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02644|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02644|040|D|clinical trials and/or post-marketing reports.(2)|
02644|041|D|   One or more of the drug pairs linked to this monograph have been included|
02644|042|D|in a list of interactions that should be considered "high-priority" for|
02644|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02644|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02644|045|D|Coordinator (ONC) for Health Information Technology.|
02644|046|B||
02644|047|R|REFERENCES:|
02644|048|B||
02644|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02644|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02644|051|R|  settings: a scientific statement from the American Heart Association and|6
02644|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02644|053|R|  2;55(9):934-47.|6
02644|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02644|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02644|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02644|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02644|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02644|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02644|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02644|061|R|  19(5):735-43.|6
02645|001|T|MONOGRAPH TITLE:  Propofol/Possible QT Prolonging Agents|
02645|002|B||
02645|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02645|004|L|take action as needed.|
02645|005|B||
02645|006|A|MECHANISM OF ACTION:  Propofol has been shown to prolong the QTc interval.|
02645|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02645|008|A|additive effects on the QTc interval.(1)|
02645|009|B||
02645|010|E|CLINICAL EFFECTS:  The concurrent use of propofol with other agents that|
02645|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02645|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02645|013|B||
02645|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02645|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02645|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02645|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02645|018|P|female gender, or advanced age.(1)|
02645|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02645|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02645|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02645|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02645|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02645|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02645|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02645|026|B||
02645|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of propofol with other|
02645|028|M|agents known to prolong the QT interval.|
02645|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02645|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02645|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02645|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02645|033|B||
02645|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02645|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02645|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02645|037|D|monograph have been shown to prolong the QTc interval either through their|
02645|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02645|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02645|040|D|clinical trials and/or post-marketing reports.(2)|
02645|041|B||
02645|042|R|REFERENCES:|
02645|043|B||
02645|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02645|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02645|046|R|  settings: a scientific statement from the American Heart Association and|6
02645|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02645|048|R|  2;55(9):934-47.|6
02645|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02645|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02645|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02645|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02646|001|T|MONOGRAPH TITLE:  Sulpiride/QT Prolonging Agents|
02646|002|B||
02646|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02646|004|L|of severe adverse interaction.|
02646|005|B||
02646|006|A|MECHANISM OF ACTION:  Sulpiride has been shown to prolong the QTc interval.|
02646|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02646|008|A|additive effects on the QTc interval.(1)|
02646|009|B||
02646|010|E|CLINICAL EFFECTS:  The concurrent use of sulpiride with other agents that|
02646|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02646|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02646|013|B||
02646|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02646|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02646|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02646|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02646|018|P|female gender, or advanced age.(1)|
02646|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02646|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02646|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02646|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02646|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02646|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02646|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02646|026|B||
02646|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of sulpiride with other|
02646|028|M|agents known to prolong the QT interval.|
02646|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02646|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02646|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02646|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02646|033|B||
02646|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02646|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02646|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02646|037|D|monograph have been shown to prolong the QTc interval either through their|
02646|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02646|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02646|040|D|clinical trials and/or post-marketing reports.(2)|
02646|041|D|   One or more of the drug pairs linked to this monograph have been included|
02646|042|D|in a list of interactions that should be considered "high-priority" for|
02646|043|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02646|044|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02646|045|D|Coordinator (ONC) for Health Information Technology.|
02646|046|B||
02646|047|R|REFERENCES:|
02646|048|B||
02646|049|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02646|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02646|051|R|  settings: a scientific statement from the American Heart Association and|6
02646|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02646|053|R|  2;55(9):934-47.|6
02646|054|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02646|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02646|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02646|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02646|058|R|3.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02646|059|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02646|060|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02646|061|R|  19(5):735-43.|6
02646|062|R|4.Sulpiride (sulpiride) prescribing information. Wockhardt UK Ltd Nov 8,|1
02646|063|R|  2019.|1
02647|001|T|MONOGRAPH TITLE:  Sulpiride/Possible QT Prolonging Agents|
02647|002|B||
02647|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02647|004|L|take action as needed.|
02647|005|B||
02647|006|A|MECHANISM OF ACTION:  Sulpiride has been shown to prolong the QTc interval.|
02647|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02647|008|A|additive effects on the QTc interval.(1)|
02647|009|B||
02647|010|E|CLINICAL EFFECTS:  The concurrent use of sulpiride with other agents that|
02647|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02647|012|E|arrhythmias, including torsades de pointes(TdP).(1)|
02647|013|B||
02647|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
02647|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
02647|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
02647|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02647|018|P|female gender, or advanced age.(1)|
02647|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02647|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02647|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02647|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02647|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02647|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02647|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
02647|026|B||
02647|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of sulpiride with other|
02647|028|M|agents known to prolong the QT interval.|
02647|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02647|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02647|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02647|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02647|033|B||
02647|034|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02647|035|D|degrees of potential to prolong the QTc interval but are generally accepted|
02647|036|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
02647|037|D|monograph have been shown to prolong the QTc interval either through their|
02647|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02647|039|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
02647|040|D|clinical trials and/or post-marketing reports.(2)|
02647|041|B||
02647|042|R|REFERENCES:|
02647|043|B||
02647|044|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02647|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02647|046|R|  settings: a scientific statement from the American Heart Association and|6
02647|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02647|048|R|  2;55(9):934-47.|6
02647|049|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02647|050|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02647|051|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02647|052|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02647|053|R|3.Sulpiride (sulpiride) prescribing information. Wockhardt UK Ltd Nov 8,|1
02647|054|R|  2019.|1
02648|001|T|MONOGRAPH TITLE:  Trabectedin/Strong CYP3A4 Inhibitors|
02648|002|B||
02648|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02648|004|L|of severe adverse interaction.|
02648|005|B||
02648|006|A|MECHANISM OF ACTION:  Agents which strongly inhibit the CYP3A4 enzyme may|
02648|007|A|impede the metabolism of trabectedin.|
02648|008|B||
02648|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
02648|010|E|systemic exposure and the risk for adverse effects from trabectedin.(1)|
02648|011|B||
02648|012|P|PREDISPOSING FACTORS:  None determined.|
02648|013|B||
02648|014|M|PATIENT MANAGEMENT:  When possible, avoid the use of strong CYP3A4|
02648|015|M|inhibitors in patients receiving trabectedin.(1)|
02648|016|M|   The US manufacturer of itraconazole states that concomitant|
02648|017|M|administration with trabectedin is not recommended during and two weeks|
02648|018|M|after itraconazole treatment.(3)|
02648|019|M|   If short term use (i.e. less than 14 days) of a CYP3A4 inhibitor is|
02648|020|M|required, administer the strong CYP3A4 inhibitor one week after trabectedin|
02648|021|M|infusion and discontinue it prior to the next trabectedin infusion.(1)|
02648|022|M|Monitor closely for adverse effects and decrease dosage if required.|
02648|023|B||
02648|024|D|DISCUSSION:  In an interaction study, a single dose of trabectedin with|
02648|025|D|ketoconazole 200 mg orally twice daily for 7.5 days increased trabectedin|
02648|026|D|exposure (AUC, area-under-curve) 66% compared with a single dose of|
02648|027|D|trabectedin given alone.(1)|
02648|028|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
02648|029|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, itraconazole,|
02648|030|D|josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone,|
02648|031|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
02648|032|D|telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2)|
02648|033|B||
02648|034|R|REFERENCES:|
02648|035|B||
02648|036|R|1.Yondelis (trabectedin) US prescribing information. Janssen Products, LP|1
02648|037|R|  June, 2018.|1
02648|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
02648|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02648|040|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02648|041|R|  Products, L.P. February, 2024.|1
02649|001|T|MONOGRAPH TITLE:  Trabectedin/Strong CYP3A4 Inducers|
02649|002|B||
02649|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02649|004|L|of severe adverse interaction.|
02649|005|B||
02649|006|A|MECHANISM OF ACTION:  Trabectedin is primarily metabolized by CYP3A4.(1)|
02649|007|B||
02649|008|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers will result in|
02649|009|E|decreased systemic concentrations of trabectedin.(1)|
02649|010|B||
02649|011|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02649|012|P|of the inducer for longer than 1-2 weeks.|
02649|013|B||
02649|014|M|PATIENT MANAGEMENT:  The manufacturer of trabectedin states that concomitant|
02649|015|M|use with CYP3A4 inducers should be avoided.(1)|
02649|016|M|   The onset of induction is gradual but may begin within one week for|
02649|017|M|potent agents (e.g. rifampin).  The time to maximal induction may be 2 or|
02649|018|M|more weeks depending upon the half-life and dose of the inducer.|
02649|019|B||
02649|020|D|DISCUSSION:  In an interaction study, coadministration of multiple doses of|
02649|021|D|rifampin (600 mg daily for 6 days) with a single dose of trabectedin on day|
02649|022|D|6 lowered trabectedin AUC by 31% compared to a single dose of trabectedin|
02649|023|D|alone.(1)|
02649|024|D|    Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
02649|025|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02649|026|D|ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone,|
02649|027|D|rifampin, rifapentine and St. John's Wort.(2)|
02649|028|B||
02649|029|R|REFERENCES:|
02649|030|B||
02649|031|R|1.Yondelis (trabectedin) US prescribing information. Janssen Products, LP|1
02649|032|R|  June, 2018.|1
02649|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
02649|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02650|001|T|MONOGRAPH TITLE:  Talimogene laherparepvec/Selected Immunosuppressants|
02650|002|B||
02650|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02650|004|L|is contraindicated and generally should not be dispensed or administered to|
02650|005|L|the same patient.|
02650|006|B||
02650|007|A|MECHANISM OF ACTION:  Talimogene laherparepvec is a live, attenuated herpes|
02650|008|A|simplex virus.(1)|
02650|009|B||
02650|010|E|CLINICAL EFFECTS:  Concurrent use of talimogene laherparepvec in patients|
02650|011|E|receiving immunosuppressive therapy may cause a life-threatening|
02650|012|E|disseminated herpetic infection.(1)|
02650|013|B||
02650|014|P|PREDISPOSING FACTORS:  None determined.|
02650|015|B||
02650|016|M|PATIENT MANAGEMENT:  Talimogene laherparepvec is contraindicated in|
02650|017|M|immunosuppressed patients.(1)  The magnitude of immunocompromise and|
02650|018|M|associated risks due to immunosuppressant drugs should be determined by a|
02650|019|M|physician.|
02650|020|B||
02650|021|D|DISCUSSION:  Concurrent use of talimogene laherparepvec in patients|
02650|022|D|receiving immunosuppressive therapy may cause a life-threatening|
02650|023|D|disseminated herpetic infection.(1)|
02650|024|B||
02650|025|R|REFERENCE:|
02650|026|B||
02650|027|R|1.Imlygic (talimogene laherparepvec) US prescribing information. Amgen Inc.|1
02650|028|R|  October 27, 2015.|1
02651|001|T|MONOGRAPH TITLE:  Osimertinib/QT Prolonging Agents|
02651|002|B||
02651|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02651|004|L|of severe adverse interaction.|
02651|005|B||
02651|006|A|MECHANISM OF ACTION:  Osimertinib prolongs the QTc interval.(1)  Concurrent|
02651|007|A|use with other agents that prolong the QTc interval may result in additive|
02651|008|A|effects on the QTc interval.(2,3)|
02651|009|B||
02651|010|E|CLINICAL EFFECTS:  The concurrent use of osimertinib with other agents that|
02651|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02651|012|E|arrhythmias, including torsades de pointes.(2,3)|
02651|013|B||
02651|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02651|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02651|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02651|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02651|018|P|gender, or advanced age.(3)|
02651|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02651|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02651|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02651|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02651|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02651|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02651|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02651|026|B||
02651|027|M|PATIENT MANAGEMENT:  Osimertinib prolongs the QT interval.  Premarket|
02651|028|M|clinical trials excluded patients with a baseline QTc > or = 470 msec.  In|
02651|029|M|these trials 11 patients (2.7%) had increase in QTc greater than 60 msec.(1)|
02651|030|M|   Manufacturer recommendations: when feasible, avoid concurrent|
02651|031|M|administrations of osimertinib with drugs known to prolong the QTc interval.|
02651|032|M|Conduct baseline and periodic monitoring with ECGs in patients with|
02651|033|M|congenital long QTc syndrome, congestive heart failure, electrolyte|
02651|034|M|abnormalities (e.g. serum calcium, magnesium, and potassium), or those|
02651|035|M|taking medications known to prolong the QT interval.(1)|
02651|036|M|   Dose adjustments (1):|
02651|037|M|    - If QTc is greater than 500 msec on at least 2 separate ECGs, withhold|
02651|038|M|osimertinib until QTc is < 481 msec or recovery to baseline (if baseline QTc|
02651|039|M|was greater than or equal to 481 msec), then resume osimertinib at 40 mg per|
02651|040|M|day.|
02651|041|M|    - For QTc prolongation with signs or symptoms of life threatening|
02651|042|M|arrhythmia, permanently discontinue osimertinib.|
02651|043|M|   During concomitant therapy with another QT prolonging agent, monitor|
02651|044|M|patients closely for prolongation of the QT interval.(1)  Obtain serum|
02651|045|M|calcium, magnesium, and potassium levels and monitoring ECG at regular|
02651|046|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
02651|047|M|report any irregular heartbeat, dizziness, or fainting.|
02651|048|B||
02651|049|D|DISCUSSION:  A retrospective review of 618 cancer patients treated with 902|
02651|050|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02651|051|D|incidence of QTc prolongation.  In patients who received osimertinib, QTc|
02651|052|D|prolongation was identified in 4 (25%) with 1 (25%) having Grade 1 (QTc|
02651|053|D|450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
02651|054|D|occurred in 1 (25%) having QTc greater than or equal to 500 ms and 1 (25%)|
02651|055|D|having QTc change greater than or equal to 60 ms.  No patients had|
02651|056|D|ventricular tachycardia, sudden cardiac death, or TdP.(4)|
02651|057|D|   In clinical studies of 1813 patients treated with osimertinib|
02651|058|D|monotherapy, 1.1% of patients were found to have a QTc interval greater than|
02651|059|D|500 ms and 4.3% of patients had an increase from baseline QTc > 60 ms.(1)|
02651|060|D|   Agents that are linked to this monograph may have varying degrees of|
02651|061|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02651|062|D|been shown to prolong the QTc interval either through their mechanism of|
02651|063|D|action, through studies on their effects on the QTc interval, or through|
02651|064|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02651|065|D|and/or postmarketing reports.(2)|
02651|066|B||
02651|067|R|REFERENCES:|
02651|068|B||
02651|069|R|1.Tagrisso (osimertinib) US prescribing information. AstraZeneca|1
02651|070|R|  Pharmaceuticals September, 2024.|1
02651|071|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02651|072|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02651|073|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02651|074|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02651|075|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02651|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02651|077|R|  settings: a scientific statement from the American Heart Association and|6
02651|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02651|079|R|  2;55(9):934-47.|6
02651|080|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02651|081|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02651|082|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02652|001|T|MONOGRAPH TITLE:  Osimertinib/Possible QT Prolonging Agents|
02652|002|B||
02652|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02652|004|L|take action as needed.|
02652|005|B||
02652|006|A|MECHANISM OF ACTION:  Osimertinib prolongs the QTc interval.(1)  Concurrent|
02652|007|A|use with other agents that prolong the QTc interval may result in additive|
02652|008|A|effects on the QTc interval.(2,3)|
02652|009|B||
02652|010|E|CLINICAL EFFECTS:  The concurrent use of osimertinib with other agents that|
02652|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02652|012|E|arrhythmias, including torsades de pointes.(2,3)|
02652|013|B||
02652|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02652|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02652|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02652|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02652|018|P|gender, or advanced age.(3)|
02652|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02652|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02652|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02652|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02652|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02652|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02652|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02652|026|B||
02652|027|M|PATIENT MANAGEMENT:  Osimertinib prolongs the QT interval.  Premarket|
02652|028|M|clinical trials excluded patients with a baseline QTc > or = 470 msec.  In|
02652|029|M|these trials 11 patients (2.7%) had increase in QTc greater than 60 msec.(1)|
02652|030|M|   Manufacturer recommendations: when feasible, avoid concurrent|
02652|031|M|administrations of osimertinib with drugs known to prolong the QTc interval.|
02652|032|M|Conduct baseline and periodic monitoring with ECGs in patients with|
02652|033|M|congenital long QTc syndrome, congestive heart failure, electrolyte|
02652|034|M|abnormalities (e.g. serum calcium, magnesium, and potassium), or those|
02652|035|M|taking medications known to prolong the QT interval.(1)|
02652|036|M|   Dose adjustments (1):|
02652|037|M|    - If QTc is greater than 500 msec on at least 2 separate ECGs, withhold|
02652|038|M|osimertinib until QTc is < 481 msec or recovery to baseline (if baseline QTc|
02652|039|M|was greater than or equal to 481 msec), then resume osimertinib at 40 mg per|
02652|040|M|day.|
02652|041|M|    - For QTc prolongation with signs or symptoms of life threatening|
02652|042|M|arrhythmia, permanently discontinue osimertinib.|
02652|043|M|   During concomitant therapy with another QT prolonging agent, monitor|
02652|044|M|patients closely for prolongation of the QT interval.(1)  Obtain serum|
02652|045|M|calcium, magnesium, and potassium levels and monitoring ECG at regular|
02652|046|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
02652|047|M|report any irregular heartbeat, dizziness, or fainting.|
02652|048|B||
02652|049|D|DISCUSSION:  A retrospective review of 618 cancer patients treated with 902|
02652|050|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02652|051|D|incidence of QTc prolongation.  In patients who received osimertinib, QTc|
02652|052|D|prolongation was identified in 4 (25%) with 1 (25%) having Grade 1 (QTc|
02652|053|D|450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
02652|054|D|occurred in 1 (25%) having QTc greater than or equal to 500 ms and 1 (25%)|
02652|055|D|having QTc change greater than or equal to 60 ms.  No patients had|
02652|056|D|ventricular tachycardia, sudden cardiac death, or TdP.(4)|
02652|057|D|   In clinical studies of 1813 patients treated with osimertinib|
02652|058|D|monotherapy, 1.1% of patients were found to have a QTc interval greater than|
02652|059|D|500 ms and 4.3% of patients had an increase from baseline QTc > 60 ms.(1)|
02652|060|D|   Agents that are linked to this monograph may have varying degrees of|
02652|061|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02652|062|D|been shown to prolong the QTc interval either through their mechanism of|
02652|063|D|action, through studies on their effects on the QTc interval, or through|
02652|064|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02652|065|D|and/or postmarketing reports.(2)|
02652|066|B||
02652|067|R|REFERENCES:|
02652|068|B||
02652|069|R|1.Tagrisso (osimertinib) US prescribing information. AstraZeneca|1
02652|070|R|  Pharmaceuticals September, 2024.|1
02652|071|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02652|072|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02652|073|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02652|074|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02652|075|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02652|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02652|077|R|  settings: a scientific statement from the American Heart Association and|6
02652|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02652|079|R|  2;55(9):934-47.|6
02652|080|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02652|081|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02652|082|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02653|001|T|MONOGRAPH TITLE:  Osimertinib/Strong CYP3A4 Inducers|
02653|002|B||
02653|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02653|004|L|of severe adverse interaction.|
02653|005|B||
02653|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02653|007|A|osimertinib via this pathway.(1)|
02653|008|B||
02653|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
02653|010|E|reduce the clinical effectiveness of osimertinib.(1)|
02653|011|B||
02653|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02653|013|P|of the inducer for longer than 1-2 weeks.|
02653|014|B||
02653|015|M|PATIENT MANAGEMENT:  Whenever possible, it would be prudent to use an|
02653|016|M|alternative agent in place of the strong CYP3A4 inducer. After|
02653|017|M|discontinuation of a strong CYP3A4 inducer, osimertinib systemic|
02653|018|M|concentrations will gradually increase due to the relatively long half-life|
02653|019|M|of osimertinib.(1)|
02653|020|M|   The US manufacturer of osimertinib states that concurrent use of CYP3A4|
02653|021|M|inducers should be avoided.(1)  If concurrent therapy cannot be avoided|
02653|022|M|increase the osimertinib dose to 160 mg daily.  Resume osimertinib at 80 mg|
02653|023|M|three weeks after the discontinuation of the strong CYP3A4 inducer.|
02653|024|B||
02653|025|D|DISCUSSION:  Osimertinib is itself an inducer of CYP3A4. The magnitude of|
02653|026|D|induction and whether osimertinib auto-induces its own metabolism has not|
02653|027|D|yet been described.(1)|
02653|028|D|   In a clinical pharmacokinetic study, the AUC of osimertinib was reduced|
02653|029|D|by 78% in patients when coadministered with rifampin (600 mg daily for 21|
02653|030|D|days).(1)|
02653|031|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
02653|032|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
02653|033|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St.|
02653|034|D|John's Wort.(4,5)|
02653|035|B||
02653|036|R|REFERENCES:|
02653|037|B||
02653|038|R|1.Tagrisso (osimertinib) US prescribing information. AstraZeneca|1
02653|039|R|  Pharmaceuticals September, 2024.|1
02653|040|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02653|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02653|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02653|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02653|044|R|  11/14/2017.|1
02653|045|R|3.This information is based on an extract from the Certara Drug Interaction|6
02653|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02654|001|T|MONOGRAPH TITLE:  Osimertinib/Strong CYP3A4 Inhibitors (mono deleted|
02654|002|T|09/11/2018)|
02654|003|B||
02654|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02654|005|L|of severe adverse interaction.|
02654|006|B||
02654|007|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
02654|008|A|metabolism of osimertinib.(1)|
02654|009|B||
02654|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
02654|011|E|systemic exposure and the risk for osimertinib toxicities such as venous|
02654|012|E|thromboembolism, severe diarrhea, heart failure, or QT prolongation.(1)|
02654|013|B||
02654|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02654|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02654|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02654|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02654|018|P|gender, or advanced age.(2)|
02654|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02654|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02654|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02654|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02654|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02654|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02654|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02654|026|B||
02654|027|M|PATIENT MANAGEMENT:  Avoid the use of Strong CYP3A4 inhibitors with|
02654|028|M|osimertinib.  If no other alternative exists, monitor patients more closely|
02654|029|M|for adverse reactions and adjust dose, hold or discontinue osimertinib based|
02654|030|M|upon manufacturer recommended adjustments.(1)|
02654|031|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
02654|032|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
02654|033|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
02654|034|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
02654|035|M|irregular heartbeat, dizziness, or fainting.|
02654|036|B||
02654|037|D|DISCUSSION:  Osimertinib was granted accelerated approval by FDA.  Clinical|
02654|038|D|studies evaluating osimertinib in the presence of strong CYP3A4 inhibitors|
02654|039|D|have not yet been conducted.(1)|
02654|040|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
02654|041|D|clarithromycin, conivaptan, cobicistat, idelalisib, itraconazole,|
02654|042|D|ketoconazole, nefazodone, nelfinavir, posaconazole, ribociclib, ritonavir,|
02654|043|D|telaprevir, telithromycin, troleandomycin, and voriconazole.(3)|
02654|044|B||
02654|045|R|REFERENCES:|
02654|046|B||
02654|047|R|1.Tagrisso (osimertinib) US prescribing information. AstraZeneca|1
02654|048|R|  Pharmaceuticals September, 2024.|1
02654|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02654|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02654|051|R|  settings: a scientific statement from the American Heart Association and|6
02654|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02654|053|R|  2;55(9):934-47.|6
02654|054|R|3.This information is based on an extract from the Certara Drug Interaction|6
02654|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02655|001|T|MONOGRAPH TITLE:  Selected BCRP Substrates/Safinamide|
02655|002|B||
02655|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02655|004|L|take action as needed.|
02655|005|B||
02655|006|A|MECHANISM OF ACTION:  Safinamide transiently inhibits BCRP in the small|
02655|007|A|intestine, which may result in increased absorption of BCRP substrates.(1)|
02655|008|B||
02655|009|E|CLINICAL EFFECTS:  Administration of safinamide with BCRP substrates may|
02655|010|E|result in elevated levels of and toxicity from these agents.(1)|
02655|011|B||
02655|012|P|PREDISPOSING FACTORS:  None determined.|
02655|013|B||
02655|014|M|PATIENT MANAGEMENT:  The EMA and UK manufacturer of safinamide recommend|
02655|015|M|monitoring patients who are on concomitant drugs that are substrates of|
02655|016|M|BCRP, including ciprofloxacin, diclofenac, methotrexate, rosuvastatin, and|
02655|017|M|topotecan.  Dose adjustment of the BCRP substrate should be performed|
02655|018|M|according to the prescribing information for the BCRP substrate.(1)|
02655|019|M|   On the other hand, the US manufacturer of safinamide states that|
02655|020|M|rosuvastatin did not have a clinically significant effect on the|
02655|021|M|pharmacokinetics of safinamide.(2)|
02655|022|B||
02655|023|D|DISCUSSION:  Safinamide transiently inhibits BCRP in the small intestine,|
02655|024|D|which may result in increased absorption of BCRP substrates.(1)|
02655|025|D|   In a clinical study, safinamide increased the AUC of rosuvastatin by|
02655|026|D|1.25- to 2-fold.(1,3)|
02655|027|D|   BCRP substrates linked to this monograph include:  ciprofloxacin,|
02655|028|D|diclofenac, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone,|
02655|029|D|rosuvastatin, sulfasalazine, and topotecan.(1,3)|
02655|030|B||
02655|031|R|REFERENCES:|
02655|032|B||
02655|033|R|1.Xadago (safinamide) EMA summary of product characteristics. Zambon S.p.A.|1
02655|034|R|  October 30, 2019.|1
02655|035|R|2.Xadago (safinamide) US prescribing information. US WorldMeds, LLC August,|1
02655|036|R|  2021.|1
02655|037|R|3.European Medicines Agency (EMA). Xadago: EPAR - Procedural steps taken and|1
02655|038|R|  scientific information after the authorisation. Accessed at:|1
02655|039|R|  https://www.ema.europa.eu/en/documents/procedural-steps-after/xadago-epar-|1
02655|040|R|  procedural-steps-taken-scientific-information-after-authorisation_en.pdf|1
02655|041|R|  October 30, 2019.|1
02656|001|T|MONOGRAPH TITLE:  Ixazomib/Slt Moderate and Strong CYP3A4 Inducers|
02656|002|B||
02656|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02656|004|L|of severe adverse interaction.|
02656|005|B||
02656|006|A|MECHANISM OF ACTION:  Ixazomib is primarily metabolized by CYP3A4.(1)|
02656|007|B||
02656|008|E|CLINICAL EFFECTS:  Concurrent use of strong or selected moderate CYP3A4|
02656|009|E|inducers will result in decreased systemic concentrations of ixazomib.(1)|
02656|010|B||
02656|011|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02656|012|P|of the inducer for longer than 1-2 weeks.|
02656|013|B||
02656|014|M|PATIENT MANAGEMENT:  The manufacturer of ixazomib states that concomitant|
02656|015|M|use with CYP3A4 inducers should be avoided.  In an interaction study,|
02656|016|M|rifampin decreased ixazomib exposure(AUC) by 74%.(1)  Use an alternative to|
02656|017|M|the inducing agent when possible.|
02656|018|M|   The onset of induction is gradual but may begin within one week for|
02656|019|M|potent agents (e.g. rifampin). The time to maximal induction may be 2 or|
02656|020|M|more weeks depending upon the half-life and dose of the inducer.|
02656|021|B||
02656|022|D|DISCUSSION:  In an interaction study, coadministration with rifampin|
02656|023|D|decreased ixazomib AUC 74% and maximum concentration (Cmax) by 54%(1)|
02656|024|D|    Selected moderate and strong CYP3A4 inducers linked to this monograph|
02656|025|D|are: apalutamide, barbiturates, belzutifan, carbamazepine, cenobamate,|
02656|026|D|dabrafenib, elagolix, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02656|027|D|lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane,|
02656|028|D|pacritinib, pexidartinib, phenobarbital, phenytoin, primidone,|
02656|029|D|repotrectinib, rifabutin, rifampin, rifapentine, St. John's Wort, sotorasib|
02656|030|D|telotristat, and tovorafenib.(2)|
02656|031|B||
02656|032|R|REFERENCES:|
02656|033|B||
02656|034|R|1.Ninlaro (ixazomib) US prescribing information. Millennium Pharmaceuticals|1
02656|035|R|  Inc March. 2021.|1
02656|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
02656|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02657|001|T|MONOGRAPH TITLE:  Arsenic/QT Prolonging Agents|
02657|002|B||
02657|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02657|004|L|of severe adverse interaction.|
02657|005|B||
02657|006|A|MECHANISM OF ACTION:  Arsenic has been shown to prolong the QTc interval.|
02657|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02657|008|A|additive effects on the QTc interval.(1)|
02657|009|B||
02657|010|E|CLINICAL EFFECTS:  The concurrent use of arsenic with other agents that|
02657|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02657|012|E|arrhythmias, including torsades de pointes.(1)|
02657|013|B||
02657|014|P|PREDISPOSING FACTORS:  The risk of torsade de pointes is related to the|
02657|015|P|extent of QT prolongation, concomitant administration of QT prolonging|
02657|016|P|drugs, a history of torsade de pointes, preexisting QT interval|
02657|017|P|prolongation, congestive heart failure, use of potassium-wasting diuretics,|
02657|018|P|or other conditions that result in hypokalemia or hypomagnesemia.(1) Risk|
02657|019|P|may also be increased in patients with other cardiovascular disease (e.g.|
02657|020|P|myocardial infarction, congenital long QT syndrome), hypocalcemia,|
02657|021|P|bradycardia, female gender, or advanced age.(2)|
02657|022|P|   Higher systemic concentrations of either QT prolonging drug are|
02657|023|P|additional risk factors for torsade de pointes.  Factors which may increase|
02657|024|P|systemic drug concentrations include rapid infusion of an intravenous dose|
02657|025|P|or impaired metabolism or elimination of the drug (e.g. coadministration|
02657|026|P|with an agent which inhibits its metabolism or elimination, genetic|
02657|027|P|impairment in drug metabolism or elimination, and/or renal/hepatic|
02657|028|P|dysfunction).(2)|
02657|029|B||
02657|030|M|PATIENT MANAGEMENT:  The manufacturer of arsenic trioxide states that, if|
02657|031|M|possible, drugs that are known to prolong the QT interval should be|
02657|032|M|discontinued prior to therapy and caution is advised during|
02657|033|M|coadministration.(1)|
02657|034|M|   In patients who reach a QTc interval value > 450 msec in men or >460 msec|
02657|035|M|in women, withhold arsenic and any other QT prolonging agents.  Monitor|
02657|036|M|electrolytes and correct abnormalities.  After the QTc normalizes, follow|
02657|037|M|manufacturer instructions concerning restarting arsenic and escalation of|
02657|038|M|dosing.(1)|
02657|039|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02657|040|M|fainting.|
02657|041|B||
02657|042|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02657|043|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02657|044|D|monograph have been shown to prolong the QTc interval either through their|
02657|045|D|mechanism of action, through studies on their effects on the QTc interval,|
02657|046|D|or through reports of QTc prolongation and/or torsades de pointes in|
02657|047|D|clinical trials and/or postmarketing reports.(3)|
02657|048|D|   One or more of the drug pairs linked to this monograph have been included|
02657|049|D|in a list of interactions that should be considered "high-priority" for|
02657|050|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02657|051|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02657|052|D|Coordinator (ONC) for Health Information Technology.|
02657|053|B||
02657|054|R|REFERENCES:|
02657|055|B||
02657|056|R|1.Trisenox (arsenic trioxide) US Prescribing information. Teva|1
02657|057|R|  Pharmaceuticals USA, Inc. October, 2020.|1
02657|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02657|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02657|060|R|  settings: a scientific statement from the American Heart Association and|6
02657|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02657|062|R|  2;55(9):934-47.|6
02657|063|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02657|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02657|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02657|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02657|067|R|4.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02657|068|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02657|069|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02657|070|R|  19(5):735-43.|6
02658|001|T|MONOGRAPH TITLE:  Bedaquiline/QT Prolonging Agents (mono deleted 11/04/2025)|
02658|002|B||
02658|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02658|004|L|of severe adverse interaction.|
02658|005|B||
02658|006|A|MECHANISM OF ACTION:  Concurrent use of bedaquiline with other agents that|
02658|007|A|prolong the QTc interval may result in additive effects on the QTc|
02658|008|A|interval.(1)|
02658|009|B||
02658|010|E|CLINICAL EFFECTS:  The use of bedaquiline patients maintained on agents that|
02658|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02658|012|E|arrhythmias, including torsades de pointes.(1)|
02658|013|B||
02658|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02658|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02658|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02658|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02658|018|P|female gender, or advanced age.(2)|
02658|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02658|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02658|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02658|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02658|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02658|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02658|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02658|026|B||
02658|027|M|PATIENT MANAGEMENT:  Bedaquiline should be used with caution in patients|
02658|028|M|receiving therapy with agents that prolong the QT interval.  Patients should|
02658|029|M|receive a baseline electrocardiogram (ECG) before initiation, 2 weeks after|
02658|030|M|initiation, during treatment as clinically indicated, and at the expected|
02658|031|M|time of maximum increase of the QT interval when receiving concurrent agents|
02658|032|M|that prolong the QT interval.|
02658|033|M|   Bedaquiline and other QT prolonging agents should be discontinued if the|
02658|034|M|patient develops a clinically significant ventricular arrhythmia or a QTcF|
02658|035|M|of greater than 500 msec confirmed by repeat ECGs.  If a patient develops|
02658|036|M|syncope, perform an ECG.(1)|
02658|037|M|   Also consider obtaining serum calcium, magnesium, and potassium levels at|
02658|038|M|baseline and regular intervals.  Correct any electrolyte abnormalities.|
02658|039|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02658|040|M|fainting.|
02658|041|B||
02658|042|D|DISCUSSION:  In a clinical trial, mean increases in QTc were greater in|
02658|043|D|patients treated with bedaquiline than with placebo.  At Week 1, bedaquiline|
02658|044|D|increased QTc by an average of 9.9 msec, compared with 2.5 msec for placebo.|
02658|045|D|At Week 24, bedaquiline increased QTc by an average of 15.7 msec, compared|
02658|046|D|with 6.2 msec for placebo.  In another clinical trial in which patients|
02658|047|D|received bedaquiline with other QT prolonging agents, QT prolongation was|
02658|048|D|additive and proportional to the number of QT prolonging drugs used.|
02658|049|D|Patients receiving bedaquiline alone averaged a QTc increase of 23.7 msec|
02658|050|D|over baseline, while patients receiving bedaquiline with at least one other|
02658|051|D|QT prolonging agent averaged a QTc increase of 30.7 msec.(1)|
02658|052|D|   In a study, bedaquiline was coadministered with QTc prolonging agents|
02658|053|D|clofazimine and levofloxacin.  In the study, 5% of patients had a QTc >= 500|
02658|054|D|ms and 43% of patients had an increase in QTc >= 60 ms from baseline.(1)|
02658|055|D|   Agents that are linked to this monograph may have varying degrees of|
02658|056|D|potential to prolong the QTc interval but are generally accepted to have a|
02658|057|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02658|058|D|been shown to prolong the QTc interval either through their mechanism of|
02658|059|D|action, through studies on their effects on the QTc interval, or through|
02658|060|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02658|061|D|and/or post-marketing reports.(3)|
02658|062|B||
02658|063|R|REFERENCES:|
02658|064|B||
02658|065|R|1.Sirturo (bedaquiline) US prescribing information. Janssen Therapeutics|1
02658|066|R|  June, 2024.|1
02658|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02658|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02658|069|R|  settings: a scientific statement from the American Heart Association and|6
02658|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02658|071|R|  2;55(9):934-47.|6
02658|072|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02658|073|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02658|074|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02658|075|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02659|001|T|MONOGRAPH TITLE:  Ceritinib/QT Prolonging Agents|
02659|002|B||
02659|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02659|004|L|of severe adverse interaction.|
02659|005|B||
02659|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02659|007|A|interval may result in additive effects on the QTc interval.(1)|
02659|008|B||
02659|009|E|CLINICAL EFFECTS:  The use of ceritinib in patients maintained on agents|
02659|010|E|that prolong the QTc interval may result in potentially life-threatening|
02659|011|E|cardiac arrhythmias, including torsades de pointes.(1)|
02659|012|B||
02659|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02659|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02659|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02659|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02659|017|P|female gender, or advanced age.(2)|
02659|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02659|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02659|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02659|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02659|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02659|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02659|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02659|025|P|   Patients with severe hepatic impairment (Child-Pugh C) may be at|
02659|026|P|increased risk of this interaction.  Ceritinib dose reduction may be|
02659|027|P|warranted in severe hepatic impairment.  See prescribing information for|
02659|028|P|recommendations.(1)|
02659|029|B||
02659|030|M|PATIENT MANAGEMENT:  When possible, avoid coadministration of ceritinib with|
02659|031|M|other QT prolonging agents.  Obtain an electrocardiogram (ECG) and monitor|
02659|032|M|serum calcium, magnesium, and potassium levels at baseline and regular|
02659|033|M|intervals in patients receiving concurrent therapy with ceritinib and|
02659|034|M|another agent that prolongs the QTc interval.(1)|
02659|035|M|   In patients who develop a QTC interval greater than 500 msec on at least|
02659|036|M|2 occasions, withhold ceritinib until the QTc interval is less than 481 msec|
02659|037|M|or recovery to baseline if baseline QTc was greater than or equal to 481|
02659|038|M|msec, then resume ceritinib with a 150 mg dose reduction.  If the patient|
02659|039|M|develops QTc interval prolongation in combination with torsades de pointes|
02659|040|M|or polymorphic ventricular tachycardia or signs/symptoms of serious|
02659|041|M|arrhythmia, permanently discontinue ceritinib.(1)|
02659|042|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02659|043|M|fainting.|
02659|044|B||
02659|045|D|DISCUSSION:  In a clinical trial 3% of patients experienced a QTc interval|
02659|046|D|increase over baseline greater than 60 msec.  Less than 1% of patients (1 of|
02659|047|D|304) treated with ceritinib was found to have a QTc greater than 500 msec.|
02659|048|D|The upper limit of the 90% confidence interval for mean QTC increase was 16|
02659|049|D|msec at ceritinib 750 mg.   Data suggested that ceritinib produces|
02659|050|D|concentration-dependent QTc interval prolongation.(1)|
02659|051|D|   Agents that are linked to this monograph may have varying degrees of|
02659|052|D|potential to prolong the QTc interval but are generally accepted to have a|
02659|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02659|054|D|been shown to prolong the QTc interval either through their mechanism of|
02659|055|D|action, through studies on their effects on the QTc interval, or through|
02659|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02659|057|D|and/or post-marketing reports.(3)|
02659|058|B||
02659|059|R|REFERENCES:|
02659|060|B||
02659|061|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
02659|062|R|  Corporation August, 2021.|1
02659|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02659|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02659|065|R|  settings: a scientific statement from the American Heart Association and|6
02659|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02659|067|R|  2;55(9):934-47.|6
02659|068|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02659|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02659|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02659|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02660|001|T|MONOGRAPH TITLE:  Crizotinib/QT Prolonging Agents|
02660|002|B||
02660|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02660|004|L|of severe adverse interaction.|
02660|005|B||
02660|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02660|007|A|interval may result in additive effects on the QTc interval.(1)|
02660|008|B||
02660|009|E|CLINICAL EFFECTS:  The use of crizotinib in patients maintained on agents|
02660|010|E|that prolong the QTc interval may result in potentially life-threatening|
02660|011|E|cardiac arrhythmias, including torsades de pointes.(1)|
02660|012|B||
02660|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02660|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02660|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02660|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02660|017|P|female gender, or advanced age.(2)|
02660|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02660|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02660|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02660|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02660|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02660|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02660|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02660|025|B||
02660|026|M|PATIENT MANAGEMENT:  Consider periodic electrocardiogram (ECG) and|
02660|027|M|electrolyte monitoring (calcium, magnesium, and potassium levels at baseline|
02660|028|M|and regular intervals) in patients receiving concurrent therapy with|
02660|029|M|crizotinib and another agent that prolongs the QTc interval.(1)|
02660|030|M|   In patients who develop a QTc greater than 500 ms on at least 2 separate|
02660|031|M|ECGs, withhold crizotinib until recovery to baseline or to a QTc less than|
02660|032|M|481 ms, then resume crizotinib at reduced dose.(1)|
02660|033|M|   In patients who develop a QTc greater than 500 ms or greater than or|
02660|034|M|equal to 60 ms change from baseline with Torsade de pointes or polymorphic|
02660|035|M|ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently|
02660|036|M|discontinue crizotinib.(1)|
02660|037|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02660|038|M|fainting.|
02660|039|B||
02660|040|D|DISCUSSION:  Crizotinib is associated with concentration-dependent QTc|
02660|041|D|interval prolongation.  In a clinical trial 2.1% of patients were found to|
02660|042|D|have a QTcF greater than or equal to 500 msec and 5% of patients had an|
02660|043|D|increase in QTcF by greater than or equal to 60 msec.(1)|
02660|044|D|   A retrospective review of 618 cancer patients treated with 902|
02660|045|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02660|046|D|incidence of QTc prolongation.  In patients who received crizotinib, QTc|
02660|047|D|prolongation was identified in 1 (50%) with 1 (100%) having Grade 1 (QTc|
02660|048|D|450-480 ms).  No patients had a QTc change greater than or equal to 60 ms,|
02660|049|D|ventricular tachycardia, sudden cardiac death, or TdP.(3)|
02660|050|D|   Agents that are linked to this monograph may have varying degrees of|
02660|051|D|potential to prolong the QTc interval but are generally accepted to have a|
02660|052|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02660|053|D|been shown to prolong the QTc interval either through their mechanism of|
02660|054|D|action, through studies on their effects on the QTc interval, or through|
02660|055|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02660|056|D|and/or post-marketing reports.(4)|
02660|057|B||
02660|058|R|REFERENCES:|
02660|059|B||
02660|060|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
02660|061|R|  2023.|1
02660|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02660|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02660|064|R|  settings: a scientific statement from the American Heart Association and|6
02660|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02660|066|R|  2;55(9):934-47.|6
02660|067|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02660|068|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02660|069|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02660|070|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
02660|071|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02660|072|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02660|073|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02661|001|T|MONOGRAPH TITLE:  Eribulin/QT Prolonging Agents|
02661|002|B||
02661|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02661|004|L|take action as needed.|
02661|005|B||
02661|006|A|MECHANISM OF ACTION:  Eribulin has been shown to prolong the QTc interval.|
02661|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
02661|008|A|additive effects on the QTc interval.(1)|
02661|009|B||
02661|010|E|CLINICAL EFFECTS:  The concurrent use of eribulin with other agents that|
02661|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02661|012|E|arrhythmias, including torsades de pointes.(1)|
02661|013|B||
02661|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02661|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02661|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02661|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02661|018|P|gender, or advanced age.(2)|
02661|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02661|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02661|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02661|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02661|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02661|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02661|025|P|dysfunction).(2)|
02661|026|B||
02661|027|M|PATIENT MANAGEMENT:  The US manufacturer of eribulin states that patients|
02661|028|M|receiving concurrent therapy with eribulin and other agents known to prolong|
02661|029|M|the QT interval should receive ECG monitoring.(1)|
02661|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02661|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02661|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02661|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02661|034|B||
02661|035|D|DISCUSSION:  QT prolongation, independent of eribulin concentration, was|
02661|036|D|observed on Day 8 of therapy but not on Day 1 in  an uncontrolled open-label|
02661|037|D|ECG study in 26 patients.(1)|
02661|038|D|   Agents that are linked to this monograph may have varying degrees of|
02661|039|D|potential to prolong the QTc interval but are generally accepted to have a|
02661|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02661|041|D|been shown to prolong the QTc interval either through their mechanism of|
02661|042|D|action, through studies on their effects on the QTc interval, or through|
02661|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02661|044|D|and/or post-marketing reports.(3)|
02661|045|B||
02661|046|R|REFERENCES:|
02661|047|B||
02661|048|R|1.Halaven (eribulin mesylate) US prescribing information. Eisai, Inc.|1
02661|049|R|  January, 2016.|1
02661|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02661|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02661|052|R|  settings: a scientific statement from the American Heart Association and|6
02661|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02661|054|R|  2;55(9):934-47.|6
02661|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02661|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02661|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02661|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02662|001|T|MONOGRAPH TITLE:  Ezogabine/QT Prolonging Agents|
02662|002|B||
02662|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02662|004|L|of severe adverse interaction.|
02662|005|B||
02662|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02662|007|A|interval may result in additive effects on the QTc interval.(1)|
02662|008|B||
02662|009|E|CLINICAL EFFECTS:  The use of ezogabine in patients maintained on agents|
02662|010|E|that prolong the QTc interval may result in potentially life-threatening|
02662|011|E|cardiac arrhythmias, including torsade de pointes.(1)|
02662|012|B||
02662|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02662|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02662|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02662|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02662|017|P|gender, or advanced age.(2)|
02662|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02662|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02662|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02662|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02662|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02662|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02662|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02662|025|B||
02662|026|M|PATIENT MANAGEMENT:  The concurrent use of ezogabine with agents known to|
02662|027|M|prolong the QT interval should be approached with caution.  Patients|
02662|028|M|receiving concurrent therapy with other QT prolongers, an electrocardiogram|
02662|029|M|(ECG) should be performed prior to ezogabine initiation.  In those patients|
02662|030|M|with a corrected QT interval greater than 440 msec at baseline, a repeat ECG|
02662|031|M|should be performed after reaching the maintenance dose of ezogabine.(1)|
02662|032|M|   Consider obtaining serum calcium, magnesium, and potassium levels at|
02662|033|M|baseline and regular intervals. Correct any electrolyte abnormalities.|
02662|034|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02662|035|M|fainting.|
02662|036|B||
02662|037|D|DISCUSSION:  In a study in healthy subjects, ezogabine titrated to 1200|
02662|038|D|mg/day increased the mean QTc interval by 6.7 msec (upper bound of 95% CI|
02662|039|D|was 12.6 msec) within three hours of dosing.(1)|
02662|040|B||
02662|041|R|REFERENCES:|
02662|042|B||
02662|043|R|1.Potiga (ezogabine) US Prescribing Information. Valeant Pharmaceuticals|1
02662|044|R|  May, 2016.|1
02662|045|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02662|046|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02662|047|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02662|048|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02662|049|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02662|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02662|051|R|  settings: a scientific statement from the American Heart Association and|6
02662|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02662|053|R|  2;55(9):934-47.|6
02663|001|T|MONOGRAPH TITLE:  Gadofosveset/QT Prolonging Agents|
02663|002|B||
02663|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02663|004|L|of severe adverse interaction.|
02663|005|B||
02663|006|A|MECHANISM OF ACTION:  QT prolongation has been reported following|
02663|007|A|gadofosveset administration.  Concurrent use with other agents that prolong|
02663|008|A|the QTc interval may result in additive effects on the QTc interval.(1)|
02663|009|B||
02663|010|E|CLINICAL EFFECTS:  The use of gadofosveset in patients maintained on agents|
02663|011|E|that prolong the QTc interval may result in potentially life-threatening|
02663|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02663|013|B||
02663|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02663|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02663|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02663|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02663|018|P|gender, or advanced age.(2)|
02663|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02663|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02663|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02663|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02663|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02663|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02663|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02663|026|B||
02663|027|M|PATIENT MANAGEMENT:  In patients maintained on agents known to prolong the|
02663|028|M|QT interval, consider a baseline ECG prior to administration of gadofosveset|
02663|029|M|to asses the risk/benefit of gadofosveset.  If gadofosveset is used,|
02663|030|M|consider ECG monitoring for 72 hours until the majority of gadofosveset is|
02663|031|M|eliminated.  Consider obtaining serum calcium, magnesium, and potassium|
02663|032|M|levels and correct any electrolyte abnormalities.  Counsel patients to|
02663|033|M|report any irregular heartbeat, dizziness, or fainting episodes during this|
02663|034|M|time frame.(1)|
02663|035|B||
02663|036|D|DISCUSSION:  In clinical trials, 6% of patients experienced an increase in|
02663|037|D|QTc of 30 msec to 60 msec 45 minutes after the administration of|
02663|038|D|gadofosveset and 0.4% of patients experienced a QTc increase of greater than|
02663|039|D|60 msec at 45 minutes post-administration.(1)|
02663|040|D|   Agents that are linked to this monograph may have varying degrees of|
02663|041|D|potential to prolong the QTc interval but are generally accepted to have a|
02663|042|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02663|043|D|been shown to prolong the QTc interval either through their mechanism of|
02663|044|D|action, through studies on their effects on the QTc interval, or through|
02663|045|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02663|046|D|and/or post-marketing reports.(3)|
02663|047|B||
02663|048|R|REFERENCES:|
02663|049|B||
02663|050|R|1.Ablavar (gadofosveset trisodium) US prescribing information. Lantheus|1
02663|051|R|  Medical Imaging, Inc. August, 2013.|1
02663|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02663|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02663|054|R|  settings: a scientific statement from the American Heart Association and|6
02663|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02663|056|R|  2;55(9):934-47.|6
02663|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02663|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02663|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02663|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02664|001|T|MONOGRAPH TITLE:  Lenvatinib/QT Prolonging Agents|
02664|002|B||
02664|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02664|004|L|of severe adverse interaction.|
02664|005|B||
02664|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02664|007|A|interval may result in additive effects on the QTc interval.(1)|
02664|008|B||
02664|009|E|CLINICAL EFFECTS:  Concurrent use of lenvatinib in patients taking other|
02664|010|E|medications that prolong the QT interval may result in additive QT|
02664|011|E|prolongation.  QT prolongation may result in potentially life-threatening|
02664|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02664|013|B||
02664|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02664|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02664|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02664|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
02664|018|P|hypoalbuminemia, bradycardia, female gender, or advanced age.(1,2)|
02664|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02664|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02664|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02664|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02664|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02664|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02664|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02664|026|B||
02664|027|M|PATIENT MANAGEMENT:  Monitor electrocardiograms during concurrent therapy|
02664|028|M|with lenvatinib and agents that prolong the QT interval.  In a clinical|
02664|029|M|trial of patients with refractory, progressive thyroid cancer, QT|
02664|030|M|prolongation was reported in 9% of lenvatinib patients.  Monitor and correct|
02664|031|M|electrolyte abnormalities in all patients.(1)  This is particularly|
02664|032|M|important in lenvatinib patients as diarrhea, nausea, vomiting, and|
02664|033|M|decreased appetite are common side effects which may increase the risk for|
02664|034|M|electrolyte disturbances.|
02664|035|M|   Monitor ECG at baseline and at regular intervals.  Lenvatinib dose must|
02664|036|M|be withheld if the QTc exceeds 500 msec until QTc resolves to less than 480|
02664|037|M|msec or baseline.  Lenvatinib must be resumed at reduced dose when QTc|
02664|038|M|prolongation resolves to less than 480 ms or to baseline.  Dose adjustments|
02664|039|M|below are indication specific and are for patients with normal hepatic and|
02664|040|M|renal function:(1)|
02664|041|M|   Dose Modifications in Differentiated Thyroid Cancer(DTC):|
02664|042|M| - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02664|043|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|044|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|045|M|dose to 20 mg once daily|
02664|046|M| - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade|
02664|047|M|3 Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|048|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|049|M|dose to 14 mg once daily|
02664|050|M| - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02664|051|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|052|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|053|M|dose 10 mg once daily|
02664|054|M|   Dose Modifications in Renal Cell Cancer (RCC):|
02664|055|M| - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02664|056|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|057|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|058|M|dose to 14 mg once daily|
02664|059|M| - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade|
02664|060|M|3 Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|061|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|062|M|dose to 10 mg once daily|
02664|063|M| - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02664|064|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|065|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|066|M|dose 8 mg once daily|
02664|067|M|   Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight 60|
02664|068|M|kg or greater:|
02664|069|M| - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02664|070|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|071|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|072|M|dose to 8 mg once daily|
02664|073|M| - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade|
02664|074|M|3 Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|075|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|076|M|dose to 4 mg once daily|
02664|077|M| - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02664|078|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|079|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|080|M|dose 4 mg every other day|
02664|081|M|   Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight|
02664|082|M|less than 60 kg:|
02664|083|M| - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02664|084|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|085|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|086|M|dose to 4 mg once daily|
02664|087|M| - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade|
02664|088|M|3 Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|089|M|   Interrupt therapy until resolved to Grade 0-1 or baseline then decrease|
02664|090|M|dose to 4 mg every other day|
02664|091|M| - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3|
02664|092|M|Adverse Reaction or Grade 4 Laboratory Abnormality:|
02664|093|M|   Interrupt therapy until resolved to Grade 0-1 or baseline and discontinue|
02664|094|M|lenvatinib (1)|
02664|095|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02664|096|B||
02664|097|D|DISCUSSION:  In a clinical trial of patients with refractory, progressive|
02664|098|D|thyroid cancer, QT prolongation was reported in 9% of lenvatinib patients|
02664|099|D|and 2% of placebo patients.  The incidence of Grade 3 QT prolongation of >|
02664|100|D|500 msec was reported in 2% of lenvatinib patients compared with no reports|
02664|101|D|in placebo patients.(1)|
02664|102|D|   In contrast, a single lenvatinib dose of 32 mg (1.3 times the recommended|
02664|103|D|daily dose) did not prolong the QT/QTc interval in a thorough QT study|
02664|104|D|performed in healthy subjects.(1)|
02664|105|D|   A retrospective review of 618 cancer patients treated with 902|
02664|106|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02664|107|D|incidence of QTc prolongation.  In patients who received lenvatinib, QTc|
02664|108|D|prolongation was identified in 9 (42.9%) with 4 (44.4%) having Grade 1 (QTc|
02664|109|D|450-480 ms) and 3 (33.3%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
02664|110|D|occurred in 0 (0%) having QTc greater than or equal to 500 ms and 1 (11.1%)|
02664|111|D|having QTc change greater than or equal to 60 ms.  Ventricular tachycardia|
02664|112|D|was seen in 1 (11.1%) patient.(3)|
02664|113|B||
02664|114|R|REFERENCES:|
02664|115|B||
02664|116|R|1.Lenvima (lenvatinib) US prescribing information. Eisai Inc. December,|1
02664|117|R|  2021.|1
02664|118|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02664|119|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02664|120|R|  settings: a scientific statement from the American Heart Association and|6
02664|121|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02664|122|R|  2;55(9):934-47.|6
02664|123|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02664|124|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02664|125|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02665|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/QT Prolonging Agents|
02665|002|B||
02665|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02665|004|L|of severe adverse interaction.|
02665|005|B||
02665|006|A|MECHANISM OF ACTION:  Levomethadone and methadone have been shown to prolong|
02665|007|A|the QTc interval. Concurrent use with other agents that prolong the QTc|
02665|008|A|interval may result in additive effects on the QTc interval.(1,2)|
02665|009|B||
02665|010|E|CLINICAL EFFECTS:  The concurrent use of levomethadone or methadone with|
02665|011|E|other agents that prolong the QTc interval may result in potentially|
02665|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)|
02665|013|B||
02665|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02665|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02665|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02665|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02665|018|P|gender, or advanced age.(3)|
02665|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02665|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02665|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02665|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02665|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02665|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02665|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02665|026|B||
02665|027|M|PATIENT MANAGEMENT:  Concurrent use of levomethadone or methadone with other|
02665|028|M|agents known to prolong the QT interval should be approached with extreme|
02665|029|M|caution.(1,2)|
02665|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02665|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02665|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02665|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02665|034|B||
02665|035|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
02665|036|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
02665|037|D|monograph have been shown to prolong the QTc interval either through their|
02665|038|D|mechanism of action, through studies on their effects on the QTc interval,|
02665|039|D|or through reports of QTc prolongation and/or torsades de pointes in|
02665|040|D|clinical trials and/or postmarketing reports.(4)|
02665|041|D|   Most cases of methadone-induced QT prolongation are associated with, but|
02665|042|D|not limited to, higher dose treatment (greater than 200 mg daily) and most|
02665|043|D|involve patients being treated for pain with large, multiple daily doses.|
02665|044|D|Cases have been reported in patients treated with doses commonly used for|
02665|045|D|maintenance treatment of opioid addiction.(2)|
02665|046|D|   Levomethadone should be used with caution in patients with a history of|
02665|047|D|QT prolongation, advanced heart disease, concomitant CYP3A4 inhibitors, or|
02665|048|D|electrolyte abnormalities.  Cases of QT prolongation and torsades de pointes|
02665|049|D|have been reported, most commonly with high doses.(1)|
02665|050|D|   One or more of the drug pairs linked to this monograph have been included|
02665|051|D|in a list of interactions that should be considered "high-priority" for|
02665|052|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02665|053|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02665|054|D|Coordinator (ONC) for Health Information Technology.|
02665|055|B||
02665|056|R|REFERENCES:|
02665|057|B||
02665|058|R|1.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
02665|059|R|  Pharma AS November 30, 2018.|1
02665|060|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
02665|061|R|  Pharmaceuticals Corp. June, 2021.|1
02665|062|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02665|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02665|064|R|  settings: a scientific statement from the American Heart Association and|6
02665|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02665|066|R|  2;55(9):934-47.|6
02665|067|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
02665|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02665|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02665|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02665|071|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02665|072|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02665|073|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02665|074|R|  19(5):735-43.|6
02666|001|T|MONOGRAPH TITLE:  Ondansetron/QT Prolonging Agents|
02666|002|B||
02666|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02666|004|L|of severe adverse interaction.|
02666|005|B||
02666|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02666|007|A|interval may result in additive effects on the QTc interval.(1-3)|
02666|008|B||
02666|009|E|CLINICAL EFFECTS:  The use of ondansetron in patients maintained on agents|
02666|010|E|that prolong the QTc interval may result in potentially life-threatening|
02666|011|E|cardiac arrhythmias, including torsades de pointes.(1-3)|
02666|012|B||
02666|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02666|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02666|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02666|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02666|017|P|female gender, or in the elderly (> or = 75 years of age).(4)|
02666|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02666|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02666|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02666|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02666|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02666|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02666|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02666|025|B||
02666|026|M|PATIENT MANAGEMENT:  The risk for QT prolongation due to ondansetron is dose|
02666|027|M|and route related.  Intravenous (IV) doses lead to higher peak|
02666|028|M|concentrations and systemic exposure and so have a greater risk for QT|
02666|029|M|prolongation compared with the same dose given orally.  Faster rates of IV|
02666|030|M|infusion are also associated with a greater risk for QT prolongation.(5)  If|
02666|031|M|concomitant therapy is needed, correct electrolyte abnormalities prior to|
02666|032|M|starting therapy.  Monitor closely, particularly in patients with|
02666|033|M|predisposing risk factors for QT prolongation (e.g. cardiac disease, female,|
02666|034|M|elderly). Electrocardiogram (ECG) monitoring should be performed in patients|
02666|035|M|receiving concurrent therapy.(1-3)|
02666|036|M|   The Canadian manufacturer of Zofran injection has specific|
02666|037|M|recommendations for use of IV ondansetron in oncology patients greater than|
02666|038|M|or equal to 75 years of age (5):|
02666|039|M|   - all IV doses must be diluted in 50 - 100 mL of compatible fluid and|
02666|040|M|infused over at least 15 minutes|
02666|041|M|   - initial and repeat IV doses must not exceed 8 mg.|
02666|042|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02666|043|M|fainting.|
02666|044|B||
02666|045|D|DISCUSSION:  In a double-blind, randomized, placebo and positive controlled|
02666|046|D|cross-over study, an ondansetron intravenous (IV) dose of 32 mg increased|
02666|047|D|the maximum mean QTcF by 19.6 msec (upper limit of 90% CI:  21.5).  A dose|
02666|048|D|of 8mg increased the QTcF by a maximum mean of 5.8 (upper limit of 90% CI:|
02666|049|D|7.8).  A dose of 16 mg was predicted to have a mean increase in QTcF of 9.1|
02666|050|D|msec (upper limit of 90% CI:  11.2).(1)|
02666|051|D|   QT prolongation and torsades de pointes have been reported in|
02666|052|D|post-marketing reports in patients receiving ondansetron.(2-3)|
02666|053|D|   In a review of published reports of QT prolongation associated with|
02666|054|D|ondansetron administration, 67% of patients were also receiving another|
02666|055|D|medication known to prolong the QT interval.(6)|
02666|056|D|   In a prospective, observational study, administration of a single|
02666|057|D|ondansetron IV dose of 4 mg in the emergency department increased the mean|
02666|058|D|and median QTc interval by 16.2 msec (95% CI 4.2-28.2 msec; p=0.01) and 12|
02666|059|D|msec (IQR 5.5-18 msec; p<0.01), respectively.  Three patients had extreme|
02666|060|D|QTc prolongation.  With exclusion of those 3 patients, the median QTc|
02666|061|D|prolongation was 10 msec (IQR 5-15 msec; p<0.01).(7)|
02666|062|D|   Agents that are linked to this monograph may have varying degrees of|
02666|063|D|potential to prolong the QTc interval but are generally accepted to have a|
02666|064|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02666|065|D|been shown to prolong the QTc interval either through their mechanism of|
02666|066|D|action, through studies on their effects on the QTc interval, or through|
02666|067|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02666|068|D|and/or post-marketing reports.(8)|
02666|069|D|   One or more of the drug pairs linked to this monograph have been included|
02666|070|D|in a list of interactions that should be considered "high-priority" for|
02666|071|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02666|072|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02666|073|D|Coordinator (ONC) for Health Information Technology.|
02666|074|B||
02666|075|R|REFERENCES:|
02666|076|B||
02666|077|R|1.Kon P. Dear UK Healthcare Professional:   Direct Healthcare Professional|1
02666|078|R|  Communication on ondansetron (Zofran and generics) and dose-dependent QT|1
02666|079|R|  interval prolongation - new dose restriction for intravenous (IV) use.|1
02666|080|R|  GlaxoSmithKline UK Ltd August 5, 2012.|1
02666|081|R|2.Zofran (ondansetron) US prescribing information. GlaxoSmithKline October,|1
02666|082|R|  2021.|1
02666|083|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Abnormal|1
02666|084|R|  heart rhythms may be associated with use of Zofran (ondansetron).|1
02666|085|R|  available at:|1
02666|086|R|  https://wayback.archive-it.org/7993/20170722185907/https:/www.fda.gov/Drug|1
02666|087|R|  s/DrugSafety/ucm271913.htm September 15, 2011.|1
02666|088|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02666|089|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02666|090|R|  settings: a scientific statement from the American Heart Association and|6
02666|091|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02666|092|R|  2;55(9):934-47.|6
02666|093|R|5.Health Canada. Zofran (ondansetron) - Dosage and Administration of|1
02666|094|R|  Intravenous Ondansetron in Geriatrics (>65 years of age). available at:|1
02666|095|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/39943a-e|1
02666|096|R|  ng.php June 12, 2014.|1
02666|097|R|6.Freedman SB, Uleryk E, Rumantir M, Finkelstein Y. Ondansetron and the risk|6
02666|098|R|  of cardiac arrhythmias: a systematic review and postmarketing analysis.|6
02666|099|R|  Ann Emerg Med 2014 Jul;64(1):19-25.e6.|6
02666|100|R|7.Li K, Vo K, Lee BK, Addo N, Coralic Z. Effect of a single dose of i.v.|2
02666|101|R|  ondansetron on QTc interval in emergency department patients. Am J Health|2
02666|102|R|  Syst Pharm 2018 Mar 1;75(5):276-282.|2
02666|103|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
02666|104|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02666|105|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02666|106|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02666|107|R|9.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02666|108|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02666|109|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02666|110|R|  19(5):735-43.|6
02667|001|T|MONOGRAPH TITLE:  Romidepsin/QT Prolonging Agents|
02667|002|B||
02667|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02667|004|L|of severe adverse interaction.|
02667|005|B||
02667|006|A|MECHANISM OF ACTION:  Romidepsin has been shown to prolong the QTc interval.|
02667|007|A|Concurrent use with other agents that prolong the QTc interval may result|
02667|008|A|in additive effects on the QTc interval.(1)|
02667|009|B||
02667|010|E|CLINICAL EFFECTS:  The concurrent use of romidepsin with other agents that|
02667|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02667|012|E|arrhythmias, including torsades de pointes.(1)|
02667|013|B||
02667|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02667|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02667|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02667|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02667|018|P|gender, or advanced age.(2)|
02667|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02667|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02667|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02667|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02667|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02667|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02667|025|P|dysfunction).(2)|
02667|026|B||
02667|027|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin states that|
02667|028|M|appropriate cardiovascular monitoring, such as baseline and regular|
02667|029|M|monitoring of ECG and obtaining serum calcium, magnesium, and potassium|
02667|030|M|levels, should be performed if concurrent therapy with agents known to|
02667|031|M|prolong the QT interval is warranted.(1)|
02667|032|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02667|033|M|fainting.|
02667|034|B||
02667|035|D|DISCUSSION:  In two clinical trials, discontinuation of romidepsin secondary|
02667|036|D|to QT prolongation occurred in at least 2% of patients.(1)|
02667|037|D|   Agents that are linked to this monograph may have varying degrees of|
02667|038|D|potential to prolong the QTc interval but are generally accepted to have a|
02667|039|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02667|040|D|been shown to prolong the QTc interval either through their mechanism of|
02667|041|D|action, through studies on their effects on the QTc interval, or through|
02667|042|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02667|043|D|and/or post-marketing reports.(3)|
02667|044|B||
02667|045|R|REFERENCES:|
02667|046|B||
02667|047|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
02667|048|R|  November, 2018.|1
02667|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02667|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02667|051|R|  settings: a scientific statement from the American Heart Association and|6
02667|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02667|053|R|  2;55(9):934-47.|6
02667|054|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02667|055|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02667|056|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02667|057|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02668|001|T|MONOGRAPH TITLE:  Sorafenib/QT Prolonging Agents|
02668|002|B||
02668|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02668|004|L|of severe adverse interaction.|
02668|005|B||
02668|006|A|MECHANISM OF ACTION:  Concurrent use of sorafenib with other agents that|
02668|007|A|prolong the QTc interval may result in additive effects on the QTc|
02668|008|A|interval.(1)|
02668|009|B||
02668|010|E|CLINICAL EFFECTS:  The use of sorafenib patients maintained on agents that|
02668|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02668|012|E|arrhythmias, including torsades de pointes.(1)|
02668|013|B||
02668|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02668|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02668|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02668|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02668|018|P|female gender, or advanced age.(2)|
02668|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02668|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02668|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02668|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02668|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02668|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02668|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02668|026|B||
02668|027|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with agents known|
02668|028|M|to prolong the QTc interval should be monitored with electrocardiograms|
02668|029|M|during treatment with sorafenib. Electrolytes (calcium, magnesium, and|
02668|030|M|potassium) should also be monitored.(1)|
02668|031|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02668|032|M|fainting.|
02668|033|B||
02668|034|D|DISCUSSION:  In a non-randomized trial in 53 patients, sorafenib resulted in|
02668|035|D|a mean change in QTc of 8.5 msec (upper bound of 90% CI:  13.3 msec).(1)|
02668|036|D|   A retrospective review of 618 cancer patients treated with 902|
02668|037|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
02668|038|D|incidence of QTc prolongation.  In patients who received sorafenib, QTc|
02668|039|D|prolongation was identified in 13 (31.7%) with 5 (38.5%) having Grade 1 (QTc|
02668|040|D|450-480 ms) and 4 (30.7%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
02668|041|D|occurred in 2 (15.4%) having QTc greater than or equal to 500 ms and 2|
02668|042|D|(15.4%) having QTc change greater than or equal to 60 ms.  No patients|
02668|043|D|developed ventricular tachycardia, sudden cardiac death, or TdP.(3)|
02668|044|D|   Agents that are linked to this monograph may have varying degrees of|
02668|045|D|potential to prolong the QTc interval but are generally accepted to have a|
02668|046|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02668|047|D|been shown to prolong the QTc interval either through their mechanism of|
02668|048|D|action, through studies on their effects on the QTc interval, or through|
02668|049|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02668|050|D|and/or post-marketing reports.(4)|
02668|051|B||
02668|052|R|REFERENCES:|
02668|053|B||
02668|054|R|1.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
02668|055|R|  Corporation July, 2020.|1
02668|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02668|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02668|058|R|  settings: a scientific statement from the American Heart Association and|6
02668|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02668|060|R|  2;55(9):934-47.|6
02668|061|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
02668|062|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
02668|063|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
02668|064|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
02668|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02668|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02668|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02669|001|T|MONOGRAPH TITLE:  Telavancin/QT Prolonging Agents|
02669|002|B||
02669|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02669|004|L|of severe adverse interaction.|
02669|005|B||
02669|006|A|MECHANISM OF ACTION:  Telavancin has been shown to prolong the QTc interval.|
02669|007|A|Concurrent use with other agents that prolong the QTc interval may result|
02669|008|A|in additive effects on the QTc interval.(1)|
02669|009|B||
02669|010|E|CLINICAL EFFECTS:  The concurrent use of telavancin with other agents that|
02669|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02669|012|E|arrhythmias, including torsades de pointes.(1)|
02669|013|B||
02669|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02669|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02669|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02669|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02669|018|P|female gender, or advanced age.(2)|
02669|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02669|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02669|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02669|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02669|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02669|024|P|an agent which inhibits its metabolism  or elimination, genetic impairment|
02669|025|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02669|026|B||
02669|027|M|PATIENT MANAGEMENT:  The US manufacturer of telavancin recommends against|
02669|028|M|the use of telavancin with other drugs known to cause QT prolongation.(1)|
02669|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02669|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02669|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02669|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02669|033|B||
02669|034|D|DISCUSSION:  In a randomized, double-blind, multiple-dose,|
02669|035|D|positive-controlled, placebo-controlled, parallel study in healthy subjects,|
02669|036|D|the mean maximum baseline-corrected, placebo-corrected QTc prolongation was|
02669|037|D|11.6 msec and 15.1 msec for telavancin at dosages of 7.5 mg/kg and 15 mg/kg,|
02669|038|D|respectively.  The estimated  mean maximum baseline-corrected,|
02669|039|D|placebo-corrected QTc prolongation for a telavancin dosage of 10 mg/kg is|
02669|040|D|12-15 msec.(1)|
02669|041|D|   In studies in patients, 21% of patients receiving telavancin (214 of|
02669|042|D|1029, 10 mg/kg) and 16% of patients receiving vancomycin (164 of 1033)|
02669|043|D|received concurrent QT prolonging agents.  The rate of QTc prolongation|
02669|044|D|greater than 60 msec was 1.5% (15 patients) in the telavancin group and 0.6%|
02669|045|D|(6 patients) in the vancomycin group.  Nine of the 15 telavancin subjects|
02669|046|D|with QTc prolongation received concurrent QT prolongers, compared with 1 of|
02669|047|D|the vancomycin patients.(1)|
02669|048|D|   Agents that are linked to this monograph may have varying degrees of|
02669|049|D|potential to prolong the QTc interval but are generally accepted to have a|
02669|050|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02669|051|D|been shown to prolong the QTc interval either through their mechanism of|
02669|052|D|action, through studies on their effects on the QTc interval, or through|
02669|053|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02669|054|D|and/or post-marketing reports.(3)|
02669|055|B||
02669|056|R|REFERENCES:|
02669|057|B||
02669|058|R|1.Vibativ (telavancin) US prescribing information. Theravance Biopharma US,|1
02669|059|R|  Inc. February, 2020.|1
02669|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02669|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02669|062|R|  settings: a scientific statement from the American Heart Association and|6
02669|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02669|064|R|  2;55(9):934-47.|6
02669|065|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02669|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02669|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02669|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02670|001|T|MONOGRAPH TITLE:  Vemurafenib/QT Prolonging Agents|
02670|002|B||
02670|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02670|004|L|of severe adverse interaction.|
02670|005|B||
02670|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
02670|007|A|interval may result in additive effects on the QTc interval.(1)|
02670|008|B||
02670|009|E|CLINICAL EFFECTS:  The use of vemurafenib in patients maintained on agents|
02670|010|E|that prolong the QTc interval may result in potentially life-threatening|
02670|011|E|cardiac arrhythmias, including torsades de pointes.(1)|
02670|012|B||
02670|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02670|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02670|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02670|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02670|017|P|female gender, or advanced age.(2)|
02670|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02670|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02670|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02670|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02670|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02670|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02670|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02670|025|B||
02670|026|M|PATIENT MANAGEMENT:  Vemurafenib should not be initiated in patients taking|
02670|027|M|medications known to prolong the QT interval, patients having a baseline QTc|
02670|028|M|greater than 500 msec, uncorrectable electrolyte abnormalities, or known|
02670|029|M|long QT syndrome is not recommended.(1)|
02670|030|M|   All patients receiving vemurafenib should undergo ECG testing at|
02670|031|M|baseline, after 15 days of treatment, monthly during the first 3 months of|
02670|032|M|treatment, and then every 3 months.  If a patient's QTc exceeds 500 msec|
02670|033|M|during treatment, vemurafenib should be discontinued and cardiac risk|
02670|034|M|factors for QT prolongation should be controlled.  Consider discontinuing|
02670|035|M|other medications known to prolong the QT interval at this time.  If the|
02670|036|M|patient's QTc decreases below 500 msec, vemurafenib may be introduced at a|
02670|037|M|lower dosage according to the current labeling recommendations.  If the|
02670|038|M|patient's QTc remains greater than 500 msec and increased >60 msec from|
02670|039|M|pre-treatment values after controlling cardiac risk factors for|
02670|040|M|prolongation, permanently discontinue vemurafenib.(1)|
02670|041|M|   Consider obtaining serum calcium, magnesium, and potassium levels at|
02670|042|M|baseline and regular intervals. Correct any electrolyte abnormalities.|
02670|043|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02670|044|M|fainting.|
02670|045|B||
02670|046|D|DISCUSSION:  Vemurafenib is associated with concentration-dependent QTc|
02670|047|D|interval prolongation.  In the first month of treatment, the largest mean|
02670|048|D|QTc change was 12.8 msec (upper boundary of 90% CI:  14.9 msec).  In the|
02670|049|D|first 6 months of treatment, the largest mean QTc change was 15.1 msec|
02670|050|D|(upper boundary of 90% CI:  17.7 msec).(1)|
02670|051|D|   Agents that are linked to this monograph may have varying degrees of|
02670|052|D|potential to prolong the QTc interval but are generally accepted to have a|
02670|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02670|054|D|been shown to prolong the QTc interval either through their mechanism of|
02670|055|D|action, through studies on their effects on the QTc interval, or through|
02670|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02670|057|D|and/or post-marketing reports.(3)|
02670|058|B||
02670|059|R|REFERENCES:|
02670|060|B||
02670|061|R|1.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02670|062|R|  November, 2017.|1
02670|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02670|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02670|065|R|  settings: a scientific statement from the American Heart Association and|6
02670|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02670|067|R|  2;55(9):934-47.|6
02670|068|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02670|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02670|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02670|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02671|001|T|MONOGRAPH TITLE:  Metformin/Trimethoprim|
02671|002|B||
02671|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02671|004|L|take action as needed.|
02671|005|B||
02671|006|A|MECHANISM OF ACTION:  Metformin renal clearance is mediated by OCT2 and|
02671|007|A|MATE1 transport. Trimethoprim inhibits elimination by these pathways.|
02671|008|B||
02671|009|E|CLINICAL EFFECTS:  Use of trimethoprim may increase levels of metformin,|
02671|010|E|which may result in lactic acidosis.|
02671|011|B||
02671|012|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
02671|013|P|include renal impairment,sepsis, dehydration, excessive alcohol intake,|
02671|014|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
02671|015|P|failure, metformin plasma levels > 5 micrograms/mL, and conditions which may|
02671|016|P|lead to tissue hypoxia.  Geriatric patients may also be at higher risk due|
02671|017|P|to slower metformin clearance and increased half-life in this population.|
02671|018|B||
02671|019|M|PATIENT MANAGEMENT:  The US labeling for metformin recommends the dose of|
02671|020|M|metformin and/or trimethoprim be adjusted as needed.  Consider the benefits|
02671|021|M|and risks of concomitant use.(1)|
02671|022|M|   Evaluate patient's renal function and consider discontinuation of one or|
02671|023|M|both agents in patients with renal impairment.|
02671|024|M|   Monitor for signs and symptoms of metformin toxicity (lactic acidosis)|
02671|025|M|such as malaise, myalgias, respiratory distress, increasing somnolence, and|
02671|026|M|respiratory distress. Laboratory results which may signal lactic acidosis|
02671|027|M|include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an|
02671|028|M|increased anion gap, and increased lactate to pyruvate ratio.|
02671|029|B||
02671|030|D|DISCUSSION:  Trimethoprim was found to cause significant inhibition of net|
02671|031|D|transcellular chloroquine transport in canine kidney-OCT2-MATE1 cells.|
02671|032|D|Chloroquine is eliminated by renal tubular secretion involving multidrug and|
02671|033|D|toxin extrusion protein 1 (MATE1). Trimethoprim caused|
02671|034|D|concentration-dependent inhibition of net metformin intake in HEK293-MATE1|
02671|035|D|cells (human embryonic kidney). (2)|
02671|036|D|   A randomized, open-label, two-phase crossover study found that|
02671|037|D|trimethoprim inhibited OCT2, MATE1, and MATE2-K-dependent transport of|
02671|038|D|metformin. Trimethoprim increased metformin area under the curve (AUC) by|
02671|039|D|29.4% and decreased metformin renal clearance by 26.4%. (3)|
02671|040|D|   24 healthy volunteers received metformin 500 mg three times daily for ten|
02671|041|D|days and trimethoprim 200 mg twice daily from days 5-10. Trimethoprim|
02671|042|D|significantly reduced the apparent systemic metformin clearance (CL/F) from|
02671|043|D|74 to 54 l/h and renal metformin clearance from 31 to 21 l/h. Metformin|
02671|044|D|half-life was prolonged from 2.7 to 3.6h. The metformin plasma concentration|
02671|045|D|(Cmax) increased 38% and the AUC by 37%. Trimethoprim was also associated|
02671|046|D|with a decrease in creatinine clearance and an increase in plasma lactate.|
02671|047|D|(4)|
02671|048|B||
02671|049|R|REFERENCES:|
02671|050|B||
02671|051|R|1.Glucophage (metformin hydrochloride) US prescribing information.|1
02671|052|R|  Bristol-Myers Squibb Company May, 2018.|1
02671|053|R|2.Muller F, Konig J, Glaeser H, Schmidt I, Zolk O, Fromm MF, Maas R.|2
02671|054|R|  Molecular mechanism of renal tubular secretion of the antimalarial drug|2
02671|055|R|  chloroquine. Antimicrob Agents Chemother 2011 Jul;55(7):3091-8.|2
02671|056|R|3.Muller F, Pontones CA, Renner B, Mieth M, Hoier E, Auge D, Maas R, Zolk O,|2
02671|057|R|  Fromm MF. N(1)-methylnicotinamide as an endogenous probe for drug|2
02671|058|R|  interactions by renal cation transporters: studies on the|2
02671|059|R|  metformin-trimethoprim interaction. Eur J Clin Pharmacol 2015 Jan;|2
02671|060|R|  71(1):85-94.|2
02671|061|R|4.Grun B, Kiessling MK, Burhenne J, Riedel KD, Weiss J, Rauch G, Haefeli WE,|2
02671|062|R|  Czock D. Trimethoprim-metformin interaction and its genetic modulation by|2
02671|063|R|  OCT2 and MATE1 transporters. Br J Clin Pharmacol 2013 Nov;76(5):787-96.|2
02671|064|R|5.Vecchio S, Giampreti A, Petrolini VM, Lonati D, Protti A, Papa P, Rognoni|2
02671|065|R|  C, Valli A, Rocchi L, Rolandi L, Manzo L, Locatelli CA. Metformin|2
02671|066|R|  accumulation: lactic acidosis and high plasmatic metformin levels in a|2
02671|067|R|  retrospective case series of 66 patients on chronic therapy. Clin Toxicol|2
02671|068|R|  (Phila) 2014 Feb;52(2):129-35.|2
02672|001|T|MONOGRAPH TITLE:  Selexipag/Strong CYP2C8 Inhibitors|
02672|002|B||
02672|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02672|004|L|is contraindicated and generally should not be dispensed or administered to|
02672|005|L|the same patient.|
02672|006|B||
02672|007|A|MECHANISM OF ACTION:  Strong CYP2C8 inhibitors may inhibit the metabolism of|
02672|008|A|selexipag.(1,2)|
02672|009|B||
02672|010|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP2C8 inhibitor may increase|
02672|011|E|levels and effects of selexipag, including headache, diarrhea, jaw pain,|
02672|012|E|nausea, myalgia, vomiting, pain in extremity, flushing, decreased|
02672|013|E|hemoglobin, and hyperthyroidism.(1,2)|
02672|014|B||
02672|015|P|PREDISPOSING FACTORS:  None determined.|
02672|016|B||
02672|017|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP2C8 inhibitors and|
02672|018|M|selexipag is contraindicated.(1,2)|
02672|019|M|   If concurrent use is warranted, monitor patients closely for increased|
02672|020|M|effects of selexipag, including headache, diarrhea, jaw pain, nausea,|
02672|021|M|myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and|
02672|022|M|hyperthyroidism.|
02672|023|B||
02672|024|D|DISCUSSION:  Gemfibrozil doubled the area-under-curve (AUC) of selexipag and|
02672|025|D|increased the AUC of its active metabolite 11-fold.(1,2)|
02672|026|D|   Strong inhibitors of CYP2C8 include gemfibrozil.(3,4)|
02672|027|B||
02672|028|R|REFERENCES:|
02672|029|B||
02672|030|R|1.Uptravi (selexipag) US prescribing information. Actelion Pharmaceuticals|1
02672|031|R|  US, Inc. October, 2021.|1
02672|032|R|2.Uptravi (selexipag) UK summary of product characteristics. Actelion|1
02672|033|R|  Pharmaceuticals UK Ltd June 2017.|1
02672|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
02672|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02672|036|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02672|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02672|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02672|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02672|040|R|  11/14/2017.|1
02673|001|T|MONOGRAPH TITLE:  Tuberculin Testing/Live Vaccines|
02673|002|B||
02673|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02673|004|L|of severe adverse interaction.|
02673|005|B||
02673|006|A|MECHANISM OF ACTION:  Measles infection and severe acute and chronic|
02673|007|A|infections may induce an anergic state resulting in a false-negative|
02673|008|A|tuberculin test.  The live measles vaccine, as well as other live vaccines|
02673|009|A|(e.g. smallpox, varicella, yellow fever) theoretically may also suppress|
02673|010|A|response to tuberculin testing, though the degree of suppression may be less|
02673|011|A|than that expected from acute infection with wild-type virus.(1-4)|
02673|012|B||
02673|013|E|CLINICAL EFFECTS:  Tuberculin testing that is performed more than one day|
02673|014|E|but less than 28 days after administration of a live vaccine may result in a|
02673|015|E|false negative tuberculin response.   Tuberculin testing may be administered|
02673|016|E|simultaneously with live vaccines.(1-4)|
02673|017|B||
02673|018|P|PREDISPOSING FACTORS:  None determined.|
02673|019|B||
02673|020|M|PATIENT MANAGEMENT:  The CDC states that live vaccines (e.g. MMR and|
02673|021|M|varicella) and tuberculin testing may be administered within one day of each|
02673|022|M|other at separate administration sites.   If it has been more than one day|
02673|023|M|since tuberculin testing has been administered, the live vaccine can be|
02673|024|M|given at any interval after the tuberculin test.  However, if the live|
02673|025|M|vaccine has been administered more than one day previously and tuberculin|
02673|026|M|testing is indicated, tuberculin testing should be deferred for at least 4-6|
02673|027|M|weeks.(1-4)|
02673|028|B||
02673|029|D|DISCUSSION:  Suppression of response to tuberculin testing has been observed|
02673|030|D|following measles infection, live measles vaccination, and live smallpox|
02673|031|D|vaccination.  The degree of suppression after live virus vaccination is|
02673|032|D|likely to be less than that from an acute infection with wild-type virus.|
02673|033|D|There is no data on suppression of response to tuberculin testing with other|
02673|034|D|live vaccines.  In the absence of data, the CDC recommends tuberculin|
02673|035|D|testing within one day that a live vaccine is administered.  Otherwise the|
02673|036|D|tuberculin test should be deferred for at least 4-6 weeks.(1-4)|
02673|037|B||
02673|038|R|REFERENCES:|
02673|039|B||
02673|040|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
02673|041|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
02673|042|R|  Practices (ACIP). MMWR.  Available at:|1
02673|043|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
02673|044|R|  February 17, 2022;60(RR No.2):1-68.|1
02673|045|R|2.Tubersol (tuberculin purified protein derivative) US prescribing|1
02673|046|R|  information. Sanofi Pasteur Limited February, 2013.|1
02673|047|R|3.Aplisol (tuberculin purified protein derivative) US prescribing|1
02673|048|R|  information. JHP Pharmaceuticals, LLC November, 2013.|1
02673|049|R|4.Brickman HF, Beaudry PH, Marks MI. The timing of tuberculin tests in|2
02673|050|R|  relation to immunization with live viral vaccines. Pediatrics 1975 Mar;|2
02673|051|R|  55(3):392-6.|2
02674|001|T|MONOGRAPH TITLE:  Alprazolam; Estazolam; Midazolam; Triazolam/Nefazodone|
02674|002|B||
02674|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02674|004|L|of severe adverse interaction.|
02674|005|B||
02674|006|A|MECHANISM OF ACTION:  Nefazodone is a strong inhibitor of CYP3A4 and may|
02674|007|A|decrease metabolism of benzodiazepines cleared by this pathway.|
02674|008|B||
02674|009|E|CLINICAL EFFECTS:  Concurrent administration of nefazodone and|
02674|010|E|benzodiazepines metabolized by CYP3A4 may result in increased clinical|
02674|011|E|effects of benzodiazepines, including toxic effects profound sedation,|
02674|012|E|respiratory depression, coma, and/or death.|
02674|013|E|   CYP3A4 is the major or only hepatic metabolism pathway for the phase I|
02674|014|E|elimination of alprazolam, estazolam, midazolam, and triazolam.|
02674|015|B||
02674|016|P|PREDISPOSING FACTORS:  None determined.|
02674|017|B||
02674|018|M|PATIENT MANAGEMENT:  Benzodiazepines that do not undergo extensive CYP|
02674|019|M|hepatic metabolism (e.g. lorazepam, oxazepam) may be an alternative in|
02674|020|M|nefazodone patients.|
02674|021|M|   If nefazodone is administered in combination with triazolam, the|
02674|022|M|manufacturer of nefazodone recommends that the initial dose triazolam be|
02674|023|M|reduced by 75%. In interaction studies nefazodone 200 mg twice daily|
02674|024|M|increased triazolam exposure (area-under-curve, AUC) 4-fold.  However,|
02674|025|M|because not all commercially available triazolam dosage forms permit a|
02674|026|M|sufficient dosage adjustment, the manufacturer of nefazodone recommends that|
02674|027|M|the combination of nefazodone and triazolam be avoided in most patients,|
02674|028|M|especially the elderly.|
02674|029|M|   When nefazodone is coadministered with alprazolam, AUC and half-life|
02674|030|M|increased approximately 2-fold.  The US manufacturers of nefazodone|
02674|031|M|recommend a 50% reduction in the initial dose of alprazolam.|
02674|032|M|   The US manufacturer of estazolam recommends caution and consideration of|
02674|033|M|an appropriate dose reduction when concomitant therapy is considered.  Two|
02674|034|M|other strong CYP3A4 inhibitors, itraconazole and oral ketoconazole, are|
02674|035|M|contraindicated with estazolam use. It would be prudent to avoid the|
02674|036|M|combination of nefazodone and estazolam.|
02674|037|M|   If nefazodone is started in a patient already receiving a benzodiazepine|
02674|038|M|primarily metabolized by CYP3A4, then monitor closely and anticipate the|
02674|039|M|need to reduce the benzodiazepine dose.|
02674|040|M|   Counsel patient to report excess drowsiness, confusion, memory problems|
02674|041|M|including sleep-driving behaviors, loss of coordination, slowed or difficult|
02674|042|M|breathing, or unresponsiveness.|
02674|043|B||
02674|044|D|DISCUSSION:  In an interaction study, nefazodone 200 mg twice daily|
02674|045|D|increased triazolam exposure (area-under-curve, AUC) 4-fold.|
02674|046|D|   When nefazodone is coadministered with alprazolam, AUC and half-life|
02674|047|D|increased approximately 2-fold.|
02674|048|B||
02674|049|R|REFERENCES:|
02674|050|B||
02674|051|R|1.Nefazodone Hydrochloride US prescribing information. Teva Pharmaceuticals|1
02674|052|R|  USA Inc. June, 2014.|1
02674|053|R|2.Estazolam tablet US prescribing information. Teva Pharmaceuticals USA Inc|1
02674|054|R|  November, 2015.|1
02674|055|R|3.Barbhaiya RH, Shukla UA, Kroboth PD, Greene DS. Coadministration of|2
02674|056|R|  nefazodone and benzodiazepines: II. A pharmacokinetic interaction study|2
02674|057|R|  with triazolam. J Clin Psychopharmacol 1995 Oct;15(5):320-6.|2
02674|058|R|4.Kroboth PD, Folan MM, Lush RM, Chaikin PC, Shukla UA, Barbhaiya R, Salazar|2
02674|059|R|  DE. Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic|2
02674|060|R|  assessment. J Clin Psychopharmacol 1995 Oct;15(5):306-19.|2
02674|061|R|5.Greene DS, Salazar DE, Dockens RC, Kroboth P, Barbhaiya RH.|2
02674|062|R|  Coadministration of nefazodone and benzodiazepines: IV. A pharmacokinetic|2
02674|063|R|  interaction study with lorazepam. J Clin Psychopharmacol 1995 Dec;|2
02674|064|R|  15(6):409-16.|2
02674|065|R|6.Greene DS, Salazar DE, Dockens RC, Kroboth P, Barbhaiya RH.|2
02674|066|R|  Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic|2
02674|067|R|  interaction study with alprazolam. J Clin Psychopharmacol 1995 Dec;|2
02674|068|R|  15(6):399-408.|2
02674|069|R|7.Xanax (alprazolam) US prescribing information. Pharmacia & Upjohn Company|1
02674|070|R|  February, 2021.|1
02675|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Lesinurad|
02675|002|B||
02675|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02675|004|L|of severe adverse interaction.|
02675|005|B||
02675|006|A|MECHANISM OF ACTION:  Lesinurad may induce the CYP3A4 mediated metabolism of|
02675|007|A|hormonal contraceptives.(1)|
02675|008|B||
02675|009|E|CLINICAL EFFECTS:  Concurrent use of lesinurad may reduce the effectiveness|
02675|010|E|of hormonal contraceptives.(1)|
02675|011|B||
02675|012|P|PREDISPOSING FACTORS:  None determined.|
02675|013|B||
02675|014|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
02675|015|M|rely on hormonal contraception (including oral contraceptives, patches,|
02675|016|M|implants, and/or IUDs) for contraception.  Women should use a back-up method|
02675|017|M|of birth control during lesinurad therapy.(1)|
02675|018|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
02675|019|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
02675|020|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
02675|021|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
02675|022|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
02675|023|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
02675|024|M|and to seek medical advice if they do become pregnant.(2)|
02675|025|B||
02675|026|D|DISCUSSION:  Lesinurad may decrease the effectiveness of hormonal|
02675|027|D|contraceptives, including oral contraceptives, patches, implants, and/or|
02675|028|D|IUDs.  Women should use a back-up method of birth control during lesinurad|
02675|029|D|therapy.(1)|
02675|030|B||
02675|031|R|REFERENCES:|
02675|032|B||
02675|033|R|1.Zurampic (lesinurad) US prescribing information. AstraZeneca|1
02675|034|R|  Pharmaceuticals LP December, 2015.|1
02675|035|R|2.Medicines and Healthcare products Regulatory Agency.|1
02675|036|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
02675|037|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
02675|038|R|  available at:|1
02675|039|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
02675|040|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
02675|041|R|  -and-contraceptive-efficacy September 15, 2016..|1
02676|001|T|MONOGRAPH TITLE:  Selected Benzodiazepines/Fluvoxamine|
02676|002|B||
02676|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02676|004|L|of severe adverse interaction.|
02676|005|B||
02676|006|A|MECHANISM OF ACTION:  Fluvoxamine, a strong CYP2C19 inhibitor and moderate|
02676|007|A|CYP3A4 inhibitor, may decrease the metabolism of Phase I hepatically|
02676|008|A|metabolized benzodiazepines.|
02676|009|B||
02676|010|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine and selected|
02676|011|E|benzodiazepines may result in increased systemic levels and clinical effects|
02676|012|E|of the benzodiazepine including profound sedation, respiratory depression,|
02676|013|E|coma, and/or death.|
02676|014|E|   Benzodiazepines linked to this monograph are chlordiazepoxide,|
02676|015|E|clorazepate, diazepam, flurazepam, halazepam, prazepam and quazepam.|
02676|016|B||
02676|017|P|PREDISPOSING FACTORS:  The interaction may be more severe in patients|
02676|018|P|receiving another CYP3A4 inhibitor.|
02676|019|B||
02676|020|M|PATIENT MANAGEMENT:  Benzodiazepines that do not undergo extensive Phase I|
02676|021|M|metabolism (lorazepam, oxazepam) may be an alternative in patients receiving|
02676|022|M|fluvoxamine.|
02676|023|M|   The US manufacturer of fluvoxamine recommends that fluvoxamine and|
02676|024|M|diazepam not be concurrently administered.|
02676|025|M|   If fluvoxamine is started in a patient already receiving a|
02676|026|M|benzodiazepine, monitor closely and anticipate the need to reduce the|
02676|027|M|benzodiazepine dose.|
02676|028|M|   Counsel patient to report excess drowsiness, confusion, memory problems|
02676|029|M|including sleep-driving behaviors, loss of coordination, unusual dizziness|
02676|030|M|of lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02676|031|M|unresponsiveness.|
02676|032|B||
02676|033|D|DISCUSSION:  In a study in healthy volunteers, administration of fluvoxamine|
02676|034|D|(150 mg daily) decreased the clearance of a single dose of diazepam (10 mg)|
02676|035|D|by 65%.  The clearance of N-desmethyldiazepam was too low to measure.|
02676|036|D|   Benzodiazepines such as lorazepam or oxazepam, would not be expected to|
02676|037|D|have a pharmacokinetic interaction with fluvoxamine.|
02676|038|B||
02676|039|R|REFERENCES:|
02676|040|B||
02676|041|R|1.Moskowitz H, Burns M. The effects on performance of two antidepressants,|2
02676|042|R|  alone and in combination with diazepam. Prog Neuropsychopharmacol Biol|2
02676|043|R|  Psychiatry 1988;12(5):783-92.|2
02676|044|R|2.Gardner MJ, Baris BA, Wilner KD, Preskorn SH. Effect of sertraline on the|4
02676|045|R|  pharmacokinetics and protein binding of diazepam in healthy volunteers.|4
02676|046|R|  Clin Pharmacokinet 1997;32 Suppl 1:43-9.|4
02676|047|R|3.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
02676|048|R|  Pharmaceuticals, Inc. August, 2023.|1
02676|049|R|4.Perucca E, Gatti G, Cipolla G, Spina E, Barel S, Soback S, Gips M, Bialer|2
02676|050|R|  M. Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic|2
02676|051|R|  study in normal volunteers. Clin Pharmacol Ther 1994 Nov;56(5):471-6.|2
02676|052|R|5.Troy SM, Lucki I, Peirgies AA, Parker VD, Klockowski PM, Chiang ST.|2
02676|053|R|  Pharmacokinetic and pharmacodynamic evaluation of the potential drug|2
02676|054|R|  interaction between venlafaxine and diazepam. J Clin Pharmacol 1995 Apr;|2
02676|055|R|  35(4):410-9.|2
02677|001|T|MONOGRAPH TITLE:  Lesinurad/Moderate CYP2C9 Inhibitors|
02677|002|B||
02677|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02677|004|L|take action as needed.|
02677|005|B||
02677|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP2C9 may inhibit the|
02677|007|A|metabolism of lesinurad.(1)|
02677|008|B||
02677|009|E|CLINICAL EFFECTS:  Concurrent use of moderate inhibitors of CYP2C9 may|
02677|010|E|result in elevated levels and toxicity from lesinurad, include|
02677|011|E|nephrotoxicity.(1)|
02677|012|B||
02677|013|P|PREDISPOSING FACTORS:  Patients with decreased renal function (CrCl less|
02677|014|P|than 60 ml/min) and patients not receiving a xanthine oxidase inhibitor may|
02677|015|P|be at increased risk of nephrotoxicity.(1)|
02677|016|B||
02677|017|M|PATIENT MANAGEMENT:  Approach the concurrent use of lesinurad and moderate|
02677|018|M|inhibitors of CYP2C9 with caution.(1)  Monitor renal function in patients|
02677|019|M|receiving concurrent therapy closely.  Interrupt therapy and measure serum|
02677|020|M|creatinine promptly in patients who report flank pain and/or|
02677|021|M|nausea/vomiting.|
02677|022|B||
02677|023|D|DISCUSSION:  Fluconazole (200 mg daily), a moderate inhibitor of CYP2C9,|
02677|024|D|increased lesinurad levels by 50%.(1)|
02677|025|B||
02677|026|R|REFERENCE:|
02677|027|B||
02677|028|R|1.Zurampic (lesinurad) US prescribing information. AstraZeneca|1
02677|029|R|  Pharmaceuticals LP December, 2015.|1
02678|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/Aspirin|
02678|002|T|(Less Than or Equal To 100 mg)|
02678|003|B||
02678|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02678|005|L|take action as needed.|
02678|006|B||
02678|007|A|MECHANISM OF ACTION:  Multiple processes are involved:  1)Aspirin is an|
02678|008|A|irreversible platelet inhibitor. It impairs platelet function, resulting in|
02678|009|A|prolonged bleeding time.  2) Aspirin may cause gastrointestinal (GI)|
02678|010|A|bleeding due to irritation.|
02678|011|B||
02678|012|E|CLINICAL EFFECTS:  The concurrent use of anticoagulants and aspirin leads to|
02678|013|E|blockade of two distinct coagulation pathways and may increase the risk for|
02678|014|E|bleeding.|
02678|015|B||
02678|016|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02678|017|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02678|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
02678|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02678|020|P|risk for bleeding (e.g. NSAIDs).|
02678|021|B||
02678|022|M|PATIENT MANAGEMENT:  Weigh the patient specific benefits versus risk for|
02678|023|M|concomitant use.|
02678|024|M|   If concurrent therapy of low dose aspirin and an anticoagulant is|
02678|025|M|warranted, monitor patients receiving concurrent therapy for signs of blood|
02678|026|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
02678|027|M|and/or decreased blood pressure and promptly evaluate patients with any|
02678|028|M|symptoms.|
02678|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR) to|
02678|030|M|monitor efficacy and safety of anticoagulation.  Discontinue anticoagulation|
02678|031|M|in patients with active pathologic bleeding.|
02678|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02678|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02678|034|M|tarry stools; red, pink or dark brown urine; severe headache, acute|
02678|035|M|abdominal or joint pain and/or swelling.|
02678|036|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02678|037|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02678|038|M|initiating, altering the dose or discontinuing either drug.|
02678|039|B||
02678|040|D|DISCUSSION:  This interaction has been reported between aspirin and warfarin|
02678|041|D|and between aspirin and dicumarol.|
02678|042|D|   The time of highest risk for a coumarin-type drug interaction is when the|
02678|043|D|precipitant drug is initiated, altered, or discontinued.|
02678|044|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
02678|045|D|pairs were reviewed and found 14% of drug pairs were associated with a|
02678|046|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
02678|047|D|of warfarin and aspirin resulted in a ratio of rate ratios (95% CI) of 2.13|
02678|048|D|(1.72-2.64).|
02678|049|D|   A large systematic review was performed on 72 warfarin drug-drug|
02678|050|D|interactions studies that reported on bleeding, thromboembolic events, or|
02678|051|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 38 of|
02678|052|D|those studies found a higher rate of clinically significant bleeding in|
02678|053|D|patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94).|
02678|054|D|Increased bleeding risk was also seen in subgroup analyses with aspirin|
02678|055|D|(OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and|
02678|056|D|aspirin plus clopidogrel or ticlopidine  (OR=2.07, 95% CI 1.33-3.21).(16)|
02678|057|B||
02678|058|R|REFERENCES:|
02678|059|B||
02678|060|R|1.Quick AJ, Clesceri L. Influence of acetylsalicylic acid and salicylamide|2
02678|061|R|  on the coagulation of blood. J Pharmacol Exp Ther 1960;128:95-8.|2
02678|062|R|2.Watson RM, Pierson RN Jr. Effect of anticoagulant therapy upon|2
02678|063|R|  aspirin-induced gastrointestinal bleeding. Circulation 1961 Sep;24:613-6.|2
02678|064|R|3.Barrow MV, Quick DT, Cunningham RW. Salicylate hypoprothrombinemia in|3
02678|065|R|  rheumatoid arthritis with liver disease. Report of two cases. Arch Intern|3
02678|066|R|  Med 1967 Nov;120(5):620-4.|3
02678|067|R|4.Weiss HJ, Aledort LM, Kochwa S. The effect of salicylates on the|2
02678|068|R|  hemostatic properties of platelets in man. J Clin Invest 1968 Sep;|2
02678|069|R|  47(9):2169-80.|2
02678|070|R|5.Udall JA. Drug interference with warfarin therapy. Clin Med 1970 Aug;|2
02678|071|R|  77:20-5.|2
02678|072|R|6.Fausa O. Salicylate-induced hypoprothrombinemia. A report of four cases.|3
02678|073|R|  Acta Med Scand 1970 Nov;188(5):403-8.|3
02678|074|R|7.Zucker MB, Peterson J. Effect of acetylsalicylic acid, other nonsteroidal|5
02678|075|R|  anti-inflammatory agents, and dipyridamole on human blood platelets. J Lab|5
02678|076|R|  Clin Med 1970 Jul;76(1):66-75.|5
02678|077|R|8.O'Reilly RA, Sahud MA, Aggeler PM. Impact of aspirin and chlorthalidone on|2
02678|078|R|  the pharmacodynamics of oral anticoagulant drugs in man. Ann N Y Acad Sci|2
02678|079|R|  1971 Jul 6;179:173-86.|2
02678|080|R|9.Dale J, Myhre E, Loew D. Bleeding during acetylsalicylic acid and|2
02678|081|R|  anticoagulant therapy in patients with reduced platelet reactivity after|2
02678|082|R|  aortic valve replacement. Am Heart J 1980 Jun;99(6):746-52.|2
02678|083|R|10.Donaldson DR, Sreeharan N, Crow MJ, Rajah SM. Assessment of the|2
02678|084|R|   interaction of warfarin with aspirin and dipyridamole. Thromb Haemost|2
02678|085|R|   1982 Feb 26;47(1):77.|2
02678|086|R|11.Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, Wallace|2
02678|087|R|   RB, Danielson GK, Orszulak TA, Piehler JM, Schaff HV. Trial of combined|2
02678|088|R|   warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve|2
02678|089|R|   replacement: danger of aspirin compared with dipyridamole. Am J Cardiol|2
02678|090|R|   1983 May 15;51(9):1537-41.|2
02678|091|R|12.Chow WH, Cheung KL, Ling HM, See T. Potentiation of warfarin|3
02678|092|R|   anticoagulation by topical methylsalicylate ointment. J R Soc Med 1989|3
02678|093|R|   Aug;82(8):501-2.|3
02678|094|R|13.Meade TW, Roderick PJ, Brennan PJ, Wilkes HC, Kelleher CC. Extra-cranial|2
02678|095|R|   bleeding and other symptoms due to low dose aspirin and low intensity|2
02678|096|R|   oral anticoagulation. Thromb Haemost 1992 Jul 6;68(1):1-6.|2
02678|097|R|14.Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral|6
02678|098|R|   anticoagulant therapy compared with oral anticoagulant therapy alone|6
02678|099|R|   among patients at risk for cardiovascular disease: a meta-analysis of|6
02678|100|R|   randomized trials. Arch Intern Med 2007 Jan 22;167(2):117-24.|6
02678|101|R|15.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
02678|102|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
02678|103|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
02678|104|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
02678|105|R|16.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
02678|106|R|   Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
02678|107|R|   interactions with warfarin: A systematic review and meta-analysis. Br J|6
02678|108|R|   Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
02679|001|T|MONOGRAPH TITLE:  Ketorolac (Non-Injectable)/Aspirin (Less Than or Equal To|
02679|002|T|300 mg)|
02679|003|B||
02679|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02679|005|L|of severe adverse interaction.|
02679|006|B||
02679|007|A|MECHANISM OF ACTION:  There are two potential mechanisms:|
02679|008|A|   1) Possible additive or synergistic pharmacodynamic side effects from|
02679|009|A|concurrent NSAID use.(1,2)|
02679|010|A|   2) Ketorolac is a reversible platelet inhibitor, while aspirin is an|
02679|011|A|irreversible platelet inhibitor.|
02679|012|B||
02679|013|E|CLINICAL EFFECTS:  Concurrent use of multiple doses of ketorolac with|
02679|014|E|aspirin may result in increased risk for NSAID-related side effects such as|
02679|015|E|bleeding.(1,2)  Nonselective NSAIDs such as ketorolac may interfere with the|
02679|016|E|antiplatelet effects of aspirin.(3)|
02679|017|B||
02679|018|P|PREDISPOSING FACTORS:  Bleeding risk may increase due to disease (e.g.|
02679|019|P|recent GI ulcer or bleed) or other concurrent drugs (e.g.anticoagulants,|
02679|020|P|heparinoids).|
02679|021|P|   Elderly patients are at increased risk for severe GI events from|
02679|022|P|ketorolac.(1,2)|
02679|023|P|   The risk for bleeding episodes may be greater in patients with|
02679|024|P|disease-associated factors (e.g. thrombocytopenia).|
02679|025|P|   Drug associated risk factors include concurrent use of multiple drugs|
02679|026|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02679|027|P|risk for bleeding (NSAIDs).|
02679|028|B||
02679|029|M|PATIENT MANAGEMENT:  The manufacturer of prescription extended-release|
02679|030|M|aspirin used for cardiovascular protection notes that concurrent treatment|
02679|031|M|with NSAIDs may interfere with the antiplatelet effect of aspirin and|
02679|032|M|increase the risk for NSAID associated bleeding or renal impairment, but|
02679|033|M|does not contraindicate concurrent use.(3)  However, manufacturers of|
02679|034|M|ketorolac state that concurrent use of ketorolac with  aspirin is|
02679|035|M|contraindicated.(1,2)|
02679|036|M|   If concurrent therapy or ketorolac with low dose aspirin is needed,|
02679|037|M|monitor patients receiving concurrent therapy for signs of blood loss,|
02679|038|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
02679|039|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02679|040|M|   Conduct periodic monitoring of renal function, especially in patients|
02679|041|M|with preexisting renal impairment.|
02679|042|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02679|043|M|unusual bruising; red or black, tarry stools; acute abdominal or joint pain|
02679|044|M|and/or swelling.|
02679|045|B||
02679|046|D|DISCUSSION:  Based upon similar pharmacodynamic effects and potentially|
02679|047|D|cumulative risks for serious NSAID-related adverse events, manufacturers of|
02679|048|D|ketorolac state the concurrent administration of ketorolac with other NSAIDs|
02679|049|D|or aspirin is contraindicated.(1,2)  Prescribing information for an FDA|
02679|050|D|approved lower strength prescription aspirin product used for cardiovascular|
02679|051|D|risk reduction describes potential interactions, but does not contraindicate|
02679|052|D|concomitant NSAID use.(3)|
02679|053|B||
02679|054|R|REFERENCES:|
02679|055|B||
02679|056|R|1.Toradol (ketorolac tromethamine) US prescribing information. Roche|1
02679|057|R|  Pharmaceuticals March, 2013.|1
02679|058|R|2.Ketorolac tromethamine oral tablets, US prescribing information. Mylan|1
02679|059|R|  Pharmaceuticals Inc. July, 2015.|1
02679|060|R|3.Durlaza (aspirin extended release) US prescribing information. New Haven|1
02679|061|R|  Pharmaceuticals, Inc. September, 2015.|1
02680|001|T|MONOGRAPH TITLE:  Ketorolac (Injectable)/Aspirin (Less Than or Equal To 300|
02680|002|T|mg)|
02680|003|B||
02680|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02680|005|L|of severe adverse interaction.|
02680|006|B||
02680|007|A|MECHANISM OF ACTION:  There are two potential mechanisms:|
02680|008|A|   1) Possible additive or synergistic pharmacodynamic side effects from|
02680|009|A|concurrent NSAID use.(1,2)|
02680|010|A|   2) Ketorolac is a reversible platelet inhibitor, while aspirin is an|
02680|011|A|irreversible platelet inhibitor.|
02680|012|B||
02680|013|E|CLINICAL EFFECTS:  Concurrent use of multiple doses of ketorolac with|
02680|014|E|aspirin may result in increased risk for NSAID-related side effects such as|
02680|015|E|bleeding.(1,2)  Nonselective NSAIDs such as ketorolac may interfere with the|
02680|016|E|antiplatelet effects of aspirin.(3)|
02680|017|B||
02680|018|P|PREDISPOSING FACTORS:  Bleeding risk may increase due to disease (e.g.|
02680|019|P|recent GI ulcer or bleed) or other concurrent drugs (e.g.anticoagulants,|
02680|020|P|heparinoids).|
02680|021|P|   Elderly patients are at increased risk for severe GI events from|
02680|022|P|ketorolac.(1,2)|
02680|023|P|   The risk for bleeding episodes may be greater in patients with|
02680|024|P|disease-associated factors (e.g. thrombocytopenia).|
02680|025|P|   Drug associated risk factors include concurrent use of multiple drugs|
02680|026|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02680|027|P|risk for bleeding (NSAIDs).|
02680|028|B||
02680|029|M|PATIENT MANAGEMENT:  The manufacturer of prescription extended-release|
02680|030|M|aspirin used for cardiovascular protection notes that concurrent treatment|
02680|031|M|with NSAIDs may interfere with the antiplatelet effect of aspirin and|
02680|032|M|increase the risk for NSAID associated bleeding or renal impairment, but|
02680|033|M|does not contraindicate concurrent use.(3)  However, manufacturers of|
02680|034|M|ketorolac state that concurrent use of ketorolac with  aspirin is|
02680|035|M|contraindicated.(1,2)|
02680|036|M|   If concurrent therapy or ketorolac with low dose aspirin is needed,|
02680|037|M|monitor patients receiving concurrent therapy for signs of blood loss,|
02680|038|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
02680|039|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02680|040|M|   Conduct periodic monitoring of renal function, especially in patients|
02680|041|M|with preexisting renal impairment.|
02680|042|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02680|043|M|unusual bruising; red or black, tarry stools; acute abdominal or joint pain|
02680|044|M|and/or swelling.|
02680|045|B||
02680|046|D|DISCUSSION:  Based upon similar pharmacodynamic effects and potentially|
02680|047|D|cumulative risks for serious NSAID-related adverse events, manufacturers of|
02680|048|D|ketorolac state the concurrent administration of ketorolac with other NSAIDs|
02680|049|D|or aspirin is contraindicated.(1,2)  Prescribing information for an FDA|
02680|050|D|approved lower strength prescription aspirin product used for cardiovascular|
02680|051|D|risk reduction describes potential interactions, but does not contraindicate|
02680|052|D|concomitant NSAID use.(3)|
02680|053|B||
02680|054|R|REFERENCES:|
02680|055|B||
02680|056|R|1.Toradol (ketorolac tromethamine) US prescribing information. Roche|1
02680|057|R|  Pharmaceuticals March, 2013.|1
02680|058|R|2.Ketorolac tromethamine oral tablets, US prescribing information. Mylan|1
02680|059|R|  Pharmaceuticals Inc. July, 2015.|1
02680|060|R|3.Durlaza (aspirin extended release) US prescribing information. New Haven|1
02680|061|R|  Pharmaceuticals, Inc. September, 2015.|1
02681|001|T|MONOGRAPH TITLE:  Rivaroxaban/Aspirin (Less Than or Equal To 100 mg)|
02681|002|B||
02681|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02681|004|L|take action as needed.|
02681|005|B||
02681|006|A|MECHANISM OF ACTION:  Additive effects on hemostasis.(1)|
02681|007|B||
02681|008|E|CLINICAL EFFECTS:  Concurrent use of rivaroxaban with antiplatelets may|
02681|009|E|increase the risk of bleeding.(1)|
02681|010|B||
02681|011|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02681|012|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02681|013|P|   Drug associated risk factors include concurrent use of multiple drugs|
02681|014|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02681|015|P|risk for bleeding (NSAIDs).|
02681|016|B||
02681|017|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
02681|018|M|of blood loss, including decreased hemoglobin, hematocrit, fecal occult|
02681|019|M|blood, and/or blood pressure and promptly evaluate patients with any|
02681|020|M|symptoms.  Discontinue rivaroxaban in patients with active pathological|
02681|021|M|bleeding.(2)|
02681|022|M|   The US manufacturer states concurrent use of rivaroxaban 2.5 mg and|
02681|023|M|aspirin 81 mg is an approved indication for the reduction of cardiovascular|
02681|024|M|events in patients with coronary artery disease (CAD) or peripheral artery|
02681|025|M|disease (PAD). Discontinue rivaroxaban in patients with active pathological|
02681|026|M|bleeding.|
02681|027|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02681|028|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02681|029|M|anticoagulation in patients with active pathologic bleeding.|
02681|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02681|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02681|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02681|033|M|and/or swelling.|
02681|034|B||
02681|035|D|DISCUSSION:  In the ROCKET AF trial, concomitant aspirin use (almost|
02681|036|D|exclusively at less than or equal to to 100 mg daily) was identified as an|
02681|037|D|independent risk factor for bleeding.(1-2)|
02681|038|D|   In a single dose study, there were no pharmacokinetic or pharmacodynamic|
02681|039|D|interactions between rivaroxaban and aspirin.(1)|
02681|040|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
02681|041|D|pairs were reviewed and found 14% of drug pairs were associated with a|
02681|042|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
02681|043|D|of rivaroxaban and aspirin resulted in a ratio of rate ratios (95% CI) of|
02681|044|D|2.19 (1.21-2.95).(3)|
02681|045|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
02681|046|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
02681|047|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
02681|048|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
02681|049|D|aspirin, with the highest allowable dose being 165 mg/day.  The use of DOACs|
02681|050|D|with antiplatelet agents was associated with an increased risk of major|
02681|051|D|bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major|
02681|052|D|bleeding (OR 1.82; 95% CI, 1.50-2.22).  There was no difference between|
02681|053|D|groups in the efficacy outcome of symptomatic recurrent venous|
02681|054|D|thromboembolism (VTE) or VTE-related death.(4)|
02681|055|D|   In the VOYAGER PAD trial, 6564 patiens were enrolled with peripheral|
02681|056|D|artery disease (PAD). Rivaroxaban 2.5 mg twice daily in combination with|
02681|057|D|aspirin 81 mg was found to reduce the total number of arterial and venous|
02681|058|D|events by 23% compared to aspirin 81 mg alone.  The combination increased|
02681|059|D|the risk of bleeding.  If 10,000 patients were treated, 181 cardiovascular|
02681|060|D|events would be prevented at a cost of 29 bleeding events, a 6:1 benefit to|
02681|061|D|risk ratio.(5)|
02681|062|D|   The COMPASS trial enrolled 27,395 patients with PAD or coronary artery|
02681|063|D|disease (CAD) to determine whether combined rivaroxaban and aspirin reduced|
02681|064|D|the risk of cardiovascular events more than aspirin alone.  The combination|
02681|065|D|of rivaroxaban 2.5 mg twice daily and aspirin 100 mg daily reduced mortality|
02681|066|D|by 18% compared to aspirin alone.(6)|
02681|067|D|   A secondary analysis of incidence and predictors of major|
02681|068|D|gastrointestinal (GI) bleeding in patients enrolled in the COMPASS trial|
02681|069|D|demonstrated that compared to the use of aspirin (100 mg daily) alone, use|
02681|070|D|of rivaroxaban (5 mg twice daily) significantly increased the odds of|
02681|071|D|overall GI bleeding (OR 1.44; 95% CI 1.05-1.99), and the use of the|
02681|072|D|combination of rivaroxaban (2.5 mg twice daily) and aspirin (100 mg daily)|
02681|073|D|further increased the odds (OR 2.17; 95% CI 1.61-2.93).(7)|
02681|074|B||
02681|075|R|REFERENCES:|
02681|076|B||
02681|077|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
02681|078|R|  Inc. March, 2020.|1
02681|079|R|2.Sherwood MW, Nessel CC, Hellkamp AS, Mahaffey KW, Piccini JP, Suh EY,|2
02681|080|R|  Becker RC, Singer DE, Halperin JL, Hankey GJ, Berkowitz SD, Fox KA, Patel|2
02681|081|R|  MR. Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated|2
02681|082|R|  With Rivaroxaban or Warfarin: ROCKET AF Trial. J Am Coll Cardiol 2015 Dec|2
02681|083|R|  1;66(21):2271-81.|2
02681|084|R|3.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
02681|085|R|  Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
02681|086|R|  Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
02681|087|R|  Pharmacol Ther 2020 Aug;108(2):377-386.|2
02681|088|R|4.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
02681|089|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
02681|090|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
02681|091|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
02681|092|R|5.Berkowitz SD, Bauersachs RM, Szarek M, Nehler MR, Debus ES. Prevention of|2
02681|093|R|  arterial and venous thrombotic events in symptomatic peripheral  arterial|2
02681|094|R|  disease patients after lower extremity revascularization in the VOYAGER|2
02681|095|R|  PAD trial: Dual anticoagulant/antiplatelet regimen vs antiplatelet therapy|2
02681|096|R|  alone. J Thromb Haemost 2022 May;20(5):1193-1205.|2
02681|097|R|6.Eikelboom JW, Bhatt DL, Fox KAA, Bosch J, Connolly SJ. Mortality Benefit|2
02681|098|R|  of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary  or|2
02681|099|R|  Peripheral Artery Disease. J Am Coll Cardiol 2021 Jul 6;78(1):14-23.|2
02681|100|R|7.Forbes N, Yi Q, Moayyedi P, Bosch J, Bhatt DL, Fox KAA, Eikelboom JW.|6
02681|101|R|  Incidence and predictors of major gastrointestinal bleeding in patients on|6
02681|102|R|  aspirin, low-dose rivaroxaban, or the combination: Secondary anaylsis of|6
02681|103|R|  the COMPASS randomised controlled trial. AP and T, Alimentary Pharmacology|6
02681|104|R|  and Therapeutics 27 August 2024;60(6):734 - 748.|6
02682|001|T|MONOGRAPH TITLE:  Talimogene|
02682|002|T|laherparepvec/Acyclovir;Valacyclovir;Famciclovir|
02682|003|B||
02682|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02682|005|L|of severe adverse interaction.|
02682|006|B||
02682|007|A|MECHANISM OF ACTION:  Talimogene laherparepvec is a live, attenuated herpes|
02682|008|A|simplex virus (HSV-1) which has been modified to express human GM-CSF.(1)|
02682|009|A|Acyclovir, famciclovir, and valacyclovir inhibit HSV virus activity.|
02682|010|B||
02682|011|E|CLINICAL EFFECTS:  Administration of antiherpetic agents may interfere with|
02682|012|E|the effectiveness of talimogene laherparepvec.(1)|
02682|013|E|   Agents linked to this monograph are systemic formulations of acyclovir,|
02682|014|E|valacyclovir and famciclovir.|
02682|015|B||
02682|016|P|PREDISPOSING FACTORS:  None determined.|
02682|017|B||
02682|018|M|PATIENT MANAGEMENT:  Avoid concomitant use when possible.|
02682|019|M|   Talimogene laherparepvec is a live, attenuated herpes simplex virus|
02682|020|M|(HSV-1) which is injected into cancerous lesions where it replicates and|
02682|021|M|produces GM-CSF, leading to lysis of tumors. It is sensitive to antiherpetic|
02682|022|M|agents such as acyclovir, valacyclovir and famciclovir and so administration|
02682|023|M|of these antivirals may impair talimogene laherparepvec effectiveness.(1)|
02682|024|B||
02682|025|D|DISCUSSION:  Acyclovir, famciclovir, valacyclovir inhibit herpes simplex|
02682|026|D|virus activity which may impair the ability of talimogene laherparepvec to|
02682|027|D|replicate and produce GM-CSF in tumors.  The impact of concurrent acyclovir,|
02682|028|D|famciclovir, valacyclovir and talimogene laherparepvec therapy has not been|
02682|029|D|studied; patients requiring antiviral prophylaxis or treatment with|
02682|030|D|acyclovir, valacyclovir and famciclovir were excluded from clinical|
02682|031|D|trials.(1)|
02682|032|B||
02682|033|R|REFERENCE:|
02682|034|B||
02682|035|R|1.Imlygic (talimogene laherparepvec) US prescribing information. Amgen Inc.|1
02682|036|R|  October 27, 2015.|1
02683|001|T|MONOGRAPH TITLE:  Tacrolimus/Schisandra chinensis|
02683|002|B||
02683|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02683|004|L|of severe adverse interaction.|
02683|005|B||
02683|006|A|MECHANISM OF ACTION:  Schisandra chinensis may inhibit the metabolism of|
02683|007|A|tacrolimus by CYP3A4 and P-glycoprotein inhibition.|
02683|008|B||
02683|009|E|CLINICAL EFFECTS:  Concurrent use of Schisandra chinensis may result in|
02683|010|E|increased levels of tacrolimus, including nephrotoxicity, neurotoxicity, and|
02683|011|E|prolongation of the QTc interval and life-threatening cardiac arrhythmias,|
02683|012|E|including torsades de pointes.|
02683|013|B||
02683|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02683|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02683|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02683|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02683|018|P|gender, or advanced age.(5)|
02683|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02683|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02683|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02683|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02683|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02683|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02683|025|P|dysfunction).(5)|
02683|026|B||
02683|027|M|PATIENT MANAGEMENT:  For patients concurrently taking tacrolimus and|
02683|028|M|Schisandra chinensis, therapeutic concentration monitoring of tacrolimus is|
02683|029|M|recommended.  Dose decreases of tacrolimus may be required.  The US|
02683|030|M|manufacturer of tacrolimus recommends that the dose of tacrolimus be reduced|
02683|031|M|and adjusted based on tacrolimus whole blood trough concentrations.|
02683|032|M|Coadministration with Schisandra chinensis may result in a rapid and sharp|
02683|033|M|rise in tacrolimus concentration despite immediate tacrolimus dose|
02683|034|M|reduction.  Frequent monitoring of tacrolimus levels should start within 1-3|
02683|035|M|days of initiation of concurrent therapy and continue as necessary.(1)|
02683|036|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
02683|037|M|monitoring ECG at baseline and at regular intervals.  Correct any|
02683|038|M|electrolyte abnormalities.  Instruct patients to report any irregular|
02683|039|M|heartbeat, dizziness, or fainting.|
02683|040|B||
02683|041|D|DISCUSSION:  In rats, coadministration of tacrolimus and Schisandra resulted|
02683|042|D|in a 128% increase in tacrolimus area-under-the-curve (AUC) (from 59.6 to|
02683|043|D|135.9 ng h/ml) and a 68% decrease in tacrolimus clearance.(2)|
02683|044|D|   In a 2-phase study, coadministration of low and high dose tacrolimus with|
02683|045|D|Schisandra resulted in an increase in tacrolimus AUC of 262% (low dose) and|
02683|046|D|339% (high dose). The average increase of tacrolimus maximum concentration|
02683|047|D|(Cmax) was 183%.(3)|
02683|048|D|   Coadministration of oral tacrolimus (2 mg) with Schisandra (three|
02683|049|D|capsules twice daily for 13 days) resulted in increases of tacrolimus AUC,|
02683|050|D|AUMC, and Cmax by 164.2%, 133.1%, and 227.1%, respectively. Tacrolimus|
02683|051|D|clearance was decreased on average 49%. (4)|
02683|052|B||
02683|053|R|REFERENCES:|
02683|054|B||
02683|055|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
02683|056|R|  August, 2023.|1
02683|057|R|2.Qin XL, Yu T, Li LJ, Wang Y, Gu HM, Wang YT, Huang M, Bi HC. Effect of|5
02683|058|R|  long-term co-administration of Wuzhi tablet (Schisandra sphenanthera|5
02683|059|R|  extract) and prednisone on the pharmacokinetics of tacrolimus.|5
02683|060|R|  Phytomedicine 2013 Feb 15;20(3-4):375-9.|5
02683|061|R|3.Jiang W, Wang X, Xu X, Kong L. Effect of Schisandra sphenanthera extract|2
02683|062|R|  on the concentration of tacrolimus in the blood of liver transplant|2
02683|063|R|  patients. Int J Clin Pharmacol Ther 2010 Mar;48(3):224-9.|2
02683|064|R|4.Xin HW, Wu XC, Li Q, Yu AR, Zhu M, Shen Y, Su D, Xiong L. Effects of|2
02683|065|R|  Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus  in|2
02683|066|R|  healthy volunteers. Br J Clin Pharmacol 2007 Oct;64(4):469-75.|2
02683|067|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02683|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02683|069|R|  settings: a scientific statement from the American Heart Association and|6
02683|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02683|071|R|  2;55(9):934-47.|6
02684|001|T|MONOGRAPH TITLE:  Elbasvir-Grazoprevir/Strong CYP3A4 Inducers|
02684|002|B||
02684|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02684|004|L|is contraindicated and generally should not be dispensed or administered to|
02684|005|L|the same patient.|
02684|006|B||
02684|007|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
02684|008|A|elbasvir and grazoprevir.(1,2)|
02684|009|B||
02684|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02684|011|E|in decreased levels and effectiveness of elbasvir and grazoprevir.(1,2)|
02684|012|B||
02684|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02684|014|P|of the inducer for longer than 1-2 weeks.|
02684|015|B||
02684|016|M|PATIENT MANAGEMENT:  Concurrent use of elbasvir-grazoprevir and strong|
02684|017|M|CYP3A4 inducers is contraindicated.(1,2)|
02684|018|M|   If concurrent use is deemed medically necessary, monitor the patient for|
02684|019|M|potential treatment failure and decreased elbasvir and grazoprevir levels.|
02684|020|B||
02684|021|D|DISCUSSION:  In single dose studies, rifampin increased levels of both|
02684|022|D|elbasvir and grazoprevir.  In a study in 14 subjects, rifampin (600 mg|
02684|023|D|single IV dose) increased the maximum concentration (Cmax), area-under-curve|
02684|024|D|(AUC), and minimum concentration (Cmin) of a single dose of elbasvir (50 mg)|
02684|025|D|by 41%, 22%, and 31%, respectively.  In a study in 14 subjects, rifampin|
02684|026|D|(600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose|
02684|027|D|of elbasvir (50 mg) by 29%, 17%, and 21%, respectively.  In a study in 12|
02684|028|D|subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin|
02684|029|D|of a single dose of grazoprevir (200 mg) by 10.94-fold, 10.21-fold, and|
02684|030|D|1.77-fold, respectively.  In a study in 12 subjects, rifampin (600 mg single|
02684|031|D|oral dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir|
02684|032|D|(200 mg) by 6.52-fold, 8.35-fold, and 1.61-fold, respectively.(1)|
02684|033|D|   However, multiple dose studies with rifampin showed decreased grazoprevir|
02684|034|D|levels.  In a study in 12 subjects, rifampin (600 mg orally) decreased the|
02684|035|D|AUC and Cmin of grazoprevir (200 mg daily) by 7% and 90%, respectively.|
02684|036|D|Cmax increased 16%.(1)|
02684|037|D|   In a study in 12 subjects, efavirenz (600 mg daily) decreased the Cmax,|
02684|038|D|AUC, and Cmin of elbasvir (50 mg daily) by 45%, 34%, and 59%,|
02684|039|D|respectively.(1)|
02684|040|D|   In a study in 12 subjects, efavirenz (600 mg daily) decreased the Cmax,|
02684|041|D|AUC, and Cmin of grazoprevir (200 mg daily) by 87%, 82%, and 69%,|
02684|042|D|respectively.(1)|
02684|043|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02684|044|D|carbamazepine, efavirenz, encorafenib, enzalutamide, fosphenytoin,|
02684|045|D|lumacaftor, mitotane, phenobarbital, primidone, phenytoin, and St. John's|
02684|046|D|wort.(1-4)|
02684|047|B||
02684|048|R|REFERENCES:|
02684|049|B||
02684|050|R|1.Zepatier (elbasvir-grazoprevir) US prescribing information. Merck & Co.,|1
02684|051|R|  Inc. December, 2019.|1
02684|052|R|2.Zepatier (elbasvir-grazoprevir) Canadian product monograph. Merck Canada|1
02684|053|R|  Inc. January 19, 2016.|1
02684|054|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02684|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02684|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02684|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02684|058|R|  11/14/2017.|1
02684|059|R|4.This information is based on an extract from the Certara Drug Interaction|6
02684|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02685|001|T|MONOGRAPH TITLE:  Elbasvir-Grazoprevir/OATP1B1-3 Inhibitors|
02685|002|B||
02685|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02685|004|L|is contraindicated and generally should not be dispensed or administered to|
02685|005|L|the same patient.|
02685|006|B||
02685|007|A|MECHANISM OF ACTION:  Inhibitors of OATP1B1/3 may decrease the hepatocyte|
02685|008|A|uptake and increase the plasma concentrations of elbasvir and|
02685|009|A|grazoprevir.(1-3)|
02685|010|B||
02685|011|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of OATP1B1/3 may result in|
02685|012|E|elevated levels of grazoprevir and an increased risk of ALT elevations.(1-3)|
02685|013|B||
02685|014|P|PREDISPOSING FACTORS:  None determined.|
02685|015|B||
02685|016|M|PATIENT MANAGEMENT:  Concurrent use of elbasvir-grazoprevir and OATP1B1/3|
02685|017|M|inhibitors is contraindicated.(1-2,4)|
02685|018|M|   If concurrent use is deemed medically necessary, monitor the patient for|
02685|019|M|toxicity and elevated AST levels.|
02685|020|B||
02685|021|D|DISCUSSION:  In a study in 10 subjects, atazanavir/ritonavir (300/100 mg|
02685|022|D|daily) increased the maximum concentration (Cmax), area-under-curve (AUC),|
02685|023|D|and minimum concentration (Cmin) of elbasvir (50 mg daily) by 4.15-fold,|
02685|024|D|4.76-fold, and 6.45-fold, respectively.  There were no clinically|
02685|025|D|significant effects on atazanavir levels.(1,2)|
02685|026|D|   In a study in 12 subjects, atazanavir/ritonavir (300/100 mg daily)|
02685|027|D|increased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by|
02685|028|D|6.24-fold, 10.58-fold, and 11.64-fold, respectively.  There were no|
02685|029|D|clinically significant effects on atazanavir levels.(1,2)|
02685|030|D|   In a study in 14 subjects, cyclosporine (400 mg single dose) increased|
02685|031|D|the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 1.95-fold, 1.98-fold,|
02685|032|D|and 2.21-fold, respectively.  The Cmax, AUC, and Cmin of grazoprevir (200 mg|
02685|033|D|daily) increased by 17-fold, 15.21-fold, and 3.39-fold, respectively.  There|
02685|034|D|were no clinically significant effects on cyclosporine levels.(1,2)|
02685|035|D|   In a study in 10 subjects, darunavir/ritonavir (600/100 mg twice daily)|
02685|036|D|increased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 1.67-fold,|
02685|037|D|1.66-fold, and 1.82-fold, respectively.  There were no clinically|
02685|038|D|significant effects on darunavir levels.(1,2)|
02685|039|D|   In a study in 13 subjects, darunavir/ritonavir (600/100 mg twice daily)|
02685|040|D|increased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by|
02685|041|D|5.27-fold, 7.50-fold, and 8.05-fold, respectively.  There were no clinically|
02685|042|D|significant effects on darunavir levels.(1,2)|
02685|043|D|   In a study in 10 subjects, lopinavir/ritonavir (400/100 mg twice daily)|
02685|044|D|increased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 2.87-fold,|
02685|045|D|3.71-fold, and 4.58-fold, respectively.  There were no clinically|
02685|046|D|significant effects on lopinavir levels.(1,2)|
02685|047|D|   In a study in 13 subjects, lopinavir/ritonavir (400/100 mg twice daily)|
02685|048|D|increased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by|
02685|049|D|7.31-fold, 12.86-fold, and 21.70-fold, respectively.  There were no|
02685|050|D|clinically significant effects on lopinavir levels.(1,2)|
02685|051|D|   In single dose studies, rifampin increased levels of both elbasvir and|
02685|052|D|grazoprevir.  In a study in 14 subjects, rifampin (600 mg single IV dose)|
02685|053|D|increased the Cmax, AUC, and Cmin of a single dose of elbasvir (50 mg) by|
02685|054|D|41%, 22%, and 31%, respectively.  In a study in 14 subjects, rifampin (600|
02685|055|D|mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose of|
02685|056|D|elbasvir (50 mg) by 29%, 17%, and 21%, respectively.  In a study in 12|
02685|057|D|subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin|
02685|058|D|of a single dose of grazoprevir (200 mg) by 10.94-fold, 10.21-fold, and|
02685|059|D|1.77-fold, respectively.  In a study in 12 subjects, rifampin (600 mg single|
02685|060|D|oral dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir|
02685|061|D|(200 mg) by 6.52-fold, 8.35-fold, and 1.61-fold, respectively.(1)|
02685|062|D|   OATP1B1/3 inhibitors include: atazanavir, belumosudil, cyclosporine,|
02685|063|D|darunavir, fostemsavir, leniolisib, letermovir, lopinavir,|
02685|064|D|nirmatrelvir/ritonavir, paritaprevir, resmetirom, roxadustat, saquinavir,|
02685|065|D|tipranavir, vadadustat, and voclosporin.(1-3)|
02685|066|B||
02685|067|R|REFERENCES:|
02685|068|B||
02685|069|R|1.Zepatier (elbasvir-grazoprevir) US prescribing information. Merck & Co.,|1
02685|070|R|  Inc. December, 2019.|1
02685|071|R|2.Zepatier (elbasvir-grazoprevir) Canadian product monograph. Merck Canada|1
02685|072|R|  Inc. January 19, 2016.|1
02685|073|R|3.Rukobia (fostemsavir) US prescribing information. ViiV Healthcare July,|1
02685|074|R|  2020.|1
02685|075|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
02685|076|R|  March, 2023.|1
02685|077|R|5.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
02685|078|R|  Squibb Company December, 2024.|1
02685|079|R|6.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
02685|080|R|  information. Pfizer Inc. February, 2025.|1
02686|001|T|MONOGRAPH TITLE:  Elbasvir-Grazoprevir/Rifampin|
02686|002|B||
02686|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02686|004|L|is contraindicated and generally should not be dispensed or administered to|
02686|005|L|the same patient.|
02686|006|B||
02686|007|A|MECHANISM OF ACTION:  Rifampin inhibits OATP1B3 transporters(1) and induces|
02686|008|A|CYP3A4.(2)|
02686|009|B||
02686|010|E|CLINICAL EFFECTS:  The addition of rifampin to a regimen containing|
02686|011|E|elbasvir-grazoprevir may initially result in elevated levels of grazoprevir|
02686|012|E|and toxicity, including elevated ALT levels.(1)  Continued use will result|
02686|013|E|in induction of elbasvir-grazoprevir metabolism, decreased levels of|
02686|014|E|elbasvir-grazoprevir, and loss of efficacy.(2)|
02686|015|E|   The addition of elbasvir-grazoprevir to a patient already receiving|
02686|016|E|rifampin or who has recently discontinued rifampin result in induction of|
02686|017|E|elbasvir-grazoprevir metabolism, decreased levels of elbasvir-grazoprevir,|
02686|018|E|and loss of efficacy.(2)|
02686|019|B||
02686|020|P|PREDISPOSING FACTORS:  None determined.|
02686|021|B||
02686|022|M|PATIENT MANAGEMENT:  Concurrent use of elbasvir-grazoprevir and rifampin is|
02686|023|M|contraindicated.(1,2)|
02686|024|M|   If concurrent use is deemed medically necessary and rifampin is being|
02686|025|M|added to elbasvir-grazoprevir therapy, initially monitor the patient for|
02686|026|M|toxicity and elevated ALT levels.  After several days, monitor for loss of|
02686|027|M|efficacy.|
02686|028|M|   If concurrent use is deemed medically necessary and elbasvir-grazoprevir|
02686|029|M|is being added to rifampin therapy (or if rifampin therapy recently ended),|
02686|030|M|monitor the patient for potential treatment failure and decreased elbasvir|
02686|031|M|and grazoprevir levels.(2)|
02686|032|B||
02686|033|D|DISCUSSION:  In single dose studies, rifampin increased levels of both|
02686|034|D|elbasvir and grazoprevir.  In a study in 14 subjects, rifampin (600 mg|
02686|035|D|single IV dose) increased the maximum concentration (Cmax), area-under-curve|
02686|036|D|(AUC), and minimum concentration (Cmin) of a single dose of elbasvir (50 mg)|
02686|037|D|by 41%, 22%, and 31%, respectively.  In a study in 14 subjects, rifampin|
02686|038|D|(600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose|
02686|039|D|of elbasvir (50 mg) by 29%, 17%, and 21%, respectively.  In a study in 12|
02686|040|D|subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin|
02686|041|D|of a single dose of grazoprevir (200 mg) by 10.94-fold, 10.21-fold, and|
02686|042|D|1.77-fold, respectively.  In a study in 12 subjects, rifampin (600 mg single|
02686|043|D|oral dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir|
02686|044|D|(200 mg) by 6.52-fold, 8.35-fold, and 1.61-fold, respectively.(1)|
02686|045|D|   However, multiple dose studies with rifampin showed decreased grazoprevir|
02686|046|D|levels.  In a study in 12 subjects, rifampin (600 mg orally) decreased the|
02686|047|D|AUC and Cmin of grazoprevir (200 mg daily) by 7% and 90%, respectively.|
02686|048|D|Cmax increased 16%.(1)|
02686|049|B||
02686|050|R|REFERENCES:|
02686|051|B||
02686|052|R|1.Zepatier (elbasvir-grazoprevir) Canadian product monograph. Merck Canada|1
02686|053|R|  Inc. January 19, 2016.|1
02686|054|R|2.Zepatier (elbasvir-grazoprevir) US prescribing information. Merck & Co.,|1
02686|055|R|  Inc. December, 2019.|1
02687|001|T|MONOGRAPH TITLE:  Atorvastatin (Greater Than 20 mg); Rosuvastatin (Greater|
02687|002|T|Than 10 mg)/Elbasvir-Grazoprevir|
02687|003|B||
02687|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02687|005|L|is contraindicated and generally should not be dispensed or administered to|
02687|006|L|the same patient.|
02687|007|B||
02687|008|A|MECHANISM OF ACTION:  Elbasvir-grazoprevir may inhibit intestinal BCRP,|
02687|009|A|resulting in increased absorption of atorvastatin and rosuvastatin.(1,2)|
02687|010|B||
02687|011|E|CLINICAL EFFECTS:  Concurrent use of elbasvir-grazoprevir may result in|
02687|012|E|elevated levels of and toxicity from atorvastatin and rosuvastatin,|
02687|013|E|including rhabdomyolysis.(1,2)|
02687|014|B||
02687|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02687|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02687|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02687|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02687|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02687|020|P|transporter OATP1B1 may have increased statin concentrations and be|
02687|021|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02687|022|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02687|023|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02687|024|B||
02687|025|M|PATIENT MANAGEMENT:  In patients requiring elbasvir-grazoprevir, do not use|
02687|026|M|more than 20 mg daily of atorvastatin or 10 mg daily of rosuvastatin.(1,2)|
02687|027|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
02687|028|M|should not exceed 5 mg daily when used with elbasvir-grazoprevir.(3)|
02687|029|M|   If concurrent use is deemed medically necessary, instruct patients to|
02687|030|M|report symptoms of muscle pain, tenderness, or weakness.|
02687|031|B||
02687|032|D|DISCUSSION:  In a study in 16 healthy subjects, elbasvir-grazoprevir (50-200|
02687|033|D|mg daily) increased the maximum concentration (Cmax) and area-under-curve|
02687|034|D|(AUC) of a single dose of atorvastatin (10 mg) by 4.34-fold and 1.94-fold,|
02687|035|D|respectively.  The minimum concentration (Cmin) of atorvastatin decreased by|
02687|036|D|81%.  There were no clinically significant effects on|
02687|037|D|elbasvir-grazoprevir.(1,2)|
02687|038|D|   In a study in 12 healthy subjects, elbasvir-grazoprevir (50-200 mg daily)|
02687|039|D|increased the Cmax and AUC of a single dose of rosuvastatin (10 mg) by|
02687|040|D|5.49-fold and 2.26-fold, respectively.  There were no clinically significant|
02687|041|D|effects on rosuvastatin Cmin or on elbasvir-grazoprevir.(1,2)|
02687|042|B||
02687|043|R|REFERENCES:|
02687|044|B||
02687|045|R|1.Zepatier (elbasvir-grazoprevir) Canadian product monograph. Merck Canada|1
02687|046|R|  Inc. January 19, 2016.|1
02687|047|R|2.Zepatier (elbasvir-grazoprevir) US prescribing information. Merck & Co.,|1
02687|048|R|  Inc. December, 2019.|1
02687|049|R|3.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
02687|050|R|  Australia Pty Ltd July 8, 2024.|1
02688|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 20 mg); Rosuvastatin|
02688|002|T|(Less Than or Equal To 10 mg)/Elbasvir-Grazoprevir|
02688|003|B||
02688|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02688|005|L|take action as needed.|
02688|006|B||
02688|007|A|MECHANISM OF ACTION:  Elbasvir-grazoprevir may inhibit intestinal BCRP,|
02688|008|A|resulting in increased absorption of atorvastatin and rosuvastatin.(1,2)|
02688|009|B||
02688|010|E|CLINICAL EFFECTS:  Concurrent use of elbasvir-grazoprevir may result in|
02688|011|E|elevated levels of and toxicity from atorvastatin and rosuvastatin,|
02688|012|E|including rhabdomyolysis.(1,2)|
02688|013|B||
02688|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02688|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02688|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02688|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02688|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02688|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02688|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02688|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02688|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02688|023|B||
02688|024|M|PATIENT MANAGEMENT:  In patients requiring elbasvir-grazoprevir, do not use|
02688|025|M|more than 20 mg daily of atorvastatin or 10 mg daily of rosuvastatin.(1,2)|
02688|026|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
02688|027|M|should not exceed 5 mg daily when used with elbasvir-grazoprevir.(3)|
02688|028|M|   Instruct patients to report symptoms of muscle pain, tenderness, or|
02688|029|M|weakness.|
02688|030|B||
02688|031|D|DISCUSSION:  In a study in 16 healthy subjects, elbasvir-grazoprevir (50-200|
02688|032|D|mg daily) increased the maximum concentration (Cmax) and area-under-curve|
02688|033|D|(AUC) of a single dose of atorvastatin (10 mg) by 4.34-fold and 1.94-fold,|
02688|034|D|respectively.  The minimum concentration (Cmin) of atorvastatin decreased by|
02688|035|D|81%.  There were no clinically significant effects on|
02688|036|D|elbasvir-grazoprevir.(1,2)|
02688|037|D|   In a study in 12 healthy subjects, elbasvir-grazoprevir (50-200 mg daily)|
02688|038|D|increased the Cmax and AUC of a single dose of rosuvastatin (10 mg) by|
02688|039|D|5.49-fold and 2.26-fold, respectively.  There were no clinically significant|
02688|040|D|effects on rosuvastatin Cmin or on elbasvir-grazoprevir.(1,2)|
02688|041|B||
02688|042|R|REFERENCES:|
02688|043|B||
02688|044|R|1.Zepatier (elbasvir-grazoprevir) Canadian product monograph. Merck Canada|1
02688|045|R|  Inc. January 19, 2016.|1
02688|046|R|2.Zepatier (elbasvir-grazoprevir) US prescribing information. Merck & Co.,|1
02688|047|R|  Inc. December, 2019.|1
02688|048|R|3.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
02688|049|R|  Australia Pty Ltd July 8, 2024.|1
02689|001|T|MONOGRAPH TITLE:  Sacubitril/ACE Inhibitors|
02689|002|B||
02689|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02689|004|L|is contraindicated and generally should not be dispensed or administered to|
02689|005|L|the same patient.|
02689|006|B||
02689|007|A|MECHANISM OF ACTION:  Sacubitril is a neprilysin inhibitor.  Overlapping|
02689|008|A|inhibition of Angiotensin Converting Enzyme (ACE) and neprilysin may|
02689|009|A|increase the risk of angioedema.(1,2)|
02689|010|B||
02689|011|E|CLINICAL EFFECTS:  Concurrent use may result in angioedema.(1-3)|
02689|012|B||
02689|013|P|PREDISPOSING FACTORS:  None determined.|
02689|014|B||
02689|015|M|PATIENT MANAGEMENT:  The concurrent use of sacubitril and an ACE inhibitor|
02689|016|M|is contraindicated.  Allow a 36 hour washout period when switching between|
02689|017|M|an ACE inhibitor and sacubitril.(1-3)|
02689|018|M|   Monitor patients for signs of angioedema (swelling of the face, lips,|
02689|019|M|tongue, and/or throat).(2)|
02689|020|B||
02689|021|D|DISCUSSION:  Higher incidence of angioedema was seen in clinical trials with|
02689|022|D|omapatrilat, a combined ACE and neprilysin inhibitor.  In the OCTAVE trial,|
02689|023|D|the incidence and severity of angioedema was worse with omapatrilat (2.2%)|
02689|024|D|than with enalapril (0.7%).(2)  For this reason, overlap of sacubitril, a|
02689|025|D|neprilysin inhibitor, with an ACE inhibitor is contraindicated and a 36 hour|
02689|026|D|washout period is recommended when switching agents.  The 36 hour window is|
02689|027|D|designed to cover at least three half-lives of all ACE inhibitors.(1)|
02689|028|B||
02689|029|R|REFERENCES:|
02689|030|B||
02689|031|R|1.FDA. CDER Application Number 207620Orig1s000 Entresto|1
02689|032|R|  (sacubitril/valsartan) Clinical Pharmacology and Biopharmaceutics|1
02689|033|R|  Review(s). available at:|1
02689|034|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620orig1s000app|1
02689|035|R|  rov.pdf August 14, 2015.|1
02689|036|R|2.FDA. CDER Application Number 207620Orig1s000 Entresto|1
02689|037|R|  (sacubitril/valsartan) Medical Review(s). available at:|1
02689|038|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620orig1s000med|1
02689|039|R|  r.pdf August 14, 2015.|1
02689|040|R|3.Entresto (sacubitril-valsartan) US prescribing information. Novartis|1
02689|041|R|  Pharmaceuticals Corporation February, 2021.|1
02690|001|T|MONOGRAPH TITLE:  Olanzapine/Ciprofloxacin|
02690|002|B||
02690|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02690|004|L|take action as needed.|
02690|005|B||
02690|006|A|MECHANISM OF ACTION:  Ciprofloxacin may inhibit the CYP1A2 mediated|
02690|007|A|metabolism of olanzapine.(1-6)|
02690|008|B||
02690|009|E|CLINICAL EFFECTS:  Concurrent use of ciprofloxacin may result in elevated|
02690|010|E|levels of and toxicity from olanzapine.|
02690|011|B||
02690|012|P|PREDISPOSING FACTORS:  Cytokines or other immune modulators secreted in|
02690|013|P|response to infection or inflammation may also inhibit CYP1A2, resulting in|
02690|014|P|additive suppression of CYP1A2 activity.(3-5)|
02690|015|B||
02690|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
02690|017|M|monitored for olanzapine side effects.  The dose of olanzapine may need to|
02690|018|M|be adjusted if ciprofloxacin is initiated or discontinued.|
02690|019|B||
02690|020|D|DISCUSSION:  In a study with fluvoxamine, another CYP1A2 inhibitor, 10 male|
02690|021|D|smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for|
02690|022|D|10 days) increased olanzapine area-under-curve (AUC), maximum concentration|
02690|023|D|(Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively.|
02690|024|D|Olanzapine volume of distribution and clearance were decreased by 4-26% and|
02690|025|D|26-38%, respectively.(6)|
02690|026|D|   In a study in 10 male smokers with schizophrenia, pretreatment with|
02690|027|D|fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve|
02690|028|D|(AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by|
02690|029|D|25-32%, respectively.  Olanzapine volume of distribution and clearance were|
02690|030|D|decreased by 4-26% and 26-38%, respectively.(1)|
02690|031|D|   In a study in 8 schizophrenic patients, the addition of fluvoxamine (100|
02690|032|D|mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from|
02690|033|D|12-112%.  N-desmethylolanzapine levels were not significantly affected.(7)|
02690|034|D|   In a retrospective review, 10 patients receiving concurrent fluvoxamine|
02690|035|D|and olanzapine were compared to 134 patients receiving olanzapine alone. The|
02690|036|D|ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients|
02690|037|D|receiving concurrent fluvoxamine.(8)|
02690|038|D|   Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and|
02690|039|D|by 52%, respectively, in female nonsmokers.  Fluvoxamine has been shown to|
02690|040|D|increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male|
02690|041|D|smokers.(9,10)|
02690|042|B||
02690|043|R|REFERENCES:|
02690|044|B||
02690|045|R|1.Chiu CC, Lane HY, Huang MC, Liu HC, Jann MW, Hon YY, Chang WH, Lu ML.|2
02690|046|R|  Dose-dependent alternations in the pharmacokinetics of olanzapine during|2
02690|047|R|  coadministration of fluvoxamine in patients with schizophrenia. J Clin|2
02690|048|R|  Pharmacol 2004 Dec;44(12):1385-90.|2
02690|049|R|2.Gandhi A, Moorthy B, Ghose R. Drug disposition in pathophysiological|6
02690|050|R|  conditions. Curr Drug Metab 2012 Nov;13(9):1327-44.|6
02690|051|R|3.Christensen H, Hermann M. Immunological response as a source to|6
02690|052|R|  variability in drug metabolism and transport. Front Pharmacol 2012;3:8.|6
02690|053|R|4.Morgan ET. Impact of infectious and inflammatory disease on cytochrome|6
02690|054|R|  P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther|6
02690|055|R|  2009 Apr;85(4):434-8.|6
02690|056|R|5.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
02690|057|R|  Corporation March, 2022.|1
02690|058|R|6.Ciproxin (ciprofloxacin hydrochloride) UK summary of product|1
02690|059|R|  characteristics. Bayer plc April 13, 2010.|1
02690|060|R|7.Hiemke C, Peled A, Jabarin M, Hadjez J, Weigmann H, Hartter S, Modai I,|2
02690|061|R|  Ritsner M, Silver H. Fluvoxamine augmentation of olanzapine in chronic|2
02690|062|R|  schizophrenia: pharmacokinetic interactions and clinical effects. J Clin|2
02690|063|R|  Psychopharmacol 2002 Oct;22(5):502-6.|2
02690|064|R|8.Weigmann H, Gerek S, Zeisig A, Muller M, Hartter S, Hiemke C. Fluvoxamine|2
02690|065|R|  but not sertraline inhibits the metabolism of olanzapine: evidence from a|2
02690|066|R|  therapeutic drug monitoring service. Ther Drug Monit 2001 Aug;23(4):410-3.|2
02690|067|R|9.Zyprexa (olanzapine) Australian prescribing information. Eli Lilly Pty Ltd|1
02690|068|R|  November 30, 2006.|1
02690|069|R|10.Zyprexa Relprevv (olanzapine ext-rel IM susp.) US prescribing|1
02690|070|R|   information. Eli Lilly and Company February, 2017.|1
02691|001|T|MONOGRAPH TITLE:  Selected HMG-CoA Reductase Inhibitors/Fenofibrate|
02691|002|B||
02691|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02691|004|L|take action as needed.|
02691|005|B||
02691|006|A|MECHANISM OF ACTION:  Unknown.|
02691|007|B||
02691|008|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
02691|009|E|and fibric acid derivatives has been associated with severe myopathy,|
02691|010|E|rhabdomyolysis and acute renal failure.|
02691|011|B||
02691|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02691|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02691|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02691|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02691|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02691|017|P|transporter OATP1B1 may have increased statin concentrations and be|
02691|018|P|predisposed to myopathy or rhabdomyolysis.  Patients on fluvastatin who are|
02691|019|P|CYP2C9 intermediate or poor metabolizers may have increased fluvastatin|
02691|020|P|concentrations and  risk of myopathy.  Patients on rosuvastatin with ABCG2|
02691|021|P|polymorphisms leading to decreased or poor BCRP transporter function may|
02691|022|P|have increased rosuvastatin concentrations and risk of myopathy.|
02691|023|B||
02691|024|M|PATIENT MANAGEMENT:  When possible, avoid administration of these drugs|
02691|025|M|concomitantly unless patients require aggressive therapy.  Instruct patients|
02691|026|M|to report any unexplained muscle pain, tenderness or weakness.  If muscular|
02691|027|M|symptoms develop, monitor serum creatine kinase levels and renal function.|
02691|028|M|One or both agents may need to be discontinued.|
02691|029|M|   The American College of Cardiology and American Heart Association|
02691|030|M|Guidelines state that fenofibrate may be considered concomitantly with a|
02691|031|M|low- or moderate-intensity statin only if the benefits from atherosclerotic|
02691|032|M|cardiovascular risk reduction or triglyceride lowering when triglycerides|
02691|033|M|are greater than or equal to 500 mg/dL are judged to outweigh the potential|
02691|034|M|risk for adverse effects.(20)|
02691|035|M|   The European Society of Cardiology and European Atherosclerosis Society|
02691|036|M|recommend concomitant statin-fenofibrate therapy in patients with|
02691|037|M|atherogenic combined dyslipidemia, especially patients with metabolic|
02691|038|M|syndrome and/or diabetes.(21)|
02691|039|M|   The US manufacturer of fenofibrate states that concurrent therapy with|
02691|040|M|HMG CO-A reductase inhibitors should be avoided unless the benefit of|
02691|041|M|further decreases in lipid levels is likely to outweigh the increased risk.|
02691|042|M|Fenofibrate may be preferred over gemfibrozil in patients who do require|
02691|043|M|concurrent statin and fibrate therapy.(9)|
02691|044|M|   The manufacturer of pravastatin states that concurrent therapy should be|
02691|045|M|avoided unless the benefits of combination therapy outweigh the risks.(6)|
02691|046|M|   The Canadian manufacturer of rosuvastatin states that concurrent therapy|
02691|047|M|with other fibrates should be approached with caution.  The Australian and|
02691|048|M|UK manufacturers of rosuvastatin state that rosuvastatin 40 mg is|
02691|049|M|contraindicated with concomitant use of fibrates.(27,28)  The risks of|
02691|050|M|concurrent use of fibrates should be carefully weighed against the benefits.|
02691|051|M|Patients taking a fibrate should start rosuvastatin therapy with the 5 mg|
02691|052|M|dose.  The US manufacturer of rosuvastatin states that the concurrent use of|
02691|053|M|fenofibrate should be carefully weighed against the benefits.  In patients|
02691|054|M|receiving concurrent fenofibrate, a dosage reduction of rosuvastatin should|
02691|055|M|be considered.(5)|
02691|056|M|   The manufacturer of simvastatin states that concurrent therapy with other|
02691|057|M|fibrates should be approached with caution.(7)|
02691|058|B||
02691|059|D|DISCUSSION:  Concurrent fenofibrate (160 mg daily) increased the AUC and|
02691|060|D|Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively.|
02691|061|D|   Concurrent fenofibrate (145 mg) with pravastatin (40 mg) increased|
02691|062|D|pravastatin Cmax and AUC by 36% (range from 69% decrease to 321% increase)|
02691|063|D|and 28% (range from 54% decrease to 128% increase), respectively, and the|
02691|064|D|3-alpha-hydroxy-iso-pravastatin Cmax and AUC by 55% (range from 32% decrease|
02691|065|D|to 314% increase) and by 39% (range from 24% decrease to 261% increase),|
02691|066|D|respectively.  A single dose of pravastatin had no effect on the kinetics of|
02691|067|D|fenofibrate.|
02691|068|D|   In a study in 24 healthy subjects, concurrent fenofibrate (160 mg daily)|
02691|069|D|increased the average AUC of pravastatin (40 mg daily) by 19-28%; however,|
02691|070|D|individual changes were variable and not statistically significant.|
02691|071|D|   Concurrent fenofibrate and rosuvastatin resulted in no significant|
02691|072|D|changes in rosuvastatin or fenofibrate levels; however, rhabdomyolysis has|
02691|073|D|been reported during concurrent therapy.|
02691|074|D|   Concurrent fenofibrate and simvastatin resulted in no significant changes|
02691|075|D|in simvastatin or fenofibrate levels; however, rhabdomyolysis has been|
02691|076|D|reported during concurrent therapy.  In a study in 29 patients, 4 patients|
02691|077|D|reported myalgia during concurrent simvastatin and fenofibrate, compared|
02691|078|D|with no reports during concurrent simvastatin and cholestyramine.|
02691|079|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
02691|080|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
02691|081|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
02691|082|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
02691|083|D|Veteran's Administration over a 2 year period, there were 149 reports of|
02691|084|D|rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil|
02691|085|D|and statin therapy compared with no reports in 1,830 patients receiving|
02691|086|D|concurrent fenofibrate and statin therapy.|
02691|087|D|   In a study in 66 healthy volunteers, concomitant administration of|
02691|088|D|fenofibrate (160 mg for 7 days) and atorvastatin (40 mg single dose) did not|
02691|089|D|result in a clinically significant change in the atorvastatin AUC.(22)|
02691|090|D|   A meta-analysis of 6 randomized controlled trials (including|
02691|091|D|approximately 1600 patients) found no cases of myopathy or rhabdomyolysis in|
02691|092|D|combination therapy of fenofibrate with simvastatin, fluvastatin, or|
02691|093|D|atorvastatin. A comparison of the incidence of creatine kinase greater than|
02691|094|D|5 times the ULN between combination statin-fenofibrate and statin|
02691|095|D|monotherapy was found to be not significant.(23)|
02691|096|D|   A meta-analysis of 13 randomized controlled trials (including|
02691|097|D|approximately 7000 patients) found no significant difference in the|
02691|098|D|incidence of elevated creatine kinase or muscle-associated adverse effects|
02691|099|D|between single-drug statin therapy or combination fenofibrate-statin|
02691|100|D|therapy.(24)|
02691|101|D|   The ACCORD trial showed that fenofibrate-simvastatin concomitant therapy|
02691|102|D|had similar rates as simvastatin alone for myopathy, myositis, or|
02691|103|D|rhabdomyolysis.(25)|
02691|104|D|   The ACCORD trial was a randomized trial of 5518 patients with type 2|
02691|105|D|diabetes receiving simvastatin (40 mg per day or less) and either|
02691|106|D|fenofibrate (initial dose of 160 mg per day, dose adjusted for renal|
02691|107|D|function) or placebo.  At the mean follow up of 4.7 years, the primary|
02691|108|D|efficacy endpoint of first occurrence of a major cardiovascular event,|
02691|109|D|including nonfatal myocardial infarction, nonfatal stroke, or death from|
02691|110|D|cardiovascular causes, occurred at an annual rate of 2.2% in the fenofibrate|
02691|111|D|group and 2.4 % in the placebo group (p=0.32).(26)|
02691|112|D|   Selected HMG-CoA reductase inhibitors linked to this monograph include:|
02691|113|D|fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and|
02691|114|D|simvastatin.|
02691|115|B||
02691|116|R|REFERENCES:|
02691|117|B||
02691|118|R|1.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
02691|119|R|  cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
02691|120|R|  polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
02691|121|R|2.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
02691|122|R|  Ltd. December, 2020.|1
02691|123|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02691|124|R|  February, 2014.|1
02691|125|R|4.McDonald KB, Garber BG, Perreault MM. Pancreatitis associated with|3
02691|126|R|  simvastatin plus fenofibrate. Ann Pharmacother 2002 Feb;36(2):275-9.|3
02691|127|R|5.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02691|128|R|  Pharmaceuticals LP July, 2024.|1
02691|129|R|6.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
02691|130|R|  Squibb Company May, 2022.|1
02691|131|R|7.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02691|132|R|  2023.|1
02691|133|R|8.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
02691|134|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
02691|135|R|9.Tricor (fenofibrate) US prescribing information. Abbott Laboratories June,|1
02691|136|R|  2021.|1
02691|137|R|10.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
02691|138|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
02691|139|R|   at:|3
02691|140|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
02691|141|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
02691|142|R|11.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
02691|143|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
02691|144|R|   95(1):120-2.|2
02691|145|R|12.Gustavson LE, Schweitzer SM, Koehne-Voss S, Achari R, Chira TO, Esslinger|2
02691|146|R|   HU, Yannicelli HD. The effects of multiple doses of fenofibrate on the|2
02691|147|R|   pharmacokinetics of pravastatin and its 3alpha-hydroxy isomeric|2
02691|148|R|   metabolite. J Clin Pharmacol 2005 Aug;45(8):947-53.|2
02691|149|R|13.Ireland JH, Eggert CH, Arendt CJ, Williams AW. Rhabdomyolysis with|2
02691|150|R|   cardiac involvement and acute renal failure in a patient taking|2
02691|151|R|   rosuvastatin and fenofibrate. Ann Intern Med 2005 Jun 7;142(11):949-50.|2
02691|152|R|14.Jacob SS, Jacob S, Williams C, Deeg MA. Simvastatin, fenofibrate, and|3
02691|153|R|   rhabdomyolysis. Diabetes Care 2005 May;28(5):1258.|3
02691|154|R|15.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
02691|155|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
02691|156|R|16.Bergman AJ, Murphy G, Burke J, Zhao JJ, Valesky R, Liu L, Lasseter KC, He|2
02691|157|R|   W, Prueksaritanont T, Qiu Y, Hartford A, Vega JM, Paolini JF. Simvastatin|2
02691|158|R|   does not have a clinically significant pharmacokinetic interaction with|2
02691|159|R|   fenofibrate in humans. J Clin Pharmacol 2004 Sep;44(9):1054-62.|2
02691|160|R|17.Martin PD, Dane AL, Schneck DW, Warwick MJ. An open-label, randomized,|2
02691|161|R|   three-way crossover trial of the effects of coadministration of|2
02691|162|R|   rosuvastatin and fenofibrate on the pharmacokinetic properties of|2
02691|163|R|   rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther|2
02691|164|R|   2003 Feb;25(2):459-71.|2
02691|165|R|18.Wierzbicki AS, Lumb PJ, Cheung J, Crook MA. Fenofibrate plus simvastatin|2
02691|166|R|   therapy versus simvastatin plus cholestyramine therapy for familial|2
02691|167|R|   hypercholesterolaemia. QJM 1997 Oct;90(10):631-4.|2
02691|168|R|19.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
02691|169|R|   America, Inc. November, 2022.|1
02691|170|R|20.Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on|6
02691|171|R|   the treatment of blood cholesterol to reduce atherosclerotic|6
02691|172|R|   cardiovascular risk in adults: a report of the American College of|6
02691|173|R|   Cardiology/American Heart Association Task Force on Practice Guidelines.|6
02691|174|R|   Circulation 2014 Jun 24;129(25 Suppl 2):S1-45.|6
02691|175|R|21.Reiner Z, Catapano AL, De Backer Get al. Guidelines for the management of|6
02691|176|R|   dyslipidaemias the Task Force for the management of dyslipidaemias of the|6
02691|177|R|   European Society of Cardiology and the  European Atherosclerosis Society.|6
02691|178|R|   Eur Heart J 2011 Jul;32(14):1769-818.|6
02691|179|R|22.Whitfield LR, Porcari AR, Alvey C, Abel R, Bullen W, Hartman D. Effect of|2
02691|180|R|   gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin. J|2
02691|181|R|   Clin Pharmacol 2011 Mar;51(3):378-88.|2
02691|182|R|23.Guo J, Meng F, Ma N, Li C, Ding Z, Wang H, Hou R, Qin Y. Meta-analysis of|6
02691|183|R|   safety of the coadministration of statin with fenofibrate in patients|6
02691|184|R|   with combined hyperlipidemia. Am J Cardiol 2012 Nov 1;110(9):1296-301.|6
02691|185|R|24.Geng Q, Ren J, Chen H, Lee C, Liang W. Adverse events following|6
02691|186|R|   statin-fenofibrate therapy versus statin alone: a meta-analysis of|6
02691|187|R|   randomized controlled trials. Clin Exp Pharmacol Physiol 2013 Mar;|6
02691|188|R|   40(3):219-26.|6
02691|189|R|25.Tonkin AM, Chen L. Effects of combination lipid therapy in the management|2
02691|190|R|   of patients with type 2 diabetes mellitus in the Action to Control|2
02691|191|R|   Cardiovascular Risk in Diabetes (ACCORD) trial. Circulation 2010 Aug 24;|2
02691|192|R|   122(8):850-2.|2
02691|193|R|26.Ginsberg HN, Elam MB, Lovato LC, Crouse JRetal. Effects of combination|2
02691|194|R|   lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010 Apr 29;|2
02691|195|R|   362(17):1563-74.|2
02691|196|R|27.Crestor (rosuvastatin) UK summary of product characteristics. AstraZeneca|1
02691|197|R|   UK Limited December 23, 2022.|1
02691|198|R|28.Crestor (rosuvastatin calcium) Australian Product Information. A.|1
02691|199|R|   Menarini Australia Pty Ltd July 8, 2024.|1
02692|001|T|MONOGRAPH TITLE:  Elbasvir-Grazoprevir/Moderate CYP3A4 Inducers|
02692|002|B||
02692|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02692|004|L|of severe adverse interaction.|
02692|005|B||
02692|006|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
02692|007|A|elbasvir and grazoprevir.(1,2)|
02692|008|B||
02692|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
02692|010|E|in decreased levels and effectiveness of elbasvir and grazoprevir.(1,2)|
02692|011|B||
02692|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02692|013|P|of the inducer for longer than 1-2 weeks.|
02692|014|B||
02692|015|M|PATIENT MANAGEMENT:  Concurrent use of elbasvir-grazoprevir and a moderate|
02692|016|M|CYP3A4 inducers is not recommended.(1,2)|
02692|017|M|   If concurrent use is required, monitor the patient for potential|
02692|018|M|treatment failure and decreased elbasvir and grazoprevir levels.|
02692|019|B||
02692|020|D|DISCUSSION:  In single dose studies, rifampin increased levels of both|
02692|021|D|elbasvir and grazoprevir.  In a study in 14 subjects, rifampin (600 mg|
02692|022|D|single IV dose) increased the maximum concentration (Cmax), area-under-curve|
02692|023|D|(AUC), and minimum concentration (Cmin) of a single dose of elbasvir (50 mg)|
02692|024|D|by 41%, 22%, and 31%, respectively.  In a study in 14 subjects, rifampin|
02692|025|D|(600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose|
02692|026|D|of elbasvir (50 mg) by 29%, 17%, and 21%, respectively.  In a study in 12|
02692|027|D|subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin|
02692|028|D|of a single dose of grazoprevir (200 mg) by 10.94-fold, 10.21-fold, and|
02692|029|D|1.77-fold, respectively.  In a study in 12 subjects, rifampin (600 mg single|
02692|030|D|oral dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir|
02692|031|D|(200 mg) by 6.52-fold, 8.35-fold, and 1.61-fold, respectively.(1)|
02692|032|D|   However, multiple dose studies with rifampin showed decreased grazoprevir|
02692|033|D|levels.  In a study in 12 subjects, rifampin (600 mg orally) decreased the|
02692|034|D|AUC and Cmin of grazoprevir (200 mg daily) by 7% and 90%, respectively.|
02692|035|D|Cmax increased 16%.(1)|
02692|036|D|   In a study in 12 subjects, efavirenz (600 mg daily) decreased the Cmax,|
02692|037|D|AUC, and Cmin of elbasvir (50 mg daily) by 45%, 34%, and 59%,|
02692|038|D|respectively.(1)|
02692|039|D|   In a study in 12 subjects, efavirenz (600 mg daily) decreased the Cmax,|
02692|040|D|AUC, and Cmin of grazoprevir (200 mg daily) by 87%, 82%, and 69%,|
02692|041|D|respectively.(1)|
02692|042|D|   Moderate inducers of CYP3A4 include belzutifan, bosentan, cenobamate,|
02692|043|D|dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib,|
02692|044|D|mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib,|
02692|045|D|repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and|
02692|046|D|tovorafenib.(1-4)|
02692|047|B||
02692|048|R|REFERENCES:|
02692|049|B||
02692|050|R|1.Zepatier (elbasvir-grazoprevir) US prescribing information. Merck & Co.,|1
02692|051|R|  Inc. December, 2019.|1
02692|052|R|2.Zepatier (elbasvir-grazoprevir) Canadian product monograph. Merck Canada|1
02692|053|R|  Inc. January 19, 2016.|1
02692|054|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02692|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02692|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02692|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02692|058|R|  11/14/2017.|1
02692|059|R|4.This information is based on an extract from the Certara Drug Interaction|6
02692|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02693|001|T|MONOGRAPH TITLE:  Zolpidem/Ciprofloxacin; Fluvoxamine|
02693|002|B||
02693|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02693|004|L|take action as needed.|
02693|005|B||
02693|006|A|MECHANISM OF ACTION:  Ciprofloxacin, a weak CYP3A4 inhibitor and a moderate|
02693|007|A|CYP1A2 inhibitor, may inhibit metabolism of zolpidem via these|
02693|008|A|pathways.(1,2)|
02693|009|A|   Fluvoxamine, a weak CYP3A4 inhibitor and a strong CYP1A2 inhibitor, may|
02693|010|A|inhibit metabolism of zolpidem via these pathways.(1,2)|
02693|011|B||
02693|012|E|CLINICAL EFFECTS:  Concurrent use of zolpidem with ciprofloxacin or|
02693|013|E|fluvoxamine may result in an increase in zolpidem systemic concentrations|
02693|014|E|and clinical effects, including profound sedation, respiratory depression,|
02693|015|E|coma, and/or death.|
02693|016|B||
02693|017|P|PREDISPOSING FACTORS:  Adult women clear zolpidem at lower rate than men|
02693|018|P|resulting in approximately 50% higher exposure compared with men taking the|
02693|019|P|same dose.(3)|
02693|020|P|   Elderly or debilitated patients are more likely to have impaired motor or|
02693|021|P|cognitive performance when treated with zolpidem.(3)|
02693|022|B||
02693|023|M|PATIENT MANAGEMENT:  Monitor for adverse effects or consider lowering the|
02693|024|M|zolpidem dose, particularly in elderly patients or adult women on higher|
02693|025|M|doses of zolpidem.(3)|
02693|026|M|   The US, UK, Australian, and Canadian manufacturers of ciprofloxacin state|
02693|027|M|the concurrent use of zolpidem with ciprofloxacin is not recommended.(4-7)|
02693|028|M|   The UK and Australian manufacturers of zolpidem state the concurrent use|
02693|029|M|of fluvoxamine is not recommended.(8,9)|
02693|030|M|   Patients should be counseled that concurrent use of ciprofloxacin or|
02693|031|M|fluvoxamine and zolpidem may result in an increase in side effects such as|
02693|032|M|confusion, amnesia, sleep-walking or sleep-driving behaviors, or daytime|
02693|033|M|drowsiness.|
02693|034|B||
02693|035|D|DISCUSSION:  An interaction study was conducted in 18 healthy, non-smoking|
02693|036|D|men. The pharmacokinetics of zolpidem 5 mg was evaluated before and after|
02693|037|D|ciprofloxacin 500 mg daily for 5 days.  Zolpidem half-life increased from|
02693|038|D|2.39 to 3.34 hours and exposure (area-under-curve, AUC) was increased by|
02693|039|D|46%.(10)|
02693|040|D|   An interaction study was conducted in healthy volunteers. The|
02693|041|D|pharmacokinetics of zolpidem 5 mg was evaluated before and after fluvoxamine|
02693|042|D|100 mg daily for 6 days.  Zolpidem half-life increased from  2.24 +/- 0.81|
02693|043|D|to 4.99 +/- 2.92 hours after pretreatment with fluvoxamine and zolpidem|
02693|044|D|exposure was increased by approximately 150%.(11)|
02693|045|B||
02693|046|R|REFERENCES:|
02693|047|B||
02693|048|R|1.Von Moltke LL, Greenblatt DJ, Granda BW, Duan SX, Grassi JM,|5
02693|049|R|  Venkatakrishnan K, Harmatz JS, Shader RI. Zolpidem metabolism in vitro:|5
02693|050|R|  responsible cytochromes, chemical inhibitors, and in vivo correlations. Br|5
02693|051|R|  J Clin Pharmacol 1999 Jul;48(1):89-97.|5
02693|052|R|2.This information is based on an extract from the Certara Drug Interaction|6
02693|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02693|054|R|3.Ambien CR (zolpidem tartrate) US prescribing information. Sanofi-Aventis|1
02693|055|R|  U.S. LLC August, 2019.|1
02693|056|R|4.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
02693|057|R|  Corporation March, 2022.|1
02693|058|R|5.Ciprofloxacin Australian prescribing information. Aspen Pharmacare Ltd 23|1
02693|059|R|  June 2022.|1
02693|060|R|6.Ciprofloxacin Canadian prescribing information. Teva Canada Limited March|1
02693|061|R|  23, 2022.|1
02693|062|R|7.Ciprofloxacin UK prescribing information. Quattro Pharma Limited 24|1
02693|063|R|  November 2023.|1
02693|064|R|8.Zolpidem Tartrate UK prescribing information. Zentiva October 2024.|1
02693|065|R|9.Zolpidem Australian prescribing information. Sandoz Pty Ltd October 2020.|1
02693|066|R|10.Vlase L, Popa A, Neag M, Muntean D, Leucuta SE. Pharmacokinetic|2
02693|067|R|   interaction between zolpidem and ciprofloxacin in healthy volunteers. Eur|2
02693|068|R|   J Drug Metab Pharmacokinet 2011 Jan;35(3-4):83-7.|2
02693|069|R|11.Vlase L, Popa A, Neag M, Muntean D, Achim M, Leucuta SE, . Effect of|2
02693|070|R|   fluvoxamine on the pharmokinetics of zolpidem: A two-treatment period|2
02693|071|R|   study in healthy volunteers. Clinical and Experimental Pharmacology and|2
02693|072|R|   Physiology January 2012;39(1):9-12.|2
02694|001|T|MONOGRAPH TITLE:  Bexarotene/Gemfibrozil|
02694|002|B||
02694|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02694|004|L|of severe adverse interaction.|
02694|005|B||
02694|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02694|007|B||
02694|008|E|CLINICAL EFFECTS:  Concurrent use of gemfibrozil may result in elevated|
02694|009|E|levels of and toxicity from bexarotene, including hypertriglyceridemia,|
02694|010|E|pancreatitis, liver problems, and neutropenia.(1)|
02694|011|B||
02694|012|P|PREDISPOSING FACTORS:  None determined.|
02694|013|B||
02694|014|M|PATIENT MANAGEMENT:  Avoid the concurrent use of bexarotene and|
02694|015|M|gemfibrozil.(1)  If concurrent use is warranted, monitor patients for signs|
02694|016|M|of toxicity, including hypertriglyceridemia, pancreatitis, liver problems,|
02694|017|M|and neutropenia.|
02694|018|B||
02694|019|D|DISCUSSION:  In a clinical trial of bexarotene in patients with cutaneous|
02694|020|D|T-cell lymphoma, a small subset of patients who also received gemfibrozil|
02694|021|D|experienced elevated bexarotene levels and toxicity.(1,2)|
02694|022|B||
02694|023|R|REFERENCES:|
02694|024|B||
02694|025|R|1.Targretin (bexarotene) Capsules US prescribing information. Valeant|1
02694|026|R|  Pharmaceuticals North America LLC July, 2015.|1
02694|027|R|2.Talpur R, Ward S, Apisarnthanarax N, Breuer-Mcham J, Duvic M. Optimizing|2
02694|028|R|  bexarotene therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 2002|2
02694|029|R|  Nov;47(5):672-84.|2
02695|001|T|MONOGRAPH TITLE:  Daclatasvir/Digoxin|
02695|002|B||
02695|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02695|004|L|take action as needed.|
02695|005|B||
02695|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but daclatasvir may|
02695|007|A|inhibit the transport of digoxin by p-glycoprotein.|
02695|008|B||
02695|009|E|CLINICAL EFFECTS:  Concurrent use of daclatasvir may result in increased|
02695|010|E|digoxin levels and signs of digoxin toxicity. Symptoms of digoxin toxicity|
02695|011|E|can include anorexia, nausea, vomiting, headache, fatigue, malaise,|
02695|012|E|drowsiness, generalized muscle weakness, disorientation, hallucinations,|
02695|013|E|visual disturbances, and arrhythmias.|
02695|014|B||
02695|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02695|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02695|017|P|risk of digoxin toxicity.|
02695|018|B||
02695|019|M|PATIENT MANAGEMENT:  Monitor digoxin levels in patients receiving concurrent|
02695|020|M|therapy with daclatasvir.  If patient is already receiving daclatasvir and|
02695|021|M|initiating digoxin, initiate treatment using the lowest appropriate digoxin|
02695|022|M|dosage and adjust digoxin doses as necessary. If the patient is already|
02695|023|M|receiving digoxin prior to initiating daclatasvir, reduce digoxin dosage by|
02695|024|M|approximately 15-30% or by modifying the dosing frequency.(1)|
02695|025|B||
02695|026|D|DISCUSSION:  In a study, concomitant administration of digoxin (0.125 mg|
02695|027|D|once daily) and daclatasvir (60 mg once daily) increased digoxin's minimum|
02695|028|D|concentration (Cmin) and area under the curve (AUC) by 65% and 27%.|
02695|029|B||
02695|030|R|REFERENCES:|
02695|031|B||
02695|032|R|1.Daklinza (daclatasvir dihydrochloride) UK summary of product|1
02695|033|R|  characteristics. Bristol-Myers Squibb Pharmaceutical Limited August 29,|1
02695|034|R|  2014.|1
02695|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02695|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02695|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02695|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02695|039|R|  11/14/2017.|1
02695|040|R|3.Daklinza (daclatasvir) US prescribing information. Bristol-Myers Squibb|1
02695|041|R|  October, 2019.|1
02696|001|T|MONOGRAPH TITLE:  Daclatasvir/Nevirapine|
02696|002|B||
02696|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02696|004|L|take action as needed.|
02696|005|B||
02696|006|A|MECHANISM OF ACTION:  Inducers of CYP3A4 (e.g. nevirapine) may induce the|
02696|007|A|metabolism of daclatasvir.(1)|
02696|008|B||
02696|009|E|CLINICAL EFFECTS:  Concurrent use of nevirapine without a dosage adjustment|
02696|010|E|of daclatasvir is expected to reduce levels and effectiveness of|
02696|011|E|daclatasvir.(1)|
02696|012|B||
02696|013|P|PREDISPOSING FACTORS:  None determined.|
02696|014|B||
02696|015|M|PATIENT MANAGEMENT:  The dose of daclatasvir should be increased to 90 mg|
02696|016|M|once daily in patients receiving nevirapine.(1)|
02696|017|B||
02696|018|D|DISCUSSION:  Inducers of CYP3A4 have been shown to decrease the the maximum|
02696|019|D|concentration (Cmax), area-under-curve (AUC), and minimum concentration|
02696|020|D|(Cmin) of daclatasvir.|
02696|021|D|   Efavirenz (600 mg daily) decreased the Cmax, AUC, and Cmin of daclatasvir|
02696|022|D|by 17%, 32%, and 59%, respectively.(1)|
02696|023|B||
02696|024|R|REFERENCES:|
02696|025|B||
02696|026|R|1.Daklinza (daclatasvir dihydrochloride) UK summary of product|1
02696|027|R|  characteristics. Bristol-Myers Squibb Pharmaceutical Limited August 29,|1
02696|028|R|  2014.|1
02696|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02696|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02696|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02696|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02696|033|R|  11/14/2017.|1
02696|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
02696|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02696|036|R|4.Daklinza (daclatasvir) US prescribing information. Bristol-Myers Squibb|1
02696|037|R|  October, 2019.|1
02697|001|T|MONOGRAPH TITLE:  Colchicine/Ombitasvir-Paritaprevir-Ritonavir (mono deleted|
02697|002|T|01/08/2020)|
02697|003|B||
02697|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02697|005|L|is contraindicated and generally should not be dispensed or administered to|
02697|006|L|the same patient.|
02697|007|B||
02697|008|A|MECHANISM OF ACTION:  Ombitasvir-Paritaprevir-Ritonavir may both inhibit and|
02697|009|A|induce the metabolism of colchicine. Colchicine is metabolized by|
02697|010|A|CYP3A4.(1,2)|
02697|011|B||
02697|012|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inhibitor may result in|
02697|013|E|elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
02697|014|E|toxicity include muscle weakness or pain; numbness or tingling in the|
02697|015|E|fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea|
02697|016|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
02697|017|E|color of the lips, tongue, or palms of hands.(1,2)|
02697|018|B||
02697|019|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
02697|020|P|patients with renal and/or hepatic impairment(1,2).|
02697|021|B||
02697|022|M|PATIENT MANAGEMENT:  The concurrent use of ombitasvir-paritaprevir-ritonavir|
02697|023|M|and colchicine is contraindicated.(4)|
02697|024|M|   Patients should be instructed to immediately report any signs of|
02697|025|M|colchicine toxicity.|
02697|026|B||
02697|027|D|DISCUSSION:  Colchicine toxicity has been reported with concurrent use of|
02697|028|D|CYP3A4 inhibitors such as clarithromycin, cyclosporine, diltiazem,|
02697|029|D|erythromycin, and verapamil.(1,2)|
02697|030|B||
02697|031|R|REFERENCES:|
02697|032|B||
02697|033|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
02697|034|R|  2011.|1
02697|035|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
02697|036|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
02697|037|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
02697|038|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
02697|039|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02697|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02697|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02697|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02697|043|R|  11/14/2017.|1
02697|044|R|4.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02697|045|R|  prescribing information. AbbVie Inc. December, 2019.|1
02698|001|T|MONOGRAPH TITLE:  Felodipine/Selected CYP3A4 Inhibitors|
02698|002|B||
02698|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02698|004|L|take action as needed.|
02698|005|B||
02698|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02698|007|A|felodipine by CYP3A4.(1)|
02698|008|B||
02698|009|E|CLINICAL EFFECTS:  The concurrent administration of strong CYP3A4 inhibitors|
02698|010|E|may result in elevated levels of felodipine leading to adverse effects,|
02698|011|E|including severe hypotension and peripheral edema.(1)|
02698|012|B||
02698|013|P|PREDISPOSING FACTORS:  None determined.|
02698|014|B||
02698|015|M|PATIENT MANAGEMENT:  The concurrent use of felodipine with strong CYP3A4|
02698|016|M|inhibitors should be approached with caution.(1)|
02698|017|M|   When these agents are used concurrently, the dose of felodipine may need|
02698|018|M|to be decreased and patients should be observed for increased effects.(1)|
02698|019|M|   If the strong CYP3A4 inhibitor is discontinued, the dose of felodipine|
02698|020|M|may need to be increased and patients should be observed for decreased|
02698|021|M|effects.(1)|
02698|022|B||
02698|023|D|DISCUSSION:  Concurrent use of an extended release formulation of felodipine|
02698|024|D|with itraconazole resulted in approximately 8-fold increase in the AUC, more|
02698|025|D|than 6-fold increase in the Cmax, and 2-fold prolongation in the half-life|
02698|026|D|of felodipine.(1)|
02698|027|D|   A double-blind, randomized, two-phase crossover study in nine subjects|
02698|028|D|examined the effects of itraconazole, a strong CYP3A4 inhibitor, on|
02698|029|D|felodipine.  The half-life of felodipine increased by 71% during concurrent|
02698|030|D|itraconazole.  In seven of the nine subjects, the maximum concentration|
02698|031|D|(Cmax) of felodipine when administered with placebo was lower than the|
02698|032|D|32-hour concentration of felodipine when administered with itraconazole.|
02698|033|D|Concurrent use also resulted in significantly greater effects on both blood|
02698|034|D|pressure and heart rate.(1,2)|
02698|035|D|   There are two case reports of patients developing edema following the|
02698|036|D|addition of itraconazole to felodipine therapy.(5)  In the second report,|
02698|037|D|the patient was rechallenged with concurrent itraconazole and again|
02698|038|D|developed edema.(3)|
02698|039|D|   Voriconazole has been shown to inhibit the metabolism of felodipine in|
02698|040|D|vitro.(4)|
02698|041|D|   Selected strong CYP3A4 inhibitors linked to this monograph are:|
02698|042|D|adagrasib, cobicistat, conivaptan, grapefruit, idelalisib, indinavir,|
02698|043|D|lopinavir, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,|
02698|044|D|ribociclib, ritonavir, saquinavir, troleandomycin, and tucatinib.(5)|
02698|045|B||
02698|046|R|REFERENCES:|
02698|047|B||
02698|048|R|1.Plendil (felodipine) US prescribing information. AstraZeneca|1
02698|049|R|  Pharmaceuticals LP November, 2003.|1
02698|050|R|2.Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma|2
02698|051|R|  concentrations and effects of felodipine. Clin Pharmacol Ther 1997 Apr;|2
02698|052|R|  61(4):410-5.|2
02698|053|R|3.Neuvonen PJ, Suhonen R. Itraconazole interacts with felodipine. J Am Acad|3
02698|054|R|  Dermatol 1995 Jul;33(1):134-5.|3
02698|055|R|4.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
02698|056|R|5.This information is based on an extract from the Certara Drug Interaction|6
02698|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02699|001|T|MONOGRAPH TITLE:  ACE Inhibitors/mTOR Inhibitors|
02699|002|B||
02699|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02699|004|L|of severe adverse interaction.|
02699|005|B||
02699|006|A|MECHANISM OF ACTION:  ACE inhibitors cause reduced bradykinin metabolism,|
02699|007|A|leading to an increase in bradykinin which can cause vasodilation.  mTOR|
02699|008|A|inhibitors may also cause a reduction in bradykinin metabolism.|
02699|009|B||
02699|010|E|CLINICAL EFFECTS:  Concomitant therapy can increase the risk of vasodilation|
02699|011|E|leading to an increase in angioedema risk.|
02699|012|B||
02699|013|P|PREDISPOSING FACTORS:  History of previous angioedema.|
02699|014|B||
02699|015|M|PATIENT MANAGEMENT:  Patients may be more susceptible to developing|
02699|016|M|angioedema if concomitantly taking an ACE inhibitor and mTOR inhibitor.|
02699|017|M|Consider switching the patient to an angiotensin receptor blocker.|
02699|018|M|   Monitor patients receiving concurrent therapy with ACE inhibitors and|
02699|019|M|mTOR inhibitors closely for signs and symptoms of angioedema (swollen skin,|
02699|020|M|hoarseness, a tight or swollen throat, or trouble breathing).  Instruct|
02699|021|M|patients to report angioedema symptoms immediately.|
02699|022|B||
02699|023|D|DISCUSSION:  A retrospective, single center analysis looked at renal|
02699|024|D|allograft recipients treated with mTOR inhibitors and ACE inhibitors over an|
02699|025|D|8 year-period.  Out of 137 patients on concomitant ACE inhibitor and mTOR|
02699|026|D|inhibitor therapy, 9 patients (6.6%) developed angioedema.  Concomitant ACE|
02699|027|D|inhibitor and mTOR inhibitor therapy increased the risk of developing|
02699|028|D|angioedema 3.7-fold.  Eight of these patients tolerated therapy with an|
02699|029|D|angiotensin receptor blocker (ARB). 2 patients (1.2%) on concomitant mTOR|
02699|030|D|inhibitor and ARB therapy developed angioedema.  Treatment with an ACE|
02699|031|D|inhibitor or mTOR inhibitor alone resulted in a significantly lower|
02699|032|D|incidence of angioedema.(1)|
02699|033|D|   In a pooled analysis of randomized double-blind oncology clinical trials,|
02699|034|D|the incidence of angioedema in patients taking everolimus with an ACE|
02699|035|D|inhibitor was 6.8% compared to 1.3% in the control arm with an ACE|
02699|036|D|inhibitor.(2)|
02699|037|D|   There are case reports of patients on concomitant ACE inhibitor and|
02699|038|D|sirolimus/everolimus that developed angioedema.  In the majority of cases,|
02699|039|D|patients had tolerated chronic therapy with an ACE inhibitor before the|
02699|040|D|addition of sirolimus/everolimus.(3-7)|
02699|041|D|   The interaction may be dose-dependent.(7)|
02699|042|B||
02699|043|R|REFERENCES:|
02699|044|B||
02699|045|R|1.Duerr M, Glander P, Diekmann F, Dragun D, Neumayer HH, Budde K. Increased|2
02699|046|R|  incidence of angioedema with ACE inhibitors in combination with mTOR|2
02699|047|R|  inhibitors in kidney transplant recipients. Clin J Am Soc Nephrol 2010|2
02699|048|R|  Apr;5(4):703-8.|2
02699|049|R|2.Afinitor (everolimus) US prescribing information. Novartaris|1
02699|050|R|  Pharmaceuticals Corporation February, 2020.|1
02699|051|R|3.Rothermundt C, Gillessen S. Angioedema in a patient with renal cell cancer|3
02699|052|R|  treated with everolimus in combination with an angiotensin-converting|3
02699|053|R|  enzyme inhibitor. J Clin Oncol 2013 Feb 10;31(5):e57-8.|3
02699|054|R|4.Jung M, Ranpura VN, Dunbar CE, Tisdale JF, Fitzhugh CD, Hsieh MM.|3
02699|055|R|  Angioedema in patients treated with sirolimus and ACE inhibitor post|3
02699|056|R|  hematopoietic SCT. Bone Marrow Transplant 2014 Nov;49(11):1448-9.|3
02699|057|R|5.Charmillon A, Deibener J, Kaminsky P, Louis G. Angioedema induced by|3
02699|058|R|  angiotensin converting enzyme inhibitors, potentiated by m-TOR inhibitors:|3
02699|059|R|  successful treatment with icatibant. Intensive Care Med 2014 Jun;|3
02699|060|R|  40(6):893-4.|3
02699|061|R|6.Burdese M, Rossetti M, Guarena C, Consiglio V, Mezza E, Soragna G, Gai M,|3
02699|062|R|  Segoloni GP, Piccoli GB. Sirolimus and ACE-inhibitors: a note of caution.|3
02699|063|R|  Transplantation 2005 Jan 27;79(2):251-2.|3
02699|064|R|7.Stallone G, Infante B, Di Paolo S, Schena A, Grandaliano G, Gesualdo L,|3
02699|065|R|  Schena FP. Sirolimus and angiotensin-converting enzyme inhibitors together|3
02699|066|R|  induce tongue oedema in renal transplant recipients. Nephrol Dial|3
02699|067|R|  Transplant 2004 Nov;19(11):2906-8.|3
02700|001|T|MONOGRAPH TITLE:  Artemether; Lumefantrine/Efavirenz|
02700|002|B||
02700|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02700|004|L|of severe adverse interaction.|
02700|005|B||
02700|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of artemether and|
02700|007|A|lumefantrine via CYP3A4.  Both artemether-lumefantrine and efavirenz can|
02700|008|A|prolong the QT interval and may result in additive risk of QT|
02700|009|A|prolongation.(1-3)|
02700|010|B||
02700|011|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inducers with artemether and|
02700|012|E|lumefantrine may result in decreased levels and effectiveness of the|
02700|013|E|antimalarial agents and treatment failure.  Concurrent use may also cause|
02700|014|E|additive effects on the QTc interval, which may result in life-threatening|
02700|015|E|cardiac arrhythmias including torsades de pointes.(1-3)|
02700|016|B||
02700|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02700|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
02700|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02700|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02700|021|P|female gender, or advanced age.(2)|
02700|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02700|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02700|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02700|025|P|drug concentrations include rapid infusion of an intravenous dose or|
02700|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02700|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02700|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02700|029|B||
02700|030|M|PATIENT MANAGEMENT:  The manufacturers of artemether-lumefantrine and|
02700|031|M|Atripla (efavirenz/tenofovir/emtricitabine) state that caution should be|
02700|032|M|used with concurrent use of artemether-lumefantrine because decreased|
02700|033|M|artemether, dihydroartemisinin, and lumefantrine concentrations may result|
02700|034|M|in decreased antimalarial efficacy of artemether-lumefantrine.(1,2)|
02700|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02700|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02700|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02700|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02700|039|B||
02700|040|D|DISCUSSION:  In a study in 6 subjects, administration of rifampin (600 mg|
02700|041|D|daily, a potent inducer of CYP3A4) with artemether-lumefantrine (6 dose|
02700|042|D|regimen over 3 days) decreased the area-under-curve (AUC) of artemether,|
02700|043|D|dihydroartemisinin (DHA), and lumefantrine by 89%, 85%, and 68%,|
02700|044|D|respectively.(1)|
02700|045|D|   In a study in 12 subjects, administration of efavirenz (600 mg daily for|
02700|046|D|26 days) with artemether-lumefantrine (6 dose regimen over 3 days) decreased|
02700|047|D|the AUC of artemether, dihydroartemisinin, and lumefantrine by 51%, 46%, and|
02700|048|D|21%, respectively.(2)|
02700|049|B||
02700|050|R|REFERENCES:|
02700|051|B||
02700|052|R|1.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
02700|053|R|  Pharmaceuticals Corporation August, 2019.|1
02700|054|R|2.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
02700|055|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
02700|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02700|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02700|058|R|  settings: a scientific statement from the American Heart Association and|6
02700|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02700|060|R|  2;55(9):934-47.|6
02701|001|T|MONOGRAPH TITLE:  Bromocriptine; Cabergoline/Selected CYP3A4 Inhibitors|
02701|002|B||
02701|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02701|004|L|take action as needed.|
02701|005|B||
02701|006|A|MECHANISM OF ACTION:  Certain azole antifungals (itraconazole(1,6),|
02701|007|A|ketoconazole(2), posaconazole(3,4), and voriconazole(5)), protease|
02701|008|A|inhibitors (amprenavir(7), atazanavir(8), boceprevir(9), darunavir(10),|
02701|009|A|fosamprenavir(11), indinavir(12), lopinavir(13), nelfinavir(14),|
02701|010|A|nirmatrelvir/ritonavir,(15) ritonavir(16), saquinavir(17), telaprevir(18),|
02701|011|A|and tipranavir(19)), and other strong CYP3A4 inhibitors (cobicistat,|
02701|012|A|idelalisib, levoketoconazole, mibefradil, nefazodone, and ribociclib(20))|
02701|013|A|may inhibit the metabolism of bromocriptine and cabergoline by CYP3A4.|
02701|014|B||
02701|015|E|CLINICAL EFFECTS:  Concurrent use of bromocriptine or cabergoline with azole|
02701|016|E|antifungals, protease inhibitors, or other strong CYP3A4 inhibitors may|
02701|017|E|result in increased levels of bromocriptine and cabergoline, which may|
02701|018|E|result in increased side effects of these agents.|
02701|019|B||
02701|020|P|PREDISPOSING FACTORS:  None determined.|
02701|021|B||
02701|022|M|PATIENT MANAGEMENT:  Use caution with concurrent therapy with bromocriptine|
02701|023|M|and cabergoline with azole antifungals, protease inhibitors, or other strong|
02701|024|M|CYP3A4 inhibitors.|
02701|025|B||
02701|026|D|DISCUSSION:  Itraconazole has been shown to increase cabergoline|
02701|027|D|concentrations with concurrent use.  A case report including 2 patients with|
02701|028|D|concurrent therapy of cabergoline and itraconazole noted plasma levels of|
02701|029|D|cabergoline to be increased by 300% in one of the patients. This increase in|
02701|030|D|cabergoline concentrations was noted to increase clinical improvement.(6)|
02701|031|D|   Posaconazole has been shown to inhibit the CYP3A4 mediated metabolism of|
02701|032|D|midazolam by 83%.(3)|
02701|033|D|   Voriconazole (400 mg every 12 hours for one day, then 200 mg every 12|
02701|034|D|hours for 8 days) increased the maximum concentration (Cmax) and|
02701|035|D|area-under-curve (AUC) of a single dose of sirolimus (2 mg) by 7-fold and|
02701|036|D|11-fold, respectively.  Ergot alkaloids are metabolized by the same|
02701|037|D|isoenzyme system.(5)|
02701|038|B||
02701|039|R|REFERENCES:|
02701|040|B||
02701|041|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02701|042|R|  Products, L.P. February, 2024.|1
02701|043|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
02701|044|R|  Pharmaceuticals February, 2014.|1
02701|045|R|3.Noxafil (posaconazole) UK summary of product characteristics.|1
02701|046|R|  Schering-Plough Ltd. January, 2022.|1
02701|047|R|4.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
02701|048|R|  January, 2022.|1
02701|049|R|5.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
02701|050|R|6.Christensen J, Dupont E, OStergaard K. Cabergoline plasma concentration is|3
02701|051|R|  increased during concomitant treatment with itraconazole. Mov Disord 2002|3
02701|052|R|  Nov;17(6):1360-2.|3
02701|053|R|7.Agenerase (amprenavir) Oral Solution US prescribing information.|1
02701|054|R|  GlaxoSmithKline May, 2005.|1
02701|055|R|8.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
02701|056|R|  Squibb Company December, 2024.|1
02701|057|R|9.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
02701|058|R|  January, 2017.|1
02701|059|R|10.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
02701|060|R|   March, 2023.|1
02701|061|R|11.Lexiva (fosamprenavir calcium) US prescribing information.|1
02701|062|R|   GlaxoSmithKline March, 2019.|1
02701|063|R|12.Crixivan (indinavir sulfate) US prescribing information. Merck & Co.,|1
02701|064|R|   Inc. September, 2016.|1
02701|065|R|13.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
02701|066|R|   Laboratories December, 2019.|1
02701|067|R|14.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
02701|068|R|   Pharmaceuticals, Inc. September, 2016.|1
02701|069|R|15.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
02701|070|R|   information. Pfizer Inc. February, 2025.|1
02701|071|R|16.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
02701|072|R|   December, 2019.|1
02701|073|R|17.Invirase (saquinavir mesylate) US prescribing information. Roche|1
02701|074|R|   Laboratories, Inc. March, 2019.|1
02701|075|R|18.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
02701|076|R|   Incorporated October, 2013.|1
02701|077|R|19.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
02701|078|R|   Pharmaceuticals, Inc. April, 2024.|1
02701|079|R|20.This information is based on an extract from the Certara Drug Interaction|6
02701|080|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02702|001|T|MONOGRAPH TITLE:  Colchicine/Tacrolimus|
02702|002|B||
02702|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02702|004|L|take action as needed.|
02702|005|B||
02702|006|A|MECHANISM OF ACTION:  Tacrolimus may inhibit the metabolism of colchicine|
02702|007|A|through inhibition of CYP3A4 metabolism.|
02702|008|B||
02702|009|E|CLINICAL EFFECTS:  Concurrent use of tacrolimus, a CYP3A4 inhibitor, may|
02702|010|E|result in elevated levels of and toxicity from colchicine.  Approximately|
02702|011|E|80% of colchicine is metabolized by CYP3A4.|
02702|012|E|   Symptoms of colchicine toxicity include abdominal pain; nausea or|
02702|013|E|vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in|
02702|014|E|the fingers or toes; myelosuppression; feeling weak or tired; increased|
02702|015|E|infections; and pale or gray color of the lips, tongue, or palms of|
02702|016|E|hands.(1-3)|
02702|017|B||
02702|018|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
02702|019|P|patients with renal and/or hepatic impairment(1,2) and in patients who|
02702|020|P|receive concurrent therapy.|
02702|021|B||
02702|022|M|PATIENT MANAGEMENT:  The concurrent use of colchicine and tacrolimus should|
02702|023|M|be approached with caution.(3)|
02702|024|M|   When concurrent therapy is required, consider following the manufacturer|
02702|025|M|recommendations for dose adjustments.  In patients without renal or hepatic|
02702|026|M|impairment who are currently taking or have taken strong CYP3A4 inhibitors|
02702|027|M|in the previous 14 days, the dosage of colchicine should be reduced.  For|
02702|028|M|gout flares, the recommended dosage is 0.6 mg (1 tablet) for one dose, then|
02702|029|M|0.3 mg (half tablet) 1 hour later.  This dose should be repeated no earlier|
02702|030|M|than in 3 days.  For gout prophylaxis, if the original dosage was 0.6 mg|
02702|031|M|twice daily, use 0.3 mg daily.  If the original dosage was 0.6 mg daily, use|
02702|032|M|0.3 mg every other day.  For Familial Mediterranean fever (FMF), the|
02702|033|M|recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg twice a|
02702|034|M|day).(1,2)|
02702|035|M|   Patients should be instructed to immediately report any signs of|
02702|036|M|colchicine toxicity, such as abdominal pain, nausea, severe|
02702|037|M|diarrhea/vomiting; muscle weakness/pain; numbness/tingling in fingers/toes;|
02702|038|M|unusual bleeding or bruising, infections, weakness/tiredness,  or pale/gray|
02702|039|M|color of the lips/tongue/palms of hands.|
02702|040|B||
02702|041|D|DISCUSSION:  In a study of 21 patients, treatment with tacrolimus (minimum|
02702|042|D|4-maximum 10 mg/daily; trough levels minimum 5-maximum 8 ng/ml) in 6 of the|
02702|043|D|kidney transplant recipients increased the maximum concentration (Cmax)|
02702|044|D|4-fold and area-under-curve (AUC) 3-fold after a single dose of colchicine|
02702|045|D|(1 mg) than those patients with normal renal function.(3)|
02702|046|D|   A case report of colchicine-induced myopathy describes a 62-year-old|
02702|047|D|patient on stable tacrolimus therapy for renal transplant immunosuppression|
02702|048|D|who was started on colchicine (0.6 mg twice daily).  A few days after|
02702|049|D|initiation of colchicine, the patient reported myopathy and labs showed a|
02702|050|D|4-fold increase in aspartate aminotransferase and elevated creatine|
02702|051|D|phosphokinase.(4)|
02702|052|B||
02702|053|R|REFERENCES:|
02702|054|B||
02702|055|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
02702|056|R|  2011.|1
02702|057|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
02702|058|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
02702|059|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
02702|060|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
02702|061|R|3.Amanova A, Kendi Celebi Z, Bakar F, Caglayan MG, Keven K. Colchicine|2
02702|062|R|  levels in chronic kidney diseases and kidney transplant recipients using|2
02702|063|R|  tacrolimus. Clin Transplant 2014 Oct;28(10):1177-83.|2
02702|064|R|4.Yousuf Bhat Z, Reddy S, Pillai U, Doshi M, Wilpula E. Colchicine-Induced|3
02702|065|R|  Myopathy in a Tacrolimus-Treated Renal Transplant Recipient: Case Report|3
02702|066|R|  and Literature Review. Am J Ther 2016 Mar-Apr;23(2):e614-6.|3
02703|001|T|MONOGRAPH TITLE:  Elvitegravir/Efavirenz; Nevirapine|
02703|002|B||
02703|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02703|004|L|is contraindicated and generally should not be dispensed or administered to|
02703|005|L|the same patient.|
02703|006|B||
02703|007|A|MECHANISM OF ACTION:  Efavirenz and nevirapine may induce the metabolism of|
02703|008|A|elvitegravir by CYP3A4.  Efavirenz may also decrease the absorption of|
02703|009|A|elvitegravir by P-glycoprotein (P-gp).(1,2)|
02703|010|B||
02703|011|E|CLINICAL EFFECTS:  Concurrent use of efavirenz or nevirapine may result in|
02703|012|E|altered and/or suboptimal pharmacokinetics of elvitegravir.(1)|
02703|013|B||
02703|014|P|PREDISPOSING FACTORS:  None determined.|
02703|015|B||
02703|016|M|PATIENT MANAGEMENT:  Elvitegravir should not be used with efavirenz or|
02703|017|M|nevirapine.(1)|
02703|018|B||
02703|019|D|DISCUSSION:  Concurrent use of elvitegravir with efavirenz or nevirapine may|
02703|020|D|result in altered and/or suboptimal pharmacokinetics of elvitegravir.(1,2)|
02703|021|B||
02703|022|R|REFERENCES:|
02703|023|B||
02703|024|R|1.Vitekta (elvitegravir) US prescribing information. Gilead Sciences Inc.|1
02703|025|R|  July, 2015.|1
02703|026|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02703|027|R|  for the use of antiretroviral agents in HIV-1-infected adults and|6
02703|028|R|  adolescents. Department of Health and Human Services. Available at|6
02703|029|R|  http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf|6
02703|030|R|  . Accessed March 31, 2016..|6
02704|001|T|MONOGRAPH TITLE:  Elvitegravir/Cobicistat Boosted Atazanavir & Darunavir|
02704|002|T|(mono deleted 04/11/2019)|
02704|003|B||
02704|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02704|005|L|is contraindicated and generally should not be dispensed or administered to|
02704|006|L|the same patient.|
02704|007|B||
02704|008|A|MECHANISM OF ACTION:  Cobicistat boosted atazanavir and darunavir may induce|
02704|009|A|the metabolism of elvitegravir.(1,2)|
02704|010|B||
02704|011|E|CLINICAL EFFECTS:  Concurrent use of cobicistat boosted atazanavir and|
02704|012|E|darunavir may result in altered and/or suboptimal pharmacokinetics of|
02704|013|E|elvitegravir.(1)|
02704|014|B||
02704|015|P|PREDISPOSING FACTORS:  None determined.|
02704|016|B||
02704|017|M|PATIENT MANAGEMENT:  Elvitegravir should not be used with cobicistat boosted|
02704|018|M|atazanavir and darunavir.(1)|
02704|019|B||
02704|020|D|DISCUSSION:  Concurrent use of elvitegravir with cobicistat boosted|
02704|021|D|atazanavir and darunavir may result in altered and/or suboptimal|
02704|022|D|pharmacokinetics of elvitegravir.(1,2)|
02704|023|B||
02704|024|R|REFERENCES:|
02704|025|B||
02704|026|R|1.Vitekta (elvitegravir) US prescribing information. Gilead Sciences Inc.|1
02704|027|R|  July, 2015.|1
02704|028|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02704|029|R|  for the use of antiretroviral agents in HIV-1-infected adults and|6
02704|030|R|  adolescents. Department of Health and Human Services. Available at|6
02704|031|R|  http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf|6
02704|032|R|  . Accessed March 31, 2016..|6
02705|001|T|MONOGRAPH TITLE:  Cobicistat-Boosted|
02705|002|T|Darunavir/Efavirenz;Etravirine;Nevirapine|
02705|003|B||
02705|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02705|005|L|of severe adverse interaction.|
02705|006|B||
02705|007|A|MECHANISM OF ACTION:  Efavirenz, etravirine, and nevirapine may induce the|
02705|008|A|metabolism of darunavir and cobicistat via CYP3A4.(1,2)|
02705|009|B||
02705|010|E|CLINICAL EFFECTS:  Concurrent use of efavirenz, etravirine, or nevirapine|
02705|011|E|may may result in altered and/or suboptimal pharmacokinetics of cobicistat,|
02705|012|E|resulting in subtherapeutic levels of darunavir.(1,2)|
02705|013|B||
02705|014|P|PREDISPOSING FACTORS:  None determined.|
02705|015|B||
02705|016|M|PATIENT MANAGEMENT:  Cobicistat boosted darunavir should not be|
02705|017|M|coadministered with efavirenz, etravirine, or nevirapine.(1,2)|
02705|018|M|   Note that there is no clinically significant interaction between|
02705|019|M|ritonavir-boosted darunavir and efavirenz, etravirine, or nevirapine, and no|
02705|020|M|dose adjustments are recommended.(2,3)|
02705|021|B||
02705|022|D|DISCUSSION:  Concurrent use of efavirenz, etravirine, or nevirapine with|
02705|023|D|cobicistat boosted darunavir may result in altered and/or suboptimal|
02705|024|D|pharmacokinetics of cobicistat(1,2)|
02705|025|D|   In a study of 30 HIV-positive patients, darunavir 800 mg once daily and|
02705|026|D|cobicistat 150 mg once daily administered with etravirine 400 mg once daily|
02705|027|D|resulted in no change to darunavir AUC and Cmax but a 56 % decrease in Cmin.|
02705|028|D|Cobicistat AUC, Cmax, and Cmin decreased 30 %, 14 % and 66 %,|
02705|029|D|respectively.(4)|
02705|030|B||
02705|031|R|REFERENCES:|
02705|032|B||
02705|033|R|1.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
02705|034|R|  Pharmaceuticals, Inc. March, 2025.|1
02705|035|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02705|036|R|  for the use of antiretroviral agents in HIV-1-infected adults and|6
02705|037|R|  adolescents. Department of Health and Human Services. Available at|6
02705|038|R|  http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf|6
02705|039|R|  . Accessed March 31, 2016..|6
02705|040|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
02705|041|R|  March, 2023.|1
02705|042|R|4.Molto J, Curran A, Miranda C, Challenger E, Santos JR, Ribera E, Khoo S,|2
02705|043|R|  Valle M, Clotet B. Pharmacokinetics of darunavir/cobicistat and etravirine|2
02705|044|R|  alone and co-administered in HIV-infected patients. J Antimicrob Chemother|2
02705|045|R|  2017 Dec 11.|2
02706|001|T|MONOGRAPH TITLE:  Lomitapide (Greater Than 30 mg)/Weak CYP3A4 Inhibitors|
02706|002|B||
02706|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02706|004|L|is contraindicated and generally should not be dispensed or administered to|
02706|005|L|the same patient.|
02706|006|B||
02706|007|A|MECHANISM OF ACTION:  Weak inhibitors of CYP3A4 may inhibit the metabolism|
02706|008|A|of lomitapide.(1)|
02706|009|A|   Lomitapide is very susceptible to CYP3A4 inhibition.  For example, in an|
02706|010|A|interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide|
02706|011|A|exposure was increased 27-fold.(2)  Thus even weak CYP3A4 inhibitors may|
02706|012|A|affect lomitapide exposure (AUC, area-under-curve).|
02706|013|B||
02706|014|E|CLINICAL EFFECTS:  Concurrent use of a weak inhibitor of CYP3A4 may result|
02706|015|E|in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)|
02706|016|B||
02706|017|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
02706|018|P|hepatic impairment or with end-stage renal disease.(1)|
02706|019|B||
02706|020|M|PATIENT MANAGEMENT:  The maximum lomitapide dose should be 30 mg daily for|
02706|021|M|patients taking concomitant weak CYP3A4 inhibitors.  Due to lomitapide's|
02706|022|M|long half-life, it may take 1 to 2 weeks to see the full effect of this|
02706|023|M|interaction.|
02706|024|M|   When initiating a weak CYP3A4 inhibitor in patients taking lomitapide 10|
02706|025|M|mg daily or more, decrease the dose of lomitapide by 50%.  In patients|
02706|026|M|taking lomitapide 5 mg daily, continue current dose.|
02706|027|B||
02706|028|D|DISCUSSION:  Lomitapide is very susceptible to CYP3A4 inhibition.  For|
02706|029|D|example, in an interaction study with a strong CYP3A4 inhibitor|
02706|030|D|(ketoconazole) lomitapide exposure was increased 27-fold.(2)  Based upon|
02706|031|D|interactions with stronger inhibitors, weak inhibitors of CYP3A4 are|
02706|032|D|predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1)|
02706|033|D|   Weak CYP3A4 inhibitors linked to this interaction include alprazolam,|
02706|034|D|amiodarone, amlodipine, anamorelin, asciminib, atorvastatin, azithromycin,|
02706|035|D|Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab,|
02706|036|D|cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin,|
02706|037|D|chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant,|
02706|038|D|delavirdine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant,|
02706|039|D|fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir,|
02706|040|D|goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine,|
02706|041|D|lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine,|
02706|042|D|linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat,|
02706|043|D|palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol,|
02706|044|D|ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib,|
02706|045|D|selpercatinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan,|
02706|046|D|trofinetide, viloxazine, vonoprazan, ziftomenib, and zileuton.(1-3)|
02706|047|B||
02706|048|R|REFERENCES:|
02706|049|B||
02706|050|R|1.Juxtapid (lomitapide) US prescribing information. Aegerion|1
02706|051|R|  Pharmaceuticals, Inc. May, 2016.|1
02706|052|R|2.This information is based on an extract from the Certara Drug Interaction|6
02706|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02706|054|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02706|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02706|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02706|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02706|058|R|  11/14/2017.|1
02707|001|T|MONOGRAPH TITLE:  Lomitapide (Less Than or Equal To 40 mg)/Hormonal|
02707|002|T|Contraceptives|
02707|003|B||
02707|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02707|005|L|of severe adverse interaction.|
02707|006|B||
02707|007|A|MECHANISM OF ACTION:  Hormonal contraceptives are weak inhibitors of CYP3A4|
02707|008|A|and may inhibit the metabolism of lomitapide.(1)|
02707|009|A|   Lomitapide is very susceptible to CYP3A4 inhibition.  For example, in an|
02707|010|A|interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide|
02707|011|A|exposure was increased 27-fold.(2)  Thus even weak CYP3A4 inhibitors may|
02707|012|A|affect lomitapide exposure (AUC, area-under-curve).|
02707|013|B||
02707|014|E|CLINICAL EFFECTS:  Concurrent use of a weak inhibitor of CYP3A4 may result|
02707|015|E|in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)|
02707|016|B||
02707|017|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
02707|018|P|hepatic impairment or with end-stage renal disease.(1)|
02707|019|B||
02707|020|M|PATIENT MANAGEMENT:  The maximum lomitapide dose should be 40 mg daily for|
02707|021|M|patients taking hormonal contraceptives.  Due to lomitapide's long|
02707|022|M|half-life, it may take 1 to 2 weeks to see the full effect of this|
02707|023|M|interaction.|
02707|024|M|   When initiating a hormonal contraceptive in patients taking lomitapide 10|
02707|025|M|mg daily or more, decrease the dose of lomitapide by 50%.  In patients|
02707|026|M|taking lomitapide 5 mg daily, continue current dose.|
02707|027|B||
02707|028|D|DISCUSSION:  Lomitapide is very susceptible to CYP3A4 inhibition.  For|
02707|029|D|example, in an interaction study with a strong CYP3A4 inhibitor|
02707|030|D|(ketoconazole) lomitapide exposure was increased 27-fold.(2)  Based upon|
02707|031|D|interactions with stronger inhibitors, weak inhibitors of CYP3A4 are|
02707|032|D|predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1)|
02707|033|B||
02707|034|R|REFERENCE:|
02707|035|B||
02707|036|R|1.Juxtapid (lomitapide) US prescribing information. Aegerion|1
02707|037|R|  Pharmaceuticals, Inc. May, 2016.|1
02708|001|T|MONOGRAPH TITLE:  Tofacitinib/Strong CYP3A4 Inducers|
02708|002|B||
02708|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02708|004|L|of severe adverse interaction.|
02708|005|B||
02708|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02708|007|A|tofacitinib.(1)|
02708|008|B||
02708|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02708|010|E|in decreased levels and effectiveness of tofacitinib(1)|
02708|011|B||
02708|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02708|013|P|of the inducer for longer than 1-2 weeks.|
02708|014|B||
02708|015|M|PATIENT MANAGEMENT:  The US manufacturer of tofacitinib states that the|
02708|016|M|concurrent use of CYP3A4 inducers is not recommended and may result in loss|
02708|017|M|of or reduced clinical response of tofacitinib(1)|
02708|018|B||
02708|019|D|DISCUSSION:  A study of 12 subjects received tofacitinib (30 mg) with|
02708|020|D|concurrent rifampin (600 mg daily), a strong inducer of CYP3A4, with a|
02708|021|D|decreased tofacitinib area-under-curve (AUC) by 84% and maximum|
02708|022|D|concentration (Cmax) by 74%.(4)|
02708|023|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
02708|024|D|carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane,|
02708|025|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
02708|026|D|wort.(1-3)|
02708|027|B||
02708|028|R|REFERENCES:|
02708|029|B||
02708|030|R|1.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. October,|1
02708|031|R|  2025.|1
02708|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02708|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02708|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02708|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02708|036|R|  11/14/2017.|1
02708|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
02708|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02708|039|R|4.Pfizer Medical Information Department. Personal Communications:|1
02708|040|R|  Xeljanz/Xeljanz XR. Pfizer Medical Information March 31, 2016.|1
02709|001|T|MONOGRAPH TITLE:  Selected Nephrotoxic Agents/Foscarnet|
02709|002|B||
02709|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02709|004|L|of severe adverse interaction.|
02709|005|B||
02709|006|A|MECHANISM OF ACTION:  Foscarnet is nephrotoxic.  Concurrent administration|
02709|007|A|of other nephrotoxic agents may result in additive or synergistic effects on|
02709|008|A|renal function.(1)|
02709|009|A|   Concurrent intravenous pentamidine may also result in hypocalcemia.(1)|
02709|010|B||
02709|011|E|CLINICAL EFFECTS:  Concurrent use of foscarnet with nephrotoxic agents such|
02709|012|E|as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B,|
02709|013|E|cyclosporine, methotrexate, non-steroidal anti-inflammatory agents,|
02709|014|E|intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin|
02709|015|E|may result in renal toxicity.(1)  Other nephrotoxic agents include|
02709|016|E|capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and|
02709|017|E|streptozocin.|
02709|018|B||
02709|019|P|PREDISPOSING FACTORS:  None determined.|
02709|020|B||
02709|021|M|PATIENT MANAGEMENT:  The US manufacturer of foscarnet state that concurrent|
02709|022|M|administration of potentially nephrotoxic agents such as acyclovir,|
02709|023|M|intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate,|
02709|024|M|tacrolimus, and intravenous pentamidine should be avoided.(1)  Other|
02709|025|M|nephrotoxic agents include adefovir, capreomycin, cisplatin, gallium|
02709|026|M|nitrate, high-dose methotrexate, non-steroidal anti-inflammatory agents,|
02709|027|M|streptozocin, tenofovir, vancomycin and voclosporin.|
02709|028|M|   If concurrent therapy is warranted, monitor renal function closely.  In|
02709|029|M|patients receiving concurrent foscarnet and pentamidine, also monitor serum|
02709|030|M|calcium levels and instruct patients to report severe muscle spasms,|
02709|031|M|mental/mood changes, and/or seizures.(1)|
02709|032|B||
02709|033|D|DISCUSSION:  The safety of foscarnet has not been studied in patients|
02709|034|D|receiving other known potentially nephrotoxic agents.  Renal impairment is|
02709|035|D|the major toxicity of foscarnet.(1)|
02709|036|B||
02709|037|R|REFERENCE:|
02709|038|B||
02709|039|R|1.Foscavir (foscarnet sodium) US prescribing information. Clinigen|1
02709|040|R|  Healthcare Limited February 24, 2017.|1
02711|001|T|MONOGRAPH TITLE:  Dexamethasone/Lenalidomide; Thalidomide|
02711|002|B||
02711|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02711|004|L|take action as needed.|
02711|005|B||
02711|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.|
02711|007|B||
02711|008|E|CLINICAL EFFECTS:  Concurrent use of dexamethasone with lenalidomide or|
02711|009|E|thalidomide may increase the risk of venous thromboembolism (VTE), ischemic|
02711|010|E|heart disease including myocardial infarction, and stroke.(1,2)|
02711|011|B||
02711|012|P|PREDISPOSING FACTORS:  The effects of the interaction are greater with|
02711|013|P|high-dose dexamethasone (480 mg/month or more).(3)  Erythropoietic agents|
02711|014|P|may also increase the risk.(1,2)|
02711|015|B||
02711|016|M|PATIENT MANAGEMENT:  The US manufacturer of lenalidomide states the risk of|
02711|017|M|deep vein thrombosis (DVT) and pulmonary embolism (PE) is significantly|
02711|018|M|increased when lenalidomide and dexamethasone are given concurrently in|
02711|019|M|patients with multiple myeloma and recommends thromboprophylaxis and the|
02711|020|M|regimen should be selected based on the patient's underlying risks.  Observe|
02711|021|M|patients for signs and symptoms of venous thromboembolism (VTE) and instruct|
02711|022|M|patients to see medical care if they develop symptoms such as shortness of|
02711|023|M|breath, chest pain, or arm or leg swelling.(1)|
02711|024|M|   The US manufacturer of thalidomide states the risk of VTE increases|
02711|025|M|significantly when thalidomide is used with concurrent therapy with standard|
02711|026|M|chemotherapeutic agents including dexamethasone therapy and recommends|
02711|027|M|considering thromboprophylaxis based on an assessment of individual|
02711|028|M|patients' underlying risk factors.  Observe patients closely for signs and|
02711|029|M|symptoms of VTE and instruct patients to see medical care if they develop|
02711|030|M|symptoms such as shortness of breath, chest pain, or arm or leg swelling.(2)|
02711|031|M|   The National Comprehensive Cancer Network (NCCN) Guidelines recommend VTE|
02711|032|M|chemoprophylaxis with low-molecular weight heparin (LMWH) with a dose|
02711|033|M|equivalent to enoxaparin 40 mg once daily or full-dose warfarin with a dose|
02711|034|M|to maintain a target international normalized ratio (INR) 2-3.(3)|
02711|035|B||
02711|036|D|DISCUSSION:  The National Comprehensive Cancer Network (NCCN) Guidelines|
02711|037|D|include lenalidomide/thalidomide plus high-dose dexamethasone as a|
02711|038|D|treatment-related venous thromboembolism (VTE) risk factor for cancer|
02711|039|D|patients.  High-dose dexamethasone is defined by NCCN as >/= 480 mg per|
02711|040|D|month.  The NCCN Guidelines recommend VTE chemoprophylaxis with|
02711|041|D|low-molecular weight heparin (LMWH) at a dose equivalent to enoxaparin 40 mg|
02711|042|D|once daily or full-dose warfarin with a dose to maintain a target|
02711|043|D|international normalized ratio (INR) 2-3.(3)|
02711|044|D|   The US manufacturer states the standard dosing for multiple myeloma|
02711|045|D|includes lenalidomide (25 mg daily) on days 1-21 of the 28-day cycle and|
02711|046|D|dexamethasone (40 mg daily) on days 1, 8, 15, and 22 of the 28-day cycle.(1)|
02711|047|D|The dexamethasone dose is adjusted for patients >75 years old to 20 mg|
02711|048|D|daily on days 1, 8, 15, and 22 of the 28-day cycle.(1)|
02711|049|D|   In 2 studies of 703 patients who received at least one dose of|
02711|050|D|lenalidomide/dexamethasone or placebo/dexamethasone, the incidence of DVT|
02711|051|D|was 9.3% and 4.3%, respectively.  In the same population, the incidence of|
02711|052|D|grade 3/4 adverse reactions the incidence of DVT was 8.2% and 3.4%,|
02711|053|D|respectively, and the incidence of serious adverse reactions of DVT was 7.4%|
02711|054|D|and 3.1%, respectively.|
02711|055|D|   The US manufacturer states the standard dosing for multiple myeloma|
02711|056|D|includes combination therapy with thalidomide (200 mg daily) and|
02711|057|D|dexamethasone (40 mg daily on days 1-4, 9-12, and 17-20) in a 28-day|
02711|058|D|treatment cycle.(2)|
02711|059|D|   The overall rate of adverse reactions in clinical trials for multiple|
02711|060|D|myeloma resulting in treatment discontinuation were 30% in the|
02711|061|D|thalidomide/dexamethasone group and 16% in the dexamethasone monotherapy|
02711|062|D|group.(2)|
02711|063|D|   In a safety study of 466 subjects, the incidence of DVT was higher in the|
02711|064|D|thalidomide/dexamethasone arm than in the placebo/dexamethasone arm with 13%|
02711|065|D|versus 2%, respectively.(2)|
02711|066|D|   In a safety study of Grade 3/4 adverse drug reactions, the|
02711|067|D|thalidomide/dexamethasone arm had a 12% incidence of DVT compared to a 2%|
02711|068|D|incidence in the placebo/dexamethasone arm.(2)|
02711|069|D|   A summary article discusses the incidence of VTE in patients receiving|
02711|070|D|treatment for multiple myeloma.  The use of thalidomide as a single agent|
02711|071|D|does not significantly increase the risk of VTE in both new diagnoses and|
02711|072|D|relapsed/refractory patients with a VTE incidence of 3-4% and 2-4%,|
02711|073|D|respectively.  The addition of dexamethasone to thalidomide increased the|
02711|074|D|risk of VTE in newly diagnosed patients with an incidence of 14-26%.|
02711|075|D|Similarly, the use of lenalidomide as a single agent does not increase the|
02711|076|D|risk of VTE.  Lenalidomide with dexamethasone increased the incidence of VTE|
02711|077|D|in newly diagnosed patients as well as relapsed/refractory patients to 75%|
02711|078|D|and 17%, respectively.  Concurrent therapy with lenalidomide and|
02711|079|D|dexamethasone showed a difference in the incidence of VTE based on the|
02711|080|D|dexamethasone dose (high dose defined as 480 mg/month and low dose defined|
02711|081|D|as 160 mg/month) with higher doses associated with an increase risk (26%|
02711|082|D|versus 12% incidence, respectively).  The incidence of VTE in studies with|
02711|083|D|thalidomide alone range from 1.5-4.6% versus studies with|
02711|084|D|thalidomide/dexamethasone at 7-26%.(4)|
02711|085|D|   Several studies have evaluated the optimal VTE prophylaxis agent with|
02711|086|D|lenalidomide-treated patients.  Patients receiving|
02711|087|D|lenalidomide/dexamethasone and no chemoprophylaxis had a VTE incidence of|
02711|088|D|11-75%, 26% with the use of aspirin, 17% with the use of|
02711|089|D|aspirin/LMWH/warfarin combination therapy, and 2-15% with the use of LMWH.|
02711|090|D|(5)|
02711|091|D|   Several studies have evaluated the optimal VTE prophylaxis agent in|
02711|092|D|thalidomide-treated patients.  Patients receiving thalidomide/dexamethasone|
02711|093|D|and no chemoprophylaxis had a VTE incidence of 26%, 10% with the use of|
02711|094|D|low-dose warfarin and 0% with the use of therapeutic warfarin/LMWH.(5)|
02711|095|D|   Lenalidomide/dexamethasone compared to placebo/dexamethasone increased|
02711|096|D|the rate of myocardial infarction (1.7% versus 0.6%, respectively) and|
02711|097|D|stroke (2.3% versus 0.9%, respectively).(1)|
02711|098|D|   Thalidomide/dexamethasone compared to placebo/dexamethasone increased the|
02711|099|D|rate of ischemic heart disease (11.1% versus 4.7%, respectively), including|
02711|100|D|myocardial infarction (1.3% versus 1.7%, respectively), and stroke (2.6%|
02711|101|D|versus 0.9%, respectively).(2)|
02711|102|B||
02711|103|R|REFERENCES:|
02711|104|B||
02711|105|R|1.Revlimid (lenalidomide) US prescribing information. Celgene Corporation|1
02711|106|R|  May 2019.|1
02711|107|R|2.Thalomid (thalidomide) US prescribing information. Celgene Corporation|1
02711|108|R|  December, 2017.|1
02711|109|R|3.Streiff M, Holmstrom B, Ashrani Aetal. Cancer-associated venous|6
02711|110|R|  thromboembolic disease.  NCCN Clinical Practice Guidelines in Oncology.|6
02711|111|R|  Available at www.nccn.org/professionals/physician_gls/f_guidelines.asp|6
02711|112|R|  January, 2015.|6
02711|113|R|4.Zamagni E, Brioli A, Tacchetti P, Zannetti B, Pantani L, Cavo M. Multiple|6
02711|114|R|  myeloma, venous thromboembolism, and treatment-related risk of thrombosis.|6
02711|115|R|  Semin Thromb Hemost 2011 Apr;37(3):209-19.|6
02711|116|R|5.Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J,|6
02711|117|R|  Barlogie B, Harousseau J, Zonder JA, Cavo M, Zangari M, Attal M, Belch A,|6
02711|118|R|  Knop S, etal. Prevention of thalidomide- and lenalidomide-associated|6
02711|119|R|  thrombosis in myeloma. Leukemia 2008 Feb;22(2):414-23.|6
02712|001|T|MONOGRAPH TITLE:  Selected Direct-Acting Sympathomimetics/Tricyclic|
02712|002|T|Compounds|
02712|003|B||
02712|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02712|005|L|of severe adverse interaction.|
02712|006|B||
02712|007|A|MECHANISM OF ACTION:  Unknown. However, it is speculated that direct-acting|
02712|008|A|sympathomimetic amines have an enhanced effect due to tricyclic blockage of|
02712|009|A|norepinephrine reuptake.|
02712|010|B||
02712|011|E|CLINICAL EFFECTS:  Increased effect of direct acting sympathomimetics.|
02712|012|B||
02712|013|P|PREDISPOSING FACTORS:  None determined.|
02712|014|B||
02712|015|M|PATIENT MANAGEMENT:  Consider avoiding the concurrent use of direct-acting|
02712|016|M|sympathomimetics and tricyclic compounds.  If concurrent use of|
02712|017|M|direct-acting sympathomimetics and tricyclic compounds is warranted, the|
02712|018|M|initial dose of the sympathomimetic should be lowered and the patient should|
02712|019|M|be monitored for adverse cardiovascular effects.  Use of tricyclic compounds|
02712|020|M|and other sympathomimetics should be approached with caution.|
02712|021|B||
02712|022|D|DISCUSSION:  Epinephrine and other direct-acting sympathomimetic amines|
02712|023|D|exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and|
02712|024|D|tachycardia) in individuals concurrently receiving or previously treated|
02712|025|D|with tricyclic antidepressants.|
02712|026|D|   Other direct and mixed acting sympathomimetic amines have also been|
02712|027|D|reported to interact with tricyclic antidepressants.  These include|
02712|028|D|norepinephrine, phenylephrine, dopamine, and methoxamine.  Protriptyline,|
02712|029|D|amitriptyline, and desipramine have also been reported to interact with|
02712|030|D|direct-acting sympathomimetics.|
02712|031|B||
02712|032|R|REFERENCES:|
02712|033|B||
02712|034|R|1.Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN.|2
02712|035|R|  Interactions between sympathomimetic amines and antidepressant agents in|2
02712|036|R|  man. Br Med J 1973 Feb 10;1(5849):311-5.|2
02712|037|R|2.Ghose K. Sympathomimetic amines and tricyclic antidepressant drugs.|2
02712|038|R|  Neuropharmacology 1980 Dec;19(12):1251-4.|2
02712|039|R|3.Svedmyr N. The influence of a tricyclic antidepressive agent|2
02712|040|R|  (protriptyline) on some of the circulatory effects of noradrenaline and|2
02712|041|R|  adrenaline in man. Life Sci 1968 Jan 1;7(1):77-84.|2
02712|042|R|4.Bonaccorsi A, Garattini S. Effect of desipramine on directly or indirectly|5
02712|043|R|  elicited catecholamine pressor responses in rats. J Pharm Pharmacol 1966|5
02712|044|R|  Jul;18(7):443-8.|5
02712|045|R|5.Cairncross KD. On the peripheral pharmacology of amitriptyline. Arch Int|5
02712|046|R|  Pharmacodyn Ther 1965 Apr;154(2):438-48.|5
02712|047|R|6.Ghose K, Gifford LA, Turner P, Leighton M. Studies of the interaction of|2
02712|048|R|  desmethylimipramine with tyramine in man after a single oral dose, and its|2
02712|049|R|  correlation with plasma concentration. Br J Clin Pharmacol 1976 Apr;|2
02712|050|R|  3(2):334-7.|2
02712|051|R|7.Jefferson JW. A review of the cardiovascular effects and toxicity of|6
02712|052|R|  tricyclic antidepressants. Psychosom Med 1975 Mar-Apr;37(2):160-79.|6
02712|053|R|8.Ragheb M. Drug interactions in psychiatric practice. Int|6
02712|054|R|  Pharmacopsychiatry 1981;16(2):92-118.|6
02712|055|R|9.Risch SC, Groom GP, Janowsky DS. Interfaces of psychopharmacology and|6
02712|056|R|  cardiology--part one. J Clin Psychiatry 1981 Jan;42(1):23-34.|6
02712|057|R|10.Maxwell RA, Keenan PD, Chaplin E, Roth B, Eckhardt SB. Molecular features|5
02712|058|R|   affecting the potency of tricyclic antidepressants and structurally|5
02712|059|R|   related compounds as inhibitors of the uptake of tritiated norepinephrine|5
02712|060|R|   by rabbit aortic strips. J Pharmacol Exp Ther 1969 Apr;166(2):320-9.|5
02713|001|T|MONOGRAPH TITLE:  Select Mixed Acting Sympathomimetics/Tricyclic Compounds|
02713|002|B||
02713|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02713|004|L|of severe adverse interaction.|
02713|005|B||
02713|006|A|MECHANISM OF ACTION:  Unknown. However, it is speculated that mixed acting|
02713|007|A|sympathomimetics will show effects based on the predominance of either|
02713|008|A|direct or indirect activity.|
02713|009|A|  Agents with predominate effects of direct-acting sympathomimetic amines|
02713|010|A|are expected to have an enhanced effect due to tricyclic blockage of|
02713|011|A|norepinephrine reuptake. Agents with predominate effects of indirect-acting|
02713|012|A|sympathomimetics would have decreased activity due to tricyclic blockage of|
02713|013|A|their uptake into the adrenergic neuron.|
02713|014|B||
02713|015|E|CLINICAL EFFECTS:  Mixed acting sympathomimetics will show effects based on|
02713|016|E|the predominance of either direct or indirect activity.|
02713|017|B||
02713|018|P|PREDISPOSING FACTORS:  None determined.|
02713|019|B||
02713|020|M|PATIENT MANAGEMENT:  Consider avoiding the concurrent use of mixed-acting|
02713|021|M|sympathomimetics and tricyclic compounds.  If concurrent is warranted, the|
02713|022|M|initial dose of the sympathomimetic should be lowered and the patient should|
02713|023|M|be monitored for adverse cardiovascular effects.|
02713|024|B||
02713|025|D|DISCUSSION:  Epinephrine and other direct-acting sympathomimetic amines|
02713|026|D|exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and|
02713|027|D|tachycardia) in individuals concurrently receiving or previously treated|
02713|028|D|with tricyclic antidepressants.  Other direct and mixed acting|
02713|029|D|sympathomimetic amines have also been reported to interact with tricyclic|
02713|030|D|antidepressants.  These include norepinephrine, phenylephrine, dopamine, and|
02713|031|D|methoxamine.  The pressor effects of the indirect-acting sympathomimetic|
02713|032|D|amines (i.e., amphetamines, ephedrine, methylphenidate, pseudoephedrine, and|
02713|033|D|tyramine) are antagonized by tricyclic antidepressants.  Protriptyline,|
02713|034|D|amitriptyline, and desipramine have also been reported to interact with|
02713|035|D|direct-acting sympathomimetics.|
02713|036|B||
02713|037|R|REFERENCES:|
02713|038|B||
02713|039|R|1.Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN.|2
02713|040|R|  Interactions between sympathomimetic amines and antidepressant agents in|2
02713|041|R|  man. Br Med J 1973 Feb 10;1(5849):311-5.|2
02713|042|R|2.Ghose K. Sympathomimetic amines and tricyclic antidepressant drugs.|2
02713|043|R|  Neuropharmacology 1980 Dec;19(12):1251-4.|2
02713|044|R|3.Svedmyr N. The influence of a tricyclic antidepressive agent|2
02713|045|R|  (protriptyline) on some of the circulatory effects of noradrenaline and|2
02713|046|R|  adrenaline in man. Life Sci 1968 Jan 1;7(1):77-84.|2
02713|047|R|4.Bonaccorsi A, Garattini S. Effect of desipramine on directly or indirectly|5
02713|048|R|  elicited catecholamine pressor responses in rats. J Pharm Pharmacol 1966|5
02713|049|R|  Jul;18(7):443-8.|5
02713|050|R|5.Cairncross KD. On the peripheral pharmacology of amitriptyline. Arch Int|5
02713|051|R|  Pharmacodyn Ther 1965 Apr;154(2):438-48.|5
02713|052|R|6.Ghose K, Gifford LA, Turner P, Leighton M. Studies of the interaction of|2
02713|053|R|  desmethylimipramine with tyramine in man after a single oral dose, and its|2
02713|054|R|  correlation with plasma concentration. Br J Clin Pharmacol 1976 Apr;|2
02713|055|R|  3(2):334-7.|2
02713|056|R|7.Jefferson JW. A review of the cardiovascular effects and toxicity of|6
02713|057|R|  tricyclic antidepressants. Psychosom Med 1975 Mar-Apr;37(2):160-79.|6
02713|058|R|8.Ragheb M. Drug interactions in psychiatric practice. Int|6
02713|059|R|  Pharmacopsychiatry 1981;16(2):92-118.|6
02713|060|R|9.Risch SC, Groom GP, Janowsky DS. Interfaces of psychopharmacology and|6
02713|061|R|  cardiology--part one. J Clin Psychiatry 1981 Jan;42(1):23-34.|6
02713|062|R|10.Maxwell RA, Keenan PD, Chaplin E, Roth B, Eckhardt SB. Molecular features|5
02713|063|R|   affecting the potency of tricyclic antidepressants and structurally|5
02713|064|R|   related compounds as inhibitors of the uptake of tritiated norepinephrine|5
02713|065|R|   by rabbit aortic strips. J Pharmacol Exp Ther 1969 Apr;166(2):320-9.|5
02714|001|T|MONOGRAPH TITLE:  Inhaled Direct-Acting Sympathomimetics/Tricyclic Compounds|
02714|002|B||
02714|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02714|004|L|take action as needed.|
02714|005|B||
02714|006|A|MECHANISM OF ACTION:  Unknown. However, it is speculated that direct-acting|
02714|007|A|sympathomimetic amines have an enhanced effect due to tricyclic blockage of|
02714|008|A|norepinephrine reuptake.|
02714|009|B||
02714|010|E|CLINICAL EFFECTS:  Increased effect of direct acting sympathomimetics.|
02714|011|B||
02714|012|P|PREDISPOSING FACTORS:  None determined.|
02714|013|B||
02714|014|M|PATIENT MANAGEMENT:  The concurrent use of inhaled sympathomimetics and|
02714|015|M|tricyclic compounds or the use of these agents within 14 days of each other|
02714|016|M|should be approached with extreme caution.|
02714|017|B||
02714|018|D|DISCUSSION:  Epinephrine and other direct-acting sympathomimetic amines|
02714|019|D|exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and|
02714|020|D|tachycardia) in individuals concurrently receiving or previously treated|
02714|021|D|with tricyclic antidepressants.  Protriptyline, amitriptyline, and|
02714|022|D|desipramine have also been reported to interact with direct-acting|
02714|023|D|sympathomimetics.  Similarity between cyclobenzaprine and the tricyclic|
02714|024|D|antidepressants consideration of tricyclic antidepressant interactions for|
02714|025|D|cyclobenzaprine.|
02714|026|B||
02714|027|R|REFERENCES:|
02714|028|B||
02714|029|R|1.Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN.|2
02714|030|R|  Interactions between sympathomimetic amines and antidepressant agents in|2
02714|031|R|  man. Br Med J 1973 Feb 10;1(5849):311-5.|2
02714|032|R|2.Ghose K. Sympathomimetic amines and tricyclic antidepressant drugs.|2
02714|033|R|  Neuropharmacology 1980 Dec;19(12):1251-4.|2
02714|034|R|3.Svedmyr N. The influence of a tricyclic antidepressive agent|2
02714|035|R|  (protriptyline) on some of the circulatory effects of noradrenaline and|2
02714|036|R|  adrenaline in man. Life Sci 1968 Jan 1;7(1):77-84.|2
02714|037|R|4.Bonaccorsi A, Garattini S. Effect of desipramine on directly or indirectly|5
02714|038|R|  elicited catecholamine pressor responses in rats. J Pharm Pharmacol 1966|5
02714|039|R|  Jul;18(7):443-8.|5
02714|040|R|5.Cairncross KD. On the peripheral pharmacology of amitriptyline. Arch Int|5
02714|041|R|  Pharmacodyn Ther 1965 Apr;154(2):438-48.|5
02714|042|R|6.Ghose K, Gifford LA, Turner P, Leighton M. Studies of the interaction of|2
02714|043|R|  desmethylimipramine with tyramine in man after a single oral dose, and its|2
02714|044|R|  correlation with plasma concentration. Br J Clin Pharmacol 1976 Apr;|2
02714|045|R|  3(2):334-7.|2
02714|046|R|7.Jefferson JW. A review of the cardiovascular effects and toxicity of|6
02714|047|R|  tricyclic antidepressants. Psychosom Med 1975 Mar-Apr;37(2):160-79.|6
02714|048|R|8.Ragheb M. Drug interactions in psychiatric practice. Int|6
02714|049|R|  Pharmacopsychiatry 1981;16(2):92-118.|6
02714|050|R|9.Risch SC, Groom GP, Janowsky DS. Interfaces of psychopharmacology and|6
02714|051|R|  cardiology--part one. J Clin Psychiatry 1981 Jan;42(1):23-34.|6
02714|052|R|10.Maxwell RA, Keenan PD, Chaplin E, Roth B, Eckhardt SB. Molecular features|5
02714|053|R|   affecting the potency of tricyclic antidepressants and structurally|5
02714|054|R|   related compounds as inhibitors of the uptake of tritiated norepinephrine|5
02714|055|R|   by rabbit aortic strips. J Pharmacol Exp Ther 1969 Apr;166(2):320-9.|5
02714|056|R|11.Ventolin (albuterol) inhalation aerosol US prescribing information.|1
02714|057|R|   GlaxoSmithKline August, 2021.|1
02715|001|T|MONOGRAPH TITLE:  Inhaled Mixed-Acting Sympathomimetics/Tricyclic Compounds|
02715|002|B||
02715|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02715|004|L|take action as needed.|
02715|005|B||
02715|006|A|MECHANISM OF ACTION:  Unknown. However, it is speculated that|
02715|007|A|indirect-acting sympathomimetics would have decreased activity due to|
02715|008|A|tricyclic blockage of their uptake into the adrenergic neuron.|
02715|009|B||
02715|010|E|CLINICAL EFFECTS:  Decreased effect of indirect acting sympathomimetics.|
02715|011|B||
02715|012|P|PREDISPOSING FACTORS:  None determined.|
02715|013|B||
02715|014|M|PATIENT MANAGEMENT:  The concurrent use of inhaled sympathomimetics and|
02715|015|M|tricyclic compounds or the use of these agents within 14 days of each other|
02715|016|M|should be approached with extreme caution.|
02715|017|B||
02715|018|D|DISCUSSION:  Mixed acting sympathomimetic amines have also been reported to|
02715|019|D|interact with tricyclic antidepressants.  These include norepinephrine,|
02715|020|D|phenylephrine, dopamine, and methoxamine.  Similarity between|
02715|021|D|cyclobenzaprine and the tricyclic antidepressants consideration of tricyclic|
02715|022|D|antidepressant interactions for cyclobenzaprine.|
02715|023|B||
02715|024|R|REFERENCES:|
02715|025|B||
02715|026|R|1.Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN.|2
02715|027|R|  Interactions between sympathomimetic amines and antidepressant agents in|2
02715|028|R|  man. Br Med J 1973 Feb 10;1(5849):311-5.|2
02715|029|R|2.Ghose K. Sympathomimetic amines and tricyclic antidepressant drugs.|2
02715|030|R|  Neuropharmacology 1980 Dec;19(12):1251-4.|2
02715|031|R|3.Svedmyr N. The influence of a tricyclic antidepressive agent|2
02715|032|R|  (protriptyline) on some of the circulatory effects of noradrenaline and|2
02715|033|R|  adrenaline in man. Life Sci 1968 Jan 1;7(1):77-84.|2
02715|034|R|4.Bonaccorsi A, Garattini S. Effect of desipramine on directly or indirectly|5
02715|035|R|  elicited catecholamine pressor responses in rats. J Pharm Pharmacol 1966|5
02715|036|R|  Jul;18(7):443-8.|5
02715|037|R|5.Cairncross KD. On the peripheral pharmacology of amitriptyline. Arch Int|5
02715|038|R|  Pharmacodyn Ther 1965 Apr;154(2):438-48.|5
02715|039|R|6.Ghose K, Gifford LA, Turner P, Leighton M. Studies of the interaction of|2
02715|040|R|  desmethylimipramine with tyramine in man after a single oral dose, and its|2
02715|041|R|  correlation with plasma concentration. Br J Clin Pharmacol 1976 Apr;|2
02715|042|R|  3(2):334-7.|2
02715|043|R|7.Jefferson JW. A review of the cardiovascular effects and toxicity of|6
02715|044|R|  tricyclic antidepressants. Psychosom Med 1975 Mar-Apr;37(2):160-79.|6
02715|045|R|8.Ragheb M. Drug interactions in psychiatric practice. Int|6
02715|046|R|  Pharmacopsychiatry 1981;16(2):92-118.|6
02715|047|R|9.Risch SC, Groom GP, Janowsky DS. Interfaces of psychopharmacology and|6
02715|048|R|  cardiology--part one. J Clin Psychiatry 1981 Jan;42(1):23-34.|6
02715|049|R|10.Maxwell RA, Keenan PD, Chaplin E, Roth B, Eckhardt SB. Molecular features|5
02715|050|R|   affecting the potency of tricyclic antidepressants and structurally|5
02715|051|R|   related compounds as inhibitors of the uptake of tritiated norepinephrine|5
02715|052|R|   by rabbit aortic strips. J Pharmacol Exp Ther 1969 Apr;166(2):320-9.|5
02715|053|R|11.Ventolin (albuterol) inhalation aerosol US prescribing information.|1
02715|054|R|   GlaxoSmithKline August, 2021.|1
02716|001|T|MONOGRAPH TITLE:  Tenofovir alafenamide/Selected P-gp Inducers;|
02716|002|T|Phenobarbital|
02716|003|B||
02716|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02716|005|L|take action as needed.|
02716|006|B||
02716|007|A|MECHANISM OF ACTION:  Tenofovir alafenamide (TAF) is a substrate of the|
02716|008|A|intestinal efflux transporter P-glycoprotein (P-gp).  Inducers of P-gp may|
02716|009|A|decrease systemic absorption of TAF.(1-4)  Phenobarbital may also induce the|
02716|010|A|metabolism of tenofovir alafenamide.(1-4)  Primidone is metabolized to|
02716|011|A|phenobarbital.|
02716|012|B||
02716|013|E|CLINICAL EFFECTS:  Concurrent or recent use of P-gp inducers, phenobarbital,|
02716|014|E|or primidone may result in decreased systemic levels and effectiveness of|
02716|015|E|tenofovir alafenamide.(1-4)|
02716|016|B||
02716|017|P|PREDISPOSING FACTORS:  None determined.|
02716|018|B||
02716|019|M|PATIENT MANAGEMENT:  Recommendations regarding concurrent use of tenofovir|
02716|020|M|alafenamide and P-gp inducers vary depending on the region and drug|
02716|021|M|formulation.|
02716|022|M|   The European manufacturer of tenofovir alafenamide (DESCOVY for HIV|
02716|023|M|infection and VEMLIDY for hepatitis B) states that concurrent use is not|
02716|024|M|recommended with carbamazepine, phenobarbital, phenytoin, primidone,|
02716|025|M|rifabutin, rifampin, rifapentine, or St. John's wort.(1,2)|
02716|026|M|   The US manufacturer of DESCOVY states that rifabutin, rifampin,|
02716|027|M|rifapentine, and St. John's wort are not recommended.  Alternatives should|
02716|028|M|be considered for carbamazepine, phenobarbital, phenytoin, and primidone.(3)|
02716|029|M|   The Australian and US manufacturers of tenofovir alafenamide (VEMLIDY for|
02716|030|M|hepatitis B) states that concurrent use with phenobarbital, phenytoin,|
02716|031|M|primidone, rifabutin, rifampin, rifapentine, or St. John's wort is not|
02716|032|M|recommended.  If concurrent therapy with carbamazepine is indicated during|
02716|033|M|treatment for Hepatitis B, the manufacturer recommends increasing the dose|
02716|034|M|of tenofovir alafenamide to two tablets (50 mg) once daily.(4-5)|
02716|035|B||
02716|036|D|DISCUSSION:  When tenofovir alafenamide (TAF) was coadministered with|
02716|037|D|carbamazepine, the maximum concentration (Cmax) and area-under-curve (AUC)|
02716|038|D|were decreased 57% and 55%, respectively.(1-4)|
02716|039|D|   A subsequent study suggests that this interaction may not have clinically|
02716|040|D|significant effects on intracellular levels of tenofovir diphosphate, the|
02716|041|D|active metabolite of tenofovir alafenamide.  In a study of 23 healthy|
02716|042|D|volunteers, the intracellular Cmax and AUC of tenofovir diphosphate were 38%|
02716|043|D|and 36% lower, respectively, when tenofovir alafenamide was coadministered|
02716|044|D|with rifampin than without rifampin.  However, these levels of tenofovir|
02716|045|D|diphosphate were 4.4- and 4.21-fold higher, respectively, than levels|
02716|046|D|obtained from tenofovir disoproxil 300 mg daily without rifampin.(6)|
02716|047|D|   Selected P-gp inducers linked to this monograph include: apalutamide,|
02716|048|D|carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifabutin, rifampin,|
02716|049|D|rifapentine, or St. John's wort.(1-7) The manufacturer of tenofovir|
02716|050|D|alafenamide also classifies phenobarbital as a P-gp inducer.(1-4)|
02716|051|B||
02716|052|R|REFERENCES:|
02716|053|B||
02716|054|R|1.Descovy (emtricitabine, tenofovir alafenamide) EMA Summary of Product|1
02716|055|R|  Characteristics. Gilead Sciences Ireland UC December 10, 2018.|1
02716|056|R|2.Vemlidy (tenofovir alafenamide fumarate) UK Summary of Product|1
02716|057|R|  Characteristics. Gilead Sciences Ltd October, 2021.|1
02716|058|R|3.Descovy (emtricitabine and tenofovir alafenamide) US prescribing|1
02716|059|R|  information. Gilead Sciences, Inc. June, 2025.|1
02716|060|R|4.Vemlidy (tenofovir alafenamide) US prescribing information. Gilead|1
02716|061|R|  Sciences, Inc. August, 2020.|1
02716|062|R|5.Vemlidy (Tenofovir alafenamide fumarate) Australian product information.|1
02716|063|R|  Gilead Sciences, Inc. January 2024.|1
02716|064|R|6.Cerrone Maddalena, Alfarisi Omamah, Neary Megan, Marzinke Mark A, Parsons|2
02716|065|R|  Teresa L, Owen Andrew, Maartens Gary, Pozniak Anton, Flexner Charles,|2
02716|066|R|  Boffito Marta. Rifampicin effect on intracellular and plasma|2
02716|067|R|  pharmacokinetics of tenofovir alafenamide. 2019 Jun;74(6):1670-1678.|2
02716|068|R|7.This information is based on an extract from the Certara Drug Interaction|6
02716|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02717|001|T|MONOGRAPH TITLE:  Atovaquone; Proguanil/Efavirenz|
02717|002|B||
02717|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02717|004|L|of severe adverse interaction.|
02717|005|B||
02717|006|A|MECHANISM OF ACTION:  The mechanism of interaction between atovaquone and|
02717|007|A|efavirenz is unknown.  Efavirenz, an inducer of CYP2C19, may induce the|
02717|008|A|metabolism of proguanil.(1,2)|
02717|009|B||
02717|010|E|CLINICAL EFFECTS:  Concurrent use of CYP2C19 inducers with atovaquone and|
02717|011|E|proguanil may result in decreased levels and effectiveness of the|
02717|012|E|antimalarial agents and treatment failure.(1)|
02717|013|B||
02717|014|P|PREDISPOSING FACTORS:  None determined.|
02717|015|B||
02717|016|M|PATIENT MANAGEMENT:  Concomitant administration of atovaquone/proguanil with|
02717|017|M|efavirenz is not recommended and may result in decreased levels of|
02717|018|M|atovaquone and proguanil.(1)  Monitor patients for signs of treatment|
02717|019|M|failure.|
02717|020|B||
02717|021|D|DISCUSSION:  In a study of 30 human immunodeficiency virus (HIV)-infected|
02717|022|D|subjects enrolled in three treatment arms (10 taking no antiretroviral|
02717|023|D|therapy, 10 taking combination antiretroviral therapy including efavirenz,|
02717|024|D|and 10 taking combination antiretroviral therapy with atazanavir/ritonavir)|
02717|025|D|received atovaquone 750 mg BID for 14 days followed by atovaquone 1500 mg|
02717|026|D|BID for 14 days, or vice-versa, with a washout period in between.  The|
02717|027|D|subjects on a combination antiretroviral regimen including efavirenz had a|
02717|028|D|47% and 44% lower atovaquone area-under-curve (AUC) on both dosing regimens,|
02717|029|D|750 mg BID and 1500 mg BID, respectively (p<0.01).  Concentrations of|
02717|030|D|atovaquone required to successfully treat Pneumocystis jiroveci pneumonia|
02717|031|D|(average Concentration > 15 mcg/ml) were achieved in 50% of the subjects|
02717|032|D|receiving an efavirenz based regimen.  Concentrations of atovaquone required|
02717|033|D|to successfully treat Toxoplasma encephalitis (average Concentration > 18.5|
02717|034|D|mcg/ml) were achieved in 20% of the subjects receiving an efavirenz based|
02717|035|D|regimen with atovaquone 750 mg BID.(3)|
02717|036|D|   In a study of 76 HIV-infected patients, 18 healthy volunteers, 20|
02717|037|D|patients with efavirenz, 19 patients with lopinavir/ritonavir, or 19|
02717|038|D|patients with atazanavir/ritonavir received a single dose of|
02717|039|D|atovaquone/proguanil 250/100 mg dose.  The geometric mean ration (GMR) [95%|
02717|040|D|confidence interval] AUC and maximum concentration (Cmax) for atovaquone,|
02717|041|D|respectively, were 0.25 and 0.56 for patients on efavirenz, 0.26  and 0.56|
02717|042|D|for patients on lopinavir/ritonavir, and 0.54 and 0.51 for patients on|
02717|043|D|atazanavir/ritonavir.  Proguanil concentrations after adjustment for|
02717|044|D|confounders including CYP2C19 genotype resulted in the GMR AUC of 0.57 for|
02717|045|D|patients on efavirenz, 0.62 for patients on lopinavir/ritonavir, and 0.59|
02717|046|D|for patients on atazanavir/ritonavir.  The Cmax for proguanil was unchanged|
02717|047|D|in all three groups compared to healthy controls.(4)|
02717|048|B||
02717|049|R|REFERENCES:|
02717|050|B||
02717|051|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
02717|052|R|  Company November, 2023.|1
02717|053|R|2.Malarone (atovaquone and proguanil hydrochloride) US prescribing|1
02717|054|R|  information. GlaxoSmithKline February, 2013.|1
02717|055|R|3.Calderon MM, Penzak SR, Pau AK, Kumar P, McManus M, Alfaro RM, Kovacs JA.|2
02717|056|R|  Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone|2
02717|057|R|  Concentrations in HIV-Infected Subjects. Clin Infect Dis 2016 Apr 15;|2
02717|058|R|  62(8):1036-42.|2
02717|059|R|4.van Luin M, Van der Ende ME, Richter C, Visser M, Faraj D, Van der Ven A,|2
02717|060|R|  Gelinck L, Kroon F, Wit FW, Van Schaik RH, Kuks PF, Burger DM. Lower|2
02717|061|R|  atovaquone/proguanil concentrations in patients taking efavirenz,|2
02717|062|R|  lopinavir/ritonavir or atazanavir/ritonavir. AIDS 2010 May 15;|2
02717|063|R|  24(8):1223-6.|2
02718|001|T|MONOGRAPH TITLE:  Vemurafenib/Strong CYP3A4 Inducers; Rifabutin|
02718|002|B||
02718|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02718|004|L|of severe adverse interaction.|
02718|005|B||
02718|006|A|MECHANISM OF ACTION:  Vemurafenib is a substrate of CYP3A4.  Strong inducers|
02718|007|A|of CYP3A4 and rifabutin may increase the metabolism of vemurafenib.(1-3)|
02718|008|B||
02718|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 or rifabutin|
02718|010|E|may result in decreased levels and effectiveness of vemurafenib.(1-3)|
02718|011|B||
02718|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02718|013|P|of the inducer for longer than 1-2 weeks.|
02718|014|B||
02718|015|M|PATIENT MANAGEMENT:  The manufacturer of vemurafenib states to avoid|
02718|016|M|concurrent use with strong CYP3A4 inducers and replace these drugs with|
02718|017|M|alternative drugs when possible.(1-3)  The Canadian and UK manufacturers|
02718|018|M|include rifabutin on their lists of CYP3A4 inducers that are to be|
02718|019|M|avoided.(2,3)  If concurrent administration with a strong CYP3A4 inducer is|
02718|020|M|unavoidable, increase the dose of vemurafenib by 240 mg (one tablet) as|
02718|021|M|tolerated.(1)|
02718|022|M|   If concurrent use of a strong CYP3A4 inducer is discontinued, allow a 2|
02718|023|M|week period to lapse and then resume the dose of vemurafenib that was taken|
02718|024|M|prior to initiation of the strong CYP3A4 inducer.(1)|
02718|025|B||
02718|026|D|DISCUSSION:  In a study in healthy subjects, coadministration of single dose|
02718|027|D|vemurafenib 960 mg with rifampin (600 mg daily, a strong CYP3A inducer)|
02718|028|D|decreased vemurafenib area-under-curve (AUC) by 40% (90% CI: 24%, 53%) with|
02718|029|D|no effect on maximum concentration (Cmax), when compared to vemurafenib|
02718|030|D|alone.(1)|
02718|031|D|   Strong CYP3A4 inducers linked to this monograph include:  apalutamide,|
02718|032|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
02718|033|D|mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin,|
02718|034|D|rifapentine, and St. John's wort.(4-5)|
02718|035|B||
02718|036|R|REFERENCES:|
02718|037|B||
02718|038|R|1.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02718|039|R|  November, 2017.|1
02718|040|R|2.Zelboraf (vemurafenib) Canadian prescribing information. Hoffman-La Roche|1
02718|041|R|  Limited December 10, 2019.|1
02718|042|R|3.Zelboraf (vemurafenib) UK Summary of Product Characteristics. Roche|1
02718|043|R|  Products Limited December 17, 2019.|1
02718|044|R|4.This information is based on an extract from the Certara Drug Interaction|6
02718|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02718|046|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02718|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02718|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02718|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02718|050|R|  11/14/2017.|1
02719|001|T|MONOGRAPH TITLE:  Vemurafenib/Strong CYP3A4 Inhibitors|
02719|002|B||
02719|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02719|004|L|of severe adverse interaction.|
02719|005|B||
02719|006|A|MECHANISM OF ACTION:  Vemurafenib is a substrate of CYP3A4.  Strong|
02719|007|A|inhibitors of CYP3A4 may inhibit the metabolism of vemurafenib.(1)|
02719|008|B||
02719|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02719|010|E|in increased levels and toxicity from vemurafenib,(1) including prolongation|
02719|011|E|of the QT interval which may result in life-threatening arrhythmia and|
02719|012|E|death.|
02719|013|B||
02719|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02719|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02719|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02719|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02719|018|P|female gender, or advanced age.(2)|
02719|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02719|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02719|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02719|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02719|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02719|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02719|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02719|026|B||
02719|027|M|PATIENT MANAGEMENT:  The manufacturer of vemurafenib states to avoid|
02719|028|M|concurrent administration with strong CYP3A4 inhibitors and replace these|
02719|029|M|drugs with alternative drugs whenever possible.(1)|
02719|030|M|   If concurrent therapy is warranted, monitor patient for signs of|
02719|031|M|vemurafenib toxicity.  Consider dose reduction of vemurafenib if clinically|
02719|032|M|indicated.  Consider obtaining serum calcium, magnesium, and potassium|
02719|033|M|levels.  Correct any electrolyte abnormalities.  Instruct patients to report|
02719|034|M|any irregular heartbeat, dizziness, or fainting.|
02719|035|M|   Vemurafenib should not be initiated in patients taking medications known|
02719|036|M|to prolong the QT interval, patients having a baseline QTc greater than 500|
02719|037|M|msec, uncorrectable electrolyte abnormalities, or known long QT syndrome.(1)|
02719|038|M|   All patients receiving vemurafenib should undergo ECG testing at|
02719|039|M|baseline, after 15 days of treatment, monthly during the first 3 months of|
02719|040|M|treatment, and then every 3 months.  If a patient's QTc exceeds 500 msec|
02719|041|M|during treatment, vemurafenib should be discontinued and cardiac risk|
02719|042|M|factors for QT prolongation should be controlled.  Consider discontinuing|
02719|043|M|other medications known to prolong the QT interval at this time.  If the|
02719|044|M|patient's QTc decreases below 500 msec, vemurafenib may be introduced at a|
02719|045|M|lower dosage according to the current labeling recommendations.  If the|
02719|046|M|patient's QTc remains greater than 500 msec and increased >60 msec from|
02719|047|M|pre-treatment values after controlling cardiac risk factors for|
02719|048|M|prolongation, permanently discontinue vemurafenib.(1)|
02719|049|B||
02719|050|D|DISCUSSION:  Vemurafenib is a substrate of CYP3A4.(1)|
02719|051|D|   A study of vemurafenib 960 mg twice daily with itraconazole 200 mg daily|
02719|052|D|increased vemurafenib area-under-curve (AUC) by 40% with a similar increase|
02719|053|D|in concentration maximum (Cmax).(1)|
02719|054|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
02719|055|D|cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
02719|056|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
02719|057|D|paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.(3,4)|
02719|058|B||
02719|059|R|REFERENCES:|
02719|060|B||
02719|061|R|1.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02719|062|R|  November, 2017.|1
02719|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02719|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02719|065|R|  settings: a scientific statement from the American Heart Association and|6
02719|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02719|067|R|  2;55(9):934-47.|6
02719|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
02719|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02719|070|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02719|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02719|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02719|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02719|074|R|  11/14/2017.|1
02719|075|R|5.Zhang W, Mathisen M, Goodman GR, Forbes H, Song Y, Bertran E, Demidov L,|2
02719|076|R|  Shin SJ. Effect of Itraconazole, a Potent CYP3A4 Inhibitor, on the|2
02719|077|R|  Steady-State Pharmacokinetics of Vemurafenib in Patients With BRAF(V600)|2
02719|078|R|  Mutation-Positive Malignancies. Clin Pharmacol Drug Dev 2021 Jan;|2
02719|079|R|  10(1):39-45.|2
02720|001|T|MONOGRAPH TITLE:  Bromocriptine; Cabergoline/Selected Macrolide Antibiotics|
02720|002|B||
02720|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02720|004|L|take action as needed.|
02720|005|B||
02720|006|A|MECHANISM OF ACTION:  Selected macrolide antibiotics may inhibit the|
02720|007|A|metabolism of bromocriptine and cabergoline by inhibition of CYP3A4.(1-3)|
02720|008|A|Erythromycin has shown to inhibit the hepatic uptake of bromocriptine|
02720|009|A|through inhibition of organic anion transporting polypeptide C (OATP-C)|
02720|010|A|mediated uptake, as well as inhibit CYP3A4 metabolism of bromocriptine.(4)|
02720|011|B||
02720|012|E|CLINICAL EFFECTS:  Concurrent use of selected macrolide antibiotics may|
02720|013|E|result in increased levels of bromocriptine and cabergoline, which may|
02720|014|E|result in increased side effects of these agents.(1-3)|
02720|015|B||
02720|016|P|PREDISPOSING FACTORS:  None determined.|
02720|017|B||
02720|018|M|PATIENT MANAGEMENT:  Use caution with concurrent therapy with bromocriptine|
02720|019|M|and cabergoline with selected macrolide antibiotics.|
02720|020|M|   The US manufacturer of bromocriptine states use caution when|
02720|021|M|co-administering drugs that are inhibitors of CYP3A4.  Bromocriptine dose|
02720|022|M|should not exceed 1.6 mg per day when used with a moderate CYP3A4 inhibitor.|
02720|023|M|Concomitant use of strong CYP3A4 inhibitors should be avoided.  Ensure|
02720|024|M|adequate washout of strong CYP3A4 inhibitor drug before initiating|
02720|025|M|bromocriptine.(2)|
02720|026|B||
02720|027|D|DISCUSSION:  Concurrent administration of selected macrolide antibiotics|
02720|028|D|with bromocriptine or cabergoline may increase the side effects of these|
02720|029|D|agents.  Erythromycin is a moderate inhibitor of CYP3A4.(5)|
02720|030|D|   A study in five healthy subjects found that concurrent administration of|
02720|031|D|erythromycin and bromocriptine resulted in a 268% increase in|
02720|032|D|area-under-curve (AUC) for bromocriptine and a 4.6-fold increase in|
02720|033|D|bromocriptine maximum concentration (Cmax).(6)|
02720|034|B||
02720|035|R|REFERENCES:|
02720|036|B||
02720|037|R|1.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
02720|038|R|  November, 2015.|1
02720|039|R|2.Cycloset (bromocriptine mesylate) tablets, US prescribing information.|1
02720|040|R|  Veroscience LLC February 2, 2016.|1
02720|041|R|3.Dostinex (cabergoline) US prescribing information. Pfizer April, 2025.|1
02720|042|R|4.Lu WJ, Huang K, Lai ML, Huang JD. Erythromycin alters the pharmacokinetics|6
02720|043|R|  of bromocriptine by inhibition of organic anion transporting polypeptide|6
02720|044|R|  C-mediated uptake. Clin Pharmacol Ther 2006 Oct;80(4):421-2.|6
02720|045|R|5.This information is based on an extract from the Certara Drug Interaction|6
02720|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02720|047|R|6.Nelson MV, Berchou RC, Kareti D, LeWitt PA. Pharmacokinetic evaluation of|2
02720|048|R|  erythromycin and caffeine administered with bromocriptine. Clin Pharmacol|2
02720|049|R|  Ther 1990 Jun;47(6):694-7.|2
02721|001|T|MONOGRAPH TITLE:  Venetoclax/Strong CYP3A4 Inducers|
02721|002|B||
02721|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02721|004|L|of severe adverse interaction.|
02721|005|B||
02721|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02721|007|A|venetoclax.(1)|
02721|008|B||
02721|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02721|010|E|in decreased levels and effectiveness of venetoclax.(1)|
02721|011|B||
02721|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02721|013|P|of the inducer for longer than 1-2 weeks.|
02721|014|B||
02721|015|M|PATIENT MANAGEMENT:  The US manufacturer of venetoclax states that the|
02721|016|M|concurrent use of CYP3A4 inducers should be avoided, and that alternative|
02721|017|M|treatments with less CYP3A4 induction should be considered.(1)|
02721|018|B||
02721|019|D|DISCUSSION:  In a study with 10 healthy subjects, co-administration of|
02721|020|D|rifampin (600 mg daily for 13 days), decreased venetoclax area-under-curve|
02721|021|D|(AUC) by 71% and maximum concentration (Cmax) by 42%.(1)|
02721|022|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
02721|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02721|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02721|025|D|rifapentine, and St. John's wort.(2-4)|
02721|026|B||
02721|027|R|REFERENCES:|
02721|028|B||
02721|029|R|1.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
02721|030|R|  2021.|1
02721|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02721|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02721|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02721|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02721|035|R|  11/14/2017.|1
02721|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
02721|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02721|038|R|4.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
02721|039|R|  Pharmaceuticals Inc. August, 2023.|1
02722|001|T|MONOGRAPH TITLE:  Venetoclax/Strong CYP3A4 Inhibitors|
02722|002|B||
02722|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02722|004|L|of severe adverse interaction.|
02722|005|B||
02722|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors inhibit the metabolism of|
02722|007|A|venetoclax.(1)|
02722|008|B||
02722|009|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
02722|010|E|in elevated levels of venetoclax, increasing the risk for tumor lysis|
02722|011|E|syndrome and other toxicities.(1)|
02722|012|B||
02722|013|P|PREDISPOSING FACTORS:  Risk factors for tumor lysis syndrome include (1):|
02722|014|P|- the ramp-up phase of venetoclax therapy when tumor burden is highest|
02722|015|P|- initial magnitude of tumor burden|
02722|016|P|- renal impairment|
02722|017|P|   The risk of venetoclax toxicities may be increased in patients with|
02722|018|P|severe hepatic impairment.(1)|
02722|019|B||
02722|020|M|PATIENT MANAGEMENT:  Recommendations vary depending on diagnosis, stage of|
02722|021|M|therapy, and strong CYP3A4 inhibitor.|
02722|022|M|   During the initiation/ramp-up phase of venetoclax therapy in patients|
02722|023|M|with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL),|
02722|024|M|strong CYP3A4 inhibitors are contraindicated due to the increased risk for|
02722|025|M|tumor lysis syndrome.|
02722|026|M|   During the initiation/ramp-up phase of venetoclax therapy in patients|
02722|027|M|with acute myeloid leukemia (AML) who are taking strong CYP3A4 inhibitors,|
02722|028|M|decrease venetoclax dose as follows:|
02722|029|M|   - With posaconazole, decrease venetoclax dose on day 1 to 10 mg, on day 2|
02722|030|M|to 20 mg, on day 3 to 50 mg, and on day 4 to 70 mg.|
02722|031|M|   - With other strong CYP3A4 inhibitors, decrease venetoclax dose on day 1|
02722|032|M|to 10 mg, on day 2 to 20 mg, on day 3 to 50 mg, and on day 4 to 100 mg.|
02722|033|M|   In patients taking a steady daily dosage for CLL, SLL, or AML (after|
02722|034|M|completion of the ramp-up phase), avoid use of a strong CYP3A4 inhibitor if|
02722|035|M|possible.|
02722|036|M|   If a strong CYP3A4 inhibitor must be used, decrease venetoclax daily dose|
02722|037|M|as follows:|
02722|038|M|   - When used concomitantly with posaconazole, decrease venetoclax to 70 mg|
02722|039|M|daily.|
02722|040|M|   - When used concomitantly with other strong CYP3A4 inhibitors, decrease|
02722|041|M|venetoclax to 100 mg daily.|
02722|042|M|   Monitor for tumor lysis syndrome, hematologic and non-hematologic|
02722|043|M|toxicity and adjust dosage as directed in prescribing information.|
02722|044|M|   If the strong CYP3A4 inhibitor is discontinued, the manufacturer of|
02722|045|M|venetoclax recommends resuming the prior (i.e. pre-inhibitor) venetoclax|
02722|046|M|dose 2 to 3 days after discontinuation of the strong CYP3A4 inhibitor.(1)|
02722|047|B||
02722|048|D|DISCUSSION:  In 11 previously treated NHL subjects, ketoconazole (a strong|
02722|049|D|CYP3A4 inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days|
02722|050|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02722|051|D|venetoclax by 130 % and 540 %, respectively.(1)|
02722|052|D|   In 12 patients with NHL, venetoclax 50 mg single dose was administered on|
02722|053|D|day 1 and day 8 with ketoconazole 400 mg once daily administered on days|
02722|054|D|5-11 to evaluate pharmacokinetic parameters of concurrent administration.|
02722|055|D|Coadministration increased venetoclax Cmax and AUC with a mean increase of|
02722|056|D|2.3-fold and 6.4-fold, respectively, with a range in AUC change of|
02722|057|D|2-12-fold.  One patient excluded from statistical analysis due to receiving|
02722|058|D|a dose of ketoconazole of 200 mg once daily had an increase in venetoclax|
02722|059|D|Cmax and AUC of 2.3-fold and 3.5-fold, respectively.(2)|
02722|060|D|   In a study in 6 healthy subjects, coadministration of venetoclax and|
02722|061|D|ritonavir (50 mg once daily) for 14 days increased venetoclax's Cmax and AUC|
02722|062|D|by 140 % and 690 %, respectively.(1)|
02722|063|D|   Coadministration of posaconazole (a strong CYP3A4 and P-gp inhibitor) 300|
02722|064|D|mg daily and venetoclax 50 mg daily for 7 days led to a 61 % and 86 %|
02722|065|D|increase in venetoclax Cmax, respectively, compared to venetoclax 400 mg|
02722|066|D|daily administered alone. Venetoclax AUC increased by 90 % and 144 %,|
02722|067|D|respectively.(1)|
02722|068|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
02722|069|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
02722|070|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
02722|071|D|nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ribociclib,|
02722|072|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
02722|073|D|tucatinib, and voriconazole.(3-4)|
02722|074|B||
02722|075|R|REFERENCES:|
02722|076|B||
02722|077|R|1.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
02722|078|R|  2021.|1
02722|079|R|2.Agarwal SK, Salem AH, Danilov AV, Hu B, Puvvada S, Gutierrez M, Chien D,|2
02722|080|R|  Lewis LD, Wong SL. Effect of ketoconazole, a strong CYP3A inhibitor, on|2
02722|081|R|  the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with|2
02722|082|R|  non-Hodgkin lymphoma. Br J Clin Pharmacol 2017 Apr;83(4):846-854.|2
02722|083|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02722|084|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02722|085|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02722|086|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02722|087|R|  11/14/2017.|1
02722|088|R|4.This information is based on an extract from the Certara Drug Interaction|6
02722|089|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02723|001|T|MONOGRAPH TITLE:  Cobicistat/Tenofovir disoproxil|
02723|002|B||
02723|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02723|004|L|of severe adverse interaction.|
02723|005|B||
02723|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.|
02723|007|B||
02723|008|E|CLINICAL EFFECTS:  Coadministration of cobicistat with tenofovir disoproxil|
02723|009|E|increases the risk of new onset or worsening renal impairment including|
02723|010|E|acute renal failure and Fanconi syndrome.(1-10)|
02723|011|B||
02723|012|P|PREDISPOSING FACTORS:  Patients with impaired baseline renal function or who|
02723|013|P|are receiving concomitant nephrotoxic agents may have an increased risk of|
02723|014|P|renal-related adverse events.(1-10)|
02723|015|B||
02723|016|M|PATIENT MANAGEMENT:  The Canadian, UK, and US manufacturers of|
02723|017|M|atazanavir/cobicistat, cobicistat and darunavir/cobicistat do not recommend|
02723|018|M|coadministration with tenofovir disoproxil fumarate (DF) in patents with a|
02723|019|M|creatinine clearance (CrCl) below 70 ml/min or with concomitant or recent|
02723|020|M|use of an additional nephrotoxic agent.(2-10)|
02723|021|M|   In patients receiving concurrent therapy, check glucose and urine protein|
02723|022|M|at baseline and routinely monitor CrCl, urine glucose, urine protein, and|
02723|023|M|serum phosphorus.  Discontinue concurrent therapy if CrCl decreases below 70|
02723|024|M|ml/min.(2-10)|
02723|025|B||
02723|026|D|DISCUSSION:  Renal toxicity has been documented with coadministration of|
02723|027|D|cobicistat with tenofovir disoproxil fumarate (DF) but not tenofovir|
02723|028|D|alafenamide (AF).  Monitoring of renal function is prudent and|
02723|029|D|discontinuation is recommended when CrCl decreases below 70 ml/min to avoid|
02723|030|D|renal impairment.(1-10)|
02723|031|B||
02723|032|R|REFERENCES:|
02723|033|B||
02723|034|R|1.Viread (tenofovir disoproxil fumarate) US prescribing information. Gilead|1
02723|035|R|  Sciences, Inc. December, 2018.|1
02723|036|R|2.Evotaz (atazanavir and cobicistat) Canada prescribing information.|1
02723|037|R|  Bristol-Myers Squibb Company September, 2015.|1
02723|038|R|3.Evotaz (atazanavir and cobicistat) UK summary of product characteristics.|1
02723|039|R|  Bristol-Myers-Squibb Company March, 2016.|1
02723|040|R|4.Evotaz (atazanavir and cobicistat) US prescribing information.|1
02723|041|R|  Bristol-Myers-Squibb Company May, 2025.|1
02723|042|R|5.Tybost (cobicistat) Canada prescribing information. Gilead Sciences Canada|1
02723|043|R|  August, 2013.|1
02723|044|R|6.Tybost (cobicistat) EMA summary of product characteristics. Gilead|1
02723|045|R|  Sciences Limited May, 2014.|1
02723|046|R|7.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02723|047|R|  June, 2025.|1
02723|048|R|8.Prezcobix (darunavir-cobicistat) Canadian prescribing information. Janssen|1
02723|049|R|  Inc. June 18, 2014.|1
02723|050|R|9.Rezolsta (darunavir/cobicistat) UK summary of product characteristics.|1
02723|051|R|  Janssen Pharmaceuticals Inc. March, 2016.|1
02723|052|R|10.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
02723|053|R|   Pharmaceuticals, Inc. March, 2025.|1
02724|001|T|MONOGRAPH TITLE:  Cobicistat; Ritonavir/Tenofovir Alafenamide (> 10 mg)|
02724|002|B||
02724|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02724|004|L|take action as needed.|
02724|005|B||
02724|006|A|MECHANISM OF ACTION:  Tenofovir alafenamide (AF) is a substrate of|
02724|007|A|P-glycoprotein (P-gp) and BCRP, which may be inhibited by cobicistat or|
02724|008|A|ritonavir.(1-6)|
02724|009|A|   Ritonavir coadministered with tipranavir has a net inductive effect on|
02724|010|A|P-gp.(7)|
02724|011|B||
02724|012|E|CLINICAL EFFECTS:  Cobicistat or ritonavir in combination with tenofovir|
02724|013|E|alafenamide (AF) may increase the concentration of tenofovir AF and the risk|
02724|014|E|of renal or other toxicities in some patients.(1-6,8-9)|
02724|015|E|   Ritonavir-boosted tipranavir may decrease the levels of tenofovir|
02724|016|E|AF.(4-6,8)|
02724|017|B||
02724|018|P|PREDISPOSING FACTORS:  Patients with baseline impairment of renal function|
02724|019|P|and/or receiving commitant nephrotoxic agents are at increased risk of|
02724|020|P|renal-related adverse events.(1-6,8-9)|
02724|021|B||
02724|022|M|PATIENT MANAGEMENT:  Regulatory agencies in different countries differ with|
02724|023|M|regard to recommendations for the coadministration of cobicistat or|
02724|024|M|ritonavir and tenofovir alafenamide (AF).|
02724|025|M|   The US manufacturer of emtricitabine-tenofovir AF states that|
02724|026|M|coadministration with atazanavir-cobicistat in pediatric patients weighing|
02724|027|M|14 kg to 35 kg is not recommended.(4)|
02724|028|M|   The US manufacturer of emtricitabine-tenofovir AF states that there are|
02724|029|M|no clinically significant interactions with cobicistat or ritonavir boosted|
02724|030|M|atazanavir, darunavir, or lopinavir in patients weighing >=35 kg.(4)  The US|
02724|031|M|National Institute of Health HIV guidelines state that no dose adjustment is|
02724|032|M|necessary when using tenofovir AF 25 mg concurrently with cobicistat or|
02724|033|M|ritonavir boosted atazanavir, darunavir, or lopinavir in patients weighing|
02724|034|M|>=35 kg.(8)|
02724|035|M|   Coadministration with tipranavir-ritonavir is not recommended.(8)|
02724|036|M|   Note that other countries have different recommendations.  The Canadian|
02724|037|M|and European manufacturers of emtricitabine-tenofovir alafenamide that that|
02724|038|M|the dose of tenofovir alafenamide should be 10 mg when coadministered with|
02724|039|M|cobicistat or ritonavir boosted atazanavir, darunavir, or lopinavir.|
02724|040|M|Coadministration with tipranavir-ritonavir is not recommended.  There are no|
02724|041|M|data to make recommendations for use of tenofovir AF with other protease|
02724|042|M|inhibitors.(5-6)|
02724|043|M|   In patients receiving concurrent therapy, check glucose and urine protein|
02724|044|M|at baseline and routinely monitor CrCl, urine glucose, urine protein, and|
02724|045|M|serum phosphorus.  Discontinue concurrent therapy if CrCL decreases below 30|
02724|046|M|ml/min.(4-6)|
02724|047|B||
02724|048|D|DISCUSSION:  In clinical trials, cobicistat 150 mg daily increased the|
02724|049|D|area-under-curve (AUC) and maximal concentration (Cmax) of tenofovir|
02724|050|D|alafenamide (AF) by 2.65-fold and 2.83-fold, respectively.  Atazanavir 300|
02724|051|D|mg daily with ritonavir 100 mg daily increased the AUC and Cmax of tenofovir|
02724|052|D|AF by 1.91-fold and 1.77-fold, respectively, whereas cobicistat-boosted|
02724|053|D|atazanavir caused 1.75-fold and 1.8-fold increases in tenofovir AF AUC and|
02724|054|D|Cmax.  Darunavir 800 mg daily with cobicistat 150 mg daily did not affect|
02724|055|D|the pharmacokinetics of tenofovir AF, but increased tenofovir AUC and Cmax|
02724|056|D|by 3.24-fold and 3.16-fold, respectively. Similarly, darunavir 800 mg daily|
02724|057|D|with ritonavir 100 mg daily did not affect the levels of  tenofovir AF, but|
02724|058|D|increased AUC and Cmax of tenofovir by 2.05-fold and 2.42-fold,|
02724|059|D|respectively. Lopinavir 800 mg daily with ritonavir 200 mg daily increased|
02724|060|D|AUC and Cmax of tenofovir AF by 1.47-fold and 2.19-fold, respectively.(4,6)|
02724|061|D|   Renal toxicity, including proximal renal tubulopathy and Fanconi|
02724|062|D|syndrome, has been documented with coadministration of cobicistat with|
02724|063|D|tenofovir disoproxil fumarate (DF) but not tenofovir alafenamide (AF).|
02724|064|D|Monitoring of renal function is prudent and discontinuation is recommended|
02724|065|D|when CrCl decreases below 30 ml/min to avoid renal impairment.(1-6,8-9)|
02724|066|D|   In a phase 3 trial of tenofovir AF versus tenofovir DF coformulated with|
02724|067|D|elvitegravir, cobicistat, and emtricitabine, at 48 weeks patients in the|
02724|068|D|tenofovir AF group had significantly smaller mean serum creatinine|
02724|069|D|increases(0.08 vs 0.12 mg/dL; p<0.0001) and significantly less proteinuria|
02724|070|D|(median % change -3 vs 20; p<0.0001).(9)|
02724|071|D|   Tenofovir AF strengths less than or equal to 10 mg are excluded from this|
02724|072|D|interaction.  In a pre-approval drug-drug interaction study, concurrent|
02724|073|D|cobicistat (150 mg daily) increased tenofovir AF exposure (area-under-curve,|
02724|074|D|AUC) 2.5-fold.  Due to this interaction, the tenofovir AF strength in the|
02724|075|D|cobicistat-elvitegravir-emtricitabine-tenofovir AF combination product was|
02724|076|D|reduced from the originally proposed 25 mg to 10 mg.(10)|
02724|077|B||
02724|078|R|REFERENCES:|
02724|079|B||
02724|080|R|1.Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02724|081|R|  prescribing information. Gilead Sciences, Inc September, 2021.|1
02724|082|R|2.Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir) UK summary of|1
02724|083|R|  product characteristics. Gilead Sciences, Inc March, 2016.|1
02724|084|R|3.Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir) Canada|1
02724|085|R|  prescribing information. Gilead Sciences Canada November, 2015.|1
02724|086|R|4.Descovy (emtricitabine and tenofovir alafenamide) US prescribing|1
02724|087|R|  information. Gilead Sciences, Inc. June, 2025.|1
02724|088|R|5.Descovy (emtricitabine, tenofovir alafenamide) Canadian prescribing|1
02724|089|R|  information. Gilead Sciences Canada, Inc. May 7, 2019.|1
02724|090|R|6.Descovy (emtricitabine, tenofovir alafenamide) EMA Summary of Product|1
02724|091|R|  Characteristics. Gilead Sciences Ireland UC December 10, 2018.|1
02724|092|R|7.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
02724|093|R|  Pharmaceuticals, Inc. April, 2024.|1
02724|094|R|8.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02724|095|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02724|096|R|  HIV. Department of Health and Human Services. Available at|6
02724|097|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
02724|098|R|  new-guidelines June 13, 2021.|6
02724|099|R|9.Sax PE, Wohl D, Yin MT, Post F, DeJesus E, etal. Tenofovir alafenamide|2
02724|100|R|  versus tenofovir disoproxil fumarate, coformulated with elvitegravir,|2
02724|101|R|  cobicistat, and emtricitabine, for initial treatment of HIV-1 infection:|2
02724|102|R|  two randomised, double-blind, phase 3, non-inferiority trials. Lancet 2015|2
02724|103|R|  Jun 27;385(9987):2606-15.|2
02724|104|R|10.FDA (US Food and Drug Administration). CDER Application number: 207561|1
02724|105|R|   Genvoya Clinical Pharmacology and Biopharmaceutics Reviews. accessed at:|1
02724|106|R|   http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207561Orig1s000Cli|1
02724|107|R|   nPharmR.pdf November 5, 2015.|1
02726|001|T|MONOGRAPH TITLE:  Pemetrexed/Aspirin (Greater Than 81 mg and Less Than or|
02726|002|T|Equal To 325 mg)|
02726|003|B||
02726|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02726|005|L|take action as needed.|
02726|006|B||
02726|007|A|MECHANISM OF ACTION:  Higher doses of aspirin may decrease the clearance of|
02726|008|A|pemetrexed.(1) This decreased clearance may be the result of chronic renal|
02726|009|A|toxicity or competition with pemetrexed for renal tubular secretion.(2)|
02726|010|B||
02726|011|E|CLINICAL EFFECTS:  Concurrent use of pemetrexed and higher aspirin doses may|
02726|012|E|result in elevated levels of and toxicity from pemetrexed, including|
02726|013|E|myelosuppression, neutropenia, renal toxicity, and gastrointestinal|
02726|014|E|toxicity.(1)|
02726|015|B||
02726|016|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
02726|017|P|patients with mild to moderate renal insufficiency (creatine clearance|
02726|018|P|(CrCl) of 45 ml/min to 79 ml/min).(1)|
02726|019|B||
02726|020|M|PATIENT MANAGEMENT:  Aspirin in low to moderate doses (325 mg every 6 hours)|
02726|021|M|does not affect the pharmacokinetics of pemetrexed.(1)|
02726|022|M|    If higher dose aspirin (or an NSAID) is required, patients should be|
02726|023|M|monitored for pemetrexed toxicity, especially myelosuppression, renal|
02726|024|M|toxicity, and gastrointestinal toxicity.(1)|
02726|025|M|   The manufacturer of pemetrexed recommends in patients with mild to|
02726|026|M|moderate renal insufficiency (CrCl from 45 ml/min to 79 ml/min), NSAIDs with|
02726|027|M|short half-lives should be avoided for 2 days before, the day of, and 2 days|
02726|028|M|after pemetrexed administration. (1)  NSAIDs and salicylates with long|
02726|029|M|half-lives should be avoided for at least 5 days before, the day of, and 2|
02726|030|M|days following pemetrexed administration in all patients.(1,2)|
02726|031|B||
02726|032|D|DISCUSSION:  In patients with normal renal function, ibuprofen (400 mg 4|
02726|033|D|times daily) decreased the clearance of pemetrexed by 20% and increased its|
02726|034|D|area-under-curve (AUC) by 20%.(1)|
02726|035|D|   In a Phase I clinical trial, two patients receiving high dose pemetrexed|
02726|036|D|therapy experienced severe toxicity, both were receiving a NSAID.  Following|
02726|037|D|these reports, all patients were required to stop aspirin or other NSAIDs 2|
02726|038|D|days before and not resume these agents until 2 days after pemetrexed.(2)|
02726|039|D|   In two randomized, controlled cross-over trials, 27 cancer patients with|
02726|040|D|a creatinine clearance (CrCl) less than or equal to 60 ml/min received|
02726|041|D|pemetrexed (500 mg/m2) infusion on Day 1 of a 21-day cycle and either|
02726|042|D|aspirin 325 mg or ibuprofen 400 mg orally every 6 hours starting 2 days|
02726|043|D|before pemetrexed administration. Coadministration of aspirin did not affect|
02726|044|D|pemetrexed pharmacokinetics. Ibuprofen decreased the clearance of pemetrexed|
02726|045|D|by 16%, increased its maximum concentration (Cmax) by 15%, and increased the|
02726|046|D|AUC by 20%.(3)|
02726|047|D|   Aspirin products linked to this monograph are single ingredient aspirin|
02726|048|D|or buffered aspirin products with strengths greater than 81 mg and less than|
02726|049|D|or equal to 325 mg strength.   Combination aspirin products (e.g. aspirin|
02726|050|D|combined with a statin) where aspirin greater than 81 mg or less than or|
02726|051|D|equal to 325 mg is used for cardiovascular protection are excluded from this|
02726|052|D|monograph.|
02726|053|B||
02726|054|R|REFERENCES:|
02726|055|B||
02726|056|R|1.Alimta (pemetrexed for injection) US prescribing information. Eli Lilly|1
02726|057|R|  and Company June, 2018.|1
02726|058|R|2.Personal Communication:  Alimta - Use with nsaids or aspirin. Eli Lilly|1
02726|059|R|  and Company February 10, 2004.|1
02726|060|R|3.Sweeney CJ, Takimoto CH, Latz JE, Baker SD, Murry DJ, Krull JH, Fife K,|2
02726|061|R|  Battiato L, Cleverly A, Chaudhary AK, Chaudhuri T, Sandler A, Mita AC,|2
02726|062|R|  Rowinsky EK. Two drug interaction studies evaluating the pharmacokinetics|2
02726|063|R|  and toxicity of pemetrexed when coadministered with aspirin or Ibuprofen|2
02726|064|R|  in patients with advanced cancer. Clin Cancer Res 2006 Jan 15;|2
02726|065|R|  12(2):536-42.|2
02727|001|T|MONOGRAPH TITLE:  Pazopanib/Selected Inhibitors of P-gp or BCRP|
02727|002|B||
02727|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02727|004|L|of severe adverse interaction.|
02727|005|B||
02727|006|A|MECHANISM OF ACTION:  Inhibitors of P-glycoprotein (P-gp) or BCRP may|
02727|007|A|increase the absorption of pazopanib.(1)|
02727|008|B||
02727|009|E|CLINICAL EFFECTS:  The concurrent administration of pazopanib with an|
02727|010|E|inhibitor of P-glycoprotein or BCRP may result in elevated levels of|
02727|011|E|pazopanib and signs of toxicity.(1)|
02727|012|B||
02727|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02727|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02727|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02727|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02727|017|P|gender, or advanced age.(2)|
02727|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02727|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02727|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02727|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02727|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02727|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02727|024|P|dysfunction).(2)|
02727|025|B||
02727|026|M|PATIENT MANAGEMENT:  The US manufacturer of pazopanib states concurrent use|
02727|027|M|of P-gp inhibitors or BCRP inhibitors should be avoided.(1)  Monitor|
02727|028|M|patients for increased side effects from pazopanib.|
02727|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02727|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02727|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02727|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02727|033|B||
02727|034|D|DISCUSSION:  Pazopanib is a substrate of P-gp and BCRP.  Inhibitors of these|
02727|035|D|transporters are expected to increase pazopanib levels.(1)|
02727|036|D|   BCRP inhibitors linked to this monograph include: asciminib, belumosudil,|
02727|037|D|clopidogrel, cyclosporine, curcumin, darolutamide, eltrombopag, enasidenib,|
02727|038|D|febuxostat, fostemsavir, grazoprevir, lazertinib, leflunomide, leniolisib,|
02727|039|D|momelotinib, oteseconazole, pirtobrutinib, regorafenib, resmetirom,|
02727|040|D|ritonavir, rolapitant, roxadustat, tafamidis, teriflunomide, tolvaptan,|
02727|041|D|turmeric, vadadustat, and zongertinib.(1,3-5)|
02727|042|D|   P-glycoprotein inhibitors linked to this monograph include: asunaprevir,|
02727|043|D|belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daridorexant,|
02727|044|D|diltiazem, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir,|
02727|045|D|imlunestrant, isavuconazonium, ivacaftor, ledipasvir, neratinib,|
02727|046|D|sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, ticagrelor,|
02727|047|D|valbenazine, verapamil, vimseltinib, and voclosporin.(3,4)|
02727|048|B||
02727|049|R|REFERENCES:|
02727|050|B||
02727|051|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
02727|052|R|  2020.|1
02727|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02727|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02727|055|R|  settings: a scientific statement from the American Heart Association and|6
02727|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02727|057|R|  2;55(9):934-47.|6
02727|058|R|3.This information is based on an extract from the Certara Drug Interaction|6
02727|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02727|060|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02727|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02727|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02727|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02727|064|R|  11/14/2017.|1
02728|001|T|MONOGRAPH TITLE:  Paclitaxel/Selected Strong and Moderate CYP2C8 Inhibitors|
02728|002|B||
02728|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02728|004|L|take action as needed.|
02728|005|B||
02728|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2C8 may inhibit paclitaxel metabolism|
02728|007|A|by this pathway.  Clopidogrel and gemfibrozil are strong inhibitors of|
02728|008|A|CYP2C8.  Deferasirox is a moderate inhibitor of CYP2C8.(1-3)|
02728|009|B||
02728|010|E|CLINICAL EFFECTS:  Concurrent use of CYP2C8 inhibitors and paclitaxel may|
02728|011|E|result in elevated levels and clinical effects of paclitaxel.(1,2)|
02728|012|B||
02728|013|P|PREDISPOSING FACTORS:  None determined.|
02728|014|B||
02728|015|M|PATIENT MANAGEMENT:  The US manufacturers of paclitaxel recommend|
02728|016|M|combination use CYP2C8 inhibitors with caution.  If concomitant use is|
02728|017|M|necessary, paclitaxel dose reduction may be required.(1,2)|
02728|018|B||
02728|019|D|DISCUSSION:  The US manufacturer of paclitaxel recommends use with CYP2C8|
02728|020|D|inhibitors with caution.(1,2)|
02728|021|B||
02728|022|R|REFERENCES:|
02728|023|B||
02728|024|R|1.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
02728|025|R|  Ltd. December, 2020.|1
02728|026|R|2.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
02728|027|R|  Company August, 2010.|1
02728|028|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02728|029|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02728|030|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02728|031|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02728|032|R|  11/14/2017.|1
02729|001|T|MONOGRAPH TITLE:  Selected Dopamine Agonists/Selected Antiemetics|
02729|002|B||
02729|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02729|004|L|of severe adverse interaction.|
02729|005|B||
02729|006|A|MECHANISM OF ACTION:  Selected dopamine agonists are used to treat|
02729|007|A|neurologic conditions such as Parkinson Disease (PD)or restless legs|
02729|008|A|syndrome (RLS), and endocrine disorders such as hyperprolactinemia by|
02729|009|A|directly or indirectly increasing dopamine concentrations at dopamine-2 (D2)|
02729|010|A|receptors in the central nervous system (CNS).  Antiemetic agents which|
02729|011|A|block CNS D2 receptors may counteract this effect.(1-5)|
02729|012|B||
02729|013|E|CLINICAL EFFECTS:  The efficacy of the dopamine agonist may be decreased,|
02729|014|E|leading to exacerbation of the disease being treated.|
02729|015|E|   In patients with Parkinson disease motor symptoms may worsen, increasing|
02729|016|E|the risk for falls, dysphagia or aspiration.(5)|
02729|017|E|   Patients with other conditions such as restless legs syndrome may also|
02729|018|E|experience symptom exacerbation due to this combination.|
02729|019|B||
02729|020|P|PREDISPOSING FACTORS:  Patients with Parkinson or Diffuse Lewy Body (DLB)|
02729|021|P|disease are particularly susceptible to adverse effects of dopamine|
02729|022|P|blockade.|
02729|023|B||
02729|024|M|PATIENT MANAGEMENT:  Reassess antiemetic therapy and use an antiemetic|
02729|025|M|without dopamine (D2) blocking effects if possible.  If clinically|
02729|026|M|appropriate and available, consider the use of a 5HT3 blocker (e.g.|
02729|027|M|ondansetron) or domperidone (not available in the US).(4)|
02729|028|M|   If concomitant treatment is needed, monitor for loss of efficacy for the|
02729|029|M|disease being treated by the dopamine agonist (e.g. Parkinson disease,|
02729|030|M|restless legs syndrome) and adjust medication(s) or dosage if needed.(1-4)|
02729|031|M|   Counsel patients to report symptoms of disease exacerbation.|
02729|032|B||
02729|033|D|DISCUSSION:  Patients with Parkinson or DLB disease are particularly|
02729|034|D|susceptible to adverse effects of dopamine blockade.  The European Academy|
02729|035|D|of Neurology guideline for late Parkinson disease states that|
02729|036|D|metoclopramide, cinnarizine and prochlorperazine must be avoided.|
02729|037|D|Ondansetron or domperidone(not available in the US) may be used for nausea|
02729|038|D|and vomiting.(5)|
02729|039|D|   Prescribing information for dopamine agonists warn of the risk for|
02729|040|D|disease exacerbation when dopamine blocking agents are co-prescribed.(1-4)|
02729|041|B||
02729|042|R|REFERENCES:|
02729|043|B||
02729|044|R|1.Requip (ropinirole hydrochloride) US prescribing information.|1
02729|045|R|  GlaxoSmithKline July, 2021.|1
02729|046|R|2.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
02729|047|R|  February, 2011.|1
02729|048|R|3.Stalveo (carbidopa; entacapone; levodopa) US Prescribing Information.|1
02729|049|R|  Orion/Novartis December, 2019.|1
02729|050|R|4.Neupro (rotigotine transdermal system) US prescribing information. UCB|1
02729|051|R|  Inc. November, 2018.|1
02729|052|R|5.Oertel WH Berardelli A Bloem Br etal. Chapter 15 - Late (complicated)|6
02729|053|R|  Parkinson's disease in European Handbook of Neurological Management. 2011;|6
02729|054|R|  Volume 1, 2nd Edition:237 - 267.|6
02730|001|T|MONOGRAPH TITLE:  Venetoclax/Moderate CYP3A4 Inhibitors|
02730|002|B||
02730|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02730|004|L|of severe adverse interaction.|
02730|005|B||
02730|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors inhibit the metabolism of|
02730|007|A|venetoclax.(1)|
02730|008|B||
02730|009|E|CLINICAL EFFECTS:  Concurrent use of moderate inhibitors of CYP3A4 may|
02730|010|E|result in elevated levels of venetoclax, increasing the risk for tumor lysis|
02730|011|E|syndrome and other toxicities.(1)|
02730|012|B||
02730|013|P|PREDISPOSING FACTORS:  Risk factors for tumor lysis syndrome include (1):|
02730|014|P|- the ramp-up phase of venetoclax therapy when tumor burden is highest|
02730|015|P|- initial magnitude of tumor burden|
02730|016|P|- renal impairment|
02730|017|P|   The risk of venetoclax toxicities may be increased in patients with|
02730|018|P|severe hepatic impairment.(1)|
02730|019|B||
02730|020|M|PATIENT MANAGEMENT:  Avoid moderate CYP3A4 inhibitors and consider|
02730|021|M|alternative treatments when possible.  If a moderate CYP3A4 inhibitor must|
02730|022|M|be used, reduce venetoclax dose by at least 50%. Monitor more closely for|
02730|023|M|signs of toxicity such as tumor lysis syndrome, hematologic and|
02730|024|M|non-hematologic toxicities.(1)|
02730|025|M|   Canadian labeling for atazanavir contraindicates concurrent use of|
02730|026|M|atazanavir/ritonavir with venetoclax at venetoclax dose initiation and|
02730|027|M|during the ramp-up phase.(2)|
02730|028|M|   If the moderate CYP3A4 inhibitor is discontinued, the manufacturer of|
02730|029|M|venetoclax recommends resuming the prior (i.e. pre-inhibitor) dose of|
02730|030|M|venetoclax 2 to 3 days after discontinuation of the moderate CYP3A4|
02730|031|M|inhibitor.|
02730|032|B||
02730|033|D|DISCUSSION:  In 11 previously treated NHL subjects, ketoconazole (a strong|
02730|034|D|CYP3A4 inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days|
02730|035|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02730|036|D|venetoclax 2.3-fold and 6.4-fold respectively.(1)|
02730|037|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
02730|038|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir,|
02730|039|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
02730|040|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
02730|041|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
02730|042|D|rilzabrutinib, schisandra, sevabertinib, stiripentol, tofisopam, treosulfan,|
02730|043|D|and verapamil.(3-4)|
02730|044|B||
02730|045|R|REFERENCES:|
02730|046|B||
02730|047|R|1.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
02730|048|R|  2021.|1
02730|049|R|2.Reyataz (atazanavir) Canadian prescribing information. Bristol-Myers|1
02730|050|R|  Squibb Canada August 31, 2023.|1
02730|051|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02730|052|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02730|053|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02730|054|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02730|055|R|  11/14/2017.|1
02730|056|R|4.This information is based on an extract from the Certara Drug Interaction|6
02730|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02731|001|T|MONOGRAPH TITLE:  Warfarin/Venetoclax|
02731|002|B||
02731|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02731|004|L|take action as needed.|
02731|005|B||
02731|006|A|MECHANISM OF ACTION:  Venetoclax may increase systemic exposure to warfarin.|
02731|007|A|The mechanism of this interaction is not clear.|
02731|008|B||
02731|009|E|CLINICAL EFFECTS:  Concurrent use of venetoclax with warfarin may increase|
02731|010|E|the risk of bleeding.|
02731|011|B||
02731|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02731|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02731|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
02731|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02731|016|P|risk for bleeding (e.g. NSAIDs).|
02731|017|B||
02731|018|M|PATIENT MANAGEMENT:  The manufacturer of venetoclax recommends more frequent|
02731|019|M|monitoring of the INR in patients taking this combination.(1)  When|
02731|020|M|initiated, venetoclax dosage gradually increases over 5 or more weeks, thus|
02731|021|M|extended INR monitoring may be required to assess interaction risk and|
02731|022|M|magnitude.|
02731|023|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02731|024|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
02731|025|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
02731|026|M|evaluate patients with any symptoms.|
02731|027|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02731|028|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02731|029|M|anticoagulation in patients with active pathologic bleeding.|
02731|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02731|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02731|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02731|033|M|and/or swelling.|
02731|034|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02731|035|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02731|036|M|initiating, altering the dose or discontinuing either drug.|
02731|037|B||
02731|038|D|DISCUSSION:  In a drug-drug interaction study in three healthy subjects,|
02731|039|D|administration of a single 400 mg dose of venetoclax with 5 mg of warfarin|
02731|040|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02731|041|D|warfarin 18% and 28% respectively.(1)|
02731|042|D|   Because only one dose of venetoclax was given in this study, the|
02731|043|D|interaction severity and recommended monitoring duration for the combination|
02731|044|D|of venetoclax and warfarin is not clear.|
02731|045|B||
02731|046|R|REFERENCE:|
02731|047|B||
02731|048|R|1.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
02731|049|R|  2021.|1
02732|001|T|MONOGRAPH TITLE:  Pimavanserin/QT Prolonging Agents|
02732|002|B||
02732|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02732|004|L|of severe adverse interaction.|
02732|005|B||
02732|006|A|MECHANISM OF ACTION:  Pimavanserin prolongs the QTc interval.(1)  Concurrent|
02732|007|A|use with other agents that prolong the QTc interval may result in additive|
02732|008|A|effects on the QTc interval.(2,3)|
02732|009|B||
02732|010|E|CLINICAL EFFECTS:  The concurrent use of pimavanserin with other agents that|
02732|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02732|012|E|arrhythmias, including torsades de pointes.(2,3)|
02732|013|B||
02732|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02732|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02732|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02732|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02732|018|P|gender, or advanced age.(3)|
02732|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02732|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02732|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02732|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02732|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02732|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02732|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02732|026|B||
02732|027|M|PATIENT MANAGEMENT:  Avoid the use of pimavanserin in patients receiving QT|
02732|028|M|prolonging agents.(1)|
02732|029|M|   During concomitant therapy with another QT prolonging agent, monitor|
02732|030|M|patients closely for prolongation of the QT interval.(1)  Obtain serum|
02732|031|M|calcium, magnesium, and potassium levels and monitoring ECG at regular|
02732|032|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
02732|033|M|report any irregular heartbeat, dizziness, or fainting.|
02732|034|B||
02732|035|D|DISCUSSION:  In thorough-QT study, pimavanserin (at twice the therapeutic|
02732|036|D|dose) found that the maximum mean change was 13.5 (16.6) msec.  In|
02732|037|D|placebo-controlled effectiveness studies, mean increases of 5-8 msec were|
02732|038|D|observed with normal dosages of 37 mg daily.  Sporadic QTcF values of equal|
02732|039|D|to or greater than 500 msec and change from baseline values equal to or|
02732|040|D|greater than 60 msec were observed at this dose as well.(1)|
02732|041|D|   Agents that are linked to this monograph may have varying degrees of|
02732|042|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02732|043|D|been shown to prolong the QTc interval either through their mechanism of|
02732|044|D|action, through studies on their effects on the QTc interval, or through|
02732|045|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02732|046|D|and/or postmarketing reports.(2)|
02732|047|B||
02732|048|R|REFERENCES:|
02732|049|B||
02732|050|R|1.Nuplazid (pimavanserin) US prescribing information. ACADIA Pharmaceuticals|1
02732|051|R|  Inc. May, 2019.|1
02732|052|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02732|053|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02732|054|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02732|055|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02732|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02732|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02732|058|R|  settings: a scientific statement from the American Heart Association and|6
02732|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02732|060|R|  2;55(9):934-47.|6
02733|001|T|MONOGRAPH TITLE:  Pimavanserin/Possible QT Prolonging Agents|
02733|002|B||
02733|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02733|004|L|take action as needed.|
02733|005|B||
02733|006|A|MECHANISM OF ACTION:  Pimavanserin prolongs the QTc interval.(1)  Concurrent|
02733|007|A|use with other agents that prolong the QTc interval may result in additive|
02733|008|A|effects on the QTc interval.(2,3)|
02733|009|B||
02733|010|E|CLINICAL EFFECTS:  The concurrent use of pimavanserin with other agents that|
02733|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02733|012|E|arrhythmias, including torsades de pointes.(2,3)|
02733|013|B||
02733|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02733|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02733|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02733|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02733|018|P|gender, or advanced age.(3)|
02733|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02733|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02733|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02733|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02733|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02733|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02733|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02733|026|B||
02733|027|M|PATIENT MANAGEMENT:  Avoid the use of pimavanserin in patients receiving QT|
02733|028|M|prolonging agents.(1)|
02733|029|M|   During concomitant therapy with another QT prolonging agent, monitor|
02733|030|M|patients closely for prolongation of the QT interval.(1)  Obtain serum|
02733|031|M|calcium, magnesium, and potassium levels and monitoring ECG at regular|
02733|032|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
02733|033|M|report any irregular heartbeat, dizziness, or fainting.|
02733|034|B||
02733|035|D|DISCUSSION:  In thorough-QT study, pimavanserin (at twice the therapeutic|
02733|036|D|dose) found that the maximum mean change was 13.5 (16.6) msec.  In|
02733|037|D|placebo-controlled effectiveness studies, mean increases of 5-8 msec were|
02733|038|D|observed with normal dosages of 37 mg daily.  Sporadic QTcF values of equal|
02733|039|D|to or greater than 500 msec and change from baseline values equal to or|
02733|040|D|greater than 60 msec were observed at this dose as well.(1)|
02733|041|D|   Agents that are linked to this monograph may have varying degrees of|
02733|042|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02733|043|D|been shown to prolong the QTc interval either through their mechanism of|
02733|044|D|action, through studies on their effects on the QTc interval, or through|
02733|045|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02733|046|D|and/or postmarketing reports.(2)|
02733|047|B||
02733|048|R|REFERENCES:|
02733|049|B||
02733|050|R|1.Nuplazid (pimavanserin) US prescribing information. ACADIA Pharmaceuticals|1
02733|051|R|  Inc. May, 2019.|1
02733|052|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02733|053|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02733|054|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02733|055|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02733|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02733|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02733|058|R|  settings: a scientific statement from the American Heart Association and|6
02733|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02733|060|R|  2;55(9):934-47.|6
02734|001|T|MONOGRAPH TITLE:  Pimavanserin/Strong and Moderate CYP3A4 Inducers|
02734|002|B||
02734|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02734|004|L|of severe adverse interaction.|
02734|005|B||
02734|006|A|MECHANISM OF ACTION:  Strong or moderate inducers of CYP3A4 may induce the|
02734|007|A|metabolism of pimavanserin.(1)|
02734|008|B||
02734|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
02734|010|E|may result in decreased levels and effectiveness of pimavanserin.(1)|
02734|011|B||
02734|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02734|013|P|of the inducer for longer than 1-2 weeks.|
02734|014|B||
02734|015|M|PATIENT MANAGEMENT:  The US manufacturer of pimavanserin recommends avoiding|
02734|016|M|concomitant use of strong or moderate CYP3A4 inducers.(1)|
02734|017|B||
02734|018|D|DISCUSSION:  Pimavanserin is primarily metabolized by CYP3A4 while other|
02734|019|D|metabolic enzymes CYP2J2, CYP2D6 and FMO play a lesser role.(1)  In a study|
02734|020|D|of subjects pretreated with 7 days of rifampin (600 mg daily, a strong|
02734|021|D|CYP3A4 inducer), a single dose of pimavanserin (34 mg) produced an|
02734|022|D|area-under-curve (AUC) and maximum concentration (Cmax) that was 91 % and 71|
02734|023|D|% lower, respectively, than when pimavanserin is given without rifampin.(1)|
02734|024|D|   A physiology-based pharmacokinetic model predicted that efavirenz (a|
02734|025|D|moderate CYP3A4 inducer) would decrease pimavanserin AUC and Cmax by 70 %|
02734|026|D|and 60 %, respectively.(1)|
02734|027|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
02734|028|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
02734|029|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
02734|030|D|wort.(3-4)|
02734|031|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
02734|032|D|dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten,|
02734|033|D|mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin,|
02734|034|D|sotorasib, telotristat, and tovorafenib.(3-4)|
02734|035|B||
02734|036|R|REFERENCES:|
02734|037|B||
02734|038|R|1.Nuplazid (pimavanserin) US prescribing information. ACADIA Pharmaceuticals|1
02734|039|R|  Inc. May, 2019.|1
02734|040|R|2.Hoffmann C. Personal communication: Nuplazid Drug-drug interactions.|1
02734|041|R|  Acadia Pharmaceuticals.|1
02734|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02734|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02734|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02734|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02734|046|R|  11/14/2017.|1
02734|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
02734|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02735|001|T|MONOGRAPH TITLE:  Pimavanserin (Less Than or Equal To 10 mg)/Strong CYP3A4|
02735|002|T|Inhibitors; Protease Inhibitors|
02735|003|B||
02735|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02735|005|L|take action as needed.|
02735|006|B||
02735|007|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
02735|008|A|metabolism of pimavanserin.(1)|
02735|009|B||
02735|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors or HIV|
02735|011|E|protease inhibitors may increase systemic exposure and the risk for|
02735|012|E|pimavanserin toxicities such as peripheral edema, confusion, or QT|
02735|013|E|prolongation.(1,2)|
02735|014|B||
02735|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02735|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02735|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02735|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02735|019|P|gender, or advanced age.(3)|
02735|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02735|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02735|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02735|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02735|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02735|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02735|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02735|027|B||
02735|028|M|PATIENT MANAGEMENT:  When concomitant use of pimavanserin and a strong|
02735|029|M|CYP3A4 inhibitor or HIV protease inhibitor is needed, the pimavanserin dose|
02735|030|M|should be reduced to 10 mg once daily.(1,2)|
02735|031|M|   With unboosted atazanavir, consider using alternative antipsychotic|
02735|032|M|agents.(2)|
02735|033|M|   During concomitant therapy with a strong CYP3A4 inhibitor or HIV protease|
02735|034|M|inhibitor, monitor patients closely for prolongation of the QT interval.|
02735|035|M|Obtain serum calcium, magnesium, and potassium levels and monitor ECG at|
02735|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02735|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02735|038|B||
02735|039|D|DISCUSSION:  In a drug interaction study, ketoconazole increased|
02735|040|D|pimavanserin maximum concentration (Cmax) 1.5-fold and area-under-curve(AUC)|
02735|041|D|3-fold.|
02735|042|D|   A thorough QTc study performed in 252 subjects found a mean maximum|
02735|043|D|change from baseline of 13.5 msec (upper bound of the 90% confidence|
02735|044|D|interval was 16.6 msec) at twice the therapeutic dose.(1) Thus,|
02735|045|D|coadministration of pimavanserin and a QT prolonging agent, even at a|
02735|046|D|reduced dose, may increase the risk for significant QT prolongation.|
02735|047|D|   CYP3A4 inhibitors linked to this monograph include: atazanavir,|
02735|048|D|boceprevir, cobicistat, darunavir, fosamprenavir, idelalisib, indinavir,|
02735|049|D|itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone,|
02735|050|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir,|
02735|051|D|troleandomycin, and tucatinib.(4)|
02735|052|B||
02735|053|R|REFERENCES:|
02735|054|B||
02735|055|R|1.Nuplazid (pimavanserin) US prescribing information. ACADIA Pharmaceuticals|1
02735|056|R|  Inc. May, 2019.|1
02735|057|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02735|058|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02735|059|R|  HIV. Department of Health and Human Services. Available at:|6
02735|060|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
02735|061|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
02735|062|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02735|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02735|064|R|  settings: a scientific statement from the American Heart Association and|6
02735|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02735|066|R|  2;55(9):934-47.|6
02735|067|R|4.This information is based on an extract from the Certara Drug Interaction|6
02735|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02736|001|T|MONOGRAPH TITLE:  Flecainide/Selected Strong CYP2D6 Inhibitors|
02736|002|B||
02736|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02736|004|L|take action as needed.|
02736|005|B||
02736|006|A|MECHANISM OF ACTION:  Bupropion, dacomitinib, fluoxetine, and paroxetine are|
02736|007|A|strong CYP2D6 inhibitors and may inhibit the CYP2D6 mediated metabolism of|
02736|008|A|flecainide.(1)|
02736|009|B||
02736|010|E|CLINICAL EFFECTS:  Concurrent use may result in prolongation of the QTc|
02736|011|E|interval and potentially life-threatening ventricular arrhythmias.(2-5)|
02736|012|B||
02736|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
02736|014|P|are CYP2D6 extensive or intermediate metabolizers.|
02736|015|P|   Renal and hepatic impairment may increase risk for excessive QTc|
02736|016|P|prolongation as flecainide is renally and hepatically eliminated. To prevent|
02736|017|P|increased serum levels and risk for ventricular arrhythmias, flecainide must|
02736|018|P|be dose adjusted in renal and hepatic insufficiency.|
02736|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02736|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02736|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02736|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02736|023|P|advanced age.(6)|
02736|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02736|025|P|higher systemic concentrations of either QT prolonging drug are additional|
02736|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02736|027|P|drug concentrations include rapid infusion of an intravenous dose or|
02736|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02736|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02736|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
02736|031|B||
02736|032|M|PATIENT MANAGEMENT:  Manufacturers of bupropion, fluoxetine, paroxetine|
02736|033|M|recommend caution with concurrent use of flecainide due to the increased|
02736|034|M|risk for ventricular arrhythmias (e.g. torsades de pointes) associated with|
02736|035|M|higher flecainide concentrations.(2-5)  Consider use of an alternative|
02736|036|M|antidepressant or antiarrhythmic if possible.|
02736|037|M|   If concurrent therapy is deemed medically necessary, consider therapeutic|
02736|038|M|drug monitoring of flecainide levels and obtain serum calcium, magnesium,|
02736|039|M|and potassium levels and monitoring ECG at baseline and at regular|
02736|040|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
02736|041|M|report any irregular heartbeat, dizziness, or fainting.|
02736|042|B||
02736|043|D|DISCUSSION:  In a drug interaction and pharmacogenomics study in 21 healthy|
02736|044|D|subjects, paroxetine 20 mg daily for 7 days increased flecainide exposure|
02736|045|D|(area-under-curve, AUC) by 28%.(7)|
02736|046|B||
02736|047|R|REFERENCES:|
02736|048|B||
02736|049|R|1.This information is based on an extract from the Certara Drug Interaction|6
02736|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02736|051|R|2.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
02736|052|R|  Technologies January, 2017.|1
02736|053|R|3.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
02736|054|R|  Therapeutics, LLC September, 2021.|1
02736|055|R|4.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
02736|056|R|  and Company August, 2023.|1
02736|057|R|5.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
02736|058|R|  GlaxoSmithKline November, 2019.|1
02736|059|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02736|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02736|061|R|  settings: a scientific statement from the American Heart Association and|6
02736|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02736|063|R|  2;55(9):934-47.|6
02736|064|R|7.Lim KS, Cho JY, Jang IJ, Kim BH, Kim J, Jeon JY, Tae YM, Yi S, Eum S, Shin|2
02736|065|R|  SG, Yu KS. Pharmacokinetic interaction of flecainide and paroxetine in|2
02736|066|R|  relation to the CYP2D6*10 allele in healthy Korean subjects. Br J Clin|2
02736|067|R|  Pharmacol 2008 Nov;66(5):660-6.|2
02737|001|T|MONOGRAPH TITLE:  Selected ARBs/Paritaprevir-ritonavir|
02737|002|B||
02737|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02737|004|L|take action as needed.|
02737|005|B||
02737|006|A|MECHANISM OF ACTION:  The combination of paritaprevir-ritonavir inhibits|
02737|007|A|multiple transport or elimination pathways: OATP1B1, OATP1B3, OATP2B1, P-gp,|
02737|008|A|BCRP, CYP3A4 and UGT1A1.(1-3)|
02737|009|A|   Selected angiotensin receptor blockers(ARBs) - candesartan, losartan,|
02737|010|A|olmesartan, telmisartan and valsartan are substrates for one or more of|
02737|011|A|these pathways.(1,2,4-8)|
02737|012|B||
02737|013|E|CLINICAL EFFECTS:  Transport inhibition of candesartan, losartan,|
02737|014|E|olmesartan, telmisartan, or valsartan may lead to higher systemic|
02737|015|E|concentrations, increasing the risk for hypotension or renal impairment.(1)|
02737|016|B||
02737|017|P|PREDISPOSING FACTORS:  Patients with renal impairment or dehydration are|
02737|018|P|more susceptible to adverse effects from angiotensin receptor|
02737|019|P|blockers(ARBs).(1)|
02737|020|B||
02737|021|M|PATIENT MANAGEMENT:  The manufacturer of paritaprevir-ritonavir(1,2)|
02737|022|M|recommends reducing the angiotensin receptor blocker (ARB) dose when this|
02737|023|M|hepatitis C therapy is started.  Monitor for hypotension and/or change in|
02737|024|M|renal function.  Further decreases in the ARB dose may be necessary.|
02737|025|B||
02737|026|D|DISCUSSION:  The interaction between ARBs and paritaprevir-ritonavir has not|
02737|027|D|been studied.(1,2)|
02737|028|D|   In vitro studies have found that OATP1B1 and/or OATP1B3 transports|
02737|029|D|olmesartan,(4,5) telmisartan(6,7) and valsartan(8) into the liver for|
02737|030|D|further metabolism or elimination.  Inhibition of transport leads to|
02737|031|D|increased systemic concentrations of the ARB.  Due to the lack of in vivo|
02737|032|D|studies, the magnitude of this effect is not clear.|
02737|033|B||
02737|034|R|REFERENCES:|
02737|035|B||
02737|036|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02737|037|R|  prescribing information. AbbVie Inc. December, 2019.|1
02737|038|R|2.Viekirax (ombitasvir, paritaprevir, ritonavir) UK summary of product|1
02737|039|R|  characteristics. AbbVie Limited January 16, 2019.|1
02737|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
02737|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02737|042|R|4.Yamada A, Maeda K, Kamiyama E, Sugiyama D, Kondo T, Shiroyanagi Y,|5
02737|043|R|  Nakazawa H, Okano T, Adachi M, Schuetz JD, Adachi Y, Hu Z, Kusuhara H,|5
02737|044|R|  Sugiyama Y. Multiple human isoforms of drug transporters contribute to the|5
02737|045|R|  hepatic and renal  transport of olmesartan, a selective antagonist of the|5
02737|046|R|  angiotensin II AT1-receptor. Drug Metab Dispos 2007 Dec;35(12):2166-76.|5
02737|047|R|5.Nakagomi-Hagihara R, Nakai D, Kawai K, Yoshigae Y, Tokui T, Abe T, Ikeda|5
02737|048|R|  T. OATP1B1, OATP1B3, and mrp2 are involved in hepatobiliary transport of|5
02737|049|R|  olmesartan, a novel angiotensin II blocker. Drug Metab Dispos 2006 May;|5
02737|050|R|  34(5):862-9.|5
02737|051|R|6.Li R, Ghosh A, Maurer TS, Kimoto E, Barton HA. Physiologically based|5
02737|052|R|  pharmacokinetic prediction of telmisartan in human. Drug Metab Dispos 2014|5
02737|053|R|  Oct;42(10):1646-55.|5
02737|054|R|7.Ishiguro N, Maeda K, Saito A, Kishimoto W, Matsushima S, Ebner T, Roth W,|5
02737|055|R|  Igarashi T, Sugiyama Y. Establishment of a set of double transfectants|5
02737|056|R|  coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux|5
02737|057|R|  transporters for the characterization of the hepatobiliary transport of|5
02737|058|R|  telmisartan acylglucuronide. Drug Metab Dispos 2008 Apr;36(4):796-805.|5
02737|059|R|8.Yamashiro W, Maeda K, Hirouchi M, Adachi Y, Hu Z, Sugiyama Y. Involvement|5
02737|060|R|  of transporters in the hepatic uptake and biliary excretion of valsartan,|5
02737|061|R|  a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug|5
02737|062|R|  Metab Dispos 2006 Jul;34(7):1247-54.|5
02738|001|T|MONOGRAPH TITLE:  Ropivacaine/Strong CYP1A2 Inhibitors|
02738|002|B||
02738|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02738|004|L|take action as needed.|
02738|005|B||
02738|006|A|MECHANISM OF ACTION:  Strong CYP1A2 inhibitors may inhibit the metabolism of|
02738|007|A|ropivacaine.|
02738|008|B||
02738|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP1A2 inhibitor may result in|
02738|010|E|increased levels of and toxicity from ropivacaine.|
02738|011|B||
02738|012|P|PREDISPOSING FACTORS:  None determined.|
02738|013|B||
02738|014|M|PATIENT MANAGEMENT:  In patients receiving concurrent strong CYP1A2|
02738|015|M|inhibitors and ropivacaine, monitor patients closely for signs of toxicity.|
02738|016|B||
02738|017|D|DISCUSSION:  In a double-blind, randomized, cross-over study in 9 healthy|
02738|018|D|subjects, ciprofloxacin (500 mg twice daily) decreased the clearance of a|
02738|019|D|single dose of ropivacaine (0.6 mg/kg) by 31%.(1)|
02738|020|D|   In a double-blind, randomized, cross-over study in 8 healthy subjects,|
02738|021|D|fluvoxamine (100 mg daily) increased the area-under-curve (AUC) of a single|
02738|022|D|dose of ropivacaine (0.6 mg/kg) by 3.7-fold.(2)|
02738|023|D|   In a randomized, cross-over study in 12 healthy subjects, fluvoxamine (25|
02738|024|D|mg daily) increased the clearance of a single dose of ropivacaine (40 mg) by|
02738|025|D|68%.  Ropivacaine half-life almost doubled.(3)|
02738|026|D|   Strong inhibitors of CYP1A2 include angelica root (angelica dahurica|
02738|027|D|radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(4,5)|
02738|028|B||
02738|029|R|REFERENCES:|
02738|030|B||
02738|031|R|1.Jokinen MJ, Olkkola KT, Ahonen J, Neuvonen PJ. Effect of ciprofloxacin on|2
02738|032|R|  the pharmacokinetics of ropivacaine. Eur J Clin Pharmacol 2003 Feb;|2
02738|033|R|  58(10):653-7.|2
02738|034|R|2.Jokinen MJ, Ahonen J, Neuvonen PJ, Olkkola KT. The effect of erythromycin,|2
02738|035|R|  fluvoxamine, and their combination on the pharmacokinetics of ropivacaine.|2
02738|036|R|  Anesth Analg 2000 Nov;91(5):1207-12.|2
02738|037|R|3.Arlander E, Ekstrom G, Alm C, Carrillo JA, Bielenstein M, Bottiger Y,|2
02738|038|R|  Bertilsson L, Gustafsson LL. Metabolism of ropivacaine in humans is|2
02738|039|R|  mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study|2
02738|040|R|  with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Pharmacol|2
02738|041|R|  Ther 1998 Nov;64(5):484-91.|2
02739|001|T|MONOGRAPH TITLE:  Clopidogrel/Isoniazid|
02739|002|B||
02739|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02739|004|L|of severe adverse interaction.|
02739|005|B||
02739|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
02739|007|A|active metabolite via a 2 step process.  The first conversion step is|
02739|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
02739|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
02739|010|A|thought to be the more important enzyme involved in formation of the|
02739|011|A|pharmacologically active metabolite.(1)|
02739|012|A|   Isoniazid may inhibit the metabolism of clopidogrel to its active|
02739|013|A|metabolite via inhibition of CYP2C19.|
02739|014|B||
02739|015|E|CLINICAL EFFECTS:  Concurrent use of isoniazid and clopidogrel may result in|
02739|016|E|decreased clopidogrel effectiveness, resulting in increased risk of adverse|
02739|017|E|cardiac events.|
02739|018|B||
02739|019|P|PREDISPOSING FACTORS:  Patients who are 'slow acetylators' of NAT2, the|
02739|020|P|enzyme which metabolizes isoniazid, may have substantially (e.g. 2 to|
02739|021|P|7-fold) higher isoniazid concentrations than 'fast acetylators'.  Higher|
02739|022|P|isoniazid levels may have greater inhibition of the CYP2C19 metabolism of|
02739|023|P|clopidogrel to its active metabolite.|
02739|024|B||
02739|025|M|PATIENT MANAGEMENT:  Evaluate the medication list or interaction alerts to|
02739|026|M|determine if patient is receiving additional drugs which may also inhibit|
02739|027|M|clopidogrel active metabolite formation.  Whenever possible, convert patient|
02739|028|M|to non-interacting medication(s).|
02739|029|M|   If potential interacting medication(s) cannot be changed, consider|
02739|030|M|alternative antiplatelet therapy or testing to assure adequate on-treatment|
02739|031|M|inhibition of platelet reactivity.|
02739|032|M|   The US manufacturer of clopidogrel states that alternatives to|
02739|033|M|clopidogrel should be considered in patients who are poor metabolizers of|
02739|034|M|CYP2C19.(1)  It would be prudent to assume that patients taking strong|
02739|035|M|inhibitors of CYP2C19 are poor metabolizers of this isoenzyme.|
02739|036|M|   Consider alternatives to isoniazid in patients stabilized on clopidogrel|
02739|037|M|and alternatives to clopidogrel in patients stabilized on isoniazid.  If|
02739|038|M|concurrent therapy is warranted, consider appropriate testing to assure|
02739|039|M|adequate inhibition of platelet reactivity.|
02739|040|B||
02739|041|D|DISCUSSION:  In pharmacogenomic studies and clinical trials, patients with a|
02739|042|D|CYP2C19 poor metabolizer phenotype have decreased active metabolite|
02739|043|D|exposure, diminished antiplatelet effects, and a higher rate of|
02739|044|D|cardiovascular events compared with extensive metabolizers.(1,3)|
02739|045|D|   Studies have not evaluated this specific drug combination; the actual|
02739|046|D|magnitude of this interaction is not known.  Given the possible consequences|
02739|047|D|of clopidogrel treatment failure, it would be prudent to avoid concomitant|
02739|048|D|use of clopidogrel and isoniazid when possible.|
02739|049|B||
02739|050|R|REFERENCES:|
02739|051|B||
02739|052|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
02739|053|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
02739|054|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
02739|055|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
02739|056|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
02739|057|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
02739|058|R|  38(1):92-9.|5
02739|059|R|3.US Food and Drug Association. Information on Clopidogrel Bisulfate|1
02739|060|R|  (marketed as Plavix). Available at:|1
02739|061|R|  http://wayback.archive-it.org/7993/20170111075953/http:/www.fda.gov/Drugs/|1
02739|062|R|  DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm19083|1
02739|063|R|  6.htm October 27, 2010.|1
02740|001|T|MONOGRAPH TITLE:  Erythropoietic agents/Lenalidomide|
02740|002|B||
02740|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02740|004|L|of severe adverse interaction.|
02740|005|B||
02740|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.|
02740|007|B||
02740|008|E|CLINICAL EFFECTS:  Concurrent use of erythropoietic agents, such as|
02740|009|E|darbepoetin or epoetin, with lenalidomide may increase the risk of|
02740|010|E|thrombosis.(1,2)|
02740|011|B||
02740|012|P|PREDISPOSING FACTORS:  None determined.|
02740|013|B||
02740|014|M|PATIENT MANAGEMENT:  The US manufacturer of lenalidomide states the risk of|
02740|015|M|venous thromboembolism (VTE) may be increased when patients are taking|
02740|016|M|concomitant therapy with erythropoietin stimulating agents.  Use caution|
02740|017|M|with concomitant use after a patient specific risk-benefit assessment has|
02740|018|M|been completed.  Observe patients for signs and symptoms of VTE and instruct|
02740|019|M|patients to seek medical care if they develop symptoms such as shortness of|
02740|020|M|breath, chest pain, or arm or leg swelling.(1)|
02740|021|M|   The National Comprehensive Cancer Network (NCCN) Guidelines include use|
02740|022|M|of erythropoietic stimulating agents as a high risk factor for venous|
02740|023|M|thromboembolism (VTE).  Other risk factors include: active cancer, advanced|
02740|024|M|stage cancer, certain cancer types, regional bulky lymphadenopathy, familial|
02740|025|M|and/or acquired hypercoagulability, medical comorbidities, poor performance|
02740|026|M|status, older age, major surgery, central venous catheter, chemotherapy|
02740|027|M|including lenalidomide plus high-dose dexamethasone, hormone replacement|
02740|028|M|therapy, contraceptives, tamoxifen/raloxifene, diethylstilbestrol, smoking,|
02740|029|M|obesity, or activity level/exercise.(3)|
02740|030|M|   The NCCN Guidelines utilize a Risk Assessment Model to determine|
02740|031|M|chemoprophylaxis.  In patients with 0-1 risk factors, consider VTE|
02740|032|M|chemoprophylaxis with aspirin 81-325 mg once daily.  In patients with >/= 2|
02740|033|M|risk factors, consider VTE chemoprophylaxis with low-molecular weight|
02740|034|M|heparin (LMWH) with a dose equivalent to enoxaparin 40 mg once daily or|
02740|035|M|full-dose warfarin with a dose to maintain a target international normalized|
02740|036|M|ratio (INR) 2-3.(3)|
02740|037|B||
02740|038|D|DISCUSSION:  The National Comprehensive Cancer Network (NCCN) Guidelines|
02740|039|D|include use of erythropoietin as an individual risk factor for venous|
02740|040|D|thromboembolism (VTE).  Patients should be assessed for total risk based on|
02740|041|D|NCCN guidelines and recommended for the appropriate VTE chemoprophylaxis|
02740|042|D|agent based on risk category.(3)|
02740|043|D|   A pooled analysis of two placebo-controlled trials in multiple myeloma|
02740|044|D|noted an incidence rate for VTE of 23% in patients receiving lenalidomide,|
02740|045|D|dexamethasone and erythropoietic therapy versus 5% in patients without|
02740|046|D|erythropoietic therapy.  A multivariate analysis indicated an independent|
02740|047|D|correlation between thrombosis and patients with concomitant erythropoietin|
02740|048|D|therapy.(4)|
02740|049|D|   A pooled analysis of 125 patients from 3 trials with multiple myeloma on|
02740|050|D|lenalidomide therapy noted a 17% incidence of VTE in patients on|
02740|051|D|lenalidomide with concurrent erythropoietin therapy.(5)|
02740|052|D|   Several studies have evaluated the optimal VTE prophylaxis agent with|
02740|053|D|lenalidomide-treated patients.  Patients receiving|
02740|054|D|lenalidomide/dexamethasone and no chemoprophylaxis had a VTE incidence of|
02740|055|D|11-75%, 26% with the use of aspirin, 17% with the use of|
02740|056|D|aspirin/LMWH/warfarin combination therapy, and 2-15% with the use of LMWH.|
02740|057|D|(6)|
02740|058|B||
02740|059|R|REFERENCES:|
02740|060|B||
02740|061|R|1.Revlimid (lenalidomide) US prescribing information. Celgene Corporation|1
02740|062|R|  May 2019.|1
02740|063|R|2.Aranesp (darbepoetin alfa) US prescribing information. Amgen Inc April 13,|1
02740|064|R|  2017.|1
02740|065|R|3.Streiff M, Holmstrom B, Ashrani Aetal. Cancer-associated venous|6
02740|066|R|  thromboembolic disease.  NCCN Clinical Practice Guidelines in Oncology.|6
02740|067|R|  Available at www.nccn.org/professionals/physician_gls/f_guidelines.asp|6
02740|068|R|  January, 2015.|6
02740|069|R|4.Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple|2
02740|070|R|  myeloma. N Engl J Med 2006 May 11;354(19):2079-80.|2
02740|071|R|5.Menon SP, Rajkumar SV, Lacy M, Falco P, Palumbo A. Thromboembolic events|2
02740|072|R|  with lenalidomide-based therapy for multiple myeloma. Cancer 2008 Apr 1;|2
02740|073|R|  112(7):1522-8.|2
02740|074|R|6.Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J,|6
02740|075|R|  Barlogie B, Harousseau J, Zonder JA, Cavo M, Zangari M, Attal M, Belch A,|6
02740|076|R|  Knop S, etal. Prevention of thalidomide- and lenalidomide-associated|6
02740|077|R|  thrombosis in myeloma. Leukemia 2008 Feb;22(2):414-23.|6
02741|001|T|MONOGRAPH TITLE:  Dofetilide/Lamotrigine|
02741|002|B||
02741|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02741|004|L|is contraindicated and generally should not be dispensed or administered to|
02741|005|L|the same patient.|
02741|006|B||
02741|007|A|MECHANISM OF ACTION:  The active tubular secretion via organic cationic|
02741|008|A|transporter 2 (OCT2) of dofetilide may be inhibited by lamotrigine.(1,2)|
02741|009|B||
02741|010|E|CLINICAL EFFECTS:  The concurrent administration of dofetilide with|
02741|011|E|lamotrigine may result in elevated levels and increased effects of|
02741|012|E|dofetilide including QT prolongation or torsades de pointes.(1,2)|
02741|013|B||
02741|014|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
02741|015|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
02741|016|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
02741|017|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
02741|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02741|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02741|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02741|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02741|022|P|advanced age.(3)|
02741|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02741|024|P|higher systemic concentrations of either QT prolonging drug are additional|
02741|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02741|026|P|drug concentrations include rapid infusion of an intravenous dose or|
02741|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02741|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02741|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02741|030|B||
02741|031|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that the|
02741|032|M|concurrent administration of dofetilide with known inhibitors of the renal|
02741|033|M|cation transport system should not be used.  If dofetilide is to be|
02741|034|M|discontinued, a washout of at least 2 days is recommended prior to starting|
02741|035|M|lamotrigine.(1)|
02741|036|M|   The manufacturer of lamotrigine states the concurrent administration of|
02741|037|M|lamotrigine with organic cationic transporter 2 (OCT2) substrates with a|
02741|038|M|narrow therapeutic index, such as dofetilide, is not recommended.(2)|
02741|039|B||
02741|040|D|DISCUSSION:  Dofetilide is primarily excreted in the urine via both|
02741|041|D|glomerular filtration and active tubular secretion via the cation transport|
02741|042|D|system.  Lamotrigine is believed to inhibit the cation transport system|
02741|043|D|(OCT2).(1,2)|
02741|044|B||
02741|045|R|REFERENCES:|
02741|046|B||
02741|047|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
02741|048|R|  2013.|1
02741|049|R|2.Lamictal (lamotrigine) US prscribing information. GlaxoSmithKline October,|1
02741|050|R|  2025.|1
02741|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02741|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02741|053|R|  settings: a scientific statement from the American Heart Association and|6
02741|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02741|055|R|  2;55(9):934-47.|6
02742|001|T|MONOGRAPH TITLE:  Obeticholic acid/Bile Acid Sequestrants; Sevelamer|
02742|002|B||
02742|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02742|004|L|take action as needed.|
02742|005|B||
02742|006|A|MECHANISM OF ACTION:  Bile acid sequestrants and sevelamer may decrease the|
02742|007|A|gastrointestinal absorption of obeticholic acid.|
02742|008|B||
02742|009|E|CLINICAL EFFECTS:  Simultaneous administration of a bile acid sequestrant or|
02742|010|E|sevelamer may result in decreased absorption and effectiveness of|
02742|011|E|obeticholic acid.(1)|
02742|012|B||
02742|013|P|PREDISPOSING FACTORS:  None determined.|
02742|014|B||
02742|015|M|PATIENT MANAGEMENT:  For maximal bioavailability, the manufacturer of|
02742|016|M|obeticholic acid states obeticholic acid should be administered at least 4|
02742|017|M|hours before or after a bile acid sequestrant or sevelamer.(1)|
02742|018|M|    Although used for hyperphosphatemia, sevelamer is linked to this|
02742|019|M|monograph due to its structural and pharmacologic similarities to|
02742|020|M|colesevelam. Both agents are non-absorbed cross linked polymers with a high|
02742|021|M|affinity for bile acids.(2)|
02742|022|B||
02742|023|D|DISCUSSION:  Bile acid sequestrants may be needed to treat pruritis due to|
02742|024|D|primary biliary cholangitis and/or obeticholic acid therapy.(1,3)|
02742|025|D|   In a clinical trial of patients receiving obeticholic acid and bile acid|
02742|026|D|sequestrants, obeticholic acid trough concentrations were slightly lower|
02742|027|D|compared with patients who did not receive bile acid sequestrants.  This|
02742|028|D|resulted in a modest attenuation of efficacy in obeticholic acid 5mg, but|
02742|029|D|did not appear to affect efficacy in patients receiving obeticholic acid 10|
02742|030|D|mg.(3)|
02742|031|B||
02742|032|R|REFERENCES:|
02742|033|B||
02742|034|R|1.Ocaliva (obeticholic acid) US prescribing information. Intercept|1
02742|035|R|  Pharmaceuticals Inc. January, 2018.|1
02742|036|R|2.Renagel (sevelamer hydrochloride) US prescribing information. Genzyme|1
02742|037|R|  Corporation March 9, 2016.|1
02742|038|R|3.FDA (US Food and Drug Administration). Gastrointestinal Drug Advisory|1
02742|039|R|  Committee (GIDAC) Meeting, FDA Background Document for NDA 207999|1
02742|040|R|  obeticholic acid. accessed at:|1
02742|041|R|  http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials|1
02742|042|R|  /drugs/gastrointestinaldrugsadvisorycommittee/ucm494108.pdf March 15,|1
02742|043|R|  2016.|1
02743|001|T|MONOGRAPH TITLE:  Selected CYP1A2 Substrates/Obeticholic acid|
02743|002|B||
02743|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02743|004|L|of severe adverse interaction.|
02743|005|B||
02743|006|A|MECHANISM OF ACTION:  Although the mechanism is not clear, authors suspect|
02743|007|A|obeticholic acid down-regulates CYP1A2 mRNA expression, resulting in lower|
02743|008|A|systemic concentrations of the CYP1A2 enzyme.(1)|
02743|009|B||
02743|010|E|CLINICAL EFFECTS:  Concurrent use of obeticholic acid with narrow|
02743|011|E|therapeutic index drugs which are primarily metabolized by CYP1A2 may lead|
02743|012|E|to elevated levels and increased side effects of the CYP1A2 substrate.|
02743|013|E|   CYP1A2 substrates linked to this monograph include: agomelatine,|
02743|014|E|pirfenidone, tacrine, theophylline, and tizanidine.|
02743|015|B||
02743|016|P|PREDISPOSING FACTORS:  With tizanidine, the risk of anticholinergic|
02743|017|P|toxicities including cognitive decline, delirium, falls and fractures is|
02743|018|P|increased in geriatric patients using more than one medicine with|
02743|019|P|anticholinergic properties.(5)|
02743|020|B||
02743|021|M|PATIENT MANAGEMENT:  Drugs linked to this monograph have a narrow|
02743|022|M|therapeutic window and are  primarily metabolized by CYP1A2.  If|
02743|023|M|coadministration cannot be avoided, the manufacturer of obeticholic acid|
02743|024|M|recommends close monitoring and possible dose reduction of the affected|
02743|025|M|drug.(2)|
02743|026|M|   The US manufacturer of tizanidine recommends avoiding concurrent therapy|
02743|027|M|with CYP1A2 inhibitors. If concurrent therapy is necessary, tizanidine|
02743|028|M|should be initiated with a 2 mg dose and increased in 2-4 mg steps daily|
02743|029|M|based on patient response to therapy. If adverse reactions such as|
02743|030|M|hypotension, bradycardia, or excessive drowsiness occur, reduce or|
02743|031|M|discontinue tizanidine therapy.(4)|
02743|032|B||
02743|033|D|DISCUSSION:  In an interaction study, multiple doses of obeticholic acid|
02743|034|D|increased systemic exposure (AUC, area-under-curve) to caffeine (a sensitive|
02743|035|D|CYP1A2 substrate) by 42%.(1)|
02743|036|B||
02743|037|R|REFERENCES:|
02743|038|B||
02743|039|R|1.FDA (US Food and Drug Administration). Gastrointestinal Drug Advisory|1
02743|040|R|  Committee (GIDAC) Meeting, FDA Background Document for NDA 207999|1
02743|041|R|  obeticholic acid. accessed at:|1
02743|042|R|  http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials|1
02743|043|R|  /drugs/gastrointestinaldrugsadvisorycommittee/ucm494108.pdf March 15,|1
02743|044|R|  2016.|1
02743|045|R|2.Ocaliva (obeticholic acid) US prescribing information. Intercept|1
02743|046|R|  Pharmaceuticals Inc. January, 2018.|1
02743|047|R|3.Esbriet (pirfenidone) US prescribing information. InterMune, Inc. October,|1
02743|048|R|  2014.|1
02743|049|R|4.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
02743|050|R|  Pharma Inc. November 22, 2024.|1
02743|051|R|5.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02743|052|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02743|053|R|  Soc 2023 Jul;71(7):2052-2081.|6
02744|001|T|MONOGRAPH TITLE:  Gallium Ga 68 Dotatate;  Gallium Ga 68|
02744|002|T|Dotatoc/Somatostatin analogs|
02744|003|B||
02744|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02744|005|L|of severe adverse interaction.|
02744|006|B||
02744|007|A|MECHANISM OF ACTION:  Both somatostatin analogs and gallium Ga 68 dotatate/|
02744|008|A|gallium Ga 68 dotatoc bind to the same somatostatin receptors, resulting in|
02744|009|A|competitive inhibition.(1)|
02744|010|B||
02744|011|E|CLINICAL EFFECTS:  Concurrent use of gallium Ga 68 dotatate/ gallium Ga 68|
02744|012|E|dotatoc and somatostatin analogs may affect the results of the scan.(1)|
02744|013|B||
02744|014|P|PREDISPOSING FACTORS:  None determined.|
02744|015|B||
02744|016|M|PATIENT MANAGEMENT:  In patients receiving somatostatin analogs, perform the|
02744|017|M|image just prior to dosing with long-acting somatostatin analogs.  Short|
02744|018|M|acting somatostatin analogs can be used up to 24 hours before imaging with|
02744|019|M|gallium Ga 68 dotatate or gallium Ga 68 dotatoc.  (1)|
02744|020|B||
02744|021|D|DISCUSSION:  Both somatostatin analogs and gallium Ga 68 dotatate/ gallium|
02744|022|D|Ga 68 dotatoc bind to the same somatostatin receptors, resulting in|
02744|023|D|competitive inhibition, which can affect the results of the scan.(1)|
02744|024|B||
02744|025|R|REFERENCE:|
02744|026|B||
02744|027|R|1.Netspot (gallium Ga 68 dotatate injection) US prescribing information.|1
02744|028|R|  Advanced Accelerator Applications USA, Inc. October, 2023.|1
02745|001|T|MONOGRAPH TITLE:  Hydroxyzine/QT Prolonging Agents|
02745|002|B||
02745|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02745|004|L|of severe adverse interaction.|
02745|005|B||
02745|006|A|MECHANISM OF ACTION:  Concurrent use of hydroxyzine with agents that prolong|
02745|007|A|the QTc interval may result in additive effects on the QTc interval.(1-4)|
02745|008|B||
02745|009|E|CLINICAL EFFECTS:  The concurrent use of hydroxyzine with agents that|
02745|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02745|011|E|arrhythmias, including torsades de pointes.(1-4)|
02745|012|B||
02745|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02745|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02745|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02745|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02745|017|P|female gender, or advanced age.(5)|
02745|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02745|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02745|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02745|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02745|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02745|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02745|024|P|dysfunction).(5)|
02745|025|P|   Doses of hydroxyzine greater than 100 mg/day may also increase the|
02745|026|P|risk.(1,2)|
02745|027|B||
02745|028|M|PATIENT MANAGEMENT:  Concurrent use of hydroxyzine with agents known to|
02745|029|M|prolong the QT interval is contraindicated in Canada(1,2) and the UK.(3)|
02745|030|M|The US manufacturer states that concurrent use should be approached with|
02745|031|M|caution.(4)|
02745|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02745|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02745|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02745|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02745|036|B||
02745|037|D|DISCUSSION:  In vitro data indicates that hydroxyzine blocks the hERG|
02745|038|D|channel, which results in the potential risk of QT interval prolongation.(6)|
02745|039|D|   In a placebo controlled, non-thorough QT study, 10 patients in the|
02745|040|D|placebo group (n=152) had a change in QT interval from baseline between 30|
02745|041|D|ms and 60 ms and one patient presented a change from baseline higher than 60|
02745|042|D|ms. In the hydroxyzine group (n=148), 14 subjects had a change in QT|
02745|043|D|interval from baseline between 30 and 60 ms and were considered to have a|
02745|044|D|potential risk factor for risk of QT interval prolongation and TdP due to|
02745|045|D|relevant medical history, concomitant medication potentially associated with|
02745|046|D|the induction of prolongation of QT interval, and/or polymedication.(6)|
02745|047|D|   Health Canada reviewed 61 cases of QT interval prolongation or torsades|
02745|048|D|de pointes with hydroxyzine.  In a majority of cases, patients had|
02745|049|D|additional risk factors for QT prolongation.  Three reports provided enough|
02745|050|D|data for a more detailed review.  Hydroxyzine was found to be either|
02745|051|D|"possible" or "probably" contribution to QT prolongation/torsades in these|
02745|052|D|reports.(1)|
02745|053|D|   The European Medicines Agency's Pharmacovigilance Risk Assessment|
02745|054|D|Committee (PRAC) reviewed 190 case reports found in a search of "torsade de|
02745|055|D|pointes/QT prolongation with hydroxyzine".  Forty-two non-fatality cases|
02745|056|D|were subdivided into torsades (n=16), QT prolongation (n=21), and|
02745|057|D|ventricular tachycardia (n=5).  All included risk factors for QT interval|
02745|058|D|prolongation and TdP (cardiac disorders, hypokalemia, long QT syndrome,|
02745|059|D|bradycardia, concomitant drugs which are known to prolong the QT interval).|
02745|060|D|Dosages ranged from <= 100 mg/day (n=10), > 100 mg/day to <=300 mg/day|
02745|061|D|(n=4), > 300 mg/day (n=8), overdosages (n=11), and premedication (n=9).|
02745|062|D|Twenty-one cases involving fatalities had at least one risk factor for QT|
02745|063|D|prolongation.  The PRAC concluded that post-marketing cases of QT interval|
02745|064|D|prolongation, TdP and ventricular tachycardia confirm the findings of the|
02745|065|D|hERG studies suggesting that hydroxyzine blocks hERG channels. No difference|
02745|066|D|in the risk of QT interval prolongation could be observed based on the|
02745|067|D|indication, age of the subject, or dose.(6)|
02745|068|D|   Agents that are linked to this monograph may have varying degrees of|
02745|069|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02745|070|D|been shown to prolong the QTc interval either through their mechanism of|
02745|071|D|action, through studies on their effects on the QTc interval, or through|
02745|072|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02745|073|D|and/or postmarketing reports.(7)|
02745|074|B||
02745|075|R|REFERENCES:|
02745|076|B||
02745|077|R|1.Health Canada. Summary Safety Review - Hydroxyzine (ATARAX and generics) -|1
02745|078|R|  Assessing the Potential Risk of Abnormal Heart Rhythm. availalble at:|1
02745|079|R|  http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/atarax-eng.php June|1
02745|080|R|  6, 2016.|1
02745|081|R|2.Atarax (hydroxyzine hydrochloride) Canadian product monograph. Erfa May|1
02745|082|R|  10, 2016.|1
02745|083|R|3.Atarax (hydroxyzine hydrochloride) UK summary of product characteristics.|1
02745|084|R|  Alliance Pharmaceuticals Limited October, 2015.|1
02745|085|R|4.Vistaril (hydroxyzine pamoate) US prescribing information. Pfizer November|1
02745|086|R|  8, 2016.|1
02745|087|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02745|088|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02745|089|R|  settings: a scientific statement from the American Heart Association and|6
02745|090|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02745|091|R|  2;55(9):934-47.|6
02745|092|R|6.European Medicines Agency (EMA) Pharmacovigilance Risk Assessment|1
02745|093|R|  Committee (PRAC). Hydroxyzine-containing medicinal products. available at:|1
02745|094|R|  http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Hy|1
02745|095|R|  droxyzine_31/Position_provided_by_CMDh/WC500185947.pdf February 12, 2015.|1
02745|096|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
02745|097|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02745|098|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02745|099|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02746|001|T|MONOGRAPH TITLE:  Hydroxyzine/Possible QT Prolonging Agents|
02746|002|B||
02746|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02746|004|L|take action as needed.|
02746|005|B||
02746|006|A|MECHANISM OF ACTION:  Concurrent use of hydroxyzine with agents that prolong|
02746|007|A|the QTc interval may result in additive effects on the QTc interval.(1-4)|
02746|008|B||
02746|009|E|CLINICAL EFFECTS:  The concurrent use of hydroxyzine with agents that|
02746|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02746|011|E|arrhythmias, including torsades de pointes.(1-4)|
02746|012|B||
02746|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02746|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02746|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02746|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02746|017|P|female gender, or advanced age.(5)|
02746|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02746|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02746|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02746|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02746|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02746|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02746|024|P|dysfunction).(5)|
02746|025|P|   Doses of hydroxyzine greater than 100 mg/day may also increase the|
02746|026|P|risk.(1,2)|
02746|027|B||
02746|028|M|PATIENT MANAGEMENT:  Concurrent use of hydroxyzine with agents known to|
02746|029|M|prolong the QT interval is contraindicated in Canada(1,2) and the UK.(3)|
02746|030|M|The US manufacturer states that concurrent use should be approached with|
02746|031|M|caution.(4)|
02746|032|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02746|033|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02746|034|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02746|035|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02746|036|B||
02746|037|D|DISCUSSION:  In vitro data indicates that hydroxyzine blocks the hERG|
02746|038|D|channel, which results in the potential risk of QT interval prolongation.(6)|
02746|039|D|   In a placebo controlled, non-thorough QT study, 10 patients in the|
02746|040|D|placebo group (n=152) had a change in QT interval from baseline between 30|
02746|041|D|ms and 60 ms and one patient presented a change from baseline higher than 60|
02746|042|D|ms. In the hydroxyzine group (n=148), 14 subjects had a change in QT|
02746|043|D|interval from baseline between 30 and 60 ms and were considered to have a|
02746|044|D|potential risk factor for risk of QT interval prolongation and TdP due to|
02746|045|D|relevant medical history, concomitant medication potentially associated with|
02746|046|D|the induction of prolongation of QT interval, and/or polymedication.(6)|
02746|047|D|   Health Canada reviewed 61 cases of QT interval prolongation or torsades|
02746|048|D|de pointes with hydroxyzine.  In a majority of cases, patients had|
02746|049|D|additional risk factors for QT prolongation.  Three reports provided enough|
02746|050|D|data for a more detailed review.  Hydroxyzine was found to be either|
02746|051|D|"possible" or "probably" contribution to QT prolongation/torsades in these|
02746|052|D|reports.(1)|
02746|053|D|   The European Medicines Agency's Pharmacovigilance Risk Assessment|
02746|054|D|Committee (PRAC) reviewed 190 case reports found in a search of "torsade de|
02746|055|D|pointes/QT prolongation with hydroxyzine".  Forty-two non-fatality cases|
02746|056|D|were subdivided into torsades (n=16), QT prolongation (n=21), and|
02746|057|D|ventricular tachycardia (n=5).  All included risk factors for QT interval|
02746|058|D|prolongation and TdP (cardiac disorders, hypokalemia, long QT syndrome,|
02746|059|D|bradycardia, concomitant drugs which are known to prolong the QT interval).|
02746|060|D|Dosages ranged from <= 100 mg/day (n=10), > 100 mg/day to <=300 mg/day|
02746|061|D|(n=4), > 300 mg/day (n=8), overdosages (n=11), and premedication (n=9).|
02746|062|D|Twenty-one cases involving fatalities had at least one risk factor for QT|
02746|063|D|prolongation.  The PRAC concluded that post-marketing cases of QT interval|
02746|064|D|prolongation, TdP and ventricular tachycardia confirm the findings of the|
02746|065|D|hERG studies suggesting that hydroxyzine blocks hERG channels. No difference|
02746|066|D|in the risk of QT interval prolongation could be observed based on the|
02746|067|D|indication, age of the subject, or dose.(6)|
02746|068|D|   Agents that are linked to this monograph may have varying degrees of|
02746|069|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02746|070|D|been shown to prolong the QTc interval either through their mechanism of|
02746|071|D|action, through studies on their effects on the QTc interval, or through|
02746|072|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02746|073|D|and/or postmarketing reports.(7)|
02746|074|B||
02746|075|R|REFERENCES:|
02746|076|B||
02746|077|R|1.Health Canada. Summary Safety Review - Hydroxyzine (ATARAX and generics) -|1
02746|078|R|  Assessing the Potential Risk of Abnormal Heart Rhythm. availalble at:|1
02746|079|R|  http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/atarax-eng.php June|1
02746|080|R|  6, 2016.|1
02746|081|R|2.Atarax (hydroxyzine hydrochloride) Canadian product monograph. Erfa May|1
02746|082|R|  10, 2016.|1
02746|083|R|3.Atarax (hydroxyzine hydrochloride) UK summary of product characteristics.|1
02746|084|R|  Alliance Pharmaceuticals Limited October, 2015.|1
02746|085|R|4.Vistaril (hydroxyzine pamoate) US prescribing information. Pfizer November|1
02746|086|R|  8, 2016.|1
02746|087|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02746|088|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02746|089|R|  settings: a scientific statement from the American Heart Association and|6
02746|090|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02746|091|R|  2;55(9):934-47.|6
02746|092|R|6.European Medicines Agency (EMA) Pharmacovigilance Risk Assessment|1
02746|093|R|  Committee (PRAC). Hydroxyzine-containing medicinal products. available at:|1
02746|094|R|  http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Hy|1
02746|095|R|  droxyzine_31/Position_provided_by_CMDh/WC500185947.pdf February 12, 2015.|1
02746|096|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
02746|097|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02746|098|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02746|099|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02747|001|T|MONOGRAPH TITLE:  Tramadol/Linezolid|
02747|002|B||
02747|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02747|004|L|of severe adverse interaction.|
02747|005|B||
02747|006|A|MECHANISM OF ACTION:  Tramadol and linezolid may lower the seizure|
02747|007|A|threshold.(1-3)|
02747|008|A|   Both tramadol and linezolid may increase serotonin and norepinephrine.|
02747|009|A|Tramadol inhibits neuronal reuptake of serotonin and norepinephrine, while|
02747|010|A|linezolid impairs metabolism of serotonin and norepinephrine via inhibition|
02747|011|A|of monoamine oxidase(MAO).(1-3)|
02747|012|B||
02747|013|E|CLINICAL EFFECTS:  Concurrent use of tramadol and linezolid may result in|
02747|014|E|seizures or serotonin syndrome.(1-3)|
02747|015|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
02747|016|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02747|017|E|rigidity.(4)|
02747|018|B||
02747|019|P|PREDISPOSING FACTORS:  CYP2D6 poor metabolizers,(5) or patients also taking|
02747|020|P|strong CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine,|
02747|021|P|terbinafine) will have reduced tramadol metabolism leading higher systemic|
02747|022|P|levels of tramadol.|
02747|023|P|   Risk of seizures may be increased in patients with epilepsy, a history of|
02747|024|P|seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or|
02747|025|P|infections of the central nervous system.(1)  The risk for seizures may also|
02747|026|P|be increased in patients receiving more than the upper daily dose limit of|
02747|027|P|tramadol, or in patients taking additional medications which lower the|
02747|028|P|seizure threshold.(1)|
02747|029|B||
02747|030|M|PATIENT MANAGEMENT:  Evaluate the patient for predisposing factors (other|
02747|031|M|drugs, diseases or conditions) which may further increase the risk for|
02747|032|M|serotonin syndrome or seizures.  When possible and clinically appropriate,|
02747|033|M|change to an alternative analgesic or antibiotic, particularly when|
02747|034|M|predisposing factors are present.|
02747|035|M|   If concomitant therapy is necessary, monitor patient for signs of|
02747|036|M|serotonin toxicity (e.g. tremor, agitation, diaphoresis, hyperreflexia,|
02747|037|M|clonus, tachycardia, hyperthermia, muscle rigidity) or seizures, especially|
02747|038|M|after tramadol dose increases.|
02747|039|M|   Manufacturer prescribing recommendations:|
02747|040|M|   The US manufacturer of tramadol states that tramadol should be used with|
02747|041|M|caution in patients taking monoamine oxidase inhibitors.(1)|
02747|042|M|   In contrast, an Australian manufacturer of tramadol states that it is|
02747|043|M|contraindicated in patients who are currently receiving monoamine oxidase|
02747|044|M|inhibitors or who have received them in the previous 14 days.(2)|
02747|045|M|   The US manufacturer of linezolid does not have specific recommendations|
02747|046|M|regarding concurrent treatment with tramadol but does state that linezolid|
02747|047|M|should not be used in patients receiving serotonergic drugs (e.g. SSRIs,|
02747|048|M|TCAs, meperidine) unless clinically appropriate and patients are carefully|
02747|049|M|observed for signs and symptoms of serotonin syndrome.(3)|
02747|050|B||
02747|051|D|DISCUSSION:  Tramadol and its M1 metabolite are pharmacologically active.|
02747|052|D|Tramadol inhibits the reuptake of norepinephrine and serotonin with minimal|
02747|053|D|opioid receptor binding.  The active M1 metabolite has 200 times greater|
02747|054|D|binding affinity for the mu-opioid receptor than tramadol and is 6 times|
02747|055|D|more potent in producing analgesia.(1)  CYP P-450-2D6 converts tramadol to|
02747|056|D|M1.(1,5)|
02747|057|D|   A study in surgery patients included 2D6 EM patients who received|
02747|058|D|concomitant treatment with tramadol and 2D6 inhibitors. Levels of the M1|
02747|059|D|metabolite were decreased by 80-90% compared with EM patients not taking 2D6|
02747|060|D|inhibitors. Authors noted some EM patients were converted to the PM|
02747|061|D|phenotype.(6)|
02747|062|B||
02747|063|R|REFERENCES:|
02747|064|B||
02747|065|R|1.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
02747|066|R|  October, 2019.|1
02747|067|R|2.Tramal (tramadol hydrochloride) Australian prescribing information. CSL|1
02747|068|R|  Limited November 27, 2002.|1
02747|069|R|3.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
02747|070|R|4.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02747|071|R|  352(11):1112-20.|6
02747|072|R|5.Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP,|5
02747|073|R|  Lake BG. Identification of cytochrome P-450 isoforms responsible for|5
02747|074|R|  cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001|5
02747|075|R|  Aug;29(8):1146-55.|5
02747|076|R|6.Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F.|2
02747|077|R|  Concentrations of tramadol and O-desmethyltramadol enantiomers in|2
02747|078|R|  different CYP2D6 genotypes. Clin Pharmacol Ther 2007 Jul;82(1):41-7.|2
02748|001|T|MONOGRAPH TITLE:  Colchicine (for Gout & FMF)/P-glycoprotein (P-gp)|
02748|002|T|Inhibitors|
02748|003|B||
02748|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02748|005|L|of severe adverse interaction.|
02748|006|B||
02748|007|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors may affect the|
02748|008|A|transport of colchicine, a P-gp substrate.(1,2)|
02748|009|B||
02748|010|E|CLINICAL EFFECTS:  Concurrent use of a P-gp inhibitor may result in elevated|
02748|011|E|levels of and toxicity from colchicine.  Symptoms of colchicine toxicity|
02748|012|E|include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness|
02748|013|E|or pain; numbness or tingling in the fingers or toes; myelosuppression;|
02748|014|E|feeling weak or tired; increased infections; and pale or gray color of the|
02748|015|E|lips, tongue, or palms of hands.(1,2)|
02748|016|B||
02748|017|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
02748|018|P|patients with renal and/or hepatic impairment(1,2) and in patients who|
02748|019|P|receive concurrent therapy.|
02748|020|B||
02748|021|M|PATIENT MANAGEMENT:  The concurrent use of colchicine with P-gp inhibitors|
02748|022|M|is contraindicated in patients with renal or hepatic impairment.(1-3)  Avoid|
02748|023|M|concurrent use in other patients, if possible.(3)  In patients without renal|
02748|024|M|or hepatic impairment who are currently taking or have taken a P-gp|
02748|025|M|inhibitor in the previous 14 days, the dosage of colchicine should be|
02748|026|M|reduced.|
02748|027|M|   For gout flares, the recommended dosage is 0.6 mg (1 tablet) for one|
02748|028|M|dose.  This dose should be repeated no earlier than in 3 days.(1,2)|
02748|029|M|   For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use|
02748|030|M|0.3 mg daily.  If the original dosage was 0.6 mg daily, use 0.3 mg every|
02748|031|M|other day.(3-12)|
02748|032|M|   For Familial Mediterranean fever (FMF), the recommended maximum daily|
02748|033|M|dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,2)|
02748|034|M|   Patients should be instructed to immediately report any signs of|
02748|035|M|colchicine toxicity, such as abdominal pain, nausea/significant diarrhea,|
02748|036|M|vomiting; muscle weakness/pain; numbness/tingling in fingers/toes; unusual|
02748|037|M|bleeding or bruising, infections, weakness/tiredness, or pale/gray color of|
02748|038|M|the lips/tongue/palms of hands.|
02748|039|B||
02748|040|D|DISCUSSION:  There are several reports of colchicine toxicity(4-6) and|
02748|041|D|death(7,8) following the addition of clarithromycin to therapy.  In a|
02748|042|D|retrospective review of 116 patients who received clarithromycin and|
02748|043|D|colchicine during the same hospitalization, 10.2% (9/88) of patients who|
02748|044|D|received simultaneous therapy died, compared to 3.6% (1/28) of patients who|
02748|045|D|received sequential therapy.(9)|
02748|046|D|   An FDA review of 117 colchicine-related deaths that were not attributable|
02748|047|D|to overdose found that 60 deaths (51%) involved concurrent use of|
02748|048|D|clarithromycin.(2)|
02748|049|D|   There is one case report of colchicine toxicity with concurrent|
02748|050|D|erythromycin.(10)|
02748|051|D|   In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for|
02748|052|D|7 days) increased the maximum concentration (Cmax) and area-under-curve|
02748|053|D|(AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to|
02748|054|D|318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1)|
02748|055|D|   In a study in 24 subjects, pretreatment with verapamil (240 mg twice|
02748|056|D|daily for 7 days) increased the Cmax and AUC of a single dose of colchicine|
02748|057|D|(0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to|
02748|058|D|217.2%), respectively.(1)|
02748|059|D|   Colchicine toxicity has been reported with concurrent use of CYP3A4 and|
02748|060|D|P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem,|
02748|061|D|erythromycin, and verapamil.(1,2)|
02748|062|D|   P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir,|
02748|063|D|azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, danicopan,|
02748|064|D|daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin,|
02748|065|D|flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir,|
02748|066|D|imlunestrant, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib,|
02748|067|D|osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra,|
02748|068|D|selpercatinib, sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib,|
02748|069|D|venetoclax, verapamil, vimseltinib, and voclosporin.(1,11,12)|
02748|070|B||
02748|071|R|REFERENCES:|
02748|072|B||
02748|073|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
02748|074|R|  2011.|1
02748|075|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
02748|076|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
02748|077|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
02748|078|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
02748|079|R|3.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
02748|080|R|  November, 2015.|1
02748|081|R|4.van der Velden W, Huussen J, Ter Laak H, de Sevaux R. Colchicine-induced|3
02748|082|R|  neuromyopathy in a patient with chronic renal failure: the role of|3
02748|083|R|  clarithromycin. Neth J Med 2008 May;66(5):204-6.|3
02748|084|R|5.Akdag I, Ersoy A, Kahvecioglu S, Gullulu M, Dilek K. Acute colchicine|3
02748|085|R|  intoxication during clarithromycin administration in patients with chronic|3
02748|086|R|  renal failure. J Nephrol 2006 Jul-Aug;19(4):515-7.|3
02748|087|R|6.Rollot F, Pajot O, Chauvelot-Moachon L, Nazal EM, Kelaidi C, Blanche P.|3
02748|088|R|  Acute colchicine intoxication during clarithromycin administration. Ann|3
02748|089|R|  Pharmacother 2004 Dec;38(12):2074-7.|3
02748|090|R|7.Cheng VC, Ho PL, Yuen KY. Two probable cases of serious drug interaction|3
02748|091|R|  between clarithromycin and colchicine. South Med J 2005 Aug;98(8):811-3.|3
02748|092|R|8.Dogukan A, Oymak FS, Taskapan H, Guven M, Tokgoz B, Utas C. Acute fatal|3
02748|093|R|  colchicine intoxication in a patient on continuous ambulatory peritoneal|3
02748|094|R|  dialysis (CAPD). Possible role of clarithromycin administration. Clin|3
02748|095|R|  Nephrol 2001 Feb;55(2):181-2.|3
02748|096|R|9.Hung IF, Wu AK, Cheng VC, Tang BS, To KW, Yeung CK, Woo PC, Lau SK, Cheung|2
02748|097|R|  BM, Yuen KY. Fatal interaction between clarithromycin and colchicine in|2
02748|098|R|  patients with renal insufficiency: a retrospective study. Clin Infect Dis|2
02748|099|R|  2005 Aug 1;41(3):291-300.|2
02748|100|R|10.Caraco Y, Putterman C, Rahamimov R, Ben-Chetrit E. Acute colchicine|3
02748|101|R|   intoxication--possible role of erythromycin administration. J Rheumatol|3
02748|102|R|   1992 Mar;19(3):494-6.|3
02748|103|R|11.US Food and Drug Administration (FDA). Drug Development and Drug|1
02748|104|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
02748|105|R|   at:|1
02748|106|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
02748|107|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02748|108|R|   11/14/2017.|1
02748|109|R|12.This information is based on an extract from the Certara Drug Interaction|6
02748|110|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02749|001|T|MONOGRAPH TITLE:  Cholera Vaccine Live/Selected Antibiotics|
02749|002|B||
02749|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02749|004|L|of severe adverse interaction.|
02749|005|B||
02749|006|A|MECHANISM OF ACTION:  Antibiotics with activity against Vibrio cholerae may|
02749|007|A|attenuate the immunization response to the live cholera vaccine.(1)|
02749|008|B||
02749|009|E|CLINICAL EFFECTS:  Concurrent or recent antibiotic use may make the cholera|
02749|010|E|vaccine ineffective.(1)|
02749|011|B||
02749|012|P|PREDISPOSING FACTORS:  None determined.|
02749|013|B||
02749|014|M|PATIENT MANAGEMENT:  The manufacturer of live cholera vaccine states that it|
02749|015|M|should not be administered to patients who have received antibiotics within|
02749|016|M|14 days prior to vaccination.(1)|
02749|017|M|   If antimalarial prophylaxis with chloroquine is required, administer the|
02749|018|M|live cholera vaccine at least 10 days before beginning chloroquine.(1)|
02749|019|M|   Antibiotics linked to this monograph are: macrolides, quinolones,|
02749|020|M|tetracyclines, ampicillin, cefprozil, chloramphenicol, furazolidone,|
02749|021|M|sulfamethoxazole-trimethoprim, and sulfametrole-trimethoprim.(2,3)|
02749|022|B||
02749|023|D|DISCUSSION:  Antibiotics with activity against Vibrio cholerae may attenuate|
02749|024|D|the immunization response to the live cholera vaccine, rendering the vaccine|
02749|025|D|ineffective.|
02749|026|B||
02749|027|R|REFERENCES:|
02749|028|B||
02749|029|R|1.Vaxchora (Cholera Vaccine, Live, Oral) US prescribing information. PaxVax|1
02749|030|R|  Inc. June, 2016.|1
02749|031|R|2.Centers for Disease Control and Prevention (CDC). Recommendations for the|6
02749|032|R|  Use of Antibiotics for the Treatment of Cholera. accessed at:|6
02749|033|R|  http://www.cdc.gov/cholera/treatment/antibiotic-treatment.html Last|6
02749|034|R|  updated January 20, 2015.|6
02749|035|R|3.Australian Government Department of Health Office of the Gene Technology|1
02749|036|R|  Regulator. Risk Assessment and Risk Management Plan for DIR126, Clinical|1
02749|037|R|  trial of a genetically modified vaccine against Cholera (applicant: PaxVax|1
02749|038|R|  Australia Pty Ltd). April, 2004.|1
02750|001|T|MONOGRAPH TITLE:  Selected 5-HT1D Agonists/Rasagiline|
02750|002|B||
02750|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02750|004|L|take action as needed.|
02750|005|B||
02750|006|A|MECHANISM OF ACTION:  Rasagiline may inhibit the monamine oxidase-A (MAO-A)|
02750|007|A|mediated metabolism of rizatriptan,(2) sumatriptan,(3-10) and|
02750|008|A|zolmitriptan.(11-12)|
02750|009|A|   At concentrations associated with recommended recommended doses of 0.5 mg|
02750|010|A|to 1 mg daily, rasagiline has a high specificity for MAO-B.  Mild hepatic|
02750|011|A|impairment, concomitant use of strong CYP1A2 inhibitors, or use of higher|
02750|012|A|than recommended doses may substantially increase rasagiline systemic|
02750|013|A|exposure and could result in MAO-A inhibition.|
02750|014|B||
02750|015|E|CLINICAL EFFECTS:  Systemic concentrations of rizatriptan, sumatriptan or|
02750|016|E|zolmitriptan may be increased.(2-12)|
02750|017|B||
02750|018|P|PREDISPOSING FACTORS:  Rasagiline concentration may be increased 2-fold or|
02750|019|P|more in patients also receiving a strong CYP1A2 inhibitor (e.g.|
02750|020|P|ciprofloxacin, fluvoxamine).(1)|
02750|021|P|   Rasagiline plasma concentrations are higher in patients with any degree|
02750|022|P|of hepatic impairment.  Rasagiline should not be used in patients with|
02750|023|P|moderate or severe hepatic impairment.(1)|
02750|024|P|   Patients with a history of cardiovascular disease, e.g. coronary artery|
02750|025|P|disease (CAD), transient ischemic attack (TIA), stroke, cardiac conduction|
02750|026|P|disorders or poorly controlled hypertension, are not considered candidates|
02750|027|P|for 5-HT1D agonist therapy and would be at greater risk for toxicity due to|
02750|028|P|this interaction.|
02750|029|B||
02750|030|M|PATIENT MANAGEMENT:  Evaluate patient for predisposing risk factors, e.g.|
02750|031|M|concomitant use with CYP1A2 inhibitors, cardiovascular disease, and hepatic|
02750|032|M|impairment.  Patients with mild hepatic impairment or receiving concurrent|
02750|033|M|therapy with a CYP1A2 inhibitor (e.g. ciprofloxacin, fluvoxamine) should be|
02750|034|M|receiving a maximum rasagiline dose of 0.5 mg daily.|
02750|035|B||
02750|036|D|DISCUSSION:  Triptan interaction studies with other MAO inhibitors:|
02750|037|D|   Rizatriptan is metabolized by the 'A' subtype of monoamine oxidase.  In a|
02750|038|D|study with 12 subjects, the concurrent administration of rizatriptan (10 mg)|
02750|039|D|with moclobemide (450 mg daily, a selective, reversible MAO-A inhibitor)|
02750|040|D|resulted in increases in the rizatriptan area-under-curve (AUC) and maximum|
02750|041|D|concentration (Cmax) by 119% and 41%, respectively.  The AUC of the active|
02750|042|D|metabolite, N-monodesmethyl rizatriptan, increased over 400%.  Plasma|
02750|043|D|concentrations of rizatriptan may be increased by selective MAO-A inhibitors|
02750|044|D|or by nonselective MAO-A&B inhibitors, although the interaction is expected|
02750|045|D|to be greater with selective MAO-A inhibitors.  The manufacturer also states|
02750|046|D|that no interaction is expected with selective MAO-B inhibitors.(2)|
02750|047|D|   Sumatriptan oral bioavailability is approximately 15%, primarily due to|
02750|048|D|presystemic clearance by MAO-A in the gut and liver.  A small study found an|
02750|049|D|approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A|
02750|050|D|inhibitor was given prior to a 25 mg oral dose of sumatriptan.(5)|
02750|051|D|  In another study, pretreatment with an MAO-A inhibitor prior to|
02750|052|D|administration of injectable sumatriptan resulted in a 2-fold increase in|
02750|053|D|sumatriptan AUC and a 40% increase in elimination half-life.(9)|
02750|054|D|Pretreatment with a MAO-B inhibitor did not produce any significant changes|
02750|055|D|in sumatriptan pharmacokinetics.  The effect of a MAOI on nasal sumatriptan|
02750|056|D|systemic absorption is expected to be less than that seen with oral|
02750|057|D|sumatriptan but greater than that seen with injectable sumatriptan.(6)|
02750|058|D|  Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg|
02750|059|D|twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold|
02750|060|D|increase in Cmax and AUC for zolmitriptan's active N-desmethyl|
02750|061|D|metabolite.(11,12)  Administration of selegiline for one week at a dosage of|
02750|062|D|10 mg daily had no effect on the pharmacokinetics of zolmitriptan or its|
02750|063|D|metabolite.(11)|
02750|064|D|  At daily doses of 10 mg, selegiline is primarily a selective MAO-B|
02750|065|D|inhibitor; however, at higher doses, selegiline is capable of inhibiting|
02750|066|D|MAO-A.  Hypertensive reactions to the addition of either tyramine or a|
02750|067|D|sympathomimetic to recommended dosages of selegiline have been reported.(15)|
02750|068|D|Therefore, patients receiving selegiline at dosages of greater than 10 mg|
02750|069|D|daily should be considered to be receiving a MAO-A inhibitor.  It would also|
02750|070|D|be prudent to monitor patients receiving selegiline at recommended dosages|
02750|071|D|for this interaction.|
02750|072|B||
02750|073|R|REFERENCES:|
02750|074|B||
02750|075|R|1.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
02750|076|R|  June, 2020.|1
02750|077|R|2.Maxalt (rizatriptan) US prescribing information. Merck & Co., Inc.|1
02750|078|R|  October, 2019.|1
02750|079|R|3.Imigran Tablets, Injection, and Nasal Spray (sumatriptan) Australian|1
02750|080|R|  prescribing information. GlaxoSmithKline February 11, 2002.|1
02750|081|R|4.Imigran Radis (sumaptriptan) UK summary of product characteristics.|1
02750|082|R|  GlaxoSmithKline UK June 8, 2004.|1
02750|083|R|5.Imitrex Tablets (sumatriptan) US prescribing information. GlaxoSmithKline|1
02750|084|R|  December 14, 2017.|1
02750|085|R|6.Imigran Nasal Spray (sumatriptan) UK summary of product characteristics.|1
02750|086|R|  GlaxoSmithKline UK July 8, 2004.|1
02750|087|R|7.Imitrex Nasal Spray (sumatriptan) US prescribing information.|1
02750|088|R|  GlaxoSmithKline December 14, 2017.|1
02750|089|R|8.Imigran Injection (sumatriptan) UK summary of product characteristics.|1
02750|090|R|  GlaxoSmithKline UK September 19, 2003.|1
02750|091|R|9.Imitrex Injection (sumatriptan) US prescribing information.|1
02750|092|R|  GlaxoSmithKline December 14, 2017.|1
02750|093|R|10.Imitrex (sumatriptan) CA prescribing information. GlaxoSmithKline Inc.|1
02750|094|R|   September 22, 2011.|1
02750|095|R|11.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
02750|096|R|   Pharmaceuticals LP September, 2012.|1
02750|097|R|12.Zomig (zolmitriptan) UK summary of product characteristics. Zeneca|1
02750|098|R|   Limited March, 1997.|1
02750|099|R|13.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
02750|100|R|   March, 2020.|1
02750|101|R|14.Frova (frovatriptan) US prescribing information. Endo Pharmaceuticals|1
02750|102|R|   August, 2018.|1
02750|103|R|15.Eldepryl (selegiline) US prescribing information. Somerset|1
02750|104|R|   Pharmaceuticals February, 1997.|1
02751|001|T|MONOGRAPH TITLE:  Methadone/Selected MAOIs|
02751|002|B||
02751|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02751|004|L|is contraindicated and generally should not be dispensed or administered to|
02751|005|L|the same patient.|
02751|006|B||
02751|007|A|MECHANISM OF ACTION:  Methadone may inhibit neural reuptake of serotonin.|
02751|008|A|MAOIs increase neuronal serotonin concentrations via inhibition of MAO-A.|
02751|009|B||
02751|010|E|CLINICAL EFFECTS:  The concurrent use of methadone with MAOIs has been|
02751|011|E|associated with serotonin syndrome.|
02751|012|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
02751|013|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02751|014|E|rigidity.|
02751|015|B||
02751|016|P|PREDISPOSING FACTORS:  Higher opioid concentrations as may occur due to|
02751|017|P|inhibition of opioid  clearance, patient specific genomic factors (e.g. poor|
02751|018|P|metabolizer status for a specific P450 enzyme), or high opioid dosage may|
02751|019|P|increase the risk for a severe interaction.|
02751|020|B||
02751|021|M|PATIENT MANAGEMENT:  When possible, avoid concomitant use of methadone, and|
02751|022|M|selected MAOIs.|
02751|023|M|   Manufacturer recommendations:|
02751|024|M|   The US manufacturer of methadone states that methadone is not recommended|
02751|025|M|during and within 14 days of therapy with MAOIs.|
02751|026|M|   The Australian manufacturer of methadone states that methadone should not|
02751|027|M|be administered to patients receiving MAOIs.|
02751|028|M|   The UK manufacturer of methadone states that concurrent use and use|
02751|029|M|within 2 weeks of discontinuation of MAOIs is contraindicated.|
02751|030|B||
02751|031|D|DISCUSSION:  FDA performed a search of its adverse event database for cases|
02751|032|D|of serotonin syndrome with selected opiates for the period of January 1,|
02751|033|D|1969 to June 12, 2013; 5 cases were associated with methadone use during|
02751|034|D|this 43 year period.|
02751|035|D|   Furazolidone is known to be monoamine oxidase inhibitor.|
02751|036|D|   Methylene blue, when administered intravenously, has been shown to reach|
02751|037|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
02751|038|D|   One or more of the drug pairs linked to this monograph have been included|
02751|039|D|in a list of interactions that should be considered "high-priority" for|
02751|040|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
02751|041|D|vetted by an expert panel commissioned by the U.S. Office of the National|
02751|042|D|Coordinator (ONC) for Health Information Technology.|
02751|043|B||
02751|044|R|REFERENCES:|
02751|045|B||
02751|046|R|1.Mitchell RS. Fatal toxic encephalitis occurring during iproniazid therapy|2
02751|047|R|  in pulmonary tuberculosis. Ann Intern Med 1955;42:417-24.|2
02751|048|R|2.Papp C, Benaim S. Toxic effects of iproniazid in a patient with angina. Br|3
02751|049|R|  Med J 1958 Nov 1;2:1070-2.|3
02751|050|R|3.London DR, Milne MD. Dangers of monoamine oxidase inhibitors. Br Med J|6
02751|051|R|  1962 Dec 29;2:1752.|6
02751|052|R|4.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
02751|053|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
02751|054|R|5.Anonymous. Analgesics and monoamine-oxidase inhibitors. Br Med J 1967 Nov|6
02751|055|R|  4;4(574):284.|6
02751|056|R|6.Barry BJ. Adverse effects of MAO inhibitors with narcotics reversed with|3
02751|057|R|  naloxone. Anaesth Intensive Care 1979 May;7(2):194.|3
02751|058|R|7.Browne B, Linter S. Monoamine oxidase inhibitors and narcotic analgesics.|6
02751|059|R|  A critical review of the implications for treatment. Br J Psychiatry 1987|6
02751|060|R|  Aug;151:210-2.|6
02751|061|R|8.Rossiter A, Souney PF. Interaction between MAOIs and opioids:|6
02751|062|R|  pharmacologic and clinical considerations. Hosp Formul 1993 Aug;28:692-8.|6
02751|063|R|9.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
02751|064|R|  2007.|1
02751|065|R|10.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
02751|066|R|   Pharmaceuticals Corp. June, 2021.|1
02751|067|R|11.Metharose (methadone hydrochloride) UK summary of product|1
02751|068|R|   characteristics. Rosemone Pharmaceuticals Limited January 9, 2008.|1
02751|069|R|12.Diskets Dispersible (methadone hydrochloride) US prescribing information.|1
02751|070|R|   Cebert Pharmaceuticals, Inc. August, 2007.|1
02751|071|R|13.Diamorphine hydrochloride Australian prescribing information. Auralis|1
02751|072|R|   March 13, 2008.|1
02751|073|R|14.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02751|074|R|   352(11):1112-20.|6
02751|075|R|15.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02751|076|R|   warns about several safety issues with opioid pain medicines; requires|1
02751|077|R|   label changes. available at:|1
02751|078|R|   http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
02751|079|R|16.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
02751|080|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
02751|081|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
02751|082|R|   19(5):735-43.|6
02752|001|T|MONOGRAPH TITLE:  Methotrexate (Oncology-Injection)/Sulfasalazine|
02752|002|B||
02752|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02752|004|L|of severe adverse interaction.|
02752|005|B||
02752|006|A|MECHANISM OF ACTION:  Sulfasalazine may decrease the renal clearance of|
02752|007|A|methotrexate or produce a synergistically-induced folate deficiency.|
02752|008|A|Sulfasalazine may decrease protein binding of methotrexate.|
02752|009|B||
02752|010|E|CLINICAL EFFECTS:  Concurrent use of sulfasalazine may increase systemic|
02752|011|E|levels of and toxicity from methotrexate, leading to increased risk of|
02752|012|E|severe neurotoxicity, stomatitis, and myelosuppression, including|
02752|013|E|neutropenia.|
02752|014|B||
02752|015|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
02752|016|P|- High-dose oncology regimens|
02752|017|P|- Impaired renal function, ascites, or pleural effusions|
02752|018|B||
02752|019|M|PATIENT MANAGEMENT:  Monitor patients who are receiving concurrent therapy|
02752|020|M|or patients who have recently finished methotrexate therapy and who are|
02752|021|M|beginning sulfasalazine therapy for signs of toxicity, including bone marrow|
02752|022|M|suppression, pancytopenia, thrombocytopenia, and stomatitis.|
02752|023|B||
02752|024|D|DISCUSSION:  In one study in pediatric leukemia patients, concurrent|
02752|025|D|administration of methotrexate and trimethoprim-sulfamethoxazole resulted in|
02752|026|D|an increase in free methotrexate and a decrease in free methotrexate|
02752|027|D|clearance.  These changes resulted in a 66% increase in systemic exposure to|
02752|028|D|methotrexate, although there were no significant changes in total|
02752|029|D|methotrexate clearance or methotrexate half-life.  In another study in|
02752|030|D|pediatric leukemia patients, concurrent therapy with methotrexate and|
02752|031|D|trimethoprim-sulfamethoxazole did not alter the intestinal absorption,|
02752|032|D|degree of plasma protein binding, or average concentration of methotrexate.|
02752|033|D|Case reports have documented methotrexate toxicities such as bone marrow|
02752|034|D|hypoplasia, pancytopenia, thrombocytopenia, and stomatitis during concurrent|
02752|035|D|therapy and during therapy with trimethoprim-sulfamethoxazole following the|
02752|036|D|conclusion of methotrexate therapy.  While some of these reports involved|
02752|037|D|patients receiving low-dose methotrexate for rheumatoid arthritis, a|
02752|038|D|randomized clinical trial of concurrent methotrexate and sulfasalazine|
02752|039|D|therapy in rheumatoid arthritis patients showed superior efficacy and|
02752|040|D|similar toxicity compared to methotrexate alone.   Methotrexate plasma|
02752|041|D|protein binding and renal clearance have been shown to be decrease by the|
02752|042|D|concurrent administration of sulfisoxazole.|
02752|043|D|   Although in one study concurrent administration of sulfasalazine had no|
02752|044|D|effect on methotrexate pharmacokinetics, both drugs are substrates for|
02752|045|D|folate transporters as well as BCRP (breast cancer resistance protein) and|
02752|046|D|so caution is still warranted during concurrent therapy.|
02752|047|B||
02752|048|R|REFERENCES:|
02752|049|B||
02752|050|R|1.Kobrinsky NL, Ramsay NK. Acute megaloblastic anemia induced by high-dose|3
02752|051|R|  trimethoprim- sulfamethoxazole. Ann Intern Med 1981 Jun;94(6):780-1.|3
02752|052|R|2.Dan M, Shapira I. Possible role of methotrexate in|3
02752|053|R|  trimethoprim-sulfamethoxazole-induced acute megaloblastic anemia. Isr J|3
02752|054|R|  Med Sci 1984 Mar;20(3):262-3.|3
02752|055|R|3.Thomas MH, Gutterman LA. Methotrexate toxicity in a patient receiving|3
02752|056|R|  trimethoprim- sulfamethoxazole. J Rheumatol 1986 Apr;13(2):440-1.|3
02752|057|R|4.Maricic M, Davis M, Gall EP. Megaloblastic pancytopenia in a patient|3
02752|058|R|  receiving concurrent methotrexate and trimethoprim-sulfamethoxazole|3
02752|059|R|  treatment. Arthritis Rheum 1986 Jan;29(1):133-5.|3
02752|060|R|5.Frain JB. Methotrexate toxicity in a patient receiving trimethoprim-|3
02752|061|R|  sulfamethoxazole. J Rheumatol 1987 Feb;14(1):176-7.|3
02752|062|R|6.Ng HW, Macfarlane AW, Graham RM, Verbov JL. Near fatal drug interactions|3
02752|063|R|  with methotrexate given for psoriasis. Br Med J (Clin Res Ed) 1987 Sep 26;|3
02752|064|R|  295(6601):752-3.|3
02752|065|R|7.Groenendal H, Rampen FH. Methotrexate and|3
02752|066|R|  trimethoprim-sulphamethoxazole--a potentially hazardous combination. Clin|3
02752|067|R|  Exp Dermatol 1990 Sep;15(5):358-60.|3
02752|068|R|8.Govert JA, Patton S, Fine RL. Pancytopenia from using trimethoprim and|3
02752|069|R|  methotrexate. Ann Intern Med 1992 Nov 15;117(10):877-8.|3
02752|070|R|9.Beach BJ, Woods WG, Howell SB. Influence of co-trimoxazole on methotrexate|2
02752|071|R|  pharmacokinetics in children with acute lymphoblastic leukemia. Am J|2
02752|072|R|  Pediatr Hematol Oncol 1981 Summer;3(2):115-9.|2
02752|073|R|10.Liegler DG, Henderson ES, Hahn MA, Oliverio VT. The effect of organic|2
02752|074|R|   acids on renal clearance of methotrexate in man. Clin Pharmacol Ther 1969|2
02752|075|R|   Nov-Dec;10(6):849-57.|2
02752|076|R|11.el-Tamtamy S. Letter: Co-trimoxazole and the blood. Lancet 1974 May 11;|3
02752|077|R|   1(7863):929-30.|3
02752|078|R|12.Bernstein LS. Adverse reactions to trimethoprim-sulfamethoxazole, with|6
02752|079|R|   particular reference to long-term therapy. Can Med Assoc J 1975 Jun 14;|6
02752|080|R|   112(13 Spec No):96-8.|6
02752|081|R|13.Haagsma CJ, van Riel PL, de Rooij DJ, Vree TB, Russel FJ, van't Hof MA,|2
02752|082|R|   van de Putte LB. Combination of methotrexate and sulphasalazine vs|2
02752|083|R|   methotrexate alone: a randomized open clinical trial in rheumatoid|2
02752|084|R|   arthritis patients resistant to sulphasalazine therapy. Br J Rheumatol|2
02752|085|R|   1994 Nov;33(11):1049-55.|2
02752|086|R|14.Ferrazzini G, Klein J, Sulh H, Chung D, Griesbrecht E, Koren G.|2
02752|087|R|   Interaction between trimethoprim-sulfamethoxazole and methotrexate in|2
02752|088|R|   children with leukemia. J Pediatr 1990 Nov;117(5):823-6.|2
02752|089|R|15.Steuer A, Gumpel JM. Methotrexate and trimethoprim: a fatal interaction.|3
02752|090|R|   Br J Rheumatol 1998 Jan;37(1):105-6.|3
02753|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 10 mg)/Sofosbuvir-Velpatasvir;|
02753|002|T|Glecaprevir-Pibrentasvir|
02753|003|B||
02753|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02753|005|L|is contraindicated and generally should not be dispensed or administered to|
02753|006|L|the same patient.|
02753|007|B||
02753|008|A|MECHANISM OF ACTION:  Velpatasvir is an inhibitor of BCRP, OATP1B1 and|
02753|009|A|OATP1B3 transport in the intestine.(1)  Glecaprevir and pibrentasvir are|
02753|010|A|inhibitors of BCRP, OATP1B1, and OATP1B3.(3) Rosuvastatin is a substrate for|
02753|011|A|these three transporters.(2)|
02753|012|B||
02753|013|E|CLINICAL EFFECTS:  Concurrent use of velpatasvir or glecaprevir-pibrentasvir|
02753|014|E|and rosuvastatin may result in increased absorption and systemic|
02753|015|E|concentration of rosuvastatin, which could result in myopathy or|
02753|016|E|rhabdomyolysis.(1,3)|
02753|017|B||
02753|018|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02753|019|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02753|020|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02753|021|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02753|022|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02753|023|P|transporter OATP1B1 may have increased statin concentrations and be|
02753|024|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02753|025|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02753|026|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02753|027|B||
02753|028|M|PATIENT MANAGEMENT:  The manufacturer of velpatasvir (Epclusa) states that|
02753|029|M|due to the increased risk for myopathy/rhabdomyolysis, the rosuvastatin dose|
02753|030|M|should not exceed 10 mg once daily.(1)|
02753|031|M|   The manufacturer of glecaprevir-pibrentasvir states that due to the|
02753|032|M|increased risk for myopathy/rhabdomyolysis, the rosuvastatin dose should not|
02753|033|M|exceed 10 mg once daily.(3)|
02753|034|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
02753|035|M|of rosuvastatin should not exceed 5 mg daily when used with|
02753|036|M|sofosbuvir-velpatasvir or glecaprevir-pibrentasvir.(4)|
02753|037|M|   If these medications are used concurrently, counsel patient to report|
02753|038|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
02753|039|B||
02753|040|D|DISCUSSION:  In an interaction study, velpatasvir 100 mg once daily|
02753|041|D|increased rosuvastatin maximum concentration (Cmax) 2.61-fold and exposure|
02753|042|D|(AUC, area-under-curve) 2.69-fold.(1)|
02753|043|D|   In an interaction study in 11 subjects, glecaprevir-pibrentasvir (400/120|
02753|044|D|mg daily) increased rosuvastatin (5 mg once daily) Cmax and AUC by 5.62-fold|
02753|045|D|and 2.15-fold, respectively.(3)|
02753|046|B||
02753|047|R|REFERENCES:|
02753|048|B||
02753|049|R|1.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
02753|050|R|  Sciences, Inc. April, 2022.|1
02753|051|R|2.This information is based on an extract from the Certara Drug Interaction|6
02753|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02753|053|R|3.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02753|054|R|  Inc. October, 2023.|1
02753|055|R|4.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
02753|056|R|  Australia Pty Ltd July 8, 2024.|1
02754|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 10|
02754|002|T|mg)/Sofosbuvir-Velpatasvir; Glecaprevir-Pibrentasvir|
02754|003|B||
02754|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02754|005|L|take action as needed.|
02754|006|B||
02754|007|A|MECHANISM OF ACTION:  Velpatasvir is an inhibitor of BCRP, OATP1B1 and|
02754|008|A|OATP1B3 transport in the intestine.(1)  Glecaprevir and pibrentasvir are|
02754|009|A|inhibitors of BCRP, OATP1B1, and OATP1B3.(3) Rosuvastatin is a substrate for|
02754|010|A|these three transporters.(2)|
02754|011|B||
02754|012|E|CLINICAL EFFECTS:  Concurrent use of velpatasvir or glecaprevir-pibrentasvir|
02754|013|E|and rosuvastatin may result in increased absorption and systemic|
02754|014|E|concentration of rosuvastatin, which could result in myopathy or|
02754|015|E|rhabdomyolysis.(1,3)|
02754|016|B||
02754|017|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02754|018|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02754|019|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02754|020|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02754|021|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02754|022|P|transporter OATP1B1 may have increased statin concentrations and be|
02754|023|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02754|024|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02754|025|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02754|026|B||
02754|027|M|PATIENT MANAGEMENT:  The manufacturer of velpatasvir (Epclusa) states that|
02754|028|M|due to the increased risk for myopathy/rhabdomyolysis, rosuvastatin dose|
02754|029|M|should not exceed 10 mg once daily.(1)|
02754|030|M|   The manufacturer of glecaprevir-pibrentasvir states that due to the|
02754|031|M|increased risk for myopathy/rhabdomyolysis, the rosuvastatin dose should not|
02754|032|M|exceed 10 mg once daily.(3)|
02754|033|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
02754|034|M|of rosuvastatin should not exceed 5 mg daily when used with|
02754|035|M|sofosbuvir-velpatasvir or glecaprevir-pibrentasvir.(4)|
02754|036|M|   If these medications are used concurrently, counsel patient to report|
02754|037|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
02754|038|B||
02754|039|D|DISCUSSION:  In an interaction study, velpatasvir 100 mg once daily|
02754|040|D|increased rosuvastatin maximum concentration (Cmax) 2.61-fold and exposure|
02754|041|D|(AUC, area-under-curve) 2.69-fold.(1)|
02754|042|D|   In an interaction study in 11 subjects, glecaprevir-pibrentasvir (400/120|
02754|043|D|mg daily) increased rosuvastatin (5 mg once daily) Cmax and AUC by 5.62-fold|
02754|044|D|and 2.15-fold, respectively.(3)|
02754|045|B||
02754|046|R|REFERENCES:|
02754|047|B||
02754|048|R|1.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
02754|049|R|  Sciences, Inc. April, 2022.|1
02754|050|R|2.This information is based on an extract from the Certara Drug Interaction|6
02754|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02754|052|R|3.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02754|053|R|  Inc. October, 2023.|1
02754|054|R|4.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
02754|055|R|  Australia Pty Ltd July 8, 2024.|1
02755|001|T|MONOGRAPH TITLE:  Defibrotide/Selected Anticoagulants; Thrombolytics|
02755|002|B||
02755|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02755|004|L|is contraindicated and generally should not be dispensed or administered to|
02755|005|L|the same patient.|
02755|006|B||
02755|007|A|MECHANISM OF ACTION:  Concurrent use may result in additive effects on|
02755|008|A|hemostasis.(1)|
02755|009|B||
02755|010|E|CLINICAL EFFECTS:  Concurrent use of defibrotide with anticoagulants or|
02755|011|E|thrombolytics may increase the risk of bleeding.(1)|
02755|012|B||
02755|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02755|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02755|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
02755|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02755|017|P|risk for bleeding (e.g. NSAIDs).|
02755|018|B||
02755|019|M|PATIENT MANAGEMENT:  The US manufacturer of defibrotide states that|
02755|020|M|concomitant use with systemic anticoagulant or antithrombotic therapy is|
02755|021|M|contraindicated.(1)  In patients who have received prior anticoagulant or|
02755|022|M|thrombolytic therapy, consider delaying the start of defibrotide until the|
02755|023|M|effects of the anticoagulant have abated.(1)|
02755|024|M|   If concurrent therapy is deemed medically necessary, closely monitor|
02755|025|M|patients receiving concurrent therapy for signs of blood loss, including|
02755|026|M|decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood|
02755|027|M|pressure and promptly evaluate patients with any symptoms.|
02755|028|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02755|029|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02755|030|M|anticoagulation in patients with active pathologic bleeding.|
02755|031|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02755|032|M|unusual bleeding; gingival bleeding; nosebleeds; unusual bruising;|
02755|033|M|orange/red urine or dark/black stools; new onset of headache, confusion,|
02755|034|M|slurred speech, or vision; acute abdominal pain; or joint pain and/or|
02755|035|M|swelling.|
02755|036|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02755|037|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02755|038|M|initiating, altering the dose or discontinuing either drug.|
02755|039|B||
02755|040|D|DISCUSSION:  In pivotal clinical trials, 176 patients received defibrotide;|
02755|041|D|the use of anticoagulants or thrombolytics was not allowed.   Bleeding|
02755|042|D|events not attributed to underlying disease were as follows: epistaxis|
02755|043|D|(14%), pulmonary alveolar hemorrhage (9%),  gastrointestinal hemorrhage|
02755|044|D|(9%), pulmonary hemorrhage (9%), intracranial hemorrhage (3%), cerebral|
02755|045|D|hemorrhage (2%).|
02755|046|B||
02755|047|R|REFERENCE:|
02755|048|B||
02755|049|R|1.Defitelio (defibrotide) US prescribing information. Jazz Pharmaceuticals,|1
02755|050|R|  Inc. March, 2016.|1
02756|001|T|MONOGRAPH TITLE:  Urokinase/Anticoagulants; Thrombolytics|
02756|002|B||
02756|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02756|004|L|of severe adverse interaction.|
02756|005|B||
02756|006|A|MECHANISM OF ACTION:  The concurrent use of urokinase with anticoagulants or|
02756|007|A|thrombolytics may increase the risk of bleeding.(1,2)|
02756|008|B||
02756|009|E|CLINICAL EFFECTS:  The concurrent use of urokinase with anticoagulants or|
02756|010|E|thrombolytics may result in bleeding episodes.(1,2)|
02756|011|B||
02756|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02756|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02756|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
02756|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02756|016|P|risk for bleeding (e.g. NSAIDs).|
02756|017|B||
02756|018|M|PATIENT MANAGEMENT:  The UK and US manufacturers of urokinase state that the|
02756|019|M|concurrent use with thrombolytic agents or anticoagulants may increase the|
02756|020|M|risk of serious bleeding.(1,2)|
02756|021|M|   If anticoagulation therapy is recommended after infusion of urokinase,|
02756|022|M|monitor aPTT and do not begin anticoagulation until the aPTT is less than|
02756|023|M|twice the normal control value.  If heparin is started after urokinase|
02756|024|M|infusion, do not administer a loading dose of heparin.|
02756|025|M|   When concurrent therapy is warranted, monitor patients receiving|
02756|026|M|concurrent therapy for signs of blood loss, including decreased hemoglobin|
02756|027|M|and/or hematocrit, fecal occult blood, and/or decreased blood pressure and|
02756|028|M|promptly evaluate patients with any symptoms.|
02756|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02756|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02756|031|M|anticoagulation in patients with active pathologic bleeding.|
02756|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02756|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02756|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02756|035|M|and/or swelling.|
02756|036|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02756|037|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02756|038|M|initiating, altering the dose or discontinuing either drug.|
02756|039|B||
02756|040|D|DISCUSSION:  The UK and US manufacturers of urokinase states that use with|
02756|041|D|agents that alter anticoagulation or platelet function may increase the risk|
02756|042|D|of serious bleeding.  The manufacturer of urokinase states administration of|
02756|043|D|urokinase prior to, during, or after thrombolytic therapy may increase the|
02756|044|D|risk of serious bleeding.  Use of urokinase with other agents that alter|
02756|045|D|coagulation or are thrombolytic, careful monitoring of bleeding is|
02756|046|D|recommended.(1,2)|
02756|047|B||
02756|048|R|REFERENCES:|
02756|049|B||
02756|050|R|1.Syner-Kinase (urokinase) UK summary of product characteristics.|1
02756|051|R|  Syner-Medica Ltd. January, 2016.|1
02756|052|R|2.Kinlytic (urokinase) US prescribing information. ImaRx Therapeutics, Inc.|1
02756|053|R|  June, 2007.|1
02757|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 10 mg)/Leflunomide;|
02757|002|T|Teriflunomide|
02757|003|B||
02757|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02757|005|L|is contraindicated and generally should not be dispensed or administered to|
02757|006|L|the same patient.|
02757|007|B||
02757|008|A|MECHANISM OF ACTION:  Teriflunomide an inhibitor of BCRP, OATP1B1 and|
02757|009|A|OATP1B3 transport in the intestine.(1)  Leflunomide is a produg and is|
02757|010|A|converted to its active metabolite teriflunomide.(2)|
02757|011|A|   Rosuvastatin is a substrate for these three transporters.(4)|
02757|012|B||
02757|013|E|CLINICAL EFFECTS:  Concurrent use of leflunomide or teriflunomide with|
02757|014|E|rosuvastatin may result in increased absorption and systemic concentration|
02757|015|E|of rosuvastatin, which could result in myopathy or rhabdomyolysis.(1)|
02757|016|B||
02757|017|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02757|018|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02757|019|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02757|020|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02757|021|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02757|022|P|transporter OATP1B1 may have increased statin concentrations and be|
02757|023|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02757|024|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02757|025|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02757|026|B||
02757|027|M|PATIENT MANAGEMENT:  Due to the increased risk for myopathy/rhabdomyolysis,|
02757|028|M|the dosage of rosuvastatin should not exceed 10 mg once daily in patients|
02757|029|M|receiving leflunomide or teriflunomide.(1)|
02757|030|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
02757|031|M|of rosuvastatin should not exceed 5 mg daily when used with leflunomide or|
02757|032|M|teriflunomide.(3)|
02757|033|M|   If these medications are used concurrently, counsel patient to report|
02757|034|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
02757|035|B||
02757|036|D|DISCUSSION:  In an interaction study, teriflunomide (repeated doses)|
02757|037|D|increased rosuvastatin maximum concentration (Cmax) and area-under-curve|
02757|038|D|(AUC) by 2.65-fold and 2.51-fold, respectively.(1,2)|
02757|039|D|   Leflunomide is a produg and is converted to its active metabolite|
02757|040|D|teriflunomide.(2)|
02757|041|B||
02757|042|R|REFERENCES:|
02757|043|B||
02757|044|R|1.Aubagio (teriflunomide) US prescribing information. Genzyme Corporation|1
02757|045|R|  November, 2020.|1
02757|046|R|2.Arava (leflunomide) US prescribing information. Aventis Pharmaceuticals,|1
02757|047|R|  Inc. November, 2012.|1
02757|048|R|3.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
02757|049|R|  Australia Pty Ltd July 8, 2024.|1
02757|050|R|4.This information is based on an extract from the Certara Drug Interaction|6
02757|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02758|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than Or Equal To 10 mg)/Leflunomide;|
02758|002|T|Teriflunomide|
02758|003|B||
02758|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02758|005|L|take action as needed.|
02758|006|B||
02758|007|A|MECHANISM OF ACTION:  Teriflunomide an inhibitor of BCRP, OATP1B1 and|
02758|008|A|OATP1B3 transport in the intestine.(1)  Leflunomide is a produg and is|
02758|009|A|converted to its active metabolite teriflunomide.(2)|
02758|010|A|   Rosuvastatin is a substrate for these three transporters.(4)|
02758|011|B||
02758|012|E|CLINICAL EFFECTS:  Concurrent use of leflunomide or teriflunomide with|
02758|013|E|rosuvastatin may result in increased absorption and systemic concentration|
02758|014|E|of rosuvastatin, which could result in myopathy or rhabdomyolysis.(1,2)|
02758|015|B||
02758|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02758|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02758|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02758|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02758|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02758|021|P|transporter OATP1B1 may have increased statin concentrations and be|
02758|022|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02758|023|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02758|024|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02758|025|B||
02758|026|M|PATIENT MANAGEMENT:  Due to the increased risk for myopathy/rhabdomyolysis,|
02758|027|M|the dosage of rosuvastatin should not exceed 10 mg once daily in patients|
02758|028|M|receiving leflunomide or teriflunomide.(1)|
02758|029|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
02758|030|M|of rosuvastatin should not exceed 5 mg daily when used with leflunomide or|
02758|031|M|teriflunomide.(3)|
02758|032|M|   If these medications are used concurrently, counsel patient to report|
02758|033|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
02758|034|B||
02758|035|D|DISCUSSION:  In an interaction study, teriflunomide (repeated doses)|
02758|036|D|increased rosuvastatin maximum concentration (Cmax) and area-under-curve|
02758|037|D|(AUC) by 2.65-fold and 2.51-fold, respectively.(1,2)|
02758|038|D|   Leflunomide is a produg and is converted to its active metabolite|
02758|039|D|teriflunomide.(2)|
02758|040|B||
02758|041|R|REFERENCES:|
02758|042|B||
02758|043|R|1.Aubagio (teriflunomide) US prescribing information. Genzyme Corporation|1
02758|044|R|  November, 2020.|1
02758|045|R|2.Arava (leflunomide) US prescribing information. Aventis Pharmaceuticals,|1
02758|046|R|  Inc. November, 2012.|1
02758|047|R|3.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
02758|048|R|  Australia Pty Ltd July 8, 2024.|1
02758|049|R|4.This information is based on an extract from the Certara Drug Interaction|6
02758|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02759|001|T|MONOGRAPH TITLE:  Methotrexate (Oncology Inj)/Levetiracetam (mono deleted|
02759|002|T|12/13/2022)|
02759|003|B||
02759|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02759|005|L|take action as needed.|
02759|006|B||
02759|007|A|MECHANISM OF ACTION:  The metabolite of levetiracetam, ucb L057, may|
02759|008|A|decrease the renal clearance of methotrexate.(1-3)|
02759|009|B||
02759|010|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and levetiracetam may|
02759|011|E|increase systemic levels of and toxicity from methotrexate, leading to|
02759|012|E|increased risk of severe neurotoxicity, stomatitis, and myelosuppression,|
02759|013|E|including neutropenia.(1-3)|
02759|014|B||
02759|015|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
02759|016|P|- High-dose oncology regimens|
02759|017|P|- Impaired renal function, ascites, or pleural effusions|
02759|018|B||
02759|019|M|PATIENT MANAGEMENT:  US manufacturer prescribing information for|
02759|020|M|methotrexate states concurrent use of drugs that also undergo tubular|
02759|021|M|secretion may increase methotrexate serum levels.(1,2)|
02759|022|M|   If concurrent therapy is warranted, methotrexate plasma levels should be|
02759|023|M|monitored and patients should be observed for methotrexate toxicity.  The|
02759|024|M|dosage of methotrexate may need to be adjusted.  Alternative seizure|
02759|025|M|management may be considered.|
02759|026|B||
02759|027|D|DISCUSSION:  Two published case reports document the delayed renal clearance|
02759|028|D|of methotrexate after initiation of levetiracetam.|
02759|029|D|   A case report of a 46 year-old male on high-dose methotrexate for|
02759|030|D|osteosarcoma received chemotherapy cycle 1 with 24-hour, 48-hour, and|
02759|031|D|72-hour methotrexate levels at 7.9 mmol/L, 0.69 mmol/L, and 0.17 mmol/L,|
02759|032|D|respectively, and time to level <0.1 mmol/L of 90 hours.  Levetiracetam was|
02759|033|D|initiated after cycle 1 for management of seizures. Methotrexate levels at|
02759|034|D|24-hours, 48-hours, and 72-hours and time to level <0.1 mmol/L were|
02759|035|D|increased during cycle 2, 3, and 4:|
02759|036|D|- Cycle 2: 16.59 mmol/L, 1.58 mmol/L, 0.58 mmol/L, and 155 hours,|
02759|037|D|respectively|
02759|038|D|- Cycle 3: 18.71 mmol/L, 1.26 mmol/L, 0.33 mmol/L, and 130 hours,|
02759|039|D|respectively|
02759|040|D|- Cycle 4: 11.97 mmol/L, 0.68 mmol/L, 0.25 mmol/L, and 106 hours,|
02759|041|D|respectively|
02759|042|D|Levetiracetam was stopped after cycle 4.  During cycle 5, methotrexate time|
02759|043|D|to level <0.1 mmol/L decreased to 95 hours.  Renal function remained|
02759|044|D|unchanged throughout the 5 cycles of methotrexate.(4)|
02759|045|D|   A case report of a 15 year-old male treated for B-cell acute|
02759|046|D|lymphoblastic leukemia on high-dose methotrexate developed seizures after|
02759|047|D|the seventh injection of methotrexate.  Levetiracetam was initiated for|
02759|048|D|management.  After the subsequent third methotrexate injection, the patient|
02759|049|D|developed symptoms of methotrexate toxicity, including uncontrollable|
02759|050|D|vomiting, renal failure, and high blood pressure.  Levetiracetam was stopped|
02759|051|D|and changed to clonazepam.  Methotrexate injections were also stopped due to|
02759|052|D|renal toxicity.(5)|
02759|053|B||
02759|054|R|REFERENCES:|
02759|055|B||
02759|056|R|1.Rheumatrex (methotrexate, oral) US prescribing information. Dava|1
02759|057|R|  Pharmaceuticals, Inc. February, 2013.|1
02759|058|R|2.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
02759|059|R|  Inc. March, 2018.|1
02759|060|R|3.Keppra (levetiracetam) US prescribing information. UCB Group of Companies|1
02759|061|R|  November, 2016.|1
02759|062|R|4.Bain E, Birhiray RE, Reeves DJ. Drug-drug interaction between methotrexate|3
02759|063|R|  and levetiracetam resulting in delayed methotrexate elimination. Ann|3
02759|064|R|  Pharmacother 2014 Feb;48(2):292-6.|3
02759|065|R|5.Parentelli AS, Phulpin-Weibel A, Mansuy L, Contet A, Trechot P, Chastagner|3
02759|066|R|  P. Drug-drug interaction between methotrexate and levetiracetam in a child|3
02759|067|R|  treated for acute lymphoblastic leukemia. Pediatr Blood Cancer 2013 Feb;|3
02759|068|R|  60(2):340-1.|3
02760|001|T|MONOGRAPH TITLE:  Bromocriptine/Moderate CYP3A4 Inhibitors|
02760|002|B||
02760|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02760|004|L|take action as needed.|
02760|005|B||
02760|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
02760|007|A|of bromocriptine.|
02760|008|B||
02760|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
02760|010|E|in increased levels of bromocriptine, which may result in increased side|
02760|011|E|effects of these agents.|
02760|012|B||
02760|013|P|PREDISPOSING FACTORS:  Patients receiving the maximum recommended (or higher|
02760|014|P|than recommended) dosages of ergotamine derivatives may be at a higher risk|
02760|015|P|of adverse effects from this combination.|
02760|016|B||
02760|017|M|PATIENT MANAGEMENT:  Use caution with concurrent therapy with bromocriptine|
02760|018|M|with azole antifungals.|
02760|019|M|   The US manufacturer of bromocriptine states use caution when|
02760|020|M|co-administering drugs that are inhibitors of CYP3A4.  Bromocriptine dose|
02760|021|M|should not exceed 1.6 mg per day when used with a moderate CYP3A4 inhibitor.|
02760|022|M|Concomitant use of strong CYP3A4 inhibitors should be avoided.  Ensure|
02760|023|M|adequate washout of strong CYP3A4 inhibitor drug before initiating|
02760|024|M|bromocriptine.(1)|
02760|025|B||
02760|026|D|DISCUSSION:  A study in five healthy subjects found that concurrent|
02760|027|D|administration of erythromycin and bromocriptine resulted in a 268% increase|
02760|028|D|in area-under-curve (AUC) for bromocriptine and a 4.6-fold increase in|
02760|029|D|bromocriptine maximum concentration (Cmax).(2)|
02760|030|D|   Inhibition of ergotamine derivative metabolism by moderate inhibitors|
02760|031|D|would also be expected, but to a lesser degree.  Moderate CYP3A4 inhibitors|
02760|032|D|linked to this monograph are aprepitant, avacopan, berotralstat,|
02760|033|D|clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib,|
02760|034|D|fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib,|
02760|035|D|isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib,|
02760|036|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and|
02760|037|D|verapamil.(3,4)|
02760|038|B||
02760|039|R|REFERENCES:|
02760|040|B||
02760|041|R|1.Cycloset (bromocriptine mesylate) tablets, US prescribing information.|1
02760|042|R|  Veroscience LLC February 2, 2016.|1
02760|043|R|2.Nelson MV, Berchou RC, Kareti D, LeWitt PA. Pharmacokinetic evaluation of|2
02760|044|R|  erythromycin and caffeine administered with bromocriptine. Clin Pharmacol|2
02760|045|R|  Ther 1990 Jun;47(6):694-7.|2
02760|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
02760|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02760|048|R|4.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
02760|049|R|  March, 2007.|1
02761|001|T|MONOGRAPH TITLE:  Metformin/Vandetanib|
02761|002|B||
02761|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02761|004|L|take action as needed.|
02761|005|B||
02761|006|A|MECHANISM OF ACTION:  Renal tubular secretion of metformin is mediated by|
02761|007|A|organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion|
02761|008|A|protein (MATE) transporter. Vandetanib inhibits elimination by the OCT2 and|
02761|009|A|MATE pathways.(1)|
02761|010|B||
02761|011|E|CLINICAL EFFECTS:  Use of vandetanib may increase levels of metformin.|
02761|012|E|Concurrent use may result in increased plasma levels of metformin and|
02761|013|E|toxicity such as lactic acidosis.  Untreated lactic acidosis may be fatal.|
02761|014|E|Symptoms of lactic acidosis include malaise, myalgias, respiratory distress,|
02761|015|E|low pH, increased anion gap and elevated blood lactate.(1)|
02761|016|B||
02761|017|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
02761|018|P|include renal impairment, sepsis, dehydration, excessive alcohol intake,|
02761|019|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
02761|020|P|failure, metformin plasma levels > 5 micrograms/mL, and conditions which may|
02761|021|P|lead to tissue hypoxia.  Geriatric patients may also be at higher risk due|
02761|022|P|to slower metformin clearance and increased half-life in this population.|
02761|023|P|   The risk for metabolic acidosis is higher with increased doses of either|
02761|024|P|agent.|
02761|025|B||
02761|026|M|PATIENT MANAGEMENT:  Use an alternative agent if possible.  The US labeling|
02761|027|M|for vandetanib recommends caution with concomitant use of metformin and|
02761|028|M|close monitoring for metformin toxicity.(1)|
02761|029|M|   Evaluate patient's renal function and consider discontinuation of one or|
02761|030|M|both agents in patients with renal impairment.|
02761|031|M|   Monitor for signs and symptoms of metformin toxicity (lactic acidosis)|
02761|032|M|such as malaise, myalgias, respiratory distress, increasing somnolence, and|
02761|033|M|respiratory distress. Laboratory results which may signal lactic acidosis|
02761|034|M|include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an|
02761|035|M|increased anion gap, and increased lactate to pyruvate ratio.|
02761|036|B||
02761|037|D|DISCUSSION:  A study in 13 healthy subjects receiving a single 1,000 mg dose|
02761|038|D|of metformin 3 hours after a single 800 mg dose of vandetanib resulted in|
02761|039|D|increases in metformin area-under-curve (AUC) of 74% and maximum|
02761|040|D|concentration (Cmax) of 50% with coadministration compared to metformin|
02761|041|D|alone.(1)|
02761|042|D|   In a study of normal healthy volunteers, concurrent metformin and oral|
02761|043|D|cimetidine (MATE inhibitor) increased metformin maximum concentration (Cmax)|
02761|044|D|in plasma and whole blood by 60% and increased metformin area-under-curve|
02761|045|D|(AUC) levels in plasma and whole blood by 40%.(1)|
02761|046|D|   In a study in 7 subjects, concurrent metformin (250 mg daily) with|
02761|047|D|cimetidine (400 mg twice daily) increased metformin AUC by 50%.  Metformin|
02761|048|D|renal clearance over 24 hours was reduced by 27%.(2)|
02761|049|B||
02761|050|R|REFERENCES:|
02761|051|B||
02761|052|R|1.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
02761|053|R|  Pharmaceuticals LP October, 2018.|1
02761|054|R|2.Somogyi A, Stockley C, Keal J, Rolan P, Bochner F. Reduction of metformin|2
02761|055|R|  renal tubular secretion by cimetidine in man. Br J Clin Pharmacol 1987|2
02761|056|R|  May;23(5):545-51.|2
02761|057|R|3.This information is based on an extract from the Certara Drug Interaction|6
02761|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02762|001|T|MONOGRAPH TITLE:  Methotrexate (low strength injection, oral)/Iodinated|
02762|002|T|Contrast Media|
02762|003|B||
02762|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02762|005|L|take action as needed.|
02762|006|B||
02762|007|A|MECHANISM OF ACTION:  One possible mechanism is renal dysfunction caused by|
02762|008|A|the nephrotoxicity of both agents.|
02762|009|B||
02762|010|E|CLINICAL EFFECTS:  Concurrent use of iodinated contrast media may result in|
02762|011|E|methotrexate toxicity, leading to increased risk of severe neurotoxicity,|
02762|012|E|stomatitis, and myelosuppression, including neutropenia.|
02762|013|B||
02762|014|P|PREDISPOSING FACTORS:  Renal impairment|
02762|015|B||
02762|016|M|PATIENT MANAGEMENT:  It is recommended that the use of iodinated contrast|
02762|017|M|media in patients receiving high dose methotrexate therapy be avoided until|
02762|018|M|the serum methotrexate level is 0.1 mcmol/L or lower.  With lower dose|
02762|019|M|methotrexate therapy, iodinated contrast media should be used with caution|
02762|020|M|and preventative measures should be considered.(1)|
02762|021|B||
02762|022|D|DISCUSSION:  There are three case reports of patients receiving concurrent|
02762|023|D|iodinated contrast agents and methotrexate therapy developing methotrexate|
02762|024|D|toxicity. One patient received iodinated contrast media the day after|
02762|025|D|receiving a methotrexate infusion while the other two patients received|
02762|026|D|contrast media 30 hours and 4.5 hours after methotrexate therapy.(1,2)|
02762|027|B||
02762|028|R|REFERENCES:|
02762|029|B||
02762|030|R|1.Harned TM, Mascarenhas L. Severe methotrexate toxicity precipitated by|3
02762|031|R|  intravenous radiographic contrast. J Pediatr Hematol Oncol 2007 Jul;|3
02762|032|R|  29(7):496-9.|3
02762|033|R|2.Fong CM, Lee AC. High-dose methotrexate-associated acute renal failure may|3
02762|034|R|  be an avoidable complication. Pediatr Hematol Oncol 2006 Jan-Feb;|3
02762|035|R|  23(1):51-7.|3
02763|001|T|MONOGRAPH TITLE:  Eplerenone/Selected Protease Inhibitors (mono deleted|
02763|002|T|12/22/2023)|
02763|003|B||
02763|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02763|005|L|of severe adverse interaction.|
02763|006|B||
02763|007|A|MECHANISM OF ACTION:  Protease inhibitors that are moderate inhibitors of|
02763|008|A|CYP3A4 may inhibit the metabolism of eplerenone.(1)|
02763|009|B||
02763|010|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors that are moderate|
02763|011|E|inhibitors of CYP3A4 may result in a 2-fold increase in eplerenone|
02763|012|E|concentration and toxicity (e.g. hyperkalemia, hypotension).(1)|
02763|013|B||
02763|014|P|PREDISPOSING FACTORS:  Severe renal disease increases the risk for|
02763|015|P|hyperkalemia.|
02763|016|B||
02763|017|M|PATIENT MANAGEMENT:  The US manufacturer of eplerenone recommends that the|
02763|018|M|starting dose of eplerenone for hypertension should be reduced to 25 mg in|
02763|019|M|patients receiving saquinavir or protease inhibitors that are moderate|
02763|020|M|CYP3A4 inhibitors. For inadequate blood pressure response, dosing may be|
02763|021|M|increased to a maximum of 25 mg twice daily. Do not exceed 25 mg once daily|
02763|022|M|in post-MI CHF patients receiving a protease inhibitor with moderate CYP3A4|
02763|023|M|inhibitor activity.(1)|
02763|024|M|   In all patients taking eplerenone who start these agents, check serum|
02763|025|M|potassium and creatinine levels after 3-7 days of concurrent therapy.(1)|
02763|026|M|   HIV guideline recommendations state eplerenone should not be used with|
02763|027|M|selected antivirals including the following protease inhibitors:|
02763|028|M|atazanavir, darunavir, fosamprenavir, lopinavir/ritonavir, saquinavir, and|
02763|029|M|tipranavir/ritonavir.(2)|
02763|030|B||
02763|031|D|DISCUSSION:  Ketoconazole (a strong inhibitor of CYP3A4, 200 mg BID)|
02763|032|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02763|033|D|single dose of eplerenone (100 mg) by 1.7-fold and 5.4-fold,|
02763|034|D|respectively.(1)|
02763|035|D|   The concurrent use of eplerenone with less potent CYP3A4 inhibitors|
02763|036|D|(erythromycin 500 mg BID, fluconazole 200 mg daily, saquinavir 1200 mg TID,|
02763|037|D|and verapamil 240 mg daily) increased the Cmax of eplerenone by 1.4-fold to|
02763|038|D|1.6-fold and the AUC of eplerenone by 2.0-fold and 2.9-fold.(1)|
02763|039|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, atazanavir,|
02763|040|D|darunavir, and fosamprenavir.(3,4)|
02763|041|B||
02763|042|R|REFERENCES:|
02763|043|B||
02763|044|R|1.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
02763|045|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02763|046|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02763|047|R|  HIV. Department of Health and Human Services. Available at|6
02763|048|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
02763|049|R|  new-guidelines June 13, 2021.|6
02763|050|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02763|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02763|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02763|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02763|054|R|  11/14/2017.|1
02763|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
02763|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02764|001|T|MONOGRAPH TITLE:  Saquinavir/Dapsone|
02764|002|B||
02764|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02764|004|L|of severe adverse interaction.|
02764|005|B||
02764|006|A|MECHANISM OF ACTION:  Saquinavir, a strong CYP3A4 inhibitor, may inhibit the|
02764|007|A|metabolism of dapsone at CYP3A4.(1)|
02764|008|B||
02764|009|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
02764|010|E|and adverse effects of dapsone.  Higher dapsone levels may increase risk for|
02764|011|E|agranulocytosis, aplastic anemia, and other blood dyscrasias; dose-related|
02764|012|E|hemolysis; toxic hepatitis and cholestatic jaundice; cutaneous reactions|
02764|013|E|including exfoliative dermatitis; and peripheral neuropathy.(2)|
02764|014|B||
02764|015|P|PREDISPOSING FACTORS:  None determined.|
02764|016|B||
02764|017|M|PATIENT MANAGEMENT:  The manufacturer of saquinavir states concurrent|
02764|018|M|administration of saquinavir/ritonavir with drugs that are CYP3A4 substrates|
02764|019|M|including dapsone is not recommended.(1)|
02764|020|M|   Patient monitoring should include frequent complete blood counts and|
02764|021|M|liver function tests.  Dapsone should be discontinued if a significant|
02764|022|M|reduction in leukocytes, platelets or hemopoiesis occurs.(2)|
02764|023|B||
02764|024|D|DISCUSSION:  In a study of 16 healthy subjects, saquinavir/ritonavir|
02764|025|D|(1000/100 mg BID) increased the area-under-curve (AUC) and maximum|
02764|026|D|concentration (Cmax) of midazolam (7.5 mg single dose) 1144% and 327%,|
02764|027|D|respectively.(1)  Midazolam is a sensitive CYP3A4 substrate.(3)|
02764|028|B||
02764|029|R|REFERENCES:|
02764|030|B||
02764|031|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
02764|032|R|  Laboratories, Inc. March, 2019.|1
02764|033|R|2.Aczone (dapsone) US prescribing information. Alvogen Inc. June, 2015.|1
02764|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
02764|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02765|001|T|MONOGRAPH TITLE:  Oral Rilpivirine/Rifabutin|
02765|002|B||
02765|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02765|004|L|of severe adverse interaction.|
02765|005|B||
02765|006|A|MECHANISM OF ACTION:  Rifabutin may induce the metabolism of rilpivirine by|
02765|007|A|CYP3A4.(1)|
02765|008|B||
02765|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifabutin may result in|
02765|010|E|decreased levels and effectiveness of rilpivirine, as well as the|
02765|011|E|development of resistance.(1)|
02765|012|B||
02765|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02765|014|P|of the inducer for longer than 1-2 weeks.|
02765|015|B||
02765|016|M|PATIENT MANAGEMENT:  The US manufacturer of oral rilpivirine states that|
02765|017|M|concurrent use of CYP3A4 inducers such as rifabutin warrants dose|
02765|018|M|adjustment.  When administering rifabutin with oral rilpivirine, increase|
02765|019|M|the dose of rilpivirine to 50 mg once daily.  When rifabutin|
02765|020|M|co-administration is stopped, the rilpivirine dose should be decreased to 25|
02765|021|M|mg once daily.  It may take several weeks after the discontinuation of an|
02765|022|M|enzyme inducer for enzyme activity to return to normal.(1)|
02765|023|B||
02765|024|D|DISCUSSION:  In a study in 18 subjects, rifabutin (300 mg daily) decreased|
02765|025|D|the maximum concentration (Cmax), area-under-curve (AUC), and minimum|
02765|026|D|concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and|
02765|027|D|48%, respectively.(1)|
02765|028|D|   A study in 18 subjects compared rilpivirine administered alone (25 mg|
02765|029|D|orally daily) to coadministration with rifabutin (300 mg daily) and|
02765|030|D|rilpivirine (50 mg orally daily). A significant difference was not found|
02765|031|D|with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (1)|
02765|032|B||
02765|033|R|REFERENCE:|
02765|034|B||
02765|035|R|1.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
02765|036|R|  March, 2024.|1
02766|001|T|MONOGRAPH TITLE:  Raltegravir/Rifapentine|
02766|002|B||
02766|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02766|004|L|of severe adverse interaction.|
02766|005|B||
02766|006|A|MECHANISM OF ACTION:  Rifapentine  may induce the metabolism of raltegravir|
02766|007|A|by UDP-glucuronosyltransferase 1A1 (UGT1A1).(1)|
02766|008|B||
02766|009|E|CLINICAL EFFECTS:  Concurrent use of once-daily rifapentine may reduce|
02766|010|E|levels and clinical effectiveness of raltegravir.(1)|
02766|011|B||
02766|012|P|PREDISPOSING FACTORS:  None determined.|
02766|013|B||
02766|014|M|PATIENT MANAGEMENT:  The concurrent use of once-daily rifapentine is not|
02766|015|M|recommended.  Once-weekly rifapentine may be used concurrently at standard|
02766|016|M|doses.(2)|
02766|017|B||
02766|018|D|DISCUSSION:  Concurrent use of rifapentine 600 mg once daily decreased|
02766|019|D|raltegravir minimum concentration (Cmin) by 41%.(2)|
02766|020|D|   Concurrent use of rifapentine 900 mg once weekly increased raltegravir|
02766|021|D|area-under-curve (AUC) by 71% and decreased Cmin 12%.(2)|
02766|022|B||
02766|023|R|REFERENCES:|
02766|024|B||
02766|025|R|1.Isentress (raltegravir) US prescribing information. Merck & CO., Inc. May,|1
02766|026|R|  2021.|1
02766|027|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02766|028|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02766|029|R|  HIV. Department of Health and Human Services. Available at|6
02766|030|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
02766|031|R|  new-guidelines June 13, 2021.|6
02767|001|T|MONOGRAPH TITLE:  Oral Contraceptives/Exenatide; Lixisenatide|
02767|002|B||
02767|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02767|004|L|take action as needed.|
02767|005|B||
02767|006|A|MECHANISM OF ACTION:  Exenatide and lixisenatide delay gastric emptying,|
02767|007|A|which may result in decreased oral contraceptive absorption.(1,2)|
02767|008|B||
02767|009|E|CLINICAL EFFECTS:  Exenatide and lixisenatide may result in decreased levels|
02767|010|E|and effectiveness of oral contraceptives.(1,2)|
02767|011|B||
02767|012|P|PREDISPOSING FACTORS:  None determined.|
02767|013|B||
02767|014|M|PATIENT MANAGEMENT:  Oral contraceptives should be taken one hour before|
02767|015|M|administering exenatide non-sustained release.(1)  No recommendations are|
02767|016|M|available for the timing of administration of extended-release exenatide and|
02767|017|M|oral contraceptives.(3)|
02767|018|M|   Oral contraceptives should be taken one hour before or 11 hours after|
02767|019|M|administering lixisenatide.(2)|
02767|020|B||
02767|021|D|DISCUSSION:  In a study in 32 healthy females, administration of an oral|
02767|022|D|contraceptive 30 minutes after exenatide (5 mcg BID) decreased the maximum|
02767|023|D|concentration (Cmax) of ethinyl estradiol and levonorgestrel by 45% and 27%,|
02767|024|D|respectively.  Time to Cmax (Tmax) of ethinyl estradiol and levonorgestrel|
02767|025|D|increased by 3 hours and 3.5 hours, respectively.  Administering the oral|
02767|026|D|contraceptive one hour before exenatide decreased the Cmax of ethinyl|
02767|027|D|estradiol by 15%, but there was no effect on levonorgestrel.  There was no|
02767|028|D|significant effect on bioavailability with either regimen.(1,3,4)|
02767|029|D|   Administration of an oral contraceptive 1 hour before or 11 hours after|
02767|030|D|lixisenatide had no effect on the pharmacokinetics of ethinyl estradiol or|
02767|031|D|levonorgestrel.  Administration of an oral contraceptive 1 hour or 4 hours|
02767|032|D|after lixisenatide did not affect the area-under-curve (AUC) of ethinyl|
02767|033|D|estradiol or levonorgestrel; however, the Cmax of ethinyl estradiol was|
02767|034|D|decreased by 52% and 39%, respectively, and the Cmax of levonorgestrel|
02767|035|D|decreased by 46% and 20%, respectively.  Tmax was delayed by 1-3 hours.(2)|
02767|036|B||
02767|037|R|REFERENCES:|
02767|038|B||
02767|039|R|1.Byetta (exenatide) US prescribing information. AstraZeneca Pharmaceuticals|1
02767|040|R|  LP November, 2021.|1
02767|041|R|2.Adlyxin (lixisenatide) US prescribing information. Sanofi-Aventis U.S. LLC|1
02767|042|R|  July 27, 2016.|1
02767|043|R|3.Bydureon (exenatide) US prescribing information. AstraZeneca|1
02767|044|R|  Pharmaceuticals LP October, 2017.|1
02767|045|R|4.Kothare PA, Seger ME, Northrup J, Mace K, Mitchell MI, Linnebjerg H.|2
02767|046|R|  Effect of exenatide on the pharmacokinetics of a combination oral|2
02767|047|R|  contraceptive in healthy women: an open-label, randomised, crossover|2
02767|048|R|  trial. BMC Clin Pharmacol 2012;12:8.|2
02768|001|T|MONOGRAPH TITLE:  Alprazolam/Fluoxetine|
02768|002|B||
02768|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02768|004|L|take action as needed.|
02768|005|B||
02768|006|A|MECHANISM OF ACTION:  Alprazolam is primarily metabolized by CYP3A4.(1)|
02768|007|A|Fluoxetine and its long-acting active metabolite norfluoxetine are both weak|
02768|008|A|inhibitors and inducers of CYP3A4.(2)  While the onset of enzyme inhibition|
02768|009|A|is an early effect, the onset of induction may take weeks for maximal|
02768|010|A|effect.|
02768|011|B||
02768|012|E|CLINICAL EFFECTS:  Addition of fluoxetine to existing alprazolam therapy may|
02768|013|E|be associated with increased alprazolam concentrations and clinical effects,|
02768|014|E|including profound sedation, respiratory depression, coma, and/or death.|
02768|015|B||
02768|016|P|PREDISPOSING FACTORS:  None determined.|
02768|017|B||
02768|018|M|PATIENT MANAGEMENT:  If fluoxetine is started in a patient already receiving|
02768|019|M|alprazolam, the alprazolam dose may need to be decreased.  With continued|
02768|020|M|(i.e. chronic) fluoxetine therapy the interaction may wane due to the|
02768|021|M|counteracting effect of weak CYP3A4 induction by fluoxetine.   Monitor and|
02768|022|M|adjust the alprazolam dose as needed.|
02768|023|M|   If clinically appropriate, a benzodiazepine which does not undergo|
02768|024|M|extensive Phase I metabolism (lorazepam, oxazepam), or clonazepam(3) may be|
02768|025|M|an alternative to alprazolam in patients receiving fluoxetine.|
02768|026|M|   Counsel patient to report excess drowsiness, confusion, memory problems|
02768|027|M|including sleep-driving behaviors, loss of coordination, slowed or difficult|
02768|028|M|breathing, or unresponsiveness.|
02768|029|B||
02768|030|D|DISCUSSION:  Manufacturer prescribing information describes an interaction|
02768|031|D|study where fluoxetine increased the maximum concentration (Cmax) of|
02768|032|D|alprazolam by 46%, decreased clearance by 21% and increased half-life by 17%|
02768|033|D|leading to decreased measured psychomotor performance.(1) Details regarding|
02768|034|D|the patient population, drug dosage, and duration of therapy were not|
02768|035|D|provided.|
02768|036|D|   The effect of fluoxetine on the pharmacokinetics of a single dose of|
02768|037|D|alprazolam was studied in 11 male volunteers.  Subjects received fluoxetine|
02768|038|D|20 mg every 12 hours for 9 days followed by a single dose of alprazolam 1|
02768|039|D|mg.  The mean elimination half-life of alprazolam increased from 17.4 to|
02768|040|D|20.3 hours, area-under-curve (AUC) increased 26%.  Clinical effects, e.g.|
02768|041|D|impairment of memory or psychomotor performance were not measured.(3)|
02768|042|D|   A study was performed to better understand the interactions of chronic|
02768|043|D|fluoxetine therapy on the activity of CYP2D6, CYP2C19 and CYP3A4 enzymes.|
02768|044|D|In this study chronic fluoxetine therapy did significantly affect the AUC,|
02768|045|D|clearance or half-life of the following CYP3A4 substrates: midazolam,|
02768|046|D|lovastatin, cortisone or 6-beta-hydroxycortisol.  Evaluation of this outcome|
02768|047|D|revealed that fluoxetine (and its active metabolite) both inhibit and induce|
02768|048|D|CYP3A4 to a similar degree.  During chronic fluoxetine therapy, these two|
02768|049|D|opposing activities were balanced, resulting in no clinical effect.|
02768|050|B||
02768|051|R|REFERENCES:|
02768|052|B||
02768|053|R|1.Xanax (alprazolam) US prescribing information. Pharmacia & Upjohn Company|1
02768|054|R|  February, 2021.|1
02768|055|R|2.Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. Fluoxetine-|2
02768|056|R|  and norfluoxetine-mediated complex drug-drug interactions: in vitro to in|2
02768|057|R|  vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol|2
02768|058|R|  Ther 2014 Jun;95(6):653-62.|2
02768|059|R|3.Greenblatt DJ, Preskorn SH, Cotreau MM, Horst WD, Harmatz JS. Fluoxetine|2
02768|060|R|  impairs clearance of alprazolam but not of clonazepam. Clin Pharmacol Ther|2
02768|061|R|  1992 Nov;52(5):479-86.|2
02768|062|R|4.Yuan R, Flockhart DA, Balian JD. Pharmacokinetic and pharmacodynamic|6
02768|063|R|  consequences of metabolism-based drug interactions with alprazolam,|6
02768|064|R|  midazolam, and triazolam. J Clin Pharmacol 1999 Nov;39(11):1109-25.|6
02769|001|T|MONOGRAPH TITLE:  Pravastatin (Greater Than 40|
02769|002|T|mg)/Ombitasvir-Paritaprevir-Ritonavir|
02769|003|B||
02769|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02769|005|L|is contraindicated and generally should not be dispensed or administered to|
02769|006|L|the same patient.|
02769|007|B||
02769|008|A|MECHANISM OF ACTION:  Pravastatin is a substrate for OATP1B1 transport.|
02769|009|A|   Paritaprevir is an inhibitor of OATP1B1 and OATP1B3.(1)|
02769|010|A|   Depending upon the specific transporter and site of activity, transport|
02769|011|A|inhibition may lead to increased systemic absorption, decreased hepatic|
02769|012|A|concentrations, or decreased hepatic elimination.|
02769|013|B||
02769|014|E|CLINICAL EFFECTS:  Transport inhibition may lead to higher systemic|
02769|015|E|concentrations of pravastatin, increasing the risk for statin-induced|
02769|016|E|myopathy or rhabdomyolysis.|
02769|017|B||
02769|018|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02769|019|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02769|020|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02769|021|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02769|022|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02769|023|P|transporter OATP1B1 may have increased statin concentrations and be|
02769|024|P|predisposed to myopathy or rhabdomyolysis.|
02769|025|B||
02769|026|M|PATIENT MANAGEMENT:  The US manufacturer of|
02769|027|M|ombitasvir-paritaprevir-ritonavir-dasabuvir (Viekira) states pravastatin|
02769|028|M|doses should not exceed 40 mg per day in patients receiving concurrent|
02769|029|M|therapy.(1)  The UK manufacturer of ombitasvir-paritaprevir-ritonavir|
02769|030|M|(Viekirax) states that the dose of pravastatin should be reduced by 50 % in|
02769|031|M|patients receiving concurrent therapy.(2)|
02769|032|B||
02769|033|D|DISCUSSION:  In a drug interaction study in 10 subjects,|
02769|034|D|ombitasvir-paritaprevir-ritonavir co-administered with pravastatin 10 mg|
02769|035|D|daily (duration not described) increased the maximum concentration (Cmax)|
02769|036|D|and area-under curve (AUC) of pravastatin by 1.37-fold and 1.82-fold|
02769|037|D|respectively.(1)|
02769|038|B||
02769|039|R|REFERENCES:|
02769|040|B||
02769|041|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02769|042|R|  prescribing information. AbbVie Inc. December, 2019.|1
02769|043|R|2.Viekirax (ombitasvir, paritaprevir, ritonavir) UK summary of product|1
02769|044|R|  characteristics. AbbVie Limited January 16, 2019.|1
02770|001|T|MONOGRAPH TITLE:  Pravastatin (Less Than or Equal To 40|
02770|002|T|mg)/Ombitasvir-Paritaprevir-Ritonavir|
02770|003|B||
02770|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02770|005|L|take action as needed.|
02770|006|B||
02770|007|A|MECHANISM OF ACTION:  Pravastatin is a substrate for OATP1B1 transport.|
02770|008|A|   Paritaprevir is an inhibitor of OATP1B1 and OATP1B3.(1)|
02770|009|A|   Depending upon the specific transporter and site of activity, transport|
02770|010|A|inhibition may lead to increased systemic absorption, decreased hepatic|
02770|011|A|concentrations, or decreased hepatic elimination.|
02770|012|B||
02770|013|E|CLINICAL EFFECTS:  Transport inhibition may lead to higher systemic|
02770|014|E|concentrations of pravastatin, increasing the risk for statin-induced|
02770|015|E|myopathy or rhabdomyolysis.|
02770|016|B||
02770|017|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02770|018|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02770|019|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02770|020|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02770|021|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02770|022|P|transporter OATP1B1 may have increased statin concentrations and be|
02770|023|P|predisposed to myopathy or rhabdomyolysis.|
02770|024|B||
02770|025|M|PATIENT MANAGEMENT:  The US manufacturer of|
02770|026|M|ombitasvir-paritaprevir-ritonavir-dasabuvir (Viekira) states pravastatin|
02770|027|M|doses should not exceed 40 mg per day in patients receiving concurrent|
02770|028|M|therapy.(1)  The UK manufacturer of ombitasvir-paritaprevir-ritonavir|
02770|029|M|(Viekirax) states that the dose of pravastatin should be reduced by 50 % in|
02770|030|M|patients receiving concurrent therapy.(2)|
02770|031|B||
02770|032|D|DISCUSSION:  In a drug interaction study in 10 subjects,|
02770|033|D|ombitasvir-paritaprevir-ritonavir co-administered with pravastatin 10 mg|
02770|034|D|daily (duration not described) increased the maximum concentration (Cmax)|
02770|035|D|and area-under curve (AUC) of pravastatin by 1.37-fold and 1.82-fold|
02770|036|D|respectively.(1)|
02770|037|B||
02770|038|R|REFERENCES:|
02770|039|B||
02770|040|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02770|041|R|  prescribing information. AbbVie Inc. December, 2019.|1
02770|042|R|2.Viekirax (ombitasvir, paritaprevir, ritonavir) UK summary of product|1
02770|043|R|  characteristics. AbbVie Limited January 16, 2019.|1
02771|001|T|MONOGRAPH TITLE:  Lomitapide/Strong or Moderate CYP3A4 Inhibitors|
02771|002|B||
02771|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02771|004|L|is contraindicated and generally should not be dispensed or administered to|
02771|005|L|the same patient.|
02771|006|B||
02771|007|A|MECHANISM OF ACTION:  Lomitapide is primarily metabolized via CYP3A4.(1)|
02771|008|B||
02771|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inhibitor of|
02771|010|E|CYP3A4 may result in high to very high levels of and toxicity from|
02771|011|E|lomitapide.(1)|
02771|012|B||
02771|013|P|PREDISPOSING FACTORS:  The interaction may be more severe in patients with|
02771|014|P|hepatic impairment or with end-stage renal disease.(1)|
02771|015|B||
02771|016|M|PATIENT MANAGEMENT:  Given the magnitude of this interaction and the|
02771|017|M|potential toxicity of lomitapide, moderate and strong CYP3A4 inhibitors are|
02771|018|M|contraindicated.(1) When possible use an alternative to the CYP3A4|
02771|019|M|inhibitor. If a moderate or strong CYP3A4 inhibitor is required, discontinue|
02771|020|M|lomitapide.  Due to its long half-life, it will take 1 to 2 weeks for|
02771|021|M|remaining lomitapide to be eliminated; thus lomitapide adverse effects could|
02771|022|M|occur after discontinuation.|
02771|023|M|   The US manufacturer of itraconazole states that concurrent use with|
02771|024|M|lomitapide is contraindicated during and two weeks after itraconazole|
02771|025|M|treatment.(4)|
02771|026|B||
02771|027|D|DISCUSSION:  Concurrent administration with ketoconazole (a strong inhibitor|
02771|028|D|of CYP3A4) increased lomitapide area-under-curve (AUC) by 27-fold.(1)|
02771|029|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02771|030|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
02771|031|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone,|
02771|032|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
02771|033|D|saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and|
02771|034|D|voriconazole.(1-3,5)|
02771|035|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
02771|036|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
02771|037|D|darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin,|
02771|038|D|fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine,|
02771|039|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir,|
02771|040|D|lefamulin, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib,|
02771|041|D|schisandra, sevabertinib, stiripentol, treosulfan, and verapamil.(1-3)|
02771|042|B||
02771|043|R|REFERENCES:|
02771|044|B||
02771|045|R|1.Juxtapid (lomitapide) US prescribing information. Aegerion|1
02771|046|R|  Pharmaceuticals, Inc. May, 2016.|1
02771|047|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02771|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02771|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02771|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02771|051|R|  11/14/2017.|1
02771|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
02771|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02771|054|R|4.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02771|055|R|  Products, L.P. February, 2024.|1
02771|056|R|5.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02771|057|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02772|001|T|MONOGRAPH TITLE:  Quetiapine/Moderate CYP3A4 Inhibitors|
02772|002|B||
02772|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02772|004|L|take action as needed.|
02772|005|B||
02772|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
02772|007|A|of quetiapine.  Quetiapine is a sensitive substrate for CYP3A4 and so an|
02772|008|A|approximately 2-fold or higher increase in exposure (AUC, area-under-curve)|
02772|009|A|is possible when quetiapine is given with a moderate CYP3A4 inhibitor.(1-4)|
02772|010|B||
02772|011|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate CYP3A4 inhibitor|
02772|012|E|may result in elevated levels of and toxicity from quetiapine, including|
02772|013|E|potentially life-threatening cardiac arrhythmias such as torsades de|
02772|014|E|pointes.(2,3)|
02772|015|B||
02772|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02772|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
02772|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02772|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02772|020|P|female gender, or advanced age.(4)|
02772|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02772|022|P|higher systemic concentrations of either QT prolonging drug are additional|
02772|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02772|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02772|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02772|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02772|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02772|028|B||
02772|029|M|PATIENT MANAGEMENT:  Monitor patients when moderate inhibitors of CYP3A4 are|
02772|030|M|co-prescribed with quetiapine as the magnitude of the interaction is highly|
02772|031|M|variable between patients.(6)  Use of higher doses of either the CYP3A4|
02772|032|M|inhibitor or quetiapine are other factors which may affect the magnitude of|
02772|033|M|this interaction.  Decrease the quetiapine dose if needed.|
02772|034|M|  If concurrent therapy is warranted, consider obtaining serum calcium,|
02772|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02772|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02772|037|M|patients to report any irregular heartbeat, dizziness, fainting, excessive|
02772|038|M|drowsiness, rapid pulse/hypotension, weakness, fatigue, dizziness, or muscle|
02772|039|M|stiffness/tremors (EPS).|
02772|040|B||
02772|041|D|DISCUSSION:  In a study in 19 Chinese patients with schizophrenia, patients|
02772|042|D|received quetiapine (200 mg twice daily) alone and with erythromycin (500 mg|
02772|043|D|3 times daily, a moderate inhibitor of CYP3A4).  Erythromycin increased the|
02772|044|D|quetiapine maximum concentration (Cmax)by 68%(range approximately 20-130%),|
02772|045|D|area-under-curve (AUC) 129% (range approximately 20-300%), and half-life by|
02772|046|D|92% (range approximately 0-250%).  Quetiapine clearance decreased 52% (range|
02772|047|D|approximately -15 to -80%).(6)|
02772|048|D|   Moderate inhibitors of CYP3A4 include:  aprepitant, avacopan,|
02772|049|D|berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fluvoxamine,|
02772|050|D|fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir,|
02772|051|D|netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam,|
02772|052|D|treosulfan, and verapamil.(4)|
02772|053|B||
02772|054|R|REFERENCES:|
02772|055|B||
02772|056|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
02772|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02772|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02772|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02772|060|R|  11/14/2017.|1
02772|061|R|2.Seroquel (quetiapine) US prescribing information. AstraZeneca|1
02772|062|R|  Pharmaceuticals LP September, 2020.|1
02772|063|R|3.Seroquel (quetiapine) Canada prescribing information. AstraZeneca Canada|1
02772|064|R|  Inc. May 15,2013.|1
02772|065|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02772|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02772|067|R|  settings: a scientific statement from the American Heart Association and|6
02772|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02772|069|R|  2;55(9):934-47.|6
02772|070|R|5.This information is based on an extract from the Certara Drug Interaction|6
02772|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02772|072|R|6.Li KY, Li X, Cheng ZN, Zhang BK, Peng WX, Li HD. Effect of erythromycin on|2
02772|073|R|  metabolism of quetiapine in Chinese suffering from schizophrenia. Eur J|2
02772|074|R|  Clin Pharmacol 2005 Jan;60(11):791-5.|2
02773|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 10 mg)/Regorafenib|
02773|002|B||
02773|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02773|004|L|take action as needed.|
02773|005|B||
02773|006|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate for breast cancer|
02773|007|A|resistance protein (BCRP). Regorafenib inhibits intestinal BCRP leading to|
02773|008|A|increased systemic absorption of rosuvastatin.(1,2)|
02773|009|B||
02773|010|E|CLINICAL EFFECTS:  High systemic concentrations of rosuvastatin increase the|
02773|011|E|risk for statin-induced myopathy or rhabdomyolysis.(1)|
02773|012|B||
02773|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02773|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02773|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02773|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02773|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02773|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02773|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02773|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02773|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02773|022|B||
02773|023|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
02773|024|M|dose of rosuvastatin should not exceed 10 mg daily when used concurrently|
02773|025|M|with regorafenib.  Monitor patients closely for signs and symptoms of|
02773|026|M|toxicity from increased rosuvastatin concentrations.(1,2)|
02773|027|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
02773|028|M|of rosuvastatin should not exceed 5 mg daily when used with regorafenib.(3)|
02773|029|B||
02773|030|D|DISCUSSION:  In a study of regorafenib 160 mg daily x 14 days followed by|
02773|031|D|rosuvastatin 5 mg single dose, rosuvastatin area-under-curve (AUC) and|
02773|032|D|maximum concentration (Cmax) increased 3.8-fold and 4.6-fold,|
02773|033|D|respectively.(1,2)|
02773|034|B||
02773|035|R|REFERENCES:|
02773|036|B||
02773|037|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02773|038|R|  Pharmaceuticals LP July, 2024.|1
02773|039|R|2.Stivarga (regorafenib) US prescribing information. Bayer HealthCare|1
02773|040|R|  Pharmaceuticals, Inc. February, 2020.|1
02773|041|R|3.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
02773|042|R|  Australia Pty Ltd July 8, 2024.|1
02774|001|T|MONOGRAPH TITLE:  Dronedarone/Coumarin Anticoagulants|
02774|002|B||
02774|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02774|004|L|take action as needed.|
02774|005|B||
02774|006|A|MECHANISM OF ACTION:  Dronedarone may inhibit the metabolism of warfarin.(1)|
02774|007|B||
02774|008|E|CLINICAL EFFECTS:  The concurrent administration of dronedarone and an|
02774|009|E|anticoagulant may result in an increase in the clinical effects of the|
02774|010|E|anticoagulant and an increased risk of bleeding.  When an interaction|
02774|011|E|occurs, most patients experience increased effects within 1 week of|
02774|012|E|dronedarone initiation.(1)|
02774|013|B||
02774|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02774|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02774|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
02774|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02774|018|P|risk for bleeding (e.g. NSAIDs).|
02774|019|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
02774|020|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
02774|021|P|are expected to be more susceptible to this interaction.|
02774|022|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
02774|023|P|are expected to be less susceptible to effects from this drug combination,|
02774|024|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
02774|025|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
02774|026|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
02774|027|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
02774|028|P|and safe anticoagulation than patients without these CYP2C9 variants.|
02774|029|B||
02774|030|M|PATIENT MANAGEMENT:  In patients already receiving warfarin, the|
02774|031|M|manufacturer of dronedarone recommends monitoring of INR after initiation of|
02774|032|M|dronedarone.  When an interaction occurs, most warfarin patients will|
02774|033|M|experience an increased INR within 1 week of dronedarone initiation.(1)|
02774|034|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02774|035|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02774|036|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02774|037|M|patients with any symptoms.|
02774|038|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02774|039|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02774|040|M|anticoagulation in patients with active pathologic bleeding.|
02774|041|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02774|042|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02774|043|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02774|044|M|and/or swelling.|
02774|045|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02774|046|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02774|047|M|initiating, altering the dose or discontinuing either drug.|
02774|048|B||
02774|049|D|DISCUSSION:  In healthy subjects, dronedarone (600 mg twice daily) increased|
02774|050|D|exposure to S-warfarin by 1.2-fold.  There were no significant changes in|
02774|051|D|exposure to R-warfarin or INR values.  There have been postmarketing reports|
02774|052|D|of increased INR values, with and without bleeding, in patients maintained|
02774|053|D|on warfarin in whom dronedarone was initiated.(1)|
02774|054|B||
02774|055|R|REFERENCE:|
02774|056|B||
02774|057|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
02774|058|R|  November, 2020.|1
02775|001|T|MONOGRAPH TITLE:  Efavirenz/QT Prolonging Agents|
02775|002|B||
02775|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02775|004|L|take action as needed.|
02775|005|B||
02775|006|A|MECHANISM OF ACTION:  Efavirenz has been observed to prolong the QTc|
02775|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
02775|008|A|may result in additive effects on the QTc interval.(1)|
02775|009|B||
02775|010|E|CLINICAL EFFECTS:  The concurrent use of efavirenz with other agents that|
02775|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02775|012|E|arrhythmias, including torsades de pointes.(1)|
02775|013|B||
02775|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02775|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02775|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02775|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02775|018|P|female gender, or advanced age.(2)|
02775|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02775|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02775|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02775|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02775|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02775|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02775|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02775|026|P|   CYP2B6 genotype may also increase the risk of this interaction.  Patients|
02775|027|P|who are most susceptible to this interaction are patients who are CYP2B6|
02775|028|P|poor metabolizers with CYP2B6 *6/*6 allele.(3)|
02775|029|B||
02775|030|M|PATIENT MANAGEMENT:  The US manufacturer of efavirenz states alternatives|
02775|031|M|should be considered when concurrent administration with a drug with a known|
02775|032|M|risk of Torsade de Pointes or when administered to patients at higher risk|
02775|033|M|of Torsade de Pointes.  Limited information is available on the potential|
02775|034|M|pharmacodynamic interaction between efavirenz and drugs that prolong the QT|
02775|035|M|interval; however, QT prolongation has been observed with efavirenz.(1)|
02775|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02775|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02775|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02775|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02775|040|B||
02775|041|D|DISCUSSION:  A thorough QT study was conducted in the general population in|
02775|042|D|120 healthy subjects receiving efavirenz 600 mg daily.  Time-matched|
02775|043|D|differences in QTc with efavirenz compared to placebo was evaluated on day|
02775|044|D|11, at 6 hours post dose.  The mean change in QTc was 5.2 msec and no change|
02775|045|D|in QTc was greater than 10 msec.(4)|
02775|046|D|   In addition to the thorough QT study, the effect of efavirenz on the QTc|
02775|047|D|interval was evaluated in 58 healthy subjects based on CYP2B6 genotype.|
02775|048|D|CYP2B6 polymorphism was evaluated for each patient and results were the|
02775|049|D|following: 65% with *1/*1 or *1/*4 allele (wild-type metabolizers), 26% with|
02775|050|D|*1/*6 allele (intermediate metabolizers) and 9% with *6/*6 allele (slow|
02775|051|D|metabolizers).  Subjects with 2 copies of the CYP2B6*6 allele had|
02775|052|D|significantly higher efavirenz exposure at steady-state (p<0.05).  At|
02775|053|D|steady-state concentrations of efavirenz, patients with CYP2B6 *1/*1 or|
02775|054|D|*1/*6 alleles had no change in the QTc interval (p>0.05).  However, patients|
02775|055|D|with CYP2B6 *6/*6 allele had an increase in QTc mean +/- SD from 406 +/-|
02775|056|D|16.4 to 423 +/- 11.8 msec (p=0.02).(3)|
02775|057|D|   Agents that are linked to this monograph may have varying degrees of|
02775|058|D|potential to prolong the QTc interval but are generally accepted to have a|
02775|059|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02775|060|D|been shown to prolong the QTc interval either through their mechanism of|
02775|061|D|action, through studies on their effects on the QTc interval, or through|
02775|062|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02775|063|D|and/or post-marketing reports.(5)|
02775|064|B||
02775|065|R|REFERENCES:|
02775|066|B||
02775|067|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
02775|068|R|  Company November, 2023.|1
02775|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02775|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02775|071|R|  settings: a scientific statement from the American Heart Association and|6
02775|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02775|073|R|  2;55(9):934-47.|6
02775|074|R|3.Abdelhady AM, Shugg T, Thong N, Lu JB, Kreutz Y, Jaynes HA, Robarge JD,|2
02775|075|R|  Tisdale JE, Desta Z, Overholser BR. Efavirenz Inhibits the Human|2
02775|076|R|  Ether-A-Go-Go Related Current (hERG) and Induces QT  Interval Prolongation|2
02775|077|R|  in CYP2B6*6*6 Allele Carriers. J Cardiovasc Electrophysiol 2016 Jun 23.|2
02775|078|R|4.Tibotec Pharmaceuticals. A Phase I, double-blind, double-dummy,|1
02775|079|R|  randomized, placebo controlled and active controlled trial to evaluate the|1
02775|080|R|  effect of TMC278 25 mg q.d. at steady-state and the effect of efavirenz|1
02775|081|R|  (EFV) 600 mg q.d. at steady-state on the QT/QTc interval. Accessed at:|1
02775|082|R|  https://clinicaltrials.gov/ct2/show/study/NCT00744809 February, 2010.|1
02775|083|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
02775|084|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02775|085|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02775|086|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02776|001|T|MONOGRAPH TITLE:  Orlistat/Selected Antiretrovirals|
02776|002|B||
02776|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02776|004|L|of severe adverse interaction.|
02776|005|B||
02776|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Orlistat may reduce|
02776|007|A|the absorption of lipophilic antiretroviral HIV drugs by retention in the|
02776|008|A|gastrointestinal tract or reduced gastrointestinal tract transit time.|
02776|009|B||
02776|010|E|CLINICAL EFFECTS:  The concurrent administration of orlistat and atazanavir,|
02776|011|E|efavirenz, emtricitabine, maraviroc, ritonavir, or tenofovir may result in a|
02776|012|E|decrease in the levels and clinical effects of the antiretroviral, including|
02776|013|E|loss of virological control.(1)|
02776|014|B||
02776|015|P|PREDISPOSING FACTORS:  None determined.|
02776|016|B||
02776|017|M|PATIENT MANAGEMENT:  HIV RNA levels should be frequently monitored in|
02776|018|M|patients taking orlistat while being treated for HIV infection. If there is|
02776|019|M|a confirmed increase in HIV viral load, orlistat should be discontinued.(1)|
02776|020|B||
02776|021|D|DISCUSSION:  Loss of virological control has been reported in HIV-infected|
02776|022|D|patients taking orlistat concomitantly with lipophilic antiretroviral|
02776|023|D|drugs.(1)|
02776|024|D|   There are three case reports of patients having an increased HIV viral|
02776|025|D|load after taking orlistat concomitantly with their HIV therapy.(2-4)|
02776|026|D|   Antiretrovirals included in this monograph are atazanavir, efavirenz,|
02776|027|D|emtricitabine, maraviroc, ritonavir, and tenofovir.|
02776|028|B||
02776|029|R|REFERENCES:|
02776|030|B||
02776|031|R|1.Xenical (orlistat) US prescribing information. Roche Laboratories, Inc.|1
02776|032|R|  November, 2022.|1
02776|033|R|2.de Truchis P, Mathez D, Abe E, Dinh A, Ledu D, Greder-Belan A, Alvarez JC.|3
02776|034|R|  Cerebrospinal fluid HIV-1 virological escape with lymphocytic meningitis|3
02776|035|R|  under lopinavir/ritonavir monotherapy. AIDS 2010 May 15;24(8):1235-6.|3
02776|036|R|3.Gervasoni C, Cattaneo D, Di Cristo V, Castoldi S, Gervasi E, Clementi E,|3
02776|037|R|  Riva A. Orlistat: weight lost at cost of HIV rebound. J Antimicrob|3
02776|038|R|  Chemother 2016 Jun;71(6):1739-41.|3
02776|039|R|4.Kent SJ. Loss of control of HIV viremia associated with the fat|3
02776|040|R|  malabsorption drug orlistat. AIDS Res Hum Retroviruses 2012 Sep;|3
02776|041|R|  28(9):961-2.|3
02776|042|R|5.Cope RJ, Fischetti BS, Kavanagh RK, Lepa TM, Sorbera MA. Safety and|6
02776|043|R|  Efficacy of Weight-Loss Pharmacotherapy in Persons Living with HIV: A|6
02776|044|R|  Review of the Literature and Potential Drug-Drug Interactions with|6
02776|045|R|  Antiretroviral Therapy. Pharmacotherapy 2019 Dec;39(12):1204-1215.|6
02777|001|T|MONOGRAPH TITLE:  Eculizumab/Meningococcal vaccine (mono deleted 02/28/2019)|
02777|002|B||
02777|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02777|004|L|of severe adverse interaction.|
02777|005|B||
02777|006|A|MECHANISM OF ACTION:  Eculizumab inhibits terminal complement activation|
02777|007|A|therefore increasing the susceptibility to certain infections.(1,2)|
02777|008|B||
02777|009|E|CLINICAL EFFECTS:  The use of eculizumab increases a patient's|
02777|010|E|susceptibility to serious meningococcal infections including septicemia and|
02777|011|E|meningitis.  Life-threatening and fatal meningococcal infections have|
02777|012|E|occurred in patients treated with eculizumab.(1,2)|
02777|013|B||
02777|014|P|PREDISPOSING FACTORS:  None determined.|
02777|015|B||
02777|016|M|PATIENT MANAGEMENT:  The US manufacturer states eculizumab is|
02777|017|M|contraindicated in patients who are not currently vaccinated against|
02777|018|M|Neisseria meningitidis, unless the risks of delaying eculizumab treatment|
02777|019|M|outweigh the risks of developing a meningococcal infection.(1)  Patients|
02777|020|M|should be immunized with meningococcal vaccine at least 2 weeks prior to the|
02777|021|M|first dose of eculizumab, unless the risks of delaying therapy outweigh the|
02777|022|M|risks of developing a meningococcal infection.  If meningococcal vaccine is|
02777|023|M|given less than 2 weeks prior to starting or at the time of eculizumab|
02777|024|M|therapy, prophylactic antibiotics should be considered until 2 weeks after|
02777|025|M|vaccination based on clinical trial data.|
02777|026|M|   Eculizumab is only available through a Risk Evaluation and Mitigation|
02777|027|M|Strategy (REMS) program.  Prescribers are required to counsel patients|
02777|028|M|regarding the risk of meningococcal infection, provide the patient with the|
02777|029|M|REMS educational materials, and ensure patients are vaccinated with a|
02777|030|M|meningococcal vaccine.|
02777|031|M|   Prescribers should follow the most current Advisory Committee on|
02777|032|M|Immunization Practices (ACIP) recommendations for meningococcal vaccination|
02777|033|M|in patients with complement deficiencies.  Revaccinate patients in|
02777|034|M|accordance with ACIP recommendations, considering the duration of eculizumab|
02777|035|M|therapy.|
02777|036|M|   The Canadian manufacturer states all patients should be vaccinated|
02777|037|M|against meningococcal infection prior to, or at the time of, initiating|
02777|038|M|eculizumab.(2,3)  Patients who initiate eculizumab treatment less than 2|
02777|039|M|weeks after meningococcal vaccination must receive treatment with|
02777|040|M|appropriate prophylactic antibiotics until 2 weeks after vaccination.|
02777|041|M|Vaccination is only recommended when the complement disease is clinically|
02777|042|M|controlled with eculizumab and when systemic eculizumab concentrations are|
02777|043|M|relatively high (within one week following eculizumab infusion).|
02777|044|M|   Closely monitor patients for early signs and symptoms of meningococcal|
02777|045|M|infection and evaluate patients immediately if an infection is suspected.|
02777|046|M|Meningococcal infection may become rapidly life-threatening or fatal if not|
02777|047|M|recognized and treated early.  Discontinue eculizumab in patients who are|
02777|048|M|undergoing treatment for serious meningococcal infections.|
02777|049|B||
02777|050|D|DISCUSSION:  In clinical studies, 2 out of 196 paroxysmal nocturnal|
02777|051|D|hemoglobinuria (PNH) patients developed meningococcal sepsis while receiving|
02777|052|D|treatment with eculizumab; both had previously received meningococcal|
02777|053|D|vaccination.  In clinical studies among non-PNH patients, meningococcal|
02777|054|D|meningitis occurred in one unvaccinated patient.  In addition, 3 out of 130|
02777|055|D|previously vaccinated patients with atypical hemolytic uremic syndrome|
02777|056|D|(aHUS) developed meningococcal infections while receiving treatment with|
02777|057|D|eculizumab.(1)|
02777|058|D|   In prospective clinical studies, 75/100 patients with aHUS were treated|
02777|059|D|with eculizumab less than 2 weeks after meningococcal vaccination and 64 of|
02777|060|D|these 75 patients received antibiotics for prophylaxis of meningococcal|
02777|061|D|infection until at least 2 weeks after meningococcal vaccination.  The|
02777|062|D|benefits and risks of antibiotic prophylaxis for prevention of meningococcal|
02777|063|D|infections in patients receiving eculizumab have not been established.(1)|
02777|064|B||
02777|065|R|REFERENCES:|
02777|066|B||
02777|067|R|1.Soliris (eculizumab) US prescribing information. Alexion Pharmaceuticals|1
02777|068|R|  Inc. September 2024.|1
02777|069|R|2.Soliris (eculizumab) Canadian prescribing information. Alexion Pharma GmbH|1
02777|070|R|  September, 2016.|1
02777|071|R|3.Health Canada. Soliris (eculizumab) - Increased risk of hemolysis or low|1
02777|072|R|  hemoglobin with serogroup B meningococcal vaccination. Accessed at:|1
02777|073|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/60752a-e|1
02777|074|R|  ng.php October 25, 2016.|1
02778|001|T|MONOGRAPH TITLE:  Fentanyl/Methylene Blue|
02778|002|B||
02778|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02778|004|L|is contraindicated and generally should not be dispensed or administered to|
02778|005|L|the same patient.|
02778|006|B||
02778|007|A|MECHANISM OF ACTION:  Methylene blue, when administered intravenously, has|
02778|008|A|been shown to reach sufficient concentrations to be a potent inhibitor of|
02778|009|A|MAO-A.(1,2)  Concomitant use of MAOIs with the known serotonin-potentiating|
02778|010|A|effects and relatively weak serotonin reuptake inhibitor, fentanyl, may|
02778|011|A|result in serotonergic toxicity.|
02778|012|B||
02778|013|E|CLINICAL EFFECTS:  The concurrent use of some opioids with MAOIs has|
02778|014|E|resulted in serotonin syndrome.  Symptoms of serotonin syndrome may include|
02778|015|E|tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
02778|016|E|hyperthermia, and muscle rigidity.(3-7)|
02778|017|B||
02778|018|P|PREDISPOSING FACTORS:  Treatment with multiple medications which increase|
02778|019|P|serotonin levels or inhibit the metabolism of serotonin are risk factors for|
02778|020|P|serotonin syndrome.|
02778|021|P|   Higher opioid concentrations, as may occur due to inhibition of opioid|
02778|022|P|clearance, patient specific genomic factors (e.g. poor metabolizer status|
02778|023|P|for a P450 enzyme), or high opioid dosage may increase the risk for an|
02778|024|P|interaction.|
02778|025|B||
02778|026|M|PATIENT MANAGEMENT:  The Australian manufacturers of fentanyl injection(8)|
02778|027|M|and fentanyl lozenges(9) state that concurrent use with or use within 2|
02778|028|M|weeks of discontinuation of an MAOI is contraindicated.|
02778|029|M|   The US manufacturers of fentanyl lozenges(10) and patches(11) state that|
02778|030|M|use in patients who have received an MAOI in the previous 14 days is not|
02778|031|M|recommended.  The US manufacturer of fentanyl injection states that use in|
02778|032|M|patients who have received an MAOI in the previous 14 days should be|
02778|033|M|monitored and vasodilators and beta-blockers should be available for the|
02778|034|M|treatment of hypertension.(12)|
02778|035|B||
02778|036|D|DISCUSSION:  Methylene blue, when administered intravenously, has been shown|
02778|037|D|to reach sufficient concentrations to be a potent inhibitor of MAO-A.(1,2)|
02778|038|D|   The interaction between meperidine and MAOIs has been well|
02778|039|D|documented.(13,14)  There are two reports of potential interactions between|
02778|040|D|MAOIs and dextromethorphan.(3,4)  In another case report, the concurrent use|
02778|041|D|of propoxyphene and phenelzine resulted in sedation and somnolence.  The|
02778|042|D|patient had previously taken both agents alone with no adverse effects.(5)|
02778|043|D|At least one fatality has been reported from the use of fentanyl during|
02778|044|D|surgery in a patient receiving an MAOI.(6)|
02778|045|B||
02778|046|R|REFERENCES:|
02778|047|B||
02778|048|R|1.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
02778|049|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
02778|050|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
02778|051|R|2.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
02778|052|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
02778|053|R|  2000 Jun;56(3):247-50.|2
02778|054|R|3.Rivers N, Horner B. Possible lethal reaction between Nardil and|3
02778|055|R|  dextromethorphan. Can Med Assoc J 1970 Jul;103:85.|3
02778|056|R|4.Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine|3
02778|057|R|  oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988 Dec 22;|3
02778|058|R|  319(25):1671.|3
02778|059|R|5.Garbutt JC. Potentiation of propoxyphene by phenelzine. Am J Psychiatry|3
02778|060|R|  1987 Feb;144(2):251-2.|3
02778|061|R|6.Noble WH, Baker A. MAO inhibitors and coronary artery surgery: a patient|3
02778|062|R|  death. Can J Anaesth 1992 Dec;39(10):1061-6.|3
02778|063|R|7.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02778|064|R|  352(11):1112-20.|6
02778|065|R|8.DBL fentanyl injection Australian prescribing information. FH Faulding &|1
02778|066|R|  Co Limited t/a David Bull Laboratories October 31, 2003.|1
02778|067|R|9.Actiq (fentanyl citrate) Australian prescribing information. Orphan|1
02778|068|R|  Australia Pty Ltd. November 2, 2002.|1
02778|069|R|10.Actiq (fentanyl citrate) US prescribing information. Cephalon, Inc.|1
02778|070|R|   October, 2019.|1
02778|071|R|11.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
02778|072|R|   Inc. October, 2019.|1
02778|073|R|12.Sublimaze (fentanyl citrate) US prescribing information. Akorn, Inc.|1
02778|074|R|   October, 2019.|1
02778|075|R|13.Huang V, Gortney JS. Risk of serotonin syndrome with concomitant|6
02778|076|R|   administration of linezolid and serotonin agonists. Pharmacotherapy 2006|6
02778|077|R|   Dec;26(12):1784-93.|6
02778|078|R|14.Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin|6
02778|079|R|   toxicity. Br J Anaesth 2005 Oct;95(4):434-41.|6
02779|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
02779|002|T|antagonists)/Oxandrolone|
02779|003|B||
02779|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02779|005|L|of severe adverse interaction.|
02779|006|B||
02779|007|A|MECHANISM OF ACTION:  Oxandrolone is a CYP2C9 inhibitor and can inhibit|
02779|008|A|metabolism of warfarin and other anticoagulants by this(1) and perhaps other|
02779|009|A|metabolic pathways.|
02779|010|B||
02779|011|E|CLINICAL EFFECTS:  The concurrent use of an anticoagulant and oxandrolone|
02779|012|E|may increase the risk for bleeding episodes.|
02779|013|B||
02779|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02779|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02779|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
02779|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02779|018|P|risk for bleeding (e.g. NSAIDs).|
02779|019|P|   Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2|
02779|020|P|copies of a reduced function VKORC1 gene are expected to be more susceptible|
02779|021|P|to this interaction.|
02779|022|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
02779|023|P|are expected to be less susceptible to effects from this drug combination,|
02779|024|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
02779|025|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
02779|026|P|warfarin-associated bleeding.  CYP2C9 poor metabolizers generally require|
02779|027|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
02779|028|P|and safe anticoagulation than patients without these CYP2C9 variants.(2)|
02779|029|B||
02779|030|M|PATIENT MANAGEMENT:  Close monitoring and anticoagulant dose adjustment|
02779|031|M|should be performed until patients have been stabilized on the combination.|
02779|032|M|   Patients on a stabile anticoagulant dose when oxandrolone therapy is|
02779|033|M|started are at risk for supratherapeutic anticoagulation and bleeding|
02779|034|M|episodes. In an interaction study, warfarin dose reductions of approximately|
02779|035|M|80% were required to maintain therapeutic INRs.(3)|
02779|036|M|   If warfarin is started in a patient already receiving oxandrolone, start|
02779|037|M|with a low anticoagulant dosage.  In a warfarin-oxandrolone interaction|
02779|038|M|study performed in healthy adults, doses of 0.75 - 1.5 mg daily maintained|
02779|039|M|subjects at targeted INR values of 1.5.(3)|
02779|040|M|   If oxandrolone is subsequently discontinued, additional monitoring is|
02779|041|M|needed to assure adequate anticoagulation.|
02779|042|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02779|043|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02779|044|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02779|045|M|patients with any symptoms.|
02779|046|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02779|047|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02779|048|M|anticoagulation in patients with active pathologic bleeding.|
02779|049|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02779|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02779|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02779|052|M|and/or swelling.|
02779|053|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02779|054|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02779|055|M|initiating, altering the dose or discontinuing either drug.|
02779|056|B||
02779|057|D|DISCUSSION:  In a study in 15 healthy subjects, oxandrolone increased the|
02779|058|D|half-life of S-warfarin from 26 to 48 hours and increased the|
02779|059|D|area-under-curve (AUC) of S-warfarin by 1.7-fold.  Although not metabolized|
02779|060|D|by CYP2C9, similar effects on R-warfarin were noted.  Subjects required an|
02779|061|D|80-85% reduction in warfarin dosage, from a mean dose of 6.13 mg daily to|
02779|062|D|1.13 mg daily, to maintain a target INR of 1.5.  Microscopic hematuria was|
02779|063|D|observed in 9 subjects and gingival bleeding was observed in another.(3)|
02779|064|D|   The time of highest risk for a coumarin-type drug interaction is when the|
02779|065|D|precipitant drug is initiated, altered, or discontinued.|
02779|066|B||
02779|067|R|REFERENCES:|
02779|068|B||
02779|069|R|1.This information is based on an extract from the Certara Drug Interaction|6
02779|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02779|071|R|2.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
02779|072|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
02779|073|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
02779|074|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
02779|075|R|  Oct;90(4):625-9.|6
02779|076|R|3.Oxandrin (oxandrolone) US prescribing information. Savient|1
02779|077|R|  Pharmaceuticals, Inc. May 20, 2005.|1
02780|001|T|MONOGRAPH TITLE:  Saquinavir/Selected QT Prolonging Agents|
02780|002|B||
02780|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02780|004|L|is contraindicated and generally should not be dispensed or administered to|
02780|005|L|the same patient.|
02780|006|B||
02780|007|A|MECHANISM OF ACTION:  QT prolongation has been reported with|
02780|008|A|ritonavir-boosted saquinavir.  Concurrent use with other agents that prolong|
02780|009|A|the QTc interval may result in additive effects on the QTc interval.(1)|
02780|010|B||
02780|011|E|CLINICAL EFFECTS:  The concurrent use of ritonavir-boosted saquinavir with|
02780|012|E|other agents that prolong the QTc interval may result in potentially|
02780|013|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
02780|014|B||
02780|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02780|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02780|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02780|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02780|019|P|gender, or advanced age.(3)|
02780|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02780|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02780|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02780|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02780|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02780|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02780|026|P|dysfunction).(3)|
02780|027|B||
02780|028|M|PATIENT MANAGEMENT:  The US manufacturer of saquinavir states that|
02780|029|M|concurrent use of atazanavir, chlorpromazine, clarithromycin, clozapine,|
02780|030|M|dasatinib, erythromycin, halofantrine, haloperidol, mesoridazine,|
02780|031|M|pentamidine, quinine, rilpivirine, sertindole, sunitinib, tacrolimus,|
02780|032|M|thioridazine, or ziprasidone is contraindicated.(1)|
02780|033|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02780|034|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02780|035|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02780|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02780|037|M|   If concurrent use with dasatinib and saquinavir is warranted, consider|
02780|038|M|decreasing the dose of dasatinib to 20 mg daily in patients taking dasatinib|
02780|039|M|70 mg daily, 20 mg daily in patients taking dasatinib 100 mg daily, and to|
02780|040|M|40 mg daily in patients taking dasatinib 140 mg daily.  If these doses are|
02780|041|M|not tolerated, either saquinavir or dasatinib must be discontinued.  If|
02780|042|M|saquinavir is discontinued, a one-week washout period should be allowed|
02780|043|M|before the dosage of dasatinib is increased.  For patients taking dasatinib|
02780|044|M|60 mg or 40 mg daily, saquinavir should not be used concurrently.|
02780|045|M|   If concurrent therapy with sunitinib is warranted, a dosage reduction of|
02780|046|M|sunitinib to a minimum of 37.5 mg daily in patients with gastrointestinal|
02780|047|M|stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a minimum|
02780|048|M|of 25 mg in patients with pancreatic neuroendocrine tumors (pNET) should be|
02780|049|M|considered.|
02780|050|B||
02780|051|D|DISCUSSION:  Ritonavir-boosted saquinavir increases the QT interval in a|
02780|052|D|dose dependent manner.(1)|
02780|053|D|   In a study in 20 subjects, concurrent atazanavir (300 mg daily) and|
02780|054|D|saquinavir/ritonavir (1600/100 mg daily) increased saquinavir AUC and Cmax|
02780|055|D|by 60% and 42%, respectively. The AUC and Cmax of atazanavir were not|
02780|056|D|reported.(1)|
02780|057|D|   In a study in 12 subjects, concurrent clarithromycin and saquinavir base|
02780|058|D|increased clarithromycin AUC and Cmax by 45% and by 39%, respectively.  The|
02780|059|D|AUC and Cmax of 14-OH-clarithromycin were decreased by 24% and by 34%,|
02780|060|D|respectively.  The AUC and Cmax of saquinavir increased by 177% and by 187%,|
02780|061|D|respectively.(1)|
02780|062|D|   Agents that are linked to this monograph may have varying degrees of|
02780|063|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02780|064|D|been shown to prolong the QTc interval either through their mechanism of|
02780|065|D|action, through studies on their effects on the QTc interval, or through|
02780|066|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02780|067|D|and/or postmarketing reports.(2)|
02780|068|D|   Selected QT prolonging agents linked to this monograph include:|
02780|069|D|atazanavir, chlorpromazine, clarithromycin, clozapine, dasatinib,|
02780|070|D|erythromycin, halofantrine, haloperidol, mesoridazine, pentamidine, quinine,|
02780|071|D|rilpivirine, sertindole, sunitinib, tacrolimus, thioridazine, and|
02780|072|D|ziprasidone.|
02780|073|B||
02780|074|R|REFERENCES:|
02780|075|B||
02780|076|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
02780|077|R|  Laboratories, Inc. March, 2019.|1
02780|078|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
02780|079|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02780|080|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02780|081|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02780|082|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02780|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02780|084|R|  settings: a scientific statement from the American Heart Association and|6
02780|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02780|086|R|  2;55(9):934-47.|6
02781|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants; Temsirolimus/Saquinavir|
02781|002|B||
02781|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02781|004|L|of severe adverse interaction.|
02781|005|B||
02781|006|A|MECHANISM OF ACTION:  Saquinavir may inhibit the metabolism of cyclosporine,|
02781|007|A|sirolimus, and temsirolimus by CYP3A4.(1-2)|
02781|008|B||
02781|009|E|CLINICAL EFFECTS:  Concurrent use of saquinavir may result in increased|
02781|010|E|levels of cyclosporine, sirolimus, or temsirolimus.(1-2)|
02781|011|B||
02781|012|P|PREDISPOSING FACTORS:  None determined.|
02781|013|B||
02781|014|M|PATIENT MANAGEMENT:  For patients concurrently taking cyclosporine,|
02781|015|M|sirolimus, or temsirolimus and saquinavir, therapeutic concentration|
02781|016|M|monitoring of the immunosuppressant is recommended.  Depending upon the|
02781|017|M|agents involved, dose decreases of the immunosuppressant agent may be|
02781|018|M|required.(1-2)|
02781|019|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
02781|020|M|with strong CYP3A4 inhibitors such as saquinavir be avoided. If concurrent|
02781|021|M|use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should|
02781|022|M|be considered.  If saquinavir is discontinued, an elimination period of 1|
02781|023|M|week should be allowed before adjusting the dosage of temsirolimus to|
02781|024|M|previous levels.(2)|
02781|025|M|   The selected immunosuppressants linked to this monograph include:|
02781|026|M|cyclosporine, sirolimus, and temsirolimus.|
02781|027|B||
02781|028|D|DISCUSSION:  Concurrent administration of ketoconazole, another inhibitor of|
02781|029|D|CYP3A4, had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC|
02781|030|D|and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of|
02781|031|D|temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is|
02781|032|D|expected to adjust levels to the range observed without inhibitors; however,|
02781|033|D|there are no data available with this dose adjustment.(2)|
02781|034|D|   In a study in 3 HIV+ transplant patients who were receiving|
02781|035|D|lopinavir/ritonavir, another strong inhibitor of CYP3A4, cyclosporine doses|
02781|036|D|were reduced to 5-20% of standard doses to prevent toxicity.(3)|
02781|037|D|   One case report describes a 52 year-old male with HIV and hepatitis C who|
02781|038|D|experienced severe tacrolimus toxicity after the addition of an HIV regimen|
02781|039|D|including nelfinavir (750 mg three times daily) following his liver|
02781|040|D|transplantation.  The HIV regimen was temporarily stopped until the|
02781|041|D|tacrolimus levels normalized at which time the medications were restarted|
02781|042|D|having replaced nelfinavir with saquinavir (400 mg twice/day) and ritonavir|
02781|043|D|(400 mg twice/day).  The patient again experienced neurological symptoms|
02781|044|D|associated with tacrolimus toxicity and was found to have a tacrolimus level|
02781|045|D|over 120 ng/ml.  The medications were held allowing for a long recovery. The|
02781|046|D|HIV regimen was rechallenged a third time using the original combination|
02781|047|D|which included nelfinavir.  The dose of tacrolimus was dramatically|
02781|048|D|decreased and the schedule changed until the tacrolimus levels finally|
02781|049|D|stabilized.(4)|
02781|050|B||
02781|051|R|REFERENCES:|
02781|052|B||
02781|053|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
02781|054|R|  Laboratories, Inc. March, 2019.|1
02781|055|R|2.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
02781|056|R|  Inc. March, 2018.|1
02781|057|R|3.Vogel M, Voigt E, Michaelis HC, Sudhop T, Wolff M, Turler A, Sauerbruch T,|2
02781|058|R|  Rockstroh JK, Spengler U. Management of drug-to-drug interactions between|2
02781|059|R|  cyclosporine A and the protease-inhibitor lopinavir/ritonavir in|2
02781|060|R|  liver-transplanted HIV-infected patients. Liver Transpl 2004 Jul;|2
02781|061|R|  10(7):939-44.|2
02781|062|R|4.Sheikh AM, Wolf DC, Lebovics E, Goldberg R, Horowitz HW. Concomitant human|3
02781|063|R|  immunodeficiency virus protease inhibitor therapy markedly reduces|3
02781|064|R|  tacrolimus metabolism and increases blood levels. Transplantation 1999 Jul|3
02781|065|R|  27;68(2):307-9.|3
02782|001|T|MONOGRAPH TITLE:  Selected Antiarrhythmics/Indinavir|
02782|002|B||
02782|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02782|004|L|take action as needed.|
02782|005|B||
02782|006|A|MECHANISM OF ACTION:  Indinavir administered with or without ritonavir(1)|
02782|007|A|may inhibit the metabolism of bepridil and quinidine at CYP3A4.|
02782|008|B||
02782|009|E|CLINICAL EFFECTS:  Concurrent use of indinavir (administered with or without|
02782|010|E|ritonavir) and bepridil or quinidine may result in elevated levels of these|
02782|011|E|antiarrhythmics and serious and/or life-threatening arrhythmias, including|
02782|012|E|torsades de pointes.|
02782|013|B||
02782|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02782|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02782|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02782|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02782|018|P|gender, or advanced age.(2)|
02782|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02782|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02782|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02782|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02782|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02782|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02782|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02782|026|B||
02782|027|M|PATIENT MANAGEMENT:  The US manufacturer of indinavir(1) recommends caution|
02782|028|M|with concurrent use of bepridil and quinidine, along with concentration|
02782|029|M|monitoring of these agents.|
02782|030|M|   In addition, consider obtaining serum calcium, magnesium, and potassium|
02782|031|M|levels and monitoring ECG at baseline and at regular intervals.  Correct any|
02782|032|M|electrolyte abnormalities.  Instruct patients to report any irregular|
02782|033|M|heartbeat, dizziness, or fainting.|
02782|034|B||
02782|035|D|DISCUSSION:  Indinavir is a strong inhibitor of CYP3A4.(4)|
02782|036|B||
02782|037|R|REFERENCES:|
02782|038|B||
02782|039|R|1.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
02782|040|R|  September, 2016.|1
02782|041|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02782|042|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02782|043|R|  settings: a scientific statement from the American Heart Association and|6
02782|044|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02782|045|R|  2;55(9):934-47.|6
02782|046|R|3.Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P.|2
02782|047|R|  Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in|2
02782|048|R|  vivo: effects of liver function. Clin Pharmacol Ther 2004 Jan;75(1):80-8.|2
02782|049|R|4.This information is based on an extract from the Certara Drug Interaction|6
02782|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02783|001|T|MONOGRAPH TITLE:  Cyclobenzaprine/Selected Tricyclic Antidepressants|
02783|002|B||
02783|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02783|004|L|take action as needed.|
02783|005|B||
02783|006|A|MECHANISM OF ACTION:  Cyclobenzaprine and selected tricyclic antidepressants|
02783|007|A|(TCAs), including amitriptyline, clomipramine, and imipramine, may act|
02783|008|A|synergistically to increase blood pressure and evoke behavioral|
02783|009|A|excitation.(1)|
02783|010|B||
02783|011|E|CLINICAL EFFECTS:  Concurrent administration of cyclobenzaprine with|
02783|012|E|amitriptyline, clomipramine, or imipramine may result in serotonin syndrome.|
02783|013|E|Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
02783|014|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
02783|015|B||
02783|016|P|PREDISPOSING FACTORS:  Predisposing factors include elderly, hepatic|
02783|017|P|dysfunction and use of multiple agents which increase central serotonin|
02783|018|P|levels.  Chronic use of cyclobenzaprine or high doses of TCAs would also be|
02783|019|P|expected to increase the risk for serotonin toxicity.(1)|
02783|020|B||
02783|021|M|PATIENT MANAGEMENT:  The US manufacturer of cyclobenzaprine recommends|
02783|022|M|limiting use to short term duration, no more than two to three weeks.  Use|
02783|023|M|alternative therapy whenever possible, particularly in patients with hepatic|
02783|024|M|impairment.(1)|
02783|025|M|   Based on serotonin receptor affinity, clomipramine would be expected to|
02783|026|M|have higher risk of serotonin syndrome than imipramine followed by|
02783|027|M|amitriptyline.  Amitriptyline at low doses would be expected to have the|
02783|028|M|lowest risk of serotonin syndrome.  Cyclobenzaprine is structurally similar|
02783|029|M|to tricyclic antidepressants (TCAs) and may affect serotonin receptors|
02783|030|M|synergistically.(2,3)|
02783|031|M|   If concurrent therapy is warranted, patients should be monitored for|
02783|032|M|signs and symptoms of serotonin syndrome, and seizure activity.  Instruct|
02783|033|M|patients to report muscle twitching, tremors, shivering and stiffness,|
02783|034|M|fever, heavy sweating, heart palpitations, restlessness, confusion,|
02783|035|M|agitation, trouble with coordination, or severe diarrhea.|
02783|036|B||
02783|037|D|DISCUSSION:  Case reports documenting serotonin syndrome with|
02783|038|D|cyclobenzaprine and other serotonergic agents are described.  The risk of|
02783|039|D|serotonin syndrome with cyclobenzaprine and TCAs may also occur based on|
02783|040|D|serotonin activity of both agents.(2,3)|
02783|041|D|   A case report of a 70 year old female on phenelzine (non-selective MAOI)|
02783|042|D|15 mg four times daily for several years developed serotonin syndrome after|
02783|043|D|the third dose of cyclobenzaprine 10 mg three times daily.  After|
02783|044|D|discontinuation of both cyclobenzaprine and phenelzine, symptoms resolved|
02783|045|D|within three days.  Within the following month, the patient was restarted on|
02783|046|D|phenelzine without any further sequelae.(4)|
02783|047|D|   A case report of a 53 year old male on duloxetine (SNRI) 60 mg daily|
02783|048|D|developed symptoms of serotonin syndrome shortly after initiation of|
02783|049|D|cyclobenzaprine 10 mg three times daily.  Both cyclobenzaprine and|
02783|050|D|duloxetine were stopped and cyproheptadine was given with resolution of|
02783|051|D|symptoms.(4)|
02783|052|D|   A case report of a 27 year old female on escitalopram (SSRI) 10 mg daily|
02783|053|D|presented with serotonin syndrome after an overdose of 5-6 cyclobenzaprine|
02783|054|D|10 mg tablets.  The patient was treated with symptomatic care and|
02783|055|D|cyproheptadine with resolution of symptoms on day two and discharged with|
02783|056|D|instructions to discontinue cyclobenzaprine use.(5)|
02783|057|B||
02783|058|R|REFERENCES:|
02783|059|B||
02783|060|R|1.Flexeril (cyclobenzaprine) US prescribing information. McNeil Consumer and|1
02783|061|R|  Speciality Pharmaceuticals April, 2013.|1
02783|062|R|2.Goodman-Gilman A. In Gilman AG, Rall TW, Nies AS, Taylor P, editors:|6
02783|063|R|  Goodman and Gilman's The Phamacological Basis of Therapeutics. 8th|6
02783|064|R|  edition. Elmsford, New York: Pergamon Press, Inc. 1990.|6
02783|065|R|3.Mestres J, Seifert SA, Oprea TI. Linking pharmacology to clinical reports:|5
02783|066|R|  cyclobenzaprine and its possible association with serotonin syndrome. Clin|5
02783|067|R|  Pharmacol Ther 2011 Nov;90(5):662-5.|5
02783|068|R|4.Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the|3
02783|069|R|  interaction of cyclobenzaprine with other serotoninergic drugs. Anesth|3
02783|070|R|  Analg 2006 Dec;103(6):1466-8.|3
02783|071|R|5.Day LT, Jeanmonod RK. Serotonin syndrome in a patient taking Lexapro and|3
02783|072|R|  Flexeril: a case report. Am J Emerg Med 2008 Nov;26(9):1069.e1-3.|3
02784|001|T|MONOGRAPH TITLE:  Droxidopa/MAOIs|
02784|002|B||
02784|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02784|004|L|of severe adverse interaction.|
02784|005|B||
02784|006|A|MECHANISM OF ACTION:  MAOIs inhibit the enzyme responsible for degradation|
02784|007|A|of norepinephrine which is formed by droxidopa.|
02784|008|B||
02784|009|E|CLINICAL EFFECTS:  Concurrent use of MAOIs and droxidopa may result in|
02784|010|E|increased effects of droxidopa, including headache, dizziness, nausea, and|
02784|011|E|hypertensive crisis.|
02784|012|B||
02784|013|P|PREDISPOSING FACTORS:  None determined.|
02784|014|B||
02784|015|M|PATIENT MANAGEMENT:  The manufacturer of droxidopa recommends concurrent use|
02784|016|M|with non-selective MAOIs should be avoided.  Selective MAO-B inhibitors,|
02784|017|M|including rasagiline and selegiline, were used concurrently in clinical|
02784|018|M|trials without an increase in risk of hypertensive crisis.|
02784|019|M|   If concurrent therapy is warranted, monitor patient closely for increases|
02784|020|M|in blood pressure.|
02784|021|B||
02784|022|D|DISCUSSION:  Hypertensive reactions are possible as a result of this|
02784|023|D|interaction.  This interaction may be possible for several weeks after the|
02784|024|D|discontinuation of a MAO inhibitor.|
02784|025|D|   Furazolidone and linezolid have been shown to inhibit MAO.|
02784|026|D|   Metaxalone is a weak inhibitor of MAO.|
02784|027|B||
02784|028|R|REFERENCES:|
02784|029|B||
02784|030|R|1.Northera (droxidopa) US prescribing information. Lundbeck NA Ltd. October,|1
02784|031|R|  2016.|1
02784|032|R|2.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
02784|033|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
02784|034|R|  Feb;34(2):346.e5-6.|3
02784|035|R|3.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
02784|036|R|  Pfizer Inc. January, 2024.|1
02785|001|T|MONOGRAPH TITLE:  Selected MAOIs/Selected Antihypertensive Agents|
02785|002|B||
02785|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02785|004|L|take action as needed.|
02785|005|B||
02785|006|A|MECHANISM OF ACTION:  Both MAOIs and antihypertensive agents may increase|
02785|007|A|the risk of postural hypotension.(1,2)|
02785|008|B||
02785|009|E|CLINICAL EFFECTS:  Postural hypotension may occur with concurrent therapy of|
02785|010|E|MAOIs and antihypertensive agents.(1,2)|
02785|011|B||
02785|012|P|PREDISPOSING FACTORS:  None determined.|
02785|013|B||
02785|014|M|PATIENT MANAGEMENT:  The manufacturer of phenelzine states all patients|
02785|015|M|should be followed closely for symptoms of postural hypotension.|
02785|016|M|Hypotensive side effects have occurred in patients who have been|
02785|017|M|hypertensive and normotensive, as well as hypotensive at initiation of|
02785|018|M|phenelzine.(1)|
02785|019|M|   The manufacturer of tranylcypromine states hypotension has been observed|
02785|020|M|most commonly but not exclusively in patients with pre-existing|
02785|021|M|hypertension.  Tranylcypromine doses greater than 30 mg daily have a major|
02785|022|M|side effect of postural hypotension and can lead to syncope.  Gradual dose|
02785|023|M|titration is recommended to decrease risk of postural hypotension.  Combined|
02785|024|M|use with other agents known to cause hypotension have shown to have additive|
02785|025|M|side effects and should be monitored closely.(2)|
02785|026|M|   Monitor the patient for signs and symptoms of postural hypotension|
02785|027|M|including dizziness, lightheadedness, or weakness, especially upon standing.|
02785|028|M|   Monitor blood pressure as well as orthostatic vitals and adjust|
02785|029|M|antihypertensive therapy, including decreasing the dose, dividing doses, or|
02785|030|M|scheduling doses at bedtime, as needed to maintain goal blood pressure.  If|
02785|031|M|blood pressure remains hypotensive, consider decreasing the dose of|
02785|032|M|phenelzine or tranylcypromine.  In some cases, discontinuation of one or|
02785|033|M|both agents may be necessary.(3)|
02785|034|M|   Normotensive patients on stable antihypertensive therapy who are started|
02785|035|M|on either phenelzine or tranylcypromine may be at increased risk for|
02785|036|M|hypotension.  Hypertensive patients on stable phenelzine or tranylcypromine|
02785|037|M|who require antihypertensive therapy would be at decreased risk for|
02785|038|M|hypotension.|
02785|039|B||
02785|040|D|DISCUSSION:  A review article describes the pharmacology of phenelzine and|
02785|041|D|tranylcypromine as non-selective MAOIs which inhibit both type A and type B|
02785|042|D|substrates.  Orthostatic hypotension is described as the most common MAOI|
02785|043|D|side effect and usually occurs between initiation and the first 3-4 weeks of|
02785|044|D|therapy.(3)|
02785|045|D|   In a double-blind study, 71 patients were randomized to receive a 4-week|
02785|046|D|trial of either tranylcypromine, amitriptyline, or the combination.  The|
02785|047|D|number of patients reporting dizziness at 4 weeks was not different between|
02785|048|D|the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%;|
02785|049|D|combination 66.7%).  Blood pressure (BP) assessment noted a significant drop|
02785|050|D|in standing BP in the tranylcypromine group compared to baseline (systolic|
02785|051|D|BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02).|
02785|052|D|Combination therapy also had a significant drop in standing BP compared to|
02785|053|D|baseline (systolic BP change = -9 mmHg; p<0.02).  Patients receiving|
02785|054|D|amitriptyline had no significant change in BP from baseline at 4 weeks.  All|
02785|055|D|three groups had a trend toward increasing orthostatic hypotension in BP|
02785|056|D|changes from lying to standing.  The change in orthostatic hypotension was|
02785|057|D|significant in the amitriptyline group with an average systolic BP|
02785|058|D|orthostatic drop of -9 mmHg (p<0.05).(4)|
02785|059|D|   A randomized, double-blind study of 16 inpatients with major depressive|
02785|060|D|disorder were treated with either phenelzine or tranylcypromine.|
02785|061|D|Cardiovascular assessments were completed at baseline and after 6 weeks of|
02785|062|D|treatment.  After 6 weeks, 5/7 patients (71%) who received phenelzine had a|
02785|063|D|decrease in standing systolic BP greater than 20 mmHg from baseline.|
02785|064|D|Head-up tilt systolic and diastolic BP decreased from baseline in patients|
02785|065|D|on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change|
02785|066|D|p=0.02 and diastolic change p=0.02).  After 6 weeks, 6/9 patients (67%) who|
02785|067|D|received tranylcypromine had a decrease in standing systolic BP greater than|
02785|068|D|20 mmHg from baseline.  Head-up tilt systolic and diastolic BP decreased|
02785|069|D|from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg,|
02785|070|D|respectively; systolic change p=0.09 and diastolic change p=0.07).(5)|
02785|071|D|   Selected MAOIs linked to this monograph include: phenelzine and|
02785|072|D|tranylcypromine.|
02785|073|D|   Selected antihypertensive agents include: ACE inhibitors, alpha blockers,|
02785|074|D|ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine,|
02785|075|D|hydralazine, moxonidine, and sparsentan.|
02785|076|B||
02785|077|R|REFERENCES:|
02785|078|B||
02785|079|R|1.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
02785|080|R|  2007.|1
02785|081|R|2.Parnate (tranylcypromine sulfate) US prescribing information.|1
02785|082|R|  GlaxoSmithKline January 4, 2018.|1
02785|083|R|3.Remick RA, Froese C. Monoamine oxidase inhibitors: clinical review. Can|6
02785|084|R|  Fam Physician 1990 Jun;36:1151-5.|6
02785|085|R|4.Razani J, White KL, White J, Simpson G, Sloane RB, Rebal R, Palmer R. The|2
02785|086|R|  safety and efficacy of combined amitriptyline and tranylcypromine|2
02785|087|R|  antidepressant treatment. A controlled trial. Arch Gen Psychiatry 1983|2
02785|088|R|  Jun;40(6):657-61.|2
02785|089|R|5.Tulen JH, Volkers AC, van den Broek WW, Bruijn JA. Sustained effects of|2
02785|090|R|  phenelzine and tranylcypromine on orthostatic challenge in|2
02785|091|R|  antidepressant-refractory depression. J Clin Psychopharmacol 2006 Oct;|2
02785|092|R|  26(5):542-4.|2
02788|001|T|MONOGRAPH TITLE:  Opioids (Cough and Cold)/Benzodiazepines|
02788|002|B||
02788|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02788|004|L|of severe adverse interaction.|
02788|005|B||
02788|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and benzodiazepines may|
02788|007|A|result in additive CNS depression.(1)|
02788|008|B||
02788|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02788|010|E|as benzodiazepines, may result in profound sedation, respiratory depression,|
02788|011|E|coma, and/or death.(1)|
02788|012|B||
02788|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02788|014|P|may increase the risk of adverse effects.|
02788|015|B||
02788|016|M|PATIENT MANAGEMENT:  Avoid prescribing opioid-including cough medications|
02788|017|M|for patients taking CNS depressants such as benzodiazepines.(1)|
02788|018|M|   Respiratory depression can occur at any time during opioid therapy,|
02788|019|M|especially during therapy initiation and following dosage increases.  The|
02788|020|M|risk of opioid-related overdose or overdose-related death is increased with|
02788|021|M|higher opioid doses, and this risk persists over the course of therapy.|
02788|022|M|Consider these risks when using concurrently with other agents that may|
02788|023|M|cause CNS depression.(2)|
02788|024|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
02788|025|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02788|026|M|unresponsiveness.(1)|
02788|027|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02788|028|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02788|029|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02788|030|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02788|031|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02788|032|M|as those taking CNS depressants) and when a patient has household|
02788|033|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02788|034|M|for obtaining an opioid reversal agent (e.g., prescription,|
02788|035|M|over-the-counter, or as part of a community-based program).(3)|
02788|036|B||
02788|037|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02788|038|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02788|039|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02788|040|D|million to 30 million patients.  During this time, the proportion of|
02788|041|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02788|042|D|million patients.(4)|
02788|043|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02788|044|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02788|045|D|per 100,000 and drug overdose deaths involving both opioids and|
02788|046|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02788|047|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02788|048|D|increased from 18% to 31% during this time.(5)|
02788|049|D|   A prospective observational cohort study in North Carolina found that the|
02788|050|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02788|051|D|benzodiazepines were 10 times higher than patients receiving opioid|
02788|052|D|analgesics alone.(6)|
02788|053|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02788|054|D|death from overdose increased with concomitant opioid analgesics and|
02788|055|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02788|056|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02788|057|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02788|058|D|increased risk of fatal overdose.(7)|
02788|059|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02788|060|D|which benzodiazepines were determined to be a cause of death and that|
02788|061|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02788|062|D|determined to be a cause of death.  This study also found that other CNS|
02788|063|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02788|064|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02788|065|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02788|066|D|where opioid analgesics were also implicated.(8)|
02788|067|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02788|068|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02788|069|D|deaths.(9)|
02788|070|D|   A study of 315,428 privately insured patients who filled at least one|
02788|071|D|prescription for an opioid from 2001 to 2013 were enrolled in a|
02788|072|D|retrospective study.  Concurrent use of a benzodiazepine was recorded as|
02788|073|D|having at least one day of overlap in a given calendar year.  Baseline|
02788|074|D|characteristics among opioid users with concurrent use of a benzodiazepine|
02788|075|D|were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%,|
02788|076|D|p<0.001), and had a higher prevalence rate of every comorbidity examined|
02788|077|D|(p<0.001).  The proportion of opioid users with concurrent benzodiazepine|
02788|078|D|use nearly doubled from 9% in 2001 to 17% in 2013.  The primary outcome was|
02788|079|D|an emergency room visit or inpatient admission for opioid overdose within a|
02788|080|D|calendar year.  Among all opioid users, the annual adjusted incidence for|
02788|081|D|the primary outcome was 1.16% without concurrent benzodiazepine use compared|
02788|082|D|to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24;|
02788|083|D|p<0.001).  Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI|
02788|084|D|1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95%|
02788|085|D|CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the|
02788|086|D|primary outcome with concurrent benzodiazepine use compared to without|
02788|087|D|concurrent benzodiazepine use, respectively.(10)|
02788|088|D|   In a nested case-control study of adults with a new opioid dispensing|
02788|089|D|between 2010-2018, patients with concurrent use of an opioid with a|
02788|090|D|benzodiazepine were significantly more likely to have opioid-related|
02788|091|D|overdose compared to patients receiving opioids, benzodiazepines, or neither|
02788|092|D|(OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90|
02788|093|D|days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of|
02788|094|D|opioid-related overdose (p<0.01). Patients with overlapping prescriptions|
02788|095|D|during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times|
02788|096|D|more likely to experience an overdose (p<0.01).(11)|
02788|097|B||
02788|098|R|REFERENCES:|
02788|099|B||
02788|100|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02788|101|R|  warns about serious risks and death when combining opioid pain or cough|1
02788|102|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02788|103|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02788|104|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02788|105|R|  prescribing information for all opioid pain medicines to provide|1
02788|106|R|  additional guidance for safe use. Available at:|1
02788|107|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02788|108|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02788|109|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02788|110|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02788|111|R|  recommends health care professionals discuss naloxone with all patients|1
02788|112|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02788|113|R|  disorder. Available at:|1
02788|114|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02788|115|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02788|116|R|  d-pain July 23, 2020.|1
02788|117|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02788|118|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02788|119|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02788|120|R|5.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02788|121|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02788|122|R|  49(4):493-501.|2
02788|123|R|6.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02788|124|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02788|125|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02788|126|R|7.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02788|127|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02788|128|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02788|129|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02788|130|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02788|131|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02788|132|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
02788|133|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
02788|134|R|  2014 Oct 10;63(40):881-5.|2
02788|135|R|10.Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association|2
02788|136|R|   between concurrent use of prescription opioids and benzodiazepines and|2
02788|137|R|   overdose: retrospective analysis. BMJ 2017 Mar 14;356:j760.|2
02788|138|R|11.Alobaidi A,  Pickard SA,  Jarrett JB,  Lee TA. Hospitalizations for|2
02788|139|R|   opioid-related overdose and timing of concurrent opioid and|2
02788|140|R|   benzodiazepine use: a nested case-control study. Pharmacotherapy 2021|2
02788|141|R|   June;41:722-732.|2
02789|001|T|MONOGRAPH TITLE:  Opioids (Cough and Cold)/Sleep Drugs|
02789|002|B||
02789|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02789|004|L|of severe adverse interaction.|
02789|005|B||
02789|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and sleep drugs or|
02789|007|A|tranquilizers may result in additive CNS depression and sleep-related|
02789|008|A|disorders.(1)|
02789|009|B||
02789|010|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02789|011|E|as sleep drugs or tranquilizers, may result in profound sedation,|
02789|012|E|respiratory depression, coma, and/or death.(1)|
02789|013|E|   Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may|
02789|014|E|increase the risk of sleep-related disorders including central sleep apnea|
02789|015|E|and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking,|
02789|016|E|sleep driving, and other activities while not fully awake.  Rarely, serious|
02789|017|E|injuries or death have resulted from complex sleep behaviors.(2)|
02789|018|B||
02789|019|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02789|020|P|may increase the risk of adverse effects.|
02789|021|B||
02789|022|M|PATIENT MANAGEMENT:  Avoid prescribing opioid-including cough medications|
02789|023|M|for patients taking CNS depressants such as sleep drugs or tranquilizers.(1)|
02789|024|M|   Respiratory depression can occur at any time during opioid therapy,|
02789|025|M|especially during therapy initiation and following dosage increases.  The|
02789|026|M|risk of opioid-related overdose or overdose-related death is increased with|
02789|027|M|higher opioid doses, and this risk persists over the course of therapy.|
02789|028|M|Consider these risks when using concurrently with other agents that may|
02789|029|M|cause CNS depression.(3)|
02789|030|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
02789|031|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02789|032|M|unresponsiveness.(1)|
02789|033|M|   Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who|
02789|034|M|have had a previous episode of complex sleep behavior.(2)|
02789|035|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02789|036|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02789|037|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02789|038|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02789|039|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02789|040|M|as those taking CNS depressants) and when a patient has household|
02789|041|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02789|042|M|for obtaining an opioid reversal agent (e.g., prescription,|
02789|043|M|over-the-counter, or as part of a community-based program).(4)|
02789|044|B||
02789|045|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02789|046|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02789|047|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02789|048|D|million to 30 million patients.  During this time, the proportion of|
02789|049|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02789|050|D|million patients.(5)|
02789|051|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02789|052|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02789|053|D|per 100,000 and drug overdose deaths involving both opioids and|
02789|054|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02789|055|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02789|056|D|increased from 18% to 31% during this time.(6)|
02789|057|D|   A prospective observational cohort study in North Carolina found that the|
02789|058|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02789|059|D|benzodiazepines were 10 times higher than patients receiving opioid|
02789|060|D|analgesics alone.(7)|
02789|061|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02789|062|D|death from overdose increased with concomitant opioid analgesics and|
02789|063|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02789|064|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02789|065|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02789|066|D|increased risk of fatal overdose.(8)|
02789|067|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02789|068|D|which benzodiazepines were determined to be a cause of death and that|
02789|069|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02789|070|D|determined to be a cause of death.  This study also found that other CNS|
02789|071|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02789|072|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02789|073|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02789|074|D|where opioid analgesics were also implicated.(9)|
02789|075|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02789|076|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02789|077|D|deaths.(10)|
02789|078|D|   As of April 2019, the FDA had identified 66 cases of complex sleep|
02789|079|D|behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases|
02789|080|D|resulted in death and the remainder resulted in serious injuries.  It was|
02789|081|D|not reported how many of the cases involved concomitant use of other CNS|
02789|082|D|depressants.(2)|
02789|083|B||
02789|084|R|REFERENCES:|
02789|085|B||
02789|086|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02789|087|R|  warns about serious risks and death when combining opioid pain or cough|1
02789|088|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02789|089|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02789|090|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA adds|1
02789|091|R|  Boxed Warning for risk of serious injuries caused by sleepwalking with|1
02789|092|R|  certain prescription insomnia medicines. Available at:|1
02789|093|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warn|1
02789|094|R|  ing-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomni|1
02789|095|R|  a April 30, 2019.|1
02789|096|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02789|097|R|  prescribing information for all opioid pain medicines to provide|1
02789|098|R|  additional guidance for safe use. Available at:|1
02789|099|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02789|100|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02789|101|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02789|102|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02789|103|R|  recommends health care professionals discuss naloxone with all patients|1
02789|104|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02789|105|R|  disorder. Available at:|1
02789|106|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02789|107|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02789|108|R|  d-pain July 23, 2020.|1
02789|109|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02789|110|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02789|111|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02789|112|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02789|113|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02789|114|R|  49(4):493-501.|2
02789|115|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02789|116|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02789|117|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02789|118|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02789|119|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02789|120|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02789|121|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02789|122|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02789|123|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02789|124|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02789|125|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02789|126|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02790|001|T|MONOGRAPH TITLE:  Opioids (Cough and Cold)/Muscle Relaxants|
02790|002|B||
02790|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02790|004|L|of severe adverse interaction.|
02790|005|B||
02790|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and muscle relaxants may|
02790|007|A|result in additive CNS depression.(1)|
02790|008|B||
02790|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02790|010|E|as muscle relaxants, may result in profound sedation, respiratory|
02790|011|E|depression, coma, and/or death.(1)|
02790|012|B||
02790|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02790|014|P|may increase the risk of adverse effects.|
02790|015|B||
02790|016|M|PATIENT MANAGEMENT:  Avoid prescribing opioid-including cough medications|
02790|017|M|for patients taking CNS depressants such as muscle relaxants.(1)|
02790|018|M|   Respiratory depression can occur at any time during opioid therapy,|
02790|019|M|especially during therapy initiation and following dosage increases.  The|
02790|020|M|risk of opioid-related overdose or overdose-related death is increased with|
02790|021|M|higher opioid doses, and this risk persists over the course of therapy.|
02790|022|M|Consider these risks when using concurrently with other agents that may|
02790|023|M|cause CNS depression.(2)|
02790|024|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
02790|025|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02790|026|M|unresponsiveness.(1)|
02790|027|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02790|028|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02790|029|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02790|030|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02790|031|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02790|032|M|as those taking CNS depressants) and when a patient has household|
02790|033|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02790|034|M|for obtaining an opioid reversal agent (e.g., prescription,|
02790|035|M|over-the-counter, or as part of a community-based program).(3)|
02790|036|B||
02790|037|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02790|038|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02790|039|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02790|040|D|million to 30 million patients.  During this time, the proportion of|
02790|041|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02790|042|D|million patients.(4)|
02790|043|D|   A retrospective cohort study compared the risk of opioid overdose|
02790|044|D|associated with concomitant use of opioids and skeletal muscle relaxants|
02790|045|D|versus opioid use alone. The study examined two types of opioid users (naive|
02790|046|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
02790|047|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
02790|048|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
02790|049|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
02790|050|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
02790|051|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
02790|052|D|respectively).  Elevated risk was associated with concomitant users with|
02790|053|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
02790|054|D|1.39, respectively).(5)|
02790|055|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02790|056|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02790|057|D|per 100,000 and drug overdose deaths involving both opioids and|
02790|058|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02790|059|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02790|060|D|increased from 18% to 31% during this time.(6)|
02790|061|D|   A prospective observational cohort study in North Carolina found that the|
02790|062|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02790|063|D|benzodiazepines were 10 times higher than patients receiving opioid|
02790|064|D|analgesics alone.(7)|
02790|065|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02790|066|D|death from overdose increased with concomitant opioid analgesics and|
02790|067|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02790|068|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02790|069|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02790|070|D|increased risk of fatal overdose.(8)|
02790|071|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02790|072|D|which benzodiazepines were determined to be a cause of death and that|
02790|073|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02790|074|D|determined to be a cause of death.  This study also found that other CNS|
02790|075|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02790|076|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02790|077|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02790|078|D|where opioid analgesics were also implicated.(9)|
02790|079|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02790|080|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02790|081|D|deaths.(10)|
02790|082|B||
02790|083|R|REFERENCES:|
02790|084|B||
02790|085|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02790|086|R|  warns about serious risks and death when combining opioid pain or cough|1
02790|087|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02790|088|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02790|089|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02790|090|R|  prescribing information for all opioid pain medicines to provide|1
02790|091|R|  additional guidance for safe use. Available at:|1
02790|092|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02790|093|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02790|094|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02790|095|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02790|096|R|  recommends health care professionals discuss naloxone with all patients|1
02790|097|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02790|098|R|  disorder. Available at:|1
02790|099|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02790|100|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02790|101|R|  d-pain July 23, 2020.|1
02790|102|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02790|103|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02790|104|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02790|105|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
02790|106|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
02790|107|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
02790|108|R|  Ther 2020 Jul;108(1):81-88.|2
02790|109|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02790|110|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02790|111|R|  49(4):493-501.|2
02790|112|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02790|113|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02790|114|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02790|115|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02790|116|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02790|117|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02790|118|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02790|119|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02790|120|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02790|121|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02790|122|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02790|123|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02791|001|T|MONOGRAPH TITLE:  Opioids (Cough and Cold)/Antipsychotics; Phenothiazines|
02791|002|B||
02791|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02791|004|L|of severe adverse interaction.|
02791|005|B||
02791|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and antipsychotics,|
02791|007|A|including phenothiazine derivatives, may result in additive CNS|
02791|008|A|depression.(1)|
02791|009|B||
02791|010|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02791|011|E|as antipsychotics, including phenothiazine derivatives, may result in|
02791|012|E|profound sedation, respiratory depression, coma, and/or death.(1)|
02791|013|B||
02791|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02791|015|P|may increase the risk of adverse effects.|
02791|016|B||
02791|017|M|PATIENT MANAGEMENT:  Avoid prescribing opioid-including cough medications|
02791|018|M|for patients taking CNS depressants such as antipsychotics, including|
02791|019|M|phenothiazine derivatives.(1)|
02791|020|M|   Respiratory depression can occur at any time during opioid therapy,|
02791|021|M|especially during therapy initiation and following dosage increases.  The|
02791|022|M|risk of opioid-related overdose or overdose-related death is increased with|
02791|023|M|higher opioid doses, and this risk persists over the course of therapy.|
02791|024|M|Consider these risks when using concurrently with other agents that may|
02791|025|M|cause CNS depression.(2)|
02791|026|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
02791|027|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02791|028|M|unresponsiveness.(1)|
02791|029|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02791|030|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02791|031|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02791|032|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02791|033|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02791|034|M|as those taking CNS depressants) and when a patient has household|
02791|035|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02791|036|M|for obtaining an opioid reversal agent (e.g., prescription,|
02791|037|M|over-the-counter, or as part of a community-based program).(3)|
02791|038|B||
02791|039|D|DISCUSSION:  A nested case-control study looked at the relationship between|
02791|040|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
02791|041|D|antipsychotics was associated with a 2.33-fold increase in risk of|
02791|042|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
02791|043|D|significantly increased in patients with recent use of antipsychotics|
02791|044|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
02791|045|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
02791|046|D|of use.(4)|
02791|047|D|   Between 2002 and 2014, the number of patients receiving an opioid|
02791|048|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
02791|049|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
02791|050|D|to 30 million patients.  During this time, the proportion of patients|
02791|051|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
02791|052|D|patients.(5)|
02791|053|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02791|054|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02791|055|D|per 100,000 and drug overdose deaths involving both opioids and|
02791|056|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02791|057|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02791|058|D|increased from 18% to 31% during this time.(6)|
02791|059|D|   A prospective observational cohort study in North Carolina found that the|
02791|060|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02791|061|D|benzodiazepines were 10 times higher than patients receiving opioid|
02791|062|D|analgesics alone.(7)|
02791|063|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02791|064|D|death from overdose increased with concomitant opioid analgesics and|
02791|065|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02791|066|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02791|067|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02791|068|D|increased risk of fatal overdose.(8)|
02791|069|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02791|070|D|which benzodiazepines were determined to be a cause of death and that|
02791|071|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02791|072|D|determined to be a cause of death.  This study also found that other CNS|
02791|073|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02791|074|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02791|075|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02791|076|D|where opioid analgesics were also implicated.(9)|
02791|077|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02791|078|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02791|079|D|deaths.(10)|
02791|080|B||
02791|081|R|REFERENCES:|
02791|082|B||
02791|083|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02791|084|R|  warns about serious risks and death when combining opioid pain or cough|1
02791|085|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02791|086|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02791|087|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02791|088|R|  prescribing information for all opioid pain medicines to provide|1
02791|089|R|  additional guidance for safe use. Available at:|1
02791|090|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02791|091|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02791|092|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02791|093|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02791|094|R|  recommends health care professionals discuss naloxone with all patients|1
02791|095|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02791|096|R|  disorder. Available at:|1
02791|097|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02791|098|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02791|099|R|  d-pain July 23, 2020.|1
02791|100|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
02791|101|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
02791|102|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
02791|103|R|  Pharmacol 2020 Apr 26.|2
02791|104|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02791|105|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02791|106|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02791|107|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02791|108|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02791|109|R|  49(4):493-501.|2
02791|110|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02791|111|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02791|112|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02791|113|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02791|114|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02791|115|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02791|116|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02791|117|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02791|118|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02791|119|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02791|120|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02791|121|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02792|001|T|MONOGRAPH TITLE:  Opioids (Extended Release)/Benzodiazepines|
02792|002|B||
02792|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02792|004|L|take action as needed.|
02792|005|B||
02792|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and benzodiazepines may|
02792|007|A|result in additive CNS depression.(1)|
02792|008|B||
02792|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02792|010|E|as benzodiazepines, may result in profound sedation, respiratory depression,|
02792|011|E|coma, and/or death.(1)|
02792|012|B||
02792|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02792|014|P|may increase the risk of adverse effects.|
02792|015|B||
02792|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
02792|017|M|depressants such as benzodiazepines to patients for whom alternatives are|
02792|018|M|ineffective, not tolerated, or otherwise inadequate to provide sufficient|
02792|019|M|management of pain.(1)|
02792|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
02792|021|M|drug to the minimum possible while achieving the desired clinical effect.|
02792|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
02792|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
02792|024|M|indicated in the absence of an opioid and titrate based upon clinical|
02792|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
02792|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
02792|027|M|clinical response.(1)|
02792|028|M|   Respiratory depression can occur at any time during opioid therapy,|
02792|029|M|especially during therapy initiation and following dosage increases.  The|
02792|030|M|risk of opioid-related overdose or overdose-related death is increased with|
02792|031|M|higher opioid doses, and this risk persists over the course of therapy.|
02792|032|M|Consider these risks when using concurrently with other agents that may|
02792|033|M|cause CNS depression.(2)|
02792|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02792|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02792|036|M|unresponsiveness.(1)|
02792|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02792|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02792|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02792|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02792|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02792|042|M|as those taking CNS depressants) and when a patient has household|
02792|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02792|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
02792|045|M|over-the-counter, or as part of a community-based program).(3)|
02792|046|B||
02792|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02792|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02792|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02792|050|D|million to 30 million patients.  During this time, the proportion of|
02792|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02792|052|D|million patients.(4)|
02792|053|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02792|054|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02792|055|D|per 100,000 and drug overdose deaths involving both opioids and|
02792|056|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02792|057|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02792|058|D|increased from 18% to 31% during this time.(5)|
02792|059|D|   A prospective observational cohort study in North Carolina found that the|
02792|060|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02792|061|D|benzodiazepines were 10 times higher than patients receiving opioid|
02792|062|D|analgesics alone.(6)|
02792|063|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02792|064|D|death from overdose increased with concomitant opioid analgesics and|
02792|065|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02792|066|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02792|067|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02792|068|D|increased risk of fatal overdose.(7)|
02792|069|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02792|070|D|which benzodiazepines were determined to be a cause of death and that|
02792|071|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02792|072|D|determined to be a cause of death.  This study also found that other CNS|
02792|073|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02792|074|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02792|075|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02792|076|D|where opioid analgesics were also implicated.(8)|
02792|077|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02792|078|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02792|079|D|deaths.(9)|
02792|080|D|   A study of 315,428 privately insured patients who filled at least one|
02792|081|D|prescription for an opioid from 2001 to 2013 were enrolled in a|
02792|082|D|retrospective study.  Concurrent use of a benzodiazepine was recorded as|
02792|083|D|having at least one day of overlap in a given calendar year.  Baseline|
02792|084|D|characteristics among opioid users with concurrent use of a benzodiazepine|
02792|085|D|were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%,|
02792|086|D|p<0.001), and had a higher prevalence rate of every comorbidity examined|
02792|087|D|(p<0.001).  The proportion of opioid users with concurrent benzodiazepine|
02792|088|D|use nearly doubled from 9% in 2001 to 17% in 2013.  The primary outcome was|
02792|089|D|an emergency room visit or inpatient admission for opioid overdose within a|
02792|090|D|calendar year.  Among all opioid users, the annual adjusted incidence for|
02792|091|D|the primary outcome was 1.16% without concurrent benzodiazepine use compared|
02792|092|D|to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24;|
02792|093|D|p<0.001).  Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI|
02792|094|D|1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95%|
02792|095|D|CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the|
02792|096|D|primary outcome with concurrent benzodiazepine use compared to without|
02792|097|D|concurrent benzodiazepine use, respectively.(10)|
02792|098|D|   In a nested case-control study of adults with a new opioid dispensing|
02792|099|D|between 2010-2018, patients with concurrent use of an opioid with a|
02792|100|D|benzodiazepine were significantly more likely to have opioid-related|
02792|101|D|overdose compared to patients receiving opioids, benzodiazepines, or neither|
02792|102|D|(OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90|
02792|103|D|days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of|
02792|104|D|opioid-related overdose (p<0.01). Patients with overlapping prescriptions|
02792|105|D|during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times|
02792|106|D|more likely to experience an overdose (p<0.01).(11)|
02792|107|B||
02792|108|R|REFERENCES:|
02792|109|B||
02792|110|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02792|111|R|  warns about serious risks and death when combining opioid pain or cough|1
02792|112|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02792|113|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02792|114|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02792|115|R|  prescribing information for all opioid pain medicines to provide|1
02792|116|R|  additional guidance for safe use. Available at:|1
02792|117|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02792|118|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02792|119|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02792|120|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02792|121|R|  recommends health care professionals discuss naloxone with all patients|1
02792|122|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02792|123|R|  disorder. Available at:|1
02792|124|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02792|125|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02792|126|R|  d-pain July 23, 2020.|1
02792|127|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02792|128|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02792|129|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02792|130|R|5.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02792|131|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02792|132|R|  49(4):493-501.|2
02792|133|R|6.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02792|134|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02792|135|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02792|136|R|7.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02792|137|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02792|138|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02792|139|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02792|140|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02792|141|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02792|142|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
02792|143|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
02792|144|R|  2014 Oct 10;63(40):881-5.|2
02792|145|R|10.Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association|2
02792|146|R|   between concurrent use of prescription opioids and benzodiazepines and|2
02792|147|R|   overdose: retrospective analysis. BMJ 2017 Mar 14;356:j760.|2
02792|148|R|11.Alobaidi A,  Pickard SA,  Jarrett JB,  Lee TA. Hospitalizations for|2
02792|149|R|   opioid-related overdose and timing of concurrent opioid and|2
02792|150|R|   benzodiazepine use: a nested case-control study. Pharmacotherapy 2021|2
02792|151|R|   June;41:722-732.|2
02793|001|T|MONOGRAPH TITLE:  Opioids (Immediate Release)/Benzodiazepines|
02793|002|B||
02793|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02793|004|L|take action as needed.|
02793|005|B||
02793|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and benzodiazepines may|
02793|007|A|result in additive CNS depression.(1)|
02793|008|B||
02793|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02793|010|E|as benzodiazepines, may result in profound sedation, respiratory depression,|
02793|011|E|coma, and/or death.(1)|
02793|012|B||
02793|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02793|014|P|may increase the risk of adverse effects.|
02793|015|B||
02793|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
02793|017|M|depressants such as benzodiazepines to patients for whom alternatives are|
02793|018|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
02793|019|M|sufficient management of pain.(1)|
02793|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
02793|021|M|drug to the minimum possible while achieving the desired clinical effect.|
02793|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
02793|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
02793|024|M|indicated in the absence of an opioid and titrate based upon clinical|
02793|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
02793|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
02793|027|M|clinical response.(1)|
02793|028|M|   Respiratory depression can occur at any time during opioid therapy,|
02793|029|M|especially during therapy initiation and following dosage increases.  The|
02793|030|M|risk of opioid-related overdose or overdose-related death is increased with|
02793|031|M|higher opioid doses, and this risk persists over the course of therapy.|
02793|032|M|Consider these risks when using concurrently with other agents that may|
02793|033|M|cause CNS depression.(2)|
02793|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02793|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02793|036|M|unresponsiveness.(1)|
02793|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02793|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02793|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02793|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02793|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02793|042|M|as those taking CNS depressants) and when a patient has household|
02793|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02793|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
02793|045|M|over-the-counter, or as part of a community-based program).(3)|
02793|046|B||
02793|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02793|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02793|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02793|050|D|million to 30 million patients.  During this time, the proportion of|
02793|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02793|052|D|million patients.(4)|
02793|053|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02793|054|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02793|055|D|per 100,000 and drug overdose deaths involving both opioids and|
02793|056|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02793|057|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02793|058|D|increased from 18% to 31% during this time.(5)|
02793|059|D|   A prospective observational cohort study in North Carolina found that the|
02793|060|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02793|061|D|benzodiazepines were 10 times higher than patients receiving opioid|
02793|062|D|analgesics alone.(6)|
02793|063|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02793|064|D|death from overdose increased with concomitant opioid analgesics and|
02793|065|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02793|066|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02793|067|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02793|068|D|increased risk of fatal overdose.(7)|
02793|069|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02793|070|D|which benzodiazepines were determined to be a cause of death and that|
02793|071|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02793|072|D|determined to be a cause of death.  This study also found that other CNS|
02793|073|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02793|074|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02793|075|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02793|076|D|where opioid analgesics were also implicated.(8)|
02793|077|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02793|078|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02793|079|D|deaths.(9)|
02793|080|D|   A study of 315,428 privately insured patients who filled at least one|
02793|081|D|prescription for an opioid from 2001 to 2013 were enrolled in a|
02793|082|D|retrospective study.  Concurrent use of a benzodiazepine was recorded as|
02793|083|D|having at least one day of overlap in a given calendar year.  Baseline|
02793|084|D|characteristics among opioid users with concurrent use of a benzodiazepine|
02793|085|D|were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%,|
02793|086|D|p<0.001), and had a higher prevalence rate of every comorbidity examined|
02793|087|D|(p<0.001).  The proportion of opioid users with concurrent benzodiazepine|
02793|088|D|use nearly doubled from 9% in 2001 to 17% in 2013.  The primary outcome was|
02793|089|D|an emergency room visit or inpatient admission for opioid overdose within a|
02793|090|D|calendar year.  Among all opioid users, the annual adjusted incidence for|
02793|091|D|the primary outcome was 1.16% without concurrent benzodiazepine use compared|
02793|092|D|to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24;|
02793|093|D|p<0.001).  Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI|
02793|094|D|1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95%|
02793|095|D|CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the|
02793|096|D|primary outcome with concurrent benzodiazepine use compared to without|
02793|097|D|concurrent benzodiazepine use, respectively.(10)|
02793|098|D|   In a nested case-control study of adults with a new opioid dispensing|
02793|099|D|between 2010-2018, patients with concurrent use of an opioid with a|
02793|100|D|benzodiazepine were significantly more likely to have opioid-related|
02793|101|D|overdose compared to patients receiving opioids, benzodiazepines, or neither|
02793|102|D|(OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90|
02793|103|D|days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of|
02793|104|D|opioid-related overdose (p<0.01). Patients with overlapping prescriptions|
02793|105|D|during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times|
02793|106|D|more likely to experience an overdose (p<0.01).(11)|
02793|107|B||
02793|108|R|REFERENCES:|
02793|109|B||
02793|110|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02793|111|R|  warns about serious risks and death when combining opioid pain or cough|1
02793|112|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02793|113|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02793|114|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02793|115|R|  prescribing information for all opioid pain medicines to provide|1
02793|116|R|  additional guidance for safe use. Available at:|1
02793|117|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02793|118|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02793|119|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02793|120|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02793|121|R|  recommends health care professionals discuss naloxone with all patients|1
02793|122|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02793|123|R|  disorder. Available at:|1
02793|124|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02793|125|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02793|126|R|  d-pain July 23, 2020.|1
02793|127|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02793|128|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02793|129|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02793|130|R|5.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02793|131|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02793|132|R|  49(4):493-501.|2
02793|133|R|6.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02793|134|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02793|135|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02793|136|R|7.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02793|137|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02793|138|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02793|139|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02793|140|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02793|141|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02793|142|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
02793|143|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
02793|144|R|  2014 Oct 10;63(40):881-5.|2
02793|145|R|10.Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association|2
02793|146|R|   between concurrent use of prescription opioids and benzodiazepines and|2
02793|147|R|   overdose: retrospective analysis. BMJ 2017 Mar 14;356:j760.|2
02793|148|R|11.Alobaidi A,  Pickard SA,  Jarrett JB,  Lee TA. Hospitalizations for|2
02793|149|R|   opioid-related overdose and timing of concurrent opioid and|2
02793|150|R|   benzodiazepine use: a nested case-control study. Pharmacotherapy 2021|2
02793|151|R|   June;41:722-732.|2
02794|001|T|MONOGRAPH TITLE:  Opioids (Extended Release)/Sleep Drugs|
02794|002|B||
02794|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02794|004|L|take action as needed.|
02794|005|B||
02794|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and sleep drugs may result|
02794|007|A|in additive CNS depression and sleep-related disorders.(1)|
02794|008|B||
02794|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02794|010|E|as sleep drugs, may result in profound sedation, respiratory depression,|
02794|011|E|coma, and/or death.(1)|
02794|012|E|   Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may|
02794|013|E|increase the risk of sleep-related disorders including central sleep apnea|
02794|014|E|and sleep-related hypoxemia and complex sleep behaviors like sleepwalking,|
02794|015|E|sleep driving, and other activities while not fully awake.  Rarely, serious|
02794|016|E|injuries or death have resulted from complex sleep behaviors.(2)|
02794|017|B||
02794|018|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02794|019|P|may increase the risk of adverse effects.|
02794|020|B||
02794|021|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
02794|022|M|depressants such as sleep drugs to patients for whom alternatives are|
02794|023|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
02794|024|M|sufficient management of pain.(1)|
02794|025|M|   If concurrent use is necessary, limit the dosages and duration of each|
02794|026|M|drug to the minimum possible while achieving the desired clinical effect.|
02794|027|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
02794|028|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
02794|029|M|indicated in the absence of an opioid and titrate based upon clinical|
02794|030|M|response.  If an opioid analgesic is indicated in a patient already taking a|
02794|031|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
02794|032|M|clinical response.(1)|
02794|033|M|   Respiratory depression can occur at any time during opioid therapy,|
02794|034|M|especially during therapy initiation and following dosage increases.  The|
02794|035|M|risk of opioid-related overdose or overdose-related death is increased with|
02794|036|M|higher opioid doses, and this risk persists over the course of therapy.|
02794|037|M|Consider these risks when using concurrently with other agents that may|
02794|038|M|cause CNS depression.(3)|
02794|039|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02794|040|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02794|041|M|unresponsiveness.(1)|
02794|042|M|   Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who|
02794|043|M|have had a previous episode of complex sleep behavior.(2)|
02794|044|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02794|045|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02794|046|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02794|047|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02794|048|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02794|049|M|as those taking CNS depressants) and when a patient has household|
02794|050|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02794|051|M|for obtaining an opioid reversal agent (e.g., prescription,|
02794|052|M|over-the-counter, or as part of a community-based program).(4)|
02794|053|B||
02794|054|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02794|055|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02794|056|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02794|057|D|million to 30 million patients.  During this time, the proportion of|
02794|058|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02794|059|D|million patients.(5)|
02794|060|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02794|061|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02794|062|D|per 100,000 and drug overdose deaths involving both opioids and|
02794|063|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02794|064|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02794|065|D|increased from 18% to 31% during this time.(6)|
02794|066|D|   A prospective observational cohort study in North Carolina found that the|
02794|067|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02794|068|D|benzodiazepines were 10 times higher than patients receiving opioid|
02794|069|D|analgesics alone.(7)|
02794|070|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02794|071|D|death from overdose increased with concomitant opioid analgesics and|
02794|072|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02794|073|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02794|074|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02794|075|D|increased risk of fatal overdose.(8)|
02794|076|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02794|077|D|which benzodiazepines were determined to be a cause of death and that|
02794|078|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02794|079|D|determined to be a cause of death.  This study also found that other CNS|
02794|080|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02794|081|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02794|082|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02794|083|D|where opioid analgesics were also implicated.(9)|
02794|084|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02794|085|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02794|086|D|deaths.(10)|
02794|087|D|   As of April 2019, the FDA had identified 66 cases of complex sleep|
02794|088|D|behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases|
02794|089|D|resulted in death and the remainder resulted in serious injuries.  It was|
02794|090|D|not reported how many of the cases involved concomitant use of other CNS|
02794|091|D|depressants.(2)|
02794|092|B||
02794|093|R|REFERENCES:|
02794|094|B||
02794|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02794|096|R|  warns about serious risks and death when combining opioid pain or cough|1
02794|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02794|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02794|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA adds|1
02794|100|R|  Boxed Warning for risk of serious injuries caused by sleepwalking with|1
02794|101|R|  certain prescription insomnia medicines. Available at:|1
02794|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warn|1
02794|103|R|  ing-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomni|1
02794|104|R|  a April 30, 2019.|1
02794|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02794|106|R|  prescribing information for all opioid pain medicines to provide|1
02794|107|R|  additional guidance for safe use. Available at:|1
02794|108|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02794|109|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02794|110|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02794|111|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02794|112|R|  recommends health care professionals discuss naloxone with all patients|1
02794|113|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02794|114|R|  disorder. Available at:|1
02794|115|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02794|116|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02794|117|R|  d-pain July 23, 2020.|1
02794|118|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02794|119|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02794|120|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02794|121|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02794|122|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02794|123|R|  49(4):493-501.|2
02794|124|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02794|125|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02794|126|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02794|127|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02794|128|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02794|129|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02794|130|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02794|131|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02794|132|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02794|133|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02794|134|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02794|135|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02795|001|T|MONOGRAPH TITLE:  Opioids (Immediate Release)/Sleep Drugs|
02795|002|B||
02795|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02795|004|L|take action as needed.|
02795|005|B||
02795|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and sleep drugs may result|
02795|007|A|in additive CNS depression and sleep-related disorders.(1)|
02795|008|B||
02795|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02795|010|E|as sleep drugs, may result in profound sedation, respiratory depression,|
02795|011|E|coma, and/or death.(1)|
02795|012|E|   Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may|
02795|013|E|increase the risk of sleep-related disorders including central sleep apnea|
02795|014|E|and sleep-related hypoxemia and complex sleep behaviors like sleepwalking,|
02795|015|E|sleep driving, and other activities while not fully awake.  Rarely, serious|
02795|016|E|injuries or death have resulted from complex sleep behaviors.(2)|
02795|017|B||
02795|018|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02795|019|P|may increase the risk of adverse effects.|
02795|020|B||
02795|021|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
02795|022|M|depressants such as sleep drugs to patients for whom alternatives are|
02795|023|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
02795|024|M|sufficient management of pain.(1)|
02795|025|M|   If concurrent use is necessary, limit the dosages and duration of each|
02795|026|M|drug to the minimum possible while achieving the desired clinical effect.|
02795|027|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
02795|028|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
02795|029|M|indicated in the absence of an opioid and titrate based upon clinical|
02795|030|M|response.  If an opioid analgesic is indicated in a patient already taking a|
02795|031|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
02795|032|M|clinical response.(1)|
02795|033|M|   Respiratory depression can occur at any time during opioid therapy,|
02795|034|M|especially during therapy initiation and following dosage increases.  The|
02795|035|M|risk of opioid-related overdose or overdose-related death is increased with|
02795|036|M|higher opioid doses, and this risk persists over the course of therapy.|
02795|037|M|Consider these risks when using concurrently with other agents that may|
02795|038|M|cause CNS depression.(3)|
02795|039|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02795|040|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02795|041|M|unresponsiveness.(1)|
02795|042|M|   Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who|
02795|043|M|have had a previous episode of complex sleep behavior.(2)|
02795|044|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02795|045|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02795|046|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02795|047|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02795|048|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02795|049|M|as those taking CNS depressants) and when a patient has household|
02795|050|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02795|051|M|for obtaining an opioid reversal agent (e.g., prescription,|
02795|052|M|over-the-counter, or as part of a community-based program).(4)|
02795|053|B||
02795|054|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02795|055|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02795|056|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02795|057|D|million to 30 million patients.  During this time, the proportion of|
02795|058|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02795|059|D|million patients.(5)|
02795|060|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02795|061|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02795|062|D|per 100,000 and drug overdose deaths involving both opioids and|
02795|063|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02795|064|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02795|065|D|increased from 18% to 31% during this time.(6)|
02795|066|D|   A prospective observational cohort study in North Carolina found that the|
02795|067|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02795|068|D|benzodiazepines were 10 times higher than patients receiving opioid|
02795|069|D|analgesics alone.(7)|
02795|070|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02795|071|D|death from overdose increased with concomitant opioid analgesics and|
02795|072|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02795|073|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02795|074|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02795|075|D|increased risk of fatal overdose.(8)|
02795|076|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02795|077|D|which benzodiazepines were determined to be a cause of death and that|
02795|078|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02795|079|D|determined to be a cause of death.  This study also found that other CNS|
02795|080|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02795|081|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02795|082|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02795|083|D|where opioid analgesics were also implicated.(9)|
02795|084|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02795|085|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02795|086|D|deaths.(10)|
02795|087|D|   As of April 2019, the FDA had identified 66 cases of complex sleep|
02795|088|D|behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases|
02795|089|D|resulted in death and the remainder resulted in serious injuries.  It was|
02795|090|D|not reported how many of the cases involved concomitant use of other CNS|
02795|091|D|depressants.(2)|
02795|092|B||
02795|093|R|REFERENCES:|
02795|094|B||
02795|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02795|096|R|  warns about serious risks and death when combining opioid pain or cough|1
02795|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02795|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02795|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA adds|1
02795|100|R|  Boxed Warning for risk of serious injuries caused by sleepwalking with|1
02795|101|R|  certain prescription insomnia medicines. Available at:|1
02795|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warn|1
02795|103|R|  ing-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomni|1
02795|104|R|  a April 30, 2019.|1
02795|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02795|106|R|  prescribing information for all opioid pain medicines to provide|1
02795|107|R|  additional guidance for safe use. Available at:|1
02795|108|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02795|109|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02795|110|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02795|111|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02795|112|R|  recommends health care professionals discuss naloxone with all patients|1
02795|113|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02795|114|R|  disorder. Available at:|1
02795|115|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02795|116|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02795|117|R|  d-pain July 23, 2020.|1
02795|118|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02795|119|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02795|120|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02795|121|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02795|122|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02795|123|R|  49(4):493-501.|2
02795|124|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02795|125|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02795|126|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02795|127|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02795|128|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02795|129|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02795|130|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02795|131|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02795|132|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02795|133|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02795|134|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02795|135|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02796|001|T|MONOGRAPH TITLE:  Opioids (Extended Release)/Muscle Relaxants|
02796|002|B||
02796|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02796|004|L|take action as needed.|
02796|005|B||
02796|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and muscle relaxants may|
02796|007|A|result in additive CNS depression.(1)|
02796|008|B||
02796|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02796|010|E|as muscle relaxants, may result in profound sedation, respiratory|
02796|011|E|depression, coma, and/or death.(1)|
02796|012|B||
02796|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02796|014|P|may increase the risk of adverse effects.|
02796|015|B||
02796|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
02796|017|M|depressants such as muscle relaxants to patients for whom alternatives are|
02796|018|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
02796|019|M|sufficient management of pain.(1)|
02796|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
02796|021|M|drug to the minimum possible while achieving the desired clinical effect.|
02796|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
02796|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
02796|024|M|indicated in the absence of an opioid and titrate based upon clinical|
02796|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
02796|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
02796|027|M|clinical response.(1)|
02796|028|M|   Respiratory depression can occur at any time during opioid therapy,|
02796|029|M|especially during therapy initiation and following dosage increases.  The|
02796|030|M|risk of opioid-related overdose or overdose-related death is increased with|
02796|031|M|higher opioid doses, and this risk persists over the course of therapy.|
02796|032|M|Consider these risks when using concurrently with other agents that may|
02796|033|M|cause CNS depression.(2)|
02796|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02796|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02796|036|M|unresponsiveness.(1)|
02796|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02796|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02796|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02796|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02796|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02796|042|M|as those taking CNS depressants) and when a patient has household|
02796|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02796|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
02796|045|M|over-the-counter, or as part of a community-based program).(3)|
02796|046|B||
02796|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02796|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02796|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02796|050|D|million to 30 million patients.  During this time, the proportion of|
02796|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02796|052|D|million patients.(4)|
02796|053|D|   A retrospective cohort study compared the risk of opioid overdose|
02796|054|D|associated with concomitant use of opioids and skeletal muscle relaxants|
02796|055|D|versus opioid use alone. The study examined two types of opioid users (naive|
02796|056|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
02796|057|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
02796|058|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
02796|059|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
02796|060|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
02796|061|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
02796|062|D|respectively).  Elevated risk was associated with concomitant users with|
02796|063|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
02796|064|D|1.39, respectively).(5)|
02796|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02796|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02796|067|D|per 100,000 and drug overdose deaths involving both opioids and|
02796|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02796|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02796|070|D|increased from 18% to 31% during this time.(6)|
02796|071|D|   A prospective observational cohort study in North Carolina found that the|
02796|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02796|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
02796|074|D|analgesics alone.(7)|
02796|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02796|076|D|death from overdose increased with concomitant opioid analgesics and|
02796|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02796|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02796|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02796|080|D|increased risk of fatal overdose.(8)|
02796|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02796|082|D|which benzodiazepines were determined to be a cause of death and that|
02796|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02796|084|D|determined to be a cause of death.  This study also found that other CNS|
02796|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02796|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02796|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02796|088|D|where opioid analgesics were also implicated.(9)|
02796|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02796|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02796|091|D|deaths.(10)|
02796|092|B||
02796|093|R|REFERENCES:|
02796|094|B||
02796|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02796|096|R|  warns about serious risks and death when combining opioid pain or cough|1
02796|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02796|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02796|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02796|100|R|  prescribing information for all opioid pain medicines to provide|1
02796|101|R|  additional guidance for safe use. Available at:|1
02796|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02796|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02796|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02796|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02796|106|R|  recommends health care professionals discuss naloxone with all patients|1
02796|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02796|108|R|  disorder. Available at:|1
02796|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02796|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02796|111|R|  d-pain July 23, 2020.|1
02796|112|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02796|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02796|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02796|115|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
02796|116|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
02796|117|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
02796|118|R|  Ther 2020 Jul;108(1):81-88.|2
02796|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02796|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02796|121|R|  49(4):493-501.|2
02796|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02796|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02796|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02796|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02796|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02796|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02796|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02796|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02796|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02796|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02796|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02796|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02797|001|T|MONOGRAPH TITLE:  Opioids (Immediate Release)/Muscle Relaxants|
02797|002|B||
02797|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02797|004|L|take action as needed.|
02797|005|B||
02797|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and muscle relaxants may|
02797|007|A|result in additive CNS depression.(1)|
02797|008|B||
02797|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02797|010|E|as muscle relaxants, may result in profound sedation, respiratory|
02797|011|E|depression, coma, and/or death.(1)|
02797|012|B||
02797|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02797|014|P|may increase the risk of adverse effects.|
02797|015|B||
02797|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
02797|017|M|depressants such as muscle relaxants to patients for whom alternatives are|
02797|018|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
02797|019|M|sufficient management of pain.(1)|
02797|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
02797|021|M|drug to the minimum possible while achieving the desired clinical effect.|
02797|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
02797|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
02797|024|M|indicated in the absence of an opioid and titrate based upon clinical|
02797|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
02797|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
02797|027|M|clinical response.(1)|
02797|028|M|   Respiratory depression can occur at any time during opioid therapy,|
02797|029|M|especially during therapy initiation and following dosage increases.  The|
02797|030|M|risk of opioid-related overdose or overdose-related death is increased with|
02797|031|M|higher opioid doses, and this risk persists over the course of therapy.|
02797|032|M|Consider these risks when using concurrently with other agents that may|
02797|033|M|cause CNS depression.(2)|
02797|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02797|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02797|036|M|unresponsiveness.(1)|
02797|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02797|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02797|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02797|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02797|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02797|042|M|as those taking CNS depressants) and when a patient has household|
02797|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02797|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
02797|045|M|over-the-counter, or as part of a community-based program).(3)|
02797|046|B||
02797|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02797|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02797|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02797|050|D|million to 30 million patients.  During this time, the proportion of|
02797|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02797|052|D|million patients.(4)|
02797|053|D|   A retrospective cohort study compared the risk of opioid overdose|
02797|054|D|associated with concomitant use of opioids and skeletal muscle relaxants|
02797|055|D|versus opioid use alone. The study examined two types of opioid users (naive|
02797|056|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
02797|057|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
02797|058|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
02797|059|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
02797|060|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
02797|061|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
02797|062|D|respectively).  Elevated risk was associated with concomitant users with|
02797|063|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
02797|064|D|1.39, respectively).(5)|
02797|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02797|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02797|067|D|per 100,000 and drug overdose deaths involving both opioids and|
02797|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02797|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02797|070|D|increased from 18% to 31% during this time.(6)|
02797|071|D|   A prospective observational cohort study in North Carolina found that the|
02797|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02797|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
02797|074|D|analgesics alone.(7)|
02797|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02797|076|D|death from overdose increased with concomitant opioid analgesics and|
02797|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02797|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02797|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02797|080|D|increased risk of fatal overdose.(8)|
02797|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02797|082|D|which benzodiazepines were determined to be a cause of death and that|
02797|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02797|084|D|determined to be a cause of death.  This study also found that other CNS|
02797|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02797|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02797|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02797|088|D|where opioid analgesics were also implicated.(9)|
02797|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02797|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02797|091|D|deaths.(10)|
02797|092|B||
02797|093|R|REFERENCES:|
02797|094|B||
02797|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02797|096|R|  warns about serious risks and death when combining opioid pain or cough|1
02797|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02797|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02797|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02797|100|R|  prescribing information for all opioid pain medicines to provide|1
02797|101|R|  additional guidance for safe use. Available at:|1
02797|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02797|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02797|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02797|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02797|106|R|  recommends health care professionals discuss naloxone with all patients|1
02797|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02797|108|R|  disorder. Available at:|1
02797|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02797|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02797|111|R|  d-pain July 23, 2020.|1
02797|112|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02797|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02797|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02797|115|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
02797|116|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
02797|117|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
02797|118|R|  Ther 2020 Jul;108(1):81-88.|2
02797|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02797|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02797|121|R|  49(4):493-501.|2
02797|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02797|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02797|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02797|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02797|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02797|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02797|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02797|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02797|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02797|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02797|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02797|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02798|001|T|MONOGRAPH TITLE:  Opioids (Extended Release)/Antipsychotics; Phenothiazines|
02798|002|B||
02798|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02798|004|L|take action as needed.|
02798|005|B||
02798|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and antipsychotics,|
02798|007|A|including phenothiazine derivatives, may result in additive CNS|
02798|008|A|depression.(1)|
02798|009|B||
02798|010|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02798|011|E|as antipsychotics, including phenothiazine derivatives, may result in|
02798|012|E|profound sedation, respiratory depression, coma, and/or death.(1)|
02798|013|B||
02798|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02798|015|P|may increase the risk of adverse effects.|
02798|016|B||
02798|017|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
02798|018|M|depressants such as antipsychotics, including phenothiazine derivatives, to|
02798|019|M|patients for whom alternatives are ineffective, not tolerated, or would be|
02798|020|M|otherwise inadequate to provide sufficient management of pain.(1)|
02798|021|M|   If concurrent use is necessary, limit the dosages and duration of each|
02798|022|M|drug to the minimum possible while achieving the desired clinical effect.|
02798|023|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
02798|024|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
02798|025|M|indicated in the absence of an opioid and titrate based upon clinical|
02798|026|M|response.  If an opioid analgesic is indicated in a patient already taking a|
02798|027|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
02798|028|M|clinical response.(1)|
02798|029|M|   Respiratory depression can occur at any time during opioid therapy,|
02798|030|M|especially during therapy initiation and following dosage increases.  The|
02798|031|M|risk of opioid-related overdose or overdose-related death is increased with|
02798|032|M|higher opioid doses, and this risk persists over the course of therapy.|
02798|033|M|Consider these risks when using concurrently with other agents that may|
02798|034|M|cause CNS depression.(2)|
02798|035|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02798|036|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02798|037|M|unresponsiveness.(1)|
02798|038|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02798|039|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02798|040|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02798|041|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02798|042|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02798|043|M|as those taking CNS depressants) and when a patient has household|
02798|044|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02798|045|M|for obtaining an opioid reversal agent (e.g., prescription,|
02798|046|M|over-the-counter, or as part of a community-based program).(3)|
02798|047|B||
02798|048|D|DISCUSSION:  A nested case-control study looked at the relationship between|
02798|049|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
02798|050|D|antipsychotics was associated with a 2.33-fold increase in risk of|
02798|051|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
02798|052|D|significantly increased in patients with recent use of antipsychotics|
02798|053|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
02798|054|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
02798|055|D|of use.(4)|
02798|056|D|   Between 2002 and 2014, the number of patients receiving an opioid|
02798|057|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
02798|058|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
02798|059|D|to 30 million patients.  During this time, the proportion of patients|
02798|060|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
02798|061|D|patients.(5)|
02798|062|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02798|063|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02798|064|D|per 100,000 and drug overdose deaths involving both opioids and|
02798|065|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02798|066|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02798|067|D|increased from 18% to 31% during this time.(6)|
02798|068|D|   A prospective observational cohort study in North Carolina found that the|
02798|069|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02798|070|D|benzodiazepines were 10 times higher than patients receiving opioid|
02798|071|D|analgesics alone.(7)|
02798|072|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02798|073|D|death from overdose increased with concomitant opioid analgesics and|
02798|074|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02798|075|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02798|076|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02798|077|D|increased risk of fatal overdose.(8)|
02798|078|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02798|079|D|which benzodiazepines were determined to be a cause of death and that|
02798|080|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02798|081|D|determined to be a cause of death.  This study also found that other CNS|
02798|082|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02798|083|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02798|084|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02798|085|D|where opioid analgesics were also implicated.(9)|
02798|086|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02798|087|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02798|088|D|deaths.(10)|
02798|089|B||
02798|090|R|REFERENCES:|
02798|091|B||
02798|092|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02798|093|R|  warns about serious risks and death when combining opioid pain or cough|1
02798|094|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02798|095|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02798|096|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02798|097|R|  prescribing information for all opioid pain medicines to provide|1
02798|098|R|  additional guidance for safe use. Available at:|1
02798|099|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02798|100|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02798|101|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02798|102|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02798|103|R|  recommends health care professionals discuss naloxone with all patients|1
02798|104|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02798|105|R|  disorder. Available at:|1
02798|106|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02798|107|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02798|108|R|  d-pain July 23, 2020.|1
02798|109|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
02798|110|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
02798|111|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
02798|112|R|  Pharmacol 2020 Apr 26.|2
02798|113|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02798|114|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02798|115|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02798|116|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02798|117|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02798|118|R|  49(4):493-501.|2
02798|119|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02798|120|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02798|121|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02798|122|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02798|123|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02798|124|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02798|125|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02798|126|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02798|127|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02798|128|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02798|129|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02798|130|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02799|001|T|MONOGRAPH TITLE:  Slt Opioids (Immediate|
02799|002|T|Release)/Antipsychotics;Phenothiazine|
02799|003|B||
02799|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02799|005|L|take action as needed.|
02799|006|B||
02799|007|A|MECHANISM OF ACTION:  Concurrent use of opioids and antipsychotics,|
02799|008|A|including phenothiazine derivatives, may result in additive CNS|
02799|009|A|depression.(1)|
02799|010|B||
02799|011|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02799|012|E|as antipsychotics, including phenothiazine derivatives, may result in|
02799|013|E|profound sedation, respiratory depression, coma, and/or death.(1)|
02799|014|B||
02799|015|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02799|016|P|may increase the risk of adverse effects.|
02799|017|B||
02799|018|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
02799|019|M|depressants such as antipsychotics, including phenothiazine derivatives, to|
02799|020|M|patients for whom alternatives are ineffective, not tolerated, or would be|
02799|021|M|otherwise inadequate to provide sufficient management of pain.(1)|
02799|022|M|   If concurrent use is necessary, limit the dosages and duration of each|
02799|023|M|drug to the minimum possible while achieving the desired clinical effect.|
02799|024|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
02799|025|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
02799|026|M|indicated in the absence of an opioid and titrate based upon clinical|
02799|027|M|response.  If an opioid analgesic is indicated in a patient already taking a|
02799|028|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
02799|029|M|clinical response.(1)|
02799|030|M|   Respiratory depression can occur at any time during opioid therapy,|
02799|031|M|especially during therapy initiation and following dosage increases.  The|
02799|032|M|risk of opioid-related overdose or overdose-related death is increased with|
02799|033|M|higher opioid doses, and this risk persists over the course of therapy.|
02799|034|M|Consider these risks when using concurrently with other agents that may|
02799|035|M|cause CNS depression.(2)|
02799|036|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02799|037|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02799|038|M|unresponsiveness.(1)|
02799|039|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02799|040|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02799|041|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02799|042|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02799|043|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02799|044|M|as those taking CNS depressants) and when a patient has household|
02799|045|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02799|046|M|for obtaining an opioid reversal agent (e.g., prescription,|
02799|047|M|over-the-counter, or as part of a community-based program).(3)|
02799|048|B||
02799|049|D|DISCUSSION:  A nested case-control study looked at the relationship between|
02799|050|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
02799|051|D|antipsychotics was associated with a 2.33-fold increase in risk of|
02799|052|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
02799|053|D|significantly increased in patients with recent use of antipsychotics|
02799|054|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
02799|055|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
02799|056|D|of use.(4)|
02799|057|D|   Between 2002 and 2014, the number of patients receiving an opioid|
02799|058|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
02799|059|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
02799|060|D|to 30 million patients.  During this time, the proportion of patients|
02799|061|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
02799|062|D|patients.(5)|
02799|063|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02799|064|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02799|065|D|per 100,000 and drug overdose deaths involving both opioids and|
02799|066|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02799|067|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02799|068|D|increased from 18% to 31% during this time.(6)|
02799|069|D|   A prospective observational cohort study in North Carolina found that the|
02799|070|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02799|071|D|benzodiazepines were 10 times higher than patients receiving opioid|
02799|072|D|analgesics alone.(7)|
02799|073|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02799|074|D|death from overdose increased with concomitant opioid analgesics and|
02799|075|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02799|076|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02799|077|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02799|078|D|increased risk of fatal overdose.(8)|
02799|079|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02799|080|D|which benzodiazepines were determined to be a cause of death and that|
02799|081|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02799|082|D|determined to be a cause of death.  This study also found that other CNS|
02799|083|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02799|084|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02799|085|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02799|086|D|where opioid analgesics were also implicated.(9)|
02799|087|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02799|088|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02799|089|D|deaths.(10)|
02799|090|B||
02799|091|R|REFERENCES:|
02799|092|B||
02799|093|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02799|094|R|  warns about serious risks and death when combining opioid pain or cough|1
02799|095|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02799|096|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02799|097|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02799|098|R|  prescribing information for all opioid pain medicines to provide|1
02799|099|R|  additional guidance for safe use. Available at:|1
02799|100|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02799|101|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02799|102|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02799|103|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02799|104|R|  recommends health care professionals discuss naloxone with all patients|1
02799|105|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02799|106|R|  disorder. Available at:|1
02799|107|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02799|108|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02799|109|R|  d-pain July 23, 2020.|1
02799|110|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
02799|111|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
02799|112|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
02799|113|R|  Pharmacol 2020 Apr 26.|2
02799|114|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02799|115|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02799|116|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02799|117|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02799|118|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02799|119|R|  49(4):493-501.|2
02799|120|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02799|121|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02799|122|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02799|123|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02799|124|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02799|125|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02799|126|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02799|127|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02799|128|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02799|129|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02799|130|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02799|131|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02800|001|T|MONOGRAPH TITLE:  Chronic Opioids/Butorphanol|
02800|002|B||
02800|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02800|004|L|of severe adverse interaction.|
02800|005|B||
02800|006|A|MECHANISM OF ACTION:  Butorphanol antagonizes mu-opiate receptors.(1)  Other|
02800|007|A|opioids agonize mu-opiate receptors.|
02800|008|B||
02800|009|E|CLINICAL EFFECTS:  Concurrent use of butorphanol with other opioids in|
02800|010|E|opioid dependent patients may result in withdrawal symptoms.  Concurrent use|
02800|011|E|in other patients may result in additive or decreased analgesia, decreased|
02800|012|E|opioid side effects, and/or renarcotization.|
02800|013|B||
02800|014|P|PREDISPOSING FACTORS:  Patients dependent on opioids or taking higher doses|
02800|015|P|of opioids may be more likely to experience withdrawal symptoms with|
02800|016|P|concurrent use.|
02800|017|B||
02800|018|M|PATIENT MANAGEMENT:  Use butorphanol with caution in patients maintained or|
02800|019|M|dependent on other opioids and monitor for signs of withdrawal.  In other|
02800|020|M|patients, also monitor for changes in analgesic effects.|
02800|021|B||
02800|022|D|DISCUSSION:  In a study in patients maintained on methadone, butorphanol|
02800|023|D|produced withdrawal symptoms comparable to naloxone.(2)|
02800|024|D|   In a case report, the use of remifentanil for conscious sedation in a|
02800|025|D|patient maintained on butorphanol produced severe withdrawal symptoms.(3)|
02800|026|B||
02800|027|R|REFERENCES:|
02800|028|B||
02800|029|R|1.Stadol (butorphanol tartrate) US prescribing information. Bristol-Myers|1
02800|030|R|  Squibb April, 2002.|1
02800|031|R|2.Preston KL, Bigelow GE, Liebson IA. Butorphanol-precipitated withdrawal in|2
02800|032|R|  opioid-dependent human volunteers. J Pharmacol Exp Ther 1988 Aug;|2
02800|033|R|  246(2):441-8.|2
02800|034|R|3.Igarashi A, Amagasa S, Yokoo N, Sato M. Acute withdrawal syndrome in a|3
02800|035|R|  butorphanol-treated patient: an adverse combination of opioids. Br J|3
02800|036|R|  Anaesth 2008 Jul;101(1):127-8.|3
02801|001|T|MONOGRAPH TITLE:  Chronic Opioids/Buprenorphine; Pentazocine|
02801|002|B||
02801|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02801|004|L|of severe adverse interaction.|
02801|005|B||
02801|006|A|MECHANISM OF ACTION:  Buprenorphine antagonizes mu-opiate receptors.(1)|
02801|007|A|Pentazocine is a mixed agonist-antagonist at opiate receptors.(2)  Other|
02801|008|A|opioids agonize mu-opiate receptors.|
02801|009|B||
02801|010|E|CLINICAL EFFECTS:  Concurrent use of buprenorphine or pentazocine with other|
02801|011|E|opioids in opioid dependent patients may result in withdrawal symptoms.|
02801|012|E|Concurrent use in other patients may result in additive or decreased|
02801|013|E|analgesia, decreased opioid side effects, and/or renarcotization.|
02801|014|B||
02801|015|P|PREDISPOSING FACTORS:  Patients dependent on opioids or taking higher doses|
02801|016|P|of opioids may be more likely to experience withdrawal symptoms with|
02801|017|P|concurrent use.|
02801|018|B||
02801|019|M|PATIENT MANAGEMENT:  Use buprenorphine and pentazocine with caution in|
02801|020|M|patients maintained or dependent on other opioids and monitor for signs of|
02801|021|M|withdrawal.  In other patients, also monitor for changes in analgesic|
02801|022|M|effects.|
02801|023|M|   The manufacturer of Sublocade states buprenorphine may precipitate opioid|
02801|024|M|withdrawal in patients who are currently physically dependent on full opioid|
02801|025|M|agonists. The risk of withdrawal may be increased if buprenorphine is given|
02801|026|M|less than 6 hours after short-acting opioids (such as heroin, morphine) and|
02801|027|M|less than 24 hours after long-acting opioids (such as methadone).(3)|
02801|028|B||
02801|029|D|DISCUSSION:  In clinical trials, administration of buprenorphine injection|
02801|030|D|produced withdrawal symptoms in patients maintained on methadone (30 mg|
02801|031|D|daily) when administered 2 hours post-methadone,(4) but not when|
02801|032|D|administered 20 hours post-methadone.(5)|
02801|033|D|   In another study, sublingual buprenorphine produced withdrawal symptoms|
02801|034|D|in patients maintained on methadone.  Symptoms were more pronounced in|
02801|035|D|patients maintained on 60 mg daily doses than in patients maintained on 30|
02801|036|D|mg daily doses.(6)|
02801|037|D|   In a study of 10 patients maintained on methadone (100 mg daily), only|
02801|038|D|three were able to tolerate escalating sublingual doses of|
02801|039|D|buprenorphine/naloxone up to 32/8 mg.  Split doses produced less withdrawal|
02801|040|D|symptoms than full doses.(7)|
02801|041|D|   In a case report, a heroin-user maintained in a buprenorphine-maintenance|
02801|042|D|program began stockpiling his buprenorphine instead of ingesting it and|
02801|043|D|began using heroin.  He then decided to re-initiate treatment on his own and|
02801|044|D|ingested between 80 and 88 mg of buprenorphine over a two day period and|
02801|045|D|experienced extreme withdrawal symptoms, despite restarting heroin during|
02801|046|D|these symptoms.  Methadone relieved his withdrawal symptoms.(8)|
02801|047|B||
02801|048|R|REFERENCES:|
02801|049|B||
02801|050|R|1.Buprenex (buprenorphine hydrochloride) US prescribing information. Reckitt|1
02801|051|R|  Benckiser Pharmaceuticals, Inc. April, 2005.|1
02801|052|R|2.Talwin (pentazocine) US Prescribing Information. Hospira, Inc. Oct 2019.|1
02801|053|R|3.Sublocade (buprenorphine extended release injection) US prescribing|1
02801|054|R|  information. Indivior Inc. February, 2025.|1
02801|055|R|4.Strain EC, Preston KL, Liebson IA, Bigelow GE. Buprenorphine effects in|2
02801|056|R|  methadone-maintained volunteers: effects at two hours after methadone. J|2
02801|057|R|  Pharmacol Exp Ther 1995 Feb;272(2):628-38.|2
02801|058|R|5.Strain EC, Preston KL, Liebson IA, Bigelow GE. Acute effects of|2
02801|059|R|  buprenorphine, hydromorphone and naloxone in methadone-maintained|2
02801|060|R|  volunteers. J Pharmacol Exp Ther 1992 Jun;261(3):985-93.|2
02801|061|R|6.Walsh SL, June HL, Schuh KJ, Preston KL, Bigelow GE, Stitzer ML. Effects|2
02801|062|R|  of buprenorphine and methadone in methadone-maintained subjects.|2
02801|063|R|  Psychopharmacology (Berl) 1995 Jun;119(3):268-76.|2
02801|064|R|7.Rosado J, Walsh SL, Bigelow GE, Strain EC. Sublingual|2
02801|065|R|  buprenorphine/naloxone precipitated withdrawal in subjects maintained on|2
02801|066|R|  100mg of daily methadone. Drug Alcohol Depend 2007 Oct 8;90(2-3):261-9.|2
02801|067|R|8.Clark NC, Lintzeris N, Muhleisen PJ. Severe opiate withdrawal in a heroin|3
02801|068|R|  user precipitated by a massive buprenorphine dose. Med J Aust 2002 Feb 18;|3
02801|069|R|  176(4):166-7.|3
02802|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Dabrafenib|
02802|002|B||
02802|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02802|004|L|take action as needed.|
02802|005|B||
02802|006|A|MECHANISM OF ACTION:  Dabrafenib, a CYP3A4 inducer, may increase hepatic|
02802|007|A|metabolism of coumarin anticoagulants.(1)|
02802|008|B||
02802|009|E|CLINICAL EFFECTS:  The hypoprothrombinemic effect of coumarin anticoagulants|
02802|010|E|may be decreased.|
02802|011|B||
02802|012|P|PREDISPOSING FACTORS:  None determined.|
02802|013|B||
02802|014|M|PATIENT MANAGEMENT:  The manufacturer of dabrafenib recommends monitoring of|
02802|015|M|anticoagulation parameters more frequently when starting or stopping|
02802|016|M|dabrafenib in a patient receiving warfarin.  Adjust the dose of warfarin|
02802|017|M|accordingly.(1)|
02802|018|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02802|019|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02802|020|M|initiating, altering the dose or discontinuing either drug.|
02802|021|B||
02802|022|D|DISCUSSION:  Coadministration of 150 mg dabrafenib twice daily for 15 days|
02802|023|D|followed by a single dose of 15 mg warfarin decreased the area-under-curve|
02802|024|D|(AUC) of S-warfarin by 37% and the AUC of R-warfarin by 33%.(1)|
02802|025|B||
02802|026|R|REFERENCE:|
02802|027|B||
02802|028|R|1.Tafinlar (dabrafenib) US prescribing information. Novartis Pharmaceuticals|1
02802|029|R|  Corporation May, 2023.|1
02803|001|T|MONOGRAPH TITLE:  Betrixaban; Dabigatran; Edoxaban/Lovastatin; Simvastatin|
02803|002|B||
02803|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02803|004|L|take action as needed.|
02803|005|B||
02803|006|A|MECHANISM OF ACTION:  Betrixaban, dabigatran etexilate, and edoxaban are|
02803|007|A|substrates for the P-glycoprotein (P-gp) system.  Inhibition of intestinal|
02803|008|A|P-gp leads to increased absorption of betrixaban, dabigatran, and|
02803|009|A|edoxaban.(1-6)  Lovastatin and simvastatin are inhibitors of intestinal|
02803|010|A|P-gp.(7,8)|
02803|011|B||
02803|012|E|CLINICAL EFFECTS:  The concurrent use of betrixaban, dabigatran, and|
02803|013|E|edoxaban with lovastatin or simvastatin may lead to elevated plasma levels|
02803|014|E|of betrixaban, dabigatran, and edoxaban, increasing the risk for bleeding.|
02803|015|B||
02803|016|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
02803|017|P|bleeding include renal impairment, concomitant use of P-gp inhibitors,|
02803|018|P|patient age >74 years, coexisting conditions (e.g. recent trauma) or use of|
02803|019|P|drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50|
02803|020|P|kg.(1-6)|
02803|021|P|   The risk for bleeding episodes may be greater in patients with|
02803|022|P|disease-associated factors (e.g. thrombocytopenia).|
02803|023|P|   Drug associated risk factors include concurrent use of multiple drugs|
02803|024|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02803|025|P|risk for bleeding (e.g. NSAIDs).|
02803|026|B||
02803|027|M|PATIENT MANAGEMENT:  Assess renal function and evaluate patient for other|
02803|028|M|pre-existing risk factors for bleeding prior to initiating concurrent|
02803|029|M|therapy.  The concurrent use of betrixaban, dabigatran, and edoxaban with|
02803|030|M|lovastatin or simvastatin should be monitored closely.  Consider alternate|
02803|031|M|therapy such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin that|
02803|032|M|are not known to inhibit P-gp.(7,8)|
02803|033|M|   Careful monitoring for signs and symptoms of bleeding is warranted during|
02803|034|M|concurrent therapy.  Consider regular monitoring of hemoglobin, platelet|
02803|035|M|levels, and/or activated partial thromboplastin time (aPTT) or ecarin|
02803|036|M|clotting time (ECT).  Instruct patients to report any signs and symptoms of|
02803|037|M|bleeding, such as bleeding from the eyes, gums or nose; unusual bruising;|
02803|038|M|dark stools; red or dark brown urine; and/or abdominal pain or swelling.|
02803|039|B||
02803|040|D|DISCUSSION:  A population-based, nested case-control study of 45,991|
02803|041|D|patients taking dabigatran aged 66 years or older were screened for ischemic|
02803|042|D|stroke or major hemorrhage with a single statin prescription in the 60 days|
02803|043|D|preceding the index date.  Each case was matched with up to 4 controls by|
02803|044|D|age and sex.  The use of lovastatin or simvastatin was not associated with|
02803|045|D|an increased risk of stroke or transient ischemic attack relative to other|
02803|046|D|statins in patients receiving dabigatran (adjusted OR 1.33, 95% CI|
02803|047|D|0.88-2.01).  However, the use of lovastatin or simvastatin was associated|
02803|048|D|with a higher risk of major hemorrhage than comparator statins (adjusted OR|
02803|049|D|1.46, 95% CI 1.17-1.82).(7)|
02803|050|D|   In the APEX randomized, double-blind study the incidence of major or|
02803|051|D|clinically relevant non-major bleeds (CRNM) in the betrixaban 40 mg and 80|
02803|052|D|mg group was higher in patients taking concomitant P-gp inhibitors (2.8% vs.|
02803|053|D|4.1% vs. 4.7%).(9)|
02803|054|D|   In a study in 12 subjects, concomitant administration of a single dose of|
02803|055|D|betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice|
02803|056|D|daily) resulted in an increase in betrixaban's maximum concentration (Cmax)|
02803|057|D|and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(10)|
02803|058|D|   An open-label study looking at concomitant administration of a single|
02803|059|D|dose of betrixaban with verapamil in 18 subjects found an increase in|
02803|060|D|betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold,|
02803|061|D|respectively.(11)|
02803|062|D|   In a study, concomitant administration of betrixaban (80 mg) with|
02803|063|D|amiodarone resulted in an increase in betrixaban's Cmax by 143%.(10)|
02803|064|D|   A summary of pharmacokinetic interactions with betrixaban and amiodarone,|
02803|065|D|diltiazem, or verapamil concluded that if concurrent use is warranted, the|
02803|066|D|betrixaban dose should be reduced to 80 mg once then 40 mg daily.  Use|
02803|067|D|should be avoided if CrCl is less than 30 ml/min.(11)|
02803|068|D|   When dabigatran was co-administered with amiodarone, a P-gp inhibitor,|
02803|069|D|the extent and rate of absorption of amiodarone and its active metabolite|
02803|070|D|DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and|
02803|071|D|maximum concentration (Cmax) were increased by about 60% and 50%,|
02803|072|D|respectively;(2,3) however, dabigatran clearance was increased by 65%.(2)|
02803|073|D|   Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000|
02803|074|D|mg), and a P-gp inhibitor, increased the AUC and Cmax of dabigatran by 53%|
02803|075|D|and 56%, respectively.(2,3)|
02803|076|D|   Chronic administration of immediate release verapamil, a P-gp inhibitor,|
02803|077|D|one hour prior to dabigatran dose increased dabigatran AUC by 154%.(6)|
02803|078|D|Administration of dabigatran two hours before verapamil results in a|
02803|079|D|negligible increase in dabigatran AUC.(2)|
02803|080|D|   In an interaction study, the effect of repeat administration of quinidine|
02803|081|D|(300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in|
02803|082|D|healthy subjects.  Both peak (Cmax) and total systemic exposure (AUC) to|
02803|083|D|edoxaban and to the active M4 metabolite increased approximately|
02803|084|D|1.75-fold.(5)|
02803|085|D|   In an interaction study, the effect of repeat administration of verapamil|
02803|086|D|(240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral|
02803|087|D|dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy|
02803|088|D|subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold|
02803|089|D|and 1.53-fold,  respectively.  Total and peak systemic exposure to the|
02803|090|D|active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(5)|
02803|091|D|   Based upon the above results, patients in the DVT/PE trial had a 50% dose|
02803|092|D|reduction (from 60 mg to 30 mg) during concomitant therapy with|
02803|093|D|P-glycoprotein inhibitors.  Approximately 0.5% of these patients required a|
02803|094|D|dose reduction solely due to P-gp inhibitor use.  This low rate of|
02803|095|D|concurrent therapy was too small to allow for detailed statistical|
02803|096|D|evaluation.  Almost all of these patients were receiving quinidine or|
02803|097|D|verapamil.  In these patients, both trough edoxaban concentrations (Ctrough)|
02803|098|D|used to evaluate bleeding risk, and total edoxaban exposure (AUC or|
02803|099|D|area-under-curve) used to evaluate treatment efficacy, were lower than|
02803|100|D|patients who did not require any edoxaban dose adjustment.  In this DVT/PE|
02803|101|D|comparator trial, subgroup analysis revealed that warfarin had numerically|
02803|102|D|better efficacy than edoxaban in patients receiving P-gp inhibitors.  Based|
02803|103|D|upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects,|
02803|104|D|both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the|
02803|105|D|edoxaban 50% dose reduction overcorrected for the difference in|
02803|106|D|exposure.(5,12)|
02803|107|D|   Consequently, EMA recommended no edoxaban dose adjustments for patients|
02803|108|D|receiving concomitant therapy with quinidine or verapamil.(12,13)|
02803|109|B||
02803|110|R|REFERENCES:|
02803|111|B||
02803|112|R|1.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
02803|113|R|  Inc. July, 2019.|1
02803|114|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
02803|115|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
02803|116|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
02803|117|R|  Boehringer Ingelheim March, 23 2020.|1
02803|118|R|4.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
02803|119|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
02803|120|R|5.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02803|121|R|  2019.|1
02803|122|R|6.Anonymous. FDA Dabigatran background package for Cardio-Renal Advisory|1
02803|123|R|  Committee. available at|1
02803|124|R|  http://wayback.archive-it.org/7993/20170405212218/https://www.fda.gov/down|1
02803|125|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascularan|1
02803|126|R|  dRenalDrugsAdvisoryCommittee/UCM247244.pdf September 20, 2010.|1
02803|127|R|7.Antoniou T, Macdonald EM, Yao Z, Hollands S, Gomes T, Tadrous M, Mamdani|2
02803|128|R|  M, Juurlink DN. Association between statin use and ischemic stroke or|2
02803|129|R|  major hemorrhage in patients taking dabigatran for atrial fibrillation.|2
02803|130|R|  CMAJ 2016 Nov 21.|2
02803|131|R|8.Holtzman CW, Wiggins BS, Spinler SA. Role of P-glycoprotein in statin drug|6
02803|132|R|  interactions. Pharmacotherapy 2006 Nov;26(11):1601-7.|6
02803|133|R|9.FDA (US Food and Drug Administration). CDER application number. 208383|1
02803|134|R|  Bevyxxa Medical Review. acessed at:|1
02803|135|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383Orig1s000Med|1
02803|136|R|  R.pdf June 23, 2017.|1
02803|137|R|10.FDA (US Food and Drug Administration). CDER application number. 208383|1
02803|138|R|   Bevyxxa Clinical Pharmacology and Biopharmaceuticals Review. accessed at:|1
02803|139|R|   https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383orig1s000na|1
02803|140|R|   mer.pdf June 23, 2017.|1
02803|141|R|11.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
02803|142|R|   Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
02803|143|R|   of  the Week..|6
02803|144|R|12.Lixiana (edoxaban tosilate) UK summary of product characteristics.|1
02803|145|R|   Daiichi Sankyo UK Limited July 2, 2015.|1
02803|146|R|13.Lixiana European Medicines Agency (EMA) Assessment report. Committee for|1
02803|147|R|   Medicinal Products for Human Use (CHMP) 23 April 2015.|1
02804|001|T|MONOGRAPH TITLE:  Erlotinib/Ciprofloxacin|
02804|002|B||
02804|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02804|004|L|of severe adverse interaction.|
02804|005|B||
02804|006|A|MECHANISM OF ACTION:  Ciprofloxacin may inhibit the metabolism of erlotinib.|
02804|007|A|Erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by|
02804|008|A|CYP1A2. Ciprofloxacin is a weak inhibitor of CYP3A4 and a moderate inhibitor|
02804|009|A|of CYP1A2.(1,2)|
02804|010|B||
02804|011|E|CLINICAL EFFECTS:  Concurrent use of ciprofloxacin may increase systemic|
02804|012|E|exposure and the risk for erlotinib toxicities.|
02804|013|B||
02804|014|P|PREDISPOSING FACTORS:  None determined.|
02804|015|B||
02804|016|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ciprofloxacin in patients|
02804|017|M|receiving therapy with erlotinib. Patients receiving concurrent therapy with|
02804|018|M|erlotinib should be monitored closely for increased levels of and toxicity|
02804|019|M|if ciprofloxacin is initiated.  The dosage of erlotinib may need to be|
02804|020|M|adjusted if ciprofloxacin is initiated or discontinued.(1)|
02804|021|M|   If concurrent use of ciprofloxacin cannot be avoided with erlotinib,|
02804|022|M|decrease the dose of erlotinib by 50 mg decrements.(1)|
02804|023|B||
02804|024|D|DISCUSSION:  Co-administration of erlotinib with ciprofloxacin increased|
02804|025|D|erlotinib area-under-curve (AUC) and maximum concentration (Cmax) by 39% and|
02804|026|D|17%, respectively.(1)|
02804|027|D|   Two patients developed gastrointestinal perforations while taking|
02804|028|D|erlotinib, corticosteroids, and ciprofloxacin.(3)|
02804|029|B||
02804|030|R|REFERENCES:|
02804|031|B||
02804|032|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
02804|033|R|  2016.|1
02804|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
02804|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02804|036|R|3.Gass-Jegu F, Gschwend A, Gairard-Dory AC, Mennecier B, Tebacher-Alt M,|3
02804|037|R|  Gourieux B, Quoix E. Gastrointestinal perforations in patients treated|3
02804|038|R|  with erlotinib: A report of two cases with fatal outcome and literature|3
02804|039|R|  review. Lung Cancer 2016 Sep;99:76-8.|3
02805|001|T|MONOGRAPH TITLE:  Furosemide/Sucralfate (mono deleted 11/18/2021)|
02805|002|B||
02805|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02805|004|L|take action as needed.|
02805|005|B||
02805|006|A|MECHANISM OF ACTION:  Furosemide may be adsorbed by sucralfate.(1,2)|
02805|007|B||
02805|008|E|CLINICAL EFFECTS:  The simultaneous administration of sucralfate and|
02805|009|E|furosemide may reduce the absorption and the natriuretic and|
02805|010|E|antihypertensive effects of furosemide.(1,2)|
02805|011|B||
02805|012|P|PREDISPOSING FACTORS:  None determined.|
02805|013|B||
02805|014|M|PATIENT MANAGEMENT:  The administration of sucralfate and furosemide should|
02805|015|M|be separated by two hours.(1)|
02805|016|B||
02805|017|D|DISCUSSION:  In an in vitro study, maximal adsorption of furosemide to|
02805|018|D|sucralfate occurred at pH 3 but was negligible at pH higher than 4.  In a|
02805|019|D|rat model, coadministration of sucralfate with furosemide did not alter the|
02805|020|D|urinary recovery of furosemide or urinary sodium and potassium excretion.(2)|
02805|021|B||
02805|022|R|REFERENCES:|
02805|023|B||
02805|024|R|1.Lasix (furosemide) US prescribing information. Sanofi-Aventis U.S. LLC|1
02805|025|R|  March, 2016.|1
02805|026|R|2.Sulochana SP, Syed M, Chandrasekar DV, Mullangi R, Srinivas NR. Clinical|6
02805|027|R|  Drug-Drug Pharmacokinetic Interaction Potential of Sucralfate with Other|6
02805|028|R|  Drugs: Review and Perspectives. Eur J Drug Metab Pharmacokinet 2016 Oct;|6
02805|029|R|  41(5):469-503.|6
02806|001|T|MONOGRAPH TITLE:  Paricalcitol/Cholestyramine|
02806|002|B||
02806|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02806|004|L|take action as needed.|
02806|005|B||
02806|006|A|MECHANISM OF ACTION:  Cholestyramine may impair intestinal absorption of|
02806|007|A|fat-soluble vitamins.  Paricalcitol is an analogue of a fat-soluble vitamin|
02806|008|A|and therefore cholestyramine may interfere with absorption of|
02806|009|A|paricalcitol.(1)|
02806|010|B||
02806|011|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
02806|012|E|clinical effects of paricalcitol.(1)|
02806|013|B||
02806|014|P|PREDISPOSING FACTORS:  None determined.|
02806|015|B||
02806|016|M|PATIENT MANAGEMENT:  The US manufacturer of paricalcitol capsules recommends|
02806|017|M|that paricalcitol be taken at least 1 hour before or 4-6 hours after taking|
02806|018|M|cholestyramine.(1)|
02806|019|B||
02806|020|D|DISCUSSION:  The manufacturer recommends that administration of paricalcitol|
02806|021|D|capsules be separated from concurrent administration with drugs that impair|
02806|022|D|intestinal absorption of fat-soluble vitamins.(1)|
02806|023|B||
02806|024|R|REFERENCE:|
02806|025|B||
02806|026|R|1.Zemplar (paricalcitol) capsule US prescribing information. AbbVie, Inc.|1
02806|027|R|  October, 2016.|1
02807|001|T|MONOGRAPH TITLE:  Temsirolimus/Sunitinib|
02807|002|B||
02807|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02807|004|L|of severe adverse interaction.|
02807|005|B||
02807|006|A|MECHANISM OF ACTION:  Possible additive or synergistic effects on the immune|
02807|007|A|system.(1)|
02807|008|B||
02807|009|E|CLINICAL EFFECTS:  Concurrent use of temsirolimus and sunitinib may increase|
02807|010|E|the risk of dose-limiting toxicity without providing any clinical|
02807|011|E|benefit.(1)|
02807|012|B||
02807|013|P|PREDISPOSING FACTORS:  None determined.|
02807|014|B||
02807|015|M|PATIENT MANAGEMENT:  Avoid concurrent therapy with temsirolimus and|
02807|016|M|sunitinib.(1)  Patients receiving concurrent therapy should be closely|
02807|017|M|monitored for signs and symptoms of toxicity.  Dose reduction or|
02807|018|M|discontinuation of therapy may be required.|
02807|019|B||
02807|020|D|DISCUSSION:  In a phase I study with temsirolimus and sunitinib utilizing a|
02807|021|D|3+3 dose escalation design, six patients required dose reduction due to|
02807|022|D|grade 3 stomatitis or grade 3 thrombocytopenia and four patients required|
02807|023|D|removal from the trial because of unacceptable toxicity.  A total of 21|
02807|024|D|grade 3 or 4 adverse events occurred.  At 50% of the FDA-approved doses of|
02807|025|D|sunitinib (25 mg) and temsirolimus (12.5 mg), significant mucositis|
02807|026|D|requiring dose reduction occurred.(2)|
02807|027|D|   In the first cohort of a phase I study with temsirolimus (15 mg|
02807|028|D|intravenously once weekly) and sunitinib (25 mg by mouth daily on days 1|
02807|029|D|through 28, followed by a 2-week rest), dose-limiting toxicities (grade 3|
02807|030|D|rash, grade 3 thrombocytopenia/cellulitis/gout) were observed in 2 of 3|
02807|031|D|patients.  The study was terminated because of the dose-limiting toxicity|
02807|032|D|observed at low starting doses of both agents.(3)|
02807|033|B||
02807|034|R|REFERENCES:|
02807|035|B||
02807|036|R|1.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
02807|037|R|  Inc. March, 2018.|1
02807|038|R|2.Campbell MT, Millikan RE, Altinmakas E, Xiao L, Wen SJ, Siefker-Radtke AO,|2
02807|039|R|  Aparicio A, Corn PG, Tannir NM. Phase I trial of sunitinib and|2
02807|040|R|  temsirolimus in metastatic renal cell carcinoma. Clin Genitourin Cancer|2
02807|041|R|  2015 Jun;13(3):218-24.|2
02807|042|R|3.Patel PH, Senico PL, Curiel RE, Motzer RJ. Phase I study combining|2
02807|043|R|  treatment with temsirolimus and sunitinib malate in patients with advanced|2
02807|044|R|  renal cell carcinoma. Clin Genitourin Cancer 2009 Jan;7(1):24-7.|2
02808|001|T|MONOGRAPH TITLE:  Paricalcitol/Mineral Oil|
02808|002|B||
02808|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02808|004|L|take action as needed.|
02808|005|B||
02808|006|A|MECHANISM OF ACTION:  Mineral oil may impair intestinal absorption of|
02808|007|A|fat-soluble vitamins.  Paricalcitol is an analogue of a fat-soluble vitamin|
02808|008|A|and therefore mineral oil may interfere with absorption of paricalcitol.(1)|
02808|009|B||
02808|010|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
02808|011|E|clinical effects of paricalcitol.(1)|
02808|012|B||
02808|013|P|PREDISPOSING FACTORS:  None determined.|
02808|014|B||
02808|015|M|PATIENT MANAGEMENT:  The US manufacturer of paricalcitol capsules recommends|
02808|016|M|that paricalcitol be taken at least 1 hour before or 4-6 hours after taking|
02808|017|M|mineral oil.(1)|
02808|018|B||
02808|019|D|DISCUSSION:  The manufacturer recommends that administration of paricalcitol|
02808|020|D|capsules be separated from concurrent administration with drugs that impair|
02808|021|D|intestinal absorption of fat-soluble vitamins.(1)|
02808|022|B||
02808|023|R|REFERENCE:|
02808|024|B||
02808|025|R|1.Zemplar (paricalcitol) capsule US prescribing information. AbbVie, Inc.|1
02808|026|R|  October, 2016.|1
02809|001|T|MONOGRAPH TITLE:  Zolpidem/Dabrafenib|
02809|002|B||
02809|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02809|004|L|take action as needed.|
02809|005|B||
02809|006|A|MECHANISM OF ACTION:  Dabrafenib is a CYP3A4 inducer.(1)  Agents that induce|
02809|007|A|CYP3A4 may induce the metabolism of zolpidem.(2)|
02809|008|B||
02809|009|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inducers may decrease levels of|
02809|010|E|and effects from zolpidem.(1,2)|
02809|011|B||
02809|012|P|PREDISPOSING FACTORS:  None determined.|
02809|013|B||
02809|014|M|PATIENT MANAGEMENT:  Consider alternative therapy for sleep or dose|
02809|015|M|adjustment in patients undergoing therapy with dabrafenib.(1,2)|
02809|016|B||
02809|017|D|DISCUSSION:  Coadministration of dabrafenib (150 mg twice daily for 15 days)|
02809|018|D|followed by midazolam 3 mg (CYP3A4 substrate) decreased midazolam|
02809|019|D|area-under-curve (AUC) 74%.(1)|
02809|020|D|   In a study in eight healthy subjects, rifampin (600 mg daily for 5 days)|
02809|021|D|decreased zolpidem AUC and maximum concentration (Cmax) by 73% and 58%,|
02809|022|D|respectively.(2)|
02809|023|B||
02809|024|R|REFERENCES:|
02809|025|B||
02809|026|R|1.Tafinlar (dabrafenib) US prescribing information. Novartis Pharmaceuticals|1
02809|027|R|  Corporation May, 2023.|1
02809|028|R|2.Ambien (zolpidem) US prescribing information. Sanofi-Aventis US LLC|1
02809|029|R|  February, 2022.|1
02810|001|T|MONOGRAPH TITLE:  Venetoclax/Selected P-glycoprotein (P-gp) Inhibitors|
02810|002|B||
02810|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02810|004|L|of severe adverse interaction.|
02810|005|B||
02810|006|A|MECHANISM OF ACTION:  Venetoclax is a substrate for the P-glycoprotein|
02810|007|A|(P-gp) system.  P-gp inhibitors may lead to increased levels of|
02810|008|A|venetoclax.(1)|
02810|009|B||
02810|010|E|CLINICAL EFFECTS:  Concurrent use of P-gp inhibitors may result in elevated|
02810|011|E|levels of venetoclax, increasing the risk for tumor lysis syndrome and other|
02810|012|E|toxicities.(1)|
02810|013|B||
02810|014|P|PREDISPOSING FACTORS:  Risk factors for tumor lysis syndrome include (1):|
02810|015|P|- the ramp-up phase of venetoclax therapy when tumor burden is highest|
02810|016|P|- initial magnitude of tumor burden|
02810|017|P|- renal impairment|
02810|018|P|   The risk of venetoclax toxicities may be increased in patients with|
02810|019|P|severe hepatic impairment.(1)|
02810|020|B||
02810|021|M|PATIENT MANAGEMENT:  Avoid P-gp inhibitors and consider alternative|
02810|022|M|treatments when possible.  If a P-gp inhibitor must be used, reduce|
02810|023|M|venetoclax dose by at least 50%.  Monitor more closely for signs of toxicity|
02810|024|M|such as tumor lysis syndrome, hematologic and non-hematologic toxicities.(1)|
02810|025|M|   If the P-gp inhibitor is discontinued, the manufacturer of venetoclax|
02810|026|M|recommends resuming the prior (i.e. pre-inhibitor) dose of venetoclax 2 to 3|
02810|027|M|days after discontinuation of the P-gp inhibitor.(1)|
02810|028|B||
02810|029|D|DISCUSSION:  In 11 healthy subjects, a single dose of rifampin (a P-gp|
02810|030|D|inhibitor) increased venetoclax maximum concentration (Cmax) and|
02810|031|D|area-under-curve (AUC) by 106% and 78%, respectively.(1)|
02810|032|D|   In 11 previously treated NHL subjects, ketoconazole (a strong CYP3A4|
02810|033|D|inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days|
02810|034|D|increased the Cmax and AUC of venetoclax 2.3-fold and 6.4-fold|
02810|035|D|respectively.(1)|
02810|036|D|   In 12 healthy subjects, coadministration of azithromycin (500 mg Day 1,|
02810|037|D|250 mg for Days 2-5) decreased venetoclax Cmax and AUC by 25% and 35%. No|
02810|038|D|dosage adjustment is needed when venetoclax is coadministered with|
02810|039|D|azithromycin.(1)|
02810|040|D|   P-gp inhibitors include:  amiodarone, asunaprevir, belumosudil,|
02810|041|D|capmatinib, carvedilol, cyclosporine, danicopan, daridorexant, diosmin,|
02810|042|D|flibanserin, fostamatinib, ginseng, imlunestrant, ivacaftor, neratinib,|
02810|043|D|osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine,|
02810|044|D|selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tezacaftor, tepotinib,|
02810|045|D|valbenazine, vemurafenib, vimseltinib, and voclosporin.(2)|
02810|046|B||
02810|047|R|REFERENCES:|
02810|048|B||
02810|049|R|1.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
02810|050|R|  2021.|1
02810|051|R|2.This information is based on an extract from the Certara Drug Interaction|6
02810|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02811|001|T|MONOGRAPH TITLE:  Sildenafil(PAH);Tadalafil(BPH,PAH)/Slt Strong 3A4|
02811|002|T|Inhibitors|
02811|003|B||
02811|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02811|005|L|of severe adverse interaction.|
02811|006|B||
02811|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02811|008|A|sildenafil(1) and tadalafil.(2)|
02811|009|B||
02811|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
02811|011|E|increased levels, clinical effects, and side effects of sildenafil(1) and|
02811|012|E|tadalafil.(2)|
02811|013|B||
02811|014|P|PREDISPOSING FACTORS:  None determined.|
02811|015|B||
02811|016|M|PATIENT MANAGEMENT:  The US manufacturer of sildenafil states that the|
02811|017|M|concurrent use of strong CYP3A4 inhibitors with sildenafil when used for the|
02811|018|M|treatment of pulmonary arterial hypertension (PAH) is not recommended.(5)|
02811|019|M|   The US manufacturer of tadalafil states that the concurrent use of strong|
02811|020|M|CYP3A4 inhibitors with tadalafil when used for the treatment of pulmonary|
02811|021|M|arterial hypertension (PAH) is not recommended.(6)|
02811|022|M|   The US manufacturer of itraconazole states that the concurrent use of|
02811|023|M|sildenafil or tadalafil is not recommended when sildenafil or tadalafil is|
02811|024|M|used for the treatment of PAH.(7)|
02811|025|M|   The US manufacturer of sildenafil recommends a starting dose of 25 mg of|
02811|026|M|sildenafil for erectile dysfunction in patients receiving concomitant|
02811|027|M|therapy with strong CYP3A4 inhibitors.(1)|
02811|028|M|   The US manufacturer of tadalafil states that the maximum recommended dose|
02811|029|M|of as needed tadalafil for erectile dysfunction in patients taking strong|
02811|030|M|inhibitors of CYP3A4 is 10 mg every 72 hours.(2)  The maximum recommended|
02811|031|M|dose of daily tadalafil for erectile dysfunction in patients taking strong|
02811|032|M|inhibitors of CYP3A4 is 2.5 mg.(3)|
02811|033|B||
02811|034|D|DISCUSSION:  Concurrent administration of a single 100 mg dose of sildenafil|
02811|035|D|with erythromycin (500 mg twice daily for five days) resulted in an increase|
02811|036|D|of sildenafil area-under-curve (AUC) by 182%.  Therefore, the manufacturer|
02811|037|D|of sildenafil recommends a starting dose of 25 mg of sildenafil in patients|
02811|038|D|receiving concomitant therapy with other strong CYP3A4 inhibitors such as|
02811|039|D|itraconazole or ketoconazole.(1)|
02811|040|D|   Concurrent administration of a single 20 mg dose of tadalafil with|
02811|041|D|ketoconazole (400 mg daily) increased tadalafil AUC and maximum|
02811|042|D|concentration (Cmax) by 312% and 22%, respectively.  Concurrent|
02811|043|D|administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg|
02811|044|D|daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(2)|
02811|045|D|   Strong CYP3A4 inhibitors include adagrasib, ceritinib, clarithromycin,|
02811|046|D|grapefruit, idelalisib, itraconazole, josamycin, ketoconazole,|
02811|047|D|levoketoconazole, lonafarnib, nefazodone, posaconazole, ribociclib,|
02811|048|D|telithromycin, and voriconazole.(1-4)|
02811|049|B||
02811|050|R|REFERENCES:|
02811|051|B||
02811|052|R|1.Viagra (sildenafil) US prescribing information. Pfizer Inc. December 14,|1
02811|053|R|  2017.|1
02811|054|R|2.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
02811|055|R|  February, 2018.|1
02811|056|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02811|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02811|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02811|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02811|060|R|  11/14/2017.|1
02811|061|R|4.This information is based on an extract from the Certara Drug Interaction|6
02811|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02811|063|R|5.Revatio (sildenafil citrate) US prescribing information. Viatris January,|1
02811|064|R|  2023.|1
02811|065|R|6.Adcirca (tadalafil) US prescribing information. Eli Lilly and Company|1
02811|066|R|  September, 2020.|1
02811|067|R|7.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02811|068|R|  Products, L.P. February, 2024.|1
02811|069|R|8.Entadfi (finasteride and tadalafil) US prescribing information. Veru Inc.|1
02811|070|R|  December, 2021.|1
02812|001|T|MONOGRAPH TITLE:  Clarithromycin; Erythromycin/Selected Strong CYP3A4|
02812|002|T|Inducers|
02812|003|B||
02812|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02812|005|L|take action as needed.|
02812|006|B||
02812|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolism of|
02812|008|A|clarithromycin and erythromycin through CYP3A4.|
02812|009|A|   In addition, clarithromycin and erythromycin may inhibit the metabolism|
02812|010|A|of phenytoin.|
02812|011|B||
02812|012|E|CLINICAL EFFECTS:  Concomitant treatment may reduce the levels and efficacy|
02812|013|E|of clarithromycin and erythromycin.|
02812|014|E|   If the patient is on phenytoin, the levels of and toxicity from phenytoin|
02812|015|E|may increase.|
02812|016|B||
02812|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02812|018|P|of the inducer for longer than 1-2 weeks.|
02812|019|B||
02812|020|M|PATIENT MANAGEMENT:  Monitor patients for reduced efficacy of clarithromycin|
02812|021|M|and erythromycin during concurrent therapy.|
02812|022|M|   Monitor phenytoin levels and for signs of phenytoin toxicity.|
02812|023|B||
02812|024|D|DISCUSSION:  In a study in 34 subjects, rifabutin (300 mg daily, an inducer|
02812|025|D|of CYP3A4) decreased clarithromycin area-under-curve (AUC) by 44%.  The AUC|
02812|026|D|of 14-hydroxyclarithromycin was 57% higher.(1)|
02812|027|D|   In a study in 21 patients, 109 blood samples were tested for phenytoin|
02812|028|D|plasma concentration.  Of the 109 samples tested, 22 samples were from|
02812|029|D|patients receiving concurrent phenytoin and clarithromycin (dose not stated)|
02812|030|D|and 87 samples were from patients receiving phenytoin without concurrent|
02812|031|D|clarithromycin.  The mean phenytoin dose in patients receiving concurrent|
02812|032|D|clarithromycin was 4.0+/-0.3mg/Kg compared to 5.5+/-0.2mg/Kg in patients not|
02812|033|D|receiving clarithromycin.  The resultant phenytoin concentration with|
02812|034|D|concurrent clarithromycin was 13.8+/-1.9mg/L compared to 7.6+/-0.6mg/L|
02812|035|D|without concurrent clarithromycin.  The concentration to dose ratio when|
02812|036|D|phenytoin was taken with clarithromycin was 3.9+/-0.8 compared to 1.6+/-0.2|
02812|037|D|when phenytoin was taken without clarithromycin.(2)|
02812|038|D|   Two separate cross-over studies in which single dose mean phenytoin|
02812|039|D|clearance was measured when given alone and during a seven day course of|
02812|040|D|therapy with erythromycin, concluded that single-dose phenytoin clearance is|
02812|041|D|unaffected by the concurrent administration of erythromycin.(3,4)  However,|
02812|042|D|in one of the above studies, occasional, large interindividual changes in|
02812|043|D|phenytoin clearance were reported when phenytoin was given with|
02812|044|D|erythromycin.(3)|
02812|045|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
02812|046|D|barbiturates, fosphenytoin, mitotane, phenobarbital, phenytoin, and St.|
02812|047|D|John's wort.(5)|
02812|048|B||
02812|049|R|REFERENCES:|
02812|050|B||
02812|051|R|1.Hafner R, Bethel J, Power M, Landry B, Banach M, Mole L, Standiford HC,|2
02812|052|R|  Follansbee S, Kumar P, Raasch R, Cohn D, Mushatt D, Drusano G. Tolerance|2
02812|053|R|  and pharmacokinetic interactions of rifabutin and clarithromycin in human|2
02812|054|R|  immunodeficiency virus-infected volunteers. Antimicrob Agents Chemother|2
02812|055|R|  1998 Mar;42(3):631-9.|2
02812|056|R|2.Burger DM, Meenhorst PL, Mulder JW, Kraaijeveld CL, Koks CH, Bult A,|2
02812|057|R|  Beijnen JH. Therapeutic drug monitoring of phenytoin in patients with the|2
02812|058|R|  acquired immunodeficiency syndrome. Ther Drug Monit 1994 Dec;16(6):616-20.|2
02812|059|R|3.Milne RW, Coulthard K, Nation RL, Penna AC, Roberts G, Sansom LN. Lack of|2
02812|060|R|  effect of erythromycin on the pharmacokinetics of single oral doses of|2
02812|061|R|  phenytoin. Br J Clin Pharmacol 1988 Sep;26(3):330-3.|2
02812|062|R|4.Bachmann K, Schwartz JI, Forney RB Jr, Jauregui L. Single dose phenytoin|2
02812|063|R|  clearance during erythromycin treatment. Res Commun Chem Pathol Pharmacol|2
02812|064|R|  1984 Nov;46(2):207-17.|2
02812|065|R|5.This information is based on an extract from the Certara Drug Interaction|6
02812|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02813|001|T|MONOGRAPH TITLE:  Patiromer/Ciprofloxacin|
02813|002|B||
02813|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02813|004|L|take action as needed.|
02813|005|B||
02813|006|A|MECHANISM OF ACTION:  Patiromer may bind to ciprofloxacin.(1)|
02813|007|B||
02813|008|E|CLINICAL EFFECTS:  Concurrent use may result in decreased gastrointestinal|
02813|009|E|absorption and loss of efficacy of ciprofloxacin.(1)|
02813|010|B||
02813|011|P|PREDISPOSING FACTORS:  None determined.|
02813|012|B||
02813|013|M|PATIENT MANAGEMENT:  The US manufacturer of patiromer recommends that you|
02813|014|M|administer patiromer at least 3 hours before or 3 hours after|
02813|015|M|ciprofloxacin.(1)|
02813|016|B||
02813|017|D|DISCUSSION:  A study in healthy volunteers showed that patiromer decreased|
02813|018|D|the systemic exposure of coadministered ciprofloxacin.  No interaction was|
02813|019|D|seen when these drugs were taken 3 hours apart.(1)|
02813|020|B||
02813|021|R|REFERENCE:|
02813|022|B||
02813|023|R|1.Veltassa (patiromer) US prescribing information. Relypasa, Inc. October,|1
02813|024|R|  2023.|1
02814|001|T|MONOGRAPH TITLE:  Probenecid/Pyrazinamide|
02814|002|B||
02814|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02814|004|L|take action as needed.|
02814|005|B||
02814|006|A|MECHANISM OF ACTION:  Pyrazinamide has been shown to inhibit urate|
02814|007|A|secretion.(1)|
02814|008|B||
02814|009|E|CLINICAL EFFECTS:  May observe hyperuricemia and gout resulting from reduced|
02814|010|E|probenecid response.|
02814|011|B||
02814|012|P|PREDISPOSING FACTORS:  None determined.|
02814|013|B||
02814|014|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent probenecid and|
02814|015|M|pyrazinamide for signs and symptoms of gout flares.|
02814|016|B||
02814|017|D|DISCUSSION:  In a study in 18 males, pyrazinamide inhibited urate secretion,|
02814|018|D|but had no effect on probenecid secretion.(1)|
02814|019|B||
02814|020|R|REFERENCE:|
02814|021|B||
02814|022|R|1.Meisel AD, Diamond HS. Inhibition of probenecid uricosuria by pyrazinamide|2
02814|023|R|  and para-aminohippurate. Am J Physiol 1977 Mar;232(3):F222-6.|2
02815|001|T|MONOGRAPH TITLE:  Patiromer/Thyroid Preparations|
02815|002|B||
02815|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02815|004|L|take action as needed.|
02815|005|B||
02815|006|A|MECHANISM OF ACTION:  Patiromer may bind to thyroid preparations.(1)|
02815|007|B||
02815|008|E|CLINICAL EFFECTS:  Concurrent use may result in decreased gastrointestinal|
02815|009|E|absorption and loss of efficacy of the thyroid preparation.(1)|
02815|010|B||
02815|011|P|PREDISPOSING FACTORS:  None determined.|
02815|012|B||
02815|013|M|PATIENT MANAGEMENT:  The US manufacturer of patiromer recommends that you|
02815|014|M|administer patiromer at least 3 hours before or 3 hours after|
02815|015|M|levothyroxine.(1)|
02815|016|B||
02815|017|D|DISCUSSION:  A study in healthy volunteers showed that patiromer decreased|
02815|018|D|the systemic exposure of coadministered levothyroxine.  No interaction was|
02815|019|D|seen when these drugs were taken 3 hours apart.(1)|
02815|020|B||
02815|021|R|REFERENCE:|
02815|022|B||
02815|023|R|1.Veltassa (patiromer) US prescribing information. Relypasa, Inc. October,|1
02815|024|R|  2023.|1
02816|001|T|MONOGRAPH TITLE:  Patiromer/Metformin|
02816|002|B||
02816|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02816|004|L|take action as needed.|
02816|005|B||
02816|006|A|MECHANISM OF ACTION:  Patiromer may bind to metformin.(1)|
02816|007|B||
02816|008|E|CLINICAL EFFECTS:  Concurrent use may result in decreased gastrointestinal|
02816|009|E|absorption and loss of efficacy of metformin.(1)|
02816|010|B||
02816|011|P|PREDISPOSING FACTORS:  None determined.|
02816|012|B||
02816|013|M|PATIENT MANAGEMENT:  The US manufacturer of patiromer recommends that you|
02816|014|M|administer patiromer at least 3 hours before or 3 hours after metformin.(1)|
02816|015|B||
02816|016|D|DISCUSSION:  A study in healthy volunteers showed that patiromer decreased|
02816|017|D|the systemic exposure of coadministered metformin.  No interaction was seen|
02816|018|D|when these drugs were taken 3 hours apart.(1)|
02816|019|B||
02816|020|R|REFERENCE:|
02816|021|B||
02816|022|R|1.Veltassa (patiromer) US prescribing information. Relypasa, Inc. October,|1
02816|023|R|  2023.|1
02817|001|T|MONOGRAPH TITLE:  Aldosterone Receptor Antagonists/NSAIDs; Salicylates|
02817|002|B||
02817|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02817|004|L|take action as needed.|
02817|005|B||
02817|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown; however, nonsteroidal|
02817|007|A|anti-inflammatory (NSAID) inhibition of prostaglandins may allow eplerenone,|
02817|008|A|finerenone, or spironolactone-induced nephrotoxicity or hyperkalemia to|
02817|009|A|occur in some patients.(1-3)|
02817|010|A|   In some patients, NSAIDs may reduce the diuretic, natriuretic and|
02817|011|A|antihypertensive effects of eplerenone, finerenone, or spironolactone.(1-3)|
02817|012|B||
02817|013|E|CLINICAL EFFECTS:  Concurrent use of eplerenone, finerenone, or|
02817|014|E|spironolactone with NSAIDs may result in renal failure or hyperkalemia.  The|
02817|015|E|effects of the diuretic, natriuretic, or antihypertensive effects of|
02817|016|E|eplerenone, finerenone, or spironolactone may be decreased.(1-3)|
02817|017|B||
02817|018|P|PREDISPOSING FACTORS:  None determined.|
02817|019|B||
02817|020|M|PATIENT MANAGEMENT:  When possible, avoid concurrent therapy with|
02817|021|M|eplerenone, finerenone, or spironolactone with NSAIDs.  If these agents are|
02817|022|M|used concurrently, monitor renal function and serum electrolytes.  If|
02817|023|M|decreased renal function or hyperkalemia develops, discontinue both agents.|
02817|024|M|   The manufacturer of eplerenone recommends checking serum potassium and|
02817|025|M|serum creatinine within 3-7 days of concurrent therapy with NSAIDs.(1)|
02817|026|M|   The manufacturer of spironolactone states concurrent use with NSAIDs may|
02817|027|M|lead to severe hyperkalemia and extreme caution should be used during|
02817|028|M|concurrent therapy.(2)|
02817|029|B||
02817|030|D|DISCUSSION:  Although acute renal failure and hyperkalemia have only been|
02817|031|D|reported in studies and case reports involving indomethacin, diclofenac,|
02817|032|D|flurbiprofen, and ibuprofen with either triamterene or amiloride, the|
02817|033|D|proposed mechanism suggests that all nonsteroidal anti-inflammatory agents|
02817|034|D|may be capable of this interaction with all potassium-sparing diuretics.|
02817|035|D|Patients receiving diuretics are at an increased risk of NSAID-induced renal|
02817|036|D|failure.|
02817|037|B||
02817|038|R|REFERENCES:|
02817|039|B||
02817|040|R|1.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
02817|041|R|2.Aldactone (spironolactone) US prescribing information. Pfizer November,|1
02817|042|R|  2025.|1
02817|043|R|3.KERENDIA (finerenone) US prescribing information. Bayer HealthCare|1
02817|044|R|  Pharmaceuticals Inc. July, 2025.|1
02818|001|T|MONOGRAPH TITLE:  Etelcalcetide/Cinacalcet; Evocalcet|
02818|002|B||
02818|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02818|004|L|of severe adverse interaction.|
02818|005|B||
02818|006|A|MECHANISM OF ACTION:  Etelcalcetide is a calcimimetic agent that binds to|
02818|007|A|the extracellular domain of the calcium-sensing receptor (CaSR) and enhances|
02818|008|A|activation of the receptor by extracellular calcium.(1)|
02818|009|A|   Cinacalcet and evocalcet also increase the sensitivity of the CaSR to|
02818|010|A|extracellular calcium but bind to the CaSR but at the transmembrane region|
02818|011|A|of the receptor.(2-4)|
02818|012|A|   Activation of the CaSR decreases parathyroid hormone (PTH) secretion and|
02818|013|A|subsequently decreases calcium levels.  Additive decreases in PTH with|
02818|014|A|subsequent additive decreases in calcium levels may occur with concurrent|
02818|015|A|use.|
02818|016|B||
02818|017|E|CLINICAL EFFECTS:  Concurrent administration of etelcalcetide with another|
02818|018|E|oral calcium-sensing receptor agonist may result in severe,|
02818|019|E|life-threatening, hypocalcemia.  Hypocalcemia can cause paresthesias,|
02818|020|E|myalgias, muscle spasms, seizures, QT prolongation, and ventricular|
02818|021|E|arrhythmias.(1)|
02818|022|B||
02818|023|P|PREDISPOSING FACTORS:  None determined.|
02818|024|B||
02818|025|M|PATIENT MANAGEMENT:  The manufacturer of etelcalcetide recommends|
02818|026|M|discontinuation of cinacalcet at least 7 days prior to starting|
02818|027|M|etelcalcetide.  When transitioning from cinacalcet to etelcalcetide,|
02818|028|M|initiate etelcalcetide at a starting dose of 5 mg.(1)|
02818|029|M|   The US manufacturer of cinacalcet recommends discontinuation of|
02818|030|M|etelcalcetide for at least 4 weeks prior to initiating cinacalcet.  Initiate|
02818|031|M|cinacalcet at a starting dose of 30 mg daily.(2)  The UK manufacturer of|
02818|032|M|cinacalcet states that an appropriate washout period of etelcalcetide has|
02818|033|M|not been studied and recommends completion of at least three subsequent|
02818|034|M|hemodialysis sessions and ensuring normal serum calcium before initiating|
02818|035|M|cinacalcet.(3)|
02818|036|M|   The manufacturer of evocalcet does not provide recommendations for|
02818|037|M|concurrent use with etelcalcetide but similar additive effects are expected|
02818|038|M|based on a similar mechanism as cinacalcet.(4)  Consider similar washout|
02818|039|M|periods when transitioning from etelcalcetide to evocalcet.|
02818|040|M|   Before initiating these calcimimetics, ensure corrected serum calcium is|
02818|041|M|at or above the lower limit of normal.  Closely monitor corrected serum|
02818|042|M|calcium and concurrent therapies known to lower serum calcium.  Serum|
02818|043|M|calcium monitoring is recommended within 1 week after initiation of|
02818|044|M|etelcalcetide and every 4 weeks during treatment.(1)|
02818|045|B||
02818|046|D|DISCUSSION:  Concurrent administration of etelcalcetide with other oral|
02818|047|D|calcium-sensing receptor agonists may result in severe, life-threatening,|
02818|048|D|hypocalcemia.|
02818|049|D|   Pooled data from two placebo-controlled clinical studies in patients with|
02818|050|D|chronic kidney disease and secondary hyperparathyroidism on hemodialysis|
02818|051|D|were reviewed with a mean duration of 23.6 weeks.  More patients on|
02818|052|D|etelcalcetide versus placebo developed at least one corrected serum calcium|
02818|053|D|level less than 7 mg/dL (7.6% v. 3.1%, respectively), less than 7.5 mg/dL|
02818|054|D|(27% v. 5.5%, respectively), and less than 8.3 mg/dL (79% v. 19%,|
02818|055|D|respectively).  Symptomatic reductions in serum calcium less than 8.3 mg/dL|
02818|056|D|occurred in 7% of patients receiving etelcalcetide versus 0.2% of patients|
02818|057|D|receiving placebo.(1)|
02818|058|B||
02818|059|R|REFERENCES:|
02818|060|B||
02818|061|R|1.Parsabiv (etelcalcetide) US prescribing information. Amgen Inc. March,|1
02818|062|R|  2019.|1
02818|063|R|2.Sensipar (cinacalcet hydrochloride) US prescribing information. Amgen Inc.|1
02818|064|R|  March, 2019.|1
02818|065|R|3.Mimpara (cinacalcet) UK Summary of Product Characteristics. Amgen Ltd.|1
02818|066|R|  July 8, 2019.|1
02818|067|R|4.Orkedia (evocalcet)  Japanese package insert. Kyowa Kirin Co., Ltd.|1
02818|068|R|  February 2025.|1
02819|001|T|MONOGRAPH TITLE:  Lovastatin (Less Than or Equal To 40 mg); Simvastatin|
02819|002|T|(Less Than or Equal To 40 mg)/Ticagrelor|
02819|003|B||
02819|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02819|005|L|take action as needed.|
02819|006|B||
02819|007|A|MECHANISM OF ACTION:  Ticagrelor may inhibit the metabolism of lovastatin|
02819|008|A|and simvastatin by CYP3A4.(1,2)|
02819|009|B||
02819|010|E|CLINICAL EFFECTS:  Concurrent use of ticagrelor may result in elevated|
02819|011|E|levels of and toxicity from lovastatin and simvastatin, including|
02819|012|E|rhabdomyolysis.(1,2)|
02819|013|B||
02819|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02819|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02819|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02819|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02819|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02819|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02819|020|P|predisposed to myopathy or rhabdomyolysis.|
02819|021|B||
02819|022|M|PATIENT MANAGEMENT:  Avoid the use of doses of lovastatin and simvastatin|
02819|023|M|greater than 40 mg in patients receiving ticagrelor.(1,2)  Monitor patients|
02819|024|M|receiving concurrent therapy for signs and symptoms of myopathy.|
02819|025|B||
02819|026|D|DISCUSSION:  Concurrent ticagrelor increased the maximum concentration|
02819|027|D|(Cmax) and area-under-curve (AUC) of simvastatin by 81% and 56%,|
02819|028|D|respectively.  The Cmax and AUC of simvastatin acid increased 64% and 52%,|
02819|029|D|respectively, with some individual increases equal to 2-fold to 3-fold.(1)|
02819|030|B||
02819|031|R|REFERENCES:|
02819|032|B||
02819|033|R|1.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
02819|034|R|  UK Limited October 24, 2012.|1
02819|035|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP November,|1
02819|036|R|  2024.|1
02820|001|T|MONOGRAPH TITLE:  Selected Oral BCRP Substrates/Oral Tedizolid|
02820|002|B||
02820|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02820|004|L|of severe adverse interaction.|
02820|005|B||
02820|006|A|MECHANISM OF ACTION:  Oral tedizolid may may inhibit Breast Cancer|
02820|007|A|Resistance Protein (BCRP) in the intestine, which may result in increased|
02820|008|A|absorption of orally administered BCRP substrates.(1-3)|
02820|009|B||
02820|010|E|CLINICAL EFFECTS:  Concurrent use of oral tedizolid may result in elevated|
02820|011|E|levels of and toxicity from orally administered BCRP substrates.(1-3)|
02820|012|B||
02820|013|P|PREDISPOSING FACTORS:  None determined.|
02820|014|B||
02820|015|M|PATIENT MANAGEMENT:  If possible, consider interrupting therapy with orally|
02820|016|M|administered BCRP substrates during therapy with oral tedizolid.  If|
02820|017|M|concurrent therapy is warranted, monitor patients for toxicity.(1-3)|
02820|018|B||
02820|019|D|DISCUSSION:  Orally administered tedizolid (200 mg) increased the|
02820|020|D|area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin (10|
02820|021|D|mg) by 70% and 55%, respectively.(1-3)|
02820|022|D|   BCRP substrates include:  imatinib, lapatinib, methotrexate,|
02820|023|D|rosuvastatin, sulfasalazine, and topotecan.(1-3)|
02820|024|B||
02820|025|R|REFERENCES:|
02820|026|B||
02820|027|R|1.Sivextro (tedizolid) US prescribing information. Merck & Co., Inc.|1
02820|028|R|  November, 2021.|1
02820|029|R|2.Sivextro (tedizolid) Canadian product monograph. Merck Canada Inc.|1
02820|030|R|  September 28, 2015.|1
02820|031|R|3.Sivextro (tedizolid) UK summary of product characteristics. Merck Sharp &|1
02820|032|R|  Dohme Limited Nocember 11, 2016.|1
02821|001|T|MONOGRAPH TITLE:  Cobicistat-Elvitegravir/Selected CYP3A4 Inducers|
02821|002|B||
02821|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02821|004|L|is contraindicated and generally should not be dispensed or administered to|
02821|005|L|the same patient.|
02821|006|B||
02821|007|A|MECHANISM OF ACTION:  Barbiturates, carbamazepine, fosphenytoin,|
02821|008|A|phenobarbital, phenytoin and primidone may induce the metabolism of|
02821|009|A|cobicistat and elvitegravir.(1)|
02821|010|B||
02821|011|E|CLINICAL EFFECTS:  Concurrent use of cobicistat-elvitegravir with|
02821|012|E|barbiturates, carbamazepine, fosphenytoin, phenobarbital, phenytoin or|
02821|013|E|primidone may result in decreased levels of elvitegravir and development of|
02821|014|E|resistance.(1)|
02821|015|B||
02821|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02821|017|P|of the inducer for longer than 1-2 weeks.|
02821|018|B||
02821|019|M|PATIENT MANAGEMENT:  Concurrent use of combination product containing|
02821|020|M|cobicistat-elvitegravir-emtricitabine-tenofovir and barbiturates,|
02821|021|M|carbamazepine, fosphenytoin, phenobarbital, phenytoin or primidone is|
02821|022|M|contraindicated.(1)|
02821|023|B||
02821|024|D|DISCUSSION:  Concurrent cobicistat-elvitegravir (150 mg each daily)|
02821|025|D|increased the maximum concentration (Cmax) of rifabutin (150 mg every other|
02821|026|D|day) by 1.09-fold.  The area-under-curve (AUC) and minimum concentration|
02821|027|D|(Cmin) of rifabutin decreased by 8% and 6%, respectively, when compared to|
02821|028|D|the administration of 300 mg daily of rifabutin.  The Cmax, AUC, and Cmin of|
02821|029|D|25-O-desacetyl-rifabutin increased by 4.84-fold, 6.25-fold, and 4.94-fold,|
02821|030|D|respectively, when compared to the administration of 300 mg daily of|
02821|031|D|rifabutin.  The Cmax, AUC, and Cmin of elvitegravir decreased by 9%, 21%,|
02821|032|D|and 67%, respectively.(1)|
02821|033|D|   Concurrent cobicistat-elvitegravir (150 mg each daily) with carbamazepine|
02821|034|D|(200 mg twice daily) decreased the Cmax, AUC, and Cmin of elvitegravir by|
02821|035|D|45%, 69%, and 97%, respectively. Concurrent cobicistat-elvitegravir (150 mg|
02821|036|D|each daily) with carbamazepine (200 mg twice daily) increased the Cmax, AUC,|
02821|037|D|and Cmin of carbamazepine by 40%, 43%, and 51%, respectively. The Cmax, AUC,|
02821|038|D|and Cmin was decreased for carbamazepine-10,11-epoxide by 29%, 35%, and 41%,|
02821|039|D|respectively. (2)|
02821|040|B||
02821|041|R|REFERENCES:|
02821|042|B||
02821|043|R|1.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02821|044|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02821|045|R|2.Vitekta (elvitegravir) US prescribing information. Gilead Sciences Inc.|1
02821|046|R|  July, 2015.|1
02822|001|T|MONOGRAPH TITLE:  Deflazacort/Strong and Moderate CYP3A4 Inhibitors|
02822|002|B||
02822|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02822|004|L|of severe adverse interaction.|
02822|005|B||
02822|006|A|MECHANISM OF ACTION:  Deflazacort is a prodrug and is rapidly metabolized to|
02822|007|A|the active metabolite, 21-desDFZ, by esterases.  The metabolite 21-desDFZ is|
02822|008|A|metabolized by CYP3A4 to inactive metabolites.(1)|
02822|009|A|   Inhibitors of CYP3A4 may inhibit the metabolism of the active metabolite|
02822|010|A|of deflazacort metabolized by CYP3A4.(1)|
02822|011|B||
02822|012|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inhibitors|
02822|013|E|may result in increased systemic exposure to and effects from|
02822|014|E|deflazacort.(1)|
02822|015|B||
02822|016|P|PREDISPOSING FACTORS:  None determined.|
02822|017|B||
02822|018|M|PATIENT MANAGEMENT:  The manufacturer recommends decreasing the dose to|
02822|019|M|one-third of the recommended dose of deflazacort when used concurrently with|
02822|020|M|strong or moderate CYP3A4 inhibitors.  For example, if the recommended dose|
02822|021|M|of deflazacort is 36 mg per day, the reduced dose would be 12 mg per day|
02822|022|M|when administered with strong or moderate CYP3A4 inhibitors.(1)|
02822|023|B||
02822|024|D|DISCUSSION:  Deflazacort is a prodrug and is rapidly metabolized to the|
02822|025|D|active metabolite, 21-desDFZ.  The metabolite 21-desDFZ is metabolized by|
02822|026|D|CYP3A4.(1)|
02822|027|D|   Coadministration of deflazacort with clarithromycin, a strong CYP3A4|
02822|028|D|inhibitor, increased total geometric mean exposure (maximum concentration|
02822|029|D|(Cmax) and area-under-curve (AUC)) to the active metabolite 21-desDFZ by|
02822|030|D|2.3- to 3.4-fold.(1)|
02822|031|B||
02822|032|R|REFERENCES:|
02822|033|B||
02822|034|R|1.Emflaza (deflazacort) US prescribing information. Marathon|1
02822|035|R|  Pharmaceuticals, LLC July, 2020.|1
02822|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
02822|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02823|001|T|MONOGRAPH TITLE:  Telotristat/Octreotide (Short-Acting)|
02823|002|B||
02823|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02823|004|L|take action as needed.|
02823|005|B||
02823|006|A|MECHANISM OF ACTION:  Short-acting octreotide may decrease the absorption of|
02823|007|A|telotristat.(1)|
02823|008|B||
02823|009|E|CLINICAL EFFECTS:  Concurrent administration of short-acting octreotide|
02823|010|E|significantly decreases systemic exposure of telotristat.(1)|
02823|011|B||
02823|012|P|PREDISPOSING FACTORS:  None determined.|
02823|013|B||
02823|014|M|PATIENT MANAGEMENT:  When used in combination, administer short-acting|
02823|015|M|octreotide at least 30 minutes after telotristat.(1)|
02823|016|B||
02823|017|D|DISCUSSION:  Concurrent administration of short-acting octreotide (200 mcg),|
02823|018|D|decreased the maximum concentration (Cmax) of telotristat ethyl and|
02823|019|D|telotristat by 86% and 79%, respectively.  The area-under-curve (AUC) of|
02823|020|D|telotristat ethyl and telotristat were decreased by 81% and 68%,|
02823|021|D|respectively.(1)|
02823|022|B||
02823|023|R|REFERENCE:|
02823|024|B||
02823|025|R|1.Xermelo (telotristat ethyl) US prescribing information. Lexicon|1
02823|026|R|  Pharmaceuticals, Inc. October, 2020.|1
02824|001|T|MONOGRAPH TITLE:  Venetoclax/Moderate CYP3A4 Inducers|
02824|002|B||
02824|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02824|004|L|of severe adverse interaction.|
02824|005|B||
02824|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
02824|007|A|of venetoclax.(1)|
02824|008|B||
02824|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
02824|010|E|in decreased levels and effectiveness of venetoclax.(1)|
02824|011|B||
02824|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02824|013|P|of the inducer for longer than 1-2 weeks.|
02824|014|B||
02824|015|M|PATIENT MANAGEMENT:  The US manufacturer of venetoclax states that the|
02824|016|M|concurrent use of CYP3A4 inducers should be avoided, and that alternative|
02824|017|M|treatments with less CYP3A4 induction should be considered.(1)|
02824|018|B||
02824|019|D|DISCUSSION:  In a study with 10 healthy subjects, co-administration of|
02824|020|D|rifampin (600 mg daily for 13 days), decreased venetoclax area-under-curve|
02824|021|D|(AUC) by 71% and maximum concentration (Cmax) by 42%.(1)|
02824|022|D|   Moderate inducers of CYP3A4 include:  belzutifan, bosentan, cenobamate,|
02824|023|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
02824|024|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
02824|025|D|pexidartinib, repotrectinib, rifabutin, telotristat, thioridazine,|
02824|026|D|tipranavir/ritonavir, and tovorafenib.(2-3)|
02824|027|B||
02824|028|R|REFERENCES:|
02824|029|B||
02824|030|R|1.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
02824|031|R|  2021.|1
02824|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02824|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02824|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02824|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02824|036|R|  11/14/2017.|1
02824|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
02824|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02825|001|T|MONOGRAPH TITLE:  Selected P-glycoprotein (P-gp) Substrates/Venetoclax|
02825|002|B||
02825|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02825|004|L|of severe adverse interaction.|
02825|005|B||
02825|006|A|MECHANISM OF ACTION:  Venetoclax is an inhibitor of the P-glycoprotein|
02825|007|A|(P-gp) system and may increase the absorption of P-gp substrates.(1)|
02825|008|B||
02825|009|E|CLINICAL EFFECTS:  Concurrent use of venetoclax with P-gp substrates may|
02825|010|E|result in elevated levels and toxicities of the substrate.(1)|
02825|011|B||
02825|012|P|PREDISPOSING FACTORS:  None determined.|
02825|013|B||
02825|014|M|PATIENT MANAGEMENT:  The US manufacturer of venetoclax states that the|
02825|015|M|concurrent use of P-gp substrates should be avoided.  If concurrent therapy|
02825|016|M|cannot be avoided, the P-gp substrate should be taken at least 6 hours|
02825|017|M|before venetoclax.(1)|
02825|018|M|   If concurrent therapy with afatinib is unavoidable and not tolerated, the|
02825|019|M|US manufacturer of afatinib states that the afatinib dose should be reduced|
02825|020|M|by 10 mg.  Resume the previous dose of afatinib if venetoclax is|
02825|021|M|discontinued.(2)|
02825|022|M|   The manufacturer of ubrogepant recommends a dosage adjustment of|
02825|023|M|ubrogepant when coadministered with P-gp inhibitors.  The initial dose of|
02825|024|M|ubrogepant should not exceed 50 mg.  If a second dose of ubrogepant is|
02825|025|M|needed, the dose should not exceed 50 mg.(8)|
02825|026|B||
02825|027|D|DISCUSSION:  In vitro data suggests venetoclax is a P-gp inhibitor at|
02825|028|D|therapeutic doses in the gut.(1)|
02825|029|D|   Administration of a single venetoclax 100 mg dose with digoxin increased|
02825|030|D|the maximum concentration (Cmax) and area-under-the-curve of digoxin by 35%|
02825|031|D|and 9%, respectively.(1)|
02825|032|D|   Selected P-gp substrates linked to this monograph include: afatinib,|
02825|033|D|aliskiren,  betrixaban, bilastine, cyclosporine, dabigatran, digoxin,|
02825|034|D|doxorubicin, edoxaban, etoposide, everolimus, loperamide, sirolimus,|
02825|035|D|talazoparib, topotecan, and ubrogepant.(1-9)|
02825|036|B||
02825|037|R|REFERENCES:|
02825|038|B||
02825|039|R|1.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
02825|040|R|  2021.|1
02825|041|R|2.Gilotrif (afatinib) prescribing information. Boehringer Ingelheim|1
02825|042|R|  Pharmaceuticals, Inc. October, 2019.|1
02825|043|R|3.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
02825|044|R|  Corporation November, 2017.|1
02825|045|R|4.Adriamycin (doxorubicin) US prescribing information. Hikma Pharmaceuticals|1
02825|046|R|  USA Inc. December, 2019.|1
02825|047|R|5.Etopophos (etoposide) US prescribing information. H2-Pharma, LLC November,|1
02825|048|R|  2022.|1
02825|049|R|6.Talzenna (talazoparib) US prescribing information. Pfizer Labs June, 2023.|1
02825|050|R|7.Hycamtin Oral (topotecan) US prescribing information. GlaxoSmithKline|1
02825|051|R|  September, 2018.|1
02825|052|R|8.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
02825|053|R|9.This information is based on an extract from the Certara Drug Interaction|6
02825|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02826|001|T|MONOGRAPH TITLE:  Ribociclib/Strong CYP3A4 Inhibitors|
02826|002|B||
02826|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02826|004|L|of severe adverse interaction.|
02826|005|B||
02826|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
02826|007|A|metabolism of ribociclib.(1)|
02826|008|B||
02826|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
02826|010|E|systemic exposure and the risk for ribociclib toxicities such as neutropenia|
02826|011|E|or QT prolongation.(1)|
02826|012|B||
02826|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02826|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02826|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02826|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02826|017|P|gender, or advanced age.(2)|
02826|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02826|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02826|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02826|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02826|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02826|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02826|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02826|025|B||
02826|026|M|PATIENT MANAGEMENT:  Avoid concomitant use of ribociclib and strong CYP3A|
02826|027|M|inhibitors. Consider an alternative concomitant medication with less|
02826|028|M|potential for CYP3A4 inhibition.|
02826|029|M|   The US manufacturer states the following dose modifications are needed if|
02826|030|M|use of a strong CYP3A4 inhibitor cannot be avoided:|
02826|031|M|   -For patients with early breast cancer, decrease ribociclib to 200 mg|
02826|032|M|once daily.|
02826|033|M|   -For patients with advanced or metastatic breast cancer, decrease|
02826|034|M|ribociclib to 400 mg once daily.|
02826|035|M|   -If the strong CYP3A4 inhibitor is discontinued, change the ribociclib|
02826|036|M|dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the|
02826|037|M|dose used prior to the initiation of the strong CYP3A4 inhibitor.(1)|
02826|038|M|   The Swedish manufacturer states that if patients must be given a strong|
02826|039|M|CYP3A4 inhibitor concurrently with ribociclib, the ribociclib dose should be|
02826|040|M|reduced to 400 mg once daily. In patients who have had their ribociclib dose|
02826|041|M|reduced to 400 mg daily and in whom coadministration of a strong CYP3A4|
02826|042|M|inhibitor cannot be avoided, the ribociclib dose should be further reduced|
02826|043|M|to 200 mg. In patients who have had their ribociclib dose reduced to 200 mg|
02826|044|M|daily and in whom coadministration of a strong CYP3A4 inhibitor cannot be|
02826|045|M|avoided, ribociclib treatment should be interrupted.(4)|
02826|046|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
02826|047|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
02826|048|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
02826|049|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
02826|050|M|irregular heartbeat, dizziness, or fainting.|
02826|051|B||
02826|052|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
02826|053|D|coadministration of ritonavir (100 mg twice a day for 14 days) with a single|
02826|054|D|dose of ribociclib (400 mg) increased ribociclib maximum concentration|
02826|055|D|(Cmax) and area-under-the-curve (AUC) by 1.7 and 3.2-fold, respectively.|
02826|056|D|Cmax and AUC for LEQ803 (ribociclib metabolite) decreased by 96% and 98%,|
02826|057|D|respectively.(1)|
02826|058|D|   Data from a pharmacokinetic simulation suggests that erythromycin, a|
02826|059|D|moderate CYP3A4 inhibitor, may increase ribociclib (600 mg)Cmax and AUC by|
02826|060|D|1.2-fold and 1.3-fold. The increase of ribociclib's Cmax and AUC was|
02826|061|D|estimated to be 1.4-fold and 2.1-fold in patients on ribociclib 400 mg. The|
02826|062|D|increase of ribociclib's Cmax and AUC was estimated to be 1.7-fold and|
02826|063|D|2.8-fold in patients on ribociclib 200 mg.(4)|
02826|064|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
02826|065|D|cobicistat, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
02826|066|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
02826|067|D|tipranavir, troleandomycin, and tucatinib.(3)|
02826|068|B||
02826|069|R|REFERENCES:|
02826|070|B||
02826|071|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02826|072|R|  Corporation September, 2024.|1
02826|073|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02826|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02826|075|R|  settings: a scientific statement from the American Heart Association and|6
02826|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02826|077|R|  2;55(9):934-47.|6
02826|078|R|3.This information is based on an extract from the Certara Drug Interaction|6
02826|079|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02826|080|R|4.Kisqali (ribociclib) Sweden prescribing information. Novartis Pharma|1
02826|081|R|  August 2017.|1
02827|001|T|MONOGRAPH TITLE:  Ribociclib/Strong CYP3A4 Inducers|
02827|002|B||
02827|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02827|004|L|of severe adverse interaction.|
02827|005|B||
02827|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02827|007|A|ribociclib.(1)|
02827|008|B||
02827|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02827|010|E|in decreased levels and effectiveness of ribociclib.(1)|
02827|011|B||
02827|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02827|013|P|of the inducer for longer than 1-2 weeks.|
02827|014|B||
02827|015|M|PATIENT MANAGEMENT:  The US manufacturer of ribociclib states that the|
02827|016|M|concurrent use of CYP3A4 inducers should be avoided, and that alternative|
02827|017|M|treatments with less CYP3A4 induction should be considered.(1)|
02827|018|B||
02827|019|D|DISCUSSION:  In a study with healthy subjects, co-administration of|
02827|020|D|rifampin(600 mg daily for 14 days), decreased ribociclib area-under-curve|
02827|021|D|(AUC) by 89% and maximum concentration (Cmax) by 81%.(1)|
02827|022|D|   A pharmacokinetic simulation suggests that a moderate CYP3A4 inducer,|
02827|023|D|efavirenz, may decrease ribociclib's Cmax and AUC by 51% and 70%.(4)|
02827|024|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
02827|025|D|enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone,|
02827|026|D|rifampin, rifapentine, and St. John's wort.(2-4)|
02827|027|B||
02827|028|R|REFERENCES:|
02827|029|B||
02827|030|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02827|031|R|  Corporation September, 2024.|1
02827|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02827|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02827|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02827|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02827|036|R|  11/14/2017.|1
02827|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
02827|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02827|039|R|4.Kisqali (ribociclib) Sweden prescribing information. Novartis Pharma|1
02827|040|R|  August 2017.|1
02828|001|T|MONOGRAPH TITLE:  Ribociclib/QT Prolonging Agents|
02828|002|B||
02828|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02828|004|L|of severe adverse interaction.|
02828|005|B||
02828|006|A|MECHANISM OF ACTION:  Concurrent use of ribociclib with agents that prolong|
02828|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
02828|008|B||
02828|009|E|CLINICAL EFFECTS:  The concurrent use of ribociclib with agents that prolong|
02828|010|E|the QTc interval may result in potentially life-threatening cardiac|
02828|011|E|arrhythmias, including torsades de pointes.(1)|
02828|012|B||
02828|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02828|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02828|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02828|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02828|017|P|female gender, or advanced age.(2)|
02828|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02828|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02828|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02828|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02828|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02828|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02828|024|P|dysfunction).(2)|
02828|025|B||
02828|026|M|PATIENT MANAGEMENT:  Avoid concurrent use of ribociclib with agents known to|
02828|027|M|prolong the QT interval.(1)|
02828|028|M|   If concurrent therapy is deemed medically necessary, monitor patients|
02828|029|M|closely.  Obtain serum calcium, magnesium, and potassium levels and correct|
02828|030|M|any electrolyte abnormalities at the beginning of each ribociclib cycle.|
02828|031|M|Monitor ECG at baseline, Day 14 of the first cycle, at the beginning of the|
02828|032|M|second cycle, and as necessary.  If a prolonged QTc is noted, refer to|
02828|033|M|ribociclib prescribing information for current dose modification and|
02828|034|M|management instructions.  Ribociclib may need to be interrupted, reduced, or|
02828|035|M|discontinued.(1)|
02828|036|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02828|037|M|fainting.|
02828|038|B||
02828|039|D|DISCUSSION:  Ribociclib has been shown to prolong the QTc interval in a|
02828|040|D|concentration-dependent manner.  At steady state, the mean increase in QTc|
02828|041|D|interval exceeded 20 msec.(1)|
02828|042|D|   Agents that are linked to this monograph may have varying degrees of|
02828|043|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02828|044|D|been shown to prolong the QTc interval either through their mechanism of|
02828|045|D|action, through studies on their effects on the QTc interval, or through|
02828|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02828|047|D|and/or postmarketing reports.(3)|
02828|048|B||
02828|049|R|REFERENCES:|
02828|050|B||
02828|051|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02828|052|R|  Corporation September, 2024.|1
02828|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02828|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02828|055|R|  settings: a scientific statement from the American Heart Association and|6
02828|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02828|057|R|  2;55(9):934-47.|6
02828|058|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02828|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02828|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02828|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02829|001|T|MONOGRAPH TITLE:  Ribociclib/Possible QT Prolonging Agents|
02829|002|B||
02829|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02829|004|L|take action as needed.|
02829|005|B||
02829|006|A|MECHANISM OF ACTION:  Concurrent use of ribociclib with agents that prolong|
02829|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
02829|008|B||
02829|009|E|CLINICAL EFFECTS:  The concurrent use of ribociclib with agents that prolong|
02829|010|E|the QTc interval may result in potentially life-threatening cardiac|
02829|011|E|arrhythmias, including torsades de pointes.(1)|
02829|012|B||
02829|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02829|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02829|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02829|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02829|017|P|female gender, or advanced age.(2)|
02829|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02829|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02829|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02829|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02829|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02829|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02829|024|P|dysfunction).(2)|
02829|025|B||
02829|026|M|PATIENT MANAGEMENT:  Avoid concurrent use of ribociclib with agents known to|
02829|027|M|prolong the QT interval.(1)|
02829|028|M|   If concurrent therapy is deemed medically necessary, monitor patients|
02829|029|M|closely.  Obtain serum calcium, magnesium, and potassium levels and correct|
02829|030|M|any electrolyte abnormalities at the beginning of each ribociclib cycle.|
02829|031|M|Monitor ECG at baseline, Day 14 of the first cycle, at the beginning of the|
02829|032|M|second cycle, and as necessary.  If a prolonged QTc is noted, refer to|
02829|033|M|ribociclib prescribing information for current dose modification and|
02829|034|M|management instructions.  Ribociclib may need to be interrupted, reduced, or|
02829|035|M|discontinued.(1)|
02829|036|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02829|037|M|fainting.|
02829|038|B||
02829|039|D|DISCUSSION:  Ribociclib has been shown to prolong the QTc interval in a|
02829|040|D|concentration-dependent manner.  At steady state, the mean increase in QTc|
02829|041|D|interval exceeded 20 msec.(1)|
02829|042|D|   In MONALEESA-7, an increase of greater than 60 ms from baseline in the|
02829|043|D|QTcF interval was observed in 14/87 (16%) of patients in the ribociclib and|
02829|044|D|tamoxifen combination group.(1)|
02829|045|D|   Agents that are linked to this monograph may have varying degrees of|
02829|046|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02829|047|D|been shown to prolong the QTc interval either through their mechanism of|
02829|048|D|action, through studies on their effects on the QTc interval, or through|
02829|049|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02829|050|D|and/or postmarketing reports.(3)|
02829|051|B||
02829|052|R|REFERENCES:|
02829|053|B||
02829|054|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02829|055|R|  Corporation September, 2024.|1
02829|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02829|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02829|058|R|  settings: a scientific statement from the American Heart Association and|6
02829|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02829|060|R|  2;55(9):934-47.|6
02829|061|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02829|062|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02829|063|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02829|064|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02830|001|T|MONOGRAPH TITLE:  Edoxaban/Aspirin (Less Than or Equal To 100 mg)|
02830|002|B||
02830|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02830|004|L|take action as needed.|
02830|005|B||
02830|006|A|MECHANISM OF ACTION:  Edoxaban and aspirin have additive effects on|
02830|007|A|hemostasis.(1)  In addition, aspirin doses greater than or equal to 325 mg|
02830|008|A|daily increase edoxaban exposure.(1)|
02830|009|B||
02830|010|E|CLINICAL EFFECTS:  Concurrent use of edoxaban with aspirin may increase the|
02830|011|E|risk of bleeding compared to either agent alone.(1)|
02830|012|B||
02830|013|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with renal|
02830|014|P|impairment and in patients greater than 75 years of age.(1)  Use of multiple|
02830|015|P|agents which affect hemostasis increases the risk for bleeding.|
02830|016|P|   The risk for bleeding episodes may be greater in patients with|
02830|017|P|disease-associated factors (e.g. thrombocytopenia).|
02830|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
02830|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02830|020|P|risk for bleeding (e.g. NSAIDs).|
02830|021|B||
02830|022|M|PATIENT MANAGEMENT:  Patients requiring concurrent therapy with edoxaban and|
02830|023|M|aspirin should be closely monitored for signs of bleeding.  Edoxaban and|
02830|024|M|aspirin at dosages of 100 mg or less may be coadministered.(2,3)|
02830|025|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
02830|026|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
02830|027|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02830|028|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02830|029|M|to monitor efficacy and safety of anticoagulation.|
02830|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02830|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02830|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02830|033|M|and/or swelling.|
02830|034|M|   Discontinue edoxaban in patients with active bleeding.|
02830|035|B||
02830|036|D|DISCUSSION:  Concomitant use of edoxaban and antiplatelet agents may|
02830|037|D|increase the risk of bleeding.|
02830|038|D|   In edoxaban clinical trials concomitant use of low dose aspirin (less|
02830|039|D|than or equal to 100 mg daily), thienopyridines, and NSAIDs was permitted|
02830|040|D|and resulted in increased rates of clinically relevant bleeding. The rates|
02830|041|D|of major bleeding on edoxaban and warfarin were generally consistent among|
02830|042|D|subgroups. Bleeding rates appeared higher in both treatment arms (edoxaban|
02830|043|D|and warfarin) in patients taking aspirin.  Co-administration of aspirin (100|
02830|044|D|mg or 325 mg) and edoxaban increased bleeding time relative to that seen|
02830|045|D|with either drug alone.(1)|
02830|046|D|   About 30% of the population in ENGAGE-AF received concomitant therapy|
02830|047|D|with aspirin because of co-morbid conditions. While aspirin is known to|
02830|048|D|increase risk for bleeds and the annualized event rate for major bleeds was|
02830|049|D|higher than that in patients not receiving aspirin (3.87% vs. 2.13%), the|
02830|050|D|risk for bleeds in patients receiving edoxaban 60 mg on a background of|
02830|051|D|aspirin was lower than that for warfarin on a background of aspirin (HR 0.78|
02830|052|D|(95%CI 0.65,0.94). Based on these data no dose adjustments/contraindications|
02830|053|D|are required.(4)|
02830|054|D|   Edoxaban and aspirin at dosages of 100 mg or less may be|
02830|055|D|coadministered.(2,3)|
02830|056|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
02830|057|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
02830|058|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
02830|059|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
02830|060|D|aspirin, with the highest allowable dose being 165 mg/day.  The use of DOACs|
02830|061|D|with antiplatelet agents was associated with an increased risk of major|
02830|062|D|bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major|
02830|063|D|bleeding (OR 1.82; 95% CI, 1.50-2.22).  There was no difference between|
02830|064|D|groups in the efficacy outcome of symptomatic recurrent venous|
02830|065|D|thromboembolism (VTE) or VTE-related death.(5)|
02830|066|B||
02830|067|R|REFERENCES:|
02830|068|B||
02830|069|R|1.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
02830|070|R|  2019.|1
02830|071|R|2.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
02830|072|R|  Sankyo UK Limited July 2, 2015.|1
02830|073|R|3.Lixiana (edoxaban) Canadian product monograph. Servier Canada Inc.|1
02830|074|R|  February, 2023.|1
02830|075|R|4.FDA Center for Drug Evaluation and Research (CDER). Application number|1
02830|076|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
02830|077|R|  Biopharmaceutics Review. available at:|1
02830|078|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
02830|079|R|  0ClinPharmR.pdf January 8, 2015.|1
02830|080|R|5.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
02830|081|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
02830|082|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
02830|083|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
02831|001|T|MONOGRAPH TITLE:  Conivaptan/Ribociclib (mono deleted 12/06/2023)|
02831|002|B||
02831|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02831|004|L|is contraindicated and generally should not be dispensed or administered to|
02831|005|L|the same patient.|
02831|006|B||
02831|007|A|MECHANISM OF ACTION:  Ribociclib may inhibit the metabolism of|
02831|008|A|conivaptan.(1) Toxicity may result from an overly rapid correction of serum|
02831|009|A|sodium.(1) Conivaptan may inhibit the metabolism of ribociclib.(2)|
02831|010|B||
02831|011|E|CLINICAL EFFECTS:  Concurrent use of ribociclib may result in increased|
02831|012|E|levels of conivaptan.(1)|
02831|013|E|   Elevated levels of these agents may lead to increased clinical effects|
02831|014|E|such as hypotension, hypovolemia, and thirst, as well as toxicity in the|
02831|015|E|form of neurologic sequelae such as osmotic demyelination syndrome (ODS).|
02831|016|E|ODS can lead to coma and death. Symptoms of ODS include dysarthria, mutism,|
02831|017|E|dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and|
02831|018|E|coma.(1)|
02831|019|E|   Concurrent use of conivaptan may increase systemic exposure and the risk|
02831|020|E|for ribociclib toxicities such as neutropenia or QT prolongation.(2)|
02831|021|B||
02831|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02831|023|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02831|024|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02831|025|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02831|026|P|gender, or advanced age.(2)|
02831|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02831|028|P|higher systemic concentrations of either QT prolonging drug are additional|
02831|029|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02831|030|P|drug concentrations include rapid infusion of an intravenous dose or|
02831|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02831|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02831|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02831|034|B||
02831|035|M|PATIENT MANAGEMENT:  Concurrent use of conivaptan and ribociclib is|
02831|036|M|contraindicated.|
02831|037|B||
02831|038|D|DISCUSSION:  Conivaptan is a substrate of CYP3A4. Coadministration of|
02831|039|D|conivaptan (10 mg) and ketoconazole (a strong CYP3A4 inhibitor, 200 mg)|
02831|040|D|resulted in a 4-fold increase in the area under the curve (AUC) and an|
02831|041|D|11-fold increase in the maximum concentration (Cmax) of conivaptan.(1)|
02831|042|D|   In a drug interaction study in healthy subjects, coadministration of|
02831|043|D|ritonavir (a strong CYP3A4 inhibitor, 100 mg twice a day for 14 days) with a|
02831|044|D|single dose of ribociclib (400 mg) increased ribociclib maximum|
02831|045|D|concentration (Cmax) and area-under-the-curve (AUC) by 1.7 and 3.2-fold,|
02831|046|D|respectively. Cmax and AUC for LEQ803 (ribociclib metabolite) decreased by|
02831|047|D|96% and 98%, respectively.(2)|
02831|048|B||
02831|049|R|REFERENCES:|
02831|050|B||
02831|051|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
02831|052|R|  Pharma US, Inc. October, 2016.|1
02831|053|R|2.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02831|054|R|  Corporation September, 2024.|1
02831|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02831|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02831|057|R|  settings: a scientific statement from the American Heart Association and|6
02831|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02831|059|R|  2;55(9):934-47.|6
02831|060|R|4.This information is based on an extract from the Certara Drug Interaction|6
02831|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02834|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Ribociclib|
02834|002|B||
02834|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02834|004|L|is contraindicated and generally should not be dispensed or administered to|
02834|005|L|the same patient.|
02834|006|B||
02834|007|A|MECHANISM OF ACTION:  Ribociclib may inhibit the metabolism of lovastatin|
02834|008|A|and simvastatin by CYP3A4.(1,2)|
02834|009|B||
02834|010|E|CLINICAL EFFECTS:  Concurrent use of ribociclib may result in elevated|
02834|011|E|levels of lovastatin and simvastatin and increase the risk of|
02834|012|E|rhabdomyolysis.(1,2)|
02834|013|B||
02834|014|P|PREDISPOSING FACTORS:  None determined.|
02834|015|B||
02834|016|M|PATIENT MANAGEMENT:  Concurrent use of strong CYP3A4 inhibitors with|
02834|017|M|lovastatin or simvastatin is contraindicated.(1,2)  Therapy with lovastatin|
02834|018|M|or simvastatin should be suspended during ribociclib therapy.|
02834|019|M|  In patients requiring long-term therapy with ribociclib, consider the use|
02834|020|M|of pravastatin or reduced dosages of atorvastatin or fluvastatin, using the|
02834|021|M|lowest dose possible.(3)  Patients should be carefully monitored for and|
02834|022|M|instructed to report any signs of myopathy.|
02834|023|B||
02834|024|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
02834|025|D|ribociclib (400 mg once daily for 8 days) with midazolam increased the|
02834|026|D|midazolam maximum concentration (Cmax) and area under the curve (AUC) by|
02834|027|D|2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg|
02834|028|D|once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold|
02834|029|D|and 5.2-fold, respectively.(4)|
02834|030|B||
02834|031|R|REFERENCES:|
02834|032|B||
02834|033|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
02834|034|R|  February, 2014.|1
02834|035|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
02834|036|R|  2023.|1
02834|037|R|3.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02834|038|R|  2020.|1
02834|039|R|4.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02834|040|R|  Corporation September, 2024.|1
02835|001|T|MONOGRAPH TITLE:  Lurasidone/Ribociclib|
02835|002|B||
02835|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02835|004|L|is contraindicated and generally should not be dispensed or administered to|
02835|005|L|the same patient.|
02835|006|B||
02835|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors such as ribociclib, may|
02835|008|A|inhibit the metabolism of lurasidone.(1)|
02835|009|B||
02835|010|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with strong inhibitors of|
02835|011|E|CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia,|
02835|012|E|Parkinsonism or other lurasidone toxicities.(1)|
02835|013|B||
02835|014|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
02835|015|P|of falls, swallowing disorders, Parkinson Disease, Lewy Body Disease, or|
02835|016|P|other dementias are more sensitive to antipsychotics and have a greater risk|
02835|017|P|for adverse effects.(1)|
02835|018|B||
02835|019|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors, such as|
02835|020|M|ribociclib, with lurasidone, is contraindicated.(1)|
02835|021|B||
02835|022|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
02835|023|D|ribociclib (400 mg once daily for 8 days) with midazolam increased the|
02835|024|D|midazolam maximum concentration (Cmax) and area under the curve (AUC) by|
02835|025|D|2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg|
02835|026|D|once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold|
02835|027|D|and 5.2-fold, respectively.(2)|
02835|028|B||
02835|029|R|REFERENCES:|
02835|030|B||
02835|031|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
02835|032|R|  Pharamceuticals, Inc. December, 2019.|1
02835|033|R|2.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02835|034|R|  Corporation September, 2024.|1
02835|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02835|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02835|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02835|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02835|039|R|  11/14/2017.|1
02836|001|T|MONOGRAPH TITLE:  Alprazolam; Estazolam; Triazolam/Ribociclib|
02836|002|B||
02836|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02836|004|L|is contraindicated and generally should not be dispensed or administered to|
02836|005|L|the same patient.|
02836|006|B||
02836|007|A|MECHANISM OF ACTION:  Ribociclib may inhibit the metabolism of alprazolam,|
02836|008|A|estazolam, and triazolam by CYP3A4.(1-4)|
02836|009|B||
02836|010|E|CLINICAL EFFECTS:  Inhibition of benzodiazepine metabolism may produce|
02836|011|E|increased levels of these agents, as well as increased clinical effects,|
02836|012|E|including profound sedation, respiratory depression, coma, and/or death.|
02836|013|B||
02836|014|P|PREDISPOSING FACTORS:  None determined.|
02836|015|B||
02836|016|M|PATIENT MANAGEMENT:  The concurrent use of alprazolam,(1) estazolam,(2) or|
02836|017|M|triazolam(3) with strong CYP3A4 inhibitors is contraindicated.|
02836|018|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
02836|019|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02836|020|M|unresponsiveness.|
02836|021|B||
02836|022|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
02836|023|D|ribociclib (400 mg once daily for 8 days) with midazolam increased the|
02836|024|D|midazolam maximum concentration (Cmax) and area under the curve (AUC) by|
02836|025|D|2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg|
02836|026|D|once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold|
02836|027|D|and 5.2-fold, respectively.(4)|
02836|028|B||
02836|029|R|REFERENCES:|
02836|030|B||
02836|031|R|1.Xanax (alprazolam) US prescribing information. Pharmacia & Upjohn Company|1
02836|032|R|  February, 2021.|1
02836|033|R|2.Prosom (estazolam) US prescribing information. Abbott Laboratories|1
02836|034|R|  January, 2004.|1
02836|035|R|3.Halcion (triazolam) US prescribing information. Pharmacia & Upjohn Company|1
02836|036|R|  October, 2019.|1
02836|037|R|4.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02836|038|R|  Corporation September, 2024.|1
02837|001|T|MONOGRAPH TITLE:  Eletriptan/Ribociclib|
02837|002|B||
02837|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02837|004|L|is contraindicated and generally should not be dispensed or administered to|
02837|005|L|the same patient.|
02837|006|B||
02837|007|A|MECHANISM OF ACTION:  Ribociclib is a strong inhibitor of CYP3A4 and may|
02837|008|A|inhibit the metabolism of eletriptan via this pathway.(1)|
02837|009|B||
02837|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
02837|011|E|adverse effects from eletriptan.(1)|
02837|012|B||
02837|013|P|PREDISPOSING FACTORS:  None determined.|
02837|014|B||
02837|015|M|PATIENT MANAGEMENT:  The US manufacturer of eletriptan states that|
02837|016|M|eletriptan should not be used within at least 72 hours of administration of|
02837|017|M|a strong CYP3A4 inhibitor.(2)  If migraine treatment is needed during|
02837|018|M|ribociclib therapy use triptans not metabolized by CYP3A4 such as|
02837|019|M|frovatriptan, sumatriptan, or zolmitriptan.(2-4)|
02837|020|B||
02837|021|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
02837|022|D|ribociclib (400 mg once daily for 8 days) with midazolam increased the|
02837|023|D|midazolam maximum concentration (Cmax) and area under the curve (AUC) by|
02837|024|D|2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg|
02837|025|D|once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold|
02837|026|D|and 5.2-fold, respectively.(5)|
02837|027|B||
02837|028|R|REFERENCES:|
02837|029|B||
02837|030|R|1.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
02837|031|R|  March, 2020.|1
02837|032|R|2.Frova (frovatriptan) US prescribing information. Endo Pharmaceuticals|1
02837|033|R|  August, 2018.|1
02837|034|R|3.Imitrex Tablets (sumatriptan) US prescribing information. GlaxoSmithKline|1
02837|035|R|  December 14, 2017.|1
02837|036|R|4.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
02837|037|R|  Pharmaceuticals LP September, 2012.|1
02837|038|R|5.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02837|039|R|  Corporation September, 2024.|1
02837|040|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
02837|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02837|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02837|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02837|044|R|  11/14/2017.|1
02838|001|T|MONOGRAPH TITLE:  Cyclosporine;Sirolimus;Temsirolimus/Ribociclib|
02838|002|B||
02838|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02838|004|L|of severe adverse interaction.|
02838|005|B||
02838|006|A|MECHANISM OF ACTION:  The metabolism of cyclosporine, sirolimus, and|
02838|007|A|temsirolimus by CYP3A4 may be inhibited by ribociclib.|
02838|008|B||
02838|009|E|CLINICAL EFFECTS:  Concurrent administration of ribociclib may result in|
02838|010|E|elevated levels of and toxicity from cyclosporine, sirolimus, or|
02838|011|E|temsirolimus.|
02838|012|B||
02838|013|P|PREDISPOSING FACTORS:  None determined.|
02838|014|B||
02838|015|M|PATIENT MANAGEMENT:  Cyclosporine, sirolimus, or temsirolimus levels and|
02838|016|M|renal function should be monitored if ribociclib is initiated or|
02838|017|M|discontinued from concurrent therapy.  The dosage of cyclosporine,|
02838|018|M|sirolimus, or temsirolimus may need to be adjusted.|
02838|019|M|   The manufacturer of ribociclib states that caution is recommended when|
02838|020|M|ribociclib is administered with CYP3A4 substrates with a narrow therapeutic|
02838|021|M|index. The dose of the sensitive CYP3A4 substrate with a narrow therapeutic|
02838|022|M|index may need to be reduced.(5)|
02838|023|M|   The manufacturer of sirolimus states that the concurrent use of strong|
02838|024|M|CYP3A4 inhibitors is not recommended and should be avoided.(1)|
02838|025|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
02838|026|M|with strong CYP3A4 inhibitors such as ribociclib be avoided.  If concurrent|
02838|027|M|use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should|
02838|028|M|be considered.  If ribociclib is discontinued, a washout period of 1 week|
02838|029|M|should be allowed before adjusting the dosage of temsirolimus to previous|
02838|030|M|levels.(2)|
02838|031|B||
02838|032|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
02838|033|D|ribociclib (400 mg once daily for 8 days) with midazolam increased the|
02838|034|D|midazolam maximum concentration (Cmax) and area under the curve (AUC) by|
02838|035|D|2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg|
02838|036|D|once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold|
02838|037|D|and 5.2-fold, respectively.(5)|
02838|038|B||
02838|039|R|REFERENCES:|
02838|040|B||
02838|041|R|1.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
02838|042|R|  Aug, 2022.|1
02838|043|R|2.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
02838|044|R|  Inc. March, 2018.|1
02838|045|R|3.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
02838|046|R|  Corporation September, 2023.|1
02838|047|R|4.Sandimmune (cyclosporine) US prescribing information. Novartis|1
02838|048|R|  Pharmaceuticals Corporation September 2023.|1
02838|049|R|5.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02838|050|R|  Corporation September, 2024.|1
02839|001|T|MONOGRAPH TITLE:  Midazolam/Ribociclib|
02839|002|B||
02839|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02839|004|L|of severe adverse interaction.|
02839|005|B||
02839|006|A|MECHANISM OF ACTION:  Ribociclib is a strong inhibitor of CYP3A4 and may|
02839|007|A|decrease metabolism of midazolam.|
02839|008|B||
02839|009|E|CLINICAL EFFECTS:  Concurrent administration of ribociclib and midazolam,|
02839|010|E|metabolized by CYP3A4, may result in increased clinical effects (e.g.|
02839|011|E|profound sedation, respiratory depression, coma, and/or death) of midazolam.|
02839|012|E|   CYP3A4 is the major or only hepatic metabolism pathway for the phase I|
02839|013|E|elimination of midazolam.|
02839|014|B||
02839|015|P|PREDISPOSING FACTORS:  None determined.|
02839|016|B||
02839|017|M|PATIENT MANAGEMENT:  Benzodiazepines that do not undergo extensive CYP|
02839|018|M|hepatic metabolism (e.g. lorazepam, oxazepam) may be an alternative in|
02839|019|M|ribociclib patients.|
02839|020|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
02839|021|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02839|022|M|unresponsiveness.|
02839|023|B||
02839|024|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
02839|025|D|ribociclib (400 mg once daily for 8 days) with midazolam increased the|
02839|026|D|midazolam maximum concentration (Cmax) and area under the curve (AUC) by|
02839|027|D|2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg|
02839|028|D|once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold|
02839|029|D|and 5.2-fold, respectively.|
02839|030|B||
02839|031|R|REFERENCE:|
02839|032|B||
02839|033|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02839|034|R|  Corporation September, 2024.|1
02840|001|T|MONOGRAPH TITLE:  Capecitabine/Proton Pump Inhibitors|
02840|002|B||
02840|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02840|004|L|of severe adverse interaction.|
02840|005|B||
02840|006|A|MECHANISM OF ACTION:  The aqueous solubility of capecitabine is pH|
02840|007|A|dependent.  Higher gastric pH leads to lower solubility and altered tablet|
02840|008|A|dissolution which may reduce capecitabine absorption.(1,2)|
02840|009|B||
02840|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) may|
02840|011|E|reduce the bioavailability of capecitabine, leading to decreased systemic|
02840|012|E|levels and effectiveness.(1,2)|
02840|013|B||
02840|014|P|PREDISPOSING FACTORS:  None determined.|
02840|015|B||
02840|016|M|PATIENT MANAGEMENT:  Coadministration of proton pump inhibitors with|
02840|017|M|capecitabine may decrease bioavailability.  When clinically appropriate,|
02840|018|M|consider using H2 blockers or antacids.|
02840|019|B||
02840|020|D|DISCUSSION:  A retrospective study in early stage colorectal cancer patients|
02840|021|D|treated with adjuvant monotherapy capecitabine examined recurrence-free|
02840|022|D|survival (RFS) and overall survival (OS) in 1335 patients with and without|
02840|023|D|concurrent proton pump inhibitor (PPI) therapy.  The PPI group was defined|
02840|024|D|as a prescription for a PPI filled at any point in time during capecitabine|
02840|025|D|treatment.  Patients in the capecitabine with concurrent PPI group had a|
02840|026|D|statistically significant decrease in 5-year RFS (74% v 83%; hazard ratio|
02840|027|D|(HR) 1.89; 95% confidence interval (CI) 1.07-3.35; p=0.03) compared to|
02840|028|D|capecitabine without PPI therapy.  OS was not significantly different|
02840|029|D|between groups (81% PPI v 78% non-PPI; HR 1.13; 95% CI 0.6-2.14; p=0.7).|
02840|030|D|After adjusting for male gender, stage III colorectal cancer, advance age|
02840|031|D|>68, poorer ECOG PS, there was a trend toward decreased RFS in PPI patients|
02840|032|D|(HR 1.65; 95% CI 0.93-2.94; p=0.09).(1)|
02840|033|D|   An ad hoc analysis of the TRIO-013/LOCiC trial examined coadministration|
02840|034|D|of PPI therapy, defined as 20% or more overlap between a PPI prescription|
02840|035|D|and trial treatment duration with capecitabine and/or lapatinib, on|
02840|036|D|progression-free survival (PFS) and overall survival (OS).  The secondary|
02840|037|D|analysis examined 545 patients in which 42% were on concurrent PPI therapy.|
02840|038|D|Patients in the non-PPI group had an improved median PFS (5.7 v 4.2 months;|
02840|039|D|HR 1.55; 95% CI 1.29-1.81; p<0.001) and median OS (11.3 v 9.2 months; HR|
02840|040|D|1.34; 95% CI 1.06-1.62; p=0.04) compared with PPI users.  A multivariate|
02840|041|D|analysis reviewed effects of PPIs on both PFS and OS with capecitabine alone|
02840|042|D|and found effects of PPI use on both PFS and OS was still significant (HR|
02840|043|D|1.68; p<0.001 and HR 1.41; p=0.001, respectively).(2)|
02840|044|D|   In a study in 12 subjects, concomitant administration of capecitabine|
02840|045|D|with aluminum-magnesium hydroxide containing antacid 20 mL increased|
02840|046|D|area-under-curve (AUC) and concentration maximum (Cmax) by 16% and 35%,|
02840|047|D|respectively.(3)|
02840|048|D|   Proton pump inhibitors linked to this monograph include: dexlansoprazole,|
02840|049|D|esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole.|
02840|050|B||
02840|051|R|REFERENCES:|
02840|052|B||
02840|053|R|1.Sun J, Ilich AI, Kim CA, Chu MP, Wong GG, Ghosh S, Danilak M, Mulder KE,|2
02840|054|R|  Spratlin JL, Chambers CR, Sawyer MB. Concomitant Administration of Proton|2
02840|055|R|  Pump Inhibitors and Capecitabine is Associated With Increased Recurrence|2
02840|056|R|  Risk in Early Stage Colorectal Cancer Patients. Clin Colorectal Cancer|2
02840|057|R|  2016 Sep;15(3):257-63.|2
02840|058|R|2.Chu MP, Hecht JR, Slamon D, Wainberg ZA, Bang YJ, Hoff PM, Sobrero A, Qin|2
02840|059|R|  S, etal. Association of Proton Pump Inhibitors and Capecitabine Efficacy|2
02840|060|R|  in Advanced Gastroesophageal Cancer: Secondary Analysis of the|2
02840|061|R|  TRIO-013/LOGiC Randomized Clinical Trial. JAMA Oncol 2017 Jun 01;|2
02840|062|R|  3(6):767-773.|2
02840|063|R|3.Xeloda (capecitabine) US prescribing information. Roche Pharmaceuticals|1
02840|064|R|  October, 2025.|1
02841|001|T|MONOGRAPH TITLE:  Atorvastatin/Ribociclib|
02841|002|B||
02841|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02841|004|L|take action as needed.|
02841|005|B||
02841|006|A|MECHANISM OF ACTION:  Ribociclib may inhibit the metabolism of atorvastatin|
02841|007|A|by CYP3A4.(1,2)|
02841|008|B||
02841|009|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
02841|010|E|of the HMG-CoA reductase inhibitor, which may result in an increased risk of|
02841|011|E|rhabdomyolysis.|
02841|012|B||
02841|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02841|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02841|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02841|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02841|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02841|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02841|019|P|predisposed to myopathy or rhabdomyolysis.|
02841|020|B||
02841|021|M|PATIENT MANAGEMENT:  Consider a reduction of atorvastatin dose with|
02841|022|M|concurrent ribociclib.  Monitor patients receiving concurrent therapy for|
02841|023|M|signs and symptoms of rhabdomyolysis if concurrent therapy is warranted.|
02841|024|B||
02841|025|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
02841|026|D|ribociclib (400 mg once daily for 8 days) with midazolam increased the|
02841|027|D|midazolam maximum concentration (Cmax) and area under the curve (AUC) by|
02841|028|D|2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg|
02841|029|D|once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold|
02841|030|D|and 5.2-fold, respectively.|
02841|031|B||
02841|032|R|REFERENCES:|
02841|033|B||
02841|034|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02841|035|R|  2020.|1
02841|036|R|2.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02841|037|R|  Corporation September, 2024.|1
02842|001|T|MONOGRAPH TITLE:  Buspirone; Diazepam/Ribociclib|
02842|002|B||
02842|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02842|004|L|take action as needed.|
02842|005|B||
02842|006|A|MECHANISM OF ACTION:  Ribociclib may inhibit the metabolism of buspirone or|
02842|007|A|diazepam by CYP3A4.(1)|
02842|008|B||
02842|009|E|CLINICAL EFFECTS:  Concurrent use of ribociclib may result in increased|
02842|010|E|levels of and effects from buspirone or diazepam.  Increased effects from|
02842|011|E|diazepam may include profound sedation, respiratory depression, coma, and/or|
02842|012|E|death.  Increased effects from buspirone may include lightheadedness,|
02842|013|E|asthenia, dizziness, and somnolence.|
02842|014|B||
02842|015|P|PREDISPOSING FACTORS:  None determined.|
02842|016|B||
02842|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with buspirone or|
02842|018|M|diazepam and ribociclib should be monitored for adverse effects.  The dosage|
02842|019|M|of buspirone or diazepam may need to be adjusted.(1,2)|
02842|020|M|   The manufacturer of buspirone states that when administered with a potent|
02842|021|M|inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended.|
02842|022|B||
02842|023|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
02842|024|D|ribociclib (400 mg once daily for 8 days) with midazolam increased the|
02842|025|D|midazolam maximum concentration (Cmax) and area-under-curve (AUC) by|
02842|026|D|2.1-fold and 3.8-fold, respectively.  Administration of ribociclib 600 mg|
02842|027|D|once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold|
02842|028|D|and 5.2-fold, respectively.|
02842|029|B||
02842|030|R|REFERENCES:|
02842|031|B||
02842|032|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
02842|033|R|  Corporation September, 2024.|1
02842|034|R|2.Valium (diazepam) US prescribing information. Roche Products Inc December,|1
02842|035|R|  2016.|1
02842|036|R|3.BuSpar (buspirone hydrochloride) US prescribing information. Bristol Myers|1
02842|037|R|  Squibb Company September, 2007.|1
02843|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Safinamide|
02843|002|B||
02843|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02843|004|L|is contraindicated and generally should not be dispensed or administered to|
02843|005|L|the same patient.|
02843|006|B||
02843|007|A|MECHANISM OF ACTION:  Methadone may inhibit neural reuptake of serotonin.|
02843|008|A|MAOIs increase neuronal serotonin concentrations via inhibition of MAO-A.|
02843|009|A|   Levomethadone is an enantiomer of methadone.|
02843|010|A|   Safinamide is a selective MAO-B inhibitor at doses </= 100 mg daily.|
02843|011|A|MAO-B selectivity decreases above the recommended dose of 100 mg daily.|
02843|012|B||
02843|013|E|CLINICAL EFFECTS:  The concurrent use of methadone with safinamide may|
02843|014|E|result in serotonin syndrome.|
02843|015|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
02843|016|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
02843|017|E|rigidity.|
02843|018|B||
02843|019|P|PREDISPOSING FACTORS:  Higher opioid concentrations may occur due to|
02843|020|P|inhibition of opioid clearance, patient specific genomic factors (e.g. poor|
02843|021|P|metabolizer status for a specific P450 enzyme), or high opioid dosage may|
02843|022|P|increase the risk for a severe interaction.|
02843|023|B||
02843|024|M|PATIENT MANAGEMENT:  The US manufacturer of safinamide states the use of|
02843|025|M|methadone is contraindicated during and within 2 two weeks after|
02843|026|M|discontinuation of safinamide.|
02843|027|M|   Methadone manufacturer recommendations:|
02843|028|M|   The US manufacturer of methadone states that if concurrent use is|
02843|029|M|necessary, a sensitivity test should be performed in which small,|
02843|030|M|incremental doses of methadone are administered over several hours while the|
02843|031|M|patient's condition and vital signs are carefully observed.|
02843|032|M|   The Australian manufacturer of methadone states that methadone should not|
02843|033|M|be administered to patients receiving MAOIs.|
02843|034|M|   The UK manufacturer of methadone states that concurrent use is|
02843|035|M|contraindicated.|
02843|036|B||
02843|037|D|DISCUSSION:  FDA performed a search of its adverse event database for cases|
02843|038|D|of serotonin syndrome with selected opiates for the period of January 1,|
02843|039|D|1969 to June 12, 2013; 5 cases were associated with methadone use during|
02843|040|D|this 43 year period.|
02843|041|B||
02843|042|R|REFERENCES:|
02843|043|B||
02843|044|R|1.London DR, Milne MD. Dangers of monoamine oxidase inhibitors. Br Med J|6
02843|045|R|  1962 Dec 29;2:1752.|6
02843|046|R|2.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
02843|047|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
02843|048|R|3.Anonymous. Analgesics and monoamine-oxidase inhibitors. Br Med J 1967 Nov|6
02843|049|R|  4;4(574):284.|6
02843|050|R|4.Barry BJ. Adverse effects of MAO inhibitors with narcotics reversed with|3
02843|051|R|  naloxone. Anaesth Intensive Care 1979 May;7(2):194.|3
02843|052|R|5.Browne B, Linter S. Monoamine oxidase inhibitors and narcotic analgesics.|6
02843|053|R|  A critical review of the implications for treatment. Br J Psychiatry 1987|6
02843|054|R|  Aug;151:210-2.|6
02843|055|R|6.Rossiter A, Souney PF. Interaction between MAOIs and opioids:|6
02843|056|R|  pharmacologic and clinical considerations. Hosp Formul 1993 Aug;28:692-8.|6
02843|057|R|7.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
02843|058|R|  Pharmaceuticals Corp. June, 2021.|1
02843|059|R|8.Metharose (methadone hydrochloride) UK summary of product characteristics.|1
02843|060|R|  Rosemone Pharmaceuticals Limited January 9, 2008.|1
02843|061|R|9.Diskets Dispersible (methadone hydrochloride) US prescribing information.|1
02843|062|R|  Cebert Pharmaceuticals, Inc. August, 2007.|1
02843|063|R|10.Diamorphine hydrochloride Australian prescribing information. Auralis|1
02843|064|R|   March 13, 2008.|1
02843|065|R|11.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
02843|066|R|   352(11):1112-20.|6
02843|067|R|12.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02843|068|R|   warns about several safety issues with opioid pain medicines; requires|1
02843|069|R|   label changes. available at:|1
02843|070|R|   http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
02843|071|R|13.Xadago (safinamide) US prescribing information. US WorldMeds, LLC August,|1
02843|072|R|   2021.|1
02843|073|R|14.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
02843|074|R|   Pharma AS November 30, 2018.|1
02844|001|T|MONOGRAPH TITLE:  Naldemedine/Strong CYP3A4 Inducers|
02844|002|B||
02844|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02844|004|L|of severe adverse interaction.|
02844|005|B||
02844|006|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
02844|007|A|naldemedine.(1)|
02844|008|B||
02844|009|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 may result in|
02844|010|E|decreased levels and effectiveness of naldemedine.(1)|
02844|011|B||
02844|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02844|013|P|of the inducer for longer than 1-2 weeks.|
02844|014|B||
02844|015|M|PATIENT MANAGEMENT:  The US manufacturer recommends avoid concurrent use of|
02844|016|M|a strong inducer of CYP3A4 with naldemedine.(1)|
02844|017|M|   The UK manufacturer states concurrent use of a strong inducer of CYP3A4|
02844|018|M|is not recommended.(2)|
02844|019|M|   If concurrent use is warranted, monitor patients for signs of decreased|
02844|020|M|naldemedine effectiveness, such as constipation.  Patients may require|
02844|021|M|additional laxative therapy.|
02844|022|B||
02844|023|D|DISCUSSION:  Rifampin (600 mg daily), a strong inducer of CYP3A4, decreased|
02844|024|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
02844|025|D|of naldemedine by 38% and 83%, respectively.(1)|
02844|026|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
02844|027|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02844|028|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02844|029|D|rifapentine, and St. John's wort.(1-4)|
02844|030|B||
02844|031|R|REFERENCES:|
02844|032|B||
02844|033|R|1.Symproic (naldemedine) US prescribing information. Shionogi Inc. January|1
02844|034|R|  24, 2018.|1
02844|035|R|2.Rizmoic (naldemedine) UK summary of product characteristics. Shionogi|1
02844|036|R|  October 11, 2019.|1
02844|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02844|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02844|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02844|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02844|041|R|  11/14/2017.|1
02844|042|R|4.This information is based on an extract from the Certara Drug Interaction|6
02844|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02845|001|T|MONOGRAPH TITLE:  Olanzapine/Selected CYP1A2 Inducers|
02845|002|B||
02845|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02845|004|L|take action as needed.|
02845|005|B||
02845|006|A|MECHANISM OF ACTION:  Inducers of CYP1A2 may increase the metabolism of|
02845|007|A|olanzapine.(1,2)|
02845|008|B||
02845|009|E|CLINICAL EFFECTS:  Concurrent use of a CYP1A2 inducer may result in|
02845|010|E|decreased levels and effectiveness of olanzapine.(1,2)|
02845|011|B||
02845|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02845|013|P|of the inducer for longer than 1-2 weeks.|
02845|014|B||
02845|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with olanzapine|
02845|016|M|and a CYP1A2 inducer may require increased dosages of olanzapine.  The|
02845|017|M|dosage of olanzapine may need to be adjusted if concurrent therapy with a|
02845|018|M|CYP1A2 inducer is initiated or discontinued.(1,2)|
02845|019|M|   If a CYP1A2 inducer is initiated in a patient maintained on olanzapine,|
02845|020|M|monitor for decreased effectiveness of olanzapine.|
02845|021|M|   If a CYP1A2 inducer is discontinued in a patient maintained on|
02845|022|M|olanzapine, monitor for olanzapine toxicity.|
02845|023|B||
02845|024|D|DISCUSSION:  Concurrent use of carbamazepine, a CYP1A2 inducer, increased|
02845|025|D|olanzapine clearance by 50%.(1,2)|
02845|026|B||
02845|027|R|REFERENCES:|
02845|028|B||
02845|029|R|1.Zyprexa Relprevv (olanzapine ext-rel IM susp.) US prescribing information.|1
02845|030|R|  Eli Lilly and Company February, 2017.|1
02845|031|R|2.Linnet K, Olesen OV. Free and glucuronidated olanzapine serum|2
02845|032|R|  concentrations in psychiatric patients:  influence of carbamazepine|2
02845|033|R|  comedication. Ther Drug Monit 2002 Aug;24(4):512-7.|2
02846|001|T|MONOGRAPH TITLE:  Chloral Hydrate/Furosemide (Intravenous)|
02846|002|B||
02846|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02846|004|L|take action as needed.|
02846|005|B||
02846|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
02846|007|A|displacement of trichloracetic acid (a metabolite of chloral hydrate) from|
02846|008|A|protein binding sites, which in turn results in increased free levothyroxine|
02846|009|A|through pH changes or displacement.(1)|
02846|010|B||
02846|011|E|CLINICAL EFFECTS:  Use of intravenous furosemide within 24 hours of chloral|
02846|012|E|hydrate may result in agitation, flushing, hot flashes, tachycardia, and|
02846|013|E|hypertension.(1-3)|
02846|014|B||
02846|015|P|PREDISPOSING FACTORS:  None determined.|
02846|016|B||
02846|017|M|PATIENT MANAGEMENT:  Avoid the use of intravenous furosemide in patients|
02846|018|M|requiring chloral hydrate.  Oral furosemide is not expected to|
02846|019|M|interact.(1-3)|
02846|020|B||
02846|021|D|DISCUSSION:  The use of intravenous furosemide within 24 hours of chloral|
02846|022|D|hydrate has resulted in flushing, hot flashes, tachycardia, and|
02846|023|D|hypertension.(1-3)|
02846|024|B||
02846|025|R|REFERENCES:|
02846|026|B||
02846|027|R|1.Chloral Hydrate Australian product information. Orion Laboratories Pty Ltd|1
02846|028|R|  September 19, 2003.|1
02846|029|R|2.Dean RP, Rudinsky BF, Kelleher MD. Interaction of chloral hydrate and|3
02846|030|R|  intravenous furosemide in a child. Clin Pharm 1991 May;10(5):385-7.|3
02846|031|R|3.Malach M, Berman N. Furosemide and chloral hydrate. Adverse drug|3
02846|032|R|  interaction. JAMA 1975 May 12;232(6):638-9.|3
02847|001|T|MONOGRAPH TITLE:  Selected Benzodiazepines/Barbiturates|
02847|002|B||
02847|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02847|004|L|take action as needed.|
02847|005|B||
02847|006|A|MECHANISM OF ACTION:  Barbiturates and phenobarbital, CYP3A4 inducers, may|
02847|007|A|induce the metabolism of some benzodiazepines.  In addition, barbiturates,|
02847|008|A|phenobarbital and benzodiazepines are CNS depressants.|
02847|009|A|   Primidone is metabolized to phenobarbital.|
02847|010|B||
02847|011|E|CLINICAL EFFECTS:  Concurrent or recent use of barbiturates or phenobarbital|
02847|012|E|may result in decreased levels and loss of effectiveness of some|
02847|013|E|benzodiazepines.|
02847|014|E|   Concurrent use of barbiturates and benzodiazepines may result in additive|
02847|015|E|CNS depression (e.g. respiratory depression, increased somnolence).|
02847|016|B||
02847|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02847|018|P|of the inducer for longer than 1-2 weeks.|
02847|019|B||
02847|020|M|PATIENT MANAGEMENT:  Monitor patients receiving phenobarbital or who have|
02847|021|M|received doses in the previous 2 weeks for decreased benzodiazepine|
02847|022|M|effectiveness.  The dose of the benzodiazepine may need to be adjusted or an|
02847|023|M|alternative agent used.|
02847|024|M|   Patients on chronic benzodiazepine therapy who are started on|
02847|025|M|phenobarbital should be initially monitored for additive CNS sedation or|
02847|026|M|respiratory depression, particularly when predisposing factors (e.g. COPD,|
02847|027|M|sleep apnea, debilitation, elderly) are present.  Continued use of|
02847|028|M|phenobarbital leads to induction of benzodiazepine metabolism.  The onset is|
02847|029|M|gradual and may not peak for several weeks.|
02847|030|M|   If phenobarbital is discontinued, benzodiazepine levels will gradually|
02847|031|M|rise as induction effects diminish. Monitor for increased benzodiazepine|
02847|032|M|effects and adjust the dose accordingly.|
02847|033|B||
02847|034|D|DISCUSSION:  In a study in 95 healthy subjects, rifampin, a CYP3A4 inducer|
02847|035|D|(450 mg daily for 5 days), decreased the plasma concentrations of a single|
02847|036|D|oral dose of alprazolam (1 mg) by 79%.(1)|
02847|037|D|   In another study in 4 healthy subjects, rifampin (given for 4 days)|
02847|038|D|decreased the area-under-curve (AUC) of a single oral dose of alprazolam (1|
02847|039|D|mg) by 88%.(2)|
02847|040|D|   In a double-blind, randomized, cross-over trial in 13 healthy subjects,|
02847|041|D|rifampin (450 mg daily for 7 days) decreased the maximum concentration|
02847|042|D|(Cmax), area-under-curve (AUC), and half-life of a single oral dose of|
02847|043|D|brotizolam (0.5 mg) by 69%, 90%, and 69%, respectively.  Concurrent rifampin|
02847|044|D|increased scores on the Digit Symbol Substitution Test (DSST) and decreased|
02847|045|D|scores on the Stanford Sleepiness Scale.(3)|
02847|046|D|   In a study in 21 healthy subjects, rifampin (600 mg or 1200 mg daily for|
02847|047|D|7 days) increased total body clearance of diazepam by 300%.(4)|
02847|048|D|   An in vitro study in human hepatocytes found that rifampin increased the|
02847|049|D|biotransformation of diazepam and midazolam by 1.9-fold.(5)|
02847|050|D|   In a study in 24 healthy subjects, rifampin (600 mg daily for 10 days)|
02847|051|D|increased the clearance of a single intravenous dose of lorazepam by|
02847|052|D|140%.(6)|
02847|053|D|   In an open-label cross-over study in 19 healthy subjects, rifampin (600|
02847|054|D|mg daily for 9 days) increased the clearance of a single oral dose of|
02847|055|D|midazolam (0.075 mg/kg) by 7-fold.(7)|
02847|056|D|   In a study in 57 healthy subjects, rifampin increased the systemic and|
02847|057|D|oral clearance of midazolam by 2-fold and 16-fold, respectively.(8)|
02847|058|D|   In a study in 8 healthy subjects, rifampin (given for 6 days)|
02847|059|D|significantly increased the clearance of midazolam.(9)|
02847|060|D|   In a study in 9 healthy subjects, received a single oral dose of|
02847|061|D|midazolam (15 mg) before, one day after the administration of rifampin (600|
02847|062|D|mg daily for 5 days), and 4 days after the last dose of rifampin.  One day|
02847|063|D|after rifampin, the AUC of midazolam was decreased by 97.7% when compared to|
02847|064|D|the administration of midazolam prior to rifampin.  Four days after the|
02847|065|D|completion of rifampin, the AUC of midazolam was decreased by 87% when|
02847|066|D|compared to the administration of midazolam prior to rifampin.(10)|
02847|067|D|   In a double-blind, randomized, cross-over study in 10 healthy subjects,|
02847|068|D|rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of|
02847|069|D|a single oral dose of midazolam (15 mg) by 94%, 96%, and 58%, respectively.|
02847|070|D|The pharmacodynamic effects of midazolam were also significantly decreased|
02847|071|D|during rifampin therapy.(11)|
02847|072|D|   In a study in 16 healthy subjects, rifampin (600 mg daily for 7 days)|
02847|073|D|increased the clearance of nitrazepam by 83%.  There were no significant|
02847|074|D|effects on the pharmacokinetics of temazepam.(12)|
02847|075|D|   In a randomized, double-blind, cross-over study in 10 healthy subjects,|
02847|076|D|rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of|
02847|077|D|a single dose of triazolam (0.5 mg) by 87.6%, 94.9%, and 54%, respectively.|
02847|078|D|The pharmacodynamic effects of triazolam were also significantly decreased|
02847|079|D|during rifampin therapy.(13)|
02847|080|D|   In an open-label, randomized, cross-over study in 27 healthy subjects,|
02847|081|D|rifaximin (200 mg three times daily for 7 days) had no effect on the|
02847|082|D|pharmacokinetics of single doses of oral or intravenous midazolam.(14)|
02847|083|D|   In a study in 98 patients with schizophrenia or bipolar disorder, the|
02847|084|D|expression of CYP3A4 was found to be the major determinant of clonazepam|
02847|085|D|plasma concentrations normalized by the dose and bodyweight (1263 +/- 482.9|
02847|086|D|and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal expressers,|
02847|087|D|respectively, p<0.0001).(18)|
02847|088|B||
02847|089|R|REFERENCES:|
02847|090|B||
02847|091|R|1.Gashaw I, Kirchheiner J, Goldammer M, Bauer S, Seidemann J, Zoller K,|2
02847|092|R|  Mrozikiewicz PM, Roots I, Brockmoller J. Cytochrome p450 3A4 messenger|2
02847|093|R|  ribonucleic acid induction by rifampin in human peripheral blood|2
02847|094|R|  mononuclear cells: correlation with alprazolam pharmacokinetics. Clin|2
02847|095|R|  Pharmacol Ther 2003 Nov;74(5):448-57.|2
02847|096|R|2.Schmider J, Brockmoller J, Arold G, Bauer S, Roots I. Simultaneous|2
02847|097|R|  assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and|2
02847|098|R|  caffeine. Pharmacogenetics 1999 Dec;9(6):725-34.|2
02847|099|R|3.Ujiie Y, Fukasawa T, Yasui-Furukori N, Suzuki A, Tateishi T, Otani K.|2
02847|100|R|  Rifampicin markedly decreases plasma concentration and hypnotic effect of|2
02847|101|R|  brotizolam. Ther Drug Monit 2006 Jun;28(3):299-302.|2
02847|102|R|4.Ohnhaus EE, Brockmeyer N, Dylewicz P, Habicht H. The effect of antipyrine|2
02847|103|R|  and rifampin on the metabolism of diazepam. Clin Pharmacol Ther 1987 Aug;|2
02847|104|R|  42(2):148-56.|2
02847|105|R|5.Reinach B, de Sousa G, Dostert P, Ings R, Gugenheim J, Rahmani R.|5
02847|106|R|  Comparative effects of rifabutin and rifampicin on cytochromes P450 and|5
02847|107|R|  UDP-glucuronosyl-transferases expression in fresh and cryopreserved human|5
02847|108|R|  hepatocytes. Chem Biol Interact 1999 Jun 1;121(1):37-48.|5
02847|109|R|6.Chung JY, Cho JY, Yu KS, Kim JR, Jung HR, Lim KS, Jang IJ, Shin SG. Effect|2
02847|110|R|  of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and|2
02847|111|R|  drug interactions of intravenous lorazepam in healthy volunteers. Clin|2
02847|112|R|  Pharmacol Ther 2005 Jun;77(6):486-94.|2
02847|113|R|7.Chung E, Nafziger AN, Kazierad DJ, Bertino JS Jr. Comparison of midazolam|2
02847|114|R|  and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther 2006|2
02847|115|R|  Apr;79(4):350-61.|2
02847|116|R|8.Floyd MD, Gervasini G, Masica AL, Mayo G, George AL Jr, Bhat K, Kim RB,|2
02847|117|R|  Wilkinson GR. Genotype-phenotype associations for common CYP3A4 and CYP3A5|2
02847|118|R|  variants in the basal and induced metabolism of midazolam in European- and|2
02847|119|R|  African-American men and women. Pharmacogenetics 2003 Oct;13(10):595-606.|2
02847|120|R|9.Eeckhoudt SL, Desager JP, Robert AR, Leclercq I, Verbeeck RK, Horsmans Y.|2
02847|121|R|  Midazolam and cortisol metabolism before and after CYP3A induction in|2
02847|122|R|  humans. Int J Clin Pharmacol Ther 2001 Jul;39(7):293-9.|2
02847|123|R|10.Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ. The area under the|2
02847|124|R|   plasma concentration-time curve for oral midazolam is 400-fold larger|2
02847|125|R|   during treatment with itraconazole than with rifampicin. Eur J Clin|2
02847|126|R|   Pharmacol 1998 Mar;54(1):53-8.|2
02847|127|R|11.Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma|2
02847|128|R|   concentrations and effects of oral midazolam. Clin Pharmacol Ther 1996|2
02847|129|R|   Jan;59(1):7-13.|2
02847|130|R|12.Brockmeyer NH, Mertins L, Klimek K, Goos M, Ohnhaus EE. Comparative|2
02847|131|R|   effects of rifampin and/or probenecid on the pharmacokinetics of|2
02847|132|R|   temazepam and nitrazepam. Int J Clin Pharmacol Ther Toxicol 1990 Sep;|2
02847|133|R|   28(9):387-93.|2
02847|134|R|13.Villikka K, Kivisto KT, Backman JT, Olkkola KT, Neuvonen PJ. Triazolam is|2
02847|135|R|   ineffective in patients taking rifampin. Clin Pharmacol Ther 1997 Jan;|2
02847|136|R|   61(1):8-14.|2
02847|137|R|14.Pentikis HS, Connolly M, Trapnell CB, Forbes WP, Bettenhausen DK. The|2
02847|138|R|   effect of multiple-dose, oral rifaximin on the pharmacokinetics of|2
02847|139|R|   intravenous and oral midazolam in healthy volunteers. Pharmacotherapy|2
02847|140|R|   2007 Oct;27(10):1361-9.|2
02847|141|R|15.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
02847|142|R|   Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
02847|143|R|16.This information is based on an extract from the Certara Drug Interaction|6
02847|144|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02847|145|R|17.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
02847|146|R|   Pharmaceuticals Inc. August, 2023.|1
02847|147|R|18.Toth K, Csukly G, Sirok D, Belic A, Kiss A, Hafra E, Deri M, Menus A,|2
02847|148|R|   Bitter I, Monostory K. Optimization of Clonazepam Therapy Adjusted to|2
02847|149|R|   Patient's CYP3A Status and NAT2 Genotype. Int J Neuropsychopharmacol 2016|2
02847|150|R|   Dec;19(12):.|2
02848|001|T|MONOGRAPH TITLE:  Valbenazine (Greater Than 40 mg)/Strong CYP3A4 Inhibitors|
02848|002|B||
02848|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02848|004|L|is contraindicated and generally should not be dispensed or administered to|
02848|005|L|the same patient.|
02848|006|B||
02848|007|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
02848|008|A|metabolism of valbenazine.(1)|
02848|009|B||
02848|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
02848|011|E|systemic exposure and the risk for valbenazine toxicities such as QT|
02848|012|E|prolongation.(1)|
02848|013|B||
02848|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02848|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02848|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02848|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02848|018|P|gender, or advanced age.(2)|
02848|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02848|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02848|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
02848|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02848|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02848|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02848|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02848|026|P|   Concurrent use of strong CYP2D6 inhibitors may further increase levels of|
02848|027|P|valbenazine.(1)|
02848|028|B||
02848|029|M|PATIENT MANAGEMENT:  Reduce the valbenazine dose to 40 mg once daily when|
02848|030|M|valbenazine is coadministered with a strong CYP3A4 inhibitor.(1)|
02848|031|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
02848|032|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
02848|033|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
02848|034|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
02848|035|M|irregular heartbeat, dizziness, or fainting.|
02848|036|B||
02848|037|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
02848|038|D|coadministration of ketoconazole with valbenazine increased valbenazine|
02848|039|D|maximum concentration (Cmax) and area-under-the-curve (AUC) by 2 and|
02848|040|D|1.5-fold, respectively. Cmax and AUC for the active metabolite of|
02848|041|D|valbenazine (alpha-HTBZ) increased by approximately 2 and 1.6-fold,|
02848|042|D|respectively.|
02848|043|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
02848|044|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir,|
02848|045|D|itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil,|
02848|046|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
02848|047|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
02848|048|D|troleandomycin, tucatinib, and voriconazole.(3)|
02848|049|B||
02848|050|R|REFERENCES:|
02848|051|B||
02848|052|R|1.Ingrezza (valbenazine) US prescribing information. Neurocrine Biosciences,|1
02848|053|R|  Inc. April, 2020.|1
02848|054|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02848|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02848|056|R|  settings: a scientific statement from the American Heart Association and|6
02848|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02848|058|R|  2;55(9):934-47.|6
02848|059|R|3.This information is based on an extract from the Certara Drug Interaction|6
02848|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02849|001|T|MONOGRAPH TITLE:  Valbenazine/Strong CYP3A4 Inducers|
02849|002|B||
02849|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02849|004|L|of severe adverse interaction.|
02849|005|B||
02849|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02849|007|A|valbenazine.(1)|
02849|008|B||
02849|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02849|010|E|in decreased levels and effectiveness of valbenazine.(1)|
02849|011|B||
02849|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02849|013|P|of the inducer for longer than 1-2 weeks.|
02849|014|B||
02849|015|M|PATIENT MANAGEMENT:  The US manufacturer of valbenazine states that the|
02849|016|M|concurrent use of CYP3A4 inducers is not recommended, and that alternative|
02849|017|M|treatments with less CYP3A4 induction should be considered.(1)|
02849|018|B||
02849|019|D|DISCUSSION:  In a study, co-administration of rifampin, approximately|
02849|020|D|decreased valbenazine area-under-curve (AUC) by 70% and maximum|
02849|021|D|concentration (Cmax) by 25%. The active metabolite of valbenazine|
02849|022|D|(alpha-HTBZ) AUC and Cmax was decreased by 50% and 75%, respectively.(1)|
02849|023|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
02849|024|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02849|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
02849|026|D|rifapentine, and St. John's wort.(2-3)|
02849|027|B||
02849|028|R|REFERENCES:|
02849|029|B||
02849|030|R|1.Ingrezza (valbenazine) US prescribing information. Neurocrine Biosciences,|1
02849|031|R|  Inc. April, 2020.|1
02849|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02849|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02849|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02849|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02849|036|R|  11/14/2017.|1
02849|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
02849|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02851|001|T|MONOGRAPH TITLE:  Valbenazine/MAOIs|
02851|002|B||
02851|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02851|004|L|of severe adverse interaction.|
02851|005|B||
02851|006|A|MECHANISM OF ACTION:  Valbenazine inhibits the vesicular monoamine|
02851|007|A|transporter 2 (VMAT2) that regulates monoamine uptake from the cytoplasm to|
02851|008|A|the synaptic vesicle for storage and release. Concomitant use with MAOIs may|
02851|009|A|increase the concentration of monoamine neurotransmitters in synapses.|
02851|010|B||
02851|011|E|CLINICAL EFFECTS:  The concurrent use of valbenazine with MAOIs may result|
02851|012|E|in serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
02851|013|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
02851|014|E|and muscle rigidity.|
02851|015|E|   Concomitant use of MAOIs with valbenazine may reduce the effectiveness of|
02851|016|E|valbenazine.|
02851|017|B||
02851|018|P|PREDISPOSING FACTORS:  Treatment with multiple medications which increase|
02851|019|P|serotonin levels or with medications which inhibit the metabolism of|
02851|020|P|serotonin increasing drugs are risk factors for serotonin syndrome.|
02851|021|B||
02851|022|M|PATIENT MANAGEMENT:  This combination should be avoided if possible. If|
02851|023|M|concurrent therapy is warranted, patients should be monitored for adverse|
02851|024|M|effects.|
02851|025|M|   If concurrent therapy is warranted, patients should be monitored for|
02851|026|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
02851|027|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02851|028|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02851|029|M|coordination, or severe diarrhea.|
02851|030|B||
02851|031|D|DISCUSSION:  Concomitant use of valbenazine with MAOIs may increase the|
02851|032|D|concentration of monoamine neurotransmitters in synapses.|
02851|033|D|   Metaxalone is a weak inhibitor of MAO.|
02851|034|B||
02851|035|R|REFERENCES:|
02851|036|B||
02851|037|R|1.Ingrezza (valbenazine) US prescribing information. Neurocrine Biosciences,|1
02851|038|R|  Inc. April, 2020.|1
02851|039|R|2.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
02851|040|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
02851|041|R|  Feb;34(2):346.e5-6.|3
02851|042|R|3.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
02851|043|R|  Pfizer Inc. January, 2024.|1
02852|001|T|MONOGRAPH TITLE:  Valbenazine (Less Than or Equal To 40 mg)/Strong CYP2D6|
02852|002|T|Inhibitors|
02852|003|B||
02852|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02852|005|L|take action as needed.|
02852|006|B||
02852|007|A|MECHANISM OF ACTION:  Valbenazine's active metabolite (alpha-HTBZ) is|
02852|008|A|metabolized by CYP2D6 and CYP3A4.(1)|
02852|009|A|  Bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine|
02852|010|A|are strong inhibitors of CYP2D6.(2,3)|
02852|011|B||
02852|012|E|CLINICAL EFFECTS:  Concurrent use of bupropion, dacomitinib, fluoxetine,|
02852|013|E|paroxetine, quinidine or terbinafine may result in elevated levels and|
02852|014|E|adverse effects of valbenazine such as somnolence and QT prolongation.|
02852|015|B||
02852|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
02852|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
02852|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
02852|019|P|syndrome, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
02852|020|P|gender, or advanced age.(4)|
02852|021|P|   Concurrent use of more more than one drug known to cause QT prolongation|
02852|022|P|or higher systemic concentrations of either QT prolonging drug are|
02852|023|P|additional risk factors for torsade de pointes. Factors which may increase|
02852|024|P|systemic drug concentrations include rapid infusion of an intravenous dose|
02852|025|P|or impaired metabolism or elimination of the drug (e.g. coadministration|
02852|026|P|with an agent which inhibits its own metabolism or elimination, genetic|
02852|027|P|impairment in drug metabolism or elimination, and/or renal/hepatic|
02852|028|P|dysfunction.(2)|
02852|029|P|   Concurrent use of strong CYP3A4 inhibitors may further increase levels of|
02852|030|P|valbenazine.(1)|
02852|031|B||
02852|032|M|PATIENT MANAGEMENT:  Reduce the valbenazine dose to 40 mg once daily when|
02852|033|M|valbenazine is coadministered with a strong CYP2D6 inhibitor.(1)|
02852|034|M|   During concomitant therapy with a strong CYP2D6 inhibitor, monitor|
02852|035|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
02852|036|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
02852|037|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
02852|038|M|irregular heartbeat, dizziness, or fainting.|
02852|039|B||
02852|040|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
02852|041|D|coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine|
02852|042|D|did not affect valbenazine maximum concentration (Cmax) or|
02852|043|D|area-under-the-curve (AUC).  However, Cmax and AUC for the active metabolite|
02852|044|D|of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold,|
02852|045|D|respectively.|
02852|046|D|   Strong CYP2D6 inhibitors linked to this monograph include bupropion,|
02852|047|D|dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.|
02852|048|B||
02852|049|R|REFERENCES:|
02852|050|B||
02852|051|R|1.Ingrezza (valbenazine) US prescribing information. Neurocrine Biosciences,|1
02852|052|R|  Inc. April, 2020.|1
02852|053|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02852|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02852|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02852|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02852|057|R|  11/14/2017.|1
02852|058|R|3.This information is based on an extract from the Certara Drug Interaction|6
02852|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02852|060|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02852|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02852|062|R|  settings: a scientific statement from the American Heart Association and|6
02852|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02852|064|R|  2;55(9):934-47.|6
02853|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Ritonavir|
02853|002|B||
02853|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02853|004|L|take action as needed.|
02853|005|B||
02853|006|A|MECHANISM OF ACTION:  Thyroid preparations are substrates for uridine|
02853|007|A|diphosphate glucuronosyltransferase (UGT).  Also, levothyroxine is converted|
02853|008|A|to the thyroid hormone triiodothyronine (T3) which is further metabolized|
02853|009|A|via UGT.(1)|
02853|010|A|   Ritonavir may induce UGT and may increase metabolism of levothyroxine and|
02853|011|A|T3.(1)|
02853|012|B||
02853|013|E|CLINICAL EFFECTS:  The concurrent use of ritonavir may result in decreased|
02853|014|E|levels and clinical effects of the thyroid preparation.|
02853|015|B||
02853|016|P|PREDISPOSING FACTORS:  None determined.|
02853|017|B||
02853|018|M|PATIENT MANAGEMENT:  Patients taking thyroid preparations and ritonavir|
02853|019|M|should be monitored for changes in thyroid function.  Symptoms of|
02853|020|M|hypothyroidism include fatigue, sluggishness, constipation, stiffness,|
02853|021|M|muscle cramps, loss of appetite, excessive weight gain, or dry skin.  The|
02853|022|M|dosage of the thyroid preparation may need to be adjusted accordingly.|
02853|023|B||
02853|024|D|DISCUSSION:  A case report of a 29 year old male with auto-immune|
02853|025|D|thyroiditis was stabilized on levothyroxine 125 mcg daily for one year when|
02853|026|D|concurrent therapy with stavudine 40 mg twice daily, lamivudine 150 mg twice|
02853|027|D|daily, ritonavir 600 mg twice daily, and saquinavir 400 mg twice daily was|
02853|028|D|started.  One month after concurrent therapy, the patient's thyroid|
02853|029|D|stimulating hormone (TSH) increased to 18.47 mIU/L (a 2.7-fold increase)|
02853|030|D|requiring a dose increase of levothyroxine to 250 mcg daily.  Subsequently,|
02853|031|D|ritonavir was discontinued with a decrease in levothyroxine dose to 125 mcg|
02853|032|D|daily with stabilization of TSH at 7.32 mIU/L.(2)|
02853|033|D|   A case report of a 58 year old female on zidovudine, lamivudine, and|
02853|034|D|lopinavir/ritonavir underwent a total thyroidectomy with subsequent|
02853|035|D|introduction of levothyroxine.  Levothyroxine was titrated to 225 mcg daily|
02853|036|D|along with the addition of liothyronine.  Due to persistently elevated TSH|
02853|037|D|values (range 47.6 - 85.1 mIU/L), lopinavir/ritonavir was then withdrawn and|
02853|038|D|two months later TSH and T4 levels returned to normal, 4.1 mIU/L and 12.1|
02853|039|D|pmol/L, respectively.  Eight months later lopinavir/ritonavir was|
02853|040|D|reintroduced and 1 month later TSH and T4 increased to 42.9 mIU/L and 10.6|
02853|041|D|mIU/L, respectively.  Again, lopinavir/ritonavir was withdrawn and TSH and|
02853|042|D|T4 values returned to normal, 1.1 mIU/L and 13.4 pmol/L, respectively.(3)|
02853|043|D|   A case report of a 37 year old female on abacavir/lamivudine and|
02853|044|D|lopinavir/ritonavir details the management course of hypothyroidism over a|
02853|045|D|six year period, including during 3 pregnancies.  After a total|
02853|046|D|thyroidectomy, the patient was started on levothyroxine 75 mcg daily.|
02853|047|D|Post-surgical levels of TSH and T4 (during patient's second pregnancy)|
02853|048|D|increased to 94.3 mIU/L and 6.1 mIU/L, respectively, and peaked at 125.89|
02853|049|D|mIU/L and 7.7 mIU/L, respectively.  Levothyroxine doses were increased to|
02853|050|D|175 mcg daily over the following year (during the patient's second and third|
02853|051|D|pregnancies) to achieve decreased TSH and T4 values of 8.58 mIU/L and 12.8|
02853|052|D|mIU/L, respectively.  TSH values rose again to 17.23 mIU/L and ritonavir was|
02853|053|D|withdrawn from therapy.  The patient was then maintained on levothyroxine|
02853|054|D|125 mcg daily with a TSH of 0.12 - 0.42 mIU/L over the next 2 years.(1)|
02853|055|B||
02853|056|R|REFERENCES:|
02853|057|B||
02853|058|R|1.Sahajpal R, Ahmed RA, Hughes CA, Foisy MM. Probable interaction between|3
02853|059|R|  levothyroxine and ritonavir: Case report and literature review. Am J|3
02853|060|R|  Health Syst Pharm 2017 Apr 15;74(8):587-592.|3
02853|061|R|2.Tseng A, Fletcher D. Interaction between ritonavir and levothyroxine. AIDS|3
02853|062|R|  1998 Nov 12;12(16):2235-6.|3
02853|063|R|3.Touzot M, Beller CL, Touzot F, Louet AL, Piketty C. Dramatic interaction|3
02853|064|R|  between levothyroxine and lopinavir/ritonavir in a HIV-infected patient.|3
02853|065|R|  AIDS 2006 May 12;20(8):1210-2.|3
02854|001|T|MONOGRAPH TITLE:  Lidocaine/Fluvoxamine|
02854|002|B||
02854|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02854|004|L|take action as needed.|
02854|005|B||
02854|006|A|MECHANISM OF ACTION:  Fluvoxamine may inhibit the metabolism of lidocaine by|
02854|007|A|CYP1A2.(1,2)|
02854|008|B||
02854|009|E|CLINICAL EFFECTS:  Concurrent or recent use of fluvoxamine may result in|
02854|010|E|increased effects of lidocaine.(1,2)|
02854|011|B||
02854|012|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients|
02854|013|P|taking strong CYP3A4 inhibitors.(1,2)  The interaction may be less|
02854|014|P|clinically significant in patients with severe liver impairment.(3)|
02854|015|B||
02854|016|M|PATIENT MANAGEMENT:  Patients receiving this combination should be monitored|
02854|017|M|for signs of lidocaine toxicity. The dosage of lidocaine should be adjusted|
02854|018|M|based on serum lidocaine levels and patient response.|
02854|019|B||
02854|020|D|DISCUSSION:  In a study in 8 subjects, pretreatment with fluvoxamine (100 mg|
02854|021|D|daily) for 6 days increased the peak concentration (Cmax) and|
02854|022|D|area-under-curve (AUC) of oral lidocaine (1 mg/kg) by 220% and 305%,|
02854|023|D|respectively.  Pretreatment with fluvoxamine (100 mg daily) and erythromycin|
02854|024|D|(1500 mg daily) for 6 days increased lidocaine Cmax and AUC by 250% and|
02854|025|D|360%, respectively.(1)|
02854|026|D|   In a study in 9 subjects, pretreatment with fluvoxamine (100 mg daily)|
02854|027|D|for 6 days decreased the clearance of intravenous lidocaine by 41%.|
02854|028|D|Pretreatment with fluvoxamine (100 mg daily) and erythromycin (1500 mg|
02854|029|D|daily) for 6 days decreased the clearance of intravenous lidocaine by|
02854|030|D|53%.(2)|
02854|031|D|   In a study in 10 healths subjects, 10 patients with mild (Child grade A)|
02854|032|D|liver impairment, and 10 patients with severe (Child grade C) liver|
02854|033|D|impairment, fluvoxamine decreased lidocaine clearance by 60% in healthy|
02854|034|D|subjects and by 44% in patients with mild liver impairment.  However, there|
02854|035|D|was no significant effect in patients with severe liver impairment.(3)|
02854|036|B||
02854|037|R|REFERENCES:|
02854|038|B||
02854|039|R|1.Isohanni MH, Neuvonen PJ, Olkkola KT. Effect of fluvoxamine and|2
02854|040|R|  erythromycin on the pharmacokinetics of oral lidocaine. Basic Clin|2
02854|041|R|  Pharmacol Toxicol 2006 Aug;99(2):168-72.|2
02854|042|R|2.Olkkola KT, Isohanni MH, Hamunen K, Neuvonen PJ. The effect of|2
02854|043|R|  erythromycin and fluvoxamine on the pharmacokinetics of intravenous|2
02854|044|R|  lidocaine. Anesth Analg 2005 May;100(5):1352-6, table of contents.|2
02854|045|R|3.Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P.|2
02854|046|R|  Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in|2
02854|047|R|  vivo: effects of liver function. Clin Pharmacol Ther 2004 Jan;75(1):80-8.|2
02855|001|T|MONOGRAPH TITLE:  Deoxycytidine Kinase Substrates/Cladribine (Oral)|
02855|002|B||
02855|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02855|004|L|of severe adverse interaction.|
02855|005|B||
02855|006|A|MECHANISM OF ACTION:  Clofarabine, cytarabine, emtricitabine, fludarabine,|
02855|007|A|gemcitabine, lamivudine, molnupiravir, nelarabine and zalcitabine may|
02855|008|A|inhibit the intracellular phosphorylation of cladribine by deoxycytidine|
02855|009|A|kinase (dCK).|
02855|010|B||
02855|011|E|CLINICAL EFFECTS:  Concurrent administration of clofarabine, cytarabine,|
02855|012|E|emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir,|
02855|013|E|nelarabine, or zalcitabine with cladribine may result in decreased clinical|
02855|014|E|efficacy of cladribine.|
02855|015|B||
02855|016|P|PREDISPOSING FACTORS:  None determined.|
02855|017|B||
02855|018|M|PATIENT MANAGEMENT:  The manufacturer of lamivudine states that the|
02855|019|M|concurrent use of lamivudine and cladribine is not recommended.(1)  The|
02855|020|M|manufacturer of cladribine states that concurrent use of compounds that|
02855|021|M|require activation by intracellular phosphorylation should be avoided.(2)|
02855|022|B||
02855|023|D|DISCUSSION:  Cladribine undergoes a series of phosphorylations to its active|
02855|024|D|metabolites.|
02855|025|D|   In a case report, a patient on lamivudine who received cladribine|
02855|026|D|concurrently did not experience a decrease in his lymphocyte count.  After|
02855|027|D|discontinuation of lamivudine and readministration of cladribine, his|
02855|028|D|lymphocytes dropped as expected.(3)|
02855|029|D|   It is expected that other compounds phosphorylated by dCK would also|
02855|030|D|decrease cladribine's efficacy.(4)|
02855|031|D|   Compounds phosphorylated by dCK include: clofarabine, cytarabine,|
02855|032|D|emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir,|
02855|033|D|nelarabine and zalcitabine.|
02855|034|B||
02855|035|R|REFERENCES:|
02855|036|B||
02855|037|R|1.Epivir (lamivudine) UK summary of product characteristics. Viiv Healthcare|1
02855|038|R|  UK Ltd July 2021.|1
02855|039|R|2.Mavenclad (cladribine) US prescribing information. EMD Serono, Inc. March,|1
02855|040|R|  2019.|1
02855|041|R|3.Chtioui H, Millius C, Lammle B, Lauterburg BH. Concomitant treatment with|3
02855|042|R|  lamivudine renders cladribine inactive by inhibition of its|3
02855|043|R|  phosphorylation. Br J Haematol 2009 Jan;144(1):136-7.|3
02855|044|R|4.Anderson PL, Kakuda TN, Lichtenstein KA. The cellular pharmacology of|6
02855|045|R|  nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors and|6
02855|046|R|  its relationship to clinical toxicities. Clin Infect Dis 2004 Mar 1;|6
02855|047|R|  38(5):743-53.|6
02856|001|T|MONOGRAPH TITLE:  Midostaurin/Strong CYP3A4 Inhibitors|
02856|002|B||
02856|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02856|004|L|take action as needed.|
02856|005|B||
02856|006|A|MECHANISM OF ACTION:  Midostaurin is a substrate of CYP3A4.  Strong|
02856|007|A|inhibitors of CYP3A4 may inhibit the metabolism of midostaurin.(1)|
02856|008|B||
02856|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02856|010|E|in increased levels and toxicity from midostaurin, including QTc|
02856|011|E|prolongation, which may result in potentially life-threatening cardiac|
02856|012|E|arrhythmias like torsades de pointes (TdP).  The increase in midostaurin|
02856|013|E|concentrations may be pronounced during the first week of concurrent|
02856|014|E|therapy.(1)|
02856|015|B||
02856|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02856|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
02856|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02856|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02856|020|P|female gender, or advanced age.(2)|
02856|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02856|022|P|higher systemic concentrations of either QT prolonging drug are additional|
02856|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02856|024|P|drug concentrations include rapid infusion of an intravenous dose or|
02856|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02856|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02856|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02856|028|B||
02856|029|M|PATIENT MANAGEMENT:  The manufacturer of midostaurin states to consider|
02856|030|M|alternative therapies that do not inhibit CYP3A4 whenever possible.(1)|
02856|031|M|   Monitor patient for signs of midostaurin toxicity with concurrent use,|
02856|032|M|especially during the first week of concurrent therapy in advanced systemic|
02856|033|M|mastocytosis (SM) population and during the first week of each cycle of|
02856|034|M|chemotherapy in acute myeloid leukemia (AML) population.(1)|
02856|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02856|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02856|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02856|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02856|039|B||
02856|040|D|DISCUSSION:  Midostaurin is a substrate of CYP3A4.(1)|
02856|041|D|   Concurrent administration of ketoconazole (400 mg daily for 10 days, a|
02856|042|D|strong CYP3A4 inhibitor) with a single 50 mg dose of midostaurin on day 6|
02856|043|D|increased the area-under-curve (AUC) of midostaurin and the active|
02856|044|D|metabolite, CGP62221, 10.4-fold and 3.5-fold, respectively.  The AUC over|
02856|045|D|time to last measurable concentration of CGP62221 increased by 1.2-fold|
02856|046|D|compared to midostaurin alone.(1)|
02856|047|D|   Concurrent administration of itraconazole (100 mg twice daily on days|
02856|048|D|22-28 for 13 doses, a strong CYP3A4 inhibitor) with multiple doses of|
02856|049|D|midostaurin (100 mg twice daily on days 1-2 and 50 mg twice daily on days|
02856|050|D|3-28) increased day 28 minimum concentration (Cmin) of midostaurin, CGP62221|
02856|051|D|and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, compared to|
02856|052|D|day 21 Cmin concentrations with midostaurin alone.(1)|
02856|053|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
02856|054|D|cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
02856|055|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
02856|056|D|paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.(3,4)|
02856|057|B||
02856|058|R|REFERENCES:|
02856|059|B||
02856|060|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
02856|061|R|  Corporation November, 2021.|1
02856|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02856|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02856|064|R|  settings: a scientific statement from the American Heart Association and|6
02856|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02856|066|R|  2;55(9):934-47.|6
02856|067|R|3.This information is based on an extract from the Certara Drug Interaction|6
02856|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02856|069|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02856|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02856|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02856|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02856|073|R|  11/14/2017.|1
02857|001|T|MONOGRAPH TITLE:  Midostaurin/Strong CYP3A4 Inducers|
02857|002|B||
02857|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02857|004|L|of severe adverse interaction.|
02857|005|B||
02857|006|A|MECHANISM OF ACTION:  Midostaurin is a substrate of CYP3A4.  Strong inducers|
02857|007|A|of CYP3A4 may induce the metabolism of midostaurin.(1)|
02857|008|B||
02857|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02857|010|E|in decreased levels and effectiveness of midostaurin.(1)|
02857|011|B||
02857|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02857|013|P|of the inducer for longer than 1-2 weeks.|
02857|014|B||
02857|015|M|PATIENT MANAGEMENT:  The manufacturer of midostaurin states to avoid|
02857|016|M|concurrent use with strong CYP3A4 inducers.(1)|
02857|017|B||
02857|018|D|DISCUSSION:  Midostaurin is a substrate of CYP3A4.(1)|
02857|019|D|   Concurrent administration of rifampicin (600 mg daily for 14 days, a|
02857|020|D|strong CYP3A4 inducer) with a single 50 mg dose of midostaurin on day 9|
02857|021|D|decreased the area-under-curve (AUC) of midostaurin and CGP62221, the active|
02857|022|D|metabolite, by 96% and 92%, respectively.  The AUC over time to last|
02857|023|D|measurable concentration of CGP62221 decreased by 59%.(1)|
02857|024|D|   Strong CYP3A4 inducers linked to this monograph include:  barbiturates,|
02857|025|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
02857|026|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
02857|027|D|wort.(2-3)|
02857|028|B||
02857|029|R|REFERENCES:|
02857|030|B||
02857|031|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
02857|032|R|  Corporation November, 2021.|1
02857|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
02857|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02857|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02857|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02857|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02857|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02857|039|R|  11/14/2017.|1
02858|001|T|MONOGRAPH TITLE:  Brigatinib/Strong CYP3A4 Inhibitors|
02858|002|B||
02858|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02858|004|L|of severe adverse interaction.|
02858|005|B||
02858|006|A|MECHANISM OF ACTION:  Brigatinib is a substrate of CYP3A4.  Strong|
02858|007|A|inhibitors of CYP3A4 may inhibit the metabolism of brigatinib.(1)|
02858|008|B||
02858|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02858|010|E|in increased levels and toxicity from brigatinib.(1)|
02858|011|B||
02858|012|P|PREDISPOSING FACTORS:  None determined.|
02858|013|B||
02858|014|M|PATIENT MANAGEMENT:  The manufacturer of brigatinib states to avoid|
02858|015|M|concurrent administration with strong CYP3A4 inhibitors.  If concurrent|
02858|016|M|therapy cannot be avoided, reduce the once daily dose of brigatinib by|
02858|017|M|approximately 50% (i.e. from 180 mg to 90 mg).  Upon discontinuation of a|
02858|018|M|strong CYP3A4 inhibitor, resume the brigatinib dose that was tolerated prior|
02858|019|M|to initiating the strong CYP3A4 inhibitor.(1)|
02858|020|M|   Monitor patient for signs of brigatinib toxicity with concurrent use.|
02858|021|B||
02858|022|D|DISCUSSION:  Brigatinib is a substrate of CYP3A4.(1)|
02858|023|D|   Concurrent administration of itraconazole (200 mg twice daily, a strong|
02858|024|D|CYP3A4 inhibitor) with a single 90 mg dose of brigatinib increased the|
02858|025|D|brigatinib maximum concentration (Cmax) by 21% and area-under-curve (AUC) by|
02858|026|D|101% compared to brigatinib alone.(1)|
02858|027|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
02858|028|D|boceprevir, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole,|
02858|029|D|josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone,|
02858|030|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
02858|031|D|saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and|
02858|032|D|voriconazole.(2,3)|
02858|033|B||
02858|034|R|REFERENCES:|
02858|035|B||
02858|036|R|1.Alunbrig (brigatinib) US prescribing information. Ariad Pharmaceuticals,|1
02858|037|R|  Inc. September, 2021.|1
02858|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
02858|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02858|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02858|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02858|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02858|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02858|044|R|  11/14/2017.|1
02859|001|T|MONOGRAPH TITLE:  Brigatinib/Strong CYP3A4 Inducers; Rifabutin|
02859|002|B||
02859|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02859|004|L|of severe adverse interaction.|
02859|005|B||
02859|006|A|MECHANISM OF ACTION:  Brigatinib is a substrate of CYP3A4.  Strong inducers|
02859|007|A|of CYP3A4 and rifabutin may induce the metabolism of brigatinib.(1,2)|
02859|008|B||
02859|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 or rifabutin|
02859|010|E|may result in decreased levels and effectiveness of brigatinib.(1,2)|
02859|011|B||
02859|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02859|013|P|of the inducer for longer than 1-2 weeks.|
02859|014|B||
02859|015|M|PATIENT MANAGEMENT:  The manufacturer of brigatinib states to avoid|
02859|016|M|concurrent administration with strong CYP3A4 inducers.(1,2)  The UK|
02859|017|M|manufacturer of brigatinib includes rifabutin on its list of strong CYP3A4|
02859|018|M|inducers that should be avoided.(2)|
02859|019|B||
02859|020|D|DISCUSSION:  Brigatinib is a substrate of CYP3A4.(1)|
02859|021|D|   Concurrent administration of rifampin (600 mg daily, a strong CYP3A4|
02859|022|D|inducer) with a single 180 mg dose of brigatinib decreased the brigatinib|
02859|023|D|maximum concentration (Cmax) by 60% and area-under-curve (AUC) by 80%|
02859|024|D|compared to brigatinib alone.(1)|
02859|025|D|   Strong CYP3A4 inducers linked to this monograph include:  apalutamide,|
02859|026|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02859|027|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
02859|028|D|rifabutin, rifampin, rifapentine, and St. John's wort.(3-4)|
02859|029|B||
02859|030|R|REFERENCES:|
02859|031|B||
02859|032|R|1.Alunbrig (brigatinib) US prescribing information. Ariad Pharmaceuticals,|1
02859|033|R|  Inc. September, 2021.|1
02859|034|R|2.Alunbrig (brigatinib) UK Summary of Product Characteristics. Takeda UK Ltd|1
02859|035|R|  January 18, 2019.|1
02859|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
02859|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02859|038|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02859|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02859|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02859|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02859|042|R|  11/14/2017.|1
02860|001|T|MONOGRAPH TITLE:  Estrogen Replacement Therapy/Rifamycins|
02860|002|B||
02860|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02860|004|L|take action as needed.|
02860|005|B||
02860|006|A|MECHANISM OF ACTION:  Rifamycins (rifampin, rifabutin and rifapentine)|
02860|007|A|induce the the CYP3A4 mediated metabolism of estrogens and progestins.|
02860|008|B||
02860|009|E|CLINICAL EFFECTS:  Concurrent use of rifampin, rifabutin, or rifapentine may|
02860|010|E|result in reduced levels and clinical effectiveness of hormone replacement|
02860|011|E|therapy.  Effects may be seen for several weeks after discontinuation of the|
02860|012|E|rifamycin.|
02860|013|B||
02860|014|P|PREDISPOSING FACTORS:  None determined.|
02860|015|B||
02860|016|M|PATIENT MANAGEMENT:  Patients receiving rifamycins should be alerted to the|
02860|017|M|risk for decreased effectiveness of their hormone replacement therapy.|
02860|018|M|   The patient should be asked to report any spotting or bleeding.|
02860|019|B||
02860|020|D|DISCUSSION:  In an open-label, randomized crossover study, 22 healthy|
02860|021|D|females received oral contraceptives for 21 days, then were randomized to|
02860|022|D|receive rifampin or rifabutin (300 mg/d for 10 days).  Rifampin and|
02860|023|D|rifabutin decreased the area-under-curve (AUC) of ethinyl estradiol by 64%|
02860|024|D|and 35%, respectively, and maximum concentration (Cmax) by 42% and 20%,|
02860|025|D|respectively.  Rifampin and rifabutin decreased the AUC of norethindrone by|
02860|026|D|60% and 20%, respectively.  Incidences of spotting were much greater in the|
02860|027|D|rifampin co-administration group.|
02860|028|D|   In a study, a single dose of oral contraceptive (ethinyl estradiol 50 mcg|
02860|029|D|and norethindrone acetate 1 mg) was administered to 7 female patients with|
02860|030|D|tuberculosis, both during TB treatment and one month after stopping rifampin|
02860|031|D|(450-600 mg/d).  Upon cessation of rifampin therapy, the AUC for ethinyl|
02860|032|D|estradiol significantly increased by 70%, and terminal plasma half-life more|
02860|033|D|than doubled.|
02860|034|D|   A similar study design analyzed the pharmacokinetics of norethisterone (1|
02860|035|D|mg) in 8 women receiving rifampin (450-600 mg/d).  Upon termination of TB|
02860|036|D|treatment, it was found that rifampin reduced the AUC of a single dose of|
02860|037|D|norethisterone (1 mg) by approximately 40%, with a half-life reduction of|
02860|038|D|50%.|
02860|039|D|   In a study, male volunteers received 50 mcg iv of ethinyl estradiol,|
02860|040|D|followed by rifampin (600 mg for 6 days).  Ethinyl estradiol half-life|
02860|041|D|decreased by approximately 55%.  The upward titration of ethinyl estradiol|
02860|042|D|to 100 mcg resulted in a more than 2-fold increase in ethinyl estradiol|
02860|043|D|metabolism caused by rifampicin treatment.|
02860|044|D|   An analytical trial evaluated liver biopsies from four patients treated|
02860|045|D|with rifampin 600 mg for a period of 6-10 days.  Hepatic microsomes from the|
02860|046|D|biopsies were incubated with hormone substrates, including oestradiol and|
02860|047|D|ethinyloestradiol.  Rifampin resulted in a fourfold increase in|
02860|048|D|hydroxylation.  Not only did rifampin increase the rate of hydroxylation|
02860|049|D|through enzyme induction, it also caused an increase in cytochrome P-450.|
02860|050|D|   There are reports of breakthrough bleeding and unintended pregnancy|
02860|051|D|during concurrent use.|
02860|052|B||
02860|053|R|REFERENCES:|
02860|054|B||
02860|055|R|1.Altschuler SL, Valenteen JW. Amenorrhea following rifampin administration|3
02860|056|R|  during oral contraceptive use. Obstet Gynecol 1974 Nov;44(5):771-2.|3
02860|057|R|2.Skolnick JL, Stoler BS, Katz DB, Anderson WH. Rifampin, oral|3
02860|058|R|  contraceptives, and pregnancy. JAMA 1976 Sep 20;236(12):1382.|3
02860|059|R|3.Back DJ, Breckenridge AM, Crawford F, MacIver M, Orme ML, Park BK, Rowe|2
02860|060|R|  PH, Smith E. The effect of rifampicin on norethisterone pharmacokinetics.|2
02860|061|R|  Eur J Clin Pharmacol 1979 Apr 17;15(3):193-7.|2
02860|062|R|4.Joshi JV, Joshi UM, Sankolli GM, Gupta K, Rao AP, Hazari K, Sheth UK,|2
02860|063|R|  Saxena BN. A study of interaction of a low-dose combination oral|2
02860|064|R|  contraceptive with anti-tubercular drugs. Contraception 1980 Jun;|2
02860|065|R|  21(6):617-29.|2
02860|066|R|5.Back DJ, Breckenridge AM, Crawford FE, Hall JM, MacIver M, Orme ML, Rowe|2
02860|067|R|  PH, Smith E, Watts MJ. The effect of rifampicin on the pharmacokinetics of|2
02860|068|R|  ethynylestradiol in women. Contraception 1980 Feb;21(2):135-43.|2
02860|069|R|6.Gupta KC, Ali MY. Failure of oral contraceptive with rifampicin. Med J|3
02860|070|R|  Zambia 1980 Dec-1981 Jan;15(1):23.|3
02860|071|R|7.Baciewicz AM, Self TH. Rifampin drug interactions. Arch Intern Med 1984|6
02860|072|R|  Aug;144(8):1667-71.|6
02860|073|R|8.Barnett ML. Inhibition of oral contraceptive effectiveness by concurrent|6
02860|074|R|  antibiotic administration. A review. J Periodontol 1985 Jan;56(1):18-20.|6
02860|075|R|9.Baciewicz AM. Oral contraceptive drug interactions. Ther Drug Monit 1985;|6
02860|076|R|  7(1):26-35.|6
02860|077|R|10.Szoka PR, Edgren RA. Drug interactions with oral contraceptives:|6
02860|078|R|   compilation and analysis of an adverse experience report database. Fertil|6
02860|079|R|   Steril 1988 May;49(5 Suppl 2):31S-38S.|6
02860|080|R|11.Nor-Q-D (norethindrone) US prescribing information. WatsonPharma March,|1
02860|081|R|   2005.|1
02860|082|R|12.Barditch-Crovo P, Trapnell CB, Ette E, Zacur HA, Coresh J, Rocco LE,|2
02860|083|R|   Hendrix CW, Flexner C. The effects of rifampin and rifabutin on the|2
02860|084|R|   pharmacokinetics and pharmacodynamics of a combination oral|2
02860|085|R|   contraceptive. Clin Pharmacol Ther 1999 Apr;65(4):428-38.|2
02860|086|R|13.LeBel M, Masson E, Guilbert E, Colborn D, Paquet F, Allard S, Vallee F,|2
02860|087|R|   Narang PK. Effects of rifabutin and rifampicin on the pharmacokinetics of|2
02860|088|R|   ethinylestradiol and norethindrone. J Clin Pharmacol 1998 Nov;|2
02860|089|R|   38(11):1042-50.|2
02860|090|R|14.Buss WC. Induction of hepatic drug metabolizing enzymes and pregnancy|3
02860|091|R|   while taking oral contraceptives. J Antimicrob Chemother 1979 Jan;|3
02860|092|R|   5(1):4-5.|3
02860|093|R|15.Gelbke HP, Gethmann U, Knuppen R. Influence of rifampicin treatment on|2
02860|094|R|   the metabolic fate of. Horm Metab Res 1977 Sep;9(5):415-9.|2
02860|095|R|16.Bolt HM, Bolt M, Kappus H. Interaction of rifampicin treatment with|2
02860|096|R|   pharmacokinetics and metabolism of ethinyloestradiol in man. Acta|2
02860|097|R|   Endocrinol (Copenh) 1977 May;85(1):189-197.|2
02860|098|R|17.Bessot JC, Vandevenne A, Petitjean R, Burghard G. Antagonistic action of|2
02860|099|R|   rifampicin and isoniazid on the metabolism of oral contraceptives. Nouv|2
02860|100|R|   Presse Med 1977 Apr 30;6(18):1568.|2
02860|101|R|18.Dommisse J. Letter: Oral contraceptive failure due to drug interaction. S|3
02860|102|R|   Afr Med J 1976 May 15;50(21):796.|3
02860|103|R|19.Bolt HM, Kappus H, Bolt M. Effect of rifampicin treatment on the|5
02860|104|R|   metabolism of oestradiol and 17alpha-ethinyloestradiol by human liver|5
02860|105|R|   microsomes. Eur J Clin Pharmacol 1975 Jun 13;8(5):301-7.|5
02860|106|R|20.Priftin (rifapentine) US prescribing information. Sanofi-Aventis U.S. LLC|1
02860|107|R|   July, 2010.|1
02860|108|R|21.This information is based on an extract from the Certara Drug Interaction|6
02860|109|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02861|001|T|MONOGRAPH TITLE:  Estrogen Replacement Therapy/St. John's Wort|
02861|002|B||
02861|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02861|004|L|take action as needed.|
02861|005|B||
02861|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of estrogen|
02861|007|A|by CYP3A4.(1-7)|
02861|008|B||
02861|009|E|CLINICAL EFFECTS:  The concurrent administration of St. John's wort may|
02861|010|E|result in reduced levels and clinical effectiveness of estrogen.(1-7)|
02861|011|B||
02861|012|P|PREDISPOSING FACTORS:  None determined.|
02861|013|B||
02861|014|M|PATIENT MANAGEMENT:  Patients receiving estrogen replacement therapy should|
02861|015|M|be alerted to the risk of decreased estrogen effectiveness from St. John's|
02861|016|M|wort.|
02861|017|M|   The dosage of hormone therapy may need to be adjusted if St. John's wort|
02861|018|M|is added to or discontinued from concurrent therapy or St. John's wort may|
02861|019|M|need to be discontinued.|
02861|020|B||
02861|021|D|DISCUSSION:  In a study in 12 healthy women taking ethinyl|
02861|022|D|estradiol-norethindrone, administration of St. John's wort (300 mg 3 times|
02861|023|D|daily) increased the oral clearance of norethindrone and decreased the|
02861|024|D|half-life of ethinyloestradiol. Serum concentrations of follicle-stimulating|
02861|025|D|hormone, luteinizing hormone, and progesterone were not significantly|
02861|026|D|affected by St. John's wort. Breakthrough bleeding occurred in 2 of 12|
02861|027|D|subjects in the control phase and 7 of 12 women during the St. John's wort|
02861|028|D|phase.(2)|
02861|029|D|   In a study in 17 healthy women, subjects receiving|
02861|030|D|ethinyloestradiol-desogestrel alone, with 300 mg St. John's wort twice|
02861|031|D|daily, and with 300 mg St. John's wort 3 times daily.  There was no|
02861|032|D|significant changes in follicle maturation, serum estrogen, or serum|
02861|033|D|progesterone concentrations during St. John's wort.  During the control|
02861|034|D|phase, 6 women reported breakthrough bleeding, compared with 13 women while|
02861|035|D|taking St. John's wort twice daily and 15 women while taking St. John's wort|
02861|036|D|3 times daily.  There were no changes in the area-under-curve (AUC) or|
02861|037|D|maximum concentration (Cmax) of ethinyloestradiol.  However, the AUC and|
02861|038|D|Cmax of 3-ketodesogestrel decreased by 43.9% and by 17.8%, respectively|
02861|039|D|during twice daily St. John's wort and by 41.7% and by 22.8%, respectively|
02861|040|D|during 3 times daily St. John's wort.(3)|
02861|041|D|   In a study in 16 healthy women, concurrent St. John's wort (300 mg three|
02861|042|D|times daily) decreased the exposure from Loestrin 1/20 (estradiol with|
02861|043|D|norethindrone) by 13% to 15%.  Breakthrough bleeding and evidence of|
02861|044|D|follicle growth and probable ovulation increased during concurrent St.|
02861|045|D|John's wort.(6)|
02861|046|D|   Unplanned pregnancies have been reported during concurrent St. John's|
02861|047|D|wort and hormonal contraception.(3,6)|
02861|048|D|   In a study in 15 healthy women, concurrent St. John's wort and Loestrin|
02861|049|D|1/20 did not affect androgen levels when compared to Loestrin 1/20 alone,|
02861|050|D|suggesting that concurrent therapy would not impair treatment of acne or|
02861|051|D|hirsutism.(7)|
02861|052|B||
02861|053|R|REFERENCES:|
02861|054|B||
02861|055|R|1.Premarin (conjugated estrogens) US prescribing information. Wyeth|1
02861|056|R|  Pharmaceuticals Inc. November 7, 2017.|1
02861|057|R|2.Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, Hilligoss JK,|2
02861|058|R|  Miller M, Gorski JC. The interaction between St John's wort and an oral|2
02861|059|R|  contraceptive. Clin Pharmacol Ther 2003 Dec;74(6):525-35.|2
02861|060|R|3.Pfrunder A, Schiesser M, Gerber S, Haschke M, Bitzer J, Drewe J.|2
02861|061|R|  Interaction of St John's wort with low-dose oral contraceptive therapy: a|2
02861|062|R|  randomized controlled trial. Br J Clin Pharmacol 2003 Dec;56(6):683-90.|2
02861|063|R|4.Nor-Q-D (norethindrone) US prescribing information. WatsonPharma March,|1
02861|064|R|  2005.|1
02861|065|R|5.Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's|2
02861|066|R|  Wort with oral contraceptives: effects on the pharmacokinetics of|2
02861|067|R|  norethindrone and ethinyl estradiol, ovarian activity and breakthrough|2
02861|068|R|  bleeding. Contraception 2005 Jun;71(6):402-8.|2
02861|069|R|6.Schwarz UI, Buschel B, Kirch W. Unwanted pregnancy on self-medication with|3
02861|070|R|  St John's wort despite hormonal contraception. Br J Clin Pharmacol 2003|3
02861|071|R|  Jan;55(1):112-3.|3
02861|072|R|7.Fogle RH, Murphy PA, Westhoff CL, Stanczyk FZ. Does St. John's wort|2
02861|073|R|  interfere with the antiandrogenic effect of oral contraceptive pills?.|2
02861|074|R|  Contraception 2006 Sep;74(3):245-8.|2
02862|001|T|MONOGRAPH TITLE:  Lamotrigine/Estrogen Replacement Therapy|
02862|002|B||
02862|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02862|004|L|of severe adverse interaction.|
02862|005|B||
02862|006|A|MECHANISM OF ACTION:  Estrogens increase glucuronidation mediated metabolism|
02862|007|A|of lamotrigine.  Lamotrigine may modestly induce the metabolism of|
02862|008|A|estrogens.(1,2)|
02862|009|B||
02862|010|E|CLINICAL EFFECTS:  Concurrent use of lamotrigine and estrogens may result in|
02862|011|E|decreased levels and effectiveness of both agents.  Increased seizure rates|
02862|012|E|have been reported in patients taking lamotrigine for epilepsy.(1,2)|
02862|013|B||
02862|014|P|PREDISPOSING FACTORS:  Increased seizure risk is more likely in when|
02862|015|P|lamotrigine is used as monotherapy for treatment of epilepsy.|
02862|016|P|   The risk for an increase in seizure rate is lower in patients already|
02862|017|P|stabilized on a combination of lamotrigine and an enzyme inducing agent such|
02862|018|P|as carbamazepine, phenytoin, phenobarbital, or primidone.|
02862|019|B||
02862|020|M|PATIENT MANAGEMENT:  Monitor closely the clinical effectiveness of|
02862|021|M|lamotrigine with concurrent use of estrogen replacement therapy. Dose|
02862|022|M|adjustment may be necessary.(1)|
02862|023|M|   During initiation of lamotrigine therapy, no adjustments to the|
02862|024|M|recommended lamotrigine dose escalation guidelines are recommended in|
02862|025|M|patients taking estrogen.(1)|
02862|026|M|   Dose adjustments will be necessary in most patients who start or stop an|
02862|027|M|estrogen in patients taking maintenance doses of lamotrigine.  The|
02862|028|M|lamotrigine dosage may need to be increased by as much as 2-fold according|
02862|029|M|to clinical response when estrogen or estrogen-containing contraceptives are|
02862|030|M|initiated in patients NOT taking other drugs which induce glucuronidation|
02862|031|M|such as carbamazepine, phenytoin, phenobarbital, primidone,|
02862|032|M|lopinavir/ritonavir, atazanavir/ritonavir, or rifampin.  If estrogen is|
02862|033|M|discontinued, the dosage of lamotrigine may need to be decreased by 50%.(1)|
02862|034|M|Initiate changes in lamotrigine dosage at the same time estrogen containing|
02862|035|M|products are started or stopped.(1)|
02862|036|M|   In patients also taking carbamazepine, phenytoin, phenobarbital,|
02862|037|M|primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin, no|
02862|038|M|lamotrigine maintenance dosage adjustments should be necessary if estrogen|
02862|039|M|is initiated or discontinued.(1)|
02862|040|B||
02862|041|D|DISCUSSION:  In a study in 16 females, concurrent ethinylestradiol (30 mcg)|
02862|042|D|and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) increased|
02862|043|D|lamotrigine clearance by 2-fold, with a mean decrease in lamotrigine|
02862|044|D|area-under-curve (AUC) and maximum concentration (Cmax) by 52% and 39%,|
02862|045|D|respectively.  Serum trough lamotrigine levels were two-fold higher at the|
02862|046|D|end of the week of inactive tablets when compared to lamotrigine levels at|
02862|047|D|the end of the active hormonal cycle.  This effect should be expected in|
02862|048|D|women not taking carbamazepine, phenytoin, phenobarbital, primidone, or|
02862|049|D|rifampin.(1)|
02862|050|D|   In a study in 16 females, concurrent ethinylestradiol (30 mcg) and|
02862|051|D|levonorgestrel (150 mcg) with lamotrigine (300 mg per day) had no effect on|
02862|052|D|ethinylestradiol levels.  Levonorgestrel AUC and Cmax decreased by 19% and|
02862|053|D|12%, respectively.  Though there was no hormonal evidence of ovulation,|
02862|054|D|there was some loss of suppression of the hypothalamic-pituitary-ovarian|
02862|055|D|axis.(1)|
02862|056|D|   In a study, mean steady-state lamotrigine levels were 13 micro mol/L in|
02862|057|D|22 women taking oral contraceptives compared to 28 micro mol/L in 30 women|
02862|058|D|who were not taking oral contraceptives.  The lamotrigine dose/body weight/|
02862|059|D|plasma concentration was 2.1 L/kg/day in patients taking oral contraceptives|
02862|060|D|compared to 0.8 L/kg/day in patients without oral contraceptives.(3)|
02862|061|D|   One set of authors reported seven cases of decreased lamotrigine levels|
02862|062|D|in patients receiving oral contraceptives.  Lamotrigine levels were|
02862|063|D|decreased by 41% to 64%, average 49%.  Most patients either experienced|
02862|064|D|increased seizure frequency or recurrence of seizures after the addition of|
02862|065|D|the oral contraceptive, or increased lamotrigine adverse effects following|
02862|066|D|the discontinuation of the oral contraceptive.(4)|
02862|067|D|   A study in 45 females compared lamotrigine pharmacokinetics in patients|
02862|068|D|taking an ethinyl estradiol-containing contraceptive (n=11) to patients|
02862|069|D|taking a progestin-only contraceptive (n=16) and to patients taking no|
02862|070|D|contraceptives (n=18).  The lamotrigine serum concentration to dose ratio|
02862|071|D|was significantly lower in patients taking ethinyl estradiol-containing|
02862|072|D|contraceptives.  There was no significant difference between patients taking|
02862|073|D|progestin-only contraceptives and those using no contraceptives.(5)|
02862|074|D|   In a double-blind, placebo-controlled study, women with epilepsy were|
02862|075|D|treated with lamotrigine monotherapy, or lamotrigine plus oral|
02862|076|D|contraceptive.  After 21 days, the mean dose-corrected lamotrigine|
02862|077|D|concentration was 84% higher in the monotherapy group verses the combined|
02862|078|D|treatment group.(6)|
02862|079|D|   Another study in 8 epileptic females assessed the pharmacokinetics of|
02862|080|D|lamotrigine in combination with hormonal contraceptives.  Serum samples were|
02862|081|D|drawn on days 18 and 21 of hormonal contraceptive therapy and during days 5|
02862|082|D|and 7 of the placebo week (hormonal contraceptive free week). Analysis found|
02862|083|D|statistically significant elevations (approximately 27%) in lamotrigine|
02862|084|D|plasma concentrations during the hormone-free week, than during cycle|
02862|085|D|intake.(7)|
02862|086|D|   In a study, 22 enrolled females took lamotrigine titrated up to 300 mg/d|
02862|087|D|for a period of 130 days and either combined it with an oral contraceptive|
02862|088|D|or took lamotrigine monotherapy.  Both ethinyl estradiol and lamotrigine|
02862|089|D|serum levels were drawn in the presence or absence of combined therapy.|
02862|090|D|Laboratory serum data showed the ratios of lamotrigine AUC (0-24h) and Cmax|
02862|091|D|at 0.48 for coadministration (lamotrigine plus oral contraceptive) and a|
02862|092|D|ratio of 0.61 for lamotrigine monotherapy.(8)|
02862|093|B||
02862|094|R|REFERENCES:|
02862|095|B||
02862|096|R|1.Lamictal (lamotrigine) US prscribing information. GlaxoSmithKline October,|1
02862|097|R|  2025.|1
02862|098|R|2.Dear Healthcare Professional, Subject:  Important new safety information|1
02862|099|R|  concerning the antiepileptic, LAMICTAL (lamotrigine). GlaxoSmithKline|1
02862|100|R|  Canada September, 2004.|1
02862|101|R|3.Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce|2
02862|102|R|  lamotrigine plasma levels. Neurology 2003 Aug 26;61(4):570-1.|2
02862|103|R|4.Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels|3
02862|104|R|  reduced by oral contraceptives. Epilepsy Res 2001 Nov;47(1-2):151-4.|3
02862|105|R|5.Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not progestogens,|2
02862|106|R|  reduces lamotrigine serum concentrations. Epilepsia 2005 Sep;46(9):1414-7.|2
02862|107|R|6.Christensen J, Petrenaite V, Atterman J, Sidenius P, Ohman I, Tomson T,|2
02862|108|R|  Sabers A. Oral contraceptives induce lamotrigine metabolism: evidence from|2
02862|109|R|  a double-blind, placebo-controlled trial. Epilepsia 2007 Mar;48(3):484-9.|2
02862|110|R|7.Contin M, Albani F, Ambrosetto G, Avoni P, Bisulli F, Riva R, Tinuper P,|2
02862|111|R|  Baruzzi A. Variation in lamotrigine plasma concentrations with hormonal|2
02862|112|R|  contraceptive monthly cycles in patients with epilepsy. Epilepsia 2006|2
02862|113|R|  Sep;47(9):1573-5.|2
02862|114|R|8.Sidhu J, Job S, Singh S, Philipson R. The pharmacokinetic and|2
02862|115|R|  pharmacodynamic consequences of the co-administration of lamotrigine and a|2
02862|116|R|  combined oral contraceptive in healthy female subjects. Br J Clin|2
02862|117|R|  Pharmacol 2006 Feb;61(2):191-9.|2
02863|001|T|MONOGRAPH TITLE:  Progestin Replacement Therapy/Ulipristal|
02863|002|B||
02863|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02863|004|L|of severe adverse interaction.|
02863|005|B||
02863|006|A|MECHANISM OF ACTION:  Ulipristal is a progesterone receptor modulator and|
02863|007|A|binds to the progesterone receptor with high affinity.(1)(2)|
02863|008|B||
02863|009|E|CLINICAL EFFECTS:  Concurrent use of ulipristal may make progesterone|
02863|010|E|products ineffective.(1,2)  These agents may also make ulipristal|
02863|011|E|ineffective.(3)|
02863|012|B||
02863|013|P|PREDISPOSING FACTORS:  None determined.|
02863|014|B||
02863|015|M|PATIENT MANAGEMENT:  Products containing progestin should not be used within|
02863|016|M|12 days of ulipristal discontinuation.(3)|
02863|017|B||
02863|018|D|DISCUSSION:  Ulipristal is a progesterone receptor modulator and binds to|
02863|019|D|the progesterone receptor with high affinity, thus it may interfere with the|
02863|020|D|efficacy of progestin products.(1-3)  These products may also make|
02863|021|D|ulipristal ineffective.(3)|
02863|022|B||
02863|023|R|REFERENCES:|
02863|024|B||
02863|025|R|1.Ellaone (ulipristal acetate) UK summary of product characteristics. HRA|1
02863|026|R|  Pharma UK Ltd May 15, 2009.|1
02863|027|R|2.Ella (ulipristal acetate) US prescribing information. Afaxys Inc June,|1
02863|028|R|  2021.|1
02863|029|R|3.Fibristal (ulipristal acetate) Canadian prescribing information. Actavis|1
02863|030|R|  Specialty Pharmaceuticals Co. January 28, 2015.|1
02864|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Brigatinib (mono deleted|
02864|002|T|09/30/2021)|
02864|003|B||
02864|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02864|005|L|take action as needed.|
02864|006|B||
02864|007|A|MECHANISM OF ACTION:  Brigatinib may induce the CYP3A4 mediated metabolism|
02864|008|A|of hormonal contraceptives.(1)|
02864|009|B||
02864|010|E|CLINICAL EFFECTS:  Concurrent use of brigatinib may reduce the effectiveness|
02864|011|E|of hormonal contraceptives.(1)|
02864|012|B||
02864|013|P|PREDISPOSING FACTORS:  None determined.|
02864|014|B||
02864|015|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
02864|016|M|rely on hormonal contraception (including oral contraceptives, patches,|
02864|017|M|implants, and/or IUDs) for contraception.  Women should use a back-up method|
02864|018|M|of birth control during brigatinib therapy.  Women of reproductive potential|
02864|019|M|should use effective non-hormonal methods of contraception during brigatinib|
02864|020|M|therapy and for at least 4 months after the final dose.(1)|
02864|021|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
02864|022|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
02864|023|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
02864|024|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
02864|025|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
02864|026|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
02864|027|M|and to seek medical advice if they do become pregnant.(2)|
02864|028|B||
02864|029|D|DISCUSSION:  Brigatinib may induce the CYP3A4 mediated metabolism of|
02864|030|D|hormonal contraceptives.  Brigatinib may decrease the effectiveness of|
02864|031|D|hormonal contraceptives, including oral contraceptives, patches, implants,|
02864|032|D|and/or IUDs.  Women should use a back-up method of birth control during|
02864|033|D|brigatinib therapy and for at least 4 months after the final dose.(1)|
02864|034|B||
02864|035|R|REFERENCES:|
02864|036|B||
02864|037|R|1.Alunbrig (brigatinib) US prescribing information. Ariad Pharmaceuticals,|1
02864|038|R|  Inc. September, 2021.|1
02864|039|R|2.Medicines and Healthcare products Regulatory Agency.|1
02864|040|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
02864|041|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
02864|042|R|  available at:|1
02864|043|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
02864|044|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
02864|045|R|  -and-contraceptive-efficacy September 15, 2016..|1
02865|001|T|MONOGRAPH TITLE:  Selected Opioids/Ceritinib; Crizotinib|
02865|002|B||
02865|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02865|004|L|of severe adverse interaction.|
02865|005|B||
02865|006|A|MECHANISM OF ACTION:  Ceritinib(1) and crizotinib(2) inhibit CYP3A4, and|
02865|007|A|thus may inhibit the metabolism of agents processed by this isoenzyme,|
02865|008|A|including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine,|
02865|009|A|oxycodone, and sufentanil.|
02865|010|B||
02865|011|E|CLINICAL EFFECTS:  Concurrent use of ceritinib(1) or crizotinib(2) with|
02865|012|E|alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone,|
02865|013|E|or sufentanil may lead to elevated drug levels and increased side effects of|
02865|014|E|the opioid, including profound sedation, respiratory depression, coma,|
02865|015|E|and/or death.(1-3)|
02865|016|B||
02865|017|P|PREDISPOSING FACTORS:  None determined.|
02865|018|B||
02865|019|M|PATIENT MANAGEMENT:  Avoid coadministration of sensitive or narrow|
02865|020|M|therapeutic window CYP3A4 substrates such as alfentanil, benzhydrocodone,|
02865|021|M|fentanyl, hydrocodone, meperidine, oxycodone, or sufentanil with ceritinib|
02865|022|M|and crizotinib.|
02865|023|M|   If concomitant use is unavoidable, dosage adjustments of the opioid|
02865|024|M|should be considered when initiating or discontinuing ceritinib(1) or|
02865|025|M|crizotinib.(2)  Patients maintained on ceritinib or crizotinib may need|
02865|026|M|lower initial doses of opioid medications.|
02865|027|M|   Respiratory depression can occur at any time during opioid therapy,|
02865|028|M|especially during therapy initiation and following dosage increases.  The|
02865|029|M|risk of opioid-related overdose or overdose-related death is increased with|
02865|030|M|higher opioid doses, and this risk persists over the course of therapy.|
02865|031|M|Consider these risks when using concurrently with other agents that may|
02865|032|M|cause CNS depression.(5)|
02865|033|M|   Monitor patients receiving concurrent therapy for adverse affects,|
02865|034|M|including unusual dizziness or lightheadedness, extreme sleepiness, slowed|
02865|035|M|or difficult breathing, or unresponsiveness.|
02865|036|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02865|037|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02865|038|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02865|039|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02865|040|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02865|041|M|as those taking CNS depressants) and when a patient has household|
02865|042|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02865|043|M|for obtaining an opioid reversal agent (e.g., prescription,|
02865|044|M|over-the-counter, or as part of a community-based program).(6)|
02865|045|B||
02865|046|D|DISCUSSION:  In a study, ceritinib (750 mg daily for 3 weeks) increased the|
02865|047|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a|
02865|048|D|CYP3A4 substrate) by 5.4-fold and 1.8-fold, respectively, compared to|
02865|049|D|midazolam alone.(1)|
02865|050|D|   Crizotinib (250 mg twice daily for 28 days) increased the AUC of oral|
02865|051|D|midazolam by 3.7-fold.(2)|
02865|052|D|   Thus, ceritinib(1) and crizotinib(2) are expected to increase levels of|
02865|053|D|opioids metabolized by CYP3A4.|
02865|054|B||
02865|055|R|REFERENCES:|
02865|056|B||
02865|057|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
02865|058|R|  Corporation August, 2021.|1
02865|059|R|2.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
02865|060|R|  2023.|1
02865|061|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02865|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02865|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02865|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02865|065|R|  11/14/2017.|1
02865|066|R|4.FDA. CDER Application number: 205755 Zykadia (ceritinib) CLINICAL|1
02865|067|R|  PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S). available at:|1
02865|068|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205755Orig1s000Clin|1
02865|069|R|  PharmR.pdf March 25, 2014.|1
02865|070|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02865|071|R|  prescribing information for all opioid pain medicines to provide|1
02865|072|R|  additional guidance for safe use. Available at:|1
02865|073|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02865|074|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02865|075|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02865|076|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02865|077|R|  recommends health care professionals discuss naloxone with all patients|1
02865|078|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02865|079|R|  disorder. Available at:|1
02865|080|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02865|081|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02865|082|R|  d-pain July 23, 2020.|1
02866|001|T|MONOGRAPH TITLE:  Selected Opioids/Mifepristone|
02866|002|B||
02866|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02866|004|L|is contraindicated and generally should not be dispensed or administered to|
02866|005|L|the same patient.|
02866|006|B||
02866|007|A|MECHANISM OF ACTION:  Mifepristone is an inhibitor of CYP3A4 and may|
02866|008|A|increase levels and effects of drugs metabolized by this enzyme, including|
02866|009|A|alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone,|
02866|010|A|and sufentanil.(1)|
02866|011|B||
02866|012|E|CLINICAL EFFECTS:  Alfentanil, benzhydrocodone, fentanyl, hydrocodone,|
02866|013|E|meperidine, oxycodone, and sufentanil are particularly susceptible to|
02866|014|E|significant toxicity, including profound sedation, respiratory depression,|
02866|015|E|coma, and/or death.(1,2)|
02866|016|B||
02866|017|P|PREDISPOSING FACTORS:  Due to the need for continuous therapy and|
02866|018|P|mifepristone's long half-life of 85 hours(1) which leads to accumulation,|
02866|019|P|patients with endogenous Cushing's syndrome may be at an increased risk for|
02866|020|P|toxicity.|
02866|021|B||
02866|022|M|PATIENT MANAGEMENT:  The US manufacturer of mifepristone for|
02866|023|M|hypercortisolism due to endogenous Cushing's syndrome states use with CYP3A4|
02866|024|M|substrates with a narrow therapeutic range, including alfentanil,|
02866|025|M|benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and|
02866|026|M|sufentanil, is contraindicated.(1)|
02866|027|M|   Respiratory depression can occur at any time during opioid therapy,|
02866|028|M|especially during therapy initiation and following dosage increases.  The|
02866|029|M|risk of opioid-related overdose or overdose-related death is increased with|
02866|030|M|higher opioid doses, and this risk persists over the course of therapy.|
02866|031|M|Consider these risks when using concurrently with other agents that may|
02866|032|M|cause CNS depression.(3)|
02866|033|M|   If concomitant use is unavoidable, monitor patients receiving concurrent|
02866|034|M|therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed|
02866|035|M|or difficult breathing, or unresponsiveness.|
02866|036|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02866|037|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02866|038|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02866|039|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02866|040|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02866|041|M|as those taking CNS depressants) and when a patient has household|
02866|042|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02866|043|M|for obtaining an opioid reversal agent (e.g., prescription,|
02866|044|M|over-the-counter, or as part of a community-based program).(4)|
02866|045|B||
02866|046|D|DISCUSSION:  Administration of mifepristone 1200 mg daily for 10 days|
02866|047|D|followed by a single dose of simvastatin 80 mg led to an increase of|
02866|048|D|simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC)|
02866|049|D|of 10.4-fold and 15.7-fold, respectively.(1)|
02866|050|B||
02866|051|R|REFERENCES:|
02866|052|B||
02866|053|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
02866|054|R|  November, 2019.|1
02866|055|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02866|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02866|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02866|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02866|059|R|  11/14/2017.|1
02866|060|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02866|061|R|  prescribing information for all opioid pain medicines to provide|1
02866|062|R|  additional guidance for safe use. Available at:|1
02866|063|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02866|064|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02866|065|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02866|066|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02866|067|R|  recommends health care professionals discuss naloxone with all patients|1
02866|068|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02866|069|R|  disorder. Available at:|1
02866|070|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02866|071|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02866|072|R|  d-pain July 23, 2020.|1
02867|001|T|MONOGRAPH TITLE:  Potassium Supplements/Trimethoprim|
02867|002|B||
02867|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02867|004|L|of severe adverse interaction.|
02867|005|B||
02867|006|A|MECHANISM OF ACTION:  Trimethoprim may increase serum potassium levels by|
02867|007|A|reduction in potassium elimination.(1-3)  The combination of trimethoprim|
02867|008|A|and potassium supplements can have an additive effect on serum potassium|
02867|009|A|resulting in potentially dangerous levels.|
02867|010|B||
02867|011|E|CLINICAL EFFECTS:  Concurrent use of trimethoprim and potassium supplements|
02867|012|E|may result in hyperkalemia, which may be severe.|
02867|013|B||
02867|014|P|PREDISPOSING FACTORS:  Patients who are elderly, have any degree of renal|
02867|015|P|insufficiency or heart failure have an increased risk for hyperkalemia.(1-9)|
02867|016|P|   Concomitant use with other drugs associated with hyperkalemia risk (e.g.|
02867|017|P|ACE Inhibitors, angiotensin II receptor antagonists, aldosterone|
02867|018|P|antagonists, NSAIDs) and high doses of trimethoprim further increase the|
02867|019|P|risk for hyperkalemia.(1-8)|
02867|020|P|   Interaction risk and severity is greater in patients with multiple risk|
02867|021|P|factors.|
02867|022|B||
02867|023|M|PATIENT MANAGEMENT:  Assure adequate monitoring for hyperkalemia.(1-9)|
02867|024|M|Patients receiving trimethoprim and a potassium supplement concurrently|
02867|025|M|should have their serum potassium monitored at baseline and during|
02867|026|M|treatment.  Potassium supplementation may need to be held during antibiotic|
02867|027|M|therapy, especially when other predisposing factors for hyperkalemia are|
02867|028|M|present.  Peak potassium increase due to trimethoprim is delayed and|
02867|029|M|generally occurs after 4 or more days of therapy.(3,5,6)|
02867|030|M|   When possible, alternative antibiotic therapy should be considered in|
02867|031|M|patients with one or more risk factors for hyperkalemia, e.g. renal|
02867|032|M|impairment, heart failure, age > 65 years, and/or receiving additional meds|
02867|033|M|associated with hyperkalemia risk (e.g. ACE inhibitors, angiotensin II|
02867|034|M|receptor blockers, aldosterone antagonists, NSAIDs).(6)|
02867|035|B||
02867|036|D|DISCUSSION:  A nested case-control study evaluated the risk for hyperkalemia|
02867|037|D|in 19,194 patients with newly diagnosed heart failure. Over a mean follow-up|
02867|038|D|of 3.9 years 2,176 cases of hyperkalemia (96.7% with a potassium value of =>|
02867|039|D|5.5 mmol/L) were identified.  Study authors found that trimethoprim|
02867|040|D|independently increased the risk for hyperkalemia (OR 2.82; 95% CI|
02867|041|D|1.88-4.23).(4)|
02867|042|D|    A retrospective cohort study evaluated the risk for hospitalization due|
02867|043|D|to hyperkalemia in 393,039 elderly women (age >65 years) treated for a|
02867|044|D|urinary tract infection (UTI) with trimethoprim-sulfamethoxazole (TMP-SMX)|
02867|045|D|or another antibiotic (amoxicillin, ciprofloxacin, norfloxacin,|
02867|046|D|nitrofurantoin).  Baseline renal function was similar in all five antibiotic|
02867|047|D|groups.  When compared with amoxicillin, TMP-SMX use was associated with a|
02867|048|D|3.3-fold increased risk for hospitalization due to hyperkalemia.|
02867|049|D|Ciprofloxacin, norfloxacin, and nitrofurantoin were not associated with a|
02867|050|D|risk for hyperkalemia.(9)|
02867|051|D|     A prospective study of hospitalized patients evaluated the risk for|
02867|052|D|hyperkalemia in patients who received standard dose TMP-SMX (<= 320 mg|
02867|053|D|trimethoprim, <= 1600 mg sulfamethoxazole daily) versus a control group who|
02867|054|D|received a different antibiotic for at least 5 days.  The two groups were|
02867|055|D|similar in age, renal function and use of potassium altering medications.|
02867|056|D|Serum potassium concentration increased in TMP-SMX patients by 1.21 mmol/L|
02867|057|D|(CI 1.09 - 1.32 mmol/L), a change which was statistically significant in|
02867|058|D|patients with a pretreatment serum creatinine = or > 1.2.  In control|
02867|059|D|patients, serum potassium decreased during antibiotic therapy (change not|
02867|060|D|quantitated by authors).(5)|
02867|061|B||
02867|062|R|REFERENCES:|
02867|063|B||
02867|064|R|1.Marinella MA. Trimethoprim-induced hyperkalemia: An analysis of reported|6
02867|065|R|  cases. Gerontology 1999 Jul-Aug;45(4):209-12.|6
02867|066|R|2.Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of|2
02867|067|R|  trimethoprim-induced hyperkalemia. Ann Intern Med 1993 Aug 15;|2
02867|068|R|  119(4):296-301.|2
02867|069|R|3.Perazella MA, Mahnensmith RL. Hyperkalemia in the elderly: drugs|6
02867|070|R|  exacerbate impaired potassium homeostasis. J Gen Intern Med 1997 Oct;|6
02867|071|R|  12(10):646-56.|6
02867|072|R|4.Michel A, Martin-Perez M, Ruigomez A, Garcia Rodriguez LA. Risk factors|2
02867|073|R|  for hyperkalaemia in a cohort of patients with newly diagnosed heart|2
02867|074|R|  failure: a nested case-control study in UK general practice. Eur J Heart|2
02867|075|R|  Fail 2015 Feb;17(2):205-13.|2
02867|076|R|5.Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients|2
02867|077|R|  treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996 Feb 1;|2
02867|078|R|  124(3):316-20.|2
02867|079|R|6.Ho JM, Juurlink DN. Considerations when prescribing|6
02867|080|R|  trimethoprim-sulfamethoxazole. CMAJ 2011 Nov 08;183(16):1851-8.|6
02867|081|R|7.Martin-Perez M, Ruigomez A, Michel A, Garcia Rodriguez LA. Impact of|2
02867|082|R|  hyperkalaemia definition on incidence assessment: implications for|2
02867|083|R|  epidemiological research based on a large cohort study in newly diagnosed|2
02867|084|R|  heart failure patients in primary care. BMC Fam Pract 2016 May 04;17:51.|2
02867|085|R|8.Bactrim Inj. (sulfamethoxazole and trimethoprim) US prescribing|1
02867|086|R|  information. Mutual Pharmaceutical Company, Inc. May, 2021.|1
02867|087|R|9.Lam N, Weir MA, Juurlink DN, Gunraj N, Gomes T, Mamdani M, Hackam DG, Jain|2
02867|088|R|  AK, Garg AX. Hospital admissions for hyperkalemia with|2
02867|089|R|  trimethoprim-sulfamethoxazole: a cohort study using health care database|2
02867|090|R|  codes for 393,039 older women with urinary tract infections. Am J Kidney|2
02867|091|R|  Dis 2011 Mar;57(3):521-3.|2
02868|001|T|MONOGRAPH TITLE:  Oxycodone/Strong CYP2D6 Inhibitors|
02868|002|B||
02868|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02868|004|L|take action as needed.|
02868|005|B||
02868|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2D6 may alter the metabolism|
02868|007|A|of oxycodone.(1)|
02868|008|A|   Oxycodone is primarily metabolized by CYP3A4 to noroxycodone then by|
02868|009|A|CYP2D6 to noroxymorphone as well as by CYP2D6 to oxymorphone.  Noroxycodone,|
02868|010|A|oxymorphone, and noroxymorphone are active metabolites.(1-3)|
02868|011|B||
02868|012|E|CLINICAL EFFECTS:  The concurrent administration of oxycodone and a strong|
02868|013|E|inhibitor of CYP2D6 may result in decreased efficacy or increased effects|
02868|014|E|and toxicity of oxycodone.  Parent and metabolite concentrations of|
02868|015|E|oxycodone may be altered.(1,2)|
02868|016|B||
02868|017|P|PREDISPOSING FACTORS:  None determined.|
02868|018|B||
02868|019|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with oxycodone|
02868|020|M|and a strong CYP2D6 inhibitor should be observed for decreased effectiveness|
02868|021|M|as well as signs of increased effects and opioid toxicity.  An alternative|
02868|022|M|analgesic, such as morphine or nonopioid analgesics, may need to be|
02868|023|M|considered.|
02868|024|B||
02868|025|D|DISCUSSION:  Strong inhibitors of CYP2D6 have been shown to alter the|
02868|026|D|metabolism of oxycodone.(1-3)|
02868|027|D|   A study in 10 healthy subjects who were CYP2D6 extensive metabolizers|
02868|028|D|were given oxycodone 20 mg with either quinidine 200 mg or placebo, followed|
02868|029|D|by quinidine 100 mg 6 hours later.  Levels of oxymorphone were undetectable|
02868|030|D|at any time point after quinidine administration.  The psychomotor or|
02868|031|D|subjective drug effects of oxycodone were unchanged.(4)|
02868|032|D|   A study in 10 healthy subjects received a single dose of quinidine 100 mg|
02868|033|D|(a strong CYP2D6 inhibitor) followed by oxycodone 0.2 mg/kg oral drops.|
02868|034|D|Oxymorphone (CYP2D6 dependent metabolite) concentration maximum (Cmax) and|
02868|035|D|area-under-curve (AUC) were both decreased by 40% with quinidine|
02868|036|D|administration compared to oxycodone alone.  Oxycodone AUC and AUC at 90|
02868|037|D|minutes post administration were increased 1.5-fold and 8.5-fold,|
02868|038|D|respectively.  Total clearance of oxycodone was decreased by 20-30%.  A|
02868|039|D|compensatory 70% increase of noroxycodone (CYP3A4 dependent metabolite) AUC|
02868|040|D|was also observed.(5)|
02868|041|D|   A study in 11 healthy subjects evaluated the effects of paroxetine 20 mg|
02868|042|D|daily on single dose oxycodone 10 mg.  Paroxetine decreased the mean AUC of|
02868|043|D|CYP2D6 dependent metabolite oxymorphone by 44% (p<0.05) and increased the|
02868|044|D|mean AUC of CYP3A4 dependent metabolite noroxycodone by 68% (p<0.001).|
02868|045|D|Administration of paroxetine increased the VAS score for deterioration of|
02868|046|D|performance for the first 6 hours following oxycodone.(6)|
02868|047|D|   A randomized crossover trial in 10 healthy subjects with differing CYP2D6|
02868|048|D|metabolizer statuses received oxycodone with either placebo, quinidine,|
02868|049|D|ketoconazole, or both quinidine and ketoconazole. CYP2D6 activity correlated|
02868|050|D|with oxymorphone and noroxymorphone AUCs and Cmax.(7)|
02868|051|D|   A retrospective cohort study in 111 patients found patients who received|
02868|052|D|oxycodone with either a CYP2D6 or CYP3A4 inhibitor had an increased risk of|
02868|053|D|gastrointestinal, dizziness, and drowsiness adverse reactions.  Use of|
02868|054|D|either a CYP2D6 or CYP3A4 inhibitor increase the risk by 20.4 and 25.4|
02868|055|D|times, respectively.  Concurrent use of both a CYP2D6 and CYP3A4 inhibitor|
02868|056|D|increased the risk with an adjusted OR of 48.6.(8)|
02868|057|D|   A cohort study evaluated the use of concurrent oxycodone and SSRIs that|
02868|058|D|inhibit CYP2D6 on the risk of opioid overdose.  The adjusted incidence rate|
02868|059|D|of opioid overdose in patients on SSRIs that inhibit CYP2D6 when initiated|
02868|060|D|on oxycodone was higher than SSRIs that do not inhibit CYP2D6 (9.47 per 1000|
02868|061|D|person years vs 7.66 per 1000 person years, respectively).(9)|
02868|062|D|   The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines|
02868|063|D|state that CYP2D6 poor metabolizers have a lower peak concentration of|
02868|064|D|oxymorphone (CYP2D6 dependent metabolite) after a dose of oxycodone compared|
02868|065|D|to extensive metabolizers; however, clinical significance of metabolizer|
02868|066|D|status on analgesia or risk of toxicity is unknown.(10)|
02868|067|D|   CPIC recommends selecting alternative drugs other than oxycodone for|
02868|068|D|CYP2D6 poor and intermediate metabolizers, or be alert to insufficient pain|
02868|069|D|relief; for CYP2D6 ultrarapid metabolizers, select an alternative to|
02868|070|D|oxycodone, or be alert for adverse events.(10)|
02868|071|D|   Strong CYP2D6 inhibitors linked to this monograph include: bupropion,|
02868|072|D|dacomitinib, fluoxetine, hydroquinidine, paroxetine, and quinidine.(11)|
02868|073|B||
02868|074|R|REFERENCES:|
02868|075|B||
02868|076|R|1.OxyContin (oxycodone hydrochloride) US prescribing information. Perdue|1
02868|077|R|  Pharma L.P. October, 2021.|1
02868|078|R|2.DePriest AZ, Puet BL, Holt AC, Roberts A, Cone EJ. Metabolism and|6
02868|079|R|  Disposition of Prescription Opioids: A Review. Forensic Sci Rev 2015 Jul;|6
02868|080|R|  27(2):115-45.|6
02868|081|R|3.Lurcott G. The effects of the genetic absence and inhibition of CYP2D6 on|6
02868|082|R|  the metabolism of  codeine and its derivatives, hydrocodone and oxycodone.|6
02868|083|R|  Anesth Prog 1998 Fall;45(4):154-6.|6
02868|084|R|4.Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the|2
02868|085|R|  pharmacokinetics and pharmacodynamics of  oxycodone. Clin Pharmacol Ther|2
02868|086|R|  1998 Dec;64(6):603-11.|2
02868|087|R|5.Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier|2
02868|088|R|  MF, Hochstrasser D, Dayer P, Desmeules JA. The effects of CYP2D6 and CYP3A|2
02868|089|R|  activities on the pharmacokinetics of immediate release oxycodone. Br J|2
02868|090|R|  Pharmacol 2010 Jun;160(4):907-18.|2
02868|091|R|6.Gronlund J, Saari TI, Hagelberg NM, Neuvonen PJ, Olkkola KT, Laine K.|2
02868|092|R|  Exposure to oral oxycodone is increased by concomitant inhibition of|2
02868|093|R|  CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone. Br J Clin|2
02868|094|R|  Pharmacol 2010 Jul;70(1):78-87.|2
02868|095|R|7.Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier|2
02868|096|R|  MF, Hochstrasser D, Dayer P, Desmeules JA. Genetic polymorphisms and drug|2
02868|097|R|  interactions modulating CYP2D6 and CYP3A activities  have a major effect|2
02868|098|R|  on oxycodone analgesic efficacy and safety. Br J Pharmacol 2010 Jun;|2
02868|099|R|  160(4):919-30.|2
02868|100|R|8.Kim JH, Kim JY, Lee N, Yee J, Gwak HS. The impact of drug interactions on|2
02868|101|R|  adverse effects of oral oxycodone in male  geriatric patients. J Clin|2
02868|102|R|  Pharm Ther 2020 Oct;45(5):976-982.|2
02868|103|R|9.Yunusa I, Gagne JJ, Yoshida K, Bykov K. Risk of Opioid Overdose Associated|2
02868|104|R|  With Concomitant Use of Oxycodone and Selective  Serotonin Reuptake|2
02868|105|R|  Inhibitors. JAMA Netw Open 2022 Feb 1;5(2):e220194.|2
02868|106|R|10.Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE,|2
02868|107|R|   Haidar CE, Shen DD, Callaghan JT, Sadhasivam S, Prows CA, Kharasch ED,|2
02868|108|R|   Skaar TC. Clinical Pharmacogenetics Implementation Consortium guidelines|2
02868|109|R|   for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin|2
02868|110|R|   Pharmacol Ther 2014 Apr;95(4):376-82.|2
02868|111|R|11.This information is based on an extract from the Certara Drug Interaction|6
02868|112|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02869|001|T|MONOGRAPH TITLE:  Selected Nephrotoxic Agents/Immune Globulin IV (IGIV)|
02869|002|B||
02869|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02869|004|L|take action as needed.|
02869|005|B||
02869|006|A|MECHANISM OF ACTION:  Immune Globulin Intravenous (IGIV) products,|
02869|007|A|particularly those containing sucrose, can cause renal dysfunction, acute|
02869|008|A|renal failure, osmotic nephrosis, and/or death.  Concurrent administration|
02869|009|A|of other nephrotoxic agents may result in additive or synergistic effects on|
02869|010|A|renal function.(1-4)|
02869|011|B||
02869|012|E|CLINICAL EFFECTS:  Concurrent use of Immune Globulin Intravenous (IGIV)|
02869|013|E|products with nephrotoxic agents such as adefovir, intravenous|
02869|014|E|aminoglycosides, amphotericin B, non-steroidal anti-inflammatory agents,|
02869|015|E|tenofovir, and vancomycin may result in renal toxicity.(1-4)  Other|
02869|016|E|nephrotoxic agents include capreomycin, gallium nitrate, and streptozocin.|
02869|017|B||
02869|018|P|PREDISPOSING FACTORS:  Patients at risk of acute renal failure include those|
02869|019|P|with any degree of pre-existing renal insufficiency, diabetes mellitus,|
02869|020|P|advanced age (above 65 years of age), volume depletion, sepsis,|
02869|021|P|paraproteinemia, or receiving known nephrotoxic drugs.(1-4)|
02869|022|P|   Renal dysfunction and acute renal failure occur more commonly in patients|
02869|023|P|receiving IGIV products containing sucrose.(3-4)|
02869|024|B||
02869|025|M|PATIENT MANAGEMENT:  For patients at risk of renal dysfunction or renal|
02869|026|M|failure, the US manufacturers of Immune Globulin Intravenous (IGIV) products|
02869|027|M|recommends administration at the minimum dose and infusion rate practicable;|
02869|028|M|ensure adequate hydration in patients before administration; and monitor|
02869|029|M|renal function and urine output with assessment of blood urea nitrogen (BUN)|
02869|030|M|and serum creatinine before initial infusion and at regular intervals during|
02869|031|M|therapy.(1-3)|
02869|032|M|   Concurrent administration of potentially nephrotoxic agents should be|
02869|033|M|avoided.(1)|
02869|034|M|   Review prescribing information for IGIV product to be administered for|
02869|035|M|sucrose content.  If concurrent therapy is warranted, monitor renal function|
02869|036|M|closely.  In high risk patients, consider selecting an IGIV product that|
02869|037|M|does not contain sucrose.|
02869|038|B||
02869|039|D|DISCUSSION:  The safety of Immune Globulin Intravenous (IGIV) has not been|
02869|040|D|studied in patients receiving other known potentially nephrotoxic agents.|
02869|041|D|Renal impairment is a major toxicity of IGIV products.(1-3)|
02869|042|D|  A review of the FDA renal adverse events (RAEs) (i.e. acute renal failure|
02869|043|D|or insufficiency) from June 1985 to November 1998 identified 120 reports|
02869|044|D|worldwide associated with IGIV administration.  In the US, the FDA received|
02869|045|D|88 reports of cases with clinical and/or laboratory findings consistent with|
02869|046|D|RAE (i.e. increased serum creatinine, oliguria, and acute renal failure).|
02869|047|D|Patient cases involved a median age of 60.5 years and 55% were male.  Of the|
02869|048|D|54 patients who developed acute renal failure, 65% were greater than 65|
02869|049|D|years, 56% had diabetes, and 26% had prior renal insufficiency; 59% had one,|
02869|050|D|35% had two, and 6% had three of these conditions.  Upon review of the IGIV|
02869|051|D|product received, 90% of cases received sucrose-containing IGIV products|
02869|052|D|with the remaining patients receiving either maltose- or glucose-containing|
02869|053|D|products.  Approximately 40% of affected patients required dialysis and RAE|
02869|054|D|may have contributed to death in 15% of patients.(4)|
02869|055|B||
02869|056|R|REFERENCES:|
02869|057|B||
02869|058|R|1.Bivigam (human immunoglobulin g injection) US prescribing information.|1
02869|059|R|  Biotest Pharmaceuticals Corporation May, 2015.|1
02869|060|R|2.Gammagard S/D (human immunoglobulin g) US prescribing information. Baxter|1
02869|061|R|  Healthcare Corporation June, 2011.|1
02869|062|R|3.Carimune Nanofiltered (human immunoglobulin g injction, powder,|1
02869|063|R|  lyophilized) US prescribing information. CSL Behring AG November, 2016.|1
02869|064|R|4.USFood and Drug Administration. MMWR Weekly: Renal Insufficiency and|6
02869|065|R|  Failure Associated with Immune Globulin Intravenous Therapy -- United|6
02869|066|R|  States, 1985-1998. Available at:|6
02869|067|R|  https://www.cdc.gov/mmwr/preview/mmwrhtml/mm4824a3.htm June 25, 1999.|6
02870|001|T|MONOGRAPH TITLE:  Selected Kinase Inhibitors/H2 Antagonists|
02870|002|B||
02870|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02870|004|L|take action as needed.|
02870|005|B||
02870|006|A|MECHANISM OF ACTION:  The solubility of dacomitinib,(1) erlotinib,(2)|
02870|007|A|gefitinib,(3) and nilotinib(4) is pH dependent.  Changes in gastric pH from|
02870|008|A|H2 antagonists may decrease the absorption of dacomitinib,(1) erlotinib,(2)|
02870|009|A|gefitinib,(3) and nilotinib(4).|
02870|010|B||
02870|011|E|CLINICAL EFFECTS:  Use of H2 antagonists may result in decreased levels and|
02870|012|E|effectiveness of dacomitinib,(1) erlotinib,(2) gefitinib,(3) and|
02870|013|E|nilotinib(4).|
02870|014|B||
02870|015|P|PREDISPOSING FACTORS:  None determined.|
02870|016|B||
02870|017|M|PATIENT MANAGEMENT:  Consider the use of short-acting antacids in patients|
02870|018|M|taking dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4).|
02870|019|M|   If antacids are used, separate the administration times by several|
02870|020|M|hours(1-7) but at least 2 hours for bosutinib,(1) and nilotinib,(4) and 6|
02870|021|M|hours for gefitinib.(3)|
02870|022|M|   If H2 antagonist therapy is required with dacomitinib, dacomitinib must|
02870|023|M|be given once daily 10 hours after the H2 blocker and 6 hours before the|
02870|024|M|next dose of the H2 blocker.(1)|
02870|025|M|   If H2 antagonist therapy is required with erlotinib or nilotinib, the|
02870|026|M|kinase inhibitor must be given 10 hours after the H2 blocker and at least 2|
02870|027|M|hours before the next dose of the H2 blocker.(2-4)|
02870|028|M|   If H2 antagonist therapy is required with gefitinib, gefitinib should be|
02870|029|M|given at least 6 hours before or after the H2 antagonist.(3)|
02870|030|M|   Avoid the use of proton pump inhibitors (PPIs) in patients receiving|
02870|031|M|treatment dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4).|
02870|032|B||
02870|033|D|DISCUSSION:  In a study, concurrent rabeprazole decreased the Cmax and AUC|
02870|034|D|of dacomitinib by 51% and 39%, respectively.(1)|
02870|035|D|   In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib|
02870|036|D|by 46% and 61%, respectively.(2)|
02870|037|D|   In a study, administration of erlotinib two hours after a dose of|
02870|038|D|ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%,|
02870|039|D|respectively.  Administration of erlotinib 10 hours after and two hours|
02870|040|D|before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by|
02870|041|D|15% and 17%, respectively.(2)|
02870|042|D|   In a case report, a patient that was given erlotinib (150 mg daily,) with|
02870|043|D|algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before|
02870|044|D|or 2 hours after erlotinib) did not see a significant reduction in serum|
02870|045|D|trough concentrations of erlotinib.  When the patient was switched to|
02870|046|D|intravenous pantoprazole via continuous infusion (8 mg per hour), serum|
02870|047|D|erlotinib levels decreased significantly below minimal trough concentrations|
02870|048|D|for effective tyrosine kinase inhibition.  When the patient was switched to|
02870|049|D|oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib|
02870|050|D|returned to therapeutic levels.(5)|
02870|051|D|   In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg|
02870|052|D|daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by|
02870|053|D|27% and 34%, respectively.(4,7)  Increasing the dosage of nilotinib or|
02870|054|D|separating the administration time of nilotinib and the proton pump|
02870|055|D|inhibitor is not expected to eliminate the interaction.(4)|
02870|056|D|   There were no significant changes in nilotinib pharmacokinetics when|
02870|057|D|famotidine was administered 10 hours before or 2 hours after nilotinib.(4)|
02870|058|D|   There were no significant changes in nilotinib pharmacokinetics when an|
02870|059|D|antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was|
02870|060|D|administered 2 hours before or after nilotinib.(4)|
02870|061|B||
02870|062|R|REFERENCES:|
02870|063|B||
02870|064|R|1.Vizimpro (dacomitinib) US prescribing information. Pfizer, Inc. September,|1
02870|065|R|  2018.|1
02870|066|R|2.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
02870|067|R|  2016.|1
02870|068|R|3.Iressa (gefitinib) US prescribing information. AstraZeneca March 6, 2012.|1
02870|069|R|4.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
02870|070|R|  Corporation September, 2021.|1
02870|071|R|5.Ter Heine R, Fanggiday JC, Lankheet NA, Beijnen JH, Van Der Westerlaken|3
02870|072|R|  MM, Staaks GH, Malingre MM. Erlotinib and pantoprazole: a relevant|3
02870|073|R|  interaction or not?. Br J Clin Pharmacol 2010 Dec;70(6):908-11.|3
02870|074|R|6.Yin OQ, Gallagher N, Fischer D, Demirhan E, Zhou W, Golor G, Schran H.|2
02870|075|R|  Effect of the Proton Pump Inhibitor Esomeprazole on the Oral Absorption|2
02870|076|R|  and Pharmacokinetics of Nilotinib. J Clin Pharmacol 2010 May 24.|2
02871|001|T|MONOGRAPH TITLE:  Quetiapine/Moderate CYP3A4 Inhibitors that Prolong QT|
02871|002|B||
02871|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02871|004|L|of severe adverse interaction.|
02871|005|B||
02871|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
02871|007|A|of quetiapine.(1)  Quetiapine is a sensitive substrate for CYP3A4 and so an|
02871|008|A|approximately 2-fold or higher increase in exposure (AUC, area-under-curve)|
02871|009|A|is possible when quetiapine is given with a moderate CYP3A4 inhibitor.(2)|
02871|010|A|   In addition, concurrent use with other agents that prolong the QTc|
02871|011|A|interval may result in additive effects on the QTc interval.(1)|
02871|012|B||
02871|013|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor that also|
02871|014|E|prolongs the QT interval may result in elevated levels of and toxicity from|
02871|015|E|quetiapine,(1-3) including potentially life-threatening cardiac arrhythmias,|
02871|016|E|such as torsades de pointes.(1,3)|
02871|017|B||
02871|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02871|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
02871|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02871|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02871|022|P|female gender, or advanced age.(4)|
02871|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02871|024|P|higher systemic concentrations of either QT prolonging drug are additional|
02871|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02871|026|P|drug concentrations include rapid infusion of an intravenous dose or|
02871|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02871|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02871|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
02871|030|B||
02871|031|M|PATIENT MANAGEMENT:  The US manufacturer of quetiapine states that|
02871|032|M|concurrent use with agents known to prolong the QT interval should be|
02871|033|M|avoided.(1)|
02871|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02871|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02871|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02871|037|M|patients to report any irregular heartbeat, dizziness, fainting, excessive|
02871|038|M|drowsiness, rapid pulse/hypotension, weakness, fatigue, dizziness, or muscle|
02871|039|M|stiffness/tremors (EPS).  Monitor patients when moderate inhibitors of|
02871|040|M|CYP3A4 are co-prescribed with quetiapine as the magnitude of the interaction|
02871|041|M|is highly variable between patients.(6)  Use of higher doses of either the|
02871|042|M|CYP3A4 inhibitor or quetiapine are other factors which may affect the|
02871|043|M|magnitude of this interaction.  Decrease the quetiapine dose if needed.|
02871|044|B||
02871|045|D|DISCUSSION:  Although quetiapine was not associated with QT or QTc changes|
02871|046|D|in clinical trials, QT prolongation has been reported in post-marketing|
02871|047|D|reports in conjunction with the use of other agents known to prolong the QT|
02871|048|D|interval.(1)|
02871|049|D|   In a study in 19 Chinese patients with schizophrenia, patients received|
02871|050|D|quetiapine (200 mg twice daily) alone and with erythromycin (500 mg 3 times|
02871|051|D|daily, a moderate inhibitor of CYP3A4).  Erythromycin increased the|
02871|052|D|quetiapine maximum concentration (Cmax)by 68%(range approximately 20-130%),|
02871|053|D|area-under-curve (AUC) 129% (range approximately 20-300%), and half-life by|
02871|054|D|92% (range approximately 0-250%).  Quetiapine clearance decreased 52% (range|
02871|055|D|approximately -15 to -80%).(5)|
02871|056|D|   Moderate inhibitors of CYP3A4 that also are known QT prolonging agents|
02871|057|D|include: dronedarone, erythromycin, and fluconazole.(2,6,7)  These agents|
02871|058|D|may have varying degrees of potential to prolong the QTc interval but are|
02871|059|D|generally accepted to have a risk of causing Torsades de Pointes.  Agents|
02871|060|D|linked to this monograph have been shown to prolong the QTc interval either|
02871|061|D|through their mechanism of action, through studies on their effects on the|
02871|062|D|QTc interval, or through reports of QTc prolongation and/or Torsades de|
02871|063|D|Pointes in clinical trials and/or post-marketing reports.(7)|
02871|064|B||
02871|065|R|REFERENCES:|
02871|066|B||
02871|067|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
02871|068|R|  Pharmaceuticals LP July, 2011.|1
02871|069|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02871|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02871|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02871|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02871|073|R|  11/14/2017.|1
02871|074|R|3.Seroquel (quetiapine) Canada prescribing information. AstraZeneca Canada|1
02871|075|R|  Inc. May 15,2013.|1
02871|076|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02871|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02871|078|R|  settings: a scientific statement from the American Heart Association and|6
02871|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02871|080|R|  2;55(9):934-47.|6
02871|081|R|5.Li KY, Li X, Cheng ZN, Zhang BK, Peng WX, Li HD. Effect of erythromycin on|2
02871|082|R|  metabolism of quetiapine in Chinese suffering from schizophrenia. Eur J|2
02871|083|R|  Clin Pharmacol 2005 Jan;60(11):791-5.|2
02871|084|R|6.This information is based on an extract from the Certara Drug Interaction|6
02871|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02871|086|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
02871|087|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02871|088|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02871|089|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02872|001|T|MONOGRAPH TITLE:  Etoposide/P-glycoprotein (P-gp) Inducers|
02872|002|B||
02872|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02872|004|L|of severe adverse interaction.|
02872|005|B||
02872|006|A|MECHANISM OF ACTION:  Etoposide is a substrate of the efflux transporter|
02872|007|A|P-glycoprotein (P-gp).(1-5)  P-gp induction may decrease cellular|
02872|008|A|concentrations of etoposide, increase biliary or renal elimination of|
02872|009|A|etoposide, and decrease systemic absorption of oral etoposide.|
02872|010|B||
02872|011|E|CLINICAL EFFECTS:  Concurrent or recent use of P-glycoprotein inducers may|
02872|012|E|result in decreased levels and effectiveness of etoposide.|
02872|013|B||
02872|014|P|PREDISPOSING FACTORS:  None determined.|
02872|015|B||
02872|016|M|PATIENT MANAGEMENT:  Avoid concurrent use of an inducer of P-gp in patients|
02872|017|M|treated with etoposide and consider use of alternative agents when possible.|
02872|018|M|If therapy with a P-gp inducer is required, consider therapeutic drug|
02872|019|M|monitoring of etoposide to assure treatment efficacy.|
02872|020|M|   The time to maximal induction may be delayed 1-2 weeks depending upon the|
02872|021|M|half-life and dose of the inducer.  After discontinuation of the inducer the|
02872|022|M|offset of induction is also gradual.|
02872|023|B||
02872|024|D|DISCUSSION:  This monograph is based upon the relatively recent|
02872|025|D|understanding of the role of transporters in the absorption, distribution|
02872|026|D|and elimination of etoposide.(1-3)|
02872|027|D|   Apalutamide, carbamazepine, efavirenz, fosphenytoin, lorlatinib,|
02872|028|D|phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and|
02872|029|D|St. John's wort may induce production of P-gp and lead to decreased systemic|
02872|030|D|or cellular exposure to etoposide.(4,6)|
02872|031|B||
02872|032|R|REFERENCES:|
02872|033|B||
02872|034|R|1.Yang J, Bogni A, Schuetz EG, Ratain M, Dolan ME, McLeod H, Gong L, Thorn|6
02872|035|R|  C, Relling MV, Klein TE, Altman RB. Etoposide pathway. Pharmacogenet|6
02872|036|R|  Genomics 2009 Jul;19(7):552-3.|6
02872|037|R|2.Rezonja R, Knez L, Cufer T, Mrhar A. Oral treatment with etoposide in|6
02872|038|R|  small cell lung cancer - dilemmas and solutions. Radiol Oncol 2013 Mar;|6
02872|039|R|  47(1):1-13.|6
02872|040|R|3.Lagas JS, Fan L, Wagenaar E, Vlaming ML, van Tellingen O, Beijnen JH,|5
02872|041|R|  Schinkel AH. P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 determine the|5
02872|042|R|  pharmacokinetics of etoposide. Clin Cancer Res 2010 Jan 01;16(1):130-40.|5
02872|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
02872|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02872|045|R|5.Hande K, Messenger M, Wagner J, Krozely M, Kaul S. Inter- and intrapatient|2
02872|046|R|  variability in etoposide kinetics with oral and intravenous drug|2
02872|047|R|  administration. Clin Cancer Res 1999 Oct;5(10):2742-7.|2
02872|048|R|6.Etopophos (etoposide) US prescribing information. H2-Pharma, LLC November,|1
02872|049|R|  2022.|1
02873|001|T|MONOGRAPH TITLE:  Slt HMG Co-A Red Inhibitors/Phenobarbital (mono deleted|
02873|002|T|11/20/2020)|
02873|003|B||
02873|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02873|005|L|take action as needed.|
02873|006|B||
02873|007|A|MECHANISM OF ACTION:  Phenobarbital may induce the metabolism of|
02873|008|A|atorvastatin, lovastatin, and simvastatin by CYP3A4.|
02873|009|A|   Primidone is metabolized to phenobarbital.|
02873|010|B||
02873|011|E|CLINICAL EFFECTS:  Concurrent phenobarbital may result in decreased levels|
02873|012|E|and clinical effectiveness of atorvastatin, lovastatin, or simvastatin.|
02873|013|B||
02873|014|P|PREDISPOSING FACTORS:  None determined.|
02873|015|B||
02873|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent phenobarbital may require|
02873|017|M|higher than normal dosages of atorvastatin, lovastatin, or simvastatin.|
02873|018|M|Monitor patients for therapeutic response and adjust the dosage of the HMG|
02873|019|M|CoA reductase inhibitor accordingly.  If phenobarbital is discontinued, the|
02873|020|M|dosage of the HMG CoA reductase inhibitor may need to be adjusted.|
02873|021|B||
02873|022|D|DISCUSSION:  In an open-label study in 52 healthy, HIV-negative subjects,|
02873|023|D|subjects received atorvastatin (10 mg daily), or simvastatin (40 mg daily)|
02873|024|D|for 3 days before and on Days 14-16 of 16 days of efavirenz (another CYP3A4|
02873|025|D|inducer, 600 mg daily).  Efavirenz decreased the area-under-curve (AUC) of|
02873|026|D|atorvastatin and total active atorvastatin by 43% and 34%, respectively.|
02873|027|D|Efavirenz decreased pravastatin AUC by 40%.  Efavirenz decreased simvastatin|
02873|028|D|acid AUC by 58% and active HMG CoA reductase inhibitory activity by 60%.|
02873|029|D|Atorvastatin, pravastatin, and simvastatin had no effect on efavirenz|
02873|030|D|pharmacokinetics.(1)|
02873|031|D|   In a study in 14 subjects, concurrent atorvastatin (10 mg daily for 4|
02873|032|D|days) and efavirenz (600 mg daily for 15 days) decreased atorvastatin AUC,|
02873|033|D|maximum concentration (Cmax), and minimum concentration (Cmin) by 43%, 14%,|
02873|034|D|and 69%, respectively.  The AUC, Cmax, and Cmin of the total active|
02873|035|D|atorvastatin decreased by 32%, 15%, and 48%, respectively.  There was no|
02873|036|D|effect on efavirenz levels.(2,3)|
02873|037|D|   In a study in 14 subjects, concurrent simvastatin (40 mg daily for 4|
02873|038|D|days) and efavirenz (600 mg daily for 15 days) decreased simvastatin AUC,|
02873|039|D|Cmax, and Cmin by 68%, 72%, and 45%, respectively.  The AUC and Cmax of the|
02873|040|D|total active simvastatin decreased by 60% and 68%, respectively.  Efavirenz|
02873|041|D|Cmax and Cmin both decreased by 12%; however, there was no effect on|
02873|042|D|efavirenz AUC.(2,3)|
02873|043|D|   In a study in 12 healthy males, pretreatment with carbamazepine (another|
02873|044|D|CYP3A4 inducer, 200 mg daily, Days 1-2; 300 mg twice daily Days 3-14)|
02873|045|D|decreased exposure (AUC) of simvastatin and simvastatin acid from a single|
02873|046|D|dose of simvastatin (80 mg) by 75% and 82%, respectively.  The Cmax of|
02873|047|D|simvastatin and simvastatin acid both decreased by 68%.(4)|
02873|048|B||
02873|049|R|REFERENCES:|
02873|050|B||
02873|051|R|1.Gerber JG, Rosenkranz SL, Fichtenbaum CJ, Vega JM, Yang A, Alston BL,|2
02873|052|R|  Brobst SW, Segal Y, Aberg JA. Effect of efavirenz on the pharmacokinetics|2
02873|053|R|  of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical|2
02873|054|R|  Trials Group 5108 Study. J Acquir Immune Defic Syndr 2005 Jul 1;|2
02873|055|R|  39(3):307-12.|2
02873|056|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
02873|057|R|  Company November, 2023.|1
02873|058|R|3.Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) US|1
02873|059|R|  prescribing information. Gilead Sciences, Inc. October, 2019.|1
02873|060|R|4.Ucar M, Neuvonen M, Luurila H, Dahlqvist R, Neuvonen PJ, Mjorndal T.|2
02873|061|R|  Carbamazepine markedly reduces serum concentrations of simvastatin and|2
02873|062|R|  simvastatin acid. Eur J Clin Pharmacol 2004 Feb;59(12):879-82.|2
02874|001|T|MONOGRAPH TITLE:  Warfarin/Cannabinoids|
02874|002|B||
02874|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02874|004|L|take action as needed.|
02874|005|B||
02874|006|A|MECHANISM OF ACTION:  Cannabidiol (CBD) and tetrahydrocannabinol (THC) have|
02874|007|A|been shown to inhibit CYP2C9-mediated metabolism of S-warfarin in vitro.(1)|
02874|008|A|   Nabilone(2) and THC(1) may also displace warfarin from protein binding|
02874|009|A|sites.|
02874|010|A|   Nabilone is an orally active synthetic cannabinoid.(2)|
02874|011|A|   Dronabinol is a synthetic form of THC.(3)|
02874|012|B||
02874|013|E|CLINICAL EFFECTS:  Concurrent use of CBD and/or THC, dronabinol, or nabilone|
02874|014|E|may result in elevated levels of warfarin and INR(1-5) and increase the risk|
02874|015|E|of bleeding.|
02874|016|B||
02874|017|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02874|018|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02874|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
02874|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02874|021|P|risk for bleeding (e.g. NSAIDs).|
02874|022|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
02874|023|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
02874|024|P|are expected to be more susceptible to this interaction.|
02874|025|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
02874|026|P|are expected to be less susceptible to effects from this drug combination,|
02874|027|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
02874|028|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
02874|029|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
02874|030|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
02874|031|P|and safe anticoagulation than patients without these CYP2C9 variants.|
02874|032|B||
02874|033|M|PATIENT MANAGEMENT:  Monitor INRs frequently until stable in patients who|
02874|034|M|start CBD and/or THC, dronabinol, or nabilone or have the dose adjusted.(1)|
02874|035|M|   A Health Canada Product InfoWatch regarding the use of cannabis and|
02874|036|M|warfarin advises healthcare professionals to ask patients about their use of|
02874|037|M|cannabis, particularly if patients are being treated with warfarin, due to|
02874|038|M|the potential for increased INR values.(6)|
02874|039|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
02874|040|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
02874|041|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
02874|042|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02874|043|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02874|044|M|anticoagulation in patients with active pathologic bleeding.|
02874|045|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02874|046|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02874|047|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02874|048|M|and/or swelling.|
02874|049|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02874|050|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02874|051|M|initiating, altering the dose or discontinuing either drug.|
02874|052|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
02874|053|B||
02874|054|D|DISCUSSION:  In a case report, a patient who had received warfarin therapy|
02874|055|D|for 11 years was hospitalized twice with bleeding episodes (gastrointestinal|
02874|056|D|and nosebleeds) and elevated INRs (10.41 and 11.55) during a period of|
02874|057|D|increased marijuana use.  After the patient ceased marijuana use, his INRs|
02874|058|D|stabilized.(4)|
02874|059|D|   As of September 30, 2020, Health Canada received 2 adverse reaction|
02874|060|D|reports of increased INR suspected of being associated with the use of|
02874|061|D|warfarin and orally ingested or sublingually administered CBD oil or|
02874|062|D|CBD-dominant cannabis oil products.  The first case involved a 76-year-old|
02874|063|D|woman who experienced an increase in INR (4.8) less than one week after|
02874|064|D|starting CBD oil.  The second case was reported in an 83-year-old man who|
02874|065|D|experienced an increase in INR (6.2) approximately 3 months after starting a|
02874|066|D|CBD-dominant cannabis oil (1 mg/mL THC and 20 mg/mL CBD).  There were no|
02874|067|D|other changes to his medications.  In both cases, the cannabis product was|
02874|068|D|discontinued, warfarin dose was adjusted and the INR went back within|
02874|069|D|therapeutic range.(6)|
02874|070|D|   A systematic review of one in vitro study and two case reports reviewed|
02874|071|D|the interaction between warfarin and cannabis.  The review noted the|
02874|072|D|interaction potential of cannabis as a CYP2C9 inhibitor at clinically|
02874|073|D|relevant concentrations that may inhibit warfarin metabolism.(7)|
02874|074|D|   In a case report, a 44-year-old male patient took warfarin 7.5 mg daily|
02874|075|D|with therapeutic INRs ranging from 2 to 2.6 for at least six months.  After|
02874|076|D|starting CBD oil 265 mg twice daily, the patient's INR increased to 6.86.|
02874|077|D|The warfarin dose was decreased by 30% and the patient's INR returned to the|
02874|078|D|therapeutic range of 2-3.(8)|
02874|079|D|   In a case report, a 46-year-old male patient was maintained on a weekly|
02874|080|D|warfarin dose of 80 mg for 5 months (INR range: 1.7 to 3.3).  He started|
02874|081|D|cannabidiol 5 mg/kg divided twice daily with a final daily dose titration of|
02874|082|D|20 mg/kg.  Over the course of multiple weeks during the cannabidiol dose|
02874|083|D|titration, an increase in INR was observed (INR increased from 3.1 before|
02874|084|D|the start of cannabidiol therapy and increased to 3.4 on week two and 3.5 on|
02874|085|D|week three).  The warfarin weekly dose was adjusted resulting in a 20%|
02874|086|D|decrease and no reported adverse bleeding events.(9)|
02874|087|D|   In a case report of a 35-year-old male patient on long term warfarin 10|
02874|088|D|mg daily with an INR goal of 2.5, an increase in INR to 7.2 occurred|
02874|089|D|following one month of edible cannabis ingestion and cannabis smoking.  The|
02874|090|D|INR dropped below 4 upon discontinuation of cannabis with dose adjustments|
02874|091|D|to warfarin.(10)|
02874|092|D|   In a case report of a 67-year-old-male patient on long term warfarin 6 mg|
02874|093|D|and 7.5 mg on alternating days, an increase in INR to 5.2 occurred with|
02874|094|D|using two different medical cannabis supplements.  Warfarin was held for 2|
02874|095|D|days and the INR dropped to 2.8.  The warfarin weekly dose was decreased by|
02874|096|D|28-29% and the patient reported no bleeding adverse events.(11)|
02874|097|D|   In a case report of a 85-year-old patient, use of oralmucosal medical|
02874|098|D|cannabis had minimal changes in INR over a 1 year period.(12)|
02874|099|D|   Delta-9-tetrahydrocannabinol was found to inhibit the CYP2C9 metabolism|
02874|100|D|of S-warfarin in vitro.  Studies performed on polycyclic aromatic|
02874|101|D|hydrocarbons found no effect of these compounds on CYP2C9, indicating that|
02874|102|D|combustion may not be required for CYP2C9 inhibition.(1)|
02874|103|B||
02874|104|R|REFERENCES:|
02874|105|B||
02874|106|R|1.Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto I, Watanabe K.|5
02874|107|R|  Comparison in the in vitro inhibitory effects of major phytocannabinoids|5
02874|108|R|  and polycyclic aromatic hydrocarbons contained in marijuana smoke on|5
02874|109|R|  cytochrome P450  2C9 activity. Drug Metab Pharmacokinet 2012;|5
02874|110|R|  27(3):294-300.|5
02874|111|R|2.Cesamet (nabilone) US prescribing information. Bausch Health US LLC|1
02874|112|R|  January, 2021.|1
02874|113|R|3.Syndros (dronabinol) US prescribing information. Insys Therapeutics, Inc.|1
02874|114|R|  September, 2022.|1
02874|115|R|4.Yamreudeewong W, Wong HK, Brausch LM, Pulley KR. Probable interaction|3
02874|116|R|  between warfarin and marijuana smoking. Ann Pharmacother 2009 Jul;|3
02874|117|R|  43(7):1347-53.|3
02874|118|R|5.Epidiolex (cannabidiol) US prescribing information. Greenwich Biosciences,|1
02874|119|R|  Inc. June, 2025.|1
02874|120|R|6.Health Canada. Health Product InfoWatch: Cannabis and warfarin--potential|6
02874|121|R|  drug interaction. Available at|6
02874|122|R|  https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-pr|6
02874|123|R|  oducts/medeffect-canada/health-product-infowatch/health-product-infowatch-|6
02874|124|R|  october-2020/health-product-infowatch-october-2020-eng.pdf October 2020.|6
02874|125|R|7.Damkier P, Lassen D, Christensen MMH, Madsen KG, Hellfritzsch M, Pottegard|6
02874|126|R|  A. Interaction between warfarin and cannabis. Basic Clin Pharmacol Toxicol|6
02874|127|R|  2018 Oct 16.|6
02874|128|R|8.Grayson L,  Vines B,  Nichol K,  Szaflarski J. An interaction between|3
02874|129|R|  warfarin and cannabidiol, a case report. Epilepsy Behav Case Rep. 2018;|3
02874|130|R|  9:10-11.|3
02874|131|R|9.Cortopassi J. Warfarin dose adjustment required after cannabidiol|3
02874|132|R|  initiation and titration. Am J Health-Syst Pharm 2020;77(22):1846-1851.|3
02874|133|R|10.Hsu A,  Painter NA. Probable interaction between warfarin and inhaled and|3
02874|134|R|   oral administration of cannabis. J Pharm Pract. 2019.|3
02874|135|R|11.Brown GW, Bellnier TJ, Janda M, Miskowitz K. Delta-9-tetrahydrocannabinol|3
02874|136|R|   dose increase leads to warfarin drug interaction and  elevated INR. J Am|3
02874|137|R|   Pharm Assoc (2003) 2021 Jan-Feb;61(1):e57-e60.|3
02874|138|R|12.Thomas TF, Metaxas ES, Nguyen T, Bennett W, Skiendzielewski KV, Quinn DH,|3
02874|139|R|   Scaletta AL. Case report: Medical cannabis-warfarin drug-drug|3
02874|140|R|   interaction. J Cannabis Res 2022 Jan 10;4(1):6.|3
02875|001|T|MONOGRAPH TITLE:  Tizanidine/Selected Antihypertensives|
02875|002|B||
02875|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02875|004|L|take action as needed.|
02875|005|B||
02875|006|A|MECHANISM OF ACTION:  Tizanidine is an alpha-2 agonist.  Concurrent use with|
02875|007|A|antihypertensive agents may result in additive effects on blood pressure.(1)|
02875|008|B||
02875|009|E|CLINICAL EFFECTS:  Concurrent use of antihypertensives and tizanidine may|
02875|010|E|result in hypotension.(1)|
02875|011|B||
02875|012|P|PREDISPOSING FACTORS:  None determined.|
02875|013|B||
02875|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
02875|015|M|monitored for hypotension.  The risk of hypotension may be decreased by|
02875|016|M|careful titration of tizanidine dosages and monitoring for hypotension prior|
02875|017|M|to dose advancement.  Counsel patients about the risk of orthostatic|
02875|018|M|hypotension.(1)|
02875|019|B||
02875|020|D|DISCUSSION:  Severe hypotension has been reported following the addition of|
02875|021|D|tizanidine to existing lisinopril therapy.(2-4)|
02875|022|B||
02875|023|R|REFERENCES:|
02875|024|B||
02875|025|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
02875|026|R|  Pharma Inc. November 22, 2024.|1
02875|027|R|2.Publow SW, Branam DL. Hypotension and bradycardia associated with|3
02875|028|R|  concomitant tizanidine and lisinopril therapy. Am J Health Syst Pharm 2010|3
02875|029|R|  Oct 01;67(19):1606-10.|3
02875|030|R|3.Kao CD, Chang JB, Chen JT, Wu ZA, Shan DE, Liao KK. Hypotension due to|3
02875|031|R|  interaction between lisinopril and tizanidine. Ann Pharmacother 2004 Nov;|3
02875|032|R|  38(11):1840-3.|3
02875|033|R|4.Johnson TR, Tobias JD. Hypotension following the initiation of tizanidine|3
02875|034|R|  in a patient treated with an angiotensin converting enzyme inhibitor for|3
02875|035|R|  chronic hypertension. J Child Neurol 2000 Dec;15(12):818-9.|3
02876|001|T|MONOGRAPH TITLE:  Baricitinib/OAT3 Inhibitors|
02876|002|B||
02876|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02876|004|L|of severe adverse interaction.|
02876|005|B||
02876|006|A|MECHANISM OF ACTION:  Inhibitors of organic anion transporter 3 (OAT3) may|
02876|007|A|inhibit the renal elimination of baricitinib.(1,2)|
02876|008|B||
02876|009|E|CLINICAL EFFECTS:  Concurrent use of organic anion transporter 3 (OAT3)|
02876|010|E|inhibitors may result in an increase in both the therapeutic and toxic|
02876|011|E|effects of baricitinib.(1,2)|
02876|012|B||
02876|013|P|PREDISPOSING FACTORS:  None determined.|
02876|014|B||
02876|015|M|PATIENT MANAGEMENT:  If concurrent therapy with a strong organic anion|
02876|016|M|transporter 3 (OAT3) inhibitor is warranted, and the recommended dosage is 4|
02876|017|M|mg once daily, reduce to 2 mg once daily.  If the recommended dosage is 2 mg|
02876|018|M|once daily, reduce dose to 1 mg once daily.  If the recommended dosage is 1|
02876|019|M|mg once daily, consider discontinuing probenecid.(2)|
02876|020|M|   OAT3 inhibitors with less inhibitor potency are not expected to cause a|
02876|021|M|clinically significant change in baricitinib levels.(1,2)|
02876|022|B||
02876|023|D|DISCUSSION:  In a clinical pharmacology study, dosing of probenecid (an OAT3|
02876|024|D|inhibitor with strong inhibition potential) resulted in approximately a|
02876|025|D|2-fold increase in area-under-curve (AUC) with no change in time maximum|
02876|026|D|(Tmax) or concentration maximum (Cmax) of baricitinib.(1,2)|
02876|027|D|   OAT3 inhibitors linked to this monograph include:  cabotegravir,|
02876|028|D|nitisinone, probenecid and vadadustat.(1-3)|
02876|029|B||
02876|030|R|REFERENCES:|
02876|031|B||
02876|032|R|1.Olumiant (baricitinib) UK summary of product characteristics. Eli Lilly|1
02876|033|R|  and Company August 26, 2019.|1
02876|034|R|2.Olumiant (baricitinib) US prescribing information. Eli Lilly and Company|1
02876|035|R|  June, 2022.|1
02876|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
02876|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02877|001|T|MONOGRAPH TITLE:  Atorvastatin/Ombitasvir-paritaprevir-ritonavir|
02877|002|B||
02877|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02877|004|L|is contraindicated and generally should not be dispensed or administered to|
02877|005|L|the same patient.|
02877|006|B||
02877|007|A|MECHANISM OF ACTION:  Combination products ombitasvir-paritaprevir-ritonavir|
02877|008|A|or ombitasvir-paritaprevir-ritonavir-dasabuvir including the protease|
02877|009|A|inhibitor ritonavir may inhibit the metabolism of atorvastatin by|
02877|010|A|CYP3A4.(1,2)|
02877|011|B||
02877|012|E|CLINICAL EFFECTS:  Concurrent use of ombitasvir-paritaprevir-ritonavir or|
02877|013|E|ombitasvir-paritaprevir-ritonavir-dasabuvir may result in elevated levels of|
02877|014|E|atorvastatin, which could result in rhabdomyolysis.(1,2)|
02877|015|B||
02877|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02877|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02877|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02877|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02877|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02877|021|P|transporter OATP1B1 may have increased statin concentrations and be|
02877|022|P|predisposed to myopathy or rhabdomyolysis.|
02877|023|B||
02877|024|M|PATIENT MANAGEMENT:  Concurrent use of atorvastatin is contraindicated with|
02877|025|M|ombitasvir-paritaprevir-ritonavir or|
02877|026|M|ombitasvir-paritaprevir-ritonavir-dasabuvir.(1,2)|
02877|027|M|   In patients receiving ombitasvir-paritaprevir-ritonavir or|
02877|028|M|ombitasvir-paritaprevir-ritonavir-dasabuvir, consider the use of|
02877|029|M|fluvastatin.|
02877|030|B||
02877|031|D|DISCUSSION:  The manufacturer of ombitasvir-paritaprevir-ritonavir and|
02877|032|D|ombitasvir-paritaprevir-ritonavir-dasabuvir state use with atorvastatin is|
02877|033|D|contraindicated due to potential for myopathy including rhabdomyolysis.(1,2)|
02877|034|B||
02877|035|R|REFERENCES:|
02877|036|B||
02877|037|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02877|038|R|  prescribing information. AbbVie Inc. December, 2019.|1
02877|039|R|2.Technivie (ombitasvir-paritaprevir-ritonavir) US prescribing information.|1
02877|040|R|  Abbvie Inc. December, 2019.|1
02878|001|T|MONOGRAPH TITLE:  Select|
02878|002|T|Immunosuppressants/Ombitasvir-paritaprevir-ritonavir|
02878|003|B||
02878|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02878|005|L|is contraindicated and generally should not be dispensed or administered to|
02878|006|L|the same patient.|
02878|007|B||
02878|008|A|MECHANISM OF ACTION:  Combination products ombitasvir-paritaprevir-ritonavir|
02878|009|A|or ombitasvir-paritaprevir-ritonavir-dasabuvir including the protease|
02878|010|A|inhibitor ritonavir may inhibit the metabolism of everolimus, sirolimus,|
02878|011|A|tacrolimus, and temsirolimus by CYP3A4.(1,2)|
02878|012|B||
02878|013|E|CLINICAL EFFECTS:  Concurrent use of ombitasvir-paritaprevir-ritonavir or|
02878|014|E|ombitasvir-paritaprevir-ritonavir-dasabuvir may result in increased levels|
02878|015|E|of everolimus, sirolimus, tacrolimus, or temsirolimus.(1,2)|
02878|016|B||
02878|017|P|PREDISPOSING FACTORS:  None determined.|
02878|018|B||
02878|019|M|PATIENT MANAGEMENT:  Concurrent administration of everolimus, sirolimus,|
02878|020|M|temsirolimus, or tacrolimus is contraindicated with either|
02878|021|M|ombitasvir-paritaprevir-ritonavir or|
02878|022|M|ombitasvir-paritaprevir-ritonavir-dasabuvir.(1,2)|
02878|023|B||
02878|024|D|DISCUSSION:  The manufacturer of ombitasvir-paritaprevir-ritonavir and|
02878|025|D|ombitasvir-paritaprevir-ritonavir-dasabuvir state use with everolimus,|
02878|026|D|sirolimus, or tacrolimus is contraindicated due to increased potential for|
02878|027|D|serious and/or life threatening immunosuppressant associated adverse|
02878|028|D|events.(1,2)|
02878|029|D|   In an interaction study, ombitasvir-paritaprevir-ritonavir increased the|
02878|030|D|area-under-curve (AUC) of everolimus 0.75 mg 27.21-fold.(1,2)  The|
02878|031|D|combination of ombitasvir-paritaprevir-ritonavir-dasabuvir increased the AUC|
02878|032|D|of everolimus 0.75 mg 27.21-fold.(1,2)|
02878|033|D|   In an interaction study, ombitasvir-paritaprevir-ritonavir increased the|
02878|034|D|AUC of sirolimus 0.5 mg 37.99-fold.(1,2)  The combination of|
02878|035|D|ombitasvir-paritaprevir-ritonavir-dasabuvir increased the AUC of sirolimus|
02878|036|D|0.5 mg 37.99-fold.(1,2)|
02878|037|D|   In an interaction study, ombitasvir-paritaprevir-ritonavir increased the|
02878|038|D|AUC of tacrolimus 0.5 mg 85.81-fold.(1,2)  The combination of|
02878|039|D|ombitasvir-paritaprevir-ritonavir-dasabuvir increased the AUC of tacrolimus|
02878|040|D|2 mg 57.13-fold.(1,2)|
02878|041|D|   The selected immunosuppressants linked to this monograph include:|
02878|042|D|everolimus, sirolimus, tacrolimus, and temsirolimus.|
02878|043|B||
02878|044|R|REFERENCES:|
02878|045|B||
02878|046|R|1.Technivie (ombitasvir-paritaprevir-ritonavir) US prescribing information.|1
02878|047|R|  Abbvie Inc. December, 2019.|1
02878|048|R|2.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02878|049|R|  prescribing information. AbbVie Inc. December, 2019.|1
02879|001|T|MONOGRAPH TITLE:  Raltegravir (600 mg HD)/Calcium Carbonate|
02879|002|B||
02879|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02879|004|L|of severe adverse interaction.|
02879|005|B||
02879|006|A|MECHANISM OF ACTION:  Calcium carbonate may alter raltegravir absorption by|
02879|007|A|altering gastric pH and binding to raltegravir in the GI tract, preventing|
02879|008|A|its absorption.(1)|
02879|009|B||
02879|010|E|CLINICAL EFFECTS:  Calcium carbonate may reduce levels and clinical|
02879|011|E|effectiveness of raltegravir.(1)|
02879|012|B||
02879|013|P|PREDISPOSING FACTORS:  None determined.|
02879|014|B||
02879|015|M|PATIENT MANAGEMENT:  Calcium carbonate is not recommended for patients|
02879|016|M|receiving one daily raltegravir (600 mg HD tablets).(1)|
02879|017|B||
02879|018|D|DISCUSSION:  Simultaneous administration of calcium carbonate (3000 mg) with|
02879|019|D|raltegravir (1200 mg singe dose given as two 600 mg HD tablets) decreased|
02879|020|D|raltegravir maximum concentration (Cmax), area-under-curve (AUC), and|
02879|021|D|minimum concentration (Cmin) by 74%, 72%, and 48%, respectively.(1,2)|
02879|022|D|   Administration of calcium carbonate (3000 mg) 12 hours after raltegravir|
02879|023|D|(1200 mg singe dose given as two 600 mg HD tablets) decreased raltegravir|
02879|024|D|Cmax, AUC, and Cmin by 2%, 10%, and 57%, respectively.(1,2)|
02879|025|D|   Data from in vitro(3) and in vivo simulations(4) suggest that magnesium's|
02879|026|D|effect on raltegravir may involve chelation as well as changes in pH.|
02879|027|D|Calcium may have a similar effect.|
02879|028|B||
02879|029|R|REFERENCES:|
02879|030|B||
02879|031|R|1.Isentress (raltegravir) US prescribing information. Merck & CO., Inc. May,|1
02879|032|R|  2021.|1
02879|033|R|2.Krishna R, East L, Larson P, Valiathan C, Butterfield K, Teng Y,|2
02879|034|R|  Hernandez-Illas M. Effect of metal-cation antacids on the pharmacokinetics|2
02879|035|R|  of 1200 mg raltegravir. J Pharm Pharmacol 2016 Nov;68(11):1359-1365.|2
02879|036|R|3.Moss DM, Siccardi M, Back DJ, Owen A. Predicting intestinal absorption of|5
02879|037|R|  raltegravir using a population-based ADME simulation. J Antimicrob|5
02879|038|R|  Chemother 2013 Jul;68(7):1627-34.|5
02879|039|R|4.Moss DM, Siccardi M, Murphy M, Piperakis MM, Khoo SH, Back DJ, Owen A.|5
02879|040|R|  Divalent metals and pH alter raltegravir disposition in vitro. Antimicrob|5
02879|041|R|  Agents Chemother 2012 Jun;56(6):3020-6.|5
02880|001|T|MONOGRAPH TITLE:  Hydroxychloroquine/QT Prolonging Agents|
02880|002|B||
02880|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02880|004|L|of severe adverse interaction.|
02880|005|B||
02880|006|A|MECHANISM OF ACTION:  Hydroxychloroquine has been observed to prolong the|
02880|007|A|QTc interval.  Concurrent use with other agents that prolong the QTc|
02880|008|A|interval may result in additive effects on the QTc interval.(1)|
02880|009|B||
02880|010|E|CLINICAL EFFECTS:  The concurrent use of hydroxychloroquine with other|
02880|011|E|agents that prolong the QTc interval may result in potentially|
02880|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
02880|013|B||
02880|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02880|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02880|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02880|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02880|018|P|female gender, or advanced age.(2)|
02880|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02880|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02880|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02880|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02880|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02880|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02880|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02880|026|B||
02880|027|M|PATIENT MANAGEMENT:  The US manufacturer of hydroxychloroquine states that|
02880|028|M|hydroxychloroquine should not be administered with other agents that prolong|
02880|029|M|the QT interval.(1)|
02880|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02880|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02880|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02880|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02880|034|B||
02880|035|D|DISCUSSION:  The manufacturer states that hydroxychloroquine has been shown|
02880|036|D|to prolong the QT interval;(1) however, conditions that hydroxychloroquine|
02880|037|D|treats have also been associated with QT prolongation.|
02880|038|D|   Agents that are linked to this monograph may have varying degrees of|
02880|039|D|potential to prolong the QTc interval but are generally accepted to have a|
02880|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02880|041|D|been shown to prolong the QTc interval either through their mechanism of|
02880|042|D|action, through studies on their effects on the QTc interval, or through|
02880|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02880|044|D|and/or post-marketing reports.(3)|
02880|045|B||
02880|046|R|REFERENCES:|
02880|047|B||
02880|048|R|1.Plaquenil (hydroxychloroquine sulfate) US prescribing information.|1
02880|049|R|  Concordia Pharmaceuticals Inc. December, 2023.|1
02880|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02880|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02880|052|R|  settings: a scientific statement from the American Heart Association and|6
02880|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02880|054|R|  2;55(9):934-47.|6
02880|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02880|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02880|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02880|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02881|001|T|MONOGRAPH TITLE:  Neratinib/Strong CYP3A4 Inhibitors;Moderate CYP3A4 & P-gp|
02881|002|T|Dual Inhibitors|
02881|003|B||
02881|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02881|005|L|of severe adverse interaction.|
02881|006|B||
02881|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
02881|008|A|neratinib.(1)|
02881|009|B||
02881|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors or moderate|
02881|011|E|CYP3A4 and P-glycoprotein (P-gp) dual inhibitors may result in increased|
02881|012|E|systemic exposure to and effects from neratinib.(1)|
02881|013|B||
02881|014|P|PREDISPOSING FACTORS:  None determined.|
02881|015|B||
02881|016|M|PATIENT MANAGEMENT:  Avoid the concurrent use of neratinib with strong|
02881|017|M|CYP3A4 inhibitors or moderate CYP3A4 and P-gp dual inhibitors.(1)|
02881|018|M|   The Australian and Canadian manufacturer of nirmatrelvir/ritonavir state|
02881|019|M|that concurrent use with neratinib is contraindicated due to the potential|
02881|020|M|for hepatotoxicity and other serious reactions.(2,3)  Canadian labeling|
02881|021|M|contraindicates concurrent use of atazanavir/ritonavir and|
02881|022|M|lopinavir/ritonavir with neratinib.(4,5)|
02881|023|M|   If concurrent use is warranted, monitor patients closely for increased|
02881|024|M|incidence and severity of diarrhea, abdominal pain, nausea, vomiting, and|
02881|025|M|dehydration.|
02881|026|B||
02881|027|D|DISCUSSION:  Ketoconazole (400 mg daily for 5 days), a strong CYP3A4|
02881|028|D|inhibitor, increased maximum concentration (Cmax) and area-under-curve (AUC)|
02881|029|D|of a single dose of neratinib by 221% and 381%, respectively.(1)|
02881|030|D|   Pharmacokinetic models predicted that verapamil, a moderate CYP3A4 and|
02881|031|D|P-gp dual inhibitor, would increase the Cmax and AUC of neratinib by 203%|
02881|032|D|and 299%, respectively.  Fluconazole, a moderate CYP3A4 inhibitor, is not|
02881|033|D|expected to have a significant interaction with neratinib.(1)|
02881|034|D|   Strong CYP3A4 inhibitors include:  adagrasib, boceprevir, clarithromycin,|
02881|035|D|cobicistat, diltiazem, grapefruit juice, idelalisib, indinavir,|
02881|036|D|itraconazole, ketoconazole, lonafarnib, mibefradil, mifepristone,|
02881|037|D|nefazodone, nelfinavir, nirmatrelvir, posaconazole, ribociclib, telaprevir,|
02881|038|D|telithromycin, troleandomycin, tucatinib, and voriconazole.(1,6)|
02881|039|D|   Moderate CYP3A4 and P-gp dual inhibitors include:  atazanavir,|
02881|040|D|conivaptan, diltiazem, dronedarone, erythromycin, isavuconazole,|
02881|041|D|istradefylline, josamycin, nilotinib, and verapamil.(1,6)|
02881|042|B||
02881|043|R|REFERENCES:|
02881|044|B||
02881|045|R|1.Nerlynx (neratinib) US prescribing information. Puma Biotechnology, Inc.|1
02881|046|R|  June, 2021.|1
02881|047|R|2.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
02881|048|R|  Monograph. Pfizer Canada ULC October, 2023.|1
02881|049|R|3.Paxlovid (nirmatrelvir-ritonavir) Australian Product Information. Pfizer|1
02881|050|R|  Australia Pty Ltd February 28, 2025.|1
02881|051|R|4.Reyataz (atazanavir) Canadian prescribing information. Bristol-Myers|1
02881|052|R|  Squibb Canada August 31, 2023.|1
02881|053|R|5.Kaletra (lopinavir/ritonavir) Canadian prescribing information. Abbott|1
02881|054|R|  Limited May 22, 2019.|1
02881|055|R|6.This information is based on an extract from the Certara Drug Interaction|6
02881|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02882|001|T|MONOGRAPH TITLE:  Neratinib/Strong and Moderate CYP3A4 Inducers|
02882|002|B||
02882|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02882|004|L|of severe adverse interaction.|
02882|005|B||
02882|006|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
02882|007|A|neratinib.(1)|
02882|008|B||
02882|009|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
02882|010|E|result in decreased effectiveness of neratinib.(1)|
02882|011|B||
02882|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02882|013|P|of the inducer for longer than 1-2 weeks.|
02882|014|B||
02882|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of neratinib with strong or|
02882|016|M|moderate inducers of CYP3A4.(1)|
02882|017|M|   If concurrent use is warranted, monitor patients closely for decreased|
02882|018|M|neratinib effectiveness.|
02882|019|B||
02882|020|D|DISCUSSION:  Rifampin, a strong CYP3A4 inducer, decreased maximum|
02882|021|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
02882|022|D|neratinib (240 mg) by 76% and 87%, respectively.(1)|
02882|023|D|   Strong CYP3A4 inducers include:  apalutamide, barbiturates,|
02882|024|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
02882|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin,|
02882|026|D|rifampin, rifapentine and St. John's wort.(1,2)|
02882|027|D|   Moderate CYP3A4 inducers include:  belzutifan, bosentan, cenobamate,|
02882|028|D|dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib,|
02882|029|D|mavacamten, mitapivat, modafinil, pacritinib, pexidartinib, repotrectinib,|
02882|030|D|sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)|
02882|031|B||
02882|032|R|REFERENCES:|
02882|033|B||
02882|034|R|1.Nerlynx (neratinib) US prescribing information. Puma Biotechnology, Inc.|1
02882|035|R|  June, 2021.|1
02882|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
02882|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02883|001|T|MONOGRAPH TITLE:  Rosuvastatin/Sofosbuvir-Velpatasvir-Voxilaprevir|
02883|002|B||
02883|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02883|004|L|is contraindicated and generally should not be dispensed or administered to|
02883|005|L|the same patient.|
02883|006|B||
02883|007|A|MECHANISM OF ACTION:  Velpatasvir and voxilaprevir are inhibitors of BCRP,|
02883|008|A|OATP1B1 and OATP1B3 transport in the intestine.(1)  Rosuvastatin is a|
02883|009|A|substrate for these three transporters.(2,3)|
02883|010|B||
02883|011|E|CLINICAL EFFECTS:  Concurrent use of sofosbuvir-velpatasvir-voxilaprevir|
02883|012|E|with rosuvastatin may result in increased absorption and systemic|
02883|013|E|concentration of rosuvastatin, which could result in myopathy or|
02883|014|E|rhabdomyolysis.(1,2)|
02883|015|B||
02883|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02883|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02883|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02883|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02883|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02883|021|P|transporter OATP1B1 may have increased statin concentrations and be|
02883|022|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02883|023|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02883|024|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02883|025|B||
02883|026|M|PATIENT MANAGEMENT:  Recommendations regarding concomitant use of|
02883|027|M|rosuvastatin and sofosbuvir-velpatasvir-voxilaprevir (Vosevi) differ in|
02883|028|M|different regions.|
02883|029|M|   The Australian, Canadian, and European manufacturers of Vosevi say that|
02883|030|M|the concurrent use of sofosbuvir-velpatasvir-voxilaprevir with rosuvastatin|
02883|031|M|is contraindicated.(4-6)|
02883|032|M|   The US manufacturers of rosuvastatin and Vosevi state that concurrent use|
02883|033|M|of sofosbuvir-velpatasvir-voxilaprevir with rosuvastatin is not|
02883|034|M|recommended.(1,2)|
02883|035|M|   If these medications are used concurrently, counsel patient to report|
02883|036|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
02883|037|B||
02883|038|D|DISCUSSION:  In an interaction study in 19 subjects,|
02883|039|D|sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg once daily) increased|
02883|040|D|rosuvastatin (10 mg single dose) maximum concentration (Cmax) 18.88-fold and|
02883|041|D|exposure (area-under-curve, AUC) 7.39-fold.(1,2)|
02883|042|B||
02883|043|R|REFERENCES:|
02883|044|B||
02883|045|R|1.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02883|046|R|  Gilead Sciences, Inc. September, 2019.|1
02883|047|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02883|048|R|  Pharmaceuticals LP July, 2024.|1
02883|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
02883|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02883|051|R|4.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) Australian product|1
02883|052|R|  information. Gilead Sciences Pty Ltd June 21, 2019.|1
02883|053|R|5.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) Canadian prescribing|1
02883|054|R|  information. Gilead Sciences Canada, Inc. June 26, 2019.|1
02883|055|R|6.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) UK Summary of Product|1
02883|056|R|  Characteristics. Gilead Sciences Ltd September 3, 2019.|1
02884|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 5|
02884|002|T|mg)/Sofosbuvir-Velpatasvir-Voxilaprevir (mono deleted 09/01/2022)|
02884|003|B||
02884|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02884|005|L|is contraindicated and generally should not be dispensed or administered to|
02884|006|L|the same patient.|
02884|007|B||
02884|008|A|MECHANISM OF ACTION:  Velpatasvir and voxilaprevir are inhibitors of BCRP,|
02884|009|A|OATP1B1 and OATP1B3 transport in the intestine.(1)  Rosuvastatin is a|
02884|010|A|substrate for these three transporters.(2,3)|
02884|011|B||
02884|012|E|CLINICAL EFFECTS:  Concurrent use of sofosbuvir-velpatasvir-voxilaprevir|
02884|013|E|with rosuvastatin may result in increased absorption and systemic|
02884|014|E|concentration of rosuvastatin, which could result in myopathy or|
02884|015|E|rhabdomyolysis.(1,2)|
02884|016|B||
02884|017|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02884|018|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02884|019|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02884|020|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02884|021|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02884|022|P|transporter OATP1B1 may have increased statin concentrations and be|
02884|023|P|predisposed to myopathy or rhabdomyolysis.|
02884|024|B||
02884|025|M|PATIENT MANAGEMENT:  Recommendations regarding concomitant use of|
02884|026|M|rosuvastatin and sofosbuvir-velpatasvir-voxilaprevir (Vosevi) differ in|
02884|027|M|different regions.|
02884|028|M|   The Australian, Canadian, and European manufacturers of Vosevi say that|
02884|029|M|the concurrent use of sofosbuvir-velpatasvir-voxilaprevir with rosuvastatin|
02884|030|M|is contraindicated.(4-6)|
02884|031|M|   The US manufacturers of rosuvastatin and Vosevi state that concurrent use|
02884|032|M|of sofosbuvir-velpatasvir-voxilaprevir with rosuvastatin is not|
02884|033|M|recommended.(1,2)|
02884|034|M|   If these medications are used concurrently, counsel patient to report|
02884|035|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
02884|036|B||
02884|037|D|DISCUSSION:  In an interaction study in 19 subjects,|
02884|038|D|sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg once daily) increased|
02884|039|D|rosuvastatin (10 mg single dose) maximum concentration (Cmax) 18.88-fold and|
02884|040|D|exposure (area-under-curve, AUC) 7.39-fold.(1,2)|
02884|041|B||
02884|042|R|REFERENCES:|
02884|043|B||
02884|044|R|1.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02884|045|R|  Gilead Sciences, Inc. September, 2019.|1
02884|046|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02884|047|R|  Pharmaceuticals LP July, 2023.|1
02884|048|R|3.This information is based on an extract from the Certara Drug Interaction|6
02884|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02884|050|R|4.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) Australian product|1
02884|051|R|  information. Gilead Sciences Pty Ltd June 21, 2019.|1
02884|052|R|5.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) Canadian prescribing|1
02884|053|R|  information. Gilead Sciences Canada, Inc. June 26, 2019.|1
02884|054|R|6.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) UK Summary of Product|1
02884|055|R|  Characteristics. Gilead Sciences Ltd September 3, 2019.|1
02885|001|T|MONOGRAPH TITLE:  Pravastatin (Less Than or Equal To 40|
02885|002|T|mg)/Sofosbuvir-Velpatasvir-Voxilaprevir|
02885|003|B||
02885|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02885|005|L|take action as needed.|
02885|006|B||
02885|007|A|MECHANISM OF ACTION:  Velpatasvir and voxilaprevir are inhibitors of OATP1B1|
02885|008|A|and OATP1B3.(1)  Pravastatin is a substrate for OATP1B1 and OATP1B3|
02885|009|A|transport.(2)|
02885|010|B||
02885|011|E|CLINICAL EFFECTS:  Concurrent use of sofosbuvir-velpatasvir-voxilaprevir may|
02885|012|E|lead to higher systemic concentrations of pravastatin, increasing the risk|
02885|013|E|for statin-induced myopathy or rhabdomyolysis.|
02885|014|B||
02885|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02885|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02885|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02885|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02885|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02885|020|P|transporter OATP1B1 may have increased statin concentrations and be|
02885|021|P|predisposed to myopathy or rhabdomyolysis.|
02885|022|B||
02885|023|M|PATIENT MANAGEMENT:  The dose of pravastatin should be limited to 40 mg|
02885|024|M|daily in patients taking sofosbuvir-velpatasvir-voxilaprevir.(1)  Instruct|
02885|025|M|patients to report unexplained muscle pain, tenderness, weakness, or dark,|
02885|026|M|cola-colored urine.|
02885|027|B||
02885|028|D|DISCUSSION:  In an interaction study in 19 subjects,|
02885|029|D|sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg once daily) increased|
02885|030|D|pravastatin (40 mg single dose) maximum concentration (Cmax) 1.89-fold and|
02885|031|D|exposure (area-under-curve, AUC) 2.16-fold. respectively.(1)|
02885|032|B||
02885|033|R|REFERENCES:|
02885|034|B||
02885|035|R|1.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02885|036|R|  Gilead Sciences, Inc. September, 2019.|1
02885|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
02885|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02886|001|T|MONOGRAPH TITLE:  Pravastatin (Greater Than 40|
02886|002|T|mg)/Sofosbuvir-Velpatasvir-Voxilaprevir|
02886|003|B||
02886|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02886|005|L|is contraindicated and generally should not be dispensed or administered to|
02886|006|L|the same patient.|
02886|007|B||
02886|008|A|MECHANISM OF ACTION:  Velpatasvir and voxilaprevir are inhibitors of OATP1B1|
02886|009|A|and OATP1B3.(1)  Pravastatin is a substrate for OATP1B1 and OATP1B3|
02886|010|A|transport.(2)|
02886|011|B||
02886|012|E|CLINICAL EFFECTS:  Concurrent use of sofosbuvir-velpatasvir-voxilaprevir may|
02886|013|E|lead to higher systemic concentrations of pravastatin, increasing the risk|
02886|014|E|for statin-induced myopathy or rhabdomyolysis.|
02886|015|B||
02886|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02886|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02886|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02886|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02886|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02886|021|P|transporter OATP1B1 may have increased statin concentrations and be|
02886|022|P|predisposed to myopathy or rhabdomyolysis.|
02886|023|B||
02886|024|M|PATIENT MANAGEMENT:  The dose of pravastatin should be limited to 40 mg|
02886|025|M|daily in patients taking sofosbuvir-velpatasvir-voxilaprevir.(1)  Instruct|
02886|026|M|patients to report unexplained muscle pain, tenderness, weakness, or dark,|
02886|027|M|cola-colored urine.|
02886|028|B||
02886|029|D|DISCUSSION:  In an interaction study in 19 subjects,|
02886|030|D|sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg once daily) increased|
02886|031|D|pravastatin (40 mg single dose) maximum concentration (Cmax) 1.89-fold and|
02886|032|D|exposure (area-under-curve, AUC) 2.16-fold. respectively.(1)|
02886|033|B||
02886|034|R|REFERENCES:|
02886|035|B||
02886|036|R|1.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02886|037|R|  Gilead Sciences, Inc. September, 2019.|1
02886|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
02886|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02887|001|T|MONOGRAPH TITLE:  Voxilaprevir/Selected OATP1B1-3 Inhibitors|
02887|002|B||
02887|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02887|004|L|of severe adverse interaction.|
02887|005|B||
02887|006|A|MECHANISM OF ACTION:  OATP1B1 and OATP1B3 inhibitors may increase exposure|
02887|007|A|to voxilaprevir.(1)|
02887|008|B||
02887|009|E|CLINICAL EFFECTS:  Concurrent use of OATP1B1 and OATP1B3 inhibitors may|
02887|010|E|result in increased levels of and toxicity from voxilaprevir.(1)|
02887|011|B||
02887|012|P|PREDISPOSING FACTORS:  None determined.|
02887|013|B||
02887|014|M|PATIENT MANAGEMENT:  Concurrent administration of voxilaprevir with OATP1B1|
02887|015|M|and OATP1B3 inhibitors is not recommended.(1,4)  If concurrent therapy is|
02887|016|M|warranted, monitor patients for adverse effects.|
02887|017|M|   The American Society of Transplantation guidelines state that the|
02887|018|M|combination of voxilaprevir and cyclosporine is contraindicated.(3)|
02887|019|B||
02887|020|D|DISCUSSION:  In a study in 25 subjects, cyclosporine (600 mg single dose)|
02887|021|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
02887|022|D|voxilaprevir (100 mg single dose) by 19.02-fold and 9.39-fold, respectively.|
02887|023|D|There were no significant effects on cyclosporine levels.(1)|
02887|024|D|   OATP inhibitors include: atazanavir, belumosudil, cyclosporine,|
02887|025|D|encorafenib, fostemsavir, leniolisib, letermovir, lopinavir, paritaprevir,|
02887|026|D|resmetirom, roxadustat, vadadustat, and voclosporin.(1,2,4)|
02887|027|B||
02887|028|R|REFERENCES:|
02887|029|B||
02887|030|R|1.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02887|031|R|  Gilead Sciences, Inc. September, 2019.|1
02887|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02887|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02887|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02887|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02887|036|R|  11/14/2017.|1
02887|037|R|3.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
02887|038|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
02887|039|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
02887|040|R|  e13510.|6
02887|041|R|4.Rukobia (fostemsavir) US prescribing information. ViiV Healthcare July,|1
02887|042|R|  2020.|1
02888|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Enasidenib|
02888|002|B||
02888|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02888|004|L|of severe adverse interaction.|
02888|005|B||
02888|006|A|MECHANISM OF ACTION:  Enasidenib may increase or decrease the metabolism of|
02888|007|A|hormonal contraceptives.(1)|
02888|008|B||
02888|009|E|CLINICAL EFFECTS:  Concurrent use of enasidenib may increase side effect|
02888|010|E|from or reduce the effectiveness of hormonal contraceptives.  Enasidenib may|
02888|011|E|cause birth defects if used by pregnant women.(1)|
02888|012|B||
02888|013|P|PREDISPOSING FACTORS:  None determined.|
02888|014|B||
02888|015|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
02888|016|M|rely on hormonal contraception (including oral contraceptives, patches,|
02888|017|M|implants, and/or IUDs) for contraception.  Women should use a back-up method|
02888|018|M|of birth control during enasidenib therapy.  Women of reproductive potential|
02888|019|M|should use effective non-hormonal methods of contraception during enasidenib|
02888|020|M|therapy and for at least 2 months after the final dose.(1)|
02888|021|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
02888|022|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
02888|023|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
02888|024|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
02888|025|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
02888|026|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
02888|027|M|and to seek medical advice if they do become pregnant.(2)|
02888|028|B||
02888|029|D|DISCUSSION:  Enasidenib may increase or decrease metabolism of hormonal|
02888|030|D|contraceptives.  Enasidenib may increase or decrease the effectiveness of|
02888|031|D|hormonal contraceptives, including oral contraceptives, patches, implants,|
02888|032|D|and/or IUDs.  Women should use a back-up method of birth control during|
02888|033|D|enasidenib therapy and for at least 1 month after the final dose.(1)|
02888|034|B||
02888|035|R|REFERENCES:|
02888|036|B||
02888|037|R|1.Idhifa (enasidenib) US prescribing information. Celgene Corporation|1
02888|038|R|  November, 2020.|1
02888|039|R|2.Medicines and Healthcare products Regulatory Agency.|1
02888|040|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
02888|041|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
02888|042|R|  available at:|1
02888|043|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
02888|044|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
02888|045|R|  -and-contraceptive-efficacy September 15, 2016..|1
02889|001|T|MONOGRAPH TITLE:  Dimethyl Sulfoxide/Dexrazoxane|
02889|002|B||
02889|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02889|004|L|of severe adverse interaction.|
02889|005|B||
02889|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.(1)|
02889|007|B||
02889|008|E|CLINICAL EFFECTS:  Concurrent use of dexrazoxane and topical dimethyl|
02889|009|E|sulfoxide may reduce the efficacy of dexrazoxane.|
02889|010|B||
02889|011|P|PREDISPOSING FACTORS:  None determined.|
02889|012|B||
02889|013|M|PATIENT MANAGEMENT:  Topical dimethyl sulfoxide should not used concurrently|
02889|014|M|with dexrazoxane.|
02889|015|B||
02889|016|D|DISCUSSION:  Anecdotal reports have shown that concurrent use of topical|
02889|017|D|dimethyl sulfoxide (DMSO) at the site of tissue injury may reduce the|
02889|018|D|benefit of dexrazoxane. Studies utilizing a mouse model simulating|
02889|019|D|extravasation of anthracyclines showed that concurrent use of topical DMSO|
02889|020|D|and dexrazoxane decreases the efficacy of dexrazoxane.(1)|
02889|021|B||
02889|022|R|REFERENCE:|
02889|023|B||
02889|024|R|1.Totect (dexrazoxane) US prescribing information. Cumberland|1
02889|025|R|  Pharmaceuticals Inc. November, 2020.|1
02890|001|T|MONOGRAPH TITLE:  Glecaprevir-Pibrentasvir/Atazanavir; Tipranavir|
02890|002|B||
02890|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02890|004|L|is contraindicated and generally should not be dispensed or administered to|
02890|005|L|the same patient.|
02890|006|B||
02890|007|A|MECHANISM OF ACTION:  Atazanavir and tipranavir, inhibitors of OATP1B1/3,|
02890|008|A|may inhibit the metabolism of glecaprevir.  Glecaprevir is a substrate of|
02890|009|A|OATP1B1 and OATP1B3.(1)|
02890|010|B||
02890|011|E|CLINICAL EFFECTS:  Concurrent use of atazanavir or tipranavir may result in|
02890|012|E|elevated levels of glecaprevir-pibrentasvir and an increased risk of ALT|
02890|013|E|elevations.(1)|
02890|014|B||
02890|015|P|PREDISPOSING FACTORS:  None determined.|
02890|016|B||
02890|017|M|PATIENT MANAGEMENT:  Concurrent use of glecaprevir-pibrentasvir and|
02890|018|M|atazanavir or tipranavir is contraindicated.(1)|
02890|019|M|   If concurrent use is deemed medically necessary, monitor the patient for|
02890|020|M|toxicity and elevated AST levels.|
02890|021|B||
02890|022|D|DISCUSSION:  In a study in 12 subjects, atazanavir/ritonavir (300/100 mg|
02890|023|D|daily) increased the maximum concentration (Cmax), area-under-the-curve|
02890|024|D|(AUC), and minimum concentration (Cmin) of glecaprevir (300 mg daily) by|
02890|025|D|4.06-fold, 6.53-fold, and 14.3-fold and of pibrentasvir (120 mg daily) by|
02890|026|D|1.29-fold, 1.64-fold, and 2.29-fold, respectively.(1)|
02890|027|B||
02890|028|R|REFERENCE:|
02890|029|B||
02890|030|R|1.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02890|031|R|  Inc. October, 2023.|1
02891|001|T|MONOGRAPH TITLE:  Glecaprevir-Pibrentasvir/Strong CYP3A4 & P-gp Inducers;|
02891|002|T|Phenobarbital|
02891|003|B||
02891|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02891|005|L|is contraindicated and generally should not be dispensed or administered to|
02891|006|L|the same patient.|
02891|007|B||
02891|008|A|MECHANISM OF ACTION:  Glecaprevir and pibrentasvir are substrates of the|
02891|009|A|P-glycoprotein (P-gp) transporter.  Glecaprevir is also a minor substrate of|
02891|010|A|CYP3A4.  Agents that are inducers of P-gp and CYP3A4 may induce efflux and|
02891|011|A|decrease the absorption as well as induce the metabolism of|
02891|012|A|glecaprevir-pibrentasvir.(1)|
02891|013|B||
02891|014|E|CLINICAL EFFECTS:  The combination of glecaprevir-pibrentasvir may not be|
02891|015|E|effective for the treatment of hepatitis C.(1)|
02891|016|B||
02891|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02891|018|P|of the inducer for longer than 1-2 weeks.|
02891|019|B||
02891|020|M|PATIENT MANAGEMENT:  Because of the risk of treatment failure, the|
02891|021|M|manufacturer of glecaprevir-pibrentasvir states that concomitant use with|
02891|022|M|rifampin is contraindicated.(1,2)|
02891|023|M|   The US manufacturer of glecaprevir-pibrentasvir states that the use of|
02891|024|M|other P-gp inducers is not recommended.(1)|
02891|025|M|   The European manufacturer of glecaprevir-pibrentasvir states that strong|
02891|026|M|P-gp and CYP3A4 inducers are contraindicated.(2)|
02891|027|B||
02891|028|D|DISCUSSION:  In a single dose study in 12 subjects, a single dose of|
02891|029|D|rifampin (600 mg) with glecaprevir/pibrentasvir (300mg/120 mg single dose)|
02891|030|D|increased glecaprevir's maximum concentration (Cmax) and|
02891|031|D|area-under-the-curve (AUC) by 6.52-fold and 8.55-fold, respectively. In|
02891|032|D|another single dose study in 12 subjects, rifampin (600 mg daily) with|
02891|033|D|glecaprevir/pibrentasvir (300 mg/120 mg single dose) decreased glecaprevir's|
02891|034|D|Cmax and AUC by 86% and 88% and pibrentasvir's Cmax and AUC by 83% and 87%,|
02891|035|D|respectively.(1)|
02891|036|D|   In a study in 10 subjects, carbamazepine (200 mg twice daily)|
02891|037|D|administered concomitantly with glecaprevir/pibrentasvir (300/120 mg daily)|
02891|038|D|decreased the Cmax and AUC of glecaprevir by 67% and 66%, and the Cmax and|
02891|039|D|AUC of pibrentasvir by 50% and 51%, respectively.(1)|
02891|040|D|   Strong CYP3A4 and P-gp inducers linked to this monograph include:|
02891|041|D|apalutamide, carbamazepine, fosphenytoin, phenobarbital, phenytoin,|
02891|042|D|primidone, rifampin, rifapentine, and St. John's wort.|
02891|043|B||
02891|044|R|REFERENCES:|
02891|045|B||
02891|046|R|1.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02891|047|R|  Inc. October, 2023.|1
02891|048|R|2.Maviret (glecaprevir-pibrentasvir) EMA summary of product characteristics.|1
02891|049|R|  AbbVie Deutschland GmbH & Co. KG August 30, 2019.|1
02892|001|T|MONOGRAPH TITLE:  Ethinyl Estradiol (Greater Than 20|
02892|002|T|mcg)/Glecaprevir-Pibrentasvir|
02892|003|B||
02892|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02892|005|L|of severe adverse interaction.|
02892|006|B||
02892|007|A|MECHANISM OF ACTION:  The mechanism of action has not been described.|
02892|008|B||
02892|009|E|CLINICAL EFFECTS:  Coadministration of greater than 20 mcg of ethinyl|
02892|010|E|estradiol with glecaprevir-pibrentasvir may increase the risk of ALT|
02892|011|E|elevations.(1)|
02892|012|B||
02892|013|P|PREDISPOSING FACTORS:  None determined.|
02892|014|B||
02892|015|M|PATIENT MANAGEMENT:  Due to the added risk for ALT elevations, the US|
02892|016|M|manufacturer of glecaprevir-pibrentasvir states that medications which|
02892|017|M|contain more than 20 mcg of ethinyl estradiol such as oral contraceptives|
02892|018|M|are not recommended to be administered with glecaprevir-pibrentasvir.  No|
02892|019|M|dose adjustment is required when glecaprevir-pibrentasvir is coadministered|
02892|020|M|with products containing 20 mcg or less of ethinyl estradiol.(1)|
02892|021|M|   The Canadian and UK manufacturers of glecaprevir-pibrentasvir state that|
02892|022|M|ethinyl estradiol-containing products are contraindicated.(2,3)|
02892|023|M|   Alternative methods of contraception, such as progestin only or|
02892|024|M|non-hormonal methods may be recommended during glecaprevir-pibrentasvir|
02892|025|M|therapy.|
02892|026|B||
02892|027|D|DISCUSSION:  Simultaneous administration of glecaprevir-pibrentasvir may|
02892|028|D|increase the risk of ALT elevations.(1)|
02892|029|B||
02892|030|R|REFERENCES:|
02892|031|B||
02892|032|R|1.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02892|033|R|  Inc. October, 2023.|1
02892|034|R|2.Maviret (glecaprevir and pibrentasvir) UK Summary of Product|1
02892|035|R|  Characteristics. AbbVie Ltd. August, 2021.|1
02892|036|R|3.Maviret (glecaprevir and pibrentasvir) CA prescribing information. AbbVie|1
02892|037|R|  Corporation November 28, 2018.|1
02893|001|T|MONOGRAPH TITLE:  Pravastatin/Glecaprevir-Pibrentasvir|
02893|002|B||
02893|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02893|004|L|take action as needed.|
02893|005|B||
02893|006|A|MECHANISM OF ACTION:  Glecaprevir and pibrentasvir are inhibitors of OATP1B1|
02893|007|A|and OATP1B3.(1)  Pravastatin is a substrate for OATP1B1 and OATP1B3|
02893|008|A|transport.(2)|
02893|009|B||
02893|010|E|CLINICAL EFFECTS:  Concurrent use of glecaprevir-pibrentasvir may lead to|
02893|011|E|higher systemic concentrations of pravastatin, increasing the risk for|
02893|012|E|statin-induced myopathy or rhabdomyolysis.|
02893|013|B||
02893|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02893|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02893|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02893|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02893|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02893|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02893|020|P|predisposed to myopathy or rhabdomyolysis.|
02893|021|B||
02893|022|M|PATIENT MANAGEMENT:  The manufacturer of glecaprevir-pibrentasvir recommends|
02893|023|M|that the dose of pravastatin be reduced by 50% when coadministered with|
02893|024|M|glecaprevir-pibrentasvir.(1)  Instruct patients to report unexplained muscle|
02893|025|M|pain, tenderness, weakness, or dark, cola-colored urine.|
02893|026|B||
02893|027|D|DISCUSSION:  In an interaction study in 12 subjects,|
02893|028|D|glecaprevir-pibrentasvir (400/120 mg once daily) increased pravastatin (10|
02893|029|D|mg single dose) maximum concentration (Cmax) 2.23-fold and exposure|
02893|030|D|(area-under-curve, AUC) 2.30-fold. respectively.(1)|
02893|031|B||
02893|032|R|REFERENCES:|
02893|033|B||
02893|034|R|1.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02893|035|R|  Inc. October, 2023.|1
02893|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
02893|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02894|001|T|MONOGRAPH TITLE:  Atorvastatin; Lovastatin;|
02894|002|T|Simvastatin/Glecaprevir-Pibrentasvir|
02894|003|B||
02894|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02894|005|L|is contraindicated and generally should not be dispensed or administered to|
02894|006|L|the same patient.|
02894|007|B||
02894|008|A|MECHANISM OF ACTION:  Glecaprevir-pibrentasvir may inhibit OATP1B1 and|
02894|009|A|OATP1B3, resulting in increased concentrations of atorvastatin, lovastatin,|
02894|010|A|or simvastatin.(1-3)|
02894|011|B||
02894|012|E|CLINICAL EFFECTS:  Concurrent use of glecaprevir-pibrentasvir may result in|
02894|013|E|elevated levels of and toxicity from atorvastatin, lovastatin, and|
02894|014|E|simvastatin including rhabdomyolysis.(1-3)|
02894|015|B||
02894|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02894|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02894|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02894|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02894|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02894|021|P|transporter OATP1B1 may have increased statin concentrations and be|
02894|022|P|predisposed to myopathy or rhabdomyolysis.|
02894|023|B||
02894|024|M|PATIENT MANAGEMENT:  The US manufacturers of glecaprevir-pibrentasvir and of|
02894|025|M|atorvastatin state that coadministration of glecaprevir-pibrentasvir with|
02894|026|M|atorvastatin, lovastatin, or simvastatin is not recommended.(1,4)  The|
02894|027|M|Canadian manufacturer of glecaprevir-pibrentasvir also states that the|
02894|028|M|coadministration of glecaprevir-pibrentasvir and lovastatin is not|
02894|029|M|recommended.(5)  If concurrent use is deemed medically necessary, instruct|
02894|030|M|patients to report symptoms of muscle pain, tenderness, or weakness.|
02894|031|M|   The Canadian and UK manufacturers of glecaprevir-pibrentasvir and of|
02894|032|M|atorvastatin state that coadministration of glecaprevir-pibrentasvir with|
02894|033|M|atorvastatin or simvastatin is contraindicated.(2,3,5,6)|
02894|034|B||
02894|035|D|DISCUSSION:  In a study in 11 healthy subjects, glecaprevir-pibrentasvir|
02894|036|D|(400/120 mg daily) increased the maximum concentration (Cmax) and|
02894|037|D|area-under-curve (AUC) of atorvastatin (10 mg daily) by 22-fold and|
02894|038|D|8.28-fold, respectively.|
02894|039|D|   In a study in 12 healthy subjects, glecaprevir-pibrentasvir (400/120 mg|
02894|040|D|daily) increased the AUC of lovastatin (10 mg once daily) by 1.70-fold. The|
02894|041|D|Cmax and AUC of lovastatin acid was increased by 5.73-fold and 4.10-fold.|
02894|042|D|   In a study in 12 healthy subjects, glecaprevir-pibrentasvir (400/120 mg|
02894|043|D|daily) increased the Cmax and AUC of simvastatin (5 mg once daily) by|
02894|044|D|1.99-fold and 2.32-fold, respectively. The Cmax and AUC of simvastatin acid|
02894|045|D|was increased by 10.7-fold and 4.48-fold, respectively.|
02894|046|B||
02894|047|R|REFERENCES:|
02894|048|B||
02894|049|R|1.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02894|050|R|  Inc. October, 2023.|1
02894|051|R|2.Maviret (glecaprevir and pibrentasvir) UK Summary of Product|1
02894|052|R|  Characteristics. AbbVie Ltd. August, 2021.|1
02894|053|R|3.Maviret (glecaprevir and pibrentasvir) CA prescribing information. AbbVie|1
02894|054|R|  Corporation November 28, 2018.|1
02894|055|R|4.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02894|056|R|  2020.|1
02894|057|R|5.Lipitor (atorvastatin) Canadian product information. Pfizer Canada Inc.|1
02894|058|R|  May 31, 2019.|1
02894|059|R|6.Lipitor (atorvastatin calcium trihydrate) UK summary of product|1
02894|060|R|  characteristics. Pfizer Limited April 1, 2019.|1
02895|001|T|MONOGRAPH TITLE:  Glecaprevir-Pibrentasvir/Darunavir; Lopinavir; Ritonavir|
02895|002|B||
02895|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02895|004|L|of severe adverse interaction.|
02895|005|B||
02895|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown but may involve|
02895|007|A|OATP1B1/3. Darunavir and lopinavir are inhibitors of OATP1B1 and OATP1B3.|
02895|008|A|Ritonavir is an inhibitor of OATP1B1. Glecaprevir is a substrate of OATP1B1|
02895|009|A|and OATP1B3.(1)|
02895|010|B||
02895|011|E|CLINICAL EFFECTS:  Darunavir, lopinavir, and ritonavir may increase the|
02895|012|E|concentrations of glecaprevir and the risk for glecaprevir toxicities|
02895|013|E|including an increased risk of ALT elevations.(1)|
02895|014|B||
02895|015|P|PREDISPOSING FACTORS:  None determined.|
02895|016|B||
02895|017|M|PATIENT MANAGEMENT:  The manufacturer of glecaprevir-pibrentasvir states|
02895|018|M|that the coadministration with darunavir, lopinavir, or ritonavir is not|
02895|019|M|recommended.(1)|
02895|020|B||
02895|021|D|DISCUSSION:  In a study in 8 subjects, the concomitant administration of|
02895|022|D|darunavir-ritonavir (800/100 mg once daily) with glecaprevir-pibrentasvir|
02895|023|D|(300/120 mg daily) increased the maximum concentration (Cmax),|
02895|024|D|area-under-the-curve (AUC), and minimum concentration (Cmin) of glecaprevir|
02895|025|D|by 3.09-fold, 4.97-fold, and 8.24-fold, respectively. (1)|
02895|026|D|   In a study in 9 subjects, the concomitant administration of|
02895|027|D|lopinavir-ritonavir (400/100 mg twice daily) with glecaprevir-pibrentasvir|
02895|028|D|(300/120 mg daily) increased the Cmax, AUC, Cmin of glecaprevir by|
02895|029|D|2.55-fold, 4.38-fold, and 18.6-fold, respectively. Pibrentasvir's AUC and|
02895|030|D|Cmin were increased by 2.46-fold and 5.24-fold, respectively.(1)|
02895|031|B||
02895|032|R|REFERENCE:|
02895|033|B||
02895|034|R|1.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02895|035|R|  Inc. October, 2023.|1
02896|001|T|MONOGRAPH TITLE:  Glecaprevir-Pibrentasvir/Cyclosporine|
02896|002|B||
02896|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02896|004|L|of severe adverse interaction.|
02896|005|B||
02896|006|A|MECHANISM OF ACTION:  Cyclosporine is an inhibitor of P-glycoprotein, BCRP,|
02896|007|A|OATP1B1 and OATP1B3.(2)  Pibrentasvir and glecaprevir are substrates of P-gp|
02896|008|A|and BCRP. Glecaprevir is also a substrate of OATP1B1 and OATP1B3.(1)|
02896|009|B||
02896|010|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine may lead to higher|
02896|011|E|systemic concentrations of glecaprevir-pibrentasvir increasing the risk for|
02896|012|E|toxicity.(1)|
02896|013|B||
02896|014|P|PREDISPOSING FACTORS:  None determined.|
02896|015|B||
02896|016|M|PATIENT MANAGEMENT:  Glecaprevir-pibrentasvir is not recommended for use in|
02896|017|M|patients requiring stable cyclosporine doses greater than 100 mg per day.(1)|
02896|018|B||
02896|019|D|DISCUSSION:  In an interaction study in 12 subjects, cyclosporine (100 mg|
02896|020|D|single dose) with glecaprevir-pibrentasvir (400/120 mg once daily) increased|
02896|021|D|glecaprevir's maximum concentration (Cmax) only 30% and exposure|
02896|022|D|(area-under-curve, AUC) 37%. respectively. In another study in 11 subjects,|
02896|023|D|cyclosporine (400 mg single dose) with glecaprevir-pibrentasvir (300/120 mg|
02896|024|D|daily) increased glecaprevir's Cmax and AUC by 4.51-fold and 5.08-fold,|
02896|025|D|respectively. Pibrentasvir's AUC was increased 1.93-fold.(1)|
02896|026|B||
02896|027|R|REFERENCES:|
02896|028|B||
02896|029|R|1.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02896|030|R|  Inc. October, 2023.|1
02896|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
02896|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02897|001|T|MONOGRAPH TITLE:  Betrixaban/Selected P-glycoprotein (P-gp) Inhibitors|
02897|002|B||
02897|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02897|004|L|take action as needed.|
02897|005|B||
02897|006|A|MECHANISM OF ACTION:  Betrixaban is a substrate for the P-glycoprotein|
02897|007|A|(P-gp) system.  Inhibition of intestinal P-gp leads to increased absorption|
02897|008|A|of betrixaban.(1)|
02897|009|B||
02897|010|E|CLINICAL EFFECTS:  The concurrent use betrixaban with P-gp inhibitors may|
02897|011|E|lead to elevated plasma levels of betrixaban, increasing the risk for|
02897|012|E|bleeding.|
02897|013|B||
02897|014|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
02897|015|P|bleeding include renal impairment, concomitant use of P-gp inhibitors,|
02897|016|P|coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs)|
02897|017|P|associated with bleeding risk, and patient weight < 50 kg.(1)|
02897|018|B||
02897|019|M|PATIENT MANAGEMENT:  Assess renal function and evaluate patient for other|
02897|020|M|pre-existing risk factors for bleeding prior to initiating concurrent|
02897|021|M|therapy.  The concurrent use of betrixaban and P-gp inhibitors should be|
02897|022|M|avoided in patients with severe renal impairment (CrCl less than 30|
02897|023|M|ml/min).(1)|
02897|024|M|   The recommended dose for patients receiving or starting concomitant P-gp|
02897|025|M|inhibitors is an initial single dose of 80 mg followed by 40 mg once daily.|
02897|026|M|The recommended duration of treatment is 35 to 42 days.(1)|
02897|027|M|   Note that if betrixaban is used with the combination of darunavir and|
02897|028|M|cobicistat, dose adjustment of betrixaban is not necessary.(2)|
02897|029|M|   The manufacturer of vimseltinib states concurrent use with P-gp|
02897|030|M|substrates should be avoided. If concurrent use cannot be avoided, take|
02897|031|M|vimseltinib at least 4 hours prior to betrixaban.(3)|
02897|032|M|   Careful monitoring for signs and symptoms of bleeding is warranted during|
02897|033|M|concurrent therapy.  Consider regular monitoring of hemoglobin, platelet|
02897|034|M|levels, and/or activated partial thromboplastin time (aPTT) or ecarin|
02897|035|M|clotting time (ECT).  Instruct patients to report any signs and symptoms of|
02897|036|M|bleeding, such as bleeding from the eyes, gums or nose; unusual bruising;|
02897|037|M|dark stools; red or dark brown urine; and/or abdominal pain or swelling.(1)|
02897|038|M|   The anticoagulant effect of betrixaban is expected to persist for at|
02897|039|M|least 72 hours after the last dose.|
02897|040|B||
02897|041|D|DISCUSSION:  In the APEX randomized, double-blind study the incidence of|
02897|042|D|major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40mg|
02897|043|D|and 80 mg group was higher in patients taking concomitant P-gp inhibitors|
02897|044|D|(2.8% vs. 4.1% vs. 4.7%).(4)|
02897|045|D|   In a study in 12 subjects, concomitant administration of a single dose of|
02897|046|D|betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice|
02897|047|D|daily) resulted in an increase in betrixaban's maximum concentration (Cmax)|
02897|048|D|and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(5)|
02897|049|D|   An open-label study looking at concomitant administration of a single|
02897|050|D|dose of betrixaban with verapamil in 18 subjects found an increase in|
02897|051|D|betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold,|
02897|052|D|respectively.(5)|
02897|053|D|   In a study, concomitant administration of betrixaban (80 mg) with|
02897|054|D|amiodarone resulted in an increase in betrixaban's Cmax by 143%.(5)|
02897|055|D|   A summary of pharmacokinetic interactions with betrixaban and amiodarone,|
02897|056|D|diltiazem, or verapamil concluded that if concurrent use is warranted, the|
02897|057|D|betrixaban dose should be reduced to 80 mg once then 40 mg daily.  Use|
02897|058|D|should be avoided if CrCl is less than 30 ml/min.(6)|
02897|059|D|   P-gp inhibitors include asunaprevir, azithromycin, belumosudil,|
02897|060|D|capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan,|
02897|061|D|cyclosporine, daclatasvir, danicopan, daridorexant, diltiazem, diosmin,|
02897|062|D|dronedarone, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir,|
02897|063|D|hydroquinidine, imlunestrant, indinavir, itraconazole, ivacaftor, josamycin,|
02897|064|D|lapatinib, ledipasvir, lonafarnib, lopinavir, mavorixafor, neratinib,|
02897|065|D|osimertinib, pibrentasvir, pirtobrutinib, propafenone, quinidine,|
02897|066|D|ranolazine, ritonavir, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir,|
02897|067|D|sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib,|
02897|068|D|valbenazine, velpatasvir, vemurafenib, vimseltinib, voclosporin and|
02897|069|D|voxilaprevir.(1,4-7)|
02897|070|B||
02897|071|R|REFERENCES:|
02897|072|B||
02897|073|R|1.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
02897|074|R|  Inc. July, 2019.|1
02897|075|R|2.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02897|076|R|  June, 2025.|1
02897|077|R|3.Romvimza (vimseltinib) US prescribing information. Deciphera|1
02897|078|R|  Pharmaceuticals, LLC February, 2025.|1
02897|079|R|4.FDA (US Food and Drug Administration). CDER application number. 208383|1
02897|080|R|  Bevyxxa Medical Review. acessed at:|1
02897|081|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383Orig1s000Med|1
02897|082|R|  R.pdf June 23, 2017.|1
02897|083|R|5.FDA (US Food and Drug Administration). CDER application number. 208383|1
02897|084|R|  Bevyxxa Clinical Pharmacology and Biopharmaceuticals Review. accessed at:|1
02897|085|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383orig1s000nam|1
02897|086|R|  er.pdf June 23, 2017.|1
02897|087|R|6.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
02897|088|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
02897|089|R|  of  the Week..|6
02897|090|R|7.This information is based on an extract from the Certara Drug Interaction|6
02897|091|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02898|001|T|MONOGRAPH TITLE:  Selexipag/Moderate CYP2C8 Inhibitors|
02898|002|B||
02898|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02898|004|L|take action as needed.|
02898|005|B||
02898|006|A|MECHANISM OF ACTION:  Moderate CYP2C8 inhibitors may inhibit the metabolism|
02898|007|A|of selexipag.(1)|
02898|008|B||
02898|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP2C8 inhibitor may|
02898|010|E|increase levels and effects of selexipag, including headache, diarrhea, jaw|
02898|011|E|pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased|
02898|012|E|hemoglobin, and hyperthyroidism.(1)|
02898|013|B||
02898|014|P|PREDISPOSING FACTORS:  None determined.|
02898|015|B||
02898|016|M|PATIENT MANAGEMENT:  When co-administered with a moderate inhibitor of|
02898|017|M|CYP2C8, reduce the dose of selexipag to once daily.  If the moderate CYP2C8|
02898|018|M|inhibitor is discontinued, increase the dose of selexipag to twice daily.(1)|
02898|019|M|   If concurrent use is warranted, monitor patients closely for increased|
02898|020|M|effects of selexipag, including headache, diarrhea, jaw pain, nausea,|
02898|021|M|myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and|
02898|022|M|hyperthyroidism.|
02898|023|B||
02898|024|D|DISCUSSION:  Clopidogrel (300 mg for 1 day then 75 mg daily, a moderate|
02898|025|D|CYP2C8 inhibitor) had no effect on exposure to selexipag but increased the|
02898|026|D|area-under-curve (AUC) of selexipag's active metabolite by 2.7-fold.(1)|
02898|027|D|   A study in healthy subjects evaluated concurrent therapy with selexipag|
02898|028|D|200 mcg twice daily with clopidogrel 300 mg single does or 75 mg daily.  The|
02898|029|D|AUC and the maximum concentration (Cmax) of ACT-333679, the major|
02898|030|D|contributor to the drug effect, increased 2.25-fold (90% confidence interval|
02898|031|D|(CI) 2.06, 2.46) and 1.69-fold (90% CI 1.55, 1.84), respectively with|
02898|032|D|clopidogrel 300 mg and 2.70-fold (90% CI 2.45, 2.96) and 1.90-fold (90% CI|
02898|033|D|1.72, 2.11), respectively with clopidogrel 75 mg.(2)|
02898|034|D|   Moderate CYP2C8 inhibitors linked include: clopidogrel, deferasirox,|
02898|035|D|leflunomide, letermovir, selpercatinib, and teriflunomide.(3-4)|
02898|036|B||
02898|037|R|REFERENCES:|
02898|038|B||
02898|039|R|1.Uptravi (selexipag) US prescribing information. Actelion Pharmaceuticals|1
02898|040|R|  US, Inc. October, 2021.|1
02898|041|R|2.Axelsen LN, Poggesi I, Rasschaert F, Perez Ruixo JJ, Bruderer S.|2
02898|042|R|  Clopidogrel, a CYP2C8 inhibitor, causes a clinically relevant increase in|2
02898|043|R|  the  systemic exposure to the active metabolite of selexipag in healthy|2
02898|044|R|  subjects. BJCP 15 May 2020.|2
02898|045|R|3.This information is based on an extract from the Certara Drug Interaction|6
02898|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02898|047|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02898|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02898|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02898|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02898|051|R|  11/14/2017.|1
02899|001|T|MONOGRAPH TITLE:  Selexipag/Rifampin|
02899|002|B||
02899|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02899|004|L|take action as needed.|
02899|005|B||
02899|006|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of selexipag by|
02899|007|A|CYP2C8 and UGT 1A3 and 2B7 enzymes.(1)|
02899|008|B||
02899|009|E|CLINICAL EFFECTS:  Concurrent use of rifampin may decrease levels and|
02899|010|E|effectiveness of selexipag.(1)|
02899|011|B||
02899|012|P|PREDISPOSING FACTORS:  None determined.|
02899|013|B||
02899|014|M|PATIENT MANAGEMENT:  When used with rifampin, increase the dose of selexipag|
02899|015|M|up to two-fold.  Reduce the dose of selexipag when rifampin is|
02899|016|M|discontinued.(1)|
02899|017|B||
02899|018|D|DISCUSSION:  Rifampin decreased the area-under-curve (AUC) of the active|
02899|019|D|metabolite of selexipag by 50%.|
02899|020|B||
02899|021|R|REFERENCES:|
02899|022|B||
02899|023|R|1.Uptravi (selexipag) US prescribing information. Actelion Pharmaceuticals|1
02899|024|R|  US, Inc. October, 2021.|1
02899|025|R|2.This information is based on an extract from the Certara Drug Interaction|6
02899|026|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02899|027|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02899|028|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02899|029|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02899|030|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02899|031|R|  11/14/2017.|1
02900|001|T|MONOGRAPH TITLE:  Betrixaban/Selected P-glycoprotein (P-gp) Inhibitors|
02900|002|B||
02900|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02900|004|L|of severe adverse interaction.|
02900|005|B||
02900|006|A|MECHANISM OF ACTION:  Betrixaban is a substrate for the P-glycoprotein|
02900|007|A|(P-gp) system.  Inhibition of intestinal P-gp leads to increased absorption|
02900|008|A|of betrixaban.(1)|
02900|009|B||
02900|010|E|CLINICAL EFFECTS:  The concurrent use betrixaban with P-gp inhibitors may|
02900|011|E|lead to elevated plasma levels of betrixaban, increasing the risk for|
02900|012|E|bleeding.|
02900|013|B||
02900|014|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
02900|015|P|bleeding include renal impairment, concomitant use of P-gp inhibitors,|
02900|016|P|coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs)|
02900|017|P|associated with bleeding risk, and patient weight < 50 kg.(1)|
02900|018|B||
02900|019|M|PATIENT MANAGEMENT:  Assess renal function and evaluate patient for other|
02900|020|M|pre-existing risk factors for bleeding prior to initiating concurrent|
02900|021|M|therapy.  The concurrent use of betrixaban and P-gp inhibitors should be|
02900|022|M|avoided in patients with severe renal impairment (CrCl less than 30|
02900|023|M|ml/min).(1)|
02900|024|M|   The recommended dose for patients receiving or starting concomitant P-gp|
02900|025|M|inhibitors is an initial single dose of 80 mg followed by 40 mg once daily.|
02900|026|M|The recommended duration of treatment is 35 to 42 days.(1)|
02900|027|M|   Careful monitoring for signs and symptoms of bleeding is warranted during|
02900|028|M|concurrent therapy.  Consider regular monitoring of hemoglobin, platelet|
02900|029|M|levels, and/or activated partial thromboplastin time (aPTT) or ecarin|
02900|030|M|clotting time (ECT).  Instruct patients to report any signs and symptoms of|
02900|031|M|bleeding, such as bleeding from the eyes, gums or nose; unusual bruising;|
02900|032|M|dark stools; red or dark brown urine; and/or abdominal pain or swelling.(1)|
02900|033|M|   The anticoagulant effect of betrixaban is expected to persist for at|
02900|034|M|least 72 hours after the last dose.|
02900|035|B||
02900|036|D|DISCUSSION:  In the APEX randomized, double-blind study the incidence of|
02900|037|D|major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40mg|
02900|038|D|and 80 mg group was higher in patients taking concomitant P-gp inhibitors|
02900|039|D|(2.8% vs. 4.1% vs. 4.7%).(2)|
02900|040|D|   In a study in 12 subjects, concomitant administration of a single dose of|
02900|041|D|betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice|
02900|042|D|daily) resulted in an increase in betrixaban's maximum concentration (Cmax)|
02900|043|D|and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(3)|
02900|044|D|   An open-label study looking at concomitant administration of a single|
02900|045|D|dose of betrixaban with verapamil in 18 subjects found an increase in|
02900|046|D|betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold,|
02900|047|D|respectively.(3)|
02900|048|D|   In a study, concomitant administration of betrixaban (80 mg) with|
02900|049|D|amiodarone resulted in an increase in betrixaban's Cmax by 143%.(3)|
02900|050|D|   A summary of pharmacokinetic interactions with betrixaban and amiodarone,|
02900|051|D|diltiazem, or verapamil concluded that if concurrent use is warranted, the|
02900|052|D|betrixaban dose should be reduced to 80 mg once then 40 mg daily.  Use|
02900|053|D|should be avoided if CrCl is less than 30 ml/min.(4)|
02900|054|D|   P-gp inhibitors linked to this monograph include amiodarone,|
02900|055|D|ketoconazole, and verapamil.(1-5)|
02900|056|B||
02900|057|R|REFERENCES:|
02900|058|B||
02900|059|R|1.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
02900|060|R|  Inc. July, 2019.|1
02900|061|R|2.FDA (US Food and Drug Administration). CDER application number. 208383|1
02900|062|R|  Bevyxxa Medical Review. acessed at:|1
02900|063|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383Orig1s000Med|1
02900|064|R|  R.pdf June 23, 2017.|1
02900|065|R|3.FDA (US Food and Drug Administration). CDER application number. 208383|1
02900|066|R|  Bevyxxa Clinical Pharmacology and Biopharmaceuticals Review. accessed at:|1
02900|067|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383orig1s000nam|1
02900|068|R|  er.pdf June 23, 2017.|1
02900|069|R|4.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
02900|070|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
02900|071|R|  of  the Week..|6
02900|072|R|5.This information is based on an extract from the Certara Drug Interaction|6
02900|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02901|001|T|MONOGRAPH TITLE:  Betrixaban/Anticoagulants; Thrombolytics|
02901|002|B||
02901|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02901|004|L|is contraindicated and generally should not be dispensed or administered to|
02901|005|L|the same patient.|
02901|006|B||
02901|007|A|MECHANISM OF ACTION:  Additive effects on hemostasis.|
02901|008|B||
02901|009|E|CLINICAL EFFECTS:  Concurrent use of betrixaban with anticoagulants or|
02901|010|E|thrombolytics may increase the risk of bleeding.|
02901|011|B||
02901|012|P|PREDISPOSING FACTORS:  Patients with severe renal impairment (CrCl< 30|
02901|013|P|ml/min) or taking a concomitant P-gp inhibitor.|
02901|014|B||
02901|015|M|PATIENT MANAGEMENT:  The long-term use of concurrent therapy with direct|
02901|016|M|oral anticoagulants (DOACs) and other anticoagulants is generally considered|
02901|017|M|contraindicated.  However, overlap may be necessary when switching therapy|
02901|018|M|from one agent to another in order to prevent thrombotic events.|
02901|019|M|Manufacturer recommendations concerning overlap (if any) and timing of|
02901|020|M|discontinuation versus initiation vary depending upon which agent is being|
02901|021|M|discontinued and initiated.  Refer to current prescribing information for|
02901|022|M|both agents for additional details.|
02901|023|M|   The use of concurrent therapy with Direct Oral Anticoagulants (DOACs) and|
02901|024|M|thrombolytics is generally considered contraindicated.|
02901|025|M|   The manufacturer of alteplase states that the use of alteplase for an|
02901|026|M|indication of acute ischemic stroke is contraindicated in patients receiving|
02901|027|M|anticoagulants.  Concurrent use of alteplase and anticoagulants is dependent|
02901|028|M|on the therapeutic indication.|
02901|029|M|   In Acute Ischemic Stroke:|
02901|030|M|   - Clinical practice guidelines for acute ischemic stroke state the use of|
02901|031|M|thrombolytic therapy for an indication of acute ischemic stroke is|
02901|032|M|contraindicated in patients who have received thrombin inhibitors or factor|
02901|033|M|Xa inhibitors in the previous 48 hours (in normal renal function) and have|
02901|034|M|abnormal laboratory tests such as activated partial thromboplastin time|
02901|035|M|(aPTT), INR, platelet count, ecarin clotting time (ECT), thrombin time, or|
02901|036|M|direct factor Xa assays at presentation.|
02901|037|M|   In Acute Myocardial Infarction:|
02901|038|M|   - Patients who are receiving thrombolytics for an indication of acute|
02901|039|M|myocardial infarction should be carefully monitored for signs of bleeding,|
02901|040|M|especially at arterial puncture sites, if betrixaban is used concurrently.|
02901|041|M|   - The use of thrombolytics in patients with acute myocardial infarction|
02901|042|M|should follow standard management of myocardial infarction, including|
02901|043|M|minimizing arterial and venous puncture; avoid noncompressible arterial|
02901|044|M|puncture; and minimize internal jugular and subclavian venous punctures to|
02901|045|M|decrease bleeding from the noncompressible sites.|
02901|046|M|   For all indications:|
02901|047|M|   - In the event of serious bleeding, anticoagulants should be discontinued|
02901|048|M|immediately.|
02901|049|M|   - If concurrent therapy is warranted, monitor patients receiving|
02901|050|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
02901|051|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
02901|052|M|evaluate patients with any symptoms.|
02901|053|M|   - When applicable, perform agent-specific laboratory test (e.g. INR,|
02901|054|M|aPTT) to monitor efficacy and safety of anticoagulation.  Discontinue|
02901|055|M|anticoagulation in patients with active pathologic bleeding.|
02901|056|M|   - Instruct patients to report any signs and symptoms of bleeding, such as|
02901|057|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02901|058|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02901|059|M|and/or swelling.|
02901|060|B||
02901|061|D|DISCUSSION:  Patients who are receiving thrombolytics should be carefully|
02901|062|D|monitored for signs of bleeding if anticoagulants are being used|
02901|063|D|concurrently or have recently been used.|
02901|064|B||
02901|065|R|REFERENCES:|
02901|066|B||
02901|067|R|1.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
02901|068|R|  Inc. July, 2019.|1
02901|069|R|2.Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC. Guidelines|6
02901|070|R|  for the Early Management of Patients With Acute Ischemic Stroke: 2019|6
02901|071|R|  Update to the 2018 Guidelines for the Early Management of Acute Ischemic|6
02901|072|R|  Stroke:  A Guideline for Healthcare Professionals From the AHA/ASA. Stroke|6
02901|073|R|  2019 Dec;50(12):e344-e418.|6
02903|001|T|MONOGRAPH TITLE:  Inotuzumab Ozogamicin/QT Prolonging Agents|
02903|002|B||
02903|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02903|004|L|of severe adverse interaction.|
02903|005|B||
02903|006|A|MECHANISM OF ACTION:  Concurrent use of inotuzumab ozogamicin with agents|
02903|007|A|that prolong the QTc interval may result in additive effects on the QTc|
02903|008|A|interval.(1)|
02903|009|B||
02903|010|E|CLINICAL EFFECTS:  The concurrent use of inotuzumab ozogamicin with agents|
02903|011|E|that prolong the QTc interval may result in potentially life-threatening|
02903|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02903|013|B||
02903|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02903|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02903|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02903|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02903|018|P|female gender, or advanced age.(2)|
02903|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02903|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02903|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02903|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02903|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02903|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02903|025|P|dysfunction).(2)|
02903|026|B||
02903|027|M|PATIENT MANAGEMENT:  When possible, discontinue QT prolonging agents prior|
02903|028|M|to therapy with inotuzumab ozogamicin or use alternative agents during|
02903|029|M|inotuzumab ozogamicin therapy.(1)|
02903|030|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
02903|031|M|values (serum calcium, magnesium, and potassium) prior to the start of|
02903|032|M|treatment, after initiation of any drug known to prolong the QT interval,|
02903|033|M|and periodically monitor during therapy.(1)  Correct any electrolyte|
02903|034|M|abnormalities.|
02903|035|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02903|036|M|fainting.(1)|
02903|037|B||
02903|038|D|DISCUSSION:  Inotuzumab ozogamicin was shown to prolong the QT interval in|
02903|039|D|clinical trials.  In the INO-VATE trial, 3% (4/162) of patients experienced|
02903|040|D|an increase in QTc equal to or greater than 60 msec.  No patients has QTc|
02903|041|D|values greater than 500 msec.  Grade 2 QT prolongation was reported in 1%|
02903|042|D|(2/164) patients.  There were no reports of Grade 3 QT prolongation or|
02903|043|D|Torsade de Pointes.(1)|
02903|044|D|   Agents that are linked to this monograph may have varying degrees of|
02903|045|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02903|046|D|been shown to prolong the QTc interval either through their mechanism of|
02903|047|D|action, through studies on their effects on the QTc interval, or through|
02903|048|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02903|049|D|and/or postmarketing reports.(3)|
02903|050|B||
02903|051|R|REFERENCES:|
02903|052|B||
02903|053|R|1.Besponsa (inotuzumab ozogamicin) US prescribing information. Wyeth|1
02903|054|R|  Pharmaceuticals, Inc. August 17, 2017.|1
02903|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02903|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02903|057|R|  settings: a scientific statement from the American Heart Association and|6
02903|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02903|059|R|  2;55(9):934-47.|6
02903|060|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02903|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02903|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02903|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02904|001|T|MONOGRAPH TITLE:  Inotuzumab Ozogamicin/Possible QT Prolonging Agents|
02904|002|B||
02904|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02904|004|L|take action as needed.|
02904|005|B||
02904|006|A|MECHANISM OF ACTION:  Concurrent use of inotuzumab ozogamicin with agents|
02904|007|A|that prolong the QTc interval may result in additive effects on the QTc|
02904|008|A|interval.(1)|
02904|009|B||
02904|010|E|CLINICAL EFFECTS:  The concurrent use of inotuzumab ozogamicin with agents|
02904|011|E|that prolong the QTc interval may result in potentially life-threatening|
02904|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
02904|013|B||
02904|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02904|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02904|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02904|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02904|018|P|female gender, or advanced age.(2)|
02904|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02904|020|P|higher systemic concentrations of either QT prolonging drug are additional|
02904|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02904|022|P|drug concentrations include rapid infusion of an intravenous dose or|
02904|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02904|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02904|025|P|dysfunction).(2)|
02904|026|B||
02904|027|M|PATIENT MANAGEMENT:  When possible, discontinue QT prolonging agents prior|
02904|028|M|to therapy with inotuzumab ozogamicin or use alternative agents during|
02904|029|M|inotuzumab ozogamicin therapy.(1)|
02904|030|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
02904|031|M|values (serum calcium, magnesium, and potassium) prior to the start of|
02904|032|M|treatment, after initiation of any drug known to prolong the QT interval,|
02904|033|M|and periodically monitor during therapy.(1)  Correct any electrolyte|
02904|034|M|abnormalities.|
02904|035|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02904|036|M|fainting.(1)|
02904|037|B||
02904|038|D|DISCUSSION:  Inotuzumab ozogamicin was shown to prolong the QT interval in|
02904|039|D|clinical trials.  In the INO-VATE trial, 3% (4/162) of patients experienced|
02904|040|D|an increase in QTc equal to or greater than 60 msec.  No patients has QTc|
02904|041|D|values greater than 500 msec.  Grade 2 QT prolongation was reported in 1%|
02904|042|D|(2/164) patients.  There were no reports of Grade 3 QT prolongation or|
02904|043|D|Torsade de Pointes.(1)|
02904|044|D|   Agents that are linked to this monograph may have varying degrees of|
02904|045|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02904|046|D|been shown to prolong the QTc interval either through their mechanism of|
02904|047|D|action, through studies on their effects on the QTc interval, or through|
02904|048|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02904|049|D|and/or postmarketing reports.(3)|
02904|050|B||
02904|051|R|REFERENCES:|
02904|052|B||
02904|053|R|1.Besponsa (inotuzumab ozogamicin) US prescribing information. Wyeth|1
02904|054|R|  Pharmaceuticals, Inc. August 17, 2017.|1
02904|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02904|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02904|057|R|  settings: a scientific statement from the American Heart Association and|6
02904|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02904|059|R|  2;55(9):934-47.|6
02904|060|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02904|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02904|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02904|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02905|001|T|MONOGRAPH TITLE:  Domperidone/Possible QT Prolonging Agents|
02905|002|B||
02905|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02905|004|L|of severe adverse interaction.|
02905|005|B||
02905|006|A|MECHANISM OF ACTION:  Concurrent use of domperidone with other agents that|
02905|007|A|prolong the QTc interval may result in additive effects on the QTc|
02905|008|A|interval.(1)|
02905|009|B||
02905|010|E|CLINICAL EFFECTS:  The use of domperidone patients maintained on agents that|
02905|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02905|012|E|arrhythmias, including torsades de pointes.(1)|
02905|013|B||
02905|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02905|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
02905|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02905|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02905|018|P|or female gender.(2)  The elderly and patients taking dosages of domperidone|
02905|019|P|greater than 30 mg may also be at increased risk.|
02905|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02905|021|P|higher systemic concentrations of either QT prolonging drug are additional|
02905|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02905|023|P|drug concentrations include rapid infusion of an intravenous dose or|
02905|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02905|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02905|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02905|027|B||
02905|028|M|PATIENT MANAGEMENT:  The concurrent use of domperidone and agents known to|
02905|029|M|prolong the QT interval is contraindicated.(1)|
02905|030|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02905|031|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02905|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02905|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02905|034|B||
02905|035|D|DISCUSSION:  Treatment with domperidone has been associated with increased|
02905|036|D|risk of sudden cardiac death.(1)|
02905|037|D|   Agents that are linked to this monograph may have varying degrees of|
02905|038|D|potential to prolong the QTc interval but are generally accepted to have a|
02905|039|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
02905|040|D|been shown to prolong the QTc interval either through their mechanism of|
02905|041|D|action, through studies on their effects on the QTc interval, or through|
02905|042|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
02905|043|D|and/or post-marketing reports.(2)|
02905|044|B||
02905|045|R|REFERENCES:|
02905|046|B||
02905|047|R|1.USDepartment of Health and Human Services Food and Drug Administration.|1
02905|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02905|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02905|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02905|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02905|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02905|053|R|  settings: a scientific statement from the American Heart Association and|6
02905|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02905|055|R|  2;55(9):934-47.|6
02905|056|R|3.Teva-Domperidone (Domperidone) Canadian product monograph. Teva Canada|1
02905|057|R|  Limited March 6, 2015.|1
02906|001|T|MONOGRAPH TITLE:  Metoclopramide/Selected Strong CYP2D6 Inhibitors|
02906|002|B||
02906|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02906|004|L|take action as needed.|
02906|005|B||
02906|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
02906|007|A|metoclopramide.|
02906|008|B||
02906|009|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of|
02906|010|E|metoclopramide, which may increase the risk of extrapyramidal symptoms such|
02906|011|E|as tardive dyskinesia, which may be permanent.  Tardive dyskinesia typically|
02906|012|E|affects the facial muscles and may result in uncontrollable lip smacking,|
02906|013|E|chewing, puckering of the mouth, frowning or scowling, sticking out the|
02906|014|E|tongue, blinking and moving the eyes, and shaking of the arms and/or legs.|
02906|015|E|   Concurrent use may also result in serotonin syndrome.  Symptoms of|
02906|016|E|serotonin syndrome include irritability, altered consciousness, double|
02906|017|E|vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone,|
02906|018|E|rigidity, myoclonus, rapid  fluctuations in vital signs, and coma. Serotonin|
02906|019|E|syndrome may result in death.|
02906|020|B||
02906|021|P|PREDISPOSING FACTORS:  Patients with renal and/or hepatic impairment may|
02906|022|P|have an increased risk from this combination.|
02906|023|B||
02906|024|M|PATIENT MANAGEMENT:  For gastroesophageal reflux, reduce the dosage of|
02906|025|M|metoclopramide to 5 mg four times daily (thirty minutes before each meal and|
02906|026|M|at bedtime) or 10 mg taken three times daily for a maximum daily dosage of|
02906|027|M|30 mg in patients taking strong CYP2D6 inhibitors.(1)|
02906|028|M|   For acute and recurrent diabetic gastroparesis, reduce the dosage of|
02906|029|M|metoclopramide to 5 mg four times daily (30 minutes before each meal and at|
02906|030|M|bedtime) for a maximum daily dosage of 20 mg in patients taking strong|
02906|031|M|CYP2D6 inhibitors.(1)|
02906|032|M|   If concurrent therapy is warranted, patients should be monitored for|
02906|033|M|extrapyramidal symptoms and signs and symptoms of serotonin syndrome.|
02906|034|M|Instruct patients to report any abnormal/uncontrollable muscle movements,|
02906|035|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
02906|036|M|heart palpitations, restlessness, confusion, agitation, trouble with|
02906|037|M|coordination, or severe diarrhea.|
02906|038|B||
02906|039|D|DISCUSSION:  In a study in 20 healthy male subjects, concurrent fluoxetine|
02906|040|D|(60 mg daily, another strong CYP2D6 inhibitor) increased the maximum|
02906|041|D|concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg|
02906|042|D|single dose) by 42% and 89%, respectively.(1,2)|
02906|043|D|   There have been case reports of serotonin syndrome in patients receiving|
02906|044|D|concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(3)|
02906|045|D|sertraline,(5-7) and venlafaxine.(7)|
02906|046|D|   Strong CYP2D6 inhibitors linked to this monograph include: bupropion,|
02906|047|D|dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and|
02906|048|D|terbinafine.(8)|
02906|049|B||
02906|050|R|REFERENCES:|
02906|051|B||
02906|052|R|1.Reglan (metoclopramide) tablets US prescribing information. ANI|1
02906|053|R|  Pharmaceuticals, Inc. August 29, 2017.|1
02906|054|R|2.Vlase L, Leucuta A, Farcau D, Nanulescu M. Pharmacokinetic interaction|2
02906|055|R|  between fluoxetine and metoclopramide in healthy volunteers. Biopharm Drug|2
02906|056|R|  Dispos 2006 Sep;27(6):285-9.|2
02906|057|R|3.Coulter DM, Pillans PI. Fluoxetine and extrapyramidal side effects. Am J|3
02906|058|R|  Psychiatry 1995 Jan;152(1):122-5.|3
02906|059|R|4.Palop V, Jimenez MJ, Catalan C, Martinez-Mir I. Acute dystonia associated|3
02906|060|R|  with fluvoxamine-metoclopramide. Ann Pharmacother 1999 Mar;33(3):382.|3
02906|061|R|5.Christensen RC, Byerly MJ. Mandibular dystonia associated with the|3
02906|062|R|  combination of sertraline and metoclopramide. J Clin Psychiatry 1996 Dec;|3
02906|063|R|  57(12):596.|3
02906|064|R|6.Vandemergel X, Beukinga I, Neve P. Serotonin syndrome secondary to the use|3
02906|065|R|  of sertraline and metoclopramide. Rev Med Brux 2000 Jun;21(3):161-3.|3
02906|066|R|7.Fisher AA, Davis MW. Serotonin syndrome caused by selective serotonin|3
02906|067|R|  reuptake-inhibitors-metoclopramide interaction. Ann Pharmacother 2002 Jan;|3
02906|068|R|  36(1):67-71.|3
02906|069|R|8.This information is based on an extract from the Certara Drug Interaction|6
02906|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02907|001|T|MONOGRAPH TITLE:  Metoclopramide/Quinidine (mono deleted 02/22/2023)|
02907|002|B||
02907|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02907|004|L|of severe adverse interaction.|
02907|005|B||
02907|006|A|MECHANISM OF ACTION:  Strong 2D6 inhibitors may inhibit the metabolism of|
02907|007|A|metoclopramide.(1)|
02907|008|B||
02907|009|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of|
02907|010|E|metoclopramide, which may increase the risk of extrapyramidal symptoms such|
02907|011|E|as tardive dyskinesia, which may be permanent.  Tardive dyskinesia typically|
02907|012|E|affects the facial muscles and may result in uncontrollable lip smacking,|
02907|013|E|chewing, puckering of the mouth, frowning or scowling, sticking out the|
02907|014|E|tongue, blinking and moving the eyes, and shaking of the arms and/or legs.|
02907|015|B||
02907|016|P|PREDISPOSING FACTORS:  Patients with renal and/or hepatic impairment may|
02907|017|P|have an increased risk from this combination.|
02907|018|B||
02907|019|M|PATIENT MANAGEMENT:  For gastroesophageal reflux, reduce the dosage of|
02907|020|M|metoclopramide to 5 mg four times daily (thirty minutes before each meal and|
02907|021|M|at bedtime) or 10 mg taken three times daily for a maximum daily dosage of|
02907|022|M|30 mg in patients taking quinidine.(1)|
02907|023|M|   For acute and recurrent diabetic gastroparesis, reduce the dosage of|
02907|024|M|metoclopramide to 5 mg four times daily (30 minutes before each meal and at|
02907|025|M|bedtime) for a maximum daily dosage of 20 mg in patients taking|
02907|026|M|quinidine.(1)|
02907|027|M|   If concurrent therapy is warranted, patients should be monitored for|
02907|028|M|extrapyramidal symptoms.  Instruct patients to report any|
02907|029|M|abnormal/uncontrollable muscle movements.|
02907|030|B||
02907|031|D|DISCUSSION:  In a study in 20 healthy male subjects, concurrent fluoxetine|
02907|032|D|(60 mg daily, another strong CYP2D6 inhibitor) increased the maximum|
02907|033|D|concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg|
02907|034|D|single dose) by 42% and 89%, respectively.(1,2)|
02907|035|B||
02907|036|R|REFERENCES:|
02907|037|B||
02907|038|R|1.Reglan (metoclopramide) tablets US prescribing information. ANI|1
02907|039|R|  Pharmaceuticals, Inc. August 29, 2017.|1
02907|040|R|2.Vlase L, Leucuta A, Farcau D, Nanulescu M. Pharmacokinetic interaction|2
02907|041|R|  between fluoxetine and metoclopramide in healthy volunteers. Biopharm Drug|2
02907|042|R|  Dispos 2006 Sep;27(6):285-9.|2
02908|001|T|MONOGRAPH TITLE:  Betrixaban/Antiplatelets; Aspirin (Greater Than 325 mg)|
02908|002|B||
02908|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02908|004|L|of severe adverse interaction.|
02908|005|B||
02908|006|A|MECHANISM OF ACTION:  Betrixaban is a factor Xa inhibitor and when taken|
02908|007|A|with agents that effect platelet aggregation increased bleeding episodes can|
02908|008|A|occur.(1,2)|
02908|009|B||
02908|010|E|CLINICAL EFFECTS:  Concurrent use of betrixaban with antiplatelet agents may|
02908|011|E|result in additive or synergistic effects resulting in unwanted bleeding|
02908|012|E|episodes.(1,2)|
02908|013|B||
02908|014|P|PREDISPOSING FACTORS:  Factors associated with an increase risk for bleeding|
02908|015|P|include renal impairment, concomitant use of P-glycoprotein inhibitors,|
02908|016|P|coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs)|
02908|017|P|associated with bleeding risk.(1-3)|
02908|018|P|   The risk for bleeding episodes may be greater in patients with|
02908|019|P|disease-associated factors (e.g. thrombocytopenia).|
02908|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
02908|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02908|022|P|risk for bleeding (e.g. NSAIDs).|
02908|023|B||
02908|024|M|PATIENT MANAGEMENT:  Patients requiring concurrent therapy with betrixaban|
02908|025|M|and an antiplatelet agent should be closely monitored for signs of bleeding.|
02908|026|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
02908|027|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
02908|028|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
02908|029|M|patients with any symptoms.|
02908|030|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02908|031|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02908|032|M|anticoagulation in patients with active pathologic bleeding.|
02908|033|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02908|034|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02908|035|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02908|036|M|and/or swelling.|
02908|037|M|   The time of highest risk for a coumarin-type drug interaction is when the|
02908|038|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
02908|039|M|initiating, altering the dose or discontinuing either drug.|
02908|040|M|   Discontinue betrixaban in patients with active bleeding.|
02908|041|M|   The anticoagulant effect of betrixaban is expected to persist for at|
02908|042|M|least 72 hours after the last dose.|
02908|043|B||
02908|044|D|DISCUSSION:  Betrixaban is a factor Xa inhibitor and when taken with agents|
02908|045|D|that effect platelet aggregation and/or other clotting factors increased|
02908|046|D|bleeding episodes can occur.(1,2)|
02908|047|D|   In the APEX trial, if aspirin was required for cardiovascular disease,|
02908|048|D|doses were limited to less than 165mg daily, with the exception of patients|
02908|049|D|who were receiving aspirin for ischemic stroke or TIA indication, who could|
02908|050|D|take 325mg daily. Concomitant use of aspirin and betrixaban resulted in a|
02908|051|D|slightly increased incidence of major/clinically relevant non-major (CRNM)|
02908|052|D|bleeding compared to those who did not use aspirin (3.7% vs. 2.89%).|
02908|053|D|Concomitant use of aspirin with betrixaban resulted in an increased|
02908|054|D|incidence of major bleeding twice as much as those who did not use aspirin|
02908|055|D|with betrixaban (0.93% vs. 0.46%).(2)|
02908|056|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
02908|057|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
02908|058|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
02908|059|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
02908|060|D|aspirin, with the highest allowable dose being 165 mg/day.  The use of DOACs|
02908|061|D|with antiplatelet agents was associated with an increased risk of major|
02908|062|D|bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI,|
02908|063|D|1.50-2.22).  There was no difference between groups in the efficacy outcome|
02908|064|D|of symptomatic recurrent venous thromboembolism (VTE) or VTE-related|
02908|065|D|death.(3)|
02908|066|B||
02908|067|R|REFERENCES:|
02908|068|B||
02908|069|R|1.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
02908|070|R|  Inc. July, 2019.|1
02908|071|R|2.FDA (US Food and Drug Administration). CDER application number. 208383|1
02908|072|R|  Bevyxxa Medical Review. acessed at:|1
02908|073|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383Orig1s000Med|1
02908|074|R|  R.pdf June 23, 2017.|1
02908|075|R|3.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
02908|076|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
02908|077|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
02908|078|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
02909|001|T|MONOGRAPH TITLE:  Betrixaban/Aspirin (Less Than or Equal To 325 mg)|
02909|002|B||
02909|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02909|004|L|take action as needed.|
02909|005|B||
02909|006|A|MECHANISM OF ACTION:  Additive effects on hemostasis.(1)|
02909|007|B||
02909|008|E|CLINICAL EFFECTS:  Concurrent use of betrixaban with aspirin may increase|
02909|009|E|the risk of bleeding.(1-2)|
02909|010|B||
02909|011|P|PREDISPOSING FACTORS:  Factors associated with an increase risk for bleeding|
02909|012|P|may include renal impairment, concomitant use of P-glycoprotein inhibitors,|
02909|013|P|coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs)|
02909|014|P|associated with bleeding risk.(1)|
02909|015|B||
02909|016|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
02909|017|M|of blood loss, including decreased hemoglobin, hematocrit, fecal occult|
02909|018|M|blood, and/or blood pressure and promptly evaluate patients with any|
02909|019|M|symptoms.|
02909|020|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02909|021|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02909|022|M|anticoagulation in patients with active pathologic bleeding.|
02909|023|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02909|024|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02909|025|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02909|026|M|and/or swelling.|
02909|027|B||
02909|028|D|DISCUSSION:  In the APEX trial, if aspirin was required for cardiovascular|
02909|029|D|disease, doses were limited to less than 165mg daily, with the exception of|
02909|030|D|patients who were receiving aspirin for ischemic stroke or TIA indication,|
02909|031|D|who could take 325mg daily. Concomitant use of aspirin and betrixaban|
02909|032|D|resulted in a slightly increased incidence of major/clinically relevant|
02909|033|D|non-major (CRNM) bleeding compared to those who did not use aspirin (3.7%|
02909|034|D|vs. 2.89%). Concomitant use of aspirin with betrixaban resulted in an|
02909|035|D|increased incidence of major bleeding twice as much as those who did not use|
02909|036|D|aspirin with betrixaban (0.93% vs. 0.46%).(2)|
02909|037|D|   A meta-analysis of 9 studies identified 13,459 patients taking direct|
02909|038|D|oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent.|
02909|039|D|Of the patients on antiplatelet agents, 1,254 took aspirin while the rest|
02909|040|D|was unspecified.  Most of the trials restricted patients to use of low-dose|
02909|041|D|aspirin, with the highest allowable dose being 165 mg/day.  The use of DOACs|
02909|042|D|with antiplatelet agents was associated with an increased risk of major|
02909|043|D|bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI,|
02909|044|D|1.50-2.22).  There was no difference between groups in the efficacy outcome|
02909|045|D|of symptomatic recurrent venous thromboembolism (VTE) or VTE-related|
02909|046|D|death.(3)|
02909|047|B||
02909|048|R|REFERENCES:|
02909|049|B||
02909|050|R|1.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
02909|051|R|  Inc. July, 2019.|1
02909|052|R|2.FDA (US Food and Drug Administration). CDER application number. 208383|1
02909|053|R|  Bevyxxa Medical Review. acessed at:|1
02909|054|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383Orig1s000Med|1
02909|055|R|  R.pdf June 23, 2017.|1
02909|056|R|3.Valeriani E, Porreca E, Weitz JI, Schulman S, Candeloro M, Di Nisio M.|6
02909|057|R|  Impact of concomitant antiplatelet therapy on the efficacy and safety of|6
02909|058|R|  direct oral  anticoagulants for acute venous thromboembolism: Systematic|6
02909|059|R|  review and  meta-analysis. J Thromb Haemost 2020 Jul;18(7):1661-1671.|6
02910|001|T|MONOGRAPH TITLE:  Drospirenone-Ethinyl Estradiol/Atazanavir-Cobicistat|
02910|002|B||
02910|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02910|004|L|is contraindicated and generally should not be dispensed or administered to|
02910|005|L|the same patient.|
02910|006|B||
02910|007|A|MECHANISM OF ACTION:  Atazanavir and cobicistat are both inhibitors of|
02910|008|A|CYP3A4 and may inhibit the metabolism of drospirenone.  Drospirenone has|
02910|009|A|anti-mineralocorticoid activity.|
02910|010|B||
02910|011|E|CLINICAL EFFECTS:  Concurrent administration may result in increased effects|
02910|012|E|from the progestin (insulin resistance, dyslipidemia, acne, and venous|
02910|013|E|thrombosis) and decreased effects of the estrogen component.(1)|
02910|014|E|   Concurrent use of atazanavir-cobicistat may result in elevated levels of|
02910|015|E|and effects from drospirenone, including hyperkalemia.(1)|
02910|016|B||
02910|017|P|PREDISPOSING FACTORS:  Renal insufficiency, hepatic dysfunction, adrenal|
02910|018|P|insufficiency, and use of potassium supplements, potassium-sparing|
02910|019|P|diuretics, heparin, and NSAIDs may increase potassium levels.|
02910|020|B||
02910|021|M|PATIENT MANAGEMENT:  The US manufacturer of cobicistat states that|
02910|022|M|concurrent use of drospirenone is contraindicated when cobicistat is also|
02910|023|M|administered with atazanavir.(1)|
02910|024|B||
02910|025|D|DISCUSSION:  Drospirenone has anti-mineralocorticoid activity comparable to|
02910|026|D|a 25mg dose of spironolactone.|
02910|027|D|   Concurrent use of cobicistat 150 mg increased the area-under-curve (AUC)|
02910|028|D|and concentration maximum (Cmax) of drospirenone (administered as|
02910|029|D|drospirenone/ethinyl estradiol 3/0.02 mg single dose) by 2.3-fold and|
02910|030|D|1.12-fold, respectively.  Concurrent use decreased the AUC and Cmax of|
02910|031|D|ethinyl estradiol by 0.78-fold and 0.82-fold, respectively.(1)|
02910|032|B||
02910|033|R|REFERENCES:|
02910|034|B||
02910|035|R|1.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02910|036|R|  June, 2025.|1
02910|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
02910|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02911|001|T|MONOGRAPH TITLE:  Atazanavir-Cobicistat/Contraceptives|
02911|002|B||
02911|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02911|004|L|of severe adverse interaction.|
02911|005|B||
02911|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.  Both|
02911|007|A|atazanavir and cobicistat may inhibit CYP3A4 but neither has been found to|
02911|008|A|induce CYP3A4.  Atazanavir also inhibits UGT1A1 and weakly inhibits CYP2C8|
02911|009|A|while cobicistat also inhibits CYP2D6, P-glycoprotein (P-gp), BCRP, OATP1B1|
02911|010|A|and OATP1B3.(1-3)|
02911|011|B||
02911|012|E|CLINICAL EFFECTS:  Atazanavir-cobicistat has been shown to decrease ethinyl|
02911|013|E|estradiol (EE) levels when used with EE-drospirenone, but did not change EE|
02911|014|E|levels when used with EE-levonorgestrel.(4)  The effect of|
02911|015|E|atazanavir-cobicistat on other contraceptives is unknown.(1)|
02911|016|E|   Progestin concentrations may be increased with the use of|
02911|017|E|atazanavir-cobicistat, which may increase the risk of insulin resistance,|
02911|018|E|dyslipidemia, and acne.(1,4)|
02911|019|B||
02911|020|P|PREDISPOSING FACTORS:  None determined.|
02911|021|B||
02911|022|M|PATIENT MANAGEMENT:  The manufacturer of atazanavir-cobicistat states that|
02911|023|M|no data is available to make recommendations on coadministration with oral|
02911|024|M|or other hormonal contraceptives. Alternative nonhormonal forms of|
02911|025|M|contraception should be considered.(1)|
02911|026|M|   The US Department of Health and Human Services HIV guidelines state that|
02911|027|M|no dose adjustment is needed when atazanavir-cobicistat is used with oral|
02911|028|M|contraceptives.(4)|
02911|029|M|   The CDC contraceptive guidelines state that intrauterine devices (copper|
02911|030|M|or levonorgestrel) may be used with any antiretroviral agent.(5)|
02911|031|B||
02911|032|D|DISCUSSION:  Concurrent use of atazanavir-cobicistat (300 mg - 150 mg once|
02911|033|D|daily) increased the area-under-curve (AUC) of drospirenone (administered as|
02911|034|D|drospirenone/ethinyl estradiol 3/0.02 mg single dose) by 2.3-fold.(2)|
02911|035|D|   Atazanavir-cobicistat (300 mg-150 mg once daily) did not change|
02911|036|D|levonorgestrel concentrations or ethinyl estradiol AUC, and decreased|
02911|037|D|ethinyl estradiol minimum concentration (Cmin) by 25%.(4)|
02911|038|D|   Concurrent administration of atazanavir (400 mg daily) with ethinyl|
02911|039|D|estradiol-norethindrone (Ortho-Novum) increased the maximum concentration|
02911|040|D|(Cmax), AUC, and Cmin of ethinyl estradiol by 15%, 48%, and 91%,|
02911|041|D|respectively, and the Cmax, AUC, and Cmin of norethindrone by 67%, 210%, and|
02911|042|D|362%, respectively.(3)|
02911|043|B||
02911|044|R|REFERENCES:|
02911|045|B||
02911|046|R|1.Evotaz (atazanavir and cobicistat) US prescribing information.|1
02911|047|R|  Bristol-Myers-Squibb Company May, 2025.|1
02911|048|R|2.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02911|049|R|  June, 2025.|1
02911|050|R|3.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
02911|051|R|  Squibb Company December, 2024.|1
02911|052|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02911|053|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02911|054|R|  HIV. Department of Health and Human Services. Available at|6
02911|055|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
02911|056|R|  new-guidelines June 13, 2021.|6
02911|057|R|5.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
02911|058|R|  Criteria for Contraceptive Use, 2016. MMWR Recomm Rep.  Available at:|6
02911|059|R|  https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf July 29, 2016;|6
02911|060|R|  65(3):.|6
02912|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 20 mg)/Darunavir-Cobicistat|
02912|002|B||
02912|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02912|004|L|is contraindicated and generally should not be dispensed or administered to|
02912|005|L|the same patient.|
02912|006|B||
02912|007|A|MECHANISM OF ACTION:  Darunavir is an inhibitor of OATP1B1 and OATP1B3.|
02912|008|A|Cobicistat is an inhibitor of BCRP, OATP1B1, and OATP1B3 transport in the|
02912|009|A|intestine. Rosuvastatin is a substrate for these three transporters.|
02912|010|B||
02912|011|E|CLINICAL EFFECTS:  Concurrent use of darunavir may result in elevated levels|
02912|012|E|of rosuvastatin, which could result in myopathy or rhabdomyolysis.|
02912|013|B||
02912|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02912|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02912|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02912|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02912|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02912|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02912|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02912|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02912|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02912|023|B||
02912|024|M|PATIENT MANAGEMENT:  In patients receiving darunavir, consider the use of|
02912|025|M|fluvastatin.|
02912|026|M|   The manufacturer of cobicistat states that the rosuvastatin dose should|
02912|027|M|not exceed 20 mg when cobicistat is coadministered with darunavir.|
02912|028|M|   If these medications are used concurrently, counsel patient to report|
02912|029|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
02912|030|B||
02912|031|D|DISCUSSION:  In a study, darunavir/cobicistat (800/150 mg once daily)|
02912|032|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02912|033|D|single dose of rosuvastatin (10 mg) by 277% and 93%, respectively.(1)|
02912|034|B||
02912|035|R|REFERENCES:|
02912|036|B||
02912|037|R|1.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02912|038|R|  June, 2025.|1
02912|039|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02912|040|R|  Pharmaceuticals LP July, 2024.|1
02913|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 20|
02913|002|T|mg)/Darunavir-Cobicistat|
02913|003|B||
02913|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02913|005|L|take action as needed.|
02913|006|B||
02913|007|A|MECHANISM OF ACTION:  Darunavir is an inhibitor of OATP1B1 and OATP1B3.|
02913|008|A|Cobicistat is an inhibitor of BCRP, OATP1B1, and OATP1B3 transport in the|
02913|009|A|intestine. Rosuvastatin is a substrate for these three transporters.|
02913|010|B||
02913|011|E|CLINICAL EFFECTS:  Concurrent use of darunavir may result in elevated levels|
02913|012|E|of rosuvastatin, which could result in myopathy or rhabdomyolysis.|
02913|013|B||
02913|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02913|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02913|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02913|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02913|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02913|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02913|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
02913|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
02913|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
02913|023|B||
02913|024|M|PATIENT MANAGEMENT:  In patients receiving darunavir, consider the use of|
02913|025|M|fluvastatin.|
02913|026|M|   The manufacturer of cobicistat states that the rosuvastatin dose should|
02913|027|M|not exceed 20mg when cobicistat is coadministered with darunavir.|
02913|028|M|   If these medications are used concurrently, counsel patient to report|
02913|029|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
02913|030|B||
02913|031|D|DISCUSSION:  In a study, darunavir/cobicistat (800/150 mg once daily)|
02913|032|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02913|033|D|single dose of rosuvastatin (10 mg) by 277% and 93%, respectively.(1)|
02913|034|B||
02913|035|R|REFERENCES:|
02913|036|B||
02913|037|R|1.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02913|038|R|  June, 2025.|1
02913|039|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
02913|040|R|  Pharmaceuticals LP July, 2024.|1
02914|001|T|MONOGRAPH TITLE:  Atorvastatin/Atazanavir|
02914|002|B||
02914|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02914|004|L|of severe adverse interaction.|
02914|005|B||
02914|006|A|MECHANISM OF ACTION:  Atazanavir may inhibit the metabolism of atorvastatin|
02914|007|A|by CYP3A4.(1-3)|
02914|008|B||
02914|009|E|CLINICAL EFFECTS:  Concurrent use of atazanavir may result in elevated|
02914|010|E|levels of atorvastatin, which could result in rhabdomyolysis or|
02914|011|E|myopathy.(1-3)|
02914|012|B||
02914|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02914|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02914|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02914|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02914|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02914|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02914|019|P|predisposed to myopathy or rhabdomyolysis.|
02914|020|B||
02914|021|M|PATIENT MANAGEMENT:  In patients receiving atazanavir, consider the use of|
02914|022|M|fluvastatin.  Administration of atazanavir-cobicistat with atorvastatin is|
02914|023|M|not recommended.(1)  Administration of atazanavir-ritonavir or unboosted|
02914|024|M|atazanavir with atorvastatin should be monitored closely.(2-3)|
02914|025|M|   If coadministration is necessary, use the lowest dose possible of|
02914|026|M|atorvastatin with careful monitoring.(1-3)|
02914|027|M|   Counsel patient to report unexplained muscle pain, tenderness, weakness,|
02914|028|M|or dark, cola-colored urine.|
02914|029|B||
02914|030|D|DISCUSSION:  A study in 16 subjects found that atazanavir-cobicistat|
02914|031|D|(300-150 mg once daily) increased atorvastatin (10 mg single dose) maximum|
02914|032|D|concentration (Cmax) and area-under-curve (AUC) by 18.85-fold, and|
02914|033|D|9.22-fold, respectively.(1)|
02914|034|B||
02914|035|R|REFERENCES:|
02914|036|B||
02914|037|R|1.Evotaz (atazanavir and cobicistat) US prescribing information.|1
02914|038|R|  Bristol-Myers-Squibb Company May, 2025.|1
02914|039|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
02914|040|R|  Squibb Company December, 2024.|1
02914|041|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02914|042|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02914|043|R|  HIV. Department of Health and Human Services. Available at:|6
02914|044|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
02914|045|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
02915|001|T|MONOGRAPH TITLE:  Copanlisib/Strong CYP3A4 Inhibitors|
02915|002|B||
02915|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02915|004|L|of severe adverse interaction.|
02915|005|B||
02915|006|A|MECHANISM OF ACTION:  Copanlisib is a substrate of CYP3A4.  Strong|
02915|007|A|inhibitors of CYP3A4 may inhibit the metabolism of copanlisib.(1)|
02915|008|B||
02915|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02915|010|E|in increased levels and toxicity from copanlisib.(1)|
02915|011|B||
02915|012|P|PREDISPOSING FACTORS:  None determined.|
02915|013|B||
02915|014|M|PATIENT MANAGEMENT:  The manufacturer of copanlisib states to avoid|
02915|015|M|concurrent administration with strong CYP3A4 inhibitors.  If concurrent|
02915|016|M|therapy cannot be avoided, reduce the dose of copanlisib to 45 mg.(1)|
02915|017|M|   Monitor patient for signs and symptoms of copanlisib toxicity with|
02915|018|M|concurrent use.|
02915|019|B||
02915|020|D|DISCUSSION:  Copanlisib is a substrate of CYP3A4.(1)|
02915|021|D|   Concurrent administration of itraconazole (200 mg once daily for 10 days,|
02915|022|D|a strong CYP3A4 inhibitor) with a single 60 mg dose of copanlisib increased|
02915|023|D|the copanlisib area-under-curve (AUC) by 53% with no effect on maximum|
02915|024|D|concentration (Cmax) compared to copanlisib alone.(1)|
02915|025|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
02915|026|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir,|
02915|027|D|itraconazole, josamycin, lonafarnib, ketoconazole, mibefradil, mifepristone,|
02915|028|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib,|
02915|029|D|ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib,|
02915|030|D|and voriconazole.(2,3)|
02915|031|B||
02915|032|R|REFERENCES:|
02915|033|B||
02915|034|R|1.Aliqopa (copanlisib) US prescribing information. Bayer October, 2019.|1
02915|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
02915|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02915|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02915|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02915|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02915|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02915|041|R|  11/14/2017.|1
02916|001|T|MONOGRAPH TITLE:  Copanlisib/Strong CYP3A4 Inducers|
02916|002|B||
02916|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02916|004|L|of severe adverse interaction.|
02916|005|B||
02916|006|A|MECHANISM OF ACTION:  Copanlisib is a substrate of CYP3A4.  Strong inducers|
02916|007|A|of CYP3A4 may induce the metabolism of copanlisib.(1)|
02916|008|B||
02916|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02916|010|E|in decreased levels and effectiveness of copanlisib.(1)|
02916|011|B||
02916|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02916|013|P|of the inducer for longer than 1-2 weeks.|
02916|014|B||
02916|015|M|PATIENT MANAGEMENT:  The manufacturer of copanlisib states to avoid|
02916|016|M|concurrent administration with strong CYP3A4 inducers.(1)|
02916|017|B||
02916|018|D|DISCUSSION:  Copanlisib is a substrate of CYP3A4.(1)|
02916|019|D|   Concurrent administration of rifampin (600 mg once daily for 12 days, a|
02916|020|D|strong CYP3A4 inducer) with a single 60 mg dose of copanlisib decreased the|
02916|021|D|copanlisib area-under-curve (AUC) by 63% and maximum concentration (Cmax) by|
02916|022|D|15% compared to copanlisib alone.(1)|
02916|023|D|   Strong CYP3A4 inducers linked to this monograph include:  apalutamide,|
02916|024|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02916|025|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
02916|026|D|rifampin, rifapentine, and St. John's wort.(2-3)|
02916|027|B||
02916|028|R|REFERENCES:|
02916|029|B||
02916|030|R|1.Aliqopa (copanlisib) US prescribing information. Bayer October, 2019.|1
02916|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
02916|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02916|033|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02916|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02916|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02916|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02916|037|R|  11/14/2017.|1
02917|001|T|MONOGRAPH TITLE:  Mifepristone (Cushing)/Anticoagulants; Antiplatelets|
02917|002|B||
02917|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02917|004|L|take action as needed.|
02917|005|B||
02917|006|A|MECHANISM OF ACTION:  Mifepristone is an antagonist at the progesterone|
02917|007|A|receptor which can result in endometrium thickening, cystic dilatation of|
02917|008|A|endometrial glands, or excessive vaginal bleeding.  Concurrent use with|
02917|009|A|anticoagulants or antiplatelets may further increase risk.|
02917|010|B||
02917|011|E|CLINICAL EFFECTS:  The concurrent use of mifepristone with anticoagulants or|
02917|012|E|antiplatelets may result in endometrium thickening, cystic dilatation of|
02917|013|E|endometrial glands, or excessive vaginal bleeding.|
02917|014|B||
02917|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
02917|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
02917|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
02917|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02917|019|P|risk for bleeding (e.g. NSAIDs).|
02917|020|B||
02917|021|M|PATIENT MANAGEMENT:  The manufacturer of mifepristone states that|
02917|022|M|mifepristone should be used with caution in patients receiving concurrent|
02917|023|M|anticoagulant or antiplatelet therapy.(1)|
02917|024|M|   If concurrent therapy is deemed medically necessary, monitor patients|
02917|025|M|receiving concurrent therapy for signs of blood loss, including decreased|
02917|026|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
02917|027|M|and promptly evaluate patients with any symptoms.|
02917|028|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02917|029|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02917|030|M|anticoagulation in patients with active pathologic bleeding.|
02917|031|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02917|032|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02917|033|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02917|034|M|and/or swelling.|
02917|035|M|   Women experiencing vaginal bleeding during concurrent use should be|
02917|036|M|referred to a gynecologist for further evaluation.|
02917|037|B||
02917|038|D|DISCUSSION:  The manufacturer of mifepristone states that mifepristone|
02917|039|D|should be used with caution in patients receiving concurrent anticoagulant|
02917|040|D|or antiplatelet therapy.(1)|
02917|041|B||
02917|042|R|REFERENCE:|
02917|043|B||
02917|044|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
02917|045|R|  November, 2019.|1
02918|001|T|MONOGRAPH TITLE:  Atorvastatin (Greater Than 20|
02918|002|T|mg)/Elvitegravir-Cobicistat-Emtricitabine-Tenofovir|
02918|003|B||
02918|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02918|005|L|is contraindicated and generally should not be dispensed or administered to|
02918|006|L|the same patient.|
02918|007|B||
02918|008|A|MECHANISM OF ACTION:  Cobicistat may inhibit the metabolism of atorvastatin|
02918|009|A|by CYP3A4.(1,2)|
02918|010|B||
02918|011|E|CLINICAL EFFECTS:  Concurrent use of|
02918|012|E|elvitegravir-cobicistat-emtricitabine-tenofovir may result in elevated|
02918|013|E|levels of and toxicity from atorvastatin, which could result in|
02918|014|E|rhabdomyolysis.(1,2)|
02918|015|B||
02918|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02918|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02918|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02918|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02918|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02918|021|P|transporter OATP1B1 may have increased statin concentrations and be|
02918|022|P|predisposed to myopathy or rhabdomyolysis.|
02918|023|B||
02918|024|M|PATIENT MANAGEMENT:  In patients requiring|
02918|025|M|elvitegravir-cobicistat-emtricitabine-tenofovir, do not use more than 20 mg|
02918|026|M|daily of atorvastatin.(1)|
02918|027|M|   In patients receiving elvitegravir-cobicistat-emtricitabine-tenofovir,|
02918|028|M|consider the use of fluvastatin.|
02918|029|M|   Instruct patients to report symptoms of muscle pain, tenderness, or|
02918|030|M|weakness.|
02918|031|B||
02918|032|D|DISCUSSION:  A study in 16 subjects found that|
02918|033|D|elvitegravir-cobicistat-emtricitabine-tenofovir increased atorvastatin|
02918|034|D|maximum concentration (Cmax) and area-under-curve (AUC) by 2.32-fold and|
02918|035|D|2.6-fold, respectively.(1)|
02918|036|B||
02918|037|R|REFERENCES:|
02918|038|B||
02918|039|R|1.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02918|040|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02918|041|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02918|042|R|  2020.|1
02919|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 20|
02919|002|T|mg)/Elvitegravir-Cobicistat-Emtricitabine-Tenofovir|
02919|003|B||
02919|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02919|005|L|take action as needed.|
02919|006|B||
02919|007|A|MECHANISM OF ACTION:  Cobicistat may inhibit the metabolism of atorvastatin|
02919|008|A|by CYP3A4.(1,2)|
02919|009|B||
02919|010|E|CLINICAL EFFECTS:  Concurrent use of|
02919|011|E|elvitegravir-cobicistat-emtricitabine-tenofovir may result in elevated|
02919|012|E|levels of atorvastatin, which could result in rhabdomyolysis.(1,2)|
02919|013|B||
02919|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02919|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02919|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02919|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02919|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02919|019|P|transporter OATP1B1 may have increased statin concentrations and be|
02919|020|P|predisposed to myopathy or rhabdomyolysis.|
02919|021|B||
02919|022|M|PATIENT MANAGEMENT:  In patients requiring|
02919|023|M|elvitegravir-cobicistat-emtricitabine-tenofovir, do not use more than 20 mg|
02919|024|M|daily of atorvastatin.(1)|
02919|025|M|   In patients receiving elvitegravir-cobicistat-emtricitabine-tenofovir,|
02919|026|M|consider the use of fluvastatin.|
02919|027|M|   Instruct patients to report symptoms of muscle pain, tenderness, or|
02919|028|M|weakness.|
02919|029|B||
02919|030|D|DISCUSSION:  A study in 16 subjects found that|
02919|031|D|elvitegravir-cobicistat-emtricitabine-tenofovir increased atorvastatin|
02919|032|D|maximum concentration (Cmax) and area-under-curve (AUC) by 2.32-fold and|
02919|033|D|2.6-fold, respectively.(1)|
02919|034|B||
02919|035|R|REFERENCES:|
02919|036|B||
02919|037|R|1.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02919|038|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02919|039|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
02919|040|R|  2020.|1
02920|001|T|MONOGRAPH TITLE:  Select Anticoagulants (Vitamin K antagonists)/Selected|
02920|002|T|Direct-Acting Antivirals|
02920|003|B||
02920|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02920|005|L|take action as needed.|
02920|006|B||
02920|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Warfarin sensitivity|
02920|008|A|may be decreased during concurrent therapy with direct-acting antivirals.|
02920|009|A|Improved hepatic function as a result of successful treatment of Hepatitis C|
02920|010|A|may also play a role.|
02920|011|B||
02920|012|E|CLINICAL EFFECTS:  Use of direct-acting antivirals in the treatment of|
02920|013|E|Hepatitis C may result in decreased warfarin effects, which may increase the|
02920|014|E|risk of thrombosis.|
02920|015|B||
02920|016|P|PREDISPOSING FACTORS:  None determined.|
02920|017|B||
02920|018|M|PATIENT MANAGEMENT:  Monitor INR response closely in patients maintained on|
02920|019|M|warfarin during treatment with direct-acting antivirals.|
02920|020|M|   Consider more frequent monitoring of INR during concurrent therapy and|
02920|021|M|after the completion of therapy with direct-acting antivirals until a stable|
02920|022|M|warfarin dose is established.|
02920|023|B||
02920|024|D|DISCUSSION:  In a clinical study of 43 patients treated with|
02920|025|D|elbasvir-grazoprevir, the warfarin sensitivity index (WSI) (steady state|
02920|026|D|INR/mean daily warfarin dose) decreased  from 0.53 +/- 0.25 to 0.4 +/- 0.22|
02920|027|D|at treatment completion with elbasvir-grazoprevir which represents a 25.2%|
02920|028|D|decrease.  Twelve weeks after treatment completion the WSI returned to 0.51|
02920|029|D|+/- 0.28.  Mean weekly warfarin dose requirement increased over the course|
02920|030|D|of therapy, from 40.3 +/- 22.0 mg to 44.6 +/- 23.4 mg, and returned to near|
02920|031|D|original warfarin dose requirement after therapy at 46 mg.  Time in|
02920|032|D|therapeutic range for INR dropped from 74.1% to 39.8% during treatment and|
02920|033|D|returned to 64.9% after treatment.(1)|
02920|034|D|   In a retrospective review of patients treated with either|
02920|035|D|ombitasvir-paritaprevir-ritonavir-dasabuvir or sofosbuvir, the warfarin|
02920|036|D|sensitivity index (steady state INR/mean daily warfarin dose) decreased 23%|
02920|037|D|during therapy.  The percentage of subtherapeutic INRs increased from 28%|
02920|038|D|prior to treatment to 58% during treatment.(2)|
02920|039|D|   Pharmacokinetic studies found no significant effects on warfarin from|
02920|040|D|either ombitasvir-paritaprevir-ritonavir(3) or|
02920|041|D|ombitasvir-paritaprevir-ritonavir-dasabuvir.(4)|
02920|042|D|   There have been case reports of decreased warfarin effects and increased|
02920|043|D|warfarin dosage requirements during the treatment of Hepatitis C with:|
02920|044|D|ombitasvir-paritaprevir-ritonavir-dasabuvir,(5) sofosbuvir,(6)|
02920|045|D|sofosbuvir-ledipasvir,(7) and sofosbuvir-velpatasvir.(8)|
02920|046|D|   There is a case report of decreased INR following the addition of|
02920|047|D|ombitasvir-paritaprevir-ritonavir-dasabuvir to acenocoumarol.(9)|
02920|048|B||
02920|049|R|REFERENCES:|
02920|050|B||
02920|051|R|1.DeCarolis DD, Chen YC, Westanmo AD, Conley C, Gravely AA, Khan FB.|2
02920|052|R|  Decreased warfarin sensitivity among patients treated with elbasvir and|2
02920|053|R|  grazoprevir for hepatitis C infection. Am J Health Syst Pharm 2019 Sep 1;|2
02920|054|R|  76(17):1273-1280.|2
02920|055|R|2.DeCarolis DD, Westanmo AD, Chen YC, Boese AL, Walquist MA, Rector TS.|2
02920|056|R|  Evaluation of a Potential Interaction Between New Regimens to Treat|2
02920|057|R|  Hepatitis C and Warfarin. Ann Pharmacother 2016 Nov;50(11):909-917.|2
02920|058|R|3.Badri PS, Dutta S, Wang H, Podsadecki TJ, Polepally AR, Khatri A, Zha J,|2
02920|059|R|  Chiu YL, Awni WM, Menon RM. Drug Interactions with the Direct-Acting|2
02920|060|R|  Antiviral Combination of Ombitasvir and  Paritaprevir-Ritonavir.|2
02920|061|R|  Antimicrob Agents Chemother 2015 Oct 12;60(1):105-14.|2
02920|062|R|4.Menon RM, Badri PS, Wang T, Polepally AR, Zha J, Khatri A, Wang H, Hu B,|2
02920|063|R|  Coakley EP, Podsadecki TJ, Awni WM, Dutta S. Drug-drug interaction profile|2
02920|064|R|  of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir,|2
02920|065|R|  ombitasvir, and dasabuvir. J Hepatol 2015 Jul;63(1):20-9.|2
02920|066|R|5.Puglisi GM, Smith SM, Jankovich RD, Ashby CR Jr, Jodlowski TZ.|3
02920|067|R|  Paritaprevir/ritonavir/ombitasvir/dasabuvir plus ribavirin therapy and|3
02920|068|R|  inhibition of the anticoagulant effect of warfarin: a case report. J Clin|3
02920|069|R|  Pharm Ther 2017 Feb;42(1):115-118.|3
02920|070|R|6.Peterson D, Van Ermen A. Increased warfarin requirements in a patient with|3
02920|071|R|  chronic hepatitis C infection receiving sofosbuvir and ribavirin. Am J|3
02920|072|R|  Health Syst Pharm 2017 Jun 15;74(12):888-892.|3
02920|073|R|7.Britnell SR, Willets AE, Vanderman AJ, Woodard CL, Britt RB. Influence of|3
02920|074|R|  Successful Chronic Hepatitis C Virus Treatment with Ledipasvir/Sofosbuvir|3
02920|075|R|  on Warfarin Dosing Requirements in Four Veterans. Pharmacotherapy 2016|3
02920|076|R|  Nov;36(11):1173-1179.|3
02920|077|R|8.Rindone JP, Mellen CK. Reduction in warfarin effect associated with|3
02920|078|R|  sofosbuvir-velpatasvir. Am J Health Syst Pharm 2017 Sep 01;|3
02920|079|R|  74(17):1308-1311.|3
02920|080|R|9.de Lorenzo-Pinto A, Gimenez-Manzorro A, Rodriguez-Gonzalez CG,|3
02920|081|R|  Ahumada-Jimenez A, Herranz-Alonso A, Marzal-Alfaro MB, Sanjurjo-Saez M.|3
02920|082|R|  Decreased INR after acenocoumarol, ombitasvir/paritaprevir/ritonavir and|3
02920|083|R|  dasabuvir co-administration. J Clin Pharm Ther 2016 Aug;41(4):444-446.|3
02921|001|T|MONOGRAPH TITLE:  Abemaciclib/Strong CYP3A4 Inhibitors|
02921|002|B||
02921|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02921|004|L|of severe adverse interaction.|
02921|005|B||
02921|006|A|MECHANISM OF ACTION:  Abemaciclib is a substrate of CYP3A4.  Strong|
02921|007|A|inhibitors of CYP3A4 may inhibit the metabolism of abemaciclib.(1)|
02921|008|B||
02921|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
02921|010|E|in increased levels and toxicity from abemaciclib.(1)|
02921|011|B||
02921|012|P|PREDISPOSING FACTORS:  None determined.|
02921|013|B||
02921|014|M|PATIENT MANAGEMENT:  Recommendations for management of this interaction vary|
02921|015|M|in different regions.|
02921|016|M|   The US manufacturer of abemaciclib states to avoid concurrent|
02921|017|M|administration with ketoconazole, a strong CYP3A4 inhibitor.(1)|
02921|018|M|   The US manufacturer of abemaciclib recommends a dose reduction of|
02921|019|M|abemaciclib if concurrent use with other strong CYP3A4 inhibitors (other|
02921|020|M|than ketoconazole).  In patients on the recommended starting dose of|
02921|021|M|abemaciclib 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib|
02921|022|M|dose to 100 mg twice daily.  In patients who have had a dose reduction of|
02921|023|M|abemaciclib to 100 mg twice daily due to adverse reactions, further reduce|
02921|024|M|the dose to 50 mg twice daily with concurrent use of a strong CYP3A4|
02921|025|M|inhibitor.(1)|
02921|026|M|   The Australian manufacturer of abemaciclib recommends specific dose|
02921|027|M|recommendations based on the concomitant strong CYP3A4 inhibitor.  If given|
02921|028|M|with ketoconazole, the recommended abemaciclib dose is 50 mg once daily.  If|
02921|029|M|given with itraconazole, the recommended abemaciclib dose is 50 mg twice|
02921|030|M|daily.  If given with clarithromycin, the recommended abemaciclib dose is|
02921|031|M|100 mg twice daily.  For other strong CYP3A4 inhibitors, the recommended|
02921|032|M|abemaciclib dose is 50 mg twice daily.(2)|
02921|033|M|   If the concurrent strong CYP3A4 inhibitor is discontinued, increase the|
02921|034|M|abemaciclib dose after 3-5 half-lives of the inhibitor to the dose that was|
02921|035|M|used prior to starting the strong inhibitor.(1,2)|
02921|036|M|   Monitor patient for signs and symptoms of abemaciclib toxicity with|
02921|037|M|concurrent use.|
02921|038|B||
02921|039|D|DISCUSSION:  Abemaciclib is a substrate of CYP3A4.(1)|
02921|040|D|   Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is|
02921|041|D|predicted to increase the area-under-curve (AUC) of abemaciclib up to|
02921|042|D|16-fold.(1)|
02921|043|D|   Concurrent administration of itraconazole (a strong CYP3A4 inhibitor) is|
02921|044|D|predicted to increase the relative potency adjusted unbound AUC of|
02921|045|D|abemaciclib and its active metabolites (M2, M18, and M20) by 2.2-fold.(1)|
02921|046|D|   Concurrent administration of clarithromycin (500 mg twice daily, a strong|
02921|047|D|CYP3A4 inhibitor) with a single dose of 50 mg of abemaciclib increased the|
02921|048|D|relative potency adjusted unbound AUC of abemaciclib and its active|
02921|049|D|metabolites (M2, M18, and M20) by 1.7-fold.(1)|
02921|050|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
02921|051|D|boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib,|
02921|052|D|indinavir, itraconazole, josamycin, levoketoconazole, lonafarnib,|
02921|053|D|mibefradil, nefazodone, nelfinavir, nirmatrelvir, posaconazole, ribociclib,|
02921|054|D|ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, troleandomycin,|
02921|055|D|and voriconazole.(3,4)|
02921|056|B||
02921|057|R|REFERENCES:|
02921|058|B||
02921|059|R|1.Verzenio (abemaciclib) US prescribing information. Eli Lilly and Company|1
02921|060|R|  October, 2021.|1
02921|061|R|2.Verzenio (abemaciclib) Australian prescribing information. Eli Lilly|1
02921|062|R|  Australia Pty Ltd. March 2024.|1
02921|063|R|3.This information is based on an extract from the Certara Drug Interaction|6
02921|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02921|065|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02921|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02921|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02921|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02921|069|R|  11/14/2017.|1
02922|001|T|MONOGRAPH TITLE:  Abemaciclib/Strong CYP3A4 Inducers|
02922|002|B||
02922|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02922|004|L|of severe adverse interaction.|
02922|005|B||
02922|006|A|MECHANISM OF ACTION:  Abemaciclib is a substrate of CYP3A4.  Strong inducers|
02922|007|A|of CYP3A4 may induce the metabolism of abemaciclib.(1)|
02922|008|B||
02922|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02922|010|E|in decreased levels and effectiveness of abemaciclib.(1)|
02922|011|B||
02922|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02922|013|P|of the inducer for longer than 1-2 weeks.|
02922|014|B||
02922|015|M|PATIENT MANAGEMENT:  The manufacturer of abemaciclib states to avoid|
02922|016|M|concurrent administration with strong CYP3A4 inducers and consider|
02922|017|M|alternative agents.(1)|
02922|018|B||
02922|019|D|DISCUSSION:  Abemaciclib is a substrate of CYP3A4.(1)|
02922|020|D|   Concurrent administration of rifampin (600 mg once daily, a strong CYP3A4|
02922|021|D|inducer) with a single 200 mg dose of abemaciclib decreased the relative|
02922|022|D|potency adjusted unbound area-under-curve (AUC) of abemaciclib and its|
02922|023|D|active metabolites (M2, M18, and M20) by 67% in healthy subjects.(1)|
02922|024|D|   Strong CYP3A4 inducers linked to this monograph include:  apalutamide,|
02922|025|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02922|026|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
02922|027|D|rifampin, rifapentine, and St. John's wort.(2-3)|
02922|028|B||
02922|029|R|REFERENCES:|
02922|030|B||
02922|031|R|1.Verzenio (abemaciclib) US prescribing information. Eli Lilly and Company|1
02922|032|R|  October, 2021.|1
02922|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
02922|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02922|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02922|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02922|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02922|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02922|039|R|  11/14/2017.|1
02923|001|T|MONOGRAPH TITLE:  Abemaciclib/Ketoconazole|
02923|002|B||
02923|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02923|004|L|of severe adverse interaction.|
02923|005|B||
02923|006|A|MECHANISM OF ACTION:  Abemaciclib is a substrate of CYP3A4.  Ketoconazole, a|
02923|007|A|strong inhibitor of CYP3A4, may inhibit the metabolism of abemaciclib.(1)|
02923|008|B||
02923|009|E|CLINICAL EFFECTS:  Concurrent use of ketoconazole, a strong inhibitor of|
02923|010|E|CYP3A4, may result in increased levels and toxicity from abemaciclib.(1)|
02923|011|B||
02923|012|P|PREDISPOSING FACTORS:  None determined.|
02923|013|B||
02923|014|M|PATIENT MANAGEMENT:  The manufacturer of abemaciclib states to avoid|
02923|015|M|concurrent administration with ketoconazole, a strong CYP3A4 inhibitor.(1)|
02923|016|M|   The manufacturer of abemaciclib recommends a dose reduction of|
02923|017|M|abemaciclib if concurrent use with other strong CYP3A4 inhibitors (other|
02923|018|M|than ketoconazole).  In patients on the recommended starting dose of|
02923|019|M|abemaciclib 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib|
02923|020|M|dose to 100 mg twice daily.  In patients who have had a dose reduction of|
02923|021|M|abemaciclib to 100 mg twice daily due to adverse reactions, further reduce|
02923|022|M|the dose to 50 mg twice daily with concurrent use of a strong CYP3A4|
02923|023|M|inhibitor.(1)|
02923|024|M|   If the concurrent strong CYP3A4 inhibitor is discontinued, increase the|
02923|025|M|abemaciclib dose after 3-5 half-lives of the inhibitor to the dose that was|
02923|026|M|used prior to starting the strong inhibitor.(1)|
02923|027|M|   Monitor patient for signs and symptoms of abemaciclib toxicity with|
02923|028|M|concurrent use.|
02923|029|B||
02923|030|D|DISCUSSION:  Abemaciclib is a substrate of CYP3A4.(1)|
02923|031|D|   Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is|
02923|032|D|predicted to increase the area-under-curve (AUC) of abemaciclib up to|
02923|033|D|16-fold.(1)|
02923|034|D|   Concurrent administration of itraconazole (a strong CYP3A4 inhibitor) is|
02923|035|D|predicted to increase the relative potency adjusted unbound AUC of|
02923|036|D|abemaciclib and its active metabolites (M2, M18, and M20) by 2.2-fold.(1)|
02923|037|D|   Concurrent administration of clarithromycin (500 mg twice daily, a strong|
02923|038|D|CYP3A4 inhibitor) with a single dose of 50 mg of abemaciclib increased the|
02923|039|D|relative potency adjusted unbound AUC of abemaciclib and its active|
02923|040|D|metabolites (M2, M18, and M20) by 1.7-fold.(1)|
02923|041|B||
02923|042|R|REFERENCES:|
02923|043|B||
02923|044|R|1.Verzenio (abemaciclib) US prescribing information. Eli Lilly and Company|1
02923|045|R|  October, 2021.|1
02923|046|R|2.This information is based on an extract from the Certara Drug Interaction|6
02923|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02923|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02923|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02923|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02923|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02923|052|R|  11/14/2017.|1
02924|001|T|MONOGRAPH TITLE:  Apixaban; Dabigatran; Rivaroxaban/Fluconazole|
02924|002|B||
02924|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02924|004|L|take action as needed.|
02924|005|B||
02924|006|A|MECHANISM OF ACTION:  Fluconazole may inhibit the metabolism of apixaban,|
02924|007|A|dabigatran, and rivaroxaban.(1)|
02924|008|B||
02924|009|E|CLINICAL EFFECTS:  Concurrent use of fluconazole with apixaban, dabigatran,|
02924|010|E|or rivaroxaban may result in elevated levels of and clinical effects of|
02924|011|E|apixaban, dabigatran, or rivaroxaban, including an increased risk of|
02924|012|E|bleeding, in patients.(1)|
02924|013|B||
02924|014|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
02924|015|P|decreased renal function.(1)|
02924|016|P|   The risk for bleeding episodes may be greater in patients with|
02924|017|P|disease-associated factors (e.g. thrombocytopenia).|
02924|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
02924|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
02924|020|P|risk for bleeding (NSAIDs)|
02924|021|B||
02924|022|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
02924|023|M|receiving concurrent therapy for signs of blood loss, including decreased|
02924|024|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
02924|025|M|and promptly evaluate patients with any symptoms.|
02924|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
02924|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
02924|028|M|anticoagulation in patients with active pathologic bleeding.|
02924|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
02924|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
02924|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
02924|032|M|and/or swelling.|
02924|033|B||
02924|034|D|DISCUSSION:  A retrospective cohort study of patients from the Taiwan|
02924|035|D|National Health Insurance database examined 91,330 patients with nonvalvular|
02924|036|D|atrial fibrillation who received therapy with apixaban, dabigatran, or|
02924|037|D|rivaroxaban for major bleeding (hospitalization or emergency department|
02924|038|D|visit with a primary diagnosis of intracranial hemorrhage,|
02924|039|D|gastrointestinal/urogenital/other bleeding) and compared the differences in|
02924|040|D|bleeding between patients taking TSOAs with or without concurrent therapy.|
02924|041|D|Exact fluconazole dosages were not stated.(1)|
02924|042|D|   The adjusted rate ratio of bleeding with concurrent apixaban and|
02924|043|D|fluconazole was 3.36 (range 1.69-6.68, p<0.01).  There were 16 incidences of|
02924|044|D|bleeding in 199 patient-quarters of concurrent therapy with apixaban and|
02924|045|D|fluconazole, compared with 432 incidences of bleeding in 36,733|
02924|046|D|patient-quarters of apixaban without fluconazole.(1)|
02924|047|D|   The adjusted rate ratio of bleeding with concurrent dabigatran and|
02924|048|D|fluconazole was 2.26 (range 1.44-3.55, p<0.01).  There were 47 incidences of|
02924|049|D|bleeding in 705 patient-quarters of concurrent therapy with dabigatran and|
02924|050|D|fluconazole, compared with 1884 incidences of bleeding in 199,433|
02924|051|D|patient-quarters of dabigatran without fluconazole.(1)|
02924|052|D|   The adjusted rate ratio of bleeding with concurrent rivaroxaban and|
02924|053|D|fluconazole was 2.25 (range 1.54-3.30, p<0.01).  There were 63 incidences of|
02924|054|D|bleeding in 1185 patient-quarters of concurrent therapy with rivaroxaban and|
02924|055|D|fluconazole, compared with 2499 incidences of bleeding in 222,604|
02924|056|D|patient-quarters of rivaroxaban without fluconazole.(1)|
02924|057|D|   In a randomized, open-label cross-over study, fluconazole (400 mg daily)|
02924|058|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02924|059|D|single dose of rivaroxaban (20 mg) by 1.28-fold and 1.42-fold, respectively.|
02924|060|D|FDA reviewers concluded no dose adjustments were warranted.(2)|
02924|061|D|   In a case-crossover study, the cross-over odds ratio of bleeding with|
02924|062|D|concurrent apixaban and fluconazole was 3.5 (range 1.4-10.6) in the 30-day|
02924|063|D|exposure window.  The cross-over odds ratio of bleeding with concurrent|
02924|064|D|rivaroxaban (OR 0.9, 0.2.-3.0) or dabigatran (OR 1.7, 0.5-5.6) with|
02924|065|D|fluconazole was not significantly elevated in the 30-day exposure window.|
02924|066|D|Concurrent use of topical azole antifungals among apixaban (OR 0.8,|
02924|067|D|0.5-1.3), rivaroxaban (OR 1.3, 0.9-2.1), or dabigatran (OR 1.2, 0.8-1.8)|
02924|068|D|users did not have a corresponding association with bleeding risk in the|
02924|069|D|30-day exposure window.  The study authors noted not many patients were|
02924|070|D|exposed to systemic fluconazole, resulting in large confidence intervals,|
02924|071|D|making interpretation of the results difficult. Further studies with narrow|
02924|072|D|confidence intervals are needed to conclude that no association exists with|
02924|073|D|rivaroxaban or dabigatran.(3)|
02924|074|D|   In a retrospective observational cohort study, the effect of concurrent|
02924|075|D|administration of fluconazole with either apixaban or rivaroxaban on|
02924|076|D|bleeding risk was assessed.  Initial results revealed more patients on|
02924|077|D|concurrent fluconazole with apixaban or rivaroxaban experienced a|
02924|078|D|statistically significant increase in the risk of bleeding at 30 days than|
02924|079|D|the group treated with apixaban or rivaroxaban alone [32% vs. 19%,|
02924|080|D|respectively).  However, when accounting for confounding variables, the|
02924|081|D|higher bleeding risk observed with concurrent fluconazole was not found to|
02924|082|D|be statistically significant (adjusted odds ratio 1.71, 95% CI 0.85-3.4).(4)|
02924|083|B||
02924|084|R|REFERENCES:|
02924|085|B||
02924|086|R|1.Chang SH, Chou IJ, Yeh YH, Chiou MJ, Wen MS, Kuo CT, See LC, Kuo CF.|2
02924|087|R|  Association Between Use of Non-Vitamin K Oral Anticoagulants With and|2
02924|088|R|  Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular|2
02924|089|R|  Atrial Fibrillation. JAMA 2017 Oct 03;318(13):1250-1259.|2
02924|090|R|2.FDA. Rivaroxaban CDER Application Number 202439Orig1s000 Clinical|1
02924|091|R|  Pharmacology and Biopharmaceutics Review Addendum. avalable at:|1
02924|092|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202439orig1s000app|1
02924|093|R|  rov.pdf January 5, 2011.|1
02924|094|R|3.Holt A, Strange JE, Rasmussen PV, Blanche P, Nouhravesh N, Jensen MH,|2
02924|095|R|  Schjerning AM, Schou M, Torp-Pedersen C, Gislason GH, Hansen ML,|2
02924|096|R|  McGettigan P, Lamberts M. Bleeding Risk Following Systemic Fluconazole or|2
02924|097|R|  Topical Azoles in Patients with  Atrial Fibrillation on Apixaban,|2
02924|098|R|  Rivaroxaban, or Dabigatran. Am J Med 2022 May;135(5):595-602.e5.|2
02924|099|R|4.Cid A, Smetana ME, Hebert C, Coe K, Smith JM. Impact of concomitant|2
02924|100|R|  fluconazole on direct oral anticoagulant bleeding risk. Pharmacotherapy|2
02924|101|R|  2022 Dec;42(12):880-889.|2
02925|001|T|MONOGRAPH TITLE:  Acalabrutinib/Strong CYP3A4 Inhibitors|
02925|002|B||
02925|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02925|004|L|of severe adverse interaction.|
02925|005|B||
02925|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
02925|007|A|metabolism of acalabrutinib.(1)|
02925|008|B||
02925|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
02925|010|E|systemic exposure and the risk for acalabrutinib toxicities such as|
02925|011|E|neutropenia, anemia, or thrombocytopenia.(1)|
02925|012|B||
02925|013|P|PREDISPOSING FACTORS:  None determined.|
02925|014|B||
02925|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of acalabrutinib and strong CYP3A|
02925|016|M|inhibitors. Consider an alternative concomitant medication with less|
02925|017|M|potential for CYP3A4 inhibition.|
02925|018|M|   If a CYP3A inhibitor will be used short-term (such as anti-infective for|
02925|019|M|up to 7 days), interrupt acalabrutinib therapy.|
02925|020|B||
02925|021|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
02925|022|D|coadministration of itraconazole (200mg once daily for 5 days) with|
02925|023|D|acalabrutinib increased acalabrutinib maximum concentration (Cmax) and|
02925|024|D|area-under-the-curve (AUC) by 3.9 and 5.1-fold, respectively.|
02925|025|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
02925|026|D|boceprevir, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole,|
02925|027|D|josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone,|
02925|028|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
02925|029|D|saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib and|
02925|030|D|voriconazole.(3)|
02925|031|B||
02925|032|R|REFERENCES:|
02925|033|B||
02925|034|R|1.Calquence (acalabrutinib) US prescribing information. AstraZeneca|1
02925|035|R|  Pharmaceuticals LP August, 2022.|1
02925|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
02925|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02925|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02925|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02925|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02925|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02925|042|R|  11/14/2017.|1
02926|001|T|MONOGRAPH TITLE:  Acalabrutinib/Selected Moderate CYP3A4 Inhibitors|
02926|002|B||
02926|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02926|004|L|take action as needed.|
02926|005|B||
02926|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
02926|007|A|the metabolism of acalabrutinib.(1)|
02926|008|B||
02926|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
02926|010|E|levels of and effects from acalabrutinib.(1)|
02926|011|B||
02926|012|P|PREDISPOSING FACTORS:  None determined.|
02926|013|B||
02926|014|M|PATIENT MANAGEMENT:  Recommendations for management of this interaction vary|
02926|015|M|in different regions.|
02926|016|M|   The US and Australian manufacturers of acalabrutinib state that the|
02926|017|M|concurrent chronic use of moderate CYP3A4 inhibitors should be approached|
02926|018|M|with caution.  If a moderate CYP3A4 inhibitor is required, reduce the dose|
02926|019|M|of acalabrutinib to 100 mg once daily.(1,2)|
02926|020|M|   The UK manufacturer of acalabrutinib states no dose adjustment is needed|
02926|021|M|for concurrent use of acalabrutinib with moderate CYP3A4 inhibitors.|
02926|022|M|Patients should be monitored closely for adverse effects.(3)|
02926|023|B||
02926|024|D|DISCUSSION:  In a study with healthy volunteers, single-dose fluconazole 400|
02926|025|D|mg and isavuconazole 200 mg daily for 5 days (both moderate CYP3A4|
02926|026|D|inhibitors) increased the maximum concentration (Cmax) and area-under-curve|
02926|027|D|(AUC) of acalabrutinib by 1.4- to 2-fold.  The Cmax and AUC of the active|
02926|028|D|metabolite ACP-5862 was decreased by 0.65- to 0.88-fold.(2)|
02926|029|D|   A physiologically based pharmacokinetic simulation with acalabrutinib and|
02926|030|D|moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) predicted|
02926|031|D|that coadministration increases acalabrutinib Cmax and AUC by 2- to almost|
02926|032|D|3-fold.(1)|
02926|033|D|   In a study in healthy subjects, itraconazole (200mg once daily for 5|
02926|034|D|days, a strong inhibitor) increased the Cmax and AUC of acalabrutinib by|
02926|035|D|3.9-fold and 5.1-fold, respectively.(1)|
02926|036|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
02926|037|D|avacopan, berotralstat, clofazimine, conivaptan,  crizotinib, darunavir,|
02926|038|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
02926|039|D|fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib,|
02926|040|D|lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib,|
02926|041|D|schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(4,5)|
02926|042|B||
02926|043|R|REFERENCES:|
02926|044|B||
02926|045|R|1.Calquence (acalabrutinib) US prescribing information. AstraZeneca|1
02926|046|R|  Pharmaceuticals LP August, 2022.|1
02926|047|R|2.Calquence (acalabrutinib) Australian prescribing information. AstraZeneca|1
02926|048|R|  Pty Ltd August 2024.|1
02926|049|R|3.Calquence (acalabrutinib) UK Summary of Product Characteristics.|1
02926|050|R|  AstraZeneca UK Limited November 29, 2021.|1
02926|051|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02926|052|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02926|053|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02926|054|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02926|055|R|  11/14/2017.|1
02926|056|R|5.This information is based on an extract from the Certara Drug Interaction|6
02926|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02927|001|T|MONOGRAPH TITLE:  Acalabrutinib/Strong CYP3A4 Inducers|
02927|002|B||
02927|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02927|004|L|of severe adverse interaction.|
02927|005|B||
02927|006|A|MECHANISM OF ACTION:  Acalabrutinib is a substrate of CYP3A4.  Strong|
02927|007|A|inducers of CYP3A4 may induce the metabolism of acalabrutinib.(1)|
02927|008|B||
02927|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02927|010|E|in decreased levels and effectiveness of acalabrutinib.(1)|
02927|011|B||
02927|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02927|013|P|of the inducer for longer than 1-2 weeks.|
02927|014|B||
02927|015|M|PATIENT MANAGEMENT:  The US, UK, and Australian manufacturers of|
02927|016|M|acalabrutinib states to avoid concurrent administration with strong CYP3A4|
02927|017|M|inducers and consider alternative agents.(1-3)|
02927|018|M|   The US manufacturer of acalabrutinib states if concomitant use with a|
02927|019|M|strong 3A4 inducer cannot be avoided, increase the acalabrutinib dose to 200|
02927|020|M|mg twice daily.(1)|
02927|021|B||
02927|022|D|DISCUSSION:  Concurrent administration of rifampin (600 mg once daily for 9|
02927|023|D|days, a strong CYP3A4 inducer) with acalabrutinib decreased the maximum|
02927|024|D|concentration (Cmax) and area-under-curve (AUC) of acalabrutinib by 68% and|
02927|025|D|77%, respectively, in healthy subjects.(1)|
02927|026|D|   Strong CYP3A4 inducers linked to this monograph include:  apalutamide,|
02927|027|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
02927|028|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
02927|029|D|rifampin, rifapentine, and St. John's wort.(4,5)|
02927|030|B||
02927|031|R|REFERENCES:|
02927|032|B||
02927|033|R|1.Calquence (acalabrutinib) US prescribing information. AstraZeneca|1
02927|034|R|  Pharmaceuticals LP August, 2022.|1
02927|035|R|2.Calquence (acalabrutinib) Australian prescribing information. AstraZeneca|1
02927|036|R|  Pty Ltd August 2024.|1
02927|037|R|3.Calquence (acalabrutinib) UK Summary of Product Characteristics.|1
02927|038|R|  AstraZeneca UK Limited November 29, 2021.|1
02927|039|R|4.This information is based on an extract from the Certara Drug Interaction|6
02927|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02927|041|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02927|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02927|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02927|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02927|045|R|  11/14/2017.|1
02928|001|T|MONOGRAPH TITLE:  Acalabrutinib Capsules/Antacids; Selected H2 Antagonists|
02928|002|B||
02928|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02928|004|L|take action as needed.|
02928|005|B||
02928|006|A|MECHANISM OF ACTION:  Acalabrutinib capsules solubility decreases with|
02928|007|A|increasing pH.  Antacid or H2 antagonist induced increase in gastric pH may|
02928|008|A|result in a decrease in acalabrutinib capsules absorption.(1)|
02928|009|B||
02928|010|E|CLINICAL EFFECTS:  Simultaneous administration of an antacid or a H2|
02928|011|E|antagonist may result in decreased levels and effectiveness of acalabrutinib|
02928|012|E|capsules.(1)|
02928|013|B||
02928|014|P|PREDISPOSING FACTORS:  None determined.|
02928|015|B||
02928|016|M|PATIENT MANAGEMENT:  Separate administration of acalabrutinib capsules and|
02928|017|M|antacids by at least 2 hours.(1)|
02928|018|M|   In patients on acalabrutinib capsules, administer acalabrutinib capsules|
02928|019|M|at least 2 hours before taking H2 antagonists.(1)|
02928|020|M|   Concurrent use of proton pump inhibitors with acalabrutinib capsules is|
02928|021|M|not recommended.(1)|
02928|022|M|   Some vitamin preparations may contain sufficient quantities of calcium|
02928|023|M|and/or magnesium salts with antacid properties to interact as well.|
02928|024|M|   Acalabrutinib tablets are not affected by coadministration with H2|
02928|025|M|antagonists or antacids, and may be used concurrently.(1)|
02928|026|B||
02928|027|D|DISCUSSION:  In a study in healthy subjects, coadministration with an|
02928|028|D|antacid (1g calcium carbonate) decreased area-under-curve (AUC) of|
02928|029|D|acalabrutinib capsules by 53%.  Coadministration with a proton pump|
02928|030|D|inhibitor (omeprazole 40 mg for 5 days) decreased AUC of acalabrutinib|
02928|031|D|capsules by 43%.(1)|
02928|032|B||
02928|033|R|REFERENCE:|
02928|034|B||
02928|035|R|1.Calquence (acalabrutinib) US prescribing information. AstraZeneca|1
02928|036|R|  Pharmaceuticals LP August, 2022.|1
02929|001|T|MONOGRAPH TITLE:  Acalabrutinib Capsules/Proton Pump Inhibitors|
02929|002|B||
02929|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02929|004|L|of severe adverse interaction.|
02929|005|B||
02929|006|A|MECHANISM OF ACTION:  The aqueous solubility of acalabrutinib capsules is pH|
02929|007|A|dependent.  Higher gastric pH leads to lower solubility which may reduce|
02929|008|A|acalabrutinib absorption.(1)|
02929|009|B||
02929|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) may|
02929|011|E|reduce the bioavailability of acalabrutinib capsules, leading to decreased|
02929|012|E|systemic levels and effectiveness.(1)|
02929|013|B||
02929|014|P|PREDISPOSING FACTORS:  None determined.|
02929|015|B||
02929|016|M|PATIENT MANAGEMENT:  Coadministration of proton pump inhibitors is not|
02929|017|M|recommended with acalabrutinib capsules.  Separation of doses may not|
02929|018|M|eliminate the interaction with acalabrutinib capsules.(1)|
02929|019|M|   Acalabrutinib tablets are not affected by coadministration with proton|
02929|020|M|pump inhibitors and may be used concurrently.(1)|
02929|021|B||
02929|022|D|DISCUSSION:  In an interaction study, omeprazole (40 mg for 5 days) given|
02929|023|D|simultaneously with acalabrutinib capsules, decreased acalabrutinib|
02929|024|D|area-under-the-curve (AUC) by 43%(1)|
02929|025|D|   Proton pump inhibitors linked to this monograph are: dexlansoprazole,|
02929|026|D|esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole.|
02929|027|B||
02929|028|R|REFERENCE:|
02929|029|B||
02929|030|R|1.Calquence (acalabrutinib) US prescribing information. AstraZeneca|1
02929|031|R|  Pharmaceuticals LP August, 2022.|1
02931|001|T|MONOGRAPH TITLE:  Ibrutinib/Posaconazole; Voriconazole|
02931|002|B||
02931|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02931|004|L|of severe adverse interaction.|
02931|005|B||
02931|006|A|MECHANISM OF ACTION:  Posaconazole and voriconazole inhibit the CYP3A4|
02931|007|A|isoenzyme and may inhibit the metabolism of ibrutinib.(1)|
02931|008|B||
02931|009|E|CLINICAL EFFECTS:  Concurrent use of posaconazole and voriconazole, strong|
02931|010|E|CYP3A4 inhibitors, may increase levels of and effects from ibrutinib.(1)|
02931|011|B||
02931|012|P|PREDISPOSING FACTORS:  None determined.|
02931|013|B||
02931|014|M|PATIENT MANAGEMENT:  For patients with B-cell malignancies, reduce the|
02931|015|M|ibrutinib dose to 140 mg once daily during coadministration with|
02931|016|M|posaconazole at doses of posaconazole suspension 100 mg daily, 100 mg twice|
02931|017|M|daily or 200 mg twice daily.  Reduce the ibrutinib dose to 70 mg once daily|
02931|018|M|with posaconazole suspension 200 mg three times daily or 400 mg twice daily;|
02931|019|M|posaconazole IV 300 mg daily; or posaconazole delayed-release tablets 300 mg|
02931|020|M|once daily.  Interrupt ibrutinib dose as recommended for adverse|
02931|021|M|reactions.(1)|
02931|022|M|   For patients with B-cell malignancies, reduce the ibrutinib dose to 140|
02931|023|M|mg once daily during coadministration with any dose of voriconazole.|
02931|024|M|Interrupt ibrutinib dose as recommended for adverse reactions.(1)|
02931|025|M|   For patients 12 years and older with chronic graft versus host disease|
02931|026|M|(cGVHD), reduce the ibrutinib dose to 280 mg once daily for patients|
02931|027|M|coadministered ibrutinib with posaconazole suspension 100 mg daily, 100 mg|
02931|028|M|twice daily, or 200 mg twice daily; or any dose of voriconazole.  Reduce the|
02931|029|M|ibrutinib dose to 140 mg once daily with posaconazole suspension 200 mg|
02931|030|M|three times daily or 400 mg twice daily; posaconazole IV 300 mg once daily;|
02931|031|M|or posaconazole delayed-release tablets 300 mg once daily.  For patients 1|
02931|032|M|year to 12 years old with cGVHD, reduce the ibrutinib dose to 160 mg/m2 once|
02931|033|M|daily with voriconazole suspension and reduce the ibrutinib dose to 80 mg/m2|
02931|034|M|once daily with any dose of posaconazole.  Interrupt ibrutinib dose as|
02931|035|M|recommended for adverse reactions.  Avoid concomitant administration of|
02931|036|M|ibrutinib with posaconazole at higher doses.(1)|
02931|037|M|   After discontinuation of posaconazole or voriconazole, resume previous|
02931|038|M|dose of ibrutinib.(1)|
02931|039|B||
02931|040|D|DISCUSSION:  The coadministration of multiple doses of voriconazole|
02931|041|D|increased ibrutinib's steady state maximum concentration (Cmax) and|
02931|042|D|area-under-the-curve (AUC) by 6.7-fold and 5.7-fold, respectively.(1)|
02931|043|D|   Simulations under fed conditions suggest that posaconazole may increase|
02931|044|D|the AUC of ibrutinib by 7-fold to 10-fold.(1)|
02931|045|D|   A randomized, placebo-controlled, three-phase crossover study in 11|
02931|046|D|healthy participants found that concomitant use of repeated doses of|
02931|047|D|posaconazole (300 mg in morning) with a single dose of ibrutinib (30, 70, or|
02931|048|D|140 mg administered 1 hour after preceding posaconazole dose) increased the|
02931|049|D|ibrutinib AUC and Cmax by 9.5-fold and 8.5-fold. Administration of|
02931|050|D|posaconazole in the evening with a single dose of ibrutinib (30, 70, or 140|
02931|051|D|mg 12 hours after preceding posaconazole dose) increased the ibrutinib AUC|
02931|052|D|and Cmax by 10.3-fold and 8.2-fold.(3)|
02931|053|B||
02931|054|R|REFERENCES:|
02931|055|B||
02931|056|R|1.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
02931|057|R|  August, 2022.|1
02931|058|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02931|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02931|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02931|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02931|062|R|  11/14/2017.|1
02931|063|R|3.Olkkola AM, Tapaninen T, Tornio A, Hauta-Aho M, Lapatto-Reiniluoto O,|2
02931|064|R|  Neuvonen M, Kiiski JI, Neuvonen PJ, Niemi M, Backman JT.|2
02931|065|R|  Posaconazole-ibrutinib interaction cannot be avoided by staggered dosing:|2
02931|066|R|  How to  optimize ibrutinib dose during posaconazole treatment. Br J Clin|2
02931|067|R|  Pharmacol 2024 Feb;90(2):557-567.|2
02932|001|T|MONOGRAPH TITLE:  Ibrutinib/Strong CYP3A4 Inhibitors|
02932|002|B||
02932|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02932|004|L|of severe adverse interaction.|
02932|005|B||
02932|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
02932|007|A|the metabolism of ibrutinib.(1)|
02932|008|B||
02932|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
02932|010|E|levels of and effects from ibrutinib.(1)|
02932|011|B||
02932|012|P|PREDISPOSING FACTORS:  None determined.|
02932|013|B||
02932|014|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
02932|015|M|undergoing therapy with ibrutinib.(1)|
02932|016|M|   The concurrent chronic use of strong CYP3A4 inhibitors with ibrutinib is|
02932|017|M|not recommended.  For short-term use of strong CYP3A4 inhibitors, such as 7|
02932|018|M|days or less of antibiotics/antifungals, consider interruption of ibrutinib|
02932|019|M|therapy.(1)|
02932|020|M|   The Australian and UK manufacturers of ibrutinib state that use of strong|
02932|021|M|CYP3A4 inhibitors should be avoided.  If the benefit outweighs the risk and|
02932|022|M|a strong CYP3A4 inhibitor must be used, reduce the ibrutinib dose to 140 mg|
02932|023|M|for the duration of the inhibitor use or withhold ibrutinib temporarily (for|
02932|024|M|7 days or less).  Monitor patient closely for toxicity and follow dose|
02932|025|M|modification guidance as needed.(2,3)|
02932|026|B||
02932|027|D|DISCUSSION:  In a study in 18 healthy subjects, ketoconazole (400 mg daily|
02932|028|D|for 7 days) increased the Cmax and AUC of ibrutinib (single 40 mg dose) by|
02932|029|D|24-fold and 29-fold, respectively.(1)|
02932|030|D|   The coadministration of multiple doses of voriconazole increased|
02932|031|D|ibrutinib's Cmax and AUC by 6.7-fold and 5.7-fold.(1)|
02932|032|D|   Simulations under fed conditions suggest that posaconazole may increase|
02932|033|D|ibrutinib's AUC by 7-fold to 10-fold.(1)|
02932|034|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02932|035|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
02932|036|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
02932|037|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, ribociclib, saquinavir,|
02932|038|D|telaprevir, telithromycin, troleandomycin and tucatinib.(4,5)|
02932|039|B||
02932|040|R|REFERENCES:|
02932|041|B||
02932|042|R|1.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
02932|043|R|  August, 2022.|1
02932|044|R|2.Imbruvica (ibrutinib) Australian Prescribing information. Janssen-Cilag|1
02932|045|R|  Pty Ltd May 27, 2025.|1
02932|046|R|3.Imbruvica (ibrutinib) UK Summary of Product Characteristics. Janssen-Cilag|1
02932|047|R|  Ltd August 22, 2025.|1
02932|048|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02932|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02932|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02932|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02932|052|R|  11/14/2017.|1
02932|053|R|5.This information is based on an extract from the Certara Drug Interaction|6
02932|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02932|055|R|6.de Zwart L, Snoeys J, De Jong J, Sukbuntherng J, Mannaert E, Monshouwer M.|6
02932|056|R|  Ibrutinib Dosing Strategies Based on Interaction Potential of CYP3A4|6
02932|057|R|  Perpetrators Using Physiologically Based Pharmacokinetic Modeling. Clin|6
02932|058|R|  Pharmacol Ther 2016 Nov;100(5):548-557.|6
02933|001|T|MONOGRAPH TITLE:  Perampanel/Strong and Moderate CYP3A4 Inducers|
02933|002|B||
02933|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02933|004|L|take action as needed.|
02933|005|B||
02933|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may induce the|
02933|007|A|metabolism of perampanel by CYP3A4.(1)|
02933|008|B||
02933|009|E|CLINICAL EFFECTS:  The concurrent use of strong and moderate CYP3A4 inducers|
02933|010|E|and perampanel may result in decreased levels and clinical effectiveness of|
02933|011|E|perampanel.(1)|
02933|012|B||
02933|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02933|014|P|of the inducer for longer than 1-2 weeks.|
02933|015|B||
02933|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with strong and|
02933|017|M|moderate CYP3A4 inducers and perampanel should be observed for decreased|
02933|018|M|anticonvulsant levels and clinical effectiveness.|
02933|019|M|   The manufacturer of perampanel recommends a starting dose of 4 mg once|
02933|020|M|daily at bedtime in patients receiving concurrent therapy with CYP3A4|
02933|021|M|inducers.  Dose increases are recommended by 2 mg increments once daily|
02933|022|M|based on clinical response and tolerability, no more frequently than at|
02933|023|M|weekly intervals.  The highest studied dose with concurrent enzyme-inducing|
02933|024|M|antiepileptic drugs was 12 mg once daily.(1)|
02933|025|M|   The dose of the anticonvulsant may need to be adjusted if a strong or|
02933|026|M|moderate CYP3A4 inducer is added to or removed from therapy.(1)|
02933|027|B||
02933|028|D|DISCUSSION:  In a study in healthy subjects, carbamazepine 300 mg BID|
02933|029|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
02933|030|D|single 2 mg tablet dose of perampanel by 26% and 67%, respectively. The|
02933|031|D|half-life (t1/2) of perampanel was shortened from 56.8 hours to 25 hours. In|
02933|032|D|clinical studies examining partial-onset and primary generalized|
02933|033|D|tonic-clonic seizures, a population pharmacokinetic analysis showed that|
02933|034|D|perampanel AUC was reduced by 64% in patients on carbamazepine compared to|
02933|035|D|the AUC in patients not on enzyme-inducing antiepileptic drugs.(1)|
02933|036|D|   In a study in partial-onset and primary generalized tonic-clonic|
02933|037|D|seizures, a population pharmacokinetic analysis showed that perampanel AUC|
02933|038|D|was reduced by 48% in patients on oxcarbazepine compared to patients not on|
02933|039|D|enzyme-inducing antiepileptic drugs.(1)|
02933|040|D|   In a study in partial-onset and primary generalized tonic-clonic|
02933|041|D|seizures, a population pharmacokinetic analysis showed that perampanel AUC|
02933|042|D|was reduced by 43% in patients on phenytoin compared to patients not on|
02933|043|D|enzyme-inducing antiepileptic drugs.(1)|
02933|044|D|   In a study in partial-onset and primary generalized tonic-clonic seizures|
02933|045|D|in clinical trials (40 patients co-administered phenobarbital and 9 patients|
02933|046|D|co-administered primidone), no significant effect on perampanel AUC was|
02933|047|D|found. A modest effect of phenobarbital and primidone on perampanel|
02933|048|D|concentrations cannot be excluded.(1)|
02933|049|D|   In a study in 76 patients, concentration-to-dose (CD) ratio of perampanel|
02933|050|D|was assessed with and without concurrent antiepileptic agents.  In patients|
02933|051|D|only on perampanel the mean CD ratio was 3963 ng/mL/mg/kg (range:|
02933|052|D|1793-13,299) compared to the mean CD ratio in patients using enzyme-inducing|
02933|053|D|AEDs [1760 (range: 892-3090), 2256 (range: 700-4703), and 1120 (range:|
02933|054|D|473-1853) ng/mL/mg/kg in patients taking phenytoin, phenobarbital, and|
02933|055|D|carbamazepine, respectively], and carbamazepine had a significantly greater|
02933|056|D|reduction in the CD ratio compared with phenytoin or phenobarbital (P <|
02933|057|D|0.001).(3)|
02933|058|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
02933|059|D|apalutamide, barbiturates, bosentan, carbamazepine, cenobamate, dabrafenib,|
02933|060|D|efavirenz, elagolix, encorafenib, enzalutamide, eslicarbazepine, etravirine,|
02933|061|D|fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mavacamten, mitapivat,|
02933|062|D|mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib, pexidartinib,|
02933|063|D|phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, sotorasib,|
02933|064|D|telotristat, thioridazine, and tovorafenib.(1,2)|
02933|065|B||
02933|066|R|REFERENCES:|
02933|067|B||
02933|068|R|1.Fycompa (perampanel) US prescribing information. Eisai Inc. January, 2024.|1
02933|069|R|2.This information is based on an extract from the Certara Drug Interaction|6
02933|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02933|071|R|3.Yamamoto Y, Usui N, Nishida T, Takahashi Y, Imai K, Kagawa Y, Inoue Y.|2
02933|072|R|  Therapeutic Drug Monitoring for Perampanel in Japanese Epilepsy Patients:|2
02933|073|R|  Influence of Concomitant Antiepileptic Drugs. Ther Drug Monit 2017 Aug;|2
02933|074|R|  39(4):446-449.|2
02933|075|R|4.Fycompa (perampanel) UK summary of product characteristics. Eisai Ltd|1
02933|076|R|  August, 2021.|1
02934|001|T|MONOGRAPH TITLE:  Lithium/Polystyrene Sulfonate|
02934|002|B||
02934|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02934|004|L|take action as needed.|
02934|005|B||
02934|006|A|MECHANISM OF ACTION:  Polystyrene sulfonate may bind and delay or prevent|
02934|007|A|the absorption of lithium from the gastrointestinal tract.(1)|
02934|008|B||
02934|009|E|CLINICAL EFFECTS:  Simultaneous administration of polystyrene sulfonate may|
02934|010|E|result in decreased levels of and effectiveness from lithium.(1)|
02934|011|B||
02934|012|P|PREDISPOSING FACTORS:  None determined.|
02934|013|B||
02934|014|M|PATIENT MANAGEMENT:  The US manufacturer of sodium polystyrene sulfonate|
02934|015|M|states that oral medications should be administered at least 3 hours apart|
02934|016|M|from polystyrene sulfonate.  Patients with gastroparesis may require a 6|
02934|017|M|hour separation.  If concurrent therapy is warranted, consider monitoring|
02934|018|M|lithium levels and clinical response.(1)|
02934|019|B||
02934|020|D|DISCUSSION:  Because polystyrene sulfonate may bind and delay or prevent the|
02934|021|D|absorption of lithium from the gastrointestinal tract, the US manufacturer|
02934|022|D|of sodium polystyrene sulfonate states that lithium should be administered|
02934|023|D|at least 3 hours apart from polystyrene sulfonate.(1)|
02934|024|B||
02934|025|R|REFERENCE:|
02934|026|B||
02934|027|R|1.Kayexalate (sodium polystyrene sulfonate) US prescribing information.|1
02934|028|R|  Concordia Pharmaceuticals Inc. July 31, 2017.|1
02935|001|T|MONOGRAPH TITLE:  T Cell Immunotherapies/Corticosteroids|
02935|002|B||
02935|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02935|004|L|of severe adverse interaction.|
02935|005|B||
02935|006|A|MECHANISM OF ACTION:  Corticosteroids suppress the immune system.|
02935|007|A|Concurrent use or premedication with a prophylactic corticosteroid may|
02935|008|A|interfere with the activity of CAR-T cell immunotherapies.(1-6)|
02935|009|B||
02935|010|E|CLINICAL EFFECTS:  Corticosteroids may decrease the efficacy of CAR-T cell|
02935|011|E|immunotherapies.(1-6)|
02935|012|B||
02935|013|P|PREDISPOSING FACTORS:  None determined.|
02935|014|B||
02935|015|M|PATIENT MANAGEMENT:  The manufacturers recommend avoiding concurrent or|
02935|016|M|prophylactic use of corticosteroids as a premedication prior to infusion of|
02935|017|M|CAR-T cell immunotherapy.|
02935|018|M|   Corticosteroids may be used and are recommended in the case of a|
02935|019|M|life-threatening emergency, including the management of cytokine release|
02935|020|M|syndrome or neurological toxicities.(1-6)|
02935|021|B||
02935|022|D|DISCUSSION:  Corticosteroids may decrease the efficacy of CAR-T cell|
02935|023|D|immunotherapy.(1-6)|
02935|024|D|   The manufacturers recommend avoiding concurrent or prophylactic use of|
02935|025|D|corticosteroids as a premedication prior to infusion of CAR-T cell|
02935|026|D|immunotherapy.(1-6)|
02935|027|D|   Corticosteroids may be used and are recommended in the case of a|
02935|028|D|life-threatening emergency, including the management of cytokine release|
02935|029|D|syndrome or neurological toxicities.(1-6)|
02935|030|B||
02935|031|R|REFERENCES:|
02935|032|B||
02935|033|R|1.Kymriah (tisagenlecleucel) US prescribing information. Novartis|1
02935|034|R|  Pharmaceuticals Corporation August, 2017.|1
02935|035|R|2.Yescarta (axicabtagene ciloleucel) US prescribing information. Kite|1
02935|036|R|  Pharma, Inc. October, 2017.|1
02935|037|R|3.Tecartus (brexucabtagene autoleucel) US prescribing information. Kite|1
02935|038|R|  Pharma July, 2020.|1
02935|039|R|4.Breyanzi (lisocabtagene maraleucel) US prescribing information. Juno|1
02935|040|R|  Therapeutics, Inc. February, 2021.|1
02935|041|R|5.Abecma (idecabtagene vicleucel) US prescribing information. Celgene|1
02935|042|R|  Corporation March, 2021.|1
02935|043|R|6.Carvykti (ciltacabtagene autoleucel) US prescribing information. Janssen|1
02935|044|R|  Biotech, Inc. February, 2022.|1
02936|001|T|MONOGRAPH TITLE:  Rasagiline (Greater Than 0.5 mg)/Selected CYP1A2|
02936|002|T|Inhibitors|
02936|003|B||
02936|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02936|005|L|is contraindicated and generally should not be dispensed or administered to|
02936|006|L|the same patient.|
02936|007|B||
02936|008|A|MECHANISM OF ACTION:  Inhibitors of CYP1A2 may inhibit the metabolism of|
02936|009|A|rasagiline.(1)|
02936|010|B||
02936|011|E|CLINICAL EFFECTS:  Concurrent use of a CYP1A2 inhibitor may increase levels|
02936|012|E|of and adverse effects from rasagiline.(1)|
02936|013|B||
02936|014|P|PREDISPOSING FACTORS:  None determined.|
02936|015|B||
02936|016|M|PATIENT MANAGEMENT:  The US manufacturer of rasagiline states that patients|
02936|017|M|receiving concurrent therapy with an inhibitor of CYP1A2 should receive no|
02936|018|M|more than 0.5 mg of rasagiline daily.(1)|
02936|019|M|   Concurrent therapy with vemurafenib may require extended monitoring for|
02936|020|M|interaction onset and severity because steady-state levels of vemurafenib|
02936|021|M|are not attained for approximately 15 days.(2)|
02936|022|B||
02936|023|D|DISCUSSION:  In a study in 12 healthy subjects, ciprofloxacin (500 mg twice|
02936|024|D|daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily)|
02936|025|D|by 83%.(1)|
02936|026|D|   Strong CYP1A2 inhibitors linked to this monograph include angelica root,|
02936|027|D|ciprofloxacin, enasidenib, enoxacin, and rofecoxib.|
02936|028|D|   Moderate CYP1A2 inhibitors linked to this monograph include capmatinib,|
02936|029|D|dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen,|
02936|030|D|mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib,|
02936|031|D|troleandomycin, and vemurafenib.(3-5)|
02936|032|B||
02936|033|R|REFERENCES:|
02936|034|B||
02936|035|R|1.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
02936|036|R|  June, 2020.|1
02936|037|R|2.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
02936|038|R|  November, 2017.|1
02936|039|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02936|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02936|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02936|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02936|043|R|  11/14/2017.|1
02936|044|R|4.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
02936|045|R|  Indiana University School of Medicine.  Available at:|1
02936|046|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
02936|047|R|5.This information is based on an extract from the Certara Drug Interaction|6
02936|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02937|001|T|MONOGRAPH TITLE:  Letermovir (Less Than or Equal To 240 mg)/Cyclosporine|
02937|002|B||
02937|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02937|004|L|take action as needed.|
02937|005|B||
02937|006|A|MECHANISM OF ACTION:  Cyclosporine, an OATP1B1/3 inhibitor, may inhibit the|
02937|007|A|metabolism of letermovir. Letermovir, a moderate CYP3A4 inhibitor, may|
02937|008|A|inhibit the metabolism of cyclosporine.(1)|
02937|009|B||
02937|010|E|CLINICAL EFFECTS:  The concurrent administration of cyclosporine and|
02937|011|E|letermovir may result in elevated levels of letermovir and/or|
02937|012|E|cyclosporine.(1)|
02937|013|B||
02937|014|P|PREDISPOSING FACTORS:  None determined.|
02937|015|B||
02937|016|M|PATIENT MANAGEMENT:  The manufacturer of letermovir states that if oral or|
02937|017|M|intravenous letermovir is coadministered with cyclosporine, the dosage of|
02937|018|M|letermovir should be decreased to 240 mg once daily in adult and pediatric|
02937|019|M|patients 12 years of age or older in the following populations:|
02937|020|M|   - Hematopoietic stem cell transplantation (HSCT) recipients weighing at|
02937|021|M|least 30 kg, or|
02937|022|M|   - Kidney transplant recipients weighing at least 40 kg.(1)|
02937|023|M|   If cyclosporine is initiated after starting letermovir, the next dose of|
02937|024|M|letermovir should be decreased to 240 mg once daily.(1)|
02937|025|M|   If cyclosporine is discontinued after starting letermovir, the next dose|
02937|026|M|of letermovir should be increased to 480 mg once daily.(1)|
02937|027|M|   If cyclosporine dosing is interrupted due to high cyclosporine levels, no|
02937|028|M|dose adjustment of letermovir is needed.(1)|
02937|029|M|   The manufacturer of letermovir states that if oral or intravenous|
02937|030|M|letermovir is coadministered with cyclosporine in pediatric HSCT recipients|
02937|031|M|6 months to less than 12 years of age, or 12 years of age and weighing less|
02937|032|M|than 30 kg, the dosage of letermovir may require adjustment as outlined:|
02937|033|M|   - 30 kg and above: Daily dose of letermovir = 240 mg|
02937|034|M|   - 15 kg to less than 30 kg: Daily dose of letermovir = 120 mg|
02937|035|M|   - 7.5 kg to less than 15 kg: Daily dose of letermovir = 60 mg|
02937|036|M|   - 6 kg to less than 7.5 kg: Daily dose of letermovir = 40 mg|
02937|037|M|   If cyclosporine is initiated after starting letermovir, the next dose of|
02937|038|M|letermovir should be the daily oral or intravenous dose co-administered with|
02937|039|M|cyclosporine.(1)|
02937|040|M|   If cyclosporine is discontinued after starting letermovir, the next dose|
02937|041|M|of letermovir should be the daily oral or intravenous dose administered|
02937|042|M|without cyclosporine.(1)|
02937|043|M|   If cyclosporine dosing is interrupted due to high cyclosporine levels, no|
02937|044|M|dose adjustment of letermovir is needed.(1)|
02937|045|M|   Refer to letermovir prescribing information for dosing recommendations|
02937|046|M|based on patient age and weight.(1)|
02937|047|M|   Frequently monitor cyclosporine whole blood concentrations during|
02937|048|M|treatment and after discontinuation of letermovir and adjust the dose of|
02937|049|M|cyclosporine accordingly.(1)|
02937|050|B||
02937|051|D|DISCUSSION:  In a study, concurrent administration of cyclosporine (200 mg|
02937|052|D|single dose, oral) with letermovir (240 mg once daily, oral) increased|
02937|053|D|letermovir's area-under-the-curve (AUC), maximum concentration (Cmax), and|
02937|054|D|C24hr by 2.11-fold, 1.48-fold, and 2.06-fold.(1)|
02937|055|D|   In a study, concurrent administration of cyclosporine (50 mg single dose,|
02937|056|D|oral) with letermovir (240 mg once daily, oral) increased cyclosporine's AUC|
02937|057|D|and C24hr by 1.66-fold and 2.19-fold.(1)|
02937|058|B||
02937|059|R|REFERENCES:|
02937|060|B||
02937|061|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02937|062|R|  2024.|1
02937|063|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02937|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02937|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02937|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02937|067|R|  11/14/2017.|1
02937|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
02937|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02938|001|T|MONOGRAPH TITLE:  Letermovir/Pimozide|
02938|002|B||
02938|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02938|004|L|is contraindicated and generally should not be dispensed or administered to|
02938|005|L|the same patient.|
02938|006|B||
02938|007|A|MECHANISM OF ACTION:  Letermovir, a moderate CYP3A4 inhibitor, may inhibit|
02938|008|A|the metabolism of pimozide at CYP3A4.(1-4)|
02938|009|B||
02938|010|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
02938|011|E|of pimozide, which may result in prolongation of the QTc interval and|
02938|012|E|potentially life-threatening ventricular arrhythmias.(1, 5-6)|
02938|013|E|   Concurrent use may also result in extrapyramidal symptoms such as|
02938|014|E|akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and|
02938|015|E|oculogyric crisis.(1)|
02938|016|B||
02938|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02938|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
02938|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02938|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02938|021|P|female gender, or advanced age.(6)|
02938|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02938|023|P|higher systemic concentrations of either QT prolonging drug are additional|
02938|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02938|025|P|drug concentrations include rapid infusion of an intravenous dose or|
02938|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02938|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02938|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
02938|029|P|   The risk of anticholinergic toxicities including cognitive decline,|
02938|030|P|delirium, falls and fractures is increased in geriatric patients using more|
02938|031|P|than one medicine with anticholinergic properties.(7)|
02938|032|B||
02938|033|M|PATIENT MANAGEMENT:  The concurrent use of pimozide and letermovir is|
02938|034|M|contraindicated.(1)|
02938|035|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
02938|036|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
02938|037|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
02938|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
02938|039|B||
02938|040|D|DISCUSSION:  An in vitro study indicates that pimozide is metabolized at|
02938|041|D|CYP3A4.(4)  Elevated levels of pimozide may prolong the QTc interval|
02938|042|D|resulting in life-threatening ventricular arrhythmias.(2)|
02938|043|B||
02938|044|R|REFERENCES:|
02938|045|B||
02938|046|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02938|047|R|  2024.|1
02938|048|R|2.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
02938|049|R|  2011.|1
02938|050|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02938|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02938|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02938|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02938|054|R|  11/14/2017.|1
02938|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
02938|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02938|057|R|5.Desta Z, Kerbusch T, Soukhova N, Richard E, Ko JW, Flockhart DA.|5
02938|058|R|  Identification and characterization of human cytochrome P450 isoforms|5
02938|059|R|  interacting with pimozide. J Pharmacol Exp Ther 1998 May;285(2):428-37.|5
02938|060|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02938|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02938|062|R|  settings: a scientific statement from the American Heart Association and|6
02938|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02938|064|R|  2;55(9):934-47.|6
02938|065|R|7.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02938|066|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02938|067|R|  Soc 2023 Jul;71(7):2052-2081.|6
02939|001|T|MONOGRAPH TITLE:  Pitavastatin, Simvastatin/Letermovir|
02939|002|B||
02939|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02939|004|L|of severe adverse interaction.|
02939|005|B||
02939|006|A|MECHANISM OF ACTION:  Letermovir may inhibit OATP1B1 and OATP1B3, resulting|
02939|007|A|in increased concentrations of pitavastatin and simvastatin. Letermovir is|
02939|008|A|also a moderate inhibitor of CYP3A4. Simvastatin is a substrate of|
02939|009|A|CYP3A4.(1)|
02939|010|B||
02939|011|E|CLINICAL EFFECTS:  Concurrent use of letermovir may result in elevated|
02939|012|E|levels of pitavastatin or simvastatin, which could result in myopathy or|
02939|013|E|rhabdomyolysis.|
02939|014|B||
02939|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02939|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02939|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02939|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02939|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02939|020|P|transporter OATP1B1 may have increased statin concentrations and be|
02939|021|P|predisposed to myopathy or rhabdomyolysis.|
02939|022|B||
02939|023|M|PATIENT MANAGEMENT:  Concurrent administration of letermovir and|
02939|024|M|pitavastatin or simvastatin is not recommended.|
02939|025|M|   Letermovir is contraindicated with pitavastatin and simvastatin when|
02939|026|M|coadministered with cyclosporine.(1)|
02939|027|M|   If these medications are used concurrently, counsel patient to report|
02939|028|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
02939|029|B||
02939|030|D|DISCUSSION:  In a study, letermovir (480 mg once daily) increased the|
02939|031|D|area-under-curve (AUC), maximum concentration (Cmax), and C24hr of a single|
02939|032|D|dose of atorvastatin (20 mg single dose, an OATP1B1/3 substrate) by|
02939|033|D|3.29-fold, 2.17-fold, 3.62-fold.(1)|
02939|034|B||
02939|035|R|REFERENCES:|
02939|036|B||
02939|037|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02939|038|R|  2024.|1
02939|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02939|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02939|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02939|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02939|043|R|  11/14/2017.|1
02939|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
02939|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02940|001|T|MONOGRAPH TITLE:  Atorvastatin (Greater Than 20 mg)/Letermovir|
02940|002|B||
02940|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02940|004|L|is contraindicated and generally should not be dispensed or administered to|
02940|005|L|the same patient.|
02940|006|B||
02940|007|A|MECHANISM OF ACTION:  Letermovir may inhibit OATP1B1 and OATP1B3 and CYP3A4,|
02940|008|A|resulting in increased concentrations of atorvastatin.|
02940|009|B||
02940|010|E|CLINICAL EFFECTS:  Concurrent use of letermovir may result in elevated|
02940|011|E|levels of atorvastatin, which could result in myopathy or rhabdomyolysis.|
02940|012|B||
02940|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02940|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02940|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02940|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02940|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02940|018|P|transporter OATP1B1 may have increased statin concentrations and be|
02940|019|P|predisposed to myopathy or rhabdomyolysis.|
02940|020|B||
02940|021|M|PATIENT MANAGEMENT:  Do not exceed an atorvastatin dose of 20 mg daily when|
02940|022|M|letermovir is coadministered with atorvastatin.(1)|
02940|023|M|   Use of atorvastatin is not recommended when administered concurrently|
02940|024|M|with both letermovir and cyclosporine.(1)|
02940|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
02940|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
02940|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
02940|028|M|urine, and/or discolored urine.|
02940|029|B||
02940|030|D|DISCUSSION:  In a study, letermovir (480 mg once daily) increased the|
02940|031|D|area-under-curve (AUC), maximum concentration (Cmax), and C24hr of a single|
02940|032|D|dose of atorvastatin (20 mg single dose, an OATP1B1/3 substrate) by|
02940|033|D|3.29-fold, 2.17-fold, 3.62-fold.(1)|
02940|034|B||
02940|035|R|REFERENCES:|
02940|036|B||
02940|037|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02940|038|R|  2024.|1
02940|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02940|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02940|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02940|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02940|043|R|  11/14/2017.|1
02940|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
02940|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02941|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 20 mg)/Letermovir|
02941|002|B||
02941|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02941|004|L|take action as needed.|
02941|005|B||
02941|006|A|MECHANISM OF ACTION:  Letermovir may inhibit OATP1B1 and OATP1B3 and CYP3A4,|
02941|007|A|resulting in increased concentrations of atorvastatin.|
02941|008|B||
02941|009|E|CLINICAL EFFECTS:  Concurrent use of letermovir may result in elevated|
02941|010|E|levels of atorvastatin, which could result in myopathy or rhabdomyolysis.|
02941|011|B||
02941|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
02941|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
02941|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
02941|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
02941|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
02941|017|P|transporter OATP1B1 may have increased statin concentrations and be|
02941|018|P|predisposed to myopathy or rhabdomyolysis.|
02941|019|B||
02941|020|M|PATIENT MANAGEMENT:  Do not exceed an atorvastatin dose of 20 mg daily when|
02941|021|M|letermovir is coadministered with atorvastatin.(1)|
02941|022|M|   Use of atorvastatin is not recommended when administered concurrently|
02941|023|M|with both letermovir and cyclosporine.(1)|
02941|024|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
02941|025|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
02941|026|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
02941|027|M|urine, and/or discolored urine.|
02941|028|B||
02941|029|D|DISCUSSION:  In a study, letermovir (480 mg once daily) increased the|
02941|030|D|area-under-curve (AUC), maximum concentration (Cmax), and C24hr of a single|
02941|031|D|dose of atorvastatin (20 mg single dose, an OATP1B1/3 substrate) by|
02941|032|D|3.29-fold, 2.17-fold, 3.62-fold.(1)|
02941|033|B||
02941|034|R|REFERENCES:|
02941|035|B||
02941|036|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02941|037|R|  2024.|1
02941|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02941|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02941|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02941|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02941|042|R|  11/14/2017.|1
02941|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
02941|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02942|001|T|MONOGRAPH TITLE:  Ergot Alkaloids/Letermovir|
02942|002|B||
02942|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02942|004|L|is contraindicated and generally should not be dispensed or administered to|
02942|005|L|the same patient.|
02942|006|B||
02942|007|A|MECHANISM OF ACTION:  Letermovir, a moderate inhibitor of CYP3A4, may|
02942|008|A|inhibit the hepatic metabolism of ergot alkaloids.(1)|
02942|009|B||
02942|010|E|CLINICAL EFFECTS:  Concurrent use may result in increased levels of the|
02942|011|E|ergot alkaloid, which may result in clinical signs of ergotism, including|
02942|012|E|vasospasm, dysesthesia, renal ischemia, and peripheral ischemia.|
02942|013|B||
02942|014|P|PREDISPOSING FACTORS:  None determined.|
02942|015|B||
02942|016|M|PATIENT MANAGEMENT:  The concurrent use of ergotamine derivatives and|
02942|017|M|letermovir is contraindicated.(1)|
02942|018|M|   It would be prudent to avoid the concurrent use of all ergot alkaloids|
02942|019|M|and letermovir.  Patients receiving concurrent therapy should be monitored|
02942|020|M|for clinical signs of ergotism.  One or both agents may need to be|
02942|021|M|discontinued.  Patients should be treated symptomatically for ergotism.|
02942|022|B||
02942|023|D|DISCUSSION:  Letermovir is a moderate inhibitor of CYP3A4. In a study,|
02942|024|D|concurrent administration of letermovir (240 mg once daily) increased the|
02942|025|D|area-under-the curve (AUC), and C24hr of midazolam (1 mg single dose|
02942|026|D|intravenous, a CYP3A4 substrate) by 1.47-fold and 2.74-fold.(1)|
02942|027|B||
02942|028|R|REFERENCES:|
02942|029|B||
02942|030|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02942|031|R|  2024.|1
02942|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02942|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02942|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02942|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02942|036|R|  11/14/2017.|1
02942|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
02942|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02944|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants;Temsirolimus/Letermovir|
02944|002|B||
02944|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02944|004|L|take action as needed.|
02944|005|B||
02944|006|A|MECHANISM OF ACTION:  Letermovir may inhibit the metabolism of sirolimus and|
02944|007|A|temsirolimus by CYP3A4.(1)|
02944|008|B||
02944|009|E|CLINICAL EFFECTS:  The concurrent administration of sirolimus or|
02944|010|E|temsirolimus with letermovir may result in elevated levels of sirolimus or|
02944|011|E|temsirolimus and possible toxicity.(1)|
02944|012|B||
02944|013|P|PREDISPOSING FACTORS:  None determined.|
02944|014|B||
02944|015|M|PATIENT MANAGEMENT:  Sirolimus and temsirolimus levels should be carefully|
02944|016|M|monitored in patients receiving concurrent therapy with letermovir.  The|
02944|017|M|dosage of sirolimus and temsirolimus may need to be adjusted during and/or|
02944|018|M|after letermovir therapy.(1)|
02944|019|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
02944|020|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
02944|021|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
02944|022|M|inhibitors should be avoided.(2)|
02944|023|B||
02944|024|D|DISCUSSION:  In a study of healthy subjects, concurrent administration of|
02944|025|D|letermovir (480 mg once daily) increased sirolimus' (2 mg single dose)|
02944|026|D|area-under-the-curve (AUC), maximum concentration (Cmax), and C24hr by|
02944|027|D|3.4-fold, 2.76-fold, and 3.15-fold.(1,3)|
02944|028|B||
02944|029|R|REFERENCES:|
02944|030|B||
02944|031|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02944|032|R|  2024.|1
02944|033|R|2.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
02944|034|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
02944|035|R|3.McCrea JB, Macha S, Adedoyin A, Marshall W, Menzel K, Cho CR, Liu F, Zhao|2
02944|036|R|  T, Levine V, Kraft WK, Yoon E, Panebianco D, Stoch SA, Iwamoto M.|2
02944|037|R|  Pharmacokinetic Drug-Drug Interactions Between Letermovir and the|2
02944|038|R|  Immunosuppressants  Cyclosporine, Tacrolimus, Sirolimus, and Mycophenolate|2
02944|039|R|  Mofetil. J Clin Pharmacol 2019 Oct;59(10):1331-1339.|2
02945|001|T|MONOGRAPH TITLE:  Midazolam/Letermovir|
02945|002|B||
02945|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02945|004|L|take action as needed.|
02945|005|B||
02945|006|A|MECHANISM OF ACTION:  Letermovir is a moderate inhibitor of CYP3A4 and may|
02945|007|A|decrease metabolism of midazolam.(1)|
02945|008|B||
02945|009|E|CLINICAL EFFECTS:  Concurrent administration of letermovir and midazolam,|
02945|010|E|metabolized by CYP3A4, may result in increased clinical effects (e.g.|
02945|011|E|profound sedation, respiratory depression, coma, and/or death) of midazolam.|
02945|012|E|   CYP3A4 is the major or only hepatic metabolism pathway for the phase I|
02945|013|E|elimination of midazolam.|
02945|014|B||
02945|015|P|PREDISPOSING FACTORS:  Concurrent use with cyclosporine.|
02945|016|B||
02945|017|M|PATIENT MANAGEMENT:  Caution is advised when midazolam is administered with|
02945|018|M|drugs known to inhibit CYP3A4, such as letermovir.(1)|
02945|019|M|   Benzodiazepines that do not undergo extensive CYP hepatic metabolism|
02945|020|M|(e.g. lorazepam, oxazepam) may be an alternative in letermovir patients.|
02945|021|M|   When letermovir is coadministered with cyclosporine, the combined effect|
02945|022|M|on midazolam may be similar to a strong CYP3A4 inhibitor.|
02945|023|M|   Monitor patients for unusual dizziness or lightheadedness, extreme|
02945|024|M|sleepiness, slowed or difficult breathing, or unresponsiveness.|
02945|025|B||
02945|026|D|DISCUSSION:  In a study, concomitant administration of letermovir (480 mg|
02945|027|D|once daily) with midazolam (1 mg single dose intravenous) increased the|
02945|028|D|midazolam area under the curve (AUC) and C24hr by 1.47-fold and 2.74-fold,|
02945|029|D|respectively. Concomitant administration of letermovir (480 mg once daily)|
02945|030|D|with midazolam (2 mg single dose oral) increased the midazolam AUC and|
02945|031|D|maximum concentration (Cmax) by 2.25-fold and 1.72-fold.(1)|
02945|032|B||
02945|033|R|REFERENCES:|
02945|034|B||
02945|035|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02945|036|R|  2024.|1
02945|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02945|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02945|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02945|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02945|041|R|  11/14/2017.|1
02945|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
02945|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02946|001|T|MONOGRAPH TITLE:  Letermovir/Amiodarone|
02946|002|B||
02946|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02946|004|L|take action as needed.|
02946|005|B||
02946|006|A|MECHANISM OF ACTION:  Letermovir, a moderate CYP3A4 inhibitor and CYP2C8|
02946|007|A|inhibitor, may inhibit the metabolism of amiodarone at CYP3A4 and CYP2C8.|
02946|008|B||
02946|009|E|CLINICAL EFFECTS:  The concurrent administration of amiodarone with|
02946|010|E|letermovir may result in increased levels, clinical effects, and toxicity of|
02946|011|E|amiodarone.|
02946|012|B||
02946|013|P|PREDISPOSING FACTORS:  Concurrent use with cyclosporine.|
02946|014|B||
02946|015|M|PATIENT MANAGEMENT:  The US manufacturer of letermovir recommends monitoring|
02946|016|M|for adverse effects and amiodarone concentrations when letermovir and|
02946|017|M|amiodarone are administered concurrently. When letermovir is coadministered|
02946|018|M|with cyclosporine, the combined effect on amiodarone may be similar to a|
02946|019|M|strong CYP3A4 inhibitor.(1)|
02946|020|B||
02946|021|D|DISCUSSION:  Letermovir has been shown to inhibit CYP3A4. In a study,|
02946|022|D|concomitant administration of letermovir (480 mg once daily) with the CYP3A4|
02946|023|D|substrate midazolam (1 mg single dose intravenous) increased the midazolam|
02946|024|D|area under the curve (AUC) and C24hr by 1.47-fold and 2.74-fold,|
02946|025|D|respectively. Concomitant administration of letermovir (480 mg once daily)|
02946|026|D|with midazolam (2 mg single dose oral) increased the midazolam AUC and|
02946|027|D|maximum concentration (Cmax) by 2.25-fold and 1.72-fold.(1)|
02946|028|B||
02946|029|R|REFERENCES:|
02946|030|B||
02946|031|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02946|032|R|  2024.|1
02946|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02946|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02946|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02946|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02946|037|R|  11/14/2017.|1
02946|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
02946|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02947|001|T|MONOGRAPH TITLE:  Voriconazole/Letermovir|
02947|002|B||
02947|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02947|004|L|of severe adverse interaction.|
02947|005|B||
02947|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown. Letermovir may induce|
02947|007|A|the metabolism of voriconazole via the CYP2C9 and CYP2C19 pathways.(1)|
02947|008|B||
02947|009|E|CLINICAL EFFECTS:  The concurrent use of letermovir and voriconazole may|
02947|010|E|result in severely reduced levels of the azole antifungal and therapeutic|
02947|011|E|failure.|
02947|012|B||
02947|013|P|PREDISPOSING FACTORS:  None determined.|
02947|014|B||
02947|015|M|PATIENT MANAGEMENT:  The US manufacturer of letermovir states that if|
02947|016|M|concurrent administration with voriconazole is necessary, closely monitor|
02947|017|M|for reduced effectiveness of voriconazole.(1)|
02947|018|B||
02947|019|D|DISCUSSION:  The concurrent use of letermovir (480 mg once daily) with|
02947|020|D|voriconazole (200 mg twice daily) decreased the maximum concentration|
02947|021|D|(Cmax), area-under-curve (AUC), and C24hr of voriconazole by 39%, 46%, and|
02947|022|D|51%, respectively.(1)|
02947|023|B||
02947|024|R|REFERENCES:|
02947|025|B||
02947|026|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02947|027|R|  2024.|1
02947|028|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02947|029|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02947|030|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02947|031|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02947|032|R|  11/14/2017.|1
02947|033|R|3.This information is based on an extract from the Certara Drug Interaction|6
02947|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02948|001|T|MONOGRAPH TITLE:  Repaglinide/Letermovir|
02948|002|B||
02948|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02948|004|L|take action as needed.|
02948|005|B||
02948|006|A|MECHANISM OF ACTION:  Letermovir may inhibit the metabolism of repaglinide|
02948|007|A|by CYP3A4, CYP2C8, and OATP-mediated hepatic uptake of repaglinide.(1)|
02948|008|B||
02948|009|E|CLINICAL EFFECTS:  Concurrent use with letermovir may result in increased|
02948|010|E|levels of and effects from repaglinide, including hypoglycemia.(1,2)|
02948|011|B||
02948|012|P|PREDISPOSING FACTORS:  Concurrent administration with cyclosporine. Patients|
02948|013|P|who achieve tight control of blood sugars, or have a history of hypoglycemic|
02948|014|P|episodes may be at greater risk for hypoglycemia with this combination.|
02948|015|B||
02948|016|M|PATIENT MANAGEMENT:  The US manufacturer of letermovir recommends that when|
02948|017|M|letermovir is coadministered with repaglinide that glucose concentrations|
02948|018|M|are frequently monitored. If letermovir is coadministered with cyclosporine,|
02948|019|M|use of repaglinide is not recommended.(1)|
02948|020|M|   When letermovir is coadministered with cyclosporine, the combined effect|
02948|021|M|on repaglinide may be similar to a strong CYP3A4 inhibitor.(1)|
02948|022|B||
02948|023|D|DISCUSSION:  Letermovir is a moderate inhibitor of CYP3A4 and a OATP1B1/3|
02948|024|D|inhibitor. In a study, concomitant administration of letermovir (480 mg once|
02948|025|D|daily) administered with the CYP3A4 substrate midazolam (1 mg single dose|
02948|026|D|intravenous) increased the midazolam area-under-the-curve (AUC) and C24hr by|
02948|027|D|1.47-fold and 2.74 fold, respectively. Concomitant administration of|
02948|028|D|letermovir (480 mg once daily) with midazolam (2 mg single dose oral)|
02948|029|D|increased the midazolam AUC and maximum concentration (Cmax) by 2.25-fold|
02948|030|D|and 1.72-fold.(1)|
02948|031|B||
02948|032|R|REFERENCES:|
02948|033|B||
02948|034|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02948|035|R|  2024.|1
02948|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02948|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02948|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02948|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02948|040|R|  11/14/2017.|1
02948|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
02948|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02949|001|T|MONOGRAPH TITLE:  Lovastatin/Letermovir|
02949|002|B||
02949|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02949|004|L|take action as needed.|
02949|005|B||
02949|006|A|MECHANISM OF ACTION:  Letermovir, a moderate CYP3A4 inhibitor, may inhibit|
02949|007|A|the metabolism of lovastatin CYP3A4.(1)|
02949|008|B||
02949|009|E|CLINICAL EFFECTS:  Concurrent use of letermovir may result in elevated|
02949|010|E|levels and side effects of lovastatin, including myopathy, muscle aches, and|
02949|011|E|rhabdomyolysis.(1)|
02949|012|B||
02949|013|P|PREDISPOSING FACTORS:  Concurrent use with cyclosporine may increase the|
02949|014|P|risk of myopathy or rhabdomyolysis.|
02949|015|P|   The risk for myopathy or rhabdomyolysis may also be greater in patients|
02949|016|P|65 years and older, inadequately treated hypothyroidism, renal impairment,|
02949|017|P|carnitine deficiency, malignant hyperthermia, or in patients with a history|
02949|018|P|of myopathy or rhabdomyolysis.  Patients with a SLCO1B1 polymorphism that|
02949|019|P|leads to decreased function of the hepatic uptake transporter OATP1B1 may|
02949|020|P|have increased statin concentrations and be predisposed to myopathy or|
02949|021|P|rhabdomyolysis.|
02949|022|B||
02949|023|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with letermovir|
02949|024|M|and lovastatin should be carefully monitored for adverse effects, including|
02949|025|M|rhabdomyolysis.  Consider reducing the dosage of the HMG Co-A reductase|
02949|026|M|inhibitor.(1)|
02949|027|M|   When letermovir is coadministered with cyclosporine, use of lovastatin is|
02949|028|M|not recommended.(1)|
02949|029|M|   When letermovir is coadministered with cyclosporine, the combined effect|
02949|030|M|on lovastatin may be similar to a strong CYP3A4 inhibitor.|
02949|031|M|   Patients receiving concurrent therapy should be instructed to report|
02949|032|M|symptoms of muscle pain, tenderness, or weakness.|
02949|033|B||
02949|034|D|DISCUSSION:  Letermovir is a moderate CYP3A4 inhibitor. In a study,|
02949|035|D|concomitant administration of letermovir (480 mg once daily) with the CYP3A4|
02949|036|D|substrate midazolam (1 mg single dose intravenous) increased the midazolam|
02949|037|D|area under the curve (AUC) and C24hr by 1.47-fold and 2.74-fold,|
02949|038|D|respectively. Concomitant administration of letermovir (480 mg once daily)|
02949|039|D|with midazolam (2 mg single dose oral) increased the midazolam AUC and|
02949|040|D|maximum concentration (Cmax) by 2.25-fold and 1.72-fold.(1)|
02949|041|B||
02949|042|R|REFERENCES:|
02949|043|B||
02949|044|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
02949|045|R|  2024.|1
02949|046|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02949|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02949|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02949|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02949|050|R|  11/14/2017.|1
02949|051|R|3.This information is based on an extract from the Certara Drug Interaction|6
02949|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02950|001|T|MONOGRAPH TITLE:  Clonazepam/Strong CYP3A4 Inhibitors|
02950|002|B||
02950|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02950|004|L|take action as needed.|
02950|005|B||
02950|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
02950|007|A|clonazepam by CYP3A4.(1,2)|
02950|008|B||
02950|009|E|CLINICAL EFFECTS:  The concurrent administration of strong CYP3A4 inhibitors|
02950|010|E|with clonazepam may result in elevated levels of and increased clinical|
02950|011|E|effects from clonazepam.  Toxic effects of increased levels of|
02950|012|E|benzodiazepines include profound sedation, respiratory depression, coma,|
02950|013|E|and/or death.(1,2)|
02950|014|B||
02950|015|P|PREDISPOSING FACTORS:  None determined.|
02950|016|B||
02950|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with strong|
02950|018|M|CYP3A4 inhibitors should be monitored for increased clonazepam effects.  The|
02950|019|M|dosage of clonazepam may need to be decreased or discontinued.(1,2)|
02950|020|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
02950|021|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02950|022|M|unresponsiveness.|
02950|023|B||
02950|024|D|DISCUSSION:  In a study in 98 patients with schizophrenia or bipolar|
02950|025|D|disorder, the expression of CYP3A4 was found to be the major determinant of|
02950|026|D|clonazepam plasma concentrations normalized by the dose and bodyweight (1263|
02950|027|D|+/- 482.9 and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal|
02950|028|D|expressers, respectively, p<0.0001).(2)|
02950|029|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
02950|030|D|boceprevir, ceritinib, clarithromycin, cobicistat, itraconazole, josamycin,|
02950|031|D|ketoconazole, mibefradil, mifepristone, nefazodone, paritaprevir,|
02950|032|D|posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin,|
02950|033|D|tucatinib, and voriconazole.(3,4)|
02950|034|B||
02950|035|R|REFERENCES:|
02950|036|B||
02950|037|R|1.Klonopin (clonazepam) US prescribing information. Genentech, Inc.|1
02950|038|R|  February, 2021.|1
02950|039|R|2.Toth K, Csukly G, Sirok D, Belic A, Kiss A, Hafra E, Deri M, Menus A,|2
02950|040|R|  Bitter I, Monostory K. Optimization of Clonazepam Therapy Adjusted to|2
02950|041|R|  Patient's CYP3A Status and NAT2 Genotype. Int J Neuropsychopharmacol 2016|2
02950|042|R|  Dec;19(12):.|2
02950|043|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02950|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02950|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02950|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02950|047|R|  11/14/2017.|1
02950|048|R|4.This information is based on an extract from the Certara Drug Interaction|6
02950|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02951|001|T|MONOGRAPH TITLE:  Disopyramide/Selected Strong CYP3A4 Inhibitors; Protease|
02951|002|T|Inhibitors|
02951|003|B||
02951|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02951|005|L|of severe adverse interaction.|
02951|006|B||
02951|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors and protease inhibitors may|
02951|008|A|inhibit the metabolism of disopyramide by inhibition of CYP3A4.(1,2)|
02951|009|B||
02951|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors and protease|
02951|011|E|inhibitors with disopyramide may result in elevated levels of disopyramide|
02951|012|E|and serious and/or life-threatening effects, including QT prolongation.(1,2)|
02951|013|B||
02951|014|P|PREDISPOSING FACTORS:  Renal and hepatic impairment may increase risk for|
02951|015|P|excessive QTc prolongation as disopyramide is eliminated renally and|
02951|016|P|hepatically. To prevent increased serum levels and risk for ventricular|
02951|017|P|arrhythmias, disopyramide must be dose adjusted in renal and hepatic|
02951|018|P|insufficiency.|
02951|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02951|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02951|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02951|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02951|023|P|advanced age.(3)|
02951|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02951|025|P|higher systemic concentrations of either QT prolonging drug are additional|
02951|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02951|027|P|drug concentrations include rapid infusion of an intravenous dose or|
02951|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02951|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02951|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
02951|031|B||
02951|032|M|PATIENT MANAGEMENT:  Coadministration of strong CYP3A4 inhibitors and|
02951|033|M|protease inhibitors with disopyramide should be avoided.  If use of the|
02951|034|M|combination is warranted, clinical monitoring is recommended.(1,2)|
02951|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
02951|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
02951|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
02951|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
02951|039|B||
02951|040|D|DISCUSSION:  Strong CYP3A4 inhibitors and protease inhibitors may inhibit|
02951|041|D|the metabolism and increase levels of disopyramide by inhibition of|
02951|042|D|CYP3A4.(1,2)|
02951|043|D|   Selected CYP3A4 inhibitors linked to this monograph include: atazanavir,|
02951|044|D|boceprevir, darunavir, fosamprenavir, idelalisib, indinavir, josamycin,|
02951|045|D|lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
02951|046|D|nirmatrelvir/ritonavir, telaprevir, tipranavir, and tucatinib.(4,5)|
02951|047|B||
02951|048|R|REFERENCES:|
02951|049|B||
02951|050|R|1.Norpace (disopyramide phosphate) US prescribing information. Pfizer Inc.|1
02951|051|R|  December, 2020.|1
02951|052|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
02951|053|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
02951|054|R|  HIV. Department of Health and Human Services. Available at|6
02951|055|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
02951|056|R|  new-guidelines June 13, 2021.|6
02951|057|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02951|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02951|059|R|  settings: a scientific statement from the American Heart Association and|6
02951|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02951|061|R|  2;55(9):934-47.|6
02951|062|R|4.This information is based on an extract from the Certara Drug Interaction|6
02951|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02951|064|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02951|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02951|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02951|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02951|068|R|  11/14/2017.|1
02952|001|T|MONOGRAPH TITLE:  Antidiabetics/Selected Ophthalmic Non-Cardioselective|
02952|002|T|Beta-Blockers|
02952|003|B||
02952|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02952|005|L|take action as needed.|
02952|006|B||
02952|007|A|MECHANISM OF ACTION:  Not fully established. Probably blockade of a variety|
02952|008|A|of beta-adrenergic responses to hypoglycemia.(1,2)|
02952|009|B||
02952|010|E|CLINICAL EFFECTS:  Diminished response to sulfonylureas and insulin may|
02952|011|E|occur. Frequency and severity of hypoglycemic episodes may be increased,|
02952|012|E|while warning symptoms of low blood sugar may be masked.(1,2)|
02952|013|B||
02952|014|P|PREDISPOSING FACTORS:  None determined.|
02952|015|B||
02952|016|M|PATIENT MANAGEMENT:  Try to avoid beta-blocker therapy, particularly in|
02952|017|M|diabetics prone to hypoglycemic attacks.  One of the cardioselective agents|
02952|018|M|may decrease risk of hypertensive attacks and allow more rapid glucose|
02952|019|M|recovery from hypoglycemia.|
02952|020|M|   Patients should be counseled not to rely on tachycardia to diagnose|
02952|021|M|hypoglycemia, since it is masked by beta-blocker therapy.  Diaphoresis is|
02952|022|M|unaffected by beta-blockade and can be used by the diabetic to recognize|
02952|023|M|hypoglycemia.|
02952|024|B||
02952|025|D|DISCUSSION:  A double blind, randomized, 12 month study of 39 patients|
02952|026|D|tested the metabolic effects of pindolol (5mg BID) compared to control group|
02952|027|D|on insulin sensitivity. The patient's insulin sensitivity index decreased|
02952|028|D|17% when on pindolol treatment compared to placebo (p<0.01). Insulin|
02952|029|D|mediated glucose uptake was significantly lower (p<0.05) with propranolol|
02952|030|D|treatment than with placebo.(3)|
02952|031|D|   A study of 26 patients with chronic heart failure showed that carvedilol|
02952|032|D|(average daily dose 27.5mg/d) caused a significant decrease in fasting|
02952|033|D|insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment|
02952|034|D|levels. This trial also showed that patients on carvedilol had significantly|
02952|035|D|(p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the|
02952|036|D|fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment|
02952|037|D|(5.9mg/d).(4)|
02952|038|D|   There have been case reports of hypoglycemia following the addition of|
02952|039|D|ophthalmic timolol to a diabetic regimen.(5-7)  Studies have shown that|
02952|040|D|ophthalmic beta-blockers, especially the aqueous solution, have significant|
02952|041|D|systemic absorption and do not undergo first-pass metabolism.(8,9)|
02952|042|B||
02952|043|R|REFERENCES:|
02952|044|B||
02952|045|R|1.Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic|2
02952|046|R|  mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic|2
02952|047|R|  hyperglycemia in insulin- dependent diabetes mellitus. J Clin Invest 1982|2
02952|048|R|  Feb;69(2):315-26.|2
02952|049|R|2.Hansten PD. Drug interactions update. Beta-blocking agents and|6
02952|050|R|  antidiabetic drugs. Drug Intell Clin Pharm 1980 Jan;14:46-50.|6
02952|051|R|3.Lithell H, Pollare T, Vessby B. Metabolic effects of pindolol and|2
02952|052|R|  propranolol in a double-blind cross-over study in hypertensive patients.|2
02952|053|R|  Blood Press 1992 Aug;1(2):92-101.|2
02952|054|R|4.Kovacic D, Marinsek M, Gobec L, Lainscak M, Podbregar M. Effect of|2
02952|055|R|  selective and non-selective beta-blockers on body weight, insulin|2
02952|056|R|  resistance and leptin concentration in chronic heart failure. Clin Res|2
02952|057|R|  Cardiol 2008 Jan;97(1):24-31.|2
02952|058|R|5.Silverstone BZ, Marcus T. Hypoglycemia due to ophthalmic timolol in a|3
02952|059|R|  diabetic. Harefuah 1990 Jun 15;118(12):693-4.|3
02952|060|R|6.Velde TM, Kaiser FE. Ophthalmic timolol treatment causing altered|3
02952|061|R|  hypoglycemic response in a diabetic  patient. Arch Intern Med 1983 Aug;|3
02952|062|R|  143(8):1627.|3
02952|063|R|7.Angelo-Nielsen K. Timolol topically and diabetes mellitus. JAMA 1980 Nov|3
02952|064|R|  21;244(20):2263.|3
02952|065|R|8.Uusitalo H, Nino J, Tahvanainen K, Turjanmaa V, Ropo A, Tuominen J,|2
02952|066|R|  Kahonen M. Efficacy and systemic side-effects of topical 0.5% timolol|2
02952|067|R|  aqueous solution and 0.1% timolol hydrogel. Acta Ophthalmol Scand 2005|2
02952|068|R|  Dec;83(6):723-8.|2
02952|069|R|9.Korte JM, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary|2
02952|070|R|  effects of 0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol 2002|2
02952|071|R|  Jun;240(6):430-5.|2
02953|001|T|MONOGRAPH TITLE:  Selected Hepatitis C Agents/Oxcarbazepine (mono deleted|
02953|002|T|12/17/2019)|
02953|003|B||
02953|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02953|005|L|of severe adverse interaction.|
02953|006|B||
02953|007|A|MECHANISM OF ACTION:  Oxcarbazepine, an inducer of P-glycoprotein (P-gp),|
02953|008|A|may decrease the absorption of ledipasvir,(1) sofosbuvir,(1-4)|
02953|009|A|velpatasvir,(3,4) voxilaprevir,(4), glecaprevir,(7), and pibrentasvir.(7)|
02953|010|B||
02953|011|E|CLINICAL EFFECTS:  Concurrent or recent use of oxcarbazepine, a P-gp|
02953|012|E|inducer, may result in decreased levels and effectiveness of ledipasvir,(1)|
02953|013|E|sofosbuvir,(1-4) velpatasvir,(3,4) voxilaprevir,(4), glecaprevir,(7) and|
02953|014|E|pibrentasvir.(7)|
02953|015|B||
02953|016|P|PREDISPOSING FACTORS:  None determined.|
02953|017|B||
02953|018|M|PATIENT MANAGEMENT:  The US manufacturers of ledipasvir-sofosbuvir,(1)|
02953|019|M|sofosbuvir,(2) sofosbuvir/velpatasvir,(3)|
02953|020|M|sofosbuvir-velpatasvir-voxilaprevir,(4) and glecaprevir-pibrentasvir (7) do|
02953|021|M|not recommend coadministration with inducers of P-gp.|
02953|022|B||
02953|023|D|DISCUSSION:  In a study in 31 subjects, rifampin (600 mg daily) decreased|
02953|024|D|the maximum concentration (Cmax) and exposure (AUC, area-under-curve) of|
02953|025|D|ledipasvir by 35% and 59%, respectively.(1)|
02953|026|D|   In a study in 17 subjects, rifampin (600 mg daily) decreased the Cmax and|
02953|027|D|AUC of sofosbuvir by 77% and 72%, respectively.(2-4)|
02953|028|D|   In a study in 12 subjects, rifampin (600 mg daily) decreased the Cmax and|
02953|029|D|AUC of velpatasvir by 71% and 82%, respectively.(3-4)|
02953|030|D|   In a study in 24 subjects, rifampin (600 mg daily) decreased the Cmax and|
02953|031|D|AUC of voxilaprevir by 9% and 73%, respectively.(4)|
02953|032|D|   In a study in 10 subjects, carbamazepine (200 mg twice daily)|
02953|033|D|administered concomitantly with glecaprevir-pibrentasvir (300/120 mg daily)|
02953|034|D|decreased the Cmax and AUC of glecaprevir by 67% and 66%, and the Cmax and|
02953|035|D|AUC of pibrentasvir by 50% and 51%, respectively.(7)|
02953|036|B||
02953|037|R|REFERENCES:|
02953|038|B||
02953|039|R|1.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
02953|040|R|  Sciences November, 2019.|1
02953|041|R|2.Sovaldi (sofosbuvir) US prescribing information. Gilead Sciences, Inc.|1
02953|042|R|  September, 2019.|1
02953|043|R|3.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
02953|044|R|  Sciences, Inc. April, 2022.|1
02953|045|R|4.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
02953|046|R|  Gilead Sciences, Inc. September, 2019.|1
02953|047|R|5.This information is based on an extract from the Certara Drug Interaction|6
02953|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02953|049|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
02953|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02953|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02953|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02953|053|R|  11/14/2017.|1
02953|054|R|7.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
02953|055|R|  Inc. October, 2023.|1
02954|001|T|MONOGRAPH TITLE:  Ibrutinib/Diltiazem|
02954|002|B||
02954|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02954|004|L|of severe adverse interaction.|
02954|005|B||
02954|006|A|MECHANISM OF ACTION:  Agents that are strong or moderate inhibitors of the|
02954|007|A|CYP3A4 isoenzyme may inhibit the metabolism of ibrutinib.(1)|
02954|008|A|   Diltiazem is a moderate to strong CYP3A4 inhibitor.(2-4)|
02954|009|B||
02954|010|E|CLINICAL EFFECTS:  Concurrent use of diltiazem may increase levels of and|
02954|011|E|effects from ibrutinib.(1)|
02954|012|B||
02954|013|P|PREDISPOSING FACTORS:  None determined.|
02954|014|B||
02954|015|M|PATIENT MANAGEMENT:  The manufacturer of ibrutinib recommends avoiding|
02954|016|M|concurrent use with strong and moderate CYP3A4 inhibitors.  If concurrent|
02954|017|M|use is warranted with moderate CYP3A4 inhibitor, consider dose|
02954|018|M|modifications.(1)|
02954|019|M|   If a moderate CYP3A4 inhibitor is required for B-cell malignancies|
02954|020|M|treatment, reduce the dose of ibrutinib to 280 mg daily.(1)|
02954|021|M|   If a moderate CYP3A4 inhibitor is required for chronic graft versus host|
02954|022|M|disease treatment, reduce the dose of ibrutinib in patients 12 years and|
02954|023|M|older to 420 mg once daily, and in patients 1 year to 12 years old to 240|
02954|024|M|mg/m2 once daily.(1)|
02954|025|M|   After discontinuation of a CYP3A4 inhibitor, resume previous dose of|
02954|026|M|ibrutinib.(1)|
02954|027|M|   Diltiazem is a moderate to strong CYP3A4 inhibitor.(2-4)|
02954|028|B||
02954|029|D|DISCUSSION:  A pharmacokinetic model simulating human pharmacokinetics and|
02954|030|D|drug interactions in healthy men predicted that diltiazem would increase|
02954|031|D|ibrutinib Cmax and AUC by 5-fold and 5.5-fold, respectively.(2)|
02954|032|D|   In a study in 18 healthy subjects, ketoconazole (400 mg daily for 7 days)|
02954|033|D|increased the Cmax and AUC of ibrutinib (single 40 mg dose) by 24-fold and|
02954|034|D|29-fold, respectively.(1)|
02954|035|D|   The coadministration of multiple doses of voriconazole increased|
02954|036|D|ibrutinib's Cmax and AUC by 6.7-fold and 5.7-fold.(1)|
02954|037|D|   Simulations under fed conditions suggest that posaconazole may increase|
02954|038|D|ibrutinib's AUC by 7-fold to 10-fold.(1)|
02954|039|B||
02954|040|R|REFERENCES:|
02954|041|B||
02954|042|R|1.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
02954|043|R|  August, 2022.|1
02954|044|R|2.de Zwart L, Snoeys J, De Jong J, Sukbuntherng J, Mannaert E, Monshouwer M.|6
02954|045|R|  Ibrutinib Dosing Strategies Based on Interaction Potential of CYP3A4|6
02954|046|R|  Perpetrators Using Physiologically Based Pharmacokinetic Modeling. Clin|6
02954|047|R|  Pharmacol Ther 2016 Nov;100(5):548-557.|6
02954|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02954|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02954|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02954|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02954|052|R|  11/14/2017.|1
02954|053|R|4.This information is based on an extract from the Certara Drug Interaction|6
02954|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02955|001|T|MONOGRAPH TITLE:  Ombitasvir-Paritaprevir/Lopinavir-Ritonavir|
02955|002|B||
02955|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02955|004|L|of severe adverse interaction.|
02955|005|B||
02955|006|A|MECHANISM OF ACTION:  Lopinavir-ritonavir may inhibit the metabolism of|
02955|007|A|paritaprevir by CYP3A4.(1,2)|
02955|008|B||
02955|009|E|CLINICAL EFFECTS:  Concurrent use of lopinavir-ritonavir may result in|
02955|010|E|increased levels of paritaprevir and toxicity from paritaprevir.(1,2)|
02955|011|B||
02955|012|P|PREDISPOSING FACTORS:  None determined.|
02955|013|B||
02955|014|M|PATIENT MANAGEMENT:  The US manufacturer of|
02955|015|M|ombitasvir-paritaprevir-ritonavir(1) and|
02955|016|M|ombitasvir-paritaprevir-ritonavir-dasabuvir(2) states that coadministration|
02955|017|M|with lopinavir/ritonavir is not recommended.|
02955|018|B||
02955|019|D|DISCUSSION:  In a study in 18 subjects, concurrent lopinavir/ritonavir|
02955|020|D|(400/100 mg twice daily) with ombitasvir-paritaprevir-ritonavir (Technivie)|
02955|021|D|increased paritaprevir maximum concentration (Cmax), area-under-curve (AUC),|
02955|022|D|and minimum concentration (Cmin) by 4.76-fold, 6.1-fold, and 12.33-fold,|
02955|023|D|respectively.  In a study in 11 subjects, concurrent lopinavir/ritonavir|
02955|024|D|(800/200 mg once daily) with ombitasvir-paritaprevir-ritonavir (Technivie)|
02955|025|D|increased paritaprevir Cmax, AUC, and Cmin by 1.78-fold, 3.55-fold, and|
02955|026|D|14.78-fold, respectively.(1)|
02955|027|D|   In a study in 6 subjects, concurrent lopinavir/ritonavir (400/100 mg|
02955|028|D|twice daily) with ombitasvir-paritaprevir-ritonavir (Viekira Pak) increased|
02955|029|D|paritaprevir Cmax, AUC, and Cmin by 2.04-fold, 2.17-fold, and 2.36-fold,|
02955|030|D|respectively.  Concurrent lopinavir/ritonavir (800/200 mg once daily) with|
02955|031|D|ombitasvir-paritaprevir-ritonavir (Viekira Pak) increased paritaprevir AUC|
02955|032|D|and Cmin by 1.87-fold and 8.23-fold, respectively.(2)|
02955|033|B||
02955|034|R|REFERENCES:|
02955|035|B||
02955|036|R|1.Technivie (ombitasvir-paritaprevir-ritonavir) US prescribing information.|1
02955|037|R|  Abbvie Inc. December, 2019.|1
02955|038|R|2.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
02955|039|R|  prescribing information. AbbVie Inc. December, 2019.|1
02955|040|R|3.FDA. CDER Application number: 2066190 Viekira Pak (ombitasvir,|1
02955|041|R|  paritaprevir, ritonavir, dasabuvir) Clinical Pharmacology and|1
02955|042|R|  Biopharmaceutics Review(s). URL:|1
02955|043|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206619Orig1s000Clin|1
02955|044|R|  PharmR.pdf December 19, 2014.|1
02956|001|T|MONOGRAPH TITLE:  Digoxin/Trimethoprim|
02956|002|B||
02956|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02956|004|L|of severe adverse interaction.|
02956|005|B||
02956|006|A|MECHANISM OF ACTION:  Trimethoprim may inhibit the renal tubular clearance|
02956|007|A|of digoxin.(1-3)|
02956|008|B||
02956|009|E|CLINICAL EFFECTS:  Concurrent use of trimethoprim may result in elevated|
02956|010|E|levels of and toxicity from digoxin.(1,2)|
02956|011|E|   Symptoms of digoxin toxicity can include anorexia, nausea, vomiting,|
02956|012|E|headache, fatigue, malaise, drowsiness, generalized muscle weakness,|
02956|013|E|disorientation, hallucinations, visual disturbances, and arrhythmias.|
02956|014|B||
02956|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
02956|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
02956|017|P|risk of digoxin toxicity.|
02956|018|B||
02956|019|M|PATIENT MANAGEMENT:  The manufacturer of digoxin states if concurrent|
02956|020|M|therapy is warranted, monitor serum digoxin levels before initiating|
02956|021|M|concurrent trimethoprim therapy and observe the patient for symptoms of|
02956|022|M|digoxin toxicity.  Upon adding trimethoprim, digoxin should first be|
02956|023|M|decreased by approximately 15-30% of the current dose or by modifying the|
02956|024|M|dosing frequency in anticipation of interaction.  Continue monitoring|
02956|025|M|digoxin levels and further adjust the dosing as necessary.(1)|
02956|026|B||
02956|027|D|DISCUSSION:  In a study of nine patients (median age 78 years, range 62-92)|
02956|028|D|treated with a constant oral dosage of digoxin (0.125-0.25 mg daily),|
02956|029|D|trimethoprim (200 mg twice daily) increased serum digoxin concentrations by|
02956|030|D|22% during concurrent therapy (p < 0.05).(3)|
02956|031|D|   In a single dose study of 6 healthy subjects (median age 29 years, range|
02956|032|D|24-31) treated with trimethoprim and digoxin (1 mg intravenous),|
02956|033|D|trimethoprim (200 mg twice daily) administration did not affect total body|
02956|034|D|clearance of digoxin.  The renal clearance of digoxin decreased by 17% (p <|
02956|035|D|0.05) and the extrarenal clearance of digoxin increased by 14%.(3)|
02956|036|D|   In a retrospective, population-based cohort study of 47,961 patients|
02956|037|D|receiving digoxin (median age 80 years, range 74-86) and initiated on|
02956|038|D|trimethoprim-sulfamethoxazole (TMP-SMX) (n=10,273) or amoxicillin|
02956|039|D|(n=37,688), the 30-day risk of a hospital encounter with digoxin toxicity|
02956|040|D|was nearly 6 times higher in older adults who were prescribed TMP-SMX versus|
02956|041|D|amoxicillin, although the absolute risk difference was low (0.4%).  Of|
02956|042|D|10,273 patients co-prescribed digoxin and TMP-SMX, 492 (5%) had evidence of|
02956|043|D|a digoxin dose reduction when the prescription for TMP-SMX was started.  A|
02956|044|D|hospital encounter with digoxin toxicity occurred in 49/10,273 (0.48%)|
02956|045|D|patients treated with TMP-SMX versus 32/37,688 (0.08%) in those treated with|
02956|046|D|amoxicillin (weighted risk ratio, 5.71 (95% confidence interval, 3.9 to|
02956|047|D|10.24)).(4)|
02956|048|B||
02956|049|R|REFERENCES:|
02956|050|B||
02956|051|R|1.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
02956|052|R|  Pharmaceuticals, Inc. August, 2018.|1
02956|053|R|2.Bactrim Inj. (sulfamethoxazole and trimethoprim) US prescribing|1
02956|054|R|  information. Mutual Pharmaceutical Company, Inc. May, 2021.|1
02956|055|R|3.Petersen P, Kastrup J, Bartram R, Molholm Hansen J. Digoxin-trimethoprim|2
02956|056|R|  interaction. Acta Med Scand 1985;217(4):423-7.|2
02956|057|R|4.Muanda FT, Weir MA, Ahmadi F, McArthur E, Sontrop JM, Urquhart BL, Sadeghi|2
02956|058|R|  H, Kim RB, Garg AX. Thirty-day risk of digoxin toxicity among older adults|2
02956|059|R|  co-prescribed trimethoprim-sulfamethoxazole versus amoxicillin: A|2
02956|060|R|  population based cohort study. Pharmacotherapy 22/05/2024;558-569.|2
02957|001|T|MONOGRAPH TITLE:  Desmopressin/Glucocorticoids|
02957|002|B||
02957|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02957|004|L|is contraindicated and generally should not be dispensed or administered to|
02957|005|L|the same patient.|
02957|006|B||
02957|007|A|MECHANISM OF ACTION:  Glucocorticoids increase the risk of|
02957|008|A|hyponatremia.(1-4)|
02957|009|B||
02957|010|E|CLINICAL EFFECTS:  Concurrent use of glucocorticoids may increase the risk|
02957|011|E|of hyponatremia with desmopressin.(1-4)|
02957|012|B||
02957|013|P|PREDISPOSING FACTORS:  Predisposing factors for hyponatremia include:|
02957|014|P|polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can|
02957|015|P|cause fluid/electrolyte imbalances, age >=65, medications that cause water|
02957|016|P|retention and/or increase the risk of hyponatremia (carbamazepine,|
02957|017|P|chlorpromazine, lamotrigine, loop diuretics, NSAIDs, opioids, SSRIs,|
02957|018|P|thiazide diuretics, and/or tricyclic antidepressants).|
02957|019|B||
02957|020|M|PATIENT MANAGEMENT:  The concurrent use of systemic or inhaled|
02957|021|M|glucocorticoids with desmopressin is contraindicated.(1-4)  Desmopressin may|
02957|022|M|be initiated 3 days or 5 half-lives after glucocorticoid discontinuation,|
02957|023|M|whichever is longer.|
02957|024|M|   If concurrent use is deemed medically necessary, make sure serum sodium|
02957|025|M|levels are normal before beginning therapy and consider using the|
02957|026|M|desmopressin nasal 0.83 mcg dose.  Consider measuring serum sodium levels|
02957|027|M|more frequently than the recommended intervals of:  within 7 days of|
02957|028|M|concurrent therapy initiation, one month after concurrent therapy initiation|
02957|029|M|and periodically during treatment.  Counsel patients to report symptoms of|
02957|030|M|hyponatremia, which may include:  headache, nausea/vomiting, feeling|
02957|031|M|restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental|
02957|032|M|state (confusion, decreased awareness/alertness), seizures, coma, and|
02957|033|M|trouble breathing.  Counsel patients to limit the amount of fluids they|
02957|034|M|drink in the evening and night-time and to stop taking desmopressin if they|
02957|035|M|develop a stomach/intestinal virus with nausea/vomiting or any nose problems|
02957|036|M|(blockage, stuffy/runny nose, drainage).(1)|
02957|037|B||
02957|038|D|DISCUSSION:  In clinical trials of desmopressin for the treatment of|
02957|039|D|nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <=|
02957|040|D|125 mmol/L) were taking systemic or inhaled glucocorticoids.  Three of these|
02957|041|D|patients were also taking NSAIDs and one was receiving a thiazide|
02957|042|D|diuretic.(2)|
02957|043|D|   Drugs associated with hyponatremia may increase the risk, including loop|
02957|044|D|diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine,|
02957|045|D|NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic|
02957|046|D|antidepressants.(1,3-4)|
02957|047|B||
02957|048|R|REFERENCES:|
02957|049|B||
02957|050|R|1.Noctiva (desmopressin acetate) Nasal Spray US prescribing information.|1
02957|051|R|  Serenity Pharmaceuticals, LLC March 3, 2017.|1
02957|052|R|2.US Food and Drug Administration (FDA) Center for Drug Evaluation and|1
02957|053|R|  Research (CDER). NDA 201656 Summary Review for Regulatory Action - Noctiva|1
02957|054|R|  (desmopressin acetate) Nasal Spray. available at:|1
02957|055|R|  https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2017/201656O|1
02957|056|R|  rig1s000SumR.pdf March 3, 2017.|1
02957|057|R|3.Nocdurna (desmopressin acetate) sublingual tablets US prescribing|1
02957|058|R|  information. Ferring June, 2018.|1
02957|059|R|4.DDAVP (desmopressin acetate) US prescribing information. Sanofi-Aventis|1
02957|060|R|  U.S. LLC September 1, 2009.|1
02958|001|T|MONOGRAPH TITLE:  Leflunomide; Teriflunomide/Bile Acid Sequestrants|
02958|002|B||
02958|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02958|004|L|of severe adverse interaction.|
02958|005|B||
02958|006|A|MECHANISM OF ACTION:  Bile acid sequestrants may interfere with the|
02958|007|A|enterohepatic recycling of teriflunomide.(1-4)  Leflunomide is metabolized|
02958|008|A|to teriflunomide.(2-3)|
02958|009|B||
02958|010|E|CLINICAL EFFECTS:  Concurrent use of bile acid sequestrants may result in|
02958|011|E|decreased levels and effectiveness of leflunomide and teriflunomide, even|
02958|012|E|when the administration times are separated.  Coadministration may result in|
02958|013|E|return of disease activity.(1-4)|
02958|014|B||
02958|015|P|PREDISPOSING FACTORS:  None determined.|
02958|016|B||
02958|017|M|PATIENT MANAGEMENT:  Avoid the use of bile acid sequestrants with|
02958|018|M|leflunomide and teriflunomide.  Teriflunomide has a prolonged half-life and|
02958|019|M|staggering administration times will not prevent the drug interaction.(1-4)|
02958|020|M|   Teriflunomide may be coadministered with bile acid sequestrants in order|
02958|021|M|to accelerate elimination for suspected drug-induced liver injury, pregnancy|
02958|022|M|occurs during teriflunomide therapy, patient taking teriflunomide wants to|
02958|023|M|become pregnant or father a child, or other situations requiring accelerated|
02958|024|M|removal of teriflunomide.(4)|
02958|025|B||
02958|026|D|DISCUSSION:  After 11 days of cholestyramine administration, plasma|
02958|027|D|concentrations of teriflunomide are reduced by greater than 98%.(4)|
02958|028|D|   In an open-label study in 18 healthy subjects, administration of|
02958|029|D|teriflunomide (days 1-5; five 14 mg tablets once daily) followed by|
02958|030|D|colesevelam (days 6-16, four 625 mg tablets in morning, three 625 mg tablets|
02958|031|D|in evening) decreased the teriflunomide plasma concentration an average of|
02958|032|D|96.1% after 11 days.(5)|
02958|033|D|   In a study in 14 healthy subjects, administration of teriflunomide (70 mg|
02958|034|D|daily for 3 days; 14 mg daily for 11 days) followed by colestipol (8 g twice|
02958|035|D|daily for 15 days) decreased the teriflunomide plasma concentration an|
02958|036|D|average of 96.9% after 11 days.(6)|
02958|037|B||
02958|038|R|REFERENCES:|
02958|039|B||
02958|040|R|1.Aubagio (teriflunomide) US prescribing information. Genzyme Corporation|1
02958|041|R|  November, 2020.|1
02958|042|R|2.Arava (leflunomide) US prescribing information. Aventis Pharmaceuticals,|1
02958|043|R|  Inc. November, 2012.|1
02958|044|R|3.Arava (leflunomide) Canadian Prescribing Information. Sanofi-Aventis|1
02958|045|R|  Canada Inc. December, 2015.|1
02958|046|R|4.Sanofi Genzyme. A guide to the accelerated elimination procedure for|1
02958|047|R|  Aubagio (teriflunomide). available at:|1
02958|048|R|  https://www.aubagiohcp.com/content/pdf/drug_elimination_guide.pdf May|1
02958|049|R|  2017.|1
02958|050|R|5.Lunven C, Guo Z, Turpault S, Delfolie A, Fauchoux N, Turner T, Baldinetti|2
02958|051|R|  F. Effectiveness and Tolerability of Colesevelam HCl for Accelerated|2
02958|052|R|  Elimination of  Teriflunomide in Healthy Participants. J Clin Pharmacol|2
02958|053|R|  2017 Jun;57(6):747-750.|2
02958|054|R|6.Robertson D, Dixon C, Aungst A, McCoy B, Moreo N, Casady L, Maldonado J.|2
02958|055|R|  Tolerability and efficacy of colestipol hydrochloride for accelerated|2
02958|056|R|  elimination of teriflunomide. Expert Rev Clin Pharmacol 2017 Dec;|2
02958|057|R|  10(12):1403-1407.|2
02959|001|T|MONOGRAPH TITLE:  Desmopressin/Loop Diuretics|
02959|002|B||
02959|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02959|004|L|is contraindicated and generally should not be dispensed or administered to|
02959|005|L|the same patient.|
02959|006|B||
02959|007|A|MECHANISM OF ACTION:  Loop diuretics increase the risk of hyponatremia.(1-4)|
02959|008|B||
02959|009|E|CLINICAL EFFECTS:  Concurrent use of loop diuretics may increase the risk of|
02959|010|E|hyponatremia with desmopressin.(1-4)|
02959|011|B||
02959|012|P|PREDISPOSING FACTORS:  Predisposing factors for hyponatremia include:|
02959|013|P|polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can|
02959|014|P|cause fluid/electrolyte imbalances, age >=65, medications that cause water|
02959|015|P|retention and/or increase the risk of hyponatremia (carbamazepine,|
02959|016|P|chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs,|
02959|017|P|thiazide diuretics, and/or tricyclic antidepressants).|
02959|018|B||
02959|019|M|PATIENT MANAGEMENT:  The concurrent use of loop diuretics with desmopressin|
02959|020|M|is contraindicated.(1-4)|
02959|021|M|   If concurrent use is deemed medically necessary, make sure serum sodium|
02959|022|M|levels are normal before beginning therapy and consider using the|
02959|023|M|desmopressin nasal 0.83 mcg dose.  Consider measuring serum sodium levels|
02959|024|M|more frequently than the recommended intervals of:  within 7 days of|
02959|025|M|concurrent therapy initiation, one month after concurrent therapy initiation|
02959|026|M|and periodically during treatment.  Counsel patients to report symptoms of|
02959|027|M|hyponatremia, which may include:  headache, nausea/vomiting, feeling|
02959|028|M|restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental|
02959|029|M|state (confusion, decreased awareness/alertness), seizures, coma, and|
02959|030|M|trouble breathing.  Counsel patients to limit the amount of fluids they|
02959|031|M|drink in the evening and night-time and to stop taking desmopressin if they|
02959|032|M|develop a stomach/intestinal virus with nausea/vomiting or any nose problems|
02959|033|M|(blockage, stuffy/runny nose, drainage).(1)|
02959|034|B||
02959|035|D|DISCUSSION:  In clinical trials of desmopressin for the treatment of|
02959|036|D|nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <=|
02959|037|D|125 mmol/L) were taking systemic or inhaled glucocorticoids.  Three of these|
02959|038|D|patients were also taking NSAIDs and one was receiving a thiazide|
02959|039|D|diuretic.(2)|
02959|040|D|   Drugs associated with hyponatremia may increase the risk, including loop|
02959|041|D|diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine,|
02959|042|D|NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic|
02959|043|D|antidepressants.(1,3-4)|
02959|044|B||
02959|045|R|REFERENCES:|
02959|046|B||
02959|047|R|1.Noctiva (desmopressin acetate) Nasal Spray US prescribing information.|1
02959|048|R|  Serenity Pharmaceuticals, LLC March 3, 2017.|1
02959|049|R|2.US Food and Drug Administration (FDA) Center for Drug Evaluation and|1
02959|050|R|  Research (CDER). NDA 201656 Summary Review for Regulatory Action - Noctiva|1
02959|051|R|  (desmopressin acetate) Nasal Spray. available at:|1
02959|052|R|  https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2017/201656O|1
02959|053|R|  rig1s000SumR.pdf March 3, 2017.|1
02959|054|R|3.Nocdurna (desmopressin acetate) sublingual tablets US prescribing|1
02959|055|R|  information. Ferring June, 2018.|1
02959|056|R|4.DDAVP (desmopressin acetate) US prescribing information. Sanofi-Aventis|1
02959|057|R|  U.S. LLC September 1, 2009.|1
02960|001|T|MONOGRAPH TITLE:  Desmopressin/Agents with Hyponatremia Risk|
02960|002|B||
02960|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02960|004|L|take action as needed.|
02960|005|B||
02960|006|A|MECHANISM OF ACTION:  Carbamazepine, chlorpromazine, lamotrigine, NSAIDs,|
02960|007|A|opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants|
02960|008|A|increase the risk of hyponatremia.(1-3)|
02960|009|B||
02960|010|E|CLINICAL EFFECTS:  Concurrent use may increase the risk of hyponatremia with|
02960|011|E|desmopressin.(1-3)|
02960|012|B||
02960|013|P|PREDISPOSING FACTORS:  Predisposing factors for hyponatremia include:|
02960|014|P|polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can|
02960|015|P|cause fluid/electrolyte imbalances, age >=65, medications that cause water|
02960|016|P|retention and/or increase the risk of hyponatremia (glucocorticoids, loop|
02960|017|P|diuretics).|
02960|018|B||
02960|019|M|PATIENT MANAGEMENT:  The concurrent use of agents with a risk of|
02960|020|M|hyponatremia with desmopressin may increase the risk of hyponatremia.|
02960|021|M|   If concurrent use is deemed medically necessary, make sure serum sodium|
02960|022|M|levels are normal before beginning therapy and consider using the|
02960|023|M|desmopressin nasal 0.83 mcg dose.  Consider measuring serum sodium levels|
02960|024|M|more frequently than the recommended intervals of:  within 7 days of|
02960|025|M|concurrent therapy initiation, one month after concurrent therapy initiation|
02960|026|M|and periodically during treatment.  Counsel patients to report symptoms of|
02960|027|M|hyponatremia, which may include:  headache, nausea/vomiting, feeling|
02960|028|M|restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental|
02960|029|M|state (confusion, decreased awareness/alertness), seizures, coma, and|
02960|030|M|trouble breathing.  Counsel patients to limit the amount of fluids they|
02960|031|M|drink in the evening and night-time and to stop taking desmopressin if they|
02960|032|M|develop a stomach/intestinal virus with nausea/vomiting or any nose problems|
02960|033|M|(blockage, stuffy/runny nose, drainage).(1)|
02960|034|B||
02960|035|D|DISCUSSION:  In clinical trials of desmopressin for the treatment of|
02960|036|D|nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <=|
02960|037|D|125 mmol/L) were taking systemic or inhaled glucocorticoids.  Three of these|
02960|038|D|patients were also taking NSAIDs and one was receiving a thiazide|
02960|039|D|diuretic.(2)|
02960|040|D|   Drugs associated with hyponatremia may increase the risk, including loop|
02960|041|D|diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine,|
02960|042|D|NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic|
02960|043|D|antidepressants.(1,3-4)|
02960|044|B||
02960|045|R|REFERENCES:|
02960|046|B||
02960|047|R|1.Noctiva (desmopressin acetate) Nasal Spray US prescribing information.|1
02960|048|R|  Serenity Pharmaceuticals, LLC March 3, 2017.|1
02960|049|R|2.US Food and Drug Administration (FDA) Center for Drug Evaluation and|1
02960|050|R|  Research (CDER). NDA 201656 Summary Review for Regulatory Action - Noctiva|1
02960|051|R|  (desmopressin acetate) Nasal Spray. available at:|1
02960|052|R|  https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2017/201656O|1
02960|053|R|  rig1s000SumR.pdf March 3, 2017.|1
02960|054|R|3.Nocdurna (desmopressin acetate) sublingual tablets US prescribing|1
02960|055|R|  information. Ferring June, 2018.|1
02960|056|R|4.DDAVP (desmopressin acetate) US prescribing information. Sanofi-Aventis|1
02960|057|R|  U.S. LLC September 1, 2009.|1
02961|001|T|MONOGRAPH TITLE:  Bosentan/Strong and Moderate CYP2C9 Inhibitors|
02961|002|B||
02961|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02961|004|L|of severe adverse interaction.|
02961|005|B||
02961|006|A|MECHANISM OF ACTION:  Bosentan is metabolized by CYP2C9 and CYP3A4.  It is|
02961|007|A|also an inducer of these enzymes.  With regular dosing bosentan auto-induces|
02961|008|A|its own metabolism.(1)  Strong and moderate CYP2C9 inhibitors may inhibit|
02961|009|A|the CYP2C9 mediated metabolism of bosentan.(1-2)|
02961|010|B||
02961|011|E|CLINICAL EFFECTS:  Concurrent use of bosentan with an inhibitor of CYP2C9|
02961|012|E|may result in elevated levels of and toxicity from bosentan.(1)|
02961|013|B||
02961|014|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, a CYP2C9 inhibitor and a|
02961|015|P|CYP3A4 inhibitor could lead to blockade of both major metabolic pathways for|
02961|016|P|bosentan, resulting in large increases in bosentan plasma concentrations.|
02961|017|B||
02961|018|M|PATIENT MANAGEMENT:  Review medication list to see if patient is also|
02961|019|M|receiving a CYP3A4 inhibitor (e.g. aprepitant, boceprevir, ceritinib,|
02961|020|M|ciprofloxacin, clarithromycin, conivaptan, crizotinib, cyclosporine,|
02961|021|M|darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fosaprepitant,|
02961|022|M|idelalisib, imatinib, isavuconazole, itraconazole, ketoconazole, letermovir,|
02961|023|M|mibefradil, nefazodone, netupitant, nilotinib, posaconazole, ribociclib,|
02961|024|M|telaprevir, telithromycin, troleandomycin, verapamil, and voriconazole).|
02961|025|M|   Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended|
02961|026|M|by the manufacturer as the combination may lead to large increases in|
02961|027|M|bosentan plasma concentrations.(1)|
02961|028|M|   For patients stabilized on bosentan when a CYP2C9 inhibitor is initiated,|
02961|029|M|monitor tolerance to concomitant therapy and adjust bosentan dose if needed.|
02961|030|M|    The manufacturer of nitisinone recommends reducing the dosage of a|
02961|031|M|CYP2C9 substrate like bosentan by one-half.(3)|
02961|032|B||
02961|033|D|DISCUSSION:  Concurrent use with CYP2C9 inhibitors has not been studied.  In|
02961|034|D|a study in healthy subjects, concurrent bosentan and ketoconazole (a strong|
02961|035|D|CYP3A4 inhibitor) increased bosentan steady-state maximum concentrations|
02961|036|D|(Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(2)|
02961|037|D|   Strong CYP2C9 inhibitors linked to this monograph include: miconazole.(4)|
02961|038|D|   Moderate CYP2C9 inhibitors linked to this monograph include: amiodarone,|
02961|039|D|apazone, asciminib, benzbromarone, nitisinone, oxandrolone, piperine,|
02961|040|D|sulfaphenazole, and phenylbutazone.(4)|
02961|041|B||
02961|042|R|REFERENCES:|
02961|043|B||
02961|044|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
02961|045|R|  US, Inc. September 5, 2017.|1
02961|046|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
02961|047|R|  Pharmaceuticals February, 2014.|1
02961|048|R|3.Harliku (nitisinone) US prescribing information. Cycle Pharmaceuticals Ltd|1
02961|049|R|  June, 2025.|1
02961|050|R|4.This information is based on an extract from the Certara Drug Interaction|6
02961|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02962|001|T|MONOGRAPH TITLE:  Macimorelin/Strong CYP3A4 Inducers|
02962|002|B||
02962|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02962|004|L|of severe adverse interaction.|
02962|005|B||
02962|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
02962|007|A|macimorelin.(1)|
02962|008|B||
02962|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
02962|010|E|in decreased levels of macimorelin and may lead to false positive test|
02962|011|E|results.(1)|
02962|012|B||
02962|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02962|014|P|of the inducer for longer than 1-2 weeks.|
02962|015|B||
02962|016|M|PATIENT MANAGEMENT:  The US manufacturer of macimorelin states concurrent|
02962|017|M|use with a strong CYP3A4 inducer may reduce the plasma macimorelin|
02962|018|M|concentrations and may lead to false positive test results.  Discontinue|
02962|019|M|strong CYP3A4 inducers prior to macimorelin use.  Sufficient washout time of|
02962|020|M|strong CYP3A4 inducers prior to administration of macimorelin is|
02962|021|M|recommended.(1)|
02962|022|B||
02962|023|D|DISCUSSION:  In vitro data suggests CYP3A4 is the major metabolism pathway|
02962|024|D|for macimorelin.(1)|
02962|025|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
02962|026|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
02962|027|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
02962|028|D|wort.(2-4)|
02962|029|B||
02962|030|R|REFERENCES:|
02962|031|B||
02962|032|R|1.Macrilen (macimorelin) US prescribing information. Aeterna Zentaris GmbH|1
02962|033|R|  December, 2017.|1
02962|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
02962|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02962|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02962|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02962|038|R|  11/14/2017.|1
02962|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
02962|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02963|001|T|MONOGRAPH TITLE:  Macimorelin/Agents Affecting Growth Hormone|
02963|002|B||
02963|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02963|004|L|of severe adverse interaction.|
02963|005|B||
02963|006|A|MECHANISM OF ACTION:  Agents affecting growth hormone may impact the|
02963|007|A|accuracy of the macimorelin diagnostic test.(1)|
02963|008|B||
02963|009|E|CLINICAL EFFECTS:  Concurrent use of agents affecting growth hormone may|
02963|010|E|impact the accuracy of the macimorelin diagnostic test.(1)|
02963|011|B||
02963|012|P|PREDISPOSING FACTORS:  None determined.|
02963|013|B||
02963|014|M|PATIENT MANAGEMENT:  The US manufacturer of macimorelin states concurrent|
02963|015|M|use with agents affecting growth hormone may impact the accuracy of the|
02963|016|M|macimorelin diagnostic test.  Discontinue growth hormone products at least 1|
02963|017|M|week before administering the macimorelin diagnostic test.  Sufficient|
02963|018|M|washout time of drugs affecting growth hormone release prior to|
02963|019|M|administration of macimorelin is recommended.(1)|
02963|020|M|   Agents affecting growth hormone include:|
02963|021|M|   - Drugs that directly affect the pituitary secretion of growth hormone|
02963|022|M|(e.g. somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors)|
02963|023|M|   - Drugs that may transiently elevate growth hormone concentrations (e.g.|
02963|024|M|clonidine, levodopa, insulin)|
02963|025|M|   - Drugs that may blunt the growth hormone response (e.g. muscarinic|
02963|026|M|antagonists, anti-thyroid medications, growth hormone products)|
02963|027|B||
02963|028|D|DISCUSSION:  Concurrent use of agents affecting growth hormone may impact|
02963|029|D|the accuracy of the macimorelin diagnostic test.(1)|
02963|030|B||
02963|031|R|REFERENCE:|
02963|032|B||
02963|033|R|1.Macrilen (macimorelin) US prescribing information. Aeterna Zentaris GmbH|1
02963|034|R|  December, 2017.|1
02964|001|T|MONOGRAPH TITLE:  Posaconazole Oral Suspension/Metoclopramide|
02964|002|B||
02964|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02964|004|L|of severe adverse interaction.|
02964|005|B||
02964|006|A|MECHANISM OF ACTION:  Metoclopramide decreases the absorption of|
02964|007|A|posaconazole oral suspension increasing gastric motility.(1-3)|
02964|008|B||
02964|009|E|CLINICAL EFFECTS:  Concurrent use of metoclopramide may result in decreased|
02964|010|E|levels and effectiveness of posaconazole oral suspension.(1-3)|
02964|011|B||
02964|012|P|PREDISPOSING FACTORS:  None determined.|
02964|013|B||
02964|014|M|PATIENT MANAGEMENT:  If possible, use the tablet formulation of posaconazole|
02964|015|M|in patients requiring metoclopramide therapy.  If concurrent use of|
02964|016|M|metoclopramide and posaconazole suspension is required, monitor the patient|
02964|017|M|for breakthrough fungal infections.(1,2)|
02964|018|B||
02964|019|D|DISCUSSION:  In a cross-over study in 12 healthy subjects, use of|
02964|020|D|metoclopramide (10 mg TID for 2 days) with Boost decreased the maximum|
02964|021|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
02964|022|D|posaconazole suspension (400 mg) by 21% and 19%, respectively.(2,3)|
02964|023|D|   In a cross-over study in 20 healthy subjects, use of metoclopramide (15|
02964|024|D|mg TID for 2 days) decreased the Cmax and AUC of a single dose of|
02964|025|D|posaconazole tablets (400 mg) by 14% and 7%, respectively.  This was not|
02964|026|D|considered clinically significant.(2,4)|
02964|027|B||
02964|028|R|REFERENCES:|
02964|029|B||
02964|030|R|1.Reglan (metoclopramide) tablets US prescribing information. ANI|1
02964|031|R|  Pharmaceuticals, Inc. August 29, 2017.|1
02964|032|R|2.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
02964|033|R|  January, 2022.|1
02964|034|R|3.Krishna G, Moton A, Ma L, Medlock MM, McLeod J. Pharmacokinetics and|2
02964|035|R|  absorption of posaconazole oral suspension under various gastric|2
02964|036|R|  conditions in healthy volunteers. Antimicrob Agents Chemother 2009 Mar;|2
02964|037|R|  53(3):958-66.|2
02964|038|R|4.Kraft WK, Chang PS, van Iersel ML, Waskin H, Krishna G, Kersemaekers WM.|2
02964|039|R|  Posaconazole tablet pharmacokinetics: lack of effect of concomitant|2
02964|040|R|  medications altering gastric pH and gastric motility in healthy subjects.|2
02964|041|R|  Antimicrob Agents Chemother 2014 Jul;58(7):4020-5.|2
02965|001|T|MONOGRAPH TITLE:  Dalfampridine/Cimetidine; Dolutegravir|
02965|002|B||
02965|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02965|004|L|of severe adverse interaction.|
02965|005|B||
02965|006|A|MECHANISM OF ACTION:  Cimetidine and dolutegravir inhibit the organic cation|
02965|007|A|transporter 2 (OCT2).  Dalfampridine is eliminated mainly via the kidneys|
02965|008|A|with active renal secretion by OCT2.(1-3)|
02965|009|B||
02965|010|E|CLINICAL EFFECTS:  The concurrent administration of dalfampridine with an|
02965|011|E|inhibitor of OCT2 may result in elevated levels of dalfampridine and signs|
02965|012|E|of toxicity.  Elevated levels of dalfampridine may increase the risk of|
02965|013|E|seizures.(1,2)|
02965|014|B||
02965|015|P|PREDISPOSING FACTORS:  Renal impairment.|
02965|016|B||
02965|017|M|PATIENT MANAGEMENT:  The US manufacturer of dalfampridine states that the|
02965|018|M|potential benefits of taking OCT2 inhibitors concurrently with dalfampridine|
02965|019|M|should be considered against the risk of seizures.  If concurrent use is|
02965|020|M|warranted, carefully monitor patients for adverse effects.  Permanently|
02965|021|M|discontinue dalfampridine in patients who have a seizure while on|
02965|022|M|treatment.(1)|
02965|023|M|   The UK and Canadian manufacturers of dalfampridine states that concurrent|
02965|024|M|use of dalfampridine and OCT2 inhibitors is contraindicated.(4,5)|
02965|025|B||
02965|026|D|DISCUSSION:  In a single dose clinical study in 23 healthy volunteers, the|
02965|027|D|combined use of cimetidine (400 mg every 6 hours) increased the|
02965|028|D|area-under-curve (AUC) of cimetidine approximately 25% due to a reduction in|
02965|029|D|the clearance of dalfampridine.(1)|
02965|030|B||
02965|031|R|REFERENCES:|
02965|032|B||
02965|033|R|1.Ampyra (dalfampridine) US prescribing information. Acorda Therapeutics|1
02965|034|R|  Inc. November, 2021.|1
02965|035|R|2.Triumeq (abacavir-dolutegravir-lamivudine) US prescribing information.|1
02965|036|R|  Viiv Healthcare June, 2023.|1
02965|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02965|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02965|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02965|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02965|041|R|  11/14/2017.|1
02965|042|R|4.Fampyra (fampridine) UK prescribing information. Biogen Idec Ltd September|1
02965|043|R|  7, 2020.|1
02965|044|R|5.Fampyra (fampridine) CA prescribing information. Biogen Idec Canada Inc|1
02965|045|R|  November 26, 2014.|1
02966|001|T|MONOGRAPH TITLE:  Sorbitol/Lamivudine|
02966|002|B||
02966|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02966|004|L|of severe adverse interaction.|
02966|005|B||
02966|006|A|MECHANISM OF ACTION:  Sorbitol increases the osmotic pressure in the|
02966|007|A|intestine, resulting in accelerated small intestinal transit time and|
02966|008|A|decreased absorption and bioavailability of lamivudine.|
02966|009|B||
02966|010|E|CLINICAL EFFECTS:  Concurrent administration of sorbitol and lamivudine may|
02966|011|E|result in decreased clinical efficacy of lamivudine.(1) Reduction in|
02966|012|E|lamivudine exposure is sorbitol dose-dependent.|
02966|013|B||
02966|014|P|PREDISPOSING FACTORS:  None determined.|
02966|015|B||
02966|016|M|PATIENT MANAGEMENT:  The manufacturer of lamivudine states that the|
02966|017|M|concurrent use of lamivudine and sorbitol should be avoided.(1)|
02966|018|M|   Consider more frequent monitoring of HBV viral load when chronic|
02966|019|M|coadministration cannot be avoided.|
02966|020|B||
02966|021|D|DISCUSSION:  In an open label, randomized sequence, 4-period, crossover|
02966|022|D|trial in 16 healthy adults, coadministration of a single dose of lamivudine|
02966|023|D|(300 mg) with sorbitol (3.2 grams) resulted in a dose-dependent decrease of|
02966|024|D|lamivudine's area-under-the-curve (AUC(0-24), AUC infinity) and maximum|
02966|025|D|concentration (Cmax) of 20%, 28%, and 28%. A single dose of lamivudine with|
02966|026|D|sorbitol (10.2 grams) resulted in a decrease of lamivudine's AUC and Cmax of|
02966|027|D|39%, 52%, and 52%. A single dose of lamivudine with sorbitol (13.4 grams)|
02966|028|D|resulted in a decrease of lamivudine's AUC and Cmax of 36%, 55%, and 55%.(1)|
02966|029|B||
02966|030|R|REFERENCES:|
02966|031|B||
02966|032|R|1.Epivir (lamivudine) US prescribing information. GlaxoSmithKline May, 2019.|1
02966|033|R|2.Adkison K, Wolstenholme A, Lou Y, Zhang Z, Eld A, Perger T, Vangerow H,|2
02966|034|R|  Hayward K, Shaefer M, McCoig C. Effect of Sorbitol on the Pharmacokinetic|2
02966|035|R|  Profile of Lamivudine Oral Solution in  Adults: An Open-Label, Randomized|2
02966|036|R|  Study. Clin Pharmacol Ther 2017 Nov 18.|2
02967|001|T|MONOGRAPH TITLE:  Macimorelin/QT Prolonging Agents|
02967|002|B||
02967|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02967|004|L|of severe adverse interaction.|
02967|005|B||
02967|006|A|MECHANISM OF ACTION:  Concurrent use of macimorelin with agents that prolong|
02967|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
02967|008|B||
02967|009|E|CLINICAL EFFECTS:  The concurrent use of macimorelin with agents that|
02967|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02967|011|E|arrhythmias, including torsades de pointes.(1)|
02967|012|B||
02967|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02967|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02967|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02967|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02967|017|P|female gender, or advanced age.(2)|
02967|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02967|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02967|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02967|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02967|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02967|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02967|024|P|dysfunction).(2)|
02967|025|B||
02967|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of macimorelin with|
02967|027|M|medications that prolong the QT interval.(1)|
02967|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
02967|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
02967|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
02967|031|M|and periodically monitor during therapy.  Correct any electrolyte|
02967|032|M|abnormalities.|
02967|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02967|034|M|fainting.|
02967|035|B||
02967|036|D|DISCUSSION:  In a thorough QT study in 60 healthy subjects, a|
02967|037|D|supra-therapeutic dose of macimorelin (2mg/kg, 4 times the recommended|
02967|038|D|dosage) produced a mean change in QTc of 9.6 msec (upper 95% CI of 11.4|
02967|039|D|msec).  Similar effects were seen in a single-ascending dose study which|
02967|040|D|examined dosages of 1.5 mg/kg, 1 mg/kg, and 2 mg/kg, suggesting an absence|
02967|041|D|of dose-dependent changes.(1)|
02967|042|D|   Agents that are linked to this monograph may have varying degrees of|
02967|043|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02967|044|D|been shown to prolong the QTc interval either through their mechanism of|
02967|045|D|action, through studies on their effects on the QTc interval, or through|
02967|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02967|047|D|and/or postmarketing reports.(3)|
02967|048|B||
02967|049|R|REFERENCES:|
02967|050|B||
02967|051|R|1.Macrilen (macimorelin) US prescribing information. Aeterna Zentaris GmbH|1
02967|052|R|  December, 2017.|1
02967|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02967|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02967|055|R|  settings: a scientific statement from the American Heart Association and|6
02967|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02967|057|R|  2;55(9):934-47.|6
02967|058|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02967|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02967|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02967|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02968|001|T|MONOGRAPH TITLE:  Macimorelin/Possible QT Prolonging Agents|
02968|002|B||
02968|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02968|004|L|take action as needed.|
02968|005|B||
02968|006|A|MECHANISM OF ACTION:  Concurrent use of macimorelin with agents that prolong|
02968|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
02968|008|B||
02968|009|E|CLINICAL EFFECTS:  The concurrent use of macimorelin with agents that|
02968|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
02968|011|E|arrhythmias, including torsades de pointes.(1)|
02968|012|B||
02968|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
02968|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
02968|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
02968|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
02968|017|P|female gender, or advanced age.(2)|
02968|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02968|019|P|higher systemic concentrations of either QT prolonging drug are additional|
02968|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02968|021|P|drug concentrations include rapid infusion of an intravenous dose or|
02968|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02968|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
02968|024|P|dysfunction).(2)|
02968|025|B||
02968|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of macimorelin with|
02968|027|M|medications that prolong the QT interval.(1)|
02968|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
02968|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
02968|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
02968|031|M|and periodically monitor during therapy.  Correct any electrolyte|
02968|032|M|abnormalities.|
02968|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
02968|034|M|fainting.|
02968|035|B||
02968|036|D|DISCUSSION:  In a thorough QT study in 60 healthy subjects, a|
02968|037|D|supra-therapeutic dose of macimorelin (2mg/kg, 4 times the recommended|
02968|038|D|dosage) produced a mean change in QTc of 9.6 msec (upper 95% CI of 11.4|
02968|039|D|msec).  Similar effects were seen in a single-ascending dose study which|
02968|040|D|examined dosages of 1.5 mg/kg, 1 mg/kg, and 2 mg/kg, suggesting an absence|
02968|041|D|of dose-dependent changes.(1)|
02968|042|D|   Agents that are linked to this monograph may have varying degrees of|
02968|043|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
02968|044|D|been shown to prolong the QTc interval either through their mechanism of|
02968|045|D|action, through studies on their effects on the QTc interval, or through|
02968|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
02968|047|D|and/or postmarketing reports.(3)|
02968|048|B||
02968|049|R|REFERENCES:|
02968|050|B||
02968|051|R|1.Macrilen (macimorelin) US prescribing information. Aeterna Zentaris GmbH|1
02968|052|R|  December, 2017.|1
02968|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02968|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02968|055|R|  settings: a scientific statement from the American Heart Association and|6
02968|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02968|057|R|  2;55(9):934-47.|6
02968|058|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
02968|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
02968|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
02968|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
02969|001|T|MONOGRAPH TITLE:  Hydroxyurea/Stavudine|
02969|002|B||
02969|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02969|004|L|of severe adverse interaction.|
02969|005|B||
02969|006|A|MECHANISM OF ACTION:  Hepatotoxicity and hepatic failure has been reported|
02969|007|A|with hydroxyurea and stavudine.  Concurrent use may result in additive or|
02969|008|A|synergistic effects.(1)|
02969|009|B||
02969|010|E|CLINICAL EFFECTS:  Concurrent use of hydroxyurea and stavudine may increase|
02969|011|E|the risk of severe hepatomegaly, pancreatitis, and/or peripheral|
02969|012|E|neuropathy.(1)|
02969|013|B||
02969|014|P|PREDISPOSING FACTORS:  Pre-existing liver disease may increase the risk of|
02969|015|P|hepatomegaly.  Concurrent therapy with didanosine, hydroxyurea, and|
02969|016|P|stavudine may further increase the risk of hepatotoxicity, pancreatitis, (1)|
02969|017|P|and neuropathy.(2,3)|
02969|018|B||
02969|019|M|PATIENT MANAGEMENT:  The US manufacturer of stavudine recommends avoiding|
02969|020|M|coadministration of stavudine and hydroxyurea.(1)|
02969|021|M|   Monitor patients for signs of pancreatitis, hepatotoxicity, and|
02969|022|M|peripheral neuropathy. Signs of peripheral neuropathy include numbness,|
02969|023|M|tingling, or pain in hands or feet. Signs of pancreatitis include severe|
02969|024|M|abdominal pain, nausea and vomiting, and fever.(1)|
02969|025|M|   Permanently discontinue hydroxyurea in patients who develop signs and|
02969|026|M|symptoms of pancreatitis.(1)|
02969|027|B||
02969|028|D|DISCUSSION:  Hepatotoxicity and hepatic failure resulting in death were|
02969|029|D|reported during postmarketing surveillance in HIV-infected patients treated|
02969|030|D|with hydroxyurea and other antiretroviral agents.(1)|
02969|031|D|   In a retrospective review, 12 cases of lactic acidosis in HIV-positive|
02969|032|D|patients during a 5 year period were identified.  Nine of the 12 patients|
02969|033|D|were receiving concurrent therapy with didanosine and stavudine. Four of the|
02969|034|D|nine were also receiving hydroxyurea.  Three of the nine died, none of whom|
02969|035|D|were taking hydroxyurea.(4)|
02969|036|D|   In a randomized trial comparing concurrent didanosine and stavudine with|
02969|037|D|and without hydroxyurea, 35% of patients receiving triple therapy developed|
02969|038|D|neuropathy, compared with only 15% of patients receiving didanosine and|
02969|039|D|stavudine without hydroxyurea.  One case of pancreatitis was reported in a|
02969|040|D|patient receiving didanosine and stavudine without hydroxyurea.(2)|
02969|041|D|   In a retrospective review, neuropathy was reported in 27% (6 of 27) of|
02969|042|D|patients receiving concurrent didanosine, stavudine, and hydroxyurea|
02969|043|D|compared to 10% (6 of 61) of patients receiving didanosine and stavudine|
02969|044|D|without hydroxyurea.(3)|
02969|045|D|   A retrospective review of HIV-positive patients found that the relative|
02969|046|D|risk of neuropathy for combination therapy relative to didanosine alone was|
02969|047|D|1.39 for stavudine alone, 2.35 for didanosine with hydroxyurea, 3.50 for|
02969|048|D|didanosine and stavudine, and 7.80 for didanosine, stavudine, and|
02969|049|D|hydroxyurea.(5)|
02969|050|B||
02969|051|R|REFERENCES:|
02969|052|B||
02969|053|R|1.Zerit (stavudine) US prescribing information. Bristol-Myers Squibb Company|1
02969|054|R|  December 19, 2017.|1
02969|055|R|2.Rutschmann OT, Vernazza PL, Bucher HC, Opravil M, Ledergerber B, Telenti|2
02969|056|R|  A, Malinverni R, Bernasconi E, Fagard C, Leduc D, Perrin L, Hirschel B.|2
02969|057|R|  Long-term hydroxyurea in combination with didanosine and stavudine for the|2
02969|058|R|  treatment of HIV-1 infection. Swiss HIV Cohort Study. AIDS 2000 Sep 29;|2
02969|059|R|  14(14):2145-51.|2
02969|060|R|3.Cepeda JA, Wilks D. Excess peripheral neuropathy in patients treated with|2
02969|061|R|  hydroxyurea plus didanosine and stavudine for HIV infection. AIDS 2000 Feb|2
02969|062|R|  18;14(3):332-3.|2
02969|063|R|4.Coghlan ME, Sommadossi JP, Jhala NC, Many WJ, Saag MS, Johnson VA.|3
02969|064|R|  Symptomatic lactic acidosis in hospitalized antiretroviral-treated|3
02969|065|R|  patients with human immunodeficiency virus infection: a report of 12|3
02969|066|R|  cases. Clin Infect Dis 2001 Dec 1;33(11):1914-21.|3
02969|067|R|5.Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in|2
02969|068|R|  HIV-infected patients on monotherapy versus those on combination therapy|2
02969|069|R|  with didanosine, stavudine and hydroxyurea. AIDS 2000 Feb 18;14(3):273-8.|2
02970|001|T|MONOGRAPH TITLE:  Selected CYP2D6 Substrates/Desvenlafaxine|
02970|002|B||
02970|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02970|004|L|take action as needed.|
02970|005|B||
02970|006|A|MECHANISM OF ACTION:  Desvenlafaxine is considered a weak inhibitor of|
02970|007|A|CYP2D6.(1)|
02970|008|B||
02970|009|E|CLINICAL EFFECTS:  Concurrent use of desvenlafaxine may lead to increased|
02970|010|E|serum levels and adverse effects of drugs sensitive to inhibition of the|
02970|011|E|CYP2D6 pathway.(1)  Agents linked to this monograph are: atomoxetine,|
02970|012|E|dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol,|
02970|013|E|perphenazine, tolterodine, and yohimbine.|
02970|014|B||
02970|015|P|PREDISPOSING FACTORS:  With perphenazine and tolterodine, the risk of|
02970|016|P|anticholinergic toxicities including cognitive decline, delirium, falls and|
02970|017|P|fractures is increased in geriatric patients using more than one medicine|
02970|018|P|with anticholinergic properties.(2)|
02970|019|B||
02970|020|M|PATIENT MANAGEMENT:  Reduce the dose of CYP2D6 substrates by up to one-half|
02970|021|M|when coadministered with desvenlafaxine 400 mg.(1)|
02970|022|M|   Studies have shown that desvenlafaxine does not have a clinically|
02970|023|M|relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. CYP2D6|
02970|024|M|substrates should be dosed at the original level when coadministered with|
02970|025|M|desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued.(1)|
02970|026|B||
02970|027|D|DISCUSSION:  In a study, coadministration of desvenlafaxine 100 mg daily|
02970|028|D|with desipramine (single dose 50 mg) increased desipramine's maximum|
02970|029|D|concentration (Cmax) and area-under-the-curve (AUC)by 25% and 17%.(1)|
02970|030|D|   In a study, coadministration of desvenlafaxine 400 mg daily with|
02970|031|D|desipramine (single dose 50 mg) increased desipramine's maximum|
02970|032|D|concentration (Cmax) and area-under-the-curve (AUC)by 50% and 90%.(1)|
02970|033|D|   Selected CYP2D6 substrates linked to this monograph are: atomoxetine,|
02970|034|D|dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol,|
02970|035|D|perphenazine, tolterodine, and yohimbine.|
02970|036|B||
02970|037|R|REFERENCES:|
02970|038|B||
02970|039|R|1.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
02970|040|R|  Pharmaceuticals, Inc. August, 2023.|1
02970|041|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
02970|042|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
02970|043|R|  Soc 2023 Jul;71(7):2052-2081.|6
02970|044|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
02970|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02970|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02970|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02970|048|R|  11/14/2017.|1
02971|001|T|MONOGRAPH TITLE:  Cladribine/Selected Inhibitors of BCRP|
02971|002|B||
02971|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02971|004|L|of severe adverse interaction.|
02971|005|B||
02971|006|A|MECHANISM OF ACTION:  Inhibitors of BCRP may increase the absorption of|
02971|007|A|cladribine.(1-2)|
02971|008|B||
02971|009|E|CLINICAL EFFECTS:  The concurrent administration of cladribine with an|
02971|010|E|inhibitor of BCRP may result in elevated levels of cladribine and signs of|
02971|011|E|toxicity.(1-2)|
02971|012|B||
02971|013|P|PREDISPOSING FACTORS:  None determined.|
02971|014|B||
02971|015|M|PATIENT MANAGEMENT:  The manufacturer of cladribine states concurrent use of|
02971|016|M|BCRP inhibitors should be avoided during the 4- to 5-day cladribine|
02971|017|M|treatment.(1-2)|
02971|018|M|   Selection of an alternative concurrent medication with no or minimal|
02971|019|M|transporter inhibiting proprieties should be considered. If this is not|
02971|020|M|possible, dose reduction to the minimum mandatory dose of the BCRP|
02971|021|M|inhibitor, separation in timing of administration, and careful patient|
02971|022|M|monitoring is recommended.(1-2)|
02971|023|M|   Monitor for signs of hematologic toxicity. Lymphocyte counts should be|
02971|024|M|monitored.|
02971|025|B||
02971|026|D|DISCUSSION:  Cladribine is a substrate of BCRP.  Inhibitors of this|
02971|027|D|transporter are expected to increase cladribine levels.(1-2)|
02971|028|D|   BCRP inhibitors linked to this monograph include:  capmatinib,|
02971|029|D|clopidogrel, curcumin, danicopan, darolutamide, dasabuvir, eltrombopag,|
02971|030|D|enasidenib, febuxostat, fostamatinib, fostemsavir, glecaprevir/pibrentasvir,|
02971|031|D|grazoprevir, lazertinib, oteseconazole, pacritinib, pantoprazole,|
02971|032|D|paritaprevir, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat,|
02971|033|D|selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tafamidis, ticagrelor,|
02971|034|D|tolvaptan, turmeric, vadadustat, and zongertinib.(1-4)|
02971|035|B||
02971|036|R|REFERENCES:|
02971|037|B||
02971|038|R|1.Mavenclad (cladribine) CA prescribing information. EMD Serono October,|1
02971|039|R|  2021.|1
02971|040|R|2.Mavenclad (cladribine) US prescribing information. EMD Serono, Inc. March,|1
02971|041|R|  2019.|1
02971|042|R|3.Vyndamax (tafamidis) US prescribing information. Pfizer, Inc. June, 2021.|1
02971|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
02971|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02972|001|T|MONOGRAPH TITLE:  Cladribine/Selected Inhibitors of CNT or ENT|
02972|002|B||
02972|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02972|004|L|of severe adverse interaction.|
02972|005|B||
02972|006|A|MECHANISM OF ACTION:  Inhibitors of concentrative nucleoside transporters|
02972|007|A|(CNT) or equilibrative nucleoside transporters (ENT) may increase the|
02972|008|A|absorption of cladribine.(1-2)|
02972|009|B||
02972|010|E|CLINICAL EFFECTS:  The concurrent administration of cladribine with an|
02972|011|E|inhibitor of CNT or ENT may result in elevated levels of cladribine and|
02972|012|E|signs of toxicity.(1-2)|
02972|013|B||
02972|014|P|PREDISPOSING FACTORS:  None determined.|
02972|015|B||
02972|016|M|PATIENT MANAGEMENT:  The manufacturer of cladribine states concurrent use of|
02972|017|M|CNT or ENT inhibitors should be avoided during the 4- to 5-day cladribine|
02972|018|M|treatment.(1-2)|
02972|019|M|   Selection of an alternative concurrent medication with no or minimal|
02972|020|M|transporter inhibiting proprieties should be considered. If this is not|
02972|021|M|possible, dose reduction to the minimum mandatory dose of the CNT or ENT|
02972|022|M|inhibitor, separation in timing of administration, and careful patient|
02972|023|M|monitoring is recommended.(1-2)|
02972|024|M|   Monitor for signs of hematologic toxicity. Lymphocyte counts should be|
02972|025|M|monitored.|
02972|026|B||
02972|027|D|DISCUSSION:  Cladribine is a substrate of CNT and ENT.  Inhibitors of these|
02972|028|D|transporters are expected to increase cladribine levels.(1-2)|
02972|029|D|   Nucleoside inhibitors linked to this monograph include: cilostazol,|
02972|030|D|dipyridamole, nifedipine, nimodipine, reserpine, and sulindac.(1-2)|
02972|031|B||
02972|032|R|REFERENCES:|
02972|033|B||
02972|034|R|1.Mavenclad (cladribine) CA prescribing information. EMD Serono October,|1
02972|035|R|  2021.|1
02972|036|R|2.Mavenclad (cladribine) US prescribing information. EMD Serono, Inc. March,|1
02972|037|R|  2019.|1
02973|001|T|MONOGRAPH TITLE:  Disulfiram/Intranasal Cocaine|
02973|002|B||
02973|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02973|004|L|of severe adverse interaction.|
02973|005|B||
02973|006|A|MECHANISM OF ACTION:  Disulfiram may inhibit the metabolism of intranasally|
02973|007|A|administered cocaine by plasma and microsomal carboxylesterases and plasma|
02973|008|A|cholinesterase.|
02973|009|B||
02973|010|E|CLINICAL EFFECTS:  Increased concentrations of cocaine may result in|
02973|011|E|increased heart rate, increased blood pressure, paranoia, and anxiety.|
02973|012|B||
02973|013|P|PREDISPOSING FACTORS:  None determined.|
02973|014|B||
02973|015|M|PATIENT MANAGEMENT:  The manufacturer of intranasal cocaine recommends|
02973|016|M|avoiding using intranasal cocaine in patients taking disulfiram. Consider|
02973|017|M|using other local anesthetic agents.(1)|
02973|018|M|   Monitor for signs of cocaine toxicity such as increased blood pressure or|
02973|019|M|heart rate.|
02973|020|B||
02973|021|D|DISCUSSION:  In a randomized, double-blind, placebo controlled study in 6|
02973|022|D|adults with cocaine and alcohol dependence, concomitant administration of|
02973|023|D|disulfiram (250 mg/day) with intranasal cocaine (1mg/kg) increased cocaine's|
02973|024|D|area-under-the-curve (AUC) by 68%. Administration of intranasal cocaine|
02973|025|D|(2mg/kg) with disulfiram increased cocaine's AUC by 77%. Significant|
02973|026|D|increases were also seen in heart rate and blood pressure.(2)|
02973|027|D|   In a study in 8 cocaine dependent subjects, concomitant administration of|
02973|028|D|disulfiram (250 mg) with cocaine (2mg/kg intranasally) increased cocaine's|
02973|029|D|maximum concentration (Cmax) by 32%. An increase in nervousness and paranoia|
02973|030|D|was seen in 3 patients.(3)|
02973|031|D|  In a case report, concomitant administration of cocaine (1 g intranasally)|
02973|032|D|with disulfiram (250 mg) caused severe paranoia, severe anxiety,  sweating,|
02973|033|D|tremor, and increased pulse rate.(4)|
02973|034|B||
02973|035|R|REFERENCES:|
02973|036|B||
02973|037|R|1.Goprelto (cocaine) nasal solution US prescribing information. Genus|1
02973|038|R|  Lifesciences Inc. December 2017.|1
02973|039|R|2.McCance-Katz EF, Kosten TR, Jatlow P. Chronic disulfiram treatment effects|2
02973|040|R|  on intranasal cocaine administration: initial results. Biol Psychiatry|2
02973|041|R|  1998 Apr 1;43(7):540-3.|2
02973|042|R|3.Hameedi FA, Rosen MI, McCance-Katz EF, McMahon TJ, Price LH, Jatlow PI,|2
02973|043|R|  Woods SW, Kosten TR. Behavioral, physiological, and pharmacological|2
02973|044|R|  interaction of cocaine and disulfiram in humans. Biol Psychiatry 1995 Apr|2
02973|045|R|  15;37(8):560-3.|2
02973|046|R|4.Mutschler J, Diehl A, Kiefer F. Pronounced paranoia as a result of|3
02973|047|R|  cocaine-disulfiram interaction: case report and mode of action. J Clin|3
02973|048|R|  Psychopharmacol 2009 Feb;29(1):99-101.|3
02974|001|T|MONOGRAPH TITLE:  Allergen Immunotherapy/Beta-Blockers|
02974|002|B||
02974|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02974|004|L|of severe adverse interaction.|
02974|005|B||
02974|006|A|MECHANISM OF ACTION:  Beta-blockers may mask early signs and symptoms of|
02974|007|A|anaphylaxis, make the treatment of anaphylaxis more difficult, and increase|
02974|008|A|the severity of the reaction.|
02974|009|B||
02974|010|E|CLINICAL EFFECTS:  Beta-blockers may reduce a patient's ability to survive a|
02974|011|E|systemic allergic reaction to allergen immunotherapy. Signs and symptoms of|
02974|012|E|anaphylaxis may be masked.|
02974|013|B||
02974|014|P|PREDISPOSING FACTORS:  Concurrent use of epinephrine with beta-blockers may|
02974|015|P|result in hypertension with reflex bradycardia.  Epinephrine resistance in|
02974|016|P|patients with anaphylaxis has been reported.|
02974|017|B||
02974|018|M|PATIENT MANAGEMENT:  Avoid concomitant administration of immunotherapy and|
02974|019|M|beta-blockers if possible.  If patients cannot safely discontinue|
02974|020|M|beta-blockers but have a history of moderate to severe sting-induced|
02974|021|M|anaphylaxis, venom immunotherapy is indicated because the risk of|
02974|022|M|anaphylaxis related to a venom sting is greater than the risk of an|
02974|023|M|immunotherapy-related systemic reaction.|
02974|024|M|   In patients taking beta-blockers for whom an acceptable alternative is|
02974|025|M|not available, withholding allergen immunotherapy may be the best option.|
02974|026|M|   If both drugs are administered, monitor closely for signs and symptoms of|
02974|027|M|anaphylaxis.|
02974|028|M|   Use caution when treating anaphylaxis with epinephrine since response may|
02974|029|M|be poor. Epinephrine administration may worsen anaphylaxis because|
02974|030|M|beta-blockers block the beta effects of epinephrine, which results in|
02974|031|M|predomination of alpha effects.  The plasma clearance of epinephrine is|
02974|032|M|decreased.|
02974|033|M|   Glucagon may help in the treatment of refractory anaphylaxis in patients|
02974|034|M|receiving beta-blockers.|
02974|035|B||
02974|036|D|DISCUSSION:  In a case report, a patient taking propranolol was administered|
02974|037|D|pollen extract immunotherapy and immediately developed anaphylaxis.|
02974|038|D|Treatment with epinephrine did not improve symptoms and patient was|
02974|039|D|subsequently intubated.(2)|
02974|040|D|   In another case report, a patient taking propranolol was given pollen|
02974|041|D|immunotherapy and developed anaphylaxis. Difficulty in maintaining an|
02974|042|D|adequate blood pressure and pulse continued for several hours despite|
02974|043|D|epinephrine and other supportive measures.(3)|
02974|044|D|   There are other case reports of patients taking propranolol with venom|
02974|045|D|immunotherapy that were refractory to treatment.(6-7)|
02974|046|B||
02974|047|R|REFERENCES:|
02974|048|B||
02974|049|R|1.Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, Nelson M,|6
02974|050|R|  etal. Allergen immunotherapy: a practice parameter third update. J Allergy|6
02974|051|R|  Clin Immunol 2011 Jan;127(1 Suppl):S1-55.|6
02974|052|R|2.Bickell WH, Dice WH. Military antishock trousers in a patient with|3
02974|053|R|  adrenergic-resistant anaphylaxis. Ann Emerg Med 1984 Mar;13(3):189-90.|3
02974|054|R|3.Jacobs RL, Rake GW, Fournier DC, Chilton RJ, Culver WG, Beckmann CH.|3
02974|055|R|  Potentiated anaphylaxis in patients with drug-induced beta-adrenergic|3
02974|056|R|  blockade. J Allergy Clin Immunol 1981;68(2):125-7.|3
02974|057|R|4.Kivity S, Yarchovsky J. Relapsing anaphylaxis to bee sting in a patient|3
02974|058|R|  treated with beta-blocker and Ca  blocker. J Allergy Clin Immunol 1990|3
02974|059|R|  Mar;85(3):669-70.|3
02974|060|R|5.Lang DM. Do beta-blockers really enhance the risk of anaphylaxis during|6
02974|061|R|  immunotherapy?. Curr Allergy Asthma Rep 2008 Mar;8(1):37-44.|6
02974|062|R|6.Awai LE, Mekori YA. Insect sting anaphylaxis and beta-adrenergic blockade:|3
02974|063|R|  a relative contraindication. Ann Allergy 1984 Jul;53(1):48-9.|3
02974|064|R|7.Newman BR, Schultz LK. Epinephrine-resistant anaphylaxis in a patient|3
02974|065|R|  taking propranolol hydrochloride. Ann Allergy 1981 Jul;47(1):35-7.|3
02975|001|T|MONOGRAPH TITLE:  PD-1 and PD-L1 Blocking Antibodies/Thalidomide Analogues|
02975|002|B||
02975|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02975|004|L|of severe adverse interaction.|
02975|005|B||
02975|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is not known.|
02975|007|B||
02975|008|E|CLINICAL EFFECTS:  Concurrent use of a thalidomide analogue with|
02975|009|E|dexamethasone and a PD-1 or PD-L1 blocking antibody may increase the risk of|
02975|010|E|mortality.|
02975|011|B||
02975|012|P|PREDISPOSING FACTORS:  Concurrent use of dexamethasone may increase the risk|
02975|013|P|of venous thromboembolism (VTE), ischemic heart disease including myocardial|
02975|014|P|infarction, and stroke.|
02975|015|B||
02975|016|M|PATIENT MANAGEMENT:  Concurrent administration of a thalidomide analogue|
02975|017|M|plus dexamethasone with a PD-1 or PD-L1 blocking antibody is not recommended|
02975|018|M|outside of controlled clinical trials.|
02975|019|B||
02975|020|D|DISCUSSION:  Two randomized clinical trials in multiple myeloma patients|
02975|021|D|showed an increase in mortality associated with the concurrent use of|
02975|022|D|pembrolizumab, a thalidomide analogue, and dexamethasone.|
02975|023|D|   In the first clinical trial, patients were randomized to receive|
02975|024|D|pomalidomide, dexamethasone, and pembrolizumab. In this trial, the relative|
02975|025|D|risk of death was increased by more than 50% in the experimental arm|
02975|026|D|containing pembrolizumab and the hazard ratio for overall survival was 1.61.|
02975|027|D|Causes of death in the experimental arm included myocarditis,|
02975|028|D|Stevens-Johnson syndrome, myocardial infarction, pericardial hemorrhage,|
02975|029|D|cardiac failure, respiratory tract infection, neutropenia sepsis, sepsis,|
02975|030|D|multiple organ dysfunction, and respiratory failure.|
02975|031|D|   In the second clinical trial, patients were randomized to receive|
02975|032|D|lenalidomide, dexamethasone, and pembrolizumab. In this trial, the relative|
02975|033|D|risk of death was increased by more than 100% in the experimental arm|
02975|034|D|containing pembrolizumab and the hazard ratio for overall survival was 2.06.|
02975|035|D|Causes of death in the experimental arm included intestinal ischemia,|
02975|036|D|cardio-respiratory arrest, pulmonary embolism, cardiac arrest, pneumonia,|
02975|037|D|sudden death, myocarditis, large intestinal perforation, and cardiac|
02975|038|D|failure.|
02975|039|D|   PD-1 and PD-L1 blocking antibodies linked to this monograph include|
02975|040|D|atezolizumab, avelumab, cemiplimab, cosibelimab, dostarlimab, durvalumab,|
02975|041|D|nivolumab, pembrolizumab, penpulimab, retifanlimab, sintilimab, sugemalimab,|
02975|042|D|and toripalimab.|
02975|043|B||
02975|044|R|REFERENCES:|
02975|045|B||
02975|046|R|1.Pomalyst (pomalidomide) US prescribing information. Celgene Corporation|1
02975|047|R|  November, 2020.|1
02975|048|R|2.Thalomid (thalidomide) US prescribing information. Celgene Corporation|1
02975|049|R|  December, 2017.|1
02975|050|R|3.Revlimid (lenalidomide) US prescribing information. Celgene Corporation|1
02975|051|R|  May 2019.|1
02975|052|R|4.Keytruda (pembrolizumab) injection US prescribing information. Merck Sharp|1
02975|053|R|  & Dohme Corp. October, 2021.|1
02976|001|T|MONOGRAPH TITLE:  Anti-thymocyte globulin/Belatacept|
02976|002|B||
02976|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02976|004|L|of severe adverse interaction.|
02976|005|B||
02976|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.(1)|
02976|007|B||
02976|008|E|CLINICAL EFFECTS:  Concurrent use of anti-thymocyte globulin with belatacept|
02976|009|E|may increase the risk of venous thrombosis of the renal allograft in de novo|
02976|010|E|kidney transplant patients.(1)|
02976|011|B||
02976|012|P|PREDISPOSING FACTORS:  None determined.|
02976|013|B||
02976|014|M|PATIENT MANAGEMENT:  The US manufacturer of belatacept states|
02976|015|M|coadministration (at the same or nearly the same time) of anti-thymocyte|
02976|016|M|globulin with the first dose of belatacept may pose a risk for venous|
02976|017|M|thrombosis of the renal allograft in patients who are de novo kidney|
02976|018|M|transplant recipients.(1)|
02976|019|M|   If anti-thymocyte globulin (or any other cell-depleting induction|
02976|020|M|treatment) and belatacept will be administered concomitantly, a twelve-hour|
02976|021|M|interval between the two administrations is suggested.(1)|
02976|022|B||
02976|023|D|DISCUSSION:  Based on postmarketing experience in de novo kidney transplant|
02976|024|D|recipients, some with other predisposing risk factors for venous thrombosis|
02976|025|D|of the renal allograft, venous thrombosis of the renal allograft has|
02976|026|D|occurred when the initial dose of anti-thymocyte globulin, as|
02976|027|D|immunosuppressive induction, was coadministered (at the same or nearly the|
02976|028|D|same time) with the first dose of belatacept.  In such patients, the|
02976|029|D|coadministration (at the same or nearly the same time) of anti-thymocyte|
02976|030|D|globulin and belatacept may pose a risk for venous thrombosis of the renal|
02976|031|D|allograft.  If anti-thymocyte globulin (or any other cell-depleting|
02976|032|D|induction treatment) and belatacept will be administered concomitantly, a|
02976|033|D|twelve-hour interval between the two administrations is suggested.(1)|
02976|034|B||
02976|035|R|REFERENCE:|
02976|036|B||
02976|037|R|1.Nulojix (belatacept) US prescribing information. Bristol-Myers Squibb|1
02976|038|R|  Company July, 2021.|1
02977|001|T|MONOGRAPH TITLE:  Lansoprazole/Sucralfate|
02977|002|B||
02977|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02977|004|L|take action as needed.|
02977|005|B||
02977|006|A|MECHANISM OF ACTION:  Sucralfate may decrease the absorption of|
02977|007|A|lansoprazole.(3)|
02977|008|B||
02977|009|E|CLINICAL EFFECTS:  The simultaneous administration of sucralfate and|
02977|010|E|lansoprazole may decrease the absorption of lansoprazole, which may result|
02977|011|E|in therapeutic failures.|
02977|012|B||
02977|013|P|PREDISPOSING FACTORS:  None determined.|
02977|014|B||
02977|015|M|PATIENT MANAGEMENT:  Lansoprazole should be taken at least 30 minutes prior|
02977|016|M|to sucralfate.(1)|
02977|017|B||
02977|018|D|DISCUSSION:  In a single-dose crossover study, concurrent administration of|
02977|019|D|lansoprazole (30 mg) with sucralfate (1 gram) resulted in delayed absorption|
02977|020|D|of lansoprazole and a 17% reduction in lansoprazole's bioavailability.(1)|
02977|021|B||
02977|022|R|REFERENCE:|
02977|023|B||
02977|024|R|1.Prevacid (lansoprazole) US prescribing information. Takeda Pharmaceuticals|1
02977|025|R|  America, Inc. June, 2018.|1
02978|001|T|MONOGRAPH TITLE:  Slt Proton Pump Inhibitors/Strong 2C19 and 3A4 Inducers|
02978|002|B||
02978|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02978|004|L|of severe adverse interaction.|
02978|005|B||
02978|006|A|MECHANISM OF ACTION:  Strong CYP2C19 and CYP3A4 inducers may induce the|
02978|007|A|metabolism of dexlansoprazole, lansoprazole, or pantoprazole.(1-3)|
02978|008|B||
02978|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2C19 and CYP3A4 inducers may|
02978|010|E|decrease systemic levels and effectiveness of lansoprazole, dexlansoprazole,|
02978|011|E|or pantoprazole.(1)|
02978|012|B||
02978|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
02978|014|P|of the inducer for longer than 1-2 weeks.|
02978|015|B||
02978|016|M|PATIENT MANAGEMENT:  The manufacturers of lansoprazole and dexlansoprazole|
02978|017|M|recommend avoiding concurrent use of CYP2C19 or CYP3A4 inducers.(1,2)|
02978|018|M|Although the manufacturer of pantoprazole does not mention an interaction|
02978|019|M|with CYP2C19 inducers, pantoprazole is also a substrate of CYP2C19 and|
02978|020|M|CYP3A4.(3)|
02978|021|M|   If concurrent therapy is warranted, monitor closely for loss of efficacy.|
02978|022|M|Although specific dosing recommendations are not available, a higher dose|
02978|023|M|of the proton pump inhibitor may be considered to maintain PPI efficacy.|
02978|024|B||
02978|025|D|DISCUSSION:  Decreased exposure of lansoprazole, dexlansoprazole, or|
02978|026|D|pantoprazole is expected when used concomitantly with strong CYP2C19 and|
02978|027|D|CYP3A4 inducers.|
02978|028|D|   Strong CYP2C19 and CYP3A4 inducers linked to this monograph include:|
02978|029|D|apalutamide, efavirenz, enzalutamide, fosphenytoin, phenytoin, rifampin, and|
02978|030|D|St. John's Wort.(4,5)|
02978|031|B||
02978|032|R|REFERENCES:|
02978|033|B||
02978|034|R|1.Prevacid (lansoprazole) US prescribing information. Takeda Pharmaceuticals|1
02978|035|R|  America, Inc. June, 2018.|1
02978|036|R|2.Dexilant (dexlansoprazole) US prescribing information. Takeda|1
02978|037|R|  Pharmaceuticals North America, Inc. October, 2017.|1
02978|038|R|3.Protonix (pantoprazole sodium) US prescribing information. Wyeth|1
02978|039|R|  Pharmaceuticals, Inc. August, 2024.|1
02978|040|R|4.This information is based on an extract from the Certara Drug Interaction|6
02978|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02978|042|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
02978|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02978|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02978|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02978|046|R|  11/14/2017.|1
02979|001|T|MONOGRAPH TITLE:  Lutetium Lu 177 dotatate/Short-Acting Somatostatin Analogs|
02979|002|B||
02979|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02979|004|L|of severe adverse interaction.|
02979|005|B||
02979|006|A|MECHANISM OF ACTION:  Somatostatin and somatostatin analogs bind to|
02979|007|A|somatostatin receptors and may interfere with the efficacy of lutetium lu|
02979|008|A|177 dotatate.(1)|
02979|009|B||
02979|010|E|CLINICAL EFFECTS:  Concurrent administration of lutetium lu 177 dotatate and|
02979|011|E|somatostatin analogs may decrease the efficacy of lutetium lu 177|
02979|012|E|dotatate.(1)|
02979|013|B||
02979|014|P|PREDISPOSING FACTORS:  None determined.|
02979|015|B||
02979|016|M|PATIENT MANAGEMENT:  The manufacturer of lutetium lu 177 dotatate recommends|
02979|017|M|the following:|
02979|018|M|   - Before initiating lutetium lu 177 dotatate, discontinue long-acting|
02979|019|M|somatostatin analogs for at least 4 weeks prior to initiation.  Administer|
02979|020|M|short-acting somatostatin analogs as needed; discontinue at least 24 hours|
02979|021|M|prior to initiation of lutetium lu 177 dotatate.|
02979|022|M|   - During lutetium lu 177 dotatate treatment, administer long-acting|
02979|023|M|octreotide 30 mg intramuscularly between 4 and 24 hours after each lutetium|
02979|024|M|lu 177 dotatate dose.  Do not administer long-acting octreotide within 4|
02979|025|M|weeks of each subsequent lutetium lu 177 dotatate dose.  Short-acting|
02979|026|M|octreotide may be given for symptomatic management during lutetium lu 177|
02979|027|M|dotatate treatment, but must be withheld for at least 24 hours before each|
02979|028|M|lutetium lu 177 dotatate dose.|
02979|029|M|   - Following lutetium lu 177 dotatate treatment, continue long-acting|
02979|030|M|octreotide 30 mg intramuscularly every 4 weeks after completing lutetium lu|
02979|031|M|177 dotatate until disease progression or for up to 18 months following|
02979|032|M|treatment initiation.(1)|
02979|033|B||
02979|034|D|DISCUSSION:  Somatostatin and somatostatin analogs bind to somatostatin|
02979|035|D|receptors and may interfere with the efficacy of lutetium lu 177|
02979|036|D|dotatate.(1)|
02979|037|B||
02979|038|R|REFERENCE:|
02979|039|B||
02979|040|R|1.Lutathera (lutetium Lu 177 dotatate) US prescribing information. Advanced|1
02979|041|R|  Accelerator Applications USA, Inc. May, 2020.|1
02980|001|T|MONOGRAPH TITLE:  Lutetium Lu 177 dotatate/Long-Acting Somatostatin Analogs|
02980|002|B||
02980|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02980|004|L|of severe adverse interaction.|
02980|005|B||
02980|006|A|MECHANISM OF ACTION:  Somatostatin and somatostatin analogs bind to|
02980|007|A|somatostatin receptors and may interfere with the efficacy of lutetium lu|
02980|008|A|177 dotatate.(1)|
02980|009|B||
02980|010|E|CLINICAL EFFECTS:  Concurrent administration of lutetium lu 177 dotatate and|
02980|011|E|somatostatin analogs may decrease the efficacy of lutetium lu 177|
02980|012|E|dotatate.(1)|
02980|013|B||
02980|014|P|PREDISPOSING FACTORS:  None determined.|
02980|015|B||
02980|016|M|PATIENT MANAGEMENT:  The manufacturer of lutetium lu 177 dotatate recommends|
02980|017|M|the following:|
02980|018|M|   - Before initiating lutetium lu 177 dotatate, discontinue long-acting|
02980|019|M|somatostatin analogs for at least 4 weeks prior to initiation.  Administer|
02980|020|M|short-acting somatostatin analogs as needed; discontinue at least 24 hours|
02980|021|M|prior to initiation of lutetium lu 177 dotatate.|
02980|022|M|   - During lutetium lu 177 dotatate treatment, administer long-acting|
02980|023|M|octreotide 30 mg intramuscularly between 4 and 24 hours after each lutetium|
02980|024|M|lu 177 dotatate dose.  Do not administer long-acting octreotide within 4|
02980|025|M|weeks of each subsequent lutetium lu 177 dotatate dose.  Short-acting|
02980|026|M|octreotide may be given for symptomatic management during lutetium lu 177|
02980|027|M|dotatate treatment, but must be withheld for at least 24 hours before each|
02980|028|M|lutetium lu 177 dotatate dose.|
02980|029|M|   - Following lutetium lu 177 dotatate treatment, continue long-acting|
02980|030|M|octreotide 30 mg intramuscularly every 4 weeks after completing lutetium lu|
02980|031|M|177 dotatate until disease progression or for up to 18 months following|
02980|032|M|treatment initiation.(1)|
02980|033|B||
02980|034|D|DISCUSSION:  Somatostatin and somatostatin analogs bind to somatostatin|
02980|035|D|receptors and may interfere with the efficacy of lutetium lu 177|
02980|036|D|dotatate.(1)|
02980|037|B||
02980|038|R|REFERENCE:|
02980|039|B||
02980|040|R|1.Lutathera (lutetium Lu 177 dotatate) US prescribing information. Advanced|1
02980|041|R|  Accelerator Applications USA, Inc. May, 2020.|1
02981|001|T|MONOGRAPH TITLE:  Abiraterone/Radium Ra 223|
02981|002|B||
02981|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02981|004|L|is contraindicated and generally should not be dispensed or administered to|
02981|005|L|the same patient.|
02981|006|B||
02981|007|A|MECHANISM OF ACTION:  The mechanism of this interaction is not known.|
02981|008|B||
02981|009|E|CLINICAL EFFECTS:  Concurrent use of radium Ra 223 dichloride with|
02981|010|E|abiraterone and prednisolone, prednisone, or methylprednisolone may increase|
02981|011|E|the risk of mortality and fractures.(1-4)|
02981|012|B||
02981|013|P|PREDISPOSING FACTORS:  None determined.|
02981|014|B||
02981|015|M|PATIENT MANAGEMENT:  The European Medicines Agency (EMA) states that the use|
02981|016|M|of radium Ra 223 with abiraterone and prednisone/prednisolone is|
02981|017|M|contraindicated.  Radium Ra 223 is not recommended to be initiated in the|
02981|018|M|first 5 days following the last dose of abiraterone and|
02981|019|M|prednisone/prednisolone.(2,5)|
02981|020|M|   The US manufacturers of radium Ra 223 and abiraterone state that radium|
02981|021|M|Ra 223 is not recommended for use in combination with abiraterone and|
02981|022|M|prednisone/prednisolone or methylprednisolone outside of clinical|
02981|023|M|trials.(3,4)|
02981|024|M|   Monitor patients for fractures.|
02981|025|B||
02981|026|D|DISCUSSION:  In the ERA 223 trial, a randomized, double-blind,|
02981|027|D|placebo-controlled trial of 806 patients with castration-resistant prostate|
02981|028|D|cancer with bone metastasis, treatment with abiraterone and|
02981|029|D|prednisone/prednisolone plus radium Ra 223 was associated with increased|
02981|030|D|incidences of fractures and deaths (28.6% and 38.5%, respectively), compared|
02981|031|D|to treatment with abiraterone and prednisone/prednisolone plus placebo|
02981|032|D|(11.4% and 35.5%, respectively).(6)|
02981|033|B||
02981|034|R|REFERENCES:|
02981|035|B||
02981|036|R|1.Mirski D. Dear Healthcare Professional letter: Important safety|1
02981|037|R|  information update regarding increased incidence of deaths and fractures|1
02981|038|R|  in an investigational Phase III clinical trial with Xofio used in|1
02981|039|R|  combination with abiraterone and prednisolone-prednisone. Bayer Healthcare|1
02981|040|R|  Pharmaceuticals, Inc. November 30, 2017.|1
02981|041|R|2.European Medicines Agency. Prostate cancer medicine Xofigo must not be|1
02981|042|R|  used with Zytiga and prednisone/prednisolone. EMA/146483/2018 March 9,|1
02981|043|R|  2018.|1
02981|044|R|3.Xofigo (radium Ra 223 dichloride) US prescribing information. Bayer|1
02981|045|R|  HealthCare Pharmaceuticals Inc. December, 2019.|1
02981|046|R|4.Yonsa (abiraterone) US prescribing information. Sun Pharma Global FZE|1
02981|047|R|  March, 2022.|1
02981|048|R|5.Xofigo (radium Ra 223 dichloride) UK summary of product characteristics.|1
02981|049|R|  Bayer AG October 17, 2018.|1
02981|050|R|6.Smith M, Parker C, Saad F, Miller K, Tombal B, Ng QS, Boegemann M, Matveev|2
02981|051|R|  V, Piulats JM, Zucca LE, Karyakin O, Kimura G, Matsubara N, Nahas WC, Nole|2
02981|052|R|  F. Addition of radium-223 to abiraterone acetate and prednisone or|2
02981|053|R|  prednisolone in  patients with castration-resistant prostate cancer and|2
02981|054|R|  bone metastases (ERA 223): a  randomised, double-blind,|2
02981|055|R|  placebo-controlled, phase 3 trial. Lancet Oncol 2019 Mar;20(3):408-419.|2
02983|001|T|MONOGRAPH TITLE:  Diazepam/Cobicistat|
02983|002|B||
02983|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02983|004|L|take action as needed.|
02983|005|B||
02983|006|A|MECHANISM OF ACTION:  Cobicistat may inhibit the metabolism of diazepam by|
02983|007|A|CYP3A4.(1-6)|
02983|008|B||
02983|009|E|CLINICAL EFFECTS:  Inhibition of diazepam metabolism by CYP3A4 may produce|
02983|010|E|increased levels of, as well as increased clinical effects, of diazepam.|
02983|011|E|Toxic effects of increased diazepam levels include profound sedation,|
02983|012|E|respiratory depression, coma, and/or death.|
02983|013|B||
02983|014|P|PREDISPOSING FACTORS:  None determined.|
02983|015|B||
02983|016|M|PATIENT MANAGEMENT:  The US manufacturer of|
02983|017|M|elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide states|
02983|018|M|concurrent administration with diazepam should be done in a setting that|
02983|019|M|ensures close clinical monitoring and appropriate medical management in the|
02983|020|M|case of respiratory depression and/or prolonged sedation.(1)|
02983|021|M|   The US manufacturer of darunavir/cobicistat states titration of diazepam|
02983|022|M|is recommended and a lower dose of diazepam should be considered with|
02983|023|M|monitoring for increased and prolonged effects or adverse reactions.(2)|
02983|024|M|   The US manufacturers of atazanavir/cobicistat(3), cobicistat(4), and|
02983|025|M|elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate(5) state|
02983|026|M|dose reduction of diazepam may be necessary and clinical monitoring is|
02983|027|M|recommended.|
02983|028|M|   Monitor patients receiving concurrent therapy with cobicistat and|
02983|029|M|diazepam carefully for increased effects including unusual dizziness or|
02983|030|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02983|031|M|unresponsiveness.|
02983|032|B||
02983|033|D|DISCUSSION:  Cobicistat is a strong CYP3A4 inhibitor.(1-5)|
02983|034|D|   Diazepam is a substrate of CYP3A4 and use with inhibitors of this pathway|
02983|035|D|may lead to increased and prolonged sedation.(6)|
02983|036|B||
02983|037|R|REFERENCES:|
02983|038|B||
02983|039|R|1.Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02983|040|R|  prescribing information. Gilead Sciences, Inc September, 2021.|1
02983|041|R|2.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
02983|042|R|  Pharmaceuticals, Inc. March, 2025.|1
02983|043|R|3.Evotaz (atazanavir and cobicistat) US prescribing information.|1
02983|044|R|  Bristol-Myers-Squibb Company May, 2025.|1
02983|045|R|4.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
02983|046|R|  June, 2025.|1
02983|047|R|5.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
02983|048|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
02983|049|R|6.Valium (diazepam) US prescribing information. Roche Products Inc December,|1
02983|050|R|  2016.|1
02984|001|T|MONOGRAPH TITLE:  Dolutegravir-Rilpivirine/Selected Oral Cations; Antacids;|
02984|002|T|H2 Antagonists|
02984|003|B||
02984|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02984|005|L|take action as needed.|
02984|006|B||
02984|007|A|MECHANISM OF ACTION:  Aluminum, calcium, iron, lanthanum, magnesium,|
02984|008|A|sucralfate, and zinc may form chelation compounds with dolutegravir.(1)|
02984|009|A|   Rilpivirine requires an acidic medium for absorption. Antacid or H2|
02984|010|A|antagonist induced decrease in gastric pH may result in decrease in|
02984|011|A|rilpivirine absorption.(1)|
02984|012|B||
02984|013|E|CLINICAL EFFECTS:  Simultaneous administration or administration of products|
02984|014|E|containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate|
02984|015|E|close to the administration time of dolutegravir may result in decreased|
02984|016|E|absorption and clinical effectiveness of dolutegravir.(1)|
02984|017|E|   Simultaneous administration of an antacid or a H2 antagonist may result|
02984|018|E|in decreased levels and effectiveness of rilpivirine, as well as the|
02984|019|E|development of resistance.(1)|
02984|020|B||
02984|021|P|PREDISPOSING FACTORS:  None determined.|
02984|022|B||
02984|023|M|PATIENT MANAGEMENT:  If possible, avoid concurrent therapy with|
02984|024|M|dolutegravir-rilpivirine and cation-containing products.  If it is necessary|
02984|025|M|to use these agents concurrently, dolutegravir-rilpivirine should be|
02984|026|M|administered 4 hours before or 6 hours after taking these medications.(1)|
02984|027|M|   Alternatively, dolutegravir-rilpivirine and supplements containing|
02984|028|M|calcium or iron can be taken together with food.(1)|
02984|029|M|   In patients maintained on dolutegravir-rilpivirine, administer|
02984|030|M|dolutegravir-rilpivirine at least 4 hours before or 6 hours after antacids|
02984|031|M|.(1)|
02984|032|M|   In patients maintained on dolutegravir-rilpivirine, administer|
02984|033|M|dolutegravir-rilpivirine at least 4 hours before or 12 hours after H2|
02984|034|M|antagonists.(1)|
02984|035|M|   Concurrent use of proton pump inhibitors will dolutegravir-rilpivirine is|
02984|036|M|contraindicated.(1)|
02984|037|B||
02984|038|D|DISCUSSION:  In a study in 16 subjects, the administration of an antacid|
02984|039|D|(Maalox - aluminum and magnesium hydroxide) simultaneously with dolutegravir|
02984|040|D|(50 mg single dose) decreased the maximum concentration (Cmax),|
02984|041|D|area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by|
02984|042|D|72%, 74%, and 74%, respectively.(1)|
02984|043|D|   In a study in 16 subjects, the administration of an antacid (Maalox -|
02984|044|D|aluminum and magnesium hydroxide) 2 hours after dolutegravir (50 mg single|
02984|045|D|dose) decreased dolutegravir Cmax, AUC, and Cmin by 18%, 26%, and 30%,|
02984|046|D|respectively.(1)|
02984|047|D|   In a study in 16 subjects, the administration of a multiple vitamin|
02984|048|D|(One-A-Day) simultaneously with dolutegravir (50 mg single dose) decreased|
02984|049|D|dolutegravir Cmax, AUC, and Cmin by 35%, 33%, and 32%, respectively.(1)|
02984|050|D|   In a study in 16 subjects, omeprazole (20 mg daily) decreased the Cmax,|
02984|051|D|AUC, and Cmin of rilpivirine (150 mg daily) by 40%, 40%, and 33%,|
02984|052|D|respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%,|
02984|053|D|respectively.(1)|
02984|054|D|   In a study in 24 subjects, famotidine (40 mg single dose) administered 12|
02984|055|D|hours before a single dose of rilpivirine (150 mg) had no significant effect|
02984|056|D|on rilpivirine Cmax or AUC.(1)|
02984|057|D|   In a study in 23 subjects, famotidine (40 mg single dose) administered 2|
02984|058|D|hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine|
02984|059|D|Cmax and AUC by 85% and 76%, respectively.(1)|
02984|060|D|   In a study in 24 subjects, famotidine (40 mg single dose) administered 4|
02984|061|D|hours before a single dose of rilpivirine (150 mg) increased the rilpivirine|
02984|062|D|Cmax and AUC by 21% and 13%, respectively.(1)|
02984|063|B||
02984|064|R|REFERENCE:|
02984|065|B||
02984|066|R|1.Juluca (dolutegravir-rilpivirine)  US prescribing information. Viiv|1
02984|067|R|  Healthcare October, 2022.|1
02985|001|T|MONOGRAPH TITLE:  Cabergoline/Moderate CYP3A4 Inhibitors|
02985|002|B||
02985|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02985|004|L|take action as needed.|
02985|005|B||
02985|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
02985|007|A|of cabergoline.|
02985|008|B||
02985|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
02985|010|E|in increased levels of cabergoline, which may result in increased side|
02985|011|E|effects of cabergoline.|
02985|012|B||
02985|013|P|PREDISPOSING FACTORS:  Patients receiving the maximum recommended (or higher|
02985|014|P|than recommended) dosages of cabergoline may be at a higher risk of adverse|
02985|015|P|effects from this combination.|
02985|016|B||
02985|017|M|PATIENT MANAGEMENT:  Use caution with concurrent therapy with cabergoline|
02985|018|M|and moderate CYP3A4 inhibitors.|
02985|019|B||
02985|020|D|DISCUSSION:  Cabergoline metabolism has been shown to be inhibited by strong|
02985|021|D|CYP3A4 inhibitors, including macrolides and itraconazole.(1,2)  Inhibition|
02985|022|D|of cabergoline metabolism by moderate inhibitors would also be expected, but|
02985|023|D|to a lesser degree.|
02985|024|D|   Moderate CYP3A4 inhibitors linked to this monograph are aprepitant,|
02985|025|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem,|
02985|026|D|dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant,|
02985|027|D|imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
02985|028|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and|
02985|029|D|verapamil.(3,4)|
02985|030|B||
02985|031|R|REFERENCES:|
02985|032|B||
02985|033|R|1.Dostinex (cabergoline) UK summary of product characteristics. Pfizer|1
02985|034|R|  Limited April, 2016.|1
02985|035|R|2.Christensen J, Dupont E, OStergaard K. Cabergoline plasma concentration is|3
02985|036|R|  increased during concomitant treatment with itraconazole. Mov Disord 2002|3
02985|037|R|  Nov;17(6):1360-2.|3
02985|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
02985|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02985|040|R|4.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
02985|041|R|  March, 2007.|1
02986|001|T|MONOGRAPH TITLE:  Dasatinib; Pazopanib/H2 Antagonists|
02986|002|B||
02986|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02986|004|L|of severe adverse interaction.|
02986|005|B||
02986|006|A|MECHANISM OF ACTION:  The solubility of dasatinib(1) and pazopanib(2) is pH|
02986|007|A|dependent.  Changes in gastric pH from H2 antagonists may decrease the|
02986|008|A|absorption of dasatinib(1) and pazopanib.(2)|
02986|009|B||
02986|010|E|CLINICAL EFFECTS:  Use of H2 antagonists may result in decreased levels and|
02986|011|E|effectiveness of dasatinib(1) and pazopanib.(2)|
02986|012|B||
02986|013|P|PREDISPOSING FACTORS:  None determined.|
02986|014|B||
02986|015|M|PATIENT MANAGEMENT:  Avoid the use of H2-antagonists and proton pump|
02986|016|M|inhibitors (PPIs) in patients receiving treatment with dasatinib(1) or|
02986|017|M|pazopanib.(2)  Consider the use of short-acting antacids in these|
02986|018|M|patients.(1)|
02986|019|M|   If antacids are used, separate the administration times by at least two|
02986|020|M|hours for dasatinib(1) and several hours for pazopanib.(2)|
02986|021|M|   The manufacturer of Phyrago states that it can be administered with|
02986|022|M|gastric acid reducing agents. Administration times should be separated with|
02986|023|M|antacids.(3)|
02986|024|B||
02986|025|D|DISCUSSION:  In a study in 24 healthy subjects, administration of a single|
02986|026|D|dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib|
02986|027|D|area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%,|
02986|028|D|respectively.(1)|
02986|029|D|   In a study in 14 healthy subjects, administration of a single dose of|
02986|030|D|dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state)|
02986|031|D|decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(1)|
02986|032|D|   In a study in 24 healthy subjects, simultaneous administration of|
02986|033|D|dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml)|
02986|034|D|decreased dasatinib AUC and Cmax by 55% and 58%, respectively.  In the same|
02986|035|D|subjects, administration of the antacid 2 hours before dasatinib decreased|
02986|036|D|dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(1)|
02986|037|D|   In a study in 13 patients, esomeprazole (40 mg daily for 5 days)|
02986|038|D|decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%,|
02986|039|D|respectively, when compared to the administration of pazopanib alone.(2)|
02986|040|D|   Phyrago is not sensitive to increased gastric pH due to its polymer|
02986|041|D|formulation. No clinically significant pharmacokinetic changes were seen|
02986|042|D|with concurrent administration of Phyrago with omeprazole (proton pump|
02986|043|D|inhibitor) or famotidine (H2 receptor antagonist).(3)|
02986|044|B||
02986|045|R|REFERENCES:|
02986|046|B||
02986|047|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
02986|048|R|  Company February, 2023.|1
02986|049|R|2.Votrient (pazopanib) US prescribing information. GlaxoSmithKline October,|1
02986|050|R|  2009.|1
02986|051|R|3.Phyrago (dasatinib) US Prescribing Information. Nanocopoeia, LLC December|1
02986|052|R|  2024.|1
02987|001|T|MONOGRAPH TITLE:  Nadolol/Itraconazole|
02987|002|B||
02987|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02987|004|L|take action as needed.|
02987|005|B||
02987|006|A|MECHANISM OF ACTION:  Nadolol is a substrate of P-glycoprotein.|
02987|007|A|Itraconazole is a P-glycoprotein inhibitor.|
02987|008|B||
02987|009|E|CLINICAL EFFECTS:  Concomitant use of nadolol with itraconazole may increase|
02987|010|E|the concentration of nadolol resulting in hypotension and excessive|
02987|011|E|bradycardia.(1)|
02987|012|B||
02987|013|P|PREDISPOSING FACTORS:  None determined.|
02987|014|B||
02987|015|M|PATIENT MANAGEMENT:  Patients receiving this combination should be monitored|
02987|016|M|for adverse effects, such as hypotension and bradycardia. A reduction in|
02987|017|M|nadolol dose may be necessary.(1)|
02987|018|M|   Monitor blood pressure and heart rate.|
02987|019|M|   Symptoms of low blood pressure include dizziness, weakness, irregular|
02987|020|M|heartbeat, nausea, dizziness, confusion, and slurred speech.|
02987|021|B||
02987|022|D|DISCUSSION:  In an open label, four-way crossover study in 10 healthy|
02987|023|D|subjects, concurrent use of nadolol (single 30 mg dose) and itraconazole|
02987|024|D|(100 mg), increased the maximum concentration (Cmax) and area-under-curve|
02987|025|D|(AUC) of nadolol by 468% and 224%, respectively.  Nadolol reduce|
02987|026|D|pharmacodynamic parameters to a greater extent during the itraconazole|
02987|027|D|phase.(2)|
02987|028|D|   In an animal study, pretreatment with itraconazole (50 mg/kg) for 30|
02987|029|D|minutes before oral administration of nadolol (10 mg/kg) significantly|
02987|030|D|increased nadolol's Cmax and AUC by 1.7-fold and 1.7-fold, respectively.(3)|
02987|031|B||
02987|032|R|REFERENCES:|
02987|033|B||
02987|034|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
02987|035|R|  Products, L.P. February, 2024.|1
02987|036|R|2.Misaka S, Miyazaki N, Yatabe MS, Ono T, Shikama Y, Fukushima T, Kimura J.|2
02987|037|R|  Pharmacokinetic and pharmacodynamic interaction of nadolol with|2
02987|038|R|  itraconazole, rifampicin and grapefruit juice in healthy volunteers. J|2
02987|039|R|  Clin Pharmacol 2013 Jul;53(7):738-45.|2
02987|040|R|3.Miyazaki N, Misaka S, Ogata H, Fukushima T, Kimura J. Effects of|5
02987|041|R|  itraconazole, dexamethasone and naringin on the pharmacokinetics of|5
02987|042|R|  nadolol in rats. Drug Metab Pharmacokinet 2013;28(4):356-61.|5
02988|001|T|MONOGRAPH TITLE:  Obeticholic acid/Cyclosporine|
02988|002|B||
02988|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02988|004|L|of severe adverse interaction.|
02988|005|B||
02988|006|A|MECHANISM OF ACTION:  Inhibitors of the bile salt efflux pump (BSEP) may|
02988|007|A|inhibit the secretion of the taurine conjugate of obeticholic acid into|
02988|008|A|bile.(1)|
02988|009|B||
02988|010|E|CLINICAL EFFECTS:  Concurrent administration of a obeticholic acid and|
02988|011|E|cyclosporine may result in accumulation of conjugated bile salts and result|
02988|012|E|in clinical symptoms.(1)|
02988|013|B||
02988|014|P|PREDISPOSING FACTORS:  None determined.|
02988|015|B||
02988|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of obeticholic acid and|
02988|017|M|inhibitors of the bile salt efflux pump (BSEP), such as cyclosporine.  If|
02988|018|M|concomitant use is deemed necessary, monitor serum transaminases and|
02988|019|M|bilirubin.(1)|
02988|020|B||
02988|021|D|DISCUSSION:  In vitro studies have shown the taurine conjugate of|
02988|022|D|obeticholic acid is a substrate of the bile salt efflux pump (BSEP).|
02988|023|D|Concomitant use of medications that inhibit BSEP may exacerbate accumulation|
02988|024|D|of conjugated bile salts and result in clinical symptoms.(1)|
02988|025|D|   Cyclosporine in an inhibitor of BSEP.(1)|
02988|026|B||
02988|027|R|REFERENCE:|
02988|028|B||
02988|029|R|1.Ocaliva (obeticholic acid) US prescribing information. Intercept|1
02988|030|R|  Pharmaceuticals Inc. January, 2018.|1
02989|001|T|MONOGRAPH TITLE:  Dofetilide/Bictegravir|
02989|002|B||
02989|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02989|004|L|is contraindicated and generally should not be dispensed or administered to|
02989|005|L|the same patient.|
02989|006|B||
02989|007|A|MECHANISM OF ACTION:  Dofetilide is primarily excreted in the urine via both|
02989|008|A|glomerular filtration and active tubular secretion via the cation transport|
02989|009|A|system.  Bictegravir is believed to inhibit the cation transport system|
02989|010|A|(OCT2) and thus may inhibit the active tubular secretion of dofetilide.(1)|
02989|011|B||
02989|012|E|CLINICAL EFFECTS:  The concurrent administration of dofetilide with|
02989|013|E|bictegravir may result in elevated levels and increased effects of|
02989|014|E|dofetilide, including torsades de pointes.(1)|
02989|015|B||
02989|016|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
02989|017|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
02989|018|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
02989|019|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
02989|020|P|   The risk of QT prolongation or torsades de pointes may be increased in|
02989|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
02989|022|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
02989|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
02989|024|P|advanced age.(2)|
02989|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
02989|026|P|higher systemic concentrations of either QT prolonging drug are additional|
02989|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
02989|028|P|drug concentrations include rapid infusion of an intravenous dose or|
02989|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
02989|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
02989|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
02989|032|B||
02989|033|M|PATIENT MANAGEMENT:  The manufacturer of bictegravir states that the|
02989|034|M|concurrent administration of dofetilide with bictegravir is contraindicated.|
02989|035|M|If dofetilide is to be discontinued, a washout of at least 2 days is|
02989|036|M|recommended prior to starting bictegravir.(1)|
02989|037|M|   If alternatives are not available and concurrent therapy is deemed|
02989|038|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
02989|039|M|and monitor ECG at baseline and at regular intervals.  Correct any|
02989|040|M|electrolyte abnormalities.  Instruct patients to report any irregular|
02989|041|M|heartbeat, dizziness, or fainting.|
02989|042|B||
02989|043|D|DISCUSSION:  The concurrent administration of dofetilide and bictegravir is|
02989|044|D|expected to increase dofetilide plasma concentrations.  Bictegravir is an|
02989|045|D|inhibitor of organic cation transporter 2 (OCT2) and multidrug and toxin|
02989|046|D|extrusion transporter 1 (MATE1) in vitro.(1)|
02989|047|B||
02989|048|R|REFERENCES:|
02989|049|B||
02989|050|R|1.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
02989|051|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
02989|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
02989|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
02989|054|R|  settings: a scientific statement from the American Heart Association and|6
02989|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
02989|056|R|  2;55(9):934-47.|6
02990|001|T|MONOGRAPH TITLE:  Bictegravir/Rifampin|
02990|002|B||
02990|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
02990|004|L|is contraindicated and generally should not be dispensed or administered to|
02990|005|L|the same patient.|
02990|006|B||
02990|007|A|MECHANISM OF ACTION:  Rifampin may induce the metabolism of bictegravir via|
02990|008|A|CYP3A4 and UGT1A1.(1)|
02990|009|B||
02990|010|E|CLINICAL EFFECTS:  The concurrent use of bictegravir and rifampin may lead|
02990|011|E|to decreased levels of bictegravir, which may result in the loss of|
02990|012|E|therapeutic effect and development of resistance to bictegravir.(1)|
02990|013|B||
02990|014|P|PREDISPOSING FACTORS:  None determined.|
02990|015|B||
02990|016|M|PATIENT MANAGEMENT:  Concurrent use of bictegravir and rifampin is|
02990|017|M|contraindicated.(1)|
02990|018|B||
02990|019|D|DISCUSSION:  In a single dose study, rifampin decreased the maximum|
02990|020|D|concentration (Cmax) and area-under-curve (AUC) levels of bictegravir by 28%|
02990|021|D|and 75%, respectively.(1)|
02990|022|B||
02990|023|R|REFERENCE:|
02990|024|B||
02990|025|R|1.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
02990|026|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
02991|001|T|MONOGRAPH TITLE:  Metformin/Bictegravir|
02991|002|B||
02991|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02991|004|L|take action as needed.|
02991|005|B||
02991|006|A|MECHANISM OF ACTION:  Metformin renal clearance is mediated by OCT2 and|
02991|007|A|MATE1 transport.  Bictegravir inhibits elimination by these pathways.(1,2)|
02991|008|B||
02991|009|E|CLINICAL EFFECTS:  Use of bictegravir may increase levels of metformin,|
02991|010|E|which may result in lactic acidosis.|
02991|011|B||
02991|012|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
02991|013|P|include renal impairment,sepsis, dehydration, excessive alcohol intake,|
02991|014|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
02991|015|P|failure, metformin plasma levels > 5 micrograms/mL, and conditions which may|
02991|016|P|lead to tissue hypoxia.  Geriatric patients may also be at higher risk due|
02991|017|P|to slower metformin clearance and increased half-life in this population.|
02991|018|B||
02991|019|M|PATIENT MANAGEMENT:  The US labeling for metformin recommends the dose of|
02991|020|M|metformin be adjusted as needed.(1)|
02991|021|M|   Evaluate patient's renal function and consider discontinuation of one or|
02991|022|M|both agents in patients with renal impairment.|
02991|023|M|   Monitor for signs and symptoms of metformin toxicity (lactic acidosis)|
02991|024|M|such as malaise, myalgias, increasing somnolence, and respiratory distress.|
02991|025|M|Laboratory results which may signal lactic acidosis include: elevated blood|
02991|026|M|lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and|
02991|027|M|increased lactate to pyruvate ratio.|
02991|028|B||
02991|029|D|DISCUSSION:  Bictegravir is an inhibitor of OCT2 and MATE1.(2)|
02991|030|D|   Trimethoprim, an inhibitor of OCT2 and MATE1, was found to cause|
02991|031|D|significant inhibition of net transcellular chloroquine transport in canine|
02991|032|D|kidney-OCT2-MATE1 cells.  Chloroquine is eliminated by renal tubular|
02991|033|D|secretion involving multidrug and toxin extrusion protein 1 (MATE1).|
02991|034|D|Trimethoprim caused concentration-dependent inhibition of net metformin|
02991|035|D|intake in HEK293-MATE1 cells (human embryonic kidney).(3)|
02991|036|D|   A randomized, open-label, two-phase crossover study found that|
02991|037|D|trimethoprim inhibited OCT2, MATE1, and MATE2-K-dependent transport of|
02991|038|D|metformin.  Trimethoprim increased metformin area-under-curve (AUC) by 29.4%|
02991|039|D|and decreased metformin renal clearance by 26.4%.(4)|
02991|040|D|   In a study in 24 healthy volunteers received metformin 500 mg three times|
02991|041|D|daily for ten days and trimethoprim 200 mg twice daily from days 5-10.|
02991|042|D|Trimethoprim significantly reduced the apparent systemic metformin clearance|
02991|043|D|(CL/F) from 74 to 54 l/h and renal metformin clearance from 31 to 21 l/h.|
02991|044|D|Metformin half-life was prolonged from 2.7 to 3.6h.  The metformin plasma|
02991|045|D|concentration (Cmax) increased 38% and the AUC by 37%.  Trimethoprim was|
02991|046|D|also associated with a decrease in creatinine clearance and an increase in|
02991|047|D|plasma lactate. (5)|
02991|048|B||
02991|049|R|REFERENCES:|
02991|050|B||
02991|051|R|1.Glucophage (metformin hydrochloride) US prescribing information.|1
02991|052|R|  Bristol-Myers Squibb Company May, 2018.|1
02991|053|R|2.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
02991|054|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
02991|055|R|3.Muller F, Konig J, Glaeser H, Schmidt I, Zolk O, Fromm MF, Maas R.|2
02991|056|R|  Molecular mechanism of renal tubular secretion of the antimalarial drug|2
02991|057|R|  chloroquine. Antimicrob Agents Chemother 2011 Jul;55(7):3091-8.|2
02991|058|R|4.Muller F, Pontones CA, Renner B, Mieth M, Hoier E, Auge D, Maas R, Zolk O,|2
02991|059|R|  Fromm MF. N(1)-methylnicotinamide as an endogenous probe for drug|2
02991|060|R|  interactions by renal cation transporters: studies on the|2
02991|061|R|  metformin-trimethoprim interaction. Eur J Clin Pharmacol 2015 Jan;|2
02991|062|R|  71(1):85-94.|2
02991|063|R|5.Grun B, Kiessling MK, Burhenne J, Riedel KD, Weiss J, Rauch G, Haefeli WE,|2
02991|064|R|  Czock D. Trimethoprim-metformin interaction and its genetic modulation by|2
02991|065|R|  OCT2 and MATE1 transporters. Br J Clin Pharmacol 2013 Nov;76(5):787-96.|2
02991|066|R|6.Vecchio S, Giampreti A, Petrolini VM, Lonati D, Protti A, Papa P, Rognoni|2
02991|067|R|  C, Valli A, Rocchi L, Rolandi L, Manzo L, Locatelli CA. Metformin|2
02991|068|R|  accumulation: lactic acidosis and high plasmatic metformin levels in a|2
02991|069|R|  retrospective case series of 66 patients on chronic therapy. Clin Toxicol|2
02991|070|R|  (Phila) 2014 Feb;52(2):129-35.|2
02992|001|T|MONOGRAPH TITLE:  Bictegravir/Polyvalent Cations; Sucralfate|
02992|002|B||
02992|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02992|004|L|take action as needed.|
02992|005|B||
02992|006|A|MECHANISM OF ACTION:  Polyvalent cations and sucralfate may bind to|
02992|007|A|bictegravir in the GI tract, preventing its absorption.(1)|
02992|008|B||
02992|009|E|CLINICAL EFFECTS:  Polyvalent cations and sucralfate may reduce levels and|
02992|010|E|clinical effectiveness of bictegravir.(1)|
02992|011|B||
02992|012|P|PREDISPOSING FACTORS:  None determined.|
02992|013|B||
02992|014|M|PATIENT MANAGEMENT:  Bictegravir must be taken 2 hours before or 6 hours|
02992|015|M|after polyvalent cations or sucralfate.  Medicines containing calcium can be|
02992|016|M|taken together with bictegravir if taken with food.(1)|
02992|017|M|   Some vitamin preparations may contain sufficient quantities of polyvalent|
02992|018|M|cations to interact as well.|
02992|019|B||
02992|020|D|DISCUSSION:  Simultaneous administration of aluminum and magnesium hydroxide|
02992|021|D|(20 ml) in a fasted state with bictegravir (50 mg single dose) decreased|
02992|022|D|bictegravir maximum concentration (Cmax) and area-under-curve (AUC) by 80%|
02992|023|D|and 79%, respectively.(1)|
02992|024|D|   Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after|
02992|025|D|bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax|
02992|026|D|and AUC by 7% and 13%, respectively.(1)|
02992|027|D|   Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before|
02992|028|D|bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax|
02992|029|D|and AUC by 58% and 52%, respectively.(1)|
02992|030|D|   Simultaneous administration of aluminum and magnesium hydroxide (20 ml)|
02992|031|D|in a fed state with bictegravir (50 mg single dose) decreased bictegravir|
02992|032|D|Cmax and AUC by 49% and 47%, respectively.(1)|
02992|033|D|   Simultaneous administration of calcium carbonate (1200 mg single dose) in|
02992|034|D|a fasted state with bictegravir (50 mg single dose) decreased bictegravir|
02992|035|D|Cmax and AUC by 42% and 33%, respectively.(1)|
02992|036|D|   Simultaneous administration of calcium carbonate (1200 mg single dose) in|
02992|037|D|a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax|
02992|038|D|by 10% and increased AUC 3%, respectively.(1)|
02992|039|D|   Simultaneous administration of ferrous fumarate (324 mg single dose) in a|
02992|040|D|fasted state with bictegravir (50 mg single dose) decreased bictegravir Cmax|
02992|041|D|and AUC by 71% and 63%, respectively.(1)|
02992|042|D|   Simultaneous administration of ferrous fumarate (324 mg single dose) in a|
02992|043|D|fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax|
02992|044|D|and AUC by 25% and 16%, respectively.(1)|
02992|045|B||
02992|046|R|REFERENCE:|
02992|047|B||
02992|048|R|1.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
02992|049|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
02993|001|T|MONOGRAPH TITLE:  Bictegravir/Calcium & Iron Containing Supplements|
02993|002|B||
02993|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02993|004|L|take action as needed.|
02993|005|B||
02993|006|A|MECHANISM OF ACTION:  Calcium or iron containing supplements may bind to|
02993|007|A|bictegravir in the GI tract, preventing its absorption.(1)|
02993|008|B||
02993|009|E|CLINICAL EFFECTS:  Calcium or iron containing supplements may reduce levels|
02993|010|E|and clinical effectiveness of bictegravir.(1)|
02993|011|B||
02993|012|P|PREDISPOSING FACTORS:  None determined.|
02993|013|B||
02993|014|M|PATIENT MANAGEMENT:  Bictegravir and calcium or iron containing supplements|
02993|015|M|may be taken together with food.  Routine administration of bictegravir|
02993|016|M|under fasting conditions simultaneously with, or within 2 hours after,|
02993|017|M|calcium or iron containing supplements is not recommended.(1)|
02993|018|M|   In pregnant patients, if bictegravir is taken on an empty stomach, take|
02993|019|M|bictegravir at least 2 hours before or 6 hours after calcium or iron|
02993|020|M|containing supplements.(1)|
02993|021|B||
02993|022|D|DISCUSSION:  Simultaneous administration of aluminum and magnesium hydroxide|
02993|023|D|(20 ml) in a fasted state with bictegravir (50 mg single dose) decreased|
02993|024|D|bictegravir maximum concentration (Cmax) and area-under-curve (AUC) by 80%|
02993|025|D|and 79%, respectively.(1)|
02993|026|D|   Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after|
02993|027|D|bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax|
02993|028|D|and AUC by 7% and 13%, respectively.(1)|
02993|029|D|   Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before|
02993|030|D|bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax|
02993|031|D|and AUC by 58% and 52%, respectively.(1)|
02993|032|D|   Simultaneous administration of aluminum and magnesium hydroxide (20 ml)|
02993|033|D|in a fed state with bictegravir (50 mg single dose) decreased bictegravir|
02993|034|D|Cmax and AUC by 49% and 47%, respectively.(1)|
02993|035|D|   Simultaneous administration of calcium carbonate (1200 mg single dose) in|
02993|036|D|a fasted state with bictegravir (50 mg single dose) decreased bictegravir|
02993|037|D|Cmax and AUC by 42% and 33%, respectively.(1)|
02993|038|D|   Simultaneous administration of calcium carbonate (1200 mg single dose) in|
02993|039|D|a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax|
02993|040|D|by 10% and increased AUC 3%, respectively.(1)|
02993|041|D|   Simultaneous administration of ferrous fumarate (324 mg single dose) in a|
02993|042|D|fasted state with bictegravir (50 mg single dose) decreased bictegravir Cmax|
02993|043|D|and AUC by 71% and 63%, respectively.(1)|
02993|044|D|   Simultaneous administration of ferrous fumarate (324 mg single dose) in a|
02993|045|D|fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax|
02993|046|D|and AUC by 25% and 16%, respectively.(1)|
02993|047|B||
02993|048|R|REFERENCE:|
02993|049|B||
02993|050|R|1.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
02993|051|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
02994|001|T|MONOGRAPH TITLE:  Selected Opioids for MAT/Benzodiazepines|
02994|002|B||
02994|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02994|004|L|take action as needed.|
02994|005|B||
02994|006|A|MECHANISM OF ACTION:  Concurrent use of diacetylmorphine or methadone and|
02994|007|A|benzodiazepines may result in additive CNS depression.(1,2)|
02994|008|A|   Levomethadone is an enantiomer of methadone.(3)|
02994|009|B||
02994|010|E|CLINICAL EFFECTS:  Concurrent use of diacetylmorphine or methadone and other|
02994|011|E|CNS depressants, such as benzodiazepines, may result in profound sedation,|
02994|012|E|respiratory depression, coma, and/or death.(1,2)|
02994|013|B||
02994|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02994|015|P|may increase the risk of adverse effects.|
02994|016|B||
02994|017|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with|
02994|018|M|diacetylmorphine or methadone is not contraindicated in patients taking|
02994|019|M|benzodiazepines or other CNS depressants; however, discontinuation of|
02994|020|M|benzodiazepines and other CNS depressants is preferred in most cases.  In|
02994|021|M|some cases, monitoring at a higher level of care for tapering may be|
02994|022|M|appropriate.  In others, gradual tapering or decreasing to the lowest|
02994|023|M|effective dose of the benzodiazapine or CNS depressant is appropriate.|
02994|024|M|Consider other medications and nonpharmacologic treatments to address|
02994|025|M|anxiety or insomnia.  Ensure that other health care providers prescribing|
02994|026|M|benzodiazepines or other CNS depressants are aware of the patient's|
02994|027|M|methadone treatment.(4)|
02994|028|M|   Respiratory depression can occur at any time during opioid therapy,|
02994|029|M|especially during therapy initiation and following dosage increases.  The|
02994|030|M|risk of opioid-related overdose or overdose-related death is increased with|
02994|031|M|higher opioid doses, and this risk persists over the course of therapy.|
02994|032|M|Consider these risks when using concurrently with other agents that may|
02994|033|M|cause CNS depression.(5)|
02994|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02994|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02994|036|M|unresponsiveness.(1)  Educate patients about the risks of concurrent use and|
02994|037|M|monitor for use of prescribed and illicit benzodiazepines or other CNS|
02994|038|M|depressants.(4)|
02994|039|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02994|040|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02994|041|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02994|042|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02994|043|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02994|044|M|as those taking CNS depressants) and when a patient has household|
02994|045|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02994|046|M|for obtaining an opioid reversal agent (e.g., prescription,|
02994|047|M|over-the-counter, or as part of a community-based program).(6)|
02994|048|B||
02994|049|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02994|050|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02994|051|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02994|052|D|million to 30 million patients.  During this time, the proportion of|
02994|053|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02994|054|D|million patients.(7)|
02994|055|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02994|056|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02994|057|D|per 100,000 and drug overdose deaths involving both opioids and|
02994|058|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02994|059|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02994|060|D|increased from 18% to 31% during this time.(8)|
02994|061|D|   A prospective observational cohort study in North Carolina found that the|
02994|062|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02994|063|D|benzodiazepines were 10 times higher than patients receiving opioid|
02994|064|D|analgesics alone.(9)|
02994|065|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02994|066|D|death from overdose increased with concomitant opioid analgesics and|
02994|067|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02994|068|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02994|069|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02994|070|D|increased risk of fatal overdose.(10)|
02994|071|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02994|072|D|which benzodiazepines were determined to be a cause of death and that|
02994|073|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02994|074|D|determined to be a cause of death.  This study also found that other CNS|
02994|075|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02994|076|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02994|077|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02994|078|D|where opioid analgesics were also implicated.(11)|
02994|079|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02994|080|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02994|081|D|deaths.(12)|
02994|082|D|   A study of 315,428 privately insured patients who filled at least one|
02994|083|D|prescription for an opioid from 2001 to 2013 were enrolled in a|
02994|084|D|retrospective study.    Concurrent use of a benzodiazepine was recorded as|
02994|085|D|having at least one day of overlap in a given calendar year.  Baseline|
02994|086|D|characteristics among opioid users with concurrent use of a benzodiazepine|
02994|087|D|were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%,|
02994|088|D|p<0.001), and had a higher prevalence rate of every comorbidity examined|
02994|089|D|(p<0.001).  The proportion of opioid users with concurrent benzodiazepine|
02994|090|D|use nearly doubled from 9% in 2001 to 17% in 2013.  The primary outcome was|
02994|091|D|an emergency room visit or inpatient admission for opioid overdose within a|
02994|092|D|calendar year.  Among all opioid users, the annual adjusted incidence for|
02994|093|D|the primary outcome was 1.16% without concurrent benzodiazepine use compared|
02994|094|D|to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24;|
02994|095|D|p<0.001).  Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI|
02994|096|D|1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95%|
02994|097|D|CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the|
02994|098|D|primary outcome with concurrent benzodiazepine use compared to without|
02994|099|D|concurrent benzodiazepine use, respectively.(13)|
02994|100|D|   In a nested case-control study of adults with a new opioid dispensing|
02994|101|D|between 2010-2018, patients with concurrent use of an opioid with a|
02994|102|D|benzodiazepine were significantly more likely to have opioid-related|
02994|103|D|overdose compared to patients receiving opioids, benzodiazepines, or neither|
02994|104|D|(OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90|
02994|105|D|days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of|
02994|106|D|opioid-related overdose (p<0.01). Patients with overlapping prescriptions|
02994|107|D|during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times|
02994|108|D|more likely to experience an overdose (p<0.01).(14)|
02994|109|D|   While concomitant use of MAT with CNS depressants increases the risk of|
02994|110|D|adverse reactions, barriers to MAT can pose a greater risk of morbidity and|
02994|111|D|mortality due to opioid use disorder.(4)|
02994|112|B||
02994|113|R|REFERENCES:|
02994|114|B||
02994|115|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02994|116|R|  warns about serious risks and death when combining opioid pain or cough|1
02994|117|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02994|118|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02994|119|R|2.Diacetylmorphine Canadian prescribing information. Pharmascience Inc.|1
02994|120|R|  February, 2022.|1
02994|121|R|3.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
02994|122|R|  Pharma AS November 30, 2018.|1
02994|123|R|4.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02994|124|R|  urges caution about withholding opioid addiction medications from patients|1
02994|125|R|  taking benzodiazepines or CNS depressants: careful medication management|1
02994|126|R|  can reduce risks. available at:|1
02994|127|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
02994|128|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02994|129|R|  prescribing information for all opioid pain medicines to provide|1
02994|130|R|  additional guidance for safe use. Available at:|1
02994|131|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02994|132|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02994|133|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02994|134|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02994|135|R|  recommends health care professionals discuss naloxone with all patients|1
02994|136|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02994|137|R|  disorder. Available at:|1
02994|138|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02994|139|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02994|140|R|  d-pain July 23, 2020.|1
02994|141|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02994|142|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02994|143|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02994|144|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02994|145|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02994|146|R|  49(4):493-501.|2
02994|147|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02994|148|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02994|149|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02994|150|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02994|151|R|   prescribing patterns and deaths from drug overdose among US veterans|2
02994|152|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
02994|153|R|   350:h2698.|2
02994|154|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02994|155|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02994|156|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02994|157|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02994|158|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02994|159|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02994|160|R|13.Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association|2
02994|161|R|   between concurrent use of prescription opioids and benzodiazepines and|2
02994|162|R|   overdose: retrospective analysis. BMJ 2017 Mar 14;356:j760.|2
02994|163|R|14.Alobaidi A,  Pickard SA,  Jarrett JB,  Lee TA. Hospitalizations for|2
02994|164|R|   opioid-related overdose and timing of concurrent opioid and|2
02994|165|R|   benzodiazepine use: a nested case-control study. Pharmacotherapy 2021|2
02994|166|R|   June;41:722-732.|2
02995|001|T|MONOGRAPH TITLE:  Selected Opioids for MAT/Sleep Drugs|
02995|002|B||
02995|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02995|004|L|take action as needed.|
02995|005|B||
02995|006|A|MECHANISM OF ACTION:  Concurrent use of buprenorphine or diacetylmorphine|
02995|007|A|and sleep drugs may result in additive CNS depression and sleep-related|
02995|008|A|disorders.(1-3)|
02995|009|B||
02995|010|E|CLINICAL EFFECTS:  Concurrent use of buprenorphine or diacetylmorphine and|
02995|011|E|other CNS depressants, such as sleep drugs, may result in profound sedation,|
02995|012|E|respiratory depression, coma, and/or death.(1-3)|
02995|013|E|   Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may|
02995|014|E|increase the risk of sleep-related disorders including central sleep apnea|
02995|015|E|and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking,|
02995|016|E|sleep driving, and other activities while not fully awake.  Rarely, serious|
02995|017|E|injuries or death have resulted from complex sleep behaviors.(4)|
02995|018|B||
02995|019|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02995|020|P|may increase the risk of adverse effects.|
02995|021|B||
02995|022|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with buprenorphine|
02995|023|M|or diacetylmorphine is not contraindicated in patients taking CNS|
02995|024|M|depressants; however, discontinuation of CNS depressants is preferred in|
02995|025|M|most cases.  In some cases, monitoring at a higher level of care may be|
02995|026|M|appropriate.  In others, gradual tapering or decreasing to the lowest|
02995|027|M|effective dose of the CNS depressant is appropriate.  Consider other|
02995|028|M|medications and nonpharmacologic treatments to address anxiety or insomnia.|
02995|029|M|Ensure that other health care providers prescribing other CNS depressants|
02995|030|M|are aware of the patient's buprenorphine or diacetylmorphine treatment.(2)|
02995|031|M|   Respiratory depression can occur at any time during opioid therapy,|
02995|032|M|especially during therapy initiation and following dosage increases.  The|
02995|033|M|risk of opioid-related overdose or overdose-related death is increased with|
02995|034|M|higher opioid doses, and this risk persists over the course of therapy.|
02995|035|M|Consider these risks when using concurrently with other agents that may|
02995|036|M|cause CNS depression.(5)|
02995|037|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02995|038|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02995|039|M|unresponsiveness.(1)|
02995|040|M|   Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who|
02995|041|M|have had a previous episode of complex sleep behavior.(4)|
02995|042|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02995|043|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02995|044|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02995|045|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02995|046|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02995|047|M|as those taking CNS depressants) and when a patient has household|
02995|048|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02995|049|M|for obtaining an opioid reversal agent (e.g., prescription,|
02995|050|M|over-the-counter, or as part of a community-based program).(6)|
02995|051|B||
02995|052|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02995|053|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02995|054|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02995|055|D|million to 30 million patients.  During this time, the proportion of|
02995|056|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02995|057|D|million patients.(7)|
02995|058|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02995|059|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02995|060|D|per 100,000 and drug overdose deaths involving both opioids and|
02995|061|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02995|062|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02995|063|D|increased from 18% to 31% during this time.(8)|
02995|064|D|   A prospective observational cohort study in North Carolina found that the|
02995|065|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02995|066|D|benzodiazepines were 10 times higher than patients receiving opioid|
02995|067|D|analgesics alone.(9)|
02995|068|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02995|069|D|death from overdose increased with concomitant opioid analgesics and|
02995|070|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02995|071|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02995|072|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02995|073|D|increased risk of fatal overdose.(10)|
02995|074|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02995|075|D|which benzodiazepines were determined to be a cause of death and that|
02995|076|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02995|077|D|determined to be a cause of death.  This study also found that other CNS|
02995|078|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02995|079|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02995|080|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02995|081|D|where opioid analgesics were also implicated.(11)|
02995|082|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02995|083|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02995|084|D|deaths.(12)|
02995|085|D|   While concomitant use of MAT with CNS depressants increases the risk of|
02995|086|D|adverse reactions, barriers to MAT can pose a greater risk of morbidity and|
02995|087|D|mortality due to opioid use disorder.(2)|
02995|088|D|   As of April 2019, the FDA had identified 66 cases of complex sleep|
02995|089|D|behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases|
02995|090|D|resulted in death and the remainder resulted in serious injuries.  It was|
02995|091|D|not reported how many of the cases involved concomitant use of other CNS|
02995|092|D|depressants.(4)|
02995|093|B||
02995|094|R|REFERENCES:|
02995|095|B||
02995|096|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02995|097|R|  warns about serious risks and death when combining opioid pain or cough|1
02995|098|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02995|099|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02995|100|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02995|101|R|  urges caution about withholding opioid addiction medications from patients|1
02995|102|R|  taking benzodiazepines or CNS depressants: careful medication management|1
02995|103|R|  can reduce risks. available at:|1
02995|104|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
02995|105|R|3.Diacetylmorphine Canadian prescribing information. Pharmascience Inc.|1
02995|106|R|  February, 2022.|1
02995|107|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA adds|1
02995|108|R|  Boxed Warning for risk of serious injuries caused by sleepwalking with|1
02995|109|R|  certain prescription insomnia medicines. Available at:|1
02995|110|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warn|1
02995|111|R|  ing-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomni|1
02995|112|R|  a April 30, 2019.|1
02995|113|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02995|114|R|  prescribing information for all opioid pain medicines to provide|1
02995|115|R|  additional guidance for safe use. Available at:|1
02995|116|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02995|117|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02995|118|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02995|119|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02995|120|R|  recommends health care professionals discuss naloxone with all patients|1
02995|121|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02995|122|R|  disorder. Available at:|1
02995|123|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02995|124|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02995|125|R|  d-pain July 23, 2020.|1
02995|126|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02995|127|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02995|128|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02995|129|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02995|130|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02995|131|R|  49(4):493-501.|2
02995|132|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02995|133|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02995|134|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02995|135|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02995|136|R|   prescribing patterns and deaths from drug overdose among US veterans|2
02995|137|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
02995|138|R|   350:h2698.|2
02995|139|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02995|140|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02995|141|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02995|142|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02995|143|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02995|144|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02996|001|T|MONOGRAPH TITLE:  Buprenorphine for MAT/Muscle Relaxants|
02996|002|B||
02996|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02996|004|L|take action as needed.|
02996|005|B||
02996|006|A|MECHANISM OF ACTION:  Concurrent use of buprenorphine and muscle relaxants|
02996|007|A|may result in additive CNS depression.(1,2)|
02996|008|B||
02996|009|E|CLINICAL EFFECTS:  Concurrent use of buprenorphine and other CNS|
02996|010|E|depressants, such as muscle relaxants, may result in profound sedation,|
02996|011|E|respiratory depression, coma, and/or death.(1,2)|
02996|012|B||
02996|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02996|014|P|may increase the risk of adverse effects.|
02996|015|B||
02996|016|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with buprenorphine|
02996|017|M|is not contraindicated in patients taking CNS depressants; however,|
02996|018|M|discontinuation of CNS depressants is preferred in most cases.  In some|
02996|019|M|cases, monitoring at a higher level of care for tapering may be appropriate.|
02996|020|M|In others, gradual tapering or decreasing to the lowest effective dose of|
02996|021|M|the CNS depressant is appropriate.  Ensure that other health care providers|
02996|022|M|prescribing other CNS depressants are aware of the patient's buprenorphine|
02996|023|M|treatment.(2)|
02996|024|M|   Respiratory depression can occur at any time during opioid therapy,|
02996|025|M|especially during therapy initiation and following dosage increases.  The|
02996|026|M|risk of opioid-related overdose or overdose-related death is increased with|
02996|027|M|higher opioid doses, and this risk persists over the course of therapy.|
02996|028|M|Consider these risks when using concurrently with other agents that may|
02996|029|M|cause CNS depression.(3)|
02996|030|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02996|031|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02996|032|M|unresponsiveness.(1)|
02996|033|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02996|034|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02996|035|M|treat opioid use disorder (OUD).  Consider prescribing opioid reversal|
02996|036|M|agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02996|037|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02996|038|M|as those taking CNS depressants) and when a patient has household|
02996|039|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02996|040|M|for obtaining an opioid reversal agent (e.g., prescription,|
02996|041|M|over-the-counter, or as part of a community-based program).(4)|
02996|042|B||
02996|043|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
02996|044|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
02996|045|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
02996|046|D|million to 30 million patients.  During this time, the proportion of|
02996|047|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
02996|048|D|million patients.(5)|
02996|049|D|   A retrospective cohort study compared the risk of opioid overdose|
02996|050|D|associated with concomitant use of opioids and skeletal muscle relaxants|
02996|051|D|versus opioid use alone. The study examined two types of opioid users (naive|
02996|052|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
02996|053|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
02996|054|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
02996|055|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
02996|056|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
02996|057|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
02996|058|D|respectively).  Elevated risk was associated with concomitant users with|
02996|059|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
02996|060|D|1.39, respectively).(6)|
02996|061|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02996|062|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02996|063|D|per 100,000 and drug overdose deaths involving both opioids and|
02996|064|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02996|065|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02996|066|D|increased from 18% to 31% during this time.(7)|
02996|067|D|   A prospective observational cohort study in North Carolina found that the|
02996|068|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02996|069|D|benzodiazepines were 10 times higher than patients receiving opioid|
02996|070|D|analgesics alone.(8)|
02996|071|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02996|072|D|death from overdose increased with concomitant opioid analgesics and|
02996|073|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02996|074|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02996|075|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02996|076|D|increased risk of fatal overdose.(9)|
02996|077|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02996|078|D|which benzodiazepines were determined to be a cause of death and that|
02996|079|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02996|080|D|determined to be a cause of death.  This study also found that other CNS|
02996|081|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02996|082|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02996|083|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02996|084|D|where opioid analgesics were also implicated.(10)|
02996|085|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02996|086|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02996|087|D|deaths.(11)|
02996|088|D|   While concomitant use of MAT with CNS depressants increases the risk of|
02996|089|D|adverse reactions, barriers to MAT can pose a greater risk of morbidity and|
02996|090|D|mortality due to opioid use disorder.(2)|
02996|091|B||
02996|092|R|REFERENCES:|
02996|093|B||
02996|094|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02996|095|R|  warns about serious risks and death when combining opioid pain or cough|1
02996|096|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02996|097|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02996|098|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02996|099|R|  urges caution about withholding opioid addiction medications from patients|1
02996|100|R|  taking benzodiazepines or CNS depressants: careful medication management|1
02996|101|R|  can reduce risks. available at:|1
02996|102|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
02996|103|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02996|104|R|  prescribing information for all opioid pain medicines to provide|1
02996|105|R|  additional guidance for safe use. Available at:|1
02996|106|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02996|107|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02996|108|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02996|109|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02996|110|R|  recommends health care professionals discuss naloxone with all patients|1
02996|111|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02996|112|R|  disorder. Available at:|1
02996|113|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02996|114|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02996|115|R|  d-pain July 23, 2020.|1
02996|116|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02996|117|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02996|118|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02996|119|R|6.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
02996|120|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
02996|121|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
02996|122|R|  Ther 2020 Jul;108(1):81-88.|2
02996|123|R|7.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02996|124|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02996|125|R|  49(4):493-501.|2
02996|126|R|8.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02996|127|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02996|128|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02996|129|R|9.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02996|130|R|  prescribing patterns and deaths from drug overdose among US veterans|2
02996|131|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
02996|132|R|10.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02996|133|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02996|134|R|11.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02996|135|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02996|136|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02996|137|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02997|001|T|MONOGRAPH TITLE:  Selected Opioids for MAT/Antipsychotics|
02997|002|B||
02997|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
02997|004|L|take action as needed.|
02997|005|B||
02997|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and antipsychotics may|
02997|007|A|result in additive CNS depression.(1-3)|
02997|008|A|   Levomethadone is an enantiomer of methadone.(4)|
02997|009|B||
02997|010|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
02997|011|E|as antipsychotics, may result in profound sedation, respiratory depression,|
02997|012|E|coma, and/or death.(1-3)|
02997|013|B||
02997|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
02997|015|P|may increase the risk of adverse effects.|
02997|016|B||
02997|017|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with buprenorphine,|
02997|018|M|diacetylmorphine, or methadone is not contraindicated in patients taking CNS|
02997|019|M|depressants; however, gradual tapering or decreasing to the lowest effective|
02997|020|M|dose of the CNS depressant may be appropriate.  Ensure that other health|
02997|021|M|care providers prescribing other CNS depressants are aware of the patient's|
02997|022|M|buprenorphine, diacetylmorphine, or methadone treatment.(2)|
02997|023|M|   Respiratory depression can occur at any time during opioid therapy,|
02997|024|M|especially during therapy initiation and following dosage increases.  The|
02997|025|M|risk of opioid-related overdose or overdose-related death is increased with|
02997|026|M|higher opioid doses, and this risk persists over the course of therapy.|
02997|027|M|Consider these risks when using concurrently with other agents that may|
02997|028|M|cause CNS depression.(5)|
02997|029|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
02997|030|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
02997|031|M|unresponsiveness.(1)|
02997|032|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
02997|033|M|patients when prescribing or renewing an opioid analgesic or medicine to|
02997|034|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
02997|035|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
02997|036|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
02997|037|M|as those taking CNS depressants) and when a patient has household|
02997|038|M|members/close contacts at risk for accidental overdose.  Discuss the options|
02997|039|M|for obtaining an opioid reversal agent (e.g., prescription,|
02997|040|M|over-the-counter, or as part of a community-based program).(6)|
02997|041|B||
02997|042|D|DISCUSSION:  A nested case-control study looked at the relationship between|
02997|043|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
02997|044|D|antipsychotics was associated with a 2.33-fold increase in risk of|
02997|045|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
02997|046|D|significantly increased in patients with recent use of antipsychotics|
02997|047|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
02997|048|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
02997|049|D|of use.(7)|
02997|050|D|   Between 2002 and 2014, the number of patients receiving an opioid|
02997|051|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
02997|052|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
02997|053|D|to 30 million patients.  During this time, the proportion of patients|
02997|054|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
02997|055|D|patients.(8)|
02997|056|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
02997|057|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
02997|058|D|per 100,000 and drug overdose deaths involving both opioids and|
02997|059|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
02997|060|D|prescription opioid analgesic deaths which also involved benzodiazepines|
02997|061|D|increased from 18% to 31% during this time.(9)|
02997|062|D|   A prospective observational cohort study in North Carolina found that the|
02997|063|D|rates of overdose death among patients co-dispensed opioid analgesics and|
02997|064|D|benzodiazepines were 10 times higher than patients receiving opioid|
02997|065|D|analgesics alone.(10)|
02997|066|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
02997|067|D|death from overdose increased with concomitant opioid analgesics and|
02997|068|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
02997|069|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
02997|070|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
02997|071|D|increased risk of fatal overdose.(11)|
02997|072|D|   A study found that opioid analgesics contributed to 77% of deaths in|
02997|073|D|which benzodiazepines were determined to be a cause of death and that|
02997|074|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
02997|075|D|determined to be a cause of death.  This study also found that other CNS|
02997|076|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
02997|077|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
02997|078|D|system drugs, and muscle relaxants) were contributory to death in many cases|
02997|079|D|where opioid analgesics were also implicated.(12)|
02997|080|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
02997|081|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
02997|082|D|deaths.(13)|
02997|083|B||
02997|084|R|REFERENCES:|
02997|085|B||
02997|086|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02997|087|R|  warns about serious risks and death when combining opioid pain or cough|1
02997|088|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
02997|089|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
02997|090|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
02997|091|R|  urges caution about withholding opioid addiction medications from patients|1
02997|092|R|  taking benzodiazepines or CNS depressants: careful medication management|1
02997|093|R|  can reduce risks. available at:|1
02997|094|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
02997|095|R|3.Diacetylmorphine Canadian prescribing information. Pharmascience Inc.|1
02997|096|R|  February, 2022.|1
02997|097|R|4.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
02997|098|R|  Pharma AS November 30, 2018.|1
02997|099|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
02997|100|R|  prescribing information for all opioid pain medicines to provide|1
02997|101|R|  additional guidance for safe use. Available at:|1
02997|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
02997|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
02997|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
02997|105|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
02997|106|R|  recommends health care professionals discuss naloxone with all patients|1
02997|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
02997|108|R|  disorder. Available at:|1
02997|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
02997|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
02997|111|R|  d-pain July 23, 2020.|1
02997|112|R|7.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
02997|113|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
02997|114|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
02997|115|R|  Pharmacol 2020 Apr 26.|2
02997|116|R|8.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
02997|117|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
02997|118|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
02997|119|R|9.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
02997|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
02997|121|R|  49(4):493-501.|2
02997|122|R|10.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
02997|123|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
02997|124|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
02997|125|R|11.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
02997|126|R|   prescribing patterns and deaths from drug overdose among US veterans|2
02997|127|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
02997|128|R|   350:h2698.|2
02997|129|R|12.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
02997|130|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
02997|131|R|13.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
02997|132|R|   reliever and benzodiazepine drug abuse-related emergency department|2
02997|133|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
02997|134|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
02998|001|T|MONOGRAPH TITLE:  Tezacaftor-Ivacaftor/Strong and Moderate CYP3A4 Inhibitors|
02998|002|B||
02998|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02998|004|L|of severe adverse interaction.|
02998|005|B||
02998|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may inhibit|
02998|007|A|the metabolism of tezacaftor-ivacaftor.(1,2)|
02998|008|B||
02998|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inhibitor of|
02998|010|E|CYP3A4 may result in elevated levels of and toxicity from|
02998|011|E|tezacaftor-ivacaftor.(1,2)|
02998|012|B||
02998|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
02998|014|P|hepatic impairment.(1,2)|
02998|015|B||
02998|016|M|PATIENT MANAGEMENT:  Refer to current prescribing information for|
02998|017|M|tezacaftor-ivacaftor for dose adjustment recommendations with strong and|
02998|018|M|moderate CYP3A4 inhibitors.(2)|
02998|019|M|   Dose modifications for concurrent use of strong CYP3A4 inhibitors:|
02998|020|M|   - In adults, patients 12 years and older, and patients 6 to 12 years old|
02998|021|M|weighing at least 30 kg who are receiving concurrent strong CYP3A4|
02998|022|M|inhibitors, the morning dose of tezacaftor 100 mg/ivacaftor 150 mg should be|
02998|023|M|given twice a week, approximately 3 to 4 days apart.  The evening dose of|
02998|024|M|ivacaftor 150 mg should not be taken.|
02998|025|M|   - In patients 6 to 12 years old weighing less than 30 kg who are|
02998|026|M|receiving concurrent strong CYP3A4 inhibitors, the morning dose of|
02998|027|M|tezacaftor 50 mg/ivacaftor 75 mg should be given twice a week, approximately|
02998|028|M|3 to 4 days apart.  The evening dose of ivacaftor 75 mg should not be|
02998|029|M|taken.(2)|
02998|030|M|   Dose modifications for concurrent use of moderate CYP3A4 inhibitors:|
02998|031|M|   - In adults, patients 12 years and older, and patients 6 to 12 years old|
02998|032|M|weighing at least 30 kg who are receiving concurrent moderate CYP3A4|
02998|033|M|inhibitors, the morning dose of tezacaftor 100 mg/ivacaftor 150 mg should be|
02998|034|M|given every other day alternating with ivacaftor 150 mg.  The evening dose|
02998|035|M|of ivacaftor 150 mg should not be taken.|
02998|036|M|   - In patients 6 to 12 years old weighing less than 30 kg who are|
02998|037|M|receiving concurrent moderate CYP3A4 inhibitors, the morning dose of|
02998|038|M|tezacaftor 50 mg/ivacaftor 75 mg should be given every other day alternating|
02998|039|M|with ivacaftor 75 mg.  The evening dose of ivacaftor 75 mg should not be|
02998|040|M|taken.(2)|
02998|041|B||
02998|042|D|DISCUSSION:  Concurrent administration with ketoconazole (a strong inhibitor|
02998|043|D|of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1)|
02998|044|D|   Concurrent administration with fluconazole (a moderate inhibitor of|
02998|045|D|CYP3A4) increased ivacaftor AUC by 3-fold.(1)|
02998|046|D|   Concurrent administration with itraconazole (a strong inhibitor of|
02998|047|D|CYP3A4) increased tezacaftor AUC by 4-fold and ivacaftor by 15.6-fold.(2)|
02998|048|D|   Concurrent administration with fluconazole (a moderate inhibitor of|
02998|049|D|CYP3A4) increased tezacaftor AUC by 2-fold.(2)|
02998|050|D|   A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with|
02998|051|D|ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B),|
02998|052|D|and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4|
02998|053|D|of ivacaftor administration (study C).  In study A, B, and C, ivacaftor AUC|
02998|054|D|increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively,|
02998|055|D|with the addition of ritonavir.  Ivacaftor concentration maximum (Cmax) was|
02998|056|D|0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(3)|
02998|057|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
02998|058|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
02998|059|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
02998|060|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib,|
02998|061|D|ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib,|
02998|062|D|and voriconazole.(4-6)|
02998|063|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
02998|064|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
02998|065|D|darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin,|
02998|066|D|fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
02998|067|D|imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
02998|068|D|rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(4-6)|
02998|069|B||
02998|070|R|REFERENCES:|
02998|071|B||
02998|072|R|1.Kalydeco (ivacaftor) US prescribing information. Vertex Pharmaceuticals|1
02998|073|R|  Incorporated May, 2023.|1
02998|074|R|2.Symdeko (tezacaftor/ivacaftor) US prescribing information. Vertex|1
02998|075|R|  Pharmaceuticals Incorporated December, 2019.|1
02998|076|R|3.Liddy AM, McLaughlin G, Schmitz S, D'Arcy DM, Barry MG. The|2
02998|077|R|  Pharmacokinetic Interaction between Ivacaftor and Ritonavir in Healthy|2
02998|078|R|  Volunteers. Br J Clin Pharmacol 2017 May 06.|2
02998|079|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
02998|080|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
02998|081|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
02998|082|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
02998|083|R|  11/14/2017.|1
02998|084|R|5.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
02998|085|R|  Indiana University School of Medicine.  Available at:|1
02998|086|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
02998|087|R|6.This information is based on an extract from the Certara Drug Interaction|6
02998|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
02999|001|T|MONOGRAPH TITLE:  Warfarin/Apalutamide|
02999|002|B||
02999|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
02999|004|L|of severe adverse interaction.|
02999|005|B||
02999|006|A|MECHANISM OF ACTION:  Apalutamide may induce the metabolism of S-warfarin by|
02999|007|A|CYP2C9.(1)|
02999|008|B||
02999|009|E|CLINICAL EFFECTS:  Concurrent use of apalutamide may result in decreased|
02999|010|E|levels and effectiveness of warfarin, which may increase the risk of|
02999|011|E|clotting.(1)|
02999|012|B||
02999|013|P|PREDISPOSING FACTORS:  None determined.|
02999|014|B||
02999|015|M|PATIENT MANAGEMENT:  Monitor INR response closely in patients maintained on|
02999|016|M|warfarin when initiating, titrating, and discontinuing apalutamide.|
02999|017|M|Patients maintained on apalutamide may require higher dosages of warfarin.|
02999|018|B||
02999|019|D|DISCUSSION:  Concurrent apalutamide and warfarin decreased the|
02999|020|D|area-under-curve (AUC) of S-warfarin by 46%.(1)|
02999|021|B||
02999|022|R|REFERENCE:|
02999|023|B||
02999|024|R|1.Erleada (apalutamide) US prescribing information. Janssen Biotech, Inc.|1
02999|025|R|  July, 2021.|1
03000|001|T|MONOGRAPH TITLE:  S-Adenosylmethionine (SAM-e)/Tranylcypromine|
03000|002|B||
03000|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03000|004|L|is contraindicated and generally should not be dispensed or administered to|
03000|005|L|the same patient.|
03000|006|B||
03000|007|A|MECHANISM OF ACTION:  S-adenosylmethionine (SAMe), and tranylcypromine are|
03000|008|A|suggested to have similar effects on the serotonin pathway, therefore their|
03000|009|A|use together may result in additive or synergistic effects.|
03000|010|B||
03000|011|E|CLINICAL EFFECTS:  Concomitant use of S-adenosylmethionine and|
03000|012|E|antidepressants which inhibit neuronal serotonin reuptake may result in|
03000|013|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
03000|014|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
03000|015|E|and muscle rigidity.(2)|
03000|016|B||
03000|017|P|PREDISPOSING FACTORS:  None determined.|
03000|018|B||
03000|019|M|PATIENT MANAGEMENT:  The manufacturer of tranylcypromine states that|
03000|020|M|concurrent use of S-adenosylmethionine and tranylcypromine is|
03000|021|M|contraindicated.(1)|
03000|022|M|   If concurrent therapy is warranted, patients should be monitored for|
03000|023|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03000|024|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03000|025|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03000|026|M|coordination, or severe diarrhea.|
03000|027|B||
03000|028|D|DISCUSSION:  There is a case report with a tricyclic antidepressant|
03000|029|D|(clomipramine) and tranylcypromine of serotonin syndrome. Tricyclic|
03000|030|D|antidepressants are also known to increase serotonin levels.(2)|
03000|031|B||
03000|032|R|REFERENCES:|
03000|033|B||
03000|034|R|1.Parnate (tranylcypromine sulfate) US prescribing information.|1
03000|035|R|  GlaxoSmithKline January 4, 2018.|1
03000|036|R|2.Iruela LM, Minguez L, Merino J, Monedero G. Toxic interaction of|3
03000|037|R|  S-adenosylmethionine and clomipramine. Am J Psychiatry 1993 Mar;|3
03000|038|R|  150(3):522.|3
03000|039|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03000|040|R|  352(11):1112-20.|6
03001|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Conivaptan|
03001|002|B||
03001|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03001|004|L|of severe adverse interaction.|
03001|005|B||
03001|006|A|MECHANISM OF ACTION:  Conivaptan increases plasma levels of cyclosporine,|
03001|007|A|sirolimus, and temsirolimus by inhibition of CYP3A4.(1-4)|
03001|008|B||
03001|009|E|CLINICAL EFFECTS:  Concurrent conivaptan may result in elevated levels of|
03001|010|E|and toxicity from cyclosporine, sirolimus, and temsirolimus.(1-4)|
03001|011|B||
03001|012|P|PREDISPOSING FACTORS:  None determined.|
03001|013|B||
03001|014|M|PATIENT MANAGEMENT:  The manufacturer of conivaptan states that concomitant|
03001|015|M|use of drugs eliminated primarily by CYP3A-mediated metabolism should be|
03001|016|M|avoided.(1)  Cyclosporine, sirolimus, or temsirolimus levels and renal|
03001|017|M|function should be monitored if conivaptan is initiated or discontinued from|
03001|018|M|concurrent therapy.  The dosage of cyclosporine, sirolimus, or temsirolimus|
03001|019|M|may need to be adjusted.|
03001|020|M|   The US manufacturer of sirolimus states that concurrent therapy with|
03001|021|M|moderate CYP3A4 inhibitors such as conivaptan should be used with caution.|
03001|022|M|The dosage of sirolimus or conivaptan may require adjustment.(3)|
03001|023|B||
03001|024|D|DISCUSSION:  Erythromycin 800 mg every 8 hours, a moderate CYP3A4 and P-gp|
03001|025|D|inhibitor, given to 24 healthy volunteers increased the maximum|
03001|026|D|concentration (Cmax) and area-under-curve (AUC) of sirolimus 2 mg by|
03001|027|D|4.4-fold and 4.2-fold, respectively.(3)|
03001|028|D|   In a study of 18 healthy volunteers, diltiazem 120 mg, a moderate CYP3A4|
03001|029|D|inhibitor and P-gp inhibitor, increased the Cmax and AUC of sirolimus 10 mg|
03001|030|D|by 1.4-fold and 1.6-fold, respectively.(3)|
03001|031|D|   In 25 healthy volunteers, verapamil 180 mg twice daily, a moderate CYP3A4|
03001|032|D|inhibitor and P-gp inhibitor, increased the max and AUC of sirolimus 2 mg by|
03001|033|D|2.3-fold and 2.2-fold, respectively.(3)|
03001|034|D|   Concurrent administration of ketoconazole, another inhibitor of CYP3A4,|
03001|035|D|had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax|
03001|036|D|increased 3.1-fold and 2.2-fold, respectively.  Dosage adjustment of|
03001|037|D|temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is|
03001|038|D|expected to adjust levels to the range observed without inhibitors;|
03001|039|D|however, there are no data available with this dose adjustment.(4)|
03001|040|B||
03001|041|R|REFERENCES:|
03001|042|B||
03001|043|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
03001|044|R|  Pharma US, Inc. October, 2016.|1
03001|045|R|2.Sandimmune (cyclosporine) US prescribing information. Novartis|1
03001|046|R|  Pharmaceuticals Corporation September 2023.|1
03001|047|R|3.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
03001|048|R|  Aug, 2022.|1
03001|049|R|4.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
03001|050|R|  Inc. March, 2018.|1
03002|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Idelalisib|
03002|002|B||
03002|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03002|004|L|of severe adverse interaction.|
03002|005|B||
03002|006|A|MECHANISM OF ACTION:  Idelalisib increases plasma levels of cyclosporine,|
03002|007|A|sirolimus, and temsirolimus by inhibition on CYP3A4.(1-3)|
03002|008|B||
03002|009|E|CLINICAL EFFECTS:  Concurrent idelalisib may result in elevated levels of|
03002|010|E|and toxicity from cyclosporine, sirolimus, and temsirolimus.(1-3)|
03002|011|B||
03002|012|P|PREDISPOSING FACTORS:  None determined.|
03002|013|B||
03002|014|M|PATIENT MANAGEMENT:  Cyclosporine, sirolimus, or temsirolimus levels and|
03002|015|M|renal function should be monitored if idelalisib is initiated or|
03002|016|M|discontinued from concurrent therapy.  The dosage of cyclosporine,|
03002|017|M|sirolimus, or temsirolimus may need to be adjusted.|
03002|018|M|   The US manufacturer of sirolimus recommends that concurrent therapy with|
03002|019|M|strong CYP3A4 inhibitors such as idelalisib by avoided.  Alternative agents|
03002|020|M|with lesser interaction potential with sirolimus should be considered.(2)|
03002|021|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
03002|022|M|with strong CYP3A4 inhibitors such as idelalisib be avoided.  If concurrent|
03002|023|M|use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should|
03002|024|M|be considered.  If idelalisib is discontinued, a washout period of 1 week|
03002|025|M|should be allowed before adjusting the dosage of temsirolimus to previous|
03002|026|M|levels.(3)|
03002|027|B||
03002|028|D|DISCUSSION:  Multiple-dose ketoconazole, another inhibitor of CYP3A4,|
03002|029|D|administration significantly affected the rate and extent of absorption and|
03002|030|D|sirolimus exposure after administration of sirolimus oral solution, as|
03002|031|D|reflected by increases in sirolimus concentration maximum (Cmax), time|
03002|032|D|maximum (tmax), and area-under-curve (AUC) of 4.3-fold, 38%, and 10.9-fold,|
03002|033|D|respectively.  However, the terminal half-life of sirolimus was not changed.|
03002|034|D|Single-dose sirolimus did not affect steady-state 12-hour plasma|
03002|035|D|ketoconazole concentrations.(2)|
03002|036|D|   Concurrent administration of ketoconazole, another inhibitor of CYP3A4,|
03002|037|D|had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax|
03002|038|D|increased 3.1-fold and 2.2-fold, respectively.  Dosage adjustment of|
03002|039|D|temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is|
03002|040|D|expected to adjust levels to the range observed without inhibitors;|
03002|041|D|however, there are no data available with this dose adjustment.(3)|
03002|042|B||
03002|043|R|REFERENCES:|
03002|044|B||
03002|045|R|1.Sandimmune (cyclosporine) US prescribing information. Novartis|1
03002|046|R|  Pharmaceuticals Corporation September 2023.|1
03002|047|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
03002|048|R|  Aug, 2022.|1
03002|049|R|3.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
03002|050|R|  Inc. March, 2018.|1
03003|001|T|MONOGRAPH TITLE:  Anticoagulants; Antiplatelets; Thrombolytics/Serrapeptase|
03003|002|B||
03003|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
03003|004|L|Assess the risk to the patient and take action as needed.|
03003|005|B||
03003|006|A|MECHANISM OF ACTION:  Serrapeptase is a proteolytic enzyme that is said to|
03003|007|A|have antiinflammatory, fibrinolytic, and caseinolytic properties.(1,2)  Use|
03003|008|A|with anticoagulants, antiplatelet agents, or thrombolytics may result in|
03003|009|A|additive effects.|
03003|010|B||
03003|011|E|CLINICAL EFFECTS:  Concurrent use of serrapeptase with anticoagulants,|
03003|012|E|antiplatelets, or thrombolytics may increase the risk of bleeding.(1,2)|
03003|013|B||
03003|014|P|PREDISPOSING FACTORS:  None determined.|
03003|015|B||
03003|016|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for signs|
03003|017|M|of bleeding.  Instruct patients to report any signs and symptoms of|
03003|018|M|bleeding, such as unusual bleeding from the gums or nose; unusual bruising;|
03003|019|M|red or black, tarry stools; red, pink or dark brown urine; acute abdominal|
03003|020|M|or joint pain and/or swelling.|
03003|021|B||
03003|022|D|DISCUSSION:  Coadministration of serrapeptase with anticoagulants,|
03003|023|D|antiplatelets, or thrombolytics may increase the risk of bleeding.|
03003|024|B||
03003|025|R|REFERENCES:|
03003|026|B||
03003|027|R|1.Serretia (serrapeptase) product information. Arthur Andrew Medical January|1
03003|028|R|  1, 2017.|1
03003|029|R|2.Bhagat S, Agarwal M, Roy V. Serratiopeptidase: a systematic review of the|6
03003|030|R|  existing evidence. Int J Surg 2013;11(3):209-17.|6
03004|001|T|MONOGRAPH TITLE:  Pitavastatin/Sofosbuvir-Velpatasvir-Voxilaprevir|
03004|002|B||
03004|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03004|004|L|take action as needed.|
03004|005|B||
03004|006|A|MECHANISM OF ACTION:  Velpatasvir and voxilaprevir are inhibitors of OATP1B1|
03004|007|A|and OATP1B3 transport in the intestine.(1)  Pitavastatin is a substrate for|
03004|008|A|these two transporters.(2,3)|
03004|009|B||
03004|010|E|CLINICAL EFFECTS:  Concurrent use of sofosbuvir-velpatasvir-voxilaprevir|
03004|011|E|with pitavastatin may result in increased absorption and systemic|
03004|012|E|concentration of pitavastatin, which could result in myopathy or|
03004|013|E|rhabdomyolysis.(1)|
03004|014|B||
03004|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03004|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03004|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03004|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03004|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03004|020|P|transporter OATP1B1 may have increased statin concentrations and be|
03004|021|P|predisposed to myopathy or rhabdomyolysis.|
03004|022|B||
03004|023|M|PATIENT MANAGEMENT:  Concurrent use of sofosbuvir-velpatasvir-voxilaprevir|
03004|024|M|with pitavastatin is not recommended.(1)  If concurrent use is warranted,|
03004|025|M|limit pitavastatin to 1 mg daily.|
03004|026|M|   If these medications are used concurrently, counsel patient to report|
03004|027|M|unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.|
03004|028|B||
03004|029|D|DISCUSSION:  In a pharmacokinetic study, when pitavastatin 2 mg daily was|
03004|030|D|used concurrently with cyclosporine 2 mg/kg (another inhibitor of OATP1B1|
03004|031|D|and OATP1B3 transporters), the area-under-curve (AUC) and maximum|
03004|032|D|concentration (Cmax) of pitavastatin was increased by 4.6-fold and 6.6-fold,|
03004|033|D|respectively.(4)|
03004|034|B||
03004|035|R|REFERENCES:|
03004|036|B||
03004|037|R|1.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
03004|038|R|  Gilead Sciences, Inc. September, 2019.|1
03004|039|R|2.Zhang L. Transporter-Mediated Drug-Drug Interactions (DDIs). March 17,|6
03004|040|R|  2010.|6
03004|041|R|3.Hirano M, Maeda K, Shitara Y, Sugiyama Y. Contribution of OATP2 (OATP1B1)|5
03004|042|R|  and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J|5
03004|043|R|  Pharmacol Exp Ther 2004 Oct;311(1):139-46.|5
03004|044|R|4.Zypitamag (pitavastatin) US prescribing information. Cadila Healthcare|1
03004|045|R|  Ltd. September, 2020.|1
03005|001|T|MONOGRAPH TITLE:  Lithium/Metronidazole|
03005|002|B||
03005|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03005|004|L|take action as needed.|
03005|005|B||
03005|006|A|MECHANISM OF ACTION:  The mechanism of action is not fully known.  Possible|
03005|007|A|renal damage may occur with concurrent use leading to decreased renal|
03005|008|A|clearance of lithium.(1,2)|
03005|009|B||
03005|010|E|CLINICAL EFFECTS:  Concurrent use of metronidazole may result in elevated|
03005|011|E|lithium levels and lithium toxicity.|
03005|012|E|   Lithium has a narrow therapeutic range. Unintended increases in lithium|
03005|013|E|concentrations may lead to lithium toxicity.  Early symptoms of lithium|
03005|014|E|toxicity may include: lethargy, muscle weakness or stiffness, new onset or|
03005|015|E|coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred|
03005|016|E|vision, bradycardia, tinnitus, or nystagmus.  Severe toxicity may produce|
03005|017|E|multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac|
03005|018|E|arrhythmias, cardiovascular collapse) and may be fatal.(3)|
03005|019|B||
03005|020|P|PREDISPOSING FACTORS:  Risk factors for lithium toxicity include: acute|
03005|021|P|renal impairment, chronic renal disease, dehydration, low sodium diet, and|
03005|022|P|concomitant use of multiple medications which may impair renal elimination|
03005|023|P|of lithium (e.g. ACEI, ARBs, NSAIDs, diuretics).(3)  Patients who require|
03005|024|P|higher therapeutic lithium levels to maintain symptom control are|
03005|025|P|particularly susceptible to these factors.|
03005|026|B||
03005|027|M|PATIENT MANAGEMENT:  The US prescribing information for metronidazole states|
03005|028|M|patients should be monitored closely with concurrent lithium therapy by|
03005|029|M|obtaining serum lithium and creatinine levels several days after initiation|
03005|030|M|of metronidazole.(2)|
03005|031|M|   If possible, lithium treatment should be tapered or withdrawn before|
03005|032|M|administering metronidazole.(1)|
03005|033|M|   If concurrent therapy cannot be avoided, monitor closely.  Evaluate renal|
03005|034|M|function and most recent lithium levels.  If renal function is not stable,|
03005|035|M|whenever possible delay initiation of concurrent therapy until renal|
03005|036|M|function is stable.|
03005|037|M|   If an interacting drug is discontinued, the lithium level may fall.|
03005|038|M|Monitor lithium concentration and adjust dose if needed.(3)|
03005|039|M|   Counsel patient to assure they know signs and symptoms of lithium|
03005|040|M|toxicity and understand the importance of follow-up laboratory testing.|
03005|041|B||
03005|042|D|DISCUSSION:  Lithium has a narrow therapeutic index with potential fatal|
03005|043|D|consequences.(2)|
03005|044|D|   Other factors, such as dehydration, acute or worsening of chronic renal|
03005|045|D|impairment, or acute changes in sodium intake may increase the occurrence of|
03005|046|D|a clinically important interaction.|
03005|047|B||
03005|048|R|REFERENCES:|
03005|049|B||
03005|050|R|1.Flagyl (metronidazole) UK summary of product characteristics. Zentiva|1
03005|051|R|  March, 2021.|1
03005|052|R|2.Flagyl (metronidazole) US prescribing information. G.D. Searle LLC|1
03005|053|R|  Division of Pfizer Inc. October, 2018.|1
03005|054|R|3.Lithobid (lithium carbonate) US prescribing information. ANI|1
03005|055|R|  Pharmaceuticals, Inc. May, 2018.|1
03006|001|T|MONOGRAPH TITLE:  Methotrexate/Nitrous Oxide|
03006|002|B||
03006|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03006|004|L|is contraindicated and generally should not be dispensed or administered to|
03006|005|L|the same patient.|
03006|006|B||
03006|007|A|MECHANISM OF ACTION:  Nitrous oxide may potentiate the effects of|
03006|008|A|methotrexate on folate-dependant metabolic pathways, resulting in increased|
03006|009|A|risk of toxicity.(1,2)|
03006|010|B||
03006|011|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and nitrous oxide may|
03006|012|E|result in an increased depletion of vitamin B12 and potentiate the effects|
03006|013|E|of methotrexate on folate-dependent metabolism pathways, leading to|
03006|014|E|increased risk of severe neurotoxicity, stomatitis, and myelosuppression,|
03006|015|E|including neutropenia.(1-3)|
03006|016|B||
03006|017|P|PREDISPOSING FACTORS:  High dose methotrexate therapy may increase the risk|
03006|018|P|for and severity of this interaction.|
03006|019|B||
03006|020|M|PATIENT MANAGEMENT:  The Canadian manufacturer of methotrexate states that|
03006|021|M|the use of nitrous oxide with methotrexate is contraindicated.(2)|
03006|022|M|   The US manufacturer of methotrexate says to avoid concomitant nitrous|
03006|023|M|oxide anesthesia in patients receiving methotrexate therapy and to consider|
03006|024|M|an alternative anesthetic.(1)|
03006|025|M|   Use with caution when administering methotrexate after a recent history|
03006|026|M|of nitrous oxide administration.(1)|
03006|027|B||
03006|028|D|DISCUSSION:  A 7 year old female diagnosed with B Precursor acute|
03006|029|D|lymphoblastic leukemia (ALL) received 2 weekly doses of intrathecal|
03006|030|D|methotrexate under nitrous oxide anesthesia.  Four days after the second|
03006|031|D|methotrexate dose the patient developed dysarthria and carpopedal spasms|
03006|032|D|eventually leading to somnolence, loss of muscle control and decreasing|
03006|033|D|Glasgow coma score of 4.  A MRI revealed brain swelling and|
03006|034|D|microhemorrhages.  At this point chemotherapy was changed and neurological|
03006|035|D|symptoms resolved slowly over the next 12 months.(4)|
03006|036|D|    A 12 year old female with acute undifferentiated leukemia received|
03006|037|D|intrathecal methotrexate under nitrous oxide anesthesia.  Four days after|
03006|038|D|her fifth dose she developed generalized tonic-seizures, disinhibition,|
03006|039|D|severe agitation and left upper limb weakness.  A MRI revealed|
03006|040|D|leukoencephalopathy; widespread hyperintense subcortical white matter|
03006|041|D|lesions in the frontal and parietal areas.  Serum B12 was low at 154 ng/L|
03006|042|D|three weeks after last methotrexate dose.(5)|
03006|043|B||
03006|044|R|REFERENCES:|
03006|045|B||
03006|046|R|1.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
03006|047|R|  Inc. March, 2018.|1
03006|048|R|2.Methotrexate (tablets, injection) Canada prescribing information. Pfizer|1
03006|049|R|  Canada Inc. July 8, 2019.|1
03006|050|R|3.Forster VJ, McDonnell A, Theobald R, McKay JA. Effect of|5
03006|051|R|  methotrexate/vitamin B12 on DNA methylation as a potential factor in|5
03006|052|R|  leukemia treatment-related neurotoxicity. Epigenomics 2017 Sep;|5
03006|053|R|  9(9):1205-1218.|5
03006|054|R|4.Lobel U, Trah J, Escherich G. Severe neurotoxicity following intrathecal|3
03006|055|R|  methotrexate with nitrous oxide sedation in a child with acute|3
03006|056|R|  lymphoblastic leukemia. Pediatr Blood Cancer 2015 Mar;62(3):539-41.|3
03006|057|R|5.Forster VJ, van Delft FW, Baird SF, Mair S, Skinner R, Halsey C. Drug|3
03006|058|R|  interactions may be important risk factors for methotrexate neurotoxicity,|3
03006|059|R|  particularly in pediatric leukemia patients. Cancer Chemother Pharmacol|3
03006|060|R|  2016 Nov;78(5):1093-1096.|3
03007|001|T|MONOGRAPH TITLE:  Amphetamines/Tramadol|
03007|002|B||
03007|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03007|004|L|take action as needed.|
03007|005|B||
03007|006|A|MECHANISM OF ACTION:  Opioids and stimulants exhibit opposing effects on the|
03007|007|A|CNS.(1)|
03007|008|A|   Amphetamines may affect serotonin release and/or reuptake, depending on|
03007|009|A|their molecular structure.  Ring substitution tends to increase|
03007|010|A|amphetamine-induced release of endogenous serotonin.  However, the effect on|
03007|011|A|serotonin release may also be dose related and is more likely if the|
03007|012|A|amphetamine is taken in doses greater than those approved and generally|
03007|013|A|employed in treating attention-deficit-hyperactivity-disorder, or if abused,|
03007|014|A|especially over long periods of time.(2)|
03007|015|A|   Concurrent administration of amphetamines with tramadol may result in|
03007|016|A|additive effects on serotonin, resulting in serotonin syndrome.(3,4)|
03007|017|B||
03007|018|E|CLINICAL EFFECTS:  Concurrent use of opioids and stimulants may have|
03007|019|E|unpredictable effects and may mask overdose symptoms of the opioid, such as|
03007|020|E|drowsiness and inability to focus.|
03007|021|E|   Concurrent use of amphetamines with other serotonergic agents may|
03007|022|E|increase the risk of serotonin syndrome, a potentially life-threatening|
03007|023|E|syndrome which may include one or more of the following symptoms: tremor,|
03007|024|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
03007|025|E|and muscle rigidity.(5)|
03007|026|B||
03007|027|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03007|028|P|may increase the risk of adverse effects.|
03007|029|P|   High doses or long-term abuse of amphetamines may increase the risk of|
03007|030|P|serotonin syndrome.  Use of multiple drugs which increase serotonin levels|
03007|031|P|is associated with an increased risk for this toxidrome.|
03007|032|B||
03007|033|M|PATIENT MANAGEMENT:  Limit prescribing tramadol with CNS stimulants such as|
03007|034|M|amphetamines to patients for whom alternatives are ineffective, not|
03007|035|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03007|036|M|of pain.|
03007|037|M|   If concurrent use is necessary, limit the dosages and duration of each|
03007|038|M|drug to the minimum possible while achieving the desired clinical effect.|
03007|039|M|Consider initiating amphetamines or tramadol at lower doses and monitor for|
03007|040|M|signs and symptoms of serotonin syndrome.  Concurrent use of amphetamines|
03007|041|M|with tramadol should be approached with appropriate monitoring.  Discontinue|
03007|042|M|medication if symptoms occur.(3,4)|
03007|043|M|   Instruct patients receiving concurrent therapy to report any signs or|
03007|044|M|symptoms of serotonin syndrome immediately.|
03007|045|M|   Monitor patients receiving concurrent therapy for signs of substance|
03007|046|M|abuse.|
03007|047|M|   Respiratory depression can occur at any time during opioid therapy,|
03007|048|M|especially during therapy initiation and following dosage increases.  The|
03007|049|M|risk of opioid-related overdose or overdose-related death is increased with|
03007|050|M|higher opioid doses, and this risk persists over the course of therapy.|
03007|051|M|Consider these risks when using concurrently with stimulants.(1)|
03007|052|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03007|053|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03007|054|M|treat opioid use disorder (OUD).  Consider prescribing opioid reversal|
03007|055|M|agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03007|056|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03007|057|M|as those taking CNS depressants) and when a patient has household|
03007|058|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03007|059|M|for obtaining an opioid reversal agent (e.g., prescription,|
03007|060|M|over-the-counter, or as part of a community-based program).(1)|
03007|061|B||
03007|062|D|DISCUSSION:  A total of 70,237 persons died from drug overdoses in the|
03007|063|D|United States in 2017; approximately two thirds of these deaths involved an|
03007|064|D|opioid.(2).  The CDC analyzed 2016-2017 changes in age-adjusted death rates|
03007|065|D|involving cocaine and psychostimulants by demographic characteristics,|
03007|066|D|urbanization levels, U.S. Census region, 34 states, and the District of|
03007|067|D|Columbia (DC).  The CDC also examined trends in age-adjusted|
03007|068|D|cocaine-involved and psychostimulant-involved death rates from 2003 to 2017|
03007|069|D|overall, as well as with and without co-involvement of opioids.  Among all|
03007|070|D|2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333|
03007|071|D|(14.7%) involved psychostimulants.  Death rates increased from 2016 to 2017|
03007|072|D|for both drug categories across demographic characteristics, urbanization|
03007|073|D|levels, Census regions, and states.  In 2017, opioids were involved in 72.7%|
03007|074|D|and 50.4% of cocaine-involved and psychostimulant-involved overdoses,|
03007|075|D|respectively, and the data suggest that increases in cocaine-involved|
03007|076|D|overdose deaths from 2012 to 2017 were driven primarily by synthetic|
03007|077|D|opioids.(7)|
03007|078|D|   There was opioid co-involvement in 72.7 percent of cocaine and 50.4|
03007|079|D|percent of stimulant-involved overdose deaths.  This was largely driven by|
03007|080|D|synthetic opioids such as fentanyl. However, stimulant-involved overdose|
03007|081|D|without opioid co-involvement is also increasing.(6)|
03007|082|B||
03007|083|R|REFERENCES:|
03007|084|B||
03007|085|R|1.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03007|086|R|  prescribing information for all opioid pain medicines to provide|1
03007|087|R|  additional guidance for safe use. Available at:|1
03007|088|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03007|089|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03007|090|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03007|091|R|2.Anonymous. Personal communication:  Adderall XR and SSRI's. Shire US Inc.|1
03007|092|R|  August 11, 2004.|1
03007|093|R|3.Adderall (amphetmine) US prescribing information. Barr Laboratories, Inc.|1
03007|094|R|  January, 2017.|1
03007|095|R|4.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
03007|096|R|  October, 2019.|1
03007|097|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03007|098|R|  352(11):1112-20.|6
03007|099|R|6.Seth P, Scholl L, Rudd RA, Bacon S. Overdose Deaths Involving Opioids,|6
03007|100|R|  Cocaine, and Psychostimulants - United States, 2015-2016. MMWR Morb Mortal|6
03007|101|R|  Wkly Rep 2018 Mar 30;67(12):349-358.|6
03007|102|R|7.Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved|6
03007|103|R|  Overdose Deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep 2018|6
03007|104|R|  Jan 4;67(5152):1419-1427.|6
03008|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Bexarotene|
03008|002|B||
03008|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03008|004|L|of severe adverse interaction.|
03008|005|B||
03008|006|A|MECHANISM OF ACTION:  Bexarotene may induce the CYP3A4 mediated metabolism|
03008|007|A|of both estrogen and progestin components of hormonal contraceptives.(1,2)|
03008|008|B||
03008|009|E|CLINICAL EFFECTS:  Concurrent use of bexarotene may result in reduced levels|
03008|010|E|and clinical effectiveness of hormone containing contraceptives.|
03008|011|E|Breakthrough bleeding and contraceptive failure/pregnancy may result.(1,2)|
03008|012|B||
03008|013|P|PREDISPOSING FACTORS:  None determined.|
03008|014|B||
03008|015|M|PATIENT MANAGEMENT:  Patients receiving bexarotene should be alerted to the|
03008|016|M|risk for decreased effectiveness (e.g. contraceptive failure) of their|
03008|017|M|hormonal contraceptive therapy and should be advised to use a reliable|
03008|018|M|non-hormonal contraceptive option.(1)|
03008|019|M|   Due to bexarotene being teratogenic in animal studies and may cause fetal|
03008|020|M|harm, the US prescribing information recommends that two reliable forms of|
03008|021|M|contraception be used simultaneously one month before, during, and at least|
03008|022|M|one month after bexarotene therapy.  Females of reproductive potential|
03008|023|M|should be advised to avoid becoming pregnant.  If treatment with bexarotene|
03008|024|M|is intended in a female with reproductive potential, it is strongly|
03008|025|M|recommended that one of the two reliable forms of contraception should be|
03008|026|M|non-hormonal.  The patient should be asked to report any spotting or|
03008|027|M|bleeding.(1)|
03008|028|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03008|029|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03008|030|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03008|031|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03008|032|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03008|033|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03008|034|M|and to seek medical advice if they do become pregnant.(3)|
03008|035|B||
03008|036|D|DISCUSSION:  In a study of bexarotene 400 mg/m2 was administered orally with|
03008|037|D|atorvastatin (another CYP3A4 substrate), the area-under-curve (AUC) of|
03008|038|D|atorvastatin was decreased by 50%.(1)|
03008|039|D|   No studies have been conducted looking specifically at hormonal|
03008|040|D|contraceptive use with bexarotene. However, due to the possibility of|
03008|041|D|intended pregnancy the use of non-hormonal contraception needs to be|
03008|042|D|considered.(1)|
03008|043|B||
03008|044|R|REFERENCES:|
03008|045|B||
03008|046|R|1.Targretin (bexarotene) Capsules US prescribing information. Valeant|1
03008|047|R|  Pharmaceuticals North America LLC July, 2015.|1
03008|048|R|2.Nor-Q-D (norethindrone) US prescribing information. WatsonPharma March,|1
03008|049|R|  2005.|1
03008|050|R|3.Centers for Disease Control and Prevention. U.S. Medical Eligibility|6
03008|051|R|  Criteria for Contraceptive Use, 2016. MMWR Recomm Rep.  Available at:|6
03008|052|R|  https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf July 29, 2016;|6
03008|053|R|  65(3):.|6
03009|001|T|MONOGRAPH TITLE:  Selected P-gp Substrates/Ibrutinib (mono deleted|
03009|002|T|04/11/2024)|
03009|003|B||
03009|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03009|005|L|take action as needed.|
03009|006|B||
03009|007|A|MECHANISM OF ACTION:  Ibrutinib may be an inhibitor of the P-glycoprotein|
03009|008|A|(P-gp) system.  P-gp substrates with a narrow therapeutic index may be|
03009|009|A|increased.(1-3)|
03009|010|B||
03009|011|E|CLINICAL EFFECTS:  Concurrent use of ibrutinib with narrow therapeutic index|
03009|012|E|P-gp substrates may result in elevated levels of the substrate, increasing|
03009|013|E|the risk for adverse effects.(1-3)|
03009|014|B||
03009|015|P|PREDISPOSING FACTORS:  None determined.|
03009|016|B||
03009|017|M|PATIENT MANAGEMENT:  The Canadian and UK prescribing information of|
03009|018|M|ibrutinib states that the concurrent use of narrow therapeutic index P-gp|
03009|019|M|substrates should be taken at least 6 hours before or after ibrutinib to|
03009|020|M|minimize the risk of a potential reaction.(2-3)|
03009|021|M|    The US FDA approval packet for ibrutinib states that ibrutinib is|
03009|022|M|quickly absorbed within 2.5 hours after administration and recommends|
03009|023|M|separating ibrutinib and P-gp substrates by at least 2.5 hours.(4)|
03009|024|B||
03009|025|D|DISCUSSION:  In vitro data suggests ibrutinib may be a P-gp inhibitor at|
03009|026|D|therapeutic doses in the gut due to higher local concentrations after an|
03009|027|D|oral dose.(4)|
03009|028|D|   Selected P-gp substrates linked to this monograph include: afatinib,|
03009|029|D|colchicine, digoxin, etoposide, everolimus, pazopanib, sirolimus, topotecan|
03009|030|D|or venetoclax.|
03009|031|B||
03009|032|R|REFERENCES:|
03009|033|B||
03009|034|R|1.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
03009|035|R|  August, 2022.|1
03009|036|R|2.Imbruvica (ibrutinib) Canadian prescribing information. Janssen Inc.|1
03009|037|R|  August, 2023.|1
03009|038|R|3.Imbruvica (ibrutinib) UK summary of product characteristics. Janssen-Cilag|1
03009|039|R|  Ltd. August, 2020.|1
03009|040|R|4.US Food and Drug Administration (FDA). Drug Approval Package Imbruvica|1
03009|041|R|  (ibrutinib) Application No.:205552. Accessed at:|1
03009|042|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205552Orig2s000Cli|1
03009|043|R|  nPharmR.pdf February 12, 2014.|1
03010|001|T|MONOGRAPH TITLE:  Carbamazepine/Selected Barbiturates|
03010|002|B||
03010|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03010|004|L|of severe adverse interaction.|
03010|005|B||
03010|006|A|MECHANISM OF ACTION:  Phenobarbital and perhaps other barbiturates induce|
03010|007|A|CYP3A4, which metabolizes carbamazepine.|
03010|008|B||
03010|009|E|CLINICAL EFFECTS:  Concurrent use of barbiturates may result in decreased|
03010|010|E|carbamazepine levels.|
03010|011|B||
03010|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03010|013|P|of the inducer for longer than 1-2 weeks.|
03010|014|B||
03010|015|M|PATIENT MANAGEMENT:  If a barbiturate is added to a regimen including|
03010|016|M|carbamazepine, monitor carbamazepine levels and adjust dosages accordingly.|
03010|017|M|Monitor patients for decreased carbamazepine efficacy (e.g. seizures).  If|
03010|018|M|the barbiturate is discontinued, monitor patients for carbamazepine toxicity|
03010|019|M|and adjust carbamazepine dosages accordingly.|
03010|020|B||
03010|021|D|DISCUSSION:  Phenobarbital has been shown to decrease serum carbamazepine|
03010|022|D|half-life and plasma concentration levels when given in combination.|
03010|023|D|Significant changes in carbamazepine serum concentrations were seen within|
03010|024|D|five days after the addition of phenobarbital to the therapeutic regimen.|
03010|025|D|Conversely, carbamazepine appears to have no effect on serum phenobarbital|
03010|026|D|levels.|
03010|027|D|   Another study involving children with seizure disorders evaluated the|
03010|028|D|effect of phenobarbital co-medication on carbamazepine serum levels.|
03010|029|D|Patients had been maintained on either carbamazepine alone or concurrent|
03010|030|D|carbamazepine and phenobarbital for at least one month.  There were no|
03010|031|D|significant differences in carbamazepine levels between patients receiving|
03010|032|D|carbamazepine alone or with concurrent phenobarbital.  However, the ratio of|
03010|033|D|carbamazepine level to dose was significantly decreased in patients|
03010|034|D|receiving concurrent phenobarbital (0.570?0.470 versus 0.627?0.353).  The|
03010|035|D|carbamazepine concentration ratios of two carbamazepine metabolites (the|
03010|036|D|10,11-epoxide metabolite and the 10,11-dihydroxy metabolite) were increased|
03010|037|D|in patients receiving concurrent carbamazepine and phenobarbital compared to|
03010|038|D|those receiving carbamazepine alone.|
03010|039|B||
03010|040|R|REFERENCES:|
03010|041|B||
03010|042|R|1.Windorfer A Jr, Sauer W. Drug interactions during anticonvulsant therapy|5
03010|043|R|  in childhood: diphenylhydantoin,  primidone, phenobarbitone, clonazepam,|5
03010|044|R|  nitrazepam, carbamazepin and dipropylacetate. Neuropadiatrie 1977 Feb;|5
03010|045|R|  8(1):29-41.|5
03010|046|R|2.Christiansen J, Dam M. Influence of phenobarbital and diphenylhydantoin on|2
03010|047|R|  plasma carbamazepine levels in patients with epilepsy. Acta Neurol Scand|2
03010|048|R|  1973;49(4):543-6.|2
03010|049|R|3.Cereghino JJ, Brock JT, Van Meter JC, Penry JK, Smith LD, White BG. The|2
03010|050|R|  efficacy of carbamazepine combinations in epilepsy. Clin Pharmacol Ther|2
03010|051|R|  1975 Dec;18(6):733-41.|2
03010|052|R|4.Dam M, Jensen A, Christiansen J. Plasma level and effect of carbamazepine|2
03010|053|R|  in grand mal and psychomotor epilepsy. Acta Neurol Scand Suppl 1975;|2
03010|054|R|  60:33-8.|2
03010|055|R|5.Liu H, Delgado MR. Interactions of phenobarbital and phenytoin with|2
03010|056|R|  carbamazepine and its metabolites' concentrations, concentration ratios,|2
03010|057|R|  and level/dose ratios in epileptic children. Epilepsia 1995 Mar;|2
03010|058|R|  36(3):249-54.|2
03010|059|R|6.Fukuoka N, Tsukamoto T, Uno J, Kimura M, Morita S. Effects of concomitant|2
03010|060|R|  antiepileptic drugs on serum carbamazepine concentration in epileptic|2
03010|061|R|  patients: quantitative analysis based on extracellular water volume  as a|2
03010|062|R|  transforming factor. Yakugaku Zasshi 2003 Jan;123(1):35-42.|2
03010|063|R|7.Sennoune S, Iliadis A, Bonneton J, Barra Y, Genton P, Mesdjian E. Steady|2
03010|064|R|  state pharmacokinetics of carbamazepine-phenobarbital interaction in|2
03010|065|R|  patients with epilepsy. Biopharm Drug Dispos 1996 Mar;17(2):155-64.|2
03010|066|R|8.Spina E, Martines C, Fazio A, Trio R, Pisani F, Tomson T. Effect of|2
03010|067|R|  phenobarbital on the pharmacokinetics of carbamazepine-10,11-epoxide, an|2
03010|068|R|  active metabolite of carbamazepine. Ther Drug Monit 1991 Mar;13(2):109-12.|2
03010|069|R|9.Benetello P, Furlanut M. Primidone-carbamazepine interaction: clinical|3
03010|070|R|  consequences. Int J Clin Pharmacol Res 1987;7(2):165-8.|3
03011|001|T|MONOGRAPH TITLE:  Eslicarbazepine/Hydantoins; Anticonvulsant Barbiturates|
03011|002|B||
03011|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03011|004|L|take action as needed.|
03011|005|B||
03011|006|A|MECHANISM OF ACTION:  Phenobarbital induces multiple metabolic enzymes|
03011|007|A|including CYP1A2, CYP2C9, CYP2C19, CYP3A4, and glucuronidation (UGT)|
03011|008|A|pathways.  Phenytoin, and perhaps other hydantoins, induce multiple|
03011|009|A|metabolic enzymes including CYP2C9, CYP2C19, CYP3A4 and UGT pathways.|
03011|010|A|Eslicarbazepine is metabolized by one or more of these induced|
03011|011|A|pathways.(1,2)|
03011|012|A|   Eslicarbazepine may inhibit the CYP2C19 mediated metabolism of phenytoin|
03011|013|A|and barbiturates.(1,2)|
03011|014|A|   Primidone is metabolized to phenobarbital.|
03011|015|B||
03011|016|E|CLINICAL EFFECTS:  Lower eslicarbazepine concentrations may lead to|
03011|017|E|diminished efficacy of eslicarbazepine, e.g loss of seizure control.  Higher|
03011|018|E|hydantoin and barbiturate concentrations may lead to increased sedation or|
03011|019|E|further CNS depression.|
03011|020|B||
03011|021|P|PREDISPOSING FACTORS:  None determined.|
03011|022|B||
03011|023|M|PATIENT MANAGEMENT:  For patients stabilized on phenytoin, monitor for|
03011|024|M|increased phenytoin levels approximately 4 to 7 days after initiation or|
03011|025|M|after an increase in the eslicarbazepine dose.|
03011|026|M|   If phenytoin or a barbiturate is added to a patient stabilized on|
03011|027|M|eslicarbazepine, the eslicarbazepine dose may need to be increased.  Onset|
03011|028|M|of induction is gradual and may not be maximal for days or weeks.|
03011|029|M|   If phenytoin or a barbiturate is discontinued in a patient stabilized on|
03011|030|M|eslicarbazepine therapy, eslicarbazepine concentrations will increase over 1|
03011|031|M|to 4 weeks.  Monitor serum levels and adjust dosages as needed.|
03011|032|B||
03011|033|D|DISCUSSION:  In a study in healthy subjects, concurrent eslicarbazepine|
03011|034|D|(1200 mg daily) and phenytoin resulted in a decrease in eslicarbazepine|
03011|035|D|exposure by 31-33% and an increase in phenytoin exposure by 31-35%.(1)|
03011|036|B||
03011|037|R|REFERENCES:|
03011|038|B||
03011|039|R|1.Aptiom (eslicarbazepine) US prescribing information. Sunovian|1
03011|040|R|  Pharmaceuticals Inc. September 13, 2017.|1
03011|041|R|2.Zebinix (eslicarbazepine) UK summary of product characteristics. Eisai Ltd|1
03011|042|R|  July, 2017.|1
03012|001|T|MONOGRAPH TITLE:  Eslicarbazepine/Selected Barbiturates|
03012|002|B||
03012|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03012|004|L|of severe adverse interaction.|
03012|005|B||
03012|006|A|MECHANISM OF ACTION:  Phenobarbital, and perhaps other barbiturates, induces|
03012|007|A|multiple metabolic enzymes including CYP1A2, CYP2C9, CYP2C19, CYP3A4, and|
03012|008|A|glucuronidation (UGT) pathways.  Eslicarbazepine is metabolized by one or|
03012|009|A|more of these induced pathways.(1,2)|
03012|010|B||
03012|011|E|CLINICAL EFFECTS:  Lower eslicarbazepine concentrations may lead to|
03012|012|E|diminished efficacy of eslicarbazepine, e.g loss of seizure control.|
03012|013|B||
03012|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03012|015|P|of the inducer for longer than 1-2 weeks.|
03012|016|B||
03012|017|M|PATIENT MANAGEMENT:  If a barbiturate is added to a patient stabilized on|
03012|018|M|eslicarbazepine, the eslicarbazepine dose may need to be increased.  Onset|
03012|019|M|of induction is gradual and may not be maximal for days or weeks.|
03012|020|M|   If the barbiturate is discontinued in a patient stabilized on|
03012|021|M|eslicarbazepine therapy, eslicarbazepine will increase over 1 to 4 weeks.|
03012|022|M|Monitor serum levels and adjust dosages as needed.|
03012|023|B||
03012|024|D|DISCUSSION:  In a study in healthy subjects, concurrent eslicarbazepine|
03012|025|D|(1200 mg daily) and phenytoin resulted in a decrease in eslicarbazepine|
03012|026|D|exposure by 31-33% and an increase in phenytoin exposure by 31-35%.(1)|
03012|027|B||
03012|028|R|REFERENCES:|
03012|029|B||
03012|030|R|1.Aptiom (eslicarbazepine) US prescribing information. Sunovian|1
03012|031|R|  Pharmaceuticals Inc. September 13, 2017.|1
03012|032|R|2.Zebinix (eslicarbazepine) UK summary of product characteristics. Eisai Ltd|1
03012|033|R|  July, 2017.|1
03013|001|T|MONOGRAPH TITLE:  Lamotrigine/Hydantoins; Anticonvulsant Barbiturates|
03013|002|B||
03013|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03013|004|L|take action as needed.|
03013|005|B||
03013|006|A|MECHANISM OF ACTION:  Phenobarbital, phenytoin, primidone and perhaps other|
03013|007|A|barbiturates and hydantoins induce glucuronidation (UGT) pathways.|
03013|008|A|Lamotrigine is primarily metabolized by glucuronidation.|
03013|009|B||
03013|010|E|CLINICAL EFFECTS:  Lower lamotrigine concentrations may lead to diminished|
03013|011|E|efficacy, e.g loss of seizure control.|
03013|012|B||
03013|013|P|PREDISPOSING FACTORS:  None determined.|
03013|014|B||
03013|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with lamotrigine|
03013|016|M|and carbamazepine, phenytoin, phenobarbital, or primidone without valproate|
03013|017|M|should be observed for decreased lamotrigine levels and clinical|
03013|018|M|effectiveness.  The dose of lamotrigine may need to be adjusted if these|
03013|019|M|agents are added to or removed from lamotrigine therapy.  Refer to the|
03013|020|M|current lamotrigine prescribing information for information on dosage|
03013|021|M|adjustments.|
03013|022|M|   Lamotrigine levels for patients whose therapeutic regimens include|
03013|023|M|coadministration of lamotrigine with either carbamazepine, phenytoin, or|
03013|024|M|phenobarbital and valproic acid should be monitored for elevation.  The dose|
03013|025|M|of lamotrigine should be adjusted accordingly while the medication is being|
03013|026|M|coadministered with valproic acid and other antiepileptic drugs.|
03013|027|M|   If the barbiturate or hydantoin is discontinued in a patient stabilized|
03013|028|M|on lamotrigine therapy, lamotrigine concentrations will increase over 1 to 4|
03013|029|M|weeks.  Monitor serum levels and adjust dosages as needed.|
03013|030|B||
03013|031|D|DISCUSSION:  In 24 epileptic adults taking carbamazepine, phenytoin,|
03013|032|D|phenobarbital, or primidone, the time to maximum concentration (Tmax),|
03013|033|D|half-life, and apparent plasma clearance for a single dose of lamotrigine|
03013|034|D|were 2.3 hours, 14.4 hours, and 1.10 ml/min/kg, respectively.  In 179|
03013|035|D|healthy adults taking no other medications, these values were 2.2 hours,|
03013|036|D|32.8 hours, and 0.44 ml/min/kg, respectively.|
03013|037|D|   In 17 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or|
03013|038|D|primidone, the Tmax, half-life, and apparent plasma clearance of multiple|
03013|039|D|dose lamotrigine were 2.0 hours, 12.6 hours, and 1.21 ml/min/kg.  These|
03013|040|D|values were 1.7 hours, 25.4 hours, and 0.58 ml/min/kg, respectively, in 36|
03013|041|D|healthy adults taking no other medications.|
03013|042|D|   In 10 pediatric patients with epilepsy aged 10 months to 5.3 years who|
03013|043|D|were taking carbamazepine, phenytoin, phenobarbital, or primidone,|
03013|044|D|lamotrigine Tmax, half-life, and apparent plasma clearance were 3.0 hours,|
03013|045|D|7.7 hours, and 3.62 ml/min/kg, respectively.  In 7 patients in the same age|
03013|046|D|range who where not taking other medications known to affect lamotrigine|
03013|047|D|clearance, these values were 5.2 hours, 19.0 hours, and 1.2 ml/min/kg,|
03013|048|D|respectively.|
03013|049|D|   In 527 adult patients with epilepsy, the mean oral clearance of|
03013|050|D|lamotrigine in patients receiving one concomitant enzyme-inducing|
03013|051|D|anti-epileptic agent and not valproic acid was estimated to be 1|
03013|052|D|ml/min/kg.(3)|
03013|053|D|   One study of 302 patients looked at the results of combining lamotrigine|
03013|054|D|with carbamazepine, phenytoin, or phenobarbital with or without valproic|
03013|055|D|acid.  The study found when the lamotrigine combinations contained valproic|
03013|056|D|acid that lamotrigine concentrations were two times higher when compared to|
03013|057|D|patients taking either lamotrigine alone or in combination with one of the|
03013|058|D|other antiepileptic drugs even when the lamotrigine doses were halved.|
03013|059|B||
03013|060|R|REFERENCES:|
03013|061|B||
03013|062|R|1.Lamictal (lamotrigine) US prscribing information. GlaxoSmithKline October,|1
03013|063|R|  2025.|1
03013|064|R|2.May TW, Rambeck B, Jurgens U. Serum concentrations of lamotrigine in|2
03013|065|R|  epileptic patients: the influence of dose and comedication. Ther Drug|2
03013|066|R|  Monit 1996 Oct;18(5):523-31.|2
03013|067|R|3.Grasela TH, Fiedler-Kelly J, Cox E, Womble GP, Risner ME, Chen C.|2
03013|068|R|  Population pharmacokinetics of lamotrigine adjunctive therapy in adults|2
03013|069|R|  with epilepsy. J Clin Pharmacol 1999 Apr;39(4):373-84.|2
03013|070|R|4.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
03013|071|R|  Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
03014|001|T|MONOGRAPH TITLE:  Lamotrigine/Selected Barbiturates|
03014|002|B||
03014|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03014|004|L|of severe adverse interaction.|
03014|005|B||
03014|006|A|MECHANISM OF ACTION:  Phenobarbital and perhaps other barbiturates induce|
03014|007|A|glucuronidation (UGT) pathways.  Lamotrigine is primarily metabolized by|
03014|008|A|glucuronidation.|
03014|009|B||
03014|010|E|CLINICAL EFFECTS:  Lower lamotrigine concentrations may lead to diminished|
03014|011|E|efficacy, e.g loss of seizure control.|
03014|012|B||
03014|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03014|014|P|of the inducer for longer than 1-2 weeks.|
03014|015|B||
03014|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with lamotrigine|
03014|017|M|and barbiturates without valproate should be observed for decreased|
03014|018|M|lamotrigine levels and clinical effectiveness.  The dose of lamotrigine may|
03014|019|M|need to be adjusted if these agents are added to or removed from lamotrigine|
03014|020|M|therapy.  Refer to the current lamotrigine prescribing information for|
03014|021|M|information on dosage adjustments.|
03014|022|M|   Lamotrigine levels for patients whose therapeutic regimens include|
03014|023|M|coadministration of lamotrigine with barbiturates and valproic acid should|
03014|024|M|be monitored for elevation.  The dose of lamotrigine should be adjusted|
03014|025|M|accordingly while the medication is being coadministered with valproic acid|
03014|026|M|and other antiepileptic drugs.|
03014|027|M|   If the barbiturate  is discontinued in a patient stabilized on|
03014|028|M|lamotrigine therapy, lamotrigine concentrations will increase over 1 to 4|
03014|029|M|weeks.  Monitor serum levels and adjust dosages as needed.|
03014|030|B||
03014|031|D|DISCUSSION:  In 24 epileptic adults taking carbamazepine, phenytoin,|
03014|032|D|phenobarbital, or primidone, the time to maximum concentration (Tmax),|
03014|033|D|half-life, and apparent plasma clearance for a single dose of lamotrigine|
03014|034|D|were 2.3 hours, 14.4 hours, and 1.10 ml/min/kg, respectively.  In 179|
03014|035|D|healthy adults taking no other medications, these values were 2.2 hours,|
03014|036|D|32.8 hours, and 0.44 ml/min/kg, respectively.|
03014|037|D|   In 17 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or|
03014|038|D|primidone, the Tmax, half-life, and apparent plasma clearance of multiple|
03014|039|D|dose lamotrigine were 2.0 hours, 12.6 hours, and 1.21 ml/min/kg.  These|
03014|040|D|values were 1.7 hours, 25.4 hours, and 0.58 ml/min/kg, respectively, in 36|
03014|041|D|healthy adults taking no other medications.|
03014|042|D|   In 10 pediatric patients with epilepsy aged 10 months to 5.3 years who|
03014|043|D|were taking carbamazepine, phenytoin, phenobarbital, or primidone,|
03014|044|D|lamotrigine Tmax, half-life, and apparent plasma clearance were 3.0 hours,|
03014|045|D|7.7 hours, and 3.62 ml/min/kg, respectively.  In 7 patients in the same age|
03014|046|D|range who where not taking other medications known to affect lamotrigine|
03014|047|D|clearance, these values were 5.2 hours, 19.0 hours, and 1.2 ml/min/kg,|
03014|048|D|respectively.|
03014|049|D|   In 527 adult patients with epilepsy, the mean oral clearance of|
03014|050|D|lamotrigine in patients receiving one concomitant enzyme-inducing|
03014|051|D|anti-epileptic agent and not valproic acid was estimated to be 1|
03014|052|D|ml/min/kg.(3)|
03014|053|D|   One study of 302 patients looked at the results of combining lamotrigine|
03014|054|D|with carbamazepine, phenytoin, or phenobarbital with or without valproic|
03014|055|D|acid.  The study found when the lamotrigine combinations contained valproic|
03014|056|D|acid that lamotrigine concentrations were two times higher when compared to|
03014|057|D|patients taking either lamotrigine alone or in combination with one of the|
03014|058|D|other antiepileptic drugs even when the lamotrigine doses were halved.|
03014|059|B||
03014|060|R|REFERENCES:|
03014|061|B||
03014|062|R|1.Lamictal (lamotrigine) US prscribing information. GlaxoSmithKline October,|1
03014|063|R|  2025.|1
03014|064|R|2.May TW, Rambeck B, Jurgens U. Serum concentrations of lamotrigine in|2
03014|065|R|  epileptic patients: the influence of dose and comedication. Ther Drug|2
03014|066|R|  Monit 1996 Oct;18(5):523-31.|2
03014|067|R|3.Grasela TH, Fiedler-Kelly J, Cox E, Womble GP, Risner ME, Chen C.|2
03014|068|R|  Population pharmacokinetics of lamotrigine adjunctive therapy in adults|2
03014|069|R|  with epilepsy. J Clin Pharmacol 1999 Apr;39(4):373-84.|2
03014|070|R|4.Anderson Gail D. Chapter 42: Pharmacokinetics and Drug Interactions. In:|6
03014|071|R|  Wyllie's Treatment of Epilepsy: Principles and Practice, 5th Ed. 2011.|6
03015|001|T|MONOGRAPH TITLE:  Slt Anticonvulsants/Hydantoins; Anticonvulsant|
03015|002|T|Barbiturates|
03015|003|B||
03015|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03015|005|L|take action as needed.|
03015|006|B||
03015|007|A|MECHANISM OF ACTION:  Phenobarbital, and perhaps other barbiturates, induce|
03015|008|A|multiple metabolic enzymes including CYP1A2, CYP2C9, CYP2C19, CYP3A4, and|
03015|009|A|glucuronidation (UGT) pathways.  Phenytoin, and perhaps other hydantoins,|
03015|010|A|induce multiple metabolic enzymes including CYP2C9, CYP2C19, CYP3A4 and UGT|
03015|011|A|pathways.  Felbamate, oxcarbazepine, and valproic acid are metabolized by|
03015|012|A|one or more of these induced pathways.|
03015|013|A|   Valproic acid may inhibit the CYP2C9 mediated metabolism of|
03015|014|A|phenobarbital, possibly other barbiturates, and hydantoins.|
03015|015|A|   Felbamate and oxcarbazepine may inhibit the CYP2C19 mediated metabolism|
03015|016|A|of phenytoin and barbiturates.|
03015|017|A|   Primidone is metabolized to phenobarbital.|
03015|018|B||
03015|019|E|CLINICAL EFFECTS:  Lower felbamate, oxcarbazepine, and valproic acid|
03015|020|E|concentrations may lead to diminished efficacy, e.g loss of seizure control,|
03015|021|E|or new onset/more difficult to control manic episodes.  Higher barbiturate|
03015|022|E|and/or hydantoin concentrations may lead to increased sedation or further|
03015|023|E|CNS depression.|
03015|024|B||
03015|025|P|PREDISPOSING FACTORS:  None determined.|
03015|026|B||
03015|027|M|PATIENT MANAGEMENT:  For patients stabilized on phenytoin or barbiturates,|
03015|028|M|monitor for increased phenytoin or barbiturate levels approximately 4 to 7|
03015|029|M|days after initiation or after an increase in the dose of felbamate or|
03015|030|M|oxcarbazepine.  The US manufacturer of felbamate recommends that the dosage|
03015|031|M|of phenobarbital and phenytoin be reduced by 20-33% when felbamate is|
03015|032|M|initiated. The US manufacturer of extended release oxcarbazepine recommends|
03015|033|M|initiating extended release oxcarbazepine at 900 mg once daily in adults and|
03015|034|M|12-15 mg/kg once daily (not to exceed 900 mg per day in the first week) in|
03015|035|M|pediatric patients.|
03015|036|M|   If phenytoin or a barbiturate is added to a patient stabilized on|
03015|037|M|felbamate or oxcarbazepine, the dose of felbamate or oxcarbazepine may need|
03015|038|M|to be increased.  Onset of induction is gradual and may not be maximal for|
03015|039|M|days or weeks.|
03015|040|M|   Initiation of barbiturate or hydantoin therapy in a patient already|
03015|041|M|stabilized on valproic acid will lead to a gradual lowering of valproic acid|
03015|042|M|concentrations over approximately 1 to 3 weeks.  Valproate concentrations|
03015|043|M|could fall by 50%.  Monitor valproate levels and adjust the dose as needed|
03015|044|M|to maintain therapeutic efficacy.  Due to valproic acid inhibition of|
03015|045|M|barbiturate and hydantoin metabolism, consider starting barbiturate or|
03015|046|M|hydantoin therapy at a lower than usual dose and increase as tolerated.|
03015|047|M|Closely monitor therapy for needed adjustments in the barbiturate or|
03015|048|M|hydantoin dose in patients maintained on valproate therapy when initiating|
03015|049|M|these agents.  Conversely, due to enzyme induction, larger than expected|
03015|050|M|valproic acid doses may be required to achieve therapeutic benefit.  Educate|
03015|051|M|the patient regarding possible adverse effects and the need for valproate|
03015|052|M|measurements to assure treatment efficacy.|
03015|053|M|   If the barbiturate or hydantoin is discontinued in a patient stabilized|
03015|054|M|on felbamate, oxcarbazepine, and valproic acid therapy, felbamate,|
03015|055|M|oxcarbazepine, and valproic acid concentrations will increase over 1 to 4|
03015|056|M|weeks.  Monitor serum levels and adjust dosages as needed.|
03015|057|B||
03015|058|D|DISCUSSION:  In interaction studies, oxcarbazepine dosage > 1200 mg daily|
03015|059|D|increased phenytoin concentrations 30 to 40%; phenytoin doses of 250 to|
03015|060|D|500mg daily decreased eslicarbazepine or oxcarbazepine concentrations|
03015|061|D|approximately 30%.|
03015|062|D|   In a study of lower dosage (900 mg daily) oxcarbazepine and phenytoin, no|
03015|063|D|effects on phenytoin levels were seen.|
03015|064|D|   Prescribing information for oxcarbazepine states that phenobarbital doses|
03015|065|D|of 100 to 150 mg daily decreased the mean concentration of its active|
03015|066|D|metabolite (eslicarbazepine) 25%.|
03015|067|D|   In a study in 10 patients with epilepsy maintained on phenytoin therapy,|
03015|068|D|phenytoin minimum concentration (Cmin) increased by 24% and 47% following|
03015|069|D|the addition of felbamate at dosages of 1200 mg/day and 1800 mg/day,|
03015|070|D|respectively.  Phenytoin dosage reductions of 40% were necessary in 8 of the|
03015|071|D|10 subjects in order to achieve a felbamate dosage of 3600 mg/day while|
03015|072|D|limiting adverse effects and maintain phenytoin levels.|
03015|073|D|   In another clinical trial, decreasing the dosage of phenytoin by 20% at|
03015|074|D|the initiation of felbamate therapy resulted in no significant changes in|
03015|075|D|phenytoin levels.|
03015|076|D|   Phenytoin has been shown to almost double the clearance of felbamate,|
03015|077|D|resulting in a 45% decrease in felbamate levels.|
03015|078|D|   In a study in 12 healthy males, administration of felbamate (2400 mg|
03015|079|D|daily) increased phenobarbital levels by 25%.|
03015|080|D|   In a study in 24 healthy subjects, administration of felbamate (2400 mg|
03015|081|D|daily) increased phenobarbital (100 mg daily) area-under-curve (AUC) and|
03015|082|D|maximum concentration (Cmax) levels by 22% and 24%, respectively.|
03015|083|D|   In clinical trials, patients receiving concurrent phenobarbital were|
03015|084|D|found to have felbamate concentrations that were 29% lower than patients not|
03015|085|D|receiving concurrent phenobarbital.  In contrast, a retrospective review of|
03015|086|D|felbamate levels found no effect by barbiturates.|
03015|087|D|   In a case report, felbamate was initiated and titrated to 50 mg/kg/day|
03015|088|D|over three weeks.  At this time, the patient's phenobarbital dosage was|
03015|089|D|decreased 13% (from 230 mg/daily to 200 mg/day).  Despite this, the|
03015|090|D|patient's phenobarbital level increased 42% and the patient developed|
03015|091|D|neurotoxicity.  The patient's phenobarbital dosage was further reduced to|
03015|092|D|35% of the original dosage (to 150 mg daily) and the patient's phenobarbital|
03015|093|D|levels returned to therapeutic range.|
03015|094|D|   Valproate metabolites are formed via three major pathways: mitochondrial|
03015|095|D|beta-oxidation (40%), glucuronidation (30-50%), and CYP P-450 (10%).|
03015|096|D|Barbiturates induce several glucuronidation and CYP450 pathways, but not|
03015|097|D|mitochondrial pathways. Manufacturer prescribing for valproic acid states|
03015|098|D|that concomitant primidone or phenobarbital therapy may double valproic acid|
03015|099|D|clearance.|
03015|100|D|   An interaction study in health subjects administered valproate 250mg BID|
03015|101|D|for 14 days with a single 60 mg dose of phenobarbital leading to a 50%|
03015|102|D|increase in half-life and a 30% decrease in the clearance of phenobarbital.|
03015|103|D|   In most patients the active form of phenytoin (the unbound drug) is not|
03015|104|D|significantly changed by valproic acid. Decreased serum phenytoin|
03015|105|D|concentrations have been reported, as have symptoms of phenytoin toxicity.|
03015|106|D|Increases in frequency of seizures have also been reported. Patients|
03015|107|D|receiving phenytoin and valproic acid concurrently tend to have lower serum|
03015|108|D|valproic acid concentrations than patients taking valproic acid alone.|
03015|109|D|Concomitant administration of valproate (400 mg three times a day) with|
03015|110|D|phenytoin (250 mg) in 7 healthy volunteers increased the free fraction of|
03015|111|D|phenytoin by 60%. The total plasma clearance and volume of distrubution of|
03015|112|D|phenytoin increased 30% with concomitant valproate.|
03015|113|B||
03015|114|R|REFERENCES:|
03015|115|B||
03015|116|R|1.Depakote (divalproex sodium) US prescribing information. AbbVie Inc.|1
03015|117|R|  February, 2023.|1
03015|118|R|2.Patel IH, Levy RH, Cutler RE. Phenobarbital--valproic acid interaction.|2
03015|119|R|  Clin Pharmacol Ther 1980 Apr;27(4):515-21.|2
03015|120|R|3.Bruni J, Wilder BJ, Perchalski RJ, Hammond EJ, Villarreal HJ. Valproic|5
03015|121|R|  acid and plasma levels of phenobarbital. Neurology 1980 Jan;30(1):94-7.|5
03015|122|R|4.Windorfer A Jr, Sauer W, Gadeke R. Elevation of diphenylhydantoin and|3
03015|123|R|  primidone serum concentration by addition of dipropylacetate, a new|3
03015|124|R|  anticonvulsant drug. Acta Paediatr Scand 1975 Sep;64(5):771-2.|3
03015|125|R|5.Bardy A, Hari R, Lehtovaara R, Majuri H. Valproate may lower|3
03015|126|R|  serum-phenytoin. Lancet 1976 Dec 11;2(7998):1297-8.|3
03015|127|R|6.Patsalos PN, Lascelles PT. Valproate may lower serum-phenytoin. Lancet|5
03015|128|R|  1977 Jan 1;1(8001):50-1.|5
03015|129|R|7.Patsalos PN, Lascelles PT. Effect of sodium valproate on plasma protein|5
03015|130|R|  binding of diphenylhydantoin. J Neurol Neurosurg Psychiatry 1977 Jun;|5
03015|131|R|  40(6):570-4.|5
03015|132|R|8.Wilder BJ, Willmore LJ, Bruni J, Villarreal HJ. Valproic acid: interaction|2
03015|133|R|  with other anticonvulsant drugs. Neurology 1978 Sep;28(9 Pt 1):892-6.|2
03015|134|R|9.Dahlqvist R, Borga O, Rane A, Walsh Z, Sjoqvist F. Decreased plasma|2
03015|135|R|  protein binding of phenytoin in patients on valproic acid. Br J Clin|2
03015|136|R|  Pharmacol 1979 Dec;8(6):547-52.|2
03015|137|R|10.Reunanen MI, Luoma P, Myllyla VV, Hokkanen E. Low serum valproic acid|2
03015|138|R|   concentrations in epileptic patients on combination therapy. Curr Ther|2
03015|139|R|   Res 1980 Sep;28(3):456-62.|2
03015|140|R|11.Sansom LN, Beran RC, Schapel GJ. Interaction between phenytoin and|3
03015|141|R|   valproate. Med J Aust 1980 Aug 23;2(4):212.|3
03015|142|R|12.Monks A, Richens A. Effect of single doses of sodium valproate on serum|2
03015|143|R|   phenytoin levels and protein binding in epileptic patients. Clin|2
03015|144|R|   Pharmacol Ther 1980 Jan;27(1):89-95.|2
03015|145|R|13.Bruni J, Gallo JM, Lee CS, Perchalski RJ, Wilder BJ. Interactions of|2
03015|146|R|   valproic acid with phenytoin. Neurology 1980 Nov;30(11):1233-6.|2
03015|147|R|14.Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on|2
03015|148|R|   sodium valproate - a 5- year follow-up study in 100 children with|2
03015|149|R|   epilepsy. Acta Neurol Scand 1982 May;65(5):504-23.|2
03015|150|R|15.Palm R, Silseth C, Alvan G. Phenytoin intoxication as the first symptom|3
03015|151|R|   of fatal liver damage induced by sodium valproate. Br J Clin Pharmacol|3
03015|152|R|   1984 May;17(5):597-9.|3
03015|153|R|16.Riva R, Albani F, Contin M, Perucca E, Ambrosetto G, Gobbi G, Santucci M,|2
03015|154|R|   Procaccianti G, Baruzzi A. Time-dependent interaction between phenytoin|2
03015|155|R|   and valproic acid. Neurology 1985 Apr;35(4):510-5.|2
03015|156|R|17.Miles MV, Snead OC 3rd, Thorn MD. Predictability of unbound antiepileptic|2
03015|157|R|   drug concentrations in children treated with valproic acid and phenytoin.|2
03015|158|R|   Clin Pharm 1988 Sep;7(9):688-93.|2
03015|159|R|18.Haidukewych D, Rodin EA, Zielinski JJ. Derivation and evaluation of an|2
03015|160|R|   equation for prediction of free phenytoin concentration in patients|2
03015|161|R|   co-medicated with valproic acid. Ther Drug Monit 1989;11(2):134-9.|2
03015|162|R|19.Johnson GJ, Kilpatrick CJ, Bury RW, Fullinfaw RO, Moulds RF. Unbound|2
03015|163|R|   phenytoin plasma concentrations in patients comedicated with sodium|2
03015|164|R|   valproate--the predictive value of plasma albumin concentration. Br J|2
03015|165|R|   Clin Pharmacol 1989 Jun;27(6):843-9.|2
03015|166|R|20.May T, Rambeck B. Fluctuations of unbound and total phenytoin|2
03015|167|R|   concentrations during the day in epileptic patients on valproic acid|2
03015|168|R|   comedication. Ther Drug Monit 1990 Mar;12(2):124-8.|2
03015|169|R|21.Trileptal (oxcarbazepine) US prescribing information. Novartis|1
03015|170|R|   Pharmaceuticals Corporation November, 2017.|1
03015|171|R|22.Oxtellar XR (oxcarbazepine) extended-release US prescribing information.|1
03015|172|R|   Supernus, Inc. December, 2018.|1
03015|173|R|23.Lakehal F, Wurden CJ, Kalhorn TF, Levy RH. Carbamazepine and|5
03015|174|R|   oxcarbazepine decrease phenytoin metabolism through inhibition of|5
03015|175|R|   CYP2C19. Epilepsy Res 2002 Dec;52(2):79-83.|5
03015|176|R|24.McKee PJ, Blacklaw J, Forrest G, Gillham RA, Walker SM, Connelly D,|2
03015|177|R|   Brodie MJ. A double-blind, placebo-controlled interaction study between|2
03015|178|R|   oxcarbazepine and carbamazepine, sodium valproate and phenytoin in|2
03015|179|R|   epileptic patients. Br J Clin Pharmacol 1994 Jan;37(1):27-32.|2
03015|180|R|25.Felbatrol (felbamate) US prescribing information. MedPoint|1
03015|181|R|   Pharmaceuticals Inc. August 27, 2012.|1
03015|182|R|26.Fuerst RH, Graves NM, Leppik IE, Brundage RC, Holmes GB, Remmel RP.|3
03015|183|R|   Felbamate increases phenytoin but decreases carbamazepine concentrations.|3
03015|184|R|   Epilepsia 1988 Jul-Aug;29(4):488-91.|3
03015|185|R|27.Graves NM, Holmes GB, Fuerst RH, Leppik IE. Effect of felbamate on|2
03015|186|R|   phenytoin and carbamazepine serum concentrations. Epilepsia 1989 Mar-Apr;|2
03015|187|R|   30(2):225-9.|2
03015|188|R|28.Wagner ML, Graves NM, Marienau K, Holmes GB, Remmel RP, Leppik IE.|2
03015|189|R|   Discontinuation of phenytoin and carbamazepine in patients receiving|2
03015|190|R|   felbamate. Epilepsia 1991 May-Jun;32(3):398-406.|2
03015|191|R|29.Reidenberg P, Glue P, Banfield CR, Colucci RD, Meehan JW, Radwanski E,|2
03015|192|R|   Mojavarian P, Lin CC, Nezamis J, Guillaume M, et al. Effects of felbamate|2
03015|193|R|   on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995 Sep;|2
03015|194|R|   58(3):279-87.|2
03015|195|R|30.Kelley MT, Walson PD, Cox S, Dusci LJ. Population pharmacokinetics of|2
03015|196|R|   felbamate in children. Ther Drug Monit 1997 Feb;19(1):29-36.|2
03015|197|R|31.Gidal BE, Zupanc ML. Potential pharmacokinetic interaction between|3
03015|198|R|   felbamate and phenobarbital. Ann Pharmacother 1994 Apr;28(4):455-8.|3
03016|001|T|MONOGRAPH TITLE:  Selected Anticonvulsants/Selected Barbiturates|
03016|002|B||
03016|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03016|004|L|of severe adverse interaction.|
03016|005|B||
03016|006|A|MECHANISM OF ACTION:  Phenobarbital, and perhaps other barbiturates, induce|
03016|007|A|multiple metabolic enzymes including CYP1A2, CYP2C9, CYP2C19, CYP3A4, and|
03016|008|A|glucuronidation (UGT) pathways.  Felbamate, oxcarbazepine, and valproic acid|
03016|009|A|are metabolized by one or more of these induced pathways.|
03016|010|A|  Valproic acid may inhibit the CYP2C9 mediated metabolism of phenobarbital,|
03016|011|A|and possibly other barbiturates.|
03016|012|A|  Felbamate and oxcarbazepine may inhibit the CYP2C19 mediated metabolism of|
03016|013|A|barbiturates.|
03016|014|B||
03016|015|E|CLINICAL EFFECTS:  Lower felbamate, oxcarbazepine, and valproic acid|
03016|016|E|concentrations may lead to diminished efficacy, e.g loss of seizure control,|
03016|017|E|or new onset/more difficult to control manic episodes.  Higher barbiturate|
03016|018|E|concentrations may lead to increased sedation or further CNS depression.|
03016|019|B||
03016|020|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03016|021|P|of the inducer for longer than 1-2 weeks.|
03016|022|B||
03016|023|M|PATIENT MANAGEMENT:  For patients stabilized on barbiturates, monitor for|
03016|024|M|increased barbiturate levels approximately 4 to 7 days after initiation or|
03016|025|M|after an increase in the dose of felbamate or oxcarbazepine.  The US|
03016|026|M|manufacturer of felbamate recommends that the dosage of phenobarbital be|
03016|027|M|reduced by 20-33% when felbamate is initiated.  The US manufacturer of|
03016|028|M|extended release oxcarbazepine recommends initiating extended release|
03016|029|M|oxcarbazepine at 900 mg once daily in adults and 12-15 mg/kg once daily (not|
03016|030|M|to exceed 900 mg per day in the first week) in pediatric patients.|
03016|031|M|   If a barbiturate is added to a patient stabilized on felbamate or|
03016|032|M|oxcarbazepine, the dose of felbamate or oxcarbazepine may need to be|
03016|033|M|increased.  Onset of induction is gradual and may not be maximal for days or|
03016|034|M|weeks.|
03016|035|M|   Initiation of barbiturate therapy in a patient already stabilized on|
03016|036|M|valproic acid will lead to a gradual lowering of valproic acid|
03016|037|M|concentrations over approximately 1 to 3 weeks.  Valproate concentrations|
03016|038|M|could fall by 50%.  Monitor valproate levels and adjust the dose as needed|
03016|039|M|to maintain therapeutic efficacy.  Due to valproic acid inhibition of|
03016|040|M|barbiturate metabolism, consider starting barbiturate therapy at a lower|
03016|041|M|than usual dose and increase as tolerated.  Closely monitor therapy for|
03016|042|M|needed adjustments in the barbiturate dose in patients maintained on|
03016|043|M|valproate therapy when initiating these agents.  Conversely, due to enzyme|
03016|044|M|induction, larger than expected valproic acid doses may be required to|
03016|045|M|achieve therapeutic benefit.  Educate the patient regarding possible adverse|
03016|046|M|effects and the need for valproate measurements to assure treatment|
03016|047|M|efficacy.|
03016|048|M|   If the barbiturate is discontinued in a patient stabilized on felbamate,|
03016|049|M|oxcarbazepine, and valproic acid therapy, felbamate, oxcarbazepine, and|
03016|050|M|valproic acid concentrations will increase over 1 to 4 weeks.  Monitor serum|
03016|051|M|levels and adjust dosages as needed.|
03016|052|B||
03016|053|D|DISCUSSION:  Prescribing information for oxcarbazepine states that|
03016|054|D|phenobarbital doses of 100 to 150 mg daily decreased the mean concentration|
03016|055|D|of its active metabolite (eslicarbazepine) 25%.|
03016|056|D|   In a study in 12 healthy males, administration of felbamate (2400 mg|
03016|057|D|daily) increased phenobarbital levels by 25%.|
03016|058|D|   In a study in 24 healthy subjects, administration of felbamate (2400 mg|
03016|059|D|daily) increased phenobarbital (100 mg daily) area-under-curve (AUC) and|
03016|060|D|maximum concentration (Cmax) levels by 22% and 24%, respectively.|
03016|061|D|   In clinical trials, patients receiving concurrent phenobarbital were|
03016|062|D|found to have felbamate concentrations that were 29% lower than patients not|
03016|063|D|receiving concurrent phenobarbital.  In contrast, a retrospective review of|
03016|064|D|felbamate levels found no effect by barbiturates.|
03016|065|D|   In a case report, felbamate was initiated and titrated to 50 mg/kg/day|
03016|066|D|over three weeks.  At this time, the patient's phenobarbital dosage was|
03016|067|D|decreased 13% (from 230 mg/daily to 200 mg/day).  Despite this, the|
03016|068|D|patient's phenobarbital level increased 42% and the patient developed|
03016|069|D|neurotoxicity.  The patient's phenobarbital dosage was further reduced to|
03016|070|D|35% of the original dosage (to 150 mg daily) and the patient's phenobarbital|
03016|071|D|levels returned to therapeutic range.|
03016|072|D|   Valproate metabolites are formed via three major pathways: mitochondrial|
03016|073|D|beta-oxidation (40%), glucuronidation (30-50%), and CYP P-450 (10%).|
03016|074|D|Barbiturates induce several glucuronidation and CYP450 pathways, but not|
03016|075|D|mitochondrial pathways. Manufacturer prescribing for valproic acid states|
03016|076|D|that concomitant primidone or phenobarbital therapy may double valproic acid|
03016|077|D|clearance.|
03016|078|D|   An interaction study in health subjects administered valproate 250mg BID|
03016|079|D|for 14 days with a single 60 mg dose of phenobarbital leading to a 50%|
03016|080|D|increase in half-life and a 30% decrease in the clearance of phenobarbital.|
03016|081|B||
03016|082|R|REFERENCES:|
03016|083|B||
03016|084|R|1.Depakote (divalproex sodium) US prescribing information. AbbVie Inc.|1
03016|085|R|  February, 2023.|1
03016|086|R|2.Patel IH, Levy RH, Cutler RE. Phenobarbital--valproic acid interaction.|2
03016|087|R|  Clin Pharmacol Ther 1980 Apr;27(4):515-21.|2
03016|088|R|3.Bruni J, Wilder BJ, Perchalski RJ, Hammond EJ, Villarreal HJ. Valproic|5
03016|089|R|  acid and plasma levels of phenobarbital. Neurology 1980 Jan;30(1):94-7.|5
03016|090|R|4.Windorfer A Jr, Sauer W, Gadeke R. Elevation of diphenylhydantoin and|3
03016|091|R|  primidone serum concentration by addition of dipropylacetate, a new|3
03016|092|R|  anticonvulsant drug. Acta Paediatr Scand 1975 Sep;64(5):771-2.|3
03016|093|R|5.Wilder BJ, Willmore LJ, Bruni J, Villarreal HJ. Valproic acid: interaction|2
03016|094|R|  with other anticonvulsant drugs. Neurology 1978 Sep;28(9 Pt 1):892-6.|2
03016|095|R|6.Reunanen MI, Luoma P, Myllyla VV, Hokkanen E. Low serum valproic acid|2
03016|096|R|  concentrations in epileptic patients on combination therapy. Curr Ther Res|2
03016|097|R|  1980 Sep;28(3):456-62.|2
03016|098|R|7.Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on|2
03016|099|R|  sodium valproate - a 5- year follow-up study in 100 children with|2
03016|100|R|  epilepsy. Acta Neurol Scand 1982 May;65(5):504-23.|2
03016|101|R|8.Johnson GJ, Kilpatrick CJ, Bury RW, Fullinfaw RO, Moulds RF. Unbound|2
03016|102|R|  phenytoin plasma concentrations in patients comedicated with sodium|2
03016|103|R|  valproate--the predictive value of plasma albumin concentration. Br J Clin|2
03016|104|R|  Pharmacol 1989 Jun;27(6):843-9.|2
03016|105|R|9.Trileptal (oxcarbazepine) US prescribing information. Novartis|1
03016|106|R|  Pharmaceuticals Corporation November, 2017.|1
03016|107|R|10.Oxtellar XR (oxcarbazepine) extended-release US prescribing information.|1
03016|108|R|   Supernus, Inc. December, 2018.|1
03016|109|R|11.Felbatrol (felbamate) US prescribing information. MedPoint|1
03016|110|R|   Pharmaceuticals Inc. August 27, 2012.|1
03016|111|R|12.Reidenberg P, Glue P, Banfield CR, Colucci RD, Meehan JW, Radwanski E,|2
03016|112|R|   Mojavarian P, Lin CC, Nezamis J, Guillaume M, et al. Effects of felbamate|2
03016|113|R|   on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995 Sep;|2
03016|114|R|   58(3):279-87.|2
03016|115|R|13.Kelley MT, Walson PD, Cox S, Dusci LJ. Population pharmacokinetics of|2
03016|116|R|   felbamate in children. Ther Drug Monit 1997 Feb;19(1):29-36.|2
03016|117|R|14.Gidal BE, Zupanc ML. Potential pharmacokinetic interaction between|3
03016|118|R|   felbamate and phenobarbital. Ann Pharmacother 1994 Apr;28(4):455-8.|3
03017|001|T|MONOGRAPH TITLE:  Dapagliflozin; Ertugliflozin/ACE Inhibitors; ARBs (mono|
03017|002|T|deleted 03/08/2023)|
03017|003|B||
03017|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03017|005|L|take action as needed.|
03017|006|B||
03017|007|A|MECHANISM OF ACTION:  Dapagliflozin and ertugliflozin produce intravascular|
03017|008|A|volume contraction through osmotic diuresis, which can result in hypotension|
03017|009|A|in patients who are volume depleted from ACE inhibitor or ARB use.(1-3)|
03017|010|B||
03017|011|E|CLINICAL EFFECTS:  Concurrent use of dapagliflozin or ertugliflozin with an|
03017|012|E|ACE inhibitor or ARB may result in dehydration and hypotension.(1-3)|
03017|013|B||
03017|014|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
03017|015|P|have a eGFR of less than 60 ml/min/1.73m2, are also taking diuretics and/or|
03017|016|P|NSAIDs, are on a low salt diet, have low systolic blood pressure prior to|
03017|017|P|initiating dapagliflozin or ertugliflozin, and/or are 65 years of age or|
03017|018|P|older.(1-3)|
03017|019|B||
03017|020|M|PATIENT MANAGEMENT:  Before initiating dapagliflozin or ertugliflozin in|
03017|021|M|patients maintained on ACE inhibitors or ARBs, assess volume status and|
03017|022|M|correct if needed and assess renal function.  Patients receiving concurrent|
03017|023|M|therapy should be monitored for hypotension, and renal failure.(1-3)|
03017|024|B||
03017|025|D|DISCUSSION:  In clinical trials of canagliflozin, increases in serum|
03017|026|D|potassium were more commonly seen in patients using ACE inhibitors and ARBs.|
03017|027|D|In a pool of eight Phase 3 clinical trials that examined patients with|
03017|028|D|post-baseline serum potassium levels, 6.8% of patients taking canagliflozin|
03017|029|D|and either an ACE inhibitor or ARB had serum potassium levels outside|
03017|030|D|pre-defined study limits, compared with 5.2% of patients not taking an ACE|
03017|031|D|inhibitor or ARB.  In this same pool of patients, 3.5% of patients taking|
03017|032|D|canagliflozin with either an ACE inhibitor or ARB experienced volume|
03017|033|D|depletion-related adverse events, compared with 1.4% of patients not taking|
03017|034|D|an ACE inhibitor or ARB.(4)|
03017|035|D|   Cases of acute renal failure, most requiring hospitalization, have been|
03017|036|D|reported in patients receiving canagliflozin and dapagliflozin.  Fifty-one|
03017|037|D|of 101 cases involved concurrent use of ACE inhibitors.(1)|
03017|038|B||
03017|039|R|REFERENCES:|
03017|040|B||
03017|041|R|1.USFood and Drug Administration. FDA Drug Safety Communication:  FDA|1
03017|042|R|  strengthens kidney warnings for diabetes medicines canagliflozin|1
03017|043|R|  (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). available|1
03017|044|R|  at:  http://www.fda.gov/downloads/Drugs/DrugSafety/UCM506772.pdf June 14,|1
03017|045|R|  2016.|1
03017|046|R|2.Farxiga (dapagliflozin) US prescribing information. AstraZeneca|1
03017|047|R|  Pharmaceuticals LP June, 2024.|1
03017|048|R|3.Steglatro (ertugliflozin) US prescribing information. Merck & Co. October|1
03017|049|R|  2022.|1
03017|050|R|4.Wolf MS. Personal communication:  Invokana - Concomitant use with|1
03017|051|R|  ACE/ARBs. Janssen Scientific Affairs, LLC June 9, 2014.|1
03018|001|T|MONOGRAPH TITLE:  Sodium Fusidate/Selected Protease Inhibitors|
03018|002|B||
03018|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03018|004|L|of severe adverse interaction.|
03018|005|B||
03018|006|A|MECHANISM OF ACTION:  Sodium fusidate and selected protease inhibitors may|
03018|007|A|inhibit the biotransformation of each other by CYP3A4.(1,2)|
03018|008|B||
03018|009|E|CLINICAL EFFECTS:  Concurrent use may result in increased levels and|
03018|010|E|toxicity from sodium fusidate and protease inhibitors, including|
03018|011|E|hepatotoxicity(1,2) and bone marrow suppression.(3)|
03018|012|B||
03018|013|P|PREDISPOSING FACTORS:  None determined.|
03018|014|B||
03018|015|M|PATIENT MANAGEMENT:  The Australian and UK manufacturers of sodium fusidate|
03018|016|M|state that concurrent use of sodium fusidate and CYP3A4 biotransformed drugs|
03018|017|M|such as ritonavir and saquinavir is not recommended.(1,2)|
03018|018|M|   The Canadian and UK manufacturers of ritonavir and the Canadian|
03018|019|M|manufacturer of nirmatrelvir/ritonavir state concurrent use with fusidic|
03018|020|M|acid is contraindicated.(3-5)|
03018|021|M|   The UK manufacturer of lopinavir/ritonavir states that concurrent use|
03018|022|M|with fusidic acid is contraindicated for dermatological infections and not|
03018|023|M|recommended for osteo-articular infections.(6)|
03018|024|M|   The US manufacturer of saquinavir states that concurrent use of|
03018|025|M|saquinavir/ritonavir and fusidic acid is not recommended due to potential|
03018|026|M|for increased mutual toxicities.(7)|
03018|027|B||
03018|028|D|DISCUSSION:  Although the specifics of sodium fusidate metabolic pathways|
03018|029|D|are not known, an interaction between sodium fusidate and drugs that are|
03018|030|D|biotransformed by CYP3A4 is suspected.(1,2)|
03018|031|B||
03018|032|R|REFERENCES:|
03018|033|B||
03018|034|R|1.Fucidin (fusidic acid) Australian prescribing information. CSL Limited|1
03018|035|R|  January 9, 2003.|1
03018|036|R|2.Fucidin (fusidic acid) UK summary of product characteristics. Leo|1
03018|037|R|  Laboratories Lmited October 24, 2012.|1
03018|038|R|3.Norvir (ritonavir) Canadian prescribing information. Abbott May 29, 2019.|1
03018|039|R|4.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
03018|040|R|  Monograph. Pfizer Canada ULC October, 2023.|1
03018|041|R|5.Norvir (ritonavir) UK summary of product characteristics. AbbVie, Ltd.|1
03018|042|R|  July 18, 2019.|1
03018|043|R|6.Kaletra (lopinavir/ritonavir) UK summary of product characteristics.|1
03018|044|R|  Abbott Laboratories, Limited July 11, 2008.|1
03018|045|R|7.Invirase (saquinavir mesylate) US prescribing information. Roche|1
03018|046|R|  Laboratories, Inc. March, 2019.|1
03019|001|T|MONOGRAPH TITLE:  Deutetrabenazine/QT Prolonging Agents (mono deleted|
03019|002|T|12/17/2020)|
03019|003|B||
03019|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03019|005|L|take action as needed.|
03019|006|B||
03019|007|A|MECHANISM OF ACTION:  Tetrabenazine has been shown to prolong the QTc|
03019|008|A|interval by about 8 msec.(1)  Deutetrabenazine may increase the QT interval|
03019|009|A|at higher than normal blood levels.(2)  Concurrent use with other agents|
03019|010|A|that prolong the QTc interval may result in additive effects on the QTc|
03019|011|A|interval.(2)|
03019|012|B||
03019|013|E|CLINICAL EFFECTS:  The concurrent use of deutetrabenazine with other agents|
03019|014|E|that prolong the QTc interval may result in potentially life-threatening|
03019|015|E|cardiac arrhythmias, including torsades de pointes.(1)|
03019|016|B||
03019|017|P|PREDISPOSING FACTORS:  Deutetrabenazine may be more likely to prolong the QT|
03019|018|P|interval at dosages greater than 24 mg per day or in patients who are CYP2D6|
03019|019|P|poor metabolizers or who are taking strong CYP2D6 inhibitors.(2)|
03019|020|P|   The risk of QT prolongation or torsade de pointes may be increased in|
03019|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03019|022|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03019|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03019|024|P|advanced age.(3)|
03019|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03019|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03019|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03019|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03019|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03019|030|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03019|031|P|dysfunction).(3)|
03019|032|B||
03019|033|M|PATIENT MANAGEMENT:  The US manufacturer of deutetrabenazine states that the|
03019|034|M|QTc interval should be assessed before and after initiating other drugs that|
03019|035|M|are known to prolong the QT interval and/or increasing the dose of|
03019|036|M|deutetrabenazine and/or the QT prolonging agent.(2)|
03019|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03019|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03019|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03019|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03019|041|B||
03019|042|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
03019|043|D|degrees of potential to prolong the QTc interval.  Agents linked to this|
03019|044|D|monograph have been shown to prolong the QTc interval either through their|
03019|045|D|mechanism of action, through studies on their effects on the QTc interval,|
03019|046|D|or through reports of QTc prolongation and/or torsades de pointes in|
03019|047|D|clinical trials and/or postmarketing reports.(4)|
03019|048|B||
03019|049|R|REFERENCES:|
03019|050|B||
03019|051|R|1.Xenazine (tetrabenazine) US prescribing information. Valeant International|1
03019|052|R|  September, 2017.|1
03019|053|R|2.Austedo (deutetrabenazine) US prescribing information. Teva|1
03019|054|R|  Pharmaceutical, Inc. July, 2019.|1
03019|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03019|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03019|057|R|  settings: a scientific statement from the American Heart Association and|6
03019|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03019|059|R|  2;55(9):934-47.|6
03019|060|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03019|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03019|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03019|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03020|001|T|MONOGRAPH TITLE:  Atazanavir/Selected Strong CYP3A4 Inducers|
03020|002|B||
03020|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03020|004|L|is contraindicated and generally should not be dispensed or administered to|
03020|005|L|the same patient.|
03020|006|B||
03020|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 are expected to increase the|
03020|008|A|metabolism of atazanavir.(1)|
03020|009|B||
03020|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong inducers of CYP3A4 may|
03020|011|E|result in decreased levels and effectiveness of atazanavir and development|
03020|012|E|of drug resistance.(1)|
03020|013|B||
03020|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03020|015|P|of the inducer for longer than 1-2 weeks.|
03020|016|B||
03020|017|M|PATIENT MANAGEMENT:  Concurrent administration of strong inducers of CYP3A4|
03020|018|M|with atazanavir is contraindicated.(1)|
03020|019|B||
03020|020|D|DISCUSSION:  Atazanavir is metabolized by CYP3A4.  Strong inducers of CYP3A4|
03020|021|D|are expected to reduce atazanavir levels, which may lead to loss of|
03020|022|D|response.(1)|
03020|023|D|   Strong inducers of CYP3A4 included on this monograph include:|
03020|024|D|apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin,|
03020|025|D|lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, and|
03020|026|D|primidone.(2,3)|
03020|027|B||
03020|028|R|REFERENCES:|
03020|029|B||
03020|030|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
03020|031|R|  Squibb Company December, 2024.|1
03020|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03020|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03020|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03020|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03020|036|R|  11/14/2017.|1
03020|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
03020|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03021|001|T|MONOGRAPH TITLE:  Piperacillin-Tazobactam/Vancomycin|
03021|002|B||
03021|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03021|004|L|take action as needed.|
03021|005|B||
03021|006|A|MECHANISM OF ACTION:  The nephrotoxic effects of piperacillin-tazobactam may|
03021|007|A|be additive with those of vancomycin.(1-5)|
03021|008|B||
03021|009|E|CLINICAL EFFECTS:  The concurrent administration of piperacillin-tazobactam|
03021|010|E|with vancomycin may result in additive nephrotoxic effects.(1-5)|
03021|011|B||
03021|012|P|PREDISPOSING FACTORS:  None determined.|
03021|013|B||
03021|014|M|PATIENT MANAGEMENT:  The manufacturer of piperacillin-tazobactam states that|
03021|015|M|the concurrent use of piperacillin-tazobactam and vancomycin warrants|
03021|016|M|routine monitoring of kidney function.(1)|
03021|017|M|   The manufacturer of vancomycin states renal function monitoring is|
03021|018|M|warranted when used concurrently and/or sequentially with other potentially|
03021|019|M|nephrotoxic drugs.(2)|
03021|020|M|   Area-under-the curve (AUC) based dosing of vancomycin when used|
03021|021|M|concurrently with piperacillin-tazobactam may reduce the risk of acute|
03021|022|M|kidney injury (AKI). Routine monitoring of kidney function is warranted.(3)|
03021|023|B||
03021|024|D|DISCUSSION:  A systematic review and metaanalysis found the concomitant use|
03021|025|D|of vancomycin and piperacillin-tazobactam was associated with acute kidney|
03021|026|D|injury in unadjusted odds ratio (OR 3.12; 95% confidence interval (CI) 2.04|
03021|027|D|- 4.78, p<0.001) and in adjusted OR (aOR 3.11; 95% CI 1.77 - 5.47, p<0.001)|
03021|028|D|analysis.  For adults only, results were similar for unadjusted (OR 2.71;|
03021|029|D|95% CI 1.72 - 4.27, p<0.001) and adjusted (aOR 3.15; 95% CI 1.72 - 5.76,|
03021|030|D|p<0.001) analysis.  For children only, concurrent use was associated with|
03021|031|D|increased risk in unadjusted (OR 5.26; 95% CI 2.71 - 10.21, p<0.001)|
03021|032|D|analysis.(4)|
03021|033|D|   A retrospective matched cohort study in patients receiving concurrent|
03021|034|D|vancomycin and piperacillin-tazobactam for a minimum of 48 hours had|
03021|035|D|significantly higher rates of acute kidney injury than patients receiving|
03021|036|D|vancomycin and cefepime (29% vs 11%, respectively; hazard ratio (HR) = 4,|
03021|037|D|p<0.001).  Results of a multivariate analysis found vancomycin and|
03021|038|D|piperacillin-tazobactam combination therapy was an independent risk factor|
03021|039|D|for RIFLE (Risk, Injury, Failure, Loss, End Stage Renal Disease) -defined|
03021|040|D|acute kidney injury (HR = 4.3; 95% CI 2.7 - 6.7; p<0.0001).  The onset of|
03021|041|D|acute kidney injury was more rapid in patients receiving vancomycin and|
03021|042|D|piperacillin-tazobactam than in patients receiving vancomycin and cefepime|
03021|043|D|(3 days vs 5 days, p<0.001).(5)|
03021|044|D|   A retrospective cohort analysis evaluated RIFLE-defined acute kidney|
03021|045|D|injury in patients receiving combination vancomycin and|
03021|046|D|piperacillin-tazobactam, vancomycin monotherapy, and piperacillin-tazobactam|
03021|047|D|monotherapy.  RIFLE-defined acute kidney injury occurred in 14.1% of|
03021|048|D|patients across the cohort.  The therapy specific acute kidney injury|
03021|049|D|occurred in combination vancomycin and piperacillin-tazobactam, vancomycin|
03021|050|D|monotherapy and piperacillin-tazobactam monotherapy in 21%, 8.3%, and 7.8%|
03021|051|D|of patients (p<0.0001), respectively.  In a multivariate analysis,|
03021|052|D|vancomycin monotherapy and piperacillin-tazobactam monotherapy were|
03021|053|D|associated with decreased odds of acute kidney injury compared to|
03021|054|D|combination vancomycin and piperacillin-tazobactam therapy (Vancomycin|
03021|055|D|Monotherapy - aOR 0.48; 95% CI 0.41 - 0.57; Piperacillin-Tazobactam|
03021|056|D|Monotherapy - aOR 0.43; 95% CI 0.37 - 0.5).  In a univariate analysis the|
03021|057|D|following factors were associated with acute kidney injury:  combination|
03021|058|D|vancomycin and piperacillin-tazobactam therapy, days of therapy, baseline|
03021|059|D|creatinine clearance, transfer from outside hospitals, Charlson Comorbidity|
03021|060|D|Index, admission type, length of hospitalization, dehydration exposure, and|
03021|061|D|hypotension exposure.(6)|
03021|062|D|   A retrospective cohort study evaluated the incidence of AKI with|
03021|063|D|Vancomycin AUC based dosing with concomitant piperacillin-tazobactam (VPT)|
03021|064|D|compared to meropenem or cefepime (VMC). AKI occurred in 13.68% of patients|
03021|065|D|with VPT compared to 4.8% of patients who received VMC. Patients in other|
03021|066|D|VPT studies utilizing traditional trough based vancomycin dosing experienced|
03021|067|D|AKI 21.4 to 34.8%.(3)|
03021|068|B||
03021|069|R|REFERENCES:|
03021|070|B||
03021|071|R|1.Zosyn (piperacillin and tazobactam) US prescribing information. Wyeth|1
03021|072|R|  Pharmaceuticals July, 2021.|1
03021|073|R|2.Vancocin (vancomycin) injection US prescribing information. Baxter|1
03021|074|R|  Healthcare September, 2017.|1
03021|075|R|3.Kiley PS, Pearston AP, Hodge LA, Kaplan MC, Baczek SM, Stanley JS, Wilson|2
03021|076|R|  TJ, Soriano KM, Yao A, Shaeffer ZA, Talt IE, Cohen JA, Ingemi AI.|2
03021|077|R|  Retrospective Cohort Study of the Incidence of Acute Kidney Injury with|2
03021|078|R|  Vancomycin Area under the Curve-Based Dosing with Concomitant|2
03021|079|R|  Piperacillin-Tazobactam Compared to Meropenem or Cefepime. Antimicrob|2
03021|080|R|  Agents Chemother 2022 Aug 16;66(8):e0004022.|2
03021|081|R|4.Hammond DA, Smith MN, Li C, Hayes SM, Lusardi K, Bookstaver PB. Systematic|2
03021|082|R|  Review and Meta-Analysis of Acute Kidney Injury Associated with|2
03021|083|R|  Concomitant Vancomycin and Piperacillin/tazobactam. Clin Infect Dis 2017|2
03021|084|R|  Mar 1;64(5):666-674.|2
03021|085|R|5.Navalkele B, Pogue JM, Karino S, Nishan B, Salim M, Solanki S. Risk of|2
03021|086|R|  Acute Kidney Injury in Patients on Concomitant Vancomycin and|2
03021|087|R|  Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime. Clin|2
03021|088|R|  Infect Dis 2017 Jan 15;64(2):116-123.|2
03021|089|R|6.Rutter WC, Burgess DR, Talbert JC, Burgess DS. Acute kidney injury in|2
03021|090|R|  patients treated with vancomycin and piperacillin-tazobactam: A|2
03021|091|R|  retrospective cohort analysis. J Hosp Med 2017 Feb;12(2):77-82.|2
03022|001|T|MONOGRAPH TITLE:  Fostamatinib/Strong CYP3A4 Inducers|
03022|002|B||
03022|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03022|004|L|of severe adverse interaction.|
03022|005|B||
03022|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03022|007|A|fostamatinib via this pathway.(1)|
03022|008|B||
03022|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
03022|010|E|reduce the clinical effectiveness of fostamatinib's metabolite, R406.(1)|
03022|011|B||
03022|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03022|013|P|of the inducer for longer than 1-2 weeks.|
03022|014|B||
03022|015|M|PATIENT MANAGEMENT:  The US manufacturer of fostamatinib states that|
03022|016|M|concurrent use of CYP3A4 inducers is not recommended.(1)|
03022|017|B||
03022|018|D|DISCUSSION:  In a clinical pharmacokinetic study, the AUC of R406 was|
03022|019|D|reduced by 75% in patients when coadministered with rifampin (600 mg daily|
03022|020|D|for 8 days).(1)|
03022|021|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
03022|022|D|barbiturates, enzalutamide, carbamazepine, fosphenytoin, encorafenib,|
03022|023|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
03022|024|D|rifampin, rifapentine, and St. John's Wort.(2,3)|
03022|025|B||
03022|026|R|REFERENCES:|
03022|027|B||
03022|028|R|1.Tavalisse (fostamatinib) prescribing information. Rigel Pharmaceuticals,|1
03022|029|R|  Inc April 2018.|1
03022|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03022|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03022|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03022|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03022|034|R|  11/14/2017.|1
03022|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
03022|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03023|001|T|MONOGRAPH TITLE:  Lofexidine/QT Prolonging Agents|
03023|002|B||
03023|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03023|004|L|of severe adverse interaction.|
03023|005|B||
03023|006|A|MECHANISM OF ACTION:  Lofexidine has been shown to prolong the QTc interval.|
03023|007|A|Concurrent use with other agents that prolong the QTc interval may result|
03023|008|A|in additive effects on the QTc interval.(1,2)|
03023|009|B||
03023|010|E|CLINICAL EFFECTS:  Concurrent use of lofexidine and agents known to prolong|
03023|011|E|the QT interval may exacerbate QT prolongation.(1,2)|
03023|012|B||
03023|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03023|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03023|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03023|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03023|017|P|gender, advanced age,(3) renal impairment, and/or hepatic impairment.(1,2)|
03023|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03023|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03023|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03023|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03023|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03023|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03023|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03023|025|B||
03023|026|M|PATIENT MANAGEMENT:  The UK manufacturer of lofexidine states that|
03023|027|M|concurrent use of lofexidine and QT prolonging agents should be avoided.(1)|
03023|028|M|The US manufacturer states that ECGs should be monitored in patients|
03023|029|M|receiving concurrent therapy with lofexidine and agents that are known to|
03023|030|M|prolong the QT interval.(2)|
03023|031|M|   Consider obtaining serum calcium, magnesium, and potassium levels at|
03023|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03023|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03023|034|B||
03023|035|D|DISCUSSION:  In a study of healthy volunteers, lofexidine 1.44 mg to 1.8 mg|
03023|036|D|had a change from baseline in QTc of 14.4 msec and 13.6 msec,|
03023|037|D|respectively.(2)|
03023|038|D|   In a dose response study, lofexidine had a mean QTc prolongation of 7.3|
03023|039|D|msec and 9.3 msec at doses of 2.16 mg/day and 2.88 mg/day, respectively.(2)|
03023|040|D|   Agents that are linked to this monograph may have varying degrees of|
03023|041|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03023|042|D|been shown to prolong the QTc interval either through their mechanism of|
03023|043|D|action, through studies on their effects on the QTc interval, or through|
03023|044|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03023|045|D|and/or postmarketing reports.(4)|
03023|046|B||
03023|047|R|REFERENCES:|
03023|048|B||
03023|049|R|1.BritLofex (lofexidine) UK summary of product characteristics. Britannia|1
03023|050|R|  Pharmaceuticals Limited August 25, 2015.|1
03023|051|R|2.Lucemyra (lofexidine) US prescribing information. US WorldMeds, LLC May|1
03023|052|R|  16, 2018.|1
03023|053|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03023|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03023|055|R|  settings: a scientific statement from the American Heart Association and|6
03023|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03023|057|R|  2;55(9):934-47.|6
03023|058|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03023|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03023|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03023|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03024|001|T|MONOGRAPH TITLE:  Lofexidine/Possible QT Prolonging Agents|
03024|002|B||
03024|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03024|004|L|take action as needed.|
03024|005|B||
03024|006|A|MECHANISM OF ACTION:  Lofexidine has been shown to prolong the QTc interval.|
03024|007|A|Concurrent use with other agents that prolong the QTc interval may result|
03024|008|A|in additive effects on the QTc interval.(1,2)|
03024|009|B||
03024|010|E|CLINICAL EFFECTS:  Concurrent use of lofexidine and agents known to prolong|
03024|011|E|the QT interval may exacerbate QT prolongation.(1,2)|
03024|012|B||
03024|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03024|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03024|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03024|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03024|017|P|gender, advanced age,(3) renal impairment, and/or hepatic impairment.(1,2)|
03024|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03024|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03024|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03024|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03024|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03024|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03024|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03024|025|B||
03024|026|M|PATIENT MANAGEMENT:  The UK manufacturer of lofexidine states that|
03024|027|M|concurrent use of lofexidine and QT prolonging agents should be avoided.(1)|
03024|028|M|The US manufacturer states that ECGs should be monitored in patients|
03024|029|M|receiving concurrent therapy with lofexidine and agents that are known to|
03024|030|M|prolong the QT interval.(2)|
03024|031|M|   Consider obtaining serum calcium, magnesium, and potassium levels at|
03024|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03024|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03024|034|B||
03024|035|D|DISCUSSION:  In a study of healthy volunteers, lofexidine 1.44 mg to 1.8 mg|
03024|036|D|had a change from baseline in QTc of 14.4 msec and 13.6 msec,|
03024|037|D|respectively.(2)|
03024|038|D|   In a dose response study, lofexidine had a mean QTc prolongation of 7.3|
03024|039|D|msec and 9.3 msec at doses of 2.16 mg/day and 2.88 mg/day, respectively.(2)|
03024|040|D|   Agents that are linked to this monograph may have varying degrees of|
03024|041|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03024|042|D|been shown to prolong the QTc interval either through their mechanism of|
03024|043|D|action, through studies on their effects on the QTc interval, or through|
03024|044|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03024|045|D|and/or postmarketing reports.(4)|
03024|046|B||
03024|047|R|REFERENCES:|
03024|048|B||
03024|049|R|1.BritLofex (lofexidine) UK summary of product characteristics. Britannia|1
03024|050|R|  Pharmaceuticals Limited August 25, 2015.|1
03024|051|R|2.Lucemyra (lofexidine) US prescribing information. US WorldMeds, LLC May|1
03024|052|R|  16, 2018.|1
03024|053|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03024|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03024|055|R|  settings: a scientific statement from the American Heart Association and|6
03024|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03024|057|R|  2;55(9):934-47.|6
03024|058|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03024|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03024|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03024|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03025|001|T|MONOGRAPH TITLE:  Trazodone (Less Than 100 mg)/QT Prolonging Agents|
03025|002|B||
03025|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03025|004|L|take action as needed.|
03025|005|B||
03025|006|A|MECHANISM OF ACTION:  Concurrent use of trazodone with other agents that|
03025|007|A|prolong the QTc interval may result in additive effects on the QTc|
03025|008|A|interval.(1,2)|
03025|009|B||
03025|010|E|CLINICAL EFFECTS:  The use of trazodone in patients maintained on agents|
03025|011|E|that prolong the QTc interval may result in potentially life-threatening|
03025|012|E|cardiac arrhythmias, including torsades de pointes.(1,2)|
03025|013|B||
03025|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03025|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03025|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03025|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03025|018|P|female gender, or advanced age.(2)|
03025|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03025|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03025|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03025|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03025|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03025|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03025|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03025|026|B||
03025|027|M|PATIENT MANAGEMENT:  The US manufacturer of trazodone states that concurrent|
03025|028|M|use with agents known to prolong the QT interval should be avoided.(1)|
03025|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03025|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03025|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03025|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03025|033|B||
03025|034|D|DISCUSSION:  Trazodone has been reported to prolong the QT interval.(1)|
03025|035|D|   A thorough QT study in 20 subjects evaluated the effects of trazodone at|
03025|036|D|doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation|
03025|037|D|at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI|
03025|038|D|3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that|
03025|039|D|exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval|
03025|040|D|by more than 5 ms. The study found a dose-dependent effect on QTc|
03025|041|D|prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI|
03025|042|D|11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of|
03025|043|D|19.8 ms (95% CI 17.6-22.1).(3)|
03025|044|D|   Agents that are linked to this monograph may have varying degrees of|
03025|045|D|potential to prolong the QTc interval but are generally accepted to have a|
03025|046|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03025|047|D|been shown to prolong the QTc interval either through their mechanism of|
03025|048|D|action, through studies on their effects on the QTc interval, or through|
03025|049|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03025|050|D|and/or post-marketing reports.(4)|
03025|051|B||
03025|052|R|REFERENCES:|
03025|053|B||
03025|054|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
03025|055|R|  Labopharm Inc. November, 2012.|1
03025|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03025|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03025|058|R|  settings: a scientific statement from the American Heart Association and|6
03025|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03025|060|R|  2;55(9):934-47.|6
03025|061|R|3.Tellone V, Rosignoli MT, Picollo R, Dragone P, Del Vecchio A, Comandini A,|2
03025|062|R|  Radicioni M, Leuratti C, Calisti F. Effect of 3 Single Doses of Trazodone|2
03025|063|R|  on QTc Interval in Healthy Subjects..|2
03025|064|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03025|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03025|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03025|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03026|001|T|MONOGRAPH TITLE:  Cosyntropin/Agents Affecting Plasma Cortisol Levels|
03026|002|B||
03026|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03026|004|L|of severe adverse interaction.|
03026|005|B||
03026|006|A|MECHANISM OF ACTION:  Agents affecting plasma cortisol levels may impact the|
03026|007|A|accuracy of the cosyntropin diagnostic test.(1)|
03026|008|B||
03026|009|E|CLINICAL EFFECTS:  Concurrent use of agents affecting plasma cortisol levels|
03026|010|E|may impact the accuracy of the cosyntropin diagnostic test.(1)|
03026|011|B||
03026|012|P|PREDISPOSING FACTORS:  None determined.|
03026|013|B||
03026|014|M|PATIENT MANAGEMENT:  The US manufacturer of cosyntropin states accuracy of|
03026|015|M|diagnosis using the cosyntropin diagnostic test may be complicated by|
03026|016|M|concomitant medications affecting plasma cortisol levels.(1)|
03026|017|M|   Agents affecting plasma cortisol levels and recommendation to stop prior|
03026|018|M|to cosyntropin diagnostic test include:|
03026|019|M|   - Glucocorticoids: May elevate plasma cortisol levels.  Stop these drugs|
03026|020|M|on the day of testing.  Long-acting glucocorticoids may need to be stopped|
03026|021|M|for a longer period before testing.|
03026|022|M|   - Spironolactone: May elevate plasma cortisol levels.  Stop|
03026|023|M|spironolactone on the day of testing.|
03026|024|M|   - Estrogen: May elevate plasma total cortisol levels.  Discontinue|
03026|025|M|estrogen containing drugs 4 to 6 weeks prior to testing to allow cortisol|
03026|026|M|binding globulin levels to return to levels within the reference range.|
03026|027|M|Alternatively, concomitant measurement of cortisol binding globulin at the|
03026|028|M|time of testing can be done; if cortisol binding globulin levels are|
03026|029|M|elevated, plasma total cortisol levels are considered inaccurate.(1)|
03026|030|B||
03026|031|D|DISCUSSION:  Concurrent use of agents affecting plasma cortisol levels may|
03026|032|D|impact the accuracy of the cosyntropin diagnostic test.(1)|
03026|033|B||
03026|034|R|REFERENCE:|
03026|035|B||
03026|036|R|1.Cosyntropin US prescribing information. Sandoz Inc. July, 2024.|1
03027|001|T|MONOGRAPH TITLE:  Aminolevulinic Acid/Selected Photosensitizers|
03027|002|B||
03027|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03027|004|L|of severe adverse interaction.|
03027|005|B||
03027|006|A|MECHANISM OF ACTION:  Aminolevulinic acid, anthralin, coal tar and|
03027|007|A|derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as|
03027|008|A|methylene blue, rose bengal, or toluidine blue), phenothiazines, selected|
03027|009|A|NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and|
03027|010|A|tiaprofenic acid), methotrexate, St. John's wort, sulfonamides,|
03027|011|A|sulfonylureas, tetracyclines, and thiazides are all known|
03027|012|A|photosensitizers.(1)|
03027|013|B||
03027|014|E|CLINICAL EFFECTS:  Concurrent use of aminolevulinic acid in patients taking|
03027|015|E|anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic|
03027|016|E|staining dyes (such as methylene blue, rose bengal, or toluidine blue),|
03027|017|E|phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone,|
03027|018|E|naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort,|
03027|019|E|sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the|
03027|020|E|risk of phototoxicity.(1)|
03027|021|B||
03027|022|P|PREDISPOSING FACTORS:  None determined.|
03027|023|B||
03027|024|M|PATIENT MANAGEMENT:  The US manufacturer states that aminolevulinic acid|
03027|025|M|should be avoided in patients receiving photosensitizers including|
03027|026|M|anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic|
03027|027|M|staining dyes (such as methylene blue, rose bengal, or toluidine blue),|
03027|028|M|phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone,|
03027|029|M|naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort,|
03027|030|M|sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours|
03027|031|M|before and after administration of aminolevulinic acid.(1)|
03027|032|B||
03027|033|D|DISCUSSION:  Because of the risk of increased photosensitivity, the US|
03027|034|D|manufacturer states that aminolevulinic acid should be avoided in patients|
03027|035|D|receiving photosensitizers including anthralin, coal tar and derivatives,|
03027|036|D|fluoroquinolones, griseofulvin, organic staining dyes (such as methylene|
03027|037|D|blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such|
03027|038|D|as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic|
03027|039|D|acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas,|
03027|040|D|tetracyclines, and thiazides for 24 hours before and after administration of|
03027|041|D|aminolevulinic acid.(1)|
03027|042|B||
03027|043|R|REFERENCE:|
03027|044|B||
03027|045|R|1.Gleolan (aminolevulinic acid hydrochloride) US prescribing information. NX|1
03027|046|R|  Development Corp. February 2019.|1
03028|001|T|MONOGRAPH TITLE:  Trazodone (Less Than 100 mg)/Possible QT Prolonging Agents|
03028|002|B||
03028|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03028|004|L|take action as needed.|
03028|005|B||
03028|006|A|MECHANISM OF ACTION:  Concurrent use of trazodone with other agents that|
03028|007|A|prolong the QTc interval may result in additive effects on the QTc|
03028|008|A|interval.(1,2)|
03028|009|B||
03028|010|E|CLINICAL EFFECTS:  The use of trazodone in patients maintained on agents|
03028|011|E|that prolong the QTc interval may result in potentially life-threatening|
03028|012|E|cardiac arrhythmias, including torsades de pointes.(1,2)|
03028|013|B||
03028|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03028|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03028|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03028|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03028|018|P|female gender, or advanced age.(2)|
03028|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03028|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03028|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03028|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03028|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03028|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03028|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03028|026|B||
03028|027|M|PATIENT MANAGEMENT:  The US manufacturer of trazodone states that concurrent|
03028|028|M|use with agents known to prolong the QT interval should be avoided.(1)|
03028|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03028|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03028|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03028|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03028|033|B||
03028|034|D|DISCUSSION:  Trazodone has been reported to prolong the QT interval.(1)|
03028|035|D|   A thorough QT study in 20 subjects evaluated the effects of trazodone at|
03028|036|D|doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation|
03028|037|D|at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI|
03028|038|D|3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that|
03028|039|D|exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval|
03028|040|D|by more than 5 ms. The study found a dose-dependent effect on QTc|
03028|041|D|prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI|
03028|042|D|11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of|
03028|043|D|19.8 ms (95% CI 17.6-22.1).(3)|
03028|044|D|   Agents that are linked to this monograph may have varying degrees of|
03028|045|D|potential to prolong the QTc interval but are generally accepted to have a|
03028|046|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03028|047|D|been shown to prolong the QTc interval either through their mechanism of|
03028|048|D|action, through studies on their effects on the QTc interval, or through|
03028|049|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03028|050|D|and/or post-marketing reports.(4)|
03028|051|B||
03028|052|R|REFERENCES:|
03028|053|B||
03028|054|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
03028|055|R|  Labopharm Inc. November, 2012.|1
03028|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03028|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03028|058|R|  settings: a scientific statement from the American Heart Association and|6
03028|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03028|060|R|  2;55(9):934-47.|6
03028|061|R|3.Tellone V, Rosignoli MT, Picollo R, Dragone P, Del Vecchio A, Comandini A,|2
03028|062|R|  Radicioni M, Leuratti C, Calisti F. Effect of 3 Single Doses of Trazodone|2
03028|063|R|  on QTc Interval in Healthy Subjects..|2
03028|064|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03028|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03028|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03028|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03029|001|T|MONOGRAPH TITLE:  Hepatitis B Vaccine (Fendrix)/Vaccines|
03029|002|B||
03029|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03029|004|L|take action as needed.|
03029|005|B||
03029|006|A|MECHANISM OF ACTION:  No data is available on the concurrent administration|
03029|007|A|of the hepatitis B vaccine Fendrix and other vaccines.(1)|
03029|008|B||
03029|009|E|CLINICAL EFFECTS:  It is unknown if concurrent administration of the|
03029|010|E|hepatitis B vaccine Fendrix and other vaccines will affect the efficacy of|
03029|011|E|either vaccine.(1)|
03029|012|B||
03029|013|P|PREDISPOSING FACTORS:  None determined.|
03029|014|B||
03029|015|M|PATIENT MANAGEMENT:  The Swedish manufacturer of Fendrix states that since|
03029|016|M|there is no data available for the concurrent administration of Fendrix with|
03029|017|M|other vaccines, the administration of Fendrix and other vaccines should be|
03029|018|M|separated by 2 to 3 weeks.(1)|
03029|019|B||
03029|020|D|DISCUSSION:  No data is available on the concurrent administration of the|
03029|021|D|hepatitis B vaccine Fendrix with other vaccines.(1)|
03029|022|B||
03029|023|R|REFERENCE:|
03029|024|B||
03029|025|R|1.Fendrix (hepatitis B (rDNA) vaccine (adjuvanted, adsorbed) Sweden|1
03029|026|R|  prescribing information. GlaxoSmithKline Biologicals S.A. December 10,|1
03029|027|R|  2009.|1
03030|001|T|MONOGRAPH TITLE:  Edoxaban (Less Than or Equal To 30 mg)/Selected P-gp|
03030|002|T|Inhibitors|
03030|003|B||
03030|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03030|005|L|take action as needed.|
03030|006|B||
03030|007|A|MECHANISM OF ACTION:  Edoxaban is a substrate for P-glycoprotein (P-gp).|
03030|008|A|Inhibitors of P-gp may increase intestinal absorption and decrease renal|
03030|009|A|tubular elimination of edoxaban.(1,2)|
03030|010|B||
03030|011|E|CLINICAL EFFECTS:  Concurrent use with selected P-gp inhibitors may result|
03030|012|E|in higher systemic concentrations of edoxaban which may increase the risk|
03030|013|E|for bleeding.(1-5)  P-gp inhibitors linked to this interaction are:|
03030|014|E|cyclosporine, dronedarone, erythromycin, and ketoconazole.|
03030|015|B||
03030|016|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with|
03030|017|P|creatinine clearance 15mL - 50 mL per minute(1) or weight less than or equal|
03030|018|P|to 60 kg.(2)|
03030|019|P|   Use of multiple agents which increase edoxaban exposure or affect|
03030|020|P|hemostasis would be expected to increase the risk for bleeding.|
03030|021|P|   The risk for bleeding episodes may be greater in patients with|
03030|022|P|disease-associated factors (thrombocytopenia).|
03030|023|P|   Drug associated risk factors include concurrent use of multiple drugs|
03030|024|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03030|025|P|risk for bleeding (e.g. NSAIDs).|
03030|026|B||
03030|027|M|PATIENT MANAGEMENT:  Management recommendations vary depending upon the|
03030|028|M|approving regulatory agency (FDA or European Medicines Agency, EMA).|
03030|029|M|   US FDA recommendations are based upon the edoxaban indication:|
03030|030|M|   - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE),|
03030|031|M|the edoxaban dose should be reduced to 30 mg daily when used concomitantly|
03030|032|M|with erythromycin or oral ketoconazole.(3)|
03030|033|M|   - For prevention of stroke or embolic events due to nonvalvular atrial|
03030|034|M|fibrillation, no edoxaban dose adjustments are recommended during|
03030|035|M|concomitant therapy with P-glycoprotein inhibitors.(1,3)|
03030|036|M|   - Concurrent use of cyclosporine was not allowed in edoxaban clinical|
03030|037|M|trials (atrial fibrillation or DVT/PE).  US prescribing information does not|
03030|038|M|provide specific management information for concurrent use of cyclosporine|
03030|039|M|with edoxaban.(3)|
03030|040|M|   EMA dosage adjustments are the same, regardless of indication:|
03030|041|M|   - Reduce edoxaban dose to 30 mg daily in patients receiving concomitant|
03030|042|M|treatment with cyclosporine, dronedarone, erythromycin or oral|
03030|043|M|ketoconazole.(4)|
03030|044|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
03030|045|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
03030|046|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03030|047|M|   When applicable, perform agent-specific laboratory test (e.g. anti Factor|
03030|048|M|Xa inhibition) to monitor efficacy and safety of anticoagulation.|
03030|049|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
03030|050|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03030|051|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03030|052|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03030|053|M|and/or swelling.|
03030|054|M|   Discontinue edoxaban in patients with active bleeding.|
03030|055|B||
03030|056|D|DISCUSSION:  Edoxaban in vivo interaction studies have been performed for|
03030|057|D|P-gp inhibitors linked to this monograph:|
03030|058|D|   In an interaction study, the effect of single oral dose of cyclosporine|
03030|059|D|500 mg on a single oral dose of edoxaban 60 mg was evaluated in healthy|
03030|060|D|subjects.  Total and peak systemic exposure to edoxaban increased 1.73-fold|
03030|061|D|and 1.74-fold, respectively. Total and peak systemic exposure to the active|
03030|062|D|M4 metabolite increased 6.87-fold and 8.71-fold respectively, likely due to|
03030|063|D|cyclosporine inhibition of OATP1B1.(1)  In the absence of OATP1B1|
03030|064|D|inhibition, M4 concentrations are generally less than or equal to 10% of|
03030|065|D|edoxaban exposure,(1) but the approximately 7-fold increase in active|
03030|066|D|metabolite exposure may result in clinically meaningful concentrations of|
03030|067|D|M4.|
03030|068|D|   In an interaction study, the effect of repeat administration of|
03030|069|D|dronedarone (400 mg bid) on a single oral dose of edoxaban 60 mg was|
03030|070|D|evaluated in healthy subjects. Total and peak systemic exposure to edoxaban|
03030|071|D|increased 1.84-fold and 1.45-fold, respectively.  Plasma edoxaban|
03030|072|D|concentrations 24 hours post dose (Ctrough) following coadministration|
03030|073|D|edoxaban and dronedarone were 2.6-fold higher compared with administration|
03030|074|D|of edoxaban alone.(1)|
03030|075|D|   In an interaction study, the effect of repeat administration of|
03030|076|D|erythromycin (oral dose of 500 mg four times daily for 8 days) on a single|
03030|077|D|oral dose of edoxaban 60 mg on on study day 7 was evaluated in healthy|
03030|078|D|subjects.  Total and peak systemic exposure to edoxaban increased 1.85-fold|
03030|079|D|and 1.68-fold, respectively.  Total and peak systemic exposure to the M4|
03030|080|D|metabolite increased 1.78-fold and 1.75-fold, respectively.(1)|
03030|081|D|   In an interaction study, the effect of repeat administration of|
03030|082|D|ketoconazole (oral dose of 400 mg QD for 7 days) on a single oral dose of|
03030|083|D|edoxaban (60 mg) was evaluated in healthy subjects. Total and peak systemic|
03030|084|D|exposure to edoxaban increased 1.87-fold and 1.89-fold, respectively.  Total|
03030|085|D|and peak systemic exposure to the M4 metabolite increased 1.46-fold and|
03030|086|D|1.56-fold, respectively.(1)|
03030|087|D|   A summary of pharmacokinetic interactions with edoxaban and dronedarone|
03030|088|D|concluded that if concurrent use is warranted, the edoxaban dose should be|
03030|089|D|reduced by 50%.(6)|
03030|090|B||
03030|091|R|REFERENCES:|
03030|092|B||
03030|093|R|1.FDA Center for Drug Evaluation and Research (CDER). Application number|1
03030|094|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
03030|095|R|  Biopharmaceutics Review. available at:|1
03030|096|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
03030|097|R|  0ClinPharmR.pdf January 8, 2015.|1
03030|098|R|2.Lixiana European Medicines Agency (EMA) Assessment report. Committee for|1
03030|099|R|  Medicinal Products for Human Use (CHMP) 23 April 2015.|1
03030|100|R|3.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
03030|101|R|  2019.|1
03030|102|R|4.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
03030|103|R|  Sankyo UK Limited July 2, 2015.|1
03030|104|R|5.FDA Center for Drug Evaluation and Research (CDER). Application no. 206316|1
03030|105|R|  Summary Review Savaysa (edoxaban tosylate). available at:|1
03030|106|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
03030|107|R|  0SumR.pdf January 8, 2015.|1
03030|108|R|6.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
03030|109|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
03030|110|R|  of  the Week..|6
03031|001|T|MONOGRAPH TITLE:  Edoxaban (Less Than or Equal To 30 mg)/Select P-gp|
03031|002|T|Inhibitors|
03031|003|B||
03031|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03031|005|L|take action as needed.|
03031|006|B||
03031|007|A|MECHANISM OF ACTION:  Edoxaban is a substrate for P-glycoprotein (P-gp).|
03031|008|A|Inhibitors of P-gp may increase intestinal absorption and decrease renal|
03031|009|A|tubular elimination of edoxaban.(1,2)|
03031|010|B||
03031|011|E|CLINICAL EFFECTS:  Concurrent use with selected P-gp inhibitors may result|
03031|012|E|in higher systemic concentrations of edoxaban which may increase the risk|
03031|013|E|for bleeding.(1,2)|
03031|014|B||
03031|015|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with|
03031|016|P|creatinine clearance below 50 mL per minute(1-4).|
03031|017|P|   Use of multiple agents which increase edoxaban exposure or affect|
03031|018|P|hemostasis would be expected to increase the risk for bleeding.|
03031|019|P|   The risk for bleeding episodes may be greater in patients with|
03031|020|P|disease-associated factors (e.g. thrombocytopenia).|
03031|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
03031|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03031|023|P|risk for bleeding (e.g. NSAIDs).|
03031|024|B||
03031|025|M|PATIENT MANAGEMENT:  Management recommendations between approving regulatory|
03031|026|M|agencies (FDA or European Medicines Agency, EMA) are conflicting.|
03031|027|M|   EMA approved prescribing information specifically states that dosage|
03031|028|M|adjustments are not required solely for concomitant use with amiodarone,|
03031|029|M|quinidine, or verapamil regardless of indication.(3,4) Potential|
03031|030|M|interactions with azithromycin, clarithromycin, or oral itraconazole are not|
03031|031|M|described.(3)|
03031|032|M|   FDA approved prescribing recommendations for edoxaban are indication|
03031|033|M|specific:(2)|
03031|034|M|   - For prevention of stroke or embolic events due to nonvalvular atrial|
03031|035|M|fibrillation, no edoxaban dose adjustments are recommended during|
03031|036|M|concomitant therapy with P-glycoprotein inhibitors.|
03031|037|M|   - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE),|
03031|038|M|the edoxaban dose should be reduced to 30 mg daily during concomitant use|
03031|039|M|with azithromycin, clarithromycin, oral itraconazole, quinidine or|
03031|040|M|verapamil.|
03031|041|M|   The manufacturer of vimseltinib states concurrent use with P-gp|
03031|042|M|substrates should be avoided. If concurrent use cannot be avoided, take|
03031|043|M|vimseltinib at least 4 hours prior to edoxaban.(6)|
03031|044|M|   Monitor patients receiving anticoagulant therapy for signs of blood loss,|
03031|045|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
03031|046|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03031|047|M|   When applicable, perform agent-specific laboratory test (e.g. anti Factor|
03031|048|M|Xa inhibition) to monitor efficacy and safety of anticoagulation.|
03031|049|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
03031|050|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03031|051|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03031|052|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03031|053|M|and/or swelling.|
03031|054|M|   Discontinue edoxaban in patients with active bleeding.|
03031|055|B||
03031|056|D|DISCUSSION:  Edoxaban in vivo interaction studies have been performed for|
03031|057|D|quinidine and verapamil.  In vivo interaction studies have not been|
03031|058|D|conducted for the remaining P-gp inhibitors linked to this monograph.(1,4)|
03031|059|D|   In an interaction study, the effect of repeat administration of quinidine|
03031|060|D|(300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in|
03031|061|D|healthy subjects.  Both peak (Cmax) and total systemic exposure (AUC) to|
03031|062|D|edoxaban and to the active M4 metabolite increased approximately|
03031|063|D|1.75-fold.(1)|
03031|064|D|   In an interaction study, the effect of repeat administration of verapamil|
03031|065|D|(240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral|
03031|066|D|dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy|
03031|067|D|subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold|
03031|068|D|and 1.53-fold, respectively. Total and peak systemic exposure to the active|
03031|069|D|M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1)|
03031|070|D|   Based upon the above results, patients in the DVT/PE trial had a 50% dose|
03031|071|D|reduction (from 60 mg to 30 mg) during concomitant therapy with|
03031|072|D|P-glycoprotein inhibitors.  Approximately 0.5% of these patients required a|
03031|073|D|dose reduction solely due to P-gp inhibitor use.  This low rate of|
03031|074|D|concurrent therapy was too small to allow for detailed statistical|
03031|075|D|evaluation.  Almost all of these patients were receiving quinidine or|
03031|076|D|verapamil.  In these patients, both trough edoxaban concentrations (Ctrough)|
03031|077|D|used to evaluate bleeding risk, and total edoxaban exposure (AUC or|
03031|078|D|area-under-curve) used to evaluate treatment efficacy, were lower than|
03031|079|D|patients who did not require any edoxaban dose adjustment.  In this DVT/PE|
03031|080|D|comparator trial, subgroup analysis revealed that warfarin had numerically|
03031|081|D|better efficacy than edoxaban in patients receiving P-gp inhibitors.  Based|
03031|082|D|upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects,|
03031|083|D|both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the|
03031|084|D|edoxaban 50% dose reduction overcorrected for the difference in|
03031|085|D|exposure.(1,4)  Consequently, EMA recommended no edoxaban dose adjustments|
03031|086|D|for patients receiving concomitant therapy with quinidine or verapamil.(3,4)|
03031|087|D|   A summary of pharmacokinetic interactions with edoxaban and verapamil|
03031|088|D|concluded that if concurrent use is considered safe.(7)|
03031|089|D|   P-gp inhibitors linked to this interaction are:  amiodarone, asunaprevir,|
03031|090|D|azithromycin, belumosudil, capmatinib, carvedilol, cimetidine,|
03031|091|D|clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan,|
03031|092|D|daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng,|
03031|093|D|glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, indinavir, oral|
03031|094|D|itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, mavorixafor,|
03031|095|D|neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine,|
03031|096|D|selpercatinib, sotorasib, telaprevir, telithromycin, tezacaftor, tepotinib,|
03031|097|D|tucatinib, valbenazine, velpatasvir, vemurafenib, verapamil, vimseltinib,|
03031|098|D|and voclosporin.(8)|
03031|099|B||
03031|100|R|REFERENCES:|
03031|101|B||
03031|102|R|1.FDA Center for Drug Evaluation and Research (CDER). Application number|1
03031|103|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
03031|104|R|  Biopharmaceutics Review. available at:|1
03031|105|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
03031|106|R|  0ClinPharmR.pdf January 8, 2015.|1
03031|107|R|2.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
03031|108|R|  2019.|1
03031|109|R|3.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
03031|110|R|  Sankyo UK Limited July 2, 2015.|1
03031|111|R|4.Lixiana European Medicines Agency (EMA) Assessment report. Committee for|1
03031|112|R|  Medicinal Products for Human Use (CHMP) 23 April 2015.|1
03031|113|R|5.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
03031|114|R|  June, 2025.|1
03031|115|R|6.Romvimza (vimseltinib) US prescribing information. Deciphera|1
03031|116|R|  Pharmaceuticals, LLC February, 2025.|1
03031|117|R|7.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
03031|118|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
03031|119|R|  of  the Week..|6
03031|120|R|8.This information is based on an extract from the Certara Drug Interaction|6
03031|121|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03032|001|T|MONOGRAPH TITLE:  Edoxaban (Less Than or Equal To 30 mg)/Lapatinib;|
03032|002|T|Ritonavir|
03032|003|B||
03032|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03032|005|L|take action as needed.|
03032|006|B||
03032|007|A|MECHANISM OF ACTION:  Edoxaban is a substrate for P-glycoprotein (P-gp).|
03032|008|A|Inhibitors of P-gp may increase intestinal absorption and decrease renal|
03032|009|A|tubular elimination of edoxaban.(1,2)|
03032|010|B||
03032|011|E|CLINICAL EFFECTS:  Concurrent use with P-gp inhibitors may result in higher|
03032|012|E|systemic concentrations of edoxaban which may increase the risk for|
03032|013|E|bleeding.(1,2)|
03032|014|E|   P-gp inhibitors linked to this interaction are: lapatinib,|
03032|015|E|lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir,|
03032|016|E|ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir.|
03032|017|B||
03032|018|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with|
03032|019|P|creatinine clearance below 50 mL per minute(1-2).|
03032|020|P|   Use of multiple agents which increase edoxaban exposure or affect|
03032|021|P|hemostasis would be expected to increase the risk for bleeding.|
03032|022|P|   The risk for bleeding episodes may be greater in patients with|
03032|023|P|disease-associated factors (e.g. thrombocytopenia).|
03032|024|P|   Drug associated risk factors include concurrent use of multiple drugs|
03032|025|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03032|026|P|risk for bleeding (e.g. NSAIDs).|
03032|027|B||
03032|028|M|PATIENT MANAGEMENT:  Interaction studies between edoxaban and lapatinib,|
03032|029|M|lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir,|
03032|030|M|ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir have not been|
03032|031|M|performed.  Concurrent use of these agents were not allowed in edoxaban|
03032|032|M|clinical trials.|
03032|033|M|   FDA approved prescribing recommendations for edoxaban are indication|
03032|034|M|specific:(2)|
03032|035|M|   - For prevention of stroke or embolic events due to nonvalvular atrial|
03032|036|M|fibrillation, no edoxaban dose adjustments are recommended during|
03032|037|M|concomitant therapy with P-glycoprotein inhibitors.|
03032|038|M|   - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE),|
03032|039|M|the edoxaban dose should be reduced to 30 mg daily during concomitant use|
03032|040|M|with azithromycin, clarithromycin, oral itraconazole, quinidine or|
03032|041|M|verapamil. No recommendations were made regarding concomitant lapatinib,|
03032|042|M|ritonavir or lopinavir-ritonavir therapy.|
03032|043|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
03032|044|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
03032|045|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03032|046|M|   When applicable, perform agent-specific laboratory test (e.g. anti Factor|
03032|047|M|Xa inhibition) to monitor efficacy and safety of anticoagulation.|
03032|048|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
03032|049|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03032|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03032|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03032|052|M|and/or swelling.|
03032|053|M|   Discontinue edoxaban in patients with active bleeding.|
03032|054|B||
03032|055|D|DISCUSSION:  Edoxaban interaction studies have not been performed for|
03032|056|D|lapatinib, lopinavir-ritonavir, ombitasvir-paritaprevir-ritonavir,|
03032|057|D|ombitasvir-paritaprevir-ritonavir-dasabuvir, and ritonavir(1) and so the|
03032|058|D|magnitude of any interaction with these agents is not known.|
03032|059|B||
03032|060|R|REFERENCES:|
03032|061|B||
03032|062|R|1.FDA Center for Drug Evaluation and Research (CDER). Application number|1
03032|063|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
03032|064|R|  Biopharmaceutics Review. available at:|1
03032|065|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
03032|066|R|  0ClinPharmR.pdf January 8, 2015.|1
03032|067|R|2.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
03032|068|R|  2019.|1
03032|069|R|3.This information is based on an extract from the Certara Drug Interaction|6
03032|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03033|001|T|MONOGRAPH TITLE:  Simvastatin (Less Than or Equal To 20 mg)/Azithromycin|
03033|002|B||
03033|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03033|004|L|take action as needed.|
03033|005|B||
03033|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Other macrolides|
03033|007|A|(e.g. erythromycin, clarithromycin) which are moderate or strong inhibitors|
03033|008|A|of CYP3A4 have been shown to increase levels of the HMG-CoA reductase|
03033|009|A|inhibitors (statins); however, azithromycin is a much weaker inhibitor of|
03033|010|A|this isoenzyme.(1,2)|
03033|011|A|   FDA has classified simvastatin as a sensitive substrate at CYP3A4.|
03033|012|A|Sensitive substrates are drugs whose plasma exposure (area-under-curve or|
03033|013|A|AUC) has been shown to increase greater than or equal to 5-fold  when|
03033|014|A|co-administered with a strong inhibitor of a specific enzyme.  A weak|
03033|015|A|inhibitor increases AUC of a sensitive substrate greater than 1.25-fold but|
03033|016|A|less than 2-fold. Azithromycin is classified as a weak inhibitor of|
03033|017|A|CYP3A4.(1)|
03033|018|B||
03033|019|E|CLINICAL EFFECTS:  Concurrent therapy may result in rhabdomyolysis.|
03033|020|E|Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness,|
03033|021|E|elevated creatine kinase levels, and reddish-brown, heme positive urine.|
03033|022|B||
03033|023|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03033|024|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03033|025|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03033|026|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03033|027|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03033|028|P|transporter OATP1B1 may have increased statin concentrations and be|
03033|029|P|predisposed to myopathy or rhabdomyolysis.|
03033|030|B||
03033|031|M|PATIENT MANAGEMENT:  In patients with one or more predisposing risk factors|
03033|032|M|for statin associated myopathy it may be prudent to suspend simvastatin|
03033|033|M|during azithromycin therapy.  Rhabdomyolysis has been reported with the|
03033|034|M|combination of simvastatin and azithromycin.|
03033|035|M|   If temporary discontinuation of the HMG-CoA reductase inhibitor is not|
03033|036|M|possible, patients should be instructed to report any unexplained muscle|
03033|037|M|pain, tenderness, weakness, or discoloration of the urine.(3,4)|
03033|038|B||
03033|039|D|DISCUSSION:  A systematic screening of the World Health Organization Adverse|
03033|040|D|Drug Reaction database found case reports suggestive of an interaction|
03033|041|D|between azithromycin and statins.  The authors found 5 lovastatin and 20|
03033|042|D|simvastatin case reports and used a dis proportionality measure which found|
03033|043|D|report rates were 1.88 and 3.55 times higher respectively than predicted.(5)|
03033|044|D|   A case report describes rhabdomyolysis in a 73 year old man with chronic|
03033|045|D|renal impairment, diabetes, hypertension, gout and hyperlipidemia with|
03033|046|D|regular medications which included allopurinol 100 mg daily, prednisone 5 mg|
03033|047|D|daily, labetalol, bumetanide, insulin, amlodipine (a weak CYP3A4 inhibitor)|
03033|048|D|and simvastatin 80 mg daily.  Azithromycin 500 mg X1 day, then 250 mg daily|
03033|049|D|X4 days was prescribed for acute bronchitis.  One week later patient was|
03033|050|D|admitted to the hospital with a 5 day history of severe weakness and pain in|
03033|051|D|his arms and legs. He developed acute renal insufficiency (creatinine|
03033|052|D|baseline 1.7 increased to 3.8) and rhabdomyolysis (CPK 11,240 units/L).|
03033|053|D|Treatment led to resolution of symptoms in 3 weeks.  Simvastatin was|
03033|054|D|restarted at 40 mg daily and subsequently increased back to 80 mg daily|
03033|055|D|without recurrence of symptoms.(6)|
03033|056|D|   A case report describes a 56 year old man receiving buspirone, nefazodone|
03033|057|D|(a strong CYP3A4 inhibitor), lisinopril, aspirin and simvastatin 80 mg daily|
03033|058|D|without reported problems.  Azithromycin and fexofenadine were prescribed|
03033|059|D|for sinusitis.  He was admitted to the hospital 5 days later with a 2-3 day|
03033|060|D|history of generalized back, leg, and flank pain along with coca-cola|
03033|061|D|colored urine.  AST, ALT and creatine kinase were 2,324, 700, and 10,738|
03033|062|D|respectively. Patient was discharged after 8 days. His simvastatin was not|
03033|063|D|resumed.(7)|
03033|064|D|   An article reported two cases of rhabdomyolysis, one following the|
03033|065|D|addition of clarithromycin to lovastatin therapy and the other following the|
03033|066|D|addition of azithromycin to lovastatin therapy.(8)|
03033|067|B||
03033|068|R|REFERENCES:|
03033|069|B||
03033|070|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
03033|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03033|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03033|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03033|074|R|  11/14/2017.|1
03033|075|R|2.This information is based on an extract from the Certara Drug Interaction|6
03033|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03033|077|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
03033|078|R|  February, 2014.|1
03033|079|R|4.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03033|080|R|  2023.|1
03033|081|R|5.Strandell J, Bate A, Hagg S, Edwards IR. Rhabdomyolysis a result of|2
03033|082|R|  azithromycin and statins: an unrecognized interaction. Br J Clin Pharmacol|2
03033|083|R|  2009 Sep;68(3):427-34.|2
03033|084|R|6.Alreja G, Inayatullah S, Goel S, Braden G. Rhabdomyolysis caused by an|3
03033|085|R|  unusual interaction between azithromycin and simvastatin. J Cardiovasc Dis|3
03033|086|R|  Res 2012 Oct;3(4):319-22.|3
03033|087|R|7.Skrabal MZ, Stading JA, Cannella CA, Monaghan MS. Two cases of|3
03033|088|R|  rhabdomyolysis associated with high-dose simvastatin. Am J Health Syst|3
03033|089|R|  Pharm 2003 Mar 15;60(6):578-81.|3
03033|090|R|8.Grunden JW, Fisher KA. Lovastatin-induced rhabdomyolysis possibly|3
03033|091|R|  associated with clarithromycin and azithromycin. Ann Pharmacother 1997|3
03033|092|R|  Jul-Aug;31(7-8):859-63.|3
03033|093|R|9.Ayanian JZ, Fuchs CS, Stone RM. Lovastatin and rhabdomyolysis. Ann Intern|3
03033|094|R|  Med 1988 Oct 15;109(8):682-3.|3
03033|095|R|10.Lilley LL, Guanci R. Drug interaction triggers weakness. Am J Nurs 1998|3
03033|096|R|   Apr;98(4):10.|3
03034|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 40 mg)/Ciprofloxacin|
03034|002|B||
03034|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03034|004|L|take action as needed.|
03034|005|B||
03034|006|A|MECHANISM OF ACTION:  Ciprofloxacin may inhibit the metabolism of|
03034|007|A|atorvastatin by CYP3A4.(1)|
03034|008|B||
03034|009|E|CLINICAL EFFECTS:  Concurrent use of ciprofloxacin may result in elevated|
03034|010|E|levels of atorvastatin which could result in rhabdomyolysis.|
03034|011|B||
03034|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03034|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03034|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03034|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03034|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03034|017|P|transporter OATP1B1 may have increased statin concentrations and be|
03034|018|P|predisposed to myopathy or rhabdomyolysis.|
03034|019|B||
03034|020|M|PATIENT MANAGEMENT:  For patients receiving atorvastatin (especially high|
03034|021|M|doses), consider holding atorvastatin therapy for the duration of|
03034|022|M|ciprofloxacin therapy.|
03034|023|M|   If atorvastatin is used with ciprofloxacin, consider limiting the dose of|
03034|024|M|atorvastatin to less than or equal to 40 mg daily for the duration of|
03034|025|M|ciprofloxacin therapy.  Monitor patient for statin-associated myopathy.|
03034|026|B||
03034|027|D|DISCUSSION:  A specific interaction study between atorvastatin and|
03034|028|D|ciprofloxacin has not been performed.|
03034|029|D|   Rhabdomyolysis has been reported with concurrent ciprofloxacin and|
03034|030|D|simvastatin.(3-5)|
03034|031|B||
03034|032|R|REFERENCES:|
03034|033|B||
03034|034|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
03034|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03034|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03034|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03034|038|R|  11/14/2017.|1
03034|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
03034|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03034|041|R|3.Goldie FC, Brogan A, Boyle JG. Ciprofloxacin and statin interaction: a|3
03034|042|R|  cautionary tale of rhabdomyolysis. BMJ Case Rep 2016 Jul 28;2016:.|3
03034|043|R|4.De Schryver N, Wittebole X, Van den Bergh P, Haufroid V, Goffin E, Hantson|3
03034|044|R|  P. Severe rhabdomyolysis associated with simvastatin and role of|3
03034|045|R|  ciprofloxacin and amlodipine coadministration. Case Rep Nephrol 2015;|3
03034|046|R|  2015:761393.|3
03034|047|R|5.Sawant RD. Rhabdomyolysis due to an uncommon interaction of ciprofloxacin|3
03034|048|R|  with simvastatin. Can J Clin Pharmacol 2009 Winter;16(1):e78-9.|3
03035|001|T|MONOGRAPH TITLE:  Sertraline (Less Than or Equal To 50 mg)/Select Tricyclic|
03035|002|T|Compounds; Trazodone|
03035|003|B||
03035|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03035|005|L|take action as needed.|
03035|006|B||
03035|007|A|MECHANISM OF ACTION:  Depending upon the interacting combination,|
03035|008|A|pharmacokinetic and/or pharmacodynamic interactions are possible.|
03035|009|A|Sertraline, a SSRI, may impair the oxidative hepatic metabolism of tricyclic|
03035|010|A|compounds and trazodone.|
03035|011|B||
03035|012|E|CLINICAL EFFECTS:  Concurrent administration of sertraline, an SSRI, with a|
03035|013|E|tricyclic compound or trazodone may result in an increase in serum levels,|
03035|014|E|toxicities (e.g. torsades de pointes and/or serotonin syndrome), and/or|
03035|015|E|clinical effects of the tricyclic compound or trazodone|
03035|016|B||
03035|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03035|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03035|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03035|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03035|021|P|female gender, or advanced age.(8)|
03035|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03035|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03035|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03035|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03035|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03035|027|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
03035|028|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(8)|
03035|029|P|   The risk of seizures may be increased in patients with a history of head|
03035|030|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
03035|031|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
03035|032|P|of over-the-counter stimulants and anorectics; diabetics treated with oral|
03035|033|P|hypoglycemics or insulin; or with concomitant medications known to lower|
03035|034|P|seizure threshold (antipsychotics, theophylline, systemic steroids).|
03035|035|P|   The risk of anticholinergic toxicities including cognitive decline,|
03035|036|P|delirium, falls and fractures is increased in geriatric patients using more|
03035|037|P|than one medicine with anticholinergic properties.(10)|
03035|038|B||
03035|039|M|PATIENT MANAGEMENT:  Patients should be observed for increased adverse|
03035|040|M|effects and clinical effects of tricyclic compounds at the initiation of|
03035|041|M|concurrent therapy with sertraline, an SSRI.  Plasma concentrations of the|
03035|042|M|tricyclic compound should be monitored and the dosage adjusted accordingly.|
03035|043|M|   If sertraline is discontinued in a patient receiving a tricyclic|
03035|044|M|compound, the dosage of the tricyclic compound may need to be adjusted.|
03035|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03035|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03035|047|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03035|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03035|049|M|   Patients receiving concurrent therapy with sertraline and clomipramine,|
03035|050|M|imipramine, and/or trazodone should be monitored for serotonin syndrome.|
03035|051|M|Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis,|
03035|052|M|intermittent tremor, and/or myoclonus.  Moderate serotonin symptoms may|
03035|053|M|include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis,|
03035|054|M|hyperactive bowel sounds, hyperreflexia, and/OR clonus.  Severe serotonin|
03035|055|M|symptoms may include: severe hypertension and tachycardia, shock, agitated|
03035|056|M|delirium, muscular rigidity, and/or hypertonicity.|
03035|057|B||
03035|058|D|DISCUSSION:  Sertraline has been shown to increase the maximum concentration|
03035|059|D|(Cmax) and AUC of desipramine by 31% and 23%, respectively.|
03035|060|D|   The affinity of the different SSRIs, SNRIs, and tricyclics for CYP450 may|
03035|061|D|vary.|
03035|062|B||
03035|063|R|REFERENCES:|
03035|064|B||
03035|065|R|1.Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of|3
03035|066|R|  combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990|3
03035|067|R|  Apr;147(4):532.|3
03035|068|R|2.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
03035|069|R|  fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
03035|070|R|  1992 Mar;51(3):239-48.|2
03035|071|R|3.Maskall DD, Lam RW. Increased plasma concentration of imipramine following|3
03035|072|R|  augmentation with fluvoxamine. Am J Psychiatry 1993 Oct;150(10):1566.|3
03035|073|R|4.Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, Harris S.|2
03035|074|R|  Pharmacokinetics of desipramine coadministered with sertraline or|2
03035|075|R|  fluoxetine. J Clin Psychopharmacol 1994 Apr;14(2):90-8.|2
03035|076|R|5.Van Hoey NM. Effect of cyclobenzaprine on tricyclic antidepressant assays.|6
03035|077|R|  Ann Pharmacother 2005 Jul-Aug;39(7-8):1314-7.|6
03035|078|R|6.Flexeril (cyclobenzaprine) US prescribing information. McNeil Consumer and|1
03035|079|R|  Speciality Pharmaceuticals April, 2013.|1
03035|080|R|7.Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the|3
03035|081|R|  interaction of cyclobenzaprine with other serotoninergic drugs. Anesth|3
03035|082|R|  Analg 2006 Dec;103(6):1466-8.|3
03035|083|R|8.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03035|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03035|085|R|  settings: a scientific statement from the American Heart Association and|6
03035|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03035|087|R|  2;55(9):934-47.|6
03035|088|R|9.Amrix (cyclobenzaprine extended release) US prescribing information. Teva|1
03035|089|R|  Pharmaceuticals Ltd. May, 2016.|1
03035|090|R|10.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03035|091|R|   potentially  inappropriate medication use in older adults. J Am Geriatr|6
03035|092|R|   Soc 2023 Jul;71(7):2052-2081.|6
03036|001|T|MONOGRAPH TITLE:  Trazodone (Less Than or Equal To 50 mg)/Meperidine;|
03036|002|T|Tramadol|
03036|003|B||
03036|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03036|005|L|take action as needed.|
03036|006|B||
03036|007|A|MECHANISM OF ACTION:  Meperidine and tramadol inhibit the reuptake of|
03036|008|A|serotonin.(1,2)  Metabolism of trazodone leads to formation of the active|
03036|009|A|metabolite, m-chlorophenylpiperazine (mCPP) which is an agonist at a variety|
03036|010|A|of serotonin receptors.(3,4)|
03036|011|A|   Both tramadol and mCPP are metabolized by CYP2D6.(2,4-6)|
03036|012|B||
03036|013|E|CLINICAL EFFECTS:  Concurrent administration could increase the risk for|
03036|014|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
03036|015|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
03036|016|E|and muscle rigidity.(7)|
03036|017|B||
03036|018|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
03036|019|P|systemic concentrations of meperidine, tramadol or mCPP would be predicted|
03036|020|P|to increase risk for serotonin toxicity.  Concomitant therapy with other|
03036|021|P|agents which increase brain serotonin concentrations may also increase|
03036|022|P|risk.(1-3,7)|
03036|023|P|   Renal dysfunction and chronic use of meperidine would be expected to|
03036|024|P|increase the risk for serotonin toxicity due to meperidine.|
03036|025|P|   Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion,|
03036|026|P|cinacalcet, duloxetine, fluoxetine, paroxetine, quinidine, or systemic|
03036|027|P|terbinafine) may also increase mCPP and tramadol concentrations, increasing|
03036|028|P|risk for serotonin toxicity.|
03036|029|P|   Patients who are poor metabolizers at CYP2D6 would be expected to have|
03036|030|P|higher tramadol and mCPP concentrations compared with extensive|
03036|031|P|metabolizers.(2,3)|
03036|032|B||
03036|033|M|PATIENT MANAGEMENT:  Assess patient for predisposing risk factors and|
03036|034|M|monitor accordingly.|
03036|035|M|   Manufacturers of meperidine, tramadol and trazodone recommend careful|
03036|036|M|monitoring for signs and symptoms of serotonin syndrome when a metabolic|
03036|037|M|inhibitor or another serotoninergic agent is started, or when the dose of|
03036|038|M|either agent is increased.(1-3)|
03036|039|B||
03036|040|D|DISCUSSION:  Meperidine, tramadol and trazodone have each been associated|
03036|041|D|with serotonin syndrome when given concurrently with one or more|
03036|042|D|serotoninergic agents.(1-3)|
03036|043|D|   MCPP has been associated with serotonin syndrome when used as a probe of|
03036|044|D|central serotonin function in human investigational studies.(8)|
03036|045|D|   CYP3A4 converts trazodone to mCPP which is then converted to an inactive|
03036|046|D|metabolite via CYP2D6.(3,4)|
03036|047|B||
03036|048|R|REFERENCES:|
03036|049|B||
03036|050|R|1.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
03036|051|R|  Pharmaceuticals LLC. December, 2023.|1
03036|052|R|2.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
03036|053|R|  October, 2019.|1
03036|054|R|3.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
03036|055|R|  Labopharm Inc. November, 2012.|1
03036|056|R|4.Wen B, Ma L, Rodrigues AD, Zhu M. Detection of novel reactive metabolites|5
03036|057|R|  of trazodone: evidence for CYP2D6-mediated bioactivation of|5
03036|058|R|  m-chlorophenylpiperazine. Drug Metab Dispos 2008 May;36(5):841-50.|5
03036|059|R|5.Schatzberg Alan F and Nemeroff  Charles B (editors). Chapter 19 Trazodone|6
03036|060|R|  and Nefazodone. American Psychiatric Press Textbook of Psychopharmacology,|6
03036|061|R|  3rd ed. 2004.|6
03036|062|R|6.Kast RE. Trazodone generates m-CPP: in 2008 risks from m-CPP might|6
03036|063|R|  outweigh benefits of trazodone. World J Biol Psychiatry 2009;10(4 Pt|6
03036|064|R|  2):682-5.|6
03036|065|R|7.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03036|066|R|  352(11):1112-20.|6
03036|067|R|8.Kovaleva J, Devuyst E, De Paepe P, Verstraete A. Acute|3
03036|068|R|  chlorophenylpiperazine overdose: a case report and review of the|3
03036|069|R|  literature. Ther Drug Monit 2008 Jun;30(3):394-8.|3
03037|001|T|MONOGRAPH TITLE:  Escitalopram (Less Than or Equal To 15 mg)/Selected|
03037|002|T|CYP2C19 Inhibitors|
03037|003|B||
03037|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03037|005|L|take action as needed.|
03037|006|B||
03037|007|A|MECHANISM OF ACTION:  At lower systemic concentrations, escitalopram is|
03037|008|A|primarily metabolized by CYP2C19; at higher concentrations is also|
03037|009|A|metabolized by CYP3A4.(1)|
03037|010|B||
03037|011|E|CLINICAL EFFECTS:  Concurrent use of an agent which significantly inhibits|
03037|012|E|CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated|
03037|013|E|concentrations and toxicity from escitalopram, including risks for serotonin|
03037|014|E|syndrome or prolongation of the QTc interval.(1,5)  Prolongation of the QT|
03037|015|E|interval may result in life-threatening arrhythmias, including torsades de|
03037|016|E|pointes.(2)  Symptoms of serotonin syndrome may include tremor, agitation,|
03037|017|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03037|018|E|rigidity.(3)|
03037|019|B||
03037|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased in|
03037|021|P|patients with congenital long QT syndrome, cardiovascular disease (e.g.|
03037|022|P|heart failure, myocardial infarction), hypokalemia, hypomagnesemia,|
03037|023|P|hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status|
03037|024|P|at CYP2C19, concurrent use of more than one agent known to cause QT|
03037|025|P|prolongation, or with higher blood concentrations of escitalopram.(2)|
03037|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03037|027|P|higher systemic concentrations of either QT prolonging drug are additional|
03037|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03037|029|P|drug concentrations include rapid infusion of an intravenous dose or|
03037|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03037|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03037|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03037|033|P|   Predisposing factors for serotonin-related adverse effects include use in|
03037|034|P|the elderly, in patients with hepatic impairment, and in patients receiving|
03037|035|P|multiple agents which increase central serotonin levels.(1,3)|
03037|036|P|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03037|037|P|magnesium, and potassium levels and monitoring ECG at baseline and at|
03037|038|P|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03037|039|P|patients to report any irregular heartbeat, dizziness, or fainting.|
03037|040|B||
03037|041|M|PATIENT MANAGEMENT:  Evaluate patient for other drugs, diseases and|
03037|042|M|conditions which may further increase risk for QT prolongation and correct|
03037|043|M|risk factors (e.g. correct hypokalemia, discontinue other QT prolonging|
03037|044|M|drugs) when possible.(2,3)  It would be prudent to limit the escitalopram|
03037|045|M|dose to 10 mg daily in patients with QT prolonging risk factors who also|
03037|046|M|receive concurrent therapy with selected CYP2C19 inhibitors.(5)  Weigh the|
03037|047|M|specific benefits versus risks for each patient.|
03037|048|M|   If concurrent therapy is warranted, patients should be monitored for|
03037|049|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03037|050|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03037|051|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03037|052|M|coordination, or severe diarrhea.|
03037|053|B||
03037|054|D|DISCUSSION:  A thorough QT study evaluating escitalopram 10 mg or 30 mg once|
03037|055|D|daily was conducted; a change of 10 msec for upper bound of the 95%|
03037|056|D|confidence level is the threshold for regulatory concern.  In this study,|
03037|057|D|changes to the upper bound of the 95% confidence interval were 6.4 msec and|
03037|058|D|12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The|
03037|059|D|Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended|
03037|060|D|escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar|
03037|061|D|to expected steady state concentrations in 2C19 poor metabolizers following|
03037|062|D|a 20 mg escitalopram dose.(1)|
03037|063|D|  In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of|
03037|064|D|CYP2C19 was administered daily for 6 days. On day 5 a single dose of|
03037|065|D|escitalopram 20 mg was also administered; the area-under-curve (AUC) of|
03037|066|D|escitalopram was increased by 50%. Manufacturer prescribing information|
03037|067|D|recommends a maximum citalopram dose of 20mg daily in patients receiving|
03037|068|D|CYP2C19 inhibitors.(1)|
03037|069|D|   Inhibitors of CYP2C19 include:  abrocitinib, allicin (garlic derivative),|
03037|070|D|berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200|
03037|071|D|mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib,|
03037|072|D|felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide,|
03037|073|D|modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol,|
03037|074|D|tecovirimat, and tipranavir.(4)|
03037|075|B||
03037|076|R|REFERENCES:|
03037|077|B||
03037|078|R|1.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03037|079|R|  Pharmaceuticals Inc. May, 2023.|1
03037|080|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03037|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03037|082|R|  settings: a scientific statement from the American Heart Association and|6
03037|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03037|084|R|  2;55(9):934-47.|6
03037|085|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03037|086|R|  352(11):1112-20.|6
03037|087|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03037|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03037|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03037|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03037|091|R|  11/14/2017.|1
03037|092|R|5.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
03037|093|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
03037|094|R|  and antidepressant use: a cross sectional study of electronic health|2
03037|095|R|  records. BMJ 2013;346:f288.|2
03038|001|T|MONOGRAPH TITLE:  Select Oral Benzodiazepines/Aprepitant (Less Than or Equal|
03038|002|T|To 40 mg)|
03038|003|B||
03038|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03038|005|L|take action as needed.|
03038|006|B||
03038|007|A|MECHANISM OF ACTION:  Aprepitant doses greater than 40 mg per day are|
03038|008|A|classified as moderate inhibitors of CYP3A4 and may inhibit the CYP3A4|
03038|009|A|mediated absorption and metabolism of alprazolam, midazolam or triazolam.|
03038|010|A|Aprepitant doses < or = to 40 mg per day would be expected to inhibit CYP3A4|
03038|011|A|to a lesser extent.(1-3)|
03038|012|B||
03038|013|E|CLINICAL EFFECTS:  Concurrent administration of aprepitant may result in|
03038|014|E|increased levels of and effects from the benzodiazepines.(1-4)  Toxic|
03038|015|E|effects of increased levels of benzodiazepines include profound sedation,|
03038|016|E|respiratory depression, coma, and/or death.|
03038|017|B||
03038|018|P|PREDISPOSING FACTORS:  None determined.|
03038|019|B||
03038|020|M|PATIENT MANAGEMENT:  Depending on patient tolerance, the benzodiazepine|
03038|021|M|dosage may need to be reduced or an alternative agent not metabolized by|
03038|022|M|CYP3A4 (e.g. lorazepam, temazepam) may be used.|
03038|023|M|   Patients receiving concurrent therapy with aprepitant and alprazolam,|
03038|024|M|midazolam, or triazolam should be closely monitored and counseled regarding|
03038|025|M|possible adverse effects due to increased benzodiazepine exposure.  Due to|
03038|026|M|its long half-life, the effects of a single dose of netupitant persist for 4|
03038|027|M|or more days.|
03038|028|B||
03038|029|D|DISCUSSION:  In an open-label, randomized single-period study in 16 healthy|
03038|030|D|subjects, administration of aprepitant (125 mg on Day 1, 80 mg on Days 2-5)|
03038|031|D|increased the area-under-curve (AUC) of a single oral dose of midazolam (2|
03038|032|D|mg on Day 1 and Day 5) by 2.3-fold on Day 1 and by 3.3-fold on Day 5 when|
03038|033|D|compared to midazolam alone.  Midazolam maximum concentration (Cmax)|
03038|034|D|increased by 1.5-fold on Day 1 and by 1.9-fold on Day 5.(1,4)  Midazolam|
03038|035|D|half-life increased from 1.7 hours for midazolam alone to 3.3 hours on Day 1|
03038|036|D|and Day 5.  In the second group, administration of aprepitant (40 mg on Day|
03038|037|D|1, 25 mg on Days 2-5) with midazolam had no significant effects on midazolam|
03038|038|D|AUC, Cmax, or half-life.(5)|
03038|039|D|   In a study, administration of a single dose of aprepitant (40 mg)|
03038|040|D|increased the AUC of a single dose of oral midazolam (2 mg) by 1.2-fold.|
03038|041|D|This was not considered clinically significant.(1)|
03038|042|D|   In a study in 12 healthy subjects, administration of aprepitant (125 mg|
03038|043|D|on Day 1, 80 mg on Days 2-3) increased the AUC of a single dose of|
03038|044|D|intravenous midazolam (2 mg on Days 4, 8, and 15) by 25% on Day 4.  The AUC|
03038|045|D|of midazolam was decreased by 19% on Day 8.  These effects were not|
03038|046|D|considered clinically significant.(1,4)|
03038|047|D|   In a study, administration of a single dose of intravenous midazolam (2|
03038|048|D|mg) 1 hour after a single dose of aprepitant (125 mg) increased midazolam|
03038|049|D|AUC by 1.5-fold.(1)|
03038|050|B||
03038|051|R|REFERENCES:|
03038|052|B||
03038|053|R|1.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
03038|054|R|  September, 2019.|1
03038|055|R|2.Emend (aprepitant) Australian prescribing information. MSD April 5, 2004.|1
03038|056|R|3.Emend (aprepitant) UK summary of product characteristics. Merck Sharp &|1
03038|057|R|  Dohme Limited January 10. 2005.|1
03038|058|R|4.Majumdar AK, McCrea JB, Panebianco DL, Hesney M, Dru J, Constanzer M,|2
03038|059|R|  Goldberg MR, Murphy G, Gottesdiener KM, Lines CR, Petty KJ, Blum RA.|2
03038|060|R|  Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a|2
03038|061|R|  probe. Clin Pharmacol Ther 2003 Sep;74(2):150-6.|2
03038|062|R|5.Shadle CR, Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, Evans|2
03038|063|R|  JK, Blum RA. Evaluation of potential inductive effects of aprepitant on|2
03038|064|R|  cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol 2004 Apr;|2
03038|065|R|  44(3):215-23.|2
03039|001|T|MONOGRAPH TITLE:  Lower Strength Select Tricyclics/Cinacalcet|
03039|002|B||
03039|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03039|004|L|take action as needed.|
03039|005|B||
03039|006|A|MECHANISM OF ACTION:  Cinacalcet may inhibit the CYP2D6 mediated metabolism|
03039|007|A|of amitriptyline, desipramine and nortriptyline.(1,2)|
03039|008|B||
03039|009|E|CLINICAL EFFECTS:  Concurrent use of cinacalcet and amitriptyline,|
03039|010|E|desipramine, or nortriptyline may result in elevated levels of and toxicity|
03039|011|E|from these tricyclic antidepressants.(1,3)|
03039|012|B||
03039|013|P|PREDISPOSING FACTORS:  Higher doses of either agent are expected to increase|
03039|014|P|the severity of the interaction.|
03039|015|P|  In patients with moderate to severe hepatic impairment, cinacalcet|
03039|016|P|exposure is 2.4 to 4.2-fold higher and the mean half-life increased from 49|
03039|017|P|to 65-84 hours compared with healthy volunteers.(1)|
03039|018|P|   The risk of seizures may be increased in patients with a history of head|
03039|019|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
03039|020|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
03039|021|P|of over-the-counter stimulants and anorectics; diabetics treated with oral|
03039|022|P|hypoglycemics or insulin; or with concomitant medications known to lower|
03039|023|P|seizure threshold (antipsychotics, theophylline, systemic steroids).|
03039|024|P|   The risk of anticholinergic toxicities including cognitive decline,|
03039|025|P|delirium, falls and fractures is increased in geriatric patients using more|
03039|026|P|than one medicine with anticholinergic properties.(4)|
03039|027|B||
03039|028|M|PATIENT MANAGEMENT:  The manufacturer describes cinacalcet as a strong|
03039|029|M|inhibitor of CYP2D6. Dose adjustments may be required for concomitant|
03039|030|M|medications predominantly metabolized by CYP2D6, particularly if they have a|
03039|031|M|narrow therapeutic index.(1)|
03039|032|M|   Cinacalcet has a long elimination half-life of 49 hours so the time to|
03039|033|M|maximal inhibition of a CYP2D6 metabolized drug may not be seen for a week|
03039|034|M|or more after starting or increasing the dose of cinacalcet.|
03039|035|M|   In an interaction study, cinacalcet 90 mg daily increased desipramine|
03039|036|M|exposure (AUC, area-under-curve) 264%.(1)|
03039|037|M|   Instruct patients to report seizures, fainting, irregular heartbeat, new|
03039|038|M|or worsening blurred vision, urinary retention, mental or mood changes,|
03039|039|M|confusion, dry mouth or constipation.|
03039|040|B||
03039|041|D|DISCUSSION:  In an interaction study, fourteen subjects who were extensive|
03039|042|D|metabolizers of CYP2D6 received one dose of desipramine 50 mg, either alone|
03039|043|D|or after 7 days of pretreatment with cinacalcet 90 mg daily. Compared with|
03039|044|D|desipramine alone, cinacalcet administration increased desipramine exposure|
03039|045|D|(AUC, area-under-curve) and maximum concentration (Cmax) 3.6 and 1.8-fold|
03039|046|D|respectively. Desipramine half-life was also longer when it was|
03039|047|D|coadministered with cinacalcet (21.0 versus 43.3 hs). Fewer subjects|
03039|048|D|reported adverse events following treatment with desipramine alone than when|
03039|049|D|receiving desipramine with cinacalcet (33% versus 86%).(2)|
03039|050|D|   In an interaction study, subjects who were extensive metabolizers of|
03039|051|D|CYP2D6 received one dose of amitriptyline 50 mg with a single dose of|
03039|052|D|cinacalcet (25 or 100 mg) resulting in a change in AUC and Cmax for|
03039|053|D|amitriptyline of 21-22% and 13-21%, respectively. The change in AUC and Cmax|
03039|054|D|for nortriptyline was 17-23% and 11-15%, respectively.(1)|
03039|055|B||
03039|056|R|REFERENCES:|
03039|057|B||
03039|058|R|1.Sensipar (cinacalcet hydrochloride) US prescribing information. Amgen Inc.|1
03039|059|R|  March, 2019.|1
03039|060|R|2.This information is based on an extract from the Certara Drug Interaction|6
03039|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03039|062|R|3.Harris RZ, Salfi M, Posvar E, Hoelscher D, Padhi D. Pharmacokinetics of|2
03039|063|R|  desipramine HCl when administered with cinacalcet HCl. Eur J Clin|2
03039|064|R|  Pharmacol 2007 Feb;63(2):159-63.|2
03039|065|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03039|066|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03039|067|R|  Soc 2023 Jul;71(7):2052-2081.|6
03040|001|T|MONOGRAPH TITLE:  Atorvastatin/Ranolazine|
03040|002|B||
03040|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03040|004|L|take action as needed.|
03040|005|B||
03040|006|A|MECHANISM OF ACTION:  Ranolazine may inhibit the metabolism of atorvastatin|
03040|007|A|by CYP3A4.(1,2,4-6)|
03040|008|B||
03040|009|E|CLINICAL EFFECTS:  Concurrent ranolazine may result in elevated levels of|
03040|010|E|atorvastatin(1,2) which may result in myopathy and rhabdomyolysis.|
03040|011|B||
03040|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03040|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03040|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03040|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03040|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03040|017|P|transporter OATP1B1 may have increased statin concentrations and be|
03040|018|P|predisposed to myopathy or rhabdomyolysis.|
03040|019|B||
03040|020|M|PATIENT MANAGEMENT:  Consider a reduction of atorvastatin dose with|
03040|021|M|concurrent ranolazine.|
03040|022|B||
03040|023|D|DISCUSSION:  In healthy subjects, ranolazine (1000 mg twice daily) increased|
03040|024|D|mean exposure to atorvastatin by 40%.  However, in one subject, exposure was|
03040|025|D|increased by approximately 400%.(1)|
03040|026|D|   In healthy subjects, ranolazine (1000 mg twice daily) increased plasma|
03040|027|D|levels of simvastatin (80 mg daily) and its active metabolite each by|
03040|028|D|2-fold.(1)|
03040|029|D|   In healthy subjects, simvastatin (20 mg daily) had no effect on|
03040|030|D|ranolazine levels.(1)|
03040|031|D|   In a study in 17 healthy volunteers, simvastatin (80 mg daily) did not|
03040|032|D|have a significant effect on ranolazine sustained release (SR, 1750 mg|
03040|033|D|initial dose followed by 1000 mg twice daily) pharmacokinetics with the mean|
03040|034|D|area under the curve (AUC), maximum concentration (Cmax), and minimum|
03040|035|D|concentration (Cmin) being within 80% to 125%. In contrast, ranolazine SR|
03040|036|D|increased the Cmax of simvastatin lactone, simvastatin acid, and HMG-CoA|
03040|037|D|reductase inhibitor activity by 2-fold with the corresponding AUC increases|
03040|038|D|in the range of 40% to 60%.(2,7)|
03040|039|D|   In a case report, a patient had been maintained on simvastatin for 12|
03040|040|D|years, one of which with concurrent cyclosporine.  Two months after the|
03040|041|D|addition of carvedilol, diltiazem, and ranolazine, the patient developed|
03040|042|D|rhabdomyolysis.(8)|
03040|043|D|   In a case report, a patient had been maintained on a stable dose of|
03040|044|D|simvastatin (80 mg). Ten days after the addition of ranolazine (500 mg|
03040|045|D|extended release) was added to the patient's medication regimen, the patient|
03040|046|D|developed rhabdomyolysis.(9)|
03040|047|B||
03040|048|R|REFERENCES:|
03040|049|B||
03040|050|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
03040|051|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
03040|052|R|  Pharma U.K. S.R.I. October 30, 2008.|1
03040|053|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
03040|054|R|  February, 2014.|1
03040|055|R|4.USFood and Drug Administration. FDA Drug Safety Communication: New|1
03040|056|R|  restrictions, contraindications, and dose limitations for Zocor|1
03040|057|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
03040|058|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
03040|059|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
03040|060|R|  June 8, 2011.|1
03040|061|R|5.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03040|062|R|  2023.|1
03040|063|R|6.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
03040|064|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
03040|065|R|7.Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to|2
03040|066|R|  investigate the pharmacokinetic interactions between ranolazine and|2
03040|067|R|  ketoconazole, diltiazem, or simvastatin during combined administration in|2
03040|068|R|  healthy subjects. J Clin Pharmacol 2005 Apr;45(4):422-33.|2
03040|069|R|8.Rifkin SI. Multiple drug interactions in a renal transplant patient|3
03040|070|R|  leading to simvastatin-induced rhabdomyolysis: a case report. Medscape J|3
03040|071|R|  Med 2008;10(11):264.|3
03040|072|R|9.Hylton AC, Ezekiel TO. Rhabdomyolysis in a patient receiving ranolazine|3
03040|073|R|  and simvastatin. Am J Health Syst Pharm 2010 Nov 1;67(21):1829-31.|3
03041|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 20 mg)/Ranolazine|
03041|002|T|(mono deleted 08/17/2022)|
03041|003|B||
03041|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03041|005|L|take action as needed.|
03041|006|B||
03041|007|A|MECHANISM OF ACTION:  Ranolazine may inhibit the metabolism of atorvastatin|
03041|008|A|by CYP3A4.(1,2,4-6)|
03041|009|B||
03041|010|E|CLINICAL EFFECTS:  Concurrent ranolazine may result in elevated levels of|
03041|011|E|atorvastatin (1,2) which may result in myopathy and rhabdomyolysis.|
03041|012|B||
03041|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03041|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03041|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03041|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03041|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03041|018|P|transporter OATP1B1 may have increased statin concentrations and be|
03041|019|P|predisposed to myopathy or rhabdomyolysis.|
03041|020|B||
03041|021|M|PATIENT MANAGEMENT:  Consider a reduction of atorvastatin dose with|
03041|022|M|concurrent ranolazine.|
03041|023|B||
03041|024|D|DISCUSSION:  In healthy subjects, ranolazine (1000 mg twice daily) increased|
03041|025|D|mean exposure to atorvastatin by 40%.  However, in one subject, exposure was|
03041|026|D|increased by approximately 400%.(1)|
03041|027|D|   In healthy subjects, ranolazine (1000 mg twice daily) increased plasma|
03041|028|D|levels of simvastatin (80 mg daily) and its active metabolite each by|
03041|029|D|2-fold.(1)|
03041|030|D|   In healthy subjects, simvastatin (20 mg daily) had no effect on|
03041|031|D|ranolazine levels.(1)|
03041|032|D|   In a study in 17 healthy volunteers, simvastatin (80 mg daily) did not|
03041|033|D|have a significant effect on ranolazine sustained release (SR, 1750 mg|
03041|034|D|initial dose followed by 1000 mg twice daily) pharmacokinetics with the mean|
03041|035|D|area under the curve (AUC), maximum concentration (Cmax), and minimum|
03041|036|D|concentration (Cmin) being within 80% to 125%. In contrast, ranolazine SR|
03041|037|D|increased the Cmax of simvastatin lactone, simvastatin acid, and HMG-CoA|
03041|038|D|reductase inhibitor activity by 2-fold with the corresponding AUC increases|
03041|039|D|in the range of 40% to 60%.(2,7)|
03041|040|D|   In a case report, a patient had been maintained on simvastatin for 12|
03041|041|D|years, one of which with concurrent cyclosporine.  Two months after the|
03041|042|D|addition of carvedilol, diltiazem, and ranolazine, the patient developed|
03041|043|D|rhabdomyolysis.(8)|
03041|044|D|   In a case report, a patient had been maintained on a stable dose of|
03041|045|D|simvastatin (80 mg). Ten days after the addition of ranolazine (500 mg|
03041|046|D|extended release) was added to the patient's medication regimen, the patient|
03041|047|D|developed rhabdomyolysis.(9)|
03041|048|B||
03041|049|R|REFERENCES:|
03041|050|B||
03041|051|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
03041|052|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
03041|053|R|  Pharma U.K. S.R.I. October 30, 2008.|1
03041|054|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
03041|055|R|  February, 2014.|1
03041|056|R|4.USFood and Drug Administration. FDA Drug Safety Communication: New|1
03041|057|R|  restrictions, contraindications, and dose limitations for Zocor|1
03041|058|R|  (simvastatin) to reduce the risk of muscle injury. available at:|1
03041|059|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
03041|060|R|  munication-new-restrictions-contraindications-and-dose-limitations-zocor|1
03041|061|R|  June 8, 2011.|1
03041|062|R|5.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03041|063|R|  2023.|1
03041|064|R|6.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
03041|065|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
03041|066|R|7.Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to|2
03041|067|R|  investigate the pharmacokinetic interactions between ranolazine and|2
03041|068|R|  ketoconazole, diltiazem, or simvastatin during combined administration in|2
03041|069|R|  healthy subjects. J Clin Pharmacol 2005 Apr;45(4):422-33.|2
03041|070|R|8.Rifkin SI. Multiple drug interactions in a renal transplant patient|3
03041|071|R|  leading to simvastatin-induced rhabdomyolysis: a case report. Medscape J|3
03041|072|R|  Med 2008;10(11):264.|3
03041|073|R|9.Hylton AC, Ezekiel TO. Rhabdomyolysis in a patient receiving ranolazine|3
03041|074|R|  and simvastatin. Am J Health Syst Pharm 2010 Nov 1;67(21):1829-31.|3
03042|001|T|MONOGRAPH TITLE:  Encorafenib/Strong and Moderate CYP3A4 Inhibitors|
03042|002|B||
03042|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03042|004|L|of severe adverse interaction.|
03042|005|B||
03042|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may inhibit|
03042|007|A|the metabolism of encorafenib.(1)|
03042|008|B||
03042|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inhibitor of|
03042|010|E|CYP3A4 may result in elevated levels of and toxicity from encorafenib,|
03042|011|E|including QT prolongation.(1)|
03042|012|B||
03042|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03042|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03042|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03042|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03042|017|P|female gender, or advanced age.(2)|
03042|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03042|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03042|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03042|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03042|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03042|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03042|024|P|dysfunction).(2)|
03042|025|B||
03042|026|M|PATIENT MANAGEMENT:  Concurrent use of strong or moderate CYP3A4 inhibitors|
03042|027|M|with encorafenib should be avoided.  If concurrent use of strong or moderate|
03042|028|M|CYP3A4 inhibitors with encorafenib is unavoidable, reduce the encorafenib|
03042|029|M|dose as follows:|
03042|030|M|   - If the current daily dose of encorafenib is 450 mg, reduce encorafenib|
03042|031|M|to 150 mg with strong CYP3A4 inhibitors, and 225 mg with moderate CYP3A4|
03042|032|M|inhibitors.|
03042|033|M|   - If the current daily dose of encorafenib is 300 mg, reduce encorafenib|
03042|034|M|to 75 mg with strong CYP3A4 inhibitors, and 150 mg with moderate CYP3A4|
03042|035|M|inhibitors.|
03042|036|M|   - If the current daily dose of encorafenib is 225 mg or 150 mg, reduce|
03042|037|M|encorafenib to 75 mg with both strong and moderate CYP3A4 inhibitors.|
03042|038|M|   - After the inhibitor has been discontinued for 3 to 5 half-lives, resume|
03042|039|M|encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor.(1)|
03042|040|M|   When concurrent therapy cannot be avoided, monitor patients closely for|
03042|041|M|prolongation of the QT interval.  Obtain ECGs and electrolyte values (serum|
03042|042|M|calcium, magnesium, and potassium) at regular intervals.  Correct any|
03042|043|M|electrolyte abnormalities.|
03042|044|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03042|045|M|fainting.|
03042|046|M|   Recommended dosage modifications for encorafenib and QTc prolongation|
03042|047|M|adverse reactions include:|
03042|048|M|   - QTcF greater than 500 ms and less than or equal to 60 ms increase from|
03042|049|M|baseline: Withhold encorafenib until QTcF less than or equal to 500 ms.|
03042|050|M|Resume at reduced dose.  If more than one recurrence, permanently|
03042|051|M|discontinue encorafenib.|
03042|052|M|   - QTcF greater than 500 ms and greater than 60 ms increase from baseline:|
03042|053|M|Permanently discontinue encorafenib.(1)|
03042|054|M|   See prescribing information for additional information regarding dose|
03042|055|M|reductions.(1)|
03042|056|B||
03042|057|D|DISCUSSION:  Coadministration of posaconazole (strong CYP3A4 inhibitor) or|
03042|058|D|diltiazem (moderate CYP3A4 inhibitor) increased the area-under-curve (AUC)|
03042|059|D|of encorafenib by 3-fold and 2-fold, respectively, and increased the maximum|
03042|060|D|concentration (Cmax) by 68% and 45%, respectively, after a single dose of|
03042|061|D|encorafenib 50 mg (0.1 times the recommended dose).(1)|
03042|062|D|   Encorafenib has been associated with a dose-dependent QTc interval|
03042|063|D|prolongation.  Following administration of encorafenib in combination with|
03042|064|D|binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms|
03042|065|D|(14-22 ms), based on central tendency analysis.(1)|
03042|066|D|   Strong inhibitors of CYP3A4 include:  indinavir, josamycin, ketoconazole,|
03042|067|D|mibefradil, nefazodone, nelfinavir, tipranavir, and troleandomycin.(4-6)|
03042|068|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, berotralstat,|
03042|069|D|conivaptan, fluvoxamine, fosamprenavir, letermovir, schisandra, stiripentol,|
03042|070|D|and treosulfan.(4-6)|
03042|071|B||
03042|072|R|REFERENCES:|
03042|073|B||
03042|074|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
03042|075|R|  BioPharma December, 2024.|1
03042|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03042|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03042|078|R|  settings: a scientific statement from the American Heart Association and|6
03042|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03042|080|R|  2;55(9):934-47.|6
03042|081|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03042|082|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03042|083|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03042|084|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03042|085|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03042|086|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03042|087|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03042|088|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03042|089|R|  11/14/2017.|1
03042|090|R|5.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03042|091|R|  Indiana University School of Medicine.  Available at:|1
03042|092|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03042|093|R|6.This information is based on an extract from the Certara Drug Interaction|6
03042|094|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03043|001|T|MONOGRAPH TITLE:  Encorafenib/Strong CYP3A4 Inducers|
03043|002|B||
03043|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03043|004|L|of severe adverse interaction.|
03043|005|B||
03043|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
03043|007|A|encorafenib.(1)|
03043|008|B||
03043|009|E|CLINICAL EFFECTS:  The concurrent use of strong CYP3A4 inducers and|
03043|010|E|encorafenib may result in decreased levels and clinical effectiveness of|
03043|011|E|encorafenib.(1)|
03043|012|B||
03043|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03043|014|P|of the inducer for longer than 1-2 weeks.|
03043|015|B||
03043|016|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inducers and|
03043|017|M|encorafenib should be avoided.  Concurrent use may decrease efficacy of|
03043|018|M|encorafenib.(1)|
03043|019|B||
03043|020|D|DISCUSSION:  Concurrent use of strong CYP3A4 inducers and encorafenib has|
03043|021|D|not been studied.  In clinical trials, steady-state encorafenib exposures|
03043|022|D|were lower than encorafenib exposure after the first dose, suggesting CYP3A4|
03043|023|D|auto-induction.(1)|
03043|024|D|   Strong CYP3A4 inducers linked to this monograph include:  apalutamide,|
03043|025|D|barbiturates, carbamazepine, fosphenytoin, mitotane, phenobarbital,|
03043|026|D|phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2)|
03043|027|B||
03043|028|R|REFERENCES:|
03043|029|B||
03043|030|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
03043|031|R|  BioPharma December, 2024.|1
03043|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
03043|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03044|001|T|MONOGRAPH TITLE:  Hormonal Contraceptive Agents/Encorafenib|
03044|002|B||
03044|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03044|004|L|of severe adverse interaction.|
03044|005|B||
03044|006|A|MECHANISM OF ACTION:  Encorafenib may induce the metabolism of hormonal|
03044|007|A|contraceptive agents by CYP3A4.(1)|
03044|008|B||
03044|009|E|CLINICAL EFFECTS:  Concurrent use of encorafenib and hormonal contraceptive|
03044|010|E|agents may decrease the effectiveness of the hormonal contraceptive agent,|
03044|011|E|which may result in contraceptive failure.  Encorafenib may cause birth|
03044|012|E|defects and/or miscarriage if used by pregnant women.(1)|
03044|013|B||
03044|014|P|PREDISPOSING FACTORS:  None determined.|
03044|015|B||
03044|016|M|PATIENT MANAGEMENT:  Women receiving encorafenib therapy should not rely|
03044|017|M|solely on hormonal contraceptive agents (including oral, implantable,|
03044|018|M|injectable, or transdermal agents) because they may not be effective.  Women|
03044|019|M|should be advised to use a highly effective non-hormonal method of|
03044|020|M|contraception during and for 2 weeks after the final dose of encorafenib.(1)|
03044|021|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03044|022|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03044|023|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03044|024|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03044|025|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03044|026|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03044|027|M|and to seek medical advice if they do become pregnant.(2)|
03044|028|B||
03044|029|D|DISCUSSION:  Based on in vitro data, encorafenib is an inducer of CYP3A4 at|
03044|030|D|clinically relevant plasma concentrations.(1)|
03044|031|D|   Hormonal contraceptives are also metabolized by CYP3A4, therefore,|
03044|032|D|hormonal contraceptive agents may not be reliable in patients taking|
03044|033|D|encorafenib.(1)|
03044|034|B||
03044|035|R|REFERENCES:|
03044|036|B||
03044|037|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
03044|038|R|  BioPharma December, 2024.|1
03044|039|R|2.Medicines and Healthcare products Regulatory Agency.|1
03044|040|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03044|041|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03044|042|R|  available at:|1
03044|043|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03044|044|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03044|045|R|  -and-contraceptive-efficacy September 15, 2016..|1
03045|001|T|MONOGRAPH TITLE:  Encorafenib/QT Prolonging Agents|
03045|002|B||
03045|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03045|004|L|of severe adverse interaction.|
03045|005|B||
03045|006|A|MECHANISM OF ACTION:  Concurrent use of encorafenib with agents that prolong|
03045|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03045|008|B||
03045|009|E|CLINICAL EFFECTS:  The concurrent use of encorafenib with agents that|
03045|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03045|011|E|arrhythmias, including torsades de pointes.(1)|
03045|012|B||
03045|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03045|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03045|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03045|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03045|017|P|female gender, or advanced age.(2)|
03045|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03045|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03045|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03045|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03045|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03045|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03045|024|P|dysfunction).(2)|
03045|025|B||
03045|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of encorafenib with|
03045|027|M|medications that prolong the QT interval.(1)|
03045|028|M|   Recommended dosage modifications for encorafenib and QTc prolongation|
03045|029|M|adverse reactions include:|
03045|030|M|   - QTcF greater than 500 ms and less than or equal to 60 ms increase from|
03045|031|M|baseline: Withhold encorafenib until QTcF less than or equal to 500 ms.|
03045|032|M|Resume at reduced dose.  If more than one recurrence, permanently|
03045|033|M|discontinue encorafenib.|
03045|034|M|   - QTcF greater than 500 ms and greater than 60 ms increase from baseline:|
03045|035|M|Permanently discontinue encorafenib.(1)|
03045|036|M|   See prescribing information for additional information regarding dose|
03045|037|M|reductions.(1)|
03045|038|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03045|039|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03045|040|M|treatment, after initiation of any drug known to prolong the QT interval,|
03045|041|M|and periodically monitor during therapy.  Correct any electrolyte|
03045|042|M|abnormalities.|
03045|043|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03045|044|M|fainting.|
03045|045|B||
03045|046|D|DISCUSSION:  Encorafenib has been associated with a dose-dependent QTc|
03045|047|D|interval prolongation.  Following administration of encorafenib in|
03045|048|D|combination with binimetinib, the largest mean (90% CI) QTcF change from|
03045|049|D|baseline was 18 ms (14-22 ms), based on central tendency analysis.(1)|
03045|050|D|   Following administration of encorafenib in combination with cetuximab and|
03045|051|D|mFOLFOX6, an increase of QTcF >500 ms was measured in 3.6% (8/222) of|
03045|052|D|patients.(1)|
03045|053|D|   Agents that are linked to this monograph may have varying degrees of|
03045|054|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03045|055|D|been shown to prolong the QTc interval either through their mechanism of|
03045|056|D|action, through studies on their effects on the QTc interval, or through|
03045|057|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03045|058|D|and/or postmarketing reports.(3)|
03045|059|B||
03045|060|R|REFERENCES:|
03045|061|B||
03045|062|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
03045|063|R|  BioPharma December, 2024.|1
03045|064|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03045|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03045|066|R|  settings: a scientific statement from the American Heart Association and|6
03045|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03045|068|R|  2;55(9):934-47.|6
03045|069|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03045|070|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03045|071|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03045|072|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03046|001|T|MONOGRAPH TITLE:  Encorafenib/Possible QT Prolonging Agents|
03046|002|B||
03046|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03046|004|L|take action as needed.|
03046|005|B||
03046|006|A|MECHANISM OF ACTION:  Concurrent use of encorafenib with agents that prolong|
03046|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03046|008|B||
03046|009|E|CLINICAL EFFECTS:  The concurrent use of encorafenib with agents that|
03046|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03046|011|E|arrhythmias, including torsades de pointes.(1)|
03046|012|B||
03046|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03046|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03046|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03046|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03046|017|P|female gender, or advanced age.(2)|
03046|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03046|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03046|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03046|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03046|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03046|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03046|024|P|dysfunction).(2)|
03046|025|B||
03046|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of encorafenib with|
03046|027|M|medications that prolong the QT interval.(1)|
03046|028|M|   Recommended dosage modifications for encorafenib and QTc prolongation|
03046|029|M|adverse reactions include:|
03046|030|M|   - QTcF greater than 500 ms and less than or equal to 60 ms increase from|
03046|031|M|baseline: Withhold encorafenib until QTcF less than or equal to 500 ms.|
03046|032|M|Resume at reduced dose.  If more than one recurrence, permanently|
03046|033|M|discontinue encorafenib.|
03046|034|M|   - QTcF greater than 500 ms and greater than 60 ms increase from baseline:|
03046|035|M|Permanently discontinue encorafenib.(1)|
03046|036|M|   See prescribing information for additional information regarding dose|
03046|037|M|reductions.(1)|
03046|038|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03046|039|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03046|040|M|treatment, after initiation of any drug known to prolong the QT interval,|
03046|041|M|and periodically monitor during therapy.  Correct any electrolyte|
03046|042|M|abnormalities.|
03046|043|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03046|044|M|fainting.|
03046|045|B||
03046|046|D|DISCUSSION:  Encorafenib has been associated with a dose-dependent QTc|
03046|047|D|interval prolongation.  Following administration of encorafenib in|
03046|048|D|combination with binimetinib, the largest mean (90% CI) QTcF change from|
03046|049|D|baseline was 18 ms (14-22 ms), based on central tendency analysis.(1)|
03046|050|D|   Following administration of encorafenib in combination with cetuximab and|
03046|051|D|mFOLFOX6, an increase of QTcF >500 ms was measured in 3.6% (8/222) of|
03046|052|D|patients.(1)|
03046|053|D|   Agents that are linked to this monograph may have varying degrees of|
03046|054|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03046|055|D|been shown to prolong the QTc interval either through their mechanism of|
03046|056|D|action, through studies on their effects on the QTc interval, or through|
03046|057|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03046|058|D|and/or postmarketing reports.(3)|
03046|059|B||
03046|060|R|REFERENCES:|
03046|061|B||
03046|062|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
03046|063|R|  BioPharma December, 2024.|1
03046|064|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03046|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03046|066|R|  settings: a scientific statement from the American Heart Association and|6
03046|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03046|068|R|  2;55(9):934-47.|6
03046|069|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03046|070|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03046|071|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03046|072|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03047|001|T|MONOGRAPH TITLE:  Aripiprazole Lauroxil Submicronized (Aristada|
03047|002|T|Initio)/Selected Strong CYP2D6 Inhibitors|
03047|003|B||
03047|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03047|005|L|of severe adverse interaction.|
03047|006|B||
03047|007|A|MECHANISM OF ACTION:  Strong 2D6 inhibitors such as dacomitinib, fluoxetine,|
03047|008|A|paroxetine, and quinidine may inhibit the metabolism of aripiprazole.(1)|
03047|009|B||
03047|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
03047|011|E|with aripiprazole may result in elevated levels of and toxicity from|
03047|012|E|aripiprazole.(1)|
03047|013|E|   Strong CYP2D6 inhibitors linked to this monograph are bupropion,|
03047|014|E|dacomitinib, fluoxetine, paroxetine and quinidine.|
03047|015|B||
03047|016|P|PREDISPOSING FACTORS:  The interaction is expected to be more severe in|
03047|017|P|patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6|
03047|018|P|inhibitor.(1)|
03047|019|B||
03047|020|M|PATIENT MANAGEMENT:  The US manufacturer of the extended release|
03047|021|M|aripiprazole lauroxil, submicronized (Aristada Initio) recommends avoiding|
03047|022|M|use of strong CYP2D6 inhibitors with Aristada Initio.  Aristada Initio is|
03047|023|M|only available in a single strength as a single-dose pre-filled syringe.|
03047|024|B||
03047|025|D|DISCUSSION:  Drug interaction studies have not been conducted with Aristada|
03047|026|D|Initio.  Aristada Initio has a long half-life (15-18 days).|
03047|027|D|   The administration of quinidine (166 mg daily for 13 days, a strong|
03047|028|D|inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in|
03047|029|D|a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35%|
03047|030|D|decrease in the AUC of dehydro-aripiprazole, the active metabolite of|
03047|031|D|aripiprazole.(1)|
03047|032|B||
03047|033|R|REFERENCES:|
03047|034|B||
03047|035|R|1.Aristada Initio (aripiprazole lauroxil, submicronized) US Prescribing|1
03047|036|R|  Information. Alkermes, Inc. June 2018.|1
03047|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
03047|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03048|001|T|MONOGRAPH TITLE:  Aripiprazole Lauroxil Submicronized (Aristada|
03048|002|T|Initio)/Strong CYP3A4 Inhibitors|
03048|003|B||
03048|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03048|005|L|of severe adverse interaction.|
03048|006|B||
03048|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03048|008|A|aripiprazole.(1)|
03048|009|B||
03048|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03048|011|E|may result in elevated levels of and toxicity from aripiprazole.(1)|
03048|012|B||
03048|013|P|PREDISPOSING FACTORS:  With aripiprazole(1), this interaction is expected to|
03048|014|P|be more severe in patients who are CYP2D6 poor metabolizers, or who receive|
03048|015|P|concomitant treatment with a strong CYP2D6 inhibitor (e.g. bupropion,|
03048|016|P|fluoxetine, paroxetine, quinidine) in addition to treatment with a strong|
03048|017|P|CYP3A4 inhibitor.|
03048|018|B||
03048|019|M|PATIENT MANAGEMENT:  The US manufacturer of the extended release injectable|
03048|020|M|aripiprazole lauroxil, submicronized (Aristada Initio) recommends avoiding|
03048|021|M|use of strong 3A4 inhibitors with Aristada Initio. Aristada Initio is only|
03048|022|M|available as a single strength as a single-dose prefilled syringe.(1)|
03048|023|B||
03048|024|D|DISCUSSION:  Drug interaction studies have not been conducted with Aristada|
03048|025|D|Initio. Aristada Initio has a long half-life (15-18 days).(1)|
03048|026|D|   The coadministration of ketoconazole (200 mg daily for 14 days) with a|
03048|027|D|single dose of aripiprazole (15 mg) resulted in increases in the|
03048|028|D|area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and|
03048|029|D|77%, respectively.  Itraconazole is expected to interact similarly.(1)|
03048|030|B||
03048|031|R|REFERENCE:|
03048|032|B||
03048|033|R|1.Aristada Initio (aripiprazole lauroxil, submicronized) US Prescribing|1
03048|034|R|  Information. Alkermes, Inc. June 2018.|1
03049|001|T|MONOGRAPH TITLE:  Selected Long-Acting Aripiprazole Injections/Strong CYP3A4|
03049|002|T|Inducers|
03049|003|B||
03049|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03049|005|L|of severe adverse interaction.|
03049|006|B||
03049|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
03049|008|A|clearance of aripiprazole.(1,2)|
03049|009|B||
03049|010|E|CLINICAL EFFECTS:  Strong CYP3A4 inducers may result in decreased levels and|
03049|011|E|effectiveness of aripiprazole.(1,2)|
03049|012|B||
03049|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03049|014|P|of the inducer for longer than 1-2 weeks.|
03049|015|B||
03049|016|M|PATIENT MANAGEMENT:  The US manufacturer of the extended release injectable|
03049|017|M|aripiprazole lauroxil, submicronized (Aristada Initio) recommends avoiding|
03049|018|M|use of strong CYP3A4 inducers with Aristada Initio.  Aristada Initio is only|
03049|019|M|available in a single strength as a single-dose prefilled syringe.(1)|
03049|020|M|   For patients receiving aripiprazole extended-release injection (Abilify|
03049|021|M|Maintena or Abilify Asimtuffi), dose adjustments are not recommended by the|
03049|022|M|manufacturer if the duration of strong CYP3A4 inducer treatment is less than|
03049|023|M|14 days.  Concurrent use of Abilify Maintena or Abilify Asimtuffi with|
03049|024|M|strong CYP3A4 inducers for greater than 14 days should be avoided.(2-3)|
03049|025|B||
03049|026|D|DISCUSSION:  Drug interaction studies have not been conducted with Aristada|
03049|027|D|Initio,(1) Abilify Maintena,(2) or Abilify Asimtuffi.(3)|
03049|028|D|   Aristada Initio has a long half-life (15-18 days).(1)|
03049|029|D|   Abilify Maintena has a half-life of 29.9 days and 46.5 days after|
03049|030|D|multiple injections for every 4-week injection with the 300 mg and 400 mg|
03049|031|D|dose, respectively.(2)|
03049|032|D|   The concurrent administration of carbamazepine (200 mg twice daily) with|
03049|033|D|aripiprazole (30 mg daily) resulted in 70% decreases in the area-under-curve|
03049|034|D|(AUC) and maximum concentration (Cmax) of both aripiprazole and|
03049|035|D|dehydro-aripiprazole, its active metabolite.(1)|
03049|036|D|   Strong CYP3A4 inducers linked to this monograph are:  apalutamide,|
03049|037|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
03049|038|D|ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone,|
03049|039|D|rifampin, rifapentine and St. John's Wort.(4-5)|
03049|040|B||
03049|041|R|REFERENCES:|
03049|042|B||
03049|043|R|1.Aristada Initio (aripiprazole lauroxil, submicronized) US Prescribing|1
03049|044|R|  Information. Alkermes, Inc. June 2018.|1
03049|045|R|2.Abilify Maintena (aripiprazole ext-rel inj.) prescribing information.|1
03049|046|R|  Otsuka Pharmaceuticals January, 2016.|1
03049|047|R|3.Abilify Asimtufii (aripiprazole extended-release injectable) US|1
03049|048|R|  prescribing information. Otsuka Pharmaceutical Co., Ltd. April, 2023.|1
03049|049|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03049|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03049|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03049|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03049|053|R|  11/14/2017.|1
03049|054|R|5.This information is based on an extract from the Certara Drug Interaction|6
03049|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03050|001|T|MONOGRAPH TITLE:  Ivosidenib/Strong CYP3A4 Inducers|
03050|002|B||
03050|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03050|004|L|of severe adverse interaction.|
03050|005|B||
03050|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03050|007|A|ivosidenib. Ivosidenib induces its own metabolism.(1)|
03050|008|B||
03050|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
03050|010|E|in decreased levels and effectiveness of ivosidenib.(1)|
03050|011|B||
03050|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03050|013|P|of the inducer for longer than 1-2 weeks.|
03050|014|B||
03050|015|M|PATIENT MANAGEMENT:  The US manufacturer of ivosidenib states that the|
03050|016|M|concurrent use of strong CYP3A4 inducers should be avoided.(1)|
03050|017|B||
03050|018|D|DISCUSSION:  Coadministration of ivosidenib with a strong 3A4 inducer (600|
03050|019|D|mg rifampin once daily for 15 days) is predicted to decrease ivosidenib|
03050|020|D|steady state area-under-the-curve (AUC) by 33%.(1)|
03050|021|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03050|022|D|carbamazepine, enzalutamide, fosphenytoin, mitotane, phenobarbital,|
03050|023|D|phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3)|
03050|024|B||
03050|025|R|REFERENCES:|
03050|026|B||
03050|027|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03050|028|R|  Inc. August, 2021.|1
03050|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03050|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03050|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03050|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03050|033|R|  11/14/2017.|1
03050|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
03050|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03051|001|T|MONOGRAPH TITLE:  Ivosidenib/Selected Strong CYP3A4 Inhibitors|
03051|002|B||
03051|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03051|004|L|of severe adverse interaction.|
03051|005|B||
03051|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03051|007|A|metabolism of ivosidenib.(1)|
03051|008|B||
03051|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03051|010|E|systemic exposure and the risk for ivosidenib toxicities such as QT|
03051|011|E|prolongation.(1)|
03051|012|B||
03051|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03051|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03051|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03051|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03051|017|P|gender, or advanced age.(2)|
03051|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03051|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03051|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03051|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03051|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03051|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03051|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03051|025|B||
03051|026|M|PATIENT MANAGEMENT:  Avoid concomitant use of ivosidenib and strong CYP3A|
03051|027|M|inhibitors. Consider an alternative concomitant medication with less|
03051|028|M|potential for CYP3A4 inhibition.(1)|
03051|029|M|   The US manufacturer of ivosidenib states when concomitant use of|
03051|030|M|ivosidenib and a strong CYP3A4 inhibitor is needed, the ivosidenib dose|
03051|031|M|should be reduced to 250 mg once daily.(1) If the strong CYP3A4 inhibitor is|
03051|032|M|discontinued, increase the ivosidenib dose to the recommended dose of 500 mg|
03051|033|M|once daily after at least 5 half-lives of the strong 3A4 inhibitor.|
03051|034|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
03051|035|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03051|036|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03051|037|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03051|038|M|irregular heartbeat, dizziness, or fainting.|
03051|039|B||
03051|040|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03051|041|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
03051|042|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
03051|043|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
03051|044|D|(Cmax).(1)|
03051|045|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03051|046|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03051|047|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03051|048|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03051|049|D|190%, respectively.(1)|
03051|050|D|   Strong CYP3A4 inhibitors linked to this monograph include:  indinavir,|
03051|051|D|josamycin, mibefradil, nefazodone, nelfinavir, tipranavir, and|
03051|052|D|troleandomycin.(3)|
03051|053|B||
03051|054|R|REFERENCES:|
03051|055|B||
03051|056|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03051|057|R|  Inc. August, 2021.|1
03051|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03051|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03051|060|R|  settings: a scientific statement from the American Heart Association and|6
03051|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03051|062|R|  2;55(9):934-47.|6
03051|063|R|3.This information is based on an extract from the Certara Drug Interaction|6
03051|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03052|001|T|MONOGRAPH TITLE:  Ivosidenib/Selected Moderate CYP3A4 Inhibitors|
03052|002|B||
03052|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03052|004|L|take action as needed.|
03052|005|B||
03052|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03052|007|A|metabolism of ivosidenib.(1)|
03052|008|B||
03052|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
03052|010|E|systemic exposure and the risk for ivosidenib toxicities such as QT|
03052|011|E|prolongation.(1)|
03052|012|B||
03052|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03052|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03052|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03052|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03052|017|P|gender, or advanced age.(2)|
03052|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03052|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03052|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03052|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03052|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03052|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03052|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03052|025|B||
03052|026|M|PATIENT MANAGEMENT:  The US manufacturer of ivosidenib recommends|
03052|027|M|considering an alternative concomitant medication with less potential for|
03052|028|M|CYP3A4 inhibition.(1)|
03052|029|M|   During concomitant therapy with a moderate CYP3A4 inhibitor, monitor|
03052|030|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03052|031|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03052|032|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03052|033|M|irregular heartbeat, dizziness, or fainting.|
03052|034|B||
03052|035|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03052|036|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
03052|037|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
03052|038|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
03052|039|D|(Cmax).(1)|
03052|040|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03052|041|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03052|042|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03052|043|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03052|044|D|190%, respectively.(1)|
03052|045|D|   Moderate CYP3A4 inhibitors linked to this monograph include amprenavir,|
03052|046|D|berotralstat, conivaptan, fluvoxamine, fosamprenavir, letermovir,|
03052|047|D|schisandra, tofisopam, and treosulfan.(3)|
03052|048|B||
03052|049|R|REFERENCES:|
03052|050|B||
03052|051|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03052|052|R|  Inc. August, 2021.|1
03052|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03052|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03052|055|R|  settings: a scientific statement from the American Heart Association and|6
03052|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03052|057|R|  2;55(9):934-47.|6
03052|058|R|3.This information is based on an extract from the Certara Drug Interaction|6
03052|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03053|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Selected Strong & Moderate CYP3A4|
03053|002|T|Inducers|
03053|003|B||
03053|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03053|005|L|of severe adverse interaction.|
03053|006|B||
03053|007|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03053|008|A|CYP3A4-mediated metabolism of hormonal contraceptives.(1-2)|
03053|009|B||
03053|010|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
03053|011|E|reduce the effectiveness of hormonal contraceptives.(1-2)  Apalutamide,|
03053|012|E|enzalutamide, ivosidenib, and mitotane may cause birth defects and/or|
03053|013|E|miscarriage if used by pregnant women.|
03053|014|B||
03053|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03053|016|P|of the inducer for longer than 1-2 weeks.|
03053|017|B||
03053|018|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
03053|019|M|rely on hormonal contraception (including oral contraceptives, patches,|
03053|020|M|implants, and/or IUDs) for contraception.  Women should use a back-up method|
03053|021|M|of birth control during therapy with a CYP3A4 inducer.  Women of|
03053|022|M|reproductive potential should use effective non-hormonal methods of|
03053|023|M|contraception during therapy with a CYP3A4 inducer.  Continuation of an|
03053|024|M|effective non-hormonal contraceptive after discontinuation of the CYP3A4|
03053|025|M|inducer is also advised for the period of time indicated below.(1-3)|
03053|026|M|   There is no specific recommendation for contraception in women on|
03053|027|M|apalutamide or enzalutamide.  Male patients with female partners of|
03053|028|M|reproductive age are advised to continue effective contraception for 3|
03053|029|M|months after discontinuation of apalutamide or enzalutamide.(4,5)|
03053|030|M|   The manufacturer of mitotane recommends continuing effective|
03053|031|M|contraception after discontinuation of mitotane for as long as mitotane|
03053|032|M|plasma levels are detectable.  Mitotane half life ranges from 18 to 159 days|
03053|033|M|(median 53 days).(3)|
03053|034|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03053|035|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03053|036|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03053|037|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03053|038|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03053|039|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03053|040|M|and to seek medical advice if they do become pregnant.(6)|
03053|041|B||
03053|042|D|DISCUSSION:  Strong and moderate CYP3A4 inducers may increase the|
03053|043|D|CYP3A4-mediated metabolism of hormonal contraceptives and decrease the|
03053|044|D|effectiveness of hormonal contraceptives, including oral contraceptives,|
03053|045|D|patches, implants, and/or IUDs.  Women should use a back-up method of birth|
03053|046|D|control during and after CYP3A4 inducer therapy.(1-3)|
03053|047|D|   An in vivo mechanism static model predicted strong interactions between|
03053|048|D|ulipristal combined with enzalutamide or mitotane.  Enzalutamide was|
03053|049|D|predicted to lower ulipristal area-under-curve (AUC) by 85%, and mitotane|
03053|050|D|was predicted to lower ulipristal AUC by 93%.(2)|
03053|051|D|   Strong and moderate CYP3A4 inducers linked include: apalutamide,|
03053|052|D|enzalutamide, ivosidenib, mitotane, nafcillin, sotorasib, telotristat, and|
03053|053|D|thioridazine.(7,8)|
03053|054|B||
03053|055|R|REFERENCES:|
03053|056|B||
03053|057|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03053|058|R|  Inc. August, 2021.|1
03053|059|R|2.Le Corvaisier C, Capelle A, France M, Bourguignon L, Tod M, Goutelle S.|5
03053|060|R|  Drug interactions between emergency contraceptive drugs and cytochrome|5
03053|061|R|  inducers:  literature review and quantitative prediction. Fundam Clin|5
03053|062|R|  Pharmacol 2021 Apr;35(2):208-216.|5
03053|063|R|3.Lysodren (mitotane) US prescribing information. E.R. Squibb & Sons, L.L.C.|1
03053|064|R|  October, 2024.|1
03053|065|R|4.Erleada (apalutamide) US prescribing information. Janssen Biotech, Inc.|1
03053|066|R|  July, 2021.|1
03053|067|R|5.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
03053|068|R|  September, 2022.|1
03053|069|R|6.Medicines and Healthcare products Regulatory Agency.|1
03053|070|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03053|071|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03053|072|R|  available at:|1
03053|073|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03053|074|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03053|075|R|  -and-contraceptive-efficacy September 15, 2016..|1
03053|076|R|7.This information is based on an extract from the Certara Drug Interaction|6
03053|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03053|078|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
03053|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03053|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03053|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03053|082|R|  11/14/2017.|1
03054|001|T|MONOGRAPH TITLE:  Ivosidenib/Itraconazole; Ketoconazole|
03054|002|B||
03054|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03054|004|L|of severe adverse interaction.|
03054|005|B||
03054|006|A|MECHANISM OF ACTION:  Itraconazole and ketoconazole, strong CYP3A4|
03054|007|A|inhibitors, may inhibit the metabolism of ivosidenib. Ivosidenib induces the|
03054|008|A|CYP3A4 enzyme and may decrease the concentrations of itraconazole and|
03054|009|A|ketoconazole. (1)|
03054|010|B||
03054|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors, such as|
03054|012|E|itraconazole and ketoconazole, may increase systemic exposure and the risk|
03054|013|E|for ivosidenib toxicities such as QT prolongation.(1)|
03054|014|E|   Ivosidenib may decrease itraconazole or ketoconazole steady-state|
03054|015|E|concentrations resulting in decreased antifungal efficacy.(1)|
03054|016|B||
03054|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03054|018|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03054|019|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03054|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03054|021|P|gender, or advanced age.(2)|
03054|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03054|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03054|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03054|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03054|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03054|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03054|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03054|029|B||
03054|030|M|PATIENT MANAGEMENT:  Avoid concomitant use of ivosidenib and|
03054|031|M|ketoconazole/itraconazole. Consider an alternative concomitant medication|
03054|032|M|with less potential for CYP3A4 inhibition.(1)|
03054|033|M|   The US manufacturer of ivosidenib states when concomitant use of|
03054|034|M|ivosidenib and a strong CYP3A4 inhibitor is needed, the ivosidenib dose|
03054|035|M|should be reduced to 250 mg once daily.(1) If the strong CYP3A4 inhibitor is|
03054|036|M|discontinued, increase the ivosidenib dose to the recommended dose of 500 mg|
03054|037|M|once daily after at least 5 half-lives of the strong 3A4 inhibitor.|
03054|038|M|   The US manufacturer of ivosidenib states that ivosidenib induces the|
03054|039|M|metabolism of CYP3A4 substrates following ivosidenib multiple dosing,|
03054|040|M|itraconazole and ketoconazole are not recommended to be used concomitantly|
03054|041|M|with ivosidenib.(1)|
03054|042|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
03054|043|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03054|044|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03054|045|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03054|046|M|irregular heartbeat, dizziness, or fainting.|
03054|047|B||
03054|048|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03054|049|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
03054|050|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
03054|051|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
03054|052|D|(Cmax).(1)|
03054|053|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03054|054|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03054|055|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03054|056|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03054|057|D|190%, respectively.(1)|
03054|058|B||
03054|059|R|REFERENCES:|
03054|060|B||
03054|061|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03054|062|R|  Inc. August, 2021.|1
03054|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03054|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03054|065|R|  settings: a scientific statement from the American Heart Association and|6
03054|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03054|067|R|  2;55(9):934-47.|6
03054|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
03054|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03055|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Elagolix|
03055|002|B||
03055|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03055|004|L|of severe adverse interaction.|
03055|005|B||
03055|006|A|MECHANISM OF ACTION:  Based on the mechanism of action of elagolix, estrogen|
03055|007|A|containing contraceptives are expected to reduce the efficacy of elagolix.|
03055|008|A|The effect of progestin-only contraceptives on elagolix is unknown.(1)|
03055|009|A|   Elagolix is a weak to moderate inducer of CYP3A4 and may increase the|
03055|010|A|metabolism of progestins.  The mechanism of elagolix's interaction with|
03055|011|A|estrogens is unknown.(1)|
03055|012|B||
03055|013|E|CLINICAL EFFECTS:  Concurrent use of hormonal contraceptives may reduce the|
03055|014|E|effectiveness of elagolix.(1)|
03055|015|E|   Elagolix 200 mg twice daily may increase the levels and toxicity of|
03055|016|E|estrogens, including thromboembolic disorders and vascular events, while|
03055|017|E|decreasing the levels and efficacy of progestin-containing hormonal|
03055|018|E|contraceptives.  Elagolix may cause birth defects and/or miscarriage if used|
03055|019|E|by pregnant women.(1)|
03055|020|B||
03055|021|P|PREDISPOSING FACTORS:  None determined.|
03055|022|B||
03055|023|M|PATIENT MANAGEMENT:  Women of reproductive potential should use effective|
03055|024|M|non-hormonal methods of contraception during elagolix therapy and for 28|
03055|025|M|days after discontinuing elagolix.  Women of reproductive age should be|
03055|026|M|counseled not to use hormonal contraception (including oral contraceptives,|
03055|027|M|patches, implants, and/or IUDs) for contraception.(1)|
03055|028|B||
03055|029|D|DISCUSSION:  Hormonal contraceptives may decrease the effectiveness of|
03055|030|D|elagolix. Women should use a non-hormonal method of birth control during|
03055|031|D|elagolix therapy.(1)|
03055|032|D|   Coadministration of elagolix 200 mg twice daily for 14 days with ethinyl|
03055|033|D|estradiol 20 mcg-levonorgestrel 0.1 mg resulted in a 2.2-fold increase in|
03055|034|D|ethinyl estradiol exposure and a 27% decrease in levonorgestrel exposure.(1)|
03055|035|D|   Coadministration of elagolix 150 mg daily did not affect exposure to|
03055|036|D|norethindrone 0.35 mg once daily nor to ethinyl estradiol 35 mcg-triphasic|
03055|037|D|norgestimate 0.18/0.215/0.25 mg once daily.(1)|
03055|038|B||
03055|039|R|REFERENCE:|
03055|040|B||
03055|041|R|1.Orilissa (elagolix) US prescribing information. AbbVie Inc. February,|1
03055|042|R|  2021.|1
03056|001|T|MONOGRAPH TITLE:  Elagolix/Strong OATP1B1 Inhibitors|
03056|002|B||
03056|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03056|004|L|is contraindicated and generally should not be dispensed or administered to|
03056|005|L|the same patient.|
03056|006|B||
03056|007|A|MECHANISM OF ACTION:  Strong inhibitors of OATP1B1 may decrease the hepatic|
03056|008|A|uptake of elagolix.(1,2)|
03056|009|B||
03056|010|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of OATP1B1 may result in|
03056|011|E|elevated levels of and side effects from elagolix, including an increased|
03056|012|E|risk of ALT elevations.(1)|
03056|013|B||
03056|014|P|PREDISPOSING FACTORS:  None determined.|
03056|015|B||
03056|016|M|PATIENT MANAGEMENT:  Concurrent use of elagolix and strong OATP1B1|
03056|017|M|inhibitors is contraindicated.(1)|
03056|018|B||
03056|019|D|DISCUSSION:  Strong OATP1B1 inhibitors linked to this monograph include:|
03056|020|D|belumosudil, cyclosporine, encorafenib, gemfibrozil, letermovir,|
03056|021|D|paritaprevir, resmetirom, roxadustat, and vadadustat.(1,2)|
03056|022|B||
03056|023|R|REFERENCES:|
03056|024|B||
03056|025|R|1.Orilissa (elagolix) US prescribing information. AbbVie Inc. February,|1
03056|026|R|  2021.|1
03056|027|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03056|028|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03056|029|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03056|030|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03056|031|R|  11/14/2017.|1
03057|001|T|MONOGRAPH TITLE:  Elagolix/Strong CYP3A4 Inhibitors|
03057|002|B||
03057|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03057|004|L|of severe adverse interaction.|
03057|005|B||
03057|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03057|007|A|metabolism of elagolix.(1)|
03057|008|B||
03057|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03057|010|E|systemic exposure and the risk for elagolix toxicities including an|
03057|011|E|increased risk of ALT elevations.(1)|
03057|012|B||
03057|013|P|PREDISPOSING FACTORS:  None determined.|
03057|014|B||
03057|015|M|PATIENT MANAGEMENT:  Concomitant use of elagolix 200 mg twice daily and|
03057|016|M|strong CYP3A4 inhibitors for more than 1 month is not recommended.|
03057|017|M|   Limit concomitant use of elagolix 150 mg once daily and strong CYP3A4|
03057|018|M|inhibitors to 6 months.|
03057|019|B||
03057|020|D|DISCUSSION:  In a drug interaction study in 11 healthy subjects,|
03057|021|D|coadministration of ketoconazole (400 mg once daily) with a single dose of|
03057|022|D|elagolix (150 mg) increased elagolix maximum concentration (Cmax) and|
03057|023|D|area-under-the-curve (AUC) by 1.77-fold and 2.2-fold, respectively.(1)|
03057|024|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
03057|025|D|boceprevir, ceritinib, clarithromycin, cobicistat, indinavir, itraconazole,|
03057|026|D|josamycin, ketoconazole, lopinavir, mibefradil, mifepristone, nefazodone,|
03057|027|D|nelfinavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
03057|028|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)|
03057|029|B||
03057|030|R|REFERENCES:|
03057|031|B||
03057|032|R|1.Orilissa (elagolix) US prescribing information. AbbVie Inc. February,|1
03057|033|R|  2021.|1
03057|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
03057|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03057|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03057|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03057|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03057|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03057|040|R|  11/14/2017.|1
03058|001|T|MONOGRAPH TITLE:  Elagolix/Rifampin|
03058|002|B||
03058|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03058|004|L|of severe adverse interaction.|
03058|005|B||
03058|006|A|MECHANISM OF ACTION:  Rifampin is an inhibitor of OATP1B1 and P-glycoprotein|
03058|007|A|(P-gp) and may inhibit the metabolism of elagolix.|
03058|008|B||
03058|009|E|CLINICAL EFFECTS:  Concurrent use of an OATP1B1 and P-gp inhibitor may|
03058|010|E|result in elevated levels of elagolix including an increased risk of ALT|
03058|011|E|elevations.(1)|
03058|012|B||
03058|013|P|PREDISPOSING FACTORS:  None determined.|
03058|014|B||
03058|015|M|PATIENT MANAGEMENT:  The US manufacturer states that the concurrent use of|
03058|016|M|elagolix 200 mg twice daily and rifampin is not recommended. Limit|
03058|017|M|concurrent use of elagolix 150 mg once daily and rifampin to 6 months.(1)|
03058|018|B||
03058|019|D|DISCUSSION:  In a drug interaction study in 12 healthy subjects,|
03058|020|D|coadministration of rifampin (600 mg single dose) with elagolix (150 mg|
03058|021|D|single dose) increased maximum concentration (Cmax) and area-under-the-curve|
03058|022|D|(AUC) by 4.37-fold and 5.58-fold, respectively.(1)|
03058|023|D|   In a drug interaction study in 12 healthy subjects, coadministration of|
03058|024|D|rifampin (600 mg once daily) with elagolix (150 mg single dose) increased|
03058|025|D|maximum concentration (Cmax) and area-under-the-curve (AUC) by 2-fold and|
03058|026|D|1.65-fold, respectively.(1)|
03058|027|B||
03058|028|R|REFERENCES:|
03058|029|B||
03058|030|R|1.Orilissa (elagolix) US prescribing information. AbbVie Inc. February,|1
03058|031|R|  2021.|1
03058|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03058|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03058|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03058|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03058|036|R|  11/14/2017.|1
03059|001|T|MONOGRAPH TITLE:  Ivosidenib/QT Prolonging Agents|
03059|002|B||
03059|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03059|004|L|of severe adverse interaction.|
03059|005|B||
03059|006|A|MECHANISM OF ACTION:  Concurrent use of ivosidenib with agents that prolong|
03059|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03059|008|B||
03059|009|E|CLINICAL EFFECTS:  The concurrent use of ivosidenib with agents that prolong|
03059|010|E|the QTc interval may result in potentially life-threatening cardiac|
03059|011|E|arrhythmias, including torsades de pointes.(1)|
03059|012|B||
03059|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03059|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03059|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03059|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03059|017|P|female gender, or advanced age.(2)|
03059|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03059|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03059|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03059|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03059|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03059|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03059|024|P|dysfunction).(2)|
03059|025|B||
03059|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ivosidenib with medications|
03059|027|M|that prolong the QT interval.(1)|
03059|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03059|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03059|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
03059|031|M|and periodically monitor during therapy.  Correct any electrolyte|
03059|032|M|abnormalities.|
03059|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03059|034|M|fainting.|
03059|035|M|   If QTc prolongation develops:|
03059|036|M|   ---Monitor and supplement electrolytes as clinically indicated|
03059|037|M|   ---Review and adjust concomitant QT prolonging medications|
03059|038|M|   ---Interrupt ivosidenib therapy|
03059|039|M|   ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
03059|040|M|prolongation|
03059|041|M|   ---Follow labeling recommendations regarding restarting ivosidenib.(1)|
03059|042|B||
03059|043|D|DISCUSSION:  In clinical trials of ivosidenib, 9% of patients experienced a|
03059|044|D|QTc interval greater than 500 msec and 14% of patients had an increased from|
03059|045|D|baseline QTc interval of greater than 60 msec.  Patients with a baseline QTc|
03059|046|D|of equal to or greater than 450 msec without pre-existing bundle branch|
03059|047|D|block, or with a history of long QT syndrome were excluded from this|
03059|048|D|trial.(1)|
03059|049|D|   Agents that are linked to this monograph may have varying degrees of|
03059|050|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03059|051|D|been shown to prolong the QTc interval either through their mechanism of|
03059|052|D|action, through studies on their effects on the QTc interval, or through|
03059|053|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03059|054|D|and/or postmarketing reports.(3)|
03059|055|B||
03059|056|R|REFERENCES:|
03059|057|B||
03059|058|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03059|059|R|  Inc. August, 2021.|1
03059|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03059|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03059|062|R|  settings: a scientific statement from the American Heart Association and|6
03059|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03059|064|R|  2;55(9):934-47.|6
03059|065|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03059|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03059|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03059|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03060|001|T|MONOGRAPH TITLE:  Ivosidenib/Possible QT Prolonging Agents|
03060|002|B||
03060|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03060|004|L|take action as needed.|
03060|005|B||
03060|006|A|MECHANISM OF ACTION:  Concurrent use of ivosidenib with agents that prolong|
03060|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03060|008|B||
03060|009|E|CLINICAL EFFECTS:  The concurrent use of ivosidenib with agents that prolong|
03060|010|E|the QTc interval may result in potentially life-threatening cardiac|
03060|011|E|arrhythmias, including torsades de pointes.(1)|
03060|012|B||
03060|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03060|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03060|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03060|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03060|017|P|female gender, or advanced age.(2)|
03060|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03060|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03060|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03060|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03060|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03060|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03060|024|P|dysfunction).(2)|
03060|025|B||
03060|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ivosidenib with medications|
03060|027|M|that prolong the QT interval.(1)|
03060|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03060|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03060|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
03060|031|M|and periodically monitor during therapy.  Correct any electrolyte|
03060|032|M|abnormalities.|
03060|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03060|034|M|fainting.|
03060|035|M|   If QTc prolongation develops:|
03060|036|M|   ---Monitor and supplement electrolytes as clinically indicated|
03060|037|M|   ---Review and adjust concomitant QT prolonging medications|
03060|038|M|   ---Interrupt ivosidenib therapy|
03060|039|M|   ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
03060|040|M|prolongation|
03060|041|M|   ---Follow labeling recommendations regarding restarting ivosidenib.(1)|
03060|042|B||
03060|043|D|DISCUSSION:  In clinical trials of ivosidenib, 9% of patients experienced a|
03060|044|D|QTc interval greater than 500 msec and 14% of patients had an increased from|
03060|045|D|baseline QTc interval of greater than 60 msec.  Patients with a baseline QTc|
03060|046|D|of equal to or greater than 450 msec without pre-existing bundle branch|
03060|047|D|block, or with a history of long QT syndrome were excluded from this|
03060|048|D|trial.(1)|
03060|049|D|   Agents that are linked to this monograph may have varying degrees of|
03060|050|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03060|051|D|been shown to prolong the QTc interval either through their mechanism of|
03060|052|D|action, through studies on their effects on the QTc interval, or through|
03060|053|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03060|054|D|and/or postmarketing reports.(3)|
03060|055|B||
03060|056|R|REFERENCES:|
03060|057|B||
03060|058|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03060|059|R|  Inc. August, 2021.|1
03060|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03060|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03060|062|R|  settings: a scientific statement from the American Heart Association and|6
03060|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03060|064|R|  2;55(9):934-47.|6
03060|065|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03060|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03060|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03060|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03061|001|T|MONOGRAPH TITLE:  Iobenguane I 131/Agents that Affect Catecholamines|
03061|002|B||
03061|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03061|004|L|of severe adverse interaction.|
03061|005|B||
03061|006|A|MECHANISM OF ACTION:  Many compounds that reduce catecholamine uptake or|
03061|007|A|that deplete catecholamine stores may interfere with iobenguane uptake into|
03061|008|A|cells.(1)|
03061|009|B||
03061|010|E|CLINICAL EFFECTS:  Compounds that reduce catecholamine uptake or that|
03061|011|E|deplete catecholamine stores may impact the dosimetry calculations or|
03061|012|E|effectiveness of iobenguane.(1)|
03061|013|B||
03061|014|P|PREDISPOSING FACTORS:  None determined.|
03061|015|B||
03061|016|M|PATIENT MANAGEMENT:  Discuss the use of agents that affect catecholamines.|
03061|017|M|Discontinue drugs that reduce catecholamine uptake or deplete catecholamine|
03061|018|M|stores for at least 5 half-lives before administration of either the|
03061|019|M|dosimetry or a therapeutic dose of iobenguane.  Do not administer these|
03061|020|M|drugs until at least 7 days after each iobenguane dose.(1)|
03061|021|B||
03061|022|D|DISCUSSION:  Many agents may reduce catecholamine uptake or deplete|
03061|023|D|catecholamine stores.(1)|
03061|024|D|   Examples include:|
03061|025|D|   - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate,|
03061|026|D|dextroamphetamine)|
03061|027|D|   - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine)|
03061|028|D|   - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol)|
03061|029|D|   - monoamine oxidase inhibitors (e.g. phenelzine, linezolid)|
03061|030|D|   - central monoamine depleting drugs (e.g. reserpine)|
03061|031|D|   - non-select beta adrenergic blocking drugs (e.g. labetalol)|
03061|032|D|   - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine,|
03061|033|D|phenylephrine, ephedrine, phenylpropanolamine, naphazoline)|
03061|034|D|   - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g.|
03061|035|D|amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine)|
03061|036|D|   - botanicals that may inhibit reuptake of norepinephrine, serotonin or|
03061|037|D|dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)|
03061|038|D|  - calcium channel blockers|
03061|039|B||
03061|040|R|REFERENCE:|
03061|041|B||
03061|042|R|1.Azedra (iobenguane I 131) injection US prescribing information. Progenics|1
03061|043|R|  Pharmaceuticals, Inc. July, 2018.|1
03062|001|T|MONOGRAPH TITLE:  Dofetilide/Tafenoquine|
03062|002|B||
03062|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03062|004|L|is contraindicated and generally should not be dispensed or administered to|
03062|005|L|the same patient.|
03062|006|B||
03062|007|A|MECHANISM OF ACTION:  The active tubular secretion via organic cationic|
03062|008|A|transporter 2 (OCT2) of dofetilide may be inhibited by tafenoquine.(1)|
03062|009|B||
03062|010|E|CLINICAL EFFECTS:  The concurrent administration of dofetilide with|
03062|011|E|tafenoquine may result in elevated levels and increased effects of|
03062|012|E|dofetilide including torsades de pointes.(1)|
03062|013|B||
03062|014|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
03062|015|P|prolongation as dofetilide is primarily renally eliminated. To prevent|
03062|016|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
03062|017|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
03062|018|P|   The risk of QT prolongation or torsade de pointes may be increased in|
03062|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03062|020|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03062|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03062|022|P|advanced age.(2)|
03062|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03062|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03062|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03062|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03062|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03062|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03062|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03062|030|B||
03062|031|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that the|
03062|032|M|concurrent administration of dofetilide with known inhibitors of the renal|
03062|033|M|cation transport system should not be used.  If dofetilide is to be|
03062|034|M|discontinued, a washout of at least 2 days is recommended prior to starting|
03062|035|M|tafenoquine.(1)|
03062|036|M|   The manufacturer of tafenoquine states the concurrent administration of|
03062|037|M|tafenoquine with organic cationic transporter 2 (OCT2) substrates, such as|
03062|038|M|dofetilide, should be avoided.  If coadministration cannot be avoided,|
03062|039|M|monitor for drug-related toxicities.(3)|
03062|040|B||
03062|041|D|DISCUSSION:  Dofetilide is primarily excreted in the urine via both|
03062|042|D|glomerular filtration and active tubular secretion via the cation transport|
03062|043|D|system.  Tafenoquine is believed to inhibit the cation transport system|
03062|044|D|(OCT2).(1,3)|
03062|045|B||
03062|046|R|REFERENCES:|
03062|047|B||
03062|048|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
03062|049|R|  2013.|1
03062|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03062|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03062|052|R|  settings: a scientific statement from the American Heart Association and|6
03062|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03062|054|R|  2;55(9):934-47.|6
03062|055|R|3.Krintafel (tafenoquine) tablets US prescribing information.|1
03062|056|R|  GlaxoSmithKline November, 2020.|1
03063|001|T|MONOGRAPH TITLE:  Metformin/Tafenoquine|
03063|002|B||
03063|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03063|004|L|of severe adverse interaction.|
03063|005|B||
03063|006|A|MECHANISM OF ACTION:  Metformin renal clearance is mediated by OCT2 and|
03063|007|A|MATE1 transporters.(1)  Tafenoquine inhibits elimination by these|
03063|008|A|pathways.(2)|
03063|009|B||
03063|010|E|CLINICAL EFFECTS:  Use of tafenoquine may increase levels of metformin,|
03063|011|E|which may result in lactic acidosis.|
03063|012|B||
03063|013|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
03063|014|P|include renal impairment, sepsis, dehydration, excessive alcohol intake,|
03063|015|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
03063|016|P|failure, metformin plasma levels > 5 micrograms/mL, and conditions which may|
03063|017|P|lead to tissue hypoxia.  Geriatric patients may also be at higher risk due|
03063|018|P|to slower metformin clearance and increased half-life in this population.|
03063|019|B||
03063|020|M|PATIENT MANAGEMENT:  The US labeling for metformin recommends the dose of|
03063|021|M|metformin be adjusted as needed.(1)|
03063|022|M|   The manufacturer of tafenoquine states the concurrent administration of|
03063|023|M|tafenoquine with OCT2 and MATE1 substrates, such as metformin, should be|
03063|024|M|avoided.  If coadministration cannot be avoided, monitor for drug-related|
03063|025|M|toxicities.(2)|
03063|026|M|   Evaluate patient's renal function and consider discontinuation in|
03063|027|M|patients with renal impairment.|
03063|028|M|   Monitor for signs and symptoms of metformin toxicity (lactic acidosis)|
03063|029|M|such as malaise, myalgias, respiratory distress, increasing somnolence, and|
03063|030|M|respiratory distress. Laboratory results which may signal lactic acidosis|
03063|031|M|include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an|
03063|032|M|increased anion gap, and increased lactate to pyruvate ratio.|
03063|033|B||
03063|034|D|DISCUSSION:  Metformin renal clearance is mediated by OCT2 and MATE1|
03063|035|D|transporters.(1)  Tafenoquine is believed to inhibit the OCT2 and MATE1|
03063|036|D|pathways.(2)|
03063|037|B||
03063|038|R|REFERENCES:|
03063|039|B||
03063|040|R|1.Glucophage (metformin hydrochloride) US prescribing information.|1
03063|041|R|  Bristol-Myers Squibb Company May, 2018.|1
03063|042|R|2.Krintafel (tafenoquine) tablets US prescribing information.|1
03063|043|R|  GlaxoSmithKline November, 2020.|1
03063|044|R|3.Vecchio S, Giampreti A, Petrolini VM, Lonati D, Protti A, Papa P, Rognoni|2
03063|045|R|  C, Valli A, Rocchi L, Rolandi L, Manzo L, Locatelli CA. Metformin|2
03063|046|R|  accumulation: lactic acidosis and high plasmatic metformin levels in a|2
03063|047|R|  retrospective case series of 66 patients on chronic therapy. Clin Toxicol|2
03063|048|R|  (Phila) 2014 Feb;52(2):129-35.|2
03064|001|T|MONOGRAPH TITLE:  Asunaprevir/Strong and Moderate CYP3A4 Inhibitors|
03064|002|B||
03064|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03064|004|L|is contraindicated and generally should not be dispensed or administered to|
03064|005|L|the same patient.|
03064|006|B||
03064|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03064|008|A|asunaprevir.(1)|
03064|009|B||
03064|010|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inhibitor of|
03064|011|E|CYP3A4 may result in increased levels of and effects from asunaprevir.(1)|
03064|012|B||
03064|013|P|PREDISPOSING FACTORS:  None determined.|
03064|014|B||
03064|015|M|PATIENT MANAGEMENT:  The concurrent use strong or moderate CYP3A4 inhibitors|
03064|016|M|with asunaprevir is contraindicated.(1)|
03064|017|B||
03064|018|D|DISCUSSION:  Asunaprevir is a sensitive CYP3A4 substrate.  Sensitive|
03064|019|D|substrates would be expected to have an area-under-curve (AUC) ratio of at|
03064|020|D|least 5-fold.(1,2)|
03064|021|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir,|
03064|022|D|clarithromycin, ceritinib, cobicistat, idelalisib, indinavir, itraconazole,|
03064|023|D|josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, lonafarnib,|
03064|024|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
03064|025|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
03064|026|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)|
03064|027|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
03064|028|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
03064|029|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03064|030|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
03064|031|D|ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
03064|032|D|rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)|
03064|033|B||
03064|034|R|REFERENCES:|
03064|035|B||
03064|036|R|1.Sunvepra (asunaprevir) Australia Prescribing Information. Bristol-Myers|1
03064|037|R|  Squibb Australia Pty Ltd April 5, 2019.|1
03064|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
03064|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03065|001|T|MONOGRAPH TITLE:  Iobenguane I 123/Agents that Affect Catecholamines|
03065|002|B||
03065|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03065|004|L|of severe adverse interaction.|
03065|005|B||
03065|006|A|MECHANISM OF ACTION:  Many compounds that reduce catecholamine uptake or|
03065|007|A|that deplete catecholamine stores may interfere with iobenguane uptake into|
03065|008|A|cells.(1)|
03065|009|B||
03065|010|E|CLINICAL EFFECTS:  Compounds that reduce catecholamine uptake or that|
03065|011|E|deplete catecholamine stores may interfere with imaging completed with|
03065|012|E|iobenguane.(1)|
03065|013|B||
03065|014|P|PREDISPOSING FACTORS:  None determined.|
03065|015|B||
03065|016|M|PATIENT MANAGEMENT:  Discuss the use of agents that affect catecholamines.|
03065|017|M|Discontinue drugs that reduce catecholamine uptake or deplete catecholamine|
03065|018|M|stores prior to imaging with iobenguane.  Before imaging with iobenguane,|
03065|019|M|discontinue agents that affect catecholamines for at least 5 biological|
03065|020|M|half-lives, as clinically tolerated.(1)|
03065|021|B||
03065|022|D|DISCUSSION:  Many agents may reduce catecholamine uptake or deplete|
03065|023|D|catecholamine stores.(1)|
03065|024|D|   Examples include:|
03065|025|D|   - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate,|
03065|026|D|dextroamphetamine)|
03065|027|D|   - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine)|
03065|028|D|   - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol)|
03065|029|D|   - monoamine oxidase inhibitors (e.g. phenelzine, linezolid)|
03065|030|D|   - central monoamine depleting drugs (e.g. reserpine)|
03065|031|D|   - non-select beta adrenergic blocking drugs (e.g. labetalol)|
03065|032|D|   - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine,|
03065|033|D|phenylephrine, ephedrine, phenylpropanolamine, naphazoline)|
03065|034|D|   - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g.|
03065|035|D|amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine)|
03065|036|D|   - botanicals that may inhibit reuptake of norepinephrine, serotonin or|
03065|037|D|dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)|
03065|038|B||
03065|039|R|REFERENCE:|
03065|040|B||
03065|041|R|1.AdreView (iobenguane I 123) injection US prescribing information. GE|1
03065|042|R|  Healthcare March, 2013.|1
03066|001|T|MONOGRAPH TITLE:  Esomeprazole; Omeprazole/Carbamazepine|
03066|002|B||
03066|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03066|004|L|take action as needed.|
03066|005|B||
03066|006|A|MECHANISM OF ACTION:  Esomeprazole and omeprazole are primarily metabolized|
03066|007|A|by CYP2C19.  CYP3A4 plays a smaller role in metabolism.(1,2)|
03066|008|A|   Carbamazepine is a strong inducer of CYP2C19 and CYP3A4.(2)|
03066|009|A|   Esomeprazole and omeprazole are weak CYP3A4 inhibitors and may also|
03066|010|A|affect the metabolism of carbamazepine by CYP3A4.(2)|
03066|011|B||
03066|012|E|CLINICAL EFFECTS:  Concurrent use of agents which induce both CYP2C19 and|
03066|013|E|CYP3A4 decrease systemic exposure and may result in decreased effectiveness|
03066|014|E|of esomeprazole and omeprazole.  Concurrent use of esomeprazole or|
03066|015|E|omeprazole with carbamazepine may increase systemic exposure and may result|
03066|016|E|in increased toxicity of carbamazepine.(1-8)|
03066|017|B||
03066|018|P|PREDISPOSING FACTORS:  None determined.|
03066|019|B||
03066|020|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
03066|021|M|carbamazepine for reduced proton pump inhibitor (PPI) effectiveness.|
03066|022|M|Although specific dosing recommendations are not available, a higher dose of|
03066|023|M|esomeprazole or omeprazole may be considered to maintain PPI efficacy.|
03066|024|M|   Monitor patients receiving concurrent therapy for increased carbamazepine|
03066|025|M|effects.  Therapeutic drug monitoring should be completed routinely when|
03066|026|M|carbamazepine is coadministered with esomeprazole or omeprazole.(7,8)|
03066|027|B||
03066|028|D|DISCUSSION:  In an interaction study, omeprazole increased the maximum|
03066|029|D|concentration (Cmax), area-under-curve (AUC) and elimination half-life|
03066|030|D|(t1/2) of carbamazepine.  The effect of carbamazepine on omeprazole was not|
03066|031|D|studied in these trials (3,4) or in other investigations.  The effects of|
03066|032|D|other CYP2C19 inducers on the pharmacokinetics of omeprazole have been|
03066|033|D|reported.|
03066|034|D|   In an interaction study, subjects with prostate cancer received|
03066|035|D|omeprazole before and after enzalutamide 160 mg daily (an inducer of CYP2C19|
03066|036|D|and CYP3A4) for at least 55 days. Enzalutamide decreased omeprazole AUC by|
03066|037|D|70.5%.(2,5)|
03066|038|D|   In an interaction study, rifampin 600 mg daily (an inducer of CYP2C19 and|
03066|039|D|CYP3A4) for 7 days decreased omeprazole AUC by 89.5%.(2,6)|
03066|040|D|   In an interaction study, St. John's wort (an inducer of CYP2C19 and|
03066|041|D|CYP3A4) decreased the Cmax and AUC of omeprazole by 37.5% and 49.6%,|
03066|042|D|respectively.  The Cmax and AUC of omeprazole sulfone (via CYP2C19)|
03066|043|D|increased by 160.3% and 136.6%, respectively.  The Cmax and AUC of|
03066|044|D|5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%,|
03066|045|D|respectively.(7,8)|
03066|046|B||
03066|047|R|REFERENCES:|
03066|048|B||
03066|049|R|1.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
03066|050|R|  Pharmaceuticals LP August, 2021.|1
03066|051|R|2.This information is based on an extract from the Certara Drug Interaction|6
03066|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03066|053|R|3.Medhi B, Singh PK, Prakash A, Avti P. Effect of esomeprazole on the|2
03066|054|R|  pharmacokinetics of carbamazepine. Indian J Pharmacol 2011 Feb;43(1):73-5.|2
03066|055|R|4.Dixit RK, Chawla AB, Kumar N, Garg SK. Effect of omeprazole on the|2
03066|056|R|  pharmacokinetics of sustained-release carbamazepine in healthy male|2
03066|057|R|  volunteers. Methods Find Exp Clin Pharmacol 2001 Jan-Feb;23(1):37-9.|2
03066|058|R|5.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
03066|059|R|  September, 2022.|1
03066|060|R|6.Bosilkovska M, Samer CF, Deglon J, Rebsamen M, Staub C, Dayer P, Walder B,|2
03066|061|R|  Desmeules JA, Daali Y. Geneva cocktail for cytochrome p450 and|2
03066|062|R|  P-glycoprotein activity assessment using  dried blood spots. Clin|2
03066|063|R|  Pharmacol Ther 2014 Sep;96(3):349-59.|2
03066|064|R|7.Wang LS, Zhou G, Zhu B, Wu J, Wang JG, Abd El-Aty AM, Li T, Liu J, Yang|2
03066|065|R|  TL, Wang D, Zhong XY, Zhou HH. St John's wort induces both cytochrome P450|2
03066|066|R|  3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of|2
03066|067|R|  omeprazole. Clin Pharmacol Ther 2004 Mar;75(3):191-7.|2
03066|068|R|8.Xie HG. Additional discussions regarding the altered metabolism and|2
03066|069|R|  transport of omeprazole after long-term use of St John's wort. Clin|2
03066|070|R|  Pharmacol Ther 2005 Oct;78(4):440-1.|2
03067|001|T|MONOGRAPH TITLE:  Rivaroxaban/Clarithromycin; Erythromycin; Verapamil|
03067|002|B||
03067|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03067|004|L|of severe adverse interaction.|
03067|005|B||
03067|006|A|MECHANISM OF ACTION:  Clarithromycin, erythromycin, and verapamil may|
03067|007|A|inhibit the metabolism of rivaroxaban by CYP3A4 and by P-glycoprotein.(1-5)|
03067|008|B||
03067|009|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
03067|010|E|P-gp and a moderate inhibitor of CYP3A4 may result in elevated levels of and|
03067|011|E|clinical effects of rivaroxaban, including an increased risk of bleeding, in|
03067|012|E|patients with decreased renal function.(1,2)|
03067|013|B||
03067|014|P|PREDISPOSING FACTORS:  It is expected that this interaction will only be|
03067|015|P|clinically significant in patients with decreased renal function.(1)|
03067|016|P|   The risk for bleeding episodes may be greater in patients with|
03067|017|P|disease-associated factors (e.g. thrombocytopenia).|
03067|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
03067|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03067|020|P|risk for bleeding (NSAIDs).|
03067|021|B||
03067|022|M|PATIENT MANAGEMENT:  The US manufacturer states no precautions are necessary|
03067|023|M|with the concurrent use of agents that are combined moderate inhibitors of|
03067|024|M|CYP3A4 and P-gp inhibitors with rivaroxaban in patients with normal renal|
03067|025|M|function; however, in patients with decreased renal function (CrCL of 15|
03067|026|M|ml/min to 80 ml/min) these agents should only be used if the benefits of|
03067|027|M|concurrent therapy outweigh the increased risk of bleeding.(1)  The Canadian|
03067|028|M|manufacturer states that if such use must be undertaken, caution is|
03067|029|M|required.(3)|
03067|030|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03067|031|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03067|032|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03067|033|M|patients with any symptoms.|
03067|034|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03067|035|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03067|036|M|anticoagulation in patients with active pathologic bleeding.|
03067|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03067|038|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03067|039|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03067|040|M|and/or swelling.|
03067|041|B||
03067|042|D|DISCUSSION:  Clarithromycin (500 mg twice daily) increased the|
03067|043|D|area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of|
03067|044|D|rivaroxaban by 54% and 40%, respectively.(1,2)  In a study in 60 healthy|
03067|045|D|males, clarithromycin (500 mg twice daily) increased the AUC and Cmax of a|
03067|046|D|single dose of rivaroxaban (40 mg) by 94% and 92%, respectively.(6)  In a|
03067|047|D|case report, a 65 year-old male developed hemoptysis, epistaxis, and|
03067|048|D|intracranial hemorrhage 3 days after the addition of clarithromycin (500 mg|
03067|049|D|twice daily) to rivaroxaban (20 mg daily).(7)|
03067|050|D|   In a review of 9 liver transplant patients, mean rivaroxaban levels were|
03067|051|D|significantly higher in patients treated with cyclosporine than with|
03067|052|D|tacrolimus (131.7 ng/ml versus 20.3 ng/ml).(8)|
03067|053|D|   In a review of 23 patients who received concurrent rivaroxaban and|
03067|054|D|dronedarone for an average of 9.1+/-6.7 months, there were no thromboembolic|
03067|055|D|or major bleeding events.  One fourth of the patients received a reduced|
03067|056|D|dose of rivaroxaban (15 mg daily), despite having normal renal function.(9)|
03067|057|D|   Erythromycin (500 mg three times daily) increased the AUC and Cmax of a|
03067|058|D|single dose of rivaroxaban by 30% and 30%, respectively.(1-3)  In patients|
03067|059|D|with mild renal impairment (CrCl of 50 ml/min to 79 ml/min) who were|
03067|060|D|receiving erythromycin, rivaroxaban AUC and Cmax were increased 76% and 56%|
03067|061|D|when compared to administration of rivaroxaban in patients with normal renal|
03067|062|D|function receiving rivaroxaban alone.  In patients with moderate renal|
03067|063|D|impairment (CrCl of 30 ml/min to 49 ml/min) who were receiving erythromycin,|
03067|064|D|rivaroxaban AUC and Cmax were increased 99% and 64% when compared to|
03067|065|D|administration of rivaroxaban in patients with normal renal function|
03067|066|D|receiving rivaroxaban alone.(1,10)|
03067|067|D|   In a post hoc analysis of the ROCKET-AF trial, concomitant use of|
03067|068|D|non-dihydropyridine calcium channel blockers and rivaroxaban was associated|
03067|069|D|with an increased risk of major bleeding and intracranial hemorrhage. There|
03067|070|D|was no difference in efficacy or safety of rivaroxaban versus warfarin and|
03067|071|D|concomitant use of CCB across renal function subgroups.(11)|
03067|072|D|   In a study in subjects who were taking verapamil, the combination of|
03067|073|D|verapamil and mild renal insufficiency produced additive effects on the AUC|
03067|074|D|of a single dose of rivaroxaban (20 mg).(12)|
03067|075|D|   These changes are not expected to be clinically significant in patients|
03067|076|D|with normal renal function.(1-3)|
03067|077|D|   A retrospective cohort study examined 24,943 patients aged 66 years and|
03067|078|D|older with concurrent therapy of an anticoagulant, either rivaroxaban|
03067|079|D|(40.0%), apixaban (31.9%), or dabigatran (28.1%), with either azithromycin|
03067|080|D|or clarithromycin.  The primary outcome of hospital admission with major|
03067|081|D|hemorrhage within 30 days on concurrent therapy was higher in patients on|
03067|082|D|clarithromycin (0.77%) compared to azithromycin (0.43%) with an adjusted|
03067|083|D|hazard ratio of 1.71 (95% CI, 1.20-2.45).  In a self-controlled case series,|
03067|084|D|744 major hemorrhage events were identified among 647 unique individuals|
03067|085|D|taking anticoagulants who were exposed to clarithromycin.  The rate of|
03067|086|D|events that occurred during clarithromycin use had a significant rate ratio|
03067|087|D|of 1.44 (95% CI, 1.08-1.92).(13)|
03067|088|D|   A propensity matched cohort evaluated the concurrent use of combined P-gp|
03067|089|D|and moderate CYP3A4 inhibitors with apixaban or rivaroxaban.  Combined|
03067|090|D|inhibitors included amiodarone, diltiazem, erythromycin, dronedarone, and|
03067|091|D|verapamil.  Bleeding occurred in 26.4% of patients in the inhibitor group|
03067|092|D|compared to 18.4% in the control group (hazard ratio 1.8; 95% CI 1.19-2.73;|
03067|093|D|p=0.006).  Although not statistically significant, patients in the inhibitor|
03067|094|D|group also had a higher rate of major bleeding (15% vs 10.3%) and minor|
03067|095|D|bleeding (8.9% vs 5.2%), respectively.(14)|
03067|096|D|   A summary of pharmacokinetic interactions with rivaroxaban and|
03067|097|D|calcium-channel blockers, including verapamil, concluded that concurrent|
03067|098|D|therapy should be avoided if CrCl < 80 ml/min.(15)|
03067|099|B||
03067|100|R|REFERENCES:|
03067|101|B||
03067|102|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
03067|103|R|  Inc. March, 2020.|1
03067|104|R|2.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
03067|105|R|  August, 2021.|1
03067|106|R|3.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
03067|107|R|  2015.|1
03067|108|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03067|109|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03067|110|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03067|111|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03067|112|R|  11/14/2017.|1
03067|113|R|5.This information is based on an extract from the Certara Drug Interaction|6
03067|114|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03067|115|R|6.Gouin-Thibault I, Delavenne X, Blanchard A, Siguret V, Salem JE, Narjoz C,|2
03067|116|R|  Gaussem P, Beaune P, Funck-Brentano C, Azizi M, Mismetti P, Loriot MA.|2
03067|117|R|  Interindividual variability in dabigatran and rivaroxaban exposure:|2
03067|118|R|  contribution  of ABCB1 genetic polymorphisms and interaction with|2
03067|119|R|  clarithromycin. J Thromb Haemost 2017 Feb;15(2):273-283.|2
03067|120|R|7.Fralick M, Juurlink DN, Marras T. Bleeding associated with|3
03067|121|R|  coadministration of rivaroxaban and clarithromycin. CMAJ 2016 Jun 14;|3
03067|122|R|  188(9):669-72.|3
03067|123|R|8.Wannhoff A, Weiss KH, Schemmer P, Stremmel W, Gotthardt DN. Increased|2
03067|124|R|  levels of rivaroxaban in patients after liver transplantation treated with|2
03067|125|R|  cyclosporine A. Transplantation 2014 Jul 27;98(2):e12-3.|2
03067|126|R|9.Escobar C, Arceluz M, Montes de Oca R, Mori R, Lopez-Sendon JL, Merino JL.|2
03067|127|R|  Concomitant Rivaroxaban and Dronedarone Administration in Patients With|2
03067|128|R|  Nonvalvular Atrial Fibrillation. Rev Esp Cardiol (Engl Ed) 2017 Feb;|2
03067|129|R|  70(2):121-122.|2
03067|130|R|10.Moore KT, Vaidyanathan S, Natarajan J, Ariyawansa J, Haskell L, Turner|2
03067|131|R|   KC. An open-label study to estimate the effect of steady-state|2
03067|132|R|   erythromycin on the pharmacokinetics, pharmacodynamics, and safety of a|2
03067|133|R|   single dose of rivaroxaban in subjects with renal impairment and normal|2
03067|134|R|   renal function. J Clin Pharmacol 2014 Dec;54(12):1407-20.|2
03067|135|R|11.Washam JB, Hellkamp AS, Lokhnygina Y, Piccini JP, Berkowitz SD, Nessel|2
03067|136|R|   CC, Becker RC, Breithardt G, Fox KAA, Halperin JL, Hankey GJ, Mahaffey|2
03067|137|R|   KW, Singer DE, Patel MR. Efficacy and Safety of Rivaroxaban Versus|2
03067|138|R|   Warfarin in Patients Taking Nondihydropyridine Calcium Channel Blockers|2
03067|139|R|   for Atrial Fibrillation (from the ROCKET AF Trial). Am J Cardiol 2017 Aug|2
03067|140|R|   15;120(4):588-594.|2
03067|141|R|12.Greenblatt DJ, Patel M, Harmatz JS, Nicholson WT, Rubino CM, Chow CR.|2
03067|142|R|   Impaired Rivaroxaban Clearance in Mild Renal Insufficiency With Verapamil|2
03067|143|R|   Coadministration: Potential Implications for Bleeding Risk and Dose|2
03067|144|R|   Selection. J Clin Pharmacol 2018 Apr;58(4):533-540.|2
03067|145|R|13.Hill K, Sucha E, Rhodes E, Carrier M, Garg AX, Harel Z, Hundemer GL,|2
03067|146|R|   Clark EG, Knoll G, McArthur E, Sood MM. Risk of Hospitalization With|2
03067|147|R|   Hemorrhage Among Older Adults Taking Clarithromycin vs  Azithromycin and|2
03067|148|R|   Direct Oral Anticoagulants..|2
03067|149|R|14.Hanigan S, Das J, Pogue K, Barnes GD, Dorsch MP. The real world use of|2
03067|150|R|   combined P-glycoprotein and moderate CYP3A4 inhibitors with  rivaroxaban|2
03067|151|R|   or apixaban increases bleeding..|2
03067|152|R|15.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
03067|153|R|   Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
03067|154|R|   of  the Week..|6
03068|001|T|MONOGRAPH TITLE:  Lacosamide/Beta-Blockers; Diltiazem; Verapamil|
03068|002|B||
03068|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03068|004|L|take action as needed.|
03068|005|B||
03068|006|A|MECHANISM OF ACTION:  Lacosamide may enhance the slow inactivation of|
03068|007|A|voltage-gated sodium channels and may cause dose-dependent bradycardia,|
03068|008|A|prolongation of the PR interval, atrioventricular (AV) block, or ventricular|
03068|009|A|tachyarrhythmia.(1)|
03068|010|B||
03068|011|E|CLINICAL EFFECTS:  Concurrent use of lacosamide and agents that affect|
03068|012|E|cardiac conduction (beta-blockers, non-dihydropyridine calcium channel|
03068|013|E|blockers) may increase the risk of bradycardia, prolongation of the PR|
03068|014|E|interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)|
03068|015|B||
03068|016|P|PREDISPOSING FACTORS:  None determined.|
03068|017|B||
03068|018|M|PATIENT MANAGEMENT:  Lacosamide should be used with caution in patients on|
03068|019|M|concomitant medications that affect cardiac conduction, including|
03068|020|M|beta-blockers and non-dihydropyridine calcium channel blockers.(1)|
03068|021|M|   If concurrent use is needed, obtain an ECG before lacosamide therapy and|
03068|022|M|after lacosamide dose is titrated to steady-state.(1)|
03068|023|M|   Patients should be monitored closely when lacosamide is given|
03068|024|M|intravenously.(1)|
03068|025|B||
03068|026|D|DISCUSSION:  In a clinical trial in patients with partial-onset seizures,|
03068|027|D|asymptomatic first-degree atrioventricular (AV) block occurred in 4/944|
03068|028|D|(0.4%) of patient who received lacosamide compared to 0/364 (0%) with|
03068|029|D|placebo.(1)|
03068|030|D|   In a clinical trial in patients with diabetic neuropathy, asymptomatic|
03068|031|D|first-degree AV block occurred in 5/1023 (0.5%) of patients who received|
03068|032|D|lacosamide compared to 0/291 (0%) with placebo.(1)|
03068|033|D|   Second-degree and complete AV block have been reported in patients with|
03068|034|D|seizures.(1)|
03068|035|D|   One case of profound bradycardia was observed in a patient during a|
03068|036|D|15-minute infusion of 150 mg of lacosamide.(1)|
03068|037|D|   Two postmarketing reports of third-degree AV block in patients with|
03068|038|D|significant cardiac history and also receiving metoprolol and amlodipine|
03068|039|D|during infusion of lacosamide injection at doses higher than recommended|
03068|040|D|have been reported.(1)|
03068|041|D|   A case report of an 88 year old female taking bisoprolol documented|
03068|042|D|complete AV block after initiation of lacosamide.  The patient required|
03068|043|D|pacemaker implementation.(2)|
03068|044|B||
03068|045|R|REFERENCES:|
03068|046|B||
03068|047|R|1.Vimpat (lacosamide) tablet, injection US prescribing information. UCB,|1
03068|048|R|  Inc. October, 2021.|1
03068|049|R|2.Lachuer C, Corny J, Bezie Y, Ferchichi S, Durand-Gasselin B. Complete|3
03068|050|R|  Atrioventricular Block in an Elderly Patient Treated with Low-Dose|3
03068|051|R|  Lacosamide. Cardiovasc Toxicol 2018 Jun 11.|3
03069|001|T|MONOGRAPH TITLE:  Eravacycline/Strong CYP3A4 Inducers|
03069|002|B||
03069|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03069|004|L|of severe adverse interaction.|
03069|005|B||
03069|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03069|007|A|eravacycline.(1)|
03069|008|B||
03069|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
03069|010|E|in decreased levels of eravacycline and may lead to decreased efficacy of|
03069|011|E|eravacycline and increase the risk of treatment failure.(1)|
03069|012|B||
03069|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03069|014|P|of the inducer for longer than 1-2 weeks.|
03069|015|B||
03069|016|M|PATIENT MANAGEMENT:  For the treatment of complicated intra-abdominal|
03069|017|M|infections, the US manufacturer of eravacycline recommends dose adjustment|
03069|018|M|of eravacycline to 1.5 mg/kg every 12 hours for a total duration of 4 to 14|
03069|019|M|days with concurrent use of a strong CYP3A4 inducer.  No dose adjustment is|
03069|020|M|warranted with concurrent use of a weak or moderate CYP3A4 inducer.(1)|
03069|021|M|   Standard dosing of eravacycline is 1 mg/kg every 12 hours for 4 to 14|
03069|022|M|days for complicated intra-abdominal infections.(1)|
03069|023|B||
03069|024|D|DISCUSSION:  Concurrent use of rifampin (a strong inducer of CYP3A4)|
03069|025|D|decreased eravacycline area-under-curve (AUC) by 35% and increased|
03069|026|D|eravacycline clearance by 54%.(1)|
03069|027|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03069|028|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03069|029|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03069|030|D|rifapentine, and St. John's wort.(2-4)|
03069|031|B||
03069|032|R|REFERENCES:|
03069|033|B||
03069|034|R|1.Xerava (eravacycline) injection US prescribing information. Tetraphase|1
03069|035|R|  Pharmaceuticals Inc. August, 2018.|1
03069|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03069|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03069|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03069|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03069|040|R|  11/14/2017.|1
03069|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
03069|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03070|001|T|MONOGRAPH TITLE:  Abemaciclib/Moderate CYP3A4 Inducers|
03070|002|B||
03070|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03070|004|L|of severe adverse interaction.|
03070|005|B||
03070|006|A|MECHANISM OF ACTION:  Abemaciclib is a substrate of CYP3A4.  Moderate|
03070|007|A|inducers of CYP3A4 may induce the metabolism of abemaciclib.(1)|
03070|008|B||
03070|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
03070|010|E|in decreased levels and effectiveness of abemaciclib.(1)|
03070|011|B||
03070|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03070|013|P|of the inducer for longer than 1-2 weeks.|
03070|014|B||
03070|015|M|PATIENT MANAGEMENT:  The manufacturer of abemaciclib states to avoid|
03070|016|M|concurrent administration with moderate CYP3A4 inducers and consider|
03070|017|M|alternative agents.(1)|
03070|018|B||
03070|019|D|DISCUSSION:  Abemaciclib is a substrate of CYP3A4.(1)|
03070|020|D|   Concurrent administration of rifampin (600 mg once daily, a strong CYP3A4|
03070|021|D|inducer) with a single 200 mg dose of abemaciclib decreased the relative|
03070|022|D|potency adjusted unbound area-under-curve (AUC) of abemaciclib and its|
03070|023|D|active metabolites (M2, M18, and M20) by 70% in healthy subjects.(1)|
03070|024|D|   Concurrent administration of efavirenz, bosentan, and modafinil (moderate|
03070|025|D|CYP3A4 inducers) are predicted to decrease the relative potency adjusted|
03070|026|D|unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by|
03070|027|D|53%, 41%, and 29%, respectively.(1)|
03070|028|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03070|029|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
03070|030|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
03070|031|D|pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
03070|032|D|thioridazine, tipranavir/ritonavir and tovorafenib.(2,3)|
03070|033|B||
03070|034|R|REFERENCES:|
03070|035|B||
03070|036|R|1.Verzenio (abemaciclib) US prescribing information. Eli Lilly and Company|1
03070|037|R|  October, 2021.|1
03070|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
03070|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03070|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03070|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03070|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03070|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03070|044|R|  11/14/2017.|1
03071|001|T|MONOGRAPH TITLE:  Abemaciclib/Moderate CYP3A4 Inhibitors|
03071|002|B||
03071|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03071|004|L|take action as needed.|
03071|005|B||
03071|006|A|MECHANISM OF ACTION:  Abemaciclib is a substrate of CYP3A4.  Moderate|
03071|007|A|inhibitors of CYP3A4 may inhibit the metabolism of abemaciclib.(1)|
03071|008|B||
03071|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
03071|010|E|result in increased levels and toxicity from abemaciclib.(1)|
03071|011|B||
03071|012|P|PREDISPOSING FACTORS:  None determined.|
03071|013|B||
03071|014|M|PATIENT MANAGEMENT:  The manufacturer of abemaciclib recommends monitoring|
03071|015|M|for adverse reactions and consider a dose reduction of abemaciclib dose in|
03071|016|M|50 mg decrements as detailed in prescribing information (based on starting|
03071|017|M|dose, previous dose reductions, and combination or monotherapy use) with|
03071|018|M|concurrent use of moderate CYP3A4 inhibitors.(1)|
03071|019|M|   Monitor patient for signs and symptoms of abemaciclib toxicity with|
03071|020|M|concurrent use.|
03071|021|B||
03071|022|D|DISCUSSION:  Abemaciclib is a substrate of CYP3A4.(1)|
03071|023|D|   Concurrent administration of verapamil and diltiazem (moderate CYP3A4|
03071|024|D|inhibitors) are predicted to increase the relative adjusted unbound|
03071|025|D|area-under-curve (AUC) of abemaciclib and its active metabolites (M2, M18,|
03071|026|D|and M20) by approximately 1.6-fold and 2.4-fold, respectively.(1)|
03071|027|D|   Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is|
03071|028|D|predicted to increase the AUC of abemaciclib up to 16-fold.(1)|
03071|029|D|   Concurrent administration of itraconazole (a strong CYP3A4 inhibitor) is|
03071|030|D|predicted to increase the relative potency adjusted unbound AUC of|
03071|031|D|abemaciclib and its active metabolites (M2, M18, and M20) by 2.2-fold.(1)|
03071|032|D|   Concurrent administration of clarithromycin (500 mg twice daily, a strong|
03071|033|D|CYP3A4 inhibitor) with a single dose of 50 mg of abemaciclib increased the|
03071|034|D|relative potency adjusted unbound AUC of abemaciclib and its active|
03071|035|D|metabolites (M2, M18, and M20) by 2.5-fold.(1)|
03071|036|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  amprenavir,|
03071|037|D|aprepitant, avacopan, berotralstat, clofazimine, conivaptan, darunavir,|
03071|038|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03071|039|D|fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir,|
03071|040|D|letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra,|
03071|041|D|stiripentol, tofisopam, treosulfan, and verapamil.(2,3)|
03071|042|B||
03071|043|R|REFERENCES:|
03071|044|B||
03071|045|R|1.Verzenio (abemaciclib) US prescribing information. Eli Lilly and Company|1
03071|046|R|  October, 2021.|1
03071|047|R|2.This information is based on an extract from the Certara Drug Interaction|6
03071|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03071|049|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03071|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03071|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03071|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03071|053|R|  11/14/2017.|1
03072|001|T|MONOGRAPH TITLE:  Repaglinide/Tecovirimat|
03072|002|B||
03072|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03072|004|L|take action as needed.|
03072|005|B||
03072|006|A|MECHANISM OF ACTION:  Tecovirimat may inhibit the metabolism of repaglinide|
03072|007|A|by CYP2C8. Repaglinide is also metabolized by CYP3A4 and tecovirimat is a|
03072|008|A|weak inducer of CYP3A4.(1)|
03072|009|B||
03072|010|E|CLINICAL EFFECTS:  Concurrent use of tecovirimat may result in elevated|
03072|011|E|levels of repaglinide and may result in mild to moderate hypoglycemia.(1)|
03072|012|B||
03072|013|P|PREDISPOSING FACTORS:  None determined.|
03072|014|B||
03072|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
03072|016|M|tecovirimat and repaglinide closely for hypoglycemic symptoms.(1)|
03072|017|B||
03072|018|D|DISCUSSION:  In a study in healthy subjects, concurrent administration of|
03072|019|D|tecovirimat and repaglinide (2 mg) resulted in 10 of 30 subjects|
03072|020|D|experiencing mild (6 subjects) and moderate hypoglycemia (4 subjects).(1)|
03072|021|D|   In a study in healthy subjects, administration of tecovirimat (600 mg|
03072|022|D|twice daily) increased the area-under-curve (AUC) and maximum concentration|
03072|023|D|(Cmax) of a single dose of repaglinide (2 mg) by 29% and 27%,|
03072|024|D|respectively.(1)|
03072|025|B||
03072|026|R|REFERENCE:|
03072|027|B||
03072|028|R|1.Tpoxx (tecovirimat) US prescribing information. SIGA Technologies, Inc.|1
03072|029|R|  May, 2022.|1
03073|001|T|MONOGRAPH TITLE:  Doravirine/Strong CYP3A4 Inducers|
03073|002|B||
03073|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03073|004|L|is contraindicated and generally should not be dispensed or administered to|
03073|005|L|the same patient.|
03073|006|B||
03073|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 are expected to increase the|
03073|008|A|metabolism of doravirine.(1)|
03073|009|B||
03073|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong inducers of CYP3A4 may|
03073|011|E|result in decreased levels and effectiveness of doravirine.(3)|
03073|012|B||
03073|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03073|014|P|of the inducer for longer than 1-2 weeks.|
03073|015|B||
03073|016|M|PATIENT MANAGEMENT:  Concurrent administration of strong inducers of CYP3A4|
03073|017|M|with doravirine is contraindicated. A washout period of 4 weeks for the|
03073|018|M|CYP3A4 inducer is recommended prior to initiation of doravirine.(1)|
03073|019|B||
03073|020|D|DISCUSSION:  Doravirine is metabolized by CYP3A4.  Strong inducers of CYP3A4|
03073|021|D|are expected to reduce doravirine levels, which may lead to loss of|
03073|022|D|response.(1)|
03073|023|D|   In a study in 10 subjects, rifampin (600 mg daily), a strong inducer of|
03073|024|D|CYP3A4, decreased the area-under-curve (AUC), maximum concentration (Cmax),|
03073|025|D|and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by|
03073|026|D|88%, 57%, and 97% respectively.(1)|
03073|027|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
03073|028|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03073|029|D|lumacaftor, mitotane, oxcarbazepine, phenobarbital, phenytoin, primidone,|
03073|030|D|rifampin, rifapentine, and St. John's wort.(1)|
03073|031|B||
03073|032|R|REFERENCES:|
03073|033|B||
03073|034|R|1.Pifeltro (doravirine) US prescribing information. Merck & Co. Inc.|1
03073|035|R|  September, 2019.|1
03073|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03073|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03073|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03073|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03073|040|R|  11/14/2017.|1
03073|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
03073|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03074|001|T|MONOGRAPH TITLE:  Doravirine/Moderate CYP3A4 Inducers|
03074|002|B||
03074|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03074|004|L|of severe adverse interaction.|
03074|005|B||
03074|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 are expected to increase|
03074|007|A|the metabolism of doravirine.(1-2)|
03074|008|B||
03074|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate CYP3A4 inducer may|
03074|010|E|result in decreased levels and effectiveness of doravirine.(1-2)|
03074|011|B||
03074|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03074|013|P|of the inducer for longer than 1-2 weeks.|
03074|014|B||
03074|015|M|PATIENT MANAGEMENT:  If concurrent therapy is necessary, increase doravirine|
03074|016|M|dosage to one tablet twice daily for the duration of coadministration with|
03074|017|M|the CYP3A4 inducer.(1)|
03074|018|M|   Patients on the fixed-dose combination of doravirine-lamivudine-tenofovir|
03074|019|M|should take 1 tablet (100 mg) of doravirine about 12 hours after their dose|
03074|020|M|of doravirine-lamivudine-tenofovir.(2)|
03074|021|B||
03074|022|D|DISCUSSION:  Doravirine is metabolized by CYP3A4.  Moderate inducers of|
03074|023|D|CYP3A4 are expected to reduce doravirine levels, which may lead to loss of|
03074|024|D|response.(1)|
03074|025|D|   In a study in 12 subjects, rifabutin (300 mg daily), a moderate inducer|
03074|026|D|of CYP3A4, decreased the area-under-curve (AUC) and 24 hour concentration|
03074|027|D|(C24) of a single dose of doravirine (100 mg) by 50% and 68%,|
03074|028|D|respectively.(1)|
03074|029|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03074|030|D|bosentan, cenobamate, dabrafenib, dexamethasone, dipyrone, elagolix,|
03074|031|D|eslicarbazepine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil,|
03074|032|D|nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib,|
03074|033|D|telotristat, thioridazine and tovorafenib.(3-4)|
03074|034|B||
03074|035|R|REFERENCES:|
03074|036|B||
03074|037|R|1.Pifeltro (doravirine) US prescribing information. Merck & Co. Inc.|1
03074|038|R|  September, 2019.|1
03074|039|R|2.Delstrigo (doravirine, lamivudine, tenofovir disoproxil) US prescribing|1
03074|040|R|  information. Merck Sharp & Dohme LLC January, 2025.|1
03074|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03074|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03074|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03074|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03074|045|R|  11/14/2017.|1
03074|046|R|4.This information is based on an extract from the Certara Drug Interaction|6
03074|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03075|001|T|MONOGRAPH TITLE:  Doravirine/Efavirenz;Etravirine;Nevirapine|
03075|002|B||
03075|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03075|004|L|of severe adverse interaction.|
03075|005|B||
03075|006|A|MECHANISM OF ACTION:  Efavirenz, etravirine, and nevirapine may induce the|
03075|007|A|metabolism of doravirine via CYP3A4.(1)|
03075|008|B||
03075|009|E|CLINICAL EFFECTS:  Concurrent use of efavirenz, etravirine, or nevirapine|
03075|010|E|may result in subtherapeutic levels of doravirine.(1)|
03075|011|B||
03075|012|P|PREDISPOSING FACTORS:  None determined.|
03075|013|B||
03075|014|M|PATIENT MANAGEMENT:  Coadministration of doravirine with efavirenz,|
03075|015|M|etravirine, or nevirapine is not recommended.(1)|
03075|016|B||
03075|017|D|DISCUSSION:  In a study in 17 healthy subjects, coadministration of|
03075|018|D|efavirenz (600 mg daily) with a single dose of doravirine (100 mg) decreased|
03075|019|D|doravirine's area-under-curve (AUC), maximum concentration (Cmax), and 24|
03075|020|D|hour concentration (C24) by 62%, 35%, and 85%, respectively.(1)|
03075|021|B||
03075|022|R|REFERENCE:|
03075|023|B||
03075|024|R|1.Pifeltro (doravirine) US prescribing information. Merck & Co. Inc.|1
03075|025|R|  September, 2019.|1
03076|001|T|MONOGRAPH TITLE:  Desmopressin/Agents with Hyponatremia Risk (mono deleted|
03076|002|T|06/05/2023)|
03076|003|B||
03076|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03076|005|L|take action as needed.|
03076|006|B||
03076|007|A|MECHANISM OF ACTION:  Carbamazepine, chlorpromazine, lamotrigine, loop|
03076|008|A|diuretics, glucocorticoids, NSAIDs, opioids, SSRIs, thiazide diuretics,|
03076|009|A|and/or tricyclic antidepressants increase the risk of hyponatremia.(1)|
03076|010|B||
03076|011|E|CLINICAL EFFECTS:  Concurrent use may increase the risk of hyponatremia with|
03076|012|E|desmopressin.(1)|
03076|013|B||
03076|014|P|PREDISPOSING FACTORS:  Predisposing factors for hyponatremia include:|
03076|015|P|polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can|
03076|016|P|cause fluid/electrolyte imbalances (cystic fibrosis, heart failure, renal|
03076|017|P|disorders), and age >=65.|
03076|018|B||
03076|019|M|PATIENT MANAGEMENT:  Use desmopressin with caution with agents that can|
03076|020|M|increase the risk of hyponatremia.(1)|
03076|021|M|   Counsel patients to report symptoms of hyponatremia, which may include:|
03076|022|M|headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness,|
03076|023|M|muscle cramps, changes in mental state (confusion, decreased|
03076|024|M|awareness/alertness), seizures, coma, and trouble breathing.  Counsel|
03076|025|M|patients to limit the amount of fluids they drink in the evening and|
03076|026|M|night-time and to stop taking desmopressin if they develop a|
03076|027|M|stomach/intestinal virus with nausea/vomiting.(2)|
03076|028|B||
03076|029|D|DISCUSSION:  In clinical trials of desmopressin for the treatment of|
03076|030|D|nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <=|
03076|031|D|125 mmol/L) were taking systemic or inhaled glucocorticoids.  Three of these|
03076|032|D|patients were also taking NSAIDs and one was receiving a thiazide|
03076|033|D|diuretic.(3)|
03076|034|B||
03076|035|R|REFERENCES:|
03076|036|B||
03076|037|R|1.DDAVP (desmopressin acetate) US prescribing information. Sanofi-Aventis|1
03076|038|R|  U.S. LLC September 1, 2009.|1
03076|039|R|2.Noctiva (desmopressin acetate) Nasal Spray US prescribing information.|1
03076|040|R|  Serenity Pharmaceuticals, LLC March 3, 2017.|1
03076|041|R|3.US Food and Drug Administration (FDA) Center for Drug Evaluation and|1
03076|042|R|  Research (CDER). NDA 201656 Summary Review for Regulatory Action - Noctiva|1
03076|043|R|  (desmopressin acetate) Nasal Spray. available at:|1
03076|044|R|  https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2017/201656O|1
03076|045|R|  rig1s000SumR.pdf March 3, 2017.|1
03077|001|T|MONOGRAPH TITLE:  Duvelisib/Strong CYP3A4 Inhibitors|
03077|002|B||
03077|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03077|004|L|of severe adverse interaction.|
03077|005|B||
03077|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03077|007|A|of duvelisib.(1)|
03077|008|B||
03077|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03077|010|E|in elevated levels and increased effects of duvelisib.(1)|
03077|011|B||
03077|012|P|PREDISPOSING FACTORS:  None determined.|
03077|013|B||
03077|014|M|PATIENT MANAGEMENT:  The manufacturer of duvelisib states that use of strong|
03077|015|M|inhibitors of CYP3A4 should be avoided.  When strong CYP3A4 inhibitors are|
03077|016|M|required, reduce the dose of duvelisib to 15 mg twice daily.(1)|
03077|017|B||
03077|018|D|DISCUSSION:  Coadministration of ketoconazole (200 mg twice daily for 5|
03077|019|D|days) with a single oral 10 mg dose of duvelisib increased the|
03077|020|D|area-under-curve (AUC) and  maximum concentration (Cmax) of duvelisib|
03077|021|D|approximately 4-fold and 1.7-fold,  respectively.  Based on|
03077|022|D|physiologically-based pharmacokinetic (PKPB) modeling, the increase in|
03077|023|D|exposure to duvelisib is estimated to be approximately 2-fold at steady|
03077|024|D|state with concurrent use of strong CYP3A4 inhibitors.  PKPB modeling showed|
03077|025|D|no effect on duvelisib exposure with concurrent use of mild or moderate|
03077|026|D|CYP3A4 inhibitors.(1)|
03077|027|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03077|028|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03077|029|D|ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone,|
03077|030|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
03077|031|D|saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and|
03077|032|D|voriconazole.(2,3)|
03077|033|B||
03077|034|R|REFERENCES:|
03077|035|B||
03077|036|R|1.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
03077|037|R|  2021.|1
03077|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
03077|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03077|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03077|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03077|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03077|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03077|044|R|  11/14/2017.|1
03078|001|T|MONOGRAPH TITLE:  Duvelisib/Strong CYP3A4 Inducers|
03078|002|B||
03078|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03078|004|L|of severe adverse interaction.|
03078|005|B||
03078|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03078|007|A|duvelisib.(1)|
03078|008|B||
03078|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03078|010|E|may result in decreased levels and effectiveness of duvelisib.(1)|
03078|011|B||
03078|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03078|013|P|of the inducer for longer than 1-2 weeks.|
03078|014|B||
03078|015|M|PATIENT MANAGEMENT:  The manufacturer of duvelisib states that concurrent|
03078|016|M|use with strong CYP3A4 inducers should be avoided. (1)|
03078|017|B||
03078|018|D|DISCUSSION:  Concurrent administration of rifampin 600 mg once daily for 7|
03078|019|D|days, a strong inducer of CYP3A4, decreased duvelisib concentration maximum|
03078|020|D|(Cmax) and area-under-curve (AUC) by 66% and 82%, respectively.(1)|
03078|021|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03078|022|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin,|
03078|023|D|primidone, rifampin, rifapentine, and St. John's wort.(2-3)|
03078|024|B||
03078|025|R|REFERENCES:|
03078|026|B||
03078|027|R|1.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
03078|028|R|  2021.|1
03078|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03078|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03078|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03078|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03078|033|R|  11/14/2017.|1
03078|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
03078|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03079|001|T|MONOGRAPH TITLE:  Eliglustat/Weak CYP2D6 Inhibitors|
03079|002|B||
03079|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03079|004|L|take action as needed.|
03079|005|B||
03079|006|A|MECHANISM OF ACTION:  Weak inhibitors of CYP2D6 may inhibit the metabolism|
03079|007|A|of eliglustat.  If the patient is also taking an inhibitor of CYP3A4,|
03079|008|A|eliglustat metabolism can be further inhibited.(1)|
03079|009|B||
03079|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that is a weak inhibitor of|
03079|011|E|CYP2D6 may result in elevated levels of and clinical effects of eliglustat,|
03079|012|E|including prolongation of the PR, QTc, and/or QRS intervals, which may|
03079|013|E|result in life-threatening cardiac arrhythmias.(1)|
03079|014|B||
03079|015|P|PREDISPOSING FACTORS:  If the patient is also taking an inhibitor of CYP3A4|
03079|016|P|and/or has hepatic impairment, eliglustat metabolism can be further|
03079|017|P|inhibited.(1)|
03079|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03079|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03079|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03079|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03079|022|P|advanced age.(2)|
03079|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03079|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03079|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03079|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03079|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03079|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03079|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03079|030|B||
03079|031|M|PATIENT MANAGEMENT:  The dosage of eliglustat with weak inhibitors of CYP2D6|
03079|032|M|in poor CYP2D6 metabolizers should be limited to 84 mg daily.(1)|
03079|033|M|   The dosage of eliglustat with weak inhibitors of CYP2D6 in extensive|
03079|034|M|CYP2D6 metabolizers with mild (Child-Pugh Class A) hepatic impairment should|
03079|035|M|be limited to 84 mg daily.(1)|
03079|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03079|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03079|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03079|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03079|040|B||
03079|041|D|DISCUSSION:  Paroxetine (30 mg daily), a strong inhibitor of CYP2D6,|
03079|042|D|increased eliglustat (84 mg BID) maximum concentration (Cmax) and|
03079|043|D|area-under-curve (AUC) by  7-fold and 8.4-fold, respectively, in extensive|
03079|044|D|metabolizers.  Physiologically-based pharmacokinetic (PKPB) models suggested|
03079|045|D|paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold,|
03079|046|D|respectively, in intermediate metabolizers.  PKPB models suggested|
03079|047|D|ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily)  by|
03079|048|D|4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1)|
03079|049|D|   PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would|
03079|050|D|increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in|
03079|051|D|extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in|
03079|052|D|intermediate metabolizers.|
03079|053|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a|
03079|054|D|strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax|
03079|055|D|and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers.|
03079|056|D|In intermediate metabolizers, eliglustat Cmax and AUC would be expected to|
03079|057|D|increase 7.5-fold and 9.8-fold, respectively.(1)|
03079|058|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine|
03079|059|D|(a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat|
03079|060|D|Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive|
03079|061|D|metabolizers.  In intermediate metabolizers, eliglustat Cmax and AUC would|
03079|062|D|be expected to increase 4.2-fold and 5-fold, respectively.(1)|
03079|063|D|   A single dose of rolapitant increased dextromethorphan, a CYP2D6|
03079|064|D|substrate, about 3-fold on days 8 and day 22 following administration.|
03079|065|D|Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single|
03079|066|D|dose rolapitant.  The inhibitory effects of rolapitant on CYP2D6 are|
03079|067|D|expected to persist beyond 28 days.(5)|
03079|068|D|   Weak inhibitors of CYP2D6 include:  alogliptin, artesunate, celecoxib,|
03079|069|D|chloroquine, clobazam, clomipramine, desvenlafaxine, dimenhydrinate,|
03079|070|D|diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, felodipine,|
03079|071|D|gefitinib, hydralazine, hydroxychloroquine, lorcaserin, methadone,|
03079|072|D|panobinostat, propafenone, sertraline, vemurafenib, and venlafaxine.(3,4)|
03079|073|B||
03079|074|R|REFERENCES:|
03079|075|B||
03079|076|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
03079|077|R|  August, 2018.|1
03079|078|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03079|079|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03079|080|R|  settings: a scientific statement from the American Heart Association and|6
03079|081|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03079|082|R|  2;55(9):934-47.|6
03079|083|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03079|084|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03079|085|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03079|086|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03079|087|R|  11/14/2017.|1
03079|088|R|4.This information is based on an extract from the Certara Drug Interaction|6
03079|089|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03080|001|T|MONOGRAPH TITLE:  Eliglustat/Weak CYP3A4 Inhibitors|
03080|002|B||
03080|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03080|004|L|of severe adverse interaction.|
03080|005|B||
03080|006|A|MECHANISM OF ACTION:  Weak inhibitors of CYP3A4 may inhibit the metabolism|
03080|007|A|of eliglustat.  If the patient is also taking an inhibitor of CYP2D6,|
03080|008|A|eliglustat metabolism can be further inhibited.(1)|
03080|009|B||
03080|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that is a weak inhibitor of|
03080|011|E|CYP3A4 may result in elevated levels of and clinical effects of eliglustat,|
03080|012|E|including prolongation of the PR, QTc, and/or QRS intervals, which may|
03080|013|E|result in life-threatening cardiac arrhythmias.(1)|
03080|014|B||
03080|015|P|PREDISPOSING FACTORS:  If the patient is also taking an inhibitor of CYP2D6,|
03080|016|P|is a poor metabolizer of CYP2D6, and/or has hepatic impairment, eliglustat|
03080|017|P|metabolism can be further inhibited.(1)|
03080|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03080|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03080|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03080|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03080|022|P|advanced age.(2)|
03080|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03080|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03080|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03080|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03080|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03080|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03080|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03080|030|B||
03080|031|M|PATIENT MANAGEMENT:  The concurrent use of eliglustat with weak inhibitors|
03080|032|M|of CYP3A4 in poor metabolizers of CYP2D6 should be avoided.(1)|
03080|033|M|   The dosage of eliglustat with weak inhibitors of CYP3A4 in extensive|
03080|034|M|metabolizers of CYP2D6 with mild (Child-Pugh Class A) hepatic impairment|
03080|035|M|should be limited to 84 mg daily.(1)|
03080|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03080|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03080|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03080|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03080|040|B||
03080|041|D|DISCUSSION:  Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4,|
03080|042|D|increased eliglustat (84 mg BID) maximum concentration (Cmax) and|
03080|043|D|area-under-curve (AUC) by  4-fold and 4.4-fold, respectively, in extensive|
03080|044|D|metabolizers.  Physiologically-based pharmacokinetic (PKPB) models suggested|
03080|045|D|ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and|
03080|046|D|5.4-fold, respectively, in intermediate metabolizers.  PKPB models suggested|
03080|047|D|ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily)  by|
03080|048|D|4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1)|
03080|049|D|   PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would|
03080|050|D|increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in|
03080|051|D|extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in|
03080|052|D|intermediate metabolizers.|
03080|053|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a|
03080|054|D|strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax|
03080|055|D|and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers.|
03080|056|D|In intermediate metabolizers, eliglustat Cmax and AUC would be expected to|
03080|057|D|increase 7.5-fold and 9.8-fold, respectively.(1)|
03080|058|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine|
03080|059|D|(a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat|
03080|060|D|Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive|
03080|061|D|metabolizers.  In intermediate metabolizers, eliglustat Cmax and AUC would|
03080|062|D|be expected to increase 4.2-fold and 5-fold, respectively.(1)|
03080|063|D|   Weak inhibitors of CYP3A4 include:  alprazolam, amlodipine, anamorelin,|
03080|064|D|asciminib, azithromycin, Baikal skullcap, belumosudil,  berberine,|
03080|065|D|bicalutamide, blueberry, brodalumab, cannabidiol, chlorzoxazone, cilostazol,|
03080|066|D|cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine,|
03080|067|D|daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin,|
03080|068|D|elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib,|
03080|069|D|gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal,|
03080|070|D|grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib,|
03080|071|D|larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin,|
03080|072|D|lomitapide, lurasidone, olaparib, osilodrostat, palbociclib, pazopanib,|
03080|073|D|peppermint oil, piperine, propiverine, propofol, ranolazine, remdesivir,|
03080|074|D|resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir,|
03080|075|D|sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan,|
03080|076|D|trofinetide, vonoprazan, and ziftomenib.(3,4)|
03080|077|B||
03080|078|R|REFERENCES:|
03080|079|B||
03080|080|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
03080|081|R|  August, 2018.|1
03080|082|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03080|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03080|084|R|  settings: a scientific statement from the American Heart Association and|6
03080|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03080|086|R|  2;55(9):934-47.|6
03080|087|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03080|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03080|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03080|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03080|091|R|  11/14/2017.|1
03080|092|R|4.This information is based on an extract from the Certara Drug Interaction|6
03080|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03081|001|T|MONOGRAPH TITLE:  Tranexamic Acid (Injectable)/Estrogenic Agents|
03081|002|B||
03081|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03081|004|L|of severe adverse interaction.|
03081|005|B||
03081|006|A|MECHANISM OF ACTION:  Tranexamic acid is an antifibrinolytic and|
03081|007|A|estrogen-containing hormonal contraceptives are known to increase the risk|
03081|008|A|of venous thromboembolism and arterial thromboses, including stroke and|
03081|009|A|myocardial infarction.  Concurrent use may increase the risk of these|
03081|010|A|events.(1,2)|
03081|011|B||
03081|012|E|CLINICAL EFFECTS:  Concurrent use of tranexamic acid in patients taking|
03081|013|E|estrogen-containing agents or hormonal contraceptives may increase the risk|
03081|014|E|of embolisms.(1,2)|
03081|015|B||
03081|016|P|PREDISPOSING FACTORS:  The risk of thrombosis may be even greater in women|
03081|017|P|who are obese or smoke, especially smokers over age 35.(1)|
03081|018|B||
03081|019|M|PATIENT MANAGEMENT:  The concurrent use of injectable tranexamic and and|
03081|020|M|estrogen-containing hormonal contraception or estrogen replacement therapy|
03081|021|M|should be approached with caution.(1)|
03081|022|B||
03081|023|D|DISCUSSION:  There are no clinical trial data on the risk of concurrent|
03081|024|D|therapy with tranexamic acid and hormonal contraceptives.  There have been|
03081|025|D|postmarketing reports of venous and arterial thrombotic events in women|
03081|026|D|receiving combination therapy with oral tranexamic acid.(2)|
03081|027|D|   Women taking hormonal contraception were excluded from safety and|
03081|028|D|efficacy trials of oral tranexamic acid.(2)|
03081|029|B||
03081|030|R|REFERENCES:|
03081|031|B||
03081|032|R|1.Cyklokapron (tranexamic acid) UK summary of product characteristics.|1
03081|033|R|  Pfizer Limited March, 2016.|1
03081|034|R|2.Lysteda (tranexamic acid) US prescribing information. Ferring|1
03081|035|R|  Pharmaceuticals, Inc. October, 2013.|1
03082|001|T|MONOGRAPH TITLE:  Anticholinesterases/Beta-Blockers|
03082|002|B||
03082|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03082|004|L|take action as needed.|
03082|005|B||
03082|006|A|MECHANISM OF ACTION:  Anticholinesterases inhibit plasma cholinesterases and|
03082|007|A|increase cholinergic activity.  Use of anticholinesterases may have|
03082|008|A|vagotonic effects on heart rate (e.g. bradycardia).  Concurrent use of|
03082|009|A|anticholinesterases and beta-blockers may have additive effects on|
03082|010|A|bradycardia.(1)|
03082|011|B||
03082|012|E|CLINICAL EFFECTS:  Concurrent use of anticholinesterases and beta-blockers|
03082|013|E|may have additive effects on bradycardia.(1)|
03082|014|B||
03082|015|P|PREDISPOSING FACTORS:  None determined.|
03082|016|B||
03082|017|M|PATIENT MANAGEMENT:  Concurrent use of anticholinesterases and beta-blockers|
03082|018|M|is not recommended.  Additive effects may be increased with cardioselective|
03082|019|M|beta-blockers (e.g. atenolol).  Monitor patients closely if concurrent use|
03082|020|M|is warranted.(1)|
03082|021|B||
03082|022|D|DISCUSSION:  Concurrent use of anticholinesterases and beta-blockers may|
03082|023|D|have additive effects on cardiac conduction and increase the risk of|
03082|024|D|bradycardia.(1)|
03082|025|D|   A case report of a 65 year old African American female had a witnessed a|
03082|026|D|presyncopal episode followed by a true syncopal episode with concurrent use|
03082|027|D|of rivastigmine and atenolol.  On day 2 of the hospital stay, the patient|
03082|028|D|developed bradycardia with a heart rate in the 40s and sinus pauses greater|
03082|029|D|than 2 seconds.  Atenolol was discontinued yet bradycardia persisted.|
03082|030|D|Following discontinuation of rivastigmine, sinus pauses resolved and heart|
03082|031|D|rate returned to normal.(2)|
03082|032|D|   A population-based cohort study in Ontario, Canada reviewed the|
03082|033|D|relationship between cholinesterase inhibitor use and syncope-related|
03082|034|D|outcomes over a two year period.  Hospital visits for syncope were more|
03082|035|D|frequent in patients receiving cholinesterase inhibitors than controls (31.5|
03082|036|D|vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95%|
03082|037|D|confidence interval (CI) 1.57-1.98).  Other syncope-related events were also|
03082|038|D|more common in patients receiving cholinesterase inhibitors than controls:|
03082|039|D|hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR|
03082|040|D|1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events|
03082|041|D|per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs|
03082|042|D|19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(3)|
03082|043|D|   A population based case-time-control study of 1,009 patients hospitalized|
03082|044|D|for bradycardia within 9 months of using a cholinesterase inhibitor were|
03082|045|D|reviewed for outcomes.  Of these patients, 11% required pacemaker insertion|
03082|046|D|during hospitalization and 4% died prior to discharge.  With adjustment for|
03082|047|D|temporal changes in drug utilization, hospitalization for bradycardia was|
03082|048|D|associated with recent initiation of a cholinesterase inhibitor drug|
03082|049|D|(adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51).  Risk was similar in|
03082|050|D|patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI|
03082|051|D|1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR|
03082|052|D|2.34; 95% CI 1.16-4.71).(4)|
03082|053|B||
03082|054|R|REFERENCES:|
03082|055|B||
03082|056|R|1.Exelon (rivastigmine tartrate) US prescribing information. Novartis|1
03082|057|R|  Pharmaceuticals Corporation December, 2018.|1
03082|058|R|2.Paulison B, Leos CL. Potential cardiotoxic reaction involving rivastigmine|3
03082|059|R|  and beta-blockers: a case report and review of the literature. Cardiovasc|3
03082|060|R|  Toxicol 2010 Dec;10(4):306-10.|3
03082|061|R|3.Gill SS, Anderson GM, Fischer HD, Bell CM, Li P, Normand SL, Rochon PA.|2
03082|062|R|  Syncope and its consequences in patients with dementia receiving|2
03082|063|R|  cholinesterase inhibitors: a population-based cohort study. Arch Intern|2
03082|064|R|  Med 2009 May 11;169(9):867-73.|2
03082|065|R|4.Park-Wyllie LY, Mamdani MM, Li P, Gill SS, Laupacis A, Juurlink DN.|2
03082|066|R|  Cholinesterase inhibitors and hospitalization for bradycardia: a|2
03082|067|R|  population-based study. PLoS Med 2009 Sep;6(9):e1000157.|2
03083|001|T|MONOGRAPH TITLE:  Selected Nephrotoxic Agents/Inotersen|
03083|002|B||
03083|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03083|004|L|of severe adverse interaction.|
03083|005|B||
03083|006|A|MECHANISM OF ACTION:  Inotersen can cause glomerulonephritis and renal|
03083|007|A|toxicity.  Concurrent administration of other nephrotoxic agents may result|
03083|008|A|in additive or synergistic effects on renal function.(1)|
03083|009|B||
03083|010|E|CLINICAL EFFECTS:  Concurrent use of inotersen with nephrotoxic agents such|
03083|011|E|as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B,|
03083|012|E|cyclosporine, methotrexate, non-steroidal anti-inflammatory agents,|
03083|013|E|intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin|
03083|014|E|may result in renal toxicity.(1)  Other nephrotoxic agents include|
03083|015|E|capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and|
03083|016|E|streptozocin.|
03083|017|B||
03083|018|P|PREDISPOSING FACTORS:  Patients with pre-existing renal impairment.|
03083|019|B||
03083|020|M|PATIENT MANAGEMENT:  The US manufacturer of inotersen state that caution|
03083|021|M|should be used when administered concurrently with potentially nephrotoxic|
03083|022|M|agents or agents that impair renal function.(1)|
03083|023|M|   If concurrent therapy is warranted, monitor renal function closely.(1)|
03083|024|B||
03083|025|D|DISCUSSION:  The safety of inotersen has not been studied in patients|
03083|026|D|receiving other known potentially nephrotoxic agents. Inotersen is only|
03083|027|D|available through a Tegsedi REMS program because of the risk of|
03083|028|D|glomerulonephritis and severe thrombocytopenia.(1)|
03083|029|B||
03083|030|R|REFERENCE:|
03083|031|B||
03083|032|R|1.Tegsedi (inotersen) US prescribing information. Ionis Pharmaceuticals,|1
03083|033|R|  Inc. October 2018.|1
03084|001|T|MONOGRAPH TITLE:  Inotersen/Anticoagulants; Antiplatelets|
03084|002|B||
03084|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03084|004|L|of severe adverse interaction.|
03084|005|B||
03084|006|A|MECHANISM OF ACTION:  Inotersen causes reductions in platelet count that may|
03084|007|A|result in sudden and unpredictable thrombocytopenia.(1)|
03084|008|B||
03084|009|E|CLINICAL EFFECTS:  Concurrent use of inotersen with anticoagulants and/or|
03084|010|E|antiplatelet agents may result in additive or synergistic effects, including|
03084|011|E|fatal and non-fatal intracranial hemorrhage.(1)|
03084|012|B||
03084|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may also be greater in|
03084|014|P|patients greater than 60 years or have a prior history of major bleeding|
03084|015|P|events.|
03084|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
03084|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03084|018|P|risk for bleeding (e.g. NSAIDs).|
03084|019|B||
03084|020|M|PATIENT MANAGEMENT:  Inotersen should be administered with caution in|
03084|021|M|patients receiving anticoagulants and/or antiplatelet agents.(1)|
03084|022|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03084|023|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03084|024|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03084|025|M|patients with any symptoms.|
03084|026|M|   Monitor platelet count frequently. If platelet count is less than 50,|
03084|027|M|stop inotersen treatment and consider discontinuation of any anticoagulant|
03084|028|M|and/or antiplatelet agents.|
03084|029|M|   Monitor for signs and symptoms of thrombocytopenia; such as, unusual or|
03084|030|M|prolonged bleeding (petechiae, easy bruising, hematoma, subconjunctival|
03084|031|M|bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier|
03084|032|M|than normal menstrual bleeding, hematemesis, hematuria, hematochezia,|
03084|033|M|melena), neck stiffness, or atypical severe headache.|
03084|034|B||
03084|035|D|DISCUSSION:  In a clinical study, platelet counts below 100 occurred in 25%|
03084|036|D|of inotersen-treated patients, compared with 2% of patients on placebo.|
03084|037|D|Platelet counts below 75 occurred in 14% of inotersen-treated patients,|
03084|038|D|compared to no patients on placebo. In study 1 and its extension study, 39%|
03084|039|D|of inotersen-treated patients with a baseline platelet count below 200 had a|
03084|040|D|nadir platelet count below 75, compared to 6% of patients with baseline|
03084|041|D|platelet counts 200 or higher. Three inotersen-treated patients (3%) had|
03084|042|D|sudden severe thrombocytopenia (platelet count below 25). One patient|
03084|043|D|experienced a fatal intracranial hemorrhage.(1)|
03084|044|D|   Inotersen is only available through a Tegsedi REMS program because of the|
03084|045|D|risk of severe thrombocytopenia and the risk of glomerulonephritis.(1)|
03084|046|B||
03084|047|R|REFERENCE:|
03084|048|B||
03084|049|R|1.Tegsedi (inotersen) US prescribing information. Ionis Pharmaceuticals,|1
03084|050|R|  Inc. October 2018.|1
03085|001|T|MONOGRAPH TITLE:  Inotersen/Non-Steroidal Anti-Inflammatory Drugs|
03085|002|B||
03085|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03085|004|L|of severe adverse interaction.|
03085|005|B||
03085|006|A|MECHANISM OF ACTION:  Inotersen causes reductions in platelet count that may|
03085|007|A|result in sudden and unpredictable thrombocytopenia. Inotersen can also|
03085|008|A|cause glomerulonephritis and renal toxicity. NSAIDs can impair|
03085|009|A|thromboxane-dependent platelet aggregation by blocking the formation of|
03085|010|A|thromboxane A2. Concurrent administration with NSAIDs may also result in|
03085|011|A|additive or synergistic effects on renal function.(1)|
03085|012|B||
03085|013|E|CLINICAL EFFECTS:  Concurrent use of inotersen with NSAIDs may result in|
03085|014|E|additive or synergistic effects, including fatal and non-fatal intracranial|
03085|015|E|hemorrhage, or renal toxicity.(1)|
03085|016|B||
03085|017|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may also be greater in|
03085|018|P|patients greater than 60 years or have a prior history of major bleeding|
03085|019|P|events.|
03085|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
03085|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03085|022|P|risk for bleeding.|
03085|023|P|   Patients with pre-existing renal impairment.|
03085|024|B||
03085|025|M|PATIENT MANAGEMENT:  Inotersen should be administered with caution in|
03085|026|M|patients receiving NSAIDs.|
03085|027|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03085|028|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03085|029|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03085|030|M|patients with any symptoms.|
03085|031|M|   Monitor platelet count frequently. If platelet count is less than 50,|
03085|032|M|stop inotersen treatment and consider discontinuation of NSAID.|
03085|033|M|   Monitor for signs and symptoms of thrombocytopenia; such as, unusual or|
03085|034|M|prolonged bleeding (petechiae, easy bruising, hematoma, subconjunctival|
03085|035|M|bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier|
03085|036|M|than normal menstrual bleeding, hematemesis, hematuria, hematochezia,|
03085|037|M|melena), neck stiffness, or atypical severe headache.|
03085|038|M|   Monitor renal function closely.|
03085|039|B||
03085|040|D|DISCUSSION:  In a clinical study, platelet counts below 100 occurred in 25%|
03085|041|D|of inotersen-treated patients, compared with 2% of patients on placebo.|
03085|042|D|Platelet counts below 75 occurred in 14% of inotersen-treated patients,|
03085|043|D|compared to no patients on placebo. In study 1 and its extension study, 39%|
03085|044|D|of inotersen-treated patients with a baseline platelet count below 200 had a|
03085|045|D|nadir platelet count below 75, compared to 6% of patients with baseline|
03085|046|D|platelet counts 200 or higher. Three inotersen-treated patients (3%) had|
03085|047|D|sudden severe thrombocytopenia (platelet count below 25). One patient|
03085|048|D|experienced a fatal intracranial hemorrhage.(1)|
03085|049|D|   The safety of inotersen has not been studied in patients receiving other|
03085|050|D|known potentially nephrotoxic agents.(1)|
03085|051|D|   Inotersen is only available through a Tegsedi REMS program because of the|
03085|052|D|risk of severe thrombocytopenia and the risk of glomerulonephritis.(1)|
03085|053|B||
03085|054|R|REFERENCE:|
03085|055|B||
03085|056|R|1.Tegsedi (inotersen) US prescribing information. Ionis Pharmaceuticals,|1
03085|057|R|  Inc. October 2018.|1
03086|001|T|MONOGRAPH TITLE:  Talazoparib/Selected P-glycoprotein (P-gp) Inhibitors|
03086|002|B||
03086|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03086|004|L|of severe adverse interaction.|
03086|005|B||
03086|006|A|MECHANISM OF ACTION:  Amiodarone, carvedilol, clarithromycin, itraconazole,|
03086|007|A|and verapamil (inhibitors of P-glycoprotein) may increase the absorption of|
03086|008|A|talazoparib.(1)|
03086|009|B||
03086|010|E|CLINICAL EFFECTS:  The concurrent administration of talazoparib with certain|
03086|011|E|inhibitors of P-glycoprotein may result in elevated levels of talazoparib|
03086|012|E|and signs of toxicity.(1)|
03086|013|B||
03086|014|P|PREDISPOSING FACTORS:  None determined.|
03086|015|B||
03086|016|M|PATIENT MANAGEMENT:  The management of this drug interaction is|
03086|017|M|indication-specific.|
03086|018|M|   For the treatment of breast cancer, coadministration of talazoparib with|
03086|019|M|the P-gp inhibitors amiodarone, carvedilol, clarithromycin, itraconazole,|
03086|020|M|and verapamil should be avoided.  If coadministration cannot be avoided, the|
03086|021|M|dose of talazoparib should be reduced to 0.75 mg once daily when|
03086|022|M|coadministered.(1)|
03086|023|M|   When the P-gp inhibitor is discontinued, increase the talazoparib dose|
03086|024|M|(after 3-5 half-lives of the P-gp inhibitor) to the dose used prior to|
03086|025|M|initiation of the P-gp inhibitor.(1)|
03086|026|M|   For the treatment of metastatic castration-resistant prostate cancer,|
03086|027|M|monitor patients for increased adverse reactions and adjust talazoparib dose|
03086|028|M|as recommended in the prescribing information for adverse reactions.(1)|
03086|029|B||
03086|030|D|DISCUSSION:  In patients with advanced solid tumors, coadministration of a|
03086|031|D|single 0.5 mg dose of talazoparib with itraconazole increased talazoparib|
03086|032|D|AUC and Cmax by 56% and 40%, respectively.(1)|
03086|033|D|   In clinical studies, coadministration of talazoparib with amiodarone,|
03086|034|D|carvedilol, clarithromycin, itraconazole, or verapamil resulted in an|
03086|035|D|approximately 45% increase in talazoparib exposure and an increase in the|
03086|036|D|rate of talazoparib dose reduction.(1)|
03086|037|D|   P-gp inhibitors linked to this monograph include amiodarone, carvedilol,|
03086|038|D|clarithromycin, itraconazole, and verapamil.|
03086|039|B||
03086|040|R|REFERENCES:|
03086|041|B||
03086|042|R|1.Talzenna (talazoparib) US prescribing information. Pfizer Labs June, 2023.|1
03086|043|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03086|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03086|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03086|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03086|047|R|  11/14/2017.|1
03087|001|T|MONOGRAPH TITLE:  Talazoparib/Selected Oral Inhibitors of BCRP (mono deleted|
03087|002|T|06/22/2023)|
03087|003|B||
03087|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03087|005|L|of severe adverse interaction.|
03087|006|B||
03087|007|A|MECHANISM OF ACTION:  Inhibitors of BCRP may increase the absorption of|
03087|008|A|talazoparib.(1)|
03087|009|B||
03087|010|E|CLINICAL EFFECTS:  The concurrent administration of talazoparib with an|
03087|011|E|inhibitor of BCRP may result in elevated levels of talazoparib and signs of|
03087|012|E|toxicity.(1)|
03087|013|B||
03087|014|P|PREDISPOSING FACTORS:  None determined.|
03087|015|B||
03087|016|M|PATIENT MANAGEMENT:  The US manufacturer of talazoparib states concurrent|
03087|017|M|use of BCRP inhibitors should be avoided during talazoparib treatment.(1)|
03087|018|M|   Selection of an alternative concurrent medication with no or minimal|
03087|019|M|transporter inhibiting proprieties should be considered. Careful patient|
03087|020|M|monitoring is recommended.(1)|
03087|021|M|   Monitor for signs of hematologic toxicity.|
03087|022|B||
03087|023|D|DISCUSSION:  Talazoparib is a substrate of BCRP.  Inhibitors of this|
03087|024|D|transporter are expected to increase talazoparib levels.(1)|
03087|025|D|   BCRP inhibitors linked to this monograph include:  capmatinib,|
03087|026|D|darolutamide, diclofenac, glyburide, grazoprevir, imatinib, irinotecan,|
03087|027|D|lapatinib, methotrexate, mitoxantrone, oteseconazole, pitavastatin,|
03087|028|D|pravastatin, rosuvastatin, roxadustat, sulfasalazine, tafamidis, and|
03087|029|D|topotecan.(1,2)|
03087|030|B||
03087|031|R|REFERENCES:|
03087|032|B||
03087|033|R|1.Talzenna (talazoparib) US prescribing information. Pfizer Labs June, 2023.|1
03087|034|R|2.Vyndamax (tafamidis) US prescribing information. Pfizer, Inc. June, 2021.|1
03088|001|T|MONOGRAPH TITLE:  Segesterone-Ethinyl Estradiol (Annovera)/Oil-Based Vaginal|
03088|002|T|Products|
03088|003|B||
03088|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03088|005|L|of severe adverse interaction.|
03088|006|B||
03088|007|A|MECHANISM OF ACTION:  The use of Annovera (segesterone-ethinyl estradiol|
03088|008|A|vaginal ring) with oil-based vaginal products may alter the vaginal system|
03088|009|A|resulting in increased concentrations of ethinyl estradiol and segesterone|
03088|010|A|because of increased rate of release of segesterone-ethinyl estradiol from|
03088|011|A|the ring. This may lead to contraceptive failure.(1)|
03088|012|B||
03088|013|E|CLINICAL EFFECTS:  Concurrent use of Annovera (segesterone-ethinyl|
03088|014|E|estradiol) with oil-based vaginal products may lead to decreased|
03088|015|E|effectiveness of contraceptive, producing breakthrough bleeding and|
03088|016|E|unintended pregnancy.|
03088|017|B||
03088|018|P|PREDISPOSING FACTORS:  None determined.|
03088|019|B||
03088|020|M|PATIENT MANAGEMENT:  Concurrent use of Annovera (segesterone-ethinyl|
03088|021|M|estradiol) with oil-based vaginal products should be avoided.(1)|
03088|022|B||
03088|023|D|DISCUSSION:  In a study in 29 females, the concurrent use of Annovera with|
03088|024|D|three different formulations of vaginal miconazole were compared. A|
03088|025|D|single-dose vaginal administration of miconazole vaginal suppository (1200|
03088|026|D|mg) on Day 8 of Annovera use increased the area-under-the-curve Day8-21|
03088|027|D|(AUCDay8-21) of ethinyl estradiol by approximately 67%. Administration of a|
03088|028|D|miconazole vaginal suppository (1200 mg) on Day 8 of Annovera use increased|
03088|029|D|the AUCDay8-9, AUCDay8-10, and AUCDay8-21 of ethinyl estradiol by|
03088|030|D|approximately 30%, 32%, and 19%. Administration of a miconazole vaginal|
03088|031|D|suppository (200 mg) on Day 8, Day 9, and Day 10 of Annovera use increased|
03088|032|D|the ethinyl estradiol AUCDay8-11 and AUCDay8-21 by 9% and 21%.|
03088|033|D|Administration of a miconazole vaginal suppository (200 mg) on Day 8, Day 9,|
03088|034|D|and Day 10 of Annovera use increased the segesterone AUCDay8-11 and|
03088|035|D|AUCDay8-21 by 28% and 27%. Water-based miconazole cream had no effect on|
03088|036|D|Annovera. (1)|
03088|037|B||
03088|038|R|REFERENCE:|
03088|039|B||
03088|040|R|1.Annovera (segesterone-ethinyl estradiol vaginal ring) US prescribing|1
03088|041|R|  information. Population Council August, 2018.|1
03089|001|T|MONOGRAPH TITLE:  Baloxavir/Polyvalent Cations|
03089|002|B||
03089|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03089|004|L|take action as needed.|
03089|005|B||
03089|006|A|MECHANISM OF ACTION:  Aluminum, calcium, iron, magnesium, selenium, and zinc|
03089|007|A|may form chelation compounds with baloxavir.(1)|
03089|008|B||
03089|009|E|CLINICAL EFFECTS:  Simultaneous administration of products containing|
03089|010|E|aluminum, calcium, iron, magnesium, selenium, and zinc may result in|
03089|011|E|decreased levels of and clinical effects from baloxavir.(1)|
03089|012|B||
03089|013|P|PREDISPOSING FACTORS:  None determined.|
03089|014|B||
03089|015|M|PATIENT MANAGEMENT:  Avoid concurrent administration of baloxavir with|
03089|016|M|cation-containing products.(1)|
03089|017|B||
03089|018|D|DISCUSSION:  A significant decrease in baloxavir exposure was observed when|
03089|019|D|baloxavir was coadministered with calcium, aluminum, magnesium, or iron in|
03089|020|D|monkeys. No studies have been conducted in humans.(1)|
03089|021|B||
03089|022|R|REFERENCE:|
03089|023|B||
03089|024|R|1.Xofluza (baloxavir) US prescribing information. Genentech USA, Inc.|1
03089|025|R|  November, 2020.|1
03090|001|T|MONOGRAPH TITLE:  Slt Anticoagulants (Vit K Antagonists)/Topical Salicylates|
03090|002|B||
03090|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03090|004|L|of severe adverse interaction.|
03090|005|B||
03090|006|A|MECHANISM OF ACTION:  Multiple processes are involved:  1) Salicylate doses|
03090|007|A|greater than 3 gm daily decrease plasma prothrombin levels. 2) Salicylates|
03090|008|A|may also displace anticoagulants from plasma protein binding sites. 3)|
03090|009|A|Aspirin is an irreversible platelet inhibitor. Salicylates impair platelet|
03090|010|A|function, resulting in prolonged bleeding time. 4) Salicylates may cause|
03090|011|A|gastrointestinal(GI) bleeding due to irritation.|
03090|012|B||
03090|013|E|CLINICAL EFFECTS:  The concurrent use of anticoagulants and salicylates|
03090|014|E|leads to blockade of two distinct coagulation pathways and may increase the|
03090|015|E|risk for bleeding.|
03090|016|B||
03090|017|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03090|018|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03090|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
03090|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03090|021|P|risk for bleeding (e.g. NSAIDs).|
03090|022|B||
03090|023|M|PATIENT MANAGEMENT:  Avoid concomitant administration of these drugs.  When|
03090|024|M|aspirin is required for cardioprotection, a low dose (< 100 mg daily) is|
03090|025|M|recommended to decrease the risk for aspirin-induced GI bleeding.|
03090|026|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03090|027|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03090|028|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03090|029|M|patients with any symptoms.|
03090|030|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03090|031|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03090|032|M|anticoagulation in patients with active pathologic bleeding.|
03090|033|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03090|034|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03090|035|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03090|036|M|and/or swelling.|
03090|037|B||
03090|038|D|DISCUSSION:  Topical use of methyl salicylate has been reported to increase|
03090|039|D|the effects of warfarin.(1-7)  In a case series on 11 patients who used|
03090|040|D|significant amounts of methyl salicylate (2-4 g of ointment for previous 2|
03090|041|D|weeks), all had significant increases in INR and positive blood levels of|
03090|042|D|salicylates.  Two patients experienced diffuse bruising and one experienced|
03090|043|D|gastrointestinal bleeding.(1)|
03090|044|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
03090|045|D|pairs were reviewed and found 14% of drug pairs were associated with a|
03090|046|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
03090|047|D|of warfarin and diflunisal resulted in a ratio of rate ratios (RR) (95% CI)|
03090|048|D|of 3.85 (1.34-11.03); and warfarin and aspirin ratio of RR 2.13 (1.72-2.64).|
03090|049|B||
03090|050|R|REFERENCES:|
03090|051|B||
03090|052|R|1.Yip AS, Chow WH, Tai YT, Cheung KL. Adverse effect of topical|3
03090|053|R|  methylsalicylate ointment on warfarin anticoagulation:  an unrecognized|3
03090|054|R|  potential hazard. Postgrad Med J 1990 May;66(775):367-9.|3
03090|055|R|2.Chow WH, Cheung KL, Ling HM, See T. Potentiation of warfarin|3
03090|056|R|  anticoagulation by topical methylsalicylate ointment. J R Soc Med 1989|3
03090|057|R|  Aug;82(8):501-2.|3
03090|058|R|3.Joss JD, LeBlond RF. Potentiation of warfarin anticoagulation associated|3
03090|059|R|  with topical methyl salicylate. Ann Pharmacother 2000 Jun;34(6):729-33.|3
03090|060|R|4.Chan TY. Potential dangers from topical preparations containing methyl|3
03090|061|R|  salicylate. Hum Exp Toxicol 1996 Sep;15(9):747-50.|3
03090|062|R|5.Ramanathan M. Warfarin--topical salicylate interactions: case reports. Med|3
03090|063|R|  J Malaysia 1995 Sep;50(3):278-9.|3
03090|064|R|6.Tam LS, Chan TY, Leung WK, Critchley JA. Warfarin interactions with|3
03090|065|R|  Chinese traditional medicines: danshen and methyl salicylate medicated|3
03090|066|R|  oil. Aust N Z J Med 1995 Jun;25(3):258.|3
03090|067|R|7.Littleton F Jr. Warfarin and topical salicylates. JAMA 1990 Jun 6;|3
03090|068|R|  263(21):2888.|3
03090|069|R|8.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
03090|070|R|  Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
03090|071|R|  Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
03090|072|R|  Pharmacol Ther 2020 Aug;108(2):377-386.|2
03091|001|T|MONOGRAPH TITLE:  Lovastatin; Pravastatin/Gemfibrozil|
03091|002|B||
03091|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03091|004|L|is contraindicated and generally should not be dispensed or administered to|
03091|005|L|the same patient.|
03091|006|B||
03091|007|A|MECHANISM OF ACTION:  Unknown.|
03091|008|B||
03091|009|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
03091|010|E|and fibric acid derivatives has been associated with severe myopathy,|
03091|011|E|rhabdomyolysis and acute renal failure.|
03091|012|B||
03091|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03091|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03091|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03091|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03091|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03091|018|P|transporter OATP1B1 may have increased statin concentrations and be|
03091|019|P|predisposed to myopathy or rhabdomyolysis.|
03091|020|B||
03091|021|M|PATIENT MANAGEMENT:  According to 2013 ACC/AHA Blood Cholesterol Guidelines,|
03091|022|M|gemfibrozil should not be initiated in patients on statin therapy.|
03091|023|M|Fenofibrate may be considered with low or moderate intensity statin therapy|
03091|024|M|only if benefits outweigh the risks.|
03091|025|M|   According to 2016 AHA guidelines on the management of drug-drug|
03091|026|M|interactions with statins, concurrent use of gemfibrozil with lovastatin,|
03091|027|M|pravastatin, or simvastatin should be avoided and concurrent use with|
03091|028|M|atorvastatin, pitavastatin, or rosuvastatin may be considered if fenofibrate|
03091|029|M|or fenofibric acid is not an option.  Concurrent therapy with atorvastatin|
03091|030|M|should be initiated at 10 mg daily and increased to 20 mg daily if tolerated|
03091|031|M|and necessary.  Concurrent therapy with pitavastatin should be initiated at|
03091|032|M|1 mg daily and increased to 2 mg daily if tolerated and necessary.|
03091|033|M|Concurrent therapy with rosuvastatin should be initiated at 5 mg daily and|
03091|034|M|increased to 10 mg daily if tolerated and necessary.|
03091|035|M|   The US, Australian, Canadian, and UK manufacturers of gemfibrozil state|
03091|036|M|that use with HMG CO-A reductase inhibitors does not outweigh the risks of|
03091|037|M|severe myopathy, rhabdomyolysis, and acute renal failure.  The US and UK|
03091|038|M|manufacturers of gemfibrozil state that concurrent use of simvastatin is|
03091|039|M|contraindicated.  The Canadian manufacturer of gemfibrozil states that HMG|
03091|040|M|CO-A reductase inhibitors should not be used concurrently.|
03091|041|M|   The US and Canadian manufacturers of lovastatin state concurrent use of|
03091|042|M|gemfibrozil should be avoided.|
03091|043|M|   The US, Canadian, and UK manufacturers of pravastatin state that|
03091|044|M|concurrent use of gemfibrozil should be avoided.|
03091|045|M|   Instruct patients receiving concurrent therapy to report any unexplained|
03091|046|M|muscle pain, tenderness or weakness.  If muscular symptoms develop, monitor|
03091|047|M|serum creatine kinase levels and renal function.  One or both agents may|
03091|048|M|need to be discontinued.|
03091|049|B||
03091|050|D|DISCUSSION:  Gemfibrozil has been shown to increase levels of cerivastatin,|
03091|051|D|lovastatin, pravastatin, rosuvastatin, and simvastatin.  Administration of|
03091|052|D|gemfibrozil with cerivastatin, lovastatin, and simvastatin has been|
03091|053|D|associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and|
03091|054|D|weakness).  Although the reaction has been reported with the statins alone,|
03091|055|D|the incidence increases dramatically with concurrent administration of|
03091|056|D|gemfibrozil.|
03091|057|D|   Concurrent fenofibrate (145 mg) with atorvastatin (20 mg) decreased the|
03091|058|D|atorvastatin area-under-curve (AUC) by 17% (range from 67% decrease to 44%|
03091|059|D|increase).  Atorvastatin maximum concentration (Cmax) and the kinetics of|
03091|060|D|fenofibrate were not significantly affected.|
03091|061|D|   Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of|
03091|062|D|pitavastatin (4 mg daily) by 18% and 11%, respectively.|
03091|063|D|   Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of|
03091|064|D|pitavastatin (4 mg daily) by 45% and 31%, respectively.|
03091|065|D|   Concurrent fenofibrate (145 mg) with pravastatin (40 mg) increased|
03091|066|D|pravastatin Cmax and AUC by 36% (range from 69% decrease to 321% increase)|
03091|067|D|and 28% (range from 54% decrease to 128% increase), respectively, and the|
03091|068|D|3-alpha-hydroxy-iso-pravastatin Cmax and AUC by 55% (range from 32% decrease|
03091|069|D|to 314% increase) and by 39% (range from 24% decrease to 261% increase),|
03091|070|D|respectively.  A single dose of pravastatin had no effect on the kinetics of|
03091|071|D|fenofibrate.|
03091|072|D|   Concurrent fenofibrate and rosuvastatin resulted in no significant|
03091|073|D|changes in rosuvastatin or fenofibrate levels.|
03091|074|D|   Concurrent gemfibrozil 600 mg twice daily for 3 days, followed by|
03091|075|D|lovastatin 40 mg increased the AUC of the active metabolite of lovastatin|
03091|076|D|2.8 fold.|
03091|077|D|   Concurrent gemfibrozil (600 mg twice daily) and rosuvastatin (80 mg)|
03091|078|D|increased the rosuvastatin AUC and Cmax by 90% and 120%, respectively.  In|
03091|079|D|healthy subjects, gemfibrozil increased the Cmax and AUC of a single dose of|
03091|080|D|rosuvastatin by 2.2-fold and 1.9-fold, respectively.|
03091|081|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
03091|082|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
03091|083|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
03091|084|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
03091|085|D|Veteran's Administration over a 2 year period, there were 149 reports of|
03091|086|D|rhabdomyolysis in 93,677 (0.16%) patients receiving concurrent gemfibrozil|
03091|087|D|and statin therapy compared with no reports in 1,830 patients receiving|
03091|088|D|concurrent fenofibrate and statin therapy.|
03091|089|D|   In a retrospective cohort study of 252,460 patients, concurrent use of|
03091|090|D|statins and fibrates increased the risk of rhabdomyolysis, especially in|
03091|091|D|patients with diabetes mellitus.  The risk of hospitalization for patients|
03091|092|D|aged 65 or older with diabetes mellitus, treated with a statin and fibrate,|
03091|093|D|increased 48-fold compared to statin monotherapy.|
03091|094|D|   In a retrospective study, of 468 patients with a diagnosis of myopathy,|
03091|095|D|61 received a statin prior to their diagnosis. Forty-one of these patients|
03091|096|D|developed confirmed myopathy, creatinine kinase more than or equal to 1000|
03091|097|D|IU/L.|
03091|098|B||
03091|099|R|REFERENCES:|
03091|100|B||
03091|101|R|1.Stone NJ, Robinson JG, Lichtenstein AH, Goff DC Jr, Lloyd-Jones DM, Smith|6
03091|102|R|  SC Jr, Blum C, Schwartz JS. Treatment of blood cholesterol to reduce|6
03091|103|R|  atherosclerotic cardiovascular disease risk in adults: synopsis of the|6
03091|104|R|  2013 American College of Cardiology/American Heart Association cholesterol|6
03091|105|R|  guideline. Ann Intern Med 2014 Mar 4;160(5):339-43.|6
03091|106|R|2.Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis JB, Lanfear|6
03091|107|R|  D, Virani S, Morris PB. Recommendations for Management of Clinically|6
03091|108|R|  Significant Drug-Drug Interactions With Statins and Select Agents Used in|6
03091|109|R|  Patients With Cardiovascular Disease: A Scientific Statement From the|6
03091|110|R|  American Heart Association. Circulation 2016 Nov 22;134(21):e468-e495.|6
03091|111|R|3.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
03091|112|R|  Ltd. December, 2020.|1
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03091|114|R|  Ltd December 5, 2011.|1
03091|115|R|5.Teva-Gemfibrozil (gemfibrozil) Canadian product monograph. Teva Canada|1
03091|116|R|  Limited June 29, 2015.|1
03091|117|R|6.Lopid (gemfibrozil) UK summary of product characteristics. Pfizer Limited|1
03091|118|R|  May, 2016.|1
03091|119|R|7.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
03091|120|R|  February, 2014.|1
03091|121|R|8.ACT-Lovastatin (lovastatin) Canadian product monograph. Actavis Pharma|1
03091|122|R|  Company October 6, 2017.|1
03091|123|R|9.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
03091|124|R|  Squibb Company May, 2022.|1
03091|125|R|10.Pravachol (pravastatin) Australian product information. Arrow Pharma Pty|1
03091|126|R|   Ltd February 23, 2005.|1
03091|127|R|11.Pravachol (pravastatin) Canadian product monograph. Bristol-Myers Squibb|1
03091|128|R|   Canada October 18, 2017.|1
03091|129|R|12.pravastatin UK summary of product characteristics. Accord Healthcare|1
03091|130|R|   Limited September 15, 2008.|1
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03091|132|R|   adjuvant therapy for refractory familial hypercholesterolaemia. Q J Med|2
03091|133|R|   1986 Aug;60(232):803-11.|2
03091|134|R|14.East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA. Rhabdomyolysis in|3
03091|135|R|   patients receiving lovastatin after cardiac transplantation. N Engl J Med|3
03091|136|R|   1988 Jan 7;318(1):47-8.|3
03091|137|R|15.Marais GE, Larson KK. Rhabdomyolysis and acute renal failure induced by|3
03091|138|R|   combination lovastatin and gemfibrozil therapy. Ann Intern Med 1990 Feb|3
03091|139|R|   1;112(3):228-30.|3
03091|140|R|16.Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated|3
03091|141|R|   with lovastatin-gemfibrozil combination therapy. JAMA 1990 Jul 4;|3
03091|142|R|   264(1):71-5.|3
03091|143|R|17.Glueck CJ, Speirs J, Tracy T. Safety and efficacy of combined|2
03091|144|R|   gemfibrozil-lovastatin therapy for primary dyslipoproteinemias. J Lab|2
03091|145|R|   Clin Med 1990 May;115(5):603-9.|2
03091|146|R|18.Glueck CJ, Oakes N, Speirs J, Tracy T, Lang J. Gemfibrozil-lovastatin|2
03091|147|R|   therapy for primary hyperlipoproteinemias. Am J Cardiol 1992 Jul 1;|2
03091|148|R|   70(1):1-9.|2
03091|149|R|19.Wirebaugh SR, Shapiro ML, McIntyre TH, Whitney EJ. A retrospective review|2
03091|150|R|   of the use of lipid-lowering agents in combination, specifically,|2
03091|151|R|   gemfibrozil and lovastatin. Pharmacotherapy 1992;12(6):445-50.|2
03091|152|R|20.Wiklund O, Angelin B, Bergman M, Berglund L, Bondjers G, Carlsson A,|2
03091|153|R|   Linden T, Miettinen T, Odman B, Olofsson SO, et al. Pravastatin and|2
03091|154|R|   gemfibrozil alone and in combination for the treatment of|2
03091|155|R|   hypercholesterolemia. Am J Med 1993 Jan;94(1):13-20.|2
03091|156|R|21.Chucrallah A, De Girolami U, Freeman R, Federman M.|3
03091|157|R|   Lovastatin/gemfibrozil myopathy: a clinical, histochemical, and|3
03091|158|R|   ultrastructural study. Eur Neurol 1992;32(5):293-6.|3
03091|159|R|22.Knoll RW, Ciafone R, Galen M. Rhabdomyolysis and renal failure secondary|3
03091|160|R|   to combination therapy of hyperlipidemia with lovastatin and gemfibozil.|3
03091|161|R|   Conn Med 1993 Sep;57(9):593-4.|3
03091|162|R|23.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
03091|163|R|   cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
03091|164|R|   polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
03091|165|R|24.Rosenson RS. Gemfibrozil-lovastatin-associated myalgia. Am J Cardiol 1993|3
03091|166|R|   Feb 15;71(5):497.|3
03091|167|R|25.Illingworth DR, Bacon S. Influence of lovastatin plus gemfibrozil on|2
03091|168|R|   plasma lipids and lipoproteins in patients with heterozygous familial|2
03091|169|R|   hypercholesterolemia. Circulation 1989 Mar;79(3):590-6.|2
03091|170|R|26.Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly|2
03091|171|R|   increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 2002|2
03091|172|R|   Dec;72(6):685-91.|2
03091|173|R|27.Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ.|2
03091|174|R|   Plasma concentrations of active lovastatin acid are markedly increased by|2
03091|175|R|   gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 2001 May;|2
03091|176|R|   69(5):340-5.|2
03091|177|R|28.Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases|2
03091|178|R|   plasma pravastatin concentrations and reduces pravastatin renal|2
03091|179|R|   clearance. Clin Pharmacol Ther 2003 Jun;73(6):538-44.|2
03091|180|R|29.Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma|2
03091|181|R|   concentrations of active simvastatin acid are increased by gemfibrozil.|2
03091|182|R|   Clin Pharmacol Ther 2000 Aug;68(2):122-9.|2
03091|183|R|30.Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with|3
03091|184|R|   simvastatin-gemfibrozil therapy. South Med J 1997 May;90(5):546-7.|3
03091|185|R|31.McDonald KB, Garber BG, Perreault MM. Pancreatitis associated with|3
03091|186|R|   simvastatin plus fenofibrate. Ann Pharmacother 2002 Feb;36(2):275-9.|3
03091|187|R|32.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of|3
03091|188|R|   a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
03091|189|R|   2002;101(7):53-6.|3
03091|190|R|33.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
03091|191|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
03091|192|R|   at:|3
03091|193|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
03091|194|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
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03091|196|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
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03091|202|R|36.Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly|2
03091|203|R|   decreases and gemfibrozil increases the plasma concentrations of|2
03091|204|R|   atorvastatin and its metabolites. Clin Pharmacol Ther 2005 Aug;|2
03091|205|R|   78(2):154-67.|2
03091|206|R|37.Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J.|5
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03091|209|R|38.Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking|3
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03091|211|R|39.Shanahan RL, Kerzee JA, Sandhoff BG, Carroll NM, Merenich JA. Low|2
03091|212|R|   myopathy rates associated with statins as monotherapy or combination|2
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03091|215|R|40.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
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03091|221|R|42.Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and|3
03091|222|R|   acute renal failure after changing statin-fibrate combinations.|3
03091|223|R|   Cardiology 2000;94(2):127-8.|3
03092|001|T|MONOGRAPH TITLE:  Lorlatinib/Strong CYP3A4 Inducers|
03092|002|B||
03092|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03092|004|L|is contraindicated and generally should not be dispensed or administered to|
03092|005|L|the same patient.|
03092|006|B||
03092|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 are expected to increase the|
03092|008|A|metabolism of lorlatinib.(1)|
03092|009|A|   Concurrent use of lorlatinib and rifampin may result in hepatotoxicity|
03092|010|A|through activation of the pregnane X receptor (PXR) by both drugs, which are|
03092|011|A|PXR agonists.(1)|
03092|012|B||
03092|013|E|CLINICAL EFFECTS:  Concurrent or recent use of strong inducers of CYP3A4 may|
03092|014|E|result in decreased levels and effectiveness of lorlatinib. Concurrent|
03092|015|E|lorlatinib and strong CYP3A4 inducers may result in hepatotoxicity. Symptoms|
03092|016|E|may include nausea, vomiting, jaundice, dark urine, abdominal pain, and|
03092|017|E|unexplained fatigue.(1)|
03092|018|B||
03092|019|P|PREDISPOSING FACTORS:  Underlying liver disease, concurrent therapy with|
03092|020|P|agents associated with liver injury, and alcoholism may predispose patients|
03092|021|P|to liver damage.|
03092|022|P|   Induction effects may be more likely with regular use of the inducer for|
03092|023|P|longer than 1-2 weeks.|
03092|024|B||
03092|025|M|PATIENT MANAGEMENT:  Concurrent administration of strong inducers of CYP3A4|
03092|026|M|with lorlatinib is contraindicated due to the potential for serious|
03092|027|M|hepatotoxicity. Discontinue strong CYP3A4 inducers for three plasma|
03092|028|M|half-lives of the strong CYP3A inducer prior to initiation of lorlatinib.(1)|
03092|029|B||
03092|030|D|DISCUSSION:  Lorlatinib is metabolized by CYP3A4.  Strong inducers of CYP3A4|
03092|031|D|are expected to reduce lorlatinib levels, which may lead to loss of|
03092|032|D|response.(1)|
03092|033|D|   In a study in 12 healthy subjects, rifampin (600 mg daily for 8 days), a|
03092|034|D|strong inducer of CYP3A4, decreased the area-under-curve (AUC) and maximum|
03092|035|D|concentration (Cmax) of a single dose of lorlatinib (100 mg) by 85% and 76%,|
03092|036|D|respectively. Severe hepatotoxicity occurred in 10 of 12 subjects. Grade 4|
03092|037|D|alanine aminotransferase (ALT) or aspartate aminotransferase (AST)|
03092|038|D|elevations occurred in 50% of subjects, Grade 3 ALT/AST elevations occurred|
03092|039|D|in 33%, and Grade 2 ALT/AST elevations occurred in 8%.(1)|
03092|040|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
03092|041|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03092|042|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03092|043|D|rifapentine, and St. John's wort.(1)|
03092|044|B||
03092|045|R|REFERENCES:|
03092|046|B||
03092|047|R|1.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
03092|048|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03092|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03092|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03092|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03092|052|R|  11/14/2017.|1
03092|053|R|3.This information is based on an extract from the Certara Drug Interaction|6
03092|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03093|001|T|MONOGRAPH TITLE:  Lorlatinib/Moderate CYP3A4 Inducers|
03093|002|B||
03093|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03093|004|L|of severe adverse interaction.|
03093|005|B||
03093|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 are expected to increase|
03093|007|A|the metabolism of lorlatinib.(1)|
03093|008|B||
03093|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate inducers of CYP3A4|
03093|010|E|may result in decreased levels and effectiveness of lorlatinib.(1)|
03093|011|B||
03093|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03093|013|P|of the inducer for longer than 1-2 weeks.|
03093|014|B||
03093|015|M|PATIENT MANAGEMENT:  Avoid concurrent administration of moderate inducers of|
03093|016|M|CYP3A4 with lorlatinib.(1)|
03093|017|M|   If concurrent use of lorlatinib and moderate CYP3A4 inducers cannot be|
03093|018|M|avoided, increase the dose of lorlatinib to 125 mg daily.(1)|
03093|019|B||
03093|020|D|DISCUSSION:  Modafinil (a moderate CYP3A4 inducer) decreased the|
03093|021|D|area-under-curve (AUC) and maximum concentration (Cmax) of a single 100 mg|
03093|022|D|dose of lorlatinib by 23% and 22%, respectively.(1)|
03093|023|D|   Moderate inducers of CYP3A4 include belzutifan, bosentan, cenobamate,|
03093|024|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, modafinil,|
03093|025|D|nafcillin, pacritinib, pexidartinib, rifabutin, sotorasib, telotristat,|
03093|026|D|thioridazine, and tovorafenib.(1)|
03093|027|B||
03093|028|R|REFERENCES:|
03093|029|B||
03093|030|R|1.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
03093|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03093|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03093|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03093|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03093|035|R|  11/14/2017.|1
03093|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
03093|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03094|001|T|MONOGRAPH TITLE:  Lorlatinib/Strong CYP3A4 Inhibitors|
03094|002|B||
03094|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03094|004|L|of severe adverse interaction.|
03094|005|B||
03094|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03094|007|A|of lorlatinib.(1)|
03094|008|B||
03094|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03094|010|E|in elevated levels and increased effects of lorlatinib.(1)|
03094|011|B||
03094|012|P|PREDISPOSING FACTORS:  None determined.|
03094|013|B||
03094|014|M|PATIENT MANAGEMENT:  The manufacturer of lorlatinib states that use of|
03094|015|M|strong inhibitors of CYP3A4 should be avoided.  When strong CYP3A4|
03094|016|M|inhibitors are required, reduce the dose of lorlatinib to 75 mg once daily.|
03094|017|M|In patients who have had a dose reduction to 75 mg once daily due to adverse|
03094|018|M|reactions and who initiate a strong CYP3A4 inhibitor, reduce the lorlatinib|
03094|019|M|dose to 50 mg once daily.(1)|
03094|020|M|   If concurrent use of a strong CYP3A4 inhibitor is discontinued, increase|
03094|021|M|the lorlatinib dose after 3 plasma half-lives of the strong CYP3A4 inhibitor|
03094|022|M|to the dose that was used before starting the strong inhibitor.(1)|
03094|023|B||
03094|024|D|DISCUSSION:  Coadministration of itraconazole with a single oral 100 mg dose|
03094|025|D|of lorlatinib increased the area-under-curve (AUC) and  maximum|
03094|026|D|concentration (Cmax) of lorlatinib approximately 42% and 24%,|
03094|027|D|respectively.(1)|
03094|028|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir,|
03094|029|D|clarithromycin, cobicistat, indinavir, itraconazole, josamycin,|
03094|030|D|ketoconazole, levoketoconazole, lopinavir/ritonavir, mibefradil,|
03094|031|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
03094|032|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03094|033|D|tucatinib, and voriconazole.(2,3)|
03094|034|B||
03094|035|R|REFERENCES:|
03094|036|B||
03094|037|R|1.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
03094|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
03094|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03094|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03094|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03094|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03094|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03094|044|R|  11/14/2017.|1
03095|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Lorlatinib|
03095|002|B||
03095|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03095|004|L|of severe adverse interaction.|
03095|005|B||
03095|006|A|MECHANISM OF ACTION:  Lorlatinib may induce the CYP3A4 mediated metabolism|
03095|007|A|of hormonal contraceptives.(1)|
03095|008|B||
03095|009|E|CLINICAL EFFECTS:  Concurrent use of lorlatinib may reduce the effectiveness|
03095|010|E|of hormonal contraceptives.(1) Lorlatinib may cause birth defects and/or|
03095|011|E|miscarriage if used by pregnant women.|
03095|012|B||
03095|013|P|PREDISPOSING FACTORS:  None determined.|
03095|014|B||
03095|015|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
03095|016|M|rely on hormonal contraception (including oral contraceptives, patches,|
03095|017|M|implants, and/or IUDs) for contraception.  Women should use a back-up method|
03095|018|M|of birth control during lorlatinib therapy and for at least 6 months after|
03095|019|M|the final dose.  Women of reproductive potential should use effective|
03095|020|M|non-hormonal methods of contraception during lorlatinib therapy and for at|
03095|021|M|least 6 months after the final dose.(1)|
03095|022|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03095|023|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03095|024|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03095|025|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03095|026|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03095|027|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03095|028|M|and to seek medical advice if they do become pregnant.(2)|
03095|029|B||
03095|030|D|DISCUSSION:  Lorlatinib may induce the CYP3A4 mediated metabolism of|
03095|031|D|hormonal contraceptives.  Lorlatinib may decrease the effectiveness of|
03095|032|D|hormonal contraceptives, including oral contraceptives, patches, implants,|
03095|033|D|and/or IUDs.  Women should use a back-up method of birth control during|
03095|034|D|lorlatinib therapy and for at least 6 months after the final dose.(1)|
03095|035|B||
03095|036|R|REFERENCES:|
03095|037|B||
03095|038|R|1.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
03095|039|R|2.Medicines and Healthcare products Regulatory Agency.|1
03095|040|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03095|041|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03095|042|R|  available at:|1
03095|043|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03095|044|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03095|045|R|  -and-contraceptive-efficacy September 15, 2016..|1
03096|001|T|MONOGRAPH TITLE:  Tamoxifen/Strong CYP3A4 Inducers|
03096|002|B||
03096|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03096|004|L|is contraindicated and generally should not be dispensed or administered to|
03096|005|L|the same patient.|
03096|006|B||
03096|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03096|008|A|tamoxifen.(1)|
03096|009|B||
03096|010|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide, barbiturates,|
03096|011|E|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
03096|012|E|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03096|013|E|wort may result in decreased levels and effectiveness of tamoxifen.(1)|
03096|014|B||
03096|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03096|016|P|of the inducer for longer than 1-2 weeks.|
03096|017|B||
03096|018|M|PATIENT MANAGEMENT:  Strong inducers of CYP3A4 should not be used in|
03096|019|M|patients receiving tamoxifen.(1)|
03096|020|B||
03096|021|D|DISCUSSION:  In a study in healthy males, rifampin (600 mg daily for 5 days)|
03096|022|D|decreased maximum concentration (Cmax) and AUC of a single dose of tamoxifen|
03096|023|D|(80 mg) by 86% and 55%, respectively.  The AUC of N-demethyltoremifene|
03096|024|D|decreased by 62%.(1,2)|
03096|025|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
03096|026|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03096|027|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03096|028|D|rifapentine, and St. John's wort.(3,4)|
03096|029|B||
03096|030|R|REFERENCES:|
03096|031|B||
03096|032|R|1.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
03096|033|R|  US Inc. September 25, 2018.|1
03096|034|R|2.Kivisto KT, Villikka K, Nyman L, Anttila M, Neuvonen PJ. Tamoxifen and|2
03096|035|R|  toremifene concentrations in plasma are greatly decreased by rifampin.|2
03096|036|R|  Clin Pharmacol Ther 1998 Dec;64(6):648-54.|2
03096|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03096|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03096|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03096|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03096|041|R|  11/14/2017.|1
03096|042|R|4.This information is based on an extract from the Certara Drug Interaction|6
03096|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03097|001|T|MONOGRAPH TITLE:  Glasdegib/Strong CYP3A4 Inhibitors|
03097|002|B||
03097|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03097|004|L|of severe adverse interaction.|
03097|005|B||
03097|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03097|007|A|metabolism of glasdegib.(1)|
03097|008|B||
03097|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03097|010|E|systemic exposure and the risk for glasdegib toxicities such as neutropenia|
03097|011|E|or QT prolongation.(1)|
03097|012|B||
03097|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03097|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03097|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03097|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03097|017|P|gender, or advanced age.(2)|
03097|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03097|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03097|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03097|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03097|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03097|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03097|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03097|025|B||
03097|026|M|PATIENT MANAGEMENT:  Consider an alternative therapy that is not a strong|
03097|027|M|3A4 inhibitor during treatment with glasdegib.(1)|
03097|028|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
03097|029|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03097|030|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03097|031|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03097|032|M|irregular heartbeat, dizziness, or fainting.|
03097|033|B||
03097|034|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03097|035|D|coadministration of ketoconazole (strong 3A4 inhibitor) with glasdegib|
03097|036|D|increased glasdegib maximum concentration (Cmax) and area-under-the-curve|
03097|037|D|(AUC) by 1.4 and 2.4-fold, respectively.(1)|
03097|038|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
03097|039|D|cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
03097|040|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
03097|041|D|paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.(3)|
03097|042|B||
03097|043|R|REFERENCES:|
03097|044|B||
03097|045|R|1.Daurismo (glasdegib) US prescribing information. Pfizer Inc. March, 2020.|1
03097|046|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03097|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03097|048|R|  settings: a scientific statement from the American Heart Association and|6
03097|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03097|050|R|  2;55(9):934-47.|6
03097|051|R|3.This information is based on an extract from the Certara Drug Interaction|6
03097|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03098|001|T|MONOGRAPH TITLE:  Glasdegib/Strong CYP3A4 Inducers|
03098|002|B||
03098|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03098|004|L|of severe adverse interaction.|
03098|005|B||
03098|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03098|007|A|glasdegib.(1)|
03098|008|B||
03098|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
03098|010|E|in decreased levels and effectiveness of glasdegib.(1)|
03098|011|B||
03098|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03098|013|P|of the inducer for longer than 1-2 weeks.|
03098|014|B||
03098|015|M|PATIENT MANAGEMENT:  The US manufacturer of glasdegib states that the|
03098|016|M|concurrent use of CYP3A4 inducers should be avoided.(1)|
03098|017|B||
03098|018|D|DISCUSSION:  In a study with healthy subjects, co-administration of rifampin|
03098|019|D|(strong 3A4 inducer), decreased glasdegib area-under-curve (AUC) by 70% and|
03098|020|D|maximum concentration (Cmax) by 35%.(1)|
03098|021|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03098|022|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
03098|023|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03098|024|D|wort.(2-3)|
03098|025|B||
03098|026|R|REFERENCES:|
03098|027|B||
03098|028|R|1.Daurismo (glasdegib) US prescribing information. Pfizer Inc. March, 2020.|1
03098|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03098|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03098|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03098|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03098|033|R|  11/14/2017.|1
03098|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
03098|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03099|001|T|MONOGRAPH TITLE:  Larotrectinib/Strong CYP3A4 Inhibitors|
03099|002|B||
03099|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03099|004|L|of severe adverse interaction.|
03099|005|B||
03099|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03099|007|A|metabolism of larotrectinib.(1)|
03099|008|B||
03099|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03099|010|E|systemic exposure and the risk for larotrectinib toxicities such as|
03099|011|E|neurotoxicity or hepatotoxicity.(1)|
03099|012|B||
03099|013|P|PREDISPOSING FACTORS:  None determined.|
03099|014|B||
03099|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of larotrectinib and strong CYP3A|
03099|016|M|inhibitors. Consider an alternative concomitant medication with less|
03099|017|M|potential for CYP3A4 inhibition.(1)|
03099|018|M|   The US manufacturer of larotrectinib states when concomitant use of|
03099|019|M|larotrectinib and a strong CYP3A4 inhibitor is needed, the larotrectinib|
03099|020|M|dose should be reduced by 50%.(1) If the strong CYP3A4 inhibitor is|
03099|021|M|discontinued, change the larotrectinib dose to the dose used prior to the|
03099|022|M|initiation of the strong CYP3A4 inhibitor after 3 to 5 elimination|
03099|023|M|half-lives.(1)|
03099|024|B||
03099|025|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03099|026|D|coadministration of itraconazole (strong 3A4 inhibitor) with a single dose|
03099|027|D|of larotrectinib (100 mg) increased larotrectinib maximum concentration|
03099|028|D|(Cmax) and area-under-the-curve (AUC) by 2.8 and 4.3-fold, respectively. (1)|
03099|029|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
03099|030|D|boceprevir, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole,|
03099|031|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir,|
03099|032|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
03099|033|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
03099|034|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)|
03099|035|B||
03099|036|R|REFERENCES:|
03099|037|B||
03099|038|R|1.Vitrakvi (larotrectinib) US prescribing information. Loxo Oncology, Inc.|1
03099|039|R|  November, 2022.|1
03099|040|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03099|041|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03099|042|R|  settings: a scientific statement from the American Heart Association and|6
03099|043|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03099|044|R|  2;55(9):934-47.|6
03099|045|R|3.This information is based on an extract from the Certara Drug Interaction|6
03099|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03100|001|T|MONOGRAPH TITLE:  Larotrectinib/Strong CYP3A4 Inducers; Rifabutin|
03100|002|B||
03100|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03100|004|L|of severe adverse interaction.|
03100|005|B||
03100|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 and rifabutin may increase|
03100|007|A|the metabolism of larotrectinib.(1,2)|
03100|008|B||
03100|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 or rifabutin|
03100|010|E|may result in decreased levels and effectiveness of larotrectinib.(1,2)|
03100|011|B||
03100|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03100|013|P|of the inducer for longer than 1-2 weeks.|
03100|014|B||
03100|015|M|PATIENT MANAGEMENT:  The manufacturer of larotrectinib states that the|
03100|016|M|concurrent use of strong CYP3A4 inducers should be avoided, and that|
03100|017|M|alternative treatments with less CYP3A4 induction should be considered.(1,2)|
03100|018|M|The Canadian manufacturer includes rifabutin on its list of CYP3A4 inducers|
03100|019|M|that should be avoided.(2)|
03100|020|M|   If coadministration of a strong 3A4 inducer cannot be avoided, double the|
03100|021|M|larotrectinib dose.  After the strong 3A4 inducer has been discontinued for|
03100|022|M|3 to 5 elimination half-lives, resume the larotrectinib dose at the dose|
03100|023|M|taken prior to initiating the 3A4 inducer.(1,2)|
03100|024|B||
03100|025|D|DISCUSSION:  In a study with healthy subjects, co-administration of rifampin|
03100|026|D|(strong 3A4 inducer) with a single dose of larotrectinib (100 mg), decreased|
03100|027|D|larotrectinib area-under-curve (AUC) by 81% and maximum concentration (Cmax)|
03100|028|D|by 71%.(1)|
03100|029|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03100|030|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03100|031|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin,|
03100|032|D|rifampin, rifapentine, and St. John's wort.(3-4)|
03100|033|B||
03100|034|R|REFERENCES:|
03100|035|B||
03100|036|R|1.Vitrakvi (larotrectinib) US prescribing information. Loxo Oncology, Inc.|1
03100|037|R|  November, 2022.|1
03100|038|R|2.Vitrakvi (larotrectinib) Canadian prescribing information. Bayer Inc|1
03100|039|R|  August, 2023.|1
03100|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03100|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03100|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03100|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03100|044|R|  11/14/2017.|1
03100|045|R|4.This information is based on an extract from the Certara Drug Interaction|6
03100|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03101|001|T|MONOGRAPH TITLE:  Glasdegib/QT Prolonging Agents|
03101|002|B||
03101|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03101|004|L|of severe adverse interaction.|
03101|005|B||
03101|006|A|MECHANISM OF ACTION:  Concurrent use of glasdegib with agents that prolong|
03101|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03101|008|B||
03101|009|E|CLINICAL EFFECTS:  The concurrent use of glasdegib with agents that prolong|
03101|010|E|the QTc interval may result in potentially life-threatening cardiac|
03101|011|E|arrhythmias, including torsades de pointes.(1)|
03101|012|B||
03101|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03101|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03101|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03101|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03101|017|P|female gender, or advanced age.(2)|
03101|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03101|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03101|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03101|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03101|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03101|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03101|024|P|dysfunction).(2)|
03101|025|B||
03101|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of glasdegib with medications|
03101|027|M|that prolong the QT interval.(1)|
03101|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03101|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03101|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
03101|031|M|and periodically monitor during therapy.  Correct any electrolyte|
03101|032|M|abnormalities.|
03101|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03101|034|M|fainting.|
03101|035|M|   If QTc prolongation develops:|
03101|036|M|   ---Monitor and supplement electrolytes as clinically indicated|
03101|037|M|   ---Review and adjust concomitant QT prolonging medications|
03101|038|M|   ---Interrupt glasdegib therapy for QTc interval greater than 500 ms.|
03101|039|M|   ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
03101|040|M|prolongation|
03101|041|M|   ---Follow labeling recommendations regarding restarting glasdegib.(1)|
03101|042|B||
03101|043|D|DISCUSSION:  In a randomized, single-dose, double-blind, 4-way cross-over,|
03101|044|D|placebo- and open-label moxifloxacin-controlled study in 36 healthy|
03101|045|D|subjects, the largest placebo and baseline-adjusted QTc interval change was|
03101|046|D|8 msec (90% CI:  6-10 msec) with a single 150 mg dose of glasdegib (The 150|
03101|047|D|mg single dose was used to achieve therapeutic plasma concentrations).  With|
03101|048|D|two-fold therapeutic plasma concentrations (achieved with a 300 mg single|
03101|049|D|dose), the QTc change was 13 msec (90% CI:  11-16 msec).(1)|
03101|050|D|   Agents that are linked to this monograph may have varying degrees of|
03101|051|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03101|052|D|been shown to prolong the QTc interval either through their mechanism of|
03101|053|D|action, through studies on their effects on the QTc interval, or through|
03101|054|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03101|055|D|and/or postmarketing reports.(3)|
03101|056|B||
03101|057|R|REFERENCES:|
03101|058|B||
03101|059|R|1.Daurismo (glasdegib) US prescribing information. Pfizer Inc. March, 2020.|1
03101|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03101|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03101|062|R|  settings: a scientific statement from the American Heart Association and|6
03101|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03101|064|R|  2;55(9):934-47.|6
03101|065|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03101|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03101|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03101|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03102|001|T|MONOGRAPH TITLE:  Glasdegib/Possible QT Prolonging Agents|
03102|002|B||
03102|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03102|004|L|take action as needed.|
03102|005|B||
03102|006|A|MECHANISM OF ACTION:  Concurrent use of glasdegib with agents that prolong|
03102|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03102|008|B||
03102|009|E|CLINICAL EFFECTS:  The concurrent use of glasdegib with agents that prolong|
03102|010|E|the QTc interval may result in potentially life-threatening cardiac|
03102|011|E|arrhythmias, including torsades de pointes.(1)|
03102|012|B||
03102|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03102|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03102|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03102|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03102|017|P|female gender, or advanced age.(2)|
03102|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03102|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03102|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03102|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03102|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03102|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03102|024|P|dysfunction).(2)|
03102|025|B||
03102|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of glasdegib with medications|
03102|027|M|that prolong the QT interval.(1)|
03102|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03102|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03102|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
03102|031|M|and periodically monitor during therapy.  Correct any electrolyte|
03102|032|M|abnormalities.|
03102|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03102|034|M|fainting.|
03102|035|M|   If QTc prolongation develops:|
03102|036|M|   ---Monitor and supplement electrolytes as clinically indicated|
03102|037|M|   ---Review and adjust concomitant QT prolonging medications|
03102|038|M|   ---Interrupt glasdegib therapy for QTc interval greater than 500 ms.|
03102|039|M|   ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
03102|040|M|prolongation|
03102|041|M|   ---Follow labeling recommendations regarding restarting glasdegib.(1)|
03102|042|B||
03102|043|D|DISCUSSION:  In a randomized, single-dose, double-blind, 4-way cross-over,|
03102|044|D|placebo- and open-label moxifloxacin-controlled study in 36 healthy|
03102|045|D|subjects, the largest placebo and baseline-adjusted QTc interval change was|
03102|046|D|8 msec (90% CI:  6-10 msec) with a single 150 mg dose of glasdegib (The 150|
03102|047|D|mg single dose was used to achieve therapeutic plasma concentrations).  With|
03102|048|D|two-fold therapeutic plasma concentrations (achieved with a 300 mg single|
03102|049|D|dose), the QTc change was 13 msec (90% CI:  11-16 msec).(1)|
03102|050|D|   Agents that are linked to this monograph may have varying degrees of|
03102|051|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03102|052|D|been shown to prolong the QTc interval either through their mechanism of|
03102|053|D|action, through studies on their effects on the QTc interval, or through|
03102|054|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03102|055|D|and/or postmarketing reports.(3)|
03102|056|B||
03102|057|R|REFERENCES:|
03102|058|B||
03102|059|R|1.Daurismo (glasdegib) US prescribing information. Pfizer Inc. March, 2020.|1
03102|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03102|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03102|062|R|  settings: a scientific statement from the American Heart Association and|6
03102|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03102|064|R|  2;55(9):934-47.|6
03102|065|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03102|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03102|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03102|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03103|001|T|MONOGRAPH TITLE:  Gilteritinib/P-gp and Strong CYP3A4 Inducers|
03103|002|B||
03103|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03103|004|L|of severe adverse interaction.|
03103|005|B||
03103|006|A|MECHANISM OF ACTION:  Strong P-gp or CYP3A4 inducers may decrease|
03103|007|A|absorption, increase elimination rate, or increase the metabolism of|
03103|008|A|gilteritinib.(1)|
03103|009|B||
03103|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong P-gp or CYP3A4|
03103|011|E|inducers may result in decreased levels and effectiveness of|
03103|012|E|gilteritinib.(1)|
03103|013|B||
03103|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03103|015|P|of the inducer for longer than 1-2 weeks.|
03103|016|B||
03103|017|M|PATIENT MANAGEMENT:  The manufacturer recommends avoiding concomitant use of|
03103|018|M|gilteritinib with agents which are inducers of both P-gp and CYP3A4 as|
03103|019|M|coadministration may decrease gilteritinib exposure.(1)|
03103|020|B||
03103|021|D|DISCUSSION:  In an interaction study, concurrent rifampin decreased the|
03103|022|D|area-under-curve (AUC) and maximum concentration (Cmax) of gilteritinib by|
03103|023|D|70% and 30%, respectively.(1)|
03103|024|D|   Inducers of both P-gp and CYP3A4 linked to this monograph are|
03103|025|D|apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine,|
03103|026|D|and St. John's wort.|
03103|027|B||
03103|028|R|REFERENCE:|
03103|029|B||
03103|030|R|1.Xospata (gilteritinib) US Prescribing Information. Astellas Pharma US,|1
03103|031|R|  Inc. January, 2022.|1
03104|001|T|MONOGRAPH TITLE:  Gilteritinib/QT Prolonging Agents|
03104|002|B||
03104|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03104|004|L|take action as needed.|
03104|005|B||
03104|006|A|MECHANISM OF ACTION:  Concurrent use of gilteritinib with agents that|
03104|007|A|prolong the QTc interval may result in additive effects on the QTc|
03104|008|A|interval.(1)|
03104|009|B||
03104|010|E|CLINICAL EFFECTS:  The concurrent use of gilteritinib with agents that|
03104|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03104|012|E|arrhythmias, including torsades de pointes.(1)|
03104|013|B||
03104|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03104|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03104|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03104|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03104|018|P|female gender, or advanced age.(1)|
03104|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03104|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03104|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03104|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03104|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03104|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03104|025|P|dysfunction).(1)|
03104|026|B||
03104|027|M|PATIENT MANAGEMENT:  When concurrent therapy cannot be avoided, obtain ECGs|
03104|028|M|and electrolyte values (serum calcium, magnesium, and potassium) prior to|
03104|029|M|the start of treatment, after initiation of any drug known to prolong the QT|
03104|030|M|interval, and periodically monitor during therapy.  Correct any electrolyte|
03104|031|M|abnormalities.|
03104|032|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03104|033|M|fainting.|
03104|034|M|   Prior to initiation of therapy with gilteritinib, obtain baseline ECG and|
03104|035|M|on days 8 and 15 of cycle 1, and prior to the start of the next two|
03104|036|M|subsequent cycles.|
03104|037|M|   If QTc prolongation develops:|
03104|038|M|   ---Monitor and supplement electrolytes as clinically indicated|
03104|039|M|   ---Review and adjust concomitant QT prolonging medications|
03104|040|M|   For a QTc interval greater than 500 msec:|
03104|041|M|   ---Interrupt gilteritinib therapy|
03104|042|M|   ---Resume gilteritinib therapy at 80 mg when the QTc interval returns to|
03104|043|M|within 30 msec of baseline or <= 480 msec.|
03104|044|M|   For QTc interval increased by > 30 msec on ECG on Day 8 of cycle 1:|
03104|045|M|   ---Confirm with ECG on Day 9|
03104|046|M|   ---If confirmed, consider dose reduction to 80 mg.(2)|
03104|047|B||
03104|048|D|DISCUSSION:  In the gilteritinib clinical trial, 1.4% of patients developed|
03104|049|D|a QTc interval greater than 500 msec and 7% of patients had an increase QTc|
03104|050|D|greater than 60 msec.(2)|
03104|051|D|   Agents that are linked to this monograph may have varying degrees of|
03104|052|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03104|053|D|been shown to prolong the QTc interval either through their mechanism of|
03104|054|D|action, through studies on their effects on the QTc interval, or through|
03104|055|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03104|056|D|and/or postmarketing reports.(3)|
03104|057|B||
03104|058|R|REFERENCES:|
03104|059|B||
03104|060|R|1.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03104|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03104|062|R|  settings: a scientific statement from the American Heart Association and|6
03104|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03104|064|R|  2;55(9):934-47.|6
03104|065|R|2.Xospata (gilteritinib) US Prescribing Information. Astellas Pharma US,|1
03104|066|R|  Inc. January, 2022.|1
03104|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03104|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03104|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03104|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03105|001|T|MONOGRAPH TITLE:  Lacosamide/Sodium Channel Blockers; Potassium Channel|
03105|002|T|Blockers|
03105|003|B||
03105|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03105|005|L|take action as needed.|
03105|006|B||
03105|007|A|MECHANISM OF ACTION:  Lacosamide may enhance the slow inactivation of|
03105|008|A|voltage-gated sodium channels and may cause dose-dependent bradycardia,|
03105|009|A|prolongation of the PR interval, atrioventricular (AV) block, or ventricular|
03105|010|A|tachyarrhythmia.(1)|
03105|011|B||
03105|012|E|CLINICAL EFFECTS:  Concurrent use of lacosamide and agents that affect|
03105|013|E|cardiac conduction (sodium channel blockers and potassium channel blockers)|
03105|014|E|may increase the risk of bradycardia, prolongation of the PR interval,|
03105|015|E|atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)|
03105|016|B||
03105|017|P|PREDISPOSING FACTORS:  None determined.|
03105|018|B||
03105|019|M|PATIENT MANAGEMENT:  Lacosamide should be used with caution in patients on|
03105|020|M|concomitant medications that affect cardiac conduction, including sodium|
03105|021|M|channel blockers and potassium channel blockers.(1)|
03105|022|M|   If concurrent use is needed, obtain an ECG before lacosamide therapy and|
03105|023|M|after lacosamide dose is titrated to steady-state.(1)|
03105|024|M|   Patients should be monitored closely when lacosamide is given|
03105|025|M|intravenously.(1)|
03105|026|B||
03105|027|D|DISCUSSION:  In a clinical trial in patients with partial-onset seizures,|
03105|028|D|asymptomatic first-degree atrioventricular (AV) block occurred in 4/944|
03105|029|D|(0.4%) of patient who received lacosamide compared to 0/364 (0%) with|
03105|030|D|placebo.(1)|
03105|031|D|   In a clinical trial in patients with diabetic neuropathy, asymptomatic|
03105|032|D|first-degree AV block occurred in 5/1023 (0.5%) of patients who received|
03105|033|D|lacosamide compared to 0/291 (0%) with placebo.(1)|
03105|034|D|   Second-degree and complete AV block have been reported in patients with|
03105|035|D|seizures.(1)|
03105|036|D|   One case of profound bradycardia was observed in a patient during a|
03105|037|D|15-minute infusion of 150 mg of lacosamide.(1)|
03105|038|D|   A case report of a 49 year old male with refractory complex partial and|
03105|039|D|generalized seizures described the development of ventricular tachycardia|
03105|040|D|four months after addition of lacosamide 400 mg/day to the existing regimen|
03105|041|D|of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG|
03105|042|D|showed first-degree AV block, posterior left fascicular block, and severe|
03105|043|D|widening of the QRS complex, all of which resolved upon discontinuation of|
03105|044|D|lacosamide.(2)|
03105|045|B||
03105|046|R|REFERENCES:|
03105|047|B||
03105|048|R|1.Vimpat (lacosamide) tablet, injection US prescribing information. UCB,|1
03105|049|R|  Inc. October, 2021.|1
03105|050|R|2.DeGiorgio AC, Desso TE, Lee L, DeGiorgio CM. Ventricular tachycardia|3
03105|051|R|  associated with lacosamide co-medication in drug-resistant epilepsy.|3
03105|052|R|  Epilepsy Behav Case Rep 2013;1:26-8.|3
03106|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Sertraline|
03106|002|B||
03106|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03106|004|L|take action as needed.|
03106|005|B||
03106|006|A|MECHANISM OF ACTION:  The mechanism by which sertraline lowers serum thyroid|
03106|007|A|hormone concentrations is uncertain.  One reported case in which sertraline|
03106|008|A|caused a low serum total thyroxine concentration is believed to be caused by|
03106|009|A|sertraline increasing the clearance of the thyroxine.(1)|
03106|010|B||
03106|011|E|CLINICAL EFFECTS:  The coadministration of thyroid preparations and|
03106|012|E|sertraline may result in decreased levels and clinical effects of thyroid|
03106|013|E|hormones.(1)|
03106|014|B||
03106|015|P|PREDISPOSING FACTORS:  None determined.|
03106|016|B||
03106|017|M|PATIENT MANAGEMENT:  Patients taking thyroid preparations and sertraline|
03106|018|M|should be monitored for changes in thyroid function. The dosage of the|
03106|019|M|thyroid preparation may need to be increased.|
03106|020|B||
03106|021|D|DISCUSSION:  In a case report of 9 levothyroxine treated patients with|
03106|022|D|hypothyroidism, who were treated with sertraline, all were found to have|
03106|023|D|elevated serum thyrotropin concentrations.  Elevated thyrotropin levels are|
03106|024|D|indicative of a decrease in the efficacy of levothyroxine. The dose of|
03106|025|D|levothyroxine was increased for all patients.  Required dosage adjustments|
03106|026|D|ranged from 11% to 50%.(1)|
03106|027|D|   In a study, patients with major depression and hypothyroidism on adequate|
03106|028|D|levothyroxine therapy were treated with either fluoxetine or sertraline.|
03106|029|D|The results of this study showed no change in thyroid levels among|
03106|030|D|hypothyroid patients on levothyroxine therapy who were treated with either|
03106|031|D|fluoxetine or sertraline.(2)|
03106|032|B||
03106|033|R|REFERENCES:|
03106|034|B||
03106|035|R|1.McCowen KC, Garber JR, Spark R. Elevated serum thyrotropin in|3
03106|036|R|  thyroxine-treated patients with hypothyroidism given sertraline. N Engl J|3
03106|037|R|  Med 1997 Oct 2;337(14):1010-1.|3
03106|038|R|2.de Carvalho GA, Bahls SC, Boeving A, Graf H. Effects of selective|2
03106|039|R|  serotonin reuptake inhibitors on thyroid function in depressed patients|2
03106|040|R|  with primary hypothyroidism or normal thyroid function. Thyroid 2009 Jul;|2
03106|041|R|  19(7):691-7.|2
03107|001|T|MONOGRAPH TITLE:  Rifampin/Barbiturates|
03107|002|B||
03107|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03107|004|L|take action as needed.|
03107|005|B||
03107|006|A|MECHANISM OF ACTION:  Rifampin and barbiturates may induce the metabolism of|
03107|007|A|each other.|
03107|008|B||
03107|009|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
03107|010|E|effectiveness of the barbiturate and/or rifampin.|
03107|011|B||
03107|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03107|013|P|of the inducer for longer than 1-2 weeks.|
03107|014|B||
03107|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy for|
03107|016|M|decreased effectiveness of both agents. If one agent is discontinued, the|
03107|017|M|dosage of the remaining agent may need to be adjusted.|
03107|018|B||
03107|019|D|DISCUSSION:  Eight days of rifampin therapy increased hexobarbital|
03107|020|D|metabolism approximately three-fold and reduced the effectiveness of|
03107|021|D|hexobarbital. (1)  Similar reports further indicated that hexobarbital|
03107|022|D|clearance was increased even in patients with chronic liver disease(2) and|
03107|023|D|returned to pre-rifampin levels within 14 days after discontinuation of|
03107|024|D|rifampin.(3)|
03107|025|D|   In a study in 15 patients taking phenobarbital (100 mg), rifampin levels|
03107|026|D|were decreased by 20% to 40% in 12 patients.(4)  In another study,|
03107|027|D|phenobarbital reduced rifampin half-life by 2.2 hours and resulted in a|
03107|028|D|non-statistically significant decrease in rifampin levels by 15%.(5)|
03107|029|B||
03107|030|R|REFERENCES:|
03107|031|B||
03107|032|R|1.Zilly W, Breimer DD, Richter E. Induction of drug metabolism in man after|2
03107|033|R|  rifampicin treatment measured by increased hexobarbital and tolbutamide|2
03107|034|R|  clearance. Eur J Clin Pharmacol 1975 Dec 19;9(2-3):219-27.|2
03107|035|R|2.Zilly W, Breimer DD, Richter E. Stimulation of drug metabolism by|2
03107|036|R|  rifampicin in patients with cirrhosis or cholestasis measured by increased|2
03107|037|R|  hexobarbital and tolbutamide clearance. Eur J Clin Pharmacol 1977 Apr 20;|2
03107|038|R|  11(4):287-93.|2
03107|039|R|3.Breimer DD, Zilly W, Richter E. Influence of rifampicin on drug|2
03107|040|R|  metabolism: differences between hexobarbital and  antipyrine. Clin|2
03107|041|R|  Pharmacol Ther 1977 Apr;21(4):470-81.|2
03107|042|R|4.Rautlin de la Roy Y DE, Beauchant G, Breuil K, Patte F. Reduction of the|2
03107|043|R|  blood level of rifampicin by phenobarbital. Presse Med 1971 Feb 13;|2
03107|044|R|  79(8):350.|2
03107|045|R|5.Acocella G, Bonollo L, Mainardi M, Margaroli P, Nicolis FB. Kinetic|2
03107|046|R|  studies on rifampicin. III. Effect of phenobarbital on the half-life of|2
03107|047|R|  the antibiotic. Tijdschr Gastroenterol 1974;17(3):151-8.|2
03108|001|T|MONOGRAPH TITLE:  Apixaban/Enzalutamide|
03108|002|B||
03108|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03108|004|L|take action as needed.|
03108|005|B||
03108|006|A|MECHANISM OF ACTION:  Enzalutamide may induce the metabolism of apixaban by|
03108|007|A|CYP3A4, but increase their absorption by inhibiting P-glycoprotein|
03108|008|A|(P-gp).(1-7)|
03108|009|B||
03108|010|E|CLINICAL EFFECTS:  Concurrent or recent use of enzalutamide may have|
03108|011|E|unpredictable effects on apixaban.  If drug levels of apixaban are|
03108|012|E|increased, concurrent use may increase the risk for bleeding.(1-7)  If drug|
03108|013|E|levels of apixaban decrease, loss of anticoagulant efficacy may result.|
03108|014|B||
03108|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03108|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03108|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
03108|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03108|019|P|risk for bleeding (e.g. NSAIDs).|
03108|020|B||
03108|021|M|PATIENT MANAGEMENT:  Consider the use of alternative agents for|
03108|022|M|anticoagulation in patients requiring therapy with enzalutamide.  Depending|
03108|023|M|on indication and renal function, dabigatran, edoxaban, or warfarin may be|
03108|024|M|alternatives.(6)|
03108|025|M|   If concurrent therapy is required, monitor patients for altered response|
03108|026|M|to apixaban.  When applicable, perform agent-specific laboratory test (e.g.|
03108|027|M|INR, aPTT) to monitor efficacy and safety of anticoagulation.|
03108|028|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03108|029|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
03108|030|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
03108|031|M|evaluate patients with any symptoms.  Discontinue anticoagulation in|
03108|032|M|patients with active pathologic bleeding.|
03108|033|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03108|034|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03108|035|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03108|036|M|and/or swelling.|
03108|037|B||
03108|038|D|DISCUSSION:  Concurrent rifampin (a strong inducer of CYP3A4 and an inducer|
03108|039|D|of P-gp) decreased the area-under-curve (AUC) and maximum concentration|
03108|040|D|(Cmax) of apixaban by 54% and 42%, respectively.(1-4)|
03108|041|D|   Concurrent ketoconazole (400 mg daily, a strong inhibitor of CYP3A4 and|
03108|042|D|P-gp) increased the area-under-curve (AUC) and maximum concentration (Cmax)|
03108|043|D|of apixaban by 2-fold and 1.6-fold, respectively.(1)|
03108|044|D|   Enzalutamide is a strong inducer of CYP3A4 and an inhibitor of P-gp.(5)|
03108|045|D|   A PKPB model study evaluated the effects of enzalutamide as a strong|
03108|046|D|CYP3A4 inducer and P-gp inhibitor on apixaban.  The model predicted a|
03108|047|D|decrease in apixaban AUC by 31% with no change in Cmax.(7)|
03108|048|B||
03108|049|R|REFERENCES:|
03108|050|B||
03108|051|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
03108|052|R|  Squibb Australia Pty. Ltd. January, 2024.|1
03108|053|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
03108|054|R|  Squibb-Pfizer January, 2025.|1
03108|055|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
03108|056|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
03108|057|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
03108|058|R|  Company April, 2025.|1
03108|059|R|5.This information is based on an extract from the Certara Drug Interaction|6
03108|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03108|061|R|6.Shatzel JJ, Daughety MM, Olson SR, Beer TM, DeLoughery TG. Management of|6
03108|062|R|  Anticoagulation in Patients With Prostate Cancer Receiving Enzalutamide. J|6
03108|063|R|  Oncol Pract 2017 Nov;13(11):720-727.|6
03108|064|R|7.Otsuka Y, Poondru S, Bonate PL, Rose RH, Jamei M, Ushigome F, Minematsu T.|5
03108|065|R|  Physiologically-based pharmacokinetic modeling to predict drug-drug|5
03108|066|R|  interaction  of enzalutamide with combined P-gp and CYP3A substrates. J|5
03108|067|R|  Pharmacokinet Pharmacodyn 2023 Oct;50(5):365-376.|5
03109|001|T|MONOGRAPH TITLE:  Brigatinib/Moderate CYP3A4 Inducers|
03109|002|B||
03109|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03109|004|L|of severe adverse interaction.|
03109|005|B||
03109|006|A|MECHANISM OF ACTION:  Brigatinib is a substrate of CYP3A4.  Moderate|
03109|007|A|inducers of CYP3A4 may induce the metabolism of brigatinib.(1)|
03109|008|B||
03109|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
03109|010|E|in decreased levels and effectiveness of brigatinib.(1)|
03109|011|B||
03109|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03109|013|P|of the inducer for longer than 1-2 weeks.|
03109|014|B||
03109|015|M|PATIENT MANAGEMENT:  The manufacturer of brigatinib states to avoid|
03109|016|M|concurrent administration with moderate CYP3A4 inducers.  If concurrent use|
03109|017|M|cannot be avoided, increase the daily dose of brigatinib in 30 mg increments|
03109|018|M|every 7 days, as tolerated, to a maximum of twice the brigatinib dose that|
03109|019|M|was tolerated prior to initiation of the moderate CYP3A4 inducer.|
03109|020|M|   After discontinuation of a moderate CYP3A4 inducer, resume the brigatinib|
03109|021|M|dose that was tolerated prior to initiation of the inducer.(1)|
03109|022|B||
03109|023|D|DISCUSSION:  Brigatinib is a substrate of CYP3A4.(1)|
03109|024|D|   Concurrent administration of rifampin (600 mg daily, a strong CYP3A4|
03109|025|D|inducer) with a single 180 mg dose of brigatinib decreased the brigatinib|
03109|026|D|maximum concentration (Cmax) by 60% and area-under-curve (AUC) by 80%|
03109|027|D|compared to brigatinib alone. Moderate CYP3A4 inducers are expected to|
03109|028|D|decrease the AUC of brigatinib by 50%.(1)|
03109|029|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03109|030|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
03109|031|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
03109|032|D|pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl,|
03109|033|D|thioridazine, tipranavir/ritonavir and tovorafenib.(2-3)|
03109|034|B||
03109|035|R|REFERENCES:|
03109|036|B||
03109|037|R|1.Alunbrig (brigatinib) US prescribing information. Ariad Pharmaceuticals,|1
03109|038|R|  Inc. September, 2021.|1
03109|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
03109|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03109|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03109|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03109|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03109|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03109|045|R|  11/14/2017.|1
03110|001|T|MONOGRAPH TITLE:  Brigatinib/Moderate CYP3A4 Inhibitors|
03110|002|B||
03110|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03110|004|L|of severe adverse interaction.|
03110|005|B||
03110|006|A|MECHANISM OF ACTION:  Brigatinib is a substrate of CYP3A4.  Moderate|
03110|007|A|inhibitors of CYP3A4 may inhibit the metabolism of brigatinib.(1)|
03110|008|B||
03110|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
03110|010|E|result in increased levels and toxicity from brigatinib.(1)|
03110|011|B||
03110|012|P|PREDISPOSING FACTORS:  None determined.|
03110|013|B||
03110|014|M|PATIENT MANAGEMENT:  The manufacturer of brigatinib states to avoid|
03110|015|M|concurrent administration with moderate CYP3A4 inhibitors.  If concurrent|
03110|016|M|therapy cannot be avoided, reduce the once daily dose of brigatinib by|
03110|017|M|approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg).  Upon|
03110|018|M|discontinuation of a moderate CYP3A4 inhibitor, resume the brigatinib dose|
03110|019|M|that was tolerated prior to initiating the moderate CYP3A4 inhibitor.(1)|
03110|020|M|   Monitor patient for signs of brigatinib toxicity with concurrent use.|
03110|021|B||
03110|022|D|DISCUSSION:  Brigatinib is a substrate of CYP3A4.(1)|
03110|023|D|   Concurrent administration of itraconazole (200 mg twice daily, a strong|
03110|024|D|CYP3A4 inhibitor) with a single 90 mg dose of brigatinib increased the|
03110|025|D|brigatinib maximum concentration (Cmax) by 21% and area-under-curve (AUC) by|
03110|026|D|101% compared to brigatinib alone.  Moderate CYP3A4 inhibitors are expected|
03110|027|D|to increase the AUC of brigatinib by approximately 40%.(1)|
03110|028|D|   Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir,|
03110|029|D|aprepitant, atazanavir, avacopan, berotralstat,  clofazimine, conivaptan,|
03110|030|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
03110|031|D|fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
03110|032|D|imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant,|
03110|033|D|nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
03110|034|D|and verapamil.(2,3)|
03110|035|B||
03110|036|R|REFERENCES:|
03110|037|B||
03110|038|R|1.Alunbrig (brigatinib) US prescribing information. Ariad Pharmaceuticals,|1
03110|039|R|  Inc. September, 2021.|1
03110|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
03110|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03110|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03110|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03110|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03110|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03110|046|R|  11/14/2017.|1
03111|001|T|MONOGRAPH TITLE:  Busulfan/Deferasirox|
03111|002|B||
03111|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03111|004|L|of severe adverse interaction.|
03111|005|B||
03111|006|A|MECHANISM OF ACTION:  Deferasirox may increase the plasma concentrations of|
03111|007|A|busulfan.(1-3)  The exact mechanism is unknown but may involve competitive|
03111|008|A|inhibition of glucuronidation enzymes.(2)|
03111|009|B||
03111|010|E|CLINICAL EFFECTS:  Concurrent use of deferasirox may result in elevated|
03111|011|E|levels of and toxicity from busulfan.(1-3)|
03111|012|B||
03111|013|P|PREDISPOSING FACTORS:  None determined.|
03111|014|B||
03111|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be closely|
03111|016|M|monitored for toxicity.  The dosage of busulfan may need to be|
03111|017|M|adjusted.(1-3)|
03111|018|B||
03111|019|D|DISCUSSION:  In a case report, co-administration of deferasirox with|
03111|020|D|busulfan led to a 1.5-fold increase in area under the curve (AUC) and 37%|
03111|021|D|decrease in drug clearance (CL).(2)|
03111|022|D|   In another case report, concomitant use of busulfan and deferasirox led|
03111|023|D|to a 2-fold increase in AUC and 46% decrease in CL.(3)|
03111|024|D|   In both reports, the dose of busulfan when used with concomitant|
03111|025|D|deferasirox was approximately half of the dose required with busulfan alone.|
03111|026|B||
03111|027|R|REFERENCES:|
03111|028|B||
03111|029|R|1.Exjade (deferasirox) US prescribing information. Novartis Pharmaceuticals|1
03111|030|R|  Corporation July, 2019.|1
03111|031|R|2.Sweiss K, Patel P, Rondelli D. Deferasirox increases BU blood|3
03111|032|R|  concentrations. Bone Marrow Transplant 2012 Feb;47(2):315-6.|3
03111|033|R|3.Kwiatkowski J, Duffner U, Abdel-Mageed A. Deferasirox Decreases Busulfan|3
03111|034|R|  Clearance. Ann Pharmacother 2018 May;52(5):497-498.|3
03112|001|T|MONOGRAPH TITLE:  Atorvastatin/Fenofibrate|
03112|002|B||
03112|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03112|004|L|take action as needed.|
03112|005|B||
03112|006|A|MECHANISM OF ACTION:  Unknown.|
03112|007|B||
03112|008|E|CLINICAL EFFECTS:  Concurrent administration of atorvastatin and fibric acid|
03112|009|E|derivatives has been associated with severe myopathy, rhabdomyolysis and|
03112|010|E|acute renal failure.|
03112|011|B||
03112|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03112|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03112|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03112|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03112|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03112|017|P|transporter OATP1B1 may have increased statin concentrations and be|
03112|018|P|predisposed to myopathy or rhabdomyolysis.|
03112|019|B||
03112|020|M|PATIENT MANAGEMENT:  When possible, avoid administration of atorvastatin and|
03112|021|M|fibric acid derivatives concomitantly unless patients require aggressive|
03112|022|M|therapy.  Instruct patients to report any unexplained muscle pain,|
03112|023|M|tenderness or weakness.  If muscular symptoms develop, monitor serum|
03112|024|M|creatine kinase levels and renal function.  One or both agents may need to|
03112|025|M|be discontinued.|
03112|026|M|   The American College of Cardiology and American Heart Association|
03112|027|M|Guidelines state that fenofibrate may be considered concomitantly with a|
03112|028|M|low- or moderate-intensity statin only if the benefits from atherosclerotic|
03112|029|M|cardiovascular risk reduction or triglyceride lowering when triglycerides|
03112|030|M|are greater than or equal to 500 mg/dL are judged to outweigh the potential|
03112|031|M|risk for adverse effects.(20)|
03112|032|M|   The European Society of Cardiology and European Atherosclerosis Society|
03112|033|M|recommend concomitant statin-fenofibrate therapy in patients with|
03112|034|M|atherogenic combined dyslipidemia, especially patients with metabolic|
03112|035|M|syndrome and/or diabetes.(21)|
03112|036|M|   The US manufacturer of fenofibrate states that concurrent therapy with|
03112|037|M|HMG CO-A reductase inhibitors should be avoided unless the benefit of|
03112|038|M|further decreases in lipid levels is likely to outweigh the increased risk.|
03112|039|M|Fenofibrate may be preferred over gemfibrozil in patients who do require|
03112|040|M|concurrent statin and fibrate therapy.(9)|
03112|041|B||
03112|042|D|DISCUSSION:  Concurrent fenofibrate (145 mg) with atorvastatin (20 mg)|
03112|043|D|decreased the atorvastatin area-under-curve (AUC) by 17% (range from 67%|
03112|044|D|decrease to 44% increase).  Atorvastatin maximum concentration (Cmax) and|
03112|045|D|the kinetics of fenofibrate were not significantly affected.|
03112|046|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
03112|047|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
03112|048|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
03112|049|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
03112|050|D|Veteran's Administration over a 2 year period, there were 149 reports of|
03112|051|D|rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil|
03112|052|D|and statin therapy compared with no reports in 1,830 patients receiving|
03112|053|D|concurrent fenofibrate and statin therapy.|
03112|054|D|   In a study in 66 healthy volunteers, concomitant administration of|
03112|055|D|fenofibrate (160 mg for 7 days) and atorvastatin (40 mg single dose) did not|
03112|056|D|result in a clinically significant change in the atorvastatin AUC.(22)|
03112|057|D|   A meta-analysis of 6 randomized controlled trials (including|
03112|058|D|approximately 1600 patients) found no cases of myopathy or rhabdomyolysis in|
03112|059|D|combination therapy of fenofibrate with simvastatin, fluvastatin, or|
03112|060|D|atorvastatin.  A comparison of the incidence of creatine kinase greater than|
03112|061|D|5 times the ULN between combination statin-fenofibrate and statin|
03112|062|D|monotherapy was found to be not significant.(23)|
03112|063|D|   A meta-analysis of 13 randomized controlled trials (including|
03112|064|D|approximately 7000 patients) found no significant difference in the|
03112|065|D|incidence of elevated creatine kinase or muscle-associated adverse effects|
03112|066|D|between single-drug statin therapy or combination fenofibrate-statin|
03112|067|D|therapy.(24)|
03112|068|B||
03112|069|R|REFERENCES:|
03112|070|B||
03112|071|R|1.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
03112|072|R|  cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
03112|073|R|  polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
03112|074|R|2.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
03112|075|R|  Ltd. December, 2020.|1
03112|076|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
03112|077|R|  February, 2014.|1
03112|078|R|4.McDonald KB, Garber BG, Perreault MM. Pancreatitis associated with|3
03112|079|R|  simvastatin plus fenofibrate. Ann Pharmacother 2002 Feb;36(2):275-9.|3
03112|080|R|5.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03112|081|R|  Pharmaceuticals LP July, 2024.|1
03112|082|R|6.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
03112|083|R|  Squibb Company May, 2022.|1
03112|084|R|7.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03112|085|R|  2023.|1
03112|086|R|8.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
03112|087|R|  Merck/Schering-Plough Pharmaceuticals February, 2024.|1
03112|088|R|9.Tricor (fenofibrate) US prescribing information. Abbott Laboratories June,|1
03112|089|R|  2021.|1
03112|090|R|10.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
03112|091|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
03112|092|R|   at:|3
03112|093|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
03112|094|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
03112|095|R|11.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
03112|096|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
03112|097|R|   95(1):120-2.|2
03112|098|R|12.Gustavson LE, Schweitzer SM, Koehne-Voss S, Achari R, Chira TO, Esslinger|2
03112|099|R|   HU, Yannicelli HD. The effects of multiple doses of fenofibrate on the|2
03112|100|R|   pharmacokinetics of pravastatin and its 3alpha-hydroxy isomeric|2
03112|101|R|   metabolite. J Clin Pharmacol 2005 Aug;45(8):947-53.|2
03112|102|R|13.Ireland JH, Eggert CH, Arendt CJ, Williams AW. Rhabdomyolysis with|2
03112|103|R|   cardiac involvement and acute renal failure in a patient taking|2
03112|104|R|   rosuvastatin and fenofibrate. Ann Intern Med 2005 Jun 7;142(11):949-50.|2
03112|105|R|14.Jacob SS, Jacob S, Williams C, Deeg MA. Simvastatin, fenofibrate, and|3
03112|106|R|   rhabdomyolysis. Diabetes Care 2005 May;28(5):1258.|3
03112|107|R|15.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
03112|108|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
03112|109|R|16.Bergman AJ, Murphy G, Burke J, Zhao JJ, Valesky R, Liu L, Lasseter KC, He|2
03112|110|R|   W, Prueksaritanont T, Qiu Y, Hartford A, Vega JM, Paolini JF. Simvastatin|2
03112|111|R|   does not have a clinically significant pharmacokinetic interaction with|2
03112|112|R|   fenofibrate in humans. J Clin Pharmacol 2004 Sep;44(9):1054-62.|2
03112|113|R|17.Martin PD, Dane AL, Schneck DW, Warwick MJ. An open-label, randomized,|2
03112|114|R|   three-way crossover trial of the effects of coadministration of|2
03112|115|R|   rosuvastatin and fenofibrate on the pharmacokinetic properties of|2
03112|116|R|   rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther|2
03112|117|R|   2003 Feb;25(2):459-71.|2
03112|118|R|18.Wierzbicki AS, Lumb PJ, Cheung J, Crook MA. Fenofibrate plus simvastatin|2
03112|119|R|   therapy versus simvastatin plus cholestyramine therapy for familial|2
03112|120|R|   hypercholesterolaemia. QJM 1997 Oct;90(10):631-4.|2
03112|121|R|19.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
03112|122|R|   America, Inc. November, 2022.|1
03112|123|R|20.Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on|6
03112|124|R|   the treatment of blood cholesterol to reduce atherosclerotic|6
03112|125|R|   cardiovascular risk in adults: a report of the American College of|6
03112|126|R|   Cardiology/American Heart Association Task Force on Practice Guidelines.|6
03112|127|R|   Circulation 2014 Jun 24;129(25 Suppl 2):S1-45.|6
03112|128|R|21.Reiner Z, Catapano AL, De Backer Get al. Guidelines for the management of|6
03112|129|R|   dyslipidaemias the Task Force for the management of dyslipidaemias of the|6
03112|130|R|   European Society of Cardiology and the  European Atherosclerosis Society.|6
03112|131|R|   Eur Heart J 2011 Jul;32(14):1769-818.|6
03112|132|R|22.Whitfield LR, Porcari AR, Alvey C, Abel R, Bullen W, Hartman D. Effect of|2
03112|133|R|   gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin. J|2
03112|134|R|   Clin Pharmacol 2011 Mar;51(3):378-88.|2
03112|135|R|23.Guo J, Meng F, Ma N, Li C, Ding Z, Wang H, Hou R, Qin Y. Meta-analysis of|6
03112|136|R|   safety of the coadministration of statin with fenofibrate in patients|6
03112|137|R|   with combined hyperlipidemia. Am J Cardiol 2012 Nov 1;110(9):1296-301.|6
03112|138|R|24.Geng Q, Ren J, Chen H, Lee C, Liang W. Adverse events following|6
03112|139|R|   statin-fenofibrate therapy versus statin alone: a meta-analysis of|6
03112|140|R|   randomized controlled trials. Clin Exp Pharmacol Physiol 2013 Mar;|6
03112|141|R|   40(3):219-26.|6
03112|142|R|25.Tonkin AM, Chen L. Effects of combination lipid therapy in the management|2
03112|143|R|   of patients with type 2 diabetes mellitus in the Action to Control|2
03112|144|R|   Cardiovascular Risk in Diabetes (ACCORD) trial. Circulation 2010 Aug 24;|2
03112|145|R|   122(8):850-2.|2
03112|146|R|26.Ginsberg HN, Elam MB, Lovato LC, Crouse JRetal. Effects of combination|2
03112|147|R|   lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010 Apr 29;|2
03112|148|R|   362(17):1563-74.|2
03113|001|T|MONOGRAPH TITLE:  Insulin/Selected Systemic Non-Cardioselective|
03113|002|T|Beta-Blockers|
03113|003|B||
03113|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03113|005|L|take action as needed.|
03113|006|B||
03113|007|A|MECHANISM OF ACTION:  Not fully established. Probably blockade of a variety|
03113|008|A|of beta-adrenergic responses to hypoglycemia.|
03113|009|B||
03113|010|E|CLINICAL EFFECTS:  Diminished response to insulin may occur. Frequency and|
03113|011|E|severity of hypoglycemic episodes may be increased, while warning symptoms|
03113|012|E|of low blood sugar may be masked.|
03113|013|B||
03113|014|P|PREDISPOSING FACTORS:  None determined.|
03113|015|B||
03113|016|M|PATIENT MANAGEMENT:  Try to avoid beta-blocker therapy, particularly in|
03113|017|M|diabetics prone to hypoglycemic attacks.  One of the cardioselective agents|
03113|018|M|may decrease risk of hypertensive attacks and allow more rapid glucose|
03113|019|M|recovery from hypoglycemia.|
03113|020|M|   Patients should be counseled not to rely on tachycardia to diagnose|
03113|021|M|hypoglycemia, since it is masked by beta-blocker therapy.  Diaphoresis is|
03113|022|M|unaffected by beta-blockade and can be used by the diabetic to recognize|
03113|023|M|hypoglycemia.|
03113|024|B||
03113|025|D|DISCUSSION:  A class effect of diminished glucose-lowering effects is|
03113|026|D|expected with concurrent use of beta-blockers and insulin. It is prudent to|
03113|027|D|monitor serum glucose closely in patients receiving beta-blocker therapy|
03113|028|D|because symptoms of hypoglycemia may be masked.|
03113|029|D|   A double blind, randomized, 12 month study of 39 patients tested the|
03113|030|D|metabolic effects of pindolol (5 mg BID) compared to control group on|
03113|031|D|insulin sensitivity. The patient's insulin sensitivity index decreased 17%|
03113|032|D|when on pindolol treatment compared to placebo (p<0.01). Insulin mediated|
03113|033|D|glucose uptake was significantly lower (p<0.05) with propranolol treatment|
03113|034|D|than with placebo. (1)|
03113|035|D|   A study of 26 patients with chronic heart failure showed that carvedilol|
03113|036|D|(average daily dose 27.5 mg/d) caused a significant decrease in fasting|
03113|037|D|insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment|
03113|038|D|levels. This trial also showed that patients on carvedilol had significantly|
03113|039|D|(p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the|
03113|040|D|fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment|
03113|041|D|(5.9mg/d).(2)|
03113|042|B||
03113|043|R|REFERENCES:|
03113|044|B||
03113|045|R|1.Lithell H, Pollare T, Vessby B. Metabolic effects of pindolol and|2
03113|046|R|  propranolol in a double-blind cross-over study in hypertensive patients.|2
03113|047|R|  Blood Press 1992 Aug;1(2):92-101.|2
03113|048|R|2.Kovacic D, Marinsek M, Gobec L, Lainscak M, Podbregar M. Effect of|2
03113|049|R|  selective and non-selective beta-blockers on body weight, insulin|2
03113|050|R|  resistance and leptin concentration in chronic heart failure. Clin Res|2
03113|051|R|  Cardiol 2008 Jan;97(1):24-31.|2
03113|052|R|3.Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic|2
03113|053|R|  mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic|2
03113|054|R|  hyperglycemia in insulin- dependent diabetes mellitus. J Clin Invest 1982|2
03113|055|R|  Feb;69(2):315-26.|2
03113|056|R|4.Hansten PD. Drug interactions update. Beta-blocking agents and|6
03113|057|R|  antidiabetic drugs. Drug Intell Clin Pharm 1980 Jan;14:46-50.|6
03114|001|T|MONOGRAPH TITLE:  Insulin/Selected Systemic Non-Cardioselective|
03114|002|T|Beta-Blockers|
03114|003|B||
03114|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03114|005|L|take action as needed.|
03114|006|B||
03114|007|A|MECHANISM OF ACTION:  Not fully established. Probably blockade of a variety|
03114|008|A|of beta-adrenergic responses to hypoglycemia.|
03114|009|B||
03114|010|E|CLINICAL EFFECTS:  Diminished response to insulin may occur. Frequency and|
03114|011|E|severity of hypoglycemic episodes may be increased, while warning symptoms|
03114|012|E|of low blood sugar may be masked.|
03114|013|B||
03114|014|P|PREDISPOSING FACTORS:  None determined.|
03114|015|B||
03114|016|M|PATIENT MANAGEMENT:  Try to avoid beta-blocker therapy, particularly in|
03114|017|M|diabetics prone to hypoglycemic attacks.  One of the cardioselective agents|
03114|018|M|may decrease risk of hypertensive attacks and allow more rapid glucose|
03114|019|M|recovery from hypoglycemia.|
03114|020|M|   Patients should be counseled not to rely on tachycardia to diagnose|
03114|021|M|hypoglycemia, since it is masked by beta-blocker therapy.  Diaphoresis is|
03114|022|M|unaffected by beta-blockade and can be used by the diabetic to recognize|
03114|023|M|hypoglycemia.|
03114|024|B||
03114|025|D|DISCUSSION:  A class effect of diminished glucose-lowering effects is|
03114|026|D|expected with concurrent use of beta-blockers and insulin. It is prudent to|
03114|027|D|monitor serum glucose closely in patients receiving beta-blocker therapy|
03114|028|D|because symptoms of hypoglycemia may be masked.|
03114|029|D|   A double blind, randomized, 12 month study of 39 patients tested the|
03114|030|D|metabolic effects of pindolol (5 mg BID) compared to control group on|
03114|031|D|insulin sensitivity. The patient's insulin sensitivity index decreased 17%|
03114|032|D|when on pindolol treatment compared to placebo (p<0.01). Insulin mediated|
03114|033|D|glucose uptake was significantly lower (p<0.05) with propranolol treatment|
03114|034|D|than with placebo. (1)|
03114|035|D|   A study of 26 patients with chronic heart failure showed that carvedilol|
03114|036|D|(average daily dose 27.5 mg/d) caused a significant decrease in fasting|
03114|037|D|insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment|
03114|038|D|levels. This trial also showed that patients on carvedilol had significantly|
03114|039|D|(p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the|
03114|040|D|fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment|
03114|041|D|(5.9mg/d).(2)|
03114|042|B||
03114|043|R|REFERENCES:|
03114|044|B||
03114|045|R|1.Lithell H, Pollare T, Vessby B. Metabolic effects of pindolol and|2
03114|046|R|  propranolol in a double-blind cross-over study in hypertensive patients.|2
03114|047|R|  Blood Press 1992 Aug;1(2):92-101.|2
03114|048|R|2.Kovacic D, Marinsek M, Gobec L, Lainscak M, Podbregar M. Effect of|2
03114|049|R|  selective and non-selective beta-blockers on body weight, insulin|2
03114|050|R|  resistance and leptin concentration in chronic heart failure. Clin Res|2
03114|051|R|  Cardiol 2008 Jan;97(1):24-31.|2
03114|052|R|3.Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic|2
03114|053|R|  mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic|2
03114|054|R|  hyperglycemia in insulin- dependent diabetes mellitus. J Clin Invest 1982|2
03114|055|R|  Feb;69(2):315-26.|2
03114|056|R|4.Hansten PD. Drug interactions update. Beta-blocking agents and|6
03114|057|R|  antidiabetic drugs. Drug Intell Clin Pharm 1980 Jan;14:46-50.|6
03115|001|T|MONOGRAPH TITLE:  Insulin/Carvedilol; Labetalol|
03115|002|B||
03115|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03115|004|L|take action as needed.|
03115|005|B||
03115|006|A|MECHANISM OF ACTION:  Not fully established. Probably blockade of a variety|
03115|007|A|of beta-adrenergic responses to hypoglycemia.|
03115|008|B||
03115|009|E|CLINICAL EFFECTS:  Diminished response to insulin may occur. Frequency and|
03115|010|E|severity of hypoglycemic episodes may be increased, while warning symptoms|
03115|011|E|of low blood sugar may be masked.|
03115|012|B||
03115|013|P|PREDISPOSING FACTORS:  None determined.|
03115|014|B||
03115|015|M|PATIENT MANAGEMENT:  Try to avoid beta-blocker therapy, particularly in|
03115|016|M|diabetics prone to hypoglycemic attacks.  One of the cardioselective agents|
03115|017|M|may decrease risk of hypertensive attacks and allow more rapid glucose|
03115|018|M|recovery from hypoglycemia.|
03115|019|M|   Patients should be counseled not to rely on tachycardia to diagnose|
03115|020|M|hypoglycemia, since it is masked by beta-blocker therapy.  Diaphoresis is|
03115|021|M|unaffected by beta-blockade and can be used by the diabetic to recognize|
03115|022|M|hypoglycemia.|
03115|023|B||
03115|024|D|DISCUSSION:  A class effect of diminished glucose-lowering effects is|
03115|025|D|expected with concurrent use of beta-blockers and insulin. It is prudent to|
03115|026|D|monitor serum glucose closely in patients receiving beta-blocker therapy|
03115|027|D|because symptoms of hypoglycemia may be masked.|
03115|028|D|   A double blind, randomized, 12 month study of 39 patients tested the|
03115|029|D|metabolic effects of pindolol (5 mg BID) compared to control group on|
03115|030|D|insulin sensitivity. The patient's insulin sensitivity index decreased 17%|
03115|031|D|when on pindolol treatment compared to placebo (p<0.01). Insulin mediated|
03115|032|D|glucose uptake was significantly lower (p<0.05) with propranolol treatment|
03115|033|D|than with placebo. (1)|
03115|034|D|   A study of 26 patients with chronic heart failure showed that carvedilol|
03115|035|D|(average daily dose 27.5 mg/d) caused a significant decrease in fasting|
03115|036|D|insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment|
03115|037|D|levels. This trial also showed that patients on carvedilol had significantly|
03115|038|D|(p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the|
03115|039|D|fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment|
03115|040|D|(5.9mg/d).(2)|
03115|041|B||
03115|042|R|REFERENCES:|
03115|043|B||
03115|044|R|1.Lithell H, Pollare T, Vessby B. Metabolic effects of pindolol and|2
03115|045|R|  propranolol in a double-blind cross-over study in hypertensive patients.|2
03115|046|R|  Blood Press 1992 Aug;1(2):92-101.|2
03115|047|R|2.Kovacic D, Marinsek M, Gobec L, Lainscak M, Podbregar M. Effect of|2
03115|048|R|  selective and non-selective beta-blockers on body weight, insulin|2
03115|049|R|  resistance and leptin concentration in chronic heart failure. Clin Res|2
03115|050|R|  Cardiol 2008 Jan;97(1):24-31.|2
03115|051|R|3.Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic|2
03115|052|R|  mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic|2
03115|053|R|  hyperglycemia in insulin- dependent diabetes mellitus. J Clin Invest 1982|2
03115|054|R|  Feb;69(2):315-26.|2
03115|055|R|4.Hansten PD. Drug interactions update. Beta-blocking agents and|6
03115|056|R|  antidiabetic drugs. Drug Intell Clin Pharm 1980 Jan;14:46-50.|6
03116|001|T|MONOGRAPH TITLE:  Nateglinide; Repaglinide/Slt Non-Cardioselective|
03116|002|T|B-Blockers|
03116|003|B||
03116|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03116|005|L|take action as needed.|
03116|006|B||
03116|007|A|MECHANISM OF ACTION:  Not fully established. Probably blockade of a variety|
03116|008|A|of beta-adrenergic responses to hypoglycemia.|
03116|009|B||
03116|010|E|CLINICAL EFFECTS:  Diminished response to nateglinide and repaglinide may|
03116|011|E|occur. Frequency and severity of hypoglycemic episodes may be increased,|
03116|012|E|while warning symptoms of low blood sugar may be masked.|
03116|013|B||
03116|014|P|PREDISPOSING FACTORS:  None determined.|
03116|015|B||
03116|016|M|PATIENT MANAGEMENT:  Try to avoid beta-blocker therapy, particularly in|
03116|017|M|diabetics prone to hypoglycemic attacks.  One of the cardioselective agents|
03116|018|M|may decrease risk of hypertensive attacks and allow more rapid glucose|
03116|019|M|recovery from hypoglycemia.|
03116|020|M|   Patients should be counseled not to rely on tachycardia to diagnose|
03116|021|M|hypoglycemia, since it is masked by beta-blocker therapy.  Diaphoresis is|
03116|022|M|unaffected by beta-blockade and can be used by the diabetic to recognize|
03116|023|M|hypoglycemia.|
03116|024|B||
03116|025|D|DISCUSSION:  A class effect of diminished glucose-lowering effects is|
03116|026|D|expected with concurrent use of beta-blockers and nateglinide or|
03116|027|D|repaglinide. It is prudent to monitor serum glucose closely in patients|
03116|028|D|receiving beta-blocker therapy because symptoms of hypoglycemia may be|
03116|029|D|masked.|
03116|030|D|   A double blind, randomized, 12 month study of 39 patients tested the|
03116|031|D|metabolic effects of pindolol (5 mg BID) compared to control group on|
03116|032|D|insulin sensitivity. The patient's insulin sensitivity index decreased 17%|
03116|033|D|when on pindolol treatment compared to placebo (p<0.01). Insulin mediated|
03116|034|D|glucose uptake was significantly lower (p<0.05) with propranolol treatment|
03116|035|D|than with placebo. (1)|
03116|036|D|   A study of 26 patients with chronic heart failure showed that carvedilol|
03116|037|D|(average daily dose 27.5 mg/d) caused a significant decrease in fasting|
03116|038|D|insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment|
03116|039|D|levels. This trial also showed that patients on carvedilol had significantly|
03116|040|D|(p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the|
03116|041|D|fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment|
03116|042|D|(5.9mg/d).(2)|
03116|043|B||
03116|044|R|REFERENCES:|
03116|045|B||
03116|046|R|1.Lithell H, Pollare T, Vessby B. Metabolic effects of pindolol and|2
03116|047|R|  propranolol in a double-blind cross-over study in hypertensive patients.|2
03116|048|R|  Blood Press 1992 Aug;1(2):92-101.|2
03116|049|R|2.Kovacic D, Marinsek M, Gobec L, Lainscak M, Podbregar M. Effect of|2
03116|050|R|  selective and non-selective beta-blockers on body weight, insulin|2
03116|051|R|  resistance and leptin concentration in chronic heart failure. Clin Res|2
03116|052|R|  Cardiol 2008 Jan;97(1):24-31.|2
03116|053|R|3.Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic|2
03116|054|R|  mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic|2
03116|055|R|  hyperglycemia in insulin- dependent diabetes mellitus. J Clin Invest 1982|2
03116|056|R|  Feb;69(2):315-26.|2
03116|057|R|4.Hansten PD. Drug interactions update. Beta-blocking agents and|6
03116|058|R|  antidiabetic drugs. Drug Intell Clin Pharm 1980 Jan;14:46-50.|6
03117|001|T|MONOGRAPH TITLE:  Nateglinide; Repaglinide/Slt Non-Cardioselective|
03117|002|T|B-Blockers|
03117|003|B||
03117|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03117|005|L|take action as needed.|
03117|006|B||
03117|007|A|MECHANISM OF ACTION:  Not fully established. Probably blockade of a variety|
03117|008|A|of beta-adrenergic responses to hypoglycemia.|
03117|009|B||
03117|010|E|CLINICAL EFFECTS:  Diminished response to nateglinide and repaglinide may|
03117|011|E|occur. Frequency and severity of hypoglycemic episodes may be increased,|
03117|012|E|while warning symptoms of low blood sugar may be masked.|
03117|013|B||
03117|014|P|PREDISPOSING FACTORS:  None determined.|
03117|015|B||
03117|016|M|PATIENT MANAGEMENT:  Try to avoid beta-blocker therapy, particularly in|
03117|017|M|diabetics prone to hypoglycemic attacks.  One of the cardioselective agents|
03117|018|M|may decrease risk of hypertensive attacks and allow more rapid glucose|
03117|019|M|recovery from hypoglycemia.|
03117|020|M|   Patients should be counseled not to rely on tachycardia to diagnose|
03117|021|M|hypoglycemia, since it is masked by beta-blocker therapy.  Diaphoresis is|
03117|022|M|unaffected by beta-blockade and can be used by the diabetic to recognize|
03117|023|M|hypoglycemia.|
03117|024|B||
03117|025|D|DISCUSSION:  A double blind, randomized, 12 month study of 39 patients|
03117|026|D|tested the metabolic effects of pindolol (5 mg BID) compared to control|
03117|027|D|group on insulin sensitivity. The patient's insulin sensitivity index|
03117|028|D|decreased 17% when on pindolol treatment compared to placebo (p<0.01).|
03117|029|D|Insulin mediated glucose uptake was significantly lower (p<0.05) with|
03117|030|D|propranolol treatment than with placebo. (1)|
03117|031|D|   A study of 26 patients with chronic heart failure showed that carvedilol|
03117|032|D|(average daily dose 27.5 mg/d) caused a significant decrease in fasting|
03117|033|D|insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment|
03117|034|D|levels. This trial also showed that patients on carvedilol had significantly|
03117|035|D|(p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the|
03117|036|D|fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment|
03117|037|D|(5.9mg/d).(2)|
03117|038|B||
03117|039|R|REFERENCES:|
03117|040|B||
03117|041|R|1.Lithell H, Pollare T, Vessby B. Metabolic effects of pindolol and|2
03117|042|R|  propranolol in a double-blind cross-over study in hypertensive patients.|2
03117|043|R|  Blood Press 1992 Aug;1(2):92-101.|2
03117|044|R|2.Kovacic D, Marinsek M, Gobec L, Lainscak M, Podbregar M. Effect of|2
03117|045|R|  selective and non-selective beta-blockers on body weight, insulin|2
03117|046|R|  resistance and leptin concentration in chronic heart failure. Clin Res|2
03117|047|R|  Cardiol 2008 Jan;97(1):24-31.|2
03117|048|R|3.Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic|2
03117|049|R|  mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic|2
03117|050|R|  hyperglycemia in insulin- dependent diabetes mellitus. J Clin Invest 1982|2
03117|051|R|  Feb;69(2):315-26.|2
03117|052|R|4.Hansten PD. Drug interactions update. Beta-blocking agents and|6
03117|053|R|  antidiabetic drugs. Drug Intell Clin Pharm 1980 Jan;14:46-50.|6
03118|001|T|MONOGRAPH TITLE:  Bupropion/Tricyclic Antidepressants|
03118|002|B||
03118|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03118|004|L|take action as needed.|
03118|005|B||
03118|006|A|MECHANISM OF ACTION:  Depending upon the antidepressant, one or two|
03118|007|A|mechanisms may be involved.|
03118|008|A|   Both bupropion and tricyclic antidepressants are known to lower the|
03118|009|A|seizure threshold.(1,2)|
03118|010|A|   Bupropion, a strong inhibitor of CYP2D6, may increase systemic exposure|
03118|011|A|(AUC, area-under-curve) to tricyclic antidepressants that are metabolized by|
03118|012|A|this pathway.  Antidepressants which are very sensitive to CYP2D6 inhibition|
03118|013|A|are: desipramine, doxepin, and trimipramine.  Antidepressants which are|
03118|014|A|moderately sensitive to CYP2D6 inhibition are: amitriptyline, imipramine,|
03118|015|A|maprotiline, and nortriptyline.  Antidepressants which are metabolized by|
03118|016|A|CYP2D6 but less susceptible to CYP2D6 inhibition includes clomipramine.(3)|
03118|017|B||
03118|018|E|CLINICAL EFFECTS:  Concurrent use of bupropion and a tricyclic|
03118|019|E|antidepressant may result in additive effects on the seizure threshold,|
03118|020|E|increasing the risk of seizures.(1,2)|
03118|021|E|   Concurrent use may also increase levels of and side effects from|
03118|022|E|antidepressants metabolized by CYP2D6, such as amitriptyline, clomipramine,|
03118|023|E|imipramine, maprotiline, and nortriptyline.(3)|
03118|024|B||
03118|025|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
03118|026|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
03118|027|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
03118|028|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics; a|
03118|029|P|total daily dose of bupropion greater than 450 mg or single doses greater|
03118|030|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
03118|031|P|oral hypoglycemics or insulin; or with concomitant medications known to|
03118|032|P|lower seizure threshold (antipsychotics, theophylline, systemic|
03118|033|P|steroids).(1,2)|
03118|034|P|   The risk of anticholinergic toxicities including cognitive decline,|
03118|035|P|delirium, falls and fractures is increased in geriatric patients using more|
03118|036|P|than one medicine with anticholinergic properties.(4)|
03118|037|B||
03118|038|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and tricyclic|
03118|039|M|antidepressants should be undertaken only with extreme caution and with low|
03118|040|M|initial bupropion dosing and small gradual dosage increases.(1,2)  Single|
03118|041|M|doses should not exceed 150 mg.(1,2)  The maximum daily dose of bupropion|
03118|042|M|should not exceed 300 mg for smoking cessation(2) or 450 mg for|
03118|043|M|depression.(1)|
03118|044|M|   If concurrent use of doxepin and bupropion is warranted, monitor doxepin|
03118|045|M|plasma concentrations and reduce the doxepin dose based on doxepin plasma|
03118|046|M|concentrations.(5)|
03118|047|B||
03118|048|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
03118|049|D|other agents that lower seizure threshold, the manufacturer of bupropion|
03118|050|D|states that the concurrent use of bupropion and antidepressants should be|
03118|051|D|undertaken only with extreme caution and with low initial bupropion dosing|
03118|052|D|and small gradual dosage increases.(1,2)|
03118|053|D|   In a study in 15 male subjects who were extensive metabolizers of CYP2D6,|
03118|054|D|bupropion (150 mg twice daily) increased the maximum concentration (Cmax),|
03118|055|D|area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine|
03118|056|D|(50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2)|
03118|057|B||
03118|058|R|REFERENCES:|
03118|059|B||
03118|060|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
03118|061|R|  GlaxoSmithKline November, 2019.|1
03118|062|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
03118|063|R|  GlaxoSmithKline July, 2019.|1
03118|064|R|3.This information is based on an extract from the Certara Drug Interaction|6
03118|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03118|066|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03118|067|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03118|068|R|  Soc 2023 Jul;71(7):2052-2081.|6
03118|069|R|5.Sinequan (doxepin) US prescribing information. Pfizer July, 2025.|1
03119|001|T|MONOGRAPH TITLE:  Bupropion/SNRIs; SSRIs|
03119|002|B||
03119|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03119|004|L|take action as needed.|
03119|005|B||
03119|006|A|MECHANISM OF ACTION:  Both bupropion and the SSRIs and SNRIs are known to|
03119|007|A|lower the seizure threshold.(1,2)|
03119|008|A|   In addition, bupropion, a strong inhibitor of CYP2D6, may inhibit the|
03119|009|A|metabolism of SSRIs and SNRIs metabolized by CYP2D6.  The potential for|
03119|010|A|bupropion to inhibit the metabolism of the antidepressant differs.|
03119|011|A|Antidepressants that are very sensitive to CYP2D6 inhibition have a greater|
03119|012|A|potential for increased effects.|
03119|013|A|   Antidepressants which are very sensitive to CYP2D6 inhibition and have|
03119|014|A|the greatest potential for increased effects are: fluoxetine,(3)|
03119|015|A|paroxetine,(4) and venlafaxine.(5)|
03119|016|A|   Antidepressants which are moderately sensitive to CYP2D6 inhibition are:|
03119|017|A|fluvoxamine.(6)|
03119|018|A|   Antidepressants which are metabolized by CYP2D6 but less susceptible to|
03119|019|A|CYP2D6 inhibition and therefore have a lower potential for increased effects|
03119|020|A|are: citalopram(7) and duloxetine.(8)|
03119|021|B||
03119|022|E|CLINICAL EFFECTS:  Concurrent use of bupropion and a SSRI or SNRI may result|
03119|023|E|in additive effects on the seizure threshold, increasing the risk of|
03119|024|E|seizures.(1,2)|
03119|025|E|   Concurrent use may also increase levels of and side effects from|
03119|026|E|antidepressants metabolized by CYP2D6, such as citalopram, duloxetine,|
03119|027|E|fluoxetine, fluvoxamine, paroxetine, and venlafaxine.(3-10)|
03119|028|B||
03119|029|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
03119|030|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
03119|031|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
03119|032|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
03119|033|P|total daily dose of bupropion greater than 450 mg or single doses greater|
03119|034|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
03119|035|P|oral hypoglycemics or insulin; or with concomitant medications known to|
03119|036|P|lower seizure threshold (antipsychotics, theophylline, systemic|
03119|037|P|steroids).(1,2)|
03119|038|P|   With paroxetine, the risk of anticholinergic toxicities including|
03119|039|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
03119|040|P|patients using more than one medicine with anticholinergic properties.(11)|
03119|041|B||
03119|042|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and SSRIs or SNRIs|
03119|043|M|should be undertaken only with extreme caution and with low initial|
03119|044|M|bupropion dosing and small gradual dosage increases.(1,2)  Single doses|
03119|045|M|should not exceed 150 mg.(1,2)|
03119|046|M|   The maximum daily dose of bupropion should not exceed 300 mg for smoking|
03119|047|M|cessation(2) or 450 mg for depression.(1)|
03119|048|B||
03119|049|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
03119|050|D|other agents that lower seizure threshold, the manufacturer of bupropion|
03119|051|D|states that the concurrent use of bupropion and antidepressants should be|
03119|052|D|undertaken only with extreme caution and with low initial bupropion dosing|
03119|053|D|and small gradual dosage increases.(1,2)|
03119|054|D|   In a study in 15 male subjects who were extensive metabolizers of CYP2D6,|
03119|055|D|bupropion (150 mg twice daily) increased the maximum concentration (Cmax),|
03119|056|D|area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine|
03119|057|D|(50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2)|
03119|058|D|   In a clinical study, citalopram steady state levels were not|
03119|059|D|significantly different in poor metabolizers and extensive metabolizers of|
03119|060|D|CYP2D6.  Coadministration of a drug that inhibits CYP2D6 with citalopram is|
03119|061|D|unlikely to have clinically significant effects on citalopram metabolism,|
03119|062|D|based on the study results in CYP2D6 poor metabolizers.(7)|
03119|063|D|   Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg|
03119|064|D|once daily) increased the AUC of duloxetine by about 60%.(8)|
03119|065|D|   An in vivo study of single-dose fluvoxamine evaluated pharmacokinetic|
03119|066|D|changes in 13 poor metabolizers (PM) compared to 16 extensive metabolizers|
03119|067|D|(EM).  The mean Cmax, AUC, and half-life were increased by 52%, 200%, and|
03119|068|D|62%, respectively, in the PM compared to the EM group.(6)|
03119|069|D|   Fluoxetine, paroxetine, and venlafaxine are classified as sensitive|
03119|070|D|CYP2D6 substrates with an increase in AUC >= 5-fold.(9)|
03119|071|D|   The FDA defines sensitive substrates as drugs that have an increase in|
03119|072|D|AUC >= 5-fold and moderate sensitive substrates have an increase in AUC >=|
03119|073|D|2-fold to <5-fold when administered with strong inhibitors.(10)|
03119|074|B||
03119|075|R|REFERENCES:|
03119|076|B||
03119|077|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
03119|078|R|  GlaxoSmithKline November, 2019.|1
03119|079|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
03119|080|R|  GlaxoSmithKline July, 2019.|1
03119|081|R|3.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
03119|082|R|  and Company August, 2023.|1
03119|083|R|4.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
03119|084|R|  Therapeutics, LLC September, 2021.|1
03119|085|R|5.Effexor XR (venlafaxine hydrochloride) US prescribing information. Viatris|1
03119|086|R|  August, 2023.|1
03119|087|R|6.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
03119|088|R|  Pharmaceuticals, Inc. August, 2023.|1
03119|089|R|7.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03119|090|R|  Laboratories Inc. August, 2023.|1
03119|091|R|8.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
03119|092|R|  and Company September, 2021.|1
03119|093|R|9.This information is based on an extract from the Certara Drug Interaction|6
03119|094|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03119|095|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
03119|096|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03119|097|R|   at:|1
03119|098|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03119|099|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03119|100|R|   11/14/2017.|1
03119|101|R|11.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03119|102|R|   potentially  inappropriate medication use in older adults. J Am Geriatr|6
03119|103|R|   Soc 2023 Jul;71(7):2052-2081.|6
03121|001|T|MONOGRAPH TITLE:  Tizanidine/Selected ACE Inhibitors|
03121|002|B||
03121|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03121|004|L|take action as needed.|
03121|005|B||
03121|006|A|MECHANISM OF ACTION:  Tizanidine is an alpha-2 agonist.  Concurrent use with|
03121|007|A|ACE inhibitors may result in additive effects on blood pressure.(1)|
03121|008|B||
03121|009|E|CLINICAL EFFECTS:  Concurrent use of antihypertensives and tizanidine may|
03121|010|E|result in hypotension.(1)|
03121|011|B||
03121|012|P|PREDISPOSING FACTORS:  None determined.|
03121|013|B||
03121|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
03121|015|M|monitored for hypotension.  The risk of hypotension may be decreased by|
03121|016|M|careful titration of tizanidine dosages and monitoring for hypotension prior|
03121|017|M|to dose advancement.  Counsel patients about the risk of orthostatic|
03121|018|M|hypotension.(1)|
03121|019|B||
03121|020|D|DISCUSSION:  Severe hypotension has been reported following the addition of|
03121|021|D|tizanidine to existing lisinopril therapy.(2-4)|
03121|022|B||
03121|023|R|REFERENCES:|
03121|024|B||
03121|025|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
03121|026|R|  Pharma Inc. November 22, 2024.|1
03121|027|R|2.Publow SW, Branam DL. Hypotension and bradycardia associated with|3
03121|028|R|  concomitant tizanidine and lisinopril therapy. Am J Health Syst Pharm 2010|3
03121|029|R|  Oct 01;67(19):1606-10.|3
03121|030|R|3.Kao CD, Chang JB, Chen JT, Wu ZA, Shan DE, Liao KK. Hypotension due to|3
03121|031|R|  interaction between lisinopril and tizanidine. Ann Pharmacother 2004 Nov;|3
03121|032|R|  38(11):1840-3.|3
03121|033|R|4.Johnson TR, Tobias JD. Hypotension following the initiation of tizanidine|3
03121|034|R|  in a patient treated with an angiotensin converting enzyme inhibitor for|3
03121|035|R|  chronic hypertension. J Child Neurol 2000 Dec;15(12):818-9.|3
03122|001|T|MONOGRAPH TITLE:  Tizanidine/Selected ACE Inhibitors|
03122|002|B||
03122|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03122|004|L|take action as needed.|
03122|005|B||
03122|006|A|MECHANISM OF ACTION:  Tizanidine is an alpha-2 agonist.  Concurrent use with|
03122|007|A|ACE inhibitors may result in additive effects on blood pressure.(1)|
03122|008|B||
03122|009|E|CLINICAL EFFECTS:  Concurrent use of ACE inhibitors and tizanidine may|
03122|010|E|result in hypotension.(1)|
03122|011|B||
03122|012|P|PREDISPOSING FACTORS:  None determined.|
03122|013|B||
03122|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
03122|015|M|monitored for hypotension.  The risk of hypotension may be decreased by|
03122|016|M|careful titration of tizanidine dosages and monitoring for hypotension prior|
03122|017|M|to dose advancement.  Counsel patients about the risk of orthostatic|
03122|018|M|hypotension.(1)|
03122|019|B||
03122|020|D|DISCUSSION:  Severe hypotension has been reported following the addition of|
03122|021|D|tizanidine to existing lisinopril therapy.(2-4)|
03122|022|B||
03122|023|R|REFERENCES:|
03122|024|B||
03122|025|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
03122|026|R|  Pharma Inc. November 22, 2024.|1
03122|027|R|2.Publow SW, Branam DL. Hypotension and bradycardia associated with|3
03122|028|R|  concomitant tizanidine and lisinopril therapy. Am J Health Syst Pharm 2010|3
03122|029|R|  Oct 01;67(19):1606-10.|3
03122|030|R|3.Kao CD, Chang JB, Chen JT, Wu ZA, Shan DE, Liao KK. Hypotension due to|3
03122|031|R|  interaction between lisinopril and tizanidine. Ann Pharmacother 2004 Nov;|3
03122|032|R|  38(11):1840-3.|3
03122|033|R|4.Johnson TR, Tobias JD. Hypotension following the initiation of tizanidine|3
03122|034|R|  in a patient treated with an angiotensin converting enzyme inhibitor for|3
03122|035|R|  chronic hypertension. J Child Neurol 2000 Dec;15(12):818-9.|3
03123|001|T|MONOGRAPH TITLE:  Tizanidine/Clonidine; Guanadrel; Guanethidine|
03123|002|B||
03123|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03123|004|L|take action as needed.|
03123|005|B||
03123|006|A|MECHANISM OF ACTION:  Tizanidine is an alpha-2 agonist.  Concurrent use with|
03123|007|A|antihypertensive agents may result in additive effects on blood pressure.(1)|
03123|008|B||
03123|009|E|CLINICAL EFFECTS:  Concurrent use of antihypertensives and tizanidine may|
03123|010|E|result in hypotension.(1)|
03123|011|B||
03123|012|P|PREDISPOSING FACTORS:  None determined.|
03123|013|B||
03123|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
03123|015|M|monitored for hypotension.  The risk of hypotension may be decreased by|
03123|016|M|careful titration of tizanidine dosages and monitoring for hypotension prior|
03123|017|M|to dose advancement.  Counsel patients about the risk of orthostatic|
03123|018|M|hypotension.(1)|
03123|019|B||
03123|020|D|DISCUSSION:  Severe hypotension has been reported following the addition of|
03123|021|D|tizanidine to existing lisinopril therapy.(2-4)|
03123|022|B||
03123|023|R|REFERENCES:|
03123|024|B||
03123|025|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
03123|026|R|  Pharma Inc. November 22, 2024.|1
03123|027|R|2.Publow SW, Branam DL. Hypotension and bradycardia associated with|3
03123|028|R|  concomitant tizanidine and lisinopril therapy. Am J Health Syst Pharm 2010|3
03123|029|R|  Oct 01;67(19):1606-10.|3
03123|030|R|3.Kao CD, Chang JB, Chen JT, Wu ZA, Shan DE, Liao KK. Hypotension due to|3
03123|031|R|  interaction between lisinopril and tizanidine. Ann Pharmacother 2004 Nov;|3
03123|032|R|  38(11):1840-3.|3
03123|033|R|4.Johnson TR, Tobias JD. Hypotension following the initiation of tizanidine|3
03123|034|R|  in a patient treated with an angiotensin converting enzyme inhibitor for|3
03123|035|R|  chronic hypertension. J Child Neurol 2000 Dec;15(12):818-9.|3
03124|001|T|MONOGRAPH TITLE:  Tizanidine/Guanfacine; Methyldopa|
03124|002|B||
03124|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03124|004|L|take action as needed.|
03124|005|B||
03124|006|A|MECHANISM OF ACTION:  Tizanidine is an alpha-2 agonist.  Concurrent use with|
03124|007|A|antihypertensive agents may result in additive effects on blood pressure.(1)|
03124|008|B||
03124|009|E|CLINICAL EFFECTS:  Concurrent use of antihypertensives and tizanidine may|
03124|010|E|result in hypotension.(1)|
03124|011|B||
03124|012|P|PREDISPOSING FACTORS:  None determined.|
03124|013|B||
03124|014|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
03124|015|M|monitored for hypotension.  The risk of hypotension may be decreased by|
03124|016|M|careful titration of tizanidine dosages and monitoring for hypotension prior|
03124|017|M|to dose advancement.  Counsel patients about the risk of orthostatic|
03124|018|M|hypotension.(1)|
03124|019|B||
03124|020|D|DISCUSSION:  Severe hypotension has been reported following the addition of|
03124|021|D|tizanidine to existing lisinopril therapy.(2-4)|
03124|022|B||
03124|023|R|REFERENCES:|
03124|024|B||
03124|025|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
03124|026|R|  Pharma Inc. November 22, 2024.|1
03124|027|R|2.Publow SW, Branam DL. Hypotension and bradycardia associated with|3
03124|028|R|  concomitant tizanidine and lisinopril therapy. Am J Health Syst Pharm 2010|3
03124|029|R|  Oct 01;67(19):1606-10.|3
03124|030|R|3.Kao CD, Chang JB, Chen JT, Wu ZA, Shan DE, Liao KK. Hypotension due to|3
03124|031|R|  interaction between lisinopril and tizanidine. Ann Pharmacother 2004 Nov;|3
03124|032|R|  38(11):1840-3.|3
03124|033|R|4.Johnson TR, Tobias JD. Hypotension following the initiation of tizanidine|3
03124|034|R|  in a patient treated with an angiotensin converting enzyme inhibitor for|3
03124|035|R|  chronic hypertension. J Child Neurol 2000 Dec;15(12):818-9.|3
03125|001|T|MONOGRAPH TITLE:  Rosuvastatin/Clarithromycin|
03125|002|B||
03125|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03125|004|L|take action as needed.|
03125|005|B||
03125|006|A|MECHANISM OF ACTION:  Clarithromycin has been shown to inhibit organic|
03125|007|A|anion-transporting polypeptide (OATP) OATP1B1 and OATP1B3.  Rosuvastatin is|
03125|008|A|a substrate of this transporter.(1,2)|
03125|009|B||
03125|010|E|CLINICAL EFFECTS:  Simultaneous use of clarithromycin may result in|
03125|011|E|increased levels and side effects from rosuvastatin, including|
03125|012|E|rhabdomyolysis.(1,2)|
03125|013|B||
03125|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03125|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03125|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03125|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03125|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03125|019|P|transporter OATP1B1 may have increased statin concentrations and be|
03125|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
03125|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
03125|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
03125|023|B||
03125|024|M|PATIENT MANAGEMENT:  Concurrent use may result in increased risk of side|
03125|025|M|effects associated with rosuvastatin.  If concurrent therapy is warranted,|
03125|026|M|close monitoring would be prudent for statin related side effects including|
03125|027|M|rhabdomyolysis.  Educate the patient of signs and symptoms of|
03125|028|M|rhabdomyolysis.(1)|
03125|029|B||
03125|030|D|DISCUSSION:  In a cohort study of over 100,000 patients who received|
03125|031|D|co-prescription of clarithromycin or azithromycin (control group) with|
03125|032|D|concurrent rosuvastatin therapy were reviewed for 30 days after index date|
03125|033|D|for outcomes including hospital admission for rhabdomyolysis, admission for|
03125|034|D|acute kidney injury, admission for hyperkalemia, and all-cause mortality.|
03125|035|D|In the cohort population, 76% of patients received rosuvastatin therapy|
03125|036|D|followed by pravastatin (21%) and fluvastatin (3%).  Concurrent use with|
03125|037|D|clarithromycin was associated with increased risk of hospital admission for|
03125|038|D|acute kidney injury (relative risk (RR) 1.46, 95% CI 1.16-1.84), hospital|
03125|039|D|admission for hyperkalemia (RR 1.87, 95% CI 1.05-3.32), and all-cause|
03125|040|D|mortality (RR 1.32, 95% CI 1.07-1.62).  The overall number of admissions for|
03125|041|D|rhabdomyolysis were limited (13 events with clarithromycin) therefore did|
03125|042|D|not reach statistical significance (RR 2.21, 95% CI 0.84-5.81).(2)|
03125|043|B||
03125|044|R|REFERENCES:|
03125|045|B||
03125|046|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03125|047|R|  Pharmaceuticals LP July, 2024.|1
03125|048|R|2.Li DQ, Kim R, McArthur E, Fleet JL, Bailey DG, Juurlink D, Shariff SZ,|2
03125|049|R|  Gomes T, Mamdani M, Gandhi S, Dixon S, Garg AX. Risk of adverse events|2
03125|050|R|  among older adults following co-prescription of clarithromycin and statins|2
03125|051|R|  not metabolized by cytochrome P450 3A4. CMAJ 2015 Feb 17;187(3):174-80.|2
03126|001|T|MONOGRAPH TITLE:  Aliskiren/NSAIDs; Salicylates|
03126|002|B||
03126|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03126|004|L|take action as needed.|
03126|005|B||
03126|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  It is believed to be|
03126|007|A|related to inhibition of prostaglandin synthesis by the NSAIDs.  Use of an|
03126|008|A|NSAID in combination with aliskiren, whose hypotensive effects may be|
03126|009|A|related to the increase in hypotensive prostaglandins, may negate any|
03126|010|A|decrease in blood pressure.|
03126|011|B||
03126|012|E|CLINICAL EFFECTS:  Concurrent use of aliskiren with NSAIDs may result in|
03126|013|E|decreased antihypertensive effects.  In patients with existing renal|
03126|014|E|impairment, the use of these agents together may also result in further|
03126|015|E|deterioration of renal clearance caused by renal hypoperfusion.|
03126|016|B||
03126|017|P|PREDISPOSING FACTORS:  None determined.|
03126|018|B||
03126|019|M|PATIENT MANAGEMENT:  Patients maintained on aliskiren should be monitored|
03126|020|M|for a loss of blood pressure control and a change in renal function if an|
03126|021|M|NSAID is added to their regimen.  Patients receiving concurrent therapy may|
03126|022|M|require higher doses of aliskiren.  If blood pressure control cannot be|
03126|023|M|achieved or if the patient's renal function deteriorates, the NSAID may need|
03126|024|M|to be discontinued.  Patients should be monitored for hypotension if NSAIDs|
03126|025|M|are withdrawn from concurrent aliskiren therapy.|
03126|026|B||
03126|027|D|DISCUSSION:  Indomethacin has been shown to inhibit the antihypertensive|
03126|028|D|effect of captopril, cilazapril, enalapril, losartan, perindopril, and|
03126|029|D|valsartan.  Ibuprofen has been shown to decrease the antihypertensive|
03126|030|D|effects of captopril.  Two separate case reports describe individuals|
03126|031|D|suspected of ACEI-associated angioedema precipitated by NSAIDs.  Both cases|
03126|032|D|reported symptom resolution after cessation of the NSAID.|
03126|033|D|   Studies have shown that sulindac does not affect the antihypertensive|
03126|034|D|effects of captopril and enalapril.|
03126|035|B||
03126|036|R|REFERENCES:|
03126|037|B||
03126|038|R|1.Swartz SL, Williams GH. Angiotensin-converting enzyme inhibition and|2
03126|039|R|  prostaglandins. Am J Cardiol 1982 Apr 21;49(6):1405-9.|2
03126|040|R|2.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03126|041|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03126|042|R|3.Abe K, Ito T, Sato M, Haruyama T, Sato K, Omata K, Hiwatari M, Sakurai Y,|2
03126|043|R|  Imai Y, Yoshinaga K. Role of prostaglandin in the antihypertensive|2
03126|044|R|  mechanism of captopril in low renin hypertension. Clin Sci (Lond) 1980|2
03126|045|R|  Dec;59 Suppl 6:141s-144s.|2
03126|046|R|4.Abe K, Itoh T, Imai Y, Sato M, Goto T, Otsuka Y, Yoshinaga K. Indomethacin|2
03126|047|R|  inhibits the antihypertensive effect of captopril, SQ 14225, in low renin|2
03126|048|R|  hypertension. Tohoku J Exp Med 1980 Sep;132(1):117-8.|2
03126|049|R|5.Moore TJ, Crantz FR, Hollenberg NK, Koletsky RJ, Leboff MS, Swartz SL,|2
03126|050|R|  Levine L, Podolsky S, Dluhy RG, Williams GH. Contribution of|2
03126|051|R|  prostaglandins to the antihypertensive action of captopril in essential|2
03126|052|R|  hypertension. Hypertension 1981 Mar-Apr;3(2):168-73.|2
03126|053|R|6.Fujita T, Yamashita N, Yamashita K. Effect of indomethacin on|2
03126|054|R|  antihypertensive action of captopril in hypertensive patients. Clin Exp|2
03126|055|R|  Hypertens 1981;3(5):939-52.|2
03126|056|R|7.Ogihara T, Maruyama A, Hata T, Mikami H, Nakamaru M, Naka T, Ohde H,|2
03126|057|R|  Kumahara Y. Hormonal responses to long-term converting enzyme inhibition|2
03126|058|R|  in hypertensive patients. Clin Pharmacol Ther 1981 Sep;30(3):328-35.|2
03126|059|R|8.Silberbauer K, Stanek B, Templ H. Acute hypotensive effect of captopril in|2
03126|060|R|  man modified by prostaglandin synthesis inhibition. Br J Clin Pharmacol|2
03126|061|R|  1982;14 Suppl 2:87S-93S.|2
03126|062|R|9.Salvetti A, Pedrinelli R, Magagna A, Ugenti P. Differential effects of|2
03126|063|R|  selective and non-selective prostaglandin-synthesis inhibition on the|2
03126|064|R|  pharmacological responses to captopril in patients with essential|2
03126|065|R|  hypertension. Clin Sci 1982;63(Suppl 8):261s-3s.|2
03126|066|R|10.Gilchrist NL, Richards AM, March R, Nicholls MG. Effect of sulindac on|2
03126|067|R|   angiotensin converting enzyme inhibitor-induced cough: randomised|2
03126|068|R|   placebo-controlled double-blind cross-over study. J Hum Hypertens 1989|2
03126|069|R|   Dec;3(6):451-5.|2
03126|070|R|11.Ohya Y, Kumamoto K, Fujishima M. Effects of crossover application of|3
03126|071|R|   sulindac and azelastine on enalapril-induced cough. J Hum Hypertens 1992|3
03126|072|R|   Feb;6(1):81-2.|3
03126|073|R|12.Allon M, Pasque CB, Rodriguez M. Interaction of captopril and ibuprofen|2
03126|074|R|   on glomerular and tubular function in humans. Am J Physiol 1990 Aug;259(2|2
03126|075|R|   Pt 2):F233-8.|2
03126|076|R|13.Allon M, Pasque CB, Rodriguez M. Acute effects of captopril and ibuprofen|2
03126|077|R|   on proteinuria in patients with nephrosis. J Lab Clin Med 1990 Oct;|2
03126|078|R|   116(4):462-8.|2
03126|079|R|14.Minuz P, Lechi A, Arosio E, Degan M, Capuzzo MG, Lechi C, Corsato M,|2
03126|080|R|   Dalla Riva A, Velo GP. Antihypertensive activity of enalapril. Effect of|2
03126|081|R|   ibuprofen and different salt intakes. J Clin Hypertens 1987 Dec;|2
03126|082|R|   3(4):645-53.|2
03126|083|R|15.Polonia J, Boaventura I, Gama G, Camoes I, Bernardo F, Andrade P, Nunes|2
03126|084|R|   JP, Brandao F, Cerqueira-Gomes M. Influence of non-steroidal|2
03126|085|R|   anti-inflammatory drugs on renal function and 24h ambulatory blood|2
03126|086|R|   pressure-reducing effects of enalapril and nifedipine gastrointestinal|2
03126|087|R|   therapeutic system in hypertensive patients. J Hypertens 1995 Aug;|2
03126|088|R|   13(8):925-31.|2
03126|089|R|16.Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood|2
03126|090|R|   pressure in elderly people with essential hypertension well controlled on|2
03126|091|R|   amlodipine or enalapril. Am J Hypertens 2000 Nov;13(11):1161-7.|2
03126|092|R|17.Conlin PR, Moore TJ, Swartz SL, Barr E, Gazdick L, Fletcher C, DeLucca P,|2
03126|093|R|   Demopoulos L. Effect of indomethacin on blood pressure lowering by|2
03126|094|R|   captopril and losartan in hypertensive patients. Hypertension 2000 Sep;|2
03126|095|R|   36(3):461-5.|2
03126|096|R|18.Fricker AF, Nussberger J, Meilenbrock S, Brunner HR, Burnier M. Effect of|2
03126|097|R|   indomethacin on the renal response to angiotensin II receptor blockade in|2
03126|098|R|   healthy subjects. Kidney Int 1998 Dec;54(6):2089-97.|2
03126|099|R|19.Morgan T, Anderson A. Interaction of indomethacin with felodipine and|2
03126|100|R|   enalapril. J Hypertens Suppl 1993 Dec;11 Suppl 5:S338-9.|2
03126|101|R|20.Halawa B. Effect of indomethacin and ibuprofen on blood pressure of|2
03126|102|R|   patients treated with nifedipine or captopril. Pol Tyg Lek 1993 Apr 5-12;|2
03126|103|R|   48(14-15):313-5.|2
03126|104|R|21.Espino DV, Lancaster MC. Neutralization of the effects of captopril by|3
03126|105|R|   the use of ibuprofen in an elderly woman. J Am Board Fam Pract 1992|3
03126|106|R|   May-Jun;5(3):319-21.|3
03126|107|R|22.Abdel-Haq B, Magagna A, Favilla S, Salvetti A. Hemodynamic and humoral|2
03126|108|R|   interactions between perindopril and indomethacin in essential|2
03126|109|R|   hypertensive subjects. J Cardiovasc Pharmacol 1991;18 Suppl 7:S33-6.|2
03126|110|R|23.Heeg JE, de Jong PE, de Zeeuw D. Additive antiproteinuric effect of|2
03126|111|R|   angiotensin-converting enzyme inhibition and non-steroidal|2
03126|112|R|   anti-inflammatory drug therapy: a clue to the mechanism of action. Clin|2
03126|113|R|   Sci (Lond) 1991 Sep;81(3):367-72.|2
03126|114|R|24.Kirch W, Stroemer K, Hoogkamer JF, Kleinbloesem CH. The influence of|2
03126|115|R|   prostaglandin inhibition by indomethacin on blood pressure and renal|2
03126|116|R|   function in hypertensive patients treated with cilazapril. Br J Clin|2
03126|117|R|   Pharmacol 1989;27 Suppl 2:297S-301S.|2
03126|118|R|25.Fogari R, Zoppi A, Carretta R, Veglio F, Salvetti A. Effect of|2
03126|119|R|   indomethacin on the antihypertensive efficacy of valsartan and|2
03126|120|R|   lisinopril: a multicentre study. J Hypertens 2002 May;20(5):1007-14.|2
03126|121|R|26.Prlesi L, Plakogiannis R. Angioedema after nonsteroidal antiinflammatory|3
03126|122|R|   drug initiation in a patient stable on an angiotensin-converting-enzyme|3
03126|123|R|   inhibitor. Am J Health Syst Pharm 2010 Aug 15;67(16):1351-3.|3
03126|124|R|27.Kampitak T. Recurrent severe angioedema associated with imidapril and|3
03126|125|R|   diclofenac. Allergol Int 2008 Dec;57(4):441-3.|3
03126|126|R|28.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03126|127|R|   Corporation November, 2017.|1
03127|001|T|MONOGRAPH TITLE:  Selected ACE Inhibitors/Indomethacin|
03127|002|B||
03127|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03127|004|L|take action as needed.|
03127|005|B||
03127|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  It is believed to be|
03127|007|A|related to inhibition of prostaglandin synthesis by the NSAIDs.  Use of an|
03127|008|A|NSAID in combination with an ACE inhibitor, whose hypotensive effects may be|
03127|009|A|related to the increase in hypotensive prostaglandins, may negate any|
03127|010|A|decrease in blood pressure.|
03127|011|B||
03127|012|E|CLINICAL EFFECTS:  Concurrent use of ACE inhibitors with NSAIDs may result|
03127|013|E|in decreased antihypertensive effects.  In patients with existing renal|
03127|014|E|impairment, the use of these agents together may also result in further|
03127|015|E|deterioration of renal clearance caused by renal hypoperfusion.|
03127|016|B||
03127|017|P|PREDISPOSING FACTORS:  None determined.|
03127|018|B||
03127|019|M|PATIENT MANAGEMENT:  Patients maintained on ACE inhibitors should be|
03127|020|M|monitored for a loss of blood pressure control and a change in renal|
03127|021|M|function if an NSAID is added to their regimen.  Patients receiving|
03127|022|M|concurrent therapy may require higher doses of ACE inhibitors.  If blood|
03127|023|M|pressure control cannot be achieved or if the patient's renal function|
03127|024|M|deteriorates, the NSAID may need to be discontinued.  Patients should be|
03127|025|M|monitored for hypotension if NSAIDs are withdrawn from concurrent ACE|
03127|026|M|inhibitor therapy.|
03127|027|B||
03127|028|D|DISCUSSION:  Indomethacin has been shown to inhibit the antihypertensive|
03127|029|D|effect of captopril, cilazapril, enalapril, losartan, perindopril, and|
03127|030|D|valsartan.   Ibuprofen has been shown to decrease the antihypertensive|
03127|031|D|effects of captopril.   Two separate case reports describe individuals|
03127|032|D|suspected of ACEI-associated angioedema precipitated by NSAIDs.  Both cases|
03127|033|D|reported symptom resolution after cessation of the NSAID.|
03127|034|D|   Studies have shown that sulindac does not affect the antihypertensive|
03127|035|D|effects of captopril and enalapril.|
03127|036|D|   One or more of the drug pairs linked to this monograph have been included|
03127|037|D|in a list of interactions that could be considered for classification as|
03127|038|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
03127|039|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
03127|040|D|Health Information Technology.|
03127|041|B||
03127|042|R|REFERENCES:|
03127|043|B||
03127|044|R|1.Swartz SL, Williams GH. Angiotensin-converting enzyme inhibition and|2
03127|045|R|  prostaglandins. Am J Cardiol 1982 Apr 21;49(6):1405-9.|2
03127|046|R|2.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03127|047|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03127|048|R|3.Abe K, Ito T, Sato M, Haruyama T, Sato K, Omata K, Hiwatari M, Sakurai Y,|2
03127|049|R|  Imai Y, Yoshinaga K. Role of prostaglandin in the antihypertensive|2
03127|050|R|  mechanism of captopril in low renin hypertension. Clin Sci (Lond) 1980|2
03127|051|R|  Dec;59 Suppl 6:141s-144s.|2
03127|052|R|4.Abe K, Itoh T, Imai Y, Sato M, Goto T, Otsuka Y, Yoshinaga K. Indomethacin|2
03127|053|R|  inhibits the antihypertensive effect of captopril, SQ 14225, in low renin|2
03127|054|R|  hypertension. Tohoku J Exp Med 1980 Sep;132(1):117-8.|2
03127|055|R|5.Moore TJ, Crantz FR, Hollenberg NK, Koletsky RJ, Leboff MS, Swartz SL,|2
03127|056|R|  Levine L, Podolsky S, Dluhy RG, Williams GH. Contribution of|2
03127|057|R|  prostaglandins to the antihypertensive action of captopril in essential|2
03127|058|R|  hypertension. Hypertension 1981 Mar-Apr;3(2):168-73.|2
03127|059|R|6.Fujita T, Yamashita N, Yamashita K. Effect of indomethacin on|2
03127|060|R|  antihypertensive action of captopril in hypertensive patients. Clin Exp|2
03127|061|R|  Hypertens 1981;3(5):939-52.|2
03127|062|R|7.Ogihara T, Maruyama A, Hata T, Mikami H, Nakamaru M, Naka T, Ohde H,|2
03127|063|R|  Kumahara Y. Hormonal responses to long-term converting enzyme inhibition|2
03127|064|R|  in hypertensive patients. Clin Pharmacol Ther 1981 Sep;30(3):328-35.|2
03127|065|R|8.Silberbauer K, Stanek B, Templ H. Acute hypotensive effect of captopril in|2
03127|066|R|  man modified by prostaglandin synthesis inhibition. Br J Clin Pharmacol|2
03127|067|R|  1982;14 Suppl 2:87S-93S.|2
03127|068|R|9.Salvetti A, Pedrinelli R, Magagna A, Ugenti P. Differential effects of|2
03127|069|R|  selective and non-selective prostaglandin-synthesis inhibition on the|2
03127|070|R|  pharmacological responses to captopril in patients with essential|2
03127|071|R|  hypertension. Clin Sci 1982;63(Suppl 8):261s-3s.|2
03127|072|R|10.Gilchrist NL, Richards AM, March R, Nicholls MG. Effect of sulindac on|2
03127|073|R|   angiotensin converting enzyme inhibitor-induced cough: randomised|2
03127|074|R|   placebo-controlled double-blind cross-over study. J Hum Hypertens 1989|2
03127|075|R|   Dec;3(6):451-5.|2
03127|076|R|11.Ohya Y, Kumamoto K, Fujishima M. Effects of crossover application of|3
03127|077|R|   sulindac and azelastine on enalapril-induced cough. J Hum Hypertens 1992|3
03127|078|R|   Feb;6(1):81-2.|3
03127|079|R|12.Allon M, Pasque CB, Rodriguez M. Interaction of captopril and ibuprofen|2
03127|080|R|   on glomerular and tubular function in humans. Am J Physiol 1990 Aug;259(2|2
03127|081|R|   Pt 2):F233-8.|2
03127|082|R|13.Allon M, Pasque CB, Rodriguez M. Acute effects of captopril and ibuprofen|2
03127|083|R|   on proteinuria in patients with nephrosis. J Lab Clin Med 1990 Oct;|2
03127|084|R|   116(4):462-8.|2
03127|085|R|14.Minuz P, Lechi A, Arosio E, Degan M, Capuzzo MG, Lechi C, Corsato M,|2
03127|086|R|   Dalla Riva A, Velo GP. Antihypertensive activity of enalapril. Effect of|2
03127|087|R|   ibuprofen and different salt intakes. J Clin Hypertens 1987 Dec;|2
03127|088|R|   3(4):645-53.|2
03127|089|R|15.Polonia J, Boaventura I, Gama G, Camoes I, Bernardo F, Andrade P, Nunes|2
03127|090|R|   JP, Brandao F, Cerqueira-Gomes M. Influence of non-steroidal|2
03127|091|R|   anti-inflammatory drugs on renal function and 24h ambulatory blood|2
03127|092|R|   pressure-reducing effects of enalapril and nifedipine gastrointestinal|2
03127|093|R|   therapeutic system in hypertensive patients. J Hypertens 1995 Aug;|2
03127|094|R|   13(8):925-31.|2
03127|095|R|16.Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood|2
03127|096|R|   pressure in elderly people with essential hypertension well controlled on|2
03127|097|R|   amlodipine or enalapril. Am J Hypertens 2000 Nov;13(11):1161-7.|2
03127|098|R|17.Conlin PR, Moore TJ, Swartz SL, Barr E, Gazdick L, Fletcher C, DeLucca P,|2
03127|099|R|   Demopoulos L. Effect of indomethacin on blood pressure lowering by|2
03127|100|R|   captopril and losartan in hypertensive patients. Hypertension 2000 Sep;|2
03127|101|R|   36(3):461-5.|2
03127|102|R|18.Fricker AF, Nussberger J, Meilenbrock S, Brunner HR, Burnier M. Effect of|2
03127|103|R|   indomethacin on the renal response to angiotensin II receptor blockade in|2
03127|104|R|   healthy subjects. Kidney Int 1998 Dec;54(6):2089-97.|2
03127|105|R|19.Morgan T, Anderson A. Interaction of indomethacin with felodipine and|2
03127|106|R|   enalapril. J Hypertens Suppl 1993 Dec;11 Suppl 5:S338-9.|2
03127|107|R|20.Halawa B. Effect of indomethacin and ibuprofen on blood pressure of|2
03127|108|R|   patients treated with nifedipine or captopril. Pol Tyg Lek 1993 Apr 5-12;|2
03127|109|R|   48(14-15):313-5.|2
03127|110|R|21.Espino DV, Lancaster MC. Neutralization of the effects of captopril by|3
03127|111|R|   the use of ibuprofen in an elderly woman. J Am Board Fam Pract 1992|3
03127|112|R|   May-Jun;5(3):319-21.|3
03127|113|R|22.Abdel-Haq B, Magagna A, Favilla S, Salvetti A. Hemodynamic and humoral|2
03127|114|R|   interactions between perindopril and indomethacin in essential|2
03127|115|R|   hypertensive subjects. J Cardiovasc Pharmacol 1991;18 Suppl 7:S33-6.|2
03127|116|R|23.Heeg JE, de Jong PE, de Zeeuw D. Additive antiproteinuric effect of|2
03127|117|R|   angiotensin-converting enzyme inhibition and non-steroidal|2
03127|118|R|   anti-inflammatory drug therapy: a clue to the mechanism of action. Clin|2
03127|119|R|   Sci (Lond) 1991 Sep;81(3):367-72.|2
03127|120|R|24.Kirch W, Stroemer K, Hoogkamer JF, Kleinbloesem CH. The influence of|2
03127|121|R|   prostaglandin inhibition by indomethacin on blood pressure and renal|2
03127|122|R|   function in hypertensive patients treated with cilazapril. Br J Clin|2
03127|123|R|   Pharmacol 1989;27 Suppl 2:297S-301S.|2
03127|124|R|25.Fogari R, Zoppi A, Carretta R, Veglio F, Salvetti A. Effect of|2
03127|125|R|   indomethacin on the antihypertensive efficacy of valsartan and|2
03127|126|R|   lisinopril: a multicentre study. J Hypertens 2002 May;20(5):1007-14.|2
03127|127|R|26.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
03127|128|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
03127|129|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
03127|130|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
03127|131|R|27.Prlesi L, Plakogiannis R. Angioedema after nonsteroidal antiinflammatory|3
03127|132|R|   drug initiation in a patient stable on an angiotensin-converting-enzyme|3
03127|133|R|   inhibitor. Am J Health Syst Pharm 2010 Aug 15;67(16):1351-3.|3
03127|134|R|28.Kampitak T. Recurrent severe angioedema associated with imidapril and|3
03127|135|R|   diclofenac. Allergol Int 2008 Dec;57(4):441-3.|3
03127|136|R|29.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03127|137|R|   Corporation November, 2017.|1
03128|001|T|MONOGRAPH TITLE:  Selected ACE Inhibitors/Indomethacin|
03128|002|B||
03128|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03128|004|L|take action as needed.|
03128|005|B||
03128|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  It is believed to be|
03128|007|A|related to inhibition of prostaglandin synthesis by the NSAIDs.  Use of an|
03128|008|A|NSAID in combination with an ACE inhibitor, whose hypotensive effects may be|
03128|009|A|related to the increase in hypotensive prostaglandins, may negate any|
03128|010|A|decrease in blood pressure.|
03128|011|B||
03128|012|E|CLINICAL EFFECTS:  Concurrent use of ACE inhibitors with NSAIDs may result|
03128|013|E|in decreased antihypertensive effects.  In patients with existing renal|
03128|014|E|impairment, the use of these agents together may also result in further|
03128|015|E|deterioration of renal clearance caused by renal hypoperfusion.|
03128|016|B||
03128|017|P|PREDISPOSING FACTORS:  None determined.|
03128|018|B||
03128|019|M|PATIENT MANAGEMENT:  Patients maintained on ACE inhibitors should be|
03128|020|M|monitored for a loss of blood pressure control and a change in renal|
03128|021|M|function if an NSAID is added to their regimen.  Patients receiving|
03128|022|M|concurrent therapy may require higher doses of ACE inhibitors.  If blood|
03128|023|M|pressure control cannot be achieved or if the patient's renal function|
03128|024|M|deteriorates, the NSAID may need to be discontinued.  Patients should be|
03128|025|M|monitored for hypotension if NSAIDs are withdrawn from concurrent ACE|
03128|026|M|inhibitor therapy.|
03128|027|B||
03128|028|D|DISCUSSION:  Indomethacin has been shown to inhibit the antihypertensive|
03128|029|D|effect of captopril, cilazapril, enalapril, losartan, perindopril, and|
03128|030|D|valsartan.  Ibuprofen has been shown to decrease the antihypertensive|
03128|031|D|effects of captopril.  Two separate case reports describe individuals|
03128|032|D|suspected of ACEI-associated angioedema precipitated by NSAIDs.  Both cases|
03128|033|D|reported symptom resolution after cessation of the NSAID.|
03128|034|D|   Studies have shown that sulindac does not affect the antihypertensive|
03128|035|D|effects of captopril and enalapril.|
03128|036|D|   One or more of the drug pairs linked to this monograph have been included|
03128|037|D|in a list of interactions that could be considered for classification as|
03128|038|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
03128|039|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
03128|040|D|Health Information Technology.|
03128|041|B||
03128|042|R|REFERENCES:|
03128|043|B||
03128|044|R|1.Swartz SL, Williams GH. Angiotensin-converting enzyme inhibition and|2
03128|045|R|  prostaglandins. Am J Cardiol 1982 Apr 21;49(6):1405-9.|2
03128|046|R|2.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03128|047|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03128|048|R|3.Abe K, Ito T, Sato M, Haruyama T, Sato K, Omata K, Hiwatari M, Sakurai Y,|2
03128|049|R|  Imai Y, Yoshinaga K. Role of prostaglandin in the antihypertensive|2
03128|050|R|  mechanism of captopril in low renin hypertension. Clin Sci (Lond) 1980|2
03128|051|R|  Dec;59 Suppl 6:141s-144s.|2
03128|052|R|4.Abe K, Itoh T, Imai Y, Sato M, Goto T, Otsuka Y, Yoshinaga K. Indomethacin|2
03128|053|R|  inhibits the antihypertensive effect of captopril, SQ 14225, in low renin|2
03128|054|R|  hypertension. Tohoku J Exp Med 1980 Sep;132(1):117-8.|2
03128|055|R|5.Moore TJ, Crantz FR, Hollenberg NK, Koletsky RJ, Leboff MS, Swartz SL,|2
03128|056|R|  Levine L, Podolsky S, Dluhy RG, Williams GH. Contribution of|2
03128|057|R|  prostaglandins to the antihypertensive action of captopril in essential|2
03128|058|R|  hypertension. Hypertension 1981 Mar-Apr;3(2):168-73.|2
03128|059|R|6.Fujita T, Yamashita N, Yamashita K. Effect of indomethacin on|2
03128|060|R|  antihypertensive action of captopril in hypertensive patients. Clin Exp|2
03128|061|R|  Hypertens 1981;3(5):939-52.|2
03128|062|R|7.Ogihara T, Maruyama A, Hata T, Mikami H, Nakamaru M, Naka T, Ohde H,|2
03128|063|R|  Kumahara Y. Hormonal responses to long-term converting enzyme inhibition|2
03128|064|R|  in hypertensive patients. Clin Pharmacol Ther 1981 Sep;30(3):328-35.|2
03128|065|R|8.Silberbauer K, Stanek B, Templ H. Acute hypotensive effect of captopril in|2
03128|066|R|  man modified by prostaglandin synthesis inhibition. Br J Clin Pharmacol|2
03128|067|R|  1982;14 Suppl 2:87S-93S.|2
03128|068|R|9.Salvetti A, Pedrinelli R, Magagna A, Ugenti P. Differential effects of|2
03128|069|R|  selective and non-selective prostaglandin-synthesis inhibition on the|2
03128|070|R|  pharmacological responses to captopril in patients with essential|2
03128|071|R|  hypertension. Clin Sci 1982;63(Suppl 8):261s-3s.|2
03128|072|R|10.Gilchrist NL, Richards AM, March R, Nicholls MG. Effect of sulindac on|2
03128|073|R|   angiotensin converting enzyme inhibitor-induced cough: randomised|2
03128|074|R|   placebo-controlled double-blind cross-over study. J Hum Hypertens 1989|2
03128|075|R|   Dec;3(6):451-5.|2
03128|076|R|11.Ohya Y, Kumamoto K, Fujishima M. Effects of crossover application of|3
03128|077|R|   sulindac and azelastine on enalapril-induced cough. J Hum Hypertens 1992|3
03128|078|R|   Feb;6(1):81-2.|3
03128|079|R|12.Allon M, Pasque CB, Rodriguez M. Interaction of captopril and ibuprofen|2
03128|080|R|   on glomerular and tubular function in humans. Am J Physiol 1990 Aug;259(2|2
03128|081|R|   Pt 2):F233-8.|2
03128|082|R|13.Allon M, Pasque CB, Rodriguez M. Acute effects of captopril and ibuprofen|2
03128|083|R|   on proteinuria in patients with nephrosis. J Lab Clin Med 1990 Oct;|2
03128|084|R|   116(4):462-8.|2
03128|085|R|14.Minuz P, Lechi A, Arosio E, Degan M, Capuzzo MG, Lechi C, Corsato M,|2
03128|086|R|   Dalla Riva A, Velo GP. Antihypertensive activity of enalapril. Effect of|2
03128|087|R|   ibuprofen and different salt intakes. J Clin Hypertens 1987 Dec;|2
03128|088|R|   3(4):645-53.|2
03128|089|R|15.Polonia J, Boaventura I, Gama G, Camoes I, Bernardo F, Andrade P, Nunes|2
03128|090|R|   JP, Brandao F, Cerqueira-Gomes M. Influence of non-steroidal|2
03128|091|R|   anti-inflammatory drugs on renal function and 24h ambulatory blood|2
03128|092|R|   pressure-reducing effects of enalapril and nifedipine gastrointestinal|2
03128|093|R|   therapeutic system in hypertensive patients. J Hypertens 1995 Aug;|2
03128|094|R|   13(8):925-31.|2
03128|095|R|16.Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood|2
03128|096|R|   pressure in elderly people with essential hypertension well controlled on|2
03128|097|R|   amlodipine or enalapril. Am J Hypertens 2000 Nov;13(11):1161-7.|2
03128|098|R|17.Conlin PR, Moore TJ, Swartz SL, Barr E, Gazdick L, Fletcher C, DeLucca P,|2
03128|099|R|   Demopoulos L. Effect of indomethacin on blood pressure lowering by|2
03128|100|R|   captopril and losartan in hypertensive patients. Hypertension 2000 Sep;|2
03128|101|R|   36(3):461-5.|2
03128|102|R|18.Fricker AF, Nussberger J, Meilenbrock S, Brunner HR, Burnier M. Effect of|2
03128|103|R|   indomethacin on the renal response to angiotensin II receptor blockade in|2
03128|104|R|   healthy subjects. Kidney Int 1998 Dec;54(6):2089-97.|2
03128|105|R|19.Morgan T, Anderson A. Interaction of indomethacin with felodipine and|2
03128|106|R|   enalapril. J Hypertens Suppl 1993 Dec;11 Suppl 5:S338-9.|2
03128|107|R|20.Halawa B. Effect of indomethacin and ibuprofen on blood pressure of|2
03128|108|R|   patients treated with nifedipine or captopril. Pol Tyg Lek 1993 Apr 5-12;|2
03128|109|R|   48(14-15):313-5.|2
03128|110|R|21.Espino DV, Lancaster MC. Neutralization of the effects of captopril by|3
03128|111|R|   the use of ibuprofen in an elderly woman. J Am Board Fam Pract 1992|3
03128|112|R|   May-Jun;5(3):319-21.|3
03128|113|R|22.Abdel-Haq B, Magagna A, Favilla S, Salvetti A. Hemodynamic and humoral|2
03128|114|R|   interactions between perindopril and indomethacin in essential|2
03128|115|R|   hypertensive subjects. J Cardiovasc Pharmacol 1991;18 Suppl 7:S33-6.|2
03128|116|R|23.Heeg JE, de Jong PE, de Zeeuw D. Additive antiproteinuric effect of|2
03128|117|R|   angiotensin-converting enzyme inhibition and non-steroidal|2
03128|118|R|   anti-inflammatory drug therapy: a clue to the mechanism of action. Clin|2
03128|119|R|   Sci (Lond) 1991 Sep;81(3):367-72.|2
03128|120|R|24.Kirch W, Stroemer K, Hoogkamer JF, Kleinbloesem CH. The influence of|2
03128|121|R|   prostaglandin inhibition by indomethacin on blood pressure and renal|2
03128|122|R|   function in hypertensive patients treated with cilazapril. Br J Clin|2
03128|123|R|   Pharmacol 1989;27 Suppl 2:297S-301S.|2
03128|124|R|25.Fogari R, Zoppi A, Carretta R, Veglio F, Salvetti A. Effect of|2
03128|125|R|   indomethacin on the antihypertensive efficacy of valsartan and|2
03128|126|R|   lisinopril: a multicentre study. J Hypertens 2002 May;20(5):1007-14.|2
03128|127|R|26.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
03128|128|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
03128|129|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
03128|130|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
03128|131|R|27.Prlesi L, Plakogiannis R. Angioedema after nonsteroidal antiinflammatory|3
03128|132|R|   drug initiation in a patient stable on an angiotensin-converting-enzyme|3
03128|133|R|   inhibitor. Am J Health Syst Pharm 2010 Aug 15;67(16):1351-3.|3
03128|134|R|28.Kampitak T. Recurrent severe angioedema associated with imidapril and|3
03128|135|R|   diclofenac. Allergol Int 2008 Dec;57(4):441-3.|3
03128|136|R|29.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03128|137|R|   Corporation November, 2017.|1
03129|001|T|MONOGRAPH TITLE:  ACE Inhibitors/Acemetacin; Proglumetacin; Salsalate|
03129|002|B||
03129|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03129|004|L|take action as needed.|
03129|005|B||
03129|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  It is believed to be|
03129|007|A|related to inhibition of prostaglandin synthesis by the NSAIDs.  Use of an|
03129|008|A|NSAID in combination with an ACE inhibitor, whose hypotensive effects may be|
03129|009|A|related to the increase in hypotensive prostaglandins, may negate any|
03129|010|A|decrease in blood pressure.|
03129|011|B||
03129|012|E|CLINICAL EFFECTS:  Concurrent use of ACE inhibitors with NSAIDs may result|
03129|013|E|in decreased antihypertensive effects.  In patients with existing renal|
03129|014|E|impairment, the use of these agents together may also result in further|
03129|015|E|deterioration of renal clearance caused by renal hypoperfusion.|
03129|016|B||
03129|017|P|PREDISPOSING FACTORS:  None determined.|
03129|018|B||
03129|019|M|PATIENT MANAGEMENT:  Patients maintained on ACE inhibitors should be|
03129|020|M|monitored for a loss of blood pressure control and a change in renal|
03129|021|M|function if an NSAID is added to their regimen.  Patients receiving|
03129|022|M|concurrent therapy may require higher doses of ACE inhibitors.  If blood|
03129|023|M|pressure control cannot be achieved or if the patient's renal function|
03129|024|M|deteriorates, the NSAID may need to be discontinued.  Patients should be|
03129|025|M|monitored for hypotension if NSAIDs are withdrawn from concurrent ACE|
03129|026|M|inhibitor therapy.|
03129|027|B||
03129|028|D|DISCUSSION:  Indomethacin has been shown to inhibit the antihypertensive|
03129|029|D|effect of captopril, cilazapril, enalapril, losartan, perindopril, and|
03129|030|D|valsartan.   Ibuprofen has been shown to decrease the antihypertensive|
03129|031|D|effects of captopril.   Two separate case reports describe individuals|
03129|032|D|suspected of ACEI-associated angioedema precipitated by NSAIDs.  Both cases|
03129|033|D|reported symptom resolution after cessation of the NSAID.|
03129|034|D|   Studies have shown that sulindac does not affect the antihypertensive|
03129|035|D|effects of captopril and enalapril.|
03129|036|D|   One or more of the drug pairs linked to this monograph have been included|
03129|037|D|in a list of interactions that could be considered for classification as|
03129|038|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
03129|039|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
03129|040|D|Health Information Technology.|
03129|041|B||
03129|042|R|REFERENCES:|
03129|043|B||
03129|044|R|1.Swartz SL, Williams GH. Angiotensin-converting enzyme inhibition and|2
03129|045|R|  prostaglandins. Am J Cardiol 1982 Apr 21;49(6):1405-9.|2
03129|046|R|2.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03129|047|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03129|048|R|3.Abe K, Ito T, Sato M, Haruyama T, Sato K, Omata K, Hiwatari M, Sakurai Y,|2
03129|049|R|  Imai Y, Yoshinaga K. Role of prostaglandin in the antihypertensive|2
03129|050|R|  mechanism of captopril in low renin hypertension. Clin Sci (Lond) 1980|2
03129|051|R|  Dec;59 Suppl 6:141s-144s.|2
03129|052|R|4.Abe K, Itoh T, Imai Y, Sato M, Goto T, Otsuka Y, Yoshinaga K. Indomethacin|2
03129|053|R|  inhibits the antihypertensive effect of captopril, SQ 14225, in low renin|2
03129|054|R|  hypertension. Tohoku J Exp Med 1980 Sep;132(1):117-8.|2
03129|055|R|5.Moore TJ, Crantz FR, Hollenberg NK, Koletsky RJ, Leboff MS, Swartz SL,|2
03129|056|R|  Levine L, Podolsky S, Dluhy RG, Williams GH. Contribution of|2
03129|057|R|  prostaglandins to the antihypertensive action of captopril in essential|2
03129|058|R|  hypertension. Hypertension 1981 Mar-Apr;3(2):168-73.|2
03129|059|R|6.Fujita T, Yamashita N, Yamashita K. Effect of indomethacin on|2
03129|060|R|  antihypertensive action of captopril in hypertensive patients. Clin Exp|2
03129|061|R|  Hypertens 1981;3(5):939-52.|2
03129|062|R|7.Ogihara T, Maruyama A, Hata T, Mikami H, Nakamaru M, Naka T, Ohde H,|2
03129|063|R|  Kumahara Y. Hormonal responses to long-term converting enzyme inhibition|2
03129|064|R|  in hypertensive patients. Clin Pharmacol Ther 1981 Sep;30(3):328-35.|2
03129|065|R|8.Silberbauer K, Stanek B, Templ H. Acute hypotensive effect of captopril in|2
03129|066|R|  man modified by prostaglandin synthesis inhibition. Br J Clin Pharmacol|2
03129|067|R|  1982;14 Suppl 2:87S-93S.|2
03129|068|R|9.Salvetti A, Pedrinelli R, Magagna A, Ugenti P. Differential effects of|2
03129|069|R|  selective and non-selective prostaglandin-synthesis inhibition on the|2
03129|070|R|  pharmacological responses to captopril in patients with essential|2
03129|071|R|  hypertension. Clin Sci 1982;63(Suppl 8):261s-3s.|2
03129|072|R|10.Gilchrist NL, Richards AM, March R, Nicholls MG. Effect of sulindac on|2
03129|073|R|   angiotensin converting enzyme inhibitor-induced cough: randomised|2
03129|074|R|   placebo-controlled double-blind cross-over study. J Hum Hypertens 1989|2
03129|075|R|   Dec;3(6):451-5.|2
03129|076|R|11.Ohya Y, Kumamoto K, Fujishima M. Effects of crossover application of|3
03129|077|R|   sulindac and azelastine on enalapril-induced cough. J Hum Hypertens 1992|3
03129|078|R|   Feb;6(1):81-2.|3
03129|079|R|12.Allon M, Pasque CB, Rodriguez M. Interaction of captopril and ibuprofen|2
03129|080|R|   on glomerular and tubular function in humans. Am J Physiol 1990 Aug;259(2|2
03129|081|R|   Pt 2):F233-8.|2
03129|082|R|13.Allon M, Pasque CB, Rodriguez M. Acute effects of captopril and ibuprofen|2
03129|083|R|   on proteinuria in patients with nephrosis. J Lab Clin Med 1990 Oct;|2
03129|084|R|   116(4):462-8.|2
03129|085|R|14.Minuz P, Lechi A, Arosio E, Degan M, Capuzzo MG, Lechi C, Corsato M,|2
03129|086|R|   Dalla Riva A, Velo GP. Antihypertensive activity of enalapril. Effect of|2
03129|087|R|   ibuprofen and different salt intakes. J Clin Hypertens 1987 Dec;|2
03129|088|R|   3(4):645-53.|2
03129|089|R|15.Polonia J, Boaventura I, Gama G, Camoes I, Bernardo F, Andrade P, Nunes|2
03129|090|R|   JP, Brandao F, Cerqueira-Gomes M. Influence of non-steroidal|2
03129|091|R|   anti-inflammatory drugs on renal function and 24h ambulatory blood|2
03129|092|R|   pressure-reducing effects of enalapril and nifedipine gastrointestinal|2
03129|093|R|   therapeutic system in hypertensive patients. J Hypertens 1995 Aug;|2
03129|094|R|   13(8):925-31.|2
03129|095|R|16.Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood|2
03129|096|R|   pressure in elderly people with essential hypertension well controlled on|2
03129|097|R|   amlodipine or enalapril. Am J Hypertens 2000 Nov;13(11):1161-7.|2
03129|098|R|17.Conlin PR, Moore TJ, Swartz SL, Barr E, Gazdick L, Fletcher C, DeLucca P,|2
03129|099|R|   Demopoulos L. Effect of indomethacin on blood pressure lowering by|2
03129|100|R|   captopril and losartan in hypertensive patients. Hypertension 2000 Sep;|2
03129|101|R|   36(3):461-5.|2
03129|102|R|18.Fricker AF, Nussberger J, Meilenbrock S, Brunner HR, Burnier M. Effect of|2
03129|103|R|   indomethacin on the renal response to angiotensin II receptor blockade in|2
03129|104|R|   healthy subjects. Kidney Int 1998 Dec;54(6):2089-97.|2
03129|105|R|19.Morgan T, Anderson A. Interaction of indomethacin with felodipine and|2
03129|106|R|   enalapril. J Hypertens Suppl 1993 Dec;11 Suppl 5:S338-9.|2
03129|107|R|20.Halawa B. Effect of indomethacin and ibuprofen on blood pressure of|2
03129|108|R|   patients treated with nifedipine or captopril. Pol Tyg Lek 1993 Apr 5-12;|2
03129|109|R|   48(14-15):313-5.|2
03129|110|R|21.Espino DV, Lancaster MC. Neutralization of the effects of captopril by|3
03129|111|R|   the use of ibuprofen in an elderly woman. J Am Board Fam Pract 1992|3
03129|112|R|   May-Jun;5(3):319-21.|3
03129|113|R|22.Abdel-Haq B, Magagna A, Favilla S, Salvetti A. Hemodynamic and humoral|2
03129|114|R|   interactions between perindopril and indomethacin in essential|2
03129|115|R|   hypertensive subjects. J Cardiovasc Pharmacol 1991;18 Suppl 7:S33-6.|2
03129|116|R|23.Heeg JE, de Jong PE, de Zeeuw D. Additive antiproteinuric effect of|2
03129|117|R|   angiotensin-converting enzyme inhibition and non-steroidal|2
03129|118|R|   anti-inflammatory drug therapy: a clue to the mechanism of action. Clin|2
03129|119|R|   Sci (Lond) 1991 Sep;81(3):367-72.|2
03129|120|R|24.Kirch W, Stroemer K, Hoogkamer JF, Kleinbloesem CH. The influence of|2
03129|121|R|   prostaglandin inhibition by indomethacin on blood pressure and renal|2
03129|122|R|   function in hypertensive patients treated with cilazapril. Br J Clin|2
03129|123|R|   Pharmacol 1989;27 Suppl 2:297S-301S.|2
03129|124|R|25.Fogari R, Zoppi A, Carretta R, Veglio F, Salvetti A. Effect of|2
03129|125|R|   indomethacin on the antihypertensive efficacy of valsartan and|2
03129|126|R|   lisinopril: a multicentre study. J Hypertens 2002 May;20(5):1007-14.|2
03129|127|R|26.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
03129|128|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
03129|129|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
03129|130|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
03129|131|R|27.Prlesi L, Plakogiannis R. Angioedema after nonsteroidal antiinflammatory|3
03129|132|R|   drug initiation in a patient stable on an angiotensin-converting-enzyme|3
03129|133|R|   inhibitor. Am J Health Syst Pharm 2010 Aug 15;67(16):1351-3.|3
03129|134|R|28.Kampitak T. Recurrent severe angioedema associated with imidapril and|3
03129|135|R|   diclofenac. Allergol Int 2008 Dec;57(4):441-3.|3
03129|136|R|29.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03129|137|R|   Corporation November, 2017.|1
03130|001|T|MONOGRAPH TITLE:  ACE Inhibitors/Selected NSAIDs; Salicylates|
03130|002|B||
03130|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03130|004|L|take action as needed.|
03130|005|B||
03130|006|A|MECHANISM OF ACTION:  ACE inhibitors can cause vasodilation of the efferent|
03130|007|A|renal arteriole which may result in decreased glomerular filtration rate.|
03130|008|A|NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar|
03130|009|A|vasoconstriction and may negate any decrease in blood pressure.|
03130|010|B||
03130|011|E|CLINICAL EFFECTS:  Concurrent use of ACE inhibitors with NSAIDs may result|
03130|012|E|in decreased antihypertensive effects.  In patients with existing renal|
03130|013|E|impairment, the use of these agents together may also result in further|
03130|014|E|deterioration of renal clearance caused by renal hypoperfusion.|
03130|015|E|    Concurrent use of ACE inhibitors with NSAIDs and diuretics may result in|
03130|016|E|increased risk of acute kidney injury (AKI).|
03130|017|B||
03130|018|P|PREDISPOSING FACTORS:  Low water intake/dehydration, drug sensitivity,|
03130|019|P|greater than 75 years of age, and renal impairment may increase an|
03130|020|P|individuals susceptibility to AKI.|
03130|021|B||
03130|022|M|PATIENT MANAGEMENT:  Patients maintained on ACE inhibitors should be|
03130|023|M|monitored for a loss of blood pressure control and a change in renal|
03130|024|M|function if an NSAID is added to their regimen.  Patients receiving|
03130|025|M|concurrent therapy may require higher doses of ACE inhibitors.  If blood|
03130|026|M|pressure control cannot be achieved or if the patient's renal function|
03130|027|M|deteriorates, the NSAID may need to be discontinued.  Patients should be|
03130|028|M|monitored for hypotension if NSAIDs are withdrawn from concurrent ACE|
03130|029|M|inhibitor therapy.|
03130|030|M|   Concurrent use of ACE inhibitors with NSAIDs and diuretics should be used|
03130|031|M|with caution and monitored closely for signs of AKI.|
03130|032|B||
03130|033|D|DISCUSSION:  In a computational study, the risk of AKI using triple therapy|
03130|034|D|with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was|
03130|035|D|assessed.  The study found the following factors may increase an|
03130|036|D|individual's susceptibility to AKI: low water intake, drug sensitivity,|
03130|037|D|greater than 75 years of age, and renal impairment.(30,31)|
03130|038|D|    In an observational study, current use of a triple therapy combination|
03130|039|D|was associated with an increased rate of acute kidney injury (rate ratio|
03130|040|D|(RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI|
03130|041|D|associated with triple therapy were observed in the first 30 days of use (RR|
03130|042|D|1.82, CI 1.35-2.46).(32)|
03130|043|D|    Indomethacin has been shown to inhibit the antihypertensive effect of|
03130|044|D|captopril, cilazapril, enalapril, losartan, perindopril, and valsartan.|
03130|045|D|Ibuprofen has been shown to decrease the antihypertensive effects of|
03130|046|D|captopril.  Two separate case reports describe individuals suspected of|
03130|047|D|ACEI-associated angioedema precipitated by NSAIDs.  Both cases reported|
03130|048|D|symptom resolution after cessation of the NSAID.|
03130|049|D|   Studies have shown that sulindac does not affect the antihypertensive|
03130|050|D|effects of captopril and enalapril.|
03130|051|D|   One or more of the drug pairs linked to this monograph have been included|
03130|052|D|in a list of interactions that could be considered for classification as|
03130|053|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
03130|054|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
03130|055|D|Health Information Technology.|
03130|056|B||
03130|057|R|REFERENCES:|
03130|058|B||
03130|059|R|1.Swartz SL, Williams GH. Angiotensin-converting enzyme inhibition and|2
03130|060|R|  prostaglandins. Am J Cardiol 1982 Apr 21;49(6):1405-9.|2
03130|061|R|2.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03130|062|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03130|063|R|3.Abe K, Ito T, Sato M, Haruyama T, Sato K, Omata K, Hiwatari M, Sakurai Y,|2
03130|064|R|  Imai Y, Yoshinaga K. Role of prostaglandin in the antihypertensive|2
03130|065|R|  mechanism of captopril in low renin hypertension. Clin Sci (Lond) 1980|2
03130|066|R|  Dec;59 Suppl 6:141s-144s.|2
03130|067|R|4.Abe K, Itoh T, Imai Y, Sato M, Goto T, Otsuka Y, Yoshinaga K. Indomethacin|2
03130|068|R|  inhibits the antihypertensive effect of captopril, SQ 14225, in low renin|2
03130|069|R|  hypertension. Tohoku J Exp Med 1980 Sep;132(1):117-8.|2
03130|070|R|5.Moore TJ, Crantz FR, Hollenberg NK, Koletsky RJ, Leboff MS, Swartz SL,|2
03130|071|R|  Levine L, Podolsky S, Dluhy RG, Williams GH. Contribution of|2
03130|072|R|  prostaglandins to the antihypertensive action of captopril in essential|2
03130|073|R|  hypertension. Hypertension 1981 Mar-Apr;3(2):168-73.|2
03130|074|R|6.Fujita T, Yamashita N, Yamashita K. Effect of indomethacin on|2
03130|075|R|  antihypertensive action of captopril in hypertensive patients. Clin Exp|2
03130|076|R|  Hypertens 1981;3(5):939-52.|2
03130|077|R|7.Ogihara T, Maruyama A, Hata T, Mikami H, Nakamaru M, Naka T, Ohde H,|2
03130|078|R|  Kumahara Y. Hormonal responses to long-term converting enzyme inhibition|2
03130|079|R|  in hypertensive patients. Clin Pharmacol Ther 1981 Sep;30(3):328-35.|2
03130|080|R|8.Silberbauer K, Stanek B, Templ H. Acute hypotensive effect of captopril in|2
03130|081|R|  man modified by prostaglandin synthesis inhibition. Br J Clin Pharmacol|2
03130|082|R|  1982;14 Suppl 2:87S-93S.|2
03130|083|R|9.Salvetti A, Pedrinelli R, Magagna A, Ugenti P. Differential effects of|2
03130|084|R|  selective and non-selective prostaglandin-synthesis inhibition on the|2
03130|085|R|  pharmacological responses to captopril in patients with essential|2
03130|086|R|  hypertension. Clin Sci 1982;63(Suppl 8):261s-3s.|2
03130|087|R|10.Gilchrist NL, Richards AM, March R, Nicholls MG. Effect of sulindac on|2
03130|088|R|   angiotensin converting enzyme inhibitor-induced cough: randomised|2
03130|089|R|   placebo-controlled double-blind cross-over study. J Hum Hypertens 1989|2
03130|090|R|   Dec;3(6):451-5.|2
03130|091|R|11.Ohya Y, Kumamoto K, Fujishima M. Effects of crossover application of|3
03130|092|R|   sulindac and azelastine on enalapril-induced cough. J Hum Hypertens 1992|3
03130|093|R|   Feb;6(1):81-2.|3
03130|094|R|12.Allon M, Pasque CB, Rodriguez M. Interaction of captopril and ibuprofen|2
03130|095|R|   on glomerular and tubular function in humans. Am J Physiol 1990 Aug;259(2|2
03130|096|R|   Pt 2):F233-8.|2
03130|097|R|13.Allon M, Pasque CB, Rodriguez M. Acute effects of captopril and ibuprofen|2
03130|098|R|   on proteinuria in patients with nephrosis. J Lab Clin Med 1990 Oct;|2
03130|099|R|   116(4):462-8.|2
03130|100|R|14.Minuz P, Lechi A, Arosio E, Degan M, Capuzzo MG, Lechi C, Corsato M,|2
03130|101|R|   Dalla Riva A, Velo GP. Antihypertensive activity of enalapril. Effect of|2
03130|102|R|   ibuprofen and different salt intakes. J Clin Hypertens 1987 Dec;|2
03130|103|R|   3(4):645-53.|2
03130|104|R|15.Polonia J, Boaventura I, Gama G, Camoes I, Bernardo F, Andrade P, Nunes|2
03130|105|R|   JP, Brandao F, Cerqueira-Gomes M. Influence of non-steroidal|2
03130|106|R|   anti-inflammatory drugs on renal function and 24h ambulatory blood|2
03130|107|R|   pressure-reducing effects of enalapril and nifedipine gastrointestinal|2
03130|108|R|   therapeutic system in hypertensive patients. J Hypertens 1995 Aug;|2
03130|109|R|   13(8):925-31.|2
03130|110|R|16.Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood|2
03130|111|R|   pressure in elderly people with essential hypertension well controlled on|2
03130|112|R|   amlodipine or enalapril. Am J Hypertens 2000 Nov;13(11):1161-7.|2
03130|113|R|17.Conlin PR, Moore TJ, Swartz SL, Barr E, Gazdick L, Fletcher C, DeLucca P,|2
03130|114|R|   Demopoulos L. Effect of indomethacin on blood pressure lowering by|2
03130|115|R|   captopril and losartan in hypertensive patients. Hypertension 2000 Sep;|2
03130|116|R|   36(3):461-5.|2
03130|117|R|18.Fricker AF, Nussberger J, Meilenbrock S, Brunner HR, Burnier M. Effect of|2
03130|118|R|   indomethacin on the renal response to angiotensin II receptor blockade in|2
03130|119|R|   healthy subjects. Kidney Int 1998 Dec;54(6):2089-97.|2
03130|120|R|19.Morgan T, Anderson A. Interaction of indomethacin with felodipine and|2
03130|121|R|   enalapril. J Hypertens Suppl 1993 Dec;11 Suppl 5:S338-9.|2
03130|122|R|20.Halawa B. Effect of indomethacin and ibuprofen on blood pressure of|2
03130|123|R|   patients treated with nifedipine or captopril. Pol Tyg Lek 1993 Apr 5-12;|2
03130|124|R|   48(14-15):313-5.|2
03130|125|R|21.Espino DV, Lancaster MC. Neutralization of the effects of captopril by|3
03130|126|R|   the use of ibuprofen in an elderly woman. J Am Board Fam Pract 1992|3
03130|127|R|   May-Jun;5(3):319-21.|3
03130|128|R|22.Abdel-Haq B, Magagna A, Favilla S, Salvetti A. Hemodynamic and humoral|2
03130|129|R|   interactions between perindopril and indomethacin in essential|2
03130|130|R|   hypertensive subjects. J Cardiovasc Pharmacol 1991;18 Suppl 7:S33-6.|2
03130|131|R|23.Heeg JE, de Jong PE, de Zeeuw D. Additive antiproteinuric effect of|2
03130|132|R|   angiotensin-converting enzyme inhibition and non-steroidal|2
03130|133|R|   anti-inflammatory drug therapy: a clue to the mechanism of action. Clin|2
03130|134|R|   Sci (Lond) 1991 Sep;81(3):367-72.|2
03130|135|R|24.Kirch W, Stroemer K, Hoogkamer JF, Kleinbloesem CH. The influence of|2
03130|136|R|   prostaglandin inhibition by indomethacin on blood pressure and renal|2
03130|137|R|   function in hypertensive patients treated with cilazapril. Br J Clin|2
03130|138|R|   Pharmacol 1989;27 Suppl 2:297S-301S.|2
03130|139|R|25.Fogari R, Zoppi A, Carretta R, Veglio F, Salvetti A. Effect of|2
03130|140|R|   indomethacin on the antihypertensive efficacy of valsartan and|2
03130|141|R|   lisinopril: a multicentre study. J Hypertens 2002 May;20(5):1007-14.|2
03130|142|R|26.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
03130|143|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
03130|144|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
03130|145|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
03130|146|R|27.Prlesi L, Plakogiannis R. Angioedema after nonsteroidal antiinflammatory|3
03130|147|R|   drug initiation in a patient stable on an angiotensin-converting-enzyme|3
03130|148|R|   inhibitor. Am J Health Syst Pharm 2010 Aug 15;67(16):1351-3.|3
03130|149|R|28.Kampitak T. Recurrent severe angioedema associated with imidapril and|3
03130|150|R|   diclofenac. Allergol Int 2008 Dec;57(4):441-3.|3
03130|151|R|29.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03130|152|R|   Corporation November, 2017.|1
03130|153|R|30.Leete J,  Wang C,  Lopez-Hernandez FJ,  Layton AT. Determining risk|6
03130|154|R|   factors for triple whammy acute kidney injury. Math Biosci 2022 Apr 4.|6
03130|155|R|31.Dreischulte T,  Morales DR,  Bell S,  Guthrie B. Combined use of|2
03130|156|R|   nonsteroidal anti-inflammatory drugs with diuretics and/or|2
03130|157|R|   renin-angiotensin system inhibitors in the community increases the risk|2
03130|158|R|   of acute kidney injury. Kidney Int 2015 Aug;88(2):396-403.|2
03130|159|R|32.Lapi F,  Azoulay L,  Yin H,  Nessim SJ,  Suissa S. Concurrent use of|2
03130|160|R|   diuretics, angiotensin converting enzyme inhibitors, and angiotensin|2
03130|161|R|   receptor blockers with non-steroidal anti-inflammatory drugs and risk of|2
03130|162|R|   acute kidney injury: nested case-control study. BMJ 2013 Jan;8(346):.|2
03130|163|R|33.Juhlin T,  Bjorkman S,  Hoglund P. Cyclooxygenase inhibition causes|2
03130|164|R|   marked impairment of renal function in elderly subjects treated with|2
03130|165|R|   diuretics and ACE-inhibitors. Eur J Heart Fail 2005 Oct;7(6):1049-56.|2
03131|001|T|MONOGRAPH TITLE:  Aliskiren/Potassium Sparing Diuretics|
03131|002|B||
03131|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03131|004|L|take action as needed.|
03131|005|B||
03131|006|A|MECHANISM OF ACTION:  Aliskiren may decrease the renal excretion of|
03131|007|A|potassium.|
03131|008|B||
03131|009|E|CLINICAL EFFECTS:  Concurrent use of potassium sparing diuretics with|
03131|010|E|aliskiren may result in hyperkalemia.|
03131|011|B||
03131|012|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
03131|013|B||
03131|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
03131|015|M|accordingly in patients receiving concurrent therapy with a potassium|
03131|016|M|sparing diuretic and aliskiren.|
03131|017|M|   In all patients taking eplerenone who start taking aliskiren, check serum|
03131|018|M|potassium and creatinine levels after 3-7 days of concurrent therapy.|
03131|019|B||
03131|020|D|DISCUSSION:  Several studies have indicated that serum potassium levels|
03131|021|D|increase when ACE inhibitors and ARB therapy is initiated and decrease when|
03131|022|D|the drug is lowered.  There are case reports of hyperkalemia during|
03131|023|D|concurrent therapy with ARBs and spironolactone and with aliskiren and|
03131|024|D|spironolactone.|
03131|025|D|   Based on this data, serum potassium levels should be monitored in|
03131|026|D|patients receiving concomitant aliskiren with potassium sparing diuretics.|
03131|027|B||
03131|028|R|REFERENCES:|
03131|029|B||
03131|030|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03131|031|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03131|032|R|2.Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal|3
03131|033|R|  failure with severe hyperkalaemia. Lancet 1980 Mar 29;1(8170):712.|3
03131|034|R|3.Warren SE, O'Connor DT. Hyperkalemia resulting from captopril|3
03131|035|R|  administration. JAMA 1980 Dec 5;244(22):2551-2.|3
03131|036|R|4.Maslowski AH, Ikram H, Nicholls MG, Espiner EA. Haemodynamic, hormonal,|2
03131|037|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
03131|038|R|  1981 Jan 10;1(8211):71-4.|2
03131|039|R|5.Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic|2
03131|040|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
03131|041|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
03131|042|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
03131|043|R|  supplementation. A potential for hyperkalemia. Arch Intern Med 1984 Dec;|3
03131|044|R|  144(12):2371-2.|3
03131|045|R|7.Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN. Interruption of the|2
03131|046|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
03131|047|R|  sustained reduction in aldosterone secretion, potassium retention and|2
03131|048|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
03131|049|R|8.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
03131|050|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
03131|051|R|9.Radley AS, Fitzpatrick RW. An evaluation of the potential interaction|2
03131|052|R|  between enalapril and amiloride. J Clin Pharm Ther 1987 Oct;12(5):319-23.|2
03131|053|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
03131|054|R|   October, 2021.|1
03131|055|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
03131|056|R|   Corporation June, 2019.|1
03131|057|R|12.Saito M, Takada M, Hirooka K, Isobe F, Yasumura Y. Serum concentration of|2
03131|058|R|   potassium in chronic heart failure patients administered spironolactone|2
03131|059|R|   plus furosemide and either enalapril maleate, losartan potassium or|2
03131|060|R|   candesartan cilexetil. J Clin Pharm Ther 2005 Dec;30(6):603-10.|2
03131|061|R|13.Fujii H, Nakahama H, Yoshihara F, Nakamura S, Inenaga T, Kawano Y.|3
03131|062|R|   Life-threatening Hyperkalemia during a Combined Therapy with the|3
03131|063|R|   Angiotensin Receptor Blocker Candesartan and Spironolactone. Kobe J Med|3
03131|064|R|   Sci 2005;51(1):1-6.|3
03131|065|R|14.Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or|2
03131|066|R|   angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney|2
03131|067|R|   Dis 2004 Oct;44(4):738-46.|2
03131|068|R|15.Kauffmann Q R, Orozco B R, Venegas G JC. Severe hyperkalemia associated|3
03131|069|R|   to the use of losartan and spironolactone: Case report. Rev Med Chil 2005|3
03131|070|R|   Aug;133(8):947-52.|3
03131|071|R|16.Venzin RM, Cohen CD, Maggiorini M, Wuthrich RP. Aliskiren-associated|3
03131|072|R|   acute renal failure with hyperkalemia. Clin Nephrol 2009 Mar;71(3):326-8.|3
03131|073|R|17.Yamauchi J, Shibagaki Y, Uehara K, Yasuda T, Kimura K.|3
03131|074|R|   Aliskiren-associated acute kidney injury in a patient with pre-existing|3
03131|075|R|   chronic kidney disease and dilated cardiomyopathy. Clin Exp Nephrol 2012|3
03131|076|R|   Apr;16(2):333-6.|3
03131|077|R|18.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03131|078|R|   Corporation November, 2017.|1
03131|079|R|19.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
03132|001|T|MONOGRAPH TITLE:  Moexipril/Selected Potassium Sparing Diuretics|
03132|002|B||
03132|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03132|004|L|take action as needed.|
03132|005|B||
03132|006|A|MECHANISM OF ACTION:  ACE inhibitors such as moexipril may decrease the|
03132|007|A|renal excretion of potassium.|
03132|008|B||
03132|009|E|CLINICAL EFFECTS:  Concurrent use of potassium sparing diuretics with an ACE|
03132|010|E|inhibitor such as moexipril may result in hyperkalemia.|
03132|011|B||
03132|012|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
03132|013|B||
03132|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
03132|015|M|accordingly in patients receiving concurrent therapy with a potassium|
03132|016|M|sparing diuretic and an ACE inhibitor such as moexipril.|
03132|017|M|   In all patients taking eplerenone who start taking moexipril, check serum|
03132|018|M|potassium and creatinine levels after 3-7 days of concurrent therapy.|
03132|019|B||
03132|020|D|DISCUSSION:  In a nested case-control study of heart failure patients|
03132|021|D|receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of|
03132|022|D|hyperkalemia was significantly associated with spironolactone use (odds|
03132|023|D|ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20)|
03132|024|D|   Several studies have indicated that serum potassium levels increase when|
03132|025|D|ACE inhibitors and ARB therapy is initiated and decrease when the drug is|
03132|026|D|lowered.  There are case reports of hyperkalemia during concurrent therapy|
03132|027|D|with ARBs and spironolactone and with aliskiren and spironolactone.|
03132|028|D|   Based on this data, serum potassium levels should be monitored in|
03132|029|D|patients receiving concomitant moexipril with potassium sparing diuretics.|
03132|030|B||
03132|031|R|REFERENCES:|
03132|032|B||
03132|033|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03132|034|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03132|035|R|2.Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal|3
03132|036|R|  failure with severe hyperkalaemia. Lancet 1980 Mar 29;1(8170):712.|3
03132|037|R|3.Warren SE, O'Connor DT. Hyperkalemia resulting from captopril|3
03132|038|R|  administration. JAMA 1980 Dec 5;244(22):2551-2.|3
03132|039|R|4.Maslowski AH, Ikram H, Nicholls MG, Espiner EA. Haemodynamic, hormonal,|2
03132|040|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
03132|041|R|  1981 Jan 10;1(8211):71-4.|2
03132|042|R|5.Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic|2
03132|043|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
03132|044|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
03132|045|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
03132|046|R|  supplementation. A potential for hyperkalemia. Arch Intern Med 1984 Dec;|3
03132|047|R|  144(12):2371-2.|3
03132|048|R|7.Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN. Interruption of the|2
03132|049|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
03132|050|R|  sustained reduction in aldosterone secretion, potassium retention and|2
03132|051|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
03132|052|R|8.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
03132|053|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
03132|054|R|9.Radley AS, Fitzpatrick RW. An evaluation of the potential interaction|2
03132|055|R|  between enalapril and amiloride. J Clin Pharm Ther 1987 Oct;12(5):319-23.|2
03132|056|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
03132|057|R|   October, 2021.|1
03132|058|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
03132|059|R|   Corporation June, 2019.|1
03132|060|R|12.Saito M, Takada M, Hirooka K, Isobe F, Yasumura Y. Serum concentration of|2
03132|061|R|   potassium in chronic heart failure patients administered spironolactone|2
03132|062|R|   plus furosemide and either enalapril maleate, losartan potassium or|2
03132|063|R|   candesartan cilexetil. J Clin Pharm Ther 2005 Dec;30(6):603-10.|2
03132|064|R|13.Fujii H, Nakahama H, Yoshihara F, Nakamura S, Inenaga T, Kawano Y.|3
03132|065|R|   Life-threatening Hyperkalemia during a Combined Therapy with the|3
03132|066|R|   Angiotensin Receptor Blocker Candesartan and Spironolactone. Kobe J Med|3
03132|067|R|   Sci 2005;51(1):1-6.|3
03132|068|R|14.Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or|2
03132|069|R|   angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney|2
03132|070|R|   Dis 2004 Oct;44(4):738-46.|2
03132|071|R|15.Kauffmann Q R, Orozco B R, Venegas G JC. Severe hyperkalemia associated|3
03132|072|R|   to the use of losartan and spironolactone: Case report. Rev Med Chil 2005|3
03132|073|R|   Aug;133(8):947-52.|3
03132|074|R|16.Venzin RM, Cohen CD, Maggiorini M, Wuthrich RP. Aliskiren-associated|3
03132|075|R|   acute renal failure with hyperkalemia. Clin Nephrol 2009 Mar;71(3):326-8.|3
03132|076|R|17.Yamauchi J, Shibagaki Y, Uehara K, Yasuda T, Kimura K.|3
03132|077|R|   Aliskiren-associated acute kidney injury in a patient with pre-existing|3
03132|078|R|   chronic kidney disease and dilated cardiomyopathy. Clin Exp Nephrol 2012|3
03132|079|R|   Apr;16(2):333-6.|3
03132|080|R|18.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03132|081|R|   Corporation November, 2017.|1
03132|082|R|19.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
03132|083|R|20.Abbas S,  Ihle P,  Harder S,  Schubert I. Risk of hyperkalemia and|2
03132|084|R|   combined use of spironolactone and long-term ACE inhibitor/angiotensin|2
03132|085|R|   receptor blocker therapy in heart failure using real-life data: a|2
03132|086|R|   population- and insurance-based cohort. Pharmacoepidemiol and Drug Saf 12|2
03132|087|R|   Feb 2015;24:406-413.|2
03133|001|T|MONOGRAPH TITLE:  Moexipril/Selected Potassium Sparing Diuretics|
03133|002|B||
03133|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03133|004|L|take action as needed.|
03133|005|B||
03133|006|A|MECHANISM OF ACTION:  ACE inhibitors such as moexipril may decrease the|
03133|007|A|renal excretion of potassium.|
03133|008|B||
03133|009|E|CLINICAL EFFECTS:  Concurrent use of potassium sparing diuretics with an ACE|
03133|010|E|inhibitor such as moexipril may result in hyperkalemia.|
03133|011|B||
03133|012|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
03133|013|B||
03133|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
03133|015|M|accordingly in patients receiving concurrent therapy with a potassium|
03133|016|M|sparing diuretic and an ACE inhibitor such as moexipril.|
03133|017|B||
03133|018|D|DISCUSSION:  In a nested case-control study of heart failure patients|
03133|019|D|receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of|
03133|020|D|hyperkalemia was significantly associated with spironolactone use (odds|
03133|021|D|ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20)|
03133|022|D|   Several studies have indicated that serum potassium levels increase when|
03133|023|D|ACE inhibitors and ARB therapy is initiated and decrease when the drug is|
03133|024|D|lowered.  There are case reports of hyperkalemia during concurrent therapy|
03133|025|D|with ARBs and spironolactone and with aliskiren and spironolactone.|
03133|026|D|   Based on this data, serum potassium levels should be monitored in|
03133|027|D|patients receiving concomitant moexipril with potassium sparing diuretics.|
03133|028|B||
03133|029|R|REFERENCES:|
03133|030|B||
03133|031|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03133|032|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03133|033|R|2.Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal|3
03133|034|R|  failure with severe hyperkalaemia. Lancet 1980 Mar 29;1(8170):712.|3
03133|035|R|3.Warren SE, O'Connor DT. Hyperkalemia resulting from captopril|3
03133|036|R|  administration. JAMA 1980 Dec 5;244(22):2551-2.|3
03133|037|R|4.Maslowski AH, Ikram H, Nicholls MG, Espiner EA. Haemodynamic, hormonal,|2
03133|038|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
03133|039|R|  1981 Jan 10;1(8211):71-4.|2
03133|040|R|5.Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic|2
03133|041|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
03133|042|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
03133|043|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
03133|044|R|  supplementation. A potential for hyperkalemia. Arch Intern Med 1984 Dec;|3
03133|045|R|  144(12):2371-2.|3
03133|046|R|7.Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN. Interruption of the|2
03133|047|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
03133|048|R|  sustained reduction in aldosterone secretion, potassium retention and|2
03133|049|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
03133|050|R|8.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
03133|051|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
03133|052|R|9.Radley AS, Fitzpatrick RW. An evaluation of the potential interaction|2
03133|053|R|  between enalapril and amiloride. J Clin Pharm Ther 1987 Oct;12(5):319-23.|2
03133|054|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
03133|055|R|   October, 2021.|1
03133|056|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
03133|057|R|   Corporation June, 2019.|1
03133|058|R|12.Saito M, Takada M, Hirooka K, Isobe F, Yasumura Y. Serum concentration of|2
03133|059|R|   potassium in chronic heart failure patients administered spironolactone|2
03133|060|R|   plus furosemide and either enalapril maleate, losartan potassium or|2
03133|061|R|   candesartan cilexetil. J Clin Pharm Ther 2005 Dec;30(6):603-10.|2
03133|062|R|13.Fujii H, Nakahama H, Yoshihara F, Nakamura S, Inenaga T, Kawano Y.|3
03133|063|R|   Life-threatening Hyperkalemia during a Combined Therapy with the|3
03133|064|R|   Angiotensin Receptor Blocker Candesartan and Spironolactone. Kobe J Med|3
03133|065|R|   Sci 2005;51(1):1-6.|3
03133|066|R|14.Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or|2
03133|067|R|   angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney|2
03133|068|R|   Dis 2004 Oct;44(4):738-46.|2
03133|069|R|15.Kauffmann Q R, Orozco B R, Venegas G JC. Severe hyperkalemia associated|3
03133|070|R|   to the use of losartan and spironolactone: Case report. Rev Med Chil 2005|3
03133|071|R|   Aug;133(8):947-52.|3
03133|072|R|16.Venzin RM, Cohen CD, Maggiorini M, Wuthrich RP. Aliskiren-associated|3
03133|073|R|   acute renal failure with hyperkalemia. Clin Nephrol 2009 Mar;71(3):326-8.|3
03133|074|R|17.Yamauchi J, Shibagaki Y, Uehara K, Yasuda T, Kimura K.|3
03133|075|R|   Aliskiren-associated acute kidney injury in a patient with pre-existing|3
03133|076|R|   chronic kidney disease and dilated cardiomyopathy. Clin Exp Nephrol 2012|3
03133|077|R|   Apr;16(2):333-6.|3
03133|078|R|18.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03133|079|R|   Corporation November, 2017.|1
03133|080|R|19.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
03133|081|R|20.Abbas S,  Ihle P,  Harder S,  Schubert I. Risk of hyperkalemia and|2
03133|082|R|   combined use of spironolactone and long-term ACE inhibitor/angiotensin|2
03133|083|R|   receptor blocker therapy in heart failure using real-life data: a|2
03133|084|R|   population- and insurance-based cohort. Pharmacoepidemiol and Drug Saf 12|2
03133|085|R|   Feb 2015;24:406-413.|2
03134|001|T|MONOGRAPH TITLE:  Selected ACE Inhibitors/Potassium Sparing Diuretics|
03134|002|B||
03134|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03134|004|L|take action as needed.|
03134|005|B||
03134|006|A|MECHANISM OF ACTION:  ACE inhibitors decrease the renal excretion of|
03134|007|A|potassium.|
03134|008|B||
03134|009|E|CLINICAL EFFECTS:  Concurrent use of potassium sparing diuretics with an ACE|
03134|010|E|inhibitor may result in hyperkalemia.|
03134|011|B||
03134|012|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
03134|013|B||
03134|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
03134|015|M|accordingly in patients receiving concurrent therapy with a potassium|
03134|016|M|sparing diuretic and an ACE inhibitor.|
03134|017|M|   In all patients taking eplerenone who start taking an ACE inhibitor,|
03134|018|M|check serum potassium and creatinine levels after 3-7 days of concurrent|
03134|019|M|therapy.|
03134|020|B||
03134|021|D|DISCUSSION:  In a nested case-control study of heart failure patients|
03134|022|D|receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of|
03134|023|D|hyperkalemia was significantly associated with spironolactone use (odds|
03134|024|D|ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20)|
03134|025|D|   In a systemic literature review and meta-analysis of 20 randomized|
03134|026|D|controlled studies, it was found that treatment with spironolactone and|
03134|027|D|ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased|
03134|028|D|the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26|
03134|029|D|mEq/L).(21)|
03134|030|D|   A retrospective cohort study in patients with hypertension, diabetes, and|
03134|031|D|albuminuria between 2008 and 2018 examined the efficacy and safety of|
03134|032|D|mineralocorticoid receptor antagonists eplerenone and spironolactone in|
03134|033|D|combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more|
03134|034|D|frequent in combination therapy patients (n=1,282) versus monotherapy|
03134|035|D|(n=5,484) (22.3 vs 10.9 per 100 person-years for combination and|
03134|036|D|monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22)|
03134|037|D|   Several studies have indicated that serum potassium levels increase when|
03134|038|D|ACE inhibitors and ARB therapy is initiated and decrease when the drug is|
03134|039|D|lowered.  There are case reports of hyperkalemia during concurrent therapy|
03134|040|D|with ARBs and spironolactone and with aliskiren and spironolactone.|
03134|041|D|   Based on this data, serum potassium levels should be monitored in|
03134|042|D|patients receiving concomitant ACE inhibitors with potassium sparing|
03134|043|D|diuretics.|
03134|044|D|   Selected ACE inhibitors linked to this monograph include: alacepril,|
03134|045|D|cilazapril, delapril, imidapril, spirapril, temocapril, and zofenopril.|
03134|046|B||
03134|047|R|REFERENCES:|
03134|048|B||
03134|049|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03134|050|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03134|051|R|2.Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal|3
03134|052|R|  failure with severe hyperkalaemia. Lancet 1980 Mar 29;1(8170):712.|3
03134|053|R|3.Warren SE, O'Connor DT. Hyperkalemia resulting from captopril|3
03134|054|R|  administration. JAMA 1980 Dec 5;244(22):2551-2.|3
03134|055|R|4.Maslowski AH, Ikram H, Nicholls MG, Espiner EA. Haemodynamic, hormonal,|2
03134|056|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
03134|057|R|  1981 Jan 10;1(8211):71-4.|2
03134|058|R|5.Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic|2
03134|059|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
03134|060|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
03134|061|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
03134|062|R|  supplementation. A potential for hyperkalemia. Arch Intern Med 1984 Dec;|3
03134|063|R|  144(12):2371-2.|3
03134|064|R|7.Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN. Interruption of the|2
03134|065|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
03134|066|R|  sustained reduction in aldosterone secretion, potassium retention and|2
03134|067|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
03134|068|R|8.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
03134|069|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
03134|070|R|9.Radley AS, Fitzpatrick RW. An evaluation of the potential interaction|2
03134|071|R|  between enalapril and amiloride. J Clin Pharm Ther 1987 Oct;12(5):319-23.|2
03134|072|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
03134|073|R|   October, 2021.|1
03134|074|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
03134|075|R|   Corporation June, 2019.|1
03134|076|R|12.Saito M, Takada M, Hirooka K, Isobe F, Yasumura Y. Serum concentration of|2
03134|077|R|   potassium in chronic heart failure patients administered spironolactone|2
03134|078|R|   plus furosemide and either enalapril maleate, losartan potassium or|2
03134|079|R|   candesartan cilexetil. J Clin Pharm Ther 2005 Dec;30(6):603-10.|2
03134|080|R|13.Fujii H, Nakahama H, Yoshihara F, Nakamura S, Inenaga T, Kawano Y.|3
03134|081|R|   Life-threatening Hyperkalemia during a Combined Therapy with the|3
03134|082|R|   Angiotensin Receptor Blocker Candesartan and Spironolactone. Kobe J Med|3
03134|083|R|   Sci 2005;51(1):1-6.|3
03134|084|R|14.Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or|2
03134|085|R|   angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney|2
03134|086|R|   Dis 2004 Oct;44(4):738-46.|2
03134|087|R|15.Kauffmann Q R, Orozco B R, Venegas G JC. Severe hyperkalemia associated|3
03134|088|R|   to the use of losartan and spironolactone: Case report. Rev Med Chil 2005|3
03134|089|R|   Aug;133(8):947-52.|3
03134|090|R|16.Venzin RM, Cohen CD, Maggiorini M, Wuthrich RP. Aliskiren-associated|3
03134|091|R|   acute renal failure with hyperkalemia. Clin Nephrol 2009 Mar;71(3):326-8.|3
03134|092|R|17.Yamauchi J, Shibagaki Y, Uehara K, Yasuda T, Kimura K.|3
03134|093|R|   Aliskiren-associated acute kidney injury in a patient with pre-existing|3
03134|094|R|   chronic kidney disease and dilated cardiomyopathy. Clin Exp Nephrol 2012|3
03134|095|R|   Apr;16(2):333-6.|3
03134|096|R|18.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03134|097|R|   Corporation November, 2017.|1
03134|098|R|19.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
03134|099|R|20.Abbas S,  Ihle P,  Harder S,  Schubert I. Risk of hyperkalemia and|2
03134|100|R|   combined use of spironolactone and long-term ACE inhibitor/angiotensin|2
03134|101|R|   receptor blocker therapy in heart failure using real-life data: a|2
03134|102|R|   population- and insurance-based cohort. Pharmacoepidemiol and Drug Saf 12|2
03134|103|R|   Feb 2015;24:406-413.|2
03134|104|R|21.Villa-Zapata L,  Carhart BS,  Horn JR,  Hansten PD,  Subbian V,  Gephart|6
03134|105|R|   S,  Tan M,  Romero A,  Malone DC. Serum potassium changes due to|6
03134|106|R|   concomitant ACEI/ARB and spironolactone therapy: a systemic review and|6
03134|107|R|   meta-analysis. Am J Health-Syst Pharm 15 December 2021;78(24):2245-2255.|6
03134|108|R|22.An J,  Niu F,  Sim JJ. Cardiovascular and kidney outcomes of|6
03134|109|R|   spironolactone or eplerenone in combination with ACEI/ARBs in patients|6
03134|110|R|   with diabetic kidney disease. Pharmacotherapy October 2021;41:998-1008.|6
03135|001|T|MONOGRAPH TITLE:  Selected ACE Inhibitors/Potassium Sparing Diuretics|
03135|002|B||
03135|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03135|004|L|take action as needed.|
03135|005|B||
03135|006|A|MECHANISM OF ACTION:  ACE inhibitors may decrease the renal excretion of|
03135|007|A|potassium.|
03135|008|B||
03135|009|E|CLINICAL EFFECTS:  Concurrent use of potassium sparing diuretics with an ACE|
03135|010|E|inhibitor may result in hyperkalemia.|
03135|011|B||
03135|012|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
03135|013|B||
03135|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
03135|015|M|accordingly in patients receiving concurrent therapy with a potassium|
03135|016|M|sparing diuretic and an ACE inhibitors.|
03135|017|M|   In all patients taking eplerenone who start taking an ACE inhibitor,|
03135|018|M|check serum potassium and creatinine levels after 3-7 days of concurrent|
03135|019|M|therapy.|
03135|020|B||
03135|021|D|DISCUSSION:  In a nested case-control study of heart failure patients|
03135|022|D|receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of|
03135|023|D|hyperkalemia was significantly associated with concomitant spironolactone|
03135|024|D|use (odds ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20)|
03135|025|D|   In a systemic literature review and meta-analysis of 20 randomized|
03135|026|D|controlled studies, it was found that treatment with spironolactone and|
03135|027|D|ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased|
03135|028|D|the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26|
03135|029|D|mEq/L).(21)|
03135|030|D|   A retrospective cohort study in patients with hypertension, diabetes, and|
03135|031|D|albuminuria between 2008 and 2018 examined the efficacy and safety of|
03135|032|D|mineralocorticoid receptor antagonists eplerenone and spironolactone in|
03135|033|D|combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more|
03135|034|D|frequent in combination therapy patients (n=1,282) versus monotherapy|
03135|035|D|(n=5,484) (22.3 vs 10.9 per 100 person-years for combination and|
03135|036|D|monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22)|
03135|037|D|   Several studies have indicated that serum potassium levels increase when|
03135|038|D|ACE inhibitors and ARB therapy is initiated and decrease when the drug is|
03135|039|D|lowered.  There are case reports of hyperkalemia during concurrent therapy|
03135|040|D|with ARBs and spironolactone and with aliskiren and spironolactone.|
03135|041|D|   Based on this data, serum potassium levels should be monitored in|
03135|042|D|patients receiving concomitant ACE inhibitors with potassium sparing|
03135|043|D|diuretics.|
03135|044|D|   Selected ACE inhibitors linked to this monograph include: benazepril,|
03135|045|D|captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril,|
03135|046|D|ramipril, and trandolapril.|
03135|047|B||
03135|048|R|REFERENCES:|
03135|049|B||
03135|050|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03135|051|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03135|052|R|2.Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal|3
03135|053|R|  failure with severe hyperkalaemia. Lancet 1980 Mar 29;1(8170):712.|3
03135|054|R|3.Warren SE, O'Connor DT. Hyperkalemia resulting from captopril|3
03135|055|R|  administration. JAMA 1980 Dec 5;244(22):2551-2.|3
03135|056|R|4.Maslowski AH, Ikram H, Nicholls MG, Espiner EA. Haemodynamic, hormonal,|2
03135|057|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
03135|058|R|  1981 Jan 10;1(8211):71-4.|2
03135|059|R|5.Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic|2
03135|060|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
03135|061|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
03135|062|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
03135|063|R|  supplementation. A potential for hyperkalemia. Arch Intern Med 1984 Dec;|3
03135|064|R|  144(12):2371-2.|3
03135|065|R|7.Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN. Interruption of the|2
03135|066|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
03135|067|R|  sustained reduction in aldosterone secretion, potassium retention and|2
03135|068|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
03135|069|R|8.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
03135|070|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
03135|071|R|9.Radley AS, Fitzpatrick RW. An evaluation of the potential interaction|2
03135|072|R|  between enalapril and amiloride. J Clin Pharm Ther 1987 Oct;12(5):319-23.|2
03135|073|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
03135|074|R|   October, 2021.|1
03135|075|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
03135|076|R|   Corporation June, 2019.|1
03135|077|R|12.Saito M, Takada M, Hirooka K, Isobe F, Yasumura Y. Serum concentration of|2
03135|078|R|   potassium in chronic heart failure patients administered spironolactone|2
03135|079|R|   plus furosemide and either enalapril maleate, losartan potassium or|2
03135|080|R|   candesartan cilexetil. J Clin Pharm Ther 2005 Dec;30(6):603-10.|2
03135|081|R|13.Fujii H, Nakahama H, Yoshihara F, Nakamura S, Inenaga T, Kawano Y.|3
03135|082|R|   Life-threatening Hyperkalemia during a Combined Therapy with the|3
03135|083|R|   Angiotensin Receptor Blocker Candesartan and Spironolactone. Kobe J Med|3
03135|084|R|   Sci 2005;51(1):1-6.|3
03135|085|R|14.Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or|2
03135|086|R|   angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney|2
03135|087|R|   Dis 2004 Oct;44(4):738-46.|2
03135|088|R|15.Kauffmann Q R, Orozco B R, Venegas G JC. Severe hyperkalemia associated|3
03135|089|R|   to the use of losartan and spironolactone: Case report. Rev Med Chil 2005|3
03135|090|R|   Aug;133(8):947-52.|3
03135|091|R|16.Venzin RM, Cohen CD, Maggiorini M, Wuthrich RP. Aliskiren-associated|3
03135|092|R|   acute renal failure with hyperkalemia. Clin Nephrol 2009 Mar;71(3):326-8.|3
03135|093|R|17.Yamauchi J, Shibagaki Y, Uehara K, Yasuda T, Kimura K.|3
03135|094|R|   Aliskiren-associated acute kidney injury in a patient with pre-existing|3
03135|095|R|   chronic kidney disease and dilated cardiomyopathy. Clin Exp Nephrol 2012|3
03135|096|R|   Apr;16(2):333-6.|3
03135|097|R|18.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03135|098|R|   Corporation November, 2017.|1
03135|099|R|19.Inspra (eplerenone) US prescribing information. Pfizer, Inc. May, 2018.|1
03135|100|R|20.Abbas S,  Ihle P,  Harder S,  Schubert I. Risk of hyperkalemia and|2
03135|101|R|   combined use of spironolactone and long-term ACE inhibitor/angiotensin|2
03135|102|R|   receptor blocker therapy in heart failure using real-life data: a|2
03135|103|R|   population- and insurance-based cohort. Pharmacoepidemiol and Drug Saf 12|2
03135|104|R|   Feb 2015;24:406-413.|2
03135|105|R|21.Villa-Zapata L,  Carhart BS,  Horn JR,  Hansten PD,  Subbian V,  Gephart|6
03135|106|R|   S,  Tan M,  Romero A,  Malone DC. Serum potassium changes due to|6
03135|107|R|   concomitant ACEI/ARB and spironolactone therapy: a systemic review and|6
03135|108|R|   meta-analysis. Am J Health-Syst Pharm 15 December 2021;78(24):2245-2255.|6
03135|109|R|22.An J,  Niu F,  Sim JJ. Cardiovascular and kidney outcomes of|6
03135|110|R|   spironolactone or eplerenone in combination with ACEI/ARBs in patients|6
03135|111|R|   with diabetic kidney disease. Pharmacotherapy October 2021;41:998-1008.|6
03136|001|T|MONOGRAPH TITLE:  Aliskiren/Potassium Supplements|
03136|002|B||
03136|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03136|004|L|take action as needed.|
03136|005|B||
03136|006|A|MECHANISM OF ACTION:  Aliskiren may decrease the renal excretion of|
03136|007|A|potassium.|
03136|008|B||
03136|009|E|CLINICAL EFFECTS:  Concurrent use of potassium supplements with aliskiren|
03136|010|E|may result in hyperkalemia.|
03136|011|B||
03136|012|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
03136|013|B||
03136|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
03136|015|M|accordingly in patients receiving concurrent therapy with potassium|
03136|016|M|supplements and aliskiren.|
03136|017|B||
03136|018|D|DISCUSSION:  Several studies have indicated that serum potassium levels|
03136|019|D|increase when ACE inhibitors and ARB therapy is initiated and decrease when|
03136|020|D|the drug is lowered.  Increased potassium levels have also been seen with|
03136|021|D|aliskiren.|
03136|022|D|   Based on this data, serum potassium levels should be monitored in|
03136|023|D|patients receiving potassium supplements with aliskiren.|
03136|024|B||
03136|025|R|REFERENCES:|
03136|026|B||
03136|027|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03136|028|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03136|029|R|2.Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal|3
03136|030|R|  failure with severe hyperkalaemia. Lancet 1980 Mar 29;1(8170):712.|3
03136|031|R|3.Warren SE, O'Connor DT. Hyperkalemia resulting from captopril|3
03136|032|R|  administration. JAMA 1980 Dec 5;244(22):2551-2.|3
03136|033|R|4.Maslowski AH, Ikram H, Nicholls MG, Espiner EA. Haemodynamic, hormonal,|2
03136|034|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
03136|035|R|  1981 Jan 10;1(8211):71-4.|2
03136|036|R|5.Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic|2
03136|037|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
03136|038|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
03136|039|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
03136|040|R|  supplementation. A potential for hyperkalemia. Arch Intern Med 1984 Dec;|3
03136|041|R|  144(12):2371-2.|3
03136|042|R|7.Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN. Interruption of the|2
03136|043|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
03136|044|R|  sustained reduction in aldosterone secretion, potassium retention and|2
03136|045|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
03136|046|R|8.Papadimitriou M, Zamboulis C, Alexopoulos E, Liamos H, Sakellariou G,|2
03136|047|R|  Memmos D, Metaxas P, Thessaloniki G. Alarming hyperkalemia during|2
03136|048|R|  captopril administration in patients on regular hemodialysis. Dialysis|2
03136|049|R|  Transplant 1985 Aug;14:473-5.|2
03136|050|R|9.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
03136|051|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
03136|052|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
03136|053|R|   October, 2021.|1
03136|054|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
03136|055|R|   Corporation June, 2019.|1
03136|056|R|12.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03136|057|R|   Corporation November, 2017.|1
03137|001|T|MONOGRAPH TITLE:  Selected ACE Inhibitors/Potassium Supplements|
03137|002|B||
03137|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03137|004|L|take action as needed.|
03137|005|B||
03137|006|A|MECHANISM OF ACTION:  ACE inhibitors may decrease the renal excretion of|
03137|007|A|potassium.|
03137|008|B||
03137|009|E|CLINICAL EFFECTS:  Concurrent use of potassium supplements with ACE|
03137|010|E|inhibitors may result in hyperkalemia.|
03137|011|B||
03137|012|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
03137|013|B||
03137|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
03137|015|M|accordingly in patients receiving concurrent therapy with potassium|
03137|016|M|supplements and ACE inhibitors.|
03137|017|B||
03137|018|D|DISCUSSION:  Several studies have indicated that serum potassium levels|
03137|019|D|increase when ACE inhibitors is initiated and decrease when the drug is|
03137|020|D|lowered.|
03137|021|D|   Based on this data, serum potassium levels should be monitored in|
03137|022|D|patients receiving potassium supplements with ACE inhibitors.|
03137|023|D|   Selected ACE inhibitors linked to this monograph include: alacepril,|
03137|024|D|cilazapril, delapril, imidapril, perindopril, spirapril, temocapril, and|
03137|025|D|zofenopril.|
03137|026|B||
03137|027|R|REFERENCES:|
03137|028|B||
03137|029|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03137|030|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03137|031|R|2.Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal|3
03137|032|R|  failure with severe hyperkalaemia. Lancet 1980 Mar 29;1(8170):712.|3
03137|033|R|3.Warren SE, O'Connor DT. Hyperkalemia resulting from captopril|3
03137|034|R|  administration. JAMA 1980 Dec 5;244(22):2551-2.|3
03137|035|R|4.Maslowski AH, Ikram H, Nicholls MG, Espiner EA. Haemodynamic, hormonal,|2
03137|036|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
03137|037|R|  1981 Jan 10;1(8211):71-4.|2
03137|038|R|5.Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic|2
03137|039|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
03137|040|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
03137|041|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
03137|042|R|  supplementation. A potential for hyperkalemia. Arch Intern Med 1984 Dec;|3
03137|043|R|  144(12):2371-2.|3
03137|044|R|7.Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN. Interruption of the|2
03137|045|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
03137|046|R|  sustained reduction in aldosterone secretion, potassium retention and|2
03137|047|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
03137|048|R|8.Papadimitriou M, Zamboulis C, Alexopoulos E, Liamos H, Sakellariou G,|2
03137|049|R|  Memmos D, Metaxas P, Thessaloniki G. Alarming hyperkalemia during|2
03137|050|R|  captopril administration in patients on regular hemodialysis. Dialysis|2
03137|051|R|  Transplant 1985 Aug;14:473-5.|2
03137|052|R|9.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
03137|053|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
03137|054|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
03137|055|R|   October, 2021.|1
03137|056|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
03137|057|R|   Corporation June, 2019.|1
03137|058|R|12.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03137|059|R|   Corporation November, 2017.|1
03138|001|T|MONOGRAPH TITLE:  Selected ACE Inhibitors/Potassium Supplements|
03138|002|B||
03138|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03138|004|L|take action as needed.|
03138|005|B||
03138|006|A|MECHANISM OF ACTION:  ACE inhibitors may decrease the renal excretion of|
03138|007|A|potassium.|
03138|008|B||
03138|009|E|CLINICAL EFFECTS:  Concurrent use of potassium supplements with ACE|
03138|010|E|inhibitors may result in hyperkalemia.|
03138|011|B||
03138|012|P|PREDISPOSING FACTORS:  Impaired renal function; diabetes mellitus.|
03138|013|B||
03138|014|M|PATIENT MANAGEMENT:  Monitor serum potassium and adjust the dosage|
03138|015|M|accordingly in patients receiving concurrent therapy with potassium|
03138|016|M|supplements and ACE inhibitors.|
03138|017|B||
03138|018|D|DISCUSSION:  Several studies have indicated that serum potassium levels|
03138|019|D|increase when ACE inhibitors is initiated and decrease when the drug is|
03138|020|D|lowered.|
03138|021|D|   Based on this data, serum potassium levels should be monitored in|
03138|022|D|patients receiving potassium supplements with ACE inhibitors.|
03138|023|D|   Selected ACE inhibitors linked to this monograph include: benazepril,|
03138|024|D|captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril,|
03138|025|D|ramipril, and trandolapril.|
03138|026|B||
03138|027|R|REFERENCES:|
03138|028|B||
03138|029|R|1.Cleary JD, Taylor JW. Enalapril: a new angiotensin converting enzyme|6
03138|030|R|  inhibitor. Drug Intell Clin Pharm 1986 Mar;20(3):177-86.|6
03138|031|R|2.Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal|3
03138|032|R|  failure with severe hyperkalaemia. Lancet 1980 Mar 29;1(8170):712.|3
03138|033|R|3.Warren SE, O'Connor DT. Hyperkalemia resulting from captopril|3
03138|034|R|  administration. JAMA 1980 Dec 5;244(22):2551-2.|3
03138|035|R|4.Maslowski AH, Ikram H, Nicholls MG, Espiner EA. Haemodynamic, hormonal,|2
03138|036|R|  and electrolyte responses to captopril in resistant heart failure. Lancet|2
03138|037|R|  1981 Jan 10;1(8211):71-4.|2
03138|038|R|5.Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic|2
03138|039|R|  patients during angiotensin-converting enzyme inhibition and aldosterone|2
03138|040|R|  reduction with captopril. Am J Med 1982 Nov;73(5):719-25.|2
03138|041|R|6.Burnakis TG, Mioduch HJ. Combined therapy with captopril and potassium|3
03138|042|R|  supplementation. A potential for hyperkalemia. Arch Intern Med 1984 Dec;|3
03138|043|R|  144(12):2371-2.|3
03138|044|R|7.Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN. Interruption of the|2
03138|045|R|  renin-angiotensin system in hypertensive patients by captopril induces|2
03138|046|R|  sustained reduction in aldosterone secretion, potassium retention and|2
03138|047|R|  natruiresis. Hypertension 1979 May-Jun;1(3):274-80.|2
03138|048|R|8.Papadimitriou M, Zamboulis C, Alexopoulos E, Liamos H, Sakellariou G,|2
03138|049|R|  Memmos D, Metaxas P, Thessaloniki G. Alarming hyperkalemia during|2
03138|050|R|  captopril administration in patients on regular hemodialysis. Dialysis|2
03138|051|R|  Transplant 1985 Aug;14:473-5.|2
03138|052|R|9.Schuna AA, Schmidt GR, Pitterle ME. Serum potassium concentrations after|2
03138|053|R|  initiation of captopril therapy. Clin Pharm 1986 Nov;5(11):920-3.|2
03138|054|R|10.Cozaar (losartan potassium) US prescribing information. Merck & Co., Inc.|1
03138|055|R|   October, 2021.|1
03138|056|R|11.Diovan (valsartan) US prescribing information. Novartis Pharmaceuticals|1
03138|057|R|   Corporation June, 2019.|1
03138|058|R|12.Tekturna (aliskiren) US prescribing information. Novartis Pharmaceuticals|1
03138|059|R|   Corporation November, 2017.|1
03139|001|T|MONOGRAPH TITLE:  Metoprolol/Selected CYP2D6 Inhibitors|
03139|002|B||
03139|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03139|004|L|take action as needed.|
03139|005|B||
03139|006|A|MECHANISM OF ACTION:  CYP2D6 inhibitors may inhibit the metabolism of|
03139|007|A|metoprolol.(1,2)|
03139|008|B||
03139|009|E|CLINICAL EFFECTS:  Concurrent use of CYP2D6 inhibitors may result in|
03139|010|E|elevated levels of and toxicity from metoprolol.(1,2)|
03139|011|B||
03139|012|P|PREDISPOSING FACTORS:  The interaction may be more severe in patients who|
03139|013|P|are ultrarapid metabolizers of CYP2D6,(1,2) elderly,(3) and on higher doses|
03139|014|P|of beta-blockers.(3)|
03139|015|B||
03139|016|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
03139|017|M|metoprolol and inhibitors of CYP2D6.  The dosage of metoprolol may need to|
03139|018|M|be adjusted.(1,2)|
03139|019|M|   The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are|
03139|020|M|expected to last at least 28 days after administration.(4)|
03139|021|B||
03139|022|D|DISCUSSION:  In a case report, a patient maintained on metoprolol developed|
03139|023|D|bradycardia following the addition of bupropion.(5)|
03139|024|D|   In a study in 20 healthy females, diphenhydramine increased the AUC of|
03139|025|D|metoprolol by 21%.  Heart rate reduction increased 29%.(6)|
03139|026|D|   In a randomized study in 16 healthy subjects, diphenhydramine decreased|
03139|027|D|metoprolol oral and nonrenal clearance by 2-fold in extensive 2D6|
03139|028|D|metabolizers.  In extensive 2D6 metabolizers, metoprolol-induced effects on|
03139|029|D|heart rate, systolic blood pressure, and aortic blood flow peak velocity|
03139|030|D|were all increased.  There were no effects of diphenhydramine in poor|
03139|031|D|metabolizers.(7)|
03139|032|D|   Fluoxetine has been shown to inhibit metoprolol metabolism in vitro.(8)|
03139|033|D|There is a case report of severe bradycardia following the addition of|
03139|034|D|fluoxetine to metoprolol.(9)|
03139|035|D|   In a 3-way, randomized, cross-over study in healthy subjects, paroxetine|
03139|036|D|(20 mg daily) increased the area-under-curve (AUC) of both S- and|
03139|037|D|R-metoprolol by 3-fold, and 4-fold, respectively, regardless of whether the|
03139|038|D|formulation of metoprolol was immediate release or extended release.|
03139|039|D|Concurrent paroxetine also significantly decreased heart rate and blood|
03139|040|D|pressure when compared to metoprolol alone.(10)|
03139|041|D|   In an open-label, randomized, cross-over study in 10 healthy subjects,|
03139|042|D|paroxetine increased the AUC of S-metoprolol and R-metoprolol from an|
03139|043|D|immediate release formulation (50 mg)by 4-fold and 5-fold, respectively.|
03139|044|D|Paroxetine increased the AUC of S-metoprolol and R-metoprolol from an|
03139|045|D|extended release formulation (100 mg) by 3-fold and 4-fold,|
03139|046|D|respectively.(11)|
03139|047|D|   In a study in patients with acute myocardial infarction and depression,|
03139|048|D|paroxetine (20 mg daily) increased the AUC of metoprolol 3-fold.  Mean heart|
03139|049|D|rate was significantly lower following the addition of paroxetine to|
03139|050|D|metoprolol.  Two patients experienced bradycardia and severe orthostatic|
03139|051|D|hypotension.(12)|
03139|052|D|   In an open trial in 8 healthy males, paroxetine (20 mg daily) increased|
03139|053|D|the AUC of S-metoprolol and R-metoprolol by 4-fold and 7-fold,|
03139|054|D|respectively.(13)|
03139|055|D|   There are case reports of complete atrioventricular block(14) and|
03139|056|D|bradycardia(15) with concurrent metoprolol and paroxetine.|
03139|057|D|   A systematic review and meta-analysis of CYP2D6 interactions between|
03139|058|D|metoprolol and either paroxetine or fluoxetine reviewed 9 articles including|
03139|059|D|4 primary and 2 observational studies as well as 3 case reports.|
03139|060|D|Experimental studies noted paroxetine increased the AUC of metoprolol 3-fold|
03139|061|D|to 5-fold and significantly decreased blood pressure and heart rate.|
03139|062|D|Paroxetine and fluoxetine have shown equipotent inhibitor capacity on|
03139|063|D|CYP2D6.  The metabolite, norfluoxetine, is also an inhibitor of CYP2D6.(16)|
03139|064|D|   A retrospective cohort study evaluated morbidity in patients on a|
03139|065|D|beta-blocker primarily metabolized by CYP2D6 (e.g., nebivolol, metoprolol,|
03139|066|D|carvedilol, propranolol, labetalol) and started on a strong or moderate|
03139|067|D|CYP2D6-inhibiting antidepressant (e.g., fluoxetine, paroxetine, bupropion,|
03139|068|D|duloxetine).  Use of such an antidepressant with a beta-blocker was|
03139|069|D|associated with an increased risk of hospitalization or ED visit due to an|
03139|070|D|adverse hemodynamic event (HR 1.53, 95% CI 1.03-2.81, p=0.04).(3)|
03139|071|D|   CYP2D6 inhibitors include: abiraterone, bupropion, celecoxib, cinacalcet,|
03139|072|D|citalopram, dacomitinib, dimenhydrinate, diphenhydramine, duloxetine,|
03139|073|D|escitalopram, fedratinib, fluoxetine, hydroxychloroquine, imatinib,|
03139|074|D|lorcaserin, osilodrostat, paroxetine, ranitidine, ranolazine, rolapitant,|
03139|075|D|and sertraline.|
03139|076|D|   One or more of the drug pairs linked to this monograph have been included|
03139|077|D|in a list of interactions that could be considered for classification as|
03139|078|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
03139|079|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
03139|080|D|Health Information Technology.|
03139|081|B||
03139|082|R|REFERENCES:|
03139|083|B||
03139|084|R|1.Lopressor (metoprolol tartrate) US prescribing information. Validus|1
03139|085|R|  Pharmaceuticals. LLC July, 2023.|1
03139|086|R|2.Toprol-XL (metoprolol succinate) US prescribing information. AstraZeneca|1
03139|087|R|  LP January, 2022.|1
03139|088|R|3.Shin J, Hills NK, Finley PR. Combining Antidepressants with Beta-Blockers:|2
03139|089|R|  Evidence of a Clinically Significant  CYP2D6 Drug Interaction.|2
03139|090|R|  Pharmacotherapy 2020 Jun;40(6):507-516.|2
03139|091|R|4.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
03139|092|R|5.McCollum DL, Greene JL, McGuire DK. Severe sinus bradycardia after|3
03139|093|R|  initiation of bupropion therapy: a probable drug-drug interaction with|3
03139|094|R|  metoprolol. Cardiovasc Drugs Ther 2004 Jul;18(4):329-30.|3
03139|095|R|6.Sharma A, Pibarot P, Pilote S, Dumesnil JG, Arsenault M, Belanger PM,|2
03139|096|R|  Meibohm B, Hamelin BA. Modulation of metoprolol pharmacokinetics and|2
03139|097|R|  hemodynamics by diphenhydramine coadministration during exercise testing|2
03139|098|R|  in healthy premenopausal women. J Pharmacol Exp Ther 2005 Jun;|2
03139|099|R|  313(3):1172-81.|2
03139|100|R|7.Hamelin BA, Bouayad A, Methot J, Jobin J, Desgagnes P, Poirier P, Allaire|2
03139|101|R|  J, Dumesnil J, Turgeon J. Significant interaction between the|2
03139|102|R|  nonprescription antihistamine diphenhydramine and the CYP2D6 substrate|2
03139|103|R|  metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol|2
03139|104|R|  Ther 2000 May;67(5):466-77.|2
03139|105|R|8.Belpaire FM, Wijnant P, Temmerman A, Rasmussen BB, Brosen K. The oxidative|5
03139|106|R|  metabolism of metoprolol in human liver microsomes: inhibition by the|5
03139|107|R|  selective serotonin reuptake inhibitors. Eur J Clin Pharmacol 1998 May;|5
03139|108|R|  54(3):261-4.|5
03139|109|R|9.Walley T, Pirmohamed M, Proudlove C, Maxwell D. Interaction of metoprolol|3
03139|110|R|  and fluoxetine. Lancet 1993 Apr 10;341(8850):967-8.|3
03139|111|R|10.Parker RB, Soberman JE. Effects of paroxetine on the pharmacokinetics and|2
03139|112|R|   pharmacodynamics of immediate-release and extended-release metoprolol.|2
03139|113|R|   Pharmacotherapy 2011 Jul;31(7):630-41.|2
03139|114|R|11.Stout SM, Nielsen J, Welage LS, Shea M, Brook R, Kerber K, Bleske BE.|2
03139|115|R|   Influence of metoprolol dosage release formulation on the pharmacokinetic|2
03139|116|R|   drug interaction with paroxetine. J Clin Pharmacol 2011 Mar;51(3):389-96.|2
03139|117|R|12.Goryachkina K, Burbello A, Boldueva S, Babak S, Bergman U, Bertilsson L.|2
03139|118|R|   Inhibition of metoprolol metabolism and potentiation of its effects by|2
03139|119|R|   paroxetine in routinely treated patients with acute myocardial infarction|2
03139|120|R|   (AMI). Eur J Clin Pharmacol 2008 Mar;64(3):275-82.|2
03139|121|R|13.Hemeryck A, Lefebvre RA, De Vriendt C, Belpaire FM. Paroxetine affects|2
03139|122|R|   metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.|2
03139|123|R|   Clin Pharmacol Ther 2000 Mar;67(3):283-91.|2
03139|124|R|14.Onalan O, Cumurcu BE, Bekar L. Complete atrioventricular block associated|3
03139|125|R|   with concomitant use of metoprolol and paroxetine. Mayo Clin Proc 2008|3
03139|126|R|   May;83(5):595-9.|3
03139|127|R|15.Konig F, Hafele M, Hauger B, Loble M, Wossner S, Wolfersdorf M.|3
03139|128|R|   Bradycardia after beginning therapy with metoprolol and paroxetine.|3
03139|129|R|   Psychiatr Prax 1996 Sep;23(5):244-5.|3
03139|130|R|16.Bahar MA, Kamp J, Borgsteede SD, Hak E, Wilffert B. The impact of CYP2D6|6
03139|131|R|   mediated drug-drug interaction: a systematic review on a combination of|6
03139|132|R|   metoprolol and paroxetine/fluoxetine. Br J Clin Pharmacol 2018 Sep 24.|6
03139|133|R|17.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
03139|134|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
03139|135|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
03139|136|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
03140|001|T|MONOGRAPH TITLE:  Metoprolol/Selected CYP2D6 Inhibitors|
03140|002|B||
03140|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03140|004|L|take action as needed.|
03140|005|B||
03140|006|A|MECHANISM OF ACTION:  CYP2D6 inhibitors may inhibit the metabolism of|
03140|007|A|metoprolol.(1,2)|
03140|008|B||
03140|009|E|CLINICAL EFFECTS:  Concurrent use of CYP2D6 inhibitors may result in|
03140|010|E|elevated levels of and toxicity from metoprolol.(1,2)|
03140|011|B||
03140|012|P|PREDISPOSING FACTORS:  The interaction may be more severe in patients who|
03140|013|P|are ultrarapid metabolizers of CYP2D6.(1,2)|
03140|014|B||
03140|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
03140|016|M|metoprolol and inhibitors of CYP2D6.  The dosage of metoprolol may need to|
03140|017|M|be adjusted.(1,2)|
03140|018|M|   Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected|
03140|019|M|to last at least 28 days after administration.(3)|
03140|020|B||
03140|021|D|DISCUSSION:  In a study, citalopram (40 mg daily for 22 days) increased|
03140|022|D|plasma concentrations of metoprolol 2-fold.(4)|
03140|023|D|   In a study in healthy subjects, duloxetine (60 mg daily), escitalopram|
03140|024|D|(20 mg daily), and sertraline (100 mg daily) increased the AUC of a single|
03140|025|D|dose of metoprolol by 180%, 89%, and 48-67%, respectively.(5)|
03140|026|D|   In a study in 7 healthy subjects, ranitidine (150 mg BID) increased the|
03140|027|D|area-under-curve (AUC) of metoprolol by 50% compared to values obtained 10|
03140|028|D|months earlier in the same subjects with metoprolol alone.(6)|
03140|029|D|   In a study in 6 subjects, pretreatment with ranitidine for 1 week|
03140|030|D|increased the maximum concentration (Cmax) of metoprolol.  However, in a|
03140|031|D|follow-up study in 12 healthy subjects, ranitidine had no effect on|
03140|032|D|metoprolol pharmacokinetics when administered concurrently for 1 week.(7)|
03140|033|D|   In a study in 6 healthy subjects, ranitidine increased the AUC and Cmax|
03140|034|D|of metoprolol by 50%.  There were no changes in metoprolol|
03140|035|D|pharmacodynamics.(8)|
03140|036|D|   In a study in healthy subjects, ranitidine increased metoprolol Cmax by|
03140|037|D|about 30%.(9)|
03140|038|D|   In a study in 12 healthy males, ranitidine had no effect on the|
03140|039|D|pharmacokinetics or pharmacodynamics of metoprolol.(10)|
03140|040|D|   In healthy subjects, ranolazine (750 mg twice daily) increased plasma|
03140|041|D|levels of a single dose of metoprolol (100 mg) by 1.8-fold.(11)|
03140|042|D|   A single dose of rolapitant increased dextromethorphan, a CYP2D6|
03140|043|D|substrate, about 3-fold on days 8 and day 22 following administration.|
03140|044|D|Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single|
03140|045|D|dose rolapitant.  The inhibitory effects of rolapitant on CYP2D6 are|
03140|046|D|expected to persist beyond 28 days.(3)|
03140|047|D|   CYP2D6 inhibitors include: abiraterone, bupropion, celecoxib, cinacalcet,|
03140|048|D|citalopram, dacomitinib, diphenhydramine, duloxetine, escitalopram,|
03140|049|D|fedratinib, fluoxetine, hydroxychloroquine, imatinib, lorcaserin,|
03140|050|D|osilodrostat, paroxetine, ranitidine, ranolazine, rolapitant, and|
03140|051|D|sertraline.|
03140|052|D|   One or more of the drug pairs linked to this monograph have been included|
03140|053|D|in a list of interactions that could be considered for classification as|
03140|054|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
03140|055|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
03140|056|D|Health Information Technology.|
03140|057|B||
03140|058|R|REFERENCES:|
03140|059|B||
03140|060|R|1.Lopressor (metoprolol tartrate) US prescribing information. Validus|1
03140|061|R|  Pharmaceuticals. LLC July, 2023.|1
03140|062|R|2.Toprol-XL (metoprolol succinate) US prescribing information. AstraZeneca|1
03140|063|R|  LP January, 2022.|1
03140|064|R|3.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
03140|065|R|4.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03140|066|R|  Laboratories Inc. August, 2023.|1
03140|067|R|5.Preskorn SH, Greenblatt DJ, Flockhart D, Luo Y, Perloff ES, Harmatz JS,|2
03140|068|R|  Baker B, Klick-Davis A, Desta Z, Burt T. Comparison of duloxetine,|2
03140|069|R|  escitalopram, and sertraline effects on cytochrome P450 2D6 function in|2
03140|070|R|  healthy volunteers. J Clin Psychopharmacol 2007 Feb;27(1):28-34.|2
03140|071|R|6.Spahn H, Mutschler E, Kirch W, Ohnhaus EE, Janisch HD. Influence of|2
03140|072|R|  ranitidine on plasma metoprolol and atenolol concentrations. Br Med J|2
03140|073|R|  (Clin Res Ed) 1983 May 14;286(6377):1546-7.|2
03140|074|R|7.Kelly JG, Salem SA, Kinney CD, Shanks RG, McDevitt DG. Effects of|2
03140|075|R|  ranitidine on the disposition of metoprolol. Br J Clin Pharmacol 1985 Feb;|2
03140|076|R|  19(2):219-24.|2
03140|077|R|8.Kirch W, Ramsch K, Janisch HD, Ohnhaus EE. The influence of two histamine|2
03140|078|R|  H2-receptor antagonists, cimetidine and ranitidine, on the plasma levels|2
03140|079|R|  and clinical effect of nifedipine and metoprolol. Arch Toxicol Suppl 1984;|2
03140|080|R|  7:256-9.|2
03140|081|R|9.Mutschler E, Spahn H, Kirch W. The interaction between H2-receptor|2
03140|082|R|  antagonists and beta-adrenoceptor blockers. Br J Clin Pharmacol 1984;17|2
03140|083|R|  Suppl 1:51S-57S.|2
03140|084|R|10.Toon S, Davidson EM, Garstang FM, Batra H, Bowes RJ, Rowland M. The|2
03140|085|R|   racemic metoprolol H2-antagonist interaction. Clin Pharmacol Ther 1988|2
03140|086|R|   Mar;43(3):283-9.|2
03140|087|R|11.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
03140|088|R|12.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
03140|089|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
03140|090|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
03140|091|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
03141|001|T|MONOGRAPH TITLE:  Metoprolol/Ethynodiol; Etonogestrel (mono deleted|
03141|002|T|06/25/2021)|
03141|003|B||
03141|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03141|005|L|take action as needed.|
03141|006|B||
03141|007|A|MECHANISM OF ACTION:  CYP2D6 inhibitors may inhibit the metabolism of|
03141|008|A|metoprolol.(1,2)|
03141|009|B||
03141|010|E|CLINICAL EFFECTS:  Concurrent use of CYP2D6 inhibitors may result in|
03141|011|E|elevated levels of and toxicity from metoprolol.(1,2)|
03141|012|B||
03141|013|P|PREDISPOSING FACTORS:  The interaction may be more severe in patients who|
03141|014|P|are extensive metabolizers of CYP2D6.(1,2)|
03141|015|B||
03141|016|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
03141|017|M|metoprolol and inhibitors of CYP2D6, such as hormonal contraceptives|
03141|018|M|containing ethynodiol or etonogestrel.  The dosage of metoprolol may need to|
03141|019|M|be adjusted.(1,2)|
03141|020|B||
03141|021|D|DISCUSSION:  In a study that compared metoprolol levels in 11 females not|
03141|022|D|receiving oral contraceptives to 12 receiving contraceptives, metoprolol AUC|
03141|023|D|was 70% higher in patients receiving concurrent oral contraceptives.(3,4)|
03141|024|B||
03141|025|R|REFERENCES:|
03141|026|B||
03141|027|R|1.Lopressor (metoprolol tartrate) US prescribing information. Validus|1
03141|028|R|  Pharmaceuticals. LLC March, 2013.|1
03141|029|R|2.Toprol-XL (metoprolol succinate) US prescribing information. AstraZeneca|1
03141|030|R|  LP January, 2022.|1
03141|031|R|3.Kendall MJ, Jack DB, Quarterman CP, Smith SR, Zaman R. Beta-adrenoceptor|2
03141|032|R|  blocker pharmacokinetics and the oral contraceptive pill. Br J Clin|2
03141|033|R|  Pharmacol 1984;17 Suppl 1:87S-89S.|2
03141|034|R|4.Kendall MJ, Quarterman CP, Jack DB, Beeley L. Metoprolol pharmacokinetics|2
03141|035|R|  and the oral contraceptive pill. Br J Clin Pharmacol 1982 Jul;14(1):120-2.|2
03142|001|T|MONOGRAPH TITLE:  Desvenlafaxine; Venlafaxine/Selected Tricyclic Compounds|
03142|002|B||
03142|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03142|004|L|take action as needed.|
03142|005|B||
03142|006|A|MECHANISM OF ACTION:  Desvenlafaxine or venlafaxine may impair the oxidative|
03142|007|A|hepatic metabolism of tricyclic compounds via CYP2D6.|
03142|008|B||
03142|009|E|CLINICAL EFFECTS:  Concurrent administration of desvenlafaxine or|
03142|010|E|venlafaxine with a tricyclic compound may result in an increase in serum|
03142|011|E|levels, toxicities, and/or clinical effects of the tricyclic compound.|
03142|012|B||
03142|013|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
03142|014|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
03142|015|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
03142|016|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
03142|017|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
03142|018|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
03142|019|P|systemic steroids).|
03142|020|P|   The risk of anticholinergic toxicities including cognitive decline,|
03142|021|P|delirium, falls and fractures is increased in geriatric patients using more|
03142|022|P|than one medicine with anticholinergic properties.(5)|
03142|023|B||
03142|024|M|PATIENT MANAGEMENT:  Patients should be observed for increased adverse|
03142|025|M|effects and clinical effects of tricyclic compounds at the initiation of|
03142|026|M|concurrent therapy with desvenlafaxine or venlafaxine.  Plasma|
03142|027|M|concentrations of the tricyclic compound should be monitored and the dosage|
03142|028|M|adjusted accordingly.|
03142|029|M|   If desvenlafaxine or venlafaxine is discontinued in a patient receiving a|
03142|030|M|tricyclic compound, the dosage of the tricyclic compound may need to be|
03142|031|M|adjusted.|
03142|032|M|   The US manufacturer of desvenlafaxine recommends the dose of desipramine|
03142|033|M|be reduced by up to one-half when administered with desvenlafaxine 400 mg.|
03142|034|B||
03142|035|D|DISCUSSION:  In a 70 year old patient, the use of venlafaxine, fluoxetine,|
03142|036|D|and nortriptyline was associated with severe anticholinergic side effects.|
03142|037|D|This interaction was thought to be due to increased nortriptyline levels.|
03142|038|D|   A case report of anticholinergic toxic syndrome with venlafaxine and|
03142|039|D|desipramine combination exist as well.|
03142|040|D|   Concomitant administration of desvenlafaxine 400 mg with a single 50 mg|
03142|041|D|dose of desipramine resulted in an increase in the Cmax and AUC of|
03142|042|D|desipramine by approximately 50% and 90%.|
03142|043|D|   The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450|
03142|044|D|may vary.|
03142|045|B||
03142|046|R|REFERENCES:|
03142|047|B||
03142|048|R|1.Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of|3
03142|049|R|  combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990|3
03142|050|R|  Apr;147(4):532.|3
03142|051|R|2.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
03142|052|R|  fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
03142|053|R|  1992 Mar;51(3):239-48.|2
03142|054|R|3.Skjelbo E, Brosen K. Inhibitors of imipramine metabolism by human liver|5
03142|055|R|  microsomes. Br J Clin Pharmacol 1992 Sep;34(3):256-61.|5
03142|056|R|4.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
03142|057|R|  Pharmaceuticals, Inc. August, 2023.|1
03142|058|R|5.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03142|059|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03142|060|R|  Soc 2023 Jul;71(7):2052-2081.|6
03143|001|T|MONOGRAPH TITLE:  Sertraline (Greater Than 50 mg)/Selected Tricyclic|
03143|002|T|Compounds|
03143|003|B||
03143|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03143|005|L|take action as needed.|
03143|006|B||
03143|007|A|MECHANISM OF ACTION:  Sertraline may impair the oxidative hepatic metabolism|
03143|008|A|of tricyclic compounds.|
03143|009|B||
03143|010|E|CLINICAL EFFECTS:  Concurrent administration of sertraline with a tricyclic|
03143|011|E|compound may result in an increase in serum levels, toxicities, and/or|
03143|012|E|clinical effects of the tricyclic compound.|
03143|013|B||
03143|014|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
03143|015|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
03143|016|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
03143|017|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
03143|018|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
03143|019|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
03143|020|P|systemic steroids).|
03143|021|P|   The risk of anticholinergic toxicities including cognitive decline,|
03143|022|P|delirium, falls and fractures is increased in geriatric patients using more|
03143|023|P|than one medicine with anticholinergic properties.(8)|
03143|024|B||
03143|025|M|PATIENT MANAGEMENT:  Patients should be observed for increased adverse|
03143|026|M|effects and clinical effects of tricyclic compounds at the initiation of|
03143|027|M|concurrent therapy with sertraline.  Plasma concentrations of the tricyclic|
03143|028|M|compound should be monitored and the dosage adjusted accordingly.|
03143|029|M|   If sertraline is discontinued in a patient receiving a tricyclic|
03143|030|M|compound, the dosage of the tricyclic compound may need to be adjusted.|
03143|031|B||
03143|032|D|DISCUSSION:  Sertraline has been shown to increase the maximum concentration|
03143|033|D|(Cmax) and AUC of desipramine by 31% and 23%, respectively.(5)|
03143|034|D|   The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450|
03143|035|D|may vary.|
03143|036|B||
03143|037|R|REFERENCES:|
03143|038|B||
03143|039|R|1.Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of|3
03143|040|R|  combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990|3
03143|041|R|  Apr;147(4):532.|3
03143|042|R|2.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
03143|043|R|  fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
03143|044|R|  1992 Mar;51(3):239-48.|2
03143|045|R|3.Maskall DD, Lam RW. Increased plasma concentration of imipramine following|3
03143|046|R|  augmentation with fluvoxamine. Am J Psychiatry 1993 Oct;150(10):1566.|3
03143|047|R|4.Skjelbo E, Brosen K. Inhibitors of imipramine metabolism by human liver|5
03143|048|R|  microsomes. Br J Clin Pharmacol 1992 Sep;34(3):256-61.|5
03143|049|R|5.Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, Harris S.|2
03143|050|R|  Pharmacokinetics of desipramine coadministered with sertraline or|2
03143|051|R|  fluoxetine. J Clin Psychopharmacol 1994 Apr;14(2):90-8.|2
03143|052|R|6.Michalets EL, Smith LK, Van Tassel ED. Torsade de pointes resulting from|3
03143|053|R|  the addition of droperidol to an existing cytochrome P450 drug|3
03143|054|R|  interaction. Ann Pharmacother 1998 Jul-Aug;32(7-8):761-5.|3
03143|055|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03143|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03143|057|R|  settings: a scientific statement from the American Heart Association and|6
03143|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03143|059|R|  2;55(9):934-47.|6
03143|060|R|8.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03143|061|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03143|062|R|  Soc 2023 Jul;71(7):2052-2081.|6
03144|001|T|MONOGRAPH TITLE:  Sertraline/Dothiepin; Melitracen|
03144|002|B||
03144|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03144|004|L|take action as needed.|
03144|005|B||
03144|006|A|MECHANISM OF ACTION:  Sertraline may impair the oxidative hepatic metabolism|
03144|007|A|of dothiepin and melitracen.|
03144|008|B||
03144|009|E|CLINICAL EFFECTS:  Concurrent administration of sertraline with dothiepin or|
03144|010|E|melitracen may result in an increase in serum levels, toxicities (e.g.|
03144|011|E|torsades de pointes), and/or clinical effects of dothiepin or melitracen.|
03144|012|B||
03144|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03144|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03144|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03144|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03144|017|P|female gender, or advanced age.(7)|
03144|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03144|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03144|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03144|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03144|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03144|023|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
03144|024|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)|
03144|025|B||
03144|026|M|PATIENT MANAGEMENT:  Patients should be observed for increased adverse|
03144|027|M|effects and clinical effects of dothiepin and melitracen at the initiation|
03144|028|M|of concurrent therapy with sertraline.  Plasma concentrations of dothiepin|
03144|029|M|and melitracen should be monitored and the dosage adjusted accordingly.|
03144|030|M|   If sertraline is discontinued in a patient receiving dothiepin or|
03144|031|M|melitracen, the dosage of dothiepin or melitracen may need to be adjusted.|
03144|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03144|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03144|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03144|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03144|036|B||
03144|037|D|DISCUSSION:  Sertraline has been shown to increase the maximum concentration|
03144|038|D|(Cmax) and AUC of desipramine by 31% and 23%, respectively.(5)|
03144|039|D|   The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450|
03144|040|D|may vary.|
03144|041|B||
03144|042|R|REFERENCES:|
03144|043|B||
03144|044|R|1.Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of|3
03144|045|R|  combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990|3
03144|046|R|  Apr;147(4):532.|3
03144|047|R|2.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
03144|048|R|  fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
03144|049|R|  1992 Mar;51(3):239-48.|2
03144|050|R|3.Maskall DD, Lam RW. Increased plasma concentration of imipramine following|3
03144|051|R|  augmentation with fluvoxamine. Am J Psychiatry 1993 Oct;150(10):1566.|3
03144|052|R|4.Skjelbo E, Brosen K. Inhibitors of imipramine metabolism by human liver|5
03144|053|R|  microsomes. Br J Clin Pharmacol 1992 Sep;34(3):256-61.|5
03144|054|R|5.Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, Harris S.|2
03144|055|R|  Pharmacokinetics of desipramine coadministered with sertraline or|2
03144|056|R|  fluoxetine. J Clin Psychopharmacol 1994 Apr;14(2):90-8.|2
03144|057|R|6.Michalets EL, Smith LK, Van Tassel ED. Torsade de pointes resulting from|3
03144|058|R|  the addition of droperidol to an existing cytochrome P450 drug|3
03144|059|R|  interaction. Ann Pharmacother 1998 Jul-Aug;32(7-8):761-5.|3
03144|060|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03144|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03144|062|R|  settings: a scientific statement from the American Heart Association and|6
03144|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03144|064|R|  2;55(9):934-47.|6
03145|001|T|MONOGRAPH TITLE:  Selected SSRIs; SNRIs/Cyclobenzaprine|
03145|002|B||
03145|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03145|004|L|take action as needed.|
03145|005|B||
03145|006|A|MECHANISM OF ACTION:  Selected serotonin or serotonin-norepinephrine|
03145|007|A|reuptake inhibitors (SSRIs or SNRIs) may impair the oxidative hepatic|
03145|008|A|metabolism of cyclobenzaprine. Cyclobenzaprine is metabolized by CYP1A2,|
03145|009|A|CYP3A4, and to a lesser extent CYP2D6.(4)|
03145|010|A|   Fluvoxamine is a strong inhibitor of CYP1A2 and a weak inhibitor of|
03145|011|A|CYP3A4 and CYP2D6.  Sertraline and venlafaxine are weak inhibitors of|
03145|012|A|CYP2D6.|
03145|013|B||
03145|014|E|CLINICAL EFFECTS:  Concurrent administration of selected SSRIs or SNRIs with|
03145|015|E|cyclobenzaprine may result in an increase in serum levels, toxicities,|
03145|016|E|and/or clinical effects of cyclobenzaprine, including serotonin syndrome.(4)|
03145|017|E|Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
03145|018|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
03145|019|B||
03145|020|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
03145|021|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
03145|022|P|patients using more than one medicine with anticholinergic properties.(5)|
03145|023|B||
03145|024|M|PATIENT MANAGEMENT:  Patients should be observed for increased adverse|
03145|025|M|effects and clinical effects of cyclobenzaprine at the initiation of|
03145|026|M|concurrent therapy with selected SSRIs or SNRIs.  Plasma concentrations of|
03145|027|M|cyclobenzaprine should be monitored and the dosage adjusted accordingly.|
03145|028|M|   If concurrent therapy is warranted, patients should be monitored for|
03145|029|M|signs and symptoms of serotonin syndrome, and seizure activity.  Instruct|
03145|030|M|patients to report muscle twitching, tremors, shivering and stiffness,|
03145|031|M|fever, heavy sweating, heart palpitations, restlessness, confusion,|
03145|032|M|agitation, trouble with coordination, or severe diarrhea.|
03145|033|M|   If the SSRI or SNRI is discontinued in a patient receiving|
03145|034|M|cyclobenzaprine, the dosage of the cyclobenzaprine may need to be adjusted.|
03145|035|B||
03145|036|D|DISCUSSION:  There have been case reports of serotonin syndrome with|
03145|037|D|trazodone and amitriptyline with lithium, and cyclobenzaprine with|
03145|038|D|duloxetine.(6)|
03145|039|D|   The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450|
03145|040|D|may vary.|
03145|041|B||
03145|042|R|REFERENCES:|
03145|043|B||
03145|044|R|1.Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of|3
03145|045|R|  combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990|3
03145|046|R|  Apr;147(4):532.|3
03145|047|R|2.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
03145|048|R|  fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
03145|049|R|  1992 Mar;51(3):239-48.|2
03145|050|R|3.Van Hoey NM. Effect of cyclobenzaprine on tricyclic antidepressant assays.|6
03145|051|R|  Ann Pharmacother 2005 Jul-Aug;39(7-8):1314-7.|6
03145|052|R|4.Flexeril (cyclobenzaprine) US prescribing information. McNeil Consumer and|1
03145|053|R|  Speciality Pharmaceuticals April, 2013.|1
03145|054|R|5.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03145|055|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03145|056|R|  Soc 2023 Jul;71(7):2052-2081.|6
03145|057|R|6.Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the|3
03145|058|R|  interaction of cyclobenzaprine with other serotoninergic drugs. Anesth|3
03145|059|R|  Analg 2006 Dec;103(6):1466-8.|3
03145|060|R|7.Michalets EL, Smith LK, Van Tassel ED. Torsade de pointes resulting from|3
03145|061|R|  the addition of droperidol to an existing cytochrome P450 drug|3
03145|062|R|  interaction. Ann Pharmacother 1998 Jul-Aug;32(7-8):761-5.|3
03145|063|R|8.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03145|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03145|065|R|  settings: a scientific statement from the American Heart Association and|6
03145|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03145|067|R|  2;55(9):934-47.|6
03145|068|R|9.Amrix (cyclobenzaprine extended release) US prescribing information. Teva|1
03145|069|R|  Pharmaceuticals Ltd. May, 2016.|1
03145|070|R|10.This information is based on an extract from the Certara Drug Interaction|6
03145|071|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03146|001|T|MONOGRAPH TITLE:  Selected SSRIs; SNRIs/Trazodone|
03146|002|B||
03146|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03146|004|L|take action as needed.|
03146|005|B||
03146|006|A|MECHANISM OF ACTION:  Selected serotonin or serotonin-norepinephrine|
03146|007|A|reuptake inhibitors (SSRIs or SNRIs) may impair the oxidative hepatic|
03146|008|A|metabolism of trazodone. Trazodone is metabolized by CYP3A4 and its active|
03146|009|A|metabolite meta-chlorophenylpiperazine (m-CPP) is metabolized by CYP2D6.|
03146|010|A|Duloxetine is a moderate inhibitor of CYP2D6.  Desvenlafaxine, fluvoxamine,|
03146|011|A|sertraline, and venlafaxine are weak inhibitors of CYP2D6.  Fluvoxamine is|
03146|012|A|also a weak inhibitor of CYP3A4.|
03146|013|B||
03146|014|E|CLINICAL EFFECTS:  Concurrent administration of selected SSRIs or SNRIs with|
03146|015|E|trazodone may result in an increase in serum levels, toxicities (e.g.|
03146|016|E|torsades de pointes), and/or clinical effects of trazodone.|
03146|017|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03146|018|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03146|019|E|rigidity.|
03146|020|B||
03146|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03146|022|P|may be increased in patients with cardiovascular disease (e.g. heart|
03146|023|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03146|024|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03146|025|P|female gender, or advanced age.(5)|
03146|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03146|027|P|higher systemic concentrations of either QT prolonging drug are additional|
03146|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03146|029|P|drug concentrations include rapid infusion of an intravenous dose or|
03146|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03146|031|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
03146|032|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03146|033|B||
03146|034|M|PATIENT MANAGEMENT:  Patients should be observed for increased adverse|
03146|035|M|effects and clinical effects of trazodone at the initiation of concurrent|
03146|036|M|therapy with selected SSRIs or SNRIs.  Plasma concentrations of trazodone|
03146|037|M|should be monitored and the dosage adjusted accordingly.|
03146|038|M|   If the SSRI or SNRI is discontinued in a patient receiving trazodone, the|
03146|039|M|dosage of trazodone may need to be adjusted.|
03146|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03146|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03146|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03146|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03146|044|M|   If concurrent therapy is warranted, patients should be monitored for|
03146|045|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03146|046|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03146|047|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03146|048|M|coordination, or severe diarrhea.|
03146|049|B||
03146|050|D|DISCUSSION:  There have been case reports of serotonin syndrome with|
03146|051|D|trazodone and amitriptyline with lithium, and cyclobenzaprine (structurally|
03146|052|D|related to the TCAs) with duloxetine.(3)|
03146|053|D|   The affinity of the different selective serotonin reuptake inhibitors,|
03146|054|D|serotonin and norepinephrine reuptake inhibitors, and tricyclics for CYP|
03146|055|D|P-450 may vary.|
03146|056|B||
03146|057|R|REFERENCES:|
03146|058|B||
03146|059|R|1.Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of|3
03146|060|R|  combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990|3
03146|061|R|  Apr;147(4):532.|3
03146|062|R|2.Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the|2
03146|063|R|  fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther|2
03146|064|R|  1992 Mar;51(3):239-48.|2
03146|065|R|3.Nisijima K, Shimizu M, Abe T, Ishiguro T. A case of serotonin syndrome|3
03146|066|R|  induced by concomitant treatment with low-dose trazodone and amitriptyline|3
03146|067|R|  and lithium. Int Clin Psychopharmacol 1996 Dec;11(4):289-90.|3
03146|068|R|4.Michalets EL, Smith LK, Van Tassel ED. Torsade de pointes resulting from|3
03146|069|R|  the addition of droperidol to an existing cytochrome P450 drug|3
03146|070|R|  interaction. Ann Pharmacother 1998 Jul-Aug;32(7-8):761-5.|3
03146|071|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03146|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03146|073|R|  settings: a scientific statement from the American Heart Association and|6
03146|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03146|075|R|  2;55(9):934-47.|6
03146|076|R|6.This information is based on an extract from the Certara Drug Interaction|6
03146|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03146|078|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
03146|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03146|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03146|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03146|082|R|  11/14/2017.|1
03146|083|R|8.Rotzinger S, Fang J, Baker GB. Trazodone is metabolized to|5
03146|084|R|  m-chlorophenylpiperazine by CYP3A4 from human sources. Drug Metab Dispos|5
03146|085|R|  1998 Jun;26(6):572-5.|5
03146|086|R|9.Rotzinger S, Fang J, Coutts RT, Baker GB. Human CYP2D6 and metabolism of|5
03146|087|R|  m-chlorophenylpiperazine. Biol Psychiatry 1998 Dec 1;44(11):1185-91.|5
03147|001|T|MONOGRAPH TITLE:  Meperidine (Immediate Release)/Chlorpromazine;|
03147|002|T|Promethazine|
03147|003|B||
03147|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03147|005|L|take action as needed.|
03147|006|B||
03147|007|A|MECHANISM OF ACTION:  Concurrent use of opioids such as meperidine and|
03147|008|A|antipsychotics such as chlorpromazine or phenothiazine derivatives such as|
03147|009|A|promethazine may result in additive CNS depression.(1)|
03147|010|B||
03147|011|E|CLINICAL EFFECTS:  Concurrent use of opioids such as meperidine and|
03147|012|E|antipsychotics such as chlorpromazine or phenothiazine derivatives such as|
03147|013|E|promethazine may result in profound sedation, respiratory depression, coma,|
03147|014|E|and/or death.(1)|
03147|015|B||
03147|016|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03147|017|P|may increase the risk of adverse effects.|
03147|018|B||
03147|019|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as meperidine|
03147|020|M|with CNS depressants such as chlorpromazine or promethazine to patients for|
03147|021|M|whom alternatives are ineffective, not tolerated, or would be otherwise|
03147|022|M|inadequate to provide sufficient management of pain.(1)|
03147|023|M|   If concurrent use is necessary, limit the dosages and duration of each|
03147|024|M|drug to the minimum possible while achieving the desired clinical effect.|
03147|025|M|If starting a CNS depressant with an opioid analgesic, prescribe a lower|
03147|026|M|initial dose of the CNS depressant than indicated in the absence of an|
03147|027|M|opioid and titrate based upon clinical response.  If an opioid analgesic is|
03147|028|M|indicated in a patient already taking a CNS depressant, prescribe a lower|
03147|029|M|dose of the opioid and titrate based upon clinical response.(1)|
03147|030|M|   Respiratory depression can occur at any time during opioid therapy,|
03147|031|M|especially during therapy initiation and following dosage increases.  The|
03147|032|M|risk of opioid-related overdose or overdose-related death is increased with|
03147|033|M|higher opioid doses, and this risk persists over the course of therapy.|
03147|034|M|Consider these risks when using concurrently with other agents that may|
03147|035|M|cause CNS depression.(2)|
03147|036|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03147|037|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03147|038|M|unresponsiveness.(1)|
03147|039|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03147|040|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03147|041|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03147|042|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03147|043|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03147|044|M|as those taking CNS depressants) and when a patient has household|
03147|045|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03147|046|M|for obtaining an opioid reversal agent (e.g., prescription,|
03147|047|M|over-the-counter, or as part of a community-based program).(3)|
03147|048|B||
03147|049|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03147|050|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03147|051|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03147|052|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03147|053|D|significantly increased in patients with recent use of antipsychotics|
03147|054|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03147|055|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03147|056|D|of use.(4)|
03147|057|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03147|058|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03147|059|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03147|060|D|to 30 million patients.  During this time, the proportion of patients|
03147|061|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03147|062|D|patients.(5)|
03147|063|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03147|064|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03147|065|D|per 100,000 and drug overdose deaths involving both opioids and|
03147|066|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03147|067|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03147|068|D|increased from 18% to 31% during this time.(6)|
03147|069|D|   A prospective observational cohort study in North Carolina found that the|
03147|070|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03147|071|D|benzodiazepines were 10 times higher than patients receiving opioid|
03147|072|D|analgesics alone.(7)|
03147|073|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03147|074|D|death from overdose increased with concomitant opioid analgesics and|
03147|075|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03147|076|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03147|077|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03147|078|D|increased risk of fatal overdose.(8)|
03147|079|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03147|080|D|which benzodiazepines were determined to be a cause of death and that|
03147|081|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03147|082|D|determined to be a cause of death.  This study also found that other CNS|
03147|083|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03147|084|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03147|085|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03147|086|D|where opioid analgesics were also implicated.(9)|
03147|087|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03147|088|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03147|089|D|deaths.(10)|
03147|090|B||
03147|091|R|REFERENCES:|
03147|092|B||
03147|093|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03147|094|R|  warns about serious risks and death when combining opioid pain or cough|1
03147|095|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03147|096|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03147|097|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03147|098|R|  prescribing information for all opioid pain medicines to provide|1
03147|099|R|  additional guidance for safe use. Available at:|1
03147|100|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03147|101|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03147|102|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03147|103|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03147|104|R|  recommends health care professionals discuss naloxone with all patients|1
03147|105|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03147|106|R|  disorder. Available at:|1
03147|107|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03147|108|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03147|109|R|  d-pain July 23, 2020.|1
03147|110|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03147|111|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03147|112|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03147|113|R|  Pharmacol 2020 Apr 26.|2
03147|114|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03147|115|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03147|116|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03147|117|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03147|118|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03147|119|R|  49(4):493-501.|2
03147|120|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03147|121|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03147|122|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03147|123|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03147|124|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03147|125|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03147|126|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03147|127|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03147|128|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03147|129|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03147|130|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03147|131|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03148|001|T|MONOGRAPH TITLE:  Meperidine (IR)/Selected Antipsychotics; Phenothiazines|
03148|002|B||
03148|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03148|004|L|take action as needed.|
03148|005|B||
03148|006|A|MECHANISM OF ACTION:  Concurrent use of opioids such as meperidine and|
03148|007|A|antipsychotics, including phenothiazine derivatives, may result in additive|
03148|008|A|CNS depression.(1)|
03148|009|B||
03148|010|E|CLINICAL EFFECTS:  Concurrent use of opioids such as meperidine and other|
03148|011|E|CNS depressants, such as antipsychotics, including phenothiazine|
03148|012|E|derivatives, may result in profound sedation, respiratory depression, coma,|
03148|013|E|and/or death.(1)|
03148|014|B||
03148|015|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03148|016|P|may increase the risk of adverse effects.|
03148|017|B||
03148|018|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as meperidine|
03148|019|M|with CNS depressants such as antipsychotics, including phenothiazine|
03148|020|M|derivatives, to patients for whom alternatives are ineffective, not|
03148|021|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03148|022|M|of pain.(1)|
03148|023|M|   If concurrent use is necessary, limit the dosages and duration of each|
03148|024|M|drug to the minimum possible while achieving the desired clinical effect.|
03148|025|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03148|026|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03148|027|M|indicated in the absence of an opioid and titrate based upon clinical|
03148|028|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03148|029|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03148|030|M|clinical response.(1)|
03148|031|M|   Respiratory depression can occur at any time during opioid therapy,|
03148|032|M|especially during therapy initiation and following dosage increases.  The|
03148|033|M|risk of opioid-related overdose or overdose-related death is increased with|
03148|034|M|higher opioid doses, and this risk persists over the course of therapy.|
03148|035|M|Consider these risks when using concurrently with other agents that may|
03148|036|M|cause CNS depression.(2)|
03148|037|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03148|038|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03148|039|M|unresponsiveness.(1)|
03148|040|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03148|041|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03148|042|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03148|043|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03148|044|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03148|045|M|as those taking CNS depressants) and when a patient has household|
03148|046|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03148|047|M|for obtaining an opioid reversal agent (e.g., prescription,|
03148|048|M|over-the-counter, or as part of a community-based program).(3)|
03148|049|B||
03148|050|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03148|051|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03148|052|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03148|053|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03148|054|D|significantly increased in patients with recent use of antipsychotics|
03148|055|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03148|056|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03148|057|D|of use.(4)|
03148|058|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03148|059|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03148|060|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03148|061|D|to 30 million patients.  During this time, the proportion of patients|
03148|062|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03148|063|D|patients.(5)|
03148|064|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03148|065|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03148|066|D|per 100,000 and drug overdose deaths involving both opioids and|
03148|067|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03148|068|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03148|069|D|increased from 18% to 31% during this time.(6)|
03148|070|D|   A prospective observational cohort study in North Carolina found that the|
03148|071|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03148|072|D|benzodiazepines were 10 times higher than patients receiving opioid|
03148|073|D|analgesics alone.(7)|
03148|074|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03148|075|D|death from overdose increased with concomitant opioid analgesics and|
03148|076|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03148|077|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03148|078|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03148|079|D|increased risk of fatal overdose.(8)|
03148|080|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03148|081|D|which benzodiazepines were determined to be a cause of death and that|
03148|082|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03148|083|D|determined to be a cause of death.  This study also found that other CNS|
03148|084|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03148|085|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03148|086|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03148|087|D|where opioid analgesics were also implicated.(9)|
03148|088|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03148|089|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03148|090|D|deaths.(10)|
03148|091|B||
03148|092|R|REFERENCES:|
03148|093|B||
03148|094|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03148|095|R|  warns about serious risks and death when combining opioid pain or cough|1
03148|096|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03148|097|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03148|098|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03148|099|R|  prescribing information for all opioid pain medicines to provide|1
03148|100|R|  additional guidance for safe use. Available at:|1
03148|101|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03148|102|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03148|103|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03148|104|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03148|105|R|  recommends health care professionals discuss naloxone with all patients|1
03148|106|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03148|107|R|  disorder. Available at:|1
03148|108|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03148|109|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03148|110|R|  d-pain July 23, 2020.|1
03148|111|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03148|112|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03148|113|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03148|114|R|  Pharmacol 2020 Apr 26.|2
03148|115|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03148|116|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03148|117|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03148|118|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03148|119|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03148|120|R|  49(4):493-501.|2
03148|121|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03148|122|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03148|123|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03148|124|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03148|125|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03148|126|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03148|127|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03148|128|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03148|129|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03148|130|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03148|131|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03148|132|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03149|001|T|MONOGRAPH TITLE:  Codeine; Levorphanol (IR)/Slt Antipsychotics;|
03149|002|T|Phenothiazines|
03149|003|B||
03149|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03149|005|L|take action as needed.|
03149|006|B||
03149|007|A|MECHANISM OF ACTION:  Concurrent use of opioids such as codeine and|
03149|008|A|levorphanol and antipsychotics, including phenothiazine derivatives, may|
03149|009|A|result in additive CNS depression.(1)|
03149|010|B||
03149|011|E|CLINICAL EFFECTS:  Concurrent use of opioids such as codeine and levorphanol|
03149|012|E|and other CNS depressants, such as antipsychotics, including phenothiazine|
03149|013|E|derivatives, may result in profound sedation, respiratory depression, coma,|
03149|014|E|and/or death.(1)|
03149|015|B||
03149|016|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03149|017|P|may increase the risk of adverse effects.|
03149|018|B||
03149|019|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as codeine and|
03149|020|M|levorphanol with CNS depressants such as antipsychotics, including|
03149|021|M|phenothiazine derivatives, to patients for whom alternatives are|
03149|022|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
03149|023|M|sufficient management of pain.(1)|
03149|024|M|   If concurrent use is necessary, limit the dosages and duration of each|
03149|025|M|drug to the minimum possible while achieving the desired clinical effect.|
03149|026|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03149|027|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03149|028|M|indicated in the absence of an opioid and titrate based upon clinical|
03149|029|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03149|030|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03149|031|M|clinical response.(1)|
03149|032|M|   Respiratory depression can occur at any time during opioid therapy,|
03149|033|M|especially during therapy initiation and following dosage increases.  The|
03149|034|M|risk of opioid-related overdose or overdose-related death is increased with|
03149|035|M|higher opioid doses, and this risk persists over the course of therapy.|
03149|036|M|Consider these risks when using concurrently with other agents that may|
03149|037|M|cause CNS depression.(2)|
03149|038|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03149|039|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03149|040|M|unresponsiveness.(1)|
03149|041|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03149|042|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03149|043|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03149|044|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03149|045|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03149|046|M|as those taking CNS depressants) and when a patient has household|
03149|047|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03149|048|M|for obtaining an opioid reversal agent (e.g., prescription,|
03149|049|M|over-the-counter, or as part of a community-based program).(3)|
03149|050|B||
03149|051|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03149|052|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03149|053|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03149|054|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03149|055|D|significantly increased in patients with recent use of antipsychotics|
03149|056|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03149|057|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03149|058|D|of use.(4)|
03149|059|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03149|060|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03149|061|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03149|062|D|to 30 million patients.  During this time, the proportion of patients|
03149|063|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03149|064|D|patients.(5)|
03149|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03149|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03149|067|D|per 100,000 and drug overdose deaths involving both opioids and|
03149|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03149|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03149|070|D|increased from 18% to 31% during this time.(6)|
03149|071|D|   A prospective observational cohort study in North Carolina found that the|
03149|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03149|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
03149|074|D|analgesics alone.(7)|
03149|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03149|076|D|death from overdose increased with concomitant opioid analgesics and|
03149|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03149|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03149|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03149|080|D|increased risk of fatal overdose.(8)|
03149|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03149|082|D|which benzodiazepines were determined to be a cause of death and that|
03149|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03149|084|D|determined to be a cause of death.  This study also found that other CNS|
03149|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03149|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03149|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03149|088|D|where opioid analgesics were also implicated.(9)|
03149|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03149|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03149|091|D|deaths.(10)|
03149|092|B||
03149|093|R|REFERENCES:|
03149|094|B||
03149|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03149|096|R|  warns about serious risks and death when combining opioid pain or cough|1
03149|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03149|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03149|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03149|100|R|  prescribing information for all opioid pain medicines to provide|1
03149|101|R|  additional guidance for safe use. Available at:|1
03149|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03149|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03149|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03149|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03149|106|R|  recommends health care professionals discuss naloxone with all patients|1
03149|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03149|108|R|  disorder. Available at:|1
03149|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03149|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03149|111|R|  d-pain July 23, 2020.|1
03149|112|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03149|113|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03149|114|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03149|115|R|  Pharmacol 2020 Apr 26.|2
03149|116|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03149|117|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03149|118|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03149|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03149|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03149|121|R|  49(4):493-501.|2
03149|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03149|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03149|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03149|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03149|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03149|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03149|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03149|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03149|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03149|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03149|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03149|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03150|001|T|MONOGRAPH TITLE:  Codeine; Dihydrocodeine; Levorphanol (IR)/Risperidone|
03150|002|B||
03150|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03150|004|L|take action as needed.|
03150|005|B||
03150|006|A|MECHANISM OF ACTION:  Concurrent use of opioids such as codeine or|
03150|007|A|levorphanol and antipsychotics such as risperidone may result in additive|
03150|008|A|CNS depression.(1)|
03150|009|B||
03150|010|E|CLINICAL EFFECTS:  Concurrent use of opioids such as codeine or levorphanol|
03150|011|E|and other CNS depressants, such as risperidone, may result in profound|
03150|012|E|sedation, respiratory depression, coma, and/or death.(1)|
03150|013|B||
03150|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03150|015|P|may increase the risk of adverse effects.|
03150|016|B||
03150|017|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as codeine or|
03150|018|M|levorphanol with CNS depressants such as risperidone to patients for whom|
03150|019|M|alternatives are ineffective, not tolerated, or would be otherwise|
03150|020|M|inadequate to provide sufficient management of pain.(1)|
03150|021|M|   If concurrent use is necessary, limit the dosages and duration of each|
03150|022|M|drug to the minimum possible while achieving the desired clinical effect.|
03150|023|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03150|024|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03150|025|M|indicated in the absence of an opioid and titrate based upon clinical|
03150|026|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03150|027|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03150|028|M|clinical response.(1)|
03150|029|M|   Respiratory depression can occur at any time during opioid therapy,|
03150|030|M|especially during therapy initiation and following dosage increases.  The|
03150|031|M|risk of opioid-related overdose or overdose-related death is increased with|
03150|032|M|higher opioid doses, and this risk persists over the course of therapy.|
03150|033|M|Consider these risks when using concurrently with other agents that may|
03150|034|M|cause CNS depression.(2)|
03150|035|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03150|036|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03150|037|M|unresponsiveness.(1)|
03150|038|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03150|039|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03150|040|M|treat opioid use disorder (OUD).  Consider prescribing opioid reversal|
03150|041|M|agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03150|042|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03150|043|M|as those taking CNS depressants) and when a patient has household|
03150|044|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03150|045|M|for obtaining an opioid reversal agent (e.g., prescription,|
03150|046|M|over-the-counter, or as part of a community-based program).(3)|
03150|047|B||
03150|048|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03150|049|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03150|050|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03150|051|D|million to 30 million patients.  During this time, the proportion of|
03150|052|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03150|053|D|million patients.(4)|
03150|054|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03150|055|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03150|056|D|per 100,000 and drug overdose deaths involving both opioids and|
03150|057|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03150|058|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03150|059|D|increased from 18% to 31% during this time.(5)|
03150|060|D|   A prospective observational cohort study in North Carolina found that the|
03150|061|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03150|062|D|benzodiazepines were 10 times higher than patients receiving opioid|
03150|063|D|analgesics alone.(6)|
03150|064|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03150|065|D|death from overdose increased with concomitant opioid analgesics and|
03150|066|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03150|067|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03150|068|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03150|069|D|increased risk of fatal overdose.(7)|
03150|070|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03150|071|D|which benzodiazepines were determined to be a cause of death and that|
03150|072|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03150|073|D|determined to be a cause of death.  This study also found that other CNS|
03150|074|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03150|075|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03150|076|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03150|077|D|where opioid analgesics were also implicated.(8)|
03150|078|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03150|079|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03150|080|D|deaths.(9)|
03150|081|B||
03150|082|R|REFERENCES:|
03150|083|B||
03150|084|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03150|085|R|  warns about serious risks and death when combining opioid pain or cough|1
03150|086|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03150|087|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03150|088|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03150|089|R|  prescribing information for all opioid pain medicines to provide|1
03150|090|R|  additional guidance for safe use. Available at:|1
03150|091|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03150|092|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03150|093|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03150|094|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03150|095|R|  recommends health care professionals discuss naloxone with all patients|1
03150|096|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03150|097|R|  disorder. Available at:|1
03150|098|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03150|099|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03150|100|R|  d-pain July 23, 2020.|1
03150|101|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03150|102|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03150|103|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03150|104|R|5.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03150|105|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03150|106|R|  49(4):493-501.|2
03150|107|R|6.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03150|108|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03150|109|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03150|110|R|7.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03150|111|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03150|112|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03150|113|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03150|114|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03150|115|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03150|116|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
03150|117|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
03150|118|R|  2014 Oct 10;63(40):881-5.|2
03151|001|T|MONOGRAPH TITLE:  Levomethadyl (IR)/Selected Antipsychotics; Phenothiazines|
03151|002|B||
03151|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03151|004|L|take action as needed.|
03151|005|B||
03151|006|A|MECHANISM OF ACTION:  Concurrent use of opioids such as levomethadyl and|
03151|007|A|antipsychotics, including phenothiazine derivatives, may result in additive|
03151|008|A|CNS depression.(1)|
03151|009|B||
03151|010|E|CLINICAL EFFECTS:  Concurrent use of opioids such as levomethadyl and other|
03151|011|E|CNS depressants, such as antipsychotics, including phenothiazine|
03151|012|E|derivatives, may result in profound sedation, respiratory depression, coma,|
03151|013|E|and/or death.(1)|
03151|014|B||
03151|015|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03151|016|P|may increase the risk of adverse effects.|
03151|017|B||
03151|018|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as|
03151|019|M|levomethadyl with CNS depressants such as antipsychotics, including|
03151|020|M|phenothiazine derivatives, to patients for whom alternatives are|
03151|021|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
03151|022|M|sufficient management of pain.(1)|
03151|023|M|   If concurrent use is necessary, limit the dosages and duration of each|
03151|024|M|drug to the minimum possible while achieving the desired clinical effect.|
03151|025|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03151|026|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03151|027|M|indicated in the absence of an opioid and titrate based upon clinical|
03151|028|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03151|029|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03151|030|M|clinical response.(1)|
03151|031|M|   Respiratory depression can occur at any time during opioid therapy,|
03151|032|M|especially during therapy initiation and following dosage increases.  The|
03151|033|M|risk of opioid-related overdose or overdose-related death is increased with|
03151|034|M|higher opioid doses, and this risk persists over the course of therapy.|
03151|035|M|Consider these risks when using concurrently with other agents that may|
03151|036|M|cause CNS depression.(2)|
03151|037|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03151|038|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03151|039|M|unresponsiveness.(1)|
03151|040|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03151|041|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03151|042|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03151|043|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03151|044|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03151|045|M|as those taking CNS depressants) and when a patient has household|
03151|046|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03151|047|M|for obtaining an opioid reversal agent (e.g., prescription,|
03151|048|M|over-the-counter, or as part of a community-based program).(3)|
03151|049|B||
03151|050|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03151|051|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03151|052|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03151|053|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03151|054|D|significantly increased in patients with recent use of antipsychotics|
03151|055|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03151|056|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03151|057|D|of use.(4)|
03151|058|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03151|059|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03151|060|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03151|061|D|to 30 million patients.  During this time, the proportion of patients|
03151|062|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03151|063|D|patients.(5)|
03151|064|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03151|065|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03151|066|D|per 100,000 and drug overdose deaths involving both opioids and|
03151|067|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03151|068|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03151|069|D|increased from 18% to 31% during this time.(6)|
03151|070|D|   A prospective observational cohort study in North Carolina found that the|
03151|071|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03151|072|D|benzodiazepines were 10 times higher than patients receiving opioid|
03151|073|D|analgesics alone.(7)|
03151|074|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03151|075|D|death from overdose increased with concomitant opioid analgesics and|
03151|076|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03151|077|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03151|078|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03151|079|D|increased risk of fatal overdose.(8)|
03151|080|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03151|081|D|which benzodiazepines were determined to be a cause of death and that|
03151|082|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03151|083|D|determined to be a cause of death.  This study also found that other CNS|
03151|084|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03151|085|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03151|086|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03151|087|D|where opioid analgesics were also implicated.(9)|
03151|088|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03151|089|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03151|090|D|deaths.(10)|
03151|091|B||
03151|092|R|REFERENCES:|
03151|093|B||
03151|094|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03151|095|R|  warns about serious risks and death when combining opioid pain or cough|1
03151|096|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03151|097|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03151|098|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03151|099|R|  prescribing information for all opioid pain medicines to provide|1
03151|100|R|  additional guidance for safe use. Available at:|1
03151|101|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03151|102|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03151|103|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03151|104|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03151|105|R|  recommends health care professionals discuss naloxone with all patients|1
03151|106|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03151|107|R|  disorder. Available at:|1
03151|108|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03151|109|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03151|110|R|  d-pain July 23, 2020.|1
03151|111|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03151|112|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03151|113|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03151|114|R|  Pharmacol 2020 Apr 26.|2
03151|115|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03151|116|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03151|117|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03151|118|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03151|119|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03151|120|R|  49(4):493-501.|2
03151|121|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03151|122|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03151|123|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03151|124|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03151|125|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03151|126|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03151|127|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03151|128|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03151|129|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03151|130|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03151|131|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03151|132|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03152|001|T|MONOGRAPH TITLE:  Levomethadyl (IR)/Ziprasidone|
03152|002|B||
03152|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03152|004|L|is contraindicated and generally should not be dispensed or administered to|
03152|005|L|the same patient.|
03152|006|B||
03152|007|A|MECHANISM OF ACTION:  Levomethadyl and ziprasidone have been shown to|
03152|008|A|prolong the QTc interval.  Concurrent use may result in additive effects on|
03152|009|A|the QTc interval.(1-3)|
03152|010|A|   Concurrent use of opioids such as levomethadyl and antipsychotics such as|
03152|011|A|ziprasidone may result in additive CNS depression.(4)|
03152|012|B||
03152|013|E|CLINICAL EFFECTS:  Concurrent use of levomethadyl and ziprasidone may result|
03152|014|E|in potentially life-threatening cardiac arrhythmias, including torsades de|
03152|015|E|pointes.(1-3)|
03152|016|E|   Concurrent use of opioids such as levomethadyl and other CNS depressants,|
03152|017|E|including antipsychotics such as ziprasidone, may result in profound|
03152|018|E|sedation, respiratory depression, coma, and/or death.(4)|
03152|019|B||
03152|020|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03152|021|P|may increase the risk of adverse effects.|
03152|022|P|   Bradycardia, hypokalemia, hypomagnesemia, and the presence of congenital|
03152|023|P|prolongation of the QT interval may increase the risk of torsades de pointes|
03152|024|P|and/or sudden death.(3)|
03152|025|P|   The risk of QT prolongation or torsade de pointes may also be increased|
03152|026|P|in patients with cardiovascular disease (e.g. heart failure, myocardial|
03152|027|P|infarction, history of torsade de pointes), hypocalcemia, female gender, or|
03152|028|P|advanced age.(5)|
03152|029|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03152|030|P|higher systemic concentrations of either QT prolonging drug are additional|
03152|031|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03152|032|P|drug concentrations include rapid infusion of an intravenous dose or|
03152|033|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03152|034|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03152|035|P|drug metabolism or elimination, and/or renal/hepatic dysfunction.(5)|
03152|036|B||
03152|037|M|PATIENT MANAGEMENT:  The manufacturer of ziprasidone states under|
03152|038|M|contraindications that ziprasidone should not be used with other drugs that|
03152|039|M|prolong the QT interval such as levomethadyl.(2)|
03152|040|M|   Limit prescribing opioid analgesics such as levomethadyl with CNS|
03152|041|M|depressants, including antipsychotics such as ziprasidone to patients for|
03152|042|M|whom alternatives are ineffective, not tolerated, or would be otherwise|
03152|043|M|inadequate to provide sufficient management of pain.(4)|
03152|044|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
03152|045|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
03152|046|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03152|047|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03152|048|M|   If concurrent use is necessary, limit the dosages and duration of each|
03152|049|M|drug to the minimum possible while achieving the desired clinical effect.|
03152|050|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03152|051|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03152|052|M|indicated in the absence of an opioid and titrate based upon clinical|
03152|053|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03152|054|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03152|055|M|clinical response.(4)|
03152|056|M|   Respiratory depression can occur at any time during opioid therapy,|
03152|057|M|especially during therapy initiation and following dosage increases.  The|
03152|058|M|risk of opioid-related overdose or overdose-related death is increased with|
03152|059|M|higher opioid doses, and this risk persists over the course of therapy.|
03152|060|M|Consider these risks when using concurrently with other agents that may|
03152|061|M|cause CNS depression.(6)|
03152|062|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03152|063|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03152|064|M|unresponsiveness.(4)|
03152|065|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03152|066|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03152|067|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03152|068|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03152|069|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03152|070|M|as those taking CNS depressants) and when a patient has household|
03152|071|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03152|072|M|for obtaining an opioid reversal agent (e.g., prescription,|
03152|073|M|over-the-counter, or as part of a community-based program).(7)|
03152|074|B||
03152|075|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03152|076|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03152|077|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03152|078|D|million to 30 million patients.  During this time, the proportion of|
03152|079|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03152|080|D|million patients.(8)|
03152|081|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03152|082|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03152|083|D|per 100,000 and drug overdose deaths involving both opioids and|
03152|084|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03152|085|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03152|086|D|increased from 18% to 31% during this time.(9)|
03152|087|D|   A prospective observational cohort study in North Carolina found that the|
03152|088|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03152|089|D|benzodiazepines were 10 times higher than patients receiving opioid|
03152|090|D|analgesics alone.(10)|
03152|091|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03152|092|D|death from overdose increased with concomitant opioid analgesics and|
03152|093|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03152|094|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03152|095|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03152|096|D|increased risk of fatal overdose.(11)|
03152|097|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03152|098|D|which benzodiazepines were determined to be a cause of death and that|
03152|099|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03152|100|D|determined to be a cause of death.  This study also found that other CNS|
03152|101|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03152|102|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03152|103|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03152|104|D|where opioid analgesics were also implicated.(12)|
03152|105|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03152|106|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03152|107|D|deaths.(13)|
03152|108|B||
03152|109|R|REFERENCES:|
03152|110|B||
03152|111|R|1.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
03152|112|R|  Roxane Laboratories, Inc. May, 2001.|1
03152|113|R|2.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
03152|114|R|  May, 2021.|1
03152|115|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03152|116|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03152|117|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03152|118|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03152|119|R|4.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03152|120|R|  warns about serious risks and death when combining opioid pain or cough|1
03152|121|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03152|122|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03152|123|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03152|124|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03152|125|R|  settings: a scientific statement from the American Heart Association and|6
03152|126|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03152|127|R|  2;55(9):934-47.|6
03152|128|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03152|129|R|  prescribing information for all opioid pain medicines to provide|1
03152|130|R|  additional guidance for safe use. Available at:|1
03152|131|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03152|132|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03152|133|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03152|134|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03152|135|R|  recommends health care professionals discuss naloxone with all patients|1
03152|136|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03152|137|R|  disorder. Available at:|1
03152|138|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03152|139|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03152|140|R|  d-pain July 23, 2020.|1
03152|141|R|8.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03152|142|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03152|143|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03152|144|R|9.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03152|145|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03152|146|R|  49(4):493-501.|2
03152|147|R|10.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03152|148|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03152|149|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03152|150|R|11.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03152|151|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03152|152|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03152|153|R|   350:h2698.|2
03152|154|R|12.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03152|155|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03152|156|R|13.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03152|157|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03152|158|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03152|159|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03153|001|T|MONOGRAPH TITLE:  Methadone (non MAT)/Selected Antipsychotics;|
03153|002|T|Phenothiazines (mono deleted 05/14/2020)|
03153|003|B||
03153|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03153|005|L|take action as needed.|
03153|006|B||
03153|007|A|MECHANISM OF ACTION:  Concurrent use of opioids such as methadone and|
03153|008|A|antipsychotics, including phenothiazine derivatives, may result in additive|
03153|009|A|CNS depression.(1)|
03153|010|B||
03153|011|E|CLINICAL EFFECTS:  Concurrent use of opioids such as methadone and other CNS|
03153|012|E|depressants, such as antipsychotics, including phenothiazine derivatives,|
03153|013|E|may result in profound sedation, respiratory depression, coma, and/or|
03153|014|E|death.(1)|
03153|015|B||
03153|016|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03153|017|P|may increase the risk of adverse effects.|
03153|018|B||
03153|019|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as methadone|
03153|020|M|with CNS depressants such as antipsychotics, including phenothiazine|
03153|021|M|derivatives, to patients for whom alternatives are inadequate.(1)|
03153|022|M|   If concurrent use is necessary, limit the dosages and duration of each|
03153|023|M|drug to the minimum possible while achieving the desired clinical effect.|
03153|024|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03153|025|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03153|026|M|indicated in the absence of an opioid and titrate based upon clinical|
03153|027|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03153|028|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03153|029|M|clinical response.(1)|
03153|030|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03153|031|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03153|032|M|unresponsiveness.(1)|
03153|033|B||
03153|034|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03153|035|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03153|036|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03153|037|D|million to 30 million patients.  During this time, the proportion of|
03153|038|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03153|039|D|million patients.(2)|
03153|040|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03153|041|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03153|042|D|per 100,000 and drug overdose deaths involving both opioids and|
03153|043|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03153|044|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03153|045|D|increased from 18% to 31% during this time.(3)|
03153|046|D|   A prospective observational cohort study in North Carolina found that the|
03153|047|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03153|048|D|benzodiazepines were 10 times higher than patients receiving opioid|
03153|049|D|analgesics alone.(4)|
03153|050|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03153|051|D|death from overdose increased with concomitant opioid analgesics and|
03153|052|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03153|053|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03153|054|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03153|055|D|increased risk of fatal overdose.(5)|
03153|056|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03153|057|D|which benzodiazepines were determined to be a cause of death and that|
03153|058|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03153|059|D|determined to be a cause of death.  This study also found that other CNS|
03153|060|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03153|061|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03153|062|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03153|063|D|where opioid analgesics were also implicated.(6)|
03153|064|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03153|065|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03153|066|D|deaths.(7)|
03153|067|B||
03153|068|R|REFERENCES:|
03153|069|B||
03153|070|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03153|071|R|  warns about serious risks and death when combining opioid pain or cough|1
03153|072|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03153|073|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03153|074|R|2.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03153|075|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03153|076|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03153|077|R|3.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03153|078|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03153|079|R|  49(4):493-501.|2
03153|080|R|4.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03153|081|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03153|082|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03153|083|R|5.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03153|084|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03153|085|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03153|086|R|6.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03153|087|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03153|088|R|7.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03153|089|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
03153|090|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
03153|091|R|  2014 Oct 10;63(40):881-5.|2
03154|001|T|MONOGRAPH TITLE:  Methadone (non MAT)/Selected Antipsychotics;|
03154|002|T|Phenothiazines|
03154|003|B||
03154|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03154|005|L|take action as needed.|
03154|006|B||
03154|007|A|MECHANISM OF ACTION:  Concurrent use of opioids such as methadone and|
03154|008|A|antipsychotics, including phenothiazine derivatives, may result in additive|
03154|009|A|CNS depression.(1)|
03154|010|B||
03154|011|E|CLINICAL EFFECTS:  Concurrent use of opioids such as methadone and other CNS|
03154|012|E|depressants, such as antipsychotics, including phenothiazine derivatives,|
03154|013|E|may result in profound sedation, respiratory depression, coma, and/or|
03154|014|E|death.(1)|
03154|015|B||
03154|016|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03154|017|P|may increase the risk of adverse effects.|
03154|018|B||
03154|019|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as methadone|
03154|020|M|with CNS depressants such as antipsychotics, including phenothiazine|
03154|021|M|derivatives, to patients for whom alternatives are ineffective, not|
03154|022|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03154|023|M|of pain.(1)|
03154|024|M|   If concurrent use is necessary, limit the dosages and duration of each|
03154|025|M|drug to the minimum possible while achieving the desired clinical effect.|
03154|026|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03154|027|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03154|028|M|indicated in the absence of an opioid and titrate based upon clinical|
03154|029|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03154|030|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03154|031|M|clinical response.(1)|
03154|032|M|   Respiratory depression can occur at any time during opioid therapy,|
03154|033|M|especially during therapy initiation and following dosage increases.  The|
03154|034|M|risk of opioid-related overdose or overdose-related death is increased with|
03154|035|M|higher opioid doses, and this risk persists over the course of therapy.|
03154|036|M|Consider these risks when using concurrently with other agents that may|
03154|037|M|cause CNS depression.(2)|
03154|038|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03154|039|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03154|040|M|unresponsiveness.(1)|
03154|041|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03154|042|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03154|043|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03154|044|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03154|045|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03154|046|M|as those taking CNS depressants) and when a patient has household|
03154|047|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03154|048|M|for obtaining an opioid reversal agent (e.g., prescription,|
03154|049|M|over-the-counter, or as part of a community-based program).(3)|
03154|050|B||
03154|051|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03154|052|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03154|053|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03154|054|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03154|055|D|significantly increased in patients with recent use of antipsychotics|
03154|056|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03154|057|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03154|058|D|of use.(4)|
03154|059|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03154|060|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03154|061|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03154|062|D|to 30 million patients.  During this time, the proportion of patients|
03154|063|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03154|064|D|patients.(5)|
03154|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03154|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03154|067|D|per 100,000 and drug overdose deaths involving both opioids and|
03154|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03154|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03154|070|D|increased from 18% to 31% during this time.(6)|
03154|071|D|   A prospective observational cohort study in North Carolina found that the|
03154|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03154|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
03154|074|D|analgesics alone.(7)|
03154|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03154|076|D|death from overdose increased with concomitant opioid analgesics and|
03154|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03154|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03154|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03154|080|D|increased risk of fatal overdose.(8)|
03154|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03154|082|D|which benzodiazepines were determined to be a cause of death and that|
03154|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03154|084|D|determined to be a cause of death.  This study also found that other CNS|
03154|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03154|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03154|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03154|088|D|where opioid analgesics were also implicated.(9)|
03154|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03154|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03154|091|D|deaths.(10)|
03154|092|B||
03154|093|R|REFERENCES:|
03154|094|B||
03154|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03154|096|R|  warns about serious risks and death when combining opioid pain or cough|1
03154|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03154|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03154|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03154|100|R|  prescribing information for all opioid pain medicines to provide|1
03154|101|R|  additional guidance for safe use. Available at:|1
03154|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03154|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03154|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03154|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03154|106|R|  recommends health care professionals discuss naloxone with all patients|1
03154|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03154|108|R|  disorder. Available at:|1
03154|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03154|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03154|111|R|  d-pain July 23, 2020.|1
03154|112|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03154|113|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03154|114|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03154|115|R|  Pharmacol 2020 Apr 26.|2
03154|116|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03154|117|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03154|118|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03154|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03154|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03154|121|R|  49(4):493-501.|2
03154|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03154|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03154|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03154|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03154|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03154|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03154|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03154|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03154|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03154|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03154|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03154|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03155|001|T|MONOGRAPH TITLE:  Tramadol (IR)/Selected Antipsychotics; Phenothiazines|
03155|002|B||
03155|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03155|004|L|take action as needed.|
03155|005|B||
03155|006|A|MECHANISM OF ACTION:  Concurrent use of opioids such as tramadol and|
03155|007|A|antipsychotics, including phenothiazine derivatives, may result in additive|
03155|008|A|CNS depression.(1)|
03155|009|B||
03155|010|E|CLINICAL EFFECTS:  Concurrent use of opioids such as tramadol and other CNS|
03155|011|E|depressants, such as antipsychotics, including phenothiazine derivatives,|
03155|012|E|may result in profound sedation, respiratory depression, coma, and/or|
03155|013|E|death.(1)|
03155|014|B||
03155|015|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03155|016|P|may increase the risk of adverse effects.|
03155|017|B||
03155|018|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as tramadol|
03155|019|M|with CNS depressants such as antipsychotics, including phenothiazine|
03155|020|M|derivatives, to patients for whom alternatives are ineffective, not|
03155|021|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03155|022|M|of pain.(1)|
03155|023|M|   If concurrent use is necessary, limit the dosages and duration of each|
03155|024|M|drug to the minimum possible while achieving the desired clinical effect.|
03155|025|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03155|026|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03155|027|M|indicated in the absence of an opioid and titrate based upon clinical|
03155|028|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03155|029|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03155|030|M|clinical response.(1)|
03155|031|M|   Respiratory depression can occur at any time during opioid therapy,|
03155|032|M|especially during therapy initiation and following dosage increases.  The|
03155|033|M|risk of opioid-related overdose or overdose-related death is increased with|
03155|034|M|higher opioid doses, and this risk persists over the course of therapy.|
03155|035|M|Consider these risks when using concurrently with other agents that may|
03155|036|M|cause CNS depression.(2)|
03155|037|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03155|038|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03155|039|M|unresponsiveness.(1)|
03155|040|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03155|041|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03155|042|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03155|043|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03155|044|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03155|045|M|as those taking CNS depressants) and when a patient has household|
03155|046|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03155|047|M|for obtaining an opioid reversal agent (e.g., prescription,|
03155|048|M|over-the-counter, or as part of a community-based program).(3)|
03155|049|B||
03155|050|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03155|051|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03155|052|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03155|053|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03155|054|D|significantly increased in patients with recent use of antipsychotics|
03155|055|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03155|056|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03155|057|D|of use.(4)|
03155|058|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03155|059|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03155|060|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03155|061|D|to 30 million patients.  During this time, the proportion of patients|
03155|062|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03155|063|D|patients.(5)|
03155|064|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03155|065|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03155|066|D|per 100,000 and drug overdose deaths involving both opioids and|
03155|067|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03155|068|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03155|069|D|increased from 18% to 31% during this time.(6)|
03155|070|D|   A prospective observational cohort study in North Carolina found that the|
03155|071|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03155|072|D|benzodiazepines were 10 times higher than patients receiving opioid|
03155|073|D|analgesics alone.(7)|
03155|074|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03155|075|D|death from overdose increased with concomitant opioid analgesics and|
03155|076|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03155|077|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03155|078|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03155|079|D|increased risk of fatal overdose.(8)|
03155|080|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03155|081|D|which benzodiazepines were determined to be a cause of death and that|
03155|082|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03155|083|D|determined to be a cause of death.  This study also found that other CNS|
03155|084|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03155|085|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03155|086|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03155|087|D|where opioid analgesics were also implicated.(9)|
03155|088|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03155|089|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03155|090|D|deaths.(10)|
03155|091|B||
03155|092|R|REFERENCES:|
03155|093|B||
03155|094|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03155|095|R|  warns about serious risks and death when combining opioid pain or cough|1
03155|096|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03155|097|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03155|098|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03155|099|R|  prescribing information for all opioid pain medicines to provide|1
03155|100|R|  additional guidance for safe use. Available at:|1
03155|101|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03155|102|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03155|103|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03155|104|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03155|105|R|  recommends health care professionals discuss naloxone with all patients|1
03155|106|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03155|107|R|  disorder. Available at:|1
03155|108|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03155|109|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03155|110|R|  d-pain July 23, 2020.|1
03155|111|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03155|112|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03155|113|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03155|114|R|  Pharmacol 2020 Apr 26.|2
03155|115|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03155|116|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03155|117|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03155|118|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03155|119|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03155|120|R|  49(4):493-501.|2
03155|121|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03155|122|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03155|123|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03155|124|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03155|125|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03155|126|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03155|127|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03155|128|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03155|129|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03155|130|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03155|131|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03155|132|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03156|001|T|MONOGRAPH TITLE:  Tramadol (IR)/Selected Antipsychotics; Phenothiazines|
03156|002|B||
03156|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03156|004|L|take action as needed.|
03156|005|B||
03156|006|A|MECHANISM OF ACTION:  Concurrent use of opioids such as tramadol and|
03156|007|A|antipsychotics, including phenothiazine derivatives, may result in additive|
03156|008|A|CNS depression.(1)|
03156|009|B||
03156|010|E|CLINICAL EFFECTS:  Concurrent use of opioids such as tramadol and other CNS|
03156|011|E|depressants, such as antipsychotics, including phenothiazine derivatives,|
03156|012|E|may result in profound sedation, respiratory depression, coma, and/or|
03156|013|E|death.(1)|
03156|014|B||
03156|015|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03156|016|P|may increase the risk of adverse effects.|
03156|017|B||
03156|018|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as tramadol|
03156|019|M|with CNS depressants such as antipsychotics, including phenothiazine|
03156|020|M|derivatives, to patients for whom alternatives are ineffective, not|
03156|021|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03156|022|M|of pain.(1)|
03156|023|M|   If concurrent use is necessary, limit the dosages and duration of each|
03156|024|M|drug to the minimum possible while achieving the desired clinical effect.|
03156|025|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03156|026|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03156|027|M|indicated in the absence of an opioid and titrate based upon clinical|
03156|028|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03156|029|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03156|030|M|clinical response.(1)|
03156|031|M|   Respiratory depression can occur at any time during opioid therapy,|
03156|032|M|especially during therapy initiation and following dosage increases.  The|
03156|033|M|risk of opioid-related overdose or overdose-related death is increased with|
03156|034|M|higher opioid doses, and this risk persists over the course of therapy.|
03156|035|M|Consider these risks when using concurrently with other agents that may|
03156|036|M|cause CNS depression.(2)|
03156|037|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03156|038|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03156|039|M|unresponsiveness.(1)|
03156|040|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03156|041|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03156|042|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03156|043|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03156|044|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03156|045|M|as those taking CNS depressants) and when a patient has household|
03156|046|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03156|047|M|for obtaining an opioid reversal agent (e.g., prescription,|
03156|048|M|over-the-counter, or as part of a community-based program).(3)|
03156|049|B||
03156|050|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03156|051|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03156|052|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03156|053|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03156|054|D|significantly increased in patients with recent use of antipsychotics|
03156|055|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03156|056|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03156|057|D|of use.(4)|
03156|058|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03156|059|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03156|060|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03156|061|D|to 30 million patients.  During this time, the proportion of patients|
03156|062|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03156|063|D|patients.(5)|
03156|064|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03156|065|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03156|066|D|per 100,000 and drug overdose deaths involving both opioids and|
03156|067|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03156|068|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03156|069|D|increased from 18% to 31% during this time.(6)|
03156|070|D|   A prospective observational cohort study in North Carolina found that the|
03156|071|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03156|072|D|benzodiazepines were 10 times higher than patients receiving opioid|
03156|073|D|analgesics alone.(7)|
03156|074|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03156|075|D|death from overdose increased with concomitant opioid analgesics and|
03156|076|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03156|077|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03156|078|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03156|079|D|increased risk of fatal overdose.(8)|
03156|080|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03156|081|D|which benzodiazepines were determined to be a cause of death and that|
03156|082|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03156|083|D|determined to be a cause of death.  This study also found that other CNS|
03156|084|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03156|085|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03156|086|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03156|087|D|where opioid analgesics were also implicated.(9)|
03156|088|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03156|089|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03156|090|D|deaths.(10)|
03156|091|B||
03156|092|R|REFERENCES:|
03156|093|B||
03156|094|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03156|095|R|  warns about serious risks and death when combining opioid pain or cough|1
03156|096|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03156|097|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03156|098|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03156|099|R|  prescribing information for all opioid pain medicines to provide|1
03156|100|R|  additional guidance for safe use. Available at:|1
03156|101|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03156|102|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03156|103|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03156|104|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03156|105|R|  recommends health care professionals discuss naloxone with all patients|1
03156|106|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03156|107|R|  disorder. Available at:|1
03156|108|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03156|109|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03156|110|R|  d-pain July 23, 2020.|1
03156|111|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03156|112|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03156|113|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03156|114|R|  Pharmacol 2020 Apr 26.|2
03156|115|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03156|116|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03156|117|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03156|118|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03156|119|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03156|120|R|  49(4):493-501.|2
03156|121|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03156|122|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03156|123|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03156|124|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03156|125|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03156|126|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03156|127|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03156|128|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03156|129|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03156|130|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03156|131|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03156|132|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03157|001|T|MONOGRAPH TITLE:  SSRIs; Vilazodone/Flurbiprofen|
03157|002|B||
03157|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03157|004|L|take action as needed.|
03157|005|B||
03157|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
03157|007|A|hemostasis.(1,2)  The increased risk of bleeding may be a result of a|
03157|008|A|decrease in serotonin reuptake by platelets.|
03157|009|B||
03157|010|E|CLINICAL EFFECTS:  Concurrent use of a SSRI(1-8) or vilazodone(9) and|
03157|011|E|flurbiprofen may result in bleeding.|
03157|012|B||
03157|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03157|014|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
03157|015|P|impairment has been associated with an elevated risk of GI bleed in patients|
03157|016|P|on SSRIs.(13)|
03157|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
03157|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03157|019|P|risk for bleeding (e.g. NSAIDs).|
03157|020|B||
03157|021|M|PATIENT MANAGEMENT:  Selective serotonin reuptake inhibitors(1-8) or|
03157|022|M|vilazodone(9) and flurbiprofen should be used concurrently with caution.|
03157|023|M|Patients should be warned about the increased risk of bleeding and be|
03157|024|M|educated about signs and symptoms of bleeding.(1-10)|
03157|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03157|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03157|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03157|028|M|patients with any symptoms.|
03157|029|M|   Discontinue anti-platelet agents in patients with active pathologic|
03157|030|M|bleeding.|
03157|031|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03157|032|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03157|033|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03157|034|M|and/or swelling.|
03157|035|B||
03157|036|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
03157|037|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03157|038|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03157|039|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03157|040|D|only based on an observed-expected ratio was 4.5 and in a patient using|
03157|041|D|low-dose aspirin only was 2.5.  Concurrent use of a SSRI with NSAIDs or|
03157|042|D|low-dose aspirin increased the risk of bleeding to 12.2 and 5.2,|
03157|043|D|respectively.(10)|
03157|044|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
03157|045|D|in patients receiving concurrent therapy with selective serotonin reuptake|
03157|046|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
03157|047|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
03157|048|D|respectively.(11)|
03157|049|B||
03157|050|R|REFERENCES:|
03157|051|B||
03157|052|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03157|053|R|  Laboratories Inc. August, 2023.|1
03157|054|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03157|055|R|  Pharmaceuticals Inc. May, 2023.|1
03157|056|R|3.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
03157|057|R|  and Company August, 2023.|1
03157|058|R|4.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
03157|059|R|  Technologies January, 2017.|1
03157|060|R|5.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
03157|061|R|  Therapeutics, LLC September, 2021.|1
03157|062|R|6.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
03157|063|R|7.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
03157|064|R|  Pharmaceuticals, Inc. August, 2023.|1
03157|065|R|8.Trintellix (vortioxetine) US prescribing information. Takeda|1
03157|066|R|  Pharmaceuticals America, Inc. November, 2020.|1
03157|067|R|9.Viibryd (vilazodone hydrochloride) US prescribing information. Forest|1
03157|068|R|  Laboratories Inc. October, 2023.|1
03157|069|R|10.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03157|070|R|   Use of selective serotonin reuptake inhibitors and risk of upper|2
03157|071|R|   gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03157|072|R|   Intern Med 2003 Jan 13;163(1):59-64.|2
03157|073|R|11.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03157|074|R|   serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03157|075|R|   population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03157|076|R|12.Russo NW, Petrucci G, Rocca B. Aspirin, stroke and drug-drug|6
03157|077|R|   interactions. Vascul Pharmacol 2016 Dec;87:14-22.|6
03157|078|R|13.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
03157|079|R|   Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
03157|080|R|   by level of kidney function: A population-based cohort study. Br J Clin|2
03157|081|R|   Pharmacol 2018 Sep;84(9):2142-2151.|2
03158|001|T|MONOGRAPH TITLE:  SNRIs/Flurbiprofen|
03158|002|B||
03158|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03158|004|L|take action as needed.|
03158|005|B||
03158|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
03158|007|A|hemostasis.(1,2)  The increased risk of bleeding may be a result of a|
03158|008|A|decrease in serotonin reuptake by platelets.|
03158|009|B||
03158|010|E|CLINICAL EFFECTS:  Concurrent use of a serotonin-norepinephrine reuptake|
03158|011|E|inhibitor(1-3) and flurbiprofen may result in bleeding.|
03158|012|B||
03158|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03158|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03158|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
03158|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03158|017|P|risk for bleeding (e.g. NSAIDs).|
03158|018|B||
03158|019|M|PATIENT MANAGEMENT:  Serotonin-norepinephrine reuptake inhibitors(1-3) and|
03158|020|M|flurbiprofen should be used concurrently with caution.  Patients should be|
03158|021|M|warned about the increased risk of bleeding and be educated about signs and|
03158|022|M|symptoms of bleeding.(1-4)|
03158|023|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03158|024|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03158|025|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03158|026|M|patients with any symptoms.|
03158|027|M|   Discontinue anti-platelet agents in patients with active pathologic|
03158|028|M|bleeding.|
03158|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03158|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03158|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03158|032|M|and/or swelling.|
03158|033|B||
03158|034|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
03158|035|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03158|036|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03158|037|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03158|038|D|only based on an observed-expected ratio was 4.5 and in a patient using|
03158|039|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
03158|040|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
03158|041|D|bleeding to 12.2 and 5.2, respectively.(4)|
03158|042|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
03158|043|D|in patients receiving concurrent therapy with selective serotonin reuptake|
03158|044|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
03158|045|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
03158|046|D|respectively.(5)|
03158|047|B||
03158|048|R|REFERENCES:|
03158|049|B||
03158|050|R|1.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
03158|051|R|  Pharmaceuticals, Inc. August, 2023.|1
03158|052|R|2.Effexor XR (venlafaxine hydrochloride) US prescribing information. Viatris|1
03158|053|R|  August, 2023.|1
03158|054|R|3.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
03158|055|R|  and Company September, 2021.|1
03158|056|R|4.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03158|057|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03158|058|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03158|059|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03158|060|R|5.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03158|061|R|  serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03158|062|R|  population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03158|063|R|6.Russo NW, Petrucci G, Rocca B. Aspirin, stroke and drug-drug interactions.|6
03158|064|R|  Vascul Pharmacol 2016 Dec;87:14-22.|6
03159|001|T|MONOGRAPH TITLE:  SSRIs; Vilazodone/Selected NSAIDs|
03159|002|B||
03159|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03159|004|L|take action as needed.|
03159|005|B||
03159|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
03159|007|A|hemostasis.(1,2)  The increased risk of bleeding may be a result of a|
03159|008|A|decrease in serotonin reuptake by platelets.|
03159|009|B||
03159|010|E|CLINICAL EFFECTS:  Concurrent use of a SSRI(1-8) or vilazodone(9) and a|
03159|011|E|NSAID may result in bleeding.|
03159|012|B||
03159|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03159|014|P|patients with multiple disease-associated factors (e.g. thrombocytopenia,|
03159|015|P|advanced liver disease).|
03159|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
03159|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03159|018|P|risk for bleeding (e.g., anticoagulants, antiplatelets, or corticosteroids.|
03159|019|P|   Risk of GI bleed may be increased in patients who are of older age, in|
03159|020|P|poor health status, or who use alcohol or smoke. Risk may also be increased|
03159|021|P|with longer duration of NSAID use and prior history of peptic ulcer disease|
03159|022|P|and/or GI bleeding.   Renal impairment has been associated with an elevated|
03159|023|P|risk of GI bleed in patients on SSRIs.(13)|
03159|024|B||
03159|025|M|PATIENT MANAGEMENT:  Selective serotonin reuptake inhibitors(1-8) or|
03159|026|M|vilazodone(9) and NSAIDs should be used concurrently with caution.  Patients|
03159|027|M|should be warned about the increased risk of bleeding and be educated about|
03159|028|M|signs and symptoms of bleeding.(1-10)|
03159|029|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03159|030|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03159|031|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03159|032|M|patients with any symptoms.|
03159|033|M|   Discontinue anti-platelet agents in patients with active pathologic|
03159|034|M|bleeding.|
03159|035|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03159|036|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03159|037|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03159|038|M|and/or swelling.|
03159|039|B||
03159|040|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
03159|041|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03159|042|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03159|043|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03159|044|D|only based on an observed-expected ratio was 4.5 and in a patient using|
03159|045|D|low-dose aspirin only was 2.5.  Concurrent use of a SSRI with NSAIDs or|
03159|046|D|low-dose aspirin increased the risk of bleeding to 12.2 and 5.2,|
03159|047|D|respectively.(10)|
03159|048|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
03159|049|D|in patients receiving concurrent therapy with selective serotonin reuptake|
03159|050|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
03159|051|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
03159|052|D|respectively.(11)|
03159|053|B||
03159|054|R|REFERENCES:|
03159|055|B||
03159|056|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03159|057|R|  Laboratories Inc. August, 2023.|1
03159|058|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03159|059|R|  Pharmaceuticals Inc. May, 2023.|1
03159|060|R|3.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
03159|061|R|  and Company August, 2023.|1
03159|062|R|4.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
03159|063|R|  Technologies January, 2017.|1
03159|064|R|5.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
03159|065|R|  Therapeutics, LLC September, 2021.|1
03159|066|R|6.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
03159|067|R|7.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
03159|068|R|  Pharmaceuticals, Inc. August, 2023.|1
03159|069|R|8.Trintellix (vortioxetine) US prescribing information. Takeda|1
03159|070|R|  Pharmaceuticals America, Inc. November, 2020.|1
03159|071|R|9.Viibryd (vilazodone hydrochloride) US prescribing information. Forest|1
03159|072|R|  Laboratories Inc. October, 2023.|1
03159|073|R|10.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03159|074|R|   Use of selective serotonin reuptake inhibitors and risk of upper|2
03159|075|R|   gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03159|076|R|   Intern Med 2003 Jan 13;163(1):59-64.|2
03159|077|R|11.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03159|078|R|   serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03159|079|R|   population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03159|080|R|12.Russo NW, Petrucci G, Rocca B. Aspirin, stroke and drug-drug|6
03159|081|R|   interactions. Vascul Pharmacol 2016 Dec;87:14-22.|6
03159|082|R|13.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
03159|083|R|   Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
03159|084|R|   by level of kidney function: A population-based cohort study. Br J Clin|2
03159|085|R|   Pharmacol 2018 Sep;84(9):2142-2151.|2
03160|001|T|MONOGRAPH TITLE:  SNRIs/Selected NSAIDs|
03160|002|B||
03160|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03160|004|L|take action as needed.|
03160|005|B||
03160|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
03160|007|A|hemostasis.(1,2)  The increased risk of bleeding may be a result of a|
03160|008|A|decrease in serotonin reuptake by platelets.|
03160|009|B||
03160|010|E|CLINICAL EFFECTS:  Concurrent use of a serotonin-norepinephrine reuptake|
03160|011|E|inhibitor(1-3) and a NSAID may result in bleeding.|
03160|012|B||
03160|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03160|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03160|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
03160|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03160|017|P|risk for bleeding (e.g. NSAIDs).|
03160|018|B||
03160|019|M|PATIENT MANAGEMENT:  Serotonin-norepinephrine reuptake inhibitors(1-3) and|
03160|020|M|NSAIDs should be used concurrently with caution.  Patients should be warned|
03160|021|M|about the increased risk of bleeding and be educated about signs and|
03160|022|M|symptoms of bleeding.(1-4)|
03160|023|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03160|024|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03160|025|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03160|026|M|patients with any symptoms.|
03160|027|M|   Discontinue anti-platelet agents in patients with active pathologic|
03160|028|M|bleeding.|
03160|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03160|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03160|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03160|032|M|and/or swelling.|
03160|033|B||
03160|034|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
03160|035|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03160|036|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03160|037|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03160|038|D|only based on an observed-expected ratio was 4.5 and in a patient using|
03160|039|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
03160|040|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
03160|041|D|bleeding to 12.2 and 5.2, respectively.(4)|
03160|042|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
03160|043|D|in patients receiving concurrent therapy with selective serotonin reuptake|
03160|044|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
03160|045|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
03160|046|D|respectively.(5)|
03160|047|B||
03160|048|R|REFERENCES:|
03160|049|B||
03160|050|R|1.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
03160|051|R|  Pharmaceuticals, Inc. August, 2023.|1
03160|052|R|2.Effexor XR (venlafaxine hydrochloride) US prescribing information. Viatris|1
03160|053|R|  August, 2023.|1
03160|054|R|3.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
03160|055|R|  and Company September, 2021.|1
03160|056|R|4.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03160|057|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03160|058|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03160|059|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03160|060|R|5.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03160|061|R|  serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03160|062|R|  population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03160|063|R|6.Russo NW, Petrucci G, Rocca B. Aspirin, stroke and drug-drug interactions.|6
03160|064|R|  Vascul Pharmacol 2016 Dec;87:14-22.|6
03161|001|T|MONOGRAPH TITLE:  Thyroid Preparations/Estrogens|
03161|002|B||
03161|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03161|004|L|take action as needed.|
03161|005|B||
03161|006|A|MECHANISM OF ACTION:  Estrogens increase thyroxine-binding globulin (TBG)|
03161|007|A|levels by increasing its biosynthesis and decreasing its clearance.(1)|
03161|008|A|Hypothyroid patients who start estrogens may be unable to compensate for|
03161|009|A|this increase and may have decreased serum free T4 (FT4) concentrations and|
03161|010|A|increased TSH.(1,2)|
03161|011|B||
03161|012|E|CLINICAL EFFECTS:  The coadministration of thyroid preparations and|
03161|013|E|estrogens may result in decreased levels and clinical effects of thyroid|
03161|014|E|hormones.(1-4)|
03161|015|B||
03161|016|P|PREDISPOSING FACTORS:  None determined.|
03161|017|B||
03161|018|M|PATIENT MANAGEMENT:  Patients taking thyroid preparations and who start or|
03161|019|M|stop estrogens should be monitored for changes in thyroid function.  The|
03161|020|M|dosage of the thyroid preparation may need to be increased.(1-4)|
03161|021|B||
03161|022|D|DISCUSSION:  In a prospective observational study, 25 post-menopausal women|
03161|023|D|with hypothyroidism on stable levothyroxine therapy for at least 9 months|
03161|024|D|started on estrogen replacement therapy.  After 12 weeks, mean serum FT4|
03161|025|D|levels decreased significantly from 1.7 +/- 0.4 ng/dL to 1.4 +/-0.3 mg/dL|
03161|026|D|and TSH increased significantly from 0.9 +/-1.1 to 3.2 +/- 3.1|
03161|027|D|milli-units/L.(1)|
03161|028|B||
03161|029|R|REFERENCES:|
03161|030|B||
03161|031|R|1.Arafah BM. Increased need for thyroxine in women with hypothyroidism|2
03161|032|R|  during estrogen therapy. N Engl J Med 2001 Jun 7;344(23):1743-9.|2
03161|033|R|2.Estrace (estradiol) US prescribing information. Allergan, Inc. May 1,|1
03161|034|R|  2018.|1
03161|035|R|3.Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper|6
03161|036|R|  DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM. Guidelines for the|6
03161|037|R|  treatment of hypothyroidism: prepared by the american thyroid  association|6
03161|038|R|  task force on thyroid hormone replacement. Thyroid 2014 Dec;|6
03161|039|R|  24(12):1670-751.|6
03161|040|R|4.Persani L, Brabant G, Dattani M, Bonomi M, Feldt-Rasmussen U, Fliers E,|6
03161|041|R|  Gruters A, Maiter D, Schoenmakers N, van Trotsenburg ASP. 2018 European|6
03161|042|R|  Thyroid Association (ETA) Guidelines on the Diagnosis and Management of|6
03161|043|R|  Central Hypothyroidism. Eur Thyroid J 2018 Oct;7(5):225-237.|6
03162|001|T|MONOGRAPH TITLE:  Pitolisant/QT Prolonging Agents|
03162|002|B||
03162|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03162|004|L|take action as needed.|
03162|005|B||
03162|006|A|MECHANISM OF ACTION:  Concurrent use of pitolisant with agents that prolong|
03162|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03162|008|B||
03162|009|E|CLINICAL EFFECTS:  The concurrent use of pitolisant with agents that prolong|
03162|010|E|the QTc interval may result in potentially life-threatening cardiac|
03162|011|E|arrhythmias, including torsades de pointes.(1)|
03162|012|B||
03162|013|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers or on|
03162|014|P|concurrent use with CYP2D6 inhibitors are at increased risk for higher|
03162|015|P|systemic exposure to pitolisant and may be at increased risk of QT|
03162|016|P|prolongation.(1)|
03162|017|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03162|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03162|019|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03162|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03162|021|P|advanced age.(2)|
03162|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03162|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03162|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03162|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03162|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03162|027|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03162|028|P|dysfunction).(2)|
03162|029|B||
03162|030|M|PATIENT MANAGEMENT:  When concurrent therapy cannot be avoided, obtain ECGs|
03162|031|M|and electrolyte values (serum calcium, magnesium, and potassium) prior to|
03162|032|M|the start of treatment, after initiation of any drug known to prolong the QT|
03162|033|M|interval, and periodically monitor during therapy.  Correct any electrolyte|
03162|034|M|abnormalities.|
03162|035|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03162|036|M|fainting.(2)|
03162|037|B||
03162|038|D|DISCUSSION:  In two dedicated QT prolongation studies, supra-therapeutic|
03162|039|D|doses of pitolisant at 3-6 times the therapeutic dose (108-216 mg) were seen|
03162|040|D|to cause mild to moderate QTc prolongation (10-13 ms).  A study in patients|
03162|041|D|who were CYP2D6 poor metabolizers had higher systemic exposure up to 3-fold|
03162|042|D|compared to CYP2D6 extensive metabolizers.(1)|
03162|043|D|   Agents that are linked to this monograph may have varying degrees of|
03162|044|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03162|045|D|been shown to prolong the QTc interval either through their mechanism of|
03162|046|D|action, through studies on their effects on the QTc interval, or through|
03162|047|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03162|048|D|and/or postmarketing reports.(3)|
03162|049|B||
03162|050|R|REFERENCES:|
03162|051|B||
03162|052|R|1.Wakix (pitolisant) UK Summary of Product Characteristics. Bioproject|1
03162|053|R|  Pharma January, 2019.|1
03162|054|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03162|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03162|056|R|  settings: a scientific statement from the American Heart Association and|6
03162|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03162|058|R|  2;55(9):934-47.|6
03162|059|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03162|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03162|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03162|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03163|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Pitolisant|
03163|002|B||
03163|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03163|004|L|of severe adverse interaction.|
03163|005|B||
03163|006|A|MECHANISM OF ACTION:  Pitolisant may induce the CYP3A4 mediated metabolism|
03163|007|A|of hormonal contraceptives.(1,2)|
03163|008|B||
03163|009|E|CLINICAL EFFECTS:  Concurrent use of pitolisant may reduce the effectiveness|
03163|010|E|of hormonal contraceptives.(1,2)  Pitolisant may cause birth defects and/or|
03163|011|E|miscarriage if used by pregnant women.|
03163|012|B||
03163|013|P|PREDISPOSING FACTORS:  None determined.|
03163|014|B||
03163|015|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
03163|016|M|rely on hormonal contraception (including oral contraceptives, patches,|
03163|017|M|implants, and/or IUDs) for contraception.  Women should use a back-up method|
03163|018|M|of birth control during pitolisant therapy and for at least 21 days after|
03163|019|M|the final dose.  Women of reproductive potential should use effective|
03163|020|M|non-hormonal methods of contraception during pitolisant therapy and for at|
03163|021|M|least 21 days after the final dose.(1,2)|
03163|022|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03163|023|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03163|024|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03163|025|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03163|026|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03163|027|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03163|028|M|and to seek medical advice if they do become pregnant.(3)|
03163|029|B||
03163|030|D|DISCUSSION:  Pitolisant may induce the CYP3A4 mediated metabolism of|
03163|031|D|hormonal contraceptives.  Pitolisant may decrease the effectiveness of|
03163|032|D|hormonal contraceptives, including oral contraceptives, patches, implants,|
03163|033|D|and/or IUDs.  Women should use a back-up method of birth control during|
03163|034|D|pitolisant therapy and for at least 21 days after the final dose.(1,2)|
03163|035|B||
03163|036|R|REFERENCES:|
03163|037|B||
03163|038|R|1.Wakix (pitolisant) UK Summary of Product Characteristics. Bioproject|1
03163|039|R|  Pharma January, 2019.|1
03163|040|R|2.Wakix (pitolisant) tablets US prescribing information. Harmony Biosciences|1
03163|041|R|  June, 2024.|1
03163|042|R|3.Medicines and Healthcare products Regulatory Agency.|1
03163|043|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03163|044|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03163|045|R|  available at:|1
03163|046|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03163|047|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03163|048|R|  -and-contraceptive-efficacy September 15, 2016..|1
03164|001|T|MONOGRAPH TITLE:  Oxcarbazepine/Selected UGT and Strong CYP3A4 Inducers|
03164|002|B||
03164|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03164|004|L|take action as needed.|
03164|005|B||
03164|006|A|MECHANISM OF ACTION:  Oxcarbazepine is metabolized by CYP3A4 to the active|
03164|007|A|metabolite, eslicarbazepine, which is conjugated by|
03164|008|A|UDP-glucuronosyltransferase (UGT) enzymes. Strong CYP3A4 inducers and UGT|
03164|009|A|inducers decrease exposure to eslicarbazepine.(3)|
03164|010|B||
03164|011|E|CLINICAL EFFECTS:  Concurrent use of oxcarbazepine with UGT inducers and|
03164|012|E|strong CYP3A4 inducers may lead to decreased levels and effectiveness of|
03164|013|E|oxcarbazepine, e.g loss of seizure control.(3)|
03164|014|B||
03164|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03164|016|P|of the inducer for longer than 1-2 weeks.|
03164|017|B||
03164|018|M|PATIENT MANAGEMENT:  For patients stabilized on UGT or strong CYP3A4|
03164|019|M|inducers, the US manufacturer of extended release oxcarbazepine recommends|
03164|020|M|initiating extended release oxcarbazepine at 900 mg once daily in adults and|
03164|021|M|12-15 mg/kg once daily (not to exceed 900 mg per day in the first week) in|
03164|022|M|pediatric patients.(3)|
03164|023|M|   If a strong CYP3A4 inducer or UGT inducer is added in a patient|
03164|024|M|stabilized on oxcarbazepine, the dose of oxcarbazepine may need to be|
03164|025|M|increased.  Onset of induction is gradual and may not be maximal for days or|
03164|026|M|weeks.|
03164|027|M|   If a strong CYP3A4 inducer or UGT inducer is discontinued in a patient|
03164|028|M|stabilized on oxcarbazepine, the concentration of oxcarbazepine will|
03164|029|M|increase over 1 to 4 weeks.  Monitor serum levels and adjust dosages as|
03164|030|M|needed.|
03164|031|B||
03164|032|D|DISCUSSION:  In interaction studies, phenytoin doses of 250 mg to 500 mg|
03164|033|D|daily decreased the  concentration of oxcarbazepine's active metabolite|
03164|034|D|(eslicarbazepine) by approximately 30%.(3)|
03164|035|D|   Similarly, phenobarbital doses of 100 mg to 150 mg daily decreased the|
03164|036|D|mean concentration of eslicarbazepine by 25%.(3)|
03164|037|D|   UGT and strong CYP3A inducers linked to this monograph include:|
03164|038|D|apalutamide, carbamazepine, efavirenz, encorafenib, enzalutamide,|
03164|039|D|etravirine, ivosidenib, lorlatinib, lumacaftor, mitotane, rifampin,|
03164|040|D|rifapentine, and St. John's wort.(1-2)|
03164|041|B||
03164|042|R|REFERENCES:|
03164|043|B||
03164|044|R|1.This information is based on an extract from the Certara Drug Interaction|6
03164|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03164|046|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03164|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03164|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03164|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03164|050|R|  11/14/2017.|1
03164|051|R|3.Oxtellar XR (oxcarbazepine) extended-release US prescribing information.|1
03164|052|R|  Supernus, Inc. December, 2018.|1
03165|001|T|MONOGRAPH TITLE:  Dapagliflozin; Ertugliflozin/Potassium-Sparing Diuretics|
03165|002|T|(mono deleted 03/08/2023)|
03165|003|B||
03165|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03165|005|L|take action as needed.|
03165|006|B||
03165|007|A|MECHANISM OF ACTION:  Dapagliflozin and ertugliflozin produce intravascular|
03165|008|A|volume contraction through osmotic diuresis, which can result in hypotension|
03165|009|A|in patients who are volume depleted from potassium-sparing diuretic|
03165|010|A|use.(1-3)|
03165|011|B||
03165|012|E|CLINICAL EFFECTS:  Concurrent use of dapagliflozin or ertugliflozin with a|
03165|013|E|potassium-sparing diuretic may result in dehydration and hypotension.(1-3)|
03165|014|B||
03165|015|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients who|
03165|016|P|have a eGFR of less than 60 ml/min/1.73m2, are also taking ACE inhibitors,|
03165|017|P|ARBs, loop diuretics and/or NSAIDs, are on a low salt diet, have low|
03165|018|P|systolic blood pressure prior to initiating dapagliflozin or ertugliflozin,|
03165|019|P|and/or are 65 years of age or older.(1-3)|
03165|020|B||
03165|021|M|PATIENT MANAGEMENT:  Before initiating dapagliflozin or ertugliflozin in|
03165|022|M|patients maintained on a potassium-sparing diuretic, assess volume status|
03165|023|M|and correct if needed and assess renal function.  Patients receiving|
03165|024|M|concurrent therapy should be monitored for hypotension, and renal|
03165|025|M|failure.(1-3)|
03165|026|B||
03165|027|D|DISCUSSION:  In clinical trials of canagliflozin, increases in serum|
03165|028|D|potassium were more commonly seen in patients using ACE inhibitors and ARBs.|
03165|029|D|In a pool of eight Phase 3 clinical trials that examined patients with|
03165|030|D|post-baseline serum potassium levels, 6.8% of patients taking canagliflozin|
03165|031|D|and either an ACE inhibitor or ARB had serum potassium levels outside|
03165|032|D|pre-defined study limits, compared with 5.2% of patients not taking an ACE|
03165|033|D|inhibitor or ARB.  In this same pool of patients, 3.5% of patients taking|
03165|034|D|canagliflozin with either an ACE inhibitor or ARB experienced volume|
03165|035|D|depletion-related adverse events, compared with 1.4% of patients not taking|
03165|036|D|an ACE inhibitor or ARB.(4)|
03165|037|D|   Cases of acute renal failure, most requiring hospitalization, have been|
03165|038|D|reported in patients receiving canagliflozin and dapagliflozin.  Fifty-one|
03165|039|D|of 101 cases involved concurrent use of ACE inhibitors.(1)|
03165|040|B||
03165|041|R|REFERENCES:|
03165|042|B||
03165|043|R|1.USFood and Drug Administration. FDA Drug Safety Communication:  FDA|1
03165|044|R|  strengthens kidney warnings for diabetes medicines canagliflozin|1
03165|045|R|  (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). available|1
03165|046|R|  at:  http://www.fda.gov/downloads/Drugs/DrugSafety/UCM506772.pdf June 14,|1
03165|047|R|  2016.|1
03165|048|R|2.Farxiga (dapagliflozin) US prescribing information. AstraZeneca|1
03165|049|R|  Pharmaceuticals LP June, 2024.|1
03165|050|R|3.Steglatro (ertugliflozin) US prescribing information. Merck & Co. October|1
03165|051|R|  2022.|1
03165|052|R|4.Wolf MS. Personal communication:  Invokana - Concomitant use with|1
03165|053|R|  ACE/ARBs. Janssen Scientific Affairs, LLC June 9, 2014.|1
03166|001|T|MONOGRAPH TITLE:  Elbasvir-Grazoprevir/Selected CYP3A4 Inhibitors|
03166|002|B||
03166|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03166|004|L|of severe adverse interaction.|
03166|005|B||
03166|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03166|007|A|of elbasvir-grazoprevir.(1-3)|
03166|008|B||
03166|009|E|CLINICAL EFFECTS:  Concurrent use of selected strong CYP3A4 inhibitors may|
03166|010|E|result in increased levels of elbasvir and grazoprevir.(1)|
03166|011|B||
03166|012|P|PREDISPOSING FACTORS:  None determined.|
03166|013|B||
03166|014|M|PATIENT MANAGEMENT:  Concurrent use of elbasvir-grazoprevir and strong|
03166|015|M|CYP3A4 inhibitors is not recommended. (1)|
03166|016|M|   Concurrent use of elbasvir-grazoprevir and itraconazole is not|
03166|017|M|recommended during and 2 weeks after treatment. (2)|
03166|018|B||
03166|019|D|DISCUSSION:  A study in seven healthy patients, concurrent therapy with|
03166|020|D|ketoconazole (400 mg once daily) increased the elbasvir area-under-curve|
03166|021|D|(AUC) and concentration maximum (Cmax) by 1.8-fold and 1.29-fold,|
03166|022|D|respectively, and increased the grazoprevir AUC and Cmax by 3.02-fold and|
03166|023|D|1.13-fold, respectively.(1)|
03166|024|D|   Selected CYP3A4 inhibitors include elvitegravir/cobicistat, itraconazole,|
03166|025|D|ketoconazole, and levoketoconazole.(3)|
03166|026|B||
03166|027|R|REFERENCES:|
03166|028|B||
03166|029|R|1.Zepatier (elbasvir-grazoprevir) US prescribing information. Merck & Co.,|1
03166|030|R|  Inc. December, 2019.|1
03166|031|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
03166|032|R|  Products, L.P. February, 2024.|1
03166|033|R|3.This information is based on an extract from the Certara Drug Interaction|6
03166|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03167|001|T|MONOGRAPH TITLE:  Acenocoumarol; Phenprocoumon/Noscapine|
03167|002|B||
03167|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03167|004|L|take action as needed.|
03167|005|B||
03167|006|A|MECHANISM OF ACTION:  Noscapine may inhibit the metabolism of acenocoumarol|
03167|007|A|or phenprocoumon by CYP2C9.(1)|
03167|008|B||
03167|009|E|CLINICAL EFFECTS:  Concurrent use of noscapine may result in increased|
03167|010|E|acenocoumarol or phenprocoumon effects.(1)|
03167|011|B||
03167|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03167|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03167|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
03167|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03167|016|P|risk for bleeding (e.g. NSAIDs).|
03167|017|P|   Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2|
03167|018|P|copies of a reduced function VKORC1 gene are expected to be more susceptible|
03167|019|P|to this interaction.|
03167|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
03167|021|P|are expected to be less susceptible to effects from this drug combination,|
03167|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
03167|023|P|*3/*3) result in an inherently higher anticoagulant half-life and risk for|
03167|024|P|bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant|
03167|025|P|doses and more time (>2 to 4 weeks) to achieve effective and safe|
03167|026|P|anticoagulation than patients without these CYP2C9 variants.|
03167|027|B||
03167|028|M|PATIENT MANAGEMENT:  Monitor patients maintained on acenocoumarol or|
03167|029|M|phenprocoumon if noscapine is initiated or discontinued.  The dose of|
03167|030|M|acenocoumarol or phenprocoumon may need to be adjusted.|
03167|031|B||
03167|032|D|DISCUSSION:  A series of eight cases of patients on noscapine with|
03167|033|D|concomitant anticoagulants  has been reported, six with acenocoumarol and|
03167|034|D|two with phenprocoumon.  Patients were stable on anticoagulants for months|
03167|035|D|to years prior to initiation of noscapine.  After a median of 5 days of|
03167|036|D|concurrent therapy, elevated INR and/or bleeding was reported.  INR was|
03167|037|D|elevated to 6.2 in one case and to 5.7 in another case.  Eye hemorrhage was|
03167|038|D|reported in two other cases and an unspecified hemorrhage was reported in|
03167|039|D|one case.(1)|
03167|040|B||
03167|041|R|REFERENCE:|
03167|042|B||
03167|043|R|1.Lokhorst B, Rolfes L, Jessurun NT. Interaction of OTC drug noscapine and|3
03167|044|R|  acenocoumarol and phenprocoumon. Br J Clin Pharmacol 2019 Feb 26.|3
03168|001|T|MONOGRAPH TITLE:  Warfarin/Ceritinib|
03168|002|B||
03168|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03168|004|L|take action as needed.|
03168|005|B||
03168|006|A|MECHANISM OF ACTION:  Ceritinib is a weak CYP2C9 inhibitor and a strong|
03168|007|A|CYP3A inhibitor(1) which may decrease the metabolism of both the|
03168|008|A|S-enantiomer and R-enantiomer of warfarin, respectively.(2-4)|
03168|009|B||
03168|010|E|CLINICAL EFFECTS:  Concurrent use of ceritinib may result in elevated levels|
03168|011|E|of warfarin and INR.(1)|
03168|012|E|   Concurrent use of warfarin and ceritinib may increase the risk for|
03168|013|E|bleeding.|
03168|014|B||
03168|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03168|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03168|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
03168|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03168|019|P|risk for bleeding (e.g. NSAIDs).|
03168|020|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
03168|021|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
03168|022|P|are expected to be more susceptible to this interaction.|
03168|023|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
03168|024|P|are expected to be less susceptible to effects from this drug combination,|
03168|025|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
03168|026|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
03168|027|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
03168|028|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
03168|029|P|and safe anticoagulation than patients without these CYP2C9 variants.|
03168|030|B||
03168|031|M|PATIENT MANAGEMENT:  Monitor INRs frequently until stable in patients who|
03168|032|M|start ceritinib therapy, or have the ceritinib dose adjusted.(1)|
03168|033|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03168|034|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
03168|035|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
03168|036|M|evaluate patients with any symptoms.|
03168|037|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03168|038|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03168|039|M|anticoagulation in patients with active pathologic bleeding.|
03168|040|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03168|041|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03168|042|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03168|043|M|and/or swelling.|
03168|044|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03168|045|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
03168|046|M|initiating, altering the dose or discontinuing either drug.|
03168|047|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
03168|048|B||
03168|049|D|DISCUSSION:  In a study, ceritinib (750 mg daily for 3 weeks) increased the|
03168|050|D|area-under-the-curve (AUC) of a single dose of warfarin by 54 %, compared to|
03168|051|D|warfarin alone.  No change in the maximum concentration (Cmax) of warfarin|
03168|052|D|was observed.(1)|
03168|053|B||
03168|054|R|REFERENCES:|
03168|055|B||
03168|056|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
03168|057|R|  Corporation August, 2021.|1
03168|058|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
03168|059|R|  Squibb Company September, 2016.|1
03168|060|R|3.This information is based on an extract from the Certara Drug Interaction|6
03168|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03168|062|R|4.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
03168|063|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
03168|064|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
03168|065|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
03168|066|R|  Oct;90(4):625-9.|6
03169|001|T|MONOGRAPH TITLE:  Lurasidone (Less Than or Equal To 80 mg)/Selected CYP3A4|
03169|002|T|Moderate Inhibitors|
03169|003|B||
03169|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03169|005|L|take action as needed.|
03169|006|B||
03169|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
03169|008|A|of lurasidone.(1)|
03169|009|B||
03169|010|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
03169|011|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
03169|012|E|or other lurasidone toxicities.(1)|
03169|013|B||
03169|014|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
03169|015|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
03169|016|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
03169|017|P|have a greater risk for adverse effects.(1)|
03169|018|B||
03169|019|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
03169|020|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
03169|021|M|CYP3A4 inhibitors.(1)|
03169|022|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor|
03169|023|M|is added to therapy, the dose of lurasidone should be decreased by 50% of|
03169|024|M|the original dose.(1)|
03169|025|M|   If a patient is currently on a moderate CYP3A4 inhibitor and lurasidone|
03169|026|M|is added to therapy, the recommended starting dose of lurasidone is 20 mg|
03169|027|M|per day.(1)|
03169|028|B||
03169|029|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
03169|030|D|moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
03169|031|D|area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold,|
03169|032|D|and 2.2-fold, respectively.(1)|
03169|033|D|   Agents linked to this monograph include berotralstat, clofazimine,|
03169|034|D|conivaptan, crizotinib, dronedarone, duvelisib, fedratinib, fluvoxamine,|
03169|035|D|imatinib, isavuconazonium, letermovir, nilotinib, nirogacestat,|
03169|036|D|rilzabrutinib, stiripentol, and tofisopam.(2,3)|
03169|037|B||
03169|038|R|REFERENCES:|
03169|039|B||
03169|040|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
03169|041|R|  Pharamceuticals, Inc. December, 2019.|1
03169|042|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03169|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03169|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03169|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03169|046|R|  11/14/2017.|1
03169|047|R|3.This information is based on an extract from the Certara Drug Interaction|6
03169|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03170|001|T|MONOGRAPH TITLE:  Lurasidone (Greater Than 80 mg)/Selected CYP3A4 Moderate|
03170|002|T|Inhibitors|
03170|003|B||
03170|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03170|005|L|is contraindicated and generally should not be dispensed or administered to|
03170|006|L|the same patient.|
03170|007|B||
03170|008|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
03170|009|A|of lurasidone.(1)|
03170|010|B||
03170|011|E|CLINICAL EFFECTS:  Concomitant use of lurasidone with inhibitors of CYP3A4|
03170|012|E|may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism|
03170|013|E|or other lurasidone toxicities.(1)|
03170|014|B||
03170|015|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
03170|016|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
03170|017|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
03170|018|P|have a greater risk for adverse effects.(1)|
03170|019|B||
03170|020|M|PATIENT MANAGEMENT:  The US manufacturer of lurasidone states that the dose|
03170|021|M|of lurasidone should not exceed 80 mg daily if coadministered with moderate|
03170|022|M|CYP3A4 inhibitors.(1)|
03170|023|M|   If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor|
03170|024|M|is added to therapy, the dose of lurasidone should be decreased by 50% of|
03170|025|M|the original dose.(1)|
03170|026|M|   If a patient is currently on a moderate CYP3A4 inhibitor and lurasidone|
03170|027|M|is added to therapy, the recommended starting dose of lurasidone is 20 mg|
03170|028|M|per day.(1)|
03170|029|B||
03170|030|D|DISCUSSION:  Pretreatment with diltiazem (240 mg daily for 5 days), another|
03170|031|D|moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and|
03170|032|D|area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold,|
03170|033|D|and 2.2-fold, respectively.(1)|
03170|034|D|   Agents linked to this monograph include berotralstat, clofazimine,|
03170|035|D|conivaptan, crizotinib, dronedarone, duvelisib, fedratinib, fluvoxamine,|
03170|036|D|imatinib, isavuconazole, letermovir, nilotinib, nirogacestat, rilzabrutinib,|
03170|037|D|stiripentol, and tofisopam.(2,3)|
03170|038|B||
03170|039|R|REFERENCES:|
03170|040|B||
03170|041|R|1.Latuda (lurasidone hydrochloride) US prescribing information. Sunovion|1
03170|042|R|  Pharamceuticals, Inc. December, 2019.|1
03170|043|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03170|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03170|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03170|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03170|047|R|  11/14/2017.|1
03170|048|R|3.This information is based on an extract from the Certara Drug Interaction|6
03170|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03171|001|T|MONOGRAPH TITLE:  Quetiapine/Protease Inhibitors|
03171|002|B||
03171|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03171|004|L|of severe adverse interaction.|
03171|005|B||
03171|006|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
03171|007|A|quetiapine.  Quetiapine is a sensitive substrate for CYP3A4 and so an|
03171|008|A|approximately 5-fold or higher increase in exposure (AUC, area-under-curve)|
03171|009|A|can be anticipated when it is given with a protease inhibitor.(1)|
03171|010|B||
03171|011|E|CLINICAL EFFECTS:  Concurrent use of a protease inhibitor may result in|
03171|012|E|elevated levels of and toxicity from quetiapine, including life-threatening|
03171|013|E|arrhythmias such as torsades de pointes.(2-4)|
03171|014|B||
03171|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03171|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03171|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03171|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03171|019|P|female gender, or advanced age.(5)|
03171|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03171|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03171|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03171|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03171|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03171|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03171|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03171|027|B||
03171|028|M|PATIENT MANAGEMENT:  If possible, avoid the use of protease inhibitors with|
03171|029|M|quetiapine.  If addition of concomitant therapy with a protease inhibitor is|
03171|030|M|required, US manufacturers state the quetiapine dose should be reduced to|
03171|031|M|1/6th of the original dose.(2,3)|
03171|032|M|   The UK manufacturer states the concurrent use of quetiapine with strong|
03171|033|M|CYP3A4 inhibitors is contraindicated.(4)|
03171|034|M|   When the inhibitor is discontinued, return to the original quetiapine|
03171|035|M|dose.(2)|
03171|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03171|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03171|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03171|039|M|patients to report any irregular heartbeat, dizziness, fainting, excessive|
03171|040|M|drowsiness, rapid pulse/hypotension, weakness, fatigue, dizziness, or muscle|
03171|041|M|stiffness/tremors (EPS).|
03171|042|B||
03171|043|D|DISCUSSION:  In a study, concurrent use of ketoconazole (200 mg daily for 4|
03171|044|D|days, a strong inhibitor of CYP3A4) and quetiapine resulted in an increase|
03171|045|D|in quetiapine Cmax and AUC by 3.35-fold and 6.2-fold, respectively.|
03171|046|D|Ketoconazole also decreased the mean apparent oral clearance of quetiapine|
03171|047|D|by 84%, and increased quetiapine mean elimination half-life by|
03171|048|D|2.6-fold.(2,6)  Protease inhibitors would be expected to cause similar|
03171|049|D|changes to quetiapine levels and elimination.|
03171|050|B||
03171|051|R|REFERENCES:|
03171|052|B||
03171|053|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
03171|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03171|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03171|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03171|057|R|  11/14/2017.|1
03171|058|R|2.Seroquel (quetiapine) US prescribing information. AstraZeneca|1
03171|059|R|  Pharmaceuticals LP September, 2020.|1
03171|060|R|3.Seroquel (quetiapine) Canada prescribing information. AstraZeneca Canada|1
03171|061|R|  Inc. May 15,2013.|1
03171|062|R|4.Seroquel (quetiapine) UK summary of product characteristics. Luye Pharma|1
03171|063|R|  Limited June, 2020.|1
03171|064|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03171|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03171|066|R|  settings: a scientific statement from the American Heart Association and|6
03171|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03171|068|R|  2;55(9):934-47.|6
03171|069|R|6.Grimm SW, Richtand NM, Winter HR, Stams KR, Reele SB. Effects of|2
03171|070|R|  cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine|2
03171|071|R|  pharmacokinetics. Br J Clin Pharmacol 2006 Jan;61(1):58-69.|2
03172|001|T|MONOGRAPH TITLE:  Siponimod/QT Prolonging Agents (mono deleted 04/15/2021)|
03172|002|B||
03172|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03172|004|L|take action as needed.|
03172|005|B||
03172|006|A|MECHANISM OF ACTION:  Siponimod causes a transient reduction in heart rate|
03172|007|A|and atrioventricular conduction and can prolong the QT interval.  Concurrent|
03172|008|A|use with QT prolonging agents may result in additive effects on the QT|
03172|009|A|interval.(1)|
03172|010|B||
03172|011|E|CLINICAL EFFECTS:  The concurrent use of siponimod with agents that prolong|
03172|012|E|the QTc interval may result in potentially life-threatening cardiac|
03172|013|E|arrhythmias, including torsades de pointes.(1)|
03172|014|B||
03172|015|P|PREDISPOSING FACTORS:  Patients with a CYP2C9*3/*3 genotype or on concurrent|
03172|016|P|therapy with inhibitors of both CYP2C9 CYP3A4 are at increased risk for|
03172|017|P|higher systemic exposure to siponimod  and may be at increased risk of QT|
03172|018|P|prolongation.(1)|
03172|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03172|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03172|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03172|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03172|023|P|advanced age.(2)|
03172|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03172|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03172|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03172|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03172|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03172|029|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03172|030|P|dysfunction).(2)|
03172|031|B||
03172|032|M|PATIENT MANAGEMENT:  Obtain cardiology advice concerning the most|
03172|033|M|appropriate monitoring strategy in patients in whom concurrent therapy with|
03172|034|M|QT prolonging agents is required.(1)|
03172|035|M|   Monitoring strategies may include overnight monitoring of ECGs and|
03172|036|M|monitoring of electrolyte values (serum calcium, magnesium, and potassium)|
03172|037|M|prior to the start of treatment, after initiation of any drug known to|
03172|038|M|prolong the QT interval, and periodically monitor during therapy.  Correct|
03172|039|M|any electrolyte abnormalities.|
03172|040|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03172|041|M|fainting.(2)|
03172|042|B||
03172|043|D|DISCUSSION:  In a thorough QT study, siponimod doses of 2 mg (recommended|
03172|044|D|dose) and 10 mg (5 times the recommended dose) increased the QTc interval|
03172|045|D|(90% CI)  by 7.8 (9.93) ms at the 2 mg dose and 7.2 (9.72) ms at the 10 mg|
03172|046|D|dose.  Siponimod also causes a transient reduction in heart rate and|
03172|047|D|atrioventricular conduction.(1)|
03172|048|D|   Agents that are linked to this monograph may have varying degrees of|
03172|049|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03172|050|D|been shown to prolong the QTc interval either through their mechanism of|
03172|051|D|action, through studies on their effects on the QTc interval, or through|
03172|052|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03172|053|D|and/or postmarketing reports.(3)|
03172|054|B||
03172|055|R|REFERENCES:|
03172|056|B||
03172|057|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03172|058|R|  Corporation August, 2025.|1
03172|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03172|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03172|061|R|  settings: a scientific statement from the American Heart Association and|6
03172|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03172|063|R|  2;55(9):934-47.|6
03172|064|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03172|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03172|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03172|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03173|001|T|MONOGRAPH TITLE:  Siponimod/Dual Inducers of CYP2C9 and CYP3A4|
03173|002|B||
03173|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03173|004|L|of severe adverse interaction.|
03173|005|B||
03173|006|A|MECHANISM OF ACTION:  Drugs that are both moderate inducers of CYP2C9 and|
03173|007|A|strong inducers of CYP3A4 may increase the metabolism of siponimod.(1)|
03173|008|B||
03173|009|E|CLINICAL EFFECTS:  Concurrent use of a siponimod with a moderate|
03173|010|E|CYP2C9/strong CYP3A4 dual inducer may result in decreased levels and|
03173|011|E|effectiveness of siponimod.(1)|
03173|012|B||
03173|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03173|014|P|of the inducer for longer than 1-2 weeks.|
03173|015|B||
03173|016|M|PATIENT MANAGEMENT:  The manufacturer of siponimod says that the combination|
03173|017|M|of siponimod with a moderate CYP2C9/strong CYP3A4 dual inducer is not|
03173|018|M|recommended.(1)|
03173|019|B||
03173|020|D|DISCUSSION:  In a study, rifampin (600 mg daily) decreased siponimod|
03173|021|D|area-under-curve (AUC) and maximum concentration (Cmax) by 57 % and 45 %,|
03173|022|D|respectively in CYP2C9 normal metabolizers.  Across all CYP2C9 genotypes,|
03173|023|D|rifampin decreased the AUC of siponimod by 78 % in an in silico|
03173|024|D|evaluation.(1)|
03173|025|D|   Drugs that are both moderate CYP2C9 inducers and strong CYP3A4 inducers|
03173|026|D|linked to this monograph include: carbamazepine, enzalutamide, and|
03173|027|D|rifampin.(1-3)|
03173|028|B||
03173|029|R|REFERENCES:|
03173|030|B||
03173|031|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03173|032|R|  Corporation August, 2025.|1
03173|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
03173|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03173|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03173|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03173|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03173|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03173|039|R|  11/14/2017.|1
03174|001|T|MONOGRAPH TITLE:  Non-Live or Non-Replicating Vaccines/Siponimod|
03174|002|B||
03174|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03174|004|L|take action as needed.|
03174|005|B||
03174|006|A|MECHANISM OF ACTION:  Siponimod is an immunosuppressant and may alter the|
03174|007|A|immune system's response to vaccines.(2)|
03174|008|B||
03174|009|E|CLINICAL EFFECTS:  Administration of a vaccine during and for up to 1 month|
03174|010|E|after discontinuation of siponimod therapy may result in decreased|
03174|011|E|effectiveness of the vaccine.  Siponimod treatment should be paused 1 week|
03174|012|E|prior and for 4 weeks after vaccination.(2)|
03174|013|B||
03174|014|P|PREDISPOSING FACTORS:  None determined.|
03174|015|B||
03174|016|M|PATIENT MANAGEMENT:  Ideally, administer vaccines prior to initiating|
03174|017|M|siponimod therapy.|
03174|018|M|   The immune response to non-live vaccines should be monitored in patients|
03174|019|M|receiving siponimod or who have received siponimod in the previous week.|
03174|020|M|Vaccinations given during and for up to 1 month after discontinuation of|
03174|021|M|siponimod therapy may need to be repeated.(2)|
03174|022|M|   The Centers for Disease Control's (CDC) Advisory Committee on|
03174|023|M|Immunization Practices (ACIP) states that non-live vaccines should be used|
03174|024|M|with caution in patients who are severely immunosuppressed.  Patients who|
03174|025|M|are vaccinated within the 14 days prior to initiating immunosuppressive|
03174|026|M|therapy should be considered unvaccinated and should be revaccinated at|
03174|027|M|least 3 months after immunosuppressive therapy is discontinued when immune|
03174|028|M|competence is restored.(3)|
03174|029|B||
03174|030|D|DISCUSSION:  Vaccinations may be less effective if administered during and|
03174|031|D|for up to 1 month after siponimod treatment(2) however they are considered|
03174|032|D|safe to administer.(1)|
03174|033|B||
03174|034|R|REFERENCES:|
03174|035|B||
03174|036|R|1.Williamson EM, Chahin S, Berger JR. Vaccines in Multiple Sclerosis. Curr|6
03174|037|R|  Neurol Neurosci Rep 2016 Apr;16(4):36.|6
03174|038|R|2.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03174|039|R|  Corporation August, 2025.|1
03174|040|R|3.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
03174|041|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
03174|042|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
03174|043|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
03174|044|R|  recs.pdf February 10, 2023;1-197.|6
03175|001|T|MONOGRAPH TITLE:  Siponimod/Beta-Blockers|
03175|002|B||
03175|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03175|004|L|of severe adverse interaction.|
03175|005|B||
03175|006|A|MECHANISM OF ACTION:  Initiation of siponimod has caused transient decreases|
03175|007|A|in heart rate and atrioventricular conduction delays after the first dose.|
03175|008|A|Decreases in heart rate start within the first hour and maximal decrease in|
03175|009|A|heart rate was seen at approximately 3-4 hours.  The first dose has also|
03175|010|A|been associated with heart block.  Beta-blockers further increase the risk|
03175|011|A|for symptomatic bradycardia or heart block.(1)|
03175|012|B||
03175|013|E|CLINICAL EFFECTS:  The heart rate lowering effect of siponimod is transient|
03175|014|E|and is usually seen with the first dose.  Bradycardia may be associated with|
03175|015|E|an increase in the QTc interval, increasing the risk for torsade de|
03175|016|E|pointes.(1)|
03175|017|B||
03175|018|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular disease (e.g. heart|
03175|019|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
03175|020|P|history of torsades de pointes, or heart block), severe untreated sleep|
03175|021|P|apnea, a prolonged QTc interval prior to siponimod initiation, or factors|
03175|022|P|associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia,|
03175|023|P|bradycardia, female gender, or advanced age) may increase risk for|
03175|024|P|cardiovascular toxicity due to siponimod.|
03175|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03175|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03175|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03175|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03175|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03175|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03175|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03175|032|B||
03175|033|M|PATIENT MANAGEMENT:  The prescribing information states temporary|
03175|034|M|interruption in beta-blocker therapy may be needed before initiation of|
03175|035|M|siponimod.  Beta-blocker therapy can be initiated in patients receiving|
03175|036|M|stable doses of siponimod.(1)|
03175|037|M|   Treatment initiation recommendations include:|
03175|038|M|   - Obtain an ECG in all patients to determine whether preexisting|
03175|039|M|conduction abnormalities are present.|
03175|040|M|   - In all patients, a dose titration is recommended for initiation of|
03175|041|M|siponimod treatment to help reduce cardiac effects.|
03175|042|M|   - In patients with sinus bradycardia (HR less than 55 bpm), first- or|
03175|043|M|second-degree [Mobitz type I] AV block, or a history of myocardial|
03175|044|M|infarction or heart failure with onset > 6 months prior to initiation, ECG|
03175|045|M|testing and first dose monitoring is recommended.|
03175|046|M|   - Since significant bradycardia may be poorly tolerated in patients with|
03175|047|M|history of cardiac arrest, cerebrovascular disease, uncontrolled|
03175|048|M|hypertension, or severe untreated sleep apnea, siponimod is not recommended|
03175|049|M|in these patients.  If treatment is considered, advice from a cardiologist|
03175|050|M|should be sought prior to initiation of treatment in order to determine the|
03175|051|M|most appropriate monitoring strategy.|
03175|052|M|   - Use of siponimod in patients with a history of recurrent syncope or|
03175|053|M|symptomatic bradycardia should be based on an overall benefit-risk|
03175|054|M|assessment.  If treatment is considered, advice from a cardiologist should|
03175|055|M|be sought prior to initiation of treatment in order to determine the most|
03175|056|M|appropriate monitoring.|
03175|057|M|   - For patients receiving a stable dose of a beta-blocker, the resting|
03175|058|M|heart rate should be considered before introducing siponimod treatment.  If|
03175|059|M|the resting heart rate is greater than 50 bpm under chronic beta-blocker|
03175|060|M|treatment, siponimod can be introduced.  If resting heart rate is less than|
03175|061|M|or equal to 50 bpm, beta-blocker treatment should be interrupted until the|
03175|062|M|baseline heart-rate is greater than 50 bpm.  Treatment with siponimod can|
03175|063|M|then be initiated and treatment with a beta-blocker can be reinitiated after|
03175|064|M|siponimod has been up-titrated to the target maintenance dosage.|
03175|065|M|   - If a titration dose is missed or if 4 or more consecutive daily doses|
03175|066|M|are missed during maintenance treatment, reinitiate Day 1 of the dose|
03175|067|M|titration and follow titration monitoring recommendations.(1)|
03175|068|B||
03175|069|D|DISCUSSION:  After the first titration dose of siponimod, the heart rate|
03175|070|D|decrease starts within an hour, and the Day 1 decline is maximal at|
03175|071|D|approximately 3-4 hours.  With continued up-titration, further heart rate|
03175|072|D|decreases are seen on subsequent days, with maximal decrease from Day|
03175|073|D|1-baseline reached on Day 5-6.  The highest daily post-dose decrease in|
03175|074|D|absolute hourly mean heart rate is observed on Day 1, with the pulse|
03175|075|D|declining on average 5-6 bpm.  Post-dose declines on the following days are|
03175|076|D|less pronounced.  With continued dosing, heart rate starts increasing after|
03175|077|D|Day 6 and reaches placebo levels within 10 days after treatment initiation.|
03175|078|D|   In Study 1, bradycardia occurred in 4.4% of siponimod-treated patients|
03175|079|D|compared to 2.9% of patients receiving placebo.  Patients who experienced|
03175|080|D|bradycardia were generally asymptomatic. Few patients experienced symptoms,|
03175|081|D|including dizziness or fatigue, and these symptoms resolved within 24 hours|
03175|082|D|without intervention.(1)|
03175|083|D|   Beta-Blockers linked to this monograph are: atenolol, betaxolol,|
03175|084|D|bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol,|
03175|085|D|nebivolol, propranolol and timolol.|
03175|086|B||
03175|087|R|REFERENCES:|
03175|088|B||
03175|089|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03175|090|R|  Corporation August, 2025.|1
03175|091|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03175|092|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03175|093|R|  settings: a scientific statement from the American Heart Association and|6
03175|094|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03175|095|R|  2;55(9):934-47.|6
03176|001|T|MONOGRAPH TITLE:  Siponimod/Agents That Cause Bradycardia|
03176|002|B||
03176|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03176|004|L|of severe adverse interaction.|
03176|005|B||
03176|006|A|MECHANISM OF ACTION:  Initiation of siponimod has caused transient decreases|
03176|007|A|in heart rate and atrioventricular conduction delays after the first dose.|
03176|008|A|Decreases in heart rate start within the first hour and maximal decrease in|
03176|009|A|heart rate was seen at approximately 3-4 hours.  The first dose has also|
03176|010|A|been associated with heart block.  Additional agents that cause bradycardia|
03176|011|A|further increase the risk for symptomatic bradycardia.(1)|
03176|012|B||
03176|013|E|CLINICAL EFFECTS:  The heart rate lowering effect of siponimod is transient|
03176|014|E|and is usually seen with the first dose.  Bradycardia may be associated with|
03176|015|E|an increase in the QTc interval, increasing the risk for torsade de|
03176|016|E|pointes.(1)|
03176|017|B||
03176|018|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular disease (e.g. heart|
03176|019|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
03176|020|P|history of torsades de pointes, or heart block), severe untreated sleep|
03176|021|P|apnea, a prolonged QTc interval prior to siponimod initiation, or factors|
03176|022|P|associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia,|
03176|023|P|bradycardia, female gender, or advanced age) may increase risk for|
03176|024|P|cardiovascular toxicity due to siponimod.(2)|
03176|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03176|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03176|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03176|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03176|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03176|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03176|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03176|032|B||
03176|033|M|PATIENT MANAGEMENT:  The prescribing information states siponimod treatment|
03176|034|M|should generally not be initiated in patients who are concurrent therapy|
03176|035|M|with additional agents that cause bradycardia.  If treatment with siponimod|
03176|036|M|is considered, advice from a cardiologist should be sought regarding|
03176|037|M|switching to non-heart rate lowering drugs or recommendations for monitoring|
03176|038|M|for treatment initiation.|
03176|039|M|   Treatment initiation recommendations include:|
03176|040|M|   - Obtain an ECG in all patients to determine whether preexisting|
03176|041|M|conduction abnormalities are present.|
03176|042|M|   - In all patients, a dose titration is recommended for initiation of|
03176|043|M|siponimod treatment to help reduce cardiac effects.|
03176|044|M|   - In patients with sinus bradycardia (HR less than 55 bpm), first- or|
03176|045|M|second-degree [Mobitz type I] AV block, or a history of myocardial|
03176|046|M|infarction or heart failure with onset > 6 months prior to initiation, ECG|
03176|047|M|testing and first dose monitoring is recommended.|
03176|048|M|   - Since significant bradycardia may be poorly tolerated in patients with|
03176|049|M|history of cardiac arrest, cerebrovascular disease, uncontrolled|
03176|050|M|hypertension, or severe untreated sleep apnea, siponimod is not recommended|
03176|051|M|in these patients. If treatment is considered, advice from a cardiologist|
03176|052|M|should be sought prior to initiation of treatment in order to determine the|
03176|053|M|most appropriate monitoring strategy.|
03176|054|M|   - Use of siponimod in patients with a history of recurrent syncope or|
03176|055|M|symptomatic bradycardia should be based on an overall benefit-risk|
03176|056|M|assessment. If treatment is considered, advice from a cardiologist should be|
03176|057|M|sought prior to initiation of treatment in order to determine the most|
03176|058|M|appropriate monitoring.|
03176|059|M|   - If a titration dose is missed or if 4 or more consecutive daily doses|
03176|060|M|are missed during maintenance treatment, reinitiate Day 1 of the dose|
03176|061|M|titration and follow titration monitoring recommendations.(1)|
03176|062|B||
03176|063|D|DISCUSSION:  Initiation of siponimod treatment has been associated with|
03176|064|D|transient atrioventricular (AV) conduction delays that follow a similar|
03176|065|D|temporal pattern as the observed decrease in heart rate during dose|
03176|066|D|titration. The AV conduction delays manifested in most of the cases as|
03176|067|D|first-degree AV block (prolonged PR interval on ECG), which occurred in 5.1%|
03176|068|D|of siponimod treated patients and in 1.9 % of patients receiving placebo in|
03176|069|D|Study 1.|
03176|070|D|   Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been|
03176|071|D|observed at the time of treatment initiation with siponimod in less than|
03176|072|D|1.7% of patients in clinical trials.|
03176|073|D|   The conduction abnormalities typically were transient, asymptomatic,|
03176|074|D|resolved within 24 hours, rarely required treatment with atropine, and did|
03176|075|D|not require discontinuation of siponimod treatment.(1)|
03176|076|B||
03176|077|R|REFERENCES:|
03176|078|B||
03176|079|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03176|080|R|  Corporation August, 2025.|1
03176|081|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03176|082|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03176|083|R|  settings: a scientific statement from the American Heart Association and|6
03176|084|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03176|085|R|  2;55(9):934-47.|6
03177|001|T|MONOGRAPH TITLE:  Siponimod/Selected Moderate CYP2C9 Inducers|
03177|002|B||
03177|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03177|004|L|of severe adverse interaction.|
03177|005|B||
03177|006|A|MECHANISM OF ACTION:  Drugs that are moderate inducers of CYP2C9 may|
03177|007|A|increase the metabolism of siponimod.(1)|
03177|008|B||
03177|009|E|CLINICAL EFFECTS:  Concurrent use of a siponimod with a moderate CYP2C9|
03177|010|E|inducer may result in decreased levels and effectiveness of siponimod.(1)|
03177|011|B||
03177|012|P|PREDISPOSING FACTORS:  Concurrent use of a strong inducer of CYP3A4 may|
03177|013|P|magnify the effect of the CYP2C9 inducer on siponimod and further decrease|
03177|014|P|the levels of siponimod.|
03177|015|P|   Induction effects may be more likely with regular use of the inducer for|
03177|016|P|longer than 1-2 weeks.|
03177|017|B||
03177|018|M|PATIENT MANAGEMENT:  The manufacturer of siponimod says that the combination|
03177|019|M|of siponimod with a moderate CYP2C9 inducer and a strong CYP3A4 inducer is|
03177|020|M|not recommended.(1)|
03177|021|B||
03177|022|D|DISCUSSION:  In a study, rifampin (600 mg daily) decreased siponimod|
03177|023|D|area-under-curve (AUC) and maximum concentration (Cmax) by 57 % and 45 %,|
03177|024|D|respectively in CYP2C9 normal metabolizers.  Across all CYP2C9 genotypes,|
03177|025|D|rifampin decreased the AUC of siponimod by 78 % in an in silico|
03177|026|D|evaluation.(1)|
03177|027|D|   Drugs that are both moderate CYP2C9 inducers linked to this monograph|
03177|028|D|include: aprepitant and ritonavir.(2-3)|
03177|029|B||
03177|030|R|REFERENCES:|
03177|031|B||
03177|032|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03177|033|R|  Corporation August, 2025.|1
03177|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
03177|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03177|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03177|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03177|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03177|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03177|040|R|  11/14/2017.|1
03178|001|T|MONOGRAPH TITLE:  Siponimod/Dual Inhibitors of CYP2C9 & CYP3A4|
03178|002|B||
03178|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03178|004|L|take action as needed.|
03178|005|B||
03178|006|A|MECHANISM OF ACTION:  Agents that both moderate inhibitors of CYP2C9 and|
03178|007|A|moderate or strong inhibitors of CYP3A4 may inhibit the metabolism of|
03178|008|A|siponimod.(1)|
03178|009|B||
03178|010|E|CLINICAL EFFECTS:  Concurrent use of a dual inhibitor of CYP2C9 and CYP3A4|
03178|011|E|may result in elevated levels of and clinical effects of siponimod,|
03178|012|E|including transient atrioventricular (AV) delays.  Conduction delays are|
03178|013|E|typically transient, asymptomatic, and resolved within 24 hours.(1)|
03178|014|B||
03178|015|P|PREDISPOSING FACTORS:  Patients may be at higher risk of conduction delays|
03178|016|P|and cardiologist input should be consulted in the following: significant QT|
03178|017|P|prolongation (QTc greater than 500 ms); concurrent use of Class Ia or Class|
03178|018|P|III antiarrhythmics; comorbidities such as ischemic heart disease, heart|
03178|019|P|failure, history of cardiac arrest or myocardial infarction, cerebrovascular|
03178|020|P|disease, uncontrolled hypertension; or conduction disorders such as history|
03178|021|P|of second-degree Mobitz II or higher AV block, sick-sinus syndrome, or|
03178|022|P|sino-atrial heart block.(1)|
03178|023|B||
03178|024|M|PATIENT MANAGEMENT:  Monitor for adverse reactions during concomitant use of|
03178|025|M|siponimod with moderate CYP2C9 and CYP3A4 dual inhibitors.(1)|
03178|026|M|   Advice from a cardiologist should be sought in patients with predisposing|
03178|027|M|factors for conduction delays prior to initiation of siponimod.  It would be|
03178|028|M|prudent to monitor patients for increased levels and effects of siponimod if|
03178|029|M|concurrent use with a dual inhibitor of CYP2C9 and CYP3A4 is initiated.(1)|
03178|030|B||
03178|031|D|DISCUSSION:  Siponimod is metabolized by CYP2C9 (79.3%) and CYP3A4 (18.5%).|
03178|032|D|Concurrent use of fluconazole (a dual moderate inhibitor of CYP2C9 and|
03178|033|D|CYP3A4, 200 mg at steady state) in healthy subjects with the CYP2C9*1/*1|
03178|034|D|genotype increased the area-under-curve (AUC) of siponimod (4 mg single|
03178|035|D|dose) by 2-fold.  Siponimod half-life increased by 50%.  Fluconazole|
03178|036|D|increased siponimod AUC by 2-fold to 4-fold across all CYP2C9 genotypes.(1)|
03178|037|B||
03178|038|R|REFERENCE:|
03178|039|B||
03178|040|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03178|041|R|  Corporation August, 2025.|1
03179|001|T|MONOGRAPH TITLE:  Siponimod/Selected Moderate CYP2C9 Inhibitors|
03179|002|B||
03179|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03179|004|L|take action as needed.|
03179|005|B||
03179|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2C9 may inhibit the metabolism of|
03179|007|A|siponimod.(1)|
03179|008|B||
03179|009|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of CYP2C9 may result in|
03179|010|E|elevated levels of and clinical effects of siponimod, including|
03179|011|E|immunosuppression and increased risk of infection.(1)|
03179|012|E|   Concurrent use of siponimod with immunosuppressive or immune-modulating|
03179|013|E|agents, such as asciminib, may result in an additive risk and increased risk|
03179|014|E|of serious infections.|
03179|015|B||
03179|016|P|PREDISPOSING FACTORS:  Concurrent use of a strong or moderate inhibitor of|
03179|017|P|CYP3A4 may increase the effects of the interaction.|
03179|018|B||
03179|019|M|PATIENT MANAGEMENT:  Monitor for adverse reactions during concomitant use of|
03179|020|M|siponimod with moderate CYP2C9 inhibitors or moderate CYP2C9 and CYP3A4 dual|
03179|021|M|inhibitors.(1)  Review the patient's therapy for concurrent use of strong or|
03179|022|M|moderate inhibitors of CYP3A4 prior to initiating siponimod.|
03179|023|M|   If concurrent use is necessary, the manufacturer of nitisinone recommends|
03179|024|M|reducing the dosage of a CYP2C9 substrate like siponimod by one-half.(2)|
03179|025|B||
03179|026|D|DISCUSSION:  Siponimod is metabolized by CYP2C9 (79.3%) and CYP3A4 (18.5%).|
03179|027|D|Concurrent use of fluconazole (a dual moderate inhibitor of CYP2C9 and|
03179|028|D|CYP3A4, 200 mg at steady state) in healthy subjects with the CYP2C9*1/*1|
03179|029|D|genotype increased the area-under-curve (AUC) of siponimod (4 mg single|
03179|030|D|dose) by 2-fold.  Siponimod half-life increased by 50%.  Fluconazole|
03179|031|D|increased siponimod AUC by 2-fold to 4-fold across all CYP2C9 genotypes.(1)|
03179|032|D|   Selected moderate CYP2C9 inhibitors linked to this monograph include:|
03179|033|D|apazone, asciminib, benzbromarone, felbamate, miconazole, milk thistle,|
03179|034|D|nitisinone, oxandrolone, phenylbutazone, piperine, silibinin, and|
03179|035|D|sulfaphenazole.(3)|
03179|036|B||
03179|037|R|REFERENCES:|
03179|038|B||
03179|039|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03179|040|R|  Corporation August, 2025.|1
03179|041|R|2.Harliku (nitisinone) US prescribing information. Cycle Pharmaceuticals Ltd|1
03179|042|R|  June, 2025.|1
03179|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
03179|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03180|001|T|MONOGRAPH TITLE:  Siponimod/Selected Moderate and Strong CYP3A4 Inducers|
03180|002|B||
03180|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03180|004|L|take action as needed.|
03180|005|B||
03180|006|A|MECHANISM OF ACTION:  Drugs that are moderate or strong inducers of CYP3A4|
03180|007|A|may increase the metabolism of siponimod.(1)  Patients with a CYP2C9*1/*3 or|
03180|008|A|*2/*3 genotype who are more dependent on CYP3A4 for the metabolism of|
03180|009|A|siponimod would experience a greater effect of CYP3A4 induction.|
03180|010|B||
03180|011|E|CLINICAL EFFECTS:  Concurrent use of a siponimod with a moderate or strong|
03180|012|E|CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype may result|
03180|013|E|in decreased levels and effectiveness of siponimod.(1)|
03180|014|B||
03180|015|P|PREDISPOSING FACTORS:  Patients with a CYP2C9*1/*3 or *2/*3 genotype who are|
03180|016|P|more dependent on CYP3A4 for the metabolism of siponimod would experience a|
03180|017|P|greater effect of CYP3A4 induction.|
03180|018|P|   Induction effects may be more likely with regular use of the inducer for|
03180|019|P|longer than 1-2 weeks.|
03180|020|B||
03180|021|M|PATIENT MANAGEMENT:  Monitor the combination of siponimod with a moderate or|
03180|022|M|strong CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype for|
03180|023|M|loss of efficacy.(1)|
03180|024|M|   Agents that are both moderate CYP3A4 inducers and moderate CYP2C9|
03180|025|M|inducers (e.g., lorlatinib) should be used with caution regardless of the|
03180|026|M|patient's CYP2C9 genotype.(1)|
03180|027|B||
03180|028|D|DISCUSSION:  In a study, efavirenz (a moderate CYP3A4 inducer) decreased the|
03180|029|D|area-under-curve (AUC) of siponimod by up to 52% across CYP2C9 genotypes.|
03180|030|D|   Drugs that are moderate or strong CYP3A4 inducers linked to this|
03180|031|D|monograph include: apalutamide, barbiturates, belzutifan, bosentan,|
03180|032|D|cenobamate, dabrafenib, elagolix, etravirine, fosphenytoin, lesinurad,|
03180|033|D|lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil,|
03180|034|D|nafcillin, pexidartinib, phenobarbital, phenytoin, primidone, rifabutin,|
03180|035|D|rifapentine, St John's Wort, sotorasib, telotristat ethyl, and|
03180|036|D|tovorafenib.(2-3)|
03180|037|B||
03180|038|R|REFERENCES:|
03180|039|B||
03180|040|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03180|041|R|  Corporation August, 2025.|1
03180|042|R|2.This information is based on an extract from the Certara Drug Interaction|6
03180|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03180|044|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03180|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03180|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03180|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03180|048|R|  11/14/2017.|1
03181|001|T|MONOGRAPH TITLE:  Protease Inhibitors/Selected Strong CYP3A4 Inducers|
03181|002|B||
03181|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03181|004|L|of severe adverse interaction.|
03181|005|B||
03181|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers are expected to increase the|
03181|007|A|metabolism of protease inhibitors.(1-2)|
03181|008|B||
03181|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
03181|010|E|result in decreased levels and effectiveness of protease inhibitors.(1-2)|
03181|011|B||
03181|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03181|013|P|of the inducer for longer than 1-2 weeks.|
03181|014|B||
03181|015|M|PATIENT MANAGEMENT:  The manufacturers of darunavir and lopinavir/ritonavir|
03181|016|M|advise caution with concurrent use of drugs that induce CYP3A4 as they would|
03181|017|M|be expected to decrease the plasma concentrations of the protease|
03181|018|M|inhibitor.(1,2)|
03181|019|M|   The manufacturers of enzalutamide and mitotane (strong CYP3A4 inducers)|
03181|020|M|advise avoiding concomitant use with narrow therapeutic drugs that are|
03181|021|M|metabolized by CYP3A4.(3-5)  If enzalutamide is discontinued, the effects of|
03181|022|M|enzyme induction may persist for one month or longer.(4)|
03181|023|B||
03181|024|D|DISCUSSION:  In a study using rifampin 600 mg once daily with|
03181|025|D|lopinavir/ritonavir 400 mg/100 mg twice daily, lopinavir area-under-curve|
03181|026|D|(AUC) and maximum concentration (Cmax) were decreased by 75% and 55%,|
03181|027|D|respectively, compared to lopinavir/ritonavir given alone.(2)|
03181|028|D|   Protease inhibitors linked to this monograph include: amprenavir,|
03181|029|D|darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, and|
03181|030|D|tipranavir.(3,4)|
03181|031|D|   Strong CYP3A4 inducers linked to this monograph include: enzalutamide and|
03181|032|D|mitotane.(6,7)|
03181|033|B||
03181|034|R|REFERENCES:|
03181|035|B||
03181|036|R|1.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
03181|037|R|  March, 2023.|1
03181|038|R|2.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
03181|039|R|  Laboratories December, 2019.|1
03181|040|R|3.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
03181|041|R|  September, 2022.|1
03181|042|R|4.Xtandi (enzalutamide) Canadian prescribing information. Astellas May 28,|1
03181|043|R|  2013.|1
03181|044|R|5.Lysodren (mitotane) US prescribing information. E.R. Squibb & Sons, L.L.C.|1
03181|045|R|  October, 2024.|1
03181|046|R|6.This information is based on an extract from the Certara Drug Interaction|6
03181|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03181|048|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
03181|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03181|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03181|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03181|052|R|  11/14/2017.|1
03182|001|T|MONOGRAPH TITLE:  Voriconazole/Hydantoins|
03182|002|B||
03182|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03182|004|L|of severe adverse interaction.|
03182|005|B||
03182|006|A|MECHANISM OF ACTION:  Phenytoin may induce the metabolism of voriconazole by|
03182|007|A|CYP3A4.  Voriconazole may inhibit the metabolism of phenytoin by|
03182|008|A|CYP2C9.(1,2)|
03182|009|B||
03182|010|E|CLINICAL EFFECTS:  Concurrent use of voriconazole and phenytoin may result|
03182|011|E|in significantly decreased levels of voriconazole, therapeutic failure of|
03182|012|E|voriconazole, significantly elevated levels of phenytoin, and phenytoin|
03182|013|E|toxicity.(1-4)|
03182|014|B||
03182|015|P|PREDISPOSING FACTORS:  Elderly patients, patients with renal and/or hepatic|
03182|016|P|impairment, and patients with hypoalbuminemia may be at higher risk of|
03182|017|P|having increased phenytoin levels and toxicity.(1)|
03182|018|B||
03182|019|M|PATIENT MANAGEMENT:  When coadministered, the manufacturer of voriconazole|
03182|020|M|recommends increasing the dose of voriconazole from 4 mg/kg to 5 mg/kg|
03182|021|M|intravenously every 12 hours, or from 200 mg to 400 mg orally every 12 hours|
03182|022|M|(100 mg to 200 mg orally every 12 hours in patients weighing less than 40|
03182|023|M|kg).(1)|
03182|024|M|   Phenytoin levels should be frequently monitored.(1,2) If voriconazole is|
03182|025|M|stopped, the dose of phenytoin may need to be adjusted.(2)|
03182|026|B||
03182|027|D|DISCUSSION:  In a study of 24 healthy volunteers, phenytoin (300 mg daily)|
03182|028|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03182|029|D|voriconazole (200 mg twice a day) by 69.4 % and 49.3 %, respectively,|
03182|030|D|compared to voriconazole alone.  When the voriconazole dose was increased to|
03182|031|D|400 mg twice day in the patients receiving concurrent phenytoin,|
03182|032|D|voriconazole levels became similar to levels attained when voriconazole (200|
03182|033|D|mg twice a day) was administered alone.|
03182|034|D|   In a second arm of the same study, voriconazole (400 mg twice a day)|
03182|035|D|increased the AUC and Cmax of phenytoin (300 mg daily) by 81 % and 67 %,|
03182|036|D|respectively.(4)|
03182|037|B||
03182|038|R|REFERENCES:|
03182|039|B||
03182|040|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
03182|041|R|2.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
03182|042|R|  March, 2022.|1
03182|043|R|3.Dolton MJ, Mikus G, Weiss J, Ray JE, McLachlan AJ. Understanding|6
03182|044|R|  variability with voriconazole using a population pharmacokinetic approach:|6
03182|045|R|  implications for optimal dosing. J Antimicrob Chemother 2014 Jun;|6
03182|046|R|  69(6):1633-41.|6
03182|047|R|4.Purkins L, Wood N, Ghahramani P, Love ER, Eve MD, Fielding A.|2
03182|048|R|  Coadministration of voriconazole and phenytoin: pharmacokinetic|2
03182|049|R|  interaction, safety, and toleration. Br J Clin Pharmacol 2003 Dec;56 Suppl|2
03182|050|R|  1:37-44.|2
03183|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Cladribine|
03183|002|B||
03183|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03183|004|L|of severe adverse interaction.|
03183|005|B||
03183|006|A|MECHANISM OF ACTION:  Cladribine may lower the efficacy of hormonal|
03183|007|A|contraceptives.  The mechanism of this potential interaction is unknown.(1)|
03183|008|B||
03183|009|E|CLINICAL EFFECTS:  Concurrent use of cladribine may reduce the effectiveness|
03183|010|E|of hormonal contraceptives.(1) Cladribine may cause birth defects and/or|
03183|011|E|miscarriage if used by pregnant women.|
03183|012|B||
03183|013|P|PREDISPOSING FACTORS:  None determined.|
03183|014|B||
03183|015|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
03183|016|M|rely on hormonal contraception (including oral contraceptives, patches,|
03183|017|M|implants, and/or IUDs) for contraception.  Women should add a back-up method|
03183|018|M|of birth control during cladribine therapy and for at least 4 weeks after|
03183|019|M|the final dose of each treatment course.(1)|
03183|020|B||
03183|021|D|DISCUSSION:  It is unknown whether cladribine reduces the effectiveness of|
03183|022|D|hormonal contraceptives.  Cladribine is teratogenic and contraindicated in|
03183|023|D|pregnancy.(1)|
03183|024|B||
03183|025|R|REFERENCE:|
03183|026|B||
03183|027|R|1.Mavenclad (cladribine) US prescribing information. EMD Serono, Inc. March,|1
03183|028|R|  2019.|1
03184|001|T|MONOGRAPH TITLE:  Clopidogrel/Selected Protease Inhibitors; Cobicistat|
03184|002|B||
03184|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03184|004|L|of severe adverse interaction.|
03184|005|B||
03184|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
03184|007|A|active metabolite via a 2 step process.  The first conversion step is|
03184|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
03184|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
03184|010|A|thought to be the more important enzyme involved in formation of the|
03184|011|A|pharmacologically active metabolite.(1)|
03184|012|A|   CYP3A4 is responsible for 39.8% of the second step of metabolism.|
03184|013|A|Protease inhibitors that are strong CYP3A4 inhibitors may inhibit the|
03184|014|A|metabolism of clopidogrel to its active form by CYP3A4.(1,3)|
03184|015|B||
03184|016|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors that are strong|
03184|017|E|CYP3A4 inhibitors may result in decreased clopidogrel effectiveness,|
03184|018|E|resulting in increased risk of adverse cardiac events.(1)|
03184|019|B||
03184|020|P|PREDISPOSING FACTORS:  None determined.|
03184|021|B||
03184|022|M|PATIENT MANAGEMENT:  The US manufacturer of clopidogrel does not make|
03184|023|M|specific recommendations for concurrent use with strong CYP3A4 inhibitors.|
03184|024|M|Patient monitoring for adequate inhibition of platelet reactivity with|
03184|025|M|clopidogrel is warranted.|
03184|026|M|   HIV treatment guidelines from the US Department of Health and Human|
03184|027|M|Services and the European AIDS Clinical Society, and the University of|
03184|028|M|Liverpool HIV Drug Interactions database all recommend not to coadminister|
03184|029|M|clopidogrel with any protease inhibitor or cobicistat.(4-6)|
03184|030|M|   Consider alternatives to protease inhibitors that are strong CYP3A4|
03184|031|M|inhibitors in patients stabilized on clopidogrel and alternatives to|
03184|032|M|clopidogrel in patients stabilized on protease inhibitors that are strong|
03184|033|M|CYP3A4 inhibitors.  If concurrent therapy is warranted, consider appropriate|
03184|034|M|testing to assure adequate inhibition of platelet reactivity.|
03184|035|B||
03184|036|D|DISCUSSION:  In a randomized, cross-over study in healthy subjects,|
03184|037|D|ketoconazole (400 mg daily) decreased the maximum concentration (Cmax) of|
03184|038|D|the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg|
03184|039|D|daily) by 61%.  The area-under-curve (AUC) of the active metabolite of|
03184|040|D|clopidogrel was decreased by 22% following the loading dose and by 29%|
03184|041|D|during maintenance dosing.  Clopidogrel-induced inhibition of platelet|
03184|042|D|aggregation was decreased by 28% following the loading dose and by 33%|
03184|043|D|during the maintenance dose.(7)|
03184|044|D|   A randomized cross over study in 12 healthy volunteers and 9 HIV-infected|
03184|045|D|patients evaluated the impact of boosted antiretroviral therapy (ARV) on the|
03184|046|D|pharmacokinetics and efficacy of clopidogrel.  Healthy patients had 3.2-fold|
03184|047|D|lower AUC (p=0.02) and Cmax of clopidogrel active metabolite (p=0.03) than|
03184|048|D|HIV patients.  Platelet reactivity was also 35% lower in health patients|
03184|049|D|compared to HIV patients (p=0.04).  All healthy patients had a platelet|
03184|050|D|reactivity below the cut-off value at 4 hours after clopidogrel dose, while|
03184|051|D|44% of HIV patients were above the cut-off value of 206.(8)|
03184|052|D|   A cross-sectional study in 240 post acute coronary syndrome (ACS)|
03184|053|D|patients compared platelet reactivity under aspirin and P2Y12 inhibitor|
03184|054|D|therapy between HIV and non-HIV patients with first episode ACS on dual|
03184|055|D|antiplatelet therapy.  Study evaluated residual platelet aggregation (RPA),|
03184|056|D|P2Y12 assay (PRU), and VASP platelet reactivity index (VASP-PRI).  HIV|
03184|057|D|patients were all on ARV therapy, most commonly with protease inhibitors|
03184|058|D|(darunavir, lopinavir, atazanavir, and indinavir in combination with|
03184|059|D|ritonavir in all but two patients).  Patients on ARV containing protease|
03184|060|D|inhibitors compared to other combinations had increased platelet reactivity|
03184|061|D|to P2Y12 inhibitors and higher prevalence of high residual platelet|
03184|062|D|reactivity (HPR) (OR 4.4 (95%CI 1.1-18.1) with RPA, P = 0.04; OR 3.1 (95%CI|
03184|063|D|= 0.84-11.5) with VASP-PRI; P = 0.09, and OR 4.3 (95%CI 1.02-18.1) with PRU,|
03184|064|D|P = 0.047).  Patients with CD4 T cell count lower than 350/mm3 also had|
03184|065|D|consistently increased platelet reactivity to P2Y12 inhibitors and higher|
03184|066|D|prevalence of HPR (OR 3.41 (95%CI 0.60-19.4) with RPA, P = 0.17; OR 7.1|
03184|067|D|(95%CI 0.94-54.2) with VASP-PRI, P = 0.06; and OR 7.9 (95%CI 1.42-44.8) with|
03184|068|D|PRU, P = 0.002), although this association was not significant for all three|
03184|069|D|tests.(9)|
03184|070|D|   Selected protease inhibitors that are strong CYP3A4 inhibitors linked to|
03184|071|D|this monograph include: atazanavir, cobicistat, darunavir, fosamprenavir,|
03184|072|D|indinavir, lopinavir, nelfinavir, paritaprevir, saquinavir, and|
03184|073|D|tipranavir.(10)|
03184|074|B||
03184|075|R|REFERENCES:|
03184|076|B||
03184|077|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
03184|078|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
03184|079|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
03184|080|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
03184|081|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
03184|082|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
03184|083|R|  38(1):92-9.|5
03184|084|R|3.Wang ZY, Chen M, Zhu LL, Yu LS, Zeng S, Xiang MX, Zhou Q. Pharmacokinetic|6
03184|085|R|  drug interactions with clopidogrel: updated review and risk management in|6
03184|086|R|  combination therapy. Ther Clin Risk Manag 2015;11:449-67.|6
03184|087|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03184|088|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03184|089|R|  HIV. Department of Health and Human Services. Available at|6
03184|090|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03184|091|R|  new-guidelines June 13, 2021.|6
03184|092|R|5.European AIDS Clinical Society. EACS Guidelines version 10.0. Available|6
03184|093|R|  at: https://eacs.sanfordguide.com/ November 2019.|6
03184|094|R|6.Liverpool Drug Interactions Group. HIV Drug Interactions. Available at:|6
03184|095|R|  https://hiv-druginteractions.org/.|6
03184|096|R|7.Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT,|2
03184|097|R|  Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by|2
03184|098|R|  ketoconazole affects prasugrel and clopidogrel pharmacokinetics and|2
03184|099|R|  pharmacodynamics differently. Clin Pharmacol Ther 2007 May;81(5):735-41.|2
03184|100|R|8.Hauguel-Moreau M, Boccara F, Boyd A, Salem JE, Brugier D, Curjol A, Hulot|2
03184|101|R|  JS, Kerneis M, Galier S, Cohen A, Montalescot G, Collet JP, Silvain J.|2
03184|102|R|  Platelet reactivity in human immunodeficiency virus infected patients on|2
03184|103|R|  dual antiplatelet therapy for an acute coronary syndrome: the EVERE2ST-HIV|2
03184|104|R|  study. Eur Heart J 2017 Jun 1;38(21):1676-1686.|2
03184|105|R|9.Marsousi N, Daali Y, Fontana P, Reny JL, Ancrenaz-Sirot V, Calmy A, Rudaz|2
03184|106|R|  S, Desmeules JA, Samer CF. Impact of Boosted Antiretroviral Therapy on the|2
03184|107|R|  Pharmacokinetics and Efficacy of  Clopidogrel and Prasugrel Active|2
03184|108|R|  Metabolites. Clin Pharmacokinet 2018 Oct;57(10):1347-1354.|2
03184|109|R|10.This information is based on an extract from the Certara Drug Interaction|6
03184|110|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03185|001|T|MONOGRAPH TITLE:  Clopidogrel/Selected Strong CYP3A4 Inhibitors|
03185|002|B||
03185|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03185|004|L|of severe adverse interaction.|
03185|005|B||
03185|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
03185|007|A|active metabolite via a 2 step process.  The first conversion step is|
03185|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
03185|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
03185|010|A|thought to be the more important enzyme involved in formation of the|
03185|011|A|pharmacologically active metabolite.(1)|
03185|012|A|   CYP3A4 is responsible for 39.8% of the second step of metabolism.  Strong|
03185|013|A|CYP3A4 inhibitors may inhibit the metabolism of clopidogrel to its active|
03185|014|A|form by CYP3A4.(1,3)|
03185|015|B||
03185|016|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
03185|017|E|decreased clopidogrel effectiveness, resulting in increased risk of adverse|
03185|018|E|cardiac events.(1)|
03185|019|B||
03185|020|P|PREDISPOSING FACTORS:  None determined.|
03185|021|B||
03185|022|M|PATIENT MANAGEMENT:  The US manufacturer of clopidogrel does not make|
03185|023|M|specific recommendations for concurrent use with strong CYP3A4 inhibitors.|
03185|024|M|Patient monitoring for adequate inhibition of platelet reactivity with|
03185|025|M|clopidogrel is warranted.|
03185|026|M|   Consider alternatives to strong CYP3A4 inhibitors in patients stabilized|
03185|027|M|on clopidogrel and alternatives to clopidogrel in patients stabilized on|
03185|028|M|strong CYP3A4 inhibitors.  If concurrent therapy is warranted, consider|
03185|029|M|appropriate testing to assure adequate inhibition of platelet reactivity.|
03185|030|B||
03185|031|D|DISCUSSION:  In a randomized, cross-over study in healthy subjects,|
03185|032|D|ketoconazole (400 mg daily) decreased the maximum concentration (Cmax) of|
03185|033|D|the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg|
03185|034|D|daily) by 61%.  The area-under-curve (AUC) of the active metabolite of|
03185|035|D|clopidogrel was decreased by 22% following the loading dose and by 29%|
03185|036|D|during maintenance dosing.  Clopidogrel-induced inhibition of platelet|
03185|037|D|aggregation was decreased by 28% following the loading dose and by 33%|
03185|038|D|during the maintenance dose.(4)|
03185|039|D|   A randomized cross over study in 12 healthy volunteers and 9 HIV-infected|
03185|040|D|patients evaluated the impact of boosted antiretroviral therapy (ARV) on the|
03185|041|D|pharmacokinetics and efficacy of clopidogrel.  Healthy patients had 3.2-fold|
03185|042|D|lower AUC (p=0.02) and Cmax of clopidogrel active metabolite (p=0.03) than|
03185|043|D|HIV patients.  Platelet reactivity was also 35% lower in health patients|
03185|044|D|compared to HIV patients (p=0.04).  All healthy patients had a platelet|
03185|045|D|reactivity below the cut-off value at 4 hours after clopidogrel dose, while|
03185|046|D|44% of HIV patients were above the cut-off value of 206.(5)|
03185|047|D|   A cross-sectional study in 240 post acute coronary syndrome (ACS)|
03185|048|D|patients compared platelet reactivity under aspirin and P2Y12 inhibitor|
03185|049|D|therapy between HIV and non-HIV patients with first episode ACS on dual|
03185|050|D|antiplatelet therapy.  Study evaluated residual platelet aggregation (RPA),|
03185|051|D|P2Y12 assay (PRU), and VASP platelet reactivity index (VASP-PRI).  HIV|
03185|052|D|patients were all on antiretroviral (ARV) therapy, most commonly with|
03185|053|D|protease inhibitors (darunavir, lopinavir, atazanavir, and indinavir in|
03185|054|D|combination with ritonavir in all but two patients).  Patients on ARV|
03185|055|D|containing protease inhibitors compared to other combinations had increased|
03185|056|D|platelet reactivity to P2Y12 inhibitors and higher prevalence of high|
03185|057|D|residual platelet reactivity (HPR) (OR 4.4 (95%CI 1.1-18.1) with RPA, P =|
03185|058|D|0.04; OR 3.1 (95%CI = 0.84-11.5) with VASP-PRI; P = 0.09, and OR 4.3 (95%CI|
03185|059|D|1.02-18.1) with PRU, P = 0.047).  Patients with CD4 T cell count lower than|
03185|060|D|350/mm3 also had consistently increased platelet reactivity to P2Y12|
03185|061|D|inhibitors and higher prevalence of HPR (OR 3.41 (95%CI 0.60-19.4) with RPA,|
03185|062|D|P = 0.17; OR 7.1 (95%CI 0.94-54.2) with VASP-PRI, P = 0.06; and OR 7.9|
03185|063|D|(95%CI 1.42-44.8) with PRU, P = 0.002), although this association was not|
03185|064|D|significant for all three tests.(6)|
03185|065|D|   Selected strong CYP3A4 inhibitors linked to this monograph include:|
03185|066|D|adagrasib, boceprevir, ceritinib, clarithromycin, idelalisib, itraconazole,|
03185|067|D|josamycin, levoketoconazole, mibefradil, nefazodone, posaconazole,|
03185|068|D|ribociclib, telaprevir, telithromycin, tucatinib, and troleandomycin.(7)|
03185|069|B||
03185|070|R|REFERENCES:|
03185|071|B||
03185|072|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
03185|073|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
03185|074|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
03185|075|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
03185|076|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
03185|077|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
03185|078|R|  38(1):92-9.|5
03185|079|R|3.Wang ZY, Chen M, Zhu LL, Yu LS, Zeng S, Xiang MX, Zhou Q. Pharmacokinetic|6
03185|080|R|  drug interactions with clopidogrel: updated review and risk management in|6
03185|081|R|  combination therapy. Ther Clin Risk Manag 2015;11:449-67.|6
03185|082|R|4.Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT,|2
03185|083|R|  Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by|2
03185|084|R|  ketoconazole affects prasugrel and clopidogrel pharmacokinetics and|2
03185|085|R|  pharmacodynamics differently. Clin Pharmacol Ther 2007 May;81(5):735-41.|2
03185|086|R|5.Marsousi N, Daali Y, Fontana P, Reny JL, Ancrenaz-Sirot V, Calmy A, Rudaz|2
03185|087|R|  S, Desmeules JA, Samer CF. Impact of Boosted Antiretroviral Therapy on the|2
03185|088|R|  Pharmacokinetics and Efficacy of  Clopidogrel and Prasugrel Active|2
03185|089|R|  Metabolites. Clin Pharmacokinet 2018 Oct;57(10):1347-1354.|2
03185|090|R|6.Hauguel-Moreau M, Boccara F, Boyd A, Salem JE, Brugier D, Curjol A, Hulot|2
03185|091|R|  JS, Kerneis M, Galier S, Cohen A, Montalescot G, Collet JP, Silvain J.|2
03185|092|R|  Platelet reactivity in human immunodeficiency virus infected patients on|2
03185|093|R|  dual antiplatelet therapy for an acute coronary syndrome: the EVERE2ST-HIV|2
03185|094|R|  study. Eur Heart J 2017 Jun 1;38(21):1676-1686.|2
03185|095|R|7.This information is based on an extract from the Certara Drug Interaction|6
03185|096|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03186|001|T|MONOGRAPH TITLE:  Erdafitinib/Strong CYP3A4 Inducers|
03186|002|B||
03186|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03186|004|L|of severe adverse interaction.|
03186|005|B||
03186|006|A|MECHANISM OF ACTION:  Erdafitinib is a substrate of CYP2C9 and CYP3A4.|
03186|007|A|Strong inducers of CYP2C9 or CYP3A4 may induce the metabolism of|
03186|008|A|erdafitinib.(1)|
03186|009|B||
03186|010|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03186|011|E|may result in decreased levels and effectiveness of erdafitinib.(1)|
03186|012|B||
03186|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03186|014|P|of the inducer for longer than 1-2 weeks.|
03186|015|B||
03186|016|M|PATIENT MANAGEMENT:  The manufacturer of erdafitinib states that concurrent|
03186|017|M|use with strong CYP3A4 inducers should be avoided. (1)|
03186|018|B||
03186|019|D|DISCUSSION:  Simulations suggested that rifampin (a strong CYP3A4 and|
03186|020|D|moderate CYP2C9 inducer) may significantly decrease the Cmax and AUC of|
03186|021|D|erdafitinib.(1)|
03186|022|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03186|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03186|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03186|025|D|rifapentine, and St. John's wort.(2-3)|
03186|026|B||
03186|027|R|REFERENCES:|
03186|028|B||
03186|029|R|1.Balversa (erdafitinib) US prescribing information. Janssen|1
03186|030|R|  Pharmaceuticals, Inc. January, 2024.|1
03186|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03186|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03186|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03186|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03186|035|R|  11/14/2017.|1
03186|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
03186|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03187|001|T|MONOGRAPH TITLE:  Erdafitinib/Moderate CYP3A4 Inducers|
03187|002|B||
03187|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03187|004|L|of severe adverse interaction.|
03187|005|B||
03187|006|A|MECHANISM OF ACTION:  Erdafitinib is a substrate of CYP2C9 and CYP3A4.|
03187|007|A|Moderate inducers of CYP3A4 may induce the metabolism of erdafitinib.(1)|
03187|008|B||
03187|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
03187|010|E|in decreased levels and effectiveness of erdafitinib.(1)|
03187|011|B||
03187|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03187|013|P|of the inducer for longer than 1-2 weeks.|
03187|014|B||
03187|015|M|PATIENT MANAGEMENT:  The manufacturer of erdafitinib states that if a|
03187|016|M|moderate CYP3A4 inducer must be co-administered, increase the erdafitinib|
03187|017|M|dose to 9 mg daily.|
03187|018|M|   If a moderate CYP3A4 inducer is discontinued, continue erdafitinib at the|
03187|019|M|same dose in the absence of drug-related toxicity.(1)|
03187|020|B||
03187|021|D|DISCUSSION:  Carbamazepine (a strong CYP3A4 inducer and weak CYP2C9 inducer)|
03187|022|D|decreased the mean maximum concentration (Cmax) and area-under-curve (AUC)|
03187|023|D|of erdafitinib by 78% and 45%, respectively.(1)|
03187|024|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03187|025|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
03187|026|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
03187|027|D|pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat|
03187|028|D|ethyl, thioridazine, and tovorafenib.(2-3)|
03187|029|B||
03187|030|R|REFERENCES:|
03187|031|B||
03187|032|R|1.Balversa (erdafitinib) US prescribing information. Janssen|1
03187|033|R|  Pharmaceuticals, Inc. January, 2024.|1
03187|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
03187|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03187|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03187|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03187|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03187|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03187|040|R|  11/14/2017.|1
03188|001|T|MONOGRAPH TITLE:  Erdafitinib/Serum Phosphate Level-Altering Drugs|
03188|002|B||
03188|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03188|004|L|of severe adverse interaction.|
03188|005|B||
03188|006|A|MECHANISM OF ACTION:  Medications that alter serum phosphate may interfere|
03188|007|A|with interpretation of phosphate levels that are needed to determine initial|
03188|008|A|erdafitinib dose.(1)|
03188|009|B||
03188|010|E|CLINICAL EFFECTS:  Serum phosphate levels that are elevated by concomitant|
03188|011|E|medications may result in an inappropriately low dose and decreased|
03188|012|E|effectiveness of erdafitinib.|
03188|013|E|   Serum phosphate levels that are decreased by concomitant medications may|
03188|014|E|result in an inappropriately high dose and increased toxicity from|
03188|015|E|erdafitinib.|
03188|016|B||
03188|017|P|PREDISPOSING FACTORS:  None determined.|
03188|018|B||
03188|019|M|PATIENT MANAGEMENT:  The manufacturer of erdafitinib states that agents that|
03188|020|M|alter serum phosphate levels should be avoided before the initial dose|
03188|021|M|increase period for erdafitinib based on serum phosphate levels (days 14 to|
03188|022|M|21).(1)|
03188|023|B||
03188|024|D|DISCUSSION:  Concomitant administration of serum phosphate level-altering|
03188|025|D|agents during the initial dose increase period of erdafitinib based on serum|
03188|026|D|phosphate levels (days 14 to 21) may interfere with serum phospate levels|
03188|027|D|and lead to incorrect dosing of erdafitinib.(1)|
03188|028|D|   Agents that may alter serum phosphate levels linked to this monograph|
03188|029|D|include: aluminum carbonate, aluminum hydroxide, calcium acetate, calcium|
03188|030|D|carbonate, calcium citrate, cod liver oil, ferric citrate, lanthanum,|
03188|031|D|magnesium carbonate, magnesium hydroxide, potassium phosphate, sevelamer,|
03188|032|D|sodium phosphate, sucroferric oxyhydroxide, tenapanor, and vitamin D.(1)|
03188|033|B||
03188|034|R|REFERENCE:|
03188|035|B||
03188|036|R|1.Balversa (erdafitinib) US prescribing information. Janssen|1
03188|037|R|  Pharmaceuticals, Inc. January, 2024.|1
03189|001|T|MONOGRAPH TITLE:  Atorvastatin; Lovastatin; Simvastatin/Palbociclib|
03189|002|B||
03189|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03189|004|L|take action as needed.|
03189|005|B||
03189|006|A|MECHANISM OF ACTION:  Palbociclib is a weak CYP3A4 inhibitor.(1)|
03189|007|A|Atorvastatin, lovastatin, and simvastatin are sensitive CYP3A4|
03189|008|A|substrates.(2)  Palbociclib may inhibit the metabolism of atorvastatin,|
03189|009|A|lovastatin, and simvastatin.|
03189|010|B||
03189|011|E|CLINICAL EFFECTS:  Concurrent palbociclib may result in increased levels of|
03189|012|E|atorvastatin, lovastatin, or simvastatin, which may result in hepatic|
03189|013|E|injury, myopathy or rhabdomyolysis.  Symptoms of rhabdomyolysis include|
03189|014|E|muscle pain, tenderness, weakness, elevated creatine kinase levels, and|
03189|015|E|reddish-brown, heme positive urine.|
03189|016|B||
03189|017|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03189|018|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03189|019|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03189|020|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03189|021|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03189|022|P|transporter OATP1B1 may have increased statin concentrations and be|
03189|023|P|predisposed to myopathy or rhabdomyolysis.|
03189|024|B||
03189|025|M|PATIENT MANAGEMENT:  The manufacturer of palbociclib states that drug levels|
03189|026|M|of sensitive CYP3A4 substrates like atorvastatin, lovastatin, and|
03189|027|M|simvastatin may be elevated by palbociclib and to consider dose reduction of|
03189|028|M|the CYP3A4 substrate.(1)|
03189|029|M|   Consider the risks versus benefits of continuing antilipidemic therapy.|
03189|030|M|Monitor patients receiving concurrent therapy for signs of rhabdomyolysis.|
03189|031|B||
03189|032|D|DISCUSSION:  A study in 26 healthy women found that palbociclib at steady|
03189|033|D|state increased the maximum concentration (Cmax) and area-under-curve (AUC)|
03189|034|D|of concomitant midazolam (a CYP3A4 substrate) by 37 % and 61 %,|
03189|035|D|respectively, compared to midazolam alone.(3)|
03189|036|D|   A case report described a potential interaction in which palbociclib (125|
03189|037|D|mg daily) was initiated in a patient with metastatic breast cancer who had|
03189|038|D|been taking atorvastatin (40 mg daily) for years.  After two cycles of|
03189|039|D|palbociclib, the patient developed rapidly progressive muscle pain and|
03189|040|D|weakness, elevated creatinine kinase of 14,572 units/L, and died after 8|
03189|041|D|days of hospitalization.(4)|
03189|042|D|   A case of transaminitis and rhabdomyolysis was reported during a phase 2|
03189|043|D|trial of palbociclib in a patient on concomitant simvastatin (80 mg daily).|
03189|044|D|The symptoms improved upon discontinuation of palbociclib.(4,5)|
03189|045|D|   In a PKPB model, concurrent use of atorvastatin (40 mg daily) with|
03189|046|D|palbociclib (125 mg daily for 2 months) increased the simulated Cmax ratio|
03189|047|D|and AUC ratio of atorvastatin by 1.16 and 1.36, respectively, and increased|
03189|048|D|the simulated Cmax ratio and AUC ratio of atorvastatin lactone by 1.58 and|
03189|049|D|1.73, respectively.(6)|
03189|050|B||
03189|051|R|REFERENCES:|
03189|052|B||
03189|053|R|1.Ibrance (palbociclib) US prescribing information. Pfizer Labs September,|1
03189|054|R|  2023.|1
03189|055|R|2.This information is based on an extract from the Certara Drug Interaction|6
03189|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03189|057|R|3.Hoffman Justin T, Plotka Anna, OGorman Melissa, Loi Cho-Ming, Kirkovsky|2
03189|058|R|  Leonid, Gallo-Stampino Corrado, Wang Diane. Abstract CT419: A phase 1|2
03189|059|R|  randomized, open-label, 2-sequence, 2-period crossover study of the effect|2
03189|060|R|  of multiple doses of palbociclib (PD-0332991) on midazolam|2
03189|061|R|  pharmacokinetics in healthy women of non-childbearing potential. Cancer|2
03189|062|R|  Res 2014/10/01;74(19 Supplement):CT419.|2
03189|063|R|4.Nelson KL, Stenehjem D, Driscoll M, Gilcrease GW. Fatal Statin-Induced|3
03189|064|R|  Rhabdomyolysis by Possible Interaction with Palbociclib. Front Oncol 2017;|3
03189|065|R|  7:150.|3
03189|066|R|5.Gopalan PK, Villegas AG, Cao C, Pinder-Schenck M, Chiappori A, Hou W,|2
03189|067|R|  Zajac-Kaye M, Ivey AM, Kaye FJ. CDK4/6 inhibition stabilizes disease in|2
03189|068|R|  patients with p16-null non-small cell lung cancer and is synergistic with|2
03189|069|R|  mTOR inhibition. Oncotarget 2018 Dec 21;9(100):37352-37366.|2
03189|070|R|6.Li S, Yu Y, Jin Z, Dai Y, Lin H, Jiao Z, Ma G, Cai W, Han B, Xiang X.|2
03189|071|R|  Prediction of pharmacokinetic drug-drug interactions causing|2
03189|072|R|  atorvastatin-induced rhabdomyolysis using physiologically based|2
03189|073|R|  pharmacokinetic modelling. Biomed Pharmacother 2019 Sep 10;119:109416.|2
03190|001|T|MONOGRAPH TITLE:  Dolutegravir/St. John's Wort|
03190|002|B||
03190|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
03190|004|L|Assess the risk to the patient and take action as needed.|
03190|005|B||
03190|006|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of|
03190|007|A|dolutegravir through UGT1 and CYP3A4.(1-2)|
03190|008|B||
03190|009|E|CLINICAL EFFECTS:  Concurrent use of St. John's wort and dolutegravir may|
03190|010|E|result in decreased levels and clinical effectiveness of dolutegravir.(1-4)|
03190|011|B||
03190|012|P|PREDISPOSING FACTORS:  None determined.|
03190|013|B||
03190|014|M|PATIENT MANAGEMENT:  Recommendations for concomitant use of dolutegravir and|
03190|015|M|St. John's wort differ by region.  The US manufacturer of dolutegravir|
03190|016|M|states that concurrent use should be avoided due to insufficient data to|
03190|017|M|make dosing recommendations for concomitant use.(3)  The US Department of|
03190|018|M|Health and Human Services antiretroviral guidelines state not to|
03190|019|M|coadminister the two agents.(4)  The Canadian and UK manufacturers of|
03190|020|M|dolutegravir state that the dosage of dolutegravir should be 50 mg twice|
03190|021|M|daily when used concurrently with St. John's wort.  When using the|
03190|022|M|combination abacavir-dolutegravir-lamivudine product, an additional 50 mg|
03190|023|M|dolutegravir tablet should be taken 12 hours apart from the combination|
03190|024|M|product.  In pediatric patients, increase the weight-based once-daily dose|
03190|025|M|to twice daily.  Refer to the current labeling for the specific dosing|
03190|026|M|recommendations.  Alternative combinations that do not induce metabolic|
03190|027|M|enzymes should be considered when possible for INSTI-resistant|
03190|028|M|patients.(1,2)|
03190|029|B||
03190|030|D|DISCUSSION:  The concomitant use of dolutegravir and St. John's wort has not|
03190|031|D|been studied.  A decrease in dolutegravir concentrations is predicted due to|
03190|032|D|expected induction of the CYP3A4 and UGT1A1 enzymes.(1,2)|
03190|033|B||
03190|034|R|REFERENCES:|
03190|035|B||
03190|036|R|1.Tivicay (dolutegravir) Canadian prescribing information. ViiV Healthcare|1
03190|037|R|  ULC August, 2018.|1
03190|038|R|2.Tivicay (dolutegravir sodium) UK summary of product characteristics. ViiV|1
03190|039|R|  Healthcare UK Ltd January, 2021.|1
03190|040|R|3.Tivicay (dolutegravir) US prescribing information. GlaxoSmithKline|1
03190|041|R|  October, 2022.|1
03190|042|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03190|043|R|  for the use of antiretroviral agents in HIV-1-infected adults and|6
03190|044|R|  adolescents. Department of Health and Human Services. Available at|6
03190|045|R|  http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf|6
03190|046|R|  . Accessed March 31, 2016..|6
03191|001|T|MONOGRAPH TITLE:  Terlipressin/QT Prolonging Agents (mono deleted|
03191|002|T|08/20/2020)|
03191|003|B||
03191|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03191|005|L|take action as needed.|
03191|006|B||
03191|007|A|MECHANISM OF ACTION:  Terlipressin has been shown to prolong the QT|
03191|008|A|interval.  Concurrent use with QT prolonging agents may result in additive|
03191|009|A|effects on the QT interval.(1)|
03191|010|B||
03191|011|E|CLINICAL EFFECTS:  The concurrent use of terlipressin with agents that|
03191|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03191|013|E|arrhythmias, including torsades de pointes.(1)|
03191|014|B||
03191|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03191|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03191|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03191|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03191|019|P|female gender, or advanced age.(2)|
03191|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03191|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03191|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03191|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03191|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03191|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03191|026|P|dysfunction).(2)|
03191|027|B||
03191|028|M|PATIENT MANAGEMENT:  Use extreme caution when using terlipressin|
03191|029|M|concurrently with other agents that can prolong the QT interval.  When|
03191|030|M|concurrent therapy cannot be avoided, obtain ECGs and electrolyte values|
03191|031|M|(serum calcium, magnesium, and potassium) prior to the start of treatment,|
03191|032|M|after initiation of any drug known to prolong the QT interval, and|
03191|033|M|periodically monitor during therapy.  Correct any electrolyte abnormalities.|
03191|034|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03191|035|M|fainting.(2)|
03191|036|B||
03191|037|D|DISCUSSION:  QT prolongation and torsades de pointes have been reported with|
03191|038|D|terlipressin.  In a study in 41 patients with HRS type 1, terlipressin|
03191|039|D|increased baseline QTcF by 8msec.(1)|
03191|040|D|   Agents that are linked to this monograph may have varying degrees of|
03191|041|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03191|042|D|been shown to prolong the QTc interval either through their mechanism of|
03191|043|D|action, through studies on their effects on the QTc interval, or through|
03191|044|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03191|045|D|and/or postmarketing reports.(3)|
03191|046|B||
03191|047|R|REFERENCES:|
03191|048|B||
03191|049|R|1.Lucassin (terlipressin) Australian Prescribing Information. Mallinckrodt|1
03191|050|R|  Pharmaceuticals June 7, 2018.|1
03191|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03191|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03191|053|R|  settings: a scientific statement from the American Heart Association and|6
03191|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03191|055|R|  2;55(9):934-47.|6
03191|056|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03191|057|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03191|058|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03191|059|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03192|001|T|MONOGRAPH TITLE:  Fluorouracil & Fluorouracil Prodrugs/Brivudine|
03192|002|B||
03192|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03192|004|L|is contraindicated and generally should not be dispensed or administered to|
03192|005|L|the same patient.|
03192|006|B||
03192|007|A|MECHANISM OF ACTION:  Brivudine is an irreversible inhibitor of|
03192|008|A|dihydropyrimidine dehydrogenase, which catalyzes the rate-limiting step in|
03192|009|A|the catabolism of fluorouracil.(1-5)  Brivudine may decrease the clearance|
03192|010|A|and increase the toxicity of fluorouracil.|
03192|011|B||
03192|012|E|CLINICAL EFFECTS:  Concurrent use of brivudine with fluorouracil or|
03192|013|E|fluorouracil prodrugs (e.g., capecitabine, tegafur) may result in elevated|
03192|014|E|levels of fluorouracil and serious toxicity, including melenic diarrhea,|
03192|015|E|mucositis, hand-foot syndrome, pancytopenia, and death.(1-5)|
03192|016|B||
03192|017|P|PREDISPOSING FACTORS:  Patients who are intermediate or poor|
03192|018|P|dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no|
03192|019|P|DPYD function.  Since DPYD is the rate-limiting enzyme involved in|
03192|020|P|fluoropyrimidine metabolism, these patients may be more susceptible to the|
03192|021|P|effects of this interaction.(3)|
03192|022|B||
03192|023|M|PATIENT MANAGEMENT:  The use of fluorouracil or fluorouracil prodrugs is|
03192|024|M|contraindicated during and for 4 weeks after therapy with brivudine.|
03192|025|M|Treatment with brivudine can be started 24 hours after the last dose of|
03192|026|M|fluorouracil or fluorouracil prodrug.  If brivudine is coadministered with|
03192|027|M|fluorouracil or fluorouracil prodrugs, immediate hospitalization is|
03192|028|M|recommended and effective measures should be taken to reduce the toxicity of|
03192|029|M|capecitabine, including prevention of systemic infections and|
03192|030|M|dehydration.(1)|
03192|031|B||
03192|032|D|DISCUSSION:  Brivudine inhibition of dihydropyrimidine dehydrogenase has|
03192|033|D|been reported to cause a 5- to 15-fold increase in 5-fluorouracil (5-FU)|
03192|034|D|concentrations.(2)|
03192|035|D|   In June 2012, the Spanish Agency of Medicines and Health Products (AEMPS)|
03192|036|D|reported that 29 cases of concomitant use of a fluoropyrimidine and|
03192|037|D|brivudine had occurred in Europe, with 23 of the cases resulting in|
03192|038|D|death.(6)  In September 2017, the AEMPS issued an update that an additional|
03192|039|D|7 fatalities had occurred since 2012 as a result of this drug|
03192|040|D|combination.(7)|
03192|041|D|   In a case report, an 80-year-old woman with metastatic colon cancer on|
03192|042|D|capecitabine was given brivudine for herpes zoster.  She took two doses of|
03192|043|D|brivudine prior to stopping therapy due to rash and mucositis.|
03192|044|D|Nevertheless, two weeks later, she was hospitalized with skin lesions that|
03192|045|D|progressed to Stevens-Johnson Syndrome, leukopenia, and thrombocytopenia.|
03192|046|D|She developed septic shock and ultimately died.(2)|
03192|047|D|   Another two case reports describe similar patients with metastatic colon|
03192|048|D|cancer who received combinations of brivudine with 5-FU.  One patient had|
03192|049|D|overlapping therapy for one day, and the other received 5-FU four days after|
03192|050|D|stopping brivudine.  Both developed mucositis, pancytopenia, and respiratory|
03192|051|D|failure and died.(3,4)|
03192|052|D|   A 66-year-old woman with metastatic breast cancer took brivudine on the|
03192|053|D|last 4 days of a chemotherapy cycle that included capecitabine.  She was|
03192|054|D|hospitalized for over 3 weeks with hand-foot syndrome, severe mucositis|
03192|055|D|requiring parenteral nutrition, pancytopenia requiring filgrastim, platelet|
03192|056|D|transfusion, and blood transfusion, and sepsis.  She recovered from symptoms|
03192|057|D|of hand-food syndrome and mucositis after about 6 weeks.(5)|
03192|058|B||
03192|059|R|REFERENCES:|
03192|060|B||
03192|061|R|1.Xeloda (capecitabine) UK Summary of Product Characteristics. Roche|1
03192|062|R|  Products Limited April, 2019.|1
03192|063|R|2.Ratz Bravo AE, Hofer S, Krahenbuhl S, Ludwig C. Fatal drug-drug|3
03192|064|R|  interaction of brivudine and capecitabine. Acta Oncol 2009;48(4):631-3.|3
03192|065|R|3.Garcia Herrera AN, Moncayola Vicen JC. Lethal interaction between|3
03192|066|R|  5-fluorouracil and brivudine. An Sist Sanit Navar 2018 Aug 29;|3
03192|067|R|  41(2):277-278.|3
03192|068|R|4.Garcia Fernandez V, Garrido Arevalo M, Labrada Gonzalez E, Hidalgo Correas|3
03192|069|R|  FJ. Fatal drug-drug interaction between 5-fluorouracil and brivudine. Farm|3
03192|070|R|  Hosp 2013 Jan-Feb;37(1):72-3.|3
03192|071|R|5.Baena-Canada JM, Martinez MJ, Garcia-Olmedo O, Jimenez-Barcenas R,|3
03192|072|R|  Muriel-Cueto P. Interaction between capecitabine and brivudin in a patient|3
03192|073|R|  with breast cancer. Nat Rev Clin Oncol 2010 Jan;7(1):55-8.|3
03192|074|R|6.Spanish Agency of Medicines and Health Products (AEMPS). Safety Note:|1
03192|075|R|  Brivudine (Brinix, Nervinex and Nervol): Life-Threatening Interaction with|1
03192|076|R|  5-Fluoropyrimidines. Available at:|1
03192|077|R|  https://www.aemps.gob.es/informa/notasInformativas/medicamentosUsoHumano/s|1
03192|078|R|  eguridad/2012/NI-MUH_FV_07-2012.htm June 1, 2012.|1
03192|079|R|7.Spanish Agency of Medicines and Health Products (AEMPS). Safety Note:|1
03192|080|R|  Brivudine (Nervinex): reminder that its administration is contraindicated|1
03192|081|R|  together with antineoplastics, especially 5-fluoropyrimidines, due to the|1
03192|082|R|  potentially deadly interaction. Available at:|1
03192|083|R|  https://www.aemps.gob.es/informa/notasInformativas/medicamentosUsoHumano/s|1
03192|084|R|  eguridad/2017/NI-MUH_FV_09-2017-brivudina-Nervinex.htm September 7, 2017.|1
03193|001|T|MONOGRAPH TITLE:  Cannabidiol/Valproate Derivatives|
03193|002|B||
03193|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03193|004|L|of severe adverse interaction.|
03193|005|B||
03193|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown, but may involve|
03193|007|A|possible additive or synergistic effects on the liver.|
03193|008|B||
03193|009|E|CLINICAL EFFECTS:  Concurrent use of cannabidiol and valproate derivatives|
03193|010|E|may result in hepatocellular injury.(1)|
03193|011|B||
03193|012|P|PREDISPOSING FACTORS:  Patients with baseline transaminase levels above the|
03193|013|P|upper limit of normal and/or taking clobazam may be predisposed to elevated|
03193|014|P|transaminase levels with cannabidiol.(1)|
03193|015|B||
03193|016|M|PATIENT MANAGEMENT:  Consider more frequent monitoring of liver enzymes in|
03193|017|M|patients receiving concurrent cannabidiol and valproate derivatives.  If|
03193|018|M|liver enzyme elevations occur, consider dosage adjustment or discontinuation|
03193|019|M|of valproate.(1)|
03193|020|M|   Monitor patients for and instruct patients to report symptoms of hepatic|
03193|021|M|dysfunction (unexplained nausea, vomiting, right upper quadrant abdominal|
03193|022|M|pain, fever, itching, fatigue, anorexia, or jaundice and/or dark urine).  In|
03193|023|M|symptomatic patients, promptly measure serum transaminases and total|
03193|024|M|bilirubin and interrupt/discontinue cannabidiol therapy.(1)|
03193|025|M|   Discontinue cannabidiol in patients with transaminase levels greater than|
03193|026|M|3 times the upper limit of normal (ULN), or bilirubin levels greater than 2|
03193|027|M|times the ULN, or sustained transaminase elevations greater than 5 times the|
03193|028|M|ULN.(1)|
03193|029|B||
03193|030|D|DISCUSSION:  The majority of alanine aminotransferase (ALT) elevations with|
03193|031|D|cannabidiol in clinical trials occurred with concurrent use of valproate.|
03193|032|D|The incidence of ALT elevations greater than 3 times the upper limit of|
03193|033|D|normal (ULN) was 21% in patients taking concurrent valproate compared with|
03193|034|D|3% in patients taking cannabidiol alone.(1)|
03193|035|D|   In a double blind, placebo controlled, clinical trial in patients with|
03193|036|D|Dravet syndrome, an increase in the incidence of ALT elevations greater than|
03193|037|D|3 times the ULN was observed in 12% of patients taking cannabidiol (10 or 20|
03193|038|D|mg/kg/day), all patients were concurrently taking valproate.(3)|
03193|039|D|   A study in 39 adults and 42 children examined the effects of concurrent|
03193|040|D|cannabidiol and antiepileptic drugs.  There were 8 adults and 14 children on|
03193|041|D|concurrent valproate.  Elevated liver function tests occurred in 1 adult and|
03193|042|D|4 children taking concurrent valproate and no patients not on concurrent|
03193|043|D|valproate.  There were no effects on valproate levels. (2)|
03193|044|B||
03193|045|R|REFERENCES:|
03193|046|B||
03193|047|R|1.Epidiolex (cannabidiol) US prescribing information. Greenwich Biosciences,|1
03193|048|R|  Inc. June, 2025.|1
03193|049|R|2.Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between|2
03193|050|R|  cannabidiol and commonly used antiepileptic drugs. Epilepsia 2017 Sep;|2
03193|051|R|  58(9):1586-1592.|2
03193|052|R|3.Miller I, Scheffer IE, Gunning B, Sanchez-Carpintero R, Gil-Nagel A, Perry|2
03193|053|R|  MS, Saneto RP, Checketts D, Dunayevich E, Knappertz V. Dose-Ranging Effect|2
03193|054|R|  of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency|2
03193|055|R|  in Dravet Syndrome: A Randomized Clinical Trial. JAMA Neurol 2020 May 1;|2
03193|056|R|  77(5):613-621.|2
03194|001|T|MONOGRAPH TITLE:  Tacrolimus/Dronedarone|
03194|002|B||
03194|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03194|004|L|of severe adverse interaction.|
03194|005|B||
03194|006|A|MECHANISM OF ACTION:  Dronedarone may inhibit the metabolism of tacrolimus|
03194|007|A|via CYP3A4.(1,2)|
03194|008|A|   In addition, concurrent use of dronedarone and agents known to prolong|
03194|009|A|the QT interval may result in additive or synergistic effects on the QTc|
03194|010|A|interval.(1,2)|
03194|011|B||
03194|012|E|CLINICAL EFFECTS:  Concurrent dronedarone and tacrolimus may result in|
03194|013|E|elevated tacrolimus levels.(1,2)|
03194|014|E|   In addition, concurrent administration of dronedarone and tacrolimus may|
03194|015|E|result in prolongation of the QTc interval and life-threatening cardiac|
03194|016|E|arrhythmias, including torsades de pointes.|
03194|017|B||
03194|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03194|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03194|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03194|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03194|022|P|gender, or advanced age.(4)|
03194|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03194|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03194|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03194|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03194|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03194|028|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03194|029|P|dysfunction).(4)|
03194|030|B||
03194|031|M|PATIENT MANAGEMENT:  If concurrent use with tacrolimus and dronedarone is|
03194|032|M|required, monitor tacrolimus levels closely.  The dose of tacrolimus may|
03194|033|M|need to be adjusted.(1)|
03194|034|M|   The US manufacturer of dronedarone states that the use of drugs or herbal|
03194|035|M|products that are known to prolong the QTc interval, including tacrolimus,|
03194|036|M|is contraindicated.(2)|
03194|037|M|   When concurrent therapy of dronedarone and possible QT prolonging agents|
03194|038|M|such as tacrolimus is warranted, consider obtaining serum calcium,|
03194|039|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03194|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03194|041|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03194|042|B||
03194|043|D|DISCUSSION:  Dronedarone may increase levels of tacrolimus via CYP3A4.(1,2)|
03194|044|B||
03194|045|R|REFERENCES:|
03194|046|B||
03194|047|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
03194|048|R|  August, 2023.|1
03194|049|R|2.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
03194|050|R|  November, 2020.|1
03194|051|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03194|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03194|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03194|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03194|055|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03194|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03194|057|R|  settings: a scientific statement from the American Heart Association and|6
03194|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03194|059|R|  2;55(9):934-47.|6
03195|001|T|MONOGRAPH TITLE:  Cyclobenzaprine/Selected SSRIs; SNRIs|
03195|002|B||
03195|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03195|004|L|take action as needed.|
03195|005|B||
03195|006|A|MECHANISM OF ACTION:  Cyclobenzaprine and SSRIs or SNRIs may have additive|
03195|007|A|effects on serotonin levels.(1)|
03195|008|B||
03195|009|E|CLINICAL EFFECTS:  Concurrent administration of cyclobenzaprine with|
03195|010|E|citalopram, duloxetine, escitalopram, levomilnacipran, milnacipran,|
03195|011|E|nefazodone, or vortioxetine may result in serotonin syndrome.  Symptoms of|
03195|012|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
03195|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
03195|014|B||
03195|015|P|PREDISPOSING FACTORS:  Predisposing factors include elderly, hepatic|
03195|016|P|dysfunction and use of multiple agents which increase central serotonin|
03195|017|P|levels.  Chronic use of cyclobenzaprine or high doses of citalopram or|
03195|018|P|escitalopram would also be expected to increase the risk for serotonin|
03195|019|P|toxicity.(1)|
03195|020|B||
03195|021|M|PATIENT MANAGEMENT:  The US manufacturer of cyclobenzaprine recommends|
03195|022|M|limiting use to short term duration, no more than two to three weeks.  Use|
03195|023|M|alternative therapy whenever possible, particularly in patients with hepatic|
03195|024|M|impairment.(1)|
03195|025|M|   If concurrent therapy is warranted, patients should be monitored for|
03195|026|M|signs and symptoms of serotonin syndrome, and seizure activity.  Instruct|
03195|027|M|patients to report muscle twitching, tremors, shivering and stiffness,|
03195|028|M|fever, heavy sweating, heart palpitations, restlessness, confusion,|
03195|029|M|agitation, trouble with coordination, or severe diarrhea.|
03195|030|B||
03195|031|D|DISCUSSION:  Case reports documenting serotonin syndrome with|
03195|032|D|cyclobenzaprine and other serotonergic agents are described.  The risk of|
03195|033|D|serotonin syndrome with cyclobenzaprine and TCAs may also occur based on|
03195|034|D|serotonin activity of both agents.(2,3)|
03195|035|D|   A case report of a 70 year old female on phenelzine (non-selective MAOI)|
03195|036|D|15 mg four times daily for several years developed serotonin syndrome after|
03195|037|D|the third dose of cyclobenzaprine 10 mg three times daily.  After|
03195|038|D|discontinuation of both cyclobenzaprine and phenelzine, symptoms resolved|
03195|039|D|within three days.  Within the following month, the patient was restarted on|
03195|040|D|phenelzine without any further sequelae.(4)|
03195|041|D|   A case report of a 53 year old male on duloxetine (SNRI) 60 mg daily|
03195|042|D|developed symptoms of serotonin syndrome shortly after initiation of|
03195|043|D|cyclobenzaprine 10 mg three times daily.  Both cyclobenzaprine and|
03195|044|D|duloxetine were stopped and cyproheptadine was given with resolution of|
03195|045|D|symptoms.(4)|
03195|046|D|   A case report of a 27 year old female on escitalopram (SSRI) 10 mg daily|
03195|047|D|presented with serotonin syndrome after an overdose of 5-6 cyclobenzaprine|
03195|048|D|10 mg tablets.  The patient was treated with symptomatic care and|
03195|049|D|cyproheptadine with resolution of symptoms on day two and discharged with|
03195|050|D|instructions to discontinue cyclobenzaprine use.(5)|
03195|051|B||
03195|052|R|REFERENCES:|
03195|053|B||
03195|054|R|1.Flexeril (cyclobenzaprine) US prescribing information. McNeil Consumer and|1
03195|055|R|  Speciality Pharmaceuticals April, 2013.|1
03195|056|R|2.Goodman-Gilman A. In Gilman AG, Rall TW, Nies AS, Taylor P, editors:|6
03195|057|R|  Goodman and Gilman's The Phamacological Basis of Therapeutics. 8th|6
03195|058|R|  edition. Elmsford, New York: Pergamon Press, Inc. 1990.|6
03195|059|R|3.Mestres J, Seifert SA, Oprea TI. Linking pharmacology to clinical reports:|5
03195|060|R|  cyclobenzaprine and its possible association with serotonin syndrome. Clin|5
03195|061|R|  Pharmacol Ther 2011 Nov;90(5):662-5.|5
03195|062|R|4.Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the|3
03195|063|R|  interaction of cyclobenzaprine with other serotoninergic drugs. Anesth|3
03195|064|R|  Analg 2006 Dec;103(6):1466-8.|3
03195|065|R|5.Day LT, Jeanmonod RK. Serotonin syndrome in a patient taking Lexapro and|3
03195|066|R|  Flexeril: a case report. Am J Emerg Med 2008 Nov;26(9):1069.e1-3.|3
03196|001|T|MONOGRAPH TITLE:  Clopidogrel/Cannabidiol|
03196|002|B||
03196|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03196|004|L|of severe adverse interaction.|
03196|005|B||
03196|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
03196|007|A|active metabolite via a 2 step process.  The first conversion step is|
03196|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
03196|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
03196|010|A|thought to be the more important enzyme involved in formation of the|
03196|011|A|pharmacologically active metabolite.(1)|
03196|012|A|   Cannabidiol may inhibit the metabolism of clopidogrel to its active form|
03196|013|A|by CYP2C19.(1)|
03196|014|B||
03196|015|E|CLINICAL EFFECTS:  Concurrent use of cannabidiol may result in decreased|
03196|016|E|clopidogrel effectiveness, resulting in increased risk of adverse cardiac|
03196|017|E|events.(1)|
03196|018|B||
03196|019|P|PREDISPOSING FACTORS:  None determined.|
03196|020|B||
03196|021|M|PATIENT MANAGEMENT:  The US manufacturer of clopidogrel states that|
03196|022|M|alternatives to clopidogrel should be considered in patients who are poor|
03196|023|M|metabolizers of CYP2C19.(1)  It would be prudent to assume that patients|
03196|024|M|taking inhibitors of CYP2C19, such as cannabidiol, are decreased activity of|
03196|025|M|this isoenzyme.|
03196|026|M|   Consider alternatives to cannabidiol in patients stabilized on|
03196|027|M|clopidogrel and alternatives to clopidogrel in patients stabilized on|
03196|028|M|cannabidiol.  If concurrent therapy is warranted, consider appropriate|
03196|029|M|testing to assure adequate inhibition of platelet reactivity.|
03196|030|B||
03196|031|D|DISCUSSION:  In an open-label, cross-over study in 8 health male volunteers,|
03196|032|D|a loading dose of clopidogrel (600 mg) was administered alone and after 5|
03196|033|D|days of fluoxetine (20 mg) (a CYP2C19 inhibitor).  The maximum concentration|
03196|034|D|(Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel|
03196|035|D|were decreased by 25.3% and 20.6%, respectively.  There was an average|
03196|036|D|decrease of approximately 25% in the antiplatelet effects of clopidogrel|
03196|037|D|when administered with fluoxetine.(3)  However, it is likely that this study|
03196|038|D|significantly underestimates the magnitude of this interaction. Both|
03196|039|D|fluoxetine and its norfluoxetine metabolite inhibit CYP2C19 and have long|
03196|040|D|half-lives of 4 to 9 days and so and is an irreversible inhibitor of|
03196|041|D|CYP2C19.|
03196|042|D|   In a randomized, cross-over study in healthy subjects, ketoconazole|
03196|043|D|(another CYP2C19 inhibitor, 400 mg daily) decreased the Cmax of the active|
03196|044|D|metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by|
03196|045|D|61%.  The AUC of the active metabolite of clopidogrel was decreased by 22%|
03196|046|D|following the loading dose and by 29% during maintenance dosing.|
03196|047|D|Clopidogrel-induced inhibition of platelet aggregation was decreased by 28%|
03196|048|D|following the loading dose and by 33% during the maintenance dose.(3)|
03196|049|D|   In a cross-over study in 72 healthy subjects, simultaneous administration|
03196|050|D|of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300|
03196|051|D|mg loading dose, followed by 75 mg daily) decreased the AUC of the active|
03196|052|D|metabolite of clopidogrel by 46% following the loading dose and by 42%|
03196|053|D|during maintenance dosing.  Clopidogrel-induced inhibition of platelet|
03196|054|D|aggregation was decreased by 47% following the loading dose and by 30%|
03196|055|D|during the maintenance dose.  In a cross-over study in 72 healthy subjects,|
03196|056|D|administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12|
03196|057|D|hours after clopidogrel (300 mg loading dose, followed by 75 mg daily)|
03196|058|D|produced similar effects.(1)|
03196|059|D|   A pharmacokinetic modeling study identified cannabidiol as having potent|
03196|060|D|inhibitory effects on CYP2C19 in human cells.(4)|
03196|061|B||
03196|062|R|REFERENCES:|
03196|063|B||
03196|064|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
03196|065|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
03196|066|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
03196|067|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
03196|068|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
03196|069|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
03196|070|R|  38(1):92-9.|5
03196|071|R|3.Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT,|2
03196|072|R|  Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by|2
03196|073|R|  ketoconazole affects prasugrel and clopidogrel pharmacokinetics and|2
03196|074|R|  pharmacodynamics differently. Clin Pharmacol Ther 2007 May;81(5):735-41.|2
03196|075|R|4.Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol is a|5
03196|076|R|  potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug|5
03196|077|R|  Metab Pharmacokinet 2013;28(4):332-8.|5
03197|001|T|MONOGRAPH TITLE:  Brexpiprazole/Strong CYP3A4 Inhibitors; Protease|
03197|002|T|Inhibitors|
03197|003|B||
03197|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03197|005|L|take action as needed.|
03197|006|B||
03197|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03197|008|A|brexpiprazole.(1)|
03197|009|B||
03197|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03197|011|E|may result in elevated levels of and toxicity from brexpiprazole.(1)|
03197|012|B||
03197|013|P|PREDISPOSING FACTORS:  With brexpiprazole(1) this interaction is expected to|
03197|014|P|be more severe in patients who are CYP2D6 poor metabolizers, or who receive|
03197|015|P|concomitant treatment with a  strong CYP2D6 inhibitor (e.g. bupropion,|
03197|016|P|fluoxetine, paroxetine, quinidine) in addition to treatment with a strong|
03197|017|P|CYP3A4 inhibitor.|
03197|018|P|   Strong CYP3A4 inhibitors are expected to increase brexpiprazole levels|
03197|019|P|4.8-fold in poor CYP2D6 metabolizers.  Concurrent use of strong CYP2D6 and|
03197|020|P|CYP3A4 inhibitors is expected to increase brexpiprazole levels 5.1-fold in|
03197|021|P|extensive metabolizers of CYP2D6.  With brexpiprazole, the interaction may|
03197|022|P|also be more severe in patients taking moderate CYP2D6 inhibitors.(1)|
03197|023|B||
03197|024|M|PATIENT MANAGEMENT:  The US manufacturer of brexpiprazole recommends the|
03197|025|M|following dose adjustments for patients who are receiving a strong CYP3A4|
03197|026|M|inhibitor:|
03197|027|M|   - in patients taking a strong CYP3A4 inhibitor without a strong or|
03197|028|M|moderate CYP2D6 inhibitor, administer half the usual dosage of|
03197|029|M|brexpiprazole.|
03197|030|M|   - in patients taking a strong CYP3A4 inhibitor who are poor CYP2D6|
03197|031|M|metabolizers or are receiving a strong or moderate inhibitor of CYP2D6,|
03197|032|M|decrease the dose to one-fourth the usual dose.(1)|
03197|033|M|   The dose of brexpiprazole should be adjusted to its original level if the|
03197|034|M|CYP3A4 inhibitor is discontinued.(1)|
03197|035|M|   The US Department of Health and Human Services HIV guidelines recommend|
03197|036|M|that patients taking any ritonavir- or cobicistat-boosted protease inhibitor|
03197|037|M|have their dose of brexpiprazole decreased to 25% of the usual dose.|
03197|038|M|Patients on unboosted atazanavir should have their dose of brexpiprazole|
03197|039|M|decreased to 50% of the usual dose.(2)|
03197|040|B||
03197|041|D|DISCUSSION:  Coadministration of ketoconazole increased the AUC of|
03197|042|D|brexpiprazole approximately 2-fold.(1)|
03197|043|D|   CYP3A4 inhibitors linked to this monograph include: adagrasib,|
03197|044|D|amprenavir, atazanavir, boceprevir, clarithromycin, cobicistat, darunavir,|
03197|045|D|fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
03197|046|D|levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03197|047|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
03197|048|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib,|
03197|049|D|and voriconazole.(3)|
03197|050|B||
03197|051|R|REFERENCES:|
03197|052|B||
03197|053|R|1.Rexulti (brexpiprazole) US prescribing information. Otsuka Pharmaceutical|1
03197|054|R|  Co., Ltd. June, 2020.|1
03197|055|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03197|056|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03197|057|R|  HIV. Department of Health and Human Services. Available at:|6
03197|058|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
03197|059|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
03197|060|R|3.This information is based on an extract from the Certara Drug Interaction|6
03197|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03198|001|T|MONOGRAPH TITLE:  Lidocaine/Selected Protease Inhibitors; Cobicistat|
03198|002|B||
03198|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03198|004|L|take action as needed.|
03198|005|B||
03198|006|A|MECHANISM OF ACTION:  Protease inhibitors(1-15) may inhibit the metabolism|
03198|007|A|of lidocaine via CYP3A4.|
03198|008|B||
03198|009|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors(1-15) with|
03198|010|E|antiarrhythmic doses of lidocaine may result in elevated levels and toxicity|
03198|011|E|from lidocaine.|
03198|012|B||
03198|013|P|PREDISPOSING FACTORS:  Lidocaine clearance is significantly impaired in|
03198|014|P|patients with moderate or severe hepatic impairment.|
03198|015|B||
03198|016|M|PATIENT MANAGEMENT:  The US manufacturers of atazanavir,(1)|
03198|017|M|atazanavir-cobicistat,(2) darunavir,(4) darunavir-cobicistat,(5)|
03198|018|M|fosamprenavir,(8) indinavir,(10) lopinavir-ritonavir,(11) nelfinavir,(12)|
03198|019|M|nirmatrelvir/ritonavir,(13) ombitasvir-paritaprevir-ritonavir,(14) and|
03198|020|M|tipranavir(15) recommend caution and therapeutic concentration monitoring|
03198|021|M|when lidocaine is administered concurrently as an antiarrhythmic.|
03198|022|M|   Recommendations differ in other regions. The UK manufacturer of|
03198|023|M|atazanavir-cobicistat(3) and the Canadian manufacturer of darunavir,(6)|
03198|024|M|darunavir-cobicistat,(7) and fosamprenavir(9) state that concurrent use of|
03198|025|M|lidocaine is contraindicated.|
03198|026|B||
03198|027|D|DISCUSSION:  The protease inhibitors are moderate to strong inhibitors of|
03198|028|D|CYP3A4, one of the metabolic pathways for lidocaine elimination.(16-17)|
03198|029|B||
03198|030|R|REFERENCES:|
03198|031|B||
03198|032|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
03198|033|R|  Squibb Company December, 2024.|1
03198|034|R|2.Evotaz (atazanavir and cobicistat) US prescribing information.|1
03198|035|R|  Bristol-Myers-Squibb Company May, 2025.|1
03198|036|R|3.Evotaz (atazanavir and cobicistat) UK summary of product characteristics.|1
03198|037|R|  Bristol-Myers-Squibb Company March, 2016.|1
03198|038|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
03198|039|R|  March, 2023.|1
03198|040|R|5.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
03198|041|R|  Pharmaceuticals, Inc. March, 2025.|1
03198|042|R|6.Prezista (darunavir) Canadian prescribing information. Jannsen-Ortho June,|1
03198|043|R|  2008.|1
03198|044|R|7.Prezcobix (darunavir-cobicistat) Canadian prescribing information. Janssen|1
03198|045|R|  Inc. June 18, 2014.|1
03198|046|R|8.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
03198|047|R|  March, 2019.|1
03198|048|R|9.Telzir (fosamprenavir calcium) Canadian product monograph. ViiV Healthcare|1
03198|049|R|  ULC February 11, 2014.|1
03198|050|R|10.Crixivan (indinavir sulfate) US prescribing information. Merck & Co.,|1
03198|051|R|   Inc. September, 2016.|1
03198|052|R|11.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
03198|053|R|   Laboratories December, 2019.|1
03198|054|R|12.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
03198|055|R|   Pharmaceuticals, Inc. September, 2016.|1
03198|056|R|13.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
03198|057|R|   information. Pfizer Inc. February, 2025.|1
03198|058|R|14.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
03198|059|R|   prescribing information. AbbVie Inc. December, 2019.|1
03198|060|R|15.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
03198|061|R|   Pharmaceuticals, Inc. April, 2024.|1
03198|062|R|16.Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P.|2
03198|063|R|   Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in|2
03198|064|R|   vivo: effects of liver function. Clin Pharmacol Ther 2004 Jan;75(1):80-8.|2
03198|065|R|17.This information is based on an extract from the Certara Drug Interaction|6
03198|066|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03199|001|T|MONOGRAPH TITLE:  Apomorphine/Selected 5-HT3 Antagonists|
03199|002|B||
03199|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03199|004|L|is contraindicated and generally should not be dispensed or administered to|
03199|005|L|the same patient.|
03199|006|B||
03199|007|A|MECHANISM OF ACTION:  The mechanism for risk of profound hypotension or loss|
03199|008|A|of consciousness is not known.|
03199|009|B||
03199|010|E|CLINICAL EFFECTS:  Concurrent use of apomorphine with a 5-HT3 antagonist may|
03199|011|E|result in profound hypotension and loss of consciousness.(1)|
03199|012|B||
03199|013|P|PREDISPOSING FACTORS:  None determined.|
03199|014|B||
03199|015|M|PATIENT MANAGEMENT:  The manufacturer of apomorphine states that concurrent|
03199|016|M|use with 5-HT3 antagonists is contraindicated.  Alternative agents, such as|
03199|017|M|trimethobenzamide, are recommended for prevention of nausea and vomiting|
03199|018|M|caused by apomorphine.(3)|
03199|019|B||
03199|020|D|DISCUSSION:  Profound hypotension and loss of consciousness have been|
03199|021|D|reported with the concurrent use of apomorphine and ondansetron.(1,2)|
03199|022|D|   Selected 5-HT3 Antagonists linked to this monograph include: alosetron,|
03199|023|D|azasetron, and ramosetron.|
03199|024|B||
03199|025|R|REFERENCES:|
03199|026|B||
03199|027|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03199|028|R|  Inc. May, 2019.|1
03199|029|R|2.Zofran (ondansetron) US prescribing information. GlaxoSmithKline October,|1
03199|030|R|  2021.|1
03199|031|R|3.Bowron A. Practical considerations in the use of apomorphine injectable.|6
03199|032|R|  Neurology 2004 Mar 23;62(6 Suppl 4):S32-6.|6
03200|001|T|MONOGRAPH TITLE:  Disopyramide/Class IB, II, and IV Antiarrhythmics|
03200|002|B||
03200|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03200|004|L|is contraindicated and generally should not be dispensed or administered to|
03200|005|L|the same patient.|
03200|006|B||
03200|007|A|MECHANISM OF ACTION:  Disopyramide has been shown to prolong the QTc|
03200|008|A|interval.  Concurrent use with other agents that affect the heart rate and|
03200|009|A|rhythm may result in unpredictable effect on heart rhythm.(1-2)|
03200|010|B||
03200|011|E|CLINICAL EFFECTS:  The concurrent use of disopyramide with other agents that|
03200|012|E|affect the heart rate and rhythm may result in in potentially|
03200|013|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1-2)|
03200|014|B||
03200|015|P|PREDISPOSING FACTORS:  None determined.|
03200|016|B||
03200|017|M|PATIENT MANAGEMENT:  The US manufacturer of disopyramide states that|
03200|018|M|concurrent use of disopyramide with antiarrhythmic agents should be reserved|
03200|019|M|for patients with life-threatening arrhythmias who are demonstrably|
03200|020|M|unresponsive to single-agent antiarrhythmic therapy.(3)|
03200|021|M|   The Australian manufacturer of disopyramide states that the concurrent|
03200|022|M|use of other antiarrhythmics, such as Class I, II, III, or IV is|
03200|023|M|contraindicated.(1)|
03200|024|M|   The US manufacturer of verapamil states that disopyramide should not be|
03200|025|M|administered within 48 hours before or 24 hours after verapamil.(2)|
03200|026|M|   The Australian manufacturer of celiprolol states that the concurrent use|
03200|027|M|of antiarrhythmics such as disopyramide is contraindicated during treatment|
03200|028|M|with celiprolol (exception: intensive care).(4)|
03200|029|M|   If concurrent therapy is deemed medically necessary, obtain serum|
03200|030|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
03200|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03200|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03200|033|B||
03200|034|D|DISCUSSION:  Because combinations of antiarrhythmics are not well researched|
03200|035|D|and concurrent use may result in unpredictable effects, the Australian|
03200|036|D|manufacturer of disopyramide states that the concurrent use of other|
03200|037|D|antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1)|
03200|038|B||
03200|039|R|REFERENCES:|
03200|040|B||
03200|041|R|1.Rythmodan (disopyramide) Australian prescribing information. Aventis|1
03200|042|R|  Pharma Pty Ltd. September 22, 2000.|1
03200|043|R|2.Calan (verapamil hydrochloride) US prescribing information. Pfizer, Inc.|1
03200|044|R|  August, 2016.|1
03200|045|R|3.Norpace (disopyramide phosphate) US prescribing information. Pfizer Inc.|1
03200|046|R|  December, 2020.|1
03200|047|R|4.Celipro Lich (celiprolol hydrochloride) German prescribing information.|1
03200|048|R|  Zentiva Pharma GmbH July 2018.|1
03201|001|T|MONOGRAPH TITLE:  Mexiletine/Cobicistat; Tipranavir|
03201|002|B||
03201|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03201|004|L|take action as needed.|
03201|005|B||
03201|006|A|MECHANISM OF ACTION:  Cobicistat and tipranavir may inhibit the metabolism|
03201|007|A|of mexiletine by CYP2D6.(1-3)|
03201|008|B||
03201|009|E|CLINICAL EFFECTS:  Concurrent use of cobicistat or tipranavir with|
03201|010|E|mexiletine may result in elevated levels of mexiletine, which may lead to|
03201|011|E|serious and/or life-threatening effects.(1)|
03201|012|B||
03201|013|P|PREDISPOSING FACTORS:  None determined.|
03201|014|B||
03201|015|M|PATIENT MANAGEMENT:  The combination of cobicistat or tipranavir with|
03201|016|M|mexiletine should be used with caution.  Clinical monitoring is recommended|
03201|017|M|with concomitant use.(1-3)|
03201|018|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03201|019|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03201|020|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03201|021|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03201|022|B||
03201|023|D|DISCUSSION:  Cobicistat is a weak CYP2D6 inhibitor,(1) and tipranavir is a|
03201|024|D|moderate CYP2D6 inhibitor.(2)  They may inhibit the metabolism and increase|
03201|025|D|levels of mexiletine.(3)|
03201|026|B||
03201|027|R|REFERENCES:|
03201|028|B||
03201|029|R|1.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
03201|030|R|  June, 2025.|1
03201|031|R|2.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
03201|032|R|  Pharmaceuticals, Inc. April, 2024.|1
03201|033|R|3.Mexiletine US Prescribing Information. Teva Pharmaceuticals USA, Inc.|1
03201|034|R|  October, 2018.|1
03202|001|T|MONOGRAPH TITLE:  Selected CYP2D6 Substrates/Panobinostat|
03202|002|B||
03202|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03202|004|L|of severe adverse interaction.|
03202|005|B||
03202|006|A|MECHANISM OF ACTION:  Panobinostat is a moderate inhibitor of CYP2D6 and is|
03202|007|A|expected to inhibit the metabolism of agents through this pathway.(1)|
03202|008|B||
03202|009|E|CLINICAL EFFECTS:  Concurrent use of panobinostat may result in elevated|
03202|010|E|levels of and toxicity from agents metabolized by CYP2D6.(1)|
03202|011|B||
03202|012|P|PREDISPOSING FACTORS:  With tricyclic antidepressants, the risk of seizures|
03202|013|P|may be increased in patients with a history of head trauma or prior seizure;|
03202|014|P|CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives;|
03202|015|P|addiction to opiates, cocaine, or stimulants; use of over-the-counter|
03202|016|P|stimulants and anorectics; diabetics treated with oral hypoglycemics or|
03202|017|P|insulin; or with concomitant medications known to lower seizure threshold|
03202|018|P|(antipsychotics, theophylline, systemic steroids).|
03202|019|P|   With anticholinergic agents, the risk of anticholinergic toxicities|
03202|020|P|including cognitive decline, delirium, falls and fractures is increased in|
03202|021|P|geriatric patients using more than one medicine with anticholinergic|
03202|022|P|properties.(4)|
03202|023|B||
03202|024|M|PATIENT MANAGEMENT:  Avoid the concurrent use of panobinostat with agents|
03202|025|M|that are sensitive CYP2D6 or CYP2D6 substrates with a narrow therapeutic|
03202|026|M|index. If concurrent use is warranted, monitor patients for toxicity.(1)|
03202|027|B||
03202|028|D|DISCUSSION:  In a study in 14 subjects with advanced cancer, panobinostat|
03202|029|D|(20 mg daily on Days 3, 5, and 8) increased the maximum concentration (Cmax)|
03202|030|D|and area-under-curve (AUC) of a single dose of dextromethorphan (60 mg) by|
03202|031|D|20-200% and 20-130%, respectively. Dextromethorphan exposures were extremely|
03202|032|D|variable.(1)|
03202|033|D|   Selected CYP2D6 substrates linked to this monograph include:|
03202|034|D|atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin,|
03202|035|D|encainide, methoxyphenamine, metoprolol, nebivolol, paroxetine,|
03202|036|D|perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and|
03202|037|D|yohimbine.|
03202|038|B||
03202|039|R|REFERENCES:|
03202|040|B||
03202|041|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
03202|042|R|  Pharmaceuticals Corporation June, 2016.|1
03202|043|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
03202|044|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03202|045|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03202|046|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03202|047|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03202|048|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03202|049|R|  settings: a scientific statement from the American Heart Association and|6
03202|050|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03202|051|R|  2;55(9):934-47.|6
03202|052|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03202|053|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03202|054|R|  Soc 2023 Jul;71(7):2052-2081.|6
03202|055|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03202|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03202|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03202|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03202|059|R|  11/14/2017.|1
03203|001|T|MONOGRAPH TITLE:  Bosutinib/Strong CYP3A4 Inhibitors|
03203|002|B||
03203|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03203|004|L|of severe adverse interaction.|
03203|005|B||
03203|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03203|007|A|the metabolism of bosutinib.(1)|
03203|008|B||
03203|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03203|010|E|levels of and effects from bosutinib.(1)|
03203|011|E|    Elevated levels of bosutinib may result in QTc prolongation, which may|
03203|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03203|013|E|torsades de pointes (TdP).  Other toxicities include nausea, vomiting,|
03203|014|E|diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity,|
03203|015|E|and cardiac failure.(1)|
03203|016|B||
03203|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03203|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03203|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03203|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03203|021|P|female gender, or advanced age.(2)|
03203|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03203|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03203|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03203|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03203|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03203|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03203|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03203|029|B||
03203|030|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03203|031|M|undergoing therapy with bosutinib.(1)  Consider alternatives with no or|
03203|032|M|minimal enzyme inhibition.|
03203|033|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03203|034|M|bosutinib should be monitored for prolongation of the QTc interval.  When|
03203|035|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03203|036|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03203|037|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03203|038|M|report any irregular heartbeat, dizziness, or fainting.|
03203|039|B||
03203|040|D|DISCUSSION:  In a randomized, phase I, double-blind, placebo-controlled,|
03203|041|D|sequential group study, 48 healthy adults received a single dose of|
03203|042|D|bosutinib 100, 200, 300, 400, 500, or 600 mg with ketoconazole 400 mg days|
03203|043|D|-1 and days 1-4. Bosutinib area-under-curve (AUC) and maximum concentration|
03203|044|D|(Cmax) increased 7.3-fold and 7.7-fold.(3)|
03203|045|D|   In an open-label, randomized, 2-period, crossover study, healthy subjects|
03203|046|D|received a single dose of bosutinib 100 mg alone and with multiple doses of|
03203|047|D|ketoconazole 400 mg.  Bosutinib Cmax and AUC increased 5.2-fold and|
03203|048|D|8.6-fold, respectively.(4)|
03203|049|D|   A retrospective review of 618 cancer patients treated with 902|
03203|050|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03203|051|D|incidence of QTc prolongation.  In patients who received bosutinib, QTc|
03203|052|D|prolongation was identified in 8 patients(38.1%), with 5 (62.5%) having|
03203|053|D|Grade 1 (QTc 450-480 ms) and 3 (37.5%) having Grade 2 (QTc 480-500 ms)|
03203|054|D|events.  Grade 3 events occurred in 1 (12.5%) patient having QTc greater|
03203|055|D|than or equal to 500 ms.  No patients had a QTc change greater than or equal|
03203|056|D|to 60 ms, ventricular tachycardia (VT), sudden cardiac death (SCD), or|
03203|057|D|TdP.(5)|
03203|058|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
03203|059|D|indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil,|
03203|060|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
03203|061|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(6,7)|
03203|062|B||
03203|063|R|REFERENCES:|
03203|064|B||
03203|065|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
03203|066|R|  2023.|1
03203|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03203|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03203|069|R|  settings: a scientific statement from the American Heart Association and|6
03203|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03203|071|R|  2;55(9):934-47.|6
03203|072|R|3.Abbas R, Leister C, El Gaaloul M, Chalon S, Sonnichsen D. Ascending|2
03203|073|R|  single-dose study of the safety profile, tolerability, and|2
03203|074|R|  pharmacokinetics of bosutinib coadministered with ketoconazole to healthy|2
03203|075|R|  adult subjects. Clin Ther 2012 Sep;34(9):2011-9.e1.|2
03203|076|R|4.Abbas R, Hug BA, Leister C, Burns J, Sonnichsen D. Effect of ketoconazole|2
03203|077|R|  on the pharmacokinetics of oral bosutinib in healthy subjects. J Clin|2
03203|078|R|  Pharmacol 2011 Dec;51(12):1721-7.|2
03203|079|R|5.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03203|080|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03203|081|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03203|082|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
03203|083|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03203|084|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03203|085|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03203|086|R|  11/14/2017.|1
03203|087|R|7.This information is based on an extract from the Certara Drug Interaction|6
03203|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03204|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Chloramphenicol|
03204|002|B||
03204|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03204|004|L|of severe adverse interaction.|
03204|005|B||
03204|006|A|MECHANISM OF ACTION:  The mechanism by which chloramphenicol increases the|
03204|007|A|levels of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus|
03204|008|A|is unknown.  Postulated mechanisms include chloramphenicol inhibition of the|
03204|009|A|CYP3A4 metabolism of the immunosuppressive agents, or chloramphenicol|
03204|010|A|inhibition of efflux transporters (e.g., p-glycoprotein).(1-3)|
03204|011|B||
03204|012|E|CLINICAL EFFECTS:  Concurrent administration of chloramphenicol may result|
03204|013|E|in elevated levels of and toxicity from cyclosporine, everolimus, sirolimus,|
03204|014|E|tacrolimus, or temsirolimus.|
03204|015|B||
03204|016|P|PREDISPOSING FACTORS:  None determined.|
03204|017|B||
03204|018|M|PATIENT MANAGEMENT:  The American Society of Transplantation guidelines|
03204|019|M|recommend lowering the dose of cyclosporine or tacrolimus by 25% and close|
03204|020|M|monitoring of immunosuppressive levels.(1)  Although there are no specific|
03204|021|M|recommendations for everolimus or sirolimus, it is expected that a similar|
03204|022|M|interaction would occur and that management would be similar.|
03204|023|M|   The US manufacturer of tacrolimus states that coadministration with|
03204|024|M|chloramphenicol may result in a rapid and sharp rise in tacrolimus|
03204|025|M|concentration despite immediate tacrolimus dose reduction.  Frequent|
03204|026|M|monitoring of tacrolimus levels should start within 1-3 days of initiation|
03204|027|M|of concurrent therapy and continue as necessary.(2)|
03204|028|B||
03204|029|D|DISCUSSION:  A retrospective study of 6 kidney transplant patients (3 on|
03204|030|D|cyclosporine and 3 on tacrolimus) who were given chloramphenicol found that|
03204|031|D|cyclosporine troughs increased by a mean of 41.3 %, and tacrolimus troughs|
03204|032|D|increased by a mean of 207 %, compared to levels prior to starting|
03204|033|D|chloramphenicol.(3)|
03204|034|D|   Case reports have described highly variable effects of chloramphenicol on|
03204|035|D|drug concentrations of immunosuppressants.  One case of an interaction with|
03204|036|D|cyclosporine described an increase in cyclosporine concentrations of 186 %,|
03204|037|D|whereas another case described an increase of 300-850 %, but interpretation|
03204|038|D|of this effect is complicated by the patient's therapy with rifampin just|
03204|039|D|prior to chloramphenicol.(3,4)|
03204|040|D|   In other case reports, tacrolimus AUC increased 7.5-fold in one|
03204|041|D|patient,(5) tacrolimus trough increased 5-fold in another patient who|
03204|042|D|received an overdose of chloramphenicol,(6) and tacrolimus trough increased|
03204|043|D|3-fold in a third patient.(7)|
03204|044|B||
03204|045|R|REFERENCES:|
03204|046|B||
03204|047|R|1.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
03204|048|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
03204|049|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
03204|050|R|  e13510.|6
03204|051|R|2.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
03204|052|R|  August, 2023.|1
03204|053|R|3.Mathis AS, Shah N, Knipp GT, Friedman GS. Interaction of chloramphenicol|2
03204|054|R|  and the calcineurin inhibitors in renal transplant recipients. Transpl|2
03204|055|R|  Infect Dis 2002 Sep;4(3):169-74.|2
03204|056|R|4.Bui L, Huang DD. Possible interaction between cyclosporine and|3
03204|057|R|  chloramphenicol. Ann Pharmacother 1999 Feb;33(2):252-3.|3
03204|058|R|5.Schulman SL, Shaw LM, Jabs K, Leonard MB, Brayman KL. Interaction between|3
03204|059|R|  tacrolimus and chloramphenicol in a renal transplant recipient.|3
03204|060|R|  Transplantation 1998 May 27;65(10):1397-8.|3
03204|061|R|6.Taber DJ, Dupuis RE, Hollar KD, Strzalka AL, Johnson MW. Drug-drug|3
03204|062|R|  interaction between chloramphenicol and tacrolimus in a liver transplant|3
03204|063|R|  recipient. Transplant Proc 2000 May;32(3):660-2.|3
03204|064|R|7.Bakri R, Breen C, Maclean D, Taylor J, Goldsmith D. Serious interaction|3
03204|065|R|  between tacrolimus FK506 and chloramphenicol in a kidney-pancreas|3
03204|066|R|  transplant recipient. Transpl Int 2003 Jun;16(6):441-3.|3
03205|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 10 mg)/Tipranavir|
03205|002|B||
03205|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03205|004|L|of severe adverse interaction.|
03205|005|B||
03205|006|A|MECHANISM OF ACTION:  Tipranavir may inhibit the metabolism of atorvastatin|
03205|007|A|by CYP3A4.(1-6)|
03205|008|B||
03205|009|E|CLINICAL EFFECTS:  Concurrent use of tipranavir may result in elevated|
03205|010|E|levels of atorvastatin, which could result in rhabdomyolysis.(1-6)|
03205|011|B||
03205|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03205|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03205|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03205|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03205|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03205|017|P|transporter OATP1B1 may have increased statin concentrations and be|
03205|018|P|predisposed to myopathy or rhabdomyolysis.|
03205|019|B||
03205|020|M|PATIENT MANAGEMENT:  The manufacturers of atorvastatin and tipranavir say to|
03205|021|M|avoid the use of atorvastatin in patients taking tipranavir.(1-6)  If|
03205|022|M|atorvastatin is used with tipranavir, use the lowest dose possible of|
03205|023|M|atorvastatin with careful monitoring.  The UK manufacturer of atorvastatin|
03205|024|M|and the Canadian and UK manufacturers of tipranavir further state that if|
03205|025|M|concurrent administration is required, do not exceed an atorvastatin dose of|
03205|026|M|10 mg daily.(4-6)|
03205|027|M|   Consider the use of fluvastatin in patients maintained on tipranavir.|
03205|028|B||
03205|029|D|DISCUSSION:  In a study in 22 subjects, pretreatment with|
03205|030|D|tipranavir/ritonavir (500/200 mg twice daily) increased the Cmax, AUC, and|
03205|031|D|Cmin of a single dose of atorvastatin (10 mg) by 8.61-fold, 9.36-fold, and|
03205|032|D|5.19-fold, respectively.  The Cmax, AUC, and Cmin of|
03205|033|D|orthohydroxy-atorvastatin decreased by 98%, 89%, and 93%, respectively.  The|
03205|034|D|AUC and Cmin of parahydroxy-atorvastatin decreased by 82% and 66%,|
03205|035|D|respectively.  There were no significant effects on tipranavir levels.(3)|
03205|036|B||
03205|037|R|REFERENCES:|
03205|038|B||
03205|039|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
03205|040|R|  2020.|1
03205|041|R|2.Lipitor (atorvastatin) Canadian product information. Pfizer Canada Inc.|1
03205|042|R|  May 31, 2019.|1
03205|043|R|3.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
03205|044|R|  Pharmaceuticals, Inc. April, 2024.|1
03205|045|R|4.Lipitor (atorvastatin calcium trihydrate) UK summary of product|1
03205|046|R|  characteristics. Pfizer Limited April 1, 2019.|1
03205|047|R|5.Aptivus (tipranavir) Canadian prescribing information. Boehringer|1
03205|048|R|  Ingelheim March 5, 2014.|1
03205|049|R|6.Aptivus (tipranavir) UK Summary of product characteristics. Boehringer|1
03205|050|R|  Ingelheim Limited October 3, 2018.|1
03206|001|T|MONOGRAPH TITLE:  Chaste tree/Hormonal Contraceptives|
03206|002|B||
03206|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
03206|004|L|Assess the risk to the patient and take action as needed.|
03206|005|B||
03206|006|A|MECHANISM OF ACTION:  Chaste tree may lower the efficacy of hormonal|
03206|007|A|contraceptives. The exact mechanism is unknown. Chaste tree(Chasteberry;|
03206|008|A|Vitex agnus-castus) may bind to estrogen receptors.(1)|
03206|009|B||
03206|010|E|CLINICAL EFFECTS:  Concurrent administration may result in decreased|
03206|011|E|clinical effectiveness of the contraceptive agent.(1)|
03206|012|B||
03206|013|P|PREDISPOSING FACTORS:  None determined.|
03206|014|B||
03206|015|M|PATIENT MANAGEMENT:  Patients taking chaste tree should be alerted to the|
03206|016|M|risk for decreased effectiveness (e.g. contraceptive failure) of their|
03206|017|M|hormonal contraceptive therapy and should be advised to use a reliable|
03206|018|M|non-hormonal contraceptive option.|
03206|019|B||
03206|020|D|DISCUSSION:  There are two case reports of unintended pregnancy following|
03206|021|D|concurrent use of chaste tree and norethisterone.(1)|
03206|022|B||
03206|023|R|REFERENCE:|
03206|024|B||
03206|025|R|1.Australian Government Department of Health Therapeutic Goods|6
03206|026|R|  Administration. Vitex agnus-castus. Safety advisory- potential for|6
03206|027|R|  interaction with oral contraceptives. Accessed at:|6
03206|028|R|  https://www.tga.gov.au/alert/vitex-agnus-castus May 2, 2019.|6
03207|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP3A4 Substrates/Schisandra|
03207|002|B||
03207|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03207|004|L|take action as needed.|
03207|005|B||
03207|006|A|MECHANISM OF ACTION:  Schisandra is considered a moderate inhibitor of|
03207|007|A|CYP3A4.  FDA defines a moderate inhibitor as a drug which increases the|
03207|008|A|area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)|
03207|009|B||
03207|010|E|CLINICAL EFFECTS:  Concurrent use of Schisandra may lead to increased serum|
03207|011|E|levels and adverse effects of drugs sensitive to inhibition of the CYP3A4|
03207|012|E|pathway.(3-7)|
03207|013|B||
03207|014|P|PREDISPOSING FACTORS:  With darifenacin, the risk of anticholinergic|
03207|015|P|toxicities including cognitive decline, delirium, falls and fractures is|
03207|016|P|increased in geriatric patients using more than one medicine with|
03207|017|P|anticholinergic properties.(8)|
03207|018|B||
03207|019|M|PATIENT MANAGEMENT:  If Schisandra must be coadministered with a sensitive|
03207|020|M|CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate|
03207|021|M|and adjust its dose as appropriate.(3-7)|
03207|022|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
03207|023|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
03207|024|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
03207|025|M|inhibitors should be avoided.(8)|
03207|026|B||
03207|027|D|DISCUSSION:  A study in 12 healthy volunteers found that Schisandra led to|
03207|028|D|an increase in midazolam area-under-curve (AUC) and maximum concentration|
03207|029|D|(Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam|
03207|030|D|administered alone.(3)|
03207|031|D|   In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by|
03207|032|D|2.07-fold and 1.96-fold, respectively when given with Schisandra compared to|
03207|033|D|sirolimus administered alone.(4)|
03207|034|D|   The effect of Schisandra on tacrolimus has been examined in several small|
03207|035|D|pharmacokinetic studies in healthy volunteers as well as liver and kidney|
03207|036|D|transplant patients.  Compared to tacrolimus given alone, tacrolimus AUC|
03207|037|D|when administered with Schisandra was consistently increased by 2.1-fold,|
03207|038|D|while the increase in Cmax varied between 1.83- and 2.11-fold in the|
03207|039|D|transplant studies(5-6) and 3-fold in the study on healthy subjects.(7)  In|
03207|040|D|the study with kidney transplant patients, a decrease in tacrolimus dose of|
03207|041|D|40.9 % was required to bring tacrolimus levels into the therapeutic|
03207|042|D|range.(5)|
03207|043|B||
03207|044|R|REFERENCES:|
03207|045|B||
03207|046|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
03207|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03207|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03207|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03207|050|R|  11/14/2017.|1
03207|051|R|2.This information is based on an extract from the Certara Drug Interaction|6
03207|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03207|053|R|3.Xin HW, Wu XC, Li Q, Yu AR, Xiong L. Effects of Schisandra sphenanthera|2
03207|054|R|  extract on the pharmacokinetics of midazolam in healthy volunteers. Br J|2
03207|055|R|  Clin Pharmacol 2009 May;67(5):541-6.|2
03207|056|R|4.Li R, Guo W, Fu Z, Ding G, Wang Z, Fu H. A study about drug combination|2
03207|057|R|  therapy of Schisandra sphenanthera extract and Rapamycin in healthy|2
03207|058|R|  subjects. Can J Physiol Pharmacol 2012 Jul;90(7):941-5.|2
03207|059|R|5.Li J, Chen S, Qin X, Fu Q, Bi H, Zhang Y, Wang X, Liu L, Wang C, Huang M.|2
03207|060|R|  Wuzhi Tablet (Schisandra sphenanthera Extract) is a Promising|2
03207|061|R|  Tacrolimus-Sparing  Agent for Renal Transplant Recipients Who are CYP3A5|2
03207|062|R|  Expressers: a Two-Phase Prospective Study. Drug Metab Dispos 2017 Nov;|2
03207|063|R|  45(11):1114-1119.|2
03207|064|R|6.Jiang W, Wang X, Xu X, Kong L. Effect of Schisandra sphenanthera extract|2
03207|065|R|  on the concentration of tacrolimus in the blood of liver transplant|2
03207|066|R|  patients. Int J Clin Pharmacol Ther 2010 Mar;48(3):224-9.|2
03207|067|R|7.Xin HW, Wu XC, Li Q, Yu AR, Zhu M, Shen Y, Su D, Xiong L. Effects of|2
03207|068|R|  Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus  in|2
03207|069|R|  healthy volunteers. Br J Clin Pharmacol 2007 Oct;64(4):469-75.|2
03207|070|R|8.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03207|071|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03207|072|R|  Soc 2023 Jul;71(7):2052-2081.|6
03207|073|R|9.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
03207|074|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
03208|001|T|MONOGRAPH TITLE:  Clozapine/Fluoxetine; Sertraline|
03208|002|B||
03208|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03208|004|L|take action as needed.|
03208|005|B||
03208|006|A|MECHANISM OF ACTION:  The metabolism of clozapine may be inhibited at|
03208|007|A|CYP1A2, 2D6 or 3A4 by fluoxetine or sertraline.(1)|
03208|008|B||
03208|009|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with|
03208|010|E|fluoxetine or sertraline may result in elevated levels of clozapine and an|
03208|011|E|increase in clozapine related side effects, orthostatic hypotension,|
03208|012|E|syncope, QT prolongation, profound sedation and seizures.|
03208|013|B||
03208|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03208|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03208|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03208|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03208|018|P|female gender, or advanced age.(2)|
03208|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03208|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03208|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03208|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03208|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03208|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03208|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03208|026|B||
03208|027|M|PATIENT MANAGEMENT:  Clozapine levels should be monitored in patients|
03208|028|M|receiving concurrent therapy with clozapine and fluoxetine or sertraline.|
03208|029|M|Patients should be monitored for signs of clozapine toxicity.  The dosage of|
03208|030|M|either clozapine, fluoxetine or sertraline may need to be adjusted, or one|
03208|031|M|or both agents may need to be discontinued.  Clozapine levels should also be|
03208|032|M|monitored following the discontinuation of fluoxetine or sertraline from|
03208|033|M|concurrent therapy.|
03208|034|M|   If concurrent therapy is warranted in patients receiving clozapine,|
03208|035|M|consider obtaining serum calcium, magnesium, and potassium levels and|
03208|036|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03208|037|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03208|038|M|heartbeat, dizziness, or fainting.|
03208|039|B||
03208|040|D|DISCUSSION:  Two studies compared subjects receiving concurrent clozapine|
03208|041|D|and fluoxetine to subjects receiving clozapine alone.  In the first,(3) the|
03208|042|D|clozapine level-to-dose and norclozapine level-to-dose ratios were 75% and|
03208|043|D|50% higher, respectively, in subjects receiving concurrent fluoxetine.  In|
03208|044|D|the second study(4), clozapine and norclozapine levels were 30.2% and 33.5%|
03208|045|D|higher, respectively, in subjects receiving concurrent fluoxetine.  A study|
03208|046|D|(5) in 10 subjects found that the concurrent administration of fluoxetine|
03208|047|D|and clozapine resulted in increases of 58%, 36%, and 38% in clozapine,|
03208|048|D|norclozapine, and clozapine-N-oxide, respectively.  One case report(6)|
03208|049|D|documented the development of myoclonic jerks following the addition of|
03208|050|D|fluoxetine to clozapine therapy.|
03208|051|D|   A study(4) in 16 subjects found that the concurrent administration of|
03208|052|D|sertraline and clozapine resulted in clozapine and norclozapine levels that|
03208|053|D|were 30.2% and 52.1% higher, respectively, than levels seen in similar|
03208|054|D|patients receiving clozapine alone.|
03208|055|B||
03208|056|R|REFERENCES:|
03208|057|B||
03208|058|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03208|059|R|  Pharmaceuticals Corporation April, 2020.|1
03208|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03208|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03208|062|R|  settings: a scientific statement from the American Heart Association and|6
03208|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03208|064|R|  2;55(9):934-47.|6
03208|065|R|3.Centorrino F, Baldessarini RJ, Kando J, Frankenburg FR, Volpicelli SA,|2
03208|066|R|  Puopolo PR, Flood JG. Serum concentrations of clozapine and its major|2
03208|067|R|  metabolites: effects of cotreatment with fluoxetine or valproate. Am J|2
03208|068|R|  Psychiatry 1994 Jan;151(1):123-5.|2
03208|069|R|4.Centorrino F, Baldessarini RJ, Frankenburg FR, Kando J, Volpicelli SA,|2
03208|070|R|  Flood JG. Serum levels of clozapine and norclozapine in patients treated|2
03208|071|R|  with selective serotonin reuptake inhibitors. Am J Psychiatry 1996 Jun;|2
03208|072|R|  153(6):820-2.|2
03208|073|R|5.Spina E, Avenoso A, Facciola G, Fabrazzo M, Monteleone P, Maj M, Perucca|2
03208|074|R|  E, Caputi AP. Effect of fluoxetine on the plasma concentrations of|2
03208|075|R|  clozapine and its major metabolites in patients with schizophrenia. Int|2
03208|076|R|  Clin Psychopharmacol 1998 May;13(3):141-5.|2
03208|077|R|6.Kingsbury SJ, Puckett KM. Effects of fluoxetine on serum clozapine levels.|3
03208|078|R|  Am J Psychiatry 1995 Mar;152(3):473-4.|3
03208|079|R|7.Bess AL, Cunningham SR. Dear Healthcare Provider:  Important drug warning|1
03208|080|R|  and new information about Clozaril. Novartis Pharmaceuticals Corporation|1
03208|081|R|  December, 2005.|1
03208|082|R|8.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03208|083|R|  Laboratories Inc. August, 2023.|1
03208|084|R|9.USDepartment of Health and Human Services Food and Drug Administration.|1
03208|085|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03208|086|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03208|087|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03209|001|T|MONOGRAPH TITLE:  Selected Antiarrhythmics/Amprenavir; Fosamprenavir|
03209|002|B||
03209|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03209|004|L|is contraindicated and generally should not be dispensed or administered to|
03209|005|L|the same patient.|
03209|006|B||
03209|007|A|MECHANISM OF ACTION:  Fosamprenavir, a CYP3A4 inhibitor, may decrease the|
03209|008|A|metabolism of some antiarrhythmics.(1-4)|
03209|009|B||
03209|010|E|CLINICAL EFFECTS:  Concurrent use of fosamprenavir(1-4) with bepridil,|
03209|011|E|disopyramide, flecainide, or propafenone may result in elevated levels of|
03209|012|E|and adverse events from (including life-threatening reactions) the|
03209|013|E|antiarrhythmics.|
03209|014|B||
03209|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03209|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03209|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03209|018|P|long QT syndrome), hypokalemia, hypomagnesemia, Hypocalcemia, bradycardia,|
03209|019|P|female gender, or advanced age.(5)|
03209|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03209|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03209|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03209|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03209|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03209|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03209|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03209|027|B||
03209|028|M|PATIENT MANAGEMENT:  The Canadian(1,2) and UK(3) manufacturers of|
03209|029|M|fosamprenavir state that the antiarrhythmics bepridil, flecainide, and|
03209|030|M|propafenone are contraindicated in patients receiving fosamprenavir.  The US|
03209|031|M|manufacturer of fosamprenavir states that, when used with ritonavir,|
03209|032|M|flecainide and propafenone are contraindicated.  The US manufacturer also|
03209|033|M|recommends caution and antiarrhythmic concentration monitoring with|
03209|034|M|concurrent use of other antiarrhythmics.(4)|
03209|035|M|   If concurrent therapy is deemed medically necessary, obtain serum|
03209|036|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
03209|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03209|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03209|039|B||
03209|040|D|DISCUSSION:  Because of the risk of serious and potentially life-threatening|
03209|041|D|reactions, the Canadian(1,2) and UK(3) manufacturers of fosamprenavir state|
03209|042|D|that the antiarrhythmics bepridil, flecainide, and propafenone are|
03209|043|D|contraindicated in patients receiving fosamprenavir.  The US manufacturer of|
03209|044|D|fosamprenavir states that, when used with ritonavir, flecainide and|
03209|045|D|propafenone are contraindicated.  The US manufacturer also recommends|
03209|046|D|caution and antiarrhythmic concentration monitoring with concurrent use of|
03209|047|D|these antiarrhythmics.(4)|
03209|048|B||
03209|049|R|REFERENCES:|
03209|050|B||
03209|051|R|1.Health Canada. New safety information for antiviral drug used in the|1
03209|052|R|  treatment of HIV (RA-38061). available at:|1
03209|053|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/38061a-e|1
03209|054|R|  ng.php February 19, 2014.|1
03209|055|R|2.Telzir (fosamprenavir calcium) Canadian product monograph. ViiV Healthcare|1
03209|056|R|  ULC February 11, 2014.|1
03209|057|R|3.Telzir (fosamprenavir calcium) UK summary of product characteristics.|1
03209|058|R|  GlaxoSmithKline UK October 18. 2013.|1
03209|059|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
03209|060|R|  March, 2019.|1
03209|061|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03209|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03209|063|R|  settings: a scientific statement from the American Heart Association and|6
03209|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03209|065|R|  2;55(9):934-47.|6
03210|001|T|MONOGRAPH TITLE:  Selected Benzodiazepines/Idelalisib|
03210|002|B||
03210|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03210|004|L|take action as needed.|
03210|005|B||
03210|006|A|MECHANISM OF ACTION:  Idelalisib may inhibit the metabolism of|
03210|007|A|benzodiazepines that are metabolized by CYP3A4.(1)|
03210|008|B||
03210|009|E|CLINICAL EFFECTS:  Inhibition of benzodiazepine CYP3A4 metabolism by|
03210|010|E|idelalisib may produce increased levels of, as well as increased clinical|
03210|011|E|effects, of benzodiazepines.  Toxic effects of increased benzodiazepine|
03210|012|E|levels include profound sedation, respiratory depression, coma, and/or|
03210|013|E|death.|
03210|014|B||
03210|015|P|PREDISPOSING FACTORS:  None determined.|
03210|016|B||
03210|017|M|PATIENT MANAGEMENT:  The manufacturer of idelalisib says to avoid|
03210|018|M|coadministration with sensitive CYP3A substrates.(1)|
03210|019|M|   The manufacturers of some benzodiazepines (i.e., clonazepam, diazepam,|
03210|020|M|estazolam, midazolam) advise caution when they are coadministered with|
03210|021|M|inhibitors of CYP3A4 and to consider dose reduction of the|
03210|022|M|benzodiazepine.(2-6)|
03210|023|M|   Monitor patients receiving concurrent therapy with idelalisib and|
03210|024|M|benzodiazepines carefully for increased effects including unusual dizziness|
03210|025|M|or lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03210|026|M|unresponsiveness.|
03210|027|B||
03210|028|D|DISCUSSION:  In a study of 12 healthy subjects, multiple doses of idelalisib|
03210|029|D|(150 mg twice daily) increased the area-under-curve (AUC) and maximum|
03210|030|D|concentration (Cmax) of midazolam 5 mg by 437 % and 138 %, respectively.(6)|
03210|031|D|   In a case report, a 71-year-old female on diazepam as needed was started|
03210|032|D|on idelalisib 150 mg twice daily.  She presented in the emergency room ten|
03210|033|D|days later with altered mental status and respiratory failure, which|
03210|034|D|resolved after discontinuation of idelalisib and diazepam.  Other causes of|
03210|035|D|her symptoms were ruled out and although the patient's other medications may|
03210|036|D|have been contributory, idelalisib potentiation of diazepam's effects was|
03210|037|D|thought to be the primary cause.(7)|
03210|038|D|   Benzodiazepines linked to this monograph include: brotizolam,|
03210|039|D|chlordiazepoxide, clonazepam, clorazepic acid, diazepam, estazolam,|
03210|040|D|etizolam, flunitrazepam, flurazepam, halazepam, midazolam, prazepam, and|
03210|041|D|quazepam.|
03210|042|B||
03210|043|R|REFERENCES:|
03210|044|B||
03210|045|R|1.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03210|046|R|  October, 2020.|1
03210|047|R|2.Klonopin (clonazepam) US prescribing information. Genentech, Inc.|1
03210|048|R|  February, 2021.|1
03210|049|R|3.Valium (diazepam) US prescribing information. Roche Products Inc December,|1
03210|050|R|  2016.|1
03210|051|R|4.Estazolam tablet US prescribing information. Teva Pharmaceuticals USA Inc|1
03210|052|R|  November, 2015.|1
03210|053|R|5.Midazolam Hydrochloride Syrup US Prescribing Information. Padagis US LLC|1
03210|054|R|  December 11, 2021.|1
03210|055|R|6.Jin F, Robeson M, Zhou H, Moyer C, Wilbert S, Murray B, Ramanathan S.|2
03210|056|R|  Clinical drug interaction profile of idelalisib in healthy subjects. J|2
03210|057|R|  Clin Pharmacol 2015 Aug;55(8):909-19.|2
03210|058|R|7.Bossaer JB, Chakraborty K. Drug interaction between idelalisib and|3
03210|059|R|  diazepam resulting in altered mental status and respiratory failure. J|3
03210|060|R|  Oncol Pharm Pract 2017 Sep;23(6):470-472.|3
03211|001|T|MONOGRAPH TITLE:  HMG Co-A Reductase Inhibitors/Pazopanib|
03211|002|B||
03211|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03211|004|L|take action as needed.|
03211|005|B||
03211|006|A|MECHANISM OF ACTION:  The mechanism of interaction is unknown.  Statins and|
03211|007|A|pazopanib individually may cause ALT elevations.(1)  They share metabolic|
03211|008|A|pathways (CYP3A4) and drug transporters (P-glycoprotein (P-gp), BCRP).|
03211|009|A|Pazopanib is a weak inhibitor of CYP3A4, and the statins inhibit P-gp.(2-5)|
03211|010|A|Their combination may result in elevated drug exposure and toxicity.|
03211|011|B||
03211|012|E|CLINICAL EFFECTS:  Concomitant use of pazopanib and simvastatin is|
03211|013|E|associated with ALT elevations greater than 3 x ULN.  Rhabdomyolysis has|
03211|014|E|been reported with the combination of pazopanib and rosuvastatin.  Symptoms|
03211|015|E|of rhabdomyolysis include muscle pain, tenderness, weakness, elevated|
03211|016|E|creatine kinase levels, and reddish-brown, heme positive urine.|
03211|017|B||
03211|018|P|PREDISPOSING FACTORS:  None determined.|
03211|019|B||
03211|020|M|PATIENT MANAGEMENT:  Consider the risks versus benefits of continuing|
03211|021|M|antilipidemic therapy.  Monitor patients receiving concurrent therapy for|
03211|022|M|signs of hepatotoxicity and rhabdomyolysis.|
03211|023|M|   The manufacturer of pazopanib states that if ALT elevation occurs in a|
03211|024|M|patient on concomitant simvastatin, pazopanib should be held or discontinued|
03211|025|M|according to recommendations in the pazopanib prescribing information.|
03211|026|M|Alternatively, consider discontinuing simvastatin.  There is insufficient|
03211|027|M|data to recommend alternative statins for use in combination with|
03211|028|M|pazopanib.(1)|
03211|029|B||
03211|030|D|DISCUSSION:  A review of 11 pazopanib clinical trials found that ALT|
03211|031|D|elevations greater than 3 x ULN occurred in 27 % (11/41) and 14 % (126/895)|
03211|032|D|of patients with and without concomitant simvastatin, respectively.  ALT|
03211|033|D|elevations also occurred more frequently in patients on atorvastatin and on|
03211|034|D|any statin, but the differences were not statistically significant. ALT|
03211|035|D|recovered to less than 2.5 x ULN in all ten patients with follow-up data.|
03211|036|D|Two patients did not have any modification to therapy, while the rest|
03211|037|D|discontinued one or both agents.(2)|
03211|038|D|   In a case report, a 73-year-old woman with metastatic renal cell|
03211|039|D|carcinoma presented with rhabdomyolysis, transaminitis, and renal injury six|
03211|040|D|months after starting pazopanib.  She had been on rosuvastatin for several|
03211|041|D|years.  Pazopanib and rosuvastatin were discontinued and the patient|
03211|042|D|recovered.  Rhabdomyolysis due to the combination of rosuvastatin and|
03211|043|D|pazopanib was suspected, though rosuvastatin is primarily metabolized by|
03211|044|D|CYP2C9 and pazopanib is not known to inhibit CYP2C9.(3)|
03211|045|B||
03211|046|R|REFERENCES:|
03211|047|B||
03211|048|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03211|049|R|  2020.|1
03211|050|R|2.Xu CF, Xue Z, Bing N, King KS, McCann LA, de Souza PL, Goodman VL, Spraggs|2
03211|051|R|  CF, Mooser VE, Pandite LN. Concomitant use of pazopanib and simvastatin|2
03211|052|R|  increases the risk of transaminase elevations in patients with cancer. Ann|2
03211|053|R|  Oncol 2012 Sep;23(9):2470-1.|2
03211|054|R|3.Logue JM, Kiani B, Bitting RL. Pazopanib and Statin-Induced|3
03211|055|R|  Rhabdomyolysis. Case Rep Oncol 2017 Sep-Dec;10(3):954-957.|3
03211|056|R|4.This information is based on an extract from the Certara Drug Interaction|6
03211|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03211|058|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03211|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03211|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03211|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03211|062|R|  11/14/2017.|1
03212|001|T|MONOGRAPH TITLE:  Dapagliflozin-Saxagliptin-Metformin/Strong CYP3A4|
03212|002|T|Inhibitors|
03212|003|B||
03212|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03212|005|L|is contraindicated and generally should not be dispensed or administered to|
03212|006|L|the same patient.|
03212|007|B||
03212|008|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03212|009|A|of saxagliptin.(1,2)|
03212|010|B||
03212|011|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03212|012|E|in elevated levels and increased effects of saxagliptin.(1,2)|
03212|013|B||
03212|014|P|PREDISPOSING FACTORS:  None determined.|
03212|015|B||
03212|016|M|PATIENT MANAGEMENT:  The US manufacturer of the combination product|
03212|017|M|containing dapagliflozin-saxagliptin-metformin states that this combination|
03212|018|M|should not be coadministered with strong inhibitors of CYP3A4.(1)|
03212|019|B||
03212|020|D|DISCUSSION:  Pretreatment with ketoconazole (200 mg every 12 hours for 9|
03212|021|D|days) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
03212|022|D|of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively.|
03212|023|D|The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and|
03212|024|D|91%, respectively.   The Cmax and AUC of ketoconazole decreased 16% and 13%,|
03212|025|D|respectively.(1,2)|
03212|026|D|   Pretreatment with ketoconazole (200 mg every 12 hours for 7 days)|
03212|027|D|increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by|
03212|028|D|2.4-fold and 3.7-fold, respectively.  The Cmax and AUC of the active|
03212|029|D|metabolite of saxagliptin decreased 96% and 90%, respectively.(1)|
03212|030|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03212|031|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03212|032|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03212|033|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03212|034|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib,|
03212|035|D|and voriconazole.(1,3)|
03212|036|B||
03212|037|R|REFERENCES:|
03212|038|B||
03212|039|R|1.Qternmet XR (dapagliflozin, saxaglipitin, metformin) US prescribing|1
03212|040|R|  information. AstraZeneca Pharmaceuticals LP May, 2019.|1
03212|041|R|2.Patel CG, Li L, Girgis S, Kornhauser DM, Frevert EU, Boulton DW. Two-way|2
03212|042|R|  pharmacokinetic interaction studies between saxagliptin and cytochrome|2
03212|043|R|  P450 substrates or inhibitors: simvastatin, diltiazem extended-release,|2
03212|044|R|  and ketoconazole. Clin Pharmacol 2011;3:13-25.|2
03212|045|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03212|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03212|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03212|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03212|049|R|  11/14/2017.|1
03213|001|T|MONOGRAPH TITLE:  Cyclosporine/Selected Fibrates|
03213|002|B||
03213|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03213|004|L|take action as needed.|
03213|005|B||
03213|006|A|MECHANISM OF ACTION:  Concurrent use of cyclosporine and fibrates may result|
03213|007|A|in additive nephrotoxicity.(1)|
03213|008|B||
03213|009|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine and fibrates may result in|
03213|010|E|additive nephrotoxicity.(1)|
03213|011|B||
03213|012|P|PREDISPOSING FACTORS:  None determined.|
03213|013|B||
03213|014|M|PATIENT MANAGEMENT:  Use concurrent cyclosporine and fibrates with caution.|
03213|015|M|If concurrent use is warranted, use the lowest effective dose of the fibrate|
03213|016|M|and monitor patients for decreased renal function.|
03213|017|B||
03213|018|D|DISCUSSION:  In a study in heart-transplant patients, concurrent fenofibrate|
03213|019|D|had no effect on cyclosporine levels, but patients developed increased serum|
03213|020|D|concentration.(2)|
03213|021|D|   Two studies in transplant patients found that gemfibrozil had no effect|
03213|022|D|on cyclosporine levels or renal function.(3,4)|
03213|023|B||
03213|024|R|REFERENCES:|
03213|025|B||
03213|026|R|1.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
03213|027|R|  Corporation September, 2023.|1
03213|028|R|2.deLorgeril M, Boissonnat P, Bizollon CA, Guidollet J, Faucon G, Guichard|2
03213|029|R|  JP, Levy-Prades-Sauron R, Renaud S, Dureau G. Pharmacokinetics of|2
03213|030|R|  cyclosporine in hyperlipidaemic long-term survivors of heart|2
03213|031|R|  transplantation. Lack of interaction with the lipid-lowering agent,|2
03213|032|R|  fenofibrate. Eur J Clin Pharmacol 1992;43(2):161-5.|2
03213|033|R|3.Hanes DS, Nicholson PG, Raval DD, Hooper FL, Behrens MT, Weir MR. A|2
03213|034|R|  crossover comparison of the efficacy and safety of lovastatin and|2
03213|035|R|  gemfibrozil in the treatment of hyperlipidemic organ transplant|2
03213|036|R|  recipients. Am J Ther 1997 Feb-Mar;4(2-3):85-91.|2
03213|037|R|4.Broeders N, Knoop C, Antoine M, Tielemans C, Abramowicz D. Fibrate-induced|2
03213|038|R|  increase in blood urea and creatinine: is gemfibrozil the only innocuous|2
03213|039|R|  agent?. Nephrol Dial Transplant 2000 Dec;15(12):1993-9.|2
03214|001|T|MONOGRAPH TITLE:  Tofacitinib (Greater Than or Equal To 20 mg|
03214|002|T|daily)/Estrogens|
03214|003|B||
03214|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03214|005|L|of severe adverse interaction.|
03214|006|B||
03214|007|A|MECHANISM OF ACTION:  Estrogens increase the risk of thrombosis, and|
03214|008|A|combining estrogens with a higher dose of tofacitinib (greater than or equal|
03214|009|A|to 10 mg twice daily, or 20 mg/day) may place patients at high risk of|
03214|010|A|thromboembolism.(1-3)|
03214|011|B||
03214|012|E|CLINICAL EFFECTS:  Concurrent use of estrogens with a higher dose of|
03214|013|E|tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may|
03214|014|E|increase the incidence of pulmonary embolism and death.(1-3)|
03214|015|B||
03214|016|P|PREDISPOSING FACTORS:  Additional risk factors include advanced age, obesity|
03214|017|P|(BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable|
03214|018|P|states, history of venous thromboembolism, malignancy, and major surgery.(1)|
03214|019|B||
03214|020|M|PATIENT MANAGEMENT:  The European manufacturer states that the 10 mg twice|
03214|021|M|daily dose of tofacitinib is not recommended in patients who are on combined|
03214|022|M|hormonal contraceptives or hormone replacement therapy, or who are otherwise|
03214|023|M|at high risk of pulmonary embolism, unless there are no suitable|
03214|024|M|alternatives.(4)  Patients at high risk of pulmonary embolism should be|
03214|025|M|switched to alternative therapies.  For the treatment of rheumatoid|
03214|026|M|arthritis and psoriatic arthritis, the dose of tofacitinib should be limited|
03214|027|M|to 5 mg twice daily or tofacitinib XR 11 mg daily.(1-4)|
03214|028|M|   The US FDA and Health Canada have not placed use restrictions|
03214|029|M|specifically on concurrent use of tofacitinib with hormonal contraceptives|
03214|030|M|or hormone replacement therapy.  Both agencies advise avoiding tofacitinib|
03214|031|M|in patients at increased risk of thrombosis.  The US and Canadian|
03214|032|M|manufacturers recommend against a dosage of tofacitinib 10 mg twice daily or|
03214|033|M|weight-based equivalent twice daily or tofacitinib XR 22 mg once daily for|
03214|034|M|rheumatoid arthritis, psoriatic arthritis, or polyarticular-course juvenile|
03214|035|M|idiopathic arthritis.  For the treatment of ulcerative colitis, the lowest|
03214|036|M|effective dose for the shortest duration possible is recommended.  Counsel|
03214|037|M|patients on the risk of thrombosis and its signs and symptoms.  Instruct|
03214|038|M|patients to promptly report any symptoms of thrombosis and discontinue|
03214|039|M|tofacitinib in patients with symptoms of thrombosis.(5-7)|
03214|040|M|   There is currently no use restriction on the combination of estrogens|
03214|041|M|with lower doses of tofacitinib (less than 20 mg daily).|
03214|042|B||
03214|043|D|DISCUSSION:  In an ongoing open-label study comparing the safety of|
03214|044|D|tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and a tumor|
03214|045|D|necrosis factor (TNF) inhibitor in rheumatoid arthritis patients 50 years|
03214|046|D|old and older, the incidence of pulmonary embolism (PE) was 6-fold higher in|
03214|047|D|the tofacitinib 10 mg twice daily arm and 3-fold higher in the tofacitinib 5|
03214|048|D|mg twice daily arm compared to the TNF inhibitor arm (17 cases/3,123|
03214|049|D|patient-years, 9 cases/3,317 patient-years, and 3 cases/3,319 patient-years,|
03214|050|D|respectively).  All-cause mortality was also higher in the tofacitinib 10 mg|
03214|051|D|twice daily and 5 mg twice daily arms compared to the TNF inhibitor arm (28|
03214|052|D|deaths/3,140 patient-years, 19 deaths/3,324 patient-years, and 9|
03214|053|D|deaths/3,323 patient-years, respectively).(3)|
03214|054|B||
03214|055|R|REFERENCES:|
03214|056|B||
03214|057|R|1.European Medicines Agency. Increased risk of blood clots in lungs and|1
03214|058|R|  death with higher dose of Xeljanz (tofacitinib) for rheumatoid arthritis.|1
03214|059|R|  https://www.ema.europa.eu/en/documents/press-release/increased-risk-blood-|1
03214|060|R|  clots-lungs-death-higher-dose-xeljanz-tofacitinib-rheumatoid-arthritis_en.|1
03214|061|R|  pdf March 20, 2019.|1
03214|062|R|2.European Medicines Agency. Restrictions in use of Xeljanz while EMA|1
03214|063|R|  reviews risk of blood clots in lungs.|1
03214|064|R|  https://www.ema.europa.eu/en/documents/referral/xeljanz-article-20-procedu|1
03214|065|R|  re-restrictions-use-xeljanz-while-ema-reviews-risk-blood-clots-lungs_en.pd|1
03214|066|R|  f May 17, 2019.|1
03214|067|R|3.European Medicines Agency (EMA). EMA confirms Xeljanz to be used with|1
03214|068|R|  caution in patients at high risk of blood clots. Accessed at:|1
03214|069|R|  https://www.ema.europa.eu/en/documents/referral/xeljanz-article-20-procedu|1
03214|070|R|  re-ema-confirms-xeljanz-be-used-caution-patients-high-risk-blood-clots_en.|1
03214|071|R|  pdf January 31, 2020.|1
03214|072|R|4.Xeljanz (tofacitinib) EMA Summary of Product Characteristics. Pfizer|1
03214|073|R|  Europe MA EEIG March 6, 2020.|1
03214|074|R|5.USFood and Drug Administration. FDA Drug Safety Communication: Safety|1
03214|075|R|  trial finds risk of blood clots in the lungs and death with higher dose of|1
03214|076|R|  tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to|1
03214|077|R|  investigate.|1
03214|078|R|  https://www.fda.gov/drugs/drug-safety-and-availability/safety-trial-finds-|1
03214|079|R|  risk-blood-clots-lungs-and-death-higher-dose-tofacitinib-xeljanz-xeljanz-x|1
03214|080|R|  r February 25, 2019.|1
03214|081|R|6.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. October,|1
03214|082|R|  2025.|1
03214|083|R|7.Xeljanz (tofacitinib) Canadian prescribing information. Pfizer Canada ULC|1
03214|084|R|  April 12, 2024.|1
03215|001|T|MONOGRAPH TITLE:  Cilostazol (Greater Than 50 mg BID)/Strong & Moderate 3A4|
03215|002|T|Inhibitors that Prolong QT|
03215|003|B||
03215|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03215|005|L|is contraindicated and generally should not be dispensed or administered to|
03215|006|L|the same patient.|
03215|007|B||
03215|008|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may inhibit|
03215|009|A|the metabolism of cilostazol at CYP3A4.(1)  Both agents have been shown to|
03215|010|A|prolong the QT interval.(1,2)|
03215|011|B||
03215|012|E|CLINICAL EFFECTS:  The concurrent use of cilostazol and strong and moderate|
03215|013|E|inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may|
03215|014|E|produce increased effects of cilostazol and adverse effects.(1)  Concurrent|
03215|015|E|use may also result in potentially life-threatening cardiac arrhythmias,|
03215|016|E|including torsades de pointes (TdP).(2)|
03215|017|B||
03215|018|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
03215|019|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
03215|020|P|failure, myocardial infarction, history of torsade de pointes, congenital|
03215|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03215|022|P|female gender, or advanced age.(1)|
03215|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03215|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03215|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03215|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03215|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03215|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03215|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)|
03215|030|P|   This interaction may also be more severe in patients taking inhibitors of|
03215|031|P|CYP2C19.(1)|
03215|032|B||
03215|033|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
03215|034|M|daily in patients receiving concurrent therapy with strong and moderate|
03215|035|M|inhibitors of CYP3A4.(1)|
03215|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03215|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03215|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03215|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03215|040|B||
03215|041|D|DISCUSSION:  In a study in 16 healthy males, the administration of a single|
03215|042|D|dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours)|
03215|043|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
03215|044|D|cilostazol by 47% and 73%, respectively.  The Cmax and AUC of|
03215|045|D|4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(3)|
03215|046|D|   Analysis of population pharmacokinetics indicated that the concurrent|
03215|047|D|administration of diltiazem with cilostazol increased cilostazol|
03215|048|D|concentrations by 53%.(1)  Concurrent administration of diltiazem and|
03215|049|D|cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%,|
03215|050|D|and increased AUC by 40%.|
03215|051|D|   In a study, the administration of a single dose of cilostazol (10 mg)|
03215|052|D|with erythromycin (500 mg every eight hours) increased the Cmax and AUC of|
03215|053|D|cilostazol by 47% and 73%, respectively.  The AUC of|
03215|054|D|4'-trans-hydroxy-cilostazol was increased by 141%.(1)  In an vitro study in|
03215|055|D|human liver microsomes, ketoconazole inhibited the metabolism of|
03215|056|D|cilostazol.(4)|
03215|057|D|   One or more of the drug pairs linked to this monograph have been included|
03215|058|D|in a list of interactions that should be considered "high-priority" for|
03215|059|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
03215|060|D|vetted by an expert panel commissioned by the U.S. Office of the National|
03215|061|D|Coordinator (ONC) for Health Information Technology.|
03215|062|B||
03215|063|R|REFERENCES:|
03215|064|B||
03215|065|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
03215|066|R|  Pharmaceutical, Inc. January, 2015.|1
03215|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03215|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03215|069|R|  settings: a scientific statement from the American Heart Association and|6
03215|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03215|071|R|  2;55(9):934-47.|6
03215|072|R|3.Suri A, Forbes WP, Bramer SL. Effects of CYP3A inhibition on the|2
03215|073|R|  metabolism of cilostazol. Clin Pharmacokinet 1999;37 Suppl 2:61-8.|2
03215|074|R|4.Abbas R, Chow CP, Browder NJ, Thacker D, Bramer SL, Fu CJ, Forbes W, Odomi|5
03215|075|R|  M, Flockhart DA. In vitro metabolism and interaction of cilostazol with|5
03215|076|R|  human hepatic cytochrome P450 isoforms. Hum Exp Toxicol 2000 Mar;|5
03215|077|R|  19(3):178-84.|5
03215|078|R|5.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
03215|079|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
03215|080|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
03215|081|R|  19(5):735-43.|6
03216|001|T|MONOGRAPH TITLE:  Cilostazol (Greater Than 50 mg BID)/Strong & Moderate|
03216|002|T|CYP2C19 Inhibitors that Prolong QT|
03216|003|B||
03216|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03216|005|L|is contraindicated and generally should not be dispensed or administered to|
03216|006|L|the same patient.|
03216|007|B||
03216|008|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP2C19 may inhibit|
03216|009|A|the metabolism of cilostazol.(1-4)   Both agents have been shown to prolong|
03216|010|A|the QT interval.(1,5)|
03216|011|B||
03216|012|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate inhibitors of|
03216|013|E|CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a|
03216|014|E|metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)|
03216|015|E|Concurrent use may also result in potentially life-threatening cardiac|
03216|016|E|arrhythmias, including torsades de pointes(TdP).(6)|
03216|017|B||
03216|018|P|PREDISPOSING FACTORS:  None determined.|
03216|019|B||
03216|020|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
03216|021|M|daily in patients receiving concurrent therapy with strong and moderate|
03216|022|M|inhibitors of CYP2C19.(1)|
03216|023|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03216|024|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03216|025|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03216|026|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03216|027|B||
03216|028|D|DISCUSSION:  In a study in 20 subjects examined the effects of omeprazole|
03216|029|D|(40 mg daily) on a single dose of cilostazol (100 mg).  Concurrent|
03216|030|D|omeprazole increased the cilostazol maximum concentration (Cmax) and|
03216|031|D|area-under-curve (AUC) by 18% and 26%, respectively.  The Cmax and AUC of|
03216|032|D|the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%,|
03216|033|D|respectively.  The Cmax and AUC of the OPC-13213 metabolite of cilostazol|
03216|034|D|decreased by 22% and 31%, respectively.(4)|
03216|035|D|   One or more of the drug pairs linked to this monograph have been included|
03216|036|D|in a list of interactions that should be considered "high-priority" for|
03216|037|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
03216|038|D|vetted by an expert panel commissioned by the U.S. Office of the National|
03216|039|D|Coordinator (ONC) for Health Information Technology.|
03216|040|B||
03216|041|R|REFERENCES:|
03216|042|B||
03216|043|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
03216|044|R|  Pharmaceutical, Inc. January, 2015.|1
03216|045|R|2.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
03216|046|R|  Pharmaceuticals LP August, 2021.|1
03216|047|R|3.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
03216|048|R|  Pharmaceuticals LP June, 2018.|1
03216|049|R|4.Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol.|2
03216|050|R|  Clin Pharmacokinet 1999;37 Suppl 2:53-9.|2
03216|051|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03216|052|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03216|053|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03216|054|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03216|055|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03216|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03216|057|R|  settings: a scientific statement from the American Heart Association and|6
03216|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03216|059|R|  2;55(9):934-47.|6
03216|060|R|7.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
03216|061|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
03216|062|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
03216|063|R|  19(5):735-43.|6
03217|001|T|MONOGRAPH TITLE:  Cilostazol (Greater than 50 mg BID)/Selected Strong &|
03217|002|T|Moderate CYP3A4 Inhibitors|
03217|003|B||
03217|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03217|005|L|is contraindicated and generally should not be dispensed or administered to|
03217|006|L|the same patient.|
03217|007|B||
03217|008|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may inhibit|
03217|009|A|the metabolism of cilostazol.(1)|
03217|010|B||
03217|011|E|CLINICAL EFFECTS:  The concurrent use of cilostazol and strong and moderate|
03217|012|E|inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may|
03217|013|E|produce increased effects of cilostazol and adverse effects.(1)|
03217|014|B||
03217|015|P|PREDISPOSING FACTORS:  None determined.|
03217|016|B||
03217|017|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
03217|018|M|daily in patients receiving concurrent therapy with strong and moderate|
03217|019|M|inhibitors of CYP3A4.(1)|
03217|020|B||
03217|021|D|DISCUSSION:  In a study in 16 healthy males, the administration of a single|
03217|022|D|dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours)|
03217|023|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
03217|024|D|cilostazol by 47% and 73%, respectively.  The Cmax and AUC of|
03217|025|D|4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(2)|
03217|026|D|   Analysis of population pharmacokinetics indicated that the concurrent|
03217|027|D|administration of diltiazem with cilostazol increased cilostazol|
03217|028|D|concentrations by 53%.  Concurrent administration of diltiazem and|
03217|029|D|cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%,|
03217|030|D|and increased AUC by 40%.(1)|
03217|031|D|   In a study, the administration of a single dose of cilostazol (10 mg)|
03217|032|D|with erythromycin (500 mg every eight hours) increased the Cmax and AUC of|
03217|033|D|cilostazol by 47% and 73%, respectively.  The AUC of|
03217|034|D|4'-trans-hydroxy-cilostazol was increased by 141%.(1)  In an vitro study in|
03217|035|D|human liver microsomes, ketoconazole inhibited the metabolism of|
03217|036|D|cilostazol.(3)|
03217|037|B||
03217|038|R|REFERENCES:|
03217|039|B||
03217|040|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
03217|041|R|  Pharmaceutical, Inc. January, 2015.|1
03217|042|R|2.Suri A, Forbes WP, Bramer SL. Effects of CYP3A inhibition on the|2
03217|043|R|  metabolism of cilostazol. Clin Pharmacokinet 1999;37 Suppl 2:61-8.|2
03217|044|R|3.Abbas R, Chow CP, Browder NJ, Thacker D, Bramer SL, Fu CJ, Forbes W, Odomi|5
03217|045|R|  M, Flockhart DA. In vitro metabolism and interaction of cilostazol with|5
03217|046|R|  human hepatic cytochrome P450 isoforms. Hum Exp Toxicol 2000 Mar;|5
03217|047|R|  19(3):178-84.|5
03218|001|T|MONOGRAPH TITLE:  Cilostazol (Less Than or Equal To 50 mg BID)/Selected|
03218|002|T|Strong & Moderate CYP2C19 Inhibitors|
03218|003|B||
03218|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03218|005|L|take action as needed.|
03218|006|B||
03218|007|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP2C19 may inhibit|
03218|008|A|the metabolism of cilostazol.(1-4)|
03218|009|B||
03218|010|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate inhibitors of|
03218|011|E|CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a|
03218|012|E|metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)|
03218|013|B||
03218|014|P|PREDISPOSING FACTORS:  None determined.|
03218|015|B||
03218|016|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
03218|017|M|daily in patients receiving concurrent therapy with strong and moderate|
03218|018|M|inhibitors of CYP2C19.(1)|
03218|019|M|   The Australian manufacturer of esomeprazole states concomitant use with|
03218|020|M|cilostazol is contraindicated.(5)|
03218|021|B||
03218|022|D|DISCUSSION:  In a study in 20 subjects examined the effects of omeprazole|
03218|023|D|(40 mg daily) on a single dose of cilostazol (100 mg).  Concurrent|
03218|024|D|omeprazole increased the cilostazol maximum concentration (Cmax) and|
03218|025|D|area-under-curve (AUC) by 18% and 26%, respectively.  The Cmax and AUC of|
03218|026|D|the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%,|
03218|027|D|respectively.  The Cmax and AUC of the OPC-13213 metabolite of cilostazol|
03218|028|D|decreased by 22% and 31%, respectively.(4)|
03218|029|B||
03218|030|R|REFERENCES:|
03218|031|B||
03218|032|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
03218|033|R|  Pharmaceutical, Inc. January, 2015.|1
03218|034|R|2.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
03218|035|R|  Pharmaceuticals LP August, 2021.|1
03218|036|R|3.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
03218|037|R|  Pharmaceuticals LP June, 2018.|1
03218|038|R|4.Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol.|2
03218|039|R|  Clin Pharmacokinet 1999;37 Suppl 2:53-9.|2
03218|040|R|5.Nexium (esomeprazole magnesium trihydrate) Australian prescribing|1
03218|041|R|  information. AstraZeneca Pty Ltd December 2022.|1
03219|001|T|MONOGRAPH TITLE:  Cilostazol (Greater Than 50 mg BID)/Selected Strong &|
03219|002|T|Moderate CYP2C19 Inhibitors|
03219|003|B||
03219|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03219|005|L|is contraindicated and generally should not be dispensed or administered to|
03219|006|L|the same patient.|
03219|007|B||
03219|008|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP2C19 may inhibit|
03219|009|A|the metabolism of cilostazol.(1-4)|
03219|010|B||
03219|011|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate inhibitors of|
03219|012|E|CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a|
03219|013|E|metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)|
03219|014|B||
03219|015|P|PREDISPOSING FACTORS:  None determined.|
03219|016|B||
03219|017|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
03219|018|M|daily in patients receiving concurrent therapy with strong and moderate|
03219|019|M|inhibitors of CYP2C19.(1)|
03219|020|M|   The Australian manufacturer of esomeprazole states concomitant use with|
03219|021|M|cilostazol is contraindicated.(5)|
03219|022|B||
03219|023|D|DISCUSSION:  In a study in 20 subjects examined the effects of omeprazole|
03219|024|D|(40 mg daily) on a single dose of cilostazol (100 mg).  Concurrent|
03219|025|D|omeprazole increased the cilostazol maximum concentration (Cmax) and|
03219|026|D|area-under-curve (AUC) by 18% and 26%, respectively.  The Cmax and AUC of|
03219|027|D|the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%,|
03219|028|D|respectively.  The Cmax and AUC of the OPC-13213 metabolite of cilostazol|
03219|029|D|decreased by 22% and 31%, respectively.(4)|
03219|030|B||
03219|031|R|REFERENCES:|
03219|032|B||
03219|033|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
03219|034|R|  Pharmaceutical, Inc. January, 2015.|1
03219|035|R|2.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
03219|036|R|  Pharmaceuticals LP August, 2021.|1
03219|037|R|3.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
03219|038|R|  Pharmaceuticals LP June, 2018.|1
03219|039|R|4.Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol.|2
03219|040|R|  Clin Pharmacokinet 1999;37 Suppl 2:53-9.|2
03219|041|R|5.Nexium (esomeprazole magnesium trihydrate) Australian prescribing|1
03219|042|R|  information. AstraZeneca Pty Ltd December 2022.|1
03220|001|T|MONOGRAPH TITLE:  Apomorphine/Selected Antihypertensives and Vasodilators|
03220|002|B||
03220|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03220|004|L|take action as needed.|
03220|005|B||
03220|006|A|MECHANISM OF ACTION:  Apomorphine causes dose-dependent decreases in blood|
03220|007|A|pressure.  Concurrent use with antihypertensive agents may result in|
03220|008|A|additive effects on blood pressure.(1)|
03220|009|B||
03220|010|E|CLINICAL EFFECTS:  Concurrent use of antihypertensives and apomorphine may|
03220|011|E|result in orthostatic hypotension with or without dizziness, nausea, or|
03220|012|E|syncope.(1)|
03220|013|B||
03220|014|P|PREDISPOSING FACTORS:  The risk of orthostatic hypotension may be increased|
03220|015|P|during dose escalation of apomorphine and in patients with renal or hepatic|
03220|016|P|impairment.(1)|
03220|017|B||
03220|018|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
03220|019|M|monitored for hypotension.  Counsel patients about the risk of orthostatic|
03220|020|M|hypotension.(1)|
03220|021|B||
03220|022|D|DISCUSSION:  Healthy volunteers who took sublingual nitroglycerin (0.4 mg)|
03220|023|D|concomitantly with apomorphine experienced a mean largest decrease in supine|
03220|024|D|systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood|
03220|025|D|pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and|
03220|026|D|DBP of 14.3 mm Hg and 13.5 mm Hg, respectively.  The maximum decrease in SBP|
03220|027|D|and DBP was 65 mm Hg and 43 mm Hg, respectively.  When apomorphine was taken|
03220|028|D|alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3|
03220|029|D|mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm|
03220|030|D|Hg, respectively.(1)|
03220|031|B||
03220|032|R|REFERENCE:|
03220|033|B||
03220|034|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03220|035|R|  Inc. May, 2019.|1
03221|001|T|MONOGRAPH TITLE:  5-Fluorouracil/High-Dose Folic Acid|
03221|002|B||
03221|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03221|004|L|of severe adverse interaction.|
03221|005|B||
03221|006|A|MECHANISM OF ACTION:  Folic acid has been shown to enhance both the|
03221|007|A|therapeutic and toxic effects of fluoropyrimidines, such as 5-fluorouracil|
03221|008|A|(5-FU).(1,2)|
03221|009|B||
03221|010|E|CLINICAL EFFECTS:  Folic acid, when used concurrently with 5-FU, has been|
03221|011|E|shown to increase side effects of 5-FU.(1,2)|
03221|012|B||
03221|013|P|PREDISPOSING FACTORS:  Patients who are intermediate or poor|
03221|014|P|dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no|
03221|015|P|DPYD function.  Since DPYD is the rate-limiting enzyme involved in|
03221|016|P|fluoropyrimidine metabolism, these patients may be more susceptible to the|
03221|017|P|effects of this interaction.(3)|
03221|018|B||
03221|019|M|PATIENT MANAGEMENT:  Folic acid intake may need to be limited in patients|
03221|020|M|experiencing toxicity from 5-fluorouracil.(1,2)|
03221|021|B||
03221|022|D|DISCUSSION:  Due to increased toxic effects, stomatitis and diarrhea are|
03221|023|D|observed more commonly, may be more severe, and may occur for a prolonged|
03221|024|D|duration when compared to therapy with 5-FU alone.|
03221|025|D|   It is postulated that the lower standard dose of 5-FU in the US versus|
03221|026|D|other regions may be due to increased folic acid supplementation within the|
03221|027|D|US food supply.(1)|
03221|028|D|   In a case report, a woman developed grade 4 diarrhea, grade 3 vomiting,|
03221|029|D|and grade 3 hand-foot syndrome 8 days after the addition of capecitabine|
03221|030|D|(2500 mg/m2/day) to high-dose folic acid supplementation.  She developed|
03221|031|D|necrotic colitis and died, despite the discontinuation of folic acid and|
03221|032|D|capecitabine.(3)  There are two other reports of excessive fluorouracil|
03221|033|D|toxicity in patients treated with folic acid.(4)|
03221|034|B||
03221|035|R|REFERENCES:|
03221|036|B||
03221|037|R|1.Midgley R, Kerr DJ. Capecitabine: have we got the dose right?. Nat Clin|6
03221|038|R|  Pract Oncol 2009 Jan;6(1):17-24.|6
03221|039|R|2.Bayraktar S, Gluck S. Management of capecitabine-related gastrointestinal|6
03221|040|R|  toxicities in women with breast cancer. Commun Oncol 2011 Feb;8:81-87.|6
03221|041|R|3.Clippe C, Freyer G, Milano G, Trillet-Lenoir V. Lethal toxicity of|3
03221|042|R|  capecitabine due to abusive folic acid prescription?. Clin Oncol (R Coll|3
03221|043|R|  Radiol) 2003 Aug;15(5):299-300.|3
03221|044|R|4.Mainwaring P, Grygiel JJ. Interaction of 5-fluorouracil with folates. Aust|3
03221|045|R|  N Z J Med 1995 Feb;25(1):60.|3
03222|001|T|MONOGRAPH TITLE:  Selected CYP2C9 Substrates/Nitisinone|
03222|002|B||
03222|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03222|004|L|take action as needed.|
03222|005|B||
03222|006|A|MECHANISM OF ACTION:  Nitisinone is a moderate inhibitor of CYP2C9.(1,2)|
03222|007|B||
03222|008|E|CLINICAL EFFECTS:  Decreased clearance may increase systemic concentrations|
03222|009|E|of drugs primarily metabolized by CYP2C9, leading to toxicity.(1,2)|
03222|010|B||
03222|011|P|PREDISPOSING FACTORS:  None determined.|
03222|012|B||
03222|013|M|PATIENT MANAGEMENT:  Decrease the dosage of the CYP2C9 substrate drug by|
03222|014|M|one-half.  Additional dose adjustments may be necessary.  Closely monitor|
03222|015|M|patients stable on CYP2C9 substrates for altered therapeutic effect or|
03222|016|M|toxicity when nitisinone therapy is started or adjusted.(1)|
03222|017|B||
03222|018|D|DISCUSSION:  In a study, 16 healthy subjects who were pre-treated with|
03222|019|D|nitisinone (80 mg daily) for 14 days and received a single dose of|
03222|020|D|tolbutamide (500 mg) had an increase in tolbutamide area-under-curve (AUC)|
03222|021|D|and maximum concentration (Cmax) of 131 % and 16 %, respectively, compared|
03222|022|D|to tolbutamide administered alone.(1,2)|
03222|023|D|   Medications linked to this interaction include fluvastatin, fosphenytoin,|
03222|024|D|glimepiride, glipizide, phenytoin, tolbutamide, and warfarin.  These drugs|
03222|025|D|have a narrow therapeutic range or are designated as CYP2C9 Sensitive|
03222|026|D|Substrates(3,4) (i.e. moderate 2C9 inhibitors are expected to increase|
03222|027|D|exposure (AUC) to these agents by 2-fold to 5-fold).|
03222|028|B||
03222|029|R|REFERENCES:|
03222|030|B||
03222|031|R|1.Orfadin (nitisinone) US prescribing information. Rare Diseases|1
03222|032|R|  Therapeutics, Inc. May, 2019.|1
03222|033|R|2.Huledal G, Olsson B, Onnestam K, Dalen P, Lindqvist D, Kruse M, Broijersen|2
03222|034|R|  A. Non randomized study on the potential of nitisinone to inhibit|2
03222|035|R|  cytochrome P450 2C9, 2D6, 2E1 and the organic anion transporters OAT1 and|2
03222|036|R|  OAT3 in healthy volunteers. Eur J Clin Pharmacol 2019 Mar;75(3):313-320.|2
03222|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
03222|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03222|039|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03222|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03222|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03222|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03222|043|R|  11/14/2017.|1
03223|001|T|MONOGRAPH TITLE:  Apomorphine/Nitroglycerin (Sublingual)|
03223|002|B||
03223|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03223|004|L|take action as needed.|
03223|005|B||
03223|006|A|MECHANISM OF ACTION:  Apomorphine causes dose-dependent decreases in blood|
03223|007|A|pressure.  Concurrent use with sublingual nitroglycerin may result in|
03223|008|A|additive effects on blood pressure.(1)|
03223|009|B||
03223|010|E|CLINICAL EFFECTS:  Concurrent use of sublingual nitroglycerin and|
03223|011|E|apomorphine may result in orthostatic hypotension with or without dizziness,|
03223|012|E|nausea, or syncope.(1)|
03223|013|B||
03223|014|P|PREDISPOSING FACTORS:  The risk of orthostatic hypotension may be increased|
03223|015|P|during dose escalation of apomorphine and in patients with renal or hepatic|
03223|016|P|impairment.(1)|
03223|017|B||
03223|018|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
03223|019|M|monitored for hypotension.  Advise the patient to lie down before and for 45|
03223|020|M|minutes after taking nitroglycerin.  Counsel patients about the risk of|
03223|021|M|orthostatic hypotension.(1)|
03223|022|B||
03223|023|D|DISCUSSION:  Healthy volunteers who took sublingual nitroglycerin (0.4 mg)|
03223|024|D|concomitantly with apomorphine experienced a mean largest decrease in supine|
03223|025|D|systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood|
03223|026|D|pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and|
03223|027|D|DBP of 14.3 mm Hg and 13.5 mm Hg, respectively.  The maximum decrease in SBP|
03223|028|D|and DBP was 65 mm Hg and 43 mm Hg, respectively.  When apomorphine was taken|
03223|029|D|alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3|
03223|030|D|mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm|
03223|031|D|Hg, respectively.(1)|
03223|032|B||
03223|033|R|REFERENCE:|
03223|034|B||
03223|035|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03223|036|R|  Inc. May, 2019.|1
03224|001|T|MONOGRAPH TITLE:  Apomorphine/Alcohol|
03224|002|B||
03224|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03224|004|L|take action as needed.|
03224|005|B||
03224|006|A|MECHANISM OF ACTION:  Apomorphine is associated with hypotension or syncopal|
03224|007|A|episodes.  High doses of alcohol (0.6 gram/kg) may increase the levels of|
03224|008|A|apomorphine.(1)|
03224|009|B||
03224|010|E|CLINICAL EFFECTS:  Concurrent use of alcohol in patients taking apomorphine|
03224|011|E|may substantially increase the risk for hypotension or syncope.(1)|
03224|012|B||
03224|013|P|PREDISPOSING FACTORS:  The risk of orthostatic hypotension may be increased|
03224|014|P|during dose escalation of apomorphine and in renal and hepatic impairment.|
03224|015|B||
03224|016|M|PATIENT MANAGEMENT:  Counsel patients to avoid alcohol while using|
03224|017|M|apomorphine due to the increased risk of hypotension.(1)|
03224|018|M|   Significant quantities of alcohol may be present in medicinal products.|
03224|019|M|Alcohol is is used to improve docetaxel and paclitaxel solubility.|
03224|020|M|   - The quantity of alcohol in paclitaxel injection formulations|
03224|021|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
03224|022|M|dose contains approximately 13 grams of alcohol.|
03224|023|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
03224|024|M|3-fold depending upon the manufacturer. FDA data on alcohol content (3):|
03224|025|M|   Product                      Manufacturer         Alcohol/200 mg dose|
03224|026|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
03224|027|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
03224|028|M|   Docetaxel Inj.               Accord                  4.0 grams|
03224|029|M|   Taxotere-one vial            Sanofi                  4.0 grams|
03224|030|M|    formulation|
03224|031|M|   Docetaxel Inj.               Hospira                 3.7 grams|
03224|032|M|   Docefrez                     Sun Pharma              2.9 grams|
03224|033|M|   Taxotere-two vial            Sanofi                  2.0 grams|
03224|034|M|    formulation|
03224|035|B||
03224|036|D|DISCUSSION:  Healthy volunteers who had high dose ethanol (0.6 gram/kg, or 3|
03224|037|D|standardized alcoholic beverages) concomitantly with apomorphine experienced|
03224|038|D|a mean largest decrease in supine systolic blood pressure (SBP) of 9.1 mm Hg|
03224|039|D|and in supine diastolic blood pressure (DBP) of 10.5 mm Hg, and a mean|
03224|040|D|largest decrease in standing SBP and DBP of 11.3 mm Hg and 12.6 mm Hg,|
03224|041|D|respectively.  The maximum decrease in SBP and DBP was 61 mm Hg and 51 mm|
03224|042|D|Hg, respectively.|
03224|043|D|   With low dose ethanol (0.3 gram/kg), a mean largest decrease in supine|
03224|044|D|SBP and DBP of 10.2 mm Hg and 9.9 mm Hg, respectively, and in standing SBP|
03224|045|D|and DBP of 8.4 mm Hg and 7.1 mm Hg were seen.|
03224|046|D|   When apomorphine was taken alone, the mean largest decrease in supine SBP|
03224|047|D|and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and|
03224|048|D|DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.|
03224|049|D|   High dose ethanol increased the maximum concentration (Cmax) of|
03224|050|D|apomorphine by 63 %.  Low dose ethanol did not significantly affect the|
03224|051|D|pharmacokinetics of apomorphine.  However, an increase in the hypotensive|
03224|052|D|effect of apomorphine was still noted, as described above.(1)|
03224|053|B||
03224|054|R|REFERENCES:|
03224|055|B||
03224|056|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03224|057|R|  Inc. May, 2019.|1
03224|058|R|2.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
03224|059|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
03224|060|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
03224|061|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
03224|062|R|  20, 2014.|1
03225|001|T|MONOGRAPH TITLE:  Colesevelam/Fat Soluble Vitamins|
03225|002|B||
03225|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03225|004|L|take action as needed.|
03225|005|B||
03225|006|A|MECHANISM OF ACTION:  Colesevelam may decrease the absorption of fat-soluble|
03225|007|A|vitamins A, D, E, and K.(1)|
03225|008|B||
03225|009|E|CLINICAL EFFECTS:  Colesevelam may reduce absorption of fat soluble|
03225|010|E|vitamins, leading to a deficiency state.|
03225|011|B||
03225|012|P|PREDISPOSING FACTORS:  A pre-existing deficiency of fat soluble vitamins|
03225|013|P|(A,D,E and K) or chronic malabsorption syndrome.|
03225|014|B||
03225|015|M|PATIENT MANAGEMENT:  The inhibition of fat soluble vitamin absorption by|
03225|016|M|colesevelam should be borne in mind during implementation of a vitamin|
03225|017|M|supplementation strategy. Oral multivitamin supplements should be taken at|
03225|018|M|least four hours before the dose of colesevelam.(1)|
03225|019|B||
03225|020|D|DISCUSSION:  Colesevelam may decrease the absorption of fat-soluble vitamins|
03225|021|D|A, D, E, and K.(1)|
03225|022|B||
03225|023|R|REFERENCE:|
03225|024|B||
03225|025|R|1.Welchol (colesevelam hydrochloride) US prescribing information. Daiichi|1
03225|026|R|  Sankyo, Inc. October, 2021.|1
03226|001|T|MONOGRAPH TITLE:  Tivozanib/St. John's Wort|
03226|002|B||
03226|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03226|004|L|is contraindicated and generally should not be dispensed or administered to|
03226|005|L|the same patient.|
03226|006|B||
03226|007|A|MECHANISM OF ACTION:  St. John's wort may induce the metabolism of tivozanib|
03226|008|A|by CYP3A4.(1)|
03226|009|B||
03226|010|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort and tivozanib may|
03226|011|E|result in decreased levels of tivozanib, which may lead to treatment|
03226|012|E|failure.(1)|
03226|013|B||
03226|014|P|PREDISPOSING FACTORS:  None determined.|
03226|015|B||
03226|016|M|PATIENT MANAGEMENT:  The manufacturer of tivozanib states that concurrent|
03226|017|M|use with St. John's wort is contraindicated.(1)|
03226|018|M|   If a patient is already taking St. John's wort, therapy with St. John's|
03226|019|M|wort should be stopped prior to starting treatment with tivozanib.  Effects|
03226|020|M|of St. John's wort may be seen up to 2 weeks after stopping therapy with St.|
03226|021|M|John's wort.(1)|
03226|022|B||
03226|023|D|DISCUSSION:  In a study in health volunteers, concurrent administration of|
03226|024|D|single dose tivozanib (1340 mcg) with rifampin 600 mg once daily (a strong|
03226|025|D|CYP3A4 inducer) decreased the half-life of tivozanib from 121 to 54 hours|
03226|026|D|and decreased single dose area-under-curve (AUC) by 48%.(1)|
03226|027|B||
03226|028|R|REFERENCE:|
03226|029|B||
03226|030|R|1.Fotida (tivozanib) UK summary of product characteristics. Almac Pharma|1
03226|031|R|  Services Limited June, 2019.|1
03227|001|T|MONOGRAPH TITLE:  Tivozanib/Strong CYP3A4 Inducers|
03227|002|B||
03227|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03227|004|L|of severe adverse interaction.|
03227|005|B||
03227|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
03227|007|A|tivozanib by CYP3A4.(1,2)|
03227|008|B||
03227|009|E|CLINICAL EFFECTS:  The concurrent use of strong CYP3A4 inducers and|
03227|010|E|tivozanib may result in decreased levels of tivozanib, which may lead to|
03227|011|E|treatment failure.(1,2)|
03227|012|B||
03227|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03227|014|P|of the inducer for longer than 1-2 weeks.|
03227|015|B||
03227|016|M|PATIENT MANAGEMENT:  The US manufacturer of tivozanib recommends avoiding|
03227|017|M|concomitant use of strong CYP3A4 inducers.(1)|
03227|018|M|   The UK manufacturer of tivozanib states that concurrent use with strong|
03227|019|M|CYP3A4 inducers should be undertaken with caution.(2)|
03227|020|B||
03227|021|D|DISCUSSION:  Concomitant use of multiple doses of rifampin (a strong CYP3A|
03227|022|D|inducer) did not change tivozanib maximum concentration (Cmax) but decreased|
03227|023|D|tivozanib area-under-curve (AUC) by 52%.(1)|
03227|024|D|   In a study in health volunteers, concurrent administration of single dose|
03227|025|D|tivozanib (1340 mcg) with rifampin 600 mg once daily (a strong CYP3A4|
03227|026|D|inducer) decreased the half-life of tivozanib from 121 to 54 hours and|
03227|027|D|decreased single dose AUC by 48%.  The clinical effects of strong CYP3A4|
03227|028|D|inducers on repeated daily dosing has not been studied.(2)|
03227|029|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
03227|030|D|barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide,|
03227|031|D|fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin,|
03227|032|D|primidone, rifampin, and rifapentine.(3,4)|
03227|033|B||
03227|034|R|REFERENCES:|
03227|035|B||
03227|036|R|1.Fotivda (tivozanib) US prescribing information. AVEO Pharmaceuticals, Inc.|1
03227|037|R|  March, 2021.|1
03227|038|R|2.Fotida (tivozanib) UK summary of product characteristics. Almac Pharma|1
03227|039|R|  Services Limited June, 2019.|1
03227|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
03227|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03227|042|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03227|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03227|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03227|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03227|046|R|  11/14/2017.|1
03228|001|T|MONOGRAPH TITLE:  Tofacitinib (Less Than 20 mg daily)/Estrogens|
03228|002|B||
03228|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03228|004|L|take action as needed.|
03228|005|B||
03228|006|A|MECHANISM OF ACTION:  Estrogens increase the risk of thrombosis, and|
03228|007|A|combining estrogens with a higher dose of tofacitinib (greater than or equal|
03228|008|A|to 10 mg twice daily, or 20 mg/day) may place patients at high risk of|
03228|009|A|thromboembolism.(1-3)|
03228|010|B||
03228|011|E|CLINICAL EFFECTS:  Concurrent use of estrogens with a higher dose of|
03228|012|E|tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may|
03228|013|E|increase the incidence of pulmonary embolism and death.(1-3)|
03228|014|B||
03228|015|P|PREDISPOSING FACTORS:  Additional risk factors include advanced age, obesity|
03228|016|P|(BMI greater than 30), smoking, prolonged immobilization, heart failure,|
03228|017|P|hypercoagulable states, history of venous thromboembolism, malignancy, and|
03228|018|P|major surgery.(1)|
03228|019|B||
03228|020|M|PATIENT MANAGEMENT:  The European manufacturer states that the 10 mg twice|
03228|021|M|daily dose of tofacitinib is not recommended in patients who are on combined|
03228|022|M|hormonal contraceptives or hormone replacement therapy, or who are otherwise|
03228|023|M|at high risk of pulmonary embolism.(4)  Patients at high risk of pulmonary|
03228|024|M|embolism should be switched to alternative therapies.  For the treatment of|
03228|025|M|rheumatoid arthritis and psoriatic arthritis, the dose of tofacitinib should|
03228|026|M|be limited to 5 mg twice daily or tofacitinib XR 11 mg daily.(1-4)|
03228|027|M|   The US FDA and Health Canada have not placed use restrictions|
03228|028|M|specifically on concurrent use of tofacitinib with hormonal contraceptives|
03228|029|M|or hormone replacement therapy.  Both agencies advise avoiding tofacitinib|
03228|030|M|in patients at increased risk of thrombosis.  The US and Canadian|
03228|031|M|manufacturers recommend against a dosage of tofacitinib 10 mg twice daily or|
03228|032|M|weight-based equivalent twice daily or tofacitinib XR 22 mg once daily for|
03228|033|M|rheumatoid arthritis, psoriatic arthritis, or polyarticular-course juvenile|
03228|034|M|idiopathic arthritis.  For the treatment of ulcerative colitis, the lowest|
03228|035|M|effective dose for the shortest duration possible is recommended.  Counsel|
03228|036|M|patients on the risk of thrombosis and its signs and symptoms.  Instruct|
03228|037|M|patients to promptly report any symptoms of thrombosis and discontinue|
03228|038|M|tofacitinib in patients with symptoms of thrombosis.(5-7)|
03228|039|M|   There is currently no use restriction on the combination of estrogens|
03228|040|M|with lower doses of tofacitinib (less than 20 mg daily).|
03228|041|B||
03228|042|D|DISCUSSION:  In an ongoing open-label study comparing the safety of|
03228|043|D|tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and a tumor|
03228|044|D|necrosis factor (TNF) inhibitor in rheumatoid arthritis patients 50 years|
03228|045|D|old and older, the incidence of pulmonary embolism (PE) was 6-fold higher in|
03228|046|D|the tofacitinib 10 mg twice daily arm and 3-fold higher in the tofacitinib 5|
03228|047|D|mg twice daily arm compared to the TNF inhibitor arm (17 cases/3,123|
03228|048|D|patient-years, 9 cases/3,317 patient-years, and 3 cases/3,319 patient-years,|
03228|049|D|respectively).  All-cause mortality was also higher in the tofacitinib 10 mg|
03228|050|D|twice daily and 5 mg twice daily arms compared to the TNF inhibitor arm (28|
03228|051|D|deaths/3,140 patient-years, 19 deaths/3,324 patient-years, and 9|
03228|052|D|deaths/3,323 patient-years, respectively).(3)|
03228|053|B||
03228|054|R|REFERENCES:|
03228|055|B||
03228|056|R|1.European Medicines Agency. Increased risk of blood clots in lungs and|1
03228|057|R|  death with higher dose of Xeljanz (tofacitinib) for rheumatoid arthritis.|1
03228|058|R|  https://www.ema.europa.eu/en/documents/press-release/increased-risk-blood-|1
03228|059|R|  clots-lungs-death-higher-dose-xeljanz-tofacitinib-rheumatoid-arthritis_en.|1
03228|060|R|  pdf March 20, 2019.|1
03228|061|R|2.European Medicines Agency. Restrictions in use of Xeljanz while EMA|1
03228|062|R|  reviews risk of blood clots in lungs.|1
03228|063|R|  https://www.ema.europa.eu/en/documents/referral/xeljanz-article-20-procedu|1
03228|064|R|  re-restrictions-use-xeljanz-while-ema-reviews-risk-blood-clots-lungs_en.pd|1
03228|065|R|  f May 17, 2019.|1
03228|066|R|3.European Medicines Agency (EMA). EMA confirms Xeljanz to be used with|1
03228|067|R|  caution in patients at high risk of blood clots. Accessed at:|1
03228|068|R|  https://www.ema.europa.eu/en/documents/referral/xeljanz-article-20-procedu|1
03228|069|R|  re-ema-confirms-xeljanz-be-used-caution-patients-high-risk-blood-clots_en.|1
03228|070|R|  pdf January 31, 2020.|1
03228|071|R|4.Xeljanz (tofacitinib) EMA Summary of Product Characteristics. Pfizer|1
03228|072|R|  Europe MA EEIG March 6, 2020.|1
03228|073|R|5.USFood and Drug Administration. FDA Drug Safety Communication: Safety|1
03228|074|R|  trial finds risk of blood clots in the lungs and death with higher dose of|1
03228|075|R|  tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to|1
03228|076|R|  investigate.|1
03228|077|R|  https://www.fda.gov/drugs/drug-safety-and-availability/safety-trial-finds-|1
03228|078|R|  risk-blood-clots-lungs-and-death-higher-dose-tofacitinib-xeljanz-xeljanz-x|1
03228|079|R|  r February 25, 2019.|1
03228|080|R|6.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. October,|1
03228|081|R|  2025.|1
03228|082|R|7.Xeljanz (tofacitinib) Canadian prescribing information. Pfizer Canada ULC|1
03228|083|R|  April 12, 2024.|1
03229|001|T|MONOGRAPH TITLE:  Amantadine; Foslevodopa; Levodopa/Bupropion|
03229|002|B||
03229|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03229|004|L|take action as needed.|
03229|005|B||
03229|006|A|MECHANISM OF ACTION:  Amantadine, levodopa, and bupropion have dopamine|
03229|007|A|agonist effects. Toxicity may result from cumulative dopamine agonist|
03229|008|A|effects.(1)|
03229|009|A|   Foslevodopa is a prodrug of levodopa.(2)|
03229|010|B||
03229|011|E|CLINICAL EFFECTS:  Concurrent administration of amantadine/levodopa and|
03229|012|E|bupropion may result in CNS toxicity, such as, restlessness, agitation,|
03229|013|E|tremor, ataxia, gait disturbance, vertigo, and dizziness.(1)|
03229|014|B||
03229|015|P|PREDISPOSING FACTORS:  None determined.|
03229|016|B||
03229|017|M|PATIENT MANAGEMENT:  Use caution when amantadine/levodopa and bupropion are|
03229|018|M|used concurrently. Monitor for signs of CNS toxicity, which may include|
03229|019|M|restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and|
03229|020|M|dizziness.(1)|
03229|021|B||
03229|022|D|DISCUSSION:  CNS toxicity has been reported with concurrent administration|
03229|023|D|of amantadine and bupropion.|
03229|024|D|   Three out of six nursing home residents administered concurrent bupropion|
03229|025|D|and amantadine developed confusion, restlessness, agitation, gross motor|
03229|026|D|tremors, ataxia, gait disturbance, dizziness, and vertigo. Two patients had|
03229|027|D|severe symptoms and were hospitalized.(3)|
03229|028|D|   In a case report, bupropion (75 mg twice daily) was added to amantadine,|
03229|029|D|haloperidol, and benztropine. The patient became disoriented and agitated,|
03229|030|D|developed visual and auditory hallucinations, impaired attention and memory,|
03229|031|D|a fluctuating level of awareness, and unsteady gait.(4)|
03229|032|B||
03229|033|R|REFERENCES:|
03229|034|B||
03229|035|R|1.Zyban (bupropion hydrochloride) US prescribing information.|1
03229|036|R|  GlaxoSmithKline July, 2019.|1
03229|037|R|2.Vyalev (foslevodopa/foscarbidopa) Canadian product monograph. AbbVie|1
03229|038|R|  Corporation May, 2023.|1
03229|039|R|3.Trappler B, Miyashiro AM. Bupropion-amantadine-associated neurotoxicity. J|6
03229|040|R|  Clin Psychiatry 2000 Jan;61(1):61-2.|6
03229|041|R|4.Liberzon I, Dequardo JR, Silk KR. Bupropion and delirium. Am J Psychiatry|3
03229|042|R|  1990 Dec;147(12):1689-90.|3
03230|001|T|MONOGRAPH TITLE:  Carbimazole; Methimazole/Thyroid Preparations|
03230|002|B||
03230|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03230|004|L|take action as needed.|
03230|005|B||
03230|006|A|MECHANISM OF ACTION:  Methimazole can affect the therapeutic response to|
03230|007|A|thyroid hormone therapy. It decreases thyroid hormone secretion. Thyroid|
03230|008|A|hormone therapy can antagonize the pharmacologic effects of methimazole by|
03230|009|A|supplying an exogenous source of thyroid hormone.|
03230|010|A|   Carbimazole is a prodrug of methimazole.(1)|
03230|011|B||
03230|012|E|CLINICAL EFFECTS:  Concurrent use of carbimazole or methimazole and thyroid|
03230|013|E|hormones may result in opposing effects.|
03230|014|B||
03230|015|P|PREDISPOSING FACTORS:  None determined.|
03230|016|B||
03230|017|M|PATIENT MANAGEMENT:  Concurrent use of carbimazole or methimazole and|
03230|018|M|thyroid hormones should be avoided.|
03230|019|B||
03230|020|D|DISCUSSION:  The 2016 American Thyroid Association guidelines recommended|
03230|021|D|avoiding the concurrent use of methimazole and thyroid preparations for|
03230|022|D|"block and replace" therapy to make a patient euthyroid. Meta-analyses have|
03230|023|D|shown that a higher prevalence of adverse events occurs with|
03230|024|D|block-and-replace regimens than dose titration.(2)|
03230|025|D|   The 2018 European Thyroid Association guidelines state that methimazole|
03230|026|D|(30 mg) may be given combined with levothyroxine supplement ion for|
03230|027|D|block-and-replace therapy to avoid drug-induced hypothyroidism but|
03230|028|D|methimazole dose titration is the preferred therapy.(3)|
03230|029|B||
03230|030|R|REFERENCES:|
03230|031|B||
03230|032|R|1.Neo-Mercazole (carbimazole) French Summary of Product Characteristics.|1
03230|033|R|  Amdipharm LTD May 26, 2020.|1
03230|034|R|2.Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees|6
03230|035|R|  SA, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid|6
03230|036|R|  Association Guidelines for Diagnosis and Management of Hyperthyroidism and|6
03230|037|R|  Other Causes of Thyrotoxicosis. Thyroid 2016 Oct;26(10):1343-1421.|6
03230|038|R|3.Kahaly GJ, Bartalena L, Hegedus L, Leenhardt L, Poppe K, Pearce SH. 2018|6
03230|039|R|  European Thyroid Association Guideline for the Management of Graves'|6
03230|040|R|  Hyperthyroidism. Eur Thyroid J 2018 Aug;7(4):167-186.|6
03231|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal To 20 mg)/Gemfibrozil|
03231|002|T|(mono deleted 09/02/2025)|
03231|003|B||
03231|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03231|005|L|is contraindicated and generally should not be dispensed or administered to|
03231|006|L|the same patient.|
03231|007|B||
03231|008|A|MECHANISM OF ACTION:  Unknown.|
03231|009|B||
03231|010|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
03231|011|E|and fibric acid derivatives has been associated with severe myopathy,|
03231|012|E|rhabdomyolysis and acute renal failure.|
03231|013|B||
03231|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03231|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03231|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03231|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03231|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03231|019|P|transporter OATP1B1 may have increased statin concentrations and be|
03231|020|P|predisposed to myopathy or rhabdomyolysis.|
03231|021|B||
03231|022|M|PATIENT MANAGEMENT:  According to the 2018 ACC/AHA Blood Cholesterol|
03231|023|M|Guidelines, gemfibrozil is contraindicated in patients on statin therapy.|
03231|024|M|   According to the 2016 AHA Scientific Statement Recommendations for|
03231|025|M|Management of Clinically Significant Drug-Drug Interactions with Statins and|
03231|026|M|Select Agents Used in Patients with Cardiovascular Disease, atorvastatin|
03231|027|M|dose should be initiated at 10 mg daily and should not exceed 20 mg daily|
03231|028|M|when used concurrently with gemfibrozil.|
03231|029|M|   According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil|
03231|030|M|should not be initiated in patients on statin therapy.  Fenofibrate may be|
03231|031|M|considered with low or moderate intensity statin therapy only if benefits|
03231|032|M|outweigh the risks.|
03231|033|M|   The US, Australian, Canadian, and UK manufacturers of gemfibrozil state|
03231|034|M|that use with HMG CO-A reductase inhibitors does not outweigh the risks of|
03231|035|M|severe myopathy, rhabdomyolysis, and acute renal failure.|
03231|036|M|   The US, Canadian, and UK manufacturers of atorvastatin state that|
03231|037|M|concurrent use of gemfibrozil should be avoided.|
03231|038|M|   Instruct patients receiving concurrent therapy to report any unexplained|
03231|039|M|muscle pain, tenderness or weakness.  If muscular symptoms develop, monitor|
03231|040|M|serum creatine kinase levels and renal function.  One or both agents may|
03231|041|M|need to be discontinued.|
03231|042|B||
03231|043|D|DISCUSSION:  Gemfibrozil has been shown to increase levels of cerivastatin,|
03231|044|D|lovastatin, pravastatin, rosuvastatin, and simvastatin.  Administration of|
03231|045|D|gemfibrozil with cerivastatin, lovastatin, and simvastatin has been|
03231|046|D|associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and|
03231|047|D|weakness).  Although the reaction has been reported with the statins alone,|
03231|048|D|the incidence increases dramatically with concurrent administration of|
03231|049|D|gemfibrozil.|
03231|050|D|   Concurrent fenofibrate (145 mg) with atorvastatin (20 mg) decreased the|
03231|051|D|atorvastatin area-under-curve (AUC) by 17% (range from 67% decrease to 44%|
03231|052|D|increase).  Atorvastatin maximum concentration (Cmax) and the kinetics of|
03231|053|D|fenofibrate were not significantly affected.|
03231|054|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
03231|055|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
03231|056|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
03231|057|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
03231|058|D|Veteran's Administration over a 2 year period, there were 149 reports of|
03231|059|D|rhabdomyolysis in 93,677 (0.16%) patients receiving concurrent gemfibrozil|
03231|060|D|and statin therapy compared with no reports in 1,830 patients receiving|
03231|061|D|concurrent fenofibrate and statin therapy.|
03231|062|D|   In a retrospective cohort study of 252,460 patients, concurrent use of|
03231|063|D|statins and fibrates increased the risk of rhabdomyolysis, especially in|
03231|064|D|patients with diabetes mellitus.  The risk of hospitalization for patients|
03231|065|D|aged 65 or older with diabetes mellitus, treated with a statin and fibrate,|
03231|066|D|increased 48-fold compared to statin monotherapy.|
03231|067|D|   In a retrospective study, of 468 patients with a diagnosis of myopathy,|
03231|068|D|61 received a statin prior to their diagnosis. Forty-one of these patients|
03231|069|D|developed confirmed myopathy, creatinine kinase more than or equal to 1000|
03231|070|D|IU/L.|
03231|071|B||
03231|072|R|REFERENCES:|
03231|073|B||
03231|074|R|1.Stone NJ, Robinson JG, Lichtenstein AH, Goff DC Jr, Lloyd-Jones DM, Smith|6
03231|075|R|  SC Jr, Blum C, Schwartz JS. Treatment of blood cholesterol to reduce|6
03231|076|R|  atherosclerotic cardiovascular disease risk in adults: synopsis of the|6
03231|077|R|  2013 American College of Cardiology/American Heart Association cholesterol|6
03231|078|R|  guideline. Ann Intern Med 2014 Mar 4;160(5):339-43.|6
03231|079|R|2.Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis JB, Lanfear|6
03231|080|R|  D, Virani S, Morris PB. Recommendations for Management of Clinically|6
03231|081|R|  Significant Drug-Drug Interactions With Statins and Select Agents Used in|6
03231|082|R|  Patients With Cardiovascular Disease: A Scientific Statement From the|6
03231|083|R|  American Heart Association. Circulation 2016 Nov 22;134(21):e468-e495.|6
03231|084|R|3.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
03231|085|R|  Ltd. December, 2020.|1
03231|086|R|4.Lipazil (gemfibrozil) Australian product information. Ascent Pharma Pty|1
03231|087|R|  Ltd December 5, 2011.|1
03231|088|R|5.Teva-Gemfibrozil (gemfibrozil) Canadian product monograph. Teva Canada|1
03231|089|R|  Limited June 29, 2015.|1
03231|090|R|6.Lopid (gemfibrozil) UK summary of product characteristics. Pfizer Limited|1
03231|091|R|  May, 2016.|1
03231|092|R|7.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
03231|093|R|  2020.|1
03231|094|R|8.Lipitor (atorvastatin) Canadian product information. Pfizer Canada Inc.|1
03231|095|R|  May 31, 2019.|1
03231|096|R|9.Lipitor (atorvastatin calcium trihydrate) UK summary of product|1
03231|097|R|  characteristics. Pfizer Limited April 1, 2019.|1
03231|098|R|10.Thompson GR, Ford J, Jenkinson M, Trayner I. Efficacy of mevinolin as|2
03231|099|R|   adjuvant therapy for refractory familial hypercholesterolaemia. Q J Med|2
03231|100|R|   1986 Aug;60(232):803-11.|2
03231|101|R|11.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
03231|102|R|   cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
03231|103|R|   polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
03231|104|R|12.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of|3
03231|105|R|   a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
03231|106|R|   2002;101(7):53-6.|3
03231|107|R|13.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
03231|108|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
03231|109|R|   at:|3
03231|110|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
03231|111|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
03231|112|R|14.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
03231|113|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
03231|114|R|   95(1):120-2.|2
03231|115|R|15.Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, Liu L, Lin|5
03231|116|R|   JH, Pearson PG, Baillie TA. Mechanistic studies on metabolic interactions|5
03231|117|R|   between gemfibrozil and statins. J Pharmacol Exp Ther 2002 Jun;|5
03231|118|R|   301(3):1042-51.|5
03231|119|R|16.Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly|2
03231|120|R|   decreases and gemfibrozil increases the plasma concentrations of|2
03231|121|R|   atorvastatin and its metabolites. Clin Pharmacol Ther 2005 Aug;|2
03231|122|R|   78(2):154-67.|2
03231|123|R|17.Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J.|5
03231|124|R|   Interaction between fibrates and statins--metabolic interactions with|5
03231|125|R|   gemfibrozil. Drug Metabol Drug Interact 2003;19(3):161-76.|5
03231|126|R|18.Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking|3
03231|127|R|   atorvastatin with gemfibrozil. Am J Cardiol 1998 Feb 1;81(3):368-9.|3
03231|128|R|19.Shanahan RL, Kerzee JA, Sandhoff BG, Carroll NM, Merenich JA. Low|2
03231|129|R|   myopathy rates associated with statins as monotherapy or combination|2
03231|130|R|   therapy with interacting drugs in a group model health maintenance|2
03231|131|R|   organization. Pharmacotherapy 2005 Mar;25(3):345-51.|2
03231|132|R|20.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
03231|133|R|   Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized|2
03231|134|R|   rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004|2
03231|135|R|   Dec 1;292(21):2585-90.|2
03231|136|R|21.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
03231|137|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
03231|138|R|22.Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and|3
03231|139|R|   acute renal failure after changing statin-fibrate combinations.|3
03231|140|R|   Cardiology 2000;94(2):127-8.|3
03231|141|R|23.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun|6
03231|142|R|   LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,|6
03231|143|R|   Heidenreich PA. 2018|6
03231|144|R|   AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the|6
03231|145|R|   Management of Blood Cholesterol: A Report of the American College of|6
03231|146|R|   Cardiology/American Heart Association Task Force on Clinical Practice|6
03231|147|R|   Guidelines. J Am Coll Cardiol 2019 Jun 25;73(24):e285-e350.|6
03232|001|T|MONOGRAPH TITLE:  Pitavastatin/Gemfibrozil|
03232|002|B||
03232|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03232|004|L|is contraindicated and generally should not be dispensed or administered to|
03232|005|L|the same patient.|
03232|006|B||
03232|007|A|MECHANISM OF ACTION:  Unknown.|
03232|008|B||
03232|009|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
03232|010|E|and fibric acid derivatives has been associated with severe myopathy,|
03232|011|E|rhabdomyolysis and acute renal failure.|
03232|012|B||
03232|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03232|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03232|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03232|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03232|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03232|018|P|transporter OATP1B1 may have increased statin concentrations and be|
03232|019|P|predisposed to myopathy or rhabdomyolysis.|
03232|020|B||
03232|021|M|PATIENT MANAGEMENT:  According to the 2018 ACC/AHA Blood Cholesterol|
03232|022|M|Guidelines, gemfibrozil is contraindicated in patients on statin therapy.|
03232|023|M|   According to the 2016 AHA Scientific Statement Recommendations for|
03232|024|M|Management of Clinically Significant Drug-Drug Interactions with Statins and|
03232|025|M|Select Agents Used in Patients with Cardiovascular Disease, pitavastatin|
03232|026|M|dose should be initiated at 1 mg daily and should not exceed 2 mg daily when|
03232|027|M|used concurrently with gemfibrozil.|
03232|028|M|   According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil|
03232|029|M|should not be initiated in patients on statin therapy.  Fenofibrate may be|
03232|030|M|considered with low or moderate intensity statin therapy only if benefits|
03232|031|M|outweigh the risks.|
03232|032|M|   The US, Australian, Canadian, and UK manufacturers of gemfibrozil state|
03232|033|M|that use with HMG CO-A reductase inhibitors does not outweigh the risks of|
03232|034|M|severe myopathy, rhabdomyolysis, and acute renal failure.  The Canadian|
03232|035|M|manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should|
03232|036|M|not be used concurrently.|
03232|037|M|   The US manufacturer of pitavastatin states concurrent use of gemfibrozil|
03232|038|M|should be avoided.|
03232|039|M|   Instruct patients receiving concurrent therapy to report any unexplained|
03232|040|M|muscle pain, tenderness or weakness.  If muscular symptoms develop, monitor|
03232|041|M|serum creatine kinase levels and renal function.  One or both agents may|
03232|042|M|need to be discontinued.|
03232|043|B||
03232|044|D|DISCUSSION:  Gemfibrozil has been shown to increase levels of cerivastatin,|
03232|045|D|lovastatin, pravastatin, rosuvastatin, and simvastatin.  Administration of|
03232|046|D|gemfibrozil with cerivastatin, lovastatin, and simvastatin has been|
03232|047|D|associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and|
03232|048|D|weakness).  Although the reaction has been reported with the statins alone,|
03232|049|D|the incidence increases dramatically with concurrent administration of|
03232|050|D|gemfibrozil.|
03232|051|D|   Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of|
03232|052|D|pitavastatin (4 mg daily) by 18% and 11%, respectively.|
03232|053|D|   Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of|
03232|054|D|pitavastatin (4 mg daily) by 45% and 31%, respectively.|
03232|055|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
03232|056|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
03232|057|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
03232|058|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
03232|059|D|Veteran's Administration over a 2 year period, there were 149 reports of|
03232|060|D|rhabdomyolysis in 93,677 (0.16%) patients receiving concurrent gemfibrozil|
03232|061|D|and statin therapy compared with no reports in 1,830 patients receiving|
03232|062|D|concurrent fenofibrate and statin therapy.|
03232|063|D|   In a retrospective cohort study of 252,460 patients, concurrent use of|
03232|064|D|statins and fibrates increased the risk of rhabdomyolysis, especially in|
03232|065|D|patients with diabetes mellitus.  The risk of hospitalization for patients|
03232|066|D|aged 65 or older with diabetes mellitus, treated with a statin and fibrate,|
03232|067|D|increased 48-fold compared to statin monotherapy.|
03232|068|D|   In a retrospective study, of 468 patients with a diagnosis of myopathy,|
03232|069|D|61 received a statin prior to their diagnosis. Forty-one of these patients|
03232|070|D|developed confirmed myopathy, creatinine kinase more than or equal to 1000|
03232|071|D|IU/L.|
03232|072|B||
03232|073|R|REFERENCES:|
03232|074|B||
03232|075|R|1.Stone NJ, Robinson JG, Lichtenstein AH, Goff DC Jr, Lloyd-Jones DM, Smith|6
03232|076|R|  SC Jr, Blum C, Schwartz JS. Treatment of blood cholesterol to reduce|6
03232|077|R|  atherosclerotic cardiovascular disease risk in adults: synopsis of the|6
03232|078|R|  2013 American College of Cardiology/American Heart Association cholesterol|6
03232|079|R|  guideline. Ann Intern Med 2014 Mar 4;160(5):339-43.|6
03232|080|R|2.Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis JB, Lanfear|6
03232|081|R|  D, Virani S, Morris PB. Recommendations for Management of Clinically|6
03232|082|R|  Significant Drug-Drug Interactions With Statins and Select Agents Used in|6
03232|083|R|  Patients With Cardiovascular Disease: A Scientific Statement From the|6
03232|084|R|  American Heart Association. Circulation 2016 Nov 22;134(21):e468-e495.|6
03232|085|R|3.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
03232|086|R|  Ltd. December, 2020.|1
03232|087|R|4.Lipazil (gemfibrozil) Australian product information. Ascent Pharma Pty|1
03232|088|R|  Ltd December 5, 2011.|1
03232|089|R|5.Teva-Gemfibrozil (gemfibrozil) Canadian product monograph. Teva Canada|1
03232|090|R|  Limited June 29, 2015.|1
03232|091|R|6.Lopid (gemfibrozil) UK summary of product characteristics. Pfizer Limited|1
03232|092|R|  May, 2016.|1
03232|093|R|7.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
03232|094|R|  America, Inc. November, 2022.|1
03232|095|R|8.Thompson GR, Ford J, Jenkinson M, Trayner I. Efficacy of mevinolin as|2
03232|096|R|  adjuvant therapy for refractory familial hypercholesterolaemia. Q J Med|2
03232|097|R|  1986 Aug;60(232):803-11.|2
03232|098|R|9.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
03232|099|R|  cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
03232|100|R|  polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
03232|101|R|10.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of|3
03232|102|R|   a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
03232|103|R|   2002;101(7):53-6.|3
03232|104|R|11.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
03232|105|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
03232|106|R|   at:|3
03232|107|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
03232|108|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
03232|109|R|12.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
03232|110|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
03232|111|R|   95(1):120-2.|2
03232|112|R|13.Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, Liu L, Lin|5
03232|113|R|   JH, Pearson PG, Baillie TA. Mechanistic studies on metabolic interactions|5
03232|114|R|   between gemfibrozil and statins. J Pharmacol Exp Ther 2002 Jun;|5
03232|115|R|   301(3):1042-51.|5
03232|116|R|14.Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J.|5
03232|117|R|   Interaction between fibrates and statins--metabolic interactions with|5
03232|118|R|   gemfibrozil. Drug Metabol Drug Interact 2003;19(3):161-76.|5
03232|119|R|15.Shanahan RL, Kerzee JA, Sandhoff BG, Carroll NM, Merenich JA. Low|2
03232|120|R|   myopathy rates associated with statins as monotherapy or combination|2
03232|121|R|   therapy with interacting drugs in a group model health maintenance|2
03232|122|R|   organization. Pharmacotherapy 2005 Mar;25(3):345-51.|2
03232|123|R|16.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
03232|124|R|   Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized|2
03232|125|R|   rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004|2
03232|126|R|   Dec 1;292(21):2585-90.|2
03232|127|R|17.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
03232|128|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
03232|129|R|18.Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and|3
03232|130|R|   acute renal failure after changing statin-fibrate combinations.|3
03232|131|R|   Cardiology 2000;94(2):127-8.|3
03232|132|R|19.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun|6
03232|133|R|   LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,|6
03232|134|R|   Heidenreich PA. 2018|6
03232|135|R|   AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the|6
03232|136|R|   Management of Blood Cholesterol: A Report of the American College of|6
03232|137|R|   Cardiology/American Heart Association Task Force on Clinical Practice|6
03232|138|R|   Guidelines. J Am Coll Cardiol 2019 Jun 25;73(24):e285-e350.|6
03233|001|T|MONOGRAPH TITLE:  Pitavastatin (Less Than or Equal To 2 mg)/Gemfibrozil|
03233|002|T|(mono deleted 09/02/2025)|
03233|003|B||
03233|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03233|005|L|is contraindicated and generally should not be dispensed or administered to|
03233|006|L|the same patient.|
03233|007|B||
03233|008|A|MECHANISM OF ACTION:  Unknown.|
03233|009|B||
03233|010|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
03233|011|E|and fibric acid derivatives has been associated with severe myopathy,|
03233|012|E|rhabdomyolysis and acute renal failure.|
03233|013|B||
03233|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03233|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03233|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03233|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03233|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03233|019|P|transporter OATP1B1 may have increased statin concentrations and be|
03233|020|P|predisposed to myopathy or rhabdomyolysis.|
03233|021|B||
03233|022|M|PATIENT MANAGEMENT:  According to the 2018 ACC/AHA Blood Cholesterol|
03233|023|M|Guidelines, gemfibrozil is contraindicated in patients on statin therapy.|
03233|024|M|   According to the 2016 AHA Scientific Statement Recommendations for|
03233|025|M|Management of Clinically Significant Drug-Drug Interactions with Statins and|
03233|026|M|Select Agents Used in Patients with Cardiovascular Disease, pitavastatin|
03233|027|M|dose should be initiated at 1 mg daily and should not exceed 2 mg daily when|
03233|028|M|used concurrently with gemfibrozil.|
03233|029|M|   According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil|
03233|030|M|should not be initiated in patients on statin therapy.  Fenofibrate may be|
03233|031|M|considered with low or moderate intensity statin therapy only if benefits|
03233|032|M|outweigh the risks.|
03233|033|M|   The US, Australian, Canadian, and UK manufacturers of gemfibrozil state|
03233|034|M|that use with HMG CO-A reductase inhibitors does not outweigh the risks of|
03233|035|M|severe myopathy, rhabdomyolysis, and acute renal failure.  The Canadian|
03233|036|M|manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should|
03233|037|M|not be used concurrently.|
03233|038|M|   The US manufacturer of pitavastatin states concurrent use of gemfibrozil|
03233|039|M|should be avoided.|
03233|040|M|   Instruct patients receiving concurrent therapy to report any unexplained|
03233|041|M|muscle pain, tenderness or weakness.  If muscular symptoms develop, monitor|
03233|042|M|serum creatine kinase levels and renal function.  One or both agents may|
03233|043|M|need to be discontinued.|
03233|044|B||
03233|045|D|DISCUSSION:  Gemfibrozil has been shown to increase levels of cerivastatin,|
03233|046|D|lovastatin, pravastatin, rosuvastatin, and simvastatin.  Administration of|
03233|047|D|gemfibrozil with cerivastatin, lovastatin, and simvastatin has been|
03233|048|D|associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and|
03233|049|D|weakness).  Although the reaction has been reported with the statins alone,|
03233|050|D|the incidence increases dramatically with concurrent administration of|
03233|051|D|gemfibrozil.|
03233|052|D|   Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of|
03233|053|D|pitavastatin (4 mg daily) by 18% and 11%, respectively.|
03233|054|D|   Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of|
03233|055|D|pitavastatin (4 mg daily) by 45% and 31%, respectively.|
03233|056|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
03233|057|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
03233|058|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
03233|059|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
03233|060|D|Veteran's Administration over a 2 year period, there were 149 reports of|
03233|061|D|rhabdomyolysis in 93,677 (0.16%) patients receiving concurrent gemfibrozil|
03233|062|D|and statin therapy compared with no reports in 1,830 patients receiving|
03233|063|D|concurrent fenofibrate and statin therapy.|
03233|064|D|   In a retrospective cohort study of 252,460 patients, concurrent use of|
03233|065|D|statins and fibrates increased the risk of rhabdomyolysis, especially in|
03233|066|D|patients with diabetes mellitus.  The risk of hospitalization for patients|
03233|067|D|aged 65 or older with diabetes mellitus, treated with a statin and fibrate,|
03233|068|D|increased 48-fold compared to statin monotherapy.|
03233|069|D|   In a retrospective study, of 468 patients with a diagnosis of myopathy,|
03233|070|D|61 received a statin prior to their diagnosis. Forty-one of these patients|
03233|071|D|developed confirmed myopathy, creatinine kinase more than or equal to 1000|
03233|072|D|IU/L.|
03233|073|B||
03233|074|R|REFERENCES:|
03233|075|B||
03233|076|R|1.Stone NJ, Robinson JG, Lichtenstein AH, Goff DC Jr, Lloyd-Jones DM, Smith|6
03233|077|R|  SC Jr, Blum C, Schwartz JS. Treatment of blood cholesterol to reduce|6
03233|078|R|  atherosclerotic cardiovascular disease risk in adults: synopsis of the|6
03233|079|R|  2013 American College of Cardiology/American Heart Association cholesterol|6
03233|080|R|  guideline. Ann Intern Med 2014 Mar 4;160(5):339-43.|6
03233|081|R|2.Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis JB, Lanfear|6
03233|082|R|  D, Virani S, Morris PB. Recommendations for Management of Clinically|6
03233|083|R|  Significant Drug-Drug Interactions With Statins and Select Agents Used in|6
03233|084|R|  Patients With Cardiovascular Disease: A Scientific Statement From the|6
03233|085|R|  American Heart Association. Circulation 2016 Nov 22;134(21):e468-e495.|6
03233|086|R|3.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
03233|087|R|  Ltd. December, 2020.|1
03233|088|R|4.Lipazil (gemfibrozil) Australian product information. Ascent Pharma Pty|1
03233|089|R|  Ltd December 5, 2011.|1
03233|090|R|5.Teva-Gemfibrozil (gemfibrozil) Canadian product monograph. Teva Canada|1
03233|091|R|  Limited June 29, 2015.|1
03233|092|R|6.Lopid (gemfibrozil) UK summary of product characteristics. Pfizer Limited|1
03233|093|R|  May, 2016.|1
03233|094|R|7.Livalo (pitavastatin) US prescribing information. Kowa Pharmaceuticals|1
03233|095|R|  America, Inc. November, 2022.|1
03233|096|R|8.Thompson GR, Ford J, Jenkinson M, Trayner I. Efficacy of mevinolin as|2
03233|097|R|  adjuvant therapy for refractory familial hypercholesterolaemia. Q J Med|2
03233|098|R|  1986 Aug;60(232):803-11.|2
03233|099|R|9.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
03233|100|R|  cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
03233|101|R|  polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
03233|102|R|10.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of|3
03233|103|R|   a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
03233|104|R|   2002;101(7):53-6.|3
03233|105|R|11.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
03233|106|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
03233|107|R|   at:|3
03233|108|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
03233|109|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
03233|110|R|12.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
03233|111|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
03233|112|R|   95(1):120-2.|2
03233|113|R|13.Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, Liu L, Lin|5
03233|114|R|   JH, Pearson PG, Baillie TA. Mechanistic studies on metabolic interactions|5
03233|115|R|   between gemfibrozil and statins. J Pharmacol Exp Ther 2002 Jun;|5
03233|116|R|   301(3):1042-51.|5
03233|117|R|14.Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J.|5
03233|118|R|   Interaction between fibrates and statins--metabolic interactions with|5
03233|119|R|   gemfibrozil. Drug Metabol Drug Interact 2003;19(3):161-76.|5
03233|120|R|15.Shanahan RL, Kerzee JA, Sandhoff BG, Carroll NM, Merenich JA. Low|2
03233|121|R|   myopathy rates associated with statins as monotherapy or combination|2
03233|122|R|   therapy with interacting drugs in a group model health maintenance|2
03233|123|R|   organization. Pharmacotherapy 2005 Mar;25(3):345-51.|2
03233|124|R|16.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
03233|125|R|   Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized|2
03233|126|R|   rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004|2
03233|127|R|   Dec 1;292(21):2585-90.|2
03233|128|R|17.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
03233|129|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
03233|130|R|18.Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and|3
03233|131|R|   acute renal failure after changing statin-fibrate combinations.|3
03233|132|R|   Cardiology 2000;94(2):127-8.|3
03233|133|R|19.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun|6
03233|134|R|   LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,|6
03233|135|R|   Heidenreich PA. 2018|6
03233|136|R|   AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the|6
03233|137|R|   Management of Blood Cholesterol: A Report of the American College of|6
03233|138|R|   Cardiology/American Heart Association Task Force on Clinical Practice|6
03233|139|R|   Guidelines. J Am Coll Cardiol 2019 Jun 25;73(24):e285-e350.|6
03234|001|T|MONOGRAPH TITLE:  Rosuvastatin/Gemfibrozil|
03234|002|B||
03234|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03234|004|L|is contraindicated and generally should not be dispensed or administered to|
03234|005|L|the same patient.|
03234|006|B||
03234|007|A|MECHANISM OF ACTION:  Unknown.|
03234|008|B||
03234|009|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
03234|010|E|and gemfibrozil has been associated with severe myopathy, rhabdomyolysis and|
03234|011|E|acute renal failure.|
03234|012|B||
03234|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03234|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03234|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03234|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03234|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03234|018|P|transporter OATP1B1 may have increased statin concentrations and be|
03234|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
03234|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
03234|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
03234|022|B||
03234|023|M|PATIENT MANAGEMENT:  According to the 2018 ACC/AHA Blood Cholesterol|
03234|024|M|Guidelines, gemfibrozil is contraindicated in patients on statin therapy.|
03234|025|M|   According to the 2016 AHA Scientific Statement Recommendations for|
03234|026|M|Management of Clinically Significant Drug-Drug Interactions with Statins and|
03234|027|M|Select Agents Used in Patients with Cardiovascular Disease, rosuvastatin|
03234|028|M|dose should be initiated at 5 mg daily and should not exceed 10 mg daily|
03234|029|M|when used concurrently with gemfibrozil.|
03234|030|M|   The manufacturer of gemfibrozil states that concurrent therapy with|
03234|031|M|gemfibrozil and HMG CO-A reductase inhibitors does not outweigh the risks of|
03234|032|M|severe myopathy, rhabdomyolysis, and acute renal failure.|
03234|033|M|   The Canadian manufacturer of rosuvastatin states that patients receiving|
03234|034|M|concurrent gemfibrozil should not receive more than 20 mg of rosuvastatin|
03234|035|M|daily and that the concurrent use of gemfibrozil and 40 mg of rosuvastatin|
03234|036|M|is contraindicated.  The Australian and US manufacturers of rosuvastatin|
03234|037|M|state that the concurrent use of gemfibrozil and rosuvastatin should be|
03234|038|M|avoided and that the risks of concurrent use of other fibrates should be|
03234|039|M|carefully weighed against the benefits.  In patients requiring concurrent|
03234|040|M|gemfibrozil, the dosage of rosuvastatin should be limited to 10 mg daily.|
03234|041|M|   When possible, avoid administration of these drugs concomitantly unless|
03234|042|M|patients require aggressive therapy.  If possible, consider the use of|
03234|043|M|fenofibrate over gemfibrozil for concurrent therapy with a statin.  Instruct|
03234|044|M|patients to report any unexplained muscle pain, tenderness or weakness.  If|
03234|045|M|muscular symptoms develop, monitor serum creatine kinase levels and renal|
03234|046|M|function.  One or both agents may need to be discontinued.|
03234|047|B||
03234|048|D|DISCUSSION:  Gemfibrozil has been shown to increase levels of cerivastatin,|
03234|049|D|lovastatin, pravastatin, rosuvastatin, and simvastatin.  Administration of|
03234|050|D|gemfibrozil with cerivastatin, lovastatin, and simvastatin has been|
03234|051|D|associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and|
03234|052|D|weakness).  Although the reaction has been reported with the statins alone,|
03234|053|D|the incidence increases dramatically with concurrent administration of|
03234|054|D|gemfibrozil.|
03234|055|D|   Concurrent gemfibrozil (600 mg twice daily) and rosuvastatin (80 mg)|
03234|056|D|increased the rosuvastatin AUC and Cmax by 90% and 120%, respectively.  In|
03234|057|D|healthy subjects, gemfibrozil increased the Cmax and AUC of a single dose of|
03234|058|D|rosuvastatin by 2.2-fold and 1.9-fold, respectively.|
03234|059|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
03234|060|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
03234|061|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
03234|062|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
03234|063|D|Veteran's Administration over a 2 year period, there were 149 reports of|
03234|064|D|rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil|
03234|065|D|and statin therapy compared with no reports in 1,830 patients receiving|
03234|066|D|concurrent fenofibrate and statin therapy.|
03234|067|D|   In a retrospective cohort study of 252,460 patients, concurrent use of|
03234|068|D|statins and fibrates increased the risk of rhabdomyolysis, especially in|
03234|069|D|patients with diabetes mellitus.  The risk of hospitalization for patients|
03234|070|D|aged 65 or older with diabetes mellitus, treated with a statin and fibrate,|
03234|071|D|increased 48-fold compared to statin monotherapy.|
03234|072|D|   In a retrospective study, of 468 patients with a diagnosis of myopathy,|
03234|073|D|61 received a statin prior to their diagnosis. Forty-one of these patients|
03234|074|D|developed confirmed myopathy, creatinine kinase more than or equal to 1000|
03234|075|D|IU/L.|
03234|076|B||
03234|077|R|REFERENCES:|
03234|078|B||
03234|079|R|1.Thompson GR, Ford J, Jenkinson M, Trayner I. Efficacy of mevinolin as|2
03234|080|R|  adjuvant therapy for refractory familial hypercholesterolaemia. Q J Med|2
03234|081|R|  1986 Aug;60(232):803-11.|2
03234|082|R|2.East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA. Rhabdomyolysis in|3
03234|083|R|  patients receiving lovastatin after cardiac transplantation. N Engl J Med|3
03234|084|R|  1988 Jan 7;318(1):47-8.|3
03234|085|R|3.Marais GE, Larson KK. Rhabdomyolysis and acute renal failure induced by|3
03234|086|R|  combination lovastatin and gemfibrozil therapy. Ann Intern Med 1990 Feb 1;|3
03234|087|R|  112(3):228-30.|3
03234|088|R|4.Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated|3
03234|089|R|  with lovastatin-gemfibrozil combination therapy. JAMA 1990 Jul 4;|3
03234|090|R|  264(1):71-5.|3
03234|091|R|5.Glueck CJ, Speirs J, Tracy T. Safety and efficacy of combined|2
03234|092|R|  gemfibrozil-lovastatin therapy for primary dyslipoproteinemias. J Lab Clin|2
03234|093|R|  Med 1990 May;115(5):603-9.|2
03234|094|R|6.Glueck CJ, Oakes N, Speirs J, Tracy T, Lang J. Gemfibrozil-lovastatin|2
03234|095|R|  therapy for primary hyperlipoproteinemias. Am J Cardiol 1992 Jul 1;|2
03234|096|R|  70(1):1-9.|2
03234|097|R|7.Wirebaugh SR, Shapiro ML, McIntyre TH, Whitney EJ. A retrospective review|2
03234|098|R|  of the use of lipid-lowering agents in combination, specifically,|2
03234|099|R|  gemfibrozil and lovastatin. Pharmacotherapy 1992;12(6):445-50.|2
03234|100|R|8.Wiklund O, Angelin B, Bergman M, Berglund L, Bondjers G, Carlsson A,|2
03234|101|R|  Linden T, Miettinen T, Odman B, Olofsson SO, et al. Pravastatin and|2
03234|102|R|  gemfibrozil alone and in combination for the treatment of|2
03234|103|R|  hypercholesterolemia. Am J Med 1993 Jan;94(1):13-20.|2
03234|104|R|9.Chucrallah A, De Girolami U, Freeman R, Federman M. Lovastatin/gemfibrozil|3
03234|105|R|  myopathy: a clinical, histochemical, and ultrastructural study. Eur Neurol|3
03234|106|R|  1992;32(5):293-6.|3
03234|107|R|10.Knoll RW, Ciafone R, Galen M. Rhabdomyolysis and renal failure secondary|3
03234|108|R|   to combination therapy of hyperlipidemia with lovastatin and gemfibozil.|3
03234|109|R|   Conn Med 1993 Sep;57(9):593-4.|3
03234|110|R|11.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
03234|111|R|   cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
03234|112|R|   polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
03234|113|R|12.Rosenson RS. Gemfibrozil-lovastatin-associated myalgia. Am J Cardiol 1993|3
03234|114|R|   Feb 15;71(5):497.|3
03234|115|R|13.Illingworth DR, Bacon S. Influence of lovastatin plus gemfibrozil on|2
03234|116|R|   plasma lipids and lipoproteins in patients with heterozygous familial|2
03234|117|R|   hypercholesterolemia. Circulation 1989 Mar;79(3):590-6.|2
03234|118|R|14.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
03234|119|R|   Ltd. December, 2020.|1
03234|120|R|15.Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly|2
03234|121|R|   increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 2002|2
03234|122|R|   Dec;72(6):685-91.|2
03234|123|R|16.Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ.|2
03234|124|R|   Plasma concentrations of active lovastatin acid are markedly increased by|2
03234|125|R|   gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 2001 May;|2
03234|126|R|   69(5):340-5.|2
03234|127|R|17.Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases|2
03234|128|R|   plasma pravastatin concentrations and reduces pravastatin renal|2
03234|129|R|   clearance. Clin Pharmacol Ther 2003 Jun;73(6):538-44.|2
03234|130|R|18.Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma|2
03234|131|R|   concentrations of active simvastatin acid are increased by gemfibrozil.|2
03234|132|R|   Clin Pharmacol Ther 2000 Aug;68(2):122-9.|2
03234|133|R|19.Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with|3
03234|134|R|   simvastatin-gemfibrozil therapy. South Med J 1997 May;90(5):546-7.|3
03234|135|R|20.McDonald KB, Garber BG, Perreault MM. Pancreatitis associated with|3
03234|136|R|   simvastatin plus fenofibrate. Ann Pharmacother 2002 Feb;36(2):275-9.|3
03234|137|R|21.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of|3
03234|138|R|   a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
03234|139|R|   2002;101(7):53-6.|3
03234|140|R|22.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03234|141|R|   Pharmaceuticals LP July, 2024.|1
03234|142|R|23.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
03234|143|R|   Squibb Company May, 2022.|1
03234|144|R|24.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03234|145|R|   2023.|1
03234|146|R|25.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
03234|147|R|   Merck/Schering-Plough Pharmaceuticals February, 2024.|1
03234|148|R|26.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
03234|149|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
03234|150|R|   at:|3
03234|151|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
03234|152|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
03234|153|R|27.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
03234|154|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
03234|155|R|   95(1):120-2.|2
03234|156|R|28.Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, Liu L, Lin|5
03234|157|R|   JH, Pearson PG, Baillie TA. Mechanistic studies on metabolic interactions|5
03234|158|R|   between gemfibrozil and statins. J Pharmacol Exp Ther 2002 Jun;|5
03234|159|R|   301(3):1042-51.|5
03234|160|R|29.Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly|2
03234|161|R|   decreases and gemfibrozil increases the plasma concentrations of|2
03234|162|R|   atorvastatin and its metabolites. Clin Pharmacol Ther 2005 Aug;|2
03234|163|R|   78(2):154-67.|2
03234|164|R|30.Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J.|5
03234|165|R|   Interaction between fibrates and statins--metabolic interactions with|5
03234|166|R|   gemfibrozil. Drug Metabol Drug Interact 2003;19(3):161-76.|5
03234|167|R|31.Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking|3
03234|168|R|   atorvastatin with gemfibrozil. Am J Cardiol 1998 Feb 1;81(3):368-9.|3
03234|169|R|32.Shanahan RL, Kerzee JA, Sandhoff BG, Carroll NM, Merenich JA. Low|2
03234|170|R|   myopathy rates associated with statins as monotherapy or combination|2
03234|171|R|   therapy with interacting drugs in a group model health maintenance|2
03234|172|R|   organization. Pharmacotherapy 2005 Mar;25(3):345-51.|2
03234|173|R|33.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
03234|174|R|   Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized|2
03234|175|R|   rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004|2
03234|176|R|   Dec 1;292(21):2585-90.|2
03234|177|R|34.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
03234|178|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
03234|179|R|35.Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and|3
03234|180|R|   acute renal failure after changing statin-fibrate combinations.|3
03234|181|R|   Cardiology 2000;94(2):127-8.|3
03234|182|R|36.USFood and Drug Administration. FDA Drug Safety Communication: New|1
03234|183|R|   restrictions, contraindications, and dose limitations for Zocor|1
03234|184|R|   (simvastatin) to reduce the risk of muscle injury. available at:|1
03234|185|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-co|1
03234|186|R|   mmunication-new-restrictions-contraindications-and-dose-limitations-zocor|1
03234|187|R|   June 8, 2011.|1
03234|188|R|37.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun|6
03234|189|R|   LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,|6
03234|190|R|   Heidenreich PA. 2018|6
03234|191|R|   AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the|6
03234|192|R|   Management of Blood Cholesterol: A Report of the American College of|6
03234|193|R|   Cardiology/American Heart Association Task Force on Clinical Practice|6
03234|194|R|   Guidelines. J Am Coll Cardiol 2019 Jun 25;73(24):e285-e350.|6
03234|195|R|38.Crestor (rosuvastatin calcium) Australian Product Information. A.|1
03234|196|R|   Menarini Australia Pty Ltd July 8, 2024.|1
03235|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 10 mg)/Gemfibrozil|
03235|002|T|(mono deleted 09/02/2025)|
03235|003|B||
03235|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03235|005|L|is contraindicated and generally should not be dispensed or administered to|
03235|006|L|the same patient.|
03235|007|B||
03235|008|A|MECHANISM OF ACTION:  Unknown.|
03235|009|B||
03235|010|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
03235|011|E|and gemfibrozil has been associated with severe myopathy, rhabdomyolysis and|
03235|012|E|acute renal failure.|
03235|013|B||
03235|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03235|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03235|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03235|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03235|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03235|019|P|transporter OATP1B1 may have increased statin concentrations and be|
03235|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
03235|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
03235|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
03235|023|B||
03235|024|M|PATIENT MANAGEMENT:  According to the 2018 ACC/AHA Blood Cholesterol|
03235|025|M|Guidelines, gemfibrozil is contraindicated in patients on statin therapy.|
03235|026|M|   According to the 2016 AHA Scientific Statement Recommendations for|
03235|027|M|Management of Clinically Significant Drug-Drug Interactions with Statins and|
03235|028|M|Select Agents Used in Patients with Cardiovascular Disease, rosuvastatin|
03235|029|M|dose should be initiated at 5 mg daily and should not exceed 10 mg daily|
03235|030|M|when used concurrently with gemfibrozil.|
03235|031|M|   The manufacturer of gemfibrozil states that concurrent therapy with|
03235|032|M|gemfibrozil and HMG CO-A reductase inhibitors does not outweigh the risks of|
03235|033|M|severe myopathy, rhabdomyolysis, and acute renal failure.|
03235|034|M|   The Canadian manufacturer of rosuvastatin states that patients receiving|
03235|035|M|concurrent gemfibrozil should not receive more than 20 mg of rosuvastatin|
03235|036|M|daily and that the concurrent use of gemfibrozil and 40 mg of rosuvastatin|
03235|037|M|is contraindicated.  The Australian and US manufacturers of rosuvastatin|
03235|038|M|state that the concurrent use of gemfibrozil and rosuvastatin should be|
03235|039|M|avoided and that the risks of concurrent use of other fibrates should be|
03235|040|M|carefully weighed against the benefits.  In patients requiring concurrent|
03235|041|M|gemfibrozil, the dosage of rosuvastatin should be limited to 10 mg daily.|
03235|042|M|   When possible, avoid administration of these drugs concomitantly unless|
03235|043|M|patients require aggressive therapy.  If possible, consider the use of|
03235|044|M|fenofibrate over gemfibrozil for concurrent therapy with a statin.  Instruct|
03235|045|M|patients to report any unexplained muscle pain, tenderness or weakness.  If|
03235|046|M|muscular symptoms develop, monitor serum creatine kinase levels and renal|
03235|047|M|function.  One or both agents may need to be discontinued.|
03235|048|B||
03235|049|D|DISCUSSION:  Gemfibrozil has been shown to increase levels of cerivastatin,|
03235|050|D|lovastatin, pravastatin, rosuvastatin, and simvastatin.  Administration of|
03235|051|D|gemfibrozil with cerivastatin, lovastatin, and simvastatin has been|
03235|052|D|associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and|
03235|053|D|weakness).  Although the reaction has been reported with the statins alone,|
03235|054|D|the incidence increases dramatically with concurrent administration of|
03235|055|D|gemfibrozil.|
03235|056|D|   Concurrent gemfibrozil (600 mg twice daily) and rosuvastatin (80 mg)|
03235|057|D|increased the rosuvastatin AUC and Cmax by 90% and 120%, respectively.  In|
03235|058|D|healthy subjects, gemfibrozil increased the Cmax and AUC of a single dose of|
03235|059|D|rosuvastatin by 2.2-fold and 1.9-fold, respectively.|
03235|060|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
03235|061|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
03235|062|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
03235|063|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
03235|064|D|Veteran's Administration over a 2 year period, there were 149 reports of|
03235|065|D|rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil|
03235|066|D|and statin therapy compared with no reports in 1,830 patients receiving|
03235|067|D|concurrent fenofibrate and statin therapy.|
03235|068|D|   In a retrospective cohort study of 252,460 patients, concurrent use of|
03235|069|D|statins and fibrates increased the risk of rhabdomyolysis, especially in|
03235|070|D|patients with diabetes mellitus.  The risk of hospitalization for patients|
03235|071|D|aged 65 or older with diabetes mellitus, treated with a statin and fibrate,|
03235|072|D|increased 48-fold compared to statin monotherapy.|
03235|073|D|   In a retrospective study, of 468 patients with a diagnosis of myopathy,|
03235|074|D|61 received a statin prior to their diagnosis. Forty-one of these patients|
03235|075|D|developed confirmed myopathy, creatinine kinase more than or equal to 1000|
03235|076|D|IU/L.|
03235|077|B||
03235|078|R|REFERENCES:|
03235|079|B||
03235|080|R|1.Thompson GR, Ford J, Jenkinson M, Trayner I. Efficacy of mevinolin as|2
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03235|087|R|  combination lovastatin and gemfibrozil therapy. Ann Intern Med 1990 Feb 1;|3
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03235|089|R|4.Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated|3
03235|090|R|  with lovastatin-gemfibrozil combination therapy. JAMA 1990 Jul 4;|3
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03235|092|R|5.Glueck CJ, Speirs J, Tracy T. Safety and efficacy of combined|2
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03235|095|R|6.Glueck CJ, Oakes N, Speirs J, Tracy T, Lang J. Gemfibrozil-lovastatin|2
03235|096|R|  therapy for primary hyperlipoproteinemias. Am J Cardiol 1992 Jul 1;|2
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03235|098|R|7.Wirebaugh SR, Shapiro ML, McIntyre TH, Whitney EJ. A retrospective review|2
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03235|101|R|8.Wiklund O, Angelin B, Bergman M, Berglund L, Bondjers G, Carlsson A,|2
03235|102|R|  Linden T, Miettinen T, Odman B, Olofsson SO, et al. Pravastatin and|2
03235|103|R|  gemfibrozil alone and in combination for the treatment of|2
03235|104|R|  hypercholesterolemia. Am J Med 1993 Jan;94(1):13-20.|2
03235|105|R|9.Chucrallah A, De Girolami U, Freeman R, Federman M. Lovastatin/gemfibrozil|3
03235|106|R|  myopathy: a clinical, histochemical, and ultrastructural study. Eur Neurol|3
03235|107|R|  1992;32(5):293-6.|3
03235|108|R|10.Knoll RW, Ciafone R, Galen M. Rhabdomyolysis and renal failure secondary|3
03235|109|R|   to combination therapy of hyperlipidemia with lovastatin and gemfibozil.|3
03235|110|R|   Conn Med 1993 Sep;57(9):593-4.|3
03235|111|R|11.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
03235|112|R|   cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
03235|113|R|   polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
03235|114|R|12.Rosenson RS. Gemfibrozil-lovastatin-associated myalgia. Am J Cardiol 1993|3
03235|115|R|   Feb 15;71(5):497.|3
03235|116|R|13.Illingworth DR, Bacon S. Influence of lovastatin plus gemfibrozil on|2
03235|117|R|   plasma lipids and lipoproteins in patients with heterozygous familial|2
03235|118|R|   hypercholesterolemia. Circulation 1989 Mar;79(3):590-6.|2
03235|119|R|14.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
03235|120|R|   Ltd. December, 2020.|1
03235|121|R|15.Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly|2
03235|122|R|   increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 2002|2
03235|123|R|   Dec;72(6):685-91.|2
03235|124|R|16.Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ.|2
03235|125|R|   Plasma concentrations of active lovastatin acid are markedly increased by|2
03235|126|R|   gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 2001 May;|2
03235|127|R|   69(5):340-5.|2
03235|128|R|17.Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases|2
03235|129|R|   plasma pravastatin concentrations and reduces pravastatin renal|2
03235|130|R|   clearance. Clin Pharmacol Ther 2003 Jun;73(6):538-44.|2
03235|131|R|18.Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma|2
03235|132|R|   concentrations of active simvastatin acid are increased by gemfibrozil.|2
03235|133|R|   Clin Pharmacol Ther 2000 Aug;68(2):122-9.|2
03235|134|R|19.Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with|3
03235|135|R|   simvastatin-gemfibrozil therapy. South Med J 1997 May;90(5):546-7.|3
03235|136|R|20.McDonald KB, Garber BG, Perreault MM. Pancreatitis associated with|3
03235|137|R|   simvastatin plus fenofibrate. Ann Pharmacother 2002 Feb;36(2):275-9.|3
03235|138|R|21.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of|3
03235|139|R|   a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
03235|140|R|   2002;101(7):53-6.|3
03235|141|R|22.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03235|142|R|   Pharmaceuticals LP July, 2024.|1
03235|143|R|23.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
03235|144|R|   Squibb Company May, 2022.|1
03235|145|R|24.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03235|146|R|   2023.|1
03235|147|R|25.Vytorin (ezetimibe/simvastatin) US prescribing information.|1
03235|148|R|   Merck/Schering-Plough Pharmaceuticals February, 2024.|1
03235|149|R|26.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
03235|150|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
03235|151|R|   at:|3
03235|152|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
03235|153|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
03235|154|R|27.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
03235|155|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
03235|156|R|   95(1):120-2.|2
03235|157|R|28.Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, Liu L, Lin|5
03235|158|R|   JH, Pearson PG, Baillie TA. Mechanistic studies on metabolic interactions|5
03235|159|R|   between gemfibrozil and statins. J Pharmacol Exp Ther 2002 Jun;|5
03235|160|R|   301(3):1042-51.|5
03235|161|R|29.Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly|2
03235|162|R|   decreases and gemfibrozil increases the plasma concentrations of|2
03235|163|R|   atorvastatin and its metabolites. Clin Pharmacol Ther 2005 Aug;|2
03235|164|R|   78(2):154-67.|2
03235|165|R|30.Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J.|5
03235|166|R|   Interaction between fibrates and statins--metabolic interactions with|5
03235|167|R|   gemfibrozil. Drug Metabol Drug Interact 2003;19(3):161-76.|5
03235|168|R|31.Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking|3
03235|169|R|   atorvastatin with gemfibrozil. Am J Cardiol 1998 Feb 1;81(3):368-9.|3
03235|170|R|32.Shanahan RL, Kerzee JA, Sandhoff BG, Carroll NM, Merenich JA. Low|2
03235|171|R|   myopathy rates associated with statins as monotherapy or combination|2
03235|172|R|   therapy with interacting drugs in a group model health maintenance|2
03235|173|R|   organization. Pharmacotherapy 2005 Mar;25(3):345-51.|2
03235|174|R|33.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
03235|175|R|   Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized|2
03235|176|R|   rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004|2
03235|177|R|   Dec 1;292(21):2585-90.|2
03235|178|R|34.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
03235|179|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
03235|180|R|35.Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and|3
03235|181|R|   acute renal failure after changing statin-fibrate combinations.|3
03235|182|R|   Cardiology 2000;94(2):127-8.|3
03235|183|R|36.USFood and Drug Administration. FDA Drug Safety Communication: New|1
03235|184|R|   restrictions, contraindications, and dose limitations for Zocor|1
03235|185|R|   (simvastatin) to reduce the risk of muscle injury. available at:|1
03235|186|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-co|1
03235|187|R|   mmunication-new-restrictions-contraindications-and-dose-limitations-zocor|1
03235|188|R|   June 8, 2011.|1
03235|189|R|37.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun|6
03235|190|R|   LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,|6
03235|191|R|   Heidenreich PA. 2018|6
03235|192|R|   AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the|6
03235|193|R|   Management of Blood Cholesterol: A Report of the American College of|6
03235|194|R|   Cardiology/American Heart Association Task Force on Clinical Practice|6
03235|195|R|   Guidelines. J Am Coll Cardiol 2019 Jun 25;73(24):e285-e350.|6
03235|196|R|38.Crestor (rosuvastatin calcium) Australian Product Information. A.|1
03235|197|R|   Menarini Australia Pty Ltd July 8, 2024.|1
03236|001|T|MONOGRAPH TITLE:  Fluvastatin/Gemfibrozil|
03236|002|B||
03236|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03236|004|L|is contraindicated and generally should not be dispensed or administered to|
03236|005|L|the same patient.|
03236|006|B||
03236|007|A|MECHANISM OF ACTION:  Unknown.|
03236|008|B||
03236|009|E|CLINICAL EFFECTS:  Concurrent administration of HMG-CoA reductase inhibitors|
03236|010|E|and fibric acid derivatives has been associated with severe myopathy,|
03236|011|E|rhabdomyolysis and acute renal failure.|
03236|012|B||
03236|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03236|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03236|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03236|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03236|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03236|018|P|transporter OATP1B1 may have increased statin concentrations and be|
03236|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on fluvastatin who are|
03236|020|P|CYP2C9 intermediate or poor metabolizers may have increased fluvastatin|
03236|021|P|concentrations and  risk of myopathy.|
03236|022|B||
03236|023|M|PATIENT MANAGEMENT:  According to the 2018 ACC/AHA Blood Cholesterol|
03236|024|M|Guidelines, gemfibrozil is contraindicated in patients on statin therapy.|
03236|025|M|   According to the 2016 AHA Scientific Statement Recommendations for|
03236|026|M|Management of Clinically Significant Drug-Drug Interactions with Statins and|
03236|027|M|Select Agents Used in Patients with Cardiovascular Disease, fluvastatin dose|
03236|028|M|does not require a dose adjustment when used concurrently with gemfibrozil.|
03236|029|M|   According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil|
03236|030|M|should not be initiated in patients on statin therapy.  Fenofibrate may be|
03236|031|M|considered with low or moderate intensity statin therapy only if benefits|
03236|032|M|outweigh the risks.|
03236|033|M|   The US, Australian, Canadian, and UK manufacturers of gemfibrozil state|
03236|034|M|that use with HMG CO-A reductase inhibitors does not outweigh the risks of|
03236|035|M|severe myopathy, rhabdomyolysis, and acute renal failure.  The Canadian|
03236|036|M|manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should|
03236|037|M|not be used concurrently.|
03236|038|M|   The US manufacturer of fluvastatin states that concurrent use of|
03236|039|M|gemfibrozil should be avoided.  The Australian, Canadian, and UK|
03236|040|M|manufacturers state concurrent use should be approached with caution.|
03236|041|M|   Instruct patients receiving concurrent therapy to report any unexplained|
03236|042|M|muscle pain, tenderness or weakness.  If muscular symptoms develop, monitor|
03236|043|M|serum creatine kinase levels and renal function.  One or both agents may|
03236|044|M|need to be discontinued.|
03236|045|B||
03236|046|D|DISCUSSION:  Gemfibrozil has been shown to increase levels of cerivastatin,|
03236|047|D|lovastatin, pravastatin, rosuvastatin, and simvastatin.  Administration of|
03236|048|D|gemfibrozil with cerivastatin, lovastatin, and simvastatin has been|
03236|049|D|associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and|
03236|050|D|weakness).  Although the reaction has been reported with the statins alone,|
03236|051|D|the incidence increases dramatically with concurrent administration of|
03236|052|D|gemfibrozil.|
03236|053|D|   The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase|
03236|054|D|inhibitor therapy appears to be greater with gemfibrozil.  Analysis of the|
03236|055|D|FDA Adverse Event Report database indicates that the rate is 30 times higher|
03236|056|D|with gemfibrozil than with fenofibrate.  In an analysis of data from the|
03236|057|D|Veteran's Administration over a 2 year period, there were 149 reports of|
03236|058|D|rhabdomyolysis in 93,677 (0.16%) patients receiving concurrent gemfibrozil|
03236|059|D|and statin therapy compared with no reports in 1,830 patients receiving|
03236|060|D|concurrent fenofibrate and statin therapy.|
03236|061|D|   In a retrospective cohort study of 252,460 patients, concurrent use of|
03236|062|D|statins and fibrates increased the risk of rhabdomyolysis, especially in|
03236|063|D|patients with diabetes mellitus.  The risk of hospitalization for patients|
03236|064|D|aged 65 or older with diabetes mellitus, treated with a statin and fibrate,|
03236|065|D|increased 48-fold compared to statin monotherapy.|
03236|066|D|   In a retrospective study, of 468 patients with a diagnosis of myopathy,|
03236|067|D|61 received a statin prior to their diagnosis. Forty-one of these patients|
03236|068|D|developed confirmed myopathy, creatinine kinase more than or equal to 1000|
03236|069|D|IU/L.|
03236|070|B||
03236|071|R|REFERENCES:|
03236|072|B||
03236|073|R|1.Stone NJ, Robinson JG, Lichtenstein AH, Goff DC Jr, Lloyd-Jones DM, Smith|6
03236|074|R|  SC Jr, Blum C, Schwartz JS. Treatment of blood cholesterol to reduce|6
03236|075|R|  atherosclerotic cardiovascular disease risk in adults: synopsis of the|6
03236|076|R|  2013 American College of Cardiology/American Heart Association cholesterol|6
03236|077|R|  guideline. Ann Intern Med 2014 Mar 4;160(5):339-43.|6
03236|078|R|2.Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis JB, Lanfear|6
03236|079|R|  D, Virani S, Morris PB. Recommendations for Management of Clinically|6
03236|080|R|  Significant Drug-Drug Interactions With Statins and Select Agents Used in|6
03236|081|R|  Patients With Cardiovascular Disease: A Scientific Statement From the|6
03236|082|R|  American Heart Association. Circulation 2016 Nov 22;134(21):e468-e495.|6
03236|083|R|3.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
03236|084|R|  Ltd. December, 2020.|1
03236|085|R|4.Lipazil (gemfibrozil) Australian product information. Ascent Pharma Pty|1
03236|086|R|  Ltd December 5, 2011.|1
03236|087|R|5.Teva-Gemfibrozil (gemfibrozil) Canadian product monograph. Teva Canada|1
03236|088|R|  Limited June 29, 2015.|1
03236|089|R|6.Lopid (gemfibrozil) UK summary of product characteristics. Pfizer Limited|1
03236|090|R|  May, 2016.|1
03236|091|R|7.Lescol (fluvastatin sodium) US prescribing information. Novartis|1
03236|092|R|  Pharmaceuticals Corporation August, 2017.|1
03236|093|R|8.Lescol XL (fluvastatin) Australian product information. Novartis|1
03236|094|R|  Pharmaceuticals Australia Pty Limited June 8, 2016.|1
03236|095|R|9.Lescol (fluvastatin) Canadian product monograph. Pharmaceuticals Canada|1
03236|096|R|  Inc. August 26, 2016.|1
03236|097|R|10.Lescol XL (fluvastatin) UK summary of product characteristics. Novartis|1
03236|098|R|   Pharmaceuticals UK Ltd August 26, 2017.|1
03236|099|R|11.Thompson GR, Ford J, Jenkinson M, Trayner I. Efficacy of mevinolin as|2
03236|100|R|   adjuvant therapy for refractory familial hypercholesterolaemia. Q J Med|2
03236|101|R|   1986 Aug;60(232):803-11.|2
03236|102|R|12.Goldman JA, Fishman AB, Lee JE, Johnson RJ. The role of|3
03236|103|R|   cholesterol-lowering agents in drug-induced rhabdomyolysis and|3
03236|104|R|   polymyositis. Arthritis Rheum 1989 Mar;32(3):358-9.|3
03236|105|R|13.Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of|3
03236|106|R|   a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ|3
03236|107|R|   2002;101(7):53-6.|3
03236|108|R|14.VHA Pharmacy Benefits Management-Strategic Healthcare Group and The|3
03236|109|R|   Medical Advisory Panel. STATIN-FIBRATE REPORT: Focus on Safety. available|3
03236|110|R|   at:|3
03236|111|R|   https://www.pbm.va.gov/PBM/vacenterformedicationsafety/nationalpbmbulleti|3
03236|112|R|   n/87ry38statinfibrateFinal.pdf September, 2004.|3
03236|113|R|15.Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate|2
03236|114|R|   + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1;|2
03236|115|R|   95(1):120-2.|2
03236|116|R|16.Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, Liu L, Lin|5
03236|117|R|   JH, Pearson PG, Baillie TA. Mechanistic studies on metabolic interactions|5
03236|118|R|   between gemfibrozil and statins. J Pharmacol Exp Ther 2002 Jun;|5
03236|119|R|   301(3):1042-51.|5
03236|120|R|17.Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J.|5
03236|121|R|   Interaction between fibrates and statins--metabolic interactions with|5
03236|122|R|   gemfibrozil. Drug Metabol Drug Interact 2003;19(3):161-76.|5
03236|123|R|18.Shanahan RL, Kerzee JA, Sandhoff BG, Carroll NM, Merenich JA. Low|2
03236|124|R|   myopathy rates associated with statins as monotherapy or combination|2
03236|125|R|   therapy with interacting drugs in a group model health maintenance|2
03236|126|R|   organization. Pharmacotherapy 2005 Mar;25(3):345-51.|2
03236|127|R|19.Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L,|2
03236|128|R|   Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized|2
03236|129|R|   rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004|2
03236|130|R|   Dec 1;292(21):2585-90.|2
03236|131|R|20.Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with|2
03236|132|R|   fibrates. Am J Cardiol 2004 Oct 1;94(7):935-8.|2
03236|133|R|21.Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and|3
03236|134|R|   acute renal failure after changing statin-fibrate combinations.|3
03236|135|R|   Cardiology 2000;94(2):127-8.|3
03236|136|R|22.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun|6
03236|137|R|   LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,|6
03236|138|R|   Heidenreich PA. 2018|6
03236|139|R|   AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the|6
03236|140|R|   Management of Blood Cholesterol: A Report of the American College of|6
03236|141|R|   Cardiology/American Heart Association Task Force on Clinical Practice|6
03236|142|R|   Guidelines. J Am Coll Cardiol 2019 Jun 25;73(24):e285-e350.|6
03237|001|T|MONOGRAPH TITLE:  Bictegravir-Emtricitabine-Tenofovir Alafenamide/Selected|
03237|002|T|Strong CYP3A4 Inducers; Oxcarbazepine|
03237|003|B||
03237|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03237|005|L|of severe adverse interaction.|
03237|006|B||
03237|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers and oxcarbazepine may induce|
03237|008|A|the metabolism of bictegravir.(1,2)|
03237|009|B||
03237|010|E|CLINICAL EFFECTS:  Concurrent use of bictegravir with strong CYP3A4 inducers|
03237|011|E|or oxcarbazepine may result in decreased levels of bictegravir, virologic|
03237|012|E|failure, and development of resistance.(1,2)|
03237|013|B||
03237|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03237|015|P|of the inducer for longer than 1-2 weeks.|
03237|016|B||
03237|017|M|PATIENT MANAGEMENT:  The manufacturer of bictegravir recommends considering|
03237|018|M|alternatives to oxcarbazepine.(1)  The National Institute of Health HIV|
03237|019|M|guidelines do not recommend coadministration of oxcarbazepine with|
03237|020|M|bictegravir.(2)|
03237|021|M|   Other CYP3A4 inducers should not be coadministered with bictegravir.(1,2)|
03237|022|B||
03237|023|D|DISCUSSION:  Coadministration of rifampin (600 mg daily, a strong CYP3A4|
03237|024|D|inducer) decreased bictegravir area-under-curve (AUC) by 75% and maximum|
03237|025|D|concentration (Cmax) by 28%.(1)  Although the other CYP3A4 inducers linked|
03237|026|D|to this monograph have not been studied with bictegravir, a similar effect|
03237|027|D|is expected.|
03237|028|D|   Coadministration of rifabutin (300 mg daily) with bictegravir decreased|
03237|029|D|bictegravir AUC and Cmax by 38% and 20%, respectively.(1)|
03237|030|D|   CYP3A4 inducers linked to this monograph include: barbiturates,|
03237|031|D|encorafenib, enzalutamide, ivosidenib, mitotane, or oxcarbazepine.(1-3)|
03237|032|B||
03237|033|R|REFERENCES:|
03237|034|B||
03237|035|R|1.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
03237|036|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
03237|037|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03237|038|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03237|039|R|  HIV. Department of Health and Human Services. Available at|6
03237|040|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03237|041|R|  new-guidelines June 13, 2021.|6
03237|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
03237|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03238|001|T|MONOGRAPH TITLE:  Selected Antineoplastics that Prolong QT/Saquinavir|
03238|002|B||
03238|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03238|004|L|of severe adverse interaction.|
03238|005|B||
03238|006|A|MECHANISM OF ACTION:  Saquinavir(1) may inhibit the metabolism of|
03238|007|A|ceritinib,(2) crizotinib,(3) lapatinib,(4) nilotinib,(5) pazopanib,(6) and|
03238|008|A|toremifene.(7)|
03238|009|B||
03238|010|E|CLINICAL EFFECTS:  Concurrent use of saquinavir may increase levels of and|
03238|011|E|effects from ceritinib,(2) crizotinib,(3) lapatinib,(4) nilotinib,(5-6)|
03238|012|E|pazopanib,(7) and toremifene.(8)|
03238|013|E|    Elevated levels of ceritinib,(2) crizotinib,(3) lapatinib,(4)|
03238|014|E|nilotinib,(5-6) pazopanib,(7) and toremifene(8) may result in QTc|
03238|015|E|prolongation, which may result in potentially life-threatening cardiac|
03238|016|E|arrhythmias, including torsades de pointes.|
03238|017|B||
03238|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03238|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03238|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03238|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03238|022|P|female gender, or advanced age.(9)|
03238|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03238|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03238|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03238|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03238|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03238|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03238|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(9)|
03238|030|P|   In patients taking ceritinib, patients with severe hepatic impairment|
03238|031|P|(Child-Pugh C) may be at increased risk of this interaction.  Ceritinib dose|
03238|032|P|reduction may be warranted in severe hepatic impairment.  See prescribing|
03238|033|P|information for recommendations.(2)|
03238|034|B||
03238|035|M|PATIENT MANAGEMENT:  The US manufacturer of saquinavir states that|
03238|036|M|concurrent use of agents known to prolong the QT interval should only be|
03238|037|M|used when there is no alternative therapy and potential benefits outweigh|
03238|038|M|the risks.(1)|
03238|039|M|   Perform an ECG prior to initiation of saquinavir or prior to concurrent|
03238|040|M|therapy with agents known to prolong the QT interval.|
03238|041|M|   Treatment-naive patients: Patients with a QT interval greater than 450|
03238|042|M|msec should not initiate therapy with saquinavir/ritonavir.  Treatment-naive|
03238|043|M|patients should receive a reduced dose of saquinavir 500 mg twice daily with|
03238|044|M|ritonavir 100 mg twice daily for the first 7 days followed by saquinavir|
03238|045|M|1000 mg twice daily with ritonavir 100 mg twice daily (standard dose).  For|
03238|046|M|patients with a baseline QT interval less than 450 msec, a repeat ECG should|
03238|047|M|be performed after 10 days of therapy.  In patients who experience an|
03238|048|M|increase in QT interval of greater than 20 msec, therapy should|
03238|049|M|discontinued.|
03238|050|M|   Treatment-experienced patients: Patients with a QT interval greater than|
03238|051|M|450 msec should not initiate concurrent therapy.  For patients with a|
03238|052|M|baseline QT interval less than 450 msec, a repeat ECG should be performed|
03238|053|M|after 3-4 days of concurrent therapy.  In patients who experience an|
03238|054|M|increase in QT interval by greater than 20 msec, consideration should be|
03238|055|M|given to discontinuing one or both agents.(1)|
03238|056|M|   In addition, if concurrent therapy is warranted, consider obtaining serum|
03238|057|M|calcium, magnesium, and potassium levels and monitoring ECG at baseline and|
03238|058|M|at regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03238|059|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03238|060|M|   Recommendations for specific antineoplastics:|
03238|061|M|   If concurrent use with ceritinib is unavoidable, reduce the dosage of|
03238|062|M|ceritinib by one-third, rounding to the nearest 150 mg dosage strength.(2)|
03238|063|M|If saquinavir is discontinued and not replaced with another strong CYP3A4|
03238|064|M|inhibitor, resume the dose that was taken prior to using saquinavir.|
03238|065|M|   In Adults: If concurrent use of crizotinib for metastatic non-small cell|
03238|066|M|lung cancer or inflammatory myofibroblastic tumor in adults and a strong|
03238|067|M|CYP3A4 inhibitor is unavoidable, a dose reduction of crizotinib to 250 mg|
03238|068|M|daily is recommended.|
03238|069|M|   In Pediatrics or Young Adults: If concurrent use of crizotinib for|
03238|070|M|systemic anaplastic large cell lymphoma (in pediatrics), inflammatory|
03238|071|M|myofibroblastic tumor (in pediatrics) or systemic anaplastic large cell|
03238|072|M|lymphoma (in young adults) and a strong CYP3A4 inhibitor is unavoidable,|
03238|073|M|dose reductions of crizotinib based on body surface area (BSA) are|
03238|074|M|recommended for both capsule and pellet formulations.  See prescribing|
03238|075|M|information for dose reductions.(3)|
03238|076|M|   If saquinavir is discontinued and not replaced with another strong CYP3A4|
03238|077|M|inhibitor, resume the dose of crizotinib that was taken prior to initiating|
03238|078|M|saquinavir.|
03238|079|M|   If concurrent use with lapatinib is warranted, a dose reduction to 500|
03238|080|M|mg/day should be considered.  If saquinavir is discontinued and not replaced|
03238|081|M|with another CYP3A4 inhibitor, at least 1 week should elapse before the|
03238|082|M|lapatinib dose is adjusted upward.(4)|
03238|083|M|   If concurrent use is warranted with nilotinib hydrochloride, a dose|
03238|084|M|reduction to 300 mg once daily in patients with resistant or intolerant|
03238|085|M|Ph+CML or to 200 mg once daily in patients with newly diagnosed Ph+CML-CP|
03238|086|M|should be considered.  If concurrent use is warranted with nilotinib|
03238|087|M|tartrate, a dose reduction to 142 mg once daily in patients with resistant|
03238|088|M|or intolerant Ph+CML or to 95 mg once daily in patients with newly diagnosed|
03238|089|M|Ph+CML-CP should be considered.  If saquinavir is discontinued and not|
03238|090|M|replaced with another CYP3A4 inhibitor, a washout period should occur before|
03238|091|M|the nilotinib dose is adjusted upward.(5-6)|
03238|092|M|   If concurrent administration with pazopanib is warranted, the dosage of|
03238|093|M|pazopanib should be reduced to 400 mg.  Additional dosage reductions may be|
03238|094|M|required if adverse events occur.(7)|
03238|095|M|   If treatment with a strong CYP3A4 inhibitor is required, toremifene|
03238|096|M|therapy should be interrupted.  If it is not possible to interrupt|
03238|097|M|toremifene therapy, electrocardiograms (ECGs) should be obtained and|
03238|098|M|patients should be closely monitored for QT prolongation.(8)|
03238|099|B||
03238|100|D|DISCUSSION:  In a study in 19 healthy subjects, ketoconazole (200 mg twice|
03238|101|D|daily for 14 days) increased the Cmax and AUC of a single dose of ceritinib|
03238|102|D|(450 mg) by 22% and 2.9-fold, respectively.  The steady-state AUC of|
03238|103|D|ceritinib at reduced doses after concurrent ketoconazole was predicted by|
03238|104|D|simulations to be similar to the steady-state AUC of ceritinib alone.(2)|
03238|105|D|   Ketoconazole (200 mg twice daily) increased Cmax and AUC of a single dose|
03238|106|D|of crizotinib (150 mg) by 44% and 216%, respectively. Itraconazole (200 mg|
03238|107|D|twice daily) increased the Cmax and AUC of crizotinib (250 mg daily) by 33%|
03238|108|D|and 57%, respectively.(3)|
03238|109|D|   In a study in healthy subjects, ketoconazole (200 mg twice daily for 7|
03238|110|D|days) increased lapatinib AUC and half-life (T1/2) by 3.6-fold and 1.7-fold,|
03238|111|D|respectively.  The dosage adjustment to 500 mg/day is based on|
03238|112|D|pharmacokinetic studies and is predicted to adjust lapatinib AUC to the|
03238|113|D|range observed without inhibitors; however, there are no clinical data with|
03238|114|D|this dosage adjustment in patients receiving strong CYP3A4 inhibitors.(4)|
03238|115|D|   In a study in healthy subjects, concurrent ketoconazole (400 mg daily)|
03238|116|D|increased nilotinib AUC 3-fold.(5-6)|
03238|117|D|   Administration of multiple doses of oral pazopanib (400 mg) with multiple|
03238|118|D|doses of oral ketoconazole (400 mg) increased the AUC and Cmax of pazopanib|
03238|119|D|by 1.7-fold and 1.5-fold, respectively.  Administration of a single dose of|
03238|120|D|pazopanib ophthalmic drops and ketoconazole increased the AUC and Cmax of|
03238|121|D|pazopanib by 220% and 150%, respectively.  Administration of lapatinib (1500|
03238|122|D|mg), a weak inhibitor of CYP3A4, P-gp, and BCRP, increased the AUC and Cmax|
03238|123|D|of pazopanib (800 mg) by 50% and 60%, respectively.  Decreasing the dosage|
03238|124|D|of pazopanib to 400 mg in patients receiving strong CYP3A4 inhibitors is|
03238|125|D|expected to adjust the AUC of pazopanib to the normal range; however, there|
03238|126|D|are no clinical data available to support this.(7)|
03238|127|D|   In a study in 18 subjects, ketoconazole (200 mg daily) increased the Cmax|
03238|128|D|and AUC of toremifene (80 mg daily) by 1.4-fold and 2.9-fold, respectively.|
03238|129|D|N-demethyltoremifene Cmax and AUC decreased by 56% and 20%, respectively.(8)|
03238|130|D|   A retrospective review of 618 cancer patients treated with 902|
03238|131|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03238|132|D|incidence of QTc prolongation.  In patients who received:|
03238|133|D|   -Crizotinib, QTc prolongation was identified in 1 (50%) with 1 (100%)|
03238|134|D|having Grade 1.  No patients had a QTc change greater than or equal to 60|
03238|135|D|ms, VT, SCD, or TdP.|
03238|136|D|   -Nilotinib, QTc prolongation was identified in 29 (38.7%) with 1 (3.5%)|
03238|137|D|having Grade 1 and 2 (7%) having Grade 2.  Grade 3 events occurred in 9|
03238|138|D|(31%) having QTc greater than or equal to 500 ms and 17 (58.6%) having QTc|
03238|139|D|change greater than or equal to 60 ms.  No patients developed VT, SCD, or|
03238|140|D|TdP.|
03238|141|D|   -Pazopanib, QTc prolongation was identified in 32 (19.4%) with 18 (56.3%)|
03238|142|D|having Grade 1 and 4 (12.5%) having Grade 2.  Grade 3 events occurred in 3|
03238|143|D|(9.3%) having QTc greater than or equal to 500 ms and 4 (12.5%) having QTc|
03238|144|D|change greater than or equal to 60 ms.  VT was seen in 2 (6.3%) of patients|
03238|145|D|and 1 (3.1%) patient experienced SCD.(10)|
03238|146|B||
03238|147|R|REFERENCES:|
03238|148|B||
03238|149|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
03238|150|R|  Laboratories, Inc. March, 2019.|1
03238|151|R|2.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
03238|152|R|  Corporation August, 2021.|1
03238|153|R|3.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
03238|154|R|  2023.|1
03238|155|R|4.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
03238|156|R|  2018.|1
03238|157|R|5.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
03238|158|R|  Corporation September, 2021.|1
03238|159|R|6.Danziten (nilotinib tartrate) US prescribing information. Novartis|1
03238|160|R|  Pharmaceuticals November 2024.|1
03238|161|R|7.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03238|162|R|  2020.|1
03238|163|R|8.Fareston (toremifene citrate) US prescribing information. GTx, Inc. March,|1
03238|164|R|  2011.|1
03238|165|R|9.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03238|166|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03238|167|R|  settings: a scientific statement from the American Heart Association and|6
03238|168|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03238|169|R|  2;55(9):934-47.|6
03238|170|R|10.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03238|171|R|   Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03238|172|R|   Inhibitors. Int J Cancer. 2020 May 25.|2
03239|001|T|MONOGRAPH TITLE:  Crizotinib/Agents That Cause Bradycardia|
03239|002|B||
03239|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03239|004|L|of severe adverse interaction.|
03239|005|B||
03239|006|A|MECHANISM OF ACTION:  Crizotinib may cause symptomatic bradycardia.|
03239|007|A|Additional agents that cause bradycardia further increase the risk for|
03239|008|A|symptomatic bradycardia.(1)|
03239|009|B||
03239|010|E|CLINICAL EFFECTS:  Bradycardia may be associated with an increase in the QTc|
03239|011|E|interval, increasing the risk for torsade de pointes.(1)|
03239|012|B||
03239|013|P|PREDISPOSING FACTORS:  None determined.|
03239|014|B||
03239|015|M|PATIENT MANAGEMENT:  The manufacturer of crizotinib recommends avoiding|
03239|016|M|concurrent use of crizotinib and other agents known to cause bradycardia to|
03239|017|M|the extent possible.|
03239|018|M|   If combination therapy is required, monitor heart rate and blood pressure|
03239|019|M|regularly.  If bradycardia occurs, withhold crizotinib until heart rate|
03239|020|M|recovers to 60 bpm or above, or patient is asymptomatic.  Re-evaluate the|
03239|021|M|use of the concomitant medication.  If the concomitant medication is|
03239|022|M|discontinued or its dose is reduced, resume crizotinib at the previous dose|
03239|023|M|upon patient's recovery.  If the concomitant medication is not discontinued|
03239|024|M|or dose adjusted, resume crizotinib at a reduced dose upon patient's|
03239|025|M|recovery.|
03239|026|M|   If life-threatening bradycardia occurs, discontinue or reduce the dose of|
03239|027|M|the concomitant medication.  Upon the patient's recovery, lower the dose of|
03239|028|M|crizotinib to 250 mg daily.  Monitor blood pressure and heart rate|
03239|029|M|frequently.(1)|
03239|030|B||
03239|031|D|DISCUSSION:  Across clinical trials, bradycardia occurred in 13 % of|
03239|032|D|patients on crizotinib, and grade 3 syncope occurred in 2.4 % of patients on|
03239|033|D|crizotinib compared with 0.6 % on chemotherapy.(1)|
03239|034|D|   Agents that may cause bradycardia and linked to this monograph include:|
03239|035|D|beta-blockers, non-dihydropyridine calcium channel blockers, clonidine,|
03239|036|D|digoxin, and moxonidine.(1)|
03239|037|B||
03239|038|R|REFERENCE:|
03239|039|B||
03239|040|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
03239|041|R|  2023.|1
03240|001|T|MONOGRAPH TITLE:  Secretin/Anticholinergics|
03240|002|B||
03240|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03240|004|L|of severe adverse interaction.|
03240|005|B||
03240|006|A|MECHANISM OF ACTION:  Anticholinergic drugs may result in an incorrect|
03240|007|A|secretin stimulation test result.(1)|
03240|008|B||
03240|009|E|CLINICAL EFFECTS:  Concurrent use of anticholinergic drugs may impact the|
03240|010|E|accuracy of the secretin stimulation test.(1)|
03240|011|B||
03240|012|P|PREDISPOSING FACTORS:  None determined.|
03240|013|B||
03240|014|M|PATIENT MANAGEMENT:  The US manufacturer of human secretin states concurrent|
03240|015|M|use of anticholinergic drugs at the time of stimulation testing may cause|
03240|016|M|the patient to be hyporesponsive to the testing and suggest false positive|
03240|017|M|results for pancreatic disease.  The manufacturer recommends discontinuing|
03240|018|M|anticholinergic drugs at least 5 half-lives prior to stimulation testing.|
03240|019|M|Consider additional testing and clinical assessment for diagnosis.(1)|
03240|020|B||
03240|021|D|DISCUSSION:  Concurrent use of anticholinergic drugs may impact the accuracy|
03240|022|D|of the secretin stimulation test.(1)|
03240|023|B||
03240|024|R|REFERENCE:|
03240|025|B||
03240|026|R|1.Chirostim (human secretin) injection US prescribing information.|1
03240|027|R|  ChiRhoClin, Inc. July, 2017.|1
03241|001|T|MONOGRAPH TITLE:  Secretin/H2 Antagonists; Proton Pump Inhibitors|
03241|002|B||
03241|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03241|004|L|of severe adverse interaction.|
03241|005|B||
03241|006|A|MECHANISM OF ACTION:  H2 antagonists and proton pump inhibitors (PPIs) may|
03241|007|A|result in an incorrect secretin stimulation test result.(1)|
03241|008|B||
03241|009|E|CLINICAL EFFECTS:  Concurrent use of H2 antagonists and proton pump|
03241|010|E|inhibitors (PPIs) may impact the accuracy of the secretin stimulation|
03241|011|E|test.(1)|
03241|012|B||
03241|013|P|PREDISPOSING FACTORS:  Patients with alcoholic or other liver disease may be|
03241|014|P|hyperresponsive to stimulation with a secretin stimulation test, masking the|
03241|015|P|presence of coexisting pancreatic disease.  Consider additional testing and|
03241|016|P|clinical assessment for diagnosis.(1)|
03241|017|B||
03241|018|M|PATIENT MANAGEMENT:  The US manufacturer of human secretin states concurrent|
03241|019|M|use of H2 antagonists and proton pump inhibitors (PPIs) at the time of|
03241|020|M|stimulation testing may cause the patient to be hyperresponsive to secretin|
03241|021|M|stimulation and suggest false gastrinoma results.  The manufacturer|
03241|022|M|recommends discontinuing H2 antagonists at least 2 days prior to testing.|
03241|023|M|   The US manufacturer of vonoprazan recommends stopping vonoprazan at least|
03241|024|M|4 weeks prior to testing.(2-3)|
03241|025|M|   Consult prescribing information for PPIs before administering prior to a|
03241|026|M|secretin stimulation test.(1)|
03241|027|B||
03241|028|D|DISCUSSION:  Concurrent use of H2 antagonists and proton pump inhibitors|
03241|029|D|(PPIs) may impact the accuracy of the secretin stimulation test.(1)|
03241|030|B||
03241|031|R|REFERENCES:|
03241|032|B||
03241|033|R|1.Chirostim (human secretin) injection US prescribing information.|1
03241|034|R|  ChiRhoClin, Inc. July, 2017.|1
03241|035|R|2.Voquezna (vonoprazan) US prescribing information. Phathom Pharmaceuticals,|1
03241|036|R|  Inc. November, 2023.|1
03241|037|R|3.Voquezna (vonoprazan-amoxicillin and|1
03241|038|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
03241|039|R|  Pharmaceuticals, Inc. November, 2023.|1
03242|001|T|MONOGRAPH TITLE:  Tiopronin (Enteric-Coated)/Alcohol|
03242|002|B||
03242|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03242|004|L|take action as needed.|
03242|005|B||
03242|006|A|MECHANISM OF ACTION:  Alcohol may result in a faster release of|
03242|007|A|delayed-release tiopronin.(1)|
03242|008|B||
03242|009|E|CLINICAL EFFECTS:  Concurrent use of alcohol in patients taking|
03242|010|E|delayed-release tiopronin may increase the risk of side effects.(1)|
03242|011|B||
03242|012|P|PREDISPOSING FACTORS:  None determined.|
03242|013|B||
03242|014|M|PATIENT MANAGEMENT:  Counsel patients to avoid alcohol 2 hours before and 3|
03242|015|M|hours after taking delayed-release tiopronin.(1)|
03242|016|M|   Significant quantities of alcohol may be present in medicinal products.|
03242|017|M|Alcohol is is used to improve docetaxel and paclitaxel solubility.|
03242|018|M|   - The quantity of alcohol in paclitaxel injection formulations|
03242|019|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
03242|020|M|dose contains approximately 13 grams of alcohol.|
03242|021|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
03242|022|M|3-fold depending upon the manufacturer. FDA data on alcohol content (3):|
03242|023|M|   Product                      Manufacturer         Alcohol/200 mg dose|
03242|024|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
03242|025|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
03242|026|M|   Docetaxel Inj.               Accord                  4.0 grams|
03242|027|M|   Taxotere-one vial            Sanofi                  4.0 grams|
03242|028|M|    formulation|
03242|029|M|   Docetaxel Inj.               Hospira                 3.7 grams|
03242|030|M|   Docefrez                     Sun Pharma              2.9 grams|
03242|031|M|   Taxotere-two vial            Sanofi                  2.0 grams|
03242|032|M|    formulation|
03242|033|B||
03242|034|D|DISCUSSION:  An in vitro study found that alcohol (5, 10, 20, and 40 %)|
03242|035|D|increased the dissolution rate of delayed-release tiopronin tablets.(1)|
03242|036|B||
03242|037|R|REFERENCES:|
03242|038|B||
03242|039|R|1.Thiola EC (tiopronin) US prescribing information. Mission Pharmacal|1
03242|040|R|  Company June, 2019.|1
03242|041|R|2.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
03242|042|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
03242|043|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
03242|044|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
03242|045|R|  20, 2014.|1
03243|001|T|MONOGRAPH TITLE:  Levomethadone/Selected MAOIs|
03243|002|B||
03243|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03243|004|L|is contraindicated and generally should not be dispensed or administered to|
03243|005|L|the same patient.|
03243|006|B||
03243|007|A|MECHANISM OF ACTION:  Levomethadone may inhibit neural reuptake of|
03243|008|A|serotonin.  MAOIs increase neuronal serotonin concentrations via inhibition|
03243|009|A|of MAO-A.|
03243|010|B||
03243|011|E|CLINICAL EFFECTS:  The concurrent use of methadone with MAOIs has been|
03243|012|E|associated with serotonin syndrome. Levomethadone is an enantiomer of|
03243|013|E|methadone.|
03243|014|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03243|015|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03243|016|E|rigidity.|
03243|017|B||
03243|018|P|PREDISPOSING FACTORS:  Higher opioid concentrations as may occur due to|
03243|019|P|inhibition of opioid clearance, patient specific genomic factors (e.g. poor|
03243|020|P|metabolizer status for a specific P450 enzyme), or high opioid dosage may|
03243|021|P|increase the risk for a severe interaction.|
03243|022|B||
03243|023|M|PATIENT MANAGEMENT:  The Swedish manufacturer of levomethadone states that|
03243|024|M|the use of levomethadone is contraindicated during and within 2 two weeks|
03243|025|M|after discontinuation of an MAO inhibitor.|
03243|026|B||
03243|027|D|DISCUSSION:  FDA performed a search of its adverse event database for cases|
03243|028|D|of serotonin syndrome with selected opiates for the period of January 1,|
03243|029|D|1969 to June 12, 2013; 5 cases were associated with methadone use during|
03243|030|D|this 43 year period.|
03243|031|D|   Furazolidone is known to be monoamine oxidase inhibitor.|
03243|032|D|   Methylene blue, when administered intravenously, has been shown to reach|
03243|033|D|sufficient concentrations to be a potent inhibitor of MAO-A.|
03243|034|D|   One or more of the drug pairs linked to this monograph have been included|
03243|035|D|in a list of interactions that should be considered "high-priority" for|
03243|036|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
03243|037|D|vetted by an expert panel commissioned by the U.S. Office of the National|
03243|038|D|Coordinator (ONC) for Health Information Technology.|
03243|039|B||
03243|040|R|REFERENCES:|
03243|041|B||
03243|042|R|1.Mitchell RS. Fatal toxic encephalitis occurring during iproniazid therapy|2
03243|043|R|  in pulmonary tuberculosis. Ann Intern Med 1955;42:417-24.|2
03243|044|R|2.Papp C, Benaim S. Toxic effects of iproniazid in a patient with angina. Br|3
03243|045|R|  Med J 1958 Nov 1;2:1070-2.|3
03243|046|R|3.London DR, Milne MD. Dangers of monoamine oxidase inhibitors. Br Med J|6
03243|047|R|  1962 Dec 29;2:1752.|6
03243|048|R|4.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
03243|049|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
03243|050|R|5.Anonymous. Analgesics and monoamine-oxidase inhibitors. Br Med J 1967 Nov|6
03243|051|R|  4;4(574):284.|6
03243|052|R|6.Barry BJ. Adverse effects of MAO inhibitors with narcotics reversed with|3
03243|053|R|  naloxone. Anaesth Intensive Care 1979 May;7(2):194.|3
03243|054|R|7.Browne B, Linter S. Monoamine oxidase inhibitors and narcotic analgesics.|6
03243|055|R|  A critical review of the implications for treatment. Br J Psychiatry 1987|6
03243|056|R|  Aug;151:210-2.|6
03243|057|R|8.Rossiter A, Souney PF. Interaction between MAOIs and opioids:|6
03243|058|R|  pharmacologic and clinical considerations. Hosp Formul 1993 Aug;28:692-8.|6
03243|059|R|9.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
03243|060|R|  2007.|1
03243|061|R|10.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03243|062|R|   Pharma AS November 30, 2018.|1
03243|063|R|11.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03243|064|R|   352(11):1112-20.|6
03243|065|R|12.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03243|066|R|   warns about several safety issues with opioid pain medicines; requires|1
03243|067|R|   label changes. available at:|1
03243|068|R|   http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
03243|069|R|13.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
03243|070|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
03243|071|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
03243|072|R|   19(5):735-43.|6
03244|001|T|MONOGRAPH TITLE:  Levomethadone/Selected CYP3A4 Inducers (mono deleted|
03244|002|T|06/17/2021)|
03244|003|B||
03244|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03244|005|L|take action as needed.|
03244|006|B||
03244|007|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
03244|008|A|levomethadone.(1-7)|
03244|009|B||
03244|010|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inducer may result in|
03244|011|E|decreased levels of levomethadone, which may result in decreased|
03244|012|E|effectiveness and may precipitate withdrawal symptoms.(1-7)|
03244|013|B||
03244|014|P|PREDISPOSING FACTORS:  None determined.|
03244|015|B||
03244|016|M|PATIENT MANAGEMENT:  Patients maintained on levomethadone may require dosage|
03244|017|M|adjustments if a CYP3A4 inducer is initiated or discontinued.  The effects|
03244|018|M|of the interaction may last for several weeks after the discontinuation of|
03244|019|M|the inducer.(1)|
03244|020|B||
03244|021|D|DISCUSSION:  In a study, efavirenz (600 mg daily) given for 3 weeks in|
03244|022|D|patients on levomethadone led to a decrease in maximum concentration (Cmax)|
03244|023|D|and area-under-curve (AUC) of levomethadone of 48 % and 57 %,|
03244|024|D|respectively.(1)|
03244|025|D|   There are three case reports of patients in methadone maintenance|
03244|026|D|programs who experienced withdrawal symptoms following the initiation of|
03244|027|D|rifampin for tuberculosis therapy.(2-3)  In one of these patients, the|
03244|028|D|methadone clearance was measured at 8.97 ml/min/kg during concurrent|
03244|029|D|administration of rifampin, compared with 2.11 ml/min/kg during methadone|
03244|030|D|alone.(2)|
03244|031|D|   Other reports have documented that methadone-treated patients who|
03244|032|D|received concurrent antituberculosis therapy which included rifampin|
03244|033|D|experienced withdrawal symptoms while methadone-treated patients who|
03244|034|D|received antituberculosis therapy which did not include rifampin did|
03244|035|D|not.(4-7)  Subsequently, it was determined that methadone plasma|
03244|036|D|concentrations were decreased 33% to 68% in patients receiving concurrent|
03244|037|D|rifampin compared with patients on non-rifampin regimens.(4,6-7)|
03244|038|D|   In a study in five patients maintained on methadone, the addition of|
03244|039|D|phenytoin to their regimens resulted in moderately severe withdrawal|
03244|040|D|symptoms and a decrease in the AUC for methadone. Methadone plasma|
03244|041|D|concentrations returned to baseline levels two to three days after the|
03244|042|D|discontinuation of phenytoin.(8)|
03244|043|D|   In a study in four patients in a methadone maintenance program, the|
03244|044|D|addition of St. John's wort (900 mg daily) decreased methadone levels by 47%|
03244|045|D|(range: 19%-60%).  Two patients reported withdrawal symptoms.(9)|
03244|046|D|   Selected CYP3A4 inducers linked to this monograph include: amprenavir,|
03244|047|D|apalutamide, carbamazepine, dexamethasone, enzalutamide, fosamprenavir,|
03244|048|D|lumacaftor, mitotane, rifabutin, rifampin, rifapentine, sotorasib, and St.|
03244|049|D|John's Wort.|
03244|050|B||
03244|051|R|REFERENCES:|
03244|052|B||
03244|053|R|1.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03244|054|R|  Pharma AS November 30, 2018.|1
03244|055|R|2.Raistrick D, Hay A, Wolff K. Methadone maintenance and tuberculosis|3
03244|056|R|  treatment. BMJ 1996 Oct 12;313(7062):925-6.|3
03244|057|R|3.Holmes VF. Rifampin-induced methadone withdrawal in AIDS. J Clin|3
03244|058|R|  Psychopharmacol 1990 Dec;10(6):443-4.|3
03244|059|R|4.Kreek MJ, Garfield JW, Gutjahr CL, Giusti LM. Rifampin-induced methadone|2
03244|060|R|  withdrawal. N Engl J Med 1976 May 13;294(20):1104-6.|2
03244|061|R|5.Bending MR, Skacel PO. Rifampicin and methadone withdrawal. Lancet 1977|3
03244|062|R|  Jun 4;1(8023):1211.|3
03244|063|R|6.Garfield JW, Kreek MJ, Giusti L. Rifampin-methadone relationship. 1. The|4
03244|064|R|  clinical effects of rifampin-methadone interaction. Am Rev Respir Dis|4
03244|065|R|  1975;3:926.|4
03244|066|R|7.Kreek MJ, Garfield JW, Gutjahr CL, Bowen D, Field F, Rothschild M.|4
03244|067|R|  Rifampin-methadone relationship. 2. Rifampin effects on plasma|4
03244|068|R|  concentration, metabolism, and excretion of methadone. Am Rev Respir Dis|4
03244|069|R|  1975;3:926-927.|4
03244|070|R|8.Tong TG, Pond SM, Kreek MJ, Jaffery NF, Benowitz NL. Phenytoin-induced|2
03244|071|R|  methadone withdrawal. Ann Intern Med 1981 Mar;94(3):349-51.|2
03244|072|R|9.Eich-Hochli D, Oppliger R, Golay KP, Baumann P, Eap CB. Methadone|2
03244|073|R|  maintenance treatment and St. John's Wort - a case report.|2
03244|074|R|  Pharmacopsychiatry 2003 Jan;36(1):35-7.|2
03245|001|T|MONOGRAPH TITLE:  Avatrombopag/Dual Inhibitors of CYP2C9 & CYP3A4|
03245|002|B||
03245|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03245|004|L|of severe adverse interaction.|
03245|005|B||
03245|006|A|MECHANISM OF ACTION:  Agents that are both moderate or strong inhibitors of|
03245|007|A|CYP2C9 and CYP3A4 may inhibit the metabolism of avatrombopag.(1-2)|
03245|008|B||
03245|009|E|CLINICAL EFFECTS:  Concurrent use of a dual inhibitor of CYP2C9 and CYP3A4|
03245|010|E|may result in elevated levels of and clinical effects of avatrombopag,|
03245|011|E|including thrombotic or thromboembolic complications.(1-2)|
03245|012|B||
03245|013|P|PREDISPOSING FACTORS:  None determined.|
03245|014|B||
03245|015|M|PATIENT MANAGEMENT:  The manufacturer of avatrombopag recommends dose|
03245|016|M|adjustment of avatrombopag when used with drugs that are dual inhibitors of|
03245|017|M|CYP2C9 and CYP3A4 in patients with persistent or chronic immune|
03245|018|M|thrombocytopenia (ITP).  When starting avatrombopag in a patient 6 years and|
03245|019|M|older with persistent or chronic ITP already taking a dual CYP2C9 and CYP3A4|
03245|020|M|inhibitor, reduce the dose of avatrombopag to 20 mg three times weekly.  In|
03245|021|M|pediatric patients 1 year to less than 6 years old who are on a dual CYP2C9|
03245|022|M|and CYP3A4 inhibitor, reduce the starting dose of avatrombopag to 10 mg|
03245|023|M|three times weekly.(1)|
03245|024|M|   When starting a dual CYP2C9 and CYP3A4 inhibitor in a chronic ITP patient|
03245|025|M|already taking avatrombopag, monitor platelet counts and adjust the dose of|
03245|026|M|avatrombopag as needed, according to the prescribing information for|
03245|027|M|avatrombopag.(1)|
03245|028|M|   No dose adjustments are required for patients with chronic liver|
03245|029|M|disease.(1)|
03245|030|B||
03245|031|D|DISCUSSION:  A study of 16 healthy subjects found that coadministration of|
03245|032|D|fluconazole (a moderate inhibitor of CYP2C9 and CYP3A4) with avatrombopag|
03245|033|D|resulted in increased area-under-curve (AUC) and maximum concentration|
03245|034|D|(Cmax) of avatrombopag of 2.16-fold and 1.17-fold, respectively, compared to|
03245|035|D|avatrombopag administered alone.(1,2)  The maximum increase in platelet|
03245|036|D|count (Emax) with fluconazole and avatrombopag coadministration was|
03245|037|D|increased by 1.66-fold, and the area-under-effect-curve (AUEC) for platelet|
03245|038|D|count was increased by 1.47-fold.(2)|
03245|039|B||
03245|040|R|REFERENCES:|
03245|041|B||
03245|042|R|1.Doptelet (avatrombopag) US prescribing information. Dova Pharmaceuticals|1
03245|043|R|  July, 2025.|1
03245|044|R|2.Nomoto M, Zamora CA, Schuck E, Boyd P, Chang MK, Aluri J, Siu YA, Lai WG,|2
03245|045|R|  Yasuda S, Ferry J, Rege B. Pharmacokinetic/pharmacodynamic drug-drug|2
03245|046|R|  interactions of avatrombopag when coadministered with dual or selective|2
03245|047|R|  CYP2C9 and CYP3A interacting drugs. Br J Clin Pharmacol 2018 May;|2
03245|048|R|  84(5):952-960.|2
03246|001|T|MONOGRAPH TITLE:  Avatrombopag/Dual Inducers of CYP2C9 and CYP3A4|
03246|002|B||
03246|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03246|004|L|of severe adverse interaction.|
03246|005|B||
03246|006|A|MECHANISM OF ACTION:  Agents that are both moderate or strong inducers of|
03246|007|A|CYP2C9 and CYP3A4 may increase the metabolism of avatrombopag.(1-2)|
03246|008|B||
03246|009|E|CLINICAL EFFECTS:  Concurrent use of a dual inducer of CYP2C9 and CYP3A4 may|
03246|010|E|result in decreased levels of and clinical effects of avatrombopag.(1-2)|
03246|011|B||
03246|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03246|013|P|of the inducer for longer than 1-2 weeks.|
03246|014|B||
03246|015|M|PATIENT MANAGEMENT:  The manufacturer of avatrombopag recommends dose|
03246|016|M|adjustment of avatrombopag when used with drugs that are dual inducers of|
03246|017|M|CYP2C9 and CYP3A4 in patients with persistent or chronic immune|
03246|018|M|thrombocytopenia (ITP).  When starting avatrombopag in a patient 6 years and|
03246|019|M|older with persistent or chronic ITP already taking a dual CYP2C9 and CYP3A4|
03246|020|M|inducer, increase the dose of avatrombopag to 40 mg once daily.  In|
03246|021|M|pediatric patients 1 year to less than 6 years old who are on a dual CYP2C9|
03246|022|M|and CYP3A4 inducer, increase the starting dose of avatrombopag to 20 mg|
03246|023|M|daily.(1)|
03246|024|M|   When starting a dual CYP2C9 and CYP3A4 inducer in a chronic ITP patient|
03246|025|M|already taking avatrombopag, monitor platelet counts and adjust the dose of|
03246|026|M|avatrombopag as needed, according to the prescribing information for|
03246|027|M|avatrombopag.(1)|
03246|028|M|   No dose adjustments are required for patients with chronic liver|
03246|029|M|disease.(1)|
03246|030|B||
03246|031|D|DISCUSSION:  A study of 16 healthy subjects found that coadministration of|
03246|032|D|rifampin (a moderate CYP2C9 and strong CYP3A4 inducer) and avatrombopag led|
03246|033|D|to a 43 % decrease in the area-under-curve (AUC) of avatrombopag compared to|
03246|034|D|avatrombopag administered alone and an approximately 5-fold reduction in the|
03246|035|D|area-under-effect-curve (AUEC).  There was no difference in the maximum|
03246|036|D|concentration (Cmax) of avatrombopag or the maximum platelet count (Emax)|
03246|037|D|with or without rifampin.(1-2)|
03246|038|D|   Drugs that are both moderate CYP2C9 inducers and strong CYP3A4 inducers|
03246|039|D|linked to this monograph include: carbamazepine, enzalutamide, mavacamten,|
03246|040|D|and rifampin.(1,3-4)|
03246|041|B||
03246|042|R|REFERENCES:|
03246|043|B||
03246|044|R|1.Doptelet (avatrombopag) US prescribing information. Dova Pharmaceuticals|1
03246|045|R|  July, 2025.|1
03246|046|R|2.Nomoto M, Zamora CA, Schuck E, Boyd P, Chang MK, Aluri J, Siu YA, Lai WG,|2
03246|047|R|  Yasuda S, Ferry J, Rege B. Pharmacokinetic/pharmacodynamic drug-drug|2
03246|048|R|  interactions of avatrombopag when coadministered with dual or selective|2
03246|049|R|  CYP2C9 and CYP3A interacting drugs. Br J Clin Pharmacol 2018 May;|2
03246|050|R|  84(5):952-960.|2
03246|051|R|3.This information is based on an extract from the Certara Drug Interaction|6
03246|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03246|053|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03246|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03246|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03246|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03246|057|R|  11/14/2017.|1
03247|001|T|MONOGRAPH TITLE:  Lidocaine/Saquinavir|
03247|002|B||
03247|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03247|004|L|is contraindicated and generally should not be dispensed or administered to|
03247|005|L|the same patient.|
03247|006|B||
03247|007|A|MECHANISM OF ACTION:  Saquinavir may inhibit the metabolism of lidocaine via|
03247|008|A|CYP3A4.  Concurrent use of saquinavir and lidocaine may increase the risk of|
03247|009|A|lidocaine toxicity.(1,2)|
03247|010|B||
03247|011|E|CLINICAL EFFECTS:  Concurrent use of saquinavir with antiarrhythmic doses of|
03247|012|E|lidocaine may result in elevated levels and toxicity from lidocaine.(1,2)|
03247|013|B||
03247|014|P|PREDISPOSING FACTORS:  Lidocaine clearance is significantly impaired in|
03247|015|P|patients with moderate or severe hepatic impairment.|
03247|016|B||
03247|017|M|PATIENT MANAGEMENT:  The US manufacturer of saquinavir mesylate states that|
03247|018|M|concurrent use with lidocaine is contraindicated in patients receiving|
03247|019|M|saquinavir.(1)|
03247|020|B||
03247|021|D|DISCUSSION:  The US manufacturer of saquinavir mesylate states that|
03247|022|D|concurrent use with lidocaine is contraindicated in patients receiving|
03247|023|D|saquinavir.(1)|
03247|024|D|   Saquinavir has been shown to be a strong inhibitor of CYP3A4,(3) one of|
03247|025|D|the metabolic pathways for lidocaine elimination.(4)|
03247|026|B||
03247|027|R|REFERENCES:|
03247|028|B||
03247|029|R|1.Invirase (saquinavir mesylate) US prescribing information. Roche|1
03247|030|R|  Laboratories, Inc. March, 2019.|1
03247|031|R|2.Fortovase (saquinavir) US prescribing information. Roche Laboratories,|1
03247|032|R|  Inc. December, 2004.|1
03247|033|R|3.This information is based on an extract from the Certara Drug Interaction|6
03247|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03247|035|R|4.Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P.|2
03247|036|R|  Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in|2
03247|037|R|  vivo: effects of liver function. Clin Pharmacol Ther 2004 Jan;75(1):80-8.|2
03248|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 10|
03248|002|T|mg)/Ombitasvir-Paritaprevir-Ritonavir|
03248|003|B||
03248|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03248|005|L|is contraindicated and generally should not be dispensed or administered to|
03248|006|L|the same patient.|
03248|007|B||
03248|008|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate for a number of|
03248|009|A|transporters including breast cancer resistance protein (BCRP), OATP1B1, and|
03248|010|A|OATP1B3.(1,2)|
03248|011|A|   Paritaprevir is an inhibitor of OATP1B1 and OATP1B3, while paritaprevir|
03248|012|A|and ritonavir are inhibitors of BCRP.(1)|
03248|013|A|   Depending upon the specific transporter and site of activity, transport|
03248|014|A|inhibition may lead to increased systemic absorption, decreased hepatic|
03248|015|A|concentrations, or decreased hepatic elimination.|
03248|016|B||
03248|017|E|CLINICAL EFFECTS:  Transport inhibition may lead to higher systemic|
03248|018|E|concentrations of rosuvastatin, increasing the risk for statin-induced|
03248|019|E|myopathy or rhabdomyolysis.|
03248|020|B||
03248|021|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03248|022|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03248|023|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03248|024|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03248|025|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03248|026|P|transporter OATP1B1 may have increased statin concentrations and be|
03248|027|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
03248|028|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
03248|029|P|may have increased rosuvastatin concentrations and risk of myopathy.|
03248|030|B||
03248|031|M|PATIENT MANAGEMENT:  The UK manufacturer of|
03248|032|M|ombitasvir-paritaprevir-ritonavir (Viekirax) states that the dose of|
03248|033|M|rosuvastatin should not exceed 10 mg per day in patients receiving|
03248|034|M|concurrent therapy.(1)|
03248|035|B||
03248|036|D|DISCUSSION:  In a drug interaction study, paritaprevir-ritonavir-ombitasvir|
03248|037|D|co-administered with rosuvastatin 5 mg daily (duration not described)|
03248|038|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
03248|039|D|rosuvastatin by 2.61-fold and 1.33-fold respectively.(1)|
03248|040|B||
03248|041|R|REFERENCES:|
03248|042|B||
03248|043|R|1.Viekirax (ombitasvir, paritaprevir, ritonavir) UK summary of product|1
03248|044|R|  characteristics. AbbVie Limited January 16, 2019.|1
03248|045|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03248|046|R|  Pharmaceuticals LP July, 2024.|1
03249|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 10|
03249|002|T|mg)/Ombitasvir-Paritaprevir-Ritonavir|
03249|003|B||
03249|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03249|005|L|take action as needed.|
03249|006|B||
03249|007|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate for a number of|
03249|008|A|transporters including breast cancer resistance protein (BCRP), OATP1B1, and|
03249|009|A|OATP1B3.(1,2)|
03249|010|A|   Paritaprevir is an inhibitor of OATP1B1 and OATP1B3, while paritaprevir|
03249|011|A|and ritonavir are inhibitors of BCRP.(1)|
03249|012|A|   Depending upon the specific transporter and site of activity, transport|
03249|013|A|inhibition may lead to increased systemic absorption, decreased hepatic|
03249|014|A|concentrations, or decreased hepatic elimination.|
03249|015|B||
03249|016|E|CLINICAL EFFECTS:  Transport inhibition may lead to higher systemic|
03249|017|E|concentrations of rosuvastatin, increasing the risk for statin-induced|
03249|018|E|myopathy or rhabdomyolysis.|
03249|019|B||
03249|020|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03249|021|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03249|022|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03249|023|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03249|024|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03249|025|P|transporter OATP1B1 may have increased statin concentrations and be|
03249|026|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
03249|027|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
03249|028|P|may have increased rosuvastatin concentrations and risk of myopathy.|
03249|029|B||
03249|030|M|PATIENT MANAGEMENT:  The UK manufacturer of|
03249|031|M|ombitasvir-paritaprevir-ritonavir (Viekirax) states that the dose of|
03249|032|M|rosuvastatin should not exceed 10 mg per day in patients receiving|
03249|033|M|concurrent therapy.(1)|
03249|034|B||
03249|035|D|DISCUSSION:  In a drug interaction study, paritaprevir-ritonavir-ombitasvir|
03249|036|D|co-administered with rosuvastatin 5 mg daily (duration not described)|
03249|037|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
03249|038|D|rosuvastatin by 2.61-fold and 1.33-fold respectively.(1)|
03249|039|B||
03249|040|R|REFERENCES:|
03249|041|B||
03249|042|R|1.Viekirax (ombitasvir, paritaprevir, ritonavir) UK summary of product|1
03249|043|R|  characteristics. AbbVie Limited January 16, 2019.|1
03249|044|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03249|045|R|  Pharmaceuticals LP July, 2024.|1
03250|001|T|MONOGRAPH TITLE:  Cyclosporine/Ombitasvir-paritaprevir-ritonavir|
03250|002|B||
03250|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03250|004|L|of severe adverse interaction.|
03250|005|B||
03250|006|A|MECHANISM OF ACTION:  Ritonavir is an inhibitor of CYP3A4 and may inhibit|
03250|007|A|the metabolism of cyclosporine by CYP3A4.(1-3)|
03250|008|B||
03250|009|E|CLINICAL EFFECTS:  Concurrent use of ombitasvir-paritaprevir-ritonavir with|
03250|010|E|or without dasabuvir may result in increased levels of cyclosporine.(1-3)|
03250|011|B||
03250|012|P|PREDISPOSING FACTORS:  None determined.|
03250|013|B||
03250|014|M|PATIENT MANAGEMENT:  For patients concurrently taking cyclosporine and|
03250|015|M|either a HIV or HCV protease inhibitor, therapeutic concentration monitoring|
03250|016|M|of the cyclosporine is recommended.(1-3)|
03250|017|M|   Guidelines from the American Society of Transplantation recommend|
03250|018|M|avoiding the use of ritonavir-based antiviral regimens with cyclosporine due|
03250|019|M|to an increased risk of graft loss and death.  If the combination must be|
03250|020|M|used, lower the dose of cyclosporine to 25-50 mg daily.  Monitor drug|
03250|021|M|concentrations closely.(1)|
03250|022|M|   The US and European manufacturer of ombitasvir-paritaprevir-ritonavir,|
03250|023|M|with or without dasabuvir, states cyclosporine therapy should be reduced to|
03250|024|M|one-fifth of the previous daily dose when ombitasvir-paritaprevir-ritonavir|
03250|025|M|is started.  Monitor cyclosporine levels and further adjust the dosage as|
03250|026|M|needed.(2-3)  Frequent assessment of renal function and cyclosporine-related|
03250|027|M|toxicity is recommended.(2)|
03250|028|B||
03250|029|D|DISCUSSION:  In an interaction study of healthy volunteers,|
03250|030|D|ombitasvir-paritaprevir-ritonavir increased the AUC of cyclosporine 10 mg by|
03250|031|D|4.28-fold.(3)  The combination of|
03250|032|D|ombitasvir-paritaprevir-ritonavir-dasabuvir increased the AUC of|
03250|033|D|cyclosporine 30 mg by 5.82-fold.(2-3)|
03250|034|D|   A case series described two liver transplant recipients who were stable|
03250|035|D|on cyclosporine and were successfully treated for HCV reinfection with|
03250|036|D|ombitasvir-paritaprevir-ritonavir.  The first patient was on cyclosporine|
03250|037|D|100 mg/day and required a reduction in her cyclosporine dose to 10 mg/day.|
03250|038|D|The second patient was on cyclosporine 60 mg/day and required a cyclosporine|
03250|039|D|dose reduction to 10 mg/day.  Neither patient had signs of liver injury|
03250|040|D|suggestive of rejection.(4)|
03250|041|B||
03250|042|R|REFERENCES:|
03250|043|B||
03250|044|R|1.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
03250|045|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
03250|046|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
03250|047|R|  e13510.|6
03250|048|R|2.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
03250|049|R|  prescribing information. AbbVie Inc. December, 2019.|1
03250|050|R|3.Viekirax (ombitasvir, paritaprevir, ritonavir) UK summary of product|1
03250|051|R|  characteristics. AbbVie Limited January 16, 2019.|1
03250|052|R|4.Orita N, Shimakami T, Sunagozaka H, Horii R, Nio K, Terashima T, Iida N,|3
03250|053|R|  Kitahara M, Takatori H, Kawaguchi K, Kitamura K, Arai K, Yamashita T,|3
03250|054|R|  Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S. Three renal failure|3
03250|055|R|  cases successfully treated with ombitasvir/paritaprevir/ritonavir for|3
03250|056|R|  genotype 1b hepatitis C virus reinfection after liver transplantation.|3
03250|057|R|  Clin J Gastroenterol 2019 Feb;12(1):63-70.|3
03251|001|T|MONOGRAPH TITLE:  Carbidopa-Levodopa-Entacapone/Selected MAOIs|
03251|002|B||
03251|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03251|004|L|is contraindicated and generally should not be dispensed or administered to|
03251|005|L|the same patient.|
03251|006|B||
03251|007|A|MECHANISM OF ACTION:  Since monoamine oxidase (MAO) and|
03251|008|A|catechol-O-methyltransferase (COMT) are the two major enzymes responsible|
03251|009|A|for the metabolism of catecholamines, the combination of|
03251|010|A|carbidopa-levodopa-entacapone and a non-selective MAOI may inhibit the|
03251|011|A|majority of catecholamine metabolic pathways.(1-5)|
03251|012|B||
03251|013|E|CLINICAL EFFECTS:  Concurrent administration of|
03251|014|E|carbidopa-levodopa-entacapone with a non-selective MAOI may result in|
03251|015|E|elevated levels of catecholamines, which may result in elevated heart rate|
03251|016|E|and blood pressure.(1)|
03251|017|B||
03251|018|P|PREDISPOSING FACTORS:  None determined.|
03251|019|B||
03251|020|M|PATIENT MANAGEMENT:  The US manufacturer of carbidopa-levodopa-entacapone|
03251|021|M|states that concomitant use with a non-selective MAOI is contraindicated.|
03251|022|M|Nonselective MAOIs should be discontinued at least 2 weeks prior to|
03251|023|M|initiating therapy with carbidopa-levodopa-entacapone.(1)|
03251|024|M|   The US manufacturer of carbidopa-levodopa states that the concurrent use|
03251|025|M|of nonselective MAO inhibitors is contraindicated.  Carbidopa-levodopa may|
03251|026|M|be administered with recommended dosages of selective MAO-B inhibitors.(2)|
03251|027|M|   The addition of a decarboxylase inhibitor to the combination of a|
03251|028|M|non-selective MAO inhibitor and levodopa may minimize risk of adverse|
03251|029|M|effects.  Phentolamine has been effective in treating hypertension caused by|
03251|030|M|this interaction.|
03251|031|M|   The Canadian(5) and UK(3) manufacturers of entacapone state that|
03251|032|M|concomitant use of entacapone with either a non-selective MAOI or a|
03251|033|M|selective MAO-A inhibitor and a MAO-B inhibitor is contraindicated.|
03251|034|M|Nonselective MAOI should be discontinued at least 2 weeks prior to|
03251|035|M|initiating entacapone therapy.(6)|
03251|036|B||
03251|037|D|DISCUSSION:  Hypertensive reactions, flushing, and palpitations have been|
03251|038|D|reported as a result of this interaction.  This interaction may be possible|
03251|039|D|for several weeks after the discontinuation of a MAO inhibitor.|
03251|040|D|   Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the|
03251|041|D|two major enzymes systems involved in the metabolism of catecholamines.|
03251|042|D|Therefore, theoretically, the combination of either entacapone, tolcapone,|
03251|043|D|or opicapone with a non-selective MAO inhibitor will result in inhibition of|
03251|044|D|the majority of catecholamine metabolism pathways.(1-5)|
03251|045|D|   At daily oral doses of 10 mg, selegiline is primarily a selective MAO-B|
03251|046|D|inhibitor; however, at higher doses, selegiline is capable of inhibiting|
03251|047|D|MAO-A.(6)  At dosages administered transdermally for the treatment of|
03251|048|D|depression, selegiline is not selective for MAO-B.(7)|
03251|049|D|   Methylene blue, when administered intravenously, has been shown to reach|
03251|050|D|sufficient concentrations to be a potent inhibitor of MAO-A.(8,9)|
03251|051|D|   Furazolidone has been shown to inhibit MAO.|
03251|052|D|   Metaxalone is a weak inhibitor of MAO.(10,11)|
03251|053|B||
03251|054|R|REFERENCES:|
03251|055|B||
03251|056|R|1.Stalveo (carbidopa; entacapone; levodopa) US Prescribing Information.|1
03251|057|R|  Orion/Novartis December, 2019.|1
03251|058|R|2.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
03251|059|R|  February, 2011.|1
03251|060|R|3.Comtess (entacapone) UK summary of product characteristics. Orion Pharma,|1
03251|061|R|  UK September 16, 1998.|1
03251|062|R|4.Comtan (entacapone) US prescribing information. Orion Corporation|1
03251|063|R|  February, 2016.|1
03251|064|R|5.Comtan (entacapone) Canadian prescribing information. Novartis|1
03251|065|R|  Pharmaceuticals Canada Inc. March, 2006.|1
03251|066|R|6.Eldepryl (selegiline) US prescribing information. Somerset Pharmaceuticals|1
03251|067|R|  February, 1997.|1
03251|068|R|7.Emsam (selegiline) US prescribing information. Somerset August, 2007.|1
03251|069|R|8.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
03251|070|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
03251|071|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
03251|072|R|9.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
03251|073|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
03251|074|R|  2000 Jun;56(3):247-50.|2
03251|075|R|10.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03251|076|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03251|077|R|   Feb;34(2):346.e5-6.|3
03251|078|R|11.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03251|079|R|   Pfizer Inc. January, 2024.|1
03252|001|T|MONOGRAPH TITLE:  Carbidopa-Levodopa-Entacapone/Rasagiline; Oral Selegiline|
03252|002|B||
03252|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03252|004|L|take action as needed.|
03252|005|B||
03252|006|A|MECHANISM OF ACTION:  Since MAOI's and COMT are the two major enzymes|
03252|007|A|responsible for the metabolism of catecholamines, the combination of|
03252|008|A|carbidopa-levodopa-entacapone and a non-selective MAOI may inhibit the|
03252|009|A|majority of catecholamine metabolism pathways.(1-5)|
03252|010|B||
03252|011|E|CLINICAL EFFECTS:  Concurrent administration of|
03252|012|E|carbidopa-levodopa-entacapone with a non-selective MAOI may result in|
03252|013|E|elevated levels of catecholamines, which may result in elevated heart rate|
03252|014|E|and blood pressure.(1)|
03252|015|B||
03252|016|P|PREDISPOSING FACTORS:  None determined.|
03252|017|B||
03252|018|M|PATIENT MANAGEMENT:  The US manufacturer of carbidopa-levodopa-entacapone|
03252|019|M|states that concomitant use with a non-selective MAOI is contraindicated.|
03252|020|M|Nonselective MAOI should be discontinued at least 2 weeks prior to|
03252|021|M|initiating therapy with carbidopa-levodopa-entacapone.  Concomitant use with|
03252|022|M|MAO-B inhibitors or other standard medications for Parkinson's disease may|
03252|023|M|be used with carbidopa-levodopa-entacapone; dose adjustments of one or both|
03252|024|M|drugs may be required.(1)|
03252|025|M|   The US manufacturer of carbidopa-levodopa states that the concurrent use|
03252|026|M|of nonselective MAO inhibitors is contraindicated.  Carbidopa-levodopa may|
03252|027|M|be administered with recommended dosages of selective MAO-B inhibitors.(2)|
03252|028|M|   The addition of a decarboxylase inhibitor to the combination of a|
03252|029|M|non-selective MAO inhibitor and levodopa may minimize risk of adverse|
03252|030|M|effects.  Phentolamine has been effective in treating hypertension caused by|
03252|031|M|this interaction.|
03252|032|M|   The Canadian(5) and UK(3) manufacturers of entacapone state that|
03252|033|M|concomitant use of either a non-selective MAOI or a selective MAO-A|
03252|034|M|inhibitor with a selective MAO-B inhibitor with entacapone is|
03252|035|M|contraindicated.  Nonselective MAOI should be discontinued at least 2 weeks|
03252|036|M|prior to initiating entacapone therapy.(6)|
03252|037|M|   Therefore, carbidopa-levodopa-entacapone may be used with oral|
03252|038|M|selegiline, provided that the daily dose of selegiline does not exceed 10|
03252|039|M|mg, and with rasagiline, provided that the daily dose of rasagiline does not|
03252|040|M|exceed 1 mg, and that patients are not also receiving a selective MAO-A|
03252|041|M|inhibitor.|
03252|042|B||
03252|043|D|DISCUSSION:  Hypertensive reactions, flushing, and palpitations have been|
03252|044|D|reported as a result of this interaction.  This interaction may be possible|
03252|045|D|for several weeks after the discontinuation of a MAO inhibitor.|
03252|046|D|   Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the|
03252|047|D|two major enzymes systems involved in the metabolism of catecholamines.|
03252|048|D|Therefore, theoretically, the combination of either entacapone, tolcapone,|
03252|049|D|or opicapone with a non-selective MAO inhibitor will result in inhibition of|
03252|050|D|the majority of catecholamine metabolism pathways.(1-5)|
03252|051|D|   At daily oral doses of 10 mg, selegiline is primarily a selective MAO-B|
03252|052|D|inhibitor; however, at higher doses, selegiline is capable of inhibiting|
03252|053|D|MAO-A.(8)  At dosages administered transdermally for the treatment of|
03252|054|D|depression, selegiline is not selective for MAO-B.(9)|
03252|055|B||
03252|056|R|REFERENCES:|
03252|057|B||
03252|058|R|1.Stalveo (carbidopa; entacapone; levodopa) US Prescribing Information.|1
03252|059|R|  Orion/Novartis December, 2019.|1
03252|060|R|2.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
03252|061|R|  February, 2011.|1
03252|062|R|3.Comtess (entacapone) UK summary of product characteristics. Orion Pharma,|1
03252|063|R|  UK September 16, 1998.|1
03252|064|R|4.Comtan (entacapone) US prescribing information. Orion Corporation|1
03252|065|R|  February, 2016.|1
03252|066|R|5.Comtan (entacapone) Canadian prescribing information. Novartis|1
03252|067|R|  Pharmaceuticals Canada Inc. March, 2006.|1
03252|068|R|6.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
03252|069|R|  June, 2020.|1
03252|070|R|7.A randomized placebo-controlled trial of rasagiline in levodopa-treated|2
03252|071|R|  patients with Parkinson disease and motor fluctuations: the PRESTO study.|2
03252|072|R|  Arch Neurol 2005 Feb;62(2):241-8.|2
03252|073|R|8.Eldepryl (selegiline) US prescribing information. Somerset Pharmaceuticals|1
03252|074|R|  February, 1997.|1
03252|075|R|9.Emsam (selegiline) US prescribing information. Somerset August, 2007.|1
03253|001|T|MONOGRAPH TITLE:  Levodopa/Rasagiline; Oral Selegiline (mono deleted|
03253|002|T|10/10/2019)|
03253|003|B||
03253|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03253|005|L|take action as needed.|
03253|006|B||
03253|007|A|MECHANISM OF ACTION:  MAOIs inhibit the enzyme responsible for degradation|
03253|008|A|of dopamine and norepinephrine which are formed by levodopa. Also, storage|
03253|009|A|and release of dopamine and norepinephrine is increased.|
03253|010|B||
03253|011|E|CLINICAL EFFECTS:  Concurrent use of MAOIs may result in increased effects|
03253|012|E|of levodopa, including tremor, hypertensive crisis, and postural|
03253|013|E|hypotension.|
03253|014|B||
03253|015|P|PREDISPOSING FACTORS:  None determined.|
03253|016|B||
03253|017|M|PATIENT MANAGEMENT:  The US manufacturer of carbidopa/levodopa states that|
03253|018|M|the concurrent use of nonselective MAO inhibitors is contraindicated.|
03253|019|M|Carbidopa/Levodopa may be administered with recommended dosages of selective|
03253|020|M|MAO-B inhibitors, including rasagiline and oral selegiline.|
03253|021|M|   Therefore, levodopa may be used with oral selegiline, provided that the|
03253|022|M|daily dose of selegiline does not exceed 10 mg, and with rasagiline,|
03253|023|M|provided that the daily dose of rasagiline does not exceed 1 mg, and that|
03253|024|M|patients are not also receiving a selective MAO-A inhibitor.|
03253|025|B||
03253|026|D|DISCUSSION:  Hypertensive reactions, flushing, and palpations have been|
03253|027|D|reported as a result of this interaction.  This interaction may be possible|
03253|028|D|for several weeks after the discontinuation of a MAO inhibitor.|
03253|029|D|   At the recommended dosage of 10 mg/day, oral selegiline is presumed to be|
03253|030|D|a selective MAO B inhibitor and would thus not be expected to interact with|
03253|031|D|levodopa.  Oral selegiline is indicated as an adjunct agent with levodopa in|
03253|032|D|the management of Parkinsonian patients.  However, selegiline administered|
03253|033|D|transdermally for the treatment of depression is not selective for MAO-B.|
03253|034|D|   Rasagiline is selective for MAO-B in humans at recommended dosages of 1|
03253|035|D|mg per day or less.|
03253|036|D|   At daily doses of 10 mg, selegiline is primarily a selective MAO-B|
03253|037|D|inhibitor; however, at higher doses, selegiline is capable of inhibiting|
03253|038|D|MAO-A.|
03253|039|B||
03253|040|R|REFERENCES:|
03253|041|B||
03253|042|R|1.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
03253|043|R|  June, 2020.|1
03253|044|R|2.A randomized placebo-controlled trial of rasagiline in levodopa-treated|2
03253|045|R|  patients with Parkinson disease and motor fluctuations: the PRESTO study.|2
03253|046|R|  Arch Neurol 2005 Feb;62(2):241-8.|2
03253|047|R|3.Eldepryl (selegiline) US prescribing information. Somerset Pharmaceuticals|1
03253|048|R|  February, 1997.|1
03253|049|R|4.Horwitz D, Goldberg LI, Sjoerdsma A. Increased blood pressure responses to|2
03253|050|R|  dopamine and norephinephrine produced by monoamine oxidase inhibitors in|2
03253|051|R|  man. J Lab Clin Med 1960 Nov;56(3):747-53.|2
03253|052|R|5.Schildkraut JJ, Klerman GL, Friend DG, Greenblatt M. Biochemical and|2
03253|053|R|  pressor effects of oral D,L-dihydroxyphenyalanine in patients pretreated|2
03253|054|R|  with antidepressant drugs. 1963;107:1005-15.|2
03253|055|R|6.Friend DG, Bell WR, Kline NS. The action of L-dihydroxyphenylalanine in|2
03253|056|R|  patients receiving nialamide. Clin Pharmacol Ther 1965;6(3):362-6.|2
03253|057|R|7.Hunter KR, Boakes AJ, Laurence DR, Stern GM. Monoamine oxidase inhibitors|3
03253|058|R|  and L-dopa. Br Med J 1970 Aug 15;3(719):388.|3
03253|059|R|8.Teychenne PF, Calne DB, Lewis PJ, Findley LJ. Interactions of levodopa|2
03253|060|R|  with inhibitors of monoamine oxidase and L- aromatic amino acid|2
03253|061|R|  decarboxylase. Clin Pharmacol Ther 1975 Sep;18(3):273-7.|2
03253|062|R|9.Birkmayer W, Riederer P, Ambrozi L, Youdim MB. Implications of combined|2
03253|063|R|  treatment with 'Madopar' and L-deprenil in Parkinson's disease. A|2
03253|064|R|  long-term study. Lancet 1977 Feb 26;1(8009):439-43.|2
03253|065|R|10.Sharpe J, Marquez-Julio A, Ashby P. Idiopathic orthostatic hypotension|3
03253|066|R|   treated with levodopa and MAO inhibitor: a preliminary report. Can Med|3
03253|067|R|   Assoc J 1972 Aug 19;107(4):296-300.|3
03253|068|R|11.Eldepryl (selegiline) US prescribing information. Somerset|1
03253|069|R|   Pharmaceuticals May, 1996.|1
03253|070|R|12.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
03253|071|R|   February, 2011.|1
03253|072|R|13.Emsam (selegiline) US prescribing information. Somerset August, 2007.|1
03254|001|T|MONOGRAPH TITLE:  Iloperidone/Selected Strong CYP3A4 Inhibitors;Protease|
03254|002|T|Inhib|
03254|003|B||
03254|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03254|005|L|take action as needed.|
03254|006|B||
03254|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors and protease inhibitors may|
03254|008|A|inhibit the metabolism of iloperidone.(1,2)|
03254|009|B||
03254|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor or|
03254|011|E|protease inhibitor may result in elevated levels of and toxicity from|
03254|012|E|iloperidone.(1,2)  Elevated levels of iloperidone may increase the risk of|
03254|013|E|QTc prolongation.(1)|
03254|014|B||
03254|015|P|PREDISPOSING FACTORS:  With iloperidone, the risk of QT prolongation or|
03254|016|P|torsades de pointes may be increased in patients with cardiovascular disease|
03254|017|P|(e.g. heart failure, myocardial infarction, history of torsades de pointes,|
03254|018|P|congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
03254|019|P|bradycardia, female gender, or advanced age.  Concurrent use of more than|
03254|020|P|one drug known to cause QT prolongation or higher systemic concentrations of|
03254|021|P|either QT prolonging drug are additional risk factors for torsades de|
03254|022|P|pointes.  Factors which may increase systemic drug concentrations include|
03254|023|P|rapid infusion of an intravenous dose or impaired metabolism or elimination|
03254|024|P|of the drug (e.g. coadministration with an agent which inhibits its|
03254|025|P|metabolism or elimination, genetic impairment in drug metabolism or|
03254|026|P|elimination, and/or renal/hepatic dysfunction).(1,3)|
03254|027|B||
03254|028|M|PATIENT MANAGEMENT:  The dose of iloperidone should be reduced to one-half|
03254|029|M|of its normal dose when strong CYP3A inhibitors or protease inhibitors are|
03254|030|M|coadministered.(1,2)  If the patient is also receiving a CYP2D6 inhibitor,|
03254|031|M|iloperidone should be reduced to one-half of its normal dose but no|
03254|032|M|additional dose reduction is required with both a CYP2D6 inhibitor and|
03254|033|M|CYP3A4 inhibitor.  When the inhibitor is discontinued, the dose of|
03254|034|M|iloperidone should be increased.(1)|
03254|035|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
03254|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03254|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03254|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03254|039|B||
03254|040|D|DISCUSSION:  Coadministration of ketoconazole (200 mg twice daily for 4|
03254|041|D|days) increased the AUC of iloperidone (3 mg single dose) and its P88 and|
03254|042|D|P95 metabolites by 57%, 55%, and 35%, respectively.(1)|
03254|043|D|   Coadministration of ketoconazole (200 mg twice daily) and iloperidone (12|
03254|044|D|mg twice daily) was associated with a mean QTcF increase of 19 msec from|
03254|045|D|baseline, compared with an increase of 9 msec with iloperidone alone.(1)|
03254|046|D|   Coadministration of ketoconazole and paroxetine (a CYP2D6 inhibitor) did|
03254|047|D|not increase the effects on iloperidone compared with either agent alone.(1)|
03254|048|D|   CYP3A4 inhibitors linked to this monograph include: atazanavir,|
03254|049|D|boceprevir, cobicistat, darunavir, fosamprenavir, idelalisib, indinavir,|
03254|050|D|itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil,|
03254|051|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
03254|052|D|telaprevir, tipranavir, and tucatinib.(2,4)|
03254|053|B||
03254|054|R|REFERENCES:|
03254|055|B||
03254|056|R|1.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
03254|057|R|  Inc May, 2016.|1
03254|058|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03254|059|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03254|060|R|  HIV. Department of Health and Human Services. Available at:|6
03254|061|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
03254|062|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
03254|063|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03254|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03254|065|R|  settings: a scientific statement from the American Heart Association and|6
03254|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03254|067|R|  2;55(9):934-47.|6
03254|068|R|4.This information is based on an extract from the Certara Drug Interaction|6
03254|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03255|001|T|MONOGRAPH TITLE:  Iloperidone/Strong CYP3A4 Inhibitors that Prolong QT|
03255|002|B||
03255|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03255|004|L|take action as needed.|
03255|005|B||
03255|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03255|007|A|iloperidone.(1)|
03255|008|B||
03255|009|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03255|010|E|may result in elevated levels of and toxicity from iloperidone.(1)  Elevated|
03255|011|E|levels of iloperidone may increase the risk of QTc prolongation.(1)|
03255|012|B||
03255|013|P|PREDISPOSING FACTORS:  With iloperidone, the risk of QT prolongation or|
03255|014|P|torsades de pointes may be increased in patients with cardiovascular disease|
03255|015|P|(e.g. heart failure, myocardial infarction, history of torsades de pointes,|
03255|016|P|congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
03255|017|P|bradycardia, female gender, or advanced age.  Concurrent use of more than|
03255|018|P|one drug known to cause QT prolongation or higher systemic concentrations of|
03255|019|P|either QT prolonging drug are additional risk factors for torsades de|
03255|020|P|pointes.  Factors which may increase systemic drug concentrations include|
03255|021|P|rapid infusion of an intravenous dose or impaired metabolism or elimination|
03255|022|P|of the drug (e.g. coadministration with an agent which inhibits its|
03255|023|P|metabolism or elimination, genetic impairment in drug metabolism or|
03255|024|P|elimination, and/or renal/hepatic dysfunction).(1,2)|
03255|025|B||
03255|026|M|PATIENT MANAGEMENT:  The US manufacturer of iloperidone states that the dose|
03255|027|M|of iloperidone should be reduced to one-half of its normal dose when strong|
03255|028|M|CYP3A inhibitors are coadministered.  If the patient is also receiving a|
03255|029|M|CYP2D6 inhibitor, iloperidone should be reduced to one-half of its normal|
03255|030|M|dose but no additional dose reduction is required with both a CYP2D6|
03255|031|M|inhibitor and CYP3A4 inhibitor.  When the inhibitor is discontinued, the|
03255|032|M|dose of iloperidone should be increased.(1)|
03255|033|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
03255|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03255|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03255|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03255|037|B||
03255|038|D|DISCUSSION:  Coadministration of ketoconazole (200 mg twice daily for 4|
03255|039|D|days) increased the AUC of iloperidone (3 mg single dose) and its P88 and|
03255|040|D|P95 metabolites by 57%, 55%, and 35%, respectively.(1)|
03255|041|D|   Coadministration of ketoconazole (200 mg twice daily) and iloperidone (12|
03255|042|D|mg twice daily) was associated with a mean QTcF increase of 19 msec from|
03255|043|D|baseline, compared with an increase of 9 msec with iloperidone alone.(1)|
03255|044|D|   Coadministration of ketoconazole and paroxetine (a CYP2D6 inhibitor) did|
03255|045|D|not increase the effects on iloperidone compared with either agent alone.(1)|
03255|046|B||
03255|047|R|REFERENCES:|
03255|048|B||
03255|049|R|1.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
03255|050|R|  Inc May, 2016.|1
03255|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03255|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03255|053|R|  settings: a scientific statement from the American Heart Association and|6
03255|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03255|055|R|  2;55(9):934-47.|6
03256|001|T|MONOGRAPH TITLE:  Fluvastatin (Less Than or Equal To 20 mg); Lovastatin|
03256|002|T|(Less Than or Equal To 20 mg); Simvastatin (Less Than or Equal To 20|
03256|003|T|mg)/Elbasvir-Grazoprevir|
03256|004|B||
03256|005|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03256|006|L|take action as needed.|
03256|007|B||
03256|008|A|MECHANISM OF ACTION:  Elbasvir-grazoprevir may inhibit intestinal BCRP,|
03256|009|A|resulting in increased absorption of simvastatin.  The mechanism of|
03256|010|A|interaction with fluvastatin and lovastatin is not known, but may be related|
03256|011|A|to competitive inhibition of OATP1B1 by elbasvir-grazoprevir.(1-3)|
03256|012|B||
03256|013|E|CLINICAL EFFECTS:  Concurrent use of elbasvir-grazoprevir may result in|
03256|014|E|elevated levels of and toxicity from fluvastatin, lovastatin, and|
03256|015|E|simvastatin, including rhabdomyolysis.(1-3)|
03256|016|B||
03256|017|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03256|018|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03256|019|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03256|020|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03256|021|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03256|022|P|transporter OATP1B1 may have increased statin concentrations and be|
03256|023|P|predisposed to myopathy or rhabdomyolysis.  Patients on fluvastatin who are|
03256|024|P|CYP2C9 intermediate or poor metabolizers may have increased fluvastatin|
03256|025|P|concentrations and  risk of myopathy.|
03256|026|B||
03256|027|M|PATIENT MANAGEMENT:  The Canadian and UK manufacturers of|
03256|028|M|elbasvir-grazoprevir and of simvastatin recommend that, in patients|
03256|029|M|requiring elbasvir-grazoprevir, doses greater than 20 mg daily of|
03256|030|M|fluvastatin, lovastatin, or simvastatin should not be used.(1,2)  The US|
03256|031|M|manufacturer of elbasvir-grazoprevir states that the lowest possible dose of|
03256|032|M|fluvastatin, lovastatin, or simvastatin should be used.(3)|
03256|033|M|   If concurrent use is deemed medically necessary, instruct patients to|
03256|034|M|report symptoms of muscle pain, tenderness, or weakness.|
03256|035|B||
03256|036|D|DISCUSSION:  Elbasvir-grazoprevir is a substrate of OATP1B1 and has been|
03256|037|D|shown to inhibit intestinal BCRP.(1,3)  Fluvastatin and lovastatin are|
03256|038|D|substrates of OATP1B1 and simvastatin is a substrate of BCRP and OATP1B1.(4)|
03256|039|D|Studies with other statins (i.e., atorvastatin, rosuvastatin) have shown|
03256|040|D|that elbasvir-grazoprevir can increase the concentrations of these statins.|
03256|041|D|While interaction studies of elbasvir-grazoprevir with fluvastatin,|
03256|042|D|lovastatin, and simvastatin have not been done, fluvastatin and lovastatin|
03256|043|D|concentrations have been shown to increase with other OATP1B1 inhibitors,|
03256|044|D|and simvastatin levels have been shown to increase with other BCRP|
03256|045|D|inhibitors.(4)|
03256|046|B||
03256|047|R|REFERENCES:|
03256|048|B||
03256|049|R|1.Zepatier (elbasvir-grazoprevir) Canadian product monograph. Merck Canada|1
03256|050|R|  Inc. January 19, 2016.|1
03256|051|R|2.Zocor (simvastatin) Canadian prescribing information. Merck Canada Inc.|1
03256|052|R|  May 24, 2019.|1
03256|053|R|3.Zepatier (elbasvir-grazoprevir) US prescribing information. Merck & Co.,|1
03256|054|R|  Inc. December, 2019.|1
03256|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
03256|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03257|001|T|MONOGRAPH TITLE:  Fluvastatin (Greater Than 20 mg); Lovastatin (Greater Than|
03257|002|T|20 mg); Simvastatin (Greater Than 20 mg)/Elbasvir-Grazoprevir|
03257|003|B||
03257|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03257|005|L|is contraindicated and generally should not be dispensed or administered to|
03257|006|L|the same patient.|
03257|007|B||
03257|008|A|MECHANISM OF ACTION:  Elbasvir-grazoprevir may inhibit intestinal BCRP,|
03257|009|A|resulting in increased absorption of simvastatin.  The mechanism of|
03257|010|A|interaction with fluvastatin and lovastatin is not known, but may be related|
03257|011|A|to competitive inhibition of OATP1B1 by elbasvir-grazoprevir.(1-3)|
03257|012|B||
03257|013|E|CLINICAL EFFECTS:  Concurrent use of elbasvir-grazoprevir may result in|
03257|014|E|elevated levels of and toxicity from fluvastatin, lovastatin, and|
03257|015|E|simvastatin, including rhabdomyolysis.(1-3)|
03257|016|B||
03257|017|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03257|018|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03257|019|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03257|020|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03257|021|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03257|022|P|transporter OATP1B1 may have increased statin concentrations and be|
03257|023|P|predisposed to myopathy or rhabdomyolysis.  Patients on fluvastatin who are|
03257|024|P|CYP2C9 intermediate or poor metabolizers may have increased fluvastatin|
03257|025|P|concentrations and  risk of myopathy.|
03257|026|B||
03257|027|M|PATIENT MANAGEMENT:  The Canadian and UK manufacturers of|
03257|028|M|elbasvir-grazoprevir and of simvastatin recommend that, in patients|
03257|029|M|requiring elbasvir-grazoprevir, doses greater than 20 mg daily of|
03257|030|M|fluvastatin, lovastatin, or simvastatin should not be used.(1,2)  The US|
03257|031|M|manufacturer of elbasvir-grazoprevir states that the lowest possible dose of|
03257|032|M|fluvastatin, lovastatin, or simvastatin should be used.(3)|
03257|033|M|   If concurrent use is deemed medically necessary, instruct patients to|
03257|034|M|report symptoms of muscle pain, tenderness, or weakness.|
03257|035|B||
03257|036|D|DISCUSSION:  Elbasvir-grazoprevir is a substrate of OATP1B1 and has been|
03257|037|D|shown to inhibit intestinal BCRP.(1,3)  Fluvastatin and lovastatin are|
03257|038|D|substrates of OATP1B1 and simvastatin is a substrate of BCRP and OATP1B1.(4)|
03257|039|D|Studies with other statins (i.e., atorvastatin, rosuvastatin) have shown|
03257|040|D|that elbasvir-grazoprevir can increase the concentrations of these statins.|
03257|041|D|While interaction studies of elbasvir-grazoprevir with fluvastatin,|
03257|042|D|lovastatin, and simvastatin have not been done, fluvastatin and lovastatin|
03257|043|D|concentrations have been shown to increase with other OATP1B1 inhibitors,|
03257|044|D|and simvastatin levels have been shown to increase with other BCRP|
03257|045|D|inhibitors.(4)|
03257|046|B||
03257|047|R|REFERENCES:|
03257|048|B||
03257|049|R|1.Zepatier (elbasvir-grazoprevir) Canadian product monograph. Merck Canada|1
03257|050|R|  Inc. January 19, 2016.|1
03257|051|R|2.Zocor (simvastatin) Canadian prescribing information. Merck Canada Inc.|1
03257|052|R|  May 24, 2019.|1
03257|053|R|3.Zepatier (elbasvir-grazoprevir) US prescribing information. Merck & Co.,|1
03257|054|R|  Inc. December, 2019.|1
03257|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
03257|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03258|001|T|MONOGRAPH TITLE:  Aripiprazole Immediate Release/Bupropion|
03258|002|B||
03258|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03258|004|L|take action as needed.|
03258|005|B||
03258|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors such as bupropion may inhibit|
03258|007|A|the metabolism of aripiprazole.(1-2)  Both agents are also known to lower|
03258|008|A|the seizure threshold.(1,3-4)|
03258|009|B||
03258|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
03258|011|E|with aripiprazole may result in elevated levels of and toxicity from|
03258|012|E|aripiprazole.(1)  Concurrent use may also result in additive effects on the|
03258|013|E|seizure threshold, increasing the risk of seizures.(3-4)|
03258|014|B||
03258|015|P|PREDISPOSING FACTORS:  The pharmacokinetic interaction is expected to be|
03258|016|P|more severe in patients taking both a strong CYP3A4 inhibitor and a strong|
03258|017|P|CYP2D6 inhibitor.(1)|
03258|018|P|   The risk of seizures may be increased in patients with a history of head|
03258|019|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
03258|020|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
03258|021|P|of over-the-counter stimulants an anorectics; a total daily dose of|
03258|022|P|bupropion greater than 450 mg or single doses greater than 150 mg; rapid|
03258|023|P|escalation of bupropion dosage; diabetics treated with oral hypoglycemics or|
03258|024|P|insulin; or with concomitant medications known to lower seizure threshold|
03258|025|P|(antidepressants, theophylline, systemic steroids).(3-4)|
03258|026|B||
03258|027|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics such|
03258|028|M|as aripiprazole should be undertaken only with extreme caution and with low|
03258|029|M|initial bupropion dosing, small gradual dosage increases of bupropion,(3-4)|
03258|030|M|and reduced dosages of aripiprazole.(1)  Single doses of bupropion should|
03258|031|M|not exceed 150 mg.(3-4)  The maximum daily dose of bupropion should not|
03258|032|M|exceed 300 mg for smoking cessation(5) or 450 mg for depression.(3)|
03258|033|M|   The US manufacturer of oral aripiprazole states that the dose of|
03258|034|M|aripiprazole should be reduced to one-half of its normal dose when strong|
03258|035|M|CYP2D6 inhibitors, such as bupropion, are coadministered, unless|
03258|036|M|aripiprazole is being used as adjunctive therapy for Major Depressive|
03258|037|M|Disorder.  If the patient is also receiving a strong CYP3A4 inhibitor, the|
03258|038|M|dose of aripiprazole should be reduced to one-fourth its normal dose.  When|
03258|039|M|the inhibitor is discontinued, the dose of aripiprazole should be|
03258|040|M|increased.(1)|
03258|041|B||
03258|042|D|DISCUSSION:  The administration of quinidine (166 mg daily for 13 days, a|
03258|043|D|strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg)|
03258|044|D|resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole|
03258|045|D|and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite|
03258|046|D|of aripiprazole.(1)|
03258|047|B||
03258|048|R|REFERENCES:|
03258|049|B||
03258|050|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
03258|051|R|  Pharmaceutical, Inc. August, 2019.|1
03258|052|R|2.This information is based on an extract from the Certara Drug Interaction|6
03258|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03258|054|R|3.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
03258|055|R|  GlaxoSmithKline November, 2019.|1
03258|056|R|4.Zyban (bupropion hydrochloride) US prescribing information.|1
03258|057|R|  GlaxoSmithKline July, 2019.|1
03259|001|T|MONOGRAPH TITLE:  Iloperidone; Zuclopenthixol/Bupropion|
03259|002|B||
03259|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03259|004|L|take action as needed.|
03259|005|B||
03259|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors such as bupropion may inhibit|
03259|007|A|the metabolism of iloperidone and zuclopenthixol.(1,2,6)  These agents are|
03259|008|A|also known to lower the seizure threshold.(1,3,4,6)|
03259|009|B||
03259|010|E|CLINICAL EFFECTS:  Concurrent administration of iloperidone or|
03259|011|E|zuclopenthixol with bupropion may result in elevated iloperidone levels and|
03259|012|E|toxicities, including the risk for QTc prolongation.(1)  Concurrent use may|
03259|013|E|also result in additive effects on the seizure threshold, increasing the|
03259|014|E|risk of seizures.(3,4)|
03259|015|B||
03259|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03259|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03259|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03259|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03259|020|P|female gender, or advanced age.(5)|
03259|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03259|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03259|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03259|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03259|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03259|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03259|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03259|028|P|   The risk of seizures may be increased in patients with a history of head|
03259|029|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
03259|030|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
03259|031|P|of over-the-counter stimulants an anorectics; a total daily dose of|
03259|032|P|bupropion greater than 450 mg or single doses greater than 150 mg; rapid|
03259|033|P|escalation of bupropion dosage; diabetics treated with oral hypoglycemics or|
03259|034|P|insulin; or with concomitant medications known to lower seizure threshold|
03259|035|P|(antidepressants, theophylline, systemic steroids).(3,4)|
03259|036|B||
03259|037|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics such|
03259|038|M|as iloperidone should be undertaken only with extreme caution and with low|
03259|039|M|initial bupropion dosing, small gradual dosage increases of bupropion,(3,4)|
03259|040|M|and reduced dosages of iloperidone.(3,4)  Single doses of bupropion should|
03259|041|M|not exceed 150 mg.(3,4)  The maximum daily dose of bupropion should not|
03259|042|M|exceed 300 mg for smoking cessation(4) or 450 mg for depression.(3)|
03259|043|M|   The US manufacturer of iloperidone states that the dose of iloperidone|
03259|044|M|should be reduced to one-half of its normal dose when strong CYP2D6|
03259|045|M|inhibitors such as bupropion are coadministered.(1)|
03259|046|M|   If bupropion is discontinued iloperidone exposure will wane, and the dose|
03259|047|M|of iloperidone should be increased.(1)|
03259|048|M|   Concurrent administration of iloperidone with both a CYP2D6 inhibitor and|
03259|049|M|CYP3A4 inhibitor does not have additive inhibitory effects compared to|
03259|050|M|either inhibitor alone. The dose of iloperidone should be reduced to|
03259|051|M|one-half of its normal dose, and further dose reduction is not required.(1)|
03259|052|M|   The UK manufacturer of zuclopenthixol states that zuclopenthixol is|
03259|053|M|partly metabolized by CYP2D6. Concurrent use with CYP2D6 inhibitors may|
03259|054|M|increase the risk of adverse effects and cardiotoxicity.(6)  The Swedish|
03259|055|M|manufacturer of zuclopenthixol states that dose adjustment of zuclopenthixol|
03259|056|M|may be required when used concurrently with CYP2D6 inhibitors.(7)|
03259|057|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03259|058|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03259|059|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03259|060|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03259|061|B||
03259|062|D|DISCUSSION:  The interactions of iloperidone and zuclopenthixol with|
03259|063|D|bupropion have not been studied. Other CYP2D6 inhibitors have been reported|
03259|064|D|to interact with iloperidone and zuclopenthixol.|
03259|065|D|   In a study in 23 healthy subjects, fluoxetine (a strong CYP2D6 inhibitor,|
03259|066|D|20 mg twice daily for 21 days) increased the area-under-curve (AUC) of|
03259|067|D|iloperidone (3 mg single dose) and its P88 metabolite by 2- to 3-fold.  The|
03259|068|D|AUC of iloperidone's P95 metabolite decreased by 50%.(2)|
03259|069|D|   In a study in patients with schizophrenia, paroxetine (a strong CYP2D6|
03259|070|D|inhibitor, 20 mg daily for 5-8 days) increased the maximum concentration|
03259|071|D|(Cmax) of iloperidone and its P88 metabolite by about 1.6-fold.  The Cmax of|
03259|072|D|iloperidone's P95 metabolite decreased by 50%.(2)|
03259|073|D|   Coadministration of paroxetine (20 mg daily) and iloperidone (12 mg twice|
03259|074|D|daily) was associated with a mean QTcF increase of 19 msec from baseline,|
03259|075|D|compared with an increase of 9 msec with iloperidone alone.(2)|
03259|076|D|   Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did|
03259|077|D|not increase the effects on iloperidone compared with either agent alone.(2)|
03259|078|D|   A retrospective review of psychiatry patients found that fluoxetine and|
03259|079|D|paroxetine increased the dose-adjusted zuclopenthixol concentration by 93%|
03259|080|D|and 78%, respectively.(8)|
03259|081|B||
03259|082|R|REFERENCES:|
03259|083|B||
03259|084|R|1.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
03259|085|R|  Inc May, 2016.|1
03259|086|R|2.This information is based on an extract from the Certara Drug Interaction|6
03259|087|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03259|088|R|3.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
03259|089|R|  GlaxoSmithKline November, 2019.|1
03259|090|R|4.Zyban (bupropion hydrochloride) US prescribing information.|1
03259|091|R|  GlaxoSmithKline July, 2019.|1
03259|092|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03259|093|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03259|094|R|  settings: a scientific statement from the American Heart Association and|6
03259|095|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03259|096|R|  2;55(9):934-47.|6
03259|097|R|6.Clopixol (zuclopenthixol acetate) UK summary of product characteristics.|1
03259|098|R|  Lundbeck Limited October 15, 2020.|1
03259|099|R|7.Cisordinol (zuclopenthixol) Swedish Summary of Product Characteristics. H.|1
03259|100|R|  Lundbeck A/S May 3, 2014.|1
03259|101|R|8.Davies SJ, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset|2
03259|102|R|  O. Characterisation of zuclopenthixol metabolism by in vitro and|2
03259|103|R|  therapeutic drug  monitoring studies. Acta Psychiatr Scand 2010 Dec;|2
03259|104|R|  122(6):444-53.|2
03260|001|T|MONOGRAPH TITLE:  Aripiprazole Lauroxil Submicronized/Bupropion|
03260|002|B||
03260|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03260|004|L|of severe adverse interaction.|
03260|005|B||
03260|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors such as bupropion may inhibit|
03260|007|A|the metabolism of aripiprazole.(1-4)  Both agents are also known to lower|
03260|008|A|the seizure threshold.(1,3,4)|
03260|009|B||
03260|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
03260|011|E|with aripiprazole may result in elevated levels of and toxicity from|
03260|012|E|aripiprazole.(1-4)  Concurrent use may also result in additive effects on|
03260|013|E|the seizure threshold, increasing the risk of seizures.(3,4)|
03260|014|B||
03260|015|P|PREDISPOSING FACTORS:  The pharmacokinetic interaction is expected to be|
03260|016|P|more severe in patients taking both a strong CYP3A4 inhibitor and a strong|
03260|017|P|CYP2D6 inhibitor.(1)|
03260|018|P|   The risk of seizures may be increased in patients with a history of head|
03260|019|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
03260|020|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
03260|021|P|of over-the-counter stimulants an anorectics; a total daily dose of|
03260|022|P|bupropion greater than 450 mg or single doses greater than 150 mg; rapid|
03260|023|P|escalation of bupropion dosage; diabetics treated with oral hypoglycemics or|
03260|024|P|insulin; or with concomitant medications known to lower seizure threshold|
03260|025|P|(antidepressants, theophylline, systemic steroids).(3,4)|
03260|026|B||
03260|027|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics such|
03260|028|M|as aripiprazole should be undertaken only with extreme caution and with low|
03260|029|M|initial bupropion dosing, small gradual dosage increases of bupropion,(3,4)|
03260|030|M|and reduced dosages of aripiprazole.(5-7)  Because Aristada Initio is only|
03260|031|M|available in a single strength as a single-dose pre-filled syringe, the US|
03260|032|M|manufacturer of the extended release aripiprazole lauroxil, submicronized|
03260|033|M|(Aristada Initio) recommends avoiding use of strong CYP2D6 inhibitors such|
03260|034|M|as bupropion with Aristada Initio.(1)|
03260|035|M|   Single doses of bupropion should not exceed 150 mg when used with|
03260|036|M|aripiprazole.(3,4)  The maximum daily dose of bupropion should not exceed|
03260|037|M|300 mg for smoking cessation(4) or 450 mg for depression.(3)|
03260|038|B||
03260|039|D|DISCUSSION:  Drug interaction studies have not been conducted with Aristada|
03260|040|D|Initio.  Aristada Initio has a long half-life (15-18 days).(1)|
03260|041|D|   The administration of quinidine (166 mg daily for 13 days, a strong|
03260|042|D|inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in|
03260|043|D|a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35%|
03260|044|D|decrease in the AUC of dehydro-aripiprazole, the active metabolite of|
03260|045|D|aripiprazole.(1)|
03260|046|B||
03260|047|R|REFERENCES:|
03260|048|B||
03260|049|R|1.Aristada Initio (aripiprazole lauroxil, submicronized) US Prescribing|1
03260|050|R|  Information. Alkermes, Inc. June 2018.|1
03260|051|R|2.This information is based on an extract from the Certara Drug Interaction|6
03260|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03260|053|R|3.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
03260|054|R|  GlaxoSmithKline November, 2019.|1
03260|055|R|4.Zyban (bupropion hydrochloride) US prescribing information.|1
03260|056|R|  GlaxoSmithKline July, 2019.|1
03260|057|R|5.Abilify (aripiprazole) US prescribing information. Otsuka America|1
03260|058|R|  Pharmaceutical, Inc. August, 2019.|1
03260|059|R|6.Abilify Maintena (aripiprazole ext-rel inj.) prescribing information.|1
03260|060|R|  Otsuka Pharmaceuticals January, 2016.|1
03260|061|R|7.Aristada (aripiprazole lauroxil) extended-release injectable US|1
03260|062|R|  prescribing information. Alkermes Inc. November, 2018.|1
03261|001|T|MONOGRAPH TITLE:  Pimozide; Thioridazine/Bupropion|
03261|002|B||
03261|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03261|004|L|is contraindicated and generally should not be dispensed or administered to|
03261|005|L|the same patient.|
03261|006|B||
03261|007|A|MECHANISM OF ACTION:  Bupropion may inhibit the metabolism of pimozide and|
03261|008|A|thioridazine at CYP2D6.(1,2)  These agents are also known to lower the|
03261|009|A|seizure threshold.(1,3,4,6)|
03261|010|B||
03261|011|E|CLINICAL EFFECTS:  Concurrent use may result in prolongation of the QTc|
03261|012|E|interval and potentially life-threatening ventricular arrhythmias.(1)|
03261|013|E|Concurrent use may also result in extrapyramidal symptoms such as akathisia,|
03261|014|E|bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric|
03261|015|E|crisis.(1,6)  As well, concurrent use may result in additive effects on the|
03261|016|E|seizure threshold, increasing the risk of seizures.(1,3,4,6)|
03261|017|B||
03261|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03261|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03261|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03261|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03261|022|P|female gender, or advanced age.(5)|
03261|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03261|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03261|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03261|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03261|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03261|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03261|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03261|030|P|   The risk of seizures may be increased in patients with a history of head|
03261|031|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
03261|032|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
03261|033|P|of over-the-counter stimulants an anorectics; a total daily dose of|
03261|034|P|bupropion greater than 450 mg or single doses greater than 150 mg; rapid|
03261|035|P|escalation of bupropion dosage; diabetics treated with oral hypoglycemics or|
03261|036|P|insulin; or with concomitant medications known to lower seizure threshold|
03261|037|P|(antidepressants, theophylline, systemic steroids).(3,4)|
03261|038|P|   The risk of anticholinergic toxicities including cognitive decline,|
03261|039|P|delirium, falls and fractures is increased in geriatric patients using more|
03261|040|P|than one medicine with anticholinergic properties.(7)|
03261|041|B||
03261|042|M|PATIENT MANAGEMENT:  The concurrent use of pimozide or thioridazine with|
03261|043|M|strong CYP2D6 inhibitors such as bupropion is contraindicated.(1,6)|
03261|044|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
03261|045|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
03261|046|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03261|047|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03261|048|M|   Concurrent use should be initiated with low initial bupropion dosing and|
03261|049|M|small gradual dosage increases of bupropion.(3,4)  Single doses of bupropion|
03261|050|M|should not exceed 150 mg.(3,4)  The maximum daily dose of bupropion should|
03261|051|M|not exceed 300 mg for smoking cessation(3) or 450 mg for depression.(4)|
03261|052|B||
03261|053|D|DISCUSSION:  The interactions of pimozide and thioridazine with bupropion|
03261|054|D|have not been studied.|
03261|055|D|   In a controlled study in healthy subjects, steady-state paroxetine (60 mg|
03261|056|D|daily, another strong inhibitor of CYP2D6) increased the area-under curve|
03261|057|D|(AUC) and maximum concentration (Cmax) of a single dose of pimozide (2 mg)|
03261|058|D|by 151% and 62%, respectively.(1)|
03261|059|B||
03261|060|R|REFERENCES:|
03261|061|B||
03261|062|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
03261|063|R|  2011.|1
03261|064|R|2.This information is based on an extract from the Certara Drug Interaction|6
03261|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03261|066|R|3.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
03261|067|R|  GlaxoSmithKline November, 2019.|1
03261|068|R|4.Zyban (bupropion hydrochloride) US prescribing information.|1
03261|069|R|  GlaxoSmithKline July, 2019.|1
03261|070|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03261|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03261|072|R|  settings: a scientific statement from the American Heart Association and|6
03261|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03261|074|R|  2;55(9):934-47.|6
03261|075|R|6.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
03261|076|R|  September, 2014.|1
03261|077|R|7.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03261|078|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03261|079|R|  Soc 2023 Jul;71(7):2052-2081.|6
03262|001|T|MONOGRAPH TITLE:  Darolutamide/P-gp and Strong CYP3A4 Inducers|
03262|002|B||
03262|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03262|004|L|of severe adverse interaction.|
03262|005|B||
03262|006|A|MECHANISM OF ACTION:  Apalutamide, carbamazepine, enzalutamide,|
03262|007|A|fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort may|
03262|008|A|induce the metabolism of darolutamide by both P-gp and CYP3A4.|
03262|009|B||
03262|010|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide, carbamazepine,|
03262|011|E|enzalutamide, fosphenytoin, phenytoin, rifampin, rifapentine, or St. John's|
03262|012|E|wort may result in decreased levels and effectiveness of darolutamide.|
03262|013|B||
03262|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03262|015|P|of the inducer for longer than 1-2 weeks.|
03262|016|B||
03262|017|M|PATIENT MANAGEMENT:  If possible, avoid the concurrent use of agents that|
03262|018|M|are combined P-gp and strong CYP3A4 inducers, such as apalutamide,|
03262|019|M|carbamazepine, enzalutamide, fosphenytoin, phenytoin, rifampin, rifapentine,|
03262|020|M|and St. John's wort, in patients receiving darolutamide.|
03262|021|B||
03262|022|D|DISCUSSION:  Concurrent rifampin (combined P-gp and strong CYP3A4 inducer)|
03262|023|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03262|024|D|darolutamide by 72% and 52%, respectively.(1)|
03262|025|B||
03262|026|R|REFERENCES:|
03262|027|B||
03262|028|R|1.Nubeqa (darolutamide) US prescribing information. Bayer Healthcare|1
03262|029|R|  Pharmaceuticals, Inc. August, 2022.|1
03262|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
03262|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03262|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03262|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03262|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03262|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03262|036|R|  11/14/2017.|1
03263|001|T|MONOGRAPH TITLE:  Bortezomib/Venetoclax|
03263|002|B||
03263|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03263|004|L|of severe adverse interaction.|
03263|005|B||
03263|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is not known.|
03263|007|B||
03263|008|E|CLINICAL EFFECTS:  Concurrent use of bortezomib with dexamethasone and|
03263|009|E|venetoclax may increase the risk of mortality.(1,2)|
03263|010|B||
03263|011|P|PREDISPOSING FACTORS:  None determined.|
03263|012|B||
03263|013|M|PATIENT MANAGEMENT:  Concurrent administration of bortezomib plus|
03263|014|M|dexamethasone with venetoclax is not recommended outside of controlled|
03263|015|M|clinical trials.  Venetoclax is not approved for the treatment of multiple|
03263|016|M|myeloma.(1,2)|
03263|017|B||
03263|018|D|DISCUSSION:  BELLINI is a phase 3, randomized, double-blind,|
03263|019|D|placebo-controlled trial of bortezomib and low-dose dexamethasone with or|
03263|020|D|without venetoclax for patients with relapsed and refractory multiple|
03263|021|D|myeloma.  At interim analysis after 17.9 months of follow-up, 41/194 (21.1%)|
03263|022|D|of patients on venetoclax had died, compared with 11/97 (11.3%) of patients|
03263|023|D|on placebo (HR 2.03, 95% CI: 1.04,3.94).  This occurred despite a higher|
03263|024|D|progression-free survival (PFS) of 22.4 months and a higher objective|
03263|025|D|response rate (ORR) of 82% in the venetoclax arm compared to 11.5 months and|
03263|026|D|68%, respectively, in the placebo arm.  The incidences of severe toxicities|
03263|027|D|and serious adverse events were similar in the two arms.(2)|
03263|028|B||
03263|029|R|REFERENCES:|
03263|030|B||
03263|031|R|1.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
03263|032|R|  2021.|1
03263|033|R|2.FDA (US Food and Drug Administration). FDA Warns about the risks|1
03263|034|R|  associated with the investigational use of Venclexta in Multiple Myeloma.|1
03263|035|R|  available at:|1
03263|036|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-ris|1
03263|037|R|  ks-associated-investigational-use-venclexta-multiple-myeloma March 21,|1
03263|038|R|  2019.|1
03264|001|T|MONOGRAPH TITLE:  Darolutamide/P-gp and Moderate CYP3A4 Inducers|
03264|002|B||
03264|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03264|004|L|of severe adverse interaction.|
03264|005|B||
03264|006|A|MECHANISM OF ACTION:  Agents that are combined P-gp and moderate CYP3A4|
03264|007|A|inducers may induce the metabolism of darolutamide by both pathways.(1)|
03264|008|B||
03264|009|E|CLINICAL EFFECTS:  Concurrent or recent use of inducers of both P-gp and|
03264|010|E|CYP3A4 may result in decreased levels and effectiveness of darolutamide.(1)|
03264|011|B||
03264|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03264|013|P|of the inducer for longer than 1-2 weeks.|
03264|014|B||
03264|015|M|PATIENT MANAGEMENT:  If possible, avoid the concurrent use of agents that|
03264|016|M|are combined P-gp and moderate CYP3A4 inducers in patients receiving|
03264|017|M|darolutamide.(1)|
03264|018|B||
03264|019|D|DISCUSSION:  Concurrent rifampin (combined P-gp and strong CYP3A4 inducer)|
03264|020|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03264|021|D|darolutamide by 72% and 52%, respectively. Combined P-gp and moderate CYP3A4|
03264|022|D|inducers are expected to decrease the AUC by 36-58%.(1)|
03264|023|D|   Agents that are combined P-gp and moderate CYP3A4 inducers linked to this|
03264|024|D|monograph include: efavirenz, lorlatinib and rifabutin.(2)|
03264|025|B||
03264|026|R|REFERENCES:|
03264|027|B||
03264|028|R|1.Nubeqa (darolutamide) US prescribing information. Bayer Healthcare|1
03264|029|R|  Pharmaceuticals, Inc. August, 2022.|1
03264|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
03264|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03264|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03264|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03264|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03264|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03264|036|R|  11/14/2017.|1
03265|001|T|MONOGRAPH TITLE:  Darolutamide/Dual P-gp and Strong CYP3A4 Inhibitors|
03265|002|B||
03265|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03265|004|L|take action as needed.|
03265|005|B||
03265|006|A|MECHANISM OF ACTION:  Combined inhibitors of P-glycoprotein (P-gp) and|
03265|007|A|CYP3A4 may increase the absorption and inhibit the metabolism of|
03265|008|A|darolutamide.(1-3)|
03265|009|B||
03265|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
03265|011|E|P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and|
03265|012|E|clinical effects of darolutamide.(1)|
03265|013|B||
03265|014|P|PREDISPOSING FACTORS:  None determined.|
03265|015|B||
03265|016|M|PATIENT MANAGEMENT:  The manufacturer of darolutamide recommends increased|
03265|017|M|monitoring if agents that are combined P-gp and strong CYP3A4 inhibitors are|
03265|018|M|used in patients receiving darolutamide.(1) Darolutamide dosage may need to|
03265|019|M|be adjusted.|
03265|020|M|   Monitor absolute neutrophil count (ANC). If patient experiences a greater|
03265|021|M|than or equal to Grade 3 toxicity, dose may need to be withheld or reduced|
03265|022|M|until symptoms improve.(1)|
03265|023|B||
03265|024|D|DISCUSSION:  Concurrent itraconazole increased the area-under-curve (AUC)|
03265|025|D|and maximum concentration (Cmax) of darolutamide by 1.7-fold and 1.4-fold,|
03265|026|D|respectively.(1)|
03265|027|D|   P-gp and strong CYP3A4 inhibitors linked to this monograph are:|
03265|028|D|adagrasib, cobicistat, indinavir, itraconazole, josamycin, ketoconazole,|
03265|029|D|levoketoconazole, lopinavir, mifepristone, nirmatrelvir/ritonavir,|
03265|030|D|posaconazole, ritonavir, saquinavir, telaprevir, tucatinib and|
03265|031|D|telithromycin.|
03265|032|B||
03265|033|R|REFERENCES:|
03265|034|B||
03265|035|R|1.Nubeqa (darolutamide) US prescribing information. Bayer Healthcare|1
03265|036|R|  Pharmaceuticals, Inc. August, 2022.|1
03265|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
03265|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03265|039|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03265|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03265|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03265|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03265|043|R|  11/14/2017.|1
03266|001|T|MONOGRAPH TITLE:  Selected BCRP Substrates/Darolutamide|
03266|002|B||
03266|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03266|004|L|of severe adverse interaction.|
03266|005|B||
03266|006|A|MECHANISM OF ACTION:  Darolutamide inhibits BCRP, which may result in|
03266|007|A|increased absorption of BCRP substrates.(1)|
03266|008|B||
03266|009|E|CLINICAL EFFECTS:  Administration of darolutamide with BCRP substrates may|
03266|010|E|result in elevated levels of and toxicity from these agents.(1)|
03266|011|B||
03266|012|P|PREDISPOSING FACTORS:  None determined.|
03266|013|B||
03266|014|M|PATIENT MANAGEMENT:  The US manufacturer recommends avoiding concurrent use|
03266|015|M|of darolutamide with BCRP substrates when possible.|
03266|016|B||
03266|017|D|DISCUSSION:  Concurrent administration of darolutamide with rosuvastatin|
03266|018|D|increased the mean area-under-the-curve (AUC) and maximum concentration|
03266|019|D|(Cmax) of rosuvastatin approximately 5-fold.(1)|
03266|020|D|   BCRP substrates linked to this monograph include: ciprofloxacin,|
03266|021|D|diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate,|
03266|022|D|mitoxantrone, sulfasalazine, and topotecan.(1-3)|
03266|023|B||
03266|024|R|REFERENCES:|
03266|025|B||
03266|026|R|1.Nubeqa (darolutamide) US prescribing information. Bayer Healthcare|1
03266|027|R|  Pharmaceuticals, Inc. August, 2022.|1
03266|028|R|2.This information is based on an extract from the Certara Drug Interaction|6
03266|029|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03266|030|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03266|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03266|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03266|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03266|034|R|  11/14/2017.|1
03267|001|T|MONOGRAPH TITLE:  Pexidartinib (200 mg)/Strong CYP3A4 Inhibitors|
03267|002|B||
03267|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03267|004|L|of severe adverse interaction.|
03267|005|B||
03267|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03267|007|A|of pexidartinib.(1,2)|
03267|008|B||
03267|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03267|010|E|in elevated levels and increased effects of pexidartinib, such as|
03267|011|E|hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark|
03267|012|E|urine, abdominal pain, and unexplained fatigue.|
03267|013|B||
03267|014|P|PREDISPOSING FACTORS:  None determined.|
03267|015|B||
03267|016|M|PATIENT MANAGEMENT:  The US manufacturer of pexidartinib states that|
03267|017|M|pexidartinib coadministration with strong inhibitors of CYP3A4 should be|
03267|018|M|avoided.(1)|
03267|019|M|   If coadministration with a strong CYP3A4 inhibitor cannot be avoided,|
03267|020|M|reduce the pexidartinib dose according to the following recommendations.|
03267|021|M|   If the planned total daily dose is currently 800 mg, modify the total|
03267|022|M|daily dose to 400 mg by administering 200 mg twice daily.|
03267|023|M|   If the planned total daily dose is currently 600 mg, modify the total|
03267|024|M|daily dose to 400 mg by administering 200 mg twice daily.|
03267|025|M|   If the planned total daily dose is currently 400 mg, modify the total|
03267|026|M|daily dose to 200 mg by administering 200 mg once daily.|
03267|027|M|   If concomitant use of a strong CYP3A4 inhibitor is discontinued, increase|
03267|028|M|the pexidartinib dose to the dose that was used before starting the|
03267|029|M|inhibitor after three plasma half-lives of the strong CYP3A4 inhibitor.|
03267|030|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
03267|031|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
03267|032|M|recommendations in the Turalio package insert. Advise patients to|
03267|033|M|immediately report any symptoms of hepatotoxicity.|
03267|034|B||
03267|035|D|DISCUSSION:  Coadministration of itraconazole (strong CYP3A4 inhibitor)|
03267|036|D|increased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
03267|037|D|(AUC) by 48% and 70%.(1)|
03267|038|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03267|039|D|clarithromycin, cobicistat, indinavir, itraconazole, josamycin,|
03267|040|D|ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone,|
03267|041|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
03267|042|D|saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(1,3)|
03267|043|B||
03267|044|R|REFERENCES:|
03267|045|B||
03267|046|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03267|047|R|  November, 2023.|1
03267|048|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03267|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03267|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03267|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03267|052|R|  11/14/2017.|1
03267|053|R|3.This information is based on an extract from the Certara Drug Interaction|6
03267|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03268|001|T|MONOGRAPH TITLE:  Pexidartinib (200 mg)/UGT1A4 Inhibitors|
03268|002|B||
03268|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03268|004|L|of severe adverse interaction.|
03268|005|B||
03268|006|A|MECHANISM OF ACTION:  Inhibitors of UGT1A4 may inhibit the metabolism of|
03268|007|A|pexidartinib.(1)|
03268|008|B||
03268|009|E|CLINICAL EFFECTS:  Concurrent use of a inhibitors of UGT1A4 may result in|
03268|010|E|elevated levels and increased effects of pexidartinib, such as|
03268|011|E|hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark|
03268|012|E|urine, abdominal pain, and unexplained fatigue.|
03268|013|B||
03268|014|P|PREDISPOSING FACTORS:  None determined.|
03268|015|B||
03268|016|M|PATIENT MANAGEMENT:  The US manufacturer of pexidartinib states that|
03268|017|M|pexidartinib coadministration with inhibitors of UGT1A4 should be|
03268|018|M|avoided.(1)|
03268|019|M|   If coadministration with a UGT1A4 inhibitor cannot be avoided, reduce the|
03268|020|M|pexidartinib dose according to the following recommendations.|
03268|021|M|   If the planned total daily dose is currently 800 mg, modify the total|
03268|022|M|daily dose to 400 mg by administering 200 mg twice daily.|
03268|023|M|   If the planned total daily dose is currently 600 mg, modify the total|
03268|024|M|daily dose to 400 mg by administering 200 mg twice daily.|
03268|025|M|   If the planned total daily dose is currently 400 mg, modify the total|
03268|026|M|daily dose to 200 mg by administering 200 mg once daily.|
03268|027|M|   If concomitant use of a UGT1A4 inhibitor is discontinued, increase the|
03268|028|M|pexidartinib dose to the dose that was used before starting the inhibitor|
03268|029|M|after three plasma half-lives of the UGT1A4 inhibitor.|
03268|030|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
03268|031|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
03268|032|M|recommendations in the Turalio package insert. Advise patients to|
03268|033|M|immediately report any symptoms of hepatotoxicity.|
03268|034|B||
03268|035|D|DISCUSSION:  Coadministration of probenecid (UGT1A4 inhibitor) increased|
03268|036|D|pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by|
03268|037|D|5% and 60%.(1)|
03268|038|D|   Inhibitors of UGT1A4 linked to this monograph include:  probenecid.(1,2)|
03268|039|B||
03268|040|R|REFERENCES:|
03268|041|B||
03268|042|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03268|043|R|  November, 2023.|1
03268|044|R|2.This information is based on an extract from the Certara Drug Interaction|6
03268|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03269|001|T|MONOGRAPH TITLE:  Pexidartinib/Strong CYP3A4 Inducers|
03269|002|B||
03269|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03269|004|L|of severe adverse interaction.|
03269|005|B||
03269|006|A|MECHANISM OF ACTION:  Pexidartinib is a substrate of CYP3A4.  Strong|
03269|007|A|inducers of CYP3A4 may induce the metabolism of pexidartinib.(1)|
03269|008|B||
03269|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03269|010|E|may result in decreased levels and effectiveness of pexidartinib.(1)|
03269|011|B||
03269|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03269|013|P|of the inducer for longer than 1-2 weeks.|
03269|014|B||
03269|015|M|PATIENT MANAGEMENT:  The manufacturer of pexidartinib states that concurrent|
03269|016|M|use with strong CYP3A4 inducers should be avoided. (1)|
03269|017|B||
03269|018|D|DISCUSSION:  Concomitant administration of rifampin (strong CYP3A4 inducer)|
03269|019|D|decreased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
03269|020|D|(AUC) by 33% and 65%.(1)|
03269|021|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03269|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03269|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03269|024|D|rifapentine, and St. John's wort.(2-3)|
03269|025|B||
03269|026|R|REFERENCES:|
03269|027|B||
03269|028|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03269|029|R|  November, 2023.|1
03269|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03269|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03269|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03269|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03269|034|R|  11/14/2017.|1
03269|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
03269|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03270|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Deferasirox|
03270|002|B||
03270|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03270|004|L|of severe adverse interaction.|
03270|005|B||
03270|006|A|MECHANISM OF ACTION:  Deferasirox may induce the CYP3A4 mediated metabolism|
03270|007|A|of hormonal contraceptives.(1)|
03270|008|B||
03270|009|E|CLINICAL EFFECTS:  Concurrent use of deferasirox may reduce the|
03270|010|E|effectiveness of hormonal contraceptives.(1)|
03270|011|B||
03270|012|P|PREDISPOSING FACTORS:  None determined.|
03270|013|B||
03270|014|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
03270|015|M|rely on hormonal contraception (including oral contraceptives, patches,|
03270|016|M|implants, and/or IUDs) for contraception.  Women should use a non-hormonal|
03270|017|M|method of birth control during deferasirox therapy.(1)|
03270|018|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03270|019|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03270|020|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03270|021|M|contraceptive (i.e., a copper IUD).  If a non-hormonal emergency|
03270|022|M|contraceptive is not an option, double the usual dose of levonorgestrel from|
03270|023|M|1.5 to 3 mg.  Advise the patient to have a pregnancy test to exclude|
03270|024|M|pregnancy after use and to seek medical advice if she does become|
03270|025|M|pregnant.(2)|
03270|026|B||
03270|027|D|DISCUSSION:  Deferasirox may induce the CYP3A4 mediated metabolism of|
03270|028|D|hormonal contraceptives.  Deferasirox may decrease the effectiveness of|
03270|029|D|hormonal contraceptives, including oral contraceptives, patches, implants,|
03270|030|D|and/or IUDs.  Women should use a non-hormonal method of birth control during|
03270|031|D|deferasirox therapy.(1)|
03270|032|B||
03270|033|R|REFERENCES:|
03270|034|B||
03270|035|R|1.Exjade (deferasirox) US prescribing information. Novartis Pharmaceuticals|1
03270|036|R|  Corporation July, 2019.|1
03270|037|R|2.Medicines and Healthcare products Regulatory Agency.|1
03270|038|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03270|039|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03270|040|R|  available at:|1
03270|041|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03270|042|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03270|043|R|  -and-contraceptive-efficacy September 15, 2016..|1
03271|001|T|MONOGRAPH TITLE:  Betrixaban/Selected P-glycoprotein (P-gp) Inducers|
03271|002|B||
03271|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03271|004|L|is contraindicated and generally should not be dispensed or administered to|
03271|005|L|the same patient.|
03271|006|B||
03271|007|A|MECHANISM OF ACTION:  Betrixaban is a P-glycoprotein (P-gp) substrate.  P-gp|
03271|008|A|induction may reduce systemic exposure to betrixaban.(1)|
03271|009|B||
03271|010|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide, carbamazepine,|
03271|011|E|fosphenytoin, lorlatinib, phenytoin, rifampin, rifapentine, or St. John's|
03271|012|E|wort may result in decreased effectiveness of betrixaban.(1-3)|
03271|013|B||
03271|014|P|PREDISPOSING FACTORS:  None determined.|
03271|015|B||
03271|016|M|PATIENT MANAGEMENT:  The US manufacturer of betrixaban recommends avoiding|
03271|017|M|the concurrent use of betrixaban with P-gp inducers.(1)  Consider|
03271|018|M|alternatives to the P-gp inducing agent.  If therapy with an inducer of P-gp|
03271|019|M|is required, alternatives to betrixaban may need to be considered.|
03271|020|M|  If a P-gp inducer is discontinued, betrixaban exposure will remain|
03271|021|M|impaired for at least one week after the completion of therapy.|
03271|022|B||
03271|023|D|DISCUSSION:  Pharmacokinetic interaction data on file with the manufacturer.|
03271|024|D|   Inducers of P-glycoprotein (P-gp) linked to this monograph include|
03271|025|D|apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampin,|
03271|026|D|rifapentine, and St. John's wort.(2,3)|
03271|027|B||
03271|028|R|REFERENCES:|
03271|029|B||
03271|030|R|1.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
03271|031|R|  Inc. July, 2019.|1
03271|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03271|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03271|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03271|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03271|036|R|  11/14/2017.|1
03271|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
03271|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03272|001|T|MONOGRAPH TITLE:  Neratinib/Ritonavir|
03272|002|B||
03272|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03272|004|L|is contraindicated and generally should not be dispensed or administered to|
03272|005|L|the same patient.|
03272|006|B||
03272|007|A|MECHANISM OF ACTION:  Ritonavir, a strong inhibitor of CYP3A4, may inhibit|
03272|008|A|the metabolism of neratinib.(1)|
03272|009|B||
03272|010|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
03272|011|E|increased systemic exposure to and effects from neratinib. Life-threatening|
03272|012|E|reactions, such as hepatotoxicity, may occur.(1)|
03272|013|B||
03272|014|P|PREDISPOSING FACTORS:  None determined.|
03272|015|B||
03272|016|M|PATIENT MANAGEMENT:  The UK manufacturer of ritonavir states that concurrent|
03272|017|M|use of neratinib with ritonavir is contraindicated.(1)|
03272|018|M|   The US manufacturer of ritonavir recommends avoiding concurrent use of|
03272|019|M|neratinib with ritonavir.(2)|
03272|020|M|   If concurrent use is warranted, monitor patients closely for increased|
03272|021|M|incidence and severity of diarrhea, abdominal pain, nausea, vomiting, and|
03272|022|M|dehydration.|
03272|023|B||
03272|024|D|DISCUSSION:  Ketoconazole (400 mg daily for 5 days), a strong CYP3A4|
03272|025|D|inhibitor, increased maximum concentration (Cmax) and area-under-curve (AUC)|
03272|026|D|of a single dose of neratinib by 321% and 481%, respectively.(2)|
03272|027|B||
03272|028|R|REFERENCES:|
03272|029|B||
03272|030|R|1.Norvir (ritonavir) UK summary of product characteristics. AbbVie, Ltd.|1
03272|031|R|  July 18, 2019.|1
03272|032|R|2.Nerlynx (neratinib) US prescribing information. Puma Biotechnology, Inc.|1
03272|033|R|  June, 2021.|1
03272|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
03272|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03273|001|T|MONOGRAPH TITLE:  Vortioxetine/Carbamazepine; Rifampin|
03273|002|B||
03273|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03273|004|L|take action as needed.|
03273|005|B||
03273|006|A|MECHANISM OF ACTION:  While vortioxetine is primarily metabolized by CYP2D6,|
03273|007|A|many other CYP enzymes also play a role, including CYP3A4/5, CYP2C19,|
03273|008|A|CYP2C9, CYP2A6, CYP2C8 and CYP2B6.(1)  Carbamazepine and rifampin may induce|
03273|009|A|these enzymes.(2-3)|
03273|010|B||
03273|011|E|CLINICAL EFFECTS:  The concurrent administration of carbamazepine or|
03273|012|E|rifampin may result in decreased levels and effectiveness of|
03273|013|E|vortioxetine.(1)|
03273|014|B||
03273|015|P|PREDISPOSING FACTORS:  None determined.|
03273|016|B||
03273|017|M|PATIENT MANAGEMENT:  The manufacturer of vortioxetine states that patients|
03273|018|M|receiving strong CYP enzyme inducers for greater than 14 days may require an|
03273|019|M|increase in their dosage of vortioxetine, up to a maximum of three times the|
03273|020|M|original dose.(1)|
03273|021|M|   If carbamazepine or rifampin is discontinued in a patient who has been|
03273|022|M|maintained on vortioxetine, the dose of vortioxetine should be reduced to|
03273|023|M|the original level within 14 days.(1)|
03273|024|B||
03273|025|D|DISCUSSION:  In a study of 14 healthy volunteers, rifampin decreased the|
03273|026|D|area-under-curve (AUC) and maximum concentration (Cmax) of vortioxetine by|
03273|027|D|72.3%  and 50.9%, respectively, compared to vortioxetine when given|
03273|028|D|alone.(4)|
03273|029|B||
03273|030|R|REFERENCES:|
03273|031|B||
03273|032|R|1.Trintellix (vortioxetine) US prescribing information. Takeda|1
03273|033|R|  Pharmaceuticals America, Inc. November, 2020.|1
03273|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03273|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03273|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03273|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03273|038|R|  11/14/2017.|1
03273|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03273|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03273|041|R|4.Chen G, Lee R, Hojer AM, Buchbjerg JK, Serenko M, Zhao Z. Pharmacokinetic|2
03273|042|R|  Drug Interactions Involving Vortioxetine (Lu AA21004), a Multimodal|2
03273|043|R|  Antidepressant. Clin Drug Investig 2013 Oct;33(10):727-36.|2
03274|001|T|MONOGRAPH TITLE:  Everolimus/Clotrimazole|
03274|002|B||
03274|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03274|004|L|of severe adverse interaction.|
03274|005|B||
03274|006|A|MECHANISM OF ACTION:  Clotrimazole is a weak inhibitor of CYP3A4.(1)|
03274|007|A|Everolimus is metabolized by CYP3A4 in the liver and the intestines.(2,3)|
03274|008|A|Although clotrimazole troches have low bioavailability, clotrimazole may|
03274|009|A|inhibit the intestinal CYP3A4 first-pass metabolism of everolimus.(3)|
03274|010|B||
03274|011|E|CLINICAL EFFECTS:  Concurrent use of clotrimazole with everolimus may result|
03274|012|E|in elevated levels of and toxicity from everolimus.  Conversely,|
03274|013|E|discontinuation of clotrimazole in a patient stabilized on everolimus may|
03274|014|E|result in subtherapeutic concentrations and decreased efficacy of|
03274|015|E|everolimus.(3)|
03274|016|B||
03274|017|P|PREDISPOSING FACTORS:  None determined.|
03274|018|B||
03274|019|M|PATIENT MANAGEMENT:  Everolimus levels should be closely monitored during|
03274|020|M|initiation and discontinuation of clotrimazole.(4)|
03274|021|B||
03274|022|D|DISCUSSION:  A case report described a heart transplant patient on stable|
03274|023|D|doses of everolimus for seven months who discontinued clotrimazole troches|
03274|024|D|according to hospital protocol at one year post-transplant.  Within three|
03274|025|D|days, his everolimus trough levels dropped from 8.4 to 2.5 ng/mL, requiring|
03274|026|D|an almost doubling of his everolimus dose.  The authors suggested that|
03274|027|D|empirically increasing everolimus dose after discontinuation of clotrimazole|
03274|028|D|troches may prevent subtherapeutic everolimus levels and avert the risk of|
03274|029|D|transplant rejection.(3)|
03274|030|B||
03274|031|R|REFERENCES:|
03274|032|B||
03274|033|R|1.This information is based on an extract from the Certara Drug Interaction|6
03274|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03274|035|R|2.Zortress (everolimus) US prescribing information. Novartis Pharmaceuticals|1
03274|036|R|  Corporation Sept, 2023.|1
03274|037|R|3.Uno T, Wada K, Matsuda S, Ikura M, Takenaka H, Terakawa N, Oita A,|3
03274|038|R|  Yokoyama S, Kawase A, Hosomi K, Takada M. Clotrimazole troches can alter|3
03274|039|R|  everolimus pharmacokinetics in post-transplant patients: A case report. Br|3
03274|040|R|  J Clin Pharmacol 2019 Jun 26.|3
03274|041|R|4.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
03274|042|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
03274|043|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
03274|044|R|  e13510.|6
03275|001|T|MONOGRAPH TITLE:  Pretomanid/Strong and Moderate CYP3A4 Inducers|
03275|002|B||
03275|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03275|004|L|of severe adverse interaction.|
03275|005|B||
03275|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may induce the|
03275|007|A|metabolism of pretomanid by CYP3A4.(1)|
03275|008|B||
03275|009|E|CLINICAL EFFECTS:  The concurrent use of strong and moderate CYP3A4 inducers|
03275|010|E|and pretomanid may result in decreased levels and clinical effectiveness of|
03275|011|E|pretomanid.(1)|
03275|012|B||
03275|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03275|014|P|of the inducer for longer than 1-2 weeks.|
03275|015|B||
03275|016|M|PATIENT MANAGEMENT:  The manufacturer of pretomanid recommends avoiding|
03275|017|M|concurrent use with strong or moderate CYP3A4 inducers during pretomanid|
03275|018|M|therapy.(1)|
03275|019|M|   Patients receiving concurrent therapy with strong and moderate CYP3A4|
03275|020|M|inducers and pretomanid should be observed for decreased levels and clinical|
03275|021|M|effectiveness.|
03275|022|B||
03275|023|D|DISCUSSION:  In a clinical study, concurrent use of pretomanid 200 mg with|
03275|024|D|efavirenz 600 mg for 7 days resulted in decreased mean area-under-curve|
03275|025|D|(AUC) by 35% and maximum concentration (Cmax) by 28%.(1)|
03275|026|D|   In a clinical study, concurrent use of pretomanid 200 mg with rifampin|
03275|027|D|600 mg for 7 days resulted in decreased mean AUC by 66% and Cmax by 53%.(1)|
03275|028|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
03275|029|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
03275|030|D|dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine,|
03275|031|D|fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten,|
03275|032|D|mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib,|
03275|033|D|phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin,|
03275|034|D|rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and|
03275|035|D|tovorafenib.(1,2)|
03275|036|B||
03275|037|R|REFERENCES:|
03275|038|B||
03275|039|R|1.Pretomanid tablets US prescribing information. Mylan August, 2019.|1
03275|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
03275|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03276|001|T|MONOGRAPH TITLE:  Pitolisant/Strong CYP2D6 Inhibitors|
03276|002|B||
03276|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03276|004|L|take action as needed.|
03276|005|B||
03276|006|A|MECHANISM OF ACTION:  Bupropion, dacomitinib, fluoxetine, paroxetine, and|
03276|007|A|terbinafine may inhibit the metabolism of pitolisant at CYP2D6.(1,2)|
03276|008|B||
03276|009|E|CLINICAL EFFECTS:  Concurrent use of CYP2D6 inhibitors may result in|
03276|010|E|elevated levels of and toxicity from pitolisant including potentially|
03276|011|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
03276|012|B||
03276|013|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers may|
03276|014|P|be affected to a greater extent by CYP2D6 inhibitors.  Patients who are|
03276|015|P|CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6|
03276|016|P|inhibition.|
03276|017|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03276|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03276|019|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03276|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03276|021|P|advanced age.(3)|
03276|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03276|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03276|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03276|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03276|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03276|027|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03276|028|P|dysfunction).(3)|
03276|029|B||
03276|030|M|PATIENT MANAGEMENT:  The US manufacturer states the concurrent use of|
03276|031|M|pitolisant with strong CYP2D6 inhibitors requires dose adjustment.|
03276|032|M|   - Adult patients currently receiving a strong CYP2D6 inhibitor prior to|
03276|033|M|initiation of pitolisant: start pitolisant at 8.9 mg once daily and increase|
03276|034|M|after 7 days to a maximum dosage of 17.8 mg daily.|
03276|035|M|   - Patients 6 years and older weighing <40 kg: start pitolisant at 4.45 mg|
03276|036|M|once daily and increase after 7 days to a maximum dosage of 8.9 mg once|
03276|037|M|daily.|
03276|038|M|   - Patients 6 years and older weighing >=40 kg: start pitolisant at 4.45|
03276|039|M|mg once daily and increase after 7 days to 8.9 mg once daily.  May increase|
03276|040|M|after another 7 days to a maximum dosage of 17.8 mg once daily.|
03276|041|M|   - All patients who are stable on pitolisant: reduce the dose of|
03276|042|M|pitolisant by half upon initiating a strong CYP2D6 inhibitor.(1)|
03276|043|M|   The UK manufacturer states concurrent use of pitolisant with CYP2D6|
03276|044|M|inhibitors should be done with caution and dose adjustment could be|
03276|045|M|considered.(2)|
03276|046|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03276|047|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03276|048|M|treatment, after initiation of any drug known to prolong the QT interval,|
03276|049|M|and periodically monitor during therapy.  Correct any electrolyte|
03276|050|M|abnormalities.|
03276|051|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03276|052|M|fainting.|
03276|053|B||
03276|054|D|DISCUSSION:  In a clinical study, concurrent use of pitolisant with|
03276|055|D|paroxetine increased the concentration maximum (Cmax) and area-under-curve|
03276|056|D|(AUC) by approximately 1.75 and 2.25, respectively.(1)|
03276|057|D|   In two dedicated QT prolongation studies, supra-therapeutic doses of|
03276|058|D|pitolisant at 3-6 times the therapeutic dose (108-216 mg) were seen to cause|
03276|059|D|mild to moderate QTc prolongation (10-13 ms).  A study in patients who were|
03276|060|D|CYP2D6 poor metabolizers had higher systemic exposure up to 3-fold compared|
03276|061|D|to CYP2D6 extensive metabolizers.(1)|
03276|062|D|   Strong CYP2D6 inhibitors linked to this monograph include: bupropion,|
03276|063|D|dacomitinib, fluoxetine, paroxetine and terbinafine.(5,6)|
03276|064|B||
03276|065|R|REFERENCES:|
03276|066|B||
03276|067|R|1.Wakix (pitolisant) tablets US prescribing information. Harmony Biosciences|1
03276|068|R|  June, 2024.|1
03276|069|R|2.Wakix (pitolisant) UK Summary of Product Characteristics. Bioproject|1
03276|070|R|  Pharma January, 2019.|1
03276|071|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03276|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03276|073|R|  settings: a scientific statement from the American Heart Association and|6
03276|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03276|075|R|  2;55(9):934-47.|6
03276|076|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03276|077|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03276|078|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03276|079|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03276|080|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03276|081|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03276|082|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03276|083|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03276|084|R|  11/14/2017.|1
03276|085|R|6.This information is based on an extract from the Certara Drug Interaction|6
03276|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03277|001|T|MONOGRAPH TITLE:  Pitolisant/Strong CYP3A4 Inducers|
03277|002|B||
03277|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03277|004|L|take action as needed.|
03277|005|B||
03277|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03277|007|A|pitolisant via this pathway.(1)|
03277|008|B||
03277|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
03277|010|E|reduce the clinical effectiveness of pitolisant.(1)|
03277|011|B||
03277|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03277|013|P|of the inducer for longer than 1-2 weeks.|
03277|014|B||
03277|015|M|PATIENT MANAGEMENT:  The US manufacturer of pitolisant states that|
03277|016|M|concurrent use of strong CYP3A4 inducers requires a dose adjustment.  For|
03277|017|M|patients stable on pitolisant 8.9 mg or 17.8 mg, increase the dose of|
03277|018|M|pitolisant to double the original daily dose (ex 17.8 mg or 35.6 mg,|
03277|019|M|respectively) over 7 days.  If concurrent use of a strong CYP3A4 inducer is|
03277|020|M|discontinued, decrease the pitolisant dose by half.(1)|
03277|021|M|   The UK manufacturer of pitolisant states that concurrent use of strong|
03277|022|M|CYP3A4 inducers should be done with caution and dose adjustment should be|
03277|023|M|considered after during concurrent therapy and for one week after|
03277|024|M|discontinuing the inducer.(2)|
03277|025|B||
03277|026|D|DISCUSSION:  In a clinical study, concurrent use of pitolisant with rifampin|
03277|027|D|decreased the concentration maximum (Cmax) and area-under-curve (AUC) by|
03277|028|D|approximately 0.75-fold and 0.5-fold change, respectively.(1)|
03277|029|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
03277|030|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
03277|031|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St.|
03277|032|D|John's Wort.(3,4)|
03277|033|B||
03277|034|R|REFERENCES:|
03277|035|B||
03277|036|R|1.Wakix (pitolisant) tablets US prescribing information. Harmony Biosciences|1
03277|037|R|  June, 2024.|1
03277|038|R|2.Wakix (pitolisant) UK Summary of Product Characteristics. Bioproject|1
03277|039|R|  Pharma January, 2019.|1
03277|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
03277|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03277|042|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03277|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03277|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03277|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03277|046|R|  11/14/2017.|1
03278|001|T|MONOGRAPH TITLE:  Entrectinib/Strong CYP3A4 Inhibitors|
03278|002|B||
03278|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03278|004|L|of severe adverse interaction.|
03278|005|B||
03278|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03278|007|A|of entrectinib.(1,2)|
03278|008|B||
03278|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03278|010|E|in elevated levels and increased effects of entrectinib, such as QT|
03278|011|E|prolongation, hepatotoxicity, CNS effects, hyperuricemia, anemia, or|
03278|012|E|neutropenia.(1,2) Symptoms of hepatotoxicity can include nausea, vomiting,|
03278|013|E|jaundice, dark urine, abdominal pain, and unexplained fatigue.|
03278|014|B||
03278|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03278|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03278|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03278|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03278|019|P|gender, or advanced age.(2)|
03278|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03278|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03278|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03278|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03278|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03278|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03278|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03278|027|B||
03278|028|M|PATIENT MANAGEMENT:  The US manufacturer of entrectinib states that|
03278|029|M|entrectinib coadministration with strong inhibitors of CYP3A4 should be|
03278|030|M|avoided.(1)|
03278|031|M|   If concurrent therapy cannot be avoided, reduce the entrectinib dose as|
03278|032|M|follows for adult and pediatric patients 2 years and older:|
03278|033|M|   -If the starting dose is 600 mg, reduce the entrectinib dose to 100 mg|
03278|034|M|daily.|
03278|035|M|   -If the starting dose is 400 mg, reduce the entrectinib dose to 50 mg|
03278|036|M|daily.|
03278|037|M|   -If the starting dose is 300 mg, reduce the entrectinib dose to 50 mg|
03278|038|M|daily.|
03278|039|M|   -If the starting dose is 200 mg, reduce the entrectinib dose to 50 mg on|
03278|040|M|alternate days.(1)|
03278|041|M|   For pediatric patients less than 2 years old, avoid coadministration with|
03278|042|M|strong CYP3A4 inhibitors.(1)|
03278|043|M|   If concomitant use of a strong CYP3A4 inhibitor is discontinued, increase|
03278|044|M|the entrectinib dose to the dose that was used before starting the inhibitor|
03278|045|M|after three to five plasma half-lives of the strong CYP3A4 inhibitor.|
03278|046|M|   Monitor liver tests, including AST and ALT. Advise patients to|
03278|047|M|immediately report any symptoms of hepatotoxicity.|
03278|048|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
03278|049|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03278|050|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03278|051|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03278|052|M|irregular heartbeat, dizziness, or fainting.|
03278|053|B||
03278|054|D|DISCUSSION:  Coadministration of itraconazole (strong CYP3A4 inhibitor) with|
03278|055|D|a single 100 mg entrectinib dose increased entrectinib maximum concentration|
03278|056|D|(Cmax) and area-under-the-curve (AUC) by 1.7-fold and 6-fold.(1)|
03278|057|D|   Coadministration of a moderate CYP3A4 inhibitor with entrectinib is|
03278|058|D|predicted to increase entrectinib Cmax and AUC by 2.9-fold and 3-fold.|
03278|059|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, grapefruit,|
03278|060|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lopinavir,|
03278|061|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
03278|062|D|paritaprevir, telaprevir, troleandomycin, and tucatinib.(1,3)|
03278|063|B||
03278|064|R|REFERENCES:|
03278|065|B||
03278|066|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03278|067|R|  October 2023.|1
03278|068|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03278|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03278|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03278|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03278|072|R|  11/14/2017.|1
03278|073|R|3.This information is based on an extract from the Certara Drug Interaction|6
03278|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03278|075|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03278|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03278|077|R|  settings: a scientific statement from the American Heart Association and|6
03278|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03278|079|R|  2;55(9):934-47.|6
03279|001|T|MONOGRAPH TITLE:  Entrectinib/Moderate CYP3A4 Inhibitors|
03279|002|B||
03279|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03279|004|L|of severe adverse interaction.|
03279|005|B||
03279|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03279|007|A|metabolism of entrectinib.(1,2)|
03279|008|B||
03279|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
03279|010|E|result in elevated levels and increased effects of entrectinib, such as QT|
03279|011|E|prolongation, hepatotoxicity, CNS effects, hyperuricemia, anemia, or|
03279|012|E|neutropenia.(1,2) Symptoms of hepatotoxicity can include nausea, vomiting,|
03279|013|E|jaundice, dark urine, abdominal pain, and unexplained fatigue.|
03279|014|B||
03279|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03279|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03279|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03279|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03279|019|P|gender, or advanced age.(2)|
03279|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03279|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03279|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03279|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03279|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03279|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03279|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03279|027|B||
03279|028|M|PATIENT MANAGEMENT:  The US manufacturer of entrectinib states that|
03279|029|M|entrectinib coadministration with moderate inhibitors of CYP3A4 should be|
03279|030|M|avoided.(1)|
03279|031|M|   If concurrent therapy cannot be avoided, reduce the entrectinib dose as|
03279|032|M|follows for adult and pediatric patients 2 years and older:|
03279|033|M|   -If the starting dose is 600 mg, reduce the entrectinib dose to 200 mg|
03279|034|M|daily.|
03279|035|M|   -If the starting dose is 400 mg, reduce the entrectinib dose to 200 mg|
03279|036|M|daily.|
03279|037|M|   -If the starting dose is 300 mg, reduce the entrectinib dose to 100 mg|
03279|038|M|daily.|
03279|039|M|   -If the starting dose is 200 mg, reduce the entrectinib dose to 50 mg|
03279|040|M|daily.(1)|
03279|041|M|   For pediatric patients less than 2 years old, avoid coadministration with|
03279|042|M|moderate CYP3A4 inhibitors.(1)|
03279|043|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
03279|044|M|increase the entrectinib dose to the dose that was used before starting the|
03279|045|M|inhibitor after three to five plasma half-lives of the moderate CYP3A4|
03279|046|M|inhibitor.|
03279|047|M|   Monitor liver tests, including AST and ALT. Advise patients to|
03279|048|M|immediately report any symptoms of hepatotoxicity.|
03279|049|M|   During concomitant therapy with a moderate CYP3A4 inhibitor, monitor|
03279|050|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03279|051|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03279|052|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03279|053|M|irregular heartbeat, dizziness, or fainting.|
03279|054|B||
03279|055|D|DISCUSSION:  Coadministration of itraconazole (strong CYP3A4 inhibitor) with|
03279|056|D|a single 100 mg entrectinib dose increased entrectinib maximum concentration|
03279|057|D|(Cmax) and area-under-the-curve (AUC) by 1.7-fold and 6-fold.(1)|
03279|058|D|   Coadministration of a moderate CYP3A4 inhibitor with entrectinib is|
03279|059|D|predicted to increase entrectinib Cmax and AUC by 2.9-fold and 3-fold.(1)|
03279|060|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
03279|061|D|atazanavir, avacopan, berotralstat, ciprofloxacin, conivaptan, darunavir,|
03279|062|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03279|063|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
03279|064|D|lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib,|
03279|065|D|schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,3)|
03279|066|B||
03279|067|R|REFERENCES:|
03279|068|B||
03279|069|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03279|070|R|  October 2023.|1
03279|071|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03279|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03279|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03279|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03279|075|R|  11/14/2017.|1
03279|076|R|3.This information is based on an extract from the Certara Drug Interaction|6
03279|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03279|078|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03279|079|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03279|080|R|  settings: a scientific statement from the American Heart Association and|6
03279|081|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03279|082|R|  2;55(9):934-47.|6
03280|001|T|MONOGRAPH TITLE:  Entrectinib/Strong CYP3A4 Inducers|
03280|002|B||
03280|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03280|004|L|of severe adverse interaction.|
03280|005|B||
03280|006|A|MECHANISM OF ACTION:  Entrectinib is a substrate of CYP3A4.  Strong inducers|
03280|007|A|of CYP3A4 may induce the metabolism of entrectinib.(1)|
03280|008|B||
03280|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03280|010|E|may result in decreased levels and effectiveness of entrectinib.(1)|
03280|011|B||
03280|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03280|013|P|of the inducer for longer than 1-2 weeks.|
03280|014|B||
03280|015|M|PATIENT MANAGEMENT:  The manufacturer of entrectinib states that concurrent|
03280|016|M|use with strong CYP3A4 inducers should be avoided. (1)|
03280|017|B||
03280|018|D|DISCUSSION:  Concomitant administration of rifampin (strong CYP3A4 inducer)|
03280|019|D|with a single 600 mg entrectinib dose decreased entrectinib maximum|
03280|020|D|concentration (Cmax) and area-under-the-curve (AUC) by 56% and 77%.(1)|
03280|021|D|   Coadministration with a moderate CYP3A4 inducer is predicted to decrease|
03280|022|D|entrectinib's AUC and Cmax by 56% and 43%.(1)|
03280|023|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03280|024|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
03280|025|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03280|026|D|wort.(2-3)|
03280|027|B||
03280|028|R|REFERENCES:|
03280|029|B||
03280|030|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03280|031|R|  October 2023.|1
03280|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03280|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03280|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03280|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03280|036|R|  11/14/2017.|1
03280|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
03280|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03281|001|T|MONOGRAPH TITLE:  Entrectinib/Moderate CYP3A4 Inducers|
03281|002|B||
03281|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03281|004|L|of severe adverse interaction.|
03281|005|B||
03281|006|A|MECHANISM OF ACTION:  Entrectinib is a substrate of CYP3A4.  Moderate|
03281|007|A|inducers of CYP3A4 may induce the metabolism of entrectinib.(1)|
03281|008|B||
03281|009|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
03281|010|E|inducer may result in decreased levels and effectiveness of entrectinib.(1)|
03281|011|B||
03281|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03281|013|P|of the inducer for longer than 1-2 weeks.|
03281|014|B||
03281|015|M|PATIENT MANAGEMENT:  The manufacturer of entrectinib states that concurrent|
03281|016|M|use with moderate CYP3A4 inducers should be avoided. (1)|
03281|017|B||
03281|018|D|DISCUSSION:  Concomitant administration of rifampin (strong CYP3A4 inducer)|
03281|019|D|with a single 600 mg entrectinib dose decreased entrectinib maximum|
03281|020|D|concentration (Cmax) and area-under-the-curve (AUC) by 56% and 77%.(1)|
03281|021|D|   Coadministration with a moderate CYP3A4 inducer is predicted to decrease|
03281|022|D|entrectinib's AUC and Cmax by 56% and 43%.(1)|
03281|023|D|   Moderate inducers of CYP3A4 include:  belzutifan, bosentan, cenobamate,|
03281|024|D|dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib,|
03281|025|D|mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib,|
03281|026|D|rifabutin, sotorasib, telotristat, and tovorafenib.(2-3)|
03281|027|B||
03281|028|R|REFERENCES:|
03281|029|B||
03281|030|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03281|031|R|  October 2023.|1
03281|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03281|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03281|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03281|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03281|036|R|  11/14/2017.|1
03281|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
03281|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03282|001|T|MONOGRAPH TITLE:  Fedratinib/Strong CYP3A4 Inhibitors|
03282|002|B||
03282|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03282|004|L|of severe adverse interaction.|
03282|005|B||
03282|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03282|007|A|of fedratinib.(1)|
03282|008|B||
03282|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03282|010|E|in elevated levels and increased effects of fedratinib, such as neutropenia,|
03282|011|E|thrombocytopenia, hepatotoxicity, or gastrointestinal toxicity.(1) Symptoms|
03282|012|E|of hepatotoxicity can include nausea, vomiting, jaundice, dark urine,|
03282|013|E|abdominal pain, and unexplained fatigue.|
03282|014|B||
03282|015|P|PREDISPOSING FACTORS:  None determined.|
03282|016|B||
03282|017|M|PATIENT MANAGEMENT:  Consider alternative therapies that do not strongly|
03282|018|M|inhibit CYP3A4 when taking fedratinib.(1)|
03282|019|M|   Reduce the fedratinib dose to 200 mg once daily when administered|
03282|020|M|concurrently with a strong CYP3A4 inhibitor.(1)|
03282|021|M|   If the strong CYP3A4 inhibitor is discontinued, the fedratinib dose|
03282|022|M|should be increased to 300 mg once daily during the first two weeks after|
03282|023|M|discontinuation of the CYP3A4 inhibitor, and then to 400 mg once daily|
03282|024|M|thereafter as tolerated.(1)|
03282|025|M|   Monitor liver tests, including AST, ALT, and bilirubin. Advise patients|
03282|026|M|to immediately report any symptoms of hepatotoxicity.|
03282|027|B||
03282|028|D|DISCUSSION:  In a pharmacokinetic study in healthy subjects,|
03282|029|D|coadministration of ketoconazole 200 mg twice daily (strong CYP3A4|
03282|030|D|inhibitor) with a single 300 mg fedratinib dose increased fedratinib|
03282|031|D|area-under-the-curve (AUC) by 3.06-fold and maximum concentration (Cmax) by|
03282|032|D|1.93-fold.  The exposure to fedratinib was determined to be similar to the|
03282|033|D|exposure from a single 500 mg dose of fedratinib alone.(1,2)|
03282|034|D|   Based on modeling and simulation, coadministration of a strong CYP3A4|
03282|035|D|inhibitor, such as ketoconazole 400 mg once daily, with fedratinib 400 mg|
03282|036|D|once daily is predicted to increased fedratinib AUC by 2-fold.(1)|
03282|037|D|   Based on modeling and simulation, coadministration of a moderate CYP3A4|
03282|038|D|inhibitor, such as erythromycin 500 mg three times daily or diltiazem 120 mg|
03282|039|D|twice daily, with fedratinib 400 mg once daily is predicted to increased|
03282|040|D|fedratinib AUC by 1.2-fold and 1.1-fold, respectively.(1)|
03282|041|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03282|042|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03282|043|D|ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone,|
03282|044|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
03282|045|D|saquinavir, telaprevir, telithromycin, and tucatinib.(1,3,4)|
03282|046|B||
03282|047|R|REFERENCES:|
03282|048|B||
03282|049|R|1.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
03282|050|R|  May, 2023.|1
03282|051|R|2.Ogasawara K, Xu C, Kanamaluru V, Palmisano M, Krishna G. Effects of|2
03282|052|R|  repeated oral doses of ketoconazole on a sequential ascending single oral|2
03282|053|R|  dose of fedratinib in healthy subjects. Cancer Chemother Pharmacol 2020|2
03282|054|R|  Apr 4.|2
03282|055|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03282|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03282|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03282|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03282|059|R|  11/14/2017.|1
03282|060|R|4.This information is based on an extract from the Certara Drug Interaction|6
03282|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03283|001|T|MONOGRAPH TITLE:  Upadacitinib/Strong CYP3A4 Inducers|
03283|002|B||
03283|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03283|004|L|of severe adverse interaction.|
03283|005|B||
03283|006|A|MECHANISM OF ACTION:  Upadacitinib is a substrate of CYP3A4.  Strong|
03283|007|A|inducers of CYP3A4 may induce the metabolism of upadacitinib. (1)|
03283|008|B||
03283|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03283|010|E|may result in decreased levels and effectiveness of upadacitinib.(1)|
03283|011|B||
03283|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03283|013|P|of the inducer for longer than 1-2 weeks.|
03283|014|B||
03283|015|M|PATIENT MANAGEMENT:  The manufacturer of upadacitinib states that concurrent|
03283|016|M|use with strong CYP3A4 inducers is not recommended. (1)|
03283|017|B||
03283|018|D|DISCUSSION:  Concomitant administration of rifampin (600 mg once daily for 9|
03283|019|D|days, strong CYP3A4 inducer) with upadacitinib decreased upadacitinib|
03283|020|D|maximum concentration (Cmax) and area-under-the-curve (AUC) by 51% and|
03283|021|D|61%.(1)|
03283|022|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03283|023|D|carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane,|
03283|024|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03283|025|D|wort.(2-3)|
03283|026|B||
03283|027|R|REFERENCES:|
03283|028|B||
03283|029|R|1.Rinvoq (upadacitinib) US prescribing information. AbbVie Inc April, 2025.|1
03283|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03283|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03283|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03283|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03283|034|R|  11/14/2017.|1
03283|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
03283|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03284|001|T|MONOGRAPH TITLE:  Fedratinib/Strong CYP3A4 Inducers|
03284|002|B||
03284|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03284|004|L|of severe adverse interaction.|
03284|005|B||
03284|006|A|MECHANISM OF ACTION:  Fedratinib is a substrate of CYP3A4.  Strong inducers|
03284|007|A|of CYP3A4 may induce the metabolism of fedratinib.(1)|
03284|008|B||
03284|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03284|010|E|may result in decreased levels and effectiveness of fedratinib.(1)|
03284|011|B||
03284|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03284|013|P|of the inducer for longer than 1-2 weeks.|
03284|014|B||
03284|015|M|PATIENT MANAGEMENT:  The manufacturer of fedratinib states that concurrent|
03284|016|M|use with strong CYP3A4 inducers should be avoided.(1)|
03284|017|B||
03284|018|D|DISCUSSION:  Coadministration with rifampin (a strong CYP3A4 inducer)|
03284|019|D|resulted in a 70% decrease in fedratinib maximum concentration (Cmax) and an|
03284|020|D|81% decrease in fedratinib area-under-curve (AUC).(2)|
03284|021|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03284|022|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin,|
03284|023|D|primidone, rifampin, rifapentine, and St. John's wort.(3-4)|
03284|024|B||
03284|025|R|REFERENCES:|
03284|026|B||
03284|027|R|1.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
03284|028|R|  May, 2023.|1
03284|029|R|2.Ogasawara K, Kam J, Thomas M, Liu L, Liu M, Xue Y, Surapaneni S,|2
03284|030|R|  Carayannopoulos LN, Zhou S, Palmisano M, Krishna G. Effects of strong and|2
03284|031|R|  moderate CYP3A4 inducers on the pharmacokinetics of fedratinib in healthy|2
03284|032|R|  adult participants. Cancer Chemother Pharmacol. 2021 Sept;88(3):369-377.|2
03284|033|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03284|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03284|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03284|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03284|037|R|  11/14/2017.|1
03284|038|R|4.This information is based on an extract from the Certara Drug Interaction|6
03284|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03285|001|T|MONOGRAPH TITLE:  Fedratinib/Moderate CYP3A4 Inducers|
03285|002|B||
03285|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03285|004|L|of severe adverse interaction.|
03285|005|B||
03285|006|A|MECHANISM OF ACTION:  Fedratinib is a substrate of CYP3A4.  Moderate|
03285|007|A|inducers of CYP3A4 may induce the metabolism of fedratinib.(1)|
03285|008|B||
03285|009|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
03285|010|E|inducer may result in decreased levels and effectiveness of fedratinib.(1)|
03285|011|B||
03285|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03285|013|P|of the inducer for longer than 1-2 weeks.|
03285|014|B||
03285|015|M|PATIENT MANAGEMENT:  The manufacturer of fedratinib states that concurrent|
03285|016|M|use with moderate CYP3A4 inducers should be avoided.(1)|
03285|017|B||
03285|018|D|DISCUSSION:  Coadministration of efavirenz (moderate CYP3A4 inducer: 600 mg|
03285|019|D|once daily) with a single dose of fedratinib (500 mg; 1.25 times the|
03285|020|D|recommended dose) decreased the area-under-curve (AUC) of fedratinib by|
03285|021|D|approximately 47%.(1)|
03285|022|D|   Moderate inducers of CYP3A4 include:  belzutifan, cenobamate, dabrafenib,|
03285|023|D|dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil,|
03285|024|D|nafcillin, rifabutin, sotorasib, telotristat, thioridazine, and|
03285|025|D|tovorafenib.(2-3)|
03285|026|B||
03285|027|R|REFERENCES:|
03285|028|B||
03285|029|R|1.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
03285|030|R|  May, 2023.|1
03285|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03285|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03285|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03285|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03285|035|R|  11/14/2017.|1
03285|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
03285|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03286|001|T|MONOGRAPH TITLE:  Fedratinib/Dual Inhibitors of CYP2C19 & CYP3A4|
03286|002|B||
03286|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03286|004|L|take action as needed.|
03286|005|B||
03286|006|A|MECHANISM OF ACTION:  Agents that are both inhibitors of CYP2C19 and CYP3A4|
03286|007|A|may inhibit the metabolism of fedratinib.(1-2)|
03286|008|B||
03286|009|E|CLINICAL EFFECTS:  Concurrent use of a dual inhibitor of CYP2C19 and CYP3A4|
03286|010|E|may result in elevated levels of and clinical effects of fedratinib, such as|
03286|011|E|neutropenia, thrombocytopenia, hepatotoxicity, or gastrointestinal|
03286|012|E|toxicity.(1-2) Symptoms of hepatotoxicity can include nausea, vomiting,|
03286|013|E|jaundice, dark urine, abdominal pain, and unexplained fatigue.|
03286|014|B||
03286|015|P|PREDISPOSING FACTORS:  Patients with hepatic impairment may be at greater|
03286|016|P|risk of experiencing toxicity from fedratinib.|
03286|017|B||
03286|018|M|PATIENT MANAGEMENT:  The manufacturer of fedratinib states that concurrent|
03286|019|M|use of dual CYP3A4 and CYP2C19 inhibitors with fedratinib requires intensive|
03286|020|M|monitoring for adverse reactions.  Fedratinib dose may require adjustment|
03286|021|M|based on adverse reactions.(1)|
03286|022|M|   If concurrent use is necessary, monitor liver tests, including AST, ALT,|
03286|023|M|and bilirubin, renal function, complete blood count and thiamine levels.|
03286|024|M|Advise patients to immediately report any symptoms of hepatotoxicity.|
03286|025|B||
03286|026|D|DISCUSSION:  In a study, fluconazole 200 mg daily, a dual CYP3A4 and CYP2C19|
03286|027|D|inhibitor, increased the area-under-curve (AUC) of single-dose fedratinib|
03286|028|D|100 mg by 1.7-fold.(1)|
03286|029|D|   Fluconazole 200 mg daily is predicted to increase the AUC of fedratinib|
03286|030|D|400 mg daily by 1.5-fold.(1)|
03286|031|D|   Dual inhibitors of CYP2C19 and CYP3A4 linked to this monograph include|
03286|032|D|fluconazole, fluvoxamine, and stiripentol.(2-3)|
03286|033|B||
03286|034|R|REFERENCES:|
03286|035|B||
03286|036|R|1.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
03286|037|R|  May, 2023.|1
03286|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
03286|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03286|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03286|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03286|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03286|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03286|044|R|  11/14/2017.|1
03287|001|T|MONOGRAPH TITLE:  Upadacitinib/Immunosuppressives; Immunomodulators|
03287|002|B||
03287|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03287|004|L|of severe adverse interaction.|
03287|005|B||
03287|006|A|MECHANISM OF ACTION:  Upadacitinib, immunosuppressives, and immunomodulators|
03287|007|A|all suppress the immune system.|
03287|008|B||
03287|009|E|CLINICAL EFFECTS:  Concurrent use of upadacitinib with immunosuppressives or|
03287|010|E|immunomodulators may result in an increased risk of serious infections.|
03287|011|B||
03287|012|P|PREDISPOSING FACTORS:  None determined.|
03287|013|B||
03287|014|M|PATIENT MANAGEMENT:  The US manufacturer of upadacitinib states that|
03287|015|M|concurrent use of upadacitinib with immunosuppressives or immunomodulators|
03287|016|M|is not recommended.|
03287|017|B||
03287|018|D|DISCUSSION:  Serious infections have been reported in patients receiving|
03287|019|D|upadacitinib.  Reported infections included pneumonia, cellulitis,|
03287|020|D|tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis,|
03287|021|D|cryptococcosis.  Reports of viral reactivation, including herpes virus|
03287|022|D|reactivation and hepatitis B reactivation, were reported in clinical studies|
03287|023|D|with upadacitinib.(1)|
03287|024|B||
03287|025|R|REFERENCE:|
03287|026|B||
03287|027|R|1.Rinvoq (upadacitinib) US prescribing information. AbbVie Inc April, 2025.|1
03288|001|T|MONOGRAPH TITLE:  Intravenous and Oral Lefamulin/Strong CYP3A4 or|
03288|002|T|P-glycoprotein (P-gp) Inducer|
03288|003|B||
03288|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03288|005|L|of severe adverse interaction.|
03288|006|B||
03288|007|A|MECHANISM OF ACTION:  Lefamulin is a substrate of CYP3A4 and of intestinal|
03288|008|A|efflux transporter P-glycoprotein (P-gp).  Strong inducers of CYP3A4 may|
03288|009|A|induce the metabolism of lefamulin.  P-gp inducers may decrease absorption|
03288|010|A|of and exposure to lefamulin.(1)|
03288|011|B||
03288|012|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 or P-gp|
03288|013|E|inducer may result in decreased levels and effectiveness of lefamulin.(1)|
03288|014|B||
03288|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03288|016|P|of the inducer for longer than 1-2 weeks.|
03288|017|B||
03288|018|M|PATIENT MANAGEMENT:  The manufacturer of lefamulin states that concurrent|
03288|019|M|use with strong CYP3A4 or P-gp inducers should be avoided. (1)|
03288|020|B||
03288|021|D|DISCUSSION:  In a study, concurrent administration of rifampin (strong|
03288|022|D|inducer) with lefamulin injection decreased lefamulin area-under-the-curve|
03288|023|D|(AUC) and maximum concentration (Cmax) by 28% and 8%.(1)|
03288|024|D|   In a study, concurrent administration of rifampin (strong inducer) with|
03288|025|D|oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1)|
03288|026|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03288|027|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin,|
03288|028|D|primidone, rifampin, rifapentine, and St. John's wort.(2-3)|
03288|029|B||
03288|030|R|REFERENCES:|
03288|031|B||
03288|032|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03288|033|R|  Inc August 2019.|1
03288|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03288|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03288|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03288|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03288|038|R|  11/14/2017.|1
03288|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03288|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03289|001|T|MONOGRAPH TITLE:  Intravenous and Oral Lefamulin/Moderate CYP3A4 Inducers|
03289|002|B||
03289|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03289|004|L|of severe adverse interaction.|
03289|005|B||
03289|006|A|MECHANISM OF ACTION:  Lefamulin is a substrate of CYP3A4.  Moderate inducers|
03289|007|A|of CYP3A4 may induce the metabolism of lefamulin.(1)|
03289|008|A|   Oral lefamulin tablets may inhibit the metabolism of agents that are also|
03289|009|A|sensitive CYP3A4 substrates.(1-3)|
03289|010|B||
03289|011|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
03289|012|E|inducer may result in decreased levels and effectiveness of lefamulin.(1)|
03289|013|E|   Coadministration of oral lefamulin with agents that are also sensitive|
03289|014|E|CYP3A4 substrates may result in elevated levels and toxicities of the|
03289|015|E|sensitive CYP3A4 substrate.|
03289|016|B||
03289|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03289|018|P|of the inducer for longer than 1-2 weeks.|
03289|019|B||
03289|020|M|PATIENT MANAGEMENT:  The manufacturer of lefamulin states that concurrent|
03289|021|M|use with moderate CYP3A4 inducers should be avoided.(1)|
03289|022|M|   Concomitant use of lefamulin tablets with sensitive CYP3A4 substrates|
03289|023|M|requires close monitoring for adverse effects of these drugs.(1)|
03289|024|B||
03289|025|D|DISCUSSION:  In a study, concurrent administration of rifampin (a strong|
03289|026|D|inducer) with lefamulin injection decreased lefamulin area-under-the-curve|
03289|027|D|(AUC) and maximum concentration (Cmax) by 28% and 8%.(1)|
03289|028|D|   In a study, concurrent administration of rifampin (a strong inducer) with|
03289|029|D|oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1)|
03289|030|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
03289|031|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the|
03289|032|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200%|
03289|033|D|and 100%, respectively.  No clinically significant effect on midazolam|
03289|034|D|pharmacokinetics was observed when co-administered with lefamulin|
03289|035|D|injection.(1)|
03289|036|D|   Moderate inducers of CYP3A4 include:  belzutifan, bosentan, cenobamate,|
03289|037|D|dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib,|
03289|038|D|modafinil, nafcillin, rifabutin, telotristat, and tovorafenib.(2-3)|
03289|039|B||
03289|040|R|REFERENCES:|
03289|041|B||
03289|042|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03289|043|R|  Inc August 2019.|1
03289|044|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03289|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03289|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03289|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03289|048|R|  11/14/2017.|1
03289|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
03289|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03290|001|T|MONOGRAPH TITLE:  Oral Lefamulin/Selected Strong CYP3A4 Inhibitors|
03290|002|B||
03290|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03290|004|L|of severe adverse interaction.|
03290|005|B||
03290|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03290|007|A|of lefamulin.(1,2)|
03290|008|A|   Oral lefamulin tablets may inhibit the metabolism of CYP3A4 inhibitors|
03290|009|A|that are also sensitive CYP3A4 substrates (i.e., indinavir).(1-3)|
03290|010|B||
03290|011|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03290|012|E|in elevated levels and increased effects of lefamulin, such as QT|
03290|013|E|prolongation.|
03290|014|E|   Coadministration of oral lefamulin with agents that are also sensitive|
03290|015|E|CYP3A4 substrates (i.e., indinavir, lopinavir) may result in elevated levels|
03290|016|E|and toxicities of the sensitive CYP3A4 substrate.|
03290|017|B||
03290|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03290|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03290|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03290|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03290|022|P|gender, or advanced age.(2)|
03290|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03290|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03290|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03290|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03290|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03290|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03290|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03290|030|B||
03290|031|M|PATIENT MANAGEMENT:  The US manufacturer of lefamulin states that oral|
03290|032|M|lefamulin tablet coadministration with strong inhibitors of CYP3A4 should be|
03290|033|M|avoided.(1)|
03290|034|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
03290|035|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03290|036|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03290|037|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03290|038|M|irregular heartbeat, dizziness, or fainting.|
03290|039|M|   Concomitant use of conivaptan, indinavir, or lopinavir requires close|
03290|040|M|monitoring for adverse effects of these drugs.(1)|
03290|041|B||
03290|042|D|DISCUSSION:  Coadministration of ketoconazole (a strong CYP3A4 and|
03290|043|D|P-glycoprotein inhibitor) with lefamulin tablets increased lefamulin|
03290|044|D|area-under-the-curve (AUC) and maximum concentration (Cmax) by 165% and|
03290|045|D|58%.(1)|
03290|046|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
03290|047|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the|
03290|048|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200%|
03290|049|D|and 100%, respectively.  No clinically significant effect on midazolam|
03290|050|D|pharmacokinetics was observed when co-administered with lefamulin|
03290|051|D|injection.(1)|
03290|052|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
03290|053|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03290|054|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03290|055|D|troleandomycin, and tucatinib.(1,3)|
03290|056|B||
03290|057|R|REFERENCES:|
03290|058|B||
03290|059|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03290|060|R|  Inc August 2019.|1
03290|061|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03290|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03290|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03290|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03290|065|R|  11/14/2017.|1
03290|066|R|3.This information is based on an extract from the Certara Drug Interaction|6
03290|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03290|068|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03290|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03290|070|R|  settings: a scientific statement from the American Heart Association and|6
03290|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03290|072|R|  2;55(9):934-47.|6
03291|001|T|MONOGRAPH TITLE:  Oral Lefamulin/Moderate CYP3A4 Inhibitors|
03291|002|B||
03291|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03291|004|L|take action as needed.|
03291|005|B||
03291|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03291|007|A|metabolism of oral lefamulin.(1,2)|
03291|008|B||
03291|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
03291|010|E|result in elevated levels and increased effects of lefamulin, such as QT|
03291|011|E|prolongation.|
03291|012|B||
03291|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03291|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03291|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03291|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03291|017|P|gender, or advanced age.(2)|
03291|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03291|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03291|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03291|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03291|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03291|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03291|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03291|025|B||
03291|026|M|PATIENT MANAGEMENT:  The US manufacturer of lefamulin states that oral|
03291|027|M|lefamulin coadministration with moderate inhibitors of CYP3A4 should be|
03291|028|M|monitored for adverse effects.(1)|
03291|029|M|   During concomitant therapy with a moderate CYP3A4 inhibitor, monitor|
03291|030|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03291|031|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03291|032|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03291|033|M|irregular heartbeat, dizziness, or fainting.|
03291|034|B||
03291|035|D|DISCUSSION:  Coadministration of ketoconazole (strong CYP3A4 inhibitor) with|
03291|036|D|lefamulin tablets increased lefamulin area-under-the-curve (AUC) and maximum|
03291|037|D|concentration (Cmax) by 165% and 58%.(1)|
03291|038|D|   Moderate inhibitors of CYP3A4 include: amprenavir, avacopan, conivaptan,|
03291|039|D|duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, lenacapavir,|
03291|040|D|letermovir, netupitant, schisandra, stiripentol, tofisopam, and|
03291|041|D|treosulfan.(1,3)|
03291|042|B||
03291|043|R|REFERENCES:|
03291|044|B||
03291|045|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03291|046|R|  Inc August 2019.|1
03291|047|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03291|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03291|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03291|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03291|051|R|  11/14/2017.|1
03291|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
03291|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03291|054|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03291|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03291|056|R|  settings: a scientific statement from the American Heart Association and|6
03291|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03291|058|R|  2;55(9):934-47.|6
03292|001|T|MONOGRAPH TITLE:  Fedratinib/Voriconazole|
03292|002|B||
03292|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03292|004|L|of severe adverse interaction.|
03292|005|B||
03292|006|A|MECHANISM OF ACTION:  Voriconazole is a dual inhibitor of CYP2C19 and CYP3A4|
03292|007|A|and may inhibit the metabolism of fedratinib, a substrate of CYP2C19 and|
03292|008|A|CYP3A4.(1)|
03292|009|B||
03292|010|E|CLINICAL EFFECTS:  Concurrent use of voriconazole with fedratinib may result|
03292|011|E|in elevated levels and clinical effects of fedratinib, such as neutropenia,|
03292|012|E|thrombocytopenia, hepatotoxicity, or gastrointestinal toxicity.(1-2)|
03292|013|E|Symptoms of hepatotoxicity can include nausea, vomiting, jaundice, dark|
03292|014|E|urine, abdominal pain, and unexplained fatigue.|
03292|015|B||
03292|016|P|PREDISPOSING FACTORS:  Patients with hepatic impairment may be at greater|
03292|017|P|risk of experiencing toxicity from fedratinib.|
03292|018|B||
03292|019|M|PATIENT MANAGEMENT:  The manufacturer of fedratinib states that concurrent|
03292|020|M|use with dual CYP3A4 and CYP2C19 inhibitors, such as voriconazole, should be|
03292|021|M|avoided.(1)|
03292|022|M|   If concurrent administration cannot be avoided, reduce the fedratinib|
03292|023|M|dose to 200 mg once daily when administered concurrently with|
03292|024|M|voriconazole.(1)|
03292|025|M|   If voriconazole is discontinued, the fedratinib dose should be increased|
03292|026|M|to 300 mg once daily during the first two weeks after discontinuation of|
03292|027|M|voriconazole, and then to 400 mg once daily thereafter as tolerated.(1)|
03292|028|M|   Monitor liver tests, including AST, ALT, and bilirubin. Advise patients|
03292|029|M|to immediately report any symptoms of hepatotoxicity.|
03292|030|B||
03292|031|D|DISCUSSION:  Coadministration of ketoconazole 200 mg twice daily (strong|
03292|032|D|CYP3A4 inhibitor) with a single 300 mg fedratinib dose increased fedratinib|
03292|033|D|area-under-the-curve (AUC) by 3-fold.(1)|
03292|034|D|   Based on modeling and simulation, coadministration of a strong CYP3A4|
03292|035|D|inhibitor, such as ketoconazole 400 mg once daily, with fedratinib 400 mg|
03292|036|D|once daily is predicted to increased fedratinib AUC by 2-fold.(1)|
03292|037|D|   Based on modeling and simulation, coadministration of a moderate CYP3A4|
03292|038|D|inhibitor, such as erythromycin 500 mg three times daily or diltiazem 120 mg|
03292|039|D|twice daily, with fedratinib 400 mg once daily is predicted to increased|
03292|040|D|fedratinib AUC by 1.2-fold and 1.1-fold, respectively.(1)|
03292|041|D|   The effect of concurrent administration of dual CYP3A4 inhibitors and|
03292|042|D|CYP2C19 inhibitors with fedratinib has not been studied. Fedratinib is a|
03292|043|D|substrate of CYP3A4 and CYP2C19.(1)|
03292|044|B||
03292|045|R|REFERENCES:|
03292|046|B||
03292|047|R|1.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
03292|048|R|  May, 2023.|1
03292|049|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03292|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03292|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03292|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03292|053|R|  11/14/2017.|1
03292|054|R|3.This information is based on an extract from the Certara Drug Interaction|6
03292|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03293|001|T|MONOGRAPH TITLE:  Oral Lefamulin/P-glycoprotein (P-gp) Inhibitors|
03293|002|B||
03293|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03293|004|L|of severe adverse interaction.|
03293|005|B||
03293|006|A|MECHANISM OF ACTION:  Inhibitors of P-glycoprotein (P-gp) may increase the|
03293|007|A|absorption of lefamulin.(1)|
03293|008|A|   Oral lefamulin tablets may inhibit the metabolism of P-gp inhibitors that|
03293|009|A|are also sensitive CYP3A4 substrates (i.e., asunaprevir, felodipine,|
03293|010|A|ivacaftor, and neratinib).(1-3)|
03293|011|B||
03293|012|E|CLINICAL EFFECTS:  The concurrent administration of lefamulin with an|
03293|013|E|inhibitor of P-gp may result in elevated levels of lefamulin and signs of|
03293|014|E|toxicity, such as QT prolongation.|
03293|015|E|   Coadministration of oral lefamulin with agents that are also sensitive|
03293|016|E|CYP3A4 substrates (i.e., asunaprevir, felodipine, ivacaftor, and neratinib)|
03293|017|E|may result in elevated levels and toxicities of the sensitive CYP3A4|
03293|018|E|substrate.|
03293|019|B||
03293|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03293|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03293|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03293|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03293|024|P|gender, or advanced age.(4)|
03293|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03293|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03293|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03293|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03293|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03293|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03293|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03293|032|B||
03293|033|M|PATIENT MANAGEMENT:  The US manufacturer of lefamulin states that oral|
03293|034|M|lefamulin tablet coadministration with P-gp inhibitors should be avoided.(1)|
03293|035|M|   If concomitant therapy with a P-gp inhibitor is necessary, monitor|
03293|036|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03293|037|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03293|038|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03293|039|M|irregular heartbeat, dizziness, or fainting.|
03293|040|M|   Concomitant use of asunaprevir, felodipine, ivacaftor, or neratinib|
03293|041|M|requires close monitoring for adverse effects of these drugs.(1)|
03293|042|M|   The manufacturer of venetoclax states that if concurrent use with a P-gp|
03293|043|M|substrate cannot be avoided, take lefamulin at least 6 hours before|
03293|044|M|venetoclax.(5)|
03293|045|B||
03293|046|D|DISCUSSION:  Coadministration of ketoconazole (a strong CYP3A4 and P-gp|
03293|047|D|inhibitor) with lefamulin tablets increased lefamulin area-under-the-curve|
03293|048|D|(AUC) and maximum concentration (Cmax) by 165% and 58%.(1)|
03293|049|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
03293|050|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the|
03293|051|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200%|
03293|052|D|and 100%, respectively.  No clinically significant effect on midazolam|
03293|053|D|pharmacokinetics was observed when co-administered with lefamulin|
03293|054|D|injection.(1)|
03293|055|D|   P-gp inhibitors include:  asunaprevir, belumosudil, capmatinib,|
03293|056|D|carvedilol, cimetidine, danicopan, daridorexant, diosmin, flibanserin,|
03293|057|D|fluvoxamine, fostamatinib, ginseng, glecaprevir/pibrentasvir,|
03293|058|D|hydroquinidine, ivacaftor, ledipasvir, neratinib, pirtobrutinib,|
03293|059|D|propafenone, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine,|
03293|060|D|venetoclax, vimseltinib, and voclosporin.(1-3)|
03293|061|B||
03293|062|R|REFERENCES:|
03293|063|B||
03293|064|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03293|065|R|  Inc August 2019.|1
03293|066|R|2.This information is based on an extract from the Certara Drug Interaction|6
03293|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03293|068|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03293|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03293|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03293|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03293|072|R|  11/14/2017.|1
03293|073|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03293|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03293|075|R|  settings: a scientific statement from the American Heart Association and|6
03293|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03293|077|R|  2;55(9):934-47.|6
03293|078|R|5.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
03293|079|R|  2021.|1
03294|001|T|MONOGRAPH TITLE:  Entrectinib/QT Prolonging Agents|
03294|002|B||
03294|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03294|004|L|of severe adverse interaction.|
03294|005|B||
03294|006|A|MECHANISM OF ACTION:  Concurrent use of entrectinib with agents that prolong|
03294|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03294|008|B||
03294|009|E|CLINICAL EFFECTS:  The concurrent use of entrectinib with agents that|
03294|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03294|011|E|arrhythmias, including torsades de pointes.(1)|
03294|012|B||
03294|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03294|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03294|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03294|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03294|017|P|female gender, or advanced age.(2)|
03294|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03294|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03294|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03294|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03294|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03294|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03294|024|P|dysfunction).(2)|
03294|025|B||
03294|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of entrectinib with|
03294|027|M|medications that prolong the QT interval.(1)|
03294|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03294|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03294|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
03294|031|M|and periodically monitor during therapy.  Correct any electrolyte|
03294|032|M|abnormalities.|
03294|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03294|034|M|fainting.|
03294|035|M|   If QTc prolongation develops:|
03294|036|M|   ---Monitor and supplement electrolytes as clinically indicated|
03294|037|M|   ---Review and adjust concomitant QT prolonging medications|
03294|038|M|   ---Interrupt entrectinib therapy for QTc interval greater than 500 ms.|
03294|039|M|   ---Follow labeling recommendations regarding restarting entrectinib.(1)|
03294|040|M|   If torsade de pointes, polymorphic ventricular tachycardia, and/or|
03294|041|M|signs/symptoms of serious arrhythmia occur, permanently discontinue|
03294|042|M|entrectinib.(1)|
03294|043|B||
03294|044|D|DISCUSSION:  In clinical trials, 3.1% of patients with at least one|
03294|045|D|post-baseline ECG experienced QTcF prolongation of greater than 60 msec|
03294|046|D|after starting entrectinib..(1)|
03294|047|D|   Agents that are linked to this monograph may have varying degrees of|
03294|048|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03294|049|D|been shown to prolong the QTc interval either through their mechanism of|
03294|050|D|action, through studies on their effects on the QTc interval, or through|
03294|051|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03294|052|D|and/or postmarketing reports.(3)|
03294|053|B||
03294|054|R|REFERENCES:|
03294|055|B||
03294|056|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03294|057|R|  October 2023.|1
03294|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03294|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03294|060|R|  settings: a scientific statement from the American Heart Association and|6
03294|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03294|062|R|  2;55(9):934-47.|6
03294|063|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03294|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03294|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03294|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03295|001|T|MONOGRAPH TITLE:  Entrectinib/Possible QT Prolonging Agents|
03295|002|B||
03295|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03295|004|L|take action as needed.|
03295|005|B||
03295|006|A|MECHANISM OF ACTION:  Concurrent use of entrectinib with agents that prolong|
03295|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03295|008|B||
03295|009|E|CLINICAL EFFECTS:  The concurrent use of entrectinib with agents that|
03295|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03295|011|E|arrhythmias, including torsades de pointes.(1)|
03295|012|B||
03295|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03295|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03295|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03295|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03295|017|P|female gender, or advanced age.(2)|
03295|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03295|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03295|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03295|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03295|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03295|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03295|024|P|dysfunction).(2)|
03295|025|B||
03295|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of entrectinib with|
03295|027|M|medications that prolong the QT interval.(1)|
03295|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03295|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03295|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
03295|031|M|and periodically monitor during therapy.  Correct any electrolyte|
03295|032|M|abnormalities.|
03295|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03295|034|M|fainting.|
03295|035|M|   If QTc prolongation develops:|
03295|036|M|   ---Monitor and supplement electrolytes as clinically indicated|
03295|037|M|   ---Review and adjust concomitant QT prolonging medications|
03295|038|M|   ---Interrupt entrectinib therapy for QTc interval greater than 500 ms.|
03295|039|M|   ---Follow labeling recommendations regarding restarting entrectinib.(1)|
03295|040|M|   If torsade de pointes, polymorphic ventricular tachycardia, and/or|
03295|041|M|signs/symptoms of serious arrhythmia occur, permanently discontinue|
03295|042|M|entrectinib.(1)|
03295|043|B||
03295|044|D|DISCUSSION:  In clinical trials, 3.1% of patients with at least one|
03295|045|D|post-baseline ECG experienced QTcF prolongation of greater than 60 msec|
03295|046|D|after starting entrectinib..(1)|
03295|047|D|   Agents that are linked to this monograph may have varying degrees of|
03295|048|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03295|049|D|been shown to prolong the QTc interval either through their mechanism of|
03295|050|D|action, through studies on their effects on the QTc interval, or through|
03295|051|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03295|052|D|and/or postmarketing reports.(3)|
03295|053|B||
03295|054|R|REFERENCES:|
03295|055|B||
03295|056|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03295|057|R|  October 2023.|1
03295|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03295|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03295|060|R|  settings: a scientific statement from the American Heart Association and|6
03295|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03295|062|R|  2;55(9):934-47.|6
03295|063|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03295|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03295|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03295|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03296|001|T|MONOGRAPH TITLE:  Entrectinib/Strong CYP3A4 Inhibitors that Prolong QT|
03296|002|B||
03296|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03296|004|L|of severe adverse interaction.|
03296|005|B||
03296|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QT|
03296|007|A|interval may inhibit the metabolism of entrectinib(1,2) and result in|
03296|008|A|additive effects on the QT interval.(1)|
03296|009|B||
03296|010|E|CLINICAL EFFECTS:  The concurrent use of entrectinib with strong inhibitors|
03296|011|E|of CYP3A4 that prolong the QTc interval may result in elevated levels of and|
03296|012|E|effects from entrectinib, including potentially life-threatening cardiac|
03296|013|E|arrhythmias, including torsades de pointes, hepatotoxicity, CNS effects,|
03296|014|E|hyperuricemia, anemia, or neutropenia.(1,2) Symptoms of hepatotoxicity can|
03296|015|E|include nausea, vomiting, jaundice, dark urine, abdominal pain, and|
03296|016|E|unexplained fatigue.(1)|
03296|017|B||
03296|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03296|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03296|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03296|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03296|022|P|female gender, or advanced age.(2)|
03296|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03296|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03296|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03296|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03296|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03296|028|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03296|029|P|dysfunction).(2)|
03296|030|B||
03296|031|M|PATIENT MANAGEMENT:  Avoid the concurrent use of entrectinib with|
03296|032|M|medications that inhibit CYP3A4 and prolong the QT interval.(1)|
03296|033|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03296|034|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03296|035|M|treatment, after initiation of any drug known to prolong the QT interval,|
03296|036|M|and periodically monitor during therapy.  Correct any electrolyte|
03296|037|M|abnormalities.  Monitor liver tests, including AST and ALT.|
03296|038|M|   For adult and pediatric patients 2 years and older, reduce the|
03296|039|M|entrectinib dose as follows:|
03296|040|M|   -If the starting dose is 600 mg, reduce the entrectinib dose to 100 mg|
03296|041|M|daily.|
03296|042|M|   -If the starting dose is 400 mg, reduce the entrectinib dose to 50 mg|
03296|043|M|daily.|
03296|044|M|   -If the starting dose is 300 mg, reduce the entrectinib dose to 50 mg|
03296|045|M|daily.|
03296|046|M|   -If the starting dose is 200 mg, reduce the entrectinib dose to 50 mg on|
03296|047|M|alternate days.(1)|
03296|048|M|   For pediatric patients less than 2 years old, avoid coadministration with|
03296|049|M|strong CYP3A4 inhibitors.(1)|
03296|050|M|   If concomitant use is discontinued, increase the entrectinib dose to the|
03296|051|M|dose that was used before starting the inhibitor after three to five plasma|
03296|052|M|half-lives of the strong CYP3A4 inhibitor.|
03296|053|M|   Advise patients to immediately report any symptoms of hepatotoxicity and|
03296|054|M|any irregular heartbeat, dizziness, or fainting.|
03296|055|M|   If QTc prolongation develops:|
03296|056|M|   ---Monitor and supplement electrolytes as clinically indicated|
03296|057|M|   ---Review and adjust concomitant QT prolonging medications|
03296|058|M|   ---Interrupt entrectinib therapy for QTc interval greater than 500 ms.|
03296|059|M|   ---Follow labeling recommendations regarding restarting entrectinib.(1)|
03296|060|M|   If torsade de pointes, polymorphic ventricular tachycardia, and/or|
03296|061|M|signs/symptoms of serious arrhythmia occur, permanently discontinue|
03296|062|M|entrectinib.(1)|
03296|063|B||
03296|064|D|DISCUSSION:  In clinical trials, 3.1% of patients with at least one|
03296|065|D|post-baseline ECG experienced QTcF prolongation of greater than 60 msec|
03296|066|D|after starting entrectinib.(1)|
03296|067|D|   Coadministration of itraconazole (strong CYP3A4 inhibitor) with a single|
03296|068|D|100 mg entrectinib dose increased entrectinib maximum concentration (Cmax)|
03296|069|D|and area-under-the-curve (AUC) by 1.7-fold and 6-fold.(1)|
03296|070|D|   Coadministration of a moderate CYP3A4 inhibitor with entrectinib is|
03296|071|D|predicted to increase entrectinib Cmax and AUC by 2.9-fold and 3-fold.|
03296|072|D|   Agents that are linked to this monograph may have varying degrees of|
03296|073|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03296|074|D|been shown to prolong the QTc interval either through their mechanism of|
03296|075|D|action, through studies on their effects on the QTc interval, or through|
03296|076|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03296|077|D|and/or postmarketing reports.(3)|
03296|078|B||
03296|079|R|REFERENCES:|
03296|080|B||
03296|081|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03296|082|R|  October 2023.|1
03296|083|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03296|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03296|085|R|  settings: a scientific statement from the American Heart Association and|6
03296|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03296|087|R|  2;55(9):934-47.|6
03296|088|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03296|089|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03296|090|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03296|091|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03297|001|T|MONOGRAPH TITLE:  Entrectinib/Moderate CYP3A4 Inhibitors that Prolong QT|
03297|002|B||
03297|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03297|004|L|of severe adverse interaction.|
03297|005|B||
03297|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong the QT|
03297|007|A|interval may inhibit the metabolism of entrectinib(1,2) and result in|
03297|008|A|additive effects on the QT interval.(1)|
03297|009|B||
03297|010|E|CLINICAL EFFECTS:  The concurrent use of entrectinib with moderate|
03297|011|E|inhibitors of CYP3A4 that prolong the QTc interval may result in elevated|
03297|012|E|levels of and effects from entrectinib, including potentially|
03297|013|E|life-threatening cardiac arrhythmias, including torsades de pointes,|
03297|014|E|hepatotoxicity, CNS effects, hyperuricemia, anemia, or neutropenia.(1,2)|
03297|015|E|Symptoms of hepatotoxicity can include nausea, vomiting, jaundice, dark|
03297|016|E|urine, abdominal pain, and unexplained fatigue.(1)|
03297|017|B||
03297|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03297|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03297|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03297|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03297|022|P|female gender, or advanced age.(2)|
03297|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03297|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03297|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03297|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03297|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03297|028|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03297|029|P|dysfunction).(2)|
03297|030|B||
03297|031|M|PATIENT MANAGEMENT:  Avoid the concurrent use of entrectinib with|
03297|032|M|medications that inhibit CYP3A4 and prolong the QT interval.(1)|
03297|033|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03297|034|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03297|035|M|treatment, after initiation of any drug known to prolong the QT interval,|
03297|036|M|and periodically monitor during therapy.  Correct any electrolyte|
03297|037|M|abnormalities.  Monitor liver tests, including AST and ALT.|
03297|038|M|   For adult and pediatric patients 2 years and older, reduce the|
03297|039|M|entrectinib dose as follows:|
03297|040|M|   -If the starting dose is 600 mg, reduce the entrectinib dose to 200 mg|
03297|041|M|daily.|
03297|042|M|   -If the starting dose is 400 mg, reduce the entrectinib dose to 200 mg|
03297|043|M|daily.|
03297|044|M|   -If the starting dose is 300 mg, reduce the entrectinib dose to 100 mg|
03297|045|M|daily.|
03297|046|M|   -If the starting dose is 200 mg, reduce the entrectinib dose to 50 mg|
03297|047|M|daily.(1)|
03297|048|M|   For pediatric patients less than 2 years old, avoid coadministration with|
03297|049|M|moderate CYP3A4 inhibitors.(1)|
03297|050|M|   If concomitant use is discontinued, increase the entrectinib dose to the|
03297|051|M|dose that was used before starting the inhibitor after three to five plasma|
03297|052|M|half-lives of the moderate CYP3A4 inhibitor.|
03297|053|M|   Advise patients to immediately report any symptoms of hepatotoxicity and|
03297|054|M|any irregular heartbeat, dizziness, or fainting.|
03297|055|M|   If QTc prolongation develops:|
03297|056|M|   ---Monitor and supplement electrolytes as clinically indicated|
03297|057|M|   ---Review and adjust concomitant QT prolonging medications|
03297|058|M|   ---Interrupt entrectinib therapy for QTc interval greater than 500 ms.|
03297|059|M|   ---Follow labeling recommendations regarding restarting entrectinib.(1)|
03297|060|M|   If torsade de pointes, polymorphic ventricular tachycardia, and/or|
03297|061|M|signs/symptoms of serious arrhythmia occur, permanently discontinue|
03297|062|M|entrectinib.(1)|
03297|063|B||
03297|064|D|DISCUSSION:  In clinical trials, 3.1% of patients with at least one|
03297|065|D|post-baseline ECG experienced QTcF prolongation of greater than 60 msec|
03297|066|D|after starting entrectinib.(1)|
03297|067|D|   Coadministration of itraconazole (strong CYP3A4 inhibitor) with a single|
03297|068|D|100 mg entrectinib dose increased entrectinib maximum concentration (Cmax)|
03297|069|D|and area-under-the-curve (AUC) by 1.7-fold and 6-fold.(1)|
03297|070|D|   Coadministration of a moderate CYP3A4 inhibitor with entrectinib is|
03297|071|D|predicted to increase entrectinib Cmax and AUC by 2.9-fold and 3-fold.|
03297|072|D|   Agents that are linked to this monograph may have varying degrees of|
03297|073|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03297|074|D|been shown to prolong the QTc interval either through their mechanism of|
03297|075|D|action, through studies on their effects on the QTc interval, or through|
03297|076|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03297|077|D|and/or postmarketing reports.(3)|
03297|078|B||
03297|079|R|REFERENCES:|
03297|080|B||
03297|081|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03297|082|R|  October 2023.|1
03297|083|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03297|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03297|085|R|  settings: a scientific statement from the American Heart Association and|6
03297|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03297|087|R|  2;55(9):934-47.|6
03297|088|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03297|089|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03297|090|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03297|091|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03298|001|T|MONOGRAPH TITLE:  Lefamulin/QT Prolonging Agents|
03298|002|B||
03298|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03298|004|L|of severe adverse interaction.|
03298|005|B||
03298|006|A|MECHANISM OF ACTION:  Concurrent use of lefamulin with agents that prolong|
03298|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03298|008|B||
03298|009|E|CLINICAL EFFECTS:  The concurrent use of lefamulin with agents that prolong|
03298|010|E|the QTc interval may result in potentially life-threatening cardiac|
03298|011|E|arrhythmias, including torsades de pointes.(1)|
03298|012|B||
03298|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03298|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03298|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03298|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03298|017|P|female gender, or advanced age.(2)|
03298|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03298|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03298|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03298|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03298|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03298|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03298|024|P|dysfunction).(2)|
03298|025|B||
03298|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of lefamulin with medications|
03298|027|M|that prolong the QT interval.(1)|
03298|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03298|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03298|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
03298|031|M|and periodically monitor during therapy.  Correct any electrolyte|
03298|032|M|abnormalities.(1)|
03298|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03298|034|M|fainting.|
03298|035|B||
03298|036|D|DISCUSSION:  In a thorough QT study, intravenous lefamulin increased the|
03298|037|D|QTcF 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF by|
03298|038|D|9.3 msec (90% CI = 10.9 msec).(1)|
03298|039|D|   Agents that are linked to this monograph may have varying degrees of|
03298|040|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03298|041|D|been shown to prolong the QTc interval either through their mechanism of|
03298|042|D|action, through studies on their effects on the QTc interval, or through|
03298|043|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03298|044|D|and/or postmarketing reports.(3)|
03298|045|B||
03298|046|R|REFERENCES:|
03298|047|B||
03298|048|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03298|049|R|  Inc August 2019.|1
03298|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03298|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03298|052|R|  settings: a scientific statement from the American Heart Association and|6
03298|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03298|054|R|  2;55(9):934-47.|6
03298|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03298|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03298|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03298|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03299|001|T|MONOGRAPH TITLE:  Lefamulin/Possible QT Prolonging Agents|
03299|002|B||
03299|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03299|004|L|take action as needed.|
03299|005|B||
03299|006|A|MECHANISM OF ACTION:  Concurrent use of lefamulin with agents that prolong|
03299|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03299|008|B||
03299|009|E|CLINICAL EFFECTS:  The concurrent use of lefamulin with agents that prolong|
03299|010|E|the QTc interval may result in potentially life-threatening cardiac|
03299|011|E|arrhythmias, including torsades de pointes.(1)|
03299|012|B||
03299|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03299|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03299|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03299|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03299|017|P|female gender, or advanced age.(2)|
03299|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03299|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03299|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03299|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03299|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03299|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03299|024|P|dysfunction).(2)|
03299|025|B||
03299|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of lefamulin with medications|
03299|027|M|that prolong the QT interval.(1)|
03299|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03299|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03299|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
03299|031|M|and periodically monitor during therapy.  Correct any electrolyte|
03299|032|M|abnormalities.(1)|
03299|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03299|034|M|fainting.|
03299|035|B||
03299|036|D|DISCUSSION:  In a thorough QT study, intravenous lefamulin increased the|
03299|037|D|QTcF 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF by|
03299|038|D|9.3 msec (90% CI = 10.9 msec).(1)|
03299|039|D|   Agents that are linked to this monograph may have varying degrees of|
03299|040|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03299|041|D|been shown to prolong the QTc interval either through their mechanism of|
03299|042|D|action, through studies on their effects on the QTc interval, or through|
03299|043|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03299|044|D|and/or postmarketing reports.(3)|
03299|045|B||
03299|046|R|REFERENCES:|
03299|047|B||
03299|048|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03299|049|R|  Inc August 2019.|1
03299|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03299|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03299|052|R|  settings: a scientific statement from the American Heart Association and|6
03299|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03299|054|R|  2;55(9):934-47.|6
03299|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03299|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03299|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03299|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03300|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP3A4 Substrates/Oral Lefamulin|
03300|002|B||
03300|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03300|004|L|of severe adverse interaction.|
03300|005|B||
03300|006|A|MECHANISM OF ACTION:  Lefamulin is considered a moderate inhibitor of|
03300|007|A|CYP3A4.  FDA defines a moderate inhibitor as a drug which increases the|
03300|008|A|area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,4)|
03300|009|B||
03300|010|E|CLINICAL EFFECTS:  Concurrent use of oral lefamulin may lead to increased|
03300|011|E|serum levels and adverse effects of drugs sensitive to inhibition of the|
03300|012|E|CYP3A4 pathway.(1)|
03300|013|B||
03300|014|P|PREDISPOSING FACTORS:  With darifenacin, the risk of anticholinergic|
03300|015|P|toxicities including cognitive decline, delirium, falls and fractures is|
03300|016|P|increased in geriatric patients using more than one medicine with|
03300|017|P|anticholinergic properties.(5)|
03300|018|B||
03300|019|M|PATIENT MANAGEMENT:  If oral lefamulin must be coadministered with a|
03300|020|M|sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse|
03300|021|M|effects of the CYP3A4 substrate.(1)|
03300|022|M|   Drug-specific recommendations:|
03300|023|M|   The manufacturer of abemaciclib recommends monitoring for adverse|
03300|024|M|reactions and considering a dose reduction of abemaciclib in 50 mg|
03300|025|M|decrements as detailed in prescribing information (based on starting dose,|
03300|026|M|previous dose reductions, and combination or monotherapy use) with|
03300|027|M|concurrent use of moderate CYP3A4 inhibitors.(2)|
03300|028|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
03300|029|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
03300|030|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
03300|031|M|inhibitors should be avoided.(3)|
03300|032|B||
03300|033|D|DISCUSSION:  In a study, oral lefamulin tablets administered concomitantly|
03300|034|D|with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate)|
03300|035|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03300|036|D|midazolam by 200% and 100%, respectively.  No clinically significant effect|
03300|037|D|on midazolam pharmacokinetics was observed when co-administered with|
03300|038|D|lefamulin injection.(1)|
03300|039|D|   Sensitive CYP3A4 substrates linked to this monograph include:|
03300|040|D|abemaciclib, acalabrutinib, alfentanil, alprazolam, atorvastatin,|
03300|041|D|brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine,|
03300|042|D|eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc,|
03300|043|D|midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, sirolimus,|
03300|044|D|ticagrelor, triazolam, and ulipristal.(1,4,6)|
03300|045|B||
03300|046|R|REFERENCES:|
03300|047|B||
03300|048|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03300|049|R|  Inc August 2019.|1
03300|050|R|2.Verzenio (abemaciclib) US prescribing information. Eli Lilly and Company|1
03300|051|R|  October, 2021.|1
03300|052|R|3.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
03300|053|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
03300|054|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03300|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03300|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03300|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03300|058|R|  11/14/2017.|1
03300|059|R|5.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03300|060|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03300|061|R|  Soc 2023 Jul;71(7):2052-2081.|6
03300|062|R|6.This information is based on an extract from the Certara Drug Interaction|6
03300|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03301|001|T|MONOGRAPH TITLE:  Oral Lefamulin/Strong & Mod CYP3A4 Inhibitor that Prolong|
03301|002|T|QT|
03301|003|B||
03301|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03301|005|L|of severe adverse interaction.|
03301|006|B||
03301|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 that prolong the QT interval may|
03301|008|A|inhibit the metabolism of oral lefamulin and may result in additive effects|
03301|009|A|on the QTc interval.(1)|
03301|010|B||
03301|011|E|CLINICAL EFFECTS:  The concurrent use of oral lefamulin with inhibitors of|
03301|012|E|CYP3A4 that prolong the QTc interval may result in elevated levels of and|
03301|013|E|effects from lefamulin, including potentially life-threatening cardiac|
03301|014|E|arrhythmias, including torsades de pointes.(1)|
03301|015|B||
03301|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03301|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03301|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03301|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03301|020|P|female gender, or advanced age.(2)|
03301|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03301|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03301|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03301|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03301|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03301|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03301|027|P|dysfunction).(2)|
03301|028|B||
03301|029|M|PATIENT MANAGEMENT:  Avoid the concurrent use of lefamulin with medications|
03301|030|M|that prolong the QT interval and inhibit CYP3A4.(1)|
03301|031|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03301|032|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03301|033|M|treatment, after initiation of any drug known to prolong the QT interval,|
03301|034|M|and periodically monitor during therapy.  Correct any electrolyte|
03301|035|M|abnormalities.(1)|
03301|036|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03301|037|M|fainting.|
03301|038|B||
03301|039|D|DISCUSSION:  In a thorough QT study, intravenous lefamulin increased the|
03301|040|D|QTcF 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF by|
03301|041|D|9.3 msec (90% CI = 10.9 msec).(1)|
03301|042|D|   Coadministration of ketoconazole (strong CYP3A4 inhibitor) with lefamulin|
03301|043|D|tablets increased lefamulin maximum concentration (Cmax) and|
03301|044|D|area-under-the-curve (AUC) by 165% and 58%.(1)|
03301|045|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
03301|046|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the|
03301|047|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200%|
03301|048|D|and 100%, respectively.  No clinically significant effect on midazolam|
03301|049|D|pharmacokinetics was observed when co-administered with lefamulin|
03301|050|D|injection.(1)|
03301|051|D|   Agents that are linked to this monograph may have varying degrees of|
03301|052|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03301|053|D|been shown to prolong the QTc interval either through their mechanism of|
03301|054|D|action, through studies on their effects on the QTc interval, or through|
03301|055|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03301|056|D|and/or postmarketing reports.(3)|
03301|057|D|   Strong and moderate CYP3A4 inhibitors linked to this monograph include:|
03301|058|D|adagrasib, ceritinib, clarithromycin, clofazimine, crizotinib, erythromycin,|
03301|059|D|fluconazole, levoketoconazole, nilotinib, posaconazole, ribociclib,|
03301|060|D|telithromycin, and voriconazole.(4)|
03301|061|B||
03301|062|R|REFERENCES:|
03301|063|B||
03301|064|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03301|065|R|  Inc August 2019.|1
03301|066|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03301|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03301|068|R|  settings: a scientific statement from the American Heart Association and|6
03301|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03301|070|R|  2;55(9):934-47.|6
03301|071|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03301|072|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03301|073|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03301|074|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03301|075|R|4.This information is based on an extract from the Certara Drug Interaction|6
03301|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03302|001|T|MONOGRAPH TITLE:  Oral Lefamulin/P-gp Inhibitors that Prolong QT|
03302|002|B||
03302|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03302|004|L|of severe adverse interaction.|
03302|005|B||
03302|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors that prolong the QT|
03302|007|A|interval may increase the absorption of lefamulin and may result in additive|
03302|008|A|effects on the QTc interval.(1)|
03302|009|B||
03302|010|E|CLINICAL EFFECTS:  The concurrent use of oral lefamulin with P-gp inhibitors|
03302|011|E|that prolong the QTc interval may result in elevated levels of and effects|
03302|012|E|from lefamulin, including potentially life-threatening cardiac arrhythmias,|
03302|013|E|including torsades de pointes.(1)|
03302|014|B||
03302|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03302|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03302|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03302|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03302|019|P|female gender, or advanced age.(2)|
03302|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03302|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03302|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03302|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03302|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03302|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03302|026|P|dysfunction).(2)|
03302|027|B||
03302|028|M|PATIENT MANAGEMENT:  Avoid the concurrent use of oral lefamulin with|
03302|029|M|medications that prolong the QT interval and inhibit P-gp.(1)|
03302|030|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03302|031|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03302|032|M|treatment, after initiation of any drug known to prolong the QT interval,|
03302|033|M|and periodically monitor during therapy.  Correct any electrolyte|
03302|034|M|abnormalities.(1)|
03302|035|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03302|036|M|fainting.|
03302|037|B||
03302|038|D|DISCUSSION:  In a thorough QT study, intravenous lefamulin increased the|
03302|039|D|QTcF 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF by|
03302|040|D|9.3 msec (90% CI = 10.9 msec).(1)|
03302|041|D|   Coadministration of ketoconazole (strong CYP3A4 inhibitor) with lefamulin|
03302|042|D|tablets increased lefamulin maximum concentration (Cmax) and|
03302|043|D|area-under-the-curve (AUC) by 165% and 58%.(1)|
03302|044|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
03302|045|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the|
03302|046|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200%|
03302|047|D|and 100%, respectively.  No clinically significant effect on midazolam|
03302|048|D|pharmacokinetics was observed when co-administered with lefamulin|
03302|049|D|injection.(1)|
03302|050|D|   Agents that are linked to this monograph may have varying degrees of|
03302|051|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03302|052|D|been shown to prolong the QTc interval either through their mechanism of|
03302|053|D|action, through studies on their effects on the QTc interval, or through|
03302|054|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03302|055|D|and/or postmarketing reports.(3)|
03302|056|D|   P-gp inhibitors linked to this monograph include: amiodarone,|
03302|057|D|azithromycin, hydroquinidine, lapatinib, osimertinib, quinidine, ranolazine,|
03302|058|D|and vemurafenib.(4)|
03302|059|B||
03302|060|R|REFERENCES:|
03302|061|B||
03302|062|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03302|063|R|  Inc August 2019.|1
03302|064|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03302|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03302|066|R|  settings: a scientific statement from the American Heart Association and|6
03302|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03302|068|R|  2;55(9):934-47.|6
03302|069|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03302|070|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03302|071|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03302|072|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03302|073|R|4.This information is based on an extract from the Certara Drug Interaction|6
03302|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03303|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Medroxyprogesterone; Megestrol|
03303|002|B||
03303|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03303|004|L|take action as needed.|
03303|005|B||
03303|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown but may|
03303|007|A|involve inhibition of anticoagulant metabolism by medroxyprogesterone and|
03303|008|A|megestrol.(1,2)|
03303|009|B||
03303|010|E|CLINICAL EFFECTS:  The concurrent use of medroxyprogesterone or megestrol|
03303|011|E|and coumarin anticoagulants may increase international normalized ratio|
03303|012|E|(INR) and result in an increased risk for bleeding.(1,2)|
03303|013|B||
03303|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03303|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03303|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
03303|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03303|018|P|risk for bleeding (e.g. NSAIDs).|
03303|019|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
03303|020|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
03303|021|P|are expected to be more susceptible to this interaction.|
03303|022|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
03303|023|P|are expected to be less susceptible to effects from this drug combination,|
03303|024|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
03303|025|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
03303|026|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
03303|027|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to|
03303|028|P|achieve effective and safe anticoagulation than patients without these|
03303|029|P|CYP2C9 variants.|
03303|030|B||
03303|031|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with|
03303|032|M|medroxyprogesterone or megestrol and a coumarin anticoagulant (e.g.|
03303|033|M|warfarin) should have their INR closely monitored.(1)|
03303|034|M|   When concurrent therapy is warranted, monitor patients receiving|
03303|035|M|concurrent therapy for signs of blood loss, including decreased hemoglobin|
03303|036|M|and/or hematocrit, fecal occult blood, and/or decreased blood pressure and|
03303|037|M|promptly evaluate patients with any symptoms.|
03303|038|M|   When applicable, perform agent-specific laboratory test (e.g. INR) to|
03303|039|M|monitor efficacy and safety of anticoagulation.  Discontinue anticoagulation|
03303|040|M|in patients with active pathologic bleeding.|
03303|041|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03303|042|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03303|043|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03303|044|M|and/or swelling.|
03303|045|B||
03303|046|D|DISCUSSION:  A study of four patients on high-dose progestins (two patients|
03303|047|D|on medroxyprogesterone 500 mg twice daily and two patients on megestrol 160|
03303|048|D|mg once daily) and warfarin found that the progestins decreased the|
03303|049|D|clearance of warfarin by 34.8% (from 2.3 to 1.5 mL/h*kg BW) and increased|
03303|050|D|the half-life of warfarin by 71.4% (from 43.4 to 74.4 hours).(2)|
03303|051|B||
03303|052|R|REFERENCES:|
03303|053|B||
03303|054|R|1.Megace (megestrol) US prescribing information. Bristol-Myers Squibb|1
03303|055|R|  Company July 2019.|1
03303|056|R|2.Lundgren S, Kvinnsland S, Utaaker E, Bakke O, Ueland PM. Effect of oral|2
03303|057|R|  high-dose progestins on the disposition of antipyrine, digitoxin,  and|2
03303|058|R|  warfarin in patients with advanced breast cancer. Cancer Chemother|2
03303|059|R|  Pharmacol 1986;18(3):270-5.|2
03304|001|T|MONOGRAPH TITLE:  Selected Sensitive 3A4 Substrates that Inhibit 3A4/Oral|
03304|002|T|Lefamulin|
03304|003|B||
03304|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03304|005|L|of severe adverse interaction.|
03304|006|B||
03304|007|A|MECHANISM OF ACTION:  Lefamulin is considered a moderate inhibitor of|
03304|008|A|CYP3A4.  FDA defines a moderate inhibitor as a drug which increases the|
03304|009|A|area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)|
03304|010|A|   Moderate inhibitors of CYP3A4 may inhibit the metabolism of oral|
03304|011|A|lefamulin.(1,2)|
03304|012|B||
03304|013|E|CLINICAL EFFECTS:  Concurrent use of oral lefamulin with a sensitive CYP3A4|
03304|014|E|substrate that also inhibits CYP3A4 may lead to increased serum levels and|
03304|015|E|adverse effects of lefamulin and the sensitive substrate, including QT|
03304|016|E|prolongation.(1)|
03304|017|B||
03304|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03304|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03304|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03304|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03304|022|P|gender, or advanced age.(2)|
03304|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03304|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03304|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03304|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03304|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03304|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03304|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03304|030|B||
03304|031|M|PATIENT MANAGEMENT:  If oral lefamulin must be coadministered with a|
03304|032|M|sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse|
03304|033|M|effects of the CYP3A4 substrate and of lefamulin.(1)|
03304|034|M|   During concomitant therapy with a moderate CYP3A4 inhibitor, monitor|
03304|035|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03304|036|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03304|037|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03304|038|M|irregular heartbeat, dizziness, or fainting.|
03304|039|B||
03304|040|D|DISCUSSION:  In a study, oral lefamulin tablets administered concomitantly|
03304|041|D|with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate)|
03304|042|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03304|043|D|midazolam by 200% and 100%, respectively.  No clinically significant effect|
03304|044|D|on midazolam pharmacokinetics was observed when co-administered with|
03304|045|D|lefamulin injection.(1)|
03304|046|D|   Coadministration of ketoconazole (strong CYP3A4 inhibitor) with lefamulin|
03304|047|D|tablets increased lefamulin area-under-the-curve (AUC) and maximum|
03304|048|D|concentration (Cmax) by 165% and 58%.(1)|
03304|049|D|   Sensitive CYP3A4 substrates linked to this monograph include: aprepitant,|
03304|050|D|atazanavir, darunavir, diltiazem, isavuconazonium, rilzabrutinib, and|
03304|051|D|verapamil.(1,3)|
03304|052|B||
03304|053|R|REFERENCES:|
03304|054|B||
03304|055|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03304|056|R|  Inc August 2019.|1
03304|057|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03304|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03304|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03304|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03304|061|R|  11/14/2017.|1
03304|062|R|3.This information is based on an extract from the Certara Drug Interaction|6
03304|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03304|064|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03304|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03304|066|R|  settings: a scientific statement from the American Heart Association and|6
03304|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03304|068|R|  2;55(9):934-47.|6
03305|001|T|MONOGRAPH TITLE:  Sofosbuvir-Containing Hepatitis C Products/Rifabutin|
03305|002|B||
03305|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03305|004|L|is contraindicated and generally should not be dispensed or administered to|
03305|005|L|the same patient.|
03305|006|B||
03305|007|A|MECHANISM OF ACTION:  Rifabutin is an inducer of P-glycoprotein (P-gp) and|
03305|008|A|may decrease the absorption of ledipasvir,(1-4) sofosbuvir,(1-12)|
03305|009|A|velpatasvir,(5-12) and voxilaprevir.(9-12)|
03305|010|B||
03305|011|E|CLINICAL EFFECTS:  Concurrent or recent use of rifabutin may result in|
03305|012|E|decreased levels and effectiveness of ledipasvir,(1-4) sofosbuvir,(1-12)|
03305|013|E|velpatasvir,(5-12) and voxilaprevir.(9-12)|
03305|014|B||
03305|015|P|PREDISPOSING FACTORS:  None determined.|
03305|016|B||
03305|017|M|PATIENT MANAGEMENT:  The Australian and US manufacturers of|
03305|018|M|ledipasvir-sofosbuvir,(1,4) velpatasvir-sofosbuvir,(5,8) and|
03305|019|M|sofosbuvir-velpatasvir-voxilaprevir,(9,12) and the Canadian manufacturer of|
03305|020|M|velpatasvir-sofosbuvir (6) do not recommend coadministration with rifabutin.|
03305|021|M|The UK manufacturer of ledipasvir-sofosbuvir,(3) velpatasvir-sofosbuvir,(7)|
03305|022|M|and sofosbuvir-velpatasvir-voxilaprevir,(11) and the Canadian manufacturer|
03305|023|M|of sofosbuvir-velpatasvir-voxilaprevir (10) state that concurrent use with|
03305|024|M|rifabutin is contraindicated.|
03305|025|B||
03305|026|D|DISCUSSION:  In a phase I pharmacokinetic study with 20 healthy subjects,|
03305|027|D|rifabutin (300 mg daily) decreased the maximum concentration (Cmax) and|
03305|028|D|area-under-curve (AUC) of sofosbuvir by 36% and 24%, respectively.(8)  The|
03305|029|D|impact of rifabutin on ledipasvir, velpatasvir, and voxilaprevir has not|
03305|030|D|been studied, but rifabutin is expected to lower plasma concentrations of|
03305|031|D|each of these substances.  Although a reduction in dose of sofosbuvir of|
03305|032|D|less than 50% is not expected to reduce its efficacy, the potential impact|
03305|033|D|of rifabutin on ledipasvir, velpatasvir, and voxilaprevir warrants caution|
03305|034|D|with concomitant use.(13)|
03305|035|D|   In a study in 31 subjects, rifampin (600 mg daily, a strong P-gp inducer)|
03305|036|D|decreased the maximum concentration (Cmax) and AUC of ledipasvir by 35% and|
03305|037|D|59%, respectively.(4)|
03305|038|D|   In a study in 17 subjects, rifampin (600 mg daily) decreased the Cmax and|
03305|039|D|AUC of sofosbuvir by 77% and 72%, respectively.(4)|
03305|040|D|   In a study in 12 subjects, rifampin (600 mg daily) decreased the Cmax and|
03305|041|D|AUC of velpatasvir by 71% and 82%, respectively.(8)|
03305|042|D|   In a study in 24 subjects, rifampin (600 mg daily) decreased the Cmax and|
03305|043|D|AUC of voxilaprevir by 9% and 73%, respectively.(12)|
03305|044|B||
03305|045|R|REFERENCES:|
03305|046|B||
03305|047|R|1.Harvoni (ledipasvir and sofosbuvir) Australian Product Information. Gilead|1
03305|048|R|  Sciences Pty Ltd June 20, 2019.|1
03305|049|R|2.Harvoni (ledipasvir and sofosbuvir) Canadian prescribing information.|1
03305|050|R|  Gilead Sciences Canada, Inc. June 27, 2019.|1
03305|051|R|3.Harvoni (ledipasvir and sofosbuvir) UK Summary of Product Characteristics.|1
03305|052|R|  Gilead Sciences Ltd July, 2020.|1
03305|053|R|4.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
03305|054|R|  Sciences November, 2019.|1
03305|055|R|5.Epclusa (sofosbuvir and velpatasvir) Australian product information.|1
03305|056|R|  Gilead Sciences Pty Ltd June 21, 2019.|1
03305|057|R|6.Epclusa (sofosbuvir and velpatasvir) Canadian prescribing information.|1
03305|058|R|  Gilead Sciences Canada, Inc. June 26, 2019.|1
03305|059|R|7.Epclusa (sofosbuvir and velpatasvir) UK Summary of Product|1
03305|060|R|  Characteristics. Gilead Sciences Ltd September 2, 2019.|1
03305|061|R|8.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
03305|062|R|  Sciences, Inc. April, 2022.|1
03305|063|R|9.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) Australian product|1
03305|064|R|  information. Gilead Sciences Pty Ltd June 21, 2019.|1
03305|065|R|10.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) Canadian prescribing|1
03305|066|R|   information. Gilead Sciences Canada, Inc. June 26, 2019.|1
03305|067|R|11.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) UK Summary of Product|1
03305|068|R|   Characteristics. Gilead Sciences Ltd September 3, 2019.|1
03305|069|R|12.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
03305|070|R|   Gilead Sciences, Inc. September, 2019.|1
03305|071|R|13.European Medicines Agency (EMA). Harvoni : EPAR - Procedural steps taken|1
03305|072|R|   and scientific information after the authorisation. Accessed at:|1
03305|073|R|   https://www.ema.europa.eu/en/documents/procedural-steps-after/harvoni-epa|1
03305|074|R|   r-procedural-steps-taken-scientific-information-after-authorisation_en.pd|1
03305|075|R|   f August 5, 2019.|1
03306|001|T|MONOGRAPH TITLE:  Istradefylline/Selected Strong CYP3A4 Inducers|
03306|002|B||
03306|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03306|004|L|of severe adverse interaction.|
03306|005|B||
03306|006|A|MECHANISM OF ACTION:  Istradefylline is a substrate of CYP3A4.  Strong|
03306|007|A|inducers of CYP3A4 may induce the metabolism of istradefylline.(1)|
03306|008|B||
03306|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03306|010|E|may result in decreased levels and effectiveness of istradefylline.(1)|
03306|011|B||
03306|012|P|PREDISPOSING FACTORS:  Tobacco smokers who smoke more than 20 cigarettes per|
03306|013|P|day may have lower exposure to istradefylline and be more susceptible to the|
03306|014|P|effects of a strong CYP3A4 inducer.(1)|
03306|015|P|   Induction effects may be more likely with regular use of the inducer for|
03306|016|P|longer than 1-2 weeks.|
03306|017|B||
03306|018|M|PATIENT MANAGEMENT:  The manufacturer of istradefylline states that|
03306|019|M|concurrent use with strong CYP3A4 inducers should be avoided.(1)|
03306|020|B||
03306|021|D|DISCUSSION:  Concomitant administration of rifampin (600 mg once daily for|
03306|022|D|20 days, strong CYP3A4 inducer) with istradefylline (40 mg) decreased|
03306|023|D|istradefylline maximum concentration (Cmax) and area-under-the-curve (AUC)|
03306|024|D|by 45% and 81%, respectively, compared to istradefylline administered|
03306|025|D|alone.(1)|
03306|026|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03306|027|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin,|
03306|028|D|primidone, rifampin, rifapentine, and St. John's wort.(2-3)|
03306|029|B||
03306|030|R|REFERENCES:|
03306|031|B||
03306|032|R|1.Nourianz (istradefylline) US prescribing information. Kyowa Kirin, Inc.|1
03306|033|R|  August, 2019.|1
03306|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03306|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03306|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03306|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03306|038|R|  11/14/2017.|1
03306|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03306|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03307|001|T|MONOGRAPH TITLE:  Istradefylline/Strong CYP3A4 Inhibitors|
03307|002|B||
03307|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03307|004|L|of severe adverse interaction.|
03307|005|B||
03307|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03307|007|A|of istradefylline.(1)|
03307|008|B||
03307|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03307|010|E|in elevated levels and increased effects of istradefylline, such as|
03307|011|E|dyskinesias, impulse control disorder, hallucinations and psychosis.(1)|
03307|012|B||
03307|013|P|PREDISPOSING FACTORS:  Patients with hepatic impairment may be exposed to|
03307|014|P|higher concentrations of istradefylline and may be more susceptible to the|
03307|015|P|effects of strong CYP3A4 inhibitors.(1)|
03307|016|B||
03307|017|M|PATIENT MANAGEMENT:  The manufacturer of istradefylline states that the|
03307|018|M|maximum dose of istradefylline in patients on concomitant strong CYP3A4|
03307|019|M|inhibitors is 20 mg daily.(1)|
03307|020|B||
03307|021|D|DISCUSSION:  Coadministration of ketoconazole (a strong CYP3A4 inhibitor)|
03307|022|D|200 mg twice daily for 4 days with a single 40 mg dose of istradefylline|
03307|023|D|increased the area-under-the-curve (AUC) of istradefylline by 2.5-fold, but|
03307|024|D|did not affect the maximum concentration (Cmax).(1)|
03307|025|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03307|026|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03307|027|D|ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone,|
03307|028|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
03307|029|D|saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(2,3)|
03307|030|B||
03307|031|R|REFERENCES:|
03307|032|B||
03307|033|R|1.Nourianz (istradefylline) US prescribing information. Kyowa Kirin, Inc.|1
03307|034|R|  August, 2019.|1
03307|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03307|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03307|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03307|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03307|039|R|  11/14/2017.|1
03307|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
03307|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03308|001|T|MONOGRAPH TITLE:  Starch-Based Thickeners/Polyethylene Glycol|
03308|002|B||
03308|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03308|004|L|of severe adverse interaction.|
03308|005|B||
03308|006|A|MECHANISM OF ACTION:  Polyethylene glycol when mixed in a starch-thickened|
03308|007|A|liquid may cause an isothermal rotational rheology reaction to occur and may|
03308|008|A|cause the starch-thickened liquid to become near-water consistency.(1,2)|
03308|009|B||
03308|010|E|CLINICAL EFFECTS:  Mixing polyethylene glycol in a starch-thickened liquid|
03308|011|E|may result in near-water consistency liquids.  Patients receiving|
03308|012|E|starch-thickened liquids due to dysphagia may be at risk when consuming|
03308|013|E|near-water consistency liquids, including aspiration of the liquid upon|
03308|014|E|consumption.(1,2)|
03308|015|B||
03308|016|P|PREDISPOSING FACTORS:  None determined.|
03308|017|B||
03308|018|M|PATIENT MANAGEMENT:  Polyethylene glycol should not be mixed together in|
03308|019|M|starch-thickened liquids.|
03308|020|M|   Literature suggests polyethylene glycol with xanthan gum based thickeners|
03308|021|M|is compatible.  Consider mixing polyethylene glycol in liquid thickened with|
03308|022|M|xanthan gum based thickeners only.(1)|
03308|023|B||
03308|024|D|DISCUSSION:  A case report details a patient on a nectar-thickened liquid|
03308|025|D|diet with constipation who was prescribed polyethylene glycol.  The|
03308|026|D|polyethylene glycol was mixed in thickened apple juice and the liquid|
03308|027|D|immediately thinned to near-water consistency.  Results of near-water|
03308|028|D|consistency were also observed when polyethylene glycol was mixed with|
03308|029|D|thickened water and coffee.(2)|
03308|030|D|   A case report details a complex patient who received polyethylene glycol|
03308|031|D|(PEG) 3350 for constipation mixed in starch-based prethickened juice and on|
03308|032|D|the second day of administration was noted to be "gurgly" after swallowing|
03308|033|D|the dose.  The patient was suspected to have aspirated during repositioning|
03308|034|D|and passed away a couple hours later.  Cause of death was unknown, however|
03308|035|D|aspiration was noted to be a contributing factor.(1)|
03308|036|B||
03308|037|R|REFERENCES:|
03308|038|B||
03308|039|R|1.Institute for Safe Medication Practices Canada. ISMP Canada Safety|6
03308|040|R|  Bulletin: Potentially Harmful Interaction between Polyethylene Glycol|6
03308|041|R|  Laxative and Starch-Based Thickeners. ISMP Canada August 28, 2019;|6
03308|042|R|  19(7):1-3.|6
03308|043|R|2.Carlisle BJ, Craft G, Harmon JP, Ilkevitch A, Nicoghosian J, Sheyner I,|3
03308|044|R|  Stewart JT. PEG and Thickeners: A Critical Interaction Between|3
03308|045|R|  Polyethylene Glycol Laxative and Starch-Based Thickeners. J Am Med Dir|3
03308|046|R|  Assoc 2016 Sep 1;17(9):860-1.|3
03309|001|T|MONOGRAPH TITLE:  Trientine/Iron Salts, Oral|
03309|002|B||
03309|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03309|004|L|take action as needed.|
03309|005|B||
03309|006|A|MECHANISM OF ACTION:  Trientine is a chelating agent.  Concurrent|
03309|007|A|administration with iron may reduce the absorption of both trientine and|
03309|008|A|iron.|
03309|009|B||
03309|010|E|CLINICAL EFFECTS:  Iron may decrease the levels and clinical effects of|
03309|011|E|trientine, and trientine may reduce serum iron levels.|
03309|012|B||
03309|013|P|PREDISPOSING FACTORS:  None determined.|
03309|014|B||
03309|015|M|PATIENT MANAGEMENT:  Avoid use of iron salts within 2 hours of trientine|
03309|016|M|dose. Monitor clinical status for decreased effectiveness and adjust the|
03309|017|M|trientine dose if necessary.|
03309|018|B||
03309|019|D|DISCUSSION:  Multivitamins with low doses of iron may decrease trientine|
03309|020|D|absorption so ensure patient is aware of the risks.  Also, as patients may|
03309|021|D|be unaware which foods contain iron, instruct patients to take trientine on|
03309|022|D|an empty stomach, at least one hour before meals or two hours after food or|
03309|023|D|milk.|
03309|024|B||
03309|025|R|REFERENCES:|
03309|026|B||
03309|027|R|1.Cuprior (trientine) EMA Summary of Product Characteristics. gmp-orphan SA|1
03309|028|R|  September 5, 2017.|1
03309|029|R|2.Syprine (trientine) US prescribing information. Valeant Pharmaceuticals|1
03309|030|R|  North America LLC December 22, 2016.|1
03310|001|T|MONOGRAPH TITLE:  Trientine/Selected Minerals, Oral|
03310|002|B||
03310|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03310|004|L|take action as needed.|
03310|005|B||
03310|006|A|MECHANISM OF ACTION:  Mineral supplements may bind to trientine and block|
03310|007|A|its absorption.|
03310|008|B||
03310|009|E|CLINICAL EFFECTS:  The levels and clinical effects of trientine may be|
03310|010|E|decreased.|
03310|011|B||
03310|012|P|PREDISPOSING FACTORS:  None determined.|
03310|013|B||
03310|014|M|PATIENT MANAGEMENT:  The US manufacturer of trientine states that mineral|
03310|015|M|supplements should not be given with trientine.  If concomitant therapy is|
03310|016|M|necessary, take trientine on an empty stomach and separate administration at|
03310|017|M|least one hour apart from any other drug.  Monitor clinical status for|
03310|018|M|decreased effectiveness and adjust the trientine dose if necessary.|
03310|019|B||
03310|020|D|DISCUSSION:  Multivitamins with minerals may decrease trientine absorption|
03310|021|D|so ensure patient is aware of the risks.|
03310|022|B||
03310|023|R|REFERENCES:|
03310|024|B||
03310|025|R|1.Cuprior (trientine) EMA Summary of Product Characteristics. gmp-orphan SA|1
03310|026|R|  September 5, 2017.|1
03310|027|R|2.Syprine (trientine) US prescribing information. Valeant Pharmaceuticals|1
03310|028|R|  North America LLC December 22, 2016.|1
03311|001|T|MONOGRAPH TITLE:  Opioids (Immediate Release)/Selected Stimulants|
03311|002|B||
03311|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03311|004|L|take action as needed.|
03311|005|B||
03311|006|A|MECHANISM OF ACTION:  Opioids and stimulants exhibit opposing effects on the|
03311|007|A|CNS.|
03311|008|B||
03311|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and stimulants may have|
03311|010|E|unpredictable effects and may mask overdose symptoms of the opioid, such as|
03311|011|E|drowsiness and inability to focus.|
03311|012|B||
03311|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03311|014|P|may increase the risk of adverse effects.|
03311|015|B||
03311|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS stimulants|
03311|017|M|such as amphetamines to patients for whom alternatives are ineffective, not|
03311|018|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03311|019|M|of pain.|
03311|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
03311|021|M|drug to the minimum possible while achieving the desired clinical effect.|
03311|022|M|   Respiratory depression can occur at any time during opioid therapy,|
03311|023|M|especially during therapy initiation and following dosage increases.  The|
03311|024|M|risk of opioid-related overdose or overdose-related death is increased with|
03311|025|M|higher opioid doses, and this risk persists over the course of therapy.|
03311|026|M|Consider these risks when using concurrently with other agents that may|
03311|027|M|cause CNS depression.(1)|
03311|028|M|   Monitor patients receiving concurrent therapy for signs of substance|
03311|029|M|abuse.|
03311|030|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03311|031|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03311|032|M|unresponsiveness.|
03311|033|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03311|034|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03311|035|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03311|036|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03311|037|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03311|038|M|as those taking CNS depressants) and when a patient has household|
03311|039|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03311|040|M|for obtaining an opioid reversal agent (e.g., prescription,|
03311|041|M|over-the-counter, or as part of a community-based program).|
03311|042|B||
03311|043|D|DISCUSSION:  A total of 70,237 persons died from drug overdoses in the|
03311|044|D|United States in 2017; approximately two thirds of these deaths involved an|
03311|045|D|opioid.(2).  The CDC analyzed 2016-2017 changes in age-adjusted death rates|
03311|046|D|involving cocaine and psychostimulants by demographic characteristics,|
03311|047|D|urbanization levels, U.S. Census region, 34 states, and the District of|
03311|048|D|Columbia (DC).  The CDC also examined trends in age-adjusted|
03311|049|D|cocaine-involved and psychostimulant-involved death rates from 2003 to 2017|
03311|050|D|overall, as well as with and without co-involvement of opioids.  Among all|
03311|051|D|2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333|
03311|052|D|(14.7%) involved psychostimulants.  Death rates increased from 2016 to 2017|
03311|053|D|for both drug categories across demographic characteristics, urbanization|
03311|054|D|levels, Census regions, and states.  In 2017, opioids were involved in 72.7%|
03311|055|D|and 50.4% of cocaine-involved and psychostimulant-involved overdoses,|
03311|056|D|respectively, and the data suggest that increases in cocaine-involved|
03311|057|D|overdose deaths from 2012 to 2017 were driven primarily by synthetic|
03311|058|D|opioids.(3)|
03311|059|D|   There was opioid co-involvement in 72.7 percent of cocaine and 50.4|
03311|060|D|percent of stimulant-involved overdose deaths.  This was largely driven by|
03311|061|D|synthetic opioids such as fentanyl. However, stimulant-involved overdose|
03311|062|D|without opioid co-involvement is also increasing.(2)|
03311|063|B||
03311|064|R|REFERENCES:|
03311|065|B||
03311|066|R|1.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03311|067|R|  prescribing information for all opioid pain medicines to provide|1
03311|068|R|  additional guidance for safe use. Available at:|1
03311|069|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03311|070|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03311|071|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03311|072|R|2.Seth P, Scholl L, Rudd RA, Bacon S. Overdose Deaths Involving Opioids,|6
03311|073|R|  Cocaine, and Psychostimulants - United States, 2015-2016. MMWR Morb Mortal|6
03311|074|R|  Wkly Rep 2018 Mar 30;67(12):349-358.|6
03311|075|R|3.Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved|6
03311|076|R|  Overdose Deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep 2018|6
03311|077|R|  Jan 4;67(5152):1419-1427.|6
03312|001|T|MONOGRAPH TITLE:  Opioids (Extended Release)/Selected Stimulants|
03312|002|B||
03312|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03312|004|L|take action as needed.|
03312|005|B||
03312|006|A|MECHANISM OF ACTION:  Opioids and stimulants exhibit opposing effects on the|
03312|007|A|CNS.|
03312|008|B||
03312|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and stimulants may have|
03312|010|E|unpredictable effects and may mask overdose symptoms of the opioid, such as|
03312|011|E|drowsiness and inability to focus.|
03312|012|B||
03312|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03312|014|P|may increase the risk of adverse effects.|
03312|015|B||
03312|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS stimulants|
03312|017|M|such as amphetamines to patients for whom alternatives are ineffective, not|
03312|018|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03312|019|M|of pain.|
03312|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
03312|021|M|drug to the minimum possible while achieving the desired clinical effect.|
03312|022|M|   Respiratory depression can occur at any time during opioid therapy,|
03312|023|M|especially during therapy initiation and following dosage increases.  The|
03312|024|M|risk of opioid-related overdose or overdose-related death is increased with|
03312|025|M|higher opioid doses, and this risk persists over the course of therapy.|
03312|026|M|Consider these risks when using concurrently with other agents that may|
03312|027|M|cause CNS depression.(1)|
03312|028|M|   Monitor patients receiving concurrent therapy for signs of substance|
03312|029|M|abuse.|
03312|030|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03312|031|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03312|032|M|unresponsiveness.|
03312|033|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03312|034|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03312|035|M|treat opioid use disorder (OUD). Consider prescribing opioid reversal agents|
03312|036|M|(e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or|
03312|037|M|opioid analgesics who are at increased risk of opioid overdose (such as|
03312|038|M|those taking CNS depressants) and when a patient has household members/close|
03312|039|M|contacts at risk for accidental overdose.  Discuss the options for obtaining|
03312|040|M|an opioid reversal agent (e.g., prescription, over-the-counter, or as part|
03312|041|M|of a community-based program).|
03312|042|B||
03312|043|D|DISCUSSION:  A total of 70,237 persons died from drug overdoses in the|
03312|044|D|United States in 2017; approximately two thirds of these deaths involved an|
03312|045|D|opioid.(2).  The CDC analyzed 2016-2017 changes in age-adjusted death rates|
03312|046|D|involving cocaine and psychostimulants by demographic characteristics,|
03312|047|D|urbanization levels, U.S. Census region, 34 states, and the District of|
03312|048|D|Columbia (DC).  The CDC also examined trends in age-adjusted|
03312|049|D|cocaine-involved and psychostimulant-involved death rates from 2003 to 2017|
03312|050|D|overall, as well as with and without co-involvement of opioids.  Among all|
03312|051|D|2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333|
03312|052|D|(14.7%) involved psychostimulants.  Death rates increased from 2016 to 2017|
03312|053|D|for both drug categories across demographic characteristics, urbanization|
03312|054|D|levels, Census regions, and states.  In 2017, opioids were involved in 72.7%|
03312|055|D|and 50.4% of cocaine-involved and psychostimulant-involved overdoses,|
03312|056|D|respectively, and the data suggest that increases in cocaine-involved|
03312|057|D|overdose deaths from 2012 to 2017 were driven primarily by synthetic|
03312|058|D|opioids.(3)|
03312|059|D|   There was opioid co-involvement in 72.7 percent of cocaine and 50.4|
03312|060|D|percent of stimulant-involved overdose deaths.  This was largely driven by|
03312|061|D|synthetic opioids such as fentanyl. However, stimulant-involved overdose|
03312|062|D|without opioid co-involvement is also increasing.(2)|
03312|063|B||
03312|064|R|REFERENCES:|
03312|065|B||
03312|066|R|1.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03312|067|R|  prescribing information for all opioid pain medicines to provide|1
03312|068|R|  additional guidance for safe use. Available at:|1
03312|069|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03312|070|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03312|071|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03312|072|R|2.Seth P, Scholl L, Rudd RA, Bacon S. Overdose Deaths Involving Opioids,|6
03312|073|R|  Cocaine, and Psychostimulants - United States, 2015-2016. MMWR Morb Mortal|6
03312|074|R|  Wkly Rep 2018 Mar 30;67(12):349-358.|6
03312|075|R|3.Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved|6
03312|076|R|  Overdose Deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep 2018|6
03312|077|R|  Jan 4;67(5152):1419-1427.|6
03313|001|T|MONOGRAPH TITLE:  Benzodiazepines/Selected Stimulants|
03313|002|B||
03313|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03313|004|L|take action as needed.|
03313|005|B||
03313|006|A|MECHANISM OF ACTION:  Benzodiazepines and stimulants exhibit opposing|
03313|007|A|effects on the CNS.|
03313|008|B||
03313|009|E|CLINICAL EFFECTS:  Concurrent use of benzodiazepine and stimulants may have|
03313|010|E|unpredictable effects and may mask overdose symptoms of the benzodiazepine,|
03313|011|E|such as drowsiness and inability to focus.|
03313|012|B||
03313|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03313|014|P|may increase the risk of adverse effects.|
03313|015|B||
03313|016|M|PATIENT MANAGEMENT:  Limit prescribing benzodiazepines with CNS stimulants|
03313|017|M|such as amphetamines to patients for whom alternatives are inadequate.|
03313|018|M|   If concurrent use is necessary, limit the dosages and duration of each|
03313|019|M|drug to the minimum possible while achieving the desired clinical effect.|
03313|020|M|   Monitor patients receiving concurrent therapy for signs of substance|
03313|021|M|abuse.|
03313|022|B||
03313|023|D|DISCUSSION:  Analysis of the 2015 and 2016 National Survey on Drug Use and|
03313|024|D|Health found that misuse of benzodiazepines was strongly associated with|
03313|025|D|misuse of or dependences on stimulants.(1)  Benzodiazepines are used to|
03313|026|D|reduce the adverse effects of stimulant use, such as insomnia.(2)  Patients|
03313|027|D|abusing benzodiazepines in combination with other drugs tend to consume|
03313|028|D|higher dosages of benzodiazepines than patients abusing only|
03313|029|D|benzodiazepines.(3)|
03313|030|B||
03313|031|R|REFERENCES:|
03313|032|B||
03313|033|R|1.Maust DT, Lin LA, Blow FC. Benzodiazepine Use and Misuse Among Adults in|6
03313|034|R|  the United States. Psychiatr Serv 2019 Feb 1;70(2):97-106.|6
03313|035|R|2.Compton WM, Volkow ND. Abuse of prescription drugs and the risk of|6
03313|036|R|  addiction. Drug Alcohol Depend 2006 Jun;83 Suppl 1:S4-7.|6
03313|037|R|3.Busto U, Sellers EM, Naranjo CA, Cappell HD, Sanchez-Craig M, Simpkins J.|6
03313|038|R|  Patterns of benzodiazepine abuse and dependence. Br J Addict 1986 Feb;|6
03313|039|R|  81(1):87-94.|6
03314|001|T|MONOGRAPH TITLE:  Opioids (Cough & Cold)/Selected Stimulants|
03314|002|B||
03314|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03314|004|L|take action as needed.|
03314|005|B||
03314|006|A|MECHANISM OF ACTION:  Opioids and stimulants exhibit opposing effects on the|
03314|007|A|CNS.|
03314|008|B||
03314|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and stimulants may have|
03314|010|E|unpredictable effects and may mask overdose symptoms of the opioid, such as|
03314|011|E|drowsiness and inability to focus.|
03314|012|B||
03314|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03314|014|P|may increase the risk of adverse effects.|
03314|015|B||
03314|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS stimulants|
03314|017|M|such as amphetamines to patients for whom alternatives are ineffective, not|
03314|018|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03314|019|M|of pain.|
03314|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
03314|021|M|drug to the minimum possible while achieving the desired clinical effect.|
03314|022|M|   Respiratory depression can occur at any time during opioid therapy,|
03314|023|M|especially during therapy initiation and following dosage increases.  The|
03314|024|M|risk of opioid-related overdose or overdose-related death is increased with|
03314|025|M|higher opioid doses, and this risk persists over the course of therapy.|
03314|026|M|Consider these risks when using concurrently with other agents that may|
03314|027|M|cause CNS depression.(1)|
03314|028|M|   Monitor patients receiving concurrent therapy for signs of substance|
03314|029|M|abuse. Monitor patients receiving concurrent therapy for unusual dizziness|
03314|030|M|or lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03314|031|M|unresponsiveness.|
03314|032|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03314|033|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03314|034|M|treat opioid use disorder (OUD). Consider prescribing opioid reversal agents|
03314|035|M|(e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or|
03314|036|M|opioid analgesics who are at increased risk of opioid overdose (such as|
03314|037|M|those taking CNS depressants) and when a patient has household members/close|
03314|038|M|contacts at risk for accidental overdose.  Discuss the options for obtaining|
03314|039|M|an opioid reversal agent (e.g., prescription, over-the-counter, or as part|
03314|040|M|of a community-based program).|
03314|041|B||
03314|042|D|DISCUSSION:  A total of 70,237 persons died from drug overdoses in the|
03314|043|D|United States in 2017; approximately two thirds of these deaths involved an|
03314|044|D|opioid.(2).  The CDC analyzed 2016-2017 changes in age-adjusted death rates|
03314|045|D|involving cocaine and psychostimulants by demographic characteristics,|
03314|046|D|urbanization levels, U.S. Census region, 34 states, and the District of|
03314|047|D|Columbia (DC).  The CDC also examined trends in age-adjusted|
03314|048|D|cocaine-involved and psychostimulant-involved death rates from 2003 to 2017|
03314|049|D|overall, as well as with and without co-involvement of opioids.  Among all|
03314|050|D|2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333|
03314|051|D|(14.7%) involved psychostimulants.  Death rates increased from 2016 to 2017|
03314|052|D|for both drug categories across demographic characteristics, urbanization|
03314|053|D|levels, Census regions, and states.  In 2017, opioids were involved in 72.7%|
03314|054|D|and 50.4% of cocaine-involved and psychostimulant-involved overdoses,|
03314|055|D|respectively, and the data suggest that increases in cocaine-involved|
03314|056|D|overdose deaths from 2012 to 2017 were driven primarily by synthetic|
03314|057|D|opioids.(3)|
03314|058|D|   There was opioid co-involvement in 72.7 percent of cocaine and 50.4|
03314|059|D|percent of stimulant-involved overdose deaths.  This was largely driven by|
03314|060|D|synthetic opioids such as fentanyl. However, stimulant-involved overdose|
03314|061|D|without opioid co-involvement is also increasing.(2)|
03314|062|B||
03314|063|R|REFERENCES:|
03314|064|B||
03314|065|R|1.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03314|066|R|  prescribing information for all opioid pain medicines to provide|1
03314|067|R|  additional guidance for safe use. Available at:|1
03314|068|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03314|069|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03314|070|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03314|071|R|2.Seth P, Scholl L, Rudd RA, Bacon S. Overdose Deaths Involving Opioids,|6
03314|072|R|  Cocaine, and Psychostimulants - United States, 2015-2016. MMWR Morb Mortal|6
03314|073|R|  Wkly Rep 2018 Mar 30;67(12):349-358.|6
03314|074|R|3.Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved|6
03314|075|R|  Overdose Deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep 2018|6
03314|076|R|  Jan 4;67(5152):1419-1427.|6
03315|001|T|MONOGRAPH TITLE:  Burosumab/Oral Phosphates; Active Vitamin D Analogs|
03315|002|B||
03315|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03315|004|L|is contraindicated and generally should not be dispensed or administered to|
03315|005|L|the same patient.|
03315|006|B||
03315|007|A|MECHANISM OF ACTION:  Both burosumab and phosphates or vitamin D may|
03315|008|A|increase serum phosphate levels.  This combination may lead to greater|
03315|009|A|increases in serum phosphate than anticipated.|
03315|010|B||
03315|011|E|CLINICAL EFFECTS:  The combination of burosumab with oral phosphates or|
03315|012|E|active vitamin D analogs may result in hyperphosphatemia and may increase|
03315|013|E|the risk of nephrocalcinosis.(1)|
03315|014|B||
03315|015|P|PREDISPOSING FACTORS:  Patients with renal impairment have alterations in|
03315|016|P|mineral metabolism that may increase the risk of hyperphosphatemia.(1)|
03315|017|B||
03315|018|M|PATIENT MANAGEMENT:  The concomitant use of burosumab with oral phosphates|
03315|019|M|or active vitamin D analogs is contraindicated.  Discontinue oral phosphate|
03315|020|M|and/or active vitamin D analogs one week before starting burosumab.(1)|
03315|021|B||
03315|022|D|DISCUSSION:  Burosumab restores dysfunctional renal phosphate reabsorption|
03315|023|D|and renal production of 1,25-dihydroxyvitamin D to treat X-linked|
03315|024|D|hypophosphatemia.  Additional oral phosphates and/or active vitamin D|
03315|025|D|analogs may raise serum phosphate higher than anticipated.|
03315|026|B||
03315|027|R|REFERENCE:|
03315|028|B||
03315|029|R|1.Crysvita (burosumab-twza) US prescribing information. Ultragenyx|1
03315|030|R|  Pharmaceutical Inc September, 2019.|1
03316|001|T|MONOGRAPH TITLE:  Lercanidipine/Strong CYP3A4 Inhibitors;|
03316|002|T|Atazanavir;Darunavir|
03316|003|B||
03316|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03316|005|L|is contraindicated and generally should not be dispensed or administered to|
03316|006|L|the same patient.|
03316|007|B||
03316|008|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03316|009|A|lercanidipine.(1)|
03316|010|B||
03316|011|E|CLINICAL EFFECTS:  Concomitant use of lercanidipine with strong inhibitors|
03316|012|E|of CYP3A4 may lead to increased lercanidipine effects.(1)|
03316|013|B||
03316|014|P|PREDISPOSING FACTORS:  None determined.|
03316|015|B||
03316|016|M|PATIENT MANAGEMENT:  The manufacturer of lercanidipine states that|
03316|017|M|concurrent use of strong CYP3A4 inhibitors is contraindicated.(1)|
03316|018|B||
03316|019|D|DISCUSSION:  In a study, concurrent administration of ketoconazole increased|
03316|020|D|lercanidipine's area-under-the-curve (AUC) and maximum concentration (Cmax)|
03316|021|D|by 15-fold and 8-fold, respectively.(1)|
03316|022|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
03316|023|D|atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir,|
03316|024|D|erythromycin, grapefruit, idelalisib, indinavir, itraconazole, josamycin,|
03316|025|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03316|026|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03316|027|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib,|
03316|028|D|and voriconazole.(2-4)|
03316|029|B||
03316|030|R|REFERENCES:|
03316|031|B||
03316|032|R|1.Zanidip (lercanidipine) UK prescribing information. Recordati|1
03316|033|R|  Pharmaceuticals Limited October 4, 2019.|1
03316|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
03316|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03316|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03316|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03316|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03316|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03316|040|R|  11/14/2017.|1
03316|041|R|4.European AIDS Clinical Society. EACS Guidelines version 10.0. Available|6
03316|042|R|  at: https://eacs.sanfordguide.com/ November 2019.|6
03317|001|T|MONOGRAPH TITLE:  Lercanidipine/Cyclosporine|
03317|002|B||
03317|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03317|004|L|is contraindicated and generally should not be dispensed or administered to|
03317|005|L|the same patient.|
03317|006|B||
03317|007|A|MECHANISM OF ACTION:  Cyclosporine, a moderate inhibitor of CYP3A4, may|
03317|008|A|inhibit the metabolism of lercanidipine.(1)|
03317|009|B||
03317|010|E|CLINICAL EFFECTS:  The concurrent use of lercanidipine and cyclosporine may|
03317|011|E|result in elevated levels of lercanidipine. This may result in increased|
03317|012|E|effects of lercanidipine.(1)|
03317|013|B||
03317|014|P|PREDISPOSING FACTORS:  None determined.|
03317|015|B||
03317|016|M|PATIENT MANAGEMENT:  The manufacturer of lercanidipine states that|
03317|017|M|concurrent use of lercanidipine and cyclosporine is contraindicated.(1)|
03317|018|B||
03317|019|D|DISCUSSION:  In a study in healthy volunteers, concurrent administration of|
03317|020|D|lercanidipine and cyclosporine increased lercanidipine's plasma|
03317|021|D|concentration 3-fold and cyclosporines area-under-the-curve (AUC) by 21%.(1)|
03317|022|B||
03317|023|R|REFERENCES:|
03317|024|B||
03317|025|R|1.Zanidip (lercanidipine) UK prescribing information. Recordati|1
03317|026|R|  Pharmaceuticals Limited October 4, 2019.|1
03317|027|R|2.This information is based on an extract from the Certara Drug Interaction|6
03317|028|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03317|029|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03317|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03317|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03317|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03317|033|R|  11/14/2017.|1
03318|001|T|MONOGRAPH TITLE:  Naldemedine/Strong CYP3A4 Inhibitors|
03318|002|B||
03318|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03318|004|L|of severe adverse interaction.|
03318|005|B||
03318|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03318|007|A|naldemedine.(1)|
03318|008|B||
03318|009|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
03318|010|E|in increased levels and potential risk of adverse reactions of|
03318|011|E|naldemedine.(1)|
03318|012|B||
03318|013|P|PREDISPOSING FACTORS:  None determined.|
03318|014|B||
03318|015|M|PATIENT MANAGEMENT:  The UK manufacturer states concurrent use of a strong|
03318|016|M|inhibitor of CYP3A4 should be avoided.(1)|
03318|017|M|   The US manufacturer recommends monitoring for potential|
03318|018|M|naldemedine-related adverse reactions.(2)|
03318|019|M|   If concurrent use is unavoidable, monitor patients for signs of|
03318|020|M|naldemedine adverse reactions, such as abdominal pain and opioid withdrawal.|
03318|021|B||
03318|022|D|DISCUSSION:  Itraconazole, a strong inhibitor of CYP3A, increased exposure|
03318|023|D|to naldemedine area-under-curve (AUC) by 2.9-fold which may result in an|
03318|024|D|increased risk of adverse reactions.(1)|
03318|025|D|   Strong inhibitors of CYP3A include:  adagrasib, boceprevir, ceritinib,|
03318|026|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03318|027|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03318|028|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib,|
03318|029|D|ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib,|
03318|030|D|and voriconazole.(1-4)|
03318|031|B||
03318|032|R|REFERENCES:|
03318|033|B||
03318|034|R|1.Rizmoic (naldemedine) UK summary of product characteristics. Shionogi|1
03318|035|R|  October 11, 2019.|1
03318|036|R|2.Symproic (naldemedine) US prescribing information. Shionogi Inc. January|1
03318|037|R|  24, 2018.|1
03318|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
03318|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03318|040|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03318|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03318|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03318|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03318|044|R|  11/14/2017.|1
03319|001|T|MONOGRAPH TITLE:  Elexacaftor-Tezacaftor-Ivacaftor/Moderate CYP3A4|
03319|002|T|Inhibitors|
03319|003|B||
03319|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03319|005|L|of severe adverse interaction.|
03319|006|B||
03319|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03319|008|A|CYP3A4-mediated metabolism of elexacaftor, tezacaftor, and ivacaftor.(1)|
03319|009|B||
03319|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
03319|011|E|result in elevated levels of and toxicity from elexacaftor, tezacaftor, and|
03319|012|E|ivacaftor.(1)|
03319|013|B||
03319|014|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
03319|015|P|hepatic impairment.(1)|
03319|016|B||
03319|017|M|PATIENT MANAGEMENT:  The dosage of elexacaftor-tezacaftor-ivacaftor should|
03319|018|M|be reduced when co-administered with moderate CYP3A4 inhibitors as follows:|
03319|019|M|   - In patients 12 years and older and patients 6 to 12 years old weighing|
03319|020|M|at least 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the|
03319|021|M|evening dose of ivacaftor should not be taken.  The morning dose of therapy|
03319|022|M|should be modified to the following alternate daily dosing schedule: Day 1 -|
03319|023|M|two tablets of elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg (total|
03319|024|M|dose of elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg); Day 2 - one|
03319|025|M|tablet of ivacaftor 150 mg.|
03319|026|M|   - In patients 6 to 12 years old weighing less than 30 kg who are|
03319|027|M|receiving concurrent moderate CYP3A4 inhibitors, the evening dose of|
03319|028|M|ivacaftor should not be taken.  The morning dose of therapy should be|
03319|029|M|modified to the following alternate daily dosing schedule: Day 1 - two|
03319|030|M|tablets of elexacaftor 50 mg-tezacaftor 25 mg-ivacaftor 37.5 mg (total daily|
03319|031|M|dose of elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg); Day 2 - one|
03319|032|M|tablet of ivacaftor 75 mg.|
03319|033|M|   - In patients 2 to less than 6 years old weighing at least 14 kg who are|
03319|034|M|receiving concurrent moderate CYP3A4 inhibitors, the evening dose of|
03319|035|M|ivacaftor should not be taken.  The morning dose of therapy should be|
03319|036|M|modified to the following alternate daily dosing schedule: Day 1 - one|
03319|037|M|packet of oral granules containing elexacaftor 100 mg-tezacaftor 50|
03319|038|M|mg-ivacaftor 75 mg; Day 2 - one packet of oral granules containing ivacaftor|
03319|039|M|75 mg.(1)|
03319|040|M|   - In patients 2 to less than 6 years old weighing less than 14 kg who are|
03319|041|M|receiving concurrent moderate CYP3A4 inhibitors, the evening dose of|
03319|042|M|ivacaftor should not be taken.  The morning dose of therapy should be|
03319|043|M|modified to the following alternate daily dosing schedule: Day 1 - one|
03319|044|M|packet of oral granules containing elexacaftor 80 mg-tezacaftor 40|
03319|045|M|mg-ivacaftor 60 mg; Day 2 - one packet of oral granules containing ivacaftor|
03319|046|M|59.5 mg.(1)|
03319|047|B||
03319|048|D|DISCUSSION:  In a study, fluconazole (400 mg on day 1 then 200 mg daily)|
03319|049|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03319|050|D|ivacaftor (150 mg every 12 hours) by 2.95-fold and 2.45-fold,|
03319|051|D|respectively.(1)|
03319|052|D|   Simulations suggest that moderate CYP3A inhibitors may increase the AUC|
03319|053|D|of elexacaftor and tezacaftor by approximately 1.9 to 2.3-fold and 2.1-fold,|
03319|054|D|respectively.(1)|
03319|055|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
03319|056|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
03319|057|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
03319|058|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
03319|059|D|isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
03319|060|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and|
03319|061|D|verapamil.(2-4)|
03319|062|B||
03319|063|R|REFERENCES:|
03319|064|B||
03319|065|R|1.Trikafta (elexacaftor, tezacaftor and ivacaftor tablets; ivacaftor|1
03319|066|R|  tablets) US prescribing information. Vertex Pharmaceuticals Incorporated|1
03319|067|R|  December, 2024.|1
03319|068|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03319|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03319|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03319|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03319|072|R|  11/14/2017.|1
03319|073|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03319|074|R|  Indiana University School of Medicine.  Available at:|1
03319|075|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03319|076|R|4.This information is based on an extract from the Certara Drug Interaction|6
03319|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03320|001|T|MONOGRAPH TITLE:  Elexacaftor-Tezacaftor-Ivacaftor/Strong CYP3A4 Inhibitors|
03320|002|B||
03320|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03320|004|L|of severe adverse interaction.|
03320|005|B||
03320|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03320|007|A|of elexacaftor-tezacaftor-ivacaftor.(1)|
03320|008|B||
03320|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
03320|010|E|elevated levels of and toxicity from elexacaftor-tezacaftor-ivacaftor.(1)|
03320|011|B||
03320|012|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
03320|013|P|hepatic impairment.(1)|
03320|014|B||
03320|015|M|PATIENT MANAGEMENT:  The dosage of elexacaftor-tezacaftor-ivacaftor should|
03320|016|M|be reduced when co-administered with strong CYP3A4 inhibitors.|
03320|017|M|   -The evening dose of ivacaftor should not be taken.|
03320|018|M|   -For individuals 12 years and older or children 6 to less than 12 years|
03320|019|M|old weighing more than 30 kg, the morning dose of therapy should be modified|
03320|020|M|as follows: Day 1 - two tablets of elexacaftor-tezacaftor-ivacaftor; Day 2 -|
03320|021|M|no dose; Day 3 - no dose; Day 4 - two tablets of|
03320|022|M|elexacaftor-tezacaftor-ivacaftor.  Thereafter, continue two|
03320|023|M|elexacaftor-tezacaftor-ivacaftor tablets twice a week, approximately 3 to 4|
03320|024|M|days apart.|
03320|025|M|   -For children 2 to less than 6 years old weighing less than 14 kg, the|
03320|026|M|morning dose of therapy should be modified as follows: Day 1 - one packet of|
03320|027|M|elexacaftor-tezacaftor-ivacaftor (elexacaftor 80 mg/tezacaftor 40|
03320|028|M|mg/ivacaftor 60 mg); Day 2 - no dose; Day 3 - no dose; Day 4 - one packet of|
03320|029|M|elexacaftor-tezacaftor-ivacaftor.  Thereafter, continue two|
03320|030|M|elexacaftor-tezacaftor-ivacaftor tablets twice a week, approximately 3 to 4|
03320|031|M|days apart.|
03320|032|M|   -For children 2 to less than 6 years old weighing 14 kg or more, the|
03320|033|M|morning dose of therapy should be modified as follows: Day 1 - one packet of|
03320|034|M|elexacaftor-tezacaftor-ivacaftor (elexacaftor 100 mg/tezacaftor 50|
03320|035|M|mg/ivacaftor 75 mg); Day 2 - no dose; Day 3 - no dose; Day 4 - one packet of|
03320|036|M|elexacaftor-tezacaftor-ivacaftor.  Thereafter, continue two|
03320|037|M|elexacaftor-tezacaftor-ivacaftor tablets twice a week, approximately 3 to 4|
03320|038|M|days apart.|
03320|039|M|   -For children 6 to less than 12 years old weighing less than 30 kg, the|
03320|040|M|morning dose of therapy should be modified as follows: Day 1 - two tablets|
03320|041|M|of elexacaftor-tezacaftor-ivacaftor (elexacaftor 50 mg/tezacaftor 25|
03320|042|M|mg/ivacaftor 37.5 mg); Day 2 - no dose; Day 3 - no dose; Day 4 - two tablets|
03320|043|M|of elexacaftor-tezacaftor-ivacaftor.  Thereafter, continue two|
03320|044|M|elexacaftor-tezacaftor-ivacaftor tablets twice a week, approximately 3 to 4|
03320|045|M|days apart.(1)|
03320|046|B||
03320|047|D|DISCUSSION:  Co-administration with itraconazole, a strong CYP3A4 inhibitor,|
03320|048|D|increased elexacaftor area-under-curve (AUC) by 2.8-fold and tezacaftor AUC|
03320|049|D|by 4 to 4.5-fold. When co-administered with itraconazole and ketoconazole,|
03320|050|D|ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively.(1)|
03320|051|D|   A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with|
03320|052|D|ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B),|
03320|053|D|and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4|
03320|054|D|of ivacaftor administration (study C).  In study A, B, and C, ivacaftor AUC|
03320|055|D|increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively,|
03320|056|D|with the addition of ritonavir.  Ivacaftor concentration maximum (Cmax) was|
03320|057|D|0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(2)|
03320|058|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03320|059|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03320|060|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
03320|061|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03320|062|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03320|063|D|troleandomycin, tucatinib, and voriconazole.(3-5)|
03320|064|B||
03320|065|R|REFERENCES:|
03320|066|B||
03320|067|R|1.Trikafta (elexacaftor, tezacaftor and ivacaftor tablets; ivacaftor|1
03320|068|R|  tablets) US prescribing information. Vertex Pharmaceuticals Incorporated|1
03320|069|R|  December, 2024.|1
03320|070|R|2.Liddy AM, McLaughlin G, Schmitz S, D'Arcy DM, Barry MG. The|2
03320|071|R|  Pharmacokinetic Interaction between Ivacaftor and Ritonavir in Healthy|2
03320|072|R|  Volunteers. Br J Clin Pharmacol 2017 May 06.|2
03320|073|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03320|074|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03320|075|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03320|076|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03320|077|R|  11/14/2017.|1
03320|078|R|4.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03320|079|R|  Indiana University School of Medicine.  Available at:|1
03320|080|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03320|081|R|5.This information is based on an extract from the Certara Drug Interaction|6
03320|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03321|001|T|MONOGRAPH TITLE:  Tamoxifen/Selected Moderate CYP2D6 Inhibitors|
03321|002|B||
03321|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03321|004|L|of severe adverse interaction.|
03321|005|B||
03321|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2D6 may inhibit the conversion of|
03321|007|A|tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2)  The role|
03321|008|A|of endoxifen in tamoxifen's efficacy has been debated and may involve a|
03321|009|A|minimum concentration level.(3-5)|
03321|010|B||
03321|011|E|CLINICAL EFFECTS:  Concurrent use of inhibitors of CYP2D6 may decrease the|
03321|012|E|effectiveness of tamoxifen in preventing breast cancer recurrence.|
03321|013|B||
03321|014|P|PREDISPOSING FACTORS:  Concurrent use of moderate CYP2D6 inhibitors in|
03321|015|P|patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers|
03321|016|P|should be avoided.  Patients who are CYP2D6 poor metabolizers lack CYP2D6|
03321|017|P|function and are not affected by CYP2D6 inhibition.|
03321|018|B||
03321|019|M|PATIENT MANAGEMENT:  Although data on this interaction are conflicting, it|
03321|020|M|may be prudent to use alternatives to CYP2D6 inhibitors when possible in|
03321|021|M|patients taking tamoxifen.  The US manufacturer of tamoxifen states that the|
03321|022|M|impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain|
03321|023|M|and makes no recommendation regarding coadministration with inhibitors of|
03321|024|M|CYP2D6.(12)  The manufacturer of paroxetine (a strong CYP2D6 inhibitor)|
03321|025|M|states that alternative agents with little or no CYP2D6 inhibition should be|
03321|026|M|considered.(13)|
03321|027|M|   The National Comprehensive Cancer Network's breast cancer guidelines|
03321|028|M|advises caution when coadministering strong CYP2D6 inhibitors with|
03321|029|M|tamoxifen.(14)|
03321|030|M|   If concurrent therapy is warranted, the risks versus benefits should be|
03321|031|M|discussed with the patient.|
03321|032|M|   Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected|
03321|033|M|to last at least 28 days after administration.(15)|
03321|034|B||
03321|035|D|DISCUSSION:  Some studies have suggested that administration of fluoxetine,|
03321|036|D|paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer|
03321|037|D|phenotype may result in a decrease in the formation of endoxifen (an active|
03321|038|D|metabolite of tamoxifen) and a shorter time to breast cancer|
03321|039|D|recurrence.(1-2,9)|
03321|040|D|   A retrospective study of 630 breast cancer patients found an increasing|
03321|041|D|risk of breast cancer mortality with increasing durations of|
03321|042|D|coadministration of tamoxifen and paroxetine.  In the adjusted analysis,|
03321|043|D|absolute increases of 25%, 50%, and 75% in the proportion of time of|
03321|044|D|overlapping use of tamoxifen with paroxetine was associated with 24%, 54%,|
03321|045|D|and 91% increase in the risk of death from breast cancer, respectively.(16)|
03321|046|D|   The CYP2D6 genotype of the patient may have a role in the effects of this|
03321|047|D|interaction.  Patients with wild-type CYP2D6 genotype may be affected to a|
03321|048|D|greater extent by this interaction.  Patients with a variant CYP2D6 genotype|
03321|049|D|may have lower baseline levels of endoxifen and may be affected to a lesser|
03321|050|D|extent by this interaction.(6-10)|
03321|051|D|   In a retrospective review, 1,325 patients treated with tamoxifen for|
03321|052|D|breast cancer were classified as being poor 2D6 metabolizers (lacking|
03321|053|D|functional CYP2D6 enzymes), intermediate metabolizers (heterozygous|
03321|054|D|alleles), or extensive metabolizers (possessing 2 functional alleles).|
03321|055|D|After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%,|
03321|056|D|20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and|
03321|057|D|poor metabolizers, respectively.(11)|
03321|058|D|   In October of 2006, the Advisory Committee Pharmaceutical Science,|
03321|059|D|Clinical Pharmacology Subcommittee of the US Food and Drug Administration|
03321|060|D|recommended that the US tamoxifen labeling be updated to include information|
03321|061|D|about the increased risk of breast cancer recurrence in poor CYP2D6|
03321|062|D|metabolizers (either by genotype or drug interaction).(17-18)  The labeling|
03321|063|D|changes were never made due to ongoing uncertainty about the effects of|
03321|064|D|CYP2D6 genotypes on tamoxifen efficacy.|
03321|065|D|   In contrast to the above information, two studies have shown no|
03321|066|D|relationship between CYP2D6 genotype and breast cancer outcome.(19-21)  As|
03321|067|D|well, a number of studies found no association between use of CYP2D6|
03321|068|D|inhibitors and/or antidepressants in patients on tamoxifen and breast cancer|
03321|069|D|recurrence,(22-26) though the studies were limited by problematic selection|
03321|070|D|of CYP2D6 inhibitors and short follow-up.|
03321|071|D|   A single dose of rolapitant increased dextromethorphan, a CYP2D6|
03321|072|D|substrate, about 3-fold on days 8 and day 22 following administration.|
03321|073|D|Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single|
03321|074|D|dose rolapitant.  The inhibitory effects of rolapitant on CYP2D6 are|
03321|075|D|expected to persist beyond 28 days.(15)|
03321|076|D|   Moderate inhibitors of CYP2D6 include abiraterone, asunaprevir,|
03321|077|D|berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat, mirabegron,|
03321|078|D|moclobemide, rolapitant, and tipranavir/ritonavir.(27-28)|
03321|079|B||
03321|080|R|REFERENCES:|
03321|081|B||
03321|082|R|1.Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes|2
03321|083|R|  DF, Desta Z, Flockhart DA. Active tamoxifen metabolite plasma|2
03321|084|R|  concentrations after coadministration of tamoxifen and the selective|2
03321|085|R|  serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003 Dec 3;|2
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03321|087|R|2.Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li|2
03321|088|R|  L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S,|2
03321|089|R|  Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype,|2
03321|090|R|  antidepressant use, and tamoxifen metabolism during adjuvant breast cancer|2
03321|091|R|  treatment. J Natl Cancer Inst 2005 Jan 5;97(1):30-9.|2
03321|092|R|3.Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z,|2
03321|093|R|  Flockhart DA, Skaar TC. Pharmacological characterization of|2
03321|094|R|  4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen.|2
03321|095|R|  Breast Cancer Res Treat 2004 May;85(2):151-9.|2
03321|096|R|4.Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of|2
03321|097|R|  tamoxifen sequential biotransformation by the human cytochrome P450 system|2
03321|098|R|  in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004|2
03321|099|R|  Sep;310(3):1062-75.|2
03321|100|R|5.Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen|2
03321|101|R|  (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast|2
03321|102|R|  cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother|2
03321|103|R|  Pharmacol 2005 May;55(5):471-8.|2
03321|104|R|6.Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, Nussler|5
03321|105|R|  A, Neuhaus P, Zanger UM, Eichelbaum M, Murdter TE. The influence of|5
03321|106|R|  CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent|5
03321|107|R|  antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol|5
03321|108|R|  2002 Aug;54(2):157-67.|5
03321|109|R|7.Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6|6
03321|110|R|  as a predictor of drug response. Clin Pharmacol Ther 2008 Jan;83(1):160-6.|6
03321|111|R|8.Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD. CYP2D6 polymorphisms|6
03321|112|R|  and the impact on tamoxifen therapy. J Pharm Sci 2007 Sep;96(9):2224-31.|6
03321|113|R|9.Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW,|2
03321|114|R|  Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM,|2
03321|115|R|  Desta Z, Nguyen A, Flockhart DA. Perez EA, Ingle JN. The impact of|2
03321|116|R|  cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.|2
03321|117|R|  Breast Cancer Res Treat 2007 Jan;101(1):113-21.|2
03321|118|R|10.Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C,|2
03321|119|R|   Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN.|2
03321|120|R|   Pharmacogenetics of tamoxifen biotransformation is associated with|2
03321|121|R|   clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005 Dec 20;|2
03321|122|R|   23(36):9312-8.|2
03321|123|R|11.Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P,|2
03321|124|R|   Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J,|2
03321|125|R|   Strick R, Beckmann MW, Koelbl H. Weinshilboum RM, Ingle JN, Eichelbaum M,|2
03321|126|R|   Schwab M, Brauch H. Association between CYP2D6 polymorphisms and outcomes|2
03321|127|R|   among women with early stage breast cancer treated with tamoxifen. JAMA|2
03321|128|R|   2009 Oct 7;302(13):1429-36.|2
03321|129|R|12.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
03321|130|R|   US Inc. September 25, 2018.|1
03321|131|R|13.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
03321|132|R|   Technologies January, 2017.|1
03321|133|R|14.Gradishar WJ, Anderson BO, Avraham J, etal. NCCN Clinical Practice|6
03321|134|R|   Guidelines in Oncology: Breast Cancer. Available at:|6
03321|135|R|   https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf September|6
03321|136|R|   6, 2019.|6
03321|137|R|15.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
03321|138|R|16.Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC,|2
03321|139|R|   Paszat LF. Selective serotonin reuptake inhibitors and breast cancer|2
03321|140|R|   mortality in women receiving tamoxifen: a population based cohort study.|2
03321|141|R|   BMJ 2010 Feb 8;340:c693.|2
03321|142|R|17.Phan MT, Venitz J. Summary minutes of the Advisory Committee|1
03321|143|R|   Pharmaceutical Science Clinical Pharmacology Subcommittee. Available at:|1
03321|144|R|   http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4248m1.pdf October|1
03321|145|R|   18-19, 2006.|1
03321|146|R|18.Rahman NA. Personal communication. Division Director, Office of Clinical|1
03321|147|R|   Pharmacology, US Food and Drug Administration March 4, 2008.|1
03321|148|R|19.Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, Salter J,|2
03321|149|R|   Sestak I, Cuzick J, Dowsett M. CYP2D6 and UGT2B7 genotype and risk of|2
03321|150|R|   recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer|2
03321|151|R|   Inst 2012 Mar 21;104(6):452-60.|2
03321|152|R|20.Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R,|2
03321|153|R|   Dell'orto P, Biasi MO, Thurlimann B, Lyng MB, Ditzel HJ, Neven P, Debled|2
03321|154|R|   M, Maibach R, Price KN, Gelber RD, Coates AS. Goldhirsch A, Rae JM, Viale|2
03321|155|R|   G,. CYP2D6 genotype and tamoxifen response in postmenopausal women with|2
03321|156|R|   endocrine-responsive breast cancer: the breast international group 1-98|2
03321|157|R|   trial. J Natl Cancer Inst 2012 Mar 21;104(6):441-51.|2
03321|158|R|21.Kelly CM, Pritchard KI. CYP2D6 genotype as a marker for benefit of|6
03321|159|R|   adjuvant tamoxifen in postmenopausal women: lessons learned. J Natl|6
03321|160|R|   Cancer Inst 2012 Mar 21;104(6):427-8.|6
03321|161|R|22.Donneyong MM, Bykov K, Bosco-Levy P, Dong YH, Levin R, Gagne JJ. Risk of|2
03321|162|R|   mortality with concomitant use of tamoxifen and selective serotonin|2
03321|163|R|   reuptake inhibitors: multi-database cohort study. BMJ 2016 Sep 30;|2
03321|164|R|   354:i5014.|2
03321|165|R|23.Haque R, Shi J, Schottinger JE, Ahmed SA, Cheetham TC, Chung J, Avila C,|2
03321|166|R|   Kleinman K, Habel LA, Fletcher SW, Kwan ML. Tamoxifen and Antidepressant|2
03321|167|R|   Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors. J Natl|2
03321|168|R|   Cancer Inst 2016 Mar;108(3):.|2
03321|169|R|24.Cronin-Fenton DP, Damkier P, Lash TL. Metabolism and transport of|2
03321|170|R|   tamoxifen in relation to its effectiveness: new perspectives on an|2
03321|171|R|   ongoing controversy. Future Oncol 2014 Jan;10(1):107-22.|2
03321|172|R|25.Azoulay L, Dell'Aniello S, Huiart L, du Fort GG, Suissa S. Concurrent use|2
03321|173|R|   of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer|2
03321|174|R|   recurrence. Breast Cancer Res Treat 2011 Apr;126(3):695-703.|2
03321|175|R|26.Dezentje VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel|2
03321|176|R|   MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ. Effect of|2
03321|177|R|   concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer|2
03321|178|R|   recurrence in early-stage breast cancer. J Clin Oncol 2010 May 10;|2
03321|179|R|   28(14):2423-9.|2
03321|180|R|27.This information is based on an extract from the Certara Drug Interaction|6
03321|181|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03321|182|R|28.US Food and Drug Administration (FDA). Drug Development and Drug|1
03321|183|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03321|184|R|   at:|1
03321|185|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03321|186|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03321|187|R|   11/14/2017.|1
03321|188|R|29.Dehal SS, Kupfer D. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human|5
03321|189|R|   liver. Cancer Res 1997 Aug 15;57(16):3402-6.|5
03321|190|R|30.Goetz MP, Sangkuhl K, Guchelaar HJ, Schwab M, Province M, Whirl-Carrillo|6
03321|191|R|   M, Symmans WF, McLeod HL, Ratain MJ, Zembutsu H, Gaedigk A, van Schaik|6
03321|192|R|   RH, Ingle JN, Caudle KE, Klein TE. Clinical Pharmacogenetics|6
03321|193|R|   Implementation Consortium (CPIC) Guideline for CYP2D6  and Tamoxifen|6
03321|194|R|   Therapy. Clin Pharmacol Ther 2018 May;103(5):770-777.|6
03322|001|T|MONOGRAPH TITLE:  Tramadol/Meperidine|
03322|002|B||
03322|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03322|004|L|of severe adverse interaction.|
03322|005|B||
03322|006|A|MECHANISM OF ACTION:  The concurrent administration of tramadol(1) with|
03322|007|A|meperidine(2) may result in additive blockade of serotonin reuptake, leading|
03322|008|A|to central serotonergic hyperstimulation, as well as additive sedation,|
03322|009|A|respiratory depression, coma, and/or death.|
03322|010|B||
03322|011|E|CLINICAL EFFECTS:  Concurrent administration may increase the risk for|
03322|012|E|adverse events, including serotonin syndrome, sedation, and respiratory|
03322|013|E|depression.  Symptoms of serotonin syndrome may include tremor, agitation,|
03322|014|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03322|015|E|rigidity.(3)|
03322|016|B||
03322|017|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers have|
03322|018|P|accelerated conversion of tramadol to its active metabolite, M1, and may be|
03322|019|P|at higher risk of sedation and respiratory depression.(1)|
03322|020|P|   Treatment with multiple medications which increase serotonin levels or|
03322|021|P|with medications which inhibit the metabolism of serotonin increasing drugs|
03322|022|P|are risk factors for serotonin syndrome.(3)|
03322|023|P|   A genetic defect in CYP2D6 leading to the slow metabolizer phenotype may|
03322|024|P|increase the risk for serotonin syndrome due to tramadol.|
03322|025|P|   Renal dysfunction and chronic use of meperidine would be expected to|
03322|026|P|increase the risk for serotonin toxicity due to meperidine.|
03322|027|B||
03322|028|M|PATIENT MANAGEMENT:  Use an alternative to meperidine whenever possible,|
03322|029|M|particularly in patients with renal impairment.|
03322|030|M|   If concurrent therapy of tramadol with meperidine is warranted, patients|
03322|031|M|should be closely monitored for signs and symptoms of sedation, respiratory|
03322|032|M|depression and serotonin syndrome.  One or both agents may need to be|
03322|033|M|discontinued.|
03322|034|M|   Respiratory depression can occur at any time during opioid therapy,|
03322|035|M|especially during therapy initiation and following dosage increases.  The|
03322|036|M|risk of opioid-related overdose or overdose-related death is increased with|
03322|037|M|higher opioid doses, and this risk persists over the course of therapy.|
03322|038|M|Consider these risks when using concurrently with other agents that may|
03322|039|M|cause CNS depression.|
03322|040|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03322|041|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03322|042|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03322|043|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03322|044|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03322|045|M|as those taking CNS depressants) and when a patient has household|
03322|046|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03322|047|M|for obtaining an opioid reversal agent (e.g., prescription,|
03322|048|M|over-the-counter, or as part of a community-based program).(2)|
03322|049|B||
03322|050|D|DISCUSSION:  There are a number of serotonin syndrome case reports following|
03322|051|D|the addition of tramadol to a stable selective serotonin reuptake inhibitor|
03322|052|D|regimen.  The syndrome developed between 12 hours to 3 weeks after the|
03322|053|D|initiation of tramadol therapy.  Patients recovered after tramadol and/or|
03322|054|D|the SSRI/SNRI was discontinued.(4-16)  One patient also developed mania.(4)|
03322|055|D|Another patient developed nightmares and hallucinations after taking|
03322|056|D|concurrent tramadol and paroxetine for 56 days.(5)|
03322|057|D|   One author suggests that although the combination of tramadol and SSRIs|
03322|058|D|or SNRIs is associated with a risk for serotonin syndrome, given the high|
03322|059|D|rate of co-prescribing for the combination it is an uncommon outcome.(17)|
03322|060|D|   Case reports describe the interaction between meperidine and|
03322|061|D|serotonin-increasing agents.(18-20)|
03322|062|D|   Although there are no reports of serotonin syndrome specifically with the|
03322|063|D|combination of tramadol and meperidine, both drugs inhibit serotonin|
03322|064|D|reuptake and caution is still warranted.|
03322|065|B||
03322|066|R|REFERENCES:|
03322|067|B||
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03322|087|R|9.Sauget D, Franco PS, Amaniou M, Mazere J, Dantoine T. Possible|3
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03322|089|R|  an elderly woman. Therapie 2002 May-Jun;57(3):309-10.|3
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03322|091|R|   a result of fluoxetine in a patient with tramadol abuse: plasma|3
03322|092|R|   level-correlated symptomatology. J Clin Psychopharmacol 2002 Aug;|3
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03322|094|R|11.Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. J|3
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03322|097|R|   to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol 1997|3
03322|098|R|   May;12(3):181-2.|3
03322|099|R|13.Lantz MS, Buchalter EN, Giambanco V. Serotonin syndrome following the|3
03322|100|R|   administration of tramadol with paroxetine. Int J Geriatr Psychiatry 1998|3
03322|101|R|   May;13(5):343-5.|3
03322|102|R|14.John AP, Koloth R. Severe serotonin toxicity and manic switch induced by|3
03322|103|R|   combined use of tramadol and paroxetine. Aust N Z J Psychiatry 2007 Feb;|3
03322|104|R|   41(2):192-3.|3
03322|105|R|15.Llinares-Tello F, Escriva-Moscardo S, Martinez-Pastor F,|3
03322|106|R|   Martinez-Mascaraque P. Possible serotoninergic syndrome associated with|3
03322|107|R|   coadministration of paroxetine and tramadol. Med Clin (Barc) 2007 Mar 24;|3
03322|108|R|   128(11):438.|3
03322|109|R|16.Venlafaxine + tramadol: serotonin syndrome. Prescrire Int 2004 Apr;|3
03322|110|R|   13(70):57.|3
03322|111|R|17.Park SH, Wackernah RC, Stimmel GL. Serotonin syndrome: is it a reason to|6
03322|112|R|   avoid the use of tramadol with antidepressants?. J Pharm Pract 2014 Feb;|6
03322|113|R|   27(1):71-8.|6
03322|114|R|18.Tissot TA. Probable meperidine-induced serotonin syndrome in a patient|3
03322|115|R|   with a history of fluoxetine use. Anesthesiology 2003 Jun;98(6):1511-2.|3
03322|116|R|19.Altman EM, Manos GH. Serotonin syndrome associated with citalopram and|3
03322|117|R|   meperidine. Psychosomatics 2007 Jul-Aug;48(4):361-3.|3
03322|118|R|20.Dougherty JA, Young H, Shafi T. Serotonin syndrome induced by|3
03322|119|R|   amitriptyline, meperidine, and venlafaxine. Ann Pharmacother 2002 Oct;|3
03322|120|R|   36(10):1647-8.|3
03322|121|R|21.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03322|122|R|   updates prescribing information for all opioid pain medicines to provide|1
03322|123|R|   additional guidance for safe use. Available at:|1
03322|124|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescr|1
03322|125|R|   ibing-information-all-opioid-pain-medicines-provide-additional-guidance-s|1
03322|126|R|   afe-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03323|001|T|MONOGRAPH TITLE:  Cyclobenzaprine/Meperidine|
03323|002|B||
03323|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03323|004|L|take action as needed.|
03323|005|B||
03323|006|A|MECHANISM OF ACTION:  Cyclobenzaprine and meperidine may have additive|
03323|007|A|effects on serotonin levels.(1,2)|
03323|008|B||
03323|009|E|CLINICAL EFFECTS:  Concurrent administration of cyclobenzaprine with|
03323|010|E|meperidine may result in serotonin syndrome.  Symptoms of serotonin syndrome|
03323|011|E|may include tremor, agitation, diaphoresis, hyperreflexia, clonus,|
03323|012|E|tachycardia, hyperthermia, and muscle rigidity.|
03323|013|B||
03323|014|P|PREDISPOSING FACTORS:  Predisposing factors include elderly, renal or|
03323|015|P|hepatic dysfunction, and use of multiple agents which increase central|
03323|016|P|serotonin levels.  Chronic use of cyclobenzaprine or meperidine would also|
03323|017|P|be expected to increase the risk for serotonin toxicity.(1,2)|
03323|018|B||
03323|019|M|PATIENT MANAGEMENT:  The US manufacturer of cyclobenzaprine recommends|
03323|020|M|limiting use to short term duration, no more than two to three weeks.  The|
03323|021|M|US manufacturer of meperidine states that it should not be used for|
03323|022|M|treatment of chronic pain.  Use alternative therapy whenever possible,|
03323|023|M|particularly in patients with renal or hepatic impairment.(1,2)|
03323|024|M|   If concurrent therapy is warranted, patients should be monitored for|
03323|025|M|signs and symptoms of serotonin syndrome, and seizure activity.  Instruct|
03323|026|M|patients to report muscle twitching, tremors, shivering and stiffness,|
03323|027|M|fever, heavy sweating, heart palpitations, restlessness, confusion,|
03323|028|M|agitation, trouble with coordination, or severe diarrhea.|
03323|029|B||
03323|030|D|DISCUSSION:  Case reports documenting serotonin syndrome with|
03323|031|D|cyclobenzaprine and other serotonergic agents are described.  The risk of|
03323|032|D|serotonin syndrome with cyclobenzaprine may occur based on serotonin|
03323|033|D|activity of both agents.(3,4)|
03323|034|D|   A case report of a 70 year old female on phenelzine (non-selective MAOI)|
03323|035|D|15 mg four times daily for several years developed serotonin syndrome after|
03323|036|D|the third dose of cyclobenzaprine 10 mg three times daily.  After|
03323|037|D|discontinuation of both cyclobenzaprine and phenelzine, symptoms resolved|
03323|038|D|within three days.  Within the following month, the patient was restarted on|
03323|039|D|phenelzine without any further sequelae.(5)|
03323|040|D|   A case report of a 53 year old male on duloxetine (SNRI) 60 mg daily|
03323|041|D|developed symptoms of serotonin syndrome shortly after initiation of|
03323|042|D|cyclobenzaprine 10 mg three times daily.  Both cyclobenzaprine and|
03323|043|D|duloxetine were stopped and cyproheptadine was given with resolution of|
03323|044|D|symptoms.(5)|
03323|045|D|   A case report of a 27 year old female on escitalopram (SSRI) 10 mg daily|
03323|046|D|presented with serotonin syndrome after an overdose of 5-6 cyclobenzaprine|
03323|047|D|10 mg tablets.  The patient was treated with symptomatic care and|
03323|048|D|cyproheptadine with resolution of symptoms on day two and discharged with|
03323|049|D|instructions to discontinue cyclobenzaprine use.(6)|
03323|050|D|   Case reports describe the interaction between meperidine and|
03323|051|D|serotonin-increasing agents.(7-9)|
03323|052|D|   Although there are no reports of serotonin syndrome specifically with the|
03323|053|D|combination of cyclobenzaprine and meperidine, both drugs inhibit serotonin|
03323|054|D|reuptake and caution is still warranted.|
03323|055|B||
03323|056|R|REFERENCES:|
03323|057|B||
03323|058|R|1.Flexeril (cyclobenzaprine) US prescribing information. McNeil Consumer and|1
03323|059|R|  Speciality Pharmaceuticals April, 2013.|1
03323|060|R|2.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
03323|061|R|  Pharmaceuticals LLC. December, 2023.|1
03323|062|R|3.Goodman-Gilman A. In Gilman AG, Rall TW, Nies AS, Taylor P, editors:|6
03323|063|R|  Goodman and Gilman's The Phamacological Basis of Therapeutics. 8th|6
03323|064|R|  edition. Elmsford, New York: Pergamon Press, Inc. 1990.|6
03323|065|R|4.Mestres J, Seifert SA, Oprea TI. Linking pharmacology to clinical reports:|5
03323|066|R|  cyclobenzaprine and its possible association with serotonin syndrome. Clin|5
03323|067|R|  Pharmacol Ther 2011 Nov;90(5):662-5.|5
03323|068|R|5.Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the|3
03323|069|R|  interaction of cyclobenzaprine with other serotoninergic drugs. Anesth|3
03323|070|R|  Analg 2006 Dec;103(6):1466-8.|3
03323|071|R|6.Day LT, Jeanmonod RK. Serotonin syndrome in a patient taking Lexapro and|3
03323|072|R|  Flexeril: a case report. Am J Emerg Med 2008 Nov;26(9):1069.e1-3.|3
03323|073|R|7.Tissot TA. Probable meperidine-induced serotonin syndrome in a patient|3
03323|074|R|  with a history of fluoxetine use. Anesthesiology 2003 Jun;98(6):1511-2.|3
03323|075|R|8.Altman EM, Manos GH. Serotonin syndrome associated with citalopram and|3
03323|076|R|  meperidine. Psychosomatics 2007 Jul-Aug;48(4):361-3.|3
03323|077|R|9.Dougherty JA, Young H, Shafi T. Serotonin syndrome induced by|3
03323|078|R|  amitriptyline, meperidine, and venlafaxine. Ann Pharmacother 2002 Oct;|3
03323|079|R|  36(10):1647-8.|3
03324|001|T|MONOGRAPH TITLE:  Amphetamines/Meperidine|
03324|002|B||
03324|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03324|004|L|take action as needed.|
03324|005|B||
03324|006|A|MECHANISM OF ACTION:  Opioids and stimulants exhibit opposing effects on the|
03324|007|A|CNS.(1)|
03324|008|A|   Amphetamines may affect serotonin release and/or reuptake, depending on|
03324|009|A|their molecular structure.  Ring substitution tends to increase|
03324|010|A|amphetamine-induced release of endogenous serotonin.  However, the effect on|
03324|011|A|serotonin release may also be dose related and is more likely if the|
03324|012|A|amphetamine is taken in doses greater than those approved and generally|
03324|013|A|employed in treating attention-deficit-hyperactivity-disorder, or if abused,|
03324|014|A|especially over long periods of time.(1)|
03324|015|A|   Meperidine blocks serotonin reuptake.  Concurrent administration of|
03324|016|A|amphetamines with meperidine may produce additive effects on serotonin,|
03324|017|A|resulting in serotonin syndrome.(2,3)|
03324|018|B||
03324|019|E|CLINICAL EFFECTS:  Concurrent use of opioids and stimulants may have|
03324|020|E|unpredictable effects and may mask overdose symptoms of the opioid, such as|
03324|021|E|drowsiness and inability to focus.|
03324|022|E|   Concurrent use of amphetamines with meperidine may increase the risk of|
03324|023|E|serotonin syndrome, a potentially life-threatening syndrome which may|
03324|024|E|include one or more of the following symptoms: tremor, agitation,|
03324|025|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03324|026|E|rigidity.(4)|
03324|027|B||
03324|028|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03324|029|P|may increase the risk of adverse effects.|
03324|030|P|   High doses or long-term abuse of amphetamines may increase the risk of|
03324|031|P|this interaction.  Renal dysfunction and chronic use of meperidine would|
03324|032|P|also be expected to increase the risk for serotonin toxicity.|
03324|033|P|   Use of multiple drugs which increase serotonin levels is associated with|
03324|034|P|an increased risk for this toxidrome.|
03324|035|B||
03324|036|M|PATIENT MANAGEMENT:  Limit prescribing meperidine with CNS stimulants such|
03324|037|M|as amphetamines to patients for whom alternatives are ineffective, not|
03324|038|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03324|039|M|of pain.(1)  Concurrent use of amphetamines with meperidine should be|
03324|040|M|approached with appropriate monitoring, especially during therapy initiation|
03324|041|M|and dose increase.|
03324|042|M|   Instruct patients receiving concurrent therapy to report any signs or|
03324|043|M|symptoms of serotonin syndrome immediately.|
03324|044|M|   Consider initiating amphetamines or meperidine at lower doses and monitor|
03324|045|M|for signs and symptoms of serotonin syndrome.  Discontinue one or both|
03324|046|M|medications if symptoms occur.|
03324|047|M|   Respiratory depression can occur at any time during opioid therapy,|
03324|048|M|especially during therapy initiation and following dosage increases.  The|
03324|049|M|risk of opioid-related overdose or overdose-related death is increased with|
03324|050|M|higher opioid doses, and this risk persists over the course of therapy.|
03324|051|M|Consider these risks when using concurrently with stimulants.|
03324|052|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03324|053|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03324|054|M|unresponsiveness.(1)  Discuss opioid reversal agents (e.g., naloxone,|
03324|055|M|nalmefene) to patients when prescribing or renewing an opioid analgesic or|
03324|056|M|medicine to treat opioid use disorder (OUD).  Consider prescribing opioid|
03324|057|M|reversal agents (e.g., naloxone, nalmefene) to patients prescribed medicines|
03324|058|M|to treat OUD or opioid analgesics who are at increased risk of opioid|
03324|059|M|overdose (such as those taking CNS depressants) and when a patient has|
03324|060|M|household members/close contacts at risk for accidental overdose.  Discuss|
03324|061|M|the options for obtaining an opioid reversal agent (e.g., prescription,|
03324|062|M|over-the-counter, or as part of a community-based program).(1)  Monitor|
03324|063|M|patients receiving concurrent therapy for signs of substance abuse.|
03324|064|B||
03324|065|D|DISCUSSION:  A total of 70,237 persons died from drug overdoses in the|
03324|066|D|United States in 2017; approximately two thirds of these deaths involved an|
03324|067|D|opioid.(2).  The CDC analyzed 2016-2017 changes in age-adjusted death rates|
03324|068|D|involving cocaine and psychostimulants by demographic characteristics,|
03324|069|D|urbanization levels, U.S. Census region, 34 states, and the District of|
03324|070|D|Columbia (DC).  The CDC also examined trends in age-adjusted|
03324|071|D|cocaine-involved and psychostimulant-involved death rates from 2003 to 2017|
03324|072|D|overall, as well as with and without co-involvement of opioids.  Among all|
03324|073|D|2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333|
03324|074|D|(14.7%) involved psychostimulants.  Death rates increased from 2016 to 2017|
03324|075|D|for both drug categories across demographic characteristics, urbanization|
03324|076|D|levels, Census regions, and states.  In 2017, opioids were involved in 72.7%|
03324|077|D|and 50.4% of cocaine-involved and psychostimulant-involved overdoses,|
03324|078|D|respectively, and the data suggest that increases in cocaine-involved|
03324|079|D|overdose deaths from 2012 to 2017 were driven primarily by synthetic|
03324|080|D|opioids.(7)|
03324|081|D|   There was opioid co-involvement in 72.7 percent of cocaine and 50.4|
03324|082|D|percent of stimulant-involved overdose deaths.  This was largely driven by|
03324|083|D|synthetic opioids such as fentanyl. However, stimulant-involved overdose|
03324|084|D|without opioid co-involvement is also increasing.(6)|
03324|085|B||
03324|086|R|REFERENCES:|
03324|087|B||
03324|088|R|1.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03324|089|R|  prescribing information for all opioid pain medicines to provide|1
03324|090|R|  additional guidance for safe use. Available at:|1
03324|091|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03324|092|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03324|093|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03324|094|R|2.Anonymous. Personal communication:  Adderall XR and SSRI's. Shire US Inc.|1
03324|095|R|  August 11, 2004.|1
03324|096|R|3.Adderall (amphetmine) US prescribing information. Barr Laboratories, Inc.|1
03324|097|R|  January, 2017.|1
03324|098|R|4.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
03324|099|R|  Pharmaceuticals LLC. December, 2023.|1
03324|100|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03324|101|R|  352(11):1112-20.|6
03324|102|R|6.Seth P, Scholl L, Rudd RA, Bacon S. Overdose Deaths Involving Opioids,|6
03324|103|R|  Cocaine, and Psychostimulants - United States, 2015-2016. MMWR Morb Mortal|6
03324|104|R|  Wkly Rep 2018 Mar 30;67(12):349-358.|6
03324|105|R|7.Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved|6
03324|106|R|  Overdose Deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep 2018|6
03324|107|R|  Jan 4;67(5152):1419-1427.|6
03325|001|T|MONOGRAPH TITLE:  Lithium/Meperidine|
03325|002|B||
03325|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03325|004|L|take action as needed.|
03325|005|B||
03325|006|A|MECHANISM OF ACTION:  The combination of lithium with meperidine may have|
03325|007|A|additive effects on serotonin levels.(1,2)|
03325|008|B||
03325|009|E|CLINICAL EFFECTS:  Some patients may develop an increase in serotonergic|
03325|010|E|activity in the CNS, which could result in serotonin syndrome.  Symptoms of|
03325|011|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
03325|012|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)|
03325|013|B||
03325|014|P|PREDISPOSING FACTORS:  Renal dysfunction and chronic use of meperidine would|
03325|015|P|be expected to increase the risk for serotonin toxicity.  The use of|
03325|016|P|multiple drugs that increase serotonin levels is associated with an|
03325|017|P|increased risk for this toxidrome.|
03325|018|B||
03325|019|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
03325|020|M|observed for signs of serotonergic side effects.  When clinically|
03325|021|M|appropriate, consider monitoring serum concentrations for toxicity.|
03325|022|M|   Counsel patients to report new or worsening muscle twitching, tremors,|
03325|023|M|shivering or stiffness, fever, heavy sweating, heart palpitations,|
03325|024|M|restlessness, confusion, agitation, decreased coordination, or severe|
03325|025|M|diarrhea.  Discontinue one or both medications if symptoms occur.|
03325|026|M|   Although toxicity has been reported, based upon cases and interaction|
03325|027|M|studies the likelihood of a drug-drug interaction appears to be uncommon,|
03325|028|M|perhaps rare.(4)|
03325|029|B||
03325|030|D|DISCUSSION:  Serotonin syndrome has been reported from the combination of|
03325|031|D|lithium with serotonergic drugs, including SSRIs, SNRIs, and tramadol.|
03325|032|D|Although there are no reports of serotonin syndrome specifically with the|
03325|033|D|combination of lithium and meperidine, a pharmacological basis for an|
03325|034|D|interaction exists, and caution is still warranted.|
03325|035|D|   While toxicity has been reported, based upon cases and interaction|
03325|036|D|studies the likelihood of a drug-drug interaction appears to be uncommon,|
03325|037|D|perhaps rare.(4)  Some of the reported cases may represent drug-disease|
03325|038|D|interactions (e.g. mania with lithium and antidepressant).|
03325|039|B||
03325|040|R|REFERENCES:|
03325|041|B||
03325|042|R|1.Lithobid (lithium carbonate) US prescribing information. ANI|1
03325|043|R|  Pharmaceuticals, Inc. May, 2018.|1
03325|044|R|2.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
03325|045|R|  Pharmaceuticals LLC. December, 2023.|1
03325|046|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03325|047|R|  352(11):1112-20.|6
03325|048|R|4.Finley PR. Drug Interactions with Lithium: An Update. Clin Pharmacokinet|6
03325|049|R|  2016 Aug;55(8):925-41.|6
03326|001|T|MONOGRAPH TITLE:  Clozapine/Vemurafenib|
03326|002|B||
03326|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03326|004|L|of severe adverse interaction.|
03326|005|B||
03326|006|A|MECHANISM OF ACTION:  Vemurafenib is a moderate inhibitor of CYP1A2.  The|
03326|007|A|FDA defines moderate inhibition as an increase in drug area-under-curve|
03326|008|A|(AUC) greater than two fold, but less than 5 fold.(1)|
03326|009|A|   Clozapine has a narrow therapeutic window and is primarily metabolized by|
03326|010|A|CYP1A2.(2)|
03326|011|B||
03326|012|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with|
03326|013|E|vemurafenib may result in elevated levels of clozapine and an increase in|
03326|014|E|clozapine related side effects such as orthostatic hypotension, syncope, QT|
03326|015|E|prolongation, profound sedation and seizures.(1,2)|
03326|016|B||
03326|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03326|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03326|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03326|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03326|021|P|female gender, or advanced age.(3)|
03326|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03326|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03326|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03326|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03326|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03326|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03326|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).|
03326|029|B||
03326|030|M|PATIENT MANAGEMENT:  If coadministration cannot be avoided, the manufacturer|
03326|031|M|of vemurafenib recommends close monitoring and possible dose reduction of|
03326|032|M|the affected drug.  Steady-state levels of vemurafenib are not attained for|
03326|033|M|approximately 15 days and so extended monitoring for interaction onset and|
03326|034|M|severity may be required.|
03326|035|M|   Clozapine levels may be considered in patients receiving concurrent|
03326|036|M|therapy with vemurafenib.  Patients receiving concurrent therapy should be|
03326|037|M|monitored for adverse clozapine effects.|
03326|038|M|   If concurrent therapy is warranted in patients receiving clozapine,|
03326|039|M|consider obtaining serum calcium, magnesium, and potassium levels and|
03326|040|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03326|041|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03326|042|M|heartbeat, dizziness, or fainting.|
03326|043|B||
03326|044|D|DISCUSSION:  An interaction study was performed in cancer patients treated|
03326|045|D|with vemurafenib 960 mg twice daily for 15 days.  The AUC of caffeine, a|
03326|046|D|sensitive substrate for CYP1A2, was increased 2.6-fold.(1)|
03326|047|D|   Coadministration with tizanidine (2 mg, a sensitive CYP1A2 substrate) on|
03326|048|D|day 21 with vemurafenib (960 mg twice daily for 21 days) increased|
03326|049|D|tizanidine AUC and Cmax by 4.7-fold and 2.2-fold in 16 cancer patients.(1)|
03326|050|B||
03326|051|R|REFERENCES:|
03326|052|B||
03326|053|R|1.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
03326|054|R|  November, 2017.|1
03326|055|R|2.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03326|056|R|  Pharmaceuticals Corporation April, 2020.|1
03326|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03326|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03326|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03326|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03326|061|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03326|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03326|063|R|  settings: a scientific statement from the American Heart Association and|6
03326|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03326|065|R|  2;55(9):934-47.|6
03327|001|T|MONOGRAPH TITLE:  Clozapine/Obeticholic acid|
03327|002|B||
03327|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03327|004|L|take action as needed.|
03327|005|B||
03327|006|A|MECHANISM OF ACTION:  Although the mechanism is not clear, authors suspect|
03327|007|A|obeticholic acid down-regulates CYP1A2 mRNA expression, resulting in lower|
03327|008|A|systemic concentrations of the CYP1A2 enzyme.(1,2)|
03327|009|A|   Clozapine has a narrow therapeutic window and is primarily metabolized by|
03327|010|A|CYP1A2.(3)|
03327|011|B||
03327|012|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with|
03327|013|E|obeticholic acid may result in elevated levels of clozapine and an increase|
03327|014|E|in clozapine related side effects such as orthostatic hypotension, syncope,|
03327|015|E|QT prolongation, profound sedation and seizures.(1-3)|
03327|016|B||
03327|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03327|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03327|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03327|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03327|021|P|female gender, or advanced age.(4)|
03327|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03327|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03327|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03327|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03327|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03327|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03327|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).|
03327|029|B||
03327|030|M|PATIENT MANAGEMENT:  If coadministration cannot be avoided, the manufacturer|
03327|031|M|of obeticholic acid recommends close monitoring and possible dose reduction|
03327|032|M|of the affected drug.(2)|
03327|033|M|   Clozapine levels may be considered in patients receiving concurrent|
03327|034|M|therapy with obeticholic acid.  Patients receiving concurrent therapy should|
03327|035|M|be monitored for adverse clozapine effects.|
03327|036|M|   If concurrent therapy is warranted in patients receiving clozapine,|
03327|037|M|consider obtaining serum calcium, magnesium, and potassium levels and|
03327|038|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03327|039|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03327|040|M|heartbeat, dizziness, or fainting.|
03327|041|B||
03327|042|D|DISCUSSION:  In an interaction study, multiple doses of obeticholic acid|
03327|043|D|increased systemic exposure (AUC, area-under-curve) to caffeine (a sensitive|
03327|044|D|CYP1A2 substrate) by 42%.(1)|
03327|045|D|   Coadministration with tizanidine (2 mg, a sensitive CYP1A2 substrate) on|
03327|046|D|day 21 with vemurafenib (960 mg twice daily for 21 days) increased|
03327|047|D|tizanidine AUC and Cmax by 4.7-fold and 2.2-fold in 16 cancer patients.(1)|
03327|048|B||
03327|049|R|REFERENCES:|
03327|050|B||
03327|051|R|1.FDA (US Food and Drug Administration). Gastrointestinal Drug Advisory|1
03327|052|R|  Committee (GIDAC) Meeting, FDA Background Document for NDA 207999|1
03327|053|R|  obeticholic acid. accessed at:|1
03327|054|R|  http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials|1
03327|055|R|  /drugs/gastrointestinaldrugsadvisorycommittee/ucm494108.pdf March 15,|1
03327|056|R|  2016.|1
03327|057|R|2.Ocaliva (obeticholic acid) US prescribing information. Intercept|1
03327|058|R|  Pharmaceuticals Inc. January, 2018.|1
03327|059|R|3.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03327|060|R|  Pharmaceuticals Corporation April, 2020.|1
03327|061|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03327|062|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03327|063|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03327|064|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03327|065|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03327|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03327|067|R|  settings: a scientific statement from the American Heart Association and|6
03327|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03327|069|R|  2;55(9):934-47.|6
03328|001|T|MONOGRAPH TITLE:  Warfarin/Milk Thistle|
03328|002|B||
03328|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03328|004|L|take action as needed.|
03328|005|B||
03328|006|A|MECHANISM OF ACTION:  Milk thistle may inhibit the metabolism of warfarin|
03328|007|A|through CYP2C9.(1)|
03328|008|B||
03328|009|E|CLINICAL EFFECTS:  Concurrent use of warfarin and milk thistle may result in|
03328|010|E|elevated INR values and increased risk of bleeding.|
03328|011|B||
03328|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03328|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03328|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
03328|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03328|016|P|risk for bleeding (e.g. NSAIDs).|
03328|017|B||
03328|018|M|PATIENT MANAGEMENT:  Advise patients against using milk thistle products|
03328|019|M|with warfarin and to report the initiation or discontinuation of any|
03328|020|M|alternative therapy agents.|
03328|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03328|022|M|therapy for signs of blood loss, including decreased hemoglobin,|
03328|023|M|hematocrit,fecal occult blood, and/or decreased blood pressure and promptly|
03328|024|M|evaluate patients with any symptoms.|
03328|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03328|026|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03328|027|M|anticoagulation in patients with active pathologic bleeding.|
03328|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03328|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,tarry|
03328|030|M|stools; red, pink or dark brown urine; acute abdominal or joint pain and/or|
03328|031|M|swelling.|
03328|032|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03328|033|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
03328|034|M|initiating, altering the dose or discontinuing either drug.|
03328|035|B||
03328|036|D|DISCUSSION:  A review of in vivo and in vitro drug interaction studies with|
03328|037|D|milk thistle suggests there is the possibility of significant CYP2C9|
03328|038|D|inhibition by milk thistle.|
03328|039|D|   In one case study, an individual stable on a warfarin dose of 36.5 mg per|
03328|040|D|week for 8 months began taking a supplement containing 200 mg of milk|
03328|041|D|thistle. At a 4-week follow up, the patient's INR had increased from 2.64 to|
03328|042|D|4.12. The patient was instructed to stop the supplement, hold one dose of|
03328|043|D|warfarin, and then continue his previous dose. At a 1-week follow-up, his|
03328|044|D|INR was slightly sub-therapeutic at 2.37, but repeat INRs were therapeutic|
03328|045|D|at 3.24 and 2.98 at 4 and 8 weeks.(2)|
03328|046|D|   A study was conducted to investigate the effects of milk thistle on the|
03328|047|D|pharmacokinetics of losartan (a CYP2C9 substrate) and its active metabolite|
03328|048|D|E-3147, and its relationship with CYP2C9 genotypes. The AUC of losartan|
03328|049|D|increased significantly following a 14-day milk thistle treatment in|
03328|050|D|subjects with CYP2C9*1/*1 genotype. The results showed that milk thistle|
03328|051|D|inhibits the metabolism of losartan to E-3147, with the magnitude of the|
03328|052|D|interaction differing in individuals with different CYP2C9 genotypes.(3)|
03328|053|B||
03328|054|R|REFERENCES:|
03328|055|B||
03328|056|R|1.This information is based on an extract from the Certara Drug Interaction|6
03328|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03328|058|R|2.Lash DB, Ward S. CYP2C9-mediated warfarin and milk thistle interaction. J|3
03328|059|R|  Clin Pharm Ther 2019 Oct 21.|3
03328|060|R|3.Han Y, Guo D, Chen Y, Chen Y, Tan ZR, Zhou HH. Effect of silymarin on the|2
03328|061|R|  pharmacokinetics of losartan and its active metabolite E-3174 in healthy|2
03328|062|R|  Chinese volunteers. Eur J Clin Pharmacol 2009 Jun;65(6):585-91.|2
03329|001|T|MONOGRAPH TITLE:  Hydroxychloroquine/Possible QT Prolonging Agents|
03329|002|B||
03329|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03329|004|L|take action as needed.|
03329|005|B||
03329|006|A|MECHANISM OF ACTION:  Hydroxychloroquine has been observed to prolong the|
03329|007|A|QTc interval.  Concurrent use with other agents that prolong the QTc|
03329|008|A|interval may result in additive effects on the QTc interval.(1)|
03329|009|B||
03329|010|E|CLINICAL EFFECTS:  The concurrent use of hydroxychloroquine with other|
03329|011|E|agents that prolong the QTc interval may result in potentially|
03329|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
03329|013|B||
03329|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03329|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03329|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03329|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03329|018|P|female gender, or advanced age.(2)|
03329|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03329|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03329|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03329|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03329|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03329|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03329|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03329|026|B||
03329|027|M|PATIENT MANAGEMENT:  The US manufacturer of hydroxychloroquine states that|
03329|028|M|hydroxychloroquine should not be administered with other agents that prolong|
03329|029|M|the QT interval.(1)|
03329|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03329|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03329|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03329|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03329|034|B||
03329|035|D|DISCUSSION:  The manufacturer states that hydroxychloroquine has been shown|
03329|036|D|to prolong the QT interval;(1) however, conditions that hydroxychloroquine|
03329|037|D|treats have also been associated with QT prolongation.|
03329|038|D|   Agents that are linked to this monograph may have varying degrees of|
03329|039|D|potential to prolong the QTc interval but are generally accepted to have a|
03329|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03329|041|D|been shown to prolong the QTc interval either through their mechanism of|
03329|042|D|action, through studies on their effects on the QTc interval, or through|
03329|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03329|044|D|and/or post-marketing reports.(3)|
03329|045|B||
03329|046|R|REFERENCES:|
03329|047|B||
03329|048|R|1.Plaquenil (hydroxychloroquine sulfate) US prescribing information.|1
03329|049|R|  Concordia Pharmaceuticals Inc. December, 2023.|1
03329|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03329|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03329|052|R|  settings: a scientific statement from the American Heart Association and|6
03329|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03329|054|R|  2;55(9):934-47.|6
03329|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03329|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03329|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03329|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03330|001|T|MONOGRAPH TITLE:  Letermovir/P-glycoprotein (P-gp) or UGT Inducers|
03330|002|B||
03330|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03330|004|L|of severe adverse interaction.|
03330|005|B||
03330|006|A|MECHANISM OF ACTION:  Letermovir is a substrate of the efflux transporter|
03330|007|A|P-glycoprotein (P-gp) and of UDP-glucuronosyltransferase (UGT) 1A1/3|
03330|008|A|enzymes.  P-gp induction may decrease systemic absorption of letermovir,|
03330|009|A|while UGT1A1/3 induction may increase the metabolism of letermovir.(1)|
03330|010|B||
03330|011|E|CLINICAL EFFECTS:  Concurrent or recent use of P-glycoprotein or UGT1A1/3|
03330|012|E|inducers may result in decreased levels and loss of effectiveness of|
03330|013|E|letermovir.|
03330|014|B||
03330|015|P|PREDISPOSING FACTORS:  None determined.|
03330|016|B||
03330|017|M|PATIENT MANAGEMENT:  The manufacturer of letermovir states that|
03330|018|M|coadministration of P-gp inducers or UGT1A1/3 inducers is not recommended.|
03330|019|B||
03330|020|D|DISCUSSION:  In a study, at 24 hours after the last dose of rifampin (600 mg|
03330|021|D|daily), the AUC of letermovir was decreased by 85 %, compared to letermovir|
03330|022|D|when taken alone.(1)|
03330|023|D|   Inducers of P-glycoprotein or of UGT1A1/3 linked to this monograph|
03330|024|D|include: apalutamide, efavirenz, etravirine, fosphenytoin, lorlatinib,|
03330|025|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, ritonavir, and|
03330|026|D|St. John's wort.(2)|
03330|027|B||
03330|028|R|REFERENCES:|
03330|029|B||
03330|030|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
03330|031|R|  2024.|1
03330|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
03330|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03331|001|T|MONOGRAPH TITLE:  Alprazolam; Triazolam/Selected Strong CYP3A4 Inhibitors|
03331|002|B||
03331|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03331|004|L|is contraindicated and generally should not be dispensed or administered to|
03331|005|L|the same patient.|
03331|006|B||
03331|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03331|008|A|alprazolam and triazolam.(1,2)|
03331|009|B||
03331|010|E|CLINICAL EFFECTS:  The concurrent administration of alprazolam or triazolam|
03331|011|E|with strong CYP3A4 inhibitors may result in elevated levels of alprazolam or|
03331|012|E|triazolam, which may result in increased adverse effects including profound|
03331|013|E|sedation, respiratory depression, coma, and/or death.|
03331|014|B||
03331|015|P|PREDISPOSING FACTORS:  None determined.|
03331|016|B||
03331|017|M|PATIENT MANAGEMENT:  The US manufacturers of alprazolam and triazolam state|
03331|018|M|that concurrent use with strong CYP3A4 inhibitors is contraindicated.(1,2)|
03331|019|B||
03331|020|D|DISCUSSION:  Many of the strong CYP3A4 inhibitors linked to this monograph|
03331|021|D|have not been studied in combination with alprazolam or triazolam.  However,|
03331|022|D|other strong CYP3A4 have been well studied and are expected to cause a|
03331|023|D|similar effect.|
03331|024|D|   In a study coadministration with ketoconazole increased alprazolam|
03331|025|D|area-under-curve (AUC) by 3.98-fold.(1)|
03331|026|D|   In a study of 12 healthy volunteers, clarithromycin (500 mg twice daily|
03331|027|D|for 2 days) increased the AUC of triazolam by 5-fold.(3)|
03331|028|D|   In a randomized, cross-over study in 10 healthy subjects, itraconazole|
03331|029|D|ingested simultaneously, or 3, 12, or 24 hours before triazolam increased|
03331|030|D|triazolam AUC by 3.1-fold, 4.8-fold, 4.6-fold, and 3.8-fold, respectively.|
03331|031|D|The increase in triazolam Cmax ranged from 1.4-fold to 1.8-fold.  Subjects|
03331|032|D|noted increased triazolam effects.(4)  In a double-blind cross-over study in|
03331|033|D|9 subjects, itraconazole increased triazolam AUC by 27-fold.(5)|
03331|034|D|   In a double-blind cross-over study in 9 subjects, ketoconazole increased|
03331|035|D|triazolam AUC by 22-fold.(4)  In a double-blind cross-over study, concurrent|
03331|036|D|ketoconazole decreased triazolam clearance by 91%.  Triazolam half-life and|
03331|037|D|Cmax increased 5.1-fold and 1.1-fold, respectively.(6)|
03331|038|D|   Serum concentrations and the half-life of triazolam were increased by|
03331|039|D|troleandomycin by as much as 258%.(7)|
03331|040|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
03331|041|D|boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib,|
03331|042|D|josamycin, lonafarnib, mibefradil, posaconazole, telaprevir, telithromycin,|
03331|043|D|troleandomycin, tucatinib, and voriconazole.(8)|
03331|044|B||
03331|045|R|REFERENCES:|
03331|046|B||
03331|047|R|1.Xanax (alprazolam) US prescribing information. Pharmacia & Upjohn Company|1
03331|048|R|  February, 2021.|1
03331|049|R|2.Halcion (triazolam) US prescribing information. Pharmacia & Upjohn Company|1
03331|050|R|  October, 2019.|1
03331|051|R|3.Greenblatt DJ, von Moltke LL, Harmatz JS, Counihan M, Graf JA, Durol AL,|2
03331|052|R|  Mertzanis P, Duan SX, Wright CE, Shader RI. Inhibition of triazolam|2
03331|053|R|  clearance by macrolide antimicrobial agents: in vitro correlates and|2
03331|054|R|  dynamic consequences. Clin Pharmacol Ther 1998 Sep;64(3):278-85.|2
03331|055|R|4.Neuvonen PJ, Varhe A, Olkkola KT. The effect of ingestion time interval on|2
03331|056|R|  the interaction between itraconazole and triazolam. Clin Pharmacol Ther|2
03331|057|R|  1996 Sep;60(3):326-31.|2
03331|058|R|5.Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous|2
03331|059|R|  to patients receiving systemic antimycotics ketoconazole or itraconazole.|2
03331|060|R|  Clin Pharmacol Ther 1994 Dec;56(6 Pt 1):601-7.|2
03331|061|R|6.This information is based on an extract from the Certara Drug Interaction|6
03331|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03331|063|R|7.Greenblatt DJ, Wright CE, von Moltke LL, Harmatz JS, Ehrenberg BL, Harrel|2
03331|064|R|  LM, Corbett K, Counihan M, Tobias S, Shader RI. Ketoconazole inhibition of|2
03331|065|R|  triazolam and alprazolam clearance: differential kinetic and dynamic|2
03331|066|R|  consequences. Clin Pharmacol Ther 1998 Sep;64(3):237-47.|2
03331|067|R|8.Warot D, Bergougnan L, Lamiable D, Berlin I, Bensimon G, Danjou P, Puech|2
03331|068|R|  AJ. Troleandomycin-triazolam interaction in healthy volunteers:|2
03331|069|R|  pharmacokinetic and psychometric evaluation. Eur J Clin Pharmacol 1987;|2
03331|070|R|  32(4):389-93.|2
03332|001|T|MONOGRAPH TITLE:  Triazolam/Erythromycin; Fluconazole; Roxithromycin|
03332|002|B||
03332|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03332|004|L|take action as needed.|
03332|005|B||
03332|006|A|MECHANISM OF ACTION:  Erythromycin, fluconazole and roxithromycin may|
03332|007|A|inhibit the metabolism of triazolam through inhibition of CYP3A4.|
03332|008|B||
03332|009|E|CLINICAL EFFECTS:  Serum concentrations of triazolam may be increased,|
03332|010|E|enhancing its pharmacological effects.  Toxic effects of increased triazolam|
03332|011|E|levels include profound sedation, respiratory depression, coma, and/or|
03332|012|E|death.|
03332|013|B||
03332|014|P|PREDISPOSING FACTORS:  None determined.|
03332|015|B||
03332|016|M|PATIENT MANAGEMENT:  Patients should be cautioned about possible increased|
03332|017|M|sedation and observed for this side effect. Decreasing the dose of the|
03332|018|M|triazolam may be necessary.|
03332|019|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
03332|020|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03332|021|M|unresponsiveness.|
03332|022|B||
03332|023|D|DISCUSSION:  This interaction has been demonstrated in controlled studies|
03332|024|D|involving concurrent oral administration of triazolam with erythromycin.|
03332|025|D|Serum concentrations and the half-life of triazolam were increased by as|
03332|026|D|much as 107%.(1)|
03332|027|D|   In a study of 12 healthy volunteers, erythromycin increased the maximum|
03332|028|D|concentration (Cmax) and area-under curve (AUC) of triazolam by 1.8-fold and|
03332|029|D|3.65-fold, respectively.(2)|
03332|030|D|   In a study in eight subjects who were given triazolam with 50 mg, 100 mg,|
03332|031|D|or 200 mg of fluconazole, the triazolam AUC increased by 1.6-fold, 2.1-fold,|
03332|032|D|and 4.4-fold, respectively. The increase in triazolam half-life ranged from|
03332|033|D|1.3-fold to 2.3-fold.  The Cmax of triazolam increased more than 2-fold when|
03332|034|D|administered with 200 mg of fluconazole.  The pharmacodynamic effects of|
03332|035|D|triazolam were significantly increased by the 100 mg and 200 mg doses of|
03332|036|D|fluconazole.(3)|
03332|037|D|   In a study in 12 subjects, fluconazole (200 mg) increased the AUC and|
03332|038|D|half-life of triazolam by more than 2-fold.  The pharmacodynamic effects|
03332|039|D|were also increased.(4)|
03332|040|B||
03332|041|R|REFERENCES:|
03332|042|B||
03332|043|R|1.Phillips JP, Antal EJ, Smith RB. A pharmacokinetic drug interaction|2
03332|044|R|  between erythromycin and triazolam. J Clin Psychopharmacol 1986 Oct;|2
03332|045|R|  6(5):297-9.|2
03332|046|R|2.Greenblatt DJ, von Moltke LL, Harmatz JS, Counihan M, Graf JA, Durol AL,|2
03332|047|R|  Mertzanis P, Duan SX, Wright CE, Shader RI. Inhibition of triazolam|2
03332|048|R|  clearance by macrolide antimicrobial agents: in vitro correlates and|2
03332|049|R|  dynamic consequences. Clin Pharmacol Ther 1998 Sep;64(3):278-85.|2
03332|050|R|3.Varhe A, Olkkola KT, Neuvonen PJ. Effect of fluconazole dose on the extent|2
03332|051|R|  of fluconazole-triazolam interaction. Br J Clin Pharmacol 1996 Oct;|2
03332|052|R|  42(4):465-70.|2
03332|053|R|4.Varhe A, Olkkola KT, Neuvonen PJ. Fluconazole, but not terbinafine,|2
03332|054|R|  enhances the effects of triazolam by inhibiting its metabolism. Br J Clin|2
03332|055|R|  Pharmacol 1996 Apr;41(4):319-23.|2
03333|001|T|MONOGRAPH TITLE:  Zanubrutinib/Strong CYP3A4 Inhibitors|
03333|002|B||
03333|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03333|004|L|take action as needed.|
03333|005|B||
03333|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03333|007|A|of zanubrutinib.(1)|
03333|008|B||
03333|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
03333|010|E|elevated levels of and toxicity from zanubrutinib.(1)|
03333|011|B||
03333|012|P|PREDISPOSING FACTORS:  Patients with severe hepatic impairment (Child-Pugh|
03333|013|P|class C) have elevated zanubrutinib plasma concentrations and may be more|
03333|014|P|susceptible to the effects of this interaction.(1)|
03333|015|B||
03333|016|M|PATIENT MANAGEMENT:  The dosage of zanubrutinib should be reduced when|
03333|017|M|coadministered with strong CYP3A4 inhibitors.  Interrupt the dose as|
03333|018|M|recommended by prescribing information for adverse reactions.(1)|
03333|019|M|   The US manufacturer of zanubrutinib states that when it is coadministered|
03333|020|M|with:|
03333|021|M|   -Clarithromycin 250 mg twice daily, limit the dose of zanubrutinib to 80|
03333|022|M|mg twice daily.|
03333|023|M|   -Clarithromycin 500 mg twice daily, limit the dose of zanubrutinib to 80|
03333|024|M|mg once daily.|
03333|025|M|   -Posaconazole suspension 100 mg once daily, limit the dose of|
03333|026|M|zanubrutinib to 80 mg twice daily.|
03333|027|M|   -Posaconazole suspension at a dosage higher than 100 mg once daily, or|
03333|028|M|posaconazole delayed-release tablets 300 mg once daily, or posaconazole|
03333|029|M|intravenous 300 mg once daily, limit the dose of zanubrutinib to 80 mg once|
03333|030|M|daily.|
03333|031|M|   -Other CYP3A4 inhibitors, limit the dose of zanubrutinib to 80 mg once|
03333|032|M|daily.(1)|
03333|033|M|   The Canadian manufacturer of zanubrutinib states that the dosage of|
03333|034|M|zanubrutinib should be reduced to 80 mg once daily when coadministered with|
03333|035|M|all strong CYP3A4 inhibitors.(2)|
03333|036|B||
03333|037|D|DISCUSSION:  Co-administration with itraconazole 200 mg once daily, a strong|
03333|038|D|CYP3A4 inhibitor, increased zanubrutinib concentration maximum (Cmax) and|
03333|039|D|area-under-curve (AUC) by 157% and 278%, respectively.(1)|
03333|040|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
03333|041|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03333|042|D|ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone,|
03333|043|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
03333|044|D|saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and|
03333|045|D|voriconazole.(3-5)|
03333|046|B||
03333|047|R|REFERENCES:|
03333|048|B||
03333|049|R|1.Brukinsa (zanubrutinib) US prescribing information. BeiGene June, 2025.|1
03333|050|R|2.Brukinsa (zanubrutinib) Canadian product monograph. BeiGene Switzerland|1
03333|051|R|  GmbH December, 2024.|1
03333|052|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03333|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03333|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03333|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03333|056|R|  11/14/2017.|1
03333|057|R|4.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03333|058|R|  Indiana University School of Medicine.  Available at:|1
03333|059|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03333|060|R|5.This information is based on an extract from the Certara Drug Interaction|6
03333|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03334|001|T|MONOGRAPH TITLE:  Zanubrutinib/Moderate CYP3A4 Inhibitors|
03334|002|B||
03334|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03334|004|L|take action as needed.|
03334|005|B||
03334|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03334|007|A|metabolism of zanubrutinib.(1)|
03334|008|B||
03334|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
03334|010|E|in elevated levels of and toxicity from zanubrutinib.(1)|
03334|011|B||
03334|012|P|PREDISPOSING FACTORS:  Patients with severe hepatic impairment (Child-Pugh|
03334|013|P|class C) have elevated zanubrutinib plasma concentrations and may be more|
03334|014|P|susceptible to the effects of this interaction.(1)|
03334|015|B||
03334|016|M|PATIENT MANAGEMENT:  The dosage of zanubrutinib should be reduced to 80 mg|
03334|017|M|twice daily when co-administered with moderate CYP3A4 inhibitors.  Modify|
03334|018|M|the dose as recommended by prescribing information for adverse reactions.(1)|
03334|019|B||
03334|020|D|DISCUSSION:  Co-administration with itraconazole 200 mg once daily, a strong|
03334|021|D|CYP3A4 inhibitor, increased zanubrutinib concentration maximum (Cmax) and|
03334|022|D|area-under-curve (AUC) by 157% and 278%, respectively.  It is predicted|
03334|023|D|co-administration with fluconazole 200 mg daily, a moderate CYP3A4|
03334|024|D|inhibitor, would increase zanubrutinib Cmax and AUC by 179% and 177%,|
03334|025|D|respectively.(1)|
03334|026|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
03334|027|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
03334|028|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
03334|029|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
03334|030|D|isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
03334|031|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
03334|032|D|and verapamil.(2-4)|
03334|033|B||
03334|034|R|REFERENCES:|
03334|035|B||
03334|036|R|1.Brukinsa (zanubrutinib) US prescribing information. BeiGene June, 2025.|1
03334|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03334|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03334|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03334|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03334|041|R|  11/14/2017.|1
03334|042|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03334|043|R|  Indiana University School of Medicine.  Available at:|1
03334|044|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03334|045|R|4.This information is based on an extract from the Certara Drug Interaction|6
03334|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03335|001|T|MONOGRAPH TITLE:  Zanubrutinib/Strong CYP3A4 Inducers|
03335|002|B||
03335|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03335|004|L|of severe adverse interaction.|
03335|005|B||
03335|006|A|MECHANISM OF ACTION:  Zanubrutinib is a substrate of CYP3A4.  Strong|
03335|007|A|inducers of CYP3A4 may induce the metabolism of zanubrutinib.(1)|
03335|008|B||
03335|009|E|CLINICAL EFFECTS:  The concurrent administration of strong CYP3A4 inducers|
03335|010|E|may result in decreased levels and effectiveness of zanubrutinib.(1)|
03335|011|B||
03335|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03335|013|P|of the inducer for longer than 1-2 weeks.|
03335|014|B||
03335|015|M|PATIENT MANAGEMENT:  The manufacturer of zanubrutinib states that concurrent|
03335|016|M|use with strong CYP3A4 inducers should be avoided.(1)|
03335|017|B||
03335|018|D|DISCUSSION:  Co-administration of multiple doses of rifampin, a strong|
03335|019|D|CYP3A4 inducer, decreased the zanubrutinib concentration maximum (Cmax) by|
03335|020|D|92% and area-under-curve (AUC) by 93%.|
03335|021|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03335|022|D|carbamazepine, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane,|
03335|023|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03335|024|D|wort.(2-3)|
03335|025|B||
03335|026|R|REFERENCES:|
03335|027|B||
03335|028|R|1.Brukinsa (zanubrutinib) US prescribing information. BeiGene June, 2025.|1
03335|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03335|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03335|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03335|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03335|033|R|  11/14/2017.|1
03335|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
03335|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03336|001|T|MONOGRAPH TITLE:  Acalabrutinib Capsules/Cimetidine (mono deleted|
03336|002|T|12/06/2023)|
03336|003|B||
03336|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03336|005|L|of severe adverse interaction.|
03336|006|B||
03336|007|A|MECHANISM OF ACTION:  Acalabrutinib is a substrate of CYP3A4.(1)|
03336|008|A|Cimetidine, a CYP3A4 inhibitor, may inhibit the metabolism of|
03336|009|A|acalabrutinib.(2,3)|
03336|010|A|   Acalabrutinib capsules solubility decreases with increasing pH.|
03336|011|A|Cimetidine increases gastric pH which may result in a decrease in|
03336|012|A|acalabrutinib capsules absorption.(1)|
03336|013|B||
03336|014|E|CLINICAL EFFECTS:  The net effect of the concurrent administration of|
03336|015|E|cimetidine and acalabrutinib is unknown.  Cimetidine may either increase or|
03336|016|E|decrease plasma levels of acalabrutinib.  CYP3A4 inhibition by cimetidine|
03336|017|E|may result in elevated levels and increased effects of acalabrutinib.|
03336|018|E|   The H2-receptor blocking effect of cimetidine may result in decreased|
03336|019|E|absorption and decreased levels and effectiveness of acalabrutinib.(1)|
03336|020|B||
03336|021|P|PREDISPOSING FACTORS:  None determined.|
03336|022|B||
03336|023|M|PATIENT MANAGEMENT:  Concurrent use of acalabrutinib capsules and cimetidine|
03336|024|M|should be avoided.  The optimal administration schedule and dosing of|
03336|025|M|acalabrutinib and cimetidine when used in combination is unknown.|
03336|026|M|Manufacturers provide recommendations for dose modification of acalabrutinib|
03336|027|M|when used with a moderate CYP3A4 inhibitor, but the recommendations may not|
03336|028|M|apply when opposing mechanisms are involved.  Dose modifications mentioned|
03336|029|M|below are informational only.|
03336|030|M|   Take acalabrutinib capsules 2 hours before H2-receptor antagonists.(1)|
03336|031|M|   If a moderate CYP3A4 inhibitor is required, reduce the dose of|
03336|032|M|acalabrutinib to 100 mg once daily.(1)|
03336|033|B||
03336|034|D|DISCUSSION:  A physiologically based pharmacokinetic simulation with|
03336|035|D|acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole,|
03336|036|D|diltiazem) showed that coadministration increased acalabrutinib Cmax and AUC|
03336|037|D|increased by 2- to almost 3-fold.(1)|
03336|038|D|  In a study in healthy subjects, coadministration with an antacid (1g|
03336|039|D|calcium carbonate) decreased area-under-curve (AUC) of acalabrutinib|
03336|040|D|capsules by 53%.  Coadministration with a proton pump inhibitor (omeprazole|
03336|041|D|40 mg for 5 days) decreased AUC of acalabrutinib capsules by 43%.(1)|
03336|042|B||
03336|043|R|REFERENCES:|
03336|044|B||
03336|045|R|1.Calquence (acalabrutinib) US prescribing information. AstraZeneca|1
03336|046|R|  Pharmaceuticals LP August, 2022.|1
03336|047|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03336|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03336|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03336|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03336|051|R|  11/14/2017.|1
03336|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
03336|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03338|001|T|MONOGRAPH TITLE:  Selected CYP1A2 or CYP2D6 Substrates/Givosiran|
03338|002|B||
03338|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03338|004|L|of severe adverse interaction.|
03338|005|B||
03338|006|A|MECHANISM OF ACTION:  Givosiran interferes with the first and rate-limiting|
03338|007|A|step in hepatic heme biosynthesis, which may lower hepatic heme levels and|
03338|008|A|decrease production and/or activity of cytochrome P450 enzymes.(1,2)|
03338|009|B||
03338|010|E|CLINICAL EFFECTS:  Concurrent use of givosiran may result in elevated levels|
03338|011|E|of and toxicity from agents metabolized by CYP1A2 or CYP2D6.(1)|
03338|012|B||
03338|013|P|PREDISPOSING FACTORS:  With tricyclic antidepressants, the risk of seizures|
03338|014|P|may be increased in patients with a history of head trauma or prior seizure;|
03338|015|P|CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives;|
03338|016|P|addiction to opiates, cocaine, or stimulants; use of over-the-counter|
03338|017|P|stimulants and anorectics; diabetics treated with oral hypoglycemics or|
03338|018|P|insulin; or with concomitant medications known to lower seizure threshold|
03338|019|P|(antipsychotics, theophylline, systemic steroids).|
03338|020|P|   With anticholinergic agents, the risk of anticholinergic toxicities|
03338|021|P|including cognitive decline, delirium, falls and fractures is increased in|
03338|022|P|geriatric patients using more than one medicine with anticholinergic|
03338|023|P|properties.(3)|
03338|024|B||
03338|025|M|PATIENT MANAGEMENT:  Avoid the concurrent use of givosiran with agents that|
03338|026|M|are sensitive substrates of CYP1A2 or CYP2D6, or CYP1A2 or CYP2D6 substrates|
03338|027|M|with a narrow therapeutic index.  If concurrent use is unavoidable, decrease|
03338|028|M|the dose of the CYP1A2 or CYP2D6 substrate and monitor patients for|
03338|029|M|toxicity.|
03338|030|B||
03338|031|D|DISCUSSION:  A study of 9 patients with acute intermittent porphyria found|
03338|032|D|that givosiran decreased the maximum concentration (Cmax) and|
03338|033|D|area-under-curve (AUC) of caffeine (a CYP1A2 substrate) by 1.3- and|
03338|034|D|3.1-fold, respectively, compared to caffeine alone.  Givosiran also|
03338|035|D|decreased the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) by 2-|
03338|036|D|and 2.4-fold, respectively, compared to dextromethorphan alone.(1,2)|
03338|037|D|   Selected CYP2D6 substrates linked to this monograph include: atomoxetine,|
03338|038|D|desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide,|
03338|039|D|methoxyphenamine, metoprolol, nebivolol, nefazodone, paroxetine,|
03338|040|D|perphenazine, risperidone, tetrabenazine, trimipramine, and venlafaxine.|
03338|041|D|   Selected CYP1A2 substrates linked to this monograph include:|
03338|042|D|agomelatine, aminophylline, rasagiline, tacrine, theophylline, tizanidine,|
03338|043|D|and yohimbine.|
03338|044|B||
03338|045|R|REFERENCES:|
03338|046|B||
03338|047|R|1.Givlaari (givosiran) US prescribing information. Alnylam Pharmaceuticals,|1
03338|048|R|  Inc. October, 2021.|1
03338|049|R|2.Vassiliou D, Sardh E, Harper P, Najafian N, Simon A, Burke A, Kim J, Garg|2
03338|050|R|  P, Robbie G, Agarwal S. A Drug-Drug Interaction Study to Investigate the|2
03338|051|R|  Effect of Givosiran on the activity of 5 major drug metabolizing CYP450|2
03338|052|R|  enzymes in Subjects with Acute Intermittent Porphyria (AIP) who are|2
03338|053|R|  Chronic High Excreters (CHE). International Congress on Porphyrins and|2
03338|054|R|  Porphyrias, Milan Italy September 10, 2019.|2
03338|055|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03338|056|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03338|057|R|  Soc 2023 Jul;71(7):2052-2081.|6
03339|001|T|MONOGRAPH TITLE:  Selected CYP2D6 Substrates that Prolong QT/Givosiran|
03339|002|B||
03339|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03339|004|L|of severe adverse interaction.|
03339|005|B||
03339|006|A|MECHANISM OF ACTION:  Givosiran interferes with the first and rate-limiting|
03339|007|A|step in hepatic heme biosynthesis, which may lower hepatic heme levels and|
03339|008|A|decrease production and/or activity of cytochrome P450 enzymes.(1,2)|
03339|009|B||
03339|010|E|CLINICAL EFFECTS:  Concurrent use of givosiran may result in elevated levels|
03339|011|E|of and toxicity from agents metabolized by CYP2D6.(1)|
03339|012|E|  Higher systemic concentrations of QT prolonging drugs which are|
03339|013|E|metabolized by CYP2D6 may increase the risk for Torsades de Pointes.|
03339|014|B||
03339|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03339|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03339|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03339|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03339|019|P|gender, or advanced age.(3)|
03339|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03339|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03339|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03339|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03339|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03339|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03339|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03339|027|P|   With pimozide, thioridazine and tolterodine, the risk of anticholinergic|
03339|028|P|toxicities including cognitive decline, delirium, falls and fractures is|
03339|029|P|increased in geriatric patients using more than one medicine with|
03339|030|P|anticholinergic properties.(4)|
03339|031|B||
03339|032|M|PATIENT MANAGEMENT:  Avoid the concurrent use of givosiran with agents that|
03339|033|M|are sensitive substrates of CYP2D6, or CYP2D6 substrates with a narrow|
03339|034|M|therapeutic index.  If concurrent use is unavoidable, decrease the dose of|
03339|035|M|the CYP2D6 substrate and monitor patients for toxicity.|
03339|036|M|   If concurrent therapy with givosiran and a CYP2D6 substrate which may|
03339|037|M|prolong the QT interval is warranted, consider obtaining serum calcium,|
03339|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03339|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03339|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03339|041|B||
03339|042|D|DISCUSSION:  A study of 9 patients with acute intermittent porphyria found|
03339|043|D|that givosiran decreased the maximum concentration (Cmax) and|
03339|044|D|area-under-curve (AUC) of caffeine (a CYP1A2 substrate) by 1.3- and|
03339|045|D|3.1-fold, respectively, compared to caffeine alone.  Givosiran also|
03339|046|D|decreased the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) by 2-|
03339|047|D|and 2.4-fold, respectively, compared to dextromethorphan alone.(1,2)|
03339|048|D|   CYP2D6 substrates that are QT prolonging drugs linked to this monograph|
03339|049|D|include:  eliglustat, perhexiline, pimozide, prajmaline, propafenone,|
03339|050|D|thioridazine, and tolterodine.|
03339|051|B||
03339|052|R|REFERENCES:|
03339|053|B||
03339|054|R|1.Givlaari (givosiran) US prescribing information. Alnylam Pharmaceuticals,|1
03339|055|R|  Inc. October, 2021.|1
03339|056|R|2.Vassiliou D, Sardh E, Harper P, Najafian N, Simon A, Burke A, Kim J, Garg|2
03339|057|R|  P, Robbie G, Agarwal S. A Drug-Drug Interaction Study to Investigate the|2
03339|058|R|  Effect of Givosiran on the activity of 5 major drug metabolizing CYP450|2
03339|059|R|  enzymes in Subjects with Acute Intermittent Porphyria (AIP) who are|2
03339|060|R|  Chronic High Excreters (CHE). International Congress on Porphyrins and|2
03339|061|R|  Porphyrias, Milan Italy September 10, 2019.|2
03339|062|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03339|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03339|064|R|  settings: a scientific statement from the American Heart Association and|6
03339|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03339|066|R|  2;55(9):934-47.|6
03339|067|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03339|068|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03339|069|R|  Soc 2023 Jul;71(7):2052-2081.|6
03340|001|T|MONOGRAPH TITLE:  Clozapine/Givosiran|
03340|002|B||
03340|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03340|004|L|take action as needed.|
03340|005|B||
03340|006|A|MECHANISM OF ACTION:  Givosiran interferes with the first and rate-limiting|
03340|007|A|step in hepatic heme biosynthesis, which may lower hepatic heme levels and|
03340|008|A|decrease production and/or activity of cytochrome P450 enzymes.(1,2)|
03340|009|B||
03340|010|E|CLINICAL EFFECTS:  Concurrent use of givosiran may result in elevated levels|
03340|011|E|of and toxicity from clozapine, such as orthostatic hypotension, syncope, QT|
03340|012|E|prolongation, profound sedation and seizures.(1-3)|
03340|013|B||
03340|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03340|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03340|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03340|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03340|018|P|female gender, or advanced age.(4)|
03340|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03340|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03340|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03340|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03340|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03340|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03340|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).|
03340|026|B||
03340|027|M|PATIENT MANAGEMENT:  Avoid the concurrent use of givosiran with clozapine.|
03340|028|M|If concurrent use is unavoidable, consider decreasing the dose of clozapine|
03340|029|M|and checking clozapine levels.  Patients receiving concurrent therapy should|
03340|030|M|be monitored for adverse clozapine effects.(1-3)|
03340|031|M|   If concurrent therapy is warranted in patients receiving clozapine,|
03340|032|M|consider obtaining serum calcium, magnesium, and potassium levels and|
03340|033|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03340|034|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03340|035|M|heartbeat, dizziness, or fainting.|
03340|036|B||
03340|037|D|DISCUSSION:  A study of 9 patients with acute intermittent porphyria found|
03340|038|D|that givosiran decreased the maximum concentration (Cmax) and|
03340|039|D|area-under-curve (AUC) of caffeine (a CYP1A2 substrate) by 1.3- and|
03340|040|D|3.1-fold, respectively, compared to caffeine alone.(1,2)|
03340|041|B||
03340|042|R|REFERENCES:|
03340|043|B||
03340|044|R|1.Givlaari (givosiran) US prescribing information. Alnylam Pharmaceuticals,|1
03340|045|R|  Inc. October, 2021.|1
03340|046|R|2.Vassiliou D, Sardh E, Harper P, Najafian N, Simon A, Burke A, Kim J, Garg|2
03340|047|R|  P, Robbie G, Agarwal S. A Drug-Drug Interaction Study to Investigate the|2
03340|048|R|  Effect of Givosiran on the activity of 5 major drug metabolizing CYP450|2
03340|049|R|  enzymes in Subjects with Acute Intermittent Porphyria (AIP) who are|2
03340|050|R|  Chronic High Excreters (CHE). International Congress on Porphyrins and|2
03340|051|R|  Porphyrias, Milan Italy September 10, 2019.|2
03340|052|R|3.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03340|053|R|  Pharmaceuticals Corporation April, 2020.|1
03340|054|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03340|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03340|056|R|  settings: a scientific statement from the American Heart Association and|6
03340|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03340|058|R|  2;55(9):934-47.|6
03341|001|T|MONOGRAPH TITLE:  Voxelotor/Selected Strong or Moderate CYP3A4 Inducers|
03341|002|B||
03341|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03341|004|L|of severe adverse interaction.|
03341|005|B||
03341|006|A|MECHANISM OF ACTION:  Voxelotor is a substrate of CYP3A4.  Strong or|
03341|007|A|moderate inducers of CYP3A4 may induce the metabolism of voxelotor.(1)|
03341|008|B||
03341|009|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
03341|010|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
03341|011|E|voxelotor.(1)|
03341|012|B||
03341|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03341|014|P|of the inducer for longer than 1-2 weeks.|
03341|015|B||
03341|016|M|PATIENT MANAGEMENT:  The manufacturer of voxelotor states that concurrent|
03341|017|M|use with strong or moderate CYP3A4 inducers should be avoided.  If|
03341|018|M|concomitant use is unavoidable, increase the dose of voxelotor as follows:|
03341|019|M|   Patients 12 years and older on concurrent strong CYP3A4 inducers:|
03341|020|M|increase voxelotor dose to 2,500 mg daily.|
03341|021|M|   Patients 12 years and older on concurrent moderate CYP3A4 inducers:|
03341|022|M|increase voxelotor dose to 2,000 mg daily.|
03341|023|M|   Patients 4 years to less than 12 years on concurrent strong or moderate|
03341|024|M|CYP3A4 inducers: refer to prescribing information for recommended|
03341|025|M|weight-based dosage adjustments.(1)|
03341|026|B||
03341|027|D|DISCUSSION:  A pharmacokinetic model predicted that co-administration of|
03341|028|D|rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC)|
03341|029|D|of voxelotor by 40%.|
03341|030|D|   Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted|
03341|031|D|to decrease the AUC of voxelotor by 24%.(1)|
03341|032|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03341|033|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin,|
03341|034|D|primidone, rifampin, rifapentine, and St. John's wort.|
03341|035|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03341|036|D|dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib,|
03341|037|D|modafinil, nafcillin, pacritinib, sotorasib, telotristat ethyl,|
03341|038|D|thioridazine, and tovorafenib.(2-3)|
03341|039|B||
03341|040|R|REFERENCES:|
03341|041|B||
03341|042|R|1.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
03341|043|R|  Inc. December, 2021.|1
03341|044|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03341|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03341|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03341|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03341|048|R|  11/14/2017.|1
03341|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
03341|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03342|001|T|MONOGRAPH TITLE:  Voxelotor/Slt Strong 3A4 Inhib; Fluconazole (mono deleted|
03342|002|T|12/21/2021)|
03342|003|B||
03342|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03342|005|L|of severe adverse interaction.|
03342|006|B||
03342|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 or fluconazole may inhibit|
03342|008|A|the metabolism of voxelotor.(1)|
03342|009|B||
03342|010|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor or|
03342|011|E|fluconazole may result in elevated levels of and toxicity from voxelotor.(1)|
03342|012|B||
03342|013|P|PREDISPOSING FACTORS:  Severe hepatic impairment (Child Pugh C) increases|
03342|014|P|voxelotor exposure. The recommended dosage for patients with severe hepatic|
03342|015|P|impairment is 1,000 mg once daily.(1)|
03342|016|B||
03342|017|M|PATIENT MANAGEMENT:  The manufacturer of voxelotor states that concurrent|
03342|018|M|use with strong CYP3A4 inhibitors or fluconazole should be avoided.  If|
03342|019|M|concomitant use of strong CYP3A4 inhibitors or fluconazole is unavoidable,|
03342|020|M|the dosage of voxelotor should be reduced to 1,000 mg once daily.(1)|
03342|021|B||
03342|022|D|DISCUSSION:  Concomitant use of voxelotor with ketoconazole, a strong CYP3A4|
03342|023|D|inhibitor, is predicted to increase voxelotor area-under-curve (AUC) by 42%|
03342|024|D|to 83%.(1)|
03342|025|D|   Concomitant use of voxelotor with fluconazole, a moderate CYP3A4|
03342|026|D|inhibitor, a moderate CYP2C9 inhibitor and a strong CYP2C19 inhibitor, is|
03342|027|D|predicted to increase voxelotor AUC in patients by 40% to 116%.(1)|
03342|028|D|   Strong inhibitors of CYP3A4 include:  boceprevir, ceritinib,|
03342|029|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03342|030|D|ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone,|
03342|031|D|nelfinavir, posaconazole, ribociclib, ritonavir, saquinavir, telaprevir,|
03342|032|D|telithromycin, troleandomycin, tucatinib, and voriconazole.(2-4)|
03342|033|B||
03342|034|R|REFERENCES:|
03342|035|B||
03342|036|R|1.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
03342|037|R|  Inc. December, 2021.|1
03342|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03342|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03342|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03342|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03342|042|R|  11/14/2017.|1
03342|043|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03342|044|R|  Indiana University School of Medicine.  Available at:|1
03342|045|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03342|046|R|4.This information is based on an extract from the Certara Drug Interaction|6
03342|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03343|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP3A4 Substrates/Voxelotor|
03343|002|B||
03343|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03343|004|L|of severe adverse interaction.|
03343|005|B||
03343|006|A|MECHANISM OF ACTION:  Voxelotor is an inhibitor of CYP3A4 and may decrease|
03343|007|A|the metabolism of drugs metabolized by the CYP3A4 enzyme.|
03343|008|B||
03343|009|E|CLINICAL EFFECTS:  Concurrent use of voxelotor may lead to increased serum|
03343|010|E|levels and adverse effects of drugs sensitive to inhibition of the CYP3A4|
03343|011|E|pathway.(1)|
03343|012|B||
03343|013|P|PREDISPOSING FACTORS:  A greater risk for serious adverse events would be|
03343|014|P|expected from drugs having a narrow therapeutic window.|
03343|015|B||
03343|016|M|PATIENT MANAGEMENT:  The manufacturer of voxelotor states that|
03343|017|M|co-administration of sensitive CYP3A4 substrates with a narrow therapeutic|
03343|018|M|index should be avoided.  If concomitant use is unavoidable, consider dose|
03343|019|M|reduction of the sensitive substrate.(1)|
03343|020|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
03343|021|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
03343|022|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
03343|023|M|inhibitors should be avoided.(2)|
03343|024|B||
03343|025|D|DISCUSSION:  In a study, voxelotor increased the AUC of a single dose of|
03343|026|D|midazolam by 1.6-fold.  After multiple doses of midazolam, a 2.5-fold|
03343|027|D|increase in AUC is predicted.(1)|
03343|028|D|   Sensitive CYP3A4 substrates with a narrow therapeutic index linked to|
03343|029|D|this monograph include: alfentanil, avanafil, conivaptan, cyclosporine,|
03343|030|D|dihydroergotamine, eplerenone, ergotamine, everolimus, felodipine, fentanyl,|
03343|031|D|lomitapide, lovastatin, methylergonovine, midazolam, nisoldipine,|
03343|032|D|sildenafil, simvastatin, sirolimus, ticagrelor, tolvaptan, triazolam, and|
03343|033|D|vardenafil.(1,3,4)|
03343|034|B||
03343|035|R|REFERENCES:|
03343|036|B||
03343|037|R|1.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
03343|038|R|  Inc. December, 2021.|1
03343|039|R|2.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
03343|040|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
03343|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03343|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03343|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03343|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03343|045|R|  11/14/2017.|1
03343|046|R|4.This information is based on an extract from the Certara Drug Interaction|6
03343|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03344|001|T|MONOGRAPH TITLE:  Select Sensitive CYP3A4 Substrates that Prolong|
03344|002|T|QT/Voxelotor|
03344|003|B||
03344|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03344|005|L|of severe adverse interaction.|
03344|006|B||
03344|007|A|MECHANISM OF ACTION:  Voxelotor is an inhibitor of CYP3A4 and may decrease|
03344|008|A|the metabolism of drugs metabolized by the CYP3A4 enzyme.|
03344|009|B||
03344|010|E|CLINICAL EFFECTS:  Concurrent use of voxelotor may lead to increased serum|
03344|011|E|levels and adverse effects of drugs sensitive to inhibition of the CYP3A4|
03344|012|E|pathway.(1)|
03344|013|E|  Higher systemic concentrations of QT prolonging drugs which are|
03344|014|E|metabolized by CYP3A4 may increase the risk for Torsades de Pointes.|
03344|015|B||
03344|016|P|PREDISPOSING FACTORS:  A greater risk for serious adverse events would be|
03344|017|P|expected from drugs having a narrow therapeutic window.|
03344|018|P|   The risk of QT prolongation or torsade de pointes may be increased in|
03344|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03344|020|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03344|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03344|022|P|advanced age.(2)|
03344|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03344|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03344|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03344|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03344|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03344|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03344|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03344|030|P|   With pimozide, the risk of anticholinergic toxicities including cognitive|
03344|031|P|decline, delirium, falls and fractures is increased in geriatric patients|
03344|032|P|using more than one medicine with anticholinergic properties.(3)|
03344|033|B||
03344|034|M|PATIENT MANAGEMENT:  The manufacturer of voxelotor states that|
03344|035|M|co-administration of sensitive CYP3A4 substrates with a narrow therapeutic|
03344|036|M|index should be avoided.  If concomitant use is unavoidable, consider dose|
03344|037|M|reduction of the sensitive substrate.(1)|
03344|038|M|   If concurrent therapy with voxelotor and a sensitive CYP3A4 substrate|
03344|039|M|which may prolong the QT interval is warranted, consider obtaining serum|
03344|040|M|calcium, magnesium, and potassium levels and monitoring ECG at baseline and|
03344|041|M|at regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03344|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03344|043|B||
03344|044|D|DISCUSSION:  In a study, voxelotor increased the AUC of a single dose of|
03344|045|D|midazolam by 1.6-fold.  After multiple doses of midazolam, a 2-fold increase|
03344|046|D|in AUC is predicted.(1)|
03344|047|D|   Sensitive CYP3A4 substrates with a narrow therapeutic index that prolong|
03344|048|D|QT include: dronedarone, hydroquinidine, pimozide, quinidine, and|
03344|049|D|tacrolimus.(1,4-5)|
03344|050|B||
03344|051|R|REFERENCES:|
03344|052|B||
03344|053|R|1.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
03344|054|R|  Inc. December, 2021.|1
03344|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03344|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03344|057|R|  settings: a scientific statement from the American Heart Association and|6
03344|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03344|059|R|  2;55(9):934-47.|6
03344|060|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03344|061|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03344|062|R|  Soc 2023 Jul;71(7):2052-2081.|6
03344|063|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03344|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03344|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03344|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03344|067|R|  11/14/2017.|1
03344|068|R|5.This information is based on an extract from the Certara Drug Interaction|6
03344|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03345|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Cenobamate|
03345|002|B||
03345|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03345|004|L|of severe adverse interaction.|
03345|005|B||
03345|006|A|MECHANISM OF ACTION:  Cenobamate may induce the CYP3A4 mediated metabolism|
03345|007|A|of hormonal contraceptives.(1)|
03345|008|B||
03345|009|E|CLINICAL EFFECTS:  Concurrent use of cenobamate may reduce the effectiveness|
03345|010|E|of hormonal contraceptives.(1)|
03345|011|B||
03345|012|P|PREDISPOSING FACTORS:  None determined.|
03345|013|B||
03345|014|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
03345|015|M|rely on hormonal contraceptives for contraception.  According to the US|
03345|016|M|manufacturer, women should use additional or alternative non-hormonal|
03345|017|M|methods of birth control during cenobamate therapy.(1)|
03345|018|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03345|019|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03345|020|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03345|021|M|contraceptive (i.e., a copper IUD).  If a non-hormonal emergency|
03345|022|M|contraceptive is not an option, double the usual dose of levonorgestrel from|
03345|023|M|1.5 to 3 mg.  Advise the patient to have a pregnancy test to exclude|
03345|024|M|pregnancy after use and to seek medical advice if she does become|
03345|025|M|pregnant.(2)|
03345|026|B||
03345|027|D|DISCUSSION:  Cenobamate may induce the CYP3A4 mediated metabolism of|
03345|028|D|hormonal contraceptives.  The effectiveness of hormonal contraceptives may|
03345|029|D|be reduced when administered concomitantly with cenobamate.  Women should|
03345|030|D|use additional or alternative non-hormonal birth control.(1)|
03345|031|B||
03345|032|R|REFERENCES:|
03345|033|B||
03345|034|R|1.Xcopri (cenobamate) US prescribing information. SK Life Science, Inc.|1
03345|035|R|  November, 2019.|1
03345|036|R|2.Medicines and Healthcare products Regulatory Agency.|1
03345|037|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03345|038|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03345|039|R|  available at:|1
03345|040|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03345|041|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03345|042|R|  -and-contraceptive-efficacy September 15, 2016..|1
03346|001|T|MONOGRAPH TITLE:  Phenytoin/Cenobamate|
03346|002|B||
03346|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03346|004|L|of severe adverse interaction.|
03346|005|B||
03346|006|A|MECHANISM OF ACTION:  Cenobamate may inhibit the CYP2C19-mediated metabolism|
03346|007|A|of phenytoin.(1)|
03346|008|B||
03346|009|E|CLINICAL EFFECTS:  Concurrent use of cenobamate and phenytoin may result in|
03346|010|E|elevated levels of phenytoin and phenytoin toxicity.(1) Phenytoin has a|
03346|011|E|narrow therapeutic range. Early symptoms of phenytoin toxicity may include|
03346|012|E|nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred|
03346|013|E|speech, blurred vision, nausea, and vomiting. Severe toxicity may produce|
03346|014|E|organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and|
03346|015|E|atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be|
03346|016|E|fatal.(2)|
03346|017|B||
03346|018|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
03346|019|P|hypoalbuminemia.|
03346|020|B||
03346|021|M|PATIENT MANAGEMENT:  Patients maintained on phenytoin should be carefully|
03346|022|M|monitored if cenobamate is initiated or discontinued.  The manufacturer of|
03346|023|M|cenobamate states that the dosage of phenytoin should be gradually decreased|
03346|024|M|by up to 50% when cenobamate is being titrated.(1,3-5)|
03346|025|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
03346|026|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
03346|027|M|vision, nausea, and vomiting).(2)|
03346|028|B||
03346|029|D|DISCUSSION:  In a study, cenobamate (200 mg daily) increased phenytoin mean|
03346|030|D|maximum concentration (Cmax) and area-under-curve (AUC) by 70% and 84%,|
03346|031|D|respectively.(1)|
03346|032|B||
03346|033|R|REFERENCES:|
03346|034|B||
03346|035|R|1.Xcopri (cenobamate) US prescribing information. SK Life Science, Inc.|1
03346|036|R|  November, 2019.|1
03346|037|R|2.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
03346|038|R|  March, 2022.|1
03346|039|R|3.Carreno M, Gil-Nagel A, Serratosa JM, Toledo M, Rodriguez-Uranga JJ,|6
03346|040|R|  Villanueva V. Spanish consensus on the management of concomitant|6
03346|041|R|  antiseizure medications when using cenobamate in adults with|6
03346|042|R|  drug-resistant focal seizures. Epilepsia Open 24 March 2024;9:1051 - 1058.|6
03346|043|R|4.Villani F, Cianci V, Di Bonaventura C, Di Gennaro G, Galimberti CA,|6
03346|044|R|  Guerrini R, La Neve A, Mecarelli O, Pietrafusa N, Specchio N, Vigevano F,|6
03346|045|R|  Perucca E. Use of cenobamate for the treatment of focal epilepsy: an|6
03346|046|R|  Italian expert opinion paper. Expert Rev Neurother 24 Jan 2023;|6
03346|047|R|  22(11-12):935-940.|6
03346|048|R|5.Smith MC, Klein P, Krauss GL, Rashid S, Seiden LG, Stern JM, Rosenfeld WE.|6
03346|049|R|  Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate|6
03346|050|R|  Treatment: Expert Opinion Consensus Recommendations. Neurol Ther 3|6
03346|051|R|  September 2022;11:1705-1720.|6
03347|001|T|MONOGRAPH TITLE:  Tacrolimus/Moderate & Weak CYP3A4 Inhibitors that Prolong|
03347|002|T|QT|
03347|003|B||
03347|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03347|005|L|take action as needed.|
03347|006|B||
03347|007|A|MECHANISM OF ACTION:  Moderate and weak inhibitors of CYP3A4 may inhibit the|
03347|008|A|metabolism of tacrolimus.(1)|
03347|009|A|   In addition, concurrent use of tacrolimus with agents known to prolong|
03347|010|A|the QT interval may result in additive or synergistic effects on the QTc|
03347|011|A|interval.(1)|
03347|012|B||
03347|013|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inhibitor may result in|
03347|014|E|elevated levels of and toxicity from tacrolimus, including nephrotoxicity|
03347|015|E|and neurotoxicity.(1)|
03347|016|E|   In addition, concurrent administration of a QT prolonging CYP3A4|
03347|017|E|inhibitor and tacrolimus may result in prolongation of the QTc interval and|
03347|018|E|life-threatening cardiac arrhythmias, including torsades de pointes.|
03347|019|B||
03347|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03347|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03347|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03347|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03347|024|P|gender, or advanced age.(2)|
03347|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03347|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03347|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03347|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03347|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03347|030|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03347|031|P|dysfunction).(2)|
03347|032|B||
03347|033|M|PATIENT MANAGEMENT:  The US manufacturer of tacrolimus recommends frequently|
03347|034|M|monitoring tacrolimus whole blood trough concentrations and reducing|
03347|035|M|tacrolimus dose if needed.(1)|
03347|036|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
03347|037|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03347|038|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03347|039|M|heartbeat, dizziness, or fainting.|
03347|040|B||
03347|041|D|DISCUSSION:  The coadministration of amiodarone and tacrolimus was described|
03347|042|D|in a case report of a 73-year-old kidney transplant recipient with normal|
03347|043|D|renal function who was on amiodarone for years.  Tacrolimus 7 mg per day was|
03347|044|D|started and after 3 months, the patient was found to have a tacrolimus level|
03347|045|D|of 63 ng/mL.  The dose of tacrolimus was lowered to 2 mg per day, and|
03347|046|D|tacrolimus levels dropped to 12.9 ng/mL.(3)|
03347|047|D|   In another case report, a 65-year-old man on amiodarone for 5 years|
03347|048|D|started tacrolimus 3 mg twice daily status-post renal transplant.  After one|
03347|049|D|day, QTc was prolonged from a baseline of 440 ms to 535 ms.  QTc dropped to|
03347|050|D|493 ms three days after discontinuation of amiodarone and dose reduction of|
03347|051|D|tacrolimus.(4)|
03347|052|D|   A case report describes the interaction between azithromycin and|
03347|053|D|tacrolimus in a 27-year old woman with acute myelogenous leukemia who had a|
03347|054|D|bone marrow transplant.  On tacrolimus 0.02 mg/kg/day IV, the patient had|
03347|055|D|stable tacrolimus levels of 15.8 to 17.5 ng/mL.  Three days after initiation|
03347|056|D|of azithromycin 500 mg daily, tacrolimus levels rose to over 30 ng/mL.(5)|
03347|057|D|   In a case report, a 64-year-old kidney transplant recipient on a stable|
03347|058|D|dose of tacrolimus 10 mg twice daily for 5 months was started on ranolazine|
03347|059|D|500 mg twice daily for angina.  Tacrolimus levels rose from the patient's|
03347|060|D|stable levels of 7 to 10 ng/mL in the previous 5 months to 17.8 ng/mL after|
03347|061|D|1 day.(6)|
03347|062|D|   Another case report describes a 54-year-old kidney transplant recipient|
03347|063|D|on tacrolimus 3 mg twice daily with trough levels of 4.5 to 7.4 ng/mL for|
03347|064|D|the previous 4 years.  After he was started on ranolazine 375 mg twice|
03347|065|D|daily, tacrolimus levels rose to 10.9 ng/mL and serum creatinine (Scr) rose|
03347|066|D|from 1.2 to 2 mg/dL.  Ranolazine was discontinued after one month, and|
03347|067|D|tacrolimus levels dropped to 3.6 ng/mL, with complete reversal of renal|
03347|068|D|failure.(7)|
03347|069|D|   A 62-year-old kidney transplant recipient on a stable dose of tacrolimus|
03347|070|D|for years was started on ranolazine and titrated to 1,000 mg twice daily|
03347|071|D|over one month.  After 2 weeks, he experienced renal failure with Scr rising|
03347|072|D|from 1.5 to 2.4 mg/dL, and tacrolimus level was elevated at 14 ng/mL.|
03347|073|D|Ranolazine was discontinued and tacrolimus levels decreased to 7 ng/mL after|
03347|074|D|3 days, with Scr returning to baseline.(8)|
03347|075|D|   Moderate CYP3A4 inhibitors that prolong QT linked to this monograph|
03347|076|D|include: ciprofloxacin, clofazimine, crizotinib, and nilotinib.(9)|
03347|077|D|   Weak CYP3A4 inhibitors the prolong QT linked to this monograph include:|
03347|078|D|amiodarone, anamorelin, azithromycin, cilostazol, entrectinib, lapatinib,|
03347|079|D|mavorixafor, osilodrostat, propofol, ranolazine, rucaparib, selpercatinib,|
03347|080|D|and ziftomenib.(9)|
03347|081|B||
03347|082|R|REFERENCES:|
03347|083|B||
03347|084|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
03347|085|R|  August, 2023.|1
03347|086|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03347|087|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03347|088|R|  settings: a scientific statement from the American Heart Association and|6
03347|089|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03347|090|R|  2;55(9):934-47.|6
03347|091|R|3.Kisters K, Cziborra M, Funke C, Brylak S, Hausberg M.|3
03347|092|R|  Amiodarone-tacrolimus interaction in kidney transplantation. Clin Nephrol|3
03347|093|R|  2008 Dec;70(6):563.|3
03347|094|R|4.Burger CI, Clase CM, Gangji AS. Case report: drug interaction between|3
03347|095|R|  tacrolimus and amiodarone with QT prolongation. Transplantation 2010 May|3
03347|096|R|  15;89(9):1166-7.|3
03347|097|R|5.Mori T, Aisa Y, Nakazato T, Yamazaki R, Ikeda Y, Okamoto S.|3
03347|098|R|  Tacrolimus-azithromycin interaction in a recipient of allogeneic bone|3
03347|099|R|  marrow transplantation. Transpl Int 2005 Jun;18(6):757-8.|3
03347|100|R|6.Pierce Dwayne A, Reeves-Daniel Amber M. Ranolazine-tacrolimus interaction.|3
03347|101|R|  Ann Pharmacother 2010 Nov;44(11):1844-1849.|3
03347|102|R|7.Seck Sidy, Bellantoni Marianna, Zoccali Carmine, Enia Giuseppe. Ranolazine|3
03347|103|R|  can markedly increase tacrolimus blood levels. NDT Plus 2011 Feb;|3
03347|104|R|  4(1):44-45.|3
03347|105|R|8.Patni Hitesh, Gitman Michael, Hazzan Azzour, Jhaveri Kenar D. Ranolazine,|3
03347|106|R|  tacrolimus, and diltiazem might be a hazardous combination in a transplant|3
03347|107|R|  patient. Ren Fail 2012 Jan;34(2):251-253.|3
03347|108|R|9.This information is based on an extract from the Certara Drug Interaction|6
03347|109|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03348|001|T|MONOGRAPH TITLE:  Tacrolimus/Moderate and Weak CYP3A4 Inhibitors|
03348|002|B||
03348|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03348|004|L|take action as needed.|
03348|005|B||
03348|006|A|MECHANISM OF ACTION:  Moderate and weak inhibitors of CYP3A4 may inhibit the|
03348|007|A|metabolism of tacrolimus.(1)|
03348|008|B||
03348|009|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inhibitor may result in|
03348|010|E|elevated levels of and toxicity from tacrolimus, including nephrotoxicity,|
03348|011|E|neurotoxicity, and prolongation of the QTc interval and life-threatening|
03348|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
03348|013|B||
03348|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03348|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03348|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03348|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03348|018|P|gender, or advanced age.(2)|
03348|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03348|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03348|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03348|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03348|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03348|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03348|025|P|dysfunction).(2)|
03348|026|B||
03348|027|M|PATIENT MANAGEMENT:  The US manufacturer of tacrolimus recommends monitoring|
03348|028|M|tacrolimus whole blood trough concentrations and reducing tacrolimus dose if|
03348|029|M|needed.(1)|
03348|030|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
03348|031|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03348|032|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03348|033|M|heartbeat, dizziness, or fainting.|
03348|034|B||
03348|035|D|DISCUSSION:  In a study of 26 renal transplant recipients, conjugated|
03348|036|D|estrogens 3.75 mg daily increased the tacrolimus dose-corrected|
03348|037|D|concentration of tacrolimus by 85.6%.  Discontinuation of the conjugated|
03348|038|D|estrogens led to a decrease in tacrolimus concentration of 46.6%.(3)|
03348|039|D|   A case report describes a 65-year-old kidney transplant recipient who was|
03348|040|D|stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL.  Ten|
03348|041|D|days after starting on estradiol gel 0.5 mg per day, her tacrolimus level|
03348|042|D|rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at|
03348|043|D|baseline to 2 mg/dL.  Tacrolimus dose was reduced by 60%, and trough levels|
03348|044|D|and Scr normalized after two weeks.(4)|
03348|045|D|   A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir|
03348|046|D|200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%,|
03348|047|D|while the maximum concentration (Cmax) of tacrolimus was decreased by|
03348|048|D|40%.(5)|
03348|049|D|  An analysis of FAERS data from  2004-2017, found a significant association|
03348|050|D|between transplant rejection and concurrent use of tacrolimus and|
03348|051|D|clotrimazole (reporting odds ratio 1.92, 95% CI). A retrospective study of 7|
03348|052|D|heart transplant patients on concurrent tacrolimus and clotrimazole troche|
03348|053|D|showed a significant correlation between tacrolimus trough concentration and|
03348|054|D|AUC after clotrimazole discontinuation. Tacrolimus clearance and|
03348|055|D|bioavailability after clotrimazole discontinuation was 2.2-fold greater|
03348|056|D|(0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL|
03348|057|D|at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7)|
03348|058|D|   A retrospective study of 26 heart transplant patients found that|
03348|059|D|discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5|
03348|060|D|expresser group had a 3.3-fold increase in apparent oral clearance and AUC|
03348|061|D|of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser|
03348|062|D|group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8)|
03348|063|D|   A study of 6 adult kidney transplant recipients found that clotrimazole|
03348|064|D|(5-day course) increased the tacrolimus AUC 250% and the blood trough|
03348|065|D|concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance|
03348|066|D|decreased 60% with coadministration of clotrimazole.(9)|
03348|067|D|   A case report describes a 23-year-old kidney transplant recipient who was|
03348|068|D|stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily,|
03348|069|D|prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche|
03348|070|D|10 mg four times daily. Discontinuation of clotrimazole resulted in a|
03348|071|D|decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a|
03348|072|D|period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting|
03348|073|D|in an increased tacrolimus level of 19.2 ng/ml.(10)|
03348|074|D|   A retrospective study in 95 heart transplant recipients on concurrent|
03348|075|D|clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7%|
03348|076|D|was required after clotrimazole discontinuation. Tacrolimus trough|
03348|077|D|concentration was found to have decreased 42.5% after clotrimazole|
03348|078|D|discontinuation.(11)|
03348|079|D|   A retrospective study in 65 pancreas transplant patients on concurrent|
03348|080|D|tacrolimus, clotrimazole, cyclosporine, and prednisone found that|
03348|081|D|clotrimazole discontinuation at 3 months after transplantation may cause|
03348|082|D|significant tacrolimus trough level reductions.(12)|
03348|083|D|   A case report describes a 6-year-old kidney transplant recipient who was|
03348|084|D|on a regimen of tacrolimus and mycophenolate mofetil. The patient was|
03348|085|D|started letermovir 240 mg via G-tube 2 months post kidney transplant.  One|
03348|086|D|week after starting letermovir, the routine tacrolimus level showed a|
03348|087|D|supratherapeutic concentration of 22.9 ng/L.  A 36% dose reduction of|
03348|088|D|tacrolimus was required.  Upon discontinuation of letermovir, the tacrolimus|
03348|089|D|level decreased by 42%.(13)|
03348|090|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  aprepitant,|
03348|091|D|berotralstat, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant,|
03348|092|D|nirogacestat, sevabertinib, stiripentol, and tofisopam.(6)|
03348|093|D|   Weak CYP3A4 inhibitors linked to this monograph include:  alprazolam,|
03348|094|D|avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab,|
03348|095|D|chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant,|
03348|096|D|delavirdine, diosmin, elinzanetant, estrogens, flibanserin, fosaprepitant,|
03348|097|D|fostamatinib, ginkgo biloba, givinostat, glecaprevir/pibrentasvir,|
03348|098|D|goldenseal,  grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine,|
03348|099|D|lazertinib, linagliptin, lomitapide, lumateperone, lurasidone, peppermint|
03348|100|D|oil, piperine, propiverine, ranitidine, remdesivir, resveratrol, rimegepant,|
03348|101|D|simeprevir, sitaxsentan, skullcap, suvorexant, ticagrelor, tolvaptan,|
03348|102|D|trofinetide, viloxazine, and vonoprazan-amoxicillin.(6)|
03348|103|B||
03348|104|R|REFERENCES:|
03348|105|B||
03348|106|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
03348|107|R|  August, 2023.|1
03348|108|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03348|109|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03348|110|R|  settings: a scientific statement from the American Heart Association and|6
03348|111|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03348|112|R|  2;55(9):934-47.|6
03348|113|R|3.Ghadimi M, Dashti-Khavidaki S, Shahali M, Gohari M, Khatami MR, Alamdari|2
03348|114|R|  A. Tacrolimus interaction with oral oestrogen in kidney transplant|2
03348|115|R|  recipients: A case-control study. J Clin Pharm Ther 2018 Aug;|2
03348|116|R|  43(4):513-518.|2
03348|117|R|4.Migali G, Tintillier M. Interaction between estradiol and tacrolimus in|3
03348|118|R|  kidney-transplanted menopausal women. NDT Plus 2008 Aug;1(4):277-8.|3
03348|119|R|5.Feng HP, Caro L, Fandozzi CM, Guo Z, Talaty J, Wolford D, Panebianco D,|2
03348|120|R|  Iwamoto M, Butterton JR, Yeh WW. Pharmacokinetic Interactions Between|2
03348|121|R|  Elbasvir/Grazoprevir and Immunosuppressant Drugs in Healthy Volunteers. J|2
03348|122|R|  Clin Pharmacol 2018 May;58(5):666-673.|2
03348|123|R|6.This information is based on an extract from the Certara Drug Interaction|6
03348|124|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03348|125|R|7.Uno T, Wada K, Hosomi K, Matsuda S, Ikura MM, Takenaka H, Terakawa N, Oita|2
03348|126|R|  A, Yokoyama S, Kawase A, Takada M. Drug interactions between tacrolimus|2
03348|127|R|  and clotrimazole troche: a data mining approach followed by a|2
03348|128|R|  pharmacokinetic study. Eur J Clin Pharmacol 2020 Jan;76(1):117-125.|2
03348|129|R|8.Uno T, Wada K, Matsuda S, Terada Y, Terakawa N, Oita A, Yokoyama S, Kawase|2
03348|130|R|  A, Hosomi K, Takada M. Effects of clotrimazole on tacrolimus|2
03348|131|R|  pharmacokinetics in patients with heart transplants with different CYP3A5|2
03348|132|R|  genotypes. Eur J Clin Pharmacol 2019 Jan;75(1):67-75.|2
03348|133|R|9.Vasquez EM, Shin GP, Sifontis N, Benedetti E. Concomitant clotrimazole|2
03348|134|R|  therapy more than doubles the relative oral bioavailability of tacrolimus.|2
03348|135|R|  Ther Drug Monit 2005 Oct;27(5):587-91.|2
03348|136|R|10.Choy M. Tacrolimus interaction with clotrimazole: a concise case report|3
03348|137|R|   and literature review. P T 2010 Oct;35(10):568-9.|3
03348|138|R|11.Laub MR, Crow SA, Personett HA, Dierkhising R, Boilson B, Razonable R.|2
03348|139|R|   Effects of clotrimazole troches on tacrolimus dosing in heart transplant|2
03348|140|R|   recipients. Transpl Infect Dis 2018 Dec;20(6):e12979.|2
03348|141|R|12.Viesselmann CW, Descourouez JL, Jorgenson MR, Radke NA, Odorico JS.|2
03348|142|R|   Clinically Significant Drug Interaction Between Clotrimazole and|2
03348|143|R|   Tacrolimus in Pancreas Transplant Recipients and Associated Risk of|2
03348|144|R|   Allograft Rejection. Pharmacotherapy 2016 Mar;36(3):335-41.|2
03348|145|R|13.Berger I, Matsuda-Abedini M, Haubrich K. Letermovir and Tacrolimus|3
03348|146|R|   Drug-Drug Interaction in a Pediatric Kidney Transplant  Patient: A Case|3
03348|147|R|   Report and Review of the Literature. Pediatr Transplant 2025 Sep;|3
03348|148|R|   29(6):e70143.|3
03349|001|T|MONOGRAPH TITLE:  Rivaroxaban/Ticagrelor (mono deleted 04/30/2024)|
03349|002|B||
03349|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03349|004|L|of severe adverse interaction.|
03349|005|B||
03349|006|A|MECHANISM OF ACTION:  Ticagrelor may inhibit the metabolism of rivaroxaban|
03349|007|A|by CYP3A4 and by P-glycoprotein. Ticagrelor may have additive effects on|
03349|008|A|hemostasis.(1,2)|
03349|009|B||
03349|010|E|CLINICAL EFFECTS:  Concurrent use of rivaroxaban with ticagrelor may result|
03349|011|E|in elevated levels of and clinical effects of rivaroxaban, including an|
03349|012|E|increased risk of bleeding.(1)|
03349|013|B||
03349|014|P|PREDISPOSING FACTORS:  Patients with decreased renal function (CrCL of|
03349|015|P|15ml/min to 80ml/min) may be predisposed to this interaction.(1)|
03349|016|P|   The risk for bleeding episodes may be greater in patients with|
03349|017|P|disease-associated factors (e.g. thrombocytopenia).|
03349|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
03349|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03349|020|P|risk for bleeding (e.g. NSAIDs).|
03349|021|B||
03349|022|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
03349|023|M|receiving concurrent therapy for signs of blood loss, including decreased|
03349|024|M|hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood|
03349|025|M|pressure and promptly evaluate patients with any symptoms.|
03349|026|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03349|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03349|028|M|anticoagulation in patients with active pathologic bleeding.|
03349|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03349|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03349|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03349|032|M|and/or swelling.|
03349|033|B||
03349|034|D|DISCUSSION:  Concurrent use of rivaroxaban with ticagrelor, a weak CYP3A4|
03349|035|D|inhibitor and P-glycoprotein inhibitor, may result in increased levels of|
03349|036|D|and clinical effects of rivaroxaban. Combined use of ticagrelor, a platelet|
03349|037|D|aggregation inhibitor, with rivaroxaban may increase the risk of|
03349|038|D|bleeding.(1,2)|
03349|039|B||
03349|040|R|REFERENCES:|
03349|041|B||
03349|042|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
03349|043|R|  Inc. March, 2020.|1
03349|044|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP November,|1
03349|045|R|  2024.|1
03350|001|T|MONOGRAPH TITLE:  Dichlorphenamide/Aspirin (Greater Than 325 mg);|
03350|002|T|Salicylates|
03350|003|B||
03350|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03350|005|L|is contraindicated and generally should not be dispensed or administered to|
03350|006|L|the same patient.|
03350|007|B||
03350|008|A|MECHANISM OF ACTION:  Dichlorphenamide may reduce blood pH, causing a shift|
03350|009|A|of salicylates from plasma into tissues (eg, central nervous system).(1)|
03350|010|A|Alternatively, toxicity may be due to salicylate-induced displacement of|
03350|011|A|dichlorphenamide from its protein binding sites and inhibition of renal|
03350|012|A|tubular secretion.|
03350|013|B||
03350|014|E|CLINICAL EFFECTS:  An increase in the pharmacologic effects of salicylates|
03350|015|E|with possible toxicity may occur.  Anorexia, tachypnea, lethargy, and coma|
03350|016|E|have been reported.(1)|
03350|017|B||
03350|018|P|PREDISPOSING FACTORS:  High doses of salicylates, low body weight.|
03350|019|B||
03350|020|M|PATIENT MANAGEMENT:  The concurrent use of high-dose aspirin or other|
03350|021|M|salicylates with dichlorphenamide is contraindicated.  If it is necessary to|
03350|022|M|administer a low-dose salicylate concurrently, use the lowest dose possible|
03350|023|M|or replace it with a non-salicylate anti-inflammatory agent.  Monitor|
03350|024|M|salicylate levels and serum bicarbonate concentrations, and monitor the|
03350|025|M|patient for symptoms of toxicity.  Adjust the dose as needed.(1)|
03350|026|B||
03350|027|D|DISCUSSION:  An 8-year-old boy with unimpaired renal and hepatic function|
03350|028|D|was found to have developed metabolic acidosis after treatment for glaucoma|
03350|029|D|and joint pain with a combination of aloxiprin 3.6 gram daily and|
03350|030|D|dichlorphenamide 25 mg three times daily.  His symptoms resolved after|
03350|031|D|discontinuation of both aloxiprin and dichlorphenamide and did not recur on|
03350|032|D|subsequent therapy with naproxen and dichlorphenamide.(2)|
03350|033|D|   A 75-year old woman taking dichlorphenamide 100 mg to 150 mg daily for|
03350|034|D|therapy of glaucoma and high doses of aspirin (975 mg 4 to 5 times daily)|
03350|035|D|for arthritis developed severe acid-base imbalance and salicylate|
03350|036|D|intoxication.  The patient did not exhibit ill effects when taking high|
03350|037|D|aspirin doses without dichlorphenamide.(3)|
03350|038|B||
03350|039|R|REFERENCES:|
03350|040|B||
03350|041|R|1.Keveyis (dichlorphenamide) US prescribing information. Strongbridge|1
03350|042|R|  Biopharma plc. December 2019.|1
03350|043|R|2.Cowan RA, Hartnell GG, Lowdell CP, Baird IM, Leak AM. Metabolic acidosis|3
03350|044|R|  induced by carbonic anhydrase inhibitors and salicylates in patients with|3
03350|045|R|  normal renal function. Br Med J (Clin Res Ed) 1984 Aug 11;289(6441):347-8.|3
03350|046|R|3.Anderson CJ, Kaufman PL, Sturm RJ. Toxicity of combined therapy with|3
03350|047|R|  carbonic anhydrase inhibitors and aspirin. Am J Ophthalmol 1978 Oct;|3
03350|048|R|  86(4):516-9.|3
03351|001|T|MONOGRAPH TITLE:  Dichlorphenamide/Aspirin (Less Than or Equal To 325 mg)|
03351|002|B||
03351|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03351|004|L|take action as needed.|
03351|005|B||
03351|006|A|MECHANISM OF ACTION:  Carbonic anhydrase inhibitors (eg, acetazolamide) may|
03351|007|A|reduce blood pH, causing a shift of salicylates from plasma into tissues|
03351|008|A|(eg, central nervous system).(1)  Alternatively, toxicity may be due to|
03351|009|A|salicylate-induced displacement of the carbonic anhydrase inhibitor from its|
03351|010|A|protein binding sites and inhibition of renal tubular secretion.|
03351|011|B||
03351|012|E|CLINICAL EFFECTS:  An increase in the pharmacologic effects of salicylates|
03351|013|E|with possible toxicity may occur.  Anorexia, tachypnea, lethargy, and coma|
03351|014|E|have been reported.(1)|
03351|015|B||
03351|016|P|PREDISPOSING FACTORS:  High doses of salicylates, low body weight.|
03351|017|B||
03351|018|M|PATIENT MANAGEMENT:  The concurrent use of high-dose aspirin or other|
03351|019|M|salicylates with dichlorphenamide is contraindicated.  If it is necessary to|
03351|020|M|administer a low-dose salicylate concurrently, use the lowest dose possible|
03351|021|M|or replace it with a non-salicylate anti-inflammatory agent.  Monitor|
03351|022|M|salicylate levels and serum bicarbonate concentrations, and monitor the|
03351|023|M|patient for symptoms of toxicity.  Adjust the dose as needed.(1)|
03351|024|B||
03351|025|D|DISCUSSION:  An 8-year-old boy with unimpaired renal and hepatic function|
03351|026|D|was found to have developed metabolic acidosis after treatment for glaucoma|
03351|027|D|and joint pain with a combination of aloxiprin 3.6 gram daily and|
03351|028|D|dichlorphenamide 25 mg three times daily.  His symptoms resolved after|
03351|029|D|discontinuation of both aloxiprin and dichlorphenamide and did not recur on|
03351|030|D|subsequent therapy with naproxen and dichlorphenamide.(2)|
03351|031|D|   A 75-year old woman taking dichlorphenamide 100 mg to 150 mg daily for|
03351|032|D|therapy of glaucoma and high doses of aspirin (975 mg 4 to 5 times daily)|
03351|033|D|for arthritis developed severe acid-base imbalance and salicylate|
03351|034|D|intoxication.  The patient did not exhibit ill effects when taking high|
03351|035|D|aspirin doses without dichlorphenamide.(3)|
03351|036|B||
03351|037|R|REFERENCES:|
03351|038|B||
03351|039|R|1.Keveyis (dichlorphenamide) US prescribing information. Strongbridge|1
03351|040|R|  Biopharma plc. December 2019.|1
03351|041|R|2.Cowan RA, Hartnell GG, Lowdell CP, Baird IM, Leak AM. Metabolic acidosis|3
03351|042|R|  induced by carbonic anhydrase inhibitors and salicylates in patients with|3
03351|043|R|  normal renal function. Br Med J (Clin Res Ed) 1984 Aug 11;289(6441):347-8.|3
03351|044|R|3.Anderson CJ, Kaufman PL, Sturm RJ. Toxicity of combined therapy with|3
03351|045|R|  carbonic anhydrase inhibitors and aspirin. Am J Ophthalmol 1978 Oct;|3
03351|046|R|  86(4):516-9.|3
03352|001|T|MONOGRAPH TITLE:  Digoxin/Mirabegron|
03352|002|B||
03352|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03352|004|L|take action as needed.|
03352|005|B||
03352|006|A|MECHANISM OF ACTION:  Mirabegron may inhibit the metabolism of digoxin via|
03352|007|A|P-glycoprotein.(1)|
03352|008|B||
03352|009|E|CLINICAL EFFECTS:  Concurrent use of mirabegron and digoxin may result in an|
03352|010|E|increased concentration of digoxin, which may lead to increased clinical|
03352|011|E|effects and toxicity.|
03352|012|E|   Symptoms of digoxin toxicity can include anorexia, nausea, vomiting,|
03352|013|E|headache, fatigue, malaise, drowsiness, generalized muscle weakness,|
03352|014|E|disorientation, hallucinations, visual disturbances, and arrhythmias.|
03352|015|B||
03352|016|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
03352|017|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
03352|018|P|risk of digoxin toxicity.|
03352|019|B||
03352|020|M|PATIENT MANAGEMENT:  Dosage of digoxin may need to be altered based on the|
03352|021|M|individual patient response.  Monitor for signs and symptoms of digoxin|
03352|022|M|toxicity and adjust dose accordingly.|
03352|023|M|   The manufacturer of mirabegron recommends initiating the lowest dose of|
03352|024|M|digoxin in combination with mirabegron.(1)|
03352|025|M|   The manufacturer of digoxin recommends reducing digoxin concentrations by|
03352|026|M|decreasing the dose by approximately 15-30% or by modifying the dosing|
03352|027|M|frequency of digoxin.  Monitor serum digoxin concentrations before|
03352|028|M|initiation of mirabegron and monitor levels closely during concurrent|
03352|029|M|therapy.(2)|
03352|030|B||
03352|031|D|DISCUSSION:  When given in combination, 100 mg mirabegron increased digoxin|
03352|032|D|maximum concentration (Cmax) by 29% and area-under curve (AUC) by 27%.(1)|
03352|033|B||
03352|034|R|REFERENCES:|
03352|035|B||
03352|036|R|1.Myrbetriq (mirabegron) US prescribing information. Astellas Pharma|1
03352|037|R|  Technologies, Inc. March 25, 2021.|1
03352|038|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
03352|039|R|  Pharmaceuticals, Inc. August, 2018.|1
03353|001|T|MONOGRAPH TITLE:  Pergolide/Selected Antiemetics|
03353|002|B||
03353|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03353|004|L|take action as needed.|
03353|005|B||
03353|006|A|MECHANISM OF ACTION:  Pergolide is a dopamine agonist.  Dopamine antagonists|
03353|007|A|may diminish the effectiveness of pergolide.(1)|
03353|008|B||
03353|009|E|CLINICAL EFFECTS:  The efficacy of pergolide may be decreased, leading to|
03353|010|E|exacerbation of the disease being treated.(1)|
03353|011|B||
03353|012|P|PREDISPOSING FACTORS:  None determined.|
03353|013|B||
03353|014|M|PATIENT MANAGEMENT:  The US manufacturer of pergolide does not recommend|
03353|015|M|concurrent administration of pergolide with dopamine antagonists.(1)|
03353|016|B||
03353|017|D|DISCUSSION:  The US manufacturer of pergolide states pergolide should not be|
03353|018|D|administered with dopamine antagonists.  These agents may diminish the|
03353|019|D|effectiveness of pergolide.(1)|
03353|020|B||
03353|021|R|REFERENCE:|
03353|022|B||
03353|023|R|1.Permax (pergolide) US prescribing information. Eli Lilly and Company July|1
03353|024|R|  12, 2004.|1
03354|001|T|MONOGRAPH TITLE:  Mefloquine/Selected Strong CYP3A4 Inhibitors;Protease|
03354|002|T|Inhibitors|
03354|003|B||
03354|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03354|005|L|take action as needed.|
03354|006|B||
03354|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03354|008|A|mefloquine.(1)|
03354|009|B||
03354|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors or protease|
03354|011|E|inhibitors with mefloquine may result in elevated levels of mefloquine and|
03354|012|E|toxicity.(1)|
03354|013|B||
03354|014|P|PREDISPOSING FACTORS:  None determined.|
03354|015|B||
03354|016|M|PATIENT MANAGEMENT:  The manufacturer of mefloquine states that concurrent|
03354|017|M|use with strong CYP3A4 inhibitors should be approached with caution.(1)|
03354|018|M|   The US Department of Health and Human Services HIV guidelines recommend|
03354|019|M|considering alternative therapies to protease inhibitors or monitoring for|
03354|020|M|adverse events and virologic response.(2)|
03354|021|B||
03354|022|D|DISCUSSION:  In a study in 8 healthy subjects, administration of|
03354|023|D|ketoconazole (400 mg daily) for 10 days followed by a single 500 mg dose of|
03354|024|D|mefloquine resulted in an increase in the AUC of mefloquine by 79%.  The|
03354|025|D|elimination half-life was increased from 322 hours to 448 hours.(1)|
03354|026|D|   Strong CYP3A4 inhibitors and protease inhibitors linked to this monograph|
03354|027|D|include:  adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin,|
03354|028|D|cobicistat, darunavir, fosamprenavir, idelalisib, indinavir, itraconazole,|
03354|029|D|josamycin, mibefradil, mifepristone, nefazodone, nelfinavir,|
03354|030|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir,|
03354|031|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
03354|032|D|voriconazole.(3,4)|
03354|033|B||
03354|034|R|REFERENCES:|
03354|035|B||
03354|036|R|1.Mefloquine (Sandoz) prescribing information. Sandoz Inc. June, 2013.|1
03354|037|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03354|038|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03354|039|R|  HIV. Department of Health and Human Services. Available at:|6
03354|040|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
03354|041|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
03354|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03354|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03354|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03354|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03354|046|R|  11/14/2017.|1
03354|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
03354|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03355|001|T|MONOGRAPH TITLE:  Pimozide/Moderate CYP3A4 Inhibitors that Prolong QT|
03355|002|B||
03355|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03355|004|L|of severe adverse interaction.|
03355|005|B||
03355|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors that prolong the QTc|
03355|007|A|interval may inhibit the metabolism of pimozide and cause an additive risk|
03355|008|A|of QTc prolongation.(1)|
03355|009|B||
03355|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
03355|011|E|QT may increase the levels and effects of pimozide including additive QTc|
03355|012|E|prolongation and potentially life-threatening cardiac arrhythmias like|
03355|013|E|torsades de pointes.|
03355|014|E|   Concurrent use may also result in extrapyramidal symptoms such as|
03355|015|E|akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and|
03355|016|E|oculogyric crisis.(1)|
03355|017|B||
03355|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03355|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03355|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03355|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03355|022|P|female gender, or advanced age.(2)|
03355|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03355|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03355|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03355|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03355|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03355|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03355|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03355|030|P|   The risk of anticholinergic toxicities including cognitive decline,|
03355|031|P|delirium, falls and fractures is increased in geriatric patients using more|
03355|032|P|than one medicine with anticholinergic properties.(3)|
03355|033|B||
03355|034|M|PATIENT MANAGEMENT:  Avoid concurrent use of pimozide and moderate CYP3A4|
03355|035|M|inhibitors, especially when other risk factors for QT prolongation are|
03355|036|M|present.|
03355|037|M|   The manufacturer of pimozide states that concomitant treatment with|
03355|038|M|strong CYP3A4 inhibitors is contraindicated and treatment with less potent|
03355|039|M|inhibitors of CYP3A4 should also be avoided.(1)|
03355|040|M|   If concurrent use cannot be avoided, then correct or minimize QT|
03355|041|M|prolonging risk factors, use the lowest effective dose of pimozide, and|
03355|042|M|discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if|
03355|043|M|possible.|
03355|044|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03355|045|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03355|046|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
03355|047|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03355|048|B||
03355|049|D|DISCUSSION:  Pimozide is metabolized at CYP3A.  Elevated levels of pimozide|
03355|050|D|may prolong the QTc interval resulting in life-threatening ventricular|
03355|051|D|arrhythmias.(1)|
03355|052|D|   A retrospective review of 618 cancer patients treated with 902|
03355|053|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03355|054|D|incidence of QTc prolongation.  In patients who received nilotinib, QTc|
03355|055|D|prolongation was identified in 29 (38.7%) with 1 (3.5%) having Grade 1 (QTc|
03355|056|D|450-480 ms) and 2 (7%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
03355|057|D|occurred in 9 (31%) having QTc greater than or equal to 500 ms and 17|
03355|058|D|(58.6%) having QTc change greater than or equal to 60 ms.  No patients|
03355|059|D|developed ventricular tachycardia, sudden cardiac death, or TdP.(4)|
03355|060|D|   Moderate inhibitors of CYP3A4 that prolong QT include: crizotinib and|
03355|061|D|nilotinib.(5,6)|
03355|062|B||
03355|063|R|REFERENCES:|
03355|064|B||
03355|065|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
03355|066|R|  2011.|1
03355|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03355|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03355|069|R|  settings: a scientific statement from the American Heart Association and|6
03355|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03355|071|R|  2;55(9):934-47.|6
03355|072|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03355|073|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03355|074|R|  Soc 2023 Jul;71(7):2052-2081.|6
03355|075|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03355|076|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03355|077|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03355|078|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03355|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03355|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03355|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03355|082|R|  11/14/2017.|1
03355|083|R|6.This information is based on an extract from the Certara Drug Interaction|6
03355|084|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03356|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/Crizotinib|
03356|002|B||
03356|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03356|004|L|of severe adverse interaction.|
03356|005|B||
03356|006|A|MECHANISM OF ACTION:  Crizotinib inhibits CYP3A4, and thus may inhibit the|
03356|007|A|metabolism of agents processed by this isoenzyme.(1)|
03356|008|B||
03356|009|E|CLINICAL EFFECTS:  Concurrent use of crizotinib with drugs primarily|
03356|010|E|metabolized by CYP3A4 may lead to elevated drug levels and increased side|
03356|011|E|effects of these agents.(1)  Drugs with a narrow therapeutic window that are|
03356|012|E|metabolized by this isoenzyme include:  abemaciclib, cisapride,|
03356|013|E|cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam,|
03356|014|E|nisoldipine, quinidine, simvastatin, and sirolimus.(1-2)|
03356|015|B||
03356|016|P|PREDISPOSING FACTORS:  Greater risk for adverse events would be expected for|
03356|017|P|drugs with a narrow therapeutic window, or for drugs especially sensitive to|
03356|018|P|CYP3A4 inhibition.|
03356|019|B||
03356|020|M|PATIENT MANAGEMENT:  Avoid coadministration of sensitive CYP3A4 substrates|
03356|021|M|with a narrow therapeutic index.  If concomitant use is unavoidable, dosage|
03356|022|M|adjustment of the CYP3A4 substrate should be considered when initiating or|
03356|023|M|discontinuing crizotinib.(1)  Patients maintained on crizotinib may need|
03356|024|M|lower initial doses of the CYP3A4 substrate.  Monitor patients receiving|
03356|025|M|concurrent therapy for adverse effects.|
03356|026|M|   Drug-specific recommendations:|
03356|027|M|   The manufacturer of abemaciclib recommends monitoring for adverse|
03356|028|M|reactions and considering a dose reduction of abemaciclib in 50 mg|
03356|029|M|decrements as detailed in prescribing information (based on starting dose,|
03356|030|M|previous dose reductions, and combination or monotherapy use) with|
03356|031|M|concurrent use of moderate CYP3A4 inhibitors.(3)|
03356|032|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
03356|033|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
03356|034|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
03356|035|M|inhibitors should be avoided.(4)|
03356|036|B||
03356|037|D|DISCUSSION:  Crizotinib (250 mg twice daily for 28 days) increased the|
03356|038|D|area-under-curve (AUC) of oral midazolam by 3.7-fold.(1)|
03356|039|D|   Thus, crizotinib is expected to increase levels of abemaciclib,|
03356|040|D|cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam,|
03356|041|D|nisoldipine, quinidine, simvastatin, and sirolimus.|
03356|042|B||
03356|043|R|REFERENCES:|
03356|044|B||
03356|045|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
03356|046|R|  2023.|1
03356|047|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03356|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03356|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03356|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03356|051|R|  11/14/2017.|1
03356|052|R|3.Verzenio (abemaciclib) US prescribing information. Eli Lilly and Company|1
03356|053|R|  October, 2021.|1
03356|054|R|4.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
03356|055|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
03357|001|T|MONOGRAPH TITLE:  Ubrogepant/Strong CYP3A4 Inhibitors|
03357|002|B||
03357|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03357|004|L|is contraindicated and generally should not be dispensed or administered to|
03357|005|L|the same patient.|
03357|006|B||
03357|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03357|008|A|of ubrogepant.(1)|
03357|009|B||
03357|010|E|CLINICAL EFFECTS:  Concurrent use of ubrogepant with strong CYP3A4|
03357|011|E|inhibitors may result in a significant increase in exposure of|
03357|012|E|ubrogepant.(1)|
03357|013|B||
03357|014|P|PREDISPOSING FACTORS:  None determined.|
03357|015|B||
03357|016|M|PATIENT MANAGEMENT:  The US manufacturer of ubrogepant states|
03357|017|M|coadministration with strong CYP3A4 inhibitors is contraindicated.(1)|
03357|018|B||
03357|019|D|DISCUSSION:  Coadministration of ubrogepant with ketoconazole, a strong|
03357|020|D|CYP3A4 inhibitor, resulted in a 9.7-fold and 5.3-fold increase in|
03357|021|D|area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1)|
03357|022|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
03357|023|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03357|024|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03357|025|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03357|026|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03357|027|D|troleandomycin, tucatinib, and voriconazole.(2,3)|
03357|028|B||
03357|029|R|REFERENCES:|
03357|030|B||
03357|031|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
03357|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
03357|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03357|034|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03357|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03357|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03357|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03357|038|R|  11/14/2017.|1
03358|001|T|MONOGRAPH TITLE:  Tramadol/Selected SSRIs; SNRIs|
03358|002|B||
03358|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03358|004|L|take action as needed.|
03358|005|B||
03358|006|A|MECHANISM OF ACTION:  The concurrent administration of tramadol with a|
03358|007|A|selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine|
03358|008|A|reuptake inhibitor (SNRI) may result in additive blockade of serotonin|
03358|009|A|reuptake, leading to central serotonergic hyperstimulation.(1)|
03358|010|A|   The combination of tramadol and SSRIs or SNRIs may also lower the seizure|
03358|011|A|threshold.(1)|
03358|012|B||
03358|013|E|CLINICAL EFFECTS:  Concurrent administration may increase the risk for|
03358|014|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
03358|015|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
03358|016|E|and muscle rigidity.(2)|
03358|017|E|   Concurrent administration may increase the risk for seizures, especially|
03358|018|E|in susceptible individuals.(1)|
03358|019|B||
03358|020|P|PREDISPOSING FACTORS:  Treatment with multiple medications which increase|
03358|021|P|serotonin levels or with medications which inhibit the metabolism of|
03358|022|P|serotonin increasing drugs are risk factors for serotonin syndrome.(2)|
03358|023|P|   Predisposing factors for a lower seizure threshold include a history of|
03358|024|P|seizures, epilepsy, or a recognized risk for seizures (e.g. head trauma,|
03358|025|P|metabolic disorders, alcohol, drug withdrawal, infections of the central|
03358|026|P|nervous system).|
03358|027|P|   A genetic defect in CYP2D6 leading to the slow metabolizer phenotype may|
03358|028|P|increase the risk for serotonin syndrome due to tramadol.|
03358|029|B||
03358|030|M|PATIENT MANAGEMENT:  If concurrent therapy of tramadol with a SSRI or SNRI|
03358|031|M|is warranted, patients should be closely monitored for signs and symptoms of|
03358|032|M|serotonin syndrome and increased seizure activity.(1)|
03358|033|B||
03358|034|D|DISCUSSION:  There are a number of serotonin syndrome case reports following|
03358|035|D|the addition of tramadol to a stable selective serotonin reuptake inhibitor|
03358|036|D|regimen.  The syndrome developed between 12 hours to 3 weeks after the|
03358|037|D|initiation of tramadol therapy.  Patients recovered after tramadol and/or|
03358|038|D|the SSRI/SNRI was discontinued.(3-14)  One patient also developed mania.(3)|
03358|039|D|Another patient developed nightmares and hallucinations after taking|
03358|040|D|concurrent tramadol and paroxetine for 56 days.(15)|
03358|041|D|   One author suggests that although the combination of tramadol and SSRIs|
03358|042|D|or SNRIs is associated with a risk for serotonin syndrome, given the high|
03358|043|D|rate of co-prescribing for the combination it is an uncommon outcome.(16)|
03358|044|D|   A review of the 124 reports of seizures following tramadol therapy|
03358|045|D|received by the FDA through July 31, 1996 revealed that 20 patients were|
03358|046|D|receiving concurrent therapy with an selective serotonin reuptake|
03358|047|D|inhibitor.(17)  The manufacturer of tramadol states that the risk of seizure|
03358|048|D|is increased in patients receiving concurrent therapy with selective|
03358|049|D|serotonin reuptake inhibitors.(1)|
03358|050|D|   Selected SSRIs and SNRIs linked to this monograph include: citalopram,|
03358|051|D|desvenlafaxine, escitalopram, fluvoxamine, levomilnacipran, milnacipran,|
03358|052|D|sertraline, sibutramine, venlafaxine, vilazodone, and vortioxetine.|
03358|053|B||
03358|054|R|REFERENCES:|
03358|055|B||
03358|056|R|1.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
03358|057|R|  October, 2019.|1
03358|058|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03358|059|R|  352(11):1112-20.|6
03358|060|R|3.Gonzalez-Pinto A, Imaz H, De Heredia JL, Gutierrez M, Mico JA. Mania and|3
03358|061|R|  tramadol-fluoxetine combination. Am J Psychiatry 2001 Jun;158(6):964-5.|3
03358|062|R|4.Mahlberg R, Kunz D, Sasse J, Kirchheiner J. Serotonin syndrome with|3
03358|063|R|  tramadol and citalopram. Am J Psychiatry 2004 Jun;161(6):1129.|3
03358|064|R|5.Mittino D, Mula M, Monaco F. Serotonin syndrome associated with|3
03358|065|R|  tramadol-sertraline coadministration. Clin Neuropharmacol 2004 May-Jun;|3
03358|066|R|  27(3):150-1.|3
03358|067|R|6.Mason BJ, Blackburn KH. Possible serotonin syndrome associated with|3
03358|068|R|  tramadol and sertraline coadministration. Ann Pharmacother 1997 Feb;|3
03358|069|R|  31(2):175-7.|3
03358|070|R|7.Sauget D, Franco PS, Amaniou M, Mazere J, Dantoine T. Possible|3
03358|071|R|  serotonergic syndrome caused by combination of tramadol and sertraline in|3
03358|072|R|  an elderly woman. Therapie 2002 May-Jun;57(3):309-10.|3
03358|073|R|8.Lange-Asschenfeldt C, Weigmann H, Hiemke C, Mann K. Serotonin syndrome as|3
03358|074|R|  a result of fluoxetine in a patient with tramadol abuse: plasma|3
03358|075|R|  level-correlated symptomatology. J Clin Psychopharmacol 2002 Aug;|3
03358|076|R|  22(4):440-1.|3
03358|077|R|9.Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. J|3
03358|078|R|  R Soc Med 1999 Sep;92(9):474-5.|3
03358|079|R|10.Egberts AC, ter Borgh J, Brodie-Meijer CC. Serotonin syndrome attributed|3
03358|080|R|   to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol 1997|3
03358|081|R|   May;12(3):181-2.|3
03358|082|R|11.Lantz MS, Buchalter EN, Giambanco V. Serotonin syndrome following the|3
03358|083|R|   administration of tramadol with paroxetine. Int J Geriatr Psychiatry 1998|3
03358|084|R|   May;13(5):343-5.|3
03358|085|R|12.John AP, Koloth R. Severe serotonin toxicity and manic switch induced by|3
03358|086|R|   combined use of tramadol and paroxetine. Aust N Z J Psychiatry 2007 Feb;|3
03358|087|R|   41(2):192-3.|3
03358|088|R|13.Llinares-Tello F, Escriva-Moscardo S, Martinez-Pastor F,|3
03358|089|R|   Martinez-Mascaraque P. Possible serotoninergic syndrome associated with|3
03358|090|R|   coadministration of paroxetine and tramadol. Med Clin (Barc) 2007 Mar 24;|3
03358|091|R|   128(11):438.|3
03358|092|R|14.Venlafaxine + tramadol: serotonin syndrome. Prescrire Int 2004 Apr;|3
03358|093|R|   13(70):57.|3
03358|094|R|15.Devulder J, De Laat M, Dumoulin K, Renson A, Rolly G. Nightmares and|3
03358|095|R|   hallucinations after long-term intake of tramadol combined with|3
03358|096|R|   antidepressants. Acta Clin Belg 1996;51(3):184-6.|3
03358|097|R|16.Park SH, Wackernah RC, Stimmel GL. Serotonin syndrome: is it a reason to|6
03358|098|R|   avoid the use of tramadol with antidepressants?. J Pharm Pract 2014 Feb;|6
03358|099|R|   27(1):71-8.|6
03358|100|R|17.Kahn LH, Alderfer RJ, Graham DJ. Seizures reported with tramadol. JAMA|3
03358|101|R|   1997 Nov 26;278(20):1661.|3
03359|001|T|MONOGRAPH TITLE:  Ubrogepant (Less Than or Equal To 50 mg)/Moderate CYP3A4|
03359|002|T|Inhibitors|
03359|003|B||
03359|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03359|005|L|take action as needed.|
03359|006|B||
03359|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03359|008|A|metabolism of ubrogepant.(1)|
03359|009|B||
03359|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
03359|011|E|in elevated levels of ubrogepant.(1)|
03359|012|B||
03359|013|P|PREDISPOSING FACTORS:  None determined.|
03359|014|B||
03359|015|M|PATIENT MANAGEMENT:  The manufacturer recommends a dosage adjustment of|
03359|016|M|ubrogepant when used concomitantly with moderate CYP3A4 inhibitors.  Initial|
03359|017|M|dose of ubrogepant should not exceed 50 mg. A second dose should be avoided|
03359|018|M|within 24 hours of the first dose when used concurrently with moderate|
03359|019|M|CYP3A4 inhibitors.(1)|
03359|020|B||
03359|021|D|DISCUSSION:  Co-administration with verapamil, a moderate CYP3A4 inhibitor,|
03359|022|D|resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and|
03359|023|D|concentration maximum (Cmax), respectively.(1)|
03359|024|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
03359|025|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
03359|026|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
03359|027|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
03359|028|D|isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
03359|029|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
03359|030|D|and verapamil.(2-4)|
03359|031|B||
03359|032|R|REFERENCES:|
03359|033|B||
03359|034|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
03359|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03359|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03359|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03359|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03359|039|R|  11/14/2017.|1
03359|040|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03359|041|R|  Indiana University School of Medicine.  Available at:|1
03359|042|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03359|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
03359|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03360|001|T|MONOGRAPH TITLE:  Lemborexant/Strong and Moderate CYP3A4 Inhibitors|
03360|002|B||
03360|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03360|004|L|of severe adverse interaction.|
03360|005|B||
03360|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03360|007|A|lemborexant.(1)|
03360|008|B||
03360|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inhibitor of|
03360|010|E|CYP3A4 may result in increased levels of and effects from lemborexant,|
03360|011|E|including somnolence, fatigue, CNS depressant effects, daytime impairment,|
03360|012|E|headache, and nightmare or abnormal dreams.(1)|
03360|013|B||
03360|014|P|PREDISPOSING FACTORS:  None determined.|
03360|015|B||
03360|016|M|PATIENT MANAGEMENT:  The concurrent use of strong or moderate CYP3A4|
03360|017|M|inhibitors with lemborexant should be avoided.(1)|
03360|018|B||
03360|019|D|DISCUSSION:  Lemborexant is a CYP3A4 substrate.  In a PKPB model, concurrent|
03360|020|D|use of lemborexant with itraconazole increased area-under-curve (AUC) and|
03360|021|D|concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively.|
03360|022|D|Concurrent use of lemborexant with fluconazole increased AUC and Cmax by|
03360|023|D|4.25-fold and 1.75-fold, respectively.(1)|
03360|024|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03360|025|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03360|026|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03360|027|D|nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ribociclib,|
03360|028|D|saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and|
03360|029|D|voriconazole.(2)|
03360|030|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
03360|031|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
03360|032|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03360|033|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral|
03360|034|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
03360|035|D|rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)|
03360|036|B||
03360|037|R|REFERENCES:|
03360|038|B||
03360|039|R|1.Dayvigo (lemborexant) US prescribing information. Eisai Inc. March, 2022.|1
03360|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
03360|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03361|001|T|MONOGRAPH TITLE:  Lemborexant (Less Than or Equal To 5 mg)/Weak CYP3A4|
03361|002|T|Inhibitors|
03361|003|B||
03361|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03361|005|L|take action as needed.|
03361|006|B||
03361|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03361|008|A|lemborexant.(1)|
03361|009|B||
03361|010|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of CYP3A4 may result in|
03361|011|E|increased levels of and effects from lemborexant, including somnolence,|
03361|012|E|fatigue, CNS depressant effects, daytime impairment, headache, and nightmare|
03361|013|E|or abnormal dreams.(1)|
03361|014|B||
03361|015|P|PREDISPOSING FACTORS:  None determined.|
03361|016|B||
03361|017|M|PATIENT MANAGEMENT:  The maximum recommended dose of lemborexant with|
03361|018|M|concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per|
03361|019|M|dose.(1)|
03361|020|B||
03361|021|D|DISCUSSION:  Lemborexant is a CYP3A4 substrate.  In a PKPB model, concurrent|
03361|022|D|use of lemborexant with itraconazole increased area-under-curve (AUC) and|
03361|023|D|concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively.|
03361|024|D|Concurrent use of lemborexant with fluconazole increased AUC and Cmax by|
03361|025|D|4.25-fold and 1.75-fold, respectively.(1)|
03361|026|D|   Weak inhibitors of CYP3A4 include:  alprazolam, amiodarone, amlodipine,|
03361|027|D|anamorelin, asciminib, azithromycin, Baikal skullcap, belumosudil,|
03361|028|D|berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib,|
03361|029|D|chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole,|
03361|030|D|cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine,|
03361|031|D|dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin,|
03361|032|D|fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat,|
03361|033|D|glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid,|
03361|034|D|istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib,|
03361|035|D|leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone,|
03361|036|D|mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil,|
03361|037|D|piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir,|
03361|038|D|resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir,|
03361|039|D|sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan,|
03361|040|D|trofinetide, viloxazine, vonoprazan, and ziftomenib.(1,2)|
03361|041|B||
03361|042|R|REFERENCES:|
03361|043|B||
03361|044|R|1.Dayvigo (lemborexant) US prescribing information. Eisai Inc. March, 2022.|1
03361|045|R|2.This information is based on an extract from the Certara Drug Interaction|6
03361|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03362|001|T|MONOGRAPH TITLE:  Ubrogepant/Strong CYP3A4 Inducers|
03362|002|B||
03362|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03362|004|L|of severe adverse interaction.|
03362|005|B||
03362|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03362|007|A|ubrogepant.(1)|
03362|008|B||
03362|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03362|010|E|may result in decreased levels and effectiveness of ubrogepant.(1)|
03362|011|B||
03362|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03362|013|P|of the inducer for longer than 1-2 weeks.|
03362|014|B||
03362|015|M|PATIENT MANAGEMENT:  The manufacturer of ubrogepant states that concurrent|
03362|016|M|use with strong CYP3A4 inducers should be avoided.(1)|
03362|017|B||
03362|018|D|DISCUSSION:  Coadministration of ubrogepant with rifampin, a strong CYP3A4|
03362|019|D|inducer, resulted in an 80% reduction in ubrogepant exposure.(1)|
03362|020|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03362|021|D|carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane,|
03362|022|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03362|023|D|wort.(2-3)|
03362|024|B||
03362|025|R|REFERENCES:|
03362|026|B||
03362|027|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
03362|028|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03362|029|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03362|030|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03362|031|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03362|032|R|  11/14/2017.|1
03362|033|R|3.This information is based on an extract from the Certara Drug Interaction|6
03362|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03363|001|T|MONOGRAPH TITLE:  Daridorexant/Strong or Moderate CYP3A4 Inducers|
03363|002|B||
03363|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03363|004|L|of severe adverse interaction.|
03363|005|B||
03363|006|A|MECHANISM OF ACTION:  Daridorexant is a substrate of CYP3A4.  Strong or|
03363|007|A|moderate inducers of CYP3A4 may induce the metabolism of daridorexant.(1)|
03363|008|B||
03363|009|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
03363|010|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
03363|011|E|daridorexant.(1)|
03363|012|B||
03363|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03363|014|P|of the inducer for longer than 1-2 weeks.|
03363|015|B||
03363|016|M|PATIENT MANAGEMENT:  The manufacturer of daridorexant states that concurrent|
03363|017|M|use with strong or moderate CYP3A4 inducers should be avoided.(1)|
03363|018|B||
03363|019|D|DISCUSSION:  Concomitant use of rifampin, a strong CYP3A4 inducer, with|
03363|020|D|daridorexant 50 mg decreased daridorexant area-under-curve (AUC) by more|
03363|021|D|than 50%.  Efavirenz 600 mg, a moderate CYP3A4 inducer, decreased|
03363|022|D|daridorexant AUC and maximum concentration (Cmax) by 60% and 40%,|
03363|023|D|respectively.(1)|
03363|024|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03363|025|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03363|026|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03363|027|D|rifapentine, and St. John's wort.|
03363|028|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03363|029|D|dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib,|
03363|030|D|mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib,|
03363|031|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and|
03363|032|D|tovorafenib.(2,3)|
03363|033|B||
03363|034|R|REFERENCES:|
03363|035|B||
03363|036|R|1.Quvivig (daridorexant) US prescribing information. Idorsia Pharmaceuticals|1
03363|037|R|  Ltd October, 2023.|1
03363|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03363|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03363|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03363|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03363|042|R|  11/14/2017.|1
03363|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
03363|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03364|001|T|MONOGRAPH TITLE:  Ubrogepant (Less Than or Equal To 50 mg)/Weak CYP3A4|
03364|002|T|Inhibitors|
03364|003|B||
03364|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03364|005|L|take action as needed.|
03364|006|B||
03364|007|A|MECHANISM OF ACTION:  Weak inhibitors of CYP3A4 may inhibit the metabolism|
03364|008|A|of ubrogepant.(1)|
03364|009|B||
03364|010|E|CLINICAL EFFECTS:  Concurrent use of ubrogepant with weak CYP3A4 inhibitors|
03364|011|E|may result in an increase in exposure of ubrogepant.(1)|
03364|012|B||
03364|013|P|PREDISPOSING FACTORS:  None determined.|
03364|014|B||
03364|015|M|PATIENT MANAGEMENT:  The manufacturer recommends a dosage adjustment of|
03364|016|M|ubrogepant when used concomitantly with weak CYP3A4 inhibitors.  Initial|
03364|017|M|dose of ubrogepant should not exceed 50 mg when used concomitantly with weak|
03364|018|M|inhibitors of CYP3A4.  A second dose may be given within 24 hours but should|
03364|019|M|not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1)|
03364|020|B||
03364|021|D|DISCUSSION:  Coadministration of ubrogepant with verapamil, a moderate|
03364|022|D|CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in|
03364|023|D|area-under-curve (AUC) and concentration maximum (Cmax), respectively.  No|
03364|024|D|dedicated drug interaction study was conducted to assess concomitant use|
03364|025|D|with weak CYP3A4 inhibitors.  The conservative prediction of the maximal|
03364|026|D|potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not|
03364|027|D|expected to be more than 2-fold.(1)|
03364|028|D|   Weak inhibitors of CYP3A4 include:  alprazolam, amiodarone, amlodipine,|
03364|029|D|anamorelin, asciminib, azithromycin, Baikal skullcap, berberine,|
03364|030|D|bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib,|
03364|031|D|chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole,|
03364|032|D|cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor,|
03364|033|D|dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin,|
03364|034|D|fosaprepitant, fostamatinib, gepotidacin, givinostat,|
03364|035|D|glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid,|
03364|036|D|istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib,|
03364|037|D|leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir,|
03364|038|D|mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil,|
03364|039|D|piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine,|
03364|040|D|remdesivir, resveratrol, roxithromycin, simeprevir, sitaxsentan, skullcap,|
03364|041|D|suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine,|
03364|042|D|vonoprazan, and ziftomenib.(2,3)|
03364|043|B||
03364|044|R|REFERENCES:|
03364|045|B||
03364|046|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
03364|047|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03364|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03364|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03364|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03364|051|R|  11/14/2017.|1
03364|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
03364|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03365|001|T|MONOGRAPH TITLE:  Ubrogepant/Moderate and Weak CYP3A4 Inducers|
03365|002|B||
03365|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03365|004|L|take action as needed.|
03365|005|B||
03365|006|A|MECHANISM OF ACTION:  Moderate or weak CYP3A4 inducers may induce the|
03365|007|A|metabolism of ubrogepant.(1)|
03365|008|B||
03365|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate or weak CYP3A4 inducer may|
03365|010|E|result in decreased levels and effectiveness of ubrogepant.(1)|
03365|011|B||
03365|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03365|013|P|of the inducer for longer than 1-2 weeks.|
03365|014|B||
03365|015|M|PATIENT MANAGEMENT:  The manufacturer recommends a dosage adjustment of|
03365|016|M|ubrogepant when coadministered with moderate or weak CYP3A4 inducers.|
03365|017|M|Initial dose of ubrogepant should be 100 mg.  If a second dose is needed,|
03365|018|M|the dose of ubrogepant should be 100 mg.(1)|
03365|019|B||
03365|020|D|DISCUSSION:  Coadministration of ubrogepant with rifampin, a strong CYP3A4|
03365|021|D|inducer, resulted in an 80% reduction in ubrogepant exposure.  No dedicated|
03365|022|D|drug interaction studies were conducted to assess concomitant use with|
03365|023|D|moderate or weak CYP3A4 inducers.  Dose adjustment for concomitant use of|
03365|024|D|ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a|
03365|025|D|conservative prediction of 50% reduction in exposure of ubrogepant.(1)|
03365|026|D|   Moderate inducers of CYP3A4 would be expected to decrease the AUC of a|
03365|027|D|sensitive 3A4 substrate by 50-80% and include:  belzutifan, bosentan,|
03365|028|D|cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
03365|029|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
03365|030|D|pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)|
03365|031|D|   Weak inducers of CYP3A4 would be expected to decrease the AUC of a|
03365|032|D|sensitive 3A4 substrate by 20-50% and include:  armodafinil, bexarotene,|
03365|033|D|brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin,|
03365|034|D|echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein,|
03365|035|D|ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone,|
03365|036|D|nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone,|
03365|037|D|pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone,|
03365|038|D|sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine,|
03365|039|D|ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and|
03365|040|D|zanubrutinib.(2,3)|
03365|041|B||
03365|042|R|REFERENCES:|
03365|043|B||
03365|044|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
03365|045|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03365|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03365|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03365|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03365|049|R|  11/14/2017.|1
03365|050|R|3.This information is based on an extract from the Certara Drug Interaction|6
03365|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03366|001|T|MONOGRAPH TITLE:  Ubrogepant (Less Than or Equal To 50 mg)/P-gp or BCRP|
03366|002|T|Inhibitors|
03366|003|B||
03366|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03366|005|L|take action as needed.|
03366|006|B||
03366|007|A|MECHANISM OF ACTION:  Inhibitors of P-glycoprotein (P-gp) or BCRP may|
03366|008|A|increase the absorption of ubrogepant.(1)|
03366|009|B||
03366|010|E|CLINICAL EFFECTS:  The concurrent administration of ubrogepant with an|
03366|011|E|inhibitor of P-glycoprotein or BCRP may result in elevated levels of|
03366|012|E|ubrogepant.(1)|
03366|013|B||
03366|014|P|PREDISPOSING FACTORS:  None determined.|
03366|015|B||
03366|016|M|PATIENT MANAGEMENT:  The manufacturer recommends a dosage adjustment of|
03366|017|M|ubrogepant when coadministered with P-gp or BCRP inhibitors.  The dose of|
03366|018|M|ubrogepant should not exceed 50 mg for initial dose.  If a second dose of|
03366|019|M|ubrogepant is needed, the dose should not exceed 50 mg.(1)|
03366|020|M|   The manufacturer of vimseltinib states concurrent use with P-gp|
03366|021|M|substrates should be avoided.  If concurrent use cannot be avoided, take|
03366|022|M|vimseltinib at least 4 hours prior to ubrogepant.(3)|
03366|023|B||
03366|024|D|DISCUSSION:  Ubrogepant is a substrate of P-gp and BCRP transporters.  Use|
03366|025|D|of P-gp or BCRP inhibitors may increase the exposure of ubrogepant.|
03366|026|D|Clinical drug interaction studies with inhibitors of these transporters were|
03366|027|D|not conducted.  The US manufacturer of ubrogepant recommends dose adjustment|
03366|028|D|if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1)|
03366|029|D|   BCRP inhibitors linked to this monograph include:  belumosudil,|
03366|030|D|clopidogrel, curcumin, eltrombopag, febuxostat, fostemsavir, leniolisib,|
03366|031|D|momelotinib, oteseconazole, pantoprazole, regorafenib, resmetirom,|
03366|032|D|ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric,|
03366|033|D|vadadustat, and zongertinib.(2-5)|
03366|034|D|   P-glycoprotein inhibitors linked to this monograph include:  asunaprevir,|
03366|035|D|belumosudil, capmatinib, carvedilol,  danicopan, daridorexant, imlunestrant,|
03366|036|D|neratinib, osimertinib, propafenone, quinidine, selpercatinib,|
03366|037|D|sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib,|
03366|038|D|and voclosporin.(2-5)|
03366|039|B||
03366|040|R|REFERENCES:|
03366|041|B||
03366|042|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
03366|043|R|2.Vyndamax (tafamidis) US prescribing information. Pfizer, Inc. June, 2021.|1
03366|044|R|3.Romvimza (vimseltinib) US prescribing information. Deciphera|1
03366|045|R|  Pharmaceuticals, LLC February, 2025.|1
03366|046|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03366|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03366|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03366|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03366|050|R|  11/14/2017.|1
03366|051|R|5.This information is based on an extract from the Certara Drug Interaction|6
03366|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03367|001|T|MONOGRAPH TITLE:  Lumateperone/CYP3A4 Inducers|
03367|002|B||
03367|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03367|004|L|of severe adverse interaction.|
03367|005|B||
03367|006|A|MECHANISM OF ACTION:  Lumateperone is a substrate of CYP3A4. Inducers of|
03367|007|A|CYP3A4 may induce the metabolism of lumateperone.(1)|
03367|008|B||
03367|009|E|CLINICAL EFFECTS:  The concurrent administration of a CYP3A4 inducer may|
03367|010|E|decrease the exposure to lumateperone.(1)|
03367|011|B||
03367|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03367|013|P|of the inducer for longer than 1-2 weeks.|
03367|014|B||
03367|015|M|PATIENT MANAGEMENT:  The manufacturer of lumateperone states that concurrent|
03367|016|M|use with CYP3A4 inducers should be avoided.(1)|
03367|017|B||
03367|018|D|DISCUSSION:  Coadministration of lumateperone with rifampin, a strong CYP3A4|
03367|019|D|inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90%|
03367|020|D|reduction in concentration maximum (Cmax).(1)|
03367|021|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03367|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03367|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03367|024|D|rifapentine, and St. John's wort.(2,3)|
03367|025|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03367|026|D|dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib,|
03367|027|D|mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib,|
03367|028|D|rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)|
03367|029|D|   Weak inducers of CYP3A4 include:  amprenavir, armodafinil, bexarotene,|
03367|030|D|brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin,|
03367|031|D|echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng,|
03367|032|D|glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone,|
03367|033|D|quercetin, rufinamide,  sotorasib, sulfinpyrazone, sunvozertinib,|
03367|034|D|tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and|
03367|035|D|vinblastine.(2,3)|
03367|036|B||
03367|037|R|REFERENCES:|
03367|038|B||
03367|039|R|1.Caplyta (lumateperone) US prescribing information. Intra-Cellular|1
03367|040|R|  Therapies, Inc. November, 2025.|1
03367|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03367|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03367|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03367|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03367|045|R|  11/14/2017.|1
03367|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
03367|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03368|001|T|MONOGRAPH TITLE:  Lumateperone (>10.5 mg)/Strong CYP3A4 Inhib; Protease|
03368|002|T|Inhib|
03368|003|B||
03368|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03368|005|L|is contraindicated and generally should not be dispensed or administered to|
03368|006|L|the same patient.|
03368|007|B||
03368|008|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 and protease inhibitors|
03368|009|A|may inhibit the metabolism of lumateperone.(1,2)|
03368|010|B||
03368|011|E|CLINICAL EFFECTS:  Concurrent use of lumateperone with strong CYP3A4|
03368|012|E|inhibitors or protease inhibitors increases lumateperone exposure, which may|
03368|013|E|increase the risk of adverse reactions.(1,2)|
03368|014|B||
03368|015|P|PREDISPOSING FACTORS:  Patients with moderate or severe hepatic impairment|
03368|016|P|(Child-Pugh class B or C) may be at higher risk of increased lumateperone|
03368|017|P|exposure.(1)|
03368|018|B||
03368|019|M|PATIENT MANAGEMENT:  The manufacturer of lumateperone recommends decreasing|
03368|020|M|the dosage of lumateperone to 10.5 mg once daily in patients receiving|
03368|021|M|strong CYP3A4 inhibitors.(1)|
03368|022|M|   The US Department of Health and Human Services HIV guidelines state that|
03368|023|M|protease inhibitors should not be coadministered with lumateperone.(2)|
03368|024|B||
03368|025|D|DISCUSSION:  Coadministration of lumateperone with itraconazole, a strong|
03368|026|D|CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in|
03368|027|D|area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1)|
03368|028|D|   Coadministration of lumateperone with diltiazem, a moderate CYP3A4|
03368|029|D|inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax,|
03368|030|D|respectively.(1)|
03368|031|D|   Strong inhibitors of CYP3A4 include:  adagrasib, amprenavir, atazanavir,|
03368|032|D|boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, fosamprenavir,|
03368|033|D|grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
03368|034|D|levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03368|035|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03368|036|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03368|037|D|troleandomycin, tucatinib, and voriconazole.(2-4)|
03368|038|B||
03368|039|R|REFERENCES:|
03368|040|B||
03368|041|R|1.Caplyta (lumateperone) US prescribing information. Intra-Cellular|1
03368|042|R|  Therapies, Inc. November, 2025.|1
03368|043|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03368|044|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03368|045|R|  HIV. Department of Health and Human Services. Available at:|6
03368|046|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
03368|047|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
03368|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03368|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03368|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03368|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03368|052|R|  11/14/2017.|1
03368|053|R|4.This information is based on an extract from the Certara Drug Interaction|6
03368|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03369|001|T|MONOGRAPH TITLE:  Lumateperone/Selected UGT Inhibitors (mono deleted|
03369|002|T|07/26/2022)|
03369|003|B||
03369|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03369|005|L|of severe adverse interaction.|
03369|006|B||
03369|007|A|MECHANISM OF ACTION:  UGT inhibitors may inhibit the metabolism of|
03369|008|A|lumateperone.(1)|
03369|009|B||
03369|010|E|CLINICAL EFFECTS:  Concurrent use of lumateperone with UGT inhibitors may|
03369|011|E|increase exposure to lumateperone and/or its metabolites.(1)|
03369|012|B||
03369|013|P|PREDISPOSING FACTORS:  None determined.|
03369|014|B||
03369|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of lumateperone with UGT|
03369|016|M|inhibitors.(1)|
03369|017|B||
03369|018|D|DISCUSSION:  According to the US manufacturer, in vitro studies show|
03369|019|D|lumateperone is a substrate of UGT enzymes.(1) Drug interaction studies have|
03369|020|D|not been completed.|
03369|021|D|   Selected UGT inhibitors linked to this interaction include: erlotinib,|
03369|022|D|gemfibrozil, lapatinib, pazopanib, probenecid, regorafenib, sorafenib, and|
03369|023|D|valproic acid.(1-3)|
03369|024|B||
03369|025|R|REFERENCES:|
03369|026|B||
03369|027|R|1.Caplyta (lumateperone) US prescribing information. Intra-Cellular|1
03369|028|R|  Therapies, Inc. November, 2025.|1
03369|029|R|2.This information is based on an extract from the Certara Drug Interaction|6
03369|030|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03369|031|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03369|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03369|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03369|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03369|035|R|  11/14/2017.|1
03370|001|T|MONOGRAPH TITLE:  Asunaprevir/Elagolix|
03370|002|B||
03370|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03370|004|L|is contraindicated and generally should not be dispensed or administered to|
03370|005|L|the same patient.|
03370|006|B||
03370|007|A|MECHANISM OF ACTION:  Elagolix is a moderate inducer of CYP3A4 may induce|
03370|008|A|the metabolism of asunaprevir treatment for hepatitis C.(1,2)|
03370|009|A|   Asunaprevir is also a substrate for the OATP1B1 transporter. OATP1B1|
03370|010|A|facilitated transport into the liver is thought to be associated with|
03370|011|A|asunaprevir efficacy.  Elagolix is also an OATP1B1 inhibitor and so may|
03370|012|A|further decrease asunaprevir efficacy by inhibiting its transport into the|
03370|013|A|liver.(1,2)|
03370|014|B||
03370|015|E|CLINICAL EFFECTS:  The combination of asunaprevir with elagolix may not be|
03370|016|E|effective for the treatment of hepatitis C.(1)|
03370|017|B||
03370|018|P|PREDISPOSING FACTORS:  None determined.|
03370|019|B||
03370|020|M|PATIENT MANAGEMENT:  Because of the risk for treatment failure, the|
03370|021|M|manufacturer of asunaprevir states that concomitant use with strong or|
03370|022|M|moderate CYP3A4 inducers is contraindicated.(1)|
03370|023|B||
03370|024|D|DISCUSSION:  A study of 20 healthy subjects found that rifampin (a strong|
03370|025|D|CYP3A4 inducer and OATP1B1 inhibitor) 600 mg daily decreased the maximum|
03370|026|D|concentration (Cmax) and area-under-curve (AUC) of asunaprevir (600 mg twice|
03370|027|D|daily) by 5% and 21%, respectively.  The expected decrease in asunaprevir|
03370|028|D|concentrations was thought to be attenuated by the inhibition of liver|
03370|029|D|uptake by OATP1B1.  Hepatic asunaprevir exposure was thought to be|
03370|030|D|significantly reduced.(3)  While there has been no studies with elagolix, a|
03370|031|D|similar effect is expected.|
03370|032|B||
03370|033|R|REFERENCES:|
03370|034|B||
03370|035|R|1.Sunvepra (asunaprevir) Australia Prescribing Information. Bristol-Myers|1
03370|036|R|  Squibb Australia Pty Ltd April 5, 2019.|1
03370|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
03370|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03370|039|R|3.Eley T,  He B, Huang SP, Stonier M, Bedford W, Kandoussi H, Gardiner DF,|2
03370|040|R|  Sims K, Li W, Bertz RJ. Effect of multiple-dose ketoconazole and the|2
03370|041|R|  effect of multiple-dose rifampin on pharmacokinetics (PK) of the HCV NS3|2
03370|042|R|  protease inhibitor asunaprevir. Presented at the 8th International|2
03370|043|R|  Workshop on Clinical Pharmacology of Hepatitis Therapy. Cambridge, MA.|2
03370|044|R|  June 26-27, 2013.|2
03371|001|T|MONOGRAPH TITLE:  Ombitasvir-Paritaprevir-Ritonavir/Thioridazine|
03371|002|B||
03371|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03371|004|L|is contraindicated and generally should not be dispensed or administered to|
03371|005|L|the same patient.|
03371|006|B||
03371|007|A|MECHANISM OF ACTION:  Thioridazine is a moderate inducer of CYP3A4 and may|
03371|008|A|induce the metabolism of ombitasvir-paritaprevir-ritonavir treatment for|
03371|009|A|hepatitis C.(1-3)|
03371|010|B||
03371|011|E|CLINICAL EFFECTS:  The combination of ombitasvir-paritaprevir-ritonavir,|
03371|012|E|with or without dasabuvir, may not be effective for the treatment of|
03371|013|E|hepatitis C.(1-3)|
03371|014|B||
03371|015|P|PREDISPOSING FACTORS:  None determined.|
03371|016|B||
03371|017|M|PATIENT MANAGEMENT:  Because of the risk for treatment failure, the|
03371|018|M|manufacturer of ombitasvir-paritaprevir-ritonavir states that concomitant|
03371|019|M|use with strong or moderate CYP3A4 inducers is contraindicated.(1-2)|
03371|020|B||
03371|021|D|DISCUSSION:  In an interaction study with 12 subjects, carbamazepine (a|
03371|022|D|strong CYP3A4 inducer) 200 mg once daily followed by 200 mg twice daily|
03371|023|D|decreased antiviral exposure (area-under-curve or AUC) of ombitasvir by 31%,|
03371|024|D|paritaprevir by 70%, ritonavir by 87%, and dasabuvir by 70%.(1)|
03371|025|B||
03371|026|R|REFERENCES:|
03371|027|B||
03371|028|R|1.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
03371|029|R|  prescribing information. AbbVie Inc. December, 2019.|1
03371|030|R|2.Viekirax (ombitasvir, paritaprevir, ritonavir) UK summary of product|1
03371|031|R|  characteristics. AbbVie Limited January 16, 2019.|1
03371|032|R|3.This information is based on an extract from the Certara Drug Interaction|6
03371|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03372|001|T|MONOGRAPH TITLE:  Salmeterol Combinations/Selected CYP3A4 Inhibitors|
03372|002|B||
03372|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03372|004|L|of severe adverse interaction.|
03372|005|B||
03372|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the CYP3A4 metabolism|
03372|007|A|of the portion of both the corticosteroid (budesonide or fluticasone) and|
03372|008|A|salmeterol that is swallowed, resulting in significant systemic|
03372|009|A|absorption.(1-18)|
03372|010|B||
03372|011|E|CLINICAL EFFECTS:  Inhibitors of CYP3A4 may result in increased systemic|
03372|012|E|exposure to and effects from budesonide or fluticasone, including Cushing's|
03372|013|E|syndrome and adrenal suppression.  Systemic effects of salmeterol, including|
03372|014|E|QTc prolongation, palpitations, and sinus tachycardia, may also occur.(1-18)|
03372|015|B||
03372|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03372|017|P|may be increased in patients with cardiovascular disease (e.g heart failure,|
03372|018|P|myocardial infarction, history of torsades de pointes, congenital long QT|
03372|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03372|020|P|gender, or advanced age.(19)|
03372|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03372|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03372|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03372|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03372|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03372|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03372|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(19)|
03372|028|P|   The risk of Cushing's syndrome and adrenal suppression may be higher in|
03372|029|P|patients with concurrent use of systemic glucocorticoids.|
03372|030|B||
03372|031|M|PATIENT MANAGEMENT:  Concurrent therapy of budesonide-salmeterol or|
03372|032|M|fluticasone-salmeterol with strong CYP3A4 inhibitors is not recommended.(18)|
03372|033|M|Alternative corticosteroids that are less affected by CYP3A4 inhibitors|
03372|034|M|should be considered, like beclomethasone.|
03372|035|M|   Canadian labeling contraindicates concurrent use of atazanavir/ritonavir,|
03372|036|M|darunavir/cobicistat, and lopinavir/ritonavir with salmeterol.(20-23)|
03372|037|M|   If concurrent therapy is warranted, patients should be closely monitored|
03372|038|M|for systemic effects.  Consider obtaining serum calcium, magnesium, and|
03372|039|M|potassium levels and monitoring ECG at baseline and at regular intervals.|
03372|040|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03372|041|M|irregular heartbeat, dizziness, or fainting.|
03372|042|M|   Advise patients receiving concurrent therapy to rinse their mouth|
03372|043|M|thoroughly after administering budesonide-salmeterol or|
03372|044|M|fluticasone-salmeterol to limit the amount of drug that is swallowed.|
03372|045|B||
03372|046|D|DISCUSSION:  A study in 18 healthy subjects examined the effects of|
03372|047|D|ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily).|
03372|048|D|In most subjects, fluticasone was undetectable (<10 pg/ml) when administered|
03372|049|D|alone.  In subjects in whom fluticasone was detectable when given alone,|
03372|050|D|maximum concentration (Cmax) and area-under-curve (AUC) averaged 11.9 pg/ml|
03372|051|D|and 8.43 pg x hr/ml, respectively.  With concurrent ritonavir, fluticasone|
03372|052|D|Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml,|
03372|053|D|respectively.(8,13,17) This reflects increases in Cmax and AUC by 25-fold|
03372|054|D|and 350-fold, respectively.  The cortisol AUC decreased by 86%.(18)|
03372|055|D|   There have been many case reports of Cushing's syndrome in patients|
03372|056|D|treated concurrently with ritonavir and fluticasone.(24-42)|
03372|057|D|   In a study in 20 healthy subjects, concurrent administration of|
03372|058|D|salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily, a|
03372|059|D|strong inhibitor of CYP3A4) for 7 days increased the plasma AUC and Cmax of|
03372|060|D|salmeterol 16-fold and 1.4-fold, respectively.  Concurrent use did not|
03372|061|D|result in clinically significant changes in heart rate, mean blood|
03372|062|D|potassium, mean blood glucose or mean QTc; however, concurrent use was|
03372|063|D|associated with more frequent increases in QTc duration.  Three subjects|
03372|064|D|were withdrawn from the study because of systemic salmeterol effects (2 with|
03372|065|D|QTc prolongation and 1 with palpitations and sinus tachycardia).(18)|
03372|066|D|   An in vitro study showed that ketoconazole completely inhibited the|
03372|067|D|metabolism of salmeterol to alpha-hydroxysalmeterol by CYP3A4.(43)|
03372|068|D|   Selected CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
03372|069|D|atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir,|
03372|070|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
03372|071|D|levoketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir,|
03372|072|D|nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir,|
03372|073|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
03372|074|D|voriconazole.(44)|
03372|075|B||
03372|076|R|REFERENCES:|
03372|077|B||
03372|078|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
03372|079|R|  Squibb Company December, 2024.|1
03372|080|R|2.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
03372|081|R|  January, 2017.|1
03372|082|R|3.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
03372|083|R|  June, 2025.|1
03372|084|R|4.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
03372|085|R|  Pharma US, Inc. October, 2016.|1
03372|086|R|5.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
03372|087|R|  March, 2023.|1
03372|088|R|6.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
03372|089|R|  March, 2019.|1
03372|090|R|7.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
03372|091|R|  September, 2016.|1
03372|092|R|8.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
03372|093|R|  Laboratories December, 2019.|1
03372|094|R|9.Serzone (nefazodone hydrochloride) US prescribing information.|1
03372|095|R|  Bristol-Myers Squibb Company January, 2005.|1
03372|096|R|10.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
03372|097|R|   Pharmaceuticals, Inc. September, 2016.|1
03372|098|R|11.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
03372|099|R|   information. Pfizer Inc. February, 2025.|1
03372|100|R|12.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
03372|101|R|   Corporation September, 2024.|1
03372|102|R|13.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
03372|103|R|   December, 2019.|1
03372|104|R|14.Invirase (saquinavir mesylate) US prescribing information. Roche|1
03372|105|R|   Laboratories, Inc. March, 2019.|1
03372|106|R|15.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
03372|107|R|   Incorporated October, 2013.|1
03372|108|R|16.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
03372|109|R|   Pharmaceuticals, Inc. April, 2024.|1
03372|110|R|17.Tukysa (tucatinib) US prescribing information. Seattle Genetics April,|1
03372|111|R|   2020.|1
03372|112|R|18.Advair (fluticasone propionate/salmeterol) US prescribing information.|1
03372|113|R|   GlaxoSmithKline October, 2008.|1
03372|114|R|19.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
03372|115|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
03372|116|R|   hospital settings: a scientific statement from the American Heart|6
03372|117|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
03372|118|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
03372|119|R|20.Reyataz (atazanavir) Canadian prescribing information. Bristol-Myers|1
03372|120|R|   Squibb Canada August 31, 2023.|1
03372|121|R|21.Prezcobix (darunavir-cobicistat) Canadian prescribing information.|1
03372|122|R|   Janssen Inc. June 18, 2014.|1
03372|123|R|22.Kaletra (lopinavir/ritonavir) Canadian prescribing information. Abbott|1
03372|124|R|   Limited May 22, 2019.|1
03372|125|R|23.Norvir (ritonavir) Canadian prescribing information. Abbott May 29, 2019.|1
03372|126|R|24.Rouanet I, Peyriere H, Mauboussin JM, Vincent D. Cushing's syndrome in a|3
03372|127|R|   patient treated by ritonavir/lopinavir and inhaled fluticasone. HIV Med|3
03372|128|R|   2003 Apr;4(2):149-50.|3
03372|129|R|25.Clevenbergh P, Corcostegui M, Gerard D, Hieronimus S, Mondain V,|3
03372|130|R|   Chichmanian RM, Sadoul JL, Dellamonica P. Iatrogenic Cushing's syndrome|3
03372|131|R|   in an HIV-infected patient treated with inhaled corticosteroids|3
03372|132|R|   (fluticasone propionate) and low dose ritonavir enhanced PI containing|3
03372|133|R|   regimen. J Infect 2002 Apr;44(3):194-5.|3
03372|134|R|26.Chen F, Kearney T, Robinson S, Daley-Yates PT, Waldron S, Churchill DR.|3
03372|135|R|   Cushing's syndrome and severe adrenal suppression in patients treated|3
03372|136|R|   with ritonavir and inhaled nasal fluticasone. Sex Transm Infect 1999 Aug;|3
03372|137|R|   75(4):274.|3
03372|138|R|27.Hillebrand-Haverkort ME, Prummel MF, ten Veen JH. Ritonavir-induced|3
03372|139|R|   Cushing's syndrome in a patient treated with nasal fluticasone. AIDS 1999|3
03372|140|R|   Sep 10;13(13):1803.|3
03372|141|R|28.Dupont C, Giraud V, Leporrier J, Greffe S, Rouveix E, Chinet T. Cushing's|3
03372|142|R|   syndrome induced by combined treatment with inhaled fluticasone and oral|3
03372|143|R|   ritonavir. Rev Mal Respir 2009 Sep;26(7):779-82.|3
03372|144|R|29.Collet-Gaudillat C, Roussin-Bretagne S, Desforges-Bullet V, Petit-Aubert|3
03372|145|R|   G, Doll J, Beressi JP. Iatrogenic Cushing's syndrome, diabetes mellitus|3
03372|146|R|   and secondary adrenal failure in a human immunodeficiency virus patient|3
03372|147|R|   treated with ritonavir boosted atazanavir and fluticasone. Ann Endocrinol|3
03372|148|R|   (Paris) 2009 Sep;70(4):252-5.|3
03372|149|R|30.Valin N, De Castro N, Garrait V, Bergeron A, Bouche C, Molina JM.|3
03372|150|R|   Iatrogenic Cushing's syndrome in HIV-infected patients receiving|3
03372|151|R|   ritonavir and inhaled fluticasone: description of 4 new cases and review|3
03372|152|R|   of the literature. J Int Assoc Physicians AIDS Care (Chic) 2009 Mar-Apr;|3
03372|153|R|   8(2):113-21.|3
03372|154|R|31.Bouldouyre MA, Moachon L, Guillevin L, Launay O. Iatrogenic Cushing|3
03372|155|R|   syndrome in an HIV-infected female patient: be careful about interaction|3
03372|156|R|   inhaled corticosteroids-ritonavir!. Presse Med 2008 Dec;37(12):1834-5.|3
03372|157|R|32.Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and|3
03372|158|R|   Cushing's syndrome secondary to an interaction between ritonavir and|3
03372|159|R|   fluticasone: a review of the literature. HIV Med 2008 Jul;9(6):389-96.|3
03372|160|R|33.Jinno S, Goshima C. Progression of Kaposi sarcoma associated with|3
03372|161|R|   iatrogenic Cushing syndrome in a person with HIV/AIDS. AIDS Read 2008|3
03372|162|R|   Feb;18(2):100-4.|3
03372|163|R|34.St Germain RM, Yigit S, Wells L, Girotto JE, Salazar JC. Cushing syndrome|3
03372|164|R|   and severe adrenal suppression caused by fluticasone and protease|3
03372|165|R|   inhibitor combination in an HIV-infected adolescent. AIDS Patient Care|3
03372|166|R|   STDS 2007 Jun;21(6):373-7.|3
03372|167|R|35.Bhumbra NA, Sahloff EG, Oehrtman SJ, Horner JM. Exogenous Cushing|3
03372|168|R|   syndrome with inhaled fluticasone in a child receiving|3
03372|169|R|   lopinavir/ritonavir. Ann Pharmacother 2007 Jul;41(7):1306-9.|3
03372|170|R|36.Pessanha TM, Campos JM, Barros AC, Pone MV, Garrido JR, Pone SM.|3
03372|171|R|   Iatrogenic Cushing's syndrome in a adolescent with AIDSs on ritonavir and|3
03372|172|R|   inhaled fluticasone. Case report and literature review. AIDS 2007 Feb 19;|3
03372|173|R|   21(4):529-32.|3
03372|174|R|37.Arrington-Sanders R, Hutton N, Siberry GK. Ritonavir-fluticasone|3
03372|175|R|   interaction causing Cushing syndrome in HIV-infected children and|3
03372|176|R|   adolescents. Pediatr Infect Dis J 2006 Nov;25(11):1044-8.|3
03372|177|R|38.Johnson SR, Marion AA, Vrchoticky T, Emmanuel PJ, Lujan-Zilbermann J.|3
03372|178|R|   Cushing syndrome with secondary adrenal insufficiency from concomitant|3
03372|179|R|   therapy with ritonavir and fluticasone. J Pediatr 2006 Mar;148(3):386-8.|3
03372|180|R|39.Gillett MJ, Cameron PU, Nguyen HV, Hurley DM, Mallal SA. Iatrogenic|3
03372|181|R|   Cushing's syndrome in an HIV-infected patient treated with ritonavir and|3
03372|182|R|   inhaled fluticasone. AIDS 2005 Apr 29;19(7):740-1.|3
03372|183|R|40.Samaras K, Pett S, Gowers A, McMurchie M, Cooper DA. Iatrogenic Cushing's|3
03372|184|R|   syndrome with osteoporosis and secondary adrenal failure in human|3
03372|185|R|   immunodeficiency virus-infected patients receiving inhaled|3
03372|186|R|   corticosteroids and ritonavir-boosted protease inhibitors: six cases. J|3
03372|187|R|   Clin Endocrinol Metab 2005 Jul;90(7):4394-8.|3
03372|188|R|41.Soldatos G, Sztal-Mazer S, Woolley I, Stockigt J. Exogenous|3
03372|189|R|   glucocorticoid excess as a result of ritonavir-fluticasone interaction.|3
03372|190|R|   Intern Med J 2005 Jan;35(1):67-8.|3
03372|191|R|42.Gupta SK, Dube MP. Exogenous cushing syndrome mimicking human|3
03372|192|R|   immunodeficiency virus lipodystrophy. Clin Infect Dis 2002 Sep 15;|3
03372|193|R|   35(6):E69-71.|3
03372|194|R|43.Manchee GR, Eddershaw PJ, Ranshaw LE, Herriott D, Park GR, Bayliss MK,|5
03372|195|R|   Tarbit MH. The aliphatic oxidation of salmeterol to|5
03372|196|R|   alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A.|5
03372|197|R|   Drug Metab Dispos 1996 May;24(5):555-9.|5
03372|198|R|44.This information is based on an extract from the Certara Drug Interaction|6
03372|199|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03372|200|R|45.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03372|201|R|   Pharmaceuticals, Inc. June, 2023.|1
03373|001|T|MONOGRAPH TITLE:  Avapritinib/Strong CYP3A4 Inhibitors|
03373|002|B||
03373|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03373|004|L|of severe adverse interaction.|
03373|005|B||
03373|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03373|007|A|of avapritinib.(1)|
03373|008|B||
03373|009|E|CLINICAL EFFECTS:  Concurrent use of avapritinib with a strong CYP3A4|
03373|010|E|inhibitor increases avapritinib plasma concentrations, which may increase|
03373|011|E|the incidence and severity of adverse reactions of avapritinib.(1)|
03373|012|B||
03373|013|P|PREDISPOSING FACTORS:  None determined.|
03373|014|B||
03373|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of avapritinib with strong CYP3A4|
03373|016|M|inhibitors.(1)|
03373|017|B||
03373|018|D|DISCUSSION:  Coadministration of avapritinib 300 mg once daily with|
03373|019|D|itraconazole 200 mg daily, a strong CYP3A4 inhibitor, is predicted to|
03373|020|D|increase avapritinib AUC by 600% at steady state.(1)|
03373|021|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
03373|022|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03373|023|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03373|024|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib,|
03373|025|D|saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and|
03373|026|D|voriconazole.(2,3)|
03373|027|B||
03373|028|R|REFERENCES:|
03373|029|B||
03373|030|R|1.Ayvakit (avapritinib) US prescribing information. Blueprint Medicines|1
03373|031|R|  Corporation June, 2021.|1
03373|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03373|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03373|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03373|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03373|036|R|  11/14/2017.|1
03373|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
03373|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03374|001|T|MONOGRAPH TITLE:  Avapritinib/Moderate CYP3A4 Inhibitors|
03374|002|B||
03374|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03374|004|L|take action as needed.|
03374|005|B||
03374|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03374|007|A|metabolism of avapritinib.(1)|
03374|008|B||
03374|009|E|CLINICAL EFFECTS:  Concurrent use of avapritinib with a moderate CYP3A4|
03374|010|E|inhibitor increases avapritinib plasma concentrations, which may increase|
03374|011|E|the incidence and severity of adverse reactions of avapritinib.(1)|
03374|012|B||
03374|013|P|PREDISPOSING FACTORS:  None determined.|
03374|014|B||
03374|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of avapritinib with strong or|
03374|016|M|moderate CYP3A4 inhibitors. If coadministration of avapritinib with a|
03374|017|M|moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of avapritinib|
03374|018|M|to 100 mg once daily for treatment of gastrointestinal stromal tumors or 50|
03374|019|M|mg once daily for treatment of advanced systemic mastocytosis.(1)|
03374|020|B||
03374|021|D|DISCUSSION:  Coadministration of avapritinib 300 mg once daily with|
03374|022|D|fluconazole 200 mg once daily, a moderate CYP3A4 inhibitor, is predicted to|
03374|023|D|increase avapritinib AUC by 210% at steady state.(1)|
03374|024|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
03374|025|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan,  crizotinib,|
03374|026|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
03374|027|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
03374|028|D|isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
03374|029|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
03374|030|D|and verapamil.(2,3)|
03374|031|B||
03374|032|R|REFERENCES:|
03374|033|B||
03374|034|R|1.Ayvakit (avapritinib) US prescribing information. Blueprint Medicines|1
03374|035|R|  Corporation June, 2021.|1
03374|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03374|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03374|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03374|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03374|040|R|  11/14/2017.|1
03374|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
03374|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03375|001|T|MONOGRAPH TITLE:  Avapritinib/Strong or Moderate CYP3A4 Inducers|
03375|002|B||
03375|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03375|004|L|of severe adverse interaction.|
03375|005|B||
03375|006|A|MECHANISM OF ACTION:  Strong or moderate CYP3A4 inducers may induce the|
03375|007|A|metabolism of avapritinib.|
03375|008|B||
03375|009|E|CLINICAL EFFECTS:  Coadministration of avapritinib with a strong or moderate|
03375|010|E|CYP3A4 inducer decreases avapritinib plasma concentrations, which may|
03375|011|E|decrease efficacy of avapritinib.(1)|
03375|012|B||
03375|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03375|014|P|of the inducer for longer than 1-2 weeks.|
03375|015|B||
03375|016|M|PATIENT MANAGEMENT:  The manufacturer of avapritinib states that concurrent|
03375|017|M|use with strong or moderate CYP3A4 inducers should be avoided.(1)|
03375|018|B||
03375|019|D|DISCUSSION:  Coadministration of avapritinib 400 mg as a single dose with|
03375|020|D|rifampin 600 mg daily, a strong CYP3A4 inducer, decreased avapritinib|
03375|021|D|concentration maximum (Cmax) by 74% and area-under-curve (AUC) by 92%.(1)|
03375|022|D|   Coadministration of avapritinib 300 mg once daily with efavirenz 600 mg|
03375|023|D|once daily, a moderate CYP3A4 inducer, is predicted to decrease avapritinib|
03375|024|D|Cmax by 55% and AUC by 62% at steady state.(1)|
03375|025|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03375|026|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03375|027|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03375|028|D|rifapentine, and St. John's wort.(2,3)|
03375|029|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03375|030|D|dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib,|
03375|031|D|mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib,|
03375|032|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine and|
03375|033|D|tovorafenib.(2,3)|
03375|034|B||
03375|035|R|REFERENCES:|
03375|036|B||
03375|037|R|1.Ayvakit (avapritinib) US prescribing information. Blueprint Medicines|1
03375|038|R|  Corporation June, 2021.|1
03375|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03375|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03375|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03375|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03375|043|R|  11/14/2017.|1
03375|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
03375|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03376|001|T|MONOGRAPH TITLE:  Neratinib/Cimetidine (mono deleted 12/06/2023)|
03376|002|B||
03376|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03376|004|L|of severe adverse interaction.|
03376|005|B||
03376|006|A|MECHANISM OF ACTION:  Neratinib solubility decreases with increasing GI|
03376|007|A|tract pH.  Changes in gastric pH from cimetidine may alter the absorption of|
03376|008|A|neratinib.|
03376|009|A|   Inhibitors of CYP3A4 may inhibit the metabolism of neratinib.|
03376|010|A|Cimetidine, a moderate CYP3A4 inhibitor, may inhibit the metabolism of|
03376|011|A|neratinib.|
03376|012|B||
03376|013|E|CLINICAL EFFECTS:  Use of cimetidine may result in altered absorption and|
03376|014|E|decreased levels and effectiveness of neratinib.  Concurrent use of|
03376|015|E|neratinib with cimetidine may result in increased neratinib concentrations|
03376|016|E|and increased risk of toxicity.  The combined effects of decreased|
03376|017|E|absorption and inhibition of metabolism is unknown.|
03376|018|B||
03376|019|P|PREDISPOSING FACTORS:  None determined.|
03376|020|B||
03376|021|M|PATIENT MANAGEMENT:  Avoid concomitant use of neratinib with cimetidine.|
03376|022|M|Consider the use of short-acting antacids or H2-receptor antagonists that do|
03376|023|M|not inhibit CYP3A4 in patients taking neratinib.|
03376|024|M|   If antacids are used, separate the dosing of neratinib by 3 hours after|
03376|025|M|antacids.|
03376|026|M|   If H2 receptor antagonist treatment is required with neratinib, the|
03376|027|M|neratinib dose must be given at least 2 hours before or 10 hours after the|
03376|028|M|H2 receptor antagonist.|
03376|029|M|   Avoid the use of proton pump inhibitors (PPIs) in patients receiving|
03376|030|M|treatment with neratinib.(1)|
03376|031|B||
03376|032|D|DISCUSSION:  In a study in 15 healthy subjects, lansoprazole 30 mg decreased|
03376|033|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
03376|034|D|of neratinib (240 mg) by 71% and 65%, respectively.(1)|
03376|035|D|   When a single oral dose of neratinib 240 mg was administered 2 hours|
03376|036|D|following a daily dose of 300 mg ranitidine, the neratinib Cmax and AUC were|
03376|037|D|reduced by 57% and 48%, respectively.  When a single oral dose of neratinib|
03376|038|D|240 mg was administered 2 hours prior to 150 mg ranitidine twice daily|
03376|039|D|(administered in the morning and evening, approximately 12 hours apart), the|
03376|040|D|neratinib Cmax and AUC were reduced by 44% and 32%, respectively.(1)|
03376|041|D|   Concomitant use of neratinib with ketoconazole, a strong CYP3A4|
03376|042|D|inhibitor, increased neratinib Cmax by 321% and AUC by 481%.(1)|
03376|043|B||
03376|044|R|REFERENCE:|
03376|045|B||
03376|046|R|1.Nerlynx (neratinib) US prescribing information. Puma Biotechnology, Inc.|1
03376|047|R|  June, 2021.|1
03377|001|T|MONOGRAPH TITLE:  Asunaprevir/Efavirenz; Nevirapine|
03377|002|B||
03377|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03377|004|L|is contraindicated and generally should not be dispensed or administered to|
03377|005|L|the same patient.|
03377|006|B||
03377|007|A|MECHANISM OF ACTION:  Efavirenz and nevirapine may induce the metabolism of|
03377|008|A|asunaprevir via CYP3A4.  Efavirenz may also decrease asunaprevir absorption|
03377|009|A|via the P-glycoprotein (P-gp) transporter.(1,2)|
03377|010|B||
03377|011|E|CLINICAL EFFECTS:  The combination of asunaprevir with efavirenz or|
03377|012|E|nevirapine may not be effective for the treatment of hepatitis C.(1)|
03377|013|B||
03377|014|P|PREDISPOSING FACTORS:  None determined.|
03377|015|B||
03377|016|M|PATIENT MANAGEMENT:  Because of the risk for treatment failure, the|
03377|017|M|manufacturer of asunaprevir states that concomitant use with efavirenz and|
03377|018|M|nevirapine is contraindicated.(1)|
03377|019|B||
03377|020|D|DISCUSSION:  A study of 20 healthy subjects found that rifampin (a strong|
03377|021|D|CYP3A4 inducer and OATP1B1 inhibitor) 600 mg daily decreased the maximum|
03377|022|D|concentration (Cmax) and area-under-curve (AUC) of asunaprevir (600 mg twice|
03377|023|D|daily) by 5% and 21%, respectively.  The expected decrease in asunaprevir|
03377|024|D|concentrations was thought to be attenuated by the inhibition of liver|
03377|025|D|uptake by OATP1B1.  Hepatic asunaprevir exposure was thought to be|
03377|026|D|significantly reduced.(3)|
03377|027|D|   There have been no studies with the concurrent use of asunaprevir and|
03377|028|D|efavirenz or nevirapine.  Unlike rifampin, neither efavirenz nor nevirapine|
03377|029|D|inhibit OATP1B1, and they are expected to lower asunaprevir plasma levels.|
03377|030|B||
03377|031|R|REFERENCES:|
03377|032|B||
03377|033|R|1.Sunvepra (asunaprevir) Australia Prescribing Information. Bristol-Myers|1
03377|034|R|  Squibb Australia Pty Ltd April 5, 2019.|1
03377|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
03377|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03377|037|R|3.Eley T,  He B, Huang SP, Stonier M, Bedford W, Kandoussi H, Gardiner DF,|2
03377|038|R|  Sims K, Li W, Bertz RJ. Effect of multiple-dose ketoconazole and the|2
03377|039|R|  effect of multiple-dose rifampin on pharmacokinetics (PK) of the HCV NS3|2
03377|040|R|  protease inhibitor asunaprevir. Presented at the 8th International|2
03377|041|R|  Workshop on Clinical Pharmacology of Hepatitis Therapy. Cambridge, MA.|2
03377|042|R|  June 26-27, 2013.|2
03378|001|T|MONOGRAPH TITLE:  Asunaprevir/Gemfibrozil|
03378|002|B||
03378|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03378|004|L|is contraindicated and generally should not be dispensed or administered to|
03378|005|L|the same patient.|
03378|006|B||
03378|007|A|MECHANISM OF ACTION:  Asunaprevir is a substrate for the OATP1B1|
03378|008|A|transporter. OATP1B1-facilitated transport into the liver is thought to be|
03378|009|A|associated with asunaprevir efficacy.  Gemfibrozil is a strong OATP1B1|
03378|010|A|inhibitor and so may decrease asunaprevir efficacy by inhibiting its|
03378|011|A|transport into the liver.(1,2)|
03378|012|B||
03378|013|E|CLINICAL EFFECTS:  The combination of asunaprevir with gemfibrozil may|
03378|014|E|result in decreased liver concentrations of asunaprevir and loss of efficacy|
03378|015|E|for treatment of hepatitis C.(1)|
03378|016|B||
03378|017|P|PREDISPOSING FACTORS:  None determined.|
03378|018|B||
03378|019|M|PATIENT MANAGEMENT:  Because of the risk for treatment failure, the|
03378|020|M|manufacturer of asunaprevir states that concomitant use with gemfibrozil is|
03378|021|M|contraindicated.(1)|
03378|022|B||
03378|023|D|DISCUSSION:  A study of 20 healthy subjects found that rifampin (a strong|
03378|024|D|CYP3A4 inducer and OATP1B1 inhibitor) 600 mg daily decreased the maximum|
03378|025|D|concentration (Cmax) and area-under-curve (AUC) of asunaprevir (600 mg twice|
03378|026|D|daily) by 5% and 21%, respectively.  The expected decrease in asunaprevir|
03378|027|D|concentrations was thought to be attenuated by the inhibition of liver|
03378|028|D|uptake by OATP1B1.  Hepatic asunaprevir exposure was thought to be|
03378|029|D|significantly reduced.(3)|
03378|030|D|   There have been no studies with the concurrent use of asunaprevir and|
03378|031|D|gemfibrozil.  Unlike rifampin, gemfibrozil does not induce CYP3A4, but it is|
03378|032|D|expected to decrease hepatic exposure to asunaprevir via OATP1B1 inhibition.|
03378|033|B||
03378|034|R|REFERENCES:|
03378|035|B||
03378|036|R|1.Sunvepra (asunaprevir) Australia Prescribing Information. Bristol-Myers|1
03378|037|R|  Squibb Australia Pty Ltd April 5, 2019.|1
03378|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
03378|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03378|040|R|3.Eley T,  He B, Huang SP, Stonier M, Bedford W, Kandoussi H, Gardiner DF,|2
03378|041|R|  Sims K, Li W, Bertz RJ. Effect of multiple-dose ketoconazole and the|2
03378|042|R|  effect of multiple-dose rifampin on pharmacokinetics (PK) of the HCV NS3|2
03378|043|R|  protease inhibitor asunaprevir. Presented at the 8th International|2
03378|044|R|  Workshop on Clinical Pharmacology of Hepatitis Therapy. Cambridge, MA.|2
03378|045|R|  June 26-27, 2013.|2
03379|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Asunaprevir|
03379|002|B||
03379|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03379|004|L|take action as needed.|
03379|005|B||
03379|006|A|MECHANISM OF ACTION:  Asunaprevir is a weak CYP3A4 inducer and may increase|
03379|007|A|the CYP3A4-mediated metabolism of both estrogen and progestin components of|
03379|008|A|hormonal contraceptives.(1)|
03379|009|B||
03379|010|E|CLINICAL EFFECTS:  Concurrent use of asunaprevir may result in reduced|
03379|011|E|levels and clinical effectiveness of hormone containing contraceptives.(1)|
03379|012|E|Breakthrough bleeding and contraceptive failure/pregnancy may result.|
03379|013|E|Effects may be seen for several weeks after discontinuation of asunaprevir.|
03379|014|B||
03379|015|P|PREDISPOSING FACTORS:  None determined.|
03379|016|B||
03379|017|M|PATIENT MANAGEMENT:  The manufacturer of asunaprevir recommends using a|
03379|018|M|high-dose oral contraceptive containing at least 30 mcg ethinyl estradiol|
03379|019|M|with norethindrone when use concurrently with asunaprevir.(1)|
03379|020|M|   Patients should be alerted to the risk for decreased effectiveness(e.g.|
03379|021|M|contraceptive failure) of their hormonal contraceptive therapy.|
03379|022|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03379|023|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03379|024|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03379|025|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03379|026|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03379|027|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03379|028|M|and to seek medical advice if they do become pregnant.(2)|
03379|029|B||
03379|030|D|DISCUSSION:  A study of 17 subjects found that asunaprevir 600 mg twice|
03379|031|D|daily decreased the maximum concentration (Cmax) and area-under-curve (AUC)|
03379|032|D|of ethinyl estradiol 35 mcg daily by 25% and 28%, respectively, and of|
03379|033|D|norgestromin by 29% and 34%, respectively.(3)|
03379|034|D|   Another study of 36 subjects found that asunaprevir 100 mg twice daily|
03379|035|D|did not significantly affect the kinetics of high-dose contraceptives|
03379|036|D|consisting of ethinyl estradiol 30 mcg daily and norethindrone 1.5 mg|
03379|037|D|daily.(3)|
03379|038|B||
03379|039|R|REFERENCES:|
03379|040|B||
03379|041|R|1.Sunvepra (asunaprevir) Australia Prescribing Information. Bristol-Myers|1
03379|042|R|  Squibb Australia Pty Ltd April 5, 2019.|1
03379|043|R|2.Medicines and Healthcare products Regulatory Agency.|1
03379|044|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03379|045|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03379|046|R|  available at:|1
03379|047|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03379|048|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03379|049|R|  -and-contraceptive-efficacy September 15, 2016..|1
03379|050|R|3.Sunvepra (asunaprevir) Canadian prescribing information. Bristol-Myers|1
03379|051|R|  Squibb Canada January 26, 2017.|1
03380|001|T|MONOGRAPH TITLE:  Bosutinib/Cimetidine (mono deleted 12/06/2023)|
03380|002|B||
03380|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03380|004|L|of severe adverse interaction.|
03380|005|B||
03380|006|A|MECHANISM OF ACTION:  The solubility of bosutinib is pH dependent.  Changes|
03380|007|A|in gastric pH from cimetidine may decrease the absorption of bosutinib.|
03380|008|A|Cimetidine, a moderate CYP3A4 inhibitor, may inhibit the metabolism of|
03380|009|A|bosutinib.|
03380|010|B||
03380|011|E|CLINICAL EFFECTS:  Coadministration of cimetidine may result in decreased|
03380|012|E|levels and effectiveness of bosutinib. Cimetidine, a moderate CYP3A4|
03380|013|E|inhibitor, may increase bosutinib plasma concentrations and increase the|
03380|014|E|risk of toxicities.  The combined effects of decreased absorption and|
03380|015|E|inhibition of metabolism is unknown.|
03380|016|B||
03380|017|P|PREDISPOSING FACTORS:  None determined.|
03380|018|B||
03380|019|M|PATIENT MANAGEMENT:  Avoid concomitant use of cimetidine and bosutinib.|
03380|020|M|Consider the use of short-acting antacids or a different H2 antagonist in|
03380|021|M|patients taking bosutinib.(1)|
03380|022|M|   If antacids or H2 antagonists that do not inhibit CYP3A4 are used,|
03380|023|M|separate the administration times with bosutinib by 2 hours.(1)|
03380|024|M|   Avoid the use of proton pump inhibitors (PPIs) in patients receiving|
03380|025|M|treatment with bosutinib.|
03380|026|B||
03380|027|D|DISCUSSION:  A single dose of bosutinib 400 mg was administered following|
03380|028|D|multiple doses of lansoprazole 60 mg. Lansoprazole decreased bosutinib|
03380|029|D|area-under-curve (AUC) and maximum concentration (Cmax) by 26% and 46%,|
03380|030|D|respectively.(1)|
03380|031|D|   A single dose of bosutinib 100 mg was administered following multiple|
03380|032|D|daily doses of 400 mg ketoconazole, a strong CYP3A4 inhibitor. Ketoconazole|
03380|033|D|increased bosutinib AUC and Cmax 5.2-fold and 8.6-fold, respectively.(1)|
03380|034|B||
03380|035|R|REFERENCE:|
03380|036|B||
03380|037|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
03380|038|R|  2023.|1
03381|001|T|MONOGRAPH TITLE:  Porfimer/Selected Photosensitizers|
03381|002|B||
03381|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03381|004|L|of severe adverse interaction.|
03381|005|B||
03381|006|A|MECHANISM OF ACTION:  Porfimer causes photosensitivity due to residual drug|
03381|007|A|which is present in all parts of the skin.  Anthralin, coal tar and|
03381|008|A|derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as|
03381|009|A|methylene blue, rose bengal, or toluidine blue), phenothiazines, selected|
03381|010|A|NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and|
03381|011|A|tiaprofenic acid), methotrexate, St. John's wort, sulfonamides,|
03381|012|A|sulfonylureas, tetracyclines, and thiazides are other known|
03381|013|A|photosensitizers.(1)|
03381|014|B||
03381|015|E|CLINICAL EFFECTS:  Concurrent use of porfimer in patients taking anthralin,|
03381|016|E|coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining|
03381|017|E|dyes (such as methylene blue, rose bengal, or toluidine blue),|
03381|018|E|phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone,|
03381|019|E|naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort,|
03381|020|E|sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the|
03381|021|E|risk of phototoxicity.(1)|
03381|022|B||
03381|023|P|PREDISPOSING FACTORS:  Patients with any hepatic impairment and patients|
03381|024|P|with severe renal impairment have reduced drug elimination and may remain|
03381|025|P|photosensitive for 90 days or longer.(1)|
03381|026|B||
03381|027|M|PATIENT MANAGEMENT:  The US manufacturer of porfimer states that concurrent|
03381|028|M|use of porfimer with photosensitizers including anthralin, coal tar and|
03381|029|M|derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as|
03381|030|M|methylene blue, rose bengal, or toluidine blue), phenothiazines, selected|
03381|031|M|NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and|
03381|032|M|tiaprofenic acid), methotrexate, St. John's wort, sulfonamides,|
03381|033|M|sulfonylureas, tetracyclines, and thiazides should be avoided.(1)  Since the|
03381|034|M|photosensitive effect of porfimer may persist for at least 30 days (and for|
03381|035|M|90 days in some patients), it would be prudent to avoid other|
03381|036|M|photosensitizing agents for at least 30 days after administration of|
03381|037|M|porfimer.|
03381|038|B||
03381|039|D|DISCUSSION:  All patients who have received porfimer become photosensitive.|
03381|040|D|It is unknown what the risk of photosensitivity reactions is when porfimer|
03381|041|D|is used concurrently with other photosensitizing agents.  When porfimer was|
03381|042|D|used in clinical trials, photosensitivity reactions occurred in about 20% of|
03381|043|D|cancer patients and in 69% of high-grade dysplasia in Barretts esophagus|
03381|044|D|patients.  Most of the reactions were mild to moderate erythema, but they|
03381|045|D|also included swelling, pruritus, burning sensation, feeling hot, or|
03381|046|D|blisters.  The majority of reactions occurred within 90 days of porfimer|
03381|047|D|administration.(1)|
03381|048|B||
03381|049|R|REFERENCE:|
03381|050|B||
03381|051|R|1.Photofrin (porfimer) US prescribing information. Pinnacle Biologics, Inc.,|1
03381|052|R|  December, 2019.|1
03382|001|T|MONOGRAPH TITLE:  Selected Antineoplastic Systemic Enzyme|
03382|002|T|Inhibitors/Rifabutin|
03382|003|B||
03382|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03382|005|L|of severe adverse interaction.|
03382|006|B||
03382|007|A|MECHANISM OF ACTION:  Rifabutin is a moderate inducer of the CYP3A4|
03382|008|A|isoenzyme and may increase the metabolism of some antineoplastic systemic|
03382|009|A|enzyme inhibitors, including cabozantinib,(1,2) ceritinib,(3) erlotinib,(4)|
03382|010|A|imatinib,(5) lapatinib,(6) and sorafenib.(7)|
03382|011|B||
03382|012|E|CLINICAL EFFECTS:  Concurrent use of rifabutin may decrease the levels and|
03382|013|E|effectiveness of some antineoplastic systemic enzyme inhibitors, including|
03382|014|E|cabozantinib,(1,2) ceritinib,(3) erlotinib,(4) imatinib,(5) lapatinib,(6)|
03382|015|E|and sorafenib.(7)|
03382|016|B||
03382|017|P|PREDISPOSING FACTORS:  None determined.|
03382|018|B||
03382|019|M|PATIENT MANAGEMENT:  Avoid the concurrent use of rifabutin in patients|
03382|020|M|receiving therapy with cabozantinib,(1,2) ceritinib,(3) erlotinib,(4)|
03382|021|M|imatinib,(5) lapatinib,(6) and sorafenib.(7)  Consider the use of|
03382|022|M|alternative agents with less enzyme induction potential.(1-7)|
03382|023|M|   If concurrent use of rifabutin cannot be avoided:|
03382|024|M|   Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg|
03382|025|M|to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg.|
03382|026|M|Resume the dose that was used prior to initiating rifabutin 2 to 3 days|
03382|027|M|after discontinuation of rifabutin.(1)|
03382|028|M|   Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to|
03382|029|M|180 mg daily or from 100 mg to 140 mg daily) as tolerated.  The daily dose|
03382|030|M|of cabozantinib should not exceed 180 mg.  If rifabutin is discontinued,|
03382|031|M|reduce the dosage of cabozantinib to the dose used prior to initiation of|
03382|032|M|rifabutin 2 to 3 days after discontinuation of rifabutin.(2)|
03382|033|M|   Consider increasing the dosage of erlotinib by 50 mg increments as|
03382|034|M|tolerated at two week intervals (to a maximum of 450 mg) while closely|
03382|035|M|monitoring the patient.  The highest dosage studied with concurrent rifampin|
03382|036|M|is 450 mg.  If the dosage of erlotinib is increased, it will need to be|
03382|037|M|decreased when rifabutin is discontinued.(4)|
03382|038|M|   The dose of imatinib should be increased by at least 50% and clinical|
03382|039|M|response should be carefully monitored.  Dosages up to 1,200 mg/day (600 mg|
03382|040|M|twice daily) have been used in patients receiving concurrent therapy with|
03382|041|M|strong CYP3A4 inducers.(5)|
03382|042|M|   The dose of lapatinib should be gradually titrated from 1,250 mg/day up|
03382|043|M|to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from|
03382|044|M|1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive|
03382|045|M|breast cancer indication) based on patient tolerability. If rifabutin is|
03382|046|M|discontinued, the dose of lapatinib should be adjusted to the normal|
03382|047|M|dose.(6)|
03382|048|B||
03382|049|D|DISCUSSION:  The US manufacturers of cabozantinib,(2) erlotinib,(4)|
03382|050|D|imatinib,(5) lapatinib,(6) and sorafenib,(7) and the UK manufacturer of|
03382|051|D|ceritinib(3)  include rifabutin in their list of strong CYP3A4 inducers to|
03382|052|D|be avoided.  Although the combinations of these agents with rifabutin have|
03382|053|D|not been studied, they have been studied with other strong CYP3A4 inducers.|
03382|054|D|   In a study in healthy subjects, rifampin (600 mg daily for 31 days)|
03382|055|D|decreased the area-under-curve (AUC) of a single dose of cabozantinib by|
03382|056|D|77%.(1)|
03382|057|D|   In a study in 19 healthy subjects, rifampin (600 mg daily for 14 days)|
03382|058|D|decreased the maximum concentration (Cmax) and AUC of a single dose of|
03382|059|D|ceritinib by 44% and 70%, respectively.(3)|
03382|060|D|   Pretreatment and concurrent therapy with rifampin increased erlotinib|
03382|061|D|clearance by 3-fold and decreased the erlotinib AUC by 66% to 80%.  This is|
03382|062|D|equivalent to a dose of about 30 mg to 50 mg in NSCLC.(4)|
03382|063|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
03382|064|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
03382|065|D|150 mg dose of erlotinib.(4)|
03382|066|D|   In a case report, coadministration of phenytoin (180mg daily) and|
03382|067|D|erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml|
03382|068|D|to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from|
03382|069|D|1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold|
03382|070|D|(from 3.53 L/h to 41.7 L/h).(8)|
03382|071|D|   Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10|
03382|072|D|days) increased the clearance of a single dose of imatinib (400 mg) by|
03382|073|D|3.8-fold. The AUC and Cmax decreased by 74% and 54%, respectively.(5,9)  The|
03382|074|D|Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588|
03382|075|D|decreased by 11%.(9)|
03382|076|D|   In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200|
03382|077|D|mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of|
03382|078|D|lapatinib by 72%.  The dose adjustment recommendations are based on|
03382|079|D|pharmacokinetic studies and are predicted to adjust lapatinib AUC to the|
03382|080|D|range observed without concurrent CYP3A4 inducers; however, there are no|
03382|081|D|clinical data with these doses in patients receiving strong CYP3A4|
03382|082|D|inducers.(6)|
03382|083|D|   Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a|
03382|084|D|single dose of sorafenib (400 mg) by 37%.(7)|
03382|085|B||
03382|086|R|REFERENCES:|
03382|087|B||
03382|088|R|1.Cabometyx (cabozantinib) tablets, US prescribing information. Exelixis|1
03382|089|R|  Inc. January, 2021.|1
03382|090|R|2.Cometriq (cabozantinib) US prescribing information. Exelixix, Inc.|1
03382|091|R|  January, 2020.|1
03382|092|R|3.Zykadia (ceritinib) UK Summary of Product Characteristics. Novartis|1
03382|093|R|  Pharmaceuticals UK Ltd April 12, 2019.|1
03382|094|R|4.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
03382|095|R|  2016.|1
03382|096|R|5.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
03382|097|R|  Pharmaceuticals Corporation August, 2022.|1
03382|098|R|6.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
03382|099|R|  2018.|1
03382|100|R|7.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
03382|101|R|  Corporation July, 2020.|1
03382|102|R|8.Ohgami M, Kaburagi T, Kurosawa A, Homma M. Drug interaction between|3
03382|103|R|  erlotinib and phenytoin for brain metastases in a patient with nonsmall|3
03382|104|R|  cell lung cancer. Lung Cancer 2016 Nov;101:9-10.|3
03382|105|R|9.Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U,|2
03382|106|R|  Seiberling M. Effect of rifampicin on the pharmacokinetics of imatinib|2
03382|107|R|  mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol|2
03382|108|R|  2004 Feb;53(2):102-6.|2
03382|109|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
03382|110|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03382|111|R|   at:|1
03382|112|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03382|113|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03382|114|R|   11/14/2017.|1
03383|001|T|MONOGRAPH TITLE:  Ibrutinib/Moderate CYP3A4 Inducers|
03383|002|B||
03383|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03383|004|L|of severe adverse interaction.|
03383|005|B||
03383|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
03383|007|A|metabolism of ibrutinib.(1)|
03383|008|B||
03383|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inducers may decrease|
03383|010|E|the levels and effectiveness of ibrutinib.(1)|
03383|011|B||
03383|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03383|013|P|of the inducer for longer than 1-2 weeks.|
03383|014|B||
03383|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of moderate CYP3A4 inducers in|
03383|016|M|patients receiving therapy with ibrutinib.(1)|
03383|017|M|   Consider the use of alternative agents with less enzyme induction|
03383|018|M|potential.(1)|
03383|019|B||
03383|020|D|DISCUSSION:  The coadministration of rifampin decreased the maximum|
03383|021|D|concentration (Cmax) and area-under-curve (AUC) of ibrutinib by more than|
03383|022|D|13-fold and 10-fold.(1)  In a pharmacokinetic model, efavirenz (600 mg|
03383|023|D|daily), a moderate CYP3A4 inducer, was predicted to decrease the Cmax and|
03383|024|D|AUC of ibrutinib (560 mg) by 2.4-fold and 2.5-fold, respectively.(2)|
03383|025|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03383|026|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
03383|027|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
03383|028|D|pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat|
03383|029|D|ethyl, thioridazine, and tovorafenib.(4)|
03383|030|B||
03383|031|R|REFERENCES:|
03383|032|B||
03383|033|R|1.Imbruvica (ibrutinib) UK summary of product characteristics. Janssen-Cilag|1
03383|034|R|  Ltd. August, 2020.|1
03383|035|R|2.de Zwart L, Snoeys J, De Jong J, Sukbuntherng J, Mannaert E, Monshouwer M.|6
03383|036|R|  Ibrutinib Dosing Strategies Based on Interaction Potential of CYP3A4|6
03383|037|R|  Perpetrators Using Physiologically Based Pharmacokinetic Modeling. Clin|6
03383|038|R|  Pharmacol Ther 2016 Nov;100(5):548-557.|6
03383|039|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03383|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03383|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03383|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03383|043|R|  11/14/2017.|1
03384|001|T|MONOGRAPH TITLE:  Rolapitant/Moderate CYP3A4 Inducers|
03384|002|B||
03384|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03384|004|L|take action as needed.|
03384|005|B||
03384|006|A|MECHANISM OF ACTION:  Rolapitant is metabolized primarily by CYP3A4.|
03384|007|A|Moderate inducers of CYP3A4 may increase the metabolism and clearance of|
03384|008|A|rolapitant via CYP3A4.(1)|
03384|009|B||
03384|010|E|CLINICAL EFFECTS:  Concurrent use with moderate inducers of CYP3A4 may|
03384|011|E|result in significantly decreased levels and effectiveness of rolapitant.(1)|
03384|012|B||
03384|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03384|014|P|of the inducer for longer than 1-2 weeks.|
03384|015|B||
03384|016|M|PATIENT MANAGEMENT:  The UK manufacturer of rolapitant states that|
03384|017|M|rolapitant is not recommended in patients already taking moderate CYP3A4|
03384|018|M|inducers.(1)|
03384|019|M|   If concomitant use is warranted, monitor the patient for decreased|
03384|020|M|antiemetic efficacy.  When possible and clinically appropriate, consider use|
03384|021|M|of an alternative antiemetic or alternatives to the moderate CYP3A4 inducer.|
03384|022|B||
03384|023|D|DISCUSSION:  The effect of moderate CYP3A4 inducers on rolapitant has not|
03384|024|D|been studied.  The UK manufacturer of rolapitant does not recommend the|
03384|025|D|concurrent use of rolapitant with moderate CYP3A4 inducers.|
03384|026|D|   Rifampin (600 mg daily for 14 days), a strong CYP3A4 inducer, decreased|
03384|027|D|the Cmax and AUC of a single dose of rolapitant (180 mg on Day 7) by 30% and|
03384|028|D|85%, respectively.  The half-life of rolapitant decreased from 176 hours to|
03384|029|D|41 hours.(3)|
03384|030|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03384|031|D|bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine,|
03384|032|D|lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pacritinib,|
03384|033|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
03384|034|D|thioridazine, and tovorafenib.(2,3)|
03384|035|B||
03384|036|R|REFERENCES:|
03384|037|B||
03384|038|R|1.Varuby (rolapitant) UK Summary of Product Characteristics. Tesaro UK|1
03384|039|R|  Limited March 15, 2019.|1
03384|040|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03384|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03384|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03384|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03384|044|R|  11/14/2017.|1
03384|045|R|3.This information is based on an extract from the Certara Drug Interaction|6
03384|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03385|001|T|MONOGRAPH TITLE:  Abiraterone; Cabazitaxel; Vincristine/Rifabutin|
03385|002|B||
03385|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03385|004|L|of severe adverse interaction.|
03385|005|B||
03385|006|A|MECHANISM OF ACTION:  Rifabutin is an inducer of CYP3A4 and may increase the|
03385|007|A|metabolism of abiraterone,(1) cabazitaxel,(2,3) and vincristine.(4)|
03385|008|B||
03385|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifabutin may result in|
03385|010|E|decreased levels and effectiveness of abiraterone,(1) cabazitaxel,(3) and|
03385|011|E|vincristine.(4)|
03385|012|B||
03385|013|P|PREDISPOSING FACTORS:  None determined.|
03385|014|B||
03385|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of rifabutin with abiraterone,(1)|
03385|016|M|cabazitaxel,(3) and vincristine.(4)  Consider the use of agents with no or|
03385|017|M|minimal induction potential if possible.  Monitor patients for decreased|
03385|018|M|response to therapy.|
03385|019|M|   If concurrent administration of abiraterone and rifabutin is required,|
03385|020|M|increase the dosing frequency of abiraterone from once daily to twice daily|
03385|021|M|during the co-administration period.  If rifabutin is discontinued, reduce|
03385|022|M|the dose of abiraterone back to the previous dose and frequency.(1)|
03385|023|B||
03385|024|D|DISCUSSION:  Abiraterone,(1) cabazitaxel,(2,3) and vincristine (3) are|
03385|025|D|metabolized by CYP3A4.  Strong inducers of this isoenzyme are expected to|
03385|026|D|decrease levels of these agents.  The US manufacturers of abiraterone(1) and|
03385|027|D|vincristine(4) and the UK manufacturer of cabazitaxel(3) include rifabutin|
03385|028|D|on the list of strong CYP3A4 inducers that should be avoided.|
03385|029|D|   In a drug interaction trial, concurrent administration of rifampin, a|
03385|030|D|strong CYP3A4 inducer, decreased abiraterone levels by 55%.(1)|
03385|031|D|   In a study in 21 advanced cancer patients, rifampin (600mg) decreased the|
03385|032|D|exposure to cabazitaxel (15mg/m2) by 17%.(2)|
03385|033|B||
03385|034|R|REFERENCES:|
03385|035|B||
03385|036|R|1.Zytiga (abiraterone acetate) US prescribing information. Centocor Ortho|1
03385|037|R|  Biotech, Inc. October, 2020.|1
03385|038|R|2.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
03385|039|R|  July, 2023.|1
03385|040|R|3.Jevtana (cabazitaxel) UK Summary of Product Characteristics. Sanofi|1
03385|041|R|  Genzyme February, 2024.|1
03385|042|R|4.Marqibo (vincristine sulfate) US prescribing information. Talon|1
03385|043|R|  Therapeutics, Inc July, 2020.|1
03385|044|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03385|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03385|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03385|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03385|048|R|  11/14/2017.|1
03385|049|R|6.This information is based on an extract from the Certara Drug Interaction|6
03385|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03386|001|T|MONOGRAPH TITLE:  Regorafenib/Strong CYP3A4 Inducers|
03386|002|B||
03386|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03386|004|L|of severe adverse interaction.|
03386|005|B||
03386|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03386|007|A|regorafenib via this pathway.|
03386|008|A|   Regorafenib and active M2 and M5 metabolites contribute to anticancer|
03386|009|A|activity.(1,2)  Although interpatient variability is high, with repeated|
03386|010|A|dosing the systemic exposure to each component (regorafenib, M2 and M5) is|
03386|011|A|similar.  CYP3A4 converts regorafenib to the active M2 metabolite.  M2 is|
03386|012|A|subsequently converted, via an unknown pathway, to the active M5|
03386|013|A|metabolite.(2)|
03386|014|B||
03386|015|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
03386|016|E|alter the clinical effectiveness of regorafenib.(1,2)|
03386|017|B||
03386|018|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03386|019|P|of the inducer for longer than 1-2 weeks.|
03386|020|B||
03386|021|M|PATIENT MANAGEMENT:  Avoid the concurrent use of regorafenib with strong|
03386|022|M|CYP3A4 inducers.(1)  When possible, select alternative agents in place of|
03386|023|M|the strong CYP3A4 inducer.  Monitor patients receiving concurrent therapy|
03386|024|M|for reduced efficacy.|
03386|025|B||
03386|026|D|DISCUSSION:  In an interaction study of rifampin and regorafenib, rifampin|
03386|027|D|was associated with a 50% decrease in exposure to regorafenib and no change|
03386|028|D|in exposure to M2.  However, the mean exposure to M5 increased 264%.  Due to|
03386|029|D|this large increase in M5, overall exposure to the combination of|
03386|030|D|regorafenib, M2 and M5 was increased by 68%.(2)|
03386|031|D|   Regorafenib was approved for use prior to completion of an|
03386|032|D|exposure-response analysis or a population pharmacokinetic study.(2)  The|
03386|033|D|outcomes of these studies will increase understanding and improve prediction|
03386|034|D|of regorafenib interaction risks.|
03386|035|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
03386|036|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
03386|037|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
03386|038|D|rifampin, rifapentine and St John's Wort.(3,4)|
03386|039|B||
03386|040|R|REFERENCES:|
03386|041|B||
03386|042|R|1.Stivarga (regorafenib) US prescribing information. Bayer HealthCare|1
03386|043|R|  Pharmaceuticals, Inc. February, 2020.|1
03386|044|R|2.FDA. Drug Approval Package: Stivarga (regorafenib) Tablets,|1
03386|045|R|  Application:203085, Clinical Pharmacology Review. accessed at:|1
03386|046|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203085Orig1s000Clin|1
03386|047|R|  PharmR.pdf approval 09/27/2012.|1
03386|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03386|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03386|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03386|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03386|052|R|  11/14/2017.|1
03386|053|R|4.This information is based on an extract from the Certara Drug Interaction|6
03386|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03387|001|T|MONOGRAPH TITLE:  Methadone for MAT/Selected Antipsychotics that Prolong QT|
03387|002|B||
03387|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03387|004|L|of severe adverse interaction.|
03387|005|B||
03387|006|A|MECHANISM OF ACTION:  Methadone has been shown to prolong the QTc interval.|
03387|007|A|Concurrent use with selected antipsychotics may result in additive effects|
03387|008|A|on the QTc interval.(1-3)|
03387|009|A|   Concurrent use of methadone and antipsychotics may result in additive CNS|
03387|010|A|depression.(1-3)|
03387|011|B||
03387|012|E|CLINICAL EFFECTS:  The concurrent use of methadone with other agents that|
03387|013|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03387|014|E|arrhythmias, including torsades de pointes.(1,2)|
03387|015|E|   Concurrent use of opioids and other CNS depressants such as|
03387|016|E|antipsychotics may result in profound sedation, respiratory depression,|
03387|017|E|coma, and/or death.(1-3)|
03387|018|B||
03387|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03387|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03387|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03387|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03387|023|P|gender, or advanced age.(4)|
03387|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03387|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03387|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03387|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03387|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03387|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03387|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03387|031|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
03387|032|P|of adverse effects.|
03387|033|B||
03387|034|M|PATIENT MANAGEMENT:  Concurrent use of methadone with other agents known to|
03387|035|M|prolong the QT interval should be approached with extreme caution.(1,2)|
03387|036|M|Limit prescribing methadone with CNS depressants such as antipsychotics to|
03387|037|M|patients for whom alternatives are ineffective, not tolerated, or would be|
03387|038|M|otherwise inadequate to provide sufficient management of pain.(3)|
03387|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03387|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03387|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03387|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03387|043|M|   Medication assisted treatment (MAT) with methadone is not contraindicated|
03387|044|M|in patients taking CNS depressants; however, gradual tapering or decreasing|
03387|045|M|to the lowest effective dose of antipsychotics may be appropriate.  Ensure|
03387|046|M|that other health care providers prescribing other CNS depressants are aware|
03387|047|M|of the patient's methadone treatment.(5)|
03387|048|M|   If concurrent use is necessary, limit the dosages and duration of each|
03387|049|M|drug to the minimum possible while achieving the desired clinical effect.|
03387|050|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03387|051|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03387|052|M|indicated in the absence of an opioid and titrate based upon clinical|
03387|053|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03387|054|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03387|055|M|clinical response.(3)|
03387|056|M|   Respiratory depression can occur at any time during opioid therapy,|
03387|057|M|especially during therapy initiation and following dosage increases.  The|
03387|058|M|risk of opioid-related overdose or overdose-related death is increased with|
03387|059|M|higher opioid doses, and this risk persists over the course of therapy.|
03387|060|M|Consider these risks when using concurrently with other agents that may|
03387|061|M|cause CNS depression.(6)|
03387|062|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03387|063|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03387|064|M|unresponsiveness.(3)|
03387|065|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03387|066|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03387|067|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03387|068|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03387|069|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03387|070|M|as those taking CNS depressants) and when a patient has household|
03387|071|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03387|072|M|for obtaining an opioid reversal agent (e.g., prescription,|
03387|073|M|over-the-counter, or as part of a community-based program).(7)|
03387|074|B||
03387|075|D|DISCUSSION:  Most cases of methadone-induced QT prolongation are associated|
03387|076|D|with, but not limited to, higher dose treatment (greater than 200 mg daily)|
03387|077|D|and most involve patients being treated for pain with large, multiple daily|
03387|078|D|doses. Cases have been reported in patients treated with doses commonly used|
03387|079|D|for maintenance treatment of opioid addiction.(2)|
03387|080|D|   Levomethadone should be used with caution in patients with a history of|
03387|081|D|QT prolongation, advanced heart disease, concomitant CYP3A4 inhibitors, or|
03387|082|D|electrolyte abnormalities.  Cases of QT prolongation and torsades de pointes|
03387|083|D|have been reported, most commonly with high doses.(1)|
03387|084|D|   A nested case-control study looked at the relationship between|
03387|085|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03387|086|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03387|087|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03387|088|D|significantly increased in patients with recent use of antipsychotics|
03387|089|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03387|090|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03387|091|D|of use.(8)|
03387|092|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03387|093|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03387|094|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03387|095|D|to 30 million patients.  During this time, the proportion of patients|
03387|096|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03387|097|D|patients.(9)|
03387|098|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03387|099|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03387|100|D|per 100,000 and drug overdose deaths involving both opioids and|
03387|101|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03387|102|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03387|103|D|increased from 18% to 31% during this time.(10)|
03387|104|D|   A prospective observational cohort study in North Carolina found that the|
03387|105|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03387|106|D|benzodiazepines were 10 times higher than patients receiving opioid|
03387|107|D|analgesics alone.(11)|
03387|108|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03387|109|D|death from overdose increased with concomitant opioid analgesics and|
03387|110|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03387|111|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03387|112|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03387|113|D|increased risk of fatal overdose.(12)|
03387|114|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03387|115|D|which benzodiazepines were determined to be a cause of death and that|
03387|116|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03387|117|D|determined to be a cause of death.  This study also found that other CNS|
03387|118|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03387|119|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03387|120|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03387|121|D|where opioid analgesics were also implicated.(13)|
03387|122|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03387|123|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03387|124|D|deaths.(14)|
03387|125|D|   Selected antipsychotics that prolong QT include: amsulpride,|
03387|126|D|chlorpromazine, chlorprothixene, clozapine, haloperidol, iloperidone,|
03387|127|D|mesoridazine, paliperidone, pimavanserin, pipamperone, promethazine,|
03387|128|D|quetiapine, sulpiride, sultopride, thioridazine, ziprasidone, and|
03387|129|D|zuclopenthixol.|
03387|130|B||
03387|131|R|REFERENCES:|
03387|132|B||
03387|133|R|1.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03387|134|R|  Pharma AS November 30, 2018.|1
03387|135|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03387|136|R|  Pharmaceuticals Corp. June, 2021.|1
03387|137|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03387|138|R|  warns about serious risks and death when combining opioid pain or cough|1
03387|139|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03387|140|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03387|141|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03387|142|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03387|143|R|  settings: a scientific statement from the American Heart Association and|6
03387|144|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03387|145|R|  2;55(9):934-47.|6
03387|146|R|5.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03387|147|R|  urges caution about withholding opioid addiction medications from patients|1
03387|148|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03387|149|R|  can reduce risks. available at:|1
03387|150|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03387|151|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03387|152|R|  prescribing information for all opioid pain medicines to provide|1
03387|153|R|  additional guidance for safe use. Available at:|1
03387|154|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03387|155|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03387|156|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03387|157|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03387|158|R|  recommends health care professionals discuss naloxone with all patients|1
03387|159|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03387|160|R|  disorder. Available at:|1
03387|161|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03387|162|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03387|163|R|  d-pain July 23, 2020.|1
03387|164|R|8.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03387|165|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03387|166|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03387|167|R|  Pharmacol 2020 Apr 26.|2
03387|168|R|9.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03387|169|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03387|170|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03387|171|R|10.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03387|172|R|   From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015|2
03387|173|R|   Oct;49(4):493-501.|2
03387|174|R|11.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03387|175|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03387|176|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03387|177|R|12.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03387|178|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03387|179|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03387|180|R|   350:h2698.|2
03387|181|R|13.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03387|182|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03387|183|R|14.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03387|184|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03387|185|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03387|186|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03388|001|T|MONOGRAPH TITLE:  Selected Opioids for MAT/Selected Antipsychotics|
03388|002|B||
03388|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03388|004|L|take action as needed.|
03388|005|B||
03388|006|A|MECHANISM OF ACTION:  Concurrent use of buprenorphine or diacetylmorphine|
03388|007|A|and antipsychotics may result in additive CNS depression.(1-3)|
03388|008|B||
03388|009|E|CLINICAL EFFECTS:  Concurrent use of buprenorphine or diacetylmorphine and|
03388|010|E|antipsychotics may result in profound sedation, respiratory depression,|
03388|011|E|coma, and/or death.(1-3)|
03388|012|B||
03388|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03388|014|P|may increase the risk of adverse effects.|
03388|015|B||
03388|016|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with buprenorphine|
03388|017|M|or diacetylmorphine is not contraindicated in patients taking CNS|
03388|018|M|depressants, such as antipsychotics; however, gradual tapering or decreasing|
03388|019|M|to the lowest effective dose of the antipsychotic may be appropriate.|
03388|020|M|Ensure that other health care providers prescribing other CNS depressants|
03388|021|M|are aware of the patient's buprenorphine or diacetylmorphine treatment.(2)|
03388|022|M|   Respiratory depression can occur at any time during opioid therapy,|
03388|023|M|especially during therapy initiation and following dosage increases.  The|
03388|024|M|risk of opioid-related overdose or overdose-related death is increased with|
03388|025|M|higher opioid doses, and this risk persists over the course of therapy.|
03388|026|M|Consider these risks when using concurrently with other agents that may|
03388|027|M|cause CNS depression.(4)|
03388|028|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03388|029|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03388|030|M|unresponsiveness.(1)|
03388|031|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03388|032|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03388|033|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03388|034|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03388|035|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03388|036|M|as those taking CNS depressants) and when a patient has household|
03388|037|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03388|038|M|for obtaining an opioid reversal agent (e.g., prescription,|
03388|039|M|over-the-counter, or as part of a community-based program).(5)|
03388|040|B||
03388|041|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03388|042|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03388|043|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03388|044|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03388|045|D|significantly increased in patients with recent use of antipsychotics|
03388|046|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03388|047|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03388|048|D|of use.(6)|
03388|049|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03388|050|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03388|051|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03388|052|D|to 30 million patients.  During this time, the proportion of patients|
03388|053|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03388|054|D|patients.(7)|
03388|055|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03388|056|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03388|057|D|per 100,000 and drug overdose deaths involving both opioids and|
03388|058|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03388|059|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03388|060|D|increased from 18% to 31% during this time.(8)|
03388|061|D|   A prospective observational cohort study in North Carolina found that the|
03388|062|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03388|063|D|benzodiazepines were 10 times higher than patients receiving opioid|
03388|064|D|analgesics alone.(9)|
03388|065|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03388|066|D|death from overdose increased with concomitant opioid analgesics and|
03388|067|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03388|068|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03388|069|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03388|070|D|increased risk of fatal overdose.(10)|
03388|071|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03388|072|D|which benzodiazepines were determined to be a cause of death and that|
03388|073|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03388|074|D|determined to be a cause of death.  This study also found that other CNS|
03388|075|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03388|076|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03388|077|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03388|078|D|where opioid analgesics were also implicated.(11)|
03388|079|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03388|080|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03388|081|D|deaths.(12)|
03388|082|D|   Selected antipsychotics linked include: amsulpride, chlorpromazine,|
03388|083|D|chlorprothixene, clozapine, droperidol, haloperidol, iloperidone,|
03388|084|D|mesoridazine, paliperidone, pimavanserin, pimozide, pipamperone,|
03388|085|D|promethazine, quetiapine, sertindole, sulpiride, sultopride, thioridazine,|
03388|086|D|ziprasidone, and zuclopenthixol.|
03388|087|B||
03388|088|R|REFERENCES:|
03388|089|B||
03388|090|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03388|091|R|  warns about serious risks and death when combining opioid pain or cough|1
03388|092|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03388|093|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03388|094|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03388|095|R|  urges caution about withholding opioid addiction medications from patients|1
03388|096|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03388|097|R|  can reduce risks. available at:|1
03388|098|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03388|099|R|3.Diacetylmorphine Canadian prescribing information. Pharmascience Inc.|1
03388|100|R|  February, 2022.|1
03388|101|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03388|102|R|  prescribing information for all opioid pain medicines to provide|1
03388|103|R|  additional guidance for safe use. Available at:|1
03388|104|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03388|105|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03388|106|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03388|107|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03388|108|R|  recommends health care professionals discuss naloxone with all patients|1
03388|109|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03388|110|R|  disorder. Available at:|1
03388|111|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03388|112|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03388|113|R|  d-pain July 23, 2020.|1
03388|114|R|6.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03388|115|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03388|116|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03388|117|R|  Pharmacol 2020 Apr 26.|2
03388|118|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03388|119|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03388|120|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03388|121|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03388|122|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03388|123|R|  49(4):493-501.|2
03388|124|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03388|125|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03388|126|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03388|127|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03388|128|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03388|129|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03388|130|R|   350:h2698.|2
03388|131|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03388|132|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03388|133|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03388|134|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03388|135|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03388|136|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03389|001|T|MONOGRAPH TITLE:  Methadone (non MAT)/Selected Antipsychotics that Prolong|
03389|002|T|QT|
03389|003|B||
03389|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03389|005|L|of severe adverse interaction.|
03389|006|B||
03389|007|A|MECHANISM OF ACTION:  Methadone has been shown to prolong the QTc interval.|
03389|008|A|Concurrent use with selected antipsychotics may result in additive effects|
03389|009|A|on the QTc interval.|
03389|010|A|   Concurrent use of methadone and antipsychotics may result in additive CNS|
03389|011|A|depression.(1,2)|
03389|012|B||
03389|013|E|CLINICAL EFFECTS:  Concurrent use of methadone with antipsychotics may|
03389|014|E|result in potentially life-threatening cardiac arrhythmias, including|
03389|015|E|torsades de pointes.(1)|
03389|016|E|   Concurrent use of methadone and other CNS depressants such as|
03389|017|E|antipsychotics may result in profound sedation, respiratory depression,|
03389|018|E|coma, and/or death.(1,2)|
03389|019|B||
03389|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03389|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
03389|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03389|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03389|024|P|female gender, or advanced age.(3)|
03389|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03389|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03389|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03389|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03389|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03389|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03389|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03389|032|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
03389|033|P|of adverse effects.|
03389|034|B||
03389|035|M|PATIENT MANAGEMENT:  Concurrent use of methadone with agents known to|
03389|036|M|prolong the QT interval should be approached with extreme caution.(1)  Limit|
03389|037|M|prescribing methadone with CNS depressants such as antipsychotics to|
03389|038|M|patients for whom alternatives are ineffective, not tolerated, or would be|
03389|039|M|otherwise inadequate to provide sufficient management of pain.(2)|
03389|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03389|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03389|042|M|regular intervals.  Correct any electrolyte abnormalities. Instruct patients|
03389|043|M|to report any irregular heartbeat, dizziness, or fainting.|
03389|044|M|   If concurrent use is necessary, limit the dosages and duration of each|
03389|045|M|drug to the minimum possible while achieving the desired clinical effect.|
03389|046|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03389|047|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03389|048|M|indicated in the absence of an opioid and titrate based upon clinical|
03389|049|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03389|050|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03389|051|M|clinical response.(2)|
03389|052|M|   Respiratory depression can occur at any time during opioid therapy,|
03389|053|M|especially during therapy initiation and following dosage increases.  The|
03389|054|M|risk of opioid-related overdose or overdose-related death is increased with|
03389|055|M|higher opioid doses, and this risk persists over the course of therapy.|
03389|056|M|Consider these risks when using concurrently with other agents that may|
03389|057|M|cause CNS depression.(4)|
03389|058|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03389|059|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03389|060|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03389|061|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03389|062|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03389|063|M|as those taking CNS depressants) and when a patient has household|
03389|064|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03389|065|M|for obtaining an opioid reversal agent (e.g., prescription,|
03389|066|M|over-the-counter, or as part of a community-based program).(5)|
03389|067|B||
03389|068|D|DISCUSSION:  Most cases of methadone-induced QT prolongation are associated|
03389|069|D|with, but not limited to, higher dose treatment (greater than 200 mg daily)|
03389|070|D|and most involve patients being treated for pain with large, multiple daily|
03389|071|D|doses. Cases have been reported in patients treated with doses commonly used|
03389|072|D|for maintenance treatment of opioid addiction.(1)|
03389|073|D|   A nested case-control study looked at the relationship between|
03389|074|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03389|075|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03389|076|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03389|077|D|significantly increased in patients with recent use of antipsychotics|
03389|078|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03389|079|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03389|080|D|of use.(6)|
03389|081|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03389|082|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03389|083|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03389|084|D|to 30 million patients.  During this time, the proportion of patients|
03389|085|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03389|086|D|patients.(7)|
03389|087|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03389|088|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03389|089|D|per 100,000 and drug overdose deaths involving both opioids and|
03389|090|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03389|091|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03389|092|D|increased from 18% to 31% during this time.(8)|
03389|093|D|   A prospective observational cohort study in North Carolina found that the|
03389|094|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03389|095|D|benzodiazepines were 10 times higher than patients receiving opioid|
03389|096|D|analgesics alone.(9)|
03389|097|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03389|098|D|death from overdose increased with concomitant opioid analgesics and|
03389|099|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03389|100|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03389|101|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03389|102|D|increased risk of fatal overdose.(10)|
03389|103|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03389|104|D|which benzodiazepines were determined to be a cause of death and that|
03389|105|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03389|106|D|determined to be a cause of death.  This study also found that other CNS|
03389|107|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03389|108|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03389|109|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03389|110|D|where opioid analgesics were also implicated.(11)|
03389|111|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03389|112|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03389|113|D|deaths.(12)|
03389|114|D|   Selected antipsychotics linked include: amsulpride, chlorpromazine,|
03389|115|D|chlorprothixene, clozapine, iloperidone, mesoridazine, paliperidone,|
03389|116|D|perphenazine, pimavanserin, pipamperone, promethazine, quetiapine,|
03389|117|D|sulpiride, sultopride, thioridazine, ziprasidone, and zuclopenthixol.|
03389|118|B||
03389|119|R|REFERENCES:|
03389|120|B||
03389|121|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03389|122|R|  Pharmaceuticals Corp. June, 2021.|1
03389|123|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03389|124|R|  warns about serious risks and death when combining opioid pain or cough|1
03389|125|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03389|126|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03389|127|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03389|128|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03389|129|R|  settings: a scientific statement from the American Heart Association and|6
03389|130|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03389|131|R|  2;55(9):934-47.|6
03389|132|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03389|133|R|  prescribing information for all opioid pain medicines to provide|1
03389|134|R|  additional guidance for safe use. Available at:|1
03389|135|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03389|136|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03389|137|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03389|138|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03389|139|R|  recommends health care professionals discuss naloxone with all patients|1
03389|140|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03389|141|R|  disorder. Available at:|1
03389|142|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03389|143|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03389|144|R|  d-pain July 23, 2020.|1
03389|145|R|6.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03389|146|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03389|147|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03389|148|R|  Pharmacol 2020 Apr 26.|2
03389|149|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03389|150|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03389|151|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03389|152|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03389|153|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03389|154|R|  49(4):493-501.|2
03389|155|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03389|156|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03389|157|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03389|158|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03389|159|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03389|160|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03389|161|R|   350:h2698.|2
03389|162|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03389|163|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03389|164|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03389|165|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03389|166|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03389|167|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03390|001|T|MONOGRAPH TITLE:  Clozapine/Myelosuppressive Agents that Prolong QT|
03390|002|B||
03390|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03390|004|L|of severe adverse interaction.|
03390|005|B||
03390|006|A|MECHANISM OF ACTION:  Concurrent use of clozapine with other agents that|
03390|007|A|prolong the QTc interval may result in additive effects on the QTc|
03390|008|A|interval.(1-3)|
03390|009|A|   Clozapine and concurrent use with other myelosuppressive agents may be|
03390|010|A|associated with additive risk of neutropenia or agranulocytosis.(4)|
03390|011|B||
03390|012|E|CLINICAL EFFECTS:  The use of clozapine in patients maintained on other|
03390|013|E|agents that prolong the QTc interval may result in potentially|
03390|014|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)|
03390|015|E|   Moderate neutropenia, even if due to combination therapy, may require|
03390|016|E|abrupt discontinuation of clozapine resulting in decompensation of the|
03390|017|E|patient's psychiatric disorder (e.g. schizophrenia).  The disease treated by|
03390|018|E|other agents may be compromised if myelosuppression requires dose reduction,|
03390|019|E|delay, or discontinuation of the myelosuppressive agent.  Undetected severe|
03390|020|E|neutropenia or agranulocytosis may be fatal.|
03390|021|B||
03390|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03390|023|P|may be increased in patients with cardiovascular disease (e.g. heart|
03390|024|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03390|025|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03390|026|P|female gender, or advanced age.(3)|
03390|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03390|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03390|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03390|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03390|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03390|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03390|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03390|034|P|   Low white blood counts prior to initiation of the myelosuppressive agent|
03390|035|P|may increase risk for clinically significant neutropenia.(2)|
03390|036|B||
03390|037|M|PATIENT MANAGEMENT:  Approach the concurrent use of clozapine and other|
03390|038|M|agents that prolong the QTc interval with caution.(1)|
03390|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03390|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03390|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03390|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03390|043|M|   If a patient stabilized on clozapine therapy requires treatment with|
03390|044|M|other myelosuppressive agents the clozapine prescriber should consult with|
03390|045|M|the prescriber of the myelosuppressive agent to discuss treatment and|
03390|046|M|monitoring options.  More frequent ANC monitoring or treatment alternatives|
03390|047|M|secondary to neutropenic episodes may need to be considered.|
03390|048|M|   Clozapine is only available through a restricted distribution system|
03390|049|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
03390|050|M|dispensing.  For most clozapine patients, clozapine treatment must be|
03390|051|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
03390|052|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
03390|053|M|interrupted for suspected clozapine-induced neutropenia < 500|
03390|054|M|cells/microliter.(1)|
03390|055|B||
03390|056|D|DISCUSSION:  Treatment with clozapine has been associated with QT|
03390|057|D|prolongation as well as ventricular arrhythmia, torsades de pointes, cardiac|
03390|058|D|arrest, and sudden death.(1)|
03390|059|D|   Clozapine is only available through a restricted distribution system|
03390|060|D|which requires documentation of the ANC prior to dispensing.(1)|
03390|061|D|   Myelosuppressive agents that prolong QT linked to this monograph include:|
03390|062|D|arsenic, crizotinib, dasatinib, encorafenib, entrectinib, epirubicin,|
03390|063|D|eribulin, fexinidazole, glasdegib, inotuzumab, lenvatinib, midostaurin,|
03390|064|D|nilotinib, osimertinib, oxaliplatin, pacritinib, panobinostat, pazopanib,|
03390|065|D|pentamidine, quinine, quizartinib, revumenib, ribociclib, romidepsin,|
03390|066|D|rucaparib, sorafenib, tacrolimus, and vinflunine.|
03390|067|B||
03390|068|R|REFERENCES:|
03390|069|B||
03390|070|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03390|071|R|  Pharmaceuticals Corporation April, 2020.|1
03390|072|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
03390|073|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03390|074|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03390|075|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03390|076|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03390|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03390|078|R|  settings: a scientific statement from the American Heart Association and|6
03390|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03390|080|R|  2;55(9):934-47.|6
03390|081|R|4.FDA (US Food and Drug Administration). Clozapine: Drug Safety|1
03390|082|R|  Communication - FDA Modifies Monitoring for Neutropenia; Approves New|1
03390|083|R|  Shared REMS Program. accessed at:|1
03390|084|R|  http://www.fda.gov/drugs/drugsafety/ucm461853.htm September 15, 2015.|1
03391|001|T|MONOGRAPH TITLE:  Bosutinib; Neratinib/Selected H2 Antagonists|
03391|002|B||
03391|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03391|004|L|take action as needed.|
03391|005|B||
03391|006|A|MECHANISM OF ACTION:  The solubility of bosutinib(1) and neratinib(2) is pH|
03391|007|A|dependent.  Changes in gastric pH from H2 antagonists may decrease the|
03391|008|A|absorption of bosutinib and neratinib.|
03391|009|B||
03391|010|E|CLINICAL EFFECTS:  Use of H2 antagonists may result in decreased levels and|
03391|011|E|effectiveness of bosutinib(1) and neratinib.(2)|
03391|012|B||
03391|013|P|PREDISPOSING FACTORS:  None determined.|
03391|014|B||
03391|015|M|PATIENT MANAGEMENT:  Consider the use of short-acting antacids in patients|
03391|016|M|taking bosutinib(1) and neratinib.(2)|
03391|017|M|   If antacids are used, separate the administration times by at least 2|
03391|018|M|hours for bosutinib(1) and 3 hours for neratinib.(2)|
03391|019|M|   If H2 antagonist therapy is required with bosutinib, separate|
03391|020|M|administration of the H2 blocker by at least 2 hours before or 2 hours after|
03391|021|M|bosutinib.(1)|
03391|022|M|   If H2 antagonist therapy is required with neratinib, then neratinib must|
03391|023|M|be given 10 hours after the H2 blocker and at least 2 hours before the next|
03391|024|M|dose of the H2 blocker.(2)|
03391|025|M|   Avoid the use of proton pump inhibitors (PPIs) in patients receiving|
03391|026|M|treatment with bosutinib(1) and neratinib.(2)|
03391|027|B||
03391|028|D|DISCUSSION:  A single dose of bosutinib 400 mg was administered alone or|
03391|029|D|following multiple doses of lansoprazole 60 mg without food. Lansoprazole|
03391|030|D|decreased bosutinib maximum concentration (Cmax) and area-under-curve (AUC)|
03391|031|D|by 46% and 26%, respectively.(1)|
03391|032|D|   In a study in 15 healthy subjects, lansoprazole 30 mg daily decreased the|
03391|033|D|Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%,|
03391|034|D|respectively.(2)|
03391|035|B||
03391|036|R|REFERENCES:|
03391|037|B||
03391|038|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
03391|039|R|  2023.|1
03391|040|R|2.Nerlynx (neratinib) US prescribing information. Puma Biotechnology, Inc.|1
03391|041|R|  June, 2021.|1
03392|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Econazole|
03392|002|B||
03392|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03392|004|L|take action as needed.|
03392|005|B||
03392|006|A|MECHANISM OF ACTION:  Econazole has been shown to be a potent inhibitor of|
03392|007|A|CYP3A4.(1)  If absorbed systemically, topical econazole may inhibit the|
03392|008|A|metabolism of coumarin anticoagulants.(2-3)|
03392|009|B||
03392|010|E|CLINICAL EFFECTS:  The concurrent use of topical econazole and coumarin|
03392|011|E|anticoagulants may increase international normalized ratio (INR) and result|
03392|012|E|in an increased risk for bleeding.(2-4)|
03392|013|B||
03392|014|P|PREDISPOSING FACTORS:  This interaction may occur if topical econazole is|
03392|015|P|absorbed systemically.  Factors contributing to increased systemic|
03392|016|P|absorption include exposure to large body surface areas, occlusion of the|
03392|017|P|area, and application onto areas of thin, macerated or broken skin.(2-4)|
03392|018|P|   The risk for bleeding episodes may be greater in patients with|
03392|019|P|disease-associated factors (e.g. thrombocytopenia).|
03392|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
03392|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03392|022|P|risk for bleeding (e.g. NSAIDs).|
03392|023|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
03392|024|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
03392|025|P|are expected to be more susceptible to this interaction.|
03392|026|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
03392|027|P|are expected to be less susceptible to effects from this drug combination,|
03392|028|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
03392|029|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
03392|030|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
03392|031|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to|
03392|032|P|achieve effective and safe anticoagulation than patients without these|
03392|033|P|CYP2C9 variants.|
03392|034|B||
03392|035|M|PATIENT MANAGEMENT:  Patients with risk factors for increased systemic|
03392|036|M|absorption of topical econazole and receiving concurrent therapy with a|
03392|037|M|coumarin anticoagulant (e.g. warfarin) should have their INR closely|
03392|038|M|monitored.(1)|
03392|039|M|   When concurrent therapy is warranted, monitor patients receiving|
03392|040|M|concurrent therapy for signs of blood loss, including decreased hemoglobin|
03392|041|M|and/or hematocrit, fecal occult blood, and/or decreased blood pressure and|
03392|042|M|promptly evaluate patients with any symptoms.|
03392|043|M|   When applicable, perform agent-specific laboratory test (e.g. INR) to|
03392|044|M|monitor efficacy and safety of anticoagulation.  Discontinue anticoagulation|
03392|045|M|in patients with active pathologic bleeding.|
03392|046|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03392|047|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03392|048|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03392|049|M|and/or swelling.|
03392|050|B||
03392|051|D|DISCUSSION:  Topical econazole is typically minimally absorbed (less than|
03392|052|D|2%).(3,4)  However absorption may be increased if it is applied to large|
03392|053|D|areas of the body or to thin, macerated, or broken skin, or if the area is|
03392|054|D|occluded.(2-4)|
03392|055|D|   A 79-year-old man on chronic warfarin therapy with stable INRs for 3|
03392|056|D|years developed severe bruising on his hip from a minor injury and bleeding|
03392|057|D|for over 24 hours from a small, superficial cut on his hand.  His INR was|
03392|058|D|found to be 12.  He had started econazole cream one week before for Candidal|
03392|059|D|infection of his scrotum and thighs.  He had no other medication or diet|
03392|060|D|changes and no acute illnesses.  He recovered after discontinuation of|
03392|061|D|econazole and treatment with vitamin K.(3)|
03392|062|D|   An 84-year-old woman stable on acenocoumarol 4 mg daily for ten years|
03392|063|D|developed a bilateral cervical hematoma causing upper airway obstruction,|
03392|064|D|dyspnea and difficulty speaking.  Her INR exceeded laboratory limits.  She|
03392|065|D|had started using econazole lotion 1% for extensive dermatitis over her|
03392|066|D|axillary, inguinal, and breast areas 17 days prior.  She had no other|
03392|067|D|changes to her medications, diet, or other chronic conditions, and no acute|
03392|068|D|illnesses.  The patient was treated with prothrombin complex concentrate and|
03392|069|D|vitamin K and recovered.(3)|
03392|070|B||
03392|071|R|REFERENCES:|
03392|072|B||
03392|073|R|1.Godamudunage MP, Grech AM, Scott EE. Comparison of Antifungal Azole|5
03392|074|R|  Interactions with Adult Cytochrome P450 3A4 versus Neonatal Cytochrome|5
03392|075|R|  P450 3A7. Drug Metab Dispos 2018 Sep;46(9):1329-1337.|5
03392|076|R|2.Lang PG Jr, LeClercq AH. Increase in anticoagulant effect of warfarin in a|3
03392|077|R|  patient using econazole cream. J Am Acad Dermatol 2006 Nov;55(5|3
03392|078|R|  Suppl):S117-9.|3
03392|079|R|3.Wey PF, Petitjeans F, Lions C, Ould-Ahmed M, Escarment J. Laryngeal|3
03392|080|R|  dyspnea in relation to an interaction between acenocoumarol and topical|3
03392|081|R|  econazole lotion. Am J Geriatr Pharmacother 2008 Aug;6(3):173-7.|3
03392|082|R|4.Econazole US prescribing information. Alvogen, Inc. January, 2020.|1
03393|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Tazemetostat|
03393|002|B||
03393|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03393|004|L|of severe adverse interaction.|
03393|005|B||
03393|006|A|MECHANISM OF ACTION:  Tazemetostat is a weak CYP3A4 inducer and may increase|
03393|007|A|the CYP3A4-mediated metabolism of both estrogen and progestin components of|
03393|008|A|hormonal contraceptives.(1)|
03393|009|B||
03393|010|E|CLINICAL EFFECTS:  Coadministration of tazemetostat with hormonal|
03393|011|E|contraceptives can result in decreased concentrations and reduced|
03393|012|E|efficacy.(1)  Breakthrough bleeding and contraceptive failure/pregnancy may|
03393|013|E|result.  Tazemetostat may cause fetal harm if administered to pregnant|
03393|014|E|women.(1)|
03393|015|B||
03393|016|P|PREDISPOSING FACTORS:  None determined.|
03393|017|B||
03393|018|M|PATIENT MANAGEMENT:  The manufacturer of tazemetostat recommends that female|
03393|019|M|patients of reproductive potential use effective non-hormonal contraception|
03393|020|M|during treatment with tazemetostat and for 6 months after the final dose.(1)|
03393|021|M|   Patients should be alerted to the risk for decreased effectiveness(e.g.|
03393|022|M|contraceptive failure) of their hormonal contraceptive therapy.|
03393|023|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03393|024|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03393|025|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03393|026|M|contraceptive (i.e., a copper IUD).(2)|
03393|027|B||
03393|028|D|DISCUSSION:  Coadministration of tazemetostat 800 mg twice daily with oral|
03393|029|D|midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam|
03393|030|D|area-under-curve (AUC) by 40% and maximum concentration (Cmax) by 21%.(1)|
03393|031|B||
03393|032|R|REFERENCES:|
03393|033|B||
03393|034|R|1.Tazverik (tazemetostat) US prescribing information. Epizyme, Inc August,|1
03393|035|R|  2024.|1
03393|036|R|2.Medicines and Healthcare products Regulatory Agency.|1
03393|037|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03393|038|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03393|039|R|  available at:|1
03393|040|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03393|041|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03393|042|R|  -and-contraceptive-efficacy September 15, 2016..|1
03394|001|T|MONOGRAPH TITLE:  Tazemetostat/Strong CYP3A4 Inhibitors|
03394|002|B||
03394|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03394|004|L|of severe adverse interaction.|
03394|005|B||
03394|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03394|007|A|of tazemetostat.(1)|
03394|008|B||
03394|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
03394|010|E|elevated levels of and toxicity from tazemetostat.(1)|
03394|011|B||
03394|012|P|PREDISPOSING FACTORS:  None determined.|
03394|013|B||
03394|014|M|PATIENT MANAGEMENT:  The US manufacturer of tazemetostat says to avoid|
03394|015|M|coadministration of strong CYP3A4 inhibitors with tazemetostat.(1) If|
03394|016|M|coadministration of strong CYP3A4 inhibitors cannot be avoided, reduce the|
03394|017|M|tazemetostat dose as follows:|
03394|018|M|   If the current tazemetostat dose is 800 mg twice daily, reduce the dose|
03394|019|M|to 400 mg twice daily.|
03394|020|M|   If the current tazemetostat dose is 600 mg twice daily, reduce the dose|
03394|021|M|to 400 mg for the first dose and 200 mg for the second dose.|
03394|022|M|   If the current tazemetostat dose is 400 mg twice daily, reduce the dose|
03394|023|M|to 200 mg twice daily.(1)|
03394|024|M|   After discontinuation of the strong CYP3A4 inhibitor for 3 elimination|
03394|025|M|half-lives, resume the prior tazemetostat dose.(1)|
03394|026|B||
03394|027|D|DISCUSSION:  Coadministration of fluconazole, a moderate CYP3A4 inhibitor,|
03394|028|D|with tazemetostat 400 mg twice daily in patients increased tazemetostat|
03394|029|D|steady-state area-under-curve (AUC) by 3.1-fold and maximum concentration|
03394|030|D|(Cmax) by 2.3-fold.(1)|
03394|031|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03394|032|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03394|033|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03394|034|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03394|035|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03394|036|D|troleandomycin, tucatinib, and voriconazole.(2-4)|
03394|037|B||
03394|038|R|REFERENCES:|
03394|039|B||
03394|040|R|1.Tazverik (tazemetostat) US prescribing information. Epizyme, Inc August,|1
03394|041|R|  2024.|1
03394|042|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03394|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03394|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03394|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03394|046|R|  11/14/2017.|1
03394|047|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03394|048|R|  Indiana University School of Medicine.  Available at:|1
03394|049|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03394|050|R|4.This information is based on an extract from the Certara Drug Interaction|6
03394|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03395|001|T|MONOGRAPH TITLE:  Tazemetostat/Moderate CYP3A4 Inhibitors|
03395|002|B||
03395|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03395|004|L|of severe adverse interaction.|
03395|005|B||
03395|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03395|007|A|metabolism of tazemetostat.(1)|
03395|008|B||
03395|009|E|CLINICAL EFFECTS:  Coadministration of tazemetostat with a moderate CYP3A4|
03395|010|E|inhibitor may increase tazemetostat plasma concentrations and increase the|
03395|011|E|frequency or severity of adverse reactions.(1)|
03395|012|B||
03395|013|P|PREDISPOSING FACTORS:  None determined.|
03395|014|B||
03395|015|M|PATIENT MANAGEMENT:  The US manufacturer of tazemetostat states to avoid|
03395|016|M|coadministration of moderate CYP3A4 inhibitors with tazemetostat.(1)  If|
03395|017|M|coadministration of moderate CYP3A4 inhibitors cannot be avoided, reduce the|
03395|018|M|tazemetostat dose as follows:|
03395|019|M|   If the current tazemetostat dose is 800 mg twice daily, reduce the dose|
03395|020|M|to 400 mg twice daily.|
03395|021|M|   If the current tazemetostat dose is 600 mg twice daily, reduce the dose|
03395|022|M|to 400 mg for the first dose and 200 mg for the second dose.|
03395|023|M|   If the current tazemetostat dose is 400 mg twice daily, reduce the dose|
03395|024|M|to 200 mg twice daily.(1)|
03395|025|M|   After discontinuation of the moderate CYP3A4 inhibitor for 3 elimination|
03395|026|M|half-lives, resume the prior tazemetostat dose.(1)|
03395|027|B||
03395|028|D|DISCUSSION:  Coadministration of fluconazole, a moderate CYP3A4 inhibitor,|
03395|029|D|with tazemetostat 400 mg twice daily in patients increased tazemetostat|
03395|030|D|area-under-curve (AUC) by 3.1-fold and maximum concentration (Cmax) by|
03395|031|D|2.3-fold.(1)|
03395|032|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
03395|033|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
03395|034|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
03395|035|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
03395|036|D|isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
03395|037|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and|
03395|038|D|verapamil.(2-4)|
03395|039|B||
03395|040|R|REFERENCES:|
03395|041|B||
03395|042|R|1.Tazverik (tazemetostat) US prescribing information. Epizyme, Inc August,|1
03395|043|R|  2024.|1
03395|044|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03395|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03395|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03395|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03395|048|R|  11/14/2017.|1
03395|049|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03395|050|R|  Indiana University School of Medicine.  Available at:|1
03395|051|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03395|052|R|4.This information is based on an extract from the Certara Drug Interaction|6
03395|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03396|001|T|MONOGRAPH TITLE:  Tazemetostat/Strong or Moderate CYP3A4 Inducers|
03396|002|B||
03396|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03396|004|L|of severe adverse interaction.|
03396|005|B||
03396|006|A|MECHANISM OF ACTION:  Strong or moderate CYP3A4 inducers may induce the|
03396|007|A|metabolism of tazemetostat.(1)|
03396|008|B||
03396|009|E|CLINICAL EFFECTS:  Coadministration of tazemetostat with a strong or|
03396|010|E|moderate CYP3A4 inducer may decrease tazemetostat plasma concentrations,|
03396|011|E|which may decrease the efficacy of tazemetostat.(1)|
03396|012|B||
03396|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03396|014|P|of the inducer for longer than 1-2 weeks.|
03396|015|B||
03396|016|M|PATIENT MANAGEMENT:  The US manufacturer of tazemetostat says to avoid|
03396|017|M|coadministration of strong or moderate CYP3A4 inducers with tazemetostat.(1)|
03396|018|B||
03396|019|D|DISCUSSION:  Tazemetostat is a known substrate of CYP3A4. According to the|
03396|020|D|manufacturer, coadministration with a strong or moderate CYP3A4 inducer may|
03396|021|D|decrease tazemetostat plasma concentrations which may decrease the efficacy|
03396|022|D|of tazemetostat. No clinical studies have been conducted.(1)|
03396|023|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03396|024|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03396|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03396|026|D|rifapentine, and St. John's wort.(2,3)|
03396|027|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03396|028|D|dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib,|
03396|029|D|mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib,|
03396|030|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and|
03396|031|D|tovorafenib.(2,3)|
03396|032|B||
03396|033|R|REFERENCES:|
03396|034|B||
03396|035|R|1.Tazverik (tazemetostat) US prescribing information. Epizyme, Inc August,|1
03396|036|R|  2024.|1
03396|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03396|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03396|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03396|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03396|041|R|  11/14/2017.|1
03396|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
03396|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03397|001|T|MONOGRAPH TITLE:  Protease Inhibitors/Apalutamide|
03397|002|B||
03397|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03397|004|L|is contraindicated and generally should not be dispensed or administered to|
03397|005|L|the same patient.|
03397|006|B||
03397|007|A|MECHANISM OF ACTION:  Apalutamide is a strong inducer of CYP3A4 and is|
03397|008|A|expected to increase the metabolism of the HIV protease inhibitors.(1-5)|
03397|009|A|   HIV protease inhibitors are moderate to strong inhibitors of CYP3A4 and|
03397|010|A|may decrease the metabolism of apalutamide.(1-5)|
03397|011|B||
03397|012|E|CLINICAL EFFECTS:  The net effect of the opposing effects of apalutamide and|
03397|013|E|the protease inhibitors on CYP3A4 is unknown.|
03397|014|E|   Concurrent or recent use of apalutamide with a protease inhibitor may|
03397|015|E|result in decreased levels and effectiveness of the protease inhibitor.|
03397|016|E|Virologic failure and drug resistance may occur.(1-3)|
03397|017|E|   Alternatively, protease inhibitors may increase the plasma concentration|
03397|018|E|and toxicities of apalutamide.(1)|
03397|019|B||
03397|020|P|PREDISPOSING FACTORS:  None determined.|
03397|021|B||
03397|022|M|PATIENT MANAGEMENT:  The manufacturer of lopinavir-ritonavir and of|
03397|023|M|ritonavir states that concurrent use with apalutamide is contraindicated due|
03397|024|M|to the risk of virologic failure and development of drug resistance.(2,3)|
03397|025|M|Since the other protease inhibitors are also CYP3A4 substrates and|
03397|026|M|frequently used with ritonavir, they are included in this monograph.|
03397|027|M|   If alternatives are not available and concurrent use is deemed medically|
03397|028|M|necessary, follow HIV viral loads closely.|
03397|029|B||
03397|030|D|DISCUSSION:  Co-administration of apalutamide with a single dose of|
03397|031|D|midazolam (a CYP3A4 substrate) led to a 92 % decrease in the|
03397|032|D|area-under-curve (AUC) of midazolam.(1)|
03397|033|D|   Ketoconazole, a strong CYP3A4 inhibitor, was predicted to increase the|
03397|034|D|AUC of single-dose apalutamide by 24% and of steady-state apalutamide by|
03397|035|D|51%.(1)|
03397|036|B||
03397|037|R|REFERENCES:|
03397|038|B||
03397|039|R|1.Erleada (apalutamide) US prescribing information. Janssen Biotech, Inc.|1
03397|040|R|  July, 2021.|1
03397|041|R|2.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
03397|042|R|  Laboratories December, 2019.|1
03397|043|R|3.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
03397|044|R|  December, 2019.|1
03397|045|R|4.This information is based on an extract from the Certara Drug Interaction|6
03397|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03397|047|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03397|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03397|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03397|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03397|051|R|  11/14/2017.|1
03398|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Apalutamide (mono deleted|
03398|002|T|02/11/2020)|
03398|003|B||
03398|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03398|005|L|of severe adverse interaction.|
03398|006|B||
03398|007|A|MECHANISM OF ACTION:  Apalutamide is a strong inducer of CYP3A4 and is|
03398|008|A|expected to increase the metabolism of protease inhibitors.(1-4)|
03398|009|B||
03398|010|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide may result in|
03398|011|E|decreased levels and effectiveness of protease inhibitors.(1-4)|
03398|012|B||
03398|013|P|PREDISPOSING FACTORS:  None determined.|
03398|014|B||
03398|015|M|PATIENT MANAGEMENT:  The manufacturer of apalutamide says that medicines|
03398|016|M|primarily metabolized by CYP3A4 should be substituted when possible.(1)|
03398|017|B||
03398|018|D|DISCUSSION:  Co-administration of apalutamide with a single dose of|
03398|019|D|midazolam (a CYP3A4 substrate) led to a 92 % decrease in the|
03398|020|D|area-under-curve (AUC) of midazolam.(1)|
03398|021|D|   Protease inhibitors linked to this monograph include: amprenavir,|
03398|022|D|atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, saquinavir, and|
03398|023|D|tipranavir.(2,3)|
03398|024|B||
03398|025|R|REFERENCES:|
03398|026|B||
03398|027|R|1.Erleada (apalutamide) US prescribing information. Janssen Biotech, Inc.|1
03398|028|R|  July, 2021.|1
03398|029|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03398|030|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03398|031|R|  HIV. Department of Health and Human Services. Available at|6
03398|032|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03398|033|R|  new-guidelines June 13, 2021.|6
03398|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
03398|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03398|036|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03398|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03398|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03398|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03398|040|R|  11/14/2017.|1
03399|001|T|MONOGRAPH TITLE:  Citalopram; Escitalopram/Cilostazol|
03399|002|B||
03399|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03399|004|L|of severe adverse interaction.|
03399|005|B||
03399|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
03399|007|A|homeostasis.(1)  The increased risk of bleeding may be a result of a|
03399|008|A|decrease in serotonin reuptake by platelets.|
03399|009|A|   Concurrent use of citalopram or escitalopram with cilostazol may result|
03399|010|A|in additive effects on the QTc interval.(1-5)|
03399|011|B||
03399|012|E|CLINICAL EFFECTS:  Concurrent use of citalopram or escitalopram and|
03399|013|E|cilostazol may result in bleeding and/or potentially life-threatening|
03399|014|E|cardiac arrhythmias, including torsades de pointes.(1-5)|
03399|015|B||
03399|016|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03399|017|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
03399|018|P|impairment has been associate with an elevated risk of GI bleed in patients|
03399|019|P|on SSRIs.(6)|
03399|020|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03399|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03399|022|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03399|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03399|024|P|advanced age.(7)|
03399|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03399|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03399|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03399|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03399|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03399|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03399|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)|
03399|032|B||
03399|033|M|PATIENT MANAGEMENT:  Concurrent use of citalopram or escitalopram with|
03399|034|M|agents known to alter hemostasis or prolong the QT interval such as|
03399|035|M|cilostazol should be avoided.(1)|
03399|036|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
03399|037|M|loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
03399|038|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03399|039|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
03399|040|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03399|041|M|anticoagulation in patients with active pathologic bleeding.|
03399|042|M|   Due to the risk of QT prolongation, citalopram doses greater than 40 mg|
03399|043|M|once daily are not recommended.  Citalopram doses should be limited to 20 mg|
03399|044|M|once daily in patients who are CYP2C19 poor metabolizers or patients|
03399|045|M|receiving CYP2C19 inhibitors.|
03399|046|M|   If patients have a persistent QTc measurement > 500 ms, discontinue|
03399|047|M|citalopram.  If a patient develops symptoms including dizziness,|
03399|048|M|palpitations, or syncope, further evaluation is warranted included cardiac|
03399|049|M|monitoring.|
03399|050|B||
03399|051|D|DISCUSSION:  Citalopram has been associated with dose-depended increases in|
03399|052|D|the QTc interval.  In healthy subjects, the maximum mean difference in QTc|
03399|053|D|interval seen with 20 mg of citalopram and 60 mg of citalopram were 8.5 msec|
03399|054|D|(90% CI = 6.2-10.8 msec) and 18.5 msec (90% CI = 16.0-21.0 msec),|
03399|055|D|respectively.  Based on extrapolation, a 40 mg dose of citalopram is|
03399|056|D|expected to produce a mean increase in the QTc interval of 12.6 msec (90% CI|
03399|057|D|= 10.9-14.3 msec).(1)|
03399|058|D|   In a clinical trial of use of citalopram for agitation in Alzheimer's|
03399|059|D|disease, citalopram (30 mg daily) was associated with a mean increase in QTc|
03399|060|D|of 18.1 msec.(8)|
03399|061|D|   In a retrospective review of 5 years of data from the|
03399|062|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03399|063|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03399|064|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03399|065|D|only based on an observed-expected ration was 4.5 and in a patient using|
03399|066|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
03399|067|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
03399|068|D|bleeding to 12.2 and 5.2, respectively.(9)|
03399|069|B||
03399|070|R|REFERENCES:|
03399|071|B||
03399|072|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03399|073|R|  Laboratories Inc. August, 2023.|1
03399|074|R|2.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
03399|075|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
03399|076|R|  Lundbeck Canada January 25, 2012.|1
03399|077|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
03399|078|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
03399|079|R|  potential risk of abnormal heart rhythms with high doses. available at:|1
03399|080|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
03399|081|R|4.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03399|082|R|  Pharmaceuticals Inc. May, 2023.|1
03399|083|R|5.Pletal (cilostazol) US prescribing information. Otsuka America|1
03399|084|R|  Pharmaceutical, Inc. January, 2015.|1
03399|085|R|6.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
03399|086|R|  Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
03399|087|R|  by level of kidney function: A population-based cohort study. Br J Clin|2
03399|088|R|  Pharmacol 2018 Sep;84(9):2142-2151.|2
03399|089|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03399|090|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03399|091|R|  settings: a scientific statement from the American Heart Association and|6
03399|092|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03399|093|R|  2;55(9):934-47.|6
03399|094|R|8.Drye LT, et al. Changes in QTc interval in the citalopram for agitation in|2
03399|095|R|  Alzheimer's disease (CitAD) randomized trial. PLoS One 2014;9(6):e98426.|2
03399|096|R|9.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03399|097|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03399|098|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03399|099|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03400|001|T|MONOGRAPH TITLE:  Citalopram (Greater Than 20 mg); Escitalopram (Greater|
03400|002|T|Than 15 mg)/Ticlopidine|
03400|003|B||
03400|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03400|005|L|of severe adverse interaction.|
03400|006|B||
03400|007|A|MECHANISM OF ACTION:  Citalopram is primarily metabolized by the CYP2C19|
03400|008|A|isoenzyme.(1)  At lower systemic concentrations, escitalopram is primarily|
03400|009|A|metabolized by CYP2C19; at higher concentrations is also metabolized by|
03400|010|A|CYP3A4.(2)|
03400|011|A|   Ticlopidine is a strong CYP2C19 inhibitor.(3)|
03400|012|B||
03400|013|E|CLINICAL EFFECTS:  Concurrent use of ticlopidine, a CYP2C19 inhibitor, may|
03400|014|E|result in elevated levels of and toxicity from citalopram or escitalopram,|
03400|015|E|including including risks for serotonin syndrome, bleeding, or prolongation|
03400|016|E|of the QTc interval.(1-7)|
03400|017|E|   Prolongation of the QT interval may result in life-threatening|
03400|018|E|arrhythmias, including torsades de pointes.(4)|
03400|019|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03400|020|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03400|021|E|rigidity.(7)|
03400|022|B||
03400|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03400|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
03400|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03400|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03400|027|P|female gender, advanced age, poor metabolizer status at CYP2C19, or higher|
03400|028|P|blood concentrations of citalopram or escitalopram.(1-3)|
03400|029|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03400|030|P|higher systemic concentrations of either QT prolonging drug are additional|
03400|031|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03400|032|P|drug concentrations include rapid infusion of an intravenous dose or|
03400|033|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03400|034|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03400|035|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03400|036|P|   Predisposing factors for serotonin-related adverse effects include use in|
03400|037|P|the elderly, in patients with hepatic impairment, and in patients receiving|
03400|038|P|multiple agents which increase central serotonin levels.(1,7)|
03400|039|P|   The risk for bleeding episodes may be greater in patients with|
03400|040|P|disease-associated factors (e.g. thrombocytopenia).  Renal impairment has|
03400|041|P|been associated with an elevated risk of GI bleed in patients on SSRIs.(8)|
03400|042|B||
03400|043|M|PATIENT MANAGEMENT:  The dose of citalopram should be limited to 20 mg in|
03400|044|M|patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,6)|
03400|045|M|Evaluate the patient for other drugs, diseases and conditions which increase|
03400|046|M|risk for QT prolongation and correct risk factors (e.g. correct hypokalemia,|
03400|047|M|hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when|
03400|048|M|possible.(1,4)  Weigh the specific benefits versus risks for each patient.|
03400|049|M|The US manufacturer recommends ECG monitoring for citalopram patients with|
03400|050|M|congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging|
03400|051|M|medications or receiving concurrent therapy.(6)  Citalopram should be|
03400|052|M|discontinued in patients with persistent QTc measurements greater than 500|
03400|053|M|ms.(4)|
03400|054|M|   It would be prudent to limit the escitalopram dose to 10 mg daily in|
03400|055|M|patients with QT prolonging risk factors who also receive concurrent therapy|
03400|056|M|with selected CYP2C19 inhibitors.(5)  Weigh the specific benefits versus|
03400|057|M|risks for each patient.|
03400|058|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03400|059|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03400|060|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03400|061|M|patients to report any irregular heartbeat, dizziness, or fainting.  Monitor|
03400|062|M|patients for signs of blood loss, including decreased hemoglobin,|
03400|063|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
03400|064|M|evaluate patients with any symptoms.|
03400|065|M|   If concurrent therapy is warranted, patients should be monitored for|
03400|066|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03400|067|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03400|068|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03400|069|M|coordination, or severe diarrhea.|
03400|070|B||
03400|071|D|DISCUSSION:  Concurrent use of citalopram (40 mg daily) and cimetidine (400|
03400|072|D|mg twice daily) for 8 days increased the maximum concentration (Cmax) and|
03400|073|D|area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1)|
03400|074|D|   A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was|
03400|075|D|conducted; a change of 10 msec for upper bound of the 95% confidence level|
03400|076|D|is the threshold for regulatory concern.  In this study, changes to the|
03400|077|D|upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for|
03400|078|D|the 10 mg and supratherapeutic 30 mg dose respectively.  The Cmax for 30 mg|
03400|079|D|was 1.7-fold higher than the Cmax for the maximum recommended escitalopram|
03400|080|D|dose of 20 mg.  Systemic exposure at the 30 mg dose was similar to expected|
03400|081|D|steady state concentrations in 2C19 poor metabolizers following a 20 mg|
03400|082|D|escitalopram dose.(2)|
03400|083|D|  In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of|
03400|084|D|CYP2C19 was administered daily for 6 days.  On day 5 a single dose of|
03400|085|D|escitalopram 20 mg was also administered; the area-under-curve (AUC) of|
03400|086|D|escitalopram was increased by 50%.  Manufacturer prescribing information|
03400|087|D|recommends a maximum citalopram dose of 20mg daily in patients receiving|
03400|088|D|CYP2C19 inhibitors.(2)|
03400|089|D|   In a retrospective review of 5 years of data from the|
03400|090|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03400|091|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03400|092|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03400|093|D|only based on an observed-expected ration was 4.5 and in a patient using|
03400|094|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
03400|095|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
03400|096|D|bleeding to 12.2 and 5.2, respectively.(9)|
03400|097|B||
03400|098|R|REFERENCES:|
03400|099|B||
03400|100|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03400|101|R|  Laboratories Inc. August, 2023.|1
03400|102|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03400|103|R|  Pharmaceuticals Inc. May, 2023.|1
03400|104|R|3.This information is based on an extract from the Certara Drug Interaction|6
03400|105|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03400|106|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03400|107|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03400|108|R|  settings: a scientific statement from the American Heart Association and|6
03400|109|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03400|110|R|  2;55(9):934-47.|6
03400|111|R|5.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
03400|112|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
03400|113|R|  and antidepressant use: a cross sectional study of electronic health|2
03400|114|R|  records. BMJ 2013;346:f288.|2
03400|115|R|6.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
03400|116|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
03400|117|R|  Lundbeck Canada January 25, 2012.|1
03400|118|R|7.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03400|119|R|  352(11):1112-20.|6
03400|120|R|8.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
03400|121|R|  Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
03400|122|R|  by level of kidney function: A population-based cohort study. Br J Clin|2
03400|123|R|  Pharmacol 2018 Sep;84(9):2142-2151.|2
03400|124|R|9.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03400|125|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03400|126|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03400|127|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03400|128|R|10.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
03400|129|R|   recommendations for Celexa (citalopram hydrobromide) related to a|1
03400|130|R|   potential risk of abnormal heart rhythms with high doses. available at:|1
03400|131|R|   http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
03401|001|T|MONOGRAPH TITLE:  Pazopanib/P-gp or BCRP Inhibitors that Prolong QT|
03401|002|B||
03401|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03401|004|L|of severe adverse interaction.|
03401|005|B||
03401|006|A|MECHANISM OF ACTION:  Concurrent use with other agents that prolong the QTc|
03401|007|A|interval and inhibit P-gp or BCRP may result in increased absorption and|
03401|008|A|higher levels of pazopanib and additive effects on the QTc interval.(1)|
03401|009|B||
03401|010|E|CLINICAL EFFECTS:  The concurrent use of pazopanib with other agents that|
03401|011|E|prolong the QTc interval and inhibit P-gp or BCRP may result in elevated|
03401|012|E|levels of pazopanib, signs of toxicity, and potentially life-threatening|
03401|013|E|cardiac arrhythmias, including torsades de pointes.(1)|
03401|014|B||
03401|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03401|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03401|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03401|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03401|019|P|gender, or advanced age.(2)|
03401|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03401|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03401|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03401|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03401|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03401|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03401|026|P|dysfunction).(2)|
03401|027|B||
03401|028|M|PATIENT MANAGEMENT:  The US manufacturer of pazopanib states concurrent use|
03401|029|M|of strong P-gp or BCRP inhibitors should be avoided. Use caution when|
03401|030|M|pazopanib is coadministered with other drugs known to prolong the QTc|
03401|031|M|interval.(1)|
03401|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03401|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03401|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03401|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03401|036|B||
03401|037|D|DISCUSSION:  Administration of 1,500 mg lapatinib, a substrate and weak|
03401|038|D|inhibitor of CYP3A4, P-gp, and BCRP, with 800 mg pazopanib resulted in an|
03401|039|D|approximately 50% to 60% increase in mean pazopanib area-under-curve (AUC)|
03401|040|D|and maximum concentration (Cmax) compared with administration of 800 mg|
03401|041|D|pazopanib alone.(1)|
03401|042|D|   In clinical studies, 2% (11/558) of patients receiving pazopanib|
03401|043|D|experienced QT prolongation.  Torsades de pointes occurred in less than 1%|
03401|044|D|(2/977) of patients who received pazopanib in monotherapy studies.  In a|
03401|045|D|randomized clinical trial, 3 of 290 patients who received pazopanib had|
03401|046|D|post-baseline QTc values between 500 and  549 msec.  None of the patients|
03401|047|D|receiving placebo had post-baseline QTc values greater than or equal to 500|
03401|048|D|msec.(1)|
03401|049|D|   A retrospective review of 618 cancer patients treated with 902|
03401|050|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03401|051|D|incidence of QTc prolongation.  In patients who received pazopanib, QTc|
03401|052|D|prolongation was identified in 32 (19.4%) with 18 (56.3%) having Grade 1|
03401|053|D|(QTc 450-480 ms) and 4 (12.5%) having Grade 2 (QTc 480-500 ms).  Grade 3|
03401|054|D|events occurred in 3 (9.3%) having QTc greater than or equal to 500 ms and 4|
03401|055|D|(12.5%) having QTc change greater than or equal to 60 ms.  Ventricular|
03401|056|D|tachycardia was seen in 2 (6.3%) of patients and 1 (3.1%) patient|
03401|057|D|experienced sudden cardiac death.(4)|
03401|058|D|   Agents that are P-gp or BCRP inhibitors that may cause QT prolongation|
03401|059|D|include: amiodarone, azithromycin, dronedarone, erythromycin,|
03401|060|D|hydroquinidine, lapatinib, mavorixafor, osimertinib, pacritinib,|
03401|061|D|propafenone, quinidine, ranolazine, selpercatinib, and vemurafenib.(3, 5-6)|
03401|062|B||
03401|063|R|REFERENCES:|
03401|064|B||
03401|065|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03401|066|R|  2020.|1
03401|067|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
03401|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03401|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03401|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03401|071|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03401|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03401|073|R|  settings: a scientific statement from the American Heart Association and|6
03401|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03401|075|R|  2;55(9):934-47.|6
03401|076|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03401|077|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03401|078|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03401|079|R|5.This information is based on an extract from the Certara Drug Interaction|6
03401|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03401|081|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
03401|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03401|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03401|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03401|085|R|  11/14/2017.|1
03402|001|T|MONOGRAPH TITLE:  Tamoxifen/Ribociclib|
03402|002|B||
03402|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03402|004|L|of severe adverse interaction.|
03402|005|B||
03402|006|A|MECHANISM OF ACTION:  Concurrent use of ribociclib with tamoxifen may result|
03402|007|A|in additive effects on the QTc interval.(1,2)|
03402|008|A|   Additionally, ribociclib is a strong CYP3A4 inhibitor and may increase|
03402|009|A|the plasma concentration of tamoxifen.(1)|
03402|010|B||
03402|011|E|CLINICAL EFFECTS:  The concurrent use of ribociclib with tamoxifen may|
03402|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03402|013|E|torsades de pointes.  As well, concurrent use may result in elevated levels|
03402|014|E|of and adverse effects from tamoxifen.(1)|
03402|015|B||
03402|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03402|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03402|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03402|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03402|020|P|female gender, or advanced age.(3)|
03402|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03402|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03402|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03402|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03402|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03402|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03402|027|P|dysfunction).(3)|
03402|028|B||
03402|029|M|PATIENT MANAGEMENT:  The manufacturer of ribociclib states that ribociclib|
03402|030|M|is not indicated for concomitant use with tamoxifen.(1)|
03402|031|B||
03402|032|D|DISCUSSION:  Ribociclib has been shown to prolong the QTc interval in a|
03402|033|D|concentration-dependent manner.  At steady state, the mean increase in QTc|
03402|034|D|interval exceeded 20 msec.(1)|
03402|035|D|   In a phase 3, randomized, double-blind, placebo-controlled trial|
03402|036|D|(MONALEESA-7), a QTcF interval increase of greater than 60 ms from baseline|
03402|037|D|was observed in 14/87 (16%) of patients in the ribociclib and tamoxifen|
03402|038|D|combination group, compared to 18/245 (7%) of patients receiving ribociclib|
03402|039|D|plus a non-steroidal aromatase inhibitor and 6/90 (7%) of patients receiving|
03402|040|D|tamoxifen alone.  None of the patients developed clinical symptoms or|
03402|041|D|arrhythmias.(1,2)|
03402|042|D|   In a clinical trial, ribociclib (600 mg) increased the maximum|
03402|043|D|concentration (Cmax) and area-under-curve (AUC) of tamoxifen by|
03402|044|D|approximately 2-fold.(1)|
03402|045|B||
03402|046|R|REFERENCES:|
03402|047|B||
03402|048|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
03402|049|R|  Corporation September, 2024.|1
03402|050|R|2.Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al.|2
03402|051|R|  Ribociclib plus endocrine therapy for premenopausal women with|2
03402|052|R|  hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a|2
03402|053|R|  randomised phase 3 trial. Lancet Oncol 2018 Jul;19(7):904-915.|2
03402|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03402|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03402|056|R|  settings: a scientific statement from the American Heart Association and|6
03402|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03402|058|R|  2;55(9):934-47.|6
03402|059|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03402|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03402|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03402|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03403|001|T|MONOGRAPH TITLE:  Romidepsin/Strong CYP3A4 Inhibitors that Prolong QT|
03403|002|B||
03403|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03403|004|L|of severe adverse interaction.|
03403|005|B||
03403|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03403|007|A|romidepsin.(1)|
03403|008|B||
03403|009|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
03403|010|E|in elevated levels of and toxicity from romidepsin, including prolongation|
03403|011|E|of the QT interval which may result in life-threatening arrhythmia and|
03403|012|E|death; myelosuppression including thrombocytopenia, neutropenia, lymphopenia|
03403|013|E|or anemia; serious infections; or tumor lysis syndrome.(1)|
03403|014|B||
03403|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03403|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03403|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03403|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03403|019|P|gender, or advanced age.|
03403|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03403|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03403|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03403|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03403|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03403|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03403|026|P|dysfunction).(2)|
03403|027|B||
03403|028|M|PATIENT MANAGEMENT:  The US manufacturer of romidepsin states that|
03403|029|M|appropriate cardiovascular monitoring, such as baseline and regular|
03403|030|M|monitoring of ECG and obtaining serum calcium, magnesium, and potassium|
03403|031|M|levels, should be performed if concurrent therapy with agents known to|
03403|032|M|prolong the ECG is warranted.|
03403|033|M|   Monitor for romidepsin toxicity and follow recommended dose modifications|
03403|034|M|for toxicity, if necessary, when romidepsin is initially co-administered|
03403|035|M|with strong CYP3A4 inhibitors.  Instruct patients to report any irregular|
03403|036|M|heartbeat, dizziness, or fainting episodes; unusual tiredness, shortness of|
03403|037|M|breath, paleness, unusual or unexplained bleeding or bruising; signs of|
03403|038|M|infection such as fever, cough, flu-like symptoms; burning on urination;|
03403|039|M|muscle aches; or worsening of skin problems.(1)|
03403|040|B||
03403|041|D|DISCUSSION:  In patients with advanced cancer, ketoconazole increased the|
03403|042|D|Cmax and AUC of romidepsin (8mg/m2) by 10% and 25%, respectively.(1)|
03403|043|D|   In two clinical trials, discontinuation of romidepsin secondary to QT|
03403|044|D|prolongation occurred in at least 2% of patients.(1)|
03403|045|D|   Strong inhibitors of CYP3A4 that prolong QT include:  adagrasib,|
03403|046|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib,|
03403|047|D|lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin,|
03403|048|D|and voriconazole.(3)|
03403|049|B||
03403|050|R|REFERENCES:|
03403|051|B||
03403|052|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
03403|053|R|  November, 2018.|1
03403|054|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03403|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03403|056|R|  settings: a scientific statement from the American Heart Association and|6
03403|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03403|058|R|  2;55(9):934-47.|6
03403|059|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03403|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03403|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03403|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03403|063|R|  11/14/2017.|1
03404|001|T|MONOGRAPH TITLE:  Selected SSRIs;SNRIs/Cilostazol; Ticlopidine|
03404|002|B||
03404|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03404|004|L|take action as needed.|
03404|005|B||
03404|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
03404|007|A|hemostasis.(1)  The increased risk of bleeding may be a result of a decrease|
03404|008|A|in serotonin reuptake by platelets.|
03404|009|B||
03404|010|E|CLINICAL EFFECTS:  Concurrent use of a selective serotonin reuptake|
03404|011|E|inhibitor(1-4) or a serotonin-norepinephrine reuptake inhibitor(5-7) and|
03404|012|E|agents that affect coagulation may result in bleeding.|
03404|013|B||
03404|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03404|015|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
03404|016|P|impairment has been associated with an elevated risk of GI bleed in patients|
03404|017|P|on SSRIs.(8)|
03404|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
03404|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03404|020|P|risk for bleeding (e.g. NSAIDs).|
03404|021|B||
03404|022|M|PATIENT MANAGEMENT:  Selective serotonin reuptake inhibitors(1-4) or|
03404|023|M|serotonin-norepinephrine reuptake inhibitors(5-7) and agents that affect|
03404|024|M|coagulation should be used concurrently with caution.|
03404|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03404|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03404|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03404|028|M|patients with any symptoms.|
03404|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03404|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03404|031|M|anticoagulation in patients with active pathologic bleeding.|
03404|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03404|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03404|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03404|035|M|and/or swelling.|
03404|036|B||
03404|037|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
03404|038|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03404|039|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03404|040|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03404|041|D|only based on an observed-expected ration was 4.5 and in a patient using|
03404|042|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
03404|043|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
03404|044|D|bleeding to 12.2 and 5.2, respectively.(9)|
03404|045|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
03404|046|D|in patients receiving concurrent therapy with selective serotonin reuptake|
03404|047|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
03404|048|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
03404|049|D|respectively.(10)|
03404|050|D|   In a case-control study conducted in users of acenocoumarol or|
03404|051|D|phenprocoumon, 1848 patients who had been hospitalized with abnormal|
03404|052|D|bleeding were each matched to 4 control patients.  When patients took both a|
03404|053|D|SSRI and a coumarin, an increased risk of hospitalization due to major|
03404|054|D|non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to|
03404|055|D|gastrointestinal bleeding (adjusted OR 0.8).(11)|
03404|056|D|   A retrospective review examined patients discharged from a hospital with|
03404|057|D|antiplatelet therapy following a myocardial infarction.  When compared to|
03404|058|D|aspirin therapy alone, both aspirin therapy with a SSRI and aspirin,|
03404|059|D|clopidogrel, and SSRI therapy were associated with an increased risk of|
03404|060|D|bleeding (hazard ratios 1.42 and 2.35, respectively.)  Compared with dual|
03404|061|D|antiplatelet therapy (aspirin and clopidogrel), use of aspirin and|
03404|062|D|clopidogrel and a SSRI was also associated with increased risk of bleeding|
03404|063|D|(hazard ration 1.57).(12)|
03404|064|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
03404|065|D|anticoagulation (hazard ratio 2.63).  Paroxetine was not associated with an|
03404|066|D|increased risk.  There were insufficient numbers of patients taking other|
03404|067|D|SSRIs to assess increased risk.(13)|
03404|068|B||
03404|069|R|REFERENCES:|
03404|070|B||
03404|071|R|1.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03404|072|R|  Pharmaceuticals Inc. May, 2023.|1
03404|073|R|2.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
03404|074|R|  Technologies January, 2017.|1
03404|075|R|3.Pexeva (paroxetine mesylate) US prescribing information. Noven|1
03404|076|R|  Therapeutics, LLC September, 2021.|1
03404|077|R|4.Zoloft (sertraline) US prescribing information. Pfizer Inc. August, 2023.|1
03404|078|R|5.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
03404|079|R|  Pharmaceuticals, Inc. August, 2023.|1
03404|080|R|6.Effexor XR (venlafaxine hydrochloride) US prescribing information. Viatris|1
03404|081|R|  August, 2023.|1
03404|082|R|7.Cymbalta (duloxetine hydrochloride) US prescribing information. Eli Lilly|1
03404|083|R|  and Company September, 2021.|1
03404|084|R|8.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
03404|085|R|  Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
03404|086|R|  by level of kidney function: A population-based cohort study. Br J Clin|2
03404|087|R|  Pharmacol 2018 Sep;84(9):2142-2151.|2
03404|088|R|9.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03404|089|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03404|090|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03404|091|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03404|092|R|10.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03404|093|R|   serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03404|094|R|   population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03404|095|R|11.Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding|2
03404|096|R|   risk with concurrent use of selective serotonin reuptake inhibitors and|2
03404|097|R|   coumarins. Arch Intern Med 2008 Jan 28;168(2):180-5.|2
03404|098|R|12.Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding|2
03404|099|R|   associated with combined use of selective serotonin reuptake inhibitors|2
03404|100|R|   and antiplatelet therapy following acute myocardial infarction. CMAJ 2011|2
03404|101|R|   Nov 8;183(16):1835-43.|2
03404|102|R|13.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
03404|103|R|   Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
03404|104|R|   antidepressants and the risk of overanticoagulation during acenocoumarol|2
03404|105|R|   maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
03405|001|T|MONOGRAPH TITLE:  Cannabidiol-Tetrahydrocannabinol/Strong CYP3A4 Inhibitors|
03405|002|B||
03405|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03405|004|L|take action as needed.|
03405|005|B||
03405|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03405|007|A|cannabidiol (CBD) and tetrahydrocannabinol (THC).(1,2)|
03405|008|B||
03405|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03405|010|E|in increased levels of and effects from CBD and THC, including|
03405|011|E|transaminitis, euphoria, somnolence, sedation, and dizziness.(1,2)|
03405|012|B||
03405|013|P|PREDISPOSING FACTORS:  None determined.|
03405|014|B||
03405|015|M|PATIENT MANAGEMENT:  The Canadian and Australian manufacturers of CBD-THC|
03405|016|M|spray state that a new dosage may be required if concomitant therapy with|
03405|017|M|strong CYP3A4 inhibitors is started or stopped.(1,2)|
03405|018|B||
03405|019|D|DISCUSSION:  In a study of 12 healthy volunteers who were given CBD-THC|
03405|020|D|buccal spray, ketoconazole 400 mg increased the maximum concentration (Cmax)|
03405|021|D|and area-under curve (AUC) of CBD by 2-fold and 1.9-fold, respectively, of|
03405|022|D|THC by 1.25-fold and 1.8-fold, respectively, and of 11-hydroxy-THC (a|
03405|023|D|primary THC metabolite) by 3.1-fold and 3.6-fold, respectively.(3)|
03405|024|D|   In a study of 32 healthy volunteers, steady state itraconazole (strong|
03405|025|D|inhibitor) did not affect the Cmax or AUC of oral CBD solution, but|
03405|026|D|increased the Cmax and AUC of 7-hydroxy-CBD by 6% and 17% and increased the|
03405|027|D|AUC of 7-carboxy-CBD by 12%.  Steady state fluconazole (moderate CYP3A4|
03405|028|D|inhibitor and CYP2C19 inhibitor) increased the Cmax and AUC of CBD by 24%|
03405|029|D|and 21% and decreased the Cmax and AUC of 7-hydroxy-CBD by 41% and 29% and|
03405|030|D|of 7-carboxy-CBD by 48% and 34%.(3)  The manufacturer of oral CBD solution|
03405|031|D|states that these changes are not clinically meaningful.(5)|
03405|032|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
03405|033|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03405|034|D|ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone,|
03405|035|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03405|036|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03405|037|D|tucatinib, and voriconazole.(6)|
03405|038|B||
03405|039|R|REFERENCES:|
03405|040|B||
03405|041|R|1.Sativex (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD))|1
03405|042|R|  Canadian prescribing information. GW Pharma Ltd. December 11, 2019.|1
03405|043|R|2.NanaBis (cannabidiol, tetrahydrocannabinol) Australian prescribing|1
03405|044|R|  information. Medlab Clinical LTD. November 2022.|1
03405|045|R|3.Stott C, White L, Wright S, Wilbraham D, Guy G. A Phase I, open-label,|2
03405|046|R|  randomized, crossover study in three parallel groups to evaluate the|2
03405|047|R|  effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics|2
03405|048|R|  of THC/CBD oromucosal spray in healthy volunteers. Springerplus 2013 Dec;|2
03405|049|R|  2(1):236.|2
03405|050|R|4.Patsalos PN, Szaflarski JP, Gidal B, VanLandingham K, Critchley D,|6
03405|051|R|  Morrison G. Clinical implications of trials investigating drug-drug|6
03405|052|R|  interactions between cannabidiol and enzyme inducers or inhibitors or|6
03405|053|R|  common antiseizure drugs. Epilepsia 2020 Sep 12.|6
03405|054|R|5.Epidiolex (cannabidiol) US prescribing information. Greenwich Biosciences,|1
03405|055|R|  Inc. June, 2025.|1
03405|056|R|6.This information is based on an extract from the Certara Drug Interaction|6
03405|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03406|001|T|MONOGRAPH TITLE:  Cannabidiol; Tetrahydrocannabinol/Strong CYP3A4 Inducers|
03406|002|B||
03406|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03406|004|L|take action as needed.|
03406|005|B||
03406|006|A|MECHANISM OF ACTION:  Cannabidiol (CBD) and tetrahydrocannabinol (THC) are|
03406|007|A|substrates of CYP3A4.  Strong inducers of CYP3A4 may induce the metabolism|
03406|008|A|of CBD and THC.(1)|
03406|009|B||
03406|010|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03406|011|E|may result in decreased levels and effectiveness of CBD and THC.(1)|
03406|012|B||
03406|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03406|014|P|of the inducer for longer than 1-2 weeks.|
03406|015|B||
03406|016|M|PATIENT MANAGEMENT:  The US manufacturer of CBD solution recommends|
03406|017|M|considering increasing cannabidiol dosage by up to 2-fold, based on the|
03406|018|M|patient's clinical response and tolerance, when used concurrently with a|
03406|019|M|strong CYP3A4 inducer.(1)|
03406|020|M|   The Canadian manufacturer of CBD-THC spray states that concurrent use|
03406|021|M|with strong CYP3A4 inducers should be avoided.  If concurrent therapy is|
03406|022|M|necessary, careful dose adjustment is recommended.  If the CYP3A4 inducer is|
03406|023|M|discontinued, the dose of CBD and THC may need to be lowered within the two|
03406|024|M|weeks following discontinuation of the CYP3A4 inducer.(2)|
03406|025|B||
03406|026|D|DISCUSSION:  In a study of 12 healthy volunteers, rifampin 600 mg (a strong|
03406|027|D|CYP3A4 inducer) decreased the maximum concentration (Cmax) and|
03406|028|D|area-under-curve (AUC) of CBD by 52% and 58%, respectively, of THC by 39%|
03406|029|D|and 24%, respectively, and of 11-hydroxy-THC (a primary metabolite of THC)|
03406|030|D|by 86% and 87%, respectively.(3)|
03406|031|D|   In a study in 16 healthy volunteers, a single dose of cannabidiol with|
03406|032|D|steady state rifampin decreased the Cmax and AUC of CBD by 34% and 32%,|
03406|033|D|respectively, of 7-hydroxy-CBD by 67% and 63%, and 7-carboxy-CBD by 3% and|
03406|034|D|44%.(4)|
03406|035|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03406|036|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03406|037|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03406|038|D|rifapentine, and St. John's wort.(5-6)|
03406|039|B||
03406|040|R|REFERENCES:|
03406|041|B||
03406|042|R|1.Epidiolex (cannabidiol) US prescribing information. Greenwich Biosciences,|1
03406|043|R|  Inc. June, 2025.|1
03406|044|R|2.Sativex (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD))|1
03406|045|R|  Canadian prescribing information. GW Pharma Ltd. December 11, 2019.|1
03406|046|R|3.Stott C, White L, Wright S, Wilbraham D, Guy G. A Phase I, open-label,|2
03406|047|R|  randomized, crossover study in three parallel groups to evaluate the|2
03406|048|R|  effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics|2
03406|049|R|  of THC/CBD oromucosal spray in healthy volunteers. Springerplus 2013 Dec;|2
03406|050|R|  2(1):236.|2
03406|051|R|4.Patsalos PN, Szaflarski JP, Gidal B, VanLandingham K, Critchley D,|6
03406|052|R|  Morrison G. Clinical implications of trials investigating drug-drug|6
03406|053|R|  interactions between cannabidiol and enzyme inducers or inhibitors or|6
03406|054|R|  common antiseizure drugs. Epilepsia 2020 Sep 12.|6
03406|055|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03406|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03406|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03406|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03406|059|R|  11/14/2017.|1
03406|060|R|6.This information is based on an extract from the Certara Drug Interaction|6
03406|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03407|001|T|MONOGRAPH TITLE:  Romidepsin/Selected Strong CYP3A4 Inhibitors|
03407|002|B||
03407|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03407|004|L|take action as needed.|
03407|005|B||
03407|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03407|007|A|romidepsin.(1)|
03407|008|B||
03407|009|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
03407|010|E|in elevated levels of and toxicity from romidepsin, including prolongation|
03407|011|E|of the QT interval which may result in life-threatening arrhythmia and|
03407|012|E|death; myelosuppression including thrombocytopenia, neutropenia, lymphopenia|
03407|013|E|or anemia; serious infections; or tumor lysis syndrome.(1)|
03407|014|B||
03407|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03407|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03407|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03407|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03407|019|P|female gender, or advanced age.(2)|
03407|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03407|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03407|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03407|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03407|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03407|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03407|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03407|027|B||
03407|028|M|PATIENT MANAGEMENT:  Monitor for romidepsin toxicity and follow recommended|
03407|029|M|dose modifications for toxicity, if necessary, when romidepsin is initially|
03407|030|M|co-administered with strong CYP3A4 inhibitors.(1)  Instruct patients to|
03407|031|M|report any irregular heartbeat, dizziness or fainting episodes; unusual|
03407|032|M|tiredness, shortness of breath, paleness; unusual or unexplained bleeding or|
03407|033|M|bruising; signs of infection such as fever, cough, flu-like symptoms;|
03407|034|M|burning on urination; muscles aches; or worsening of skin problems.|
03407|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03407|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03407|037|M|regular intervals.  Correct any electrolyte abnormalities.|
03407|038|B||
03407|039|D|DISCUSSION:  In patients with advanced cancer, ketoconazole increased the|
03407|040|D|Cmax and AUC of romidepsin (8 mg/m2) by 10% and 25%, respectively.(1)|
03407|041|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, idelalisib,|
03407|042|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03407|043|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03407|044|D|tipranavir, troleandomycin, and tucatinib.(3,4)|
03407|045|B||
03407|046|R|REFERENCES:|
03407|047|B||
03407|048|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
03407|049|R|  November, 2018.|1
03407|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03407|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03407|052|R|  settings: a scientific statement from the American Heart Association and|6
03407|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03407|054|R|  2;55(9):934-47.|6
03407|055|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03407|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03407|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03407|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03407|059|R|  11/14/2017.|1
03407|060|R|4.This information is based on an extract from the Certara Drug Interaction|6
03407|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03408|001|T|MONOGRAPH TITLE:  Dabigatran/Cobicistat|
03408|002|B||
03408|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03408|004|L|is contraindicated and generally should not be dispensed or administered to|
03408|005|L|the same patient.|
03408|006|B||
03408|007|A|MECHANISM OF ACTION:  Dabigatran etexilate is a substrate for the|
03408|008|A|P-glycoprotein (P-gp) system.  Cobicistat may inhibit intestinal P-gp,|
03408|009|A|leading to increased absorption of dabigatran.(1-4)|
03408|010|B||
03408|011|E|CLINICAL EFFECTS:  The concurrent use of dabigatran with cobicistat may lead|
03408|012|E|to elevated plasma levels of dabigatran, increasing the risk for bleeding.|
03408|013|B||
03408|014|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
03408|015|P|bleeding include renal impairment, patient age >74 years, coexisting|
03408|016|P|conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated|
03408|017|P|with bleeding risk, and patient weight < 50 kg.(1-2)|
03408|018|B||
03408|019|M|PATIENT MANAGEMENT:  The UK manufacturers of products containing cobicistat|
03408|020|M|state that dabigatran is contraindicated with cobicistat-containing|
03408|021|M|products.(4-7)|
03408|022|M|   The US manufacturers of cobicistat(3) and of the combination products|
03408|023|M|containing atazanavir-cobicistat(8) and elvitegravir-cobicistat(9) state|
03408|024|M|that dosing recommendations for dabigatran depend on indication and renal|
03408|025|M|function.  If coadministration is necessary, assess renal function and|
03408|026|M|evaluate the patient for other pre-existing risk factors for bleeding prior|
03408|027|M|to initiating concomitant therapy.  The combination of dabigatran and|
03408|028|M|cobicistat should be avoided in atrial fibrillation patients with severe|
03408|029|M|renal impairment (CrCl less than 30 ml/min) and in patients with moderate|
03408|030|M|renal impairment (CrCl less than 50 ml/min) being treated for or undergoing|
03408|031|M|prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE).|
03408|032|M|   The US manufacturer of the combination of darunavir-cobicistat states|
03408|033|M|that concurrent use with dabigatran should be monitored closely.  Refer to|
03408|034|M|dabigatran prescribing information for specific recommendations depending on|
03408|035|M|the indication for dabigatran and patient's renal function.(10)  The US|
03408|036|M|Department of Health and Human Services guidelines for the use of|
03408|037|M|antiretroviral agents in HIV state that there is no data on the concomitant|
03408|038|M|use of darunavir-cobicistat with dabigatran, and alternative agents should|
03408|039|M|be considered.(11)|
03408|040|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
03408|041|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
03408|042|M|and/or decreased blood pressure and promptly evaluate patients with any|
03408|043|M|symptoms.  Consider regular monitoring of hemoglobin, platelet levels,|
03408|044|M|and/or activated partial thromboplastin time (aPTT) or ecarin clotting time|
03408|045|M|(ECT).|
03408|046|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03408|047|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03408|048|M|anticoagulation in patients with active pathologic bleeding.|
03408|049|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03408|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03408|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03408|052|M|and/or swelling.|
03408|053|B||
03408|054|D|DISCUSSION:  In healthy volunteers, simultaneous administration and|
03408|055|D|separation of administration by 2 hours of cobicistat (150 mg daily) with|
03408|056|D|dabigatran (150 mg single dose) increased dabigatran area-under-curve (AUC)|
03408|057|D|by 127% and 110%, respectively.  Thrombin time (TT) at 24 hours|
03408|058|D|post-dabigatran dose was also increased with simultaneous and separation of|
03408|059|D|dose by 2 hours by 51% and 46%, respectively.(12)|
03408|060|D|   In healthy volunteers, a single dose of darunavir 800 mg-cobicistat 150|
03408|061|D|mg daily increased dabigatran maximum concentration (Cmax) by 2.64-fold and|
03408|062|D|AUC by 2.64-fold. In healthy volunteers, darunavir 800 mg-cobicistat 150 mg|
03408|063|D|daily (administered for 14 days before dabigatran) increased dabigatran Cmax|
03408|064|D|by 1.99-fold and AUC by 1.88-fold.(10)|
03408|065|B||
03408|066|R|REFERENCES:|
03408|067|B||
03408|068|R|1.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
03408|069|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
03408|070|R|2.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
03408|071|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
03408|072|R|3.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
03408|073|R|  June, 2025.|1
03408|074|R|4.Tybost (cobicistat) EMA summary of product characteristics. Gilead|1
03408|075|R|  Sciences Limited May, 2014.|1
03408|076|R|5.Evotaz (atazanavir and cobicistat) UK summary of product characteristics.|1
03408|077|R|  Bristol-Myers-Squibb Company March, 2016.|1
03408|078|R|6.Rezolsta (darunavir/cobicistat) UK summary of product characteristics.|1
03408|079|R|  Janssen Pharmaceuticals Inc. March, 2016.|1
03408|080|R|7.Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir) UK summary of|1
03408|081|R|  product characteristics. Gilead Sciences, Inc March, 2016.|1
03408|082|R|8.Evotaz (atazanavir and cobicistat) US prescribing information.|1
03408|083|R|  Bristol-Myers-Squibb Company May, 2025.|1
03408|084|R|9.Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
03408|085|R|  prescribing information. Gilead Sciences, Inc September, 2021.|1
03408|086|R|10.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
03408|087|R|   Pharmaceuticals, Inc. March, 2025.|1
03408|088|R|11.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03408|089|R|   for the use of antiretroviral agents in adults and adolescents Living|6
03408|090|R|   with HIV. Department of Health and Human Services. Available at|6
03408|091|R|   https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats|6
03408|092|R|   -new-guidelines June 13, 2021.|6
03408|093|R|12.Gordon LA, Kumar P, Brooks KM, Kellogg A, McManus M, Alfaro RM, Nghiem K,|2
03408|094|R|   George JM, Lozier J, Penzak SR, Hadigan C. Antiretroviral Boosting Agent|2
03408|095|R|   Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant|2
03408|096|R|   Effect of Dabigatran in HIV-Negative Healthy Volunteers. Circulation 2016|2
03408|097|R|   Dec 06;134(23):1909-1911.|2
03409|001|T|MONOGRAPH TITLE:  Nimodipine/Strong CYP3A4 Inhibitors|
03409|002|B||
03409|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03409|004|L|of severe adverse interaction.|
03409|005|B||
03409|006|A|MECHANISM OF ACTION:  Nimodipine is metabolized by CYP3A4.  Strong|
03409|007|A|inhibitors of CYP3A4 may decrease the metabolism of nimodipine.(1-3)|
03409|008|B||
03409|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
03409|010|E|increased levels of and toxicity from nimodipine.(1-3)|
03409|011|B||
03409|012|P|PREDISPOSING FACTORS:  None determined.|
03409|013|B||
03409|014|M|PATIENT MANAGEMENT:  The US manufacturer of nimodipine capsules states that|
03409|015|M|the concurrent use of strong CYP3A4 inhibitors is contraindicated due to the|
03409|016|M|risk of significant hypotension.(1)  The US manufacturer of nimodipine|
03409|017|M|solution states that strong CYP3A4 inhibitors should generally be|
03409|018|M|avoided.(2)|
03409|019|M|   The US manufacturers of some strong CYP3A4 inhibitors, including|
03409|020|M|cobicistat(4) and ritonavir,(5) state that concurrent use of CYP3A4|
03409|021|M|substrates for which increased levels may cause serious or life-threatening|
03409|022|M|events are contraindicated.|
03409|023|M|   If coadministration is necessary, monitor the patient closely and adjust|
03409|024|M|the dose of nimodipine as needed.(3)|
03409|025|B||
03409|026|D|DISCUSSION:  In 7 healthy volunteers, cimetidine (a moderate CYP3A4|
03409|027|D|inhibitor) 200 mg 3 times daily with meals and 400 mg at bedtime increased|
03409|028|D|the area-under-curve (AUC) and maximum concentration (Cmax) of nimodipine|
03409|029|D|(30 mg 3 times daily) by 82% and 54%, respectively.  There was no change in|
03409|030|D|blood pressure, heart rate, or tolerability of nimodipine, and no dose|
03409|031|D|adjustment was required.(6)  The combination of nimodipine with strong|
03409|032|D|CYP3A4 inhibitors has not been studied, but a more marked effect is|
03409|033|D|expected.|
03409|034|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03409|035|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03409|036|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03409|037|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03409|038|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03409|039|D|troleandomycin, tucatinib, and voriconazole.(7-8)|
03409|040|B||
03409|041|R|REFERENCES:|
03409|042|B||
03409|043|R|1.Nimodipine capsule US prescribing information. BIONPHARMA INC. January,|1
03409|044|R|  2020.|1
03409|045|R|2.Nymalize (nimodipine) solution US prescribing information. Arbor|1
03409|046|R|  Pharmaceuticals April, 2020.|1
03409|047|R|3.Nimotop (nimodipine) Canadian prescribing information. Bayer Inc. November|1
03409|048|R|  2011.|1
03409|049|R|4.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
03409|050|R|  June, 2025.|1
03409|051|R|5.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
03409|052|R|  December, 2019.|1
03409|053|R|6.Muck W, Wingender W, Seiberling M, Woelke E, Ramsch KD, Kuhlmann J.|2
03409|054|R|  Influence of the H2-receptor antagonists cimetidine and ranitidine on the|2
03409|055|R|  pharmacokinetics of nimodipine in healthy volunteers. Eur J Clin Pharmacol|2
03409|056|R|  1992;42(3):325-8.|2
03409|057|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
03409|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03409|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03409|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03409|061|R|  11/14/2017.|1
03409|062|R|8.This information is based on an extract from the Certara Drug Interaction|6
03409|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03410|001|T|MONOGRAPH TITLE:  Clozapine/Anticholinergics|
03410|002|B||
03410|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03410|004|L|of severe adverse interaction.|
03410|005|B||
03410|006|A|MECHANISM OF ACTION:  Clozapine has potent anticholinergic properties and|
03410|007|A|inhibits serotonin receptors, including 5-HT3.(1-4)  Both of these|
03410|008|A|properties may cause inhibition of gastrointestinal (GI) smooth muscle|
03410|009|A|contraction, resulting in decreased peristalsis.(3,4)  These effects may be|
03410|010|A|compounded by concurrent use of anticholinergic agents.(1-6)|
03410|011|B||
03410|012|E|CLINICAL EFFECTS:  Concurrent use of clozapine with other anticholinergic|
03410|013|E|agents may increase the risk of constipation (common) and serious bowel|
03410|014|E|complications (uncommon), including complete bowel obstruction, fecal|
03410|015|E|impaction, paralytic ileus and intestinal ischemia or infarction.(1-6)|
03410|016|B||
03410|017|P|PREDISPOSING FACTORS:  The risk for serious bowel complications is higher|
03410|018|P|with increasing age, higher frequency of constipation, and in patients on|
03410|019|P|higher doses of clozapine or multiple anticholinergic agents.(1,5)|
03410|020|B||
03410|021|M|PATIENT MANAGEMENT:  Avoid the use of other anticholinergic agents with|
03410|022|M|clozapine.(1-6)  If concurrent use is necessary, evaluate the patient's|
03410|023|M|bowel function regularly.  Monitor for symptoms of constipation and GI|
03410|024|M|hypomotility, including having bowel movements less than three times weekly|
03410|025|M|or less than usual, difficulty having a bowel movement or passing gas,|
03410|026|M|nausea, vomiting, and abdominal pain or distention.(2)|
03410|027|M|   Consider a prophylactic laxative in those with a history of constipation|
03410|028|M|or bowel obstruction.(2)  Review patient medication list for other|
03410|029|M|anticholinergic agents.  When possible, decrease the dosage or number of|
03410|030|M|prescribed anticholinergic agents, particularly in the elderly.|
03410|031|M|   Counsel the patient about the importance of maintaining adequate|
03410|032|M|hydration.  Encourage regular exercise and eating a high-fiber diet.(2)|
03410|033|B||
03410|034|D|DISCUSSION:  In a prospective cohort study of 26,720 schizophrenic patients|
03410|035|D|in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for|
03410|036|D|ileus was 1.99 with clozapine and 1.48 with anticholinergics.  The OR for|
03410|037|D|fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics.  Use of|
03410|038|D|anticholinergics with 1st generation antipsychotics (FGA) increased the risk|
03410|039|D|of ileus compare to FGA alone, but this analysis was not done with|
03410|040|D|clozapine.(5)|
03410|041|D|   A retrospective cohort study of 24,970 schizophrenic patients from the|
03410|042|D|Taiwanese National Health Insurance Research Database found that the hazard|
03410|043|D|ratio (HR) for clozapine-induced constipation increased from 1.64 when|
03410|044|D|clozapine is used alone, to 2.15 when used concomitantly with|
03410|045|D|anticholinergics.  However, there was no significant difference in the HR|
03410|046|D|for ileus when clozapine is used with and without anticholinergics (1.95 and|
03410|047|D|2.02, respectively).(6)|
03410|048|D|   In the French Pharmacovigilance Database, 7 of 38 cases of|
03410|049|D|antipsychotic-associated ischemic colitis or intestinal necrosis involved|
03410|050|D|clozapine, and 5 of these cases involved use of concomitant anticholinergic|
03410|051|D|agents.  Three patients died, one of whom was on concomitant|
03410|052|D|anticholinergics.(3)|
03410|053|D|   In a case series, 4 of 9 cases of fatal clozapine-associated GI|
03410|054|D|dysfunction involved concurrent anticholinergic agents.(4)|
03410|055|B||
03410|056|R|REFERENCES:|
03410|057|B||
03410|058|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03410|059|R|  Pharmaceuticals Corporation April, 2020.|1
03410|060|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA|6
03410|061|R|  strengthens warning that untreated constipation caused by schizophrenia|6
03410|062|R|  medicine clozapine (Clozaril) can lead to serious bowel problems.|6
03410|063|R|  Available at:|6
03410|064|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-strengthens-war|6
03410|065|R|  ning-untreated-constipation-caused-schizophrenia-medicine-clozapine-clozar|6
03410|066|R|  il-can February 18, 2020.|6
03410|067|R|3.Peyriere H, Roux C, Ferard C, Deleau N, Kreft-Jais C, Hillaire-Buys D,|6
03410|068|R|  Boulenger JP, Blayac JP. Antipsychotics-induced ischaemic colitis and|6
03410|069|R|  gastrointestinal necrosis: a review  of the French pharmacovigilance|6
03410|070|R|  database. Pharmacoepidemiol Drug Saf 2009 Oct;18(10):948-55.|6
03410|071|R|4.Hibbard KR, Propst A, Frank DE, Wyse J. Fatalities associated with|3
03410|072|R|  clozapine-related constipation and bowel obstruction:  a literature review|3
03410|073|R|  and two case reports. Psychosomatics 2009 Jul-Aug;50(4):416-9.|3
03410|074|R|5.Nielsen J, Meyer JM. Risk factors for ileus in patients with|2
03410|075|R|  schizophrenia. Schizophr Bull 2012 May;38(3):592-8.|2
03410|076|R|6.Chen HK, Hsieh CJ. Risk of gastrointestinal Hypomotility in schizophrenia|2
03410|077|R|  and schizoaffective disorder treated with antipsychotics: A retrospective|2
03410|078|R|  cohort study. Schizophr Res 2018 May;195:237-244.|2
03411|001|T|MONOGRAPH TITLE:  Pravastatin (Greater Than 40 mg); Simvastatin (Greater|
03411|002|T|Than 20 mg)/Bempedoic Acid|
03411|003|B||
03411|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03411|005|L|is contraindicated and generally should not be dispensed or administered to|
03411|006|L|the same patient.|
03411|007|B||
03411|008|A|MECHANISM OF ACTION:  Bempedoic acid weakly inhibits OATP1B1.(1) Pravastatin|
03411|009|A|and simvastatin are substrates for OATP1B1 transport.(2,3)  OATP transport|
03411|010|A|inhibition may decrease influx of substrates from the blood into hepatocytes|
03411|011|A|and decrease hepatic elimination.|
03411|012|B||
03411|013|E|CLINICAL EFFECTS:  Transport inhibition may lead to higher plasma|
03411|014|E|concentrations of pravastatin or simvastatin, increasing the risk for|
03411|015|E|statin-induced myopathy or rhabdomyolysis.(1)|
03411|016|B||
03411|017|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03411|018|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03411|019|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03411|020|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03411|021|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03411|022|P|transporter OATP1B1 may have increased statin concentrations and be|
03411|023|P|predisposed to myopathy or rhabdomyolysis.|
03411|024|B||
03411|025|M|PATIENT MANAGEMENT:  The manufacturer of bempedoic acid recommends avoiding|
03411|026|M|concomitant use of pravastatin doses greater than 40 mg and simvastatin|
03411|027|M|doses greater than 20 mg.(1) Instruct patients to report unexplained muscle|
03411|028|M|pain, tenderness, weakness, or dark, cola-colored urine.|
03411|029|B||
03411|030|D|DISCUSSION:  In healthy volunteers, bempedoic acid (240 mg daily) increased|
03411|031|D|the area-under-curve (AUC) and maximum concentration (Cmax) of pravastatin|
03411|032|D|40 mg both by 2-fold. Bempedoic acid 240 mg daily given with simvastatin 20|
03411|033|D|mg and bempedoic acid 180 mg daily given with simvastatin 40 mg both|
03411|034|D|increased the AUC and Cmax of simvastatin by 2-fold and 1.5-fold,|
03411|035|D|respectively.(1)|
03411|036|B||
03411|037|R|REFERENCES:|
03411|038|B||
03411|039|R|1.Nexletol (bempedoic acid) US prescribing information. Esperion|1
03411|040|R|  Therapeutics, Inc. March, 2024.|1
03411|041|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03411|042|R|  2023.|1
03411|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
03411|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03412|001|T|MONOGRAPH TITLE:  Pravastatin (Less Than or Equal To 40 mg); Simvastatin|
03412|002|T|(Less Than or Equal To 20 mg)/Bempedoic Acid|
03412|003|B||
03412|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03412|005|L|take action as needed.|
03412|006|B||
03412|007|A|MECHANISM OF ACTION:  Bempedoic acid weakly inhibits OATP1B1.(1) Pravastatin|
03412|008|A|and simvastatin are substrates for OATP1B1 transport.(2,3)  OATP transport|
03412|009|A|inhibition may decrease influx of substrates from the blood into hepatocytes|
03412|010|A|and decrease hepatic elimination.|
03412|011|B||
03412|012|E|CLINICAL EFFECTS:  Transport inhibition may lead to higher plasma|
03412|013|E|concentrations of pravastatin or simvastatin, increasing the risk for|
03412|014|E|statin-induced myopathy or rhabdomyolysis.(1)|
03412|015|B||
03412|016|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03412|017|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03412|018|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03412|019|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03412|020|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03412|021|P|transporter OATP1B1 may have increased statin concentrations and be|
03412|022|P|predisposed to myopathy or rhabdomyolysis.|
03412|023|B||
03412|024|M|PATIENT MANAGEMENT:  The manufacturer of bempedoic acid recommends avoiding|
03412|025|M|concomitant use of pravastatin doses greater than 40 mg and simvastatin|
03412|026|M|doses greater than 20 mg.(1) Instruct patients to report unexplained muscle|
03412|027|M|pain, tenderness, weakness, or dark, cola-colored urine.|
03412|028|B||
03412|029|D|DISCUSSION:  In healthy volunteers, bempedoic acid (240 mg daily) increased|
03412|030|D|the area-under-curve (AUC) and maximum concentration (Cmax) of pravastatin|
03412|031|D|40 mg both by 2-fold. Bempedoic acid 240 mg daily given with simvastatin 20|
03412|032|D|mg and bempedoic acid 180 mg daily given with simvastatin 40 mg both|
03412|033|D|increased the AUC and Cmax of simvastatin by 2-fold and 1.5-fold,|
03412|034|D|respectively.(1)|
03412|035|B||
03412|036|R|REFERENCES:|
03412|037|B||
03412|038|R|1.Nexletol (bempedoic acid) US prescribing information. Esperion|1
03412|039|R|  Therapeutics, Inc. March, 2024.|1
03412|040|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03412|041|R|  2023.|1
03412|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
03412|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03413|001|T|MONOGRAPH TITLE:  Rimegepant/Strong CYP3A4 Inhibitors|
03413|002|B||
03413|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03413|004|L|of severe adverse interaction.|
03413|005|B||
03413|006|A|MECHANISM OF ACTION:  Rimegepant is primarily metabolized by CYP3A4.  Strong|
03413|007|A|inhibitors of CYP3A4 may decrease the metabolism of rimegepant.(1)|
03413|008|B||
03413|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
03413|010|E|increased levels of and toxicity from rimegepant.(1)|
03413|011|B||
03413|012|P|PREDISPOSING FACTORS:  None determined.|
03413|013|B||
03413|014|M|PATIENT MANAGEMENT:  The US manufacturer of rimegepant recommends avoiding|
03413|015|M|concomitant use of agents that are strong CYP3A4 inhibitors due to a|
03413|016|M|significant increase in exposure to rimegepant.(1)|
03413|017|B||
03413|018|D|DISCUSSION:  In a drug interaction study, itraconazole, a strong CYP3A4|
03413|019|D|inhibitor, increased the area-under-curve (AUC) and maximum concentration|
03413|020|D|(Cmax) of rimegepant (75 mg) by 4-fold and 1.5-fold, respectively.(1)|
03413|021|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03413|022|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03413|023|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03413|024|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03413|025|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03413|026|D|tucatinib, and voriconazole.(2-3)|
03413|027|B||
03413|028|R|REFERENCES:|
03413|029|B||
03413|030|R|1.Nurtec ODT (rimegepant) US prescribing information. Biohaven|1
03413|031|R|  Pharmaceuticals, Inc. December, 2021.|1
03413|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03413|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03413|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03413|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03413|036|R|  11/14/2017.|1
03413|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
03413|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03414|001|T|MONOGRAPH TITLE:  Rimegepant/Moderate CYP3A4 Inhibitors|
03414|002|B||
03414|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03414|004|L|take action as needed.|
03414|005|B||
03414|006|A|MECHANISM OF ACTION:  Rimegepant is primarily metabolized by CYP3A4.|
03414|007|A|Moderate inhibitors of CYP3A4 may decrease the metabolism of rimegepant.(1)|
03414|008|B||
03414|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
03414|010|E|in increased levels of and toxicity from rimegepant.(1)|
03414|011|B||
03414|012|P|PREDISPOSING FACTORS:  None determined.|
03414|013|B||
03414|014|M|PATIENT MANAGEMENT:  The US manufacturer of rimegepant recommends avoiding a|
03414|015|M|second dose of rimegepant within 48 hours of a first dose when used|
03414|016|M|concomitantly with moderate CYP3A4 inhibitors.(1)|
03414|017|B||
03414|018|D|DISCUSSION:  In a drug interaction study (n=23), fluconazole, a moderate|
03414|019|D|CYP3A4 inhibitor, increased rimegepant mean area-under-curve from time 0 to|
03414|020|D|infinity (AUC 0-inf) by 1.8-fold (90% confidence interval 1.68-1.93), with|
03414|021|D|no impact on the maximum concentration (Cmax) (1.04-fold; 90% CI 0.94-1.15).|
03414|022|D|(2)|
03414|023|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
03414|024|D|atazanavir, avacopan, clofazimine, conivaptan, crizotinib, darunavir,|
03414|025|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03414|026|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
03414|027|D|lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra,|
03414|028|D|stiripentol, tofisopam, and treosulfan.(3-4)|
03414|029|B||
03414|030|R|REFERENCES:|
03414|031|B||
03414|032|R|1.Nurtec ODT (rimegepant) US prescribing information. Biohaven|1
03414|033|R|  Pharmaceuticals, Inc. December, 2021.|1
03414|034|R|2.Bhardwaj R, Morris B, Matschke KT, Bertz R, Croop R, Liu J.|2
03414|035|R|  Characterization of rimegepant drug-drug interactions using the cytochrome|2
03414|036|R|  P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam.|2
03414|037|R|  Headache: The Journal of Head and Face Pain July 2024;00:1-12.|2
03414|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03414|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03414|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03414|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03414|042|R|  11/14/2017.|1
03414|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
03414|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03415|001|T|MONOGRAPH TITLE:  Rimegepant/Strong and Moderate CYP3A4 Inducers|
03415|002|B||
03415|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03415|004|L|of severe adverse interaction.|
03415|005|B||
03415|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03415|007|A|metabolism of rimegepant by CYP3A4.(1)|
03415|008|B||
03415|009|E|CLINICAL EFFECTS:  The concurrent use of strong and moderate CYP3A4 inducers|
03415|010|E|and rimegepant may result in decreased levels and clinical effectiveness of|
03415|011|E|rimegepant.(1)|
03415|012|B||
03415|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03415|014|P|of the inducer for longer than 1-2 weeks.|
03415|015|B||
03415|016|M|PATIENT MANAGEMENT:  The manufacturer of rimegepant recommends avoiding|
03415|017|M|concurrent use with strong or moderate CYP3A4 inducers due to potential|
03415|018|M|decrease in exposure to rimegepant and loss of efficacy.(1)|
03415|019|M|   Patients receiving concurrent therapy with strong and moderate CYP3A4|
03415|020|M|inducers and rimegepant should be observed for decreased clinical|
03415|021|M|effectiveness.|
03415|022|B||
03415|023|D|DISCUSSION:  In a drug interaction study, rifampin, a strong CYP3A4 inducer,|
03415|024|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03415|025|D|rimegepant (75 mg) by 80% and 64%, respectively.(1)|
03415|026|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
03415|027|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
03415|028|D|dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine,|
03415|029|D|fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten,|
03415|030|D|mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib,|
03415|031|D|phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin,|
03415|032|D|rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and|
03415|033|D|tovorafenib.(1,2)|
03415|034|B||
03415|035|R|REFERENCES:|
03415|036|B||
03415|037|R|1.Nurtec ODT (rimegepant) US prescribing information. Biohaven|1
03415|038|R|  Pharmaceuticals, Inc. December, 2021.|1
03415|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
03415|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03416|001|T|MONOGRAPH TITLE:  Clozapine/Anticholinergics that Prolong QT|
03416|002|B||
03416|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03416|004|L|of severe adverse interaction.|
03416|005|B||
03416|006|A|MECHANISM OF ACTION:  Concurrent use of clozapine with anticholinergic|
03416|007|A|agents that prolong the QTc interval may result in additive effects on the|
03416|008|A|QTc interval and increased risk of anticholinergic toxicity.(1)|
03416|009|A|   In particular, the anticholinergic agents may compound the|
03416|010|A|anticholinergic and anti-serotonergic effects of clozapine to inhibit|
03416|011|A|gastrointestinal (GI) smooth muscle contraction, resulting in decreased|
03416|012|A|peristalsis.(1-6)|
03416|013|B||
03416|014|E|CLINICAL EFFECTS:  The use of clozapine in patients maintained on agents|
03416|015|E|that prolong the QTc interval may result in potentially life-threatening|
03416|016|E|cardiac arrhythmias, including torsades de pointes.(1)|
03416|017|E|   Concurrent use of clozapine with anticholinergic agents may increase the|
03416|018|E|risk of  constipation (common) and serious bowel complications (uncommon),|
03416|019|E|including complete bowel obstruction, fecal impaction, paralytic ileus and|
03416|020|E|intestinal ischemia or infarction.(1-6)|
03416|021|B||
03416|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03416|023|P|may be increased in patients with cardiovascular disease (e.g. heart|
03416|024|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03416|025|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03416|026|P|female gender, or advanced age.(7)|
03416|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03416|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03416|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03416|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03416|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03416|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03416|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)|
03416|034|P|   The risk for serious bowel complications is higher with increasing age|
03416|035|P|and in patients on multiple anticholinergic agents.(5)|
03416|036|B||
03416|037|M|PATIENT MANAGEMENT:  Avoid the use of other QT-prolonging anticholinergic|
03416|038|M|agents with clozapine.  If concurrent therapy is necessary, approach the use|
03416|039|M|of this combination with caution.(1)|
03416|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03416|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03416|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03416|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03416|044|M|   In addition, evaluate the patient's bowel function regularly.  Monitor|
03416|045|M|for symptoms of constipation and GI hypomotility, including having bowel|
03416|046|M|movements less than three times weekly or less than usual, difficulty having|
03416|047|M|a bowel movement or passing gas, nausea, vomiting, and abdominal pain or|
03416|048|M|distention.(2)|
03416|049|M|   Consider a prophylactic laxative in those with a history of constipation|
03416|050|M|or bowel obstruction.(2)  Review patient medication list for other|
03416|051|M|anticholinergic agents.  When possible, decrease the dosage or number of|
03416|052|M|prescribed anticholinergic agents, particularly in the elderly.|
03416|053|M|   Counsel the patient about the importance of maintaining adequate|
03416|054|M|hydration.  Encourage regular exercise and eating a high-fiber diet.(2)|
03416|055|B||
03416|056|D|DISCUSSION:  Treatment with clozapine has been associated with QT|
03416|057|D|prolongation as well as ventricular arrhythmia, Torsades de Pointes, cardiac|
03416|058|D|arrest, and sudden death.(1)|
03416|059|D|   Agents that are linked to this monograph may have varying degrees of|
03416|060|D|potential to prolong the QTc interval but are generally accepted to have a|
03416|061|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03416|062|D|been shown to prolong the QTc interval either through their mechanism of|
03416|063|D|action, through studies on their effects on the QTc interval, or through|
03416|064|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03416|065|D|and/or post-marketing reports.(8)|
03416|066|D|   In a prospective cohort study of 26,720 schizophrenic patients in the|
03416|067|D|Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus|
03416|068|D|was 1.99 with clozapine and 1.48 with anticholinergics.  The OR for fatal|
03416|069|D|ileus was 6.73 with clozapine and 5.88 with anticholinergics.  Use of|
03416|070|D|anticholinergics with 1st generation antipsychotics (FGA) increased the risk|
03416|071|D|of ileus compare to FGA alone, but this analysis was not done with|
03416|072|D|clozapine.(5)|
03416|073|D|   A retrospective cohort study of 24,970 schizophrenic patients from the|
03416|074|D|Taiwanese National Health Insurance Research Database found that the hazard|
03416|075|D|ratio (HR) for clozapine-induced constipation increased from 1.64 when|
03416|076|D|clozapine is used alone, to 2.15 when used concomitantly with|
03416|077|D|anticholinergics.  However, there was no significant difference in the HR|
03416|078|D|for ileus when clozapine is used with and without anticholinergics (1.95 and|
03416|079|D|2.02, respectively).(6)|
03416|080|D|   In the French Pharmacovigilance Database, 7 of 38 cases of|
03416|081|D|antipsychotic-associated ischemic colitis or intestinal necrosis involved|
03416|082|D|clozapine, and 5 of these cases involved use of concomitant anticholinergic|
03416|083|D|agents.  Three patients died, one of whom was on concomitant|
03416|084|D|anticholinergics.(3)|
03416|085|D|   In a case series, 4 of 9 cases of fatal clozapine-associated GI|
03416|086|D|dysfunction involved concurrent anticholinergic agents.(4)|
03416|087|B||
03416|088|R|REFERENCES:|
03416|089|B||
03416|090|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03416|091|R|  Pharmaceuticals Corporation April, 2020.|1
03416|092|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA|6
03416|093|R|  strengthens warning that untreated constipation caused by schizophrenia|6
03416|094|R|  medicine clozapine (Clozaril) can lead to serious bowel problems.|6
03416|095|R|  Available at:|6
03416|096|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-strengthens-war|6
03416|097|R|  ning-untreated-constipation-caused-schizophrenia-medicine-clozapine-clozar|6
03416|098|R|  il-can February 18, 2020.|6
03416|099|R|3.Peyriere H, Roux C, Ferard C, Deleau N, Kreft-Jais C, Hillaire-Buys D,|6
03416|100|R|  Boulenger JP, Blayac JP. Antipsychotics-induced ischaemic colitis and|6
03416|101|R|  gastrointestinal necrosis: a review  of the French pharmacovigilance|6
03416|102|R|  database. Pharmacoepidemiol Drug Saf 2009 Oct;18(10):948-55.|6
03416|103|R|4.Hibbard KR, Propst A, Frank DE, Wyse J. Fatalities associated with|3
03416|104|R|  clozapine-related constipation and bowel obstruction:  a literature review|3
03416|105|R|  and two case reports. Psychosomatics 2009 Jul-Aug;50(4):416-9.|3
03416|106|R|5.Nielsen J, Meyer JM. Risk factors for ileus in patients with|2
03416|107|R|  schizophrenia. Schizophr Bull 2012 May;38(3):592-8.|2
03416|108|R|6.Chen HK, Hsieh CJ. Risk of gastrointestinal Hypomotility in schizophrenia|2
03416|109|R|  and schizoaffective disorder treated with antipsychotics: A retrospective|2
03416|110|R|  cohort study. Schizophr Res 2018 May;195:237-244.|2
03416|111|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03416|112|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03416|113|R|  settings: a scientific statement from the American Heart Association and|6
03416|114|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03416|115|R|  2;55(9):934-47.|6
03416|116|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
03416|117|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03416|118|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03416|119|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03417|001|T|MONOGRAPH TITLE:  Clozapine/Carbamazepine|
03417|002|B||
03417|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03417|004|L|of severe adverse interaction.|
03417|005|B||
03417|006|A|MECHANISM OF ACTION:  While clozapine is primarily metabolized by CYP1A2,|
03417|007|A|CYP3A4 also plays a role.  Carbamazepine induces both of these metabolic|
03417|008|A|pathways.|
03417|009|A|   In addition, due to its anticholinergic activity, carbamazepine may|
03417|010|A|compound the anticholinergic and anti-serotonergic effects of clozapine to|
03417|011|A|inhibit gastrointestinal (GI) smooth muscle contraction, resulting in|
03417|012|A|decreased peristalsis.(1-6)|
03417|013|B||
03417|014|E|CLINICAL EFFECTS:  Concomitant administration may result in decreased|
03417|015|E|concentration and effectiveness of clozapine.|
03417|016|E|   Additionally, concomitant administration of carbamazepine and clozapine|
03417|017|E|may increase the risk for neutropenia or agranulocytosis,(7) as well as the|
03417|018|E|risk of constipation (common) and serious bowel complications (uncommon),|
03417|019|E|including complete bowel obstruction, fecal impaction, paralytic ileus and|
03417|020|E|intestinal ischemia or infarction.(1-6)|
03417|021|B||
03417|022|P|PREDISPOSING FACTORS:  Low white blood counts prior to initiation of the|
03417|023|P|myelosuppressive agents may increase risk for clinically significant|
03417|024|P|neutropenia.|
03417|025|P|   The risk for serious bowel complications is higher with increasing age|
03417|026|P|and in patients on multiple anticholinergic agents.(5)|
03417|027|B||
03417|028|M|PATIENT MANAGEMENT:  The manufacturer of clozapine states that clozapine|
03417|029|M|should not be used concurrently with agents known to cause agranulocytosis|
03417|030|M|because of the possibility of synergistic effects on the risk and/or|
03417|031|M|severity of bone marrow suppression.(1)  If concurrent therapy of clozapine|
03417|032|M|with carbamazepine is required, close monitoring for increased clozapine|
03417|033|M|toxicity and decreased clozapine efficacy is needed.|
03417|034|M|   Hematological effects:|
03417|035|M|   More frequent ANC monitoring or treatment alternatives secondary to|
03417|036|M|neutropenic episodes may need to be considered.|
03417|037|M|   Clozapine is only available through a restricted distribution system|
03417|038|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
03417|039|M|dispensing.(1,8)  For most clozapine patients, clozapine treatment must be|
03417|040|M|interrupted for a suspected clozapine-induced ANC < 1,000 cells/microliter.|
03417|041|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
03417|042|M|interrupted for suspected clozapine-induced neutropenia < 500|
03417|043|M|cells/microliter.(1)|
03417|044|M|   Gastrointestinal effects:|
03417|045|M|   Evaluate the patient's bowel function regularly.  Monitor for symptoms of|
03417|046|M|constipation and GI hypomotility, including having bowel movements less than|
03417|047|M|three times weekly or less than usual, difficulty having a bowel movement or|
03417|048|M|passing gas, nausea, vomiting, and abdominal pain or distention.(2)|
03417|049|M|   Consider a prophylactic laxative in those with a history of constipation|
03417|050|M|or bowel obstruction.(2)  Review patient medication list for other|
03417|051|M|anticholinergic agents.  When possible, decrease the dosage or number of|
03417|052|M|prescribed anticholinergic agents, particularly in the elderly.|
03417|053|M|   Counsel the patient about the importance of maintaining adequate|
03417|054|M|hydration.  Encourage regular exercise and eating a high-fiber diet.(2)|
03417|055|M|   Pharmacokinetic effects:|
03417|056|M|   The onset of induction is gradual.  It may take as little as one week to|
03417|057|M|more than 4 weeks to see maximal induction effects.|
03417|058|M|   In stable clozapine patients beginning treatment with carbamazepine,|
03417|059|M|consider measurement of clozapine levels prior to start of concomitant|
03417|060|M|therapy.  The magnitude of this interaction can be large; combined CYP1A2|
03417|061|M|and CYP3A4 enzyme inducers may decrease clozapine levels = or > 50%.  Adjust|
03417|062|M|clozapine dose accordingly.|
03417|063|M|   After stabilization on concomitant therapy, if carbamazepine is|
03417|064|M|subsequently discontinued, then the clozapine dosage will need to be|
03417|065|M|gradually decreased to the original dose as the effects of enzyme induction|
03417|066|M|wane over approximately 2-3 weeks.|
03417|067|B||
03417|068|D|DISCUSSION:  Hematological effects:  There is one published case report of|
03417|069|D|fatal agranulocytosis during concurrent administration of carbamazepine and|
03417|070|D|clozapine.  The patient died ten weeks after the addition of clozapine to|
03417|071|D|therapy with carbamazepine, lithium, benztropine, and clonazepam.  Lithium|
03417|072|D|was withdrawn from therapy one week prior to the patient's death.(7)  There|
03417|073|D|is one case report of neuroleptic malignant syndrome which developed three|
03417|074|D|days after the addition of clozapine to therapy with carbamazepine.|
03417|075|D|Symptoms resolved following the discontinuation of clozapine.(9)|
03417|076|D|   Gastrointestinal effects:|
03417|077|D|   In a prospective cohort study of 26,720 schizophrenic patients in the|
03417|078|D|Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus|
03417|079|D|was 1.99 with clozapine and 1.48 with anticholinergics.  The OR for fatal|
03417|080|D|ileus was 6.73 with clozapine and 5.88 with anticholinergics.  Use of|
03417|081|D|anticholinergics with 1st generation antipsychotics (FGA) increased the risk|
03417|082|D|of ileus compare to FGA alone, but this analysis was not done with|
03417|083|D|clozapine.(5)|
03417|084|D|   A retrospective cohort study of 24,970 schizophrenic patients from the|
03417|085|D|Taiwanese National Health Insurance Research Database found that the hazard|
03417|086|D|ratio (HR) for clozapine-induced constipation increased from 1.64 when|
03417|087|D|clozapine is used alone, to 2.15 when used concomitantly with|
03417|088|D|anticholinergics.  However, there was no significant difference in the HR|
03417|089|D|for ileus when clozapine is used with and without anticholinergics (1.95 and|
03417|090|D|2.02, respectively).(6)|
03417|091|D|   In the French Pharmacovigilance Database, 7 of 38 cases of|
03417|092|D|antipsychotic-associated ischemic colitis or intestinal necrosis involved|
03417|093|D|clozapine, and 5 of these cases involved use of concomitant anticholinergic|
03417|094|D|agents.  Three patients died, one of whom was on concomitant|
03417|095|D|anticholinergics.(3)|
03417|096|D|   In a case series, 4 of 9 cases of fatal clozapine-associated GI|
03417|097|D|dysfunction involved concurrent anticholinergic agents.(4)|
03417|098|D|   Pharmacokinetic effects:|
03417|099|D|   In two case reports, the discontinuation of carbamazepine from concurrent|
03417|100|D|therapy with clozapine resulted in increased clozapine levels within two|
03417|101|D|weeks of carbamazepine withdrawal.  Clozapine levels increased from 1.4 to|
03417|102|D|2.4 mcg-mol/L and from 1.5 to 3.0 mcg-mol/L.(10)  In three case reports,|
03417|103|D|clozapine levels increased following the switch of carbamazepine to|
03417|104|D|oxcarbazepine.(11)  A retrospective chart review of eight patients found a|
03417|105|D|decrease of 50% in the clozapine level-to-dose ratio during concurrent|
03417|106|D|therapy with carbamazepine when compared to levels before concurrent therapy|
03417|107|D|with carbamazepine.(12)|
03417|108|B||
03417|109|R|REFERENCES:|
03417|110|B||
03417|111|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03417|112|R|  Pharmaceuticals Corporation April, 2020.|1
03417|113|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA|6
03417|114|R|  strengthens warning that untreated constipation caused by schizophrenia|6
03417|115|R|  medicine clozapine (Clozaril) can lead to serious bowel problems.|6
03417|116|R|  Available at:|6
03417|117|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-strengthens-war|6
03417|118|R|  ning-untreated-constipation-caused-schizophrenia-medicine-clozapine-clozar|6
03417|119|R|  il-can February 18, 2020.|6
03417|120|R|3.Peyriere H, Roux C, Ferard C, Deleau N, Kreft-Jais C, Hillaire-Buys D,|6
03417|121|R|  Boulenger JP, Blayac JP. Antipsychotics-induced ischaemic colitis and|6
03417|122|R|  gastrointestinal necrosis: a review  of the French pharmacovigilance|6
03417|123|R|  database. Pharmacoepidemiol Drug Saf 2009 Oct;18(10):948-55.|6
03417|124|R|4.Hibbard KR, Propst A, Frank DE, Wyse J. Fatalities associated with|3
03417|125|R|  clozapine-related constipation and bowel obstruction:  a literature review|3
03417|126|R|  and two case reports. Psychosomatics 2009 Jul-Aug;50(4):416-9.|3
03417|127|R|5.Nielsen J, Meyer JM. Risk factors for ileus in patients with|2
03417|128|R|  schizophrenia. Schizophr Bull 2012 May;38(3):592-8.|2
03417|129|R|6.Chen HK, Hsieh CJ. Risk of gastrointestinal Hypomotility in schizophrenia|2
03417|130|R|  and schizoaffective disorder treated with antipsychotics: A retrospective|2
03417|131|R|  cohort study. Schizophr Res 2018 May;195:237-244.|2
03417|132|R|7.Gerson SL, Lieberman JA, Friedenberg WR, Lee D, Marx JJ Jr, Meltzer H.|3
03417|133|R|  Polypharmacy in fatal clozapine-associated agranulocytosis. Lancet 1991|3
03417|134|R|  Jul 27;338(8761):262-3.|3
03417|135|R|8.FDA (US Food and Drug Administration). Clozapine: Drug Safety|1
03417|136|R|  Communication - FDA Modifies Monitoring for Neutropenia; Approves New|1
03417|137|R|  Shared REMS Program. accessed at:|1
03417|138|R|  http://www.fda.gov/drugs/drugsafety/ucm461853.htm September 15, 2015.|1
03417|139|R|9.Muller T, Becker T, Fritze J. Neuroleptic malignant syndrome after|3
03417|140|R|  clozapine plus carbamazepine. Lancet 1988 Dec 24-31;2(8626-8627):1500.|3
03417|141|R|10.Raitasuo V, Lehtovaara R, Huttunen MO. Carbamazepine and plasma levels of|3
03417|142|R|   clozapine. Am J Psychiatry 1993 Jan;150(1):169.|3
03417|143|R|11.Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching carbamazepine|3
03417|144|R|   to oxcarbazepine on the plasma levels of neuroleptics. A case report.|3
03417|145|R|   Psychopharmacology (Berl) 1994 Sep;116(1):115-6.|3
03417|146|R|12.Jerling M, Lindstrom L, Bondesson U, Bertilsson L. Fluvoxamine inhibition|2
03417|147|R|   and carbamazepine induction of the metabolism of clozapine: evidence from|2
03417|148|R|   a therapeutic drug monitoring service. Ther Drug Monit 1994 Aug;|2
03417|149|R|   16(4):368-74.|2
03420|001|T|MONOGRAPH TITLE:  Clozapine/Paroxetine|
03420|002|B||
03420|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03420|004|L|of severe adverse interaction.|
03420|005|B||
03420|006|A|MECHANISM OF ACTION:  The metabolism of clozapine may be inhibited at CYP2D6|
03420|007|A|by paroxetine.|
03420|008|A|   In addition, due to its anticholinergic activity, paroxetine may compound|
03420|009|A|the anticholinergic and anti-serotonergic effects of clozapine to inhibit|
03420|010|A|gastrointestinal (GI) smooth muscle contraction, resulting in decreased|
03420|011|A|peristalsis.(1-6)|
03420|012|B||
03420|013|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with|
03420|014|E|paroxetine may result in elevated levels of clozapine and an increase in|
03420|015|E|clozapine related side effects, orthostatic hypotension, syncope, QT|
03420|016|E|prolongation, profound sedation and seizures.|
03420|017|E|   Concurrent use may also increase the risk of constipation (common) and|
03420|018|E|serious bowel complications (uncommon), including complete bowel|
03420|019|E|obstruction, fecal impaction, paralytic ileus and intestinal ischemia or|
03420|020|E|infarction.(1-6)|
03420|021|B||
03420|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03420|023|P|may be increased in patients with cardiovascular disease (e.g. heart|
03420|024|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03420|025|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03420|026|P|female gender, or advanced age.(7)|
03420|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03420|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03420|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03420|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03420|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03420|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03420|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)|
03420|034|P|   The risk for serious bowel complications is higher with increasing age|
03420|035|P|and in patients on multiple anticholinergic agents.(5)|
03420|036|B||
03420|037|M|PATIENT MANAGEMENT:  Clozapine levels should be monitored in patients|
03420|038|M|receiving concurrent therapy with clozapine and paroxetine.  Patients should|
03420|039|M|be monitored for signs of clozapine toxicity.  The dosage of either|
03420|040|M|clozapine or paroxetine may need to be adjusted or one or both agents may|
03420|041|M|need to be discontinued.  Clozapine levels should also be monitored|
03420|042|M|following the discontinuation of paroxetine from concurrent therapy.|
03420|043|M|   If concurrent therapy is warranted in patients receiving clozapine,|
03420|044|M|consider obtaining serum calcium, magnesium, and potassium levels and|
03420|045|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03420|046|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03420|047|M|heartbeat, dizziness, or fainting.|
03420|048|M|   In addition, evaluate the patient's bowel function regularly.  Monitor|
03420|049|M|for symptoms of constipation and GI hypomotility, including having bowel|
03420|050|M|movements less than three times weekly or less than usual, difficulty having|
03420|051|M|a bowel movement or passing gas, nausea, vomiting, and abdominal pain or|
03420|052|M|distention.(2)|
03420|053|M|   Consider a prophylactic laxative in those with a history of constipation|
03420|054|M|or bowel obstruction.(2)  Review patient medication list for other|
03420|055|M|anticholinergic agents.  When possible, decrease the dosage or number of|
03420|056|M|prescribed anticholinergic agents, particularly in the elderly.|
03420|057|M|   Counsel the patient about the importance of maintaining adequate|
03420|058|M|hydration.  Encourage regular exercise and eating a high-fiber diet.(2)|
03420|059|B||
03420|060|D|DISCUSSION:  A study(8) in 16 subjects found that the concurrent|
03420|061|D|administration of paroxetine and clozapine resulted in clozapine and|
03420|062|D|norclozapine levels that were 57.4% and 50% higher, respectively, than|
03420|063|D|levels seen in similar patients receiving clozapine alone.  In a case|
03420|064|D|report(9), a patient developed anticholinergic syndrome and her clozapine|
03420|065|D|level had doubled into the toxic range 19 days after the addition of|
03420|066|D|paroxetine to her therapy.  In contrast, two studies(10,11) found no|
03420|067|D|significant changes in clozapine levels following the addition of|
03420|068|D|paroxetine.|
03420|069|D|   Gastrointestinal effects with paroxetine coadministration:|
03420|070|D|   In a prospective cohort study of 26,720 schizophrenic patients in the|
03420|071|D|Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus|
03420|072|D|was 1.99 with clozapine and 1.48 with anticholinergics.  The OR for fatal|
03420|073|D|ileus was 6.73 with clozapine and 5.88 with anticholinergics.  Use of|
03420|074|D|anticholinergics with 1st generation antipsychotics (FGA) increased the risk|
03420|075|D|of ileus compare to FGA alone, but this analysis was not done with|
03420|076|D|clozapine.(5)|
03420|077|D|   A retrospective cohort study of 24,970 schizophrenic patients from the|
03420|078|D|Taiwanese National Health Insurance Research Database found that the hazard|
03420|079|D|ratio (HR) for clozapine-induced constipation increased from 1.64 when|
03420|080|D|clozapine is used alone, to 2.15 when used concomitantly with|
03420|081|D|anticholinergics.  However, there was no significant difference in the HR|
03420|082|D|for ileus when clozapine is used with and without anticholinergics (1.95 and|
03420|083|D|2.02, respectively).(6)|
03420|084|D|   In the French Pharmacovigilance Database, 7 of 38 cases of|
03420|085|D|antipsychotic-associated ischemic colitis or intestinal necrosis involved|
03420|086|D|clozapine, and 5 of these cases involved use of concomitant anticholinergic|
03420|087|D|agents.  Three patients died, one of whom was on concomitant|
03420|088|D|anticholinergics.(3)|
03420|089|D|   In a case series, 4 of 9 cases of fatal clozapine-associated GI|
03420|090|D|dysfunction involved concurrent anticholinergic agents.(4)|
03420|091|B||
03420|092|R|REFERENCES:|
03420|093|B||
03420|094|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03420|095|R|  Pharmaceuticals Corporation April, 2020.|1
03420|096|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA|6
03420|097|R|  strengthens warning that untreated constipation caused by schizophrenia|6
03420|098|R|  medicine clozapine (Clozaril) can lead to serious bowel problems.|6
03420|099|R|  Available at:|6
03420|100|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-strengthens-war|6
03420|101|R|  ning-untreated-constipation-caused-schizophrenia-medicine-clozapine-clozar|6
03420|102|R|  il-can February 18, 2020.|6
03420|103|R|3.Peyriere H, Roux C, Ferard C, Deleau N, Kreft-Jais C, Hillaire-Buys D,|6
03420|104|R|  Boulenger JP, Blayac JP. Antipsychotics-induced ischaemic colitis and|6
03420|105|R|  gastrointestinal necrosis: a review  of the French pharmacovigilance|6
03420|106|R|  database. Pharmacoepidemiol Drug Saf 2009 Oct;18(10):948-55.|6
03420|107|R|4.Hibbard KR, Propst A, Frank DE, Wyse J. Fatalities associated with|3
03420|108|R|  clozapine-related constipation and bowel obstruction:  a literature review|3
03420|109|R|  and two case reports. Psychosomatics 2009 Jul-Aug;50(4):416-9.|3
03420|110|R|5.Nielsen J, Meyer JM. Risk factors for ileus in patients with|2
03420|111|R|  schizophrenia. Schizophr Bull 2012 May;38(3):592-8.|2
03420|112|R|6.Chen HK, Hsieh CJ. Risk of gastrointestinal Hypomotility in schizophrenia|2
03420|113|R|  and schizoaffective disorder treated with antipsychotics: A retrospective|2
03420|114|R|  cohort study. Schizophr Res 2018 May;195:237-244.|2
03420|115|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03420|116|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03420|117|R|  settings: a scientific statement from the American Heart Association and|6
03420|118|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03420|119|R|  2;55(9):934-47.|6
03420|120|R|8.Centorrino F, Baldessarini RJ, Frankenburg FR, Kando J, Volpicelli SA,|2
03420|121|R|  Flood JG. Serum levels of clozapine and norclozapine in patients treated|2
03420|122|R|  with selective serotonin reuptake inhibitors. Am J Psychiatry 1996 Jun;|2
03420|123|R|  153(6):820-2.|2
03420|124|R|9.Joos AA, Konig F, Frank UG, Kaschka WP, Morike KE, Ewald R. Dose-dependent|3
03420|125|R|  pharmacokinetic interaction of clozapine and paroxetine in an extensive|3
03420|126|R|  metabolizer. Pharmacopsychiatry 1997 Nov;30(6):266-70.|3
03420|127|R|10.Wetzel H, Anghelescu I, Szegedi A, Wiesner J, Weigmann H, Harter S,|2
03420|128|R|   Hiemke C. Pharmacokinetic interactions of clozapine with selective|2
03420|129|R|   serotonin reuptake inhibitors: differential effects of fluvoxamine and|2
03420|130|R|   paroxetine in a prospective study. J Clin Psychopharmacol 1998 Feb;|2
03420|131|R|   18(1):2-9.|2
03420|132|R|11.Anghelescu I, Szegedi A, Schlegel S, Weigmann H, Hiemke C, Wetzel H.|2
03420|133|R|   Combination treatment with clozapine and paroxetine in schizophrenia:|2
03420|134|R|   safety and tolerability data from a prospective open clinical trial. Eur|2
03420|135|R|   Neuropsychopharmacol 1998 Dec;8(4):315-20.|2
03420|136|R|12.Bess AL, Cunningham SR. Dear Healthcare Provider:  Important drug warning|1
03420|137|R|   and new information about Clozaril. Novartis Pharmaceuticals Corporation|1
03420|138|R|   December, 2005.|1
03420|139|R|13.USDepartment of Health and Human Services Food and Drug Administration.|1
03420|140|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03420|141|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03420|142|R|   https://www.fda.gov/media/71372/download October, 2005.|1
03421|001|T|MONOGRAPH TITLE:  Osilodrostat/Strong CYP3A4 Inhibitors|
03421|002|B||
03421|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03421|004|L|take action as needed.|
03421|005|B||
03421|006|A|MECHANISM OF ACTION:  Osilodrostat is metabolized by CYP3A4.  Strong|
03421|007|A|inhibitors of CYP3A4 may decrease the metabolism of osilodrostat.(1)|
03421|008|B||
03421|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
03421|010|E|increased levels of and toxicity from osilodrostat.(1)|
03421|011|B||
03421|012|P|PREDISPOSING FACTORS:  The risk of an adverse event is higher if the|
03421|013|P|coadministered drug also inhibits other CYP or UDP-glucuronosyltransferases|
03421|014|P|(UGT) enzymes, or if the patient is taking other drugs that inhibit other|
03421|015|P|CYP or UGT enzymes.|
03421|016|B||
03421|017|M|PATIENT MANAGEMENT:  The US manufacturer of osilodrostat recommends a dose|
03421|018|M|reduction by half the current dose of osilodrostat with concomitant use of|
03421|019|M|agents that are strong CYP3A4 inhibitors due to a significant increase in|
03421|020|M|exposure to osilodrostat.(1)|
03421|021|B||
03421|022|D|DISCUSSION:  Osilodrostat is metabolized by multiple CYP and UGT enzymes.|
03421|023|D|Strong CYP3A4 inhibitors are predicted to inhibit metabolism of|
03421|024|D|osilodrostat.(1)|
03421|025|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, idelalisib,|
03421|026|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03421|027|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03421|028|D|tipranavir, troleandomycin, and tucatinib.(2-3)|
03421|029|B||
03421|030|R|REFERENCES:|
03421|031|B||
03421|032|R|1.Isturisa (osilodrostat) US prescribing information. Recordati Rare|1
03421|033|R|  Diseases, Inc. March, 2020.|1
03421|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03421|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03421|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03421|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03421|038|R|  11/14/2017.|1
03421|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03421|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03422|001|T|MONOGRAPH TITLE:  Amisulpride/QT Prolonging Agents|
03422|002|B||
03422|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03422|004|L|take action as needed.|
03422|005|B||
03422|006|A|MECHANISM OF ACTION:  Amisulpride has been shown to prolong the QT interval.|
03422|007|A|Concurrent use with QT prolonging agents may result in additive effects on|
03422|008|A|the QT interval.(1)|
03422|009|B||
03422|010|E|CLINICAL EFFECTS:  The concurrent use of amisulpride with agents that|
03422|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03422|012|E|arrhythmias, including torsades de pointes.(1)|
03422|013|B||
03422|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03422|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03422|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03422|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03422|018|P|female gender, or advanced age.(2)|
03422|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03422|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03422|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03422|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03422|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03422|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03422|025|P|dysfunction).(2)|
03422|026|B||
03422|027|M|PATIENT MANAGEMENT:  Use caution when using amisulpride concurrently with|
03422|028|M|other agents that can prolong the QT interval.  Amisulpride may cause a dose|
03422|029|M|and concentration dependent increase in the QTc interval.  When concurrent|
03422|030|M|therapy cannot be avoided, obtain ECGs and electrolyte values (serum|
03422|031|M|calcium, magnesium, and potassium) prior to the start of treatment, after|
03422|032|M|initiation of any drug known to prolong the QT interval, and periodically|
03422|033|M|monitor during therapy.  ECG monitoring is recommended in patients with|
03422|034|M|pre-existing arrhythmias or cardiac conduction disorders; electrolyte|
03422|035|M|abnormalities; congestive heart failure; or in patients taking medications|
03422|036|M|or with other medical conditions known to prolong the QT interval.  Correct|
03422|037|M|any electrolyte abnormalities.(1)|
03422|038|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03422|039|M|fainting.(2)|
03422|040|B||
03422|041|D|DISCUSSION:  QT prolongation and torsades de pointes have been reported with|
03422|042|D|amisulpride.  In a study in 40 patients with post operative nausea and|
03422|043|D|vomiting, amisulpride increased baseline QTcF by 5 msec after a 2-minute|
03422|044|D|intravenous infusion of 5 mg and by 23.4 msec after an 8-minute intravenous|
03422|045|D|infusion of 40 mg.  Based on an exposure-response relationship, it is|
03422|046|D|expected that a 10 mg intravenous infusion over 1 minute may increase the|
03422|047|D|QTcF by 13.4 msec.(1)|
03422|048|D|   Agents that are linked to this monograph may have varying degrees of|
03422|049|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03422|050|D|been shown to prolong the QTc interval either through their mechanism of|
03422|051|D|action, through studies on their effects on the QTc interval, or through|
03422|052|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03422|053|D|and/or postmarketing reports.(3)|
03422|054|B||
03422|055|R|REFERENCES:|
03422|056|B||
03422|057|R|1.Barhemsys (amisulpride) US prescribing information. Acacia Pharma|1
03422|058|R|  February, 2020.|1
03422|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03422|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03422|061|R|  settings: a scientific statement from the American Heart Association and|6
03422|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03422|063|R|  2;55(9):934-47.|6
03422|064|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03422|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03422|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03422|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03423|001|T|MONOGRAPH TITLE:  Osilodrostat/QT Prolonging Agents|
03423|002|B||
03423|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03423|004|L|take action as needed.|
03423|005|B||
03423|006|A|MECHANISM OF ACTION:  Osilodrostat has been shown to prolong the QT|
03423|007|A|interval.  Concurrent use with QT prolonging agents may result in additive|
03423|008|A|effects on the QT interval.(1)|
03423|009|B||
03423|010|E|CLINICAL EFFECTS:  The concurrent use of osilodrostat with agents that|
03423|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03423|012|E|arrhythmias, including torsades de pointes.(1)|
03423|013|B||
03423|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03423|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03423|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03423|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03423|018|P|female gender, or advanced age.(2)|
03423|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03423|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03423|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03423|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03423|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03423|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03423|025|P|dysfunction).(2)|
03423|026|B||
03423|027|M|PATIENT MANAGEMENT:  Use caution when using osilodrostat concurrently with|
03423|028|M|other agents that can prolong the QT interval and consider more frequent ECG|
03423|029|M|monitoring.  A dose-dependent QT interval prolongation was noted in clinical|
03423|030|M|studies.  Prior to initiating therapy with osilodrostat, obtain a baseline|
03423|031|M|ECG and monitor for QTc interval changes thereafter.  Consider temporary|
03423|032|M|discontinuation of therapy if the QTc interval increases > 480 msec.|
03423|033|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03423|034|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03423|035|M|treatment, after initiation of any drug known to prolong the QT interval,|
03423|036|M|and periodically monitor during therapy.  Correct any electrolyte|
03423|037|M|abnormalities.|
03423|038|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03423|039|M|fainting.(2)|
03423|040|B||
03423|041|D|DISCUSSION:  QTc prolongation has been reported with osilodrostat.  In a|
03423|042|D|thorough QT study in 86 healthy patients, osilodrostat increased baseline|
03423|043|D|QTcF by 1.73 msec at a 10 mg dose and 25.38 msec at a 150 mg dose (up to 2.5|
03423|044|D|times the maximum recommended dosage).  The predicted mean placebo-corrected|
03423|045|D|QTcF at the highest recommended dose in clinical practice (30 mg twice|
03423|046|D|daily) was estimated as 5.3 msec.(1)|
03423|047|D|   In a clinical study, five patients (4%) were reported to have an event of|
03423|048|D|QT prolongation, three patients (2%) had a QTcF increase of > 60 msec from|
03423|049|D|baseline, and 18 patients (13%) had a new QTcF value of > 450 msec.(1)|
03423|050|D|   Agents that are linked to this monograph may have varying degrees of|
03423|051|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03423|052|D|been shown to prolong the QTc interval either through their mechanism of|
03423|053|D|action, through studies on their effects on the QTc interval, or through|
03423|054|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03423|055|D|and/or postmarketing reports.(3)|
03423|056|B||
03423|057|R|REFERENCES:|
03423|058|B||
03423|059|R|1.Isturisa (osilodrostat) US prescribing information. Recordati Rare|1
03423|060|R|  Diseases, Inc. March, 2020.|1
03423|061|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03423|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03423|063|R|  settings: a scientific statement from the American Heart Association and|6
03423|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03423|065|R|  2;55(9):934-47.|6
03423|066|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03423|067|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03423|068|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03423|069|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03424|001|T|MONOGRAPH TITLE:  Oxaliplatin/QT Prolonging Agents|
03424|002|B||
03424|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03424|004|L|of severe adverse interaction.|
03424|005|B||
03424|006|A|MECHANISM OF ACTION:  Concurrent use of oxaliplatin with agents that prolong|
03424|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03424|008|B||
03424|009|E|CLINICAL EFFECTS:  The concurrent use of oxaliplatin with agents that|
03424|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03424|011|E|arrhythmias, including torsades de pointes.(1)|
03424|012|B||
03424|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03424|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03424|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03424|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03424|017|P|female gender, or advanced age.(2)|
03424|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03424|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03424|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03424|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03424|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03424|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03424|024|P|dysfunction).(2)|
03424|025|B||
03424|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of oxaliplatin in patients|
03424|027|M|with congenital long QT syndrome.  ECG monitoring is recommended if|
03424|028|M|oxaliplatin therapy is initiated in patients with congestive heart failure,|
03424|029|M|bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte|
03424|030|M|abnormalities.(1)|
03424|031|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03424|032|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03424|033|M|treatment, after initiation of any drug known to prolong the QT interval,|
03424|034|M|and periodically monitor during therapy.  Correct any electrolyte|
03424|035|M|abnormalities.|
03424|036|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03424|037|M|fainting.|
03424|038|B||
03424|039|D|DISCUSSION:  Prescribing information for oxaliplatin states post-marketing|
03424|040|D|cases of QT prolongation and ventricular arrhythmias, including fatal|
03424|041|D|Torsades de Pointes, have been reported.(1)|
03424|042|D|   Case reports have documented QT prolongation in patients with varying|
03424|043|D|cancer indications for oxaliplatin.(3-6)|
03424|044|D|   Agents that are linked to this monograph may have varying degrees of|
03424|045|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03424|046|D|been shown to prolong the QTc interval either through their mechanism of|
03424|047|D|action, through studies on their effects on the QTc interval, or through|
03424|048|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03424|049|D|and/or postmarketing reports.(7)|
03424|050|B||
03424|051|R|REFERENCES:|
03424|052|B||
03424|053|R|1.Eloxatin (oxaliplatin) US prescribing information. Sanofi-Aventis U.S. LLC|1
03424|054|R|  October, 2015.|1
03424|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03424|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03424|057|R|  settings: a scientific statement from the American Heart Association and|6
03424|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03424|059|R|  2;55(9):934-47.|6
03424|060|R|3.Hancox JC, Caves RE, Choisy SC, James AF. QT interval prolongation and|3
03424|061|R|  torsades de pointes with oxaliplatin..|3
03424|062|R|4.Chang RY, Lee MY, Kan CB, Hsu WP, Hsiao PC. Oxaliplatin-induced acquired|3
03424|063|R|  long QT syndrome with torsades de pointes and myocardial injury in a|3
03424|064|R|  patient with dilated cardiomyopathy and rectal cancer..|3
03424|065|R|5.Kim HJ, An SH, Cho YH, Kim SY, Lee HG, Yoon SY. Oxaliplatin-induced|3
03424|066|R|  Torsades de pointes and long QT syndrome in a patient with gastric|3
03424|067|R|  cancer..|3
03424|068|R|6.Woei Chung L, Liao YM, Hsieh CY, Lin CY. Oxaliplatin-induced long QT|3
03424|069|R|  syndrome in a patient with appendiceal adenocarcinoma..|3
03424|070|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
03424|071|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03424|072|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03424|073|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03425|001|T|MONOGRAPH TITLE:  Oxaliplatin/Possible QT Prolonging Agents|
03425|002|B||
03425|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03425|004|L|take action as needed.|
03425|005|B||
03425|006|A|MECHANISM OF ACTION:  Concurrent use of oxaliplatin with agents that prolong|
03425|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03425|008|B||
03425|009|E|CLINICAL EFFECTS:  The concurrent use of oxaliplatin with agents that|
03425|010|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03425|011|E|arrhythmias, including torsades de pointes.(1)|
03425|012|B||
03425|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03425|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03425|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03425|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03425|017|P|female gender, or advanced age.(2)|
03425|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03425|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03425|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03425|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03425|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03425|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03425|024|P|dysfunction).(2)|
03425|025|B||
03425|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of oxaliplatin in patients|
03425|027|M|with congenital long QT syndrome.  ECG monitoring is recommended if|
03425|028|M|oxaliplatin therapy is initiated in patients with congestive heart failure,|
03425|029|M|bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte|
03425|030|M|abnormalities.(1)|
03425|031|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03425|032|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03425|033|M|treatment, after initiation of any drug known to prolong the QT interval,|
03425|034|M|and periodically monitor during therapy.  Correct any electrolyte|
03425|035|M|abnormalities.|
03425|036|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03425|037|M|fainting.|
03425|038|B||
03425|039|D|DISCUSSION:  Prescribing information for oxaliplatin states post-marketing|
03425|040|D|cases of QT prolongation and ventricular arrhythmias, including fatal|
03425|041|D|Torsades de Pointes, have been reported.(1)|
03425|042|D|   Case reports have documented QT prolongation in patients with varying|
03425|043|D|cancer indications for oxaliplatin.(3-6)|
03425|044|D|   Agents that are linked to this monograph may have varying degrees of|
03425|045|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03425|046|D|been shown to prolong the QTc interval either through their mechanism of|
03425|047|D|action, through studies on their effects on the QTc interval, or through|
03425|048|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03425|049|D|and/or postmarketing reports.(7)|
03425|050|B||
03425|051|R|REFERENCES:|
03425|052|B||
03425|053|R|1.Eloxatin (oxaliplatin) US prescribing information. Sanofi-Aventis U.S. LLC|1
03425|054|R|  October, 2015.|1
03425|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03425|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03425|057|R|  settings: a scientific statement from the American Heart Association and|6
03425|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03425|059|R|  2;55(9):934-47.|6
03425|060|R|3.Hancox JC, Caves RE, Choisy SC, James AF. QT interval prolongation and|3
03425|061|R|  torsades de pointes with oxaliplatin..|3
03425|062|R|4.Chang RY, Lee MY, Kan CB, Hsu WP, Hsiao PC. Oxaliplatin-induced acquired|3
03425|063|R|  long QT syndrome with torsades de pointes and myocardial injury in a|3
03425|064|R|  patient with dilated cardiomyopathy and rectal cancer..|3
03425|065|R|5.Kim HJ, An SH, Cho YH, Kim SY, Lee HG, Yoon SY. Oxaliplatin-induced|3
03425|066|R|  Torsades de pointes and long QT syndrome in a patient with gastric|3
03425|067|R|  cancer..|3
03425|068|R|6.Woei Chung L, Liao YM, Hsieh CY, Lin CY. Oxaliplatin-induced long QT|3
03425|069|R|  syndrome in a patient with appendiceal adenocarcinoma..|3
03425|070|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
03425|071|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03425|072|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03425|073|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03426|001|T|MONOGRAPH TITLE:  Citalopram (Less Than or Equal To 20 mg); Escitalopram|
03426|002|T|(Less Than or Equal to 15 mg)/Ticlopidine|
03426|003|B||
03426|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03426|005|L|take action as needed.|
03426|006|B||
03426|007|A|MECHANISM OF ACTION:  Citalopram is primarily metabolized by the CYP2C19|
03426|008|A|isoenzyme.(1)|
03426|009|A|   At lower systemic concentrations, escitalopram is primarily metabolized|
03426|010|A|by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(2)|
03426|011|A|   Ticlopidine is a strong CYP2C19 inhibitor.(3)|
03426|012|B||
03426|013|E|CLINICAL EFFECTS:  Concurrent use of ticlopidine, a CYP2C19 inhibitor, may|
03426|014|E|result in elevated levels of and toxicity from citalopram or escitalopram,|
03426|015|E|including including risks for serotonin syndrome, bleeding, or prolongation|
03426|016|E|of the QTc interval.(1-7)|
03426|017|E|   Prolongation of the QT interval may result in life-threatening|
03426|018|E|arrhythmias, including torsades de pointes.(4)|
03426|019|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03426|020|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03426|021|E|rigidity.(7)|
03426|022|B||
03426|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03426|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
03426|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03426|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03426|027|P|female gender, advanced age, poor metabolizer status at CYP2C19, or higher|
03426|028|P|blood concentrations of citalopram or escitalopram.(1-3)|
03426|029|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03426|030|P|higher systemic concentrations of either QT prolonging drug are additional|
03426|031|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03426|032|P|drug concentrations include rapid infusion of an intravenous dose or|
03426|033|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03426|034|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03426|035|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03426|036|P|   Predisposing factors for serotonin-related adverse effects include use in|
03426|037|P|the elderly, in patients with hepatic impairment, and in patients receiving|
03426|038|P|multiple agents which increase central serotonin levels.(1,7)|
03426|039|P|   The risk for bleeding episodes may be greater in patients with|
03426|040|P|disease-associated factors (e.g. thrombocytopenia).  Renal impairment has|
03426|041|P|been associated with an elevated risk of GI bleed in patients on SSRIs.(8)|
03426|042|B||
03426|043|M|PATIENT MANAGEMENT:  The dose of citalopram should be limited to 20 mg in|
03426|044|M|patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,6)|
03426|045|M|Evaluate the patient for other drugs, diseases and conditions which increase|
03426|046|M|risk for QT prolongation and correct risk factors (e.g. correct hypokalemia,|
03426|047|M|hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when|
03426|048|M|possible.(1,4)  Weigh the specific benefits versus risks for each patient.|
03426|049|M|   The US manufacturer recommends ECG monitoring for citalopram patients|
03426|050|M|with congestive heart failure, bradyarrhythmias, taking concomitant QT|
03426|051|M|prolonging medications or receiving concurrent therapy.(6)  Citalopram|
03426|052|M|should be discontinued in patients with persistent QTc measurements greater|
03426|053|M|than 500 ms.(4)|
03426|054|M|   It would be prudent to limit the escitalopram dose to 10 mg daily in|
03426|055|M|patients with QT prolonging risk factors who also receive concurrent therapy|
03426|056|M|with selected CYP2C19 inhibitors.(5)  Weigh the specific benefits versus|
03426|057|M|risks for each patient.|
03426|058|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03426|059|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03426|060|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03426|061|M|patients to report any irregular heartbeat, dizziness, or fainting.  Monitor|
03426|062|M|patients for signs of blood loss, including decreased hemoglobin,|
03426|063|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
03426|064|M|evaluate patients with any symptoms.|
03426|065|M|   If concurrent therapy is warranted, patients should be monitored for|
03426|066|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03426|067|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03426|068|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03426|069|M|coordination, or severe diarrhea.|
03426|070|B||
03426|071|D|DISCUSSION:  Concurrent use of citalopram (40 mg daily) and cimetidine (400|
03426|072|D|mg twice daily) for 8 days increased the maximum concentration (Cmax) and|
03426|073|D|area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1)|
03426|074|D|   A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was|
03426|075|D|conducted; a change of 10 msec for upper bound of the 95% confidence level|
03426|076|D|is the threshold for regulatory concern.  In this study, changes to the|
03426|077|D|upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for|
03426|078|D|the 10 mg and supratherapeutic 30 mg dose respectively.  The Cmax for 30 mg|
03426|079|D|was 1.7-fold higher than the Cmax for the maximum recommended escitalopram|
03426|080|D|dose of 20 mg.  Systemic exposure at the 30 mg dose was similar to expected|
03426|081|D|steady state concentrations in 2C19 poor metabolizers following a 20 mg|
03426|082|D|escitalopram dose.(2)|
03426|083|D|  In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of|
03426|084|D|CYP2C19 was administered daily for 6 days.  On day 5 a single dose of|
03426|085|D|escitalopram 20 mg was also administered; the area-under-curve (AUC) of|
03426|086|D|escitalopram was increased by 50%.  Manufacturer prescribing information|
03426|087|D|recommends a maximum citalopram dose of 20mg daily in patients receiving|
03426|088|D|CYP2C19 inhibitors.(2)|
03426|089|D|   In a retrospective review of 5 years of data from the|
03426|090|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03426|091|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03426|092|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03426|093|D|only based on an observed-expected ration was 4.5 and in a patient using|
03426|094|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
03426|095|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
03426|096|D|bleeding to 12.2 and 5.2, respectively.(8)|
03426|097|B||
03426|098|R|REFERENCES:|
03426|099|B||
03426|100|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03426|101|R|  Laboratories Inc. August, 2023.|1
03426|102|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03426|103|R|  Pharmaceuticals Inc. May, 2023.|1
03426|104|R|3.This information is based on an extract from the Certara Drug Interaction|6
03426|105|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03426|106|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03426|107|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03426|108|R|  settings: a scientific statement from the American Heart Association and|6
03426|109|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03426|110|R|  2;55(9):934-47.|6
03426|111|R|5.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
03426|112|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
03426|113|R|  and antidepressant use: a cross sectional study of electronic health|2
03426|114|R|  records. BMJ 2013;346:f288.|2
03426|115|R|6.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
03426|116|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
03426|117|R|  Lundbeck Canada January 25, 2012.|1
03426|118|R|7.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03426|119|R|  352(11):1112-20.|6
03426|120|R|8.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
03426|121|R|  Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
03426|122|R|  by level of kidney function: A population-based cohort study. Br J Clin|2
03426|123|R|  Pharmacol 2018 Sep;84(9):2142-2151.|2
03426|124|R|9.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03426|125|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03426|126|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03426|127|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03426|128|R|10.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
03426|129|R|   recommendations for Celexa (citalopram hydrobromide) related to a|1
03426|130|R|   potential risk of abnormal heart rhythms with high doses. available at:|1
03426|131|R|   http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
03427|001|T|MONOGRAPH TITLE:  Selected Immunosuppressive CYP3A4 Substrates/Cannabidiol|
03427|002|B||
03427|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03427|004|L|take action as needed.|
03427|005|B||
03427|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is not fully|
03427|007|A|understood, but may involve inhibition of CYP3A4 and of the P-glycoprotein|
03427|008|A|transporter by cannabidiol (CBD).(1)  Everolimus and sirolimus are|
03427|009|A|substrates of both CYP3A4 and P-gp.(1)|
03427|010|B||
03427|011|E|CLINICAL EFFECTS:  Concurrent use of CBD may result in increased levels and|
03427|012|E|effects of everolimus and sirolimus.(1-3)|
03427|013|B||
03427|014|P|PREDISPOSING FACTORS:  None determined.|
03427|015|B||
03427|016|M|PATIENT MANAGEMENT:  The Canadian manufacturer of the combination of the|
03427|017|M|CBD-THC buccal spray advises caution when it is used concurrently with|
03427|018|M|CYP3A4 substrates.(2)  For patients concurrently taking everolimus or|
03427|019|M|sirolimus, therapeutic concentration monitoring of the immunosuppressant is|
03427|020|M|recommended.  Depending upon the agents involved, dose decreases of the|
03427|021|M|immunosuppressant agent may be required.(3,4)|
03427|022|B||
03427|023|D|DISCUSSION:  Elevation of everolimus levels by cannabinoids has been|
03427|024|D|reported in a retrospective study and a case report.  In the retrospective|
03427|025|D|study, everolimus levels in 18 patients with tuberous sclerosis complex|
03427|026|D|(TSC) were examined before and after initiation of CBD for epilepsy.|
03427|027|D|Everolimus levels increased by a median of 9.8 ng/mL.  No patients|
03427|028|D|experienced serious adverse events.(3)  In the case report, a 6.5-year-old|
03427|029|D|girl who was stable for 3 years on everolimus 0.3 mg/kg/day for TSC was|
03427|030|D|started on CBD for refractory epilepsy.  Everolimus levels became unstable,|
03427|031|D|ranging between 1.7 up to 16 mcg/L.(4)|
03427|032|D|   In a study with healthy volunteers, cannabidiol (12.5 mg/kg twice daily)|
03427|033|D|increased everolimus AUC and Cmax by 2.5-fold.(5,6)|
03427|034|D|   In a retrospective study, sirolimus levels in 7 patients with tuberous|
03427|035|D|sclerosis complex were examined before and after initiation of CBD for|
03427|036|D|epilepsy.  Sirolimus levels increased by a median of 5.1 ng/mL.  No patients|
03427|037|D|experienced serious adverse events.(3)|
03427|038|B||
03427|039|R|REFERENCES:|
03427|040|B||
03427|041|R|1.This information is based on an extract from the Certara Drug Interaction|6
03427|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03427|043|R|2.Sativex (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD))|1
03427|044|R|  Canadian prescribing information. GW Pharma Ltd. December 11, 2019.|1
03427|045|R|3.Ebrahimi-Fakhari D, Agricola KD, Tudor C, Krueger D, Franz DN. Cannabidiol|2
03427|046|R|  Elevates Mechanistic Target of Rapamycin Inhibitor Levels in Patients With|2
03427|047|R|  Tuberous Sclerosis Complex. Pediatr Neurol 2019 Dec 9.|2
03427|048|R|4.Wiemer-Kruel A, Stiller B, Bast T. Cannabidiol Interacts Significantly|3
03427|049|R|  with Everolimus-Report of a Patient with Tuberous Sclerosis Complex.|3
03427|050|R|  Neuropediatrics 2019 Dec;50(6):400-403.|3
03427|051|R|5.Epidiolex (cannabidiol) US prescribing information. Greenwich Biosciences,|1
03427|052|R|  Inc. June, 2025.|1
03427|053|R|6.Wray L, Berwaerts J, Critchley D, Hyland K, Chen C, Thai C, Tayo B.|2
03427|054|R|  Pharmacokinetic Drug-Drug Interaction With Coadministration of Cannabidiol|2
03427|055|R|  and Everolimus in a Phase 1 Healthy Volunteer Trial. American College of|2
03427|056|R|  Clinical Pharmacology 2023;12(9):911-919.|2
03428|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Cannabidiol|
03428|002|B||
03428|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03428|004|L|take action as needed.|
03428|005|B||
03428|006|A|MECHANISM OF ACTION:  Cannabidiol (CBD) may induce the CYP3A4-mediated|
03428|007|A|metabolism of hormonal contraceptives.(1)|
03428|008|B||
03428|009|E|CLINICAL EFFECTS:  Concurrent use of CBD may reduce the effectiveness of|
03428|010|E|hormonal contraceptives.(1)|
03428|011|B||
03428|012|P|PREDISPOSING FACTORS:  None determined.|
03428|013|B||
03428|014|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
03428|015|M|rely on hormonal contraception (including oral contraceptives, patches,|
03428|016|M|implants, and/or IUDs) for contraception.  Women should use an effective|
03428|017|M|non-hormonal method of contraception or a back-up method of birth control|
03428|018|M|during CBD therapy.(1)|
03428|019|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03428|020|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03428|021|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03428|022|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03428|023|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03428|024|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03428|025|M|and to seek medical advice if they do become pregnant.(2)|
03428|026|B||
03428|027|D|DISCUSSION:  An in vitro, CYP induction study showed that CBD may increase|
03428|028|D|expression of CYP3A4.  The effectiveness of hormonal contraceptives,|
03428|029|D|including oral contraceptives, patches, implants, and/or IUDs may be|
03428|030|D|decreased.  Women should use a back-up method of birth control during CBD or|
03428|031|D|THC therapy.(1)|
03428|032|B||
03428|033|R|REFERENCES:|
03428|034|B||
03428|035|R|1.Sativex (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD))|1
03428|036|R|  Canadian prescribing information. GW Pharma Ltd. December 11, 2019.|1
03428|037|R|2.Medicines and Healthcare products Regulatory Agency.|1
03428|038|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03428|039|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03428|040|R|  available at:|1
03428|041|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03428|042|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03428|043|R|  -and-contraceptive-efficacy September 15, 2016..|1
03429|001|T|MONOGRAPH TITLE:  Selected CYP1A2 Substrates/Osilodrostat|
03429|002|B||
03429|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03429|004|L|take action as needed.|
03429|005|B||
03429|006|A|MECHANISM OF ACTION:  Osilodrostat is a moderate inhibitor of CYP1A2.(1)|
03429|007|A|The FDA defines moderate inhibition as an increase in drug area-under-curve|
03429|008|A|(AUC) greater than two fold, but less than 5 fold.(2)|
03429|009|B||
03429|010|E|CLINICAL EFFECTS:  Concurrent use of osilodrostat with drugs primarily|
03429|011|E|metabolized by CYP1A2 may lead to elevated drug levels and increased side|
03429|012|E|effects.(1)|
03429|013|B||
03429|014|P|PREDISPOSING FACTORS:  Greater risk for adverse events would be expected for|
03429|015|P|drugs with a narrow therapeutic window, or for drugs especially sensitive to|
03429|016|P|CYP1A2 inhibition.|
03429|017|B||
03429|018|M|PATIENT MANAGEMENT:  Drugs linked to this monograph have a narrow|
03429|019|M|therapeutic window or are sensitive to CYP1A2 inhibition.  Use caution when|
03429|020|M|osilodrostat is coadministered with CYP1A2 substrates with narrow|
03429|021|M|therapeutic index.(1)|
03429|022|B||
03429|023|D|DISCUSSION:  In a study of 20 healthy volunteers, a single dose of|
03429|024|D|osilodrostat 50 mg increased the AUC of caffeine, a CYP1A2 substrate, by|
03429|025|D|2.5-fold.(1)|
03429|026|B||
03429|027|R|REFERENCES:|
03429|028|B||
03429|029|R|1.Isturisa (osilodrostat) US prescribing information. Recordati Rare|1
03429|030|R|  Diseases, Inc. March, 2020.|1
03429|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03429|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03429|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03429|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03429|035|R|  11/14/2017.|1
03430|001|T|MONOGRAPH TITLE:  Osilodrostat/Strong CYP3A4 Inhibitors that Prolong QT|
03430|002|B||
03430|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03430|004|L|of severe adverse interaction.|
03430|005|B||
03430|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QT|
03430|007|A|interval may inhibit the metabolism of osilodrostat(1,2) and result in|
03430|008|A|additive effects on the QT interval.(1)|
03430|009|B||
03430|010|E|CLINICAL EFFECTS:  The concurrent use of osilodrostat with strong inhibitors|
03430|011|E|of CYP3A4 that prolong the QTc interval may result in elevated levels of and|
03430|012|E|effects from osilodrostat, including potentially life-threatening cardiac|
03430|013|E|arrhythmias, including torsades de pointes.(1)|
03430|014|B||
03430|015|P|PREDISPOSING FACTORS:  The risk of increased exposure to osilodrostat is|
03430|016|P|higher if the coadministered drug also inhibits other CYP or|
03430|017|P|UDP-glucuronosyltransferases (UGT) enzymes, or if the patient is taking|
03430|018|P|other drugs that inhibit other CYP or UGT enzymes.(1)|
03430|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03430|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03430|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03430|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03430|023|P|advanced age.(2)|
03430|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03430|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03430|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03430|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03430|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03430|029|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03430|030|P|dysfunction).(2)|
03430|031|B||
03430|032|M|PATIENT MANAGEMENT:  The US manufacturer of osilodrostat recommends a dose|
03430|033|M|reduction by half the current dose of osilodrostat with concomitant use of|
03430|034|M|agents that are strong CYP3A4 inhibitors due to a significant increase in|
03430|035|M|exposure to osilodrostat.(1)|
03430|036|M|   Use caution when using osilodrostat concurrently with other agents that|
03430|037|M|can prolong the QT interval and consider more frequent ECG monitoring.  A|
03430|038|M|dose-dependent QT interval prolongation was noted in clinical studies.|
03430|039|M|Prior to initiating therapy with osilodrostat, obtain a baseline ECG and|
03430|040|M|monitor for QTc interval changes thereafter.  Consider temporary|
03430|041|M|discontinuation of therapy if the QTc interval increases > 480 msec.|
03430|042|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03430|043|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03430|044|M|treatment, after initiation of any drug known to prolong the QT interval,|
03430|045|M|and periodically monitor during therapy.  Correct any electrolyte|
03430|046|M|abnormalities.|
03430|047|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03430|048|M|fainting.(2)|
03430|049|B||
03430|050|D|DISCUSSION:  Osilodrostat is metabolized by multiple CYP and UGT enzymes.|
03430|051|D|Strong CYP3A4 inhibitors are predicted to inhibit metabolism of|
03430|052|D|osilodrostat.(1)|
03430|053|D|   QTc prolongation has been reported with osilodrostat.  In a thorough QT|
03430|054|D|study in 86 healthy patients, osilodrostat increased baseline QTcF by 1.73|
03430|055|D|msec at a 10 mg dose and 25.38 msec at a 150 mg dose (up to 2.5 times the|
03430|056|D|maximum recommended dosage).  The predicted mean placebo-corrected QTcF at|
03430|057|D|the highest recommended dose in clinical practice (30 mg twice daily) was|
03430|058|D|estimated as 5.3 msec.(1)|
03430|059|D|   In a clinical study, five patients (4%) were reported to have an event of|
03430|060|D|QT prolongation, three patients (2%) had a QTcF increase of > 60 msec from|
03430|061|D|baseline, and 18 patients (13%) had a new QTcF value of > 450 msec.(1)|
03430|062|D|   Agents that are linked to this monograph may have varying degrees of|
03430|063|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03430|064|D|been shown to prolong the QTc interval either through their mechanism of|
03430|065|D|action, through studies on their effects on the QTc interval, or through|
03430|066|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03430|067|D|and/or postmarketing reports.(3)|
03430|068|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
03430|069|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib,|
03430|070|D|lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin,|
03430|071|D|and voriconazole.(4,5)|
03430|072|B||
03430|073|R|REFERENCES:|
03430|074|B||
03430|075|R|1.Isturisa (osilodrostat) US prescribing information. Recordati Rare|1
03430|076|R|  Diseases, Inc. March, 2020.|1
03430|077|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03430|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03430|079|R|  settings: a scientific statement from the American Heart Association and|6
03430|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03430|081|R|  2;55(9):934-47.|6
03430|082|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03430|083|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03430|084|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03430|085|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03430|086|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03430|087|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03430|088|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03430|089|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03430|090|R|  11/14/2017.|1
03430|091|R|5.This information is based on an extract from the Certara Drug Interaction|6
03430|092|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03431|001|T|MONOGRAPH TITLE:  Clozapine/Osilodrostat|
03431|002|B||
03431|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03431|004|L|take action as needed.|
03431|005|B||
03431|006|A|MECHANISM OF ACTION:  Osilodrostat is a moderate inhibitor of CYP1A2.(1)|
03431|007|A|Concurrent use with clozapine, a substrate of CYP1A2, may result in|
03431|008|A|inhibition of clozapine metabolism.(2)|
03431|009|B||
03431|010|E|CLINICAL EFFECTS:  Concurrent use of osilodrostat may result in higher|
03431|011|E|levels of clozapine and increased risk of side effects including neutropenia|
03431|012|E|and QT prolongation.|
03431|013|E|   Moderate neutropenia, even if due to combination therapy, may require|
03431|014|E|abrupt discontinuation of clozapine resulting in decompensation of the|
03431|015|E|patient's psychiatric disorder (e.g. schizophrenia).  The disease treated by|
03431|016|E|pentamidine may be compromised if myelosuppression requires dose reduction,|
03431|017|E|delay, or discontinuation of the myelosuppressive agent.  Undetected severe|
03431|018|E|neutropenia or agranulocytosis may be fatal.(2,3)|
03431|019|B||
03431|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03431|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
03431|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03431|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03431|024|P|female gender, or advanced age.(4)|
03431|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03431|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03431|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03431|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03431|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03431|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03431|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03431|032|P|   Low white blood counts prior to initiation of the myelosuppressive agent|
03431|033|P|may increase risk for clinically significant neutropenia.(2,3)|
03431|034|B||
03431|035|M|PATIENT MANAGEMENT:  Use caution if osilodrostat and clozapine are used|
03431|036|M|concomitantly.(1,2)  The manufacturer of clozapine recommends monitoring|
03431|037|M|patients for adverse reactions of clozapine and lowering the dose of|
03431|038|M|clozapine if necessary.(2)|
03431|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03431|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03431|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03431|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03431|043|M|   If a patient stabilized on clozapine therapy requires treatment with|
03431|044|M|osilodrostat, the clozapine prescriber should consult with the prescriber of|
03431|045|M|osilodrostat to discuss treatment and monitoring options.  More frequent ANC|
03431|046|M|monitoring or treatment alternatives secondary to neutropenic episodes may|
03431|047|M|need to be considered.|
03431|048|M|   Clozapine is only available through a restricted distribution system|
03431|049|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
03431|050|M|dispensing.  For most clozapine patients, clozapine treatment must be|
03431|051|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
03431|052|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
03431|053|M|interrupted for suspected clozapine-induced neutropenia < 500|
03431|054|M|cells/microliter.(3)|
03431|055|B||
03431|056|D|DISCUSSION:  Treatment with clozapine has been associated with QT|
03431|057|D|prolongation as well as ventricular arrhythmia, torsades de pointes, cardiac|
03431|058|D|arrest, and sudden death.(2)  Osilodrostat is associated with a|
03431|059|D|dose-dependent QT interval prolongation (maximum mean estimated QTcF|
03431|060|D|increase of up to 5.3 ms at 30 mg), which may cause cardiac arrhythmias.(1)|
03431|061|D|   Clozapine is only available through a restricted distribution system|
03431|062|D|which requires documentation of the ANC prior to dispensing.(3)|
03431|063|B||
03431|064|R|REFERENCES:|
03431|065|B||
03431|066|R|1.Isturisa (osilodrostat) US prescribing information. Recordati Rare|1
03431|067|R|  Diseases, Inc. March, 2020.|1
03431|068|R|2.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03431|069|R|  Pharmaceuticals Corporation April, 2020.|1
03431|070|R|3.FDA (US Food and Drug Administration). Clozapine: Drug Safety|1
03431|071|R|  Communication - FDA Modifies Monitoring for Neutropenia; Approves New|1
03431|072|R|  Shared REMS Program. accessed at:|1
03431|073|R|  http://www.fda.gov/drugs/drugsafety/ucm461853.htm September 15, 2015.|1
03431|074|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03431|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03431|076|R|  settings: a scientific statement from the American Heart Association and|6
03431|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03431|078|R|  2;55(9):934-47.|6
03432|001|T|MONOGRAPH TITLE:  Tizanidine/Osilodrostat|
03432|002|B||
03432|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03432|004|L|take action as needed.|
03432|005|B||
03432|006|A|MECHANISM OF ACTION:  Osilodrostat is a moderate inhibitor of CYP1A2.(1)|
03432|007|A|Concurrent use of osilodrostat with tizanidine may inhibit the metabolism of|
03432|008|A|tizanidine by CYP1A2.(1,2)|
03432|009|B||
03432|010|E|CLINICAL EFFECTS:  Concurrent use of osilodrostat may result in elevated|
03432|011|E|levels of and effects from tizanidine, including hypotension, bradycardia,|
03432|012|E|drowsiness, sedation, and decreased psychomotor function.|
03432|013|B||
03432|014|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
03432|015|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
03432|016|P|patients using more than one medicine with anticholinergic properties.(3)|
03432|017|B||
03432|018|M|PATIENT MANAGEMENT:  Concomitant use of tizanidine with CYP1A2 inhibitors|
03432|019|M|such as osilodrostat should be avoided.|
03432|020|M|   If therapy is warranted, tizanidine therapy should be initiated with 2 mg|
03432|021|M|dose and increased in 2-4 mg steps daily based on patient response to|
03432|022|M|therapy.|
03432|023|M|   If adverse reactions such as hypotension, bradycardia, or excessive|
03432|024|M|drowsiness occur, reduce or discontinue tizanidine therapy.(2)|
03432|025|B||
03432|026|D|DISCUSSION:  In a study in 10 healthy subjects, concurrent fluvoxamine,|
03432|027|D|another inhibitor of CYP1A2, increased tizanidine maximum concentration|
03432|028|D|(Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold,|
03432|029|D|and 3-fold, respectively. Significant decreases in blood pressure and|
03432|030|D|increases in drowsiness and psychomotor impairment occurred.(2)|
03432|031|D|   In a study in 10 healthy subjects, concurrent ciprofloxacin, another|
03432|032|D|CYP1A2 inhibitor, increased tizanidine Cmax and AUC by 7-fold and 10-fold,|
03432|033|D|respectively. Significant decreases in blood pressure and increased|
03432|034|D|drowsiness and psychomotor impairment occurred.(2)|
03432|035|D|   In a study in 20 healthy volunteers, a single dose of osilodrostat 50 mg|
03432|036|D|increased the AUC of caffeine, a CYP1A2 substrate, by 2.5-fold.(1)|
03432|037|B||
03432|038|R|REFERENCES:|
03432|039|B||
03432|040|R|1.Isturisa (osilodrostat) US prescribing information. Recordati Rare|1
03432|041|R|  Diseases, Inc. March, 2020.|1
03432|042|R|2.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
03432|043|R|  Pharma Inc. November 22, 2024.|1
03432|044|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03432|045|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03432|046|R|  Soc 2023 Jul;71(7):2052-2081.|6
03433|001|T|MONOGRAPH TITLE:  Methadone for MAT/Selected Antipsychotics that Prolong QT|
03433|002|B||
03433|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03433|004|L|is contraindicated and generally should not be dispensed or administered to|
03433|005|L|the same patient.|
03433|006|B||
03433|007|A|MECHANISM OF ACTION:  Methadone has been shown to prolong the QTc interval.|
03433|008|A|Concurrent use with selected antipsychotics may result in additive effects|
03433|009|A|on the QTc interval.(1-3)|
03433|010|A|   Concurrent use of methadone and antipsychotics may result in additive CNS|
03433|011|A|depression.(1-3)|
03433|012|B||
03433|013|E|CLINICAL EFFECTS:  The concurrent use of methadone with other agents that|
03433|014|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03433|015|E|arrhythmias, including torsades de pointes.(1,2)|
03433|016|E|   Concurrent use of opioids and other CNS depressants such as|
03433|017|E|antipsychotics may result in profound sedation, respiratory depression,|
03433|018|E|coma, and/or death.(1-3)|
03433|019|B||
03433|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03433|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03433|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03433|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03433|024|P|gender, or advanced age.(4)|
03433|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03433|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03433|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03433|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03433|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03433|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03433|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03433|032|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
03433|033|P|of adverse effects.|
03433|034|B||
03433|035|M|PATIENT MANAGEMENT:  Concurrent use of methadone with droperidol, pimozide,|
03433|036|M|or sertindole is contraindicated.|
03433|037|M|   If therapeutic alternatives are inadequate and concurrent use therapy is|
03433|038|M|warranted, consider obtaining serum calcium, magnesium, and potassium levels|
03433|039|M|and monitoring ECG at baseline and at regular intervals.  Correct any|
03433|040|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03433|041|M|heartbeat, dizziness, or fainting.|
03433|042|M|   If concurrent use is necessary, limit the dosages and duration of each|
03433|043|M|drug to the minimum possible while achieving the desired clinical effect.|
03433|044|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03433|045|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03433|046|M|indicated in the absence of an opioid and titrate based upon clinical|
03433|047|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03433|048|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03433|049|M|clinical response.(3)  Gradual tapering or decreasing to the lowest|
03433|050|M|effective dose of antipsychotic may be appropriate. Ensure that other health|
03433|051|M|care providers prescribing other CNS depressants are aware of the patient's|
03433|052|M|methadone treatment.(5)|
03433|053|M|   Respiratory depression can occur at any time during opioid therapy,|
03433|054|M|especially during therapy initiation and following dosage increases.  The|
03433|055|M|risk of opioid-related overdose or overdose-related death is increased with|
03433|056|M|higher opioid doses, and this risk persists over the course of therapy.|
03433|057|M|Consider these risks when using concurrently with other agents that may|
03433|058|M|cause CNS depression.(6)|
03433|059|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03433|060|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03433|061|M|unresponsiveness.(3)|
03433|062|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03433|063|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03433|064|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03433|065|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03433|066|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03433|067|M|as those taking CNS depressants) and when a patient has household|
03433|068|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03433|069|M|for obtaining an opioid reversal agent (e.g., prescription,|
03433|070|M|over-the-counter, or as part of a community-based program).(7)|
03433|071|B||
03433|072|D|DISCUSSION:  Most cases of methadone-induced QT prolongation are associated|
03433|073|D|with, but not limited to, higher dose treatment (greater than 200 mg daily)|
03433|074|D|and most involve patients being treated for pain with large, multiple daily|
03433|075|D|doses. Cases have been reported in patients treated with doses commonly used|
03433|076|D|for maintenance treatment of opioid addiction.(2)|
03433|077|D|   Levomethadone should be used with caution in patients with a history of|
03433|078|D|QT prolongation, advanced heart disease, concomitant CYP3A4 inhibitors, or|
03433|079|D|electrolyte abnormalities.  Cases of QT prolongation and torsades de pointes|
03433|080|D|have been reported, most commonly with high doses.(1)|
03433|081|D|   A nested case-control study looked at the relationship between|
03433|082|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03433|083|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03433|084|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03433|085|D|significantly increased in patients with recent use of antipsychotics|
03433|086|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03433|087|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03433|088|D|of use.(8)|
03433|089|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03433|090|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03433|091|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03433|092|D|to 30 million patients.  During this time, the proportion of patients|
03433|093|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03433|094|D|patients.(9)|
03433|095|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03433|096|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03433|097|D|per 100,000 and drug overdose deaths involving both opioids and|
03433|098|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03433|099|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03433|100|D|increased from 18% to 31% during this time.(10)|
03433|101|D|   A prospective observational cohort study in North Carolina found that the|
03433|102|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03433|103|D|benzodiazepines were 10 times higher than patients receiving opioid|
03433|104|D|analgesics alone.(11)|
03433|105|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03433|106|D|death from overdose increased with concomitant opioid analgesics and|
03433|107|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03433|108|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03433|109|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03433|110|D|increased risk of fatal overdose.(12)|
03433|111|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03433|112|D|which benzodiazepines were determined to be a cause of death and that|
03433|113|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03433|114|D|determined to be a cause of death.  This study also found that other CNS|
03433|115|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03433|116|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03433|117|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03433|118|D|where opioid analgesics were also implicated.(13)|
03433|119|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03433|120|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03433|121|D|deaths.(14)|
03433|122|D|   Selected antipsychotics linked include: droperidol, pimozide, and|
03433|123|D|sertindole.|
03433|124|B||
03433|125|R|REFERENCES:|
03433|126|B||
03433|127|R|1.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03433|128|R|  Pharma AS November 30, 2018.|1
03433|129|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03433|130|R|  Pharmaceuticals Corp. June, 2021.|1
03433|131|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03433|132|R|  warns about serious risks and death when combining opioid pain or cough|1
03433|133|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03433|134|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03433|135|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03433|136|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03433|137|R|  settings: a scientific statement from the American Heart Association and|6
03433|138|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03433|139|R|  2;55(9):934-47.|6
03433|140|R|5.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03433|141|R|  urges caution about withholding opioid addiction medications from patients|1
03433|142|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03433|143|R|  can reduce risks. available at:|1
03433|144|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03433|145|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03433|146|R|  prescribing information for all opioid pain medicines to provide|1
03433|147|R|  additional guidance for safe use. Available at:|1
03433|148|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03433|149|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03433|150|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03433|151|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03433|152|R|  recommends health care professionals discuss naloxone with all patients|1
03433|153|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03433|154|R|  disorder. Available at:|1
03433|155|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03433|156|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03433|157|R|  d-pain July 23, 2020.|1
03433|158|R|8.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03433|159|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03433|160|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03433|161|R|  Pharmacol 2020 Apr 26.|2
03433|162|R|9.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03433|163|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03433|164|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03433|165|R|10.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03433|166|R|   From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015|2
03433|167|R|   Oct;49(4):493-501.|2
03433|168|R|11.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03433|169|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03433|170|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03433|171|R|12.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03433|172|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03433|173|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03433|174|R|   350:h2698.|2
03433|175|R|13.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03433|176|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03433|177|R|14.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03433|178|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03433|179|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03433|180|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03434|001|T|MONOGRAPH TITLE:  Methadone (non MAT)/Selected Antipsychotics that Prolong|
03434|002|T|QT|
03434|003|B||
03434|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03434|005|L|is contraindicated and generally should not be dispensed or administered to|
03434|006|L|the same patient.|
03434|007|B||
03434|008|A|MECHANISM OF ACTION:  Methadone has been shown to prolong the QTc interval.|
03434|009|A|Concurrent use with selected antipsychotics may result in additive effects|
03434|010|A|on the QTc interval.|
03434|011|A|   Concurrent use of methadone and antipsychotics may result in additive CNS|
03434|012|A|depression.(1,2)|
03434|013|B||
03434|014|E|CLINICAL EFFECTS:  Concurrent use of methadone with selected antipsychotics|
03434|015|E|may result in potentially life-threatening cardiac arrhythmias, including|
03434|016|E|torsades de pointes.(1)|
03434|017|E|   Concurrent use of methadone and other CNS depressants such as|
03434|018|E|antipsychotics may result in profound sedation, respiratory depression,|
03434|019|E|coma, and/or death.(1,2)|
03434|020|B||
03434|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03434|022|P|may be increased in patients with cardiovascular disease (e.g. heart|
03434|023|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03434|024|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03434|025|P|female gender, or advanced age.(3)|
03434|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03434|027|P|higher systemic concentrations of either QT prolonging drug are additional|
03434|028|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03434|029|P|drug concentrations include rapid infusion of an intravenous dose or|
03434|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03434|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03434|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03434|033|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
03434|034|P|of adverse effects.|
03434|035|B||
03434|036|M|PATIENT MANAGEMENT:  Concurrent use of methadone with droperidol, pimozide,|
03434|037|M|or sertindole is contraindicated.|
03434|038|M|   If therapeutic alternatives are inadequate and concurrent use therapy is|
03434|039|M|warranted, consider obtaining serum calcium, magnesium, and potassium levels|
03434|040|M|and monitoring ECG at baseline and at regular intervals.  Correct any|
03434|041|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03434|042|M|heartbeat, dizziness, or fainting.|
03434|043|M|   If concurrent use is necessary, limit the dosages and duration of each|
03434|044|M|drug to the minimum possible while achieving the desired clinical effect.|
03434|045|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03434|046|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03434|047|M|indicated in the absence of an opioid and titrate based upon clinical|
03434|048|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03434|049|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03434|050|M|clinical response.(3)  Gradual tapering or decreasing to the lowest|
03434|051|M|effective dose of antipsychotic may be appropriate. Ensure that other health|
03434|052|M|care providers prescribing other CNS depressants are aware of the patient's|
03434|053|M|methadone treatment.(4)|
03434|054|M|   Respiratory depression can occur at any time during opioid therapy,|
03434|055|M|especially during therapy initiation and following dosage increases.  The|
03434|056|M|risk of opioid-related overdose or overdose-related death is increased with|
03434|057|M|higher opioid doses, and this risk persists over the course of therapy.|
03434|058|M|Consider these risks when using concurrently with other agents that may|
03434|059|M|cause CNS depression.(5)|
03434|060|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03434|061|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03434|062|M|unresponsiveness.(2)|
03434|063|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03434|064|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03434|065|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03434|066|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03434|067|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03434|068|M|as those taking CNS depressants) and when a patient has household|
03434|069|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03434|070|M|for obtaining an opioid reversal agent (e.g., prescription,|
03434|071|M|over-the-counter, or as part of a community-based program).(6)|
03434|072|B||
03434|073|D|DISCUSSION:  Most cases of methadone-induced QT prolongation are associated|
03434|074|D|with, but not limited to, higher dose treatment (greater than 200 mg daily)|
03434|075|D|and most involve patients being treated for pain with large, multiple daily|
03434|076|D|doses. Cases have been reported in patients treated with doses commonly used|
03434|077|D|for maintenance treatment of opioid addiction.(1)|
03434|078|D|   A nested case-control study looked at the relationship between|
03434|079|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03434|080|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03434|081|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03434|082|D|significantly increased in patients with recent use of antipsychotics|
03434|083|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03434|084|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03434|085|D|of use.(7)|
03434|086|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03434|087|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03434|088|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03434|089|D|to 30 million patients.  During this time, the proportion of patients|
03434|090|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03434|091|D|patients.(8)|
03434|092|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03434|093|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03434|094|D|per 100,000 and drug overdose deaths involving both opioids and|
03434|095|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03434|096|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03434|097|D|increased from 18% to 31% during this time.(9)|
03434|098|D|   A prospective observational cohort study in North Carolina found that the|
03434|099|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03434|100|D|benzodiazepines were 10 times higher than patients receiving opioid|
03434|101|D|analgesics alone.(10)|
03434|102|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03434|103|D|death from overdose increased with concomitant opioid analgesics and|
03434|104|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03434|105|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03434|106|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03434|107|D|increased risk of fatal overdose.(11)|
03434|108|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03434|109|D|which benzodiazepines were determined to be a cause of death and that|
03434|110|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03434|111|D|determined to be a cause of death.  This study also found that other CNS|
03434|112|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03434|113|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03434|114|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03434|115|D|where opioid analgesics were also implicated.(12)|
03434|116|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03434|117|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03434|118|D|deaths.(13)|
03434|119|D|   Selected antipsychotics linked include: droperidol, pimozide, and|
03434|120|D|sertindole.|
03434|121|B||
03434|122|R|REFERENCES:|
03434|123|B||
03434|124|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03434|125|R|  Pharmaceuticals Corp. June, 2021.|1
03434|126|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03434|127|R|  warns about serious risks and death when combining opioid pain or cough|1
03434|128|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03434|129|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03434|130|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03434|131|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03434|132|R|  settings: a scientific statement from the American Heart Association and|6
03434|133|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03434|134|R|  2;55(9):934-47.|6
03434|135|R|4.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03434|136|R|  urges caution about withholding opioid addiction medications from patients|1
03434|137|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03434|138|R|  can reduce risks. available at:|1
03434|139|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03434|140|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03434|141|R|  prescribing information for all opioid pain medicines to provide|1
03434|142|R|  additional guidance for safe use. Available at:|1
03434|143|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03434|144|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03434|145|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03434|146|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03434|147|R|  recommends health care professionals discuss naloxone with all patients|1
03434|148|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03434|149|R|  disorder. Available at:|1
03434|150|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03434|151|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03434|152|R|  d-pain July 23, 2020.|1
03434|153|R|7.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03434|154|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03434|155|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03434|156|R|  Pharmacol 2020 Apr 26.|2
03434|157|R|8.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03434|158|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03434|159|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03434|160|R|9.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03434|161|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03434|162|R|  49(4):493-501.|2
03434|163|R|10.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03434|164|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03434|165|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03434|166|R|11.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03434|167|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03434|168|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03434|169|R|   350:h2698.|2
03434|170|R|12.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03434|171|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03434|172|R|13.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03434|173|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03434|174|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03434|175|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03435|001|T|MONOGRAPH TITLE:  Levomethadyl (IR)/Selected Antipsychotics that Prolong QT|
03435|002|B||
03435|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03435|004|L|of severe adverse interaction.|
03435|005|B||
03435|006|A|MECHANISM OF ACTION:  Levomethadyl has been shown to prolong the QTc|
03435|007|A|interval.  Concurrent use with selected antipsychotics may result in|
03435|008|A|additive effects on the QTc interval.(1,2)|
03435|009|A|   Concurrent use of opioids such as levomethadyl and antipsychotics,|
03435|010|A|including phenothiazine derivatives, may result in additive CNS|
03435|011|A|depression.(3)|
03435|012|B||
03435|013|E|CLINICAL EFFECTS:  The concurrent use of levomethadyl with other agents that|
03435|014|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03435|015|E|arrhythmias, including torsades de pointes.(1,2)|
03435|016|E|   Concurrent use of opioids such as levomethadyl and other CNS depressants,|
03435|017|E|such as antipsychotics, including phenothiazine derivatives, may result in|
03435|018|E|profound sedation, respiratory depression, coma, and/or death.(3)|
03435|019|B||
03435|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03435|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03435|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03435|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03435|024|P|gender, or advanced age.(2)|
03435|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03435|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03435|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03435|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03435|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03435|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03435|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03435|032|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
03435|033|P|of adverse effects.|
03435|034|B||
03435|035|M|PATIENT MANAGEMENT:  The manufacturer of levomethadyl states under|
03435|036|M|contraindications that levomethadyl is contraindicated in patients being|
03435|037|M|treated concomitantly with other drug products known to prolong the QT|
03435|038|M|interval.(1,2)  Limit prescribing opioid analgesics such as levomethadyl|
03435|039|M|with CNS depressants such as antipsychotics, including phenothiazine|
03435|040|M|derivatives, to patients for whom alternatives are ineffective, not|
03435|041|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03435|042|M|of pain.(3)|
03435|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03435|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03435|045|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03435|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03435|047|M|   If concurrent use is necessary, limit the dosages and duration of each|
03435|048|M|drug to the minimum possible while achieving the desired clinical effect.|
03435|049|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03435|050|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03435|051|M|indicated in the absence of an opioid and titrate based upon clinical|
03435|052|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03435|053|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03435|054|M|clinical response.(3)|
03435|055|M|   Respiratory depression can occur at any time during opioid therapy,|
03435|056|M|especially during therapy initiation and following dosage increases.  The|
03435|057|M|risk of opioid-related overdose or overdose-related death is increased with|
03435|058|M|higher opioid doses, and this risk persists over the course of therapy.|
03435|059|M|Consider these risks when using concurrently with other agents that may|
03435|060|M|cause CNS depression.(4)|
03435|061|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03435|062|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03435|063|M|unresponsiveness.(3)|
03435|064|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03435|065|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03435|066|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03435|067|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03435|068|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03435|069|M|as those taking CNS depressants) and when a patient has household|
03435|070|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03435|071|M|for obtaining an opioid reversal agent (e.g., prescription,|
03435|072|M|over-the-counter, or as part of a community-based program).(5)|
03435|073|B||
03435|074|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03435|075|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03435|076|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03435|077|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03435|078|D|significantly increased in patients with recent use of antipsychotics|
03435|079|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03435|080|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03435|081|D|of use.(6)|
03435|082|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03435|083|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03435|084|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03435|085|D|to 30 million patients.  During this time, the proportion of patients|
03435|086|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03435|087|D|patients.(7)|
03435|088|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03435|089|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03435|090|D|per 100,000 and drug overdose deaths involving both opioids and|
03435|091|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03435|092|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03435|093|D|increased from 18% to 31% during this time.(8)|
03435|094|D|   A prospective observational cohort study in North Carolina found that the|
03435|095|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03435|096|D|benzodiazepines were 10 times higher than patients receiving opioid|
03435|097|D|analgesics alone.(9)|
03435|098|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03435|099|D|death from overdose increased with concomitant opioid analgesics and|
03435|100|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03435|101|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03435|102|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03435|103|D|increased risk of fatal overdose.(10)|
03435|104|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03435|105|D|which benzodiazepines were determined to be a cause of death and that|
03435|106|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03435|107|D|determined to be a cause of death.  This study also found that other CNS|
03435|108|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03435|109|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03435|110|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03435|111|D|where opioid analgesics were also implicated.(11)|
03435|112|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03435|113|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03435|114|D|deaths.(12)|
03435|115|B||
03435|116|R|REFERENCES:|
03435|117|B||
03435|118|R|1.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
03435|119|R|  Roxane Laboratories, Inc. May, 2001.|1
03435|120|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03435|121|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03435|122|R|  settings: a scientific statement from the American Heart Association and|6
03435|123|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03435|124|R|  2;55(9):934-47.|6
03435|125|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03435|126|R|  warns about serious risks and death when combining opioid pain or cough|1
03435|127|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03435|128|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03435|129|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03435|130|R|  prescribing information for all opioid pain medicines to provide|1
03435|131|R|  additional guidance for safe use. Available at:|1
03435|132|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03435|133|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03435|134|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03435|135|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03435|136|R|  recommends health care professionals discuss naloxone with all patients|1
03435|137|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03435|138|R|  disorder. Available at:|1
03435|139|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03435|140|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03435|141|R|  d-pain July 23, 2020.|1
03435|142|R|6.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03435|143|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03435|144|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03435|145|R|  Pharmacol 2020 Apr 26.|2
03435|146|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03435|147|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03435|148|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03435|149|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03435|150|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03435|151|R|  49(4):493-501.|2
03435|152|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03435|153|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03435|154|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03435|155|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03435|156|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03435|157|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03435|158|R|   350:h2698.|2
03435|159|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03435|160|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03435|161|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03435|162|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03435|163|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03435|164|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03436|001|T|MONOGRAPH TITLE:  Levomethadyl (IR)/Selected Antipsychotics that Prolong QT|
03436|002|B||
03436|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03436|004|L|is contraindicated and generally should not be dispensed or administered to|
03436|005|L|the same patient.|
03436|006|B||
03436|007|A|MECHANISM OF ACTION:  Levomethadyl has been shown to prolong the QTc|
03436|008|A|interval.  Concurrent use with selected antipsychotics may result in|
03436|009|A|additive effects on the QTc interval.(1,2)|
03436|010|A|   Concurrent use of opioids such as levomethadyl and antipsychotics,|
03436|011|A|including phenothiazine derivatives, may result in additive CNS|
03436|012|A|depression.(3)|
03436|013|B||
03436|014|E|CLINICAL EFFECTS:  The concurrent use of levomethadyl with other agents that|
03436|015|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03436|016|E|arrhythmias, including torsades de pointes.(1,2)|
03436|017|E|   Concurrent use of opioids such as levomethadyl and other CNS depressants,|
03436|018|E|such as antipsychotics, including phenothiazine derivatives, may result in|
03436|019|E|profound sedation, respiratory depression, coma, and/or death.(3)|
03436|020|B||
03436|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03436|022|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03436|023|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03436|024|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03436|025|P|gender, or advanced age.(2)|
03436|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03436|027|P|higher systemic concentrations of either QT prolonging drug are additional|
03436|028|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03436|029|P|drug concentrations include rapid infusion of an intravenous dose or|
03436|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03436|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03436|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03436|033|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
03436|034|P|of adverse effects.|
03436|035|B||
03436|036|M|PATIENT MANAGEMENT:  The manufacturer of levomethadyl states under|
03436|037|M|contraindications that levomethadyl is contraindicated in patients being|
03436|038|M|treated concomitantly with other drug products known to prolong the QT|
03436|039|M|interval.(1,2)  Limit prescribing opioid analgesics such as levomethadyl|
03436|040|M|with CNS depressants such as antipsychotics, including phenothiazine|
03436|041|M|derivatives, to patients for whom alternatives are ineffective, not|
03436|042|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03436|043|M|of pain.(3)|
03436|044|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03436|045|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03436|046|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03436|047|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03436|048|M|   If concurrent use is necessary, limit the dosages and duration of each|
03436|049|M|drug to the minimum possible while achieving the desired clinical effect.|
03436|050|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03436|051|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03436|052|M|indicated in the absence of an opioid and titrate based upon clinical|
03436|053|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03436|054|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03436|055|M|clinical response.(3)|
03436|056|M|   Respiratory depression can occur at any time during opioid therapy,|
03436|057|M|especially during therapy initiation and following dosage increases.  The|
03436|058|M|risk of opioid-related overdose or overdose-related death is increased with|
03436|059|M|higher opioid doses, and this risk persists over the course of therapy.|
03436|060|M|Consider these risks when using concurrently with other agents that may|
03436|061|M|cause CNS depression.(4)|
03436|062|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03436|063|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03436|064|M|unresponsiveness.(3)|
03436|065|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03436|066|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03436|067|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03436|068|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03436|069|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03436|070|M|as those taking CNS depressants) and when a patient has household|
03436|071|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03436|072|M|for obtaining an opioid reversal agent (e.g., prescription,|
03436|073|M|over-the-counter, or as part of a community-based program).(5)|
03436|074|B||
03436|075|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03436|076|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03436|077|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03436|078|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03436|079|D|significantly increased in patients with recent use of antipsychotics|
03436|080|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03436|081|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03436|082|D|of use.(6)|
03436|083|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03436|084|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03436|085|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03436|086|D|to 30 million patients.  During this time, the proportion of patients|
03436|087|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03436|088|D|patients.(7)|
03436|089|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03436|090|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03436|091|D|per 100,000 and drug overdose deaths involving both opioids and|
03436|092|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03436|093|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03436|094|D|increased from 18% to 31% during this time.(8)|
03436|095|D|   A prospective observational cohort study in North Carolina found that the|
03436|096|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03436|097|D|benzodiazepines were 10 times higher than patients receiving opioid|
03436|098|D|analgesics alone.(9)|
03436|099|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03436|100|D|death from overdose increased with concomitant opioid analgesics and|
03436|101|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03436|102|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03436|103|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03436|104|D|increased risk of fatal overdose.(10)|
03436|105|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03436|106|D|which benzodiazepines were determined to be a cause of death and that|
03436|107|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03436|108|D|determined to be a cause of death.  This study also found that other CNS|
03436|109|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03436|110|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03436|111|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03436|112|D|where opioid analgesics were also implicated.(11)|
03436|113|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03436|114|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03436|115|D|deaths.(12)|
03436|116|B||
03436|117|R|REFERENCES:|
03436|118|B||
03436|119|R|1.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
03436|120|R|  Roxane Laboratories, Inc. May, 2001.|1
03436|121|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03436|122|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03436|123|R|  settings: a scientific statement from the American Heart Association and|6
03436|124|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03436|125|R|  2;55(9):934-47.|6
03436|126|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03436|127|R|  warns about serious risks and death when combining opioid pain or cough|1
03436|128|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03436|129|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03436|130|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03436|131|R|  prescribing information for all opioid pain medicines to provide|1
03436|132|R|  additional guidance for safe use. Available at:|1
03436|133|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03436|134|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03436|135|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03436|136|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03436|137|R|  recommends health care professionals discuss naloxone with all patients|1
03436|138|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03436|139|R|  disorder. Available at:|1
03436|140|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03436|141|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03436|142|R|  d-pain July 23, 2020.|1
03436|143|R|6.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03436|144|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03436|145|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03436|146|R|  Pharmacol 2020 Apr 26.|2
03436|147|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03436|148|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03436|149|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03436|150|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03436|151|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03436|152|R|  49(4):493-501.|2
03436|153|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03436|154|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03436|155|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03436|156|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03436|157|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03436|158|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03436|159|R|   350:h2698.|2
03436|160|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03436|161|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03436|162|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03436|163|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03436|164|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03436|165|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03437|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/CYP2B6 and Selected CYP3A4|
03437|002|T|Inducers|
03437|003|B||
03437|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03437|005|L|take action as needed.|
03437|006|B||
03437|007|A|MECHANISM OF ACTION:  CYP2B6 inducers, phenytoin, and St. John's wort may|
03437|008|A|increase the metabolism of levomethadone and methadone.(1-7)|
03437|009|B||
03437|010|E|CLINICAL EFFECTS:  Concurrent use of CYP2B6 inducers, phenytoin, or St.|
03437|011|E|John's wort may result in decreased levels of levomethadone and methadone,|
03437|012|E|which may result in decreased effectiveness and may precipitate withdrawal|
03437|013|E|symptoms.(1-7)|
03437|014|B||
03437|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03437|016|P|of the inducer for longer than 1-2 weeks.|
03437|017|B||
03437|018|M|PATIENT MANAGEMENT:  Patients maintained on levomethadone or methadone may|
03437|019|M|require dosage adjustments if a CYP2B6 inducer, phenytoin, or St. John's|
03437|020|M|wort is initiated or discontinued.  The effects of the interaction may last|
03437|021|M|for several weeks after the discontinuation of the inducer.|
03437|022|B||
03437|023|D|DISCUSSION:  In a study, efavirenz (600 mg daily) given for 3 weeks in|
03437|024|D|patients on levomethadone led to a decrease in maximum concentration (Cmax)|
03437|025|D|and area-under-curve (AUC) of levomethadone of 48 % and 57 %,|
03437|026|D|respectively.(2)|
03437|027|D|   There are three case reports of patients in methadone maintenance|
03437|028|D|programs who experienced withdrawal symptoms following the initiation of|
03437|029|D|rifampin for tuberculosis therapy.(7,8)  In one of these patients, the|
03437|030|D|methadone clearance was measured at 8.97 ml/min/kg during concurrent|
03437|031|D|administration of rifampin, compared with 2.11 ml/min/kg during methadone|
03437|032|D|alone.(7)|
03437|033|D|   Other reports have documented that methadone-treated patients who|
03437|034|D|received concurrent antituberculosis therapy which included rifampin|
03437|035|D|experienced withdrawal symptoms while methadone-treated patients who|
03437|036|D|received antituberculosis therapy which did not include rifampin did|
03437|037|D|not.(9-12)  Subsequently, it was determined that methadone plasma|
03437|038|D|concentrations were decreased 33% to 68% in patients receiving concurrent|
03437|039|D|rifampin compared with patients on non-rifampin regimens.(9,11-12)|
03437|040|D|   In a study in five patients maintained on methadone, the addition of|
03437|041|D|phenytoin to their regimens resulted in moderately severe withdrawal|
03437|042|D|symptoms and a decrease in the area-under-curve (AUC) for methadone.|
03437|043|D|Methadone plasma concentrations returned to baseline levels two to three|
03437|044|D|days after the discontinuation of phenytoin.(6)|
03437|045|D|   In a study in four patients in a methadone maintenance program, the|
03437|046|D|addition of St. John's wort (900 mg daily) decreased methadone levels by 47%|
03437|047|D|(range: 19%-60%).  Two patients reported withdrawal symptoms.(7)|
03437|048|D|   CYP2B6 inducers linked to this monograph include: carbamazepine,|
03437|049|D|dipyrone, isavuconazonium, ledipasvir/sofosbuvir, phenobarbital, primidone,|
03437|050|D|and rifampin. Fosphenytoin, phenytoin and St. John's wort are also linked.|
03437|051|B||
03437|052|R|REFERENCES:|
03437|053|B||
03437|054|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03437|055|R|  Pharmaceuticals Corp. June, 2021.|1
03437|056|R|2.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03437|057|R|  Pharma AS November 30, 2018.|1
03437|058|R|3.Kharasch ED. Current Concepts in Methadone Metabolism and Transport. Clin|6
03437|059|R|  Pharmacol Drug Dev 2017 Mar;6(2):125-134.|6
03437|060|R|4.Tong TG, Pond SM, Kreek MJ, Jaffery NF, Benowitz NL. Phenytoin-induced|2
03437|061|R|  methadone withdrawal. Ann Intern Med 1981 Mar;94(3):349-51.|2
03437|062|R|5.Eich-Hochli D, Oppliger R, Golay KP, Baumann P, Eap CB. Methadone|2
03437|063|R|  maintenance treatment and St. John's Wort - a case report.|2
03437|064|R|  Pharmacopsychiatry 2003 Jan;36(1):35-7.|2
03437|065|R|6.Raistrick D, Hay A, Wolff K. Methadone maintenance and tuberculosis|3
03437|066|R|  treatment. BMJ 1996 Oct 12;313(7062):925-6.|3
03437|067|R|7.Holmes VF. Rifampin-induced methadone withdrawal in AIDS. J Clin|3
03437|068|R|  Psychopharmacol 1990 Dec;10(6):443-4.|3
03437|069|R|8.Kreek MJ, Garfield JW, Gutjahr CL, Giusti LM. Rifampin-induced methadone|2
03437|070|R|  withdrawal. N Engl J Med 1976 May 13;294(20):1104-6.|2
03437|071|R|9.Bending MR, Skacel PO. Rifampicin and methadone withdrawal. Lancet 1977|3
03437|072|R|  Jun 4;1(8023):1211.|3
03437|073|R|10.Garfield JW, Kreek MJ, Giusti L. Rifampin-methadone relationship. 1. The|4
03437|074|R|   clinical effects of rifampin-methadone interaction. Am Rev Respir Dis|4
03437|075|R|   1975;3:926.|4
03437|076|R|11.Kreek MJ, Garfield JW, Gutjahr CL, Bowen D, Field F, Rothschild M.|4
03437|077|R|   Rifampin-methadone relationship. 2. Rifampin effects on plasma|4
03437|078|R|   concentration, metabolism, and excretion of methadone. Am Rev Respir Dis|4
03437|079|R|   1975;3:926-927.|4
03437|080|R|12.Younis IR, Lakota EA, Volpe DA, Patel V, Xu Y, Sahajwalla CG. Drug-Drug|6
03437|081|R|   Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned. J|6
03437|082|R|   Clin Pharmacol 2019 Aug;59(8):1035-1043.|6
03437|083|R|13.Bell J, Seres V, Bowron P, Lewis J, Batey R. The use of serum methadone|2
03437|084|R|   levels in patients receiving methadone maintenance. Clin Pharmacol Ther|2
03437|085|R|   1988 Jun;43(6):623-9.|2
03438|001|T|MONOGRAPH TITLE:  Methadone/Ivosidenib (mono deleted 06/17/2021)|
03438|002|B||
03438|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03438|004|L|of severe adverse interaction.|
03438|005|B||
03438|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 such as ivosidenib may|
03438|007|A|induce the metabolism of methadone.(1-6)|
03438|008|A|   Methadone has been shown to prolong the QTc interval.  Concurrent use|
03438|009|A|with other agents that prolong the QTc interval such as ivosidenib may|
03438|010|A|result in additive effects on the QTc interval.(1)|
03438|011|B||
03438|012|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer may result in|
03438|013|E|decreased levels of methadone, which may result in decreased effectiveness|
03438|014|E|and may precipitate withdrawal symptoms.(1-6)|
03438|015|E|   The concurrent use of methadone with other agents that prolong the QTc|
03438|016|E|interval may result in potentially life-threatening cardiac arrhythmias,|
03438|017|E|including torsades de pointes.(1,7)|
03438|018|B||
03438|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03438|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03438|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03438|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03438|023|P|gender, or advanced age.(7)|
03438|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03438|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03438|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03438|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03438|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03438|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03438|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)|
03438|031|B||
03438|032|M|PATIENT MANAGEMENT:  Patients maintained on methadone may require dosage|
03438|033|M|adjustments if a strong CYP3A4 inducer is initiated or discontinued.  The|
03438|034|M|effects of the interaction may last for several weeks after the|
03438|035|M|discontinuation of the inducer.|
03438|036|M|   Concurrent use of methadone with other agents known to prolong the QT|
03438|037|M|interval should be approached with extreme caution.(1,2)|
03438|038|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03438|039|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03438|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03438|041|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03438|042|B||
03438|043|D|DISCUSSION:  There are three case reports of patients in methadone|
03438|044|D|maintenance programs who experienced withdrawal symptoms following the|
03438|045|D|initiation of rifampin for tuberculosis therapy.(1-2)  In one of these|
03438|046|D|patients, the methadone clearance was measured at 8.97 ml/min/kg during|
03438|047|D|concurrent administration of rifampin, compared with 2.11 ml/min/kg during|
03438|048|D|methadone alone.(1)|
03438|049|D|   Other reports have documented that methadone-treated patients who|
03438|050|D|received concurrent antituberculosis therapy which included rifampin|
03438|051|D|experienced withdrawal symptoms while methadone-treated patients who|
03438|052|D|received antituberculosis therapy which did not include rifampin did|
03438|053|D|not.(3-6)  Subsequently, it was determined that methadone plasma|
03438|054|D|concentrations were decreased 33% to 68% in patients receiving concurrent|
03438|055|D|rifampin compared with patients on non-rifampin regimens.(3,5-6)|
03438|056|D|   In a study in five patients maintained on methadone, the addition of|
03438|057|D|phenytoin to their regimens resulted in moderately severe withdrawal|
03438|058|D|symptoms and a decrease in the area-under-curve (AUC) for methadone.|
03438|059|D|Methadone plasma concentrations returned to baseline levels two to three|
03438|060|D|days after the discontinuation of phenytoin.(8)|
03438|061|D|   In a study in four patients in a methadone maintenance program, the|
03438|062|D|addition of St. John's wort (900 mg daily) decreased methadone levels by 47%|
03438|063|D|(range: 19%-60%).  Two patients reported withdrawal symptoms.(9)|
03438|064|D|   Most cases of methadone-induced QT prolongation are associated with, but|
03438|065|D|not limited to, higher dose treatment (greater than 200 mg daily) and most|
03438|066|D|involve patients being treated for pain with large, multiple daily doses.|
03438|067|D|Cases have been reported in patients treated with doses commonly used for|
03438|068|D|maintenance treatment of opioid addiction.(1)|
03438|069|B||
03438|070|R|REFERENCES:|
03438|071|B||
03438|072|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03438|073|R|  Pharmaceuticals Corp. June, 2021.|1
03438|074|R|2.Raistrick D, Hay A, Wolff K. Methadone maintenance and tuberculosis|3
03438|075|R|  treatment. BMJ 1996 Oct 12;313(7062):925-6.|3
03438|076|R|3.Holmes VF. Rifampin-induced methadone withdrawal in AIDS. J Clin|3
03438|077|R|  Psychopharmacol 1990 Dec;10(6):443-4.|3
03438|078|R|4.Kreek MJ, Garfield JW, Gutjahr CL, Giusti LM. Rifampin-induced methadone|2
03438|079|R|  withdrawal. N Engl J Med 1976 May 13;294(20):1104-6.|2
03438|080|R|5.Bending MR, Skacel PO. Rifampicin and methadone withdrawal. Lancet 1977|3
03438|081|R|  Jun 4;1(8023):1211.|3
03438|082|R|6.Garfield JW, Kreek MJ, Giusti L. Rifampin-methadone relationship. 1. The|4
03438|083|R|  clinical effects of rifampin-methadone interaction. Am Rev Respir Dis|4
03438|084|R|  1975;3:926.|4
03438|085|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03438|086|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03438|087|R|  settings: a scientific statement from the American Heart Association and|6
03438|088|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03438|089|R|  2;55(9):934-47.|6
03438|090|R|8.Kreek MJ, Garfield JW, Gutjahr CL, Bowen D, Field F, Rothschild M.|4
03438|091|R|  Rifampin-methadone relationship. 2. Rifampin effects on plasma|4
03438|092|R|  concentration, metabolism, and excretion of methadone. Am Rev Respir Dis|4
03438|093|R|  1975;3:926-927.|4
03438|094|R|9.Tong TG, Pond SM, Kreek MJ, Jaffery NF, Benowitz NL. Phenytoin-induced|2
03438|095|R|  methadone withdrawal. Ann Intern Med 1981 Mar;94(3):349-51.|2
03438|096|R|10.Eich-Hochli D, Oppliger R, Golay KP, Baumann P, Eap CB. Methadone|2
03438|097|R|   maintenance treatment and St. John's Wort - a case report.|2
03438|098|R|   Pharmacopsychiatry 2003 Jan;36(1):35-7.|2
03439|001|T|MONOGRAPH TITLE:  Methadone (Immediate Release)/Selected Muscle Relaxants|
03439|002|B||
03439|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03439|004|L|take action as needed.|
03439|005|B||
03439|006|A|MECHANISM OF ACTION:  Concurrent use of methadone and muscle relaxants may|
03439|007|A|result in additive CNS depression.(1)|
03439|008|B||
03439|009|E|CLINICAL EFFECTS:  Concurrent use of methadone and other CNS depressants,|
03439|010|E|such as muscle relaxants, may result in profound sedation, respiratory|
03439|011|E|depression, coma, and/or death.(1)|
03439|012|B||
03439|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03439|014|P|may increase the risk of adverse effects.|
03439|015|B||
03439|016|M|PATIENT MANAGEMENT:  Limit prescribing methadone with CNS depressants such|
03439|017|M|as muscle relaxants to patients for whom alternatives are ineffective, not|
03439|018|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03439|019|M|of pain.(1)|
03439|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
03439|021|M|drug to the minimum possible while achieving the desired clinical effect.|
03439|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03439|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03439|024|M|indicated in the absence of an opioid and titrate based upon clinical|
03439|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03439|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03439|027|M|clinical response.(1)|
03439|028|M|   Respiratory depression can occur at any time during opioid therapy,|
03439|029|M|especially during therapy initiation and following dosage increases.  The|
03439|030|M|risk of opioid-related overdose or overdose-related death is increased with|
03439|031|M|higher opioid doses, and this risk persists over the course of therapy.|
03439|032|M|Consider these risks when using concurrently with other agents that may|
03439|033|M|cause CNS depression.(2)|
03439|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03439|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03439|036|M|unresponsiveness.(1)|
03439|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03439|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03439|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03439|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03439|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03439|042|M|as those taking CNS depressants) and when a patient has household|
03439|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03439|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
03439|045|M|over-the-counter, or as part of a community-based program).(3)|
03439|046|B||
03439|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03439|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03439|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03439|050|D|million to 30 million patients.  During this time, the proportion of|
03439|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03439|052|D|million patients.(4)|
03439|053|D|   A retrospective cohort study compared the risk of opioid overdose|
03439|054|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03439|055|D|versus opioid use alone. The study examined two types of opioid users (naive|
03439|056|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03439|057|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03439|058|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03439|059|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03439|060|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03439|061|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03439|062|D|respectively).  Elevated risk was associated with concomitant users with|
03439|063|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03439|064|D|1.39, respectively).(5)|
03439|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03439|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03439|067|D|per 100,000 and drug overdose deaths involving both opioids and|
03439|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03439|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03439|070|D|increased from 18% to 31% during this time.(6)|
03439|071|D|   A prospective observational cohort study in North Carolina found that the|
03439|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03439|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
03439|074|D|analgesics alone.(7)|
03439|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03439|076|D|death from overdose increased with concomitant opioid analgesics and|
03439|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03439|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03439|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03439|080|D|increased risk of fatal overdose.(8)|
03439|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03439|082|D|which benzodiazepines were determined to be a cause of death and that|
03439|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03439|084|D|determined to be a cause of death.  This study also found that other CNS|
03439|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03439|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03439|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03439|088|D|where opioid analgesics were also implicated.(9)|
03439|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03439|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03439|091|D|deaths.(10)|
03439|092|B||
03439|093|R|REFERENCES:|
03439|094|B||
03439|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03439|096|R|  warns about serious risks and death when combining opioid pain or cough|1
03439|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03439|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03439|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03439|100|R|  prescribing information for all opioid pain medicines to provide|1
03439|101|R|  additional guidance for safe use. Available at:|1
03439|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03439|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03439|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03439|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03439|106|R|  recommends health care professionals discuss naloxone with all patients|1
03439|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03439|108|R|  disorder. Available at:|1
03439|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03439|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03439|111|R|  d-pain July 23, 2020.|1
03439|112|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03439|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03439|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03439|115|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
03439|116|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
03439|117|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
03439|118|R|  Ther 2020 Jul;108(1):81-88.|2
03439|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03439|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03439|121|R|  49(4):493-501.|2
03439|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03439|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03439|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03439|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03439|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03439|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03439|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03439|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03439|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03439|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03439|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03439|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03440|001|T|MONOGRAPH TITLE:  Methadone (Immediate Release)/Tizanidine|
03440|002|B||
03440|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03440|004|L|take action as needed.|
03440|005|B||
03440|006|A|MECHANISM OF ACTION:  Concurrent use of methadone and muscle relaxants may|
03440|007|A|result in additive CNS depression.(1-3)|
03440|008|A|   Levomethadone is an enantiomer of methadone.(4)|
03440|009|A|   Levomethadone and methadone have been shown to prolong the QTc interval.|
03440|010|A|Concurrent use with other agents that prolong the QTc interval may result in|
03440|011|A|additive effects on the QTc interval.(1,4-6)|
03440|012|B||
03440|013|E|CLINICAL EFFECTS:  Concurrent use of methadone and other CNS depressants,|
03440|014|E|such as muscle relaxants, may result in profound sedation, respiratory|
03440|015|E|depression, coma, and/or death.(1-3)|
03440|016|E|   The concurrent use of levomethadone or methadone with other agents that|
03440|017|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03440|018|E|arrhythmias, including torsades de pointes.(1,4-6)|
03440|019|B||
03440|020|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03440|021|P|may increase the risk of adverse effects.|
03440|022|P|   The risk of QT prolongation or torsade de pointes may be increased in|
03440|023|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03440|024|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03440|025|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03440|026|P|advanced age.(5)|
03440|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03440|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03440|029|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03440|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03440|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03440|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03440|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03440|034|B||
03440|035|M|PATIENT MANAGEMENT:  Limit prescribing methadone with CNS depressants such|
03440|036|M|as tizanidine to patients for whom alternatives are ineffective, not|
03440|037|M|tolerated, or would be otherwise inadequate to provide sufficient management|
03440|038|M|of pain.(1)|
03440|039|M|   If concurrent use is necessary, limit the dosages and duration of each|
03440|040|M|drug to the minimum possible while achieving the desired clinical effect.|
03440|041|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03440|042|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03440|043|M|indicated in the absence of an opioid and titrate based upon clinical|
03440|044|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03440|045|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03440|046|M|clinical response.(1)|
03440|047|M|   Respiratory depression can occur at any time during opioid therapy,|
03440|048|M|especially during therapy initiation and following dosage increases.  The|
03440|049|M|risk of opioid-related overdose or overdose-related death is increased with|
03440|050|M|higher opioid doses, and this risk persists over the course of therapy.|
03440|051|M|Consider these risks when using concurrently with other agents that may|
03440|052|M|cause CNS depression.(7)|
03440|053|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03440|054|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03440|055|M|unresponsiveness.(1)|
03440|056|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03440|057|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03440|058|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03440|059|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03440|060|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03440|061|M|as those taking CNS depressants) and when a patient has household|
03440|062|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03440|063|M|for obtaining an opioid reversal agent (e.g., prescription,|
03440|064|M|over-the-counter, or as part of a community-based program).(8)|
03440|065|M|   Concurrent use of methadone with other agents known to prolong the QT|
03440|066|M|interval should be approached with extreme caution.(1-2,5)|
03440|067|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03440|068|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03440|069|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03440|070|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03440|071|B||
03440|072|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03440|073|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03440|074|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03440|075|D|million to 30 million patients.  During this time, the proportion of|
03440|076|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03440|077|D|million patients.(2)|
03440|078|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03440|079|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03440|080|D|per 100,000 and drug overdose deaths involving both opioids and|
03440|081|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03440|082|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03440|083|D|increased from 18% to 31% during this time.(3)|
03440|084|D|   A prospective observational cohort study in North Carolina found that the|
03440|085|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03440|086|D|benzodiazepines were 10 times higher than patients receiving opioid|
03440|087|D|analgesics alone.(4)|
03440|088|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03440|089|D|death from overdose increased with concomitant opioid analgesics and|
03440|090|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03440|091|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03440|092|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03440|093|D|increased risk of fatal overdose.(5)|
03440|094|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03440|095|D|which benzodiazepines were determined to be a cause of death and that|
03440|096|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03440|097|D|determined to be a cause of death.  This study also found that other CNS|
03440|098|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03440|099|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03440|100|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03440|101|D|where opioid analgesics were also implicated.(6)|
03440|102|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03440|103|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03440|104|D|deaths.(9)|
03440|105|D|   Most cases of methadone-induced QT prolongation are associated with, but|
03440|106|D|not limited to, higher dose treatment (greater than 200 mg daily) and most|
03440|107|D|involve patients being treated for pain with large, multiple daily doses.|
03440|108|D|Cases have been reported in patients treated with doses commonly used for|
03440|109|D|maintenance treatment of opioid addiction.(1)|
03440|110|D|   Levomethadone should be used with caution in patients with a history of|
03440|111|D|QT prolongation, advanced heart disease, concomitant CYP3A4 inhibitors, or|
03440|112|D|electrolyte abnormalities.  Cases of QT prolongation and torsades de pointes|
03440|113|D|have been reported, most commonly with high doses.(2)|
03440|114|B||
03440|115|R|REFERENCES:|
03440|116|B||
03440|117|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03440|118|R|  Pharmaceuticals Corp. June, 2021.|1
03440|119|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03440|120|R|  warns about serious risks and death when combining opioid pain or cough|1
03440|121|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03440|122|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03440|123|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03440|124|R|  urges caution about withholding opioid addiction medications from patients|1
03440|125|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03440|126|R|  can reduce risks. available at:|1
03440|127|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03440|128|R|4.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03440|129|R|  Pharma AS November 30, 2018.|1
03440|130|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03440|131|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03440|132|R|  settings: a scientific statement from the American Heart Association and|6
03440|133|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03440|134|R|  2;55(9):934-47.|6
03440|135|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
03440|136|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03440|137|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03440|138|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03440|139|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03440|140|R|  prescribing information for all opioid pain medicines to provide|1
03440|141|R|  additional guidance for safe use. Available at:|1
03440|142|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03440|143|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03440|144|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03440|145|R|8.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03440|146|R|  recommends health care professionals discuss naloxone with all patients|1
03440|147|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03440|148|R|  disorder. Available at:|1
03440|149|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03440|150|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03440|151|R|  d-pain July 23, 2020.|1
03440|152|R|9.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03440|153|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03440|154|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03441|001|T|MONOGRAPH TITLE:  Selected Opioids for MAT/Selected Muscle Relaxants|
03441|002|B||
03441|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03441|004|L|take action as needed.|
03441|005|B||
03441|006|A|MECHANISM OF ACTION:  Concurrent use of diacetylmorphine or methadone and|
03441|007|A|muscle relaxants may result in additive CNS depression.(1-3)|
03441|008|A|   Levomethadone is an enantiomer of methadone.(4)|
03441|009|B||
03441|010|E|CLINICAL EFFECTS:  Concurrent use of diacetylmorphine or methadone and other|
03441|011|E|CNS depressants, such as muscle relaxants, may result in profound sedation,|
03441|012|E|respiratory depression, coma, and/or death.(1-3)|
03441|013|B||
03441|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03441|015|P|may increase the risk of adverse effects.|
03441|016|B||
03441|017|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with|
03441|018|M|diacetylmorphine or methadone is not contraindicated in patients taking CNS|
03441|019|M|depressants; however, discontinuation of CNS depressants is preferred in|
03441|020|M|most cases.  In some cases, monitoring at a higher level of care for|
03441|021|M|tapering may be appropriate.  In others, gradual tapering or decreasing to|
03441|022|M|the lowest effective dose of the CNS depressant is appropriate.  Ensure that|
03441|023|M|other health care providers prescribing other CNS depressants are aware of|
03441|024|M|the patient's diacetylmorphine or methadone treatment.(2)|
03441|025|M|   Respiratory depression can occur at any time during opioid therapy,|
03441|026|M|especially during therapy initiation and following dosage increases.  The|
03441|027|M|risk of opioid-related overdose or overdose-related death is increased with|
03441|028|M|higher opioid doses, and this risk persists over the course of therapy.|
03441|029|M|Consider these risks when using concurrently with other agents that may|
03441|030|M|cause CNS depression.(5)|
03441|031|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03441|032|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03441|033|M|unresponsiveness.(1)|
03441|034|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03441|035|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03441|036|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03441|037|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03441|038|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03441|039|M|as those taking CNS depressants) and when a patient has household|
03441|040|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03441|041|M|for obtaining an opioid reversal agent (e.g., prescription,|
03441|042|M|over-the-counter, or as part of a community-based program).(6)|
03441|043|B||
03441|044|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03441|045|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03441|046|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03441|047|D|million to 30 million patients.  During this time, the proportion of|
03441|048|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03441|049|D|million patients.(7)|
03441|050|D|   A retrospective cohort study compared the risk of opioid overdose|
03441|051|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03441|052|D|versus opioid use alone. The study examined two types of opioid users (naive|
03441|053|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03441|054|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03441|055|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03441|056|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03441|057|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03441|058|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03441|059|D|respectively).  Elevated risk was associated with concomitant users with|
03441|060|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03441|061|D|1.39, respectively).(8)|
03441|062|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03441|063|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03441|064|D|per 100,000 and drug overdose deaths involving both opioids and|
03441|065|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03441|066|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03441|067|D|increased from 18% to 31% during this time.(9)|
03441|068|D|   A prospective observational cohort study in North Carolina found that the|
03441|069|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03441|070|D|benzodiazepines were 10 times higher than patients receiving opioid|
03441|071|D|analgesics alone.(10)|
03441|072|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03441|073|D|death from overdose increased with concomitant opioid analgesics and|
03441|074|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03441|075|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03441|076|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03441|077|D|increased risk of fatal overdose.(11)|
03441|078|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03441|079|D|which benzodiazepines were determined to be a cause of death and that|
03441|080|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03441|081|D|determined to be a cause of death.  This study also found that other CNS|
03441|082|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03441|083|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03441|084|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03441|085|D|where opioid analgesics were also implicated.(12)|
03441|086|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03441|087|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03441|088|D|deaths.(13)|
03441|089|D|   While concomitant use of MAT with CNS depressants increases the risk of|
03441|090|D|adverse reactions, barriers to MAT can pose a greater risk of morbidity and|
03441|091|D|mortality due to opioid use disorder.(2)|
03441|092|B||
03441|093|R|REFERENCES:|
03441|094|B||
03441|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03441|096|R|  warns about serious risks and death when combining opioid pain or cough|1
03441|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03441|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03441|099|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03441|100|R|  urges caution about withholding opioid addiction medications from patients|1
03441|101|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03441|102|R|  can reduce risks. available at:|1
03441|103|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03441|104|R|3.Diacetylmorphine Canadian prescribing information. Pharmascience Inc.|1
03441|105|R|  February, 2022.|1
03441|106|R|4.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03441|107|R|  Pharma AS November 30, 2018.|1
03441|108|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03441|109|R|  prescribing information for all opioid pain medicines to provide|1
03441|110|R|  additional guidance for safe use. Available at:|1
03441|111|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03441|112|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03441|113|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03441|114|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03441|115|R|  recommends health care professionals discuss naloxone with all patients|1
03441|116|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03441|117|R|  disorder. Available at:|1
03441|118|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03441|119|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03441|120|R|  d-pain July 23, 2020.|1
03441|121|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03441|122|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03441|123|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03441|124|R|8.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
03441|125|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
03441|126|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
03441|127|R|  Ther 2020 Jul;108(1):81-88.|2
03441|128|R|9.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03441|129|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03441|130|R|  49(4):493-501.|2
03441|131|R|10.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03441|132|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03441|133|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03441|134|R|11.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03441|135|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03441|136|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03441|137|R|   350:h2698.|2
03441|138|R|12.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03441|139|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03441|140|R|13.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03441|141|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03441|142|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03441|143|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03442|001|T|MONOGRAPH TITLE:  Methadone for MAT/Tizanidine|
03442|002|B||
03442|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03442|004|L|take action as needed.|
03442|005|B||
03442|006|A|MECHANISM OF ACTION:  Concurrent use of methadone and muscle relaxants may|
03442|007|A|result in additive CNS depression.(1-3)|
03442|008|A|   Levomethadone is an enantiomer of methadone.(4)|
03442|009|A|   Levomethadone and methadone have been shown to prolong the QTc interval.|
03442|010|A|Concurrent use with other agents that prolong the QTc interval, such as|
03442|011|A|tizanidine, may result in additive effects on the QTc interval.(1,4-6)|
03442|012|B||
03442|013|E|CLINICAL EFFECTS:  Concurrent use of methadone and other CNS depressants,|
03442|014|E|such as muscle relaxants, may result in profound sedation, respiratory|
03442|015|E|depression, coma, and/or death.(1-3)|
03442|016|E|   The concurrent use of levomethadone or methadone with other agents that|
03442|017|E|prolong the QTc interval, such as tizanidine, may result in potentially|
03442|018|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1,4-6)|
03442|019|B||
03442|020|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03442|021|P|may increase the risk of adverse effects.|
03442|022|P|   The risk of QT prolongation or torsade de pointes may be increased in|
03442|023|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03442|024|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03442|025|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03442|026|P|advanced age.(5)|
03442|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03442|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03442|029|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03442|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03442|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03442|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03442|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03442|034|B||
03442|035|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with methadone is|
03442|036|M|not contraindicated in patients taking CNS depressants; however,|
03442|037|M|discontinuation of CNS depressants is preferred in most cases.  In some|
03442|038|M|cases, monitoring at a higher level of care for tapering may be appropriate.|
03442|039|M|In others, gradual tapering or decreasing to the lowest effective dose of|
03442|040|M|the CNS depressant is appropriate.  Ensure that other health care providers|
03442|041|M|prescribing other CNS depressants are aware of the patient's methadone|
03442|042|M|treatment.(2)|
03442|043|M|   Respiratory depression can occur at any time during opioid therapy,|
03442|044|M|especially during therapy initiation and following dosage increases.  The|
03442|045|M|risk of opioid-related overdose or overdose-related death is increased with|
03442|046|M|higher opioid doses, and this risk persists over the course of therapy.|
03442|047|M|Consider these risks when using concurrently with other agents that may|
03442|048|M|cause CNS depression.(7)|
03442|049|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03442|050|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03442|051|M|unresponsiveness.(2)|
03442|052|M|   Concurrent use of levomethadone or methadone with other agents known to|
03442|053|M|prolong the QT interval should be approached with extreme caution.(1-2,5)|
03442|054|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03442|055|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03442|056|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03442|057|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03442|058|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03442|059|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03442|060|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03442|061|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03442|062|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03442|063|M|as those taking CNS depressants) and when a patient has household|
03442|064|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03442|065|M|for obtaining an opioid reversal agent (e.g., prescription,|
03442|066|M|over-the-counter, or as part of a community-based program).(8)|
03442|067|B||
03442|068|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03442|069|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03442|070|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03442|071|D|million to 30 million patients.  During this time, the proportion of|
03442|072|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03442|073|D|million patients.(9)|
03442|074|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03442|075|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03442|076|D|per 100,000 and drug overdose deaths involving both opioids and|
03442|077|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03442|078|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03442|079|D|increased from 18% to 31% during this time.(10)|
03442|080|D|   A prospective observational cohort study in North Carolina found that the|
03442|081|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03442|082|D|benzodiazepines were 10 times higher than patients receiving opioid|
03442|083|D|analgesics alone.(11)|
03442|084|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03442|085|D|death from overdose increased with concomitant opioid analgesics and|
03442|086|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03442|087|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03442|088|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03442|089|D|increased risk of fatal overdose.(12)|
03442|090|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03442|091|D|which benzodiazepines were determined to be a cause of death and that|
03442|092|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03442|093|D|determined to be a cause of death.  This study also found that other CNS|
03442|094|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03442|095|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03442|096|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03442|097|D|where opioid analgesics were also implicated.(13)|
03442|098|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03442|099|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03442|100|D|deaths.(14)|
03442|101|D|   While concomitant use of MAT with CNS depressants increases the risk of|
03442|102|D|adverse reactions, barriers to MAT can pose a greater risk of morbidity and|
03442|103|D|mortality due to opioid use disorder.(3)|
03442|104|D|   Most cases of methadone-induced QT prolongation are associated with, but|
03442|105|D|not limited to, higher dose treatment (greater than 200 mg daily) and most|
03442|106|D|involve patients being treated for pain with large, multiple daily doses.|
03442|107|D|Cases have been reported in patients treated with doses commonly used for|
03442|108|D|maintenance treatment of opioid addiction.(1)|
03442|109|D|   Levomethadone should be used with caution in patients with a history of|
03442|110|D|QT prolongation, advanced heart disease, concomitant CYP3A4 inhibitors, or|
03442|111|D|electrolyte abnormalities.  Cases of QT prolongation and torsades de pointes|
03442|112|D|have been reported, most commonly with high doses.(2)|
03442|113|B||
03442|114|R|REFERENCES:|
03442|115|B||
03442|116|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03442|117|R|  Pharmaceuticals Corp. June, 2021.|1
03442|118|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03442|119|R|  warns about serious risks and death when combining opioid pain or cough|1
03442|120|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03442|121|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03442|122|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03442|123|R|  urges caution about withholding opioid addiction medications from patients|1
03442|124|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03442|125|R|  can reduce risks. available at:|1
03442|126|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03442|127|R|4.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03442|128|R|  Pharma AS November 30, 2018.|1
03442|129|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03442|130|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03442|131|R|  settings: a scientific statement from the American Heart Association and|6
03442|132|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03442|133|R|  2;55(9):934-47.|6
03442|134|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
03442|135|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03442|136|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03442|137|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03442|138|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03442|139|R|  prescribing information for all opioid pain medicines to provide|1
03442|140|R|  additional guidance for safe use. Available at:|1
03442|141|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03442|142|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03442|143|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03442|144|R|8.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03442|145|R|  recommends health care professionals discuss naloxone with all patients|1
03442|146|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03442|147|R|  disorder. Available at:|1
03442|148|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03442|149|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03442|150|R|  d-pain July 23, 2020.|1
03442|151|R|9.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03442|152|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03442|153|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03442|154|R|10.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03442|155|R|   From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015|2
03442|156|R|   Oct;49(4):493-501.|2
03442|157|R|11.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03442|158|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03442|159|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03442|160|R|12.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03442|161|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03442|162|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03442|163|R|   350:h2698.|2
03442|164|R|13.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03442|165|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03442|166|R|14.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03442|167|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03442|168|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03442|169|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03443|001|T|MONOGRAPH TITLE:  Methadone (Cough and Cold)/Selected Muscle Relaxants|
03443|002|B||
03443|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03443|004|L|of severe adverse interaction.|
03443|005|B||
03443|006|A|MECHANISM OF ACTION:  Concurrent use of methadone and muscle relaxants may|
03443|007|A|result in additive CNS depression.(1)|
03443|008|B||
03443|009|E|CLINICAL EFFECTS:  Concurrent use of methadone and other CNS depressants,|
03443|010|E|such as muscle relaxants, may result in profound sedation, respiratory|
03443|011|E|depression, coma, and/or death.(1)|
03443|012|B||
03443|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03443|014|P|may increase the risk of adverse effects.|
03443|015|B||
03443|016|M|PATIENT MANAGEMENT:  Avoid prescribing methadone-including cough and cold|
03443|017|M|medications for patients taking CNS depressants such as muscle relaxants.(1)|
03443|018|M|   Respiratory depression can occur at any time during opioid therapy,|
03443|019|M|especially during therapy initiation and following dosage increases.  The|
03443|020|M|risk of opioid-related overdose or overdose-related death is increased with|
03443|021|M|higher opioid doses, and this risk persists over the course of therapy.|
03443|022|M|Consider these risks when using concurrently with other agents that may|
03443|023|M|cause CNS depression.(2)|
03443|024|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
03443|025|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03443|026|M|unresponsiveness.(1)|
03443|027|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03443|028|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03443|029|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03443|030|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03443|031|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03443|032|M|as those taking CNS depressants) and when a patient has household|
03443|033|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03443|034|M|for obtaining an opioid reversal agent (e.g., prescription,|
03443|035|M|over-the-counter, or as part of a community-based program).(3)|
03443|036|B||
03443|037|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03443|038|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03443|039|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03443|040|D|million to 30 million patients.  During this time, the proportion of|
03443|041|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03443|042|D|million patients.(4)|
03443|043|D|   A retrospective cohort study compared the risk of opioid overdose|
03443|044|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03443|045|D|versus opioid use alone. The study examined two types of opioid users (naive|
03443|046|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03443|047|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03443|048|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03443|049|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03443|050|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03443|051|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03443|052|D|respectively).  Elevated risk was associated with concomitant users with|
03443|053|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03443|054|D|1.39, respectively).(5)|
03443|055|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03443|056|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03443|057|D|per 100,000 and drug overdose deaths involving both opioids and|
03443|058|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03443|059|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03443|060|D|increased from 18% to 31% during this time.(6)|
03443|061|D|   A prospective observational cohort study in North Carolina found that the|
03443|062|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03443|063|D|benzodiazepines were 10 times higher than patients receiving opioid|
03443|064|D|analgesics alone.(7)|
03443|065|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03443|066|D|death from overdose increased with concomitant opioid analgesics and|
03443|067|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03443|068|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03443|069|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03443|070|D|increased risk of fatal overdose.(8)|
03443|071|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03443|072|D|which benzodiazepines were determined to be a cause of death and that|
03443|073|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03443|074|D|determined to be a cause of death.  This study also found that other CNS|
03443|075|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03443|076|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03443|077|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03443|078|D|where opioid analgesics were also implicated.(9)|
03443|079|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03443|080|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03443|081|D|deaths.(10)|
03443|082|B||
03443|083|R|REFERENCES:|
03443|084|B||
03443|085|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03443|086|R|  warns about serious risks and death when combining opioid pain or cough|1
03443|087|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03443|088|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03443|089|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03443|090|R|  prescribing information for all opioid pain medicines to provide|1
03443|091|R|  additional guidance for safe use. Available at:|1
03443|092|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03443|093|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03443|094|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03443|095|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03443|096|R|  recommends health care professionals discuss naloxone with all patients|1
03443|097|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03443|098|R|  disorder. Available at:|1
03443|099|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03443|100|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03443|101|R|  d-pain July 23, 2020.|1
03443|102|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03443|103|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03443|104|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03443|105|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
03443|106|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
03443|107|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
03443|108|R|  Ther 2020 Jul;108(1):81-88.|2
03443|109|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03443|110|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03443|111|R|  49(4):493-501.|2
03443|112|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03443|113|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03443|114|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03443|115|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03443|116|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03443|117|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03443|118|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03443|119|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03443|120|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03443|121|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03443|122|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03443|123|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03444|001|T|MONOGRAPH TITLE:  Methadone (Cough and Cold)/Tizanidine|
03444|002|B||
03444|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03444|004|L|of severe adverse interaction.|
03444|005|B||
03444|006|A|MECHANISM OF ACTION:  Concurrent use of methadone and tizanidine may result|
03444|007|A|in additive CNS depression.(1)|
03444|008|A|   Methadone has been shown to prolong the QTc interval.  Concurrent use|
03444|009|A|with other agents that prolong the QTc interval may result in additive|
03444|010|A|effects on the QTc interval.(1,4-5)|
03444|011|B||
03444|012|E|CLINICAL EFFECTS:  Concurrent use of methadone and other CNS depressants,|
03444|013|E|such as tizanidine, may result in profound sedation, respiratory depression,|
03444|014|E|coma, and/or death.(1-3)|
03444|015|E|   The concurrent use of methadone with other agents that prolong the QTc|
03444|016|E|interval may result in potentially life-threatening cardiac arrhythmias,|
03444|017|E|including torsades de pointes.(1,4-5)|
03444|018|B||
03444|019|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03444|020|P|may increase the risk of adverse effects.|
03444|021|P|   The risk of QT prolongation or torsade de pointes may be increased in|
03444|022|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03444|023|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03444|024|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03444|025|P|advanced age.(4)|
03444|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03444|027|P|higher systemic concentrations of either QT prolonging drug are additional|
03444|028|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03444|029|P|drug concentrations include rapid infusion of an intravenous dose or|
03444|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03444|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03444|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03444|033|B||
03444|034|M|PATIENT MANAGEMENT:  Avoid prescribing methadone-including cough medications|
03444|035|M|for patients taking CNS depressants such as tizanidine.(1)|
03444|036|M|   Respiratory depression can occur at any time during opioid therapy,|
03444|037|M|especially during therapy initiation and following dosage increases.|
03444|038|M|Consider this risk when using concurrently with other agents that may cause|
03444|039|M|CNS depression.(6)|
03444|040|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
03444|041|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03444|042|M|unresponsiveness.(1)|
03444|043|M|   Discuss naloxone with all patients when prescribing or renewing an opioid|
03444|044|M|analgesic or medicine to treat opioid use disorder (OUD).  Consider|
03444|045|M|prescribing naloxone to patients prescribed medicines to treat OUD or opioid|
03444|046|M|analgesics who are at increased risk of opioid overdose (such as those|
03444|047|M|taking CNS depressants) and when a patient has household members/close|
03444|048|M|contacts at risk for accidental overdose.(7)|
03444|049|M|   Concurrent use of methadone with other agents known to prolong the QT|
03444|050|M|interval should be approached with extreme caution.(1-2,4)|
03444|051|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03444|052|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03444|053|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03444|054|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03444|055|B||
03444|056|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03444|057|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03444|058|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03444|059|D|million to 30 million patients.  During this time, the proportion of|
03444|060|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03444|061|D|million patients.(2)|
03444|062|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03444|063|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03444|064|D|per 100,000 and drug overdose deaths involving both opioids and|
03444|065|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03444|066|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03444|067|D|increased from 18% to 31% during this time.(3)|
03444|068|D|   A prospective observational cohort study in North Carolina found that the|
03444|069|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03444|070|D|benzodiazepines were 10 times higher than patients receiving opioid|
03444|071|D|analgesics alone.(4)|
03444|072|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03444|073|D|death from overdose increased with concomitant opioid analgesics and|
03444|074|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03444|075|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03444|076|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03444|077|D|increased risk of fatal overdose.(5)|
03444|078|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03444|079|D|which benzodiazepines were determined to be a cause of death and that|
03444|080|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03444|081|D|determined to be a cause of death.  This study also found that other CNS|
03444|082|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03444|083|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03444|084|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03444|085|D|where opioid analgesics were also implicated.(8)|
03444|086|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03444|087|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03444|088|D|deaths.(9)|
03444|089|D|   Most cases of methadone-induced QT prolongation are associated with, but|
03444|090|D|not limited to, higher dose treatment (greater than 200 mg daily) and most|
03444|091|D|involve patients being treated for pain with large, multiple daily doses.|
03444|092|D|Cases have been reported in patients treated with doses commonly used for|
03444|093|D|maintenance treatment of opioid addiction.(1)|
03444|094|B||
03444|095|R|REFERENCES:|
03444|096|B||
03444|097|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03444|098|R|  Pharmaceuticals Corp. June, 2021.|1
03444|099|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03444|100|R|  warns about serious risks and death when combining opioid pain or cough|1
03444|101|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03444|102|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03444|103|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03444|104|R|  urges caution about withholding opioid addiction medications from patients|1
03444|105|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03444|106|R|  can reduce risks. available at:|1
03444|107|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03444|108|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03444|109|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03444|110|R|  settings: a scientific statement from the American Heart Association and|6
03444|111|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03444|112|R|  2;55(9):934-47.|6
03444|113|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03444|114|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03444|115|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03444|116|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03444|117|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03444|118|R|  prescribing information for all opioid pain medicines to provide|1
03444|119|R|  additional guidance for safe use. Available at:|1
03444|120|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03444|121|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03444|122|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03444|123|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03444|124|R|  recommends health care professionals discuss naloxone with all patients|1
03444|125|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03444|126|R|  disorder. Available at:|1
03444|127|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03444|128|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03444|129|R|  d-pain July 23, 2020.|1
03444|130|R|8.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03444|131|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03444|132|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03444|133|R|9.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03444|134|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03444|135|R|  49(4):493-501.|2
03445|001|T|MONOGRAPH TITLE:  Levomethadyl/Selected Strong CYP3A4 Inducers|
03445|002|B||
03445|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03445|004|L|take action as needed.|
03445|005|B||
03445|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03445|007|A|levomethadyl.(1)|
03445|008|B||
03445|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer may result in|
03445|010|E|decreased levels of levomethadyl, which may result in decreased|
03445|011|E|effectiveness and may precipitate withdrawal symptoms.(1)|
03445|012|B||
03445|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03445|014|P|of the inducer for longer than 1-2 weeks.|
03445|015|B||
03445|016|M|PATIENT MANAGEMENT:  Patients maintained on levomethadyl may require dosage|
03445|017|M|adjustments if a strong CYP3A4 inducer is initiated or discontinued.  The|
03445|018|M|effects of the interaction may last for several weeks after the|
03445|019|M|discontinuation of the inducer.|
03445|020|B||
03445|021|D|DISCUSSION:  Interaction studies have not been conducted in humans.  The|
03445|022|D|primary metabolism pathway for levomethadyl is CYP3A4.  The addition of|
03445|023|D|drugs that induce CYP3A4 may increase levels of the active metabolite.(1)|
03445|024|D|   Selected strong CYP3A4 inducers linked to this monograph include:|
03445|025|D|apalutamide, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
03445|026|D|mitotane, phenytoin, rifampin, rifapentine, and St. John's Wort.|
03445|027|B||
03445|028|R|REFERENCE:|
03445|029|B||
03445|030|R|1.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
03445|031|R|  Roxane Laboratories, Inc. May, 2001.|1
03446|001|T|MONOGRAPH TITLE:  Levomethadyl/Strong CYP3A4 Inducers that Prolong QT|
03446|002|B||
03446|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03446|004|L|of severe adverse interaction.|
03446|005|B||
03446|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03446|007|A|levomethadyl.(1)|
03446|008|A|   Levomethadyl has been shown to prolong the QTc interval.  Concurrent use|
03446|009|A|with other agents that prolong the QTc interval may result in additive|
03446|010|A|effects on the QTc interval.(1)|
03446|011|B||
03446|012|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer may result in|
03446|013|E|decreased levels of levomethadyl, which may result in decreased|
03446|014|E|effectiveness and may precipitate withdrawal symptoms.(1)|
03446|015|E|   The concurrent use of levomethadyl with other agents that prolong the QTc|
03446|016|E|interval may result in potentially life-threatening cardiac arrhythmias,|
03446|017|E|including torsades de pointes.(1)|
03446|018|B||
03446|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03446|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03446|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03446|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03446|023|P|gender, or advanced age.(2)|
03446|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03446|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03446|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03446|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03446|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03446|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03446|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03446|031|P|   Induction effects may be more likely with regular use of the inducer for|
03446|032|P|longer than 1-2 weeks.|
03446|033|B||
03446|034|M|PATIENT MANAGEMENT:  Patients maintained on levomethadyl may require dosage|
03446|035|M|adjustments if a strong CYP3A4 inducer is initiated or discontinued.  The|
03446|036|M|effects of the interaction may last for several weeks after the|
03446|037|M|discontinuation of the inducer.|
03446|038|M|   Concurrent use of levomethadyl with other agents known to prolong the QT|
03446|039|M|interval are contraindicated.(1)|
03446|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03446|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03446|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03446|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03446|044|B||
03446|045|D|DISCUSSION:  Interaction studies have not been conducted in humans.  The|
03446|046|D|primary metabolism pathway for levomethadyl is CYP3A4.  The addition of|
03446|047|D|drugs that induce CYP3A4 may increase levels of the active metabolite.(1)|
03446|048|D|   Strong CYP3A4 inducers linked to this monograph include: encorafenib and|
03446|049|D|ivosidenib.(3)|
03446|050|B||
03446|051|R|REFERENCES:|
03446|052|B||
03446|053|R|1.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
03446|054|R|  Roxane Laboratories, Inc. May, 2001.|1
03446|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03446|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03446|057|R|  settings: a scientific statement from the American Heart Association and|6
03446|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03446|059|R|  2;55(9):934-47.|6
03446|060|R|3.This information is based on an extract from the Certara Drug Interaction|6
03446|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03447|001|T|MONOGRAPH TITLE:  Levomethadyl/Selected Muscle Relaxants|
03447|002|B||
03447|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03447|004|L|take action as needed.|
03447|005|B||
03447|006|A|MECHANISM OF ACTION:  Concurrent use of levomethadyl and muscle relaxants|
03447|007|A|may result in additive CNS depression.(1)|
03447|008|B||
03447|009|E|CLINICAL EFFECTS:  Concurrent use of levomethadyl and other CNS depressants,|
03447|010|E|such as muscle relaxants, may result in profound sedation, respiratory|
03447|011|E|depression, coma, and/or death.(1)|
03447|012|B||
03447|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03447|014|P|may increase the risk of adverse effects.|
03447|015|B||
03447|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
03447|017|M|depressants such as muscle relaxants to patients for whom alternatives are|
03447|018|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
03447|019|M|sufficient management of pain.(1)|
03447|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
03447|021|M|drug to the minimum possible while achieving the desired clinical effect.|
03447|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03447|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03447|024|M|indicated in the absence of an opioid and titrate based upon clinical|
03447|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03447|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03447|027|M|clinical response.(1)|
03447|028|M|   Respiratory depression can occur at any time during opioid therapy,|
03447|029|M|especially during therapy initiation and following dosage increases.  The|
03447|030|M|risk of opioid-related overdose or overdose-related death is increased with|
03447|031|M|higher opioid doses, and this risk persists over the course of therapy.|
03447|032|M|Consider these risks when using concurrently with other agents that may|
03447|033|M|cause CNS depression.(2)|
03447|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03447|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03447|036|M|unresponsiveness.(1)|
03447|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03447|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03447|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03447|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03447|041|M|OUD or opioid analgesics ho are at increased risk of opioid overdose (such|
03447|042|M|as those taking CNS depressants) and when a patient has household|
03447|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03447|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
03447|045|M|over-the-counter, or as part of a community-based program).(3)|
03447|046|B||
03447|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03447|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03447|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03447|050|D|million to 30 million patients.  During this time, the proportion of|
03447|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03447|052|D|million patients.(4)|
03447|053|D|   A retrospective cohort study compared the risk of opioid overdose|
03447|054|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03447|055|D|versus opioid use alone. The study examined two types of opioid users (naive|
03447|056|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03447|057|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03447|058|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03447|059|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03447|060|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03447|061|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03447|062|D|respectively).  Elevated risk was associated with concomitant users with|
03447|063|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03447|064|D|1.39, respectively).(5)|
03447|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03447|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03447|067|D|per 100,000 and drug overdose deaths involving both opioids and|
03447|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03447|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03447|070|D|increased from 18% to 31% during this time.(6)|
03447|071|D|   A prospective observational cohort study in North Carolina found that the|
03447|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03447|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
03447|074|D|analgesics alone.(7)|
03447|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03447|076|D|death from overdose increased with concomitant opioid analgesics and|
03447|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03447|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03447|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03447|080|D|increased risk of fatal overdose.(8)|
03447|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03447|082|D|which benzodiazepines were determined to be a cause of death and that|
03447|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03447|084|D|determined to be a cause of death.  This study also found that other CNS|
03447|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03447|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03447|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03447|088|D|where opioid analgesics were also implicated.(9)|
03447|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03447|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03447|091|D|deaths.(10)|
03447|092|B||
03447|093|R|REFERENCES:|
03447|094|B||
03447|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03447|096|R|  warns about serious risks and death when combining opioid pain or cough|1
03447|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03447|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03447|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03447|100|R|  prescribing information for all opioid pain medicines to provide|1
03447|101|R|  additional guidance for safe use. Available at:|1
03447|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03447|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03447|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03447|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03447|106|R|  recommends health care professionals discuss naloxone with all patients|1
03447|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03447|108|R|  disorder. Available at:|1
03447|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03447|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03447|111|R|  d-pain July 23, 2020.|1
03447|112|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03447|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03447|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03447|115|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
03447|116|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
03447|117|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
03447|118|R|  Ther 2020 Jul;108(1):81-88.|2
03447|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03447|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03447|121|R|  49(4):493-501.|2
03447|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03447|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03447|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03447|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03447|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03447|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03447|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03447|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03447|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03447|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03447|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03447|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03448|001|T|MONOGRAPH TITLE:  Levomethadyl/Tizanidine|
03448|002|B||
03448|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03448|004|L|of severe adverse interaction.|
03448|005|B||
03448|006|A|MECHANISM OF ACTION:  Concurrent use of levomethadyl and tizanidine may|
03448|007|A|result in additive CNS depression.(1,2)|
03448|008|A|   Levomethadyl has been shown to prolong the QTc interval and induce|
03448|009|A|torsades de pointes. Concurrent use with other agents that prolong the QTc|
03448|010|A|interval may result in additive effects on the QTc interval.(1)|
03448|011|B||
03448|012|E|CLINICAL EFFECTS:  Concurrent use of levomethadyl and other CNS depressants,|
03448|013|E|such as tizanidine, may result in profound sedation, respiratory depression,|
03448|014|E|coma, and/or death.(1,2)|
03448|015|E|   The concurrent use of levomethadyl with other agents that prolong the QTc|
03448|016|E|interval may result in potentially life-threatening cardiac arrhythmias,|
03448|017|E|including torsades de pointes.(1)|
03448|018|B||
03448|019|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03448|020|P|may increase the risk of adverse effects.|
03448|021|P|   Congestive heart failure, bradycardia, diuretic use, cardiac hypertrophy,|
03448|022|P|hypokalemia, or hypomagnesemia may increase the risk of torsades de pointes|
03448|023|P|and/or sudden death.(1)|
03448|024|P|   The risk of QT prolongation or torsade de pointes may also be increased|
03448|025|P|in patients with cardiovascular disease (e.g. myocardial infarction, history|
03448|026|P|of torsade de pointes, congenital long QT syndrome), hypocalcemia, female|
03448|027|P|gender, or advanced age.(3)|
03448|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03448|029|P|higher systemic concentrations of either QT prolonging drug are additional|
03448|030|P|risk factors for torsade de pointes.   Factors which may increase systemic|
03448|031|P|drug concentrations include rapid infusion of an intravenous dose or|
03448|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03448|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03448|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03448|035|B||
03448|036|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
03448|037|M|depressants such as tizanidine to patients for whom alternatives are|
03448|038|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
03448|039|M|sufficient management of pain.(1)|
03448|040|M|   If concurrent use is necessary, limit the dosages and duration of each|
03448|041|M|drug to the minimum possible while achieving the desired clinical effect.|
03448|042|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03448|043|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03448|044|M|indicated in the absence of an opioid and titrate based upon clinical|
03448|045|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03448|046|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03448|047|M|clinical response.(1,2)|
03448|048|M|   Respiratory depression can occur at any time during opioid therapy,|
03448|049|M|especially during therapy initiation and following dosage increases.  The|
03448|050|M|risk of opioid-related overdose or overdose-related death is increased with|
03448|051|M|higher opioid doses, and this risk persists over the course of therapy.|
03448|052|M|Consider these risks when using concurrently with other agents that may|
03448|053|M|cause CNS depression.(5)|
03448|054|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03448|055|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03448|056|M|unresponsiveness.(1,2)|
03448|057|M|   The manufacturer of levomethadyl states under contraindications that|
03448|058|M|levomethadyl is contraindicated in patients being treated concomitantly with|
03448|059|M|other drug products known to prolong the QT interval.(1)|
03448|060|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03448|061|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03448|062|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03448|063|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03448|064|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03448|065|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03448|066|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03448|067|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03448|068|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03448|069|M|as those taking CNS depressants) and when a patient has household|
03448|070|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03448|071|M|for obtaining an opioid reversal agent (e.g., prescription,|
03448|072|M|over-the-counter, or as part of a community-based program).(6)|
03448|073|B||
03448|074|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03448|075|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03448|076|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03448|077|D|million to 30 million patients.  During this time, the proportion of|
03448|078|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03448|079|D|million patients.(7)|
03448|080|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03448|081|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03448|082|D|per 100,000 and drug overdose deaths involving both opioids and|
03448|083|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03448|084|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03448|085|D|increased from 18% to 31% during this time.(8)|
03448|086|D|   A prospective observational cohort study in North Carolina found that the|
03448|087|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03448|088|D|benzodiazepines were 10 times higher than patients receiving opioid|
03448|089|D|analgesics alone.(9)|
03448|090|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03448|091|D|death from overdose increased with concomitant opioid analgesics and|
03448|092|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03448|093|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03448|094|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03448|095|D|increased risk of fatal overdose.(10)|
03448|096|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03448|097|D|which benzodiazepines were determined to be a cause of death and that|
03448|098|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03448|099|D|determined to be a cause of death.  This study also found that other CNS|
03448|100|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03448|101|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03448|102|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03448|103|D|where opioid analgesics were also implicated.(11)|
03448|104|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03448|105|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03448|106|D|deaths.(12)|
03448|107|B||
03448|108|R|REFERENCES:|
03448|109|B||
03448|110|R|1.Orlaam (levomethadyl acetate hydrochloride) US prescribing information.|1
03448|111|R|  Roxane Laboratories, Inc. May, 2001.|1
03448|112|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03448|113|R|  warns about serious risks and death when combining opioid pain or cough|1
03448|114|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03448|115|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03448|116|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03448|117|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03448|118|R|  settings: a scientific statement from the American Heart Association and|6
03448|119|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03448|120|R|  2;55(9):934-47.|6
03448|121|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03448|122|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03448|123|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03448|124|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03448|125|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03448|126|R|  prescribing information for all opioid pain medicines to provide|1
03448|127|R|  additional guidance for safe use. Available at:|1
03448|128|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03448|129|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03448|130|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03448|131|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03448|132|R|  recommends health care professionals discuss naloxone with all patients|1
03448|133|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03448|134|R|  disorder. Available at:|1
03448|135|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03448|136|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03448|137|R|  d-pain July 23, 2020.|1
03448|138|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03448|139|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03448|140|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03448|141|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03448|142|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03448|143|R|  49(4):493-501.|2
03448|144|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03448|145|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03448|146|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03448|147|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03448|148|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03448|149|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03448|150|R|   350:h2698.|2
03448|151|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03448|152|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03448|153|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03448|154|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03448|155|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03448|156|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03449|001|T|MONOGRAPH TITLE:  Brexpiprazole/Levomethadone for MAT|
03449|002|B||
03449|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03449|004|L|take action as needed.|
03449|005|B||
03449|006|A|MECHANISM OF ACTION:  CYP2D6 inhibitors may inhibit the metabolism of|
03449|007|A|brexpiprazole.(1)  Levomethadone is a moderate CYP2D6 inhibitor.(2)|
03449|008|A|   Concurrent use of opioids and antipsychotics may result in additive CNS|
03449|009|A|depression.(3,4)|
03449|010|B||
03449|011|E|CLINICAL EFFECTS:  Concurrent administration of a moderate CYP2D6 inhibitor|
03449|012|E|may result in elevated levels of and toxicity from brexpiprazole.(1)|
03449|013|E|   Concurrent use of opioids and other CNS depressants, such as|
03449|014|E|antipsychotics, may result in profound sedation, respiratory depression,|
03449|015|E|coma, and/or death.(3,4)|
03449|016|B||
03449|017|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
03449|018|P|patients who are receiving concomitant treatment with a strong or moderate|
03449|019|P|CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor.|
03449|020|P|Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to|
03449|021|P|increase brexpiprazole levels 5.1-fold in extensive metabolizers of|
03449|022|P|CYP2D6.(1)|
03449|023|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
03449|024|P|of adverse effects.|
03449|025|B||
03449|026|M|PATIENT MANAGEMENT:  The US manufacturer of brexpiprazole recommends the|
03449|027|M|following dose adjustments for patients who are receiving a moderate CYP2D6|
03449|028|M|inhibitor:|
03449|029|M|   - in patients with schizophrenia or major depressive disorder who are|
03449|030|M|taking a moderate CYP2D6 inhibitor AND who are receiving a strong or|
03449|031|M|moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual|
03449|032|M|dose.|
03449|033|M|   - no empiric dosage adjustment is recommended for patients receiving|
03449|034|M|moderate CYP2D6 inhibitors without a strong or moderate inhibitor of CYP3A4.|
03449|035|M|   The dose of brexpiprazole should be adjusted to its original level if the|
03449|036|M|CYP2D6 inhibitor is discontinued.(1)|
03449|037|M|   Medication assisted treatment (MAT) with levomethadone is not|
03449|038|M|contraindicated in patients taking CNS depressants; however, gradual|
03449|039|M|tapering or decreasing to the lowest effective dose of the CNS depressant|
03449|040|M|may be appropriate.  Ensure that other health care providers prescribing|
03449|041|M|other CNS depressants are aware of the patient's levomethadone treatment.(4)|
03449|042|M|   Respiratory depression can occur at any time during opioid therapy,|
03449|043|M|especially during therapy initiation and following dosage increases.  The|
03449|044|M|risk of opioid-related overdose or overdose-related death is increased with|
03449|045|M|higher opioid doses, and this risk persists over the course of therapy.|
03449|046|M|Consider these risks when using concurrently with other agents that may|
03449|047|M|cause CNS depression.(5)|
03449|048|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03449|049|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03449|050|M|unresponsiveness.(3)|
03449|051|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03449|052|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03449|053|M|treat opioid use disorder (OUD).  Consider prescribing opioid reversal|
03449|054|M|agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03449|055|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03449|056|M|as those taking CNS depressants) and when a patient has household|
03449|057|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03449|058|M|for obtaining an opioid reversal agent (e.g., prescription,|
03449|059|M|over-the-counter, or as part of a community-based program).(6)|
03449|060|B||
03449|061|D|DISCUSSION:  Coadministration of quinidine, a strong inhibitor of CYP2D6,|
03449|062|D|increased the area-under-curve (AUC) of brexpiprazole approximately|
03449|063|D|2-fold.(1)|
03449|064|D|   A nested case-control study looked at the relationship between|
03449|065|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03449|066|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03449|067|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03449|068|D|significantly increased in patients with recent use of antipsychotics|
03449|069|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03449|070|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03449|071|D|of use.(7)|
03449|072|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03449|073|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03449|074|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03449|075|D|to 30 million patients.  During this time, the proportion of patients|
03449|076|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03449|077|D|patients.(8)|
03449|078|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03449|079|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03449|080|D|per 100,000 and drug overdose deaths involving both opioids and|
03449|081|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03449|082|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03449|083|D|increased from 18% to 31% during this time.(9)|
03449|084|D|   A prospective observational cohort study in North Carolina found that the|
03449|085|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03449|086|D|benzodiazepines were 10 times higher than patients receiving opioid|
03449|087|D|analgesics alone.(10)|
03449|088|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03449|089|D|death from overdose increased with concomitant opioid analgesics and|
03449|090|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03449|091|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03449|092|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03449|093|D|increased risk of fatal overdose.(11)|
03449|094|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03449|095|D|which benzodiazepines were determined to be a cause of death and that|
03449|096|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03449|097|D|determined to be a cause of death.  This study also found that other CNS|
03449|098|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03449|099|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03449|100|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03449|101|D|where opioid analgesics were also implicated.(12)|
03449|102|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03449|103|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03449|104|D|deaths.(13)|
03449|105|B||
03449|106|R|REFERENCES:|
03449|107|B||
03449|108|R|1.Rexulti (brexpiprazole) US prescribing information. Otsuka Pharmaceutical|1
03449|109|R|  Co., Ltd. June, 2020.|1
03449|110|R|2.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03449|111|R|  Pharma AS November 30, 2018.|1
03449|112|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03449|113|R|  warns about serious risks and death when combining opioid pain or cough|1
03449|114|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03449|115|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03449|116|R|4.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03449|117|R|  urges caution about withholding opioid addiction medications from patients|1
03449|118|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03449|119|R|  can reduce risks. available at:|1
03449|120|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03449|121|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03449|122|R|  prescribing information for all opioid pain medicines to provide|1
03449|123|R|  additional guidance for safe use. Available at:|1
03449|124|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03449|125|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03449|126|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03449|127|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03449|128|R|  recommends health care professionals discuss naloxone with all patients|1
03449|129|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03449|130|R|  disorder. Available at:|1
03449|131|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03449|132|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03449|133|R|  d-pain July 23, 2020.|1
03449|134|R|7.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03449|135|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03449|136|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03449|137|R|  Pharmacol 2020 Apr 26.|2
03449|138|R|8.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03449|139|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03449|140|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03449|141|R|9.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03449|142|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03449|143|R|  49(4):493-501.|2
03449|144|R|10.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03449|145|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03449|146|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03449|147|R|11.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03449|148|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03449|149|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03449|150|R|   350:h2698.|2
03449|151|R|12.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03449|152|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03449|153|R|13.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03449|154|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03449|155|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03449|156|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03450|001|T|MONOGRAPH TITLE:  Brexpiprazole/Levomethadone (non MAT)|
03450|002|B||
03450|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03450|004|L|take action as needed.|
03450|005|B||
03450|006|A|MECHANISM OF ACTION:  CYP2D6 inhibitors may inhibit the metabolism of|
03450|007|A|brexpiprazole.(1)  Levomethadone is a moderate CYP2D6 inhibitor.(2)|
03450|008|A|   Concurrent use of opioids such as levomethadone and antipsychotics,|
03450|009|A|including brexpiprazole, may result in additive CNS depression.(3)|
03450|010|B||
03450|011|E|CLINICAL EFFECTS:  Concurrent administration of a moderate CYP2D6 inhibitor|
03450|012|E|may result in elevated levels of and toxicity from brexpiprazole.(1)|
03450|013|E|   Concurrent use of opioids such as levomethadone and other CNS|
03450|014|E|depressants, such as antipsychotics, including brexpiprazole, may result in|
03450|015|E|profound sedation, respiratory depression, coma, and/or death.(3)|
03450|016|B||
03450|017|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
03450|018|P|patients who are receiving concomitant treatment with a strong or moderate|
03450|019|P|CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor.|
03450|020|P|Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to|
03450|021|P|increase brexpiprazole levels 5.1-fold in extensive metabolizers of|
03450|022|P|CYP2D6.(1)|
03450|023|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
03450|024|P|of adverse effects.|
03450|025|B||
03450|026|M|PATIENT MANAGEMENT:  The US manufacturer of brexpiprazole recommends the|
03450|027|M|following dose adjustments for patients who are receiving a moderate CYP2D6|
03450|028|M|inhibitor:|
03450|029|M|   - in patients with schizophrenia or major depressive disorder who are|
03450|030|M|taking a moderate CYP2D6 inhibitor AND who are receiving a strong or|
03450|031|M|moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual|
03450|032|M|dose.|
03450|033|M|   - no empiric dosage adjustment is recommended for patients receiving|
03450|034|M|moderate CYP2D6 inhibitors without a strong or moderate inhibitor of CYP3A4.|
03450|035|M|   The dose of brexpiprazole should be adjusted to its original level if the|
03450|036|M|CYP2D6 inhibitor is discontinued.(1)|
03450|037|M|   Limit prescribing opioid analgesics such as methadone with CNS|
03450|038|M|depressants such as antipsychotics, including brexpiprazole, to patients for|
03450|039|M|whom alternatives are inadequate.(3)|
03450|040|M|   If concurrent use is necessary, limit the dosages and duration of each|
03450|041|M|drug to the minimum possible while achieving the desired clinical effect.|
03450|042|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03450|043|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03450|044|M|indicated in the absence of an opioid and titrate based upon clinical|
03450|045|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03450|046|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03450|047|M|clinical response.(3)|
03450|048|M|   Respiratory depression can occur at any time during opioid therapy,|
03450|049|M|especially during therapy initiation and following dosage increases.|
03450|050|M|Consider this risk when using concurrently with other agents that may cause|
03450|051|M|CNS depression.(4)|
03450|052|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03450|053|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03450|054|M|unresponsiveness.(3)|
03450|055|M|   Discuss naloxone with all patients when prescribing or renewing an opioid|
03450|056|M|analgesic or medicine to treat opioid use disorder (OUD).  Consider|
03450|057|M|prescribing naloxone to patients prescribed medicines to treat OUD or opioid|
03450|058|M|analgesics who are at increased risk of opioid overdose (such as those|
03450|059|M|taking CNS depressants) and when a patient has household members/close|
03450|060|M|contacts at risk for accidental overdose.(5)|
03450|061|B||
03450|062|D|DISCUSSION:  Coadministration of quinidine, a strong inhibitor of CYP2D6,|
03450|063|D|increased the area-under-curve (AUC) of brexpiprazole approximately|
03450|064|D|2-fold.(1)|
03450|065|D|   A nested case-control study looked at the relationship between|
03450|066|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03450|067|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03450|068|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03450|069|D|significantly increased in patients with recent use of antipsychotics|
03450|070|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03450|071|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03450|072|D|of use.(6)|
03450|073|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03450|074|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03450|075|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03450|076|D|to 30 million patients.  During this time, the proportion of patients|
03450|077|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03450|078|D|patients.(7)|
03450|079|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03450|080|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03450|081|D|per 100,000 and drug overdose deaths involving both opioids and|
03450|082|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03450|083|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03450|084|D|increased from 18% to 31% during this time.(8)|
03450|085|D|   A prospective observational cohort study in North Carolina found that the|
03450|086|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03450|087|D|benzodiazepines were 10 times higher than patients receiving opioid|
03450|088|D|analgesics alone.(9)|
03450|089|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03450|090|D|death from overdose increased with concomitant opioid analgesics and|
03450|091|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03450|092|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03450|093|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03450|094|D|increased risk of fatal overdose.(10)|
03450|095|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03450|096|D|which benzodiazepines were determined to be a cause of death and that|
03450|097|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03450|098|D|determined to be a cause of death.  This study also found that other CNS|
03450|099|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03450|100|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03450|101|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03450|102|D|where opioid analgesics were also implicated.(11)|
03450|103|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03450|104|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03450|105|D|deaths.(12)|
03450|106|B||
03450|107|R|REFERENCES:|
03450|108|B||
03450|109|R|1.Rexulti (brexpiprazole) US prescribing information. Otsuka Pharmaceutical|1
03450|110|R|  Co., Ltd. June, 2020.|1
03450|111|R|2.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03450|112|R|  Pharma AS November 30, 2018.|1
03450|113|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03450|114|R|  warns about serious risks and death when combining opioid pain or cough|1
03450|115|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03450|116|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03450|117|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03450|118|R|  prescribing information for all opioid pain medicines to provide|1
03450|119|R|  additional guidance for safe use. Available at:|1
03450|120|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03450|121|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03450|122|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03450|123|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03450|124|R|  recommends health care professionals discuss naloxone with all patients|1
03450|125|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03450|126|R|  disorder. Available at:|1
03450|127|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03450|128|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03450|129|R|  d-pain July 23, 2020.|1
03450|130|R|6.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03450|131|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03450|132|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03450|133|R|  Pharmacol 2020 Apr 26.|2
03450|134|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03450|135|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03450|136|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03450|137|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03450|138|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03450|139|R|  49(4):493-501.|2
03450|140|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03450|141|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03450|142|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03450|143|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03450|144|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03450|145|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03450|146|R|   350:h2698.|2
03450|147|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03450|148|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03450|149|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03450|150|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03450|151|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03450|152|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03451|001|T|MONOGRAPH TITLE:  Selected Opioids for MAT/Brexpiprazole|
03451|002|B||
03451|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03451|004|L|take action as needed.|
03451|005|B||
03451|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and antipsychotics, such as|
03451|007|A|brexpiprazole, may result in additive CNS depression.(1,2)|
03451|008|B||
03451|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
03451|010|E|as antipsychotics, may result in profound sedation, respiratory depression,|
03451|011|E|coma, and/or death.(1,2)|
03451|012|B||
03451|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03451|014|P|may increase the risk of adverse effects.|
03451|015|B||
03451|016|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with buprenorphine,|
03451|017|M|diacetylmorphine or methadone is not contraindicated in patients taking CNS|
03451|018|M|depressants; however, gradual tapering or decreasing to the lowest effective|
03451|019|M|dose of the CNS depressant may be appropriate.  Ensure that other health|
03451|020|M|care providers prescribing other CNS depressants are aware of the patient's|
03451|021|M|buprenorphine, diacetylmorphine, or methadone treatment.(2,3)|
03451|022|M|   Respiratory depression can occur at any time during opioid therapy,|
03451|023|M|especially during therapy initiation and following dosage increases.  The|
03451|024|M|risk of opioid-related overdose or overdose-related death is increased with|
03451|025|M|higher opioid doses, and this risk persists over the course of therapy.|
03451|026|M|Consider these risks when using concurrently with other agents that may|
03451|027|M|cause CNS depression.(4)|
03451|028|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03451|029|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03451|030|M|unresponsiveness.(1)|
03451|031|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03451|032|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03451|033|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03451|034|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03451|035|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03451|036|M|as those taking CNS depressants) and when a patient has household|
03451|037|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03451|038|M|for obtaining an opioid reversal agent (e.g., prescription,|
03451|039|M|over-the-counter, or as part of a community-based program).(5)|
03451|040|B||
03451|041|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03451|042|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03451|043|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03451|044|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03451|045|D|significantly increased in patients with recent use of antipsychotics|
03451|046|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03451|047|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03451|048|D|of use.(6)|
03451|049|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03451|050|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03451|051|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03451|052|D|to 30 million patients.  During this time, the proportion of patients|
03451|053|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03451|054|D|patients.(7)|
03451|055|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03451|056|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03451|057|D|per 100,000 and drug overdose deaths involving both opioids and|
03451|058|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03451|059|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03451|060|D|increased from 18% to 31% during this time.(8)|
03451|061|D|   A prospective observational cohort study in North Carolina found that the|
03451|062|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03451|063|D|benzodiazepines were 10 times higher than patients receiving opioid|
03451|064|D|analgesics alone.(9)|
03451|065|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03451|066|D|death from overdose increased with concomitant opioid analgesics and|
03451|067|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03451|068|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03451|069|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03451|070|D|increased risk of fatal overdose.(10)|
03451|071|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03451|072|D|which benzodiazepines were determined to be a cause of death and that|
03451|073|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03451|074|D|determined to be a cause of death.  This study also found that other CNS|
03451|075|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03451|076|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03451|077|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03451|078|D|where opioid analgesics were also implicated.(11)|
03451|079|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03451|080|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03451|081|D|deaths.(12)|
03451|082|B||
03451|083|R|REFERENCES:|
03451|084|B||
03451|085|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03451|086|R|  warns about serious risks and death when combining opioid pain or cough|1
03451|087|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03451|088|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03451|089|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03451|090|R|  urges caution about withholding opioid addiction medications from patients|1
03451|091|R|  taking benzodiazepines or CNS depressants: careful medication management|1
03451|092|R|  can reduce risks. available at:|1
03451|093|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03451|094|R|3.Diacetylmorphine Canadian prescribing information. Pharmascience Inc.|1
03451|095|R|  February, 2022.|1
03451|096|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03451|097|R|  prescribing information for all opioid pain medicines to provide|1
03451|098|R|  additional guidance for safe use. Available at:|1
03451|099|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03451|100|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03451|101|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03451|102|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03451|103|R|  recommends health care professionals discuss naloxone with all patients|1
03451|104|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03451|105|R|  disorder. Available at:|1
03451|106|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03451|107|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03451|108|R|  d-pain July 23, 2020.|1
03451|109|R|6.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03451|110|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03451|111|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03451|112|R|  Pharmacol 2020 Apr 26.|2
03451|113|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03451|114|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03451|115|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03451|116|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03451|117|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03451|118|R|  49(4):493-501.|2
03451|119|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03451|120|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03451|121|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03451|122|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03451|123|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03451|124|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03451|125|R|   350:h2698.|2
03451|126|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03451|127|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03451|128|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03451|129|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03451|130|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03451|131|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03452|001|T|MONOGRAPH TITLE:  Methadone (non MAT)/Brexpiprazole|
03452|002|B||
03452|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03452|004|L|take action as needed.|
03452|005|B||
03452|006|A|MECHANISM OF ACTION:  Concurrent use of opioids such as methadone and|
03452|007|A|antipsychotics, including brexpiprazole, may result in additive CNS|
03452|008|A|depression.(1)|
03452|009|B||
03452|010|E|CLINICAL EFFECTS:  Concurrent use of opioids such as methadone and other CNS|
03452|011|E|depressants, such as antipsychotics, including brexpiprazole, may result in|
03452|012|E|profound sedation, respiratory depression, coma, and/or death.(1)|
03452|013|B||
03452|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03452|015|P|may increase the risk of adverse effects.|
03452|016|B||
03452|017|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as methadone|
03452|018|M|with CNS depressants such as antipsychotics, including brexpiprazole, to|
03452|019|M|patients for whom alternatives are ineffective, not tolerated, or would be|
03452|020|M|otherwise inadequate to provide sufficient management of pain.(1)|
03452|021|M|   If concurrent use is necessary, limit the dosages and duration of each|
03452|022|M|drug to the minimum possible while achieving the desired clinical effect.|
03452|023|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03452|024|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03452|025|M|indicated in the absence of an opioid and titrate based upon clinical|
03452|026|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03452|027|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03452|028|M|clinical response.(1)|
03452|029|M|   Respiratory depression can occur at any time during opioid therapy,|
03452|030|M|especially during therapy initiation and following dosage increases.  The|
03452|031|M|risk of opioid-related overdose or overdose-related death is increased with|
03452|032|M|higher opioid doses, and this risk persists over the course of therapy.|
03452|033|M|Consider these risks when using concurrently with other agents that may|
03452|034|M|cause CNS depression.(2)|
03452|035|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03452|036|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03452|037|M|unresponsiveness.(1)|
03452|038|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03452|039|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03452|040|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03452|041|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03452|042|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03452|043|M|as those taking CNS depressants) and when a patient has household|
03452|044|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03452|045|M|for obtaining an opioid reversal agent (e.g., prescription,|
03452|046|M|over-the-counter, or as part of a community-based program).(3)|
03452|047|B||
03452|048|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03452|049|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03452|050|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03452|051|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03452|052|D|significantly increased in patients with recent use of antipsychotics|
03452|053|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03452|054|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03452|055|D|of use.(4)|
03452|056|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03452|057|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03452|058|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03452|059|D|to 30 million patients.  During this time, the proportion of patients|
03452|060|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03452|061|D|patients.(5)|
03452|062|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03452|063|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03452|064|D|per 100,000 and drug overdose deaths involving both opioids and|
03452|065|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03452|066|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03452|067|D|increased from 18% to 31% during this time.(6)|
03452|068|D|   A prospective observational cohort study in North Carolina found that the|
03452|069|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03452|070|D|benzodiazepines were 10 times higher than patients receiving opioid|
03452|071|D|analgesics alone.(7)|
03452|072|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03452|073|D|death from overdose increased with concomitant opioid analgesics and|
03452|074|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03452|075|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03452|076|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03452|077|D|increased risk of fatal overdose.(8)|
03452|078|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03452|079|D|which benzodiazepines were determined to be a cause of death and that|
03452|080|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03452|081|D|determined to be a cause of death.  This study also found that other CNS|
03452|082|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03452|083|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03452|084|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03452|085|D|where opioid analgesics were also implicated.(9)|
03452|086|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03452|087|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03452|088|D|deaths.(10)|
03452|089|B||
03452|090|R|REFERENCES:|
03452|091|B||
03452|092|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03452|093|R|  warns about serious risks and death when combining opioid pain or cough|1
03452|094|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03452|095|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03452|096|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03452|097|R|  prescribing information for all opioid pain medicines to provide|1
03452|098|R|  additional guidance for safe use. Available at:|1
03452|099|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03452|100|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03452|101|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03452|102|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03452|103|R|  recommends health care professionals discuss naloxone with all patients|1
03452|104|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03452|105|R|  disorder. Available at:|1
03452|106|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03452|107|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03452|108|R|  d-pain July 23, 2020.|1
03452|109|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03452|110|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03452|111|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03452|112|R|  Pharmacol 2020 Apr 26.|2
03452|113|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03452|114|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03452|115|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03452|116|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03452|117|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03452|118|R|  49(4):493-501.|2
03452|119|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03452|120|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03452|121|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03452|122|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03452|123|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03452|124|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03452|125|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03452|126|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03452|127|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03452|128|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03452|129|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03452|130|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03453|001|T|MONOGRAPH TITLE:  Glasdegib/Moderate CYP3A4 Inducers|
03453|002|B||
03453|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03453|004|L|of severe adverse interaction.|
03453|005|B||
03453|006|A|MECHANISM OF ACTION:  Glasdegib is a substrate of CYP3A4.  Moderate inducers|
03453|007|A|of CYP3A4 may induce the metabolism of glasdegib.(1)|
03453|008|B||
03453|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
03453|010|E|in decreased levels and effectiveness of glasdegib.(1)|
03453|011|B||
03453|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03453|013|P|of the inducer for longer than 1-2 weeks.|
03453|014|B||
03453|015|M|PATIENT MANAGEMENT:  The manufacturer of glasdegib states to avoid|
03453|016|M|concurrent administration with moderate CYP3A4 inducers.  If concurrent use|
03453|017|M|cannot be avoided, increase the daily dose of glasdegib as tolerated as|
03453|018|M|follows:|
03453|019|M|   - If current dose of glasdegib is 100 mg once daily, increase to 200 mg|
03453|020|M|once daily|
03453|021|M|   - If current dose of glasdegib is 50 mg once daily, increase to 100 mg|
03453|022|M|once daily|
03453|023|M|   After the moderate CYP3A4 inducer has been discontinued for 7 days,|
03453|024|M|resume the glasdegib dose that was tolerated prior to initiation of the|
03453|025|M|inducer.(1)|
03453|026|B||
03453|027|D|DISCUSSION:  A population-based pharmacokinetic model predicts that|
03453|028|D|efavirenz would decrease glasdegib area-under-curve (AUC) by 55% and maximum|
03453|029|D|concentration (Cmax) by 25%.(1)|
03453|030|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03453|031|D|bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad,|
03453|032|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib,|
03453|033|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl, and|
03453|034|D|tovorafenib.(2-3)|
03453|035|B||
03453|036|R|REFERENCES:|
03453|037|B||
03453|038|R|1.Daurismo (glasdegib) US prescribing information. Pfizer Inc. March, 2020.|1
03453|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
03453|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03453|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03453|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03453|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03453|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03453|045|R|  11/14/2017.|1
03454|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K|
03454|002|T|antagonists)/Clomipramine|
03454|003|B||
03454|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03454|005|L|take action as needed.|
03454|006|B||
03454|007|A|MECHANISM OF ACTION:  Clomipramine inhibition of platelet serotonin may|
03454|008|A|result in impaired platelet aggregation.(1)  This effect may be additive or|
03454|009|A|synergistic when combined with other agents which impair hemostasis.|
03454|010|B||
03454|011|E|CLINICAL EFFECTS:  Concurrent use of selected anticoagulants and|
03454|012|E|clomipramine may increase the risk for bleeding.|
03454|013|B||
03454|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03454|015|P|patients with disease-associated factors (e.g. thrombocytopenia).  Drug|
03454|016|P|associated risk factors include concurrent use of multiple drugs which|
03454|017|P|inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk|
03454|018|P|for bleeding (e.g. NSAIDs).|
03454|019|B||
03454|020|M|PATIENT MANAGEMENT:  If concurrent therapy is warranted, monitor patients|
03454|021|M|for signs of blood loss, including decreased hemoglobin and/or hematocrit,|
03454|022|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03454|023|M|patients with any symptoms.|
03454|024|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03454|025|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03454|026|M|anticoagulation in patients with active pathologic bleeding.|
03454|027|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03454|028|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03454|029|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03454|030|M|and/or swelling.|
03454|031|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03454|032|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
03454|033|M|before initiating, altering the dose, or discontinuing either drug.|
03454|034|B||
03454|035|D|DISCUSSION:  Clomipramine is a potent inhibitor of platelet serotonin.  In a|
03454|036|D|study of clomipramine and fluoxetine effects on platelet and plasma 5-HT|
03454|037|D|levels, clomipramine significantly reduced platelet 5-HT content to 8% and|
03454|038|D|19% and plasma 5-HT levels to 40% and 23% of their pretreatment values after|
03454|039|D|12 weeks, respectively.(1)|
03454|040|D|   In a review describing the bleeding risk with SRIs, warfarin was|
03454|041|D|associated with an increased rate of hemorrhage among SRI users (adjusted|
03454|042|D|relative risk = 1.41).(2)|
03454|043|D|   In a cohort study of patients taking warfarin in combination with an SSRI|
03454|044|D|versus warfarin treatment alone, an analysis including first bleedings|
03454|045|D|revealed a hazard ratio of 3.49 for bleeding during treatment with a|
03454|046|D|combination of SSRI and warfarin compared with warfarin only.(3)|
03454|047|D|   A retrospective study of warfarin-treated patients prescribed or not|
03454|048|D|prescribed an antidepressant showed that use of an SSRI with warfarin was|
03454|049|D|significantly associated with increased risk of any bleed (overall risk|
03454|050|D|(OR)=2.6), major bleeding (OR=4.4), and hospitalization secondary to|
03454|051|D|bleeding (OR=7.0) as compared to those not taking an SSRI.(4)|
03454|052|D|   A population based study of patient outcomes in 176 primary intracerebral|
03454|053|D|hemorrhage patients showed that 19 patients taking SSRI/SNRIs together with|
03454|054|D|warfarin had an increased 30-day case fatality rate of 78.9% compared to|
03454|055|D|warfarin alone (50.7%).(5)|
03454|056|D|   In a study of the Anticoagulation and Risk factors in Atrial fibrillation|
03454|057|D|(ATRIA) cohort, hemorrhage rates were higher during periods of SSRI exposure|
03454|058|D|compared with periods on no antidepressants (2.32 per 100 person-years vs|
03454|059|D|1.35 per 100 person-years).  After adjusting for bleeding risk and time in|
03454|060|D|INR range > 3, SSRI exposure was associated with an increased rate of|
03454|061|D|hemorrhage compared with no antidepressants (adjusted relative risk =|
03454|062|D|1.41).(6)|
03454|063|D|   Increased bleeding risk has been found when patients receive 3 agents|
03454|064|D|which can affect bleeding risk: an anticoagulant, SSRI and NSAID.(7)|
03454|065|D|   In a retrospective review of 5 years of data from the|
03454|066|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03454|067|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03454|068|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03454|069|D|only based on an observed-expected ratio was 4.5 and in a patient using|
03454|070|D|low-dose aspirin only was 2.5.  Concurrent use of a SSRI with NSAIDs or|
03454|071|D|low-dose aspirin increased the risk of bleeding to 12.2 and 5.2,|
03454|072|D|respectively.(7)|
03454|073|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
03454|074|D|in patients receiving concurrent therapy with SSRIs and NSAIDs.  Adjusted|
03454|075|D|relative risk of bleeding with NSAIDs, SSRIs, or both were 3.7, 2.6, or|
03454|076|D|15.6, respectively.(8)|
03454|077|B||
03454|078|R|REFERENCES:|
03454|079|B||
03454|080|R|1.Alvarez JC, Gluck N, Arnulf I, Quintin P, Leboyer M, Pecquery R, Launay|2
03454|081|R|  JM, Perez-Diaz F,  Spreux-Varoquaux O. Decreased platelet serotonin|2
03454|082|R|  transporter sites and increased platelet inositol triphosphate levels in|2
03454|083|R|  patients with unipolar depression: Effects of clomipramine and fluoxetine.|2
03454|084|R|  Clin Pharmacol Ther 1999;66:617-624.|2
03454|085|R|2.Bixby AL, VandenBerg A, Bostwick JR. Clinical management of bleeding risk|6
03454|086|R|  with antidepressants. Ann Pharmacother. 2019;53(2):186-194.|6
03454|087|R|3.Wallerstedt SM, Gleerup H, Sundstrom A, Stigendal L, Ny L. Risk of|6
03454|088|R|  clinically relevant bleeding in warfarin-treated patients--influence of|6
03454|089|R|  SSRI treatment. Pharmacoepidemiol Drug Saf. 2009;18:412-416.|6
03454|090|R|4.Cochran KA, Cavallari LH, Shapiro NL, Bishop JR. Bleeding incidence with|6
03454|091|R|  concomitant use of antidepressants and warfarin. Ther Drug Monit 2011;|6
03454|092|R|  33(4):433-438.|6
03454|093|R|5.Lopponen P, Tetri S, Juvela S, Huhtakangas J, Saloheimo P, Bode MK,|6
03454|094|R|  Hillbom M. Association between warfarin combined with serotonin-modulating|6
03454|095|R|  antidepressants and increased case fatality in primary intracerebral|6
03454|096|R|  hemorrhage: a population-based study. J Neurosurg 2014;120:1358-1363.|6
03454|097|R|6.Quinn GR, Singer DE, Chang Y, Go AS, Borowsky LH, Udaltsova N, Fang MC.|6
03454|098|R|  Effect of selective serotonin reuptake inhibitors on bleeding risk in|6
03454|099|R|  patients with atrial fibrillation taking warfarin. Am J Cardiol 2014;|6
03454|100|R|  114(4):583-586.|6
03454|101|R|7.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03454|102|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03454|103|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03454|104|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03454|105|R|8.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03454|106|R|  serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03454|107|R|  population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03455|001|T|MONOGRAPH TITLE:  Selected Antidiabetic Agents/Chloroquine;|
03455|002|T|Hydroxychloroquine|
03455|003|B||
03455|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03455|005|L|take action as needed.|
03455|006|B||
03455|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown. Chloroquine and|
03455|008|A|hydroxychloroquine may increase insulin sensitivity by inhibiting insulin|
03455|009|A|metabolism and inflammation and increasing cellular uptake of glucose and|
03455|010|A|glycogen synthesis.(1,2)  These effects may result in additive hypoglycemia|
03455|011|A|with anti-diabetic agents.|
03455|012|B||
03455|013|E|CLINICAL EFFECTS:  Concurrent use of chloroquine or hydroxychloroquine and|
03455|014|E|antidiabetic agents may result in severe hypoglycemia.(3)  Hypoglycemia can|
03455|015|E|lead to coma.|
03455|016|B||
03455|017|P|PREDISPOSING FACTORS:  Elderly patients, especially those with decreased|
03455|018|P|renal function may be predisposed to this interaction.|
03455|019|B||
03455|020|M|PATIENT MANAGEMENT:  Patients maintained on antidiabetic agents who require|
03455|021|M|concurrent therapy with chloroquine or hydroxychloroquine should be closely|
03455|022|M|monitored for hypoglycemia.  A decrease in the dose of insulin or other|
03455|023|M|anti-diabetic medications may be required.  Patients should be advised of|
03455|024|M|the risk and symptoms of hypoglycemia and to contact their doctor if|
03455|025|M|hypoglycemia occurs.(3)|
03455|026|M|   Signs of hypoglycemia may include confusion, dizziness, feeling shaky,|
03455|027|M|unusual hunger, headaches, irritability, pounding heart or very fast pulse,|
03455|028|M|pale skin, sweating, trembling, weakness, or unusual anxiety.|
03455|029|B||
03455|030|D|DISCUSSION:  Hydroxychloroquine has been shown to cause severe hypoglycemia|
03455|031|D|including loss of consciousness that could be life threatening.(3)|
03455|032|D|Concomitant hypoglycemic agents may increase the risk and/or severity of|
03455|033|D|this effect.|
03455|034|D|   A 77 year old man who was stable on twice daily insulin suffered two|
03455|035|D|episodes of  hypoglycemic coma 2 weeks after starting prednisone 5 mg daily|
03455|036|D|and hydroxychloroquine 400 mg daily for rheumatoid arthritis.  His insulin|
03455|037|D|dosage required a decrease of 37%.(4)|
03455|038|D|   Many studies have investigated the glucose-lowering effect of|
03455|039|D|hydroxychloroquine.  In a clinical trial of type II diabetics on maximal|
03455|040|D|doses of sulfonylureas, addition of hydroxychloroquine lowered hemoglobin|
03455|041|D|A1C (HbA1C) up to 1% more than placebo.(5)  Another clinical trial of type|
03455|042|D|II diabetics on metformin and glimepiride or gliclazide found that|
03455|043|D|hydroxychloroquine 400 mg daily reduced fasting blood glucose (FBG),|
03455|044|D|post-prandial glucose (PPG), and HbA1C to a similar degree as pioglitazone|
03455|045|D|15 mg daily at 24 weeks.(6)|
03455|046|D|   In a prospective observational study, 250 uncontrolled type II diabetics|
03455|047|D|on metformin, glimepiride, pioglitazone, sitagliptin, and a SGLT-2 inhibitor|
03455|048|D|received hydroxychloroquine 400 mg daily for 48 weeks. HbA1C decreased from|
03455|049|D|8.83% to 6.44%, FBG decreased by 40.78%, and PPG decreased by 58.95%. The|
03455|050|D|doses of metformin were reduced by 50%, glimepiride and sitagliptin by 75%,|
03455|051|D|and SGLT-2 inhibitors were discontinued in most patients.(7)|
03455|052|B||
03455|053|R|REFERENCES:|
03455|054|B||
03455|055|R|1.Smith GD, Amos TA, Mahler R, Peters TJ. Effect of chloroquine on insulin|2
03455|056|R|  and glucose homoeostasis in normal subjects and  patients with|2
03455|057|R|  non-insulin-dependent diabetes mellitus. Br Med J (Clin Res Ed) 1987 Feb|2
03455|058|R|  21;294(6570):465-7.|2
03455|059|R|2.Wondafrash DZ, Desalegn TZ, Yimer EM, Tsige AG, Adamu BA, Zewdie KA.|6
03455|060|R|  Potential Effect of Hydroxychloroquine in Diabetes Mellitus: A Systematic|6
03455|061|R|  Review  on Preclinical and Clinical Trial Studies. J Diabetes Res 2020;|6
03455|062|R|  2020:5214751.|6
03455|063|R|3.Plaquenil (hydroxychloroquine sulfate) US prescribing information.|1
03455|064|R|  Concordia Pharmaceuticals Inc. December, 2023.|1
03455|065|R|4.Shojania K, Koehler BE, Elliott T. Hypoglycemia induced by|3
03455|066|R|  hydroxychloroquine in a type II diabetic treated for polyarthritis. J|3
03455|067|R|  Rheumatol 1999 Jan;26(1):195-6.|3
03455|068|R|5.Gerstein HC, Thorpe KE, Taylor DW, Haynes RB. The effectiveness of|2
03455|069|R|  hydroxychloroquine in patients with type 2 diabetes mellitus who are|2
03455|070|R|  refractory to sulfonylureas--a randomized trial. Diabetes Res Clin Pract|2
03455|071|R|  2002 Mar;55(3):209-19.|2
03455|072|R|6.Pareek A, Chandurkar N, Thomas N, Viswanathan V, Deshpande A, Gupta OP,|2
03455|073|R|  Shah A, Kakrani A, Bhandari S, Thulasidharan NK, Saboo B, Devaramani S,|2
03455|074|R|  Vijaykumar NB, Sharma S, Agrawal N, Mahesh M, Kothari K. Efficacy and|2
03455|075|R|  safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus:|2
03455|076|R|  a double blind, randomized comparison with pioglitazone. Curr Med Res Opin|2
03455|077|R|  2014 Jul;30(7):1257-66.|2
03455|078|R|7.Gupta A. Real-World Clinical Effectiveness and Tolerability of|2
03455|079|R|  Hydroxychloroquine 400 Mg in Uncontrolled Type 2 Diabetes Subjects who are|2
03455|080|R|  not Willing to Initiate Insulin  Therapy (HYQ-Real-World Study). Curr|2
03455|081|R|  Diabetes Rev 2019;15(6):510-519.|2
03456|001|T|MONOGRAPH TITLE:  Ozanimod/Selected Oral Inhibitors of BCRP (mono deleted|
03456|002|T|06/10/2021)|
03456|003|B||
03456|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03456|005|L|of severe adverse interaction.|
03456|006|B||
03456|007|A|MECHANISM OF ACTION:  Inhibitors of BCRP may increase the exposure of active|
03456|008|A|metabolites of ozanimod.(1)|
03456|009|B||
03456|010|E|CLINICAL EFFECTS:  The concurrent administration of ozanimod with an|
03456|011|E|inhibitor of BCRP may result in elevated levels of active metabolites of|
03456|012|E|ozanimod and signs of toxicity, including increased infection risk,|
03456|013|E|bradyarrhythmias, atrioventricular conduction delays, liver injury, and|
03456|014|E|hypertension.(1)|
03456|015|B||
03456|016|P|PREDISPOSING FACTORS:  None determined.|
03456|017|B||
03456|018|M|PATIENT MANAGEMENT:  The US manufacturer of ozanimod states concurrent use|
03456|019|M|of BCRP inhibitors is not recommended during ozanimod treatment.(1)|
03456|020|M|   Selection of an alternative concurrent medication with no or minimal|
03456|021|M|transporter inhibiting proprieties should be considered. Careful patient|
03456|022|M|monitoring is recommended.(1)|
03456|023|B||
03456|024|D|DISCUSSION:  Coadministration of ozanimod with cyclosporine (a BCRP|
03456|025|D|inhibitor) had no effect on ozanimod exposure, but doubled the exposure of|
03456|026|D|RP101988 and RP101075 (direct precursors of the major active metabolite|
03456|027|D|CC112273).  Exposure of CC112273 and CC1084037 may also be increased.(1)|
03456|028|D|   BCRP inhibitors linked to this monograph include:  capmatinib,|
03456|029|D|cyclosporine, eltrombopag.(1)|
03456|030|B||
03456|031|R|REFERENCE:|
03456|032|B||
03456|033|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03456|034|R|  2024.|1
03457|001|T|MONOGRAPH TITLE:  Ozanimod/Moderate CYP2C8 Inducers|
03457|002|B||
03457|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03457|004|L|of severe adverse interaction.|
03457|005|B||
03457|006|A|MECHANISM OF ACTION:  Ozanimod is a substrate of CYP2C8.  Moderate inducers|
03457|007|A|of CYP2C8 may induce the metabolism of ozanimod.(1)|
03457|008|B||
03457|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP2C8 may result|
03457|010|E|in decreased levels and effectiveness of ozanimod and the active metabolites|
03457|011|E|CC112273 and CC1084037.(1)|
03457|012|B||
03457|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03457|014|P|of the inducer for longer than 1-2 weeks.|
03457|015|B||
03457|016|M|PATIENT MANAGEMENT:  The manufacturer of ozanimod states to avoid concurrent|
03457|017|M|administration with moderate CYP2C8 inducers.(1)|
03457|018|B||
03457|019|D|DISCUSSION:  Coadministration of rifampin (a strong CYP3A4 and P-gp inducer,|
03457|020|D|and moderate CYP2C8 inducer - 600 mg once daily) decreased the|
03457|021|D|area-under-curve (AUC) of ozanimod, CC112273, and CC1084037 by 24%, 60%, and|
03457|022|D|55%, respectively.(1)|
03457|023|D|   Moderate CYP2C8 inducers linked to this monograph include: carbamazepine|
03457|024|D|and rifampin.(2-3)|
03457|025|B||
03457|026|R|REFERENCES:|
03457|027|B||
03457|028|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03457|029|R|  2024.|1
03457|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
03457|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03457|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03457|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03457|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03457|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03457|036|R|  11/14/2017.|1
03458|001|T|MONOGRAPH TITLE:  Ozanimod/Strong CYP2C8 Inhibitors|
03458|002|B||
03458|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03458|004|L|of severe adverse interaction.|
03458|005|B||
03458|006|A|MECHANISM OF ACTION:  Strong CYP2C8 inhibitors may inhibit the metabolism of|
03458|007|A|ozanimod.(1)|
03458|008|B||
03458|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP2C8 inhibitor may increase|
03458|010|E|levels and effects of ozanimod, including increased infection risk,|
03458|011|E|bradyarrhythmias, atrioventricular conduction delays, liver injury, and|
03458|012|E|hypertension.(1)|
03458|013|B||
03458|014|P|PREDISPOSING FACTORS:  None determined.|
03458|015|B||
03458|016|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP2C8 inhibitors and|
03458|017|M|ozanimod is not recommended.(1)|
03458|018|M|   If concurrent use is warranted, monitor patients closely for increased|
03458|019|M|effects of ozanimod, including increased infection risk, bradyarrhythmias,|
03458|020|M|atrioventricular conduction delays, liver injury, and hypertension.|
03458|021|B||
03458|022|D|DISCUSSION:  Concurrent use of ozanimod with gemfibrozil increased the|
03458|023|D|area-under-curve (AUC) of active metabolites CC112273 and CC1084037 by 47%|
03458|024|D|and 69%, respectively.  There were no clinically significant changes in the|
03458|025|D|AUC of ozanimod.(1)|
03458|026|D|   Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)|
03458|027|B||
03458|028|R|REFERENCES:|
03458|029|B||
03458|030|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03458|031|R|  2024.|1
03458|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
03458|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03458|034|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03458|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03458|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03458|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03458|038|R|  11/14/2017.|1
03459|001|T|MONOGRAPH TITLE:  Ozanimod/MAOIs|
03459|002|B||
03459|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03459|004|L|is contraindicated and generally should not be dispensed or administered to|
03459|005|L|the same patient.|
03459|006|B||
03459|007|A|MECHANISM OF ACTION:  Ozanimod is metabolized by CYP3A4 to RP101075 (a minor|
03459|008|A|active metabolite), which is further metabolized by monoamine oxidase-B|
03459|009|A|(MAO-B) to major active metabolites that make up the predominant circulating|
03459|010|A|active species in the plasma.  The major and minor active metabolites have|
03459|011|A|similar activity as ozanimod.  Inhibition of MAO-B may alter exposure to|
03459|012|A|ozanimod and its metabolites.(1)|
03459|013|B||
03459|014|E|CLINICAL EFFECTS:  Concurrent use of ozanimod and MAO inhibitors may result|
03459|015|E|in altered exposure to ozanimod and its active metabolites and may result in|
03459|016|E|decreased efficacy.(1)|
03459|017|B||
03459|018|P|PREDISPOSING FACTORS:  None determined.|
03459|019|B||
03459|020|M|PATIENT MANAGEMENT:  The concurrent use of ozanimod with MAO inhibitors is|
03459|021|M|contraindicated.  At least 14 days should elapse between discontinuation of|
03459|022|M|ozanimod and initiation of MAO inhibitors.(1)|
03459|023|B||
03459|024|D|DISCUSSION:  The combination of ozanimod with MAO inhibitors has not been|
03459|025|D|studied.  The combination of steady state ozanimod 0.92 mg or 1.84 mg with|
03459|026|D|tyramine, an MAO substrate, did not have an effect on tyramine plasma|
03459|027|D|concentrations or tyramine-induced pressor response.  However, MAO|
03459|028|D|inhibitors may alter the exposure to ozanimod and its metabolites.(1)|
03459|029|D|   Metaxalone is a weak inhibitor of MAO.(2,3)|
03459|030|B||
03459|031|R|REFERENCES:|
03459|032|B||
03459|033|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03459|034|R|  2024.|1
03459|035|R|2.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03459|036|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03459|037|R|  Feb;34(2):346.e5-6.|3
03459|038|R|3.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03459|039|R|  Pfizer Inc. January, 2024.|1
03460|001|T|MONOGRAPH TITLE:  Selumetinib/Strong and Moderate CYP3A4 Inhibitors|
03460|002|B||
03460|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03460|004|L|of severe adverse interaction.|
03460|005|B||
03460|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03460|007|A|selumetinib.(1)|
03460|008|B||
03460|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inhibitor of|
03460|010|E|CYP3A4 may result in increased levels of and effects from selumetinib,|
03460|011|E|including vomiting, diarrhea, skin rashes, ocular toxicity (e.g., blurred|
03460|012|E|vision, visual loss), cardiomyopathy, and rhabdomyolysis.(1)|
03460|013|B||
03460|014|P|PREDISPOSING FACTORS:  None determined.|
03460|015|B||
03460|016|M|PATIENT MANAGEMENT:  The US manufacturer of selumetinib states that the|
03460|017|M|coadministration of selumetinib with strong or moderate CYP3A4 inhibitors|
03460|018|M|should be avoided.  If coadministration cannot be avoided, the dosage of|
03460|019|M|selumetinib should be reduced as follows:|
03460|020|M|   -If the current dose is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice|
03460|021|M|daily.|
03460|022|M|   -If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice|
03460|023|M|daily.|
03460|024|M|   If the strong or moderate CYP3A4 inhibitor is discontinued, resume the|
03460|025|M|selumetinib dose that was taken prior to the initiation of the inhibitor|
03460|026|M|after 3 half-lives of the CYP3A4 inhibitor have elapsed.(1)|
03460|027|B||
03460|028|D|DISCUSSION:  In a study of 26 healthy subjects, itraconazole 200 mg twice|
03460|029|D|daily (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and|
03460|030|D|maximum concentration (Cmax) of selumetinib 25 mg by 49% and 19%,|
03460|031|D|respectively.  Fluconazole 400 mg loading dose then 200 mg daily (a moderate|
03460|032|D|CYP3A4 inhibitor and strong CYP2C19 inhibitor) increased AUC and Cmax of|
03460|033|D|selumetinib (25 mg) by 53% and 26%.(1,2)|
03460|034|D|   In a pharmacokinetic model, erythromycin (a moderate CYP3A4 inhibitor)|
03460|035|D|was predicted to increase selumetinib AUC and Cmax by 41% and 23%,|
03460|036|D|respectively.(1)|
03460|037|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03460|038|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03460|039|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
03460|040|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
03460|041|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03460|042|D|troleandomycin, tucatinib and voriconazole.(3)|
03460|043|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
03460|044|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
03460|045|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03460|046|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
03460|047|D|lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra,|
03460|048|D|stiripentol, tofisopam, treosulfan, and verapamil.(3)|
03460|049|B||
03460|050|R|REFERENCES:|
03460|051|B||
03460|052|R|1.Koselugo (selumetinib) US prescribing information. AstraZeneca|1
03460|053|R|  Pharmaceuticals LP December, 2021.|1
03460|054|R|2.Dymond AW, So K, Martin P, Huang Y, Severin P, Mathews D, Lisbon E,|2
03460|055|R|  Mariani G. Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and|2
03460|056|R|  induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy|2
03460|057|R|  subjects: results from two clinical trials. Eur J Clin Pharmacol 2017 Feb;|2
03460|058|R|  73(2):175-184.|2
03460|059|R|3.This information is based on an extract from the Certara Drug Interaction|6
03460|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03461|001|T|MONOGRAPH TITLE:  Selumetinib/Strong and Moderate CYP3A4 Inducers|
03461|002|B||
03461|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03461|004|L|of severe adverse interaction.|
03461|005|B||
03461|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03461|007|A|metabolism of selumetinib by CYP3A4.(1)|
03461|008|B||
03461|009|E|CLINICAL EFFECTS:  The concurrent use of strong and moderate CYP3A4 inducers|
03461|010|E|and selumetinib may result in decreased levels and clinical effectiveness of|
03461|011|E|selumetinib.(1)|
03461|012|B||
03461|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03461|014|P|of the inducer for longer than 1-2 weeks.|
03461|015|B||
03461|016|M|PATIENT MANAGEMENT:  The manufacturer of selumetinib recommends avoiding|
03461|017|M|concurrent use with strong or moderate CYP3A4 inducers due to potential|
03461|018|M|decrease in exposure to selumetinib and loss of efficacy.(1)|
03461|019|M|   Patients receiving concurrent therapy with strong and moderate CYP3A4|
03461|020|M|inducers and selumetinib should be observed for decreased clinical|
03461|021|M|effectiveness.|
03461|022|B||
03461|023|D|DISCUSSION:  In a study of 22 healthy subjects, rifampin 600 mg daily (a|
03461|024|D|strong CYP3A4 inducer) decreased selumetinib area-under-curve (AUC) and|
03461|025|D|maximum concentration (Cmax) by 51% and 26%, respectively.(2)|
03461|026|D|   Concomitant use of efavirenz, a moderate CYP3A4 inducer, is predicted to|
03461|027|D|decrease selumetinib AUC and Cmax by 38% and 22%, respectively.(1)|
03461|028|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
03461|029|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
03461|030|D|dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine,|
03461|031|D|fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten,|
03461|032|D|mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib,|
03461|033|D|phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin,|
03461|034|D|rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and|
03461|035|D|tovorafenib.(3)|
03461|036|B||
03461|037|R|REFERENCES:|
03461|038|B||
03461|039|R|1.Koselugo (selumetinib) US prescribing information. AstraZeneca|1
03461|040|R|  Pharmaceuticals LP December, 2021.|1
03461|041|R|2.Dymond AW, So K, Martin P, Huang Y, Severin P, Mathews D, Lisbon E,|2
03461|042|R|  Mariani G. Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and|2
03461|043|R|  induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy|2
03461|044|R|  subjects: results from two clinical trials. Eur J Clin Pharmacol 2017 Feb;|2
03461|045|R|  73(2):175-184.|2
03461|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
03461|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03462|001|T|MONOGRAPH TITLE:  Naloxegol/Bevacizumab|
03462|002|B||
03462|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03462|004|L|take action as needed.|
03462|005|B||
03462|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Both naloxegol and|
03462|007|A|bevacizumab have been reported to cause gastrointestinal perforation.|
03462|008|B||
03462|009|E|CLINICAL EFFECTS:  Concurrent use of bevacizumab may increase the risk of|
03462|010|E|gastrointestinal perforation in patients receiving naloxegol.(1)|
03462|011|B||
03462|012|P|PREDISPOSING FACTORS:  Patients with infiltrative gastrointestinal tract|
03462|013|P|malignancy, recent gastrointestinal tract surgery, diverticular disease|
03462|014|P|including diverticulitis, and/or ischemic colitis may be at increased risk|
03462|015|P|of gastrointestinal perforation.(1)|
03462|016|B||
03462|017|M|PATIENT MANAGEMENT:  Consider the risk-benefit profile when using naloxegol|
03462|018|M|in patients on concurrent bevacizumab, especially if they have conditions|
03462|019|M|which might result in impaired integrity of the gastrointestinal tract wall|
03462|020|M|(e.g., Crohn's disease).  Monitor for the development of severe, persistent|
03462|021|M|or worsening abdominal pain.  Discontinue naloxegol in patients who develop|
03462|022|M|gastrointestinal perforation.(1)|
03462|023|B||
03462|024|D|DISCUSSION:  There are no published reports of gastrointestinal perforation|
03462|025|D|with the combination of naloxegol and bevacizumab.  The FDA Adverse Events|
03462|026|D|Reporting System (FAERS) database contains one report of a 45 year old man|
03462|027|D|with metastatic rectal cancer who developed small intestinal perforation|
03462|028|D|while on naloxegol and bevacizumab.|
03462|029|B||
03462|030|R|REFERENCE:|
03462|031|B||
03462|032|R|1.Movantik (naloxegol) US prescribing information. AstraZeneca|1
03462|033|R|  Pharmaceuticals LP April, 2020.|1
03463|001|T|MONOGRAPH TITLE:  Pemigatinib/Strong and Moderate CYP3A4 Inducers|
03463|002|B||
03463|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03463|004|L|of severe adverse interaction.|
03463|005|B||
03463|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03463|007|A|metabolism of pemigatinib by CYP3A4.(1)|
03463|008|B||
03463|009|E|CLINICAL EFFECTS:  The concurrent use of strong and moderate CYP3A4 inducers|
03463|010|E|and pemigatinib may result in decreased levels and clinical effectiveness of|
03463|011|E|pemigatinib.(1)|
03463|012|B||
03463|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03463|014|P|of the inducer for longer than 1-2 weeks.|
03463|015|B||
03463|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong and moderate CYP3A4|
03463|017|M|inducers with pemigatinib.(1)|
03463|018|B||
03463|019|D|DISCUSSION:  Rifampin, a strong CYP3A4 inducer, decreased pemigatinib|
03463|020|D|maximum concentration (Cmax) by 62% and area-under-curve (AUC) by 85%|
03463|021|D|following a single pemigatinib oral dose of 13.5 mg.  Concomitant use of a|
03463|022|D|moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by|
03463|023|D|more than 50%.|
03463|024|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
03463|025|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
03463|026|D|dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine,|
03463|027|D|fosphenytoin, ivosidenib, lesinurad, lorlatinib, mavacamten, lumacaftor,|
03463|028|D|mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib,|
03463|029|D|phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin,|
03463|030|D|rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and|
03463|031|D|tovorafenib.(3)|
03463|032|B||
03463|033|R|REFERENCES:|
03463|034|B||
03463|035|R|1.Pemazyre (pemigatinib) US prescribing information. Incyte Corporation|1
03463|036|R|  February, 2021.|1
03463|037|R|2.Dymond AW, So K, Martin P, Huang Y, Severin P, Mathews D, Lisbon E,|2
03463|038|R|  Mariani G. Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and|2
03463|039|R|  induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy|2
03463|040|R|  subjects: results from two clinical trials. Eur J Clin Pharmacol 2017 Feb;|2
03463|041|R|  73(2):175-184.|2
03463|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
03463|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03464|001|T|MONOGRAPH TITLE:  Pemigatinib/Strong and Moderate CYP3A4 Inhibitors|
03464|002|B||
03464|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03464|004|L|of severe adverse interaction.|
03464|005|B||
03464|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03464|007|A|pemigatinib.(1)|
03464|008|B||
03464|009|E|CLINICAL EFFECTS:  Concomitant use of a strong or moderate CYP3A4 inhibitor|
03464|010|E|increases pemigatinib plasma concentrations, which may increase the|
03464|011|E|incidence and severity of adverse reactions.(1)|
03464|012|B||
03464|013|P|PREDISPOSING FACTORS:  None determined.|
03464|014|B||
03464|015|M|PATIENT MANAGEMENT:  The US manufacturer of pemigatinib states that|
03464|016|M|coadministration with strong or moderate CYP3A4 inhibitors should be|
03464|017|M|avoided.  If coadministration cannot be avoided, the dosage of pemigatinib|
03464|018|M|should be reduced as follows:|
03464|019|M|   -Reduce dose from 13.5 mg to 9 mg.|
03464|020|M|   -Reduce dose from 9 mg to 4.5 mg.|
03464|021|M|   If the strong or moderate CYP3A4 inhibitor is discontinued, resume the|
03464|022|M|pemigatinib dose that was taken prior to the initiation of the inhibitor|
03464|023|M|after 3 half-lives of the CYP3A4 inhibitor have elapsed.(1)|
03464|024|B||
03464|025|D|DISCUSSION:  Itraconazole, a strong CYP3A4 inhibitor, increased the maximum|
03464|026|D|concentration (Cmax) by 17% and area-under-curve (AUC) by 88% following a|
03464|027|D|single oral pemigatinib dose of 4.5 mg.  Concomitant use of moderate CYP3A4|
03464|028|D|inhibitors is predicted to increase pemigatinib exposure by approximately|
03464|029|D|50-80%.(1)|
03464|030|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03464|031|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
03464|032|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir,|
03464|033|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
03464|034|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
03464|035|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)|
03464|036|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
03464|037|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
03464|038|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03464|039|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
03464|040|D|lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra,|
03464|041|D|stiripentol, tofisopam, treosulfan, and verapamil.(2)|
03464|042|B||
03464|043|R|REFERENCES:|
03464|044|B||
03464|045|R|1.Pemazyre (pemigatinib) US prescribing information. Incyte Corporation|1
03464|046|R|  February, 2021.|1
03464|047|R|2.This information is based on an extract from the Certara Drug Interaction|6
03464|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03465|001|T|MONOGRAPH TITLE:  Tucatinib/Strong CYP2C8 Inhibitors|
03465|002|B||
03465|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03465|004|L|of severe adverse interaction.|
03465|005|B||
03465|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2C8 may inhibit the metabolism|
03465|007|A|of tucatinib.(1)|
03465|008|B||
03465|009|E|CLINICAL EFFECTS:  Concomitant use of a strong CYP2C8 inhibitor may increase|
03465|010|E|tucatinib plasma concentrations, which may increase the risk of tucatinib|
03465|011|E|toxicity.(1)|
03465|012|B||
03465|013|P|PREDISPOSING FACTORS:  None determined.|
03465|014|B||
03465|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of tucatinib with strong CYP2C8|
03465|016|M|inhibitors.  If concomitant use with a strong CYP2C8 inhibitor cannot be|
03465|017|M|avoided, reduce the recommended dosage to 100 mg twice daily.|
03465|018|M|   After discontinuation of the strong CYP2C8 inhibitor for 3 elimination|
03465|019|M|half-lives, resume the tucatinib dose that was taken prior to initiating the|
03465|020|M|inhibitor.(1)|
03465|021|B||
03465|022|D|DISCUSSION:  A single dose of tucatinib 300 mg was given with gemfibrozil|
03465|023|D|(600 mg twice daily), a strong CYP2C8 inhibitor, and the tucatinib|
03465|024|D|area-under-curve (AUC) and maximum concentration (Cmax) increased 3-fold and|
03465|025|D|1.6-fold, respectively.(1)|
03465|026|D|   Strong CYP2C8 inhibitors linked to this monograph include gemfibrozil.(2)|
03465|027|B||
03465|028|R|REFERENCES:|
03465|029|B||
03465|030|R|1.Tukysa (tucatinib) US prescribing information. Seattle Genetics April,|1
03465|031|R|  2020.|1
03465|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
03465|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03466|001|T|MONOGRAPH TITLE:  Tucatinib/Strong CYP3A4 Inducers; Moderate CYP2C8 Inducers|
03466|002|B||
03466|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03466|004|L|of severe adverse interaction.|
03466|005|B||
03466|006|A|MECHANISM OF ACTION:  Tucatinib is a substrate of CYP3A4 and CYP2C8.  Strong|
03466|007|A|inducers of CYP3A4 or moderate inducers of CYP2C8 may induce the metabolism|
03466|008|A|of tucatinib.(1)|
03466|009|B||
03466|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 or a|
03466|011|E|moderate inducer of CYP2C8 may result in decreased levels and effectiveness|
03466|012|E|of tucatinib.(1)|
03466|013|B||
03466|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03466|015|P|of the inducer for longer than 1-2 weeks.|
03466|016|B||
03466|017|M|PATIENT MANAGEMENT:  The manufacturer of tucatinib states to avoid|
03466|018|M|concurrent administration with strong CYP3A4 inducers or moderate CYP2C8|
03466|019|M|inducers.(1)|
03466|020|B||
03466|021|D|DISCUSSION:  Coadministration of rifampin (a strong CYP3A4 and moderate|
03466|022|D|CYP2C8 inducer- 600 mg once daily) decreased the area-under-the-curve (AUC)|
03466|023|D|and maximum concentration (Cmax) of tucatinib (300 mg single dose) by 50%|
03466|024|D|and 40%, respectively.(1)|
03466|025|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
03466|026|D|barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital,|
03466|027|D|phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3)|
03466|028|D|   Moderate CYP2C8 inducers linked to this monograph include: rifampin.(2-3)|
03466|029|B||
03466|030|R|REFERENCES:|
03466|031|B||
03466|032|R|1.Tukysa (tucatinib) US prescribing information. Seattle Genetics April,|1
03466|033|R|  2020.|1
03466|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
03466|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03466|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03466|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03466|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03466|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03466|040|R|  11/14/2017.|1
03467|001|T|MONOGRAPH TITLE:  Amlodipine/Apalutamide; Carbamazepine|
03467|002|B||
03467|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03467|004|L|take action as needed.|
03467|005|B||
03467|006|A|MECHANISM OF ACTION:  Concurrent use of apalutamide or carbamazepine may|
03467|007|A|induce the CYP3A4 mediated metabolism of amlodipine.(1-3)|
03467|008|B||
03467|009|E|CLINICAL EFFECTS:  Concurrent use of apalutamide or carbamazepine may|
03467|010|E|decrease levels and effectiveness of amlodipine.(1-3)|
03467|011|B||
03467|012|P|PREDISPOSING FACTORS:  None determined.|
03467|013|B||
03467|014|M|PATIENT MANAGEMENT:  The US manufacturer of apalutamide recommends|
03467|015|M|substituting amlodipine with a drug not metabolized by CYP3A4 when possible.|
03467|016|M|If concurrent therapy with apalutamide or carbamazepine is necessary,|
03467|017|M|monitor the patient for a decrease in the therapeutic effects of amlodipine.|
03467|018|M|The dose of amlodipine may need to be adjusted.(1-3)|
03467|019|B||
03467|020|D|DISCUSSION:  Apalutamide is a strong inducer of CYP3A4.  Amlodipine is|
03467|021|D|metabolized by CYP3A4 and has been shown to be affected by other strong|
03467|022|D|CYP3A4 inducers.  In a study in 16 hypertensive chronic kidney disease|
03467|023|D|patients, amlodipine levels decreased an average of 82% after initiation of|
03467|024|D|rifampin. In eight of the 16 patients, the levels were undetectable.(4)|
03467|025|D|   A case report describes a 53-year-old women with schizophrenia and|
03467|026|D|hypertension who was stable on paliperidone and amlodipine 5 mg daily.  Upon|
03467|027|D|carbamazepine initiation, amlodipine levels decreased by 68%, and blood|
03467|028|D|pressure increased from a baseline of 138/91 to 160/103.  Blood pressure|
03467|029|D|normalized after discontinuation of carbamazepine.(5)|
03467|030|B||
03467|031|R|REFERENCES:|
03467|032|B||
03467|033|R|1.Norvasc (amlodipine) US Prescribing Information. Pfizer Labs October,|1
03467|034|R|  2017.|1
03467|035|R|2.Erleada (apalutamide) US prescribing information. Janssen Biotech, Inc.|1
03467|036|R|  July, 2021.|1
03467|037|R|3.Tegretol (carbamazepine) US prescribing information. Novartis|1
03467|038|R|  Pharmaceuticals Corporation September, 2023.|1
03467|039|R|4.Agrawal A, Agarwal SK, Kaleekal T, Gupta YK. Rifampicin and|2
03467|040|R|  anti-hypertensive drugs in chronic kidney disease: Pharmacokinetic|2
03467|041|R|  interactions and their clinical impact. Indian J Nephrol 2016 Sep;|2
03467|042|R|  26(5):322-328.|2
03467|043|R|5.Akamine Y, Uehara H, Miura M, Yasui-Furukori N, Uno T. Multiple inductive|3
03467|044|R|  effects of carbamazepine on combined therapy with paliperidone  and|3
03467|045|R|  amlodipine. J Clin Pharm Ther 2015 Aug;40(4):480-2.|3
03468|001|T|MONOGRAPH TITLE:  Pimozide/Strong CYP3A4 Inhibitors that Prolong QT|
03468|002|B||
03468|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03468|004|L|is contraindicated and generally should not be dispensed or administered to|
03468|005|L|the same patient.|
03468|006|B||
03468|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
03468|008|A|may inhibit the metabolism of pimozide and cause an additive risk of QTc|
03468|009|A|prolongation.(1)|
03468|010|B||
03468|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
03468|012|E|QT may increase the levels and effects of pimozide including additive QTc|
03468|013|E|prolongation and potentially life-threatening cardiac arrhythmias like|
03468|014|E|torsades de pointes.|
03468|015|E|   Concurrent use may also result in extrapyramidal symptoms such as|
03468|016|E|akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and|
03468|017|E|oculogyric crisis.(1)|
03468|018|B||
03468|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03468|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03468|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03468|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03468|023|P|female gender, or advanced age.(2)|
03468|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03468|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03468|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03468|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03468|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03468|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03468|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03468|031|P|   The risk of anticholinergic toxicities including cognitive decline,|
03468|032|P|delirium, falls and fractures is increased in geriatric patients using more|
03468|033|P|than one medicine with anticholinergic properties.(3)|
03468|034|B||
03468|035|M|PATIENT MANAGEMENT:  The use of pimozide with strong CYP3A4 inhibitors that|
03468|036|M|prolong QT is contraindicated, especially when other risk factors for QT|
03468|037|M|prolongation are present.|
03468|038|M|   The manufacturer of pimozide states that concomitant treatment with|
03468|039|M|strong CYP3A4 inhibitors is contraindicated and treatment with less potent|
03468|040|M|inhibitors of CYP3A4 should also be avoided.(1)|
03468|041|M|   If concurrent use cannot be avoided, then correct or minimize QT|
03468|042|M|prolonging risk factors, use the lowest effective dose of pimozide, and|
03468|043|M|discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if|
03468|044|M|possible.|
03468|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03468|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03468|047|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
03468|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03468|049|B||
03468|050|D|DISCUSSION:  Pimozide is metabolized at CYP3A.  Elevated levels of pimozide|
03468|051|D|may prolong the QTc interval resulting in life-threatening ventricular|
03468|052|D|arrhythmias.(1)|
03468|053|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
03468|054|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
03468|055|D|posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(5,6)|
03468|056|B||
03468|057|R|REFERENCES:|
03468|058|B||
03468|059|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
03468|060|R|  2011.|1
03468|061|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03468|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03468|063|R|  settings: a scientific statement from the American Heart Association and|6
03468|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03468|065|R|  2;55(9):934-47.|6
03468|066|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03468|067|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03468|068|R|  Soc 2023 Jul;71(7):2052-2081.|6
03468|069|R|4.Desta Z, Kerbusch T, Soukhova N, Richard E, Ko JW, Flockhart DA.|5
03468|070|R|  Identification and characterization of human cytochrome P450 isoforms|5
03468|071|R|  interacting with pimozide. J Pharmacol Exp Ther 1998 May;285(2):428-37.|5
03468|072|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03468|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03468|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03468|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03468|076|R|  11/14/2017.|1
03468|077|R|6.This information is based on an extract from the Certara Drug Interaction|6
03468|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03469|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP3A4 Substrates/Tucatinib|
03469|002|B||
03469|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03469|004|L|of severe adverse interaction.|
03469|005|B||
03469|006|A|MECHANISM OF ACTION:  Tucatinib is a strong inhibitor of CYP3A4 and may|
03469|007|A|decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Tucatinib|
03469|008|A|is also an inhibitor of P-glycoprotein (P-gp) and may increase the|
03469|009|A|absorption of sirolimus.|
03469|010|B||
03469|011|E|CLINICAL EFFECTS:  Concurrent use of tucatinib may lead to increased serum|
03469|012|E|levels and adverse effects of drugs sensitive to inhibition of the CYP3A4|
03469|013|E|pathway or P-gp.(1)|
03469|014|B||
03469|015|P|PREDISPOSING FACTORS:  None determined.|
03469|016|B||
03469|017|M|PATIENT MANAGEMENT:  The manufacturer of tucatinib states that|
03469|018|M|coadministration of CYP3A4 substrates should be avoided.  If concomitant use|
03469|019|M|is unavoidable, consider dose reduction of the CYP3A4 substrate.(1)|
03469|020|M|   The manufacturer of tucatinib states that the dose of P-gp substrates may|
03469|021|M|need to be reduced with coadministration with tucatinib.(1)|
03469|022|B||
03469|023|D|DISCUSSION:  In a study, tucatinib increased the area-under-the-curve (AUC)|
03469|024|D|and maximum concentration (Cmax) of a single dose of midazolam (2 mg) by|
03469|025|D|5.7-fold and 3-fold, respectively.(1)|
03469|026|D|   In a study, tucatinib increased the AUC and Cmax of digoxin (0.5 mg|
03469|027|D|single dose) by 1.5-fold and 2.4-fold, respectively.(1)|
03469|028|D|   CYP3A4 substrates with a narrow therapeutic index linked to this|
03469|029|D|monograph include: cyclosporine, midazolam, nisoldipine, and sirolimus.(1-3)|
03469|030|B||
03469|031|R|REFERENCES:|
03469|032|B||
03469|033|R|1.Tukysa (tucatinib) US prescribing information. Seattle Genetics April,|1
03469|034|R|  2020.|1
03469|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03469|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03469|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03469|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03469|039|R|  11/14/2017.|1
03469|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
03469|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03470|001|T|MONOGRAPH TITLE:  Select Sensitive CYP3A4 Substrates that Prolong|
03470|002|T|QT/Tucatinib|
03470|003|B||
03470|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03470|005|L|of severe adverse interaction.|
03470|006|B||
03470|007|A|MECHANISM OF ACTION:  Tucatinib is an inhibitor of CYP3A4 and may increase|
03470|008|A|the metabolism of drugs metabolized by the CYP3A4 enzyme.|
03470|009|B||
03470|010|E|CLINICAL EFFECTS:  Concurrent use of tucatinib may lead to increased serum|
03470|011|E|levels and adverse effects of drugs sensitive to inhibition of the CYP3A4|
03470|012|E|pathway.(1)|
03470|013|E|  Higher systemic concentrations of QT prolonging drugs which are|
03470|014|E|metabolized by CYP3A4 may increase the risk for Torsades de Pointes.|
03470|015|B||
03470|016|P|PREDISPOSING FACTORS:  A greater risk for serious adverse events would be|
03470|017|P|expected from drugs having a narrow therapeutic window.|
03470|018|P|   The risk of QT prolongation or torsade de pointes may be increased in|
03470|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03470|020|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03470|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03470|022|P|advanced age.(2)|
03470|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03470|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03470|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03470|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03470|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03470|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03470|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03470|030|B||
03470|031|M|PATIENT MANAGEMENT:  The manufacturer of tucatinib states that|
03470|032|M|coadministration of CYP3A4 substrates should be avoided.  If concomitant use|
03470|033|M|is unavoidable, consider dose reduction of the CYP3A4 substrate.(1)|
03470|034|M|   The US manufacturer of tacrolimus states that coadministration with a|
03470|035|M|strong CYP3A4 inhibitor like tucatinib may result in a rapid and sharp rise|
03470|036|M|in tacrolimus concentration despite immediate tacrolimus dose reduction.|
03470|037|M|Frequent monitoring of tacrolimus levels should start within 1-3 days of|
03470|038|M|initiation of concurrent therapy and continue as necessary.(3)|
03470|039|M|   If concurrent therapy with tucatinib and a sensitive CYP3A4 substrate|
03470|040|M|which may prolong the QT interval is warranted, consider obtaining serum|
03470|041|M|calcium, magnesium, and potassium levels and monitoring ECG at baseline and|
03470|042|M|at regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03470|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03470|044|B||
03470|045|D|DISCUSSION:  In a study, tucatinib increased the area-under-the-curve (AUC)|
03470|046|D|and maximum concentration (Cmax) of a single dose of midazolam (2 mg) by|
03470|047|D|5.7-fold and 3-fold, respectively.(1)|
03470|048|D|   Sensitive CYP3A4 substrates with a narrow therapeutic index that prolong|
03470|049|D|QT include: quinidine and tacrolimus.(1,3,5)|
03470|050|B||
03470|051|R|REFERENCES:|
03470|052|B||
03470|053|R|1.Tukysa (tucatinib) US prescribing information. Seattle Genetics April,|1
03470|054|R|  2020.|1
03470|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03470|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03470|057|R|  settings: a scientific statement from the American Heart Association and|6
03470|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03470|059|R|  2;55(9):934-47.|6
03470|060|R|3.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
03470|061|R|  August, 2023.|1
03470|062|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03470|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03470|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03470|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03470|066|R|  11/14/2017.|1
03470|067|R|5.This information is based on an extract from the Certara Drug Interaction|6
03470|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03471|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Tucatinib|
03471|002|B||
03471|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03471|004|L|is contraindicated and generally should not be dispensed or administered to|
03471|005|L|the same patient.|
03471|006|B||
03471|007|A|MECHANISM OF ACTION:  Tucatinib may inhibit the metabolism of lovastatin and|
03471|008|A|simvastatin by CYP3A4.(1,2)|
03471|009|B||
03471|010|E|CLINICAL EFFECTS:  Concurrent use of tucatinib may result in elevated levels|
03471|011|E|of lovastatin and simvastatin and increase the risk of rhabdomyolysis.(1,2)|
03471|012|B||
03471|013|P|PREDISPOSING FACTORS:  None determined.|
03471|014|B||
03471|015|M|PATIENT MANAGEMENT:  Concurrent use of strong CYP3A4 inhibitors with|
03471|016|M|lovastatin or simvastatin is contraindicated.(1,2)|
03471|017|M|  In patients requiring long-term therapy with tucatinib, consider the use|
03471|018|M|of pravastatin or reduced dosages of atorvastatin or fluvastatin, using the|
03471|019|M|lowest dose possible.(3)  Patients should be carefully monitored for and|
03471|020|M|instructed to report any signs of myopathy.|
03471|021|B||
03471|022|D|DISCUSSION:  A single dose of midazolam 2 mg given with tucatinib 300 mg|
03471|023|D|twice daily increased the maximum concentration (Cmax) and area-under-curve|
03471|024|D|(AUC) of midazolam by 3-fold and 5.7-fold, respectively.(4)|
03471|025|B||
03471|026|R|REFERENCES:|
03471|027|B||
03471|028|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
03471|029|R|  February, 2014.|1
03471|030|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03471|031|R|  2023.|1
03471|032|R|3.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
03471|033|R|  2020.|1
03471|034|R|4.Tukysa (tucatinib) US prescribing information. Seattle Genetics April,|1
03471|035|R|  2020.|1
03472|001|T|MONOGRAPH TITLE:  Digoxin/Tucatinib|
03472|002|B||
03472|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03472|004|L|take action as needed.|
03472|005|B||
03472|006|A|MECHANISM OF ACTION:  Tucatinib may increase the absorption of digoxin by|
03472|007|A|inhibiting P-glycoprotein (P-gp).(1)|
03472|008|B||
03472|009|E|CLINICAL EFFECTS:  Concurrent use of tucatinib may result in elevated levels|
03472|010|E|of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can include|
03472|011|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
03472|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
03472|013|E|disturbances, and arrhythmias.|
03472|014|B||
03472|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
03472|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
03472|017|P|risk of digoxin toxicity.|
03472|018|B||
03472|019|M|PATIENT MANAGEMENT:  Monitor digoxin concentrations before and during the|
03472|020|M|administration of tucatinib.  If digoxin serum concentration is greater than|
03472|021|M|1.2 ng/ml, reduce the dosage of digoxin by one-half during concurrent|
03472|022|M|therapy.(1)|
03472|023|M|   The manufacturer of digoxin recommends decreasing the dose of digoxin by|
03472|024|M|approximately 30-50% or by modifying the dosing frequency to reduce digoxin|
03472|025|M|concentrations.(2)|
03472|026|B||
03472|027|D|DISCUSSION:  Concurrent tucatinib (300 mg twice daily) increased the|
03472|028|D|area-under-curve (AUC) and maximum concentration (Cmax) of oral digoxin by|
03472|029|D|1.5-fold and 2.4-fold, respectively.(1)|
03472|030|B||
03472|031|R|REFERENCES:|
03472|032|B||
03472|033|R|1.Tukysa (tucatinib) US prescribing information. Seattle Genetics April,|1
03472|034|R|  2020.|1
03472|035|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
03472|036|R|  Pharmaceuticals, Inc. August, 2018.|1
03473|001|T|MONOGRAPH TITLE:  Sacituzumab Govitecan/UGT1A1 Inhibitors|
03473|002|B||
03473|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03473|004|L|of severe adverse interaction.|
03473|005|B||
03473|006|A|MECHANISM OF ACTION:  Inhibitors of UGT1A1 may inhibit the metabolism of|
03473|007|A|SN-38, the topoisomerase inhibitor which is the antineoplastic component of|
03473|008|A|sacituzumab govitecan.(1)|
03473|009|B||
03473|010|E|CLINICAL EFFECTS:  Concurrent use of UGT1A1 inhibitors may result in|
03473|011|E|increased exposure to and toxicity from sacituzumab govitecan.  Toxicities|
03473|012|E|from sacituzumab govitecan include neutropenia, severe diarrhea, nausea, and|
03473|013|E|vomiting.(1)|
03473|014|B||
03473|015|P|PREDISPOSING FACTORS:  None determined.|
03473|016|B||
03473|017|M|PATIENT MANAGEMENT:  Avoid the use of inhibitors of UGT1A1 in patients|
03473|018|M|receiving sacituzumab govitecan.(1)|
03473|019|B||
03473|020|D|DISCUSSION:  SN-38, the small molecule moiety of sacituzumab govitecan, is|
03473|021|D|metabolized by UGT1A1, and inhibitors of UGT1A1 are expected to increase|
03473|022|D|SN-38 levels and dose limiting toxicities.(1)|
03473|023|D|   In a clinical trial, patients homozygous for decreased function UGT1A1*28|
03473|024|D|allele had a 26% incidence of Grade 4 neutropenia, compared to 13% of|
03473|025|D|patients heterozygous for the UGT1A1*28 allele and 11% of patients|
03473|026|D|homozygous for the wild type allele.(1)|
03473|027|D|   Coadministration of ketoconazole (a CYP3A4 and UGT1A1 inhibitor) with|
03473|028|D|irinotecan, has been reported to result in increased exposure to SN-38, an|
03473|029|D|active metabolite of irinotecan.(2)|
03473|030|D|   UGT1A1 inhibitors linked to this monograph include: atazanavir,|
03473|031|D|belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole,|
03473|032|D|lapatinib, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib.|
03473|033|B||
03473|034|R|REFERENCES:|
03473|035|B||
03473|036|R|1.Trodelvy (sacituzumab govitecan-hziy) US prescribing information.|1
03473|037|R|  Immunomedics, Inc. April, 2020.|1
03473|038|R|2.Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia|1
03473|039|R|  & Upjohn Company January, 2020.|1
03474|001|T|MONOGRAPH TITLE:  Sacituzumab Govitecan/UGT1A1 Inducers|
03474|002|B||
03474|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03474|004|L|of severe adverse interaction.|
03474|005|B||
03474|006|A|MECHANISM OF ACTION:  Inducers of UGT1A1 may increase the metabolism of|
03474|007|A|SN-38, the topoisomerase inhibitor which is the antineoplastic component of|
03474|008|A|sacituzumab govitecan.(1)|
03474|009|B||
03474|010|E|CLINICAL EFFECTS:  Concurrent use of UGT1A1 inducers may result in decreased|
03474|011|E|exposure to sacituzumab govitecan and therapeutic failure.(1)|
03474|012|B||
03474|013|P|PREDISPOSING FACTORS:  None determined.|
03474|014|B||
03474|015|M|PATIENT MANAGEMENT:  Avoid the use of UGT1A1 inducers in patients receiving|
03474|016|M|sacituzumab govitecan.(1)|
03474|017|B||
03474|018|D|DISCUSSION:  SN-38, the small molecule moiety of sacituzumab govitecan, is|
03474|019|D|metabolized by UGT1A1, and inducers of UGT1A1 are expected to decrease SN-38|
03474|020|D|levels and effectiveness.(1)|
03474|021|D|   In a clinical trial, patients homozygous for decreased function UGT1A1*28|
03474|022|D|allele had a 26% incidence of Grade 4 neutropenia, compared to 13% of|
03474|023|D|patients heterozygous for the UGT1A1*28 allele and 11% of patients|
03474|024|D|homozygous for the wild type allele.(1)|
03474|025|D|   UGT1A1 inducers linked to this monograph include:  carbamazepine,|
03474|026|D|efavirenz, etravirine, fosphenytoin, lorlatinib, phenobarbital, phenytoin,|
03474|027|D|primidone, rifampin, ritonavir.|
03474|028|B||
03474|029|R|REFERENCE:|
03474|030|B||
03474|031|R|1.Trodelvy (sacituzumab govitecan-hziy) US prescribing information.|1
03474|032|R|  Immunomedics, Inc. April, 2020.|1
03475|001|T|MONOGRAPH TITLE:  Ivabradine/Dronedarone|
03475|002|B||
03475|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03475|004|L|is contraindicated and generally should not be dispensed or administered to|
03475|005|L|the same patient.|
03475|006|B||
03475|007|A|MECHANISM OF ACTION:  Concurrent use of dronedarone, a moderate CYP3A4|
03475|008|A|inhibitor, may inhibit the metabolism of ivabradine and result in additive|
03475|009|A|effects on the QTc interval.(1,2)|
03475|010|B||
03475|011|E|CLINICAL EFFECTS:  Concurrent administration may result in increased|
03475|012|E|concentrations of and toxicity from ivabradine and life-threatening cardiac|
03475|013|E|arrhythmias, including torsades de pointes.(1,2)|
03475|014|B||
03475|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03475|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03475|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03475|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03475|019|P|gender, or advanced age.(3)|
03475|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03475|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03475|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03475|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03475|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03475|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03475|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03475|027|B||
03475|028|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that the use|
03475|029|M|of drugs or herbal products that are known to prolong the QTc interval is|
03475|030|M|contraindicated.|
03475|031|M|   The UK, AU, and Canadian manufacturer of ivabradine states that|
03475|032|M|concurrent use with cardiovascular and non-cardiovascular QT prolonging|
03475|033|M|agents should be avoided.(1,4,5)|
03475|034|M|   The Canadian manufacturer states that if concurrent therapy is deemed|
03475|035|M|necessary, close cardiac monitoring (12-lead ECG) is required. Depending on|
03475|036|M|the ECG results, ivabradine dosing may need to be decreased or stopped.(4)|
03475|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03475|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03475|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03475|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03475|041|B||
03475|042|D|DISCUSSION:  Concurrent with moderate CYP3A4 inhibitors diltiazem and|
03475|043|D|verapamil increased ivabradine area-under-curve (AUC) by 2- to 3-fold and|
03475|044|D|reduced heart rate by an additional 5 bpm.(1)|
03475|045|B||
03475|046|R|REFERENCES:|
03475|047|B||
03475|048|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
03475|049|R|  Les Laboratoires Servier March, 2015.|1
03475|050|R|2.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
03475|051|R|  November, 2020.|1
03475|052|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03475|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03475|054|R|  settings: a scientific statement from the American Heart Association and|6
03475|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03475|056|R|  2;55(9):934-47.|6
03475|057|R|4.Lancora (ivabradine) Canadian prescribing  information. Servier Canada|1
03475|058|R|  Inc. December 20, 2016.|1
03475|059|R|5.Coralan (ivabradine) AU prescribing information. Servier Laboratories|1
03475|060|R|  (Aust.) PTY LTD September 11, 2017.|1
03476|001|T|MONOGRAPH TITLE:  Ivabradine/Strong CYP3A4 Inhibitors that Prolong QT|
03476|002|B||
03476|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03476|004|L|is contraindicated and generally should not be dispensed or administered to|
03476|005|L|the same patient.|
03476|006|B||
03476|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03476|008|A|interval may inhibit the metabolism of ivabradine and result in additive|
03476|009|A|risk of QT prolongation.(1,2)|
03476|010|B||
03476|011|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03476|012|E|prolong QT may result in elevated levels of and toxicity from ivabradine|
03476|013|E|including an additive reduction in heart rate which can contribute to QT|
03476|014|E|prolongation or torsades de pointes.(1,2)|
03476|015|B||
03476|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03476|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03476|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03476|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03476|020|P|gender, or advanced age.(3)|
03476|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03476|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03476|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03476|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03476|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03476|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03476|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03476|028|B||
03476|029|M|PATIENT MANAGEMENT:  The manufacturer of ivabradine states that concurrent|
03476|030|M|use with strong CYP3A4 inhibitors is contraindicated.(1,2,4,5)  Guideline|
03476|031|M|recommendations state ivabradine should not be used with protease|
03476|032|M|inhibitors.(6)|
03476|033|M|   If concurrent therapy is deemed medically necessary, monitor patients|
03476|034|M|receiving concurrent therapy for bradycardia (heart rate less than 50 bpm),|
03476|035|M|dizziness, fatigue, hypotension, and/or symptoms of atrial fibrillation|
03476|036|M|(heart palpitations, chest pressure, shortness of breath).|
03476|037|B||
03476|038|D|DISCUSSION:  Concurrent use of potent CYP3A4 inhibitors ketoconazole (200 mg|
03476|039|D|daily) and josamycin (1000 mg twice daily) increased mean ivabradine plasma|
03476|040|D|exposure by 7- to 8-fold.(1)|
03476|041|D|   Strong CYP3A4 inhibitors that prolong QT linked to this monograph|
03476|042|D|include:  adagrasib, ceritinib, clarithromycin, levoketoconazole,|
03476|043|D|lonafarnib, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir,|
03476|044|D|telithromycin, and voriconazole.|
03476|045|B||
03476|046|R|REFERENCES:|
03476|047|B||
03476|048|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
03476|049|R|  Les Laboratoires Servier March, 2015.|1
03476|050|R|2.Corlanor (ivabradine) US prescribing information. Amgen, Inc. August,|1
03476|051|R|  2021.|1
03476|052|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03476|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03476|054|R|  settings: a scientific statement from the American Heart Association and|6
03476|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03476|056|R|  2;55(9):934-47.|6
03476|057|R|4.Coralan (ivabradine) AU prescribing information. Servier Laboratories|1
03476|058|R|  (Aust.) PTY LTD September 11, 2017.|1
03476|059|R|5.Lancora (ivabradine) Canadian prescribing  information. Servier Canada|1
03476|060|R|  Inc. December 20, 2016.|1
03476|061|R|6.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03476|062|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03476|063|R|  HIV. Department of Health and Human Services. Available at|6
03476|064|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03476|065|R|  new-guidelines June 13, 2021.|6
03477|001|T|MONOGRAPH TITLE:  Ivabradine/Moderate CYP3A4 Inhibitors that Prolong QT|
03477|002|B||
03477|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03477|004|L|of severe adverse interaction.|
03477|005|B||
03477|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong the QTc|
03477|007|A|interval may inhibit the metabolism of ivabradine and result in additive|
03477|008|A|risk of QT prolongation.(1,2)|
03477|009|B||
03477|010|E|CLINICAL EFFECTS:  Concurrent use of moderate inhibitors of CYP3A4 may|
03477|011|E|result in elevated levels of and toxicity from ivabradine including an|
03477|012|E|additive reduction in heart rate which can contribute to QT prolongation or|
03477|013|E|torsades de pointes.(1,2)|
03477|014|B||
03477|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03477|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03477|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03477|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03477|019|P|gender, or advanced age.(3)|
03477|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03477|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03477|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03477|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03477|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03477|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03477|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03477|027|B||
03477|028|M|PATIENT MANAGEMENT:  The US manufacturer of ivabradine states that|
03477|029|M|concurrent use of moderate inhibitors of CYP3A4, including diltiazem and|
03477|030|M|verapamil, should be avoided.(2)|
03477|031|M|   The UK manufacturer of ivabradine states that concurrent use of diltiazem|
03477|032|M|or verapamil is contraindicated but that other moderate inhibitors of CYP3A4|
03477|033|M|may be considered with monitoring of heart rate and with a starting dose of|
03477|034|M|2.5 mg ivabradine twice daily if resting heart rate is above 70 bpm.(1)|
03477|035|M|   The UK, AU, and Canadian manufacturer of ivabradine states that|
03477|036|M|concurrent use with cardiovascular and non-cardiovascular QT prolonging|
03477|037|M|agents should be avoided.(1,4,5)|
03477|038|M|   The Canadian manufacturer states that if concurrent therapy is deemed|
03477|039|M|necessary, close cardiac monitoring (12-lead ECG) is required. Depending on|
03477|040|M|the ECG results, ivabradine dosing may need to be decreased or stopped.(5)|
03477|041|M|   If concurrent therapy is deemed medically necessary, monitor patients|
03477|042|M|receiving concurrent therapy for bradycardia (heart rate less than 50 bpm),|
03477|043|M|dizziness, fatigue, hypotension, and/or symptoms of atrial fibrillation|
03477|044|M|(heart palpitations, chest pressure, shortness of breath).|
03477|045|B||
03477|046|D|DISCUSSION:  Concurrent use of potent CYP3A4 inhibitors ketoconazole (200 mg|
03477|047|D|daily) and josamycin (1000 mg twice daily) increased mean ivabradine plasma|
03477|048|D|exposure by 7- to 8-fold.(1)  Concurrent use of moderate CYP3A4 inhibitors|
03477|049|D|diltiazem and verapamil increased ivabradine area-under-curve (AUC) by 2- to|
03477|050|D|3-fold and reduced heart rate by an additional 5 bpm.(2)|
03477|051|D|   CYP3A4 inhibitors that prolong QT linked to this monograph include:|
03477|052|D|clofazimine, crizotinib, erythromycin, fluconazole, and nilotinib.|
03477|053|B||
03477|054|R|REFERENCES:|
03477|055|B||
03477|056|R|1.Procoralan (ivabradine hydrochloride) summary of product characteristics.|1
03477|057|R|  Les Laboratoires Servier March, 2015.|1
03477|058|R|2.Corlanor (ivabradine) US prescribing information. Amgen, Inc. August,|1
03477|059|R|  2021.|1
03477|060|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03477|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03477|062|R|  settings: a scientific statement from the American Heart Association and|6
03477|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03477|064|R|  2;55(9):934-47.|6
03477|065|R|4.Coralan (ivabradine) AU prescribing information. Servier Laboratories|1
03477|066|R|  (Aust.) PTY LTD September 11, 2017.|1
03477|067|R|5.Lancora (ivabradine) Canadian prescribing  information. Servier Canada|1
03477|068|R|  Inc. December 20, 2016.|1
03478|001|T|MONOGRAPH TITLE:  Gabapentinoids/Benzodiazepines|
03478|002|B||
03478|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03478|004|L|take action as needed.|
03478|005|B||
03478|006|A|MECHANISM OF ACTION:  Concurrent use may result in profound sedation,|
03478|007|A|respiratory depression, coma, and/or death.(1-3)|
03478|008|B||
03478|009|E|CLINICAL EFFECTS:  Concurrent use of benzodiazepines may result in elevated|
03478|010|E|levels of and toxicity from gabapentin and pregabalin, including profound|
03478|011|E|sedation, respiratory depression, coma, and/or death.(1-3)|
03478|012|B||
03478|013|P|PREDISPOSING FACTORS:  Patients who are elderly, are taking other CNS|
03478|014|P|depressants, have decreased renal function, and/or have conditions that|
03478|015|P|reduce lung function (e.g. Chronic Obstructive Pulmonary Disease [COPD]) may|
03478|016|P|be at a higher risk of this interaction.|
03478|017|B||
03478|018|M|PATIENT MANAGEMENT:  Limit prescribing benzodiazepines and gabapentinoids to|
03478|019|M|patients for whom alternatives are ineffective, not tolerated, or would be|
03478|020|M|otherwise inadequate to provide sufficient management of pain.(1)|
03478|021|M|   If concurrent use is necessary, limit the dosages and duration of each|
03478|022|M|drug to the minimum possible while achieving the desired clinical effect.|
03478|023|M|If starting a gabapentinoid with an benzodiazepine, prescribe a lower|
03478|024|M|initial dose of the gabapentinoid than indicated in the absence of an opioid|
03478|025|M|and titrate based upon clinical response.  If a benzodiazepine is indicated|
03478|026|M|(other than an indication of epilepsy) in a patient already taking a|
03478|027|M|gabapentinoid, prescribe a lower dose of the benzodiazepine and titrate|
03478|028|M|based upon clinical response.(1)|
03478|029|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03478|030|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03478|031|M|unresponsiveness.(1)|
03478|032|B||
03478|033|D|DISCUSSION:  Clinical trials have shown no pharmacokinetic interaction|
03478|034|D|between pregabalin (300 mg BID) and lorazepam (1 mg single dose).(2)|
03478|035|D|   Among 49 case reports submitted to FDA over a 5 year period (2012-2017),|
03478|036|D|12 people died from respiratory depression with gabapentinoids. Two|
03478|037|D|randomized, double-blind, placebo-controlled clinical trials in healthy|
03478|038|D|people, three observational studies, and several studies in animals were|
03478|039|D|reviewed. A trial showed that using pregabalin alone and using it with an|
03478|040|D|opioid pain reliever can depress breathing function. Three observational|
03478|041|D|studies showed a relationship between gabapentinoids given before surgery|
03478|042|D|and respiratory depression occurring after surgery. Several animal studies|
03478|043|D|also showed that pregabalin plus opioids can depress respiratory function.|
03478|044|D|Benzodiazepines are expected to have a similar effect when used with|
03478|045|D|gabapentinoids.(1)|
03478|046|B||
03478|047|R|REFERENCES:|
03478|048|B||
03478|049|R|1.FDA (US Food and Drug Administration). FDA MedWatch Safety Alert: FDA|6
03478|050|R|  warns about serious breathing problems with seizure and nerve pain|6
03478|051|R|  medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin|6
03478|052|R|  (Lyrica). Available at:|6
03478|053|R|  https://www.fda.gov/drugs/drug-safety-and-availability Dec19, 2019.|6
03478|054|R|2.Lyrica (pregabalin) US prescribing information. Pfizer, Inc. May, 2019.|1
03478|055|R|3.Neurontin (gabapentin) US prescribing information. Pfizer, Inc. December,|1
03478|056|R|  2020.|1
03479|001|T|MONOGRAPH TITLE:  Pexidartinib (200 mg)/Moderate CYP3A4 Inhibitors|
03479|002|B||
03479|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03479|004|L|of severe adverse interaction.|
03479|005|B||
03479|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03479|007|A|metabolism of pexidartinib.(1,2)|
03479|008|B||
03479|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
03479|010|E|result in elevated levels and increased effects of pexidartinib, such as|
03479|011|E|hepatotoxicity.(1,2)  Symptoms can include nausea, vomiting, jaundice, dark|
03479|012|E|urine, abdominal pain, and unexplained fatigue.|
03479|013|B||
03479|014|P|PREDISPOSING FACTORS:  None determined.|
03479|015|B||
03479|016|M|PATIENT MANAGEMENT:  The US manufacturer of pexidartinib states that|
03479|017|M|pexidartinib coadministration with moderate inhibitors of CYP3A4 should be|
03479|018|M|avoided.(1)|
03479|019|M|   If coadministration with a moderate CYP3A4 inhibitor cannot be avoided,|
03479|020|M|reduce the pexidartinib dose according to the following recommendations.|
03479|021|M|   If the planned total daily dose is currently 800 mg, modify the total|
03479|022|M|daily dose to 400 mg by administering 200 mg twice daily.|
03479|023|M|   If the planned total daily dose is currently 600 mg, modify the total|
03479|024|M|daily dose to 400 mg by administering 200 mg twice daily.|
03479|025|M|   If the planned total daily dose is currently 400 mg, modify the total|
03479|026|M|daily dose to 200 mg by administering 200 mg once daily.|
03479|027|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
03479|028|M|increase the pexidartinib dose to the dose that was used before starting the|
03479|029|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
03479|030|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
03479|031|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
03479|032|M|recommendations in the Turalio package insert. Advise patients to|
03479|033|M|immediately report any symptoms of hepatotoxicity.|
03479|034|B||
03479|035|D|DISCUSSION:  Coadministration of fluconazole (a moderate CYP3A4 inhibitor)|
03479|036|D|increased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
03479|037|D|(AUC) by 41% and 67%.(1)|
03479|038|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
03479|039|D|atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem,|
03479|040|D|erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
03479|041|D|imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra,|
03479|042|D|stiripentol, tofisopam, treosulfan, and verapamil.(1,3)|
03479|043|B||
03479|044|R|REFERENCES:|
03479|045|B||
03479|046|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03479|047|R|  November, 2023.|1
03479|048|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03479|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03479|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03479|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03479|052|R|  11/14/2017.|1
03479|053|R|3.This information is based on an extract from the Certara Drug Interaction|6
03479|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03480|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Pexidartinib|
03480|002|B||
03480|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03480|004|L|of severe adverse interaction.|
03480|005|B||
03480|006|A|MECHANISM OF ACTION:  Pexidartinib is a moderate CYP3A4 inducer and may|
03480|007|A|increase the CYP3A4-mediated metabolism of both estrogen and progestin|
03480|008|A|components of hormonal contraceptives.(1)|
03480|009|B||
03480|010|E|CLINICAL EFFECTS:  Coadministration of pexidartinib with hormonal|
03480|011|E|contraceptives can result in decreased concentrations and reduced|
03480|012|E|efficacy.(1)  Breakthrough bleeding and contraceptive failure/pregnancy may|
03480|013|E|result.  Pexidartinib may cause fetal harm if administered to pregnant|
03480|014|E|women.(1)|
03480|015|B||
03480|016|P|PREDISPOSING FACTORS:  None determined.|
03480|017|B||
03480|018|M|PATIENT MANAGEMENT:  The manufacturer of pexidartinib recommends that female|
03480|019|M|patients of reproductive potential use effective non-hormonal contraception|
03480|020|M|during treatment with pexidartinib and for 1 month after the final dose.(1)|
03480|021|M|   Patients should be alerted to the risk for decreased effectiveness(e.g.|
03480|022|M|contraceptive failure) of their hormonal contraceptive therapy.|
03480|023|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03480|024|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03480|025|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03480|026|M|contraceptive (i.e., a copper IUD).(2)|
03480|027|B||
03480|028|D|DISCUSSION:  Coadministration of pexidartinib 400 mg twice daily with oral|
03480|029|D|midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam|
03480|030|D|area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1)|
03480|031|B||
03480|032|R|REFERENCES:|
03480|033|B||
03480|034|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03480|035|R|  November, 2023.|1
03480|036|R|2.Medicines and Healthcare products Regulatory Agency.|1
03480|037|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03480|038|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03480|039|R|  available at:|1
03480|040|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03480|041|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03480|042|R|  -and-contraceptive-efficacy September 15, 2016..|1
03481|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/Pexidartinib|
03481|002|B||
03481|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03481|004|L|of severe adverse interaction.|
03481|005|B||
03481|006|A|MECHANISM OF ACTION:  Pexidartinib is a moderate inducer of CYP3A4 and may|
03481|007|A|increase the metabolism of drugs metabolized by the CYP3A4 enzyme.|
03481|008|B||
03481|009|E|CLINICAL EFFECTS:  Concurrent use of pexidartinib may lead to decreased|
03481|010|E|serum levels and effectiveness of drugs metabolized by the CYP3A4|
03481|011|E|pathway.(1)|
03481|012|B||
03481|013|P|PREDISPOSING FACTORS:  None determined.|
03481|014|B||
03481|015|M|PATIENT MANAGEMENT:  The manufacturer of pexidartinib states that|
03481|016|M|co-administration of CYP3A4 substrates for which minimal concentration|
03481|017|M|decreases may lead to serious therapeutic failure should be avoided.  If|
03481|018|M|concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in|
03481|019|M|accordance with approved product labeling.(1)|
03481|020|B||
03481|021|D|DISCUSSION:  Coadministration of pexidartinib 400 mg twice daily with oral|
03481|022|D|midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam|
03481|023|D|area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1)|
03481|024|D|   CYP3A4 substrates with a narrow therapeutic index linked to this|
03481|025|D|monograph include: alfentanil, everolimus, felodipine, fentanyl,|
03481|026|D|hydroquinidine, midazolam, nisoldipine, quinidine, sirolimus, tacrolimus,|
03481|027|D|ticagrelor, and triazolam.(1-3)|
03481|028|B||
03481|029|R|REFERENCES:|
03481|030|B||
03481|031|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03481|032|R|  November, 2023.|1
03481|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03481|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03481|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03481|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03481|037|R|  11/14/2017.|1
03481|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
03481|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03482|001|T|MONOGRAPH TITLE:  Gabapentinoids/Opioids (Cough & Cold)|
03482|002|B||
03482|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03482|004|L|of severe adverse interaction.|
03482|005|B||
03482|006|A|MECHANISM OF ACTION:  Opioid-induced reduction in GI motility may increase|
03482|007|A|the absorption of gabapentin and pregabalin.(1)  Gabapentin and pregabalin|
03482|008|A|may reverse opioid-induced tolerance of respiratory depression.(2)|
03482|009|A|Concurrent use may result in profound sedation, respiratory depression,|
03482|010|A|coma, and/or death.(3)|
03482|011|B||
03482|012|E|CLINICAL EFFECTS:  Concurrent use of opioids may result in elevated levels|
03482|013|E|of and toxicity from gabapentin and pregabalin, including profound sedation,|
03482|014|E|respiratory depression, coma, and/or death.(1-7)|
03482|015|B||
03482|016|P|PREDISPOSING FACTORS:  Patients who are elderly, are taking other CNS|
03482|017|P|depressants, have decreased renal function, and/or have conditions that|
03482|018|P|reduce lung function (e.g. Chronic Obstructive Pulmonary Disease [COPD]) may|
03482|019|P|be at a higher risk of this interaction.|
03482|020|B||
03482|021|M|PATIENT MANAGEMENT:  Avoid prescribing opioid-including cough medications|
03482|022|M|for patients taking CNS depressants.(8)|
03482|023|M|   If concurrent use is necessary, limit the dosages and duration of each|
03482|024|M|drug to the minimum possible while achieving the desired clinical effect.|
03482|025|M|If starting a gabapentinoid with an opioid analgesic, prescribe a lower|
03482|026|M|initial dose of the gabapentinoid than indicated in the absence of an opioid|
03482|027|M|and titrate based upon clinical response.  If an opioid analgesic is|
03482|028|M|indicated in a patient already taking a gabapentinoid, prescribe a lower|
03482|029|M|dose of the opioid and titrate based upon clinical response.(1)|
03482|030|M|   Respiratory depression can occur at any time during opioid therapy,|
03482|031|M|especially during therapy initiation and following dosage increases.  The|
03482|032|M|risk of opioid-related overdose or overdose-related death is increased with|
03482|033|M|higher opioid doses, and this risk persists over the course of therapy.|
03482|034|M|Consider these risks when using concurrently with other agents that may|
03482|035|M|cause CNS depression.(9)|
03482|036|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03482|037|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03482|038|M|unresponsiveness.(1)|
03482|039|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03482|040|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03482|041|M|treat opioid use disorder (OUD). Consider prescribing an opioid reversal|
03482|042|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03482|043|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03482|044|M|as those taking CNS depressants) and when a patient has household|
03482|045|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03482|046|M|for obtaining an opioid reversal agent (e.g., prescription,|
03482|047|M|over-the-counter, or as part of a community-based program).(9)|
03482|048|B||
03482|049|D|DISCUSSION:  In a study in 12 healthy males, administration of a single dose|
03482|050|D|of morphine (60 mg sustained release) increased the area-under-curve (AUC)|
03482|051|D|of a single dose of gabapentin (600 mg) by 44%.(1,3,4)  There were no|
03482|052|D|affects on the pharmacokinetics of morphine.(1,3,4)  The combination of|
03482|053|D|gabapentin plus morphine increased pain tolerance over the combination of|
03482|054|D|morphine plus placebo.  Side effects were not significantly different|
03482|055|D|between morphine plus placebo and morphine plus gabapentin.(1)|
03482|056|D|   A retrospective, case-control study of opioid users in Ontario, Canada|
03482|057|D|between August 1, 1997 and December 31, 2013 who died of an opioid-related|
03482|058|D|cause matched cases to up to 4 controls who also used opioids.  Use of|
03482|059|D|gabapentin in the 120 days prior to death resulted in a significant increase|
03482|060|D|in odds of opioid-related death (OR 1.99, CI=1.61-2.47, p<0.001), compared|
03482|061|D|to opioid use alone.  Use of moderate dose (900 mg to 1,799 mg daily) or|
03482|062|D|high dose (>= 1,800 mg daily) gabapentin increased the odds of|
03482|063|D|opioid-related death 60% compared to opioid use without gabapentin.  Review|
03482|064|D|of gabapentin prescriptions from calendar year 2013 found that 46% of|
03482|065|D|gabapentin users received at least 1 opioid prescription.(3)|
03482|066|D|   Among 49 case reports submitted to FDA over a 5 year period (2012-2017),|
03482|067|D|12 people died from respiratory depression with gabapentinoids. Two|
03482|068|D|randomized, double-blind, placebo-controlled clinical trials in healthy|
03482|069|D|people, three observational studies, and several studies in animals were|
03482|070|D|reviewed. A trial showed that using pregabalin alone and using it with an|
03482|071|D|opioid pain reliever can depress breathing function. Three observational|
03482|072|D|studies showed a relationship between gabapentinoids given before surgery|
03482|073|D|and respiratory depression occurring after surgery. Several animal studies|
03482|074|D|also showed that pregabalin plus opioids can depress respiratory|
03482|075|D|function.(7)|
03482|076|D|   A retrospective cohort study evaluated the risk of mortality among|
03482|077|D|Medicare beneficiaries aged 65 and older who were taking gabapentin with or|
03482|078|D|without concurrent use of opioids.  All-cause mortality in gabapentin users|
03482|079|D|compared to duloxetine users was 12.16 per 1,000 person years vs. 9.94 per|
03482|080|D|1,000 person years, respectively.  Adjusted for covariates, the risk of|
03482|081|D|all-cause mortality among gabapentin users on high-dose opioids was more|
03482|082|D|than double the control group (hazard ratio (HR) 2.03, CI=1.19-3.46).(10)|
03482|083|B||
03482|084|R|REFERENCES:|
03482|085|B||
03482|086|R|1.Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin|2
03482|087|R|  enhances the analgesic effect of morphine in healthy volunteers. Anesth|2
03482|088|R|  Analg 2000 Jul;91(1):185-91.|2
03482|089|R|2.Hill R, Dewey WL, Kelly E, Henderson G. Oxycodone-induced tolerance to|5
03482|090|R|  respiratory depression: reversal by ethanol,  pregabalin and protein|5
03482|091|R|  kinase C inhibition. Br J Pharmacol 2018 Jun;175(12):2492-2503.|5
03482|092|R|3.Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink|2
03482|093|R|  W. Gabapentin, opioids, and the risk of opioid-related death: A|2
03482|094|R|  population-based nested case-control study. PLoS Med 2017 Oct;|2
03482|095|R|  14(10):e1002396.|2
03482|096|R|4.Neurontin (gabapentin) US prescribing information. Pfizer, Inc. December,|1
03482|097|R|  2020.|1
03482|098|R|5.Gralise (gabapentin) US prescribing information. Abbott Laboratories|1
03482|099|R|  August, 2012.|1
03482|100|R|6.Health Canada. Health Canada MedEffect e-Notice: Health Canada advises|6
03482|101|R|  Canadians to exercise caution when taking gabapentin or pregabalin with|6
03482|102|R|  opioids. available at:|6
03482|103|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/71003a-e|6
03482|104|R|  ng.php Sept 17, 2019.|6
03482|105|R|7.FDA (US Food and Drug Administration). FDA MedWatch Safety Alert: FDA|6
03482|106|R|  warns about serious breathing problems with seizure and nerve pain|6
03482|107|R|  medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin|6
03482|108|R|  (Lyrica). Available at:|6
03482|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability Dec19, 2019.|6
03482|110|R|8.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03482|111|R|  warns about serious risks and death when combining opioid pain or cough|1
03482|112|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03482|113|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03482|114|R|9.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03482|115|R|  prescribing information for all opioid pain medicines to provide|1
03482|116|R|  additional guidance for safe use. Available at:|1
03482|117|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03482|118|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03482|119|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03482|120|R|10.Corriere MA, Daniel LL, Dickson AL, Nepal P, Hall K, Plummer WD, Dupont|2
03482|121|R|   WD, Murray KT, Stein CM, Ray WA, Chung CP. Concurrent Gabapentin and|2
03482|122|R|   Opioid Use and Risk of Mortality in Medicare Recipients  with Non-Cancer|2
03482|123|R|   Pain. Clin Pharmacol Ther 2023 Aug 7.|2
03483|001|T|MONOGRAPH TITLE:  Pexidartinib (200 mg)/Dronedarone|
03483|002|B||
03483|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03483|004|L|of severe adverse interaction.|
03483|005|B||
03483|006|A|MECHANISM OF ACTION:  Dronedarone may moderately inhibit the CYP3A4|
03483|007|A|metabolism of pexidartinib.(1,2)|
03483|008|A|   Pexidartinib is a moderate inducer of CYP3A4 and may increase the|
03483|009|A|metabolism of dronedarone.(1)|
03483|010|B||
03483|011|E|CLINICAL EFFECTS:  Concurrent use of dronedarone may result in elevated|
03483|012|E|levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2)|
03483|013|E|Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain,|
03483|014|E|and unexplained fatigue.|
03483|015|E|   Concurrent use of dronedarone may also result in decreased serum levels|
03483|016|E|and effectiveness of dronedarone.(1)|
03483|017|B||
03483|018|P|PREDISPOSING FACTORS:  None determined.|
03483|019|B||
03483|020|M|PATIENT MANAGEMENT:  The US manufacturer of pexidartinib states that|
03483|021|M|co-administration of CYP3A4 substrates with a narrow therapeutic window,|
03483|022|M|like dronedarone, should be avoided.  Pexidartinib coadministration with|
03483|023|M|moderate inhibitors of CYP3A4 should also be avoided.(1)|
03483|024|M|   The optimal dosing of pexidartinib and dronedarone when used in|
03483|025|M|combination is unknown.  Manufacturers provide recommendations for dose|
03483|026|M|modification of pexidartinib when used with a moderate CYP3A4 inhibitor, but|
03483|027|M|the recommendations may not apply when there is a multi-directional|
03483|028|M|interaction.  Dose modifications mentioned below are informational only.|
03483|029|M|   If coadministration of pexidartinib with moderate CYP3A4 inhibitors|
03483|030|M|cannot be avoided, reduce the pexidartinib dose according to the following|
03483|031|M|recommendations.|
03483|032|M|   If the planned total daily dose is currently 800 mg, modify the total|
03483|033|M|daily dose to 400 mg by administering 200 mg twice daily.|
03483|034|M|   If the planned total daily dose is currently 600 mg, modify the total|
03483|035|M|daily dose to 400 mg by administering 200 mg twice daily.|
03483|036|M|   If the planned total daily dose is currently 400 mg, modify the total|
03483|037|M|daily dose to 200 mg by administering 200 mg once daily.|
03483|038|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
03483|039|M|increase the pexidartinib dose to the dose that was used before starting the|
03483|040|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
03483|041|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
03483|042|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
03483|043|M|recommendations in the Turalio package insert. Advise patients to|
03483|044|M|immediately report any symptoms of hepatotoxicity.|
03483|045|M|   There are no recommendations to guide dosing of dronedarone in the|
03483|046|M|presence of a moderate CYP3A4 inducer.|
03483|047|B||
03483|048|D|DISCUSSION:  Coadministration of fluconazole (a moderate CYP3A4 inhibitor)|
03483|049|D|increased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
03483|050|D|(AUC) by 41% and 67%.(1)|
03483|051|D|   Coadministration of pexidartinib 400 mg twice daily with oral midazolam,|
03483|052|D|a sensitive CYP3A4 substrate, in patients decreased midazolam|
03483|053|D|area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1)|
03483|054|B||
03483|055|R|REFERENCES:|
03483|056|B||
03483|057|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03483|058|R|  November, 2023.|1
03483|059|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03483|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03483|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03483|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03483|063|R|  11/14/2017.|1
03483|064|R|3.This information is based on an extract from the Certara Drug Interaction|6
03483|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03484|001|T|MONOGRAPH TITLE:  Capmatinib/Strong and Moderate CYP3A4 Inducers|
03484|002|B||
03484|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03484|004|L|of severe adverse interaction.|
03484|005|B||
03484|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03484|007|A|metabolism of capmatinib by CYP3A4.(1)|
03484|008|B||
03484|009|E|CLINICAL EFFECTS:  The concurrent use of strong and moderate CYP3A4 inducers|
03484|010|E|and capmatinib may result in decreased exposure to capmatinib and decreased|
03484|011|E|anti-tumor activity.(1)|
03484|012|B||
03484|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03484|014|P|of the inducer for longer than 1-2 weeks.|
03484|015|B||
03484|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong and moderate CYP3A4|
03484|017|M|inducers with capmatinib.(1)|
03484|018|B||
03484|019|D|DISCUSSION:  Coadministration with rifampin (a strong CYP3A4 inducer)|
03484|020|D|decreased capmatinib area-under-curve (AUC) by 67% and maximum concentration|
03484|021|D|(Cmax) by 56%.  Coadministration with efavirenz (a moderate CYP3A4 inducer)|
03484|022|D|was predicted to decrease capmatinib AUC by 44% and Cmax by 34%.(1)|
03484|023|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
03484|024|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
03484|025|D|dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine,|
03484|026|D|fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten,|
03484|027|D|mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib,|
03484|028|D|phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin,|
03484|029|D|rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and|
03484|030|D|tovorafenib.(2)|
03484|031|B||
03484|032|R|REFERENCES:|
03484|033|B||
03484|034|R|1.Tabrecta (capmatinib) US prescribing information. Novartis Pharmaceuticals|1
03484|035|R|  Corporation May, 2020.|1
03484|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
03484|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03485|001|T|MONOGRAPH TITLE:  Selected CYP1A2 Substrates/Capmatinib|
03485|002|B||
03485|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03485|004|L|of severe adverse interaction.|
03485|005|B||
03485|006|A|MECHANISM OF ACTION:  Capmatinib is a moderate inhibitor of CYP1A2.(1)  The|
03485|007|A|FDA defines moderate inhibition as an increase in drug area-under-curve|
03485|008|A|(AUC) greater than two fold, but less than 5 fold.(2)|
03485|009|B||
03485|010|E|CLINICAL EFFECTS:  Concurrent use of capmatinib with drugs primarily|
03485|011|E|metabolized by CYP1A2 may lead to elevated drug levels and increased side|
03485|012|E|effects.(1)|
03485|013|B||
03485|014|P|PREDISPOSING FACTORS:  Greater risk for adverse events would be expected for|
03485|015|P|drugs with a narrow therapeutic window, or for drugs especially sensitive to|
03485|016|P|CYP1A2 inhibition.|
03485|017|B||
03485|018|M|PATIENT MANAGEMENT:  Drugs linked to this monograph have a narrow|
03485|019|M|therapeutic window or are sensitive to CYP1A2 inhibition.  If|
03485|020|M|coadministration is unavoidable, decrease the CYP1A2 substrate dosage in|
03485|021|M|accordance with the approved prescribing information.(1)|
03485|022|B||
03485|023|D|DISCUSSION:  Coadministration with caffeine (a CYP1A2 substrate) increased|
03485|024|D|area-under-curve (AUC) by 134% with no change in its maximum concentration|
03485|025|D|(Cmax).(1)|
03485|026|D|   CYP1A2 substrates linked to this monograph include: agomelatine,|
03485|027|D|aminophylline, and theophylline.(2)|
03485|028|B||
03485|029|R|REFERENCES:|
03485|030|B||
03485|031|R|1.Tabrecta (capmatinib) US prescribing information. Novartis Pharmaceuticals|1
03485|032|R|  Corporation May, 2020.|1
03485|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03485|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03485|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03485|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03485|037|R|  11/14/2017.|1
03486|001|T|MONOGRAPH TITLE:  Selected P-glycoprotein (P-gp) Substrates/Capmatinib (mono|
03486|002|T|deleted 11/05/2025)|
03486|003|B||
03486|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03486|005|L|of severe adverse interaction.|
03486|006|B||
03486|007|A|MECHANISM OF ACTION:  Capmatinib is an inhibitor of the P-glycoprotein|
03486|008|A|(P-gp) system.  P-gp substrates with a narrow therapeutic index may be|
03486|009|A|increased.(1)|
03486|010|B||
03486|011|E|CLINICAL EFFECTS:  Concurrent use of capmatinib with narrow therapeutic|
03486|012|E|index P-gp substrates may result in elevated levels of the substrate,|
03486|013|E|increasing the risk for adverse effects.(1)|
03486|014|B||
03486|015|P|PREDISPOSING FACTORS:  None determined.|
03486|016|B||
03486|017|M|PATIENT MANAGEMENT:  The US manufacturer of capmatinib states that the|
03486|018|M|concurrent use of narrow therapeutic index P-gp substrates should be|
03486|019|M|avoided.  If concurrent therapy cannot be avoided, the dosage of the narrow|
03486|020|M|therapeutic index P-gp substrate should be decreased according to the|
03486|021|M|substrate prescribing information.(1)|
03486|022|B||
03486|023|D|DISCUSSION:  In a study, capmatinib increased digoxin's area-under-curve|
03486|024|D|(AUC) by 47% and maximum concentration (Cmax) by 74%.(1)|
03486|025|D|   Selected narrow therapeutic index P-gp substrates include: afatinib,|
03486|026|D|betrixaban, digoxin, etoposide, everolimus, loperamide, sirolimus, and|
03486|027|D|ubrogepant.(1,2)|
03486|028|B||
03486|029|R|REFERENCES:|
03486|030|B||
03486|031|R|1.Tabrecta (capmatinib) US prescribing information. Novartis Pharmaceuticals|1
03486|032|R|  Corporation May, 2020.|1
03486|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
03486|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03487|001|T|MONOGRAPH TITLE:  Selected BCRP Substrates/Capmatinib|
03487|002|B||
03487|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03487|004|L|of severe adverse interaction.|
03487|005|B||
03487|006|A|MECHANISM OF ACTION:  Capmatinib inhibits BCRP, which may result in|
03487|007|A|increased absorption of BCRP substrates.(1)|
03487|008|B||
03487|009|E|CLINICAL EFFECTS:  Administration of capmatinib with BCRP substrates may|
03487|010|E|result in elevated levels of and toxicity from these agents.(1)|
03487|011|B||
03487|012|P|PREDISPOSING FACTORS:  None determined.|
03487|013|B||
03487|014|M|PATIENT MANAGEMENT:  The US manufacturer of capmatinib states that the|
03487|015|M|concurrent use of narrow therapeutic index BCRP substrates should be|
03487|016|M|avoided.  If concurrent therapy cannot be avoided, the dosage of the narrow|
03487|017|M|therapeutic index BCRP substrate should be decreased according to the|
03487|018|M|substrate prescribing information.(1)|
03487|019|B||
03487|020|D|DISCUSSION:  In a study, capmatinib increased rosuvastatin (a BCRP|
03487|021|D|substrate) area-under-curve (AUC) by 108% and maximum concentration (Cmax)|
03487|022|D|by 204%.(1)|
03487|023|D|   BCRP substrates linked to this monograph include:  ciprofloxacin,|
03487|024|D|glyburide, imatinib, irinotecan, lapatinib, methotrexate, and|
03487|025|D|mitoxantrone.(1-2)|
03487|026|B||
03487|027|R|REFERENCES:|
03487|028|B||
03487|029|R|1.Tabrecta (capmatinib) US prescribing information. Novartis Pharmaceuticals|1
03487|030|R|  Corporation May, 2020.|1
03487|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
03487|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03488|001|T|MONOGRAPH TITLE:  Tizanidine/Capmatinib|
03488|002|B||
03488|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03488|004|L|of severe adverse interaction.|
03488|005|B||
03488|006|A|MECHANISM OF ACTION:  Capmatinib may inhibit the metabolism of tizanidine by|
03488|007|A|CYP1A2.(1,2)|
03488|008|B||
03488|009|E|CLINICAL EFFECTS:  Concurrent use of capmatinib may result in elevated|
03488|010|E|levels of and effects from tizanidine, including hypotension, bradycardia,|
03488|011|E|drowsiness, sedation, and decreased psychomotor function.|
03488|012|B||
03488|013|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
03488|014|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
03488|015|P|patients using more than one medicine with anticholinergic properties.(3)|
03488|016|B||
03488|017|M|PATIENT MANAGEMENT:  Concomitant use of tizanidine with CYP1A2 inhibitors|
03488|018|M|such as capmatinib should be avoided.(1,2)|
03488|019|M|   If concurrent therapy is warranted, tizanidine therapy should be|
03488|020|M|initiated with a 2 mg dose and increased in 2-4 mg steps daily based on|
03488|021|M|patient response to therapy.|
03488|022|M|   If adverse reactions such as hypotension, bradycardia, or excessive|
03488|023|M|drowsiness occur, reduce or discontinue tizanidine therapy.(1)|
03488|024|B||
03488|025|D|DISCUSSION:  In a study in 10 healthy subjects, concurrent fluvoxamine,|
03488|026|D|another inhibitor of CYP1A2, increased tizanidine maximum concentration|
03488|027|D|(Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold,|
03488|028|D|and 3-fold, respectively. Significant decreases in blood pressure and|
03488|029|D|increases in drowsiness and psychomotor impairment occurred.(1)|
03488|030|D|   In a study in 10 healthy subjects, concurrent ciprofloxacin, another|
03488|031|D|CYP1A2 inhibitor, increased tizanidine Cmax and AUC by 7-fold and 10-fold,|
03488|032|D|respectively. Significant decreases in blood pressure and increased|
03488|033|D|drowsiness and psychomotor impairment occurred.(1)|
03488|034|D|   Coadministration of capmatinib increased caffeine (a CYP1A2 substrate)|
03488|035|D|AUC by 134% with no change to its Cmax.(2)|
03488|036|B||
03488|037|R|REFERENCES:|
03488|038|B||
03488|039|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
03488|040|R|  Pharma Inc. November 22, 2024.|1
03488|041|R|2.Tabrecta (capmatinib) US prescribing information. Novartis Pharmaceuticals|1
03488|042|R|  Corporation May, 2020.|1
03488|043|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03488|044|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03488|045|R|  Soc 2023 Jul;71(7):2052-2081.|6
03489|001|T|MONOGRAPH TITLE:  Clozapine/Capmatinib|
03489|002|B||
03489|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03489|004|L|of severe adverse interaction.|
03489|005|B||
03489|006|A|MECHANISM OF ACTION:  Capmatinib may inhibit the metabolism of clozapine via|
03489|007|A|CYP1A2.(1,2)|
03489|008|B||
03489|009|E|CLINICAL EFFECTS:  Concurrent use may result in higher levels of clozapine|
03489|010|E|and increased risk of side effects including neutropenia and QT|
03489|011|E|prolongation.(2)|
03489|012|E|   Moderate neutropenia, even if due to combination therapy, may require|
03489|013|E|abrupt discontinuation of clozapine resulting in decompensation of the|
03489|014|E|patient's psychiatric disorder (e.g. schizophrenia).  Undetected severe|
03489|015|E|neutropenia or agranulocytosis may be fatal.(2,3)|
03489|016|B||
03489|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03489|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03489|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03489|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03489|021|P|female gender, or advanced age.(4)|
03489|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03489|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03489|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03489|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03489|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03489|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03489|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03489|029|P|   Low white blood counts prior to initiation of the myelosuppressive agent|
03489|030|P|may increase risk for clinically significant neutropenia.(2,3)|
03489|031|B||
03489|032|M|PATIENT MANAGEMENT:  The manufacturer of capmatinib recommends avoiding|
03489|033|M|coadministration of narrow therapeutic index CYP1A2 substrates with|
03489|034|M|capmatinib.(1)  The manufacturer of clozapine recommends monitoring patients|
03489|035|M|for adverse reactions of clozapine and lowering the dose of clozapine if|
03489|036|M|necessary.(2)|
03489|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03489|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03489|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03489|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03489|041|M|   If a patient stabilized on clozapine therapy requires treatment with|
03489|042|M|capmatinib, the clozapine prescriber should consult with the prescriber of|
03489|043|M|capmatinib to discuss treatment and monitoring options.  More frequent ANC|
03489|044|M|monitoring or treatment alternatives secondary to neutropenic episodes may|
03489|045|M|need to be considered.|
03489|046|M|   Clozapine is only available through a restricted distribution system|
03489|047|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
03489|048|M|dispensing.  For most clozapine patients, clozapine treatment must be|
03489|049|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
03489|050|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
03489|051|M|interrupted for suspected clozapine-induced neutropenia < 500|
03489|052|M|cells/microliter.(3)|
03489|053|B||
03489|054|D|DISCUSSION:  Coadministration of capmatinib increased caffeine (a CYP1A2|
03489|055|D|substrate) area-under-curve (AUC) by 134% with no change in its maximum|
03489|056|D|concentration (Cmax).|
03489|057|D|   Treatment with clozapine has been associated with QT prolongation as well|
03489|058|D|as ventricular arrhythmia, torsades de pointes, cardiac arrest, and sudden|
03489|059|D|death.(2)  Clozapine is only available through a restricted distribution|
03489|060|D|system which requires documentation of the ANC prior to dispensing.(3)|
03489|061|B||
03489|062|R|REFERENCES:|
03489|063|B||
03489|064|R|1.Tabrecta (capmatinib) US prescribing information. Novartis Pharmaceuticals|1
03489|065|R|  Corporation May, 2020.|1
03489|066|R|2.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03489|067|R|  Pharmaceuticals Corporation April, 2020.|1
03489|068|R|3.FDA (US Food and Drug Administration). Clozapine: Drug Safety|1
03489|069|R|  Communication - FDA Modifies Monitoring for Neutropenia; Approves New|1
03489|070|R|  Shared REMS Program. accessed at:|1
03489|071|R|  http://www.fda.gov/drugs/drugsafety/ucm461853.htm September 15, 2015.|1
03489|072|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03489|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03489|074|R|  settings: a scientific statement from the American Heart Association and|6
03489|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03489|076|R|  2;55(9):934-47.|6
03490|001|T|MONOGRAPH TITLE:  Selpercatinib/QT Prolonging Agents|
03490|002|B||
03490|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03490|004|L|of severe adverse interaction.|
03490|005|B||
03490|006|A|MECHANISM OF ACTION:  Selpercatinib prolongs the QTc interval.(1)|
03490|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
03490|008|A|additive effects on the QTc interval.(2,3)|
03490|009|B||
03490|010|E|CLINICAL EFFECTS:  The concurrent use of selpercatinib with other agents|
03490|011|E|that prolong the QTc interval may result in potentially life-threatening|
03490|012|E|cardiac arrhythmias, including torsades de pointes.(2,3)|
03490|013|B||
03490|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03490|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03490|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03490|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03490|018|P|gender, or advanced age.(3)|
03490|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03490|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03490|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03490|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03490|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03490|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03490|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03490|026|B||
03490|027|M|PATIENT MANAGEMENT:  Selpercatinib prolongs the QT interval. An increase in|
03490|028|M|QT interval to > 500 ms was measured in 6% of patients and increase in the|
03490|029|M|QT interval of at least 60 ms over baseline was measured in 15% of patients.|
03490|030|M|   Monitor patients at significant risk of developing QT prolongation,|
03490|031|M|including patients with known long QT syndromes, clinically significant|
03490|032|M|bradyarrhythmias, and severe or uncontrolled heart failure.  Assess QT|
03490|033|M|interval, electrolytes, and TSH at baseline and periodically during|
03490|034|M|treatment.  Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to|
03490|035|M|initiation and during treatment.|
03490|036|M|   Dose adjustments (1): For grade 3 QT interval prolongation, withhold|
03490|037|M|selpercatinib until recovery to baseline or grade 0 or 1. Resume at a|
03490|038|M|reduced dose.|
03490|039|M|   -1st dose reduction: For patients weighing less than 50 kg: 80 mg twice|
03490|040|M|daily. For patients weighing 50 kg or greater: 120 mg twice daily.|
03490|041|M|   -2nd dose reduction: For patients weighing less than 50 kg: 40 mg twice|
03490|042|M|daily. For patients weighing 50 kg or greater: 80 mg twice daily.|
03490|043|M|   -3rd dose reduction: For patients weighing less than 50 kg: 40 mg once|
03490|044|M|daily. For patients weighing 50 kg or greater: 40 mg twice daily.|
03490|045|M|   -For grade 4 QT prolongation, discontinue selpercatinib.|
03490|046|B||
03490|047|D|DISCUSSION:  The effect of selpercatinib on the QT interval was evaluated in|
03490|048|D|a thorough QT study in healthy subjects. The largest mean increase in QT is|
03490|049|D|predicted to be 10.6 ms (upper 90% confidence interval: 12.1 ms) at the mean|
03490|050|D|steady state maximum concentration (Cmax) observed in patients after|
03490|051|D|administration of 160 mg twice daily. The increase in QT was|
03490|052|D|concentration-dependent.|
03490|053|D|   Agents that are linked to this monograph may have varying degrees of|
03490|054|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03490|055|D|been shown to prolong the QTc interval either through their mechanism of|
03490|056|D|action, through studies on their effects on the QTc interval, or through|
03490|057|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03490|058|D|and/or postmarketing reports.(2)|
03490|059|B||
03490|060|R|REFERENCES:|
03490|061|B||
03490|062|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03490|063|R|  2024.|1
03490|064|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
03490|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03490|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03490|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03490|068|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03490|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03490|070|R|  settings: a scientific statement from the American Heart Association and|6
03490|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03490|072|R|  2;55(9):934-47.|6
03491|001|T|MONOGRAPH TITLE:  Selpercatinib/Possible QT Prolonging Agents|
03491|002|B||
03491|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03491|004|L|take action as needed.|
03491|005|B||
03491|006|A|MECHANISM OF ACTION:  Selpercatinib prolongs the QTc interval.(1)|
03491|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
03491|008|A|additive effects on the QTc interval.(2,3)|
03491|009|B||
03491|010|E|CLINICAL EFFECTS:  The concurrent use of selpercatinib with other agents|
03491|011|E|that prolong the QTc interval may result in potentially life-threatening|
03491|012|E|cardiac arrhythmias, including torsades de pointes.(2,3)|
03491|013|B||
03491|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03491|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03491|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03491|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03491|018|P|gender, or advanced age.(3)|
03491|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03491|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03491|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03491|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03491|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03491|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03491|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03491|026|B||
03491|027|M|PATIENT MANAGEMENT:  Selpercatinib prolongs the QT interval. An increase in|
03491|028|M|QT interval to > 500 ms was measured in 6% of patients and increase in the|
03491|029|M|QT interval of at least 60 ms over baseline was measured in 15% of patients.|
03491|030|M|   Monitor patients at significant risk of developing QT prolongation,|
03491|031|M|including patients with known long QT syndromes, clinically significant|
03491|032|M|bradyarrhythmias, and severe or uncontrolled heart failure.  Assess QT|
03491|033|M|interval, electrolytes, and TSH at baseline and periodically during|
03491|034|M|treatment.  Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to|
03491|035|M|initiation and during treatment.|
03491|036|M|   Dose adjustments (1): For grade 3 QT interval prolongation, withhold|
03491|037|M|selpercatinib until recovery to baseline or grade 0 or 1. Resume at a|
03491|038|M|reduced dose.|
03491|039|M|   -1st dose reduction: For patients weighing less than 50 kg: 80 mg twice|
03491|040|M|daily. For patients weighing 50 kg or greater: 120 mg twice daily.|
03491|041|M|   -2nd dose reduction: For patients weighing less than 50 kg: 40 mg twice|
03491|042|M|daily. For patients weighing 50 kg or greater: 80 mg twice daily.|
03491|043|M|   -3rd dose reduction: For patients weighing less than 50 kg: 40 mg once|
03491|044|M|daily. For patients weighing 50 kg or greater: 40 mg twice daily.|
03491|045|M|   -For grade 4 QT prolongation, discontinue selpercatinib.|
03491|046|B||
03491|047|D|DISCUSSION:  The effect of selpercatinib on the QT interval was evaluated in|
03491|048|D|a thorough QT study in healthy subjects. The largest mean increase in QT is|
03491|049|D|predicted to be 10.6 ms (upper 90% confidence interval: 12.1 ms) at the mean|
03491|050|D|steady state maximum concentration (Cmax) observed in patients after|
03491|051|D|administration of 160 mg twice daily. The increase in QT was|
03491|052|D|concentration-dependent.|
03491|053|D|   Agents that are linked to this monograph may have varying degrees of|
03491|054|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03491|055|D|been shown to prolong the QTc interval either through their mechanism of|
03491|056|D|action, through studies on their effects on the QTc interval, or through|
03491|057|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03491|058|D|and/or postmarketing reports.(2)|
03491|059|B||
03491|060|R|REFERENCES:|
03491|061|B||
03491|062|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03491|063|R|  2024.|1
03491|064|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
03491|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03491|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03491|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03491|068|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03491|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03491|070|R|  settings: a scientific statement from the American Heart Association and|6
03491|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03491|072|R|  2;55(9):934-47.|6
03492|001|T|MONOGRAPH TITLE:  Selpercatinib/Strong CYP3A4 Inhibitors|
03492|002|B||
03492|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03492|004|L|of severe adverse interaction.|
03492|005|B||
03492|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03492|007|A|selpercatinib.(1)|
03492|008|B||
03492|009|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03492|010|E|may result in elevated levels of and toxicity from selpercatinib.(1)|
03492|011|E|Elevated levels of selpercatinib may increase the risk of QTc prolongation|
03492|012|E|and potentially life-threatening arrhythmias, including torsades de pointes,|
03492|013|E|hepatotoxicity, hypertension, and severe or life-threatening hemorrhagic|
03492|014|E|events.(1)|
03492|015|B||
03492|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03492|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03492|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03492|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03492|020|P|female gender, or advanced age.(2)|
03492|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03492|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03492|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03492|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03492|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03492|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03492|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03492|028|B||
03492|029|M|PATIENT MANAGEMENT:  The US manufacturer of selpercatinib recommends|
03492|030|M|avoiding concomitant use of strong CYP3A4 inhibitors with selpercatinib.  If|
03492|031|M|concomitant use cannot be avoided, reduce the dose of selpercatinib as|
03492|032|M|follows:|
03492|033|M|   - If the current dose of selpercatinib is 160 mg twice daily, decrease|
03492|034|M|the dose to 80 mg twice daily.|
03492|035|M|   - If the current dose of selpercatinib is 120 mg twice daily, decrease|
03492|036|M|the dose to 40 mg twice daily.|
03492|037|M|   - If the concurrent dose of selpercatinib is 80 mg twice daily, decrease|
03492|038|M|the dose to 40 mg twice daily.|
03492|039|M|   - If the concurrent dose of selpercatinib is 40 mg three times daily,|
03492|040|M|decrease the dose to 40 mg once daily.|
03492|041|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
03492|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03492|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03492|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03492|045|M|   If grade 3 QT interval prolongation occurs, withhold selpercatinib until|
03492|046|M|recovery to baseline or Grades 0 or 1, then resume selpercatinib at a|
03492|047|M|reduced dose.  If grade 4 QT interval prolongation occurs, discontinue|
03492|048|M|selpercatinib.(1)|
03492|049|M|   After the inhibitor has been discontinued for 3 to 5 elimination|
03492|050|M|half-lives, resume selpercatinib at the dose taken prior to initiating the|
03492|051|M|CYP3A inhibitor.|
03492|052|B||
03492|053|D|DISCUSSION:  In a study, itraconazole (a strong CYP3A inhibitor) increased|
03492|054|D|the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib|
03492|055|D|by 133% and 30%, respectively.(1)|
03492|056|D|   In a thorough QT study, selpercatinib 160 mg twice daily increased QTc by|
03492|057|D|a mean of 10.6 msec (upper 90% confidence interval: 12.1 msec).  An increase|
03492|058|D|in QTcF interval to greater than 500 msec was measured in 6% of patients and|
03492|059|D|an increase in the QTcF interval of at least 60 msec over baseline was|
03492|060|D|measured in 15% of patients.(1)|
03492|061|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
03492|062|D|cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
03492|063|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
03492|064|D|paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.(3)|
03492|065|B||
03492|066|R|REFERENCES:|
03492|067|B||
03492|068|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03492|069|R|  2024.|1
03492|070|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03492|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03492|072|R|  settings: a scientific statement from the American Heart Association and|6
03492|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03492|074|R|  2;55(9):934-47.|6
03492|075|R|3.This information is based on an extract from the Certara Drug Interaction|6
03492|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03493|001|T|MONOGRAPH TITLE:  Selpercatinib/Strong CYP3A4 Inhibitors that Prolong QT|
03493|002|B||
03493|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03493|004|L|of severe adverse interaction.|
03493|005|B||
03493|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QT interval|
03493|007|A|may inhibit the metabolism of selpercatinib and result in additive effects|
03493|008|A|on the QT interval.(1)|
03493|009|B||
03493|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03493|011|E|that prolongs the QT interval may result in elevated levels of and toxicity|
03493|012|E|from selpercatinib.(1)  Elevated levels of selpercatinib may increase the|
03493|013|E|risk of QTc prolongation and potentially life-threatening cardiac|
03493|014|E|arrhythmias, including torsades de pointes, hepatotoxicity, hypertension,|
03493|015|E|and severe or life-threatening hemorrhagic events.(1)|
03493|016|B||
03493|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03493|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03493|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03493|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03493|021|P|female gender, or advanced age.(2)|
03493|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03493|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03493|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03493|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03493|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03493|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03493|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03493|029|B||
03493|030|M|PATIENT MANAGEMENT:  The US manufacturer of selpercatinib recommends|
03493|031|M|avoiding concomitant use of strong CYP3A4 inhibitors with selpercatinib.  If|
03493|032|M|concomitant use cannot be avoided, monitor the QTc interval more frequently|
03493|033|M|and reduce the dose of selpercatinib as follows:|
03493|034|M|   - If the current dose of selpercatinib is 160 mg twice daily, decrease|
03493|035|M|the dose to 80 mg twice daily.|
03493|036|M|   - If the current dose of selpercatinib is 120 mg twice daily, decrease|
03493|037|M|the dose to 40 mg twice daily.|
03493|038|M|   - If the current dose of selpercatinib is 80 mg twice daily, decrease the|
03493|039|M|dose to 40 mg twice daily.|
03493|040|M|   - If the current dose of selpercatinib is 40 mg three times daily,|
03493|041|M|decrease the dose to 40 mg once daily.(1)|
03493|042|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
03493|043|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03493|044|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03493|045|M|patients to report any irregular heartbeat, dizziness, or fainting.(2)|
03493|046|M|   If grade 3 QT interval prolongation occurs, withhold selpercatinib until|
03493|047|M|recovery to baseline or Grades 0 or 1, then resume selpercatinib at a|
03493|048|M|reduced dose.  If grade 4 QT interval prolongation occurs, discontinue|
03493|049|M|selpercatinib.(1)|
03493|050|M|   After the CYP3A4 inhibitor has been discontinued for 3 to 5 elimination|
03493|051|M|half-lives, resume selpercatinib at the dose taken prior to initiating the|
03493|052|M|CYP3A inhibitor.(1)|
03493|053|B||
03493|054|D|DISCUSSION:  In a thorough QT study, selpercatinib 160 mg twice daily|
03493|055|D|increased QTc by a mean of 10.6 msec (upper 90% confidence interval: 12.1|
03493|056|D|msec).  An increase in QTcF interval to greater than 500 msec was measured|
03493|057|D|in 6% of patients and an increase in the QTcF interval of at least 60 msec|
03493|058|D|over baseline was measured in 15% of patients.(1)|
03493|059|D|   In a study, itraconazole (a strong CYP3A inhibitor) increased the|
03493|060|D|area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib by|
03493|061|D|133% and 30%, respectively.(1)|
03493|062|D|   Agents that are linked to this monograph may have varying degrees of|
03493|063|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03493|064|D|been shown to prolong the QTc interval either through their mechanism of|
03493|065|D|action, through studies on their effects on the QTc interval, or through|
03493|066|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03493|067|D|and/or postmarketing reports.(3)|
03493|068|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
03493|069|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib,|
03493|070|D|lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin,|
03493|071|D|and voriconazole.(4)|
03493|072|B||
03493|073|R|REFERENCES:|
03493|074|B||
03493|075|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03493|076|R|  2024.|1
03493|077|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03493|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03493|079|R|  settings: a scientific statement from the American Heart Association and|6
03493|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03493|081|R|  2;55(9):934-47.|6
03493|082|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03493|083|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03493|084|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03493|085|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03493|086|R|4.This information is based on an extract from the Certara Drug Interaction|6
03493|087|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03494|001|T|MONOGRAPH TITLE:  Selpercatinib/Moderate CYP3A4 Inhibitors that Prolong QT|
03494|002|B||
03494|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03494|004|L|of severe adverse interaction.|
03494|005|B||
03494|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors that prolong the QT|
03494|007|A|interval may inhibit the metabolism of selpercatinib and result in additive|
03494|008|A|effects on the QT interval.(1)|
03494|009|B||
03494|010|E|CLINICAL EFFECTS:  Concurrent administration of a moderate CYP3A4 inhibitor|
03494|011|E|that prolongs the QT interval may result in elevated levels of and toxicity|
03494|012|E|from selpercatinib.(1)  Elevated levels of selpercatinib may increase the|
03494|013|E|risk of QTc prolongation and potentially life-threatening cardiac|
03494|014|E|arrhythmias, including torsades de pointes, hepatotoxicity, hypertension,|
03494|015|E|and severe or life-threatening hemorrhagic events.(1)|
03494|016|B||
03494|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03494|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03494|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03494|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03494|021|P|female gender, or advanced age.(2)|
03494|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03494|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03494|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03494|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03494|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03494|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03494|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03494|029|B||
03494|030|M|PATIENT MANAGEMENT:  The US manufacturer of selpercatinib recommends|
03494|031|M|avoiding concomitant use of moderate CYP3A4 inhibitors with selpercatinib.|
03494|032|M|If concomitant use cannot be avoided, monitor the QTc interval more|
03494|033|M|frequently and reduce the dose of selpercatinib as follows:|
03494|034|M|   - If the current dose of selpercatinib is 160 mg twice daily, decrease|
03494|035|M|the dose to 120 mg twice daily.|
03494|036|M|   - If the current dose of selpercatinib is 120 mg twice daily, decrease|
03494|037|M|the dose to 80 mg twice daily.|
03494|038|M|   - If the current dose of selpercatinib is 80 mg twice daily, decrease the|
03494|039|M|dose to 40 mg twice daily.|
03494|040|M|   - If the current dose of selpercatinib is 40 mg three times daily,|
03494|041|M|decrease the dose to 40 mg once daily.(1)|
03494|042|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
03494|043|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03494|044|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03494|045|M|patients to report any irregular heartbeat, dizziness, or fainting.(2)|
03494|046|M|   If grade 3 QT interval prolongation occurs, withhold selpercatinib until|
03494|047|M|recovery to baseline or Grades 0 or 1, then resume selpercatinib at a|
03494|048|M|reduced dose.  If grade 4 QT interval prolongation occurs, discontinue|
03494|049|M|selpercatinib.(1)|
03494|050|M|   After the CYP3A4 inhibitor has been discontinued for 3 to 5 elimination|
03494|051|M|half-lives, resume selpercatinib at the dose taken prior to initiating the|
03494|052|M|CYP3A inhibitor.(1)|
03494|053|B||
03494|054|D|DISCUSSION:  In a thorough QT study, selpercatinib 160 mg twice daily|
03494|055|D|increased QTc by a mean of 10.6 msec (upper 90% confidence interval: 12.1|
03494|056|D|msec).  An increase in QTcF interval to greater than 500 msec was measured|
03494|057|D|in 6% of patients and an increase in the QTcF interval of at least 60 msec|
03494|058|D|over baseline was measured in 15% of patients.(1)|
03494|059|D|   Coadministration of diltiazem, fluconazole, or verapamil (moderate CYP3A|
03494|060|D|inhibitors) is predicted to increase the area-under-curve (AUC) and maximum|
03494|061|D|concentration (Cmax) of selpercatinib by 60-99% and 46-76%, respectively.(1)|
03494|062|D|   Agents that are linked to this monograph may have varying degrees of|
03494|063|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03494|064|D|been shown to prolong the QTc interval either through their mechanism of|
03494|065|D|action, through studies on their effects on the QTc interval, or through|
03494|066|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03494|067|D|and/or postmarketing reports.(3)|
03494|068|D|   Moderate CYP3A4 inhibitors linked to this monograph include:|
03494|069|D|clofazimine, crizotinib, dronedarone, erythromycin, fluconazole, oral|
03494|070|D|lefamulin, and nilotinib.(4)|
03494|071|B||
03494|072|R|REFERENCES:|
03494|073|B||
03494|074|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03494|075|R|  2024.|1
03494|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03494|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03494|078|R|  settings: a scientific statement from the American Heart Association and|6
03494|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03494|080|R|  2;55(9):934-47.|6
03494|081|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03494|082|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03494|083|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03494|084|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03494|085|R|4.This information is based on an extract from the Certara Drug Interaction|6
03494|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03495|001|T|MONOGRAPH TITLE:  Selpercatinib/Moderate CYP3A4 Inhibitors|
03495|002|B||
03495|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03495|004|L|of severe adverse interaction.|
03495|005|B||
03495|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
03495|007|A|of selpercatinib.(1)|
03495|008|A|   Cimetidine increases gastric pH and may decrease pH-dependent solubility|
03495|009|A|and absorption of selpercatinib.(1)|
03495|010|B||
03495|011|E|CLINICAL EFFECTS:  Concurrent administration of a moderate CYP3A4 inhibitor|
03495|012|E|may result in elevated levels of and toxicity from selpercatinib.(1)|
03495|013|E|Elevated levels of selpercatinib may increase the risk of QTc prolongation|
03495|014|E|and potentially life-threatening arrhythmias, including torsades de pointes,|
03495|015|E|hepatotoxicity, hypertension, and severe or life-threatening hemorrhagic|
03495|016|E|events.(1)|
03495|017|E|   Conversely, concurrent use of cimetidine may result in decreased levels|
03495|018|E|and effectiveness of selpercatinib.  The overall effect of cimetidine on|
03495|019|E|selpercatinib pharmacokinetics is unknown.(1)|
03495|020|B||
03495|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03495|022|P|may be increased in patients with cardiovascular disease (e.g. heart|
03495|023|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03495|024|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03495|025|P|female gender, or advanced age.(2)|
03495|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03495|027|P|higher systemic concentrations of either QT prolonging drug are additional|
03495|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03495|029|P|drug concentrations include rapid infusion of an intravenous dose or|
03495|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03495|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03495|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03495|033|B||
03495|034|M|PATIENT MANAGEMENT:  The US manufacturer of selpercatinib recommends|
03495|035|M|avoiding concomitant use of moderate CYP3A4 inhibitors with selpercatinib.|
03495|036|M|If concomitant use cannot be avoided, reduce the dose of selpercatinib as|
03495|037|M|follows:|
03495|038|M|   - If the current dose of selpercatinib is 160 mg twice daily, decrease|
03495|039|M|the dose to 120 mg twice daily.|
03495|040|M|   - If the current dose of selpercatinib is 120 mg twice daily, decrease|
03495|041|M|the dose to 80 mg twice daily.|
03495|042|M|   - If the current dose of selpercatinib is 80 mg twice daily, decrease the|
03495|043|M|dose to 40 mg twice daily.|
03495|044|M|   - If the current dose of selpercatinib is 40 mg three times daily,|
03495|045|M|decrease the dose to 40 mg once daily.|
03495|046|M|   If concomitant use of cimetidine is unavoidable, take selpercatinib at|
03495|047|M|least 2 hours before or 10 hours after cimetidine.|
03495|048|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
03495|049|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03495|050|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03495|051|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03495|052|M|   If grade 3 QT interval prolongation occurs, withhold selpercatinib until|
03495|053|M|recovery to baseline or Grades 0 or 1, then resume selpercatinib at a|
03495|054|M|reduced dose.  If grade 4 QT interval prolongation occurs, discontinue|
03495|055|M|selpercatinib.(1)|
03495|056|M|   After the inhibitor has been discontinued for 3 to 5 elimination|
03495|057|M|half-lives, resume selpercatinib at the dose taken prior to initiating the|
03495|058|M|CYP3A inhibitor.(1)|
03495|059|B||
03495|060|D|DISCUSSION:  Coadministration of diltiazem, fluconazole, or verapamil|
03495|061|D|(moderate CYP3A inhibitors) is predicted to increase the area-under-curve|
03495|062|D|(AUC) and maximum concentration (Cmax) of selpercatinib by 60-99% and|
03495|063|D|46-76%, respectively.(1)|
03495|064|D|   In a thorough QT study, selpercatinib 160 mg twice daily increased QTc by|
03495|065|D|a mean of 10.6 msec (upper 90% confidence interval: 12.1 msec).  An increase|
03495|066|D|in QTcF interval to greater than 500 msec was measured in 6% of patients and|
03495|067|D|an increase in the QTcF interval of at least 60 msec over baseline was|
03495|068|D|measured in 15% of patients.(1)|
03495|069|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
03495|070|D|atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem,|
03495|071|D|fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
03495|072|D|isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib,|
03495|073|D|schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3)|
03495|074|B||
03495|075|R|REFERENCES:|
03495|076|B||
03495|077|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03495|078|R|  2024.|1
03495|079|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03495|080|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03495|081|R|  settings: a scientific statement from the American Heart Association and|6
03495|082|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03495|083|R|  2;55(9):934-47.|6
03495|084|R|3.This information is based on an extract from the Certara Drug Interaction|6
03495|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03496|001|T|MONOGRAPH TITLE:  Selpercatinib/Strong and Moderate CYP3A4 Inducers|
03496|002|B||
03496|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03496|004|L|of severe adverse interaction.|
03496|005|B||
03496|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03496|007|A|metabolism of selpercatinib.(1)|
03496|008|B||
03496|009|E|CLINICAL EFFECTS:  Coadministration of selpercatinib with a strong or|
03496|010|E|moderate CYP3A4 inducer decreases selpercatinib plasma concentrations, which|
03496|011|E|may decrease the efficacy of selpercatinib.(1)|
03496|012|B||
03496|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03496|014|P|of the inducer for longer than 1-2 weeks.|
03496|015|B||
03496|016|M|PATIENT MANAGEMENT:  The manufacturer of selpercatinib states that|
03496|017|M|concurrent use with strong and moderate CYP3A4 inducers should be|
03496|018|M|avoided.(1)|
03496|019|B||
03496|020|D|DISCUSSION:  In a study, multiple doses of rifampin (a strong CYP3A inducer)|
03496|021|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03496|022|D|selpercatinib by 87% and 70%, respectively.(1)|
03496|023|D|   Coadministration of multiple doses of bosentan or efavirenz (moderate|
03496|024|D|CYP3A inducers) is predicted to decrease the AUC and Cmax of selpercatinib|
03496|025|D|40-70% and 34-57%, respectively.(1)|
03496|026|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03496|027|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
03496|028|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03496|029|D|wort.(2,3)|
03496|030|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03496|031|D|dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten,|
03496|032|D|mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin,|
03496|033|D|sotorasib, and telotristat ethyl.(2,3)|
03496|034|B||
03496|035|R|REFERENCES:|
03496|036|B||
03496|037|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03496|038|R|  2024.|1
03496|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03496|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03496|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03496|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03496|043|R|  11/14/2017.|1
03496|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
03496|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03497|001|T|MONOGRAPH TITLE:  Selpercatinib/Proton Pump Inhibitors|
03497|002|B||
03497|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03497|004|L|of severe adverse interaction.|
03497|005|B||
03497|006|A|MECHANISM OF ACTION:  The solubility of selpercatinib is pH dependent.|
03497|007|A|Increase in gastric pH from proton pump inhibitors (PPIs) may decrease the|
03497|008|A|solubility and absorption of selpercatinib.(1)|
03497|009|B||
03497|010|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
03497|011|E|levels and effectiveness of selpercatinib.(1)|
03497|012|B||
03497|013|P|PREDISPOSING FACTORS:  None determined.|
03497|014|B||
03497|015|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs), H2|
03497|016|M|antagonists, and locally acting antacids in patients receiving treatment|
03497|017|M|with selpercatinib.  If coadministration with PPIs cannot be avoided, take|
03497|018|M|selpercatinib with food.(1)|
03497|019|M|   If the PPI is replaced with a H2 antagonist, take selpercatinib 2 hours|
03497|020|M|before or 10 hours after the H2 antagonist.(1)|
03497|021|M|   If the PPI is replaced with an antacid, take selpercatinib 2 hours before|
03497|022|M|or 2 hours after the antacid.(1)|
03497|023|B||
03497|024|D|DISCUSSION:  In a study, omeprazole decreased the area-under-curve (AUC) and|
03497|025|D|maximum concentration (Cmax) of selpercatinib (administered fasting) by 69%|
03497|026|D|and 88%, respectively.  When selpercatinib was administered with food,|
03497|027|D|omeprazole did not significantly affect selpercatinib levels.(1)|
03497|028|B||
03497|029|R|REFERENCE:|
03497|030|B||
03497|031|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03497|032|R|  2024.|1
03498|001|T|MONOGRAPH TITLE:  Infigratinib; Selpercatinib/Selected H2 Antagonists|
03498|002|B||
03498|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03498|004|L|of severe adverse interaction.|
03498|005|B||
03498|006|A|MECHANISM OF ACTION:  The solubility of infigratinib and selpercatinib is pH|
03498|007|A|dependent.  Changes in gastric pH from H2 antagonists may decrease the|
03498|008|A|absorption of infigratinib and selpercatinib.(1,2)|
03498|009|B||
03498|010|E|CLINICAL EFFECTS:  Use of H2 antagonists may result in decreased levels and|
03498|011|E|effectiveness of infigratinib and selpercatinib.(1,2)|
03498|012|B||
03498|013|P|PREDISPOSING FACTORS:  None determined.|
03498|014|B||
03498|015|M|PATIENT MANAGEMENT:  Avoid the use of H2 antagonists, proton pump|
03498|016|M|inhibitors, and locally-acting antacids in patients receiving treatment with|
03498|017|M|infigratinib or selpercatinib.  If coadministration with H2 antagonists|
03498|018|M|cannot be avoided, take infigratinib or selpercatinib at least 2 hours|
03498|019|M|before or 10 hours after the H2 antagonist.(1,2)|
03498|020|M|   If the H2 antagonist is replaced with an antacid, take infigratinib or|
03498|021|M|selpercatinib 2 hours before or 2 hours after the antacid.(1,2)|
03498|022|M|   If the H2 antagonist is replaced with a proton pump inhibitor, take|
03498|023|M|selpercatinib with food.(2)  Avoid taking proton pump inhibitors with|
03498|024|M|infigratinib.(1)|
03498|025|B||
03498|026|D|DISCUSSION:  Infigratinib is practically insoluble at pH 6.8.(1)|
03498|027|D|   In a study, ranitidine given 10 hours before and 2 hours after|
03498|028|D|selpercatinib did not have a clinically significant effect on selpercatinib|
03498|029|D|pharmacokinetics.(2)|
03498|030|B||
03498|031|R|REFERENCES:|
03498|032|B||
03498|033|R|1.Truseltiq (infigratinib) US prescribing information. QED Therapeutics,|1
03498|034|R|  Inc. May, 2021.|1
03498|035|R|2.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03498|036|R|  2024.|1
03499|001|T|MONOGRAPH TITLE:  Infigratinib; Selpercatinib/Antacids|
03499|002|B||
03499|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03499|004|L|take action as needed.|
03499|005|B||
03499|006|A|MECHANISM OF ACTION:  The solubility of infigratinib and selpercatinib is pH|
03499|007|A|dependent.  Antacid-induced changes in gastric pH may decrease the|
03499|008|A|absorption of infigratinib and selpercatinib.(1,2)|
03499|009|B||
03499|010|E|CLINICAL EFFECTS:  Simultaneous administration of antacids may result in|
03499|011|E|decreased levels and effectiveness of infigratinib and selpercatinib.(1,2)|
03499|012|B||
03499|013|P|PREDISPOSING FACTORS:  None determined.|
03499|014|B||
03499|015|M|PATIENT MANAGEMENT:  Avoid the use of antacids, proton pump inhibitors|
03499|016|M|(PPIs), and H2 antagonists, in patients receiving treatment with|
03499|017|M|infigratinib or selpercatinib.  If coadministration with antacids cannot be|
03499|018|M|avoided, take infigratinib or selpercatinib at least 2 hours before or 2|
03499|019|M|hours after the antacid.(1,2)|
03499|020|M|   If the antacid is replaced with a H2 antagonist, take infigratinib or|
03499|021|M|selpercatinib 2 hours before or 10 hours after the H2 antagonist.(1,2)|
03499|022|M|   If the antacid is replaced with a PPI, take selpercatinib with food.(2)|
03499|023|B||
03499|024|D|DISCUSSION:  Infigratinib is practically insoluble at pH 6.8.(1)|
03499|025|D|Selpercatinib solubility is pH dependent.(2)  Antacids may decrease the|
03499|026|D|solubility and absorption of infigratinib and selpercatinib and decrease|
03499|027|D|their effectiveness.|
03499|028|B||
03499|029|R|REFERENCES:|
03499|030|B||
03499|031|R|1.Truseltiq (infigratinib) US prescribing information. QED Therapeutics,|1
03499|032|R|  Inc. May, 2021.|1
03499|033|R|2.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03499|034|R|  2024.|1
03500|001|T|MONOGRAPH TITLE:  Ripretinib/Strong CYP3A4 Inducers|
03500|002|B||
03500|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03500|004|L|of severe adverse interaction.|
03500|005|B||
03500|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03500|007|A|ripretinib via this pathway.|
03500|008|A|   Ripretinib and the active metabolite DP-5439 contribute to anticancer|
03500|009|A|activity.  CYP3A4 is the primary metabolism pathway for both ripretinib and|
03500|010|A|the active metabolite DP-5439.(1)|
03500|011|B||
03500|012|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
03500|013|E|alter the clinical effectiveness of ripretinib.(1)|
03500|014|B||
03500|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03500|016|P|of the inducer for longer than 1-2 weeks.|
03500|017|B||
03500|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ripretinib with strong|
03500|019|M|CYP3A4 inducers.(1)  When possible, select alternative agents in place of|
03500|020|M|the strong CYP3A4 inducer.  Monitor patients receiving concurrent therapy|
03500|021|M|for reduced efficacy.|
03500|022|M|   The Australian and UK manufacturers of ripretinib state if|
03500|023|M|co-administration of a strong CYP3A4 inducer cannot be avoided, the dose of|
03500|024|M|ripretinib can be increased from 150 mg once daily to 150 mg twice daily.|
03500|025|M|Co-administration of ripretinib with a strong CYP3A4 inducer must be|
03500|026|M|balanced against a risk of reduced efficacy due to reduced exposure. Monitor|
03500|027|M|for clinical response and tolerability.(2,3)|
03500|028|M|  If the strong CYP3A4 inducer is discontinued, reduce the dose of|
03500|029|M|ripretinib back to 150 mg once daily 14 days after discontinuation of the|
03500|030|M|strong CYP3A4 inducer.|
03500|031|M|   If a dose of ripretinib is missed (in patients taking twice daily|
03500|032|M|dosing):|
03500|033|M|   -If less than 4 hours have passed since missed dose, patient should take|
03500|034|M|the dose as soon as possible and then take the next dose at the regularly|
03500|035|M|scheduled time.|
03500|036|M|   -If more than 4 hours have passed since missed dose, patient should skip|
03500|037|M|the missed dose and then take the next dose at the regularly scheduled|
03500|038|M|time.(2,3)|
03500|039|B||
03500|040|D|DISCUSSION:  The primary metabolism pathway for ripretinib and DP-5439 is|
03500|041|D|via CYP3A4.(1)|
03500|042|D|   In an interaction study of rifampin (a strong CYP3A inducer) and|
03500|043|D|ripretinib, concurrent use decreased ripretinib concentration maximum (Cmax)|
03500|044|D|by 18% and area-under-curve (AUC) by 61%, as well as decreased the active|
03500|045|D|metabolite DP-5439 AUC by 57% and increased Cmax by 37%.(1)|
03500|046|D|   In an interaction study of efavirenz (a moderate CYP3A inducer),|
03500|047|D|concurrent use was predicted to decrease ripretinib Cmax by 24% and decrease|
03500|048|D|AUC by 56%.(1)|
03500|049|D|   In the presence of a strong CYP3A inducer, a doubled ripretinib dose|
03500|050|D|(twice daily rather than once daily), is predicted to result in a 40%|
03500|051|D|reduction in combined AUC of ripretinib and active metabolite DP-5439,|
03500|052|D|compared to the usual recommended once daily dose with no inducer|
03500|053|D|present.(2)|
03500|054|D|   In an interaction study of itraconazole (a strong CYP3A4 inhibitor) and|
03500|055|D|ripretinib, concurrent use increased ripretinib Cmax by 36% and AUC by 99%.|
03500|056|D|Concurrent use increased the AUC of DP-5439 by 99% with no change in|
03500|057|D|Cmax.(1)|
03500|058|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
03500|059|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
03500|060|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
03500|061|D|rifampin, rifapentine and St John's Wort.(4,5)|
03500|062|B||
03500|063|R|REFERENCES:|
03500|064|B||
03500|065|R|1.Qinlock (ripretinib) US prescribing information. Deciphera|1
03500|066|R|  Pharmaceuticals, LLC October, 2023.|1
03500|067|R|2.Qinlock (ripretinib) Australian prescribing information. Specialised|1
03500|068|R|  Therapeutics PM Pty Ltd 25 July 2025.|1
03500|069|R|3.Qinlock (ripretinib) UK Summary of Product Characteristics. Deciphera 14|1
03500|070|R|  March 2023.|1
03500|071|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03500|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03500|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03500|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03500|075|R|  11/14/2017.|1
03500|076|R|5.This information is based on an extract from the Certara Drug Interaction|6
03500|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03501|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Nintedanib (mono deleted|
03501|002|T|01/22/2021)|
03501|003|B||
03501|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03501|005|L|of severe adverse interaction.|
03501|006|B||
03501|007|A|MECHANISM OF ACTION:  The mechanism of this potential interaction is|
03501|008|A|unknown.(1)|
03501|009|B||
03501|010|E|CLINICAL EFFECTS:  The clinical effects of nintedanib use with hormonal|
03501|011|E|contraceptives is currently unknown.  Nintedanib may cause birth defects|
03501|012|E|and/or miscarriage if used by pregnant women.(1)|
03501|013|B||
03501|014|P|PREDISPOSING FACTORS:  None determined.|
03501|015|B||
03501|016|M|PATIENT MANAGEMENT:  The manufacturer of nintedanib recommends that female|
03501|017|M|patients of reproductive potential who are using hormonal contraceptives add|
03501|018|M|a barrier method of contraception during treatment with nintedanib and for|
03501|019|M|at least 3 months after the final dose.(1)  Patients should be alerted to|
03501|020|M|the risk for decreased effectiveness(e.g. contraceptive failure) of their|
03501|021|M|hormonal contraceptive therapy.  For emergency contraception, the UK's|
03501|022|M|Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that|
03501|023|M|women who have used a CYP3A4 inducer in the previous 4 weeks should consider|
03501|024|M|a non-hormonal emergency contraceptive (i.e., a copper IUD).(2)|
03501|025|B||
03501|026|D|DISCUSSION:  It is unknown whether nintedanib reduces the effectiveness of|
03501|027|D|hormonal contraceptives. Nintedanib may cause fetal harm and women receiving|
03501|028|D|treatment with nintedanib should avoid becoming pregnant.(1)|
03501|029|B||
03501|030|R|REFERENCES:|
03501|031|B||
03501|032|R|1.Ofev (nintedanib) US prescribing information. Boehringer Ingelheim|1
03501|033|R|  Pharmaceuticals Inc. September, 2019.|1
03501|034|R|2.Medicines and Healthcare products Regulatory Agency.|1
03501|035|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03501|036|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03501|037|R|  available at:|1
03501|038|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03501|039|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03501|040|R|  -and-contraceptive-efficacy September 15, 2016..|1
03502|001|T|MONOGRAPH TITLE:  Quetiapine/Moderate CYP3A4 Inhibitors that Prolong QT|
03502|002|B||
03502|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03502|004|L|take action as needed.|
03502|005|B||
03502|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
03502|007|A|of quetiapine.(1)  Quetiapine is a sensitive substrate for CYP3A4 and so an|
03502|008|A|approximately 2-fold or higher increase in exposure (AUC, area-under-curve)|
03502|009|A|is possible when quetiapine is given with a moderate CYP3A4 inhibitor.(2)|
03502|010|A|   In addition, concurrent use with other agents that prolong the QTc|
03502|011|A|interval may result in additive effects on the QTc interval.(1)|
03502|012|B||
03502|013|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor that also|
03502|014|E|prolongs the QT interval may result in elevated levels of and toxicity from|
03502|015|E|quetiapine,(1-3) including potentially life-threatening cardiac arrhythmias,|
03502|016|E|such as torsades de pointes.(1,3)|
03502|017|B||
03502|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03502|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03502|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03502|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03502|022|P|female gender, or advanced age.(4)|
03502|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03502|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03502|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03502|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03502|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03502|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03502|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03502|030|B||
03502|031|M|PATIENT MANAGEMENT:  The US manufacturer of quetiapine states that|
03502|032|M|concurrent use with agents known to prolong the QT interval should be|
03502|033|M|avoided.(1)|
03502|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03502|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03502|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03502|037|M|patients to report any irregular heartbeat, dizziness, fainting, excessive|
03502|038|M|drowsiness, rapid pulse/hypotension, weakness, fatigue, dizziness, or muscle|
03502|039|M|stiffness/tremors (EPS).  Monitor patients when moderate inhibitors of|
03502|040|M|CYP3A4 are co-prescribed with quetiapine as the magnitude of the interaction|
03502|041|M|is highly variable between patients.  Use of higher doses of either the|
03502|042|M|CYP3A4 inhibitor or quetiapine are other factors which may affect the|
03502|043|M|magnitude of this interaction.  Decrease the quetiapine dose if needed.|
03502|044|B||
03502|045|D|DISCUSSION:  Although quetiapine was not associated with QT or QTc changes|
03502|046|D|in clinical trials, QT prolongation has been reported in post-marketing|
03502|047|D|reports in conjunction with the use of other agents known to prolong the QT|
03502|048|D|interval.(1)|
03502|049|D|   In a study in 19 Chinese patients with schizophrenia, patients received|
03502|050|D|quetiapine (200 mg twice daily) alone and with erythromycin (500 mg 3 times|
03502|051|D|daily, a moderate inhibitor of CYP3A4).  Erythromycin increased the|
03502|052|D|quetiapine maximum concentration (Cmax)by 68%(range approximately 20-130%),|
03502|053|D|area-under-curve (AUC) 129% (range approximately 20-300%), and half-life by|
03502|054|D|92% (range approximately 0-250%).  Quetiapine clearance decreased 52% (range|
03502|055|D|approximately -15 to -80%).(5)|
03502|056|D|   Moderate inhibitors of CYP3A4 that also are known QT prolonging agents|
03502|057|D|include: crizotinib and nilotinib.(2,6,7)  These agents may have varying|
03502|058|D|degrees of potential to prolong the QTc interval but are generally accepted|
03502|059|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
03502|060|D|monograph have been shown to prolong the QTc interval either through their|
03502|061|D|mechanism of action, through studies on their effects on the QTc interval,|
03502|062|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
03502|063|D|clinical trials and/or post-marketing reports.(7)|
03502|064|B||
03502|065|R|REFERENCES:|
03502|066|B||
03502|067|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
03502|068|R|  Pharmaceuticals LP July, 2011.|1
03502|069|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03502|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03502|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03502|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03502|073|R|  11/14/2017.|1
03502|074|R|3.Seroquel (quetiapine) Canada prescribing information. AstraZeneca Canada|1
03502|075|R|  Inc. May 15,2013.|1
03502|076|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03502|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03502|078|R|  settings: a scientific statement from the American Heart Association and|6
03502|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03502|080|R|  2;55(9):934-47.|6
03502|081|R|5.Li KY, Li X, Cheng ZN, Zhang BK, Peng WX, Li HD. Effect of erythromycin on|2
03502|082|R|  metabolism of quetiapine in Chinese suffering from schizophrenia. Eur J|2
03502|083|R|  Clin Pharmacol 2005 Jan;60(11):791-5.|2
03502|084|R|6.This information is based on an extract from the Certara Drug Interaction|6
03502|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03502|086|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
03502|087|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03502|088|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03502|089|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03503|001|T|MONOGRAPH TITLE:  Quetiapine/Strong CYP3A4 Inhibitors that Prolong QT|
03503|002|B||
03503|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03503|004|L|of severe adverse interaction.|
03503|005|B||
03503|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03503|007|A|quetiapine.(1)  Quetiapine is a sensitive substrate for CYP3A4 and so an|
03503|008|A|approximately 5-fold or higher increase in exposure (AUC, area-under-curve)|
03503|009|A|is possible when quetiapine is given with a strong CYP3A4 inhibitor.(2)|
03503|010|A|   In addition, concurrent use with other agents that prolong the QTc|
03503|011|A|interval may result in additive effects on the QTc interval.(1)|
03503|012|B||
03503|013|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor that also|
03503|014|E|prolongs the QT interval may result in elevated levels of and toxicity from|
03503|015|E|quetiapine,(1-4) including potentially life-threatening cardiac arrhythmias,|
03503|016|E|such as torsades de pointes.(1,5)|
03503|017|B||
03503|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03503|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03503|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03503|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03503|022|P|female gender, or advanced age.(5)|
03503|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03503|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03503|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03503|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03503|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03503|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03503|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03503|030|B||
03503|031|M|PATIENT MANAGEMENT:  The US manufacturer of quetiapine states that|
03503|032|M|concurrent use with agents known to prolong the QT interval should be|
03503|033|M|avoided.(1)|
03503|034|M|   If addition of concomitant therapy with a strong CYP3A4 inhibitor is|
03503|035|M|required, US manufacturers state the quetiapine dose should be reduced to|
03503|036|M|1/6th of the original dose.  When the inhibitor is discontinued, return to|
03503|037|M|the original quetiapine dose.(1)|
03503|038|M|   The UK manufacturer states the concurrent use of quetiapine with strong|
03503|039|M|CYP3A4 inhibitors is contraindicated.(5)|
03503|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03503|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03503|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03503|043|M|patients to report any irregular heartbeat, dizziness, fainting, excessive|
03503|044|M|drowsiness, rapid pulse/hypotension, weakness, fatigue, dizziness, or muscle|
03503|045|M|stiffness/tremors (EPS).  Monitor patients when strong inhibitors of CYP3A4|
03503|046|M|are co-prescribed with quetiapine as the magnitude of the interaction is|
03503|047|M|highly variable between patients.  Use of higher doses of either the CYP3A4|
03503|048|M|inhibitor or quetiapine are other factors which may affect the magnitude of|
03503|049|M|this interaction.  Decrease the quetiapine dose if needed.|
03503|050|B||
03503|051|D|DISCUSSION:  In a study, concurrent use of ketoconazole (200 mg daily for 4|
03503|052|D|days, a strong inhibitor of CYP3A4) and quetiapine resulted in an increase|
03503|053|D|in quetiapine Cmax and AUC by 3.35-fold and 6.2-fold, respectively.|
03503|054|D|Ketoconazole also decreased the mean apparent oral clearance of quetiapine|
03503|055|D|by 84%, and increased quetiapine mean elimination half-life by|
03503|056|D|2.6-fold.(1,6)|
03503|057|D|   Although quetiapine was not associated with QT or QTc changes in clinical|
03503|058|D|trials, QT prolongation has been reported in post-marketing reports in|
03503|059|D|conjunction with the use of other agents known to prolong the QT|
03503|060|D|interval.(1)|
03503|061|D|   Strong inhibitors of CYP3A4 that also are known QT prolonging agents|
03503|062|D|include:  adagrasib, ceritinib, clarithromycin, levoketoconazole,|
03503|063|D|lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin,|
03503|064|D|and voriconazole.(7,8)  These agents may have varying degrees of potential|
03503|065|D|to prolong the QTc interval but are generally accepted to have a risk of|
03503|066|D|causing Torsades de Pointes.  Agents linked to this monograph have been|
03503|067|D|shown to prolong the QTc interval either through their mechanism of action,|
03503|068|D|through studies on their effects on the QTc interval, or through reports of|
03503|069|D|QTc prolongation and/or Torsades de Pointes in clinical trials and/or|
03503|070|D|post-marketing reports.(8)|
03503|071|B||
03503|072|R|REFERENCES:|
03503|073|B||
03503|074|R|1.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
03503|075|R|  Pharmaceuticals LP July, 2011.|1
03503|076|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03503|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03503|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03503|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03503|080|R|  11/14/2017.|1
03503|081|R|3.Seroquel (quetiapine) Canada prescribing information. AstraZeneca Canada|1
03503|082|R|  Inc. May 15,2013.|1
03503|083|R|4.Seroquel (quetiapine) UK summary of product characteristics. Luye Pharma|1
03503|084|R|  Limited June, 2020.|1
03503|085|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03503|086|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03503|087|R|  settings: a scientific statement from the American Heart Association and|6
03503|088|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03503|089|R|  2;55(9):934-47.|6
03503|090|R|6.Grimm SW, Richtand NM, Winter HR, Stams KR, Reele SB. Effects of|2
03503|091|R|  cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine|2
03503|092|R|  pharmacokinetics. Br J Clin Pharmacol 2006 Jan;61(1):58-69.|2
03503|093|R|7.This information is based on an extract from the Certara Drug Interaction|6
03503|094|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03503|095|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
03503|096|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03503|097|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03503|098|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03504|001|T|MONOGRAPH TITLE:  Apomorphine/Select Atypical Antipsychotics|
03504|002|B||
03504|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03504|004|L|take action as needed.|
03504|005|B||
03504|006|A|MECHANISM OF ACTION:  Apomorphine is a dopamine agonist.  Antipsychotic|
03504|007|A|agents counteract this effect by blocking dopamine activity at CNS D2|
03504|008|A|receptors.(1)|
03504|009|B||
03504|010|E|CLINICAL EFFECTS:  The efficacy of either agent may be decreased, leading to|
03504|011|E|exacerbation of the disease being treated, e.g. Parkinson disease or a|
03504|012|E|psychotic disorder.|
03504|013|B||
03504|014|P|PREDISPOSING FACTORS:  Patients with Parkinson or Diffuse Lewy Body(DLB)|
03504|015|P|disease are particularly susceptible to adverse effects of dopamine blockade|
03504|016|P|by antipsychotics.|
03504|017|B||
03504|018|M|PATIENT MANAGEMENT:  Reassess the need for antipsychotic therapy. If|
03504|019|M|psychosis or hallucinations are due to an antiparkinson agent, when possible|
03504|020|M|consider reducing the dose or changing the antiparkinson agent before|
03504|021|M|initiating antipsychotic therapy.  In patients with PD and dementia,|
03504|022|M|addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve|
03504|023|M|psychosis.  If an antipsychotic is required, then an atypical antipsychotic|
03504|024|M|should be used.(2,3)|
03504|025|M|   The US manufacturer of apomorphine states patients with major psychotic|
03504|026|M|disorders treated with neuroleptics should be treated with dopamine agonists|
03504|027|M|only if the potential benefits outweigh the risks.(1)|
03504|028|B||
03504|029|D|DISCUSSION:  An epidemiologic study evaluated 21,043 elderly patients with|
03504|030|D|Parkinson disease to determine if recent initiation of a typical or atypical|
03504|031|D|antipsychotic was associated with increased mortality.  They found an|
03504|032|D|adjusted odds ratio of 2.0 for death associated with atypical antipsychotics|
03504|033|D|versus no antipsychotic. They found an adjusted odds ratio of 2.4 for death|
03504|034|D|associated with typical versus atypical antipsychotics.  The authors noted|
03504|035|D|the increased mortality found with typical antipsychotics supports current|
03504|036|D|treatment recommendations to use atypical antipsychotic agents in patients|
03504|037|D|with Parkinson disease.(2,3)|
03504|038|D|   Two clozapine trials showed significant improvement in psychosis without|
03504|039|D|worsening of motor symptoms.  In contrast, two olanzapine trials were|
03504|040|D|associated with unacceptable worsening of motor symptoms.  Risperidone has|
03504|041|D|also been associated with motor worsening in case reports.  Quetiapine|
03504|042|D|evaluations have been conflicting with several small studies showing|
03504|043|D|improvement in psychotic symptoms while a more rigorous trial showed no|
03504|044|D|improvement.(2)|
03504|045|B||
03504|046|R|REFERENCES:|
03504|047|B||
03504|048|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03504|049|R|  Inc. May, 2019.|1
03504|050|R|2.Marras C, Gruneir A, Wang X, Fischer H, Gill SS, Herrmann N, Anderson GM,|2
03504|051|R|  Hyson C, Rochon PA. Antipsychotics and mortality in Parkinsonism. Am J|2
03504|052|R|  Geriatr Psychiatry 2012 Feb;20(2):149-58.|2
03504|053|R|3.Oertel WH Berardelli A Bloem Br etal. Chapter 15 - Late (complicated)|6
03504|054|R|  Parkinson's disease in European Handbook of Neurological Management. 2011;|6
03504|055|R|  Volume 1, 2nd Edition:237 - 267.|6
03505|001|T|MONOGRAPH TITLE:  Apomorphine/Selected Atypical Antipsychotics that Prolong|
03505|002|T|QT|
03505|003|B||
03505|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03505|005|L|of severe adverse interaction.|
03505|006|B||
03505|007|A|MECHANISM OF ACTION:  Concurrent use of apomorphine and certain atypical|
03505|008|A|antipsychotics may have additive effects on the QTc interval.(1-4)|
03505|009|A|   In addition, apomorphine is a dopamine agonist.  Antipsychotics may|
03505|010|A|decrease apomorphine's effectiveness by blocking dopamine activity at CNS D2|
03505|011|A|receptors.(1)|
03505|012|B||
03505|013|E|CLINICAL EFFECTS:  The concurrent use of apomorphine with certain atypical|
03505|014|E|antipsychotics may result in potentially life-threatening cardiac|
03505|015|E|arrhythmias, including torsades de pointes.(1)|
03505|016|E|   The efficacy of either agent may be decreased, leading to exacerbation of|
03505|017|E|the disease being treated, e.g. Parkinson disease or a psychotic disorder.|
03505|018|B||
03505|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03505|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03505|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03505|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03505|023|P|female gender, or advanced age.|
03505|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03505|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03505|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03505|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03505|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03505|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03505|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03505|031|P|   Patients with Parkinson or Diffuse Lewy Body(DLB) disease are|
03505|032|P|particularly susceptible to adverse effects of dopamine blockade by|
03505|033|P|antipsychotics.|
03505|034|B||
03505|035|M|PATIENT MANAGEMENT:  Concurrent use of iloperidone, paliperidone, or|
03505|036|M|quetiapine with other agents known to prolong the QT interval, like|
03505|037|M|apomorphine, should be avoided.(2-4)|
03505|038|M|   The US manufacturer of apomorphine states that patients with major|
03505|039|M|psychotic disorders treated with neuroleptics should be treated with|
03505|040|M|dopamine agonists only if the potential benefits outweigh the risks.(1)|
03505|041|M|   Reassess the need for antipsychotic therapy.  If psychosis or|
03505|042|M|hallucinations are due to an antiparkinson agent, when possible consider|
03505|043|M|reducing the dose or changing the antiparkinson agent before initiating|
03505|044|M|antipsychotic therapy.  In patients with PD and dementia, addition of a|
03505|045|M|cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis.  If an|
03505|046|M|antipsychotic is required, then an atypical antipsychotic should be|
03505|047|M|used.(6,7)|
03505|048|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03505|049|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03505|050|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03505|051|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03505|052|B||
03505|053|D|DISCUSSION:  An epidemiologic study evaluated 21,043 elderly patients with|
03505|054|D|Parkinson disease to determine if recent initiation of a typical or atypical|
03505|055|D|antipsychotic was associated with increased mortality.  They found an|
03505|056|D|adjusted odds ratio of 2.0 for death associated with atypical antipsychotics|
03505|057|D|versus no antipsychotic.  They found an adjusted odds ratio of 2.4 for death|
03505|058|D|associated with typical versus atypical antipsychotics.  The authors noted|
03505|059|D|the increased mortality found with typical antipsychotics supports current|
03505|060|D|treatment recommendations to use atypical antipsychotic agents in patients|
03505|061|D|with Parkinson disease.(6,7)|
03505|062|D|   Agents that are linked to this monograph may have varying degrees of|
03505|063|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03505|064|D|been shown to prolong the QTc interval either through their mechanism of|
03505|065|D|action, through studies on their effects on the QTc interval, or through|
03505|066|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03505|067|D|and/or postmarketing reports.(8)|
03505|068|D|   Coadministration of ketoconazole (200 mg twice daily, an inhibitor of|
03505|069|D|CYP3A4) and iloperidone (12 mg twice daily) was associated with a mean QTcF|
03505|070|D|increase of 19 msec from baseline, compared with an increase of 9 msec with|
03505|071|D|iloperidone alone.(2)|
03505|072|D|   Coadministration of paroxetine (20 mg daily, an inhibitor of CYP2D6) and|
03505|073|D|iloperidone (12 mg twice daily) was associated with a mean QTcF increase of|
03505|074|D|19 msec from baseline, compared with an increase of 9 msec with iloperidone|
03505|075|D|alone.(2)|
03505|076|D|   Although quetiapine was not associated with QT or QTc changes in clinical|
03505|077|D|trials, QT prolongation has been reported in post-marketing reports in|
03505|078|D|conjunction with the use of other agents known to prolong the QT|
03505|079|D|interval.(4)|
03505|080|B||
03505|081|R|REFERENCES:|
03505|082|B||
03505|083|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03505|084|R|  Inc. May, 2019.|1
03505|085|R|2.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
03505|086|R|  Inc May, 2016.|1
03505|087|R|3.Invega (paliperidone) US prescribing information. Janssen Pharmaceuticals,|1
03505|088|R|  Inc. February 23, 2017.|1
03505|089|R|4.Seroquel (quetiapine fumarate) US prescribing information. AstraZeneca|1
03505|090|R|  Pharmaceuticals LP July, 2011.|1
03505|091|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03505|092|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03505|093|R|  settings: a scientific statement from the American Heart Association and|6
03505|094|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03505|095|R|  2;55(9):934-47.|6
03505|096|R|6.Marras C, Gruneir A, Wang X, Fischer H, Gill SS, Herrmann N, Anderson GM,|2
03505|097|R|  Hyson C, Rochon PA. Antipsychotics and mortality in Parkinsonism. Am J|2
03505|098|R|  Geriatr Psychiatry 2012 Feb;20(2):149-58.|2
03505|099|R|7.Oertel WH Berardelli A Bloem Br etal. Chapter 15 - Late (complicated)|6
03505|100|R|  Parkinson's disease in European Handbook of Neurological Management. 2011;|6
03505|101|R|  Volume 1, 2nd Edition:237 - 267.|6
03505|102|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
03505|103|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03505|104|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03505|105|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03506|001|T|MONOGRAPH TITLE:  Selected SSRIs; Selected SNRIs/Clomipramine; Imipramine|
03506|002|B||
03506|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03506|004|L|take action as needed.|
03506|005|B||
03506|006|A|MECHANISM OF ACTION:  The combination of clomipramine or imipramine with the|
03506|007|A|selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake|
03506|008|A|inhibitors may have additive effects on serotonin levels.|
03506|009|B||
03506|010|E|CLINICAL EFFECTS:  Some patients may develop an increase in serotonergic|
03506|011|E|activity in the CNS, which could result in serotonin syndrome. Symptoms of|
03506|012|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
03506|013|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)|
03506|014|B||
03506|015|P|PREDISPOSING FACTORS:  Use of multiple drugs which increase serotonin|
03506|016|P|levels.(1)|
03506|017|B||
03506|018|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy should be|
03506|019|M|observed for signs of increased serotonergic side effects.|
03506|020|M|   Counsel patients to report new or worsening muscle twitching, tremors,|
03506|021|M|shivering or stiffness, fever, heavy sweating, heart palpitations,|
03506|022|M|restlessness, confusion, agitation, decreased coordination, or severe|
03506|023|M|diarrhea.|
03506|024|B||
03506|025|D|DISCUSSION:  The tricyclic antidepressants clomipramine and imipramine|
03506|026|D|possess significant serotonin reuptake inhibition properties.(2)  Concurrent|
03506|027|D|or recent use of other serotoninergic agents can increase the risk of|
03506|028|D|serotonin syndrome.(1,2)|
03506|029|B||
03506|030|R|REFERENCES:|
03506|031|B||
03506|032|R|1.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03506|033|R|  352(11):1112-20.|6
03506|034|R|2.Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug|6
03506|035|R|  interactions updated. Br J Pharmacol 2007 Jul;151(6):737-48.|6
03507|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 5 mg)/Darolutamide|
03507|002|B||
03507|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03507|004|L|is contraindicated and generally should not be dispensed or administered to|
03507|005|L|the same patient.|
03507|006|B||
03507|007|A|MECHANISM OF ACTION:  Darolutamide inhibits BCRP, which may result in|
03507|008|A|increased absorption of rosuvastatin.(1,2)|
03507|009|B||
03507|010|E|CLINICAL EFFECTS:  Administration of darolutamide with rosuvastatin may|
03507|011|E|result in elevated levels of rosuvastatin, which could result in|
03507|012|E|rhabdomyolysis.(1,2)|
03507|013|B||
03507|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03507|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03507|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03507|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03507|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03507|019|P|transporter OATP1B1 may have increased statin concentrations and be|
03507|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
03507|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
03507|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
03507|023|B||
03507|024|M|PATIENT MANAGEMENT:  The US manufacturer of darolutamide recommends avoiding|
03507|025|M|concomitant use of BCRP substrates, like rosuvastatin, whenever possible.(1)|
03507|026|M|The manufacturer of rosuvastatin states that the dose of rosuvastatin|
03507|027|M|should not exceed 5 mg daily when used concurrently with darolutamide.(2)|
03507|028|M|   If these drugs are used concurrently, patients should be monitored more|
03507|029|M|closely for rosuvastatin toxicity.|
03507|030|B||
03507|031|D|DISCUSSION:  Concurrent administration of darolutamide 600 mg twice daily|
03507|032|D|for 5 days with single-dose rosuvastatin 5 mg increased the mean|
03507|033|D|area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin|
03507|034|D|approximately 5-fold.(1,2)|
03507|035|B||
03507|036|R|REFERENCES:|
03507|037|B||
03507|038|R|1.Nubeqa (darolutamide) US prescribing information. Bayer Healthcare|1
03507|039|R|  Pharmaceuticals, Inc. August, 2022.|1
03507|040|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03507|041|R|  Pharmaceuticals LP July, 2024.|1
03508|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 5 mg)/Darolutamide|
03508|002|B||
03508|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03508|004|L|take action as needed.|
03508|005|B||
03508|006|A|MECHANISM OF ACTION:  Darolutamide inhibits BCRP, which may result in|
03508|007|A|increased absorption of rosuvastatin.(1,2)|
03508|008|B||
03508|009|E|CLINICAL EFFECTS:  Administration of darolutamide with rosuvastatin may|
03508|010|E|result in elevated levels of rosuvastatin, which could result in|
03508|011|E|rhabdomyolysis.(1,2)|
03508|012|B||
03508|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03508|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03508|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03508|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03508|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03508|018|P|transporter OATP1B1 may have increased statin concentrations and be|
03508|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
03508|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
03508|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
03508|022|B||
03508|023|M|PATIENT MANAGEMENT:  The US manufacturer of darolutamide recommends avoiding|
03508|024|M|concomitant use of BCRP substrates, like rosuvastatin, whenever possible.(1)|
03508|025|M|The manufacturer of rosuvastatin states that the dose of rosuvastatin|
03508|026|M|should not exceed 5 mg daily when used concurrently with darolutamide.(2)|
03508|027|M|   If these drugs are used concurrently, patients should be monitored more|
03508|028|M|closely for rosuvastatin toxicity.|
03508|029|B||
03508|030|D|DISCUSSION:  Concurrent administration of darolutamide 600 mg twice daily|
03508|031|D|for 5 days with single-dose rosuvastatin 5 mg increased the mean|
03508|032|D|area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin|
03508|033|D|approximately 5-fold.(1,2)|
03508|034|B||
03508|035|R|REFERENCES:|
03508|036|B||
03508|037|R|1.Nubeqa (darolutamide) US prescribing information. Bayer Healthcare|1
03508|038|R|  Pharmaceuticals, Inc. August, 2022.|1
03508|039|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03508|040|R|  Pharmaceuticals LP July, 2024.|1
03509|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 10 mg)/Regorafenib|
03509|002|B||
03509|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03509|004|L|is contraindicated and generally should not be dispensed or administered to|
03509|005|L|the same patient.|
03509|006|B||
03509|007|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate for breast cancer|
03509|008|A|resistance protein (BCRP). Regorafenib inhibits intestinal BCRP leading to|
03509|009|A|increased systemic absorption of rosuvastatin.(1,2)|
03509|010|B||
03509|011|E|CLINICAL EFFECTS:  High systemic concentrations of rosuvastatin increase the|
03509|012|E|risk for statin-induced myopathy or rhabdomyolysis.(1)|
03509|013|B||
03509|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03509|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03509|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03509|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03509|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03509|019|P|transporter OATP1B1 may have increased statin concentrations and be|
03509|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
03509|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
03509|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
03509|023|B||
03509|024|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
03509|025|M|dose of rosuvastatin should not exceed 10 mg daily when used concurrently|
03509|026|M|with regorafenib.  Monitor patients closely for signs and symptoms of|
03509|027|M|toxicity from increased rosuvastatin concentrations.(1,2)|
03509|028|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
03509|029|M|of    rosuvastatin should not exceed 5 mg daily when used with|
03509|030|M|regorafenib.(3)|
03509|031|B||
03509|032|D|DISCUSSION:  In a study of regorafenib 160 mg daily x 14 days followed by|
03509|033|D|rosuvastatin 5 mg single dose, rosuvastatin area-under-curve (AUC) and|
03509|034|D|maximum concentration (Cmax) increased 3.8-fold and 4.6-fold,|
03509|035|D|respectively.(1,2)|
03509|036|B||
03509|037|R|REFERENCES:|
03509|038|B||
03509|039|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03509|040|R|  Pharmaceuticals LP July, 2024.|1
03509|041|R|2.Stivarga (regorafenib) US prescribing information. Bayer HealthCare|1
03509|042|R|  Pharmaceuticals, Inc. February, 2020.|1
03509|043|R|3.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
03509|044|R|  Australia Pty Ltd July 8, 2024.|1
03510|001|T|MONOGRAPH TITLE:  Artesunate/Strong UGT Inducers; Nevirapine|
03510|002|B||
03510|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03510|004|L|take action as needed.|
03510|005|B||
03510|006|A|MECHANISM OF ACTION:  Strong inducers of UDP-glucuronosyltransferase (UGT)|
03510|007|A|and nevirapine may increase the metabolism of dihydroartemisinin (DHA, the|
03510|008|A|active metabolite of artesunate).(1)|
03510|009|B||
03510|010|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, efavirenz, etravirine,|
03510|011|E|fosphenytoin, nevirapine, phenobarbital, phenytoin, primidone, rifampin, or|
03510|012|E|ritonavir may result in decreased levels and effectiveness of DHA.(1)|
03510|013|B||
03510|014|P|PREDISPOSING FACTORS:  None determined.|
03510|015|B||
03510|016|M|PATIENT MANAGEMENT:  If coadministration of strong UGT inducers or|
03510|017|M|nevirapine with artesunate is necessary, monitor for possible reduced|
03510|018|M|antimalarial efficacy.(1)|
03510|019|B||
03510|020|D|DISCUSSION:  In a study, nevirapine decreased the maximum concentration|
03510|021|D|(Cmax) and area-under-curve (AUC) of DHA by 59% and 68%, respectively.(1)|
03510|022|D|   In a study of healthy volunteers, ritonavir (100 mg twice daily for 7|
03510|023|D|days) decreased the Cmax and AUC of DHA by 27% and 38%, respectively.(1,2)|
03510|024|D|   A study of healthy subjects who were coadministered lopinavir-ritonavir|
03510|025|D|400 mg-100 mg twice daily for 14 days) and artesunate-mefloquine found that|
03510|026|D|artesunate Cmax and AUC decreased by 37% and 45%, respectively, compared to|
03510|027|D|artesunate-mefloquine alone.(3)|
03510|028|D|   Agents linked to this monograph include: carbamazepine, efavirenz,|
03510|029|D|etravirine, fosphenytoin, nevirapine, phenobarbital, phenytoin, primidone,|
03510|030|D|rifampin, and ritonavir.|
03510|031|B||
03510|032|R|REFERENCES:|
03510|033|B||
03510|034|R|1.Artesunate US prescribing information. Amivas LLC March, 2023.|1
03510|035|R|2.Morris CA, Lopez-Lazaro L, Jung D, Methaneethorn J, Duparc S,|2
03510|036|R|  Borghini-Fuhrer I, Pokorny R, Shin CS, Fleckenstein L. Drug-drug|2
03510|037|R|  interaction analysis of pyronaridine/artesunate and ritonavir in healthy|2
03510|038|R|  volunteers. Am J Trop Med Hyg 2012 Mar;86(3):489-495.|2
03510|039|R|3.Rattanapunya S, Cressey TR, Rueangweerayut R, Tawon Y, Kongjam P,|2
03510|040|R|  Na-Bangchang K. Pharmacokinetic interactions between artesunate-mefloquine|2
03510|041|R|  and ritonavir-boosted  lopinavir in healthy Thai adults. Malar J 2015 Oct|2
03510|042|R|  9;14:400.|2
03512|001|T|MONOGRAPH TITLE:  Selected P-glycoprotein (P-gp) Substrates/Lorlatinib|
03512|002|B||
03512|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03512|004|L|of severe adverse interaction.|
03512|005|B||
03512|006|A|MECHANISM OF ACTION:  Lorlatinib is an inducer of the P-glycoprotein (P-gp)|
03512|007|A|system.  The absorption of P-gp substrates with a narrow therapeutic index|
03512|008|A|may be decreased.(1)|
03512|009|B||
03512|010|E|CLINICAL EFFECTS:  Concurrent use of lorlatinib with narrow therapeutic|
03512|011|E|index P-gp substrates may result in decreased levels and effectiveness of|
03512|012|E|the substrate.(1)|
03512|013|B||
03512|014|P|PREDISPOSING FACTORS:  None determined.|
03512|015|B||
03512|016|M|PATIENT MANAGEMENT:  The US manufacturer of lorlatinib states that the|
03512|017|M|concurrent use of narrow therapeutic index P-gp substrates should be|
03512|018|M|avoided.  If concurrent therapy cannot be avoided, the dosage of the narrow|
03512|019|M|therapeutic index P-gp substrate should be increased according to the|
03512|020|M|substrate prescribing information.(1)|
03512|021|B||
03512|022|D|DISCUSSION:  In a study, lorlatinib 100 mg daily for 15 days decreased the|
03512|023|D|area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
03512|024|D|fexofenadine 60 mg (a P-gp substrate) by 67% and 63%, respectively.(1)|
03512|025|D|   Selected narrow therapeutic index P-gp substrates include: digoxin,|
03512|026|D|everolimus, pazopanib, sirolimus, and topotecan.(1,2)|
03512|027|B||
03512|028|R|REFERENCES:|
03512|029|B||
03512|030|R|1.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
03512|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
03512|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03513|001|T|MONOGRAPH TITLE:  Selected CYP2C9 Substrates/Lorlatinib|
03513|002|B||
03513|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03513|004|L|take action as needed.|
03513|005|B||
03513|006|A|MECHANISM OF ACTION:  Lorlatinib is a moderate inducer of CYP2C9 and may|
03513|007|A|increase the metabolism of drugs metabolized by the CYP2C9 enzyme.(1)|
03513|008|B||
03513|009|E|CLINICAL EFFECTS:  Concurrent use of lorlatinib may lead to decreased serum|
03513|010|E|levels and effectiveness of drugs metabolized by the CYP2C9 pathway.(1)|
03513|011|B||
03513|012|P|PREDISPOSING FACTORS:  None determined.|
03513|013|B||
03513|014|M|PATIENT MANAGEMENT:  Patients maintained on a CYP2C9 substrate who start|
03513|015|M|therapy with lorlatinib may require closer monitoring and dose adjustment of|
03513|016|M|the CYP2C9 substrate.|
03513|017|B||
03513|018|D|DISCUSSION:  In a study, lorlatinib 100 mg daily for 15 days decreased the|
03513|019|D|area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
03513|020|D|tolbutamide 100 mg (a sensitive CYP2C9 substrate) by 43% and 15%,|
03513|021|D|respectively.(1)|
03513|022|D|   CYP2C9 substrates with a narrow therapeutic index linked to this|
03513|023|D|monograph include: dasabuvir, paclitaxel, and warfarin.(2,3)|
03513|024|B||
03513|025|R|REFERENCES:|
03513|026|B||
03513|027|R|1.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
03513|028|R|2.This information is based on an extract from the Certara Drug Interaction|6
03513|029|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03513|030|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03513|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03513|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03513|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03513|034|R|  11/14/2017.|1
03514|001|T|MONOGRAPH TITLE:  Slt HMG-CoA Reductase Inhibitors/Ketoconazole;|
03514|002|T|Posaconazole|
03514|003|B||
03514|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03514|005|L|is contraindicated and generally should not be dispensed or administered to|
03514|006|L|the same patient.|
03514|007|B||
03514|008|A|MECHANISM OF ACTION:  Ketoconazole(1) and posaconazole(2,3) may inhibit the|
03514|009|A|metabolism of cerivastatin(4), lovastatin(5) or simvastatin(6) by CYP3A4.|
03514|010|B||
03514|011|E|CLINICAL EFFECTS:  Concurrent administration of ketoconazole or posaconazole|
03514|012|E|may result in increased levels of cerivastatin, lovastatin or simvastatin,|
03514|013|E|which may result in an increased risk of rhabdomyolysis.(1-6)|
03514|014|B||
03514|015|P|PREDISPOSING FACTORS:  The risk of myopathy or rhabdomyolysis may be greater|
03514|016|P|in patients 65 years and older, inadequately treated hypothyroidism, renal|
03514|017|P|impairment, carnitine deficiency, malignant hyperthermia, or in patients|
03514|018|P|with a history of myopathy or rhabdomyolysis.  Patients with a SLCOB1|
03514|019|P|polymorphism that leads to decreased function of the hepatic uptake|
03514|020|P|transporter OATP1B1 may have increased statin concentrations and be|
03514|021|P|predisposed to myopathy or rhabdomyolysis.|
03514|022|B||
03514|023|M|PATIENT MANAGEMENT:  Strong CYP3A4 inhibitors such as ketoconazole and|
03514|024|M|posaconazole are contraindicated with cerivastatin, lovastatin and|
03514|025|M|simvastatin.(1-6)|
03514|026|B||
03514|027|D|DISCUSSION:  In a double-blind cross-over study in 12 healthy subjects,|
03514|028|D|administration of lovastatin (40 mg single dose) after 4 days of|
03514|029|D|itraconazole (200 mg daily) increased lovastatin maximum concentration|
03514|030|D|(Cmax) by more than 20-fold.  Lovastatin area-under-curve (AUC) and|
03514|031|D|half-life (T1/2) increased from undetectable levels in all but 3 subjects|
03514|032|D|during placebo phase to 546 ng/ml and 3.6+/-1 hours, respectively, during|
03514|033|D|itraconazole coadministration.  The lovastatin acid Cmax and AUC increased|
03514|034|D|13-fold and 23-fold, respectively, during concurrent itraconazole.  The T1/2|
03514|035|D|of lovastatin acid increased from undetectable levels in the placebo phase|
03514|036|D|to 6+/-1.1 hours in the itraconazole phase.(7)|
03514|037|D|   In a double-blind cross-over study in 10 subjects, administration of|
03514|038|D|lovastatin (40 mg single dose) after 4 days of itraconazole (100 mg daily)|
03514|039|D|increased lovastatin Cmax and AUC by about 15-fold.  The lovastatin Cmax and|
03514|040|D|AUC increased 12-fold and 15-fold, respectively, during itraconazole.  The|
03514|041|D|lovastatin and lovastatin acid T1/2 increased from undetectable levels to|
03514|042|D|3.7+/-3.8 hours and 4.7+/-4.0 hours, respectively, during itraconazole.(8)|
03514|043|D|   In a study, pretreatment with posaconazole (100 mg daily for 13 days)|
03514|044|D|increased the Cmax and AUC of a single dose of simvastatin (40 mg) by 841%|
03514|045|D|and 931%, respectively.  The Cmax and AUC of simvastatin acid increased 817%|
03514|046|D|and 634%, respectively.(3)|
03514|047|D|   In a study, pretreatment with posaconazole (200 mg daily for 13 days)|
03514|048|D|increased the Cmax and AUC of a single dose of simvastatin (40 mg) by 1041%|
03514|049|D|and 960%, respectively.  The Cmax and AUC of simvastatin acid increased 851%|
03514|050|D|and 748%, respectively.(3)|
03514|051|D|   In a randomized, fixed-sequence, parallel-group, single-center,|
03514|052|D|open-label study, administration of different strengths of posaconazole (50,|
03514|053|D|100, or 200 mg) were evaluated with regards to its effects on simvastatin|
03514|054|D|concentration.  The regimen consisted of midazolam 2 mg orally 9 days prior|
03514|055|D|to the initiation of posaconazole and simvastatin 40 mg orally 6 days prior|
03514|056|D|to initiation of posaconazole.  Posaconazole was then given alone on days|
03514|057|D|1-7 once daily followed by coadministration with midazolam on day 8 and then|
03514|058|D|posaconazole again alone on days 9-10.  On day 11 simvastatin was given with|
03514|059|D|posaconazole followed by posaconazole alone on days 12-13. Results showed a|
03514|060|D|significant increase in the Cmax and AUC of simvastatin when given with|
03514|061|D|posaconazole vs. given alone.(9)|
03514|062|D|   Administration of cerivastatin (0.3 mg) with itraconazole (200 mg daily X|
03514|063|D|10 days) increased cerivastatin AUC and Cmax 38% and 12%, respectively.|
03514|064|D|There was no effect on itraconazole pharmacokinetics. Administration of|
03514|065|D|cerivastatin (0.8 mg single dose) with itraconazole increased cerivastatin|
03514|066|D|AUC and Cmax by 27% and 25%, respectively.(10)|
03514|067|D|   In a randomized, double-blind, cross-over study in 10 healthy subjects,|
03514|068|D|the administration of cerivastatin (0.3 mg single dose) on day 4 of|
03514|069|D|itraconazole (200 mg) increased cerivastatin parent compound AUC 15%.|
03514|070|D|Cerivastatin lactone AUC, Cmax, and T1/2 increased 2.6-fold, 1.8-fold, and|
03514|071|D|3.2-fold, respectively.  The M-23 active metabolite AUC increased 36%.  The|
03514|072|D|AUC and T1/2 of all active cerivastatin derivatives increased 27% and 40%,|
03514|073|D|respectively.(11)|
03514|074|D|   There are case reports of rhabdomyolysis with concurrent itraconazole and|
03514|075|D|lovastatin(12-14) and with concurrent itraconazole(15-19) or|
03514|076|D|ketoconazole(20-22) and simvastatin.|
03514|077|D|   One or more of the drug pairs linked to this monograph have been included|
03514|078|D|in a list of interactions that should be considered "high-priority" for|
03514|079|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
03514|080|D|vetted by an expert panel commissioned by the U.S. Office of the National|
03514|081|D|Coordinator (ONC) for Health Information Technology.|
03514|082|B||
03514|083|R|REFERENCES:|
03514|084|B||
03514|085|R|1.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
03514|086|R|  Pharmaceuticals February, 2014.|1
03514|087|R|2.Noxafil (posaconazole) UK summary of product characteristics.|1
03514|088|R|  Schering-Plough Ltd. January, 2022.|1
03514|089|R|3.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
03514|090|R|  January, 2022.|1
03514|091|R|4.Baycol (cerivastatin) US prescribing information. Bayer Corporation|1
03514|092|R|  December, 2000.|1
03514|093|R|5.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
03514|094|R|  February, 2014.|1
03514|095|R|6.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03514|096|R|  2023.|1
03514|097|R|7.Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma|2
03514|098|R|  concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996|2
03514|099|R|  Jul;60(1):54-61.|2
03514|100|R|8.Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on|2
03514|101|R|  the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol|2
03514|102|R|  1998 Jul;46(1):49-53.|2
03514|103|R|9.Krishna G, Ma L, Prasad P, Moton A, Martinho M, O'Mara E. Effect of|2
03514|104|R|  posaconazole on the pharmacokinetics of simvastatin and midazolam in|2
03514|105|R|  healthy volunteers. Expert Opin Drug Metab Toxicol 2012 Jan;8(1):1-10.|2
03514|106|R|10.Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on|2
03514|107|R|   cerivastatin pharmacokinetics. Eur J Clin Pharmacol 1999 Jan;|2
03514|108|R|   54(11):851-5.|2
03514|109|R|11.Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P.|2
03514|110|R|   Itraconazole alters the pharmacokinetics of atorvastatin to a greater|2
03514|111|R|   extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000|2
03514|112|R|   Oct;68(4):391-400.|2
03514|113|R|12.Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin|3
03514|114|R|   and the antifungal agent itraconazole. N Engl J Med 1995 Sep 7;|3
03514|115|R|   333(10):664-5.|3
03514|116|R|13.Horn M. Coadministration of itraconazole with hypolipidemic agents may|3
03514|117|R|   induce rhabdomyolysis in healthy individuals. Arch Dermatol 1996 Oct;|3
03514|118|R|   132(10):1254.|3
03514|119|R|14.Segaert MF, De Soete C, Vandewiele I, Verbanck J.|3
03514|120|R|   Drug-interaction-induced rhabdomyolysis. Nephrol Dial Transplant 1996|3
03514|121|R|   Sep;11(9):1846-7.|3
03514|122|R|15.Roques S, Lytrivi M, Rusu D, Devriendt J, De Bels D.|3
03514|123|R|   Rhabdomyolysis-induced acute renal failure due to itraconazole and|3
03514|124|R|   simvastatin association. Drug Metabol Drug Interact 2011;26(2):79-80.|3
03514|125|R|16.Tiessen RG, Lagerwey HJ, Jager GJ, Sprenger HG. Drug interaction caused|3
03514|126|R|   by communication problems. Rhabdomyolysis due to a combination of|3
03514|127|R|   itraconazole and simvastatin. Ned Tijdschr Geneeskd 2010;154:A762.|3
03514|128|R|17.Saliba WR, Elias M. Severe myopathy induced by the co-administration of|3
03514|129|R|   simvastatin and itraconazole. Eur J Intern Med 2005 Aug;16(4):305.|3
03514|130|R|18.Vlahakos DV, Manginas A, Chilidou D, Zamanika C, Alivizatos PA.|3
03514|131|R|   Itraconazole-induced rhabdomyolysis and acute renal failure in a heart|3
03514|132|R|   transplant recipient treated with simvastatin and cyclosporine.|3
03514|133|R|   Transplantation 2002 Jun 27;73(12):1962-4.|3
03514|134|R|19.Maxa JL, Melton LB, Ogu CC, Sills MN, Limanni A. Rhabdomyolysis after|3
03514|135|R|   concomitant use of cyclosporine, simvastatin, gemfibrozil, and|3
03514|136|R|   itraconazole. Ann Pharmacother 2002 May;36(5):820-3.|3
03514|137|R|20.Gilad R, Lampl Y. Rhabdomyolysis induced by simvastatin and ketoconazole|3
03514|138|R|   treatment. Clin Neuropharmacol 1999 Sep-Oct;22(5):295-7.|3
03514|139|R|21.Watkins JL, Atkinson BJ, Pagliaro LC. Rhabdomyolysis in a Prostate Cancer|3
03514|140|R|   Patient Taking Ketoconazole and Simvastatin:  Case Report and Review of|3
03514|141|R|   the Literature (February). Ann Pharmacother 2011 Feb 8.|3
03514|142|R|22.Itakura H, Vaughn D, Haller DG, O'Dwyer PJ. Rhabdomyolysis from|3
03514|143|R|   cytochrome p-450 interaction of ketoconazole and simvastatin  in prostate|3
03514|144|R|   cancer. J Urol 2003 Feb;169(2):613.|3
03514|145|R|23.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
03514|146|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
03514|147|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
03514|148|R|   19(5):735-43.|6
03515|001|T|MONOGRAPH TITLE:  Inebilizumab/Immunosuppressives; Immunomodulators|
03515|002|B||
03515|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03515|004|L|of severe adverse interaction.|
03515|005|B||
03515|006|A|MECHANISM OF ACTION:  Inebilizumab, immunosuppressives, and immunomodulators|
03515|007|A|all suppress the immune system.(1)|
03515|008|B||
03515|009|E|CLINICAL EFFECTS:  Concurrent use of inebilizumab with immunosuppressive or|
03515|010|E|immunomodulating agents may result in myelosuppression including neutropenia|
03515|011|E|resulting in an increased risk for serious infections.(1)|
03515|012|B||
03515|013|P|PREDISPOSING FACTORS:  None determined.|
03515|014|B||
03515|015|M|PATIENT MANAGEMENT:  The US manufacturer of inebilizumab states that the|
03515|016|M|concurrent use of inebilizumab with immunosuppressive agents, including|
03515|017|M|systemic corticosteroids, may increase the risk of infection.  If concurrent|
03515|018|M|therapy is warranted, consider the risk of additive immune suppression and|
03515|019|M|monitor based on prescribing information for both agents.(1)|
03515|020|B||
03515|021|D|DISCUSSION:  Inebilizumab has not been studied in combination with other|
03515|022|D|immunosuppressants. If concurrent therapy is warranted, consider the|
03515|023|D|potential for increased immunosuppressive risks from both agents.|
03515|024|D|   The most common infections reported by inebilizumab treated patients in|
03515|025|D|the randomized and open-label clinical trial periods included urinary tract|
03515|026|D|infections (20%), nasopharyngitis (13%), upper respiratory tract infections|
03515|027|D|(8%), and influenza (7%). Although there been no cases of Hepatitis B virus|
03515|028|D|reactivation or progressive multifocal leukoencephalopathy reported in|
03515|029|D|patients taking inebilizumab, these infections have been observed in|
03515|030|D|patients taking other B-cell-depleting antibodies.(1)|
03515|031|B||
03515|032|R|REFERENCE:|
03515|033|B||
03515|034|R|1.Uplizna (inebilizumab-cdon) US prescribing information. Viela Bio June,|1
03515|035|R|  2020.|1
03516|001|T|MONOGRAPH TITLE:  Lurbinectedin/Strong CYP3A4 Inhibitors|
03516|002|B||
03516|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03516|004|L|of severe adverse interaction.|
03516|005|B||
03516|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03516|007|A|lurbinectedin.(1)|
03516|008|B||
03516|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors with|
03516|010|E|lurbinectedin may increase systemic exposure and the risk for toxicities|
03516|011|E|such as myelosuppression, hepatotoxicity, neuropathy, fatigue, nausea, and|
03516|012|E|musculoskeletal pain.(1)|
03516|013|B||
03516|014|P|PREDISPOSING FACTORS:  None determined.|
03516|015|B||
03516|016|M|PATIENT MANAGEMENT:  The US manufacturer of lurbinectedin states that the|
03516|017|M|concurrent use of lurbinectedin with strong CYP3A4 inhibitors should be|
03516|018|M|avoided.  If the use of a strong CYP3A4 inhibitor cannot be avoided, reduce|
03516|019|M|the dose of lurbinectedin by 50%.  After discontinuation of the strong|
03516|020|M|CYP3A4 inhibitor for 5 half-lives of the inhibitor, resume the lurbinectedin|
03516|021|M|dose used before starting the inhibitor.(1)|
03516|022|B||
03516|023|D|DISCUSSION:  Itraconazole (a strong CYP3A4 inhibitor) increased the|
03516|024|D|area-under-curve (AUC) of total lurbinectedin by 2.7-fold and unbound|
03516|025|D|lurbinectedin by 2.4-fold.(1)|
03516|026|D|   In a study including data from 443 patients with solid and hematologic|
03516|027|D|malignancies treated in six phase I and three phase II trials with|
03516|028|D|lurbinectedin as a single agent or combined with other agents, lurbinectedin|
03516|029|D|clearance decreased by 30%, area-under-curve (AUC) increased by 42%, and|
03516|030|D|concentration maximum (Cmax) increased by 7% when coadministered with a|
03516|031|D|CYP3A inhibitor.(2)|
03516|032|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03516|033|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
03516|034|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir,|
03516|035|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
03516|036|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
03516|037|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4)|
03516|038|B||
03516|039|R|REFERENCES:|
03516|040|B||
03516|041|R|1.Zepzelca (lurbinectedin) US prescribing information. Pharma Mar USA Inc.|1
03516|042|R|  April, 2024.|1
03516|043|R|2.Fernandez-Teruel C, Gonzalez I, Troconiz IF, Lubomirov R, Soto A, Fudio S.|2
03516|044|R|  Population-Pharmacokinetic and Covariate Analysis of Lurbinectedin|2
03516|045|R|  (PM01183), a New  RNA Polymerase II Inhibitor, in Pooled Phase I/II Trials|2
03516|046|R|  in Patients with Cancer. Clinical Pharmacokinetics August 09, 2018.;|2
03516|047|R|  58(1179-1926):363-374.|2
03516|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03516|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03516|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03516|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03516|052|R|  11/14/2017.|1
03516|053|R|4.This information is based on an extract from the Certara Drug Interaction|6
03516|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03517|001|T|MONOGRAPH TITLE:  Lurbinectedin/Strong CYP3A4 Inducers|
03517|002|B||
03517|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03517|004|L|of severe adverse interaction.|
03517|005|B||
03517|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolism of|
03517|007|A|lurbinectedin.(1)|
03517|008|B||
03517|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
03517|010|E|serum levels and effectiveness of lurbinectedin.(1)|
03517|011|B||
03517|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03517|013|P|of the inducer for longer than 1-2 weeks.|
03517|014|B||
03517|015|M|PATIENT MANAGEMENT:  The US manufacturer of lurbinectedin states that the|
03517|016|M|concurrent use of lurbinectedin with strong CYP3A4 inducers should be|
03517|017|M|avoided.(1)|
03517|018|B||
03517|019|D|DISCUSSION:  Pharmacokinetic studies have not been conducted with extended|
03517|020|D|doses of CYP3A4 inducers with concurrent lurbinectedin therapy.(1)|
03517|021|D|   Bosentan (a moderate CYP3A4 inducer) decreased the area-under-curve (AUC)|
03517|022|D|of total lurbinectedin by 20% and unbound lurbinectedin by 19%.  This change|
03517|023|D|was not considered to be clinically significant.(1)  Strong CYP3A4 inducers|
03517|024|D|would be expected to have a larger impact on lurbinectedin levels and may|
03517|025|D|affect therapeutic effects.|
03517|026|D|   In a study including data from 443 patients with solid and hematologic|
03517|027|D|malignancies treated in six phase I and three phase II trials with|
03517|028|D|lurbinectedin as a single agent or combined with other agents, CYP3A|
03517|029|D|inducers were coadministered in 52.2% of the patients but no changes in|
03517|030|D|lurbinectedin pharmacokinetics were observed in in these patients. This is|
03517|031|D|likely due to the CYP3A inducers mostly consisting of single-dose|
03517|032|D|corticosteroids given as per-protocol antiemetic prophylaxis, minutes before|
03517|033|D|lurbinectedin infusion.(2)|
03517|034|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03517|035|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03517|036|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03517|037|D|rifapentine, and St. John's wort.(3,4)|
03517|038|B||
03517|039|R|REFERENCES:|
03517|040|B||
03517|041|R|1.Zepzelca (lurbinectedin) US prescribing information. Pharma Mar USA Inc.|1
03517|042|R|  April, 2024.|1
03517|043|R|2.Fernandez-Teruel C, Gonzalez I, Troconiz IF, Lubomirov R, Soto A, Fudio S.|2
03517|044|R|  Population-Pharmacokinetic and Covariate Analysis of Lurbinectedin|2
03517|045|R|  (PM01183), a New  RNA Polymerase II Inhibitor, in Pooled Phase I/II Trials|2
03517|046|R|  in Patients with Cancer. Clinical Pharmacokinetics August 09, 2018.;|2
03517|047|R|  58(1179-1926):363-374.|2
03517|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03517|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03517|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03517|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03517|052|R|  11/14/2017.|1
03517|053|R|4.This information is based on an extract from the Certara Drug Interaction|6
03517|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03518|001|T|MONOGRAPH TITLE:  Remdesivir/Chloroquine; Hydroxychloroquine|
03518|002|B||
03518|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03518|004|L|of severe adverse interaction.|
03518|005|B||
03518|006|A|MECHANISM OF ACTION:  Chloroquine may inhibit the intracellular metabolic|
03518|007|A|activation and antiviral activity of remdesivir.(1,2)|
03518|008|B||
03518|009|E|CLINICAL EFFECTS:  Concurrent use of chloroquine or hydroxychloroquine may|
03518|010|E|result in decreased effectiveness of remdesivir.(1,2)|
03518|011|B||
03518|012|P|PREDISPOSING FACTORS:  None determined.|
03518|013|B||
03518|014|M|PATIENT MANAGEMENT:  The concurrent use of chloroquine or hydroxychloroquine|
03518|015|M|with remdesivir is not recommended.(1,2)  Monitor patients receiving|
03518|016|M|concurrent therapy for decreased remdesivir effects.|
03518|017|B||
03518|018|D|DISCUSSION:  In vitro tests in HEp-2 cells infected with respiratory|
03518|019|D|syncytial virus (RSV) found that the antiviral activity of remdesivir was|
03518|020|D|antagonized by chloroquine phosphate in a dose-dependent manner at|
03518|021|D|clinically relevant concentrations.(1,2)  Higher remdesivir EC50 values were|
03518|022|D|seen with increasing concentrations of chloroquine phosphate.  Reduced|
03518|023|D|formation of remdesivir triphosphate (the pharmacologically active|
03518|024|D|metabolite) in normal human bronchial epithelial cells was also seen with|
03518|025|D|increasing concentration of chloroquine phosphate.(1,2)|
03518|026|B||
03518|027|R|REFERENCES:|
03518|028|B||
03518|029|R|1.Veklury (remdesivir) US Prescribing Information. Gilead Sciences, Inc.|1
03518|030|R|  December, 2024.|1
03518|031|R|2.Veklury (remdesivir injection) Canadian prescribing information. Gilead|1
03518|032|R|  Sciences Canada, Inc. October, 2020.|1
03519|001|T|MONOGRAPH TITLE:  Tamoxifen/Selected Strong CYP2D6 Inhibitors|
03519|002|B||
03519|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03519|004|L|of severe adverse interaction.|
03519|005|B||
03519|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2D6 may inhibit the conversion of|
03519|007|A|tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2)  The role|
03519|008|A|of endoxifen in tamoxifen's efficacy has been debated and may involve a|
03519|009|A|minimum concentration level.(3-5)|
03519|010|B||
03519|011|E|CLINICAL EFFECTS:  Concurrent use of inhibitors of CYP2D6 may decrease the|
03519|012|E|effectiveness of tamoxifen in preventing breast cancer recurrence.|
03519|013|B||
03519|014|P|PREDISPOSING FACTORS:  Concurrent use of strong CYP2D6 inhibitors in|
03519|015|P|patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers|
03519|016|P|should be avoided.  Patients who are CYP2D6 poor metabolizers lack CYP2D6|
03519|017|P|function and are not affected by CYP2D6 inhibition.|
03519|018|B||
03519|019|M|PATIENT MANAGEMENT:  Although data on this interaction are conflicting, it|
03519|020|M|may be prudent to use alternatives to CYP2D6 inhibitors when possible in|
03519|021|M|patients taking tamoxifen.  The US manufacturer of tamoxifen states that the|
03519|022|M|impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain|
03519|023|M|and makes no recommendation regarding coadministration with inhibitors of|
03519|024|M|CYP2D6.(12)  The manufacturer of paroxetine (a strong CYP2D6 inhibitor)|
03519|025|M|states that alternative agents with little or no CYP2D6 inhibition should be|
03519|026|M|considered.(13)|
03519|027|M|   The National Comprehensive Cancer Network's breast cancer guidelines|
03519|028|M|advises caution when coadministering strong CYP2D6 inhibitors with|
03519|029|M|tamoxifen.(14)|
03519|030|M|   If concurrent therapy is warranted, the risks versus benefits should be|
03519|031|M|discussed with the patient.|
03519|032|B||
03519|033|D|DISCUSSION:  Some studies have suggested that administration of fluoxetine,|
03519|034|D|paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer|
03519|035|D|phenotype may result in a decrease in the formation of endoxifen (an active|
03519|036|D|metabolite of tamoxifen) and a shorter time to breast cancer|
03519|037|D|recurrence.(1-2,9)|
03519|038|D|   A retrospective study of 630 breast cancer patients found an increasing|
03519|039|D|risk of breast cancer mortality with increasing durations of|
03519|040|D|coadministration of tamoxifen and paroxetine.  In the adjusted analysis,|
03519|041|D|absolute increases of 25%, 50%, and 75% in the proportion of time of|
03519|042|D|overlapping use of tamoxifen with paroxetine was associated with 24%, 54%,|
03519|043|D|and 91% increase in the risk of death from breast cancer, respectively.(15)|
03519|044|D|   The CYP2D6 genotype of the patient may have a role in the effects of this|
03519|045|D|interaction.  Patients with wild-type CYP2D6 genotype may be affected to a|
03519|046|D|greater extent by this interaction.  Patients with a variant CYP2D6 genotype|
03519|047|D|may have lower baseline levels of endoxifen and may be affected to a lesser|
03519|048|D|extent by this interaction.(6-10)|
03519|049|D|   In a retrospective review, 1,325 patients treated with tamoxifen for|
03519|050|D|breast cancer were classified as being poor 2D6 metabolizers (lacking|
03519|051|D|functional CYP2D6 enzymes), intermediate metabolizers (heterozygous|
03519|052|D|alleles), or extensive metabolizers (possessing 2 functional alleles).|
03519|053|D|After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%,|
03519|054|D|20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and|
03519|055|D|poor metabolizers, respectively.(11)|
03519|056|D|   In October of 2006, the Advisory Committee Pharmaceutical Science,|
03519|057|D|Clinical Pharmacology Subcommittee of the US Food and Drug Administration|
03519|058|D|recommended that the US tamoxifen labeling be updated to include information|
03519|059|D|about the increased risk of breast cancer recurrence in poor CYP2D6|
03519|060|D|metabolizers (either by genotype or drug interaction).(16-17)  The labeling|
03519|061|D|changes were never made due to ongoing uncertainty about the effects of|
03519|062|D|CYP2D6 genotypes on tamoxifen efficacy.|
03519|063|D|   In contrast to the above information, two studies have shown no|
03519|064|D|relationship between CYP2D6 genotype and breast cancer outcome.(18-20)  As|
03519|065|D|well, a number of studies found no association between use of CYP2D6|
03519|066|D|inhibitors and/or antidepressants in patients on tamoxifen and breast cancer|
03519|067|D|recurrence,(21-25) though the studies were limited by problematic selection|
03519|068|D|of CYP2D6 inhibitors and short follow-up.|
03519|069|D|   Strong CYP2D6 inhibitors include hydroquinidine, mavorixafor, and|
03519|070|D|quinidine.(26-27)|
03519|071|B||
03519|072|R|REFERENCES:|
03519|073|B||
03519|074|R|1.Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes|2
03519|075|R|  DF, Desta Z, Flockhart DA. Active tamoxifen metabolite plasma|2
03519|076|R|  concentrations after coadministration of tamoxifen and the selective|2
03519|077|R|  serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003 Dec 3;|2
03519|078|R|  95(23):1758-64.|2
03519|079|R|2.Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li|2
03519|080|R|  L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S,|2
03519|081|R|  Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype,|2
03519|082|R|  antidepressant use, and tamoxifen metabolism during adjuvant breast cancer|2
03519|083|R|  treatment. J Natl Cancer Inst 2005 Jan 5;97(1):30-9.|2
03519|084|R|3.Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z,|2
03519|085|R|  Flockhart DA, Skaar TC. Pharmacological characterization of|2
03519|086|R|  4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen.|2
03519|087|R|  Breast Cancer Res Treat 2004 May;85(2):151-9.|2
03519|088|R|4.Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of|2
03519|089|R|  tamoxifen sequential biotransformation by the human cytochrome P450 system|2
03519|090|R|  in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004|2
03519|091|R|  Sep;310(3):1062-75.|2
03519|092|R|5.Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen|2
03519|093|R|  (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast|2
03519|094|R|  cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother|2
03519|095|R|  Pharmacol 2005 May;55(5):471-8.|2
03519|096|R|6.Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, Nussler|5
03519|097|R|  A, Neuhaus P, Zanger UM, Eichelbaum M, Murdter TE. The influence of|5
03519|098|R|  CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent|5
03519|099|R|  antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol|5
03519|100|R|  2002 Aug;54(2):157-67.|5
03519|101|R|7.Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6|6
03519|102|R|  as a predictor of drug response. Clin Pharmacol Ther 2008 Jan;83(1):160-6.|6
03519|103|R|8.Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD. CYP2D6 polymorphisms|6
03519|104|R|  and the impact on tamoxifen therapy. J Pharm Sci 2007 Sep;96(9):2224-31.|6
03519|105|R|9.Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW,|2
03519|106|R|  Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM,|2
03519|107|R|  Desta Z, Nguyen A, Flockhart DA. Perez EA, Ingle JN. The impact of|2
03519|108|R|  cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.|2
03519|109|R|  Breast Cancer Res Treat 2007 Jan;101(1):113-21.|2
03519|110|R|10.Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C,|2
03519|111|R|   Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN.|2
03519|112|R|   Pharmacogenetics of tamoxifen biotransformation is associated with|2
03519|113|R|   clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005 Dec 20;|2
03519|114|R|   23(36):9312-8.|2
03519|115|R|11.Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P,|2
03519|116|R|   Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J,|2
03519|117|R|   Strick R, Beckmann MW, Koelbl H. Weinshilboum RM, Ingle JN, Eichelbaum M,|2
03519|118|R|   Schwab M, Brauch H. Association between CYP2D6 polymorphisms and outcomes|2
03519|119|R|   among women with early stage breast cancer treated with tamoxifen. JAMA|2
03519|120|R|   2009 Oct 7;302(13):1429-36.|2
03519|121|R|12.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
03519|122|R|   US Inc. September 25, 2018.|1
03519|123|R|13.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
03519|124|R|   Technologies January, 2017.|1
03519|125|R|14.Gradishar WJ, Anderson BO, Avraham J, etal. NCCN Clinical Practice|6
03519|126|R|   Guidelines in Oncology: Breast Cancer. Available at:|6
03519|127|R|   https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf September|6
03519|128|R|   6, 2019.|6
03519|129|R|15.Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC,|2
03519|130|R|   Paszat LF. Selective serotonin reuptake inhibitors and breast cancer|2
03519|131|R|   mortality in women receiving tamoxifen: a population based cohort study.|2
03519|132|R|   BMJ 2010 Feb 8;340:c693.|2
03519|133|R|16.Phan MT, Venitz J. Summary minutes of the Advisory Committee|1
03519|134|R|   Pharmaceutical Science Clinical Pharmacology Subcommittee. Available at:|1
03519|135|R|   http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4248m1.pdf October|1
03519|136|R|   18-19, 2006.|1
03519|137|R|17.Rahman NA. Personal communication. Division Director, Office of Clinical|1
03519|138|R|   Pharmacology, US Food and Drug Administration March 4, 2008.|1
03519|139|R|18.Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, Salter J,|2
03519|140|R|   Sestak I, Cuzick J, Dowsett M. CYP2D6 and UGT2B7 genotype and risk of|2
03519|141|R|   recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer|2
03519|142|R|   Inst 2012 Mar 21;104(6):452-60.|2
03519|143|R|19.Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R,|2
03519|144|R|   Dell'orto P, Biasi MO, Thurlimann B, Lyng MB, Ditzel HJ, Neven P, Debled|2
03519|145|R|   M, Maibach R, Price KN, Gelber RD, Coates AS. Goldhirsch A, Rae JM, Viale|2
03519|146|R|   G,. CYP2D6 genotype and tamoxifen response in postmenopausal women with|2
03519|147|R|   endocrine-responsive breast cancer: the breast international group 1-98|2
03519|148|R|   trial. J Natl Cancer Inst 2012 Mar 21;104(6):441-51.|2
03519|149|R|20.Kelly CM, Pritchard KI. CYP2D6 genotype as a marker for benefit of|6
03519|150|R|   adjuvant tamoxifen in postmenopausal women: lessons learned. J Natl|6
03519|151|R|   Cancer Inst 2012 Mar 21;104(6):427-8.|6
03519|152|R|21.Donneyong MM, Bykov K, Bosco-Levy P, Dong YH, Levin R, Gagne JJ. Risk of|2
03519|153|R|   mortality with concomitant use of tamoxifen and selective serotonin|2
03519|154|R|   reuptake inhibitors: multi-database cohort study. BMJ 2016 Sep 30;|2
03519|155|R|   354:i5014.|2
03519|156|R|22.Haque R, Shi J, Schottinger JE, Ahmed SA, Cheetham TC, Chung J, Avila C,|2
03519|157|R|   Kleinman K, Habel LA, Fletcher SW, Kwan ML. Tamoxifen and Antidepressant|2
03519|158|R|   Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors. J Natl|2
03519|159|R|   Cancer Inst 2016 Mar;108(3):.|2
03519|160|R|23.Cronin-Fenton DP, Damkier P, Lash TL. Metabolism and transport of|2
03519|161|R|   tamoxifen in relation to its effectiveness: new perspectives on an|2
03519|162|R|   ongoing controversy. Future Oncol 2014 Jan;10(1):107-22.|2
03519|163|R|24.Azoulay L, Dell'Aniello S, Huiart L, du Fort GG, Suissa S. Concurrent use|2
03519|164|R|   of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer|2
03519|165|R|   recurrence. Breast Cancer Res Treat 2011 Apr;126(3):695-703.|2
03519|166|R|25.Dezentje VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel|2
03519|167|R|   MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ. Effect of|2
03519|168|R|   concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer|2
03519|169|R|   recurrence in early-stage breast cancer. J Clin Oncol 2010 May 10;|2
03519|170|R|   28(14):2423-9.|2
03519|171|R|26.This information is based on an extract from the Certara Drug Interaction|6
03519|172|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03519|173|R|27.US Food and Drug Administration (FDA). Drug Development and Drug|1
03519|174|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03519|175|R|   at:|1
03519|176|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03519|177|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03519|178|R|   11/14/2017.|1
03519|179|R|28.Dehal SS, Kupfer D. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human|5
03519|180|R|   liver. Cancer Res 1997 Aug 15;57(16):3402-6.|5
03519|181|R|29.Goetz MP, Sangkuhl K, Guchelaar HJ, Schwab M, Province M, Whirl-Carrillo|6
03519|182|R|   M, Symmans WF, McLeod HL, Ratain MJ, Zembutsu H, Gaedigk A, van Schaik|6
03519|183|R|   RH, Ingle JN, Caudle KE, Klein TE. Clinical Pharmacogenetics|6
03519|184|R|   Implementation Consortium (CPIC) Guideline for CYP2D6  and Tamoxifen|6
03519|185|R|   Therapy. Clin Pharmacol Ther 2018 May;103(5):770-777.|6
03520|001|T|MONOGRAPH TITLE:  Tamoxifen/Select Moderate CYP2D6 Inhibitors|
03520|002|B||
03520|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03520|004|L|of severe adverse interaction.|
03520|005|B||
03520|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2D6 may inhibit the conversion of|
03520|007|A|tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2)  The role|
03520|008|A|of endoxifen in tamoxifen's efficacy has been debated and may involve a|
03520|009|A|minimum concentration level.(3-5)|
03520|010|B||
03520|011|E|CLINICAL EFFECTS:  Concurrent use of inhibitors of CYP2D6 may decrease the|
03520|012|E|effectiveness of tamoxifen in preventing breast cancer recurrence.|
03520|013|B||
03520|014|P|PREDISPOSING FACTORS:  Concurrent use of moderate CYP2D6 inhibitors in|
03520|015|P|patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers|
03520|016|P|should be avoided.  Patients who are CYP2D6 poor metabolizers lack CYP2D6|
03520|017|P|function and are not affected by CYP2D6 inhibition.|
03520|018|B||
03520|019|M|PATIENT MANAGEMENT:  Although data on this interaction are conflicting, it|
03520|020|M|may be prudent to use alternatives to CYP2D6 inhibitors when possible in|
03520|021|M|patients taking tamoxifen.  The US manufacturer of tamoxifen states that the|
03520|022|M|impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain|
03520|023|M|and makes no recommendation regarding coadministration with inhibitors of|
03520|024|M|CYP2D6.(12)  The manufacturer of paroxetine (a strong CYP2D6 inhibitor)|
03520|025|M|states that alternative agents with little or no CYP2D6 inhibition should be|
03520|026|M|considered.(13)|
03520|027|M|   The National Comprehensive Cancer Network's breast cancer guidelines|
03520|028|M|advises caution when coadministering strong CYP2D6 inhibitors with|
03520|029|M|tamoxifen.(14)|
03520|030|M|   If concurrent therapy is warranted, the risks versus benefits should be|
03520|031|M|discussed with the patient.|
03520|032|M|   Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected|
03520|033|M|to last at least 28 days after administration.(15)|
03520|034|B||
03520|035|D|DISCUSSION:  Some studies have suggested that administration of fluoxetine,|
03520|036|D|paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer|
03520|037|D|phenotype may result in a decrease in the formation of endoxifen (an active|
03520|038|D|metabolite of tamoxifen) and a shorter time to breast cancer|
03520|039|D|recurrence.(1-2,9)|
03520|040|D|   A retrospective study of 630 breast cancer patients found an increasing|
03520|041|D|risk of breast cancer mortality with increasing durations of|
03520|042|D|coadministration of tamoxifen and paroxetine.  In the adjusted analysis,|
03520|043|D|absolute increases of 25%, 50%, and 75% in the proportion of time of|
03520|044|D|overlapping use of tamoxifen with paroxetine was associated with 24%, 54%,|
03520|045|D|and 91% increase in the risk of death from breast cancer, respectively.(16)|
03520|046|D|   The CYP2D6 genotype of the patient may have a role in the effects of this|
03520|047|D|interaction.  Patients with wild-type CYP2D6 genotype may be affected to a|
03520|048|D|greater extent by this interaction.  Patients with a variant CYP2D6 genotype|
03520|049|D|may have lower baseline levels of endoxifen and may be affected to a lesser|
03520|050|D|extent by this interaction.(6-10)|
03520|051|D|   In a retrospective review, 1,325 patients treated with tamoxifen for|
03520|052|D|breast cancer were classified as being poor 2D6 metabolizers (lacking|
03520|053|D|functional CYP2D6 enzymes), intermediate metabolizers (heterozygous|
03520|054|D|alleles), or extensive metabolizers (possessing 2 functional alleles).|
03520|055|D|After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%,|
03520|056|D|20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and|
03520|057|D|poor metabolizers, respectively.(11)|
03520|058|D|   In October of 2006, the Advisory Committee Pharmaceutical Science,|
03520|059|D|Clinical Pharmacology Subcommittee of the US Food and Drug Administration|
03520|060|D|recommended that the US tamoxifen labeling be updated to include information|
03520|061|D|about the increased risk of breast cancer recurrence in poor CYP2D6|
03520|062|D|metabolizers (either by genotype or drug interaction).(17-18)  The labeling|
03520|063|D|changes were never made due to ongoing uncertainty about the effects of|
03520|064|D|CYP2D6 genotypes on tamoxifen efficacy.|
03520|065|D|   In contrast to the above information, two studies have shown no|
03520|066|D|relationship between CYP2D6 genotype and breast cancer outcome.(19-21)  As|
03520|067|D|well, a number of studies found no association between use of CYP2D6|
03520|068|D|inhibitors and/or antidepressants in patients on tamoxifen and breast cancer|
03520|069|D|recurrence,(22-26) though the studies were limited by problematic selection|
03520|070|D|of CYP2D6 inhibitors and short follow-up.|
03520|071|D|   A single dose of rolapitant increased dextromethorphan, a CYP2D6|
03520|072|D|substrate, about 3-fold on days 8 and day 22 following administration.|
03520|073|D|Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single|
03520|074|D|dose rolapitant.  The inhibitory effects of rolapitant on CYP2D6 are|
03520|075|D|expected to persist beyond 28 days.(15)|
03520|076|D|   Moderate CYP2D6 inhibitors that prolong the QT interval include|
03520|077|D|adagrasib, dronedarone, levomethadone, and quinine.(27-28)|
03520|078|B||
03520|079|R|REFERENCES:|
03520|080|B||
03520|081|R|1.Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes|2
03520|082|R|  DF, Desta Z, Flockhart DA. Active tamoxifen metabolite plasma|2
03520|083|R|  concentrations after coadministration of tamoxifen and the selective|2
03520|084|R|  serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003 Dec 3;|2
03520|085|R|  95(23):1758-64.|2
03520|086|R|2.Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li|2
03520|087|R|  L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S,|2
03520|088|R|  Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype,|2
03520|089|R|  antidepressant use, and tamoxifen metabolism during adjuvant breast cancer|2
03520|090|R|  treatment. J Natl Cancer Inst 2005 Jan 5;97(1):30-9.|2
03520|091|R|3.Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z,|2
03520|092|R|  Flockhart DA, Skaar TC. Pharmacological characterization of|2
03520|093|R|  4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen.|2
03520|094|R|  Breast Cancer Res Treat 2004 May;85(2):151-9.|2
03520|095|R|4.Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of|2
03520|096|R|  tamoxifen sequential biotransformation by the human cytochrome P450 system|2
03520|097|R|  in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004|2
03520|098|R|  Sep;310(3):1062-75.|2
03520|099|R|5.Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen|2
03520|100|R|  (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast|2
03520|101|R|  cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother|2
03520|102|R|  Pharmacol 2005 May;55(5):471-8.|2
03520|103|R|6.Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, Nussler|5
03520|104|R|  A, Neuhaus P, Zanger UM, Eichelbaum M, Murdter TE. The influence of|5
03520|105|R|  CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent|5
03520|106|R|  antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol|5
03520|107|R|  2002 Aug;54(2):157-67.|5
03520|108|R|7.Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6|6
03520|109|R|  as a predictor of drug response. Clin Pharmacol Ther 2008 Jan;83(1):160-6.|6
03520|110|R|8.Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD. CYP2D6 polymorphisms|6
03520|111|R|  and the impact on tamoxifen therapy. J Pharm Sci 2007 Sep;96(9):2224-31.|6
03520|112|R|9.Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW,|2
03520|113|R|  Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM,|2
03520|114|R|  Desta Z, Nguyen A, Flockhart DA. Perez EA, Ingle JN. The impact of|2
03520|115|R|  cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.|2
03520|116|R|  Breast Cancer Res Treat 2007 Jan;101(1):113-21.|2
03520|117|R|10.Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C,|2
03520|118|R|   Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN.|2
03520|119|R|   Pharmacogenetics of tamoxifen biotransformation is associated with|2
03520|120|R|   clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005 Dec 20;|2
03520|121|R|   23(36):9312-8.|2
03520|122|R|11.Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P,|2
03520|123|R|   Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J,|2
03520|124|R|   Strick R, Beckmann MW, Koelbl H. Weinshilboum RM, Ingle JN, Eichelbaum M,|2
03520|125|R|   Schwab M, Brauch H. Association between CYP2D6 polymorphisms and outcomes|2
03520|126|R|   among women with early stage breast cancer treated with tamoxifen. JAMA|2
03520|127|R|   2009 Oct 7;302(13):1429-36.|2
03520|128|R|12.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
03520|129|R|   US Inc. September 25, 2018.|1
03520|130|R|13.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
03520|131|R|   Technologies January, 2017.|1
03520|132|R|14.Gradishar WJ, Anderson BO, Avraham J, etal. NCCN Clinical Practice|6
03520|133|R|   Guidelines in Oncology: Breast Cancer. Available at:|6
03520|134|R|   https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf September|6
03520|135|R|   6, 2019.|6
03520|136|R|15.Varubi (rolapitant) US prescribing information. Tesaro Inc. August, 2020.|1
03520|137|R|16.Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC,|2
03520|138|R|   Paszat LF. Selective serotonin reuptake inhibitors and breast cancer|2
03520|139|R|   mortality in women receiving tamoxifen: a population based cohort study.|2
03520|140|R|   BMJ 2010 Feb 8;340:c693.|2
03520|141|R|17.Phan MT, Venitz J. Summary minutes of the Advisory Committee|1
03520|142|R|   Pharmaceutical Science Clinical Pharmacology Subcommittee. Available at:|1
03520|143|R|   http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4248m1.pdf October|1
03520|144|R|   18-19, 2006.|1
03520|145|R|18.Rahman NA. Personal communication. Division Director, Office of Clinical|1
03520|146|R|   Pharmacology, US Food and Drug Administration March 4, 2008.|1
03520|147|R|19.Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, Salter J,|2
03520|148|R|   Sestak I, Cuzick J, Dowsett M. CYP2D6 and UGT2B7 genotype and risk of|2
03520|149|R|   recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer|2
03520|150|R|   Inst 2012 Mar 21;104(6):452-60.|2
03520|151|R|20.Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R,|2
03520|152|R|   Dell'orto P, Biasi MO, Thurlimann B, Lyng MB, Ditzel HJ, Neven P, Debled|2
03520|153|R|   M, Maibach R, Price KN, Gelber RD, Coates AS. Goldhirsch A, Rae JM, Viale|2
03520|154|R|   G,. CYP2D6 genotype and tamoxifen response in postmenopausal women with|2
03520|155|R|   endocrine-responsive breast cancer: the breast international group 1-98|2
03520|156|R|   trial. J Natl Cancer Inst 2012 Mar 21;104(6):441-51.|2
03520|157|R|21.Kelly CM, Pritchard KI. CYP2D6 genotype as a marker for benefit of|6
03520|158|R|   adjuvant tamoxifen in postmenopausal women: lessons learned. J Natl|6
03520|159|R|   Cancer Inst 2012 Mar 21;104(6):427-8.|6
03520|160|R|22.Donneyong MM, Bykov K, Bosco-Levy P, Dong YH, Levin R, Gagne JJ. Risk of|2
03520|161|R|   mortality with concomitant use of tamoxifen and selective serotonin|2
03520|162|R|   reuptake inhibitors: multi-database cohort study. BMJ 2016 Sep 30;|2
03520|163|R|   354:i5014.|2
03520|164|R|23.Haque R, Shi J, Schottinger JE, Ahmed SA, Cheetham TC, Chung J, Avila C,|2
03520|165|R|   Kleinman K, Habel LA, Fletcher SW, Kwan ML. Tamoxifen and Antidepressant|2
03520|166|R|   Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors. J Natl|2
03520|167|R|   Cancer Inst 2016 Mar;108(3):.|2
03520|168|R|24.Cronin-Fenton DP, Damkier P, Lash TL. Metabolism and transport of|2
03520|169|R|   tamoxifen in relation to its effectiveness: new perspectives on an|2
03520|170|R|   ongoing controversy. Future Oncol 2014 Jan;10(1):107-22.|2
03520|171|R|25.Azoulay L, Dell'Aniello S, Huiart L, du Fort GG, Suissa S. Concurrent use|2
03520|172|R|   of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer|2
03520|173|R|   recurrence. Breast Cancer Res Treat 2011 Apr;126(3):695-703.|2
03520|174|R|26.Dezentje VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel|2
03520|175|R|   MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ. Effect of|2
03520|176|R|   concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer|2
03520|177|R|   recurrence in early-stage breast cancer. J Clin Oncol 2010 May 10;|2
03520|178|R|   28(14):2423-9.|2
03520|179|R|27.This information is based on an extract from the Certara Drug Interaction|6
03520|180|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03520|181|R|28.US Food and Drug Administration (FDA). Drug Development and Drug|1
03520|182|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03520|183|R|   at:|1
03520|184|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03520|185|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03520|186|R|   11/14/2017.|1
03520|187|R|29.Dehal SS, Kupfer D. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human|5
03520|188|R|   liver. Cancer Res 1997 Aug 15;57(16):3402-6.|5
03520|189|R|30.Goetz MP, Sangkuhl K, Guchelaar HJ, Schwab M, Province M, Whirl-Carrillo|6
03520|190|R|   M, Symmans WF, McLeod HL, Ratain MJ, Zembutsu H, Gaedigk A, van Schaik|6
03520|191|R|   RH, Ingle JN, Caudle KE, Klein TE. Clinical Pharmacogenetics|6
03520|192|R|   Implementation Consortium (CPIC) Guideline for CYP2D6  and Tamoxifen|6
03520|193|R|   Therapy. Clin Pharmacol Ther 2018 May;103(5):770-777.|6
03521|001|T|MONOGRAPH TITLE:  Tamoxifen/Hydroxychloroquine|
03521|002|B||
03521|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03521|004|L|take action as needed.|
03521|005|B||
03521|006|A|MECHANISM OF ACTION:  Hydroxychloroquine, a weak inhibitor of CYP2D6, may|
03521|007|A|inhibit the conversion of tamoxifen to endoxifen (an active metabolite of|
03521|008|A|tamoxifen).(1-2)  The role of endoxifen in tamoxifen's efficacy has been|
03521|009|A|debated and may involve a minimum concentration level.(3-5)|
03521|010|B||
03521|011|E|CLINICAL EFFECTS:  Concurrent use of hydroxychloroquine may decrease the|
03521|012|E|effectiveness of tamoxifen in preventing breast cancer recurrence.|
03521|013|B||
03521|014|P|PREDISPOSING FACTORS:  Concurrent use of weak CYP2D6 inhibitors in patients|
03521|015|P|who are CYP2D6 intermediate metabolizers should be avoided.  Patients who|
03521|016|P|are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by|
03521|017|P|CYP2D6 inhibition.|
03521|018|B||
03521|019|M|PATIENT MANAGEMENT:  Although data on this interaction are conflicting, it|
03521|020|M|may be prudent to use alternatives to CYP2D6 inhibitors when possible in|
03521|021|M|patients taking tamoxifen.  The US manufacturer of tamoxifen states that the|
03521|022|M|impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain|
03521|023|M|and makes no recommendation regarding coadministration with inhibitors of|
03521|024|M|CYP2D6.(12)  The manufacturer of paroxetine (a strong CYP2D6 inhibitor)|
03521|025|M|states that alternative agents with little or no CYP2D6 inhibition should be|
03521|026|M|considered.(13)|
03521|027|M|   The National Comprehensive Cancer Network's breast cancer guidelines|
03521|028|M|advises caution when coadministering strong CYP2D6 inhibitors with|
03521|029|M|tamoxifen.(14)|
03521|030|M|   If concurrent therapy is warranted, the risks versus benefits should be|
03521|031|M|discussed with the patient.|
03521|032|B||
03521|033|D|DISCUSSION:  Some studies have suggested that administration of fluoxetine,|
03521|034|D|paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer|
03521|035|D|phenotype may result in a decrease in the formation of endoxifen (an active|
03521|036|D|metabolite of tamoxifen) and a shorter time to breast cancer|
03521|037|D|recurrence.(1-2,9)|
03521|038|D|   A retrospective study of 630 breast cancer patients found an increasing|
03521|039|D|risk of breast cancer mortality with increasing durations of|
03521|040|D|coadministration of tamoxifen and paroxetine.  In the adjusted analysis,|
03521|041|D|absolute increases of 25%, 50%, and 75% in the proportion of time of|
03521|042|D|overlapping use of tamoxifen with paroxetine was associated with 24%, 54%,|
03521|043|D|and 91% increase in the risk of death from breast cancer, respectively.(15)|
03521|044|D|   The CYP2D6 genotype of the patient may have a role in the effects of this|
03521|045|D|interaction.  Patients with wild-type CYP2D6 genotype may be affected to a|
03521|046|D|greater extent by this interaction.  Patients with a variant CYP2D6 genotype|
03521|047|D|may have lower baseline levels of endoxifen and may be affected to a lesser|
03521|048|D|extent by this interaction.(6-10)|
03521|049|D|   In a retrospective review, 1,325 patients treated with tamoxifen for|
03521|050|D|breast cancer were classified as being poor 2D6 metabolizers (lacking|
03521|051|D|functional CYP2D6 enzymes), intermediate metabolizers (heterozygous|
03521|052|D|alleles), or extensive metabolizers (possessing 2 functional alleles).|
03521|053|D|After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%,|
03521|054|D|20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and|
03521|055|D|poor metabolizers, respectively.(11)|
03521|056|D|   In October of 2006, the Advisory Committee Pharmaceutical Science,|
03521|057|D|Clinical Pharmacology Subcommittee of the US Food and Drug Administration|
03521|058|D|recommended that the US tamoxifen labeling be updated to include information|
03521|059|D|about the increased risk of breast cancer recurrence in poor CYP2D6|
03521|060|D|metabolizers (either by genotype or drug interaction).(16-17)  The labeling|
03521|061|D|changes were never made due to ongoing uncertainty about the effects of|
03521|062|D|CYP2D6 genotypes on tamoxifen efficacy.|
03521|063|D|   In contrast to the above information, two studies have shown no|
03521|064|D|relationship between CYP2D6 genotype and breast cancer outcome.(18-20)  As|
03521|065|D|well, a number of studies found no association between use of CYP2D6|
03521|066|D|inhibitors and/or antidepressants in patients on tamoxifen and breast cancer|
03521|067|D|recurrence,(21-25) though the studies were limited by problematic selection|
03521|068|D|of CYP2D6 inhibitors and short follow-up.|
03521|069|B||
03521|070|R|REFERENCES:|
03521|071|B||
03521|072|R|1.Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes|2
03521|073|R|  DF, Desta Z, Flockhart DA. Active tamoxifen metabolite plasma|2
03521|074|R|  concentrations after coadministration of tamoxifen and the selective|2
03521|075|R|  serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003 Dec 3;|2
03521|076|R|  95(23):1758-64.|2
03521|077|R|2.Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li|2
03521|078|R|  L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S,|2
03521|079|R|  Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype,|2
03521|080|R|  antidepressant use, and tamoxifen metabolism during adjuvant breast cancer|2
03521|081|R|  treatment. J Natl Cancer Inst 2005 Jan 5;97(1):30-9.|2
03521|082|R|3.Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z,|2
03521|083|R|  Flockhart DA, Skaar TC. Pharmacological characterization of|2
03521|084|R|  4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen.|2
03521|085|R|  Breast Cancer Res Treat 2004 May;85(2):151-9.|2
03521|086|R|4.Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of|2
03521|087|R|  tamoxifen sequential biotransformation by the human cytochrome P450 system|2
03521|088|R|  in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004|2
03521|089|R|  Sep;310(3):1062-75.|2
03521|090|R|5.Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen|2
03521|091|R|  (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast|2
03521|092|R|  cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother|2
03521|093|R|  Pharmacol 2005 May;55(5):471-8.|2
03521|094|R|6.Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, Nussler|5
03521|095|R|  A, Neuhaus P, Zanger UM, Eichelbaum M, Murdter TE. The influence of|5
03521|096|R|  CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent|5
03521|097|R|  antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol|5
03521|098|R|  2002 Aug;54(2):157-67.|5
03521|099|R|7.Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6|6
03521|100|R|  as a predictor of drug response. Clin Pharmacol Ther 2008 Jan;83(1):160-6.|6
03521|101|R|8.Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD. CYP2D6 polymorphisms|6
03521|102|R|  and the impact on tamoxifen therapy. J Pharm Sci 2007 Sep;96(9):2224-31.|6
03521|103|R|9.Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW,|2
03521|104|R|  Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM,|2
03521|105|R|  Desta Z, Nguyen A, Flockhart DA. Perez EA, Ingle JN. The impact of|2
03521|106|R|  cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.|2
03521|107|R|  Breast Cancer Res Treat 2007 Jan;101(1):113-21.|2
03521|108|R|10.Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C,|2
03521|109|R|   Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN.|2
03521|110|R|   Pharmacogenetics of tamoxifen biotransformation is associated with|2
03521|111|R|   clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005 Dec 20;|2
03521|112|R|   23(36):9312-8.|2
03521|113|R|11.Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P,|2
03521|114|R|   Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J,|2
03521|115|R|   Strick R, Beckmann MW, Koelbl H. Weinshilboum RM, Ingle JN, Eichelbaum M,|2
03521|116|R|   Schwab M, Brauch H. Association between CYP2D6 polymorphisms and outcomes|2
03521|117|R|   among women with early stage breast cancer treated with tamoxifen. JAMA|2
03521|118|R|   2009 Oct 7;302(13):1429-36.|2
03521|119|R|12.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
03521|120|R|   US Inc. September 25, 2018.|1
03521|121|R|13.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
03521|122|R|   Technologies January, 2017.|1
03521|123|R|14.Gradishar WJ, Anderson BO, Avraham J, etal. NCCN Clinical Practice|6
03521|124|R|   Guidelines in Oncology: Breast Cancer. Available at:|6
03521|125|R|   https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf September|6
03521|126|R|   6, 2019.|6
03521|127|R|15.Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC,|2
03521|128|R|   Paszat LF. Selective serotonin reuptake inhibitors and breast cancer|2
03521|129|R|   mortality in women receiving tamoxifen: a population based cohort study.|2
03521|130|R|   BMJ 2010 Feb 8;340:c693.|2
03521|131|R|16.Phan MT, Venitz J. Summary minutes of the Advisory Committee|1
03521|132|R|   Pharmaceutical Science Clinical Pharmacology Subcommittee. Available at:|1
03521|133|R|   http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4248m1.pdf October|1
03521|134|R|   18-19, 2006.|1
03521|135|R|17.Rahman NA. Personal communication. Division Director, Office of Clinical|1
03521|136|R|   Pharmacology, US Food and Drug Administration March 4, 2008.|1
03521|137|R|18.Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, Salter J,|2
03521|138|R|   Sestak I, Cuzick J, Dowsett M. CYP2D6 and UGT2B7 genotype and risk of|2
03521|139|R|   recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer|2
03521|140|R|   Inst 2012 Mar 21;104(6):452-60.|2
03521|141|R|19.Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R,|2
03521|142|R|   Dell'orto P, Biasi MO, Thurlimann B, Lyng MB, Ditzel HJ, Neven P, Debled|2
03521|143|R|   M, Maibach R, Price KN, Gelber RD, Coates AS. Goldhirsch A, Rae JM, Viale|2
03521|144|R|   G,. CYP2D6 genotype and tamoxifen response in postmenopausal women with|2
03521|145|R|   endocrine-responsive breast cancer: the breast international group 1-98|2
03521|146|R|   trial. J Natl Cancer Inst 2012 Mar 21;104(6):441-51.|2
03521|147|R|20.Kelly CM, Pritchard KI. CYP2D6 genotype as a marker for benefit of|6
03521|148|R|   adjuvant tamoxifen in postmenopausal women: lessons learned. J Natl|6
03521|149|R|   Cancer Inst 2012 Mar 21;104(6):427-8.|6
03521|150|R|21.Donneyong MM, Bykov K, Bosco-Levy P, Dong YH, Levin R, Gagne JJ. Risk of|2
03521|151|R|   mortality with concomitant use of tamoxifen and selective serotonin|2
03521|152|R|   reuptake inhibitors: multi-database cohort study. BMJ 2016 Sep 30;|2
03521|153|R|   354:i5014.|2
03521|154|R|22.Haque R, Shi J, Schottinger JE, Ahmed SA, Cheetham TC, Chung J, Avila C,|2
03521|155|R|   Kleinman K, Habel LA, Fletcher SW, Kwan ML. Tamoxifen and Antidepressant|2
03521|156|R|   Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors. J Natl|2
03521|157|R|   Cancer Inst 2016 Mar;108(3):.|2
03521|158|R|23.Cronin-Fenton DP, Damkier P, Lash TL. Metabolism and transport of|2
03521|159|R|   tamoxifen in relation to its effectiveness: new perspectives on an|2
03521|160|R|   ongoing controversy. Future Oncol 2014 Jan;10(1):107-22.|2
03521|161|R|24.Azoulay L, Dell'Aniello S, Huiart L, du Fort GG, Suissa S. Concurrent use|2
03521|162|R|   of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer|2
03521|163|R|   recurrence. Breast Cancer Res Treat 2011 Apr;126(3):695-703.|2
03521|164|R|25.Dezentje VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel|2
03521|165|R|   MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ. Effect of|2
03521|166|R|   concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer|2
03521|167|R|   recurrence in early-stage breast cancer. J Clin Oncol 2010 May 10;|2
03521|168|R|   28(14):2423-9.|2
03521|169|R|26.This information is based on an extract from the Certara Drug Interaction|6
03521|170|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03521|171|R|27.US Food and Drug Administration (FDA). Drug Development and Drug|1
03521|172|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03521|173|R|   at:|1
03521|174|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03521|175|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03521|176|R|   11/14/2017.|1
03521|177|R|28.Goetz MP, Sangkuhl K, Guchelaar HJ, Schwab M, Province M, Whirl-Carrillo|6
03521|178|R|   M, Symmans WF, McLeod HL, Ratain MJ, Zembutsu H, Gaedigk A, van Schaik|6
03521|179|R|   RH, Ingle JN, Caudle KE, Klein TE. Clinical Pharmacogenetics|6
03521|180|R|   Implementation Consortium (CPIC) Guideline for CYP2D6  and Tamoxifen|6
03521|181|R|   Therapy. Clin Pharmacol Ther 2018 May;103(5):770-777.|6
03522|001|T|MONOGRAPH TITLE:  Tacrolimus/Tigecycline|
03522|002|B||
03522|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03522|004|L|take action as needed.|
03522|005|B||
03522|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown but may be|
03522|007|A|related to competitive inhibition of P-glycoprotein-mediated biliary|
03522|008|A|excretion of tigecycline and tacrolimus.(1)|
03522|009|B||
03522|010|E|CLINICAL EFFECTS:  Concurrent use of tigecycline may result in elevated|
03522|011|E|levels of and toxicity from tacrolimus, including nephrotoxicity,|
03522|012|E|neurotoxicity, and prolongation of the QTc interval and life-threatening|
03522|013|E|cardiac arrhythmias, including torsades de pointes.(2,3)|
03522|014|B||
03522|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03522|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03522|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03522|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03522|019|P|gender, or advanced age.(4)|
03522|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03522|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03522|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03522|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03522|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03522|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03522|026|P|dysfunction).(4)|
03522|027|B||
03522|028|M|PATIENT MANAGEMENT:  Monitor tacrolimus levels during and after therapy with|
03522|029|M|tigecycline.  The dosage of tacrolimus may need to be adjusted.(2,3)|
03522|030|M|   When concurrent therapy of tigecycline and tacrolimus is warranted,|
03522|031|M|consider obtaining serum calcium, magnesium, and potassium levels and|
03522|032|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03522|033|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03522|034|M|heartbeat, dizziness, or fainting.|
03522|035|B||
03522|036|D|DISCUSSION:  A 43-year-old kidney transplant recipient on tacrolimus 7 mg|
03522|037|D|daily with a trough level of 11.5 mcg/L was started on intravenous|
03522|038|D|tigecycline for a urinary tract infection.  Concomitant medications included|
03522|039|D|mycophenolate, prednisolone, insulin, amlodipine, cotrimoxazole, acyclovir|
03522|040|D|and diltiazem.  Tacrolimus trough level rose to 28.2 mcg/L after 6 days of|
03522|041|D|tigecycline and 43.6 mcg/L after 10 days, and potassium increased to 5.7|
03522|042|D|mmol/L.(5)|
03522|043|D|   A 51-year-old kidney transplant recipient on a stable dose of tacrolimus|
03522|044|D|was started on intravenous tigecycline for sepsis.  Her tacrolimus trough|
03522|045|D|level rose, and she required a reduction in tacrolimus dose.  After|
03522|046|D|tigecycline was discontinued, her tacrolimus levels became subtherapeutic|
03522|047|D|within one day and she resumed her previous dose of tacrolimus.(6)|
03522|048|D|   A 58-year-old kidney transplant recipient on tacrolimus 1.5 mg daily|
03522|049|D|received 2 weeks of intravenous tigecycline for Brucellosis.  His tacrolimus|
03522|050|D|levels and serum creatinine remain stable during concomitant therapy.(7)|
03522|051|B||
03522|052|R|REFERENCES:|
03522|053|B||
03522|054|R|1.Srinivas NR. Tigecycline and cyclosporine interaction-an interesting case|3
03522|055|R|  of biliary-excreted  drug enhancing the oral bioavailability of|3
03522|056|R|  cyclosporine. Eur J Clin Pharmacol 2009 May;65(5):543-4.|3
03522|057|R|2.Tygacil (tigecycline) Canadian prescribing information. Pfizer Canada ULC|1
03522|058|R|  April 21, 2020.|1
03522|059|R|3.Tygacil (tigecycline) UK summary of product characteristics. Pfizer|1
03522|060|R|  Limited April 26, 2021.|1
03522|061|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03522|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03522|063|R|  settings: a scientific statement from the American Heart Association and|6
03522|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03522|065|R|  2;55(9):934-47.|6
03522|066|R|5.Chow KM, Pang WF, Chan GCK, Leung CB, Szeto CC, Li PKT. Beware of drug|3
03522|067|R|  interaction between tigecycline and tacrolimus. Nephrology (Carlton) 2020|3
03522|068|R|  Jan;25(1):99-100.|3
03522|069|R|6.Pavan M, Chaudhari AP, Ranganth R. Altered bioavailability of tacrolimus|3
03522|070|R|  following intravenous administration of  tigecycline. Am J Kidney Dis 2011|3
03522|071|R|  Feb;57(2):354.|3
03522|072|R|7.Ting IW, Ho MW, Sung YJ, Tien N, Chi CY, Ho HC, Huang CC. Brucellosis in a|3
03522|073|R|  renal transplant recipient. Transpl Infect Dis 2013 Oct;15(5):E191-5.|3
03523|001|T|MONOGRAPH TITLE:  Cyclosporine/Tigecycline|
03523|002|B||
03523|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03523|004|L|take action as needed.|
03523|005|B||
03523|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown but may be|
03523|007|A|related to competitive inhibition of P-glycoprotein-mediated biliary|
03523|008|A|excretion of tigecycline and cyclosporine.(1)|
03523|009|B||
03523|010|E|CLINICAL EFFECTS:  Concurrent use of tigecycline may result in elevated|
03523|011|E|levels of and toxicity from cyclosporine, including nephrotoxicity.(2,3)|
03523|012|B||
03523|013|P|PREDISPOSING FACTORS:  None determined.|
03523|014|B||
03523|015|M|PATIENT MANAGEMENT:  Monitor cyclosporine levels during and after therapy|
03523|016|M|with tigecycline.  The dosage of cyclosporine may need to be adjusted.(2,3)|
03523|017|B||
03523|018|D|DISCUSSION:  A 61-year-old renal transplant recipient on cyclosporine 120 mg|
03523|019|D|daily was started on intravenous tigecycline for a urinary tract infection.|
03523|020|D|Cyclosporine levels and serum creatinine rose markedly and the dose of|
03523|021|D|cyclosporine was reduced by 50%.  After tigecycline was discontinued for 3|
03523|022|D|days, the dose of cyclosporine had to be increased back to 120 mg daily to|
03523|023|D|maintain therapeutic levels.(4)|
03523|024|B||
03523|025|R|REFERENCES:|
03523|026|B||
03523|027|R|1.Srinivas NR. Tigecycline and cyclosporine interaction-an interesting case|3
03523|028|R|  of biliary-excreted  drug enhancing the oral bioavailability of|3
03523|029|R|  cyclosporine. Eur J Clin Pharmacol 2009 May;65(5):543-4.|3
03523|030|R|2.Tygacil (tigecycline) Canadian prescribing information. Pfizer Canada ULC|1
03523|031|R|  April 21, 2020.|1
03523|032|R|3.Tygacil (tigecycline) UK summary of product characteristics. Pfizer|1
03523|033|R|  Limited April 26, 2021.|1
03523|034|R|4.Stumpf AN, Schmidt C, Hiddemann W, Gerbitz A. High serum concentrations of|3
03523|035|R|  cyclosporin related to administration of tigecycline. Eur J Clin Pharmacol|3
03523|036|R|  2009 Jan;65(1):101-3.|3
03524|001|T|MONOGRAPH TITLE:  Atorvastatin/Ketoconazole; Posaconazole|
03524|002|B||
03524|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03524|004|L|of severe adverse interaction.|
03524|005|B||
03524|006|A|MECHANISM OF ACTION:  Ketoconazole(1) and posaconazole(2,3) may inhibit the|
03524|007|A|metabolism of atorvastatin(4) by CYP3A4.|
03524|008|B||
03524|009|E|CLINICAL EFFECTS:  Concurrent administration of ketoconazole or posaconazole|
03524|010|E|may result in increased levels of atorvastatin, which may result in an|
03524|011|E|increased risk of rhabdomyolysis.|
03524|012|B||
03524|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03524|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03524|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03524|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03524|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03524|018|P|transporter OATP1B1 may have increased statin concentrations and be|
03524|019|P|predisposed to myopathy or rhabdomyolysis.|
03524|020|B||
03524|021|M|PATIENT MANAGEMENT:  The manufacturer of posaconazole(2,3) states that|
03524|022|M|atorvastatin is contraindicated.  However, the manufacturer of atorvastatin|
03524|023|M|states that patients receiving ketoconazole or posaconazole should use the|
03524|024|M|lowest dose necessary of atorvastatin,(4) and the manufacturer of|
03524|025|M|ketoconazole states that coadministration with atorvastatin should be done|
03524|026|M|with caution.(1)|
03524|027|B||
03524|028|D|DISCUSSION:  In a study, itraconazole (200 mg daily for 4 days) increased|
03524|029|D|the area-under-curve (AUC) and maximum concentration (Cmax) of atorvastatin|
03524|030|D|(40 mg single dose) by 3.3-fold and 20%, respectively.(4)|
03524|031|D|   In a randomized, double-blind, cross-over study, administration of|
03524|032|D|atorvastatin (40 mg single dose) on day 4 of itraconazole (200 mg daily X 5|
03524|033|D|days) increased atorvastatin AUC and half-life (T1/2) 3-fold.  There were no|
03524|034|D|significant change in atorvastatin Cmax.  Atorvastatin lactone AUC, Cmax,|
03524|035|D|and T1/2 increased 4-fold, 2-fold, and 2-fold respectively.  The AUC of|
03524|036|D|active and total HMG-CoA reductase inhibitors increased 1.6-fold and|
03524|037|D|1.7-fold, respectively.(5)|
03524|038|D|   In healthy subjects, itraconazole increased atorvastatin T1/2, AUC, and|
03524|039|D|Cmax by 60%, 2.4-fold, and 47%, respectively.  Itraconazole had no effect on|
03524|040|D|pravastatin pharmacokinetics.(6)|
03524|041|D|   In a study in 18 healthy subjects, itraconazole (400 mg) increased the|
03524|042|D|Cmax, AUC, and half-life of a single dose of atorvastatin (20 mg) by 38%,|
03524|043|D|150%, 30%, respectively.(7)|
03524|044|B||
03524|045|R|REFERENCES:|
03524|046|B||
03524|047|R|1.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
03524|048|R|  Pharmaceuticals February, 2014.|1
03524|049|R|2.Noxafil (posaconazole) UK summary of product characteristics.|1
03524|050|R|  Schering-Plough Ltd. January, 2022.|1
03524|051|R|3.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
03524|052|R|  January, 2022.|1
03524|053|R|4.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
03524|054|R|  2020.|1
03524|055|R|5.Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the|2
03524|056|R|  pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998 Jul;|2
03524|057|R|  64(1):58-65.|2
03524|058|R|6.Jacobson TA. Comparative pharmacokinetic interaction profiles of|2
03524|059|R|  pravastatin, simvastatin, and atorvastatin when coadministered with|2
03524|060|R|  cytochrome P450 inhibitors. Am J Cardiol 2004 Nov 1;94(9):1140-6.|2
03524|061|R|7.Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P.|2
03524|062|R|  Itraconazole alters the pharmacokinetics of atorvastatin to a greater|2
03524|063|R|  extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000|2
03524|064|R|  Oct;68(4):391-400.|2
03525|001|T|MONOGRAPH TITLE:  Fenfluramine/Strong CYP1A2, CYP2B6 or CYP3A4 Inducers|
03525|002|B||
03525|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03525|004|L|of severe adverse interaction.|
03525|005|B||
03525|006|A|MECHANISM OF ACTION:  Strong inducers of CYP1A2, CYP2B6, or CYP3A4 may|
03525|007|A|increase the metabolism of fenfluramine.(1)|
03525|008|A|   Over 75% of fenfluramine is metabolized to norfenfluramine prior to|
03525|009|A|elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.  CYP2C9, CYP2C19, and|
03525|010|A|CYP3A4 play a minor role in fenfluramine metabolism.(1)|
03525|011|B||
03525|012|E|CLINICAL EFFECTS:  Concurrent use of agents that are strong inducers of|
03525|013|E|CYP1A2, CYP2B6, or CYP3A4 may result in decreased levels and effectiveness|
03525|014|E|of fenfluramine.(1)|
03525|015|B||
03525|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03525|017|P|of the inducer for longer than 1-2 weeks.|
03525|018|B||
03525|019|M|PATIENT MANAGEMENT:  The manufacturer of fenfluramine recommends avoiding|
03525|020|M|coadministration with strong CYP1A2, CYP2B6, or CYP3A4 inducers.  Patients|
03525|021|M|who must receive concurrent therapy should be monitored for decreased|
03525|022|M|efficacy and may require increased dosages of fenfluramine, not to exceed|
03525|023|M|the maximum fenfluramine dosages below.(1)|
03525|024|M|   The maximum daily dose for patients with concomitant stiripentol and|
03525|025|M|clobazam is 17 mg.(1)|
03525|026|M|   The maximum daily dose for patients without concomitant stiripentol is 26|
03525|027|M|mg.(1)|
03525|028|M|   If a strong CYP1A2, CYP2B6, or CYP3A4 inducer is discontinued, gradually|
03525|029|M|lower the fenfluramine dosage to the dose administered before initiation of|
03525|030|M|the inducer.(1)|
03525|031|B||
03525|032|D|DISCUSSION:  In a study with healthy volunteers, steady-state rifampin (a|
03525|033|D|CYP1A2, CYP2B6, and CYP3A4 inducer) 600 mg daily decreased the area-under|
03525|034|D|curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4|
03525|035|D|mg/kg by 58% and 40%, respectively, and increased the AUC and Cmax of|
03525|036|D|norfenfluramine by 50% and 13%, respectively.(1)|
03525|037|D|   Strong inducers of CYP1A2, CYP2B6, or CYP3A4 linked to this monograph|
03525|038|D|include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide,|
03525|039|D|fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin,|
03525|040|D|primidone, rifampin, and rifapentine.(1-3)|
03525|041|B||
03525|042|R|REFERENCES:|
03525|043|B||
03525|044|R|1.Fintepla (fenfluramine) US prescribing information. Zogenix Inc. January|1
03525|045|R|  2023.|1
03525|046|R|2.This information is based on an extract from the Certara Drug Interaction|6
03525|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03525|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03525|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03525|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03525|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03525|052|R|  11/14/2017.|1
03526|001|T|MONOGRAPH TITLE:  Selected Cephalosporins/Long Acting Antacids; H2s;PPIs|
03526|002|B||
03526|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03526|004|L|of severe adverse interaction.|
03526|005|B||
03526|006|A|MECHANISM OF ACTION:  Absorption of oral cefpodoxime or cefuroxime may be|
03526|007|A|reduced in patients receiving concomitant treatment with acid reducing|
03526|008|A|agents.(1-5)|
03526|009|B||
03526|010|E|CLINICAL EFFECTS:  Antibiotic efficacy against organisms with a high minimum|
03526|011|E|inhibitory concentration (MIC) to cefpodoxime or cefuroxime could be|
03526|012|E|decreased.|
03526|013|B||
03526|014|P|PREDISPOSING FACTORS:  Taking cefpodoxime or cefuroxime on an empty stomach|
03526|015|P|magnifies this effect.|
03526|016|B||
03526|017|M|PATIENT MANAGEMENT:  If possible, avoid the use of H2 antagonists and proton|
03526|018|M|pump inhibitors(PPIs) in patients taking cefpodoxime or cefuroxime.|
03526|019|M|   If concurrent therapy is needed with antacids, H2 antagonists, or PPIs,|
03526|020|M|administer cefpodoxime or cefuroxime after eating to maximize oral|
03526|021|M|absorption.  Some vitamin preparations may contain sufficient quantities of|
03526|022|M|calcium and/or magnesium salts with antacid properties to interact as well.|
03526|023|B||
03526|024|D|DISCUSSION:  In a study of ten subjects, administration of cefpodoxime after|
03526|025|D|single dose famotidine 40 mg decreased both maximum concentration (Cmax) and|
03526|026|D|area-under-curve (AUC) by approximately 40 percent compared with|
03526|027|D|administration of cefpodoxime on an empty stomach.(3)|
03526|028|D|   In a study of 17 subjects, administration of cefpodoxime after single|
03526|029|D|dose ranitidine 150 mg decreased Cmax and AUC by approximately 40 percent|
03526|030|D|compared with administration of cefpodoxime on an empty stomach.(4)|
03526|031|D|   In a study performed prior to the introduction of PPIs, administration of|
03526|032|D|ranitidine 300 mg and sodium bicarbonate followed by cefuroxime taken on a|
03526|033|D|empty stomach lowered both Cmax and AUC of cefuroxime by approximately 40|
03526|034|D|per cent compared with administration of cefuroxime alone on an empty|
03526|035|D|stomach.  Postprandial administration of cefuroxime in subjects taking|
03526|036|D|ranitidine was similar to that of subjects taking cefuroxime on an empty|
03526|037|D|stomach.(5)|
03526|038|B||
03526|039|R|REFERENCES:|
03526|040|B||
03526|041|R|1.Vantin (cefpodoxime proxetil) US prescribing information. Pharmacia &|1
03526|042|R|  Upjohn Company April, 2007.|1
03526|043|R|2.Ceftin (cefuroxime axetil) US prescribing information. GlaxoSmithKline|1
03526|044|R|  January, 2010.|1
03526|045|R|3.Saathoff N, Lode H, Neider K, Depperman KM, Borner K, Koeppe P.|2
03526|046|R|  Pharmacokinetics of cefpodoxime proxetil and interactions with an antacid|2
03526|047|R|  and an  H2 receptor antagonist. Antimicrob Agents Chemother 1992 Apr;|2
03526|048|R|  36(4):796-800.|2
03526|049|R|4.Hughes GS, Heald DL, Barker KB, Patel RK, Spillers CR, Watts KC, Batts DH,|2
03526|050|R|  Euler AR. The effects of gastric pH and food on the pharmacokinetics of a|2
03526|051|R|  new oral cephalosporin, cefpodoxime proxetil. Clin Pharmacol Ther 1989|2
03526|052|R|  Dec;46(6):674-85.|2
03526|053|R|5.Sommers DK, van Wyk M, Moncrieff J, Schoeman HS. Influence of food and|2
03526|054|R|  reduced gastric acidity on the bioavailability of bacampicillin and|2
03526|055|R|  cefuroxime axetil. Br J Clin Pharmacol 1984 Oct;18(4):535-9.|2
03527|001|T|MONOGRAPH TITLE:  Triheptanoin/Orlistat|
03527|002|B||
03527|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03527|004|L|of severe adverse interaction.|
03527|005|B||
03527|006|A|MECHANISM OF ACTION:  Triheptanoin is hydrolyzed by pancreatic enzymes in|
03527|007|A|the intestines to heptanoate and glycerol, which are then absorbed.|
03527|008|A|Pancreatic lipase inhibitors (i.e., orlistat) can reduce the formation of|
03527|009|A|heptanoate from triheptanoin.(1)|
03527|010|B||
03527|011|E|CLINICAL EFFECTS:  Orlistat may reduce absorption of heptanoate, leading to|
03527|012|E|insufficient supplementation of medium-chain fatty acids.(1)|
03527|013|B||
03527|014|P|PREDISPOSING FACTORS:  None determined.|
03527|015|B||
03527|016|M|PATIENT MANAGEMENT:  The manufacturer of triheptanoin states that concurrent|
03527|017|M|use of pancreatic lipase inhibitors should be avoided.(1)|
03527|018|B||
03527|019|D|DISCUSSION:  Orlistat may decrease exposure to the triheptanoin metabolite,|
03527|020|D|heptanoate, and decrease the effectiveness of triheptanoin.(1)|
03527|021|B||
03527|022|R|REFERENCE:|
03527|023|B||
03527|024|R|1.Dojolvi (triheptanoin) US prescribing information. Ultragenyx|1
03527|025|R|  Pharmaceutical Inc. June, 2020.|1
03528|001|T|MONOGRAPH TITLE:  Ethinyl Estradiol (greater than 30 mcg)/Fostemsavir|
03528|002|B||
03528|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03528|004|L|is contraindicated and generally should not be dispensed or administered to|
03528|005|L|the same patient.|
03528|006|B||
03528|007|A|MECHANISM OF ACTION:  The mechanism of action has not been described.|
03528|008|B||
03528|009|E|CLINICAL EFFECTS:  Coadministration of ethinyl estradiol and fostemsavir may|
03528|010|E|increase the plasma concentrations and toxicities of ethinyl estradiol.(1)|
03528|011|B||
03528|012|P|PREDISPOSING FACTORS:  Patients with risk factors for thrombosis may be at|
03528|013|P|higher risk of adverse events, including those with advanced age, obesity|
03528|014|P|(BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable|
03528|015|P|states, history of venous thromboembolism, malignancy, and major surgery.|
03528|016|B||
03528|017|M|PATIENT MANAGEMENT:  The manufacturer of fostemsavir states that the daily|
03528|018|M|dose of ethinyl estradiol should not exceed 30 mcg when used in patients|
03528|019|M|concurrently on fostemsavir.(1)|
03528|020|B||
03528|021|D|DISCUSSION:  In a study, coadministration of ethinyl estradiol 30|
03528|022|D|mcg/norethindrone 1.5 mg once daily and fostemsavir 600 mg twice daily|
03528|023|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03528|024|D|ethinyl estradiol by 1.4-fold and 1.39-fold, respectively.  The exposure to|
03528|025|D|norethindrone was not significantly different.(1)|
03528|026|B||
03528|027|R|REFERENCE:|
03528|028|B||
03528|029|R|1.Rukobia (fostemsavir) US prescribing information. ViiV Healthcare July,|1
03528|030|R|  2020.|1
03529|001|T|MONOGRAPH TITLE:  Ethinyl Estradiol (less than or equal to 30|
03529|002|T|mcg)/Fostemsavir|
03529|003|B||
03529|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03529|005|L|take action as needed.|
03529|006|B||
03529|007|A|MECHANISM OF ACTION:  The mechanism of action has not been described.|
03529|008|B||
03529|009|E|CLINICAL EFFECTS:  Coadministration of ethinyl estradiol and fostemsavir may|
03529|010|E|increase the plasma concentrations and toxicities of ethinyl estradiol.(1)|
03529|011|B||
03529|012|P|PREDISPOSING FACTORS:  Patients with risk factors for thrombosis may be at|
03529|013|P|higher risk of adverse events, including those with advanced age, obesity|
03529|014|P|(BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable|
03529|015|P|states, history of venous thromboembolism, malignancy, and major surgery.|
03529|016|B||
03529|017|M|PATIENT MANAGEMENT:  The manufacturer of fostemsavir states that the daily|
03529|018|M|dose of ethinyl estradiol should not exceed 30 mcg when used in patients|
03529|019|M|concurrently on fostemsavir.(1)|
03529|020|B||
03529|021|D|DISCUSSION:  In a study, coadministration of ethinyl estradiol 30|
03529|022|D|mcg/norethindrone 1.5 mg once daily and fostemsavir 600 mg twice daily|
03529|023|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03529|024|D|ethinyl estradiol by 1.4-fold and 1.39-fold, respectively.  The exposure to|
03529|025|D|norethindrone was not significantly different.(1)|
03529|026|B||
03529|027|R|REFERENCE:|
03529|028|B||
03529|029|R|1.Rukobia (fostemsavir) US prescribing information. ViiV Healthcare July,|1
03529|030|R|  2020.|1
03530|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP3A4; CYP2C19 Substrates/Apalutamide|
03530|002|B||
03530|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03530|004|L|of severe adverse interaction.|
03530|005|B||
03530|006|A|MECHANISM OF ACTION:  Apalutamide may induce the metabolism of sensitive|
03530|007|A|CYP3A4 or CYP2C19 substrates.(1)|
03530|008|B||
03530|009|E|CLINICAL EFFECTS:  Concurrent use of apalutamide with drugs primarily|
03530|010|E|metabolized by CYP3A4 or CYP2C19 can result in lower exposure to these|
03530|011|E|medications.|
03530|012|B||
03530|013|P|PREDISPOSING FACTORS:  None determined.|
03530|014|B||
03530|015|M|PATIENT MANAGEMENT:  The US manufacturer of apalutamide recommends|
03530|016|M|substitution for medications primarily metabolized by CYP3A4 or CYP2C19 when|
03530|017|M|possible or evaluate for loss of activity.(1)|
03530|018|B||
03530|019|D|DISCUSSION:  Coadministration of apalutamide with single oral doses of|
03530|020|D|sensitive CYP substrates resulted in a 92% decrease in the area-under-curve|
03530|021|D|(AUC) of midazolam (a CYP3A4 substrate) and an 85% decrease in the AUC of|
03530|022|D|omeprazole (a CYP2C19 substrate).(1)|
03530|023|D|   Selected sensitive CYP3A4 substrates linked to this monograph:|
03530|024|D|astemizole, dihydroergotamine, ergonovine, ergotamine, and terfenadine.|
03530|025|D|   Selected sensitive CYP2C19 substrates linked to this monograph:|
03530|026|D|mephenytoin.(2,3)|
03530|027|B||
03530|028|R|REFERENCES:|
03530|029|B||
03530|030|R|1.Erleada (apalutamide) US prescribing information. Janssen Biotech, Inc.|1
03530|031|R|  July, 2021.|1
03530|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03530|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03530|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03530|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03530|036|R|  11/14/2017.|1
03530|037|R|3.FDA. CDER Application number: 205755 Zykadia (ceritinib) CLINICAL|1
03530|038|R|  PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S). available at:|1
03530|039|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205755Orig1s000Clin|1
03530|040|R|  PharmR.pdf March 25, 2014.|1
03531|001|T|MONOGRAPH TITLE:  Selected HMG-CoA Reductase Inhibitors/Fostemsavir|
03531|002|B||
03531|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03531|004|L|take action as needed.|
03531|005|B||
03531|006|A|MECHANISM OF ACTION:  Fostemsavir may inhibit OATP1B1 and OATP1B3, resulting|
03531|007|A|in decreased hepatocyte uptake and increased plasma concentrations of|
03531|008|A|atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and simvastatin.(1)|
03531|009|B||
03531|010|E|CLINICAL EFFECTS:  Concurrent use of fostemsavir may result in elevated|
03531|011|E|levels of and toxicity from atorvastatin, fluvastatin, pitavastatin,|
03531|012|E|rosuvastatin, or simvastatin, including rhabdomyolysis.(1)|
03531|013|B||
03531|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03531|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03531|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03531|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03531|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03531|019|P|transporter OATP1B1 may have increased statin concentrations and be|
03531|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on fluvastatin who are|
03531|021|P|CYP2C9 intermediate or poor metabolizers may have increased fluvastatin|
03531|022|P|concentrations and  risk of myopathy.  Patients on rosuvastatin with ABCG2|
03531|023|P|polymorphisms leading to decreased or poor BCRP transporter function may|
03531|024|P|have increased rosuvastatin concentrations and risk of myopathy.|
03531|025|B||
03531|026|M|PATIENT MANAGEMENT:  The manufacturer of fostemsavir states that the lowest|
03531|027|M|possible starting dose of statins should be used.  Patients should be|
03531|028|M|monitored for statin-associated adverse events.(1)|
03531|029|B||
03531|030|D|DISCUSSION:  In a study, fostemsavir 600 mg twice daily increased the|
03531|031|D|area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
03531|032|D|rosuvastatin 10 mg by 1.69-fold and 1.78-fold, respectively.(1)|
03531|033|B||
03531|034|R|REFERENCE:|
03531|035|B||
03531|036|R|1.Rukobia (fostemsavir) US prescribing information. ViiV Healthcare July,|1
03531|037|R|  2020.|1
03532|001|T|MONOGRAPH TITLE:  Fostemsavir/Strong CYP3A4 Inducers|
03532|002|B||
03532|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03532|004|L|is contraindicated and generally should not be dispensed or administered to|
03532|005|L|the same patient.|
03532|006|B||
03532|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03532|008|A|fostemsavir via this pathway.(1)|
03532|009|B||
03532|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
03532|011|E|result in reduced plasma levels of fostemsavir, resulting in loss of|
03532|012|E|virologic response.(1)|
03532|013|B||
03532|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03532|015|P|of the inducer for longer than 1-2 weeks.|
03532|016|B||
03532|017|M|PATIENT MANAGEMENT:  The concurrent use of fostemsavir with strong CYP3A4|
03532|018|M|inducers is contraindicated.(1)|
03532|019|B||
03532|020|D|DISCUSSION:  In an interaction study of rifampin 600 mg daily (a strong|
03532|021|D|CYP3A4 inducer) and a single 1200 mg dose of fostemsavir, concurrent use|
03532|022|D|decreased fostemsavir concentration maximum (Cmax) by 76% and|
03532|023|D|area-under-curve (AUC) by 82%.(1)|
03532|024|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
03532|025|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
03532|026|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
03532|027|D|rifampin, rifapentine and St John's Wort.(2,3)|
03532|028|B||
03532|029|R|REFERENCES:|
03532|030|B||
03532|031|R|1.Rukobia (fostemsavir) US prescribing information. ViiV Healthcare July,|1
03532|032|R|  2020.|1
03532|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03532|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03532|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03532|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03532|037|R|  11/14/2017.|1
03532|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
03532|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03533|001|T|MONOGRAPH TITLE:  Rasagiline; Oral Selegiline/Selected MAOIs|
03533|002|B||
03533|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03533|004|L|is contraindicated and generally should not be dispensed or administered to|
03533|005|L|the same patient.|
03533|006|B||
03533|007|A|MECHANISM OF ACTION:  Rasagiline and selegiline are monoamine oxidase (MAO)|
03533|008|A|inhibitors.|
03533|009|A|   Rasagiline is a selective, irreversible MAO-B inhibitor.  MAO-B|
03533|010|A|selectivity decreases as dose increases.(1)|
03533|011|A|   Selegiline has greater affinity for MAO-B at lower doses and inhibits|
03533|012|A|both MAO-A and MOA-B at higher antidepressant doses.(2)|
03533|013|B||
03533|014|E|CLINICAL EFFECTS:  Concurrent use of rasagiline or selegiline and MAO|
03533|015|E|inhibitors may result in additive MAO inhibition and toxicity, including|
03533|016|E|hypertensive crisis and serotonin syndrome.(1)|
03533|017|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03533|018|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03533|019|E|rigidity.|
03533|020|B||
03533|021|P|PREDISPOSING FACTORS:  None determined.|
03533|022|B||
03533|023|M|PATIENT MANAGEMENT:  The concurrent use of rasagiline with MAO inhibitors is|
03533|024|M|contraindicated.  At least 14 days should elapse between discontinuation of|
03533|025|M|rasagiline and initiation of MAO inhibitors.(1)|
03533|026|M|   The concurrent use of selegiline with agents that affect MAO is|
03533|027|M|contraindicated.  At least 14 days should elapse between discontinuation of|
03533|028|M|selegiline and initiation of any drug that is contraindicated due to risk of|
03533|029|M|hypertensive crisis and serotonin syndrome.(2)|
03533|030|B||
03533|031|D|DISCUSSION:  Rasagiline and selegiline are MAO inhibitors.  Concurrent use|
03533|032|D|with MAO inhibitors may result in a hypertensive crisis and serotonin|
03533|033|D|syndrome.(1,2)|
03533|034|D|   Metaxalone is a weak inhibitor of MAO.(3,4)|
03533|035|B||
03533|036|R|REFERENCES:|
03533|037|B||
03533|038|R|1.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
03533|039|R|  June, 2020.|1
03533|040|R|2.Emsam (selegline) US prescribing information. Somerset July, 2017.|1
03533|041|R|3.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03533|042|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03533|043|R|  Feb;34(2):346.e5-6.|3
03533|044|R|4.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03533|045|R|  Pfizer Inc. January, 2024.|1
03534|001|T|MONOGRAPH TITLE:  Icosapent Ethyl/Anticoagulant;Antiplatelet;Thrombolytic|
03534|002|B||
03534|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03534|004|L|take action as needed.|
03534|005|B||
03534|006|A|MECHANISM OF ACTION:  In vitro data suggests that fish oils can|
03534|007|A|competitively inhibit cyclooxygenase which decreases synthesis of|
03534|008|A|thromboxane A1 leading to a decrease in platelet aggregation.(1)|
03534|009|B||
03534|010|E|CLINICAL EFFECTS:  Concurrent use of anticoagulant, antiplatelet, or|
03534|011|E|thrombolytic agents increase bleeding risks.|
03534|012|B||
03534|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03534|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03534|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
03534|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03534|017|P|risk for bleeding (e.g. NSAIDs).|
03534|018|B||
03534|019|M|PATIENT MANAGEMENT:  If concurrent therapy is deemed medically necessary,|
03534|020|M|monitor patients receiving concurrent therapy for signs of blood loss,|
03534|021|M|including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
03534|022|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03534|023|M|    When applicable, perform agent-specific laboratory tests (e.g. INR,|
03534|024|M|aPTT) to monitor efficacy and safety of anticoagulation. Discontinue|
03534|025|M|anticoagulation in patients with active pathologic bleeding.|
03534|026|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03534|027|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03534|028|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03534|029|M|and/or swelling.|
03534|030|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03534|031|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
03534|032|M|initiating, altering the dose or discontinuing either drug.|
03534|033|B||
03534|034|D|DISCUSSION:  Specific studies with icosapent ethyl and affects on bleeding|
03534|035|D|risk have not been conducted.  Concurrent use of anticoagulant,|
03534|036|D|antiplatelet, or thrombolytic agents may increase bleeding risks by|
03534|037|D|impairing platelet function and prolonging bleeding time.(1)|
03534|038|D|   Several case reports have shown increased bleeding time and an increased|
03534|039|D|risk of adverse effects from concurrent therapy.(2,3,4)|
03534|040|D|   A randomized placebo controlled study of 40 people taking omega-3 fatty|
03534|041|D|acids and oral anticoagulants showed a significant prolongation in bleeding|
03534|042|D|time.(5)|
03534|043|B||
03534|044|R|REFERENCES:|
03534|045|B||
03534|046|R|1.Vascepa (icosapent ethyl) US prescribing information. Amarin Pharms|1
03534|047|R|  December, 2019.|1
03534|048|R|2.Jalili M, Dehpour AR. Extremely prolonged INR associated with warfarin in|3
03534|049|R|  combination with both trazodone  and omega-3 fatty acids. Arch Med Res|3
03534|050|R|  2007 Nov;38(8):901-4.|3
03534|051|R|3.McClaskey EM, Michalets EL. Subdural hematoma after a fall in an elderly|3
03534|052|R|  patient taking high-dose omega-3 fatty  acids with warfarin and aspirin:|3
03534|053|R|  case report and review of the literature. Pharmacotherapy 2007 Jan;|3
03534|054|R|  27(1):152-60.|3
03534|055|R|4.Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann|3
03534|056|R|  Pharmacother 2004 Jan;38(1):50-2.|3
03534|057|R|5.Smith P, Arnesen H, Opstad T, Dahl KH, Eritsland J. Influence of highly|2
03534|058|R|  concentrated n-3 fatty acids on serum lipids and hemostatic  variables in|2
03534|059|R|  survivors of myocardial infarction receiving either oral anticoagulants|2
03534|060|R|  or matching placebo. Thromb Res 1989 Mar 1;53(5):467-74.|2
03535|001|T|MONOGRAPH TITLE:  Raltegravir/Selected UGT1A1 Inducers|
03535|002|B||
03535|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03535|004|L|of severe adverse interaction.|
03535|005|B||
03535|006|A|MECHANISM OF ACTION:  Strong inducers of UDP-glucuronosyltransferase 1A1|
03535|007|A|(UGT1A1) may induce the metabolism of raltegravir.(1)|
03535|008|B||
03535|009|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine, fosphenytoin,|
03535|010|E|phenobarbital, phenytoin, or primidone may result in decreased levels and|
03535|011|E|effectiveness of raltegravir.(1)|
03535|012|B||
03535|013|P|PREDISPOSING FACTORS:  None determined.|
03535|014|B||
03535|015|M|PATIENT MANAGEMENT:  The US manufacturer of raltegravir(1) and Department of|
03535|016|M|Health and Human Services HIV guidelines(2) state that the concurrent use of|
03535|017|M|carbamazepine, fosphenytoin, phenobarbital, phenytoin, or primidone with|
03535|018|M|raltegravir is not recommended.|
03535|019|M|   The European AIDS Clinical Society HIV guidelines state that additional|
03535|020|M|monitoring or dose adjustment is likely to be required if these agents are|
03535|021|M|used concurrently.(3)|
03535|022|B||
03535|023|D|DISCUSSION:  Concurrent rifampin (600 mg daily) with raltegravir (400 mg|
03535|024|D|single dose) decreased raltegravir maximum concentration (Cmax),|
03535|025|D|area-under-curve (AUC), and minimum concentration (Cmin) by 38%, 40%, and|
03535|026|D|61%, respectively.  When raltegravir was given at a dosage of 800 mg twice|
03535|027|D|daily with rifampin (600 mg daily), the Cmax and AUC of raltegravir were|
03535|028|D|increased 62% and 27%, respectively, and the Cmin was decreased 53% when|
03535|029|D|compared to the administration of raltegravir (400 mg twice daily)|
03535|030|D|alone.(1,4)|
03535|031|D|   Strong inducers of UGT1A1, such as carbamazepine, fosphenytoin,|
03535|032|D|phenobarbital, phenytoin, and primidone are expected to produce similar|
03535|033|D|results.(1,2)|
03535|034|B||
03535|035|R|REFERENCES:|
03535|036|B||
03535|037|R|1.Isentress (raltegravir) US prescribing information. Merck & CO., Inc. May,|1
03535|038|R|  2021.|1
03535|039|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03535|040|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03535|041|R|  HIV. Department of Health and Human Services. Available at|6
03535|042|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03535|043|R|  new-guidelines June 13, 2021.|6
03535|044|R|3.European AIDS Clinical Society. EACS Guidelines version 10.0. Available|6
03535|045|R|  at: https://eacs.sanfordguide.com/ November 2019.|6
03535|046|R|4.Wenning LA, Hanley WD, Brainard DM, Petry AS, Ghosh K, Jin B, Mangin E,|2
03535|047|R|  Marbury TC, Berg JK, Chodakewitz JA, Stone JA, Gottesdiener KM, Wagner JA,|2
03535|048|R|  Iwamoto M. Effect of rifampin, a potent inducer of drug-metabolizing|2
03535|049|R|  enzymes, on the  pharmacokinetics of raltegravir. Antimicrob Agents|2
03535|050|R|  Chemother 2009 Jul;53(7):2852-6.|2
03536|001|T|MONOGRAPH TITLE:  Vemurafenib/Strong CYP3A4 Inhibitors that Prolong QT|
03536|002|B||
03536|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03536|004|L|of severe adverse interaction.|
03536|005|B||
03536|006|A|MECHANISM OF ACTION:  Vemurafenib is a substrate of CYP3A4.  Strong|
03536|007|A|inhibitors of CYP3A4 may inhibit the metabolism of vemurafenib.(1)|
03536|008|A|   Use of CYP3A4 inhibitors that prolong the QTc interval may result in|
03536|009|A|additive effects on the QTc interval.|
03536|010|B||
03536|011|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 that|
03536|012|E|prolongs the QTc interval may result in increased levels and toxicity from|
03536|013|E|vemurafenib, including additive QT prolongation and life-threatening cardiac|
03536|014|E|arrhythmias like torsades de pointes.(1)|
03536|015|B||
03536|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03536|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03536|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03536|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03536|020|P|female gender, or advanced age.(2)|
03536|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03536|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03536|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03536|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03536|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03536|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03536|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03536|028|B||
03536|029|M|PATIENT MANAGEMENT:  The manufacturer of vemurafenib states to avoid|
03536|030|M|concurrent administration with strong CYP3A4 inhibitors and replace these|
03536|031|M|drugs with alternative drugs whenever possible.(1)|
03536|032|M|   If concurrent therapy is warranted, monitor the patient for signs of|
03536|033|M|vemurafenib toxicity.  Consider dose reduction of vemurafenib if clinically|
03536|034|M|indicated.  Consider obtaining serum calcium, magnesium, and potassium|
03536|035|M|levels.  Correct any electrolyte abnormalities.  Instruct patients to report|
03536|036|M|any irregular heartbeat, dizziness, or fainting.|
03536|037|M|   Vemurafenib should not be initiated in patients taking medications known|
03536|038|M|to prolong the QT interval, patients having a baseline QTc greater than 500|
03536|039|M|msec, uncorrectable electrolyte abnormalities, or known long QT syndrome.(1)|
03536|040|M|   All patients receiving vemurafenib should undergo ECG testing at|
03536|041|M|baseline, after 15 days of treatment, monthly during the first 3 months of|
03536|042|M|treatment, and then every 3 months.  If a patient's QTc exceeds 500 msec|
03536|043|M|during treatment, vemurafenib should be discontinued and cardiac risk|
03536|044|M|factors for QT prolongation should be controlled.  Consider discontinuing|
03536|045|M|other medications known to prolong the QT interval at this time.  If the|
03536|046|M|patient's QTc decreases below 500 msec, vemurafenib may be introduced at a|
03536|047|M|lower dosage according to the current labeling recommendations.  If the|
03536|048|M|patient's QTc remains greater than 500 msec and increased >60 msec from|
03536|049|M|pre-treatment values after controlling cardiac risk factors for|
03536|050|M|prolongation, permanently discontinue vemurafenib.(1)|
03536|051|B||
03536|052|D|DISCUSSION:  A study of vemurafenib 960 mg twice daily with itraconazole 200|
03536|053|D|mg daily increased vemurafenib area-under-curve (AUC) by 40% with a similar|
03536|054|D|increase in concentration maximum (Cmax).(1)|
03536|055|D|   Vemurafenib is associated with concentration-dependent QTc interval|
03536|056|D|prolongation.  In the first month of treatment, the largest mean QTc change|
03536|057|D|was 12.8 msec (upper boundary of 90% CI:  14.9 msec).  In the first 6 months|
03536|058|D|of treatment, the largest mean QTc change was 15.1 msec (upper boundary of|
03536|059|D|90% CI:  17.7 msec).(1)|
03536|060|D|   Strong CYP3A4 inhibitors that prolong QT linked to this monograph|
03536|061|D|include:  adagrasib, ceritinib, clarithromycin, levoketoconazole,|
03536|062|D|lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin,|
03536|063|D|and voriconazole.(3,4)|
03536|064|B||
03536|065|R|REFERENCES:|
03536|066|B||
03536|067|R|1.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
03536|068|R|  November, 2017.|1
03536|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03536|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03536|071|R|  settings: a scientific statement from the American Heart Association and|6
03536|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03536|073|R|  2;55(9):934-47.|6
03536|074|R|3.This information is based on an extract from the Certara Drug Interaction|6
03536|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03536|076|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03536|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03536|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03536|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03536|080|R|  11/14/2017.|1
03537|001|T|MONOGRAPH TITLE:  Eliglustat/Dual CYP2D6 and CYP3A4 Inhibitors|
03537|002|B||
03537|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03537|004|L|of severe adverse interaction.|
03537|005|B||
03537|006|A|MECHANISM OF ACTION:  Dual inhibitors of both CYP3A4 and CYP2D6 may inhibit|
03537|007|A|the metabolism of eliglustat.(1)|
03537|008|A|   Berotralstat and dronedarone are moderate inhibitors of CYP3A4 and|
03537|009|A|CYP2D6, and tipranavir is a strong inhibitor of CYP3A4 and a moderate|
03537|010|A|inhibitor of CYP2D6.(4)|
03537|011|B||
03537|012|E|CLINICAL EFFECTS:  Concurrent use of an agent that is dual inhibitor of|
03537|013|E|CYP3A4 and CYP2D6 may result in elevated levels of and clinical effects of|
03537|014|E|eliglustat, including prolongation of the PR, QTc, and/or QRS intervals,|
03537|015|E|which may result in life-threatening cardiac arrhythmias.(1)|
03537|016|B||
03537|017|P|PREDISPOSING FACTORS:  If the patient has hepatic impairment, eliglustat|
03537|018|P|metabolism can be further inhibited.(1)|
03537|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03537|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03537|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03537|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03537|023|P|advanced age.(2)|
03537|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03537|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03537|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03537|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03537|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03537|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03537|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03537|031|B||
03537|032|M|PATIENT MANAGEMENT:  The concurrent use of eliglustat with dual inhibitors|
03537|033|M|of CYP3A4 and CYP2D6 in both extensive and intermediate CYP2D6 metabolizers|
03537|034|M|is contraindicated.(1)|
03537|035|M|   The concurrent use of eliglustat with strong inhibitors of CYP3A4 and|
03537|036|M|strong or moderate inhibitors of CYP2D6 is contraindicated.|
03537|037|M|   The concurrent use of eliglustat with moderate inhibitors of CYP3A4 and|
03537|038|M|strong or moderate inhibitors of CYP2D6 in extensive and intermediate CYP2D6|
03537|039|M|metabolizers is contraindicated.(1)|
03537|040|M|   The concurrent use of eliglustat with moderate inhibitors of CYP3A4 and|
03537|041|M|strong or moderate inhibitors of CYP2D6 in poor CYP2D6 metabolizers should|
03537|042|M|be avoided.(1)|
03537|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03537|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03537|045|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03537|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03537|047|B||
03537|048|D|DISCUSSION:  Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4,|
03537|049|D|increased eliglustat (84 mg BID) maximum concentration (Cmax) and|
03537|050|D|area-under-curve (AUC) by  4-fold and 4.4-fold, respectively, in extensive|
03537|051|D|metabolizers.  Physiologically-based pharmacokinetic (PKPB) models suggested|
03537|052|D|ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and|
03537|053|D|5.4-fold, respectively, in intermediate metabolizers.  PKPB models suggested|
03537|054|D|ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily)  by|
03537|055|D|4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1)|
03537|056|D|   PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would|
03537|057|D|increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in|
03537|058|D|extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in|
03537|059|D|intermediate metabolizers.|
03537|060|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a|
03537|061|D|strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax|
03537|062|D|and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers.|
03537|063|D|In intermediate metabolizers, eliglustat Cmax and AUC would be expected to|
03537|064|D|increase 7.5-fold and 9.8-fold, respectively.(1)|
03537|065|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine|
03537|066|D|(a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat|
03537|067|D|Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive|
03537|068|D|metabolizers.  In intermediate metabolizers, eliglustat Cmax and AUC would|
03537|069|D|be expected to increase 4.2-fold and 5-fold, respectively.(1)|
03537|070|D|   Dual inhibitors of CYP3A4 and CYP2D6 linked to this monograph include:|
03537|071|D|berotralstat, dronedarone and tipranavir.(3,4)|
03537|072|B||
03537|073|R|REFERENCES:|
03537|074|B||
03537|075|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
03537|076|R|  August, 2018.|1
03537|077|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03537|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03537|079|R|  settings: a scientific statement from the American Heart Association and|6
03537|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03537|081|R|  2;55(9):934-47.|6
03537|082|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03537|083|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03537|084|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03537|085|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03537|086|R|  11/14/2017.|1
03537|087|R|4.This information is based on an extract from the Certara Drug Interaction|6
03537|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03538|001|T|MONOGRAPH TITLE:  St. John's Wort/MAOIs|
03538|002|B||
03538|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03538|004|L|is contraindicated and generally should not be dispensed or administered to|
03538|005|L|the same patient.|
03538|006|B||
03538|007|A|MECHANISM OF ACTION:  St. John's wort may inhibit neuronal reuptake of|
03538|008|A|serotonin.(1)  MAOIs increase neuronal serotonin concentration via|
03538|009|A|inhibition of MAO-A.|
03538|010|B||
03538|011|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort with MAOIs may|
03538|012|E|result in symptoms of serotonin syndrome, including hypertension,|
03538|013|E|hyperpyrexia, sedation, somnolence, and death.(2-6)|
03538|014|B||
03538|015|P|PREDISPOSING FACTORS:  None determined.|
03538|016|B||
03538|017|M|PATIENT MANAGEMENT:  St. John's wort is contraindicated concurrently with|
03538|018|M|and for 14 days after discontinuation of MAO inhibitors.(2-6)|
03538|019|B||
03538|020|D|DISCUSSION:  Serotonin syndrome has been reported with concurrent St. John's|
03538|021|D|wort and nefazodone,(7) paroxetine,(8) sertraline,(7) and venlafaxine.(9)|
03538|022|D|The use of MAOIs concurrently with St. John's wort is contraindicated.|
03538|023|D|   Metaxalone is a weak inhibitor of MAO.(10,11)|
03538|024|B||
03538|025|R|REFERENCES:|
03538|026|B||
03538|027|R|1.Nicolussi S, Drewe J, Butterweck V, Meyer Zu Schwabedissen HE. Clinical|6
03538|028|R|  relevance of St. John's wort drug interactions revisited. Br J Pharmacol|6
03538|029|R|  2020 Mar;177(6):1212-1226.|6
03538|030|R|2.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
03538|031|R|  June, 2020.|1
03538|032|R|3.Xadago (safinamide) US prescribing information. US WorldMeds, LLC August,|1
03538|033|R|  2021.|1
03538|034|R|4.Zelapar (selegiline hydrochloride) US prescribing information. Valeant|1
03538|035|R|  Pharmaceuticals June, 2021.|1
03538|036|R|5.Nardil (phenelzine sulfate) US prescribing information. Parke-Davis May,|1
03538|037|R|  2007.|1
03538|038|R|6.Parnate (tranylcypromine sulfate) US prescribing information.|1
03538|039|R|  GlaxoSmithKline January 4, 2018.|1
03538|040|R|7.Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant|3
03538|041|R|  drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999 Spring;|3
03538|042|R|  12(1):7-10.|3
03538|043|R|8.Gordon JB. SSRIs and St.John's Wort: possible toxicity?. Am Fam Physician|3
03538|044|R|  1998 Mar 1;57(5):950,953.|3
03538|045|R|9.Prost N, Tichadou L, Rodor F, Nguyen N, David JM, Jean-Pastor MJ. St.|3
03538|046|R|  Johns wort-venlafaxine interaction. Presse Med 2000 Jul 1;29(23):1285-6.|3
03538|047|R|10.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03538|048|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03538|049|R|   Feb;34(2):346.e5-6.|3
03538|050|R|11.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03538|051|R|   Pfizer Inc. January, 2024.|1
03539|001|T|MONOGRAPH TITLE:  Baricitinib/Immunosuppressives; Immunomodulators|
03539|002|B||
03539|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03539|004|L|of severe adverse interaction.|
03539|005|B||
03539|006|A|MECHANISM OF ACTION:  Concurrent use of baricitinib with other biologic|
03539|007|A|disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants|
03539|008|A|such as azathioprine or cyclosporine may result in additive or synergistic|
03539|009|A|effects on the immune system.|
03539|010|B||
03539|011|E|CLINICAL EFFECTS:  Concurrent use of baricitinib with other biologic DMARDs|
03539|012|E|or potent immunosuppressants such as azathioprine or cyclosporine may|
03539|013|E|increase the risk of serious infections.(1)|
03539|014|B||
03539|015|P|PREDISPOSING FACTORS:  None determined.|
03539|016|B||
03539|017|M|PATIENT MANAGEMENT:  The US manufacturer of baricitinib states that|
03539|018|M|concurrent use of baricitinib with biologic DMARDs or potent|
03539|019|M|immunosuppressants is not recommended.(1)|
03539|020|B||
03539|021|D|DISCUSSION:  Most patients who developed serious infections while being|
03539|022|D|treated with baricitinib were on concomitant immunosuppressants like|
03539|023|D|methotrexate and corticosteroids.  The combination of baricitinib with other|
03539|024|D|biologic DMARDs has not been studied.(1)|
03539|025|B||
03539|026|R|REFERENCE:|
03539|027|B||
03539|028|R|1.Olumiant (baricitinib) US prescribing information. Eli Lilly and Company|1
03539|029|R|  June, 2022.|1
03540|001|T|MONOGRAPH TITLE:  Methacholine/Beta-Agonists; Anticholinergics; Theophylline|
03540|002|B||
03540|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03540|004|L|take action as needed.|
03540|005|B||
03540|006|A|MECHANISM OF ACTION:  Beta-agonists, anticholinergics, and theophylline may|
03540|007|A|inhibit the action of methacholine on the airway.(1)|
03540|008|B||
03540|009|E|CLINICAL EFFECTS:  The result of the methacholine challenge test may not be|
03540|010|E|accurate.(1)|
03540|011|B||
03540|012|P|PREDISPOSING FACTORS:  None determined.|
03540|013|B||
03540|014|M|PATIENT MANAGEMENT:  The following drugs should be held before a|
03540|015|M|methacholine challenge for the the duration indicated:(1)|
03540|016|M|   - short-acting beta-agonists: 6 hours|
03540|017|M|   - long-acting beta-agonists: 36 hours|
03540|018|M|   - short-acting anti-cholinergics: 12 hours|
03540|019|M|   - long-acting anti-cholinergics: at least 168 hours (7 days)|
03540|020|M|   - oral theophylline: 12-48 hours|
03540|021|B||
03540|022|D|DISCUSSION:  Beta-agonists, anticholinergics, and theophylline may inhibit|
03540|023|D|the action of methacholine on the airway and cause inaccurate test results.|
03540|024|B||
03540|025|R|REFERENCE:|
03540|026|B||
03540|027|R|1.Provocholine (methacholine) US prescribing information. Methapharm Inc.|1
03540|028|R|  June, 2020.|1
03541|001|T|MONOGRAPH TITLE:  Fostamatinib/Strong CYP3A4 Inhibitors|
03541|002|B||
03541|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03541|004|L|take action as needed.|
03541|005|B||
03541|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03541|007|A|R406, the active metabolite of fostamatinib.(1)|
03541|008|B||
03541|009|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03541|010|E|may result in elevated levels of and toxicity from R406, the major|
03541|011|E|metabolite of fostamatinib.(1)  Elevated levels of fostamatinib may increase|
03541|012|E|the risk of hepatotoxicity, hypertension, diarrhea, and neutropenia.(1)|
03541|013|B||
03541|014|P|PREDISPOSING FACTORS:  None determined.|
03541|015|B||
03541|016|M|PATIENT MANAGEMENT:  Recommendations for concurrent use of fostamatinib with|
03541|017|M|strong CYP3A4 inhibitors differ in different regions.|
03541|018|M|   The US manufacturer of fostamatinib advises monitoring for fostamatinib|
03541|019|M|toxicities that may require a dose reduction.(1)|
03541|020|M|   The UK manufacturer of fostamatinib states that a 50% dose reduction of|
03541|021|M|fostamatinib may be warranted for short-term use of a strong CYP3A4|
03541|022|M|inhibitor (e.g., antifungals, antibacterials).  After discontinuation of the|
03541|023|M|CYP3A4 inhibitor for 2-3 days, the original dose of fostamatinib that was|
03541|024|M|used prior to the start of the inhibitor should be resumed.  Monitor the|
03541|025|M|patient for fostamatinib toxicities that may require dose reduction.(2)|
03541|026|B||
03541|027|D|DISCUSSION:  In a study of 8 healthy males, ketoconazole (200 mg twice|
03541|028|D|daily), a strong CYP3A4 inhibitor, increased the area-under-curve (AUC) and|
03541|029|D|maximum concentration (Cmax) of single-dose fostamatinib 80 mg by 102% and|
03541|030|D|37%, respectively.(3)|
03541|031|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
03541|032|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir,|
03541|033|D|itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil,|
03541|034|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
03541|035|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03541|036|D|troleandomycin, tucatinib, and voriconazole.(3)|
03541|037|B||
03541|038|R|REFERENCES:|
03541|039|B||
03541|040|R|1.Tavalisse (fostamatinib) prescribing information. Rigel Pharmaceuticals,|1
03541|041|R|  Inc April 2018.|1
03541|042|R|2.Tavlesse (fostamatinib) UK summary of product characteristics. Grifols UK|1
03541|043|R|  Ltd June 4, 2020.|1
03541|044|R|3.Martin P, Gillen M, Millson D, Oliver S, Brealey C, Grossbard EB, Baluom|2
03541|045|R|  M, Lau D, Sweeny D, Mant T, Craven K. Effects of CYP3A4 Inhibitors|2
03541|046|R|  Ketoconazole and Verapamil and the CYP3A4 Inducer  Rifampicin on the|2
03541|047|R|  Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro  and|2
03541|048|R|  Phase I Clinical Studies. Drugs R D 2016 Mar;16(1):81-92.|2
03541|049|R|4.This information is based on an extract from the Certara Drug Interaction|6
03541|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03542|001|T|MONOGRAPH TITLE:  Sorafenib/Neomycin|
03542|002|B||
03542|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03542|004|L|of severe adverse interaction.|
03542|005|B||
03542|006|A|MECHANISM OF ACTION:  Sorafenib is partially glucuronidated in the liver,|
03542|007|A|and its conjugates may be cleaved by bacterial glucuronidases, allowing it|
03542|008|A|to be reabsorbed systemically.  Neomycin may disrupt the intestinal flora|
03542|009|A|and decrease the enterohepatic recycling of sorafenib.(1)|
03542|010|B||
03542|011|E|CLINICAL EFFECTS:  Neomycin may reduce the plasma concentrations of|
03542|012|E|sorafenib and decrease its antitumor activity.(1,2)|
03542|013|B||
03542|014|P|PREDISPOSING FACTORS:  None determined.|
03542|015|B||
03542|016|M|PATIENT MANAGEMENT:  The US manufacturer of sorafenib states that|
03542|017|M|concomitant use of neomycin should be avoided.(2)|
03542|018|B||
03542|019|D|DISCUSSION:  In a study of healthy subjects, neomycin (1 gram three times|
03542|020|D|daily for 5 days) decreased the area-under-curve (AUC) of single-dose|
03542|021|D|sorafenib (400 mg) by 54%.(1,2)|
03542|022|B||
03542|023|R|REFERENCES:|
03542|024|B||
03542|025|R|1.Nexavar (sorafenib) EMA summary of product characteristics. Bayer AG|1
03542|026|R|  November 18, 2019.|1
03542|027|R|2.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
03542|028|R|  Corporation July, 2020.|1
03543|001|T|MONOGRAPH TITLE:  Ethyl Alcohol/Nifurtimox|
03543|002|B||
03543|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03543|004|L|is contraindicated and generally should not be dispensed or administered to|
03543|005|L|the same patient.|
03543|006|B||
03543|007|A|MECHANISM OF ACTION:  Nifurtimox may increase the risk of the|
03543|008|A|disulfiram-like reaction.  In vitro studies of similar agents including|
03543|009|A|other nitrofurans and nitroheterocyclic compounds demonstrated inhibition of|
03543|010|A|aldehyde dehydrogenase and other alcohol-oxidizing enzymes.(1)  This results|
03543|011|A|in the accumulation of acetaldehyde, which is responsible for the|
03543|012|A|disulfiram-like reaction.|
03543|013|B||
03543|014|E|CLINICAL EFFECTS:  Concurrent use of nifurtimox with alcohol may contribute|
03543|015|E|to a disulfiram-type reaction resulting in symptoms of hypotension,|
03543|016|E|tachycardia, nausea, sweating, facial flushing, headache, and vomiting.(1)|
03543|017|B||
03543|018|P|PREDISPOSING FACTORS:  None determined.|
03543|019|B||
03543|020|M|PATIENT MANAGEMENT:  Patients should be advised that concurrent use of|
03543|021|M|nifurtimox and alcohol is contraindicated.  Caution patients of the possible|
03543|022|M|effects that may result from ingestion or application of products that|
03543|023|M|contain alcohol while taking nifurtimox.(1)|
03543|024|M|   Patients should be informed about unsuspected sources of alcohol such as|
03543|025|M|elixirs and topical preparations.|
03543|026|M|   Caution is also warranted when using intravenous preparations containing|
03543|027|M|alcohol solvents in patients receiving nifurtimox.|
03543|028|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
03543|029|M|   - The quantity of alcohol in paclitaxel injection formulations|
03543|030|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
03543|031|M|dose contains approximately 13 grams of alcohol.|
03543|032|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
03543|033|M|3-fold depending upon the manufacturer. FDA data on alcohol content (2):|
03543|034|M|   Product                      Manufacturer           Alcohol/200 mg dose|
03543|035|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
03543|036|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
03543|037|M|   Docetaxel Inj.               Accord                  4.0 grams|
03543|038|M|   Taxotere-one vial            Sanofi                  4.0 grams|
03543|039|M|    formulation|
03543|040|M|   Docetaxel Inj.               Hospira                 3.7 grams|
03543|041|M|   Docefrez                     Sun Pharma              2.9 grams|
03543|042|M|   Taxotere-two vial            Sanofi                  2.0 grams|
03543|043|M|    formulation|
03543|044|B||
03543|045|D|DISCUSSION:  Clinical studies have not been conducted.  Concomitant use of|
03543|046|D|nifurtimox with alcohol may increase the incidence and severity of|
03543|047|D|undesirable effects similar to other nitrofurans and nitroheterocyclic|
03543|048|D|compounds.(1)|
03543|049|B||
03543|050|R|REFERENCES:|
03543|051|B||
03543|052|R|1.Lampit (nifurtimox) US prescribing information. Bayer HealthCare|1
03543|053|R|  Pharmaceuticals Inc. August, 2020.|1
03543|054|R|2.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
03543|055|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
03543|056|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
03543|057|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
03543|058|R|  20, 2014.|1
03544|001|T|MONOGRAPH TITLE:  Non-Live or Non-Replicating Vaccines/Satralizumab|
03544|002|B||
03544|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03544|004|L|take action as needed.|
03544|005|B||
03544|006|A|MECHANISM OF ACTION:  Satralizumab is an immunosuppressant and may alter the|
03544|007|A|immune system's response to vaccines.(1)|
03544|008|B||
03544|009|E|CLINICAL EFFECTS:  Administration of a vaccine during satralizumab therapy|
03544|010|E|may result in decreased effectiveness of the vaccine.  If possible, non-live|
03544|011|E|vaccines should be administered at least two weeks prior to initiation of|
03544|012|E|satralizumab.(1)|
03544|013|B||
03544|014|P|PREDISPOSING FACTORS:  None determined.|
03544|015|B||
03544|016|M|PATIENT MANAGEMENT:  Ideally, administer vaccines two weeks prior to|
03544|017|M|initiating satralizumab therapy.|
03544|018|M|   The immune response to non-live vaccines should be monitored in patients|
03544|019|M|receiving satralizumab.  Vaccinations given during satralizumab therapy may|
03544|020|M|need to be repeated.(1)  Patients who are vaccinated within the 14 days|
03544|021|M|prior to initiating immunosuppressive therapy should be considered|
03544|022|M|unvaccinated and should be revaccinated at least 3 months after|
03544|023|M|immunosuppressive therapy is discontinued when immune competence is|
03544|024|M|restored.(2)|
03544|025|B||
03544|026|D|DISCUSSION:  Vaccinations may be less effective if administered during|
03544|027|D|satralizumab treatment.(1)|
03544|028|B||
03544|029|R|REFERENCES:|
03544|030|B||
03544|031|R|1.Enspryng (satralizumab-mwge) US Prescribing Information. Genentech, Inc.|1
03544|032|R|  August 2020.|1
03544|033|R|2.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
03544|034|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
03544|035|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
03544|036|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
03544|037|R|  recs.pdf February 10, 2023;1-197.|6
03545|001|T|MONOGRAPH TITLE:  Zonisamide/Anticholinergics|
03545|002|B||
03545|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03545|004|L|take action as needed.|
03545|005|B||
03545|006|A|MECHANISM OF ACTION:  Zonisamide can cause decreased sweating and elevated|
03545|007|A|body temperature.  Agents with anticholinergic activity can predispose|
03545|008|A|patients to heat-related disorders.(1-2)|
03545|009|B||
03545|010|E|CLINICAL EFFECTS:  Concurrent use of zonisamide with agents with|
03545|011|E|anticholinergic activity may increase the incidence of oligohidrosis and|
03545|012|E|hyperthermia, especially in pediatric or adolescent patients.(1-2)|
03545|013|E|Overheating and dehydration can lead to brain damage and death.|
03545|014|B||
03545|015|P|PREDISPOSING FACTORS:  Pediatric and adolescent patients and patients with|
03545|016|P|dehydration may be more likely to experience heat-related disorders.(1)|
03545|017|B||
03545|018|M|PATIENT MANAGEMENT:  The UK and US manufacturers of zonisamide state that|
03545|019|M|caution should be used in adults when zonisamide is prescribed with other|
03545|020|M|medicinal products that predispose to heat-related disorders, such as agents|
03545|021|M|with anticholinergic activity.(1-2)|
03545|022|M|   Pediatric and adolescent patients must not take anticholinergic agents|
03545|023|M|(e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine,|
03545|024|M|and oxybutynin) concurrently with zonisamide.(1)|
03545|025|M|   Monitor for signs and symptoms of heat stroke: skin feels very hot with|
03545|026|M|little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid|
03545|027|M|breathing.|
03545|028|M|   Monitor for signs and symptoms of dehydration: dry mouth, urinating less|
03545|029|M|than usual, dark-colored urine, dry skin, feeling tired, dizziness, or|
03545|030|M|irritability.|
03545|031|M|   If signs or symptoms of dehydration, oligohidrosis, or elevated body|
03545|032|M|temperature occur, discontinuation of zonisamide should be considered.|
03545|033|B||
03545|034|D|DISCUSSION:  Case reports of decreased sweating and elevated temperature|
03545|035|D|have been reported, especially in pediatric patients.  Some cases resulted|
03545|036|D|in heat stroke that required hospital treatment and resulted in death.(1)|
03545|037|B||
03545|038|R|REFERENCES:|
03545|039|B||
03545|040|R|1.Zonisamide Dr. Reddy's UK summary of product characteristics. Dr. Reddy's|1
03545|041|R|  Laboratories (UK) Ltd April 17, 2018.|1
03545|042|R|2.Zonegran (zonisamide) US prescribing information. Sunovion Pharms Inc|1
03545|043|R|  April 13, 2020.|1
03546|001|T|MONOGRAPH TITLE:  Oliceridine/Strong CYP2D6 Inhibitors|
03546|002|B||
03546|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03546|004|L|take action as needed.|
03546|005|B||
03546|006|A|MECHANISM OF ACTION:  Oliceridine is metabolized equally by CYP2D6 and|
03546|007|A|CYP3A4.  Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or|
03546|008|A|CYP3A4.(1)|
03546|009|B||
03546|010|E|CLINICAL EFFECTS:  The concurrent administration of a strong or moderate|
03546|011|E|CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels|
03546|012|E|of and toxicity from oliceridine including profound sedation, respiratory|
03546|013|E|depression, coma, and/or death.(1)|
03546|014|B||
03546|015|P|PREDISPOSING FACTORS:  Inhibition of both CYP2D6 and CYP3A4 pathways may|
03546|016|P|result in a greater increase in the levels of and toxcity of oliceridine.(1)|
03546|017|B||
03546|018|M|PATIENT MANAGEMENT:  Caution should be used when administering oliceridine|
03546|019|M|to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4.|
03546|020|M|Dosage adjustments should be made if warranted.  Closely monitor these|
03546|021|M|patients for respiratory depression and sedation at frequent intervals and|
03546|022|M|evaluate subsequent doses based on response.|
03546|023|M|   If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is|
03546|024|M|necessary, less frequent dosing of oliceridine may be required.|
03546|025|M|   If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued,|
03546|026|M|increase of the oliceridine dosage may be necessary.  Monitor for signs of|
03546|027|M|opioid withdrawal.|
03546|028|M|   Patients receiving concurrent therapy with both a strong or moderate|
03546|029|M|CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse|
03546|030|M|effects.|
03546|031|M|   Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and|
03546|032|M|a strong CYP3A4 inhibitor may require less frequent dosing of|
03546|033|M|oliceridine.(1)|
03546|034|M|   Respiratory depression can occur at any time during opioid therapy,|
03546|035|M|especially during therapy initiation and following dosage increases.  The|
03546|036|M|risk of opioid-related overdose or overdose-related death is increased with|
03546|037|M|higher opioid doses, and this risk persists over the course of therapy.|
03546|038|M|Consider these risks when using concurrently with other agents that may|
03546|039|M|cause CNS depression.(2)|
03546|040|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03546|041|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03546|042|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03546|043|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03546|044|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03546|045|M|as those taking CNS depressants) and when a patient has household|
03546|046|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03546|047|M|for obtaining an opioid reversal agent (e.g., prescription,|
03546|048|M|over-the-counter, or as part of a community-based program).(3)|
03546|049|B||
03546|050|D|DISCUSSION:  In a study of four healthy subjects who are CYP2D6 poor|
03546|051|D|metabolizers, itraconazole (200 mg daily for 5 days) increased the|
03546|052|D|area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1)|
03546|053|D|   In a study of subjects who were not CYP2D6 poor metabolizers,|
03546|054|D|ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the|
03546|055|D|pharmacokinetics of oliceridine.(1)|
03546|056|D|   Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine,|
03546|057|D|hydroquinidine, paroxetine, quinidine and terbinafine.(4)|
03546|058|B||
03546|059|R|REFERENCES:|
03546|060|B||
03546|061|R|1.Olinvyk (oliceridine) US prescribing information. Trevena Inc December,|1
03546|062|R|  2023.|1
03546|063|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03546|064|R|  prescribing information for all opioid pain medicines to provide|1
03546|065|R|  additional guidance for safe use. Available at:|1
03546|066|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03546|067|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03546|068|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03546|069|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03546|070|R|  recommends health care professionals discuss naloxone with all patients|1
03546|071|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03546|072|R|  disorder. Available at:|1
03546|073|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03546|074|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03546|075|R|  d-pain July 23, 2020.|1
03546|076|R|4.This information is based on an extract from the Certara Drug Interaction|6
03546|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03547|001|T|MONOGRAPH TITLE:  Atovaquone/Rifampin; Rifapentine|
03547|002|B||
03547|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03547|004|L|of severe adverse interaction.|
03547|005|B||
03547|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.(1,2)|
03547|007|B||
03547|008|E|CLINICAL EFFECTS:  Concurrent use may lead to decreased levels and clinical|
03547|009|E|effects of atovaquone and increased levels of and side effects from the|
03547|010|E|rifamycin.(1,2)|
03547|011|B||
03547|012|P|PREDISPOSING FACTORS:  None determined.|
03547|013|B||
03547|014|M|PATIENT MANAGEMENT:  Concomitant administration with rifampin or rifapentine|
03547|015|M|is not recommended by the US manufacturer of atovaquone and the National|
03547|016|M|Institute of Health HIV guidelines.(1-3)|
03547|017|B||
03547|018|D|DISCUSSION:  In a study of 13 HIV-positive patients, rifampin (600 mg every|
03547|019|D|24 hours) and atovaquone (750 mg every 12 hours) resulted in a decrease in|
03547|020|D|average atovaquone steady-state plasma concentration by 52% and an increase|
03547|021|D|in average rifampin steady-state plasma concentration by 37%.(1)|
03547|022|B||
03547|023|R|REFERENCES:|
03547|024|B||
03547|025|R|1.Mepron (atovaquone) US prescribing information. GlaxoSmithKline July,|1
03547|026|R|  2019.|1
03547|027|R|2.Malarone (atovaquone and proguanil hydrochloride) US prescribing|1
03547|028|R|  information. GlaxoSmithKline March, 2010.|1
03547|029|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03547|030|R|  for the prevention and treatment of opportunistic infections in adults and|6
03547|031|R|  adolescents with HIV. Department of Health and Human Services. Available|6
03547|032|R|  at|6
03547|033|R|  https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/Adul|6
03547|034|R|  t_OI.pdf Accessed October 26, 2020..|6
03548|001|T|MONOGRAPH TITLE:  Plitidepsin/Strong CYP3A4 Inhibitors|
03548|002|B||
03548|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03548|004|L|of severe adverse interaction.|
03548|005|B||
03548|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03548|007|A|plitidepsin.(1)|
03548|008|B||
03548|009|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03548|010|E|may result in elevated levels of and toxicity from plitidepsin.(1)|
03548|011|B||
03548|012|P|PREDISPOSING FACTORS:  None determined.|
03548|013|B||
03548|014|M|PATIENT MANAGEMENT:  Coadministration with strong CYP3A4 inhibitors should|
03548|015|M|be avoided.  Strong CYP3A4 inhibitors should be discontinued at least 1 week|
03548|016|M|prior to starting treatment and while on treatment with plitidepsin.|
03548|017|B||
03548|018|D|DISCUSSION:  In vitro studies indicate that CYP3A4 is the main enzyme|
03548|019|D|involved in the metabolism of plitidepsin.  The Australian manufacturer of|
03548|020|D|plitidepsin states that coadministration with strong CYP3A4 inhibitors|
03548|021|D|should be avoided.(1)|
03548|022|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
03548|023|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir,|
03548|024|D|itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir,|
03548|025|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
03548|026|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, tipranavir,|
03548|027|D|troleandomycin, tucatinib, and voriconazole.(2,3)|
03548|028|B||
03548|029|R|REFERENCES:|
03548|030|B||
03548|031|R|1.Aplidin (plitidepsin) Australian prescribing information. Specialised|1
03548|032|R|  Therapeutics Pharma Pty Ltd September, 2019.|1
03548|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
03548|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03548|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03548|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03548|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03548|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03548|039|R|  11/14/2017.|1
03549|001|T|MONOGRAPH TITLE:  Sunitinib/QT Prolonging Agents|
03549|002|B||
03549|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03549|004|L|take action as needed.|
03549|005|B||
03549|006|A|MECHANISM OF ACTION:  Concurrent use of sunitinib with other agents that|
03549|007|A|prolong the QTc interval may result in additive effects on the QTc|
03549|008|A|interval.(1)|
03549|009|B||
03549|010|E|CLINICAL EFFECTS:  The use of sunitinib in patients maintained on agents|
03549|011|E|that prolong the QTc interval may result in potentially life-threatening|
03549|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
03549|013|B||
03549|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03549|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03549|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03549|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03549|018|P|gender, advanced age or when receiving concomitant treatment with an|
03549|019|P|inhibitor of CYP3A4.(1,2)|
03549|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03549|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03549|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03549|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03549|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03549|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03549|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03549|027|B||
03549|028|M|PATIENT MANAGEMENT:  The concurrent use of sunitinib with agents known to|
03549|029|M|prolong the QT interval should be approached with caution.(1)|
03549|030|M|   If concurrent therapy is warranted, monitor ECG more frequently and|
03549|031|M|consider obtaining serum calcium, magnesium, and potassium levels at|
03549|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03549|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03549|034|B||
03549|035|D|DISCUSSION:  Sunitinib has been shown to prolong the QT interval in a dose|
03549|036|D|dependent manner.  Torsade de pointes has been observed in less than 0.1% of|
03549|037|D|patients receiving sunitinib.(1)|
03549|038|D|   A retrospective review of 618 cancer patients treated with 902|
03549|039|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03549|040|D|incidence of QTc prolongation.  In patients who received sunitinib, QTc|
03549|041|D|prolongation was identified in 26 (19.4%) with 16 (61.5%) having Grade 1|
03549|042|D|(QTc 450-480 ms) and 6 (23.1%) having Grade 2 (QTc 480-500 ms).  Grade 3|
03549|043|D|events occurred in 1 (3.8%) having QTc greater than or equal to 500 ms and 1|
03549|044|D|(3.8%) having QTc change greater than or equal to 60 ms.  Ventricular|
03549|045|D|tachycardia was seen in 1 (3.8%) of patients and 1 (3.8%) patient|
03549|046|D|experienced sudden cardiac death.(3)|
03549|047|D|   Agents that are linked to this monograph may have varying degrees of|
03549|048|D|potential to prolong the QTc interval but are generally accepted to have a|
03549|049|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03549|050|D|been shown to prolong the QTc interval either through their mechanism of|
03549|051|D|action, through studies on their effects on the QTc interval, or through|
03549|052|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03549|053|D|and/or post-marketing reports.(4)|
03549|054|B||
03549|055|R|REFERENCES:|
03549|056|B||
03549|057|R|1.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
03549|058|R|  2021.|1
03549|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03549|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03549|061|R|  settings: a scientific statement from the American Heart Association and|6
03549|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03549|063|R|  2;55(9):934-47.|6
03549|064|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03549|065|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03549|066|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03549|067|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03549|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03549|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03549|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03550|001|T|MONOGRAPH TITLE:  Plitidepsin/Strong CYP3A4 Inducers|
03550|002|B||
03550|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03550|004|L|of severe adverse interaction.|
03550|005|B||
03550|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03550|007|A|plitidepsin.(1)|
03550|008|B||
03550|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer may result in a|
03550|010|E|loss of plitidepsin efficacy.(1)|
03550|011|B||
03550|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03550|013|P|of the inducer for longer than 1-2 weeks.|
03550|014|B||
03550|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of plitidepsin with strong|
03550|016|M|CYP3A4 inducers.(1)  When possible, select alternative agents in place of|
03550|017|M|the strong CYP3A4 inducer.  Monitor patients receiving concurrent therapy|
03550|018|M|for reduced efficacy.|
03550|019|M|   Consider substituting with non-enzyme inducing therapies at least 2 weeks|
03550|020|M|prior to initiation and while on treatment with plitidepsin therapy.(1)|
03550|021|B||
03550|022|D|DISCUSSION:  In vitro studies indicate that CYP3A4 is the main enzyme|
03550|023|D|involved in the metabolism of plitidepsin.  The Australian manufacturer|
03550|024|D|states that coadministration with strong CYP3A4 inducers should be|
03550|025|D|avoided.(1)|
03550|026|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
03550|027|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
03550|028|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
03550|029|D|rifampin, rifapentine and St John's Wort.(2,3)|
03550|030|B||
03550|031|R|REFERENCES:|
03550|032|B||
03550|033|R|1.Aplidin (plitidepsin) Australian prescribing information. Specialised|1
03550|034|R|  Therapeutics Pharma Pty Ltd September, 2019.|1
03550|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03550|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03550|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03550|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03550|039|R|  11/14/2017.|1
03550|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
03550|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03551|001|T|MONOGRAPH TITLE:  Pazopanib/QT Prolonging Agents|
03551|002|B||
03551|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03551|004|L|of severe adverse interaction.|
03551|005|B||
03551|006|A|MECHANISM OF ACTION:  Pazopanib has been shown to prolong the QTc interval.|
03551|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
03551|008|A|additive effects on the QTc interval.(1)|
03551|009|B||
03551|010|E|CLINICAL EFFECTS:  The concurrent use of pazopanib with other agents that|
03551|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03551|012|E|arrhythmias, including torsades de pointes.(1)|
03551|013|B||
03551|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03551|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03551|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03551|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03551|018|P|gender, or advanced age.(3)|
03551|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03551|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03551|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03551|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03551|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03551|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03551|025|P|dysfunction).(3)|
03551|026|B||
03551|027|M|PATIENT MANAGEMENT:  The US manufacturer of pazopanib states that pazopanib|
03551|028|M|should be avoided in patients receiving other drugs known to cause QT|
03551|029|M|prolongation.(1)|
03551|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03551|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03551|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03551|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03551|034|B||
03551|035|D|DISCUSSION:  In clinical studies, 2% (11/558) of patients receiving|
03551|036|D|pazopanib experienced QT prolongation.  Torsades de pointes occurred in less|
03551|037|D|than 1% (2/977) of patients who received pazopanib in monotherapy studies.|
03551|038|D|In a randomized clinical trial, 3 of 290 patients who received pazopanib had|
03551|039|D|post-baseline QTc values between 500 and  549 msec.  None of the patients|
03551|040|D|receiving placebo had post-baseline QTc values greater than or equal to 500|
03551|041|D|msec.(1)|
03551|042|D|   A retrospective review of 618 cancer patients treated with 902|
03551|043|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03551|044|D|incidence of QTc prolongation.  In patients who received pazopanib, QTc|
03551|045|D|prolongation was identified in 32 (19.4%) with 18 (56.3%) having Grade 1|
03551|046|D|(QTc 450-480 ms) and 4 (12.5%) having Grade 2 (QTc 480-500 ms).  Grade 3|
03551|047|D|events occurred in 3 (9.3%) having QTc greater than or equal to 500 ms and 4|
03551|048|D|(12.5%) having QTc change greater than or equal to 60 ms.  Ventricular|
03551|049|D|tachycardia was seen in 2 (6.3%) of patients and 1 (3.1%) patient|
03551|050|D|experienced sudden cardiac death.(4)|
03551|051|D|   Agents that are linked to this monograph may have varying degrees of|
03551|052|D|potential to prolong the QTc interval but are generally accepted to have a|
03551|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03551|054|D|been shown to prolong the QTc interval either through their mechanism of|
03551|055|D|action, through studies on their effects on the QTc interval, or through|
03551|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03551|057|D|and/or post-marketing reports.(2)|
03551|058|B||
03551|059|R|REFERENCES:|
03551|060|B||
03551|061|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03551|062|R|  2020.|1
03551|063|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
03551|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03551|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03551|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03551|067|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03551|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03551|069|R|  settings: a scientific statement from the American Heart Association and|6
03551|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03551|071|R|  2;55(9):934-47.|6
03551|072|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03551|073|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03551|074|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03552|001|T|MONOGRAPH TITLE:  Clopidogrel/Selected Strong CYP2C19 Inducers|
03552|002|B||
03552|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03552|004|L|of severe adverse interaction.|
03552|005|B||
03552|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
03552|007|A|active metabolite via a 2 step process.  The first conversion step is|
03552|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
03552|009|A|CYP3A4, CYP2B6 and CYP2C19.(1-3)  As CYP2C19 contributes to both steps, it|
03552|010|A|is thought to be the more important enzyme involved in formation of the|
03552|011|A|pharmacologically active metabolite.|
03552|012|A|   Strong inducers of CYP2C19 may increase the conversion of clopidogrel to|
03552|013|A|its active metabolite.(1,2)|
03552|014|B||
03552|015|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2C19 inducers with|
03552|016|E|clopidogrel may increase the effects and toxicity of clopidogrel, including|
03552|017|E|bleeding.(1,2)|
03552|018|B||
03552|019|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03552|020|P|patient with disease-associated factors (e.g. thrombocytopenia).|
03552|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
03552|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03552|023|P|risk for bleeding (e.g. NSAIDs).|
03552|024|P|   Induction effects may be more likely with regular use of the inducer for|
03552|025|P|longer than 1-2 weeks.|
03552|026|B||
03552|027|M|PATIENT MANAGEMENT:  The manufacturer of clopidogrel states that concomitant|
03552|028|M|use of strong CYP2C19 inducers should be avoided.(1,2)|
03552|029|M|   If concurrent therapy cannot be avoided, monitor patients for signs of|
03552|030|M|blood loss, including decreased hemoglobin, hematocrit, fecal occult blood,|
03552|031|M|and/or decreased blood pressure and promptly evaluate patients with any|
03552|032|M|symptoms.|
03552|033|M|   Discontinue clopidogrel in patients with active pathologic bleeding.|
03552|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03552|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03552|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03552|037|M|and/or swelling.|
03552|038|B||
03552|039|D|DISCUSSION:  In a study of 12 healthy volunteers, rifampin (300 mg twice|
03552|040|D|daily for 7 days) increased the maximum concentration (Cmax) and|
03552|041|D|area-under-curve (AUC) of the active metabolite of clopidogrel by|
03552|042|D|approximately 4-fold.  In conjunction with this, there was a higher level of|
03552|043|D|P2Y12 receptor blockade by clopidogrel after rifampin pre-treatment.|
03552|044|D|Clopidogrel 600 mg alone decreased the number of unblocked receptors at 4|
03552|045|D|hours from 248 +/- 40 to 48 +/- 24 per platelet.  After rifampin|
03552|046|D|pre-treatment, clopidogrel decreased the number of unblocked receptors from|
03552|047|D|266 +/- 63 to 4 +/- 2 (p < 0.0001).(4)|
03552|048|D|   A study of 10 healthy volunteers found that rifampin 300 mg twice daily|
03552|049|D|for 4 days then combined with clopidogrel 75 mg daily for 6 days led to a|
03552|050|D|significantly greater inhibition of platelet aggregation compared to|
03552|051|D|clopidogrel alone (56% versus 33%, respectively).  Three subjects who were|
03552|052|D|initially clopidogrel nonresponders and 1 subject who was a low responder|
03552|053|D|all became responders after treatment with rifampin.(5)|
03552|054|D|   Strong CYP2C19 inducers linked to this monograph include: apalutamide,|
03552|055|D|rifabutin and rifampin.(6,7)|
03552|056|B||
03552|057|R|REFERENCES:|
03552|058|B||
03552|059|R|1.Plavix (clopidogrel hydrogen sulphate) UK summary of product|1
03552|060|R|  characteristics. Sanofi Pharma Bristol-Myers Squibb SNC July 23, 2020.|1
03552|061|R|2.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
03552|062|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
03552|063|R|3.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
03552|064|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
03552|065|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
03552|066|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
03552|067|R|  38(1):92-9.|5
03552|068|R|4.Judge HM, Patil SB, Buckland RJ, Jakubowski JA, Storey RF. Potentiation of|2
03552|069|R|  clopidogrel active metabolite formation by rifampicin leads to  greater|2
03552|070|R|  P2Y12 receptor blockade and inhibition of platelet aggregation after|2
03552|071|R|  clopidogrel. J Thromb Haemost 2010 Aug;8(8):1820-7.|2
03552|072|R|5.Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE,|2
03552|073|R|  Tait AR, Bates ER. Contribution of hepatic cytochrome P450 3A4 metabolic|2
03552|074|R|  activity to the phenomenon of  clopidogrel resistance. Circulation 2004|2
03552|075|R|  Jan 20;109(2):166-71.|2
03552|076|R|6.This information is based on an extract from the Certara Drug Interaction|6
03552|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03552|078|R|7.MacDougall C, Canonica T, Keh C, P Phan BA, Louie J. Systematic review of|6
03552|079|R|  drug-drug interactions between rifamycins and anticoagulant  and|6
03552|080|R|  antiplatelet agents and considerations for management. Pharmacotherapy|6
03552|081|R|  2022 Apr;42(4):343-361.|6
03553|001|T|MONOGRAPH TITLE:  Mexiletine/Strong CYP2D6 Inhibitors|
03553|002|B||
03553|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03553|004|L|take action as needed.|
03553|005|B||
03553|006|A|MECHANISM OF ACTION:  Bupropion, dacomitinib, fluoxetine, paroxetine, and|
03553|007|A|quinidine may inhibit the metabolism of mexiletine at CYP2D6.(1-7)|
03553|008|B||
03553|009|E|CLINICAL EFFECTS:  Concurrent use of CYP2D6 inhibitors may result in|
03553|010|E|elevated levels of and toxicity from mexiletine, including vertigo,|
03553|011|E|insomnia, and abdominal pain.(1-5)|
03553|012|B||
03553|013|P|PREDISPOSING FACTORS:  The interaction may be more severe in patients who|
03553|014|P|are ultrarapid metabolizers of CYP2D6.(1-5)|
03553|015|B||
03553|016|M|PATIENT MANAGEMENT:  The UK manufacturer states coadministration of|
03553|017|M|mexiletine with a strong CYP2D6 inhibitor may lead to increased levels and|
03553|018|M|toxicity from mexiletine.  Clinical monitoring is recommended during and|
03553|019|M|after concurrent therapy for changes in mexiletine levels.(1)|
03553|020|M|   The US manufacturer states if concurrent use is warranted, mexiletine|
03553|021|M|should be slowly titrated to response and closely monitored.(2)|
03553|022|B||
03553|023|D|DISCUSSION:  Mexiletine is 90% metabolized in the liver, with CYP2D6 as the|
03553|024|D|primary pathway.  CYP2D6 phenotypes significantly affect drug levels of|
03553|025|D|mexiletine.(3-5)|
03553|026|D|   In an interaction study (8 extensive and 7 poor metabolizers of CYP2D6),|
03553|027|D|coadministration of propafenone did not alter the kinetics of mexiletine in|
03553|028|D|the poor CYP2D6 metabolizer group.  However, the metabolic clearance of|
03553|029|D|mexiletine in the extensive metabolizer phenotype decreased by about 70%|
03553|030|D|making the poor and extensive metabolizer groups indistinguishable.(2)|
03553|031|D|   In a pharmacokinetic study in CYP2D6 phenotypes, patients with CYP2D6|
03553|032|D|extensive metabolizers had a decreased extent of the formation of both|
03553|033|D|metabolites by more than 50% and 85% for the microsomes from CYP2D6*1/*10|
03553|034|D|and 10/*10 livers, respectively.(3)|
03553|035|D|   Strong CYP2D6 inhibitors linked to this monograph include: bupropion,|
03553|036|D|dacomitinib, fluoxetine, paroxetine, and quinidine.(6-7)|
03553|037|B||
03553|038|R|REFERENCES:|
03553|039|B||
03553|040|R|1.Namuscla (mexiletine) UK summary of product characteristics. Lupin|1
03553|041|R|  Healthcare (UK) LLC December, 2018.|1
03553|042|R|2.Mexiletine US Prescribing Information. Teva Pharmaceuticals USA, Inc.|1
03553|043|R|  October, 2018.|1
03553|044|R|3.Senda C, Yamaura Y, Kobayashi K, Fujii H, Minami H, Sasaki Y, Igarashi T,|2
03553|045|R|  Chiba K. Influence of the CYP2D6*10 allele on the metabolism of mexiletine|2
03553|046|R|  by human liver  microsomes. Br J Clin Pharmacol 2001 Jul;52(1):100-3.|2
03553|047|R|4.Labb L, O'Hara G, Lefebvre M, Lessard E, Gilbert M, Adedoyin A, Champagne|2
03553|048|R|  J, Hamelin B, Turgeon J. Pharmacokinetic and pharmacodynamic interaction|2
03553|049|R|  between mexiletine and propafenone  in human beings. Clin Pharmacol Ther|2
03553|050|R|  2000 Jul;68(1):44-57.|2
03553|051|R|5.Nakajima M, Kobayashi K, Shimada N, Tokudome S, Yamamoto T, Kuroiwa Y.|2
03553|052|R|  Involvement of CYP1A2 in mexiletine metabolism. Br J Clin Pharmacol 1998|2
03553|053|R|  Jul;46(1):55-62.|2
03553|054|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
03553|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03553|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03553|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03553|058|R|  11/14/2017.|1
03553|059|R|7.This information is based on an extract from the Certara Drug Interaction|6
03553|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03554|001|T|MONOGRAPH TITLE:  Copper Cu 64 Dotatate/Long-Acting Somatostatin Analogs|
03554|002|B||
03554|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03554|004|L|of severe adverse interaction.|
03554|005|B||
03554|006|A|MECHANISM OF ACTION:  Both somatostatin analogs and copper Cu 64 dotatate|
03554|007|A|bind to the same somatostatin receptors (SSTR2), resulting in competitive|
03554|008|A|inhibition.(1)|
03554|009|B||
03554|010|E|CLINICAL EFFECTS:  Concurrent use of copper Cu 64 dotatate and somatostatin|
03554|011|E|analogs may affect the results of the scan.(1)|
03554|012|B||
03554|013|P|PREDISPOSING FACTORS:  None determined.|
03554|014|B||
03554|015|M|PATIENT MANAGEMENT:  In patients receiving somatostatin analogs, perform the|
03554|016|M|image just prior to dosing with long-acting somatostatin analogs.|
03554|017|M|   For patients on long-acting somatostatin analogs, a washout period of 28|
03554|018|M|days is recommended prior to imaging.|
03554|019|M|   For patients on short-acting somatostatin analogs, a washout period of 2|
03554|020|M|days is recommended prior to imaging.(1)|
03554|021|B||
03554|022|D|DISCUSSION:  Both somatostatin analogs and copper Cu 64 dotatate bind to the|
03554|023|D|same somatostatin receptors (SSTR2), resulting in competitive inhibition,|
03554|024|D|which can affect the results of the scan.(1)|
03554|025|B||
03554|026|R|REFERENCE:|
03554|027|B||
03554|028|R|1.Detectnet (copper Cu 64 dotatate injection) US prescribing information.|1
03554|029|R|  Radiomedix Inc. September, 2020.|1
03555|001|T|MONOGRAPH TITLE:  Copper Cu 64 Dotatate/Short-Acting Somatostatin Analogs|
03555|002|B||
03555|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03555|004|L|of severe adverse interaction.|
03555|005|B||
03555|006|A|MECHANISM OF ACTION:  Both somatostatin analogs and copper Cu 64 dotatate|
03555|007|A|bind to the same somatostatin receptors (SSTR2), resulting in competitive|
03555|008|A|inhibition.(1)|
03555|009|B||
03555|010|E|CLINICAL EFFECTS:  Concurrent use of copper Cu 64 dotatate and somatostatin|
03555|011|E|analogs may affect the results of the scan.(1)|
03555|012|B||
03555|013|P|PREDISPOSING FACTORS:  None determined.|
03555|014|B||
03555|015|M|PATIENT MANAGEMENT:  In patients receiving somatostatin analogs, perform the|
03555|016|M|image just prior to dosing with long-acting somatostatin analogs.|
03555|017|M|   For patients on long-acting somatostatin analogs, a washout period of 28|
03555|018|M|days is recommended prior to imaging.|
03555|019|M|   For patients on short-acting somatostatin analogs, a washout period of 2|
03555|020|M|days is recommended prior to imaging.(1)|
03555|021|B||
03555|022|D|DISCUSSION:  Both somatostatin analogs and copper Cu 64 dotatate bind to the|
03555|023|D|same somatostatin receptors (SSTR2), resulting in competitive inhibition,|
03555|024|D|which can affect the results of the scan.(1)|
03555|025|B||
03555|026|R|REFERENCE:|
03555|027|B||
03555|028|R|1.Detectnet (copper Cu 64 dotatate injection) US prescribing information.|1
03555|029|R|  Radiomedix Inc. September, 2020.|1
03556|001|T|MONOGRAPH TITLE:  Pralsetinib/Strong CYP3A4 Inducers|
03556|002|B||
03556|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03556|004|L|of severe adverse interaction.|
03556|005|B||
03556|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03556|007|A|pralsetinib.(1)|
03556|008|B||
03556|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer may result in a|
03556|010|E|loss of pralsetinib efficacy.(1)|
03556|011|B||
03556|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03556|013|P|of the inducer for longer than 1-2 weeks.|
03556|014|B||
03556|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pralsetinib with strong|
03556|016|M|CYP3A4 inducers.(1)|
03556|017|M|   If coadministration cannot be avoided, increase the starting dose of|
03556|018|M|pralsetinib to double the current dose on day 7 of coadministration with a|
03556|019|M|strong CYP3A4 inducer.  After discontinuation of a strong CYP3A4 inducer for|
03556|020|M|at least 14 days, resume the previous pralsetinib dose prior to initiating|
03556|021|M|the strong CYP3A4 inducer.(1)|
03556|022|M|   Monitor patients receiving concurrent therapy for reduced efficacy.|
03556|023|B||
03556|024|D|DISCUSSION:  Coadministration of rifampin 600 mg once daily with a single|
03556|025|D|pralsetinib 400 mg dose decreased pralsetinib concentration maximum (Cmax)|
03556|026|D|by 30% and area-under-curve (AUC) by 68%.(1)|
03556|027|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
03556|028|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
03556|029|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
03556|030|D|rifampin, rifapentine and St John's Wort.(2,3)|
03556|031|B||
03556|032|R|REFERENCES:|
03556|033|B||
03556|034|R|1.Gavreto (pralsetinib) US prescribing information. Rigel Pharmaceuticals,|1
03556|035|R|  Inc. June, 2024.|1
03556|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03556|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03556|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03556|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03556|040|R|  11/14/2017.|1
03556|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
03556|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03557|001|T|MONOGRAPH TITLE:  Pralsetinib/Strong and Moderate CYP3A4 Inhibitors|
03557|002|B||
03557|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03557|004|L|of severe adverse interaction.|
03557|005|B||
03557|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inhibitors (including|
03557|007|A|combined moderate CYP3A4 and P-glycoprotein (P-gp) inhibitors) may inhibit|
03557|008|A|the metabolism of pralsetinib.(1)|
03557|009|B||
03557|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong or moderate CYP3A4|
03557|011|E|inhibitor (including combined moderate CYP3A4 and P-gp inhibitors) may|
03557|012|E|result in elevated levels of and toxicity from pralsetinib, including QTc|
03557|013|E|prolongation which may lead to potentially life-threatening cardiac|
03557|014|E|arrhythmias like torsades de pointes (TdP).  Other toxicities include|
03557|015|E|hemorrhagic events, pneumonitis, hepatotoxicity, and hypertension.(1-3)|
03557|016|B||
03557|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03557|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03557|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03557|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03557|021|P|female gender, or advanced age.(4)|
03557|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03557|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03557|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03557|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03557|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03557|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03557|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03557|029|B||
03557|030|M|PATIENT MANAGEMENT:  Coadministration of pralsetinib with strong or moderate|
03557|031|M|CYP3A4 inhibitors (including combined moderate CYP3A4 and P-gp inhibitors)|
03557|032|M|should be avoided.(1)|
03557|033|M|   If coadministration with a strong or moderate CYP3A4 inhibitor cannot be|
03557|034|M|avoided, use with caution and reduce the dose of pralsetinib as follows:|
03557|035|M|   -If the current dose is 400 mg once daily, decrease the dose to 300 mg|
03557|036|M|daily.|
03557|037|M|   -If the current dose is 300 mg once daily, decrease the dose to 200 mg|
03557|038|M|daily.|
03557|039|M|   -If the current dose is 200 mg once daily, decrease the dose to 100 mg|
03557|040|M|daily.|
03557|041|M|   After the inhibitor is discontinued for three to five half-lives, resume|
03557|042|M|the dose of pralsetinib at the dose taken prior to initiation of the|
03557|043|M|inhibitor.(1)|
03557|044|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
03557|045|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03557|046|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
03557|047|M|report any irregular heartbeat, dizziness, or fainting.|
03557|048|M|   If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until|
03557|049|M|QTc is <470 ms.  Resume pralsetinib at the same dose if risk factors that|
03557|050|M|cause QT prolongation an are identified and corrected.  If risk factors that|
03557|051|M|cause QT prolongation are not identified, resume pralsetinib at a reduced|
03557|052|M|dose.  Permanently discontinue pralsetinib if the patient develops|
03557|053|M|life-threatening arrhythmia.(3)|
03557|054|B||
03557|055|D|DISCUSSION:  Coadministration of voriconazole 400 mg twice daily for 1 day|
03557|056|D|then 200 mg twice daily (a strong CYP3A inhibitor) resulted in 122% and 20%|
03557|057|D|increase in pralsetinib area-under-curve (AUC) and maximum concentration|
03557|058|D|(Cmax), respectively.(1)|
03557|059|D|   Fluconazole 400 mg daily (a moderate CYP3A4 inhibitor) increased|
03557|060|D|pralsetinib AUC and Cmax by 71% and 15%, respectively.(1)|
03557|061|D|   Verapamil 80 mg three times daily (a moderate CYP3A4 and P-glycoprotein|
03557|062|D|inhibitor) increased pralsetinib AUC and Cmax by 108% and 60%,|
03557|063|D|respectively.(1)|
03557|064|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
03557|065|D|idelalisib, nelfinavir, and troleandomycin.(5,6)|
03557|066|D|   Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir,|
03557|067|D|avacopan, clofazimine, conivaptan, darunavir, duvelisib, fedratinib,|
03557|068|D|fosamprenavir, fosnetupitant, imatinib, letermovir, netupitant, nilotinib,|
03557|069|D|rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(5,6)|
03557|070|D|   Dual moderate CYP3A4 and P-gp inhibitors include: berotralstat,|
03557|071|D|diltiazem, fluvoxamine, isavuconazonium, lenacapavir, schisandra, and|
03557|072|D|verapamil.(5,6)|
03557|073|B||
03557|074|R|REFERENCES:|
03557|075|B||
03557|076|R|1.Gavreto (pralsetinib) US prescribing information. Rigel Pharmaceuticals,|1
03557|077|R|  Inc. June, 2024.|1
03557|078|R|2.EMA Committee for Medicinal Products for Human Use (CHMP). Gavreto|1
03557|079|R|  (pralsetinib) European Medicines Agency Assessment Report|1
03557|080|R|  EMA/CHMP/41191/2021. Roche Registration GmbH. September 12, 2021.|1
03557|081|R|3.Gavreto (pralsetinib) Canadian Product Monograph. Hoffmann-La Roche|1
03557|082|R|  Limited May, 2024.|1
03557|083|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03557|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03557|085|R|  settings: a scientific statement from the American Heart Association and|6
03557|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03557|087|R|  2;55(9):934-47.|6
03557|088|R|5.This information is based on an extract from the Certara Drug Interaction|6
03557|089|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03557|090|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
03557|091|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03557|092|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03557|093|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03557|094|R|  11/14/2017.|1
03558|001|T|MONOGRAPH TITLE:  Pralsetinib/Dual Strong CYP3A4 and P-gp Inhibitors|
03558|002|B||
03558|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03558|004|L|of severe adverse interaction.|
03558|005|B||
03558|006|A|MECHANISM OF ACTION:  Combined strong CYP3A4 and P-glycoprotein (P-gp)|
03558|007|A|inhibitors may inhibit the metabolism of pralsetinib.(1)|
03558|008|B||
03558|009|E|CLINICAL EFFECTS:  Concurrent administration of a combined strong CYP3A4 and|
03558|010|E|P-gp inhibitor may result in elevated levels of and toxicity from|
03558|011|E|pralsetinib, including hemorrhagic events, pneumonitis, hepatotoxicity,|
03558|012|E|hypertension, and QTc prolongation, which may result in potentially|
03558|013|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1-3)|
03558|014|B||
03558|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03558|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03558|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03558|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03558|019|P|female gender, or advanced age.(4)|
03558|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03558|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03558|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03558|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03558|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03558|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03558|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03558|027|B||
03558|028|M|PATIENT MANAGEMENT:  Coadministration of pralsetinib with combined strong|
03558|029|M|CYP3A4 and P-gp inhibitors should be avoided.|
03558|030|M|   If coadministration with a combined strong CYP3A4 and P-gp inhibitor|
03558|031|M|cannot be avoided, use with caution reduce the dose of pralsetinib as|
03558|032|M|follows:|
03558|033|M|   -If the current dose is 400 mg once daily, decrease the dose to 200 mg|
03558|034|M|daily.|
03558|035|M|   -If the current dose is 300 mg once daily, decrease the dose to 200 mg|
03558|036|M|daily.|
03558|037|M|   -If the current dose is 200 mg once daily, decrease the dose to 100 mg|
03558|038|M|daily.|
03558|039|M|   After the inhibitor is discontinued for three to five half-lives, resume|
03558|040|M|the dose of pralsetinib at the dose taken prior to initiation of the|
03558|041|M|inhibitor.(1)|
03558|042|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
03558|043|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03558|044|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
03558|045|M|report any irregular heartbeat, dizziness, or fainting.|
03558|046|M|   If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until|
03558|047|M|QTc is <470 ms.  Resume pralsetinib at the same dose if risk factors that|
03558|048|M|cause QT prolongation an are identified and corrected.  If risk factors that|
03558|049|M|cause QT prolongation are not identified, resume pralsetinib at a reduced|
03558|050|M|dose.  Permanently discontinue pralsetinib if the patient develops|
03558|051|M|life-threatening arrhythmia.(3)|
03558|052|B||
03558|053|D|DISCUSSION:  Coadministration of itraconazole 200 mg once daily (a strong|
03558|054|D|CYP3A4 and P-gp inhibitor) with a single pralsetinib 200 mg dose increased|
03558|055|D|pralsetinib concentration maximum (Cmax) by 84% and area-under-curve (AUC)|
03558|056|D|by 251%.(1)|
03558|057|D|   Combined strong CYP3A4 and P-gp inhibitors linked to this monograph|
03558|058|D|include:  cobicistat, grapefruit, indinavir, itraconazole, josamycin,|
03558|059|D|ketoconazole,  mibefradil, mifepristone, nefazodone, nirmatrelvir/ritonavir,|
03558|060|D|paritaprevir, telaprevir, tipranavir, and tucatinib.(5,6)|
03558|061|B||
03558|062|R|REFERENCES:|
03558|063|B||
03558|064|R|1.Gavreto (pralsetinib) US prescribing information. Rigel Pharmaceuticals,|1
03558|065|R|  Inc. June, 2024.|1
03558|066|R|2.EMA Committee for Medicinal Products for Human Use (CHMP). Gavreto|1
03558|067|R|  (pralsetinib) European Medicines Agency Assessment Report|1
03558|068|R|  EMA/CHMP/41191/2021. Roche Registration GmbH. September 12, 2021.|1
03558|069|R|3.Gavreto (pralsetinib) Canadian Product Monograph. Hoffmann-La Roche|1
03558|070|R|  Limited May, 2024.|1
03558|071|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03558|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03558|073|R|  settings: a scientific statement from the American Heart Association and|6
03558|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03558|075|R|  2;55(9):934-47.|6
03558|076|R|5.This information is based on an extract from the Certara Drug Interaction|6
03558|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03558|078|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
03558|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03558|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03558|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03558|082|R|  11/14/2017.|1
03559|001|T|MONOGRAPH TITLE:  Ivosidenib/Strong CYP3A4 Inhibitors that Prolong QT|
03559|002|B||
03559|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03559|004|L|of severe adverse interaction.|
03559|005|B||
03559|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03559|007|A|metabolism of ivosidenib.(1)|
03559|008|A|   Use of CYP3A4 inhibitors that prolong the QTc interval may result in|
03559|009|A|additive effects on the QTc interval.|
03559|010|B||
03559|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03559|012|E|systemic exposure and the risk for ivosidenib toxicities such as QT|
03559|013|E|prolongation.(1)|
03559|014|B||
03559|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03559|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03559|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03559|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03559|019|P|gender, or advanced age.(2)|
03559|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03559|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03559|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03559|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03559|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03559|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03559|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03559|027|B||
03559|028|M|PATIENT MANAGEMENT:  Avoid concomitant use of ivosidenib and strong CYP3A|
03559|029|M|inhibitors.  Consider an alternative concomitant medication with less|
03559|030|M|potential for CYP3A4 inhibition.(1)|
03559|031|M|   The US manufacturer of ivosidenib states when concomitant use of|
03559|032|M|ivosidenib and a strong CYP3A4 inhibitor is needed, the ivosidenib dose|
03559|033|M|should be reduced to 250 mg once daily.(1)  If the strong CYP3A4 inhibitor|
03559|034|M|is discontinued, increase the ivosidenib dose to the recommended dose of 500|
03559|035|M|mg once daily after at least 5 half-lives of the strong 3A4 inhibitor.|
03559|036|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
03559|037|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03559|038|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03559|039|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03559|040|M|irregular heartbeat, dizziness, or fainting.|
03559|041|B||
03559|042|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03559|043|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
03559|044|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
03559|045|D|(AUC) by 269%.  No change was seen in ivosidenib's maximum concentration|
03559|046|D|(Cmax).(1)|
03559|047|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03559|048|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03559|049|D|by 173%.  In regards to multiple-dosing, coadministration of ivosidenib with|
03559|050|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03559|051|D|190%, respectively.(1)|
03559|052|D|   In clinical trials of ivosidenib, 9% of patients experienced a QTc|
03559|053|D|interval greater than 500 msec and 14% of patients had an increased from|
03559|054|D|baseline QTc interval of greater than 60 msec.  Patients with a baseline QTc|
03559|055|D|of equal to or greater than 450 msec without pre-existing bundle branch|
03559|056|D|block, or with a history of long QT syndrome were excluded from this|
03559|057|D|trial.(1)|
03559|058|D|   Strong CYP3A4 inhibitors linked to this monograph include:|
03559|059|D|lopinavir/ritonavir, posaconazole, saquinavir, and telithromycin.(3)|
03559|060|B||
03559|061|R|REFERENCES:|
03559|062|B||
03559|063|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03559|064|R|  Inc. August, 2021.|1
03559|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03559|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03559|067|R|  settings: a scientific statement from the American Heart Association and|6
03559|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03559|069|R|  2;55(9):934-47.|6
03559|070|R|3.This information is based on an extract from the Certara Drug Interaction|6
03559|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03560|001|T|MONOGRAPH TITLE:  Ivosidenib/Moderate CYP3A4 Inhibitors that Prolong QT|
03560|002|B||
03560|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03560|004|L|take action as needed.|
03560|005|B||
03560|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03560|007|A|metabolism of ivosidenib.(1)|
03560|008|A|   Use of CYP3A4 inhibitors that prolong the QTc interval may result in|
03560|009|A|additive effects on the QTc interval.|
03560|010|B||
03560|011|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
03560|012|E|systemic exposure and the risk for ivosidenib toxicities such as QT|
03560|013|E|prolongation.(1)|
03560|014|B||
03560|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03560|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03560|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03560|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03560|019|P|gender, or advanced age.(2)|
03560|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03560|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03560|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03560|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03560|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03560|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03560|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03560|027|B||
03560|028|M|PATIENT MANAGEMENT:  The US manufacturer of ivosidenib recommends|
03560|029|M|considering an alternative concomitant medication with less potential for|
03560|030|M|CYP3A4 inhibition.(1)|
03560|031|M|   Avoid the concurrent use of ivosidenib with medications that prolong the|
03560|032|M|QT interval.(1)|
03560|033|M|   During concomitant therapy with a moderate CYP3A4 inhibitor, monitor|
03560|034|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03560|035|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03560|036|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03560|037|M|irregular heartbeat, dizziness, or fainting.|
03560|038|M|   If QTc prolongation develops:|
03560|039|M|   ---Monitor and supplement electrolytes as clinically indicated|
03560|040|M|   ---Review and adjust concomitant QT prolonging medications|
03560|041|M|   ---Interrupt ivosidenib therapy|
03560|042|M|   ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
03560|043|M|prolongation|
03560|044|M|   ---Follow labeling recommendations regarding restarting ivosidenib.(1)|
03560|045|B||
03560|046|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03560|047|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
03560|048|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
03560|049|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
03560|050|D|(Cmax).(1)|
03560|051|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03560|052|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03560|053|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03560|054|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03560|055|D|190%, respectively.(1)|
03560|056|D|   In clinical trials of ivosidenib, 9% of patients experienced a QTc|
03560|057|D|interval greater than 500 msec and 14% of patients had an increased from|
03560|058|D|baseline QTc interval of greater than 60 msec.  Patients with a baseline QTc|
03560|059|D|of equal to or greater than 450 msec without pre-existing bundle branch|
03560|060|D|block, or with a history of long QT syndrome were excluded from this|
03560|061|D|trial.(1)|
03560|062|D|   Moderate CYP3A4 inhibitors linked to this monograph include:|
03560|063|D|fluconazole.(3)|
03560|064|B||
03560|065|R|REFERENCES:|
03560|066|B||
03560|067|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03560|068|R|  Inc. August, 2021.|1
03560|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03560|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03560|071|R|  settings: a scientific statement from the American Heart Association and|6
03560|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03560|073|R|  2;55(9):934-47.|6
03560|074|R|3.This information is based on an extract from the Certara Drug Interaction|6
03560|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03561|001|T|MONOGRAPH TITLE:  Ivosidenib/Dronedarone|
03561|002|B||
03561|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03561|004|L|of severe adverse interaction.|
03561|005|B||
03561|006|A|MECHANISM OF ACTION:  Ivosidenib is a CYP3A4 substrate and a strong CYP3A4|
03561|007|A|inducer.  Strong and moderate inhibitors of CYP3A4 like dronedarone may|
03561|008|A|inhibit the metabolism of ivosidenib.  Also, the metabolism of sensitive|
03561|009|A|substrates of CYP3A4 may be induced by ivosidenib.(1-2)|
03561|010|A|   Ivosidenib and dronedarone both prolong the QTc interval.  Concomitant|
03561|011|A|use may result in additive effects on the QTc interval.(2)|
03561|012|B||
03561|013|E|CLINICAL EFFECTS:  Concurrent use of dronedarone may increase systemic|
03561|014|E|exposure to ivosidenib and the risk for ivosidenib toxicities such as QT|
03561|015|E|prolongation.  Concomitant use may also result in decreased levels and|
03561|016|E|effectiveness of dronedarone.(1-2)|
03561|017|B||
03561|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03561|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03561|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03561|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03561|022|P|gender, or advanced age.(3)|
03561|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03561|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03561|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03561|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03561|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03561|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03561|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03561|030|P|   Induction effects may be more likely with regular use of the inducer for|
03561|031|P|longer than 1-2 weeks.|
03561|032|B||
03561|033|M|PATIENT MANAGEMENT:  Avoid the concomitant use of ivosidenib with|
03561|034|M|dronedarone.  Consider an alternative concomitant medication with less|
03561|035|M|potential for CYP3A4 interaction.(1)|
03561|036|M|   The US manufacturer of ivosidenib states that if coadministration with a|
03561|037|M|sensitive CYP3A4 substrate cannot be avoided, monitor patients for loss of|
03561|038|M|therapeutic effect of these drugs.(1)|
03561|039|M|   When concurrent therapy cannot be avoided, monitor patients closely for|
03561|040|M|prolongation of the QT interval.  Obtain ECGs and electrolyte values (serum|
03561|041|M|calcium, magnesium, and potassium) at regular intervals.  Correct any|
03561|042|M|electrolyte abnormalities.(1)|
03561|043|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03561|044|M|fainting.|
03561|045|M|   Recommended dosage modifications for ivosidenib and QTc interval|
03561|046|M|prolongation adverse reactions include:|
03561|047|M|   - QTc interval greater than 480 msec (millisecond) and less than 500|
03561|048|M|msec: Monitor and supplement electrolyte levels as clinically indicated.|
03561|049|M|Review and adjust concomitant medications with known QTc interval-prolonging|
03561|050|M|effects.  Withhold ivosidenib until after the QT interval returns to less|
03561|051|M|than or equal to 480 msec.  Resume ivosidenib at a dose of 500 mg once|
03561|052|M|daily.  Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
03561|053|M|prolongation.|
03561|054|M|   - QTc interval greater than 500 msec: Monitor and supplement electrolyte|
03561|055|M|levels as clinically indicated.  Review and adjust concomitant medications|
03561|056|M|with known QTc interval-prolonging effects.   Withhold ivosidenib until|
03561|057|M|after the QT interval returns to within 30 msec of baseline or less than or|
03561|058|M|equal to 480 msec.  Resume ivosidenib at a reduced dose of 250 mg once|
03561|059|M|daily.  Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
03561|060|M|prolongation.  Consider re-escalating the dose of ivosidenib to 500 mg daily|
03561|061|M|if an alternative etiology for QTc prolongation can be identified.|
03561|062|M|   - QTc interval prolongation with signs/symptoms of life-threatening|
03561|063|M|arrhythmia: Permanently discontinue ivosidenib.(1)|
03561|064|M|   See ivosidenib prescribing information for additional information|
03561|065|M|regarding dose reductions.(1)|
03561|066|B||
03561|067|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03561|068|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
03561|069|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
03561|070|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
03561|071|D|(Cmax).(1)|
03561|072|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03561|073|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03561|074|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03561|075|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03561|076|D|190%, respectively.(1)|
03561|077|D|   In a PBPK model, ivosidenib 500 mg for 15 days was predicted to decrease|
03561|078|D|the AUC and Cmax of midazolam 5 mg by 82% and 73%, respectively.(4)|
03561|079|D|   In clinical trials of ivosidenib, 9% of patients experienced a QTc|
03561|080|D|interval greater than 500 msec and 14% of patients had an increased from|
03561|081|D|baseline QTc interval of greater than 60 msec.  Patients with a baseline QTc|
03561|082|D|of equal to or greater than 450 msec without pre-existing bundle branch|
03561|083|D|block, or with a history of long QT syndrome were excluded from this|
03561|084|D|trial.(1)|
03561|085|B||
03561|086|R|REFERENCES:|
03561|087|B||
03561|088|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03561|089|R|  Inc. August, 2021.|1
03561|090|R|2.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
03561|091|R|  November, 2020.|1
03561|092|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03561|093|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03561|094|R|  settings: a scientific statement from the American Heart Association and|6
03561|095|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03561|096|R|  2;55(9):934-47.|6
03561|097|R|4.Bolleddula J, Ke A, Yang H, Prakash C. PBPK modeling to predict drug-drug|2
03561|098|R|  interactions of ivosidenib as a perpetrator in  cancer patients and|2
03561|099|R|  qualification of the Simcyp platform for CYP3A4 induction. CPT|2
03561|100|R|  Pharmacometrics Syst Pharmacol 2021 Jun;10(6):577-588.|2
03562|001|T|MONOGRAPH TITLE:  Lumacaftor-Ivacaftor/Strong CYP3A4 Inducers and Substrates|
03562|002|B||
03562|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03562|004|L|of severe adverse interaction.|
03562|005|B||
03562|006|A|MECHANISM OF ACTION:  Lumacaftor is a strong CYP3A4 inducer and ivacaftor is|
03562|007|A|a CYP3A4 substrate.(1)|
03562|008|A|   Strong CYP3A4 inducers may induce the metabolism of the ivacaftor|
03562|009|A|component of lumacaftor-ivacaftor.(1)|
03562|010|A|   Lumacaftor may induce the metabolism of CYP3A4 substrates.(1)|
03562|011|B||
03562|012|E|CLINICAL EFFECTS:  Concurrent or recent use of agents that are both strong|
03562|013|E|CYP3A4 inducers and CYP3A4 substrates with lumacaftor-ivacaftor may result|
03562|014|E|in decreased levels and effectiveness of both the CYP3A4 substrate and|
03562|015|E|lumacaftor-ivacaftor.(1)|
03562|016|B||
03562|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03562|018|P|of the inducer for longer than 1-2 weeks.|
03562|019|B||
03562|020|M|PATIENT MANAGEMENT:  The US manufacturer of lumacaftor-ivacaftor states to|
03562|021|M|avoid the use of strong CYP3A4 inducers in patients maintained on|
03562|022|M|lumacaftor-ivacaftor.(1)  Enzyme induction may last for several weeks after|
03562|023|M|discontinuation a CYP3A4 inducer.|
03562|024|M|   The US manufacturers of encorafenib and ivosidenib state that the|
03562|025|M|concurrent use of strong CYP3A4 inducers should be avoided.(2,3)|
03562|026|B||
03562|027|D|DISCUSSION:  Concurrent administration of the combination of|
03562|028|D|lumacaftor-ivacaftor with rifampin decreased ivacaftor area-under-curve|
03562|029|D|(AUC) 57%.(1)|
03562|030|D|   Coadministration of ivosidenib with a strong 3A4 inducer (600 mg rifampin|
03562|031|D|once daily for 15 days) is predicted to decrease ivosidenib steady state AUC|
03562|032|D|by 33%.(2)|
03562|033|D|   The concurrent use of strong CYP3A4 inducers with encorafenib has not|
03562|034|D|been studied.  Modafinil, a moderate CYP3A4 inducer, decreased the AUC and|
03562|035|D|Cmax of encorafenib 450 mg daily by 24% and 20%, respectively compared to|
03562|036|D|encorafenib alone.(3)|
03562|037|D|   Agents that are both strong CYP3A4 inducers and CYP3A4 substrates linked|
03562|038|D|to this monograph include: encorafenib and ivosidenib.(4,5)|
03562|039|B||
03562|040|R|REFERENCES:|
03562|041|B||
03562|042|R|1.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
03562|043|R|  Pharmaceuticals Inc. August, 2023.|1
03562|044|R|2.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03562|045|R|  Inc. August, 2021.|1
03562|046|R|3.Braftovi (encorafenib) capsules US prescribing information. Array|1
03562|047|R|  BioPharma December, 2024.|1
03562|048|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03562|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03562|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03562|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03562|052|R|  11/14/2017.|1
03562|053|R|5.This information is based on an extract from the Certara Drug Interaction|6
03562|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03563|001|T|MONOGRAPH TITLE:  Ivosidenib/Fedratinib|
03563|002|B||
03563|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03563|004|L|of severe adverse interaction.|
03563|005|B||
03563|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03563|007|A|metabolism of ivosidenib.(1)  Fedratinib is a moderate CYP3A4|
03563|008|A|inhibitor.(2,3)|
03563|009|A|   Fedratinib is a substrate of CYP3A4.  Strong inducers of CYP3A4 may|
03563|010|A|induce the metabolism of fedratinib.(2)  Ivosidenib is a strong CYP3A4|
03563|011|A|inducer.(1,3)|
03563|012|B||
03563|013|E|CLINICAL EFFECTS:  Concurrent use of fedratinib may increase systemic|
03563|014|E|exposure and the risk for ivosidenib toxicities such as QT prolongation.(1)|
03563|015|E|   The concurrent administration of ivosidenib, a strong CYP3A4 inducer, may|
03563|016|E|result in decreased levels and effectiveness of fedratinib.(2)|
03563|017|B||
03563|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03563|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03563|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03563|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03563|022|P|gender, or advanced age.(4)|
03563|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03563|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03563|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03563|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03563|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03563|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03563|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03563|030|B||
03563|031|M|PATIENT MANAGEMENT:  The US manufacturer of ivosidenib recommends|
03563|032|M|considering an alternative concomitant medication with less potential for|
03563|033|M|CYP3A4 inhibition.(1)|
03563|034|M|   The US manufacturer of fedratinib states that concurrent use with strong|
03563|035|M|CYP3A4 inducers like ivosidenib should be avoided.(2)|
03563|036|M|   During concomitant therapy with fedratinib and ivosidenib, monitor|
03563|037|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03563|038|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03563|039|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03563|040|M|irregular heartbeat, dizziness, or fainting.|
03563|041|B||
03563|042|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03563|043|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
03563|044|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
03563|045|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
03563|046|D|(Cmax).(1)|
03563|047|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03563|048|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03563|049|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03563|050|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03563|051|D|190%, respectively.(1)|
03563|052|D|   The effect of CYP3A4 inducers has not been studied with fedratinib.|
03563|053|D|Fedratinib is metabolized by CYP3A4.(2)|
03563|054|B||
03563|055|R|REFERENCES:|
03563|056|B||
03563|057|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03563|058|R|  Inc. August, 2021.|1
03563|059|R|2.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
03563|060|R|  May, 2023.|1
03563|061|R|3.This information is based on an extract from the Certara Drug Interaction|6
03563|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03563|063|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03563|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03563|065|R|  settings: a scientific statement from the American Heart Association and|6
03563|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03563|067|R|  2;55(9):934-47.|6
03564|001|T|MONOGRAPH TITLE:  Ivosidenib/Tucatinib|
03564|002|B||
03564|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03564|004|L|of severe adverse interaction.|
03564|005|B||
03564|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03564|007|A|metabolism of ivosidenib.(1)  Tucatinib is a strong CYP3A4 inhibitor.(2,3)|
03564|008|A|   Tucatinib is a substrate of CYP3A4 and CYP2C8.  Strong inducers of CYP3A4|
03564|009|A|or moderate inducers of CYP2C8 may induce the metabolism of tucatinib.(2)|
03564|010|A|Ivosidenib is a strong CYP3A4 and moderate CYP2C8 inducer.(1,3)|
03564|011|B||
03564|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03564|013|E|systemic exposure and the risk for ivosidenib toxicities such as QT|
03564|014|E|prolongation.(1)|
03564|015|E|   Concurrent use of a strong inducer of CYP3A4 or a moderate inducer of|
03564|016|E|CYP2C8 may result in decreased levels and effectiveness of tucatinib.(2)|
03564|017|E|Ivosidenib is an inducers of both metabolism pathways.(1,3)|
03564|018|B||
03564|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03564|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03564|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03564|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03564|023|P|gender, or advanced age.(4)|
03564|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03564|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03564|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03564|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03564|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03564|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03564|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03564|031|B||
03564|032|M|PATIENT MANAGEMENT:  Avoid concomitant use of ivosidenib and strong CYP3A|
03564|033|M|inhibitors. Consider an alternative concomitant medication with less|
03564|034|M|potential for CYP3A4 inhibition.(1)|
03564|035|M|   The US manufacturer of ivosidenib states when concomitant use of|
03564|036|M|ivosidenib and a strong CYP3A4 inhibitor is needed, the ivosidenib dose|
03564|037|M|should be reduced to 250 mg once daily.(1) If the strong CYP3A4 inhibitor is|
03564|038|M|discontinued, increase the ivosidenib dose to the recommended dose of 500 mg|
03564|039|M|once daily after at least 5 half-lives of the strong 3A4 inhibitor.|
03564|040|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
03564|041|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03564|042|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03564|043|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03564|044|M|irregular heartbeat, dizziness, or fainting.|
03564|045|M|   The manufacturer of tucatinib states to avoid concurrent administration|
03564|046|M|with strong CYP3A4 inducers or moderate CYP2C8 inducers.(2)|
03564|047|B||
03564|048|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03564|049|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
03564|050|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
03564|051|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
03564|052|D|(Cmax).(1)|
03564|053|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03564|054|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03564|055|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03564|056|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03564|057|D|190%, respectively.(1)|
03564|058|D|   Coadministration of rifampin (a strong CYP3A4 and moderate CYP2C8 inducer|
03564|059|D|- 600 mg once daily) decreased the area-under-the-curve (AUC) and maximum|
03564|060|D|concentration (Cmax) of tucatinib (300 mg single dose) by 50% and 40%,|
03564|061|D|respectively.(2)|
03564|062|B||
03564|063|R|REFERENCES:|
03564|064|B||
03564|065|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03564|066|R|  Inc. August, 2021.|1
03564|067|R|2.Tukysa (tucatinib) US prescribing information. Seattle Genetics April,|1
03564|068|R|  2020.|1
03564|069|R|3.This information is based on an extract from the Certara Drug Interaction|6
03564|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03564|071|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03564|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03564|073|R|  settings: a scientific statement from the American Heart Association and|6
03564|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03564|075|R|  2;55(9):934-47.|6
03565|001|T|MONOGRAPH TITLE:  Lumacaftor-Ivacaftor/Strong CYP3A4 Inducers|
03565|002|B||
03565|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03565|004|L|of severe adverse interaction.|
03565|005|B||
03565|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03565|007|A|lumacaftor-ivacaftor.(1)|
03565|008|B||
03565|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
03565|010|E|may result in decreased levels and effectiveness of lumacaftor-ivacaftor.(1)|
03565|011|B||
03565|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03565|013|P|of the inducer for longer than 1-2 weeks.|
03565|014|B||
03565|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inducers in patients|
03565|016|M|maintained on lumacaftor-ivacaftor.(1)  Enzyme induction may last for|
03565|017|M|several weeks after discontinuation a CYP3A4 inducer.|
03565|018|B||
03565|019|D|DISCUSSION:  Concurrent administration of the combination of|
03565|020|D|lumacaftor-ivacaftor with rifampin decreased ivacaftor area-under-curve|
03565|021|D|(AUC) 57%.(1)|
03565|022|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03565|023|D|carbamazepine, enzalutamide, fosphenytoin, mitotane, phenobarbital,|
03565|024|D|phenytoin, primidone, rifampin, rifapentine and St. John's wort.(1-2)|
03565|025|B||
03565|026|R|REFERENCES:|
03565|027|B||
03565|028|R|1.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
03565|029|R|  Pharmaceuticals Inc. August, 2023.|1
03565|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03565|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03565|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03565|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03565|034|R|  11/14/2017.|1
03566|001|T|MONOGRAPH TITLE:  Elvitegravir-Cobicistat-Tenofovir disoproxil/Ledipasvir|
03566|002|B||
03566|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03566|004|L|take action as needed.|
03566|005|B||
03566|006|A|MECHANISM OF ACTION:  Tenofovir is a substrate of the P-glycoprotein (P-gp)|
03566|007|A|and BCRP transporters.(1)  Ledipasvir inhibits P-gp and BCRP.(2)|
03566|008|B||
03566|009|E|CLINICAL EFFECTS:  Coadministration of ledipasvir with tenofovir disoproxil|
03566|010|E|(TDF) (given as the fixed-dose combination of|
03566|011|E|elvitegravir-cobicistat-TDF-emtricitabine) may increase the levels and|
03566|012|E|toxicity of tenofovir, including new onset or worsening renal impairment,|
03566|013|E|acute renal failure and Fanconi syndrome.(2,3)|
03566|014|B||
03566|015|P|PREDISPOSING FACTORS:  Patients with baseline impaired renal function or who|
03566|016|P|are receiving concomitant nephrotoxic agents may have an increased risk of|
03566|017|P|renal-related adverse events.(3)|
03566|018|B||
03566|019|M|PATIENT MANAGEMENT:  The manufacturers of ledipasvir-sofosbuvir and|
03566|020|M|elvitegravir-cobicistat-TDF-emtricitabine state that coadministration of|
03566|021|M|these two combinations is not recommended.(2,3)|
03566|022|B||
03566|023|D|DISCUSSION:  Concurrent use of ledipasvir-sofosbuvir and|
03566|024|D|elvitegravir-cobicistat-TDF-emtricitabine has not been studied.  Since the|
03566|025|D|safety of this combination is unknown, coadministration is not|
03566|026|D|recommended.(2,3)|
03566|027|D|   Ledipasvir-sofosbuvir has been studied in combination with|
03566|028|D|elvitegravir-cobicistat-tenofovir alafenamide-emtricitabine.  In healthy|
03566|029|D|subjects, the area-under-curve (AUC) of tenofovir decreased by 14% when|
03566|030|D|coadministered with ledipasvir-sofosbuvir.(4)|
03566|031|D|   In clinical trials, ledipasvir-sofosbuvir increased the AUC of TDF (given|
03566|032|D|in combination with atazanavir-ritonavir or darunavir-ritonavir) by 1.35- to|
03566|033|D|1.5-fold.  When TDF was given in combination with efavirenz, rilpivirine, or|
03566|034|D|dolutegravir, concurrent use of ledipasvir-sofosbuvir increased the AUC of|
03566|035|D|tenofovir by about 2-fold.(1)|
03566|036|B||
03566|037|R|REFERENCES:|
03566|038|B||
03566|039|R|1.Viread (tenofovir disoproxil fumarate) US prescribing information. Gilead|1
03566|040|R|  Sciences, Inc. December, 2018.|1
03566|041|R|2.Harvoni (ledipasvir and sofosbuvir) US prescribing information. Gilead|1
03566|042|R|  Sciences November, 2019.|1
03566|043|R|3.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
03566|044|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
03566|045|R|4.Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
03566|046|R|  prescribing information. Gilead Sciences, Inc September, 2021.|1
03567|001|T|MONOGRAPH TITLE:  Chenodiol/Aluminum-Based Antacids; Bile Acid Sequestrants|
03567|002|B||
03567|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03567|004|L|take action as needed.|
03567|005|B||
03567|006|A|MECHANISM OF ACTION:  Aluminum-based antacids, cholestyramine, or colestipol|
03567|007|A|may bind to chenodiol, which may decrease gastrointestinal absorption and|
03567|008|A|impair enterohepatic recirculation of chenodiol.(1,2)|
03567|009|B||
03567|010|E|CLINICAL EFFECTS:  Simultaneous administration of an aluminum-based antacid,|
03567|011|E|cholestyramine, or colestipol may result in decreased absorption and|
03567|012|E|effectiveness of chenodiol.(1,2)|
03567|013|B||
03567|014|P|PREDISPOSING FACTORS:  None determined.|
03567|015|B||
03567|016|M|PATIENT MANAGEMENT:  If concomitant therapy with aluminum-based antacids or|
03567|017|M|colestipol is necessary, administer chenodiol at least 2 hours before or|
03567|018|M|after the antacid or colestipol.|
03567|019|M|   If concomitant therapy with cholestyramine is necessary, administer|
03567|020|M|chenodiol at least 1 hour before or 4-6 hours after cholestyramine.(2)|
03567|021|B||
03567|022|D|DISCUSSION:  Aluminum-based antacids have been shown to adsorb bile acids in|
03567|023|D|vitro.  Bile acid sequestrants reduce bile acid absorption.(1)|
03567|024|B||
03567|025|R|REFERENCES:|
03567|026|B||
03567|027|R|1.Chenodol (chenodiol) US prescribing information. Retrophin, Inc. June,|1
03567|028|R|  2020.|1
03567|029|R|2.Chenodeoxycholic Acid Leadiant EMA Summary of Product Characteristics.|1
03567|030|R|  Leadiant GmbH November 24, 2017.|1
03568|001|T|MONOGRAPH TITLE:  Warfarin/Melatonin|
03568|002|B||
03568|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
03568|004|L|Assess the risk to the patient and take action as needed.|
03568|005|B||
03568|006|A|MECHANISM OF ACTION:  Concurrent use of melatonin with warfarin may result|
03568|007|A|in altered prothrombin time, although exact mechanism is unknown.(1-4)|
03568|008|B||
03568|009|E|CLINICAL EFFECTS:  Concurrent use of warfarin and melatonin may result in|
03568|010|E|altered INR values and increased risk of bleeding or thrombosis.|
03568|011|B||
03568|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03568|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03568|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
03568|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03568|016|P|risk for bleeding (e.g. NSAIDs).|
03568|017|B||
03568|018|M|PATIENT MANAGEMENT:  Advise patients against using alternative therapy|
03568|019|M|agents with warfarin and to report the initiation or discontinuation of any|
03568|020|M|alternative therapy agents.|
03568|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03568|022|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03568|023|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03568|024|M|patients with any symptoms.|
03568|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03568|026|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03568|027|M|anticoagulation in patients with active pathologic bleeding.|
03568|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03568|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03568|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03568|031|M|and/or swelling.|
03568|032|M|   The time of highest risk for a coumarin-type drug interaction is when|
03568|033|M|melatonin is initiated or discontinued. Contact the prescriber before|
03568|034|M|initiating, altering the dose or discontinuing either drug.|
03568|035|B||
03568|036|D|DISCUSSION:  There are several case reports of potential interactions with|
03568|037|D|warfarin and melatonin.  Three cases report an increased prothrombin time|
03568|038|D|and three cases report decreased prothrombin time while taking melatonin|
03568|039|D|with warfarin.(1)  One study reports melatonin may reduce levels of several|
03568|040|D|coagulation factors, increasing the risk of bleeding.(2)|
03568|041|D|   Melatonin is also metabolized via CYP2C9, the major CYP enzyme in which|
03568|042|D|metabolizes warfarin.  Theoretically, this may cause an interaction.(3,4)|
03568|043|B||
03568|044|R|REFERENCES:|
03568|045|B||
03568|046|R|1.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
03568|047|R|  Squibb Company September, 2016.|1
03568|048|R|2.Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet|6
03568|049|R|  lag. Cochrane Database Syst Rev 2002;CD001520.|6
03568|050|R|3.Wirtz PH, Spillmann M, BCoschi C, Ehlert U, von Konel R. Oral melatonin|6
03568|051|R|  reduces blood coagulation activity: a placebo-controlled study in  healthy|6
03568|052|R|  young men. J Pineal Res 2008 Mar;44(2):127-33.|6
03568|053|R|4.Zhou SF, Zhou ZW, Yang LP, Cai JP. Substrates, inducers, inhibitors and|6
03568|054|R|  structure-activity relationships of human  Cytochrome P450 2C9 and|6
03568|055|R|  implications in drug development. Curr Med Chem 2009;16(27):3480-675.|6
03569|001|T|MONOGRAPH TITLE:  Bosentan/Fluconazole|
03569|002|B||
03569|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03569|004|L|of severe adverse interaction.|
03569|005|B||
03569|006|A|MECHANISM OF ACTION:  Bosentan is metabolized by CYP2C9 and CYP3A4.  It is|
03569|007|A|also an inducer of these enzymes.  With regular dosing bosentan auto-induces|
03569|008|A|its own metabolism.(1)  Fluconazole is a moderate inhibitor of CYP2C9 and|
03569|009|A|CYP3A4 and may inhibit the metabolism of bosentan.(1,2)|
03569|010|B||
03569|011|E|CLINICAL EFFECTS:  Concurrent use of bosentan with fluconazole may result in|
03569|012|E|elevated levels of and toxicity from bosentan.(1)|
03569|013|B||
03569|014|P|PREDISPOSING FACTORS:  None determined.|
03569|015|B||
03569|016|M|PATIENT MANAGEMENT:  The US manufacturer of bosentan states that|
03569|017|M|coadministration of bosentan and fluconazole is not recommended due to|
03569|018|M|possible large increases in bosentan plasma concentrations.(1)|
03569|019|M|   For patients stabilized on bosentan when fluconazole is initiated,|
03569|020|M|monitor tolerance to concomitant therapy and adjust bosentan dose if needed.|
03569|021|B||
03569|022|D|DISCUSSION:  The combination of bosentan and fluconazole has not been|
03569|023|D|studied.  In a study in healthy subjects, concurrent bosentan and|
03569|024|D|ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan|
03569|025|D|steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by|
03569|026|D|2.1-fold and 2.3-fold, respectively.(1)|
03569|027|B||
03569|028|R|REFERENCES:|
03569|029|B||
03569|030|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
03569|031|R|  US, Inc. September 5, 2017.|1
03569|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
03569|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03570|001|T|MONOGRAPH TITLE:  Entacapone/Oral Iron Supplements|
03570|002|B||
03570|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03570|004|L|take action as needed.|
03570|005|B||
03570|006|A|MECHANISM OF ACTION:  Entacapone may chelate with iron within the|
03570|007|A|gastrointestinal tract, reducing the absorption of both drugs.|
03570|008|B||
03570|009|E|CLINICAL EFFECTS:  Simultaneous administration of entacapone and orally|
03570|010|E|administered iron may decrease the clinical effects of both medications.|
03570|011|B||
03570|012|P|PREDISPOSING FACTORS:  None determined.|
03570|013|B||
03570|014|M|PATIENT MANAGEMENT:  Iron supplements should not be taken within 2-3 hours|
03570|015|M|before or after entacapone to minimize the effects of this interaction.(1)|
03570|016|M|   Some multivitamin preparations that contain sufficient quantities of iron|
03570|017|M|may interact and not be properly absorbed as well.|
03570|018|B||
03570|019|D|DISCUSSION:  Entacapone may form chelates with iron in the gastrointestinal|
03570|020|D|tract, and preparations should be taken at least 2-3 hours apart.(1)|
03570|021|D|  Although the impact on the body's iron stores is unknown, clinical studies|
03570|022|D|showed decreasing serum iron concentrations with coadministration of|
03570|023|D|entacapone.(2) In repeated dose toxicity studies, anemia was observed most|
03570|024|D|likely due to the iron chelating properties of entacapone.(1)  Prescribing|
03570|025|D|information of entacapone/levodopa/carbidopa states chelation of entacapone|
03570|026|D|with iron may decrease bioavailability of entacapone/levodopa/carbidopa.(3)|
03570|027|B||
03570|028|R|REFERENCES:|
03570|029|B||
03570|030|R|1.Entacapone UK summary of prescribing characteristics. Mylan|1
03570|031|R|  Pharmaceuticals Inc. December, 2017.|1
03570|032|R|2.Comtan (entacapone) US prescribing information. Orion Corporation|1
03570|033|R|  February, 2016.|1
03570|034|R|3.Stalveo (carbidopa; entacapone; levodopa) US Prescribing Information.|1
03570|035|R|  Orion/Novartis December, 2019.|1
03571|001|T|MONOGRAPH TITLE:  Pioglitazone; Repaglinide/Abiraterone|
03571|002|B||
03571|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03571|004|L|of severe adverse interaction.|
03571|005|B||
03571|006|A|MECHANISM OF ACTION:  The mechanism of interaction is not fully understood|
03571|007|A|but may at least partially involve CYP2C8 inhibition by abiraterone,|
03571|008|A|resulting in decreased metabolism of pioglitazone and repaglinide.(1,2)|
03571|009|B||
03571|010|E|CLINICAL EFFECTS:  Concurrent use of pioglitazone or repaglinide with|
03571|011|E|abiraterone may result in elevated levels and clinical effects of the|
03571|012|E|anti-diabetic agents, including severe hypoglycemia.(1)|
03571|013|B||
03571|014|P|PREDISPOSING FACTORS:  None determined.|
03571|015|B||
03571|016|M|PATIENT MANAGEMENT:  Monitor blood glucose in patients with diabetes during|
03571|017|M|and after discontinuation of treatment with abiraterone.  Consider dosage|
03571|018|M|adjustment of pioglitazone or repaglinide to minimize the risk of|
03571|019|M|hypoglycemia.(1)|
03571|020|B||
03571|021|D|DISCUSSION:  Severe hypoglycemia has been reported in diabetic patients|
03571|022|D|receiving pioglitazone or repaglinide concurrently with abiraterone.|
03571|023|D|   A review of the FDA Adverse Events Reporting database found 2 reports of|
03571|024|D|hypoglycemia in patients receiving concurrent abiraterone and repaglinide.|
03571|025|D|One patient was hospitalized with life-threatening outcomes, and the other|
03571|026|D|died, though he also had sepsis and cardiac failure.|
03571|027|D|   In a study of 16 healthy volunteers, single-dose abiraterone 1,000 mg|
03571|028|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
03571|029|D|single-dose pioglitazone 15 mg by 23% and 46%.(3)|
03571|030|B||
03571|031|R|REFERENCES:|
03571|032|B||
03571|033|R|1.Zytiga (abiraterone acetate) US prescribing information. Centocor Ortho|1
03571|034|R|  Biotech, Inc. October, 2020.|1
03571|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
03571|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03571|037|R|3.Monbaliu J, Gonzalez M, Bernard A, Jiao J, Sensenhauser C, Snoeys J,|2
03571|038|R|  Stieltjes H, Wynant I, Smit JW, Chien C. In Vitro and In Vivo Drug-Drug|2
03571|039|R|  Interaction Studies to Assess the Effect of  Abiraterone Acetate,|2
03571|040|R|  Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity. Drug Metab|2
03571|041|R|  Dispos 2016 Oct;44(10):1682-91.|2
03572|001|T|MONOGRAPH TITLE:  Ustekinumab/Immunosuppressives; Immunomodulators|
03572|002|B||
03572|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03572|004|L|take action as needed.|
03572|005|B||
03572|006|A|MECHANISM OF ACTION:  Ustekinumab, immunosuppressives, and immunomodulators|
03572|007|A|all suppress the immune system.(1)|
03572|008|B||
03572|009|E|CLINICAL EFFECTS:  Concurrent use of ustekinumab with immunosuppressive or|
03572|010|E|immunomodulating agents may result in an increased risk for serious|
03572|011|E|infections.(1)|
03572|012|B||
03572|013|P|PREDISPOSING FACTORS:  None determined.|
03572|014|B||
03572|015|M|PATIENT MANAGEMENT:  The US manufacturer of ustekinumab recommends caution|
03572|016|M|because the concurrent use of ustekinumab with immunosuppressive agents may|
03572|017|M|increase the risk of infection.  If concurrent therapy is warranted,|
03572|018|M|consider the risk of additive immune suppression and monitor based on|
03572|019|M|prescribing information for both agents.(1)|
03572|020|B||
03572|021|D|DISCUSSION:  Ustekinumab has not been studied in combination with other|
03572|022|D|immunosuppressants in psoriasis studies.  In psoriatic arthritis studies,|
03572|023|D|concomitant methotrexate use did not appear to influence the safety or|
03572|024|D|efficacy of ustekinumab.  In Crohn's disease and ulcerative colitis studies,|
03572|025|D|concomitant use of immunosuppressants or corticosteroids did not appear to|
03572|026|D|influence the safety or efficacy of ustekinumab.  If concurrent therapy is|
03572|027|D|warranted, consider the potential for increased immunosuppressive risks from|
03572|028|D|both agents.(1)|
03572|029|D|   The most common infections reported by ustekinumab treated patients in|
03572|030|D|the clinical trial periods included nasopharyngitis(8%) and upper|
03572|031|D|respiratory tract infection(5%).  Serious bacterial, mycobacterial, fungal,|
03572|032|D|and viral infections were observed in patients receiving ustekinumab.  Cases|
03572|033|D|of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic|
03572|034|D|organizing pneumonia resulting in respiratory failure or prolonged|
03572|035|D|hospitalization have been reported in patients receiving ustekinumab.(1)|
03572|036|B||
03572|037|R|REFERENCE:|
03572|038|B||
03572|039|R|1.Stelara (ustekinumab) US prescribing information. Janssen Biotech, Inc.|1
03572|040|R|  March, 2024.|1
03573|001|T|MONOGRAPH TITLE:  Long-acting Bupivacaine/Local Anesthetics|
03573|002|B||
03573|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03573|004|L|of severe adverse interaction.|
03573|005|B||
03573|006|A|MECHANISM OF ACTION:  Concurrent use of other local anesthetics or use of|
03573|007|A|other local anesthetics within 96 hours following long-acting bupivacaine|
03573|008|A|may result in additive neurologic and cardiovascular effects.  Use of|
03573|009|A|articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine,|
03573|010|A|procaine, ropivacaine, and tetracaine may also increase the risk of|
03573|011|A|methemoglobinemia.(1,2)|
03573|012|A|   Non-liposomal bupivacaine may impact the pharmacokinetic and/or|
03573|013|A|physicochemical properties of the liposomal formulation when administered in|
03573|014|A|the same syringe or used simultaneously unless the ratio of mg of|
03573|015|A|non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed|
03573|016|A|1:2.(1)|
03573|017|A|   Local anesthetics other than bupivacaine may trigger the immediate|
03573|018|A|release of bupivacaine from the liposomal formulation when administered|
03573|019|A|together locally.(1)|
03573|020|B||
03573|021|E|CLINICAL EFFECTS:  Concurrent or use of local anesthetics with 96 hours of|
03573|022|E|use of long-acting bupivacaine may result in neurologic and cardiovascular|
03573|023|E|toxicity.  Use of articaine, benzocaine, bupivacaine, lidocaine,|
03573|024|E|mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also|
03573|025|E|result in methemoglobinemia.(1,2)|
03573|026|E|   Non-liposomal bupivacaine may impact the pharmacokinetic and/or|
03573|027|E|physicochemical properties of the liposomal formulation when administered in|
03573|028|E|the same syringe or used simultaneously unless the ratio of mg of|
03573|029|E|non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed|
03573|030|E|1:2.(1)|
03573|031|E|   Local anesthetics other than bupivacaine may trigger the immediate|
03573|032|E|release of bupivacaine from the liposomal formulation when administered|
03573|033|E|together locally.(1)|
03573|034|B||
03573|035|P|PREDISPOSING FACTORS:  Use of additional agents that are associated with|
03573|036|P|methemoglobinemia may further increase the risk of methemoglobinemia.(1)|
03573|037|P|   Patients who are at increased risk of developing methemoglobinemia|
03573|038|P|include those with glucose-6-phosphate dehydrogenase deficiency, congenital|
03573|039|P|or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants|
03573|040|P|under 6 months of age, and concurrent exposure to oxidizing agents or their|
03573|041|P|metabolites are more susceptible to developing clinical manifestations of|
03573|042|P|the condition.  If local anesthetics must be used in these patients, close|
03573|043|P|monitoring for symptoms and signs of methemoglobinemia is recommended.(1)|
03573|044|B||
03573|045|M|PATIENT MANAGEMENT:  Avoid the use of other local anesthetics within 96|
03573|046|M|hours following the administration of long-acting bupivacaine.  In patients|
03573|047|M|for whom use is required, monitor for neurologic and cardiovascular effects.|
03573|048|M|Also monitor for methemoglobinemia with use of articaine, benzocaine,|
03573|049|M|bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and|
03573|050|M|tetracaine.(1,2)|
03573|051|M|   Non-liposomal bupivacaine may be administered in the same syringe as|
03573|052|M|bupivacaine liposomal or injected immediately before bupivacaine liposomal|
03573|053|M|as long as the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine|
03573|054|M|liposomal does not exceed 1:2.(1)|
03573|055|M|   Lidocaine may be administered 20 minutes or more prior to bupivacaine.|
03573|056|M|It is unknown if other local anesthetics may be used without compromising|
03573|057|M|the release characteristic of bupivacaine liposomal.(1)|
03573|058|B||
03573|059|D|DISCUSSION:  Concurrent use of other local anesthetics or use of other local|
03573|060|D|anesthetics within 96 hours following long-acting bupivacaine may result in|
03573|061|D|additive neurologic and cardiovascular effects.  Use of articaine,|
03573|062|D|benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine,|
03573|063|D|ropivacaine, and tetracaine may also increase the risk of|
03573|064|D|methemoglobinemia.(1,2)|
03573|065|D|   Non-liposome bupivacaine may impact the pharmacokinetic and/or|
03573|066|D|physicochemical properties of the liposomal formulation when administered in|
03573|067|D|the same syringe or used simultaneously unless the ratio of mg of|
03573|068|D|non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed|
03573|069|D|1:2.(1)|
03573|070|D|   Local anesthetics other than bupivacaine may trigger the immediate|
03573|071|D|release of bupivacaine from the liposomal formulation when administered|
03573|072|D|together locally.  Lidocaine may be administered 20 minutes or more prior to|
03573|073|D|bupivacaine.  It is unknown if other local anesthetics may be used without|
03573|074|D|compromising the release characteristic of bupivacaine liposomal.(1)|
03573|075|B||
03573|076|R|REFERENCES:|
03573|077|B||
03573|078|R|1.Exparel (bupivacaine liposomal) US prescribing information. Pacira|1
03573|079|R|  Pharmaceuticals, Inc. March 26, 2021.|1
03573|080|R|2.Zynrelef (bupivacaine and meloxicam) US prescribing information. Heron|1
03573|081|R|  Therapeutics, Inc. December, 2021.|1
03574|001|T|MONOGRAPH TITLE:  Selected MATE Substrates/MATE Inhibitors|
03574|002|B||
03574|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03574|004|L|of severe adverse interaction.|
03574|005|B||
03574|006|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
03574|007|A|renal protein transporters in the kidneys may inhibit the transport of MATE|
03574|008|A|substrates.(1)|
03574|009|A|   Acyclovir, cephalexin, and valacyclovir are MATE substrates.|
03574|010|B||
03574|011|E|CLINICAL EFFECTS:  Concurrent use of MATE renal transporter inhibitors may|
03574|012|E|result in increased levels of and toxicity from MATE substrates.(1)|
03574|013|B||
03574|014|P|PREDISPOSING FACTORS:  None determined.|
03574|015|B||
03574|016|M|PATIENT MANAGEMENT:  Avoid concurrent use of acyclovir, cephalexin, or|
03574|017|M|valacyclovir with MATE renal transporter inhibitors.  If concurrent use|
03574|018|M|cannot be avoided, monitor for toxicity of the MATE substrate and consider|
03574|019|M|dosage reduction of the MATE substrate.(1)|
03574|020|B||
03574|021|D|DISCUSSION:  Based upon in vitro data, risdiplam is expected to produce|
03574|022|D|clinically significant inhibition of MATE1 and MATE2-K transporters at|
03574|023|D|clinically relevant concentrations.(1)|
03574|024|D|   Selected MATE substrates linked include: acyclovir, cephalexin, and|
03574|025|D|valacyclovir.(1,2)|
03574|026|D|   MATE inhibitors include: cimetidine, pyrimethamine, risdiplam, and|
03574|027|D|vandetanib.(2)|
03574|028|B||
03574|029|R|REFERENCES:|
03574|030|B||
03574|031|R|1.Evrysdi (risdiplam) US prescribing information. Genentech, Inc. September|1
03574|032|R|  30, 2020.|1
03574|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
03574|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03575|001|T|MONOGRAPH TITLE:  Selected Mesalamine/Antacids|
03575|002|B||
03575|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03575|004|L|of severe adverse interaction.|
03575|005|B||
03575|006|A|MECHANISM OF ACTION:  Certain mesalamine formulations (namely Apriso)|
03575|007|A|contain granules with an enteric coating that dissolves at pH 6 and above.|
03575|008|A|Antacids may raise the intragastric pH, resulting in premature release of|
03575|009|A|the drug in the stomach.(1)|
03575|010|B||
03575|011|E|CLINICAL EFFECTS:  Simultaneous administration of certain mesalamine|
03575|012|E|formulations (namely Apriso) with an antacid may result in premature release|
03575|013|E|of mesalamine in the stomach and decreased effectiveness in the intestines|
03575|014|E|and colon.(1-2)|
03575|015|B||
03575|016|P|PREDISPOSING FACTORS:  None determined.|
03575|017|B||
03575|018|M|PATIENT MANAGEMENT:  The manufacturer of Apriso states that coadministration|
03575|019|M|with antacids should be avoided.(1)|
03575|020|M|   Some vitamin preparations may contain sufficient quantities of calcium|
03575|021|M|and/or magnesium salts with antacid properties to interact as well.|
03575|022|B||
03575|023|D|DISCUSSION:  Dissolution of the enteric coating of mesalamine is|
03575|024|D|pH-dependent.  Coadministration of certain mesalamine formulations (namely|
03575|025|D|Apriso) with antacids should be avoided.(1)|
03575|026|B||
03575|027|R|REFERENCE:|
03575|028|B||
03575|029|R|1.Apriso (mesalamine) US prescribing information. Salix Pharmaceuticals,|1
03575|030|R|  Inc. November, 2022.|1
03576|001|T|MONOGRAPH TITLE:  Ticagrelor/Tipranavir|
03576|002|B||
03576|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03576|004|L|is contraindicated and generally should not be dispensed or administered to|
03576|005|L|the same patient.|
03576|006|B||
03576|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03576|008|A|of ticagrelor.(1,2)  Tipranavir is a strong inhibitor of CYP3A4.(3)|
03576|009|A|   In addition, tipranavir has been shown to inhibit platelet aggregation in|
03576|010|A|vitro in human platelets(4-6) and in rodents.(4,5)  The mechanism behind|
03576|011|A|this platelet aggregation is unknown.(4,5)|
03576|012|B||
03576|013|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03576|014|E|in a substantial increase in exposure to and effects from ticagrelor.(1,2)|
03576|015|E|   Concurrent use of tipranavir with ticagrelor may also result in additive|
03576|016|E|or synergistic effects on inhibition of platelet aggregation, including|
03576|017|E|fatal and non-fatal intracranial hemorrhage.(4-6)|
03576|018|B||
03576|019|P|PREDISPOSING FACTORS:  The risk of intracranial hemorrhage may be increased|
03576|020|P|by CNS lesions, head trauma, neurosurgery, coagulopathy, hypertension, or|
03576|021|P|alcohol abuse.(4-6)|
03576|022|P|   The risk for bleeding episodes may also be greater in patients with other|
03576|023|P|disease-associated factors (e.g. thrombocytopenia).|
03576|024|P|   Drug associated risk factors include concurrent use of multiple drugs|
03576|025|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03576|026|P|risk for bleeding (e.g. NSAIDs).|
03576|027|B||
03576|028|M|PATIENT MANAGEMENT:  The UK manufacturer of ticagrelor states that|
03576|029|M|concurrent use of strong CYP3A4 inhibitors is contraindicated.(1)|
03576|030|M|   The US manufacturer of ticagrelor states that concurrent use of strong|
03576|031|M|CYP3A4 inhibitors should be avoided.(2)|
03576|032|M|   Tipranavir should be administered with caution in patients receiving|
03576|033|M|anticoagulants and/or antiplatelet agents.|
03576|034|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03576|035|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03576|036|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03576|037|M|patients with any symptoms.|
03576|038|M|   Patients should be warned that tipranavir has been associated with fatal|
03576|039|M|and non-fatal intracranial hemorrhage and instructed to report any unusual|
03576|040|M|or unexplained bleeding to their physician.(4-6)  Signs or symptoms of|
03576|041|M|bleeding may include unusual bleeding from the gums or nose; unusual|
03576|042|M|bruising; red or black, tarry stools; red, pink or dark brown urine; acute|
03576|043|M|abdominal or joint pain and/or swelling.|
03576|044|B||
03576|045|D|DISCUSSION:  Concurrent ketoconazole (strong CYP3A4 inhibitor) increased|
03576|046|D|ticagrelor maximum concentration (Cmax) and area-under-curve (AUC) by|
03576|047|D|2.4-fold and 7.3-fold, respectively.  The Cmax and AUC of the active|
03576|048|D|ticagrelor metabolite decreased by 89% and 56%, respectively.(1)|
03576|049|D|   As of June 7, 2006,(4) the manufacturer of tipranavir has has identified|
03576|050|D|14 cases of intracranial hemorrhage, including 8 fatalities, in 13 out of|
03576|051|D|6,840 HIV+ subjects in clinical trials.(4,6)  No pattern of abnormal|
03576|052|D|coagulation parameters has been noted in patients receiving tipranavir in|
03576|053|D|general or preceding the development of intracranial hemorrhage.(4-6)|
03576|054|D|   In vitro tests showed that tipranavir inhibits human platelet aggregation|
03576|055|D|at concentrations consistent with normal exposure during therapy.  In|
03576|056|D|rodents, tipranavir resulted in increased prothrombin and activated partial|
03576|057|D|thromboplastin times.  At higher doses and in extreme cases, these changes|
03576|058|D|resulted in bleeding in multiple organs and death.  This effect was not seen|
03576|059|D|in studies in dogs.(4,5)|
03576|060|B||
03576|061|R|REFERENCES:|
03576|062|B||
03576|063|R|1.Brilique (ticagrelor) UK summary of product characteristics. AstraZeneca|1
03576|064|R|  UK Limited October 24, 2012.|1
03576|065|R|2.Brilinta (ticagrelor) US prescribing information. AstraZeneca LP November,|1
03576|066|R|  2024.|1
03576|067|R|3.This information is based on an extract from the Certara Drug Interaction|6
03576|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03576|069|R|4.Dear Healthcare Professional:  Subject:  Important safety information:|1
03576|070|R|  Intracranial hemorrhage in patients receiving Aptivus (tipranavir)|1
03576|071|R|  capsules. Boehringer Ingelheim June 30, 2006.|1
03576|072|R|5.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
03576|073|R|  Pharmaceuticals, Inc. April, 2024.|1
03576|074|R|6.Dear Canadian Healthcare Professional:  Subject:  Important safety|1
03576|075|R|  information:  Intracranial hemorrhage in patients receiving Aptivus|1
03576|076|R|  (tipranavir) capsules. Boehringer Ingelheim June 29, 2006.|1
03577|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Posaconazole|
03577|002|B||
03577|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03577|004|L|is contraindicated and generally should not be dispensed or administered to|
03577|005|L|the same patient.|
03577|006|B||
03577|007|A|MECHANISM OF ACTION:  Posaconazole may inhibit CYP3A4 mediated metabolism of|
03577|008|A|methadone, resulting in elevated methadone levels.(1,2)  Methadone and|
03577|009|A|posaconazole have been associated with prolongation of the QTc|
03577|010|A|interval.(1,2)|
03577|011|A|   Levomethadone is an enantiomer of methadone.(3)|
03577|012|B||
03577|013|E|CLINICAL EFFECTS:  Increased methadone levels may be associated with|
03577|014|E|profound sedation, respiratory depression, coma, and/or death or other|
03577|015|E|opioid toxicities, and with an increased risk for QT prolongation.(4)|
03577|016|E|   Concurrent use of multiple agents that prolong the QTc interval may|
03577|017|E|result in potentially life-threatening cardiac arrhythmias, including|
03577|018|E|torsades de pointes.|
03577|019|E|   Methadone has been associated with serotonin syndrome.  Symptoms of|
03577|020|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
03577|021|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.|
03577|022|B||
03577|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03577|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
03577|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03577|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03577|027|P|female gender, advanced age, or high daily doses of methadone.(4)|
03577|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03577|029|P|higher systemic concentrations of either QT prolonging drug are additional|
03577|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03577|031|P|drug concentrations include rapid infusion of an intravenous dose or|
03577|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03577|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03577|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03577|035|B||
03577|036|M|PATIENT MANAGEMENT:  The US manufacturer of posaconazole states concurrent|
03577|037|M|use with CYP3A4 substrates that prolong the QTc interval is|
03577|038|M|contraindicated.(1)|
03577|039|M|   The US manufacturer of methadone states concurrent use with CYP3A4|
03577|040|M|inhibitors may require a dosage reduction of methadone until stable effects|
03577|041|M|are achieved.(2)|
03577|042|M|   Respiratory depression can occur at any time during opioid therapy,|
03577|043|M|especially during therapy initiation and following dosage increases.  The|
03577|044|M|risk of opioid-related overdose or overdose-related death is increased with|
03577|045|M|higher opioid doses, and this risk persists over the course of therapy.|
03577|046|M|Consider these risks when using concurrently with agents that may increase|
03577|047|M|opioid drug levels.(5)|
03577|048|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
03577|049|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03577|050|M|unresponsiveness.  The dosage of methadone may need to be lowered.(1,2)|
03577|051|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03577|052|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03577|053|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03577|054|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03577|055|M|   If concurrent therapy is warranted, patients should be monitored for|
03577|056|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03577|057|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03577|058|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03577|059|M|coordination, or severe diarrhea.|
03577|060|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03577|061|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03577|062|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03577|063|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03577|064|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03577|065|M|as those taking CNS depressants) and when a patient has household|
03577|066|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03577|067|M|for obtaining an opioid reversal agent (e.g., prescription,|
03577|068|M|over-the-counter, or as part of a community-based program).(6)|
03577|069|B||
03577|070|D|DISCUSSION:  Voriconazole (400 mg twice daily Day 1, 200 mg twice daily Days|
03577|071|D|2-5) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
03577|072|D|of R-methadone by 31% and 47%, respectively, and the Cmax and AUC of|
03577|073|D|S-methadone by 65% and 103%, respectively, in patients receiving maintenance|
03577|074|D|doses (30-100 mg daily) of methadone.(2)|
03577|075|B||
03577|076|R|REFERENCES:|
03577|077|B||
03577|078|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
03577|079|R|  January, 2022.|1
03577|080|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03577|081|R|  Pharmaceuticals Corp. June, 2021.|1
03577|082|R|3.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03577|083|R|  Pharma AS November 30, 2018.|1
03577|084|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03577|085|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03577|086|R|  settings: a scientific statement from the American Heart Association and|6
03577|087|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03577|088|R|  2;55(9):934-47.|6
03577|089|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03577|090|R|  prescribing information for all opioid pain medicines to provide|1
03577|091|R|  additional guidance for safe use. Available at:|1
03577|092|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03577|093|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03577|094|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03577|095|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03577|096|R|  recommends health care professionals discuss naloxone with all patients|1
03577|097|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03577|098|R|  disorder. Available at:|1
03577|099|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03577|100|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03577|101|R|  d-pain July 23, 2020.|1
03578|001|T|MONOGRAPH TITLE:  Levomepromazine/QT Prolonging Agents|
03578|002|B||
03578|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03578|004|L|of severe adverse interaction.|
03578|005|B||
03578|006|A|MECHANISM OF ACTION:  Levomepromazine has been shown to prolong the QTc|
03578|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
03578|008|A|may result in additive effects on the QTc interval.(1)|
03578|009|B||
03578|010|E|CLINICAL EFFECTS:  The concurrent use of levomepromazine with other agents|
03578|011|E|that prolong the QTc interval may result in potentially life-threatening|
03578|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
03578|013|B||
03578|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03578|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03578|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03578|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03578|018|P|gender, or advanced age.(2)|
03578|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03578|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03578|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03578|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03578|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03578|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03578|025|P|dysfunction).(2)|
03578|026|B||
03578|027|M|PATIENT MANAGEMENT:  The manufacturer of levomepromazine states that|
03578|028|M|levomepromazine is not recommended in patients receiving other drugs known|
03578|029|M|to cause QT prolongation.(1)|
03578|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03578|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03578|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03578|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03578|034|B||
03578|035|D|DISCUSSION:  Case reports of QTc prolongation associated with|
03578|036|D|levomepromazine have been reported.(1,3)|
03578|037|D|   Agents that are linked to this monograph may have varying degrees of|
03578|038|D|potential to prolong the QTc interval but are generally accepted to have a|
03578|039|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03578|040|D|been shown to prolong the QTc interval either through their mechanism of|
03578|041|D|action, through studies on their effects on the QTc interval, or through|
03578|042|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03578|043|D|and/or post-marketing reports.(4)|
03578|044|B||
03578|045|R|REFERENCES:|
03578|046|B||
03578|047|R|1.Nozinan (methotrimeprazine) Canadian prescribing information.|1
03578|048|R|  sanofi-aventis Canada Inc. February, 2020.|1
03578|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03578|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03578|051|R|  settings: a scientific statement from the American Heart Association and|6
03578|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03578|053|R|  2;55(9):934-47.|6
03578|054|R|3.Ozeki Y, Fujii K, Kurimoto N, Yamada N, Okawa M, Aoki T, Takahashi J,|2
03578|055|R|  Ishida N, Horie M, Kunugi H. QTc prolongation and antipsychotic|2
03578|056|R|  medications in a sample of 1017 patients with  schizophrenia. Prog|2
03578|057|R|  Neuropsychopharmacol Biol Psychiatry 2010 Mar 17;34(2):401-5.|2
03578|058|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03578|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03578|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03578|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03579|001|T|MONOGRAPH TITLE:  Methotrexate (low strength injections, oral)/Ciprofloxacin|
03579|002|B||
03579|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03579|004|L|take action as needed.|
03579|005|B||
03579|006|A|MECHANISM OF ACTION:  Ciprofloxacin inhibits renal tubular elimination of|
03579|007|A|methotrexate.(1,2)|
03579|008|B||
03579|009|E|CLINICAL EFFECTS:  The concurrent use of methotrexate and ciprofloxacin may|
03579|010|E|result in elevated levels of methotrexate and increased methotrexate-related|
03579|011|E|adverse effects and toxicities, leading to increased risk of severe|
03579|012|E|neurotoxicity, stomatitis, and myelosuppression, including neutropenia.|
03579|013|B||
03579|014|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
03579|015|P|- High-dose oncology regimens|
03579|016|P|- Impaired renal function, ascites, or pleural effusions|
03579|017|B||
03579|018|M|PATIENT MANAGEMENT:  For patients receiving high dose methotrexate, consider|
03579|019|M|an alternative antibiotic or discontinuation of ciprofloxacin for the|
03579|020|M|duration of therapy.(3)  Manufacturers recommend patients receiving|
03579|021|M|concomitant ciprofloxacin and methotrexate therapy should be closely|
03579|022|M|monitored for elevated methotrexate levels and methotrexate toxicity.(1,2)|
03579|023|B||
03579|024|D|DISCUSSION:  A 90-year-old woman with severe plaque psoriasis vulgaris|
03579|025|D|treated with methotrexate 12.5 mg weekly developed nausea, vomiting, and|
03579|026|D|oral ulcerations after completing a 2-week course of ciprofloxacin 500 mg|
03579|027|D|twice daily for foot ulcers.  She had previously tolerated methotrexate for|
03579|028|D|4 years.  Her past medical history is significant for type 2 diabetes|
03579|029|D|mellitus, hypertension, hyperlipidemia, arthritis and nephrolithiasis.  The|
03579|030|D|serum methotrexate level was 0.05 micromol/L, under the level of toxicity,|
03579|031|D|but the patient's last dose of methotrexate was 5 days prior.  Methotrexate|
03579|032|D|levels typically become undetectable after 18 to 24 hours.(3)|
03579|033|B||
03579|034|R|REFERENCES:|
03579|035|B||
03579|036|R|1.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
03579|037|R|  Corporation March, 2022.|1
03579|038|R|2.Methotrexate (tablets, injection) Canada prescribing information. Pfizer|1
03579|039|R|  Canada Inc. July 8, 2019.|1
03579|040|R|3.Kamangar F, Berger TG, Fazel N, Koo JY. Methotrexate toxicity induced by|3
03579|041|R|  ciprofloxacin leading to psoriatic plaque  ulceration: a case report.|3
03579|042|R|  Cutis 2013 Sep;92(3):148-50.|3
03580|001|T|MONOGRAPH TITLE:  Levomepromazine/Possible QT Prolonging Agents|
03580|002|B||
03580|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03580|004|L|take action as needed.|
03580|005|B||
03580|006|A|MECHANISM OF ACTION:  Levomepromazine has been shown to prolong the QTc|
03580|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
03580|008|A|may result in additive effects on the QTc interval.(1)|
03580|009|B||
03580|010|E|CLINICAL EFFECTS:  The concurrent use of levomepromazine with other agents|
03580|011|E|that prolong the QTc interval may result in potentially life-threatening|
03580|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
03580|013|B||
03580|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03580|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03580|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03580|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03580|018|P|gender, or advanced age.(2)|
03580|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03580|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03580|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03580|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03580|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03580|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03580|025|P|dysfunction).(2)|
03580|026|B||
03580|027|M|PATIENT MANAGEMENT:  The manufacturer of levomepromazine states that|
03580|028|M|levomepromazine is not recommended in patients receiving other drugs known|
03580|029|M|to cause QT prolongation.(1)|
03580|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03580|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03580|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03580|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03580|034|B||
03580|035|D|DISCUSSION:  Case reports of QTc prolongation associated with|
03580|036|D|levomepromazine have been reported.(1,3)|
03580|037|D|   Agents that are linked to this monograph may have varying degrees of|
03580|038|D|potential to prolong the QTc interval but are generally accepted to have a|
03580|039|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03580|040|D|been shown to prolong the QTc interval either through their mechanism of|
03580|041|D|action, through studies on their effects on the QTc interval, or through|
03580|042|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03580|043|D|and/or post-marketing reports.(4)|
03580|044|B||
03580|045|R|REFERENCES:|
03580|046|B||
03580|047|R|1.Nozinan (methotrimeprazine) Canadian prescribing information.|1
03580|048|R|  sanofi-aventis Canada Inc. February, 2020.|1
03580|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03580|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03580|051|R|  settings: a scientific statement from the American Heart Association and|6
03580|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03580|053|R|  2;55(9):934-47.|6
03580|054|R|3.Ozeki Y, Fujii K, Kurimoto N, Yamada N, Okawa M, Aoki T, Takahashi J,|2
03580|055|R|  Ishida N, Horie M, Kunugi H. QTc prolongation and antipsychotic|2
03580|056|R|  medications in a sample of 1017 patients with  schizophrenia. Prog|2
03580|057|R|  Neuropsychopharmacol Biol Psychiatry 2010 Mar 17;34(2):401-5.|2
03580|058|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03580|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03580|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03580|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03581|001|T|MONOGRAPH TITLE:  Zonisamide/Carbonic Anhydrase Inhibitors|
03581|002|B||
03581|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03581|004|L|of severe adverse interaction.|
03581|005|B||
03581|006|A|MECHANISM OF ACTION:  Zonisamide is a carbonic anhydrase inhibitor and can|
03581|007|A|induce renal bicarbonate loss, resulting in metabolic acidosis.  It can also|
03581|008|A|reduce urinary citrate excretion and increase urinary pH, posing a risk for|
03581|009|A|nephrolithiasis.  As well, carbonic anhydrase inhibitors can cause decreased|
03581|010|A|sweating and elevated body temperature, predisposing patients to|
03581|011|A|heat-related disorders.  Concurrent use of zonisamide with other carbonic|
03581|012|A|anhydrase inhibitors may result in an additive risk of all these|
03581|013|A|effects.(1-2)|
03581|014|B||
03581|015|E|CLINICAL EFFECTS:  The concurrent use of zonisamide with another carbonic|
03581|016|E|anhydrase inhibitor may increase the risk of metabolic acidosis and kidney|
03581|017|E|stone formation.(1)|
03581|018|E|   Concurrent use of zonisamide with other carbonic anhydrase inhibitors may|
03581|019|E|increase the incidence of oligohidrosis and hyperthermia, especially in|
03581|020|E|pediatric or adolescent patients.(1-2)  Overheating and dehydration can lead|
03581|021|E|to brain damage and death.|
03581|022|B||
03581|023|P|PREDISPOSING FACTORS:  Patients with conditions that predispose to acidosis|
03581|024|P|(such as renal disease, severe respiratory disorders, status epilepticus,|
03581|025|P|diarrhea, and being on a ketogenic diet) may be at increased risk of|
03581|026|P|experiencing adverse effects from concurrent carbonic anhydrase|
03581|027|P|inhibitors.(1)|
03581|028|P|   Pediatric and adolescent patients and patients with dehydration may be|
03581|029|P|more likely to experience heat-related disorders.(1)|
03581|030|B||
03581|031|M|PATIENT MANAGEMENT:  The UK and US manufacturers of zonisamide state that|
03581|032|M|caution should be used in adults when zonisamide is prescribed with other|
03581|033|M|carbonic anhydrase inhibitors.(1-2)|
03581|034|M|   Pediatric and adolescent patients must not take carbonic anhydrase|
03581|035|M|inhibitors concurrently with zonisamide.(1)|
03581|036|M|   Check serum bicarbonate at baseline and periodically during treatment.|
03581|037|M|Monitor for signs and symptoms of metabolic acidosis: hyperventilation,|
03581|038|M|fatigue, anorexia, arrhythmias, stupor.|
03581|039|M|   Monitor for signs and symptoms of heat stroke: skin feels very hot with|
03581|040|M|little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid|
03581|041|M|breathing.|
03581|042|M|   Monitor for signs and symptoms of dehydration: dry mouth, urinating less|
03581|043|M|than usual, dark-colored urine, dry skin, feeling tired, dizziness, or|
03581|044|M|irritability.|
03581|045|M|   If signs or symptoms of metabolic acidosis, dehydration, oligohidrosis,|
03581|046|M|or elevated body temperature occur, a decreased dose or discontinuation of|
03581|047|M|zonisamide should be considered.|
03581|048|B||
03581|049|D|DISCUSSION:  Zonisamide is a carbonic anhydrase inhibitor.  Carbonic|
03581|050|D|anhydrase inhibitors increase urinary bicarbonate excretion, reduce urinary|
03581|051|D|citrate excretion and increase urinary pH.  Concurrent use of zonisamide|
03581|052|D|with other carbonic anhydrase inhibitors may increase the risk of metabolic|
03581|053|D|acidosis and kidney stone formation and should therefore be avoided.(1)|
03581|054|D|   Case reports of decreased sweating and elevated temperature have been|
03581|055|D|reported, especially in pediatric patients.  Some cases resulted in heat|
03581|056|D|stroke that required hospital treatment and resulted in death.(1)|
03581|057|B||
03581|058|R|REFERENCES:|
03581|059|B||
03581|060|R|1.Zonisamide Dr. Reddy's UK summary of product characteristics. Dr. Reddy's|1
03581|061|R|  Laboratories (UK) Ltd April 17, 2018.|1
03581|062|R|2.Zonegran (zonisamide) US prescribing information. Sunovion Pharms Inc|1
03581|063|R|  April 13, 2020.|1
03582|001|T|MONOGRAPH TITLE:  Topiramate/Anticholinergics|
03582|002|B||
03582|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03582|004|L|take action as needed.|
03582|005|B||
03582|006|A|MECHANISM OF ACTION:  Topiramate can cause decreased sweating and elevated|
03582|007|A|body temperature.  Agents with anticholinergic activity can predispose|
03582|008|A|patients to heat-related disorders.(1-2)|
03582|009|B||
03582|010|E|CLINICAL EFFECTS:  Concurrent use of topiramate with agents with|
03582|011|E|anticholinergic activity may increase the incidence of oligohidrosis and|
03582|012|E|hyperthermia, especially in pediatric or adolescent patients.(1-2)|
03582|013|E|Overheating and dehydration can lead to brain damage and death.|
03582|014|B||
03582|015|P|PREDISPOSING FACTORS:  Pediatric and adolescent patients and patients with|
03582|016|P|dehydration may be more likely to experience heat-related disorders.(1)|
03582|017|B||
03582|018|M|PATIENT MANAGEMENT:  The manufacturer of topiramate states that caution|
03582|019|M|should be used when topiramate is prescribed with other medicinal products|
03582|020|M|that predispose to heat-related disorders, such as agents with|
03582|021|M|anticholinergic activity (e.g. clomipramine, hydroxyzine, diphenhydramine,|
03582|022|M|haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1)|
03582|023|M|   Monitor for signs and symptoms of heat stroke: skin feels very hot with|
03582|024|M|little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid|
03582|025|M|breathing.|
03582|026|M|   Monitor for signs and symptoms of dehydration: dry mouth, urinating less|
03582|027|M|than usual, dark-colored urine, dry skin, feeling tired, dizziness, or|
03582|028|M|irritability.|
03582|029|M|   If signs or symptoms of dehydration, oligohidrosis, or elevated body|
03582|030|M|temperature occur, discontinuation of zonisamide should be considered.|
03582|031|B||
03582|032|D|DISCUSSION:  Case reports of decreased sweating and elevated temperature|
03582|033|D|have been reported, especially in pediatric patients.  Some cases resulted|
03582|034|D|in heat stroke that required hospital treatment.(1)|
03582|035|D|   A 64-year old woman developed non-exertional hyperthemia while taking|
03582|036|D|multiple psychiatric medications with topiramate.(2)|
03582|037|B||
03582|038|R|REFERENCES:|
03582|039|B||
03582|040|R|1.Topamax (topiramate) US prescribing information. Janssen Pharmaceuticals,|1
03582|041|R|  Inc. May, 2023.|1
03582|042|R|2.Manivannan A, Kabbani D, Levine D. Use of multiple anticholinergic|3
03582|043|R|  medications can predispose patients to severe non-exertional hyperthermia.|3
03582|044|R|  BMJ Case Rep 2021 Mar 23;14(3):.|3
03583|001|T|MONOGRAPH TITLE:  Atorvastatin; Lovastatin; Simvastatin/Lonafarnib|
03583|002|B||
03583|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03583|004|L|is contraindicated and generally should not be dispensed or administered to|
03583|005|L|the same patient.|
03583|006|B||
03583|007|A|MECHANISM OF ACTION:  Lonafarnib may inhibit the metabolism of atorvastatin,|
03583|008|A|lovastatin and simvastatin by CYP3A4.(1-4)|
03583|009|B||
03583|010|E|CLINICAL EFFECTS:  Concurrent use of lonafarnib may result in elevated|
03583|011|E|levels of atorvastatin, lovastatin and simvastatin and increase the risk of|
03583|012|E|rhabdomyolysis.(1-4)|
03583|013|B||
03583|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03583|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03583|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03583|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03583|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03583|019|P|transporter OATP1B1 may have increased statin concentrations and be|
03583|020|P|predisposed to myopathy or rhabdomyolysis.|
03583|021|B||
03583|022|M|PATIENT MANAGEMENT:  Concurrent use of strong CYP3A4 inhibitors with|
03583|023|M|atorvastatin, lovastatin or simvastatin is contraindicated.(1-4)  Therapy|
03583|024|M|with atorvastatin, lovastatin or simvastatin should be suspended during|
03583|025|M|lonafarnib therapy.|
03583|026|M|   Patients should be carefully monitored for and instructed to report any|
03583|027|M|signs of myopathy.|
03583|028|B||
03583|029|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
03583|030|D|midazolam (3 mg single dose) with lonafarnib (100 mg twice daily for 5 days)|
03583|031|D|increased the concentration maximum (Cmax) and area-under-curve (AUC) of|
03583|032|D|midazolam by 180% and 639%, respectively.(4)|
03583|033|B||
03583|034|R|REFERENCES:|
03583|035|B||
03583|036|R|1.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
03583|037|R|  February, 2014.|1
03583|038|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03583|039|R|  2023.|1
03583|040|R|3.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
03583|041|R|  2020.|1
03583|042|R|4.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03583|043|R|  Inc. November, 2020.|1
03584|001|T|MONOGRAPH TITLE:  Midazolam/Lonafarnib|
03584|002|B||
03584|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03584|004|L|is contraindicated and generally should not be dispensed or administered to|
03584|005|L|the same patient.|
03584|006|B||
03584|007|A|MECHANISM OF ACTION:  The metabolism of midazolam by CYP3A4 may be inhibited|
03584|008|A|by lonafarnib.(1)|
03584|009|B||
03584|010|E|CLINICAL EFFECTS:  The concurrent administration of lonafarnib may result in|
03584|011|E|elevated levels of midazolam, which may result in increased adverse effects|
03584|012|E|including profound sedation, respiratory depression, coma, and/or death.(1)|
03584|013|B||
03584|014|P|PREDISPOSING FACTORS:  None determined.|
03584|015|B||
03584|016|M|PATIENT MANAGEMENT:  The US manufacturers of lonafarnib states that|
03584|017|M|concurrent use of midazolam is contraindicated.  Temporarily discontinue|
03584|018|M|lonafarnib 10-14 days before and 2 days after administration of|
03584|019|M|midazolam.(1)|
03584|020|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
03584|021|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03584|022|M|unresponsiveness.|
03584|023|B||
03584|024|D|DISCUSSION:  In a study in healthy subjects, concomitant administration of|
03584|025|D|midazolam (3 mg single dose) with lonafarnib (100 mg twice daily for 5 days)|
03584|026|D|increased the concentration maximum (Cmax) and area-under-curve (AUC) of|
03584|027|D|midazolam by 180% and 639%, respectively.(1)|
03584|028|B||
03584|029|R|REFERENCE:|
03584|030|B||
03584|031|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03584|032|R|  Inc. November, 2020.|1
03585|001|T|MONOGRAPH TITLE:  Lonafarnib/Strong CYP3A4 Inhibitors|
03585|002|B||
03585|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03585|004|L|is contraindicated and generally should not be dispensed or administered to|
03585|005|L|the same patient.|
03585|006|B||
03585|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03585|008|A|lonafarnib.(1)|
03585|009|B||
03585|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors with|
03585|011|E|lonafarnib may increase the risk of adverse reactions including QTc|
03585|012|E|prolongation and potentially life-threatening cardiac arrhythmias like|
03585|013|E|torsades de pointes, nausea and vomiting, increased liver enzymes,|
03585|014|E|myelosuppression, and hypertension.(1)|
03585|015|B||
03585|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03585|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03585|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03585|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03585|020|P|female gender, or advanced age.(2)|
03585|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03585|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03585|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03585|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03585|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03585|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03585|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03585|028|B||
03585|029|M|PATIENT MANAGEMENT:  The use of lonafarnib with strong CYP3A4 inhibitors is|
03585|030|M|contraindicated.(1)|
03585|031|M|   Lonafarnib dose modification recommendation: if the QTc interval is|
03585|032|M|greater than or equal to 500 msec, withhold lonafarnib until the QTc|
03585|033|M|interval is less than 470 msec, then resume lonafarnib at the same|
03585|034|M|dosage.(1)|
03585|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03585|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03585|037|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
03585|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03585|039|B||
03585|040|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg lonafarnib|
03585|041|D|following 200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5|
03585|042|D|days, the area-under-curve (AUC) and maximum concentration (Cmax) were|
03585|043|D|increased by 425% and 270%, respectively.(1)|
03585|044|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, idelalisib,|
03585|045|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03585|046|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03585|047|D|tipranavir, troleandomycin, and tucatinib.(3,4)|
03585|048|B||
03585|049|R|REFERENCES:|
03585|050|B||
03585|051|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03585|052|R|  Inc. November, 2020.|1
03585|053|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
03585|054|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03585|055|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03585|056|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03585|057|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03585|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03585|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03585|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03585|061|R|  11/14/2017.|1
03585|062|R|4.This information is based on an extract from the Certara Drug Interaction|6
03585|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03586|001|T|MONOGRAPH TITLE:  Lonafarnib/Strong and Moderate CYP3A4 Inducers|
03586|002|B||
03586|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03586|004|L|is contraindicated and generally should not be dispensed or administered to|
03586|005|L|the same patient.|
03586|006|B||
03586|007|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03586|008|A|metabolism of lonafarnib.(1)|
03586|009|B||
03586|010|E|CLINICAL EFFECTS:  Concurrent use of strong and moderate CYP3A4 inducers may|
03586|011|E|decrease the serum levels and effectiveness of lonafarnib.(1)|
03586|012|B||
03586|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03586|014|P|of the inducer for longer than 1-2 weeks.|
03586|015|B||
03586|016|M|PATIENT MANAGEMENT:  The use of strong or moderate CYP3A4 inducers with|
03586|017|M|lonafarnib is contraindicated.|
03586|018|B||
03586|019|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg lonafarnib|
03586|020|D|(combined with a single oral dose of 100 mg ritonavir) following 600 mg|
03586|021|D|rifampin (a strong CYP3A4 inducer) for 8 days, the area-under-curve (AUC)|
03586|022|D|was reduced by 98% and the maximum concentration (Cmax) was reduced by|
03586|023|D|92%.(1)|
03586|024|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03586|025|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
03586|026|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03586|027|D|wort.(2,3)|
03586|028|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03586|029|D|dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, modafinil,|
03586|030|D|nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat|
03586|031|D|ethyl, and tovorafenib.(2,3)|
03586|032|B||
03586|033|R|REFERENCES:|
03586|034|B||
03586|035|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03586|036|R|  Inc. November, 2020.|1
03586|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03586|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03586|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03586|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03586|041|R|  11/14/2017.|1
03586|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
03586|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03587|001|T|MONOGRAPH TITLE:  Lonafarnib/Weak CYP3A4 Inhibitors (mono deleted|
03587|002|T|05/30/2024)|
03587|003|B||
03587|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03587|005|L|of severe adverse interaction.|
03587|006|B||
03587|007|A|MECHANISM OF ACTION:  Weak inhibitors of CYP3A4 may inhibit the metabolism|
03587|008|A|of lonafarnib.(1)|
03587|009|B||
03587|010|E|CLINICAL EFFECTS:  Concurrent use with weak CYP3A4 inhibitors may increase|
03587|011|E|the risk of adverse reactions of lonafarnib including nausea and vomiting,|
03587|012|E|increased liver enzymes, myelosuppression, and hypertension.(1)|
03587|013|B||
03587|014|P|PREDISPOSING FACTORS:  None determined.|
03587|015|B||
03587|016|M|PATIENT MANAGEMENT:  Avoid coadministration of lonafarnib and weak CYP3A4|
03587|017|M|inhibitors.  If coadministration is unavoidable, reduce the dose of|
03587|018|M|lonafarnib to 115 mg/m2 or continue at 115 mg/m2 without further dosage|
03587|019|M|increases.(1)|
03587|020|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03587|021|M|heart palpitations because lonafarnib exposures may be increased despite the|
03587|022|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03587|023|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03587|024|M|inhibitor.(1)|
03587|025|B||
03587|026|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg lonafarnib|
03587|027|D|following 200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5|
03587|028|D|days, the area-under-curve (AUC) and maximum concentration (Cmax) were|
03587|029|D|increased by 425% and 270%, respectively.(1)|
03587|030|D|   Weak inhibitors of CYP3A4 include:  amlodipine, asciminib, atorvastatin,|
03587|031|D|azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry,|
03587|032|D|brodalumab, cannabidiol, chlorzoxazone, cimetidine, ciprofloxacin,|
03587|033|D|clotrimazole, cranberry, cyclosporine, delavirdine, dihydroberberine,|
03587|034|D|diosmin, fosaprepitant, ginkgo, glecaprevir/pibrentasvir, goldenseal,|
03587|035|D|grazoprevir, isoniazid, istradefylline, lacidipine, leflunomide,|
03587|036|D|levamlodipine, linagliptin, peppermint oil, piperine, propiverine, propofol,|
03587|037|D|ranitidine, resveratrol, roxithromycin, rucaparib, sitaxsentan, skullcap,|
03587|038|D|teriflunomide, trofinetide, viloxazine, and vonoprazan.(2,3)|
03587|039|B||
03587|040|R|REFERENCES:|
03587|041|B||
03587|042|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03587|043|R|  Inc. November, 2020.|1
03587|044|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03587|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03587|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03587|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03587|048|R|  11/14/2017.|1
03587|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
03587|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03588|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/Lonafarnib|
03588|002|B||
03588|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03588|004|L|of severe adverse interaction.|
03588|005|B||
03588|006|A|MECHANISM OF ACTION:  Lonafarnib is a strong inhibitor of CYP3A4 and may|
03588|007|A|decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.|
03588|008|A|Lonafarnib is also an inhibitor of P-glycoprotein (P-gp) and may increase|
03588|009|A|the absorption of sirolimus.|
03588|010|B||
03588|011|E|CLINICAL EFFECTS:  Concurrent use of lonafarnib may lead to increased serum|
03588|012|E|levels and adverse effects of drugs sensitive to inhibition of the CYP3A4|
03588|013|E|pathway or P-gp.(1)|
03588|014|B||
03588|015|P|PREDISPOSING FACTORS:  None determined.|
03588|016|B||
03588|017|M|PATIENT MANAGEMENT:  The manufacturer of lonafarnib states that|
03588|018|M|coadministration of CYP3A4 substrates should be avoided.  If concomitant use|
03588|019|M|is unavoidable, monitor for adverse effects and consider dose reduction of|
03588|020|M|the CYP3A4 substrate according to its prescribing information.(1)|
03588|021|M|   The manufacturer of lonafarnib states that the dose of P-gp substrates|
03588|022|M|may need to be reduced with coadministration with lonafarnib.(1)|
03588|023|B||
03588|024|D|DISCUSSION:  In a study of healthy volunteers, lonafarnib (100 mg twice|
03588|025|D|daily for 5 days) increased the area-under-the-curve (AUC) and maximum|
03588|026|D|concentration (Cmax) of a single dose of midazolam (3 mg) by 639% and 180%,|
03588|027|D|respectively.(1)|
03588|028|D|   In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5|
03588|029|D|days) increased the AUC and Cmax of single-dose fexofenadine (180 mg) by 24%|
03588|030|D|and 21%, respectively.(1)|
03588|031|D|   CYP3A4 substrates with a narrow therapeutic index linked to this|
03588|032|D|monograph include:  bromocriptine, cabergoline,|
03588|033|D|cannabidiol-tetrahydrocannabinol, clonazepam, darolutamide, felodipine,|
03588|034|D|mefloquine, nisoldipine, oliceridine, pomalidomide, regorafenib, sirolimus,|
03588|035|D|and zanubrutinib.(1-3)|
03588|036|B||
03588|037|R|REFERENCES:|
03588|038|B||
03588|039|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03588|040|R|  Inc. November, 2020.|1
03588|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03588|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03588|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03588|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03588|045|R|  11/14/2017.|1
03588|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
03588|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03589|001|T|MONOGRAPH TITLE:  Quinidine/Lonafarnib|
03589|002|B||
03589|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03589|004|L|of severe adverse interaction.|
03589|005|B||
03589|006|A|MECHANISM OF ACTION:  Lonafarnib is an inhibitor of CYP3A4 and may decrease|
03589|007|A|the metabolism of drugs metabolized by the CYP3A4 enzyme.(1)  Quinidine is|
03589|008|A|metabolized by CYP3A4.(2)|
03589|009|A|   Both agents have been shown to prolong the QTc interval.  Concurrent use|
03589|010|A|may result in additive effects on the QTc interval.(1,2)|
03589|011|B||
03589|012|E|CLINICAL EFFECTS:  Concurrent use of quinidine with lonafarnib may lead to|
03589|013|E|increased serum levels and adverse effects of quinidine, including|
03589|014|E|potentially life-threatening cardiac arrhythmias like torsades de pointes|
03589|015|E|(TdP).(1,2)|
03589|016|B||
03589|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03589|018|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03589|019|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03589|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03589|021|P|gender, or advanced age.(3)|
03589|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03589|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03589|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03589|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03589|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03589|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03589|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03589|029|B||
03589|030|M|PATIENT MANAGEMENT:  The manufacturer of lonafarnib states that|
03589|031|M|coadministration of other drugs known to prolong the QTc interval as well as|
03589|032|M|sensitive CYP3A4 substrates should be avoided.  If concomitant use is|
03589|033|M|unavoidable, monitor for adverse effects and consider dose reduction of|
03589|034|M|quinidine according to its prescribing information.(1)|
03589|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03589|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03589|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03589|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03589|039|B||
03589|040|D|DISCUSSION:  In a study of healthy volunteers, lonafarnib (100 mg twice|
03589|041|D|daily for 5 days) increased the area-under-the-curve (AUC) and maximum|
03589|042|D|concentration (Cmax) of a single dose of midazolam (3 mg), a sensitive|
03589|043|D|CYP3A4 substrate, by 639% and 180%, respectively.(1)|
03589|044|D|   In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive|
03589|045|D|days and a single 200 mg dose on day 10 increased the mean QTc interval by|
03589|046|D|19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48|
03589|047|D|hours after administration of the morning dose of lonafarnib 200 mg.  The|
03589|048|D|maximum concentration (Cmax) on Day 10 was 2233 ng/ml, which is similar to|
03589|049|D|the mean Cmax of 2695 ng/ml observed in the Hutchinson-Gilford Progeria|
03589|050|D|Syndrome patient population.(1)|
03589|051|B||
03589|052|R|REFERENCES:|
03589|053|B||
03589|054|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03589|055|R|  Inc. November, 2020.|1
03589|056|R|2.Quinidine sulfate US prescribing informaiton. Epic Pharma, LLC November,|1
03589|057|R|  2023.|1
03589|058|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03589|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03589|060|R|  settings: a scientific statement from the American Heart Association and|6
03589|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03589|062|R|  2;55(9):934-47.|6
03589|063|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03589|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03589|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03589|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03589|067|R|  11/14/2017.|1
03589|068|R|5.This information is based on an extract from the Certara Drug Interaction|6
03589|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03590|001|T|MONOGRAPH TITLE:  BCRP, OATP1B1, and OATP1B3 Substrates/Enasidenib|
03590|002|B||
03590|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03590|004|L|take action as needed.|
03590|005|B||
03590|006|A|MECHANISM OF ACTION:  Enasidenib is an inhibitor of the BCRP, OATP1B1, and|
03590|007|A|OATP1B3 transporters and may increase the absorption and/or decrease the|
03590|008|A|elimination of drugs that are substrates of these transporters.(1)|
03590|009|B||
03590|010|E|CLINICAL EFFECTS:  Concurrent use of enasidenib with drugs that are|
03590|011|E|substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in|
03590|012|E|increased frequency and severity of toxicity of the substrate.(1)|
03590|013|B||
03590|014|P|PREDISPOSING FACTORS:  None determined.|
03590|015|B||
03590|016|M|PATIENT MANAGEMENT:  The dose of the BCRP, OATP1B1, and OATP1B3 substrate|
03590|017|M|should be reduced as recommended in the substrate prescribing information|
03590|018|M|and as clinically indicated.(1)|
03590|019|B||
03590|020|D|DISCUSSION:  In a study, enasidenib 100 mg daily increased the maximum|
03590|021|D|concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by|
03590|022|D|366% and 244%, respectively.(1)|
03590|023|D|   Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this|
03590|024|D|monograph include: atorvastatin, glecaprevir, pibrentasvir, simvastatin,|
03590|025|D|velpatasvir, and voxilaprevir.(1,2)|
03590|026|B||
03590|027|R|REFERENCES:|
03590|028|B||
03590|029|R|1.Idhifa (enasidenib) US prescribing information. Celgene Corporation|1
03590|030|R|  November, 2020.|1
03590|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
03590|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03591|001|T|MONOGRAPH TITLE:  Apomorphine/Selected Antipsychotics that Prolong QT|
03591|002|B||
03591|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03591|004|L|of severe adverse interaction.|
03591|005|B||
03591|006|A|MECHANISM OF ACTION:  Concurrent use of apomorphine with certain|
03591|007|A|antipsychotics may have additive effects on the QTc interval.(1)|
03591|008|A|   In addition, apomorphine is used to treat Parkinson Disease (PD) by|
03591|009|A|increasing dopamine concentrations at D2 receptors in the central nervous|
03591|010|A|system (CNS).  Antipsychotic agents counteract this effect by blocking|
03591|011|A|dopamine activity at CNS D2 receptors.(1,2)|
03591|012|B||
03591|013|E|CLINICAL EFFECTS:  The concurrent use of apomorphine with certain|
03591|014|E|antipsychotics may result in potentially life-threatening cardiac|
03591|015|E|arrhythmias, including torsades de pointes.(1)|
03591|016|E|   In addition, the efficacy of either agent may be decreased, leading to|
03591|017|E|exacerbation of PD.  Motor symptoms may worsen, increasing the risk for|
03591|018|E|falls, dysphagia or aspiration.(3)  Compared with Parkinson patients not|
03591|019|E|receiving antipsychotic therapy, Parkinson patients receiving antipsychotics|
03591|020|E|appear to have an increased mortality risk.(2)|
03591|021|B||
03591|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03591|023|P|may be increased in patients with cardiovascular disease (e.g. heart|
03591|024|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03591|025|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03591|026|P|female gender, or advanced age.|
03591|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03591|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03591|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03591|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03591|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03591|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03591|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03591|034|P|   Patients with Parkinson or Diffuse Lewy Body (DLB) disease are|
03591|035|P|particularly susceptible to adverse effects of dopamine blockade by|
03591|036|P|antipsychotics.|
03591|037|B||
03591|038|M|PATIENT MANAGEMENT:  The US manufacturer of apomorphine states that patients|
03591|039|M|with major psychotic disorders treated with neuroleptics should be treated|
03591|040|M|with dopamine agonists only if the potential benefits outweigh the risks.|
03591|041|M|Concurrent use with agents known to prolong the QT interval should be|
03591|042|M|approached with caution.(1)|
03591|043|M|   The Canadian manufacturer of levomepromazine states concomitant use with|
03591|044|M|other QT prolonging medications is not recommended.(5)  The UK manufacturer|
03591|045|M|of zuclopenthixol states that coadministration of other QT prolonging|
03591|046|M|medications should be avoided.(6)  Manufacturers of other QT-prolonging|
03591|047|M|antipsychotics generally recommend using caution when coadministered with|
03591|048|M|medications that prolong the QT interval.|
03591|049|M|   Reassess the need for antipsychotic therapy.  If psychosis or|
03591|050|M|hallucinations are due to an antiparkinson agent, when possible consider|
03591|051|M|reducing the dose or changing the antiparkinson agent before initiating|
03591|052|M|antipsychotic therapy.  In patients with PD and dementia, addition of a|
03591|053|M|cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis.  If an|
03591|054|M|antipsychotic is required, then an atypical antipsychotic should be|
03591|055|M|used.(2,3)|
03591|056|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03591|057|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03591|058|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03591|059|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03591|060|B||
03591|061|D|DISCUSSION:  An epidemiologic study evaluated 21,043 elderly patients with|
03591|062|D|Parkinson disease to determine if recent initiation of a typical or atypical|
03591|063|D|antipsychotic was associated with increased mortality.  They found an|
03591|064|D|adjusted odds ratio of 2.0 for death associated with atypical antipsychotics|
03591|065|D|versus no antipsychotic.  They also found an adjusted odds ratio of 2.4 for|
03591|066|D|death associated with typical versus atypical antipsychotics.  The authors|
03591|067|D|noted the increased mortality found with typical antipsychotics supports|
03591|068|D|current treatment recommendations to use atypical antipsychotic agents in|
03591|069|D|patients with Parkinson disease.(3,4)|
03591|070|D|   Agents that are linked to this monograph may have varying degrees of|
03591|071|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03591|072|D|been shown to prolong the QTc interval either through their mechanism of|
03591|073|D|action, through studies on their effects on the QTc interval, or through|
03591|074|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03591|075|D|and/or postmarketing reports.(7)|
03591|076|B||
03591|077|R|REFERENCES:|
03591|078|B||
03591|079|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03591|080|R|  Inc. May, 2019.|1
03591|081|R|2.Marras C, Gruneir A, Wang X, Fischer H, Gill SS, Herrmann N, Anderson GM,|2
03591|082|R|  Hyson C, Rochon PA. Antipsychotics and mortality in Parkinsonism. Am J|2
03591|083|R|  Geriatr Psychiatry 2012 Feb;20(2):149-58.|2
03591|084|R|3.Oertel WH Berardelli A Bloem Br etal. Chapter 15 - Late (complicated)|6
03591|085|R|  Parkinson's disease in European Handbook of Neurological Management. 2011;|6
03591|086|R|  Volume 1, 2nd Edition:237 - 267.|6
03591|087|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03591|088|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03591|089|R|  settings: a scientific statement from the American Heart Association and|6
03591|090|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03591|091|R|  2;55(9):934-47.|6
03591|092|R|5.Nozinan (methotrimeprazine) Canadian prescribing information.|1
03591|093|R|  sanofi-aventis Canada Inc. February, 2020.|1
03591|094|R|6.Clopixol (zuclopenthixol acetate) UK summary of product characteristics.|1
03591|095|R|  Lundbeck Limited October 15, 2020.|1
03591|096|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
03591|097|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03591|098|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03591|099|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03592|001|T|MONOGRAPH TITLE:  Apomorphine/Promethazine|
03592|002|B||
03592|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03592|004|L|take action as needed.|
03592|005|B||
03592|006|A|MECHANISM OF ACTION:  Apomorphine is used to treat Parkinson Disease (PD) by|
03592|007|A|increasing dopamine concentrations at dopamine-2 (D2) receptors in the|
03592|008|A|central nervous system (CNS).  Antiemetic agents which block CNS D2|
03592|009|A|receptors, like promethazine, may counteract this effect.(1-2)|
03592|010|B||
03592|011|E|CLINICAL EFFECTS:  The efficacy of apomorphine may be decreased, leading to|
03592|012|E|exacerbation of the disease being treated.  In patients with Parkinson|
03592|013|E|disease motor symptoms may worsen, increasing the risk for falls, dysphagia|
03592|014|E|or aspiration.(2)|
03592|015|B||
03592|016|P|PREDISPOSING FACTORS:  Patients with Parkinson or Diffuse Lewy Body (DLB)|
03592|017|P|disease are particularly susceptible to adverse effects of dopamine blockade|
03592|018|P|by antipsychotics.|
03592|019|B||
03592|020|M|PATIENT MANAGEMENT:  The US manufacturer of apomorphine states that|
03592|021|M|anti-emetics with anti-dopaminergic actions may worsen the symptoms of PD|
03592|022|M|and should be avoided.(1)  Reassess antiemetic therapy and use an antiemetic|
03592|023|M|without dopamine (D2) blocking effects if possible.  If clinically|
03592|024|M|appropriate and available, consider the use of a 5-HT3 blocker (e.g.,|
03592|025|M|palonosetron).(1,2)|
03592|026|M|   If concomitant treatment is needed, monitor for loss of efficacy for PD|
03592|027|M|and adjust medication(s) or dosage if needed.(1)  Counsel patients to report|
03592|028|M|symptoms of disease exacerbation.|
03592|029|B||
03592|030|D|DISCUSSION:  Patients with Parkinson or Diffuse Lewy Body(DLB) disease are|
03592|031|D|particularly susceptible to adverse effects of dopamine blockade.|
03592|032|D|Palonosetron may be used for nausea and vomiting.(2)|
03592|033|D|   Prescribing information for apomorphine warns of the risk for disease|
03592|034|D|exacerbation when dopamine blocking agents are co-prescribed.(1)|
03592|035|B||
03592|036|R|REFERENCES:|
03592|037|B||
03592|038|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03592|039|R|  Inc. May, 2019.|1
03592|040|R|2.Oertel WH Berardelli A Bloem Br etal. Chapter 15 - Late (complicated)|6
03592|041|R|  Parkinson's disease in European Handbook of Neurological Management. 2011;|6
03592|042|R|  Volume 1, 2nd Edition:237 - 267.|6
03593|001|T|MONOGRAPH TITLE:  Live Vaccines; Live BCG/Hydroxyurea|
03593|002|B||
03593|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03593|004|L|of severe adverse interaction.|
03593|005|B||
03593|006|A|MECHANISM OF ACTION:  Hydroxyurea may suppress the immune system.(1)|
03593|007|A|Immunocompromised patients may be at increased risk for uninhibited|
03593|008|A|replication after administration of live, attenuated vaccines or|
03593|009|A|intravesicular BCG.|
03593|010|A|   Immune response to vaccines may be decreased during periods of|
03593|011|A|immunocompromise.(2)|
03593|012|B||
03593|013|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained|
03593|014|E|and/or the vaccine may result in illness.(2)|
03593|015|E|   After instillation of intravesicular BCG, immunosuppression may interfere|
03593|016|E|with local immune response, or increase the severity of mycobacterial|
03593|017|E|infection following inadvertent systemic exposure.(3)|
03593|018|B||
03593|019|P|PREDISPOSING FACTORS:  Immunosuppressive diseases (e.g. hematologic|
03593|020|P|malignancies), treatments (e.g. radiation) and cytotoxic drugs may all|
03593|021|P|increase the magnitude of immunodeficiency.|
03593|022|B||
03593|023|M|PATIENT MANAGEMENT:  Recommendations for administration of live vaccines in|
03593|024|M|patients on hydroxyurea are dependent on the indication.|
03593|025|M|   The US manufacturers of hydroxyurea recommend avoiding live vaccine use|
03593|026|M|in patients taking hydroxyurea.  Evaluate hematologic status prior to and|
03593|027|M|during treatment with hydroxyurea.  Provide supportive care and modify the|
03593|028|M|dose or discontinue hydroxyurea as needed.(1)|
03593|029|M|   The Centers for Disease Control (CDC) Advisory Committee on Immunization|
03593|030|M|Practices (ACIP) states that live-virus and live, attenuated vaccines should|
03593|031|M|not be administered to patients who are immunocompromised.  The magnitude of|
03593|032|M|immunocompromise and associated risks should be determined by a physician.|
03593|033|M|Patients who are vaccinated within the 14 days prior to initiating|
03593|034|M|immunosuppressive therapy should be considered unvaccinated and should be|
03593|035|M|revaccinated at least 3 months after immunosuppressive therapy is|
03593|036|M|discontinued.(2)|
03593|037|M|   The ACIP recommendations state that routine vaccinations patients with|
03593|038|M|secondary immunodeficiency such as sickle cell disease are likely effective.|
03593|039|M|Live viral and bacterial vaccines are contraindicated in patients with|
03593|040|M|generalized malignant neoplasm, immunosuppressive, or radiation therapy,|
03593|041|M|depending on immune status.(4)|
03593|042|B||
03593|043|D|DISCUSSION:  Killed or inactivated vaccines do not pose a danger to|
03593|044|D|immunocompromised patients.(2)|
03593|045|D|   Patients with a history of leukemia who are in remission and have not|
03593|046|D|received chemotherapy for at least 3 months are not considered to be|
03593|047|D|immunocompromised.(2)|
03593|048|D|   A multicenter, randomized, double-blind, placebo-controlled trial in|
03593|049|D|infants and young children with sickle cell disease (BABY HUG) studied the|
03593|050|D|response to pneumococcal and measles, mumps, and rubella vaccines in|
03593|051|D|patients using hydroxyurea.  The authors concluded that hydroxyurea does not|
03593|052|D|appear to have significant deleterious effects on the immune function of|
03593|053|D|infants and children with sickle cell disease.  Additional assessments of|
03593|054|D|lymphocyte parameters of hydroxyurea-treated children may be warranted.  No|
03593|055|D|changes in current immunization schedules are recommended; however, for|
03593|056|D|endemic disease or epidemics, adherence to accelerated immunization|
03593|057|D|schedules for the measles, mumps, and rubella vaccine should be|
03593|058|D|reinforced.(5)|
03593|059|B||
03593|060|R|REFERENCES:|
03593|061|B||
03593|062|R|1.Hydrea (hydroxyurea) US prescribing information. Bristol-Myers Squibb|1
03593|063|R|  Company November, 2023.|1
03593|064|R|2.Centers for Disease Control and Prevention. General Recommendations on|1
03593|065|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
03593|066|R|  Practices (ACIP). MMWR.  Available at:|1
03593|067|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
03593|068|R|  February 17, 2022;60(RR No.2):1-68.|1
03593|069|R|3.TICE BCG (BCG live, for intravesical use) prescribing information. Organon|1
03593|070|R|  USA Inc. October, 2010.|1
03593|071|R|4.Centers for Disease Control and Prevention. General Best Practice|1
03593|072|R|  Guidelines for Immunization: Altered Immunocompetence. ACIP Vaccine|1
03593|073|R|  Recommendations and Guidelines. Available at:|1
03593|074|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.h|1
03593|075|R|  tml. Accessed July 2024.;123-148.|1
03593|076|R|5.Lederman HM,  Connolly MA,  Kalpatthi R,  Ware RE,  Wang WC,|2
03593|077|R|  Luchtman-Jones L,  Waclawiw M,  Goldsmith JC,  Swift A,  Casella JF.|2
03593|078|R|  Immunologic effects of hydroxyurea in sickle cell anemia. Pediatrics. 2014|2
03593|079|R|  Oct;134(4):686-695.|2
03594|001|T|MONOGRAPH TITLE:  Apomorphine/Ziprasidone|
03594|002|B||
03594|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03594|004|L|of severe adverse interaction.|
03594|005|B||
03594|006|A|MECHANISM OF ACTION:  Concurrent use of apomorphine and ziprasidone may have|
03594|007|A|additive effects on the QTc interval.(1,2)|
03594|008|A|   In addition, apomorphine is a dopamine agonist.  Ziprasidone may decrease|
03594|009|A|apomorphine's effectiveness by blocking dopamine activity at CNS D2|
03594|010|A|receptors.(1)|
03594|011|B||
03594|012|E|CLINICAL EFFECTS:  The concurrent use of apomorphine with ziprasidone may|
03594|013|E|result in potentially life-threatening cardiac arrhythmias, including|
03594|014|E|torsades de pointes.(1)|
03594|015|E|   The efficacy of either agent may be decreased, leading to exacerbation of|
03594|016|E|the disease being treated, e.g. Parkinson disease or a psychotic disorder.|
03594|017|B||
03594|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03594|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03594|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03594|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03594|022|P|female gender, or advanced age.|
03594|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03594|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03594|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03594|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03594|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03594|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03594|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03594|030|P|   Patients with Parkinson or Diffuse Lewy Body(DLB) disease are|
03594|031|P|particularly susceptible to adverse effects of dopamine blockade by|
03594|032|P|antipsychotics.|
03594|033|B||
03594|034|M|PATIENT MANAGEMENT:  The US manufacturer of ziprasidone states other agents|
03594|035|M|known to prolong the QT interval should not be used concomitantly.(2)|
03594|036|M|   The US manufacturer of apomorphine states that patients with major|
03594|037|M|psychotic disorders treated with neuroleptics should be treated with|
03594|038|M|dopamine agonists only if the potential benefits outweigh the risks.(1)|
03594|039|M|   Reassess the need for antipsychotic therapy.  If psychosis or|
03594|040|M|hallucinations are due to an antiparkinson agent, when possible consider|
03594|041|M|reducing the dose or changing the antiparkinson agent before initiating|
03594|042|M|antipsychotic therapy.  In patients with PD and dementia, addition of a|
03594|043|M|cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis.  If an|
03594|044|M|antipsychotic is required, then an atypical antipsychotic should be|
03594|045|M|used.(4,5)|
03594|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03594|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03594|048|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03594|049|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03594|050|B||
03594|051|D|DISCUSSION:  An epidemiologic study evaluated 21,043 elderly patients with|
03594|052|D|Parkinson disease to determine if recent initiation of a typical or atypical|
03594|053|D|antipsychotic was associated with increased mortality.  They found an|
03594|054|D|adjusted odds ratio of 2.0 for death associated with atypical antipsychotics|
03594|055|D|versus no antipsychotic. They found an adjusted odds ratio of 2.4 for death|
03594|056|D|associated with typical versus atypical antipsychotics. The authors noted|
03594|057|D|the increased mortality found with typical antipsychotics supports current|
03594|058|D|treatment recommendations to use atypical antipsychotic agents in patients|
03594|059|D|with Parkinson disease.(4,5)|
03594|060|D|   Agents that are linked to this monograph may have varying degrees of|
03594|061|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03594|062|D|been shown to prolong the QTc interval either through their mechanism of|
03594|063|D|action, through studies on their effects on the QTc interval, or through|
03594|064|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03594|065|D|and/or postmarketing reports.(6)|
03594|066|B||
03594|067|R|REFERENCES:|
03594|068|B||
03594|069|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03594|070|R|  Inc. May, 2019.|1
03594|071|R|2.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
03594|072|R|  May, 2021.|1
03594|073|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03594|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03594|075|R|  settings: a scientific statement from the American Heart Association and|6
03594|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03594|077|R|  2;55(9):934-47.|6
03594|078|R|4.Marras C, Gruneir A, Wang X, Fischer H, Gill SS, Herrmann N, Anderson GM,|2
03594|079|R|  Hyson C, Rochon PA. Antipsychotics and mortality in Parkinsonism. Am J|2
03594|080|R|  Geriatr Psychiatry 2012 Feb;20(2):149-58.|2
03594|081|R|5.Oertel WH Berardelli A Bloem Br etal. Chapter 15 - Late (complicated)|6
03594|082|R|  Parkinson's disease in European Handbook of Neurological Management. 2011;|6
03594|083|R|  Volume 1, 2nd Edition:237 - 267.|6
03594|084|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
03594|085|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03594|086|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03594|087|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03595|001|T|MONOGRAPH TITLE:  Larotrectinib/Lonafarnib (mono deleted 05/28/2024)|
03595|002|B||
03595|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03595|004|L|of severe adverse interaction.|
03595|005|B||
03595|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03595|007|A|metabolism of larotrectinib.(1)  Lonafarnib is a strong CYP3A4 inhibitor.(2)|
03595|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03595|009|A|Larotrectinib is a weak CYP3A4 inhibitor.(3)|
03595|010|B||
03595|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03595|012|E|systemic exposure and the risk for larotrectinib toxicities such as|
03595|013|E|neurotoxicity or hepatotoxicity.(1)|
03595|014|E|  Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03595|015|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03595|016|E|liver enzymes, myelosuppression, and hypertension.(2)|
03595|017|B||
03595|018|P|PREDISPOSING FACTORS:  None determined.|
03595|019|B||
03595|020|M|PATIENT MANAGEMENT:  Avoid concomitant use of larotrectinib and strong CYP3A|
03595|021|M|inhibitors. Consider an alternative concomitant medication with less|
03595|022|M|potential for CYP3A4 inhibition.(1)|
03595|023|M|   The US manufacturer of larotrectinib states when concomitant use of|
03595|024|M|larotrectinib and a strong CYP3A4 inhibitor is needed, the larotrectinib|
03595|025|M|dose should be reduced by 50%.(1) If the strong CYP3A4 inhibitor is|
03595|026|M|discontinued, change the larotrectinib dose to the dose used prior to the|
03595|027|M|initiation of the strong CYP3A4 inhibitor after 3 to 5 elimination|
03595|028|M|half-lives.(1)|
03595|029|M|   Avoid coadministration of lonafarnib and weak CYP3A4 inhibitors.  If|
03595|030|M|coadministration is unavoidable, reduce to or continue lonafarnib at a|
03595|031|M|dosage of 115 mg/m2.(2)|
03595|032|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03595|033|M|heart palpitations because lonafarnib exposures may be increased despite the|
03595|034|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03595|035|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03595|036|M|inhibitor.(2)|
03595|037|B||
03595|038|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03595|039|D|coadministration of itraconazole (strong 3A4 inhibitor) with a single dose|
03595|040|D|of larotrectinib (100 mg) increased larotrectinib maximum concentration|
03595|041|D|(Cmax) and area-under-the-curve (AUC) by 2.8 and 4.3-fold, respectively. (1)|
03595|042|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03595|043|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03595|044|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03595|045|B||
03595|046|R|REFERENCES:|
03595|047|B||
03595|048|R|1.Vitrakvi (larotrectinib) US prescribing information. Loxo Oncology, Inc.|1
03595|049|R|  November, 2022.|1
03595|050|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03595|051|R|  Inc. November, 2020.|1
03595|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
03595|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03596|001|T|MONOGRAPH TITLE:  Selpercatinib/Lonafarnib (mono deleted 05/28/2024)|
03596|002|B||
03596|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03596|004|L|of severe adverse interaction.|
03596|005|B||
03596|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03596|007|A|selpercatinib.(1)  Lonafarnib is a strong CYP3A4 inhibitor.(2)|
03596|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib, a|
03596|009|A|sensitive CYP3A4 substrate.(1  Selpercatinib is a weak CYP3A4 inhibitor.(1)|
03596|010|B||
03596|011|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03596|012|E|with selpercatinib may result in elevated levels of and toxicity from|
03596|013|E|selpercatinib.(1)  Elevated levels of selpercatinib may increase the risk of|
03596|014|E|QTc prolongation and potentially life-threatening arrhythmias, including|
03596|015|E|torsades de pointes, hepatotoxicity, hypertension, and severe or|
03596|016|E|life-threatening hemorrhagic events.(1)|
03596|017|E|   Concurrent use with weak CYP3A4 inhibitors with lonafarnib may increase|
03596|018|E|the risk of adverse reactions of lonafarnib including nausea and vomiting,|
03596|019|E|increased liver enzymes, myelosuppression, and hypertension.(2)|
03596|020|B||
03596|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03596|022|P|may be increased in patients with cardiovascular disease (e.g. heart|
03596|023|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03596|024|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03596|025|P|female gender, or advanced age.(3)|
03596|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03596|027|P|higher systemic concentrations of either QT prolonging drug are additional|
03596|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03596|029|P|drug concentrations include rapid infusion of an intravenous dose or|
03596|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03596|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03596|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03596|033|B||
03596|034|M|PATIENT MANAGEMENT:  The US manufacturer of selpercatinib recommends|
03596|035|M|avoiding concomitant use of strong CYP3A4 inhibitors with selpercatinib.  If|
03596|036|M|concomitant use cannot be avoided, reduce the dose of selpercatinib as|
03596|037|M|follows:|
03596|038|M|   - If the current dose of selpercatinib is 160 mg twice daily, decrease|
03596|039|M|the dose to 80 mg twice daily.|
03596|040|M|   - If the current dose of selpercatinib is 120 mg twice daily, decrease|
03596|041|M|the dose to 40 mg twice daily.|
03596|042|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
03596|043|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03596|044|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03596|045|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03596|046|M|   If grade 3 QT interval prolongation occurs, withhold selpercatinib until|
03596|047|M|recovery to baseline or Grades 0 or 1, then resume selpercatinib at a|
03596|048|M|reduced dose.  If grade 4 QT interval prolongation occurs, discontinue|
03596|049|M|selpercatinib.(1)|
03596|050|M|   After the inhibitor has been discontinued for 3 to 5 elimination|
03596|051|M|half-lives, resume selpercatinib at the dose taken prior to initiating the|
03596|052|M|CYP3A inhibitor.(1)|
03596|053|M|   Avoid coadministration of lonafarnib and weak CYP3A4 inhibitors.  If|
03596|054|M|coadministration is unavoidable, reduce to or continue lonafarnib at a|
03596|055|M|dosage of 115 mg/m2.(2)|
03596|056|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03596|057|M|heart palpitations because lonafarnib exposures may be increased despite the|
03596|058|M|dosage reduction and the effect on the QT interval is unknown. Resume|
03596|059|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03596|060|M|inhibitor.(2)|
03596|061|B||
03596|062|D|DISCUSSION:  In a study, itraconazole (a strong CYP3A inhibitor) increased|
03596|063|D|the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib|
03596|064|D|by 133% and 30%, respectively.(1)|
03596|065|D|   In a thorough QT study, selpercatinib 160 mg twice daily increased QTc by|
03596|066|D|a mean of 10.6 msec (upper 90% confidence interval: 12.1 msec).  An increase|
03596|067|D|in QTcF interval to greater than 500 msec was measured in 6% of patients and|
03596|068|D|an increase in the QTcF interval of at least 60 msec over baseline was|
03596|069|D|measured in 15% of patients.(1)|
03596|070|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03596|071|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03596|072|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03596|073|B||
03596|074|R|REFERENCES:|
03596|075|B||
03596|076|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly April, 2024.|1
03596|077|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03596|078|R|  Inc. November, 2020.|1
03596|079|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03596|080|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03596|081|R|  settings: a scientific statement from the American Heart Association and|6
03596|082|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03596|083|R|  2;55(9):934-47.|6
03596|084|R|4.This information is based on an extract from the Certara Drug Interaction|6
03596|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03596|086|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03596|087|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03596|088|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03596|089|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03596|090|R|  11/14/2017.|1
03597|001|T|MONOGRAPH TITLE:  Simeprevir/Lonafarnib (mono deleted 05/28/2024)|
03597|002|B||
03597|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03597|004|L|of severe adverse interaction.|
03597|005|B||
03597|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may slow down the|
03597|007|A|metabolism of simeprevir.(1)  Lonafarnib is a strong CYP3A4 inhibitor.(2)|
03597|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03597|009|A|Simeprevir is a weak CYP3A4 inhibitor.(1)|
03597|010|B||
03597|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
03597|012|E|elevated levels of and toxicity from simeprevir.(1)|
03597|013|E|   Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03597|014|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03597|015|E|liver enzymes, myelosuppression, and hypertension.(2)|
03597|016|B||
03597|017|P|PREDISPOSING FACTORS:  None determined.|
03597|018|B||
03597|019|M|PATIENT MANAGEMENT:  The US manufacturer of simeprevir states that|
03597|020|M|concurrent administration of strong or moderate inhibitors of CYP3A4 is not|
03597|021|M|recommended due to risk of toxicity.(1)|
03597|022|M|   Avoid coadministration of lonafarnib and weak CYP3A4 inhibitors.  If|
03597|023|M|coadministration is unavoidable, reduce to or continue lonafarnib at a|
03597|024|M|dosage of 115 mg/m2.(2)|
03597|025|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03597|026|M|heart palpitations because lonafarnib exposures may be increased despite the|
03597|027|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03597|028|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03597|029|M|inhibitor.(2)|
03597|030|B||
03597|031|D|DISCUSSION:  In a study in 24 subjects, erythromycin (500 mg TID for 7 days)|
03597|032|D|increased the maximum concentration (Cmax), area-under-curve (AUC) and Cmin|
03597|033|D|of simeprevir (150 mg daily for 7 days) by 4.53-fold, 7.47-fold, and|
03597|034|D|12.74-fold, respectively.  The Cmax and AUC of erythromycin increased by|
03597|035|D|1.59-fold and 1.39-fold, respectively.(1)|
03597|036|D|   In a study in 9 subjects, an individualized dose of cyclosporine|
03597|037|D|increased the Cmax and AUC of simeprevir (150 mg daily for 14 days) by 4.74|
03597|038|D|fold and 5.81-fold.(1)|
03597|039|D|   In a study in 25 subjects, simeprevir (50 mg once daily) increased the|
03597|040|D|Cmax, AUC, and Cmin of darunavir (800 mg once daily) by 4%, 18%, and 31%.(3)|
03597|041|D|   In a study in 25 subjects, darunavir-ritonavir (800 mg-100 mg once daily)|
03597|042|D|increased the Cmax, AUC, and Cmin of simeprevir (50 mg once daily) by|
03597|043|D|1.79-fold, 2.59-fold, and 4.58-fold.(3)|
03597|044|D|   In a study in 12 subjects, ritonavir (100 mg twice daily, 15 days)|
03597|045|D|increased the AUC, Cmax, and Cmin of simeprevir (200 mg daily, 7 days) by|
03597|046|D|618% (463-815%), 370% (284-476%), and 1335% (929-1901%).(4)|
03597|047|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03597|048|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03597|049|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03597|050|B||
03597|051|R|REFERENCES:|
03597|052|B||
03597|053|R|1.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
03597|054|R|  November, 2017.|1
03597|055|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03597|056|R|  Inc. November, 2020.|1
03597|057|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
03597|058|R|  March, 2023.|1
03597|059|R|4.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
03597|060|R|  December, 2019.|1
03598|001|T|MONOGRAPH TITLE:  Osilodrostat/Lonafarnib (mono deleted 05/28/2024)|
03598|002|B||
03598|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03598|004|L|of severe adverse interaction.|
03598|005|B||
03598|006|A|MECHANISM OF ACTION:  Osilodrostat is metabolized by CYP3A4.  Strong|
03598|007|A|inhibitors of CYP3A4 may decrease the metabolism of osilodrostat.(1)|
03598|008|A|Lonafarnib is a strong CYP3A4 inhibitor.(2)|
03598|009|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03598|010|A|Osilodrostat is a weak CYP3A4 inhibitor.(1)|
03598|011|B||
03598|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors with|
03598|013|E|osilodrostat may result in increased levels of and toxicity from|
03598|014|E|osilodrostat.(1)|
03598|015|E|   Concurrent use with weak CYP3A4 inhibitors with lonafarnib may increase|
03598|016|E|the risk of adverse reactions of lonafarnib including nausea and vomiting,|
03598|017|E|increased liver enzymes, myelosuppression, and hypertension.(2)|
03598|018|B||
03598|019|P|PREDISPOSING FACTORS:  The risk of an adverse event with osilodrostat is|
03598|020|P|higher if the patient is taking other drugs that inhibit other CYP or UGT|
03598|021|P|enzymes.|
03598|022|B||
03598|023|M|PATIENT MANAGEMENT:  The US manufacturer of osilodrostat recommends a dose|
03598|024|M|reduction by half the current dose of osilodrostat with concomitant use of|
03598|025|M|agents that are strong CYP3A4 inhibitors due to a significant increase in|
03598|026|M|exposure to osilodrostat.(1)|
03598|027|M|   Avoid coadministration of lonafarnib and weak CYP3A4 inhibitors.  If|
03598|028|M|coadministration is unavoidable, reduce to or continue lonafarnib at a|
03598|029|M|dosage of 115 mg/m2.(2)|
03598|030|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03598|031|M|heart palpitations because lonafarnib exposures may be increased despite the|
03598|032|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03598|033|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03598|034|M|inhibitor.(2)|
03598|035|B||
03598|036|D|DISCUSSION:  Osilodrostat is metabolized by multiple CYP and UGT enzymes.|
03598|037|D|Strong CYP3A4 inhibitors are predicted to inhibit metabolism of|
03598|038|D|osilodrostat.(1)|
03598|039|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03598|040|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03598|041|D|area-under-curve (AUC) and maximum concentration (Cmax) were increased by|
03598|042|D|425% and 270%, respectively.(2)|
03598|043|B||
03598|044|R|REFERENCES:|
03598|045|B||
03598|046|R|1.Isturisa (osilodrostat) US prescribing information. Recordati Rare|1
03598|047|R|  Diseases, Inc. March, 2020.|1
03598|048|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03598|049|R|  Inc. November, 2020.|1
03599|001|T|MONOGRAPH TITLE:  Tacrolimus/Lonafarnib (mono deleted 05/28/2024)|
03599|002|B||
03599|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03599|004|L|of severe adverse interaction.|
03599|005|B||
03599|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03599|007|A|tacrolimus.(1)  Lonafarnib is a strong CYP3A4 inhibitor.(2)|
03599|008|A|  Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03599|009|A|Tacrolimus is a weak CYP3A4 inhibitor.(1)|
03599|010|B||
03599|011|E|CLINICAL EFFECTS:  Concurrent use lonafarnib may result in increased levels|
03599|012|E|of tacrolimus.(1)|
03599|013|E|   Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03599|014|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03599|015|E|liver enzymes, myelosuppression, and hypertension.(2)|
03599|016|B||
03599|017|P|PREDISPOSING FACTORS:  None determined.|
03599|018|B||
03599|019|M|PATIENT MANAGEMENT:  For patients concurrently taking tacrolimus and|
03599|020|M|lonafarnib, therapeutic concentration monitoring of the immunosuppressant is|
03599|021|M|recommended.  Dose decreases of tacrolimus may be required.  The US|
03599|022|M|manufacturer of tacrolimus states that coadministration with a strong CYP3A4|
03599|023|M|inhibitor like lonafarnib may result in a rapid and sharp rise in tacrolimus|
03599|024|M|concentration despite immediate tacrolimus dose reduction.  Frequent|
03599|025|M|monitoring of tacrolimus levels should start within 1-3 days of initiation|
03599|026|M|of concurrent therapy and continue as necessary.(1)|
03599|027|M|   Avoid coadministration of lonafarnib and weak CYP3A4 inhibitors.  If|
03599|028|M|coadministration is unavoidable, reduce to or continue lonafarnib at a|
03599|029|M|dosage of 115 mg/m2.(2)|
03599|030|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03599|031|M|heart palpitations because lonafarnib exposures may be increased despite the|
03599|032|M|dosage reduction and the effect on the QT interval is unknown. Resume|
03599|033|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03599|034|M|inhibitor.(2)|
03599|035|B||
03599|036|D|DISCUSSION:  In a case report, tacrolimus levels in a 50 year-old male|
03599|037|D|kidney transplant recipient increased from 7.5 ng/ml to 111.2 ng/ml one week|
03599|038|D|after initiation of an HIV regimen including elvitegravir 150 mg, cobicistat|
03599|039|D|150 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg once|
03599|040|D|daily.  The patient experienced headache, insomnia, stomachache,|
03599|041|D|hyperkalemia, and increased SCr at which time the HIV regimen was stopped.|
03599|042|D|On day 15 the patient's tacrolimus level returned to 4.0 ng/ml at which time|
03599|043|D|the patient resumed tacrolimus at previous stable dose and the HIV regimen|
03599|044|D|was changed to abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg|
03599|045|D|daily without any further increase in tacrolimus levels.(3)|
03599|046|D|   In a case report, tacrolimus levels in a 41 year-old male kidney|
03599|047|D|transplant recipient increased from 8.7 ng/ml to 106 ng/ml within 3 days of|
03599|048|D|the addition of tenofovir and darunavir/ritonavir therapy, despite the|
03599|049|D|patient's tacrolimus dosage being decreased 12%.  Concurrent therapy was|
03599|050|D|eventually titrated to 0.5 mg of tacrolimus given once weekly.(4)|
03599|051|D|   There are several case reports of decreased tacrolimus requirements|
03599|052|D|and/or toxicity during concurrent indinavir,(5) lopinavir/ritonavir,(6-7)|
03599|053|D|and nelfinavir.(8)  In a study in 5 HIV+ liver transplant patients,|
03599|054|D|tacrolimus needs were 38 times lower with concurrent nelfinavir.(9)|
03599|055|D|   A case report describes a 52 year-old male with HIV and hepatitis C who|
03599|056|D|experienced severe tacrolimus toxicity after the addition of an HIV regimen|
03599|057|D|including nelfinavir (750 mg three times daily) following his liver|
03599|058|D|transplantation.  The HIV regimen was temporarily stopped until the|
03599|059|D|tacrolimus levels normalized at which time the medications were restarted|
03599|060|D|having replaced nelfinavir with saquinavir (400 mg twice/day) and ritonavir|
03599|061|D|(400 mg twice/day).  The patient again experienced neurological symptoms|
03599|062|D|associated with tacrolimus toxicity and was found to have a tacrolimus level|
03599|063|D|over 120 ng/ml.  The medications were held allowing for a long recovery. The|
03599|064|D|HIV regimen was rechallenged a third time using the original combination|
03599|065|D|which included nelfinavir.  The dose of tacrolimus was dramatically|
03599|066|D|decreased and the schedule changed until the tacrolimus levels finally|
03599|067|D|stabilized.(10)|
03599|068|D|  With coadministration of a single oral dose of 50 mg lonafarnib following|
03599|069|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03599|070|D|area-under-curve (AUC) and maximum concentration (Cmax) were increased by|
03599|071|D|425% and 270%, respectively.(2)|
03599|072|B||
03599|073|R|REFERENCES:|
03599|074|B||
03599|075|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
03599|076|R|  August, 2023.|1
03599|077|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03599|078|R|  Inc. November, 2020.|1
03599|079|R|3.Han Z, Kane BM, Petty LA, Josephson MA, Sutor J, Pursell KJ. Cobicistat|3
03599|080|R|  Significantly Increases Tacrolimus Serum Concentrations in a Renal|3
03599|081|R|  Transplant Recipient with Human Immunodeficiency Virus Infection.|3
03599|082|R|  Pharmacotherapy 2016 Jun;36(6):e50-e53.|3
03599|083|R|4.Mertz D, Battegay M, Marzolini C, Mayr M. Drug-drug interaction in a|3
03599|084|R|  kidney transplant recipient receiving HIV salvage therapy and tacrolimus.|3
03599|085|R|  Am J Kidney Dis 2009 Jul;54(1):e1-4.|3
03599|086|R|5.Jain AK, Venkataramanan R, Shapiro R, Scantlebury VP, Potdar S, Bonham CA,|2
03599|087|R|  Ragni M, Fung JJ. The interaction between antiretroviral agents and|2
03599|088|R|  tacrolimus in liver and kidney transplant patients. Liver Transpl 2002|2
03599|089|R|  Sep;8(9):841-5.|2
03599|090|R|6.Schonder KS, Shullo MA, Okusanya O. Tacrolimus and lopinavir/ritonavir|3
03599|091|R|  interaction in liver transplantation. Ann Pharmacother 2003 Dec;|3
03599|092|R|  37(12):1793-6.|3
03599|093|R|7.Jain AB, Venkataramanan R, Eghtesad B, Marcos A, Ragni M, Shapiro R,|3
03599|094|R|  Rafail AB, Fung JJ. Effect of coadministered lopinavir and ritonavir|3
03599|095|R|  (Kaletra) on tacrolimus blood concentration in liver transplantation|3
03599|096|R|  patients. Liver Transpl 2003 Sep;9(9):954-60.|3
03599|097|R|8.Guaraldi G, Cocchi S, Codeluppi M, Di Benedetto F, Bonora S, Pecorari M,|3
03599|098|R|  Gennari W, Cautero N, Pinna AD, Gerunda GE, Esposito R. Role of|3
03599|099|R|  therapeutic drug monitoring in a patient with human immunodeficiency virus|3
03599|100|R|  infection and end-stage liver disease undergoing orthotopic liver|3
03599|101|R|  transplantation. Transplant Proc 2005 Jul-Aug;37(6):2609-10.|3
03599|102|R|9.Schvarcz R, Rudbeck G, Soderdahl G, Stahle L. Interaction between|3
03599|103|R|  nelfinavir and tacrolimus after orthoptic liver transplantation in a|3
03599|104|R|  patient coinfected with HIV and hepatitis C virus (HCV). Transplantation|3
03599|105|R|  2000 May 27;69(10):2194-5.|3
03599|106|R|10.Sheikh AM, Wolf DC, Lebovics E, Goldberg R, Horowitz HW. Concomitant|3
03599|107|R|   human immunodeficiency virus protease inhibitor therapy markedly reduces|3
03599|108|R|   tacrolimus metabolism and increases blood levels. Transplantation 1999|3
03599|109|R|   Jul 27;68(2):307-9.|3
03600|001|T|MONOGRAPH TITLE:  Daclatasvir/Lonafarnib (mono deleted 05/28/2024)|
03600|002|B||
03600|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03600|004|L|of severe adverse interaction.|
03600|005|B||
03600|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03600|007|A|metabolism of daclatasvir.(1)  Lonafarnib is a strong CYP3A4 inhibitor.(2)|
03600|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03600|009|A|Daclatasvir is a weak CYP3A4 inhibitor.(3)|
03600|010|B||
03600|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03600|012|E|systemic exposure and the risk for daclatasvir toxicities.(1)|
03600|013|E|  Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03600|014|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03600|015|E|liver enzymes, myelosuppression, and hypertension.(2)|
03600|016|B||
03600|017|P|PREDISPOSING FACTORS:  None determined.|
03600|018|B||
03600|019|M|PATIENT MANAGEMENT:  Avoid concomitant use of daclatasvir and lonafarnib.|
03600|020|M|   If concurrent use is necessary, the dose of daclatasvir should be reduced|
03600|021|M|to 30 mg daily.(1)  Reduce the dose of lonafarnib to or continue at a dosage|
03600|022|M|of 115 mg/m2.(2)|
03600|023|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03600|024|M|heart palpitations because lonafarnib exposures may be increased despite the|
03600|025|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03600|026|M|previous lonafarnib dosage 14 days after discontinuing the daclatasvir.(2)|
03600|027|B||
03600|028|D|DISCUSSION:  Atazanavir/ritonavir (300/100 mg daily) increased the maximum|
03600|029|D|concentration (Cmax), area-under-curve (AUC), and minimum concentration|
03600|030|D|(Cmin) of daclatasvir by 1.35-fold, 2.10-fold, and 3.65-fold,|
03600|031|D|respectively.(1)|
03600|032|D|   Ketoconazole (400 mg daily) increased the Cmax and AUC of daclatasvir by|
03600|033|D|1.57-fold and 3.00-fold, respectively.(1)|
03600|034|D|   Telaprevir (500 mg q12h) increased the Cmax and AUC of daclatasvir by|
03600|035|D|1.46-fold and 2.32-fold, respectively.  There were no significant changes in|
03600|036|D|telaprevir concentrations.(1)|
03600|037|D|   Telaprevir (750 mg q8h) increased the Cmax and AUC of daclatasvir by|
03600|038|D|1.22-fold and 2.15-fold, respectively.  There were no significant changes in|
03600|039|D|telaprevir concentrations.(1)|
03600|040|D|   In a study, concomitant administration of daclatasvir (30 mg once daily)|
03600|041|D|with lopinavir/ritonavir (400 mg/100 mg twice daily) did not result in any|
03600|042|D|clinically relevant changes of exposure.(1)|
03600|043|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03600|044|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03600|045|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03600|046|B||
03600|047|R|REFERENCES:|
03600|048|B||
03600|049|R|1.Daklinza (daclatasvir dihydrochloride) UK summary of product|1
03600|050|R|  characteristics. Bristol-Myers Squibb Pharmaceutical Limited August 29,|1
03600|051|R|  2014.|1
03600|052|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03600|053|R|  Inc. November, 2020.|1
03600|054|R|3.This information is based on an extract from the Certara Drug Interaction|6
03600|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03601|001|T|MONOGRAPH TITLE:  Everolimus/Lonafarnib (mono deleted 05/28/2024)|
03601|002|B||
03601|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03601|004|L|of severe adverse interaction.|
03601|005|B||
03601|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03601|007|A|metabolism of everolimus.(1,2)  Lonafarnib is a strong CYP3A4 inhibitor.(3)|
03601|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03601|009|A|Everolimus is a weak CYP3A4 inhibitor.(4)|
03601|010|B||
03601|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03601|012|E|systemic exposure and the risk for everolimus toxicities.(1)|
03601|013|E|  Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03601|014|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03601|015|E|liver enzymes, myelosuppression, and hypertension.(2)|
03601|016|B||
03601|017|P|PREDISPOSING FACTORS:  None determined.|
03601|018|B||
03601|019|M|PATIENT MANAGEMENT:  Avoid concomitant use of everolimus and lonafarnib.|
03601|020|M|   If concurrent use is necessary, reduce the dose of lonafarnib to or|
03601|021|M|continue at a dosage of 115 mg/m2.(2)|
03601|022|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03601|023|M|heart palpitations because lonafarnib exposures may be increased despite the|
03601|024|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03601|025|M|previous lonafarnib dosage 14 days after discontinuing the everolimus.(2)|
03601|026|B||
03601|027|D|DISCUSSION:  In a study in healthy subjects, concurrent use of ketoconazole,|
03601|028|D|a strong CYP3A4 inhibitor and a Pg-p inhibitor, increased everolimus|
03601|029|D|area-under-curve (AUC) and maximum concentration (Cmax) by 3.9-fold and|
03601|030|D|15.0-fold, respectively.(1)|
03601|031|D|   In a case report, a renal transplant patient on everolimus and started on|
03601|032|D|voriconazole experienced an increase in everolimus trough concentration|
03601|033|D|(Cmin) of 7.5-fold, which was normalized with a lowering of everolimus dose|
03601|034|D|from 1.5 mg twice daily to 0.25 mg twice daily.  Voriconazole was|
03601|035|D|discontinued after one month, and another month later, posaconazole was|
03601|036|D|started.  Cmin increased by 3.8-fold, which led to an adjustment of|
03601|037|D|everolimus dose from 1 mg twice daily to 0.5 mg twice daily.(5)|
03601|038|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03601|039|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03601|040|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03601|041|B||
03601|042|R|REFERENCES:|
03601|043|B||
03601|044|R|1.Afinitor (everolimus) US prescribing information. Novartaris|1
03601|045|R|  Pharmaceuticals Corporation February, 2020.|1
03601|046|R|2.Zortress (everolimus) US prescribing information. Novartis Pharmaceuticals|1
03601|047|R|  Corporation Sept, 2023.|1
03601|048|R|3.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03601|049|R|  Inc. November, 2020.|1
03601|050|R|4.This information is based on an extract from the Certara Drug Interaction|6
03601|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03601|052|R|5.Billaud EM, Antoine C, Berge M, Abboud I, Lefeuvre S, Benammar M, Glotz D.|3
03601|053|R|  Management of metabolic cytochrome P450 3A4 drug-drug interaction between|3
03601|054|R|  everolimus and azole antifungals in a renal transplant patient. Clin Drug|3
03601|055|R|  Investig 2009;29(7):481-6.|3
03602|001|T|MONOGRAPH TITLE:  Rimegepant/Lonafarnib (mono deleted 05/28/2024)|
03602|002|B||
03602|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03602|004|L|of severe adverse interaction.|
03602|005|B||
03602|006|A|MECHANISM OF ACTION:  Rimegepant is primarily metabolized by CYP3A4 and is a|
03602|007|A|substrate of P-glycoprotein (P-gp).  Strong inhibitors of CYP3A4 may|
03602|008|A|decrease the metabolism of rimegepant.(1)  P-gp inhibitors may significantly|
03602|009|A|increase the absorption of rimegepant. Lonafarnib is a strong CYP3A4|
03602|010|A|inhibitor and P-gp inhibitor.(2)|
03602|011|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03602|012|A|Rimegepant is a weak CYP3A4 inhibitor.(3)|
03602|013|B||
03602|014|E|CLINICAL EFFECTS:  Concurrent use of a dual CYP3A4 and P-gp inhibitor may|
03602|015|E|result in increased levels of and toxicity from rimegepant.(1)|
03602|016|E|   Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03602|017|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03602|018|E|liver enzymes, myelosuppression, and hypertension.(2)|
03602|019|B||
03602|020|P|PREDISPOSING FACTORS:  None determined.|
03602|021|B||
03602|022|M|PATIENT MANAGEMENT:  The US manufacturer of rimegepant recommends avoiding|
03602|023|M|concomitant use of agents that are strong CYP3A4 inhibitors or P-gp|
03602|024|M|inhibitors due to a significant increase in exposure to rimegepant.(1)|
03602|025|M|   Avoid coadministration of lonafarnib and weak CYP3A4 inhibitors.  If|
03602|026|M|coadministration is unavoidable, reduce to or continue lonafarnib at a|
03602|027|M|dosage of 115 mg/m2.(2)|
03602|028|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03602|029|M|heart palpitations because lonafarnib exposures may be increased despite the|
03602|030|M|dosage reduction and the effect on the QT interval is unknown. Resume|
03602|031|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03602|032|M|inhibitor.(2)|
03602|033|B||
03602|034|D|DISCUSSION:  In a drug interaction study, itraconazole, a strong CYP3A4|
03602|035|D|inhibitor, increased the area-under-curve (AUC) and maximum concentration|
03602|036|D|(Cmax) of rimegepant (75 mg) by 4-fold and 1.5-fold, respectively.(1)|
03602|037|D|   Rimegepant is a substrate of P-gp and BCRP transporters.  Use of P-gp or|
03602|038|D|BCRP inhibitors may increase the exposure of rimegepant.  Clinical drug|
03602|039|D|interaction studies with inhibitors of these transporters were not|
03602|040|D|conducted.(4)|
03602|041|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03602|042|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03602|043|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03602|044|B||
03602|045|R|REFERENCES:|
03602|046|B||
03602|047|R|1.Nurtec ODT (rimegepant) US prescribing information. Biohaven|1
03602|048|R|  Pharmaceuticals, Inc. December, 2021.|1
03602|049|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03602|050|R|  Inc. November, 2020.|1
03602|051|R|3.This information is based on an extract from the Certara Drug Interaction|6
03602|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03603|001|T|MONOGRAPH TITLE:  Fostamatinib/Lonafarnib (mono deleted 05/28/2024)|
03603|002|B||
03603|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03603|004|L|of severe adverse interaction.|
03603|005|B||
03603|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03603|007|A|metabolism of fostamatinib.(1)  Lonafarnib is a strong CYP3A4 inhibitor.(2)|
03603|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03603|009|A|Fostamatinib is a weak CYP3A4 inhibitor.(3)|
03603|010|B||
03603|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03603|012|E|systemic exposure and the risk for fostamatinib toxicities.(1)|
03603|013|E|  Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03603|014|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03603|015|E|liver enzymes, myelosuppression, and hypertension.(2)|
03603|016|B||
03603|017|P|PREDISPOSING FACTORS:  None determined.|
03603|018|B||
03603|019|M|PATIENT MANAGEMENT:  Avoid concomitant use of fostamatinib and lonafarnib.|
03603|020|M|   If concurrent use is necessary, reduce the dose of lonafarnib to or|
03603|021|M|continue at a dosage of 115 mg/m2.(2)|
03603|022|M|   Monitor for adverse effects that may require dose reduction of|
03603|023|M|fostamatinib.(1)|
03603|024|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03603|025|M|heart palpitations because lonafarnib exposures may be increased despite the|
03603|026|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03603|027|M|previous lonafarnib dosage 14 days after discontinuing the fostamatinib.(2)|
03603|028|B||
03603|029|D|DISCUSSION:  In a study of 8 healthy males, ketoconazole (200 mg twice|
03603|030|D|daily), a strong CYP3A4 inhibitor, increased the area-under-curve (AUC) and|
03603|031|D|maximum concentration (Cmax) of single-dose fostamatinib 80 mg by 102% and|
03603|032|D|37%, respectively.(1)|
03603|033|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03603|034|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03603|035|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03603|036|B||
03603|037|R|REFERENCES:|
03603|038|B||
03603|039|R|1.Tavalisse (fostamatinib) prescribing information. Rigel Pharmaceuticals,|1
03603|040|R|  Inc April 2018.|1
03603|041|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03603|042|R|  Inc. November, 2020.|1
03603|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
03603|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03604|001|T|MONOGRAPH TITLE:  Lumateperone/Lonafarnib (mono deleted 07/27/2022)|
03604|002|B||
03604|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03604|004|L|of severe adverse interaction.|
03604|005|B||
03604|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may inhibit|
03604|007|A|the metabolism of lumateperone.(1)  Lonafarnib is a strong CYP3A4|
03604|008|A|inhibitor.(2)|
03604|009|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03604|010|A|Lumateperone is a weak CYP3A4 inhibitor.(3)|
03604|011|B||
03604|012|E|CLINICAL EFFECTS:  Concurrent use of lumateperone with strong or moderate|
03604|013|E|CYP3A4 inhibitors increases lumateperone exposure, which may increase the|
03604|014|E|risk of adverse reactions.(1)|
03604|015|E|   Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03604|016|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03604|017|E|liver enzymes, myelosuppression, and hypertension.(2)|
03604|018|B||
03604|019|P|PREDISPOSING FACTORS:  None determined.|
03604|020|B||
03604|021|M|PATIENT MANAGEMENT:  Avoid concomitant use of lumateperone with strong or|
03604|022|M|moderate CYP3A4 inhibitors.(1)|
03604|023|M|   Avoid coadministration of lonafarnib and weak CYP3A4 inhibitors.  If|
03604|024|M|coadministration is unavoidable, reduce to or continue lonafarnib at a|
03604|025|M|dosage of 115 mg/m2.(2)|
03604|026|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03604|027|M|heart palpitations because lonafarnib exposures may be increased despite the|
03604|028|M|dosage reduction and the effect on the QT interval is unknown. Resume|
03604|029|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03604|030|M|inhibitor.(2)|
03604|031|B||
03604|032|D|DISCUSSION:  Coadministration of lumateperone with itraconazole, a strong|
03604|033|D|CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in|
03604|034|D|area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1)|
03604|035|D|   Coadministration of lumateperone with diltiazem, a moderate CYP3A4|
03604|036|D|inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax,|
03604|037|D|respectively.(1)|
03604|038|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03604|039|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03604|040|D|area-under-curve (AUC) and maximum concentration (Cmax) were increased by|
03604|041|D|425% and 270%, respectively.(2)|
03604|042|B||
03604|043|R|REFERENCES:|
03604|044|B||
03604|045|R|1.Caplyta (lumateperone) US prescribing information. Intra-Cellular|1
03604|046|R|  Therapies, Inc. November, 2025.|1
03604|047|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03604|048|R|  Inc. November, 2020.|1
03604|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
03604|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03605|001|T|MONOGRAPH TITLE:  Ivacaftor/Lonafarnib (mono deleted 05/28/2024)|
03605|002|B||
03605|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03605|004|L|of severe adverse interaction.|
03605|005|B||
03605|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03605|007|A|metabolism of ivacaftor.(1)  Lonafarnib is a strong CYP3A4 inhibitor.(2)|
03605|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03605|009|A|Ivacaftor is a weak CYP3A4 inhibitor.(3)|
03605|010|B||
03605|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03605|012|E|systemic exposure and the risk for ivacaftor toxicities.(1)|
03605|013|E|  Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03605|014|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03605|015|E|liver enzymes, myelosuppression, and hypertension.(2)|
03605|016|B||
03605|017|P|PREDISPOSING FACTORS:  None determined.|
03605|018|B||
03605|019|M|PATIENT MANAGEMENT:  Avoid concomitant use of ivacaftor and lonafarnib.|
03605|020|M|   If concurrent use is necessary, the dose of ivacaftor should be reduced|
03605|021|M|to one 150 mg tablet or one packet (25 mg if body weight 5 kg to < 7 kg, 50|
03605|022|M|mg if body weight < 14 kg, 75 mg if weight equal or > 14 kg) two times a|
03605|023|M|week.(1)|
03605|024|M|   If concurrent use is necessary, reduce the dose of lonafarnib to or|
03605|025|M|continue at a dosage of 115 mg/m2.(2)|
03605|026|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03605|027|M|heart palpitations because lonafarnib exposures may be increased despite the|
03605|028|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03605|029|M|previous lonafarnib dosage 14 days after discontinuing the ivacaftor.(2)|
03605|030|B||
03605|031|D|DISCUSSION:  Concurrent administration with ketoconazole (a strong inhibitor|
03605|032|D|of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1)|
03605|033|D|   A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with|
03605|034|D|ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B),|
03605|035|D|and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4|
03605|036|D|of ivacaftor administration (study C).  In study A, B, and C, ivacaftor AUC|
03605|037|D|increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively,|
03605|038|D|with the addition of ritonavir.  Ivacaftor concentration maximum (Cmax) was|
03605|039|D|0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(4)|
03605|040|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03605|041|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03605|042|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03605|043|B||
03605|044|R|REFERENCES:|
03605|045|B||
03605|046|R|1.Kalydeco (ivacaftor) US prescribing information. Vertex Pharmaceuticals|1
03605|047|R|  Incorporated May, 2023.|1
03605|048|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03605|049|R|  Inc. November, 2020.|1
03605|050|R|3.This information is based on an extract from the Certara Drug Interaction|6
03605|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03605|052|R|4.Liddy AM, McLaughlin G, Schmitz S, D'Arcy DM, Barry MG. The|2
03605|053|R|  Pharmacokinetic Interaction between Ivacaftor and Ritonavir in Healthy|2
03605|054|R|  Volunteers. Br J Clin Pharmacol 2017 May 06.|2
03606|001|T|MONOGRAPH TITLE:  Entrectinib/Lonafarnib (mono deleted 05/28/2024)|
03606|002|B||
03606|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03606|004|L|of severe adverse interaction.|
03606|005|B||
03606|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
03606|007|A|metabolism of entrectinib.(1)  Lonafarnib is a strong CYP3A4 inhibitor.(2)|
03606|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.(2)|
03606|009|A|Entrectinib is a weak CYP3A4 inhibitor.(3)|
03606|010|B||
03606|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03606|012|E|systemic exposure and the risk for entrectinib toxicities, such as QT|
03606|013|E|prolongation, hepatotoxicity, CNS effects, hyperuricemia, anemia, or|
03606|014|E|neutropenia.(1)|
03606|015|E|  Concurrent use with weak CYP3A4 inhibitors may increase the risk of|
03606|016|E|adverse reactions of lonafarnib including nausea and vomiting, increased|
03606|017|E|liver enzymes, myelosuppression, and hypertension.(2)|
03606|018|B||
03606|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03606|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03606|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03606|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03606|023|P|gender, or advanced age.(4)|
03606|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03606|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03606|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03606|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03606|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03606|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03606|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03606|031|B||
03606|032|M|PATIENT MANAGEMENT:  Avoid concomitant use of entrectinib and lonafarnib.|
03606|033|M|   If concomitant use is necessary, reduce the dose of lonafarnib to or|
03606|034|M|continue at a dosage of 115 mg/m2.|
03606|035|M|   For adult and pediatric patients 2 years and older, reduce the|
03606|036|M|entrectinib dose as follows:|
03606|037|M|   -If the starting dose is 600 mg, reduce the entrectinib dose to 100 mg|
03606|038|M|daily.|
03606|039|M|   -If the starting dose is 400 mg, reduce the entrectinib dose to 50 mg|
03606|040|M|daily.|
03606|041|M|   -If the starting dose is 300 mg, reduce the entrectinib dose to 50 mg|
03606|042|M|daily.|
03606|043|M|   -If the starting dose is 200 mg, reduce the entrectinib dose to 50 mg on|
03606|044|M|alternate days.(1)|
03606|045|M|   For pediatric patients less than 2 years old, avoid coadministration of|
03606|046|M|entrectinib with lonafarnib.(1)|
03606|047|M|   If concomitant use of entrectinib is discontinued, resume previous|
03606|048|M|lonafarnib dosage 14 days after discontinuing the entrectinib.(2)  If|
03606|049|M|concomitant use of lonafarnib is discontinued, increase the entrectinib dose|
03606|050|M|to the dose that was used before starting lonafarnib after three to five|
03606|051|M|plasma half-lives of lonafarnib.(1)|
03606|052|M|   Monitor liver tests, including AST and ALT. Advise patients to|
03606|053|M|immediately report any symptoms of hepatotoxicity.|
03606|054|M|   During concomitant therapy, monitor patients closely for prolongation of|
03606|055|M|the QT interval.  Obtain serum calcium, magnesium, and potassium levels and|
03606|056|M|monitor ECG at regular intervals.  Correct any electrolyte abnormalities.|
03606|057|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03606|058|B||
03606|059|D|DISCUSSION:  Coadministration of itraconazole (strong CYP3A4 inhibitor) with|
03606|060|D|a single 100 mg entrectinib dose increased entrectinib maximum concentration|
03606|061|D|(Cmax) and area-under-the-curve (AUC) by 1.7-fold and 6-fold.(1)|
03606|062|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03606|063|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03606|064|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03606|065|B||
03606|066|R|REFERENCES:|
03606|067|B||
03606|068|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03606|069|R|  October 2023.|1
03606|070|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03606|071|R|  Inc. November, 2020.|1
03606|072|R|3.This information is based on an extract from the Certara Drug Interaction|6
03606|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03606|074|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03606|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03606|076|R|  settings: a scientific statement from the American Heart Association and|6
03606|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03606|078|R|  2;55(9):934-47.|6
03607|001|T|MONOGRAPH TITLE:  Berotralstat/P-gp or BCRP Inhibitors (mono deleted|
03607|002|T|02/13/2024)|
03607|003|B||
03607|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03607|005|L|take action as needed.|
03607|006|B||
03607|007|A|MECHANISM OF ACTION:  Inhibitors of P-glycoprotein (P-gp) or BCRP may|
03607|008|A|increase the absorption of berotralstat.(1)|
03607|009|B||
03607|010|E|CLINICAL EFFECTS:  The concurrent administration of berotralstat with an|
03607|011|E|inhibitor of P-glycoprotein or BCRP may result in elevated levels of|
03607|012|E|berotralstat.(1)|
03607|013|B||
03607|014|P|PREDISPOSING FACTORS:  None determined.|
03607|015|B||
03607|016|M|PATIENT MANAGEMENT:  The manufacturer recommends a dose of 110 mg once daily|
03607|017|M|of berotralstat when coadministered chronically with P-gp or BCRP|
03607|018|M|inhibitors.(1)|
03607|019|B||
03607|020|D|DISCUSSION:  Berotralstat is a substrate of P-gp and BCRP transporters.  Use|
03607|021|D|of P-gp or BCRP inhibitors may increase the exposure of berotralstat. The US|
03607|022|D|manufacturer of berotralstat recommends dose adjustment if berotralstat is|
03607|023|D|coadministered with P-gp or BCRP inhibitors.(1)|
03607|024|D|   Administration of cyclosporine, a P-gp and BCRP inhibitor, with|
03607|025|D|berotralstat, increased berotralstat maximum concentration (Cmax) and|
03607|026|D|area-under-the-curve(0-last) (AUC 0-last), area-under-the-curve(0-inf) (AUC|
03607|027|D|0-inf) by 25%, 55%, and 69%.(1)|
03607|028|D|   BCRP inhibitors linked to this monograph include: curcumin, darolutamide,|
03607|029|D|eltrombopag, gefitinib, grazoprevir, leflunomide, momelotinib,|
03607|030|D|oteseconazole, rolapitant, roxadustat, safinamide, tafamidis, oral|
03607|031|D|tedizolid, teriflunomide, and vadadustat.(2,3)|
03607|032|D|   P-glycoprotein inhibitors linked to this monograph include: carvedilol,|
03607|033|D|cimetidine, diosmin, fostamatinib, neratinib, osimertinib, pirtobrutinib,|
03607|034|D|propafenone, quinidine, sofosbuvir/velpatasvir/voxilaprevir, sotorasib,|
03607|035|D|tepotinib, and valbenazine.(2,3)|
03607|036|B||
03607|037|R|REFERENCES:|
03607|038|B||
03607|039|R|1.Orladeyo (berotralstat) US prescribing information. BioCryst|1
03607|040|R|  Pharmaceuticals, Inc. November 2023.|1
03607|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03607|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03607|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03607|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03607|045|R|  11/14/2017.|1
03607|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
03607|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03608|001|T|MONOGRAPH TITLE:  Brexpiprazole/Berotralstat|
03608|002|B||
03608|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03608|004|L|take action as needed.|
03608|005|B||
03608|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2D6 and CYP3A4 may inhibit the|
03608|007|A|metabolism of brexpiprazole.  Berotralstat is a moderate inhibitor of CYP3A4|
03608|008|A|and CYP2D6.(1,2)|
03608|009|B||
03608|010|E|CLINICAL EFFECTS:  Concurrent administration of berotralstat may result in|
03608|011|E|elevated levels of and toxicity from brexpiprazole.(1,2)|
03608|012|B||
03608|013|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
03608|014|P|patients who are receiving concomitant treatment with a strong or moderate|
03608|015|P|CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor.|
03608|016|P|Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to|
03608|017|P|increase brexpiprazole levels 5.1-fold in extensive metabolizers of|
03608|018|P|CYP2D6.(1)|
03608|019|P|   This interaction is expected to be more severe in patients who are CYP2D6|
03608|020|P|poor metabolizers, or who receive concomitant treatment with a strong or|
03608|021|P|moderate CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine,|
03608|022|P|quinidine) in addition to treatment with a moderate CYP3A4 inhibitor.(1)|
03608|023|B||
03608|024|M|PATIENT MANAGEMENT:  The US manufacturer of brexpiprazole recommends the|
03608|025|M|following dose adjustments for patients who are receiving a moderate CYP2D6|
03608|026|M|and moderate CYP3A4 inhibitor:|
03608|027|M|   - decrease the dose to one-fourth the usual dose.|
03608|028|M|   The dose of brexpiprazole should be adjusted to its original level if|
03608|029|M|berotralstat is discontinued.(1)|
03608|030|B||
03608|031|D|DISCUSSION:  Coadministration of quinidine, a strong inhibitor of CYP2D6,|
03608|032|D|increased the area-under-curve (AUC) of brexpiprazole approximately|
03608|033|D|2-fold.(1)|
03608|034|D|   Coadministration of ketoconazole, a strong inhibitor of CYP3A4, increased|
03608|035|D|the AUC of brexpiprazole approximately 2-fold.(1)|
03608|036|B||
03608|037|R|REFERENCES:|
03608|038|B||
03608|039|R|1.Rexulti (brexpiprazole) US prescribing information. Otsuka Pharmaceutical|1
03608|040|R|  Co., Ltd. June, 2020.|1
03608|041|R|2.Orladeyo (berotralstat) US prescribing information. BioCryst|1
03608|042|R|  Pharmaceuticals, Inc. November 2023.|1
03609|001|T|MONOGRAPH TITLE:  Berotralstat/Selected P-gp Inducers|
03609|002|B||
03609|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03609|004|L|of severe adverse interaction.|
03609|005|B||
03609|006|A|MECHANISM OF ACTION:  Berotralstat is a substrate of the intestinal efflux|
03609|007|A|transporter P-glycoprotein (P-gp).  Inducers of P-gp may decrease systemic|
03609|008|A|absorption of berotralstat.(1)|
03609|009|B||
03609|010|E|CLINICAL EFFECTS:  Concurrent or recent use of P-gp inducers may result in|
03609|011|E|decreased systemic levels and effectiveness of berotralstat.(1)|
03609|012|B||
03609|013|P|PREDISPOSING FACTORS:  None determined.|
03609|014|B||
03609|015|M|PATIENT MANAGEMENT:  The US manufacturer of berotralstat states concurrent|
03609|016|M|use is not recommended with P-gp inducers.(1)|
03609|017|B||
03609|018|D|DISCUSSION:  Berotralstat is a substrate P-gp. Concomitant administration|
03609|019|D|with a P-gp inducer may decrease berotralstat plasma concentration leading|
03609|020|D|to reduced efficacy of berotralstat.(1)|
03609|021|D|   Selected P-gp inducers linked to this monograph include: apalutamide,|
03609|022|D|carbamazepine, efavirenz, fosphenytoin, lorlatinib, phenytoin, rifabutin,|
03609|023|D|rifampin, rifapentine, and St. John's wort.(1)|
03609|024|B||
03609|025|R|REFERENCES:|
03609|026|B||
03609|027|R|1.Orladeyo (berotralstat) US prescribing information. BioCryst|1
03609|028|R|  Pharmaceuticals, Inc. November 2023.|1
03609|029|R|2.This information is based on an extract from the Certara Drug Interaction|6
03609|030|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03610|001|T|MONOGRAPH TITLE:  Cilostazol (Greater Than 50 mg BID)/Lonafarnib|
03610|002|B||
03610|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03610|004|L|of severe adverse interaction.|
03610|005|B||
03610|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03610|007|A|of cilostazol.  Lonafarnib is a strong CYP3A4 inhibitor.(1)|
03610|008|A|   Both agents have been shown to prolong the QTc interval.(1,2)|
03610|009|B||
03610|010|E|CLINICAL EFFECTS:  The concurrent use of cilostazol and strong inhibitors of|
03610|011|E|CYP3A4 may result in elevated levels of cilostazol, which may produce|
03610|012|E|increased effects of cilostazol and adverse effects.(1)  Concurrent use may|
03610|013|E|also result in potentially life-threatening cardiac arrhythmias, including|
03610|014|E|torsades de pointes (TdP).(2)|
03610|015|B||
03610|016|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
03610|017|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
03610|018|P|failure, myocardial infarction, history of torsade de pointes, congenital|
03610|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03610|020|P|female gender, or advanced age.(3)|
03610|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03610|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03610|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03610|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03610|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03610|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03610|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03610|028|P|   This interaction may also be more severe in patients taking inhibitors of|
03610|029|P|CYP2C19.(1)|
03610|030|B||
03610|031|M|PATIENT MANAGEMENT:  Avoid coadministration of cilostazol and|
03610|032|M|lonafarnib.(1,2)  If coadministration is unavoidable, the dose of cilostazol|
03610|033|M|should be limited to 50 mg twice daily.(1)|
03610|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03610|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03610|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03610|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03610|038|B||
03610|039|D|DISCUSSION:  In a study, ketoconazole 400 mg (a strong CYP3A4 inhibitor)|
03610|040|D|increased cilostazol maximum concentration (Cmax) by 94% and|
03610|041|D|area-under-curve (AUC) by 117%.(1)|
03610|042|D|   Agents that are linked to this monograph may have varying degrees of|
03610|043|D|potential to prolong the QTc interval but are generally accepted to have a|
03610|044|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03610|045|D|been shown to prolong the QTc interval either through their mechanism of|
03610|046|D|action, through studies on their effects on the QTc interval, or through|
03610|047|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03610|048|D|and/or post-marketing reports.(4)|
03610|049|B||
03610|050|R|REFERENCES:|
03610|051|B||
03610|052|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
03610|053|R|  Pharmaceutical, Inc. January, 2015.|1
03610|054|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03610|055|R|  Inc. November, 2020.|1
03610|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03610|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03610|058|R|  settings: a scientific statement from the American Heart Association and|6
03610|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03610|060|R|  2;55(9):934-47.|6
03610|061|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03610|062|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03610|063|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03610|064|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03611|001|T|MONOGRAPH TITLE:  Cilostazol (Less Than or Equal To 50 mg BID)/Lonafarnib|
03611|002|B||
03611|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03611|004|L|of severe adverse interaction.|
03611|005|B||
03611|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03611|007|A|of cilostazol.  Lonafarnib is a strong CYP3A4 inhibitor.(1)|
03611|008|A|   Both agents have been shown to prolong the QTc interval.(1,2)|
03611|009|B||
03611|010|E|CLINICAL EFFECTS:  The concurrent use of cilostazol and strong inhibitors of|
03611|011|E|CYP3A4 may result in elevated levels of cilostazol, which may produce|
03611|012|E|increased effects of cilostazol and adverse effects.(1)  Concurrent use may|
03611|013|E|also result in potentially life-threatening cardiac arrhythmias, including|
03611|014|E|torsades de pointes (TdP).(2)|
03611|015|B||
03611|016|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
03611|017|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
03611|018|P|failure, myocardial infarction, history of torsade de pointes, congenital|
03611|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03611|020|P|female gender, or advanced age.(3)|
03611|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03611|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03611|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03611|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03611|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03611|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03611|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03611|028|P|   This interaction may also be more severe in patients taking inhibitors of|
03611|029|P|CYP2C19.(1)|
03611|030|B||
03611|031|M|PATIENT MANAGEMENT:  Avoid coadministration of cilostazol and|
03611|032|M|lonafarnib.(1,2)  If coadministration is unavoidable, the dose of cilostazol|
03611|033|M|should be limited to 50 mg twice daily.(1)|
03611|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03611|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03611|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03611|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03611|038|B||
03611|039|D|DISCUSSION:  In a study, ketoconazole 400 mg (a strong CYP3A4 inhibitor)|
03611|040|D|increased cilostazol maximum concentration (Cmax) by 94% and|
03611|041|D|area-under-curve (AUC) by 117%.(1)|
03611|042|D|   Agents that are linked to this monograph may have varying degrees of|
03611|043|D|potential to prolong the QTc interval but are generally accepted to have a|
03611|044|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03611|045|D|been shown to prolong the QTc interval either through their mechanism of|
03611|046|D|action, through studies on their effects on the QTc interval, or through|
03611|047|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03611|048|D|and/or post-marketing reports.(4)|
03611|049|B||
03611|050|R|REFERENCES:|
03611|051|B||
03611|052|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
03611|053|R|  Pharmaceutical, Inc. January, 2015.|1
03611|054|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03611|055|R|  Inc. November, 2020.|1
03611|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03611|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03611|058|R|  settings: a scientific statement from the American Heart Association and|6
03611|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03611|060|R|  2;55(9):934-47.|6
03611|061|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03611|062|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03611|063|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03611|064|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03612|001|T|MONOGRAPH TITLE:  Suvorexant/Lonafarnib (mono deleted 05/28/2024)|
03612|002|B||
03612|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03612|004|L|of severe adverse interaction.|
03612|005|B||
03612|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03612|007|A|of suvorexant.  Lonafarnib is a strong CYP3A4 inhibitor.(1)|
03612|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.|
03612|009|A|Suvorexant is a weak CYP3A4 inhibitor.(2)|
03612|010|B||
03612|011|E|CLINICAL EFFECTS:  Concurrent use of suvorexant with lonafarnib may result|
03612|012|E|in an increase in suvorexant levels and clinical adverse effects such as|
03612|013|E|confusion, memory loss, sleep-walking or sleep-driving behaviors, thought or|
03612|014|E|behavioral changes, or excessive daytime drowsiness, as well as toxic|
03612|015|E|effects such as profound sedation, respiratory depression, coma, and/or|
03612|016|E|death.(1)  Concurrent use may also increase the risk of adverse reactions of|
03612|017|E|lonafarnib including nausea and vomiting, increased liver enzymes,|
03612|018|E|myelosuppression, and hypertension.(2)|
03612|019|B||
03612|020|P|PREDISPOSING FACTORS:  None determined.|
03612|021|B||
03612|022|M|PATIENT MANAGEMENT:  Avoid coadministration of suvorexant and lonafarnib.|
03612|023|M|   If coadministration is unavoidable, reduce the dose of lonafarnib to or|
03612|024|M|continue at 115 mg/m2.(2)|
03612|025|M|   The US manufacturer of suvorexant states that concurrent use with strong|
03612|026|M|inhibitors of CYP3A4 is not recommended.(2)  Consider alternative agents|
03612|027|M|with less CYP3A4 inhibition when possible.  Patients requiring concurrent|
03612|028|M|therapy will need a substantially lower doses of suvorexant.(2)|
03612|029|M|   Patients should be counseled that concurrent use of lonafarnib with|
03612|030|M|suvorexant may result in an increase in side effects such as confusion,|
03612|031|M|memory loss, sleep-walking or sleep-driving behaviors, or daytime|
03612|032|M|drowsiness.|
03612|033|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03612|034|M|heart palpitations because lonafarnib exposures may be increased despite the|
03612|035|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03612|036|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03612|037|M|inhibitor.(2)|
03612|038|B||
03612|039|D|DISCUSSION:  Ketoconazole increased suvorexant AUC and Cmax by approximately|
03612|040|D|2.75-fold and 1.25-fold, respectively.(4)|
03612|041|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03612|042|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03612|043|D|area-under-curve (AUC) and maximum concentration (Cmax) were increased by|
03612|044|D|425% and 270%, respectively.(2)|
03612|045|B||
03612|046|R|REFERENCES:|
03612|047|B||
03612|048|R|1.Belsomra (suvorexant) US prescribing information. Merck & Co., Inc. March,|1
03612|049|R|  2021.|1
03612|050|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03612|051|R|  Inc. November, 2020.|1
03612|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
03612|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03612|054|R|4.Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Brentano C, Jaillon|5
03612|055|R|  P. Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism. Drug|5
03612|056|R|  Metab Dispos 1999 Sep;27(9):1068-73.|5
03613|001|T|MONOGRAPH TITLE:  Suvorexant/Strong CYP3A4 Inhibitors; Atazanavir; Darunavir|
03613|002|B||
03613|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03613|004|L|of severe adverse interaction.|
03613|005|B||
03613|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 impair the metabolism of|
03613|007|A|suvorexant.(1)|
03613|008|B||
03613|009|E|CLINICAL EFFECTS:  Concurrent use of suvorexant with a CYP3A4 inhibitor may|
03613|010|E|result in an increase in hypnotic levels and clinical adverse effects such|
03613|011|E|as confusion, memory loss, sleep-walking or sleep-driving behaviors, thought|
03613|012|E|or behavioral changes, or excessive daytime drowsiness, as well as toxic|
03613|013|E|effects such as profound sedation, respiratory depression, coma, and/or|
03613|014|E|death.(1)|
03613|015|B||
03613|016|P|PREDISPOSING FACTORS:  Systemic exposure may also be increased in patients|
03613|017|P|with severe hepatic impairment.|
03613|018|P|   Elderly and debilitated patients are more likely to have impaired motor|
03613|019|P|or cognitive performance when treated with hypnotics.|
03613|020|B||
03613|021|M|PATIENT MANAGEMENT:  The US manufacturer of suvorexant states that|
03613|022|M|concurrent use with strong inhibitors of CYP3A4 is not recommended.|
03613|023|M|Consider alternative agents with less CYP3A4 inhibition when possible.(1)|
03613|024|M|The US Department of Health and Human Services HIV guidelines state that|
03613|025|M|suvorexant should not be coadministered with protease inhibitors.(2)|
03613|026|M|   Patients requiring concurrent therapy will need a substantially lower|
03613|027|M|dose of suvorexant.  Patients should be counseled that concurrent use of a|
03613|028|M|strong CYP3A4 inhibitor with suvorexant may result in an increase in side|
03613|029|M|effects such as confusion, memory loss, sleep-walking or sleep-driving|
03613|030|M|behaviors, or daytime drowsiness.|
03613|031|M|   With moderate inhibitors of CYP3A4, the manufacturer recommends a|
03613|032|M|starting dose of 5 mg daily and a maximum dose of 10 mg daily.(1)|
03613|033|B||
03613|034|D|DISCUSSION:  Ketoconazole increased suvorexant AUC and Cmax by approximately|
03613|035|D|2.75-fold and 1.25-fold, respectively.(1)|
03613|036|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir,|
03613|037|D|clarithromycin, cobicistat, elvitegravir, indinavir, itraconazole,|
03613|038|D|josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
03613|039|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03613|040|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, and|
03613|041|D|voriconazole.(3,4)|
03613|042|B||
03613|043|R|REFERENCES:|
03613|044|B||
03613|045|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03613|046|R|  Inc. November, 2020.|1
03613|047|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03613|048|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03613|049|R|  HIV. Department of Health and Human Services. Available at:|6
03613|050|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
03613|051|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
03613|052|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03613|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03613|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03613|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03613|056|R|  11/14/2017.|1
03613|057|R|4.This information is based on an extract from the Certara Drug Interaction|6
03613|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03614|001|T|MONOGRAPH TITLE:  Tezacaftor-Ivacaftor/Berotralstat (mono deleted|
03614|002|T|02/15/2024)|
03614|003|B||
03614|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03614|005|L|of severe adverse interaction.|
03614|006|B||
03614|007|A|MECHANISM OF ACTION:  Berotralstat, a moderate inhibitor of CYP3A4, may|
03614|008|A|inhibit the metabolism of tezacaftor-ivacaftor.(1-3)|
03614|009|A|   Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption|
03614|010|A|of berotralstat.(3)  Tezacaftor-ivacaftor is a P-gp inhibitor.(4)|
03614|011|B||
03614|012|E|CLINICAL EFFECTS:  Concurrent use of berotralstat, a moderate inhibitor of|
03614|013|E|CYP3A4, may result in elevated levels of and toxicity from|
03614|014|E|tezacaftor-ivacaftor and berotralstat.(1,2)|
03614|015|B||
03614|016|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
03614|017|P|hepatic impairment.(1,2)|
03614|018|B||
03614|019|M|PATIENT MANAGEMENT:  Refer to current prescribing information for|
03614|020|M|tezacaftor-ivacaftor for dose adjustment recommendations with moderate|
03614|021|M|CYP3A4 inhibitors.(2)|
03614|022|M|   Dose modifications for concurrent use of moderate CYP3A4 inhibitors:|
03614|023|M|   - In adults, patients 12 years and older, and patients 6 to 12 years old|
03614|024|M|weighing at least 30 kg who are receiving concurrent moderate CYP3A4|
03614|025|M|inhibitors, the morning dose of tezacaftor 100 mg/ivacaftor 150 mg should be|
03614|026|M|given every other day alternating with ivacaftor 150 mg.  The evening dose|
03614|027|M|of ivacaftor 150 mg should not be taken.|
03614|028|M|   - In patients 6 to 12 years old weighing less than 30 kg who are|
03614|029|M|receiving concurrent moderate CYP3A4 inhibitors, the morning dose of|
03614|030|M|tezacaftor 50 mg/ivacaftor 75 mg should be given every other day alternating|
03614|031|M|with ivacaftor 75 mg.  The evening dose of ivacaftor 75 mg should not be|
03614|032|M|taken.(2)|
03614|033|M|   The manufacturer of berotralstat recommends a dose of 110 mg once daily|
03614|034|M|of berotralstat when coadministered chronically with P-gp or BCRP inhibitors|
03614|035|M|such as tezacaftor-ivacaftor.(1)|
03614|036|B||
03614|037|D|DISCUSSION:  Concurrent administration with ketoconazole (a strong inhibitor|
03614|038|D|of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1)|
03614|039|D|   Concurrent administration with fluconazole (a moderate inhibitor of|
03614|040|D|CYP3A4) increased ivacaftor AUC by 3-fold.(1)|
03614|041|D|   Concurrent administration with itraconazole (a strong inhibitor of|
03614|042|D|CYP3A4) increased tezacaftor AUC by 4-fold and ivacaftor by 15.6-fold.(2)|
03614|043|D|   Concurrent administration with fluconazole (a moderate inhibitor of|
03614|044|D|CYP3A4) increased tezacaftor AUC by 2-fold.(2)|
03614|045|D|   A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with|
03614|046|D|ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B),|
03614|047|D|and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4|
03614|048|D|of ivacaftor administration (study C).  In study A, B, and C, ivacaftor AUC|
03614|049|D|increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively,|
03614|050|D|with the addition of ritonavir.  Ivacaftor concentration maximum (Cmax) was|
03614|051|D|0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(5)|
03614|052|D|   Administration of cyclosporine, a P-gp and BCRP inhibitor, with|
03614|053|D|berotralstat, increased berotralstat maximum concentration (Cmax) and|
03614|054|D|area-under-the-curve(0-last) (AUC 0-last), area-under-the-curve(0-inf) (AUC|
03614|055|D|0-inf) by 25%, 55%, and 69%.(2)|
03614|056|B||
03614|057|R|REFERENCES:|
03614|058|B||
03614|059|R|1.Kalydeco (ivacaftor) US prescribing information. Vertex Pharmaceuticals|1
03614|060|R|  Incorporated May, 2023.|1
03614|061|R|2.Symdeko (tezacaftor/ivacaftor) US prescribing information. Vertex|1
03614|062|R|  Pharmaceuticals Incorporated December, 2019.|1
03614|063|R|3.Orladeyo (berotralstat) US prescribing information. BioCryst|1
03614|064|R|  Pharmaceuticals, Inc. November 2023.|1
03614|065|R|4.This information is based on an extract from the Certara Drug Interaction|6
03614|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03614|067|R|5.Liddy AM, McLaughlin G, Schmitz S, D'Arcy DM, Barry MG. The|2
03614|068|R|  Pharmacokinetic Interaction between Ivacaftor and Ritonavir in Healthy|2
03614|069|R|  Volunteers. Br J Clin Pharmacol 2017 May 06.|2
03614|070|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
03614|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03614|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03614|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03614|074|R|  11/14/2017.|1
03614|075|R|7.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03614|076|R|  Indiana University School of Medicine.  Available at:|1
03614|077|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03615|001|T|MONOGRAPH TITLE:  Ivacaftor/Berotralstat (mono deleted 02/15/2024)|
03615|002|B||
03615|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03615|004|L|of severe adverse interaction.|
03615|005|B||
03615|006|A|MECHANISM OF ACTION:  Berotralstat, a moderate inhibitor of CYP3A4, may|
03615|007|A|inhibit the metabolism of ivacaftor.(1,2)|
03615|008|A|   Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption|
03615|009|A|of berotralstat.(2)  Ivacaftor is a P-gp inhibitor.(3)|
03615|010|B||
03615|011|E|CLINICAL EFFECTS:  Concurrent use of berotralstat, a moderate inhibitor of|
03615|012|E|CYP3A4, with ivacaftor may result in elevated levels of and toxicity from|
03615|013|E|ivacaftor and berotralstat.(1,2)|
03615|014|B||
03615|015|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
03615|016|P|hepatic impairment.(1)|
03615|017|B||
03615|018|M|PATIENT MANAGEMENT:  In patients receiving concurrent moderate CYP3A4|
03615|019|M|inhibitors such as berotralstat, the dose of ivacaftor should be reduced to|
03615|020|M|one 150 mg tablet or one packet (25 mg if body weight 5 kg to < 7 kg, 50 mg|
03615|021|M|if body weight < 14 kg, 75 mg if weight equal or > 14 kg) daily.(1)|
03615|022|M|   The manufacturer of berotralstat recommends a dose of 110 mg once daily|
03615|023|M|of berotralstat when coadministered chronically with P-gp or BCRP inhibitors|
03615|024|M|such as ivacaftor.(1)|
03615|025|B||
03615|026|D|DISCUSSION:  Concurrent administration with ketoconazole (a strong inhibitor|
03615|027|D|of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1)|
03615|028|D|   Concurrent administration with fluconazole (a moderate inhibitor of|
03615|029|D|CYP3A4) increased ivacaftor area-under-curve (AUC) by 3-fold.(1)|
03615|030|D|   A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with|
03615|031|D|ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B),|
03615|032|D|and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4|
03615|033|D|of ivacaftor administration (study C).  In study A, B, and C, ivacaftor AUC|
03615|034|D|increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively,|
03615|035|D|with the addition of ritonavir.  Ivacaftor concentration maximum (Cmax) was|
03615|036|D|0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(4)|
03615|037|D|   Administration of cyclosporine, a P-gp and BCRP inhibitor, with|
03615|038|D|berotralstat, increased berotralstat maximum concentration (Cmax) and|
03615|039|D|area-under-the-curve(0-last) (AUC 0-last), area-under-the-curve(0-inf) (AUC|
03615|040|D|0-inf) by 25%, 55%, and 69%.(2)|
03615|041|B||
03615|042|R|REFERENCES:|
03615|043|B||
03615|044|R|1.Kalydeco (ivacaftor) US prescribing information. Vertex Pharmaceuticals|1
03615|045|R|  Incorporated May, 2023.|1
03615|046|R|2.Orladeyo (berotralstat) US prescribing information. BioCryst|1
03615|047|R|  Pharmaceuticals, Inc. November 2023.|1
03615|048|R|3.This information is based on an extract from the Certara Drug Interaction|6
03615|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03615|050|R|4.Liddy AM, McLaughlin G, Schmitz S, D'Arcy DM, Barry MG. The|2
03615|051|R|  Pharmacokinetic Interaction between Ivacaftor and Ritonavir in Healthy|2
03615|052|R|  Volunteers. Br J Clin Pharmacol 2017 May 06.|2
03615|053|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03615|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03615|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03615|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03615|057|R|  11/14/2017.|1
03615|058|R|6.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03615|059|R|  Indiana University School of Medicine.  Available at:|1
03615|060|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03616|001|T|MONOGRAPH TITLE:  Elexacaftor-Tezacaftor-Ivacaftor/Berotralstat (mono|
03616|002|T|deleted 02/15/2024)|
03616|003|B||
03616|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03616|005|L|of severe adverse interaction.|
03616|006|B||
03616|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4, such as berotralstat,|
03616|008|A|may inhibit the CYP3A4-mediated metabolism of elexacaftor, tezacaftor, and|
03616|009|A|ivacaftor.(1,2)|
03616|010|A|   Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption|
03616|011|A|of berotralstat.(2)  Ivacaftor is a P-gp inhibitor.(3)|
03616|012|B||
03616|013|E|CLINICAL EFFECTS:  Concurrent use of berotralstat, a moderate inhibitor of|
03616|014|E|CYP3A4, may result in elevated levels of and toxicity from|
03616|015|E|elexacaftor-tezacaftor-ivacaftor and berotralstat.(1,2)|
03616|016|B||
03616|017|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
03616|018|P|hepatic impairment.(1)|
03616|019|B||
03616|020|M|PATIENT MANAGEMENT:  The dosage of elexacaftor-tezacaftor-ivacaftor should|
03616|021|M|be reduced when co-administered with moderate CYP3A4 inhibitors.|
03616|022|M|   -The evening dose of ivacaftor should not be taken.|
03616|023|M|   -The morning dose of therapy should be modified as follows: Day 1 - two|
03616|024|M|tablets of elexacaftor-tezacaftor-ivacaftor; Day 2 - one tablet of ivacaftor|
03616|025|M|150 mg; Day 3 - two tablets of elexacaftor-tezacaftor-ivacaftor; Day 4 - one|
03616|026|M|tablet of ivacaftor 150 mg.  This alternate day dosing should be continued|
03616|027|M|thereafter.(1)|
03616|028|M|   The manufacturer of berotralstat recommends a dose of 110 mg once daily|
03616|029|M|of berotralstat when coadministered chronically with P-gp or BCRP inhibitors|
03616|030|M|such as elexacaftor-tezacaftor-ivacaftor.(2)|
03616|031|B||
03616|032|D|DISCUSSION:  In a study, fluconazole (400 mg on day 1 then 200 mg daily)|
03616|033|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03616|034|D|ivacaftor (150 mg every 12 hours) by 2.95-fold and 2.45-fold,|
03616|035|D|respectively.(1)|
03616|036|D|   Simulations suggest that moderate CYP3A inhibitors may increase the AUC|
03616|037|D|of elexacaftor and tezacaftor by approximately 1.9 to 2.3-fold and 2.1-fold,|
03616|038|D|respectively.(1)|
03616|039|D|   Administration of cyclosporine, a P-gp and BCRP inhibitor, with|
03616|040|D|berotralstat, increased berotralstat maximum concentration (Cmax) and|
03616|041|D|area-under-the-curve(0-last) (AUC 0-last), area-under-the-curve(0-inf) (AUC|
03616|042|D|0-inf) by 25%, 55%, and 69%.(2)|
03616|043|B||
03616|044|R|REFERENCES:|
03616|045|B||
03616|046|R|1.Trikafta (elexacaftor, tezacaftor and ivacaftor tablets; ivacaftor|1
03616|047|R|  tablets) US prescribing information. Vertex Pharmaceuticals Incorporated|1
03616|048|R|  October, 2021.|1
03616|049|R|2.Orladeyo (berotralstat) US prescribing information. BioCryst|1
03616|050|R|  Pharmaceuticals, Inc. November 2023.|1
03616|051|R|3.This information is based on an extract from the Certara Drug Interaction|6
03616|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03616|053|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03616|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03616|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03616|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03616|057|R|  11/14/2017.|1
03616|058|R|5.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03616|059|R|  Indiana University School of Medicine.  Available at:|1
03616|060|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03617|001|T|MONOGRAPH TITLE:  Axitinib/Strong CYP3A4 Inhibitors|
03617|002|B||
03617|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03617|004|L|of severe adverse interaction.|
03617|005|B||
03617|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03617|007|A|the metabolism of axitinib.(1)|
03617|008|B||
03617|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03617|010|E|levels of and effects from axitinib, including hypertension, thromboembolic|
03617|011|E|events, or hepatotoxicity.(1)|
03617|012|B||
03617|013|P|PREDISPOSING FACTORS:  None determined.|
03617|014|B||
03617|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03617|016|M|undergoing therapy with axitinib.(1)  Consider alternatives with no or|
03617|017|M|minimal enzyme inhibition.|
03617|018|M|   If concurrent use with axitinib is warranted, consider decreasing the|
03617|019|M|dose of axitinib by one-half (e.g. start with an initial dose of 2 mg twice|
03617|020|M|daily).  Subsequent doses may be increased or decreased based on patient|
03617|021|M|response.  When the CYP3A4 inhibitor has been discontinued, allow a washout|
03617|022|M|period equal to 3-5 half-lives of the inhibitor before increasing the dose|
03617|023|M|of axitinib.(1)|
03617|024|B||
03617|025|D|DISCUSSION:  Ketoconazole (400 mg twice daily, a strong inhibitor of CYP3A4)|
03617|026|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
03617|027|D|axitinib (5 mg) by approximately 1.5-fold and 2-fold, respectively.|
03617|028|D|Recommended dosage adjustments are expected to produce AUC levels comparable|
03617|029|D|to axitinib administered without a strong CYP3A4 inhibitor; however, no data|
03617|030|D|is available.(1)|
03617|031|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03617|032|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03617|033|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03617|034|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03617|035|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03617|036|D|tucatinib, or voriconazole.(2,3)|
03617|037|B||
03617|038|R|REFERENCES:|
03617|039|B||
03617|040|R|1.Inlyta (axitinib) US prescribing information. Pfizer Inc. September, 2022.|1
03617|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03617|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03617|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03617|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03617|045|R|  11/14/2017.|1
03617|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
03617|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03618|001|T|MONOGRAPH TITLE:  Cabazitaxel/Strong CYP3A4 Inhibitors|
03618|002|B||
03618|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03618|004|L|of severe adverse interaction.|
03618|005|B||
03618|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03618|007|A|the metabolism of cabazitaxel.(1)|
03618|008|B||
03618|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03618|010|E|levels of and effects from cabazitaxel, including bone marrow suppression,|
03618|011|E|renal failure, cystitis, or pulmonary dysfunction.(1)|
03618|012|B||
03618|013|P|PREDISPOSING FACTORS:  None determined.|
03618|014|B||
03618|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03618|016|M|undergoing therapy with cabazitaxel.(1)  Consider alternatives with no or|
03618|017|M|minimal enzyme inhibition.|
03618|018|M|   If concurrent use is required, consider a 25% cabazitaxel dose|
03618|019|M|reduction.(1)|
03618|020|B||
03618|021|D|DISCUSSION:  In a study in 23 advanced cancer patients, ketoconazole (400 mg|
03618|022|D|daily) increased the exposure of cabazitaxel (5 mg/m2) by 25%.(1)|
03618|023|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03618|024|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03618|025|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03618|026|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03618|027|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03618|028|D|tucatinib, or voriconazole.(2,3)|
03618|029|B||
03618|030|R|REFERENCES:|
03618|031|B||
03618|032|R|1.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
03618|033|R|  July, 2023.|1
03618|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03618|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03618|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03618|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03618|038|R|  11/14/2017.|1
03618|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03618|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03619|001|T|MONOGRAPH TITLE:  Cabozantinib/Strong CYP3A4 Inhibitors|
03619|002|B||
03619|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03619|004|L|of severe adverse interaction.|
03619|005|B||
03619|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03619|007|A|the metabolism of cabozantinib.(1,2)|
03619|008|B||
03619|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03619|010|E|levels of and effects from cabozantinib, including hemorrhage, thrombotic|
03619|011|E|events, hypertension and hypertensive crisis, diarrhea, proteinuria, or|
03619|012|E|osteonecrosis of the jaw.(1,2)|
03619|013|B||
03619|014|P|PREDISPOSING FACTORS:  None determined.|
03619|015|B||
03619|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03619|017|M|undergoing therapy with cabozantinib.(1,2)  Consider alternatives with no or|
03619|018|M|minimal enzyme inhibition.|
03619|019|M|   Dosage adjustments are specific to the formulation of cabozantinib|
03619|020|M|prescribed.(1,2)|
03619|021|M|   If concurrent use of cabozantinib TABlets are warranted, reduce the daily|
03619|022|M|dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 40 mg daily, or|
03619|023|M|from 40 mg to 20 mg daily).(1)|
03619|024|M|   If concurrent use of cabozantinib CAPsules are warranted, the dose of|
03619|025|M|cabozantinib CAPsules should be reduced by 40 mg (e.g. from 140 mg to 100 mg|
03619|026|M|daily or from 100 mg to 60 mg daily).(2)|
03619|027|M|   When the CYP3A4 inhibitor has been discontinued, resume the dose of|
03619|028|M|cabozantinib that was used previously 2-3 days after discontinuation of the|
03619|029|M|inhibitor.(1,2)|
03619|030|B||
03619|031|D|DISCUSSION:  In a study in healthy subjects, ketoconazole (400 mg daily for|
03619|032|D|27 days) increased the area-under-curve (AUC) of a single dose of|
03619|033|D|cabozantinib by 38%.(3,4)|
03619|034|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03619|035|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03619|036|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
03619|037|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
03619|038|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03619|039|D|troleandomycin, tucatinib, or voriconazole.(2,3)|
03619|040|B||
03619|041|R|REFERENCES:|
03619|042|B||
03619|043|R|1.Cabometyx (cabozantinib) tablets, US prescribing information. Exelixis|1
03619|044|R|  Inc. January, 2021.|1
03619|045|R|2.Cometriq (cabozantinib) US prescribing information. Exelixix, Inc.|1
03619|046|R|  January, 2020.|1
03619|047|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03619|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03619|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03619|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03619|051|R|  11/14/2017.|1
03619|052|R|4.This information is based on an extract from the Certara Drug Interaction|6
03619|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03620|001|T|MONOGRAPH TITLE:  Cobimetinib/Strong CYP3A4 Inhibitors|
03620|002|B||
03620|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03620|004|L|of severe adverse interaction.|
03620|005|B||
03620|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03620|007|A|the metabolism of cobimetinib.(1)|
03620|008|B||
03620|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03620|010|E|levels of and effects from cobimetinib, including hemorrhage,|
03620|011|E|cardiomyopathy, dermatologic reactions, retinopathy, hepatotoxicity, or|
03620|012|E|rhabdomyolysis.(1)|
03620|013|B||
03620|014|P|PREDISPOSING FACTORS:  None determined.|
03620|015|B||
03620|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03620|017|M|undergoing therapy with cobimetinib.(1)  Consider alternatives with no or|
03620|018|M|minimal enzyme inhibition.|
03620|019|M|   The manufacturer of cobimetinib states an alternative to a strong or|
03620|020|M|moderate CYP3A4 inhibitor in patients taking cobimetinib 20 mg or 40 mg|
03620|021|M|daily is recommended.(1)|
03620|022|B||
03620|023|D|DISCUSSION:  In a study, itraconazole 200 mg once daily for 14 days followed|
03620|024|D|by a single dose of cobimetinib 10 mg increased mean cobimetinib|
03620|025|D|area-under-curve (AUC) 6.7-fold (90% CI 5.6, 8.0).(1)|
03620|026|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
03620|027|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03620|028|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03620|029|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03620|030|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03620|031|D|tucatinib, or voriconazole.(2,3)|
03620|032|B||
03620|033|R|REFERENCES:|
03620|034|B||
03620|035|R|1.Cotellic (cobimetinib) US prescribing information. Genentech, Inc.|1
03620|036|R|  October, 2022.|1
03620|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03620|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03620|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03620|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03620|041|R|  11/14/2017.|1
03620|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
03620|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03621|001|T|MONOGRAPH TITLE:  Dabrafenib/Strong CYP3A4 Inhibitors|
03621|002|B||
03621|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03621|004|L|of severe adverse interaction.|
03621|005|B||
03621|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03621|007|A|the metabolism of dabrafenib.(1)|
03621|008|B||
03621|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03621|010|E|levels of and effects from dabrafenib, including hemorrhage, cardiomyopathy,|
03621|011|E|uveitis, skin toxicities, or hyperglycemia.(1)|
03621|012|B||
03621|013|P|PREDISPOSING FACTORS:  None determined.|
03621|014|B||
03621|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03621|016|M|undergoing therapy with dabrafenib.(1)  Consider alternatives with no or|
03621|017|M|minimal enzyme inhibition.  If concomitant use is unavoidable, monitor|
03621|018|M|patients closely for toxicity.|
03621|019|B||
03621|020|D|DISCUSSION:  Ketoconazole (400 mg daily for 4 days) increased the|
03621|021|D|area-under-curve (AUC) of dabrafenib (75 mg BID) by 71%.  The AUC of|
03621|022|D|hydroxy-dabrafenib and desmethyl-dabrafenib increased by 82% and 68%,|
03621|023|D|respectively.(1)|
03621|024|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03621|025|D|clarithromycin, cobicistat, indinavir, itraconazole, josamycin,|
03621|026|D|ketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
03621|027|D|nirmatrelvir/ritonavir, posaconazole, ribociclib, saquinavir, telaprevir,|
03621|028|D|telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)|
03621|029|B||
03621|030|R|REFERENCES:|
03621|031|B||
03621|032|R|1.Tafinlar (dabrafenib) US prescribing information. Novartis Pharmaceuticals|1
03621|033|R|  Corporation May, 2023.|1
03621|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03621|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03621|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03621|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03621|038|R|  11/14/2017.|1
03621|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03621|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03622|001|T|MONOGRAPH TITLE:  Docetaxel/Strong CYP3A4 Inhibitors|
03622|002|B||
03622|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03622|004|L|of severe adverse interaction.|
03622|005|B||
03622|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03622|007|A|the metabolism of docetaxel.(1)|
03622|008|B||
03622|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03622|010|E|levels of and effects from docetaxel, including cutaneous reactions,|
03622|011|E|neurologic reactions, eye disorders, or asthenia.(1)|
03622|012|B||
03622|013|P|PREDISPOSING FACTORS:  None determined.|
03622|014|B||
03622|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03622|016|M|undergoing therapy with docetaxel.(1)  Consider alternatives with no or|
03622|017|M|minimal enzyme inhibition.|
03622|018|M|   If concurrent therapy with docetaxel is required, consider a 50%|
03622|019|M|reduction in the dose of docetaxel.  Monitor patients receiving concurrent|
03622|020|M|therapy closely for signs of toxicity.(1)|
03622|021|B||
03622|022|D|DISCUSSION:  In a randomized, cross-over study in 7 cancer patients,|
03622|023|D|patients received docetaxel (100 mg/m2 intravenous) alone and docetaxel (10|
03622|024|D|mg/m2 intravenous) with ketoconazole (200 mg daily for 3 days).  The mean|
03622|025|D|dose-normalized area-under-curve (AUC) of docetaxel increased 2.2-fold and|
03622|026|D|docetaxel clearance decreased 49% when administered with ketoconazole.(1)|
03622|027|D|   In a randomized, cross-over study in 7 subjects, subjects received|
03622|028|D|docetaxel (100 mg/m2) alone and docetaxel (15 mg/m2) with ketoconazole (400|
03622|029|D|mg 3 times daily).  Ketoconazole decreased docetaxel clearance by 50%.|
03622|030|D|There was large inter-patient variability.(2)|
03622|031|D|   In a study in 15 subjects, ketoconazole increased fecal docetaxel|
03622|032|D|excretion by 2-fold but did not affect urinary parent drug excretion.(3)|
03622|033|D|   In a study in 41 patients, concurrent ketoconazole allowed a dose of 70|
03622|034|D|mg docetaxel with similar docetaxel AUC and toxicity compared to the|
03622|035|D|administration of docetaxel (75 mg/m2) alone.(4)|
03622|036|D|   A study in 42 patients examined escalating doses of ketoconazole on|
03622|037|D|docetaxel pharmacokinetics.  Ketoconazole at doses of 1200 mg daily, 800 mg|
03622|038|D|daily, and 600 mg daily increased docetaxel exposure 2.6-fold, 1.6-fold, and|
03622|039|D|1.3 to 1.5-fold, respectively.(5)|
03622|040|D|   A parallel study in 82 subjects compared docetaxel (75 mg/m2) alone with|
03622|041|D|docetaxel (70 mg) with ketoconazole.  Concurrent ketoconazole decreased|
03622|042|D|docetaxel clearance by 40%.  Similar docetaxel AUC and tumor efficacy were|
03622|043|D|noted, with decreased toxicity during concurrent ketoconazole and|
03622|044|D|reduced-dose docetaxel therapy.(6)|
03622|045|D|   In a study in 12 patients, the administration of ritonavir (100 mg)|
03622|046|D|simultaneously or 60 minutes before docetaxel (100 mg orally) increased the|
03622|047|D|bioavailability of docetaxel by 131% and 161%, respectively.(7)|
03622|048|D|   Data from two clinical trials involving patients taking docetaxel|
03622|049|D|concurrently with ritonavir and patients taking docetaxel oral or I.V. alone|
03622|050|D|were analyzed in order to determine the impact of ritonavir's strong|
03622|051|D|inhibition of CYP3A4 on the pharmacokinetics of docetaxel.  Patients from|
03622|052|D|the first trial were randomly assigned to receive either ritonavir 100 mg|
03622|053|D|followed by oral docetaxel 10 mg 60 minutes later on day 1, ritonavir 100 mg|
03622|054|D|and docetaxel 10 mg simultaneously on day 8, and I.V. docetaxel 100 mg on|
03622|055|D|day 22 or an identical regimen with the only difference being that days 1|
03622|056|D|and 8 were reversed.  The second trial was utilized solely for the data on|
03622|057|D|patients being administered oral docetaxel 75 mg/m2 alone or I.V. docetaxel|
03622|058|D|100 mg/m2.  The results of the study showed an increase in the gut|
03622|059|D|bioavailability of docetaxel from 19 to 39% with co-administration of|
03622|060|D|ritonavir as well as a reduction in the clearance of docetaxel by|
03622|061|D|approximately 90%.(8)|
03622|062|D|   There are several case reports of docetaxel toxicity in patients treated|
03622|063|D|with concurrent ritonavir.(9,10)|
03622|064|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03622|065|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03622|066|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03622|067|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03622|068|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03622|069|D|tucatinib, or voriconazole.(11,12)|
03622|070|B||
03622|071|R|REFERENCES:|
03622|072|B||
03622|073|R|1.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
03622|074|R|  January, 2023.|1
03622|075|R|2.Engels FK, Mathot RA, Loos WJ, van Schaik RH, Verweij J. Influence of|2
03622|076|R|  high-dose ketoconazole on the pharmacokinetics of docetaxel. Cancer Biol|2
03622|077|R|  Ther 2006 Jul;5(7):833-9.|2
03622|078|R|3.Engels FK, Loos WJ, Mathot RA, van Schaik RH, Verweij J. Influence of|2
03622|079|R|  ketoconazole on the fecal and urinary disposition of docetaxel. Cancer|2
03622|080|R|  Chemother Pharmacol 2007 Sep;60(4):569-79.|2
03622|081|R|4.Yong WP, Wang LZ, Tham LS, Wong CI, Lee SC, Soo R, Sukri N, Lee HS, Goh|2
03622|082|R|  BC. A phase I study of docetaxel with ketoconazole modulation in patients|2
03622|083|R|  with advanced cancers. Cancer Chemother Pharmacol 2008 Jul;62(2):243-51.|2
03622|084|R|5.Figg WD, Woo S, Zhu W, Chen X, Ajiboye AS, Steinberg SM, Price DK, Wright|2
03622|085|R|  JJ, Parnes HL, Arlen PM, Gulley JL, Dahut WL. A phase I clinical study of|2
03622|086|R|  high dose ketoconazole plus weekly docetaxel for metastatic castration|2
03622|087|R|  resistant prostate cancer. J Urol 2010 Jun;183(6):2219-26.|2
03622|088|R|6.Lim YW, Goh BC, Wang LZ, Tan SH, Chuah BY, Lim SE, Iau P, Buhari SA, Chan|2
03622|089|R|  CW, Sukri NB, Cordero MT, Soo R, Lee SC. Pharmacokinetics and|2
03622|090|R|  pharmacodynamics of docetaxel with or without ketoconazole modulation in|2
03622|091|R|  chemonaive breast cancer patients. Ann Oncol 2010 Apr 29.|2
03622|092|R|7.Oostendorp RL, Huitema A, Rosing H, Jansen RS, Ter Heine R, Keessen M,|2
03622|093|R|  Beijnen JH, Schellens JH. Coadministration of ritonavir strongly enhances|2
03622|094|R|  the apparent oral bioavailability of docetaxel in patients with solid|2
03622|095|R|  tumors. Clin Cancer Res 2009 Jun 15;15(12):4228-33.|2
03622|096|R|8.Koolen SL, Oostendorp RL, Beijnen JH, Schellens JH, Huitema AD. Population|2
03622|097|R|  pharmacokinetics of intravenously and orally administered docetaxel with|2
03622|098|R|  or without co-administration of ritonavir in patients with advanced|2
03622|099|R|  cancer. Br J Clin Pharmacol 2010 May;69(5):465-74.|2
03622|100|R|9.Mir O, Dessard-Diana B, Louet AL, Loulergue P, Viard JP, Langlois A,|3
03622|101|R|  Durdux C, Le Beller C. Severe toxicity related to a pharmacokinetic|3
03622|102|R|  interaction between docetaxel and ritonavir in HIV-infected patients. Br J|3
03622|103|R|  Clin Pharmacol 2010 Jan;69(1):99-101.|3
03622|104|R|10.Loulergue P, Mir O, Allali J, Viard JP. Possible pharmacokinetic|3
03622|105|R|   interaction involving ritonavir and docetaxel in a patient with Kaposi's|3
03622|106|R|   sarcoma. AIDS 2008 Jun 19;22(10):1237-9.|3
03622|107|R|11.US Food and Drug Administration (FDA). Drug Development and Drug|1
03622|108|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03622|109|R|   at:|1
03622|110|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03622|111|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03622|112|R|   11/14/2017.|1
03622|113|R|12.This information is based on an extract from the Certara Drug Interaction|6
03622|114|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03623|001|T|MONOGRAPH TITLE:  Doxorubicin/Strong CYP3A4 Inhibitors|
03623|002|B||
03623|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03623|004|L|of severe adverse interaction.|
03623|005|B||
03623|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03623|007|A|the metabolism of doxorubicin.(1)|
03623|008|B||
03623|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03623|010|E|levels of and effects from doxorubicin, including cardiomyopathy,|
03623|011|E|myelosuppression, or hepatic impairment.(1)|
03623|012|B||
03623|013|P|PREDISPOSING FACTORS:  None determined.|
03623|014|B||
03623|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03623|016|M|undergoing therapy with doxorubicin.(1)  Consider alternatives with no or|
03623|017|M|minimal enzyme inhibition.|
03623|018|B||
03623|019|D|DISCUSSION:  Doxorubicin is a substrate of CYP3A4.(1)|
03623|020|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03623|021|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03623|022|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03623|023|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03623|024|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03623|025|D|tucatinib, or voriconazole.(2,3)|
03623|026|B||
03623|027|R|REFERENCES:|
03623|028|B||
03623|029|R|1.Doxorubicin US prescribing information. Pfizer Labs August, 2019.|1
03623|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03623|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03623|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03623|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03623|034|R|  11/14/2017.|1
03623|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
03623|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03624|001|T|MONOGRAPH TITLE:  Erlotinib/Strong CYP3A4 Inhibitors|
03624|002|B||
03624|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03624|004|L|of severe adverse interaction.|
03624|005|B||
03624|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03624|007|A|the metabolism of erlotinib.(1)|
03624|008|B||
03624|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03624|010|E|levels of and effects from erlotinib, including interstitial lung disease,|
03624|011|E|renal failure, hepatotoxicity, gastrointestinal perforation, skin disorders,|
03624|012|E|ocular disorders, or cerebrovascular events.(1)|
03624|013|B||
03624|014|P|PREDISPOSING FACTORS:  None determined.|
03624|015|B||
03624|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03624|017|M|undergoing therapy with erlotinib.(1)  Consider alternatives with no or|
03624|018|M|minimal enzyme inhibition.|
03624|019|M|   If concurrent therapy with erlotinib is required, decrease the dose of|
03624|020|M|erlotinib by 50 mg decrements.(1)|
03624|021|B||
03624|022|D|DISCUSSION:  Co-administration of erlotinib with a strong CYP3A4 inhibitor,|
03624|023|D|ketoconazole, increased erlotinib area-under-curve (AUC) by 67%.(1)|
03624|024|D|   In a study, 24 healthy subjects received a single erlotinib 100 mg dose|
03624|025|D|alone or after ketoconazole 200 mg twice daily for 5 days. Mean AUC and|
03624|026|D|concentration maximum (Cmax) increased by approximately 2-fold.(2)|
03624|027|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03624|028|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03624|029|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03624|030|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03624|031|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03624|032|D|tucatinib, or voriconazole.(3,4)|
03624|033|B||
03624|034|R|REFERENCES:|
03624|035|B||
03624|036|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
03624|037|R|  2016.|1
03624|038|R|2.Rakhit A, Pantze MP, Fettner S, Jones HM, Charoin JE, Riek M, Lum BL,|2
03624|039|R|  Hamilton M. The effects of CYP3A4 inhibition on erlotinib|2
03624|040|R|  pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo|2
03624|041|R|  metabolic inhibition. Eur J Clin Pharmacol 2008 Jan;64(1):31-41.|2
03624|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03624|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03624|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03624|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03624|046|R|  11/14/2017.|1
03624|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
03624|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03625|001|T|MONOGRAPH TITLE:  Idelalisib/Strong CYP3A4 Inhibitors|
03625|002|B||
03625|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03625|004|L|of severe adverse interaction.|
03625|005|B||
03625|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03625|007|A|the metabolism of idelalisib.(1)|
03625|008|B||
03625|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03625|010|E|levels of and effects from idelalisib, including hepatotoxicity, diarrhea,|
03625|011|E|colitis, pneumonitis, neutropenia or intestinal perforation.(1)|
03625|012|B||
03625|013|P|PREDISPOSING FACTORS:  None determined.|
03625|014|B||
03625|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03625|016|M|undergoing therapy with idelalisib.(1)  Consider alternatives with no or|
03625|017|M|minimal enzyme inhibition.|
03625|018|M|   If concurrent use with idelalisib is warranted, monitor patients for|
03625|019|M|toxicity and follow toxicity dose modification guidelines.(1)|
03625|020|B||
03625|021|D|DISCUSSION:  In a study in healthy subjects, ketoconazole (400 mg daily for|
03625|022|D|4 days) increased the area-under-curve (AUC) of idelalisib (400 mg single|
03625|023|D|dose) by 1.8-fold.(1)|
03625|024|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir,|
03625|025|D|clarithromycin, cobicistat, indinavir, itraconazole, josamycin,|
03625|026|D|ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir,|
03625|027|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, saquinavir, telaprevir,|
03625|028|D|telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)|
03625|029|B||
03625|030|R|REFERENCES:|
03625|031|B||
03625|032|R|1.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03625|033|R|  October, 2020.|1
03625|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03625|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03625|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03625|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03625|038|R|  11/14/2017.|1
03625|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03625|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03626|001|T|MONOGRAPH TITLE:  Ixabepilone/Strong CYP3A4 Inhibitors|
03626|002|B||
03626|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03626|004|L|of severe adverse interaction.|
03626|005|B||
03626|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03626|007|A|the metabolism of ixabepilone.(1)|
03626|008|B||
03626|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03626|010|E|levels of and effects from ixabepilone, including hepatotoxicity, peripheral|
03626|011|E|neuropathy, myelosuppression, or neutropenia.(1)|
03626|012|B||
03626|013|P|PREDISPOSING FACTORS:  None determined.|
03626|014|B||
03626|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03626|016|M|undergoing therapy with ixabepilone.(1)  Consider alternatives with no or|
03626|017|M|minimal enzyme inhibition.|
03626|018|M|   If concurrent use with ixabepilone is warranted, a dose reduction to 20|
03626|019|M|mg/m2 of ixabepilone should be considered.  Patients receiving concurrent|
03626|020|M|therapy should be closely monitored for acute toxicities (e.g. frequent|
03626|021|M|monitoring of peripheral blood counts).  If the inhibitor is discontinued,|
03626|022|M|allow a 1 week washout period before adjusting the dose of ixabepilone to|
03626|023|M|recommended amounts.(1)|
03626|024|B||
03626|025|D|DISCUSSION:  In vitro studies indicate that CYP3A4 is the main route of|
03626|026|D|metabolism for ixabepilone.(1)|
03626|027|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03626|028|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03626|029|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03626|030|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03626|031|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03626|032|D|tucatinib, or voriconazole.(2,3)|
03626|033|B||
03626|034|R|REFERENCES:|
03626|035|B||
03626|036|R|1.Ixempra (ixabepilone) US prescribing information. Bristol-Myers Squibb|1
03626|037|R|  Company October, 2011.|1
03626|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03626|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03626|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03626|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03626|042|R|  11/14/2017.|1
03626|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
03626|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03627|001|T|MONOGRAPH TITLE:  Olaparib/Strong CYP3A4 Inhibitors|
03627|002|B||
03627|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03627|004|L|of severe adverse interaction.|
03627|005|B||
03627|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03627|007|A|the metabolism of olaparib.(1,2)|
03627|008|B||
03627|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03627|010|E|levels of and effects from olaparib, including myelodysplastic syndrome,|
03627|011|E|pneumonitis, thromboembolic events, anemia, neutropenia or|
03627|012|E|thrombocytopenia.(1,2)|
03627|013|B||
03627|014|P|PREDISPOSING FACTORS:  None determined.|
03627|015|B||
03627|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03627|017|M|undergoing therapy with olaparib.(1,2)  Consider alternatives with no or|
03627|018|M|minimal enzyme inhibition.|
03627|019|M|   If concomitant use with olaparib cannot be avoided, reduce the olaparib|
03627|020|M|dose.  Dosage adjustments are specific to the formulation of olaparib|
03627|021|M|(CAPsules or TABlets).(1,2)|
03627|022|M|   -Reduce the dosage of the CAPsule formulation to 150 mg (3 CAPsules)|
03627|023|M|taken twice daily.(1)|
03627|024|M|   -Reduce the dosage of the TABlet formulation to 100 mg (one 100 mg|
03627|025|M|TABlet) twice daily).(2)|
03627|026|M|   If the CYP3A4 inhibitor is discontinued, resume the dose of olaparib|
03627|027|M|taken prior to initiation of the CYP3A4 inhibitor after 3 to 5|
03627|028|M|half-lives.(1,2)|
03627|029|B||
03627|030|D|DISCUSSION:  In an interaction study, the area-under-curve (AUC) and|
03627|031|D|concentration maximum (Cmax) of olaparib was increased 2.7- and 1.4-fold,|
03627|032|D|respectively when it was administered with itraconazole (dose not|
03627|033|D|specified), a strong CYP3A4 inhibitor.(1,2,3)|
03627|034|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03627|035|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03627|036|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03627|037|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03627|038|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03627|039|D|tucatinib, and voriconazole.(4,5)|
03627|040|B||
03627|041|R|REFERENCES:|
03627|042|B||
03627|043|R|1.Lynparza (olaparib) capsules US prescribing information. AstraZenica|1
03627|044|R|  Pharmaceuticals October 23, 2017.|1
03627|045|R|2.Lynparza (olaparib) tablets US prescribing information. AstraZenica|1
03627|046|R|  Pharmaceuticals March, 2021.|1
03627|047|R|3.Dirix L, Swaisland H, Verheul HM. Effect of Itraconazole and Rifampin on|2
03627|048|R|  the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors:|2
03627|049|R|  Results of Two Phase I Open-label Studies. Clin Ther 2016 Oct;|2
03627|050|R|  38(10):2286-2299.|2
03627|051|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03627|052|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03627|053|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03627|054|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03627|055|R|  11/14/2017.|1
03627|056|R|5.This information is based on an extract from the Certara Drug Interaction|6
03627|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03628|001|T|MONOGRAPH TITLE:  Paclitaxel/Strong CYP3A4 Inhibitors|
03628|002|B||
03628|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03628|004|L|of severe adverse interaction.|
03628|005|B||
03628|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03628|007|A|the metabolism of paclitaxel.(1)|
03628|008|B||
03628|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03628|010|E|levels of and effects from paclitaxel, including myelosuppression,|
03628|011|E|neutropenia, sensory neuropathy, pneumonitis, anemia, or|
03628|012|E|thrombocytopenia.(1)|
03628|013|B||
03628|014|P|PREDISPOSING FACTORS:  None determined.|
03628|015|B||
03628|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03628|017|M|undergoing therapy with paclitaxel.(1)  Consider alternatives with no or|
03628|018|M|minimal enzyme inhibition.|
03628|019|B||
03628|020|D|DISCUSSION:  In vitro studies indicate CYP3A4 may be the secondary pathway|
03628|021|D|for two minor metabolites of paclitaxel.(1)|
03628|022|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03628|023|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03628|024|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03628|025|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03628|026|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03628|027|D|tucatinib, or voriconazole.(2,3)|
03628|028|B||
03628|029|R|REFERENCES:|
03628|030|B||
03628|031|R|1.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
03628|032|R|  Company August, 2010.|1
03628|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03628|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03628|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03628|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03628|037|R|  11/14/2017.|1
03628|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
03628|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03629|001|T|MONOGRAPH TITLE:  Palbociclib/Strong CYP3A4 Inhibitors|
03629|002|B||
03629|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03629|004|L|of severe adverse interaction.|
03629|005|B||
03629|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03629|007|A|the metabolism of palbociclib.(1)|
03629|008|B||
03629|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03629|010|E|levels of and effects from palbociclib, including neutropenia, interstitial|
03629|011|E|lung disease, or pneumonitis.(1)|
03629|012|B||
03629|013|P|PREDISPOSING FACTORS:  None determined.|
03629|014|B||
03629|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03629|016|M|undergoing therapy with palbociclib.(1)  Consider alternatives with no or|
03629|017|M|minimal enzyme inhibition.|
03629|018|M|   If concurrent use with palbociclib cannot be avoided, reduce the dose of|
03629|019|M|palbociclib to 75 mg daily.  If the 3A4 inhibitor is discontinued, a washout|
03629|020|M|period of 3-5 half-lives of the inhibitor should occur before the|
03629|021|M|palbociclib dose is adjusted upward.(1)|
03629|022|B||
03629|023|D|DISCUSSION:  In a study in 12 healthy subjects, itraconazole (200 mg daily)|
03629|024|D|increased the concentration maximum (Cmax) and area-under-curve (AUC) of a|
03629|025|D|single dose of palbociclib by 34% and 87%, respectively.(1)|
03629|026|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03629|027|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03629|028|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03629|029|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03629|030|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03629|031|D|tucatinib, or voriconazole.(2,3)|
03629|032|B||
03629|033|R|REFERENCES:|
03629|034|B||
03629|035|R|1.Ibrance (palbociclib) US prescribing information. Pfizer Labs September,|1
03629|036|R|  2023.|1
03629|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03629|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03629|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03629|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03629|041|R|  11/14/2017.|1
03629|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
03629|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03630|001|T|MONOGRAPH TITLE:  Ponatinib/Strong CYP3A4 Inhibitors|
03630|002|B||
03630|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03630|004|L|of severe adverse interaction.|
03630|005|B||
03630|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03630|007|A|the metabolism of ponatinib.(1)|
03630|008|B||
03630|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03630|010|E|levels of and effects from ponatinib, including thromboembolic events,|
03630|011|E|hepatotoxicity, heart failure, hypertension, pancreatitis, neuropathy,|
03630|012|E|ocular toxicity, hemorrhage, myelosuppression, or tumor lysis syndrome.(1)|
03630|013|B||
03630|014|P|PREDISPOSING FACTORS:  None determined.|
03630|015|B||
03630|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03630|017|M|undergoing therapy with ponatinib.(1)  Consider alternatives with no or|
03630|018|M|minimal enzyme inhibition.|
03630|019|M|   If concurrent administration with ponatinib is warranted, the recommended|
03630|020|M|ponatinib dose should be reduced based on current daily dose during|
03630|021|M|concomitant treatment:(1)|
03630|022|M|   -If current daily dose is 45 mg, reduce to 30 mg daily.|
03630|023|M|   -If current daily dose is 30 mg, reduce to 15 mg daily.|
03630|024|M|   -If current daily dose is 15 mg, reduce to 10 mg daily.|
03630|025|M|   -If current daily dose is 10 mg, avoid concurrent use with strong CYP3A4|
03630|026|M|inhibitors.|
03630|027|M|   Even with the dose reduction, patients receiving concomitant therapy may|
03630|028|M|be at increased risk for adverse reactions.  Assure recommended monitoring|
03630|029|M|(e.g. complete blood counts, liver function, lipase, blood pressure|
03630|030|M|measurement) is scheduled and patient is aware of signs of thrombosis (e.g.|
03630|031|M|symptoms of myocardial infarction or stroke).|
03630|032|M|   If the ponatinib dose has been reduced due to coadministration of a|
03630|033|M|CYP3A4 inhibitor, and the inhibitor is subsequently discontinued, reevaluate|
03630|034|M|ponatinib efficacy and safety to determine if a dose increase is|
03630|035|M|appropriate.(1)|
03630|036|B||
03630|037|D|DISCUSSION:  In 22 healthy volunteers, ketoconazole (400 mg once daily)|
03630|038|D|increased the concentration maximum (Cmax) and area-under-curve (AUC) of a|
03630|039|D|single 15 mg dose of ponatinib by 47% and 78%, respectively.(1)|
03630|040|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03630|041|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03630|042|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03630|043|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03630|044|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03630|045|D|tucatinib, or voriconazole.(2,3)|
03630|046|B||
03630|047|R|REFERENCES:|
03630|048|B||
03630|049|R|1.Iclusig (ponatinib) US prescribing information. ARIAD Pharmaceuticals Inc.|1
03630|050|R|  December, 2020.|1
03630|051|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03630|052|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03630|053|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03630|054|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03630|055|R|  11/14/2017.|1
03630|056|R|3.This information is based on an extract from the Certara Drug Interaction|6
03630|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03631|001|T|MONOGRAPH TITLE:  Ruxolitinib/Strong CYP3A4 Inhibitors|
03631|002|B||
03631|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03631|004|L|of severe adverse interaction.|
03631|005|B||
03631|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03631|007|A|the metabolism of ruxolitinib.(1)|
03631|008|B||
03631|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03631|010|E|levels of and effects from ruxolitinib, including thrombocytopenia, risk of|
03631|011|E|infection, non-melanoma skin cancer, lipid elevations.(1)|
03631|012|B||
03631|013|P|PREDISPOSING FACTORS:  In patients taking ruxolitinib, this interaction may|
03631|014|P|be more severe in patients with a low platelet count.(1)|
03631|015|B||
03631|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03631|017|M|undergoing therapy with ruxolitinib.(1)  Consider alternatives with no or|
03631|018|M|minimal enzyme inhibition.|
03631|019|M|   Dose modifications of ruxolitinib in patients on concomitant strong|
03631|020|M|CYP3A4 inhibitors depend on the indication.|
03631|021|M|   For myelofibrosis, starting doses of ruxolitinib therapy in patients|
03631|022|M|concurrently taking strong CYP3A4 inhibitors should be made based on|
03631|023|M|platelet count:|
03631|024|M|   -In patients with a platelet count greater than or equal to 100 X 10x9/L|
03631|025|M|who are receiving a strong inhibitor of CYP3A4, the recommended starting|
03631|026|M|dose of ruxolitinib is 10 mg twice daily.|
03631|027|M|   -In patients with a platelet count greater than 50 X 10x9/L to less than|
03631|028|M|100 X 10x9/L who are receiving a strong inhibitor of CYP3A4, the recommended|
03631|029|M|starting dose of ruxolitinib is 5 mg once daily.|
03631|030|M|   For polycythemia vera, the starting dose of ruxolitinib in patients|
03631|031|M|concurrently taking a strong CYP3A4 inhibitor is 5 mg twice daily.|
03631|032|M|   In patients with a diagnosis of myelofibrosis or polycythemia vera who|
03631|033|M|are stabilized on ruxolitinib doses of 10 mg twice daily or more and in whom|
03631|034|M|a strong CYP3A4 inhibitor is initiated, reduce the dose of ruxolitinib by|
03631|035|M|50% (rounded up to the closest available tablet strength).|
03631|036|M|   In patients who are stabilized on ruxolitinib doses of 5 mg twice daily|
03631|037|M|in whom a strong CYP3A4 inhibitor is initiated, reduce the dose of|
03631|038|M|ruxolitinib to 5 mg once daily.|
03631|039|M|   In patients stabilized on ruxolitinib doses of 5 mg once daily, avoid the|
03631|040|M|use of strong CYP3A4 inhibitors or interrupt ruxolitinib therapy for the|
03631|041|M|duration of the CYP3A4 inhibitor treatment.|
03631|042|M|   For acute graft-versus-host disease, the dose of ruxolitinib in patients|
03631|043|M|concurrently taking ketoconazole is 5 mg once daily.  No dose adjustment is|
03631|044|M|recommended for concurrent use of other CYP3A4 inhibitors in patients on|
03631|045|M|ruxolitinib for acute graft-versus-host disease.  It is recommended to|
03631|046|M|increase the frequency of blood count monitoring when ruxolitinib is used|
03631|047|M|with itraconazole for acute graft-versus-host disease.  The dose should be|
03631|048|M|adjusted based on monitoring of safety and efficacy.(1)|
03631|049|B||
03631|050|D|DISCUSSION:  In healthy subjects, ketoconazole (200 mg twice daily for 4|
03631|051|D|days) increased the concentration maximum (Cmax), area-under-curve (AUC),|
03631|052|D|and half-life of a single dose of ruxolitinib (10 mg) by 33%, 91%, and 62%,|
03631|053|D|respectively.  There was also a corresponding increase in pSTAT3 inhibition,|
03631|054|D|a pharmacodynamic marker for ruxolitinib.(1)|
03631|055|D|   In healthy subjects, erythromycin (a moderate inhibitor of CYP3A4, 500 mg|
03631|056|D|twice daily for 4 days) increased the Cmax and AUC of a single dose of|
03631|057|D|ruxolitinib (10 mg) by 8% and 27%, respectively.  Therefore, no dosage|
03631|058|D|adjustment is recommended with moderate or mild inhibitors of CYP3A4.(1)|
03631|059|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03631|060|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03631|061|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03631|062|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03631|063|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03631|064|D|tucatinib, or voriconazole.(2,3)|
03631|065|B||
03631|066|R|REFERENCES:|
03631|067|B||
03631|068|R|1.Jakafi (ruxolitinib) US prescribing information. Incyte Corporation|1
03631|069|R|  September, 2021.|1
03631|070|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03631|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03631|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03631|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03631|074|R|  11/14/2017.|1
03631|075|R|3.This information is based on an extract from the Certara Drug Interaction|6
03631|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03632|001|T|MONOGRAPH TITLE:  Sonidegib/Strong CYP3A4 Inhibitors|
03632|002|B||
03632|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03632|004|L|of severe adverse interaction.|
03632|005|B||
03632|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03632|007|A|the metabolism of sonidegib.(1)|
03632|008|B||
03632|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03632|010|E|levels of and effects from sonidegib, including musculoskeletal adverse|
03632|011|E|reactions (elevated creatine kinase) or rhabdomyolysis.(1)|
03632|012|B||
03632|013|P|PREDISPOSING FACTORS:  None determined.|
03632|014|B||
03632|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03632|016|M|undergoing therapy with sonidegib.(1)  Consider alternatives with no or|
03632|017|M|minimal enzyme inhibition.|
03632|018|B||
03632|019|D|DISCUSSION:  In a study, 15 healthy subjects received a single sonidegib 800|
03632|020|D|mg alone or after ketoconazole 200 mg twice daily for 14 days.  Mean|
03632|021|D|area-under-curve (AUC) and concentration maximum (Cmax) increased by|
03632|022|D|2.2-fold and 1.5-fold respectively.(1)|
03632|023|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03632|024|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03632|025|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03632|026|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03632|027|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03632|028|D|tucatinib, or voriconazole.(2,3)|
03632|029|B||
03632|030|R|REFERENCES:|
03632|031|B||
03632|032|R|1.Odomzo (sonidegib) US prescribing information. Novartis Pharmaceuticals|1
03632|033|R|  May, 2019.|1
03632|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03632|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03632|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03632|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03632|038|R|  11/14/2017.|1
03632|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03632|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03633|001|T|MONOGRAPH TITLE:  Tofacitinib/Strong CYP3A4 Inhibitors|
03633|002|B||
03633|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03633|004|L|take action as needed.|
03633|005|B||
03633|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03633|007|A|the metabolism of tofacitinib.(1)|
03633|008|B||
03633|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03633|010|E|levels of and effects from tofacitinib, including serious infections,|
03633|011|E|thrombosis, gastrointestinal perforation, neutropenia, anemia, elevated|
03633|012|E|liver enzymes, or lipid elevations.(1)|
03633|013|B||
03633|014|P|PREDISPOSING FACTORS:  None determined.|
03633|015|B||
03633|016|M|PATIENT MANAGEMENT:  In patients taking a strong CYP3A4 inhibitor, the|
03633|017|M|starting dose of tofacitinib should be reduced as follows:|
03633|018|M|   - Xeljanz for rheumatoid arthritis, psoriatic arthritis, and ankylosing|
03633|019|M|spondylitis: reduce to 5 mg once daily.|
03633|020|M|   - Xeljanz XR for rheumatoid arthritis, psoriatic arthritis, and|
03633|021|M|ankylosing spondylitis: switch to Xeljanz 5 mg once daily.|
03633|022|M|   - Xeljanz for ulcerative colitis:|
03633|023|M|      - Induction: 5 mg twice daily for 8 weeks. If needed continue for|
03633|024|M|maximum of 16 weeks.|
03633|025|M|      - Maintenance: 5 mg once daily. May consider 5 mg twice daily if loss|
03633|026|M|of response.|
03633|027|M|   - Xeljanz XR for ulcerative colitis:|
03633|028|M|      - Induction: 11 mg once daily for 8 weeks. If needed continue for|
03633|029|M|maximum of 16 weeks.|
03633|030|M|      - Maintenance: Not recommended. Switch to Xeljanz and follow strong|
03633|031|M|CYP3A4 inhibitor recommendation.|
03633|032|M|   - Xeljanz oral solution for polyarticular course juvenile idiopathic|
03633|033|M|arthritis (pcJIA) or psoriatic arthritis (patients 2 years or older):|
03633|034|M|      - >= 10 kg to <20 kg: 3.2 mg once daily|
03633|035|M|      - >= 20 kg to <40 kg: 4 mg once daily|
03633|036|M|      - >= 40 kg: 5 mg once daily  (1)(1)|
03633|037|M|   For concurrent treatment with nirmatrelvir-ritonavir, dose adjustments|
03633|038|M|should be considered throughout the nirmatrelvir-ritonavir treatment and for|
03633|039|M|3 days following the last dose of nirmatrelvir-ritonavir.(2)|
03633|040|B||
03633|041|D|DISCUSSION:  In a study, administration of ketoconazole, increased the|
03633|042|D|area-under-curve (AUC) of tofacitinib by more than 2-fold.(1)|
03633|043|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03633|044|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
03633|045|D|josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone,|
03633|046|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03633|047|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03633|048|D|troleandomycin, tucatinib, or voriconazole.(3,4)|
03633|049|B||
03633|050|R|REFERENCES:|
03633|051|B||
03633|052|R|1.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. October,|1
03633|053|R|  2025.|1
03633|054|R|2.Quah KSE, Huang X, Renia L, Oon HH. Drug interactions between common|6
03633|055|R|  dermatological medications and the oral  anti-COVID-19 agents|6
03633|056|R|  nirmatrelvir-ritonavir and molnupiravir. Ann Acad Med Singap 2022 Dec;|6
03633|057|R|  51(12):774-786.|6
03633|058|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03633|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03633|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03633|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03633|062|R|  11/14/2017.|1
03633|063|R|4.This information is based on an extract from the Certara Drug Interaction|6
03633|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03634|001|T|MONOGRAPH TITLE:  Vinblastine/Strong CYP3A4 Inhibitors|
03634|002|B||
03634|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03634|004|L|of severe adverse interaction.|
03634|005|B||
03634|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03634|007|A|the metabolism of vinblastine.(1)|
03634|008|B||
03634|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03634|010|E|levels of and effects from vinblastine, including leukopenia, alopecia,|
03634|011|E|hypertension, or constipation.(1)|
03634|012|B||
03634|013|P|PREDISPOSING FACTORS:  None determined.|
03634|014|B||
03634|015|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03634|016|M|undergoing therapy with vinblastine.(1)  Consider alternatives with no or|
03634|017|M|minimal enzyme inhibition.|
03634|018|M|   The manufacturer of vinblastine states that caution should be used if|
03634|019|M|coadministered with strong CYP3A4 inhibitors.(1)|
03634|020|M|   The manufacturer of lopinavir/ritonavir states that patients who develop|
03634|021|M|significant hematological or gastrointestinal toxicity on concomitant|
03634|022|M|vinblastine should temporarily hold lopinavir/ritonavir, or use alternative|
03634|023|M|medications that do not inhibit CYP3A4 or P-gp.(2)|
03634|024|B||
03634|025|D|DISCUSSION:  There have been 2 case reports of vinblastine hematologic|
03634|026|D|toxicity during concurrent lopinavir-ritonavir therapy.  In both cases,|
03634|027|D|vinblastine was administered without toxicity when lopinavir-ritonavir|
03634|028|D|therapy was suspended.(3,4)|
03634|029|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03634|030|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03634|031|D|ketoconazole, lonafarnib, lopinavir, mifepristone, nefazodone, nelfinavir,|
03634|032|D|nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir,|
03634|033|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or|
03634|034|D|voriconazole.(5,6)|
03634|035|B||
03634|036|R|REFERENCES:|
03634|037|B||
03634|038|R|1.Vinblastine US prescribing information. APP Pharmaceuticals, LLC January,|1
03634|039|R|  2012.|1
03634|040|R|2.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
03634|041|R|  Laboratories December, 2019.|1
03634|042|R|3.Makinson A, Martelli N, Peyriere H, Turriere C, Le Moing V, Reynes J.|3
03634|043|R|  Profound neutropenia resulting from interaction between antiretroviral|3
03634|044|R|  therapy and vinblastine in a patient with HIV-associated Hodgkin's|3
03634|045|R|  disease. Eur J Haematol 2007 Apr;78(4):358-60.|3
03634|046|R|4.Kotb R, Vincent I, Dulioust A, Peretti D, Taburet AM, Delfraissy JF,|3
03634|047|R|  Goujard C. Life-threatening interaction between antiretroviral therapy and|3
03634|048|R|  vinblastine in HIV-associated multicentric Castleman's disease. Eur J|3
03634|049|R|  Haematol 2006 Mar;76(3):269-71.|3
03634|050|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03634|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03634|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03634|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03634|054|R|  11/14/2017.|1
03634|055|R|6.This information is based on an extract from the Certara Drug Interaction|6
03634|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03635|001|T|MONOGRAPH TITLE:  Vincristine/Strong CYP3A4 Inhibitors|
03635|002|B||
03635|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03635|004|L|of severe adverse interaction.|
03635|005|B||
03635|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03635|007|A|the metabolism of vincristine.(1)|
03635|008|B||
03635|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03635|010|E|levels of and effects from vincristine, including myelosuppression,|
03635|011|E|neurologic toxicity, tumor lysis syndrome, hepatotoxicity, constipation, or|
03635|012|E|bowel obstruction.(1)|
03635|013|B||
03635|014|P|PREDISPOSING FACTORS:  None determined.|
03635|015|B||
03635|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03635|017|M|undergoing therapy with vincristine.(1)  Consider alternatives with no or|
03635|018|M|minimal enzyme inhibition.|
03635|019|M|   The manufacturer of vincristine states that concomitant use of strong|
03635|020|M|CYP3A4 inhibitors should be avoided.(1)|
03635|021|M|   The manufacturer of lopinavir/ritonavir states that patients who develop|
03635|022|M|significant hematological or gastrointestinal toxicity on concomitant|
03635|023|M|vincristine should temporarily hold lopinavir/ritonavir, or use alternative|
03635|024|M|medications that do not inhibit CYP3A4 or P-gp.(2)|
03635|025|B||
03635|026|D|DISCUSSION:  Vincristine is a substrate of CYP3A4.  Inhibitors of CYP3A4 may|
03635|027|D|increase toxicity of vincristine.(1)|
03635|028|D|   There are several case reports of neurotoxicity with concurrent|
03635|029|D|administration of vincristine and itraconazole (6,12-16), posaconazole (8),|
03635|030|D|and voriconazole.(11)|
03635|031|D|   There is a case report of neurotoxicity with concurrent administration of|
03635|032|D|lopinavir-ritonavir with vincristine.(9)|
03635|033|D|   In a retrospective study of 29 adults with acute lymphoplastic leukemia|
03635|034|D|(ALL) receiving concurrent vincristine and azole therapy (fluconazole,|
03635|035|D|voriconazole, or posaconazole), patients were more likely to have a dose|
03635|036|D|modification (dose reduction or discontinue drug, 58.6% vs. 23.8%, p = 0.02)|
03635|037|D|and more likely to have symptoms of decreased peristalsis (65.5% vs. 28.6%,|
03635|038|D|p = 0.019). A mean dose reduction of vincristine when combined with an azole|
03635|039|D|was 46.5%. Six patients had to withhold treatment with vincristine because|
03635|040|D|of the severity of the neurotoxicity.(10)|
03635|041|D|   In a prospective study in 22 children receiving various chemotherapy with|
03635|042|D|prophylactic itraconazole oral solution (0.5 ml/kg per day), two children|
03635|043|D|receiving vincristine developed non-alcoholic steatohepatitis (NASH) and one|
03635|044|D|child developed syndrome of inappropriate anti-diuretic hormone secretion|
03635|045|D|(SIADH).(17)|
03635|046|D|   In a retrospective review, 8 ALL patients on vincristine and voriconazole|
03635|047|D|prophylaxis (200 mg twice a day) did not show any signs of|
03635|048|D|neurotoxicity.(18)|
03635|049|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03635|050|D|clarithromycin, cobicistat, fusidic acid, idelalisib, indinavir,|
03635|051|D|itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mifepristone,|
03635|052|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
03635|053|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03635|054|D|troleandomycin, tucatinib, or voriconazole.(3,4)|
03635|055|B||
03635|056|R|REFERENCES:|
03635|057|B||
03635|058|R|1.Marqibo (vincristine sulfate) US prescribing information. Talon|1
03635|059|R|  Therapeutics, Inc July, 2020.|1
03635|060|R|2.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
03635|061|R|  Laboratories December, 2019.|1
03635|062|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03635|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03635|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03635|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03635|066|R|  11/14/2017.|1
03635|067|R|4.This information is based on an extract from the Certara Drug Interaction|6
03635|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03635|069|R|5.Moriyama B, Henning SA, Leung J, Falade-Nwulia O, Jarosinski P, Penzak SR,|6
03635|070|R|  Walsh TJ. Adverse interactions between antifungal azoles and vincristine:|6
03635|071|R|  review and analysis of cases. Mycoses 2012 Jul;55(4):290-7.|6
03635|072|R|6.Takahashi N, Kameoka Y, Yamanaka Y, Ubukawa K, Saito K, Fujishima M,|3
03635|073|R|  Fujishima N, Saito H, Hirokawa M, Scott SA, Sawada K. Itraconazole oral|3
03635|074|R|  solution enhanced vincristine neurotoxicity in five patients with|3
03635|075|R|  malignant lymphoma. Intern Med 2008;47(7):651-3.|3
03635|076|R|7.Pana ZD, Roilides E. Risk of azole-enhanced vincristine neurotoxicity in|6
03635|077|R|  pediatric patients with hematological malignancies: old problem - new|6
03635|078|R|  dilemma. Pediatr Blood Cancer 2011 Jul 15;57(1):30-5.|6
03635|079|R|8.Jain S, Kapoor G. Severe life threatening neurotoxicity in a child with|3
03635|080|R|  acute lymphoblastic leukemia receiving posaconazole and vincristine.|3
03635|081|R|  Pediatr Blood Cancer 2010 May;54(5):783.|3
03635|082|R|9.Leveque D, Santucci R, Pavillet J, Herbrecht R, Bergerat JP. Paralytic|3
03635|083|R|  ileus possibly associated with interaction between ritonavir/lopinavir|3
03635|084|R|  and vincristine. Pharm World Sci 2009 Dec;31(6):619-21.|3
03635|085|R|10.Harnicar S, Adel N, Jurcic J. Modification of vincristine dosing during|2
03635|086|R|   concomitant azole therapy in adult acute lymphoblastic leukemia patients.|2
03635|087|R|   J Oncol Pharm Pract 2009 Sep;15(3):175-82.|2
03635|088|R|11.Porter CC, Carver AE, Albano EA. Vincristine induced peripheral|3
03635|089|R|   neuropathy potentiated by voriconazole in a patient with previously|3
03635|090|R|   undiagnosed CMT1X. Pediatr Blood Cancer 2009 Feb;52(2):298-300.|3
03635|091|R|12.Ariffin H, Omar KZ, Ang EL, Shekhar K. Severe vincristine neurotoxicity|3
03635|092|R|   with concomitant use of itraconazole. J Paediatr Child Health 2003 Nov;|3
03635|093|R|   39(8):638-9.|3
03635|094|R|13.Sathiapalan RK, El-Solh H. Enhanced vincristine neurotoxicity from drug|3
03635|095|R|   interactions: case report and review of literature. Pediatr Hematol Oncol|3
03635|096|R|   2001 Dec;18(8):543-6.|3
03635|097|R|14.Jeng MR, Feusner J. Itraconazole-enhanced vincristine neurotoxicity in a|3
03635|098|R|   child with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2001 Mar;|3
03635|099|R|   18(2):137-42.|3
03635|100|R|15.Gillies J, Hung KA, Fitzsimons E, Soutar R. Severe vincristine toxicity|3
03635|101|R|   in combination with itraconazole. Clin Lab Haematol 1998 Apr;20(2):123-4.|3
03635|102|R|16.Murphy JA, Ross LM, Gibson BE. Vincristine toxicity in five children with|3
03635|103|R|   acute lymphoblastic leukaemia. Lancet 1995 Aug 12;346(8972):443.|3
03635|104|R|17.Kobayashi R, Suzuki D, Yasuda K, Kobayashi K. Itraconazole for invasive|2
03635|105|R|   fungal infection with pediatric malignancies. Pediatr Int 2010 Oct;|2
03635|106|R|   52(5):707-10.|2
03635|107|R|18.Whittle AM, Ali S. Primary prophylaxis with voriconazole in patients|6
03635|108|R|   receiving induction chemotherapy on the MRC adult acute lymphoblastic|6
03635|109|R|   leukaemia trial (UK-ALL XII) to avoid itraconazole-enhanced vinca|6
03635|110|R|   neurotoxicity. Int J Lab Hematol 2008 Apr;30(2):173-4.|6
03636|001|T|MONOGRAPH TITLE:  Vinflunine/Strong CYP3A4 Inhibitors|
03636|002|B||
03636|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03636|004|L|of severe adverse interaction.|
03636|005|B||
03636|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03636|007|A|the metabolism of vinflunine.(1)|
03636|008|B||
03636|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03636|010|E|levels of and effects from vinflunine, including neutropenia,|
03636|011|E|thrombocytopenia, anemia, constipation, stomatitis, diarrhea, or|
03636|012|E|alopecia.(1)|
03636|013|B||
03636|014|P|PREDISPOSING FACTORS:  None determined.|
03636|015|B||
03636|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03636|017|M|undergoing therapy with vinflunine.(1)  Consider alternatives with no or|
03636|018|M|minimal enzyme inhibition.|
03636|019|M|   The manufacturer of vinflunine states that concomitant use with strong|
03636|020|M|CYP3A4 inhibitors should be avoided.(1)|
03636|021|B||
03636|022|D|DISCUSSION:  In a phase I study, concurrent use of ketoconazole (400 mg|
03636|023|D|orally daily for 8 days) increased the exposure to vinflunine and DVFL by|
03636|024|D|30% and 50%, respectively.(1)|
03636|025|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03636|026|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03636|027|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03636|028|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03636|029|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03636|030|D|tucatinib, or voriconazole.(2,3)|
03636|031|B||
03636|032|R|REFERENCES:|
03636|033|B||
03636|034|R|1.Javlor (vinflunine) UK summary of product information. Pierre Fabre|1
03636|035|R|  Medicament Production May, 2014.|1
03636|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03636|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03636|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03636|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03636|040|R|  11/14/2017.|1
03636|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
03636|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03638|001|T|MONOGRAPH TITLE:  Dabrafenib/Idelalisib|
03638|002|B||
03638|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03638|004|L|of severe adverse interaction.|
03638|005|B||
03638|006|A|MECHANISM OF ACTION:  Idelalisib is both a substrate and a strong inhibitor|
03638|007|A|of the CYP3A4 isoenzyme.(1)  Dabrafenib is both a substrate and a moderate|
03638|008|A|inducer of CYP3A4.(2)  Concurrent use of dabrafenib and idelalisib may alter|
03638|009|A|exposure to one or both agents.|
03638|010|B||
03638|011|E|CLINICAL EFFECTS:  Concurrent use of dabrafenib and idelalisib may result in|
03638|012|E|elevated levels of and toxicity from dabrafenib(2) and decreased levels and|
03638|013|E|efficacy of idelalisib.(1)  The net effect and magnitude of the two-way|
03638|014|E|interaction between dabrafenib and idelalisib is unknown.|
03638|015|E|   Potential toxicities of dabrafenib include: hyperglycemia, fever,|
03638|016|E|hemorrhage, cardiomyopathy, serious dermatological reactions, and|
03638|017|E|uveitis.(2)|
03638|018|B||
03638|019|P|PREDISPOSING FACTORS:  None determined.|
03638|020|B||
03638|021|M|PATIENT MANAGEMENT:  Avoid the concurrent use of dabrafenib and|
03638|022|M|idelalisib.(2,3)  Consider alternatives with no or minimal effect on the|
03638|023|M|CYP3A4 isoenzyme.|
03638|024|M|   There is currently no FDA-approved indication for the concurrent use of|
03638|025|M|dabrafenib and idelalisib.  The optimal doses of dabrafenib and idelalisib|
03638|026|M|when used in combination is unknown.  Combination therapy with dabrafenib|
03638|027|M|and idelalisib would ideally be utilized within the context of a clinical|
03638|028|M|trial.|
03638|029|M|   Patients receiving concurrent therapy with dabrafenib and idelalisib|
03638|030|M|should be monitored closely for efficacy and signs of toxicities.(1,2)|
03638|031|B||
03638|032|D|DISCUSSION:  Ketoconazole (400 mg daily for 4 days, a strong CYP3A4|
03638|033|D|inhibitor) increased the area-under-curve (AUC) of dabrafenib (75 mg BID) by|
03638|034|D|71%.  The AUC of hydroxy-dabrafenib and desmethyl-dabrafenib increased by|
03638|035|D|82% and 68%, respectively.(2)|
03638|036|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
03638|037|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
03638|038|D|75%, respectively.(3)|
03638|039|B||
03638|040|R|REFERENCES:|
03638|041|B||
03638|042|R|1.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03638|043|R|  October, 2020.|1
03638|044|R|2.Tafinlar (dabrafenib) US prescribing information. Novartis Pharmaceuticals|1
03638|045|R|  Corporation May, 2023.|1
03638|046|R|3.Zydelig (idelalisib) UK Summary of Product Characteristics. Gilead|1
03638|047|R|  Sciences Ltd December 17, 2019.|1
03638|048|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03638|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03638|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03638|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03638|052|R|  11/14/2017.|1
03638|053|R|5.This information is based on an extract from the Certara Drug Interaction|6
03638|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03639|001|T|MONOGRAPH TITLE:  Olaparib/Lonafarnib (mono deleted 05/28/2024)|
03639|002|B||
03639|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03639|004|L|of severe adverse interaction.|
03639|005|B||
03639|006|A|MECHANISM OF ACTION:  Olaparib and lonafarnib are both inhibitors as well as|
03639|007|A|substrates of CYP3A4.(1-3)|
03639|008|B||
03639|009|E|CLINICAL EFFECTS:  Concurrent use of olaparib and lonafarnib may result in|
03639|010|E|elevated levels of and toxicity from both agents.  The magnitude of effect|
03639|011|E|of the two-way inhibition of the metabolism of olaparib and lonafarnib is|
03639|012|E|unknown.|
03639|013|E|   Potential toxicities include: hypertension, venous thrombosis,|
03639|014|E|pneumonitis, retinal toxicity, and nephrotoxicity.(1-3)|
03639|015|B||
03639|016|P|PREDISPOSING FACTORS:  None determined.|
03639|017|B||
03639|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of olaparib and|
03639|019|M|lonafarnib.(1-3)  Consider alternatives with no or minimal enzyme|
03639|020|M|inhibition.|
03639|021|M|   The magnitude of effect of the two-way inhibition of the metabolism of|
03639|022|M|olaparib and lonafarnib is unknown.  The optimal doses of olaparib and|
03639|023|M|lonafarnib when used concurrently have not been determined.  Manufacturers|
03639|024|M|provide recommendations for dose modification of olaparib and lonafarnib|
03639|025|M|when each is used with a CYP3A4 inhibitor, but the recommendations may not|
03639|026|M|apply when there is a two-way inhibition.  Dose modifications mentioned|
03639|027|M|below are informational only.|
03639|028|M|   If concomitant use of a strong CYP3A4 inhibitor with olaparib cannot be|
03639|029|M|avoided, reduce the olaparib dose.  Dosage adjustments are specific to the|
03639|030|M|formulation of olaparib.(1,2)  Reduce the dosage of the CAPsule formulation|
03639|031|M|to 150 mg (3 CAPsules) taken twice daily.(1)  Reduce the dosage of the|
03639|032|M|TABlet formulation to 100 mg (one 100 mg TABlet) twice daily.(2)  If the|
03639|033|M|CYP3A4 inhibitor is discontinued, resume the dose of olaparib taken prior to|
03639|034|M|initiation of the CYP3A4 inhibitor after 3 to 5 half-lives.(1,2)|
03639|035|M|   If coadministration of a weak CYP3A4 inhibitor with lonafarnib is|
03639|036|M|unavoidable, reduce the dose of lonafarnib to or continue at 115 mg/m2.(3)|
03639|037|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03639|038|M|heart palpitations because lonafarnib exposures may be increased despite the|
03639|039|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03639|040|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03639|041|M|inhibitor.(3)|
03639|042|B||
03639|043|D|DISCUSSION:  The magnitude of effect of the two-way inhibition of the|
03639|044|D|metabolism of olaparib and lonafarnib is unknown.|
03639|045|D|   In an interaction study, the area-under-curve (AUC) and maximum|
03639|046|D|concentration (Cmax) of olaparib was increased 2.7 and 1.4-fold respectively|
03639|047|D|when it was administered with itraconazole (dose not specified), a strong|
03639|048|D|CYP3A4 inhibitor.(1,2,4)|
03639|049|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03639|050|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, AUC|
03639|051|D|and Cmax were increased by 425% and 270%, respectively.(3)|
03639|052|B||
03639|053|R|REFERENCES:|
03639|054|B||
03639|055|R|1.Lynparza (olaparib) capsules US prescribing information. AstraZenica|1
03639|056|R|  Pharmaceuticals October 23, 2017.|1
03639|057|R|2.Lynparza (olaparib) tablets US prescribing information. AstraZenica|1
03639|058|R|  Pharmaceuticals March, 2021.|1
03639|059|R|3.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03639|060|R|  Inc. November, 2020.|1
03639|061|R|4.Dirix L, Swaisland H, Verheul HM. Effect of Itraconazole and Rifampin on|2
03639|062|R|  the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors:|2
03639|063|R|  Results of Two Phase I Open-label Studies. Clin Ther 2016 Oct;|2
03639|064|R|  38(10):2286-2299.|2
03639|065|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03639|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03639|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03639|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03639|069|R|  11/14/2017.|1
03639|070|R|6.This information is based on an extract from the Certara Drug Interaction|6
03639|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03640|001|T|MONOGRAPH TITLE:  Palbociclib/Lonafarnib (mono deleted 05/28/2024)|
03640|002|B||
03640|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03640|004|L|of severe adverse interaction.|
03640|005|B||
03640|006|A|MECHANISM OF ACTION:  Palbociclib and lonafarnib are both inhibitors as well|
03640|007|A|as substrates of CYP3A4.(1-2)|
03640|008|B||
03640|009|E|CLINICAL EFFECTS:  Concurrent use of palbociclib and lonafarnib may result|
03640|010|E|in elevated levels of and toxicity from both agents.  The magnitude of|
03640|011|E|effect of the two-way inhibition of the metabolism of palbociclib and|
03640|012|E|lonafarnib is unknown.|
03640|013|E|   Potential toxicities include: neutropenia, hypertension, interstitial|
03640|014|E|lung disease, retinal toxicity, and nephrotoxicity.(1-2)|
03640|015|B||
03640|016|P|PREDISPOSING FACTORS:  None determined.|
03640|017|B||
03640|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of palbociclib and|
03640|019|M|lonafarnib.(1-2)  Consider alternatives with no or minimal enzyme|
03640|020|M|inhibition.|
03640|021|M|   The magnitude of effect of the two-way inhibition of the metabolism of|
03640|022|M|palbociclib and lonafarnib is unknown.  The optimal doses of palbociclib and|
03640|023|M|lonafarnib when used concurrently have not been determined.  Manufacturers|
03640|024|M|provide recommendations for dose modification of palbociclib and lonafarnib|
03640|025|M|when each is used with a CYP3A4 inhibitor, but the recommendations may not|
03640|026|M|apply when there is a two-way inhibition.  Dose modifications mentioned|
03640|027|M|below are informational only.|
03640|028|M|   If concurrent use of a strong CYP3A4 inhibitor with palbociclib cannot be|
03640|029|M|avoided, reduce the dose of palbociclib to 75 mg daily.  If the 3A4|
03640|030|M|inhibitor is discontinued, a washout period of 3-5 half-lives of the|
03640|031|M|inhibitor should occur before the palbociclib dose is adjusted upward.(1)|
03640|032|M|   If coadministration of a weak CYP3A4 inhibitor with lonafarnib is|
03640|033|M|unavoidable, reduce the dose of lonafarnib to or continue at 115 mg/m2.(2)|
03640|034|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03640|035|M|heart palpitations because lonafarnib exposures may be increased despite the|
03640|036|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03640|037|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03640|038|M|inhibitor.(2)|
03640|039|B||
03640|040|D|DISCUSSION:  The magnitude of effect of the two-way inhibition of the|
03640|041|D|metabolism of palbociclib and lonafarnib is unknown.|
03640|042|D|   In a study in 12 healthy subjects, itraconazole (200 mg daily) increased|
03640|043|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
03640|044|D|of palbociclib by 34% and 87%, respectively.(1)|
03640|045|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03640|046|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, AUC|
03640|047|D|and Cmax were increased by 425% and 270%, respectively.(2)|
03640|048|B||
03640|049|R|REFERENCES:|
03640|050|B||
03640|051|R|1.Ibrance (palbociclib) US prescribing information. Pfizer Labs September,|1
03640|052|R|  2023.|1
03640|053|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03640|054|R|  Inc. November, 2020.|1
03640|055|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03640|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03640|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03640|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03640|059|R|  11/14/2017.|1
03640|060|R|4.This information is based on an extract from the Certara Drug Interaction|6
03640|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03641|001|T|MONOGRAPH TITLE:  Idelalisib/Moderate CYP3A4 Inducers|
03641|002|B||
03641|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03641|004|L|of severe adverse interaction.|
03641|005|B||
03641|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
03641|007|A|metabolism of idelalisib.(1)|
03641|008|B||
03641|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inducers may decrease|
03641|010|E|the levels and effectiveness of idelalisib.(1)|
03641|011|B||
03641|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03641|013|P|of the inducer for longer than 1-2 weeks.|
03641|014|B||
03641|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of moderate CYP3A4 inducers in|
03641|016|M|patients receiving therapy with idelalisib.(1)  Consider the use of|
03641|017|M|alternative agents with less enzyme induction potential.(1)|
03641|018|B||
03641|019|D|DISCUSSION:  In a study in healthy subjects, rifampin (600 mg daily for 8|
03641|020|D|days) decreased the concentration maximum (Cmax) and area-under-curve (AUC)|
03641|021|D|of idelalisib (150 mg single dose) by 58% and 75%, respectively.(1)|
03641|022|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03641|023|D|cenobamate, dipyrone, efavirenz, etravirine, lesinurad, modafinil,|
03641|024|D|nafcillin, rifabutin, sotorasib, telotristat ethyl, thioridazine, and|
03641|025|D|tovorafenib.(2)|
03641|026|B||
03641|027|R|REFERENCES:|
03641|028|B||
03641|029|R|1.Zydelig (idelalisib) UK Summary of Product Characteristics. Gilead|1
03641|030|R|  Sciences Ltd December 17, 2019.|1
03641|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03641|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03641|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03641|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03641|035|R|  11/14/2017.|1
03646|001|T|MONOGRAPH TITLE:  Bosutinib/Strong CYP3A4 Inhibitors that Prolong QT|
03646|002|B||
03646|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03646|004|L|of severe adverse interaction.|
03646|005|B||
03646|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03646|007|A|interval may inhibit the metabolism of bosutinib and result in additive risk|
03646|008|A|of QT prolongation.(1)|
03646|009|B||
03646|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03646|011|E|prolong QT may result in elevated levels of and toxicity from bosutinib,|
03646|012|E|including additive QTc prolongation, which may result in potentially|
03646|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03646|014|E|(TdP).(1)|
03646|015|E|   Other toxicities include nausea, vomiting, diarrhea, abdominal pain,|
03646|016|E|myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1)|
03646|017|B||
03646|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03646|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03646|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03646|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03646|022|P|female gender, or advanced age.(2)|
03646|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03646|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03646|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03646|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03646|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03646|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03646|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03646|030|B||
03646|031|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors that prolong|
03646|032|M|QT in patients undergoing therapy with bosutinib.(1)  Consider alternatives|
03646|033|M|with no or minimal enzyme inhibition and with no effect on the QTc interval.|
03646|034|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03646|035|M|bosutinib should be monitored for prolongation of the QTc interval.  When|
03646|036|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03646|037|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03646|038|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03646|039|M|report any irregular heartbeat, dizziness, or fainting.|
03646|040|B||
03646|041|D|DISCUSSION:  In a randomized, phase I, double-blind, placebo-controlled,|
03646|042|D|sequential group study, 48 healthy adults received a single dose of|
03646|043|D|bosutinib 100, 200, 300, 400, 500, or 600 mg with ketoconazole 400 mg days|
03646|044|D|-1 and days 1-4. Bosutinib area-under-curve (AUC) and maximum concentration|
03646|045|D|(Cmax) increased 7.3-fold and 7.7-fold.(3)|
03646|046|D|   In an open-label, randomized, 2-period, crossover study, healthy subjects|
03646|047|D|received a single dose of bosutinib 100 mg alone and with multiple doses of|
03646|048|D|ketoconazole 400 mg.  Bosutinib Cmax and AUC increased 5.2-fold and|
03646|049|D|8.6-fold, respectively.(4)|
03646|050|D|   A retrospective review of 618 cancer patients treated with 902|
03646|051|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03646|052|D|incidence of QTc prolongation.  In patients who received bosutinib, QTc|
03646|053|D|prolongation was identified in 8 patients(38.1%), with 5 patients (62.5%)|
03646|054|D|having Grade 1 (QTc 450-480 ms) and 3 patients(37.5%) having Grade 2 (QTc|
03646|055|D|480-500 ms) events.  Grade 3 events occurred in 1 (12.5%) patient having QTc|
03646|056|D|greater than or equal to 500 ms.  No patients had a QTc change greater than|
03646|057|D|or equal to 60 ms, ventricular tachycardia (VT), sudden cardiac death (SCD),|
03646|058|D|or TdP.(5)|
03646|059|D|   Agents that are linked to this monograph may have varying degrees of|
03646|060|D|potential to prolong the QTc interval but are generally accepted to have a|
03646|061|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03646|062|D|been shown to prolong the QTc interval either through their mechanism of|
03646|063|D|action, through studies on their effects on the QTc interval, or through|
03646|064|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03646|065|D|and/or post-marketing reports.(6)|
03646|066|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
03646|067|D|ceritinib, clarithromycin, levoketoconazole, lopinavir, posaconazole,|
03646|068|D|ribociclib, saquinavir, telithromycin, and voriconazole.(7,8)|
03646|069|B||
03646|070|R|REFERENCES:|
03646|071|B||
03646|072|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
03646|073|R|  2023.|1
03646|074|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03646|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03646|076|R|  settings: a scientific statement from the American Heart Association and|6
03646|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03646|078|R|  2;55(9):934-47.|6
03646|079|R|3.Abbas R, Leister C, El Gaaloul M, Chalon S, Sonnichsen D. Ascending|2
03646|080|R|  single-dose study of the safety profile, tolerability, and|2
03646|081|R|  pharmacokinetics of bosutinib coadministered with ketoconazole to healthy|2
03646|082|R|  adult subjects. Clin Ther 2012 Sep;34(9):2011-9.e1.|2
03646|083|R|4.Abbas R, Hug BA, Leister C, Burns J, Sonnichsen D. Effect of ketoconazole|2
03646|084|R|  on the pharmacokinetics of oral bosutinib in healthy subjects. J Clin|2
03646|085|R|  Pharmacol 2011 Dec;51(12):1721-7.|2
03646|086|R|5.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03646|087|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03646|088|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03646|089|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
03646|090|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03646|091|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03646|092|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03646|093|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
03646|094|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03646|095|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03646|096|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03646|097|R|  11/14/2017.|1
03646|098|R|8.This information is based on an extract from the Certara Drug Interaction|6
03646|099|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03647|001|T|MONOGRAPH TITLE:  Ceritinib/Strong CYP3A4 Inhibitors|
03647|002|B||
03647|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03647|004|L|of severe adverse interaction.|
03647|005|B||
03647|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03647|007|A|the metabolism of ceritinib.(1)|
03647|008|B||
03647|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03647|010|E|levels of and effects from ceritinib.(1)|
03647|011|E|    Elevated levels of ceritinib may result in QTc prolongation, which may|
03647|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03647|013|E|torsades de pointes (TdP).  Other toxicities include bradycardia, nausea,|
03647|014|E|vomiting, diarrhea, abdominal pain, transaminitis, hyperglycemia,|
03647|015|E|interstitial lung disease, and pancreatitis.(1)|
03647|016|B||
03647|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03647|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03647|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03647|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03647|021|P|female gender, or advanced age.(2)|
03647|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03647|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03647|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03647|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03647|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03647|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03647|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03647|029|P|   Patients with severe hepatic impairment (Child-Pugh C) may be at|
03647|030|P|increased risk of this interaction.  Ceritinib dose reduction may be|
03647|031|P|warranted in severe hepatic impairment.  See prescribing information for|
03647|032|P|recommendations.(1)|
03647|033|B||
03647|034|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03647|035|M|undergoing therapy with ceritinib.(1)  Consider alternatives with no or|
03647|036|M|minimal enzyme inhibition.|
03647|037|M|   If concurrent use with ceritinib is unavoidable, reduce the dosage of|
03647|038|M|ceritinib by one-third, rounding to the nearest 150 mg dosage strength.  If|
03647|039|M|the strong CYP3A4 inhibitor is discontinued, resume the dose that was taken|
03647|040|M|prior to using the inhibitor.(1)|
03647|041|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03647|042|M|ceritinib should be monitored for prolongation of the QTc interval.  When|
03647|043|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03647|044|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03647|045|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03647|046|M|report any irregular heartbeat, dizziness, or fainting.(1)|
03647|047|B||
03647|048|D|DISCUSSION:  In a study in 19 healthy subjects, ketoconazole (200 mg twice|
03647|049|D|daily for 14 days) increased the maximum concentration (Cmax) and area under|
03647|050|D|curve (AUC) of a single dose of ceritinib (450 mg) by 22% and 2.9-fold,|
03647|051|D|respectively.  The steady-state AUC of ceritinib at reduced doses after|
03647|052|D|concurrent ketoconazole was predicted by simulations to be similar to the|
03647|053|D|steady-state AUC of ceritinib alone.(1)|
03647|054|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, indinavir,|
03647|055|D|itraconazole, josamycin, ketoconazole, mibefradil, nefazodone, nelfinavir,|
03647|056|D|nirmatrelvir, paritaprevir, telaprevir, tipranavir, troleandomycin, and|
03647|057|D|tucatinib.(3,4)|
03647|058|B||
03647|059|R|REFERENCES:|
03647|060|B||
03647|061|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
03647|062|R|  Corporation August, 2021.|1
03647|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03647|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03647|065|R|  settings: a scientific statement from the American Heart Association and|6
03647|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03647|067|R|  2;55(9):934-47.|6
03647|068|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03647|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03647|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03647|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03647|072|R|  11/14/2017.|1
03647|073|R|4.This information is based on an extract from the Certara Drug Interaction|6
03647|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03648|001|T|MONOGRAPH TITLE:  Ceritinib/Strong CYP3A4 Inhibitors that Prolong QT|
03648|002|B||
03648|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03648|004|L|of severe adverse interaction.|
03648|005|B||
03648|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03648|007|A|interval may inhibit the metabolism of ceritinib and result in additive risk|
03648|008|A|of QT prolongation.(1)|
03648|009|B||
03648|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03648|011|E|prolong QT may result in elevated levels of and toxicity from ceritinib,|
03648|012|E|including additive QTc prolongation, which may result in potentially|
03648|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03648|014|E|(TdP).(1)|
03648|015|E|    Other toxicities include bradycardia, nausea, vomiting, diarrhea,|
03648|016|E|abdominal pain, transaminitis, hyperglycemia, interstitial lung disease, and|
03648|017|E|pancreatitis.(1)|
03648|018|B||
03648|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03648|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03648|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03648|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03648|023|P|female gender, or advanced age.(2)|
03648|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03648|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03648|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03648|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03648|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03648|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03648|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03648|031|P|   Patients with severe hepatic impairment (Child-Pugh C) may be at|
03648|032|P|increased risk of this interaction.  Ceritinib dose reduction may be|
03648|033|P|warranted in severe hepatic impairment.  See prescribing information for|
03648|034|P|recommendations.(1)|
03648|035|B||
03648|036|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors that prolong|
03648|037|M|QT in patients undergoing therapy with ceritinib.(1)  Consider alternatives|
03648|038|M|with no or minimal enzyme inhibition and with no effect on the QTc interval.|
03648|039|M|   If concurrent use with ceritinib is unavoidable, reduce the dosage of|
03648|040|M|ceritinib by one-third, rounding to the nearest 150 mg dosage strength.  If|
03648|041|M|the strong CYP3A4 inhibitor is discontinued, resume the dose that was taken|
03648|042|M|prior to using the inhibitor.(1)|
03648|043|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03648|044|M|ceritinib should be monitored for prolongation of the QTc interval.  When|
03648|045|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03648|046|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03648|047|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03648|048|M|report any irregular heartbeat, dizziness, or fainting.(1)|
03648|049|B||
03648|050|D|DISCUSSION:  In a study in 19 healthy subjects, ketoconazole (200 mg twice|
03648|051|D|daily for 14 days) increased the maximum concentration (Cmax) and|
03648|052|D|area-under-curve (AUC) of a single dose of ceritinib (450 mg) by 22% and|
03648|053|D|2.9-fold, respectively.  The steady-state AUC of ceritinib at reduced doses|
03648|054|D|after concurrent ketoconazole was predicted by simulations to be similar to|
03648|055|D|the steady-state AUC of ceritinib alone.(1)|
03648|056|D|   In a clinical trial 3% of patients experienced a QTc interval increase|
03648|057|D|over baseline greater than 60 msec.  Less than 1% of patients (1 of 304)|
03648|058|D|treated with ceritinib was found to have a QTc greater than 500 msec.  The|
03648|059|D|upper limit of the 90% confidence interval for mean QTC increase was 16 msec|
03648|060|D|at ceritinib 750 mg.  Data suggested that ceritinib produces|
03648|061|D|concentration-dependent QTc interval prolongation.(1)|
03648|062|D|   Agents that are linked to this monograph may have varying degrees of|
03648|063|D|potential to prolong the QTc interval but are generally accepted to have a|
03648|064|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03648|065|D|been shown to prolong the QTc interval either through their mechanism of|
03648|066|D|action, through studies on their effects on the QTc interval, or through|
03648|067|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03648|068|D|and/or post-marketing reports.(3)|
03648|069|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
03648|070|D|clarithromycin, lopinavir, posaconazole, telithromycin, and|
03648|071|D|voriconazole.(4,5)|
03648|072|B||
03648|073|R|REFERENCES:|
03648|074|B||
03648|075|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
03648|076|R|  Corporation August, 2021.|1
03648|077|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03648|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03648|079|R|  settings: a scientific statement from the American Heart Association and|6
03648|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03648|081|R|  2;55(9):934-47.|6
03648|082|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03648|083|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03648|084|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03648|085|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03648|086|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03648|087|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03648|088|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03648|089|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03648|090|R|  11/14/2017.|1
03648|091|R|5.This information is based on an extract from the Certara Drug Interaction|6
03648|092|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03649|001|T|MONOGRAPH TITLE:  Ceritinib/Ribociclib|
03649|002|B||
03649|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03649|004|L|of severe adverse interaction.|
03649|005|B||
03649|006|A|MECHANISM OF ACTION:  Ceritinib and ribociclib are both strong inhibitors as|
03649|007|A|well as substrates of CYP3A4 and can both prolong the QTc interval.(1,2)|
03649|008|B||
03649|009|E|CLINICAL EFFECTS:  Concurrent use of ceritinib and ribociclib may result in|
03649|010|E|elevated levels of and toxicity from both agents.  The magnitude of effect|
03649|011|E|of the two-way inhibition of the metabolism of ceritinib and ribociclib is|
03649|012|E|unknown.|
03649|013|E|   Potential toxicities include: additive QTc prolongation, which may result|
03649|014|E|in potentially life-threatening cardiac arrhythmias including torsades de|
03649|015|E|pointes (TdP), neutropenia, severe cutaneous reactions, nausea, vomiting,|
03649|016|E|diarrhea, abdominal pain, transaminitis, hyperglycemia, interstitial lung|
03649|017|E|disease, and pancreatitis.(1,2)|
03649|018|B||
03649|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03649|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03649|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03649|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03649|023|P|female gender, or advanced age.(3)|
03649|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03649|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03649|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03649|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03649|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03649|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03649|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03649|031|P|   Patients with severe hepatic impairment (Child-Pugh C) may be at|
03649|032|P|increased risk of this interaction.  Ceritinib dose reduction may be|
03649|033|P|warranted in severe hepatic impairment.  See prescribing information for|
03649|034|P|recommendations.(1)|
03649|035|B||
03649|036|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ceritinib and|
03649|037|M|ribociclib.(1,2)  Consider alternatives with no or minimal enzyme inhibition|
03649|038|M|and with no effect on the QTc interval.|
03649|039|M|   There is currently no FDA-approved indication for the concurrent use of|
03649|040|M|ceritinib and ribociclib.  The optimal doses of ceritinib and ribociclib|
03649|041|M|when used in combination is unknown.  Combination therapy with ceritinib and|
03649|042|M|ribociclib would ideally be utilized within the context of a clinical trial.|
03649|043|M|   Patients receiving concurrent therapy with ceritinib and ribociclib|
03649|044|M|should be monitored for prolongation of the QTc interval.  When concurrent|
03649|045|M|therapy is warranted: consider obtaining serum calcium, magnesium, and|
03649|046|M|potassium levels and monitoring EKG at baseline and regular intervals.|
03649|047|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03649|048|M|irregular heartbeat, dizziness, or fainting.|
03649|049|B||
03649|050|D|DISCUSSION:  The magnitude of effect of a two-way inhibition of the|
03649|051|D|metabolism of ceritinib and ribociclib is unknown.  There is currently no|
03649|052|D|FDA-approved indication for the concurrent use of ceritinib and ribociclib.|
03649|053|D|Combination therapy with ceritinib and ribociclib would ideally be utilized|
03649|054|D|within the context of a clinical trial.|
03649|055|D|   In a study in 19 healthy subjects, ketoconazole (200 mg twice daily for|
03649|056|D|14 days) increased the maximum concentration (Cmax) and area-under-curve|
03649|057|D|(AUC) of a single dose of ceritinib (450 mg) by 22% and 2.9-fold,|
03649|058|D|respectively.  The steady-state AUC of ceritinib at reduced doses after|
03649|059|D|concurrent ketoconazole was predicted by simulations to be similar to the|
03649|060|D|steady-state AUC of ceritinib alone.(1)|
03649|061|D|   In a clinical trial 3% of patients experienced a QTc interval increase|
03649|062|D|over baseline greater than 60 msec.  Less than 1% of patients (1 of 304)|
03649|063|D|treated with ceritinib was found to have a QTc greater than 500 msec.  The|
03649|064|D|upper limit of the 90% confidence interval for mean QTC increase was 16 msec|
03649|065|D|at ceritinib 750 mg.  Data suggested that ceritinib produces|
03649|066|D|concentration-dependent QTc interval prolongation.(1)|
03649|067|D|   In a drug interaction study in healthy subjects, coadministration of|
03649|068|D|ritonavir (100 mg twice a day for 14 days) with a single dose of ribociclib|
03649|069|D|(400 mg) increased ribociclib Cmax and AUC by 1.7 and 3.2-fold,|
03649|070|D|respectively. Cmax and AUC for LEQ803 (ribociclib metabolite) decreased by|
03649|071|D|96% and 98%, respectively.(2)|
03649|072|D|   Ribociclib has been shown to prolong the QTc interval in a|
03649|073|D|concentration-dependent manner.  At steady state, the mean increase in QTc|
03649|074|D|interval exceeded 20 msec.(2)|
03649|075|B||
03649|076|R|REFERENCES:|
03649|077|B||
03649|078|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
03649|079|R|  Corporation August, 2021.|1
03649|080|R|2.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
03649|081|R|  Corporation September, 2024.|1
03649|082|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03649|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03649|084|R|  settings: a scientific statement from the American Heart Association and|6
03649|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03649|086|R|  2;55(9):934-47.|6
03649|087|R|4.Kisqali (ribociclib) Sweden prescribing information. Novartis Pharma|1
03649|088|R|  August 2017.|1
03649|089|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03649|090|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03649|091|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03649|092|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03649|093|R|  11/14/2017.|1
03649|094|R|6.This information is based on an extract from the Certara Drug Interaction|6
03649|095|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03650|001|T|MONOGRAPH TITLE:  Crizotinib/Strong CYP3A4 Inhibitors|
03650|002|B||
03650|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03650|004|L|of severe adverse interaction.|
03650|005|B||
03650|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03650|007|A|the metabolism of crizotinib.(1)|
03650|008|B||
03650|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03650|010|E|levels of and effects from crizotinib.(1)|
03650|011|E|    Elevated levels of crizotinib may result in QTc prolongation, which may|
03650|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03650|013|E|torsades de pointes (TdP).  Other toxicities include neutropenia,|
03650|014|E|bradycardia, hepatotoxicity, interstitial lung disease, and severe visual|
03650|015|E|loss.(1)|
03650|016|B||
03650|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03650|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03650|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03650|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03650|021|P|female gender, or advanced age.(2)|
03650|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03650|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03650|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03650|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03650|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03650|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03650|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03650|029|B||
03650|030|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03650|031|M|undergoing therapy with crizotinib.(1)  Consider alternatives with no or|
03650|032|M|minimal enzyme inhibition.|
03650|033|M|   In Adults: If concurrent use of crizotinib for metastatic non-small cell|
03650|034|M|lung cancer or inflammatory myofibroblastic tumor in adults and a strong|
03650|035|M|CYP3A4 inhibitor is unavoidable, a dose reduction of crizotinib to 250 mg|
03650|036|M|daily is recommended.|
03650|037|M|   In Pediatrics or Young Adults: If concurrent use of crizotinib for|
03650|038|M|systemic anaplastic large cell lymphoma (in pediatrics), inflammatory|
03650|039|M|myofibroblastic tumor (in pediatrics) or systemic anaplastic large cell|
03650|040|M|lymphoma (in young adults) and a strong CYP3A4 inhibitor is unavoidable,|
03650|041|M|dose reductions of crizotinib based on body surface area (BSA) are|
03650|042|M|recommended for both capsule and pellet formulations.  See prescribing|
03650|043|M|information for dose reductions.|
03650|044|M|   If the strong CYP3A4 inhibitor is discontinued and not replaced with|
03650|045|M|another strong CYP3A4 inhibitor, resume the dose of crizotinib that was|
03650|046|M|taken prior to initiating the inhibitor.(1)|
03650|047|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor with|
03650|048|M|crizotinib should be monitored for prolongation of the QTc interval.(1)|
03650|049|M|When concurrent therapy is warranted: consider obtaining serum calcium,|
03650|050|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03650|051|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03650|052|M|report any irregular heartbeat, dizziness, or fainting.|
03650|053|B||
03650|054|D|DISCUSSION:  Ketoconazole (200 mg twice daily) increased maximum|
03650|055|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
03650|056|D|crizotinib (150 mg) by 44% and 216%, respectively.  Itraconazole (200 mg|
03650|057|D|twice daily) increased the Cmax and AUC of crizotinib (250 mg daily) by 33%|
03650|058|D|and 57%, respectively.(1)|
03650|059|D|   A retrospective review of 618 cancer patients treated with 902|
03650|060|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03650|061|D|incidence of QTc prolongation.  In patients who received crizotinib, QTc|
03650|062|D|prolongation was identified in 1 patient (50%) with 1 (100%) having Grade 1.|
03650|063|D|No patients had a QTc change greater than or equal to 60 ms, VT, SCD, or|
03650|064|D|TdP.(3)|
03650|065|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
03650|066|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03650|067|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03650|068|D|tipranavir, troleandomycin, and tucatinib.(4,5)|
03650|069|B||
03650|070|R|REFERENCES:|
03650|071|B||
03650|072|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
03650|073|R|  2023.|1
03650|074|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03650|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03650|076|R|  settings: a scientific statement from the American Heart Association and|6
03650|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03650|078|R|  2;55(9):934-47.|6
03650|079|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03650|080|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03650|081|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03650|082|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03650|083|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03650|084|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03650|085|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03650|086|R|  11/14/2017.|1
03650|087|R|5.This information is based on an extract from the Certara Drug Interaction|6
03650|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03651|001|T|MONOGRAPH TITLE:  Crizotinib/Strong CYP3A4 Inhibitors that Prolong QT|
03651|002|B||
03651|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03651|004|L|of severe adverse interaction.|
03651|005|B||
03651|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03651|007|A|interval may inhibit the metabolism of crizotinib and result in additive|
03651|008|A|risk of QT prolongation.(1)|
03651|009|B||
03651|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03651|011|E|prolong QT may result in elevated levels of and toxicity from crizotinib,|
03651|012|E|including additive QTc prolongation, which may result in potentially|
03651|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03651|014|E|(TdP).(1)|
03651|015|E|    Other toxicities include neutropenia, bradycardia, hepatotoxicity,|
03651|016|E|interstitial lung disease, and severe visual loss.(1)|
03651|017|B||
03651|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03651|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03651|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03651|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03651|022|P|female gender, or advanced age.(2)|
03651|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03651|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03651|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03651|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03651|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03651|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03651|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03651|030|B||
03651|031|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors that prolong|
03651|032|M|the QTc interval in patients undergoing therapy with crizotinib.(1)|
03651|033|M|Consider alternatives with no or minimal enzyme inhibition and with no|
03651|034|M|effect on the QTc interval.|
03651|035|M|   In Adults: If concurrent use of crizotinib for metastatic non-small cell|
03651|036|M|lung cancer or inflammatory myofibroblastic tumor in adults and a strong|
03651|037|M|CYP3A4 inhibitor is unavoidable, a dose reduction of crizotinib to 250 mg|
03651|038|M|daily is recommended.|
03651|039|M|   In Pediatrics or Young Adults: If concurrent use of crizotinib for|
03651|040|M|systemic anaplastic large cell lymphoma (in pediatrics), inflammatory|
03651|041|M|myofibroblastic tumor (in pediatrics) or systemic anaplastic large cell|
03651|042|M|lymphoma (in young adults) and a strong CYP3A4 inhibitor is unavoidable,|
03651|043|M|dose reductions of crizotinib based on body surface area (BSA) are|
03651|044|M|recommended for both capsule and pellet formulations.  See prescribing|
03651|045|M|information for dose reductions.|
03651|046|M|   If the strong CYP3A4 inhibitor is discontinued and not replaced with|
03651|047|M|another strong CYP3A4 inhibitor, resume the dose of crizotinib that was|
03651|048|M|taken prior to initiating the inhibitor.(1)|
03651|049|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor with|
03651|050|M|crizotinib should be monitored for prolongation of the QTc interval.(1)|
03651|051|M|When concurrent therapy is warranted, consider obtaining serum calcium,|
03651|052|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03651|053|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
03651|054|M|report any irregular heartbeat, dizziness, or fainting.|
03651|055|B||
03651|056|D|DISCUSSION:  Ketoconazole (200 mg twice daily) increased maximum|
03651|057|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
03651|058|D|crizotinib (150 mg) by 44% and 216%, respectively.  Itraconazole (200 mg|
03651|059|D|twice daily) increased the Cmax and AUC of crizotinib (250 mg daily) by 33%|
03651|060|D|and 57%, respectively.(1)|
03651|061|D|   A retrospective review of 618 cancer patients treated with 902|
03651|062|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03651|063|D|incidence of QTc prolongation.  In patients who received crizotinib, QTc|
03651|064|D|prolongation was identified in 1 patient (50%) with 1 patient (100%) having|
03651|065|D|a Grade 1 event.  No patients had a QTc change greater than or equal to 60|
03651|066|D|ms, VT, SCD, or TdP.(3)|
03651|067|D|   Agents that are linked to this monograph may have varying degrees of|
03651|068|D|potential to prolong the QTc interval but are generally accepted to have a|
03651|069|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03651|070|D|been shown to prolong the QTc interval either through their mechanism of|
03651|071|D|action, through studies on their effects on the QTc interval, or through|
03651|072|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03651|073|D|and/or post-marketing reports.(4)|
03651|074|D|   Strong inhibitors of CYP3A4 that prolong QT include:  adagrasib,|
03651|075|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
03651|076|D|posaconazole, ribociclib, telithromycin, and voriconazole.(5,6)|
03651|077|B||
03651|078|R|REFERENCES:|
03651|079|B||
03651|080|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
03651|081|R|  2023.|1
03651|082|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03651|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03651|084|R|  settings: a scientific statement from the American Heart Association and|6
03651|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03651|086|R|  2;55(9):934-47.|6
03651|087|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03651|088|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03651|089|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03651|090|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03651|091|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03651|092|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03651|093|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03651|094|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03651|095|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03651|096|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03651|097|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03651|098|R|  11/14/2017.|1
03651|099|R|6.This information is based on an extract from the Certara Drug Interaction|6
03651|100|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03652|001|T|MONOGRAPH TITLE:  Dasatinib/Strong CYP3A4 Inhibitors|
03652|002|B||
03652|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03652|004|L|of severe adverse interaction.|
03652|005|B||
03652|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03652|007|A|the metabolism of dasatinib.(1)|
03652|008|B||
03652|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03652|010|E|levels of and effects from dasatinib.(1)|
03652|011|E|    Elevated levels of dasatinib may result in QTc prolongation, which may|
03652|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03652|013|E|torsades de pointes (TdP).  Other toxicities include myelosuppression,|
03652|014|E|serious hemorrhages, fluid retention, pulmonary hypertension, cardiac|
03652|015|E|ischemia, transient ischemic attacks, and severe dermatological|
03652|016|E|reactions.(1)|
03652|017|B||
03652|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03652|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03652|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03652|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03652|022|P|female gender, or advanced age.(2)|
03652|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03652|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03652|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03652|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03652|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03652|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03652|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03652|030|B||
03652|031|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03652|032|M|undergoing therapy with dasatinib.(1)  Consider alternatives with no or|
03652|033|M|minimal enzyme inhibition.|
03652|034|M|   If concurrent use with dasatinib and a strong inhibitor of CYP3A4 is|
03652|035|M|warranted, consider decreasing the dose of dasatinib to 20 mg daily in|
03652|036|M|patients taking dasatinib 70 mg daily, 20 mg daily in patients taking|
03652|037|M|dasatinib 100 mg daily, and to 40 mg daily in patients taking dasatinib 140|
03652|038|M|mg daily.  If this dose is not tolerated, either the strong CYP3A4 inhibitor|
03652|039|M|must be discontinued or dasatinib should be stopped until therapy with the|
03652|040|M|CYP3A4 inhibitor has been completed.  When the CYP3A4 inhibitor has been|
03652|041|M|discontinued, a one-week washout period should be allowed before the dosage|
03652|042|M|of dasatinib is increased.  For patients taking 60 mg or 40 mg daily,|
03652|043|M|consider interrupting dasatinib until the inhibitor is discontinued.  Allow|
03652|044|M|a washout period of approximately one week after the inhibitor is stopped|
03652|045|M|before reinitiating dasatinib.(1)|
03652|046|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03652|047|M|dasatinib should be monitored for prolongation of the QTc interval.  When|
03652|048|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03652|049|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03652|050|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03652|051|M|report any irregular heartbeat, dizziness, or fainting.|
03652|052|B||
03652|053|D|DISCUSSION:  In a study in healthy subjects, concurrent ketoconazole (200 mg|
03652|054|D|twice daily) with dasatinib (20 mg) increased dasatinib maximum|
03652|055|D|concentration (Cmax) and area-under-curve (AUC) by 4-fold and 5-fold,|
03652|056|D|respectively.  Recommended dosage adjustments are expected to adjust the|
03652|057|D|dasatinib AUC to ranges observed without CYP3A4 inhibitors; however, there|
03652|058|D|are no clinical data available.(1)|
03652|059|D|   A retrospective review of 618 cancer patients treated with 902|
03652|060|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03652|061|D|incidence of QTc prolongation.  In patients who received dasatinib, QTc|
03652|062|D|prolongation was identified in 48 patients(41.7%) with 8 (16.7%) having|
03652|063|D|Grade 1 and 15 (31.3%) having Grade 2.  Grade 3 events occurred in 8 (16.7%)|
03652|064|D|having QTc greater than or equal to 500 ms and 14 (29.2%) having QTc change|
03652|065|D|greater than or equal to 60 ms.  VT was seen in 2 (4.2%) of patients and 1|
03652|066|D|(2.1%) patient experienced TdP.(3)|
03652|067|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, idelalisib,|
03652|068|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03652|069|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, telaprevir, tipranavir,|
03652|070|D|troleandomycin, or tucatinib.(4,5)|
03652|071|B||
03652|072|R|REFERENCES:|
03652|073|B||
03652|074|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
03652|075|R|  Company February, 2023.|1
03652|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03652|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03652|078|R|  settings: a scientific statement from the American Heart Association and|6
03652|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03652|080|R|  2;55(9):934-47.|6
03652|081|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03652|082|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03652|083|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03652|084|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03652|085|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03652|086|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03652|087|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03652|088|R|  11/14/2017.|1
03652|089|R|5.This information is based on an extract from the Certara Drug Interaction|6
03652|090|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03653|001|T|MONOGRAPH TITLE:  Dasatinib/Strong CYP3A4 Inhibitors that Prolong QT|
03653|002|B||
03653|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03653|004|L|of severe adverse interaction.|
03653|005|B||
03653|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03653|007|A|interval may inhibit the metabolism of dasatinib and result in additive risk|
03653|008|A|of QT prolongation.(1)|
03653|009|B||
03653|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03653|011|E|prolong QT may result in elevated levels of and toxicity from dasatinib,|
03653|012|E|including additive QTc prolongation, which may result in potentially|
03653|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03653|014|E|(TdP).(1)|
03653|015|E|   Other toxicities include myelosuppression, serious hemorrhages, fluid|
03653|016|E|retention, pulmonary hypertension, cardiac ischemia, transient ischemic|
03653|017|E|attacks, and severe dermatological reactions.(1)|
03653|018|B||
03653|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03653|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03653|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03653|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03653|023|P|female gender, or advanced age.(2)|
03653|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03653|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03653|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03653|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03653|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03653|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03653|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03653|031|B||
03653|032|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors that prolong|
03653|033|M|QT in patients undergoing therapy with dasatinib.(1)  Consider alternatives|
03653|034|M|with no or minimal enzyme inhibition and with no effect on the QTc interval.|
03653|035|M|   If concurrent use with dasatinib and a strong inhibitor of CYP3A4 is|
03653|036|M|warranted, consider decreasing the dose of dasatinib to 20 mg daily in|
03653|037|M|patients taking dasatinib 70 mg daily, 20 mg daily in patients taking|
03653|038|M|dasatinib 100 mg daily, and to 40 mg daily in patients taking dasatinib 140|
03653|039|M|mg daily.  If this dose is not tolerated, either the strong CYP3A4 inhibitor|
03653|040|M|must be discontinued or dasatinib should be stopped until therapy with the|
03653|041|M|CYP3A4 inhibitor has been completed.  When the CYP3A4 inhibitor has been|
03653|042|M|discontinued, a one-week washout period should be allowed before the dosage|
03653|043|M|of dasatinib is increased.  For patients taking 60 mg or 40 mg daily,|
03653|044|M|consider interrupting dasatinib until the inhibitor is discontinued.  Allow|
03653|045|M|a washout period of approximately one week after the inhibitor is stopped|
03653|046|M|before reinitiating dasatinib.(1)|
03653|047|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03653|048|M|dasatinib should be monitored for prolongation of the QTc interval.  When|
03653|049|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03653|050|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03653|051|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03653|052|M|report any irregular heartbeat, dizziness, or fainting.|
03653|053|B||
03653|054|D|DISCUSSION:  In a study in healthy subjects, concurrent ketoconazole (200 mg|
03653|055|D|twice daily) with dasatinib (20 mg) increased dasatinib maximum|
03653|056|D|concentration (Cmax) and area-under-curve (AUC) by 4-fold and 5-fold,|
03653|057|D|respectively.  Recommended dosage adjustments are expected to adjust the|
03653|058|D|dasatinib AUC to ranges observed without CYP3A4 inhibitors; however, there|
03653|059|D|are no clinical data available.(1)|
03653|060|D|   A retrospective review of 618 cancer patients treated with 902|
03653|061|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03653|062|D|incidence of QTc prolongation.  In patients who received dasatinib, QTc|
03653|063|D|prolongation was identified in 48 patients(41.7%) with 8 patients(16.7%)|
03653|064|D|having Grade 1 and 15 patients(31.3%) having Grade 2 events.  Grade 3 events|
03653|065|D|occurred in 8 patients(16.7%) having QTc greater than or equal to 500 ms and|
03653|066|D|14 patients (29.2%) having QTc change greater than or equal to 60 ms.  VT|
03653|067|D|was seen in 2 (4.2%) patients and 1 (2.1%) patient experienced TdP.(3)|
03653|068|D|   Agents that are linked to this monograph may have varying degrees of|
03653|069|D|potential to prolong the QTc interval but are generally accepted to have a|
03653|070|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03653|071|D|been shown to prolong the QTc interval either through their mechanism of|
03653|072|D|action, through studies on their effects on the QTc interval, or through|
03653|073|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03653|074|D|and/or post-marketing reports.(4)|
03653|075|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
03653|076|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
03653|077|D|posaconazole, ribociclib, telithromycin, and voriconazole.(5,6)|
03653|078|B||
03653|079|R|REFERENCES:|
03653|080|B||
03653|081|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
03653|082|R|  Company February, 2023.|1
03653|083|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03653|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03653|085|R|  settings: a scientific statement from the American Heart Association and|6
03653|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03653|087|R|  2;55(9):934-47.|6
03653|088|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03653|089|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03653|090|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03653|091|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03653|092|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03653|093|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03653|094|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03653|095|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03653|096|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03653|097|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03653|098|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03653|099|R|  11/14/2017.|1
03653|100|R|6.This information is based on an extract from the Certara Drug Interaction|6
03653|101|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03654|001|T|MONOGRAPH TITLE:  Lapatinib/Strong CYP3A4 Inhibitors|
03654|002|B||
03654|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03654|004|L|of severe adverse interaction.|
03654|005|B||
03654|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03654|007|A|the metabolism of lapatinib.(1)|
03654|008|B||
03654|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03654|010|E|levels of and effects from lapatinib.(1)|
03654|011|E|    Elevated levels of lapatinib may result in QTc prolongation, which may|
03654|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03654|013|E|torsades de pointes (TdP).  Other toxicities include severe diarrhea,|
03654|014|E|cardiotoxicity, hepatotoxicity, interstitial lung disease, and severe|
03654|015|E|dermatological reactions.(1)|
03654|016|B||
03654|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03654|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03654|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03654|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03654|021|P|female gender, or advanced age.(2)|
03654|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03654|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03654|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03654|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03654|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03654|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03654|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03654|029|B||
03654|030|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03654|031|M|undergoing therapy with lapatinib.(1)  Consider alternatives with no or|
03654|032|M|minimal enzyme inhibition.|
03654|033|M|   If concurrent use with lapatinib is warranted, a dose reduction to 500|
03654|034|M|mg/day should be considered.  If the 3A4 inhibitor is discontinued, at least|
03654|035|M|1 week should elapse before the lapatinib dose is adjusted upward.(1)|
03654|036|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03654|037|M|lapatinib should be monitored for prolongation of the QTc interval.  When|
03654|038|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03654|039|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03654|040|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03654|041|M|report any irregular heartbeat, dizziness, or fainting.|
03654|042|B||
03654|043|D|DISCUSSION:  In a study in healthy subjects, ketoconazole (200 mg twice|
03654|044|D|daily for 7 days) increased lapatinib area-under-curve (AUC) and half-life|
03654|045|D|(T1/2) by 3.6-fold and 1.7-fold, respectively.  The dosage adjustment to 500|
03654|046|D|mg/day is based on pharmacokinetic studies and is predicted to adjust|
03654|047|D|lapatinib AUC to the range observed without inhibitors; however, there are|
03654|048|D|no clinical data with this dosage adjustment in patients receiving strong|
03654|049|D|CYP3A4 inhibitors.(1)|
03654|050|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
03654|051|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03654|052|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03654|053|D|tipranavir, troleandomycin, and tucatinib.(3,4)|
03654|054|B||
03654|055|R|REFERENCES:|
03654|056|B||
03654|057|R|1.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
03654|058|R|  2018.|1
03654|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03654|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03654|061|R|  settings: a scientific statement from the American Heart Association and|6
03654|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03654|063|R|  2;55(9):934-47.|6
03654|064|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03654|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03654|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03654|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03654|068|R|  11/14/2017.|1
03654|069|R|4.This information is based on an extract from the Certara Drug Interaction|6
03654|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03655|001|T|MONOGRAPH TITLE:  Lapatinib/Strong CYP3A4 Inhibitors that Prolong QT|
03655|002|B||
03655|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03655|004|L|of severe adverse interaction.|
03655|005|B||
03655|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03655|007|A|interval may inhibit the metabolism of lapatinib and result in additive risk|
03655|008|A|of QT prolongation.(1)|
03655|009|B||
03655|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03655|011|E|prolong QT may result in elevated levels of and toxicity from dasatinib,|
03655|012|E|including additive QTc prolongation, which may result in potentially|
03655|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03655|014|E|(TdP).(1)|
03655|015|E|   Other toxicities include severe diarrhea, cardiotoxicity, hepatotoxicity,|
03655|016|E|interstitial lung disease, and severe dermatological reactions.(1)|
03655|017|B||
03655|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03655|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03655|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03655|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03655|022|P|female gender, or advanced age.(2)|
03655|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03655|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03655|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03655|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03655|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03655|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03655|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03655|030|B||
03655|031|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03655|032|M|undergoing therapy with lapatinib.(1)  Consider alternatives with no or|
03655|033|M|minimal enzyme inhibition and with no effect on the QTc interval.|
03655|034|M|   If concurrent use with lapatinib is warranted, a dose reduction to 500|
03655|035|M|mg/day should be considered.  If the 3A4 inhibitor is discontinued, at least|
03655|036|M|1 week should elapse before the lapatinib dose is adjusted upward.(1)|
03655|037|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03655|038|M|lapatinib should be monitored for prolongation of the QTc interval.  When|
03655|039|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03655|040|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03655|041|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03655|042|M|report any irregular heartbeat, dizziness, or fainting.|
03655|043|B||
03655|044|D|DISCUSSION:  In a study in healthy subjects, ketoconazole (200 mg twice|
03655|045|D|daily for 7 days) increased lapatinib area-under-curve (AUC) and half-life|
03655|046|D|(T1/2) by 3.6-fold and 1.7-fold, respectively.  The dosage adjustment to 500|
03655|047|D|mg/day is based on pharmacokinetic studies and is predicted to adjust|
03655|048|D|lapatinib AUC to the range observed without inhibitors; however, there are|
03655|049|D|no clinical data with this dosage adjustment in patients receiving strong|
03655|050|D|CYP3A4 inhibitors.(1)|
03655|051|D|   Agents that are linked to this monograph may have varying degrees of|
03655|052|D|potential to prolong the QTc interval but are generally accepted to have a|
03655|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03655|054|D|been shown to prolong the QTc interval either through their mechanism of|
03655|055|D|action, through studies on their effects on the QTc interval, or through|
03655|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03655|057|D|and/or post-marketing reports.(3)|
03655|058|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
03655|059|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
03655|060|D|posaconazole, ribociclib, telithromycin, and voriconazole.(4,5)|
03655|061|B||
03655|062|R|REFERENCES:|
03655|063|B||
03655|064|R|1.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
03655|065|R|  2018.|1
03655|066|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03655|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03655|068|R|  settings: a scientific statement from the American Heart Association and|6
03655|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03655|070|R|  2;55(9):934-47.|6
03655|071|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03655|072|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03655|073|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03655|074|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03655|075|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03655|076|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03655|077|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03655|078|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03655|079|R|  11/14/2017.|1
03655|080|R|5.This information is based on an extract from the Certara Drug Interaction|6
03655|081|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03656|001|T|MONOGRAPH TITLE:  Lapatinib/Lonafarnib (mono deleted 05/28/2024)|
03656|002|B||
03656|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03656|004|L|of severe adverse interaction.|
03656|005|B||
03656|006|A|MECHANISM OF ACTION:  Lapatinib and lonafarnib are both inhibitors as well|
03656|007|A|as substrates of CYP3A4.(1,2)|
03656|008|B||
03656|009|E|CLINICAL EFFECTS:  Concurrent use of lapatinib and lonafarnib may result in|
03656|010|E|elevated levels of and toxicity from both agents.  The magnitude of effect|
03656|011|E|of the two-way inhibition of the metabolism of lapatinib and lonafarnib is|
03656|012|E|unknown.|
03656|013|E|   Potential toxicities include: QTc prolongation, which may result in|
03656|014|E|potentially life-threatening cardiac arrhythmias including torsades de|
03656|015|E|pointes (TdP), nausea, vomiting, severe diarrhea, hypertension,|
03656|016|E|cardiotoxicity, hepatotoxicity, myelosuppression, interstitial lung disease,|
03656|017|E|and severe dermatological reactions.(1,2)|
03656|018|B||
03656|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03656|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03656|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03656|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03656|023|P|female gender, or advanced age.(2)|
03656|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03656|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03656|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03656|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03656|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03656|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03656|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03656|031|B||
03656|032|M|PATIENT MANAGEMENT:  Avoid the concurrent use of lapatinib and|
03656|033|M|lonafarnib.(1,2)  Consider alternatives with no or minimal enzyme inhibition|
03656|034|M|and with no effect on the QTc interval.|
03656|035|M|   The magnitude of effect of the two-way inhibition of the metabolism of|
03656|036|M|lapatinib and lonafarnib is unknown.  The optimal doses of lapatinib and|
03656|037|M|lonafarnib when used concurrently have not been determined.  Manufacturers|
03656|038|M|provide recommendations for dose modification of lapatinib and lonafarnib|
03656|039|M|when each is used with a CYP3A4 inhibitor, but the recommendations may not|
03656|040|M|apply when there is a two-way inhibition.  Dose modifications mentioned|
03656|041|M|below are informational only.|
03656|042|M|   If concurrent use of a strong CYP3A4 inhibitor with lapatinib is|
03656|043|M|warranted, a dose reduction to 500 mg/day should be considered.  If the 3A4|
03656|044|M|inhibitor is discontinued, at least 1 week should elapse before the|
03656|045|M|lapatinib dose is adjusted upward.(1)|
03656|046|M|   If coadministration of a weak CYP3A4 inhibitor with lonafarnib is|
03656|047|M|unavoidable, reduce the dose of lonafarnib to or continue at 115 mg/m2.(2)|
03656|048|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03656|049|M|heart palpitations because lonafarnib exposures may be increased despite the|
03656|050|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03656|051|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03656|052|M|inhibitor.(2)|
03656|053|M|   Patients receiving concurrent therapy with lapatinib and lonafarnib|
03656|054|M|should be monitored for prolongation of the QTc interval.  When concurrent|
03656|055|M|therapy is warranted: consider obtaining serum calcium, magnesium, and|
03656|056|M|potassium levels and monitoring EKG at baseline and regular intervals.|
03656|057|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03656|058|M|irregular heartbeat, dizziness, or fainting.|
03656|059|B||
03656|060|D|DISCUSSION:  The magnitude of effect of the two-way inhibition of the|
03656|061|D|metabolism of lapatinib and lonafarnib is unknown.|
03656|062|D|   In a study in healthy subjects, ketoconazole (200 mg twice daily for 7|
03656|063|D|days) increased lapatinib the area-under-curve (AUC) and half-life (T1/2) by|
03656|064|D|3.6-fold and 1.7-fold, respectively.  The dosage adjustment to 500 mg/day is|
03656|065|D|based on pharmacokinetic studies and is predicted to adjust lapatinib AUC to|
03656|066|D|the range observed without inhibitors; however, there are no clinical data|
03656|067|D|with this dosage adjustment in patients receiving strong CYP3A4|
03656|068|D|inhibitors.(1)|
03656|069|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03656|070|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, AUC|
03656|071|D|and maximum concentration (Cmax) were increased by 425% and 270%,|
03656|072|D|respectively.(2)|
03656|073|B||
03656|074|R|REFERENCES:|
03656|075|B||
03656|076|R|1.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
03656|077|R|  2018.|1
03656|078|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03656|079|R|  Inc. November, 2020.|1
03656|080|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03656|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03656|082|R|  settings: a scientific statement from the American Heart Association and|6
03656|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03656|084|R|  2;55(9):934-47.|6
03656|085|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03656|086|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03656|087|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03656|088|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03656|089|R|  11/14/2017.|1
03656|090|R|5.This information is based on an extract from the Certara Drug Interaction|6
03656|091|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03657|001|T|MONOGRAPH TITLE:  Nilotinib/Strong CYP3A4 Inhibitors|
03657|002|B||
03657|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03657|004|L|of severe adverse interaction.|
03657|005|B||
03657|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03657|007|A|the metabolism of nilotinib.(1-2)|
03657|008|B||
03657|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03657|010|E|levels of and effects from nilotinib.(1-2)|
03657|011|E|    Elevated levels of nilotinib may result in QTc prolongation, which may|
03657|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03657|013|E|torsades de pointes (TdP).  Other toxicities include myelosuppression,|
03657|014|E|severe hemorrhage, vascular occlusive events, hepatotoxicity, pancreatitis,|
03657|015|E|and fluid retention.(1-2)|
03657|016|B||
03657|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03657|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03657|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03657|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03657|021|P|female gender, or advanced age.(3)|
03657|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03657|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03657|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03657|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03657|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03657|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03657|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03657|029|B||
03657|030|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03657|031|M|undergoing therapy with nilotinib.(1-2)  Consider alternatives with no or|
03657|032|M|minimal enzyme inhibition.|
03657|033|M|   Consider interrupting nilotinib therapy if a strong CYP3A4 inhibitor is|
03657|034|M|needed.  If concurrent use is warranted with nilotinib hydrochloride, a dose|
03657|035|M|reduction to 300 mg once daily in patients with resistant or intolerant|
03657|036|M|Ph+CML or to 200 mg once daily in patients with newly diagnosed Ph+CML-CP|
03657|037|M|should be considered.(1)|
03657|038|M|   If concurrent use is warranted with nilotinib tartrate, a dose reduction|
03657|039|M|to 142 mg once daily in patients with resistant or intolerant Ph+CML or to|
03657|040|M|95 mg once daily in patients with newly diagnosed Ph+CML-CP should be|
03657|041|M|considered.(2)|
03657|042|M|   If the 3A4 inhibitor is discontinued, a washout period should occur|
03657|043|M|before the nilotinib dose is adjusted upward.(1-2)|
03657|044|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03657|045|M|nilotinib should be monitored for prolongation of the QTc interval.  When|
03657|046|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03657|047|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03657|048|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03657|049|M|report any irregular heartbeat, dizziness, or fainting.|
03657|050|B||
03657|051|D|DISCUSSION:  In a study in healthy subjects, concurrent ketoconazole (400 mg|
03657|052|D|daily) increased nilotinib area-under-curve (AUC) by 3-fold.(1)|
03657|053|D|   A retrospective review of 618 cancer patients treated with 902|
03657|054|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03657|055|D|incidence of QTc prolongation.  In patients who received nilotinib, QTc|
03657|056|D|prolongation was identified in 29 patients (38.7%) with 1 (3.5%) having|
03657|057|D|Grade 1 and 2 (7%) having Grade 2.  Grade 3 events occurred in 9 (31%)|
03657|058|D|having QTc greater than or equal to 500 ms and 17 (58.6%) having QTc change|
03657|059|D|greater than or equal to 60 ms.  No patients developed VT, SCD, or TdP.(4)|
03657|060|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, grapefruit,|
03657|061|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
03657|062|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
03657|063|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(5,6)|
03657|064|B||
03657|065|R|REFERENCES:|
03657|066|B||
03657|067|R|1.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
03657|068|R|  Corporation September, 2021.|1
03657|069|R|2.Danziten (nilotinib tartrate) US prescribing information. Novartis|1
03657|070|R|  Pharmaceuticals November 2024.|1
03657|071|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03657|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03657|073|R|  settings: a scientific statement from the American Heart Association and|6
03657|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03657|075|R|  2;55(9):934-47.|6
03657|076|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03657|077|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03657|078|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03657|079|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03657|080|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03657|081|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03657|082|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03657|083|R|  11/14/2017.|1
03657|084|R|6.This information is based on an extract from the Certara Drug Interaction|6
03657|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03657|086|R|7.Tasigna (nilotinib) UK prescribing information. Novartis Pharmaceuticals|1
03657|087|R|  Corporation November, 2020.|1
03658|001|T|MONOGRAPH TITLE:  Nilotinib/Strong CYP3A4 Inhibitors that Prolong QT|
03658|002|B||
03658|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03658|004|L|of severe adverse interaction.|
03658|005|B||
03658|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03658|007|A|the metabolism of nilotinib.(1-2)|
03658|008|B||
03658|009|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03658|010|E|prolong QT may result in elevated levels of and toxicity from nilotinib,|
03658|011|E|including additive QTc prolongation, which may result in potentially|
03658|012|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03658|013|E|(TdP).(1-2)|
03658|014|E|   Other toxicities include myelosuppression, severe hemorrhage, vascular|
03658|015|E|occlusive events, hepatotoxicity, pancreatitis, and fluid retention.(1-2)|
03658|016|B||
03658|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03658|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03658|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03658|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03658|021|P|female gender, or advanced age.(3)|
03658|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03658|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03658|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03658|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03658|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03658|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03658|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03658|029|B||
03658|030|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors that prolong|
03658|031|M|QT in patients undergoing therapy with nilotinib.(1)  Consider alternatives|
03658|032|M|with no or minimal enzyme inhibition and with no effect on the QTc interval.|
03658|033|M|   Consider interrupting nilotinib therapy if a strong CYP3A4 inhibitor is|
03658|034|M|needed.  If concurrent use is warranted with nilotinib hydrochloride, a dose|
03658|035|M|reduction to 300 mg once daily in patients with resistant or intolerant|
03658|036|M|Ph+CML or to 200 mg once daily in patients with newly diagnosed Ph+CML-CP|
03658|037|M|should be considered.(1)|
03658|038|M|   If concurrent use is warranted with nilotinib tartrate, a dose reduction|
03658|039|M|to 142 mg once daily in patients with resistant or intolerant Ph+CML or to|
03658|040|M|95 mg once daily in patients with newly diagnosed Ph+CML-CP should be|
03658|041|M|considered.(2)|
03658|042|M|   If the 3A4 inhibitor is discontinued, a washout period should occur|
03658|043|M|before the nilotinib dose is adjusted upward.(1-2)|
03658|044|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03658|045|M|nilotinib should be monitored for prolongation of the QTc interval.  When|
03658|046|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03658|047|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03658|048|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03658|049|M|report any irregular heartbeat, dizziness, or fainting.|
03658|050|B||
03658|051|D|DISCUSSION:  In a study in healthy subjects, concurrent ketoconazole (400 mg|
03658|052|D|daily) increased nilotinib area-under-curve (AUC) by 3-fold.(1-2)|
03658|053|D|   A retrospective review of 618 cancer patients treated with 902|
03658|054|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03658|055|D|incidence of QTc prolongation.  In patients who received nilotinib, QTc|
03658|056|D|prolongation was identified in 29 patients (38.7%) with 1 patient(3.5%)|
03658|057|D|having Grade 1 and 2 patients(7%) having Grade 2 events.  Grade 3 events|
03658|058|D|occurred in 9 patients (31%) having QTc greater than or equal to 500 ms and|
03658|059|D|17 patients(58.6%) having QTc change greater than or equal to 60 ms.  No|
03658|060|D|patients developed VT, SCD, or TdP.(4)|
03658|061|D|   Agents that are linked to this monograph may have varying degrees of|
03658|062|D|potential to prolong the QTc interval but are generally accepted to have a|
03658|063|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03658|064|D|been shown to prolong the QTc interval either through their mechanism of|
03658|065|D|action, through studies on their effects on the QTc interval, or through|
03658|066|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03658|067|D|and/or post-marketing reports.(5)|
03658|068|D|   Strong inhibitors of CYP3A4 that prolong QT include:  adagrasib,|
03658|069|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
03658|070|D|posaconazole, ribociclib, telithromycin, and voriconazole.(6,7)|
03658|071|B||
03658|072|R|REFERENCES:|
03658|073|B||
03658|074|R|1.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
03658|075|R|  Corporation September, 2021.|1
03658|076|R|2.Danziten (nilotinib tartrate) US prescribing information. Novartis|1
03658|077|R|  Pharmaceuticals November 2024.|1
03658|078|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03658|079|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03658|080|R|  settings: a scientific statement from the American Heart Association and|6
03658|081|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03658|082|R|  2;55(9):934-47.|6
03658|083|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03658|084|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03658|085|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03658|086|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03658|087|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03658|088|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03658|089|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03658|090|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
03658|091|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03658|092|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03658|093|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03658|094|R|  11/14/2017.|1
03658|095|R|7.This information is based on an extract from the Certara Drug Interaction|6
03658|096|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03659|001|T|MONOGRAPH TITLE:  Pazopanib/Strong CYP3A4 Inhibitors|
03659|002|B||
03659|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03659|004|L|of severe adverse interaction.|
03659|005|B||
03659|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03659|007|A|the metabolism of pazopanib.(1)|
03659|008|B||
03659|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03659|010|E|levels of and effects from pazopanib.(1)|
03659|011|E|    Elevated levels of pazopanib may result in QTc prolongation, which may|
03659|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03659|013|E|torsades de pointes (TdP).  Other toxicities include hepatotoxicity, cardiac|
03659|014|E|dysfunction, serious hemorrhage, arterial and venous thrombosis, thrombotic|
03659|015|E|microangiopathy, gastrointestinal perforation and fistula, hypertension,|
03659|016|E|hypothyroidism, interstitial lung disease, and proteinuria.(1)|
03659|017|B||
03659|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03659|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03659|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03659|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03659|022|P|female gender, or advanced age.(2)|
03659|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03659|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03659|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03659|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03659|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03659|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03659|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03659|030|B||
03659|031|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03659|032|M|undergoing therapy with pazopanib.(1)  Consider alternatives with no or|
03659|033|M|minimal enzyme inhibition.|
03659|034|M|   If concurrent administration with pazopanib is warranted, the dosage of|
03659|035|M|pazopanib should be reduced to 400 mg.  Additional dosage reductions may be|
03659|036|M|required if adverse events occur.(1)|
03659|037|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03659|038|M|pazopanib should be monitored for prolongation of the QTc interval.  When|
03659|039|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03659|040|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03659|041|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03659|042|M|report any irregular heartbeat, dizziness, or fainting.|
03659|043|B||
03659|044|D|DISCUSSION:  Administration of multiple doses of oral pazopanib (400 mg)|
03659|045|D|with multiple doses of oral ketoconazole (400 mg) increased the|
03659|046|D|area-under-curve (AUC) and maximum concentration (Cmax) of pazopanib by|
03659|047|D|1.7-fold and 1.5-fold, respectively.  Administration of a single dose of|
03659|048|D|pazopanib ophthalmic drops and ketoconazole, an inhibitor of CYP3A4 and|
03659|049|D|P-gp, increased the AUC and Cmax of pazopanib by 220% and 150%,|
03659|050|D|respectively.  Administration of lapatinib (1500 mg), a weak inhibitor of|
03659|051|D|CYP3A4, P-gp, and BCRP, increased the AUC and Cmax of pazopanib (800 mg) by|
03659|052|D|50% and 60%, respectively.  Decreasing the dosage of pazopanib to 400 mg in|
03659|053|D|patients receiving strong CYP3A4 inhibitors is expected to adjust the AUC of|
03659|054|D|pazopanib to the normal range; however, there are no clinical data available|
03659|055|D|to support this.(1)|
03659|056|D|   A retrospective review of 618 cancer patients treated with 902|
03659|057|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03659|058|D|incidence of QTc prolongation.  In patients who received pazopanib, QTc|
03659|059|D|prolongation was identified in 32 patients (19.4%) with 18 patients (56.3%)|
03659|060|D|having Grade 1 and 4 patients (12.5%) having Grade 2 events.  Grade 3 events|
03659|061|D|occurred in 3 patients (9.3%) having QTc greater than or equal to 500 ms and|
03659|062|D|4 patients (12.5%) having QTc change greater than or equal to 60 ms.  VT was|
03659|063|D|seen in 2 (6.3%) patients and 1 (3.1%) patient experienced SCD.(3)|
03659|064|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, grapefruit,|
03659|065|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
03659|066|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
03659|067|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(4,5)|
03659|068|B||
03659|069|R|REFERENCES:|
03659|070|B||
03659|071|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03659|072|R|  2020.|1
03659|073|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03659|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03659|075|R|  settings: a scientific statement from the American Heart Association and|6
03659|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03659|077|R|  2;55(9):934-47.|6
03659|078|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03659|079|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03659|080|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03659|081|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03659|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03659|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03659|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03659|085|R|  11/14/2017.|1
03659|086|R|5.This information is based on an extract from the Certara Drug Interaction|6
03659|087|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03660|001|T|MONOGRAPH TITLE:  Pazopanib/Strong CYP3A4 Inhibitors that Prolong QT|
03660|002|B||
03660|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03660|004|L|of severe adverse interaction.|
03660|005|B||
03660|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03660|007|A|interval may inhibit the metabolism of pazopanib and result in additive risk|
03660|008|A|of QT prolongation.(1)|
03660|009|B||
03660|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03660|011|E|prolong QT may result in elevated levels of and toxicity from pazopanib,|
03660|012|E|including additive QTc prolongation, which may result in potentially|
03660|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03660|014|E|(TdP).(1)|
03660|015|E|   Other toxicities include hepatotoxicity, cardiac dysfunction, serious|
03660|016|E|hemorrhage, arterial and venous thrombosis, thrombotic microangiopathy,|
03660|017|E|gastrointestinal perforation and fistula, hypertension, hypothyroidism,|
03660|018|E|interstitial lung disease, and proteinuria.(1)|
03660|019|B||
03660|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03660|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
03660|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03660|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03660|024|P|female gender, or advanced age.(2)|
03660|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03660|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03660|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03660|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03660|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03660|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03660|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03660|032|B||
03660|033|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03660|034|M|undergoing therapy with pazopanib.(1)  Consider alternatives with no or|
03660|035|M|minimal enzyme inhibition.|
03660|036|M|   If concurrent administration with pazopanib is warranted, the dosage of|
03660|037|M|pazopanib should be reduced to 400 mg.  Additional dosage reductions may be|
03660|038|M|required if adverse events occur.(1)|
03660|039|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03660|040|M|pazopanib should be monitored for prolongation of the QTc interval.  When|
03660|041|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03660|042|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03660|043|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03660|044|M|report any irregular heartbeat, dizziness, or fainting.|
03660|045|B||
03660|046|D|DISCUSSION:  Administration of multiple doses of oral pazopanib (400 mg)|
03660|047|D|with multiple doses of oral ketoconazole (400 mg) increased the|
03660|048|D|area-under-curve (AUC) and maximum concentration (Cmax) of pazopanib by|
03660|049|D|1.7-fold and 1.5-fold, respectively.  Administration of a single dose of|
03660|050|D|pazopanib ophthalmic drops and ketoconazole, an inhibitor of CYP3A4 and|
03660|051|D|P-gp, increased the AUC and Cmax of pazopanib by 220% and 150%,|
03660|052|D|respectively.  Administration of lapatinib (1500 mg), a weak inhibitor of|
03660|053|D|CYP3A4, P-gp, and BCRP, increased the AUC and Cmax of pazopanib (800 mg) by|
03660|054|D|50% and 60%, respectively.  Decreasing the dosage of pazopanib to 400 mg in|
03660|055|D|patients receiving strong CYP3A4 inhibitors is expected to adjust the AUC of|
03660|056|D|pazopanib to the normal range; however, there are no clinical data available|
03660|057|D|to support this.(1)|
03660|058|D|   A retrospective review of 618 cancer patients treated with 902|
03660|059|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03660|060|D|incidence of QTc prolongation.  In patients who received pazopanib, QTc|
03660|061|D|prolongation was identified in 32 patients (19.4%) with 18 patients (56.3%)|
03660|062|D|having Grade 1 and 4 patients (12.5%) having Grade 2 events.  Grade 3 events|
03660|063|D|occurred in 3 patients (9.3%) having QTc greater than or equal to 500 ms and|
03660|064|D|4 patients (12.5%) having QTc change greater than or equal to 60 ms.  VT was|
03660|065|D|seen in 2 (6.3%) patients and 1 (3.1%) patient experienced SCD.(3)|
03660|066|D|   Agents that are linked to this monograph may have varying degrees of|
03660|067|D|potential to prolong the QTc interval but are generally accepted to have a|
03660|068|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03660|069|D|been shown to prolong the QTc interval either through their mechanism of|
03660|070|D|action, through studies on their effects on the QTc interval, or through|
03660|071|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03660|072|D|and/or post-marketing reports.(4)|
03660|073|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
03660|074|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
03660|075|D|posaconazole, ribociclib, telithromycin, and voriconazole.(5,6)|
03660|076|B||
03660|077|R|REFERENCES:|
03660|078|B||
03660|079|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03660|080|R|  2020.|1
03660|081|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03660|082|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03660|083|R|  settings: a scientific statement from the American Heart Association and|6
03660|084|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03660|085|R|  2;55(9):934-47.|6
03660|086|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03660|087|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03660|088|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03660|089|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03660|090|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03660|091|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03660|092|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03660|093|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03660|094|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03660|095|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03660|096|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03660|097|R|  11/14/2017.|1
03660|098|R|6.This information is based on an extract from the Certara Drug Interaction|6
03660|099|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03661|001|T|MONOGRAPH TITLE:  Pazopanib/Lonafarnib (mono deleted 05/28/2024)|
03661|002|B||
03661|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03661|004|L|of severe adverse interaction.|
03661|005|B||
03661|006|A|MECHANISM OF ACTION:  Pazopanib and lonafarnib are both inhibitors as well|
03661|007|A|as substrates of CYP3A4.(1,2)|
03661|008|A|   Lonafarnib is an inhibitor of P-glycoprotein (P-gp).(2)  Pazopanib is a|
03661|009|A|substrate of P-gp.(1)|
03661|010|B||
03661|011|E|CLINICAL EFFECTS:  Concurrent use of pazopanib and lonafarnib may result in|
03661|012|E|elevated levels of and toxicity from both agents.  The magnitude of effect|
03661|013|E|of the two-way inhibition of the metabolism of pazopanib and lonafarnib is|
03661|014|E|unknown.|
03661|015|E|   Potential toxicities include: QTc prolongation, which may result in|
03661|016|E|potentially life-threatening cardiac arrhythmias including torsades de|
03661|017|E|pointes (TdP), myelosuppression, hepatotoxicity, hypertension, cardiac|
03661|018|E|dysfunction, serious hemorrhage, arterial and venous thrombosis, thrombotic|
03661|019|E|microangiopathy, gastrointestinal perforation and fistula, hypothyroidism,|
03661|020|E|interstitial lung disease, and proteinuria.(1)|
03661|021|B||
03661|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03661|023|P|may be increased in patients with cardiovascular disease (e.g. heart|
03661|024|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03661|025|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03661|026|P|female gender, or advanced age.(3)|
03661|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03661|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03661|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03661|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03661|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03661|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03661|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03661|034|B||
03661|035|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pazopanib and|
03661|036|M|lonafarnib.(1,2)  Consider alternatives with no or minimal enzyme or|
03661|037|M|transporter inhibition and with no effect on the QTc interval.|
03661|038|M|   The magnitude of effect of the two-way inhibition of the metabolism of|
03661|039|M|pazopanib and lonafarnib is unknown.  The optimal doses of pazopanib and|
03661|040|M|lonafarnib when used concurrently have not been determined.  Manufacturers|
03661|041|M|provide recommendations for dose modification of pazopanib and lonafarnib|
03661|042|M|when each is used with a CYP3A4 inhibitor, but the recommendations may not|
03661|043|M|apply when there is a two-way inhibition.  Dose modifications mentioned|
03661|044|M|below are informational only.|
03661|045|M|   If concurrent administration of a strong CYP3A4 inhibitor with pazopanib|
03661|046|M|is warranted, the dosage of pazopanib should be reduced to 400 mg.|
03661|047|M|Additional dosage reductions may be required if adverse events occur.(1)|
03661|048|M|   If coadministration of a weak CYP3A4 inhibitor with lonafarnib is|
03661|049|M|unavoidable, reduce the dose of lonafarnib to or continue at 115 mg/m2.(2)|
03661|050|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03661|051|M|heart palpitations because lonafarnib exposures may be increased despite the|
03661|052|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03661|053|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03661|054|M|inhibitor.(2)|
03661|055|M|   Patients receiving concurrent therapy with pazopanib and lonafarnib|
03661|056|M|should be monitored for prolongation of the QTc interval.  When concurrent|
03661|057|M|therapy is warranted: consider obtaining serum calcium, magnesium, and|
03661|058|M|potassium levels and monitoring EKG at baseline and regular intervals.|
03661|059|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03661|060|M|irregular heartbeat, dizziness, or fainting.|
03661|061|B||
03661|062|D|DISCUSSION:  The magnitude of effect of the two-way inhibition of the|
03661|063|D|metabolism of pazopanib and lonafarnib is unknown.|
03661|064|D|   Administration of multiple doses of oral pazopanib (400 mg) with multiple|
03661|065|D|doses of oral ketoconazole (400 mg) increased the area-under-curve (AUC) and|
03661|066|D|maximum concentration (Cmax) of pazopanib by 1.7-fold and 1.5-fold,|
03661|067|D|respectively.  Administration of a single dose of pazopanib ophthalmic drops|
03661|068|D|and ketoconazole, an inhibitor of CYP3A4 and P-gp, increased the AUC and|
03661|069|D|Cmax of pazopanib by 220% and 150%, respectively.  Administration of|
03661|070|D|lapatinib (1500 mg), a weak inhibitor of CYP3A4, P-gp, and BCRP, increased|
03661|071|D|the AUC and Cmax of pazopanib (800 mg) by 50% and 60%, respectively.|
03661|072|D|Decreasing the dosage of pazopanib to 400 mg in patients receiving strong|
03661|073|D|CYP3A4 inhibitors is expected to adjust the AUC of pazopanib to the normal|
03661|074|D|range; however, there are no clinical data available to support this.(7)|
03661|075|D|   A retrospective review of 618 cancer patients treated with 902|
03661|076|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03661|077|D|incidence of QTc prolongation.  In patients who received pazopanib, QTc|
03661|078|D|prolongation was identified in 32 patients (19.4%) with 18 patients (56.3%)|
03661|079|D|having Grade 1 and 4 patients (12.5%) having Grade 2 events.  Grade 3 events|
03661|080|D|occurred in 3 patients (9.3%) having QTc greater than or equal to 500 ms and|
03661|081|D|4 patients (12.5%) having QTc change greater than or equal to 60 ms.  VT was|
03661|082|D|seen in 2 (6.3%) patients and 1 (3.1%) patient experienced SCD.(4)|
03661|083|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03661|084|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, AUC|
03661|085|D|and maximum concentration (Cmax) were increased by 425% and 270%,|
03661|086|D|respectively.(2)|
03661|087|B||
03661|088|R|REFERENCES:|
03661|089|B||
03661|090|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03661|091|R|  2020.|1
03661|092|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03661|093|R|  Inc. November, 2020.|1
03661|094|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03661|095|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03661|096|R|  settings: a scientific statement from the American Heart Association and|6
03661|097|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03661|098|R|  2;55(9):934-47.|6
03661|099|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03661|100|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03661|101|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03661|102|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03661|103|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03661|104|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03661|105|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03661|106|R|  11/14/2017.|1
03661|107|R|6.This information is based on an extract from the Certara Drug Interaction|6
03661|108|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03662|001|T|MONOGRAPH TITLE:  Sunitinib/Strong CYP3A4 Inhibitors|
03662|002|B||
03662|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03662|004|L|of severe adverse interaction.|
03662|005|B||
03662|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03662|007|A|the metabolism of sunitinib.(1)|
03662|008|B||
03662|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03662|010|E|levels of and effects from sunitinib.(1)|
03662|011|E|    Elevated levels of sunitinib may result in QTc prolongation, which may|
03662|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03662|013|E|torsades de pointes (TdP).  Other toxicities include neutropenia,|
03662|014|E|hepatotoxicity, hypertension, cardiotoxicity, hemorrhagic events, thrombotic|
03662|015|E|microangiopathy, proteinuria, severe dermatological reactions, thyroid|
03662|016|E|dysfunction, hypoglycemia, and osteonecrosis of the jaw.(1)|
03662|017|B||
03662|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03662|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03662|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03662|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03662|022|P|female gender, or advanced age.(2)|
03662|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03662|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03662|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03662|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03662|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03662|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03662|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03662|030|B||
03662|031|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03662|032|M|undergoing therapy with sunitinib.(1)  Consider alternatives with no or|
03662|033|M|minimal enzyme inhibition.|
03662|034|M|   If concurrent therapy with sunitinib is warranted, a dosage reduction of|
03662|035|M|sunitinib to a minimum of 37.5 mg daily in patients with gastrointestinal|
03662|036|M|stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a minimum|
03662|037|M|of 25 mg in patients with pancreatic neuroendocrine tumors (pNET) should be|
03662|038|M|considered.  Monitor QT interval more frequently.(1)|
03662|039|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03662|040|M|sunitinib should be monitored for prolongation of the QTc interval.  When|
03662|041|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03662|042|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03662|043|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03662|044|M|report any irregular heartbeat, dizziness, or fainting.|
03662|045|B||
03662|046|D|DISCUSSION:  In a study in healthy subjects, concurrent ketoconazole|
03662|047|D|increased the combined (sunitinib plus primary active metabolite) maximum|
03662|048|D|concentration (Cmax) and area-under-curve (AUC) by 49% and 51%,|
03662|049|D|respectively, of a single dose of sunitinib.(1)|
03662|050|D|   A retrospective review of 618 cancer patients treated with 902|
03662|051|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03662|052|D|incidence of QTc prolongation.  In patients who received sunitinib, QTc|
03662|053|D|prolongation was identified in 26 patients(19.4%) with 16 patients(61.5%)|
03662|054|D|having Grade 1 and 6 patients(23.1%) having Grade 2 events.  Grade 3 events|
03662|055|D|occurred in 1 patient(3.8%) having QTc greater than or equal to 500 ms and 1|
03662|056|D|patient(3.8%) having QTc change greater than or equal to 60 ms.  VT was seen|
03662|057|D|in 1 (3.8%) patient and 1 (3.8%) patient experienced SCD.(3)|
03662|058|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
03662|059|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03662|060|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03662|061|D|tipranavir, troleandomycin, and tucatinib.(4,5)|
03662|062|B||
03662|063|R|REFERENCES:|
03662|064|B||
03662|065|R|1.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
03662|066|R|  2021.|1
03662|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03662|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03662|069|R|  settings: a scientific statement from the American Heart Association and|6
03662|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03662|071|R|  2;55(9):934-47.|6
03662|072|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03662|073|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03662|074|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03662|075|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03662|076|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03662|077|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03662|078|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03662|079|R|  11/14/2017.|1
03662|080|R|5.This information is based on an extract from the Certara Drug Interaction|6
03662|081|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03662|082|R|6.Amaya GM, Durandis R, Bourgeois DS, Perkins JA, Abouda AA, Wines KJ,|5
03662|083|R|  Mohamud M, Starks SA, Daniels RN, Jackson KD. Cytochromes P450 1A2 and 3A4|5
03662|084|R|  Catalyze the Metabolic Activation of Sunitinib. Chem Res Toxicol 2018 Jul|5
03662|085|R|  16;31(7):570-584.|5
03663|001|T|MONOGRAPH TITLE:  Sunitinib/Strong CYP3A4 Inhibitors that Prolong QT|
03663|002|B||
03663|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03663|004|L|of severe adverse interaction.|
03663|005|B||
03663|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03663|007|A|interval may inhibit the metabolism of sunitinib and result in additive risk|
03663|008|A|of QT prolongation.(1)|
03663|009|B||
03663|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03663|011|E|prolong QT may result in elevated levels of and toxicity from sunitinib,|
03663|012|E|including additive QTc prolongation, which may result in potentially|
03663|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03663|014|E|(TdP).(1)|
03663|015|E|   Other toxicities include neutropenia, hepatotoxicity, hypertension,|
03663|016|E|cardiotoxicity, hemorrhagic events, thrombotic microangiopathy, proteinuria,|
03663|017|E|severe dermatological reactions, thyroid dysfunction, hypoglycemia, and|
03663|018|E|osteonecrosis of the jaw.(1)|
03663|019|B||
03663|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03663|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
03663|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03663|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03663|024|P|female gender, or advanced age.(2)|
03663|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03663|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03663|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03663|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03663|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03663|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03663|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03663|032|B||
03663|033|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors that prolong|
03663|034|M|QT in patients undergoing therapy with sunitinib.(1)  Consider alternatives|
03663|035|M|with no or minimal enzyme inhibition and with no effect on the QTc interval.|
03663|036|M|   If concurrent therapy with sunitinib is warranted, a dosage reduction of|
03663|037|M|sunitinib to a minimum of 37.5 mg daily in patients with gastrointestinal|
03663|038|M|stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a minimum|
03663|039|M|of 25 mg in patients with pancreatic neuroendocrine tumors (pNET) should be|
03663|040|M|considered.  Monitor QT interval more frequently.(1)|
03663|041|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03663|042|M|sunitinib should be monitored for prolongation of the QTc interval.  When|
03663|043|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03663|044|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03663|045|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03663|046|M|report any irregular heartbeat, dizziness, or fainting.|
03663|047|B||
03663|048|D|DISCUSSION:  In a study in healthy subjects, concurrent ketoconazole|
03663|049|D|increased the combined (sunitinib plus primary active metabolite) maximum|
03663|050|D|concentration (Cmax) and area-under-curve (AUC) by 49% and 51%,|
03663|051|D|respectively, of a single dose of sunitinib.(1)|
03663|052|D|   A retrospective review of 618 cancer patients treated with 902|
03663|053|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03663|054|D|incidence of QTc prolongation.  In patients who received sunitinib, QTc|
03663|055|D|prolongation was identified in 26 patients(19.4%) with 16 patients(61.5%)|
03663|056|D|having Grade 1 and 6 patients(23.1%) having Grade 2 events.  Grade 3 events|
03663|057|D|occurred in 1 patient(3.8%) having QTc greater than or equal to 500 ms and 1|
03663|058|D|patient(3.8%) having QTc change greater than or equal to 60 ms.  VT was seen|
03663|059|D|in 1 (3.8%) patient and 1 (3.8%) patient experienced SCD.(3)|
03663|060|D|   Strong inhibitors of CYP3A4 that prolong QT include:  adagrasib,|
03663|061|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
03663|062|D|posaconazole, ribociclib, telithromycin, and voriconazole.(4,5)|
03663|063|B||
03663|064|R|REFERENCES:|
03663|065|B||
03663|066|R|1.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
03663|067|R|  2021.|1
03663|068|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03663|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03663|070|R|  settings: a scientific statement from the American Heart Association and|6
03663|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03663|072|R|  2;55(9):934-47.|6
03663|073|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03663|074|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03663|075|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03663|076|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03663|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03663|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03663|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03663|080|R|  11/14/2017.|1
03663|081|R|5.This information is based on an extract from the Certara Drug Interaction|6
03663|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03663|083|R|6.Amaya GM, Durandis R, Bourgeois DS, Perkins JA, Abouda AA, Wines KJ,|5
03663|084|R|  Mohamud M, Starks SA, Daniels RN, Jackson KD. Cytochromes P450 1A2 and 3A4|5
03663|085|R|  Catalyze the Metabolic Activation of Sunitinib. Chem Res Toxicol 2018 Jul|5
03663|086|R|  16;31(7):570-584.|5
03664|001|T|MONOGRAPH TITLE:  Toremifene/Strong CYP3A4 Inhibitors|
03664|002|B||
03664|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03664|004|L|of severe adverse interaction.|
03664|005|B||
03664|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03664|007|A|the metabolism of toremifene.(1)|
03664|008|B||
03664|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03664|010|E|levels of and effects from toremifene.(1)|
03664|011|E|    Elevated levels of toremifene may result in QTc prolongation, which may|
03664|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03664|013|E|torsades de pointes (TdP).  Other toxicities include hepatotoxicity and|
03664|014|E|hypercalcemia.(1)|
03664|015|B||
03664|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03664|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03664|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03664|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03664|020|P|female gender, or advanced age.(2)|
03664|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03664|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03664|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03664|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03664|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03664|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03664|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03664|028|B||
03664|029|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03664|030|M|undergoing therapy with toremifene.(1)  Consider alternatives with no or|
03664|031|M|minimal enzyme inhibition.|
03664|032|M|   If treatment with a strong CYP3A4 inhibitor is required, toremifene|
03664|033|M|therapy should be interrupted.  If it is not possible to interrupt|
03664|034|M|toremifene therapy, electrocardiograms (ECGs) should be obtained and|
03664|035|M|patients should be closely monitored for QT prolongation.(1)  Consider|
03664|036|M|obtaining serum calcium, magnesium, and potassium levels at baseline and|
03664|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03664|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03664|039|B||
03664|040|D|DISCUSSION:  In a study in 18 subjects, ketoconazole (200 mg daily)|
03664|041|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
03664|042|D|toremifene (80 mg daily) by 1.4-fold and 2.9-fold, respectively.|
03664|043|D|N-demethyltoremifene Cmax and AUC decreased by 56% and 20%, respectively.(1)|
03664|044|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
03664|045|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03664|046|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03664|047|D|tipranavir, troleandomycin, and tucatinib.(3,4)|
03664|048|B||
03664|049|R|REFERENCES:|
03664|050|B||
03664|051|R|1.Fareston (toremifene citrate) US prescribing information. GTx, Inc. March,|1
03664|052|R|  2011.|1
03664|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03664|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03664|055|R|  settings: a scientific statement from the American Heart Association and|6
03664|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03664|057|R|  2;55(9):934-47.|6
03664|058|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03664|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03664|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03664|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03664|062|R|  11/14/2017.|1
03664|063|R|4.This information is based on an extract from the Certara Drug Interaction|6
03664|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03665|001|T|MONOGRAPH TITLE:  Toremifene/Strong CYP3A4 Inhibitors that Prolong QT|
03665|002|B||
03665|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03665|004|L|of severe adverse interaction.|
03665|005|B||
03665|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03665|007|A|interval may inhibit the metabolism of toremifene and result in additive|
03665|008|A|risk of QT prolongation.(1)|
03665|009|B||
03665|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03665|011|E|prolong QT may result in elevated levels of and toxicity from toremifene,|
03665|012|E|including additive QTc prolongation, which may result in potentially|
03665|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03665|014|E|(TdP).(1)|
03665|015|E|   Other toxicities include hepatotoxicity and hypercalcemia.(1)|
03665|016|B||
03665|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03665|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03665|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03665|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03665|021|P|female gender, or advanced age.(2)|
03665|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03665|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03665|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03665|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03665|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03665|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03665|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03665|029|B||
03665|030|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors that prolong|
03665|031|M|QT in patients undergoing therapy with toremifene.(1)  Consider alternatives|
03665|032|M|with no or minimal enzyme inhibition and with no effect on the QTc interval.|
03665|033|M|   If treatment with a strong CYP3A4 inhibitor is required, toremifene|
03665|034|M|therapy should be interrupted.  If it is not possible to interrupt|
03665|035|M|toremifene therapy, electrocardiograms (ECGs) should be obtained and|
03665|036|M|patients should be closely monitored for QT prolongation.(1)  Consider|
03665|037|M|obtaining serum calcium, magnesium, and potassium levels at baseline and|
03665|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03665|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03665|040|B||
03665|041|D|DISCUSSION:  In a study in 18 subjects, ketoconazole (200 mg daily)|
03665|042|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
03665|043|D|toremifene (80 mg daily) by 1.4-fold and 2.9-fold, respectively.|
03665|044|D|N-demethyltoremifene Cmax and AUC decreased by 56% and 20%, respectively.(1)|
03665|045|D|   Strong inhibitors of CYP3A4 that prolong QT include:  adagrasib,|
03665|046|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
03665|047|D|posaconazole, ribociclib, telithromycin, and voriconazole.(3,4)|
03665|048|B||
03665|049|R|REFERENCES:|
03665|050|B||
03665|051|R|1.Fareston (toremifene citrate) US prescribing information. GTx, Inc. March,|1
03665|052|R|  2011.|1
03665|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03665|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03665|055|R|  settings: a scientific statement from the American Heart Association and|6
03665|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03665|057|R|  2;55(9):934-47.|6
03665|058|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03665|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03665|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03665|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03665|062|R|  11/14/2017.|1
03665|063|R|4.This information is based on an extract from the Certara Drug Interaction|6
03665|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03666|001|T|MONOGRAPH TITLE:  Relugolix/P-glycoprotein (P-gp) Inhibitors|
03666|002|B||
03666|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03666|004|L|of severe adverse interaction.|
03666|005|B||
03666|006|A|MECHANISM OF ACTION:  Relugolix is a substrate of the intestinal|
03666|007|A|P-glycoprotein (P-gp) efflux transporter.  Inhibitors of P-gp may increase|
03666|008|A|the absorption of relugolix.(1)|
03666|009|B||
03666|010|E|CLINICAL EFFECTS:  The concurrent administration of relugolix with an|
03666|011|E|inhibitor of P-glycoprotein may result in elevated levels of relugolix and|
03666|012|E|adverse effects, including hot flashes, skin flushing, musculoskeletal pain,|
03666|013|E|hyperglycemia, acute renal injury, transaminitis, arrhythmias, and|
03666|014|E|hemorrhage.(1)|
03666|015|B||
03666|016|P|PREDISPOSING FACTORS:  None determined.|
03666|017|B||
03666|018|M|PATIENT MANAGEMENT:  The US manufacturer of relugolix states that the|
03666|019|M|coadministration of relugolix with P-gp inhibitors should be avoided.  If|
03666|020|M|the P-gp inhibitor is to be used short-term, relugolix may be held for up to|
03666|021|M|2 weeks.  If treatment with relugolix is interrupted for longer than 7 days,|
03666|022|M|resume relugolix with a loading dose of 360 mg on the first day, followed by|
03666|023|M|120 mg once daily.(1)|
03666|024|M|   If coadministration with a P-gp inhibitor cannot be avoided, relugolix|
03666|025|M|should be taken at least 6 hours before the P-gp inhibitor.  Monitor the|
03666|026|M|patient more frequently for adverse events.(1)|
03666|027|B||
03666|028|D|DISCUSSION:  Coadministration of relugolix with erythromycin (a P-gp and|
03666|029|D|moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum|
03666|030|D|concentration (Cmax) of relugolix by 6.2-fold.  Voriconazole (a strong|
03666|031|D|CYP3A4 inhibitor) did not have a clinically significant effect on the|
03666|032|D|pharmacokinetics of relugolix.(1)|
03666|033|D|   P-gp inhibitors linked to this monograph include:  amiodarone,|
03666|034|D|asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine,|
03666|035|D|clarithromycin, cobicistat, conivaptan, curcumin, cyclosporine, daclatasvir,|
03666|036|D|danicopan, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone,|
03666|037|D|eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo,|
03666|038|D|ginseng, glecaprevir/pibrentasvir, indinavir, itraconazole, ivacaftor,|
03666|039|D|josamycin, ketoconazole, lapatinib, lonafarnib, mavorixafor, mibefradil,|
03666|040|D|mifepristone, neratinib, osimertinib, paroxetine, pirtobrutinib,|
03666|041|D|propafenone, quinidine, quinine, ranolazine, ritonavir, sarecycline,|
03666|042|D|schisandra, selpercatinib, simeprevir, sotorasib, telaprevir, telithromycin,|
03666|043|D|tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, venetoclax,|
03666|044|D|verapamil, vimseltinib, and voclosporin.(2,3)|
03666|045|B||
03666|046|R|REFERENCES:|
03666|047|B||
03666|048|R|1.Orgovyx (relugolix) US prescribing information. Myovant Sciences, Inc.|1
03666|049|R|  October, 2025.|1
03666|050|R|2.This information is based on an extract from the Certara Drug Interaction|6
03666|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03666|052|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03666|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03666|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03666|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03666|056|R|  11/14/2017.|1
03667|001|T|MONOGRAPH TITLE:  Selected Nephrotoxic Agents/Bacitracin|
03667|002|B||
03667|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03667|004|L|is contraindicated and generally should not be dispensed or administered to|
03667|005|L|the same patient.|
03667|006|B||
03667|007|A|MECHANISM OF ACTION:  Bacitracin may cause renal failure due to glomerular|
03667|008|A|and tubular necrosis.  Concurrent administration of other nephrotoxic agents|
03667|009|A|may result in additive renal toxicity.(1-3)|
03667|010|B||
03667|011|E|CLINICAL EFFECTS:  Concurrent use of bacitracin with other potentially|
03667|012|E|nephrotoxic agents may result in renal toxicity.(1-3)|
03667|013|B||
03667|014|P|PREDISPOSING FACTORS:  Dehydration and high-dose bacitracin may predispose|
03667|015|P|to adverse renal effects.(1)|
03667|016|B||
03667|017|M|PATIENT MANAGEMENT:  Health Canada states that bacitracin is contraindicated|
03667|018|M|in patients with renal impairment, including those taking other nephrotoxic|
03667|019|M|drugs.(1)|
03667|020|M|   The Canadian and US manufacturers of bacitracin state that concomitant|
03667|021|M|use of bacitracin with other potentially nephrotoxic agents should be|
03667|022|M|avoided.(2,3)|
03667|023|B||
03667|024|D|DISCUSSION:  Renal impairment is a major toxicity of bacitracin.  Cases of|
03667|025|D|nephrotoxicity have been reported when bacitracin was used off-label.(1-3)|
03667|026|B||
03667|027|R|REFERENCES:|
03667|028|B||
03667|029|R|1.Health Canada. Health Canada MedEffect e-Notice: Bacitracin for Injection|6
03667|030|R|  (50,000 IU per vial)  Risk of Nephrotoxicity and Anaphylactic Reactions.|6
03667|031|R|  available at:|6
03667|032|R|  https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/74605a-|6
03667|033|R|  eng.php#issue-problem December 21, 2020.|6
03667|034|R|2.Bacitracin for Injection Canadian prescribing information. Auro Pharma Inc|1
03667|035|R|  July 29, 2019.|1
03667|036|R|3.Bacitracin Injection US prescribing information. Pharmacia and Upjohn|1
03667|037|R|  Company December, 2020.|1
03668|001|T|MONOGRAPH TITLE:  Relugolix/P-gp and Strong CYP3A4 Inducers|
03668|002|B||
03668|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03668|004|L|of severe adverse interaction.|
03668|005|B||
03668|006|A|MECHANISM OF ACTION:  Relugolix is a substrate of the intestinal|
03668|007|A|P-glycoprotein (P-gp) efflux transporter and is primarily metabolized by|
03668|008|A|CYP3A4.  Agents that induce both P-gp and CYP3A4 may reduce the plasma|
03668|009|A|levels of relugolix.(1)|
03668|010|B||
03668|011|E|CLINICAL EFFECTS:  Concurrent or recent use of P-gp and strong CYP3A4|
03668|012|E|inducers may result in decreased levels and effectiveness of relugolix.(1)|
03668|013|B||
03668|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03668|015|P|of the inducer for longer than 1-2 weeks.|
03668|016|B||
03668|017|M|PATIENT MANAGEMENT:  If possible, avoid the concurrent use of agents that|
03668|018|M|are combined P-gp and strong CYP3A4 inducers in patients receiving|
03668|019|M|relugolix.(1)|
03668|020|M|   If coadministration is necessary, increase the dose of relugolix to 240|
03668|021|M|mg daily. If the P-gp/CYP3A4 inducer is discontinued, resume the recommended|
03668|022|M|dose of 120 mg once daily.(1)|
03668|023|B||
03668|024|D|DISCUSSION:  Concurrent rifampin (combined P-gp and strong CYP3A4 inducer)|
03668|025|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03668|026|D|relugolix by 55% and 23%, respectively.(1)|
03668|027|D|   Dual P-gp and CYP3A4 inducers linked to this monograph include:|
03668|028|D|apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine,|
03668|029|D|and St. John's wort.(2,3)|
03668|030|B||
03668|031|R|REFERENCES:|
03668|032|B||
03668|033|R|1.Orgovyx (relugolix) US prescribing information. Myovant Sciences, Inc.|1
03668|034|R|  October, 2025.|1
03668|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
03668|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03668|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03668|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03668|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03668|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03668|041|R|  11/14/2017.|1
03669|001|T|MONOGRAPH TITLE:  COVID-19 Vaccines/COVID-19 Monoclonal Antibodies|
03669|002|B||
03669|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03669|004|L|take action as needed.|
03669|005|B||
03669|006|A|MECHANISM OF ACTION:  COVID-19 monoclonal antibodies such as|
03669|007|A|tixagevimab-cilgavimab and pemivibart may prevent the immune system from|
03669|008|A|properly responding to the COVID-19 vaccine.(1-3)|
03669|009|B||
03669|010|E|CLINICAL EFFECTS:  Administration of a COVID-19 monoclonal antibody such as|
03669|011|E|tixagevimab-cilgavimab and pemivibart, soon after receipt of a COVID-19|
03669|012|E|vaccine may interfere with vaccine-induced immune responses and impair the|
03669|013|E|efficacy of the vaccine.(1-3)|
03669|014|B||
03669|015|P|PREDISPOSING FACTORS:  None determined.|
03669|016|B||
03669|017|M|PATIENT MANAGEMENT:  In individuals who have received a COVID-19 vaccine, a|
03669|018|M|COVID-19 monoclonal antibody (such as tixagevimab-cilgavimab and pemivibart)|
03669|019|M|should be administered at least two weeks after vaccination.(2,3)|
03669|020|M|   Patients who previously received a COVID-19 monoclonal antibody may be|
03669|021|M|vaccinated against COVID-19 at any time.(1)|
03669|022|B||
03669|023|D|DISCUSSION:  There is no data on the safety or efficacy of COVID-19 vaccines|
03669|024|D|in patients who subsequently receive COVID-19 monoclonal antibodies.  Given|
03669|025|D|a lack of data, the CDC recommends that tixagevimab-cilgavimab be|
03669|026|D|temporarily deferred for 2 weeks in patients who previously received|
03669|027|D|COVID-19 vaccines.(1)|
03669|028|B||
03669|029|R|REFERENCES:|
03669|030|B||
03669|031|R|1.Centers for Disease Control and Prevention (CDC). Interim Clinical|6
03669|032|R|  Considerations for Use of COVID-19 Vaccines Currently Approved or|6
03669|033|R|  Authorized in the United States. Accessed at:|6
03669|034|R|  https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vac|6
03669|035|R|  cines-us.html Last updated: September 15, 2023.|6
03669|036|R|2.Evushield (tixagemivab co-packaged with cilgavimab) Fact Sheet for|1
03669|037|R|  Healthcare Providers (EUA). AstraZeneca December 2021.|1
03669|038|R|3.Pemgarda (pemivibart) injection US prescribing information. Invivyd, Inc|1
03669|039|R|  03/2024.|1
03670|001|T|MONOGRAPH TITLE:  Ceritinib/Mifepristone|
03670|002|B||
03670|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03670|004|L|of severe adverse interaction.|
03670|005|B||
03670|006|A|MECHANISM OF ACTION:  Ceritinib and mifepristone are both strong inhibitors|
03670|007|A|as well as substrates of CYP3A4.(1,2)|
03670|008|B||
03670|009|E|CLINICAL EFFECTS:  Concurrent use of ceritinib and mifepristone may result|
03670|010|E|in elevated levels of and toxicity from both agents.  The magnitude of|
03670|011|E|effect of the two-way inhibition of the metabolism of ceritinib and|
03670|012|E|mifepristone is unknown.|
03670|013|E|   Potential toxicities include: QTc prolongation, which may result in|
03670|014|E|potentially life-threatening cardiac arrhythmias including torsades de|
03670|015|E|pointes (TdP), nausea, vomiting, diarrhea, abdominal pain, transaminitis,|
03670|016|E|hyper- or hypoglycemia, adrenal insufficiency, hypokalemia, interstitial|
03670|017|E|lung disease, and pancreatitis.(1,2)|
03670|018|B||
03670|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03670|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03670|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03670|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03670|023|P|female gender, or advanced age.(3)|
03670|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03670|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03670|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03670|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03670|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03670|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03670|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03670|031|P|   Patients with severe hepatic impairment (Child-Pugh C) may be at|
03670|032|P|increased risk of this interaction.  Ceritinib dose reduction may be|
03670|033|P|warranted in severe hepatic impairment.  See prescribing information for|
03670|034|P|recommendations.(1)|
03670|035|B||
03670|036|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ceritinib and|
03670|037|M|mifepristone.(1,2)  Consider alternatives with no or minimal enzyme|
03670|038|M|inhibition and with no effect on the QTc interval.|
03670|039|M|   The magnitude of effect of the two-way inhibition of the metabolism of|
03670|040|M|ceritinib and mifepristone is unknown.  The optimal doses of ceritinib and|
03670|041|M|mifepristone when used concurrently have not been determined.  Manufacturers|
03670|042|M|provide recommendations for dose modification of ceritinib and mifepristone|
03670|043|M|when each is used with a strong CYP3A4 inhibitor, but the recommendations|
03670|044|M|may not apply when there is a two-way inhibition.  Dose modifications|
03670|045|M|mentioned below are informational only.|
03670|046|M|   If concurrent use of a strong CYP3A4 inhibitor with ceritinib is|
03670|047|M|unavoidable, reduce the dosage of ceritinib by one-third, rounding to the|
03670|048|M|nearest 150 mg dosage strength.  If the strong CYP3A4 inhibitor is|
03670|049|M|discontinued, resume the dose that was taken prior to using the|
03670|050|M|inhibitor.(1)|
03670|051|M|   The manufacturer of mifepristone for use in patients with endogenous|
03670|052|M|Cushing's syndrome states the benefit of the CYP3A4 inhibitor must be|
03670|053|M|carefully weighed against the potential risks and concurrent use should only|
03670|054|M|occur when necessary.(2)|
03670|055|M|   If starting mifepristone in a patient already taking a strong CYP3A4|
03670|056|M|inhibitor, initiate mifepristone at 300 mg and titrate if clinically|
03670|057|M|indicated to a maximum dose of 900 mg.(2)|
03670|058|M|   If a strong CYP3A4 inhibitor is started in a patient already taking|
03670|059|M|mifepristone, the following dose adjustments are recommended:|
03670|060|M| - If current mifepristone dose is 300 mg, no dose change warranted;|
03670|061|M| - If current mifepristone dose is 600 mg, reduce dose to 300 mg and titrate|
03670|062|M|if clinically indicated to a maximum dose of 600 mg;|
03670|063|M| - If current mifepristone dose is 900 mg, reduce dose to 600 mg and titrate|
03670|064|M|if clinically indicated to a maximum dose of 900 mg; and|
03670|065|M| - If current mifepristone dose if 1200 mg, reduce dose to 900 mg.(2)|
03670|066|M|   Patients receiving concurrent therapy with ceritinib and mifepristone|
03670|067|M|should be monitored for prolongation of the QTc interval.  When concurrent|
03670|068|M|therapy is warranted: consider obtaining serum calcium, magnesium, and|
03670|069|M|potassium levels and monitoring EKG at baseline and regular intervals.|
03670|070|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03670|071|M|irregular heartbeat, dizziness, or fainting.|
03670|072|B||
03670|073|D|DISCUSSION:  The magnitude of effect of a two-way inhibition of the|
03670|074|D|metabolism of ceritinib and mifepristone is unknown.|
03670|075|D|   In a study in 19 healthy subjects, ketoconazole (200 mg twice daily for|
03670|076|D|14 days) increased the maximum concentration (Cmax) and area-under-curve|
03670|077|D|(AUC) of a single dose of ceritinib (450 mg) by 22% and 2.9-fold,|
03670|078|D|respectively.  The steady-state AUC of ceritinib at reduced doses after|
03670|079|D|concurrent ketoconazole was predicted by simulations to be similar to the|
03670|080|D|steady-state AUC of ceritinib alone.(1)|
03670|081|D|   In a clinical trial 3% of patients experienced a QTc interval increase|
03670|082|D|over baseline greater than 60 msec.  Less than 1% of patients (1 of 304)|
03670|083|D|treated with ceritinib was found to have a QTc greater than 500 msec.  The|
03670|084|D|upper limit of the 90% confidence interval for mean QTC increase was 16 msec|
03670|085|D|at ceritinib 750 mg.  Data suggested that ceritinib produces|
03670|086|D|concentration-dependent QTc interval prolongation.(1)|
03670|087|D|   A drug interaction study examined mifepristone 600 mg daily with|
03670|088|D|concurrent ketoconazole 200 mg twice daily on days 13-17.  Concurrent|
03670|089|D|administration increased mifepristone AUC and Cmax by 1.38-fold and|
03670|090|D|1.28-fold, respectively.(2)|
03670|091|D|   A drug interaction study of 33 healthy subjects on itraconazole 200 mg|
03670|092|D|daily coadministered with mifepristone 900 mg daily for 14 days found that|
03670|093|D|itraconazole increased the Cmax and AUC of mifepristone by 1.1-fold and|
03670|094|D|1.2-fold, respectively.(2)|
03670|095|B||
03670|096|R|REFERENCES:|
03670|097|B||
03670|098|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
03670|099|R|  Corporation August, 2021.|1
03670|100|R|2.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
03670|101|R|  November, 2019.|1
03670|102|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03670|103|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03670|104|R|  settings: a scientific statement from the American Heart Association and|6
03670|105|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03670|106|R|  2;55(9):934-47.|6
03671|001|T|MONOGRAPH TITLE:  Ribociclib/Mifepristone|
03671|002|B||
03671|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03671|004|L|of severe adverse interaction.|
03671|005|B||
03671|006|A|MECHANISM OF ACTION:  Ribociclib and mifepristone are both strong inhibitors|
03671|007|A|as well as substrates of CYP3A4.(1,2)|
03671|008|B||
03671|009|E|CLINICAL EFFECTS:  Concurrent use of ribociclib and mifepristone may result|
03671|010|E|in elevated levels of and toxicity from both agents.  The magnitude of|
03671|011|E|effect of the two-way inhibition of the metabolism of ribociclib and|
03671|012|E|mifepristone is unknown.|
03671|013|E|   Potential toxicities include: QTc prolongation, which may result in|
03671|014|E|potentially life-threatening cardiac arrhythmias including torsades de|
03671|015|E|pointes (TdP), neutropenia, severe cutaneous reactions, nausea, vomiting,|
03671|016|E|diarrhea, abdominal pain, transaminitis, hypoglycemia, adrenal|
03671|017|E|insufficiency, hypokalemia, and interstitial lung disease.(1,2)|
03671|018|B||
03671|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03671|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03671|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03671|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03671|023|P|female gender, or advanced age.(3)|
03671|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03671|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03671|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03671|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03671|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03671|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03671|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03671|031|B||
03671|032|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ribociclib and|
03671|033|M|mifepristone.(1,2)  Consider alternatives with no or minimal enzyme|
03671|034|M|inhibition and with no effect on the QTc interval.|
03671|035|M|   The magnitude of effect of the two-way inhibition of the metabolism of|
03671|036|M|ribociclib and mifepristone is unknown.  The optimal doses of ribociclib and|
03671|037|M|mifepristone when used concurrently have not been determined.  Manufacturers|
03671|038|M|provide recommendations for dose modification of ribociclib and mifepristone|
03671|039|M|when each is used with a strong CYP3A4 inhibitor, but the recommendations|
03671|040|M|may not apply when there is a two-way inhibition.  Dose modifications|
03671|041|M|mentioned below are informational only.|
03671|042|M|   The US manufacturer of ribociclib states that the following dose|
03671|043|M|modifications are needed if use of a strong CYP3A4 inhibitor cannot be|
03671|044|M|avoided:|
03671|045|M|   -For patients with early breast cancer, decrease ribociclib to 200 mg|
03671|046|M|once daily.|
03671|047|M|   -For patients with advanced or metastatic breast cancer, decrease|
03671|048|M|ribociclib to 400 mg once daily.|
03671|049|M|   -If the strong CYP3A4 inhibitor is discontinued, change the ribociclib|
03671|050|M|dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the|
03671|051|M|dose used prior to the initiation of the strong CYP3A4 inhibitor.(1)|
03671|052|M|   The Swedish manufacturer of ribociclib states that if patients must be|
03671|053|M|given a strong CYP3A4 inhibitor concurrently with ribociclib, the ribociclib|
03671|054|M|dose should be reduced to 400 mg once daily. In patients who have had their|
03671|055|M|ribociclib dose reduced to 400 mg daily and in whom coadministration of a|
03671|056|M|strong CYP3A4 inhibitor cannot be avoided, the ribociclib dose should be|
03671|057|M|further reduced to 200 mg. In patients who have had their ribociclib dose|
03671|058|M|reduced to 200 mg daily and in whom coadministration of a strong CYP3A4|
03671|059|M|inhibitor cannot be avoided, ribociclib treatment should be interrupted.(4)|
03671|060|M|   The manufacturer of mifepristone for use in patients with endogenous|
03671|061|M|Cushing's syndrome states the benefit of the CYP3A4 inhibitor must be|
03671|062|M|carefully weighed against the potential risks and concurrent use should only|
03671|063|M|occur when necessary.(2)|
03671|064|M|   If starting mifepristone in a patient already taking a strong CYP3A4|
03671|065|M|inhibitor, initiate mifepristone at 300 mg and titrate if clinically|
03671|066|M|indicated to a maximum dose of 900 mg.(2)|
03671|067|M|   If a strong CYP3A4 inhibitor is started in a patient already taking|
03671|068|M|mifepristone, the following dose adjustments are recommended:|
03671|069|M| - If current mifepristone dose is 300 mg, no dose change warranted;|
03671|070|M| - If current mifepristone dose is 600 mg, reduce dose to 300 mg and titrate|
03671|071|M|if clinically indicated to a maximum dose of 600 mg;|
03671|072|M| - If current mifepristone dose is 900 mg, reduce dose to 600 mg and titrate|
03671|073|M|if clinically indicated to a maximum dose of 900 mg; and|
03671|074|M| - If current mifepristone dose if 1200 mg, reduce dose to 900 mg.(2)|
03671|075|M|   Patients receiving concurrent therapy with ribociclib and mifepristone|
03671|076|M|should be monitored for prolongation of the QTc interval.  When concurrent|
03671|077|M|therapy is warranted: consider obtaining serum calcium, magnesium, and|
03671|078|M|potassium levels at baseline and regular intervals. Correct any electrolyte|
03671|079|M|abnormalities.  Instruct patients to report any irregular heartbeat,|
03671|080|M|dizziness, or fainting.|
03671|081|B||
03671|082|D|DISCUSSION:  The magnitude of effect of a two-way inhibition of the|
03671|083|D|metabolism of ribociclib and mifepristone is unknown.|
03671|084|D|   In a drug interaction study in healthy subjects, coadministration of|
03671|085|D|ritonavir (100 mg twice a day for 14 days) with a single dose of ribociclib|
03671|086|D|(400 mg) increased ribociclib maximum concentration (Cmax) and|
03671|087|D|area-under-the-curve (AUC) by 1.7 and 3.2-fold, respectively. Cmax and AUC|
03671|088|D|for LEQ803 (ribociclib metabolite) decreased by 96% and 98%,|
03671|089|D|respectively.(1)|
03671|090|D|   Ribociclib has been shown to prolong the QTc interval in a|
03671|091|D|concentration-dependent manner.  At steady state, the mean increase in QTc|
03671|092|D|interval exceeded 20 msec.(1)|
03671|093|D|   A drug interaction study examined mifepristone 600 mg daily with|
03671|094|D|concurrent ketoconazole 200 mg twice daily on days 13-17.  Concurrent|
03671|095|D|administration increased mifepristone AUC and Cmax by 1.38-fold and|
03671|096|D|1.28-fold, respectively.(2)|
03671|097|D|   A drug interaction study of 33 healthy subjects on itraconazole 200 mg|
03671|098|D|daily coadministered with mifepristone 900 mg daily for 14 days found that|
03671|099|D|itraconazole increased the Cmax and AUC of mifepristone by 1.1-fold and|
03671|100|D|1.2-fold, respectively.(2)|
03671|101|B||
03671|102|R|REFERENCES:|
03671|103|B||
03671|104|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
03671|105|R|  Corporation September, 2024.|1
03671|106|R|2.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
03671|107|R|  November, 2019.|1
03671|108|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03671|109|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03671|110|R|  settings: a scientific statement from the American Heart Association and|6
03671|111|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03671|112|R|  2;55(9):934-47.|6
03671|113|R|4.Kisqali (ribociclib) Sweden prescribing information. Novartis Pharma|1
03671|114|R|  August 2017.|1
03672|001|T|MONOGRAPH TITLE:  Flecainide/MATE Inhibitors|
03672|002|B||
03672|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03672|004|L|take action as needed.|
03672|005|B||
03672|006|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
03672|007|A|protein transporters in the kidneys may interfere with the renal elimination|
03672|008|A|of flecainide.(1)|
03672|009|B||
03672|010|E|CLINICAL EFFECTS:  Concurrent use of MATE renal transporter inhibitors may|
03672|011|E|result in increased levels of and toxicity from flecainide.(1)|
03672|012|B||
03672|013|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
03672|014|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
03672|015|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
03672|016|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
03672|017|P|concurrent use of agents known to cause QT prolongation.(2)|
03672|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03672|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03672|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03672|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03672|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03672|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03672|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03672|025|B||
03672|026|M|PATIENT MANAGEMENT:  Monitor serum flecainide concentrations and observe the|
03672|027|M|patients for signs of toxicity.|
03672|028|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03672|029|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03672|030|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03672|031|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03672|032|B||
03672|033|D|DISCUSSION:  In a pharmacokinetic study, concurrent use of cimetidine (1|
03672|034|D|gram daily) increased flecainide levels by 30% and increased half-life by|
03672|035|D|10%.(1)|
03672|036|D|   MATE inhibitors linked include: abemaciclib, bictegravir, cimetidine,|
03672|037|D|isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(4,5)|
03672|038|B||
03672|039|R|REFERENCES:|
03672|040|B||
03672|041|R|1.Tambocor (flecainide) US prescribing information. Medicis December, 2011.|1
03672|042|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03672|043|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03672|044|R|  settings: a scientific statement from the American Heart Association and|6
03672|045|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03672|046|R|  2;55(9):934-47.|6
03672|047|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03672|048|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03672|049|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03672|050|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03672|051|R|4.This information is based on an extract from the Certara Drug Interaction|6
03672|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03672|053|R|5.Evrysdi (risdiplam) US prescribing information. Genentech, Inc. September|1
03672|054|R|  30, 2020.|1
03673|001|T|MONOGRAPH TITLE:  Oxaliplatin/MATE Inhibitors|
03673|002|B||
03673|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03673|004|L|take action as needed.|
03673|005|B||
03673|006|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
03673|007|A|protein transporters in the kidneys may inhibit the renal transport of|
03673|008|A|oxaliplatin.(1)|
03673|009|A|   Oxaliplatin is a MATE substrate.(2,3)|
03673|010|B||
03673|011|E|CLINICAL EFFECTS:  Concurrent use of MATE renal transporter inhibitors may|
03673|012|E|result in increased levels of and toxicity from oxaliplatin, including QT|
03673|013|E|prolongation and neutropenia.(1)|
03673|014|B||
03673|015|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
03673|016|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
03673|017|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
03673|018|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
03673|019|P|concurrent use of agents known to cause QT prolongation.(4)|
03673|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03673|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03673|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03673|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03673|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03673|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03673|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03673|027|B||
03673|028|M|PATIENT MANAGEMENT:  Concurrent use of oxaliplatin with MATE renal|
03673|029|M|transporter inhibitors should be approached with caution and monitored|
03673|030|M|closely.  If concurrent use is warranted, monitor for toxicities of|
03673|031|M|oxaliplatin and consider dosage reduction based on toxicity dose|
03673|032|M|recommendations.(1)|
03673|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03673|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03673|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03673|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03673|037|B||
03673|038|D|DISCUSSION:  Oxaliplatin is a MATE substrate.(2,3)|
03673|039|D|   MATE inhibitors include: abemaciclib, bictegravir, cimetidine,|
03673|040|D|isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(6,7)|
03673|041|B||
03673|042|R|REFERENCES:|
03673|043|B||
03673|044|R|1.Eloxatin (oxaliplatin) US prescribing information. Sanofi-Aventis U.S. LLC|1
03673|045|R|  October, 2015.|1
03673|046|R|2.Yonezawa A, Inui K. Organic cation transporter OCT/SLC22A and H(+)/organic|2
03673|047|R|  cation antiporter  MATE/SLC47A are key molecules for nephrotoxicity of|2
03673|048|R|  platinum agents. Biochem Pharmacol 2011 Mar 1;81(5):563-8.|2
03673|049|R|3.Yokoo S, Yonezawa A, Masuda S, Fukatsu A, Katsura T, Inui K. Differential|2
03673|050|R|  contribution of organic cation transporters, OCT2 and MATE1, in  platinum|2
03673|051|R|  agent-induced nephrotoxicity. Biochem Pharmacol 2007 Aug 1;74(3):477-87.|2
03673|052|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03673|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03673|054|R|  settings: a scientific statement from the American Heart Association and|6
03673|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03673|056|R|  2;55(9):934-47.|6
03673|057|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03673|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03673|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03673|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03673|061|R|6.This information is based on an extract from the Certara Drug Interaction|6
03673|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03673|063|R|7.Evrysdi (risdiplam) US prescribing information. Genentech, Inc. September|1
03673|064|R|  30, 2020.|1
03674|001|T|MONOGRAPH TITLE:  Dabigatran/Risdiplam|
03674|002|B||
03674|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03674|004|L|of severe adverse interaction.|
03674|005|B||
03674|006|A|MECHANISM OF ACTION:  Risdiplam may inhibit the renal excretion of|
03674|007|A|substrates of Multidrug and Toxin Extrusion (MATE) protein transporters in|
03674|008|A|the kidneys.(1)  Dabigatran is a MATE substrate.|
03674|009|B||
03674|010|E|CLINICAL EFFECTS:  Concurrent use of risdiplam may result in increased|
03674|011|E|levels of and toxicity from dabigatran (a MATE substrate), including|
03674|012|E|increased risk of bleeding.(1)|
03674|013|B||
03674|014|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
03674|015|P|bleeding include renal impairment, concomitant use of P-gp inhibitors,|
03674|016|P|patient age greater than 74 years, coexisting conditions (e.g. recent|
03674|017|P|trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and|
03674|018|P|patient weight less than 50 kg.(2-5)|
03674|019|B||
03674|020|M|PATIENT MANAGEMENT:  Avoid concurrent use of dabigatran, a MATE substrate,|
03674|021|M|with risdiplam.  If concurrent use cannot be avoided, monitor for toxicities|
03674|022|M|of dabigatran or consider alternative anticoagulant therapy.(1)|
03674|023|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
03674|024|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
03674|025|M|and/or decreased blood pressure and promptly evaluate patients with any|
03674|026|M|symptoms.  Consider regular monitoring of hemoglobin, platelet levels,|
03674|027|M|and/or activated partial thromboplastin time (aPTT) or ecarin clotting time|
03674|028|M|(ECT).|
03674|029|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
03674|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03674|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03674|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03674|033|M|and/or swelling.|
03674|034|B||
03674|035|D|DISCUSSION:  Based upon in vitro data, risdiplam is expected to produce|
03674|036|D|clinically significant inhibition of MATE1 and MATE2-K transporters at|
03674|037|D|clinically relevant concentrations.(1)|
03674|038|B||
03674|039|R|REFERENCES:|
03674|040|B||
03674|041|R|1.Evrysdi (risdiplam) US prescribing information. Genentech, Inc. September|1
03674|042|R|  30, 2020.|1
03674|043|R|2.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
03674|044|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
03674|045|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
03674|046|R|  Boehringer Ingelheim March, 23 2020.|1
03674|047|R|4.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
03674|048|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
03674|049|R|5.Anonymous. FDA Dabigatran background package for Cardio-Renal Advisory|1
03674|050|R|  Committee. available at|1
03674|051|R|  http://wayback.archive-it.org/7993/20170405212218/https://www.fda.gov/down|1
03674|052|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascularan|1
03674|053|R|  dRenalDrugsAdvisoryCommittee/UCM247244.pdf September 20, 2010.|1
03675|001|T|MONOGRAPH TITLE:  Myelosuppressive MATE Substrates/Risdiplam (mono deleted|
03675|002|T|10/03/2024)|
03675|003|B||
03675|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03675|005|L|of severe adverse interaction.|
03675|006|B||
03675|007|A|MECHANISM OF ACTION:  Risdiplam may inhibit the renal excretion of|
03675|008|A|substrates of Multidrug and Toxin Extrusion (MATE) protein transporters in|
03675|009|A|the kidneys.(1)  Abemaciclib, baricitinib, ganciclovir, topotecan and|
03675|010|A|trastuzumab deruxtecan are MATE substrates.|
03675|011|B||
03675|012|E|CLINICAL EFFECTS:  Concurrent use of risdiplam may result in increased|
03675|013|E|levels of and toxicity from MATE substrates, including myelosuppression.(1)|
03675|014|B||
03675|015|P|PREDISPOSING FACTORS:  None determined.|
03675|016|B||
03675|017|M|PATIENT MANAGEMENT:  Avoid concurrent use of MATE substrates, including|
03675|018|M|abemaciclib, baricitinib, ganciclovir, topotecan and trastuzumab deruxtecan|
03675|019|M|with risdiplam.  If concurrent use cannot be avoided, monitor for toxicity|
03675|020|M|of the MATE substrate and consider dosage reduction of the MATE|
03675|021|M|substrate.(1)|
03675|022|B||
03675|023|D|DISCUSSION:  Based upon in vitro data, risdiplam is expected to produce|
03675|024|D|clinically significant inhibition of MATE1 and MATE2-K transporters at|
03675|025|D|clinically relevant concentrations.(1)|
03675|026|D|   Selected MATE substrates linked include: abemaciclib, baricitinib,|
03675|027|D|ganciclovir, topotecan and trastuzumab deruxtecan.|
03675|028|B||
03675|029|R|REFERENCE:|
03675|030|B||
03675|031|R|1.Evrysdi (risdiplam) US prescribing information. Genentech, Inc. September|1
03675|032|R|  30, 2020.|1
03676|001|T|MONOGRAPH TITLE:  Propranolol/Fluvoxamine|
03676|002|B||
03676|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03676|004|L|take action as needed.|
03676|005|B||
03676|006|A|MECHANISM OF ACTION:  Fluvoxamine may inhibit the metabolism of propranolol|
03676|007|A|by CYP1A2 and CYP2C19.(1,2)|
03676|008|B||
03676|009|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine and propranolol may result|
03676|010|E|in increased levels of and effects from propranolol.(1,2)|
03676|011|B||
03676|012|P|PREDISPOSING FACTORS:  None determined.|
03676|013|B||
03676|014|M|PATIENT MANAGEMENT:  The initial dose of propranolol in patients who are on|
03676|015|M|fluvoxamine should be lower in the beginning and titrated more cautiously.|
03676|016|M|Closely monitor patients for adverse effects in patients on concurrent|
03676|017|M|therapy.  The dosage of propranolol may need to be adjusted if fluvoxamine|
03676|018|M|is discontinued.(1)|
03676|019|B||
03676|020|D|DISCUSSION:  In a study of healthy volunteers, fluvoxamine 100 mg daily|
03676|021|D|increased the minimum concentration (Cmin) of propranolol 160 mg daily by a|
03676|022|D|mean of five-fold (range: 2-17).  Subjects experienced a slight reduction in|
03676|023|D|heart rate and in exercise diastolic pressure.(1)|
03676|024|B||
03676|025|R|REFERENCES:|
03676|026|B||
03676|027|R|1.Fluvoxamine US prescribing information. Teva Pharmaceuticals November,|1
03676|028|R|  2017.|1
03676|029|R|2.Inderal LA (propranolol) US prescribing information. ANI Pharmaceuticals,|1
03676|030|R|  Inc. August, 2024.|1
03677|001|T|MONOGRAPH TITLE:  Heparin/Coagulation Factor Xa, Inactivated (Andexanet)|
03677|002|B||
03677|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03677|004|L|of severe adverse interaction.|
03677|005|B||
03677|006|A|MECHANISM OF ACTION:  Inactivated coagulation factor Xa may bind to the|
03677|007|A|heparin-antithrombin III (ATIII) complex, resulting in heparin|
03677|008|A|unresponsiveness.(1)|
03677|009|B||
03677|010|E|CLINICAL EFFECTS:  Inactivated coagulation factor Xa may inhibit the|
03677|011|E|anticoagulant effect of heparin.  The extent and duration of this|
03677|012|E|interaction is unknown.(1,2)|
03677|013|B||
03677|014|P|PREDISPOSING FACTORS:  None determined.|
03677|015|B||
03677|016|M|PATIENT MANAGEMENT:  Avoid the use of inactivated coagulation factor Xa|
03677|017|M|prior to heparinization.(1,2)|
03677|018|M|   If anticoagulation is anticipated before the inactivated coagulation|
03677|019|M|factor Xa has been given, consider the use of 4-factor prothrombin complex|
03677|020|M|concentration for factor X inhibitor reversal.(3)|
03677|021|M|   If anticoagulation is needed after inactivated coagulation factor Xa has|
03677|022|M|been given, consider an alternative anticoagulant to heparin, like|
03677|023|M|argatroban or bivalirudin.(3)|
03677|024|B||
03677|025|D|DISCUSSION:  A 70-year-old man on rivaroxaban for atrial fibrillation|
03677|026|D|presented with a ruptured abdominal aortic aneurysm (AAA).  He was given|
03677|027|D|inactivated coagulation factor Xa to reverse anticoagulation and taken to|
03677|028|D|surgery for AAA repair.  During the procedure, he received a total of 14,000|
03677|029|D|units of unfractionated heparin (UFH) without a change in his activated|
03677|030|D|clotting time (ACT).  The patient developed an iliac artery thrombus thought|
03677|031|D|to be a result of the failure to achieve therapeutic anticoagulation during|
03677|032|D|the procedure.(3,4)|
03677|033|D|   A 72-year-old man on apixaban for atrial fibrillation underwent an|
03677|034|D|elective radiofrequency ablation procedure complicated by cardiac tamponade.|
03677|035|D|Inactivated coagulation factor Xa was started to reverse anticoagulation.|
03677|036|D|Subsequently, a left ventricular free wall rupture was discovered, and the|
03677|037|D|patient was placed under cardiopulmonary bypass (CPB) for repair.  Despite|
03677|038|D|administration of 80,000 units of UFH, the patient's ACT was minimally|
03677|039|D|increased and thrombi formed in the operating field and CPB circuit.|
03677|040|D|Inactivated coagulation factor Xa was stopped and antithrombin III 1,000|
03677|041|D|units was given, leading to an out of range ACT (>999 seconds).  ACT|
03677|042|D|subsequently normalized after administration of protamine sulphate.(5)|
03677|043|B||
03677|044|R|REFERENCES:|
03677|045|B||
03677|046|R|1.Andexxa (coagulation factor Xa (recombinant), inactivated-zhzo) US|1
03677|047|R|  prescribing information. Portola Pharmaceuticals September, 2020.|1
03677|048|R|2.Goldmann U. Dear Healthcare Professional letter: Ondexxya (andexanet|1
03677|049|R|  alfa): Avoid use of andexanet prior to heparinization. Portola|1
03677|050|R|  Netherlands, B.V. November 4, 2020.|1
03677|051|R|3.Eche IM, Elsamadisi P, Wex N, Wyers MC, Brat GA, Cunningham K, Bauer KA.|3
03677|052|R|  Intraoperative Unfractionated Heparin Unresponsiveness during Endovascular|3
03677|053|R|  Repair of  a Ruptured Abdominal Aortic Aneurysm following Administration|3
03677|054|R|  of Andexanet Alfa for  the Reversal of Rivaroxaban. Pharmacotherapy 2019|3
03677|055|R|  Aug;39(8):861-865.|3
03677|056|R|4.Watson CJ, Zettervall SL, Hall MM, Ganetsky M. Difficult Intraoperative|3
03677|057|R|  Heparinization Following Andexanet Alfa Administration. Clin Pract Cases|3
03677|058|R|  Emerg Med 2019 Nov;3(4):390-394.|3
03677|059|R|5.Apostel  HJCL, Winckers K, Bidar E, Schreiber JU. Successful Antithrombin|3
03677|060|R|  Administration in Andexanet Alfa-Associated Heparin  Resistance. J|3
03677|061|R|  Cardiothorac Vasc Anesth 2020 Oct 24.|3
03678|001|T|MONOGRAPH TITLE:  Vericiguat/PDE Inhibitors|
03678|002|B||
03678|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03678|004|L|of severe adverse interaction.|
03678|005|B||
03678|006|A|MECHANISM OF ACTION:  Vericiguat stimulates the nitric oxide-soluble|
03678|007|A|guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway and also|
03678|008|A|increases cGMP.(1)  Aminophylline, avanafil, dipyridamole, sildenafil,|
03678|009|A|tadalafil, theophylline, and vardenafil inhibit phosphodiesterase (PDE),|
03678|010|A|which is responsible for the breakdown of cGMP.(1-6)|
03678|011|B||
03678|012|E|CLINICAL EFFECTS:  The concurrent use of PDE inhibitors and vericiguat|
03678|013|E|potentiates the hypotensive effects of both agents, which may result in|
03678|014|E|dizziness, syncope, heart attack, or stroke.(1)|
03678|015|B||
03678|016|P|PREDISPOSING FACTORS:  Plasma levels of the PDE type-5 inhibitors may be|
03678|017|P|higher in the following patients:  those older than 65, with hepatic|
03678|018|P|impairment, or with severe renal impairment.  This may increase the severity|
03678|019|P|of the interaction.|
03678|020|B||
03678|021|M|PATIENT MANAGEMENT:  The manufacturer of vericiguat states that|
03678|022|M|administration of vericiguat to patients receiving PDE inhibitors, including|
03678|023|M|specific PDE-5 inhibitors (avanafil,(2) sildenafil,(3) tadalafil,(4,5) or|
03678|024|M|vardenafil(6)) and nonspecific PDE inhibitors (aminophylline, dipyridamole,|
03678|025|M|theophylline) is not recommended.(1)|
03678|026|M|   The manufacturers of the PDE-5 inhibitors state that concurrent use of|
03678|027|M|guanylate cyclase stimulators is contraindicated.(2-6)|
03678|028|B||
03678|029|D|DISCUSSION:  Concomitant use of vericiguat 10 mg with single doses of|
03678|030|D|sildenafil (25, 50, or 100 mg) was associated with additional seated BP|
03678|031|D|reduction of up to 5.4 mm Hg (systolic/diastolic BP, MAP), compared to|
03678|032|D|administration of vericiguat alone.(1)|
03678|033|B||
03678|034|R|REFERENCES:|
03678|035|B||
03678|036|R|1.Verquvo (vericiguat) US prescribing information. Merck Sharp & Dohm Corp|1
03678|037|R|  January, 2021.|1
03678|038|R|2.Stendra (avanafil) US prescribing information. Vivus, Inc. October, 2022.|1
03678|039|R|3.Revatio (sildenafil citrate) US prescribing information. Viatris January,|1
03678|040|R|  2023.|1
03678|041|R|4.Adcirca (tadalafil) US prescribing information. Eli Lilly and Company|1
03678|042|R|  September, 2020.|1
03678|043|R|5.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
03678|044|R|  February, 2018.|1
03678|045|R|6.Levitra (vardenafil hydrochloride) US prescribing information. Bayer|1
03678|046|R|  Pharmaceuticals Corporation March, 2023.|1
03679|001|T|MONOGRAPH TITLE:  Azole Antifungal Agents/Rifabutin|
03679|002|B||
03679|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03679|004|L|of severe adverse interaction.|
03679|005|B||
03679|006|A|MECHANISM OF ACTION:  Multiple mechanisms may be involved:|
03679|007|A|   1) Rifabutin may induce the CYP3A4 metabolism of the azole antifungal|
03679|008|A|agents.|
03679|009|A|   2) The azole antifungals may inhibit the CYP3A4 metabolism of|
03679|010|A|rifabutin.(1)|
03679|011|B||
03679|012|E|CLINICAL EFFECTS:  The levels and effectiveness of the azole antifungals may|
03679|013|E|decrease.  The levels and toxicities of rifabutin may increase, including|
03679|014|E|uveitis.(1)|
03679|015|B||
03679|016|P|PREDISPOSING FACTORS:  None determined.|
03679|017|B||
03679|018|M|PATIENT MANAGEMENT:  Rifabutin is not recommended two weeks before, during,|
03679|019|M|and two weeks after treatment with itraconazole or ketoconazole.(2,3)|
03679|020|M|   If co-administration cannot be avoided, observe the patient for a|
03679|021|M|decrease in the therapeutic effect of the antifungal agent.  It may be|
03679|022|M|necessary to increase the dose of the antifungal agent.|
03679|023|M|   Monitor for rifabutin-associated adverse events.  Reduce the rifabutin|
03679|024|M|dose or suspend rifabutin use if toxicity is suspected.(1)  If uveitis|
03679|025|M|occurs, temporary discontinuance of rifabutin and ophthalmologic evaluation|
03679|026|M|are recommended.  In most mild cases, rifabutin may be restarted; however,|
03679|027|M|if signs or symptoms recur, use of rifabutin should be discontinued.(1)|
03679|028|B||
03679|029|D|DISCUSSION:  Concurrent fluconazole (200 mg daily for 2 weeks) with|
03679|030|D|rifabutin (300 mg daily for 2 weeks) in 12 HIV-infected patients resulted in|
03679|031|D|an increase in rifabutin's area-under-the-curve (AUC) and maximum|
03679|032|D|concentration (Cmax) by 82% and 88%, respectively. No change was seen in|
03679|033|D|fluconazole's AUC or Cmax.(1,4)|
03679|034|D|   Concurrent itraconazole (200 mg daily) with rifabutin (300 mg daily) in|
03679|035|D|six HIV-infected patients resulted in an increased effect on rifabutin and a|
03679|036|D|decrease in itraconazole's AUC and Cmax by 70% and 75%, respectively.(2)|
03679|037|B||
03679|038|R|REFERENCES:|
03679|039|B||
03679|040|R|1.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
03679|041|R|  2021.|1
03679|042|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
03679|043|R|  Products, L.P. February, 2024.|1
03679|044|R|3.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
03679|045|R|  Pharmaceuticals February, 2014.|1
03679|046|R|4.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
03679|047|R|  2024.|1
03680|001|T|MONOGRAPH TITLE:  Cabotegravir-Rilpivirine/Strong CYP3A4 & UGT1A1 Inducers|
03680|002|B||
03680|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03680|004|L|is contraindicated and generally should not be dispensed or administered to|
03680|005|L|the same patient.|
03680|006|B||
03680|007|A|MECHANISM OF ACTION:  Apalutamide, barbiturates, carbamazepine,|
03680|008|A|dexamethasone, efavirenz, encorafenib, enzalutamide, eslicarbazepine,|
03680|009|A|fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine,|
03680|010|A|phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine,|
03680|011|A|ritonavir, or St. John's wort may induce the metabolism of|
03680|012|A|cabotegravir-rilpivirine by CYP3A4 and uridine diphosphate|
03680|013|A|(UDP)-glucuronosyl transferase 1A1 (UGT1A1).(1)|
03680|014|B||
03680|015|E|CLINICAL EFFECTS:  Concurrent or recent use of apalutamide, barbiturates,|
03680|016|E|carbamazepine, dexamethasone, efavirenz, encorafenib, enzalutamide,|
03680|017|E|eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine,|
03680|018|E|oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin,|
03680|019|E|rifapentine, ritonavir, or St. John's wort may result in decreased levels|
03680|020|E|and effectiveness of cabotegravir-rilpivirine, as well as the development of|
03680|021|E|resistance.(1)|
03680|022|B||
03680|023|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03680|024|P|of the inducer for longer than 1-2 weeks.|
03680|025|B||
03680|026|M|PATIENT MANAGEMENT:  The US manufacturer of cabotegravir-rilpivirine states|
03680|027|M|that concurrent use of CYP3A4 inducers and/or UGT1A1 inducers is|
03680|028|M|contraindicated.(1)|
03680|029|M|   It may take several weeks after the discontinuation of an enzyme inducer|
03680|030|M|for enzyme activity to return to normal.(1)|
03680|031|B||
03680|032|D|DISCUSSION:  In a study in 16 subjects, rifampin (600 mg daily) decreased|
03680|033|D|the concentration maximum (Cmax), area-under-curve (AUC), and concentration|
03680|034|D|minimum (Cmin) of rilpivirine (150 mg daily) by 69%, 80%, and 89%,|
03680|035|D|respectively.  There were no significant effects on the Cmax or AUC of|
03680|036|D|rifampin or 25-desacetylrifampin.(1)|
03680|037|D|   In a study in 15 subjects, rifampin (600 mg daily) decreased the Cmax,|
03680|038|D|AUC, and Cmin of cabotegravir by 6%, 59%, and 50%, respectively.(1)|
03680|039|D|   Strong CYP3A4 inducers linked include: apalutamide, barbiturates,|
03680|040|D|carbamazepine, dexamethasone, encorafenib, enzalutamide, eslicarbazepine,|
03680|041|D|fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine,|
03680|042|D|phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or|
03680|043|D|St. John's wort.(1,2)|
03680|044|D|   UGT1A1 inducers linked include: carbamazepine, efavirenz, fosphenytoin,|
03680|045|D|oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin,|
03680|046|D|and ritonavir.(1,2)|
03680|047|B||
03680|048|R|REFERENCES:|
03680|049|B||
03680|050|R|1.Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine|1
03680|051|R|  extended-release injectable suspension) US prescribing information. ViiV|1
03680|052|R|  Healthcare November, 2024.|1
03680|053|R|2.This information is based on an extract from the Certara Drug Interaction|6
03680|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03681|001|T|MONOGRAPH TITLE:  Cabotegravir/UGT1A1 Inducers|
03681|002|B||
03681|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03681|004|L|is contraindicated and generally should not be dispensed or administered to|
03681|005|L|the same patient.|
03681|006|B||
03681|007|A|MECHANISM OF ACTION:  Carbamazepine, efavirenz, fosphenytoin, oxcarbazepine,|
03681|008|A|phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir|
03681|009|A|may induce the metabolism of cabotegravir by uridine diphosphate|
03681|010|A|(UDP)-glucuronosyl transferase 1A1 (UGT1A1).(1)|
03681|011|B||
03681|012|E|CLINICAL EFFECTS:  Concurrent or recent use of carbamazepine, efavirenz,|
03681|013|E|fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone,|
03681|014|E|rifapentine, rifampin, or ritonavir may result in decreased levels and|
03681|015|E|effectiveness of cabotegravir, as well as the development of resistance.(1)|
03681|016|B||
03681|017|P|PREDISPOSING FACTORS:  None determined.|
03681|018|B||
03681|019|M|PATIENT MANAGEMENT:  The US manufacturer of cabotegravir states that|
03681|020|M|concurrent use of UGT1A1 inducers such as carbamazepine, fosphenytoin,|
03681|021|M|oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin,|
03681|022|M|and ritonavir is contraindicated.(1)|
03681|023|M|   It may take several weeks after the discontinuation of an enzyme inducer|
03681|024|M|for enzyme activity to return to normal.(1)|
03681|025|B||
03681|026|D|DISCUSSION:  In a study in 15 subjects, rifampin (600 mg daily) decreased|
03681|027|D|the concentration maximum (Cmax), area-under-curve (AUC), and concentration|
03681|028|D|minimum (Cmin) of cabotegravir by 6%, 59%, and 50%, respectively.(1)|
03681|029|D|   UGT1A1 inducers linked include: carbamazepine, efavirenz, fosphenytoin,|
03681|030|D|oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin,|
03681|031|D|and ritonavir.(1,2)|
03681|032|B||
03681|033|R|REFERENCES:|
03681|034|B||
03681|035|R|1.Vocabria (cabotegravir) tablets US prescribing information. ViiV|1
03681|036|R|  Healthcare January, 2021.|1
03681|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
03681|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03682|001|T|MONOGRAPH TITLE:  Selected Dopamine Agonists/Slt Antipsychotics|
03682|002|B||
03682|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03682|004|L|of severe adverse interaction.|
03682|005|B||
03682|006|A|MECHANISM OF ACTION:  Selected dopamine agonists are used to treat|
03682|007|A|neurologic conditions such as Parkinson Disease (PD) or restless legs|
03682|008|A|syndrome, and endocrine disorders such as hyperprolactinemia by directly or|
03682|009|A|indirectly increasing dopamine concentrations at D2 receptors in the central|
03682|010|A|nervous system (CNS).  Antipsychotic agents counteract this effect by|
03682|011|A|blocking dopamine activity at CNS D2 receptors.(1-5)|
03682|012|B||
03682|013|E|CLINICAL EFFECTS:  The efficacy of either agent may be decreased, leading to|
03682|014|E|exacerbation of the disease being treated.|
03682|015|E|   In patients with Parkinson disease motor symptoms may worsen, increasing|
03682|016|E|the risk for falls, dysphagia or aspiration.(4,7)  Compared with Parkinson|
03682|017|E|patients not receiving antipsychotic therapy, Parkinson patients receiving|
03682|018|E|antipsychotics appear to have an increased mortality risk.(6)|
03682|019|E|   Patients with other conditions such as restless legs syndrome or a|
03682|020|E|psychotic disorder may also experience symptom exacerbation due to this|
03682|021|E|combination.|
03682|022|B||
03682|023|P|PREDISPOSING FACTORS:  Patients with Parkinson or Diffuse Lewy Body (DLB)|
03682|024|P|disease are particularly susceptible to adverse effects of dopamine blockade|
03682|025|P|by antipsychotics.|
03682|026|B||
03682|027|M|PATIENT MANAGEMENT:  Reassess the need for antipsychotic therapy.  If|
03682|028|M|psychosis or hallucinations are due to an antiparkinson agent, when possible|
03682|029|M|consider reducing the dose or changing the antiparkinson agent before|
03682|030|M|initiating antipsychotic therapy.  In patients with PD and dementia,|
03682|031|M|addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve|
03682|032|M|psychosis.  If an antipsychotic is required, then an atypical antipsychotic|
03682|033|M|should be used.(6,7)|
03682|034|M|   In patients with major psychotic disorders, consider reducing the dose,|
03682|035|M|changing or stopping the dopamine agonist.  The US manufacturer of|
03682|036|M|ropinirole recommends treatment with dopamine agonists only if potential|
03682|037|M|benefits outweigh risks.(1)  The US manufacturer of entacapone states it|
03682|038|M|should not ordinarily be used in patients with major psychotic disorders as|
03682|039|M|entacapone may lead to an exacerbation of psychosis.(4)|
03682|040|B||
03682|041|D|DISCUSSION:  An epidemiologic study evaluated 21,043 elderly patients with|
03682|042|D|Parkinson disease to determine if recent initiation of a typical or atypical|
03682|043|D|antipsychotic was associated with increased mortality.  They found an|
03682|044|D|adjusted odds ratio of 2.0 for death associated with atypical antipsychotics|
03682|045|D|versus no antipsychotic  They found an adjusted odds ratio of 2.4 for death|
03682|046|D|associated with typical versus atypical antipsychotics. The authors noted|
03682|047|D|the increased mortality found with typical antipsychotics supports current|
03682|048|D|treatment recommendations to use atypical antipsychotic agents in patients|
03682|049|D|with Parkinson disease.(6,7)|
03682|050|B||
03682|051|R|REFERENCES:|
03682|052|B||
03682|053|R|1.Requip (ropinirole hydrochloride) US prescribing information.|1
03682|054|R|  GlaxoSmithKline July, 2021.|1
03682|055|R|2.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
03682|056|R|  February, 2011.|1
03682|057|R|3.Stalveo (carbidopa; entacapone; levodopa) US Prescribing Information.|1
03682|058|R|  Orion/Novartis December, 2019.|1
03682|059|R|4.Comtan (entacapone) US prescribing information. Orion Corporation|1
03682|060|R|  February, 2016.|1
03682|061|R|5.Neupro (rotigotine transdermal system) US prescribing information. UCB|1
03682|062|R|  Inc. November, 2018.|1
03682|063|R|6.Marras C, Gruneir A, Wang X, Fischer H, Gill SS, Herrmann N, Anderson GM,|2
03682|064|R|  Hyson C, Rochon PA. Antipsychotics and mortality in Parkinsonism. Am J|2
03682|065|R|  Geriatr Psychiatry 2012 Feb;20(2):149-58.|2
03682|066|R|7.Oertel WH Berardelli A Bloem Br etal. Chapter 15 - Late (complicated)|6
03682|067|R|  Parkinson's disease in European Handbook of Neurological Management. 2011;|6
03682|068|R|  Volume 1, 2nd Edition:237 - 267.|6
03683|001|T|MONOGRAPH TITLE:  Apomorphine/Lofexidine|
03683|002|B||
03683|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03683|004|L|take action as needed.|
03683|005|B||
03683|006|A|MECHANISM OF ACTION:  Apomorphine causes dose-dependent decreases in blood|
03683|007|A|pressure and has been shown to prolong the QTc interval.  Concurrent use|
03683|008|A|with other drugs that lower blood pressure and prolong the QTc interval may|
03683|009|A|result in additive effects on blood pressure and the QTc interval.(1)|
03683|010|B||
03683|011|E|CLINICAL EFFECTS:  Concurrent use of lofexidine with apomorphine may result|
03683|012|E|in orthostatic hypotension with or without dizziness, nausea, or syncope,|
03683|013|E|and potentially life-threatening cardiac arrhythmias, including torsades de|
03683|014|E|pointes.(1)|
03683|015|B||
03683|016|P|PREDISPOSING FACTORS:  The risk of orthostatic hypotension may be increased|
03683|017|P|during dose escalation of apomorphine and in patients with renal or hepatic|
03683|018|P|impairment.(1)|
03683|019|P|   The risk of QT prolongation or torsade de pointes may be increased in|
03683|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03683|021|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03683|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03683|023|P|advanced age.(2)|
03683|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03683|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03683|026|P|factors for torsade de pointes.  Factors which may increase systemic drug|
03683|027|P|concentrations include rapid infusion of an intravenous dose or impaired|
03683|028|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03683|029|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03683|030|P|metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03683|031|B||
03683|032|M|PATIENT MANAGEMENT:  The manufacturer of apomorphine states that the use of|
03683|033|M|apomorphine with other agents known to prolong the QT interval should be|
03683|034|M|done with caution.(1)|
03683|035|M|   The UK manufacturer of lofexidine states that concurrent use of|
03683|036|M|lofexidine and QT prolonging agents should be avoided.(3)  The US|
03683|037|M|manufacturer states that ECGs should be monitored in patients receiving|
03683|038|M|concurrent therapy with lofexidine and agents that are known to prolong the|
03683|039|M|QT interval.(4)|
03683|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03683|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03683|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03683|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03683|044|M|   Patients receiving concurrent therapy should also be monitored for|
03683|045|M|hypotension.  Counsel patients about the risk of orthostatic hypotension.(1)|
03683|046|B||
03683|047|D|DISCUSSION:  Healthy volunteers who took sublingual nitroglycerin (0.4 mg)|
03683|048|D|concomitantly with apomorphine experienced a mean largest decrease in supine|
03683|049|D|systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood|
03683|050|D|pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and|
03683|051|D|DBP of 14.3 mm Hg and 13.5 mm Hg, respectively.  The maximum decrease in SBP|
03683|052|D|and DBP was 65 mm Hg and 43 mm Hg, respectively.  When apomorphine was taken|
03683|053|D|alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3|
03683|054|D|mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm|
03683|055|D|Hg, respectively.(1)|
03683|056|D|   Agents that are linked to this monograph may have varying degrees of|
03683|057|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03683|058|D|been shown to prolong the QTc interval either through their mechanism of|
03683|059|D|action, through studies on their effects on the QTc interval, or through|
03683|060|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03683|061|D|and/or postmarketing reports.(5)|
03683|062|B||
03683|063|R|REFERENCES:|
03683|064|B||
03683|065|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
03683|066|R|  Inc. May, 2019.|1
03683|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03683|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03683|069|R|  settings: a scientific statement from the American Heart Association and|6
03683|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03683|071|R|  2;55(9):934-47.|6
03683|072|R|3.Lucemyra (lofexidine) US prescribing information. US WorldMeds, LLC May|1
03683|073|R|  16, 2018.|1
03683|074|R|4.BritLofex (lofexidine) UK summary of product characteristics. Britannia|1
03683|075|R|  Pharmaceuticals Limited August 25, 2015.|1
03683|076|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03683|077|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03683|078|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03683|079|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03684|001|T|MONOGRAPH TITLE:  Ranolazine/Strong CYP3A4 Inhibitors that Prolong QT|
03684|002|B||
03684|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03684|004|L|is contraindicated and generally should not be dispensed or administered to|
03684|005|L|the same patient.|
03684|006|B||
03684|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03684|008|A|interval may inhibit the metabolism of ranolazine and result in additive|
03684|009|A|effects on the QTc interval.(1,2)|
03684|010|B||
03684|011|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03684|012|E|prolong the QTc interval may result in elevated levels of and clinical|
03684|013|E|effects from ranolazine, including additive QTc prolongation and|
03684|014|E|life-threatening cardiac arrhythmia like torsades de pointes.(1,2)|
03684|015|B||
03684|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03684|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03684|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03684|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03684|020|P|female gender, or advanced age.(3)|
03684|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03684|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03684|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03684|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03684|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03684|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03684|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03684|028|B||
03684|029|M|PATIENT MANAGEMENT:  The concurrent use of ranolazine with strong CYP3A4|
03684|030|M|inhibitors is contraindicated.(1,2)|
03684|031|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
03684|032|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
03684|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03684|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03684|035|B||
03684|036|D|DISCUSSION:  Concurrent use of ketoconazole (200 mg twice daily), a strong|
03684|037|D|CYP3A4 inhibitor, increased plasma levels of ranolazine (1000 mg twice|
03684|038|D|daily) by 220%.(1)|
03684|039|D|   Ranolazine-induced QTc prolongation is dose and|
03684|040|D|concentration-related.(1,2)|
03684|041|D|   Strong inhibitors of CYP3A4 that prolong the QTc interval include:|
03684|042|D|adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib,|
03684|043|D|lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and|
03684|044|D|voriconazole.(1,2,4,5)|
03684|045|B||
03684|046|R|REFERENCES:|
03684|047|B||
03684|048|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
03684|049|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
03684|050|R|  Pharma U.K. S.R.I. October 30, 2008.|1
03684|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03684|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03684|053|R|  settings: a scientific statement from the American Heart Association and|6
03684|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03684|055|R|  2;55(9):934-47.|6
03684|056|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03684|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03684|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03684|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03684|060|R|  11/14/2017.|1
03684|061|R|5.This information is based on an extract from the Certara Drug Interaction|6
03684|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03685|001|T|MONOGRAPH TITLE:  Tacrolimus/Ribociclib|
03685|002|B||
03685|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03685|004|L|of severe adverse interaction.|
03685|005|B||
03685|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 such as ribociclib may|
03685|007|A|inhibit the metabolism of tacrolimus.(1,2)|
03685|008|A|   In addition, concurrent use of tacrolimus with ribociclib may result in|
03685|009|A|additive or synergistic effects on the QTc interval.(1,2)|
03685|010|B||
03685|011|E|CLINICAL EFFECTS:  Concurrent use with ribociclib may result in elevated|
03685|012|E|levels of and toxicity from tacrolimus, including nephrotoxicity and|
03685|013|E|neurotoxicity.(1)|
03685|014|E|   In addition, concurrent administration may result in prolongation of the|
03685|015|E|QTc interval and life-threatening cardiac arrhythmias, including torsades de|
03685|016|E|pointes.|
03685|017|B||
03685|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03685|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03685|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03685|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03685|022|P|gender, or advanced age.(3)|
03685|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03685|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03685|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03685|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03685|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03685|028|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03685|029|P|dysfunction).(3)|
03685|030|B||
03685|031|M|PATIENT MANAGEMENT:  Avoid concurrent use of ribociclib with agents known to|
03685|032|M|prolong the QT interval.(2)|
03685|033|M|   If concurrent therapy is deemed medically necessary, monitor patients|
03685|034|M|closely.  Obtain serum calcium, magnesium, and potassium levels and correct|
03685|035|M|any electrolyte abnormalities at the beginning of each ribociclib cycle.|
03685|036|M|Monitor ECG at baseline, Day 14 of the first cycle, at the beginning of the|
03685|037|M|second cycle, and as necessary.  If a prolonged QTc is noted, refer to|
03685|038|M|ribociclib prescribing information for current dose modification and|
03685|039|M|management instructions.  Ribociclib may need to be interrupted, reduced, or|
03685|040|M|discontinued.(2)|
03685|041|M|   The US manufacturer of tacrolimus states that coadministration with a|
03685|042|M|strong CYP3A4 inhibitor like ribociclib may result in a rapid and sharp rise|
03685|043|M|in tacrolimus concentration despite immediate tacrolimus dose reduction.|
03685|044|M|Frequent monitoring of tacrolimus levels should start within 1-3 days of|
03685|045|M|initiation of concurrent therapy and continue as necessary.(1)|
03685|046|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
03685|047|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03685|048|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03685|049|M|heartbeat, dizziness, or fainting.|
03685|050|B||
03685|051|D|DISCUSSION:  Coadministration of midazolam (a sensitive CYP3A4 substrate)|
03685|052|D|with multiple doses of ribociclib (400 mg) increased the midazolam exposure|
03685|053|D|by 3.8-fold in healthy subjects, compared with administration of midazolam|
03685|054|D|alone. Ribociclib given at the clinically relevant dose of 600 mg is|
03685|055|D|predicted to increase the midazolam AUC by 5.2-fold.(2)|
03685|056|D|   The coadministration of amiodarone (a weak CYP3A4 inhibitor) and|
03685|057|D|tacrolimus was described in a case report of a 73-year-old kidney transplant|
03685|058|D|recipient with normal renal function who was on amiodarone for years.|
03685|059|D|Tacrolimus 7 mg per day was started and after 3 months, the patient was|
03685|060|D|found to have a tacrolimus level of 63 ng/mL.  The dose of tacrolimus was|
03685|061|D|lowered to 2 mg per day, and tacrolimus levels dropped to 12.9 ng/mL.(4)|
03685|062|D|   In another case report, a 65-year-old man on amiodarone for 5 years|
03685|063|D|started tacrolimus 3 mg twice daily status-post renal transplant.  After one|
03685|064|D|day, QTc was prolonged from a baseline of 440 ms to 535 ms.  QTc dropped to|
03685|065|D|493 ms three days after discontinuation of amiodarone and dose reduction of|
03685|066|D|tacrolimus.(5)|
03685|067|D|   A case report describes the interaction between azithromycin (a weak|
03685|068|D|CYP3A4 inhibitor) and tacrolimus in a 27-year old woman with acute|
03685|069|D|myelogenous leukemia who had a bone marrow transplant.  On tacrolimus 0.02|
03685|070|D|mg/kg/day IV, the patient had stable tacrolimus levels of 15.8 to 17.5|
03685|071|D|ng/mL.  Three days after initiation of azithromycin 500 mg daily, tacrolimus|
03685|072|D|levels rose to over 30 ng/mL.(6)|
03685|073|D|   In a case report, a 64-year-old kidney transplant recipient on a stable|
03685|074|D|dose of tacrolimus 10 mg twice daily for 5 months was started on ranolazine|
03685|075|D|(a weak CYP3A4 inhibitor) 500 mg twice daily for angina.  Tacrolimus levels|
03685|076|D|rose from the patient's stable levels of 7 to 10 ng/mL in the previous 5|
03685|077|D|months to 17.8 ng/mL after 1 day.(7)|
03685|078|D|   Another case report describes a 54-year-old kidney transplant recipient|
03685|079|D|on tacrolimus 3 mg twice daily with trough levels of 4.5 to 7.4 ng/mL for|
03685|080|D|the previous 4 years.  After he was started on ranolazine 375 mg twice|
03685|081|D|daily, tacrolimus levels rose to 10.9 ng/mL and serum creatinine (Scr) rose|
03685|082|D|from 1.2 to 2 mg/dL.  Ranolazine was discontinued after one month, and|
03685|083|D|tacrolimus levels dropped to 3.6 ng/mL, with complete reversal of renal|
03685|084|D|failure.(8)|
03685|085|D|   A 62-year-old kidney transplant recipient on a stable dose of tacrolimus|
03685|086|D|for years was started on ranolazine and titrated to 1,000 mg twice daily|
03685|087|D|over one month.  After 2 weeks, he experienced renal failure with Scr rising|
03685|088|D|from 1.5 to 2.4 mg/dL, and tacrolimus level was elevated at 14 ng/mL.|
03685|089|D|Ranolazine was discontinued and tacrolimus levels decreased to 7 ng/mL after|
03685|090|D|3 days, with Scr returning to baseline.(9)|
03685|091|B||
03685|092|R|REFERENCES:|
03685|093|B||
03685|094|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
03685|095|R|  August, 2023.|1
03685|096|R|2.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
03685|097|R|  Corporation September, 2024.|1
03685|098|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03685|099|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03685|100|R|  settings: a scientific statement from the American Heart Association and|6
03685|101|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03685|102|R|  2;55(9):934-47.|6
03685|103|R|4.Kisters K, Cziborra M, Funke C, Brylak S, Hausberg M.|3
03685|104|R|  Amiodarone-tacrolimus interaction in kidney transplantation. Clin Nephrol|3
03685|105|R|  2008 Dec;70(6):563.|3
03685|106|R|5.Burger CI, Clase CM, Gangji AS. Case report: drug interaction between|3
03685|107|R|  tacrolimus and amiodarone with QT prolongation. Transplantation 2010 May|3
03685|108|R|  15;89(9):1166-7.|3
03685|109|R|6.Mori T, Aisa Y, Nakazato T, Yamazaki R, Ikeda Y, Okamoto S.|3
03685|110|R|  Tacrolimus-azithromycin interaction in a recipient of allogeneic bone|3
03685|111|R|  marrow transplantation. Transpl Int 2005 Jun;18(6):757-8.|3
03685|112|R|7.Pierce Dwayne A, Reeves-Daniel Amber M. Ranolazine-tacrolimus interaction.|3
03685|113|R|  Ann Pharmacother 2010 Nov;44(11):1844-1849.|3
03685|114|R|8.Seck Sidy, Bellantoni Marianna, Zoccali Carmine, Enia Giuseppe. Ranolazine|3
03685|115|R|  can markedly increase tacrolimus blood levels. NDT Plus 2011 Feb;|3
03685|116|R|  4(1):44-45.|3
03685|117|R|9.Patni Hitesh, Gitman Michael, Hazzan Azzour, Jhaveri Kenar D. Ranolazine,|3
03685|118|R|  tacrolimus, and diltiazem might be a hazardous combination in a transplant|3
03685|119|R|  patient. Ren Fail 2012 Jan;34(2):251-253.|3
03686|001|T|MONOGRAPH TITLE:  Cabotegravir/Polyvalent Cations|
03686|002|B||
03686|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03686|004|L|take action as needed.|
03686|005|B||
03686|006|A|MECHANISM OF ACTION:  Cabotegravir chelates polyvalent cations such as|
03686|007|A|aluminum, calcium, iron, magnesium, selenium, and zinc.(1)|
03686|008|B||
03686|009|E|CLINICAL EFFECTS:  Simultaneous administration of cabotegravir and|
03686|010|E|polyvalent cations may decrease the absorption and clinical effects of|
03686|011|E|cabotegravir.(1)|
03686|012|B||
03686|013|P|PREDISPOSING FACTORS:  None determined.|
03686|014|B||
03686|015|M|PATIENT MANAGEMENT:  The US manufacturer of cabotegravir states that it|
03686|016|M|should be administered at least 2 hours before or 4 hours after any|
03686|017|M|medications or products containing polyvalent cations such as antacids or|
03686|018|M|mineral supplements.(1)|
03686|019|B||
03686|020|D|DISCUSSION:  Clinical studies have not been conducted.  Prescribing|
03686|021|D|information states cabotegravir levels may be decreased when coadministered|
03686|022|D|with antacids containing polyvalent cations (examples include aluminum or|
03686|023|D|magnesium hydroxide, calcium carbonate) suggesting cabotegravir is|
03686|024|D|susceptible to chelation.(1)|
03686|025|B||
03686|026|R|REFERENCE:|
03686|027|B||
03686|028|R|1.Vocabria (cabotegravir) tablets US prescribing information. ViiV|1
03686|029|R|  Healthcare January, 2021.|1
03687|001|T|MONOGRAPH TITLE:  Voclosporin/Strong CYP3A4 Inhibitors|
03687|002|B||
03687|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03687|004|L|is contraindicated and generally should not be dispensed or administered to|
03687|005|L|the same patient.|
03687|006|B||
03687|007|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03687|008|A|the metabolism of voclosporin.(1)|
03687|009|B||
03687|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03687|011|E|levels of and effects from voclosporin, including infection, neurotoxicity,|
03687|012|E|nephrotoxicity, hypertension, or hyperkalemia.(1)|
03687|013|B||
03687|014|P|PREDISPOSING FACTORS:  None determined.|
03687|015|B||
03687|016|M|PATIENT MANAGEMENT:  The prescribing information for voclosporin states the|
03687|017|M|use of strong CYP3A4 inhibitors in patients undergoing therapy with|
03687|018|M|voclosporin is contraindicated.(1)  Consider alternatives with no or minimal|
03687|019|M|enzyme inhibition.|
03687|020|B||
03687|021|D|DISCUSSION:  Concurrent use of voclosporin and ketoconazole 400 mg daily|
03687|022|D|(strong CYP3A4 inhibitor)for 9 days increased the concentration maximum|
03687|023|D|(Cmax) and area-under-curve (AUC) by 6.45-fold and 18.55-fold,|
03687|024|D|respectively.(1)|
03687|025|D|   Concurrent use of voclosporin and verapamil 80 mg three times a day for|
03687|026|D|10 days (moderate CYP3A4 inhibitor and P-gp inhibitor) increased Cmax and|
03687|027|D|AUC by 2.08-fold and 2.71-fold, respectively.(1)|
03687|028|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
03687|029|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03687|030|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03687|031|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03687|032|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03687|033|D|tucatinib, or voriconazole.(2,3)|
03687|034|B||
03687|035|R|REFERENCES:|
03687|036|B||
03687|037|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
03687|038|R|  April, 2024.|1
03687|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03687|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03687|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03687|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03687|043|R|  11/14/2017.|1
03687|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
03687|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03688|001|T|MONOGRAPH TITLE:  Voclosporin/Moderate CYP3A4 Inhibitors|
03688|002|B||
03688|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03688|004|L|of severe adverse interaction.|
03688|005|B||
03688|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03688|007|A|the metabolism of voclosporin.(1)|
03688|008|B||
03688|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
03688|010|E|levels of and effects from voclosporin, including infection, neurotoxicity,|
03688|011|E|nephrotoxicity, hypertension, or hyperkalemia.(1)|
03688|012|B||
03688|013|P|PREDISPOSING FACTORS:  None determined.|
03688|014|B||
03688|015|M|PATIENT MANAGEMENT:  The prescribing information for voclosporin states the|
03688|016|M|use of moderate CYP3A4 inhibitors in patients undergoing therapy with|
03688|017|M|voclosporin requires a dose adjustment.  Voclosporin dose should be reduced|
03688|018|M|to 15.8 mg in the morning and 7.9 mg in the evening.(1)  Consider|
03688|019|M|alternatives with no or minimal enzyme inhibition.|
03688|020|B||
03688|021|D|DISCUSSION:  Concurrent use of voclosporin and ketoconazole 400 mg daily|
03688|022|D|(strong CYP3A4 inhibitor) for 9 days increased the concentration maximum|
03688|023|D|(Cmax) and area-under-curve (AUC) by 6.45-fold and 18.55-fold,|
03688|024|D|respectively.(1)|
03688|025|D|   Concurrent use of voclosporin and verapamil 80 mg three times a day for|
03688|026|D|10 days (moderate CYP3A4 inhibitor and P-gp inhibitor) increased Cmax and|
03688|027|D|AUC by 2.08-fold and 2.71-fold, respectively.(1)|
03688|028|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
03688|029|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
03688|030|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
03688|031|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
03688|032|D|isavuconazonium, oral lefamulin, lenacapavir, netupitant, nilotinib,|
03688|033|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
03688|034|D|verapamil, and voxelotor.(2,3)|
03688|035|B||
03688|036|R|REFERENCES:|
03688|037|B||
03688|038|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
03688|039|R|  April, 2024.|1
03688|040|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03688|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03688|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03688|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03688|044|R|  11/14/2017.|1
03688|045|R|3.This information is based on an extract from the Certara Drug Interaction|6
03688|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03689|001|T|MONOGRAPH TITLE:  Voclosporin/Strong and Moderate CYP3A4 Inducers|
03689|002|B||
03689|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03689|004|L|of severe adverse interaction.|
03689|005|B||
03689|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03689|007|A|metabolism of voclosporin.(1)|
03689|008|B||
03689|009|E|CLINICAL EFFECTS:  Concurrent use of strong and moderate CYP3A4 inducers may|
03689|010|E|decrease the serum levels and effectiveness of voclosporin.(1)|
03689|011|B||
03689|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03689|013|P|of the inducer for longer than 1-2 weeks.|
03689|014|B||
03689|015|M|PATIENT MANAGEMENT:  The use of strong or moderate CYP3A4 inducers with|
03689|016|M|voclosporin should be avoided.(1)|
03689|017|B||
03689|018|D|DISCUSSION:  Concurrent use of voclosporin with rifampin 600 mg daily for 10|
03689|019|D|days (strong CYP3A4 inducer) decreased the concentration maximum (Cmax) and|
03689|020|D|area-under-curve (AUC) by 0.32-fold and 0.13-fold, respectively.(1)|
03689|021|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03689|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03689|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03689|024|D|rifapentine, and St. John's wort.(2,3)|
03689|025|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03689|026|D|dabrafenib, efavirenz, etravirine, lesinurad, lorlatinib, mavacamten,|
03689|027|D|mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib,|
03689|028|D|rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)|
03689|029|B||
03689|030|R|REFERENCES:|
03689|031|B||
03689|032|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
03689|033|R|  April, 2024.|1
03689|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03689|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03689|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03689|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03689|038|R|  11/14/2017.|1
03689|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03689|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03690|001|T|MONOGRAPH TITLE:  Cyclophosphamide/Voclosporin|
03690|002|B||
03690|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03690|004|L|is contraindicated and generally should not be dispensed or administered to|
03690|005|L|the same patient.|
03690|006|B||
03690|007|A|MECHANISM OF ACTION:  Safety and efficacy of concurrent use of|
03690|008|A|cyclophosphamide and voclosporin has not been studied.  Concurrent use may|
03690|009|A|increase the toxicity of cyclophosphamide and/or voclosporin.(1)|
03690|010|B||
03690|011|E|CLINICAL EFFECTS:  Concurrent use may increase toxicity from|
03690|012|E|cyclophosphamide and/or voclosporin.(1)|
03690|013|B||
03690|014|P|PREDISPOSING FACTORS:  None determined.|
03690|015|B||
03690|016|M|PATIENT MANAGEMENT:  The prescribing information for voclosporin states|
03690|017|M|concurrent use with cyclophosphamide is not recommended.  Safety and|
03690|018|M|efficacy of concurrent use of cyclophosphamide and voclosporin has not been|
03690|019|M|studied.(1)|
03690|020|B||
03690|021|D|DISCUSSION:  Concurrent use of voclosporin and cyclophosphamide has not been|
03690|022|D|studied.  Safety and efficacy has not been established and therefore|
03690|023|D|concurrent use should be avoided.(1)|
03690|024|B||
03690|025|R|REFERENCES:|
03690|026|B||
03690|027|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
03690|028|R|  April, 2024.|1
03690|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03690|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03690|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03690|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03690|033|R|  11/14/2017.|1
03690|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
03690|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03691|001|T|MONOGRAPH TITLE:  Erythromycin/Lumacaftor-Ivacaftor|
03691|002|B||
03691|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03691|004|L|of severe adverse interaction.|
03691|005|B||
03691|006|A|MECHANISM OF ACTION:  Lumacaftor, a strong inducer of CYP3A4, may induce the|
03691|007|A|metabolism of erythromycin.(1)|
03691|008|B||
03691|009|E|CLINICAL EFFECTS:  Serum levels of erythromycin may be decreased, resulting|
03691|010|E|in reduced effectiveness and/or therapeutic failure of erythromycin therapy.|
03691|011|B||
03691|012|P|PREDISPOSING FACTORS:  None determined.|
03691|013|B||
03691|014|M|PATIENT MANAGEMENT:  Since the effectiveness of erythromycin may be|
03691|015|M|compromised by concomitant lumacaftor-ivacaftor, consider use of alternative|
03691|016|M|antibiotics that are not metabolized by CYP3A4, such as ciprofloxacin,|
03691|017|M|azithromycin, and levofloxacin.(1)|
03691|018|B||
03691|019|D|DISCUSSION:  In an interaction study lumacaftor reduced exposure to|
03691|020|D|ivacaftor, a CYP3A4 sensitive substrate, by 80%.(1)|
03691|021|B||
03691|022|R|REFERENCES:|
03691|023|B||
03691|024|R|1.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
03691|025|R|  Pharmaceuticals Inc. August, 2023.|1
03691|026|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03691|027|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03691|028|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03691|029|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03691|030|R|  11/14/2017.|1
03692|001|T|MONOGRAPH TITLE:  Bosentan/Idelalisib|
03692|002|B||
03692|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03692|004|L|of severe adverse interaction.|
03692|005|B||
03692|006|A|MECHANISM OF ACTION:  Bosentan is metabolized by CYP2C9 and CYP3A4.  It is|
03692|007|A|also an inducer of these enzymes.  With regular dosing bosentan auto-induces|
03692|008|A|its own metabolism.(1)  Strong and moderate CYP3A4 inhibitors may inhibit|
03692|009|A|the CYP3A4 mediated metabolism of bosentan.(1,2)  Idelalisib is a strong|
03692|010|A|CYP3A4 inhibitor.(3,4)|
03692|011|A|   Idelalisib is a substrate of CYP3A4.  Agents that induce the CYP3A4|
03692|012|A|isoenzyme may induce the metabolism of idelalisib.(3)|
03692|013|B||
03692|014|E|CLINICAL EFFECTS:  Concurrent use of bosentan with an inhibitor of CYP3A4|
03692|015|E|may result in elevated levels of and toxicity from bosentan.(1)|
03692|016|E|   Concurrent use of moderate CYP3A4 inducers may decrease the levels and|
03692|017|E|effectiveness of idelalisib.(2)|
03692|018|B||
03692|019|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, idelalisib, and a CYP2C9|
03692|020|P|inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
03692|021|P|sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major|
03692|022|P|metabolic pathways for bosentan, resulting in large increases in bosentan|
03692|023|P|plasma concentrations.(1,3)|
03692|024|B||
03692|025|M|PATIENT MANAGEMENT:  Avoid the concurrent use of bosentan, a moderate CYP3A4|
03692|026|M|inducer, in patients receiving therapy with idelalisib.  Consider the use of|
03692|027|M|alternative agents with less enzyme induction potential.(3)|
03692|028|M|   Review medication list to see if patient is also receiving a CYP2C9|
03692|029|M|inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
03692|030|M|sulfinpyrazone, or phenylbutazone).  Concomitant use of both a CYP2C9 and|
03692|031|M|CYP3A4 inhibitor is not recommended by the manufacturer as the combination|
03692|032|M|may lead to large increases in bosentan plasma concentrations.(1)|
03692|033|M|   For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated,|
03692|034|M|monitor tolerance to concomitant therapy and adjust bosentan dose if needed.|
03692|035|M|   In patients who have been receiving a strong CYP3A4 inhibitor for at|
03692|036|M|least 10 days, start bosentan at 62.5 mg once daily or every other day based|
03692|037|M|upon individual tolerability.|
03692|038|M|   Discontinue use of bosentan at least 36 hours prior to initiation of a|
03692|039|M|strong CYP3A4 inhibitor.|
03692|040|M|   After at least 10 days following the initiation of a strong CYP3A4|
03692|041|M|inhibitor, resume bosentan at 62.5 mg once daily or every other day based|
03692|042|M|upon individual tolerability.(1)|
03692|043|B||
03692|044|D|DISCUSSION:  In a study in healthy subjects, concurrent bosentan and|
03692|045|D|ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan|
03692|046|D|steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by|
03692|047|D|2.1-fold and 2.3-fold, respectively.(2)|
03692|048|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
03692|049|D|decreased the concentration maximum (Cmax) and area-under-curve (AUC) of|
03692|050|D|idelalisib (150 mg single dose) by 58% and 75%, respectively.(3)|
03692|051|B||
03692|052|R|REFERENCES:|
03692|053|B||
03692|054|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
03692|055|R|  US, Inc. September 5, 2017.|1
03692|056|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
03692|057|R|  Pharmaceuticals February, 2014.|1
03692|058|R|3.Zydelig (idelalisib) UK Summary of Product Characteristics. Gilead|1
03692|059|R|  Sciences Ltd December 17, 2019.|1
03692|060|R|4.This information is based on an extract from the Certara Drug Interaction|6
03692|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03693|001|T|MONOGRAPH TITLE:  Ceritinib/Idelalisib|
03693|002|B||
03693|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03693|004|L|of severe adverse interaction.|
03693|005|B||
03693|006|A|MECHANISM OF ACTION:  Ceritinib and idelalisib are both agents that inhibit|
03693|007|A|the CYP3A4 isoenzyme and are substrates of CYP3A4.(1,2)|
03693|008|B||
03693|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03693|010|E|levels of and effects from both ceritinib and idelalisib.(1)|
03693|011|E|    Elevated levels of ceritinib may result in QTc prolongation, which may|
03693|012|E|result in potentially life-threatening cardiac arrhythmias, including|
03693|013|E|torsades de pointes (TdP).  Other toxicities include bradycardia, nausea,|
03693|014|E|vomiting, diarrhea, abdominal pain, transaminitis, hyperglycemia,|
03693|015|E|interstitial lung disease, and pancreatitis.(1)|
03693|016|E|   Elevated levels of idelalisib may result in hepatotoxicity, diarrhea,|
03693|017|E|colitis, pneumonitis, neutropenia or intestinal perforation.(2)|
03693|018|B||
03693|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03693|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03693|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03693|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03693|023|P|female gender, or advanced age.(3)|
03693|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03693|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03693|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03693|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03693|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03693|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03693|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03693|031|P|   Patients with severe hepatic impairment (Child-Pugh C) may be at|
03693|032|P|increased risk of this interaction.  Ceritinib dose reduction may be|
03693|033|P|warranted in severe hepatic impairment.  See prescribing information for|
03693|034|P|recommendations.(1)|
03693|035|B||
03693|036|M|PATIENT MANAGEMENT:  Avoid the use of idelalisib with ceritinib.(1)|
03693|037|M|Consider alternatives with no or minimal enzyme inhibition.|
03693|038|M|   The optimal doses of ceritinib and idelalisib when used in combination is|
03693|039|M|unknown.  Combination therapy with ceritinib and idelalisib would ideally be|
03693|040|M|utilized within the context of a clinical trial.  Manufacturers provide|
03693|041|M|recommendations for dose modification of ceritinib and idelalisib when each|
03693|042|M|is used with a strong CYP3A4 inhibitor, but the recommendations may not|
03693|043|M|apply when there is a two-way inhibition.  Dose modifications mentioned|
03693|044|M|below are informational only.|
03693|045|M|   If concurrent use with ceritinib is unavoidable, reduce the dosage of|
03693|046|M|ceritinib by one-third, rounding to the nearest 150 mg dosage strength.  If|
03693|047|M|the strong CYP3A4 inhibitor is discontinued, resume the dose that was taken|
03693|048|M|prior to using the inhibitor.(1)|
03693|049|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
03693|050|M|ceritinib should be monitored for prolongation of the QTc interval.  When|
03693|051|M|concurrent therapy is warranted: consider obtaining serum calcium,|
03693|052|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
03693|053|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
03693|054|M|report any irregular heartbeat, dizziness, or fainting.(1)|
03693|055|M|   If concurrent use with idelalisib is warranted, monitor patients for|
03693|056|M|toxicity and follow toxicity dose modification guidelines.(2)|
03693|057|B||
03693|058|D|DISCUSSION:  In a study in 19 healthy subjects, ketoconazole (200 mg twice|
03693|059|D|daily for 14 days) increased the maximum concentration (Cmax) and area under|
03693|060|D|curve (AUC) of a single dose of ceritinib (450 mg) by 22% and 2.9-fold,|
03693|061|D|respectively.  The steady-state AUC of ceritinib at reduced doses after|
03693|062|D|concurrent ketoconazole was predicted by simulations to be similar to the|
03693|063|D|steady-state AUC of ceritinib alone.(1)|
03693|064|D|   In a study in healthy subjects, ketoconazole (400 mg daily for 4 days)|
03693|065|D|increased the AUC of idelalisib (400 mg single dose) by 1.8-fold.(2)|
03693|066|B||
03693|067|R|REFERENCES:|
03693|068|B||
03693|069|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
03693|070|R|  Corporation August, 2021.|1
03693|071|R|2.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03693|072|R|  October, 2020.|1
03693|073|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03693|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03693|075|R|  settings: a scientific statement from the American Heart Association and|6
03693|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03693|077|R|  2;55(9):934-47.|6
03693|078|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03693|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03693|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03693|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03693|082|R|  11/14/2017.|1
03693|083|R|5.This information is based on an extract from the Certara Drug Interaction|6
03693|084|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03694|001|T|MONOGRAPH TITLE:  Crizotinib/Selected Moderate CYP3A4 Inducers|
03694|002|B||
03694|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03694|004|L|of severe adverse interaction.|
03694|005|B||
03694|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
03694|007|A|metabolism of crizotinib.(1)|
03694|008|B||
03694|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inducers may decrease|
03694|010|E|the levels and effectiveness of crizotinib.(1)|
03694|011|B||
03694|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03694|013|P|of the inducer for longer than 1-2 weeks.|
03694|014|B||
03694|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of moderate CYP3A4 inducers in|
03694|016|M|patients receiving therapy with crizotinib.(1)|
03694|017|M|   Consider the use of alternative agents with less enzyme induction|
03694|018|M|potential.(1)|
03694|019|B||
03694|020|D|DISCUSSION:  Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the|
03694|021|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
03694|022|D|crizotinib (250 mg) by 69% and 82%, respectively.(1)|
03694|023|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03694|024|D|cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib,|
03694|025|D|modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl, and|
03694|026|D|tovorafenib.(2)|
03694|027|B||
03694|028|R|REFERENCES:|
03694|029|B||
03694|030|R|1.Xalkori (crizotinib) UK Summary of Product Characteristics. Pfizer Limited|1
03694|031|R|  July, 2021.|1
03694|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03694|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03694|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03694|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03694|036|R|  11/14/2017.|1
03695|001|T|MONOGRAPH TITLE:  Crizotinib/Bosentan|
03695|002|B||
03695|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03695|004|L|of severe adverse interaction.|
03695|005|B||
03695|006|A|MECHANISM OF ACTION:  Crizotinib is a substrate and moderate inhibitor of|
03695|007|A|CYP3A4.(1)  Bosentan is a substrate and moderate inducer of CYP2C9 and|
03695|008|A|CYP3A4.(2)|
03695|009|A|   Agents that induce the CYP3A4 isoenzyme may induce the metabolism of|
03695|010|A|crizotinib.(1)|
03695|011|A|   Moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of|
03695|012|A|bosentan.(2)|
03695|013|B||
03695|014|E|CLINICAL EFFECTS:  Concurrent use of crizotinib and bosentan may decrease|
03695|015|E|the levels and effectiveness of crizotinib(1) while increasing levels and|
03695|016|E|toxicity of bosentan(2).|
03695|017|B||
03695|018|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, idelalisib, and a CYP2C9|
03695|019|P|inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
03695|020|P|sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major|
03695|021|P|metabolic pathways for bosentan, resulting in large increases in bosentan|
03695|022|P|plasma concentrations.(1,3)|
03695|023|B||
03695|024|M|PATIENT MANAGEMENT:  Avoid the concurrent use of crizotinib and bosentan.|
03695|025|M|Consider the use of alternative agents with less or no effect on the CYP3A4|
03695|026|M|enzyme.(1)|
03695|027|M|   Review medication list to see if patient is also receiving a CYP2C9|
03695|028|M|inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
03695|029|M|sulfinpyrazone, or phenylbutazone).  Concomitant use of both a CYP2C9 and|
03695|030|M|CYP3A4 inhibitor is not recommended by the manufacturer as the combination|
03695|031|M|may lead to large increases in bosentan plasma concentrations.(2)|
03695|032|M|   For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated,|
03695|033|M|monitor tolerance to concomitant therapy and adjust bosentan dose if|
03695|034|M|needed.(2)|
03695|035|B||
03695|036|D|DISCUSSION:  Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the|
03695|037|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
03695|038|D|crizotinib (250 mg) by 69% and 82%, respectively.(1)|
03695|039|D|   In a study in healthy subjects, concurrent bosentan and ketoconazole (a|
03695|040|D|strong CYP3A4 inhibitor) administration increased bosentan steady-state Cmax|
03695|041|D|and AUC by 2.1-fold and 2.3-fold, respectively.(2)|
03695|042|B||
03695|043|R|REFERENCES:|
03695|044|B||
03695|045|R|1.Xalkori (crizotinib) UK Summary of Product Characteristics. Pfizer Limited|1
03695|046|R|  July, 2021.|1
03695|047|R|2.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
03695|048|R|  US, Inc. September 5, 2017.|1
03695|049|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03695|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03695|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03695|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03695|053|R|  11/14/2017.|1
03696|001|T|MONOGRAPH TITLE:  Crizotinib/Moderate CYP3A4 Inducers that Prolong QT|
03696|002|B||
03696|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03696|004|L|of severe adverse interaction.|
03696|005|B||
03696|006|A|MECHANISM OF ACTION:  Efavirenz and thioridazine, moderate CYP3A4 inducers,|
03696|007|A|may induce the CYP3A4 isoenzyme and increase the metabolism of|
03696|008|A|crizotinib.(1)|
03696|009|A|   Crizotinib as well as efavirenz and thioridazine have all been observed|
03696|010|A|to prolong the QTc interval.  Concurrent use of agents that prolong the QTc|
03696|011|A|interval may result in additive effects on the QTc interval.(1,2)|
03696|012|B||
03696|013|E|CLINICAL EFFECTS:  Concurrent use of crizotinib with efavirenz or|
03696|014|E|thioridazine may decrease the levels and effectiveness of crizotinib(1) and|
03696|015|E|increase the risk of potentially life-threatening arrhythmias, including|
03696|016|E|torsades de pointes.(1,2)|
03696|017|B||
03696|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03696|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03696|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03696|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03696|022|P|female gender, or advanced age.(3)|
03696|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03696|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03696|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03696|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03696|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03696|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03696|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03696|030|P|   CYP2B6 genotype may also increase the risk of this interaction.  Patients|
03696|031|P|who are most susceptible to this interaction are patients who are CYP2B6|
03696|032|P|poor metabolizers with CYP2B6 *6/*6 allele.(4)|
03696|033|P|   Induction effects may be more likely with regular use of the inducer for|
03696|034|P|longer than 1-2 weeks.|
03696|035|B||
03696|036|M|PATIENT MANAGEMENT:  Avoid the concurrent use of moderate CYP3A4 inducers,|
03696|037|M|including efavirenz and thioridazine, in patients receiving therapy with|
03696|038|M|crizotinib.  Consider the use of alternative agents with less enzyme|
03696|039|M|induction potential and less potential to affect the QTc interval.(1,2)|
03696|040|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
03696|041|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
03696|042|M|baseline and regular intervals.(1)  Correct any electrolyte abnormalities.|
03696|043|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03696|044|M|   In patients who develop a QTc greater than 500 ms on at least 2 separate|
03696|045|M|ECGs, withhold crizotinib until recovery to baseline or to a QTc less than|
03696|046|M|481 ms, then resume crizotinib at reduced dose.(1)|
03696|047|M|   In patients who develop a QTc greater than 500 ms or greater than or|
03696|048|M|equal to 60 ms change from baseline with Torsade de pointes or polymorphic|
03696|049|M|ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently|
03696|050|M|discontinue crizotinib.(1)|
03696|051|B||
03696|052|D|DISCUSSION:  Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the|
03696|053|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
03696|054|D|crizotinib (250 mg) by 69% and 82%, respectively.(1)|
03696|055|D|   Crizotinib is associated with concentration-dependent QTc interval|
03696|056|D|prolongation.  In a clinical trial 2.1% of patients were found to have a|
03696|057|D|QTcF greater than or equal to 500 msec and 5% of patients had an increase in|
03696|058|D|QTcF by greater than or equal to 60 msec.(1)|
03696|059|D|   A retrospective review of 618 cancer patients treated with 902|
03696|060|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03696|061|D|incidence of QTc prolongation.  In patients who received crizotinib, QTc|
03696|062|D|prolongation was identified in 1 (50%) with 1 (100%) having Grade 1 (QTc|
03696|063|D|450-480 ms).  No patients had a QTc change greater than or equal to 60 ms,|
03696|064|D|ventricular tachycardia, sudden cardiac death, or TdP.(5)|
03696|065|D|   A thorough QT study was conducted in the general population in 120|
03696|066|D|healthy subjects receiving efavirenz 600 mg daily.  Time-matched differences|
03696|067|D|in QTc with efavirenz compared to placebo was evaluated on day 11, at 6|
03696|068|D|hours post dose.  The mean change in QTc was 5.2 msec and no change in QTc|
03696|069|D|was greater than 10 msec.(6)|
03696|070|D|   In addition to the thorough QT study, the effect of efavirenz on the QTc|
03696|071|D|interval was evaluated in 58 healthy subjects based on CYP2B6 genotype.|
03696|072|D|CYP2B6 polymorphism was evaluated for each patient and results were the|
03696|073|D|following: 65% with *1/*1 or *1/*4 allele (wild-type metabolizers), 26% with|
03696|074|D|*1/*6 allele (intermediate metabolizers) and 9% with *6/*6 allele (slow|
03696|075|D|metabolizers).  Subjects with 2 copies of the CYP2B6*6 allele had|
03696|076|D|significantly higher efavirenz exposure at steady-state (p<0.05).  At|
03696|077|D|steady-state concentrations of efavirenz, patients with CYP2B6 *1/*1 or|
03696|078|D|*1/*6 alleles had no change in the QTc interval (p>0.05).  However, patients|
03696|079|D|with CYP2B6 *6/*6 allele had an increase in QTc mean +/- SD from 406 +/-|
03696|080|D|16.4 to 423 +/- 11.8 msec (p=0.02).(4)|
03696|081|B||
03696|082|R|REFERENCES:|
03696|083|B||
03696|084|R|1.Xalkori (crizotinib) UK Summary of Product Characteristics. Pfizer Limited|1
03696|085|R|  July, 2021.|1
03696|086|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
03696|087|R|  Company November, 2023.|1
03696|088|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03696|089|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03696|090|R|  settings: a scientific statement from the American Heart Association and|6
03696|091|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03696|092|R|  2;55(9):934-47.|6
03696|093|R|4.Abdelhady AM, Shugg T, Thong N, Lu JB, Kreutz Y, Jaynes HA, Robarge JD,|2
03696|094|R|  Tisdale JE, Desta Z, Overholser BR. Efavirenz Inhibits the Human|2
03696|095|R|  Ether-A-Go-Go Related Current (hERG) and Induces QT  Interval Prolongation|2
03696|096|R|  in CYP2B6*6*6 Allele Carriers. J Cardiovasc Electrophysiol 2016 Jun 23.|2
03696|097|R|5.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03696|098|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03696|099|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03696|100|R|6.Tibotec Pharmaceuticals. A Phase I, double-blind, double-dummy,|1
03696|101|R|  randomized, placebo controlled and active controlled trial to evaluate the|1
03696|102|R|  effect of TMC278 25 mg q.d. at steady-state and the effect of efavirenz|1
03696|103|R|  (EFV) 600 mg q.d. at steady-state on the QT/QTc interval. Accessed at:|1
03696|104|R|  https://clinicaltrials.gov/ct2/show/study/NCT00744809 February, 2010.|1
03696|105|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
03696|106|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03696|107|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03696|108|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03696|109|R|  11/14/2017.|1
03697|001|T|MONOGRAPH TITLE:  Crizotinib/Pexidartinib|
03697|002|B||
03697|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03697|004|L|of severe adverse interaction.|
03697|005|B||
03697|006|A|MECHANISM OF ACTION:  Crizotinib is a substrate and moderate inhibitor of|
03697|007|A|CYP3A4.(1)  Pexidartinib is a substrate and moderate inducer of CYP3A4.(2)|
03697|008|A|   Agents that induce the CYP3A4 isoenzyme may induce the metabolism of|
03697|009|A|crizotinib.(1)|
03697|010|A|Moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of|
03697|011|A|pexidartinib.(2)|
03697|012|B||
03697|013|E|CLINICAL EFFECTS:  Concurrent use of crizotinib and pexidartinib may|
03697|014|E|decrease the levels and effectiveness of crizotinib(1) while increasing|
03697|015|E|levels and toxicity of pexidartinib, such as hepatotoxicity.(2)  Symptoms|
03697|016|E|can include nausea, vomiting, jaundice, dark urine, abdominal pain, and|
03697|017|E|unexplained fatigue.|
03697|018|B||
03697|019|P|PREDISPOSING FACTORS:  None determined.|
03697|020|B||
03697|021|M|PATIENT MANAGEMENT:  Avoid the concurrent use of crizotinib and|
03697|022|M|pexidartinib.  Consider the use of alternative agents with less or no effect|
03697|023|M|on the CYP3A4 enzyme.(1)|
03697|024|M|   There is currently no FDA-approved indication for the concurrent use of|
03697|025|M|crizotinib and pexidartinib.  The optimal doses of crizotinib and|
03697|026|M|pexidartinib when used in combination is unknown.  Combination therapy with|
03697|027|M|crizotinib and pexidartinib would ideally be utilized within the context of|
03697|028|M|a clinical trial.|
03697|029|B||
03697|030|D|DISCUSSION:  Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the|
03697|031|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
03697|032|D|crizotinib (250 mg) by 69% and 82%, respectively.(1)|
03697|033|D|   Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased|
03697|034|D|pexidartinib Cmax and AUC by 41% and 67%.(2)|
03697|035|B||
03697|036|R|REFERENCES:|
03697|037|B||
03697|038|R|1.Xalkori (crizotinib) UK Summary of Product Characteristics. Pfizer Limited|1
03697|039|R|  July, 2021.|1
03697|040|R|2.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03697|041|R|  November, 2023.|1
03697|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03697|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03697|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03697|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03697|046|R|  11/14/2017.|1
03697|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
03697|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03698|001|T|MONOGRAPH TITLE:  Mifepristone/Idelalisib|
03698|002|B||
03698|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03698|004|L|of severe adverse interaction.|
03698|005|B||
03698|006|A|MECHANISM OF ACTION:  Mifepristone and idelalisib are both agents that are|
03698|007|A|strong inhibitors of CYP3A4 and are substrates of CYP3A4.(1,2)|
03698|008|B||
03698|009|E|CLINICAL EFFECTS:  Concurrent use of mifepristone with a strong inhibitor of|
03698|010|E|CYP3A4 may result in a 5-fold increase in area-under-curve (AUC) or 80 per|
03698|011|E|cent decrease in mifepristone clearance, leading to toxicity such as adrenal|
03698|012|E|insufficiency, or hypokalemia.|
03698|013|E|   Concurrent use of strong CYP3A4 inhibitors may increase levels of and|
03698|014|E|effects from idelalisib, including hepatotoxicity, diarrhea, colitis,|
03698|015|E|pneumonitis, neutropenia or intestinal perforation.(1)|
03698|016|B||
03698|017|P|PREDISPOSING FACTORS:  None determined.|
03698|018|B||
03698|019|M|PATIENT MANAGEMENT:  The optimal doses of mifepristone and idelalisib when|
03698|020|M|used in combination is unknown.  Monitor for toxicity of both agents.|
03698|021|M|   Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy|
03698|022|M|with idelalisib.(1)  Consider alternatives with no or minimal enzyme|
03698|023|M|inhibition.(2)|
03698|024|M|   If concurrent use with idelalisib is warranted, monitor patients for|
03698|025|M|toxicity and follow toxicity dose modification guidelines.(2)|
03698|026|M|   The manufacturer of mifepristone for use in patients with endogenous|
03698|027|M|Cushing's syndrome states the benefit of the CYP3A4 inhibitor must be|
03698|028|M|carefully weighed against the potential risks and concurrent use should only|
03698|029|M|occur when necessary.(1)|
03698|030|M|   If starting mifepristone in a patient already taking a strong CYP3A4|
03698|031|M|inhibitor, initiate mifepristone at 300 mg and titrate if clinically|
03698|032|M|indicated to a maximum dose of 900 mg.(1)|
03698|033|M|   If a strong CYP3A4 inhibitor is started in a patient already taking|
03698|034|M|mifepristone, the following dose adjustments are recommended:|
03698|035|M| - If current mifepristone dose is 300 mg, no dose change warranted;|
03698|036|M| - If current mifepristone dose is 600 mg, reduce dose to 300 mg and titrate|
03698|037|M|if clinically indicated to a maximum dose of 600 mg;|
03698|038|M| - If current mifepristone dose is 900 mg, reduce dose to 600 mg and titrate|
03698|039|M|if clinically indicated to a maximum dose of 900 mg; and|
03698|040|M| - If current mifepristone dose if 1200 mg, reduce dose to 900 mg.(1)|
03698|041|B||
03698|042|D|DISCUSSION:  A drug interaction study examined mifepristone 600 mg daily|
03698|043|D|with concurrent ketoconazole 200 mg twice daily on days 13-17.  Concurrent|
03698|044|D|administration increased mifepristone area-under-curve (AUC) and maximum|
03698|045|D|concentration (Cmax) by 1.38-fold and 1.28-fold, respectively.(1)|
03698|046|D|   A drug interaction study of 33 healthy subjects on itraconazole 200 mg|
03698|047|D|daily coadministered with mifepristone 900 mg daily for 14 days found that|
03698|048|D|itraconazole increased the Cmax and AUC of mifepristone by 1.1-fold and|
03698|049|D|1.2-fold, respectively.(1)|
03698|050|D|   In a study in healthy subjects, ketoconazole (400 mg daily for 4 days)|
03698|051|D|increased the area-under-curve (AUC) of idelalisib (400 mg single dose) by|
03698|052|D|1.8-fold.(2)|
03698|053|B||
03698|054|R|REFERENCES:|
03698|055|B||
03698|056|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
03698|057|R|  November, 2019.|1
03698|058|R|2.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03698|059|R|  October, 2020.|1
03698|060|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03698|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03698|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03698|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03698|064|R|  11/14/2017.|1
03699|001|T|MONOGRAPH TITLE:  Ribociclib/Idelalisib|
03699|002|B||
03699|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03699|004|L|of severe adverse interaction.|
03699|005|B||
03699|006|A|MECHANISM OF ACTION:  Ribociclib and idelalisib are both strong inhibitors|
03699|007|A|of the CYP3A4 enzyme and are substrates of CYP3A4.(1,2)|
03699|008|B||
03699|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03699|010|E|systemic exposure and the risk for ribociclib toxicities such as neutropenia|
03699|011|E|or QT prolongation.(1)|
03699|012|E|   Concurrent use of strong CYP3A4 inhibitors may increase levels of and|
03699|013|E|effects from idelalisib, including hepatotoxicity, diarrhea, colitis,|
03699|014|E|pneumonitis, neutropenia or intestinal perforation.(2)|
03699|015|B||
03699|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03699|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03699|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03699|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03699|020|P|gender, or advanced age.(3)|
03699|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03699|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03699|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03699|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03699|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03699|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03699|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03699|028|B||
03699|029|M|PATIENT MANAGEMENT:  Avoid concomitant use of ribociclib and idelalisib.|
03699|030|M|Consider an alternative concomitant medication with less potential for|
03699|031|M|CYP3A4 inhibition.(1,2)|
03699|032|M|   The optimal dosing of ribociclib and idelalisib when used in combination|
03699|033|M|is unknown.  Manufacturers provide recommendations for dose modification of|
03699|034|M|ribociclib and idelalisib when each is used with a strong CYP3A4 inhibitor,|
03699|035|M|but the recommendations may not apply when there is a two-way inhibition.|
03699|036|M|Dose modifications mentioned below are informational only.|
03699|037|M|   The US manufacturer of ribociclib states that the following dose|
03699|038|M|modifications are needed if use of a strong CYP3A4 inhibitor cannot be|
03699|039|M|avoided:|
03699|040|M|   -For patients with early breast cancer, decrease ribociclib to 200 mg|
03699|041|M|once daily.|
03699|042|M|   -For patients with advanced or metastatic breast cancer, decrease|
03699|043|M|ribociclib to 400 mg once daily.|
03699|044|M|   -If the strong CYP3A4 inhibitor is discontinued, change the ribociclib|
03699|045|M|dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the|
03699|046|M|dose used prior to the initiation of the strong CYP3A4 inhibitor.(1)|
03699|047|M|   The Swedish manufacturer states that if patients must be given a strong|
03699|048|M|CYP3A4 inhibitor concurrently with ribociclib, the ribociclib dose should be|
03699|049|M|reduced to 400 mg once daily.  In patients who have had their ribociclib|
03699|050|M|dose reduced to 400 mg daily and in whom coadministration of a strong CYP3A4|
03699|051|M|inhibitor cannot be avoided, the ribociclib dose should be further reduced|
03699|052|M|to 200 mg.  In patients who have had their ribociclib dose reduced to 200 mg|
03699|053|M|daily and in whom coadministration of a strong CYP3A4 inhibitor cannot be|
03699|054|M|avoided, ribociclib treatment should be interrupted.(5)|
03699|055|M|   If concurrent use with idelalisib is warranted, monitor patients for|
03699|056|M|toxicity and follow toxicity dose modification guidelines.(2)|
03699|057|M|   During concomitant therapy with ribociclib and idelalisib, monitor|
03699|058|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03699|059|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03699|060|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03699|061|M|irregular heartbeat, dizziness, or fainting.|
03699|062|B||
03699|063|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03699|064|D|coadministration of ritonavir (100 mg twice a day for 14 days) with a single|
03699|065|D|dose of ribociclib (400 mg) increased ribociclib maximum concentration|
03699|066|D|(Cmax) and area-under-the-curve (AUC) by 1.7 and 3.2-fold, respectively.|
03699|067|D|Cmax and AUC for LEQ803 (ribociclib metabolite) decreased by 96% and 98%,|
03699|068|D|respectively.(1)|
03699|069|D|   Data from a pharmacokinetic simulation suggests that erythromycin, a|
03699|070|D|moderate CYP3A4 inhibitor, may increase ribociclib (600 mg)Cmax and AUC by|
03699|071|D|1.2-fold and 1.3-fold. The increase of ribociclib's Cmax and AUC was|
03699|072|D|estimated to be 1.4-fold and 2.1-fold in patients on ribociclib 400 mg. The|
03699|073|D|increase of ribociclib's Cmax and AUC was estimated to be 1.7-fold and|
03699|074|D|2.8-fold in patients on ribociclib 200 mg.(5)|
03699|075|D|   In a study in healthy subjects, ketoconazole (400 mg daily for 4 days)|
03699|076|D|increased the area-under-curve (AUC) of idelalisib (400 mg single dose) by|
03699|077|D|1.8-fold.(2)|
03699|078|B||
03699|079|R|REFERENCES:|
03699|080|B||
03699|081|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
03699|082|R|  Corporation September, 2024.|1
03699|083|R|2.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03699|084|R|  October, 2020.|1
03699|085|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03699|086|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03699|087|R|  settings: a scientific statement from the American Heart Association and|6
03699|088|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03699|089|R|  2;55(9):934-47.|6
03699|090|R|4.This information is based on an extract from the Certara Drug Interaction|6
03699|091|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03699|092|R|5.Kisqali (ribociclib) Sweden prescribing information. Novartis Pharma|1
03699|093|R|  August 2017.|1
03700|001|T|MONOGRAPH TITLE:  Elagolix/Idelalisib|
03700|002|B||
03700|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03700|004|L|of severe adverse interaction.|
03700|005|B||
03700|006|A|MECHANISM OF ACTION:  Idelalisib is both a substrate and a strong inhibitor|
03700|007|A|of the CYP3A4 isoenzyme.(1)  Elagolix is both a substrate and a moderate|
03700|008|A|inducer of CYP3A4.(2)  Concurrent use of elagolix and idelalisib may alter|
03700|009|A|exposure to one or both agents.|
03700|010|B||
03700|011|E|CLINICAL EFFECTS:  Concurrent use of elagolix and idelalisib may result in|
03700|012|E|elevated levels of and toxicity from elagolix(2) and decreased levels and|
03700|013|E|efficacy of idelalisib.(1)  The net effect and magnitude of the two-way|
03700|014|E|interaction between elagolix and idelalisib is unknown.|
03700|015|B||
03700|016|P|PREDISPOSING FACTORS:  None determined.|
03700|017|B||
03700|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of elagolix and|
03700|019|M|idelalisib.(1,3)  Consider alternatives with no or minimal effect on the|
03700|020|M|CYP3A4 isoenzyme.|
03700|021|M|   Concomitant use of elagolix 200 mg twice daily with strong CYP3A4|
03700|022|M|inhibitors for more than 1 month is not recommended. Limit concomitant use|
03700|023|M|of elagolix 150 mg once daily and strong CYP3A4 inhibitors to 6 months.(2)|
03700|024|M|   Patients receiving concurrent therapy with elagolix and idelalisib should|
03700|025|M|be monitored closely for efficacy and signs of toxicities.(1,2)|
03700|026|B||
03700|027|D|DISCUSSION:  Ketoconazole 400 mg daily (a strong CYP3A4 inhibitor) increased|
03700|028|D|the area-under-curve (AUC) of elagolix (150 mg single dose) by 1.77-fold and|
03700|029|D|maximum concentration (Cmax) by 2.2-fold.(2)|
03700|030|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
03700|031|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
03700|032|D|75%, respectively.(3)|
03700|033|B||
03700|034|R|REFERENCES:|
03700|035|B||
03700|036|R|1.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03700|037|R|  October, 2020.|1
03700|038|R|2.Orilissa (elagolix) US prescribing information. AbbVie Inc. February,|1
03700|039|R|  2021.|1
03700|040|R|3.Zydelig (idelalisib) UK Summary of Product Characteristics. Gilead|1
03700|041|R|  Sciences Ltd December 17, 2019.|1
03700|042|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03700|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03700|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03700|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03700|046|R|  11/14/2017.|1
03700|047|R|5.This information is based on an extract from the Certara Drug Interaction|6
03700|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03701|001|T|MONOGRAPH TITLE:  Lorlatinib/Idelalisib|
03701|002|B||
03701|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03701|004|L|of severe adverse interaction.|
03701|005|B||
03701|006|A|MECHANISM OF ACTION:  Idelalisib is both a substrate and a strong inhibitor|
03701|007|A|of the CYP3A4 isoenzyme.(1)  Lorlatinib is both a substrate and a moderate|
03701|008|A|inducer of CYP3A4.(2)  Concurrent use of lorlatinib and idelalisib may alter|
03701|009|A|exposure to one or both agents.|
03701|010|B||
03701|011|E|CLINICAL EFFECTS:  Concurrent use of lorlatinib and idelalisib may result in|
03701|012|E|elevated levels of and toxicity from lorlatinib(2) and decreased levels and|
03701|013|E|efficacy of idelalisib.(1)  The net effect and magnitude of the two-way|
03701|014|E|interaction between lorlatinib and idelalisib is unknown.|
03701|015|B||
03701|016|P|PREDISPOSING FACTORS:  None determined.|
03701|017|B||
03701|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of lorlatinib and|
03701|019|M|idelalisib.(2,3)  Consider alternatives with no or minimal effect on the|
03701|020|M|CYP3A4 isoenzyme.|
03701|021|M|   The optimal dosing of lorlatinib and idelalisib when used in combination|
03701|022|M|is unknown.  Manufacturers provide recommendations for dose modification of|
03701|023|M|lorlatinib  when used with a strong CYP3A4 inhibitor, but the|
03701|024|M|recommendations may not apply when there is a multi-directional interaction.|
03701|025|M|Dose modifications mentioned below informational only.|
03701|026|M|   If concomitant use of strong CYP3A4 inhibitors cannot be avoided, reduce|
03701|027|M|the starting dose of lorlatinib from 100 mg daily to 75 mg daily.  In|
03701|028|M|patients who have had a dose reduction to 75 mg daily, reduce the dose to 50|
03701|029|M|mg daily.(2)|
03701|030|M|   If the strong CYP3A4 inhibitor is discontinued, increase lorlatinib dose|
03701|031|M|to the dose that was used before starting the strong inhibitor.(2)|
03701|032|M|   Patients receiving concurrent therapy with lorlatinib and idelalisib|
03701|033|M|should be monitored closely for efficacy and signs of toxicities.(1,2)|
03701|034|B||
03701|035|D|DISCUSSION:  Itraconazole, a strong CYP3A4 inhibitor, increased the|
03701|036|D|area-under-curve (AUC) and concentration (Cmax) of a single dose of|
03701|037|D|lorlatinib 100 mg by 42% and 24%, respectively.(2)|
03701|038|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
03701|039|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
03701|040|D|75%, respectively.(3)|
03701|041|B||
03701|042|R|REFERENCES:|
03701|043|B||
03701|044|R|1.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03701|045|R|  October, 2020.|1
03701|046|R|2.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
03701|047|R|3.Zydelig (idelalisib) UK Summary of Product Characteristics. Gilead|1
03701|048|R|  Sciences Ltd December 17, 2019.|1
03701|049|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03701|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03701|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03701|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03701|053|R|  11/14/2017.|1
03701|054|R|5.This information is based on an extract from the Certara Drug Interaction|6
03701|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03702|001|T|MONOGRAPH TITLE:  Pexidartinib (200 mg)/Idelalisib|
03702|002|B||
03702|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03702|004|L|of severe adverse interaction.|
03702|005|B||
03702|006|A|MECHANISM OF ACTION:  Idelalisib is both a substrate and a strong inhibitor|
03702|007|A|of the CYP3A4 isoenzyme.(1)  Pexidartinib is both a substrate and a moderate|
03702|008|A|inducer of CYP3A4.(2)  Concurrent use of pexidartinib and idelalisib may|
03702|009|A|alter exposure to one or both agents.|
03702|010|B||
03702|011|E|CLINICAL EFFECTS:  Concurrent use of pexidartinib and idelalisib may result|
03702|012|E|in elevated levels of and toxicity from pexidartinib(2) and decreased levels|
03702|013|E|and efficacy of idelalisib.(1)  The net effect and magnitude of the two-way|
03702|014|E|interaction between pexidartinib and idelalisib is unknown.|
03702|015|B||
03702|016|P|PREDISPOSING FACTORS:  None determined.|
03702|017|B||
03702|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pexidartinib and|
03702|019|M|idelalisib.(2,3)  Consider alternatives with no or minimal effect on the|
03702|020|M|CYP3A4 isoenzyme.|
03702|021|M|   The optimal dosing of pexidartinib and idelalisib when used in|
03702|022|M|combination is unknown.  Manufacturers provide recommendations for dose|
03702|023|M|modification of pexidartinib when used with a strong CYP3A4 inhibitor, but|
03702|024|M|the recommendations may not apply when there is a multi-directional|
03702|025|M|interaction.  Dose modifications mentioned below are informational only.|
03702|026|M|   If coadministration of pexidartinib with a strong CYP3A4 inhibitor cannot|
03702|027|M|be avoided, reduce the pexidartinib dose according to the following|
03702|028|M|recommendations.|
03702|029|M|   If the planned total daily dose is currently 800 mg, modify the total|
03702|030|M|daily dose to 400 mg by administering 200 mg twice daily.|
03702|031|M|   If the planned total daily dose is currently 600 mg, modify the total|
03702|032|M|daily dose to 400 mg by administering 200 mg twice daily.|
03702|033|M|   If the planned total daily dose is currently 400 mg, modify the total|
03702|034|M|daily dose to 200 mg by administering 200 mg once daily.|
03702|035|M|   If concomitant use of a strong CYP3A4 inhibitor is discontinued, increase|
03702|036|M|the pexidartinib dose to the dose that was used before starting the|
03702|037|M|inhibitor after three plasma half-lives of the strong CYP3A4 inhibitor.|
03702|038|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
03702|039|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
03702|040|M|recommendations in the Turalio package insert. Advise patients to|
03702|041|M|immediately report any symptoms of hepatotoxicity.|
03702|042|M|   Patients receiving concurrent therapy with pexidartinib and idelalisib|
03702|043|M|should be monitored closely for efficacy and signs of toxicities.(1,2)|
03702|044|B||
03702|045|D|DISCUSSION:  Coadministration of itraconazole, a strong CYP3A inhibitor,|
03702|046|D|increased pexidartinib area-under curve (AUC) by 70% and maximum|
03702|047|D|concentration (Cmax) by 48%.(2)|
03702|048|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
03702|049|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
03702|050|D|75%, respectively.(3)|
03702|051|B||
03702|052|R|REFERENCES:|
03702|053|B||
03702|054|R|1.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03702|055|R|  October, 2020.|1
03702|056|R|2.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03702|057|R|  November, 2023.|1
03702|058|R|3.Zydelig (idelalisib) UK Summary of Product Characteristics. Gilead|1
03702|059|R|  Sciences Ltd December 17, 2019.|1
03702|060|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03702|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03702|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03702|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03702|064|R|  11/14/2017.|1
03702|065|R|5.This information is based on an extract from the Certara Drug Interaction|6
03702|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03703|001|T|MONOGRAPH TITLE:  Tepotinib/Dual Strong CYP3A4 Inhibitor & P-gp Inhibitors|
03703|002|T|(mono deleted 03/30/2023)|
03703|003|B||
03703|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03703|005|L|of severe adverse interaction.|
03703|006|B||
03703|007|A|MECHANISM OF ACTION:  Dual strong inhibitors of CYP3A4 and P-glycoprotein|
03703|008|A|(P-gp) may inhibit the metabolism of tepotinib.(1)|
03703|009|B||
03703|010|E|CLINICAL EFFECTS:  Concurrent use of dual strong CYP3A4 and P-gp inhibitors|
03703|011|E|may result in increased systemic exposure to and effects from tepotinib,|
03703|012|E|including pneumonitis, or hepatotoxicity.(1)|
03703|013|B||
03703|014|P|PREDISPOSING FACTORS:  None determined.|
03703|015|B||
03703|016|M|PATIENT MANAGEMENT:  Avoid the concurrent use of tepotinib with drugs that|
03703|017|M|are strong CYP3A4 inhibitors and P-gp inhibitors.(1)|
03703|018|M|   If concurrent use is warranted, monitor patients closely for increased|
03703|019|M|incidence and severity of dyspnea, cough, fever, abdominal pain, nausea,|
03703|020|M|vomiting, fatigue, dark-colored urine, or jaundice.  Monitor liver function|
03703|021|M|tests (ALT, AST, and total bilirubin).|
03703|022|B||
03703|023|D|DISCUSSION:  The effect of dual strong CYP3A4 and P-gp inhibitors has not|
03703|024|D|been studied clinically with tepotinib.  Tepotinib is metabolized by CYP3A4|
03703|025|D|and a substrate of P-gp. Metabolism and in vitro data suggest concurrent use|
03703|026|D|of a dual strong CYP3A4 inhibitor and P-gp inhibitor may increase tepotinib|
03703|027|D|exposure.|
03703|028|D|   Combined strong CYP3A4 and P-gp inhibitors linked to this monograph|
03703|029|D|include: clarithromycin, cobicistat, conivaptan, indinavir, itraconazole,|
03703|030|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir,|
03703|031|D|mibefradil, mifepristone, nefazodone, nirmatrelvir/ritonavir, paritaprevir,|
03703|032|D|posaconazole, saquinavir, telaprevir, telithromycin, tipranavir, and|
03703|033|D|tucatinib.(2,3)|
03703|034|B||
03703|035|R|REFERENCES:|
03703|036|B||
03703|037|R|1.Tepmetko (tepotinib) US prescribing information. EMD Serono, Inc.|1
03703|038|R|  February, 2024.|1
03703|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
03703|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03703|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03703|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03703|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03703|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03703|045|R|  11/14/2017.|1
03704|001|T|MONOGRAPH TITLE:  Tepotinib/Strong CYP3A4 Inducers (mono deleted 03/30/2023)|
03704|002|B||
03704|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03704|004|L|of severe adverse interaction.|
03704|005|B||
03704|006|A|MECHANISM OF ACTION:  Tepotinib is a substrate of CYP3A4.  Strong inducers|
03704|007|A|of CYP3A4 may induce the metabolism of tepotinib.(1)|
03704|008|B||
03704|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03704|010|E|may result in decreased levels and effectiveness of tepotinib.(1)|
03704|011|B||
03704|012|P|PREDISPOSING FACTORS:  None determined.|
03704|013|B||
03704|014|M|PATIENT MANAGEMENT:  The manufacturer of tepotinib states that concurrent|
03704|015|M|use with strong CYP3A4 inducers should be avoided. (1)|
03704|016|B||
03704|017|D|DISCUSSION:  The effect of CYP3A4 inducers has not been studied. Tepotinib|
03704|018|D|is metabolized by CYP3A4 and CYP2C8.|
03704|019|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03704|020|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
03704|021|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03704|022|D|wort.(2-3)|
03704|023|B||
03704|024|R|REFERENCES:|
03704|025|B||
03704|026|R|1.Tepmetko (tepotinib) US prescribing information. EMD Serono, Inc.|1
03704|027|R|  February, 2024.|1
03704|028|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03704|029|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03704|030|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03704|031|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03704|032|R|  11/14/2017.|1
03704|033|R|3.This information is based on an extract from the Certara Drug Interaction|6
03704|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03706|001|T|MONOGRAPH TITLE:  Riociguat/Abacavir|
03706|002|B||
03706|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03706|004|L|of severe adverse interaction.|
03706|005|B||
03706|006|A|MECHANISM OF ACTION:  Riociguat is primarily metabolized by CYP1A1 and to a|
03706|007|A|lesser extent by CYP3A4/3A5 and CYP2J2.(1,2)  Abacavir has been shown to|
03706|008|A|inhibit CYP1A1 in vitro and may decrease the metabolism of riociguat.(2,3)|
03706|009|B||
03706|010|E|CLINICAL EFFECTS:  Concurrent use of abacavir with riociguat may result in|
03706|011|E|elevated systemic levels and toxicity (e.g. hypotension) from|
03706|012|E|riociguat.(2,3)|
03706|013|B||
03706|014|P|PREDISPOSING FACTORS:  The risk for riociguat-associated hypotension is|
03706|015|P|higher in patients with a systolic blood pressure (SBP) < or = 110 prior to|
03706|016|P|treatment initiation or dose increase.|
03706|017|P|   Patient specific factors such as renal or hepatic impairment, or age > 65|
03706|018|P|years are associated with higher systemic exposure to riociguat and may|
03706|019|P|increase interaction risk or severity.(1,4)|
03706|020|B||
03706|021|M|PATIENT MANAGEMENT:  The US manufacturer of abacavir states that the dose of|
03706|022|M|riociguat may need to be reduced when used concurrently.(3)  Although the|
03706|023|M|manufacturer of riociguat does not make any recommendations for dose|
03706|024|M|adjustment when used with a CYP1A1 inhibitor, it has been suggested that the|
03706|025|M|initial dose of riociguat be reduced to 0.5 mg 3 times daily.  This is the|
03706|026|M|same dose modification recommended during concurrent therapy with strong CYP|
03706|027|M|and P-gp/BCRP inhibitors, based on a similar magnitude of interaction|
03706|028|M|between riociguat and ketoconazole.(2)|
03706|029|M|   Monitor blood pressure and counsel patient to report low blood pressure,|
03706|030|M|lightheadedness or chest pain.|
03706|031|M|   Patients stabilized on concomitant therapy may need to have their|
03706|032|M|riociguat dose retitrated upward after discontinuation of abacavir.|
03706|033|B||
03706|034|D|DISCUSSION:  In an interaction study of 8 HIV-positive patients without|
03706|035|D|pulmonary hypertension, abacavir (given as a fixed-dose combination of|
03706|036|D|abacavir 600 mg-dolutegravir 50 mg-lamivudine 300 mg once daily) increased|
03706|037|D|the area-under-curve (AUC) of single-dose riociguat 0.5 mg by about 3-fold,|
03706|038|D|compared to historical healthy volunteers administered single-dose riociguat|
03706|039|D|0.5 mg alone.(2)|
03706|040|D|   The frequency or magnitude of this interaction is difficult to predict in|
03706|041|D|a specific patient due to significant interpatient variability in drug|
03706|042|D|kinetics.  For example, between patient variability in systemic exposure|
03706|043|D|(AUC) relative to dose is 90%.  The amount of riociguat metabolized may be|
03706|044|D|as low as 27% or as high as 72%.  Cigarette smoking induces the CYP1A1|
03706|045|D|mediated metabolism of riociguat leading to about a 50% decrease in systemic|
03706|046|D|exposure compared with non-smoking patients.|
03706|047|B||
03706|048|R|REFERENCES:|
03706|049|B||
03706|050|R|1.Adempas (riociguat) US prescribing information. Bayer HealthCare|1
03706|051|R|  Pharmaceuticals, Inc. September, 2021.|1
03706|052|R|2.DeJesus E, Saleh S, Cheng S, van der Mey D, Becker C, Frey R, Unger S,|2
03706|053|R|  Mueck W. Pharmacokinetic interaction of riociguat and antiretroviral|2
03706|054|R|  combination regimens in  HIV-1-infected adults. Pulm Circ 2019 Apr-Jun;|2
03706|055|R|  9(2):2045894019848644.|2
03706|056|R|3.Ziagen (abacavir) US prescribing information. ViiV Healthcare Company|1
03706|057|R|  November, 2020.|1
03706|058|R|4.Halank M, Tausche K, Grunig E, Ewert R, Preston IR. Practical management|6
03706|059|R|  of riociguat in patients with pulmonary arterial hypertension. Ther Adv|6
03706|060|R|  Respir Dis 2019 Jan-Dec;13:1753466619868938.|6
03707|001|T|MONOGRAPH TITLE:  BCRP or OATP1B1 Substrates/Eltrombopag|
03707|002|B||
03707|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03707|004|L|take action as needed.|
03707|005|B||
03707|006|A|MECHANISM OF ACTION:  Eltrombopag has been shown to inhibit BCRP and|
03707|007|A|OATP1B1.(1-3)  Inhibition of BCRP may increase absorption and/or decrease|
03707|008|A|biliary excretion of substrates, while inhibition of OATP1B1 may decrease|
03707|009|A|hepatic uptake of substrates.|
03707|010|B||
03707|011|E|CLINICAL EFFECTS:  Simultaneous use of eltrombopag with BCRP or OATP1B1|
03707|012|E|substrates may result in increased levels and side effects from the|
03707|013|E|substrates.(1)|
03707|014|B||
03707|015|P|PREDISPOSING FACTORS:  None determined.|
03707|016|B||
03707|017|M|PATIENT MANAGEMENT:  The manufacturer of eltrombopag states that concomitant|
03707|018|M|BCRP or OATP1B1 substrates should be used cautiously.  Patients on|
03707|019|M|concurrent therapy should be closely monitored for adverse effects, and dose|
03707|020|M|reduction of the substrate should be considered.(1)|
03707|021|B||
03707|022|D|DISCUSSION:  In a clinical trial in 39 healthy subjects, administration of|
03707|023|D|eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum|
03707|024|D|concentration (Cmax) of a single dose of rosuvastatin (10 mg, a BCRP and|
03707|025|D|OATP1B1 substrate) by 55% and 103%, respectively.(1,4)|
03707|026|D|   In a physiologically-based pharmacokinetic (PBPK) model, eltrombopag 75|
03707|027|D|mg was predicted to increase the AUC and Cmax of pitavastatin 1 mg by|
03707|028|D|approximately 2-fold.(5)|
03707|029|D|   BCRP substrates linked to this monograph include: ciprofloxacin,|
03707|030|D|imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and|
03707|031|D|topotecan.(1)|
03707|032|D|   OATP1B1 substrates linked to this monograph include: atorvastatin,|
03707|033|D|bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin,|
03707|034|D|pravastatin, repaglinide, and simvastatin.(1)|
03707|035|B||
03707|036|R|REFERENCES:|
03707|037|B||
03707|038|R|1.Promacta (eltrombopag) US prescribing information. GlaxoSmithKline|1
03707|039|R|  February, 2021.|1
03707|040|R|2.Takeuchi K, Sugiura T, Matsubara K, Sato R, Shimizu T, Masuo Y, Horikawa|5
03707|041|R|  M, Nakamichi N, Ishiwata N, Kato Y. Interaction of novel|5
03707|042|R|  platelet-increasing agent eltrombopag with rosuvastatin via  breast cancer|5
03707|043|R|  resistance protein in humans. Drug Metab Dispos 2014 Apr;42(4):726-34.|5
03707|044|R|3.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
03707|045|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
03707|046|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
03707|047|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
03707|048|R|  44(3):398-408.|5
03707|049|R|4.Allred AJ, Bowen CJ, Park JW, Peng B, Williams DD, Wire MB, Lee E.|2
03707|050|R|  Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers.|2
03707|051|R|  Br J Clin Pharmacol 2011 Aug;72(2):321-9.|2
03707|052|R|5.Carter SJ, Chouhan B, Sharma P, Chappell MJ. Prediction of Clinical|5
03707|053|R|  Transporter-Mediated Drug-Drug Interactions via Comeasurement  of|5
03707|054|R|  Pitavastatin and Eltrombopag in Human Hepatocyte Models. CPT|5
03707|055|R|  Pharmacometrics Syst Pharmacol 2020 Apr;9(4):211-221.|5
03708|001|T|MONOGRAPH TITLE:  Repaglinide/Favipiravir|
03708|002|B||
03708|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03708|004|L|take action as needed.|
03708|005|B||
03708|006|A|MECHANISM OF ACTION:  Favipiravir is a dose-dependent inhibitor of CYP2C8|
03708|007|A|and may decrease the metabolism of repaglinide by CYP2C8.(1,2)|
03708|008|B||
03708|009|E|CLINICAL EFFECTS:  Concurrent use of favipiravir may result in elevated|
03708|010|E|levels of repaglinide and increase the risk of hypoglycemia.(1)|
03708|011|B||
03708|012|P|PREDISPOSING FACTORS:  Patients with severe renal impairment or moderate to|
03708|013|P|severe hepatic impairment,(2) who achieve tight control of blood sugars, or|
03708|014|P|who have a history of multiple hypoglycemic episodes may be at greater risk|
03708|015|P|for hypoglycemia with this combination.|
03708|016|B||
03708|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent repaglinide and|
03708|018|M|favipiravir should be monitored for signs and symptoms of hypoglycemia.(1)|
03708|019|M|The dosage of repaglinide may need to be adjusted during favipiravir|
03708|020|M|therapy.|
03708|021|M|   Patients should be counseled on signs of hypoglycemia and instructed to|
03708|022|M|contact their doctor if hypoglycemia occurs.|
03708|023|M|   Signs of hypoglycemia may include diaphoresis, shakiness, unusual hunger,|
03708|024|M|headaches, pallor, weakness, palpitations, dizziness, irritability, unusual|
03708|025|M|anxiety, or confusion.|
03708|026|B||
03708|027|D|DISCUSSION:  In a study, favipiravir (1,200 mg twice daily on day 1 then 800|
03708|028|D|mg twice daily on days 2-4 then 800 mg daily from day 5) increased the|
03708|029|D|maximum concentration (Cmax) and area-under-curve (AUC) of single-dose|
03708|030|D|repaglinide (0.5 mg on day 13) by 28% and 52%, respectively.(1)|
03708|031|B||
03708|032|R|REFERENCES:|
03708|033|B||
03708|034|R|1.Avigan (favipiravir) Japanese prescribing information. Toyama Chemical|1
03708|035|R|  Co., LTD November, 2017.|1
03708|036|R|2.Prandin (repaglinide) US prescribing information. Novo Nordisk|1
03708|037|R|  Pharmaceuticals, Inc. February 8, 2017.|1
03709|001|T|MONOGRAPH TITLE:  Favipiravir/Theophylline Derivatives|
03709|002|B||
03709|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03709|004|L|take action as needed.|
03709|005|B||
03709|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is not fully|
03709|007|A|understood but may involve competitive inhibition of xanthine oxidase by|
03709|008|A|theophylline derivatives.  Favipiravir is primarily metabolized by aldehyde|
03709|009|A|oxidase and partly metabolized by xanthine oxidase.(1)|
03709|010|B||
03709|011|E|CLINICAL EFFECTS:  The plasma concentrations of favipiravir may increase and|
03709|012|E|result in a greater risk of toxicity from favipiravir, including|
03709|013|E|hyperuricemia, diarrhea, and hepatotoxicity.(1)|
03709|014|B||
03709|015|P|PREDISPOSING FACTORS:  None determined.|
03709|016|B||
03709|017|M|PATIENT MANAGEMENT:  Concurrent therapy with favipiravir and theophylline|
03709|018|M|derivatives should be undertaken with caution.  Monitor patients for signs|
03709|019|M|and symptoms of adverse effects of favipiravir.(1)|
03709|020|B||
03709|021|D|DISCUSSION:  In a study, theophylline (200 mg twice daily on Days 1 to 9|
03709|022|D|then 200 mg daily on Day 10) increased the maximum concentration (Cmax) and|
03709|023|D|area-under-curve (AUC) of favipiravir (600 mg twice daily on Day 6 then 600|
03709|024|D|mg daily on Days 7 to 10) by 33% and 27%, respectively.(1)|
03709|025|B||
03709|026|R|REFERENCE:|
03709|027|B||
03709|028|R|1.Avigan (favipiravir) Japanese prescribing information. Toyama Chemical|1
03709|029|R|  Co., LTD November, 2017.|1
03710|001|T|MONOGRAPH TITLE:  Dalfampridine/OCT2 Inhibitors|
03710|002|B||
03710|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03710|004|L|take action as needed.|
03710|005|B||
03710|006|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
03710|007|A|(OCT2) may inhibit the excretion of dalfampridine by OCT2 in the|
03710|008|A|kidneys.(1,2)|
03710|009|B||
03710|010|E|CLINICAL EFFECTS:  Concurrent use of OCT2 renal transport inhibitors may|
03710|011|E|result in increased levels of and toxicity from dalfampridine.(1,2)|
03710|012|B||
03710|013|P|PREDISPOSING FACTORS:  The risk of seizures from dalfampridine may be|
03710|014|P|increased in patients with a history of head trauma or prior seizure; CNS|
03710|015|P|tumor; CNS infections; severe hepatic cirrhosis; excessive use of alcohol or|
03710|016|P|sedatives; addiction to opiates, cocaine, or stimulants; use of|
03710|017|P|over-the-counter stimulants and anorectics; diabetics treated with oral|
03710|018|P|hypoglycemics or insulin; or with concomitant medications known to lower|
03710|019|P|seizure threshold (antidepressants, theophylline, systemic steroids).|
03710|020|B||
03710|021|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
03710|022|M|concurrent use of dalfampridine with OCT2 renal transport inhibitors.  If|
03710|023|M|concurrent use is appropriate, monitor for toxicities of dalfampridine and|
03710|024|M|consider dosage reduction of dalfampridine.(1,2)|
03710|025|B||
03710|026|D|DISCUSSION:  In a study, givinostat increased the levels of creatinine (OCT2|
03710|027|D|substrate) by 4.76 umol/L from baseline.(1)|
03710|028|D|   In a study, trilaciclib increased the area-under-curve (AUC) and maximum|
03710|029|D|concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by|
03710|030|D|approximately 65% and 81%, respectively.  Renal clearance of metformin was|
03710|031|D|decreased by 37%.  Trilaciclib did not cause significant changes in the|
03710|032|D|pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2)|
03710|033|D|   OCT2 inhibitors linked to this monograph include: abemaciclib,|
03710|034|D|arimoclomol, bictegravir, givinostat, isavuconazole, ranolazine,|
03710|035|D|trilaciclib, trimethoprim, tucatinib, and vimseltinib.(3)|
03710|036|B||
03710|037|R|REFERENCES:|
03710|038|B||
03710|039|R|1.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
03710|040|R|  March, 2024.|1
03710|041|R|2.Cosela (trilaciclib) US prescribing information. G1 Therapeutics, Inc.|1
03710|042|R|  February, 2021.|1
03710|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
03710|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03711|001|T|MONOGRAPH TITLE:  Cisplatin/OCT2 Inhibitors|
03711|002|B||
03711|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03711|004|L|take action as needed.|
03711|005|B||
03711|006|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
03711|007|A|(OCT2) may inhibit the excretion of cisplatin by OCT2 in the kidneys.(1,2)|
03711|008|B||
03711|009|E|CLINICAL EFFECTS:  Concurrent use of OCT2 renal transport inhibitors may|
03711|010|E|result in increased levels of and toxicities from cisplatin, including|
03711|011|E|nephrotoxicity, ototoxicity, neuropathy, and myelosuppression.(1,2)|
03711|012|B||
03711|013|P|PREDISPOSING FACTORS:  Pre-existing renal insufficiency, advanced age, and|
03711|014|P|dehydration may increase the risk of nephrotoxicity.|
03711|015|B||
03711|016|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
03711|017|M|concurrent use of cisplatin with OCT2 renal transport inhibitors.  If|
03711|018|M|concurrent use is appropriate, monitor closely for toxicities of cisplatin|
03711|019|M|and consider dosage reduction of cisplatin.(1,2)|
03711|020|B||
03711|021|D|DISCUSSION:  In a study, givinostat increased the levels of creatinine (OCT2|
03711|022|D|substrate) by 4.76 umol/L from baseline.(1)|
03711|023|D|   In a study, trilaciclib increased the area-under-curve (AUC) and maximum|
03711|024|D|concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by|
03711|025|D|approximately 65% and 81%, respectively.  Renal clearance of metformin was|
03711|026|D|decreased by 37%.  Trilaciclib did not cause significant changes in the|
03711|027|D|pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2)|
03711|028|D|   OCT2 inhibitors linked to this monograph include: abemaciclib,|
03711|029|D|arimoclomol, bictegravir, dolutegravir, givinostat, isavuconazole,|
03711|030|D|ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(3)|
03711|031|B||
03711|032|R|REFERENCES:|
03711|033|B||
03711|034|R|1.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
03711|035|R|  March, 2024.|1
03711|036|R|2.Cosela (trilaciclib) US prescribing information. G1 Therapeutics, Inc.|1
03711|037|R|  February, 2021.|1
03711|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
03711|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03712|001|T|MONOGRAPH TITLE:  Clofarabine/OCT2 Inhibitors|
03712|002|B||
03712|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03712|004|L|take action as needed.|
03712|005|B||
03712|006|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
03712|007|A|(OCT2) may inhibit the excretion of clofarabine by OCT2 in the kidneys.(1,2)|
03712|008|B||
03712|009|E|CLINICAL EFFECTS:  Concurrent use of OCT2 renal transport inhibitors may|
03712|010|E|result in increased levels of and toxicity from clofarabine, including|
03712|011|E|myelosuppression, serious hemorrhages, enterocolitis, nephrotoxicity, and|
03712|012|E|hepatotoxicity.(1)|
03712|013|B||
03712|014|P|PREDISPOSING FACTORS:  None determined.|
03712|015|B||
03712|016|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
03712|017|M|concurrent use of clofarabine with OCT2 renal transport inhibitors.  If|
03712|018|M|concurrent use is appropriate, monitor for toxicities of the clofarabine and|
03712|019|M|consider dosage reduction of clofarabine.(1)|
03712|020|B||
03712|021|D|DISCUSSION:  In an animal study, cimetidine, an OCT2 inhibitor, decreased|
03712|022|D|the clearance of clofarabine in rats by 61%. The clinical implications of|
03712|023|D|this finding are unclear.(1,2)|
03712|024|D|   In a study, givinostat increased the levels of creatinine (OCT2|
03712|025|D|substrate) by 4.76 umol/L from baseline.(3)|
03712|026|D|   In a study, trilaciclib increased the area-under-curve (AUC) and maximum|
03712|027|D|concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by|
03712|028|D|approximately 65% and 81%, respectively.  Renal clearance of metformin was|
03712|029|D|decreased by 37%.  Trilaciclib did not cause significant changes in the|
03712|030|D|pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4)|
03712|031|D|   OCT2 inhibitors linked to this monograph include: abemaciclib,|
03712|032|D|arimoclomol, bictegravir, cimetidine, dolutegravir, givinostat,|
03712|033|D|isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and|
03712|034|D|vimseltinib.(5)|
03712|035|B||
03712|036|R|REFERENCES:|
03712|037|B||
03712|038|R|1.Clolar (clofarabine) US prescribing information. Sanofi-Aventis U.S. LLC|1
03712|039|R|  October 15, 2020.|1
03712|040|R|2.Ajavon AD, Bonate PL, Taft DR. Renal excretion of clofarabine: assessment|5
03712|041|R|  of dose-linearity and role of renal  transport systems on drug excretion.|5
03712|042|R|  Eur J Pharm Sci 2010 Jun 14;40(3):209-16.|5
03712|043|R|3.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
03712|044|R|  March, 2024.|1
03712|045|R|4.Cosela (trilaciclib) US prescribing information. G1 Therapeutics, Inc.|1
03712|046|R|  February, 2021.|1
03712|047|R|5.This information is based on an extract from the Certara Drug Interaction|6
03712|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03713|001|T|MONOGRAPH TITLE:  Procainamide/OCT2 Inhibitors|
03713|002|B||
03713|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03713|004|L|take action as needed.|
03713|005|B||
03713|006|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
03713|007|A|(OCT2) may inhibit the excretion of procainamide by OCT2 in the|
03713|008|A|kidneys.(1,2)|
03713|009|B||
03713|010|E|CLINICAL EFFECTS:  Concurrent use of OCT2 renal transport inhibitors may|
03713|011|E|result in increased levels of and toxicities of procainamide,(1,2) including|
03713|012|E|potentially life-threatening cardiac arrhythmias, like torsades de pointes|
03713|013|E|(TdP).(3)|
03713|014|B||
03713|015|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
03713|016|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
03713|017|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
03713|018|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
03713|019|P|concurrent use of agents known to cause QT prolongation.(3)|
03713|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03713|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03713|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03713|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03713|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03713|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03713|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03713|027|B||
03713|028|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
03713|029|M|concurrent use of procainamide with OCT2 renal transport inhibitors.  If|
03713|030|M|concurrent use is appropriate, monitor for toxicities of procainamide and|
03713|031|M|consider dosage reduction of procainamide.(1)|
03713|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03713|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03713|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03713|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03713|036|B||
03713|037|D|DISCUSSION:  In a study, givinostat increased the levels of creatinine (OCT2|
03713|038|D|substrate) by 4.76 umol/L from baseline.(1)|
03713|039|D|   In a study, trilaciclib increased the area-under-curve (AUC) and maximum|
03713|040|D|concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by|
03713|041|D|approximately 65% and 81%, respectively.  Renal clearance of metformin was|
03713|042|D|decreased by 37%.  Trilaciclib did not cause significant changes in the|
03713|043|D|pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2)|
03713|044|D|   OCT2 inhibitors linked to this monograph include: abemaciclib,|
03713|045|D|arimoclomol, bictegravir, cimetidine, dolutegravir, givinostat,|
03713|046|D|isavuconazole, trilaciclib, tucatinib, and vimseltinib.(4)|
03713|047|B||
03713|048|R|REFERENCES:|
03713|049|B||
03713|050|R|1.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
03713|051|R|  March, 2024.|1
03713|052|R|2.Cosela (trilaciclib) US prescribing information. G1 Therapeutics, Inc.|1
03713|053|R|  February, 2021.|1
03713|054|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03713|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03713|056|R|  settings: a scientific statement from the American Heart Association and|6
03713|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03713|058|R|  2;55(9):934-47.|6
03713|059|R|4.This information is based on an extract from the Certara Drug Interaction|6
03713|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03714|001|T|MONOGRAPH TITLE:  Crizotinib/OCT2 Inhibitors (mono deleted 10/03/2024)|
03714|002|B||
03714|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03714|004|L|take action as needed.|
03714|005|B||
03714|006|A|MECHANISM OF ACTION:  Inhibitors of the organic cation transporter 2 (OCT2)|
03714|007|A|in the kidneys may inhibit the renal excretion of crizotinib, a substrate of|
03714|008|A|OCT2.(1)|
03714|009|B||
03714|010|E|CLINICAL EFFECTS:  Concurrent use of organic cation transporter 2 (OCT2)|
03714|011|E|inhibitors may result in increased levels of and toxicity from crizotinib,|
03714|012|E|including myelosuppression and potentially life-threatening cardiac|
03714|013|E|arrhythmias, including torsades de pointes (TdP).(1)|
03714|014|B||
03714|015|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
03714|016|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
03714|017|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
03714|018|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
03714|019|P|concurrent use of agents known to cause QT prolongation.(2)|
03714|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03714|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03714|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03714|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03714|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03714|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03714|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03714|027|B||
03714|028|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
03714|029|M|concurrent use of crizotinib with OCT2 inhibitors.  If concurrent use is|
03714|030|M|appropriate, monitor for toxicities of crizotinib and consider dosage|
03714|031|M|reduction.(1)|
03714|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03714|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03714|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03714|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03714|036|B||
03714|037|D|DISCUSSION:  In a study, givinostat increased the levels of creatinine (OCT2|
03714|038|D|substrate) by 4.76 umol/L from baseline.(3)|
03714|039|D|   In a study, trilaciclib increased the area-under-curve (AUC) and maximum|
03714|040|D|concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by|
03714|041|D|approximately 65% and 81%, respectively.  Renal clearance of metformin was|
03714|042|D|decreased by 37%.  Trilaciclib did not cause significant changes in the|
03714|043|D|pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4)|
03714|044|D|   OCT2 inhibitors linked to this monograph include: givinostat and|
03714|045|D|trilaciclib.|
03714|046|B||
03714|047|R|REFERENCES:|
03714|048|B||
03714|049|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
03714|050|R|  2023.|1
03714|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03714|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03714|053|R|  settings: a scientific statement from the American Heart Association and|6
03714|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03714|055|R|  2;55(9):934-47.|6
03714|056|R|3.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
03714|057|R|  March, 2024.|1
03714|058|R|4.Cosela (trilaciclib) US prescribing information. G1 Therapeutics, Inc.|1
03714|059|R|  February, 2021.|1
03715|001|T|MONOGRAPH TITLE:  Dofetilide/OCT2 Inhibitors|
03715|002|B||
03715|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03715|004|L|is contraindicated and generally should not be dispensed or administered to|
03715|005|L|the same patient.|
03715|006|B||
03715|007|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
03715|008|A|(OCT2) may inhibit the excretion of dofetilide by OCT2 in the kidneys.(1)|
03715|009|B||
03715|010|E|CLINICAL EFFECTS:  Concurrent use of OCT2 inhibitors may result in increased|
03715|011|E|levels of and toxicities of dofetilide, including potentially|
03715|012|E|life-threatening cardiac arrhythmias, like torsades de pointes (TdP).(1-3)|
03715|013|B||
03715|014|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
03715|015|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
03715|016|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
03715|017|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
03715|018|P|concurrent use of agents known to cause QT prolongation.(2)|
03715|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03715|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03715|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03715|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03715|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03715|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03715|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03715|026|P|   Renal impairment may increase risk for excessive QTc prolongation as|
03715|027|P|dofetilide is primarily renally eliminated. To prevent increased serum|
03715|028|P|levels and risk for ventricular arrhythmias, dofetilide must be dose|
03715|029|P|adjusted for creatinine clearance < or = to 60 mL/min.(1)|
03715|030|B||
03715|031|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that all renal|
03715|032|M|cation transport inhibitors are contraindicated.   If dofetilide is to be|
03715|033|M|discontinued, a washout of at least 2 days is recommended prior to starting|
03715|034|M|OCT2 inhibitors.(1)|
03715|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03715|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03715|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03715|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03715|039|B||
03715|040|D|DISCUSSION:  Dofetilide is primarily excreted in the urine via both|
03715|041|D|glomerular filtration and active tubular secretion via the cation transport|
03715|042|D|system.  The concurrent administration of dofetilide (500 mcg twice daily)|
03715|043|D|with cimetidine (an OCT2 inhibitor)(400 mg twice daily) resulted in an|
03715|044|D|increase in dofetilide plasma levels by 58%.  The concurrent administration|
03715|045|D|of dofetilide (500 mcg single dose) with cimetidine (100 mg twice daily)|
03715|046|D|resulted in an increase in dofetilide plasma levels by 13%.(1)|
03715|047|D|   In a study, givinostat increased the levels of creatinine (OCT2|
03715|048|D|substrate) by 4.76 umol/L from baseline.(3)|
03715|049|D|   In a study, trilaciclib increased the area-under-curve (AUC) and maximum|
03715|050|D|concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by|
03715|051|D|approximately 65% and 81%, respectively.  Renal clearance of metformin was|
03715|052|D|decreased by 37%.  Trilaciclib did not cause significant changes in the|
03715|053|D|pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4)|
03715|054|D|   OCT2 inhibitors linked to this monograph include: abemaciclib,|
03715|055|D|arimoclomol, givinostat, isavuconazole, trilaciclib, tucatinib, and|
03715|056|D|vimseltinib. (5)|
03715|057|B||
03715|058|R|REFERENCES:|
03715|059|B||
03715|060|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
03715|061|R|  2013.|1
03715|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03715|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03715|064|R|  settings: a scientific statement from the American Heart Association and|6
03715|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03715|066|R|  2;55(9):934-47.|6
03715|067|R|3.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
03715|068|R|  March, 2024.|1
03715|069|R|4.Cosela (trilaciclib) US prescribing information. G1 Therapeutics, Inc.|1
03715|070|R|  February, 2021.|1
03715|071|R|5.This information is based on an extract from the Certara Drug Interaction|6
03715|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03716|001|T|MONOGRAPH TITLE:  Betrixaban; Dabigatran/P-gp Inhibitors that Cause Bleeding|
03716|002|B||
03716|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03716|004|L|of severe adverse interaction.|
03716|005|B||
03716|006|A|MECHANISM OF ACTION:  This combination may interact via both a|
03716|007|A|pharmacodynamic and a pharmacokinetic mechanism.|
03716|008|A|   Pharmacodynamically, serotonin release by platelets plays a role in|
03716|009|A|hemostasis.(1)  Fluvoxamine may cause a decrease in serotonin reuptake by|
03716|010|A|platelets, resulting in an additive risk of bleeding with oral|
03716|011|A|anticoagulants.(1)  Mifepristone is an antagonist at the progesterone|
03716|012|A|receptor which can result in endometrium thickening, cystic dilatation of|
03716|013|A|endometrial glands, or excessive vaginal bleeding.  Concurrent use with|
03716|014|A|anticoagulants may further increase risk.(2)|
03716|015|A|   Pharmacokinetically, fluvoxamine and mifepristone are inhibitors of the|
03716|016|A|P-glycoprotein (P-gp) transporter and may increase the absorption of|
03716|017|A|betrixaban and dabigatran.(3)|
03716|018|B||
03716|019|E|CLINICAL EFFECTS:  Concurrent use of P-gp inhibitors with betrixaban or|
03716|020|E|dabigatran may result in bleeding.|
03716|021|E|   The concurrent use of mifepristone with anticoagulants may result in|
03716|022|E|endometrium thickening, cystic dilatation of endometrial glands, or|
03716|023|E|excessive vaginal bleeding.(2)|
03716|024|B||
03716|025|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03716|026|P|patients with disease-associated factors (e.g. thrombocytopenia, recent|
03716|027|P|trauma).  Renal impairment has been associated with an elevated risk of GI|
03716|028|P|bleed in patients on SSRIs.(4)|
03716|029|P|   Patient-associated risk factors include age greater than 74 years and|
03716|030|P|weight less than 50 kg.(5,6)|
03716|031|P|   Drug associated risk factors include concurrent use of multiple drugs|
03716|032|P|which inhibit anticoagulant/antiplatelet transport or metabolism and/or have|
03716|033|P|an inherent risk for bleeding (e.g. NSAIDs).|
03716|034|B||
03716|035|M|PATIENT MANAGEMENT:  Concurrent therapy of P-gp inhibitors with betrixaban|
03716|036|M|or dabigatran should be undertaken with caution.  Assess renal function and|
03716|037|M|evaluate the patient for other pre-existing risk factors for bleeding prior|
03716|038|M|to initiating concurrent therapy.|
03716|039|M|   The concurrent use of betrixaban and P-gp inhibitors should be avoided in|
03716|040|M|patients with severe renal impairment (CrCl less than 30 ml/min).  The|
03716|041|M|recommended dose of betrixaban for patients receiving or starting|
03716|042|M|concomitant P-gp inhibitors is an initial single dose of 80 mg followed by|
03716|043|M|40 mg once daily. The recommended duration of treatment is 35 to 42 days.(5)|
03716|044|M|   The US manufacturer of dabigatran states that the concurrent use of|
03716|045|M|dabigatran and P-gp inhibitors should be avoided in atrial fibrillation|
03716|046|M|patients with severe renal impairment (CrCl less than 30 ml/min) and in|
03716|047|M|patients being treated for or undergoing prophylaxis for deep vein|
03716|048|M|thrombosis (DVT) or pulmonary embolism (PE) who have moderate renal|
03716|049|M|impairment (CrCl less than 50 ml/min).  The interaction with P-gp inhibitors|
03716|050|M|can be minimized by taking dabigatran several hours apart from the P-gp|
03716|051|M|inhibitor dose.(6)|
03716|052|M|   The manufacturer of mifepristone states that mifepristone should be used|
03716|053|M|with caution in patients receiving concurrent anticoagulant therapy.(2)|
03716|054|M|Women experiencing vaginal bleeding during concurrent use should be referred|
03716|055|M|to a gynecologist for further evaluation.|
03716|056|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
03716|057|M|loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
03716|058|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03716|059|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03716|060|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03716|061|M|anticoagulation in patients with active pathologic bleeding.|
03716|062|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03716|063|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03716|064|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03716|065|M|and/or swelling.|
03716|066|B||
03716|067|D|DISCUSSION:  In the APEX randomized, double-blind study the incidence of|
03716|068|D|major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40mg|
03716|069|D|and 80 mg group was higher in patients taking concomitant P-gp inhibitors|
03716|070|D|(2.8% vs. 4.1% vs. 4.7%).(7)|
03716|071|D|   In a study in 12 subjects, concomitant administration of betrixaban (40|
03716|072|D|mg) following a 5-day regimen of ketoconazole (200 mg twice daily) resulted|
03716|073|D|in an increase in betrixaban's maximum concentration (Cmax) and|
03716|074|D|area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(8)|
03716|075|D|   An open-label study, concomitant administration of a single dose of|
03716|076|D|betrixaban with verapamil resulted in an increase in betrixaban's Cmax and|
03716|077|D|AUC of approximately 4.7-fold and 3-fold, respectively.(8)  Coadministration|
03716|078|D|with amiodarone resulted in an increase in betrixaban's Cmax by 143%.(8)|
03716|079|D|   When dabigatran was co-administered with amiodarone, dabigatran AUC and|
03716|080|D|Cmax were increased by about 60% and 50%, respectively.(9)  Chronic|
03716|081|D|administration of verapamil one hour prior to dabigatran increased|
03716|082|D|dabigatran AUC by 154%.(11) Administration of dabigatran two hours before|
03716|083|D|verapamil results in a negligible increase in dabigatran AUC.(9)|
03716|084|D|   A retrospective cohort study evaluated adverse bleeding rates with|
03716|085|D|standard doses of oral anticoagulants with concurrent verapamil or diltiazem|
03716|086|D|in patients with normal kidney function.  Concomitant dabigatran use with|
03716|087|D|verapamil or diltiazem was associated with increased overall bleeding|
03716|088|D|(hazard ratio (HR) 1.52; HR 1.43) and increased overall GI bleeding (HR|
03716|089|D|2.16; HR 2.32) when compared to amlodipine and metoprolol, respectively.  No|
03716|090|D|association was found between increased bleeding of any kind and concurrent|
03716|091|D|use of rivaroxaban or apixaban with verapamil or diltiazem.(14)|
03716|092|D|   A retrospective cohort study examined 24,943 patients with concurrent|
03716|093|D|therapy of an anticoagulant, either rivaroxaban (40.0%), apixaban (31.9%),|
03716|094|D|or dabigatran (28.1%), with either azithromycin or clarithromycin.  The|
03716|095|D|primary outcome of hospital admission with major hemorrhage within 30 days|
03716|096|D|on concurrent therapy was higher in patients on clarithromycin (0.77%)|
03716|097|D|compared to azithromycin (0.43%) with an adjusted HR of 1.71.(12)|
03716|098|D|   In a retrospective review of 5 years of data from the|
03716|099|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03716|100|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03716|101|D|non-antidepressant users.  Concurrent use of a selective serotonin reuptake|
03716|102|D|inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to|
03716|103|D|12.2 and 5.2, respectively.(13)|
03716|104|D|   In a case-control study conducted in users of acenocoumarol or|
03716|105|D|phenprocoumon, 1,848 patients who had been hospitalized with abnormal|
03716|106|D|bleeding were each matched to 4 control patients.  When patients took both a|
03716|107|D|SSRI and a coumarin, an increased risk of hospitalization due to major|
03716|108|D|non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to|
03716|109|D|gastrointestinal bleeding (adjusted OR 0.8).(15)|
03716|110|D|   A retrospective review examined patients discharged from a hospital with|
03716|111|D|antiplatelet therapy following a myocardial infarction.  When compared to|
03716|112|D|aspirin therapy alone, both aspirin therapy with a SSRI and aspirin,|
03716|113|D|clopidogrel, and SSRI therapy were associated with an increased risk of|
03716|114|D|bleeding (HR 1.42 and 2.35, respectively).  Compared with dual antiplatelet|
03716|115|D|therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI|
03716|116|D|was also associated with increased risk of bleeding (HR 1.57).(16)|
03716|117|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
03716|118|D|anticoagulation (HR 2.63).  Paroxetine was not associated with an increased|
03716|119|D|risk.  There were insufficient numbers of patients taking other SSRIs to|
03716|120|D|assess increased risk.(17)|
03716|121|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
03716|122|D|pairs were reviewed and found 14% of drug pairs were associated with a|
03716|123|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
03716|124|D|of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of|
03716|125|D|1.69 (1.11-2.57).(18)|
03716|126|B||
03716|127|R|REFERENCES:|
03716|128|B||
03716|129|R|1.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
03716|130|R|  Pharmaceuticals, Inc. August, 2023.|1
03716|131|R|2.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
03716|132|R|  November, 2019.|1
03716|133|R|3.This information is based on an extract from the Certara Drug Interaction|6
03716|134|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03716|135|R|4.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
03716|136|R|  Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
03716|137|R|  by level of kidney function: A population-based cohort study. Br J Clin|2
03716|138|R|  Pharmacol 2018 Sep;84(9):2142-2151.|2
03716|139|R|5.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
03716|140|R|  Inc. July, 2019.|1
03716|141|R|6.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
03716|142|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
03716|143|R|7.FDA (US Food and Drug Administration). CDER application number. 208383|1
03716|144|R|  Bevyxxa Medical Review. acessed at:|1
03716|145|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383Orig1s000Med|1
03716|146|R|  R.pdf June 23, 2017.|1
03716|147|R|8.FDA (US Food and Drug Administration). CDER application number. 208383|1
03716|148|R|  Bevyxxa Clinical Pharmacology and Biopharmaceuticals Review. accessed at:|1
03716|149|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383orig1s000nam|1
03716|150|R|  er.pdf June 23, 2017.|1
03716|151|R|9.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
03716|152|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
03716|153|R|  of  the Week..|6
03716|154|R|10.Anonymous. FDA Dabigatran background package for Cardio-Renal Advisory|1
03716|155|R|   Committee. available at|1
03716|156|R|   http://wayback.archive-it.org/7993/20170405212218/https://www.fda.gov/dow|1
03716|157|R|   nloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascular|1
03716|158|R|   andRenalDrugsAdvisoryCommittee/UCM247244.pdf September 20, 2010.|1
03716|159|R|11.Pham P, Schmidt S, Lesko L, Lip GYH, Brown JD. Association of Oral|2
03716|160|R|   Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding  Events|2
03716|161|R|   in Patients With Nonvalvular Atrial Fibrillation and Normal Kidney|2
03716|162|R|   Function. JAMA Netw Open;3(4)(2574-3805 (Electronic). 2574-3805|2
03716|163|R|   (Linking)):.|2
03716|164|R|12.Hill K, Sucha E, Rhodes E, Carrier M, Garg AX, Harel Z, Hundemer GL,|2
03716|165|R|   Clark EG, Knoll G, McArthur E, Sood MM. Risk of Hospitalization With|2
03716|166|R|   Hemorrhage Among Older Adults Taking Clarithromycin vs  Azithromycin and|2
03716|167|R|   Direct Oral Anticoagulants..|2
03716|168|R|13.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03716|169|R|   Use of selective serotonin reuptake inhibitors and risk of upper|2
03716|170|R|   gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03716|171|R|   Intern Med 2003 Jan 13;163(1):59-64.|2
03716|172|R|14.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03716|173|R|   serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03716|174|R|   population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03716|175|R|15.Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding|2
03716|176|R|   risk with concurrent use of selective serotonin reuptake inhibitors and|2
03716|177|R|   coumarins. Arch Intern Med 2008 Jan 28;168(2):180-5.|2
03716|178|R|16.Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding|2
03716|179|R|   associated with combined use of selective serotonin reuptake inhibitors|2
03716|180|R|   and antiplatelet therapy following acute myocardial infarction. CMAJ 2011|2
03716|181|R|   Nov 8;183(16):1835-43.|2
03716|182|R|17.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
03716|183|R|   Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
03716|184|R|   antidepressants and the risk of overanticoagulation during acenocoumarol|2
03716|185|R|   maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
03716|186|R|18.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
03716|187|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
03716|188|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
03716|189|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
03717|001|T|MONOGRAPH TITLE:  Edoxaban (Greater Than 30 mg)/P-gp Inhibitors that Cause|
03717|002|T|Bleeding|
03717|003|B||
03717|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03717|005|L|take action as needed.|
03717|006|B||
03717|007|A|MECHANISM OF ACTION:  This combination may interact via both a|
03717|008|A|pharmacodynamic and a pharmacokinetic mechanism.|
03717|009|A|   Pharmacodynamically, serotonin release by platelets plays a role in|
03717|010|A|hemostasis.(1)  Fluvoxamine may cause a decrease in serotonin reuptake by|
03717|011|A|platelets, resulting in an additive risk of bleeding with oral|
03717|012|A|anticoagulants.(1)  Mifepristone is an antagonist at the progesterone|
03717|013|A|receptor which can result in endometrium thickening, cystic dilatation of|
03717|014|A|endometrial glands, or excessive vaginal bleeding.  Concurrent use with|
03717|015|A|anticoagulants may further increase risk.(2)|
03717|016|A|   Pharmacokinetically, fluvoxamine, and mifepristone are inhibitors of the|
03717|017|A|P-glycoprotein (P-gp) transporter and may increase the absorption of|
03717|018|A|edoxaban.(3)|
03717|019|B||
03717|020|E|CLINICAL EFFECTS:  Concurrent use of P-gp inhibitors and edoxaban may result|
03717|021|E|in bleeding.(4,5)|
03717|022|E|   The concurrent use of mifepristone with anticoagulants may result in|
03717|023|E|endometrium thickening, cystic dilatation of endometrial glands, or|
03717|024|E|excessive vaginal bleeding.(2)|
03717|025|B||
03717|026|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03717|027|P|patients with disease-associated factors (e.g. thrombocytopenia).  Bleeding|
03717|028|P|risk may be increased in patients with creatinine clearance below 50 mL per|
03717|029|P|minute and in patients greater than 75 years of age.(4,5)|
03717|030|P|   Use of multiple agents which increase edoxaban exposure or affect|
03717|031|P|hemostasis would be expected to increase the risk for bleeding.|
03717|032|B||
03717|033|M|PATIENT MANAGEMENT:  The combination of P-gp inhibitors and edoxaban should|
03717|034|M|be used with caution.  Fluvoxamine and mifepristone are P-gp inhibitors.|
03717|035|M|FDA approved prescribing recommendations for edoxaban are indication|
03717|036|M|specific:|
03717|037|M|   - For prevention of stroke or embolic events due to nonvalvular atrial|
03717|038|M|fibrillation, no edoxaban dose adjustments are recommended during|
03717|039|M|concomitant therapy with P-gp inhibitors.|
03717|040|M|   - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE),|
03717|041|M|the edoxaban dose is recommended to be reduced to 30 mg daily when used|
03717|042|M|concurrently with specific P-gp inhibitors (azithromycin, clarithromycin,|
03717|043|M|oral itraconazole, quinidine and verapamil).(5)|
03717|044|M|   The manufacturer of mifepristone states that mifepristone should be used|
03717|045|M|with caution in patients receiving concurrent anticoagulant therapy.  Women|
03717|046|M|experiencing vaginal bleeding during concurrent use should be referred to a|
03717|047|M|gynecologist for further evaluation.(2)|
03717|048|M|   Monitor patients receiving anticoagulant therapy for signs of blood loss,|
03717|049|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
03717|050|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03717|051|M|   When applicable, perform agent-specific laboratory test (e.g. anti Factor|
03717|052|M|Xa inhibition) to monitor efficacy and safety of anticoagulation.|
03717|053|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
03717|054|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03717|055|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03717|056|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03717|057|M|and/or swelling.|
03717|058|M|   Discontinue edoxaban in patients with active bleeding.|
03717|059|B||
03717|060|D|DISCUSSION:  Edoxaban in vivo interactions studies have not been conducted|
03717|061|D|with fluvoxamine and there is no recommendation on the appropriate dose of|
03717|062|D|edoxaban with concomitant fluvoxamine.|
03717|063|D|   In an edoxaban DVT/PE trial, patients who had a 50% dose reduction (from|
03717|064|D|60 mg to 30 mg) during concomitant therapy with P-gp inhibitors (mostly|
03717|065|D|verapamil and quinidine) had lower trough edoxaban concentrations (Ctrough)|
03717|066|D|and lower total edoxaban exposure (AUC or area-under-curve) than patients|
03717|067|D|who did not require any edoxaban dose adjustment.  In this DVT/PE comparator|
03717|068|D|trial, subgroup analysis revealed that warfarin had numerically better|
03717|069|D|efficacy than edoxaban in patients receiving P-gp inhibitors.  Based upon|
03717|070|D|the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both|
03717|071|D|EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the|
03717|072|D|edoxaban 50% dose reduction overcorrected for the difference in|
03717|073|D|exposure.(4,6)  Consequently, EMA recommended no edoxaban dose adjustments|
03717|074|D|for patients receiving concomitant therapy with quinidine or verapamil.(6,7)|
03717|075|D|   In a retrospective review of 5 years of data from the|
03717|076|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03717|077|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03717|078|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03717|079|D|only based on an observed-expected ration was 4.5 and in a patient using|
03717|080|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
03717|081|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
03717|082|D|bleeding to 12.2 and 5.2, respectively.(8)|
03717|083|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
03717|084|D|in patients receiving concurrent therapy with selective serotonin reuptake|
03717|085|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
03717|086|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
03717|087|D|respectively.(9)|
03717|088|D|   In a case-control study conducted in users of acenocoumarol or|
03717|089|D|phenprocoumon, 1848 patients who had been hospitalized with abnormal|
03717|090|D|bleeding were each matched to 4 control patients.  When patients took both a|
03717|091|D|SSRI and a coumarin, an increased risk of hospitalization due to major|
03717|092|D|non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to|
03717|093|D|gastrointestinal bleeding (adjusted OR 0.8).(10)|
03717|094|D|   A retrospective review examined patients discharged from a hospital with|
03717|095|D|antiplatelet therapy following a myocardial infarction.  When compared to|
03717|096|D|aspirin therapy alone, both aspirin therapy with a SSRI and aspirin,|
03717|097|D|clopidogrel, and SSRI therapy were associated with an increased risk of|
03717|098|D|bleeding (hazard ratios 1.42 and 2.35, respectively.)  Compared with dual|
03717|099|D|antiplatelet therapy (aspirin and clopidogrel), use of aspirin and|
03717|100|D|clopidogrel and a SSRI was also associated with increased risk of bleeding|
03717|101|D|(hazard ratio 1.57).(11)|
03717|102|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
03717|103|D|anticoagulation (hazard ratio 2.63).  Paroxetine was not associated with an|
03717|104|D|increased risk.  There were insufficient numbers of patients taking other|
03717|105|D|SSRIs to assess increased risk.(12)|
03717|106|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
03717|107|D|pairs were reviewed and found 14% of drug pairs were associated with a|
03717|108|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
03717|109|D|of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of|
03717|110|D|1.69 (1.11-2.57).(13)|
03717|111|B||
03717|112|R|REFERENCES:|
03717|113|B||
03717|114|R|1.Viibryd (vilazodone hydrochloride) US prescribing information. Forest|1
03717|115|R|  Laboratories Inc. October, 2023.|1
03717|116|R|2.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
03717|117|R|  November, 2019.|1
03717|118|R|3.This information is based on an extract from the Certara Drug Interaction|6
03717|119|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03717|120|R|4.FDA Center for Drug Evaluation and Research (CDER). Application number|1
03717|121|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
03717|122|R|  Biopharmaceutics Review. available at:|1
03717|123|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
03717|124|R|  0ClinPharmR.pdf January 8, 2015.|1
03717|125|R|5.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
03717|126|R|  2019.|1
03717|127|R|6.Lixiana European Medicines Agency (EMA) Assessment report. Committee for|1
03717|128|R|  Medicinal Products for Human Use (CHMP) 23 April 2015.|1
03717|129|R|7.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
03717|130|R|  Sankyo UK Limited July 2, 2015.|1
03717|131|R|8.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03717|132|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03717|133|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03717|134|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03717|135|R|9.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03717|136|R|  serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03717|137|R|  population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03717|138|R|10.Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding|2
03717|139|R|   risk with concurrent use of selective serotonin reuptake inhibitors and|2
03717|140|R|   coumarins. Arch Intern Med 2008 Jan 28;168(2):180-5.|2
03717|141|R|11.Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding|2
03717|142|R|   associated with combined use of selective serotonin reuptake inhibitors|2
03717|143|R|   and antiplatelet therapy following acute myocardial infarction. CMAJ 2011|2
03717|144|R|   Nov 8;183(16):1835-43.|2
03717|145|R|12.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
03717|146|R|   Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
03717|147|R|   antidepressants and the risk of overanticoagulation during acenocoumarol|2
03717|148|R|   maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
03717|149|R|13.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
03717|150|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
03717|151|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
03717|152|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
03717|153|R|14.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03717|154|R|   2024.|1
03718|001|T|MONOGRAPH TITLE:  Edoxaban (Less Than or Equal To 30 mg)/P-gp Inhibitors|
03718|002|T|that Cause Bleeding|
03718|003|B||
03718|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03718|005|L|take action as needed.|
03718|006|B||
03718|007|A|MECHANISM OF ACTION:  This combination may interact via both a|
03718|008|A|pharmacodynamic and a pharmacokinetic mechanism.|
03718|009|A|   Pharmacodynamically, serotonin release by platelets plays a role in|
03718|010|A|hemostasis.(1)  Fluvoxamine may cause a decrease in serotonin reuptake by|
03718|011|A|platelets, resulting in an additive risk of bleeding with oral|
03718|012|A|anticoagulants.(1)  Mifepristone is an antagonist at the progesterone|
03718|013|A|receptor which can result in endometrium thickening, cystic dilatation of|
03718|014|A|endometrial glands, or excessive vaginal bleeding.  Concurrent use with|
03718|015|A|anticoagulants may further increase risk.(2)|
03718|016|A|   Pharmacokinetically, fluvoxamine and mifepristone are inhibitors of the|
03718|017|A|P-glycoprotein (P-gp) transporter and may increase the absorption of|
03718|018|A|edoxaban.(3)|
03718|019|B||
03718|020|E|CLINICAL EFFECTS:  Concurrent use of P-gp inhibitors and edoxaban may result|
03718|021|E|in bleeding.(2)|
03718|022|E|   The concurrent use of mifepristone with anticoagulants may result in|
03718|023|E|endometrium thickening, cystic dilatation of endometrial glands, or|
03718|024|E|excessive vaginal bleeding.(2)|
03718|025|B||
03718|026|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03718|027|P|patients with disease-associated factors (e.g. thrombocytopenia).  Bleeding|
03718|028|P|risk may be increased in patients with creatinine clearance below 50 mL per|
03718|029|P|minute and in patients greater than 75 years of age.(4,5)|
03718|030|P|   Use of multiple agents which increase edoxaban exposure or affect|
03718|031|P|hemostasis would be expected to increase the risk for bleeding.|
03718|032|B||
03718|033|M|PATIENT MANAGEMENT:  The combination of P-gp inhibitors and edoxaban should|
03718|034|M|be used with caution.  Fluvoxamine and mifepristone are P-gp inhibitors.|
03718|035|M|FDA approved prescribing recommendations for edoxaban are indication|
03718|036|M|specific:|
03718|037|M|   - For prevention of stroke or embolic events due to nonvalvular atrial|
03718|038|M|fibrillation, no edoxaban dose adjustments are recommended during|
03718|039|M|concomitant therapy with P-gp inhibitors.|
03718|040|M|   - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE),|
03718|041|M|the edoxaban dose is recommended to be reduced to 30 mg daily when used|
03718|042|M|concurrently with specific P-gp inhibitors (azithromycin, clarithromycin,|
03718|043|M|oral itraconazole, quinidine and verapamil).(5)|
03718|044|M|   The manufacturer of mifepristone states that mifepristone should be used|
03718|045|M|with caution in patients receiving concurrent anticoagulant therapy.  Women|
03718|046|M|experiencing vaginal bleeding during concurrent use should be referred to a|
03718|047|M|gynecologist for further evaluation.(2)|
03718|048|M|   Monitor patients receiving anticoagulant therapy for signs of blood loss,|
03718|049|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
03718|050|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03718|051|M|   When applicable, perform agent-specific laboratory test (e.g. anti Factor|
03718|052|M|Xa inhibition) to monitor efficacy and safety of anticoagulation.|
03718|053|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
03718|054|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03718|055|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03718|056|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03718|057|M|and/or swelling.|
03718|058|M|   Discontinue edoxaban in patients with active bleeding.|
03718|059|B||
03718|060|D|DISCUSSION:  Edoxaban in vivo interactions studies have not been conducted|
03718|061|D|with fluvoxamine and there is no recommendation on the appropriate dose of|
03718|062|D|edoxaban with concomitant fluvoxamine.|
03718|063|D|   In an edoxaban DVT/PE trial, patients who had a 50% dose reduction (from|
03718|064|D|60 mg to 30 mg) during concomitant therapy with P-gp inhibitors (mostly|
03718|065|D|verapamil and quinidine) had lower trough edoxaban concentrations (Ctrough)|
03718|066|D|and lower total edoxaban exposure (AUC or area-under-curve) than patients|
03718|067|D|who did not require any edoxaban dose adjustment.  In this DVT/PE comparator|
03718|068|D|trial, subgroup analysis revealed that warfarin had numerically better|
03718|069|D|efficacy than edoxaban in patients receiving P-gp inhibitors.  Based upon|
03718|070|D|the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both|
03718|071|D|EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the|
03718|072|D|edoxaban 50% dose reduction overcorrected for the difference in|
03718|073|D|exposure.(4,6)  Consequently, EMA recommended no edoxaban dose adjustments|
03718|074|D|for patients receiving concomitant therapy with quinidine or verapamil.(6,7)|
03718|075|D|   In a retrospective review of 5 years of data from the|
03718|076|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03718|077|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03718|078|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03718|079|D|only based on an observed-expected ration was 4.5 and in a patient using|
03718|080|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
03718|081|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
03718|082|D|bleeding to 12.2 and 5.2, respectively.(8)|
03718|083|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
03718|084|D|in patients receiving concurrent therapy with selective serotonin reuptake|
03718|085|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
03718|086|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
03718|087|D|respectively.(9)|
03718|088|D|   In a case-control study conducted in users of acenocoumarol or|
03718|089|D|phenprocoumon, 1848 patients who had been hospitalized with abnormal|
03718|090|D|bleeding were each matched to 4 control patients.  When patients took both a|
03718|091|D|SSRI and a coumarin, an increased risk of hospitalization due to major|
03718|092|D|non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to|
03718|093|D|gastrointestinal bleeding (adjusted OR 0.8).(10)|
03718|094|D|   A retrospective review examined patients discharged from a hospital with|
03718|095|D|antiplatelet therapy following a myocardial infarction.  When compared to|
03718|096|D|aspirin therapy alone, both aspirin therapy with a SSRI and aspirin,|
03718|097|D|clopidogrel, and SSRI therapy were associated with an increased risk of|
03718|098|D|bleeding (hazard ratios 1.42 and 2.35, respectively.)  Compared with dual|
03718|099|D|antiplatelet therapy (aspirin and clopidogrel), use of aspirin and|
03718|100|D|clopidogrel and a SSRI was also associated with increased risk of bleeding|
03718|101|D|(hazard ratio 1.57).(11)|
03718|102|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
03718|103|D|anticoagulation (hazard ratio 2.63).  Paroxetine was not associated with an|
03718|104|D|increased risk.  There were insufficient numbers of patients taking other|
03718|105|D|SSRIs to assess increased risk.(12)|
03718|106|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
03718|107|D|pairs were reviewed and found 14% of drug pairs were associated with a|
03718|108|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
03718|109|D|of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of|
03718|110|D|1.69 (1.11-2.57).(13)|
03718|111|B||
03718|112|R|REFERENCES:|
03718|113|B||
03718|114|R|1.Viibryd (vilazodone hydrochloride) US prescribing information. Forest|1
03718|115|R|  Laboratories Inc. October, 2023.|1
03718|116|R|2.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
03718|117|R|  November, 2019.|1
03718|118|R|3.This information is based on an extract from the Certara Drug Interaction|6
03718|119|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03718|120|R|4.FDA Center for Drug Evaluation and Research (CDER). Application number|1
03718|121|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
03718|122|R|  Biopharmaceutics Review. available at:|1
03718|123|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
03718|124|R|  0ClinPharmR.pdf January 8, 2015.|1
03718|125|R|5.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
03718|126|R|  2019.|1
03718|127|R|6.Lixiana European Medicines Agency (EMA) Assessment report. Committee for|1
03718|128|R|  Medicinal Products for Human Use (CHMP) 23 April 2015.|1
03718|129|R|7.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
03718|130|R|  Sankyo UK Limited July 2, 2015.|1
03718|131|R|8.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03718|132|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03718|133|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03718|134|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03718|135|R|9.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03718|136|R|  serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03718|137|R|  population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03718|138|R|10.Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding|2
03718|139|R|   risk with concurrent use of selective serotonin reuptake inhibitors and|2
03718|140|R|   coumarins. Arch Intern Med 2008 Jan 28;168(2):180-5.|2
03718|141|R|11.Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding|2
03718|142|R|   associated with combined use of selective serotonin reuptake inhibitors|2
03718|143|R|   and antiplatelet therapy following acute myocardial infarction. CMAJ 2011|2
03718|144|R|   Nov 8;183(16):1835-43.|2
03718|145|R|12.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
03718|146|R|   Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
03718|147|R|   antidepressants and the risk of overanticoagulation during acenocoumarol|2
03718|148|R|   maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
03718|149|R|13.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
03718|150|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
03718|151|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
03718|152|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
03719|001|T|MONOGRAPH TITLE:  Slt Anticoagulants;Antiplatelets;Thrombolytics/Fluvoxamine|
03719|002|B||
03719|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03719|004|L|take action as needed.|
03719|005|B||
03719|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
03719|007|A|hemostasis.(1)  Fluvoxamine may cause a decrease in serotonin reuptake by|
03719|008|A|platelets, resulting in an additive risk of bleeding with anticoagulants,|
03719|009|A|antiplatelets, and thrombolytics.|
03719|010|B||
03719|011|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine and agents that affect|
03719|012|E|coagulation may result in bleeding.|
03719|013|B||
03719|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03719|015|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
03719|016|P|impairment has been associated with an elevated risk of GI bleed in patients|
03719|017|P|on SSRIs.(2)|
03719|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
03719|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03719|020|P|risk for bleeding (e.g. NSAIDs).|
03719|021|B||
03719|022|M|PATIENT MANAGEMENT:  Concurrent therapy of fluvoxamine and agents that|
03719|023|M|affect coagulation should be undertaken with caution.|
03719|024|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03719|025|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03719|026|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03719|027|M|patients with any symptoms.|
03719|028|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT,|
03719|029|M|anti Factor Xa inhibition) to monitor efficacy and safety of|
03719|030|M|anticoagulation.  Discontinue anticoagulation in patients with active|
03719|031|M|pathologic bleeding.|
03719|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03719|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03719|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03719|035|M|and/or swelling.|
03719|036|B||
03719|037|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
03719|038|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
03719|039|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
03719|040|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
03719|041|D|only based on an observed-expected ration was 4.5 and in a patient using|
03719|042|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
03719|043|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
03719|044|D|bleeding to 12.2 and 5.2, respectively.(3)|
03719|045|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
03719|046|D|in patients receiving concurrent therapy with selective serotonin reuptake|
03719|047|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
03719|048|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
03719|049|D|respectively.(4)|
03719|050|D|   In a case-control study conducted in users of acenocoumarol or|
03719|051|D|phenprocoumon, 1,848 patients who had been hospitalized with abnormal|
03719|052|D|bleeding were each matched to 4 control patients.  When patients took both a|
03719|053|D|SSRI and a coumarin, an increased risk of hospitalization due to major|
03719|054|D|non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to|
03719|055|D|gastrointestinal bleeding (adjusted OR 0.8).(5)|
03719|056|D|   A retrospective review examined patients discharged from a hospital with|
03719|057|D|antiplatelet therapy following a myocardial infarction.  When compared to|
03719|058|D|aspirin therapy alone, both aspirin therapy with a SSRI and aspirin,|
03719|059|D|clopidogrel, and SSRI therapy were associated with an increased risk of|
03719|060|D|bleeding (hazard ratios 1.42 and 2.35, respectively.)  Compared with dual|
03719|061|D|antiplatelet therapy (aspirin and clopidogrel), use of aspirin and|
03719|062|D|clopidogrel and a SSRI was also associated with increased risk of bleeding|
03719|063|D|(hazard ratio 1.57).(6)|
03719|064|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
03719|065|D|anticoagulation (hazard ratio 2.63).  Paroxetine was not associated with an|
03719|066|D|increased risk.  There were insufficient numbers of patients taking other|
03719|067|D|SSRIs to assess increased risk.(7)|
03719|068|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
03719|069|D|pairs were reviewed and found 14% of drug pairs were associated with a|
03719|070|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
03719|071|D|of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of|
03719|072|D|1.69 (1.11-2.57).(8)|
03719|073|B||
03719|074|R|REFERENCES:|
03719|075|B||
03719|076|R|1.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
03719|077|R|  Pharmaceuticals, Inc. August, 2023.|1
03719|078|R|2.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
03719|079|R|  Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
03719|080|R|  by level of kidney function: A population-based cohort study. Br J Clin|2
03719|081|R|  Pharmacol 2018 Sep;84(9):2142-2151.|2
03719|082|R|3.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
03719|083|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
03719|084|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
03719|085|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
03719|086|R|4.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
03719|087|R|  serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
03719|088|R|  population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
03719|089|R|5.Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding risk|2
03719|090|R|  with concurrent use of selective serotonin reuptake inhibitors and|2
03719|091|R|  coumarins. Arch Intern Med 2008 Jan 28;168(2):180-5.|2
03719|092|R|6.Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding|2
03719|093|R|  associated with combined use of selective serotonin reuptake inhibitors|2
03719|094|R|  and antiplatelet therapy following acute myocardial infarction. CMAJ 2011|2
03719|095|R|  Nov 8;183(16):1835-43.|2
03719|096|R|7.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
03719|097|R|  Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
03719|098|R|  antidepressants and the risk of overanticoagulation during acenocoumarol|2
03719|099|R|  maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
03719|100|R|8.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
03719|101|R|  Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
03719|102|R|  Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
03719|103|R|  Pharmacol Ther 2020 Aug;108(2):377-386.|2
03720|001|T|MONOGRAPH TITLE:  Leflunomide; Teriflunomide/Selected Immunosuppressants|
03720|002|B||
03720|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03720|004|L|of severe adverse interaction.|
03720|005|B||
03720|006|A|MECHANISM OF ACTION:  Concurrent use of leflunomide or teriflunomide and|
03720|007|A|potent immunosuppressants may result in additive or synergistic effects on|
03720|008|A|the immune system.(1,2)|
03720|009|A|   Leflunomide is a prodrug and is converted to its active metabolite|
03720|010|A|teriflunomide.(1)|
03720|011|B||
03720|012|E|CLINICAL EFFECTS:  Concurrent use of leflunomide or teriflunomide with|
03720|013|E|immunosuppressants may result in an increased risk of serious infections,|
03720|014|E|including opportunistic infections, especially Pneumocystis jiroveci|
03720|015|E|pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and|
03720|016|E|aspergillosis.|
03720|017|B||
03720|018|P|PREDISPOSING FACTORS:  None determined.|
03720|019|B||
03720|020|M|PATIENT MANAGEMENT:  If leflunomide or teriflunomide is used concurrently|
03720|021|M|with immunosuppressive agents, chronic CBC monitoring should be performed|
03720|022|M|more frequently, every month instead of every 6 to 8 weeks.  If bone marrow|
03720|023|M|suppression or a serious infection occurs, leflunomide or teriflunomide|
03720|024|M|should be stopped and rapid drug elimination procedure should be|
03720|025|M|performed.(1,2)|
03720|026|B||
03720|027|D|DISCUSSION:  Pancytopenia, agranulocytosis and thrombocytopenia have been|
03720|028|D|reported in patients receiving leflunomide or teriflunomide alone, but most|
03720|029|D|frequently in patients taking concurrent immunosuppressants.(1,2)|
03720|030|D|   Severe and potentially fatal infections, including sepsis, have been|
03720|031|D|reported in patients receiving leflunomide or teriflunomide, especially|
03720|032|D|Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also|
03720|033|D|been reported.(1,2)|
03720|034|B||
03720|035|R|REFERENCES:|
03720|036|B||
03720|037|R|1.Arava (leflunomide) US prescribing information. Aventis Pharmaceuticals,|1
03720|038|R|  Inc. November, 2012.|1
03720|039|R|2.Aubagio (teriflunomide) US prescribing information. Genzyme Corporation|1
03720|040|R|  November, 2020.|1
03721|001|T|MONOGRAPH TITLE:  Glasdegib/Strong CYP3A4 Inhibitors that Prolong QT|
03721|002|B||
03721|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03721|004|L|of severe adverse interaction.|
03721|005|B||
03721|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
03721|007|A|may inhibit the metabolism of glasdegib and result in additive effects on|
03721|008|A|the QTc interval.(1)|
03721|009|B||
03721|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
03721|011|E|the QTc interval may increase systemic exposure and the risk for glasdegib|
03721|012|E|toxicities such as neutropenia.|
03721|013|E|   Concurrent use may also result in additive QTc prolongation, which may|
03721|014|E|lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)|
03721|015|B||
03721|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03721|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03721|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03721|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03721|020|P|gender, or advanced age.(2)|
03721|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03721|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03721|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03721|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03721|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03721|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03721|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03721|028|B||
03721|029|M|PATIENT MANAGEMENT:  Avoid concurrent use of glasdegib with medications that|
03721|030|M|prolong the QT interval.(1)|
03721|031|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03721|032|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03721|033|M|treatment, after initiation of any drug known to prolong the QT interval,|
03721|034|M|and periodically monitor during therapy.  Correct any electrolyte|
03721|035|M|abnormalities.|
03721|036|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03721|037|M|fainting.|
03721|038|M|   If QTc prolongation develops:|
03721|039|M|   ---Monitor and supplement electrolytes as clinically indicated.|
03721|040|M|   ---Review and adjust concomitant QT prolonging medications.|
03721|041|M|   ---Interrupt glasdegib therapy for QTc interval greater than 500 ms.|
03721|042|M|   ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
03721|043|M|prolongation.|
03721|044|M|   ---Follow labeling recommendations regarding restarting glasdegib.(1)|
03721|045|B||
03721|046|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03721|047|D|coadministration of ketoconazole (strong 3A4 inhibitor) with glasdegib|
03721|048|D|increased glasdegib maximum concentration (Cmax) and area-under-the-curve|
03721|049|D|(AUC) by 1.4 and 2.4-fold, respectively.(1)|
03721|050|D|   In a randomized, single-dose, double-blind, 4-way cross-over, placebo-|
03721|051|D|and open-label moxifloxacin-controlled study in 36 healthy subjects, the|
03721|052|D|largest placebo and baseline-adjusted QTc interval change was 8 msec (90%|
03721|053|D|CI:  6-10 msec) with a single 150 mg dose of glasdegib. (The 150 mg single|
03721|054|D|dose was used to achieve therapeutic plasma concentrations.)  With two-fold|
03721|055|D|therapeutic plasma concentrations (achieved with a 300 mg single dose), the|
03721|056|D|QTc change was 13 msec (90% CI:  11-16 msec).(1)|
03721|057|D|   Strong CYP3A4 inhibitors that prolong QT linked to this monograph|
03721|058|D|include:  adagrasib, ceritinib, clarithromycin, levoketoconazole,|
03721|059|D|lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin,|
03721|060|D|and voriconazole.(3)|
03721|061|B||
03721|062|R|REFERENCES:|
03721|063|B||
03721|064|R|1.Daurismo (glasdegib) US prescribing information. Pfizer Inc. March, 2020.|1
03721|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03721|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03721|067|R|  settings: a scientific statement from the American Heart Association and|6
03721|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03721|069|R|  2;55(9):934-47.|6
03721|070|R|3.This information is based on an extract from the Certara Drug Interaction|6
03721|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03722|001|T|MONOGRAPH TITLE:  Haloperidol/Barbiturates|
03722|002|B||
03722|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03722|004|L|take action as needed.|
03722|005|B||
03722|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolism of|
03722|007|A|haloperidol.  The concurrent administration of haloperidol and barbiturates|
03722|008|A|may result in additive CNS depressant effects.(1)|
03722|009|B||
03722|010|E|CLINICAL EFFECTS:  Concurrent use may result in potentiation of CNS|
03722|011|E|depression, which may result in hypotension, increased sedation, and|
03722|012|E|respiratory depression.(1)|
03722|013|E|   Some barbiturates may reduce the effectiveness of haloperidol.(1)|
03722|014|B||
03722|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03722|016|P|of the inducer for longer than 1-2 weeks.|
03722|017|B||
03722|018|M|PATIENT MANAGEMENT:  Respiration and blood pressure should be closely|
03722|019|M|monitored in patients receiving concurrent barbiturate and haloperidol|
03722|020|M|therapy.  The dosage of the barbiturate may need to be adjusted in patients|
03722|021|M|receiving barbiturates for indications other than anticonvulsant use.|
03722|022|M|   Carefully monitor clinical response in patients maintained on haloperidol|
03722|023|M|when initiating or discontinuing inducers of CYP3A4 such as barbiturates.|
03722|024|M|The dose of haloperidol may need to be adjusted.(1)|
03722|025|B||
03722|026|D|DISCUSSION:  A nested case-control study looked at the relationship between|
03722|027|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03722|028|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03722|029|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03722|030|D|significantly increased in patients with recent use of antipsychotics|
03722|031|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03722|032|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03722|033|D|of use.(2)|
03722|034|D|   In a retrospective review of 231 schizophrenic patients, patients|
03722|035|D|receiving concurrent carbamazepine or phenobarbital (strong CYP3A4 inducers)|
03722|036|D|had haloperidol levels that were 37% and 22% lower, respectively, than|
03722|037|D|patients taking haloperidol without these agents.(3)|
03722|038|D|   In a study in schizophrenic patients, the addition of rifampin (a strong|
03722|039|D|CYP3A4 inducer) in 12 patients resulted in decreases in haloperidol levels|
03722|040|D|by 37%, 58.7%, and 70% by Day 3, Day 7, and Day 28, respectively, of|
03722|041|D|concurrent therapy.  Mean scores on the Brief Psychiatric Rating Scale|
03722|042|D|decreased from baseline.  Discontinuation of rifampin from concurrent|
03722|043|D|therapy in 5 patients increased haloperidol levels by 140.7%, 228.7%, and|
03722|044|D|329% of baseline by Day 3, Day 7, and Day 28, respectively, after rifampin|
03722|045|D|discontinuation.(1,4)|
03722|046|D|   In a study in 7 schizophrenic patients, rifampin decreased the half-life|
03722|047|D|of haloperidol by 48%.(5)|
03722|048|B||
03722|049|R|REFERENCES:|
03722|050|B||
03722|051|R|1.Haldol injection (haloperidol) US prescribing information. Janssen|1
03722|052|R|  Pharmaceuticals, Inc. October, 2025.|1
03722|053|R|2.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03722|054|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03722|055|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03722|056|R|  Pharmacol 2020 Apr 26.|2
03722|057|R|3.Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching carbamazepine|3
03722|058|R|  to oxcarbazepine on the plasma levels of neuroleptics. A case report.|3
03722|059|R|  Psychopharmacology (Berl) 1994 Sep;116(1):115-6.|3
03722|060|R|4.Kim YH, Cha IJ, Shim JC, Shin JG, Yoon YR, Kim YK, Kim JI, Park GH, Jang|2
03722|061|R|  IJ, Woo JI, Shin SG. Effect of rifampin on the plasma concentration and|2
03722|062|R|  the clinical effect of haloperidol concomitantly administered to|2
03722|063|R|  schizophrenic patients. J Clin Psychopharmacol 1996 Jun;16(3):247-52.|2
03722|064|R|5.Takeda M, Nishinuma K, Yamashita S, Matsubayashi T, Tanino S, Nishimura T.|2
03722|065|R|  Serum haloperidol levels of schizophrenics receiving treatment for|2
03722|066|R|  tuberculosis. Clin Neuropharmacol 1986;9(4):386-97.|2
03723|001|T|MONOGRAPH TITLE:  Haloperidol/Selected Strong CYP3A4 Inducers|
03723|002|B||
03723|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03723|004|L|take action as needed.|
03723|005|B||
03723|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
03723|007|A|clearance of haloperidol.(1)|
03723|008|B||
03723|009|E|CLINICAL EFFECTS:  Coadministration with a strong CYP3A4 inducer may result|
03723|010|E|in decreased levels and effectiveness of haloperidol.(1)|
03723|011|B||
03723|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03723|013|P|of the inducer for longer than 1-2 weeks.|
03723|014|B||
03723|015|M|PATIENT MANAGEMENT:  Monitor clinical response in patients maintained on|
03723|016|M|haloperidol when initiating or discontinuing strong CYP3A4 inducers.  The|
03723|017|M|dosage of haloperidol may need to be adjusted.(1)|
03723|018|B||
03723|019|D|DISCUSSION:  In a study in 11 schizophrenic patients, the addition of|
03723|020|D|carbamazepine resulted in a dose related decrease in haloperidol levels.|
03723|021|D|Haloperidol levels were decreased by 2%, 61%, and 85%, respectively, from|
03723|022|D|baseline following the addition and increase of carbamazepine at 100 mg/day,|
03723|023|D|300 mg/day, and 600 mg/day.(1,2)|
03723|024|D|   In a study in 27 patients with schizophrenia or schizoaffective disorder,|
03723|025|D|the use of haloperidol with carbamazepine was associated with lower|
03723|026|D|haloperidol levels and worse clinical outcomes than the use of haloperidol|
03723|027|D|alone.(3)|
03723|028|D|   In a study in schizophrenic patients, haloperidol levels were|
03723|029|D|significantly decreased in patients receiving concurrent carbamazepine.(4)|
03723|030|D|   In a study in 7 patients, haloperidol levels fell 60% following the|
03723|031|D|addition of carbamazepine to therapy.  Haloperidol levels were undetectable|
03723|032|D|in 2 subjects, whose symptoms worsened.(5)|
03723|033|D|   In a study in 23 patients, the addition of carbamazepine to haloperidol|
03723|034|D|resulted in improvement in symptoms.(6)|
03723|035|D|   In a retrospective review of 231 schizophrenic patients, patients|
03723|036|D|receiving concurrent carbamazepine or phenobarbital had haloperidol levels|
03723|037|D|that were 37% and 22% lower, respectively, than patients taking haloperidol|
03723|038|D|without these agents.(7)|
03723|039|D|   In a study in 6 schizophrenic patients, switching carbamazepine to|
03723|040|D|oxcarbazepine resulted in increased in haloperidol levels by 50% to 200%|
03723|041|D|after 2-4 weeks of therapy.(8)|
03723|042|D|   In a study in schizophrenic patients, carbamazepine decreased haloperidol|
03723|043|D|levels by 50%.  One subject developed worsening of symptoms, while two|
03723|044|D|improved.(9)|
03723|045|D|   There are also case reports documenting decreased haloperidol levels and|
03723|046|D|effectiveness with concurrent carbamazepine.(10-14)|
03723|047|D|   In a study in schizophrenic patients, the addition of rifampin in 12|
03723|048|D|patients resulted in decreases in haloperidol levels by 37%, 58.7%, and 70%|
03723|049|D|by Day 3, Day 7, and Day 28, respectively, of concurrent therapy.  Mean|
03723|050|D|scores on the Brief Psychiatric Rating Scale decreased from baseline.|
03723|051|D|Discontinuation of rifampin from concurrent therapy in 5 patients increased|
03723|052|D|haloperidol levels by 140.7%, 228.7%, and 329% of baseline by Day 3, Day 7,|
03723|053|D|and Day 28, respectively, after rifampin discontinuation.(1,15)|
03723|054|D|   In a study in 7 schizophrenic patients, rifampin decreased the half-life|
03723|055|D|of haloperidol by 48%.(16)|
03723|056|D|   Strong CYP3A4 inducers linked to this monograph are:  carbamazepine,|
03723|057|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenytoin, rifampin,|
03723|058|D|rifapentine and St. John's Wort.(17,18)|
03723|059|B||
03723|060|R|REFERENCES:|
03723|061|B||
03723|062|R|1.Haldol injection (haloperidol) US prescribing information. Janssen|1
03723|063|R|  Pharmaceuticals, Inc. October, 2025.|1
03723|064|R|2.Yasui-Furukori N, Kondo T, Mihara K, Suzuki A, Inoue Y, Kaneko S.|2
03723|065|R|  Significant dose effect of carbamazepine on reduction of steady-state|2
03723|066|R|  plasma concentration of haloperidol in schizophrenic patients. J Clin|2
03723|067|R|  Psychopharmacol 2003 Oct;23(5):435-40.|2
03723|068|R|3.Hesslinger B, Normann C, Langosch JM, Klose P, Berger M, Walden J. Effects|2
03723|069|R|  of carbamazepine and valproate on haloperidol plasma levels and on|2
03723|070|R|  psychopathologic outcome in schizophrenic patients. J Clin Psychopharmacol|2
03723|071|R|  1999 Aug;19(4):310-5.|2
03723|072|R|4.Iwahashi K, Miyatake R, Suwaki H, Hosokawa K, Ichikawa Y. The drug-drug|2
03723|073|R|  interaction effects of haloperidol on plasma carbamazepine levels. Clin|2
03723|074|R|  Neuropharmacol 1995 Jun;18(3):233-6.|2
03723|075|R|5.Arana GW, Goff DC, Friedman H, Ornsteen M, Greenblatt DJ, Black B, Shader|2
03723|076|R|  RI. Does carbamazepine-induced reduction of plasma haloperidol levels|2
03723|077|R|  worsen psychotic symptoms?. Am J Psychiatry 1986 May;143(5):650-1.|2
03723|078|R|6.Klein E, Bental E, Lerer B, Belmaker RH. Carbamazepine and haloperidol v|2
03723|079|R|  placebo and haloperidol in excited psychoses. A controlled study. Arch Gen|2
03723|080|R|  Psychiatry 1984 Feb;41(2):165-70.|2
03723|081|R|7.Hirokane G, Someya T, Takahashi S, Morita S, Shimoda K. Interindividual|2
03723|082|R|  variation of plasma haloperidol concentrations and the impact of|2
03723|083|R|  concomitant medications: the analysis of therapeutic drug monitoring data.|2
03723|084|R|  Ther Drug Monit 1999 Feb;21(1):82-6.|2
03723|085|R|8.Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching carbamazepine|3
03723|086|R|  to oxcarbazepine on the plasma levels of neuroleptics. A case report.|3
03723|087|R|  Psychopharmacology (Berl) 1994 Sep;116(1):115-6.|3
03723|088|R|9.Kahn EM, Schulz SC, Perel JM, Alexander JE. Change in haloperidol level|2
03723|089|R|  due to carbamazepine--a complicating factor in combined medication for|2
03723|090|R|  schizophrenia. J Clin Psychopharmacol 1990 Feb;10(1):54-7.|2
03723|091|R|10.Fast DK, Jones BD, Kusalic M, Erickson M. Effect of carbamazepine on|3
03723|092|R|   neuroleptic plasma levels and efficacy. Am J Psychiatry 1986 Jan;|3
03723|093|R|   143(1):117-8.|3
03723|094|R|11.Jann MW, Ereshefsky L, Saklad SR, Seidel DR, Davis CM, Burch NR, Bowden|3
03723|095|R|   CL. Effects of carbamazepine on plasma haloperidol levels. J Clin|3
03723|096|R|   Psychopharmacol 1985 Apr;5(2):106-9.|3
03723|097|R|12.Cohen D, Diemont WL. Deterioration of schizoaffective disorder due to an|3
03723|098|R|   interaction between haloperidol and carbamazepine. Ned Tijdschr Geneeskd|3
03723|099|R|   2002 Oct 12;146(41):1942-4.|3
03723|100|R|13.Kanter GL, Yerevanian BI, Ciccone JR. Case report of a possible|3
03723|101|R|   interaction between neuroleptics and carbamazepine. Am J Psychiatry 1984|3
03723|102|R|   Sep;141(9):1101-2.|3
03723|103|R|14.Brayley J, Yellowlees P. An interaction between haloperidol and|3
03723|104|R|   carbamazepine in a patient with cerebral palsy. Aust N Z J Psychiatry|3
03723|105|R|   1987 Dec;21(4):605-7.|3
03723|106|R|15.Kim YH, Cha IJ, Shim JC, Shin JG, Yoon YR, Kim YK, Kim JI, Park GH, Jang|2
03723|107|R|   IJ, Woo JI, Shin SG. Effect of rifampin on the plasma concentration and|2
03723|108|R|   the clinical effect of haloperidol concomitantly administered to|2
03723|109|R|   schizophrenic patients. J Clin Psychopharmacol 1996 Jun;16(3):247-52.|2
03723|110|R|16.Takeda M, Nishinuma K, Yamashita S, Matsubayashi T, Tanino S, Nishimura|2
03723|111|R|   T. Serum haloperidol levels of schizophrenics receiving treatment for|2
03723|112|R|   tuberculosis. Clin Neuropharmacol 1986;9(4):386-97.|2
03723|113|R|17.US Food and Drug Administration (FDA). Drug Development and Drug|1
03723|114|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03723|115|R|   at:|1
03723|116|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03723|117|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03723|118|R|   11/14/2017.|1
03723|119|R|18.This information is based on an extract from the Certara Drug Interaction|6
03723|120|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03724|001|T|MONOGRAPH TITLE:  Haloperidol/Natisedine|
03724|002|B||
03724|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03724|004|L|of severe adverse interaction.|
03724|005|B||
03724|006|A|MECHANISM OF ACTION:  Phenobarbital, a component of natisedine, induces the|
03724|007|A|metabolism of haloperidol by CYP3A4.  The concurrent administration of|
03724|008|A|haloperidol and phenobarbital may result in additive CNS depressant|
03724|009|A|effects.(1-3)|
03724|010|A|    Torsades de pointes has been reported with haloperidol.(1-3)  Quinidine,|
03724|011|A|a component of natisedine, is a Class IA antiarrhythmic agent and may|
03724|012|A|prolong the QT interval.(4)  Concurrent use may result in additive effects|
03724|013|A|on the QTc interval.(1-3)|
03724|014|B||
03724|015|E|CLINICAL EFFECTS:  Concurrent use of haloperidol with phenobarbital may|
03724|016|E|result in decreased levels and effectiveness of haloperidol.  Concurrent use|
03724|017|E|of haloperidol and phenobarbital without dosage adjustment may result in|
03724|018|E|potentiation of CNS depression, which may result in hypotension, increased|
03724|019|E|sedation, and respiratory depression.(1-3)|
03724|020|E|   Concurrent use of haloperidol with quinidine may result in prolongation|
03724|021|E|of the QTc interval, which may result in potentially life-threatening|
03724|022|E|arrhythmias, including torsades de pointes.(1-3)|
03724|023|B||
03724|024|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by:|
03724|025|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, use|
03724|026|P|of multiple medications, intravenous haloperidol, or higher than recommended|
03724|027|P|dosages of haloperidol.|
03724|028|P|   The risk of QT prolongation or torsade de pointes may also be increased|
03724|029|P|in patients with cardiovascular disease (e.g. heart failure, myocardial|
03724|030|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03724|031|P|bradycardia, or advanced age.(5)|
03724|032|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03724|033|P|higher systemic concentrations of either QT prolonging drug are additional|
03724|034|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03724|035|P|drug concentrations include rapid infusion of an intravenous dose or|
03724|036|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03724|037|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03724|038|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03724|039|B||
03724|040|M|PATIENT MANAGEMENT:  Monitor clinical response in patients maintained on|
03724|041|M|haloperidol when initiating or discontinuing strong CYP3A4 inducers.  The|
03724|042|M|dosage of haloperidol may need to be adjusted.(1)|
03724|043|M|   Respiration and blood pressure should be closely monitored in patients|
03724|044|M|receiving concurrent haloperidol and phenobarbital therapy.  The dosage of|
03724|045|M|the barbiturate may need to be adjusted in patients receiving barbiturates|
03724|046|M|for indications other than anticonvulsant use.|
03724|047|M|   The Australian,(1) UK(2) and US(3) manufacturers of haloperidol state|
03724|048|M|that haloperidol should be used with caution when given with other agents|
03724|049|M|known to prolong the QT interval.|
03724|050|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03724|051|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03724|052|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03724|053|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03724|054|B||
03724|055|D|DISCUSSION:  Sudden death, QT-prolongation, and torsades de pointes have|
03724|056|D|been reported with haloperidol.(3)|
03724|057|D|   A nested case-control study looked at the relationship between|
03724|058|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
03724|059|D|antipsychotics was associated with a 2.33-fold increase in risk of|
03724|060|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
03724|061|D|significantly increased in patients with recent use of antipsychotics|
03724|062|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
03724|063|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
03724|064|D|of use.(6)|
03724|065|D|   In a retrospective review of 231 schizophrenic patients, patients|
03724|066|D|receiving concurrent carbamazepine or phenobarbital (strong CYP3A4 inducers)|
03724|067|D|had haloperidol levels that were 37% and 22% lower, respectively, than|
03724|068|D|patients taking haloperidol without these agents.(7)|
03724|069|D|   In a study in schizophrenic patients, the addition of rifampin (another|
03724|070|D|strong CYP3A4 inducer) in 12 patients resulted in decreases in haloperidol|
03724|071|D|levels by 37%, 58.7%, and 70% by Day 3, Day 7, and Day 28, respectively, of|
03724|072|D|concurrent therapy.  Mean scores on the Brief Psychiatric Rating Scale|
03724|073|D|decreased from baseline.  Discontinuation of rifampin from concurrent|
03724|074|D|therapy in 5 patients increased haloperidol levels by 140.7%, 228.7%, and|
03724|075|D|329% of baseline by Day 3, Day 7, and Day 28, respectively, after rifampin|
03724|076|D|discontinuation.(1,8)|
03724|077|D|   In a study in 7 schizophrenic patients, rifampin decreased the half-life|
03724|078|D|of haloperidol by 48%.(9)|
03724|079|B||
03724|080|R|REFERENCES:|
03724|081|B||
03724|082|R|1.Serenace (haloperidol) Australian prescribing information. Sigma|1
03724|083|R|  Pharmaceuticals Pty Ltd. June 5, 2001.|1
03724|084|R|2.Dozic (haloperidol) UK summary of product characteristics. Rosemont|1
03724|085|R|  Pharmaceuticals Limited September 10, 2007.|1
03724|086|R|3.Haldol injection (haloperidol) US prescribing information. Janssen|1
03724|087|R|  Pharmaceuticals, Inc. October, 2025.|1
03724|088|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03724|089|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03724|090|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03724|091|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03724|092|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03724|093|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03724|094|R|  settings: a scientific statement from the American Heart Association and|6
03724|095|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03724|096|R|  2;55(9):934-47.|6
03724|097|R|6.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
03724|098|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
03724|099|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
03724|100|R|  Pharmacol 2020 Apr 26.|2
03724|101|R|7.Hirokane G, Someya T, Takahashi S, Morita S, Shimoda K. Interindividual|2
03724|102|R|  variation of plasma haloperidol concentrations and the impact of|2
03724|103|R|  concomitant medications: the analysis of therapeutic drug monitoring data.|2
03724|104|R|  Ther Drug Monit 1999 Feb;21(1):82-6.|2
03724|105|R|8.Kim YH, Cha IJ, Shim JC, Shin JG, Yoon YR, Kim YK, Kim JI, Park GH, Jang|2
03724|106|R|  IJ, Woo JI, Shin SG. Effect of rifampin on the plasma concentration and|2
03724|107|R|  the clinical effect of haloperidol concomitantly administered to|2
03724|108|R|  schizophrenic patients. J Clin Psychopharmacol 1996 Jun;16(3):247-52.|2
03724|109|R|9.Takeda M, Nishinuma K, Yamashita S, Matsubayashi T, Tanino S, Nishimura T.|2
03724|110|R|  Serum haloperidol levels of schizophrenics receiving treatment for|2
03724|111|R|  tuberculosis. Clin Neuropharmacol 1986;9(4):386-97.|2
03725|001|T|MONOGRAPH TITLE:  Citalopram; Escitalopram/Slt Dual CYP2C19 & CYP3A4|
03725|002|T|Inducers|
03725|003|B||
03725|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03725|005|L|take action as needed.|
03725|006|B||
03725|007|A|MECHANISM OF ACTION:  Dual CYP2C19 and CYP3A4 inducers may induce the|
03725|008|A|metabolism of citalopram and escitalopram.(1,2)  Citalopram and escitalopram|
03725|009|A|are metabolized by CYP2C19 and CYP3A4.(1,2)|
03725|010|B||
03725|011|E|CLINICAL EFFECTS:  Concurrent use of dual CYP2C19 and CYP3A4 inducers may|
03725|012|E|decrease systemic levels and effectiveness of citalopram and|
03725|013|E|escitalopram.(1,2)|
03725|014|B||
03725|015|P|PREDISPOSING FACTORS:  The degree to which citalopram and escitalopram|
03725|016|P|systemic levels are decreased may be related to higher doses of|
03725|017|P|carbamazepine.(3)|
03725|018|P|   Induction effects may be more likely with regular use of the inducer for|
03725|019|P|longer than 1-2 weeks.|
03725|020|B||
03725|021|M|PATIENT MANAGEMENT:  When used concomitantly with dual CYP2C19 and CYP3A4|
03725|022|M|inducers, monitoring of concentrations or dosage adjustment of citalopram|
03725|023|M|and escitalopram may be necessary.(1,2)|
03725|024|B||
03725|025|D|DISCUSSION:  Combined administration of racemic citalopram (40 mg/day for 14|
03725|026|D|days) and carbamazepine (a dual CYP3A4 and CYP2C19 inducer) titrated to 400|
03725|027|D|mg/day for 35 days did not affect citalopram plasma trough levels.  Given|
03725|028|D|the enzyme-inducing properties of carbamazepine, the possibility that|
03725|029|D|carbamazepine might increase the clearance of escitalopram should be|
03725|030|D|considered if the two drugs are coadministered.(1,2)|
03725|031|D|   In an open pilot study of six patients who were nonresponders to a 4-week|
03725|032|D|pretreatment with 40 to 60 mg/day of citalopram, carbamazepine (200-400|
03725|033|D|mg/day) augmentation therapy resulted in a decrease of plasma concentrations|
03725|034|D|of S-citalopram and R-citalopram by 27% and 31%, respectively.(3)|
03725|035|D|   A case report of a 55-year-old man receiving citalopram 60 mg daily for|
03725|036|D|panic disorder reported decreased therapeutic efficacy when rifampin 600 mg|
03725|037|D|twice daily was started.  His condition improved when rifampin was|
03725|038|D|stopped.(4)|
03725|039|D|   In two case reports, patients on concomitant citalopram and carbamazepine|
03725|040|D|experienced an increase in citalopram serum concentrations one month after|
03725|041|D|carbamazepine therapy was changed to oxcarbazepine.  A 31-year-old man|
03725|042|D|taking citalopram 30 mg daily and carbamazepine 800 mg daily experienced an|
03725|043|D|8-fold increase in citalopram serum concentration after carbamazepine was|
03725|044|D|discontinued, and a 42-year-old woman taking concomitant citalopram 80 mg|
03725|045|D|daily and carbamazepine 400 mg daily experienced a 3.4-fold increase in|
03725|046|D|citalopram serum concentration after carbamazepine was discontinued.(5)|
03725|047|D|   A case report of a 27-year-old female patient treated with citalopram 20|
03725|048|D|mg daily for two years describes a recurrence of panic attacks 5 days after|
03725|049|D|starting rifampin 600 mg daily.(6)|
03725|050|D|   Dual CYP2C19 and CYP3A4 inducers linked to this monograph include:|
03725|051|D|apalutamide, carbamazepine, enzalutamide, fosphenytoin, phenytoin, and|
03725|052|D|rifampin.(7,8)|
03725|053|B||
03725|054|R|REFERENCES:|
03725|055|B||
03725|056|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03725|057|R|  Laboratories Inc. August, 2023.|1
03725|058|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03725|059|R|  Pharmaceuticals Inc. May, 2023.|1
03725|060|R|3.Steinacher L, Vandel P, Zullino DF, Eap CB, Brawand-Amey M, Baumann P.|2
03725|061|R|  Carbamazepine augmentation in depressive patients non-responding to|2
03725|062|R|  citalopram: a pharmacokinetic and clinical pilot study. Eur.|2
03725|063|R|  Neuropsychopharmacol. September 2001.;12:255-260.|2
03725|064|R|4.Kukoyi O, Argo TR, Carnahan RM. Exacerbation of panic disorder with|3
03725|065|R|  rifampin therapy in a patient receiving citalopram. Pharmacotherapy 2005;|3
03725|066|R|  25(3):435-437.|3
03725|067|R|5.Leinonen E, Lepola U, Koponen H. Substituting carbamazepine with|3
03725|068|R|  oxcarbazepine increases citalopram levels: a report on two cases.|3
03725|069|R|  Pharmacopsychiat. 1996;29:156-158.|3
03725|070|R|6.Khalili H, Dashti-Khavidaki S, Amini S, Mousavi M. Recurrence of panic|3
03725|071|R|  attacks after brucellosis treatment--highly probable citalopram and|3
03725|072|R|  rifampin drug interaction. J. Clin. Psychopharmacol. December 2012;|3
03725|073|R|  32(6):842-844.|3
03725|074|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
03725|075|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03725|076|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03725|077|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03725|078|R|  11/14/2017.|1
03725|079|R|8.This information is based on an extract from the Certara Drug Interaction|6
03725|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03726|001|T|MONOGRAPH TITLE:  Citalopram;Escitalopram/Slt 2C19&3A4 Inducer that Prolong|
03726|002|T|QT|
03726|003|B||
03726|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03726|005|L|take action as needed.|
03726|006|B||
03726|007|A|MECHANISM OF ACTION:  Dual CYP2C19 and CYP3A4 inducers that prolong the QTc|
03726|008|A|interval may induce the metabolism of citalopram and escitalopram and result|
03726|009|A|in additive risk of QT prolongation.(1,2)|
03726|010|B||
03726|011|E|CLINICAL EFFECTS:  Concurrent use of dual CYP2C19 and CYP3A4 inducers that|
03726|012|E|prolong QT may decrease systemic levels and effectiveness of citalopram and|
03726|013|E|escitalopram and may cause additive effects on the QTc interval, which may|
03726|014|E|result in life-threatening cardiac arrhythmias including torsades de|
03726|015|E|pointes.(1,2)|
03726|016|B||
03726|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03726|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03726|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03726|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03726|021|P|female gender, or advanced age.(2)|
03726|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03726|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03726|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03726|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03726|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03726|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03726|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03726|029|P|   Induction effects may be more likely with regular use of the inducer for|
03726|030|P|longer than 1-2 weeks.|
03726|031|B||
03726|032|M|PATIENT MANAGEMENT:  When used concomitantly with CYP2C19 and CYP3A4|
03726|033|M|inducers, monitoring of concentrations or dosage adjustment of citalopram|
03726|034|M|may be necessary.(1)|
03726|035|M|   Concurrent use of citalopram with agents known to prolong the QT interval|
03726|036|M|should be avoided.(1)|
03726|037|M|   Due to the risk of QT prolongation, citalopram doses greater than 40 mg|
03726|038|M|once daily are not recommended.  Citalopram doses should be limited to 20 mg|
03726|039|M|once daily in patients who are CYP2C19 poor metabolizers or patients|
03726|040|M|receiving CYP2C19 inhibitors.(1)|
03726|041|M|   If patients have a persistent QTc measurement > 500 ms, discontinue|
03726|042|M|citalopram.  If a patient develops symptoms including dizziness,|
03726|043|M|palpitations, or syncope, further evaluation is warranted included cardiac|
03726|044|M|monitoring.(1)|
03726|045|M|   While the US FDA and manufacturer recommend no special precautions when|
03726|046|M|escitalopram is used with QT prolonging agents,(3,4) Health Canada and the|
03726|047|M|Canadian manufacturer of escitalopram discourage the concurrent use of|
03726|048|M|agents known to prolong the QT interval(5,6) and the UK manufacturer states|
03726|049|M|that concurrent use is contraindicated.(7)|
03726|050|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03726|051|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03726|052|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03726|053|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03726|054|B||
03726|055|D|DISCUSSION:  Citalopram has been associated with dose-depended increases in|
03726|056|D|the QTc interval.  In healthy subjects, the maximum mean difference in QTc|
03726|057|D|interval seen with 20 mg of citalopram and 60 mg of citalopram were 8.5 msec|
03726|058|D|(90% CI = 6.2-10.8 msec) and 18.5 msec (90% CI = 16.0-21.0 msec),|
03726|059|D|respectively.  Based on extrapolation, a 40 mg dose of citalopram is|
03726|060|D|expected to produce a mean increase in the QTc interval of 12.6 msec (90% CI|
03726|061|D|= 10.9-14.3 msec).(1)|
03726|062|D|   In a clinical trial of use of citalopram for agitation in Alzheimer's|
03726|063|D|disease, citalopram (30 mg daily) was associated with a mean increase in QTc|
03726|064|D|of 18.1 msec.(8)|
03726|065|D|   Combined administration of racemic citalopram (40 mg/day for 14 days) and|
03726|066|D|carbamazepine (a dual CYP3A4 and CYP2C19 inducer) titrated to 400 mg/day for|
03726|067|D|35 days did not affect citalopram plasma trough levels.  Given the|
03726|068|D|enzyme-inducing properties of carbamazepine, the possibility that|
03726|069|D|carbamazepine might increase the clearance of escitalopram should be|
03726|070|D|considered if the two drugs are coadministered.(1,3)|
03726|071|D|   A case report of a 55-year-old man receiving citalopram for panic|
03726|072|D|disorder reported a decrease in the agent's therapeutic efficacy when|
03726|073|D|rifampin was started. His condition improved when rifampin was stopped.(9)|
03726|074|D|   Dual CYP2C19 and CYP3A4 inducers that prolong QT linked to this monograph|
03726|075|D|include: efavirenz and pacritinib.(10,11)|
03726|076|B||
03726|077|R|REFERENCES:|
03726|078|B||
03726|079|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03726|080|R|  Laboratories Inc. August, 2023.|1
03726|081|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03726|082|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03726|083|R|  settings: a scientific statement from the American Heart Association and|6
03726|084|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03726|085|R|  2;55(9):934-47.|6
03726|086|R|3.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03726|087|R|  Pharmaceuticals Inc. May, 2023.|1
03726|088|R|4.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
03726|089|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
03726|090|R|  potential risk of abnormal heart rhythms with high doses. Available at:|1
03726|091|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
03726|092|R|5.Health Canada. Antidepressant Cipralex (escitalopram): Updated information|1
03726|093|R|  regarding dose-related heart risk. Available at:|1
03726|094|R|  http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/1367|1
03726|095|R|  4a-eng.php May 7, 2012.|1
03726|096|R|6.Cipralex (escitalopram oxalate) Canadian prescribing information. Lundbeck|1
03726|097|R|  August 13, 2012.|1
03726|098|R|7.Cipralex (escitalopram oxalate) UK summary of product characteristics.|1
03726|099|R|  Lunbeck Limited June 25, 2020.|1
03726|100|R|8.Drye LT, et al. Changes in QTc interval in the citalopram for agitation in|2
03726|101|R|  Alzheimer's disease (CitAD) randomized trial. PLoS One 2014;9(6):e98426.|2
03726|102|R|9.Kukoyi O, Argo TR, Carnahan RM. Exacerbation of panic disorder with|3
03726|103|R|  rifampin therapy in a patient receiving citalopram. Pharmacotherapy 2005;|3
03726|104|R|  25(3):435-437.|3
03726|105|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
03726|106|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03726|107|R|   at:|1
03726|108|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03726|109|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03726|110|R|   11/14/2017.|1
03726|111|R|11.This information is based on an extract from the Certara Drug Interaction|6
03726|112|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03727|001|T|MONOGRAPH TITLE:  Citalopram; Escitalopram/St. John's Wort|
03727|002|B||
03727|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
03727|004|L|Assess the risk to the patient and take action as needed.|
03727|005|B||
03727|006|A|MECHANISM OF ACTION:  The exact mechanism for this interaction is unknown|
03727|007|A|because the mechanism of action of St. John's wort is unknown.  While early|
03727|008|A|studies showed that St. John's wort inhibited monoamine oxidase,(1,2) other|
03727|009|A|studies have shown that the MAOI effects of St. John's wort are too weak to|
03727|010|A|explain its therapeutic effects.(3,4)  The active component of St. John's|
03727|011|A|wort is thought to be hypericin,(5) a weak MAO inhibitor(1) whose|
03727|012|A|concentration in humans may not reach the levels required to inhibit MAO.(2)|
03727|013|A|Another study theorized that St. John's wort may inhibit serotonin|
03727|014|A|reuptake.(6)|
03727|015|A|   St. John's wort may induce the metabolism of citalopram and escitalopram|
03727|016|A|by CYP2C19 and CYP3A4 induction.(7,8)|
03727|017|B||
03727|018|E|CLINICAL EFFECTS:  The concurrent use of St. John's wort and citalopram or|
03727|019|E|escitalopram may result in serotonin syndrome.  Symptoms of serotonin|
03727|020|E|syndrome may include irritability, altered consciousness, double vision,|
03727|021|E|nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity,|
03727|022|E|myoclonus, rapid fluctuations in vital signs, and coma.  Serotonin syndrome|
03727|023|E|may result in death.|
03727|024|E|   Concurrent use of a dual CYP2C19 and CYP3A4 inducer may decrease systemic|
03727|025|E|levels and effectiveness of citalopram and escitalopram.(7,8)|
03727|026|B||
03727|027|P|PREDISPOSING FACTORS:  None determined.|
03727|028|B||
03727|029|M|PATIENT MANAGEMENT:  Consider a 14 day washout period for patients who have|
03727|030|M|taken St. John's wort before initiating citalopram or escitalopram.|
03727|031|M|Patients on these antidepressants should be cautioned about and observed for|
03727|032|M|the potential of developing serotonin syndrome if they add St. John's wort|
03727|033|M|to their regimen.|
03727|034|M|   If concurrent therapy is warranted, patients should be monitored for|
03727|035|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03727|036|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03727|037|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03727|038|M|coordination, or severe diarrhea.|
03727|039|M|   When used concomitantly with a dual CYP2C19 and CYP3A4 inducer like St.|
03727|040|M|John's wort, monitoring of concentrations or dosage adjustment of citalopram|
03727|041|M|and escitalopram may be necessary.(7,8)|
03727|042|B||
03727|043|D|DISCUSSION:  In a case report, a patient had stopped taking paroxetine ten|
03727|044|D|days prior to initiating St. John's wort.  The evening after initiating St.|
03727|045|D|John's wort, the patient took a paroxetine because she was having trouble|
03727|046|D|sleeping.  At noon the next day, the patient was able to be awakened, but|
03727|047|D|was incoherent, groggy, slow-moving, and almost unable to get up.  Two hours|
03727|048|D|later during an examination, she was groggy and lethargic, but able to|
03727|049|D|respond appropriately.  She complained of nausea, weakness, and fatigue.|
03727|050|D|Her vital signs and physical exam were normal, except for a slow response|
03727|051|D|time and limp muscle tone.  She did not take any additional paroxetine and|
03727|052|D|was normal the next day.(9)|
03727|053|D|   Serotonin syndrome has also been reported with concurrent St. John's wort|
03727|054|D|and nefazodone,(9) sertraline,(9) and venlafaxine.(10)  Mania has also been|
03727|055|D|reported with concurrent St. John's wort and sertraline.(11)|
03727|056|D|   Combined administration of racemic citalopram (40 mg/day for 14 days) and|
03727|057|D|carbamazepine (a dual CYP3A4 and CYP2C19 inducer) titrated to 400 mg/day for|
03727|058|D|35 days did not affect citalopram plasma trough levels.  Given the|
03727|059|D|enzyme-inducing properties of carbamazepine, the possibility that|
03727|060|D|carbamazepine might increase the clearance of escitalopram should be|
03727|061|D|considered if the two drugs are coadministered.(7,8)|
03727|062|D|   St. John's wort with low hyperforin content (< 1 mg) is not expected to|
03727|063|D|induce CYP3A4 or CYP2C19.(13)|
03727|064|B||
03727|065|R|REFERENCES:|
03727|066|B||
03727|067|R|1.Muller WE, Rolli M, Schafer C, Hafner U. Effects of hypericum extract (LI|5
03727|068|R|  160) in biochemical models of antidepressant activity. Pharmacopsychiatry|5
03727|069|R|  1997 Sep;30 Suppl 2:102-7.|5
03727|070|R|2.Cott JM. In vitro receptor binding and enzyme inhibition by Hypericum|5
03727|071|R|  perforatum extract. Pharmacopsychiatry 1997 Sep;30 Suppl 2:108-12.|5
03727|072|R|3.Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and|5
03727|073|R|  hypericin. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S54-6.|5
03727|074|R|4.Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of|5
03727|075|R|  hypericum extract. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S57-9.|5
03727|076|R|5.Anonymous. St. John's wort. Med Lett Drugs Ther 1997 Nov 21;|6
03727|077|R|  39(1014):107-8.|6
03727|078|R|6.Perovic S, Muller WE. Pharmacological profile of hypericum extract. Effect|5
03727|079|R|  on serotonin uptake by postsynaptic receptors. Arzneimittelforschung 1995|5
03727|080|R|  Nov;45(11):1145-8.|5
03727|081|R|7.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
03727|082|R|  Laboratories Inc. August, 2023.|1
03727|083|R|8.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
03727|084|R|  Pharmaceuticals Inc. May, 2023.|1
03727|085|R|9.Gordon JB. SSRIs and St.John's Wort: possible toxicity?. Am Fam Physician|3
03727|086|R|  1998 Mar 1;57(5):950,953.|3
03727|087|R|10.Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant|3
03727|088|R|   drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999|3
03727|089|R|   Spring;12(1):7-10.|3
03727|090|R|11.Prost N, Tichadou L, Rodor F, Nguyen N, David JM, Jean-Pastor MJ. St.|3
03727|091|R|   Johns wort-venlafaxine interaction. Presse Med 2000 Jul 1;29(23):1285-6.|3
03727|092|R|12.Barbenel DM, Yusufi B, O'Shea D, Bench CJ. Mania in a patient receiving|3
03727|093|R|   testosterone replacement postorchidectomy taking St John's wort and|3
03727|094|R|   sertraline. J Psychopharmacol 2000 Mar;14(1):84-6.|3
03727|095|R|13.Remotiv (St. John's wort) Israeli Prescribing Information. Max Zeller|1
03727|096|R|   Sohne AG September, 2024.|1
03728|001|T|MONOGRAPH TITLE:  Fruquintinib; Surufatinib/Anticoagulants; Antiplatelets|
03728|002|B||
03728|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03728|004|L|take action as needed.|
03728|005|B||
03728|006|A|MECHANISM OF ACTION:  Bleeding has been reported with the use of|
03728|007|A|fruquintinib and surufatinib.(1,2)|
03728|008|B||
03728|009|E|CLINICAL EFFECTS:  Concurrent use of fruquintinib or surufatinib with either|
03728|010|E|anticoagulants or antiplatelets may increase the risk of hemorrhage.(1,2)|
03728|011|B||
03728|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03728|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03728|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
03728|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03728|016|P|risk for bleeding (e.g. NSAIDs).|
03728|017|B||
03728|018|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with fruquintinib|
03728|019|M|and anticoagulants and/or antiplatelets should be closely monitored for|
03728|020|M|changes in platelet count or in International Normalized Ratio (INR).  If a|
03728|021|M|serious bleeding event occurs, the manufacturer recommends permanent|
03728|022|M|discontinuation of fruquintinib.(1)|
03728|023|M|   Patients receiving concurrent therapy with surufatinib and anticoagulants|
03728|024|M|and/or antiplatelets should be closely monitored for changes in platelet|
03728|025|M|count or in INR.If a serious bleeding event occurs, the manufacturer|
03728|026|M|recommends permanent discontinuation of surufatinib.(2)|
03728|027|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03728|028|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03728|029|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03728|030|M|patients with any symptoms.|
03728|031|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
03728|032|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03728|033|M|anticoagulation in patients with active pathologic bleeding.|
03728|034|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03728|035|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03728|036|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03728|037|M|and/or swelling.|
03728|038|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03728|039|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
03728|040|M|before initiating, altering the dose or discontinuing either drug.|
03728|041|B||
03728|042|D|DISCUSSION:  Bleeding has been reported with fruquintinib in three|
03728|043|D|randomized, double-blinded, placebo-controlled clinical trials. The|
03728|044|D|incidence of grade 1 and grade 2 bleeding events was 28.2%, including|
03728|045|D|gastrointestinal bleeding (10.9%), hematuria (10.6%), and epistaxis (7.5%).|
03728|046|D|The incidence of grade 3 or higher bleeding events was 2.1% and included|
03728|047|D|gastrointestinal bleeding (1.6%) and hemoptysis (0.5%).(1)|
03728|048|D|   Bleeding has been reported with surufatinib in clinical trials. Grade 1|
03728|049|D|and 2 bleeding events included gastrointestinal bleeding, blood in the|
03728|050|D|urine, and gum bleeding. The incidence of grade 3 or greater bleeding events|
03728|051|D|was 4.5%, including gastrointestinal hemorrhage (1.9%), and cerebral|
03728|052|D|hemorrhage (1.1%). Fatalities due to bleeding were reported in 0.3% of|
03728|053|D|patients. The incidence of permanent discontinuation due to bleeding was|
03728|054|D|2.6% and the incidence of suspension of surufatinib due to bleeding was|
03728|055|D|3.8%.(2)|
03728|056|B||
03728|057|R|REFERENCES:|
03728|058|B||
03728|059|R|1.Elunate (fruquintinib) Chinese prescribing information. Hutchison|1
03728|060|R|  Medipharma (Suzhou) Ltd. May, 2019.|1
03728|061|R|2.Fruzaqla (fruquintinib) US prescribing information. Takeda Pharmaceuticals|1
03728|062|R|  America, Inc. November 2023.|1
03728|063|R|3.Sulanda (surufatinib) Hong Kong prescribing information. Hutchison Whampoa|1
03728|064|R|  Pharmaceuticals (Suzhou) Co., Ltd June 28, 2021.|1
03729|001|T|MONOGRAPH TITLE:  Carbamazepine/Clarithromycin; Telithromycin|
03729|002|B||
03729|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03729|004|L|of severe adverse interaction.|
03729|005|B||
03729|006|A|MECHANISM OF ACTION:  Carbamazepine may induce the metabolism of|
03729|007|A|clarithromycin and telithromycin by CYP3A4.(1-4)|
03729|008|A|   Clarithromycin and telithromycin may inhibit the hepatic metabolism of|
03729|009|A|carbamazepine by CYP3A4.(1-6)|
03729|010|B||
03729|011|E|CLINICAL EFFECTS:  Concurrent use of carbamazepine with clarithromycin or|
03729|012|E|telithromycin may result in decreased levels and effectiveness of the|
03729|013|E|macrolide.(1-4)|
03729|014|E|   In addition, serum carbamazepine levels may increase, with subsequent|
03729|015|E|increases in the pharmacological and toxic effects of carbamazepine,|
03729|016|E|including dizziness, ataxia, blurred vision, or SIADH.(5-6)|
03729|017|B||
03729|018|P|PREDISPOSING FACTORS:  Factors that may increase the risk of a severe|
03729|019|P|interaction include simultaneous use of other drugs (i.e., other|
03729|020|P|anticonvulsants) or high carbamazepine blood levels near the toxic range|
03729|021|P|before initiation of a CYP3A4 inhibitor.|
03729|022|B||
03729|023|M|PATIENT MANAGEMENT:  Concurrent use of carbamazepine with clarithromycin|
03729|024|M|should be approached with caution and may require clarithromycin dose|
03729|025|M|adjustment.(1)  Consideration of alternative therapies to carbamazepine may|
03729|026|M|be required.(1-2)|
03729|027|M|   Concurrent treatment of carbamazepine with telithromycin should be|
03729|028|M|avoided.(4-5)  The UK manufacturer of telithromycin states that treatment|
03729|029|M|with telithromycin should be avoided during and for two weeks after|
03729|030|M|treatment with carbamazepine.(4)|
03729|031|M|   The manufacturer of carbamazepine states CYP3A4 inhibitors may increase|
03729|032|M|plasma levels.  If concurrent use is warranted, close monitoring of|
03729|033|M|carbamazepine levels is indicated and dosage adjustment may be required.(5)|
03729|034|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
03729|035|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
03729|036|M|observed for signs of toxicity (dizziness, ataxia, blurred vision, or|
03729|037|M|SIADH).  The dosage of carbamazepine may need to be adjusted or|
03729|038|M|carbamazepine may need to be discontinued.(5)|
03729|039|B||
03729|040|D|DISCUSSION:  Concurrent use of telithromycin with potent CYP3A4 inducers|
03729|041|D|such as carbamazepine could result in major reductions of telithromycin|
03729|042|D|plasma concentrations and decreased telithromycin clinical effectiveness.|
03729|043|D|The induction effect decreases during the two weeks following the|
03729|044|D|discontinuation of the inducer.(3)|
03729|045|D|   Carbamazepine is almost completely metabolized to|
03729|046|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
03729|047|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
03729|048|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
03729|049|D|CYP3A5.(5,6)|
03729|050|B||
03729|051|R|REFERENCES:|
03729|052|B||
03729|053|R|1.Clarithromycin UK Summary of Product Characteristics. Ranbaxy (UK) Limited|1
03729|054|R|  January 26, 2022.|1
03729|055|R|2.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
03729|056|R|  September, 2019.|1
03729|057|R|3.Ketek (telithromycin) UK summary of product characteristics.|1
03729|058|R|  Sanofi-Aventis June 2, 2009.|1
03729|059|R|4.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
03729|060|R|  November, 2015.|1
03729|061|R|5.Tegretol (carbamazepine) US prescribing information. Novartis|1
03729|062|R|  Pharmaceuticals Corporation September, 2023.|1
03729|063|R|6.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
03729|064|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
03729|065|R|  Dec;21(12):906-10.|6
03729|066|R|7.Albani F, Riva R, Baruzzi A. Clarithromycin-carbamazepine interaction: a|3
03729|067|R|  case report. Epilepsia 1993 Jan-Feb;34(1):161-2.|3
03730|001|T|MONOGRAPH TITLE:  Letermovir/Carbamazepine|
03730|002|B||
03730|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03730|004|L|of severe adverse interaction.|
03730|005|B||
03730|006|A|MECHANISM OF ACTION:  Letermovir is a substrate of the efflux transporter|
03730|007|A|P-glycoprotein (P-gp) and of UDP-glucuronosyltransferase (UGT) 1A1/3|
03730|008|A|enzymes.  P-gp induction may decrease systemic absorption of letermovir,|
03730|009|A|while UGT1A1/3 induction may increase the metabolism of letermovir.(1)|
03730|010|A|   Inhibitors of CYP3A4 may inhibit the hepatic metabolism of|
03730|011|A|carbamazepine.(2,3)  Letermovir is a CYP3A4 inhibitor.(4)|
03730|012|B||
03730|013|E|CLINICAL EFFECTS:  Concurrent or recent use of P-glycoprotein or UGT1A1/3|
03730|014|E|inducers may result in decreased levels and loss of effectiveness of|
03730|015|E|letermovir.(1)|
03730|016|E|   Increased serum carbamazepine levels with subsequent increases in the|
03730|017|E|pharmacological and toxic effects of carbamazepine, including dizziness,|
03730|018|E|ataxia, blurred vision, or SIADH.|
03730|019|B||
03730|020|P|PREDISPOSING FACTORS:  Simultaneous use of other drugs, i.e. other|
03730|021|P|anticonvulsants, or carbamazepine blood levels already near the toxic range|
03730|022|P|before initiation of a CYP3A4 inhibitor may increase the risk of a severe|
03730|023|P|interaction.|
03730|024|B||
03730|025|M|PATIENT MANAGEMENT:  The manufacturer of letermovir states that|
03730|026|M|coadministration of P-gp inducers or UGT1A1/3 inducers is not|
03730|027|M|recommended.(1)|
03730|028|M|   The manufacturer of carbamazepine states CYP3A4 inhibitors may increase|
03730|029|M|plasma carbamazepine levels.  If concurrent use is warranted, close|
03730|030|M|monitoring of carbamazepine levels is indicated and dosage adjustment may be|
03730|031|M|required.(2)|
03730|032|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
03730|033|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
03730|034|M|observed for signs of toxicity (dizziness, ataxia, blurred vision, or|
03730|035|M|SIADH).  The dosage of carbamazepine may need to be adjusted or|
03730|036|M|carbamazepine may need to be discontinued.(2)|
03730|037|B||
03730|038|D|DISCUSSION:  In a study, at 24 hours after the last dose of rifampin (600 mg|
03730|039|D|daily),  a P-gp and UGT inducer, the AUC of letermovir was decreased by 85|
03730|040|D|%, compared to letermovir when taken alone.(1)|
03730|041|D|   Carbamazepine is almost completely metabolized to|
03730|042|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
03730|043|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
03730|044|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
03730|045|D|CYP3A5.(2,3)|
03730|046|B||
03730|047|R|REFERENCES:|
03730|048|B||
03730|049|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
03730|050|R|  2024.|1
03730|051|R|2.Tegretol (carbamazepine) US prescribing information. Novartis|1
03730|052|R|  Pharmaceuticals Corporation September, 2023.|1
03730|053|R|3.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
03730|054|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
03730|055|R|  Dec;21(12):906-10.|6
03730|056|R|4.This information is based on an extract from the Certara Drug Interaction|6
03730|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03731|001|T|MONOGRAPH TITLE:  Letermovir/Rifabutin|
03731|002|B||
03731|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03731|004|L|of severe adverse interaction.|
03731|005|B||
03731|006|A|MECHANISM OF ACTION:  Letermovir is a substrate of the efflux transporter|
03731|007|A|P-glycoprotein (P-gp) and of UDP-glucuronosyltransferase (UGT) 1A1/3|
03731|008|A|enzymes.  P-gp induction may decrease systemic absorption of letermovir,|
03731|009|A|while UGT1A1/3 induction may increase the metabolism of letermovir.(1)|
03731|010|A|Rifabutin is an inducer of P-gp and UGT.(2,3)|
03731|011|A|   Rifabutin is a CYP3A4 substrate.(2)  Letermovir may inhibit the CYP3A4|
03731|012|A|metabolism of rifabutin.(1,3)|
03731|013|B||
03731|014|E|CLINICAL EFFECTS:  Concurrent or recent use of P-glycoprotein or UGT1A1/3|
03731|015|E|inducers may result in decreased levels and loss of effectiveness of|
03731|016|E|letermovir.(1)  The levels and toxicities of rifabutin may increase,|
03731|017|E|including uveitis.(2)|
03731|018|B||
03731|019|P|PREDISPOSING FACTORS:  None determined.|
03731|020|B||
03731|021|M|PATIENT MANAGEMENT:  The manufacturer of letermovir states that|
03731|022|M|coadministration of P-gp inducers or UGT1A1/3 inducers is not|
03731|023|M|recommended.(1)|
03731|024|M|   Monitor for rifabutin-associated adverse events.  Reduce the rifabutin|
03731|025|M|dose or suspend rifabutin use if toxicity is suspected.(1)  If uveitis|
03731|026|M|occurs, temporary discontinuance of rifabutin and ophthalmologic evaluation|
03731|027|M|are recommended.  In most mild cases, rifabutin may be restarted; however,|
03731|028|M|if signs or symptoms recur, use of rifabutin should be discontinued.(2)|
03731|029|B||
03731|030|D|DISCUSSION:  In a study, at 24 hours after the last dose of rifampin (600 mg|
03731|031|D|daily), a P-gp and UGT inducer, the area-under-curve (AUC) of letermovir was|
03731|032|D|decreased by 85 %, compared to letermovir when taken alone.(1)|
03731|033|D|   In a study of five healthy subjects, concurrent use of rifabutin (150 mg|
03731|034|D|daily for 16 days) and ritonavir (500 mg BID for 10 days), a CYP3A4|
03731|035|D|inhibitor, increased the AUC and concentration maximum (Cmax) by 300% and|
03731|036|D|150%, respectively.(2)|
03731|037|B||
03731|038|R|REFERENCES:|
03731|039|B||
03731|040|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
03731|041|R|  2024.|1
03731|042|R|2.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
03731|043|R|  2021.|1
03731|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
03731|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03732|001|T|MONOGRAPH TITLE:  Aprepitant; Netupitant/Selected Strong CYP3A4 Inducers|
03732|002|B||
03732|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03732|004|L|of severe adverse interaction.|
03732|005|B||
03732|006|A|MECHANISM OF ACTION:  Aprepitant and netupitant are metabolized primarily by|
03732|007|A|CYP3A4.  Strong inducers of CYP3A4 may increase their metabolism and|
03732|008|A|clearance via CYP3A4.(1,2)|
03732|009|B||
03732|010|E|CLINICAL EFFECTS:  Concurrent use with strong inducers of CYP3A4 may result|
03732|011|E|in significantly decreased levels and effectiveness of aprepitant and|
03732|012|E|netupitant.(1,2)|
03732|013|B||
03732|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03732|015|P|of the inducer for longer than 1-2 weeks.|
03732|016|B||
03732|017|M|PATIENT MANAGEMENT:  The manufacturer of aprepitant recommends avoiding|
03732|018|M|concurrent use with strong CYP3A4 inducers.(1)|
03732|019|M|   The manufacturer of netupitant recommends avoiding use of netupitant in|
03732|020|M|patients who are chronically using strong CYP3A4 inducers.(2)|
03732|021|M|   Patients treated concurrently with a strong CYP3A4 inducer should be|
03732|022|M|monitored for decreased antiemetic efficacy.  When possible and clinically|
03732|023|M|appropriate, consider use of an alternative antiemetic or alternatives to|
03732|024|M|the strong CYP3A4 inducer.|
03732|025|B||
03732|026|D|DISCUSSION:  Rifampin (600 mg daily) decreased the area-under-curve (AUC)|
03732|027|D|and half-life of aprepitant (375 mg single dose) by 11-fold and 3-fold,|
03732|028|D|respectively.(1)|
03732|029|D|   Rifampin (600 mg daily for 17 days) decreased the mean maximum|
03732|030|D|concentration (Cmax) and AUC of netupitant by 62% and 82% respectively.(2)|
03732|031|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
03732|032|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin,|
03732|033|D|primidone, rifampin, rifapentine, and St. John's Wort.(3,4)|
03732|034|D|   FDA defines a Strong CYP inducer as an agent which decreases the|
03732|035|D|area-under-curve (AUC) of a Sensitive Substrate by > or = 80 per cent.(3)|
03732|036|B||
03732|037|R|REFERENCES:|
03732|038|B||
03732|039|R|1.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
03732|040|R|  September, 2019.|1
03732|041|R|2.Akynzeo (netupitant and palonsetron). Helsinn Birex Pharmaceuticals June,|1
03732|042|R|  2021.|1
03732|043|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03732|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03732|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03732|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03732|047|R|  11/14/2017.|1
03732|048|R|4.This information is based on an extract from the Certara Drug Interaction|6
03732|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03733|001|T|MONOGRAPH TITLE:  Aprepitant; Netupitant/Carbamazepine|
03733|002|B||
03733|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03733|004|L|of severe adverse interaction.|
03733|005|B||
03733|006|A|MECHANISM OF ACTION:  Aprepitant and netupitant are metabolized primarily by|
03733|007|A|CYP3A4.  Carbamazepine, a strong inducer of CYP3A4, may increase their|
03733|008|A|metabolism and clearance via CYP3A4.(1,2)|
03733|009|A|   Aprepitant and netupitant, inhibitors of CYP3A4, may inhibit the hepatic|
03733|010|A|metabolism of carbamazepine.(3,4)|
03733|011|B||
03733|012|E|CLINICAL EFFECTS:  Concurrent use with carbamazepine may result in|
03733|013|E|significantly decreased levels and effectiveness of aprepitant and|
03733|014|E|netupitant.(1,2)|
03733|015|E|   In addition, serum carbamazepine levels may increase, with subsequent|
03733|016|E|increases in the pharmacological and toxic effects of carbamazepine,|
03733|017|E|including dizziness, ataxia, blurred vision, or SIADH.(3)|
03733|018|B||
03733|019|P|PREDISPOSING FACTORS:  Simultaneous use of other drugs, i.e. other|
03733|020|P|anticonvulsants, or carbamazepine blood levels already near the toxic range|
03733|021|P|before initiation of a CYP3A4 inhibitor may increase the risk of a severe|
03733|022|P|interaction.|
03733|023|B||
03733|024|M|PATIENT MANAGEMENT:  The manufacturers of aprepitant and netupitant|
03733|025|M|recommend avoiding strong CYP3A4 inducers.(1,2)|
03733|026|M|   Patients treated concurrently with carbamazepine should be monitored for|
03733|027|M|decreased antiemetic efficacy.  When possible and clinically appropriate,|
03733|028|M|consider use of an alternative antiemetic or alternatives to carbamazepine.|
03733|029|M|   The manufacturer of carbamazepine states CYP3A4 inhibitors may increase|
03733|030|M|plasma carbamazepine levels.  If concurrent use is warranted, close|
03733|031|M|monitoring of carbamazepine levels is indicated and dosage adjustment may be|
03733|032|M|required.(3)|
03733|033|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
03733|034|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
03733|035|M|observed for signs of toxicity (dizziness, ataxia, blurred vision, or|
03733|036|M|SIADH).  The dosage of carbamazepine may need to be adjusted or|
03733|037|M|carbamazepine may need to be discontinued.(3)|
03733|038|B||
03733|039|D|DISCUSSION:  Rifampin (600 mg daily) decreased the area-under-curve (AUC)|
03733|040|D|and half-life of aprepitant (375 mg single dose) by 11-fold and 3-fold,|
03733|041|D|respectively.(1)|
03733|042|D|   Rifampin (600 mg daily for 17 days) decreased the mean maximum|
03733|043|D|concentration (Cmax) and AUC of netupitant by 62% and 82% respectively.(2)|
03733|044|D|   Carbamazepine is almost completely metabolized to|
03733|045|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
03733|046|D|Pharmacokinetics studies have indicated the major pathway for carbamazepine|
03733|047|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
03733|048|D|CYP3A5.(3,4)|
03733|049|B||
03733|050|R|REFERENCES:|
03733|051|B||
03733|052|R|1.Emend (aprepitant) US prescribing information. Merck & Co., Inc.|1
03733|053|R|  September, 2019.|1
03733|054|R|2.Akynzeo (netupitant and palonsetron). Helsinn Birex Pharmaceuticals June,|1
03733|055|R|  2021.|1
03733|056|R|3.Tegretol (carbamazepine) US prescribing information. Novartis|1
03733|057|R|  Pharmaceuticals Corporation September, 2023.|1
03733|058|R|4.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
03733|059|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
03733|060|R|  Dec;21(12):906-10.|6
03733|061|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03733|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03733|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03733|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03733|065|R|  11/14/2017.|1
03733|066|R|6.This information is based on an extract from the Certara Drug Interaction|6
03733|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03734|001|T|MONOGRAPH TITLE:  Lefamulin/Carbamazepine|
03734|002|B||
03734|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03734|004|L|of severe adverse interaction.|
03734|005|B||
03734|006|A|MECHANISM OF ACTION:  Lefamulin is a substrate of CYP3A4 and of intestinal|
03734|007|A|efflux transporter P-glycoprotein (P-gp).  Strong inducers of CYP3A4 may|
03734|008|A|induce the metabolism of lefamulin.  P-gp inducers may decrease absorption|
03734|009|A|of and exposure to lefamulin.(1)  Carbamazepine is a strong CYP3A4 inducer|
03734|010|A|and a P-gp inducer.(2)|
03734|011|A|   Inhibitors of CYP3A4 may inhibit the hepatic metabolism of|
03734|012|A|carbamazepine.(2,3)  Lefamulin is an inhibitor of CYP3A4.(1)|
03734|013|B||
03734|014|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 or P-gp|
03734|015|E|inducer may result in decreased levels and effectiveness of lefamulin.(1)|
03734|016|E|   Increased serum carbamazepine levels with subsequent increases in the|
03734|017|E|pharmacological and toxic effects of carbamazepine, including dizziness,|
03734|018|E|ataxia, blurred vision, or SIADH.(2)|
03734|019|B||
03734|020|P|PREDISPOSING FACTORS:  Simultaneous use of other drugs, i.e. other|
03734|021|P|anticonvulsants, or carbamazepine blood levels already near the toxic range|
03734|022|P|before initiation of a CYP3A4 inhibitor may increase the risk of a severe|
03734|023|P|interaction.|
03734|024|B||
03734|025|M|PATIENT MANAGEMENT:  The manufacturer of lefamulin states that concurrent|
03734|026|M|use with strong CYP3A4 or P-gp inducers should be avoided. (1)|
03734|027|M|   The manufacturer of carbamazepine state CYP3A4 inhibitors may increase|
03734|028|M|plasma carbamazepine levels.  If concurrent use is warranted, close|
03734|029|M|monitoring of carbamazepine levels is indicated and dosage adjustment may be|
03734|030|M|required.(2)|
03734|031|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
03734|032|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
03734|033|M|observed for signs of toxicity (dizziness, ataxia, blurred vision, or|
03734|034|M|SIADH).  The dosage of carbamazepine may need to be adjusted or|
03734|035|M|carbamazepine may need to be discontinued.(2)|
03734|036|B||
03734|037|D|DISCUSSION:  In a study, concurrent administration of rifampin (strong|
03734|038|D|inducer) with lefamulin injection decreased lefamulin area-under-the-curve|
03734|039|D|(AUC) and maximum concentration (Cmax) by 28% and 8%.(1)|
03734|040|D|   In a study, concurrent administration of rifampin (strong inducer) with|
03734|041|D|oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1)|
03734|042|D|   Carbamazepine is almost completely metabolized to|
03734|043|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
03734|044|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
03734|045|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
03734|046|D|CYP3A5.(2,3)|
03734|047|B||
03734|048|R|REFERENCES:|
03734|049|B||
03734|050|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03734|051|R|  Inc August 2019.|1
03734|052|R|2.Tegretol (carbamazepine) US prescribing information. Novartis|1
03734|053|R|  Pharmaceuticals Corporation September, 2023.|1
03734|054|R|3.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
03734|055|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
03734|056|R|  Dec;21(12):906-10.|6
03734|057|R|4.This information is based on an extract from the Certara Drug Interaction|6
03734|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03734|059|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03734|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03734|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03734|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03734|063|R|  11/14/2017.|1
03735|001|T|MONOGRAPH TITLE:  Istradefylline/Carbamazepine|
03735|002|B||
03735|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03735|004|L|of severe adverse interaction.|
03735|005|B||
03735|006|A|MECHANISM OF ACTION:  Istradefylline is a substrate of CYP3A4.  Strong|
03735|007|A|inducers of CYP3A4 may induce the metabolism of istradefylline.(1)|
03735|008|A|Carbamazepine is a strong CYP3A4 inducer.(2)|
03735|009|A|   Inhibitors of CYP3A4 may inhibit the hepatic metabolism of|
03735|010|A|carbamazepine.(2,3)  Istradefylline is an inhibitor of CYP3A4.(1)|
03735|011|B||
03735|012|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03735|013|E|may result in decreased levels and effectiveness of istradefylline.(1)|
03735|014|E|   Increased serum carbamazepine levels with subsequent increases in the|
03735|015|E|pharmacological and toxic effects of carbamazepine, including dizziness,|
03735|016|E|ataxia, blurred vision, or SIADH.(2)|
03735|017|B||
03735|018|P|PREDISPOSING FACTORS:  Tobacco smokers who smoke more than 20 cigarettes per|
03735|019|P|day may have lower exposure to istradefylline and be more susceptible to the|
03735|020|P|effects of a strong CYP3A4 inducer.(1)|
03735|021|B||
03735|022|M|PATIENT MANAGEMENT:  The manufacturer of istradefylline states that|
03735|023|M|concurrent use with strong CYP3A4 inducers should be avoided.(1)|
03735|024|M|   The manufacturer of carbamazepine states CYP3A4 inhibitors may increase|
03735|025|M|plasma carbamazepine levels.  If concurrent use is warranted, close|
03735|026|M|monitoring of carbamazepine levels is indicated and dosage adjustment may be|
03735|027|M|required.(2)|
03735|028|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
03735|029|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
03735|030|M|observed for signs of toxicity (dizziness, ataxia, blurred vision, or|
03735|031|M|SIADH).  The dosage of carbamazepine may need to be adjusted or|
03735|032|M|carbamazepine may need to be discontinued.(2)|
03735|033|B||
03735|034|D|DISCUSSION:  Concomitant administration of rifampin (600 mg once daily for|
03735|035|D|20 days, strong CYP3A4 inducer) with istradefylline (40 mg) decreased|
03735|036|D|istradefylline maximum concentration (Cmax) and area-under-the-curve (AUC)|
03735|037|D|by 45% and 81%, respectively, compared to istradefylline administered|
03735|038|D|alone.(1)|
03735|039|D|   Carbamazepine is almost completely metabolized to|
03735|040|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
03735|041|D|Pharmacokinetics studies have indicated the major pathway for carbamazepine|
03735|042|D|is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
03735|043|D|CYP3A5.(2,3)|
03735|044|B||
03735|045|R|REFERENCES:|
03735|046|B||
03735|047|R|1.Nourianz (istradefylline) US prescribing information. Kyowa Kirin, Inc.|1
03735|048|R|  August, 2019.|1
03735|049|R|2.Tegretol (carbamazepine) US prescribing information. Novartis|1
03735|050|R|  Pharmaceuticals Corporation September, 2023.|1
03735|051|R|3.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
03735|052|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
03735|053|R|  Dec;21(12):906-10.|6
03735|054|R|4.This information is based on an extract from the Certara Drug Interaction|6
03735|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03735|056|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03735|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03735|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03735|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03735|060|R|  11/14/2017.|1
03736|001|T|MONOGRAPH TITLE:  Istradefylline/Ivosidenib|
03736|002|B||
03736|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03736|004|L|of severe adverse interaction.|
03736|005|B||
03736|006|A|MECHANISM OF ACTION:  Istradefylline is a substrate of CYP3A4.  Strong|
03736|007|A|inducers of CYP3A4 may induce the metabolism of istradefylline.(1)|
03736|008|A|Ivosidenib is a strong CYP3A4 inducer.(2)|
03736|009|A|   Inhibitors of CYP3A4 may inhibit the hepatic metabolism of ivosidenib.(2)|
03736|010|A|Istradefylline is a CYP3A4 inhibitor.(1)|
03736|011|B||
03736|012|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03736|013|E|such as ivosidenib may result in decreased levels and effectiveness of|
03736|014|E|istradefylline.(1)|
03736|015|E|   Concurrent use of istradefylline may increase serum ivosidenib levels|
03736|016|E|with subsequent increases in the pharmacological and toxic effects of|
03736|017|E|ivosidenib including QT prolongation.(2)|
03736|018|B||
03736|019|P|PREDISPOSING FACTORS:  Tobacco smokers who smoke more than 20 cigarettes per|
03736|020|P|day may have lower exposure to istradefylline and be more susceptible to the|
03736|021|P|effects of a strong CYP3A4 inducer.(1)|
03736|022|P|   The risk of QT prolongation or torsade de pointes may be increased in|
03736|023|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03736|024|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
03736|025|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03736|026|P|advanced age.(3)|
03736|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03736|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03736|029|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03736|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03736|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03736|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03736|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03736|034|B||
03736|035|M|PATIENT MANAGEMENT:  The manufacturer of istradefylline states that|
03736|036|M|concurrent use with strong CYP3A4 inducers should be avoided.(1)|
03736|037|M|   The US manufacturer of ivosidenib recommends considering an alternative|
03736|038|M|concomitant medication with less potential for CYP3A4 inhibition.(2)|
03736|039|M|   During concomitant therapy with istradefylline and ivosidenib, monitor|
03736|040|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03736|041|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03736|042|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03736|043|M|irregular heartbeat, dizziness, or fainting.|
03736|044|B||
03736|045|D|DISCUSSION:  Concomitant administration of rifampin (600 mg once daily for|
03736|046|D|20 days, strong CYP3A4 inducer) with istradefylline (40 mg) decreased|
03736|047|D|istradefylline maximum concentration (Cmax) and area-under-the-curve (AUC)|
03736|048|D|by 45% and 81%, respectively, compared to istradefylline administered|
03736|049|D|alone.(1)|
03736|050|D|   In a drug interaction study in healthy subjects, coadministration of|
03736|051|D|itraconazole (200 mg once daily for 18 days) with a single dose of|
03736|052|D|ivosidenib (250 mg) increased ivosidenib AUC by 269%.  No change was seen in|
03736|053|D|ivosidenib's Cmax.(2)|
03736|054|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03736|055|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03736|056|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03736|057|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03736|058|D|190%, respectively.(2)|
03736|059|B||
03736|060|R|REFERENCES:|
03736|061|B||
03736|062|R|1.Nourianz (istradefylline) US prescribing information. Kyowa Kirin, Inc.|1
03736|063|R|  August, 2019.|1
03736|064|R|2.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03736|065|R|  Inc. August, 2021.|1
03736|066|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03736|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03736|068|R|  settings: a scientific statement from the American Heart Association and|6
03736|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03736|070|R|  2;55(9):934-47.|6
03736|071|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03736|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03736|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03736|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03736|075|R|  11/14/2017.|1
03736|076|R|5.This information is based on an extract from the Certara Drug Interaction|6
03736|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03737|001|T|MONOGRAPH TITLE:  Voxelotor/Carbamazepine|
03737|002|B||
03737|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03737|004|L|of severe adverse interaction.|
03737|005|B||
03737|006|A|MECHANISM OF ACTION:  Voxelotor is a substrate of CYP3A4.  Strong or|
03737|007|A|moderate inducers of CYP3A4 may induce the metabolism of voxelotor.(1)|
03737|008|A|Carbamazepine is a strong CYP3A4 inducer.(2)|
03737|009|A|   Inhibitors of CYP3A4 may inhibit the hepatic metabolism of|
03737|010|A|carbamazepine.(2,3)  Voxelotor is an inhibitor of CYP3A4.(4)|
03737|011|B||
03737|012|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
03737|013|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
03737|014|E|voxelotor.(1)|
03737|015|E|   Increased serum carbamazepine levels with subsequent increases in the|
03737|016|E|pharmacological and toxic effects of carbamazepine, including dizziness,|
03737|017|E|ataxia, blurred vision, or SIADH.(2)|
03737|018|B||
03737|019|P|PREDISPOSING FACTORS:  Simultaneous use of other drugs, i.e. other|
03737|020|P|anticonvulsants, or carbamazepine blood levels already near the toxic range|
03737|021|P|before initiation of a CYP3A4 inhibitor may increase the risk of a severe|
03737|022|P|interaction.|
03737|023|B||
03737|024|M|PATIENT MANAGEMENT:  The manufacturer of voxelotor states that concurrent|
03737|025|M|use with strong or moderate CYP3A4 inducers should be avoided.  If|
03737|026|M|concomitant use is unavoidable in patients 12 years and older, increase the|
03737|027|M|dose of voxelotor to 2,500 mg daily.  For patients 4 years to less than 12|
03737|028|M|years who require concurrent carbamazepine, refer to voxelotor prescribing|
03737|029|M|information for recommended weight-based voxelotor dose adjustments.(1)|
03737|030|M|   The manufacturer of carbamazepine states CYP3A4 inhibitors may increase|
03737|031|M|plasma carbamazepine levels.  If concurrent use is warranted, close|
03737|032|M|monitoring of carbamazepine levels is indicated and dosage adjustment may be|
03737|033|M|required.(2)|
03737|034|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
03737|035|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
03737|036|M|observed for signs of toxicity (dizziness, ataxia, blurred vision, or|
03737|037|M|SIADH).  The dosage of carbamazepine may need to be adjusted or|
03737|038|M|carbamazepine may need to be discontinued.(2)|
03737|039|B||
03737|040|D|DISCUSSION:  A pharmacokinetic model predicted that co-administration of|
03737|041|D|rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC)|
03737|042|D|of voxelotor by 40%.|
03737|043|D|   Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted|
03737|044|D|to decrease the AUC of voxelotor by 24%.(1)|
03737|045|D|   Carbamazepine is almost completely metabolized to|
03737|046|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
03737|047|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
03737|048|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
03737|049|D|CYP3A5.(2,3)|
03737|050|B||
03737|051|R|REFERENCES:|
03737|052|B||
03737|053|R|1.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
03737|054|R|  Inc. December, 2021.|1
03737|055|R|2.Tegretol (carbamazepine) US prescribing information. Novartis|1
03737|056|R|  Pharmaceuticals Corporation September, 2023.|1
03737|057|R|3.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
03737|058|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
03737|059|R|  Dec;21(12):906-10.|6
03737|060|R|4.This information is based on an extract from the Certara Drug Interaction|6
03737|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03737|062|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03737|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03737|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03737|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03737|066|R|  11/14/2017.|1
03738|001|T|MONOGRAPH TITLE:  Voxelotor/Ivosidenib|
03738|002|B||
03738|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03738|004|L|of severe adverse interaction.|
03738|005|B||
03738|006|A|MECHANISM OF ACTION:  Voxelotor is a substrate of CYP3A4.  Strong or|
03738|007|A|moderate inducers of CYP3A4 may induce the metabolism of voxelotor.(1)|
03738|008|A|Ivosidenib is a strong CYP3A4 inducer.(2,3)|
03738|009|A|   Inhibitors of CYP3A4 may inhibit the hepatic metabolism of ivosidenib.(2)|
03738|010|A|Voxelotor is a CYP3A4 inhibitor.(3)|
03738|011|B||
03738|012|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
03738|013|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
03738|014|E|voxelotor.(1)|
03738|015|E|   Concurrent use of voxelotor may increase serum ivosidenib levels with|
03738|016|E|subsequent increases in the pharmacological and toxic effects of ivosidenib|
03738|017|E|including QT prolongation.(2)|
03738|018|B||
03738|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03738|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03738|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03738|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03738|023|P|gender, or advanced age.(5)|
03738|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03738|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03738|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03738|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03738|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03738|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03738|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03738|031|B||
03738|032|M|PATIENT MANAGEMENT:  The manufacturer of voxelotor states that concurrent|
03738|033|M|use with strong or moderate CYP3A4 inducers should be avoided.  If|
03738|034|M|concomitant use is unavoidable in patients 12 years and older, increase the|
03738|035|M|dose of voxelotor to 2,500 mg daily.  For patients 4 years to less than 12|
03738|036|M|years who require concurrent ivosidenib, refer to voxelotor prescribing|
03738|037|M|information for recommended weight-based voxelotor dose adjustments.(1)|
03738|038|M|   The US manufacturer of ivosidenib recommends considering an alternative|
03738|039|M|concomitant medication with less potential for CYP3A4 inhibition.(2)|
03738|040|M|   During concomitant therapy with istradefylline and ivosidenib, monitor|
03738|041|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03738|042|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03738|043|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03738|044|M|irregular heartbeat, dizziness, or fainting.(2)|
03738|045|B||
03738|046|D|DISCUSSION:  A pharmacokinetic model predicted that co-administration of|
03738|047|D|rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC)|
03738|048|D|of voxelotor by 40%.(1)|
03738|049|D|   Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted|
03738|050|D|to decrease the AUC of voxelotor by 24%.(1)|
03738|051|D|   In a drug interaction study in healthy subjects, coadministration of|
03738|052|D|itraconazole (200 mg once daily for 18 days) with a single dose of|
03738|053|D|ivosidenib (250 mg) increased ivosidenib AUC by 269%.  No change was seen in|
03738|054|D|ivosidenib's Cmax.(2)|
03738|055|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03738|056|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03738|057|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03738|058|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03738|059|D|190%, respectively.(2)|
03738|060|B||
03738|061|R|REFERENCES:|
03738|062|B||
03738|063|R|1.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
03738|064|R|  Inc. December, 2021.|1
03738|065|R|2.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03738|066|R|  Inc. August, 2021.|1
03738|067|R|3.This information is based on an extract from the Certara Drug Interaction|6
03738|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03738|069|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03738|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03738|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03738|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03738|073|R|  11/14/2017.|1
03738|074|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03738|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03738|076|R|  settings: a scientific statement from the American Heart Association and|6
03738|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03738|078|R|  2;55(9):934-47.|6
03739|001|T|MONOGRAPH TITLE:  Voxelotor/Rifabutin|
03739|002|B||
03739|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03739|004|L|of severe adverse interaction.|
03739|005|B||
03739|006|A|MECHANISM OF ACTION:  Voxelotor is a substrate of CYP3A4.  Strong or|
03739|007|A|moderate inducers of CYP3A4 may induce the metabolism of voxelotor.(1)|
03739|008|A|   Rifabutin is a CYP3A4 substrate.(2)  Voxelotor may inhibit the CYP3A4|
03739|009|A|metabolism of rifabutin.(1,3)|
03739|010|B||
03739|011|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
03739|012|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
03739|013|E|voxelotor.(1)  The levels and toxicities of rifabutin may increase,|
03739|014|E|including uveitis.(2)|
03739|015|B||
03739|016|P|PREDISPOSING FACTORS:  None determined.|
03739|017|B||
03739|018|M|PATIENT MANAGEMENT:  The manufacturer of voxelotor states that concurrent|
03739|019|M|use with strong or moderate CYP3A4 inducers should be avoided.  If|
03739|020|M|concomitant rifabutin is unavoidable in patients 12 years and older,|
03739|021|M|increase the dose of voxelotor to 2,000 mg daily.  For patients 4 years to|
03739|022|M|less than 12 years who require concurrent rifabutin, refer to voxelotor|
03739|023|M|prescribing information for recommended weight-based voxelotor dosage|
03739|024|M|adjustments.(1)|
03739|025|M|   Monitor for rifabutin-associated adverse events.  Reduce the rifabutin|
03739|026|M|dose or suspend rifabutin use if toxicity is suspected.(1)  If uveitis|
03739|027|M|occurs, temporary discontinuance of rifabutin and ophthalmologic evaluation|
03739|028|M|are recommended.  In most mild cases, rifabutin may be restarted; however,|
03739|029|M|if signs or symptoms recur, use of rifabutin should be discontinued.(2)|
03739|030|B||
03739|031|D|DISCUSSION:  A pharmacokinetic model predicted that co-administration of|
03739|032|D|rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC)|
03739|033|D|of voxelotor by 40%.|
03739|034|D|   Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted|
03739|035|D|to decrease the AUC of voxelotor by 24%.(1)|
03739|036|D|   In a study of five healthy subjects, concurrent use of rifabutin (150 mg|
03739|037|D|daily for 16 days) and ritonavir (500 mg BID for 10 days), a CYP3A4|
03739|038|D|inhibitor, increased the AUC and concentration maximum (Cmax) by 300% and|
03739|039|D|150%, respectively.(2)|
03739|040|B||
03739|041|R|REFERENCES:|
03739|042|B||
03739|043|R|1.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
03739|044|R|  Inc. December, 2021.|1
03739|045|R|2.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
03739|046|R|  2021.|1
03739|047|R|3.This information is based on an extract from the Certara Drug Interaction|6
03739|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03739|049|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03739|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03739|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03739|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03739|053|R|  11/14/2017.|1
03740|001|T|MONOGRAPH TITLE:  Antineoplastic Syst Enzyme Inh that Inhibit|
03740|002|T|3A4/Carbamazepine|
03740|003|B||
03740|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03740|005|L|of severe adverse interaction.|
03740|006|B||
03740|007|A|MECHANISM OF ACTION:  Ceritinib,(1) crizotinib,(2) duvelisib,(3)|
03740|008|A|fedratinib,(4) idelalisib,(5) imatinib,(6) nilotinib,(7) ribociclib,(8) and|
03740|009|A|tucatinib(9) are substrates and inhibitors of CYP3A4.  Carbamazepine, a|
03740|010|A|strong CYP3A4 inducer, may increase the metabolism of these agents, and they|
03740|011|A|may inhibit the hepatic metabolism of carbamazepine.|
03740|012|B||
03740|013|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
03740|014|E|levels and effectiveness of antineoplastic systemic enzyme inhibitors,|
03740|015|E|including ceritinib,(1) crizotinib,(2) duvelisib,(3) fedratinib,(4)|
03740|016|E|idelalisib,(5) imatinib,(6) nilotinib,(7) ribociclib,(8) sevabertinib,(15)|
03740|017|E|and tucatinib.(9)|
03740|018|E|   In addition, serum carbamazepine levels may increase with subsequent|
03740|019|E|increases in the pharmacological and toxic effects of carbamazepine,|
03740|020|E|including dizziness, ataxia, blurred vision, or SIADH.(10)|
03740|021|B||
03740|022|P|PREDISPOSING FACTORS:  Simultaneous use of other drugs, i.e. other|
03740|023|P|anticonvulsants, or carbamazepine blood levels already near the toxic range|
03740|024|P|before initiation of a CYP3A4 inhibitor may increase the risk of a severe|
03740|025|P|interactions.(10)|
03740|026|B||
03740|027|M|PATIENT MANAGEMENT:  Avoid the concurrent use of carbamazepine in patients|
03740|028|M|receiving therapy with antineoplastic enzyme inhibitors.  Consider the use|
03740|029|M|of alternative agents with less enzyme induction potential.(1-9)|
03740|030|M|   Because of the nonlinear pharmacokinetic profile of nilotinib, increasing|
03740|031|M|its dose is unlikely to compensate for enzyme induction.(7)|
03740|032|M|   If concurrent use of a CYP3A4 inducer cannot be avoided with imatinib,|
03740|033|M|the dose of imatinib should be increased by at least 50% and clinical|
03740|034|M|response should be carefully monitored.  Dosages up to 1,200 mg/day (600 mg|
03740|035|M|twice daily) have been used in patients receiving concurrent therapy with|
03740|036|M|strong CYP3A4 inducers.(6)|
03740|037|M|   The manufacturer of carbamazepine states CYP3A4 inhibitors may increase|
03740|038|M|plasma carbamazepine levels.  If concurrent use is warranted, close|
03740|039|M|monitoring of carbamazepine levels is indicated and dosage adjustment may be|
03740|040|M|required.(10)|
03740|041|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
03740|042|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
03740|043|M|observed for signs of toxicity (dizziness, ataxia, blurred vision, or|
03740|044|M|SIADH).  The dosage of carbamazepine may need to be adjusted or|
03740|045|M|carbamazepine may need to be discontinued.(10)|
03740|046|B||
03740|047|D|DISCUSSION:  In a study in 19 healthy subjects, rifampin (600 mg daily for|
03740|048|D|14 days) decreased the Cmax and AUC of a single dose of ceritinib by 44% and|
03740|049|D|70%, respectively.(1)|
03740|050|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
03740|051|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
03740|052|D|75%, respectively.(5)|
03740|053|D|   Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10|
03740|054|D|days) increased the clearance of a single dose of imatinib (400 mg) by|
03740|055|D|3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax)|
03740|056|D|decreased by 74% and 54%, respectively.(6,12)  The Cmax of the CGP74588|
03740|057|D|metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(12)|
03740|058|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily for 12|
03740|059|D|days) decreased nilotinib AUC by 80%.(7)|
03740|060|D|   Carbamazepine is almost completely metabolized to|
03740|061|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
03740|062|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
03740|063|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
03740|064|D|CYP3A5.(10,11)|
03740|065|D|   In a study, carbamazepine decreased sevabertinib's AUC 79% and Cmax|
03740|066|D|57%.(15)|
03740|067|B||
03740|068|R|REFERENCES:|
03740|069|B||
03740|070|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
03740|071|R|  Corporation August, 2021.|1
03740|072|R|2.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
03740|073|R|  2023.|1
03740|074|R|3.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
03740|075|R|  2021.|1
03740|076|R|4.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
03740|077|R|  May, 2023.|1
03740|078|R|5.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03740|079|R|  October, 2020.|1
03740|080|R|6.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
03740|081|R|  Pharmaceuticals Corporation August, 2022.|1
03740|082|R|7.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
03740|083|R|  Corporation September, 2021.|1
03740|084|R|8.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
03740|085|R|  Corporation September, 2024.|1
03740|086|R|9.Tukysa (tucatinib) US prescribing information. Seattle Genetics April,|1
03740|087|R|  2020.|1
03740|088|R|10.Tegretol (carbamazepine) US prescribing information. Novartis|1
03740|089|R|   Pharmaceuticals Corporation September, 2023.|1
03740|090|R|11.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
03740|091|R|   RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
03740|092|R|   Dec;21(12):906-10.|6
03740|093|R|12.Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U,|2
03740|094|R|   Seiberling M. Effect of rifampicin on the pharmacokinetics of imatinib|2
03740|095|R|   mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother|2
03740|096|R|   Pharmacol 2004 Feb;53(2):102-6.|2
03740|097|R|13.This information is based on an extract from the Certara Drug Interaction|6
03740|098|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03740|099|R|14.US Food and Drug Administration (FDA). Drug Development and Drug|1
03740|100|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03740|101|R|   at:|1
03740|102|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03740|103|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03740|104|R|   11/14/2017.|1
03740|105|R|15.Hyrnuo (sevabertinib) US prescribing information. Bayer HealthCare|1
03740|106|R|   Pharmaceuticals Inc. November 2025.|1
03741|001|T|MONOGRAPH TITLE:  Antineoplastic Systemic Enzyme Inhibitors/Carbamazepine|
03741|002|B||
03741|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03741|004|L|of severe adverse interaction.|
03741|005|B||
03741|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme, such as|
03741|007|A|carbamazepine, may induce the metabolism of antineoplastic systemic enzyme|
03741|008|A|inhibitors, including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4)|
03741|009|A|erlotinib,(5) gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9)|
03741|010|A|sorafenib,(10) sunitinib,(11) and vandetanib.(12)|
03741|011|B||
03741|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
03741|013|E|levels and effectiveness of antineoplastic systemic enzyme inhibitors,|
03741|014|E|including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4) erlotinib,(5)|
03741|015|E|gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9) sorafenib,(10)|
03741|016|E|sunitinib,(11) and vandetanib.(12)|
03741|017|B||
03741|018|P|PREDISPOSING FACTORS:  None determined.|
03741|019|B||
03741|020|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
03741|021|M|patients receiving therapy with antineoplastic enzyme inhibitors.  Consider|
03741|022|M|the use of alternative agents with less enzyme induction potential.(1-12)|
03741|023|M|   Pazopanib should not be administered to patients who cannot avoid chronic|
03741|024|M|use of strong CYP3A4 inducers.(8)|
03741|025|M|   If concurrent use of a CYP3A4 inducer cannot be avoided with other|
03741|026|M|antineoplastic enzyme inhibitors:|
03741|027|M|   Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg|
03741|028|M|to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg.|
03741|029|M|Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3|
03741|030|M|days after discontinuation of the strong inducer.(2)|
03741|031|M|   Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to|
03741|032|M|180 mg daily or from 100 mg to 140 mg daily) as tolerated.  The daily dose|
03741|033|M|of cabozantinib should not exceed 180 mg.  If the CYP3A4 inducer is|
03741|034|M|discontinued, reduce the dosage of cabozantinib to the dose used prior to|
03741|035|M|initiation of the inducer 2 to 3 days after discontinuation of the strong|
03741|036|M|inducer.(3)|
03741|037|M|   Consider increasing the dose of dasatinib.(4)|
03741|038|M|   Consider increasing the dosage of erlotinib by 50 mg increments as|
03741|039|M|tolerated at two week intervals (to a maximum of 450 mg) while closely|
03741|040|M|monitoring the patient.  The highest dosage studied with concurrent rifampin|
03741|041|M|is 450 mg.  If the dosage of erlotinib is increased, it will need to be|
03741|042|M|decreased when the inducer is discontinued.  If the inducer is|
03741|043|M|dexamethasone, monitor the patient for sign of gastrointestinal perforation.|
03741|044|M|Discontinue erlotinib in patients who develop gastrointestinal|
03741|045|M|perforation.(5)|
03741|046|M|   Consider a dose increase to 500 mg daily of gefitinib in the absence of|
03741|047|M|severe adverse drug reaction.  Clinical response and adverse events should|
03741|048|M|be closely monitored.(6)|
03741|049|M|   The dose of lapatinib should be gradually titrated from 1,250 mg/day up|
03741|050|M|to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from|
03741|051|M|1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive|
03741|052|M|breast cancer indication) based on patient tolerability. If the inducer is|
03741|053|M|discontinued, the dose of lapatinib should be adjusted to the normal|
03741|054|M|dose.(8)|
03741|055|M|   A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients|
03741|056|M|with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma|
03741|057|M|(RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine|
03741|058|M|tumors (pNET) should be considered.(11)|
03741|059|B||
03741|060|D|DISCUSSION:  In a study in 24 healthy subjects, rifampin (a strong CYP3A4|
03741|061|D|inducer) decreased bosutinib area-under-curve (AUC) and maximum|
03741|062|D|concentration (Cmax) by 94% and 86%.  Bosutinib clearance increased by|
03741|063|D|13-fold.(1,14)|
03741|064|D|   In a study in healthy subjects, rifampin (600 mg daily for 31 days)|
03741|065|D|decreased the AUC of a single dose of cabozantinib by 77%.(2)|
03741|066|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily)|
03741|067|D|decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%,|
03741|068|D|respectively.(4)|
03741|069|D|   Pretreatment and concurrent therapy with rifampin increased erlotinib|
03741|070|D|clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by|
03741|071|D|66% to 80%.  This is equivalent to a dose of about 30 mg to 50 mg in|
03741|072|D|NSCLC.(5)|
03741|073|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
03741|074|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
03741|075|D|150 mg dose of erlotinib.(5)|
03741|076|D|   In a case report, coadministration of phenytoin (180mg daily) and|
03741|077|D|erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml|
03741|078|D|to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from|
03741|079|D|1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold|
03741|080|D|(from 3.53 L/h to 41.7 L/h).(14)|
03741|081|D|   In a study in healthy male volunteers, rifampicin decreased AUC of|
03741|082|D|gefitinib by 85%.(6)|
03741|083|D|   The coadministration of rifampin decreased the Cmax and AUC of ibrutinib|
03741|084|D|by more than 13-fold and 10-fold.(7)|
03741|085|D|   In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200|
03741|086|D|mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of|
03741|087|D|lapatinib by 72%.  The dose adjustment recommendations are based on|
03741|088|D|pharmacokinetic studies and are predicted to adjust lapatinib AUC to the|
03741|089|D|range observed without concurrent CYP3A4 inducers; however, there are no|
03741|090|D|clinical data with these doses in patients receiving strong CYP3A4|
03741|091|D|inducers.(8)|
03741|092|D|   Pazopanib is primarily metabolized by CYP3A4.(9)|
03741|093|D|   Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a|
03741|094|D|single dose of sorafenib (400 mg) by 37%.(10)|
03741|095|D|   In a study with healthy subjects, concurrent rifampin decreased the|
03741|096|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and|
03741|097|D|46%, respectively, of a single dose of sunitinib.(11)|
03741|098|D|   Strong CYP3A4 inducers are expected to alter vandetanib concentrations.|
03741|099|D|The patient developed nystagmus, a sign of phenytoin toxicity.(12)|
03741|100|B||
03741|101|R|REFERENCES:|
03741|102|B||
03741|103|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
03741|104|R|  2023.|1
03741|105|R|2.Cabometyx (cabozantinib) tablets, US prescribing information. Exelixis|1
03741|106|R|  Inc. January, 2021.|1
03741|107|R|3.Cometriq (cabozantinib) US prescribing information. Exelixix, Inc.|1
03741|108|R|  January, 2020.|1
03741|109|R|4.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
03741|110|R|  Company February, 2023.|1
03741|111|R|5.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
03741|112|R|  2016.|1
03741|113|R|6.Iressa (gefitinib tablets) US prescribing information. AstraZeneca|1
03741|114|R|  Pharmaceuticals LP April 7, 2004.|1
03741|115|R|7.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
03741|116|R|  August, 2022.|1
03741|117|R|8.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
03741|118|R|  2018.|1
03741|119|R|9.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03741|120|R|  2020.|1
03741|121|R|10.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
03741|122|R|   Corporation July, 2020.|1
03741|123|R|11.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
03741|124|R|   2021.|1
03741|125|R|12.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
03741|126|R|   Pharmaceuticals LP October, 2018.|1
03741|127|R|13.Abbas R, Boni J, Sonnichsen D. Effect of rifampin on the pharmacokinetics|2
03741|128|R|   of bosutinib, a dual Src/Abl tyrosine  kinase inhibitor, when|2
03741|129|R|   administered concomitantly to healthy subjects. Drug Metab Pers Ther 2015|2
03741|130|R|   Mar;30(1):57-63.|2
03741|131|R|14.Ohgami M, Kaburagi T, Kurosawa A, Homma M. Drug interaction between|3
03741|132|R|   erlotinib and phenytoin for brain metastases in a patient with nonsmall|3
03741|133|R|   cell lung cancer. Lung Cancer 2016 Nov;101:9-10.|3
03741|134|R|15.This information is based on an extract from the Certara Drug Interaction|6
03741|135|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03741|136|R|16.US Food and Drug Administration (FDA). Drug Development and Drug|1
03741|137|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03741|138|R|   at:|1
03741|139|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03741|140|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03741|141|R|   11/14/2017.|1
03742|001|T|MONOGRAPH TITLE:  Antineoplastic Syst Enzyme Inhibitors/Apalutamide|
03742|002|B||
03742|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03742|004|L|of severe adverse interaction.|
03742|005|B||
03742|006|A|MECHANISM OF ACTION:  Apalutamide(1) may induce the metabolism of certain|
03742|007|A|antineoplastic systemic enzyme inhibitors, including  ceritinib,(2)|
03742|008|A|crizotinib,(3) dasatinib,(4) lapatinib,(5) nilotinib,(6) pazopanib,(7)|
03742|009|A|sorafenib,(8) sunitinib,(9) and vandetanib.(10)|
03742|010|B||
03742|011|E|CLINICAL EFFECTS:  Concurrent use of apalutamide(1) may decrease the levels|
03742|012|E|and effectiveness of certain antineoplastic systemic enzyme inhibitors,|
03742|013|E|including ceritinib,(2) crizotinib,(3) dasatinib,(4) lapatinib,(5)|
03742|014|E|nilotinib,(6) pazopanib,(7) sorafenib,(8) sunitinib,(9) and vandetanib.(10)|
03742|015|B||
03742|016|P|PREDISPOSING FACTORS:  None determined.|
03742|017|B||
03742|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of apalutamide in patients|
03742|019|M|receiving therapy with antineoplastic enzyme inhibitors.  Consider the use|
03742|020|M|of alternative agents with less enzyme induction potential.(1-10)|
03742|021|M|   Because of the nonlinear pharmacokinetic profile of nilotinib, increasing|
03742|022|M|its dose is unlikely to compensate for enzyme induction.(6)|
03742|023|M|   Pazopanib should not be administered to patients who cannot avoid chronic|
03742|024|M|use of strong CYP3A4 inducers like apalutamide.(7)|
03742|025|M|   If concurrent use of apalutamide cannot be avoided with other|
03742|026|M|antineoplastic enzyme inhibitors:|
03742|027|M|   Consider increasing the dose of dasatinib.(4)|
03742|028|M|   The dose of lapatinib should be gradually titrated from 1,250 mg/day up|
03742|029|M|to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from|
03742|030|M|1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive|
03742|031|M|breast cancer indication) based on patient tolerability. If the inducer is|
03742|032|M|discontinued, the dose of lapatinib should be adjusted to the normal|
03742|033|M|dose.(5)|
03742|034|M|   A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients|
03742|035|M|with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma|
03742|036|M|(RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine|
03742|037|M|tumors (pNET) should be considered.(9)|
03742|038|B||
03742|039|D|DISCUSSION:  In a study in 19 healthy subjects, rifampin (600 mg daily for|
03742|040|D|14 days) decreased the Cmax and AUC of a single dose of ceritinib by 44% and|
03742|041|D|70%, respectively.(2)|
03742|042|D|   Rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of|
03742|043|D|crizotinib (250 mg) by 69% and 82%, respectively.(3)|
03742|044|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily)|
03742|045|D|decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%,|
03742|046|D|respectively.(4)|
03742|047|D|   In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200|
03742|048|D|mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of|
03742|049|D|lapatinib by 72%.  The dose adjustment recommendations are based on|
03742|050|D|pharmacokinetic studies and are predicted to adjust lapatinib AUC to the|
03742|051|D|range observed without concurrent CYP3A4 inducers; however, there are no|
03742|052|D|clinical data with these doses in patients receiving strong CYP3A4|
03742|053|D|inducers.(5)|
03742|054|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily for 12|
03742|055|D|days) decreased nilotinib AUC by 80%.(6)|
03742|056|D|   Pazopanib is primarily metabolized by CYP3A4.(7)|
03742|057|D|   Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a|
03742|058|D|single dose of sorafenib (400 mg) by 37%.(8)|
03742|059|D|   In a study with healthy subjects, concurrent rifampin decreased the|
03742|060|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and|
03742|061|D|46%, respectively, of a single dose of sunitinib.(9)|
03742|062|D|   Strong CYP3A4 inducers are expected to alter vandetanib concentrations.|
03742|063|D|The patient developed nystagmus, a sign of phenytoin toxicity.(10)|
03742|064|D|   In an open-label, uncontrolled study of 45 patients with|
03742|065|D|castration-resistant prostate cancer, the maximum mean QTcF change from|
03742|066|D|baseline caused by apalutamide was 12.4 ms (2-sided 90% upper CI: 16.0|
03742|067|D|ms).(1)|
03742|068|B||
03742|069|R|REFERENCES:|
03742|070|B||
03742|071|R|1.Erleada (apalutamide) US prescribing information. Janssen Biotech, Inc.|1
03742|072|R|  July, 2021.|1
03742|073|R|2.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
03742|074|R|  Corporation August, 2021.|1
03742|075|R|3.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
03742|076|R|  2023.|1
03742|077|R|4.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
03742|078|R|  Company February, 2023.|1
03742|079|R|5.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
03742|080|R|  2018.|1
03742|081|R|6.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
03742|082|R|  Corporation September, 2021.|1
03742|083|R|7.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03742|084|R|  2020.|1
03742|085|R|8.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
03742|086|R|  Corporation July, 2020.|1
03742|087|R|9.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
03742|088|R|  2021.|1
03742|089|R|10.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
03742|090|R|   Pharmaceuticals LP October, 2018.|1
03743|001|T|MONOGRAPH TITLE:  Antineoplastic Systemic Enzyme Inhibitors/Apalutamide|
03743|002|B||
03743|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03743|004|L|of severe adverse interaction.|
03743|005|B||
03743|006|A|MECHANISM OF ACTION:  Apalutamide(1) may induce the metabolism of|
03743|007|A|antineoplastic systemic enzyme inhibitors, including bosutinib,(2)|
03743|008|A|cabozantinib,(3) erlotinib,(4) gefitinib,(5) ibrutinib,(6) idelalisib,(7)|
03743|009|A|and imatinib.(8)|
03743|010|B||
03743|011|E|CLINICAL EFFECTS:  Concurrent use of apalutamide may decrease the levels and|
03743|012|E|effectiveness of antineoplastic systemic enzyme inhibitors, including|
03743|013|E|bosutinib,(2) cabozantinib,(3) erlotinib,(4) gefitinib,(5) ibrutinib,(6)|
03743|014|E|idelalisib,(7) and imatinib.(8)|
03743|015|B||
03743|016|P|PREDISPOSING FACTORS:  None determined.|
03743|017|B||
03743|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of apalutamide in patients|
03743|019|M|receiving therapy with antineoplastic enzyme inhibitors.  Consider the use|
03743|020|M|of alternative agents with less enzyme induction potential.(1-8)|
03743|021|M|   If concurrent use of apalutamide cannot be avoided with antineoplastic|
03743|022|M|enzyme inhibitors:|
03743|023|M|   Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg|
03743|024|M|to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg.|
03743|025|M|Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3|
03743|026|M|days after discontinuation of the strong inducer.(9)|
03743|027|M|   Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to|
03743|028|M|180 mg daily or from 100 mg to 140 mg daily) as tolerated.  The daily dose|
03743|029|M|of cabozantinib should not exceed 180 mg.  If the CYP3A4 inducer is|
03743|030|M|discontinued, reduce the dosage of cabozantinib to the dose used prior to|
03743|031|M|initiation of the inducer 2 to 3 days after discontinuation of the strong|
03743|032|M|inducer.(3)|
03743|033|M|   Consider increasing the dosage of erlotinib by 50 mg increments as|
03743|034|M|tolerated at two week intervals (to a maximum of 450 mg) while closely|
03743|035|M|monitoring the patient.  The highest dosage studied with concurrent rifampin|
03743|036|M|is 450 mg.  If the dosage of erlotinib is increased, it will need to be|
03743|037|M|decreased when the inducer is discontinued.(4)|
03743|038|M|   Consider a dose increase to 500 mg daily of gefitinib in the absence of|
03743|039|M|severe adverse drug reaction.  Clinical response and adverse events should|
03743|040|M|be closely monitored.(5)|
03743|041|M|   The dose of imatinib should be increased by at least 50% and clinical|
03743|042|M|response should be carefully monitored.  Dosages up to 1200 mg/day (600 mg|
03743|043|M|twice daily) have been used in patients receiving concurrent therapy with|
03743|044|M|strong CYP3A4 inducers.(8)|
03743|045|B||
03743|046|D|DISCUSSION:  In a study in 24 healthy subjects, rifampin (a strong CYP3A4|
03743|047|D|inducer) decreased bosutinib area-under-curve (AUC) and maximum|
03743|048|D|concentration (Cmax) by 94% and 86%.  Bosutinib clearance increased by|
03743|049|D|13-fold.(2,11)|
03743|050|D|   In a study in healthy subjects, rifampin (600 mg daily for 31 days)|
03743|051|D|decreased the AUC of a single dose of cabozantinib by 77%.(3)|
03743|052|D|   Pretreatment and concurrent therapy with rifampin increased erlotinib|
03743|053|D|clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by|
03743|054|D|66% to 80%.  This is equivalent to a dose of about 30 mg to 50 mg in|
03743|055|D|NSCLC.(4)|
03743|056|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
03743|057|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
03743|058|D|150 mg dose of erlotinib.(4)|
03743|059|D|   In a case report, coadministration of phenytoin (180mg daily) and|
03743|060|D|erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml|
03743|061|D|to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from|
03743|062|D|1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold|
03743|063|D|(from 3.53 L/h to 41.7 L/h).(10)|
03743|064|D|   In a study in healthy male volunteers, rifampicin decreased AUC of|
03743|065|D|gefitinib by 85%.(5)|
03743|066|D|   The coadministration of rifampin decreased the Cmax and AUC of ibrutinib|
03743|067|D|by more than 13-fold and 10-fold.(6)|
03743|068|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
03743|069|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
03743|070|D|75%, respectively.(7)|
03743|071|D|   Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10|
03743|072|D|days) increased the clearance of a single dose of imatinib (400 mg) by|
03743|073|D|3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax)|
03743|074|D|decreased by 74% and 54%, respectively.(8,12)  The Cmax of the CGP74588|
03743|075|D|metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(12)|
03743|076|B||
03743|077|R|REFERENCES:|
03743|078|B||
03743|079|R|1.Erleada (apalutamide) US prescribing information. Janssen Biotech, Inc.|1
03743|080|R|  July, 2021.|1
03743|081|R|2.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
03743|082|R|  2023.|1
03743|083|R|3.Cometriq (cabozantinib) US prescribing information. Exelixix, Inc.|1
03743|084|R|  January, 2020.|1
03743|085|R|4.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
03743|086|R|  2016.|1
03743|087|R|5.Iressa (gefitinib tablets) US prescribing information. AstraZeneca|1
03743|088|R|  Pharmaceuticals LP April 7, 2004.|1
03743|089|R|6.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
03743|090|R|  August, 2022.|1
03743|091|R|7.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03743|092|R|  October, 2020.|1
03743|093|R|8.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
03743|094|R|  Pharmaceuticals Corporation August, 2022.|1
03743|095|R|9.Cabometyx (cabozantinib) tablets, US prescribing information. Exelixis|1
03743|096|R|  Inc. January, 2021.|1
03743|097|R|10.Ohgami M, Kaburagi T, Kurosawa A, Homma M. Drug interaction between|3
03743|098|R|   erlotinib and phenytoin for brain metastases in a patient with nonsmall|3
03743|099|R|   cell lung cancer. Lung Cancer 2016 Nov;101:9-10.|3
03743|100|R|11.Abbas R, Boni J, Sonnichsen D. Effect of rifampin on the pharmacokinetics|2
03743|101|R|   of bosutinib, a dual Src/Abl tyrosine  kinase inhibitor, when|2
03743|102|R|   administered concomitantly to healthy subjects. Drug Metab Pers Ther 2015|2
03743|103|R|   Mar;30(1):57-63.|2
03743|104|R|12.Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U,|2
03743|105|R|   Seiberling M. Effect of rifampicin on the pharmacokinetics of imatinib|2
03743|106|R|   mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother|2
03743|107|R|   Pharmacol 2004 Feb;53(2):102-6.|2
03744|001|T|MONOGRAPH TITLE:  Tamoxifen/Selected Weak CYP2D6 Inhibitors|
03744|002|B||
03744|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03744|004|L|take action as needed.|
03744|005|B||
03744|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2D6 may inhibit the conversion of|
03744|007|A|tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2)  The role|
03744|008|A|of endoxifen in tamoxifen's efficacy has been debated and may involve a|
03744|009|A|minimum concentration level.(3-5)|
03744|010|B||
03744|011|E|CLINICAL EFFECTS:  Concurrent use of inhibitors of CYP2D6 may decrease the|
03744|012|E|effectiveness of tamoxifen in preventing breast cancer recurrence.|
03744|013|B||
03744|014|P|PREDISPOSING FACTORS:  Concurrent use of weak CYP2D6 inhibitors in patients|
03744|015|P|who are CYP2D6 intermediate metabolizers should be avoided.  Patients who|
03744|016|P|are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by|
03744|017|P|CYP2D6 inhibition.|
03744|018|B||
03744|019|M|PATIENT MANAGEMENT:  Although data on this interaction are conflicting, it|
03744|020|M|may be prudent to use alternatives to CYP2D6 inhibitors when possible in|
03744|021|M|patients taking tamoxifen.  The US manufacturer of tamoxifen states that the|
03744|022|M|impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain|
03744|023|M|and makes no recommendation regarding coadministration with inhibitors of|
03744|024|M|CYP2D6.(12)  The manufacturer of paroxetine (a strong CYP2D6 inhibitor)|
03744|025|M|states that alternative agents with little or no CYP2D6 inhibition should be|
03744|026|M|considered.(13)|
03744|027|M|   The National Comprehensive Cancer Network's breast cancer guidelines|
03744|028|M|advises caution when coadministering strong CYP2D6 inhibitors with|
03744|029|M|tamoxifen.(14)|
03744|030|M|   If concurrent therapy is warranted, the risks versus benefits should be|
03744|031|M|discussed with the patient.|
03744|032|B||
03744|033|D|DISCUSSION:  Some studies have suggested that administration of fluoxetine,|
03744|034|D|paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer|
03744|035|D|phenotype may result in a decrease in the formation of endoxifen (an active|
03744|036|D|metabolite of tamoxifen) and a shorter time to breast cancer|
03744|037|D|recurrence.(1-2,9)|
03744|038|D|   A retrospective study of 630 breast cancer patients found an increasing|
03744|039|D|risk of breast cancer mortality with increasing durations of|
03744|040|D|coadministration of tamoxifen and paroxetine.  In the adjusted analysis,|
03744|041|D|absolute increases of 25%, 50%, and 75% in the proportion of time of|
03744|042|D|overlapping use of tamoxifen with paroxetine was associated with 24%, 54%,|
03744|043|D|and 91% increase in the risk of death from breast cancer, respectively.(15)|
03744|044|D|   The CYP2D6 genotype of the patient may have a role in the effects of this|
03744|045|D|interaction.  Patients with wild-type CYP2D6 genotype may be affected to a|
03744|046|D|greater extent by this interaction.  Patients with a variant CYP2D6 genotype|
03744|047|D|may have lower baseline levels of endoxifen and may be affected to a lesser|
03744|048|D|extent by this interaction.(6-10)|
03744|049|D|   In a retrospective review, 1,325 patients treated with tamoxifen for|
03744|050|D|breast cancer were classified as being poor 2D6 metabolizers (lacking|
03744|051|D|functional CYP2D6 enzymes), intermediate metabolizers (heterozygous|
03744|052|D|alleles), or extensive metabolizers (possessing 2 functional alleles).|
03744|053|D|After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%,|
03744|054|D|20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and|
03744|055|D|poor metabolizers, respectively.(11)|
03744|056|D|   In October of 2006, the Advisory Committee Pharmaceutical Science,|
03744|057|D|Clinical Pharmacology Subcommittee of the US Food and Drug Administration|
03744|058|D|recommended that the US tamoxifen labeling be updated to include information|
03744|059|D|about the increased risk of breast cancer recurrence in poor CYP2D6|
03744|060|D|metabolizers (either by genotype or drug interaction).(16-17)  The labeling|
03744|061|D|changes were never made due to ongoing uncertainty about the effects of|
03744|062|D|CYP2D6 genotypes on tamoxifen efficacy.|
03744|063|D|   In contrast to the above information, two studies have shown no|
03744|064|D|relationship between CYP2D6 genotype and breast cancer outcome.(18-20)  As|
03744|065|D|well, a number of studies found no association between use of CYP2D6|
03744|066|D|inhibitors and/or antidepressants in patients on tamoxifen and breast cancer|
03744|067|D|recurrence,(21-25) though the studies were limited by problematic selection|
03744|068|D|of CYP2D6 inhibitors and short follow-up.|
03744|069|D|   Weak CYP2D6 inhibitors include: amiodarone, chlorpromazine, citalopram,|
03744|070|D|escitalopram, flecainide, methadone, panobinostat, propafenone,|
03744|071|D|telithromycin, vemurafenib, and venlafaxine.(26-27)|
03744|072|B||
03744|073|R|REFERENCES:|
03744|074|B||
03744|075|R|1.Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes|2
03744|076|R|  DF, Desta Z, Flockhart DA. Active tamoxifen metabolite plasma|2
03744|077|R|  concentrations after coadministration of tamoxifen and the selective|2
03744|078|R|  serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003 Dec 3;|2
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03744|080|R|2.Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li|2
03744|081|R|  L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S,|2
03744|082|R|  Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype,|2
03744|083|R|  antidepressant use, and tamoxifen metabolism during adjuvant breast cancer|2
03744|084|R|  treatment. J Natl Cancer Inst 2005 Jan 5;97(1):30-9.|2
03744|085|R|3.Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z,|2
03744|086|R|  Flockhart DA, Skaar TC. Pharmacological characterization of|2
03744|087|R|  4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen.|2
03744|088|R|  Breast Cancer Res Treat 2004 May;85(2):151-9.|2
03744|089|R|4.Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of|2
03744|090|R|  tamoxifen sequential biotransformation by the human cytochrome P450 system|2
03744|091|R|  in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004|2
03744|092|R|  Sep;310(3):1062-75.|2
03744|093|R|5.Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen|2
03744|094|R|  (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast|2
03744|095|R|  cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother|2
03744|096|R|  Pharmacol 2005 May;55(5):471-8.|2
03744|097|R|6.Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, Nussler|5
03744|098|R|  A, Neuhaus P, Zanger UM, Eichelbaum M, Murdter TE. The influence of|5
03744|099|R|  CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent|5
03744|100|R|  antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol|5
03744|101|R|  2002 Aug;54(2):157-67.|5
03744|102|R|7.Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6|6
03744|103|R|  as a predictor of drug response. Clin Pharmacol Ther 2008 Jan;83(1):160-6.|6
03744|104|R|8.Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD. CYP2D6 polymorphisms|6
03744|105|R|  and the impact on tamoxifen therapy. J Pharm Sci 2007 Sep;96(9):2224-31.|6
03744|106|R|9.Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW,|2
03744|107|R|  Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM,|2
03744|108|R|  Desta Z, Nguyen A, Flockhart DA. Perez EA, Ingle JN. The impact of|2
03744|109|R|  cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.|2
03744|110|R|  Breast Cancer Res Treat 2007 Jan;101(1):113-21.|2
03744|111|R|10.Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C,|2
03744|112|R|   Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN.|2
03744|113|R|   Pharmacogenetics of tamoxifen biotransformation is associated with|2
03744|114|R|   clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005 Dec 20;|2
03744|115|R|   23(36):9312-8.|2
03744|116|R|11.Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P,|2
03744|117|R|   Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J,|2
03744|118|R|   Strick R, Beckmann MW, Koelbl H. Weinshilboum RM, Ingle JN, Eichelbaum M,|2
03744|119|R|   Schwab M, Brauch H. Association between CYP2D6 polymorphisms and outcomes|2
03744|120|R|   among women with early stage breast cancer treated with tamoxifen. JAMA|2
03744|121|R|   2009 Oct 7;302(13):1429-36.|2
03744|122|R|12.Soltamox (tamoxifen citrate) US prescribing information. Midatech Pharma|1
03744|123|R|   US Inc. September 25, 2018.|1
03744|124|R|13.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
03744|125|R|   Technologies January, 2017.|1
03744|126|R|14.Gradishar WJ, Anderson BO, Avraham J, etal. NCCN Clinical Practice|6
03744|127|R|   Guidelines in Oncology: Breast Cancer. Available at:|6
03744|128|R|   https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf September|6
03744|129|R|   6, 2019.|6
03744|130|R|15.Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC,|2
03744|131|R|   Paszat LF. Selective serotonin reuptake inhibitors and breast cancer|2
03744|132|R|   mortality in women receiving tamoxifen: a population based cohort study.|2
03744|133|R|   BMJ 2010 Feb 8;340:c693.|2
03744|134|R|16.Phan MT, Venitz J. Summary minutes of the Advisory Committee|1
03744|135|R|   Pharmaceutical Science Clinical Pharmacology Subcommittee. Available at:|1
03744|136|R|   http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4248m1.pdf October|1
03744|137|R|   18-19, 2006.|1
03744|138|R|17.Rahman NA. Personal communication. Division Director, Office of Clinical|1
03744|139|R|   Pharmacology, US Food and Drug Administration March 4, 2008.|1
03744|140|R|18.Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, Salter J,|2
03744|141|R|   Sestak I, Cuzick J, Dowsett M. CYP2D6 and UGT2B7 genotype and risk of|2
03744|142|R|   recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer|2
03744|143|R|   Inst 2012 Mar 21;104(6):452-60.|2
03744|144|R|19.Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R,|2
03744|145|R|   Dell'orto P, Biasi MO, Thurlimann B, Lyng MB, Ditzel HJ, Neven P, Debled|2
03744|146|R|   M, Maibach R, Price KN, Gelber RD, Coates AS. Goldhirsch A, Rae JM, Viale|2
03744|147|R|   G,. CYP2D6 genotype and tamoxifen response in postmenopausal women with|2
03744|148|R|   endocrine-responsive breast cancer: the breast international group 1-98|2
03744|149|R|   trial. J Natl Cancer Inst 2012 Mar 21;104(6):441-51.|2
03744|150|R|20.Kelly CM, Pritchard KI. CYP2D6 genotype as a marker for benefit of|6
03744|151|R|   adjuvant tamoxifen in postmenopausal women: lessons learned. J Natl|6
03744|152|R|   Cancer Inst 2012 Mar 21;104(6):427-8.|6
03744|153|R|21.Donneyong MM, Bykov K, Bosco-Levy P, Dong YH, Levin R, Gagne JJ. Risk of|2
03744|154|R|   mortality with concomitant use of tamoxifen and selective serotonin|2
03744|155|R|   reuptake inhibitors: multi-database cohort study. BMJ 2016 Sep 30;|2
03744|156|R|   354:i5014.|2
03744|157|R|22.Haque R, Shi J, Schottinger JE, Ahmed SA, Cheetham TC, Chung J, Avila C,|2
03744|158|R|   Kleinman K, Habel LA, Fletcher SW, Kwan ML. Tamoxifen and Antidepressant|2
03744|159|R|   Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors. J Natl|2
03744|160|R|   Cancer Inst 2016 Mar;108(3):.|2
03744|161|R|23.Cronin-Fenton DP, Damkier P, Lash TL. Metabolism and transport of|2
03744|162|R|   tamoxifen in relation to its effectiveness: new perspectives on an|2
03744|163|R|   ongoing controversy. Future Oncol 2014 Jan;10(1):107-22.|2
03744|164|R|24.Azoulay L, Dell'Aniello S, Huiart L, du Fort GG, Suissa S. Concurrent use|2
03744|165|R|   of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer|2
03744|166|R|   recurrence. Breast Cancer Res Treat 2011 Apr;126(3):695-703.|2
03744|167|R|25.Dezentje VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel|2
03744|168|R|   MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ. Effect of|2
03744|169|R|   concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer|2
03744|170|R|   recurrence in early-stage breast cancer. J Clin Oncol 2010 May 10;|2
03744|171|R|   28(14):2423-9.|2
03744|172|R|26.This information is based on an extract from the Certara Drug Interaction|6
03744|173|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03744|174|R|27.US Food and Drug Administration (FDA). Drug Development and Drug|1
03744|175|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03744|176|R|   at:|1
03744|177|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03744|178|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03744|179|R|   11/14/2017.|1
03744|180|R|28.Goetz MP, Sangkuhl K, Guchelaar HJ, Schwab M, Province M, Whirl-Carrillo|6
03744|181|R|   M, Symmans WF, McLeod HL, Ratain MJ, Zembutsu H, Gaedigk A, van Schaik|6
03744|182|R|   RH, Ingle JN, Caudle KE, Klein TE. Clinical Pharmacogenetics|6
03744|183|R|   Implementation Consortium (CPIC) Guideline for CYP2D6  and Tamoxifen|6
03744|184|R|   Therapy. Clin Pharmacol Ther 2018 May;103(5):770-777.|6
03745|001|T|MONOGRAPH TITLE:  Slt Antineoplastic Systemic Enzyme|
03745|002|T|Inh/Lumacaftor-Ivacaftor|
03745|003|B||
03745|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03745|005|L|of severe adverse interaction.|
03745|006|B||
03745|007|A|MECHANISM OF ACTION:  Lumacaftor-ivacaftor(1) may induce the metabolism of|
03745|008|A|antineoplastic systemic enzyme inhibitors, including bosutinib,(2)|
03745|009|A|cabozantinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6) gefitinib,(7)|
03745|010|A|ibrutinib,(8) imatinib,(9) lapatinib,(10) nilotinib,(11) pazopanib,(12)|
03745|011|A|sorafenib,(13) sunitinib,(14) and vandetanib.(15)|
03745|012|B||
03745|013|E|CLINICAL EFFECTS:  Concurrent use of lumacaftor-ivacaftor may decrease the|
03745|014|E|levels and effectiveness of antineoplastic systemic enzyme inhibitors,|
03745|015|E|including bosutinib,(2) cabozantinib,(3) crizotinib,(4) dasatinib,(5)|
03745|016|E|erlotinib,(6) gefitinib,(7) ibrutinib,(8) imatinib,(9) lapatinib,(10)|
03745|017|E|nilotinib,(11) pazopanib,(12) sorafenib,(13) sunitinib,(14) and|
03745|018|E|vandetanib.(15)|
03745|019|B||
03745|020|P|PREDISPOSING FACTORS:  None determined.|
03745|021|B||
03745|022|M|PATIENT MANAGEMENT:  Avoid the concurrent use of lumacaftor-ivacaftor in|
03745|023|M|patients receiving therapy with antineoplastic enzyme inhibitors.  Consider|
03745|024|M|the use of alternative agents with less enzyme induction potential.(2-15)|
03745|025|M|   Because of the nonlinear pharmacokinetic profile of nilotinib, increasing|
03745|026|M|its dose is unlikely to compensate for enzyme induction.(11)|
03745|027|M|   Pazopanib should not be administered to patients who cannot avoid chronic|
03745|028|M|use of strong CYP3A4 inducers.(12)|
03745|029|M|   If concurrent use of a CYP3A4 inducer cannot be avoided with other|
03745|030|M|antineoplastic enzyme inhibitors:|
03745|031|M|   Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg|
03745|032|M|to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg.|
03745|033|M|Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3|
03745|034|M|days after discontinuation of the strong inducer.(16)|
03745|035|M|   Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to|
03745|036|M|180 mg daily or from 100 mg to 140 mg daily) as tolerated.  The daily dose|
03745|037|M|of cabozantinib should not exceed 180 mg.  If the CYP3A4 inducer is|
03745|038|M|discontinued, reduce the dosage of cabozantinib to the dose used prior to|
03745|039|M|initiation of the inducer 2 to 3 days after discontinuation of the strong|
03745|040|M|inducer.(2)|
03745|041|M|   Consider increasing the dose of dasatinib.(5)|
03745|042|M|   Consider increasing the dosage of erlotinib by 50 mg increments as|
03745|043|M|tolerated at two week intervals (to a maximum of 450 mg) while closely|
03745|044|M|monitoring the patient.  The highest dosage studied with concurrent rifampin|
03745|045|M|is 450 mg.  If the dosage of erlotinib is increased, it will need to be|
03745|046|M|decreased when the inducer is discontinued.  If the inducer is|
03745|047|M|dexamethasone, monitor the patient for sign of gastrointestinal perforation.|
03745|048|M|Discontinue erlotinib in patients who develop gastrointestinal|
03745|049|M|perforation.(6)|
03745|050|M|   Consider a dose increase to 500 mg daily of gefitinib in the absence of|
03745|051|M|severe adverse drug reaction.  Clinical response and adverse events should|
03745|052|M|be closely monitored.(7)|
03745|053|M|   The dose of imatinib should be increased by at least 50% and clinical|
03745|054|M|response should be carefully monitored.  Dosages up to 1200 mg/day (600 mg|
03745|055|M|twice daily) have been used in patients receiving concurrent therapy with|
03745|056|M|strong CYP3A4 inducers.(9)|
03745|057|M|   The dose of lapatinib should be gradually titrated from 1,250 mg/day up|
03745|058|M|to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from|
03745|059|M|1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive|
03745|060|M|breast cancer indication) based on patient tolerability. If the inducer is|
03745|061|M|discontinued, the dose of lapatinib should be adjusted to the normal|
03745|062|M|dose.(10)|
03745|063|M|   A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients|
03745|064|M|with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma|
03745|065|M|(RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine|
03745|066|M|tumors (pNET) should be considered.(14)|
03745|067|B||
03745|068|D|DISCUSSION:  In a study, 24 healthy subjects received a single dose of|
03745|069|D|bosutinib 500 mg (days 1 and 14) and rifampin 600 mg (days 8-17). Bosutinib|
03745|070|D|Cmax and AUC decreased by 86% and 92%, respectively. Bosutinib clearance|
03745|071|D|increased by 13-fold.(2,17)|
03745|072|D|   In a study in healthy subjects, rifampin (600 mg daily for 31 days)|
03745|073|D|decreased the AUC of a single dose of cabozantinib by 77%.(3)|
03745|074|D|   Rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of|
03745|075|D|crizotinib (250 mg) by 69% and 82%, respectively.(4)|
03745|076|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily)|
03745|077|D|decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%,|
03745|078|D|respectively.(5)|
03745|079|D|   Pretreatment and concurrent therapy with rifampin increased erlotinib|
03745|080|D|clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by|
03745|081|D|66% to 80%.  This is equivalent to a dose of about 30 mg to 50 mg in|
03745|082|D|NSCLC.(6)|
03745|083|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
03745|084|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
03745|085|D|150 mg dose of erlotinib.(6)|
03745|086|D|   In a case report, coadministration of phenytoin (180mg daily) and|
03745|087|D|erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml|
03745|088|D|to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from|
03745|089|D|1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold|
03745|090|D|(from 3.53 L/h to 41.7 L/h).(18)|
03745|091|D|   In a study in healthy male volunteers, rifampicin decreased AUC of|
03745|092|D|gefitinib by 85%.(7)|
03745|093|D|   The coadministration of rifampin decreased the Cmax and AUC of ibrutinib|
03745|094|D|by more than 13-fold and 10-fold.(8)|
03745|095|D|   Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10|
03745|096|D|days) increased the clearance of a single dose of imatinib (400 mg) by|
03745|097|D|3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax)|
03745|098|D|decreased by 74% and 54%, respectively.(9,19)  The Cmax of the CGP74588|
03745|099|D|metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(19)|
03745|100|D|   In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200|
03745|101|D|mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of|
03745|102|D|lapatinib by 72%.  The dose adjustment recommendations are based on|
03745|103|D|pharmacokinetic studies and are predicted to adjust lapatinib AUC to the|
03745|104|D|range observed without concurrent CYP3A4 inducers; however, there are no|
03745|105|D|clinical data with these doses in patients receiving strong CYP3A4|
03745|106|D|inducers.(10)|
03745|107|D|   In a study in healthy subjects, concurrent rifampin (600 mg daily for 12|
03745|108|D|days) decreased nilotinib AUC by 80%.(11)|
03745|109|D|   Pazopanib is primarily metabolized by CYP3A4.(12)|
03745|110|D|   Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a|
03745|111|D|single dose of sorafenib (400 mg) by 37%.(13)|
03745|112|D|   In a study with healthy subjects, concurrent rifampin decreased the|
03745|113|D|combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and|
03745|114|D|46%, respectively, of a single dose of sunitinib.(14)|
03745|115|D|   Strong CYP3A4 inducers are expected to alter vandetanib concentrations.|
03745|116|D|The patient developed nystagmus, a sign of phenytoin toxicity.(15)|
03745|117|B||
03745|118|R|REFERENCES:|
03745|119|B||
03745|120|R|1.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
03745|121|R|  Pharmaceuticals Inc. August, 2023.|1
03745|122|R|2.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
03745|123|R|  2023.|1
03745|124|R|3.Cometriq (cabozantinib) US prescribing information. Exelixix, Inc.|1
03745|125|R|  January, 2020.|1
03745|126|R|4.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
03745|127|R|  2023.|1
03745|128|R|5.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
03745|129|R|  Company February, 2023.|1
03745|130|R|6.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
03745|131|R|  2016.|1
03745|132|R|7.Iressa (gefitinib tablets) US prescribing information. AstraZeneca|1
03745|133|R|  Pharmaceuticals LP April 7, 2004.|1
03745|134|R|8.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
03745|135|R|  August, 2022.|1
03745|136|R|9.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
03745|137|R|  Pharmaceuticals Corporation August, 2022.|1
03745|138|R|10.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
03745|139|R|   2018.|1
03745|140|R|11.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
03745|141|R|   Corporation September, 2021.|1
03745|142|R|12.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
03745|143|R|   2020.|1
03745|144|R|13.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
03745|145|R|   Corporation July, 2020.|1
03745|146|R|14.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
03745|147|R|   2021.|1
03745|148|R|15.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
03745|149|R|   Pharmaceuticals LP October, 2018.|1
03745|150|R|16.Cabometyx (cabozantinib) tablets, US prescribing information. Exelixis|1
03745|151|R|   Inc. January, 2021.|1
03745|152|R|17.Abbas R, Boni J, Sonnichsen D. Effect of rifampin on the pharmacokinetics|2
03745|153|R|   of bosutinib, a dual Src/Abl tyrosine  kinase inhibitor, when|2
03745|154|R|   administered concomitantly to healthy subjects. Drug Metab Pers Ther 2015|2
03745|155|R|   Mar;30(1):57-63.|2
03745|156|R|18.Ohgami M, Kaburagi T, Kurosawa A, Homma M. Drug interaction between|3
03745|157|R|   erlotinib and phenytoin for brain metastases in a patient with nonsmall|3
03745|158|R|   cell lung cancer. Lung Cancer 2016 Nov;101:9-10.|3
03745|159|R|19.Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U,|2
03745|160|R|   Seiberling M. Effect of rifampicin on the pharmacokinetics of imatinib|2
03745|161|R|   mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother|2
03745|162|R|   Pharmacol 2004 Feb;53(2):102-6.|2
03746|001|T|MONOGRAPH TITLE:  Red Yeast Rice/Cyclosporine|
03746|002|B||
03746|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
03746|004|L|Assess the risk to the patient and take action as needed.|
03746|005|B||
03746|006|A|MECHANISM OF ACTION:  Unknown.|
03746|007|B||
03746|008|E|CLINICAL EFFECTS:  Myopathy and muscle aches, tenderness and weakness|
03746|009|E|(rhabdomyolysis) may occur with concurrent administration of red yeast rice|
03746|010|E|and cyclosporine.|
03746|011|E|   Red yeast rice contains monacolins, including monacolin K, also called|
03746|012|E|mevinolin.  Mevinolin is equivalent to lovastatin.(1)|
03746|013|B||
03746|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03746|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03746|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03746|017|P|patients with a history of myopathy or rhabdomyolysis.|
03746|018|B||
03746|019|M|PATIENT MANAGEMENT:  Avoid the concurrent use of red yeast rice with|
03746|020|M|cyclosporine.(1)|
03746|021|M|   Patients receiving concurrent therapy should be instructed to report|
03746|022|M|symptoms of muscle pain, tenderness, or weakness.|
03746|023|B||
03746|024|D|DISCUSSION:  Since this reaction may occur with red yeast rice alone, a|
03746|025|D|causal relationship is difficult to establish.  However, the risk of|
03746|026|D|myopathy and rhabdomyolysis appears to increase with concurrent|
03746|027|D|administration of cyclosporine.|
03746|028|D|   A case report of a 28-year-old woman on cyclosporine 300 mg daily|
03746|029|D|developed elevated serum creatine phosphokinase (CPK) while taking an|
03746|030|D|unlicensed herbal preparation containing rice fermented with red yeast.|
03746|031|D|Routine blood work detected a CPK of 1050 U/L with a trough cyclosporine|
03746|032|D|level 255 ng/mL.  Based on routine blood work, the patient had the CPK|
03746|033|D|repeated showing further elevation to 2,600 U/L.  The patient denied|
03746|034|D|symptoms.  Upon investigation, the patient was noted to have started taking|
03746|035|D|an unlicensed herbal containing rice fermented with red yeast for the prior|
03746|036|D|2 months.  The herbal product was discontinued and CPK declined to 600 U/L|
03746|037|D|in 2 weeks with no further complications.(2)|
03746|038|B||
03746|039|R|REFERENCES:|
03746|040|B||
03746|041|R|1.Red Yeast Rice In: Natural Medicines Comprehensive Database [database on|6
03746|042|R|  the internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2021.|6
03746|043|R|  Cited 12 March 2021. Available from: http://www.naturaldatabase.com.|6
03746|044|R|  Subscription required to view.|6
03746|045|R|2.Prasad GV, Wong T, Meliton G, Bhaloo S. Rhabdomyolysis due to red yeast|3
03746|046|R|  rice (Monascus purpureus) in a renal transplant  recipient.|3
03746|047|R|  Transplantation 2002 Oct 27;74(8):1200-1.|3
03747|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Ixazomib|
03747|002|B||
03747|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03747|004|L|of severe adverse interaction.|
03747|005|B||
03747|006|A|MECHANISM OF ACTION:  Ixazomib does not interact with hormonal|
03747|007|A|contraceptives, but the dexamethasone used with ixazomib is a weak to|
03747|008|A|moderate CYP3A4 inducer and may increase the CYP3A4 mediated metabolism of|
03747|009|A|hormonal contraceptives.(1)|
03747|010|B||
03747|011|E|CLINICAL EFFECTS:  Concurrent use of ixazomib with dexamethasone may reduce|
03747|012|E|the effectiveness of hormonal contraceptives.(1)  Ixazomib may cause birth|
03747|013|E|defects and/or miscarriage if used by pregnant women.|
03747|014|B||
03747|015|P|PREDISPOSING FACTORS:  None determined.|
03747|016|B||
03747|017|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
03747|018|M|rely on hormonal contraceptives (including oral contraceptives, patches,|
03747|019|M|implants, and/or IUDs) for contraception.  Women should use an effective|
03747|020|M|non-hormonal back-up method of birth control during and for 90 days after|
03747|021|M|ixazomib-dexamethasone therapy.(1)|
03747|022|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03747|023|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03747|024|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03747|025|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03747|026|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03747|027|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03747|028|M|and to seek medical advice if they do become pregnant.(2)|
03747|029|B||
03747|030|D|DISCUSSION:  Ixazomib-dexamethasone has not been studied with hormonal|
03747|031|D|contraceptives.  Dexamethasone may decrease the effectiveness of hormonal|
03747|032|D|contraceptives, including oral contraceptives, patches, implants, and/or|
03747|033|D|IUDs.  Women should use a back-up method of birth control during|
03747|034|D|ixazomib-dexamethasone therapy.(1)|
03747|035|B||
03747|036|R|REFERENCES:|
03747|037|B||
03747|038|R|1.Ninlaro (ixazomib) US prescribing information. Millennium Pharmaceuticals|1
03747|039|R|  Inc March. 2021.|1
03747|040|R|2.Medicines and Healthcare products Regulatory Agency.|1
03747|041|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03747|042|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03747|043|R|  available at:|1
03747|044|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03747|045|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03747|046|R|  -and-contraceptive-efficacy September 15, 2016..|1
03748|001|T|MONOGRAPH TITLE:  Carbamazepine/Selected CYP3A4 Inhibitors|
03748|002|B||
03748|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03748|004|L|of severe adverse interaction.|
03748|005|B||
03748|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the hepatic|
03748|007|A|metabolism of carbamazepine.(1,2)|
03748|008|B||
03748|009|E|CLINICAL EFFECTS:  Increased serum carbamazepine levels with subsequent|
03748|010|E|increases in the pharmacological and toxic effects of carbamazepine.|
03748|011|B||
03748|012|P|PREDISPOSING FACTORS:  Simultaneous use of other drugs (i.e., other|
03748|013|P|anticonvulsants) or carbamazepine blood levels already near the toxic range|
03748|014|P|before initiation of a CYP3A4 inhibitor may increase the risk of a severe|
03748|015|P|interaction.|
03748|016|B||
03748|017|M|PATIENT MANAGEMENT:  The manufacturer of carbamazepine states that CYP3A4|
03748|018|M|inhibitors may increase plasma carbamazepine levels.  If concurrent use is|
03748|019|M|warranted, close monitoring of carbamazepine levels is indicated and dosage|
03748|020|M|adjustment may be required.(1)|
03748|021|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
03748|022|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
03748|023|M|should be observed for signs of toxicity (dizziness, ataxia, blurred vision,|
03748|024|M|or SIADH).  The dosage of carbamazepine may need to be adjusted or|
03748|025|M|carbamazepine may need to be discontinued.(1)|
03748|026|B||
03748|027|D|DISCUSSION:  Carbamazepine is almost completely metabolized to|
03748|028|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
03748|029|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
03748|030|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
03748|031|D|CYP3A5.(1,2)|
03748|032|D|   In a randomized, cross-over study of ten seizure patients, the effects of|
03748|033|D|grapefruit juice on the pharmacokinetics of carbamazepine were determined.|
03748|034|D|Results indicate a statistically significant increase in serum|
03748|035|D|concentrations and area under the concentration-time curve (AUC) in the|
03748|036|D|grapefruit juice arm.(3)|
03748|037|D|   Selected CYP3A4 inhibitors linked to this monograph include: conivaptan,|
03748|038|D|grapefruit, mibefradil, schisandra, and tofisopam.(4)|
03748|039|B||
03748|040|R|REFERENCES:|
03748|041|B||
03748|042|R|1.Tegretol (carbamazepine) US prescribing information. Novartis|1
03748|043|R|  Pharmaceuticals Corporation September, 2023.|1
03748|044|R|2.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
03748|045|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
03748|046|R|  Dec;21(12):906-10.|6
03748|047|R|3.Garg SK, Kumar N, Bhargava VK, Prabhakar SK. Effect of grapefruit juice on|2
03748|048|R|  carbamazepine bioavailability in patients with epilepsy. Clin Pharmacol|2
03748|049|R|  Ther 1998 Sep;64(3):286-8.|2
03748|050|R|4.This information is based on an extract from the Certara Drug Interaction|6
03748|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03749|001|T|MONOGRAPH TITLE:  Cyclophosphamide/Etanercept|
03749|002|B||
03749|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03749|004|L|of severe adverse interaction.|
03749|005|B||
03749|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.|
03749|007|B||
03749|008|E|CLINICAL EFFECTS:  Concurrent use of cyclophosphamide and etanercept may|
03749|009|E|increase the risk of non-cutaneous solid malignancies.(1)|
03749|010|B||
03749|011|P|PREDISPOSING FACTORS:  None determined.|
03749|012|B||
03749|013|M|PATIENT MANAGEMENT:  The US manufacturer of etanercept states that the use|
03749|014|M|of etanercept in patients receiving concurrent cyclophosphamide therapy is|
03749|015|M|not recommended.(1)|
03749|016|B||
03749|017|D|DISCUSSION:  In the Wegener's Granulomatosis Etanercept Trial (WGET),|
03749|018|D|patients with granulomatosis with polyangiitis who received etanercept in|
03749|019|D|addition to standard therapy (including cyclophosphamide) had a higher|
03749|020|D|incidence of non-cutaneous solid malignancies and did not have improved|
03749|021|D|clinical outcomes when compared with standard therapy alone.  Six patients|
03749|022|D|(7%) in the etanercept group developed solid malignancies over a median|
03749|023|D|follow-up of 2 years, compared to none in the placebo group (p=0.01).  The|
03749|024|D|solid malignancies included 2 cases of mucinous adenocarcinoma of the colon,|
03749|025|D|1 each of metastatic cholangiocarcinoma, renal cell carcinoma, and breast|
03749|026|D|carcinoma, and 1 recurrent liposarcoma.(2)|
03749|027|D|   In a 5-year follow-up of the WGET cohort, 8 new solid malignancies were|
03749|028|D|diagnosed in the etanercept group since the close of the WGET, compared to 5|
03749|029|D|new malignancies in the placebo group.  This difference was not|
03749|030|D|statistically significant.(3)|
03749|031|B||
03749|032|R|REFERENCES:|
03749|033|B||
03749|034|R|1.Enbrel (etanercept) US prescribing information. Amgen December, 2023.|1
03749|035|R|2.Stone JH, Holbrook JT, Marriott MA, Tibbs AK, Sejismundo LP, Min YI,|2
03749|036|R|  Specks U, Merkel PA, Spiera R, Davis JC, St Clair EW, McCune WJ, Ytterberg|2
03749|037|R|  SR, Allen NB, Hoffman GS. Solid malignancies among patients in the|2
03749|038|R|  Wegener's Granulomatosis Etanercept Trial. Arthritis Rheum 2006 May;|2
03749|039|R|  54(5):1608-18.|2
03749|040|R|3.Silva F, Seo P, Schroeder DR, Stone JH, Merkel PA, Hoffman GS, Spiera R,|2
03749|041|R|  Sebastian JK, Davis JC Jr, St Clair EW, Allen NB, McCune WJ, Ytterberg SR,|2
03749|042|R|  Specks U. Solid malignancies among etanercept-treated patients with|2
03749|043|R|  granulomatosis with  polyangiitis (Wegener's): long-term followup of a|2
03749|044|R|  multicenter longitudinal cohort. Arthritis Rheum 2011 Aug;63(8):2495-503.|2
03750|001|T|MONOGRAPH TITLE:  Chloroquine; Hydroxychloroquine/MATE Inhibitors|
03750|002|B||
03750|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03750|004|L|of severe adverse interaction.|
03750|005|B||
03750|006|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
03750|007|A|protein transporters in the kidneys may inhibit the renal tubular secretion|
03750|008|A|of chloroquine or hydroxychloroquine via the MATE1 transporter.(1,2)|
03750|009|B||
03750|010|E|CLINICAL EFFECTS:  Concurrent use of MATE inhibitors may result in increased|
03750|011|E|levels of and toxicity from chloroquine or hydroxychloroquine, including|
03750|012|E|irreversible retinopathy, potentially life-threatening cardiac arrhythmias|
03750|013|E|like torsades de pointes (TdP), hypoglycemia, or myopathy.(1,2)|
03750|014|B||
03750|015|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
03750|016|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
03750|017|P|failure, myocardial infarction, history of torsade de pointes, congenital|
03750|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03750|019|P|female gender, or advanced age.(3)|
03750|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03750|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03750|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03750|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03750|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03750|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03750|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03750|027|B||
03750|028|M|PATIENT MANAGEMENT:  The manufacturers of chloroquine and hydroxychloroquine|
03750|029|M|state that concomitant use of MATE inhibitors should be avoided.(1,2)|
03750|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03750|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03750|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03750|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03750|034|B||
03750|035|D|DISCUSSION:  In a study of healthy volunteers, cimetidine (400 mg daily for|
03750|036|D|4 days) decreased the clearance of single-dose chloroquine (300 mg) by 53%|
03750|037|D|and half-life by 49%, compared to subjects not on cimetidine.(4)|
03750|038|D|   MATE inhibitors linked to this monograph include: bictegravir,|
03750|039|D|cimetidine, isavuconazole, pyrimethamine, risdiplam, trimethoprim, and|
03750|040|D|tucatinib.(5)|
03750|041|B||
03750|042|R|REFERENCES:|
03750|043|B||
03750|044|R|1.Aralen (chloroquine) US prescribing information. Sanofi-Aventis U.S. LLC|1
03750|045|R|  October, 2018.|1
03750|046|R|2.Plaquenil (hydroxychloroquine sulfate) US prescribing information.|1
03750|047|R|  Concordia Pharmaceuticals Inc. December, 2023.|1
03750|048|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03750|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03750|050|R|  settings: a scientific statement from the American Heart Association and|6
03750|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03750|052|R|  2;55(9):934-47.|6
03750|053|R|4.Ette EI, Brown-Awala EA, Essien EE. Chloroquine elimination in humans:|2
03750|054|R|  effect of low-dose cimetidine. J Clin Pharmacol 1987 Oct;27(10):813-6.|2
03750|055|R|5.This information is based on an extract from the Certara Drug Interaction|6
03750|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03751|001|T|MONOGRAPH TITLE:  Selected Benzodiazepines/Protease Inhibitors|
03751|002|B||
03751|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03751|004|L|take action as needed.|
03751|005|B||
03751|006|A|MECHANISM OF ACTION:  Protease inhibitors may inhibit the metabolism of|
03751|007|A|benzodiazepines that are metabolized by CYP3A4.(1)|
03751|008|B||
03751|009|E|CLINICAL EFFECTS:  Inhibition of benzodiazepine CYP3A4 metabolism by|
03751|010|E|protease inhibitors may produce increased levels of, as well as increased|
03751|011|E|clinical effects, of benzodiazepines.  Toxic effects of increased|
03751|012|E|benzodiazepine levels include profound sedation, respiratory depression,|
03751|013|E|coma, and/or death.|
03751|014|B||
03751|015|P|PREDISPOSING FACTORS:  None determined.|
03751|016|B||
03751|017|M|PATIENT MANAGEMENT:  The NIH Guidelines for Use of Antiretroviral Agents|
03751|018|M|advise considering use of alternative benzodiazepines that do not undergo|
03751|019|M|CYP metabolism, like lorazepam, oxazepam, and temazepam.(1)|
03751|020|M|   The manufacturers of the protease inhibitors recommend close clinical|
03751|021|M|monitoring for respiratory depression and/or prolonged sedation and|
03751|022|M|consideration of dosage adjustment of the benzodiazepine.(2-5)|
03751|023|M|   The manufacturers of some benzodiazepines (i.e., diazepam, estazolam,|
03751|024|M|midazolam) advise caution when they are coadministered with inhibitors of|
03751|025|M|CYP3A4 and to consider dose reduction of the benzodiazepine.(6-8)|
03751|026|M|   Monitor patients receiving concurrent therapy with protease inhibitors|
03751|027|M|and benzodiazepines carefully for increased effects including unusual|
03751|028|M|dizziness or lightheadedness, extreme sleepiness, slowed or difficult|
03751|029|M|breathing, or unresponsiveness.|
03751|030|B||
03751|031|D|DISCUSSION:  The interaction between most benzodiazepines and protease|
03751|032|D|inhibitors has not been studied.  Benzodiazepines are primarily metabolized|
03751|033|D|by CYP3A4 and CYP2C19.  Protease inhibitors are moderate to strong|
03751|034|D|inhibitors of CYP3A4, and an elevation in benzodiazepine effects and|
03751|035|D|concentrations with concomitant therapy can be expected.|
03751|036|D|   Benzodiazepines linked to this monograph include: brotizolam,|
03751|037|D|chlordiazepoxide, clonazepam, clorazepic acid, diazepam, estazolam,|
03751|038|D|etizolam, flunitrazepam, flurazepam, halazepam, non-oral midazolam,|
03751|039|D|prazepam, and quazepam.|
03751|040|D|   Protease inhibitors linked to this monograph include: ritonavir-boosted|
03751|041|D|lopinavir, nirmatrelvir, saquinavir, tipranavir; cobicistat- or|
03751|042|D|ritonavir-boosted darunavir; cobicistat-boosted, ritonavir-boosted or|
03751|043|D|unboosted atazanavir; ritonavir-boosted or unboosted amprenavir,|
03751|044|D|fosamprenavir, indinavir; and nelfinavir.|
03751|045|B||
03751|046|R|REFERENCES:|
03751|047|B||
03751|048|R|1.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03751|049|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03751|050|R|  HIV. Department of Health and Human Services. Available at|6
03751|051|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03751|052|R|  new-guidelines June 13, 2021.|6
03751|053|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
03751|054|R|  Squibb Company December, 2024.|1
03751|055|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
03751|056|R|  March, 2023.|1
03751|057|R|4.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
03751|058|R|  Laboratories December, 2019.|1
03751|059|R|5.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
03751|060|R|  December, 2019.|1
03751|061|R|6.Valium (diazepam) US prescribing information. Roche Products Inc December,|1
03751|062|R|  2016.|1
03751|063|R|7.Estazolam tablet US prescribing information. Teva Pharmaceuticals USA Inc|1
03751|064|R|  November, 2015.|1
03751|065|R|8.Versed Injection (midazolam hydrochloride) US prescribing information.|1
03751|066|R|  Roche Pharmaceuticals June, 2000.|1
03751|067|R|9.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
03751|068|R|  information. Pfizer Inc. February, 2025.|1
03751|069|R|10.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
03751|070|R|   Monograph. Pfizer Canada ULC October, 2023.|1
03752|001|T|MONOGRAPH TITLE:  Enzalutamide/Clopidogrel|
03752|002|B||
03752|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03752|004|L|of severe adverse interaction.|
03752|005|B||
03752|006|A|MECHANISM OF ACTION:  Clopidogrel metabolism to its active metabolite occurs|
03752|007|A|primarily through CYP2C19, with contributions from other CYP enzymes|
03752|008|A|including CYP3A4.(1)  Enzalutamide is a strong CYP3A4 inducer and a moderate|
03752|009|A|CYP2C9 and CYP2C19 inducer and may increase the conversion of clopidogrel to|
03752|010|A|its active form.(2)|
03752|011|B||
03752|012|E|CLINICAL EFFECTS:  Concurrent use of enzalutamide with clopidogrel may|
03752|013|E|increase the effects and toxicity of clopidogrel, including bleeding.(1,2)|
03752|014|B||
03752|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03752|016|P|patient with disease-associated factors (e.g. thrombocytopenia).|
03752|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
03752|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03752|019|P|risk for bleeding (e.g. NSAIDs).|
03752|020|B||
03752|021|M|PATIENT MANAGEMENT:  Avoid concurrent use of clopidogrel with enzalutamide.|
03752|022|M|   Monitor patients for signs of blood loss, including decreased hemoglobin,|
03752|023|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
03752|024|M|evaluate patients with any symptoms.|
03752|025|M|   Discontinue clopidogrel in patients with active pathologic bleeding.|
03752|026|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03752|027|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03752|028|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03752|029|M|and/or swelling.|
03752|030|B||
03752|031|D|DISCUSSION:  In a study of 12 healthy volunteers, rifampin (a strong CYP3A4|
03752|032|D|inducer, 300 mg twice daily for 7 days) increased the maximum concentration|
03752|033|D|(Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel by|
03752|034|D|approximately 4-fold.  In conjunction with this, there was a higher level of|
03752|035|D|P2Y12 receptor blockade by clopidogrel after rifampin pre-treatment.|
03752|036|D|Clopidogrel 600 mg alone decreased the number of unblocked receptors at 4|
03752|037|D|hours from 248 +/- 40 to 48 +/- 24 per platelet.  After rifampin|
03752|038|D|pre-treatment, clopidogrel decreased the number of unblocked receptors from|
03752|039|D|266 +/- 63 to 4 +/- 2 (p < 0.0001).(3)|
03752|040|D|   A study of 10 healthy volunteers found that rifampin 300 mg twice daily|
03752|041|D|for 4 days then combined with clopidogrel 75 mg daily for 6 days led to a|
03752|042|D|significantly greater inhibition of platelet aggregation compared to|
03752|043|D|clopidogrel alone (56% versus 33%, respectively).  Three subjects who were|
03752|044|D|initially clopidogrel nonresponders and 1 subject who was a low responder|
03752|045|D|all became responders after treatment with rifampin.(4)|
03752|046|B||
03752|047|R|REFERENCES:|
03752|048|B||
03752|049|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
03752|050|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
03752|051|R|2.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
03752|052|R|  September, 2022.|1
03752|053|R|3.Judge HM, Patil SB, Buckland RJ, Jakubowski JA, Storey RF. Potentiation of|2
03752|054|R|  clopidogrel active metabolite formation by rifampicin leads to  greater|2
03752|055|R|  P2Y12 receptor blockade and inhibition of platelet aggregation after|2
03752|056|R|  clopidogrel. J Thromb Haemost 2010 Aug;8(8):1820-7.|2
03752|057|R|4.Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE,|2
03752|058|R|  Tait AR, Bates ER. Contribution of hepatic cytochrome P450 3A4 metabolic|2
03752|059|R|  activity to the phenomenon of  clopidogrel resistance. Circulation 2004|2
03752|060|R|  Jan 20;109(2):166-71.|2
03753|001|T|MONOGRAPH TITLE:  Enzalutamide/Fosphenytoin; Phenytoin|
03753|002|B||
03753|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03753|004|L|of severe adverse interaction.|
03753|005|B||
03753|006|A|MECHANISM OF ACTION:  Phenytoin is a strong inducer of CYP3A4 and may|
03753|007|A|increase the metabolism of enzalutamide.(1)  Fosphenytoin is a prodrug of|
03753|008|A|phenytoin.|
03753|009|A|   Enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and may increase|
03753|010|A|the metabolism of fosphenytoin and phenytoin.(2)|
03753|011|B||
03753|012|E|CLINICAL EFFECTS:  Concurrent use of fosphenytoin or phenytoin with|
03753|013|E|enzalutamide may decrease the levels and effectiveness of both agents.(1,2)|
03753|014|B||
03753|015|P|PREDISPOSING FACTORS:  None determined.|
03753|016|B||
03753|017|M|PATIENT MANAGEMENT:  Avoid concurrent use of fosphenytoin or phenytoin with|
03753|018|M|enzalutamide.  Consider the use of agents with no or minimal induction|
03753|019|M|potential if possible.(2)|
03753|020|M|   If concurrent therapy with fosphenytoin or phenytoin is necessary,|
03753|021|M|increase the enzalutamide dose from 160 mg to 240 mg once daily.  If|
03753|022|M|concurrent therapy with fosphenytoin or phenytoin is discontinued, the|
03753|023|M|enzalutamide dose should be returned to the dose used prior to initiation of|
03753|024|M|the strong CYP3A4 inducer.(2)|
03753|025|M|   Phenytoin plasma levels and seizure frequency should be monitored closely|
03753|026|M|when enzalutamide is added to or discontinued from therapy.  The phenytoin|
03753|027|M|dose should be adjusted as needed based on phenytoin levels and symptoms of|
03753|028|M|seizure activity.|
03753|029|B||
03753|030|D|DISCUSSION:  In vitro data indicates that enzalutamide is primarily|
03753|031|D|metabolized by CYP2C8 and CYP3A4.  Inhibitors of these isoenzymes have been|
03753|032|D|shown to increase enzalutamide levels and inducers of these isoenzymes are|
03753|033|D|expected to decrease enzalutamide levels.(2)|
03753|034|D|   Coadministration of rifampin (strong CYP3A4 inducer and moderate CYP2C8|
03753|035|D|inducer) decreased the composite AUC of enzalutamide and its active|
03753|036|D|metabolite by 37%.(2)|
03753|037|D|   In a clinical trial in healthy subjects, enzalutamide was shown to reduce|
03753|038|D|the area-under-curve (AUC) of midazolam (a sensitive CYP3A4 substrate),|
03753|039|D|warfarin (a sensitive CYP2C9 substrate), and omeprazole (a sensitive CYP2C19|
03753|040|D|substrate.(2)|
03753|041|D|   A case report in a 77-year-old Caucasian male was initiated on 160 mg of|
03753|042|D|enzalutamide after being stable on warfarin with an INR of 3.5.  The INR|
03753|043|D|dropped to 1.4 after approximately 20 days on enzalutamide therapy.  Due to|
03753|044|D|the drop in INR, the warfarin dose was increased by 50% which lead to a|
03753|045|D|therapeutic INR.  When enzalutamide was discontinued, the warfarin dose was|
03753|046|D|decreased by 33% to remain at a therapeutic level.  Upon reinitiation, the|
03753|047|D|warfarin dose was increased once by 50% to achieve a therapeutic INR.(3)|
03753|048|B||
03753|049|R|REFERENCES:|
03753|050|B||
03753|051|R|1.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
03753|052|R|  March, 2022.|1
03753|053|R|2.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
03753|054|R|  September, 2022.|1
03753|055|R|3.Parrett JL, Reaves AB, Self TH, Owens RE. Enzalutamide-warfarin|3
03753|056|R|  interaction necessitating warfarin dosage adjustment: A case report of|3
03753|057|R|  successful clinical management. J Clin Pharm Ther 2018 Apr;43(2):276-279.|3
03754|001|T|MONOGRAPH TITLE:  Ponesimod/Immunosuppressives; Immunomodulators|
03754|002|B||
03754|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03754|004|L|of severe adverse interaction.|
03754|005|B||
03754|006|A|MECHANISM OF ACTION:  Ponesimod in combination with immunosuppressives and|
03754|007|A|immune-modulators all suppress the immune system.(1)|
03754|008|B||
03754|009|E|CLINICAL EFFECTS:  Concurrent use of ponesimod with immunosuppressive or|
03754|010|E|immune-modulating agents may result in an increased risk of serious|
03754|011|E|infections, such as disseminated herpetic infection, cryptococcal infection,|
03754|012|E|or progressive multifocal leukoencephalopathy (PML), an opportunistic|
03754|013|E|infection caused by the JC virus (JCV).(1)|
03754|014|B||
03754|015|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03754|016|P|immunosuppressive or immune-modulating medications.|
03754|017|B||
03754|018|M|PATIENT MANAGEMENT:  The ponesimod US prescribing information states|
03754|019|M|ponesimod has not been studied in combination with anti-neoplastic,|
03754|020|M|immune-modulating, or immunosuppressive therapies.|
03754|021|M|   Caution should be used during concomitant administration because of the|
03754|022|M|risk of additive immune effects during therapy and in the weeks following|
03754|023|M|administration.|
03754|024|M|   When switching from drugs with prolonged immune effects, the half-life|
03754|025|M|and mode of action of these drugs must be considered in order to avoid|
03754|026|M|unintended additive immunosuppressive effects.|
03754|027|M|   Initiating treatment with ponesimod after alemtuzumab is not recommended.|
03754|028|M|However, ponesimod can generally be started immediately after|
03754|029|M|discontinuation of beta interferon or glatiramer acetate.(1)|
03754|030|B||
03754|031|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections,|
03754|032|D|cryptococcal meningitis, disseminated cryptococcal infections, and cases of|
03754|033|D|progressive multifocal leukoencephalopathy (PML) have been reported in|
03754|034|D|patients who previously received immunomodulators or immunosuppressants.(1)|
03754|035|B||
03754|036|R|REFERENCE:|
03754|037|B||
03754|038|R|1.Ponvory (ponesimod) US prescribing information. Janssen Pharmaceuticals,|1
03754|039|R|  Inc. March, 2021.|1
03755|001|T|MONOGRAPH TITLE:  Ponesimod/Beta-Blockers|
03755|002|B||
03755|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03755|004|L|of severe adverse interaction.|
03755|005|B||
03755|006|A|MECHANISM OF ACTION:  Initiation of ponesimod has caused transient decreases|
03755|007|A|in heart rate and atrioventricular conduction delays after the first dose.|
03755|008|A|Decreases in heart rate start within the first hour and maximal decrease in|
03755|009|A|heart rate was seen at approximately 2-4 hours.  The first dose has also|
03755|010|A|been associated with heart block.  Beta-blockers further increase the risk|
03755|011|A|for symptomatic bradycardia or heart block.(1)|
03755|012|B||
03755|013|E|CLINICAL EFFECTS:  The heart rate lowering effect of ponesimod is transient|
03755|014|E|and is usually seen with the first dose.  Bradycardia may be associated with|
03755|015|E|an increase in the QTc interval, increasing the risk for torsade de|
03755|016|E|pointes.(1)|
03755|017|B||
03755|018|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular disease (e.g. heart|
03755|019|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
03755|020|P|history of torsades de pointes, or heart block), severe untreated sleep|
03755|021|P|apnea, a prolonged QTc interval prior to siponimod initiation, or factors|
03755|022|P|associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia,|
03755|023|P|bradycardia, female gender, or advanced age) may increase risk for|
03755|024|P|cardiovascular toxicity due to siponimod.|
03755|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03755|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03755|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03755|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03755|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03755|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03755|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03755|032|B||
03755|033|M|PATIENT MANAGEMENT:  The prescribing information states temporary|
03755|034|M|interruption in beta-blocker therapy may be needed before initiation of|
03755|035|M|ponesimod.  Beta-blocker therapy can be initiated in patients receiving|
03755|036|M|stable doses of ponesimod.(1)|
03755|037|M|   Treatment initiation recommendations include:|
03755|038|M|   - Obtain an ECG in all patients to determine whether preexisting|
03755|039|M|conduction abnormalities are present.|
03755|040|M|   - In all patients, a dose titration is recommended for initiation of|
03755|041|M|ponesimod treatment to help reduce cardiac effects.|
03755|042|M|   - In patients with sinus bradycardia (HR less than 55 bpm), first- or|
03755|043|M|second-degree [Mobitz type I] AV block, or a history of myocardial|
03755|044|M|infarction or heart failure with onset > 6 months prior to initiation, ECG|
03755|045|M|testing and first dose monitoring is recommended.|
03755|046|M|   - Since significant bradycardia may be poorly tolerated in patients with|
03755|047|M|history of cardiac arrest, cerebrovascular disease, uncontrolled|
03755|048|M|hypertension, or severe untreated sleep apnea, ponesimod is not recommended|
03755|049|M|in these patients.  If treatment is considered, advice from a cardiologist|
03755|050|M|should be sought prior to initiation of treatment in order to determine the|
03755|051|M|most appropriate monitoring strategy.|
03755|052|M|   - Use of ponesimod in patients with a history of recurrent syncope or|
03755|053|M|symptomatic bradycardia should be based on an overall benefit-risk|
03755|054|M|assessment.  If treatment is considered, advice from a cardiologist should|
03755|055|M|be sought prior to initiation of treatment in order to determine the most|
03755|056|M|appropriate monitoring.|
03755|057|M|   - For patients receiving a stable dose of a beta-blocker, the resting|
03755|058|M|heart rate should be considered before introducing ponesimod treatment.  If|
03755|059|M|the resting heart rate is greater than 55 bpm under chronic beta-blocker|
03755|060|M|treatment, ponesimod can be introduced.  If resting heart rate is less than|
03755|061|M|or equal to 55 bpm, beta-blocker treatment should be interrupted until the|
03755|062|M|baseline heart-rate is greater than 55 bpm.  Treatment with ponesimod can|
03755|063|M|then be initiated and treatment with a beta-blocker can be reinitiated after|
03755|064|M|ponesimod has been up-titrated to the target maintenance dosage.|
03755|065|M|   - If a titration dose is missed or if 4 or more consecutive daily doses|
03755|066|M|are missed during maintenance treatment, reinitiate Day 1 of the dose|
03755|067|M|titration and follow titration monitoring recommendations.(1)|
03755|068|B||
03755|069|D|DISCUSSION:  After the first titration dose of ponesimod the heart rate|
03755|070|D|decrease starts within an hour, and the Day 1 decline is maximal at|
03755|071|D|approximately 2-4 hours.  With continued up-titration, further heart rate|
03755|072|D|decreases are seen on subsequent days, with maximal decrease from Day|
03755|073|D|1-baseline reached on Day 4-5.  The highest daily post-dose decrease in|
03755|074|D|absolute hourly mean heart rate is observed on Day 1, with the pulse|
03755|075|D|declining on average 6 bpm.  Post-dose declines on the following days are|
03755|076|D|less pronounced.  With continued dosing, heart rate starts increasing after|
03755|077|D|Day 6 and reaches placebo levels within 10 days after treatment initiation.|
03755|078|D|   In a study, bradycardia occurred in 5.8% of ponesimod-treated patients|
03755|079|D|compared to 1.6% of patients receiving placebo.  Patients who experienced|
03755|080|D|bradycardia were generally asymptomatic.  Few patients experienced symptoms,|
03755|081|D|including dizziness or fatigue, and these symptoms resolved within 24 hours|
03755|082|D|without intervention.(1)|
03755|083|D|   Beta-Blockers linked to this monograph are: atenolol, betaxolol,|
03755|084|D|bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol,|
03755|085|D|nebivolol, propranolol and timolol.|
03755|086|B||
03755|087|R|REFERENCES:|
03755|088|B||
03755|089|R|1.Ponvory (ponesimod) US prescribing information. Janssen Pharmaceuticals,|1
03755|090|R|  Inc. March, 2021.|1
03755|091|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03755|092|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03755|093|R|  settings: a scientific statement from the American Heart Association and|6
03755|094|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03755|095|R|  2;55(9):934-47.|6
03756|001|T|MONOGRAPH TITLE:  Ponesimod/Agents That Cause Bradycardia|
03756|002|B||
03756|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03756|004|L|of severe adverse interaction.|
03756|005|B||
03756|006|A|MECHANISM OF ACTION:  Initiation of ponesimod has caused transient decreases|
03756|007|A|in heart rate and atrioventricular conduction delays after the first dose.|
03756|008|A|Decreases in heart rate start within the first hour and maximal decrease in|
03756|009|A|heart rate was seen at approximately 2-4 hours.  The first dose has also|
03756|010|A|been associated with heart block.  Additional agents that cause bradycardia|
03756|011|A|further increase the risk for symptomatic bradycardia.(1)|
03756|012|B||
03756|013|E|CLINICAL EFFECTS:  The heart rate lowering effect of ponesimod is transient|
03756|014|E|and is usually seen with the first dose.  Bradycardia may be associated with|
03756|015|E|an increase in the QTc interval, increasing the risk for torsade de|
03756|016|E|pointes.(1)|
03756|017|B||
03756|018|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular disease (e.g. heart|
03756|019|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
03756|020|P|history of torsades de pointes, or heart block), severe untreated sleep|
03756|021|P|apnea, a prolonged QTc interval prior to siponimod initiation, or factors|
03756|022|P|associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia,|
03756|023|P|bradycardia, female gender, or advanced age) may increase risk for|
03756|024|P|cardiovascular toxicity due to siponimod.(2)|
03756|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03756|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03756|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03756|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03756|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03756|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03756|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03756|032|B||
03756|033|M|PATIENT MANAGEMENT:  The prescribing information states ponesimod treatment|
03756|034|M|should generally not be initiated in patients who are on concurrent therapy|
03756|035|M|with additional agents that cause bradycardia.  If treatment with ponesimod|
03756|036|M|is considered, advice from a cardiologist should be sought regarding|
03756|037|M|switching to non-heart rate lowering drugs or monitoring during treatment|
03756|038|M|initiation.|
03756|039|M|   Treatment initiation recommendations include:|
03756|040|M|   - Obtain an ECG in all patients to determine whether preexisting|
03756|041|M|conduction abnormalities are present.|
03756|042|M|   - In all patients, a dose titration is recommended for initiation of|
03756|043|M|ponesimod treatment to help reduce cardiac effects.|
03756|044|M|   - In patients with sinus bradycardia (HR less than 55 bpm), first- or|
03756|045|M|second-degree [Mobitz type I] AV block, or a history of myocardial|
03756|046|M|infarction or heart failure with onset > 6 months prior to initiation, ECG|
03756|047|M|testing and first dose monitoring is recommended.|
03756|048|M|   - Since significant bradycardia may be poorly tolerated in patients with|
03756|049|M|history of cardiac arrest, cerebrovascular disease, uncontrolled|
03756|050|M|hypertension, or severe untreated sleep apnea, ponesimod is not recommended|
03756|051|M|in these patients. If treatment is considered, advice from a cardiologist|
03756|052|M|should be sought prior to initiation of treatment in order to determine the|
03756|053|M|most appropriate monitoring strategy.|
03756|054|M|   - Use of ponesimod in patients with a history of recurrent syncope or|
03756|055|M|symptomatic bradycardia should be based on an overall benefit-risk|
03756|056|M|assessment. If treatment is considered, advice from a cardiologist should be|
03756|057|M|sought prior to initiation of treatment in order to determine the most|
03756|058|M|appropriate monitoring.|
03756|059|M|   - If a titration dose is missed or if 4 or more consecutive daily doses|
03756|060|M|are missed during maintenance treatment, reinitiate Day 1 of the dose|
03756|061|M|titration and follow titration monitoring recommendations.(1)|
03756|062|B||
03756|063|D|DISCUSSION:  Initiation of ponesimod treatment has been associated with|
03756|064|D|transient atrioventricular (AV) conduction delays that follow a similar|
03756|065|D|temporal pattern as the observed decrease in heart rate during dose|
03756|066|D|titration.  The AV conduction delays manifested in most of the cases as|
03756|067|D|first-degree AV block (prolonged PR interval on ECG), which occurred in 3.4%|
03756|068|D|of ponesimod treated patients and in 1.2% of patients receiving|
03756|069|D|teriflunomide in Study 1.|
03756|070|D|   Second-degree or third-degree AV blocks have not been reported in|
03756|071|D|patients in clinical trials.|
03756|072|D|   The conduction abnormalities typically were transient, asymptomatic,|
03756|073|D|resolved within 24 hours, and did not require discontinuation of ponesimod|
03756|074|D|treatment.(1)|
03756|075|B||
03756|076|R|REFERENCES:|
03756|077|B||
03756|078|R|1.Ponvory (ponesimod) US prescribing information. Janssen Pharmaceuticals,|1
03756|079|R|  Inc. March, 2021.|1
03756|080|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03756|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03756|082|R|  settings: a scientific statement from the American Heart Association and|6
03756|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03756|084|R|  2;55(9):934-47.|6
03757|001|T|MONOGRAPH TITLE:  Tacrolimus/Metoclopramide|
03757|002|B||
03757|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03757|004|L|take action as needed.|
03757|005|B||
03757|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown but is possibly due to|
03757|007|A|a metoclopramide-induced increase in gastric emptying time leading to an|
03757|008|A|increase in tacrolimus absorption.(1)|
03757|009|B||
03757|010|E|CLINICAL EFFECTS:  Concurrent use of metoclopramide may result in elevated|
03757|011|E|levels of and toxicity from tacrolimus, including nephrotoxicity,|
03757|012|E|neurotoxicity, and prolongation of the QTc interval and life-threatening|
03757|013|E|cardiac arrhythmias, including torsades de pointes.(1)|
03757|014|B||
03757|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03757|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03757|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03757|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03757|019|P|gender, or advanced age.(2)|
03757|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03757|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03757|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03757|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03757|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03757|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03757|026|P|dysfunction).(2)|
03757|027|B||
03757|028|M|PATIENT MANAGEMENT:  Monitor tacrolimus levels in patients receiving|
03757|029|M|concurrent metoclopramide.  The dosage of tacrolimus may need to be adjusted|
03757|030|M|if metoclopramide is initiated or discontinued.(1)|
03757|031|M|   When concurrent therapy of metoclopramide and tacrolimus is warranted,|
03757|032|M|consider obtaining serum calcium, magnesium, and potassium levels and|
03757|033|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03757|034|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03757|035|M|heartbeat, dizziness, or fainting.|
03757|036|B||
03757|037|D|DISCUSSION:  A 47-year-old lung transplant patient on a stable dose of|
03757|038|D|tacrolimus 3 mg every 12 hours with tacrolimus levels of 7-8 ng/mL was|
03757|039|D|admitted for acute rejection and lymphocytic bronchiolitis.  On hospital day|
03757|040|D|3, he was started on IV metoclopramide 10 mg every 8 hours for nausea and|
03757|041|D|vomiting.  After 2 days, his tacrolimus level had increased from 8.4 ng/mL|
03757|042|D|at baseline to 36 ng/mL.  Metoclopramide was discontinued and tacrolimus|
03757|043|D|dose was reduced.  Tacrolimus levels normalized after 3 days, and after 15|
03757|044|D|days, the patient was back on tacrolimus 3.5 mg every 12 hours with normal|
03757|045|D|tacrolimus levels.(3)|
03757|046|D|   A 52-year-old liver transplant recipient who was stable on tacrolimus|
03757|047|D|developed subtherapeutic tacrolimus levels that were subsequently thought to|
03757|048|D|be due to impaired gastric emptying.  Despite increase of tacrolimus dose|
03757|049|D|from 7 mg to 28 mg twice daily, tacrolimus levels remained undetectable.|
03757|050|D|Concurrently, as a result of nausea and vomiting, she was started on|
03757|051|D|metoclopramide 10 mg 4 times daily.  Two days later, her tacrolimus levels|
03757|052|D|exceed the maximum detectable level of 30 ng/mL, and she developed|
03757|053|D|nephrotoxicity and neurotoxicity.(4)|
03757|054|B||
03757|055|R|REFERENCES:|
03757|056|B||
03757|057|R|1.Reglan (metoclopramide) tablets US prescribing information. ANI|1
03757|058|R|  Pharmaceuticals, Inc. August 29, 2017.|1
03757|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03757|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03757|061|R|  settings: a scientific statement from the American Heart Association and|6
03757|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03757|063|R|  2;55(9):934-47.|6
03757|064|R|3.Provenzani A, D'alessandro N, Polidori P. Toxic Tacrolimus Concentrations|3
03757|065|R|  Associated With Intravenous Use of Metoclopramide in  a Lung Transplant|3
03757|066|R|  Patient. Ann Pharmacother 2019 May;53(5):548-549.|3
03757|067|R|4.Prescott WA Jr, Callahan BL, Park JM. Tacrolimus toxicity associated with|3
03757|068|R|  concomitant metoclopramide therapy. Pharmacotherapy 2004 Apr;24(4):532-7.|3
03758|001|T|MONOGRAPH TITLE:  Selected CYP1A2 Substrates/Viloxazine|
03758|002|B||
03758|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03758|004|L|is contraindicated and generally should not be dispensed or administered to|
03758|005|L|the same patient.|
03758|006|B||
03758|007|A|MECHANISM OF ACTION:  Viloxazine is a strong inhibitor of CYP1A2 and may|
03758|008|A|increase the total exposure of sensitive CYP1A2 substrates.(1)  The FDA|
03758|009|A|defines strong inhibition as an increase in drug area-under-curve (AUC)|
03758|010|A|greater than 5-fold.(2)|
03758|011|B||
03758|012|E|CLINICAL EFFECTS:  Concurrent use of viloxazine with drugs primarily|
03758|013|E|metabolized by CYP1A2 may lead to elevated drug levels and increase the risk|
03758|014|E|of adverse reactions associated with the CYP1A2 substrate.(1)|
03758|015|B||
03758|016|P|PREDISPOSING FACTORS:  None determined.|
03758|017|B||
03758|018|M|PATIENT MANAGEMENT:  Drugs linked to this monograph have a narrow|
03758|019|M|therapeutic window or are sensitive to CYP1A2 inhibition.  Coadministration|
03758|020|M|of viloxazine with sensitive CYP1A2 substrates or CYP1A2 substrates with a|
03758|021|M|narrow therapeutic window is contraindicated.(1)|
03758|022|B||
03758|023|D|DISCUSSION:  Concomitant use of viloxazine significantly increases the total|
03758|024|D|exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may|
03758|025|D|increase the risk of adverse reactions associated with these CYP1A2|
03758|026|D|substrates.  In a study, viloxazine increased the AUC of caffeine by almost|
03758|027|D|6-fold.(1)|
03758|028|D|   CYP1A2 substrates linked to this monograph include: agomelatine,|
03758|029|D|alosetron, aminophylline, duloxetine, ramelteon, tasimelteon, and|
03758|030|D|theophylline.(2,3)|
03758|031|B||
03758|032|R|REFERENCES:|
03758|033|B||
03758|034|R|1.Qelbree (viloxazine) US prescribing information. Catalent Pharma|1
03758|035|R|  Solutions, LLC April, 2021.|1
03758|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03758|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03758|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03758|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03758|040|R|  11/14/2017.|1
03758|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
03758|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03759|001|T|MONOGRAPH TITLE:  Selected CYP1A2 Substrates/Viloxazine|
03759|002|B||
03759|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03759|004|L|of severe adverse interaction.|
03759|005|B||
03759|006|A|MECHANISM OF ACTION:  Viloxazine is a strong inhibitor of CYP1A2 and may|
03759|007|A|increase the total exposure of sensitive CYP1A2 substrates.(1)  The FDA|
03759|008|A|defines strong inhibition as an increase in drug area-under-curve (AUC)|
03759|009|A|greater than 5-fold.(2)|
03759|010|B||
03759|011|E|CLINICAL EFFECTS:  Concurrent use of viloxazine with drugs primarily|
03759|012|E|metabolized by CYP1A2 may lead to elevated drug levels and increase the risk|
03759|013|E|of adverse reactions associated with the CYP1A2 substrate.(1)|
03759|014|B||
03759|015|P|PREDISPOSING FACTORS:  None determined.|
03759|016|B||
03759|017|M|PATIENT MANAGEMENT:  Drugs linked to this monograph are moderately sensitive|
03759|018|M|to CYP1A2 inhibition.  Coadministration of viloxazine with moderately|
03759|019|M|sensitive CYP1A2 substrates is not recommended.  If coadministered, dose|
03759|020|M|reduction of the CYP1A2 substrate may be warranted.(1)|
03759|021|B||
03759|022|D|DISCUSSION:  Concomitant use of viloxazine significantly increases the total|
03759|023|D|exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may|
03759|024|D|increase the risk of adverse reactions associated with these CYP1A2|
03759|025|D|substrates.  In a study, viloxazine increased the AUC of caffeine by almost|
03759|026|D|6-fold.(1)|
03759|027|D|   Though not designed to evaluate drug interactions, the open-label portion|
03759|028|D|of a pediatric randomized controlled trial looking at the association of|
03759|029|D|riluzole concentrations with efficacy and adverse effects found that|
03759|030|D|fluvoxamine (a strong CYP1A2 inhibitor) increased riluzole concentrations by|
03759|031|D|about 2-fold.(3)|
03759|032|D|   CYP1A2 substrates linked to this monograph include: caffeine and|
03759|033|D|riluzole.(2,4)|
03759|034|B||
03759|035|R|REFERENCES:|
03759|036|B||
03759|037|R|1.Qelbree (viloxazine) US prescribing information. Catalent Pharma|1
03759|038|R|  Solutions, LLC April, 2021.|1
03759|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03759|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03759|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03759|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03759|043|R|  11/14/2017.|1
03759|044|R|3.Grant P, Farmer C, Song J, Kish T, Swedo S. Riluzole Serum Concentration|2
03759|045|R|  in Pediatric Patients Treated for Obsessive-Compulsive  Disorder. J Clin|2
03759|046|R|  Psychopharmacol 2017 Dec;37(6):713-716.|2
03759|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
03759|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03760|001|T|MONOGRAPH TITLE:  Tizanidine/Viloxazine (mono deleted 03/13/2024)|
03760|002|B||
03760|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03760|004|L|is contraindicated and generally should not be dispensed or administered to|
03760|005|L|the same patient.|
03760|006|B||
03760|007|A|MECHANISM OF ACTION:  Viloxazine is a strong inhibitor of CYP1A2 and may|
03760|008|A|increase the total exposure of sensitive CYP1A2 substrates like|
03760|009|A|tizanidine.(1-3)|
03760|010|B||
03760|011|E|CLINICAL EFFECTS:  Concurrent use of viloxazine may result in elevated|
03760|012|E|levels of and effects from tizanidine, including hypotension, bradycardia,|
03760|013|E|drowsiness, sedation, and decreased psychomotor function.|
03760|014|B||
03760|015|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
03760|016|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
03760|017|P|patients using more than one medicine with anticholinergic properties.(4)|
03760|018|B||
03760|019|M|PATIENT MANAGEMENT:  The US manufacturers of viloxazine(1) and tizanidine(2)|
03760|020|M|state that concurrent use of these agents is contraindicated.|
03760|021|B||
03760|022|D|DISCUSSION:  Concomitant use of viloxazine significantly increases the total|
03760|023|D|exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may|
03760|024|D|increase the risk of adverse reactions associated with these CYP1A2|
03760|025|D|substrates.  In a study, viloxazine increased the AUC of caffeine (a|
03760|026|D|sensitive CYP1A2 substrate) by almost 6-fold.(1)|
03760|027|D|   In a study in 10 healthy subjects, pretreatment with fluvoxamine (100 mg|
03760|028|D|daily for 4 days, a strong CYP1A2 inhibitor) increased the area-under-curve|
03760|029|D|(AUC) and maximum concentration (Cmax) of a single dose of tizanidine (4 mg)|
03760|030|D|by 33-fold (range:  14-fold to 103-fold) and by 12-fold (range 5-fold to|
03760|031|D|33-fold), respectively.  Tizanidine half-life increased from 1.5 hours to|
03760|032|D|4.3 hours.  The mean decrease in systolic blood pressure was 35 mmHg.  The|
03760|033|D|mean decrease in diastolic blood pressure was 20 mmHg.  Heart rate decreased|
03760|034|D|by 4 beats/minute.  There were also significant effects on the Digit|
03760|035|D|Substitution Test, subjective drug effects, and drowsiness.(5)|
03760|036|B||
03760|037|R|REFERENCES:|
03760|038|B||
03760|039|R|1.Qelbree (viloxazine) US prescribing information. Catalent Pharma|1
03760|040|R|  Solutions, LLC April, 2021.|1
03760|041|R|2.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
03760|042|R|  Pharma Inc. November 22, 2024.|1
03760|043|R|3.Granfors MT, Backman JT, Laitila J, Neuvonen PJ. Tizanidine is mainly|5
03760|044|R|  metabolized by cytochrome p450 1A2 in vitro. Br J Clin Pharmacol 2004 Mar;|5
03760|045|R|  57(3):349-53.|5
03760|046|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03760|047|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03760|048|R|  Soc 2023 Jul;71(7):2052-2081.|6
03760|049|R|5.Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine|2
03760|050|R|  drastically increases concentrations and effects of tizanidine: a|2
03760|051|R|  potentially hazardous interaction. Clin Pharmacol Ther 2004 Apr;|2
03760|052|R|  75(4):331-41.|2
03760|053|R|6.Momo K, Doki K, Hosono H, Homma M, Kohda Y. Drug interaction of tizanidine|3
03760|054|R|  and fluvoxamine. Clin Pharmacol Ther 2004 Nov;76(5):509-10.|3
03761|001|T|MONOGRAPH TITLE:  Clozapine/Viloxazine|
03761|002|B||
03761|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03761|004|L|of severe adverse interaction.|
03761|005|B||
03761|006|A|MECHANISM OF ACTION:  Viloxazine is a strong inhibitor of CYP1A2 and may|
03761|007|A|increase the total exposure of sensitive CYP1A2 substrates like|
03761|008|A|clozapine.(1-2)|
03761|009|B||
03761|010|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with|
03761|011|E|viloxazine may result in elevated levels of clozapine and an increase in|
03761|012|E|clozapine related side effects such as orthostatic hypotension, syncope, QT|
03761|013|E|prolongation, profound sedation and seizures.(2)|
03761|014|B||
03761|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03761|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03761|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03761|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03761|019|P|female gender, or advanced age.(3)|
03761|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03761|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03761|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03761|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03761|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03761|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03761|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).|
03761|027|B||
03761|028|M|PATIENT MANAGEMENT:  The manufacturer recommends reducing the clozapine dose|
03761|029|M|to one-third the original dose with concurrent strong CYP1A2 inhibitors like|
03761|030|M|viloxazine.  Close monitoring is required to prevent clozapine toxicity.|
03761|031|M|Clozapine levels should be monitored in patients receiving concurrent|
03761|032|M|therapy with viloxazine.  Patients should also be monitored for adverse|
03761|033|M|clozapine effects and QT prolongation.(2)|
03761|034|M|   If concurrent therapy is warranted in patients receiving clozapine,|
03761|035|M|consider obtaining serum calcium, magnesium, and potassium levels and|
03761|036|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03761|037|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03761|038|M|heartbeat, dizziness, or fainting.|
03761|039|M|   If viloxazine is discontinued, the clozapine dose should be increased|
03761|040|M|based on clinical response.(2)  Serum clozapine measurements may be useful.|
03761|041|B||
03761|042|D|DISCUSSION:  Concomitant use of viloxazine significantly increases the total|
03761|043|D|exposure, but not peak exposure, of sensitive CYP1A2 substrates like|
03761|044|D|clozapine, which may increase the risk of adverse reactions.  In a study,|
03761|045|D|viloxazine increased the AUC of caffeine (a sensitive CYP1A2 substrate) by|
03761|046|D|almost 6-fold.(1)|
03761|047|D|   Several case reports have documented increased levels of clozapine when|
03761|048|D|fluvoxamine (a strong CYP1A2 inhibitor) was added to therapy.(4-7)  The|
03761|049|D|increases in clozapine levels ranged from 231% to 780%.  Several case|
03761|050|D|reports describe increased clozapine-related side effects following the|
03761|051|D|addition of fluvoxamine to clozapine therapy.(5,8-9)  In a study in 16|
03761|052|D|subjects(2,10), the addition of fluvoxamine to patients receiving clozapine|
03761|053|D|resulted in 3-fold increases in clozapine, N-desmethylclozapine, and|
03761|054|D|clozapine N-oxide.  The half-life of clozapine increased from 17 hours to 50|
03761|055|D|hours.  Another study (11) compared patients receiving clozapine monotherapy|
03761|056|D|to patients receiving concurrent therapy with clozapine and fluvoxamine and|
03761|057|D|found that the dose-normalized clozapine concentration increased by a factor|
03761|058|D|of 5-10 when fluvoxamine was added.|
03761|059|B||
03761|060|R|REFERENCES:|
03761|061|B||
03761|062|R|1.Qelbree (viloxazine) US prescribing information. Catalent Pharma|1
03761|063|R|  Solutions, LLC April, 2021.|1
03761|064|R|2.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03761|065|R|  Pharmaceuticals Corporation April, 2020.|1
03761|066|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03761|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03761|068|R|  settings: a scientific statement from the American Heart Association and|6
03761|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03761|070|R|  2;55(9):934-47.|6
03761|071|R|4.Markowitz JS, Gill HS, Lavia M, Brewerton TD, DeVane CL.|3
03761|072|R|  Fluvoxamine-clozapine dose-dependent interaction. Can J Psychiatry 1996|3
03761|073|R|  Dec;41(10):670-1.|3
03761|074|R|5.Dequardo JR, Roberts M. Elevated clozapine levels after fluvoxamine|3
03761|075|R|  initiation. Am J Psychiatry 1996 Jun;153(6):840-1.|3
03761|076|R|6.DuMortier G, Lochu A, Colen de Melo P, Ghribi O, Roche-Rabreau D,|3
03761|077|R|  DeGrassat K, Desce JM. Elevated clozapine plasma concentrations after|3
03761|078|R|  fluvoxamine initiation. Am J Psychiatry 1996 May;153(5):738-9.|3
03761|079|R|7.Hiemke C, Weigmann H, Hartter S, Dahmen N, Wetzel H, Muller H. Elevated|3
03761|080|R|  levels of clozapine in serum after addition of fluvoxamine. J Clin|3
03761|081|R|  Psychopharmacol 1994 Aug;14(4):279-81.|3
03761|082|R|8.Szegedi A, Wiesner J, Hiemke C. Improved efficacy and fewer side effects|3
03761|083|R|  under clozapine treatment after addition of fluvoxamine. J Clin|3
03761|084|R|  Psychopharmacol 1995 Apr;15(2):141-3.|3
03761|085|R|9.Silver H, Kaplan A, Jahjah N. Fluvoxamine augmentation for|3
03761|086|R|  clozapine-resistant schizophrenia. Am J Psychiatry 1995 Jul;152(7):1098.|3
03761|087|R|10.Wetzel H, Anghelescu I, Szegedi A, Wiesner J, Weigmann H, Harter S,|2
03761|088|R|   Hiemke C. Pharmacokinetic interactions of clozapine with selective|2
03761|089|R|   serotonin reuptake inhibitors: differential effects of fluvoxamine and|2
03761|090|R|   paroxetine in a prospective study. J Clin Psychopharmacol 1998 Feb;|2
03761|091|R|   18(1):2-9.|2
03761|092|R|11.Jerling M, Lindstrom L, Bondesson U, Bertilsson L. Fluvoxamine inhibition|2
03761|093|R|   and carbamazepine induction of the metabolism of clozapine: evidence from|2
03761|094|R|   a therapeutic drug monitoring service. Ther Drug Monit 1994 Aug;|2
03761|095|R|   16(4):368-74.|2
03762|001|T|MONOGRAPH TITLE:  Eliglustat/Viloxazine|
03762|002|B||
03762|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03762|004|L|of severe adverse interaction.|
03762|005|B||
03762|006|A|MECHANISM OF ACTION:  Eliglustat is primarily metabolized by CYP2D6 and to a|
03762|007|A|lesser extent by CYP3A4.  Viloxazine weakly inhibits CYP2D6 and CYP3A4.(1,2)|
03762|008|B||
03762|009|E|CLINICAL EFFECTS:  Concurrent use of viloxazine may result in elevated|
03762|010|E|levels of and clinical effects of eliglustat, including prolongation of the|
03762|011|E|PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac|
03762|012|E|arrhythmias.(1)|
03762|013|B||
03762|014|P|PREDISPOSING FACTORS:  If the patient hepatic impairment or if the patient|
03762|015|P|is a CYP2D6 poor metabolizer, eliglustat metabolism can be further|
03762|016|P|inhibited.(1)|
03762|017|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03762|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03762|019|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03762|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03762|021|P|advanced age.(2)|
03762|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03762|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03762|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03762|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03762|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03762|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03762|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03762|029|B||
03762|030|M|PATIENT MANAGEMENT:  Prescribing information has no specific recommendation|
03762|031|M|on the use of eliglustat with drugs that are weak inhibitors of both CYP2D6|
03762|032|M|and CYP3A4.  Viloxazine is a weak inhibitor of both CYP2D6 and CYP3A4.|
03762|033|M|   In CYP2D6 poor metabolizers, coadministration of viloxazine and|
03762|034|M|eliglustat should be avoided.|
03762|035|M|   In CYP2D6 extensive metabolizers with mild (Child-Pugh Class A) hepatic|
03762|036|M|impairment, the dosage of eliglustat with weak inhibitors of CYP2D6 or|
03762|037|M|CYP3A4 should be limited to 84 mg daily.|
03762|038|M|   In CYP2D6 intermediate metabolizers and CYP2D6 extensive metabolizers|
03762|039|M|without hepatic impairment, no dose adjustment of eliglustat is necessary|
03762|040|M|when taken with a weak CYP2D6 inhibitor or a weak CYP3A4 inhibitor.(1)|
03762|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03762|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03762|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03762|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03762|045|B||
03762|046|D|DISCUSSION:  There is no data on the interaction between eliglustat and dual|
03762|047|D|weak inhibitors of CYP2D6 and CYP3A4.|
03762|048|D|   Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased|
03762|049|D|eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve|
03762|050|D|(AUC) by  7-fold and 8.4-fold, respectively, in extensive metabolizers.|
03762|051|D|Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine|
03762|052|D|would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold,|
03762|053|D|respectively, in intermediate metabolizers.(1)|
03762|054|D|   PKPB models suggested ketoconazole (a strong CYP3A4 inhibitor) may|
03762|055|D|increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and|
03762|056|D|6.2-fold, respectively, in poor metabolizers.(1)|
03762|057|D|   PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would|
03762|058|D|increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in|
03762|059|D|extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in|
03762|060|D|intermediate metabolizers.|
03762|061|D|   PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would|
03762|062|D|increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in|
03762|063|D|extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in|
03762|064|D|intermediate metabolizers.|
03762|065|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a|
03762|066|D|strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax|
03762|067|D|and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers.|
03762|068|D|In intermediate metabolizers, eliglustat Cmax and AUC would be expected to|
03762|069|D|increase 7.5-fold and 9.8-fold, respectively.(1)|
03762|070|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine|
03762|071|D|(a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat|
03762|072|D|Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive|
03762|073|D|metabolizers.  In intermediate metabolizers, eliglustat Cmax and AUC would|
03762|074|D|be expected to increase 4.2-fold and 5-fold, respectively.(1)|
03762|075|B||
03762|076|R|REFERENCES:|
03762|077|B||
03762|078|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
03762|079|R|  August, 2018.|1
03762|080|R|2.Qelbree (viloxazine) US prescribing information. Catalent Pharma|1
03762|081|R|  Solutions, LLC April, 2021.|1
03762|082|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03762|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03762|084|R|  settings: a scientific statement from the American Heart Association and|6
03762|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03762|086|R|  2;55(9):934-47.|6
03762|087|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03762|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03762|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03762|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03762|091|R|  11/14/2017.|1
03762|092|R|5.This information is based on an extract from the Certara Drug Interaction|6
03762|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03763|001|T|MONOGRAPH TITLE:  Mexiletine/Phenytoin|
03763|002|B||
03763|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03763|004|L|take action as needed.|
03763|005|B||
03763|006|A|MECHANISM OF ACTION:  Phenytoin, a moderate CYP1A2 inducer, may induce the|
03763|007|A|metabolism of mexiletine.(1)|
03763|008|B||
03763|009|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
03763|010|E|effectiveness of mexiletine.(1)|
03763|011|B||
03763|012|P|PREDISPOSING FACTORS:  None determined.|
03763|013|B||
03763|014|M|PATIENT MANAGEMENT:  Monitoring of mexiletine plasma levels is recommended|
03763|015|M|during concurrent use to avoid ineffective therapy.(1)   The dose of|
03763|016|M|mexiletine may need to be adjusted when phenytoin therapy is started or|
03763|017|M|discontinued.|
03763|018|B||
03763|019|D|DISCUSSION:  Coadministration of mexiletine and rifampin (a moderate CYP1A2|
03763|020|D|inducer) have been reported to decrease the elimination half-life and|
03763|021|D|increase the nonrenal clearance of mexiletine.(2)|
03763|022|D|   A pharmacokinetic study in 6 healthy volunteers found a decrease in the|
03763|023|D|mean area-under-curve (AUC) of a single dose of mexiletine 400 mg when given|
03763|024|D|with a seven day course of phenytoin 300 mg.  The mean AUC of a single dose|
03763|025|D|of mexiletine 400 mg alone was 17.2 ng/ml compared to 8.01 ng/ml when given|
03763|026|D|with phenytoin 300 mg.(3)|
03763|027|B||
03763|028|R|REFERENCES:|
03763|029|B||
03763|030|R|1.Mexiletine US Prescribing Information. Teva Pharmaceuticals USA, Inc.|1
03763|031|R|  October, 2018.|1
03763|032|R|2.Pentikainen PJ, Koivula IH, Hiltunen HA. Effect of rifampicin treatment on|2
03763|033|R|  the kinetics of mexiletine. Eur J Clin Pharmacol 1982;23(3):261-6.|2
03763|034|R|3.Begg EJ, Chinwah PM, Webb C, Day RO, Wade DN. Enhanced metabolism of|2
03763|035|R|  mexiletine after phenytoin administration. Br J Clin Pharmacol 1982;|2
03763|036|R|  14:219-223.|2
03764|001|T|MONOGRAPH TITLE:  Efavirenz/Phenytoin|
03764|002|B||
03764|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03764|004|L|of severe adverse interaction.|
03764|005|B||
03764|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of phenytoin via|
03764|007|A|CYP2C19 or inhibit the metabolism of phenytoin via CYP2C9 and/or CYP2C19.|
03764|008|A|Phenytoin may induce the metabolism of efavirenz by CYP3A4 and CYP2B6.(1)|
03764|009|B||
03764|010|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels of and|
03764|011|E|effectiveness of efavirenz.|
03764|012|E|   Concurrent use may also result in decreased levels of phenytoin or|
03764|013|E|elevated levels of and toxicity from phenytoin.  Phenytoin has a narrow|
03764|014|E|therapeutic range.  Early symptoms of phenytoin toxicity may include|
03764|015|E|nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred|
03764|016|E|speech, blurred vision, nausea, and vomiting.  Severe toxicity may produce|
03764|017|E|organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and|
03764|018|E|atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be|
03764|019|E|fatal.(1)|
03764|020|B||
03764|021|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
03764|022|P|hypoalbuminemia.|
03764|023|B||
03764|024|M|PATIENT MANAGEMENT:  Efavirenz levels should be monitored if phenytoin is|
03764|025|M|initiated or discontinued or if phenytoin dosage adjustments are made.  The|
03764|026|M|dosage of efavirenz may need to be adjusted.(1,2)|
03764|027|M|   Phenytoin levels should be monitored if efavirenz is initiated or|
03764|028|M|discontinued or if efavirenz dosage adjustments are made.  The dosage of|
03764|029|M|phenytoin may need to be adjusted.(1,2)|
03764|030|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
03764|031|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
03764|032|M|vision, nausea, and vomiting).|
03764|033|M|   The US HIV guidelines state an alternative antiretroviral or|
03764|034|M|anticonvulsant should be considered.  If coadministration is necessary,|
03764|035|M|monitor anticonvulsant and efavirenz concentrations.(4)|
03764|036|B||
03764|037|D|DISCUSSION:  In one case report, an HIV+ patient stable on phenytoin (200 mg|
03764|038|D|twice daily) was started on efavirenz (800 mg once daily) and|
03764|039|D|emtricitabine/tenofovir (200/300 mg once daily).  Efavirenz concentrations|
03764|040|D|at Day 5 and 15 were undetectable.  Efavirenz concentrations increased after|
03764|041|D|increasing the efavirenz dose (600 mg twice daily) and stopping|
03764|042|D|phenytoin.(5)|
03764|043|D|   In another case report, a man stable on phenytoin (300 mg twice daily)|
03764|044|D|was started on efavirenz (600 mg once daily).  One week later efavirenz|
03764|045|D|concentration (340 ng/ml) was found to be below the target concentration of|
03764|046|D|1000 ng/ml.  The phenytoin dosage was rapidly tapered and efavirenz dosage|
03764|047|D|was increased (800 mg once daily).  Eighteen days after initiating|
03764|048|D|efavirenz, the efavirenz concentration was still reduced.  Phenytoin|
03764|049|D|concentrations were also measured while receiving efavirenz (600 mg once|
03764|050|D|daily).  A gradual increase was seen over three weeks (11 mcg/ml to 23.5|
03764|051|D|mcg/ml).(6)|
03764|052|B||
03764|053|R|REFERENCES:|
03764|054|B||
03764|055|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
03764|056|R|  Company November, 2023.|1
03764|057|R|2.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
03764|058|R|  March, 2022.|1
03764|059|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03764|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03764|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03764|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03764|063|R|  11/14/2017.|1
03764|064|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03764|065|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03764|066|R|  HIV. Department of Health and Human Services. Available at|6
03764|067|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03764|068|R|  new-guidelines June 13, 2021.|6
03764|069|R|5.Spak CW, Dhanireddy S, Kosel BW. Clinical interaction between efavirenz|3
03764|070|R|  and phenytoin. AIDS 2008 Jan 2;22(1):164-5.|3
03764|071|R|6.Robertson SM, Penzak SR, Lane J, Pau AK, Mican JM. A potentially|3
03764|072|R|  significant interaction between efavirenz and phenytoin: a case report and|3
03764|073|R|  review of the literature. Clin Infect Dis 2005 Jul 15;41(2):e15-8.|3
03765|001|T|MONOGRAPH TITLE:  Repaglinide/Strong CYP3A4 Inhibitors|
03765|002|B||
03765|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03765|004|L|take action as needed.|
03765|005|B||
03765|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03765|007|A|repaglinide by CYP3A4.(1-3)|
03765|008|B||
03765|009|E|CLINICAL EFFECTS:  Concurrent use of repaglinide and strong CYP3A4|
03765|010|E|inhibitors may result in elevated levels of and effects from repaglinide,|
03765|011|E|including hypoglycemia.|
03765|012|B||
03765|013|P|PREDISPOSING FACTORS:  Concurrent administration with a CYP2C8 inhibitor.|
03765|014|B||
03765|015|M|PATIENT MANAGEMENT:  Patients maintained on repaglinide should be closely|
03765|016|M|monitored if a strong CYP3A4 inhibitor is added to or withdrawn from|
03765|017|M|concurrent therapy.  A dosage adjustment of the antidiabetic agent may be|
03765|018|M|required during therapy with a strong CYP3A4 inhibitor.|
03765|019|B||
03765|020|D|DISCUSSION:  In a study, concurrent administration of itraconazole (100 mg|
03765|021|D|twice daily for 3 days) increased the area-under-curve (AUC) and maximum|
03765|022|D|concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 1.4 fold|
03765|023|D|and 1.5 fold, respectively. Concurrent administration of itraconazole (100|
03765|024|D|mg twice daily for 3 days) and gemfibrozil (600 mg twice daily for 3 days)|
03765|025|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of a|
03765|026|D|single dose of repaglinide (0.25 mg) by 19 fold and 2.8 fold,|
03765|027|D|respectively.(1,5)|
03765|028|D|   In a randomized, double-blind, crossover study in nine healthy subjects,|
03765|029|D|clarithromycin (250 mg daily for 5 days) increased the area-under-curve|
03765|030|D|(AUC) and maximum concentration (Cmax) of a single dose of repaglinide (0.25|
03765|031|D|mg) by 40% and 67%, respectively.  The AUC and Cmax of insulin increased by|
03765|032|D|51% and 61%, respectively.(2)|
03765|033|D|   In a randomized, cross-over study of 12 healthy volunteers, telithromycin|
03765|034|D|(800 mg for 3 days) raised the mean Cmax and AUC of repaglinide (0.25 mg|
03765|035|D|single dose on day 3) to 138% and 177% respectively. Telithromycin did not|
03765|036|D|effect the elimination half-life of repaglinide. Telithromycin increased the|
03765|037|D|urinary excretion of unchanged repaglinide to 229%. The renal clearance of|
03765|038|D|repaglinide was increased by telithromycin to 138%. Telithromycin also|
03765|039|D|lowered the Cmax of blood glucose by 10% and mean concentration of blood|
03765|040|D|glucose by as much as 12% after repaglinide intake.(3)|
03765|041|D|   Severe hypoglycemia has been reported in patients following the addition|
03765|042|D|of clarithromycin to repaglinide therapy.(4)|
03765|043|B||
03765|044|R|REFERENCES:|
03765|045|B||
03765|046|R|1.Prandin (repaglinide) US prescribing information. Novo Nordisk|1
03765|047|R|  Pharmaceuticals, Inc. February 8, 2017.|1
03765|048|R|2.Niemi M, Neuvonen PJ, Kivisto KT. The cytochrome P4503A4 inhibitor|2
03765|049|R|  clarithromycin increases the plasma concentrations and effects of|2
03765|050|R|  repaglinide. Clin Pharmacol Ther 2001 Jul;70(1):58-65.|2
03765|051|R|3.Kajosaari LI, Niemi M, Backman JT, Neuvonen PJ. Telithromycin, but not|2
03765|052|R|  montelukast, increases the plasma concentrations and effects of the|2
03765|053|R|  cytochrome P450 3A4 and 2C8 substrate repaglinide. Clin Pharmacol Ther|2
03765|054|R|  2006 Mar;79(3):231-42.|2
03765|055|R|4.Khamaisi M, Leitersdorf E. Severe hypoglycemia from|3
03765|056|R|  clarithromycin-repaglinide drug interaction. Pharmacotherapy 2008 May;|3
03765|057|R|  28(5):682-4.|3
03765|058|R|5.Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil,|2
03765|059|R|  itraconazole, and their combination on the pharmacokinetics and|2
03765|060|R|  pharmacodynamics of repaglinide: potentially hazardous interaction between|2
03765|061|R|  gemfibrozil and repaglinide. Diabetologia 2003 Mar;46(3):347-51.|2
03766|001|T|MONOGRAPH TITLE:  Dapsone/Rifamycins|
03766|002|B||
03766|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03766|004|L|of severe adverse interaction.|
03766|005|B||
03766|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown but likely involves|
03766|007|A|induction of hepatic enzymes resulting in increased clearance of|
03766|008|A|dapsone.(1-3)|
03766|009|B||
03766|010|E|CLINICAL EFFECTS:  Concurrent use may lead to decreased levels and clinical|
03766|011|E|effects of dapsone when it is used for treatment or prophylaxis of|
03766|012|E|Pneumocystis jiroveci pneumonia (PCP).(1-5)|
03766|013|E|   Since dapsone is extremely potent for treatment of leprosy, this|
03766|014|E|interaction is not clinically relevant in the setting of leprosy.(5)|
03766|015|B||
03766|016|P|PREDISPOSING FACTORS:  None determined.|
03766|017|B||
03766|018|M|PATIENT MANAGEMENT:  The US Department of Health and Human Service|
03766|019|M|guidelines for prevention and treatment of opportunistic infections in|
03766|020|M|patients with HIV recommend avoiding concomitant administration of dapsone|
03766|021|M|with rifamycins if possible and considering use of alternatives to|
03766|022|M|dapsone.(4)|
03766|023|M|   Since dapsone is extremely potent for treatment of leprosy, this|
03766|024|M|interaction is not clinically relevant in the setting of leprosy.(5)|
03766|025|B||
03766|026|D|DISCUSSION:  When given with rifampin, dapsone levels have been found to|
03766|027|D|decrease by 7- to 10-fold.(3,4)  In a trial of 16 HIV-positive patients,|
03766|028|D|rifabutin (300 mg daily) lowered the area-under-curve (AUC) of dapsone (50|
03766|029|D|mg daily) by 27% to 40%.(2,4)|
03766|030|D|   Although dapsone dose adjustment is not necessary when it is used for|
03766|031|D|leprosy, the implications of this interaction when dapsone is used for PCP|
03766|032|D|is unknown.  Mycobacterium leprae is very sensitive to dapsone, with a|
03766|033|D|minimum inhibitory concentration (MIC) of 2.5 to 10 mcg/L.  In contrast, the|
03766|034|D|MIC of dapsone against P. jiroveci is 100 to 10,000 mcg/L.  Dapsone|
03766|035|D|concentrations reached with typical PCP therapy is in the range of 100 to|
03766|036|D|7,000 mcg/L.  Thus, a 10-fold reduction in dapsone levels could result in|
03766|037|D|dapsone levels below the MIC for PCP.(5)|
03766|038|B||
03766|039|R|REFERENCES:|
03766|040|B||
03766|041|R|1.Rifadin (rifampin) US prescribing information. Sanofi-Aventis U.S. LLC|1
03766|042|R|  October, 2024.|1
03766|043|R|2.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
03766|044|R|  2021.|1
03766|045|R|3.Dapsone US prescribing information. Virtus Pharmaceuticals November, 2019.|1
03766|046|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03766|047|R|  for the prevention and treatment of opportunistic infections in adults and|6
03766|048|R|  adolescents with HIV. Department of Health and Human Services. Available|6
03766|049|R|  at|6
03766|050|R|  https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/Adul|6
03766|051|R|  t_OI.pdf Accessed October 26, 2020..|6
03766|052|R|5.Jorde UP, Horowitz HW, Wormser GP. Significance of drug interactions with|6
03766|053|R|  rifampin in Pneumocystis carinii pneumonia  prophylaxis. Arch Intern Med|6
03766|054|R|  1992 Nov;152(11):2348.|6
03767|001|T|MONOGRAPH TITLE:  Indinavir/Proton Pump Inhibitors|
03767|002|B||
03767|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03767|004|L|of severe adverse interaction.|
03767|005|B||
03767|006|A|MECHANISM OF ACTION:  The aqueous solubility of indinavir is pH dependent.|
03767|007|A|Higher gastric pH leads to lower solubility which may reduce indinavir|
03767|008|A|absorption.(1-2)|
03767|009|B||
03767|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors may reduce the|
03767|011|E|bioavailability of indinavir, leading to decreased systemic levels and|
03767|012|E|effectiveness.(1-3)|
03767|013|B||
03767|014|P|PREDISPOSING FACTORS:  None determined.|
03767|015|B||
03767|016|M|PATIENT MANAGEMENT:  Concomitant administration of indinavir and proton pump|
03767|017|M|inhibitors is not recommended unless indinavir is accompanied by ritonavir,|
03767|018|M|typically dosed as indinavir 800 mg twice daily with ritonavir 100 mg twice|
03767|019|M|daily.  Monitor patients receiving concurrent therapy for changes in|
03767|020|M|indinavir effectiveness.(1)|
03767|021|B||
03767|022|D|DISCUSSION:  A retrospective analysis in 9 HIV+ patients found that|
03767|023|D|indinavir administration with omeprazole (20 mg) decreased the maximum|
03767|024|D|concentration (Cmax) of indinavir by 29%. Indinavir administration with|
03767|025|D|omeprazole (40 mg) decreased the Cmax of indinavir by 41%.(1)|
03767|026|D|   In a crossover study in 16 healthy volunteers, concurrent administration|
03767|027|D|of omeprazole (20 mg to 40 mg for 7 days) decreased the indinavir (800 mg|
03767|028|D|single dose) Cmax and area-under-the-curve (AUC) by 29-41% and 34-47%,|
03767|029|D|respectively.(2)|
03767|030|D|   Coadministration of omeprazole (40 mg) and indinavir (800 mg single dose)|
03767|031|D|to 14 HIV+ subjects resulted in a 47% decrease in indinavir AUC and a 55%|
03767|032|D|decrease in minimum concentration (Cmin). The addition of ritonavir (200 mg|
03767|033|D|single dose) reversed the effects of omeprazole.(3)|
03767|034|D|   In a crossover study in 5 healthy volunteers, concurrent administration|
03767|035|D|of indinavir (400 mg single dose) with a proton pump inhibitor resulted in|
03767|036|D|increased gastric pH and a smaller fraction of indinavir being dissolved and|
03767|037|D|lower intestinal concentrations.(4)|
03767|038|D|   In an animal study investigating the solubility of indinavir, solubility|
03767|039|D|of indinavir in aqueous media decreased from more than 100 mg/mL at pH 3 to|
03767|040|D|less than 0.1 mg/mL at pH 5 or above.(5)|
03767|041|B||
03767|042|R|REFERENCES:|
03767|043|B||
03767|044|R|1.Tappouni HL, Rublein JC, Donovan BJ, Hollowell SB, Tien HC, Min SS,|2
03767|045|R|  Theodore D, Rezk NL, Smith PC, Tallman MN, Raasch RH, Kashuba AD. Effect|2
03767|046|R|  of omeprazole on the plasma concentrations of indinavir when administered|2
03767|047|R|  alone and in combination with ritonavir. Am J Health Syst Pharm 2008 Mar|2
03767|048|R|  1;65(5):422-8.|2
03767|049|R|2.Burger DM, Hugen PW, Kroon FP, Groeneveld P, Brinkman K, Foudraine NA,|6
03767|050|R|  Sprenger H, Koopmans PP, Hekster YA. Pharmacokinetic interaction between|6
03767|051|R|  the proton pump inhibitor omeprazole and the HIV protease inhibitor|6
03767|052|R|  indinavir. AIDS 1998 Oct 22;12(15):2080-2.|6
03767|053|R|3.Rublein JC, Donovan BJ, Hollowell SB. Effects of omeprazole on the plasma|4
03767|054|R|  concentrations of indinavir in HIV-negative subjects. 43rd ICAAC 2003 Sep;|4
03767|055|R|  A-1611.|4
03767|056|R|4.Rubbens J, Brouwers J, Tack J, Augustijns P. Gastrointestinal dissolution,|2
03767|057|R|  supersaturation and precipitation of the weak base  indinavir in healthy|2
03767|058|R|  volunteers. Eur J Pharm Biopharm 2016 Dec;109:122-129.|2
03767|059|R|5.Lin JH, Chen IW, Vastag KJ, Ostovic D. pH-dependent oral absorption of|5
03767|060|R|  L-735,524, a potent HIV protease inhibitor, in rats and dogs. Drug Metab|5
03767|061|R|  Dispos 1995 Jul;23(7):730-5.|5
03768|001|T|MONOGRAPH TITLE:  Antibody-Based Therapies/Imlifidase|
03768|002|B||
03768|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03768|004|L|of severe adverse interaction.|
03768|005|B||
03768|006|A|MECHANISM OF ACTION:  Imlifidase is a cysteine protease that cleaves|
03768|007|A|immunoglobulin G (IgG), which results in degradation of all subclasses of|
03768|008|A|human and rabbit IgG.  Therapies based on human or rabbit IgG may be|
03768|009|A|inactivated if given concurrently with imlifidase.(1)|
03768|010|B||
03768|011|E|CLINICAL EFFECTS:  Antibody therapies based on human or rabbit IgG may be|
03768|012|E|inactivated and lead to decreased efficacy.(1)|
03768|013|B||
03768|014|P|PREDISPOSING FACTORS:  None determined.|
03768|015|B||
03768|016|M|PATIENT MANAGEMENT:  Concurrent use of imlifidase and antibody-based|
03768|017|M|therapies should be closely evaluated for timing of administration to avoid|
03768|018|M|decreased efficacy of the antibody-based therapy.(1)|
03768|019|M|   Antibody-based therapies cleaved by imlifidase include, but are not|
03768|020|M|limited to, basiliximab, rituximab, alemtuzumab, adalimumab, denosumab,|
03768|021|M|belatacept, etanercept, rabbit anti-human thymocyte globulin (rATG) and|
03768|022|M|intravenous immunoglobulin (IVIg).|
03768|023|M|   The prescribing information recommends the following time intervals for|
03768|024|M|administration of antibody-based therapies after administration of|
03768|025|M|imlifidase:|
03768|026|M|   -Equine anti-thymocyte globulin: No time interval needed (may be|
03768|027|M|administered concurrently)|
03768|028|M|   -Intravenous immunoglobulin (IVIg): 12 hours|
03768|029|M|   -Adalimumab, alemtuzumab, basiliximab, denosumab, etanercept, or|
03768|030|M|rituximab: 4 days|
03768|031|M|   -Rabbit anti-human thymocyte globulin (rATG) or belatacept: 1 week|
03768|032|M|   In addition, IVIg may contain neutralizing antibodies against imlifidase,|
03768|033|M|which may inactivate imlifidase if IVIg is given before imlifidase.|
03768|034|M|Consider the half-life of IVIg (3-4 weeks) before imlifidase administration|
03768|035|M|to patients treated with IVIg.|
03768|036|M|   Eculizumab is not cleaved by imlifidase at the recommended dose level.(1)|
03768|037|B||
03768|038|D|DISCUSSION:  Imlifidase is a cysteine protease that cleaves IgG, which|
03768|039|D|results in degradation of all subclasses of human and rabbit IgG.  Antibody|
03768|040|D|therapies based on human or rabbit IgG may be inactivated if given in|
03768|041|D|connection with imlifidase.(1)|
03768|042|D|   IVIg may contain neutralizing antibodies against imlifidase, which may|
03768|043|D|inactivate imlifidase if IVIg is given before imlifidase.  In clinical|
03768|044|D|studies, IVIg was not administered within 4 weeks before imlifidase|
03768|045|D|infusion.(1)|
03768|046|B||
03768|047|R|REFERENCE:|
03768|048|B||
03768|049|R|1.Idefirix (imlifidase) UK Summary of Product Characteristics. Hansa|1
03768|050|R|  Biopharma AB August, 2020.|1
03769|001|T|MONOGRAPH TITLE:  Eluxadoline/Anticholinergics; Opioids|
03769|002|B||
03769|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03769|004|L|of severe adverse interaction.|
03769|005|B||
03769|006|A|MECHANISM OF ACTION:  Eluxadoline is a mixed mu-opioid and kappa-opioid|
03769|007|A|agonist and delta-opioid antagonist and may alter or slow down|
03769|008|A|gastrointestinal transit.(1)|
03769|009|B||
03769|010|E|CLINICAL EFFECTS:  Constipation related adverse events that sometimes|
03769|011|E|required hospitalization have been reported, including the development of|
03769|012|E|intestinal obstruction, intestinal perforation, and fecal impaction.(1)|
03769|013|B||
03769|014|P|PREDISPOSING FACTORS:  None determined.|
03769|015|B||
03769|016|M|PATIENT MANAGEMENT:  Avoid use with other drugs that may cause constipation.|
03769|017|M|If concurrent use is necessary, evaluate the patient's bowel function|
03769|018|M|regularly.  Monitor for symptoms of constipation and GI hypomotility,|
03769|019|M|including having bowel movements less than three times weekly or less than|
03769|020|M|usual, difficulty having a bowel movement or passing gas, nausea, vomiting,|
03769|021|M|and abdominal pain or distention.(1)|
03769|022|M|   Instruct patients to stop eluxadoline and immediately contact their|
03769|023|M|healthcare provider if they experience severe constipation.  Loperamide may|
03769|024|M|be used occasionally for acute management of severe diarrhea, but must be|
03769|025|M|discontinued if constipation develops.(1)|
03769|026|B||
03769|027|D|DISCUSSION:  In phase 3 clinical trials, constipation was the most commonly|
03769|028|D|reported adverse reaction (8%).  Approximately 50% of constipation events|
03769|029|D|occurred within the first 2 weeks of treatment while the majority occurred|
03769|030|D|within the first 3 months of therapy. Rates of severe constipation were less|
03769|031|D|than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1)|
03769|032|B||
03769|033|R|REFERENCE:|
03769|034|B||
03769|035|R|1.Viberzi (eluxadoline) US prescribing information. Allergan USA, Inc. June,|1
03769|036|R|  2020.|1
03770|001|T|MONOGRAPH TITLE:  Galantamine/QT Prolonging Agents|
03770|002|B||
03770|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03770|004|L|take action as needed.|
03770|005|B||
03770|006|A|MECHANISM OF ACTION:  Galantamine may reduce heart rate by increasing|
03770|007|A|acetylcholine in the heart and increasing vagal tone.  Bradycardia has been|
03770|008|A|associated with increased risk of QTc interval prolongation.(1)|
03770|009|A|   Concurrent use of galantamine with other agents that prolong the QTc|
03770|010|A|interval may result in additive effects on the QTc interval.(2)|
03770|011|B||
03770|012|E|CLINICAL EFFECTS:  The use of galantamine in patients maintained on agents|
03770|013|E|that prolong the QTc interval may result in potentially life-threatening|
03770|014|E|cardiac arrhythmias, including torsades de pointes.(2)|
03770|015|B||
03770|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03770|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03770|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03770|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03770|020|P|gender, advanced age or when receiving concomitant treatment with an|
03770|021|P|inhibitor of CYP3A4.(3)|
03770|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03770|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03770|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03770|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03770|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03770|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03770|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03770|029|B||
03770|030|M|PATIENT MANAGEMENT:  The UK manufacturer of galantamine states that it|
03770|031|M|should be used with caution in patients treated with drugs that affect the|
03770|032|M|QTc interval.(2)|
03770|033|M|   If concurrent therapy is warranted, monitor ECG more frequently and|
03770|034|M|consider obtaining serum calcium, magnesium, and potassium levels at|
03770|035|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03770|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03770|037|B||
03770|038|D|DISCUSSION:  Therapeutic doses of galantamine have been reported to cause|
03770|039|D|QTc prolongation in patients.(2)|
03770|040|D|   An 85 year old male with dementia was restarted on galantamine 8 mg daily|
03770|041|D|after a 2-week treatment interruption due to a syncopal episode that|
03770|042|D|occurred 3 months previously.  During his prior syncopal episode, he was|
03770|043|D|hypotensive and bradycardic, but QTc interval was normal.  After restarting|
03770|044|D|galantamine, he was found to be hypotension and bradycardiac again, and QTc|
03770|045|D|interval was significantly prolonged to 503 msec, over 60 msec longer than|
03770|046|D|when he was off galantamine.  Galantamine was discontinued and his QTc|
03770|047|D|interval returned to baseline.(4)|
03770|048|D|   A 47 year old schizophrenic male experienced prolongation of the QTc|
03770|049|D|interval to 518 msec after galantamine was increased from 8 mg daily to 12|
03770|050|D|mg daily.  Although he was also on quetiapine and metoprolol, he had been|
03770|051|D|stable on his other medications.  His QTc interval normalized after|
03770|052|D|galantamine was stopped.(5)|
03770|053|D|   The European pharmacovigilance (Eudravigilance) database contains 14|
03770|054|D|reports of torsades de pointe in patients on galantamine as of October|
03770|055|D|2019.(1)|
03770|056|D|   A pharmacovigilance study based on the FDA Adverse Event Reporting System|
03770|057|D|(FAERS) database found that, of a total of 33,626 cases of TdP/QT|
03770|058|D|prolongation reported between January 2004 and September 2022, 54 cases|
03770|059|D|occurred in patients on galantamine.  The disproportionality analysis found|
03770|060|D|a ROR = 5.12, 95% CI (3.92,6.68) and a PRR = 5.11, chi-square = 175.44.(6)|
03770|061|D|   Agents that are linked to this monograph may have varying degrees of|
03770|062|D|potential to prolong the QTc interval but are generally accepted to have a|
03770|063|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03770|064|D|been shown to prolong the QTc interval either through their mechanism of|
03770|065|D|action, through studies on their effects on the QTc interval, or through|
03770|066|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03770|067|D|and/or post-marketing reports.(7)|
03770|068|B||
03770|069|R|REFERENCES:|
03770|070|B||
03770|071|R|1.Malone K, Hancox JC. QT interval prolongation and Torsades de Pointes with|6
03770|072|R|  donepezil, rivastigmine and  galantamine. Ther Adv Drug Saf 2020;|6
03770|073|R|  11:2042098620942416.|6
03770|074|R|2.Reminyl XL (galantamine) UK Summary of Product Characteristics. Shire|1
03770|075|R|  Pharmaceuticals Limited March, 2021.|1
03770|076|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03770|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03770|078|R|  settings: a scientific statement from the American Heart Association and|6
03770|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03770|080|R|  2;55(9):934-47.|6
03770|081|R|4.Fisher AA, Davis MW. Prolonged QT interval, syncope, and delirium with|3
03770|082|R|  galantamine. Ann Pharmacother 2008 Feb;42(2):278-83.|3
03770|083|R|5.Nelson MW, Buchanan RW. Galantamine-induced QTc prolongation. J Clin|3
03770|084|R|  Psychiatry 2006 Jan;67(1):166-7.|3
03770|085|R|6.Zhang N, Gan L, Xiang G, Xu J, Jiang T, Li Y, Wu Y, Ni R, Liu Y.|6
03770|086|R|  Cholinesterase inhibitors-associated torsade de pointes/QT prolongation: a|6
03770|087|R|  real-world pharmacovigilance study. Front Pharmacol 2023;14:1343650.|6
03770|088|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
03770|089|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03770|090|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03770|091|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03771|001|T|MONOGRAPH TITLE:  Pimavanserin (Less Than or Equal To 10 mg)/Strong CYP3A4|
03771|002|T|Inhibitors that Prolong QT|
03771|003|B||
03771|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03771|005|L|of severe adverse interaction.|
03771|006|B||
03771|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03771|008|A|interval may inhibit the metabolism of pimavanserin and result in additive|
03771|009|A|effects on the QTc interval.(1)|
03771|010|B||
03771|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
03771|012|E|the QTc interval may increase systemic exposure and the risk for|
03771|013|E|pimavanserin toxicities such as peripheral edema, confusion, or additive QTc|
03771|014|E|prolongation and life-threatening cardiac arrhythmias like torsades de|
03771|015|E|pointes.(1)|
03771|016|B||
03771|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03771|018|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03771|019|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03771|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03771|021|P|gender, or advanced age.(2)|
03771|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03771|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03771|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03771|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03771|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03771|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03771|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03771|029|B||
03771|030|M|PATIENT MANAGEMENT:  The manufacturer of pimavanserin recommends avoiding|
03771|031|M|use with agents that prolong the QTc interval.(1)  The US Department of|
03771|032|M|Health and Human Services HIV guidelines state that pimavanserin should not|
03771|033|M|be coadministered with saquinavir or lopinavir due to the risk of QTc|
03771|034|M|prolongation.(3)|
03771|035|M|   If concomitant use of pimavanserin and a strong CYP3A4 inhibitor is|
03771|036|M|needed, the pimavanserin dose should be reduced to 10 mg once daily.(1)|
03771|037|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
03771|038|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03771|039|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03771|040|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03771|041|M|irregular heartbeat, dizziness, or fainting.|
03771|042|B||
03771|043|D|DISCUSSION:  In a drug interaction study, ketoconazole increased|
03771|044|D|pimavanserin maximum concentration (Cmax) 1.5-fold and area-under-curve(AUC)|
03771|045|D|3-fold.|
03771|046|D|   A thorough QTc study performed in 252 subjects found a mean maximum|
03771|047|D|change from baseline of 13.5 msec (upper bound of the 90% confidence|
03771|048|D|interval was 16.6 msec) at twice the therapeutic dose.(1) Thus,|
03771|049|D|coadministration of pimavanserin and a QT prolonging agent, even at a|
03771|050|D|reduced dose, may increase the risk for significant QT prolongation.|
03771|051|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
03771|052|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
03771|053|D|posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(4)|
03771|054|B||
03771|055|R|REFERENCES:|
03771|056|B||
03771|057|R|1.Nuplazid (pimavanserin) US prescribing information. ACADIA Pharmaceuticals|1
03771|058|R|  Inc. May, 2019.|1
03771|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03771|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03771|061|R|  settings: a scientific statement from the American Heart Association and|6
03771|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03771|063|R|  2;55(9):934-47.|6
03771|064|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03771|065|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03771|066|R|  HIV. Department of Health and Human Services. Available at:|6
03771|067|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
03771|068|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
03771|069|R|4.This information is based on an extract from the Certara Drug Interaction|6
03771|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03772|001|T|MONOGRAPH TITLE:  Donepezil/Sotalol|
03772|002|B||
03772|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03772|004|L|of severe adverse interaction.|
03772|005|B||
03772|006|A|MECHANISM OF ACTION:  Donepezil inhibits plasma cholinesterases and|
03772|007|A|increases cholinergic activity.  Use of donepezil may have vagotonic effects|
03772|008|A|on heart rate (e.g. bradycardia).  Concurrent use of donepezil and sotalol|
03772|009|A|may have additive effects on bradycardia and result in additive effects on|
03772|010|A|the QTc interval.(1)|
03772|011|B||
03772|012|E|CLINICAL EFFECTS:  Concurrent use of donepezil and sotalol may have additive|
03772|013|E|effects on bradycardia and prolongation of the QTc interval.(1)|
03772|014|B||
03772|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03772|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03772|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03772|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03772|019|P|gender, or advanced age.(2)|
03772|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03772|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03772|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03772|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03772|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03772|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03772|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03772|027|B||
03772|028|M|PATIENT MANAGEMENT:  Concurrent use of donepezil and sotalol is not|
03772|029|M|recommended.  Monitor patients closely if concurrent use is warranted.(1)|
03772|030|M|   During concomitant therapy, monitor patients closely for prolongation of|
03772|031|M|the QT interval.  Obtain serum calcium, magnesium, and potassium levels and|
03772|032|M|monitor ECG at regular intervals.  Correct any electrolyte abnormalities.|
03772|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03772|034|B||
03772|035|D|DISCUSSION:  Concurrent use of anticholinesterases and beta-blockers may|
03772|036|D|have additive effects on cardiac conduction and increase the risk of|
03772|037|D|bradycardia.(1)|
03772|038|D|   A case report of a 65 year old African American female had a witnessed a|
03772|039|D|presyncopal episode followed by a true syncopal episode with concurrent use|
03772|040|D|of rivastigmine and atenolol.  On day 2 of the hospital stay, the patient|
03772|041|D|developed bradycardia with a heart rate in the 40s and sinus pauses greater|
03772|042|D|than 2 seconds.  Atenolol was discontinued yet bradycardia persisted.|
03772|043|D|Following discontinuation of rivastigmine, sinus pauses resolved and heart|
03772|044|D|rate returned to normal.(3)|
03772|045|D|   A population-based cohort study in Ontario, Canada reviewed the|
03772|046|D|relationship between cholinesterase inhibitor use and syncope-related|
03772|047|D|outcomes over a two year period.  Hospital visits for syncope were more|
03772|048|D|frequent in patients receiving cholinesterase inhibitors than controls (31.5|
03772|049|D|vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95%|
03772|050|D|confidence interval (CI) 1.57-1.98).  Other syncope-related events were also|
03772|051|D|more common in patients receiving cholinesterase inhibitors than controls:|
03772|052|D|hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR|
03772|053|D|1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events|
03772|054|D|per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs|
03772|055|D|19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(4)|
03772|056|D|   A population based case-time-control study of 1,009 patients hospitalized|
03772|057|D|for bradycardia within 9 months of using a cholinesterase inhibitor were|
03772|058|D|reviewed for outcomes.  Of these patients, 11% required pacemaker insertion|
03772|059|D|during hospitalization and 4% died prior to discharge.  With adjustment for|
03772|060|D|temporal changes in drug utilization, hospitalization for bradycardia was|
03772|061|D|associated with recent initiation of a cholinesterase inhibitor drug|
03772|062|D|(adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51).  Risk was similar in|
03772|063|D|patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI|
03772|064|D|1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR|
03772|065|D|2.34; 95% CI 1.16-4.71).(5)|
03772|066|D|   A pharmacovigilance study based on the FDA Adverse Event Reporting System|
03772|067|D|(FAERS) database found that, of a total of 33,626 cases of TdP/QT|
03772|068|D|prolongation reported between January 2004 and September 2022, 430 cases|
03772|069|D|occurred in patients on donepezil.  The disproportionality analysis found a|
03772|070|D|ROR = 8.98, 95% CI (8.16, 9.89) and a PRR = 8.88, chi-square = 2944.95.(6)|
03772|071|B||
03772|072|R|REFERENCES:|
03772|073|B||
03772|074|R|1.Aricept (donepezil) US prescribing information. Eisai Inc. July, 2015.|1
03772|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03772|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03772|077|R|  settings: a scientific statement from the American Heart Association and|6
03772|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03772|079|R|  2;55(9):934-47.|6
03772|080|R|3.Paulison B, Leos CL. Potential cardiotoxic reaction involving rivastigmine|3
03772|081|R|  and beta-blockers: a case report and review of the literature. Cardiovasc|3
03772|082|R|  Toxicol 2010 Dec;10(4):306-10.|3
03772|083|R|4.Gill SS, Anderson GM, Fischer HD, Bell CM, Li P, Normand SL, Rochon PA.|2
03772|084|R|  Syncope and its consequences in patients with dementia receiving|2
03772|085|R|  cholinesterase inhibitors: a population-based cohort study. Arch Intern|2
03772|086|R|  Med 2009 May 11;169(9):867-73.|2
03772|087|R|5.Park-Wyllie LY, Mamdani MM, Li P, Gill SS, Laupacis A, Juurlink DN.|2
03772|088|R|  Cholinesterase inhibitors and hospitalization for bradycardia: a|2
03772|089|R|  population-based study. PLoS Med 2009 Sep;6(9):e1000157.|2
03772|090|R|6.Zhang N, Gan L, Xiang G, Xu J, Jiang T, Li Y, Wu Y, Ni R, Liu Y.|6
03772|091|R|  Cholinesterase inhibitors-associated torsade de pointes/QT prolongation: a|6
03772|092|R|  real-world pharmacovigilance study. Front Pharmacol 2023;14:1343650.|6
03773|001|T|MONOGRAPH TITLE:  Galantamine/Sotalol|
03773|002|B||
03773|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03773|004|L|take action as needed.|
03773|005|B||
03773|006|A|MECHANISM OF ACTION:  Galantamine inhibits plasma cholinesterases and|
03773|007|A|increases cholinergic activity.  Use of galantamine may have vagotonic|
03773|008|A|effects on heart rate (e.g. bradycardia).  Concurrent use of galantamine and|
03773|009|A|sotalol may have additive effects on bradycardia and result in additive|
03773|010|A|effects on the QTc interval.(1)|
03773|011|B||
03773|012|E|CLINICAL EFFECTS:  Concurrent use of galantamine and sotalol may have|
03773|013|E|additive effects on bradycardia and prolongation of the QTc interval.(1)|
03773|014|B||
03773|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03773|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03773|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03773|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03773|019|P|gender, or advanced age.(2)|
03773|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03773|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03773|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03773|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03773|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03773|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03773|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03773|027|B||
03773|028|M|PATIENT MANAGEMENT:  Concurrent use of galantamine and sotalol is not|
03773|029|M|recommended.  Monitor patients closely if concurrent use is warranted.(1)|
03773|030|M|   During concomitant therapy, monitor patients closely for prolongation of|
03773|031|M|the QT interval.  Obtain serum calcium, magnesium, and potassium levels and|
03773|032|M|monitor ECG at regular intervals.  Correct any electrolyte abnormalities.|
03773|033|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03773|034|B||
03773|035|D|DISCUSSION:  Concurrent use of anticholinesterases and beta-blockers may|
03773|036|D|have additive effects on cardiac conduction and increase the risk of|
03773|037|D|bradycardia.(1)|
03773|038|D|   A case report of a 65 year old African American female had a witnessed a|
03773|039|D|presyncopal episode followed by a true syncopal episode with concurrent use|
03773|040|D|of rivastigmine and atenolol.  On day 2 of the hospital stay, the patient|
03773|041|D|developed bradycardia with a heart rate in the 40s and sinus pauses greater|
03773|042|D|than 2 seconds.  Atenolol was discontinued yet bradycardia persisted.|
03773|043|D|Following discontinuation of rivastigmine, sinus pauses resolved and heart|
03773|044|D|rate returned to normal.(3)|
03773|045|D|   A population-based cohort study in Ontario, Canada reviewed the|
03773|046|D|relationship between cholinesterase inhibitor use and syncope-related|
03773|047|D|outcomes over a two year period.  Hospital visits for syncope were more|
03773|048|D|frequent in patients receiving cholinesterase inhibitors than controls (31.5|
03773|049|D|vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95%|
03773|050|D|confidence interval (CI) 1.57-1.98).  Other syncope-related events were also|
03773|051|D|more common in patients receiving cholinesterase inhibitors than controls:|
03773|052|D|hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR|
03773|053|D|1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events|
03773|054|D|per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs|
03773|055|D|19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(4)|
03773|056|D|   A population based case-time-control study of 1,009 patients hospitalized|
03773|057|D|for bradycardia within 9 months of using a cholinesterase inhibitor were|
03773|058|D|reviewed for outcomes.  Of these patients, 11% required pacemaker insertion|
03773|059|D|during hospitalization and 4% died prior to discharge.  With adjustment for|
03773|060|D|temporal changes in drug utilization, hospitalization for bradycardia was|
03773|061|D|associated with recent initiation of a cholinesterase inhibitor drug|
03773|062|D|(adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51).  Risk was similar in|
03773|063|D|patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI|
03773|064|D|1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR|
03773|065|D|2.34; 95% CI 1.16-4.71).(5)|
03773|066|D|   A pharmacovigilance study based on the FDA Adverse Event Reporting System|
03773|067|D|(FAERS) database found that, of a total of 33,626 cases of TdP/QT|
03773|068|D|prolongation reported between January 2004 and September 2022, 54 cases|
03773|069|D|occurred in patients on galantamine.  The disproportionality analysis found|
03773|070|D|a ROR = 5.12, 95% CI (3.92,6.68) and a PRR = 5.11, chi-square = 175.44.(6)|
03773|071|B||
03773|072|R|REFERENCES:|
03773|073|B||
03773|074|R|1.Razadyne (galantamine) US prescribing information. Janssen|1
03773|075|R|  Pharmaceuticals, Inc. September, 2016.|1
03773|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03773|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03773|078|R|  settings: a scientific statement from the American Heart Association and|6
03773|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03773|080|R|  2;55(9):934-47.|6
03773|081|R|3.Paulison B, Leos CL. Potential cardiotoxic reaction involving rivastigmine|3
03773|082|R|  and beta-blockers: a case report and review of the literature. Cardiovasc|3
03773|083|R|  Toxicol 2010 Dec;10(4):306-10.|3
03773|084|R|4.Gill SS, Anderson GM, Fischer HD, Bell CM, Li P, Normand SL, Rochon PA.|2
03773|085|R|  Syncope and its consequences in patients with dementia receiving|2
03773|086|R|  cholinesterase inhibitors: a population-based cohort study. Arch Intern|2
03773|087|R|  Med 2009 May 11;169(9):867-73.|2
03773|088|R|5.Park-Wyllie LY, Mamdani MM, Li P, Gill SS, Laupacis A, Juurlink DN.|2
03773|089|R|  Cholinesterase inhibitors and hospitalization for bradycardia: a|2
03773|090|R|  population-based study. PLoS Med 2009 Sep;6(9):e1000157.|2
03773|091|R|6.Zhang N, Gan L, Xiang G, Xu J, Jiang T, Li Y, Wu Y, Ni R, Liu Y.|6
03773|092|R|  Cholinesterase inhibitors-associated torsade de pointes/QT prolongation: a|6
03773|093|R|  real-world pharmacovigilance study. Front Pharmacol 2023;14:1343650.|6
03774|001|T|MONOGRAPH TITLE:  Donepezil; Galantamine/Beta-Blockers|
03774|002|B||
03774|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03774|004|L|take action as needed.|
03774|005|B||
03774|006|A|MECHANISM OF ACTION:  Anticholinesterases like donepezil and galantamine|
03774|007|A|inhibit plasma cholinesterases and increase cholinergic activity.  Use of|
03774|008|A|anticholinesterases may have vagotonic effects on heart rate (e.g.|
03774|009|A|bradycardia).  Concurrent use of anticholinesterases and beta-blockers may|
03774|010|A|have additive effects on bradycardia.(1,2)|
03774|011|B||
03774|012|E|CLINICAL EFFECTS:  Concurrent use of donepezil or galantamine with|
03774|013|E|beta-blockers may have additive effects on bradycardia.(1,2)|
03774|014|B||
03774|015|P|PREDISPOSING FACTORS:  None determined.|
03774|016|B||
03774|017|M|PATIENT MANAGEMENT:  Concurrent use of anticholinesterases like donepezil or|
03774|018|M|galantamine with beta-blockers is not recommended.  Additive effects may be|
03774|019|M|increased with cardioselective beta-blockers (e.g. atenolol).  Monitor|
03774|020|M|patients closely if concurrent use is warranted.(1,2)|
03774|021|B||
03774|022|D|DISCUSSION:  Concurrent use of anticholinesterases and beta-blockers may|
03774|023|D|have additive effects on cardiac conduction and increase the risk of|
03774|024|D|bradycardia.(1,2)|
03774|025|D|   A case report of a 65 year old African American female had a witnessed a|
03774|026|D|presyncopal episode followed by a true syncopal episode with concurrent use|
03774|027|D|of rivastigmine and atenolol.  On day 2 of the hospital stay, the patient|
03774|028|D|developed bradycardia with a heart rate in the 40s and sinus pauses greater|
03774|029|D|than 2 seconds.  Atenolol was discontinued yet bradycardia persisted.|
03774|030|D|Following discontinuation of rivastigmine, sinus pauses resolved and heart|
03774|031|D|rate returned to normal.(3)|
03774|032|D|   A population-based cohort study in Ontario, Canada reviewed the|
03774|033|D|relationship between cholinesterase inhibitor use and syncope-related|
03774|034|D|outcomes over a two year period.  Hospital visits for syncope were more|
03774|035|D|frequent in patients receiving cholinesterase inhibitors than controls (31.5|
03774|036|D|vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95%|
03774|037|D|confidence interval (CI) 1.57-1.98).  Other syncope-related events were also|
03774|038|D|more common in patients receiving cholinesterase inhibitors than controls:|
03774|039|D|hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR|
03774|040|D|1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events|
03774|041|D|per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs|
03774|042|D|19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(4)|
03774|043|D|   A population based case-time-control study of 1,009 patients hospitalized|
03774|044|D|for bradycardia within 9 months of using a cholinesterase inhibitor were|
03774|045|D|reviewed for outcomes.  Of these patients, 11% required pacemaker insertion|
03774|046|D|during hospitalization and 4% died prior to discharge.  With adjustment for|
03774|047|D|temporal changes in drug utilization, hospitalization for bradycardia was|
03774|048|D|associated with recent initiation of a cholinesterase inhibitor drug|
03774|049|D|(adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51).  Risk was similar in|
03774|050|D|patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI|
03774|051|D|1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR|
03774|052|D|2.34; 95% CI 1.16-4.71).(5)|
03774|053|B||
03774|054|R|REFERENCES:|
03774|055|B||
03774|056|R|1.Aricept (donepezil) US prescribing information. Eisai Inc. July, 2015.|1
03774|057|R|2.Razadyne (galantamine) US prescribing information. Janssen|1
03774|058|R|  Pharmaceuticals, Inc. September, 2016.|1
03774|059|R|3.Paulison B, Leos CL. Potential cardiotoxic reaction involving rivastigmine|3
03774|060|R|  and beta-blockers: a case report and review of the literature. Cardiovasc|3
03774|061|R|  Toxicol 2010 Dec;10(4):306-10.|3
03774|062|R|4.Gill SS, Anderson GM, Fischer HD, Bell CM, Li P, Normand SL, Rochon PA.|2
03774|063|R|  Syncope and its consequences in patients with dementia receiving|2
03774|064|R|  cholinesterase inhibitors: a population-based cohort study. Arch Intern|2
03774|065|R|  Med 2009 May 11;169(9):867-73.|2
03774|066|R|5.Park-Wyllie LY, Mamdani MM, Li P, Gill SS, Laupacis A, Juurlink DN.|2
03774|067|R|  Cholinesterase inhibitors and hospitalization for bradycardia: a|2
03774|068|R|  population-based study. PLoS Med 2009 Sep;6(9):e1000157.|2
03775|001|T|MONOGRAPH TITLE:  Intramuscular Rilpivirine/Rifabutin|
03775|002|B||
03775|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03775|004|L|is contraindicated and generally should not be dispensed or administered to|
03775|005|L|the same patient.|
03775|006|B||
03775|007|A|MECHANISM OF ACTION:  Rifabutin may induce the metabolism of rilpivirine by|
03775|008|A|CYP3A4.(1)|
03775|009|B||
03775|010|E|CLINICAL EFFECTS:  Concurrent or recent use of rifabutin may result in|
03775|011|E|decreased levels and effectiveness of rilpivirine, as well as the|
03775|012|E|development of resistance.(1)|
03775|013|B||
03775|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03775|015|P|of the inducer for longer than 1-2 weeks.|
03775|016|B||
03775|017|M|PATIENT MANAGEMENT:  The Swedish manufacturer of intramuscular rilpivirine|
03775|018|M|states that concurrent use of rifabutin is contraindicated.(1)|
03775|019|M|   It may take several weeks after the discontinuation of an enzyme inducer|
03775|020|M|for enzyme activity to return to normal.(1)|
03775|021|B||
03775|022|D|DISCUSSION:  Coadministration of rifabutin (300 mg once daily) with|
03775|023|D|rilpivirine (25 mg once daily) decreased rilpivirine's area-under-the-curve|
03775|024|D|(AUC), minimum concentration (Cmin), and maximum concentration (Cmax) by|
03775|025|D|42%, 48%, and 31%.(1)|
03775|026|D|   Coadministration of rifabutin (300 mg once daily) with rilpivirine (50 mg|
03775|027|D|once daily) increased rilpivirine's AUC and Cmax by 16% and 43%.(1)|
03775|028|B||
03775|029|R|REFERENCES:|
03775|030|B||
03775|031|R|1.Rekambys (rilpivirine) Sweden Prescribing Information. Janssen Cilag|1
03775|032|R|  International NV April 2021.|1
03775|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
03775|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03776|001|T|MONOGRAPH TITLE:  Lorlatinib/Fluconazole|
03776|002|B||
03776|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03776|004|L|of severe adverse interaction.|
03776|005|B||
03776|006|A|MECHANISM OF ACTION:  Lorlatinib is metabolized primarily by CYP3A4 and|
03776|007|A|UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3, in|
03776|008|A|vitro.(1)  Fluconazole is a strong CYP2C19 inhibitor and a moderate CYP3A4|
03776|009|A|inhibitor.(2)|
03776|010|B||
03776|011|E|CLINICAL EFFECTS:  Concurrent use of fluconazole may result in elevated|
03776|012|E|levels and increased effects of lorlatinib.(1)|
03776|013|B||
03776|014|P|PREDISPOSING FACTORS:  None determined.|
03776|015|B||
03776|016|M|PATIENT MANAGEMENT:  The manufacturer of lorlatinib states that concurrent|
03776|017|M|use of fluconazole should be avoided.  If concurrent use cannot be avoided,|
03776|018|M|reduce the dose of lorlatinib from 100 mg once daily to 75 mg once daily.(1)|
03776|019|B||
03776|020|D|DISCUSSION:  A pharmacokinetic model predicted that coadministration of|
03776|021|D|fluconazole 200 mg once daily with lorlatinib 100 mg once daily increased|
03776|022|D|the area-under-curve (AUC) and maximum concentration (Cmax) of lorlatinib by|
03776|023|D|approximately 59% and 28%, respectively.(1)|
03776|024|B||
03776|025|R|REFERENCES:|
03776|026|B||
03776|027|R|1.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
03776|028|R|2.This information is based on an extract from the Certara Drug Interaction|6
03776|029|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03776|030|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03776|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03776|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03776|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03776|034|R|  11/14/2017.|1
03777|001|T|MONOGRAPH TITLE:  Ivosidenib/Crizotinib|
03777|002|B||
03777|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03777|004|L|of severe adverse interaction.|
03777|005|B||
03777|006|A|MECHANISM OF ACTION:  Moderate inhibitors of the CYP3A4 enzyme may inhibit|
03777|007|A|the metabolism of ivosidenib.(1)  Crizotinib is a moderate CYP3A4|
03777|008|A|inhibitor.(2)|
03777|009|A|   Ivosidenib, a strong CYP3A4 inducer(2), may induce the CYP3A4 isoenzyme|
03777|010|A|and increase the metabolism of crizotinib.(3)|
03777|011|A|   Concurrent use of crizotinib and ivosidenib may result in additive|
03777|012|A|effects on the QTc interval.|
03777|013|B||
03777|014|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
03777|015|E|systemic exposure and the risk for ivosidenib toxicities such as QT|
03777|016|E|prolongation.(1)|
03777|017|E|   Concurrent use of crizotinib with ivosidenib may decrease the levels and|
03777|018|E|effectiveness of crizotinib and may cause additive effects on the QTc|
03777|019|E|interval, which may result in life-threatening cardiac arrhythmias including|
03777|020|E|torsades de pointes.(3)|
03777|021|B||
03777|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03777|023|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03777|024|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03777|025|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03777|026|P|gender, or advanced age.(4)|
03777|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03777|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03777|029|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03777|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03777|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03777|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03777|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03777|034|B||
03777|035|M|PATIENT MANAGEMENT:  The US manufacturer of ivosidenib recommends|
03777|036|M|considering an alternative concomitant medication with less potential for|
03777|037|M|CYP3A4 inhibition.(1)|
03777|038|M|   The US manufacturer of crizotinib states to avoid the concurrent use of|
03777|039|M|strong CYP3A4 inducers, including ivosidenib, in patients receiving therapy|
03777|040|M|with crizotinib.  Consider the use of alternative agents with less enzyme|
03777|041|M|induction potential and less potential to affect the QTc interval.(3)|
03777|042|M|   In patients who develop a QTc greater than 500 ms on at least 2 separate|
03777|043|M|ECGs, withhold crizotinib until recovery to baseline or to a QTc less than|
03777|044|M|481 ms, then resume crizotinib at reduced dose.(3)|
03777|045|M|   In patients who develop a QTc greater than 500 ms or greater than or|
03777|046|M|equal to 60 ms change from baseline with Torsade de pointes or polymorphic|
03777|047|M|ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently|
03777|048|M|discontinue crizotinib.(3)|
03777|049|M|   If concomitant therapy is warranted, monitor patients closely for|
03777|050|M|prolongation of the QT interval.  Obtain serum calcium, magnesium, and|
03777|051|M|potassium levels and monitor ECG at regular intervals.  Correct any|
03777|052|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03777|053|M|heartbeat, dizziness, or fainting.|
03777|054|B||
03777|055|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
03777|056|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
03777|057|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
03777|058|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
03777|059|D|(Cmax).(1)|
03777|060|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
03777|061|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
03777|062|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
03777|063|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
03777|064|D|190%, respectively.(1)|
03777|065|D|   Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the maximum|
03777|066|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
03777|067|D|crizotinib (250 mg) by 69% and 82%, respectively.(3)|
03777|068|D|   Crizotinib is associated with concentration-dependent QTc interval|
03777|069|D|prolongation.  In a clinical trial 2.1% of patients were found to have a|
03777|070|D|QTcF greater than or equal to 500 msec and 5% of patients had an increase in|
03777|071|D|QTcF by greater than or equal to 60 msec.(3)|
03777|072|D|   A retrospective review of 618 cancer patients treated with 902|
03777|073|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
03777|074|D|incidence of QTc prolongation.  In patients who received crizotinib, QTc|
03777|075|D|prolongation was identified in 1 (50%) with 1 (100%) having Grade 1 (QTc|
03777|076|D|450-480 ms).  No patients had a QTc change greater than or equal to 60 ms,|
03777|077|D|ventricular tachycardia, sudden cardiac death, or TdP.(5)|
03777|078|B||
03777|079|R|REFERENCES:|
03777|080|B||
03777|081|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03777|082|R|  Inc. August, 2021.|1
03777|083|R|2.This information is based on an extract from the Certara Drug Interaction|6
03777|084|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03777|085|R|3.Xalkori (crizotinib) UK Summary of Product Characteristics. Pfizer Limited|1
03777|086|R|  July, 2021.|1
03777|087|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03777|088|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03777|089|R|  settings: a scientific statement from the American Heart Association and|6
03777|090|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03777|091|R|  2;55(9):934-47.|6
03777|092|R|5.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
03777|093|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
03777|094|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
03778|001|T|MONOGRAPH TITLE:  Encorafenib/Ivosidenib|
03778|002|B||
03778|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03778|004|L|of severe adverse interaction.|
03778|005|B||
03778|006|A|MECHANISM OF ACTION:  Encorafenib and ivosidenib are both inducers and|
03778|007|A|substrates of CYP3A4. Concurrent use may increase the metabolism of both|
03778|008|A|drugs.(1-4)|
03778|009|A|   Encorafenib and ivosidenib both prolong the QTc interval.  Concomitant|
03778|010|A|use may result in additive effects on the QTc interval.(1,2)|
03778|011|B||
03778|012|E|CLINICAL EFFECTS:  Concurrent use of encorafenib and ivosidenib may decrease|
03778|013|E|the levels and effectiveness of both drugs and cause additive effects on the|
03778|014|E|QTc interval, which may result in life-threatening cardiac arrhythmias,|
03778|015|E|including torsades de pointes.(1,2)|
03778|016|B||
03778|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03778|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03778|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03778|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03778|021|P|female gender, or advanced age.(5)|
03778|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03778|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03778|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03778|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03778|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03778|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03778|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03778|029|P|   Induction effects may be more likely with regular use of the inducer for|
03778|030|P|longer than 1-2 weeks.|
03778|031|B||
03778|032|M|PATIENT MANAGEMENT:  Avoid the concurrent use of encorafenib with|
03778|033|M|ivosidenib.(1,2)|
03778|034|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03778|035|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03778|036|M|treatment, after initiation of any drug known to prolong the QT interval,|
03778|037|M|and periodically monitor during therapy.  Correct any electrolyte|
03778|038|M|abnormalities.|
03778|039|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03778|040|M|fainting.(2)|
03778|041|B||
03778|042|D|DISCUSSION:  No interaction studies have been conducted between encorafenib|
03778|043|D|and ivosidenib.|
03778|044|D|   The effect of a strong CYP3A4 inducer on encorafenib exposure has not|
03778|045|D|been studied.  Repeat dose administration of encorafenib and binimetinib|
03778|046|D|with modafinil, a moderate CYP3A4 inducer, decreased encorafenib|
03778|047|D|steady-state area-under-curve (AUC) by 24% and maximum concentration (Cmax)|
03778|048|D|by 20%, compared to encorafenib alone.  Repeat dose administration of|
03778|049|D|encorafenib and binimetinib with a single dose of midazolam, a sensitive|
03778|050|D|CYP3A4 substrate, decreased midazolam AUC by 82% and Cmax by 74% relative to|
03778|051|D|midazolam 2 mg alone.(1)|
03778|052|D|   Encorafenib has been associated with a dose-dependent QTc interval|
03778|053|D|prolongation.  Following administration of encorafenib in combination with|
03778|054|D|binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms|
03778|055|D|(14-22 ms), based on central tendency analysis.(1)|
03778|056|D|   Co-administration of ivosidenib with a strong CYP3A4 inducer (600 mg|
03778|057|D|rifampin once daily for 15 days) is predicted to decrease ivosidenib|
03778|058|D|steady-state AUC by 33%.(2)|
03778|059|D|   In a PBPK model, ivosidenib 500 mg for 15 days was predicted to decrease|
03778|060|D|the AUC and Cmax of midazolam 5 mg by 82% and 73%, respectively.(6)|
03778|061|D|   In clinical trials of ivosidenib, 9% of patients experienced a QTc|
03778|062|D|interval greater than 500 msec and 14% of patients had an increased from|
03778|063|D|baseline QTc interval of greater than 60 msec.  Patients with a baseline QTc|
03778|064|D|of equal to or greater than 450 msec without pre-existing bundle branch|
03778|065|D|block, or with a history of long QT syndrome were excluded from this|
03778|066|D|trial.(2)|
03778|067|B||
03778|068|R|REFERENCES:|
03778|069|B||
03778|070|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
03778|071|R|  BioPharma December, 2024.|1
03778|072|R|2.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03778|073|R|  Inc. August, 2021.|1
03778|074|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03778|075|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03778|076|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03778|077|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03778|078|R|  11/14/2017.|1
03778|079|R|4.This information is based on an extract from the Certara Drug Interaction|6
03778|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03778|081|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03778|082|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03778|083|R|  settings: a scientific statement from the American Heart Association and|6
03778|084|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03778|085|R|  2;55(9):934-47.|6
03778|086|R|6.Bolleddula J, Ke A, Yang H, Prakash C. PBPK modeling to predict drug-drug|2
03778|087|R|  interactions of ivosidenib as a perpetrator in  cancer patients and|2
03778|088|R|  qualification of the Simcyp platform for CYP3A4 induction. CPT|2
03778|089|R|  Pharmacometrics Syst Pharmacol 2021 Jun;10(6):577-588.|2
03779|001|T|MONOGRAPH TITLE:  Glasdegib/Strong and Moderate CYP3A4 Inducers that Prolong|
03779|002|T|QT|
03779|003|B||
03779|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03779|005|L|of severe adverse interaction.|
03779|006|B||
03779|007|A|MECHANISM OF ACTION:  Glasdegib is a substrate of CYP3A4.  Strong and|
03779|008|A|moderate inducers of CYP3A4 that prolong the QTc interval may induce the|
03779|009|A|metabolism of glasdegib and result in additive risk of QT prolongation.(1)|
03779|010|B||
03779|011|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
03779|012|E|that prolongs QT may result in decreased levels and effectiveness of|
03779|013|E|glasdegib and may cause additive effects on the QTc interval, which may|
03779|014|E|result in life-threatening cardiac arrhythmias including torsades de|
03779|015|E|pointes.(1)|
03779|016|B||
03779|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03779|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03779|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03779|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03779|021|P|female gender, or advanced age.(2)|
03779|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03779|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03779|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03779|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03779|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03779|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03779|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03779|029|P|   Induction effects may be more likely with regular use of the inducer for|
03779|030|P|longer than 1-2 weeks.|
03779|031|B||
03779|032|M|PATIENT MANAGEMENT:  The manufacturer of glasdegib states to avoid|
03779|033|M|concurrent administration with strong or moderate CYP3A4 inducers.  If|
03779|034|M|concurrent use with a moderate CYP3A4 inducer cannot be avoided, increase|
03779|035|M|the daily dose of glasdegib as tolerated as follows:|
03779|036|M|   - If current dose of glasdegib is 100 mg once daily, increase to 200 mg|
03779|037|M|once daily|
03779|038|M|   - If current dose of glasdegib is 50 mg once daily, increase to 100 mg|
03779|039|M|once daily|
03779|040|M|   After the moderate CYP3A4 inducer has been discontinued for 7 days,|
03779|041|M|resume the glasdegib dose that was tolerated prior to initiation of the|
03779|042|M|inducer.(1)|
03779|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03779|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03779|045|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03779|046|M|patients to report any irregular heartbeat, dizziness, or fainting.(2)|
03779|047|B||
03779|048|D|DISCUSSION:  A population-based pharmacokinetic model predicts that|
03779|049|D|efavirenz would decrease glasdegib area-under-curve (AUC) by 55% and maximum|
03779|050|D|concentration (Cmax) by 25%.(1)|
03779|051|D|   Strong and moderate CYP3A4 inducers that prolong QT linked to this|
03779|052|D|monograph include: efavirenz, encorafenib, ivosidenib, pacritinib, and|
03779|053|D|thioridazine.(3,4)|
03779|054|B||
03779|055|R|REFERENCES:|
03779|056|B||
03779|057|R|1.Daurismo (glasdegib) US prescribing information. Pfizer Inc. March, 2020.|1
03779|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03779|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03779|060|R|  settings: a scientific statement from the American Heart Association and|6
03779|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03779|062|R|  2;55(9):934-47.|6
03779|063|R|3.This information is based on an extract from the Certara Drug Interaction|6
03779|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03779|065|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03779|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03779|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03779|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03779|069|R|  11/14/2017.|1
03780|001|T|MONOGRAPH TITLE:  Entrectinib/Strong and Moderate CYP3A4 Inducers that|
03780|002|T|Prolong QT|
03780|003|B||
03780|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03780|005|L|of severe adverse interaction.|
03780|006|B||
03780|007|A|MECHANISM OF ACTION:  Entrectinib is a substrate of CYP3A4.  Strong and|
03780|008|A|moderate inducers of CYP3A4 that prolong QT may induce the metabolism of|
03780|009|A|entrectinib and result in additive risk of QT prolongation.(1,2)|
03780|010|B||
03780|011|E|CLINICAL EFFECTS:  The concurrent administration of a strong or moderate|
03780|012|E|CYP3A4 inducer that prolongs QT may result in decreased levels and|
03780|013|E|effectiveness of entrectinib and may cause additive effects on the QTc|
03780|014|E|interval, which may result in life-threatening cardiac arrhythmias including|
03780|015|E|torsades de points.(1,2)|
03780|016|B||
03780|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03780|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03780|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03780|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03780|021|P|female gender, or advanced age.(2)|
03780|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03780|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03780|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03780|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03780|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03780|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03780|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03780|029|P|   Induction effects may be more likely with regular use of the inducer for|
03780|030|P|longer than 1-2 weeks.|
03780|031|B||
03780|032|M|PATIENT MANAGEMENT:  The manufacturer of entrectinib states that concurrent|
03780|033|M|use with strong or moderate CYP3A4 inducers should be avoided.(1)|
03780|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03780|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03780|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03780|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03780|038|B||
03780|039|D|DISCUSSION:  Concomitant administration of rifampin (strong CYP3A4 inducer)|
03780|040|D|with a single 600 mg entrectinib dose decreased entrectinib maximum|
03780|041|D|concentration (Cmax) and area-under-the-curve (AUC) by 56% and 77%.(1)|
03780|042|D|   Coadministration with a moderate CYP3A4 inducer is predicted to decrease|
03780|043|D|entrectinib's AUC and Cmax by 56% and 43%.(1)|
03780|044|D|   Strong and moderate inducers of CYP3A4 that prolong QT include:|
03780|045|D|efavirenz, encorafenib, ivosidenib, pacritinib, and thioridazine.(3,4)|
03780|046|B||
03780|047|R|REFERENCES:|
03780|048|B||
03780|049|R|1.Rozlytrek (entrectinib) US prescribing information. Genentech USA, Inc|1
03780|050|R|  October 2023.|1
03780|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03780|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03780|053|R|  settings: a scientific statement from the American Heart Association and|6
03780|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03780|055|R|  2;55(9):934-47.|6
03780|056|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03780|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03780|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03780|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03780|060|R|  11/14/2017.|1
03780|061|R|4.This information is based on an extract from the Certara Drug Interaction|6
03780|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03781|001|T|MONOGRAPH TITLE:  Intravenous and Oral Lefamulin/Moderate CYP3A4 Inducers|
03781|002|T|that Prolong QT|
03781|003|B||
03781|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03781|005|L|of severe adverse interaction.|
03781|006|B||
03781|007|A|MECHANISM OF ACTION:  Lefamulin is a substrate of CYP3A4.  Moderate CYP3A4|
03781|008|A|inducers that prolong the QTc interval may result in additive risk of QT|
03781|009|A|prolongation.(1,2)|
03781|010|B||
03781|011|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
03781|012|E|inducer that prolongs QT may result in decreased levels and effectiveness of|
03781|013|E|lefamulin and may cause additive effects on the QTc interval, which may|
03781|014|E|result in life-threatening cardiac arrhythmias including torsades de|
03781|015|E|pointes.(1,2)|
03781|016|B||
03781|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03781|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03781|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03781|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03781|021|P|female gender, or advanced age.(2)|
03781|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03781|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03781|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03781|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03781|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03781|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03781|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03781|029|P|   Induction effects may be more likely with regular use of the inducer for|
03781|030|P|longer than 1-2 weeks.|
03781|031|B||
03781|032|M|PATIENT MANAGEMENT:  The manufacturer of lefamulin states that concurrent|
03781|033|M|use with moderate CYP3A4 inducers should be avoided.(1)|
03781|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03781|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03781|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03781|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03781|038|B||
03781|039|D|DISCUSSION:  In a study, concurrent administration of rifampin (strong|
03781|040|D|inducer) with lefamulin injection decreased lefamulin area-under-the-curve|
03781|041|D|(AUC) and maximum concentration (Cmax) by 28% and 8%.(1)|
03781|042|D|   In a study, concurrent administration of rifampin (strong inducer) with|
03781|043|D|oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1)|
03781|044|D|   Moderate inducers of CYP3A4 that prolong QT include:  efavirenz and|
03781|045|D|thioridazine.(3,4)|
03781|046|B||
03781|047|R|REFERENCES:|
03781|048|B||
03781|049|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03781|050|R|  Inc August 2019.|1
03781|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03781|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03781|053|R|  settings: a scientific statement from the American Heart Association and|6
03781|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03781|055|R|  2;55(9):934-47.|6
03781|056|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03781|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03781|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03781|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03781|060|R|  11/14/2017.|1
03781|061|R|4.This information is based on an extract from the Certara Drug Interaction|6
03781|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03782|001|T|MONOGRAPH TITLE:  Selpercatinib/Strong and Moderate CYP3A4 Inducers that|
03782|002|T|Prolong QT|
03782|003|B||
03782|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03782|005|L|of severe adverse interaction.|
03782|006|B||
03782|007|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03782|008|A|metabolism of selpercatinib.(1)|
03782|009|A|   Selpercatinib prolongs the QTc interval.(1)  Some CYP3A4 inducers (e.g.,|
03782|010|A|efavirenz, encorafenib, ivosidenib, thioridazine) can also prolong the QTc|
03782|011|A|interval.(2)|
03782|012|B||
03782|013|E|CLINICAL EFFECTS:  Coadministration of selpercatinib with a strong or|
03782|014|E|moderate CYP3A4 inducer decreases selpercatinib plasma concentrations, which|
03782|015|E|may decrease the efficacy of selpercatinib.(1)|
03782|016|E|   It is unknown how decreased levels of selpercatinib affects the risk of|
03782|017|E|QTc interval prolongation when selpercatinib is used concurrently with QT|
03782|018|E|prolonging CYP3A4 inducers.  The concurrent use of selpercatinib with other|
03782|019|E|QT prolonging agents may result in potentially life-threatening cardiac|
03782|020|E|arrhythmias, including torsades de pointes.(1,2)|
03782|021|B||
03782|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03782|023|P|may be increased in patients with cardiovascular disease (e.g. heart|
03782|024|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03782|025|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03782|026|P|female gender, or advanced age.(3)|
03782|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03782|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03782|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03782|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03782|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03782|032|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03782|033|P|dysfunction).(3)|
03782|034|P|   Induction effects may be more likely with regular use of the inducer for|
03782|035|P|longer than 1-2 weeks.|
03782|036|B||
03782|037|M|PATIENT MANAGEMENT:  The manufacturer of selpercatinib states that|
03782|038|M|concurrent use with strong and moderate CYP3A4 inducers should be|
03782|039|M|avoided.(1)|
03782|040|M|   When concurrent therapy with QT prolonging CYP3A4 inducers is warranted,|
03782|041|M|consider obtaining serum calcium, magnesium, and potassium levels and|
03782|042|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03782|043|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03782|044|M|heartbeat, dizziness, or fainting.(3)|
03782|045|B||
03782|046|D|DISCUSSION:  In a study, multiple doses of rifampin (a strong CYP3A inducer)|
03782|047|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03782|048|D|selpercatinib by 87% and 70%, respectively.(1)|
03782|049|D|   Coadministration of multiple doses of bosentan or efavirenz (moderate|
03782|050|D|CYP3A inducers) is predicted to decrease the AUC and Cmax of selpercatinib|
03782|051|D|40-70% and 34-57%, respectively.(1)|
03782|052|D|   Strong and moderate CYP3A4 inducers that prolong QT include: efavirenz,|
03782|053|D|encorafenib, ivosidenib, pacritinib, and thioridazine.(4,5)|
03782|054|B||
03782|055|R|REFERENCES:|
03782|056|B||
03782|057|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
03782|058|R|  2024.|1
03782|059|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
03782|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03782|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03782|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03782|063|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03782|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03782|065|R|  settings: a scientific statement from the American Heart Association and|6
03782|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03782|067|R|  2;55(9):934-47.|6
03782|068|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03782|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03782|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03782|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03782|072|R|  11/14/2017.|1
03782|073|R|5.This information is based on an extract from the Certara Drug Interaction|6
03782|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03783|001|T|MONOGRAPH TITLE:  Bedaquiline/Strong & Moderate CYP3A4 Inducers that Prolong|
03783|002|T|QT|
03783|003|B||
03783|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03783|005|L|of severe adverse interaction.|
03783|006|B||
03783|007|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers that prolong the|
03783|008|A|QTc interval may induce the metabolism of bedaquiline and result in additive|
03783|009|A|risk of QT prolongation.(1,2)|
03783|010|B||
03783|011|E|CLINICAL EFFECTS:  Concurrent or recent use of strong or moderate CYP3A4|
03783|012|E|inducers that prolong the QTc interval may result in decreased levels and|
03783|013|E|effectiveness of bedaquiline and may cause additive effects on the QTc|
03783|014|E|interval, which may result in life-threatening cardiac arrhythmias including|
03783|015|E|torsades de pointes.(1,2)|
03783|016|B||
03783|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03783|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03783|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03783|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03783|021|P|female gender, or advanced age.(2)|
03783|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03783|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03783|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03783|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03783|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03783|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03783|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03783|029|P|   Induction effects may be more likely with regular use of the inducer for|
03783|030|P|longer than 1-2 weeks.|
03783|031|B||
03783|032|M|PATIENT MANAGEMENT:  The concurrent administration of strong or moderate|
03783|033|M|CYP3A4 inducers and bedaquiline should be avoided.(1)|
03783|034|M|   Bedaquiline should be used with caution in patients receiving therapy|
03783|035|M|with agents that prolong the QT interval.  Patients should receive a|
03783|036|M|baseline electrocardiogram (ECG) before initiation, 2 weeks after|
03783|037|M|initiation, during treatment as clinically indicated, and at the expected|
03783|038|M|time of maximum increase of the QT interval when receiving concurrent agents|
03783|039|M|that prolong the QT interval.|
03783|040|M|   Bedaquiline and other QT prolonging agents should be discontinued if the|
03783|041|M|patient develops a clinically significant ventricular arrhythmia or a QTcF|
03783|042|M|of greater than 500 msec confirmed by repeat ECGs.  If a patient develops|
03783|043|M|syncope, perform an ECG.(1)|
03783|044|M|   Also consider obtaining serum calcium, magnesium, and potassium levels at|
03783|045|M|baseline and regular intervals.  Correct any electrolyte abnormalities.|
03783|046|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03783|047|M|fainting.|
03783|048|B||
03783|049|D|DISCUSSION:  In a study in healthy subjects, concurrent administration of|
03783|050|D|rifampin (600 mg daily) and bedaquiline (300 mg daily) for 21 days decreased|
03783|051|D|the area-under-curve (AUC) of bedaquiline by 52%.(1)|
03783|052|D|   In a study in healthy subjects, pretreatment with efavirenz (600 mg daily|
03783|053|D|for 27 days) decreased the AUC of a single dose of bedaquiline by 20%.|
03783|054|D|There was no effect on bedaquiline Cmax.  The AUC and Cmax of the primary|
03783|055|D|metabolite of bedaquiline increased by 70% and 80%, respectively.(1)|
03783|056|D|   In a clinical trial, mean increases in QTc were greater in patients|
03783|057|D|treated with bedaquiline than with placebo.  At Week 1, bedaquiline|
03783|058|D|increased QTc by an average of 9.9 msec, compared with 2.5 msec for placebo.|
03783|059|D|At Week 24, bedaquiline increased QTc by an average of 15.7 msec, compared|
03783|060|D|with 6.2 msec for placebo.  In another clinical trial in which patients|
03783|061|D|received bedaquiline with other QT prolonging agents, QT prolongation was|
03783|062|D|additive and proportional to the number of QT prolonging drugs used.|
03783|063|D|Patients receiving bedaquiline alone averaged a QTc increase of 23.7 msec|
03783|064|D|over baseline, while patients receiving bedaquiline with at least one other|
03783|065|D|QT prolonging agent averaged a QTc increase of 30.7 msec.(1)|
03783|066|D|   In a study, bedaquiline was coadministered with QTc prolonging agents|
03783|067|D|clofazimine and levofloxacin.  In the study, 5% of patients had a QTc >= 500|
03783|068|D|ms and 43% of patients had an increase in QTc >= 60 ms from baseline.(1)|
03783|069|D|   Strong and moderate inducers of CYP3A4 that prolong QT include:|
03783|070|D|efavirenz, encorafenib, ivosidenib, pacritinib, and thioridazine.(3,4)|
03783|071|B||
03783|072|R|REFERENCES:|
03783|073|B||
03783|074|R|1.Sirturo (bedaquiline) US prescribing information. Janssen Therapeutics|1
03783|075|R|  June, 2024.|1
03783|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03783|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03783|078|R|  settings: a scientific statement from the American Heart Association and|6
03783|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03783|080|R|  2;55(9):934-47.|6
03783|081|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03783|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03783|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03783|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03783|085|R|  11/14/2017.|1
03783|086|R|4.This information is based on an extract from the Certara Drug Interaction|6
03783|087|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03784|001|T|MONOGRAPH TITLE:  Pimavanserin/Strong and Moderate CYP3A4 Inducers that|
03784|002|T|Prolong QT|
03784|003|B||
03784|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03784|005|L|of severe adverse interaction.|
03784|006|B||
03784|007|A|MECHANISM OF ACTION:  Strong or moderate inducers of CYP3A4 that prolong the|
03784|008|A|QTc interval may induce the metabolism of pimavanserin and result in|
03784|009|A|additive risk of QT prolongation.(1,2)|
03784|010|B||
03784|011|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
03784|012|E|that prolongs the QTc interval may result in decreased levels and|
03784|013|E|effectiveness of pimavanserin and may cause additive effects on the QTc|
03784|014|E|interval, which may result in life-threatening cardiac arrhythmias including|
03784|015|E|torsades de pointes.(1,2)|
03784|016|B||
03784|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03784|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03784|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03784|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03784|021|P|female gender, or advanced age.(2)|
03784|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03784|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03784|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03784|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03784|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03784|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03784|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03784|029|P|   Induction effects may be more likely with regular use of the inducer for|
03784|030|P|longer than 1-2 weeks.|
03784|031|B||
03784|032|M|PATIENT MANAGEMENT:  The US manufacturer of pimavanserin recommends avoiding|
03784|033|M|concomitant use of strong or moderate CYP3A4 inducers.(1)|
03784|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03784|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03784|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03784|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03784|038|B||
03784|039|D|DISCUSSION:  Pimavanserin is primarily metabolized by CYP3A4 while other|
03784|040|D|metabolic enzymes CYP2J2, CYP2D6 and FMO play a lesser role.(1)  In a study|
03784|041|D|of subjects pretreated with 7 days of rifampin (600 mg daily, a strong|
03784|042|D|CYP3A4 inducer), a single dose of pimavanserin (34 mg) produced an|
03784|043|D|area-under-curve (AUC) and maximum concentration (Cmax) that was 91 % and 71|
03784|044|D|% lower, respectively, than when pimavanserin is given without rifampin.(1)|
03784|045|D|   A physiology-based pharmacokinetic model predicted that efavirenz (a|
03784|046|D|moderate CYP3A4 inducer) would decrease pimavanserin AUC and Cmax by 70 %|
03784|047|D|and 60 %, respectively.(1)|
03784|048|D|   Strong and moderate inducers of CYP3A4 that prolong QT include:|
03784|049|D|efavirenz, encorafenib, ivosidenib, pacritinib, and thioridazine.(4,5)|
03784|050|B||
03784|051|R|REFERENCES:|
03784|052|B||
03784|053|R|1.Nuplazid (pimavanserin) US prescribing information. ACADIA Pharmaceuticals|1
03784|054|R|  Inc. May, 2019.|1
03784|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03784|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03784|057|R|  settings: a scientific statement from the American Heart Association and|6
03784|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03784|059|R|  2;55(9):934-47.|6
03784|060|R|3.Hoffmann C. Personal communication: Nuplazid Drug-drug interactions.|1
03784|061|R|  Acadia Pharmaceuticals.|1
03784|062|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03784|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03784|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03784|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03784|066|R|  11/14/2017.|1
03784|067|R|5.This information is based on an extract from the Certara Drug Interaction|6
03784|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03785|001|T|MONOGRAPH TITLE:  Haloperidol/Apalutamide|
03785|002|B||
03785|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03785|004|L|take action as needed.|
03785|005|B||
03785|006|A|MECHANISM OF ACTION:  Apalutamide, a strong CYP3A4 inducer, may increase the|
03785|007|A|metabolic clearance of haloperidol.(1-3)|
03785|008|B||
03785|009|E|CLINICAL EFFECTS:  Coadministration with apalutamide, a strong CYP3A4|
03785|010|E|inducer, may result in decreased levels and effectiveness of haloperidol.|
03785|011|B||
03785|012|P|PREDISPOSING FACTORS:  None determined.|
03785|013|B||
03785|014|M|PATIENT MANAGEMENT:  Monitor clinical response in patients maintained on|
03785|015|M|haloperidol when initiating or discontinuing strong CYP3A4 inducers.  The|
03785|016|M|dosage of haloperidol may need to be adjusted.(1)|
03785|017|B||
03785|018|D|DISCUSSION:  In a study in 11 schizophrenic patients, the addition of|
03785|019|D|carbamazepine resulted in a dose related decrease in haloperidol levels.|
03785|020|D|Haloperidol levels were decreased by 2%, 61%, and 85%, respectively, from|
03785|021|D|baseline following the addition and increase of carbamazepine at 100 mg/day,|
03785|022|D|300 mg/day, and 600 mg/day.(1,4)|
03785|023|D|   In a study in 27 patients with schizophrenia or schizoaffective disorder,|
03785|024|D|the use of haloperidol with carbamazepine was associated with lower|
03785|025|D|haloperidol levels and worse clinical outcomes than the use of haloperidol|
03785|026|D|alone.(5)|
03785|027|D|   In a study in schizophrenic patients, haloperidol levels were|
03785|028|D|significantly decreased in patients receiving concurrent carbamazepine.(6)|
03785|029|D|   In a study in 7 patients, haloperidol levels fell 60% following the|
03785|030|D|addition of carbamazepine to therapy.  Haloperidol levels were undetectable|
03785|031|D|in 2 subjects, whose symptoms worsened.(7)|
03785|032|D|   In a study in 23 patients, the addition of carbamazepine to haloperidol|
03785|033|D|resulted in improvement in symptoms.(8)|
03785|034|D|   In a retrospective review of 231 schizophrenic patients, patients|
03785|035|D|receiving concurrent carbamazepine or phenobarbital had haloperidol levels|
03785|036|D|that were 37% and 22% lower, respectively, than patients taking haloperidol|
03785|037|D|without these agents.(9)|
03785|038|D|   In a study in 6 schizophrenic patients, switching carbamazepine to|
03785|039|D|oxcarbazepine resulted in increased in haloperidol levels by 50% to 200%|
03785|040|D|after 2-4 weeks of therapy.(10)|
03785|041|D|   In a study in schizophrenic patients, carbamazepine decreased haloperidol|
03785|042|D|levels by 50%.  One subject developed worsening of symptoms, while two|
03785|043|D|improved.(11)|
03785|044|D|   There are also case reports documenting decreased haloperidol levels and|
03785|045|D|effectiveness with concurrent carbamazepine.(12-16)|
03785|046|D|   In a study in schizophrenic patients, the addition of rifampin in 12|
03785|047|D|patients resulted in decreases in haloperidol levels by 37%, 58.7%, and 70%|
03785|048|D|by Day 3, Day 7, and Day 28, respectively, of concurrent therapy.  Mean|
03785|049|D|scores on the Brief Psychiatric Rating Scale decreased from baseline.|
03785|050|D|Discontinuation of rifampin from concurrent therapy in 5 patients increased|
03785|051|D|haloperidol levels by 140.7%, 228.7%, and 329% of baseline by Day 3, Day 7,|
03785|052|D|and Day 28, respectively, after rifampin discontinuation.(1,17)|
03785|053|D|   In a study in 7 schizophrenic patients, rifampin decreased the half-life|
03785|054|D|of haloperidol by 48%.(18)|
03785|055|B||
03785|056|R|REFERENCES:|
03785|057|B||
03785|058|R|1.Haldol injection (haloperidol) US prescribing information. Janssen|1
03785|059|R|  Pharmaceuticals, Inc. October, 2025.|1
03785|060|R|2.This information is based on an extract from the Certara Drug Interaction|6
03785|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03785|062|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03785|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03785|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03785|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03785|066|R|  11/14/2017.|1
03785|067|R|4.Yasui-Furukori N, Kondo T, Mihara K, Suzuki A, Inoue Y, Kaneko S.|2
03785|068|R|  Significant dose effect of carbamazepine on reduction of steady-state|2
03785|069|R|  plasma concentration of haloperidol in schizophrenic patients. J Clin|2
03785|070|R|  Psychopharmacol 2003 Oct;23(5):435-40.|2
03785|071|R|5.Hesslinger B, Normann C, Langosch JM, Klose P, Berger M, Walden J. Effects|2
03785|072|R|  of carbamazepine and valproate on haloperidol plasma levels and on|2
03785|073|R|  psychopathologic outcome in schizophrenic patients. J Clin Psychopharmacol|2
03785|074|R|  1999 Aug;19(4):310-5.|2
03785|075|R|6.Iwahashi K, Miyatake R, Suwaki H, Hosokawa K, Ichikawa Y. The drug-drug|2
03785|076|R|  interaction effects of haloperidol on plasma carbamazepine levels. Clin|2
03785|077|R|  Neuropharmacol 1995 Jun;18(3):233-6.|2
03785|078|R|7.Arana GW, Goff DC, Friedman H, Ornsteen M, Greenblatt DJ, Black B, Shader|2
03785|079|R|  RI. Does carbamazepine-induced reduction of plasma haloperidol levels|2
03785|080|R|  worsen psychotic symptoms?. Am J Psychiatry 1986 May;143(5):650-1.|2
03785|081|R|8.Klein E, Bental E, Lerer B, Belmaker RH. Carbamazepine and haloperidol v|2
03785|082|R|  placebo and haloperidol in excited psychoses. A controlled study. Arch Gen|2
03785|083|R|  Psychiatry 1984 Feb;41(2):165-70.|2
03785|084|R|9.Hirokane G, Someya T, Takahashi S, Morita S, Shimoda K. Interindividual|2
03785|085|R|  variation of plasma haloperidol concentrations and the impact of|2
03785|086|R|  concomitant medications: the analysis of therapeutic drug monitoring data.|2
03785|087|R|  Ther Drug Monit 1999 Feb;21(1):82-6.|2
03785|088|R|10.Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching carbamazepine|3
03785|089|R|   to oxcarbazepine on the plasma levels of neuroleptics. A case report.|3
03785|090|R|   Psychopharmacology (Berl) 1994 Sep;116(1):115-6.|3
03785|091|R|11.Kahn EM, Schulz SC, Perel JM, Alexander JE. Change in haloperidol level|2
03785|092|R|   due to carbamazepine--a complicating factor in combined medication for|2
03785|093|R|   schizophrenia. J Clin Psychopharmacol 1990 Feb;10(1):54-7.|2
03785|094|R|12.Fast DK, Jones BD, Kusalic M, Erickson M. Effect of carbamazepine on|3
03785|095|R|   neuroleptic plasma levels and efficacy. Am J Psychiatry 1986 Jan;|3
03785|096|R|   143(1):117-8.|3
03785|097|R|13.Jann MW, Ereshefsky L, Saklad SR, Seidel DR, Davis CM, Burch NR, Bowden|3
03785|098|R|   CL. Effects of carbamazepine on plasma haloperidol levels. J Clin|3
03785|099|R|   Psychopharmacol 1985 Apr;5(2):106-9.|3
03785|100|R|14.Cohen D, Diemont WL. Deterioration of schizoaffective disorder due to an|3
03785|101|R|   interaction between haloperidol and carbamazepine. Ned Tijdschr Geneeskd|3
03785|102|R|   2002 Oct 12;146(41):1942-4.|3
03785|103|R|15.Kanter GL, Yerevanian BI, Ciccone JR. Case report of a possible|3
03785|104|R|   interaction between neuroleptics and carbamazepine. Am J Psychiatry 1984|3
03785|105|R|   Sep;141(9):1101-2.|3
03785|106|R|16.Brayley J, Yellowlees P. An interaction between haloperidol and|3
03785|107|R|   carbamazepine in a patient with cerebral palsy. Aust N Z J Psychiatry|3
03785|108|R|   1987 Dec;21(4):605-7.|3
03785|109|R|17.Kim YH, Cha IJ, Shim JC, Shin JG, Yoon YR, Kim YK, Kim JI, Park GH, Jang|2
03785|110|R|   IJ, Woo JI, Shin SG. Effect of rifampin on the plasma concentration and|2
03785|111|R|   the clinical effect of haloperidol concomitantly administered to|2
03785|112|R|   schizophrenic patients. J Clin Psychopharmacol 1996 Jun;16(3):247-52.|2
03785|113|R|18.Takeda M, Nishinuma K, Yamashita S, Matsubayashi T, Tanino S, Nishimura|2
03785|114|R|   T. Serum haloperidol levels of schizophrenics receiving treatment for|2
03785|115|R|   tuberculosis. Clin Neuropharmacol 1986;9(4):386-97.|2
03786|001|T|MONOGRAPH TITLE:  Haloperidol/Strong CYP3A4 Inducers that Prolong QT|
03786|002|B||
03786|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03786|004|L|of severe adverse interaction.|
03786|005|B||
03786|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
03786|007|A|clearance of haloperidol.(1-3)|
03786|008|A|   Haloperidol can prolong the QTc interval. Concurrent use with other|
03786|009|A|agents that prolong the QTc interval may result in an additive risk of QT|
03786|010|A|prolongation.(1-4)|
03786|011|B||
03786|012|E|CLINICAL EFFECTS:  Coadministration with strong CYP3A4 inducers may result|
03786|013|E|in decreased levels and effectiveness of haloperidol.  Coadministration with|
03786|014|E|other QT prolonging agents may cause additive effects on the QTc interval,|
03786|015|E|which may result in life-threatening cardiac arrhythmias including torsades|
03786|016|E|de pointes.(1-4)|
03786|017|B||
03786|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03786|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03786|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03786|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03786|022|P|female gender, or advanced age.(4)|
03786|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03786|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03786|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03786|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03786|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03786|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03786|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03786|030|P|   Induction effects may be more likely with regular use of the inducer for|
03786|031|P|longer than 1-2 weeks.|
03786|032|B||
03786|033|M|PATIENT MANAGEMENT:  Monitor clinical response in patients maintained on|
03786|034|M|haloperidol when initiating or discontinuing strong CYP3A4 inducers.  The|
03786|035|M|dosage of haloperidol may need to be adjusted.(1)|
03786|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03786|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03786|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03786|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03786|040|B||
03786|041|D|DISCUSSION:  In a study in 11 schizophrenic patients, the addition of|
03786|042|D|carbamazepine resulted in a dose related decrease in haloperidol levels.|
03786|043|D|Haloperidol levels were decreased by 2%, 61%, and 85%, respectively, from|
03786|044|D|baseline following the addition and increase of carbamazepine at 100 mg/day,|
03786|045|D|300 mg/day, and 600 mg/day.(1,5)|
03786|046|D|   In a study in 27 patients with schizophrenia or schizoaffective disorder,|
03786|047|D|the use of haloperidol with carbamazepine was associated with lower|
03786|048|D|haloperidol levels and worse clinical outcomes than the use of haloperidol|
03786|049|D|alone.(6)|
03786|050|D|   In a study in schizophrenic patients, haloperidol levels were|
03786|051|D|significantly decreased in patients receiving concurrent carbamazepine.(7)|
03786|052|D|   In a study in 7 patients, haloperidol levels fell 60% following the|
03786|053|D|addition of carbamazepine to therapy.  Haloperidol levels were undetectable|
03786|054|D|in 2 subjects, whose symptoms worsened.(8)|
03786|055|D|   In a study in 23 patients, the addition of carbamazepine to haloperidol|
03786|056|D|resulted in improvement in symptoms.(9)|
03786|057|D|   In a retrospective review of 231 schizophrenic patients, patients|
03786|058|D|receiving concurrent carbamazepine or phenobarbital had haloperidol levels|
03786|059|D|that were 37% and 22% lower, respectively, than patients taking haloperidol|
03786|060|D|without these agents.(10)|
03786|061|D|   In a study in 6 schizophrenic patients, switching carbamazepine to|
03786|062|D|oxcarbazepine resulted in increased in haloperidol levels by 50% to 200%|
03786|063|D|after 2-4 weeks of therapy.(11)|
03786|064|D|   In a study in schizophrenic patients, carbamazepine decreased haloperidol|
03786|065|D|levels by 50%.  One subject developed worsening of symptoms, while two|
03786|066|D|improved.(12)|
03786|067|D|   There are also case reports documenting decreased haloperidol levels and|
03786|068|D|effectiveness with concurrent carbamazepine.(13-17)|
03786|069|D|   In a study in schizophrenic patients, the addition of rifampin in 12|
03786|070|D|patients resulted in decreases in haloperidol levels by 37%, 58.7%, and 70%|
03786|071|D|by Day 3, Day 7, and Day 28, respectively, of concurrent therapy.  Mean|
03786|072|D|scores on the Brief Psychiatric Rating Scale decreased from baseline.|
03786|073|D|Discontinuation of rifampin from concurrent therapy in 5 patients increased|
03786|074|D|haloperidol levels by 140.7%, 228.7%, and 329% of baseline by Day 3, Day 7,|
03786|075|D|and Day 28, respectively, after rifampin discontinuation.(1,18)|
03786|076|D|   In a study in 7 schizophrenic patients, rifampin decreased the half-life|
03786|077|D|of haloperidol by 48%.(19)|
03786|078|D|   Agents that are linked to this monograph may have varying degrees of|
03786|079|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03786|080|D|been shown to prolong the QTc interval either through their mechanism of|
03786|081|D|action, through studies on their effects on the QTc interval, or through|
03786|082|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03786|083|D|and/or postmarketing reports.(20)|
03786|084|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
03786|085|D|encorafenib and ivosidenib.(2,3)|
03786|086|B||
03786|087|R|REFERENCES:|
03786|088|B||
03786|089|R|1.Haldol injection (haloperidol) US prescribing information. Janssen|1
03786|090|R|  Pharmaceuticals, Inc. October, 2025.|1
03786|091|R|2.This information is based on an extract from the Certara Drug Interaction|6
03786|092|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03786|093|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03786|094|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03786|095|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03786|096|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03786|097|R|  11/14/2017.|1
03786|098|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03786|099|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03786|100|R|  settings: a scientific statement from the American Heart Association and|6
03786|101|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03786|102|R|  2;55(9):934-47.|6
03786|103|R|5.Yasui-Furukori N, Kondo T, Mihara K, Suzuki A, Inoue Y, Kaneko S.|2
03786|104|R|  Significant dose effect of carbamazepine on reduction of steady-state|2
03786|105|R|  plasma concentration of haloperidol in schizophrenic patients. J Clin|2
03786|106|R|  Psychopharmacol 2003 Oct;23(5):435-40.|2
03786|107|R|6.Hesslinger B, Normann C, Langosch JM, Klose P, Berger M, Walden J. Effects|2
03786|108|R|  of carbamazepine and valproate on haloperidol plasma levels and on|2
03786|109|R|  psychopathologic outcome in schizophrenic patients. J Clin Psychopharmacol|2
03786|110|R|  1999 Aug;19(4):310-5.|2
03786|111|R|7.Iwahashi K, Miyatake R, Suwaki H, Hosokawa K, Ichikawa Y. The drug-drug|2
03786|112|R|  interaction effects of haloperidol on plasma carbamazepine levels. Clin|2
03786|113|R|  Neuropharmacol 1995 Jun;18(3):233-6.|2
03786|114|R|8.Arana GW, Goff DC, Friedman H, Ornsteen M, Greenblatt DJ, Black B, Shader|2
03786|115|R|  RI. Does carbamazepine-induced reduction of plasma haloperidol levels|2
03786|116|R|  worsen psychotic symptoms?. Am J Psychiatry 1986 May;143(5):650-1.|2
03786|117|R|9.Klein E, Bental E, Lerer B, Belmaker RH. Carbamazepine and haloperidol v|2
03786|118|R|  placebo and haloperidol in excited psychoses. A controlled study. Arch Gen|2
03786|119|R|  Psychiatry 1984 Feb;41(2):165-70.|2
03786|120|R|10.Hirokane G, Someya T, Takahashi S, Morita S, Shimoda K. Interindividual|2
03786|121|R|   variation of plasma haloperidol concentrations and the impact of|2
03786|122|R|   concomitant medications: the analysis of therapeutic drug monitoring|2
03786|123|R|   data. Ther Drug Monit 1999 Feb;21(1):82-6.|2
03786|124|R|11.Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching carbamazepine|3
03786|125|R|   to oxcarbazepine on the plasma levels of neuroleptics. A case report.|3
03786|126|R|   Psychopharmacology (Berl) 1994 Sep;116(1):115-6.|3
03786|127|R|12.Kahn EM, Schulz SC, Perel JM, Alexander JE. Change in haloperidol level|2
03786|128|R|   due to carbamazepine--a complicating factor in combined medication for|2
03786|129|R|   schizophrenia. J Clin Psychopharmacol 1990 Feb;10(1):54-7.|2
03786|130|R|13.Fast DK, Jones BD, Kusalic M, Erickson M. Effect of carbamazepine on|3
03786|131|R|   neuroleptic plasma levels and efficacy. Am J Psychiatry 1986 Jan;|3
03786|132|R|   143(1):117-8.|3
03786|133|R|14.Jann MW, Ereshefsky L, Saklad SR, Seidel DR, Davis CM, Burch NR, Bowden|3
03786|134|R|   CL. Effects of carbamazepine on plasma haloperidol levels. J Clin|3
03786|135|R|   Psychopharmacol 1985 Apr;5(2):106-9.|3
03786|136|R|15.Cohen D, Diemont WL. Deterioration of schizoaffective disorder due to an|3
03786|137|R|   interaction between haloperidol and carbamazepine. Ned Tijdschr Geneeskd|3
03786|138|R|   2002 Oct 12;146(41):1942-4.|3
03786|139|R|16.Kanter GL, Yerevanian BI, Ciccone JR. Case report of a possible|3
03786|140|R|   interaction between neuroleptics and carbamazepine. Am J Psychiatry 1984|3
03786|141|R|   Sep;141(9):1101-2.|3
03786|142|R|17.Brayley J, Yellowlees P. An interaction between haloperidol and|3
03786|143|R|   carbamazepine in a patient with cerebral palsy. Aust N Z J Psychiatry|3
03786|144|R|   1987 Dec;21(4):605-7.|3
03786|145|R|18.Kim YH, Cha IJ, Shim JC, Shin JG, Yoon YR, Kim YK, Kim JI, Park GH, Jang|2
03786|146|R|   IJ, Woo JI, Shin SG. Effect of rifampin on the plasma concentration and|2
03786|147|R|   the clinical effect of haloperidol concomitantly administered to|2
03786|148|R|   schizophrenic patients. J Clin Psychopharmacol 1996 Jun;16(3):247-52.|2
03786|149|R|19.Takeda M, Nishinuma K, Yamashita S, Matsubayashi T, Tanino S, Nishimura|2
03786|150|R|   T. Serum haloperidol levels of schizophrenics receiving treatment for|2
03786|151|R|   tuberculosis. Clin Neuropharmacol 1986;9(4):386-97.|2
03786|152|R|20.USDepartment of Health and Human Services Food and Drug Administration.|1
03786|153|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03786|154|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03786|155|R|   https://www.fda.gov/media/71372/download October, 2005.|1
03787|001|T|MONOGRAPH TITLE:  Artemether; Lumefantrine/Strong CYP3A4 Inducers Prolong QT|
03787|002|B||
03787|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03787|004|L|is contraindicated and generally should not be dispensed or administered to|
03787|005|L|the same patient.|
03787|006|B||
03787|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 that prolong the QTc|
03787|008|A|interval may induce the metabolism of artemether and lumefantrine and result|
03787|009|A|in additive risk of QT prolongation.(1)|
03787|010|B||
03787|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong the|
03787|012|E|QTc interval with artemether and lumefantrine may result in decreased levels|
03787|013|E|and effectiveness of the antimalarial agents and treatment failure and may|
03787|014|E|cause additive effects on the QTc interval, which may result in|
03787|015|E|life-threatening cardiac arrhythmias including torsades de pointes.(1,2)|
03787|016|B||
03787|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03787|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03787|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03787|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03787|021|P|female gender, or advanced age.(2)|
03787|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03787|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03787|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03787|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03787|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03787|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03787|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03787|029|P|   Induction effects may be more likely with regular use of the inducer for|
03787|030|P|longer than 1-2 weeks.|
03787|031|B||
03787|032|M|PATIENT MANAGEMENT:  The manufacturer of artemether-lumefantrine states that|
03787|033|M|the concurrent use of artemether-lumefantrine with strong CYP3A4 inducers is|
03787|034|M|contraindicated.(1)|
03787|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03787|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03787|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03787|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03787|039|B||
03787|040|D|DISCUSSION:  In a study in 6 subjects, administration of rifampin (600 mg|
03787|041|D|daily, a strong inducer of CYP3A4) with artemether-lumefantrine (6 dose|
03787|042|D|regimen over 3 days) decreased the area-under-curve (AUC) of artemether,|
03787|043|D|dihydroartemisinin (DHA), and lumefantrine by 89%, 85%, and 68%,|
03787|044|D|respectively.(1)|
03787|045|D|   Strong CYP3A4 inducers linked to this monograph include:  encorafenib and|
03787|046|D|ivosidenib.(2)|
03787|047|B||
03787|048|R|REFERENCES:|
03787|049|B||
03787|050|R|1.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
03787|051|R|  Pharmaceuticals Corporation August, 2019.|1
03787|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03787|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03787|054|R|  settings: a scientific statement from the American Heart Association and|6
03787|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03787|056|R|  2;55(9):934-47.|6
03787|057|R|3.This information is based on an extract from the Certara Drug Interaction|6
03787|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03788|001|T|MONOGRAPH TITLE:  Pitolisant/Strong CYP3A4 Inducers that Prolong QT|
03788|002|B||
03788|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03788|004|L|take action as needed.|
03788|005|B||
03788|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 that prolong the QTc|
03788|007|A|interval may induce the metabolism of pitolisant via this pathway and result|
03788|008|A|in additive risk of QT prolongation.(1-3)|
03788|009|B||
03788|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers that|
03788|011|E|prolong QT may reduce the clinical effectiveness of pitolisant and may cause|
03788|012|E|additive effects on the QTc interval, which may result in life-threatening|
03788|013|E|cardiac arrhythmias including torsades de pointes.(1-3)|
03788|014|B||
03788|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03788|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03788|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03788|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03788|019|P|female gender, or advanced age.(3)|
03788|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03788|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03788|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03788|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03788|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03788|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03788|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03788|027|P|   Induction effects may be more likely with regular use of the inducer for|
03788|028|P|longer than 1-2 weeks.|
03788|029|B||
03788|030|M|PATIENT MANAGEMENT:  The US manufacturer of pitolisant states that|
03788|031|M|concurrent use of strong CYP3A4 inducers requires a dose adjustment.  For|
03788|032|M|patients stable on pitolisant 8.9 mg or 17.8 mg, increase the dose of|
03788|033|M|pitolisant to double the original daily dose (ex 17.8 mg or 35.6 mg,|
03788|034|M|respectively) over 7 days.  If concurrent use of a strong CYP3A4 inducer is|
03788|035|M|discontinued, decrease the pitolisant dose by half.(1)|
03788|036|M|   The UK manufacturer of pitolisant states that concurrent use of strong|
03788|037|M|CYP3A4 inducers should be done with caution and dose adjustment should be|
03788|038|M|considered after during concurrent therapy and for one week after|
03788|039|M|discontinuing the inducer.(2)|
03788|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03788|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03788|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03788|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03788|044|B||
03788|045|D|DISCUSSION:  In a clinical study, concurrent use of pitolisant with rifampin|
03788|046|D|decreased the concentration maximum (Cmax) and area-under-curve (AUC) by|
03788|047|D|approximately 0.75-fold and 0.5-fold change, respectively.(1)|
03788|048|D|   Strong CYP3A4 inducers linked to this monograph are: encorafenib and|
03788|049|D|ivosidenib.(3,4)|
03788|050|B||
03788|051|R|REFERENCES:|
03788|052|B||
03788|053|R|1.Wakix (pitolisant) tablets US prescribing information. Harmony Biosciences|1
03788|054|R|  June, 2024.|1
03788|055|R|2.Wakix (pitolisant) UK Summary of Product Characteristics. Bioproject|1
03788|056|R|  Pharma January, 2019.|1
03788|057|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03788|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03788|059|R|  settings: a scientific statement from the American Heart Association and|6
03788|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03788|061|R|  2;55(9):934-47.|6
03788|062|R|4.This information is based on an extract from the Certara Drug Interaction|6
03788|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03788|064|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03788|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03788|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03788|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03788|068|R|  11/14/2017.|1
03789|001|T|MONOGRAPH TITLE:  Romidepsin/Strong CYP3A4 Inducers that Prolong QT|
03789|002|B||
03789|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03789|004|L|of severe adverse interaction.|
03789|005|B||
03789|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 that prolong the QTc|
03789|007|A|interval may increase the metabolism of romidepsin and result in additive|
03789|008|A|risk of QT prolongation.(1-3)|
03789|009|B||
03789|010|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer that prolong QT|
03789|011|E|may result in decreased levels and effectiveness of romidepsin and may cause|
03789|012|E|additive effects on the QTc interval, which may result in life-threatening|
03789|013|E|cardiac arrhythmias including torsades de pointes.(1-3)|
03789|014|B||
03789|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03789|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03789|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03789|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03789|019|P|female gender, or advanced age.(3)|
03789|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03789|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03789|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03789|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03789|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03789|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03789|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03789|027|P|   Induction effects may be more likely with regular use of the inducer for|
03789|028|P|longer than 1-2 weeks.|
03789|029|B||
03789|030|M|PATIENT MANAGEMENT:  The manufacturer of romidepsin recommends avoiding the|
03789|031|M|use of potent inducers of CYP3A4 in patients receiving romidepsin.(1,2)  The|
03789|032|M|Canadian manufacturer includes rifabutin on its list of CYP3A4 inducers that|
03789|033|M|should be avoided.(2)|
03789|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03789|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03789|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03789|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03789|038|B||
03789|039|D|DISCUSSION:  In a study in advanced cancer patients, rifampin, a strong|
03789|040|D|inducer of CYP3A4 and an inhibitor and inducer of other CYP enzymes and|
03789|041|D|transporters, unexpectedly increased the maximum concentration (Cmax) and|
03789|042|D|area-under-curve (AUC) of romidepsin (14 mg/m2) by 60% and 80%,|
03789|043|D|respectively.  Romidepsin clearance and volume of distribution decreased by|
03789|044|D|44% and 52%, respectively.  This is likely due to inhibition of an|
03789|045|D|undetermined hepatic uptake process responsible for the disposition of|
03789|046|D|romidepsin.(1)|
03789|047|D|   Strong inducers of CYP3A4 include:  encorafenib and ivosidenib.(1-3)|
03789|048|B||
03789|049|R|REFERENCES:|
03789|050|B||
03789|051|R|1.Istodax (romidepsin) US prescribing information. Celgene Corporation|1
03789|052|R|  November, 2018.|1
03789|053|R|2.Istodax (romidepsin) Canadian prescribing information. Celgene Inc July|1
03789|054|R|  25, 2019.|1
03789|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03789|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03789|057|R|  settings: a scientific statement from the American Heart Association and|6
03789|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03789|059|R|  2;55(9):934-47.|6
03789|060|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03789|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03789|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03789|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03789|064|R|  11/14/2017.|1
03790|001|T|MONOGRAPH TITLE:  Tricyclic; Tetracyclic Agents; Carbamazepine/Linezolid|
03790|002|B||
03790|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03790|004|L|of severe adverse interaction.|
03790|005|B||
03790|006|A|MECHANISM OF ACTION:  Linezolid is a weak, reversible inhibitor of monoamine|
03790|007|A|oxidase.(1)  Tricyclic and tetracyclic compounds may sensitize post-synaptic|
03790|008|A|receptors to amines that are accumulating extraneuronally as a result of MAO|
03790|009|A|inhibition.(2)|
03790|010|A|   Carbamazepine is structurally related to the tricyclic|
03790|011|A|antidepressants.(3)  Similarity between cyclobenzaprine and tricyclics|
03790|012|A|warrants consideration of tricyclic interactions for cyclobenzaprine.(4)|
03790|013|A|Mirtazapine, a tetracyclic antidepressant, should also be considered for|
03790|014|A|this interaction.(5)|
03790|015|B||
03790|016|E|CLINICAL EFFECTS:  Concurrent use with linezolid may result in a severe|
03790|017|E|reaction including hyperpyrexia, convulsions, excitability, fluctuations in|
03790|018|E|blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma,|
03790|019|E|and death.(1)|
03790|020|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03790|021|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03790|022|E|rigidity.(6)|
03790|023|B||
03790|024|P|PREDISPOSING FACTORS:  High doses of tricyclics or tetracyclics, or|
03790|025|P|concurrent use of multiple drugs which increase CNS serotonin levels may|
03790|026|P|increase risk for serotonin syndrome.|
03790|027|B||
03790|028|M|PATIENT MANAGEMENT:  The manufacturers of the tricyclic antidepressants,|
03790|029|M|carbamazepine, cyclobenzaprine and mirtazapine state that coadministration|
03790|030|M|with MAO inhibitors is contraindicated.  Concurrent linezolid is|
03790|031|M|specifically contraindicated by the manufacturers of clomipramine,|
03790|032|M|desipramine, mirtazapine, nortriptyline, and trimipramine.(1,3-5,7-12)|
03790|033|M|   The manufacturer of linezolid does not contraindicate the use of|
03790|034|M|serotonergic agents but states that they should not be coadministered unless|
03790|035|M|clinically appropriate and the patient is closely monitored.(1)  This|
03790|036|M|recommendation is consistent with the 2011 FDA Drug Safety Communication on|
03790|037|M|linezolid and serotonergic psychiatric medications.(13,14)|
03790|038|M|   In non-emergency situations in patients maintained on tricyclics or|
03790|039|M|tetracyclics when linezolid therapy is planned, discontinue the patient's|
03790|040|M|tricyclic or tetracyclic at least 2 weeks in advance of linezolid therapy.|
03790|041|M|   In emergency situations in patients maintained on tricyclics or|
03790|042|M|tetracyclics, weigh the availability and safety of alternatives to linezolid|
03790|043|M|against the risk of serotonin syndrome.  If linezolid therapy is required,|
03790|044|M|the patient's tricyclic or tetracyclic should be immediately discontinued.|
03790|045|M|Patients should be monitored for serotonin syndrome for 2 weeks or until 24|
03790|046|M|hours after the last dose of linezolid, whichever comes first.|
03790|047|M|   The patient's tricyclic or tetracyclic therapy may be resumed 24 hours|
03790|048|M|after the last dose of linezolid.(13)|
03790|049|M|   Clinical studies have found a low incidence of serotonin syndrome in|
03790|050|M|patients on concomitant linezolid and serotonergic agents, ranging from|
03790|051|M|0.24% to 4%, depending on the quality and size of the study.  While|
03790|052|M|linezolid-associated serotonin syndrome is potentially serious and fatal, if|
03790|053|M|treated early, it is quickly reversible with discontinuation of offending|
03790|054|M|agents and supportive care.  Therefore, some authors suggest that use of|
03790|055|M|serotonergic medications should not preclude the use of linezolid but that|
03790|056|M|the clinical situation should be assessed.  If concurrent use or use of|
03790|057|M|linezolid without a washout is warranted, the patient should be closely|
03790|058|M|monitored.(15-20)|
03790|059|M|   If concurrent therapy is warranted, patients should be monitored for|
03790|060|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03790|061|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03790|062|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03790|063|M|coordination, or severe diarrhea.|
03790|064|B||
03790|065|D|DISCUSSION:  It should be noted that if this interaction occurs, the|
03790|066|D|consequences will be immediate and severe.  Effects may continue to be seen|
03790|067|D|for several days after discontinuing linezolid.|
03790|068|D|   The FDA FAERS contains reports of serotonin syndrome with the concurrent|
03790|069|D|use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram,|
03790|070|D|fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine.  The risk|
03790|071|D|of serotonin syndrome with other psychiatric drugs is unclear.(14)|
03790|072|B||
03790|073|R|REFERENCES:|
03790|074|B||
03790|075|R|1.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
03790|076|R|2.Blier P, de Montigny C, Chaput Y. A role for the serotonin system in the|6
03790|077|R|  mechanism of action of antidepressant  treatments: preclinical evidence. J|6
03790|078|R|  Clin Psychiatry 1990 Apr;51 Suppl:14-20; discussion 21.|6
03790|079|R|3.Tegretol (carbamazepine) US prescribing information. Novartis|1
03790|080|R|  Pharmaceuticals Corporation September, 2023.|1
03790|081|R|4.Amrix (cyclobenzaprine extended release) US prescribing information. Teva|1
03790|082|R|  Pharmaceuticals Ltd. May, 2016.|1
03790|083|R|5.Remeron (mirtazapine) US prescribing information. Organon Inc. November,|1
03790|084|R|  2021.|1
03790|085|R|6.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03790|086|R|  352(11):1112-20.|6
03790|087|R|7.Anafranil (clompiramine hydrochloride) US prescribing information.|1
03790|088|R|  Mallinckrodt Inc. May 10, 2019.|1
03790|089|R|8.Pamelor (nortriptyline hydrochloride) US prescribing information.|1
03790|090|R|  Mallinckrodt Inc. October, 2012.|1
03790|091|R|9.Norpramin (desipramine) US prescribing information. US Pharm Holdings|1
03790|092|R|  November, 2018.|1
03790|093|R|10.Amitriptyline hydrochloride, US prescribing information. Sandoz Inc.|1
03790|094|R|   January, 2010.|1
03790|095|R|11.Trofanil (imipramine) US prescribing information. Novartis September,|1
03790|096|R|   1998.|1
03790|097|R|12.Surmontil (trimipramine) US prescribing information. Odyssey Pharms July,|1
03790|098|R|   2014.|1
03790|099|R|13.USFood and Drug Administration. FDA Drug Safety Communication: Serious|1
03790|100|R|   CNS reactions possible when linezolid (Zyvox) is given to patients taking|1
03790|101|R|   certain psychiatric medications. available at:|1
03790|102|R|   http://wayback.archive-it.org/7993/20170722185915/https://www.fda.gov/Dru|1
03790|103|R|   gs/DrugSafety/ucm265305.htm July 26, 2011.|1
03790|104|R|14.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
03790|105|R|   information about the drug interaction between linezolid (Zyvox) and|1
03790|106|R|   serotonergic psychiatric medications. available at:|1
03790|107|R|   http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm October 21, 2011.|1
03790|108|R|15.Lodise TP, Patel N, Rivera A, Tristani L, Lazariu V, Vandewall H, McNutt|2
03790|109|R|   LA. Comparative evaluation of serotonin toxicity among veterans affairs|2
03790|110|R|   patients  receiving linezolid and vancomycin. Antimicrob Agents Chemother|2
03790|111|R|   2013 Dec;57(12):5901-11.|2
03790|112|R|16.Ramsey TD, Lau TT, Ensom MH. Serotonergic and adrenergic drug|6
03790|113|R|   interactions associated with linezolid: a critical  review and practical|6
03790|114|R|   management approach. Ann Pharmacother 2013 Apr;47(4):543-60.|6
03790|115|R|17.Woytowish MR, Maynor LM. Clinical relevance of linezolid-associated|6
03790|116|R|   serotonin toxicity. Ann Pharmacother 2013 Mar;47(3):388-97.|6
03790|117|R|18.Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, Lodise TP.|2
03790|118|R|   Comparison of serotonin toxicity with concomitant use of either linezolid|2
03790|119|R|   or  comparators and serotonergic agents: an analysis of Phase III and IV|2
03790|120|R|   randomized  clinical trial data. J Antimicrob Chemother 2012 Feb;|2
03790|121|R|   67(2):494-502.|2
03790|122|R|19.Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion|6
03790|123|R|   J Clin Psychiatry 2009;11(6):353-6.|6
03790|124|R|20.Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug|2
03790|125|R|   interactions: a retrospective survey. Clin Infect Dis 2006 Jul 15;|2
03790|126|R|   43(2):180-7.|2
03791|001|T|MONOGRAPH TITLE:  Bupropion; Solriamfetol/Linezolid|
03791|002|B||
03791|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03791|004|L|of severe adverse interaction.|
03791|005|B||
03791|006|A|MECHANISM OF ACTION:  Bupropion and solriamfetol increase dopamine and|
03791|007|A|norepinephrine concentrations via blockade of the dopamine and|
03791|008|A|norepinephrine reuptake transporters.(1-4)  Linezolid is a weak,|
03791|009|A|nonselective monoamine oxidase inhibitor (MAOI) that blocks the metabolism|
03791|010|A|of norepinephrine and dopamine, also leading to increased neuronal|
03791|011|A|concentrations of norepinephrine and dopamine.(5)|
03791|012|B||
03791|013|E|CLINICAL EFFECTS:  The concurrent administration of bupropion or|
03791|014|E|solriamfetol and linezolid may increase the risk for serotonin syndrome|
03791|015|E|and/or severe hypertensive, or other adverse reactions, including mania,|
03791|016|E|psychosis or agitation with bupropion, and headache, nausea, anorexia, or|
03791|017|E|anxiety with solriamfetol.(1-2)|
03791|018|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03791|019|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03791|020|E|rigidity.|
03791|021|B||
03791|022|P|PREDISPOSING FACTORS:  Patients with pre-existing hypertension may be more|
03791|023|P|likely to experience treatment-emergent hypertension.(1)|
03791|024|P|   Patients with moderate to severe renal impairment may be at higher risk|
03791|025|P|for increases in blood pressure and heart rate from solriamfetol due to|
03791|026|P|prolonged drug exposure.(2)|
03791|027|B||
03791|028|M|PATIENT MANAGEMENT:  The US manufacturers of bupropion and solriamfetol|
03791|029|M|state that concurrent use of bupropion or solriamfetol with a MAOI is|
03791|030|M|contraindicated due to the risk for hypertensive reactions.(1,2)|
03791|031|M|   The manufacturer of linezolid does not contraindicate the use of|
03791|032|M|serotonergic agents but states that they should not be coadministered unless|
03791|033|M|clinically appropriate and the patient is closely monitored.(5)  This|
03791|034|M|recommendation is consistent with the 2011 FDA Drug Safety Communication on|
03791|035|M|linezolid and serotonergic psychiatric medications.(6,7)|
03791|036|M|   In non-emergency situations in patients maintained on bupropion or|
03791|037|M|solriamfetol when linezolid therapy is planned, discontinue the patient's|
03791|038|M|bupropion or solriamfetol at least 2 weeks in advance of linezolid|
03791|039|M|therapy.(1,6)|
03791|040|M|   In emergency situations in patients maintained on bupropion or|
03791|041|M|solriamfetol, weigh the availability and safety of alternatives to linezolid|
03791|042|M|against the risk of acute hypertension.  If linezolid therapy is required,|
03791|043|M|the patient's bupropion or solriamfetol should be immediately discontinued.|
03791|044|M|Patients' blood pressure should be closely monitored for 2 weeks or until 24|
03791|045|M|hours after the last dose of linezolid, whichever comes first.(1,6)|
03791|046|M|   The patient's bupropion or solriamfetol therapy may be resumed 24 hours|
03791|047|M|after the last dose of linezolid.(1,6)|
03791|048|M|   Clinical studies have found a low incidence of serotonin syndrome in|
03791|049|M|patients on concomitant linezolid and serotonergic agents, ranging from|
03791|050|M|0.24% to 4%, depending on the quality and size of the study.  While|
03791|051|M|linezolid-associated serotonin syndrome is potentially serious and fatal, if|
03791|052|M|treated early, it is quickly reversible with discontinuation of offending|
03791|053|M|agents and supportive care.  Therefore, some authors suggest that use of|
03791|054|M|serotonergic medications should not preclude the use of linezolid but that|
03791|055|M|the clinical situation should be assessed.  If concurrent use of linezolid|
03791|056|M|without a washout is warranted, the patient should be closely|
03791|057|M|monitored.(8-13)|
03791|058|M|   If concurrent therapy is warranted, patients should be monitored for|
03791|059|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03791|060|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03791|061|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03791|062|M|coordination, or severe diarrhea.|
03791|063|B||
03791|064|D|DISCUSSION:  The US manufacturers of bupropion and solriamfetol state that|
03791|065|D|concurrent use of bupropion or solriamfetol with a MAOI is|
03791|066|D|contraindicated.(1,2)|
03791|067|D|   An FDA alert in July 2011(6) described the risk for serotonin syndrome|
03791|068|D|when bupropion is used concurrently with linezolid.  In October 2011 FDA|
03791|069|D|updated these alerts, describing the risk for serotonin syndrome when MAOIs|
03791|070|D|are combined with bupropion (and selected other psychiatric agents not|
03791|071|D|associated with case reports of serotonin syndrome) as unclear.(7)|
03791|072|D|Subsequent bupropion and solriamfetol prescribing information describes an|
03791|073|D|increased risk for hypertensive reactions when co-prescribed with|
03791|074|D|MAOIs.(1,2)|
03791|075|B||
03791|076|R|REFERENCES:|
03791|077|B||
03791|078|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
03791|079|R|  GlaxoSmithKline November, 2019.|1
03791|080|R|2.Sunosi (solriamfetol) US Prescribing Information. Jazz Pharmaceuticals,|1
03791|081|R|  Inc. October, 2021.|1
03791|082|R|3.Zhu AZ, Cox LS, Nollen N, Faseru B, Okuyemi KS, Ahluwalia JS, Benowitz NL,|2
03791|083|R|  Tyndale RF. CYP2B6 and bupropion's smoking-cessation pharmacology: the|2
03791|084|R|  role of hydroxybupropion. Clin Pharmacol Ther 2012 Dec;92(6):771-7.|2
03791|085|R|4.Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ,|5
03791|086|R|  Martin BR. Enantioselective effects of hydroxy metabolites of bupropion on|5
03791|087|R|  behavior and on function of monoamine transporters and nicotinic|5
03791|088|R|  receptors. Mol Pharmacol 2004 Sep;66(3):675-82.|5
03791|089|R|5.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
03791|090|R|6.USFood and Drug Administration. FDA Drug Safety Communication: Serious CNS|1
03791|091|R|  reactions possible when linezolid (Zyvox) is given to patients taking|1
03791|092|R|  certain psychiatric medications. available at:|1
03791|093|R|  http://wayback.archive-it.org/7993/20170722185915/https://www.fda.gov/Drug|1
03791|094|R|  s/DrugSafety/ucm265305.htm July 26, 2011.|1
03791|095|R|7.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
03791|096|R|  information about the drug interaction between linezolid (Zyvox) and|1
03791|097|R|  serotonergic psychiatric medications. available at:|1
03791|098|R|  http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm October 21, 2011.|1
03791|099|R|8.Lodise TP, Patel N, Rivera A, Tristani L, Lazariu V, Vandewall H, McNutt|2
03791|100|R|  LA. Comparative evaluation of serotonin toxicity among veterans affairs|2
03791|101|R|  patients  receiving linezolid and vancomycin. Antimicrob Agents Chemother|2
03791|102|R|  2013 Dec;57(12):5901-11.|2
03791|103|R|9.Ramsey TD, Lau TT, Ensom MH. Serotonergic and adrenergic drug interactions|6
03791|104|R|  associated with linezolid: a critical  review and practical management|6
03791|105|R|  approach. Ann Pharmacother 2013 Apr;47(4):543-60.|6
03791|106|R|10.Woytowish MR, Maynor LM. Clinical relevance of linezolid-associated|6
03791|107|R|   serotonin toxicity. Ann Pharmacother 2013 Mar;47(3):388-97.|6
03791|108|R|11.Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, Lodise TP.|2
03791|109|R|   Comparison of serotonin toxicity with concomitant use of either linezolid|2
03791|110|R|   or  comparators and serotonergic agents: an analysis of Phase III and IV|2
03791|111|R|   randomized  clinical trial data. J Antimicrob Chemother 2012 Feb;|2
03791|112|R|   67(2):494-502.|2
03791|113|R|12.Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion|6
03791|114|R|   J Clin Psychiatry 2009;11(6):353-6.|6
03791|115|R|13.Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug|2
03791|116|R|   interactions: a retrospective survey. Clin Infect Dis 2006 Jul 15;|2
03791|117|R|   43(2):180-7.|2
03792|001|T|MONOGRAPH TITLE:  Buspirone; Dexfenfluramine; Fenfluramine/Linezolid|
03792|002|B||
03792|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03792|004|L|of severe adverse interaction.|
03792|005|B||
03792|006|A|MECHANISM OF ACTION:  Linezolid is a weak, reversible inhibitor of monoamine|
03792|007|A|oxidase.  Buspirone is a 5-HT1A and moderate D2 agonist, while fenfluramine|
03792|008|A|is an agonist of 5HT-2.  Combination of these agents may result an increase|
03792|009|A|in endogenous serotonin and dopamine.(1-6)|
03792|010|B||
03792|011|E|CLINICAL EFFECTS:  Concurrent use of buspirone, dexfenfluramine or|
03792|012|E|fenfluramine with linezolid may result in elevated blood pressure leading to|
03792|013|E|hypertensive crisis.(1-3)|
03792|014|B||
03792|015|P|PREDISPOSING FACTORS:  None determined.|
03792|016|B||
03792|017|M|PATIENT MANAGEMENT:  The US manufacturers of buspirone and fenfluramine|
03792|018|M|state that concurrent use of linezolid is contraindicated.(1,2)|
03792|019|M|   The manufacturer of linezolid does not contraindicate the use of|
03792|020|M|serotonergic agents but states that they should not be coadministered unless|
03792|021|M|clinically appropriate and the patient is closely monitored.(3)  This|
03792|022|M|recommendation is consistent with the 2011 FDA Drug Safety Communication on|
03792|023|M|linezolid and serotonergic psychiatric medications.(8,9)|
03792|024|M|   In non-emergency situations in patients maintained on buspirone,|
03792|025|M|dexfenfluramine or fenfluramine, when linezolid therapy is planned,|
03792|026|M|discontinue the patient's buspirone, dexfenfluramine or fenfluramine at|
03792|027|M|least 2 weeks in advance of linezolid therapy.(6)|
03792|028|M|   In emergency situations in patients maintained on buspirone,|
03792|029|M|dexfenfluramine or fenfluramine, weigh the availability and safety of|
03792|030|M|alternatives to linezolid against the risk of hypertensive crisis.  If|
03792|031|M|linezolid therapy is required, the patient's buspirone, dexfenfluramine or|
03792|032|M|fenfluramine should be immediately discontinued.  Patients should be|
03792|033|M|monitored for hypertensive crisis for 2 weeks or until 24 hours after the|
03792|034|M|last dose of linezolid, whichever comes first.(6)|
03792|035|M|   The patient's buspirone, dexfenfluramine or fenfluramine therapy may be|
03792|036|M|resumed 24 hours after the last dose of linezolid.(6)|
03792|037|M|   If concurrent therapy is warranted, patients should be monitored closely|
03792|038|M|for hypertensive crisis.|
03792|039|B||
03792|040|D|DISCUSSION:  Several cases of elevated blood pressure have been reported in|
03792|041|D|patients receiving MAOIs who were given buspirone.(1)  No adverse sequelae|
03792|042|D|have been reported in these patients.|
03792|043|B||
03792|044|R|REFERENCES:|
03792|045|B||
03792|046|R|1.BuSpar (buspirone hydrochloride) US prescribing information. Bristol Myers|1
03792|047|R|  Squibb Company September, 2007.|1
03792|048|R|2.Fintepla (fenfluramine) US prescribing information. Zogenix Inc. January|1
03792|049|R|  2023.|1
03792|050|R|3.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
03792|051|R|4.Shaikh ZS, Krueper S, Malins TJ. Serotonin syndrome: take a closer look at|6
03792|052|R|  the unwell surgical patient. Ann R Coll Surg Engl 2011 Nov;93(8):569-72.|6
03792|053|R|5.Loane C, Politis M. Buspirone: what is it all about?. Brain Res 2012 Jun|6
03792|054|R|  21;1461:111-8.|6
03792|055|R|6.Iqbal MM, Basil MJ, Kaplan J, Iqbal MT. Overview of serotonin syndrome.|6
03792|056|R|  Ann Clin Psychiatry 2012 Nov;24(4):310-8.|6
03792|057|R|7.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03792|058|R|  352(11):1112-20.|6
03792|059|R|8.USFood and Drug Administration. FDA Drug Safety Communication: Serious CNS|1
03792|060|R|  reactions possible when linezolid (Zyvox) is given to patients taking|1
03792|061|R|  certain psychiatric medications. available at:|1
03792|062|R|  http://wayback.archive-it.org/7993/20170722185915/https://www.fda.gov/Drug|1
03792|063|R|  s/DrugSafety/ucm265305.htm July 26, 2011.|1
03792|064|R|9.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
03792|065|R|  information about the drug interaction between linezolid (Zyvox) and|1
03792|066|R|  serotonergic psychiatric medications. available at:|1
03792|067|R|  http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm October 21, 2011.|1
03792|068|R|10.Lodise TP, Patel N, Rivera A, Tristani L, Lazariu V, Vandewall H, McNutt|2
03792|069|R|   LA. Comparative evaluation of serotonin toxicity among veterans affairs|2
03792|070|R|   patients  receiving linezolid and vancomycin. Antimicrob Agents Chemother|2
03792|071|R|   2013 Dec;57(12):5901-11.|2
03792|072|R|11.Ramsey TD, Lau TT, Ensom MH. Serotonergic and adrenergic drug|6
03792|073|R|   interactions associated with linezolid: a critical  review and practical|6
03792|074|R|   management approach. Ann Pharmacother 2013 Apr;47(4):543-60.|6
03792|075|R|12.Woytowish MR, Maynor LM. Clinical relevance of linezolid-associated|6
03792|076|R|   serotonin toxicity. Ann Pharmacother 2013 Mar;47(3):388-97.|6
03792|077|R|13.Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, Lodise TP.|2
03792|078|R|   Comparison of serotonin toxicity with concomitant use of either linezolid|2
03792|079|R|   or  comparators and serotonergic agents: an analysis of Phase III and IV|2
03792|080|R|   randomized  clinical trial data. J Antimicrob Chemother 2012 Feb;|2
03792|081|R|   67(2):494-502.|2
03792|082|R|14.Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion|6
03792|083|R|   J Clin Psychiatry 2009;11(6):353-6.|6
03792|084|R|15.Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug|2
03792|085|R|   interactions: a retrospective survey. Clin Infect Dis 2006 Jul 15;|2
03792|086|R|   43(2):180-7.|2
03792|087|R|16.Morrison EK, Rowe AS. Probable drug-drug interaction leading to serotonin|3
03792|088|R|   syndrome in a patient treated with concomitant buspirone and linezolid in|3
03792|089|R|   the setting of therapeutic hypothermia. J Clin Pharm Ther 2012 Mar 27.|3
03793|001|T|MONOGRAPH TITLE:  Fentanyl; Levomethadone; Methadone/Linezolid|
03793|002|B||
03793|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03793|004|L|of severe adverse interaction.|
03793|005|B||
03793|006|A|MECHANISM OF ACTION:  Fentanyl, levomethadone, and methadone may inhibit|
03793|007|A|neuronal reuptake of serotonin.  Linezolid increases neuronal serotonin|
03793|008|A|concentration via inhibition of monoamine oxidase.|
03793|009|B||
03793|010|E|CLINICAL EFFECTS:  The concurrent use of fentanyl and methadone with MAOIs|
03793|011|E|has been associated with serotonin syndrome.(1-4)  Levomethadone is an|
03793|012|E|enantiomer of methadone.(5)|
03793|013|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03793|014|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03793|015|E|rigidity.|
03793|016|B||
03793|017|P|PREDISPOSING FACTORS:  Higher opioid concentrations as may occur due to|
03793|018|P|inhibition of opioid clearance, patient specific genomic factors (e.g. poor|
03793|019|P|metabolizer status for a specific P450 enzyme), or high opioid dosage may|
03793|020|P|increase the risk for a severe interaction.|
03793|021|B||
03793|022|M|PATIENT MANAGEMENT:  Recommendations regarding concomitant use of MAOIs like|
03793|023|M|linezolid with fentanyl, levomethadone, and methadone vary in different|
03793|024|M|regions.  In general, the combination of linezolid with these opioids is not|
03793|025|M|recommended.(1-9)  Some regions make stronger recommendations for certain|
03793|026|M|agents.|
03793|027|M|   In Australia, fentanyl and methadone are contraindicated with MAOIs.(6-8)|
03793|028|M|In the UK, methadone is contraindicated with MAOIs.(9)  In Sweden,|
03793|029|M|levomethadone is contraindicated with MAOIs.(5)|
03793|030|M|   The US manufacturer of linezolid does not contraindicate the use of|
03793|031|M|serotonergic agents but states that they should not be coadministered unless|
03793|032|M|clinically appropriate and the patient is closely monitored.(10)|
03793|033|M|   Clinical studies have found a low incidence of serotonin syndrome in|
03793|034|M|patients on concomitant linezolid and serotonergic agents, ranging from|
03793|035|M|0.24% to 4%, depending on the quality and size of the study.  While|
03793|036|M|linezolid-associated serotonin syndrome is potentially serious and fatal, if|
03793|037|M|treated early, it is quickly reversible with discontinuation of offending|
03793|038|M|agents and supportive care.  Therefore, some authors suggest that use of|
03793|039|M|serotonergic medications should not preclude the use of linezolid but that|
03793|040|M|the clinical situation should be assessed.  If concurrent use or use of|
03793|041|M|linezolid without a washout is warranted, the patient should be closely|
03793|042|M|monitored.(11-16)|
03793|043|M|   If concurrent therapy is warranted, patients should be monitored for|
03793|044|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03793|045|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03793|046|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03793|047|M|coordination, or severe diarrhea.|
03793|048|B||
03793|049|D|DISCUSSION:  The interaction between another opioid, meperidine, and MAOIs|
03793|050|D|has been well documented.(17,18)  There are two reports of potential|
03793|051|D|interactions between MAOIs and dextromethorphan.(19,20)|
03793|052|D|   At least one fatality has been reported from the use of fentanyl during|
03793|053|D|surgery in a patient receiving an MAOI.(21)|
03793|054|D|   FDA performed a search of its adverse event database for cases of|
03793|055|D|serotonin syndrome with selected opiates for the period of January 1, 1969|
03793|056|D|to June 12, 2013; five cases were associated with methadone use during this|
03793|057|D|43 year period.(22)|
03793|058|B||
03793|059|R|REFERENCES:|
03793|060|B||
03793|061|R|1.Actiq (fentanyl citrate) US prescribing information. Cephalon, Inc.|1
03793|062|R|  October, 2019.|1
03793|063|R|2.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
03793|064|R|  Inc. October, 2019.|1
03793|065|R|3.Sublimaze (fentanyl citrate) US prescribing information. Akorn, Inc.|1
03793|066|R|  October, 2019.|1
03793|067|R|4.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03793|068|R|  Pharmaceuticals Corp. June, 2021.|1
03793|069|R|5.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03793|070|R|  Pharma AS November 30, 2018.|1
03793|071|R|6.DBL fentanyl injection Australian prescribing information. FH Faulding &|1
03793|072|R|  Co Limited t/a David Bull Laboratories October 31, 2003.|1
03793|073|R|7.Actiq (fentanyl citrate) Australian prescribing information. Orphan|1
03793|074|R|  Australia Pty Ltd. November 2, 2002.|1
03793|075|R|8.Diamorphine hydrochloride Australian prescribing information. Auralis|1
03793|076|R|  March 13, 2008.|1
03793|077|R|9.Metharose (methadone hydrochloride) UK summary of product characteristics.|1
03793|078|R|  Rosemone Pharmaceuticals Limited January 9, 2008.|1
03793|079|R|10.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
03793|080|R|11.Lodise TP, Patel N, Rivera A, Tristani L, Lazariu V, Vandewall H, McNutt|2
03793|081|R|   LA. Comparative evaluation of serotonin toxicity among veterans affairs|2
03793|082|R|   patients  receiving linezolid and vancomycin. Antimicrob Agents Chemother|2
03793|083|R|   2013 Dec;57(12):5901-11.|2
03793|084|R|12.Ramsey TD, Lau TT, Ensom MH. Serotonergic and adrenergic drug|6
03793|085|R|   interactions associated with linezolid: a critical  review and practical|6
03793|086|R|   management approach. Ann Pharmacother 2013 Apr;47(4):543-60.|6
03793|087|R|13.Woytowish MR, Maynor LM. Clinical relevance of linezolid-associated|6
03793|088|R|   serotonin toxicity. Ann Pharmacother 2013 Mar;47(3):388-97.|6
03793|089|R|14.Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, Lodise TP.|2
03793|090|R|   Comparison of serotonin toxicity with concomitant use of either linezolid|2
03793|091|R|   or  comparators and serotonergic agents: an analysis of Phase III and IV|2
03793|092|R|   randomized  clinical trial data. J Antimicrob Chemother 2012 Feb;|2
03793|093|R|   67(2):494-502.|2
03793|094|R|15.Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion|6
03793|095|R|   J Clin Psychiatry 2009;11(6):353-6.|6
03793|096|R|16.Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug|2
03793|097|R|   interactions: a retrospective survey. Clin Infect Dis 2006 Jul 15;|2
03793|098|R|   43(2):180-7.|2
03793|099|R|17.Huang V, Gortney JS. Risk of serotonin syndrome with concomitant|6
03793|100|R|   administration of linezolid and serotonin agonists. Pharmacotherapy 2006|6
03793|101|R|   Dec;26(12):1784-93.|6
03793|102|R|18.Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin|6
03793|103|R|   toxicity. Br J Anaesth 2005 Oct;95(4):434-41.|6
03793|104|R|19.Rivers N, Horner B. Possible lethal reaction between Nardil and|3
03793|105|R|   dextromethorphan. Can Med Assoc J 1970 Jul;103:85.|3
03793|106|R|20.Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine|3
03793|107|R|   oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988 Dec 22;|3
03793|108|R|   319(25):1671.|3
03793|109|R|21.Noble WH, Baker A. MAO inhibitors and coronary artery surgery: a patient|3
03793|110|R|   death. Can J Anaesth 1992 Dec;39(10):1061-6.|3
03793|111|R|22.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03793|112|R|   warns about several safety issues with opioid pain medicines; requires|1
03793|113|R|   label changes. available at:|1
03793|114|R|   http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
03794|001|T|MONOGRAPH TITLE:  Dronedarone/Atazanavir; Fosamprenavir|
03794|002|B||
03794|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03794|004|L|of severe adverse interaction.|
03794|005|B||
03794|006|A|MECHANISM OF ACTION:  Atazanavir and fosamprenavir, moderate inhibitors of|
03794|007|A|CYP3A4, may decrease the metabolism of dronedarone.(1-4)|
03794|008|B||
03794|009|E|CLINICAL EFFECTS:  Concurrent use of atazanavir or fosamprenavir may result|
03794|010|E|in prolongation of the QTc interval and life-threatening cardiac|
03794|011|E|arrhythmias, including torsades de pointes.(1-4)|
03794|012|B||
03794|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03794|014|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03794|015|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03794|016|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03794|017|P|gender, or advanced age.(5)|
03794|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03794|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03794|020|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03794|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03794|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03794|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03794|024|P|dysfunction).(5)|
03794|025|B||
03794|026|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that|
03794|027|M|concurrent administration of strong CYP3A4 inhibitors is contraindicated.|
03794|028|M|There are no recommendations for use of dronedarone with moderate CYP3A4|
03794|029|M|inhibitors.(1)|
03794|030|M|   The US Department of Health and Human Services guidelines for use of|
03794|031|M|antiretroviral agents state that ritonavir-boosted atazanavir (a moderate|
03794|032|M|CYP3A4 inhibitor) is contraindicated with dronedarone, and that unboosted|
03794|033|M|atazanavir should not be coadministered.  Since fosamprenavir is also a|
03794|034|M|moderate CYP3A4 inhibitor, it may be prudent to apply the same guidance to|
03794|035|M|ritonavir-boosted and unboosted fosamprenavir.(4)|
03794|036|M|   If alternatives are not available and concurrent therapy is deemed|
03794|037|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
03794|038|M|and monitor ECG at baseline and at regular intervals.  Correct any|
03794|039|M|electrolyte abnormalities.  Instruct patients to report any irregular|
03794|040|M|heartbeat, dizziness, or fainting.|
03794|041|B||
03794|042|D|DISCUSSION:  Concurrent use of ketoconazole (a strong CYP3A4 inhibitor) and|
03794|043|D|dronedarone (dosages not stated) increased the area-under-curve (AUC) and|
03794|044|D|maximum concentration (Cmax) of dronedarone by 17-fold and 9-fold,|
03794|045|D|respectively.(1)|
03794|046|B||
03794|047|R|REFERENCES:|
03794|048|B||
03794|049|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
03794|050|R|  November, 2020.|1
03794|051|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
03794|052|R|  Squibb Company December, 2024.|1
03794|053|R|3.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
03794|054|R|  March, 2019.|1
03794|055|R|4.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03794|056|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03794|057|R|  HIV. Department of Health and Human Services. Available at|6
03794|058|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03794|059|R|  new-guidelines June 13, 2021.|6
03794|060|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03794|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03794|062|R|  settings: a scientific statement from the American Heart Association and|6
03794|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03794|064|R|  2;55(9):934-47.|6
03795|001|T|MONOGRAPH TITLE:  Flecainide; Propafenone/Selected Protease Inhibitors|
03795|002|B||
03795|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03795|004|L|of severe adverse interaction.|
03795|005|B||
03795|006|A|MECHANISM OF ACTION:  Atazanavir (unboosted or boosted with ritonavir or|
03795|007|A|cobicistat), darunavir (with ritonavir or cobicistat), indinavir (unboosted|
03795|008|A|or boosted with ritonavir), lopinavir/ritonavir, nelfinavir, and|
03795|009|A|paritaprevir/ritonavir may inhibit the metabolism of flecainide and|
03795|010|A|propafenone.(1-10)|
03795|011|B||
03795|012|E|CLINICAL EFFECTS:  Concurrent administration may result in increased levels|
03795|013|E|and clinical effects of flecainide and propafenone, including serious and/or|
03795|014|E|life-threatening effects like QT prolongation and torsades de pointes.(1-10)|
03795|015|B||
03795|016|P|PREDISPOSING FACTORS:  Renal and hepatic impairment may increase risk for|
03795|017|P|excessive QTc prolongation as flecainide and propafenone are both renally|
03795|018|P|and hepatically eliminated.|
03795|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03795|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03795|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03795|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03795|023|P|advanced age.(11)|
03795|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03795|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03795|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03795|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03795|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03795|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03795|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(11)|
03795|031|B||
03795|032|M|PATIENT MANAGEMENT:  The US Department of Health and Human Service|
03795|033|M|guidelines for the use of antiretrovirals state that flecainide and|
03795|034|M|propafenone should not be coadministered with protease inhibitors.(1)|
03795|035|M|   The Canadian manufacturer of atazanavir states that concurrent use of|
03795|036|M|ritonavir-boosted atazanavir with flecainide or propafenone is|
03795|037|M|contraindicated.(3)|
03795|038|M|   The US manufacturers of atazanavir/cobicistat,(4) darunavir,(5-6) and|
03795|039|M|paritaprevir/ritonavir(10) recommend clinical monitoring and therapeutic|
03795|040|M|drug monitoring of flecainide and propafenone if coadministration is|
03795|041|M|necessary.|
03795|042|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03795|043|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03795|044|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03795|045|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03795|046|B||
03795|047|D|DISCUSSION:  Atazanavir (unboosted or boosted with ritonavir or cobicistat),|
03795|048|D|darunavir (with ritonavir or cobicistat), indinavir (unboosted or boosted|
03795|049|D|with ritonavir), lopinavir/ritonavir, nelfinavir, and paritaprevir/ritonavir|
03795|050|D|have been shown to inhibit CYP3A4 in vitro and in vivo.  Agents that are|
03795|051|D|extensively metabolized by CYP3A4 and have high first pass metabolism, like|
03795|052|D|flecainide and propafenone, may be the most susceptible to large increases|
03795|053|D|when coadministered with these protease inhibitors.(2-10)|
03795|054|B||
03795|055|R|REFERENCES:|
03795|056|B||
03795|057|R|1.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03795|058|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03795|059|R|  HIV. Department of Health and Human Services. Available at|6
03795|060|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03795|061|R|  new-guidelines June 13, 2021.|6
03795|062|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
03795|063|R|  Squibb Company December, 2024.|1
03795|064|R|3.Reyataz (atazanavir) Canadian prescribing information. Bristol-Myers|1
03795|065|R|  Squibb Canada August 31, 2023.|1
03795|066|R|4.Evotaz (atazanavir and cobicistat) US prescribing information.|1
03795|067|R|  Bristol-Myers-Squibb Company May, 2025.|1
03795|068|R|5.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
03795|069|R|  March, 2023.|1
03795|070|R|6.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
03795|071|R|  Pharmaceuticals, Inc. March, 2025.|1
03795|072|R|7.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
03795|073|R|  September, 2016.|1
03795|074|R|8.Kaletra (lopinavir/ritonavir) Australian prescribing information. Abbott|1
03795|075|R|  Australasia Pty. Ltd. April 1, 2004.|1
03795|076|R|9.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
03795|077|R|  Pharmaceuticals, Inc. September, 2016.|1
03795|078|R|10.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
03795|079|R|   prescribing information. AbbVie Inc. December, 2019.|1
03795|080|R|11.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
03795|081|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
03795|082|R|   hospital settings: a scientific statement from the American Heart|6
03795|083|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
03795|084|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
03796|001|T|MONOGRAPH TITLE:  Relugolix-Hormonal Combinations/Dual P-gp & Strong 3A4|
03796|002|T|Inducers|
03796|003|B||
03796|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03796|005|L|of severe adverse interaction.|
03796|006|B||
03796|007|A|MECHANISM OF ACTION:  Relugolix, estradiol, and norethindrone are substrates|
03796|008|A|of the intestinal P-glycoprotein (P-gp) efflux transporter and are primarily|
03796|009|A|metabolized by CYP3A4.  Agents that induce both P-gp and CYP3A4 may reduce|
03796|010|A|the plasma levels of relugolix, estradiol, and norethindrone.(1)|
03796|011|B||
03796|012|E|CLINICAL EFFECTS:  Concurrent or recent use of P-gp and strong CYP3A4|
03796|013|E|inducers may result in decreased levels and effectiveness of relugolix,|
03796|014|E|estradiol, and norethindrone.(1)|
03796|015|B||
03796|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03796|017|P|of the inducer for longer than 1-2 weeks.|
03796|018|B||
03796|019|M|PATIENT MANAGEMENT:  Avoid use of relugolix-estradiol-norethindrone with|
03796|020|M|combined P-gp and strong CYP3A4 inducers.(1)|
03796|021|B||
03796|022|D|DISCUSSION:  Coadministration with rifampin (P-gp and strong CYP3A4 inducer)|
03796|023|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
03796|024|D|relugolix by 55% and 23%, respectively.(1)|
03796|025|D|   Dual P-gp and CYP3A4 inducers linked to this monograph include:|
03796|026|D|apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine,|
03796|027|D|and St. John's wort.(2,3)|
03796|028|B||
03796|029|R|REFERENCES:|
03796|030|B||
03796|031|R|1.Myfembree (relugolix, estradiol, and norethindrone) US prescribing|1
03796|032|R|  information. Myovant Sciences, Inc. May, 2021.|1
03796|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03796|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03796|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03796|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03796|037|R|  11/14/2017.|1
03796|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
03796|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03797|001|T|MONOGRAPH TITLE:  Tenecteplase/Heparins|
03797|002|B||
03797|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03797|004|L|of severe adverse interaction.|
03797|005|B||
03797|006|A|MECHANISM OF ACTION:  The concurrent use of tenecteplase and heparins may|
03797|007|A|increase the risk of bleeding.|
03797|008|B||
03797|009|E|CLINICAL EFFECTS:  The concurrent use of tenecteplase and heparins may|
03797|010|E|result in bleeding episodes.|
03797|011|B||
03797|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03797|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03797|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
03797|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03797|016|P|risk for bleeding (e.g. NSAIDs).|
03797|017|B||
03797|018|M|PATIENT MANAGEMENT:  Use of tenecteplase and anticoagulants, including|
03797|019|M|heparins, may increase the risk of bleeding if administered prior to,|
03797|020|M|during, or after tenecteplase therapy.  Concurrent use of tenecteplase and|
03797|021|M|heparins is dependent on the therapeutic indication.|
03797|022|M|   In Acute Ischemic Stroke:|
03797|023|M|   - Clinical practice guidelines for acute ischemic stroke state the use of|
03797|024|M|thrombolytic therapy for an indication of acute ischemic stroke is|
03797|025|M|contraindicated in patients who have received full treatment doses of|
03797|026|M|heparins within 24 hours preceding the onset of stroke or who have an|
03797|027|M|elevated activated partial thromboplastin time (aPTT) > 40 seconds,|
03797|028|M|prothrombin time (PT) > 15 seconds, INR > 1.7, or platelets <100,000/mm3 at|
03797|029|M|presentation.|
03797|030|M|   In Acute Myocardial Infarction:|
03797|031|M|   - Patients who are receiving tenecteplase for an indication of acute|
03797|032|M|myocardial infarction should be carefully monitored for signs of bleeding,|
03797|033|M|especially at arterial puncture sites, if heparin is used concurrently.|
03797|034|M|   - The use of tenecteplase in patients with acute myocardial infarction|
03797|035|M|should follow standard management of myocardial infarction, including|
03797|036|M|minimizing arterial and venous puncture; avoid noncompressible arterial|
03797|037|M|puncture; and minimize internal jugular and subclavian venous punctures to|
03797|038|M|decrease bleeding from the noncompressible sites.|
03797|039|M|   For all indications:|
03797|040|M|   - In the event of serious bleeding, heparins should be discontinued|
03797|041|M|immediately and consider protamine administration for reversal of heparin.|
03797|042|M|   - If concurrent therapy is warranted, monitor patients receiving|
03797|043|M|concurrent therapy for signs of blood loss, including decreased hemoglobin,|
03797|044|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
03797|045|M|evaluate patients with any symptoms.|
03797|046|M|   - When applicable, perform agent-specific laboratory test (e.g. INR,|
03797|047|M|aPTT) to monitor efficacy and safety of anticoagulation.  Discontinue|
03797|048|M|anticoagulation in patients with active pathologic bleeding.|
03797|049|M|   - Instruct patients to report any signs and symptoms of bleeding, such as|
03797|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03797|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03797|052|M|and/or swelling.|
03797|053|B||
03797|054|D|DISCUSSION:  The manufacturer of tenecteplase states that formal interaction|
03797|055|D|studies of tenecteplase with other drugs have not been performed.|
03797|056|D|   Clinical practice guidelines for acute ischemic stroke state the use of|
03797|057|D|thrombolytic therapy for an indication of acute ischemic stroke is|
03797|058|D|contraindicated in patients who have received heparin within 24 hours|
03797|059|D|preceding the onset of stroke and who have an elevated activated partial|
03797|060|D|thromboplastin time (aPTT) at presentation.|
03797|061|D|   Clinical trials of tenecteplase in acute myocardial infarction included|
03797|062|D|concomitant use with heparins.|
03797|063|D|   Patients who are receiving tenecteplase with heparin should be carefully|
03797|064|D|monitored for signs of bleeding, especially at arterial puncture sites.|
03797|065|B||
03797|066|R|REFERENCES:|
03797|067|B||
03797|068|R|1.TNKase (tenecteplase) US prescribing information. Genentech, Inc.|1
03797|069|R|  February, 2018.|1
03797|070|R|2.TNKase (tenecteplase) Canada Product Monographh. Genentech, Inc. May 27,|1
03797|071|R|  2008.|1
03797|072|R|3.Adams HPJr Brott TGFurlan AJGomez CRGrotta JHelgason CMKwiatkowski TLyden|6
03797|073|R|  PDMarler JRTorner JFeinberg WMayberg MThies W. Guidelines for thrombolytic|6
03797|074|R|  therapy for acute stroke: a supplement to the guidelines for the|6
03797|075|R|  management of patients with acute ischemic stroke. A statement for|6
03797|076|R|  healthcare professionals from a Special Writing Group of the Stroke|6
03797|077|R|  Council,  AHA. Circulation 1996 Sep 1;94(5):1167-74.|6
03797|078|R|4.Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC. Guidelines|6
03797|079|R|  for the Early Management of Patients With Acute Ischemic Stroke: 2019|6
03797|080|R|  Update to the 2018 Guidelines for the Early Management of Acute Ischemic|6
03797|081|R|  Stroke:  A Guideline for Healthcare Professionals From the AHA/ASA. Stroke|6
03797|082|R|  2019 Dec;50(12):e344-e418.|6
03798|001|T|MONOGRAPH TITLE:  Alprazolam/Selected Moderate CYP3A4 Inhibitors|
03798|002|B||
03798|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03798|004|L|of severe adverse interaction.|
03798|005|B||
03798|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03798|007|A|metabolism of alprazolam.(1)|
03798|008|B||
03798|009|E|CLINICAL EFFECTS:  Concurrent use may result in increased pharmacologic or|
03798|010|E|toxic effects of alprazolam.  Toxic effects include profound sedation,|
03798|011|E|respiratory depression, coma, and/or death.(1)|
03798|012|B||
03798|013|P|PREDISPOSING FACTORS:  None determined.|
03798|014|B||
03798|015|M|PATIENT MANAGEMENT:  Avoid concomitant use with moderate CYP3A4 inhibitors.|
03798|016|M|Consider reducing the dose of alprazolam when coadministered with a moderate|
03798|017|M|CYP3A4 inhibitor.|
03798|018|M|   If fluvoxamine is concurrently administered with alprazolam, the|
03798|019|M|manufacturer of fluvoxamine recommends that the initial dose of alprazolam|
03798|020|M|be reduced by 50%, followed by titration to the lowest effective dose.(2)|
03798|021|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
03798|022|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03798|023|M|unresponsiveness.|
03798|024|B||
03798|025|D|DISCUSSION:  Coadministration of cimetidine, a moderate CYP3A4 inhibitor,|
03798|026|D|increased the maximum concentration (Cmax) of alprazolam by 82%.(1)|
03798|027|D|   Coadministration with erythromycin, a moderate CYP3A4 inhibitor,|
03798|028|D|increased the area-under-curve (AUC) of alprazolam by 1.61-fold.(1)|
03798|029|D|   Coadministration of fluvoxamine 100 mg daily and alprazolam 1 mg given 4|
03798|030|D|times per day resulted in a 2-fold increase of AUC, Cmax, and half-life of|
03798|031|D|alprazolam.(2)|
03798|032|D|   Selected moderate CYP3A4 inhibitors linked to this monograph include:|
03798|033|D|aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
03798|034|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03798|035|D|fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir,|
03798|036|D|letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol,|
03798|037|D|tofisopam, treosulfan, and verapamil.(3,4)|
03798|038|B||
03798|039|R|REFERENCES:|
03798|040|B||
03798|041|R|1.Xanax (alprazolam) US prescribing information. Pharmacia & Upjohn Company|1
03798|042|R|  February, 2021.|1
03798|043|R|2.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
03798|044|R|  Pharmaceuticals, Inc. August, 2023.|1
03798|045|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03798|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03798|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03798|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03798|049|R|  11/14/2017.|1
03798|050|R|4.This information is based on an extract from the Certara Drug Interaction|6
03798|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03799|001|T|MONOGRAPH TITLE:  Sotorasib/Strong CYP3A4 Inducers|
03799|002|B||
03799|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03799|004|L|of severe adverse interaction.|
03799|005|B||
03799|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03799|007|A|sotorasib.(1)|
03799|008|B||
03799|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer may result in a|
03799|010|E|loss of sotorasib efficacy.(1)|
03799|011|B||
03799|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03799|013|P|of the inducer for longer than 1-2 weeks.|
03799|014|B||
03799|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of sotorasib with strong|
03799|016|M|CYP3A4 inducers.(1)|
03799|017|B||
03799|018|D|DISCUSSION:  Coadministration of repeat doses of rifampin (a strong CYP3A4|
03799|019|D|inducer) with a single dose of sotorasib decreased sotorasib|
03799|020|D|area-under-curve (AUC) and maximum concentration (Cmax) by 51% and 35%,|
03799|021|D|respectively.(1)|
03799|022|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
03799|023|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
03799|024|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
03799|025|D|rifampin, rifapentine and St John's Wort.(2,3)|
03799|026|B||
03799|027|R|REFERENCES:|
03799|028|B||
03799|029|R|1.Lumakras (sotorasib) US prescribing information. Amgen Inc November, 2022.|1
03799|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03799|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03799|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03799|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03799|034|R|  11/14/2017.|1
03799|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
03799|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03800|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/Sotorasib|
03800|002|B||
03800|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03800|004|L|of severe adverse interaction.|
03800|005|B||
03800|006|A|MECHANISM OF ACTION:  Sotorasib is a moderate inducer of CYP3A4 and may|
03800|007|A|increase the metabolism of drugs metabolized by the CYP3A4 enzyme.|
03800|008|B||
03800|009|E|CLINICAL EFFECTS:  Concurrent use of sotorasib may lead to decreased serum|
03800|010|E|levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)|
03800|011|B||
03800|012|P|PREDISPOSING FACTORS:  None determined.|
03800|013|B||
03800|014|M|PATIENT MANAGEMENT:  The manufacturer of sotorasib states that|
03800|015|M|co-administration of CYP3A4 substrates for which minimal concentration|
03800|016|M|decreases may lead to serious therapeutic failure should be avoided.  If|
03800|017|M|concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in|
03800|018|M|accordance with approved product labeling.(1)|
03800|019|B||
03800|020|D|DISCUSSION:  Coadministration of sotorasib with midazolam, a sensitive|
03800|021|D|CYP3A4 substrate, decreased midazolam area-under-curve (AUC) by 53% and|
03800|022|D|maximum concentration (Cmax) by 48%.(1)|
03800|023|D|   CYP3A4 substrates with a narrow therapeutic index linked to this|
03800|024|D|monograph include: alfentanil, felodipine, fentanyl, hydroquinidine,|
03800|025|D|parenteral lefamulin, midazolam, nisoldipine, quinidine, tacrolimus,|
03800|026|D|ticagrelor, and triazolam.(2,3)|
03800|027|B||
03800|028|R|REFERENCES:|
03800|029|B||
03800|030|R|1.Lumakras (sotorasib) US prescribing information. Amgen Inc November, 2022.|1
03800|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03800|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03800|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03800|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03800|035|R|  11/14/2017.|1
03800|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
03800|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03801|001|T|MONOGRAPH TITLE:  Selected P-glycoprotein (P-gp) Substrates/Sotorasib (mono|
03801|002|T|deleted 11/05/2025)|
03801|003|B||
03801|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03801|005|L|of severe adverse interaction.|
03801|006|B||
03801|007|A|MECHANISM OF ACTION:  Sotorasib is an inhibitor of the P-glycoprotein (P-gp)|
03801|008|A|system.  P-gp substrates with a narrow therapeutic index may be|
03801|009|A|increased.(1)|
03801|010|B||
03801|011|E|CLINICAL EFFECTS:  Concurrent use of sotorasib with narrow therapeutic index|
03801|012|E|P-gp substrates may result in elevated levels of the substrate, increasing|
03801|013|E|the risk for adverse effects.(1)|
03801|014|B||
03801|015|P|PREDISPOSING FACTORS:  None determined.|
03801|016|B||
03801|017|M|PATIENT MANAGEMENT:  The US manufacturer of sotorasib states that the|
03801|018|M|concurrent use of narrow therapeutic index P-gp substrates should be|
03801|019|M|avoided.  If concurrent therapy cannot be avoided, the dosage of the narrow|
03801|020|M|therapeutic index P-gp substrate should be decreased according to the|
03801|021|M|substrate prescribing information.(1)|
03801|022|B||
03801|023|D|DISCUSSION:  In a study, sotorasib increased digoxin's area-under-curve|
03801|024|D|(AUC) by 21% and maximum concentration (Cmax) by 91%.(1)|
03801|025|D|   Selected narrow therapeutic index P-gp substrates include: afatinib,|
03801|026|D|betrixaban, digoxin, edoxaban, etoposide, and loperamide.(1,2)|
03801|027|B||
03801|028|R|REFERENCES:|
03801|029|B||
03801|030|R|1.Lumakras (sotorasib) US prescribing information. Amgen Inc November, 2022.|1
03801|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
03801|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03802|001|T|MONOGRAPH TITLE:  Infigratinib/Strong and Moderate CYP3A4 Inhibitors|
03802|002|B||
03802|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03802|004|L|of severe adverse interaction.|
03802|005|B||
03802|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03802|007|A|infigratinib.(1)|
03802|008|B||
03802|009|E|CLINICAL EFFECTS:  Concomitant use of a strong or moderate CYP3A4 inhibitor|
03802|010|E|increases infigratinib plasma concentrations, which may increase the|
03802|011|E|incidence and severity of adverse reactions.(1)|
03802|012|B||
03802|013|P|PREDISPOSING FACTORS:  None determined.|
03802|014|B||
03802|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong or moderate CYP3A4|
03802|016|M|inhibitors with infigratinib.(1)|
03802|017|B||
03802|018|D|DISCUSSION:  Coadministration of multiple doses of itraconazole (a strong|
03802|019|D|CYP3A4 inhibitor) increased infigratinib area-under-curve (AUC) and maximum|
03802|020|D|concentration (Cmax) by 622% and 164%, respectively.(1)|
03802|021|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03802|022|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03802|023|D|ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
03802|024|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03802|025|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03802|026|D|troleandomycin, tucatinib, and voriconazole.(2)|
03802|027|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
03802|028|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
03802|029|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03802|030|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
03802|031|D|lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib,|
03802|032|D|schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)|
03802|033|B||
03802|034|R|REFERENCES:|
03802|035|B||
03802|036|R|1.Truseltiq (infigratinib) US prescribing information. QED Therapeutics,|1
03802|037|R|  Inc. May, 2021.|1
03802|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
03802|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03803|001|T|MONOGRAPH TITLE:  Infigratinib/Strong and Moderate CYP3A4 Inducers|
03803|002|B||
03803|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03803|004|L|of severe adverse interaction.|
03803|005|B||
03803|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03803|007|A|metabolism of infigratinib by CYP3A4.(1)|
03803|008|B||
03803|009|E|CLINICAL EFFECTS:  The concurrent use of strong and moderate CYP3A4 inducers|
03803|010|E|and infigratinib may result in decreased levels and clinical effectiveness|
03803|011|E|of infigratinib.(1)|
03803|012|B||
03803|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03803|014|P|of the inducer for longer than 1-2 weeks.|
03803|015|B||
03803|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong and moderate CYP3A4|
03803|017|M|inducers with infigratinib.(1)|
03803|018|B||
03803|019|D|DISCUSSION:  Coadministration of multiple doses of rifampin (a strong CYP3A4|
03803|020|D|inducer) decreased infigratinib area-under-curve (AUC) and maximum|
03803|021|D|concentration (Cmax) by 56% and 44%, respectively.(1)|
03803|022|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
03803|023|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
03803|024|D|dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine,|
03803|025|D|fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten,|
03803|026|D|mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib,|
03803|027|D|phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin,|
03803|028|D|rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and|
03803|029|D|tovorafenib.(3)|
03803|030|B||
03803|031|R|REFERENCES:|
03803|032|B||
03803|033|R|1.Truseltiq (infigratinib) US prescribing information. QED Therapeutics,|1
03803|034|R|  Inc. May, 2021.|1
03803|035|R|2.Dymond AW, So K, Martin P, Huang Y, Severin P, Mathews D, Lisbon E,|2
03803|036|R|  Mariani G. Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and|2
03803|037|R|  induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy|2
03803|038|R|  subjects: results from two clinical trials. Eur J Clin Pharmacol 2017 Feb;|2
03803|039|R|  73(2):175-184.|2
03803|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
03803|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03804|001|T|MONOGRAPH TITLE:  Sotorasib/H2 Antagonists; Proton Pump Inhibitors|
03804|002|B||
03804|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03804|004|L|of severe adverse interaction.|
03804|005|B||
03804|006|A|MECHANISM OF ACTION:  The aqueous solubility of sotorasib is pH dependent.|
03804|007|A|Higher gastric pH leads to lower solubility which may reduce sotorasib|
03804|008|A|absorption.(1)|
03804|009|B||
03804|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) or H2|
03804|011|E|antagonists may reduce the bioavailability of sotorasib, leading to|
03804|012|E|decreased systemic levels and effectiveness.(1)|
03804|013|B||
03804|014|P|PREDISPOSING FACTORS:  None determined.|
03804|015|B||
03804|016|M|PATIENT MANAGEMENT:  Coadministration of sotorasib with proton pump|
03804|017|M|inhibitors, H2 antagonists, and antacids should be avoided.|
03804|018|M|   If coadministration with an acid-reducing agent is unavoidable, take|
03804|019|M|sotorasib 4 hours before or 10 hours after a locally acting antacid.(1)|
03804|020|M|   The UK manufacturer of sotorasib states if co-administration with an|
03804|021|M|acid-reducing agent (such as a PPI or an H2 antagonist) is required,|
03804|022|M|sotorasib should be taken with an acidic beverage (such as cola).|
03804|023|M|Alternatively, sotorasib should be taken 4 hours before or 10 hours after|
03804|024|M|administration of a local antacid.(2)|
03804|025|B||
03804|026|D|DISCUSSION:  The solubility of sotorasib in the aqueous media decreases over|
03804|027|D|the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL.|
03804|028|D|   In an interaction study, coadministration of repeat doses of omeprazole|
03804|029|D|with a single dose of sotorasib decreased sotorasib maximum concentration|
03804|030|D|(Cmax) by 65% and area-under-curve (AUC) by 57% under fed conditions, and|
03804|031|D|decreased sotorasib Cmax by 57% and AUC by 42% under fasted conditions.|
03804|032|D|Under fasted conditions, co-administration of repeat doses of omeprazole|
03804|033|D|with a single dose of sotorasib and 240ml of an acidic beverage (non-diet|
03804|034|D|cola) decreased sotorasib Cmax by 32% and AUC by 23%.  The UK manufacturer|
03804|035|D|of sotorasib states the clinical relevance of the decreased sotorasib|
03804|036|D|exposure when co-administered with omeprazole and cola is unclear and|
03804|037|D|sotorasib efficacy might be reduced.(2)|
03804|038|D|   Coadministration of a single dose of famotidine given 10 hours prior to|
03804|039|D|and 2 hours after a single dose of sotorasib under fed conditions decreased|
03804|040|D|sotorasib Cmax by 35% and AUC by 38%.(1)|
03804|041|B||
03804|042|R|REFERENCES:|
03804|043|B||
03804|044|R|1.Lumakras (sotorasib) US prescribing information. Amgen Inc November, 2022.|1
03804|045|R|2.Lumykras (sotorasib) UK Prescribing Information. Amgen Ltd May 2024.|1
03805|001|T|MONOGRAPH TITLE:  Sotorasib/Antacids|
03805|002|B||
03805|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03805|004|L|take action as needed.|
03805|005|B||
03805|006|A|MECHANISM OF ACTION:  The aqueous solubility of sotorasib is pH dependent.|
03805|007|A|Higher gastric pH leads to lower solubility which may reduce sotorasib|
03805|008|A|absorption.(1)|
03805|009|B||
03805|010|E|CLINICAL EFFECTS:  Coadministration of antacids may reduce the|
03805|011|E|bioavailability of sotorasib, leading to decreased systemic levels and|
03805|012|E|effectiveness.(1)|
03805|013|B||
03805|014|P|PREDISPOSING FACTORS:  None determined.|
03805|015|B||
03805|016|M|PATIENT MANAGEMENT:  Coadministration of sotorasib with proton pump|
03805|017|M|inhibitors, H2 antagonists, and antacids should be avoided.  If|
03805|018|M|coadministration with an acid-reducing agent is unavoidable, take sotorasib|
03805|019|M|4 hours before or 10 hours after a locally acting antacid.(1)|
03805|020|B||
03805|021|D|DISCUSSION:  The solubility of sotorasib in the aqueous media decreases over|
03805|022|D|the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL.|
03805|023|D|   In an interaction study, coadministration of repeat doses of omeprazole|
03805|024|D|with a single dose of sotorasib decreased sotorasib maximum concentration|
03805|025|D|(Cmax) by 65% and area-under-curve (AUC) by 57% under fed conditions, and|
03805|026|D|decreased sotorasib Cmax by 57% and AUC by 42% under fasted conditions.|
03805|027|D|Coadministration of a single dose of famotidine given 10 hours prior to and|
03805|028|D|2 hours after a single dose of sotorasib under fed conditions decreased|
03805|029|D|sotorasib Cmax by 35% and AUC by 38%.(1)|
03805|030|B||
03805|031|R|REFERENCE:|
03805|032|B||
03805|033|R|1.Lumakras (sotorasib) US prescribing information. Amgen Inc November, 2022.|1
03806|001|T|MONOGRAPH TITLE:  Infigratinib/Proton Pump Inhibitors|
03806|002|B||
03806|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03806|004|L|of severe adverse interaction.|
03806|005|B||
03806|006|A|MECHANISM OF ACTION:  The aqueous solubility of infigratinib is pH|
03806|007|A|dependent.  Higher gastric pH leads to lower solubility which may reduce|
03806|008|A|infigratinib absorption.(1)|
03806|009|B||
03806|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) may|
03806|011|E|reduce the bioavailability of infigratinib, leading to decreased systemic|
03806|012|E|levels and effectiveness.(1)|
03806|013|B||
03806|014|P|PREDISPOSING FACTORS:  None determined.|
03806|015|B||
03806|016|M|PATIENT MANAGEMENT:  Avoid the use of PPIs, H2 antagonists, and locally|
03806|017|M|acting antacids in patients receiving treatment with infigratinib.(1)|
03806|018|M|   If coadministration cannot be avoided and the PPI is replaced with a H2|
03806|019|M|antagonist, take infigratinib 2 hours before or 10 hours after the H2|
03806|020|M|antagonist.(1)|
03806|021|M|   If coadministration cannot be avoided and the PPI is replaced with an|
03806|022|M|antacid, take infigratinib 2 hours before or 2 hours after the antacid.(1)|
03806|023|B||
03806|024|D|DISCUSSION:  Infigratinib is practically insoluble at pH 6.8.(1)|
03806|025|D|   In a clinical study, lansoprazole decreased the area-under-curve (AUC)|
03806|026|D|and maximum concentration (Cmax) of infigratinib by 45% and 49%,|
03806|027|D|respectively.  The AUC and Cmax of the active metabolite BHS697 were|
03806|028|D|decreased by 32% and 44%, respectively, and the active metabolite CQM157's|
03806|029|D|AUC and Cmax were decreased by 72% and 55%, respectively.(1)|
03806|030|B||
03806|031|R|REFERENCE:|
03806|032|B||
03806|033|R|1.Truseltiq (infigratinib) US prescribing information. QED Therapeutics,|1
03806|034|R|  Inc. May, 2021.|1
03807|001|T|MONOGRAPH TITLE:  Selected Sensitive P-gp and CYP3A4 Substrates/Sotorasib|
03807|002|B||
03807|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03807|004|L|of severe adverse interaction.|
03807|005|B||
03807|006|A|MECHANISM OF ACTION:  Sotorasib is a moderate inducer of CYP3A4 and an|
03807|007|A|inhibitor of P-glycoprotein (P-gp).(1)|
03807|008|B||
03807|009|E|CLINICAL EFFECTS:  Concurrent use of sotorasib may lead to increased or|
03807|010|E|decreased serum levels of drugs that are substrates of CYP3A4 and P-gp.(1)|
03807|011|E|The magnitude of this interaction is unknown.|
03807|012|B||
03807|013|P|PREDISPOSING FACTORS:  None determined.|
03807|014|B||
03807|015|M|PATIENT MANAGEMENT:  The manufacturer of sotorasib states that|
03807|016|M|co-administration of CYP3A4 or P-gp substrates for which minimal|
03807|017|M|concentration decreases may lead to serious therapeutic failure or increased|
03807|018|M|risk of adverse effects should be avoided.  If concomitant use is|
03807|019|M|unavoidable, dose modification of the substrate may be necessary.(1)|
03807|020|B||
03807|021|D|DISCUSSION:  Coadministration of sotorasib with midazolam, a sensitive|
03807|022|D|CYP3A4 substrate, decreased midazolam area-under-curve (AUC) by 53% and|
03807|023|D|maximum concentration (Cmax) by 48%.(1)|
03807|024|D|   Coadministration of sotorasib with digoxin, a sensitive P-gp substrate,|
03807|025|D|increased digoxin AUC and Cmax by 21% and 91%, respectively.|
03807|026|D|   CYP3A4 and P-gp substrates linked to this monograph include: everolimus,|
03807|027|D|lefamulin, and venetoclax.(2,3)|
03807|028|B||
03807|029|R|REFERENCES:|
03807|030|B||
03807|031|R|1.Lumakras (sotorasib) US prescribing information. Amgen Inc November, 2022.|1
03807|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03807|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03807|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03807|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03807|036|R|  11/14/2017.|1
03807|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
03807|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03808|001|T|MONOGRAPH TITLE:  Macitentan/Dual Moderate CYP2C9 & CYP3A4 Inhibitors|
03808|002|B||
03808|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03808|004|L|of severe adverse interaction.|
03808|005|B||
03808|006|A|MECHANISM OF ACTION:  Dual moderate inhibitors of CYP2C9 and CYP3A4 may|
03808|007|A|inhibit the metabolism of macitentan.(1)|
03808|008|B||
03808|009|E|CLINICAL EFFECTS:  Concurrent use of a dual moderate inhibitor of CYP2C9 and|
03808|010|E|CYP3A4 may result in elevated levels and increased effects of macitentan.(1)|
03808|011|B||
03808|012|P|PREDISPOSING FACTORS:  None determined.|
03808|013|B||
03808|014|M|PATIENT MANAGEMENT:  The manufacturer of macitentan states that use of dual|
03808|015|M|moderate inhibitors of CYP2C9 and CYP3A4 should be avoided.  Concomitant use|
03808|016|M|of both a moderate CYP3A4 inhibitor and a moderate CYP2C9 inhibit should|
03808|017|M|also be avoided.(1)|
03808|018|B||
03808|019|D|DISCUSSION:  Based on pharmacokinetic (PBPK) modeling, dual moderate|
03808|020|D|inhibitors of CYP2C9 and CYP3A4 such as fluconazole are predicted to|
03808|021|D|increase macitentan exposure by 4-fold.(1)|
03808|022|D|   Dual moderate inhibitors of CYP2C9 and CYP3A4 include: amiodarone and|
03808|023|D|fluconazole.(2)|
03808|024|B||
03808|025|R|REFERENCES:|
03808|026|B||
03808|027|R|1.Opsumit (macitentan) US prescribing information. Actelion Pharmaceuticals|1
03808|028|R|  US, Inc. October, 2021.|1
03808|029|R|2.This information is based on an extract from the Certara Drug Interaction|6
03808|030|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03809|001|T|MONOGRAPH TITLE:  Conivaptan/Voxelotor (mono deleted 12/21/2021)|
03809|002|B||
03809|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03809|004|L|of severe adverse interaction.|
03809|005|B||
03809|006|A|MECHANISM OF ACTION:  Conivaptan may inhibit the metabolism of voxelotor via|
03809|007|A|CYP3A4.(1)  Voxelotor may inhibit the metabolism of conivaptan via|
03809|008|A|CYP3A4.(2)|
03809|009|B||
03809|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
03809|011|E|toxicity from both conivaptan and voxelotor.(1,2)|
03809|012|B||
03809|013|P|PREDISPOSING FACTORS:  The systemic exposure to unbound conivaptan doubled|
03809|014|P|in subjects with moderate and severe hepatic impairment.  In patients with|
03809|015|P|moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic|
03809|016|P|impairment, initiate conivaptan with a loading dose of 10 mg over 30 minutes|
03809|017|P|followed by 10 mg per day as a continuous infusion for 2 to 4 days.|
03809|018|P|Conivaptan may be titrated upward to 20 mg per day if serum sodium is not|
03809|019|P|rising at the desired rate.(1)|
03809|020|P|   Severe hepatic impairment (Child-Pugh C) increases voxelotor exposure.|
03809|021|P|The recommended dosage for patients with severe hepatic impairment is 1,000|
03809|022|P|mg once daily.(2)|
03809|023|B||
03809|024|M|PATIENT MANAGEMENT:  Conivaptan is a sensitive CYP3A4 substrate.(1)  Avoid|
03809|025|M|coadministration of voxelotor with sensitive CYP3A4 substrates with a narrow|
03809|026|M|therapeutic index.  If concomitant use is unavoidable, consider dose|
03809|027|M|reduction of the sensitive CYP3A4 substrate.(2)|
03809|028|M|   The manufacturer of voxelotor states that concurrent use with strong|
03809|029|M|CYP3A4 inhibitors like conivaptan should be avoided.  If concomitant use is|
03809|030|M|unavoidable, the dosage of voxelotor should be reduced to 1,000 mg once|
03809|031|M|daily.(2)|
03809|032|B||
03809|033|D|DISCUSSION:  Concomitant use of ketoconazole, a strong CYP3A4 inhibitor,|
03809|034|D|with oral conivaptan resulted in an increased area-under-curve (AUC) and|
03809|035|D|maximum concentration (Cmax) of 4-fold and 11-fold, respectively.(1)|
03809|036|D|   Concomitant use of conivaptan with midazolam, a sensitive CYP3A4|
03809|037|D|substrate, increased the AUC of midazolam 1 mg (oral dose) by 100% and|
03809|038|D|increased midazolam 2 mg (intravenous dose) AUC by 200%.(1)|
03809|039|D|   Concomitant use of voxelotor with ketoconazole, a strong CYP3A4|
03809|040|D|inhibitor, is predicted to increase voxelotor AUC by 42% to 83%.(2)|
03809|041|D|   Concomitant use of voxelotor with midazolam increased midazolam AUC|
03809|042|D|1.6-fold after one dose and 2-fold after multiple doses.(2)|
03809|043|B||
03809|044|R|REFERENCES:|
03809|045|B||
03809|046|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
03809|047|R|  Pharma US, Inc. October, 2016.|1
03809|048|R|2.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
03809|049|R|  Inc. December, 2021.|1
03810|001|T|MONOGRAPH TITLE:  Samidorphan/Strong CYP3A4 Inducers|
03810|002|B||
03810|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03810|004|L|of severe adverse interaction.|
03810|005|B||
03810|006|A|MECHANISM OF ACTION:  Samidorphan is a substrate of CYP3A4.  Strong inducers|
03810|007|A|of CYP3A4 may increase the metabolism of samidorphan.(1)|
03810|008|A|   For co-formulations of samidorphan with olanzapine, strong CYP3A4|
03810|009|A|inducers that also induce CYP1A2 (e.g., carbamazepine, phenytoin, rifampin),|
03810|010|A|may increase olanzapine metabolism.(1,2)|
03810|011|B||
03810|012|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03810|013|E|may result in decreased levels and effectiveness of samidorphan.(1)|
03810|014|E|   In co-formulations of samidorphan with olanzapine, dual inducers of|
03810|015|E|CYP1A2 and CYP3A4 (e.g., carbamazepine, phenytoin, rifampin) may decrease|
03810|016|E|the levels and effectiveness of olanzapine.(1,2)|
03810|017|B||
03810|018|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03810|019|P|of the inducer for longer than 1-2 weeks.|
03810|020|B||
03810|021|M|PATIENT MANAGEMENT:  The manufacturer of olanzapine-samidorphan states that|
03810|022|M|concurrent use with strong CYP3A4 inducers is not recommended. (1)|
03810|023|B||
03810|024|D|DISCUSSION:  In a clinical study of healthy subjects, rifampin (600 mg daily|
03810|025|D|for 7 days, a strong CYP3A4 inducer and moderate CYP1A2 inducer) decreased|
03810|026|D|the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
03810|027|D|samidorphan 10 mg by 73% and 44%, respectively, and the AUC and Cmax of|
03810|028|D|single-dose olanzapine 10 mg by 48% and 11%.(1,3)|
03810|029|D|   Concurrent use of carbamazepine increased olanzapine clearance by 50%,|
03810|030|D|probably due to CYP1A2 induction by carbamazepine.(1,4)|
03810|031|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
03810|032|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03810|033|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03810|034|D|rifapentine, and St. John's wort.(2,5)|
03810|035|B||
03810|036|R|REFERENCES:|
03810|037|B||
03810|038|R|1.Lybalvi (olanzapine-samidorphan) US prescribing information. Alkermes,|1
03810|039|R|  Inc. January, 2024.|1
03810|040|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03810|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03810|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03810|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03810|044|R|  11/14/2017.|1
03810|045|R|3.Sun L, McDonnell D, Yu M, Kumar V, von Moltke L. A Phase I Open-Label|2
03810|046|R|  Study to Evaluate the Effects of Rifampin on the  Pharmacokinetics of|2
03810|047|R|  Olanzapine and Samidorphan Administered in Combination in  Healthy Human|2
03810|048|R|  Subjects. Clin Drug Investig 2019 May;39(5):477-484.|2
03810|049|R|4.Linnet K, Olesen OV. Free and glucuronidated olanzapine serum|2
03810|050|R|  concentrations in psychiatric patients:  influence of carbamazepine|2
03810|051|R|  comedication. Ther Drug Monit 2002 Aug;24(4):512-7.|2
03810|052|R|5.This information is based on an extract from the Certara Drug Interaction|6
03810|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03811|001|T|MONOGRAPH TITLE:  Olanzapine-Samidorphan/Selected CYP1A2 Inducers|
03811|002|B||
03811|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03811|004|L|take action as needed.|
03811|005|B||
03811|006|A|MECHANISM OF ACTION:  Inducers of CYP1A2 may increase the metabolism of|
03811|007|A|olanzapine.(1,2)|
03811|008|B||
03811|009|E|CLINICAL EFFECTS:  Concurrent use of a CYP1A2 inducer may result in|
03811|010|E|decreased levels and effectiveness of olanzapine.(1,2)|
03811|011|B||
03811|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03811|013|P|of the inducer for longer than 1-2 weeks.|
03811|014|B||
03811|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with olanzapine|
03811|016|M|and a CYP1A2 inducer may require increased dosages of olanzapine.  The|
03811|017|M|dosage of olanzapine may need to be adjusted if concurrent therapy with a|
03811|018|M|CYP1A2 inducer is initiated or discontinued.(1,2)|
03811|019|M|   If a CYP1A2 inducer is initiated in a patient maintained on olanzapine,|
03811|020|M|monitor for decreased effectiveness of olanzapine.|
03811|021|M|   If a CYP1A2 inducer is discontinued in a patient maintained on|
03811|022|M|olanzapine, monitor for olanzapine toxicity.|
03811|023|B||
03811|024|D|DISCUSSION:  Concurrent use of carbamazepine, a CYP1A2 inducer, increased|
03811|025|D|olanzapine clearance by 50%.(1,2)|
03811|026|D|   CYP1A2 inducers linked to this monograph include:  leflunomide,|
03811|027|D|nelfinavir, ritonavir and teriflunomide.(3,4)|
03811|028|B||
03811|029|R|REFERENCES:|
03811|030|B||
03811|031|R|1.Lybalvi (olanzapine-samidorphan) US prescribing information. Alkermes,|1
03811|032|R|  Inc. January, 2024.|1
03811|033|R|2.Linnet K, Olesen OV. Free and glucuronidated olanzapine serum|2
03811|034|R|  concentrations in psychiatric patients:  influence of carbamazepine|2
03811|035|R|  comedication. Ther Drug Monit 2002 Aug;24(4):512-7.|2
03811|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
03811|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03811|038|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03811|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03811|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03811|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03811|042|R|  11/14/2017.|1
03812|001|T|MONOGRAPH TITLE:  Brincidofovir/OATP1B1-3 Inhibitors|
03812|002|B||
03812|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03812|004|L|of severe adverse interaction.|
03812|005|B||
03812|006|A|MECHANISM OF ACTION:  OATP1B1 and 1B3 inhibitors may increase the absorption|
03812|007|A|and/or decrease the hepatic uptake of brincidofovir.(1)|
03812|008|B||
03812|009|E|CLINICAL EFFECTS:  Concurrent use of OATP1B1 or 1B3 inhibitors may result in|
03812|010|E|elevated levels of and side effects from brincidofovir.(1)|
03812|011|B||
03812|012|P|PREDISPOSING FACTORS:  None determined.|
03812|013|B||
03812|014|M|PATIENT MANAGEMENT:  The manufacturer of brincidofovir states that|
03812|015|M|alternative medications that are not OATP1B1 or 1B3 inhibitors should be|
03812|016|M|considered.  If concurrent use is necessary, instruct the patient to take|
03812|017|M|the OATP1B1 or 1B3 inhibitor at least 3 hours after brincidofovir and|
03812|018|M|increase monitoring for side effects, including transaminase and bilirubin|
03812|019|M|elevations and GI side effects like diarrhea.(1)|
03812|020|B||
03812|021|D|DISCUSSION:  In a clinical trial, single-dose oral cyclosporine (600 mg, an|
03812|022|D|OATP1B1 and 1B3 inhibitor) increased the mean brincidofovir area-under-curve|
03812|023|D|(AUC) and maximum concentration (Cmax) by 374% and 269%, respectively.(1)|
03812|024|D|   OATP1B1 and 1B3 inhibitors include: atazanavir, belumosudil, boceprevir,|
03812|025|D|clarithromycin, cyclosporine, darunavir, eltrombopag, encorafenib,|
03812|026|D|erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir,|
03812|027|D|leflunomide, leniolisib, letermovir, lopinavir, ombitasvir-paritaprevir,|
03812|028|D|paritaprevir, resmetirom, rifampin, ritonavir, roxadustat, saquinavir,|
03812|029|D|simeprevir, sofosbuvir, telaprevir, teriflunomide, tipranavir, vadadustat,|
03812|030|D|velpatasvir, and voclosporin.(1,2)|
03812|031|B||
03812|032|R|REFERENCES:|
03812|033|B||
03812|034|R|1.Tembexa (brincidofovir) US prescribing information. Chimerix, Inc. June,|1
03812|035|R|  2021.|1
03812|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
03812|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03813|001|T|MONOGRAPH TITLE:  Ibrexafungerp/Strong CYP3A4 Inhibitors|
03813|002|B||
03813|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03813|004|L|take action as needed.|
03813|005|B||
03813|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03813|007|A|the metabolism of ibrexafungerp.(1)|
03813|008|B||
03813|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03813|010|E|levels of and effects from ibrexafungerp.(1)|
03813|011|B||
03813|012|P|PREDISPOSING FACTORS:  None determined.|
03813|013|B||
03813|014|M|PATIENT MANAGEMENT:  The prescribing information for ibrexafungerp advises|
03813|015|M|that patients on concomitant strong CYP3A4 inhibitors should receive a|
03813|016|M|reduced ibrexafungerp dose of 150 mg approximately 12 hours apart, in the|
03813|017|M|morning and in the evening, for one day.(1)|
03813|018|B||
03813|019|D|DISCUSSION:  In a study of healthy subjects, ketoconazole (400 mg once daily|
03813|020|D|for 15 days, a strong CYP3A4 inhibitor), increased the ibrexafungerp|
03813|021|D|area-under-curve (AUC) by 5.8-fold and maximum concentration (Cmax) by|
03813|022|D|2.5-fold.(1)|
03813|023|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03813|024|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03813|025|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03813|026|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03813|027|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03813|028|D|tucatinib, or voriconazole.(2,3)|
03813|029|B||
03813|030|R|REFERENCES:|
03813|031|B||
03813|032|R|1.Brexafemme (ibrexafungerp) US prescribing information. Scynexis, Inc.|1
03813|033|R|  June, 2021.|1
03813|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03813|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03813|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03813|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03813|038|R|  11/14/2017.|1
03813|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03813|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03814|001|T|MONOGRAPH TITLE:  Ibrexafungerp/Strong and Moderate CYP3A4 Inducers|
03814|002|B||
03814|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03814|004|L|of severe adverse interaction.|
03814|005|B||
03814|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03814|007|A|metabolism of ibrexafungerp by CYP3A4.(1)|
03814|008|B||
03814|009|E|CLINICAL EFFECTS:  The concurrent use of strong or moderate CYP3A4 inducers|
03814|010|E|with ibrexafungerp may result in decreased levels and clinical effectiveness|
03814|011|E|of ibrexafungerp.(1)|
03814|012|B||
03814|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03814|014|P|of the inducer for longer than 1-2 weeks.|
03814|015|B||
03814|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong and moderate CYP3A4|
03814|017|M|inducers with ibrexafungerp.(1)|
03814|018|B||
03814|019|D|DISCUSSION:  Ibrexafungerp is a substrate of CYP3A4.  The manufacturer of|
03814|020|D|ibrexafungerp states that concurrent use of strong or moderate CYP3A4|
03814|021|D|inducers are likely to significantly reduce ibrexafungerp exposure, but this|
03814|022|D|interaction has not been studied.(1)|
03814|023|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
03814|024|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
03814|025|D|dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine,|
03814|026|D|fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten,|
03814|027|D|mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib,|
03814|028|D|phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin,|
03814|029|D|rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and|
03814|030|D|tovorafenib.(2,3)|
03814|031|B||
03814|032|R|REFERENCES:|
03814|033|B||
03814|034|R|1.Brexafemme (ibrexafungerp) US prescribing information. Scynexis, Inc.|1
03814|035|R|  June, 2021.|1
03814|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03814|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03814|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03814|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03814|040|R|  11/14/2017.|1
03814|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
03814|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03815|001|T|MONOGRAPH TITLE:  Filgotinib/Immunosuppressives; Immunomodulators|
03815|002|B||
03815|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03815|004|L|of severe adverse interaction.|
03815|005|B||
03815|006|A|MECHANISM OF ACTION:  Concurrent use of filgotinib with other|
03815|007|A|immunosuppressants or immunomodulators including azathioprine, cyclosporine,|
03815|008|A|tacrolimus, biologic disease-modifying antirheumatic drugs (DMARDs), or|
03815|009|A|other Janus kinase (JAK) inhibitors may result in additive or synergistic|
03815|010|A|effects on the immune system.(1)|
03815|011|B||
03815|012|E|CLINICAL EFFECTS:  Concurrent use of filgotinib with other|
03815|013|E|immunosuppressants or immunomodulators including azathioprine, cyclosporine,|
03815|014|E|tacrolimus, biologic DMARDs, or other JAK inhibitors may increase the risk|
03815|015|E|of serious infections.(1)|
03815|016|B||
03815|017|P|PREDISPOSING FACTORS:  None determined.|
03815|018|B||
03815|019|M|PATIENT MANAGEMENT:  The UK manufacturer of filgotinib states that|
03815|020|M|concurrent use of filgotinib with other immunosuppressants or|
03815|021|M|immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic|
03815|022|M|DMARDs, or other JAK inhibitors is not recommended.(1)|
03815|023|B||
03815|024|D|DISCUSSION:  Serious infections have been reported in patients receiving|
03815|025|D|filgotinib.  Caution should be used in patients with a higher incidence of|
03815|026|D|serious infection, including elderly patients aged 75 years and older.(1)|
03815|027|B||
03815|028|R|REFERENCE:|
03815|029|B||
03815|030|R|1.Jyseleca (filgotinib) UK summary of product characteristics. Gilead|1
03815|031|R|  Sciences July, 2021.|1
03816|001|T|MONOGRAPH TITLE:  Plasminogen/Anticoagulants; Antiplatelets|
03816|002|B||
03816|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03816|004|L|take action as needed.|
03816|005|B||
03816|006|A|MECHANISM OF ACTION:  Bleeding has been reported with the use of|
03816|007|A|plasminogen.(1)|
03816|008|B||
03816|009|E|CLINICAL EFFECTS:  Concurrent use of plasminogen with either anticoagulants|
03816|010|E|or antiplatelets may increase the risk of active bleeding during plasminogen|
03816|011|E|therapy, including bleeding from mucosal disease-related lesions that may|
03816|012|E|manifest as gastrointestinal (GI) bleeding, hemoptysis, epistaxis, vaginal|
03816|013|E|bleeding, or hematuria.(1)|
03816|014|B||
03816|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03816|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03816|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
03816|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03816|019|P|risk for bleeding (e.g. NSAIDs).|
03816|020|B||
03816|021|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with plasminogen|
03816|022|M|and anticoagulants and/or antiplatelets should be closely monitored during|
03816|023|M|plasminogen therapy for active bleeding from mucosal disease-related|
03816|024|M|lesions, including GI bleeding, hemoptysis, epistaxis, vaginal bleeding, or|
03816|025|M|hematuria.(1)|
03816|026|M|   Prior to initiation of treatment with plasminogen, confirm healing of|
03816|027|M|lesions or wounds suspected as a source of a recent bleeding event.  Monitor|
03816|028|M|patients during and for 4 hours after infusion when administering|
03816|029|M|plasminogen with concurrent anticoagulants, antiplatelet drugs, or other|
03816|030|M|agents which may interfere with normal coagulation.(1)|
03816|031|M|   If patient experiences uncontrolled bleeding (defined as any|
03816|032|M|gastrointestinal bleeding or bleeding from any other site that persists|
03816|033|M|longer than 30 minutes), seek emergency care and discontinue plasminogen|
03816|034|M|immediately.(1)|
03816|035|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03816|036|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03816|037|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03816|038|M|patients with any symptoms.|
03816|039|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
03816|040|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03816|041|M|anticoagulation in patients with active pathologic bleeding.|
03816|042|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03816|043|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03816|044|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03816|045|M|and/or swelling.|
03816|046|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03816|047|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
03816|048|M|before initiating, altering the dose or discontinuing either drug.|
03816|049|B||
03816|050|D|DISCUSSION:  Plasminogen has not been studied in patients at an increased|
03816|051|D|risk of bleeding.  Bleeding has been reported with plasminogen in a two|
03816|052|D|single-arm, open-label clinical trials as well as in compassionate use|
03816|053|D|programs.  The incidence of hemorrhage in patients with Plasminogen|
03816|054|D|Deficiency Type 1 was 16% (3/19 patients).(1)|
03816|055|D|   One of the bleeding events occurred two days after receiving the second|
03816|056|D|dose of plasminogen in a patient with a recent history of GI bleeding due to|
03816|057|D|gastric ulcers.  The patient received plasminogen through a compassionate|
03816|058|D|use program and the dose was 6.6 mg/kg body weight every 2 days.  Endoscopy|
03816|059|D|showed multiple ulcers with one actively bleeding ulcer near the pylorus.(1)|
03816|060|B||
03816|061|R|REFERENCE:|
03816|062|B||
03816|063|R|1.RYPLAZIM (plasminogen, human-tvmh) US prescribing information. Prometic|1
03816|064|R|  June, 2021.|1
03817|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/CYP2B6 Inhibitors|
03817|002|B||
03817|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03817|004|L|take action as needed.|
03817|005|B||
03817|006|A|MECHANISM OF ACTION:  Methadone is metabolized primarily by CYP2B6.|
03817|007|A|Inhibitors of CYP2B6 may decrease the metabolism of methadone.(1-3)|
03817|008|A|   Levomethadone is the active (R)-enantiomer of methadone.(4)|
03817|009|B||
03817|010|E|CLINICAL EFFECTS:  Concurrent administration of CYP2B6 inhibitors may result|
03817|011|E|in increased levels and clinical effects of levomethadone or methadone,|
03817|012|E|which may result in QTc prolongation and life-threatening arrhythmias.|
03817|013|E|   Elevated levels can also cause profound sedation, respiratory depression,|
03817|014|E|coma, and/or death.|
03817|015|E|   The discontinuation of CYP2B6 inhibitors in patients maintained on|
03817|016|E|levomethadone or methadone may result in symptoms of opiate withdrawal.|
03817|017|E|   Levomethadone and methadone have been associated with serotonin syndrome.|
03817|018|E|Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
03817|019|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)|
03817|020|B||
03817|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03817|022|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03817|023|P|myocardial infarction, history of torsades de pointes, congenital long QT|
03817|024|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03817|025|P|gender, or advanced age.(5)|
03817|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03817|027|P|higher systemic concentrations of either QT prolonging drug are additional|
03817|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03817|029|P|drug concentrations include rapid infusion of an intravenous dose or|
03817|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03817|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03817|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03817|033|B||
03817|034|M|PATIENT MANAGEMENT:  If concomitant use of levomethadone or methadone and|
03817|035|M|CYP2B6 inhibitors is necessary, closely monitor the patient when a CYP2B6|
03817|036|M|inhibitor is initiated or withdrawn.  The dosage of levomethadone or|
03817|037|M|methadone may need to be adjusted.(3)|
03817|038|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
03817|039|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
03817|040|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03817|041|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03817|042|M|   Respiratory depression can occur at any time during opioid therapy,|
03817|043|M|especially during therapy initiation and following dosage increases.  The|
03817|044|M|risk of opioid-related overdose or overdose-related death is increased with|
03817|045|M|higher opioid doses, and this risk persists over the course of therapy.|
03817|046|M|Consider these risks when using concurrently with agents that may increase|
03817|047|M|opioid drug levels.(6)|
03817|048|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
03817|049|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03817|050|M|unresponsiveness.|
03817|051|M|   If concurrent therapy is warranted, patients should be monitored for|
03817|052|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03817|053|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03817|054|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03817|055|M|coordination, or severe diarrhea.|
03817|056|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03817|057|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03817|058|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03817|059|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03817|060|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03817|061|M|as those taking CNS depressants) and when a patient has household|
03817|062|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03817|063|M|for obtaining an opioid reversal agent (e.g., prescription,|
03817|064|M|over-the-counter, or as part of a community-based program).(7)|
03817|065|B||
03817|066|D|DISCUSSION:  In a clinical study, oral voriconazole (400 mg every 12 hours|
03817|067|D|for 1 day, then 200 mg every 12 hours for 4 days, a CYP2B6 inhibitor)|
03817|068|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
03817|069|D|(R)-methadone by 31% and 47%, respectively, in subjects receiving a|
03817|070|D|methadone maintenance dose of 30 mg to 100 mg daily. The Cmax and AUC of|
03817|071|D|(S)-methadone increased by 65% and 103%, respectively.(3)|
03817|072|D|   In healthy subjects, ticlopidine (250 mg twice daily for 4 days, a CYP2B6|
03817|073|D|inhibitor) increased the dose-adjusted AUC of (R)-methadone and|
03817|074|D|(S)-methadone by about 20% and 60%, respectively.(8)|
03817|075|D|   Inhibitors of CYP2B6 linked to this monograph include: clopidogrel,|
03817|076|D|disulfiram, prasugrel, rolapitant, and ticlopidine.(9)|
03817|077|B||
03817|078|R|REFERENCES:|
03817|079|B||
03817|080|R|1.Kharasch ED. Current Concepts in Methadone Metabolism and Transport. Clin|6
03817|081|R|  Pharmacol Drug Dev 2017 Mar;6(2):125-134.|6
03817|082|R|2.Younis IR, Lakota EA, Volpe DA, Patel V, Xu Y, Sahajwalla CG. Drug-Drug|6
03817|083|R|  Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned. J|6
03817|084|R|  Clin Pharmacol 2019 Aug;59(8):1035-1043.|6
03817|085|R|3.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03817|086|R|  Pharmaceuticals Corp. June, 2021.|1
03817|087|R|4.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03817|088|R|  Pharma AS November 30, 2018.|1
03817|089|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03817|090|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03817|091|R|  settings: a scientific statement from the American Heart Association and|6
03817|092|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03817|093|R|  2;55(9):934-47.|6
03817|094|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03817|095|R|  prescribing information for all opioid pain medicines to provide|1
03817|096|R|  additional guidance for safe use. Available at:|1
03817|097|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03817|098|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03817|099|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03817|100|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03817|101|R|  recommends health care professionals discuss naloxone with all patients|1
03817|102|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03817|103|R|  disorder. Available at:|1
03817|104|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03817|105|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03817|106|R|  d-pain July 23, 2020.|1
03817|107|R|8.Kharasch ED, Stubbert K. Role of cytochrome P4502B6 in methadone|2
03817|108|R|  metabolism and clearance. J Clin Pharmacol 2013 Mar;53(3):305-13.|2
03817|109|R|9.This information is based on an extract from the Certara Drug Interaction|6
03817|110|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03818|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Paroxetine|
03818|002|B||
03818|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03818|004|L|take action as needed.|
03818|005|B||
03818|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown but may|
03818|007|A|involve CYP2D6 inhibition by paroxetine.|
03818|008|A|   Levomethadone is the active (R)-enantiomer of methadone.(1)|
03818|009|B||
03818|010|E|CLINICAL EFFECTS:  Concurrent administration of paroxetine may result in|
03818|011|E|increased levels and clinical effects of levomethadone and methadone,(2)|
03818|012|E|which may result in QTc prolongation and life-threatening arrhythmias.|
03818|013|E|Elevated levels can also cause profound sedation, respiratory depression,|
03818|014|E|coma, and/or death.|
03818|015|E|   The discontinuation of paroxetine in patients maintained on levomethadone|
03818|016|E|or methadone may result in symptoms of opiate withdrawal.|
03818|017|E|   Levomethadone, methadone and paroxetine have been associated with|
03818|018|E|serotonin syndrome.(1,3,4)  Symptoms of serotonin syndrome may include|
03818|019|E|tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
03818|020|E|hyperthermia, and muscle rigidity.|
03818|021|B||
03818|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03818|023|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03818|024|P|myocardial infarction, history of torsades de pointes, congenital long QT|
03818|025|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03818|026|P|gender, or advanced age.(5)|
03818|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03818|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03818|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03818|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03818|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03818|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03818|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03818|034|B||
03818|035|M|PATIENT MANAGEMENT:  If concomitant use of levomethadone or methadone and|
03818|036|M|paroxetine is necessary, closely monitor the patient when paroxetine is|
03818|037|M|initiated or withdrawn.  The dosage of levomethadone or methadone may need|
03818|038|M|to be adjusted.(3)|
03818|039|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
03818|040|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
03818|041|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03818|042|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03818|043|M|   Respiratory depression can occur at any time during opioid therapy,|
03818|044|M|especially during therapy initiation and following dosage increases.  The|
03818|045|M|risk of opioid-related overdose or overdose-related death is increased with|
03818|046|M|higher opioid doses, and this risk persists over the course of therapy.|
03818|047|M|Consider these risks when using concurrently with agents that may increase|
03818|048|M|opioid drug levels.(6)|
03818|049|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
03818|050|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03818|051|M|unresponsiveness.|
03818|052|M|   If concurrent therapy is warranted, patients should be monitored for|
03818|053|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03818|054|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03818|055|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03818|056|M|coordination, or severe diarrhea.|
03818|057|M|   Discuss an opioid reversal agent (e.g., naloxone, nalmefene) with all|
03818|058|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03818|059|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03818|060|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03818|061|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03818|062|M|as those taking CNS depressants) and when a patient has household|
03818|063|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03818|064|M|for obtaining an opioid reversal agent (e.g., prescription,|
03818|065|M|over-the-counter, or as part of a community-based program).(7)|
03818|066|B||
03818|067|D|DISCUSSION:  A study of patients in a methadone maintenance program found|
03818|068|D|that paroxetine 20 mg daily for 12 days significantly increased|
03818|069|D|concentrations of (R)-methadone and (S)-methadone by 26% and 49%,|
03818|070|D|respectively.  Most of this increase was driven by patients who were CYP2D6|
03818|071|D|extensive metabolizers, who experienced a 32% and 53% increase in|
03818|072|D|(R)-methadone and (S)-methadone levels, respectively.  Poor CYP2D6|
03818|073|D|metabolizers did not have an increase in (R)-methadone concentrations, but|
03818|074|D|(S)-methadone concentrations were increased by 36%.(2)|
03818|075|B||
03818|076|R|REFERENCES:|
03818|077|B||
03818|078|R|1.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03818|079|R|  Pharma AS November 30, 2018.|1
03818|080|R|2.Begre S, von Bardeleben U, Ladewig D, Jaquet-Rochat S, Cosendai-Savary L,|2
03818|081|R|  Golay KP, Kosel M, Baumann P, Eap CB. Paroxetine increases steady-state|2
03818|082|R|  concentrations of (R)-methadone in CYP2D6  extensive but not poor|2
03818|083|R|  metabolizers. J Clin Psychopharmacol 2002 Apr;22(2):211-5.|2
03818|084|R|3.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03818|085|R|  Pharmaceuticals Corp. June, 2021.|1
03818|086|R|4.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
03818|087|R|  Technologies January, 2017.|1
03818|088|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03818|089|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03818|090|R|  settings: a scientific statement from the American Heart Association and|6
03818|091|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03818|092|R|  2;55(9):934-47.|6
03818|093|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03818|094|R|  prescribing information for all opioid pain medicines to provide|1
03818|095|R|  additional guidance for safe use. Available at:|1
03818|096|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03818|097|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03818|098|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03818|099|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03818|100|R|  recommends health care professionals discuss naloxone with all patients|1
03818|101|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03818|102|R|  disorder. Available at:|1
03818|103|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03818|104|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03818|105|R|  d-pain July 23, 2020.|1
03819|001|T|MONOGRAPH TITLE:  Posaconazole (Powder for Suspension)/Alcohol|
03819|002|B||
03819|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03819|004|L|of severe adverse interaction.|
03819|005|B||
03819|006|A|MECHANISM OF ACTION:  Concomitant use of alcohol with the delayed-release|
03819|007|A|powder for suspension formulation of posaconazole may result in faster|
03819|008|A|release of posaconazole and interfere with the delayed-release|
03819|009|A|characteristics of the formulation.(1)|
03819|010|B||
03819|011|E|CLINICAL EFFECTS:  Concurrent use of alcohol may result in the powder for|
03819|012|E|suspension formulation having more similar kinetics to the immediate-release|
03819|013|E|oral suspension formulation, which has lower and more variable|
03819|014|E|bioavailability of posaconazole.  This may lead to decreased blood levels|
03819|015|E|and efficacy of posaconazole.(1,2)|
03819|016|B||
03819|017|P|PREDISPOSING FACTORS:  None determined.|
03819|018|B||
03819|019|M|PATIENT MANAGEMENT:  The manufacturer of posaconazole states that the|
03819|020|M|administration of posaconazole powder for suspension with alcohol is not|
03819|021|M|recommended.(1)|
03819|022|M|   Patients are advised to avoid alcohol and elixirs containing a|
03819|023|M|high-percentage of alcohol while taking this product.|
03819|024|B||
03819|025|D|DISCUSSION:  An in vitro dissolution study demonstrated the potential for|
03819|026|D|alcohol-induced dose-dumping with posaconazole delayed-release powder for|
03819|027|D|suspension in the presence of alcohol (5, 10, 20, and 40%), especially at|
03819|028|D|higher concentrations.(1,2)|
03819|029|B||
03819|030|R|REFERENCES:|
03819|031|B||
03819|032|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
03819|033|R|  January, 2022.|1
03819|034|R|2.US Food and Drug Administration (FDA). Drug Approval Package Noxafil|1
03819|035|R|  (posaconazole) Application No.: 214770Orig1s000. Accessed at:|1
03819|036|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214770Orig1s000Mul|1
03819|037|R|  tidisciplineR.pdf May 31, 2021.|1
03820|001|T|MONOGRAPH TITLE:  Ripretinib/Moderate CYP3A4 Inducers|
03820|002|B||
03820|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03820|004|L|of severe adverse interaction.|
03820|005|B||
03820|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
03820|007|A|of ripretinib via this pathway.(1)|
03820|008|A|   Ripretinib and the active metabolite DP-5439 contribute to anticancer|
03820|009|A|activity.  CYP3A4 is the primary metabolism pathway for both ripretinib and|
03820|010|A|the active metabolite DP-5439.(1)|
03820|011|B||
03820|012|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
03820|013|E|alter the clinical effectiveness of ripretinib.(1)|
03820|014|B||
03820|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03820|016|P|of the inducer for longer than 1-2 weeks.|
03820|017|B||
03820|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ripretinib with moderate|
03820|019|M|CYP3A4 inducers.(1-3)  When possible, select alternative agents in place of|
03820|020|M|the moderate CYP3A4 inducer.|
03820|021|M|   If the moderate CYP3A4 inducer cannot be avoided, increase the dose of|
03820|022|M|ripretinib from 150 mg once daily to 150 mg twice daily during concurrent|
03820|023|M|therapy.  Monitor patients receiving concurrent therapy for reduced|
03820|024|M|efficacy.(1-3)|
03820|025|M|   If the moderate CYP3A4 inducer is discontinued, reduce the dose of|
03820|026|M|ripretinib back to 150 mg once daily 14 days after discontinuation of the|
03820|027|M|moderate CYP3A4 inducer.(1-3)|
03820|028|M|   If a dose of ripretinib is missed (in patients taking twice daily|
03820|029|M|dosing):|
03820|030|M|   -If less than 4 hours have passed since missed dose, patient should take|
03820|031|M|the dose as soon as possible and then take the next dose at the regularly|
03820|032|M|scheduled time.|
03820|033|M|   -If more than 4 hours have passed since missed dose, patient should skip|
03820|034|M|the missed dose and then take the next dose at the regularly scheduled|
03820|035|M|time.(1-3)|
03820|036|B||
03820|037|D|DISCUSSION:  The primary metabolism pathway for ripretinib and DP-5439 is|
03820|038|D|via CYP3A4.(1)|
03820|039|D|   In an interaction study of rifampin (a strong CYP3A inducer) and|
03820|040|D|ripretinib, concurrent use decreased ripretinib concentration maximum (Cmax)|
03820|041|D|by 18% and area-under-curve (AUC) by 61%, as well as decreased the active|
03820|042|D|metabolite DP-5439 AUC by 57% and increased Cmax by 37%.(1)|
03820|043|D|   In a pharmacokinetic model of efavirenz (a moderate CYP3A inducer),|
03820|044|D|concurrent use was predicted to decrease ripretinib Cmax by 24% and decrease|
03820|045|D|AUC by 56%.(1)|
03820|046|D|   In the presence of a moderate CYP3A inducer, a doubled ripretinib dose|
03820|047|D|(twice daily rather than once daily), is predicted to result in a 17%|
03820|048|D|reduction in combined AUC of ripretinib and active metabolite DP-5439,|
03820|049|D|compared to the usual recommended once daily dose with no inducer|
03820|050|D|present.(2)|
03820|051|D|   In an interaction study of itraconazole (a strong CYP3A4 inhibitor) and|
03820|052|D|ripretinib, concurrent use increased ripretinib Cmax by 36% and AUC by 99%.|
03820|053|D|Concurrent use increased the AUC of DP-5439 by 99% with no change in|
03820|054|D|Cmax.(1)|
03820|055|D|   Moderate CYP3A4 inducers linked to this monograph are: belzutifan,|
03820|056|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
03820|057|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
03820|058|D|pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat|
03820|059|D|ethyl, thioridazine, and tovorafenib.(4,5)|
03820|060|B||
03820|061|R|REFERENCES:|
03820|062|B||
03820|063|R|1.Qinlock (ripretinib) US prescribing information. Deciphera|1
03820|064|R|  Pharmaceuticals, LLC October, 2023.|1
03820|065|R|2.Qinlock (ripretinib) Australian prescribing information. Specialised|1
03820|066|R|  Therapeutics PM Pty Ltd 25 July 2025.|1
03820|067|R|3.Qinlock (ripretinib) UK Summary of Product Characteristics. Deciphera 14|1
03820|068|R|  March 2023.|1
03820|069|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03820|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03820|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03820|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03820|073|R|  11/14/2017.|1
03820|074|R|5.This information is based on an extract from the Certara Drug Interaction|6
03820|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03821|001|T|MONOGRAPH TITLE:  CYP3A4 Substrates that Prolong QT/Posaconazole|
03821|002|B||
03821|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03821|004|L|is contraindicated and generally should not be dispensed or administered to|
03821|005|L|the same patient.|
03821|006|B||
03821|007|A|MECHANISM OF ACTION:  Posaconazole is a strong inhibitor of CYP3A4 and may|
03821|008|A|inhibit the metabolism of CYP3A4 substrates.  Use of posaconazole with|
03821|009|A|agents that prolong the QTc interval may result in an additive effect on the|
03821|010|A|QTc interval.(1,2)|
03821|011|B||
03821|012|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
03821|013|E|of the CYP3A4 substrate and/or prolongation of the QTc interval, which may|
03821|014|E|result in life-threatening cardiac arrhythmias, including torsades de|
03821|015|E|pointes.(1,2)|
03821|016|B||
03821|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03821|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03821|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03821|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03821|021|P|female gender, or advanced age.(3)|
03821|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03821|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03821|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03821|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03821|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03821|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03821|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03821|029|B||
03821|030|M|PATIENT MANAGEMENT:  The US manufacturer of posaconazole states that the|
03821|031|M|concurrent use of agents that prolong the QTc interval that are metabolized|
03821|032|M|by CYP3A4 is contraindicated.(1)  The UK manufacturer of posaconazole states|
03821|033|M|that CYP3A4 substrates that are known to prolong the QTc interval must not|
03821|034|M|be coadministered.(2)|
03821|035|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
03821|036|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
03821|037|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03821|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03821|039|B||
03821|040|D|DISCUSSION:  Posaconazole has been shown to inhibit CYP3A4.  Elevated levels|
03821|041|D|of CYP3A4 substrates that are known to prolong the QTc interval may have an|
03821|042|D|additive effect on the QTc interval.(1,2)|
03821|043|D|   CYP3A4 substrates that prolong the QTc interval and that are linked to|
03821|044|D|this monograph include: aclarubicin, adagrasib, amiodarone,|
03821|045|D|artemether-lumefantrine, bepridil, clarithromycin, dofetilide, erythromycin,|
03821|046|D|fexinidazole, levomethadyl, lonafarnib, mobocertinib, quizartinib,|
03821|047|D|revumenib, savolitinib, taletrectinib, and telithromycin.|
03821|048|B||
03821|049|R|REFERENCES:|
03821|050|B||
03821|051|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
03821|052|R|  January, 2022.|1
03821|053|R|2.Noxafil (posaconazole) UK summary of product characteristics.|1
03821|054|R|  Schering-Plough Ltd. January, 2022.|1
03821|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03821|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03821|057|R|  settings: a scientific statement from the American Heart Association and|6
03821|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03821|059|R|  2;55(9):934-47.|6
03822|001|T|MONOGRAPH TITLE:  Artemether;Lumefantrine/Strong CYP3A4 Inhib that Prolong|
03822|002|T|QT|
03822|003|B||
03822|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03822|005|L|of severe adverse interaction.|
03822|006|B||
03822|007|A|MECHANISM OF ACTION:  Potent inhibitors of CYP3A4 that prolong the QTc|
03822|008|A|interval may inhibit the metabolism of artemether and lumefantrine and|
03822|009|A|result in additive effects on the QTc interval.(1)|
03822|010|B||
03822|011|E|CLINICAL EFFECTS:  Concurrent use of potent CYP3A4 inhibitors that prolong|
03822|012|E|the QTc interval with artemether-lumefantrine may result in elevated levels|
03822|013|E|of the antimalarial agents and increased risk of toxicities, including|
03822|014|E|additive prolongation of the QTc interval, which may result in life|
03822|015|E|threatening arrhythmia and death.(1)|
03822|016|B||
03822|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03822|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03822|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03822|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03822|021|P|female gender, or advanced age.(2)|
03822|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03822|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03822|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03822|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03822|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03822|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03822|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03822|029|B||
03822|030|M|PATIENT MANAGEMENT:  The US manufacturer of artemether-lumefantrine states|
03822|031|M|that the use of artemether-lumefantrine should be avoided in patients taking|
03822|032|M|drugs that are known to prolong the QTc interval.  Concurrent use with|
03822|033|M|potent CYP3A4 inhibitors should be approached with caution.(1)|
03822|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03822|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03822|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03822|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03822|038|B||
03822|039|D|DISCUSSION:  In a study in 13 healthy subjects, administration of|
03822|040|D|ketoconazole (400 mg Day 1, 200 mg Days 2-5, a potent inhibitor of CYP3A4)|
03822|041|D|with a single dose of artemether-lumefantrine (20 mg/120 mg) increased the|
03822|042|D|area-under-curve (AUC) of artemether and lumefantrine by 2.3-fold and|
03822|043|D|1.6-fold, respectively.(1)|
03822|044|D|   Agents that are linked to this monograph may have varying degrees of|
03822|045|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03822|046|D|been shown to prolong the QTc interval either through their mechanism of|
03822|047|D|action, through studies on their effects on the QTc interval, or through|
03822|048|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03822|049|D|and/or postmarketing reports.(3)|
03822|050|D|    Strong CYP3A4 inhibitors that prolong the QTc interval linked to this|
03822|051|D|monograph include: ceritinib, clarithromycin, lopinavir, ribociclib,|
03822|052|D|saquinavir, telithromycin, and voriconazole.(4,5)|
03822|053|B||
03822|054|R|REFERENCES:|
03822|055|B||
03822|056|R|1.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
03822|057|R|  Pharmaceuticals Corporation August, 2019.|1
03822|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03822|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03822|060|R|  settings: a scientific statement from the American Heart Association and|6
03822|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03822|062|R|  2;55(9):934-47.|6
03822|063|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03822|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03822|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03822|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03822|067|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03822|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03822|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03822|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03822|071|R|  11/14/2017.|1
03822|072|R|5.This information is based on an extract from the Certara Drug Interaction|6
03822|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03823|001|T|MONOGRAPH TITLE:  Sodium Iodide I 131/Myelosuppressives; Immunomodulators|
03823|002|B||
03823|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03823|004|L|of severe adverse interaction.|
03823|005|B||
03823|006|A|MECHANISM OF ACTION:  Sodium iodide I 131 can cause depression of the|
03823|007|A|hematopoetic system.  Myelosuppressives and immunomodulators also suppress|
03823|008|A|the immune system.(1)|
03823|009|B||
03823|010|E|CLINICAL EFFECTS:  Concurrent use of sodium iodide I 131 with agents that|
03823|011|E|cause bone marrow depression, including myelosuppressives or|
03823|012|E|immunomodulators, may result in an enhanced risk of hematologic disorders,|
03823|013|E|including anemia, blood dyscrasias, bone marrow depression, leukopenia, and|
03823|014|E|thrombocytopenia.  Bone marrow depression may increase the risk of serious|
03823|015|E|infections and bleeding.(1)|
03823|016|B||
03823|017|P|PREDISPOSING FACTORS:  None determined.|
03823|018|B||
03823|019|M|PATIENT MANAGEMENT:  The US manufacturer of sodium iodide I 131 states that|
03823|020|M|concurrent use with bone marrow depressants may enhance the depression of|
03823|021|M|the hematopoetic system caused by large doses of sodium iodide I 131.(1)|
03823|022|M|   Sodium iodide I 131 causes a dose-dependent bone marrow suppression,|
03823|023|M|including neutropenia or thrombocytopenia, in the 3 to 5 weeks following|
03823|024|M|administration.  Patients may be at increased risk of infections or bleeding|
03823|025|M|during this time.|
03823|026|M|   Monitor complete blood counts within one month of therapy.  If results|
03823|027|M|indicate leukopenia or thrombocytopenia, dosimetry should be used to|
03823|028|M|determine a safe sodium iodide I 131 activity.(1)|
03823|029|B||
03823|030|D|DISCUSSION:  Hematologic disorders including death have been reported with|
03823|031|D|sodium iodide I 131.  The most common hematologic disorders reported include|
03823|032|D|anemia, blood dyscrasias, bone marrow depression, leukopenia, and|
03823|033|D|thrombocytopenia.(1)|
03823|034|B||
03823|035|R|REFERENCE:|
03823|036|B||
03823|037|R|1.Hicon (sodium iodide I-131) US prescribing information. Jubilant DraxImage|1
03823|038|R|  Inc June, 2021.|1
03824|001|T|MONOGRAPH TITLE:  Glecaprevir-Pibrentasvir/Moderate CYP3A4 and P-gp Inducers|
03824|002|B||
03824|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03824|004|L|of severe adverse interaction.|
03824|005|B||
03824|006|A|MECHANISM OF ACTION:  Glecaprevir and pibrentasvir are substrates of the|
03824|007|A|P-glycoprotein (P-gp) transporter.  Glecaprevir is also a minor substrate of|
03824|008|A|CYP3A4.  Agents that are inducers of P-gp and CYP3A4 may induce efflux and|
03824|009|A|decrease the absorption as well as induce the metabolism of|
03824|010|A|glecaprevir-pibrentasvir.(1)|
03824|011|B||
03824|012|E|CLINICAL EFFECTS:  The combination of glecaprevir-pibrentasvir may not be|
03824|013|E|effective for the treatment of hepatitis C.(1)|
03824|014|B||
03824|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03824|016|P|of the inducer for longer than 1-2 weeks.|
03824|017|B||
03824|018|M|PATIENT MANAGEMENT:  Because of the risk of treatment failure, the UK|
03824|019|M|manufacturer of glecaprevir-pibrentasvir states that concomitant use with|
03824|020|M|moderate CYP3A4 and P-gp inducers is not recommended.(1)|
03824|021|B||
03824|022|D|DISCUSSION:  While not designed to evaluate effects on|
03824|023|D|glecaprevir-pibrentasvir, a study of the effects of glecaprevir-pibrentasvir|
03824|024|D|on efavirenz-emtricitabine-tenofovir observed that geometric mean exposures|
03824|025|D|of glecaprevir and pibrentasvir were 47% lower than historical controls.(2)|
03824|026|D|   In a single dose study in 12 subjects, a single dose of rifampin (600 mg,|
03824|027|D|a strong CYP3A4 and P-gp inducer) with glecaprevir/pibrentasvir (300mg/120|
03824|028|D|mg single dose) increased glecaprevir's maximum concentration (Cmax) and|
03824|029|D|area-under-the-curve (AUC) by 6.52-fold and 8.55-fold, respectively. In|
03824|030|D|another single dose study in 12 subjects, rifampin (600 mg daily) with|
03824|031|D|glecaprevir/pibrentasvir (300 mg/120 mg single dose) decreased glecaprevir's|
03824|032|D|Cmax and AUC by 86% and 88% and pibrentasvir's Cmax and AUC by 83% and 87%,|
03824|033|D|respectively.(1)|
03824|034|D|   In a study in 10 subjects, carbamazepine (200 mg twice daily, a strong|
03824|035|D|CYP3A4 and P-gp inducer) administered concomitantly with|
03824|036|D|glecaprevir/pibrentasvir (300/120 mg daily) decreased the Cmax and AUC of|
03824|037|D|glecaprevir by 67% and 66%, and the Cmax and AUC of pibrentasvir by 50% and|
03824|038|D|51%, respectively.(1)|
03824|039|D|   Moderate CYP3A4 and P-gp inducers linked to this monograph include:|
03824|040|D|lorlatinib and rifabutin.(3)|
03824|041|B||
03824|042|R|REFERENCES:|
03824|043|B||
03824|044|R|1.Maviret (glecaprevir and pibrentasvir) UK Summary of Product|1
03824|045|R|  Characteristics. AbbVie Ltd. August, 2021.|1
03824|046|R|2.Kosloski MP, Oberoi R, Wang S, Viani RM, Asatryan A, Hu B, Ding B, Qi X,|2
03824|047|R|  Kim EJ, Mensa F, Kort J, Liu W. Drug-Drug Interactions of Glecaprevir and|2
03824|048|R|  Pibrentasvir Coadministered With Human  Immunodeficiency Virus|2
03824|049|R|  Antiretrovirals. J Infect Dis 2020 Jan 2;221(2):223-231.|2
03824|050|R|3.This information is based on an extract from the Certara Drug Interaction|6
03824|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03825|001|T|MONOGRAPH TITLE:  Warfarin/Regorafenib|
03825|002|B||
03825|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03825|004|L|take action as needed.|
03825|005|B||
03825|006|A|MECHANISM OF ACTION:  Regorafenib is a CYP2C9 inhibitor(1) which may|
03825|007|A|decrease the metabolism of the S-enantiomer of warfarin.(2-4)  Also,|
03825|008|A|regorafenib and warfarin therapy may both increase the risk of|
03825|009|A|bleeding.(1-2)|
03825|010|B||
03825|011|E|CLINICAL EFFECTS:  Concurrent use of regorafenib may result in elevated|
03825|012|E|levels of warfarin and INR.(1)|
03825|013|E|   Concurrent use of warfarin and regorafenib may increase the risk for|
03825|014|E|bleeding.|
03825|015|B||
03825|016|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03825|017|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03825|018|P|   Drug associated risk factors include concurrent use of multiple drugs|
03825|019|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03825|020|P|risk for bleeding (e.g. NSAIDs).|
03825|021|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
03825|022|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
03825|023|P|are expected to be more susceptible to this interaction.|
03825|024|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
03825|025|P|are expected to be less susceptible to effects from this drug combination,|
03825|026|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
03825|027|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
03825|028|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
03825|029|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
03825|030|P|and safe anticoagulation than patients without these CYP2C9 variants.|
03825|031|B||
03825|032|M|PATIENT MANAGEMENT:  Monitor INRs more frequently until stable in patients|
03825|033|M|who start regorafenib therapy.(1)|
03825|034|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03825|035|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
03825|036|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
03825|037|M|evaluate patients with any symptoms.|
03825|038|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03825|039|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03825|040|M|anticoagulation in patients with active pathologic bleeding.|
03825|041|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03825|042|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03825|043|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03825|044|M|and/or swelling.|
03825|045|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03825|046|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
03825|047|M|initiating, altering the dose or discontinuing either drug.|
03825|048|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
03825|049|B||
03825|050|D|DISCUSSION:  In a study of 8 healthy subjects, regorafenib (160 mg once|
03825|051|D|daily) increased the area-under-the-curve (AUC) of a single dose of warfarin|
03825|052|D|by 25%, compared to warfarin alone.(1)|
03825|053|D|   In clinical studies, regorafenib increased the risk of hemorrhage, with|
03825|054|D|an overall incidence of hemorrhage Grades 1-5 of 18.2% compared to 9.5% in|
03825|055|D|the placebo group.  The incidence of grade 3 or higher hemorrhage was 3% in|
03825|056|D|patients treated with regorafenib, including an incidence of 0.7% of fatal|
03825|057|D|hemorrhagic events.(1)|
03825|058|D|   In a case report of a 76 year old man with liver metastasis of colon|
03825|059|D|cancer, three weeks after starting regorafenib therapy the INR increased|
03825|060|D|significantly.  The INR before starting regorafenib was 1.26 and|
03825|061|D|significantly increased to 2.1 on day 8, 2.98 on day 15, and 6.4 on day 22.|
03825|062|D|Both regorafenib and warfarin were stopped, and the INR decreased to 1.31|
03825|063|D|within one week.  Warfarin was resumed at a lower dose and titrated based on|
03825|064|D|INR during subsequent regorafenib therapy without further elevation.(5)|
03825|065|B||
03825|066|R|REFERENCES:|
03825|067|B||
03825|068|R|1.Stivarga (regorafenib) US prescribing information. Bayer HealthCare|1
03825|069|R|  Pharmaceuticals, Inc. February, 2020.|1
03825|070|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
03825|071|R|  Squibb Company September, 2016.|1
03825|072|R|3.This information is based on an extract from the Certara Drug Interaction|6
03825|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03825|074|R|4.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
03825|075|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
03825|076|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
03825|077|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
03825|078|R|  Oct;90(4):625-9.|6
03825|079|R|5.Kitade H, Hiromasa-Yamasaki A, Hokkoku K, Mori M, Watanabe M, Nakai M,|3
03825|080|R|  Yano S. Elevated prothrombin time/international normalized ratio|3
03825|081|R|  associated with concurrent  administration of regorafenib and warfarin in|3
03825|082|R|  a patient with advanced colorectal  cancer. J Pharm Health Care Sci 2016;|3
03825|083|R|  2:15.|3
03826|001|T|MONOGRAPH TITLE:  Keratinocyte-Fibroblast Skin Tissue/Antimicrobial Topicals|
03826|002|B||
03826|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03826|004|L|take action as needed.|
03826|005|B||
03826|006|A|MECHANISM OF ACTION:  Antimicrobial topicals or dressings containing|
03826|007|A|chlorhexidine, mafenide, or silver may decrease the viability of|
03826|008|A|keratinocytes and fibroblasts used for wound healing in skin tissue|
03826|009|A|replacement products.|
03826|010|B||
03826|011|E|CLINICAL EFFECTS:  The use of antimicrobial topicals or dressings containing|
03826|012|E|chlorhexidine, mafenide, or silver may disrupt the integrity of keratinocyte|
03826|013|E|human skin substitutes and decrease the viability of keratinocytes and|
03826|014|E|fibroblasts.|
03826|015|B||
03826|016|P|PREDISPOSING FACTORS:  None determined.|
03826|017|B||
03826|018|M|PATIENT MANAGEMENT:  The use of antimicrobial topicals or dressings|
03826|019|M|containing chlorhexidine, mafenide, or silver is not recommended.|
03826|020|B||
03826|021|D|DISCUSSION:  Mafenide acetate has been shown to reduce keratinocyte|
03826|022|D|viability and disrupt the integrity of tissue-engineered human skin|
03826|023|D|substitutes.|
03826|024|D|   In vitro data suggest silver may decrease the viability of keratinocytes|
03826|025|D|and human dermal fibroblasts.|
03826|026|D|   Chlorhexidine has been shown to be toxic to keratinocytes and human|
03826|027|D|dermal fibroblasts.(1)|
03826|028|B||
03826|029|R|REFERENCE:|
03826|030|B||
03826|031|R|1.StrataGraft (allogeneic cultured keratinocytes and dermal fibroblasts in|1
03826|032|R|  murine collagen-dsat) US prescribing information. Stratatech Corporation|1
03826|033|R|  June 2021.|1
03827|001|T|MONOGRAPH TITLE:  Thalidomide Analogues/Estrogen-Containing Contraceptives|
03827|002|B||
03827|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03827|004|L|of severe adverse interaction.|
03827|005|B||
03827|006|A|MECHANISM OF ACTION:  Both the thalidomide analogues and estrogen-containing|
03827|007|A|contraceptives are associated with an increased risk of thromboembolic|
03827|008|A|disorders.(1-9)  The US manufacturer of thalidomide states that it is|
03827|009|A|unknown if these risks are additive.(1)|
03827|010|B||
03827|011|E|CLINICAL EFFECTS:  Use of lenalidomide, pomalidomide, or thalidomide in|
03827|012|E|patients taking estrogen-containing hormonal contraceptives may increase the|
03827|013|E|risk of venous or arterial thromboembolism, including deep vein thrombosis|
03827|014|E|(DVT), pulmonary embolism (PE), myocardial infarction (MI), and stroke.(1-9)|
03827|015|B||
03827|016|P|PREDISPOSING FACTORS:  Previous history of thromboembolic events or|
03827|017|P|concomitant administration of erythropoietic agents may increase the|
03827|018|P|thrombotic risk.  Modifiable risk factors (e.g., diabetes, hyperlipidemia,|
03827|019|P|hypertension, smoking) should be minimized.(1-9)|
03827|020|B||
03827|021|M|PATIENT MANAGEMENT:  The Canadian manufacturer of the thalidomide analogues|
03827|022|M|states that use of hormonal contraceptives is not recommended.(2-4)|
03827|023|M|   The UK manufacturer of the thalidomide analogues states that concurrent|
03827|024|M|combined hormonal contraceptives is not recommended and that patients should|
03827|025|M|be switched to a progesterone-only or non-hormonal contraceptive (e.g.,|
03827|026|M|progestin-only pills, progestin implant or intrauterine device, depot|
03827|027|M|medroxyprogesterone acetate, tubal sterilization).(5-7)|
03827|028|M|   The US manufacturer of the thalidomide analogues does not recommend|
03827|029|M|against use of hormonal contraceptives but instead includes them as an|
03827|030|M|option for highly effective contraception.  Estrogen-containing therapies|
03827|031|M|should be used with caution after assessment of their risks and|
03827|032|M|benefits.(1,8-9)|
03827|033|M|   The risk of venous thromboembolism continues for 4-6 weeks after|
03827|034|M|discontinuing combined oral contraception.(5-7)|
03827|035|M|   If the estrogen-containing contraceptive is not used, two other|
03827|036|M|simultaneous, effective methods of contraception are still required in the|
03827|037|M|US and Canada.(1-4,8,9)  In the UK, at least one effective method of|
03827|038|M|contraception is required.(5-7)|
03827|039|B||
03827|040|D|DISCUSSION:  Lenalidomide, pomalidomide, and thalidomide can all cause|
03827|041|D|thromboembolism.  Concurrent use of other agents that may increase the risk|
03827|042|D|of thrombosis, like estrogen-containing therapies, may result in an|
03827|043|D|increased risk of thrombosis.|
03827|044|B||
03827|045|R|REFERENCES:|
03827|046|B||
03827|047|R|1.Thalomid (thalidomide) US prescribing information. Celgene Corporation|1
03827|048|R|  December, 2017.|1
03827|049|R|2.Revlimid (lenalidomide) Canadian prescribing information. Celgene Inc.|1
03827|050|R|  August, 2019.|1
03827|051|R|3.Pomalyst (pomalidomide) Canadian prescribing information. Celgene Inc.|1
03827|052|R|  February, 2021.|1
03827|053|R|4.Thalomid (thalidomide) Canadian prescribing information. Celgene Inc.|1
03827|054|R|  March, 2021.|1
03827|055|R|5.Revlimid (lenalidomide) UK Summary of Product Characteristics.|1
03827|056|R|  Bristol-Myers Squibb Pharmaceuticals limited May 7, 2021.|1
03827|057|R|6.Imnovid (pomalidomide) UK Summary of Product Characteristics. Celgene Ltd|1
03827|058|R|  May 21, 2021.|1
03827|059|R|7.Thalidomide Celgene UK Summary of Product Characteristics. Celgene Ltd May|1
03827|060|R|  7, 2021.|1
03827|061|R|8.Revlimid (lenalidomide) US prescribing information. Celgene Corporation|1
03827|062|R|  May 2019.|1
03827|063|R|9.Pomalyst (pomalidomide) US prescribing information. Celgene Corporation|1
03827|064|R|  November, 2020.|1
03828|001|T|MONOGRAPH TITLE:  Finerenone/Strong CYP3A4 Inhibitors|
03828|002|B||
03828|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03828|004|L|is contraindicated and generally should not be dispensed or administered to|
03828|005|L|the same patient.|
03828|006|B||
03828|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03828|008|A|of finerenone.(1)|
03828|009|B||
03828|010|E|CLINICAL EFFECTS:  Concurrent use of finerenone with a strong inhibitor of|
03828|011|E|CYP3A4 increases finerenone concentrations and may increase the risk of|
03828|012|E|toxicity (e.g. hyperkalemia, hypotension).(1)|
03828|013|B||
03828|014|P|PREDISPOSING FACTORS:  Severe renal disease increases the risk for|
03828|015|P|hyperkalemia.|
03828|016|B||
03828|017|M|PATIENT MANAGEMENT:  The manufacturer of finerenone states that the|
03828|018|M|concurrent use of strong CYP3A4 inhibitors is contraindicated.(1)|
03828|019|M|   In all patients taking finerenone with a moderate or weak CYP3A4|
03828|020|M|inhibitor, monitor serum potassium during drug initiation or dosage|
03828|021|M|adjustment of either finerenone or the moderate or weak CYP3A4 inhibitor.|
03828|022|M|Dose adjustment may be necessary.(1)|
03828|023|B||
03828|024|D|DISCUSSION:  Concurrent use of finerenone with itraconazole, a strong CYP3A4|
03828|025|D|inhibitor, increased finerenone area-under-curve (AUC) by greater than|
03828|026|D|400%.(1)|
03828|027|D|   Concurrent use of finerenone with erythromycin, a moderate CYP3A4|
03828|028|D|inhibitor, increased finerenone mean AUC by 248% and concentration maximum|
03828|029|D|(Cmax) by 88%.(1)|
03828|030|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03828|031|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03828|032|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03828|033|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03828|034|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03828|035|D|tucatinib, and voriconazole.(2,3)|
03828|036|B||
03828|037|R|REFERENCES:|
03828|038|B||
03828|039|R|1.KERENDIA (finerenone) US prescribing information. Bayer HealthCare|1
03828|040|R|  Pharmaceuticals Inc. July, 2025.|1
03828|041|R|2.This information is based on an extract from the Certara Drug Interaction|6
03828|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03828|043|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03828|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03828|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03828|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03828|047|R|  11/14/2017.|1
03829|001|T|MONOGRAPH TITLE:  Finerenone/Strong and Moderate CYP3A4 Inducers|
03829|002|B||
03829|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03829|004|L|of severe adverse interaction.|
03829|005|B||
03829|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
03829|007|A|metabolism of finerenone by CYP3A4.(1)|
03829|008|B||
03829|009|E|CLINICAL EFFECTS:  The concurrent use of strong or moderate CYP3A4 inducers|
03829|010|E|with finerenone may result in decreased levels and clinical effectiveness of|
03829|011|E|finerenone.(1)|
03829|012|B||
03829|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03829|014|P|of the inducer for longer than 1-2 weeks.|
03829|015|B||
03829|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong or moderate CYP3A4|
03829|017|M|inducers with finerenone.(1)|
03829|018|B||
03829|019|D|DISCUSSION:  Finerenone is a substrate of CYP3A4.  Concurrent use of|
03829|020|D|efavirenz (a moderate CYP3A4 inducer) and rifampicin (a strong CYP3A4|
03829|021|D|inducer) decreased finerenone area-under-curve (AUC) by 80% and 90%,|
03829|022|D|respectively.(1)|
03829|023|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
03829|024|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
03829|025|D|dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine,|
03829|026|D|fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten,|
03829|027|D|mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib,|
03829|028|D|phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin,|
03829|029|D|rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and|
03829|030|D|tovorafenib.(2,3)|
03829|031|B||
03829|032|R|REFERENCES:|
03829|033|B||
03829|034|R|1.KERENDIA (finerenone) US prescribing information. Bayer HealthCare|1
03829|035|R|  Pharmaceuticals Inc. July, 2025.|1
03829|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
03829|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03829|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03829|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03829|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03829|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03829|042|R|  11/14/2017.|1
03830|001|T|MONOGRAPH TITLE:  Methylphenidate XR-ODT/H2 Antagonists;Proton Pump|
03830|002|T|Inhibitors|
03830|003|B||
03830|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03830|005|L|of severe adverse interaction.|
03830|006|B||
03830|007|A|MECHANISM OF ACTION:  The solubility of methylphenidate extended release|
03830|008|A|orally disintegrating tablets (XR-ODT) is pH-dependent.  At elevated pH,|
03830|009|A|methylphenidate may be released from the tablets more quickly, resulting in|
03830|010|A|increased absorption.(1)|
03830|011|B||
03830|012|E|CLINICAL EFFECTS:  Coadministration of H2 antagonists or proton pump|
03830|013|E|inhibitors (PPIs) may result in an altered pharmacokinetic profile of|
03830|014|E|methylphenidate XR-ODT, which may change the effectiveness and/or adverse|
03830|015|E|effects of methylphenidate XR-ODT.(1,2)|
03830|016|B||
03830|017|P|PREDISPOSING FACTORS:  None determined.|
03830|018|B||
03830|019|M|PATIENT MANAGEMENT:  Coadministration of methylphenidate XR-ODT with H2|
03830|020|M|antagonists or PPIs is not recommended.(1,2)|
03830|021|B||
03830|022|D|DISCUSSION:  In in vitro studies, when media pH was increased from 1.2 to|
03830|023|D|6.8, percentage release of methylphenidate from the XR-ODT tablet was|
03830|024|D|increased by 67% at 0.5 hours, and by 93% at 2.5 hours.  The increased|
03830|025|D|dissolution of methylphenidate at higher pH may result in increased drug|
03830|026|D|absorption and change the concentration-time profile of methylphenidate,|
03830|027|D|which is correlated with pharmacological effect.(1)|
03830|028|B||
03830|029|R|REFERENCES:|
03830|030|B||
03830|031|R|1.FDA Center for Drug Evaluation and Research (CDER). CDER Application|1
03830|032|R|  number: 205489 Cotempla XR-ODT (methylphenidate) Clinical Pharmacology and|1
03830|033|R|  Biopharmaceutics Review. available at:|1
03830|034|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/205489Orig1s000Cli|1
03830|035|R|  nPharmR.pdf December, 2016.|1
03830|036|R|2.Cotempla XR-ODT (methylphenidate extended-release orally disintegrating|1
03830|037|R|  tablets) US prescribing information. Neo Therapeutics, Inc. July, 2021.|1
03831|001|T|MONOGRAPH TITLE:  Belumosudil/Strong CYP3A4 Inducers|
03831|002|B||
03831|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03831|004|L|take action as needed.|
03831|005|B||
03831|006|A|MECHANISM OF ACTION:  Belumosudil is primarily metabolized by CYP3A4.(1)|
03831|007|B||
03831|008|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers and belumosudil|
03831|009|E|may result in decreased systemic concentrations of belumosudil, which may|
03831|010|E|decrease the efficacy of belumosudil.(1)|
03831|011|B||
03831|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03831|013|P|of the inducer for longer than 1-2 weeks.|
03831|014|B||
03831|015|M|PATIENT MANAGEMENT:  Increase the dosage of belumosudil to 200 mg twice|
03831|016|M|daily when coadministered with strong CYP3A inducers.(1)|
03831|017|B||
03831|018|D|DISCUSSION:  Coadministration of rifampin decreased belumosudil maximum|
03831|019|D|concentration (Cmax) by 59% and area-under-curve (AUC) by 72% in healthy|
03831|020|D|subjects.|
03831|021|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
03831|022|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
03831|023|D|ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone,|
03831|024|D|rifampin, rifapentine and St. John's Wort.(2,3)|
03831|025|B||
03831|026|R|REFERENCES:|
03831|027|B||
03831|028|R|1.Rezurock (belumosudil) US prescribing information. Kadmon Pharmaceuticals,|1
03831|029|R|  LLC April, 2024.|1
03831|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03831|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03831|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03831|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03831|034|R|  11/14/2017.|1
03831|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
03831|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03832|001|T|MONOGRAPH TITLE:  Belumosudil/Proton Pump Inhibitors|
03832|002|B||
03832|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03832|004|L|take action as needed.|
03832|005|B||
03832|006|A|MECHANISM OF ACTION:  Belumosudil is best absorbed in an acidic environment.|
03832|007|A|Proton pump inhibitors (PPIs) decrease gastric acidity and may decrease|
03832|008|A|belumosudil absorption and systemic concentrations.(1)|
03832|009|B||
03832|010|E|CLINICAL EFFECTS:  Coadministration of PPIs with belumosudil decreases|
03832|011|E|systemic concentrations of belumosudil, which may decrease the efficacy of|
03832|012|E|belumosudil.(1)|
03832|013|B||
03832|014|P|PREDISPOSING FACTORS:  None determined.|
03832|015|B||
03832|016|M|PATIENT MANAGEMENT:  Increase the dosage of belumosudil to 200 mg twice|
03832|017|M|daily when coadministered with PPIs.(1)|
03832|018|B||
03832|019|D|DISCUSSION:  Coadministration of rabeprazole decreased belumosudil maximum|
03832|020|D|concentration (Cmax) by 87% and area-under-curve (AUC) by 80%, and|
03832|021|D|omeprazole decreased belumosudil Cmax by 68% and AUC by 47% in healthy|
03832|022|D|subjects.(1)|
03832|023|B||
03832|024|R|REFERENCE:|
03832|025|B||
03832|026|R|1.Rezurock (belumosudil) US prescribing information. Kadmon Pharmaceuticals,|1
03832|027|R|  LLC April, 2024.|1
03833|001|T|MONOGRAPH TITLE:  Maralixibat; Odevixibat/Bile Acid Sequestrants|
03833|002|B||
03833|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03833|004|L|take action as needed.|
03833|005|B||
03833|006|A|MECHANISM OF ACTION:  Bile acid sequestrants may bind to maralixibat and|
03833|007|A|odevixibat in the gut, resulting in decreased absorption of maralixibat or|
03833|008|A|odevixibat.(1,2)|
03833|009|B||
03833|010|E|CLINICAL EFFECTS:  Coadministration of bile acid sequestrants with|
03833|011|E|maralixibat or odevixibat may cause reduced efficacy of maralixibat or|
03833|012|E|odevixibat.(1,2)|
03833|013|B||
03833|014|P|PREDISPOSING FACTORS:  None determined.|
03833|015|B||
03833|016|M|PATIENT MANAGEMENT:  The US manufacturers states to administer bile acid|
03833|017|M|sequestrants (cholestyramine, colesevelam, and colestipol) at least 4 hours|
03833|018|M|before or 4 hours after administration of maralixibat or odevixibat.(1,2)|
03833|019|B||
03833|020|D|DISCUSSION:  Bile acid sequestrants are known to bind to drugs when given|
03833|021|D|concurrently.  Administration with maralixibat or odevixibat may result in|
03833|022|D|decreased systemic absorption.(1,2)|
03833|023|B||
03833|024|R|REFERENCES:|
03833|025|B||
03833|026|R|1.Bylvay (odevixibat) US prescribing information. Albireo Pharma, Inc. Oct,|1
03833|027|R|  2022.|1
03833|028|R|2.Livmarli (Maralixibat) US prescribing information. Mirum Pharmaceuticals,|1
03833|029|R|  Inc. September, 2021.|1
03834|001|T|MONOGRAPH TITLE:  Vorapaxar/Aspirin (> 100 mg)|
03834|002|B||
03834|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03834|004|L|of severe adverse interaction.|
03834|005|B||
03834|006|A|MECHANISM OF ACTION:  Additive effects on hemostasis.(1-3)|
03834|007|B||
03834|008|E|CLINICAL EFFECTS:  Concurrent use of vorapaxar with high-dose aspirin may|
03834|009|E|increase the risk of bleeding while decreasing the efficacy of|
03834|010|E|vorapaxar.(1-3)|
03834|011|B||
03834|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03834|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03834|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
03834|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03834|016|P|risk for bleeding (e.g. NSAIDs).|
03834|017|B||
03834|018|M|PATIENT MANAGEMENT:  Vorapaxar is indicated for concurrent use with|
03834|019|M|antiplatelet dosages of aspirin.  Use of high-dose aspirin should be avoided|
03834|020|M|with vorapaxar.  Patients requiring concurrent therapy with vorapaxar and|
03834|021|M|high-dose aspirin should be closely monitored for signs of bleeding.(1-3)|
03834|022|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
03834|023|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
03834|024|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03834|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03834|026|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03834|027|M|anticoagulation in patients with active pathologic bleeding.|
03834|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03834|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03834|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03834|031|M|and/or swelling.|
03834|032|M|   Discontinue vorapaxar in patients with active bleeding.|
03834|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03834|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
03834|035|M|initiating, altering the dose or discontinuing either drug.|
03834|036|B||
03834|037|D|DISCUSSION:  In the TRA2P and TRACER clinical trials, GUSTO moderate/severe|
03834|038|D|bleeding was increased with higher dosages of aspirin (>= 300 mg), while|
03834|039|D|efficacy of vorapaxar was decreased.(2,3)|
03834|040|B||
03834|041|R|REFERENCES:|
03834|042|B||
03834|043|R|1.Zontivity (vorapaxar) US prescribing information. Merck & Co., Inc.|1
03834|044|R|  November, 2019.|1
03834|045|R|2.Mahaffey KW, Huang Z, Wallentin L, Storey RF, Jennings LK, et al.|2
03834|046|R|  Association of aspirin dose and vorapaxar safety and efficacy in patients|2
03834|047|R|  with  non-ST-segment elevation acute coronary syndrome (from the TRACER|2
03834|048|R|  Trial). Am J Cardiol 2014 Mar 15;113(6):936-44.|2
03834|049|R|3.Serebruany VL, Fortmann SD, Kim MH. Vorapaxar and optimal aspirin dose:|6
03834|050|R|  The FDA outlook. Int J Cardiol 2016 Jan 15;203:903-5.|6
03835|001|T|MONOGRAPH TITLE:  Fexinidazole/QT Prolonging Agents|
03835|002|B||
03835|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03835|004|L|of severe adverse interaction.|
03835|005|B||
03835|006|A|MECHANISM OF ACTION:  Fexinidazole has been shown to prolong the QTc|
03835|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
03835|008|A|may result in additive effects on the QTc interval.(1)|
03835|009|B||
03835|010|E|CLINICAL EFFECTS:  The concurrent use of fexinidazole with other agents that|
03835|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03835|012|E|arrhythmias, including torsades de pointes.(1)|
03835|013|B||
03835|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03835|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03835|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03835|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03835|018|P|gender, or advanced age.(2)|
03835|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03835|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03835|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03835|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03835|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03835|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03835|025|P|dysfunction).(2)|
03835|026|B||
03835|027|M|PATIENT MANAGEMENT:  The US manufacturer of fexinidazole states that|
03835|028|M|fexinidazole should be avoided in patients receiving other drugs known to|
03835|029|M|cause QT prolongation.(1)|
03835|030|M|   Avoid use of fexinidazole in patients who have a baseline QTcF interval|
03835|031|M|greater than 470 msec, a history of torsade de pointes, congenital long QT|
03835|032|M|syndrome, cardiac arrhythmias, uncompensated heart failure, or family|
03835|033|M|history of sudden death, or uncorrected hypokalemia.(1)|
03835|034|M|   If patients are, or need to be, treated with drugs known to prolong QTcF|
03835|035|M|interval or to induce bradycardia, do not initiate therapy with fexinidazole|
03835|036|M|until such drugs are eliminated from the body (allow a washout period of 5|
03835|037|M|half-lives for such other drugs).  Do not start such drugs until|
03835|038|M|fexinidazole therapy is eliminated (allow a washout period of 7 days).(1)|
03835|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03835|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03835|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03835|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03835|043|B||
03835|044|D|DISCUSSION:  In clinical studies, fexinidazole was associated with a|
03835|045|D|concentration-dependent QTcF prolongation.  At recommended therapeutic|
03835|046|D|doses, the mean (upper 90% confidence interval) increase in QTcF is|
03835|047|D|predicted to be 19.0 msec (23.3 msec).  The observed increase in QTcF|
03835|048|D|appears to be associated with the M2 (sulfone) metabolite of|
03835|049|D|fexinidazole.(1)|
03835|050|D|   Agents that are linked to this monograph may have varying degrees of|
03835|051|D|potential to prolong the QTc interval but are generally accepted to have a|
03835|052|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03835|053|D|been shown to prolong the QTc interval either through their mechanism of|
03835|054|D|action, through studies on their effects on the QTc interval, or through|
03835|055|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03835|056|D|and/or post-marketing reports.(3)|
03835|057|B||
03835|058|R|REFERENCES:|
03835|059|B||
03835|060|R|1.Fexinidazole US prescribing information. Sanofi-Aventis U.S. LLC July,|1
03835|061|R|  2021.|1
03835|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03835|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03835|064|R|  settings: a scientific statement from the American Heart Association and|6
03835|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03835|066|R|  2;55(9):934-47.|6
03835|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03835|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03835|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03835|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03836|001|T|MONOGRAPH TITLE:  Fexinidazole/Possible QT Prolonging Agents|
03836|002|B||
03836|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03836|004|L|take action as needed.|
03836|005|B||
03836|006|A|MECHANISM OF ACTION:  Fexinidazole has been shown to prolong the QTc|
03836|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
03836|008|A|may result in additive effects on the QTc interval.(1)|
03836|009|B||
03836|010|E|CLINICAL EFFECTS:  The concurrent use of fexinidazole with other agents that|
03836|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03836|012|E|arrhythmias, including torsades de pointes.(1)|
03836|013|B||
03836|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03836|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03836|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03836|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03836|018|P|gender, or advanced age.(2)|
03836|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03836|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03836|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03836|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03836|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03836|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03836|025|P|dysfunction).(2)|
03836|026|B||
03836|027|M|PATIENT MANAGEMENT:  The US manufacturer of fexinidazole states that|
03836|028|M|fexinidazole should be avoided in patients receiving other drugs known to|
03836|029|M|cause QT prolongation.(1)|
03836|030|M|   Avoid use of fexinidazole in patients who have a baseline QTcF interval|
03836|031|M|greater than 470 msec, a history of torsade de pointes, congenital long QT|
03836|032|M|syndrome, cardiac arrhythmias, uncompensated heart failure, or family|
03836|033|M|history of sudden death, or uncorrected hypokalemia.(1)|
03836|034|M|   If patients are, or need to be, treated with drugs known to prolong QTcF|
03836|035|M|interval or to induce bradycardia do not initiate therapy with fexinidazole|
03836|036|M|until such drugs are eliminated from the body (allow a washout period of 5|
03836|037|M|half-lives for such other drugs).  Do not start such drugs until|
03836|038|M|fexinidazole therapy is eliminated (allow a washout period of 7 days).(1)|
03836|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03836|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03836|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03836|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03836|043|B||
03836|044|D|DISCUSSION:  In clinical studies, fexinidazole was associated with a|
03836|045|D|concentration-dependent QTcF prolongation.  At recommended therapeutic|
03836|046|D|doses, the mean (upper 90% confidence interval) increase in QTcF is|
03836|047|D|predicted to be 19.0 msec (23.3 msec).  The observed increase in QTcF|
03836|048|D|appears to be associated with the M2 (sulfone) metabolite of|
03836|049|D|fexinidazole.(1)|
03836|050|D|   Agents that are linked to this monograph may have varying degrees of|
03836|051|D|potential to prolong the QTc interval but are generally accepted to have a|
03836|052|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03836|053|D|been shown to prolong the QTc interval either through their mechanism of|
03836|054|D|action, through studies on their effects on the QTc interval, or through|
03836|055|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03836|056|D|and/or post-marketing reports.(3)|
03836|057|B||
03836|058|R|REFERENCES:|
03836|059|B||
03836|060|R|1.Fexinidazole US prescribing information. Sanofi-Aventis U.S. LLC July,|1
03836|061|R|  2021.|1
03836|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03836|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03836|064|R|  settings: a scientific statement from the American Heart Association and|6
03836|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03836|066|R|  2;55(9):934-47.|6
03836|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03836|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03836|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03836|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03837|001|T|MONOGRAPH TITLE:  Fexinidazole/Strong & Moderate 3A4 Inhibitor that Prolong|
03837|002|T|QT|
03837|003|B||
03837|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03837|005|L|of severe adverse interaction.|
03837|006|B||
03837|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 that prolong the QT interval may|
03837|008|A|inhibit the metabolism of fexinidazole to its active metabolites.|
03837|009|A|   Fexinidazole may increase the QTc interval.(1)|
03837|010|B||
03837|011|E|CLINICAL EFFECTS:  The concurrent use of fexinidazole with inhibitors of|
03837|012|E|CYP3A4 that prolong the QTc interval may result in decreased levels of its|
03837|013|E|active metabolites, resulting in decreased efficacy.|
03837|014|E|   Concurrent administration of fexinidazole with agents that prolong the|
03837|015|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
03837|016|E|including torsades de pointes.(1)|
03837|017|B||
03837|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03837|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03837|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03837|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03837|022|P|female gender, or advanced age.(2)|
03837|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03837|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03837|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03837|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03837|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03837|028|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03837|029|P|dysfunction).(2)|
03837|030|B||
03837|031|M|PATIENT MANAGEMENT:  Avoid the concurrent use of fexinidazole with|
03837|032|M|medications that prolong the QT interval and inhibit CYP3A4.  If|
03837|033|M|coadministration cannot be avoided, monitor for lack of efficacy of|
03837|034|M|fexinidazole.(1)|
03837|035|M|   Avoid use of fexinidazole in patients who have a baseline QTcF interval|
03837|036|M|greater than 470 msec, a history of torsades de pointes, congenital long QT|
03837|037|M|syndrome, cardiac arrhythmias, uncompensated heart failure, or family|
03837|038|M|history of sudden death, or uncorrected hypokalemia.(1)|
03837|039|M|   If patients are, or need to be, treated with drugs known to prolong the|
03837|040|M|QTcF interval or to induce bradycardia, either do not initiate therapy with|
03837|041|M|fexinidazole until such drugs are eliminated from the body (allow a washout|
03837|042|M|period of 5 half-lives for such other drugs).  Do not start such drugs until|
03837|043|M|fexinidazole therapy is eliminated (allow a washout period of 7 days).(1)|
03837|044|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03837|045|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03837|046|M|treatment, after initiation of any drug known to prolong the QT interval,|
03837|047|M|and periodically monitor during therapy.  Correct any electrolyte|
03837|048|M|abnormalities.  Instruct patients to report any irregular heartbeat,|
03837|049|M|dizziness, or fainting.|
03837|050|B||
03837|051|D|DISCUSSION:  In clinical studies, fexinidazole was associated with a|
03837|052|D|concentration-dependent QTcF prolongation.  At recommended therapeutic|
03837|053|D|doses, the mean (upper 90% confidence interval) increase in QTcF is|
03837|054|D|predicted to be 19.0 msec (23.3 msec).  The observed increase in QTcF|
03837|055|D|appears to be associated with the M2 (sulfone) metabolite of|
03837|056|D|fexinidazole.(1)|
03837|057|D|   Although no clinical drug interaction studies were performed with CYP3A4|
03837|058|D|inhibitors, the formation of the M1 and M2 metabolites may be decreased.(1)|
03837|059|D|   Agents that are linked to this monograph may have varying degrees of|
03837|060|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03837|061|D|been shown to prolong the QTc interval either through their mechanism of|
03837|062|D|action, through studies on their effects on the QTc interval, or through|
03837|063|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03837|064|D|and/or postmarketing reports.(3)|
03837|065|B||
03837|066|R|REFERENCES:|
03837|067|B||
03837|068|R|1.Fexinidazole US prescribing information. Sanofi-Aventis U.S. LLC July,|1
03837|069|R|  2021.|1
03837|070|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03837|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03837|072|R|  settings: a scientific statement from the American Heart Association and|6
03837|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03837|074|R|  2;55(9):934-47.|6
03837|075|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03837|076|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03837|077|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03837|078|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03838|001|T|MONOGRAPH TITLE:  Fexinidazole/Agents That Cause Bradycardia|
03838|002|B||
03838|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03838|004|L|of severe adverse interaction.|
03838|005|B||
03838|006|A|MECHANISM OF ACTION:  Fexinidazole has been shown to prolong the QTc|
03838|007|A|interval.  Concurrent use with agents that cause bradycardia may increase|
03838|008|A|the risk of QTc prolongation.(1)|
03838|009|B||
03838|010|E|CLINICAL EFFECTS:  Bradycardia may be associated with an increase in the QTc|
03838|011|E|interval, increasing the risk for torsade de pointes.(1)|
03838|012|B||
03838|013|P|PREDISPOSING FACTORS:  None determined.|
03838|014|B||
03838|015|M|PATIENT MANAGEMENT:  The manufacturer of fexinidazole recommends avoiding|
03838|016|M|concurrent use of fexinidazole and other agents known to cause|
03838|017|M|bradycardia.(1)|
03838|018|M|   Avoid use of fexinidazole in patients who have a baseline QTcF interval|
03838|019|M|greater than 470 msec, a history of torsade de pointes, congenital long QT|
03838|020|M|syndrome, cardiac arrhythmias, uncompensated heart failure, or family|
03838|021|M|history of sudden death, or uncorrected hypokalemia.(1)|
03838|022|M|   If patients are, or need to be, treated with drugs known to induce|
03838|023|M|bradycardia or prolong the QTc interval do not initiate therapy with|
03838|024|M|fexinidazole until such drugs are eliminated from the body (allow a washout|
03838|025|M|period of 5 half-lives for such other drugs).  Do not start such drugs until|
03838|026|M|fexinidazole therapy is eliminated (allow a washout period of 7 days).(1)|
03838|027|B||
03838|028|D|DISCUSSION:  Bradycardia increases the risk of QTc interval prolongation and|
03838|029|D|torsade de pointes.(1)|
03838|030|D|   In clinical studies, fexinidazole was associated with a|
03838|031|D|concentration-dependent QTcF prolongation.  At recommended therapeutic|
03838|032|D|doses, the mean (upper 90% confidence interval) increase in QTcF is|
03838|033|D|predicted to be 19.0 msec (23.3 msec).  The observed increase in QTcF|
03838|034|D|appears to be associated with the M2 (sulfone) metabolite of|
03838|035|D|fexinidazole.(1)|
03838|036|D|   Agents that may cause bradycardia and linked to this monograph include:|
03838|037|D|beta-blockers, clonidine, digoxin and moxonidine.(1)|
03838|038|B||
03838|039|R|REFERENCE:|
03838|040|B||
03838|041|R|1.Fexinidazole US prescribing information. Sanofi-Aventis U.S. LLC July,|1
03838|042|R|  2021.|1
03839|001|T|MONOGRAPH TITLE:  Fexinidazole/Strong & Moderate 3A4 Inducers that Prolong|
03839|002|T|QT|
03839|003|B||
03839|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03839|005|L|of severe adverse interaction.|
03839|006|B||
03839|007|A|MECHANISM OF ACTION:  Strong and moderate inducers of CYP3A4 that prolong|
03839|008|A|the QTc interval may increase the metabolism of fexinidazole to its active|
03839|009|A|metabolites and result in increased systemic exposure and increased risk for|
03839|010|A|adverse reactions, including additive risk of QT prolongation.(1)|
03839|011|B||
03839|012|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate CYP3A4 inducers|
03839|013|E|that prolongs QT may result in increased levels of fexinidazole's active|
03839|014|E|metabolites (M1 and M2), which may lead to increased risk of adverse|
03839|015|E|reactions.(1)|
03839|016|E|   Concurrent use may cause additive effects on the QTc interval, which may|
03839|017|E|result in life-threatening cardiac arrhythmias including torsades de|
03839|018|E|pointes.(1)|
03839|019|B||
03839|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03839|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
03839|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03839|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03839|024|P|female gender, or advanced age.(2)|
03839|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03839|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03839|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03839|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03839|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03839|030|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03839|031|P|dysfunction).(2)|
03839|032|P|   Induction effects may be more likely with regular use of the inducer for|
03839|033|P|longer than 1-2 weeks.|
03839|034|B||
03839|035|M|PATIENT MANAGEMENT:  Avoid the concurrent use of fexinidazole with|
03839|036|M|medications that prolong the QT interval and induce CYP3A4.(1)|
03839|037|M|   Avoid use of fexinidazole in patients who have a baseline QTcF interval|
03839|038|M|greater than 470 msec, a history of torsades de pointes, congenital long QT|
03839|039|M|syndrome, cardiac arrhythmias, uncompensated heart failure, or family|
03839|040|M|history of sudden death, or uncorrected hypokalemia.(1)|
03839|041|M|   If patients are, or need to be, treated with drugs known to prolong the|
03839|042|M|QTcF interval or to induce bradycardia, do not initiate therapy with|
03839|043|M|fexinidazole until such drugs are eliminated from the body (allow a washout|
03839|044|M|period of 5 half-lives for such other drugs).  Do not start such drugs until|
03839|045|M|fexinidazole therapy is eliminated (allow a washout period of 7 days).(1)|
03839|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03839|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03839|048|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03839|049|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03839|050|B||
03839|051|D|DISCUSSION:  Fexinidazole is metabolized to its active metabolites, M1 and|
03839|052|D|M2, by CYP3A4.  M2 plasma concentrations have been associated with the|
03839|053|D|increased risk of QT prolongation.(1)|
03839|054|D|   In clinical studies, fexinidazole was associated with a|
03839|055|D|concentration-dependent QTcF prolongation.  At recommended therapeutic|
03839|056|D|doses, the mean (upper 90% confidence interval) increase in QTcF is|
03839|057|D|predicted to be 19.0 msec (23.3 msec).  The observed increase in QTcF|
03839|058|D|appears to be associated with the M2 (sulfone) metabolite of|
03839|059|D|fexinidazole.(1)|
03839|060|D|   Agents that are linked to this monograph may have varying degrees of|
03839|061|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03839|062|D|been shown to prolong the QTc interval either through their mechanism of|
03839|063|D|action, through studies on their effects on the QTc interval, or through|
03839|064|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03839|065|D|and/or postmarketing reports.(3)|
03839|066|D|   Strong and moderate inducers of CYP3A4 that prolong QT include:|
03839|067|D|efavirenz, encorafenib, ivosidenib, pacritinib, and thioridazine.(3)|
03839|068|B||
03839|069|R|REFERENCES:|
03839|070|B||
03839|071|R|1.Fexinidazole US prescribing information. Sanofi-Aventis U.S. LLC July,|1
03839|072|R|  2021.|1
03839|073|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03839|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03839|075|R|  settings: a scientific statement from the American Heart Association and|6
03839|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03839|077|R|  2;55(9):934-47.|6
03839|078|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03839|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03839|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03839|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03839|082|R|  11/14/2017.|1
03840|001|T|MONOGRAPH TITLE:  Fexinidazole/Strong and Moderate CYP3A4 Inducers|
03840|002|B||
03840|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03840|004|L|of severe adverse interaction.|
03840|005|B||
03840|006|A|MECHANISM OF ACTION:  Strong and moderate inducers of CYP3A4 may increase|
03840|007|A|the metabolism of fexinidazole to its active metabolites and result in|
03840|008|A|increased systemic exposure and increased risk for adverse reactions,|
03840|009|A|including the risk of QT prolongation.(1)|
03840|010|B||
03840|011|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate CYP3A4 inducer may|
03840|012|E|result in increased levels of fexinidazole's active metabolites (M1 and M2),|
03840|013|E|which may lead to increased risk of adverse reactions and life-threatening|
03840|014|E|cardiac arrhythmias, including torsades des pointes.(1)|
03840|015|B||
03840|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03840|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03840|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03840|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03840|020|P|female gender, or advanced age.(2)|
03840|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03840|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03840|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03840|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03840|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03840|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03840|027|P|dysfunction).(2)|
03840|028|P|   Induction effects may be more likely with regular use of the inducer for|
03840|029|P|longer than 1-2 weeks.|
03840|030|B||
03840|031|M|PATIENT MANAGEMENT:  Avoid the concurrent use of fexinidazole with|
03840|032|M|medications that induce CYP3A4.(1)|
03840|033|M|   Avoid use of fexinidazole in patients who have a baseline QTcF interval|
03840|034|M|greater than 470 msec, a history of torsades de pointes, congenital long QT|
03840|035|M|syndrome, cardiac arrhythmias, uncompensated heart failure, or family|
03840|036|M|history of sudden death, or uncorrected hypokalemia.(1)|
03840|037|M|   If patients are, or need to be, treated with drugs known to prolong the|
03840|038|M|QTcF interval or to induce bradycardia, either do not initiate therapy with|
03840|039|M|fexinidazole until such drugs are eliminated from the body (allow a washout|
03840|040|M|period of 5 half-lives for such other drugs).  Do not start such drugs until|
03840|041|M|fexinidazole therapy is eliminated (allow a washout period of 7 days).(1)|
03840|042|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03840|043|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03840|044|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03840|045|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03840|046|B||
03840|047|D|DISCUSSION:  Fexinidazole is metabolized to its active metabolites, M1 and|
03840|048|D|M2, by CYP3A4.  M2 plasma concentrations have been associated with the|
03840|049|D|increased risk of QT prolongation.(1)|
03840|050|D|   In clinical studies, fexinidazole was associated with a|
03840|051|D|concentration-dependent QTcF prolongation.  At recommended therapeutic|
03840|052|D|doses, the mean (upper 90% confidence interval) increase in QTcF is|
03840|053|D|predicted to be 19.0 msec (23.3 msec).  The observed increase in QTcF|
03840|054|D|appears to be associated with the M2 (sulfone) metabolite of|
03840|055|D|fexinidazole.(1)|
03840|056|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03840|057|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
03840|058|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03840|059|D|wort.(3,4)|
03840|060|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03840|061|D|dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten,|
03840|062|D|mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin,|
03840|063|D|sotorasib, telotristat ethyl, and tovorafenib.(3,4)|
03840|064|B||
03840|065|R|REFERENCES:|
03840|066|B||
03840|067|R|1.Fexinidazole US prescribing information. Sanofi-Aventis U.S. LLC July,|1
03840|068|R|  2021.|1
03840|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03840|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03840|071|R|  settings: a scientific statement from the American Heart Association and|6
03840|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03840|073|R|  2;55(9):934-47.|6
03840|074|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03840|075|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03840|076|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03840|077|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03840|078|R|  11/14/2017.|1
03840|079|R|4.This information is based on an extract from the Certara Drug Interaction|6
03840|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03841|001|T|MONOGRAPH TITLE:  Fexinidazole/Strong and Moderate CYP3A4 Inhibitors|
03841|002|B||
03841|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03841|004|L|of severe adverse interaction.|
03841|005|B||
03841|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
03841|007|A|fexinidazole to its active metabolites.(1)|
03841|008|B||
03841|009|E|CLINICAL EFFECTS:  The concurrent use of fexinidazole with inhibitors of|
03841|010|E|CYP3A4 may result in decreased levels of its active metabolites, resulting|
03841|011|E|in decreased efficacy.(1)|
03841|012|B||
03841|013|P|PREDISPOSING FACTORS:  None determined.|
03841|014|B||
03841|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of fexinidazole with strong|
03841|016|M|and moderate CYP3A4 inhibitors.  If coadministration cannot be avoided,|
03841|017|M|monitor for lack of efficacy of fexinidazole.(1)|
03841|018|B||
03841|019|D|DISCUSSION:  Although no clinical drug interaction studies were performed|
03841|020|D|with CYP3A4 inhibitors, the formation of the M1 and M2 metabolites may be|
03841|021|D|decreased.(1)|
03841|022|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
03841|023|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03841|024|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03841|025|D|tipranavir, troleandomycin, and tucatinib.(2,3)|
03841|026|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  amprenavir,|
03841|027|D|aprepitant, avacopan, berotralstat, conivaptan, diltiazem, duvelisib,|
03841|028|D|fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
03841|029|D|isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib,|
03841|030|D|schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)|
03841|031|B||
03841|032|R|REFERENCES:|
03841|033|B||
03841|034|R|1.Fexinidazole US prescribing information. Sanofi-Aventis U.S. LLC July,|1
03841|035|R|  2021.|1
03841|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
03841|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03841|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03841|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03841|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03841|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03841|042|R|  11/14/2017.|1
03842|001|T|MONOGRAPH TITLE:  COVID-19 Vaccines/Immunosuppressives; Immunomodulators|
03842|002|B||
03842|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03842|004|L|take action as needed.|
03842|005|B||
03842|006|A|MECHANISM OF ACTION:  Immunosuppressants and immunomodulators may prevent|
03842|007|A|the immune system from properly responding to the COVID-19 vaccine.(1,2)|
03842|008|B||
03842|009|E|CLINICAL EFFECTS:  Administration of a COVID-19 vaccine with|
03842|010|E|immunosuppressants or immunomodulators may interfere with vaccine-induced|
03842|011|E|immune response and impair the efficacy of the vaccine.  However, patients|
03842|012|E|should be offered and given a COVID-19 vaccine even if the use and timing of|
03842|013|E|immunosuppressive agents cannot be adjusted.(1,2)|
03842|014|B||
03842|015|P|PREDISPOSING FACTORS:  None determined.|
03842|016|B||
03842|017|M|PATIENT MANAGEMENT:  In an effort to optimize COVID-19 vaccine response, the|
03842|018|M|American College of Rheumatology (ACR) published conditional recommendations|
03842|019|M|for administration of COVID-19 vaccines with immunosuppressants and|
03842|020|M|immunomodulators.(1)  The CDC also provides clinical considerations for|
03842|021|M|COVID-19 vaccination in patients on immunosuppressants.(2)|
03842|022|M|   The CDC states that all immunocompromised patients over 6 months of age|
03842|023|M|should receive at least 1 dose of COVID-19 vaccine if eligible.  See the|
03842|024|M|CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for|
03842|025|M|specific recommendations based on age, vaccination history, and vaccine|
03842|026|M|manufacturer.(2)|
03842|027|M|   The ACR states that in general, immunosuppressants and immunomodulators|
03842|028|M|should be held for 1-2 weeks after each vaccine dose.  See below for|
03842|029|M|specific recommendations for certain agents.(1)  The CDC advises planning|
03842|030|M|for vaccination at least 2 weeks before starting or resuming|
03842|031|M|immunosuppressive therapy.(2)  Patients should be offered and given a|
03842|032|M|COVID-19 vaccine even if the use and timing of immunosuppressive agents|
03842|033|M|cannot be adjusted.(1,2)|
03842|034|M|   B-cell depleting agents, including rituximab: The ACR recommends|
03842|035|M|consulting with the rheumatologist to determine optimal timing of COVID-19|
03842|036|M|vaccination.  Measuring CD19 B cells may be considered to determine need for|
03842|037|M|a booster vaccine dose.  If B cell levels are not measured, a supplemental|
03842|038|M|vaccine dose 2-4 weeks before the next scheduled dose of rituximab is|
03842|039|M|recommended.(1)  The CDC states that the utility of B-cell quantification to|
03842|040|M|guide clinical care is not known and is not recommended.  Patients who|
03842|041|M|receive B-cell depleting therapy should receive COVID-19 vaccines about 4|
03842|042|M|weeks before the next scheduled dose.  For patients who received 1 or more|
03842|043|M|doses of COVID-19 vaccine during treatment with B-cell-depleting therapies|
03842|044|M|that were administered over a limited period (e.g., as part of a treatment|
03842|045|M|regimen for certain malignancies), revaccination may be considered.  The|
03842|046|M|suggested interval to start revaccination is about 6 months after completion|
03842|047|M|of the B-cell-depleting therapy.(2)|
03842|048|M|   Abatacept:|
03842|049|M|   - Subcutaneous abatacept should be withheld for 1-2 weeks after each|
03842|050|M|vaccine dose, as disease activity allows.|
03842|051|M|   - For intravenous abatacept, time administration so that vaccination will|
03842|052|M|occur 1 week before the next abatacept infusion.(1)|
03842|053|M|   Cyclophosphamide: When feasible, administer cyclophosphamide one week|
03842|054|M|after each COVID-19 vaccine dose.(1)|
03842|055|M|   Recipients of hematopoietic cell transplant or CAR-T-cell therapy who|
03842|056|M|received one or more doses of COVID-19 vaccine prior to or during treatment|
03842|057|M|should undergo revaccination following the current CDC recommendations for|
03842|058|M|unvaccinated patients.  Revaccination should start at least 3 months (12|
03842|059|M|weeks) after transplant or CAR-T-cell therapy.(2)|
03842|060|M|   TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to|
03842|061|M|reach consensus on whether to modify dosing or timing of these agents with|
03842|062|M|COVID-19 vaccination.(1)  The CDC includes these agents in their general|
03842|063|M|recommendation to hold therapy for at least 2 weeks following|
03842|064|M|vaccination.(2)|
03842|065|B||
03842|066|D|DISCUSSION:  The ACR convened a COVID-19 Vaccine Guidance Task Force to|
03842|067|D|provide guidance on optimal use of COVID-19 vaccines in rheumatology|
03842|068|D|patients.  These recommendations are based on limited clinical evidence of|
03842|069|D|COVID-19 vaccines in patients without rheumatic and musculoskeletal|
03842|070|D|disorders and evidence of other vaccines in this patient population.(1)|
03842|071|D|   The ACR recommendation for rituximab is based on studies of humoral|
03842|072|D|immunity following receipt of other vaccines.  These studies have uncertain|
03842|073|D|generalizability to vaccination against COVID-19, as it is unknown if|
03842|074|D|efficacy is attributable to induction of host T cells versus B cell|
03842|075|D|(antibody-based) immunity.(1)|
03842|076|D|   The ACR recommendation for mycophenolate is based on preexisting data of|
03842|077|D|mycophenolate on non-COVID-19 vaccine immunogenicity.  Emerging data|
03842|078|D|suggests that mycophenolate may impair SARS-CoV-2 vaccine response in|
03842|079|D|rheumatic and musculoskeletal disease and transplant patients.(1)|
03842|080|D|   The ACR recommendation for methotrexate is based on data from influenza|
03842|081|D|vaccines and pneumococcal vaccines with methotrexate.(1)|
03842|082|D|   The ACR recommendation for JAK inhibitors is based on concerns related to|
03842|083|D|the effects of JAK inhibitors on interferon signaling that may result in a|
03842|084|D|diminished vaccine response.(1)|
03842|085|D|   The ACR recommendation for subcutaneous abatacept is based on several|
03842|086|D|studies suggesting a negative effect of abatacept on vaccine immunogenicity.|
03842|087|D|The first vaccine dose primes naive T cells, naive T cell priming is|
03842|088|D|inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct.  CTLA-4 should|
03842|089|D|not inhibit boosts of already primed T cells at the time of the second|
03842|090|D|vaccine dose.(1)|
03842|091|B||
03842|092|R|REFERENCES:|
03842|093|B||
03842|094|R|1.Curtis JR, Johnson SR, Anthony DD, Arasaratnam RJ, Baden LR, Bass AR,|6
03842|095|R|  etal. American College of Rheumatology COVID-19 Vaccine Clinical Guidance|6
03842|096|R|  Summary for Patients with Rheumatic and Musucloskeletal Diseases - Version|6
03842|097|R|  5. Arthritis and Rheumatology. Available at:|6
03842|098|R|  https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Gui|6
03842|099|R|  dance-Rheumatic-Diseases-Summary.pdf February 2, 2022.|6
03842|100|R|2.Centers for Disease Control and Prevention (CDC). Interim Clinical|6
03842|101|R|  Considerations for Use of COVID-19 Vaccines Currently Approved or|6
03842|102|R|  Authorized in the United States. Accessed at:|6
03842|103|R|  https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vac|6
03842|104|R|  cines-us.html Last updated: September 15, 2023.|6
03843|001|T|MONOGRAPH TITLE:  Alfuzosin/Selected Strong CYP3A4 Inhibitors|
03843|002|B||
03843|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03843|004|L|is contraindicated and generally should not be dispensed or administered to|
03843|005|L|the same patient.|
03843|006|B||
03843|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03843|008|A|alfuzosin.(1)|
03843|009|B||
03843|010|E|CLINICAL EFFECTS:  Coadministration of strong CYP3A4 inhibitors may cause an|
03843|011|E|increase in alfuzosin levels and effects, including severe hypotension and|
03843|012|E|potentially life-threatening cardiac arrhythmias, including torsades de|
03843|013|E|pointes.(1)|
03843|014|B||
03843|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03843|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03843|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03843|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03843|019|P|gender, or advanced age.(2)|
03843|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03843|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03843|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03843|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03843|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03843|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03843|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03843|027|B||
03843|028|M|PATIENT MANAGEMENT:  The US manufacturer of alfuzosin states that concurrent|
03843|029|M|use of strong CYP3A4 inhibitors is contraindicated.(1)|
03843|030|M|   The US manufacturer of itraconazole states that alfuzosin should not be|
03843|031|M|administered until at least 2 weeks after itraconazole treatment.(3)|
03843|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03843|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03843|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03843|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03843|036|B||
03843|037|D|DISCUSSION:  Repeated administration of ketoconazole (400 mg, a strong|
03843|038|D|inhibitor of CYP3A4) increased the maximum concentration (Cmax) and|
03843|039|D|area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and|
03843|040|D|3.2-fold, respectively.(1)|
03843|041|D|   Administration of ketoconazole (200 mg daily) increased the Cmax and AUC|
03843|042|D|of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold,|
03843|043|D|respectively.(1)|
03843|044|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, idelalisib,|
03843|045|D|itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone,|
03843|046|D|telaprevir, troleandomycin, and tucatinib.(4)|
03843|047|B||
03843|048|R|REFERENCES:|
03843|049|B||
03843|050|R|1.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
03843|051|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
03843|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03843|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03843|054|R|  settings: a scientific statement from the American Heart Association and|6
03843|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03843|056|R|  2;55(9):934-47.|6
03843|057|R|3.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
03843|058|R|  Products, L.P. February, 2024.|1
03843|059|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03843|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03843|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03843|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03843|063|R|  11/14/2017.|1
03844|001|T|MONOGRAPH TITLE:  Alfuzosin/Strong CYP3A4 Inhibitors that Prolong QT|
03844|002|B||
03844|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03844|004|L|is contraindicated and generally should not be dispensed or administered to|
03844|005|L|the same patient.|
03844|006|B||
03844|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors decrease the metabolism of|
03844|008|A|alfuzosin.  Concurrent use of alfuzosin with other agents that prolong the|
03844|009|A|QTc interval may result in additive effects on the QTc interval.(1)|
03844|010|B||
03844|011|E|CLINICAL EFFECTS:  Coadministration of strong CYP3A4 inhibitors that prolong|
03844|012|E|the QTc interval may cause an increase in alfuzosin levels and effects,|
03844|013|E|including severe hypotension. Coadministration may lead to additive risk of|
03844|014|E|potentially life-threatening cardiac arrhythmias, including torsades de|
03844|015|E|pointes.(1)|
03844|016|B||
03844|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03844|018|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03844|019|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03844|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03844|021|P|gender, or advanced age.(2)|
03844|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03844|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03844|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03844|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03844|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03844|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03844|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03844|029|B||
03844|030|M|PATIENT MANAGEMENT:  The US manufacturer of alfuzosin states that concurrent|
03844|031|M|use of strong CYP3A4 inhibitors is contraindicated.(1)|
03844|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03844|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03844|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03844|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03844|036|B||
03844|037|D|DISCUSSION:  Repeated administration of ketoconazole (400 mg, a strong|
03844|038|D|inhibitor of CYP3A4) increased the maximum concentration (Cmax) and|
03844|039|D|area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and|
03844|040|D|3.2-fold, respectively.(1)|
03844|041|D|   Administration of ketoconazole (200 mg daily) increased the Cmax and AUC|
03844|042|D|of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold,|
03844|043|D|respectively.(1)|
03844|044|D|   Strong inhibitors of CYP3A4 that prolong the QTc interval include:|
03844|045|D|adagrasib, ceritinib, clarithromycin, lonafarnib, posaconazole, ribociclib,|
03844|046|D|telithromycin, and voriconazole.(3)|
03844|047|B||
03844|048|R|REFERENCES:|
03844|049|B||
03844|050|R|1.Uroxatral (alfuzosin hydrochloride) US prescribing information.|1
03844|051|R|  Sanofi-Synthelabo, Inc. May, 2020.|1
03844|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03844|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03844|054|R|  settings: a scientific statement from the American Heart Association and|6
03844|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03844|056|R|  2;55(9):934-47.|6
03844|057|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03844|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03844|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03844|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03844|061|R|  11/14/2017.|1
03845|001|T|MONOGRAPH TITLE:  Midostaurin/Strong CYP3A4 Inhibitors that Prolong QT|
03845|002|B||
03845|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03845|004|L|take action as needed.|
03845|005|B||
03845|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03845|007|A|interval may inhibit the metabolism of midostaurin and result in additive|
03845|008|A|risk of QT prolongation.(1)|
03845|009|B||
03845|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03845|011|E|prolong QT may result in elevated levels of and toxicity from midostaurin,|
03845|012|E|including additive QTc prolongation, which may result in potentially|
03845|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03845|014|E|(TdP).(1)|
03845|015|B||
03845|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03845|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03845|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03845|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03845|020|P|female gender, or advanced age.(2)|
03845|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03845|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03845|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03845|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03845|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03845|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03845|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03845|028|B||
03845|029|M|PATIENT MANAGEMENT:  The manufacturer of midostaurin states to consider|
03845|030|M|alternative therapies that do not inhibit CYP3A4 whenever possible.|
03845|031|M|Consider interval assessments of QT by electrocardiogram (ECG) if taken|
03845|032|M|concurrently with medications that can prolong the QT interval.(1)|
03845|033|M|   Monitor patient for signs of midostaurin toxicity with concurrent use,|
03845|034|M|especially during the first week of concurrent therapy in advanced systemic|
03845|035|M|mastocytosis (SM) population and during the first week of each cycle of|
03845|036|M|chemotherapy in acute myeloid leukemia (AML) population.(1)|
03845|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03845|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03845|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03845|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03845|041|B||
03845|042|D|DISCUSSION:  Midostaurin is a substrate of CYP3A4.(1)|
03845|043|D|   Concurrent administration of ketoconazole (400 mg daily for 10 days, a|
03845|044|D|strong CYP3A4 inhibitor) with a single 50 mg dose of midostaurin on day 6|
03845|045|D|increased the area-under-curve (AUC) of midostaurin and the active|
03845|046|D|metabolite, CGP62221, 10.4-fold and 3.5-fold, respectively.  The AUC over|
03845|047|D|time to last measurable concentration of CGP62221 increased by 1.2-fold|
03845|048|D|compared to midostaurin alone.(1)|
03845|049|D|   Concurrent administration of itraconazole (100 mg twice daily on days|
03845|050|D|22-28 for 13 doses, a strong CYP3A4 inhibitor) with multiple doses of|
03845|051|D|midostaurin (100 mg twice daily on days 1-2 and 50 mg twice daily on days|
03845|052|D|3-28) increased day 28 minimum concentration (Cmin) of midostaurin, CGP62221|
03845|053|D|and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, compared to|
03845|054|D|day 21 Cmin concentrations with midostaurin alone.(1)|
03845|055|D|   Strong CYP3A4 inhibitors linked to this monograph include: ceritinib,|
03845|056|D|clarithromycin, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir,|
03845|057|D|telithromycin, and voriconazole.(3,4)|
03845|058|B||
03845|059|R|REFERENCES:|
03845|060|B||
03845|061|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
03845|062|R|  Corporation November, 2021.|1
03845|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03845|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03845|065|R|  settings: a scientific statement from the American Heart Association and|6
03845|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03845|067|R|  2;55(9):934-47.|6
03845|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
03845|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03845|070|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03845|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03845|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03845|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03845|074|R|  11/14/2017.|1
03846|001|T|MONOGRAPH TITLE:  Conivaptan/Selected Strong CYP3A4 Inhibitors|
03846|002|B||
03846|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03846|004|L|is contraindicated and generally should not be dispensed or administered to|
03846|005|L|the same patient.|
03846|006|B||
03846|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03846|008|A|of conivaptan.(1)  Toxicity may result from an overly rapid correction of|
03846|009|A|serum sodium.|
03846|010|A|   Conivaptan may also increase levels of levoketoconazole.(4)|
03846|011|B||
03846|012|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03846|013|E|in increased levels of conivaptan.(1)|
03846|014|E|   Elevated levels of these agents may lead to increased clinical effects|
03846|015|E|such as hypotension, hypovolemia, and thirst, as well as toxicity in the|
03846|016|E|form of neurologic sequelae such as osmotic demyelination syndrome (ODS).|
03846|017|E|ODS can lead to coma and death.  Symptoms of ODS include dysarthria, mutism,|
03846|018|E|dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and|
03846|019|E|coma.(1)|
03846|020|B||
03846|021|P|PREDISPOSING FACTORS:  None determined.|
03846|022|B||
03846|023|M|PATIENT MANAGEMENT:  Concurrent use of conivaptan and strong CYP3A4|
03846|024|M|inhibitors is contraindicated.(1)|
03846|025|M|   The US manufacturer of itraconazole states that concurrent use with|
03846|026|M|conivaptan is contraindicated during and two weeks after itraconazole|
03846|027|M|treatment.(2)|
03846|028|B||
03846|029|D|DISCUSSION:  Conivaptan is a substrate of CYP3A4.|
03846|030|D|   Coadministration of conivaptan (10mg) and ketoconazole (a strong CYP3A4|
03846|031|D|inhibitor, 200 mg) resulted in a 4-fold increase in the AUC and an 11-fold|
03846|032|D|increase in the Cmax of conivaptan.(1)|
03846|033|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
03846|034|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03846|035|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil,|
03846|036|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
03846|037|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03846|038|D|tucatinib, and voriconazole.(3)|
03846|039|B||
03846|040|R|REFERENCES:|
03846|041|B||
03846|042|R|1.Vaprisol (conivaptan hydrochloride) US prescribing information. Astellas|1
03846|043|R|  Pharma US, Inc. October, 2016.|1
03846|044|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
03846|045|R|  Products, L.P. February, 2024.|1
03846|046|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03846|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03846|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03846|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03846|050|R|  11/14/2017.|1
03846|051|R|4.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03846|052|R|  Pharmaceuticals, Inc. June, 2023.|1
03847|001|T|MONOGRAPH TITLE:  Pexidartinib/Selected H2 Antagonists|
03847|002|B||
03847|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03847|004|L|take action as needed.|
03847|005|B||
03847|006|A|MECHANISM OF ACTION:  The solubility of pexidartinib is pH dependent.|
03847|007|A|Changes in gastric pH from H2 antagonists may decrease the absorption of|
03847|008|A|pexidartinib.(1)|
03847|009|B||
03847|010|E|CLINICAL EFFECTS:  Use of H2 antagonists may result in decreased levels and|
03847|011|E|effectiveness of pexidartinib.(1)|
03847|012|B||
03847|013|P|PREDISPOSING FACTORS:  None determined.|
03847|014|B||
03847|015|M|PATIENT MANAGEMENT:  Consider the use of short-acting antacids in patients|
03847|016|M|taking pexidartinib.  If antacids are used, separate the administration|
03847|017|M|times by at least 2 hours.|
03847|018|M|   If H2 antagonist therapy is required, the pexidartinib must be given 10|
03847|019|M|hours after the H2 blocker and at least 2 hours before the next dose of the|
03847|020|M|H2 blocker.|
03847|021|M|   Avoid the use of proton pump inhibitors (PPIs).(1)|
03847|022|B||
03847|023|D|DISCUSSION:  Coadministration of esomeprazole decreased pexidartinib maximum|
03847|024|D|concentration (Cmax) and area-under-curve (AUC) by 55% and 50%,|
03847|025|D|respectively.(1)|
03847|026|B||
03847|027|R|REFERENCE:|
03847|028|B||
03847|029|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03847|030|R|  November, 2023.|1
03848|001|T|MONOGRAPH TITLE:  Pexidartinib (200 mg)/Cimetidine (mono deleted 12/06/2023)|
03848|002|B||
03848|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03848|004|L|of severe adverse interaction.|
03848|005|B||
03848|006|A|MECHANISM OF ACTION:  Cimetidine, a moderate inhibitor of CYP3A4, may|
03848|007|A|inhibit the metabolism of pexidartinib.(1,2)|
03848|008|A|   The solubility of pexidartinib is pH dependent.  Changes in gastric pH|
03848|009|A|from H2 antagonists may decrease the absorption of pexidartinib.(1)|
03848|010|B||
03848|011|E|CLINICAL EFFECTS:  The net effect of the concurrent administration of|
03848|012|E|cimetidine and pexidartinib is unknown.  Cimetidine may either increase or|
03848|013|E|decrease plasma levels of pexidartinib.  CYP3A4 inhibition by cimetidine may|
03848|014|E|result in elevated levels and increased effects of pexidartinib, such as|
03848|015|E|hepatotoxicity.(1,2)  Symptoms can include nausea, vomiting, jaundice, dark|
03848|016|E|urine, abdominal pain, and unexplained fatigue.|
03848|017|E|   The H2-receptor blocking effect of cimetidine may result in decreased|
03848|018|E|absorption and decreased levels and effectiveness of pexidartinib.(1)|
03848|019|B||
03848|020|P|PREDISPOSING FACTORS:  None determined.|
03848|021|B||
03848|022|M|PATIENT MANAGEMENT:  The optimal administration schedule and dosing of|
03848|023|M|pexidartinib and cimetidine when used in combination is unknown.|
03848|024|M|Manufacturers provide recommendations for dose modification of pexidartinib|
03848|025|M|when used with a moderate CYP3A4 inhibitor, but the recommendations may not|
03848|026|M|apply when opposing mechanisms are involved.  Dose modifications mentioned|
03848|027|M|below are informational only.|
03848|028|M|   Consider the use of short-acting antacids in patients taking|
03848|029|M|pexidartinib.  If antacids are used, separate the administration times by at|
03848|030|M|least 2 hours.|
03848|031|M|   If H2 antagonist therapy is required, the pexidartinib must be given 10|
03848|032|M|hours after the H2 blocker and at least 2 hours before the next dose of the|
03848|033|M|H2 blocker.|
03848|034|M|   The US manufacturer of pexidartinib states that pexidartinib|
03848|035|M|coadministration with moderate inhibitors of CYP3A4 should be avoided.  If|
03848|036|M|coadministration of pexidartinib with moderate CYP3A4 inhibitors cannot be|
03848|037|M|avoided, reduce the pexidartinib dose according to the following|
03848|038|M|recommendations.(1)|
03848|039|M|   If the planned total daily dose is currently 800 mg, modify the total|
03848|040|M|daily dose to 400 mg by administering 200 mg twice daily.|
03848|041|M|   If the planned total daily dose is currently 600 mg, modify the total|
03848|042|M|daily dose to 400 mg by administering 200 mg twice daily.|
03848|043|M|   If the planned total daily dose is currently 400 mg, modify the total|
03848|044|M|daily dose to 200 mg by administering 200 mg once daily.|
03848|045|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
03848|046|M|increase the pexidartinib dose to the dose that was used before starting the|
03848|047|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
03848|048|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
03848|049|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
03848|050|M|recommendations in the Turalio package insert. Advise patients to|
03848|051|M|immediately report any symptoms of hepatotoxicity.|
03848|052|B||
03848|053|D|DISCUSSION:  Coadministration of fluconazole (a moderate CYP3A4 inhibitor)|
03848|054|D|increased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
03848|055|D|(AUC) by 41% and 67%.(1)|
03848|056|D|      Coadministration of esomeprazole decreased pexidartinib Cmax and AUC|
03848|057|D|by 55% and 50%.(1)|
03848|058|B||
03848|059|R|REFERENCES:|
03848|060|B||
03848|061|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03848|062|R|  November, 2023.|1
03848|063|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03848|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03848|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03848|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03848|067|R|  11/14/2017.|1
03848|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
03848|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03849|001|T|MONOGRAPH TITLE:  Siponimod/QT Prolonging Agents|
03849|002|B||
03849|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03849|004|L|take action as needed.|
03849|005|B||
03849|006|A|MECHANISM OF ACTION:  Siponimod is a sphingosine-1-phosphate (S1P) receptor|
03849|007|A|modulator.  Initiation of siponimod has a negative chronotropic effect.|
03849|008|A|   Siponimod blocks the capacity of lymphocytes to egress from lymph nodes,|
03849|009|A|reducing the number of lymphocytes in peripheral blood.  The mechanism by|
03849|010|A|which siponimod exerts therapeutic effects in multiple sclerosis is unknown,|
03849|011|A|but may involve reduction of lymphocyte migration into the central nervous|
03849|012|A|system.(1,2)|
03849|013|B||
03849|014|E|CLINICAL EFFECTS:  The heart rate lowering effect of siponimod starts within|
03849|015|E|an hour, and the Day 1 decline is maximal at approximately 3-4 hours.  This|
03849|016|E|leads to a mean decrease in heart rate of 5-6 beats per minute after the|
03849|017|E|first dose.  The first dose has also been associated with heart block.  With|
03849|018|E|continued up-titration, further heart rate decreases are seen on subsequent|
03849|019|E|days, with maximal decrease from Day 1-baseline reached on Day 5-6.|
03849|020|E|Symptomatic bradycardia has been observed.  Bradycardia may be associated|
03849|021|E|with an increase in the QTc interval, increasing the risk for torsades de|
03849|022|E|pointes.(1)|
03849|023|B||
03849|024|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
03849|025|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
03849|026|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
03849|027|P|prolonged QTc interval prior to siponimod initiation, factors associated|
03849|028|P|with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant|
03849|029|P|treatment with QT prolonging agents may increase risk for cardiovascular|
03849|030|P|toxicity due to siponimod.|
03849|031|P|   The risk of QT prolongation or torsades de pointes may also be increased|
03849|032|P|in patients with a history of torsades de pointes, hypocalcemia,|
03849|033|P|bradycardia, female gender, or advanced age.(3)|
03849|034|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03849|035|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03849|036|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03849|037|P|concentrations include rapid infusion of an intravenous dose or impaired|
03849|038|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03849|039|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03849|040|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03849|041|B||
03849|042|M|PATIENT MANAGEMENT:  Prior to initiation of siponimod, obtain an ECG to|
03849|043|M|determine if preexisting conduction abnormalities are present.(1)|
03849|044|M|   Advice from a cardiologist is recommended in patients with preexisting|
03849|045|M|heart and cerebrovascular conditions, prolonged QTc interval before or|
03849|046|M|during the 6 hour observation, risk factors for QT prolongation, concurrent|
03849|047|M|therapy with QT prolonging drugs or drugs that slow the heart rate or AV|
03849|048|M|conduction.(1)|
03849|049|M|   In patients with heart rate (HR) less than 55 beats per minute (bpm),|
03849|050|M|first- or second-degree AV block, or history of myocardial infarction or|
03849|051|M|heart failure, first dose monitoring is recommended with hourly pulse and|
03849|052|M|blood pressure to monitor for bradycardia for the first 6 hours.  ECG|
03849|053|M|monitoring is recommended prior to dosing and at the end of the observation|
03849|054|M|period.(1)|
03849|055|M|   Additional US monitoring recommendations include:|
03849|056|M|   If HR is less than 45 bpm, the heart rate 6 hours postdose is at the|
03849|057|M|lowest value postdose or if the ECG shows new onset of second degree or|
03849|058|M|higher AV block at the end of the monitoring period, then monitoring should|
03849|059|M|continue until the finding has resolved.|
03849|060|M|   If patient requires treatment for symptomatic bradycardia, second-degree|
03849|061|M|or higher AV block, or QTc interval greater than or equal to 500 msec,|
03849|062|M|perform continuous overnight ECG monitoring.  Repeat the first dose|
03849|063|M|monitoring strategy for the second dose of siponimod.|
03849|064|M|   If a titration dose is missed or if 4 or more consecutive daily doses are|
03849|065|M|missed during maintenance treatment, reinitiate Day 1 of the dose titration|
03849|066|M|and follow titration monitoring recommendations.  Patient will need to be|
03849|067|M|observed in the doctor's office or other facility for at least 6 hours after|
03849|068|M|the first dose and after reinitiation if treatment is interrupted or|
03849|069|M|discontinued for certain periods.|
03849|070|M|   Consult the prescribing information for full monitoring recommendations.|
03849|071|M|   United Kingdom recommendations:(3)|
03849|072|M|   In certain patients, it is recommended that an electrocardiogram (ECG) is|
03849|073|M|obtained prior to dosing and at the end of the observation period.  If|
03849|074|M|post-dose bradyarrhythmia or conduction-related symptoms occur or if ECG 6|
03849|075|M|hours post-dose shows new onset second-degree or higher AV block or QTc >|
03849|076|M|500 msec, appropriate management should be initiated and observation|
03849|077|M|continued until the symptoms/findings have resolved.  If pharmacological|
03849|078|M|treatment is required, monitoring should be continued overnight and 6-hour|
03849|079|M|monitoring should be repeated after the second dose.|
03849|080|M|   During the first 6 days of treatment, if a titration dose is missed on|
03849|081|M|one day, treatment needs to be re-initiated with a new titration pack.  If|
03849|082|M|there is a missed dose after day 6 the prescribed dose should be taken at|
03849|083|M|the next scheduled time; the next dose should not be doubled.  If|
03849|084|M|maintenance treatment is interrupted for 4 or more consecutive daily doses,|
03849|085|M|siponimod needs to be re-initiated with a new titration pack.(1,2)|
03849|086|B||
03849|087|D|DISCUSSION:  After the first dose of siponimod, heart rate decrease may|
03849|088|D|begin within an hour.  Decline is usually maximal at approximately 3-4|
03849|089|D|hours.  With continued, chronic dosing, heart rate gradually returns to|
03849|090|D|baseline in about 10 days.(1,2)|
03849|091|D|   A transient, dose-dependent decrease in heart rate was observed during|
03849|092|D|the initial dosing phase of siponimod, which plateaued at doses greater than|
03849|093|D|or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses)|
03849|094|D|were detected at a higher incidence under siponimod treatment than placebo.|
03849|095|D|AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with|
03849|096|D|notably higher incidence under non-titrated conditions compared to dose|
03849|097|D|titration conditions.(1)|
03849|098|B||
03849|099|R|REFERENCES:|
03849|100|B||
03849|101|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03849|102|R|  Corporation August, 2025.|1
03849|103|R|2.Mayzent (siponimod) UK summary of product characteristics. Novartis|1
03849|104|R|  Pharmaceuticals UK Ltd January, 2021.|1
03849|105|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03849|106|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03849|107|R|  settings: a scientific statement from the American Heart Association and|6
03849|108|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03849|109|R|  2;55(9):934-47.|6
03850|001|T|MONOGRAPH TITLE:  Ponesimod/QT Prolonging Agents|
03850|002|B||
03850|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03850|004|L|take action as needed.|
03850|005|B||
03850|006|A|MECHANISM OF ACTION:  Ponesimod is a sphingosine 1-phosphate (S1P) receptor|
03850|007|A|1 modulator.  Initiation of ponesimod has a negative chronotropic effect|
03850|008|A|leading to a mean decrease in heart rate of 6 beats per minute (bpm) after|
03850|009|A|the first dose.  The first dose has also been associated with heart|
03850|010|A|block.(1)|
03850|011|B||
03850|012|E|CLINICAL EFFECTS:  After a dose of ponesimod, a decrease in heart rate|
03850|013|E|typically begins within an hour and reaches its nadir within 2-4 hours.  The|
03850|014|E|heart rate typically recovers to baseline levels 4-5 hours after|
03850|015|E|administration.  All patients recovered from bradycardia.  The conduction|
03850|016|E|abnormalities typically were transient, asymptomatic, and resolved within 24|
03850|017|E|hours.  Second- and third-degree AV blocks were not reported.  With|
03850|018|E|up-titration after Day 1, the post-dose decrease in heart rate is less|
03850|019|E|pronounced.  Bradycardia may be associated with an increase in the QTc|
03850|020|E|interval, increasing the risk for torsades de pointes.(1,2)|
03850|021|B||
03850|022|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
03850|023|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
03850|024|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
03850|025|P|prolonged QTc interval prior to ponesimod initiation, factors associated|
03850|026|P|with QTc prolongation, or concomitant treatment with QT prolonging agents|
03850|027|P|may increase risk for cardiovascular toxicity due to ponesimod.(1)|
03850|028|P|   The risk of QT prolongation or torsades de pointes may also be increased|
03850|029|P|in patients with a history of torsades de pointes, hypocalcemia,|
03850|030|P|bradycardia, female gender, or advanced age.(2)|
03850|031|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03850|032|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03850|033|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03850|034|P|concentrations include rapid infusion of an intravenous dose or impaired|
03850|035|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03850|036|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03850|037|P|metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03850|038|B||
03850|039|M|PATIENT MANAGEMENT:  Prior to initiation of ponesimod, obtain an ECG to|
03850|040|M|determine if preexisting conduction abnormalities are present.|
03850|041|M|   Ponesimod is generally not recommended in patients who are receiving|
03850|042|M|concurrent treatment with a QT prolonging agent, anti-arrhythmic drugs, or|
03850|043|M|drugs that may decrease heart rate.  Consultation with a cardiologist is|
03850|044|M|recommended.(1)|
03850|045|M|   In patients with heart rate (HR) less than 55 beats per minute (bpm),|
03850|046|M|first- or second-degree AV block, or history of myocardial infarction or|
03850|047|M|heart failure, monitor patients for 4 hours after the first dose for signs|
03850|048|M|and symptoms of bradycardia with a minimum of hourly pulse and blood|
03850|049|M|pressure measurements.  Obtain an ECG in these patients prior to dosing and|
03850|050|M|at the end of the 4-hour observation period.(1)|
03850|051|M|   Additional US monitoring recommendations include:|
03850|052|M|   If HR is less than 45 bpm, the heart rate 4 hours post-dose is at the|
03850|053|M|lowest value post-dose or if the ECG shows new onset of second degree or|
03850|054|M|higher AV block at the end of the monitoring period, then monitoring should|
03850|055|M|continue until the finding has resolved.|
03850|056|M|   If patient requires treatment for symptomatic bradycardia, second-degree|
03850|057|M|or higher AV block, or QTc interval greater than or equal to 500 msec,|
03850|058|M|perform continuous overnight ECG monitoring and repeat the first dose|
03850|059|M|monitoring strategy for the second dose of ponesimod.|
03850|060|M|   Consult the prescribing information for full monitoring recommendations.|
03850|061|M|   If fewer than 4 consecutive doses are missed during titration: resume|
03850|062|M|treatment with the first missed titration dose and resume the titration|
03850|063|M|schedule at that dose and titration day.  If fewer than 4 consecutive doses|
03850|064|M|are missed during maintenance: resume treatment with the maintenance dosage.|
03850|065|M|   If 4 or more consecutive daily doses are missed during treatment|
03850|066|M|initiation or maintenance treatment, reinitiate Day 1 of the dose titration|
03850|067|M|(new starter pack) and follow first-dose monitoring recommendations.|
03850|068|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03850|069|M|fainting.|
03850|070|B||
03850|071|D|DISCUSSION:  After the first dose of ponesimod, heart rate decrease may|
03850|072|D|begin within the first hour.  Decline is usually maximal at approximately 4|
03850|073|D|hours.  With continued, chronic dosing, post-dose decrease in heart rate is|
03850|074|D|less pronounced.  Heart rate gradually returns to baseline in about 4-5|
03850|075|D|hours.(1)|
03850|076|B||
03850|077|R|REFERENCES:|
03850|078|B||
03850|079|R|1.Ponvory (ponesimod) US prescribing information. Janssen Pharmaceuticals,|1
03850|080|R|  Inc. March, 2021.|1
03850|081|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03850|082|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03850|083|R|  settings: a scientific statement from the American Heart Association and|6
03850|084|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03850|085|R|  2;55(9):934-47.|6
03851|001|T|MONOGRAPH TITLE:  Ozanimod/QT Prolonging Agents|
03851|002|B||
03851|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03851|004|L|take action as needed.|
03851|005|B||
03851|006|A|MECHANISM OF ACTION:  Ozanimod is a sphingosine 1-phosphate (S1P) receptor|
03851|007|A|modulator.  Initiation of ozanimod has a negative chronotropic effect|
03851|008|A|leading to a mean decrease in heart rate of 13 beats per minute (bpm) after|
03851|009|A|the first dose.  The first dose has also been associated with heart|
03851|010|A|block.(1,2)|
03851|011|A|   Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes,|
03851|012|A|reducing the number of lymphocytes in peripheral blood.  The mechanism by|
03851|013|A|which ozanimod exerts therapeutic effects in multiple sclerosis is unknown|
03851|014|A|but may involve the reduction of lymphocyte migration into the central|
03851|015|A|nervous system.|
03851|016|B||
03851|017|E|CLINICAL EFFECTS:  The initial heart rate lowering effect of ozanimod|
03851|018|E|usually occurs within 5 hours.  With continued up-titration, the maximal|
03851|019|E|heart rate effect of ozanimod occurred on Day 8.  Symptomatic bradycardia|
03851|020|E|and heart block, including third degree block, have been observed.|
03851|021|E|Bradycardia may be associated with an increase in the QTc interval,|
03851|022|E|increasing the risk for torsades de pointes.(1,2)|
03851|023|B||
03851|024|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
03851|025|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
03851|026|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
03851|027|P|prolonged QTc interval prior to ozanimod initiation, factors associated with|
03851|028|P|QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant|
03851|029|P|treatment with QT prolonging agents may increase risk for cardiovascular|
03851|030|P|toxicity due to ozanimod.(1,2)|
03851|031|P|   The risk of QT prolongation or torsades de pointes may also be increased|
03851|032|P|in patients with a history of torsades de pointes, hypocalcemia,|
03851|033|P|bradycardia, female gender, or advanced age.(3)|
03851|034|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03851|035|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03851|036|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03851|037|P|concentrations include rapid infusion of an intravenous dose or impaired|
03851|038|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03851|039|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03851|040|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03851|041|B||
03851|042|M|PATIENT MANAGEMENT:  Prior to initiation of ozanimod, obtain an ECG to|
03851|043|M|determine if preexisting conduction abnormalities are present.|
03851|044|M|   Patients with preexisting cardiac conditions, significant QT prolongation|
03851|045|M|(QTc >450 msec in males, >470 msec in females), concurrent Class Ia or Class|
03851|046|M|III antiarrhythmics, or receiving concurrent treatment with a QT prolonging|
03851|047|M|agent at the time ozanimod is initiated or resumed should be referred to a|
03851|048|M|cardiologist.(1)|
03851|049|M|   The US recommendations state: Dose titration is recommended with|
03851|050|M|initiation of ozanimod due to transient decrease in heart rate and AV|
03851|051|M|conduction delays.(1)|
03851|052|M|   United Kingdom recommendations:(2)|
03851|053|M|   Due to the risk of transient decreases in HR with the initiation of|
03851|054|M|ozanimod, first dose, 6-hour monitoring for signs and symptoms of|
03851|055|M|symptomatic bradycardia is recommended in patients with resting HR <55 bpm,|
03851|056|M|second-degree [Mobitz type I] AV block or a history of myocardial infarction|
03851|057|M|or heart failure.|
03851|058|M|   Patients should be monitored with hourly pulse and blood pressure|
03851|059|M|measurement during this 6-hour period.  An ECG prior to and at the end of|
03851|060|M|this 6-hour period is recommended.|
03851|061|M|  Additional monitoring after 6 hours is recommended in patients with: heart|
03851|062|M|rate less than 45 bpm, heart rate at the lowest value post-dose (suggesting|
03851|063|M|that the maximum decrease in HR may not have occurred yet), evidence of a|
03851|064|M|new onset second-degree or higher AV block at the 6-hour post dose ECG, or|
03851|065|M|QTc interval greater than 500 msec.  In these cases, appropriate management|
03851|066|M|should be initiated and observation continued until the symptoms/findings|
03851|067|M|have resolved.|
03851|068|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03851|069|M|fainting.(2,3)|
03851|070|B||
03851|071|D|DISCUSSION:  After the first dose of ozanimod heart rate decline is usually|
03851|072|D|maximal at approximately 5 hours, returning to baseline at 6 hours.  With|
03851|073|D|continued, chronic dosing, maximum heart rate effect occurred on day 8.(1,2)|
03851|074|B||
03851|075|R|REFERENCES:|
03851|076|B||
03851|077|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03851|078|R|  2024.|1
03851|079|R|2.Zeposia (ozanimod) UK summary of product characteristics. Bristol-Myers|1
03851|080|R|  Squibb Pharmaceuticals Ltd June, 2021.|1
03851|081|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03851|082|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03851|083|R|  settings: a scientific statement from the American Heart Association and|6
03851|084|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03851|085|R|  2;55(9):934-47.|6
03852|001|T|MONOGRAPH TITLE:  Thioridazine/Selected Strong CYP2D6 Inhibitors|
03852|002|B||
03852|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03852|004|L|is contraindicated and generally should not be dispensed or administered to|
03852|005|L|the same patient.|
03852|006|B||
03852|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2D6 may inhibit the metabolism|
03852|008|A|of thioridazine.(1-4)|
03852|009|B||
03852|010|E|CLINICAL EFFECTS:  The concurrent administration of strong CYP2D6 inhibitors|
03852|011|E|with thioridazine may result in elevated levels of thioridazine.(1-4)|
03852|012|E|Elevated levels of thioridazine may augment thioridazine-induced|
03852|013|E|prolongation of the QTc interval, increasing the risk of serious,|
03852|014|E|potentially fatal, cardiac arrhythmias such as torsades de pointes.(1)|
03852|015|B||
03852|016|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 ultrarapid metabolizers may|
03852|017|P|be affected to a greater extent by CYP2D6 inhibitors.  Patients who are|
03852|018|P|CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6|
03852|019|P|inhibition.|
03852|020|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03852|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03852|022|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03852|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03852|024|P|advanced age.(5)|
03852|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03852|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03852|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03852|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03852|029|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
03852|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03852|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03852|032|P|   The risk of anticholinergic toxicities including cognitive decline,|
03852|033|P|delirium, falls and fractures is increased in geriatric patients using more|
03852|034|P|than one medicine with anticholinergic properties.(6)|
03852|035|B||
03852|036|M|PATIENT MANAGEMENT:  The concurrent use of thioridazine with CYP2D6|
03852|037|M|inhibitors is contraindicated.(1)   Use an alternative agent, or change to|
03852|038|M|another antipsychotic agent.|
03852|039|M|   If alternative treatments are not possible for either agent and|
03852|040|M|concurrent therapy is deemed medically necessary, strongly consider|
03852|041|M|obtaining serum calcium, magnesium, and potassium levels and monitoring ECG|
03852|042|M|at baseline and at regular intervals.  Correct any electrolyte|
03852|043|M|abnormalities.  Instruct patients to report any irregular heartbeat,|
03852|044|M|dizziness, or fainting.|
03852|045|M|   Thioridazine should not be initiated in patients with a QTc interval|
03852|046|M|greater than 450 msec and should be discontinued in patients found to have a|
03852|047|M|corrected QTc greater than 500 msec.(3)|
03852|048|B||
03852|049|D|DISCUSSION:  A study in six slow and 13 rapid metabolizers of debrisoquin, a|
03852|050|D|marker of CYP2D6 activity, showed that slow metabolizers of debrisoquin had|
03852|051|D|2.4-fold and 4.5-fold higher thioridazine maximum concentration (Cmax) and|
03852|052|D|area-under-curve (AUC), respectively, than rapid metabolizers.(4)|
03852|053|D|   A study in 9 healthy male subjects showed a thioridazine dose-related|
03852|054|D|prolongation of the QTc interval.  One subtherapeutic thioridazine 10 mg|
03852|055|D|dose increased QTc 9 msec (range -1 to 19 msec), and a single|
03852|056|D|low-therapeutic thioridazine dose of 50 mg increased QTc 22 msec (range 11|
03852|057|D|to 33 msec).(7)|
03852|058|D|   Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib|
03852|059|D|and terbinafine.(3)|
03852|060|B||
03852|061|R|REFERENCES:|
03852|062|B||
03852|063|R|1.Thioridazine tablet, US prescribing information. Mutual Pharmaceutical|1
03852|064|R|  September, 2014.|1
03852|065|R|2.Vizimpro (dacomitinib) US prescribing information. Pfizer, Inc. September,|1
03852|066|R|  2018.|1
03852|067|R|3.This information is based on an extract from the Certara Drug Interaction|6
03852|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03852|069|R|4.von Bahr C, Movin G, Nordin C, Liden A, Hammarlund-Udenaes M, Hedberg A,|2
03852|070|R|  Ring H, Sjoqvist F. Plasma levels of thioridazine and metabolites are|2
03852|071|R|  influenced by the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther|2
03852|072|R|  1991 Mar;49(3):234-40.|2
03852|073|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03852|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03852|075|R|  settings: a scientific statement from the American Heart Association and|6
03852|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03852|077|R|  2;55(9):934-47.|6
03852|078|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03852|079|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03852|080|R|  Soc 2023 Jul;71(7):2052-2081.|6
03852|081|R|7.Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH.|2
03852|082|R|  Concentration-related pharmacodynamic effects of thioridazine and its|2
03852|083|R|  metabolites in humans. Clin Pharmacol Ther 1996 Nov;60(5):543-53.|2
03854|001|T|MONOGRAPH TITLE:  Rimegepant/P-gp Inhibitors|
03854|002|B||
03854|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03854|004|L|take action as needed.|
03854|005|B||
03854|006|A|MECHANISM OF ACTION:  Rimegepant is a calcitonin gene-related peptide|
03854|007|A|receptor antagonist.  Rimegepant is a substrate of the P-glycoprotein (P-gp)|
03854|008|A|transporter.  P-gp inhibitors may significantly increase the absorption of|
03854|009|A|rimegepant.(1)|
03854|010|B||
03854|011|E|CLINICAL EFFECTS:  The concurrent administration of rimegepant with an|
03854|012|E|inhibitor of P-glycoprotein may result in elevated levels of rimegepant.(1)|
03854|013|B||
03854|014|P|PREDISPOSING FACTORS:  None determined.|
03854|015|B||
03854|016|M|PATIENT MANAGEMENT:  The US manufacturer of rimegepant recommends avoiding a|
03854|017|M|second dose of rimegepant within 48 hours of a first dose when used|
03854|018|M|concomitantly with P-gp inhibitors.(1)|
03854|019|B||
03854|020|D|DISCUSSION:  Rimegepant is a substrate of P-gp.  Use of P-gp inhibitors may|
03854|021|D|increase the exposure of rimegepant.  In a study, cyclosporine (a potent|
03854|022|D|P-gp and BCRP inhibitor) increased rimegepant area-under curve (AUC) and|
03854|023|D|maximum concentration (Cmax) by 1.6- and 1.4-fold, respectively.  Quinidine|
03854|024|D|(a potent P-gp inhibitor) similarly increased rimegepant AUC and Cmax by|
03854|025|D|1.6- and 1.7-fold, respectively.  Therefore, the effect of these drug|
03854|026|D|interactions were concluded to be due entirely to P-gp and not BCRP.(1)|
03854|027|D|   P-glycoprotein inhibitors linked to this monograph include:  amiodarone,|
03854|028|D|azithromycin, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan,|
03854|029|D|daridorexant, diosmin, flibanserin, fostamatinib, glecaprevir/pibrentasvir,|
03854|030|D|imlunestrant, lapatinib, mavorixafor, osimertinib, pirtobrutinib,|
03854|031|D|propafenone, quinidine, ranolazine, selpercatinib,|
03854|032|D|sofosbuvir/velpatasvir/voxilaprevir, tepotinib, vemurafenib, vimseltinib,|
03854|033|D|and verapamil.(1-3)|
03854|034|B||
03854|035|R|REFERENCES:|
03854|036|B||
03854|037|R|1.Nurtec ODT (rimegepant) US prescribing information. Biohaven|1
03854|038|R|  Pharmaceuticals, Inc. December, 2021.|1
03854|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03854|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03854|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03854|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03854|043|R|  11/14/2017.|1
03854|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
03854|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03855|001|T|MONOGRAPH TITLE:  Ponesimod/Immunosuppressives; Immunomodulators that|
03855|002|T|Prolong QT|
03855|003|B||
03855|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03855|005|L|of severe adverse interaction.|
03855|006|B||
03855|007|A|MECHANISM OF ACTION:  Ponesimod in combination with immunosuppressives and|
03855|008|A|immune-modulators all suppress the immune system.(1)|
03855|009|A|   Initiation of ponesimod has a negative chronotropic effect leading to a|
03855|010|A|mean decrease in heart rate of 6 beats per minute (bpm) after the first|
03855|011|A|dose.  The first dose has also been associated with heart block.(1)|
03855|012|B||
03855|013|E|CLINICAL EFFECTS:  Concurrent use of ponesimod with immunosuppressive or|
03855|014|E|immune-modulating agents may result in an increased risk of serious|
03855|015|E|infections, such as disseminated herpetic infection, cryptococcal infection,|
03855|016|E|or progressive multifocal leukoencephalopathy (PML), an opportunistic|
03855|017|E|infection caused by the JC virus (JCV).(1)|
03855|018|E|   The heart rate lowering effect of ponesimod reaches an initial decrease|
03855|019|E|within an hour and reaches its nadir within 2-4 hours.  The heart rate|
03855|020|E|typically recovers to baseline levels 4-5 hours after administration.  All|
03855|021|E|patients recovered from bradycardia.  The conduction abnormalities typically|
03855|022|E|were transient, asymptomatic, resolved within 24 hours.  Second- and|
03855|023|E|third-degree AV blocks were not reported.  With up-titration after Day 1,|
03855|024|E|the post-dose decrease in heart rate is less pronounced.  Bradycardia may be|
03855|025|E|associated with an increase in the QTc interval, increasing the risk for|
03855|026|E|torsades de pointes.(1,2)|
03855|027|B||
03855|028|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03855|029|P|immunosuppressive or immune-modulating medications may increase the risk|
03855|030|P|from this interaction.|
03855|031|P|   Pre-existing cardiovascular or cerebrovascular disease (e.g. heart|
03855|032|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
03855|033|P|or heart block), severe untreated sleep apnea, a prolonged QTc interval|
03855|034|P|prior to ponesimod initiation, factors associated with QTc prolongation, or|
03855|035|P|concomitant treatment with QT prolonging agents may increase risk for|
03855|036|P|cardiovascular toxicity due to ponesimod.(1)|
03855|037|P|   The risk of QT prolongation or torsades de pointes may also be increased|
03855|038|P|in patients with a history of torsades de pointes, hypocalcemia,|
03855|039|P|bradycardia, female gender, or advanced age.(2)|
03855|040|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03855|041|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03855|042|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03855|043|P|concentrations include rapid infusion of an intravenous dose or impaired|
03855|044|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03855|045|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03855|046|P|metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03855|047|B||
03855|048|M|PATIENT MANAGEMENT:  The ponesimod US prescribing information states|
03855|049|M|ponesimod has not been studied in combination with anti-neoplastic,|
03855|050|M|immune-modulating, or immunosuppressive therapies.|
03855|051|M|   Caution should be used during concomitant administration because of the|
03855|052|M|risk of additive immune effects during therapy and in the weeks following|
03855|053|M|administration.|
03855|054|M|   When switching from drugs with prolonged immune effects, the half-life|
03855|055|M|and mode of action of these drugs must be considered in order to avoid|
03855|056|M|unintended additive immunosuppressive effects.|
03855|057|M|   Initiating treatment with ponesimod after alemtuzumab is not recommended.|
03855|058|M|However, ponesimod can generally be started immediately after|
03855|059|M|discontinuation of beta interferon or glatiramer acetate.(1)|
03855|060|M|   Ponesimod is generally not recommended in patients receiving concurrent|
03855|061|M|treatment with a QT prolonging agent, anti-arrhythmic drugs, or drugs that|
03855|062|M|may decrease heart rate.  Consultation with a cardiologist is recommended.|
03855|063|M|Consult the prescribing information for recommendations regarding cardiac|
03855|064|M|monitoring.(1)|
03855|065|B||
03855|066|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections,|
03855|067|D|cryptococcal meningitis, disseminated cryptococcal infections, and cases of|
03855|068|D|progressive multifocal leukoencephalopathy (PML) have been reported in|
03855|069|D|patients who previously received immunomodulators or immunosuppressants.(1)|
03855|070|D|   After the first dose of ponesimod, heart rate decrease may begin within|
03855|071|D|the first hour.  Decline is usually maximal at approximately 4 hours.  With|
03855|072|D|continued, chronic dosing, post-dose decrease in heart rate is less|
03855|073|D|pronounced.  Heart rate gradually returns to baseline in about 4-5 hours.(1)|
03855|074|B||
03855|075|R|REFERENCES:|
03855|076|B||
03855|077|R|1.Ponvory (ponesimod) US prescribing information. Janssen Pharmaceuticals,|1
03855|078|R|  Inc. March, 2021.|1
03855|079|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03855|080|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03855|081|R|  settings: a scientific statement from the American Heart Association and|6
03855|082|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03855|083|R|  2;55(9):934-47.|6
03856|001|T|MONOGRAPH TITLE:  Fingolimod/Immunosuppressives; Immunomodulators|
03856|002|B||
03856|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03856|004|L|of severe adverse interaction.|
03856|005|B||
03856|006|A|MECHANISM OF ACTION:  Fingolimod in combination with immunosuppressives and|
03856|007|A|immune-modulators all suppress the immune system.(1-3)|
03856|008|B||
03856|009|E|CLINICAL EFFECTS:  Concurrent use of fingolimod with immunosuppressive or|
03856|010|E|immune-modulating agents may result in an increased risk of serious|
03856|011|E|infections, such as disseminated herpetic infection or progressive|
03856|012|E|multifocal leukoencephalopathy (PML), an opportunistic infection caused by|
03856|013|E|the JC virus (JCV).(1-3)|
03856|014|B||
03856|015|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03856|016|P|immunosuppressive or immune-modulating medications.|
03856|017|B||
03856|018|M|PATIENT MANAGEMENT:  Recommendations for fingolimod regarding this|
03856|019|M|interaction differ between regulatory approving agencies.|
03856|020|M|   The fingolimod US prescribing information states:|
03856|021|M|   - Antineoplastic, immune-modulating, or immunosuppressive therapies,|
03856|022|M|(including corticosteroids) are expected to increase the risk of|
03856|023|M|immunosuppression, and the risk of additive immune system effects must be|
03856|024|M|considered if these therapies are coadministered with fingolimod.  When|
03856|025|M|switching from drugs with prolonged immune effects, such as natalizumab,|
03856|026|M|teriflunomide or mitoxantrone, the duration and mode of action of these|
03856|027|M|drugs must be considered to avoid unintended additive immunosuppressive|
03856|028|M|effects when initiating fingolimod.(1)|
03856|029|M|   The fingolimod Canadian prescribing information states:|
03856|030|M|   - Concurrent use with immunosuppressive or immunomodulatory agents is|
03856|031|M|contraindicated due to the risk of additive immune system effects. However,|
03856|032|M|co-administration of a short course of corticosteroids (up to 5 days) did|
03856|033|M|not increase the overall rate of infection in patients participating Phase|
03856|034|M|III clinical trials.(2)|
03856|035|M|   The fingolimod UK specific product characteristics states:|
03856|036|M|   - Fingolimod is contraindicated in patients currently receiving|
03856|037|M|immunosuppressive therapies or those immunocompromised by prior therapies.|
03856|038|M|When switching patients from another disease modifying therapy to Gilenya,|
03856|039|M|the half-life and mode of action of the other therapy must be considered in|
03856|040|M|order to avoid an additive immune effect whilst at the same time minimizing|
03856|041|M|the risk of disease activation.(3)|
03856|042|B||
03856|043|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections|
03856|044|D|and cases of progressive multifocal leukoencephalopathy (PML) have been|
03856|045|D|reported in patients who previously received immunomodulators or|
03856|046|D|immunosuppressants.(1-3)|
03856|047|B||
03856|048|R|REFERENCES:|
03856|049|B||
03856|050|R|1.Gilenya (fingolimod) US prescribing information. Novartis Pharmaceuticals|1
03856|051|R|  Corporation June, 2024.|1
03856|052|R|2.Gilenya (fingolimod) Health Canada prescribing information. Novartis|1
03856|053|R|  Pharmaceuticals September 23, 2011.|1
03856|054|R|3.Gilenya (fingolimod) UK summary of product characteristics. Novartis|1
03856|055|R|  Pharmaceuticals UK Ltd June 30, 2015.|1
03857|001|T|MONOGRAPH TITLE:  Ozanimod/Immunosuppressives; Immunomodulators|
03857|002|B||
03857|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03857|004|L|of severe adverse interaction.|
03857|005|B||
03857|006|A|MECHANISM OF ACTION:  Ozanimod in combination with immunosuppressives and|
03857|007|A|immune-modulators all suppress the immune system.(1)|
03857|008|B||
03857|009|E|CLINICAL EFFECTS:  Concurrent use of ozanimod with immunosuppressive or|
03857|010|E|immune-modulating agents may result in an increased risk of serious|
03857|011|E|infections, such as disseminated herpetic infection or progressive|
03857|012|E|multifocal leukoencephalopathy (PML), an opportunistic infection caused by|
03857|013|E|the JC virus (JCV).(1)|
03857|014|B||
03857|015|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03857|016|P|immunosuppressive or immune-modulating medications.|
03857|017|B||
03857|018|M|PATIENT MANAGEMENT:  The ozanimod  US prescribing information state this|
03857|019|M|information regarding this interaction:|
03857|020|M|   -Ozanimod has not been studied in combination with anti-neoplastic,|
03857|021|M|immune-modulating, or immunosuppressive therapies.  Caution should be used|
03857|022|M|during concomitant administration because of the risk of additive immune|
03857|023|M|effects during therapy and in the week following administration.  When|
03857|024|M|switching from drugs with prolonged immune effects, the half-life and mode|
03857|025|M|of action of these drugs must be considered in order to avoid unintended|
03857|026|M|additive immunosuppressive effects.  Initiating treatment with ozanimod|
03857|027|M|after alemtuzumab is not recommended.  However, ozanimod can generally be|
03857|028|M|started immediately after discontinuation of beta interferon or glatiramer|
03857|029|M|acetate.(1)|
03857|030|B||
03857|031|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections|
03857|032|D|and cases of progressive multifocal leukoencephalopathy (PML) have been|
03857|033|D|reported in patients who previously received immunomodulators or|
03857|034|D|immunosuppressants.(1)|
03857|035|B||
03857|036|R|REFERENCE:|
03857|037|B||
03857|038|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03857|039|R|  2024.|1
03858|001|T|MONOGRAPH TITLE:  Siponimod/Immunosuppressives; Immunomodulators|
03858|002|B||
03858|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03858|004|L|of severe adverse interaction.|
03858|005|B||
03858|006|A|MECHANISM OF ACTION:  Siponimod in combination with immunosuppressives and|
03858|007|A|immune-modulators all suppress the immune system.(1)|
03858|008|B||
03858|009|E|CLINICAL EFFECTS:  Concurrent use of siponimod with immunosuppressive or|
03858|010|E|immune-modulating agents may result in an increased risk of serious|
03858|011|E|infections, such as disseminated herpetic infection or progressive|
03858|012|E|multifocal leukoencephalopathy (PML), an opportunistic infection caused by|
03858|013|E|the JC virus (JCV).(1)|
03858|014|B||
03858|015|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03858|016|P|immunosuppressive or immune-modulating medications.|
03858|017|B||
03858|018|M|PATIENT MANAGEMENT:  The siponimod US prescribing information state this|
03858|019|M|information regarding this interaction:|
03858|020|M|   -Siponimod has not been studied in combination with anti-neoplastic,|
03858|021|M|immune-modulating, or immunosuppressive therapies.  Caution should be used|
03858|022|M|during concomitant administration because of the risk of additive immune|
03858|023|M|effects during therapy and in the week following administration.  When|
03858|024|M|switching from drugs with prolonged immune effects, the half-life and mode|
03858|025|M|of action of these drugs must be considered in order to avoid unintended|
03858|026|M|additive immunosuppressive effects.  Initiating treatment with siponimod|
03858|027|M|after alemtuzumab is not recommended.  However, siponimod can generally be|
03858|028|M|started immediately after discontinuation of beta interferon or glatiramer|
03858|029|M|acetate.(1)|
03858|030|B||
03858|031|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections|
03858|032|D|and cases of progressive multifocal leukoencephalopathy (PML) have been|
03858|033|D|reported in patients who previously received immunomodulators or|
03858|034|D|immunosuppressants.(1)|
03858|035|B||
03858|036|R|REFERENCE:|
03858|037|B||
03858|038|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03858|039|R|  Corporation August, 2025.|1
03859|001|T|MONOGRAPH TITLE:  Fingolimod/Immunosuppressives; Immunomodulators that|
03859|002|T|Prolong QT|
03859|003|B||
03859|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03859|005|L|of severe adverse interaction.|
03859|006|B||
03859|007|A|MECHANISM OF ACTION:  Fingolimod in combination with immunosuppressives and|
03859|008|A|immune-modulators all suppress the immune system.(1-3)|
03859|009|A|   Initiation of fingolimod has a negative chronotropic effect leading to a|
03859|010|A|mean decrease in heart rate of 13 beats per minute (bpm) after the first|
03859|011|A|dose.  The first dose has also been associated with heart block.(1-3)|
03859|012|B||
03859|013|E|CLINICAL EFFECTS:  Concurrent use of fingolimod with immunosuppressive or|
03859|014|E|immune-modulating agents may result in an increased risk of serious|
03859|015|E|infections, such as disseminated herpetic infection or progressive|
03859|016|E|multifocal leukoencephalopathy (PML), an opportunistic infection caused by|
03859|017|E|the JC virus (JCV).(1-3)|
03859|018|E|   The heart rate lowering effect of fingolimod is biphasic with an initial|
03859|019|E|decrease usually within 6 hours, followed by a second decrease 12 to 24|
03859|020|E|hours after the first dose.  Symptomatic bradycardia and heart block,|
03859|021|E|including third degree block, have been observed.  Bradycardia may be|
03859|022|E|associated with an increase in the QTc interval, increasing the risk for|
03859|023|E|torsades de pointes.  There is no consistent signal of increased incidence|
03859|024|E|of QTc outliers, either absolute or change from baseline, associated with|
03859|025|E|fingolimod treatment.(1-3)|
03859|026|B||
03859|027|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03859|028|P|immunosuppressive or immune-modulating medications may increase the risk|
03859|029|P|from this interaction.|
03859|030|P|   Pre-existing cardiovascular or cerebrovascular disease (e.g. heart|
03859|031|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
03859|032|P|or heart block), severe untreated sleep apnea, a prolonged QTc interval|
03859|033|P|prior to fingolimod initiation, factors associated with QTc prolongation|
03859|034|P|(e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT|
03859|035|P|prolonging agents may increase risk for cardiovascular toxicity due to|
03859|036|P|fingolimod.|
03859|037|P|   The risk of QT prolongation or torsades de pointes may also be increased|
03859|038|P|in patients with a history of torsades de pointes, hypocalcemia,|
03859|039|P|bradycardia, female gender, or advanced age.(4)|
03859|040|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03859|041|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03859|042|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03859|043|P|concentrations include rapid infusion of an intravenous dose or impaired|
03859|044|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03859|045|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03859|046|P|metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03859|047|B||
03859|048|M|PATIENT MANAGEMENT:  Recommendations for managing this interaction differ|
03859|049|M|between regulatory approving agencies.|
03859|050|M|   The fingolimod US prescribing information states:|
03859|051|M|   - Antineoplastic, immune-modulating, or immunosuppressive therapies|
03859|052|M|(including corticosteroids) are expected to increase the risk of|
03859|053|M|immunosuppression, and the risk of additive immune system effects must be|
03859|054|M|considered if these therapies are coadministered with fingolimod.  When|
03859|055|M|switching from drugs with prolonged immune effects, such as natalizumab,|
03859|056|M|teriflunomide or mitoxantrone, the duration and mode of action of these|
03859|057|M|drugs must be considered to avoid unintended additive immunosuppressive|
03859|058|M|effects when initiating fingolimod.(1)|
03859|059|M|   The fingolimod Canadian prescribing information states:|
03859|060|M|   - Concurrent use with immunosuppressive or immunomodulatory agents is|
03859|061|M|contraindicated due to the risk of additive immune system effects.  However,|
03859|062|M|co-administration of a short course of corticosteroids (up to 5 days) did|
03859|063|M|not increase the overall rate of infection in patients participating Phase|
03859|064|M|III clinical trials.(2)|
03859|065|M|   The fingolimod UK summary of product characteristics states:|
03859|066|M|   - Fingolimod is contraindicated in patients currently receiving|
03859|067|M|immunosuppressive therapies or those immunocompromised by prior therapies.|
03859|068|M|When switching patients from another disease modifying therapy to|
03859|069|M|fingolimod, the half-life and mode of action of the other therapy must be|
03859|070|M|considered in order to avoid an additive immune effect whilst at the same|
03859|071|M|time minimizing the risk of disease activation.(3)|
03859|072|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03859|073|M|time fingolimod is initiated or resumed should be monitored overnight with|
03859|074|M|continuous ECG monitoring in a medical facility.  Consult the prescribing|
03859|075|M|information for recommendations regarding cardiac monitoring.(1)|
03859|076|M|   Correct hypokalemia or hypomagnesemia prior to starting fingolimod.|
03859|077|B||
03859|078|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections|
03859|079|D|and cases of progressive multifocal leukoencephalopathy (PML) have been|
03859|080|D|reported in patients who previously received immunomodulators or|
03859|081|D|immunosuppressants.(1-3)|
03859|082|D|   After the first dose of fingolimod, heart rate decrease may begin within|
03859|083|D|an hour.  Decline is usually maximal at approximately 6 hours followed by a|
03859|084|D|second decrease 12 to 24 hours after the first dose.  The second dose may|
03859|085|D|further decrease heart rate, but the magnitude of change is smaller than the|
03859|086|D|first dose. With continued, chronic dosing, heart rate gradually returns to|
03859|087|D|baseline in about one month.(1,2)|
03859|088|D|   In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at|
03859|089|D|steady-state, when a negative chronotropic effect of fingolimod was still|
03859|090|D|present, fingolimod treatment resulted in a prolongation of QTc, with the|
03859|091|D|upper boundary of the 90% confidence interval (CI) of 14.0 msec.  The cause|
03859|092|D|of death in a patient who died within 24 hours after taking the first dose|
03859|093|D|of fingolimod was not conclusive; however a link to fingolimod or a drug|
03859|094|D|interaction with fingolimod could not be ruled out.(1)|
03859|095|B||
03859|096|R|REFERENCES:|
03859|097|B||
03859|098|R|1.Gilenya (fingolimod) US prescribing information. Novartis Pharmaceuticals|1
03859|099|R|  Corporation June, 2024.|1
03859|100|R|2.Gilenya (fingolimod) Health Canada prescribing information. Novartis|1
03859|101|R|  Pharmaceuticals September 23, 2011.|1
03859|102|R|3.Gilenya (fingolimod) UK summary of product characteristics. Novartis|1
03859|103|R|  Pharmaceuticals UK Ltd June 30, 2015.|1
03859|104|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03859|105|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03859|106|R|  settings: a scientific statement from the American Heart Association and|6
03859|107|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03859|108|R|  2;55(9):934-47.|6
03860|001|T|MONOGRAPH TITLE:  Ozanimod/Immunosuppressives;Immunomodulators that Prolong|
03860|002|T|QT|
03860|003|B||
03860|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03860|005|L|of severe adverse interaction.|
03860|006|B||
03860|007|A|MECHANISM OF ACTION:  Ozanimod in combination with immunosuppressives and|
03860|008|A|immune-modulators all suppress the immune system.(1,2)|
03860|009|A|   Initiation of ozanimod has a negative chronotropic effect leading to a|
03860|010|A|mean decrease in heart rate of 13 beats per minute (bpm) after the first|
03860|011|A|dose.  The first dose has also been associated with heart block.(1,2)|
03860|012|B||
03860|013|E|CLINICAL EFFECTS:  Concurrent use of ozanimod with immunosuppressive or|
03860|014|E|immune-modulating agents may result in an increased risk of serious|
03860|015|E|infections, such as disseminated herpetic infection or progressive|
03860|016|E|multifocal leukoencephalopathy (PML), an opportunistic infection caused by|
03860|017|E|the JC virus (JCV).(1,2)|
03860|018|E|   The initial heart rate lowering effect of ozanimod usually occurs within|
03860|019|E|5 hours.  With continued up-titration, the maximal heart rate effect of|
03860|020|E|ozanimod occurred on Day 8.  Symptomatic bradycardia and heart block,|
03860|021|E|including third degree block, have been observed.  Bradycardia may be|
03860|022|E|associated with an increase in the QTc interval, increasing the risk for|
03860|023|E|torsades de pointes.(1,2)|
03860|024|B||
03860|025|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03860|026|P|immunosuppressive or immune-modulating medications may increase the risk|
03860|027|P|from this interaction.|
03860|028|P|   Pre-existing cardiovascular or cerebrovascular disease (e.g. heart|
03860|029|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
03860|030|P|or heart block), severe untreated sleep apnea, a prolonged QTc interval|
03860|031|P|prior to ozanimod initiation, factors associated with QTc prolongation (e.g.|
03860|032|P|hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging|
03860|033|P|agents may increase risk for cardiovascular toxicity due to ozanimod.(1,2)|
03860|034|P|   The risk of QT prolongation or torsades de pointes may also be increased|
03860|035|P|in patients with a history of torsades de pointes, hypocalcemia,|
03860|036|P|bradycardia, female gender, or advanced age.(3)|
03860|037|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03860|038|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03860|039|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03860|040|P|concentrations include rapid infusion of an intravenous dose or impaired|
03860|041|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03860|042|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03860|043|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03860|044|B||
03860|045|M|PATIENT MANAGEMENT:  The ozanimod US prescribing information includes this|
03860|046|M|information regarding this interaction:|
03860|047|M|   -Ozanimod has not been studied in combination with anti-neoplastic,|
03860|048|M|immune-modulating, or immunosuppressive therapies.  Caution should be used|
03860|049|M|during concomitant administration because of the risk of additive immune|
03860|050|M|effects during therapy and in the week following administration.  When|
03860|051|M|switching from drugs with prolonged immune effects, the half-life and mode|
03860|052|M|of action of these drugs must be considered in order to avoid unintended|
03860|053|M|additive immunosuppressive effects.  Initiating treatment with ozanimod|
03860|054|M|after alemtuzumab is not recommended.  However, ozanimod can generally be|
03860|055|M|started immediately after discontinuation of beta interferon or glatiramer|
03860|056|M|acetate.(1,2)|
03860|057|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03860|058|M|time ozanimod is initiated or resumed should receive consultation with a|
03860|059|M|cardiologist.  Consult the prescribing information for recommendations|
03860|060|M|regarding cardiac monitoring.(1)|
03860|061|B||
03860|062|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections|
03860|063|D|and cases of progressive multifocal leukoencephalopathy (PML) have been|
03860|064|D|reported in patients who previously received immunomodulators or|
03860|065|D|immunosuppressants.(1,2)|
03860|066|D|   After the first dose of ozanimod heart rate decline is usually maximal at|
03860|067|D|approximately 5 hours, returning to baseline at 6 hours.  With continued,|
03860|068|D|chronic dosing, max heart rate effect occurred on day 8.(1,2)|
03860|069|B||
03860|070|R|REFERENCES:|
03860|071|B||
03860|072|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03860|073|R|  2024.|1
03860|074|R|2.Zeposia (ozanimod) UK summary of product characteristics. Bristol-Myers|1
03860|075|R|  Squibb Pharmaceuticals Ltd June, 2021.|1
03860|076|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03860|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03860|078|R|  settings: a scientific statement from the American Heart Association and|6
03860|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03860|080|R|  2;55(9):934-47.|6
03861|001|T|MONOGRAPH TITLE:  Siponimod/Immunosuppressives; Immunomodulators that|
03861|002|T|Prolong QT|
03861|003|B||
03861|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03861|005|L|of severe adverse interaction.|
03861|006|B||
03861|007|A|MECHANISM OF ACTION:  Siponimod in combination with immunosuppressives and|
03861|008|A|immune-modulators all suppress the immune system.(1,2)|
03861|009|A|   Initiation of siponimod has a negative chronotropic effect and can cause|
03861|010|A|bradycardia.(1,2)|
03861|011|B||
03861|012|E|CLINICAL EFFECTS:  Concurrent use of siponimod with immunosuppressive or|
03861|013|E|immune-modulating agents may result in an increased risk of serious|
03861|014|E|infections, such as disseminated herpetic infection or progressive|
03861|015|E|multifocal leukoencephalopathy (PML), an opportunistic infection caused by|
03861|016|E|the JC virus (JCV).(1,2)|
03861|017|E|   The heart rate lowering effect of siponimod starts within an hour, and|
03861|018|E|the Day 1 decline is maximal at approximately 3-4 hours.  This leads to a|
03861|019|E|mean decrease in heart rate of 5-6 beats per minute after the first dose.|
03861|020|E|The first dose has also been associated with heart block.  With continued|
03861|021|E|up-titration, further heart rate decreases are seen on subsequent days, with|
03861|022|E|maximal decrease from Day 1-baseline reached on Day 5-6.  Symptomatic|
03861|023|E|bradycardia has been observed.  Bradycardia may be associated with an|
03861|024|E|increase in the QTc interval, increasing the risk for torsade de pointes.(1)|
03861|025|B||
03861|026|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03861|027|P|immunosuppressive or immune-modulating medications may increase the risk|
03861|028|P|from this interaction.|
03861|029|P|   Pre-existing cardiovascular or cerebrovascular disease (e.g. heart|
03861|030|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
03861|031|P|or heart block), severe untreated sleep apnea, a prolonged QTc interval|
03861|032|P|prior to siponimod initiation, factors associated with QTc prolongation|
03861|033|P|(e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT|
03861|034|P|prolonging agents may increase risk for cardiovascular toxicity due to|
03861|035|P|siponimod.|
03861|036|P|   The risk of QT prolongation or torsades de pointes may also be increased|
03861|037|P|in patients with a history of torsades de pointes, hypocalcemia,|
03861|038|P|bradycardia, female gender, or advanced age.(3)|
03861|039|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03861|040|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03861|041|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03861|042|P|concentrations include rapid infusion of an intravenous dose or impaired|
03861|043|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03861|044|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03861|045|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03861|046|B||
03861|047|M|PATIENT MANAGEMENT:  The siponimod US prescribing information includes this|
03861|048|M|information regarding this interaction:|
03861|049|M|   -Siponimod has not been studied in combination with anti-neoplastic,|
03861|050|M|immune-modulating, or immunosuppressive therapies.  Caution should be used|
03861|051|M|during concomitant administration because of the risk of additive immune|
03861|052|M|effects during therapy and in the week following administration.  When|
03861|053|M|switching from drugs with prolonged immune effects, the half-life and mode|
03861|054|M|of action of these drugs must be considered in order to avoid unintended|
03861|055|M|additive immunosuppressive effects.  Initiating treatment with siponimod|
03861|056|M|after alemtuzumab is not recommended.  However, siponimod can generally be|
03861|057|M|started immediately after discontinuation of beta interferon or glatiramer|
03861|058|M|acetate.(1,2)|
03861|059|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03861|060|M|time siponimod is initiated or resumed should be referred to a cardiologist.|
03861|061|M|Consult the prescribing information for recommendations regarding cardiac|
03861|062|M|monitoring.(1)|
03861|063|B||
03861|064|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections|
03861|065|D|and cases of progressive multifocal leukoencephalopathy (PML) have been|
03861|066|D|reported in patients who previously received immunomodulators or|
03861|067|D|immunosuppressants.(1,2)|
03861|068|D|   After the first dose of siponimod, heart rate decrease may begin within|
03861|069|D|an hour.  Decline is usually maximal at approximately 3-4 hours.  With|
03861|070|D|continued, chronic dosing, heart rate gradually returns to baseline in about|
03861|071|D|10 days.(1,2)|
03861|072|D|   A transient, dose-dependent decrease in heart rate was observed during|
03861|073|D|the initial dosing phase of siponimod, which plateaued at doses greater than|
03861|074|D|or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses)|
03861|075|D|were detected at a higher incidence under siponimod treatment than placebo.|
03861|076|D|AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with|
03861|077|D|notably higher incidence under non-titrated conditions compared to dose|
03861|078|D|titration conditions.(1)|
03861|079|B||
03861|080|R|REFERENCES:|
03861|081|B||
03861|082|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03861|083|R|  Corporation August, 2025.|1
03861|084|R|2.Mayzent (siponimod) UK summary of product characteristics. Novartis|1
03861|085|R|  Pharmaceuticals UK Ltd January, 2021.|1
03861|086|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03861|087|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03861|088|R|  settings: a scientific statement from the American Heart Association and|6
03861|089|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03861|090|R|  2;55(9):934-47.|6
03862|001|T|MONOGRAPH TITLE:  Siponimod/Strong & Moderate CYP3A4 Inducers that Prolong|
03862|002|T|QT|
03862|003|B||
03862|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03862|005|L|take action as needed.|
03862|006|B||
03862|007|A|MECHANISM OF ACTION:  Drugs that are moderate or strong inducers of CYP3A4|
03862|008|A|may increase the metabolism of siponimod.(1)  Patients with a CYP2C9*1/*3 or|
03862|009|A|*2/*3 genotype who are more dependent on CYP3A4 for the metabolism of|
03862|010|A|siponimod would experience a greater effect of CYP3A4 induction.|
03862|011|A|   Initiation of siponimod has a negative chronotropic effect and may cause|
03862|012|A|bradycardia.  Concurrent use with CYP3A4 inducers that prolong the QT|
03862|013|A|interval may increase the risk of bradycardia and QT prolongation.(1,2)|
03862|014|B||
03862|015|E|CLINICAL EFFECTS:  Concurrent use of a siponimod with a moderate or strong|
03862|016|E|CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype may result|
03862|017|E|in decreased levels and effectiveness of siponimod.(1)|
03862|018|E|   The heart rate lowering effect of siponimod starts within an hour, and|
03862|019|E|the Day 1 decline is maximal at approximately 3-4 hours.  This leads to a|
03862|020|E|mean decrease in heart rate of 5-6 beats per minute after the first dose.|
03862|021|E|The first dose has also been associated with heart block.  With continued|
03862|022|E|up-titration, further heart rate decreases are seen on subsequent days, with|
03862|023|E|maximal decrease from Day 1-baseline reached on Day 5-6.  Symptomatic|
03862|024|E|bradycardia has been observed.  Bradycardia may be associated with an|
03862|025|E|increase in the QTc interval, increasing the risk for torsades de|
03862|026|E|pointes.(1,2)|
03862|027|B||
03862|028|P|PREDISPOSING FACTORS:  Patients with a CYP2C9*1/*3 or *2/*3 genotype who are|
03862|029|P|more dependent on CYP3A4 for the metabolism of siponimod would experience a|
03862|030|P|greater effect of CYP3A4 induction.|
03862|031|P|   Pre-existing cardiovascular or cerebrovascular disease (e.g. heart|
03862|032|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
03862|033|P|or heart block), severe untreated sleep apnea, a prolonged QTc interval|
03862|034|P|prior to siponimod initiation, factors associated with QTc prolongation|
03862|035|P|(e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT|
03862|036|P|prolonging agents may increase risk for cardiovascular toxicity due to|
03862|037|P|siponimod.|
03862|038|P|   The risk of QT prolongation or torsades de pointes may also be increased|
03862|039|P|in patients with a history of torsades de pointes, hypocalcemia,|
03862|040|P|bradycardia, female gender, or advanced age.(3)|
03862|041|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03862|042|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03862|043|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03862|044|P|concentrations include rapid infusion of an intravenous dose or impaired|
03862|045|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03862|046|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03862|047|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03862|048|P|   Induction effects may be more likely with regular use of the inducer for|
03862|049|P|longer than 1-2 weeks.|
03862|050|B||
03862|051|M|PATIENT MANAGEMENT:  Monitor the combination of siponimod with a moderate or|
03862|052|M|strong CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype for|
03862|053|M|loss of efficacy.(1)|
03862|054|M|   Agents that are both moderate CYP3A4 inducers and moderate CYP2C9|
03862|055|M|inducers (e.g., lorlatinib) should be used with caution regardless of the|
03862|056|M|patient's CYP2C9 genotype.(1)|
03862|057|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03862|058|M|time siponimod is initiated or resumed should be referred to a cardiologist.|
03862|059|M|Consult the prescribing information for recommendations regarding cardiac|
03862|060|M|monitoring.(1)|
03862|061|B||
03862|062|D|DISCUSSION:  In a study, efavirenz (a moderate CYP3A4 inducer) decreased the|
03862|063|D|area-under-curve (AUC) of siponimod by up to 52% across CYP2C9 genotypes.|
03862|064|D|   After the first dose of siponimod, heart rate decrease may begin within|
03862|065|D|an hour.  Decline is usually maximal at approximately 3-4 hours.  With|
03862|066|D|continued, chronic dosing, heart rate gradually returns to baseline in about|
03862|067|D|10 days.(1,2)|
03862|068|D|   A transient, dose-dependent decrease in heart rate was observed during|
03862|069|D|the initial dosing phase of siponimod, which plateaued at doses greater than|
03862|070|D|or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses)|
03862|071|D|were detected at a higher incidence under siponimod treatment than placebo.|
03862|072|D|AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with|
03862|073|D|notably higher incidence under non-titrated conditions compared to dose|
03862|074|D|titration conditions.(1)|
03862|075|D|   Drugs that are moderate or strong CYP3A4 inducers linked to this|
03862|076|D|monograph include: efavirenz, ivosidenib, pacritinib and thioridazine.(4,5)|
03862|077|B||
03862|078|R|REFERENCES:|
03862|079|B||
03862|080|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03862|081|R|  Corporation August, 2025.|1
03862|082|R|2.Mayzent (siponimod) UK summary of product characteristics. Novartis|1
03862|083|R|  Pharmaceuticals UK Ltd January, 2021.|1
03862|084|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03862|085|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03862|086|R|  settings: a scientific statement from the American Heart Association and|6
03862|087|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03862|088|R|  2;55(9):934-47.|6
03862|089|R|4.This information is based on an extract from the Certara Drug Interaction|6
03862|090|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03862|091|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03862|092|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03862|093|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03862|094|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03862|095|R|  11/14/2017.|1
03863|001|T|MONOGRAPH TITLE:  Siponimod/Mitotane (mono deleted 10/01/2021)|
03863|002|B||
03863|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03863|004|L|of severe adverse interaction.|
03863|005|B||
03863|006|A|MECHANISM OF ACTION:  Drugs that are moderate or strong inducers of CYP3A4|
03863|007|A|may increase the metabolism of siponimod.(1)  Patients with a CYP2C9*1/*3 or|
03863|008|A|*2/*3 genotype who are more dependent on CYP3A4 for the metabolism of|
03863|009|A|siponimod would experience a greater effect of CYP3A4 induction.|
03863|010|A|   Siponimod in combination with immunosuppressives and immune-modulators|
03863|011|A|all suppress the immune system.  Mitotane suppresses the immune system.(1)|
03863|012|B||
03863|013|E|CLINICAL EFFECTS:  Concurrent use of a siponimod with a moderate or strong|
03863|014|E|CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype may result|
03863|015|E|in decreased levels and effectiveness of siponimod.(1)|
03863|016|E|   Concurrent use of siponimod with immunosuppressive or immune-modulating|
03863|017|E|agents may result in an increased risk of serious infections, such as|
03863|018|E|disseminated herpetic infection or progressive multifocal|
03863|019|E|leukoencephalopathy (PML), an opportunistic infection caused by the JC virus|
03863|020|E|(JCV).(1)|
03863|021|B||
03863|022|P|PREDISPOSING FACTORS:  Patients with a CYP2C9*1/*3 or *2/*3 genotype who are|
03863|023|P|more dependent on CYP3A4 for the metabolism of siponimod would experience a|
03863|024|P|greater effect of CYP3A4 induction.|
03863|025|P|   Incomplete washout of previously prescribed immunosuppressive or|
03863|026|P|immune-modulating medications may result in a greater immunosuppressive|
03863|027|P|effect.|
03863|028|B||
03863|029|M|PATIENT MANAGEMENT:  The manufacturer of siponimod says that the combination|
03863|030|M|of siponimod with a moderate or strong CYP3A4 inducer is not recommended for|
03863|031|M|patients with a CYP2C9*1/*3 or *2/*3 genotype.(1)|
03863|032|M|   Agents that are both moderate CYP3A4 inducers and moderate CYP2C9|
03863|033|M|inducers(e.g., lorlatinib) should be used with caution regardless of the|
03863|034|M|patient's CYP2C9 genotype.(1)|
03863|035|M|   The siponimod US prescribing information provides this information|
03863|036|M|regarding myelosuppression risk from this interaction:|
03863|037|M|   Siponimod has not been studied in combination with anti-neoplastic,|
03863|038|M|immune-modulating, or immunosuppressive therapies.  Caution should be used|
03863|039|M|during concomitant administration because of the risk of additive immune|
03863|040|M|effects during therapy and in the week following administration.  When|
03863|041|M|switching from drugs with prolonged immune effects, the half-life and mode|
03863|042|M|of action of these drugs must be considered in order to avoid unintended|
03863|043|M|additive immunosuppressive effects.(1)|
03863|044|B||
03863|045|D|DISCUSSION:  In a study, efavirenz (a moderate CYP3A4 inducer) decreased the|
03863|046|D|area-under-curve (AUC) of siponimod by up to 52% across CYP2C9 genotypes.|
03863|047|D|   Fatal disseminated herpes zoster and herpes simplex infections and cases|
03863|048|D|of progressive multifocal leukoencephalopathy (PML) have been reported in|
03863|049|D|patients who previously received immunomodulators or immunosuppressants.(1)|
03863|050|D|   Drugs that are moderate or strong CYP3A4 inducers with myelosuppression|
03863|051|D|risk linked to this monograph include: mitotane.(2-3)|
03863|052|B||
03863|053|R|REFERENCES:|
03863|054|B||
03863|055|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03863|056|R|  Corporation August, 2025.|1
03863|057|R|2.This information is based on an extract from the Certara Drug Interaction|6
03863|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03863|059|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03863|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03863|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03863|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03863|063|R|  11/14/2017.|1
03864|001|T|MONOGRAPH TITLE:  Siponimod/Select Moderate CYP2C9 Inhibitors that Prolong|
03864|002|T|QT|
03864|003|B||
03864|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03864|005|L|take action as needed.|
03864|006|B||
03864|007|A|MECHANISM OF ACTION:  Inhibitors of CYP2C9 may inhibit the metabolism of|
03864|008|A|siponimod.(1)|
03864|009|A|   Initiation of siponimod has a negative chronotropic effect and may|
03864|010|A|increase the risk of bradycardia.(1,2)|
03864|011|B||
03864|012|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of CYP2C9 may result in|
03864|013|E|elevated levels of and clinical effects of siponimod, including|
03864|014|E|immunosuppression and increased risk of infection.(1,2)|
03864|015|E|   The heart rate lowering effect of siponimod starts within an hour, and|
03864|016|E|the Day 1 decline is maximal at approximately 3-4 hours.  This leads to a|
03864|017|E|mean decrease in heart rate of 5-6 beats per minute after the first dose.|
03864|018|E|The first dose has also been associated with heart block.  With continued|
03864|019|E|up-titration, further heart rate decreases are seen on subsequent days, with|
03864|020|E|maximal decrease from Day 1-baseline reached on Day 5-6.  Symptomatic|
03864|021|E|bradycardia has been observed.  Bradycardia may be associated with an|
03864|022|E|increase in the QTc interval, increasing the risk for torsades de|
03864|023|E|pointes.(1)|
03864|024|B||
03864|025|P|PREDISPOSING FACTORS:  Concurrent use of a strong or moderate inhibitor of|
03864|026|P|CYP3A4 may increase the effects of the interaction.(1)|
03864|027|P|   Concurrent use of other drugs that may decrease heart rate (e.g., beta|
03864|028|P|blockers, verapamil, diltiazem, ivabradine, digoxin) may increase risk for|
03864|029|P|cardiovascular toxicity due to siponimod, including QT prolongation or|
03864|030|P|torsades de pointes.(1)|
03864|031|B||
03864|032|M|PATIENT MANAGEMENT:  Monitor for adverse reactions during concomitant use of|
03864|033|M|siponimod with moderate CYP2C9 inhibitors or dual CYP2C9 and CYP3A4|
03864|034|M|inhibitors.(1)  Review the patient's therapy for concurrent use of strong or|
03864|035|M|moderate inhibitors of CYP3A4 prior to initiating siponimod.|
03864|036|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03864|037|M|time siponimod is initiated or resumed should be referred to a cardiologist.|
03864|038|M|Consult the prescribing information for recommendations regarding cardiac|
03864|039|M|monitoring.(1)|
03864|040|B||
03864|041|D|DISCUSSION:  Siponimod is metabolized by CYP2C9 (79.3%) and CYP3A4 (18.5%).|
03864|042|D|Concurrent use of fluconazole (a dual moderate inhibitor of CYP2C9 and|
03864|043|D|CYP3A4, 200 mg at steady state) in healthy subjects with the CYP2C9*1/*1|
03864|044|D|genotype increased the area-under-curve (AUC) of siponimod (4 mg single|
03864|045|D|dose) by 2-fold.  Siponimod half-life increased by 50%.  Fluconazole|
03864|046|D|increased siponimod AUC by 2-fold to 4-fold across all CYP2C9 genotypes.(1)|
03864|047|D|   After the first dose of siponimod, heart rate decrease may begin within|
03864|048|D|an hour.  Decline is usually maximal at approximately 3-4 hours.  With|
03864|049|D|continued, chronic dosing, heart rate gradually returns to baseline in about|
03864|050|D|10 days.(1,2)|
03864|051|D|   A transient, dose-dependent decrease in heart rate was observed during|
03864|052|D|the initial dosing phase of siponimod, which plateaued at doses greater than|
03864|053|D|or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses)|
03864|054|D|were detected at a higher incidence under siponimod treatment than placebo.|
03864|055|D|AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with|
03864|056|D|notably higher incidence under non-titrated conditions compared to dose|
03864|057|D|titration conditions.(1)|
03864|058|D|   Selected moderate CYP2C9 inhibitors that prolong QT linked to this|
03864|059|D|monograph include: amiodarone.(4)|
03864|060|B||
03864|061|R|REFERENCES:|
03864|062|B||
03864|063|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03864|064|R|  Corporation August, 2025.|1
03864|065|R|2.Mayzent (siponimod) UK summary of product characteristics. Novartis|1
03864|066|R|  Pharmaceuticals UK Ltd January, 2021.|1
03864|067|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03864|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03864|069|R|  settings: a scientific statement from the American Heart Association and|6
03864|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03864|071|R|  2;55(9):934-47.|6
03864|072|R|4.This information is based on an extract from the Certara Drug Interaction|6
03864|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03865|001|T|MONOGRAPH TITLE:  Cladribine Oral/Immunosuppressives; Immunomodulators|
03865|002|B||
03865|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03865|004|L|of severe adverse interaction.|
03865|005|B||
03865|006|A|MECHANISM OF ACTION:  Cladribine in combination with immunosuppressives and|
03865|007|A|immune-modulators all suppress the immune system.(1-2)|
03865|008|B||
03865|009|E|CLINICAL EFFECTS:  Concurrent use of cladribine with immunosuppressive or|
03865|010|E|immune-modulating agents may result in an increased risk of serious|
03865|011|E|infections, such as disseminated herpetic infection or progressive|
03865|012|E|multifocal leukoencephalopathy (PML), an opportunistic infection caused by|
03865|013|E|the JC virus (JCV).(1-2)|
03865|014|B||
03865|015|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03865|016|P|immunosuppressive or immune-modulating medications.|
03865|017|B||
03865|018|M|PATIENT MANAGEMENT:  Recommendations for cladribine regarding this|
03865|019|M|interaction differ between regulatory approving agencies.|
03865|020|M|   The cladribine US prescribing information states:|
03865|021|M|   -Concomitant use with myelosuppressive or other immunosuppressive drugs|
03865|022|M|is not recommended. Acute short-term therapy with corticosteroids can be|
03865|023|M|administered.|
03865|024|M|   In patients who have previously been treated with immunomodulatory or|
03865|025|M|immunosuppressive drugs, consider potential additive effect, the mode of|
03865|026|M|action, and duration of effect of the other drugs prior to initiation of|
03865|027|M|cladribine.(1)|
03865|028|M|   The cladribine Canadian prescribing information states:|
03865|029|M|   -Use of cladribine in immunocompromised patients is contraindicated|
03865|030|M|because of a risk of additive effects on the immune system. Acute short-term|
03865|031|M|therapy with corticosteroids can be administered during cladribine|
03865|032|M|treatment.(2)|
03865|033|B||
03865|034|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections|
03865|035|D|and cases of progressive multifocal leukoencephalopathy (PML) have been|
03865|036|D|reported in patients who previously received immunomodulators or|
03865|037|D|immunosuppressants.(1-2)|
03865|038|B||
03865|039|R|REFERENCES:|
03865|040|B||
03865|041|R|1.Mavenclad (cladribine) US prescribing information. EMD Serono, Inc. March,|1
03865|042|R|  2019.|1
03865|043|R|2.Mavenclad (cladribine) CA prescribing information. EMD Serono October,|1
03865|044|R|  2021.|1
03866|001|T|MONOGRAPH TITLE:  Cladribine/Selected Inhibitors of BCRP with|
03866|002|T|Myelosuppression|
03866|003|B||
03866|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03866|005|L|of severe adverse interaction.|
03866|006|B||
03866|007|A|MECHANISM OF ACTION:  Inhibitors of BCRP may increase the absorption of|
03866|008|A|cladribine.(1-2)  Also, cladribine in combination with immunosuppressives|
03866|009|A|and immune-modulators all suppress the immune system.(1-2)|
03866|010|B||
03866|011|E|CLINICAL EFFECTS:  The concurrent administration of cladribine with an|
03866|012|E|inhibitor of BCRP may result in elevated levels of cladribine and signs of|
03866|013|E|toxicity.(1-2)|
03866|014|E|   Concurrent use of cladribine with immunosuppressive or immune-modulating|
03866|015|E|agents may result in an increased risk of serious infections, such as|
03866|016|E|disseminated herpetic infection or progressive multifocal|
03866|017|E|leukoencephalopathy (PML), an opportunistic infection caused by the JC virus|
03866|018|E|(JCV).(1-2)|
03866|019|B||
03866|020|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03866|021|P|immunosuppressive or immune-modulating medications.|
03866|022|B||
03866|023|M|PATIENT MANAGEMENT:  The manufacturer of cladribine states concurrent use of|
03866|024|M|BCRP inhibitors should be avoided during the 4- to 5-day cladribine|
03866|025|M|treatment.(1-2)|
03866|026|M|   Selection of an alternative concurrent medication with no or minimal|
03866|027|M|transporter inhibiting proprieties should be considered. If this is not|
03866|028|M|possible, dose reduction to the minimum mandatory dose of the BCRP|
03866|029|M|inhibitor, separation in timing of administration, and careful patient|
03866|030|M|monitoring is recommended.(1-2)|
03866|031|M|   Myelosuppression risk recommendations for cladribine regarding this|
03866|032|M|interaction differ between regulatory approving agencies.|
03866|033|M|   The cladribine US prescribing information states:|
03866|034|M|   -Concomitant use with myelosuppressive or other immunosuppressive drugs|
03866|035|M|is not recommended. Acute short-term therapy with corticosteroids can be|
03866|036|M|administered.|
03866|037|M|In patients who have previously been treated with immunomodulatory or|
03866|038|M|immunosuppressive drugs, consider potential additive effect, the mode of|
03866|039|M|action, and duration of effect of the other drugs prior to initiation of|
03866|040|M|cladribine.(1)|
03866|041|M|   The cladribine Canadian prescribing information states:|
03866|042|M|   -Use of cladribine in immunocompromised patients is contraindicated|
03866|043|M|because of a risk of additive effects on the immune system. Acute short-term|
03866|044|M|therapy with corticosteroids can be administered during cladribine|
03866|045|M|treatment.(2)|
03866|046|M|   Monitor for signs of hematologic toxicity.  Lymphocyte counts should be|
03866|047|M|monitored.|
03866|048|B||
03866|049|D|DISCUSSION:  Cladribine is a substrate of BCRP.  Inhibitors of this|
03866|050|D|transporter are expected to increase cladribine levels.(1-2)|
03866|051|D|   BCRP inhibitors linked to this monograph include:  asciminib,|
03866|052|D|belumosudil, cyclosporine, encorafenib, leflunomide, leniolisib,|
03866|053|D|momelotinib, pirtobrutinib, and teriflunomide.(1,2)|
03866|054|D|   Fatal disseminated herpes zoster and herpes simplex infections and cases|
03866|055|D|of progressive multifocal leukoencephalopathy (PML) have been reported in|
03866|056|D|patients who previously received immunomodulators or|
03866|057|D|immunosuppressants.(1-2)|
03866|058|B||
03866|059|R|REFERENCES:|
03866|060|B||
03866|061|R|1.Mavenclad (cladribine) CA prescribing information. EMD Serono October,|1
03866|062|R|  2021.|1
03866|063|R|2.Mavenclad (cladribine) US prescribing information. EMD Serono, Inc. March,|1
03866|064|R|  2019.|1
03867|001|T|MONOGRAPH TITLE:  Clozapine/Fingolimod|
03867|002|B||
03867|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03867|004|L|of severe adverse interaction.|
03867|005|B||
03867|006|A|MECHANISM OF ACTION:  Concurrent use of clozapine with other agents that|
03867|007|A|prolong the QTc interval may result in additive effects on the QTc|
03867|008|A|interval.(1)  Initiation of fingolimod has a negative chronotropic effect|
03867|009|A|and may cause bradycardia, which may increase the risk of QT|
03867|010|A|prolongation.(2-4)|
03867|011|A|   Clozapine and concurrent use with other myelosuppressive agents,|
03867|012|A|including fingolimod, may be associated with additive risk of neutropenia or|
03867|013|A|agranulocytosis.(1)|
03867|014|B||
03867|015|E|CLINICAL EFFECTS:  Concurrent use of clozapine with agents that prolong the|
03867|016|E|QTc interval may result in potentially life-threatening cardiac|
03867|017|E|arrhythmias.(1)|
03867|018|E|   Fingolimod causes a biphasic lowering of the heart rate (HR), initially|
03867|019|E|within 6 hours, and then at 12-24 hours after the first dose.  Symptomatic|
03867|020|E|bradycardia and heart block, including third degree block, have been|
03867|021|E|observed.  Bradycardia may be associated with an increase in the QTc|
03867|022|E|interval, increasing the risk for torsade de pointes.  There is no|
03867|023|E|consistent signal of increased incidence of QTc outliers, either absolute or|
03867|024|E|change from baseline, associated with fingolimod treatment.(2-4)|
03867|025|E|   Moderate neutropenia may require abrupt discontinuation of clozapine|
03867|026|E|resulting in decompensation of the patient's psychiatric disorder (e.g.|
03867|027|E|schizophrenia).  Fingolimod therapy may be compromised if myelosuppression|
03867|028|E|requires dose reduction, delay, or discontinuation of fingolimod. Undetected|
03867|029|E|severe neutropenia or agranulocytosis may be fatal.|
03867|030|B||
03867|031|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03867|032|P|may be increased in patients with cardiovascular disease (e.g. heart|
03867|033|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03867|034|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03867|035|P|female gender, or advanced age.(5)|
03867|036|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03867|037|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03867|038|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03867|039|P|concentrations include rapid infusion of an intravenous dose or impaired|
03867|040|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03867|041|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03867|042|P|metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
03867|043|P|   Low white blood counts prior to initiation of the myelosuppressive agent|
03867|044|P|may increase risk for clinically significant neutropenia.(1)|
03867|045|B||
03867|046|M|PATIENT MANAGEMENT:  Approach the concurrent use of clozapine and other|
03867|047|M|agents that prolong the QTc interval with caution.(1)|
03867|048|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03867|049|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03867|050|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03867|051|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03867|052|M|   If a patient stabilized on clozapine therapy requires treatment with|
03867|053|M|other myelosuppressive agents the clozapine prescriber should consult with|
03867|054|M|the prescriber of the myelosuppressive agent to discuss treatment and|
03867|055|M|monitoring options.  More frequent ANC monitoring or treatment alternatives|
03867|056|M|secondary to neutropenic episodes may need to be considered.|
03867|057|M|   Clozapine is only available through a restricted distribution system|
03867|058|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
03867|059|M|dispensing.  For most clozapine patients, clozapine treatment must be|
03867|060|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
03867|061|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
03867|062|M|interrupted for suspected clozapine-induced neutropenia < 500|
03867|063|M|cells/microliter.(1)|
03867|064|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03867|065|M|time fingolimod is initiated or resumed should be referred to a|
03867|066|M|cardiologist.  Consult the prescribing information for recommendations|
03867|067|M|regarding cardiac monitoring.(2-4)|
03867|068|B||
03867|069|D|DISCUSSION:  Treatment with clozapine has been associated with QT|
03867|070|D|prolongation as well as ventricular arrhythmia, torsades de pointes, cardiac|
03867|071|D|arrest, and sudden death.(1)|
03867|072|D|   Clozapine is only available through a restricted distribution system|
03867|073|D|which requires documentation of the ANC prior to dispensing.(1,7)|
03867|074|D|   After the first dose of fingolimod, heart rate decrease may begin within|
03867|075|D|an hour.  Decline is usually maximal at approximately 6 hours followed by a|
03867|076|D|second decrease 12 to 24 hours after the first dose.  The second dose may|
03867|077|D|further decrease heart rate, but the magnitude of change is smaller than the|
03867|078|D|first dose. With continued, chronic dosing, heart rate gradually returns to|
03867|079|D|baseline in about one month.(2,3)|
03867|080|D|   In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at|
03867|081|D|steady-state, when a negative chronotropic effect of fingolimod was still|
03867|082|D|present, fingolimod treatment resulted in a prolongation of QTc, with the|
03867|083|D|upper boundary of the 90% confidence interval (CI) of 14.0 msec.  The cause|
03867|084|D|of death in a patient who died within 24 hour after taking the first dose of|
03867|085|D|fingolimod was not conclusive; however a link to fingolimod or a drug|
03867|086|D|interaction with fingolimod could not be ruled out.(2)|
03867|087|B||
03867|088|R|REFERENCES:|
03867|089|B||
03867|090|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03867|091|R|  Pharmaceuticals Corporation April, 2020.|1
03867|092|R|2.Gilenya (fingolimod) US prescribing information. Novartis Pharmaceuticals|1
03867|093|R|  Corporation June, 2024.|1
03867|094|R|3.Gilenya (fingolimod) Health Canada prescribing information. Novartis|1
03867|095|R|  Pharmaceuticals September 23, 2011.|1
03867|096|R|4.Gilenya (fingolimod) UK summary of product characteristics. Novartis|1
03867|097|R|  Pharmaceuticals UK Ltd June 30, 2015.|1
03867|098|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03867|099|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03867|100|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03867|101|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03867|102|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03867|103|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03867|104|R|  settings: a scientific statement from the American Heart Association and|6
03867|105|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03867|106|R|  2;55(9):934-47.|6
03867|107|R|7.FDA (US Food and Drug Administration). Clozapine: Drug Safety|1
03867|108|R|  Communication - FDA Modifies Monitoring for Neutropenia; Approves New|1
03867|109|R|  Shared REMS Program. accessed at:|1
03867|110|R|  http://www.fda.gov/drugs/drugsafety/ucm461853.htm September 15, 2015.|1
03868|001|T|MONOGRAPH TITLE:  Clozapine/Siponimod|
03868|002|B||
03868|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03868|004|L|of severe adverse interaction.|
03868|005|B||
03868|006|A|MECHANISM OF ACTION:  Concurrent use of clozapine with other agents that|
03868|007|A|prolong the QTc interval may result in additive effects on the QTc|
03868|008|A|interval.(1)  Initiation of siponimod has a negative chronotropic effect and|
03868|009|A|may cause bradycardia, which may increase the risk of QT prolongation.(2-3)|
03868|010|A|   Clozapine and concurrent use with other myelosuppressive agents,|
03868|011|A|including siponimod, may be associated with additive risk of neutropenia or|
03868|012|A|agranulocytosis.(1)|
03868|013|B||
03868|014|E|CLINICAL EFFECTS:  Concurrent use of clozapine with agents that prolong the|
03868|015|E|QTc interval may result in life-threatening cardiac arrhythmias.(1)|
03868|016|E|   Siponimod lowers heart rate within an hour of the 1st dose, and the Day 1|
03868|017|E|decline is maximal at 3-4 hours.  This leads to a mean decrease in heart|
03868|018|E|rate of 5-6 beats per minute after the first dose.  The first dose has also|
03868|019|E|been associated with heart block.  With continued up-titration, further|
03868|020|E|heart rate decreases are seen, with maximal decrease from Day 1-baseline|
03868|021|E|reached on Day 5-6. Symptomatic bradycardia has been observed. Bradycardia|
03868|022|E|may be associated with an increase in the QTc interval.(2,3)|
03868|023|E|   Moderate neutropenia may require abrupt discontinuation of clozapine|
03868|024|E|resulting in decompensation of the patient's psychiatric disorder.|
03868|025|E|Siponimod therapy may be compromised if myelosuppression requires dose|
03868|026|E|reduction, delay, or discontinuation of siponimod.  Undetected severe|
03868|027|E|neutropenia or agranulocytosis may be fatal.|
03868|028|B||
03868|029|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03868|030|P|may be increased in patients with cardiovascular disease (e.g. heart|
03868|031|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03868|032|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03868|033|P|female gender, or advanced age.(4)|
03868|034|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03868|035|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03868|036|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03868|037|P|concentrations include rapid infusion of an intravenous dose or impaired|
03868|038|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03868|039|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03868|040|P|metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03868|041|P|   Low white blood counts prior to initiation of the myelosuppressive agent|
03868|042|P|may increase risk for clinically significant neutropenia.(1)|
03868|043|B||
03868|044|M|PATIENT MANAGEMENT:  Approach the concurrent use of clozapine and other|
03868|045|M|agents that prolong the QTc interval with caution.(1)|
03868|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03868|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03868|048|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03868|049|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03868|050|M|   If a patient stabilized on clozapine therapy requires treatment with|
03868|051|M|other myelosuppressive agents the clozapine prescriber should consult with|
03868|052|M|the prescriber of the myelosuppressive agent to discuss treatment and|
03868|053|M|monitoring options.  More frequent ANC monitoring or treatment alternatives|
03868|054|M|secondary to neutropenic episodes may need to be considered.|
03868|055|M|   Clozapine is only available through a restricted distribution system|
03868|056|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
03868|057|M|dispensing.  For most clozapine patients, clozapine treatment must be|
03868|058|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
03868|059|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
03868|060|M|interrupted for suspected clozapine-induced neutropenia < 500|
03868|061|M|cells/microliter.(1)|
03868|062|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03868|063|M|time siponimod is initiated or resumed should be referred to a cardiologist.|
03868|064|M|Consult the prescribing information for recommendations regarding cardiac|
03868|065|M|monitoring.(2-3)|
03868|066|B||
03868|067|D|DISCUSSION:  Treatment with clozapine has been associated with QT|
03868|068|D|prolongation as well as ventricular arrhythmia, torsades de pointes, cardiac|
03868|069|D|arrest, and sudden death.(1)|
03868|070|D|   After the first dose of siponimod, heart rate decrease may begin within|
03868|071|D|an hour.  Decline is usually maximal at approximately 3-4 hours.  With|
03868|072|D|continued, chronic dosing, heart rate gradually returns to baseline in about|
03868|073|D|10 days.(2,3)|
03868|074|D|   A transient, dose-dependent decrease in heart rate was observed during|
03868|075|D|the initial dosing phase of siponimod, which plateaued at doses greater than|
03868|076|D|or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses)|
03868|077|D|were detected at a higher incidence under siponimod treatment than placebo.|
03868|078|D|AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with|
03868|079|D|notably higher incidence under non-titrated conditions compared to dose|
03868|080|D|titration conditions.(2)|
03868|081|D|   Clozapine is only available through a restricted distribution system|
03868|082|D|which requires documentation of the ANC prior to dispensing.(1,6)|
03868|083|B||
03868|084|R|REFERENCES:|
03868|085|B||
03868|086|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03868|087|R|  Pharmaceuticals Corporation April, 2020.|1
03868|088|R|2.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
03868|089|R|  Corporation August, 2025.|1
03868|090|R|3.Mayzent (siponimod) UK summary of product characteristics. Novartis|1
03868|091|R|  Pharmaceuticals UK Ltd January, 2021.|1
03868|092|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03868|093|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03868|094|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03868|095|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03868|096|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03868|097|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03868|098|R|  settings: a scientific statement from the American Heart Association and|6
03868|099|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03868|100|R|  2;55(9):934-47.|6
03868|101|R|6.FDA (US Food and Drug Administration). Clozapine: Drug Safety|1
03868|102|R|  Communication - FDA Modifies Monitoring for Neutropenia; Approves New|1
03868|103|R|  Shared REMS Program. accessed at:|1
03868|104|R|  http://www.fda.gov/drugs/drugsafety/ucm461853.htm September 15, 2015.|1
03869|001|T|MONOGRAPH TITLE:  Clozapine/Ponesimod|
03869|002|B||
03869|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03869|004|L|of severe adverse interaction.|
03869|005|B||
03869|006|A|MECHANISM OF ACTION:  Concurrent use of clozapine with other agents that|
03869|007|A|prolong the QTc interval may result in additive effects on the QTc|
03869|008|A|interval.(1)  Initiation of ponesimod has a negative chronotropic effect and|
03869|009|A|may cause bradycardia, which may increase the risk of QT prolongation.(2)|
03869|010|A|   Clozapine and concurrent use with other myelosuppressive agents,|
03869|011|A|including ponesimod, may be associated with additive risk of neutropenia or|
03869|012|A|agranulocytosis.(1)|
03869|013|B||
03869|014|E|CLINICAL EFFECTS:  Concurrent use of clozapine with agents that prolong the|
03869|015|E|QTc interval may result in life-threatening cardiac arrhythmias.(1)|
03869|016|E|   Ponesimod lowers heart rate (HR) within 1 hour of the 1st dose.  HR|
03869|017|E|reaches its nadir within 2-4 hours and typically recovers to baseline levels|
03869|018|E|4-5 hours after dose.  The conduction abnormalities typically were|
03869|019|E|transient, asymptomatic, and resolved within 24 hours.  With up-titration|
03869|020|E|after Day 1, the post-dose decrease in heart rate is less pronounced.|
03869|021|E|Bradycardia may be associated with an increase in the QTc interval.(2)|
03869|022|E|   Moderate neutropenia may require abrupt discontinuation of clozapine|
03869|023|E|resulting in decompensation of the patient's psychiatric disorder.|
03869|024|E|Ponesimod therapy may be compromised if myelosuppression requires dose|
03869|025|E|reduction, delay, or discontinuation of ponesimod.  Undetected severe|
03869|026|E|neutropenia or agranulocytosis may be fatal.|
03869|027|B||
03869|028|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03869|029|P|may be increased in patients with cardiovascular disease (e.g. heart|
03869|030|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03869|031|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03869|032|P|female gender, or advanced age.(3)|
03869|033|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03869|034|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03869|035|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03869|036|P|concentrations include rapid infusion of an intravenous dose or impaired|
03869|037|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03869|038|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03869|039|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03869|040|P|   Low white blood counts prior to initiation of the myelosuppressive agent|
03869|041|P|may increase risk for clinically significant neutropenia.(1)|
03869|042|B||
03869|043|M|PATIENT MANAGEMENT:  Approach the concurrent use of clozapine and other|
03869|044|M|agents that prolong the QTc interval with caution.(1)|
03869|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03869|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03869|047|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03869|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03869|049|M|   If a patient stabilized on clozapine therapy requires treatment with|
03869|050|M|other myelosuppressive agents the clozapine prescriber should consult with|
03869|051|M|the prescriber of the myelosuppressive agent to discuss treatment and|
03869|052|M|monitoring options.  More frequent ANC monitoring or treatment alternatives|
03869|053|M|secondary to neutropenic episodes may need to be considered.|
03869|054|M|   Clozapine is only available through a restricted distribution system|
03869|055|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
03869|056|M|dispensing.  For most clozapine patients, clozapine treatment must be|
03869|057|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
03869|058|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
03869|059|M|interrupted for suspected clozapine-induced neutropenia < 500|
03869|060|M|cells/microliter.(1)|
03869|061|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03869|062|M|time ponesimod is initiated or resumed should be referred to a cardiologist.|
03869|063|M|Consult the prescribing information for recommendations regarding cardiac|
03869|064|M|monitoring.(2)|
03869|065|B||
03869|066|D|DISCUSSION:  Treatment with clozapine has been associated with QT|
03869|067|D|prolongation as well as ventricular arrhythmia, torsades de pointes, cardiac|
03869|068|D|arrest, and sudden death.(1)|
03869|069|D|   After the first dose of ponesimod, heart rate decrease may begin within|
03869|070|D|the first hour.  Decline is usually maximal at approximately 4 hours.  With|
03869|071|D|continued, chronic dosing, post-dose decrease in heart rate is less|
03869|072|D|pronounced.  Heart rate gradually returns to baseline in about 4-5 hours.(2)|
03869|073|D|   Clozapine is only available through a restricted distribution system|
03869|074|D|which requires documentation of the ANC prior to dispensing.(1,5)|
03869|075|B||
03869|076|R|REFERENCES:|
03869|077|B||
03869|078|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03869|079|R|  Pharmaceuticals Corporation April, 2020.|1
03869|080|R|2.Ponvory (ponesimod) US prescribing information. Janssen Pharmaceuticals,|1
03869|081|R|  Inc. March, 2021.|1
03869|082|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03869|083|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03869|084|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03869|085|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03869|086|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03869|087|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03869|088|R|  settings: a scientific statement from the American Heart Association and|6
03869|089|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03869|090|R|  2;55(9):934-47.|6
03869|091|R|5.FDA (US Food and Drug Administration). Clozapine: Drug Safety|1
03869|092|R|  Communication - FDA Modifies Monitoring for Neutropenia; Approves New|1
03869|093|R|  Shared REMS Program. accessed at:|1
03869|094|R|  http://www.fda.gov/drugs/drugsafety/ucm461853.htm September 15, 2015.|1
03870|001|T|MONOGRAPH TITLE:  Clozapine/Ozanimod|
03870|002|B||
03870|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03870|004|L|of severe adverse interaction.|
03870|005|B||
03870|006|A|MECHANISM OF ACTION:  Concurrent use of clozapine with other agents that|
03870|007|A|prolong the QTc interval may result in additive effects on the QTc|
03870|008|A|interval.(1)  Initiation of ozanimod has a negative chronotropic effect and|
03870|009|A|may cause bradycardia, which may increase the risk of QT prolongation.(2-3)|
03870|010|A|   Clozapine and concurrent use with other myelosuppressive agents,|
03870|011|A|including ozanimod, may be associated with additive risk of neutropenia or|
03870|012|A|agranulocytosis.(1)|
03870|013|B||
03870|014|E|CLINICAL EFFECTS:  Concurrent use of clozapine with agents that prolong the|
03870|015|E|QTc interval may result in life-threatening cardiac arrhythmias.(1)|
03870|016|E|   Ozanimod lowers heart rate (HR) within 5 hours of the 1st dose. With|
03870|017|E|continued up-titration, the maximal heart rate effect of ozanimod occurred|
03870|018|E|on Day 8.  Symptomatic bradycardia and heart block, including third degree|
03870|019|E|block, have been observed.  Bradycardia may be associated with an increase|
03870|020|E|in the QTc interval.(2,3)|
03870|021|E|   Moderate neutropenia may require abrupt discontinuation of clozapine|
03870|022|E|resulting in decompensation of the patient's psychiatric disorder.  Ozanimod|
03870|023|E|therapy may be compromised if myelosuppression requires dose reduction,|
03870|024|E|delay, or discontinuation of ozanimod.  Undetected severe neutropenia or|
03870|025|E|agranulocytosis may be fatal.|
03870|026|B||
03870|027|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03870|028|P|may be increased in patients with cardiovascular disease (e.g. heart|
03870|029|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03870|030|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03870|031|P|female gender, or advanced age.(4)|
03870|032|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03870|033|P|higher systemic concentrations of the QT prolonging drug are additional risk|
03870|034|P|factors for torsades de pointes.  Factors which may increase systemic drug|
03870|035|P|concentrations include rapid infusion of an intravenous dose or impaired|
03870|036|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
03870|037|P|which inhibits its metabolism or elimination, genetic impairment in drug|
03870|038|P|metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
03870|039|P|   Low white blood counts prior to initiation of the myelosuppressive agent|
03870|040|P|may increase risk for clinically significant neutropenia.(1)|
03870|041|B||
03870|042|M|PATIENT MANAGEMENT:  Approach the concurrent use of clozapine and other|
03870|043|M|agents that prolong the QTc interval with caution.(1)|
03870|044|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03870|045|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03870|046|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03870|047|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03870|048|M|   If a patient stabilized on clozapine therapy requires treatment with|
03870|049|M|other myelosuppressive agents the clozapine prescriber should consult with|
03870|050|M|the prescriber of the myelosuppressive agent to discuss treatment and|
03870|051|M|monitoring options.  More frequent ANC monitoring or treatment alternatives|
03870|052|M|secondary to neutropenic episodes may need to be considered.|
03870|053|M|   Clozapine is only available through a restricted distribution system|
03870|054|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
03870|055|M|dispensing.  For most clozapine patients, clozapine treatment must be|
03870|056|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
03870|057|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
03870|058|M|interrupted for suspected clozapine-induced neutropenia < 500|
03870|059|M|cells/microliter.(1)|
03870|060|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03870|061|M|time ozanimod is initiated or resumed should be referred to a cardiologist.|
03870|062|M|Consult the prescribing information for recommendations regarding cardiac|
03870|063|M|monitoring.(2-3)|
03870|064|B||
03870|065|D|DISCUSSION:  Treatment with clozapine has been associated with QT|
03870|066|D|prolongation as well as ventricular arrhythmia, torsades de pointes, cardiac|
03870|067|D|arrest, and sudden death.(1)|
03870|068|D|   After the first dose of ozanimod heart rate decline is usually maximal at|
03870|069|D|approximately 5 hours, returning to baseline at 6 hours.  With continued,|
03870|070|D|chronic dosing, max heart rate effect occurred on day 8.(2,3)|
03870|071|D|   Clozapine is only available through a restricted distribution system|
03870|072|D|which requires documentation of the ANC prior to dispensing.(1,6)|
03870|073|B||
03870|074|R|REFERENCES:|
03870|075|B||
03870|076|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
03870|077|R|  Pharmaceuticals Corporation April, 2020.|1
03870|078|R|2.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03870|079|R|  2024.|1
03870|080|R|3.Zeposia (ozanimod) UK summary of product characteristics. Bristol-Myers|1
03870|081|R|  Squibb Pharmaceuticals Ltd June, 2021.|1
03870|082|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03870|083|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03870|084|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03870|085|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03870|086|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03870|087|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03870|088|R|  settings: a scientific statement from the American Heart Association and|6
03870|089|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03870|090|R|  2;55(9):934-47.|6
03870|091|R|6.FDA (US Food and Drug Administration). Clozapine: Drug Safety|1
03870|092|R|  Communication - FDA Modifies Monitoring for Neutropenia; Approves New|1
03870|093|R|  Shared REMS Program. accessed at:|1
03870|094|R|  http://www.fda.gov/drugs/drugsafety/ucm461853.htm September 15, 2015.|1
03871|001|T|MONOGRAPH TITLE:  Metaxalone/MAOIs|
03871|002|B||
03871|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03871|004|L|of severe adverse interaction.|
03871|005|B||
03871|006|A|MECHANISM OF ACTION:  Metaxalone is a weak inhibitor of monoamine oxidase|
03871|007|A|(MAO).(1,2)|
03871|008|B||
03871|009|E|CLINICAL EFFECTS:  Concurrent use of metaxalone and other MAO inhibitors may|
03871|010|E|result in additive effects and toxicity.(1,2)|
03871|011|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03871|012|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03871|013|E|rigidity.|
03871|014|B||
03871|015|P|PREDISPOSING FACTORS:  None determined.|
03871|016|B||
03871|017|M|PATIENT MANAGEMENT:  The US manufacturer of metaxalone states serotonin|
03871|018|M|syndrome has resulted from concurrent use with other serotonergic drugs when|
03871|019|M|metaxalone was used as doses within the recommended dosing range.  If|
03871|020|M|concurrent use is warranted, monitor the patient closely for signs or|
03871|021|M|symptoms of serotonin syndrome, particularly during initiation or dose|
03871|022|M|adjustment.(1)|
03871|023|M|   If concurrent therapy is warranted, patients should be monitored for|
03871|024|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
03871|025|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03871|026|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03871|027|M|coordination, or severe diarrhea.|
03871|028|B||
03871|029|D|DISCUSSION:  In vitro analysis of metaxalone at concentrations ranging from|
03871|030|D|1.56 to 400 microM resulted in significant dose-related inhibition of|
03871|031|D|MAO-A.(2)|
03871|032|D|   Case reports of suspected serotonin syndrome with metaxalone use at both|
03871|033|D|therapeutic doses and in overdose have been reported.(3-5)|
03871|034|B||
03871|035|R|REFERENCES:|
03871|036|B||
03871|037|R|1.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03871|038|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03871|039|R|  Feb;34(2):346.e5-6.|3
03871|040|R|2.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03871|041|R|  Pfizer Inc. January, 2024.|1
03871|042|R|3.Cherrington B, Englich U, Niruntari S, Grant W, Hodgman M. Monoamine|5
03871|043|R|  oxidase A inhibition by toxic concentrations of metaxalone. Clin Toxicol|5
03871|044|R|  (Phila) 2020 May;58(5):383-387.|5
03871|045|R|4.Martini DI, Nacca N, Haswell D, Cobb T, Hodgman M. Serotonin syndrome|3
03871|046|R|  following metaxalone overdose and therapeutic use of a selective|3
03871|047|R|  serotonin reuptake inhibitor. Clin Toxicol (Phila) 2015 Mar;53(3):185-7.|3
03871|048|R|5.Bosak AR, Skolnik AB. Serotonin syndrome associated with metaxalone|3
03871|049|R|  overdose. J Med Toxicol 2014 Dec;10(4):402-5.|3
03872|001|T|MONOGRAPH TITLE:  Ozanimod/Moderate CYP2C8 Inducers that Prolong QT|
03872|002|B||
03872|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03872|004|L|of severe adverse interaction.|
03872|005|B||
03872|006|A|MECHANISM OF ACTION:  Ozanimod is a substrate of CYP2C8.  Moderate inducers|
03872|007|A|of CYP2C8 may induce the metabolism of ozanimod.(1)|
03872|008|A|   Initiation of ozanimod has a negative chronotropic effect and may cause|
03872|009|A|bradycardia.  Concurrent use with CYP2C8 inducers that prolong the QT|
03872|010|A|interval may increase the risk of bradycardia and QT prolongation.(1,2)|
03872|011|B||
03872|012|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP2C8 may result|
03872|013|E|in decreased levels and effectiveness of ozanimod and the active metabolites|
03872|014|E|CC112273 and CC1084037.(1)|
03872|015|E|   The heart rate lowering effect of ozanimod in the initial decrease is|
03872|016|E|usually within 5 hours.  With continued up-titration, the maximal heart rate|
03872|017|E|effect of ozanimod occurred on Day 8.  Symptomatic bradycardia and heart|
03872|018|E|block, including third degree block, have been observed.  Bradycardia may be|
03872|019|E|associated with an increase in the QTc interval, increasing the risk for|
03872|020|E|torsade de pointes.(1,2)|
03872|021|B||
03872|022|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
03872|023|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
03872|024|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
03872|025|P|prolonged QTc interval prior to ozanimod initiation, factors associated with|
03872|026|P|QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant|
03872|027|P|treatment with QT prolonging agents may increase risk for cardiovascular|
03872|028|P|toxicity due to ozanimod.(1,2)|
03872|029|P|   The risk of QT prolongation or torsades de pointes may also be increased|
03872|030|P|in patients with a history of torsades de pointes, hypocalcemia,|
03872|031|P|bradycardia, female gender, or advanced age.(2)|
03872|032|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03872|033|P|higher systemic concentrations of either QT prolonging drug are additional|
03872|034|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03872|035|P|drug concentrations include rapid infusion of an intravenous dose or|
03872|036|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03872|037|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03872|038|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03872|039|P|   Induction effects may be more likely with regular use of the inducer for|
03872|040|P|longer than 1-2 weeks.|
03872|041|B||
03872|042|M|PATIENT MANAGEMENT:  The manufacturer of ozanimod states to avoid concurrent|
03872|043|M|administration with moderate CYP2C8 inducers.(1)|
03872|044|M|   Patients receiving concurrent treatment with a QT prolonging agent at the|
03872|045|M|time ozanimod is initiated or resumed should be consult with a cardiologist.|
03872|046|M|Consult the prescribing information for recommendations regarding cardiac|
03872|047|M|monitoring.(1)|
03872|048|B||
03872|049|D|DISCUSSION:  Coadministration of rifampin (a strong CYP3A4 and P-gp inducer,|
03872|050|D|and moderate CYP2C8 inducer - 600 mg once daily) decreased the|
03872|051|D|area-under-curve (AUC) of ozanimod, CC112273, and CC1084037 by 24%, 60%, and|
03872|052|D|55%, respectively.(1)|
03872|053|D|   After the first dose of ozanimod heart rate decline is usually maximal at|
03872|054|D|approximately 5 hours, returning to baseline at 6 hours.  With continued,|
03872|055|D|chronic dosing, max heart rate effect occurred on day 8.(1)|
03872|056|D|   Moderate CYP2C8 inducers linked to this monograph include:|
03872|057|D|ivosidenib.(3-4)|
03872|058|B||
03872|059|R|REFERENCES:|
03872|060|B||
03872|061|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03872|062|R|  2024.|1
03872|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03872|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03872|065|R|  settings: a scientific statement from the American Heart Association and|6
03872|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03872|067|R|  2;55(9):934-47.|6
03872|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
03872|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03872|070|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03872|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03872|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03872|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03872|074|R|  11/14/2017.|1
03873|001|T|MONOGRAPH TITLE:  Ozanimod/Procarbazine|
03873|002|B||
03873|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03873|004|L|is contraindicated and generally should not be dispensed or administered to|
03873|005|L|the same patient.|
03873|006|B||
03873|007|A|MECHANISM OF ACTION:  Ozanimod is metabolized by CYP3A4 to RP101075 (a minor|
03873|008|A|active metabolite), which is further metabolized by monoamine oxidase-B|
03873|009|A|(MAO-B) to major active metabolites that make up the predominant circulating|
03873|010|A|active species in the plasma.  The major and minor active metabolites have|
03873|011|A|similar activity as ozanimod.  Inhibition of MAO-B may alter exposure to|
03873|012|A|ozanimod and its metabolites.(1)|
03873|013|A|   Procarbazine, although used therapeutically as an antineoplastic agent,|
03873|014|A|is an inhibitor of monoamine oxidase (MAO).(2)|
03873|015|A|   Ozanimod in combination with immunosuppressives such as procarbazine|
03873|016|A|suppress the immune system.(1)|
03873|017|B||
03873|018|E|CLINICAL EFFECTS:  Concurrent use of ozanimod and MAO inhibitors may result|
03873|019|E|in altered exposure to ozanimod and its active metabolites and may result in|
03873|020|E|decreased efficacy.(1)|
03873|021|E|   Concurrent use of ozanimod with immunosuppressive or immune-modulating|
03873|022|E|agents may result in an increased risk of serious infections, such as|
03873|023|E|disseminated herpetic infection or progressive multifocal|
03873|024|E|leukoencephalopathy (PML), an opportunistic infection caused by the JC virus|
03873|025|E|(JCV).(1)|
03873|026|B||
03873|027|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
03873|028|P|immunosuppressive or immune-modulating medications.|
03873|029|B||
03873|030|M|PATIENT MANAGEMENT:  The concurrent use of ozanimod with MAO inhibitors is|
03873|031|M|contraindicated.  At least 14 days should elapse between discontinuation of|
03873|032|M|ozanimod and initiation of MAO inhibitors.(1)|
03873|033|M|   The ozanimod  US prescribing information state this information regarding|
03873|034|M|this interaction:|
03873|035|M|   Ozanimod has not been studied in combination with anti-neoplastic,|
03873|036|M|immune-modulating, or immunosuppressive therapies.  Caution should be used|
03873|037|M|during concomitant administration because of the risk of additive immune|
03873|038|M|effects during therapy and in the week following administration.  When|
03873|039|M|switching from drugs with prolonged immune effects, the half-life and mode|
03873|040|M|of action of these drugs must be considered in order to avoid unintended|
03873|041|M|additive immunosuppressive effects.(1)|
03873|042|B||
03873|043|D|DISCUSSION:  The combination of ozanimod with MAO inhibitors has not been|
03873|044|D|studied.  The combination of steady state ozanimod 0.92 mg or 1.84 mg with|
03873|045|D|tyramine, an MAO substrate, did not have an effect on tyramine plasma|
03873|046|D|concentrations or tyramine-induced pressor response.  However, MAO|
03873|047|D|inhibitors may alter the exposure to ozanimod and its metabolites.(1)|
03873|048|D|   Fatal disseminated herpes zoster and herpes simplex infections and cases|
03873|049|D|of progressive multifocal leukoencephalopathy (PML) have been reported in|
03873|050|D|patients taking ozanimod who previously received immunomodulators or|
03873|051|D|immunosuppressants.(1)|
03873|052|B||
03873|053|R|REFERENCES:|
03873|054|B||
03873|055|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
03873|056|R|  2024.|1
03873|057|R|2.Matulane (procarbazine) US prescribing information. Sigma-Tua April 15,|1
03873|058|R|  2008.|1
03874|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Belzutifan|
03874|002|B||
03874|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03874|004|L|of severe adverse interaction.|
03874|005|B||
03874|006|A|MECHANISM OF ACTION:  Belzutifan is a weak to moderate CYP3A4 inducer.|
03874|007|A|Coadministration of belzutifan with hormonal contraceptives may lead to|
03874|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
03874|009|A|decreased hormonal concentrations.(1)|
03874|010|B||
03874|011|E|CLINICAL EFFECTS:  Concurrent use of belzutifan can lead to ineffective|
03874|012|E|hormonal contraceptive and cause fetal harm when administered to a pregnant|
03874|013|E|woman.(1)|
03874|014|B||
03874|015|P|PREDISPOSING FACTORS:  None determined.|
03874|016|B||
03874|017|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
03874|018|M|rely on hormonal contraceptives (including oral contraceptives, patches,|
03874|019|M|implants, and/or IUDs) for contraception.  Pregnant women and females of|
03874|020|M|reproductive potential should be counseled on the potential risk to the|
03874|021|M|fetus.(1)|
03874|022|M|   Advise females of reproductive potential to use effective non-hormonal|
03874|023|M|contraception during treatment with belzutifan and for 1 week after the last|
03874|024|M|dose.  Advise male patients with female partners of reproductive potential|
03874|025|M|to use effective contraception during treatment with belzutifan and for 1|
03874|026|M|week after the last dose.(1)|
03874|027|M|   Verify the pregnancy status of females of reproductive potential prior to|
03874|028|M|initiating treatment with belzutifan.(1)|
03874|029|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03874|030|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03874|031|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03874|032|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03874|033|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03874|034|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03874|035|M|and to seek medical advice if they do become pregnant.(2)|
03874|036|B||
03874|037|D|DISCUSSION:  Belzutifan has not been studied with hormonal contraceptives.|
03874|038|D|It can render some hormonal contraceptives ineffective and cause|
03874|039|D|embryo-fetal harm.  Women should use non-hormonal contraception during|
03874|040|D|therapy.(1)|
03874|041|D|   In an animal reproduction study, oral administration of belzutifan to|
03874|042|D|pregnant rats during the period of organogenesis caused embryo-fetal|
03874|043|D|lethality, reduced fetal body weight, and fetal skeletal malformations at|
03874|044|D|maternal exposures greater than or equal to 0.2 times the human exposure|
03874|045|D|(AUC) at the recommended dose of 120 mg daily.(1)|
03874|046|B||
03874|047|R|REFERENCES:|
03874|048|B||
03874|049|R|1.Welireg (belzutifan) US prescribing information. Merck Sharp & Dohme Corp.|1
03874|050|R|  August, 2021.|1
03874|051|R|2.Medicines and Healthcare products Regulatory Agency.|1
03874|052|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03874|053|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03874|054|R|  available at:|1
03874|055|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03874|056|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03874|057|R|  -and-contraceptive-efficacy September 15, 2016..|1
03875|001|T|MONOGRAPH TITLE:  Belzutifan/Strong CYP2C19 Inhibitors|
03875|002|B||
03875|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03875|004|L|take action as needed.|
03875|005|B||
03875|006|A|MECHANISM OF ACTION:  Belzutifan is primarily metabolized by CYP2C19 and|
03875|007|A|UGT2B17, and to a lesser extent by CYP3A4.  Agents that are inhibitors of|
03875|008|A|CYP2C19 may inhibit the metabolism of belzutifan.(1)|
03875|009|B||
03875|010|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of CYP2C19 increases|
03875|011|E|plasma exposure of belzutifan which may increase the incidence and severity|
03875|012|E|of adverse reactions of belzutifan.  This may increase the incidence or|
03875|013|E|severity of anemia or hypoxia that can require a blood transfusion.(1)|
03875|014|B||
03875|015|P|PREDISPOSING FACTORS:  UGT2B17 and CYP2C19 ultrarapid metabolizers may|
03875|016|P|increase the incidence or severity of adverse effects, including anemia.(1)|
03875|017|B||
03875|018|M|PATIENT MANAGEMENT:  The manufacturer of belzutifan states concurrent|
03875|019|M|administration of CYP2C19 inhibitors with belzutifan increases plasma|
03875|020|M|exposure which may increase the incidence and severity of anemia or|
03875|021|M|hypoxemia.  Monitor patients closely for anemia or hypoxemia and reduce the|
03875|022|M|dose of belzutifan as recommended.(1)|
03875|023|M|   Monitor for anemia before initiation of, and periodically throughout,|
03875|024|M|treatment with belzutifan.  Closely monitor patients who are dual UGT2B17|
03875|025|M|and CYP2C19 poor metabolizers due to potential increases in exposure that|
03875|026|M|may increase the incidence or severity of anemia.(1)|
03875|027|M|   For patients with hemoglobin <9 g/dL, withhold belzutifan until the|
03875|028|M|hemoglobin is greater than or equal to 9 g/dL, then resume at reduced dose|
03875|029|M|or permanently discontinue belzutifan, depending on the severity|
03875|030|M|of anemia.(1)|
03875|031|M|   See full prescribing information for dose modifications and|
03875|032|M|recommendations.(1)|
03875|033|B||
03875|034|D|DISCUSSION:  The effect of concurrent administration inhibitors of CYP2C19|
03875|035|D|may cause an increase in plasma levels that can increase side effects,|
03875|036|D|including anemia.(1)|
03875|037|D|   In clinical studies, patients who are poor metabolizers of UGT2B17 and|
03875|038|D|CYP2C19 had higher belzutifan area-under-curve (AUC).  The belzutifan AUC|
03875|039|D|increased by 2-fold, 1.6-fold, and 3.2-fold in patients who were UGT2B17,|
03875|040|D|CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolizers, respectively.(1)|
03875|041|D|   Strong CYP2C19 inhibitors linked to this monograph include: fluconazole,|
03875|042|D|fluoxetine, fluvoxamine, and ticlopidine.(2,3)|
03875|043|B||
03875|044|R|REFERENCES:|
03875|045|B||
03875|046|R|1.Welireg (belzutifan) US prescribing information. Merck Sharp & Dohme Corp.|1
03875|047|R|  August, 2021.|1
03875|048|R|2.This information is based on an extract from the Certara Drug Interaction|6
03875|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03875|050|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03875|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03875|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03875|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03875|054|R|  11/14/2017.|1
03876|001|T|MONOGRAPH TITLE:  Gallium Ga 68 Dotatate/Corticosteroids|
03876|002|B||
03876|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03876|004|L|take action as needed.|
03876|005|B||
03876|006|A|MECHANISM OF ACTION:  High-dose corticosteroids may down-regulate|
03876|007|A|somatostatin subtype 2 receptors, the main binding site for gallium Ga 68|
03876|008|A|dotatate.(1)|
03876|009|B||
03876|010|E|CLINICAL EFFECTS:  Repeated use of high doses of corticosteroids before use|
03876|011|E|of gallium Ga 68 dotatate may result in false negative imaging results.(1)|
03876|012|B||
03876|013|P|PREDISPOSING FACTORS:  None determined.|
03876|014|B||
03876|015|M|PATIENT MANAGEMENT:  In patients receiving high-dose corticosteroids prior|
03876|016|M|to use of gallium Ga 68 dotatate, interpret imaging results with caution and|
03876|017|M|in the context of the patient's clinical presentation.|
03876|018|B||
03876|019|D|DISCUSSION:  Repeated use of high doses of corticosteroids before use of|
03876|020|D|gallium Ga 68 dotatate may result in false negative imaging results due to|
03876|021|D|down-regulation of the somatostatin subtype 2 receptor.(1)|
03876|022|B||
03876|023|R|REFERENCE:|
03876|024|B||
03876|025|R|1.Netspot (gallium Ga 68 dotatate injection) US prescribing information.|1
03876|026|R|  Advanced Accelerator Applications USA, Inc. October, 2023.|1
03877|001|T|MONOGRAPH TITLE:  Secnidazole/Alcohol; Propylene Glycol|
03877|002|B||
03877|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03877|004|L|take action as needed.|
03877|005|B||
03877|006|A|MECHANISM OF ACTION:  Alcohol and propylene glycol may potentiate the|
03877|007|A|adverse effects of secnidazole.(1)|
03877|008|B||
03877|009|E|CLINICAL EFFECTS:  Concurrent use of alcohol or preparations containing|
03877|010|E|ethanol or propylene glycol in patients taking secnidazole may increase the|
03877|011|E|risk of side effects, including nausea, vomiting, diarrhea, abdominal pain,|
03877|012|E|headache and dizziness.(1)|
03877|013|B||
03877|014|P|PREDISPOSING FACTORS:  None determined.|
03877|015|B||
03877|016|M|PATIENT MANAGEMENT:  Counsel patients to avoid alcohol and preparations|
03877|017|M|containing ethanol or propylene glycol until at least 2 days after|
03877|018|M|completing therapy with secnidazole.(1)|
03877|019|M|   Significant quantities of alcohol may be present in medicinal products.|
03877|020|M|Alcohol is is used to improve docetaxel and paclitaxel solubility.|
03877|021|M|   - The quantity of alcohol in paclitaxel injection formulations|
03877|022|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
03877|023|M|dose contains approximately 13 grams of alcohol.|
03877|024|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
03877|025|M|3-fold depending upon the manufacturer. FDA data on alcohol content (3):|
03877|026|M|   Product                      Manufacturer         Alcohol/200 mg dose|
03877|027|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
03877|028|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
03877|029|M|   Docetaxel Inj.               Accord                  4.0 grams|
03877|030|M|   Taxotere-one vial            Sanofi                  4.0 grams|
03877|031|M|    formulation|
03877|032|M|   Docetaxel Inj.               Hospira                 3.7 grams|
03877|033|M|   Docefrez                     Sun Pharma              2.9 grams|
03877|034|M|   Taxotere-two vial            Sanofi                  2.0 grams|
03877|035|M|    formulation|
03877|036|B||
03877|037|D|DISCUSSION:  In vitro studies showed that secnidazole had no effect on|
03877|038|D|aldehyde dehydrogenase activity.|
03877|039|D|   However, postmarketing observations of adverse reactions of nausea,|
03877|040|D|vomiting, diarrhea, abdominal pain, dizziness, and headache with concomitant|
03877|041|D|use of secnidazole and alcohol have been reported.(1)|
03877|042|B||
03877|043|R|REFERENCES:|
03877|044|B||
03877|045|R|1.Solosec (secnidazole) US prescribing information. : Lupin Pharmaceuticals,|1
03877|046|R|  Inc June, 2021.|1
03877|047|R|2.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
03877|048|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
03877|049|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
03877|050|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
03877|051|R|  20, 2014.|1
03878|001|T|MONOGRAPH TITLE:  Delamanid/Strong 3A4 Inhibitors that Prolong QT|
03878|002|B||
03878|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03878|004|L|take action as needed.|
03878|005|B||
03878|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
03878|007|A|may inhibit the metabolism of delamanid and result in additive risk of QT|
03878|008|A|prolongation.(1)|
03878|009|B||
03878|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
03878|011|E|the QTc interval may result in increased levels of and toxicity from|
03878|012|E|delamanid, including QT prolongation.  QT prolongation may result in|
03878|013|E|potentially life-threatening cardiac arrhythmias, including torsades de|
03878|014|E|pointes.(1)|
03878|015|B||
03878|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03878|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03878|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03878|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03878|020|P|female gender, or advanced age.(2)|
03878|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03878|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03878|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03878|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03878|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03878|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03878|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03878|028|B||
03878|029|M|PATIENT MANAGEMENT:  Concurrent use of delamanid and strong CYP3A4|
03878|030|M|inhibitors that prolong the QTc interval should be approached with caution.|
03878|031|M|If concurrent use is necessary, frequently monitor ECGs (more frequently|
03878|032|M|than the standard recommended monthly ECG during delamanid therapy)|
03878|033|M|throughout the full delamanid treatment period.  Discontinue delamanid if a|
03878|034|M|QTcF greater than 500 msec is observed.  Discontinue delamanid if albumin|
03878|035|M|falls below 2.8 g/DL.(1)|
03878|036|M|   If concurrent therapy with either delamanid and a strong CYP3A4 inhibitor|
03878|037|M|that prolongs the QTc interval is warranted, consider obtaining serum|
03878|038|M|calcium, magnesium, and potassium levels and monitoring ECG at baseline and|
03878|039|M|at regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03878|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03878|041|B||
03878|042|D|DISCUSSION:  In a study in healthy subjects, lopinavir/ritonavir (400/100 mg|
03878|043|D|daily) administered with delamanid (100 mg twice daily) increased exposure|
03878|044|D|to delamanid exposed by 30%.  There was no effect on delamanid levels.(1)|
03878|045|D|   QT prolongation has been observed with delamanid and increases over the|
03878|046|D|first 6-10 weeks of therapy.  In a placebo controlled study in healthy|
03878|047|D|subjects, the mean increase in QTcF from baseline during delamanid therapy|
03878|048|D|was 7/6 msec at 1 month and 12.1 msec at 2 months.  Three percent of|
03878|049|D|patients experienced an increase of 60 msec or greater at some point during|
03878|050|D|therapy.  One patient had a QTcF greater than 500 msec.  All patients with a|
03878|051|D|QTcF greater than 60 msec were also taking a fluoroquinolone.(1)|
03878|052|D|   Strong inhibitors of CYP3A4 that prolong the QTc interval include:|
03878|053|D|adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib,|
03878|054|D|lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and|
03878|055|D|voriconazole.(3,4)|
03878|056|B||
03878|057|R|REFERENCES:|
03878|058|B||
03878|059|R|1.Deltyba (delamanid) EMA summary of products characteristics. Otsuka Novel|1
03878|060|R|  Products GmbH March, 2023.|1
03878|061|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03878|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03878|063|R|  settings: a scientific statement from the American Heart Association and|6
03878|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03878|065|R|  2;55(9):934-47.|6
03878|066|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03878|067|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03878|068|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03878|069|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03878|070|R|  11/14/2017.|1
03878|071|R|4.This information is based on an extract from the Certara Drug Interaction|6
03878|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03879|001|T|MONOGRAPH TITLE:  Pitolisant/Strong CYP2D6 Inhibitors that Prolong QT|
03879|002|B||
03879|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03879|004|L|take action as needed.|
03879|005|B||
03879|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
03879|007|A|pitolisant by CYP2D6.(1,2)|
03879|008|A|   Concurrent use of pitolisant with strong CYP2D6 inhibitors that prolong|
03879|009|A|QT may result in additive effects on the QTc interval.(1)|
03879|010|B||
03879|011|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
03879|012|E|toxicity from pitolisant and additive risk of potentially life-threatening|
03879|013|E|cardiac arrhythmias, including torsades de pointes.(1)|
03879|014|B||
03879|015|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers or on|
03879|016|P|concurrent use with CYP2D6 inhibitors are at increased risk for higher|
03879|017|P|systemic exposure to pitolisant and may be at increased risk of QT|
03879|018|P|prolongation.(1)|
03879|019|P|   Patients who are CYP2D6 ultrarapid metabolizers may be affected to a|
03879|020|P|greater extent by CYP2D6 inhibitors.  Patients who are CYP2D6 poor|
03879|021|P|metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.|
03879|022|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03879|023|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03879|024|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03879|025|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03879|026|P|advanced age.(3)|
03879|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03879|028|P|higher systemic concentrations of either QT prolonging drug are additional|
03879|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03879|030|P|drug concentrations include rapid infusion of an intravenous dose or|
03879|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03879|032|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03879|033|P|dysfunction).(3)|
03879|034|B||
03879|035|M|PATIENT MANAGEMENT:  The US manufacturer states the concurrent use of|
03879|036|M|pitolisant with strong inhibitors of CYP2D6 such as hydroquinidine or|
03879|037|M|quinidine requires dose adjustment.|
03879|038|M|   - Adult patients currently receiving a strong CYP2D6 inhibitor prior to|
03879|039|M|initiation of pitolisant: start pitolisant at 8.9 mg once daily and increase|
03879|040|M|after 7 days to a maximum dosage of 17.8 mg daily.|
03879|041|M|   - Patients 6 years and older weighing <40 kg: start pitolisant at 4.45 mg|
03879|042|M|once daily and increase after 7 days to a maximum dosage of 8.9 mg once|
03879|043|M|daily.|
03879|044|M|   - Patients 6 years and older weighing >=40 kg: start pitolisant at 4.45|
03879|045|M|mg once daily and increase after 7 days to 8.9 mg once daily.  May increase|
03879|046|M|after another 7 days to a maximum dosage of 17.8 mg once daily.|
03879|047|M|   - All patients who are stable on pitolisant: reduce the dose of|
03879|048|M|pitolisant by half upon initiating a strong CYP2D6 inhibitor.(1)|
03879|049|M|   The UK manufacturer states concurrent use of pitolisant with CYP2D6|
03879|050|M|inhibitors should be done with caution and dose adjustment could be|
03879|051|M|considered.(2)|
03879|052|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03879|053|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03879|054|M|treatment, after initiation of any drug known to prolong the QT interval,|
03879|055|M|and periodically monitor during therapy.  Correct any electrolyte|
03879|056|M|abnormalities.|
03879|057|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03879|058|M|fainting.|
03879|059|B||
03879|060|D|DISCUSSION:  In a clinical study, concurrent use of pitolisant with|
03879|061|D|paroxetine (a strong CYP2D6 inhibitor) increased the concentration maximum|
03879|062|D|(Cmax) and area-under-curve (AUC) by approximately 1.75 and 2.25,|
03879|063|D|respectively.(1)|
03879|064|D|   In two dedicated QT prolongation studies, supra-therapeutic doses of|
03879|065|D|pitolisant at 3-6 times the therapeutic dose (108-216 mg) were seen to cause|
03879|066|D|mild to moderate QTc prolongation (10-13 ms).  A study in patients who were|
03879|067|D|CYP2D6 poor metabolizers had higher systemic exposure up to 3-fold compared|
03879|068|D|to CYP2D6 extensive metabolizers.(1)|
03879|069|D|   Strong CYP2D6 inhibitors that prolong QT include: hydroquinidine and|
03879|070|D|quinidine.(5,6)|
03879|071|B||
03879|072|R|REFERENCES:|
03879|073|B||
03879|074|R|1.Wakix (pitolisant) tablets US prescribing information. Harmony Biosciences|1
03879|075|R|  June, 2024.|1
03879|076|R|2.Wakix (pitolisant) UK Summary of Product Characteristics. Bioproject|1
03879|077|R|  Pharma January, 2019.|1
03879|078|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03879|079|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03879|080|R|  settings: a scientific statement from the American Heart Association and|6
03879|081|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03879|082|R|  2;55(9):934-47.|6
03879|083|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03879|084|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03879|085|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03879|086|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03879|087|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03879|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03879|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03879|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03879|091|R|  11/14/2017.|1
03879|092|R|6.This information is based on an extract from the Certara Drug Interaction|6
03879|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03880|001|T|MONOGRAPH TITLE:  Ulipristal/Selected Anticonvulsants|
03880|002|B||
03880|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03880|004|L|of severe adverse interaction.|
03880|005|B||
03880|006|A|MECHANISM OF ACTION:  Eslicarbazepine, mephenytoin, oxcarbazepine,|
03880|007|A|rufinamide, and topiramate may induce the metabolism of ulipristal by|
03880|008|A|CYP3A4.(1,2)|
03880|009|B||
03880|010|E|CLINICAL EFFECTS:  Concurrent use or use of eslicarbazepine, mephenytoin,|
03880|011|E|oxcarbazepine, rufinamide, or topiramate within the previous 2-3 weeks may|
03880|012|E|result in decreased levels and effectiveness of ulipristal.(1,2)|
03880|013|E|   In addition, topiramate has been associated with an increased risk of|
03880|014|E|birth defects, including cleft palate.(3)|
03880|015|B||
03880|016|P|PREDISPOSING FACTORS:  None determined.|
03880|017|B||
03880|018|M|PATIENT MANAGEMENT:  The US and UK manufacturers of ulipristal states that|
03880|019|M|concurrent use with CYP3A4 inducers such as eslicarbazepine, mephenytoin,|
03880|020|M|oxcarbazepine, rufinamide, or topiramate is not recommended.  Decreased|
03880|021|M|effectiveness of ulipristal may occur even 2-3 weeks after discontinuation|
03880|022|M|of these agents.(1,2)|
03880|023|B||
03880|024|D|DISCUSSION:  CYP3A4 inducers may decrease levels and effectiveness of|
03880|025|D|ulipristal.  Enzyme induction may take 2-3 weeks to wear off.  Plasma levels|
03880|026|D|of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in|
03880|027|D|the previous 2-3 weeks.(1)|
03880|028|D|   Concurrent administration of ulipristal 30 mg and rifampin 600 mg,|
03880|029|D|another CYP3A4 inducer, for 9 days decreased the maximum concentration|
03880|030|D|(Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax|
03880|031|D|and AUC of monodemethyl-ulipristal decreased by 84% and 90%,|
03880|032|D|respectively.(2)|
03880|033|B||
03880|034|R|REFERENCES:|
03880|035|B||
03880|036|R|1.Ellaone (ulipristal acetate) UK summary of product characteristics. HRA|1
03880|037|R|  Pharma UK Ltd May 15, 2009.|1
03880|038|R|2.Ella (ulipristal acetate) US prescribing information. Afaxys Inc June,|1
03880|039|R|  2021.|1
03880|040|R|3.Topamax (topiramate) US prescribing information. Janssen Pharmaceuticals,|1
03880|041|R|  Inc. May, 2023.|1
03881|001|T|MONOGRAPH TITLE:  Trazodone/Venlafaxine (mono deleted 11/26/2023)|
03881|002|B||
03881|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03881|004|L|take action as needed.|
03881|005|B||
03881|006|A|MECHANISM OF ACTION:  Concurrent use of trazodone with other agents that|
03881|007|A|prolong the QTc interval such as venlafaxine may result in additive effects|
03881|008|A|on the QTc interval.(1,2)|
03881|009|A|   Concurrent use may also result in increased levels of serotonin.(1)|
03881|010|B||
03881|011|E|CLINICAL EFFECTS:  Concurrent administration of venlafaxine with trazodone|
03881|012|E|may result in an increase in serum levels, and/or prolongation of the QTc|
03881|013|E|interval and potentially life-threatening cardiac arrhythmias, including|
03881|014|E|torsades de pointes.(1)|
03881|015|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03881|016|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03881|017|E|rigidity.|
03881|018|B||
03881|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03881|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03881|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03881|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03881|023|P|female gender, or advanced age.(2)|
03881|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03881|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03881|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03881|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03881|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03881|029|P|an agent which inhibitors its metabolism or elimination, genetic impairment|
03881|030|P|in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03881|031|B||
03881|032|M|PATIENT MANAGEMENT:  The US manufacturer of trazodone states that concurrent|
03881|033|M|use with agents known to prolong the QT interval such as venlafaxine should|
03881|034|M|be avoided.(1)|
03881|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03881|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03881|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03881|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03881|039|M|   Patients should be observed for increased adverse effects and clinical|
03881|040|M|effects of trazodone at the initiation of concurrent therapy with|
03881|041|M|venlafaxine.  Plasma concentrations of trazodone should be monitored and the|
03881|042|M|dosage adjusted accordingly.|
03881|043|M|   Patients should be monitored for signs and symptoms of serotonin|
03881|044|M|syndrome.  Instruct patients to report muscle twitching, tremors, shivering|
03881|045|M|and stiffness, fever, heavy sweating, heart palpitations, restlessness,|
03881|046|M|confusion, agitation, trouble with coordination, or severe diarrhea.|
03881|047|M|   If venlafaxine is discontinued in a patient receiving trazodone, the|
03881|048|M|dosage of trazodone may need to be adjusted.|
03881|049|B||
03881|050|D|DISCUSSION:  Trazodone has been reported to prolong the QT interval.(1)|
03881|051|D|   A thorough QT study in 20 subjects evaluated the effects of trazodone at|
03881|052|D|doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation|
03881|053|D|at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI|
03881|054|D|3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that|
03881|055|D|exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval|
03881|056|D|by more than 5 ms. The study found a dose-dependent effect on QTc|
03881|057|D|prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI|
03881|058|D|11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of|
03881|059|D|19.8 ms (95% CI 17.6-22.1).(3)|
03881|060|B||
03881|061|R|REFERENCES:|
03881|062|B||
03881|063|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
03881|064|R|  Labopharm Inc. November, 2012.|1
03881|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03881|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03881|067|R|  settings: a scientific statement from the American Heart Association and|6
03881|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03881|069|R|  2;55(9):934-47.|6
03881|070|R|3.Tellone V, Rosignoli MT, Picollo R, Dragone P, Del Vecchio A, Comandini A,|2
03881|071|R|  Radicioni M, Leuratti C, Calisti F. Effect of 3 Single Doses of Trazodone|2
03881|072|R|  on QTc Interval in Healthy Subjects..|2
03882|001|T|MONOGRAPH TITLE:  Lorazepam Extended Release/UGT Inhibitors|
03882|002|B||
03882|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03882|004|L|of severe adverse interaction.|
03882|005|B||
03882|006|A|MECHANISM OF ACTION:  Inhibitors of UDP-glucuronosyltransferases (UGT) may|
03882|007|A|inhibit the metabolism of lorazepam.(1)|
03882|008|B||
03882|009|E|CLINICAL EFFECTS:  Concurrent use of UGT inhibitors may result in increased|
03882|010|E|exposure to and toxicity from lorazepam, including profound sedation,|
03882|011|E|respiratory depression, and coma.(1)|
03882|012|B||
03882|013|P|PREDISPOSING FACTORS:  None determined.|
03882|014|B||
03882|015|M|PATIENT MANAGEMENT:  The US manufacturer of lorazepam extended release|
03882|016|M|capsules states the initiating a UGT inhibitor during therapy with lorazepam|
03882|017|M|extended release capsules should be avoided.  If a UGT inhibitor is|
03882|018|M|initiated, discontinue lorazepam extended release capsules and switch|
03882|019|M|patient to a reduced dose of lorazepam tablets during concurrent therapy.(1)|
03882|020|B||
03882|021|D|DISCUSSION:  In a study in 8 healthy males, pretreatment with valproate (250|
03882|022|D|mg twice daily for 3 days) decreased the total clearance of a single dose of|
03882|023|D|lorazepam (2 mg intravenously) by 40% in 6 subjects.  The formation rate of|
03882|024|D|lorazepam glucuronide was decreased by 55% in these subjects.  Lorazepam|
03882|025|D|concentrations were about 2-fold higher for at least 12 hours post-dose|
03882|026|D|during concurrent valproate.(2,4)|
03882|027|D|   In a randomized, double-blind, placebo-controlled study in 16 healthy|
03882|028|D|males, concurrent divalproex (500 mg every 12 hours for 12 days) increased|
03882|029|D|the area-under-curve (AUC), maximum concentration (Cmax), and minimum|
03882|030|D|concentration (Cmin) of lorazepam (1 mg every 12 hours, Days 6-10) by 20%,|
03882|031|D|8%, and 31%, respectively.  Lorazepam clearance was decreased by 31% during|
03882|032|D|concurrent divalproex.(5)|
03882|033|D|   There is one case report of coma following the injection of 6 mg of|
03882|034|D|lorazepam over 24 hours in a patient maintained on valproate (1000 mg).  The|
03882|035|D|patient remained in a coma for between 48 and 72 hours.(6)|
03882|036|D|   In a study in 9 healthy subjects, pretreatment with probenecid (500 mg|
03882|037|D|every 6 hours) increased the half-life (T1/2) of a single intravenous dose|
03882|038|D|of lorazepam (2 mg) by 130%.  Lorazepam clearance was decreased by 45%.|
03882|039|D|There was no change in lorazepam apparent volume of distribution.(2,7)|
03882|040|D|   UGT inhibitors linked to this monograph include: atazanavir, belumosudil,|
03882|041|D|capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib,|
03882|042|D|mefenamic acid, nilotinib, pazopanib, probenecid, regorafenib, sorafenib,|
03882|043|D|and valproic acid.|
03882|044|B||
03882|045|R|REFERENCES:|
03882|046|B||
03882|047|R|1.Loreev XR (lorazepam) extended-release capsules US prescribing|1
03882|048|R|  information. Almatica Pharma LLC August, 2021.|1
03882|049|R|2.Ativan (lorazepam injection) US prescribing information. Biovail|1
03882|050|R|  Laboratories International SRL April 27, 2017.|1
03882|051|R|3.Ativan (lorazepam tablets) US prescribing information. Biovail|1
03882|052|R|  Pharmaceuticals February 5, 2021.|1
03882|053|R|4.Anderson GD, Gidal BE, Kantor ED, Wilensky AJ. Lorazepam-valproate|2
03882|054|R|  interaction: studies in normal subjects and isolated perfused rat liver.|2
03882|055|R|  Epilepsia 1994 Jan-Feb;35(1):221-5.|2
03882|056|R|5.Samara EE, Granneman RG, Witt GF, Cavanaugh JH. Effect of valproate on the|2
03882|057|R|  pharmacokinetics and pharmacodynamics of lorazepam. J Clin Pharmacol 1997|2
03882|058|R|  May;37(5):442-50.|2
03882|059|R|6.von Moltke LL, Manis M, Harmatz JS, Poorman R, Greenblatt DJ. Inhibition|5
03882|060|R|  of acetaminophen and lorazepam glucuronidation in vitro by probenecid.|5
03882|061|R|  Biopharm Drug Dispos 1993 Mar;14(2):119-30.|5
03882|062|R|7.Abernethy DR, Greenblatt DJ, Ameer B, Shader RI. Probenecid impairment of|2
03882|063|R|  acetaminophen and lorazepam clearance: direct inhibition of ether|2
03882|064|R|  glucuronide formation. J Pharmacol Exp Ther 1985 Aug;234(2):345-9.|2
03883|001|T|MONOGRAPH TITLE:  Doxorubicin/P-glycoprotein (P-gp) Inhibitors|
03883|002|B||
03883|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03883|004|L|of severe adverse interaction.|
03883|005|B||
03883|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibition may increase|
03883|007|A|doxorubicin cellular concentration, as well as decrease biliary or renal|
03883|008|A|elimination.(1)|
03883|009|B||
03883|010|E|CLINICAL EFFECTS:  Increased cellular or systemic levels of doxorubicin may|
03883|011|E|result in doxorubicin toxicity, including cardiomyopathy, myelosuppression,|
03883|012|E|or hepatic impairment.(1)|
03883|013|B||
03883|014|P|PREDISPOSING FACTORS:  The interaction magnitude may be greater in patients|
03883|015|P|with impaired renal or hepatic function.|
03883|016|B||
03883|017|M|PATIENT MANAGEMENT:  Avoid the concurrent use of P-gp inhibitors in patients|
03883|018|M|undergoing therapy with doxorubicin.(1)  Consider alternatives with no or|
03883|019|M|minimal inhibition.  If concurrent therapy is warranted, monitor the patient|
03883|020|M|closely for signs and symptoms of doxorubicin toxicity.|
03883|021|B||
03883|022|D|DISCUSSION:  Doxorubicin is a substrate of P-gp.(1)  Clinical studies have|
03883|023|D|identified and evaluated the concurrent use of doxorubicin and P-gp|
03883|024|D|inhibitors as a target to overcome P-gp mediated multidrug resistance.(2,3)|
03883|025|D|   P-gp inhibitors linked to this monograph include:  amiodarone, asciminib,|
03883|026|D|asunaprevir, azithromycin, belumosudil, capmatinib, cimetidine,|
03883|027|D|cyclosporine, daclatasvir, danicopan, daridorexant, deutivacaftor,|
03883|028|D|diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin,|
03883|029|D|fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir,|
03883|030|D|hydroquinidine, imlunestrant, istradefylline, ivacaftor, lapatinib,|
03883|031|D|ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib,|
03883|032|D|propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline,|
03883|033|D|schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir,|
03883|034|D|sotorasib, tepotinib, valbenazine, vemurafenib, verapamil, vimseltinib, and|
03883|035|D|voclosporin.(4,5)|
03883|036|B||
03883|037|R|REFERENCES:|
03883|038|B||
03883|039|R|1.Adriamycin (doxorubicin) US prescribing information. Hikma Pharmaceuticals|1
03883|040|R|  USA Inc. December, 2019.|1
03883|041|R|2.Esim O, Sarper M, Ozkan CK, Oren S, Baykal B, Savaser A, Ozkan Y. Effect|5
03883|042|R|  simultaneous delivery with P-glycoprotein inhibitor and nanoparticle|5
03883|043|R|  administration of doxorubicin on cellular uptake and in vitro anticancer|5
03883|044|R|  activity. Saudi Pharm J 2020 Apr;28(4):465-472.|5
03883|045|R|3.Wang L, Sun Y. Efflux mechanism and pathway of verapamil pumping by human|5
03883|046|R|  P-glycoprotein. Arch Biochem Biophys 2020 Dec 15;696:108675.|5
03883|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
03883|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03883|049|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03883|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03883|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03883|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03883|053|R|  11/14/2017.|1
03884|001|T|MONOGRAPH TITLE:  Mobocertinib/Strong CYP3A4 Inhibitors|
03884|002|B||
03884|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03884|004|L|of severe adverse interaction.|
03884|005|B||
03884|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03884|007|A|of mobocertinib.(1)|
03884|008|B||
03884|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03884|010|E|levels of and effects from mobocertinib.(1)|
03884|011|E|    Elevated levels of mobocertinib may result in QTc prolongation, which|
03884|012|E|may result in potentially life-threatening cardiac arrhythmias, including|
03884|013|E|torsades de pointes.(1)|
03884|014|B||
03884|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03884|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03884|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03884|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03884|019|P|female gender, or advanced age.(2)|
03884|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03884|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03884|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03884|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03884|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03884|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03884|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03884|027|B||
03884|028|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03884|029|M|undergoing therapy with mobocertinib.(1)|
03884|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03884|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03884|032|M|regular intervals.  Correct any electrolyte abnormalities.|
03884|033|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03884|034|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03884|035|M|or electrolyte abnormalities.|
03884|036|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03884|037|M|fainting.|
03884|038|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03884|039|M|modifications are recommended:|
03884|040|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03884|041|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03884|042|M|resume mobocertinib at the same dose.|
03884|043|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03884|044|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03884|045|M|dose or permanently discontinue.|
03884|046|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03884|047|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03884|048|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03884|049|M|the next lower dose or permanently discontinue.|
03884|050|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03884|051|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03884|052|M|signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.|
03884|053|B||
03884|054|D|DISCUSSION:  Coadministration of mobocertinib with multiple doses of|
03884|055|D|itraconazole or ketoconazole (strong CYP3A4 inhibitors) is predicted to|
03884|056|D|increase the steady-state combined molar area-under curve (AUC) of|
03884|057|D|mobocertinib and its active metabolites by 374 to 419%.(1)|
03884|058|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
03884|059|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03884|060|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03884|061|D|tipranavir, troleandomycin, and tucatinib.(3,4)|
03884|062|B||
03884|063|R|REFERENCES:|
03884|064|B||
03884|065|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03884|066|R|  America, Inc. September, 2021.|1
03884|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03884|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03884|069|R|  settings: a scientific statement from the American Heart Association and|6
03884|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03884|071|R|  2;55(9):934-47.|6
03884|072|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03884|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03884|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03884|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03884|076|R|  11/14/2017.|1
03884|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
03884|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03885|001|T|MONOGRAPH TITLE:  Mobocertinib/Strong CYP3A4 Inhibitors that Prolong QT|
03885|002|B||
03885|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03885|004|L|of severe adverse interaction.|
03885|005|B||
03885|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03885|007|A|interval may inhibit the metabolism of mobocertinib and result in additive|
03885|008|A|risk of QT prolongation.(1)|
03885|009|B||
03885|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03885|011|E|prolong QT may result in elevated levels of and toxicity from mobocertinib|
03885|012|E|including additive QTc prolongation, which may result in potentially|
03885|013|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
03885|014|B||
03885|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03885|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03885|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03885|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03885|019|P|female gender, or advanced age.(2)|
03885|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03885|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03885|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03885|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03885|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03885|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03885|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03885|027|B||
03885|028|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors that prolong|
03885|029|M|QT in patients undergoing therapy with mobocertinib.(1)|
03885|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03885|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03885|032|M|regular intervals.  Correct any electrolyte abnormalities.|
03885|033|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03885|034|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03885|035|M|or electrolyte abnormalities.|
03885|036|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03885|037|M|fainting.|
03885|038|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03885|039|M|modifications are recommended:|
03885|040|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03885|041|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03885|042|M|resume mobocertinib at the same dose.|
03885|043|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03885|044|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03885|045|M|dose or permanently discontinue.|
03885|046|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03885|047|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03885|048|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03885|049|M|the next lower dose or permanently discontinue.|
03885|050|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03885|051|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03885|052|M|signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.|
03885|053|B||
03885|054|D|DISCUSSION:  Coadministration of mobocertinib with multiple doses of|
03885|055|D|itraconazole or ketoconazole (strong CYP3A inhibitors) is predicted to|
03885|056|D|increase the steady-state combined molar area-under curve (AUC) of|
03885|057|D|mobocertinib and its active metabolites by 374 to 419%.(1)|
03885|058|D|   In a clinical study, mobocertinib 160 mg once daily was associated with a|
03885|059|D|concentration-dependent increase in QTc, with the largest mean increase in|
03885|060|D|QTc of 23 msec.(1)|
03885|061|D|   In clinical studies, patients were excluded if baseline QTc was greater|
03885|062|D|than 470 msec.  In a subset of 250 patient with scheduled and unscheduled|
03885|063|D|electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and|
03885|064|D|11% of patients had a change-from-baseline QTc interval >60 msec.  Grade 4|
03885|065|D|Torsades de Pointes occurred in 1 patient (0.4%).(1)|
03885|066|D|   Strong inhibitors of CYP3A4 that prolong QT include:  adagrasib,|
03885|067|D|ceritinib, clarithromycin, lonafarnib, lopinavir, ribociclib, saquinavir,|
03885|068|D|telithromycin, and voriconazole.(3,4)|
03885|069|B||
03885|070|R|REFERENCES:|
03885|071|B||
03885|072|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03885|073|R|  America, Inc. September, 2021.|1
03885|074|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03885|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03885|076|R|  settings: a scientific statement from the American Heart Association and|6
03885|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03885|078|R|  2;55(9):934-47.|6
03885|079|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03885|080|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03885|081|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03885|082|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03885|083|R|  11/14/2017.|1
03885|084|R|4.This information is based on an extract from the Certara Drug Interaction|6
03885|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03886|001|T|MONOGRAPH TITLE:  Mobocertinib/Strong or Moderate CYP3A4 Inducers|
03886|002|B||
03886|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03886|004|L|of severe adverse interaction.|
03886|005|B||
03886|006|A|MECHANISM OF ACTION:  Strong or moderate inducers of CYP3A4 may induce the|
03886|007|A|metabolism of mobocertinib.(1)|
03886|008|B||
03886|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate CYP3A4 inducer may|
03886|010|E|result in a loss of mobocertinib efficacy.(1)|
03886|011|B||
03886|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03886|013|P|of the inducer for longer than 1-2 weeks.|
03886|014|B||
03886|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of mobocertinib with strong or|
03886|016|M|moderate CYP3A4 inducers.(1)|
03886|017|B||
03886|018|D|DISCUSSION:  Coadministration of mobocertinib with multiple doses of|
03886|019|D|rifampin (a strong CYP3A inducer) is predicted to decrease the steady-state|
03886|020|D|combined molar area-under-curve (AUC) of mobocertinib and its active|
03886|021|D|metabolites by 92%.(1)|
03886|022|D|   Coadministration of mobocertinib with multiple doses of efavirenz (a|
03886|023|D|moderate CYP3A inducer) is predicted to decrease the steady-state combined|
03886|024|D|molar AUC of mobocertinib and its active metabolites by 58%.(1)|
03886|025|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03886|026|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
03886|027|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03886|028|D|wort.(2,3)|
03886|029|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
03886|030|D|dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten,|
03886|031|D|mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin,|
03886|032|D|sotorasib, telotristat ethyl, and tovorafenib.(2,3)|
03886|033|B||
03886|034|R|REFERENCES:|
03886|035|B||
03886|036|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03886|037|R|  America, Inc. September, 2021.|1
03886|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03886|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03886|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03886|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03886|042|R|  11/14/2017.|1
03886|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
03886|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03887|001|T|MONOGRAPH TITLE:  Mobocertinib/Strong or Moderate 3A4 Inducers that Prolong|
03887|002|T|QT|
03887|003|B||
03887|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03887|005|L|of severe adverse interaction.|
03887|006|B||
03887|007|A|MECHANISM OF ACTION:  Strong or moderate inducers of CYP3A4 that prolong the|
03887|008|A|QTc interval may accelerate the metabolism of mobocertinib.(1)|
03887|009|A|   Mobocertinib prolongs the QTc interval.(1)  Some CYP3A4 inducers (e.g.,|
03887|010|A|efavirenz, ivosidenib, thioridazine) can also prolong the QTc interval.(2)|
03887|011|B||
03887|012|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers that|
03887|013|E|prolong the QTc interval may result in a loss of mobocertinib efficacy.|
03887|014|E|   Additive QTc prolongation may occur and result in potentially|
03887|015|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
03887|016|B||
03887|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03887|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03887|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03887|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03887|021|P|female gender, or advanced age.(3)|
03887|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03887|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03887|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03887|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03887|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03887|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03887|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03887|029|P|   Induction effects may be more likely with regular use of the inducer for|
03887|030|P|longer than 1-2 weeks.|
03887|031|B||
03887|032|M|PATIENT MANAGEMENT:  Avoid the use of strong or moderate CYP3A4 inducers|
03887|033|M|that prolong QT in patients undergoing therapy with mobocertinib.(1)|
03887|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03887|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03887|036|M|regular intervals.  Correct any electrolyte abnormalities.|
03887|037|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03887|038|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03887|039|M|or electrolyte abnormalities.|
03887|040|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03887|041|M|fainting.|
03887|042|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03887|043|M|modifications are recommended:|
03887|044|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03887|045|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03887|046|M|resume mobocertinib at the same dose.|
03887|047|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03887|048|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03887|049|M|dose or permanently discontinue.|
03887|050|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03887|051|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03887|052|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03887|053|M|the next lower dose or permanently discontinue.|
03887|054|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03887|055|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03887|056|M|signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.|
03887|057|B||
03887|058|D|DISCUSSION:  Coadministration of mobocertinib with multiple doses of|
03887|059|D|rifampin (a strong CYP3A inducer) is predicted to decrease the steady-state|
03887|060|D|combined molar area-under-curve (AUC) of mobocertinib and its active|
03887|061|D|metabolites by 92%.(1)|
03887|062|D|   Coadministration of mobocertinib with multiple doses of efavirenz (a|
03887|063|D|moderate CYP3A inducer) is predicted to decrease the steady-state combined|
03887|064|D|molar AUC of mobocertinib and its active metabolites by 58%.(1)|
03887|065|D|   In a clinical study, mobocertinib 160 mg once daily was associated with a|
03887|066|D|concentration-dependent increase in QTc, with the largest mean increase in|
03887|067|D|QTc of 23 msec.(1)|
03887|068|D|   In clinical studies, patients were excluded if baseline QTc was greater|
03887|069|D|than 470 msec.  In a subset of 250 patient with scheduled and unscheduled|
03887|070|D|electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and|
03887|071|D|11% of patients had a change-from-baseline QTc interval >60 msec.  Grade 4|
03887|072|D|Torsades de Pointes occurred in 1 patient (0.4%).(1)|
03887|073|D|   Strong inducers of CYP3A4 that prolong the QTc interval include:|
03887|074|D|encorafenib and ivosidenib.|
03887|075|D|   Moderate inducers of CYP3A4 that prolong the QTc interval include:|
03887|076|D|efavirenz, pacritinib, and thioridazine.(4,5)|
03887|077|B||
03887|078|R|REFERENCES:|
03887|079|B||
03887|080|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03887|081|R|  America, Inc. September, 2021.|1
03887|082|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
03887|083|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03887|084|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03887|085|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03887|086|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03887|087|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03887|088|R|  settings: a scientific statement from the American Heart Association and|6
03887|089|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03887|090|R|  2;55(9):934-47.|6
03887|091|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03887|092|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03887|093|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03887|094|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03887|095|R|  11/14/2017.|1
03887|096|R|5.This information is based on an extract from the Certara Drug Interaction|6
03887|097|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03888|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Mobocertinib|
03888|002|B||
03888|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03888|004|L|of severe adverse interaction.|
03888|005|B||
03888|006|A|MECHANISM OF ACTION:  Mobocertinib is a weak CYP3A4 inducer.|
03888|007|A|Coadministration of mobocertinib with hormonal contraceptives may lead to|
03888|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
03888|009|A|decreased hormonal concentrations.(1)|
03888|010|B||
03888|011|E|CLINICAL EFFECTS:  Concurrent use of mobocertinib can lead to ineffective|
03888|012|E|hormonal contraceptive and cause fetal harm when administered to a pregnant|
03888|013|E|woman.(1)|
03888|014|B||
03888|015|P|PREDISPOSING FACTORS:  None determined.|
03888|016|B||
03888|017|M|PATIENT MANAGEMENT:  Avoid concomitant use of hormonal contraceptives with|
03888|018|M|mobocertinib.  Advise females of reproductive potential to use effective|
03888|019|M|non-hormonal contraception during treatment with mobocertinib and for 1|
03888|020|M|month after the last dose.|
03888|021|M|   Women of reproductive age should be counseled not to rely on hormonal|
03888|022|M|contraceptives (including oral contraceptives, patches, implants, and/or|
03888|023|M|IUDs) for contraception.  Pregnant women and females of reproductive|
03888|024|M|potential should be counseled on the potential risk to a fetus.(1)|
03888|025|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
03888|026|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
03888|027|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
03888|028|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
03888|029|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
03888|030|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
03888|031|M|and to seek medical advice if she does become pregnant.(2)|
03888|032|B||
03888|033|D|DISCUSSION:  Mobocertinib has not been studied with hormonal contraceptives.|
03888|034|D|It can render some hormonal contraceptives ineffective and cause|
03888|035|D|embryo-fetal harm.  Women should use non-hormonal contraception during|
03888|036|D|therapy and for one month after the last dose.(1)|
03888|037|D|   In an animal study, oral administration of mobocertinib to pregnant rats|
03888|038|D|during the period of organogenesis resulted in embryolethality at maternal|
03888|039|D|exposures approximately 1.7 times the human exposure based on area under the|
03888|040|D|curve (AUC) at the 160 mg once daily clinical dose.(1)|
03888|041|D|   Coadministration of mobocertinib 160 mg once daily with oral or|
03888|042|D|intravenous midazolam (a CYP3A substrate) decreased the AUC of midazolam by|
03888|043|D|32% and 16%, respectively.(1)|
03888|044|B||
03888|045|R|REFERENCES:|
03888|046|B||
03888|047|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03888|048|R|  America, Inc. September, 2021.|1
03888|049|R|2.Medicines and Healthcare products Regulatory Agency.|1
03888|050|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
03888|051|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
03888|052|R|  available at:|1
03888|053|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
03888|054|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
03888|055|R|  -and-contraceptive-efficacy September 15, 2016..|1
03889|001|T|MONOGRAPH TITLE:  Mobocertinib/QT Prolonging Agents|
03889|002|B||
03889|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03889|004|L|of severe adverse interaction.|
03889|005|B||
03889|006|A|MECHANISM OF ACTION:  Mobocertinib has been shown to prolong the QTc|
03889|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
03889|008|A|may result in additive effects on the QTc interval.(1)|
03889|009|B||
03889|010|E|CLINICAL EFFECTS:  The concurrent use of mobocertinib with other agents that|
03889|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03889|012|E|arrhythmias, including torsades de pointes.(1)|
03889|013|B||
03889|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03889|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03889|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03889|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03889|018|P|gender, or advanced age.(2)|
03889|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03889|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03889|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03889|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03889|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03889|024|P|an agent which inhibits its metabolism or elimination, and/or renal or|
03889|025|P|hepatic dysfunction).(2)|
03889|026|B||
03889|027|M|PATIENT MANAGEMENT:  The US manufacturer of mobocertinib states that|
03889|028|M|mobocertinib may cause life-threatening QTc prolongation, including torsades|
03889|029|M|de pointes.  Mobocertinib should be avoided in patients receiving other|
03889|030|M|drugs known to cause QT prolongation.(1)|
03889|031|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03889|032|M|modifications are recommended:|
03889|033|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03889|034|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03889|035|M|resume mobocertinib at the same dose.|
03889|036|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03889|037|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03889|038|M|dose or permanently discontinue.|
03889|039|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03889|040|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03889|041|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03889|042|M|the next lower dose or permanently discontinue.|
03889|043|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03889|044|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03889|045|M|signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.|
03889|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03889|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03889|048|M|regular intervals.  Correct any electrolyte abnormalities.|
03889|049|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03889|050|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03889|051|M|or electrolyte abnormalities.|
03889|052|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03889|053|M|fainting.|
03889|054|B||
03889|055|D|DISCUSSION:  In a clinical study, mobocertinib 160 mg once daily was|
03889|056|D|associated with a concentration-dependent increase in QTc, with the largest|
03889|057|D|mean increase in QTc of 23 msec.(1)|
03889|058|D|   In clinical studies, patients were excluded if baseline QTc was greater|
03889|059|D|than 470 msec.  In a subset of 250 patient with scheduled and unscheduled|
03889|060|D|electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and|
03889|061|D|11% of patients had a change-from-baseline QTc interval >60 msec.  Grade 4|
03889|062|D|Torsades de Pointes occurred in 1 patient (0.4%).(1)|
03889|063|D|   Agents that are linked to this monograph may have varying degrees of|
03889|064|D|potential to prolong the QTc interval but are generally accepted to have a|
03889|065|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03889|066|D|been shown to prolong the QTc interval either through their mechanism of|
03889|067|D|action, through studies on their effects on the QTc interval, or through|
03889|068|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03889|069|D|and/or post-marketing reports.(3)|
03889|070|B||
03889|071|R|REFERENCES:|
03889|072|B||
03889|073|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03889|074|R|  America, Inc. September, 2021.|1
03889|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03889|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03889|077|R|  settings: a scientific statement from the American Heart Association and|6
03889|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03889|079|R|  2;55(9):934-47.|6
03889|080|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03889|081|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03889|082|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03889|083|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03890|001|T|MONOGRAPH TITLE:  Mobocertinib/Possible QT Prolonging Agents|
03890|002|B||
03890|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03890|004|L|take action as needed.|
03890|005|B||
03890|006|A|MECHANISM OF ACTION:  Mobocertinib has been shown to prolong the QTc|
03890|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
03890|008|A|may result in additive effects on the QTc interval.(1)|
03890|009|B||
03890|010|E|CLINICAL EFFECTS:  The concurrent use of mobocertinib with other agents that|
03890|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03890|012|E|arrhythmias, including torsades de pointes.(1)|
03890|013|B||
03890|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03890|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03890|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03890|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03890|018|P|gender, or advanced age.(2)|
03890|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03890|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03890|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03890|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03890|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03890|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03890|025|P|dysfunction).(2)|
03890|026|B||
03890|027|M|PATIENT MANAGEMENT:  The US manufacturer of mobocertinib states that|
03890|028|M|mobocertinib may cause life-threatening QTc prolongation, including torsades|
03890|029|M|de pointes.  Mobocertinib should be avoided in patients receiving other|
03890|030|M|drugs known to cause QT prolongation.(1)|
03890|031|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03890|032|M|modifications are recommended:|
03890|033|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03890|034|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03890|035|M|resume mobocertinib at the same dose.|
03890|036|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03890|037|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03890|038|M|dose or permanently discontinue.|
03890|039|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03890|040|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03890|041|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03890|042|M|the next lower dose or permanently discontinue.|
03890|043|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03890|044|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03890|045|M|signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.|
03890|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03890|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03890|048|M|regular intervals.  Correct any electrolyte abnormalities.|
03890|049|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03890|050|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03890|051|M|or electrolyte abnormalities.|
03890|052|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03890|053|M|fainting.|
03890|054|B||
03890|055|D|DISCUSSION:  In a clinical study, mobocertinib 160 mg once daily was|
03890|056|D|associated with a concentration-dependent increase in QTc, with the largest|
03890|057|D|mean increase in QTc of 23 msec.(1)|
03890|058|D|   In clinical studies, patients were excluded if baseline QTc was greater|
03890|059|D|than 470 msec.  In a subset of 250 patient with scheduled and unscheduled|
03890|060|D|electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and|
03890|061|D|11% of patients had a change-from-baseline QTc interval >60 msec.  Grade 4|
03890|062|D|Torsades de Pointes occurred in 1 patient (0.4%).(1)|
03890|063|D|   Agents that are linked to this monograph may have varying degrees of|
03890|064|D|potential to prolong the QTc interval but are generally accepted to have a|
03890|065|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03890|066|D|been shown to prolong the QTc interval either through their mechanism of|
03890|067|D|action, through studies on their effects on the QTc interval, or through|
03890|068|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03890|069|D|and/or post-marketing reports.(3)|
03890|070|B||
03890|071|R|REFERENCES:|
03890|072|B||
03890|073|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03890|074|R|  America, Inc. September, 2021.|1
03890|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03890|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03890|077|R|  settings: a scientific statement from the American Heart Association and|6
03890|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03890|079|R|  2;55(9):934-47.|6
03890|080|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03890|081|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03890|082|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03890|083|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03891|001|T|MONOGRAPH TITLE:  Mobocertinib/Moderate CYP3A4 Inhibitors|
03891|002|B||
03891|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03891|004|L|of severe adverse interaction.|
03891|005|B||
03891|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03891|007|A|metabolism of mobocertinib.(1)|
03891|008|B||
03891|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
03891|010|E|levels of and effects from mobocertinib.(1)|
03891|011|E|    Elevated levels of mobocertinib may result in QTc prolongation, which|
03891|012|E|may result in potentially life-threatening cardiac arrhythmias, including|
03891|013|E|torsades de pointes (TdP).(1)|
03891|014|B||
03891|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03891|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03891|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03891|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03891|019|P|female gender, or advanced age.(2)|
03891|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03891|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03891|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03891|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03891|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03891|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03891|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03891|027|B||
03891|028|M|PATIENT MANAGEMENT:  Avoid the use of moderate CYP3A4 inhibitors in patients|
03891|029|M|undergoing therapy with mobocertinib.(1)|
03891|030|M|   If concurrent therapy with a moderate CYP3A4 inhibitor is warranted,|
03891|031|M|reduce the dose of mobocertinib by approximately 50% (ie, 160 to 80 mg, 120|
03891|032|M|to 40 mg, or 80 to 40 mg) and monitor the QTc interval more frequently.|
03891|033|M|After the moderate CYP3A4 inhibitor has been discontinued for 3 to 5|
03891|034|M|elimination half-lives, resume mobocertinib at the dose taken prior to|
03891|035|M|initiating the moderate CYP3A4 inhibitor.|
03891|036|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
03891|037|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03891|038|M|electrolyte abnormalities.|
03891|039|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03891|040|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03891|041|M|or electrolyte abnormalities.|
03891|042|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03891|043|M|fainting.|
03891|044|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03891|045|M|modifications are recommended:|
03891|046|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03891|047|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03891|048|M|resume mobocertinib at the same dose.|
03891|049|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03891|050|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03891|051|M|dose or permanently discontinue.|
03891|052|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03891|053|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03891|054|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03891|055|M|the next lower dose or permanently discontinue.|
03891|056|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03891|057|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03891|058|M|signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.|
03891|059|B||
03891|060|D|DISCUSSION:  Coadministration of mobocertinib with multiple doses of a|
03891|061|D|moderate CYP3A inhibitor is predicted to increase the steady-state combined|
03891|062|D|molar area-under curve (AUC) of mobocertinib and its active metabolites by|
03891|063|D|approximately 100 to 200%.(1)|
03891|064|D|   Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir,|
03891|065|D|aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir,|
03891|066|D|diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant,|
03891|067|D|imatinib, isavuconazonium, lenacapavir, letermovir, netupitant,|
03891|068|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
03891|069|D|verapamil, and voxelotor.(3,4)|
03891|070|B||
03891|071|R|REFERENCES:|
03891|072|B||
03891|073|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03891|074|R|  America, Inc. September, 2021.|1
03891|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03891|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03891|077|R|  settings: a scientific statement from the American Heart Association and|6
03891|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03891|079|R|  2;55(9):934-47.|6
03891|080|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03891|081|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03891|082|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03891|083|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03891|084|R|  11/14/2017.|1
03891|085|R|4.This information is based on an extract from the Certara Drug Interaction|6
03891|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03892|001|T|MONOGRAPH TITLE:  Mobocertinib/Moderate 3A4 Inhibitors that Prolong QT|
03892|002|B||
03892|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03892|004|L|of severe adverse interaction.|
03892|005|B||
03892|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong the QTc|
03892|007|A|interval may inhibit the metabolism of mobocertinib and result in additive|
03892|008|A|risk of QT prolongation.(1)|
03892|009|B||
03892|010|E|CLINICAL EFFECTS:  Concurrent use of moderate inhibitors of CYP3A4 that|
03892|011|E|prolong QT may result in elevated levels of and toxicity from mobocertinib|
03892|012|E|including additive QTc prolongation, which may result in potentially|
03892|013|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
03892|014|B||
03892|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03892|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03892|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03892|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03892|019|P|female gender, or advanced age.(2)|
03892|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03892|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03892|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03892|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03892|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03892|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03892|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03892|027|B||
03892|028|M|PATIENT MANAGEMENT:  Avoid the use of moderate CYP3A4 inhibitors that|
03892|029|M|prolong QT in patients undergoing therapy with mobocertinib.(1)|
03892|030|M|   If concurrent therapy with a moderate CYP3A4 inhibitor is warranted,|
03892|031|M|reduce the dose of mobocertinib by approximately 50% (ie, 160 to 80 mg, 120|
03892|032|M|to 40 mg, or 80 to 40 mg) and monitor the QTc interval more frequently.|
03892|033|M|After the moderate CYP3A4 inhibitor has been discontinued for 3 to 5|
03892|034|M|elimination half-lives, resume mobocertinib at the dose taken prior to|
03892|035|M|initiating the moderate CYP3A4 inhibitor.|
03892|036|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
03892|037|M|monitoring ECG at baseline and at regular intervals.  Correct any|
03892|038|M|electrolyte abnormalities.|
03892|039|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03892|040|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03892|041|M|or electrolyte abnormalities.|
03892|042|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03892|043|M|fainting.|
03892|044|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03892|045|M|modifications are recommended:|
03892|046|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03892|047|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03892|048|M|resume mobocertinib at the same dose.|
03892|049|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03892|050|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03892|051|M|dose or permantely discontinue.|
03892|052|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03892|053|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03892|054|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03892|055|M|the next lower dose or permanently discontinue.|
03892|056|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03892|057|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03892|058|M|signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.|
03892|059|B||
03892|060|D|DISCUSSION:  Coadministration of mobocertinib with multiple doses of a|
03892|061|D|moderate CYP3A inhibitor is predicted to increase the steady-state combined|
03892|062|D|molar area-under-curve (AUC) of mobocertinib and its active metabolites by|
03892|063|D|approximately 100-200%.|
03892|064|D|   In a clinical study, mobocertinib 160 mg once daily was associated with a|
03892|065|D|concentration-dependent increase in QTc, with the largest mean increase in|
03892|066|D|QTc of 23 msec.(1)|
03892|067|D|   In clinical studies, patients were excluded if baseline QTc was greater|
03892|068|D|than 470 msec.  In a subset of 250 patient with scheduled and unscheduled|
03892|069|D|electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and|
03892|070|D|11% of patients had a change-from-baseline QTc interval >60 msec.  Grade 4|
03892|071|D|Torsades de Pointes occurred in 1 patient (0.4%).(1)|
03892|072|D|   Moderate CYP3A4 inhibitors that prolong QT linked to this monograph|
03892|073|D|include:  clofazimine, crizotinib, erythromycin, fluconazole, and|
03892|074|D|nilotinib.(3,4)|
03892|075|B||
03892|076|R|REFERENCES:|
03892|077|B||
03892|078|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03892|079|R|  America, Inc. September, 2021.|1
03892|080|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03892|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03892|082|R|  settings: a scientific statement from the American Heart Association and|6
03892|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03892|084|R|  2;55(9):934-47.|6
03892|085|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03892|086|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03892|087|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03892|088|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03892|089|R|  11/14/2017.|1
03892|090|R|4.This information is based on an extract from the Certara Drug Interaction|6
03892|091|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03893|001|T|MONOGRAPH TITLE:  Mobocertinib/Dronedarone|
03893|002|B||
03893|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03893|004|L|is contraindicated and generally should not be dispensed or administered to|
03893|005|L|the same patient.|
03893|006|B||
03893|007|A|MECHANISM OF ACTION:  Dronedarone, a moderate CYP3A4 inhibitor, may inhibit|
03893|008|A|the metabolism of mobocertinib.  Concurrent use of these medicines may also|
03893|009|A|result in additive risk of QT prolongation.(1,2)|
03893|010|B||
03893|011|E|CLINICAL EFFECTS:  Concurrent use of dronedarone and mobocertinib may result|
03893|012|E|in elevated levels of and toxicity from mobocertinib including additive QTc|
03893|013|E|prolongation, which may lead to potentially life-threatening cardiac|
03893|014|E|arrhythmias like torsades de pointes.(1,2)|
03893|015|B||
03893|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03893|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03893|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03893|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03893|020|P|female gender, or advanced age.(3)|
03893|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03893|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03893|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03893|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03893|025|P|impaired metabolism or elimination of the drug (e.g., coadministration with|
03893|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03893|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03893|028|B||
03893|029|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that|
03893|030|M|concurrent use of drugs or herbal products that are known to prolong the QTc|
03893|031|M|interval is contraindicated.(2)|
03893|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03893|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03893|034|M|regular intervals.  Correct any electrolyte abnormalities.|
03893|035|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03893|036|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03893|037|M|or electrolyte abnormalities.|
03893|038|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03893|039|M|fainting.|
03893|040|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03893|041|M|modifications are recommended:|
03893|042|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03893|043|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03893|044|M|resume mobocertinib at the same dose.|
03893|045|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03893|046|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03893|047|M|dose or permanently discontinue.|
03893|048|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03893|049|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03893|050|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03893|051|M|the next lower dose or permanently discontinue.|
03893|052|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03893|053|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03893|054|M|signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.|
03893|055|B||
03893|056|D|DISCUSSION:  Coadministration of mobocertinib with multiple doses of a|
03893|057|D|moderate CYP3A inhibitor is predicted to increase the steady-state combined|
03893|058|D|molar area-under-curve (AUC) of mobocertinib and its active metabolites by|
03893|059|D|approximately 100-200%.|
03893|060|D|   In a clinical study, mobocertinib 160 mg once daily was associated with a|
03893|061|D|concentration-dependent increase in QTc, with the largest mean increase in|
03893|062|D|QTc of 23 msec.(1)|
03893|063|D|   In mobocertinib clinical studies, patients were excluded if baseline QTc|
03893|064|D|was greater than 470 msec.  In a subset of 250 patient with scheduled and|
03893|065|D|unscheduled electrocardiograms (ECGs), 1.2% of patients had a QTc interval|
03893|066|D|>500 msec and 11% of patients had a change-from-baseline QTc interval >60|
03893|067|D|msec.  Grade 4 Torsades de Pointes occurred in 1 patient (0.4%).(1)|
03893|068|B||
03893|069|R|REFERENCES:|
03893|070|B||
03893|071|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03893|072|R|  America, Inc. September, 2021.|1
03893|073|R|2.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
03893|074|R|  November, 2020.|1
03893|075|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03893|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03893|077|R|  settings: a scientific statement from the American Heart Association and|6
03893|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03893|079|R|  2;55(9):934-47.|6
03893|080|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03893|081|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03893|082|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03893|083|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03893|084|R|  11/14/2017.|1
03893|085|R|5.This information is based on an extract from the Certara Drug Interaction|6
03893|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03894|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/Mobocertinib|
03894|002|B||
03894|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03894|004|L|of severe adverse interaction.|
03894|005|B||
03894|006|A|MECHANISM OF ACTION:  Mobocertinib is a weak inducer of CYP3A4 and may|
03894|007|A|increase the metabolism of drugs metabolized by the CYP3A4 enzyme.|
03894|008|B||
03894|009|E|CLINICAL EFFECTS:  Concurrent use of mobocertinib may lead to decreased|
03894|010|E|serum levels and effectiveness of drugs metabolized by the CYP3A4|
03894|011|E|pathway.(1)|
03894|012|B||
03894|013|P|PREDISPOSING FACTORS:  None determined.|
03894|014|B||
03894|015|M|PATIENT MANAGEMENT:  The manufacturer of mobocertinib states that|
03894|016|M|co-administration of CYP3A4 substrates for which minimal concentration|
03894|017|M|decreases may lead to serious therapeutic failure should be avoided.  If|
03894|018|M|concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in|
03894|019|M|accordance with approved product labeling.(1)|
03894|020|B||
03894|021|D|DISCUSSION:  In a clinical study, coadministration of mobocertinib 160 mg|
03894|022|D|once daily with oral or intravenous midazolam, a sensitive CYP3A4 substrate,|
03894|023|D|decreased midazolam area-under-curve (AUC) by 32% and 16%, respectively.(1)|
03894|024|D|   CYP3A4 substrates with a narrow therapeutic index linked to this|
03894|025|D|monograph include: everolimus and sirolimus.(2-4)|
03894|026|B||
03894|027|R|REFERENCES:|
03894|028|B||
03894|029|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03894|030|R|  America, Inc. September, 2021.|1
03894|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
03894|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03894|033|R|3.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
03894|034|R|  August, 2023.|1
03894|035|R|4.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
03894|036|R|  Aug, 2022.|1
03895|001|T|MONOGRAPH TITLE:  Intravenous Lefamulin/Selected QT Prolonging Agents|
03895|002|B||
03895|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03895|004|L|of severe adverse interaction.|
03895|005|B||
03895|006|A|MECHANISM OF ACTION:  Concurrent use of lefamulin with agents that prolong|
03895|007|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03895|008|B||
03895|009|E|CLINICAL EFFECTS:  The concurrent use of lefamulin with agents that prolong|
03895|010|E|the QTc interval may result in potentially life-threatening cardiac|
03895|011|E|arrhythmias, including torsades de pointes.(1)|
03895|012|B||
03895|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03895|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
03895|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03895|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03895|017|P|female gender, or advanced age.(2)|
03895|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03895|019|P|higher systemic concentrations of either QT prolonging drug are additional|
03895|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03895|021|P|drug concentrations include rapid infusion of an intravenous dose or|
03895|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03895|023|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03895|024|P|dysfunction).(2)|
03895|025|B||
03895|026|M|PATIENT MANAGEMENT:  Avoid the concurrent use of lefamulin with other|
03895|027|M|medications that prolong the QT interval.(1)|
03895|028|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03895|029|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03895|030|M|treatment, after initiation of any drug known to prolong the QT interval,|
03895|031|M|and periodically monitor during therapy.  Correct any electrolyte|
03895|032|M|abnormalities.(1)|
03895|033|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03895|034|M|fainting.|
03895|035|B||
03895|036|D|DISCUSSION:  In a thorough QT study, intravenous lefamulin increased the|
03895|037|D|QTcF by 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF|
03895|038|D|by 9.3 msec (90% CI = 10.9 msec).(1)|
03895|039|D|   Agents that are linked to this monograph may have varying degrees of|
03895|040|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03895|041|D|been shown to prolong the QTc interval either through their mechanism of|
03895|042|D|action, through studies on their effects on the QTc interval, or through|
03895|043|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03895|044|D|and/or postmarketing reports.(3)|
03895|045|B||
03895|046|R|REFERENCES:|
03895|047|B||
03895|048|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03895|049|R|  Inc August 2019.|1
03895|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03895|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03895|052|R|  settings: a scientific statement from the American Heart Association and|6
03895|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03895|054|R|  2;55(9):934-47.|6
03895|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03895|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03895|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03895|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03896|001|T|MONOGRAPH TITLE:  Tisotumab/Anticoagulants; Antiplatelets|
03896|002|B||
03896|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03896|004|L|take action as needed.|
03896|005|B||
03896|006|A|MECHANISM OF ACTION:  Bleeding, including hemorrhage, has been reported with|
03896|007|A|the use of tisotumab.(1)|
03896|008|B||
03896|009|E|CLINICAL EFFECTS:  Concurrent use of tisotumab with either anticoagulants,|
03896|010|E|antiplatelets, or NSAIDs may increase the risk of hemorrhage.(1)|
03896|011|B||
03896|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03896|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03896|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
03896|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03896|016|P|risk for bleeding (e.g. NSAIDs).|
03896|017|B||
03896|018|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with tisotumab|
03896|019|M|and anticoagulants, antiplatelets, and/or NSAIDs should be closely monitored|
03896|020|M|for signs and symptoms of bleeding and changes in platelet count or|
03896|021|M|International Normalized Ratio (INR).|
03896|022|M|   For patients experiencing pulmonary or central nervous system (CNS)|
03896|023|M|hemorrhage, permanently discontinue tisotumab.|
03896|024|M|   For grade 2 or greater hemorrhage in any other location, withhold until|
03896|025|M|bleeding has resolved, blood hemoglobin is stable, there is no bleeding|
03896|026|M|diathesis that could increase the risk of continuing therapy, and there is|
03896|027|M|no anatomical or pathologic condition that can increase the risk of|
03896|028|M|hemorrhage.  After resolution, either resume treatment or permanently|
03896|029|M|discontinue tisotumab.(1)|
03896|030|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03896|031|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
03896|032|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
03896|033|M|patients with any symptoms.|
03896|034|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
03896|035|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03896|036|M|anticoagulation in patients with active pathologic bleeding.|
03896|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03896|038|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03896|039|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03896|040|M|and/or swelling.|
03896|041|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03896|042|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
03896|043|M|before initiating, altering the dose or discontinuing either drug.|
03896|044|B||
03896|045|D|DISCUSSION:  Hemorrhage occurred in 62% of patients with cervical cancer|
03896|046|D|treated with tisotumab across clinical trials.  The most common all grade|
03896|047|D|hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and|
03896|048|D|vaginal hemorrhage (10%).  Grade 3 hemorrhage occurred in 5% of patients.(1)|
03896|049|B||
03896|050|R|REFERENCE:|
03896|051|B||
03896|052|R|1.Tivdak (tisotumab vedotin-tftv) US prescribing information. Seagen Inc.|1
03896|053|R|  September, 2021.|1
03897|001|T|MONOGRAPH TITLE:  Intravenous Lefamulin/Selected Possible QT Prolonging|
03897|002|T|Agents|
03897|003|B||
03897|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03897|005|L|take action as needed.|
03897|006|B||
03897|007|A|MECHANISM OF ACTION:  Concurrent use of lefamulin with agents that prolong|
03897|008|A|the QTc interval may result in additive effects on the QTc interval.(1)|
03897|009|B||
03897|010|E|CLINICAL EFFECTS:  The concurrent use of lefamulin with agents that prolong|
03897|011|E|the QTc interval may result in potentially life-threatening cardiac|
03897|012|E|arrhythmias, including torsades de pointes.(1)|
03897|013|B||
03897|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03897|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03897|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03897|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03897|018|P|female gender, or advanced age.(2)|
03897|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03897|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03897|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03897|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03897|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03897|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03897|025|P|dysfunction).(2)|
03897|026|B||
03897|027|M|PATIENT MANAGEMENT:  Avoid the concurrent use of lefamulin with other|
03897|028|M|medications that prolong the QT interval.(1)|
03897|029|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
03897|030|M|values (serum calcium, magnesium, and potassium) prior to the start of|
03897|031|M|treatment, after initiation of any drug known to prolong the QT interval,|
03897|032|M|and periodically monitor during therapy.  Correct any electrolyte|
03897|033|M|abnormalities.(1)|
03897|034|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03897|035|M|fainting.|
03897|036|B||
03897|037|D|DISCUSSION:  In a thorough QT study, intravenous lefamulin increased the|
03897|038|D|QTcF by 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF|
03897|039|D|by 9.3 msec (90% CI = 10.9 msec).(1)|
03897|040|D|   Agents that are linked to this monograph may have varying degrees of|
03897|041|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03897|042|D|been shown to prolong the QTc interval either through their mechanism of|
03897|043|D|action, through studies on their effects on the QTc interval, or through|
03897|044|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03897|045|D|and/or postmarketing reports.(3)|
03897|046|B||
03897|047|R|REFERENCES:|
03897|048|B||
03897|049|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
03897|050|R|  Inc August 2019.|1
03897|051|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03897|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03897|053|R|  settings: a scientific statement from the American Heart Association and|6
03897|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03897|055|R|  2;55(9):934-47.|6
03897|056|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03897|057|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03897|058|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03897|059|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03898|001|T|MONOGRAPH TITLE:  Tacrolimus/Mobocertinib|
03898|002|B||
03898|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03898|004|L|of severe adverse interaction.|
03898|005|B||
03898|006|A|MECHANISM OF ACTION:  Mobocertinib is a weak inducer of CYP3A4 and may|
03898|007|A|accelerate the metabolism of drugs metabolized by the CYP3A4 enzyme.|
03898|008|A|   Mobocertinib has been shown to prolong the QTc interval.  Concurrent use|
03898|009|A|with other agents that prolong the QTc interval, like tacrolimus, may result|
03898|010|A|in additive effects on the QTc interval.(1)|
03898|011|B||
03898|012|E|CLINICAL EFFECTS:  Concurrent use of mobocertinib may lead to decreased|
03898|013|E|serum levels and effectiveness of tacrolimus.(1)|
03898|014|E|   The concurrent use of mobocertinib with other agents that prolong the QTc|
03898|015|E|interval like tacrolimus may result in potentially life-threatening cardiac|
03898|016|E|arrhythmias, including torsades de pointes.(1)|
03898|017|B||
03898|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03898|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03898|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03898|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03898|022|P|gender, or advanced age.(2)|
03898|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03898|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03898|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03898|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03898|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03898|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03898|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03898|030|B||
03898|031|M|PATIENT MANAGEMENT:  The US manufacturer of mobocertinib states that|
03898|032|M|co-administration of CYP3A4 substrates for which minimal concentration|
03898|033|M|decreases may lead to serious therapeutic failure should be avoided.  If|
03898|034|M|concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in|
03898|035|M|accordance with approved product labeling.(1)|
03898|036|M|   The US manufacturer of mobocertinib states that mobocertinib may cause|
03898|037|M|life-threatening QTc prolongation, including torsades de pointes.|
03898|038|M|Mobocertinib should be avoided in patients receiving other drugs known to|
03898|039|M|cause QT prolongation.(1)|
03898|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03898|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03898|042|M|regular intervals.  Correct any electrolyte abnormalities.|
03898|043|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03898|044|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03898|045|M|or electrolyte abnormalities.|
03898|046|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03898|047|M|fainting.   The US manufacturer of mobocertinib states that mobocertinib may|
03898|048|M|cause life-threatening QTc prolongation, including torsades de pointes.|
03898|049|M|Mobocertinib should be avoided in patients receiving other drugs known to|
03898|050|M|cause QT prolongation.(1)|
03898|051|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03898|052|M|modifications are recommended:|
03898|053|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03898|054|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03898|055|M|resume mobocertinib at the same dose.|
03898|056|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03898|057|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03898|058|M|dose or permanently discontinue.|
03898|059|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03898|060|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03898|061|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03898|062|M|the next lower dose or permanently discontinue.|
03898|063|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03898|064|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03898|065|M|signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.|
03898|066|B||
03898|067|D|DISCUSSION:  In a clinical study, coadministration of mobocertinib 160 mg|
03898|068|D|once daily with oral or intravenous midazolam, a sensitive CYP3A4 substrate,|
03898|069|D|decreased midazolam area-under-curve (AUC) by 32% and 16%, respectively.(1)|
03898|070|D|   In a clinical study, mobocertinib 160 mg once daily was associated with a|
03898|071|D|concentration-dependent increase in QTc, with the largest mean increase in|
03898|072|D|QTc of 23 msec.(1)|
03898|073|D|   In clinical studies, patients were excluded if baseline QTc was greater|
03898|074|D|than 470 msec.  In a subset of 250 patient with scheduled and unscheduled|
03898|075|D|electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and|
03898|076|D|11% of patients had a change-from-baseline QTc interval >60 msec.  Grade 4|
03898|077|D|Torsades de Pointes occurred in 1 patient (0.4%).(1)|
03898|078|B||
03898|079|R|REFERENCES:|
03898|080|B||
03898|081|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03898|082|R|  America, Inc. September, 2021.|1
03898|083|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03898|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03898|085|R|  settings: a scientific statement from the American Heart Association and|6
03898|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03898|087|R|  2;55(9):934-47.|6
03898|088|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03898|089|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03898|090|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03898|091|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03898|092|R|  11/14/2017.|1
03898|093|R|4.This information is based on an extract from the Certara Drug Interaction|6
03898|094|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03899|001|T|MONOGRAPH TITLE:  Bromazepam/Strong CYP1A2 Inhibitors|
03899|002|B||
03899|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03899|004|L|take action as needed.|
03899|005|B||
03899|006|A|MECHANISM OF ACTION:  Strong CYP1A2 inhibitors may decrease the metabolism|
03899|007|A|of bromazepam.(1)|
03899|008|B||
03899|009|E|CLINICAL EFFECTS:  The concurrent administration of bromazepam with strong|
03899|010|E|CYP1A2 inhibitors may result in elevated levels of bromazepam, which may|
03899|011|E|result in increased adverse effects including profound sedation, respiratory|
03899|012|E|depression, coma, and/or death.(1)|
03899|013|B||
03899|014|P|PREDISPOSING FACTORS:  None determined.|
03899|015|B||
03899|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with bromazepam|
03899|017|M|and strong CYP1A2 inhibitors should be monitored for increased|
03899|018|M|benzodiazepine effects.  If concurrent use is necessary, monitor patients|
03899|019|M|for unusual dizziness or lightheadedness, extreme sleepiness, slowed or|
03899|020|M|difficult breathing, or unresponsiveness.  The dosage of the bromazepam may|
03899|021|M|need to be decreased.  Bromazepam may need to be discontinued.(2)|
03899|022|M|   Counsel patient to report excess drowsiness, confusion, memory problems|
03899|023|M|including sleep-driving behaviors, loss of coordination, unusual dizziness|
03899|024|M|of lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03899|025|M|unresponsiveness.|
03899|026|M|   Benzodiazepines that do not undergo extensive Phase I metabolism|
03899|027|M|(lorazepam, oxazepam) may be an alternative in patients receiving a strong|
03899|028|M|CYP1A2 inhibitor.|
03899|029|B||
03899|030|D|DISCUSSION:  Fluvoxamine, a strong CYP1A2 inhibitor, increased bromazepam|
03899|031|D|area-under-curve (AUC) by 2.4-fold and half life by 1.9-fold.(1-3)|
03899|032|D|   Strong CYP1A2 inhibitors linked to this monograph include: angelica root,|
03899|033|D|enasidenib, enoxacin, fluvoxamine, and rofecoxib. (4)|
03899|034|B||
03899|035|R|REFERENCES:|
03899|036|B||
03899|037|R|1.Apo-Bromazepam Canadian prescribing information. Apotex, Inc. March 10,|1
03899|038|R|  2016.|1
03899|039|R|2.Lexotan (bromazepam) Australian prescribing information. Pharmaco|1
03899|040|R|  (Australia) Ltd October 8, 2020.|1
03899|041|R|3.Van Harten J, Holland RL, Wesnes K. Influence of multiple-dose|2
03899|042|R|  administration of fluvoxamine on the pharmacokinetics of the|2
03899|043|R|  benzodiazepinen bromazepam and lorazepam: a randomised, cross-over study.|2
03899|044|R|  Eur Neuropsychopharmacol 1992 Sept;2(3):381.|2
03899|045|R|4.This information is based on an extract from the Certara Drug Interaction|6
03899|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03900|001|T|MONOGRAPH TITLE:  Atogepant/Strong CYP3A4 Inhibitors|
03900|002|B||
03900|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03900|004|L|take action as needed.|
03900|005|B||
03900|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03900|007|A|the metabolism of atogepant.(1)|
03900|008|B||
03900|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03900|010|E|levels of and effects from atogepant, including nausea, constipation, and|
03900|011|E|fatigue.(1)|
03900|012|B||
03900|013|P|PREDISPOSING FACTORS:  None determined.|
03900|014|B||
03900|015|M|PATIENT MANAGEMENT:  The manufacturer of atogepant recommends that patients|
03900|016|M|on concomitant strong CYP3A4 inhibitors receive atogepant 10 mg once daily|
03900|017|M|for prevention of episodic migraines and for prevention of chronic|
03900|018|M|migraines.(1)|
03900|019|B||
03900|020|D|DISCUSSION:  In a study of healthy subjects, itraconazole, a strong CYP3A4|
03900|021|D|inhibitor, increased the atogepant area-under-curve (AUC) by 5.5-fold and|
03900|022|D|maximum concentration (Cmax) by 2.15-fold.(1)|
03900|023|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
03900|024|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03900|025|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
03900|026|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
03900|027|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
03900|028|D|tucatinib, or voriconazole.(2,3)|
03900|029|B||
03900|030|R|REFERENCES:|
03900|031|B||
03900|032|R|1.Qulipta (atogepant) US prescribing information. Abbvie September, 2025.|1
03900|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03900|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03900|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03900|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03900|037|R|  11/14/2017.|1
03900|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
03900|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03901|001|T|MONOGRAPH TITLE:  Atogepant/Strong CYP3A4 Inducers|
03901|002|B||
03901|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03901|004|L|of severe adverse interaction.|
03901|005|B||
03901|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolism of|
03901|007|A|atogepant by CYP3A4.(1)|
03901|008|B||
03901|009|E|CLINICAL EFFECTS:  The concurrent use of strong CYP3A4 inducers with|
03901|010|E|atogepant may result in decreased levels and clinical effectiveness of|
03901|011|E|atogepant.(1)|
03901|012|B||
03901|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03901|014|P|of the inducer for longer than 1-2 weeks.|
03901|015|B||
03901|016|M|PATIENT MANAGEMENT:  The manufacturer of atogepant recommends that patients|
03901|017|M|on concomitant strong CYP3A4 inducers receive atogepant 60 mg once daily for|
03901|018|M|prevention of episodic migraines and use of atogepant is not recommended for|
03901|019|M|prevention of chronic migraines.(1)|
03901|020|M|   Patients receiving concurrent therapy with CYP3A4 inducers and atogepant|
03901|021|M|should be observed for decreased clinical effectiveness.|
03901|022|B||
03901|023|D|DISCUSSION:  In a study of healthy subjects, rifampin, a strong CYP3A4|
03901|024|D|inducer, decreased the area-under-curve (AUC) and maximum concentration|
03901|025|D|(Cmax) of atogepant by 60% and 30%, respectively.  Topiramate, a weak CYP3A4|
03901|026|D|inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1)|
03901|027|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
03901|028|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib,|
03901|029|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and|
03901|030|D|St. John's wort.(1,2)|
03901|031|B||
03901|032|R|REFERENCES:|
03901|033|B||
03901|034|R|1.Qulipta (atogepant) US prescribing information. Abbvie September, 2025.|1
03901|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
03901|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03901|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03901|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03901|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03901|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03901|041|R|  11/14/2017.|1
03902|001|T|MONOGRAPH TITLE:  Atogepant/OATP1B1-3 Inhibitors|
03902|002|B||
03902|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03902|004|L|take action as needed.|
03902|005|B||
03902|006|A|MECHANISM OF ACTION:  Atogepant is a substrate of OATP1B1 and 1B3.|
03902|007|A|Inhibitors of these transporters may increase the GI absorption and/or|
03902|008|A|decrease the hepatic uptake of atogepant.(1)|
03902|009|B||
03902|010|E|CLINICAL EFFECTS:  Concurrent use of OATP1B1 or 1B3 inhibitors may result in|
03902|011|E|elevated levels of and side effects from atogepant, including nausea,|
03902|012|E|constipation and fatigue.(1)|
03902|013|B||
03902|014|P|PREDISPOSING FACTORS:  None determined.|
03902|015|B||
03902|016|M|PATIENT MANAGEMENT:  The manufacturer of atogepant states that, when used|
03902|017|M|concurrently with an OATP inhibitor for prevention of episodic migraine, the|
03902|018|M|atogepant dose should be limited to 10 mg or 30 mg once daily.  When used|
03902|019|M|concurrently with an OATP inhibitor for prevention of chronic migraines, the|
03902|020|M|atogepant dose should be limited to 30 mg once daily.(1)|
03902|021|B||
03902|022|D|DISCUSSION:  In a clinical trial of healthy subjects, single-dose rifampin,|
03902|023|D|an OATP inhibitor, increased the atogepant area-under-curve (AUC) and|
03902|024|D|maximum concentration (Cmax) by 2.85-fold and 2.23-fold, respectively.(1)|
03902|025|D|   OATP1B1 and 1B3 inhibitors include: atazanavir, belumosudil,|
03902|026|D|cyclosporine, darunavir, eltrombopag, erythromycin, gemfibrozil,|
03902|027|D|glecaprevir-pibrentasvir, ledipasvir, leflunomide, leniolisib, letermovir,|
03902|028|D|paritaprevir, resmetirom, ritonavir, roxadustat, simeprevir, sofosbuvir,|
03902|029|D|teriflunomide, vadadustat, velpatasvir, and voclosporin.(1,2)|
03902|030|B||
03902|031|R|REFERENCES:|
03902|032|B||
03902|033|R|1.Qulipta (atogepant) US prescribing information. Abbvie September, 2025.|1
03902|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
03902|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03902|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03902|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03902|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03902|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03902|040|R|  11/14/2017.|1
03903|001|T|MONOGRAPH TITLE:  Eliglustat/Dual Weak CYP2D6 and CYP3A4 Inhibitors|
03903|002|B||
03903|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03903|004|L|of severe adverse interaction.|
03903|005|B||
03903|006|A|MECHANISM OF ACTION:  Eliglustat is primarily metabolized by CYP2D6 and to a|
03903|007|A|lesser extent by CYP3A4.(1)  Amiodarone, fluvoxamine, oral contraceptives,|
03903|008|A|and ranitidine weakly inhibit CYP2D6 and CYP3A4.|
03903|009|B||
03903|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
03903|011|E|clinical effects of eliglustat, including prolongation of the PR, QTc,|
03903|012|E|and/or QRS intervals, which may result in life-threatening cardiac|
03903|013|E|arrhythmias.(1)|
03903|014|B||
03903|015|P|PREDISPOSING FACTORS:  If the patient has hepatic impairment or if the|
03903|016|P|patient is a CYP2D6 poor metabolizer, eliglustat metabolism can be further|
03903|017|P|inhibited.(1)|
03903|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03903|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03903|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03903|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03903|022|P|advanced age.(2)|
03903|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03903|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03903|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03903|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03903|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03903|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03903|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03903|030|B||
03903|031|M|PATIENT MANAGEMENT:  Prescribing information has no specific recommendation|
03903|032|M|on the use of eliglustat with drugs that are weak inhibitors of both CYP2D6|
03903|033|M|and CYP3A4.|
03903|034|M|   In CYP2D6 poor metabolizers, coadministration with dual weak inhibitors|
03903|035|M|of CYP2D6 and CYP3A4 should be avoided.|
03903|036|M|   In CYP2D6 extensive metabolizers with mild (Child-Pugh Class A) hepatic|
03903|037|M|impairment, the dosage of eliglustat with weak inhibitors of CYP2D6 or|
03903|038|M|CYP3A4 should be limited to 84 mg daily.|
03903|039|M|   In CYP2D6 intermediate metabolizers and CYP2D6 extensive metabolizers|
03903|040|M|without hepatic impairment, no dose adjustment of eliglustat is necessary|
03903|041|M|when taken with a weak CYP2D6 inhibitor or a weak CYP3A4 inhibitor.(1)|
03903|042|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03903|043|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03903|044|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03903|045|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03903|046|B||
03903|047|D|DISCUSSION:  There is no data on the interaction between eliglustat and dual|
03903|048|D|weak inhibitors of CYP2D6 and CYP3A4.|
03903|049|D|   Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased|
03903|050|D|eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve|
03903|051|D|(AUC) by  7-fold and 8.4-fold, respectively, in extensive metabolizers.|
03903|052|D|Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine|
03903|053|D|would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold,|
03903|054|D|respectively, in intermediate metabolizers.  PKPB models suggested|
03903|055|D|ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily)  by|
03903|056|D|4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1)|
03903|057|D|   PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would|
03903|058|D|increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in|
03903|059|D|extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in|
03903|060|D|intermediate metabolizers.|
03903|061|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a|
03903|062|D|strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax|
03903|063|D|and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers.|
03903|064|D|In intermediate metabolizers, eliglustat Cmax and AUC would be expected to|
03903|065|D|increase 7.5-fold and 9.8-fold, respectively.(1)|
03903|066|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine|
03903|067|D|(a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat|
03903|068|D|Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive|
03903|069|D|metabolizers.  In intermediate metabolizers, eliglustat Cmax and AUC would|
03903|070|D|be expected to increase 4.2-fold and 5-fold, respectively.(1)|
03903|071|D|   A single dose of rolapitant increased dextromethorphan, a CYP2D6|
03903|072|D|substrate, about 3-fold on days 8 and day 22 following administration.|
03903|073|D|Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single|
03903|074|D|dose rolapitant.  The inhibitory effects of rolapitant on CYP2D6 are|
03903|075|D|expected to persist beyond 28 days.(5)|
03903|076|D|   Weak dual inhibitors of CYP2D6 and CYP3A4 include: amiodarone and|
03903|077|D|ranitidine.(3,4)|
03903|078|B||
03903|079|R|REFERENCES:|
03903|080|B||
03903|081|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
03903|082|R|  August, 2018.|1
03903|083|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03903|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03903|085|R|  settings: a scientific statement from the American Heart Association and|6
03903|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03903|087|R|  2;55(9):934-47.|6
03903|088|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03903|089|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03903|090|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03903|091|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03903|092|R|  11/14/2017.|1
03903|093|R|4.This information is based on an extract from the Certara Drug Interaction|6
03903|094|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03904|001|T|MONOGRAPH TITLE:  Atogepant/Encorafenib; Rifampin|
03904|002|B||
03904|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03904|004|L|of severe adverse interaction.|
03904|005|B||
03904|006|A|MECHANISM OF ACTION:  Atogepant is a substrate of CYP3A4 and OATP1B1/1B3.(1)|
03904|007|A|Encorafenib and rifampin are inhibitors of the OATP transporters may|
03904|008|A|decrease the hepatic uptake of atogepant.  Encorafenib and rifampin are also|
03904|009|A|strong CYP3A4 inducers and may increase the metabolism of atogepant.(2,3)|
03904|010|B||
03904|011|E|CLINICAL EFFECTS:  The exact course of this interaction is unknown.  When|
03904|012|E|encorafenib or rifampin is first started and before CYP enzyme induction|
03904|013|E|occurs, atogepant levels may increase and result in side effects from|
03904|014|E|atogepant, including nausea, constipation and fatigue.  After CYP3A4 enzymes|
03904|015|E|are induced, atogepant levels and effectiveness may decrease.(1)|
03904|016|B||
03904|017|P|PREDISPOSING FACTORS:  None determined.|
03904|018|B||
03904|019|M|PATIENT MANAGEMENT:  When used concurrently with an OATP inhibitor, the|
03904|020|M|recommended atogepant dose for episodic migraine is 10 mg or 30 mg once|
03904|021|M|daily, and the recommended atogepant dose for chronic migraine is 30 mg once|
03904|022|M|daily.|
03904|023|M|   When used concurrently with a strong CYP3A4 inducer, the recommended|
03904|024|M|atogepant dose for episodic migraine is 30 mg or 60 mg daily.  When|
03904|025|M|atogepant is used for chronic migraine, concurrent CYP3A4 inducers should be|
03904|026|M|avoided.(1)|
03904|027|M|   Atogepant dose may need to be adjusted in the first weeks of concurrent|
03904|028|M|therapy with encorafenib or rifampin.  Monitor the patient for side effects|
03904|029|M|and efficacy.|
03904|030|B||
03904|031|D|DISCUSSION:  In a clinical trial of healthy subjects, single-dose rifampin|
03904|032|D|increased the atogepant area-under-curve (AUC) and maximum concentration|
03904|033|D|(Cmax) by 2.85-fold and 2.23-fold, respectively.(1)|
03904|034|D|   In a study of healthy subjects, steady state rifampin decreased the AUC|
03904|035|D|and Cmax of atogepant by 60% and 30%, respectively.(1)|
03904|036|B||
03904|037|R|REFERENCES:|
03904|038|B||
03904|039|R|1.Qulipta (atogepant) US prescribing information. Abbvie September, 2025.|1
03904|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
03904|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03904|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03904|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03904|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03904|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03904|046|R|  11/14/2017.|1
03905|001|T|MONOGRAPH TITLE:  Ribociclib/Strong CYP3A4 Inhibitors that Prolong QT|
03905|002|B||
03905|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03905|004|L|of severe adverse interaction.|
03905|005|B||
03905|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03905|007|A|interval may inhibit the metabolism of ribociclib and result in additive|
03905|008|A|risk of QT prolongation.(1)|
03905|009|B||
03905|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03905|011|E|systemic exposure and the risk for ribociclib toxicities such as neutropenia|
03905|012|E|or QT prolongation.  QT prolongation may result in potentially|
03905|013|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
03905|014|B||
03905|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03905|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03905|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03905|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03905|019|P|gender, or advanced age.(2)|
03905|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03905|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03905|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03905|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03905|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03905|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03905|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03905|027|B||
03905|028|M|PATIENT MANAGEMENT:  Avoid concomitant use of ribociclib and strong CYP3A|
03905|029|M|inhibitors that prolong the QTc interval.  Consider an alternative|
03905|030|M|concomitant medication with less potential for CYP3A4 inhibition.|
03905|031|M|   The US manufacturer states the following dose modifications are needed if|
03905|032|M|use of a strong CYP3A4 inhibitor cannot be avoided:|
03905|033|M|   -For patients with early breast cancer, decrease ribociclib to 200 mg|
03905|034|M|once daily.|
03905|035|M|   -For patients with advanced or metastatic breast cancer, decrease|
03905|036|M|ribociclib to 400 mg once daily.|
03905|037|M|   -If the strong CYP3A4 inhibitor is discontinued, change the ribociclib|
03905|038|M|dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the|
03905|039|M|dose used prior to the initiation of the strong CYP3A4 inhibitor.(1)|
03905|040|M|   The Swedish manufacturer states that if patients must be given a strong|
03905|041|M|CYP3A4 inhibitor concurrently with ribociclib, the ribociclib dose should be|
03905|042|M|reduced to 400 mg once daily.  In patients who have had their ribociclib|
03905|043|M|dose reduced to 400 mg daily and in whom coadministration of a strong CYP3A4|
03905|044|M|inhibitor cannot be avoided, the ribociclib dose should be further reduced|
03905|045|M|to 200 mg.  In patients who have had their ribociclib dose reduced to 200 mg|
03905|046|M|daily and in whom coadministration of a strong CYP3A4 inhibitor cannot be|
03905|047|M|avoided, ribociclib treatment should be interrupted.(4)|
03905|048|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
03905|049|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
03905|050|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
03905|051|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
03905|052|M|irregular heartbeat, dizziness, or fainting.|
03905|053|B||
03905|054|D|DISCUSSION:  Ribociclib has been shown to prolong the QTc interval in a|
03905|055|D|concentration-dependent manner.  At steady state, the mean increase in QTc|
03905|056|D|interval exceeded 20 msec.(1)|
03905|057|D|   In a drug interaction study in healthy subjects, coadministration of|
03905|058|D|ritonavir (100 mg twice a day for 14 days) with a single dose of ribociclib|
03905|059|D|(400 mg) increased ribociclib maximum concentration (Cmax) and|
03905|060|D|area-under-the-curve (AUC) by 1.7 and 3.2-fold, respectively. Cmax and AUC|
03905|061|D|for LEQ803 (ribociclib metabolite) decreased by 96% and 98%,|
03905|062|D|respectively.(1)|
03905|063|D|   Data from a pharmacokinetic simulation suggests that erythromycin, a|
03905|064|D|moderate CYP3A4 inhibitor, may increase ribociclib (600 mg)Cmax and AUC by|
03905|065|D|1.2-fold and 1.3-fold. The increase of ribociclib's Cmax and AUC was|
03905|066|D|estimated to be 1.4-fold and 2.1-fold in patients on ribociclib 400 mg. The|
03905|067|D|increase of ribociclib's Cmax and AUC was estimated to be 1.7-fold and|
03905|068|D|2.8-fold in patients on ribociclib 200 mg.(4)|
03905|069|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
03905|070|D|clarithromycin, lopinavir, posaconazole, saquinavir, telithromycin, and|
03905|071|D|voriconazole.(3)|
03905|072|B||
03905|073|R|REFERENCES:|
03905|074|B||
03905|075|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
03905|076|R|  Corporation September, 2024.|1
03905|077|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03905|078|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03905|079|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03905|080|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03905|081|R|  11/14/2017.|1
03905|082|R|3.This information is based on an extract from the Certara Drug Interaction|6
03905|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03905|084|R|4.Kisqali (ribociclib) Sweden prescribing information. Novartis Pharma|1
03905|085|R|  August 2017.|1
03906|001|T|MONOGRAPH TITLE:  Avacopan/Strong CYP3A4 Inhibitors|
03906|002|B||
03906|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03906|004|L|of severe adverse interaction.|
03906|005|B||
03906|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
03906|007|A|the metabolism of avacopan.(1)|
03906|008|B||
03906|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03906|010|E|levels of and effects from avacopan, including serious infections, elevated|
03906|011|E|liver enzymes, or hepatotoxicity.(1)|
03906|012|B||
03906|013|P|PREDISPOSING FACTORS:  None determined.|
03906|014|B||
03906|015|M|PATIENT MANAGEMENT:  Reduce the dose of avacopan to 30 mg once daily when|
03906|016|M|coadministered with strong CYP3A4 inhibitors.(1)|
03906|017|M|   Australian and UK manufacturers of avacopan state coadministration with|
03906|018|M|strong CYP3A4 inhibitors should be used with caution.  Patients must be|
03906|019|M|monitored for potential increase of side effects due to the increased|
03906|020|M|exposure of avacopan.(2,3)|
03906|021|M|   Monitor liver tests, including AST, ALT, alkaline phosphatase, and total|
03906|022|M|bilirubin.  Advise patients to report any symptoms of hepatotoxicity.|
03906|023|B||
03906|024|D|DISCUSSION:  In a study, administration of itraconazole 200 mg once daily|
03906|025|D|for 4 days increased the maximum concentration (Cmax) and area-under-curve|
03906|026|D|(AUC) of avacopan by 1.87-fold and 2.19-fold.(1)|
03906|027|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03906|028|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03906|029|D|ketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
03906|030|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir,|
03906|031|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or|
03906|032|D|voriconazole.(4,5)|
03906|033|B||
03906|034|R|REFERENCES:|
03906|035|B||
03906|036|R|1.Tavneos (avacopan) US prescribing information. ChemoCentryx, Inc. June,|1
03906|037|R|  2024.|1
03906|038|R|2.Tavneos (avacopan) Australian prescribing information. Seqirus Pty Ltd Aug|1
03906|039|R|  13, 2024.|1
03906|040|R|3.Avacopan Vifor UK Summary of Product Characteristics. Vifor Fresenius|1
03906|041|R|  Medical Care Renal Pharma UK Ltd 12 May 2025.|1
03906|042|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03906|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03906|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03906|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03906|046|R|  11/14/2017.|1
03906|047|R|5.This information is based on an extract from the Certara Drug Interaction|6
03906|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03907|001|T|MONOGRAPH TITLE:  Avacopan/Strong or Moderate CYP3A4 Inducers|
03907|002|B||
03907|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03907|004|L|of severe adverse interaction.|
03907|005|B||
03907|006|A|MECHANISM OF ACTION:  Avacopan is a substrate of CYP3A4.  Strong or moderate|
03907|007|A|inducers of CYP3A4 may induce the metabolism of avacopan.(1)|
03907|008|B||
03907|009|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
03907|010|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
03907|011|E|avacopan.(1)|
03907|012|B||
03907|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03907|014|P|of the inducer for longer than 1-2 weeks.|
03907|015|B||
03907|016|M|PATIENT MANAGEMENT:  The manufacturer of avacopan states that concurrent use|
03907|017|M|with strong or moderate CYP3A4 inducers should be avoided.(1)|
03907|018|M|   The Australian  manufacturer of avacopan states that patients anticipated|
03907|019|M|to require long-term administration of a CYP3A4 inducer should not be|
03907|020|M|treated with avacopan. If short term co-administration cannot be avoided in|
03907|021|M|a patient already on avacopan, closely monitor for reoccurrence of disease|
03907|022|M|activity.(4)|
03907|023|B||
03907|024|D|DISCUSSION:  Co-administration of rifampin 600 mg once daily for 11 days, a|
03907|025|D|strong CYP3A4 inducer, decreased the avacopan concentration maximum (Cmax)|
03907|026|D|by 79% and area-under-curve (AUC) by 93%.(1)|
03907|027|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03907|028|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
03907|029|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
03907|030|D|wort.|
03907|031|D|   Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dabrafenib,|
03907|032|D|efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil,|
03907|033|D|nafcillin, rifabutin, sotorasib, telotristat ethyl, thioridazine and|
03907|034|D|tovorafenib.(2-3)|
03907|035|B||
03907|036|R|REFERENCES:|
03907|037|B||
03907|038|R|1.Tavneos (avacopan) US prescribing information. ChemoCentryx, Inc. June,|1
03907|039|R|  2024.|1
03907|040|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03907|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03907|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03907|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03907|044|R|  11/14/2017.|1
03907|045|R|3.This information is based on an extract from the Certara Drug Interaction|6
03907|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03907|047|R|4.Tavneos (avacopan) Australian prescribing information. Seqirus Pty Ltd Aug|1
03907|048|R|  13, 2024.|1
03908|001|T|MONOGRAPH TITLE:  Surufatinib/Strong CYP3A4 Inhibitors|
03908|002|B||
03908|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03908|004|L|of severe adverse interaction.|
03908|005|B||
03908|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03908|007|A|of surufatinib.(1)|
03908|008|B||
03908|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
03908|010|E|elevated levels of and toxicity from surufatinib, including increased risk|
03908|011|E|of bleeding, hepatotoxicity, hypertension, and proteinuria.(1)|
03908|012|B||
03908|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03908|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03908|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
03908|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03908|017|P|risk for bleeding (e.g. NSAIDs).|
03908|018|B||
03908|019|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03908|020|M|undergoing therapy with surufatinib.  Consider alternatives with minimal or|
03908|021|M|little enzyme inhibition.  If concurrent use is necessary, closely monitor|
03908|022|M|for adverse effects.(1)|
03908|023|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
03908|024|M|loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
03908|025|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03908|026|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03908|027|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03908|028|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03908|029|M|and/or swelling.|
03908|030|B||
03908|031|D|DISCUSSION:  In vitro data shows that surufatinib is metabolized by CYP3A4.|
03908|032|D|The manufacturer of surufatinib states that concomitant use with strong|
03908|033|D|CYP3A4 inhibitors should be avoided.(1)|
03908|034|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03908|035|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03908|036|D|ketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir,|
03908|037|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir,|
03908|038|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
03908|039|D|voriconazole.(2-4)|
03908|040|B||
03908|041|R|REFERENCES:|
03908|042|B||
03908|043|R|1.Sulanda (surufatinib) Hong Kong prescribing information. Hutchison Whampoa|1
03908|044|R|  Pharmaceuticals (Suzhou) Co., Ltd June 28, 2021.|1
03908|045|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03908|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03908|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03908|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03908|049|R|  11/14/2017.|1
03908|050|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03908|051|R|  Indiana University School of Medicine.  Available at:|1
03908|052|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03908|053|R|4.This information is based on an extract from the Certara Drug Interaction|6
03908|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03909|001|T|MONOGRAPH TITLE:  Surufatinib/Strong CYP3A4 Inducers|
03909|002|B||
03909|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03909|004|L|of severe adverse interaction.|
03909|005|B||
03909|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may accelerate the|
03909|007|A|metabolism of surufatinib.(1)|
03909|008|B||
03909|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03909|010|E|may result in decreased levels and effectiveness of surufatinib.(1)|
03909|011|B||
03909|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03909|013|P|of the inducer for longer than 1-2 weeks.|
03909|014|B||
03909|015|M|PATIENT MANAGEMENT:  The manufacturer of surufatinib states that concurrent|
03909|016|M|use with strong CYP3A4 inducers should be avoided.  If concurrent use is|
03909|017|M|necessary, closely monitor for treatment response.(1)|
03909|018|B||
03909|019|D|DISCUSSION:  In vitro data shows that surufatinib is metabolized by CYP3A4.|
03909|020|D|The manufacturer of surufatinib recommends avoiding concurrent use with|
03909|021|D|strong CYP3A4 inducers.(1)|
03909|022|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03909|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03909|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03909|025|D|rifapentine, and St. John's wort.(2-3)|
03909|026|B||
03909|027|R|REFERENCES:|
03909|028|B||
03909|029|R|1.Sulanda (surufatinib) Hong Kong prescribing information. Hutchison Whampoa|1
03909|030|R|  Pharmaceuticals (Suzhou) Co., Ltd June 28, 2021.|1
03909|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03909|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03909|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03909|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03909|035|R|  11/14/2017.|1
03909|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
03909|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03910|001|T|MONOGRAPH TITLE:  Surufatinib/Mifepristone|
03910|002|B||
03910|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03910|004|L|of severe adverse interaction.|
03910|005|B||
03910|006|A|MECHANISM OF ACTION:  Mifepristone may inhibit the metabolism of|
03910|007|A|surufatinib.  Concurrent use of mifepristone and surufatinib may result in|
03910|008|A|an additive risk of bleeding.(1)|
03910|009|B||
03910|010|E|CLINICAL EFFECTS:  Concurrent use of mifepristone may result in elevated|
03910|011|E|levels of and toxicity from surufatinib, including an increased risk of|
03910|012|E|bleeding, hepatotoxicity, hypertension, and proteinuria.(1)|
03910|013|B||
03910|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03910|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03910|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
03910|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03910|018|P|risk for bleeding (e.g. NSAIDs).|
03910|019|B||
03910|020|M|PATIENT MANAGEMENT:  Avoid the use of mifepristone, a strong CYP3A4|
03910|021|M|inhibitor, in patients undergoing therapy with surufatinib.  Consider|
03910|022|M|alternatives with minimal of little enzyme inhibition.  If concurrent use is|
03910|023|M|necessary, closely monitor for adverse effects.(1)|
03910|024|M|   If concurrent therapy is deemed medically necessary, monitor patients|
03910|025|M|receiving concurrent therapy for signs of blood loss, including decreased|
03910|026|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
03910|027|M|and promptly evaluate patients with any symptoms.|
03910|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03910|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03910|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03910|031|M|and/or swelling.|
03910|032|B||
03910|033|D|DISCUSSION:  In vitro data shows that surufatinib is metabolized by CYP3A4.|
03910|034|D|The manufacturer of surufatinib states that concomitant use with strong|
03910|035|D|CYP3A4 inhibitors should be avoided.(1)|
03910|036|B||
03910|037|R|REFERENCES:|
03910|038|B||
03910|039|R|1.Sulanda (surufatinib) Hong Kong prescribing information. Hutchison Whampoa|1
03910|040|R|  Pharmaceuticals (Suzhou) Co., Ltd June 28, 2021.|1
03910|041|R|2.Mifeprex (mifepristone) US prescribing information. Danco Laboratories,|1
03910|042|R|  LLC January, 2023.|1
03910|043|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03910|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03910|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03910|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03910|047|R|  11/14/2017.|1
03910|048|R|4.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03910|049|R|  Indiana University School of Medicine.  Available at:|1
03910|050|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03910|051|R|5.This information is based on an extract from the Certara Drug Interaction|6
03910|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03911|001|T|MONOGRAPH TITLE:  Avacopan/Lonafarnib (mono deleted 05/28/2024)|
03911|002|B||
03911|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03911|004|L|of severe adverse interaction.|
03911|005|B||
03911|006|A|MECHANISM OF ACTION:  Avacopan and lonafarnib are both substrates of CYP3A4.|
03911|007|A|Lonafarnib is a strong CYP3A4 inhibitor and may inhibit the metabolism of|
03911|008|A|avacopan.  Avacopan is a weak CYP3A4 inhibitor and may inhibit the|
03911|009|A|metabolism of lonafarnib.(1,2)|
03911|010|B||
03911|011|E|CLINICAL EFFECTS:  Concurrent use of avacopan and lonafarnib may increase|
03911|012|E|the risk of adverse reactions of both agents, including nausea and vomiting,|
03911|013|E|hepatotoxicity, myelosuppression, and hypertension.(1,2)|
03911|014|B||
03911|015|P|PREDISPOSING FACTORS:  None determined.|
03911|016|B||
03911|017|M|PATIENT MANAGEMENT:  The manufacturer of avacopan states to reduce the dose|
03911|018|M|of avacopan to 30 mg once daily when coadministered with strong CYP3A4|
03911|019|M|inhibitors.(1)|
03911|020|M|   Monitor liver tests, including AST, ALT, alkaline phosphatase, and total|
03911|021|M|bilirubin.  Advise patients to report any symptoms of hepatotoxicity.|
03911|022|M|   The manufacturer of lonafarnib states to avoid coadministration of|
03911|023|M|lonafarnib and weak CYP3A4 inhibitors.  If coadministration is unavoidable,|
03911|024|M|reduce the dose of lonafarnib to or continue at 115 mg/m2.(2)|
03911|025|M|   Closely monitor patients for arrhythmias and events such as syncope and|
03911|026|M|heart palpitations because lonafarnib exposures may be increased despite the|
03911|027|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
03911|028|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
03911|029|M|inhibitor.(2)|
03911|030|B||
03911|031|D|DISCUSSION:  In a study, administration of itraconazole 200 mg once daily|
03911|032|D|for 4 days increased the maximum concentration (Cmax) and area-under-curve|
03911|033|D|(AUC) of avacopan by 1.87-fold and 2.19-fold.(1)|
03911|034|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
03911|035|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
03911|036|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
03911|037|B||
03911|038|R|REFERENCES:|
03911|039|B||
03911|040|R|1.Tavneos (avacopan) US prescribing information. ChemoCentryx, Inc. June,|1
03911|041|R|  2024.|1
03911|042|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03911|043|R|  Inc. November, 2020.|1
03911|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
03911|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03912|001|T|MONOGRAPH TITLE:  Selected CYP2C9 Substrates/Asciminib|
03912|002|B||
03912|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03912|004|L|of severe adverse interaction.|
03912|005|B||
03912|006|A|MECHANISM OF ACTION:  Asciminib is a moderate inhibitor of CYP2C9.(1)|
03912|007|A|Asciminib may decrease the metabolism of drugs that are CYP2C9 substrates.|
03912|008|B||
03912|009|E|CLINICAL EFFECTS:  Decreased clearance may increase systemic concentrations|
03912|010|E|of drugs primarily metabolized by CYP2C9, leading to toxicity.(1)|
03912|011|B||
03912|012|P|PREDISPOSING FACTORS:  None determined.|
03912|013|B||
03912|014|M|PATIENT MANAGEMENT:  The manufacturer of asciminib states coadministration|
03912|015|M|of the CYP2C9 substrate drug with asciminib should be avoided.  Consider an|
03912|016|M|alternative agent that does not depend on CYP2C9 for metabolism.  If a|
03912|017|M|patient is taking asciminib 80 mg total daily dose and coadministration of|
03912|018|M|the CYP2C9 substrate is unavoidable, reduce the dosage of the CYP2C9|
03912|019|M|substrate according to its product labeling.(1)|
03912|020|M|   Closely monitor patients stable on CYP2C9 substrates for altered|
03912|021|M|therapeutic effect or toxicity when asciminib therapy is started, adjusted,|
03912|022|M|or stopped.(1)|
03912|023|B||
03912|024|D|DISCUSSION:  In clinical studies, coadministration of asciminib 40 mg twice|
03912|025|D|daily, 80 mg once daily, and 200 mg twice daily, the area-under-the-curve|
03912|026|D|(AUC) of S-warfarin increased by 41%, 52%, and 314%, respectively.|
03912|027|D|Additionally, the maximum concentration (Cmax) of S-warfarin increased by|
03912|028|D|8%, 4%, and 7%, respectively.(1)|
03912|029|D|   Medications linked to this interaction include fluvastatin, fosphenytoin,|
03912|030|D|glimepiride, glipizide, phenytoin, and tolbutamide.  These drugs have a|
03912|031|D|narrow therapeutic range or are designated as CYP2C9 Sensitive Substrates|
03912|032|D|(i.e. moderate 2C9 inhibitors are expected to increase exposure (AUC) to|
03912|033|D|these agents by 2-fold to 5-fold).(2,3)|
03912|034|B||
03912|035|R|REFERENCES:|
03912|036|B||
03912|037|R|1.Scemblix (asciminib) US prescribing information. Novartis Pharmaceuticals|1
03912|038|R|  Corporation October, 2025.|1
03912|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
03912|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03912|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03912|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03912|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03912|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03912|045|R|  11/14/2017.|1
03913|001|T|MONOGRAPH TITLE:  Warfarin/Asciminib|
03913|002|B||
03913|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03913|004|L|take action as needed.|
03913|005|B||
03913|006|A|MECHANISM OF ACTION:  Asciminib in a moderate CYP2C9 inhibitor(1) which may|
03913|007|A|decrease the metabolism of the S-enantiomer of warfarin.  Also, asciminib|
03913|008|A|and warfarin therapy may both increase the risk of bleeding.(1,2)|
03913|009|B||
03913|010|E|CLINICAL EFFECTS:  Concurrent use of asciminib may result in elevated levels|
03913|011|E|of warfarin and increased INR.(1)|
03913|012|E|   Concurrent use of warfarin and asciminib may increase the risk for|
03913|013|E|bleeding.|
03913|014|B||
03913|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03913|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03913|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
03913|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03913|019|P|risk for bleeding (e.g. NSAIDs).|
03913|020|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
03913|021|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
03913|022|P|are expected to be more susceptible to this interaction.|
03913|023|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
03913|024|P|are expected to be less susceptible to effects from this drug combination,|
03913|025|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
03913|026|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
03913|027|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
03913|028|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
03913|029|P|and safe anticoagulation than patients without these CYP2C9 variants.|
03913|030|B||
03913|031|M|PATIENT MANAGEMENT:  Monitor INRs more frequently until stable in patients|
03913|032|M|who start asciminib therapy, or have the asciminib dose adjusted.(1)|
03913|033|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03913|034|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
03913|035|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
03913|036|M|evaluate patients with any symptoms.|
03913|037|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03913|038|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03913|039|M|anticoagulation in patients with active pathologic bleeding.|
03913|040|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03913|041|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03913|042|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03913|043|M|and/or swelling.|
03913|044|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03913|045|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
03913|046|M|initiating, altering the dose or discontinuing either drug.|
03913|047|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
03913|048|B||
03913|049|D|DISCUSSION:  In clinical studies, coadministration of asciminib 40 mg twice|
03913|050|D|daily, 80 mg once daily, and 200 mg twice daily, the area-under-the-curve|
03913|051|D|(AUC) of S-warfarin increased by 41%, 52%, and 314%, respectively.|
03913|052|D|Additionally, the maximum concentration (Cmax) of S-warfarin increased by|
03913|053|D|8%, 4%, and 7%, respectively.(1)|
03913|054|B||
03913|055|R|REFERENCES:|
03913|056|B||
03913|057|R|1.Scemblix (asciminib) US prescribing information. Novartis Pharmaceuticals|1
03913|058|R|  Corporation October, 2025.|1
03913|059|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
03913|060|R|  Squibb Company September, 2016.|1
03913|061|R|3.This information is based on an extract from the Certara Drug Interaction|6
03913|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03913|063|R|4.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
03913|064|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
03913|065|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
03913|066|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
03913|067|R|  Oct;90(4):625-9.|6
03914|001|T|MONOGRAPH TITLE:  Asciminib/Hydroxypropyl betadex (Itraconazole Solution)|
03914|002|B||
03914|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03914|004|L|of severe adverse interaction.|
03914|005|B||
03914|006|A|MECHANISM OF ACTION:  Concurrent use of hydroxypropyl-beta-cyclodextrin,(1)|
03914|007|A|a solubilizer in itraconazole oral solution,(2) may bind to asciminib and|
03914|008|A|decrease its absorption.(1)  Hydroxypropyl-beta-cyclodextrin is also known|
03914|009|A|as hydroxypropyl betadex.|
03914|010|B||
03914|011|E|CLINICAL EFFECTS:  Concurrent use of asciminib and|
03914|012|E|hydroxypropyl-beta-cyclodextrin may result in decreased levels and|
03914|013|E|effectiveness of asciminib.(1)|
03914|014|B||
03914|015|P|PREDISPOSING FACTORS:  None determined.|
03914|016|B||
03914|017|M|PATIENT MANAGEMENT:  The manufacturer of asciminib states to avoid|
03914|018|M|concurrent use of asciminib at all recommended doses with itraconazole oral|
03914|019|M|solution containing hydroxypropyl-beta-cyclodextrin.(1)|
03914|020|M|   Consider alternative formulations of itraconazole or a different azole|
03914|021|M|antifungal that is not formulated with hydroxypropyl-beta-cyclodextrin.|
03914|022|B||
03914|023|D|DISCUSSION:  Concurrent use of multiple doses of itraconazole oral solution|
03914|024|D|containing hydroxypropyl-beta-cyclodextrin with a single asciminib dose of|
03914|025|D|40 mg decreased asciminib area-under-curve (AUC) and concentration maximum|
03914|026|D|(Cmax) by 40% and 50%, respectively.(1)|
03914|027|D|   Itraconazole 10 mg/mL solution contains 400 mg/mL of|
03914|028|D|hydroxypropyl-beta-cyclodextrin.(2)|
03914|029|D|   Concurrent use of other oral products containing|
03914|030|D|hydroxypropyl-beta-cyclodextrin with asciminib have not been fully|
03914|031|D|characterized.(1)|
03914|032|B||
03914|033|R|REFERENCES:|
03914|034|B||
03914|035|R|1.Scemblix (asciminib) US prescribing information. Novartis Pharmaceuticals|1
03914|036|R|  Corporation October, 2025.|1
03914|037|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
03914|038|R|  Products, L.P. February, 2024.|1
03915|001|T|MONOGRAPH TITLE:  Encorafenib/Strong & Moderate 3A4 Inhib that Prolong QT|
03915|002|B||
03915|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03915|004|L|of severe adverse interaction.|
03915|005|B||
03915|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 that prolong|
03915|007|A|the QTc interval may inhibit the metabolism of encorafenib and cause|
03915|008|A|additive risk of QT prolongation.(1)|
03915|009|B||
03915|010|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inhibitor of|
03915|011|E|CYP3A4 may result in elevated levels of and toxicity from encorafenib,|
03915|012|E|including QT prolongation.(1)|
03915|013|B||
03915|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03915|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03915|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03915|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03915|018|P|female gender, or advanced age.(2)|
03915|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03915|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03915|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03915|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03915|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03915|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
03915|025|P|dysfunction).(2)|
03915|026|B||
03915|027|M|PATIENT MANAGEMENT:  Concurrent use of strong or moderate CYP3A4 inhibitors|
03915|028|M|that prolong the QTc interval with encorafenib should be avoided.  If|
03915|029|M|concurrent use of strong or moderate CYP3A4 inhibitors with encorafenib is|
03915|030|M|unavoidable, reduce the encorafenib dose as follows:|
03915|031|M|   - If the current daily dose of encorafenib is 450 mg, reduce encorafenib|
03915|032|M|to 150 mg with strong CYP3A4 inhibitors, and 225 mg with moderate CYP3A4|
03915|033|M|inhibitors.|
03915|034|M|   - If the current daily dose of encorafenib is 300 mg, reduce encorafenib|
03915|035|M|to 75 mg with strong CYP3A4 inhibitors, and 150 mg with moderate CYP3A4|
03915|036|M|inhibitors.|
03915|037|M|   - If the current daily dose of encorafenib is 225 mg or 150 mg, reduce|
03915|038|M|encorafenib to 75 mg with both strong and moderate CYP3A4 inhibitors.|
03915|039|M|   - After the inhibitor has been discontinued for 3 to 5 half-lives, resume|
03915|040|M|encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor.(1)|
03915|041|M|   When concurrent therapy cannot be avoided, monitor patients closely for|
03915|042|M|prolongation of the QT interval.  Obtain ECGs and electrolyte values (serum|
03915|043|M|calcium, magnesium, and potassium) at regular intervals.  Correct any|
03915|044|M|electrolyte abnormalities.|
03915|045|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03915|046|M|fainting.|
03915|047|M|   Recommended dosage modifications for encorafenib and QTc prolongation|
03915|048|M|adverse reactions include:|
03915|049|M|   - QTcF greater than 500 ms and less than or equal to 60 ms increase from|
03915|050|M|baseline: Withhold encorafenib until QTcF less than or equal to 500 ms.|
03915|051|M|Resume at reduced dose.  If more than one recurrence, permanently|
03915|052|M|discontinue encorafenib.|
03915|053|M|   - QTcF greater than 500 ms and greater than 60 ms increase from baseline:|
03915|054|M|Permanently discontinue encorafenib.(1)|
03915|055|M|   See prescribing information for additional information regarding dose|
03915|056|M|reductions.(1)|
03915|057|B||
03915|058|D|DISCUSSION:  Encorafenib has been associated with a dose-dependent QTc|
03915|059|D|interval prolongation.  Following administration of encorafenib in|
03915|060|D|combination with binimetinib, the largest mean (90% CI) QTcF change from|
03915|061|D|baseline was 18 ms (14-22 ms), based on central tendency analysis.(1)|
03915|062|D|   Coadministration of posaconazole (strong CYP3A4 inhibitor) or diltiazem|
03915|063|D|(moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) of|
03915|064|D|encorafenib by 3-fold and 2-fold, respectively, and increased the maximum|
03915|065|D|concentration (Cmax) by 68% and 45%, respectively, after a single dose of|
03915|066|D|encorafenib 50 mg (0.1 times the recommended dose).(1)|
03915|067|D|   Encorafenib has been associated with a dose-dependent QTc interval|
03915|068|D|prolongation.  Following administration of encorafenib in combination with|
03915|069|D|binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms|
03915|070|D|(14-22 ms), based on central tendency analysis.(1)|
03915|071|D|   Following administration of encorafenib in combination with cetuximab and|
03915|072|D|mFOLFOX6, an increase of QTcF >500 ms was measured in 3.6% (8/222) of|
03915|073|D|patients.(1)|
03915|074|D|   Strong inhibitors of CYP3A4 include: lopinavir/ritonavir, posaconazole,|
03915|075|D|saquinavir, and telithromycin.(4-6)|
03915|076|D|   Moderate inhibitors of CYP3A4 include: clofazimine and fluconazole.(4-6)|
03915|077|B||
03915|078|R|REFERENCES:|
03915|079|B||
03915|080|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
03915|081|R|  BioPharma December, 2024.|1
03915|082|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03915|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03915|084|R|  settings: a scientific statement from the American Heart Association and|6
03915|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03915|086|R|  2;55(9):934-47.|6
03915|087|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03915|088|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03915|089|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03915|090|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03915|091|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03915|092|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03915|093|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03915|094|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03915|095|R|  11/14/2017.|1
03915|096|R|5.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03915|097|R|  Indiana University School of Medicine.  Available at:|1
03915|098|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03915|099|R|6.This information is based on an extract from the Certara Drug Interaction|6
03915|100|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03916|001|T|MONOGRAPH TITLE:  Trazodone/Select CYP3A4 Inhibitors that Prolong QT|
03916|002|B||
03916|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03916|004|L|of severe adverse interaction.|
03916|005|B||
03916|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
03916|007|A|trazodone.(1-7)  Trazodone has been shown to prolong the QT interval.  Other|
03916|008|A|agents that prolong the QT interval may have an additive effect.|
03916|009|A|   Trazodone's active metabolite meta-chlorophenylpiperazine (m-CPP) is|
03916|010|A|metabolized by CYP2D6. Telithromycin and lopinavir-ritonavir are also weak|
03916|011|A|CYP2D6 inhibitors.(1)|
03916|012|B||
03916|013|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
03916|014|E|elevated levels of and adverse effects from trazodone, including nausea,|
03916|015|E|dizziness, hypotension, syncope, serotonin syndrome, and cardiac arrhythmias|
03916|016|E|including QT prolongation or torsades de pointes, which may be|
03916|017|E|life-threatening.(1)|
03916|018|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03916|019|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03916|020|E|rigidity.|
03916|021|B||
03916|022|P|PREDISPOSING FACTORS:  This interaction may be more severe with larger|
03916|023|P|and/or routine doses of trazodone.|
03916|024|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03916|025|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03916|026|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03916|027|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03916|028|P|advanced age.(8)|
03916|029|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03916|030|P|higher systemic concentrations of either QT prolonging drug are additional|
03916|031|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03916|032|P|drug concentrations include rapid infusion of an intravenous dose or|
03916|033|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03916|034|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03916|035|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(8)|
03916|036|B||
03916|037|M|PATIENT MANAGEMENT:  The US manufacturer of trazodone states that concurrent|
03916|038|M|use with agents known to prolong the QT interval should be avoided.(1)  If|
03916|039|M|concurrent use is warranted, a lower dose of trazodone should be considered|
03916|040|M|in patients receiving CYP3A4 inhibitors.(1-7)|
03916|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03916|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03916|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03916|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03916|045|M|   In addition to QT prolongation, patients should be monitored for signs|
03916|046|M|and symptoms of serotonin syndrome.  Instruct patients to report muscle|
03916|047|M|twitching, tremors, shivering and stiffness, fever, heavy sweating, heart|
03916|048|M|palpitations, restlessness, confusion, agitation, trouble with coordination,|
03916|049|M|or severe diarrhea.|
03916|050|B||
03916|051|D|DISCUSSION:  In a cross-over study in 10 healthy subjects, pretreatment with|
03916|052|D|clarithromycin (500 mg, 4 doses given over 32 hours) increased the maximum|
03916|053|D|concentration, (Cmax) half-life, and area-under-curve (AUC) of a single dose|
03916|054|D|of trazodone (50 mg) by 35% (p<0.005), 96% (p<0.02), and 99% (p<0.001),|
03916|055|D|respectively.  Trazodone oral clearance decreased by 46% (p<0.001).|
03916|056|D|Pharmacodynamic effects of trazodone were also increased, as shown by|
03916|057|D|changes in self-rated sedation, observer-rated sedation, digit-symbol|
03916|058|D|substitution test (DSST) scores.(9)|
03916|059|D|   In a study in 10 healthy subjects, short-term ritonavir (four doses of|
03916|060|D|200 mg twice daily) increased the AUC and half-life of a single dose of|
03916|061|D|trazodone (50 mg) by 2.4-fold and 2.2-fold, respectively.  The Cmax of|
03916|062|D|trazodone increased 34% and its clearance decreased 52%.  Three subjects|
03916|063|D|experienced nausea, dizziness, or hypotension and one of these subjects also|
03916|064|D|experienced syncope during concurrent administration.(1-3)|
03916|065|D|   In a single case report, a female experienced serotonin syndrome|
03916|066|D|characterized by high blood pressure (240/120 mmHg); intermittent numbness|
03916|067|D|of the right side of her lips and nose and fingers of the right hand;|
03916|068|D|nausea; loose stools; flushed, pruritic skin; confusion; and difficulty|
03916|069|D|concentrating four days after the addition of trazodone (25-50 mg daily) to|
03916|070|D|nefazodone.(7)|
03916|071|D|   An in vitro study in human liver microsomes showed that indinavir,|
03916|072|D|ketoconazole, and ritonavir inhibited the metabolism of trazodone.(6)|
03916|073|D|   Strong and moderate CYP3A4 inhibitors linked to this monograph include:|
03916|074|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib,|
03916|075|D|lopinavir/ritonavir, posaconazole, ribociclib, telithromycin, and|
03916|076|D|voriconazole are considered to be potent inhibitors of the CYP3A4|
03916|077|D|isoenzyme.(10)  Fluconazole's inhibition of CYP3A4 is dose dependent.(11)|
03916|078|B||
03916|079|R|REFERENCES:|
03916|080|B||
03916|081|R|1.Oleptro (trazodone hydrochloride) US prescribing information. Angelini|1
03916|082|R|  Labopharm Inc. November, 2012.|1
03916|083|R|2.Greenblatt DJ, von Moltke LL, Harmatz JS, Fogelman SM, Chen G, Graf JA,|2
03916|084|R|  Mertzanis P, Byron S, Culm KE, Granda BW, Daily JP, Shader RI. Short-term|2
03916|085|R|  exposure to low-dose ritonavir impairs clearance and enhances adverse|2
03916|086|R|  effects of trazodone. J Clin Pharmacol 2003 Apr;43(4):414-22.|2
03916|087|R|3.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
03916|088|R|  December, 2019.|1
03916|089|R|4.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
03916|090|R|  Laboratories December, 2019.|1
03916|091|R|5.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
03916|092|R|  2024.|1
03916|093|R|6.Zalma A, von Moltke LL, Granda BW, Harmatz JS, Shader RI, Greenblatt DJ.|5
03916|094|R|  In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and|5
03916|095|R|  human immunodeficiency viral protease inhibitors. Biol Psychiatry 2000 Apr|5
03916|096|R|  1;47(7):655-61.|5
03916|097|R|7.Margolese HC, Chouinard G. Serotonin syndrome from addition of low-dose|3
03916|098|R|  trazodone to nefazodone. Am J Psychiatry 2000 Jun;157(6):1022.|3
03916|099|R|8.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03916|100|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03916|101|R|  settings: a scientific statement from the American Heart Association and|6
03916|102|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03916|103|R|  2;55(9):934-47.|6
03916|104|R|9.Farkas D, Volak LP, Harmatz JS, von Moltke LL, Court MH, Greenblatt DJ.|2
03916|105|R|  Short-term clarithromycin administration impairs clearance and enhances|2
03916|106|R|  pharmacodynamic effects of trazodone but not of zolpidem. Clin Pharmacol|2
03916|107|R|  Ther 2009 Jun;85(6):644-50.|2
03916|108|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
03916|109|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
03916|110|R|   at:|1
03916|111|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
03916|112|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03916|113|R|   11/14/2017.|1
03916|114|R|11.Kharasch ED, Walker A, Hoffer C, Sheffels P. Sensitivity of intravenous|5
03916|115|R|   and oral alfentanil and pupillary miosis as minimally  invasive and|5
03916|116|R|   noninvasive probes for hepatic and first-pass CYP3A activity. J Clin|5
03916|117|R|   Pharmacol 2005 Oct;45(10):1187-97.|5
03916|118|R|12.This information is based on an extract from the Certara Drug Interaction|6
03916|119|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03917|001|T|MONOGRAPH TITLE:  Roxadustat/Bile Acid Sequestrants; Sevelamer|
03917|002|B||
03917|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03917|004|L|take action as needed.|
03917|005|B||
03917|006|A|MECHANISM OF ACTION:  Bile acid sequestrants and sevelamer may decrease the|
03917|007|A|gastrointestinal absorption of roxadustat.(1)|
03917|008|B||
03917|009|E|CLINICAL EFFECTS:  Simultaneous administration of a bile acid sequestrant or|
03917|010|E|sevelamer may result in decreased absorption and effectiveness of|
03917|011|E|roxadustat.(1)|
03917|012|B||
03917|013|P|PREDISPOSING FACTORS:  None determined.|
03917|014|B||
03917|015|M|PATIENT MANAGEMENT:  For maximal bioavailability, the manufacturer of|
03917|016|M|roxadustat states roxadustat should be administered at least 1 hour before|
03917|017|M|or 1 hour after a bile acid sequestrant or sevelamer.(1)|
03917|018|M|    Although used for hyperphosphatemia, sevelamer is linked to this|
03917|019|M|monograph due to its structural and pharmacologic similarities to|
03917|020|M|colesevelam.  Both agents are non-absorbed cross linked polymers with a high|
03917|021|M|affinity for bile acids.(2)|
03917|022|B||
03917|023|D|DISCUSSION:  In a study in health subjects, concurrent use of roxadustat|
03917|024|D|with sevelamer carbonate or calcium acetate decreased roxadustat|
03917|025|D|area-under-curve (AUC) by 67% and 46% and concentration maximum (Cmax) by|
03917|026|D|66% and 52%, respectively.(1)|
03917|027|B||
03917|028|R|REFERENCES:|
03917|029|B||
03917|030|R|1.Evrenzo (roxadustat) UK summary of product characteristics. Atellas Pharma|1
03917|031|R|  Europe B.V. November, 2021.|1
03917|032|R|2.Renagel (sevelamer hydrochloride) US prescribing information. Genzyme|1
03917|033|R|  Corporation March 9, 2016.|1
03917|034|R|3.FDA (US Food and Drug Administration). Gastrointestinal Drug Advisory|1
03917|035|R|  Committee (GIDAC) Meeting, FDA Background Document for NDA 207999|1
03917|036|R|  obeticholic acid. accessed at:|1
03917|037|R|  http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials|1
03917|038|R|  /drugs/gastrointestinaldrugsadvisorycommittee/ucm494108.pdf March 15,|1
03917|039|R|  2016.|1
03918|001|T|MONOGRAPH TITLE:  Roxadustat/Polyvalent Cations|
03918|002|B||
03918|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03918|004|L|take action as needed.|
03918|005|B||
03918|006|A|MECHANISM OF ACTION:  Roxadustat chelates polyvalent cations such as|
03918|007|A|aluminum, calcium, iron, magnesium, selenium, and zinc.(1)|
03918|008|B||
03918|009|E|CLINICAL EFFECTS:  Simultaneous administration of roxadustat and polyvalent|
03918|010|E|cations may decrease the absorption and clinical effects of roxadustat.(1)|
03918|011|B||
03918|012|P|PREDISPOSING FACTORS:  None determined.|
03918|013|B||
03918|014|M|PATIENT MANAGEMENT:  The manufacturer of roxadustat states that it should be|
03918|015|M|administered at least 1 hour before or 1 hour after any medications or|
03918|016|M|products containing polyvalent cations such as antacids or mineral|
03918|017|M|supplements.(1)|
03918|018|B||
03918|019|D|DISCUSSION:  Clinical studies with polyvalent cations have not been|
03918|020|D|conducted.|
03918|021|D|   In a study in health subjects, concurrent use of roxadustat with|
03918|022|D|sevelamer carbonate or calcium acetate decreased roxadustat area-under-curve|
03918|023|D|(AUC) by 67% and 46% and concentration maximum (Cmax) by 66% and 52%,|
03918|024|D|respectively.(1)|
03918|025|B||
03918|026|R|REFERENCE:|
03918|027|B||
03918|028|R|1.Evrenzo (roxadustat) UK summary of product characteristics. Atellas Pharma|1
03918|029|R|  Europe B.V. November, 2021.|1
03919|001|T|MONOGRAPH TITLE:  Sirolimus Protein-Bound/Slt Moderate and Weak CYP3A4|
03919|002|T|Inhibit|
03919|003|B||
03919|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03919|005|L|take action as needed.|
03919|006|B||
03919|007|A|MECHANISM OF ACTION:  Moderate and weak CYP3A4 inhibitors may inhibit the|
03919|008|A|metabolism of sirolimus by CYP3A4.(1)|
03919|009|B||
03919|010|E|CLINICAL EFFECTS:  Concurrent use of moderate or weak CYP3A4 inhibitors may|
03919|011|E|result in elevated levels of and side effects from sirolimus.(1)|
03919|012|B||
03919|013|P|PREDISPOSING FACTORS:  None determined.|
03919|014|B||
03919|015|M|PATIENT MANAGEMENT:  The US manufacturer of sirolimus protein-bound|
03919|016|M|injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when|
03919|017|M|used concurrently with moderate or weak CYP3A4 inhibitors.  Concurrent use|
03919|018|M|with strong CYP3A4 inhibitors should be avoided.(1)|
03919|019|B||
03919|020|D|DISCUSSION:  In an open, randomized, cross-over trial in 18 healthy|
03919|021|D|subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10|
03919|022|D|mg) increased sirolimus area-under-curve (AUC) and maximum concentration|
03919|023|D|(Cmax) by 60% and by 43%, respectively.  Sirolimus apparent oral clearance|
03919|024|D|and volume of distribution decreased by 38% and 45%, respectively.  There|
03919|025|D|were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2)|
03919|026|D|   In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with|
03919|027|D|verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold|
03919|028|D|and 2.3-fold, respectively.  The AUC and Cmax of the active S-enantiomer of|
03919|029|D|verapamil each increased by 1.5-fold.  Verapamil time to Cmax (Tmax) was|
03919|030|D|increased by 1.2 hours.(2)|
03919|031|D|   Moderate and weak CYP3A4 inhibitors linked to this monograph include:|
03919|032|D|alprazolam, amlodipine, anamorelin, aprepitant, avacopan, azithromycin,|
03919|033|D|berberine, berotralstat, bicalutamide, blueberry, brodalumab, chlorzoxazone,|
03919|034|D|cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, daclatasvir,|
03919|035|D|daridorexant, delavirdine, diosmin, elinzanetant, entrectinib, erythromycin,|
03919|036|D|estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant,|
03919|037|D|fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal,|
03919|038|D|grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib,|
03919|039|D|lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone,|
03919|040|D|lurasidone, mavorixafor, netupitant, omeprazole, osilodrostat, peppermint|
03919|041|D|oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir,|
03919|042|D|resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib,|
03919|043|D|simeprevir, sitaxsentan, stiripentol, suvorexant, ticagrelor, tofisopam,|
03919|044|D|tolvaptan, trofinetide, and vonoprazan.(3,4)|
03919|045|B||
03919|046|R|REFERENCES:|
03919|047|B||
03919|048|R|1.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
03919|049|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
03919|050|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
03919|051|R|  Aug, 2022.|1
03919|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
03919|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03919|054|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03919|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03919|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03919|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03919|058|R|  11/14/2017.|1
03920|001|T|MONOGRAPH TITLE:  Tizanidine/Selected Moderate and Weak CYP1A2 Inhibitors|
03920|002|B||
03920|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03920|004|L|of severe adverse interaction.|
03920|005|B||
03920|006|A|MECHANISM OF ACTION:  Moderate and weak CYP1A2 inhibitors may inhibit the|
03920|007|A|metabolism of tizanidine by CYP1A2.(1)|
03920|008|B||
03920|009|E|CLINICAL EFFECTS:  Concurrent use of moderate and weak CYP1A2 inhibitors may|
03920|010|E|result in elevated levels of and effects from tizanidine, including|
03920|011|E|hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor|
03920|012|E|function.|
03920|013|B||
03920|014|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
03920|015|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
03920|016|P|patients using more than one medicine with anticholinergic properties.(2)|
03920|017|B||
03920|018|M|PATIENT MANAGEMENT:  The US manufacturer of tizanidine states that|
03920|019|M|concurrent use of tizanidine with inhibitors of CYP1A2 should be avoided.(3)|
03920|020|M|   If adverse reactions such as hypotension, bradycardia or excessive|
03920|021|M|drowsiness occur, reduce tizanidine dosage or discontinue tizanidine|
03920|022|M|therapy.(3)|
03920|023|B||
03920|024|D|DISCUSSION:  In a study, cannabidiol 750 mg twice daily (a weak CYP1A2|
03920|025|D|inhibitor) increased the maximum concentration (Cmax) and area-under-curve|
03920|026|D|(AUC) of a 200 mg single dose of caffeine (a sensitive CYP1A2 substrate) by|
03920|027|D|15% and 95%, respectively.(1)|
03920|028|D|   In a study in 10 healthy subjects, concurrent fluvoxamine, a strong|
03920|029|D|inhibitor of CYP1A2, increased tizanidine Cmax, AUC, and half-life (T1/2) by|
03920|030|D|12-fold, 33-fold, and 3-fold, respectively.  Significant decreases in blood|
03920|031|D|pressure and increases in drowsiness and psychomotor impairment occurred.(3)|
03920|032|D|   In a study in 10 healthy subjects, concurrent ciprofloxacin, a strong|
03920|033|D|inhibitor of CYP1A2, increased tizanidine Cmax and AUC by 7-fold and|
03920|034|D|10-fold, respectively.  Significant decreases in blood pressure and|
03920|035|D|increases in drowsiness and psychomotor impairment occurred.(3)|
03920|036|D|   Moderate CYP1A2 inhibitors linked to this monograph include: dipyrone,|
03920|037|D|fexinidazole, genistein, methoxsalen, phenylpropanolamine, pipemidic acid,|
03920|038|D|propranolol, rucaparib, and troleandomycin.|
03920|039|D|   Weak CYP1A2 inhibitors linked to this monograph include: allopurinol,|
03920|040|D|artemisinin, caffeine, cannabidiol, curcumin, dan-shen, disulfiram,|
03920|041|D|Echinacea, ginseng, parsley, piperine, ribociclib, simeprevir,|
03920|042|D|thiabendazole, and triclabendazole.(4)|
03920|043|B||
03920|044|R|REFERENCES:|
03920|045|B||
03920|046|R|1.Epidiolex (cannabidiol) US prescribing information. Greenwich Biosciences,|1
03920|047|R|  Inc. June, 2025.|1
03920|048|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03920|049|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03920|050|R|  Soc 2023 Jul;71(7):2052-2081.|6
03920|051|R|3.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
03920|052|R|  Pharma Inc. November 22, 2024.|1
03920|053|R|4.This information is based on an extract from the Certara Drug Interaction|6
03920|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03921|001|T|MONOGRAPH TITLE:  Maribavir/Selected Strong CYP3A4 Inducers|
03921|002|B||
03921|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03921|004|L|of severe adverse interaction.|
03921|005|B||
03921|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may accelerate the|
03921|007|A|metabolism of maribavir.(1)|
03921|008|B||
03921|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03921|010|E|may result in decreased levels and effectiveness of maribavir.(1)|
03921|011|B||
03921|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03921|013|P|of the inducer for longer than 1-2 weeks.|
03921|014|B||
03921|015|M|PATIENT MANAGEMENT:  The manufacturer of maribavir states that concurrent|
03921|016|M|use with strong CYP3A4 inducers is not recommended.  If concurrent use is|
03921|017|M|necessary, closely monitor for treatment response.(1)|
03921|018|B||
03921|019|D|DISCUSSION:  In vitro data shows that maribavir is metabolized by CYP3A4.  A|
03921|020|D|study in 14 subjects with concurrent maribavir 400 mg twice daily and|
03921|021|D|rifampin 600 mg daily resulted in a decrease in maribavir area-under-curve|
03921|022|D|(AUC) and maximum concentration (Cmax) by 60% and 39%, respectively.(1)|
03921|023|D|   Strong inducers of CYP3A4 include: apalutamide, encorafenib,|
03921|024|D|enzalutamide, ivosidenib, lumacaftor, mitotane, rifampin, rifapentine, and|
03921|025|D|St. John's wort.(2-3)|
03921|026|B||
03921|027|R|REFERENCES:|
03921|028|B||
03921|029|R|1.Livtencity (maribavir) US prescribing information. Takeda Pharmaceuticals|1
03921|030|R|  America, Inc. November, 2021.|1
03921|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03921|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03921|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03921|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03921|035|R|  11/14/2017.|1
03921|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
03921|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03922|001|T|MONOGRAPH TITLE:  Maribavir/Selected Anticonvulsants|
03922|002|B||
03922|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03922|004|L|of severe adverse interaction.|
03922|005|B||
03922|006|A|MECHANISM OF ACTION:  Selected anticonvulsants that are strong inducers of|
03922|007|A|CYP3A4 may accelerate the metabolism of maribavir.(1)|
03922|008|B||
03922|009|E|CLINICAL EFFECTS:  The concurrent administration of selected anticonvulsants|
03922|010|E|may result in decreased levels and effectiveness of maribavir.(1)|
03922|011|B||
03922|012|P|PREDISPOSING FACTORS:  None determined.|
03922|013|B||
03922|014|M|PATIENT MANAGEMENT:  The manufacturer of maribavir states that concurrent|
03922|015|M|use with selected anticonvulsants requires a dose adjustment of maribavir.|
03922|016|M|If maribavir is coadministered with carbamazepine, increase the maribavir|
03922|017|M|dose to 800 mg twice daily.  If maribavir is coadministered with|
03922|018|M|fosphenytoin, phenobarbital, phenytoin, or primidone, increase the maribavir|
03922|019|M|dose to 1200 mg twice daily.(1)|
03922|020|M|   If concurrent use is necessary, closely monitor for treatment|
03922|021|M|response.(1)|
03922|022|B||
03922|023|D|DISCUSSION:  In vitro data shows that maribavir is metabolized by CYP3A4.|
03922|024|D|   A study in 200 subjects with concurrent maribavir 800 mg twice daily or|
03922|025|D|400 mg twice daily and carbamazepine 600 mg daily resulted in an increase in|
03922|026|D|maribavir area-under-curve (AUC) and maximum concentration (Cmax) by 40% and|
03922|027|D|53%, respectively.(1)|
03922|028|D|   A study in 200 subjects with concurrent maribavir 1200 mg twice daily or|
03922|029|D|400 mg twice daily and phenobarbital 100 mg daily resulted in an increase in|
03922|030|D|maribavir AUC and Cmax by 80% and 117%, respectively.(1)|
03922|031|D|   A study in 200 subjects with concurrent maribavir 1200 mg twice daily or|
03922|032|D|400 mg twice daily and phenytoin 300 mg daily resulted in an increase in|
03922|033|D|maribavir AUC and Cmax by 70% and 205%, respectively.(1)|
03922|034|D|   Selected anticonvulsants linked include: barbiturates, carbamazepine,|
03922|035|D|fosphenytoin, phenobarbital, phenytoin, and primidone.(2-3)|
03922|036|B||
03922|037|R|REFERENCES:|
03922|038|B||
03922|039|R|1.Livtencity (maribavir) US prescribing information. Takeda Pharmaceuticals|1
03922|040|R|  America, Inc. November, 2021.|1
03922|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03922|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03922|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03922|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03922|045|R|  11/14/2017.|1
03922|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
03922|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03923|001|T|MONOGRAPH TITLE:  Rupatadine/Strong CYP3A4 Inhibitors|
03923|002|B||
03923|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03923|004|L|of severe adverse interaction.|
03923|005|B||
03923|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03923|007|A|of rupatadine.(1,2)|
03923|008|B||
03923|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
03923|010|E|elevated levels of and toxicity from rupatadine, including increased risk of|
03923|011|E|somnolence, headache, tiredness, asthenia, or dry mouth.(1,2)|
03923|012|B||
03923|013|P|PREDISPOSING FACTORS:  None determined.|
03923|014|B||
03923|015|M|PATIENT MANAGEMENT:  The Canadian prescribing information states concurrent|
03923|016|M|use of rupatadine with strong CYP3A4 inhibitors is not recommended.(1)|
03923|017|M|   The UK prescribing information states concurrent use of rupatadine with|
03923|018|M|strong CYP3A4 inhibitors should be avoided.(2)|
03923|019|B||
03923|020|D|DISCUSSION:  Concurrent use of rupatadine 20 mg and ketoconazole increased|
03923|021|D|the systemic exposure of rupatadine 10-fold.(1,2)|
03923|022|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03923|023|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03923|024|D|ketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir,|
03923|025|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir,|
03923|026|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
03923|027|D|voriconazole.(3-4)|
03923|028|B||
03923|029|R|REFERENCES:|
03923|030|B||
03923|031|R|1.Rupall (rupatadine) Canadian prescribing information. Medexus|1
03923|032|R|  Pharmaceuticals, Inc. June, 2020.|1
03923|033|R|2.Rupatadine UK summary of product characteristics. Aspire Pharma Ltd|1
03923|034|R|  November, 2020.|1
03923|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03923|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03923|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03923|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03923|039|R|  11/14/2017.|1
03923|040|R|4.This information is based on an extract from the Certara Drug Interaction|6
03923|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03924|001|T|MONOGRAPH TITLE:  Duvelisib/Moderate CYP3A4 Inducers|
03924|002|B||
03924|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03924|004|L|of severe adverse interaction.|
03924|005|B||
03924|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may accelerate the|
03924|007|A|metabolism of duvelisib.(1)|
03924|008|B||
03924|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
03924|010|E|alter the clinical effectiveness of duvelisib.(1)|
03924|011|B||
03924|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03924|013|P|of the inducer for longer than 1-2 weeks.|
03924|014|B||
03924|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of duvelisib with moderate|
03924|016|M|CYP3A4 inducers.(1)  When possible, select alternative agents in place of|
03924|017|M|the moderate CYP3A4 inducer.|
03924|018|M|   If the moderate CYP3A4 inducer cannot be avoided, increase the dose of|
03924|019|M|duvelisib on day 12 of concurrent therapy as follows:|
03924|020|M|   - If the initial dose of duvelisib is 25 mg twice daily, increase the|
03924|021|M|duvelisib dose to 40 mg twice daily.|
03924|022|M|   - If the initial dose of duvelisib is 15 mg twice daily, increase the|
03924|023|M|duvelisib dose to 25 mg twice daily.|
03924|024|M|   Monitor patients receiving concurrent therapy for reduced efficacy.(1)|
03924|025|M|   If the moderate CYP3A4 inducer is discontinued, reduce the dose of|
03924|026|M|duvelisib back to the initial dose 14 days after discontinuation of the|
03924|027|M|moderate CYP3A4 inducer.(1)|
03924|028|B||
03924|029|D|DISCUSSION:  The primary metabolism pathway for duvelisib is CYP3A4.(1)|
03924|030|D|   In an interaction study, etravirine (a moderate CYP3A inducer) 200 mg|
03924|031|D|twice daily decreased the maximum concentration (Cmax) and area-under-curve|
03924|032|D|(AUC) of single dose duvelisib 25 mg by 16% and 35%, respectively.(1)|
03924|033|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
03924|034|D|cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
03924|035|D|lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, sotorasib,|
03924|036|D|telotristat ethyl, thioridazine, and tovorafenib.(2-4)|
03924|037|B||
03924|038|R|REFERENCES:|
03924|039|B||
03924|040|R|1.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
03924|041|R|  2021.|1
03924|042|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03924|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03924|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03924|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03924|046|R|  11/14/2017.|1
03924|047|R|3.This information is based on an extract from the Certara Drug Interaction|6
03924|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03924|049|R|4.Welireg (belzutifan) US prescribing information. Merck Sharp & Dohme Corp.|1
03924|050|R|  August, 2021.|1
03925|001|T|MONOGRAPH TITLE:  Duvelisib/Bosentan|
03925|002|B||
03925|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03925|004|L|of severe adverse interaction.|
03925|005|B||
03925|006|A|MECHANISM OF ACTION:  Duvelisib and bosentan are both metabolized by CYP3A4.|
03925|007|A|Bosentan is a moderate CYP3A4 inducer while duvelisib is a moderate CYP3A4|
03925|008|A|inhibitor.(1-2)|
03925|009|B||
03925|010|E|CLINICAL EFFECTS:  The net effect of coadministration of duvelisib and|
03925|011|E|bosentan on CYP3A4 enzyme activity is unknown.  Concurrent or recent use of|
03925|012|E|bosentan may either decrease the clinical effectiveness of duvelisib(1) or|
03925|013|E|increase the levels and toxicities of bosentan.(2)|
03925|014|B||
03925|015|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, duvelisib, and a CYP2C9|
03925|016|P|inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
03925|017|P|sulfinpyrazone, or phenylbutazone)(4) could lead to blockade of both major|
03925|018|P|metabolic pathways for bosentan, resulting in large increases in bosentan|
03925|019|P|plasma concentrations.(2)|
03925|020|B||
03925|021|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
03925|022|M|duvelisib with bosentan.  Concurrent therapy should be avoided.  If use of|
03925|023|M|this combination is necessary, the patient should be closely monitored for|
03925|024|M|duvelisib efficacy and bosentan toxicity.|
03925|025|M|   The manufacturer of duvelisib makes the recommendations below|
03925|026|M|for concurrent use with CYP3A4 inducers.|
03925|027|M|   Avoid the concurrent use of duvelisib with moderate CYP3A4 inducers.(1)|
03925|028|M|When possible, select alternative agents in place of the moderate CYP3A4|
03925|029|M|inducer.|
03925|030|M|   If the moderate CYP3A4 inducer cannot be avoided, increase the dose of|
03925|031|M|duvelisib on day 12 of concurrent therapy as follows:|
03925|032|M|   - If the initial dose of duvelisib is 25 mg twice daily, increase the|
03925|033|M|duvelisib dose to 40 mg twice daily.|
03925|034|M|   - If the initial dose of duvelisib is 15 mg twice daily, increase the|
03925|035|M|duvelisib dose to 25 mg twice daily.|
03925|036|M|   If the moderate CYP3A4 inducer is discontinued, reduce the dose of|
03925|037|M|duvelisib back to the initial dose 14 days after discontinuation of the|
03925|038|M|moderate CYP3A4 inducer.(1)|
03925|039|M|   The manufacturer of bosentan makes the recommendations below for|
03925|040|M|concurrent use with CYP3A4 inhibitors.|
03925|041|M|   Review medication list to see if patient is also receiving a CYP2C9|
03925|042|M|inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
03925|043|M|sulfinpyrazone, or phenylbutazone).|
03925|044|M|   Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended|
03925|045|M|by the manufacturer as the combination may lead to large increases in|
03925|046|M|bosentan plasma concentrations.(2)|
03925|047|M|   For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated,|
03925|048|M|monitor tolerance to concomitant therapy and adjust bosentan dose if needed.|
03925|049|B||
03925|050|D|DISCUSSION:  In an interaction study, etravirine (a moderate CYP3A inducer)|
03925|051|D|200 mg twice daily decreased the maximum concentration (Cmax) and|
03925|052|D|area-under-curve (AUC) of single dose duvelisib 25 mg by 16% and 35%,|
03925|053|D|respectively.(1)|
03925|054|D|   In a study in healthy subjects, concurrent bosentan and ketoconazole (a|
03925|055|D|strong CYP3A4 inhibitor) administration increased bosentan steady-state Cmax|
03925|056|D|and AUC by 2.1-fold and 2.3-fold, respectively.(2)|
03925|057|B||
03925|058|R|REFERENCES:|
03925|059|B||
03925|060|R|1.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
03925|061|R|  2021.|1
03925|062|R|2.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
03925|063|R|  US, Inc. September 5, 2017.|1
03925|064|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03925|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03925|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03925|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03925|068|R|  11/14/2017.|1
03925|069|R|4.This information is based on an extract from the Certara Drug Interaction|6
03925|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03926|001|T|MONOGRAPH TITLE:  Duvelisib/Pexidartinib|
03926|002|B||
03926|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03926|004|L|of severe adverse interaction.|
03926|005|B||
03926|006|A|MECHANISM OF ACTION:  Duvelisib and pexidartinib are both metabolized by|
03926|007|A|CYP3A4.  Pexidartinib is a moderate CYP3A4 inducer while duvelisib is a|
03926|008|A|moderate CYP3A4 inhibitor.(1-2)|
03926|009|B||
03926|010|E|CLINICAL EFFECTS:  The net effect of coadministration of duvelisib and|
03926|011|E|pexidartinib on CYP3A4 enzyme activity is unknown.  Concurrent or recent use|
03926|012|E|of pexidartinib may either decrease the clinical effectiveness of|
03926|013|E|duvelisib(1) or increase the levels and toxicities of pexidartinib.(2)|
03926|014|B||
03926|015|P|PREDISPOSING FACTORS:  None determined.|
03926|016|B||
03926|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
03926|018|M|duvelisib with pexidartinib.  Concurrent therapy should be avoided.  If use|
03926|019|M|of this combination is necessary, the patient should be closely monitored|
03926|020|M|for duvelisib efficacy and pexidartinib toxicity.|
03926|021|M|   The manufacturer of duvelisib makes the recommendations below for|
03926|022|M|concurrent use with CYP3A4 inducers.|
03926|023|M|   Avoid the concurrent use of duvelisib with moderate CYP3A4 inducers.(1)|
03926|024|M|When possible, select alternative agents in place of the moderate CYP3A4|
03926|025|M|inducer.|
03926|026|M|   If the moderate CYP3A4 inducer cannot be avoided, increase the dose of|
03926|027|M|duvelisib on day 12 of concurrent therapy as follows:|
03926|028|M|   - If the initial dose of duvelisib is 25 mg twice daily, increase the|
03926|029|M|duvelisib dose to 40 mg twice daily.|
03926|030|M|   - If the initial dose of duvelisib is 15 mg twice daily, increase the|
03926|031|M|duvelisib dose to 25 mg twice daily.|
03926|032|M|   If the moderate CYP3A4 inducer is discontinued, reduce the dose of|
03926|033|M|duvelisib back to the initial dose 14 days after discontinuation of the|
03926|034|M|moderate CYP3A4 inducer.(1)|
03926|035|M|   The manufacturer of pexidartinib makes the recommendations below for|
03926|036|M|concurrent use with CYP3A4 inhibitors.|
03926|037|M|   Coadministration with moderate inhibitors of CYP3A4 should be avoided.(2)|
03926|038|M|If coadministration with a moderate CYP3A4 inhibitor cannot be avoided,|
03926|039|M|reduce the pexidartinib dose according to the following recommendations.|
03926|040|M|   If the planned total daily dose is currently 800 mg, modify the total|
03926|041|M|daily dose to 400 mg by administering 200 mg twice daily.|
03926|042|M|   If the planned total daily dose is currently 600 mg, modify the total|
03926|043|M|daily dose to 400 mg by administering 200 mg twice daily.|
03926|044|M|   If the planned total daily dose is currently 400 mg, modify the total|
03926|045|M|daily dose to 200 mg by administering 200 mg once daily.|
03926|046|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
03926|047|M|increase the pexidartinib dose to the dose that was used before starting the|
03926|048|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
03926|049|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
03926|050|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
03926|051|M|recommendations in the Turalio package insert.  Advise patients to|
03926|052|M|immediately report any symptoms of hepatotoxicity.|
03926|053|B||
03926|054|D|DISCUSSION:  In an interaction study, etravirine (a moderate CYP3A inducer)|
03926|055|D|200 mg twice daily decreased the maximum concentration (Cmax) and|
03926|056|D|area-under-curve (AUC) of single dose duvelisib 25 mg by 16% and 35%,|
03926|057|D|respectively.(1)|
03926|058|D|   Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased|
03926|059|D|pexidartinib Cmax and AUC by 41% and 67%, respectively.(2)|
03926|060|B||
03926|061|R|REFERENCES:|
03926|062|B||
03926|063|R|1.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
03926|064|R|  2021.|1
03926|065|R|2.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
03926|066|R|  November, 2023.|1
03926|067|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03926|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03926|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03926|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03926|071|R|  11/14/2017.|1
03926|072|R|4.This information is based on an extract from the Certara Drug Interaction|6
03926|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03927|001|T|MONOGRAPH TITLE:  Pafolacianine/Folic Acid|
03927|002|B||
03927|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03927|004|L|take action as needed.|
03927|005|B||
03927|006|A|MECHANISM OF ACTION:  Folate, folic acid, and folate-containing supplements|
03927|007|A|may reduce binding of pafolacianine to folate receptors expressed on ovarian|
03927|008|A|cancer cells.|
03927|009|B||
03927|010|E|CLINICAL EFFECTS:  Folate, folic acid, and folate-containing supplements|
03927|011|E|could reduce the detection of malignant lesions with pafolacianine.|
03927|012|B||
03927|013|P|PREDISPOSING FACTORS:  None determined.|
03927|014|B||
03927|015|M|PATIENT MANAGEMENT:  Avoid administration of folate, folic acid, or|
03927|016|M|folate-containing supplements within 48 hours before administration of|
03927|017|M|pafolacianine.|
03927|018|B||
03927|019|D|DISCUSSION:  Folate, folic acid, and folate-containing supplements may|
03927|020|D|reduce binding of pafolacianine to folate receptors expressed on cancer|
03927|021|D|cells, which could result in reduced detection of malignant lesions with|
03927|022|D|pafolacianine.|
03927|023|B||
03927|024|R|REFERENCE:|
03927|025|B||
03927|026|R|1.Cytalux (pafolacianine) US prescribing information. Grand River Aseptic|1
03927|027|R|  Manufacturing Nov, 2021.|1
03928|001|T|MONOGRAPH TITLE:  Midostaurin/QT Prolonging Agents|
03928|002|B||
03928|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03928|004|L|take action as needed.|
03928|005|B||
03928|006|A|MECHANISM OF ACTION:  Concurrent use of midostaurin with other agents that|
03928|007|A|prolong the QTc interval may result in additive effects on the QTc|
03928|008|A|interval.(2)|
03928|009|B||
03928|010|E|CLINICAL EFFECTS:  The use of midostaurin in patients maintained on agents|
03928|011|E|that prolong the QTc interval may result in potentially life-threatening|
03928|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
03928|013|B||
03928|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03928|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03928|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03928|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03928|018|P|gender, or advanced age.(2)|
03928|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03928|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03928|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03928|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03928|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03928|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03928|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03928|026|B||
03928|027|M|PATIENT MANAGEMENT:  The US manufacturer of midostaurin recommends caution|
03928|028|M|in patients treated with drugs that affect the QTc interval.  If concurrent|
03928|029|M|use with QT prolonging agents is warranted, consider routine interval ECG|
03928|030|M|monitoring of the QT interval.(1)|
03928|031|M|   If concurrent therapy is warranted, monitor ECG more frequently and|
03928|032|M|consider obtaining serum calcium, magnesium, and potassium levels at|
03928|033|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03928|034|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03928|035|B||
03928|036|D|DISCUSSION:  In a randomized study of midostaurin 75 mg twice daily for 3|
03928|037|D|days there was no clinically significant prolongation of QTc interval or|
03928|038|D|relationship between changes in QTc and concentrations for midostaurin and|
03928|039|D|its active metabolites (CGP62221 and CGP52421).  However the study noted the|
03928|040|D|duration was not long enough to estimate the effects of the metabolite|
03928|041|D|CGP52421 on the QTc interval.(1)|
03928|042|D|   In a pooled analysis in patients with advanced systemic mastocytosis|
03928|043|D|(SM), 4.7% patients had a post-baseline QTcF > 480 ms, no patients had a|
03928|044|D|QTcF > 500 ms, and 6.3% patients had a QTcF > 60 ms compared to baseline.(2)|
03928|045|D|   In a randomized placebo-controlled study in patients with acute myeloid|
03928|046|D|leukemia (AML), the proportion of patients with QTc prolongation was higher|
03928|047|D|in the midostaurin group compared to placebo (QTcF > 480 ms: 10.1% vs 5.7%;|
03928|048|D|QTcF > 500 ms: 6.2% vs 2.6%; QTcF > 60 ms change from baseline: 18.4% vs|
03928|049|D|10.7%).(1)|
03928|050|D|   Agents that are linked to this monograph may have varying degrees of|
03928|051|D|potential to prolong the QTc interval but are generally accepted to have a|
03928|052|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03928|053|D|been shown to prolong the QTc interval either through their mechanism of|
03928|054|D|action, through studies on their effects on the QTc interval, or through|
03928|055|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03928|056|D|and/or post-marketing reports.(3)|
03928|057|B||
03928|058|R|REFERENCES:|
03928|059|B||
03928|060|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
03928|061|R|  Corporation November, 2021.|1
03928|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03928|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03928|064|R|  settings: a scientific statement from the American Heart Association and|6
03928|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03928|066|R|  2;55(9):934-47.|6
03928|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03928|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03928|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03928|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03929|001|T|MONOGRAPH TITLE:  Aducanumab/Anticoagulants; Fibrinolytics|
03929|002|B||
03929|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03929|004|L|of severe adverse interaction.|
03929|005|B||
03929|006|A|MECHANISM OF ACTION:  Microhemorrhage has been reported with the use of|
03929|007|A|aducanumab.  Radiographic changes on brain MRI have been noted as amyloid|
03929|008|A|related imaging abnormalities-hemosiderin deposition (ARIA-H) which included|
03929|009|A|microhemorrhage.(1)|
03929|010|B||
03929|011|E|CLINICAL EFFECTS:  Concurrent use of aducanumab with either anticoagulants|
03929|012|E|or fibrinolytics may increase the risk of hemorrhage.(1-3)|
03929|013|B||
03929|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03929|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03929|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
03929|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03929|018|P|risk for bleeding (e.g. NSAIDs).|
03929|019|B||
03929|020|M|PATIENT MANAGEMENT:  Evaluate concurrent use of aducanumab with|
03929|021|M|anticoagulants or fibrinolytics.(1-3)|
03929|022|M|   Patients receiving concurrent therapy with aducanumab and anticoagulants|
03929|023|M|or fibrinolytics should be closely monitored for signs and symptoms of|
03929|024|M|bleeding and changes in platelet count or International Normalized Ratio|
03929|025|M|(INR).(1)|
03929|026|M|   Enhanced observation is recommended for the first 8 doses of aducanumab,|
03929|027|M|particularly with dose titration.  MRI should be considered if a patient|
03929|028|M|develops clinical symptoms of microhemorrhage.(1)|
03929|029|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
03929|030|M|therapy for signs of microhemorrhage, including headache, nausea/vomiting,|
03929|031|M|confusion, dizziness, visual disturbance, gait difficulties, and loss of|
03929|032|M|coordination.  General signs of blood loss include decreased hemoglobin,|
03929|033|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
03929|034|M|evaluate patients with any symptoms.|
03929|035|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
03929|036|M|to monitor efficacy and safety of anticoagulation. Discontinue|
03929|037|M|anticoagulation in patients with active pathologic bleeding.|
03929|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03929|039|M|confusion, headache, dizziness, nausea, visual changes, unusual bleeding|
03929|040|M|from the gums or nose; unusual bruising; red or black, tarry stools; red,|
03929|041|M|pink or dark brown urine; acute abdominal or joint pain and/or swelling.|
03929|042|B||
03929|043|D|DISCUSSION:  In two phase 3 studies, aducanumab was observed to increase|
03929|044|D|ARIA-H, including microhemorrhage.  Radiographic changes were classified as|
03929|045|D|mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10|
03929|046|D|or more new incidences.  Patients were excluded from clinical trials if|
03929|047|D|taking concurrent anticoagulants or anti-platelets.(1)|
03929|048|D|   In Studies 1 and 2, ARIA was observed in 41% of patients treated with|
03929|049|D|aducanumab with a planned dose of 10 mg/kg, compared to 10% of patients on|
03929|050|D|placebo.(1)|
03929|051|B||
03929|052|R|REFERENCES:|
03929|053|B||
03929|054|R|1.Aduhelm (aducanumab) US prescribing information. Biogen Inc. June, 2021.|1
03929|055|R|2.Salloway S, Chalkias S, Barkhof F, Burkett P, Barakos J, Purcell D, Suhy|2
03929|056|R|  J, Forrestal F, Tian Y, Umans K, Wang G, Singhal P, Budd Haeberlein S,|2
03929|057|R|  Smirnakis K. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies|2
03929|058|R|  Evaluating Aducanumab in  Patients With Early Alzheimer Disease. JAMA|2
03929|059|R|  Neurol 2021 Nov 22.|2
03929|060|R|3.Cummings J, Aisen P, Apostolova LG, Atri A, Salloway S, Weiner M.|6
03929|061|R|  Aducanumab: Appropriate Use Recommendations. J Prev Alzheimers Dis 2021;|6
03929|062|R|  8(4):398-410.|6
03930|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP2B6 Substrates/Midostaurin|
03930|002|B||
03930|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03930|004|L|take action as needed.|
03930|005|B||
03930|006|A|MECHANISM OF ACTION:  Midostaurin may induce the metabolism of CYP2B6|
03930|007|A|substrates.(1)|
03930|008|B||
03930|009|E|CLINICAL EFFECTS:  Concurrent midostaurin may result in decreased levels of|
03930|010|E|sensitive CYP2B6 substrates, which may result in a decrease in clinical|
03930|011|E|response.(1,2)|
03930|012|B||
03930|013|P|PREDISPOSING FACTORS:  None determined.|
03930|014|B||
03930|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent midostaurin for|
03930|016|M|an adequate clinical response.  The dosage of the CYP2B6 substrate may need|
03930|017|M|to be adjusted.(1,2)  An alternative agent may need to be selected.|
03930|018|B||
03930|019|D|DISCUSSION:  In a study, multiple doses of midostaurin (50 mg twice daily)|
03930|020|D|decreased the area-under-curve (AUC) of a single dose of bupropion by 48%|
03930|021|D|and of bupropion's metabolite, hydroxybupropion by 65%.(1)|
03930|022|D|   Sensitive CYP2B6 substrates linked to this monograph include: bupropion|
03930|023|D|and esketamine.(3,4)|
03930|024|B||
03930|025|R|REFERENCES:|
03930|026|B||
03930|027|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
03930|028|R|  Corporation November, 2021.|1
03930|029|R|2.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
03930|030|R|  GlaxoSmithKline November, 2019.|1
03930|031|R|3.This information is based on an extract from the Certara Drug Interaction|6
03930|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03930|033|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03930|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03930|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03930|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03930|037|R|  11/14/2017.|1
03931|001|T|MONOGRAPH TITLE:  Sensitive CYP2B6 Substrates that Prolong QT/Midostaurin|
03931|002|B||
03931|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03931|004|L|take action as needed.|
03931|005|B||
03931|006|A|MECHANISM OF ACTION:  Midostaurin may induce the metabolism of CYP2B6|
03931|007|A|substrates.(1)|
03931|008|A|   Midostaurin may also prolong the QT interval.  Concurrent use of|
03931|009|A|midostaurin with other agents that prolong the QTc interval may result in|
03931|010|A|additive effects on the QTc interval.(1)|
03931|011|B||
03931|012|E|CLINICAL EFFECTS:  Concurrent midostaurin may result in decreased levels of|
03931|013|E|sensitive CYP2B6 substrates, which may result in a decrease in or failure of|
03931|014|E|clinical response.(1)|
03931|015|E|   The use of midostaurin in patients maintained on agents that prolong the|
03931|016|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
03931|017|E|including torsades de pointes.(1)|
03931|018|B||
03931|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
03931|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
03931|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
03931|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
03931|023|P|gender, or advanced age.(2)|
03931|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03931|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03931|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
03931|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03931|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03931|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03931|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03931|031|B||
03931|032|M|PATIENT MANAGEMENT:  The US manufacturer of midostaurin recommends caution|
03931|033|M|in patients treated with CYP2B6 substrates that affect the QTc interval.  If|
03931|034|M|concurrent use is warranted, monitor patients for an adequate clinical|
03931|035|M|response.  The dosage of the CYP2B6 substrate may need to be adjusted, or|
03931|036|M|alternative agents may need to be selected.  Monitor ECG more frequently and|
03931|037|M|consider obtaining serum calcium, magnesium, and potassium levels at|
03931|038|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03931|039|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03931|040|B||
03931|041|D|DISCUSSION:  In a study, multiple doses of midostaurin (50 mg twice daily)|
03931|042|D|decreased the area-under-curve (AUC) of a single dose of bupropion by 48%|
03931|043|D|and of bupropion's metabolite, hydroxybupropion by 65%.(1)|
03931|044|D|   In a randomized study of midostaurin 75 mg twice daily for 3 days there|
03931|045|D|was no clinically significant prolongation of QTc interval or relationship|
03931|046|D|between changes in QTc and concentrations for midostaurin and its active|
03931|047|D|metabolites (CGP62221 and CGP52421).  However the study noted the duration|
03931|048|D|was not long enough to estimate the effects of the metabolite CGP52421 on|
03931|049|D|the QTc interval.(1)|
03931|050|D|   In a pooled analysis in patients with advanced systemic mastocytosis|
03931|051|D|(SM), 4.7% of patients had a post-baseline QTcF > 480 ms, no patients had a|
03931|052|D|QTcF > 500 ms, and 6.3% of patients had a QTcF > 60 ms compared to|
03931|053|D|baseline.(1)|
03931|054|D|   In a randomized placebo-controlled study in patients with acute myeloid|
03931|055|D|leukemia (AML), the proportion of patients with QTc prolongation was higher|
03931|056|D|in the midostaurin group compared to placebo (QTcF > 480 ms: 10.1% vs 5.7%;|
03931|057|D|QTcF > 500 ms: 6.2% vs 2.6%; QTcF > 60 ms change from baseline: 18.4% vs|
03931|058|D|10.7%).(1)|
03931|059|D|   Sensitive CYP2B6 substrates that prolong QT that are linked to this|
03931|060|D|monograph include: efavirenz, levomethadone, and methadone.(3,4)|
03931|061|B||
03931|062|R|REFERENCES:|
03931|063|B||
03931|064|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
03931|065|R|  Corporation November, 2021.|1
03931|066|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03931|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03931|068|R|  settings: a scientific statement from the American Heart Association and|6
03931|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03931|070|R|  2;55(9):934-47.|6
03931|071|R|3.This information is based on an extract from the Certara Drug Interaction|6
03931|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03931|073|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03931|074|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03931|075|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03931|076|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03931|077|R|  11/14/2017.|1
03932|001|T|MONOGRAPH TITLE:  OATP1B1 Substrates/Midostaurin|
03932|002|B||
03932|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03932|004|L|take action as needed.|
03932|005|B||
03932|006|A|MECHANISM OF ACTION:  Midostaurin has been shown to inhibit OATP1B1.(1)|
03932|007|A|Inhibition of OATP1B1 may decrease hepatic uptake of substrates.|
03932|008|B||
03932|009|E|CLINICAL EFFECTS:  Simultaneous use of midostaurin with OATP1B1 substrates|
03932|010|E|may result in increased levels and side effects from the substrates.(1)|
03932|011|B||
03932|012|P|PREDISPOSING FACTORS:  None determined.|
03932|013|B||
03932|014|M|PATIENT MANAGEMENT:  The manufacturer of midostaurin states that concomitant|
03932|015|M|OATP1B1 substrates should be used cautiously.  Patients on concurrent|
03932|016|M|therapy should be closely monitored for adverse effects as dose adjustments|
03932|017|M|of the substrate may be necessary.(1)|
03932|018|B||
03932|019|D|DISCUSSION:  In a study, single dose midostaurin 100 mg increased the|
03932|020|D|area-under-curve (AUC) of single dose rosuvastatin by 48%.  With a 50 mg|
03932|021|D|twice daily dose, midostaurin is predicted to increase the AUC of an OATP1B1|
03932|022|D|substrate by up to 2-fold.(1)|
03932|023|D|   OATP1B1 substrates linked to this monograph include: atorvastatin,|
03932|024|D|bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin,|
03932|025|D|pravastatin, repaglinide, rosuvastatin and simvastatin.|
03932|026|B||
03932|027|R|REFERENCES:|
03932|028|B||
03932|029|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
03932|030|R|  Corporation November, 2021.|1
03932|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03932|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03932|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03932|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03932|035|R|  11/14/2017.|1
03933|001|T|MONOGRAPH TITLE:  Midostaurin/Apalutamide|
03933|002|B||
03933|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03933|004|L|of severe adverse interaction.|
03933|005|B||
03933|006|A|MECHANISM OF ACTION:  Midostaurin is a substrate of CYP3A4.  Strong inducers|
03933|007|A|of CYP3A4 such as apalutamide may induce the metabolism of midostaurin.(1)|
03933|008|B||
03933|009|E|CLINICAL EFFECTS:  Concurrent use of apalutamide, a strong inducer of|
03933|010|E|CYP3A4, may result in decreased levels and effectiveness of midostaurin.(1)|
03933|011|B||
03933|012|P|PREDISPOSING FACTORS:  None determined.|
03933|013|B||
03933|014|M|PATIENT MANAGEMENT:  The manufacturer of midostaurin states to avoid|
03933|015|M|concurrent use with strong CYP3A4 inducers.(1)|
03933|016|B||
03933|017|D|DISCUSSION:  Midostaurin is a substrate of CYP3A4.(1)|
03933|018|D|   Concurrent administration of rifampicin (600 mg daily for 14 days, a|
03933|019|D|strong CYP3A4 inducer) with a single 50 mg dose of midostaurin on day 9|
03933|020|D|decreased the area-under-curve (AUC) of midostaurin and CGP62221, the active|
03933|021|D|metabolite, by 96% and 92%, respectively.  The AUC over time to last|
03933|022|D|measurable concentration of CGP62221 decreased by 59%.(1)|
03933|023|B||
03933|024|R|REFERENCES:|
03933|025|B||
03933|026|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
03933|027|R|  Corporation November, 2021.|1
03933|028|R|2.This information is based on an extract from the Certara Drug Interaction|6
03933|029|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03933|030|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03933|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03933|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03933|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03933|034|R|  11/14/2017.|1
03934|001|T|MONOGRAPH TITLE:  Tadalafil (BPH, PAH)/Strong CYP3A4 Inducers|
03934|002|B||
03934|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03934|004|L|of severe adverse interaction.|
03934|005|B||
03934|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may accelerate the|
03934|007|A|metabolism of tadalafil.(1-3)|
03934|008|B||
03934|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03934|010|E|may result in decreased levels and effectiveness of tadalafil.(1-3)|
03934|011|B||
03934|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03934|013|P|of the inducer for longer than 1-2 weeks.|
03934|014|B||
03934|015|M|PATIENT MANAGEMENT:  Concurrent use of strong CYP3A4 inducers with tadalafil|
03934|016|M|is not recommended.  If concurrent use is necessary, closely monitor for|
03934|017|M|treatment response.(1-3)|
03934|018|B||
03934|019|D|DISCUSSION:  Rifampin (600 mg daily), a strong CYP3A4 inducer, reduced|
03934|020|D|tadalafil 10 mg single-dose exposure AUC by 88% and Cmax by 46%,|
03934|021|D|respectively, compared to tadalafil alone.(1-3)|
03934|022|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03934|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
03934|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
03934|025|D|rifapentine, and St. John's wort.(4,5)|
03934|026|B||
03934|027|R|REFERENCES:|
03934|028|B||
03934|029|R|1.Adcirca (tadalafil) US prescribing information. Eli Lilly and Company|1
03934|030|R|  September, 2020.|1
03934|031|R|2.Entadfi (finasteride and tadalafil) US prescribing information. Veru Inc.|1
03934|032|R|  December, 2021.|1
03934|033|R|3.Opsynvi (macitentan, tadalafil) Canadian prescribing information. Janssen|1
03934|034|R|  Inc. October 14, 2021.|1
03934|035|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03934|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03934|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03934|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03934|039|R|  11/14/2017.|1
03934|040|R|5.This information is based on an extract from the Certara Drug Interaction|6
03934|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03935|001|T|MONOGRAPH TITLE:  Upadacitinib (Greater Than or Equal To 30 mg)/Strong|
03935|002|T|CYP3A4 Inhibitors|
03935|003|B||
03935|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03935|005|L|of severe adverse interaction.|
03935|006|B||
03935|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03935|008|A|of upadacitinib.(1,2)|
03935|009|B||
03935|010|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
03935|011|E|elevated levels of and toxicity from upadacitinib, including neutropenia,|
03935|012|E|serious infections, thrombosis, myocardial infarction, stroke, GI|
03935|013|E|perforation, and transaminitis.(1,2)|
03935|014|E|   Concurrent use of upadacitinib with immunosuppressives or|
03935|015|E|immunomodulators, including idelalisib, lonafarnib, and ribociclib, may|
03935|016|E|result in an increased risk of serious infections.|
03935|017|B||
03935|018|P|PREDISPOSING FACTORS:  None determined.|
03935|019|B||
03935|020|M|PATIENT MANAGEMENT:  The manufacturer of upadacitinib states that|
03935|021|M|upadacitinib requires a dose adjustment with concurrent strong CYP3A4|
03935|022|M|inhibitors.(1)|
03935|023|M|   If upadacitinib is being used for atopic dermatitis concurrently with|
03935|024|M|strong CYP3A4 inhibitors, limit the upadacitinib dose to 15 mg once daily.|
03935|025|M|Coadministration of upadacitinib 30 mg once daily with strong CYP3A4|
03935|026|M|inhibitors is not recommended.(1)|
03935|027|M|   If upadacitinib is being used for ulcerative colitis concurrently with|
03935|028|M|strong CYP3A4 inhibitors, limit the upadacitinib dose to 30 mg once daily|
03935|029|M|for 8 weeks during the induction phase and then 15 mg once daily in the|
03935|030|M|maintenance phase.(1)|
03935|031|M|   If upadacitinib is being used for Crohn's disease concurrently with|
03935|032|M|strong CYP3A4 inhibitors, limit the upadacitinib dose to 30 mg once daily|
03935|033|M|for 12 weeks during the induction phase and then 15 mg once daily in the|
03935|034|M|maintenance phase.(1)|
03935|035|M|   If upadacitinib is being used for rheumatoid arthritis, psoriatic|
03935|036|M|arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis,|
03935|037|M|polyarticular juvenile idiopathic arthritis, or giant cell arteritis, no|
03935|038|M|dose adjustment is needed with strong CYP3A4 inhibitors.  Monitor closely|
03935|039|M|for adverse reactions.(1)|
03935|040|M|   Concurrent use of upadacitinib 15 mg with strong CYP3A4 inhibitors should|
03935|041|M|be approached with caution.  Patients should be closely monitored for|
03935|042|M|adverse reactions.(1,2)|
03935|043|M|   For concurrent treatment with nirmatrelvir-ritonavir, dose adjustments|
03935|044|M|should be considered throughout the nirmatrelvir-ritonavir treatment and for|
03935|045|M|3 days following the last dose of nirmatrelvir-ritonavir.(3)|
03935|046|B||
03935|047|D|DISCUSSION:  In a study of 11 subjects, ketoconazole (400 mg daily for 6|
03935|048|D|days, a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax)|
03935|049|D|and area-under-curve (AUC) of single-dose upadacitinib 3 mg by 1.7-fold and|
03935|050|D|1.75-fold, respectively.(1,2)|
03935|051|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03935|052|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
03935|053|D|josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone,|
03935|054|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03935|055|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03935|056|D|troleandomycin, tucatinib, and voriconazole.(4,5)|
03935|057|B||
03935|058|R|REFERENCES:|
03935|059|B||
03935|060|R|1.Rinvoq (upadacitinib) Canadian prescribing information. AbbVie Corporation|1
03935|061|R|  July, 2024.|1
03935|062|R|2.Rinvoq (upadacitinib) US prescribing information. AbbVie Inc April, 2025.|1
03935|063|R|3.Quah KSE, Huang X, Renia L, Oon HH. Drug interactions between common|6
03935|064|R|  dermatological medications and the oral  anti-COVID-19 agents|6
03935|065|R|  nirmatrelvir-ritonavir and molnupiravir. Ann Acad Med Singap 2022 Dec;|6
03935|066|R|  51(12):774-786.|6
03935|067|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03935|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03935|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03935|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03935|071|R|  11/14/2017.|1
03935|072|R|5.This information is based on an extract from the Certara Drug Interaction|6
03935|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03936|001|T|MONOGRAPH TITLE:  Upadacitinib (Less Than 30 mg)/Strong CYP3A4 Inhibitors|
03936|002|B||
03936|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03936|004|L|take action as needed.|
03936|005|B||
03936|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03936|007|A|of upadacitinib.(1,2)|
03936|008|B||
03936|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
03936|010|E|elevated levels of and toxicity from upadacitinib, including neutropenia,|
03936|011|E|serious infections, thrombosis, myocardial infarction, stroke, GI|
03936|012|E|perforation, and transaminitis.(1,2)|
03936|013|E|   Concurrent use of upadacitinib with immunosuppressives or|
03936|014|E|immunomodulators, including idelalisib, lonafarnib, and ribociclib, may|
03936|015|E|result in an increased risk of serious infections.|
03936|016|B||
03936|017|P|PREDISPOSING FACTORS:  None determined.|
03936|018|B||
03936|019|M|PATIENT MANAGEMENT:  The manufacturer of upadacitinib states that|
03936|020|M|upadacitinib requires a dose adjustment with concurrent strong CYP3A4|
03936|021|M|inhibitors.(1)|
03936|022|M|   If upadacitinib is being used for atopic dermatitis concurrently with|
03936|023|M|strong CYP3A4 inhibitors, limit the upadacitinib dose to 15 mg once daily.|
03936|024|M|Coadministration of upadacitinib 30 mg once daily with strong CYP3A4|
03936|025|M|inhibitors is not recommended.(1)|
03936|026|M|   If upadacitinib is being used for ulcerative colitis concurrently with|
03936|027|M|strong CYP3A4 inhibitors, limit the upadacitinib dose to 30 mg once daily|
03936|028|M|for 8 weeks during the induction phase and then 15 mg once daily in the|
03936|029|M|maintenance phase.(1)|
03936|030|M|   If upadacitinib is being used for Crohn's disease concurrently with|
03936|031|M|strong CYP3A4 inhibitors, limit the upadacitinib dose to 30 mg once daily|
03936|032|M|for 12 weeks during the induction phase and then 15 mg once daily in the|
03936|033|M|maintenance phase.(1)|
03936|034|M|   If upadacitinib is being used for rheumatoid arthritis, psoriatic|
03936|035|M|arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis,|
03936|036|M|polyarticular juvenile idiopathic arthritis, or giant cell arteritis, no|
03936|037|M|dose adjustment is needed with strong CYP3A4 inhibitors.  Monitor closely|
03936|038|M|for adverse reactions.(1)|
03936|039|M|   Concurrent use of upadacitinib 15 mg with strong CYP3A4 inhibitors should|
03936|040|M|be approached with caution.  Patients should be closely monitored for|
03936|041|M|adverse reactions.(1,2)|
03936|042|M|   For concurrent treatment with nirmatrelvir-ritonavir, dose adjustments|
03936|043|M|should be considered throughout the nirmatrelvir-ritonavir treatment and for|
03936|044|M|3 days following the last dose of nirmatrelvir-ritonavir.(3)|
03936|045|B||
03936|046|D|DISCUSSION:  In a study of 11 subjects, ketoconazole (400 mg daily for 6|
03936|047|D|days, a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax)|
03936|048|D|and area-under-curve (AUC) of single-dose upadacitinib 3 mg by 1.7-fold and|
03936|049|D|1.75-fold, respectively.(1,2)|
03936|050|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03936|051|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
03936|052|D|josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone,|
03936|053|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
03936|054|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03936|055|D|troleandomycin, tucatinib, and voriconazole.(4,5)|
03936|056|B||
03936|057|R|REFERENCES:|
03936|058|B||
03936|059|R|1.Rinvoq (upadacitinib) Canadian prescribing information. AbbVie Corporation|1
03936|060|R|  July, 2024.|1
03936|061|R|2.Rinvoq (upadacitinib) US prescribing information. AbbVie Inc April, 2025.|1
03936|062|R|3.Quah KSE, Huang X, Renia L, Oon HH. Drug interactions between common|6
03936|063|R|  dermatological medications and the oral  anti-COVID-19 agents|6
03936|064|R|  nirmatrelvir-ritonavir and molnupiravir. Ann Acad Med Singap 2022 Dec;|6
03936|065|R|  51(12):774-786.|6
03936|066|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03936|067|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03936|068|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03936|069|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03936|070|R|  11/14/2017.|1
03936|071|R|5.This information is based on an extract from the Certara Drug Interaction|6
03936|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03937|001|T|MONOGRAPH TITLE:  Bilastine/P-glycoprotein (P-gp) Inhibitors|
03937|002|B||
03937|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03937|004|L|of severe adverse interaction.|
03937|005|B||
03937|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibition may increase the|
03937|007|A|absorption of bilastine.(1,2)|
03937|008|B||
03937|009|E|CLINICAL EFFECTS:  Concurrent use of P-gp inhibitors may result in elevated|
03937|010|E|levels and toxicities from bilastine, including headache and|
03937|011|E|somnolence.(1,2)|
03937|012|B||
03937|013|P|PREDISPOSING FACTORS:  The interaction magnitude may be greater in patients|
03937|014|P|with moderate to severe renal impairment.|
03937|015|B||
03937|016|M|PATIENT MANAGEMENT:  The Canadian manufacturer of bilastine states that|
03937|017|M|concomitant use of P-gp inhibitors with bilastine is not recommended.|
03937|018|M|Coadministration should be avoided in patients with moderate or severe renal|
03937|019|M|impairment.(1)|
03937|020|M|   The UK manufacturer of bilastine states that coadministration of|
03937|021|M|bilastine and P-gp inhibitors should be avoided in patients with moderate to|
03937|022|M|severe renal impairment.(2)|
03937|023|B||
03937|024|D|DISCUSSION:  In a study, ketoconazole and erythromycin both increased|
03937|025|D|bilastine area-under-curve (AUC) and maximum concentration (Cmax) by 2-fold|
03937|026|D|and 2- to 3-fold, respectively.(1)  The UK manufacturer of bilastine states|
03937|027|D|that these changes do not appear to affect the safety of bilastine.(2)|
03937|028|D|   P-gp inhibitors linked to this monograph include: amiodarone,|
03937|029|D|asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine,|
03937|030|D|cyclosporine, daclatasvir, danicopan, daridorexant, deutivacaftor,|
03937|031|D|diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin,|
03937|032|D|fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir,|
03937|033|D|hydroquinidine, imlunestrant, istradefylline, ivacaftor, lapatinib,|
03937|034|D|ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib,|
03937|035|D|propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline,|
03937|036|D|schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir,|
03937|037|D|sotorasib, tepotinib, valbenazine, vemurafenib, verapamil, vimseltinib, and|
03937|038|D|voclosporin.(4,5)|
03937|039|B||
03937|040|R|REFERENCES:|
03937|041|B||
03937|042|R|1.Blexten (bilastine) Canadian product monograph. Aralez Pharmaceuticals|1
03937|043|R|  Canada Inc. August 10, 2021.|1
03937|044|R|2.Ilaxten (bilastine) UK summary of product characteristics. A. Menarini|1
03937|045|R|  Farmaceutica Internazionale SRL May 15, 2021.|1
03937|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
03937|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03937|048|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03937|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03937|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03937|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03937|052|R|  11/14/2017.|1
03938|001|T|MONOGRAPH TITLE:  IgG Antibodies and Derivatives/Efgartigimod-alfa|
03938|002|B||
03938|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03938|004|L|of severe adverse interaction.|
03938|005|B||
03938|006|A|MECHANISM OF ACTION:  The neonatal Fc receptor (FcRn) prevents catabolism|
03938|007|A|and mediates recycling of IgG and albumin, which leads to their long|
03938|008|A|persistence in the body.(1,2)  Efgartigimod-alfa binds to FcRn and may|
03938|009|A|decrease systemic exposure of other ligands of FcRn, like immunoglobulins|
03938|010|A|and IgG-based antibodies.(3)|
03938|011|B||
03938|012|E|CLINICAL EFFECTS:  The effectiveness of medicines that bind to FcRn may be|
03938|013|E|decreased.(3)|
03938|014|B||
03938|015|P|PREDISPOSING FACTORS:  None determined.|
03938|016|B||
03938|017|M|PATIENT MANAGEMENT:  The manufacturer of efgartigimod-alfa states that|
03938|018|M|efgartigimod-alfa should not be combined with long-term use of FcRn-binding|
03938|019|M|medications.  If the medication is essential for the patient,|
03938|020|M|efgartigimod-alfa should be discontinued.(3)|
03938|021|B||
03938|022|D|DISCUSSION:  Clinical drug interaction studies with efgartigimod-alfa have|
03938|023|D|not been performed.  Efgartigimod-alfa may decrease concentrations of|
03938|024|D|compounds that bind to the human FcRn.(3)|
03938|025|B||
03938|026|R|REFERENCES:|
03938|027|B||
03938|028|R|1.Sockolosky JT, Szoka FC. The neonatal Fc receptor, FcRn, as a target for|6
03938|029|R|  drug delivery and therapy. Adv Drug Deliv Rev 2015 Aug 30;91:109-24.|6
03938|030|R|2.Kuo TT, Aveson VG. Neonatal Fc receptor and IgG-based therapeutics. MAbs|6
03938|031|R|  2011 Sep-Oct;3(5):422-30.|6
03938|032|R|3.Vyvgart (efgartigimod alfa-fcab) US prescribing information. argenx BV|1
03938|033|R|  August, 2024.|1
03939|001|T|MONOGRAPH TITLE:  Atorvastatin; Rosuvastatin/Nirmatrelvir-Ritonavir|
03939|002|B||
03939|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03939|004|L|of severe adverse interaction.|
03939|005|B||
03939|006|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the metabolism of|
03939|007|A|atorvastatin and rosuvastatin by CYP3A4.(1-3)|
03939|008|B||
03939|009|E|CLINICAL EFFECTS:  Concurrent use of nirmatrelvir-ritonavir may result in|
03939|010|E|elevated levels of atorvastatin and rosuvastatin, which could result in|
03939|011|E|rhabdomyolysis.(1-3)|
03939|012|B||
03939|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03939|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03939|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03939|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03939|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03939|018|P|transporter OATP1B1 may have increased statin concentrations and be|
03939|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
03939|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
03939|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
03939|022|B||
03939|023|M|PATIENT MANAGEMENT:  In patients receiving nirmatrelvir-ritonavir, consider|
03939|024|M|temporary discontinuation of atorvastatin and rosuvastatin during therapy|
03939|025|M|with nirmatrelvir-ritonavir.  Atorvastatin and rosuvastatin do not need to|
03939|026|M|be withheld prior to or after completing therapy with|
03939|027|M|nirmatrelvir-ritonavir.(1)|
03939|028|B||
03939|029|D|DISCUSSION:  Nirmatrelvir-ritonavir is a CYP3A4 inhibitor.(1)|
03939|030|B||
03939|031|R|REFERENCES:|
03939|032|B||
03939|033|R|1.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
03939|034|R|  information. Pfizer Inc. February, 2025.|1
03939|035|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
03939|036|R|  2020.|1
03939|037|R|3.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
03939|038|R|  Pharmaceuticals LP July, 2024.|1
03940|001|T|MONOGRAPH TITLE:  Intramuscular Cabotegravir/Rifabutin|
03940|002|B||
03940|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03940|004|L|of severe adverse interaction.|
03940|005|B||
03940|006|A|MECHANISM OF ACTION:  Rifabutin may induce the metabolism of cabotegravir by|
03940|007|A|CYP3A4.(1,2)|
03940|008|B||
03940|009|E|CLINICAL EFFECTS:  Concurrent or recent use of rifabutin may result in|
03940|010|E|decreased levels and effectiveness of cabotegravir.(1,2)|
03940|011|B||
03940|012|P|PREDISPOSING FACTORS:  None determined.|
03940|013|B||
03940|014|M|PATIENT MANAGEMENT:  The implications of this interaction differs depending|
03940|015|M|on the indication for cabotegravir.|
03940|016|M|   If cabotegravir is used with rilpivirine for treatment of HIV infection:|
03940|017|M|   - Rifabutin should be avoided.(1)|
03940|018|M|   If cabotegravir is used alone for pre-exposure prophylaxis:|
03940|019|M|   - In a patient already on or just starting rifabutin, increase the|
03940|020|M|frequency of cabotegravir doses to 600 mg every 2 weeks for the first 2|
03940|021|M|doses, then 600 mg monthly thereafter while on rifabutin.|
03940|022|M|   - In a patient starting rifabutin after the second injection or later of|
03940|023|M|cabotegravir, increase cabotegravir injections to 600 mg monthly while on|
03940|024|M|rifabutin.|
03940|025|M|   After stopping rifabutin, the recommended dosing schedule of cabotegravir|
03940|026|M|is 600 mg every 2 months.(2)|
03940|027|B||
03940|028|D|DISCUSSION:  Coadministration of rifabutin (300 mg once daily) with|
03940|029|D|cabotegravir (30 mg once daily) decreased cabotegravir's|
03940|030|D|area-under-the-curve (AUC), minimum concentration (Cmin), and maximum|
03940|031|D|concentration (Cmax) by 23%, 26%, and 17%.(1,2)|
03940|032|B||
03940|033|R|REFERENCES:|
03940|034|B||
03940|035|R|1.Vocabria (cabotegravir) tablets US prescribing information. ViiV|1
03940|036|R|  Healthcare January, 2021.|1
03940|037|R|2.Apretude (cabotegravir) US prescribing information. ViiV Healthcare|1
03940|038|R|  December, 2023.|1
03940|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
03940|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03941|001|T|MONOGRAPH TITLE:  Levoketoconazole/QT Prolonging Agents|
03941|002|B||
03941|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03941|004|L|is contraindicated and generally should not be dispensed or administered to|
03941|005|L|the same patient.|
03941|006|B||
03941|007|A|MECHANISM OF ACTION:  Levoketoconazole has been observed to prolong the QTc|
03941|008|A|interval in a dose-dependent manner.  Concurrent use with other agents that|
03941|009|A|prolong the QTc interval may result in additive effects on the QTc|
03941|010|A|interval.(1)|
03941|011|B||
03941|012|E|CLINICAL EFFECTS:  The concurrent use of levoketoconazole with other agents|
03941|013|E|that prolong the QTc interval may result in potentially life-threatening|
03941|014|E|cardiac arrhythmias, including torsades de pointes.(1)|
03941|015|B||
03941|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03941|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03941|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03941|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03941|020|P|female gender, or advanced age.(2)|
03941|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03941|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03941|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03941|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03941|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03941|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03941|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03941|028|B||
03941|029|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
03941|030|M|levoketoconazole is contraindicated with other agents that prolong the QT|
03941|031|M|interval.(1)|
03941|032|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
03941|033|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
03941|034|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
03941|035|M|syndrome (including first-degree family history).|
03941|036|M|   Use caution in patients with other risk factors for QT prolongation|
03941|037|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
03941|038|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
03941|039|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03941|040|M|hypokalemia or hypomagnesemia.|
03941|041|M|   If a patient develops QT prolongation with a QTc interval greater than|
03941|042|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03941|043|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03941|044|M|QTc interval prolongation recurs, permanently discontinue|
03941|045|M|levoketoconazole.(1)|
03941|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03941|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03941|048|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03941|049|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03941|050|B||
03941|051|D|DISCUSSION:  During phase 1 and 2 studies, which excluded patients with|
03941|052|D|baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced|
03941|053|D|QTcF > 500 msec, and 23 (14.7%) patients experienced change-from-baseline|
03941|054|D|QTcF > 60 msec.(1)|
03941|055|D|   Agents that are linked to this monograph may have varying degrees of|
03941|056|D|potential to prolong the QTc interval but are generally accepted to have a|
03941|057|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03941|058|D|been shown to prolong the QTc interval either through their mechanism of|
03941|059|D|action, through studies on their effects on the QTc interval, or through|
03941|060|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03941|061|D|and/or post-marketing reports.(3)|
03941|062|B||
03941|063|R|REFERENCES:|
03941|064|B||
03941|065|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03941|066|R|  Pharmaceuticals, Inc. June, 2023.|1
03941|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03941|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03941|069|R|  settings: a scientific statement from the American Heart Association and|6
03941|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03941|071|R|  2;55(9):934-47.|6
03941|072|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03941|073|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03941|074|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03941|075|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03942|001|T|MONOGRAPH TITLE:  Levoketoconazole/Possible QT Prolonging Agents|
03942|002|B||
03942|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03942|004|L|of severe adverse interaction.|
03942|005|B||
03942|006|A|MECHANISM OF ACTION:  Levoketoconazole has been observed to prolong the QTc|
03942|007|A|interval in a dose-dependent manner.  Concurrent use with other agents that|
03942|008|A|prolong the QTc interval may result in additive effects on the QTc|
03942|009|A|interval.(1)|
03942|010|B||
03942|011|E|CLINICAL EFFECTS:  The concurrent use of levoketoconazole with other agents|
03942|012|E|that prolong the QTc interval may result in potentially life-threatening|
03942|013|E|cardiac arrhythmias, including torsades de pointes.(1)|
03942|014|B||
03942|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03942|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03942|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03942|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03942|019|P|female gender, or advanced age.(2)|
03942|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03942|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03942|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03942|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03942|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03942|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03942|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03942|027|B||
03942|028|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
03942|029|M|levoketoconazole is contraindicated with other agents that prolong the QT|
03942|030|M|interval.(1)|
03942|031|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
03942|032|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
03942|033|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
03942|034|M|syndrome (including first-degree family history).|
03942|035|M|   Use caution in patients with other risk factors for QT prolongation|
03942|036|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
03942|037|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
03942|038|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03942|039|M|hypokalemia or hypomagnesemia.|
03942|040|M|   If a patient develops QT prolongation with a QTc interval greater than|
03942|041|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03942|042|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03942|043|M|QTc interval prolongation recurs, permanently discontinue|
03942|044|M|levoketoconazole.(1)|
03942|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03942|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03942|047|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03942|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03942|049|B||
03942|050|D|DISCUSSION:  During phase 1 and 2 studies, which excluded patients with|
03942|051|D|baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced|
03942|052|D|QTcF > 500 msec, and 23 (14.7%) patients experienced change-from-baseline|
03942|053|D|QTcF > 60 msec.(1)|
03942|054|D|   Agents that are linked to this monograph may have varying degrees of|
03942|055|D|potential to prolong the QTc interval but are generally accepted to have a|
03942|056|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03942|057|D|been shown to prolong the QTc interval either through their mechanism of|
03942|058|D|action, through studies on their effects on the QTc interval, or through|
03942|059|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03942|060|D|and/or post-marketing reports.(3)|
03942|061|B||
03942|062|R|REFERENCES:|
03942|063|B||
03942|064|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03942|065|R|  Pharmaceuticals, Inc. June, 2023.|1
03942|066|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03942|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03942|068|R|  settings: a scientific statement from the American Heart Association and|6
03942|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03942|070|R|  2;55(9):934-47.|6
03942|071|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03942|072|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03942|073|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03942|074|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03943|001|T|MONOGRAPH TITLE:  Dofetilide/Levoketoconazole|
03943|002|B||
03943|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03943|004|L|is contraindicated and generally should not be dispensed or administered to|
03943|005|L|the same patient.|
03943|006|B||
03943|007|A|MECHANISM OF ACTION:  Levoketoconazole may inhibit the elimination of|
03943|008|A|dofetilide by the renal organic cation transporter (OCT2) and Multidrug and|
03943|009|A|Toxin Extrusion (MATE) protein transporters in the kidneys.(1,2)|
03943|010|B||
03943|011|E|CLINICAL EFFECTS:  Concurrent use of levoketoconazole may result in elevated|
03943|012|E|levels of dofetilide.(1)  Dofetilide and levoketoconazole have been shown to|
03943|013|E|prolong the QTc interval in a dose-dependent fashion.(1,2)|
03943|014|E|   Concurrent use with other agents that prolong the QTc interval may result|
03943|015|E|in additive effects on the QTc interval which may result in potentially|
03943|016|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03943|017|E|(TdP).(2)|
03943|018|B||
03943|019|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
03943|020|P|prolongation as dofetilide is primarily renally eliminated.  To prevent|
03943|021|P|increased serum levels and risk for ventricular arrhythmias, dofetilide must|
03943|022|P|be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)|
03943|023|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03943|024|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03943|025|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03943|026|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03943|027|P|advanced age.(3)|
03943|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03943|029|P|higher systemic concentrations of either QT prolonging drug are additional|
03943|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03943|031|P|drug concentrations include rapid infusion of an intravenous dose or|
03943|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03943|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03943|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03943|035|B||
03943|036|M|PATIENT MANAGEMENT:  Concurrent use of dofetilide and levoketoconazole is|
03943|037|M|contraindicated.  If dofetilide is to be discontinued, a washout of at least|
03943|038|M|2 days is recommended prior to starting levoketoconazole.(1,2)|
03943|039|M|   If concurrent therapy is deemed medically necessary, obtain serum|
03943|040|M|calcium, magnesium, and potassium levels and monitor ECG at baseline and at|
03943|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03943|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03943|043|B||
03943|044|D|DISCUSSION:  Levoketoconazole has been shown to inhibit OCT2 and MATE in|
03943|045|D|vitro and in vivo and is expected to inhibit the excretion of dofetilide.(1)|
03943|046|B||
03943|047|R|REFERENCES:|
03943|048|B||
03943|049|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03943|050|R|  Pharmaceuticals, Inc. June, 2023.|1
03943|051|R|2.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
03943|052|R|  2013.|1
03943|053|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03943|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03943|055|R|  settings: a scientific statement from the American Heart Association and|6
03943|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03943|057|R|  2;55(9):934-47.|6
03944|001|T|MONOGRAPH TITLE:  Levoketoconazole/Strong CYP3A4 Inhibitors that Prolong QT|
03944|002|B||
03944|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03944|004|L|is contraindicated and generally should not be dispensed or administered to|
03944|005|L|the same patient.|
03944|006|B||
03944|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QT interval|
03944|008|A|may inhibit the metabolism of levoketoconazole and result in additive|
03944|009|A|effects on the QT interval.(1)|
03944|010|B||
03944|011|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03944|012|E|that prolongs the QT interval may result in elevated levels of and toxicity|
03944|013|E|from levoketoconazole.(1)  Elevated levels of levoketoconazole may increase|
03944|014|E|the risk of QTc prolongation and potentially life-threatening cardiac|
03944|015|E|arrhythmias, including torsades de pointes, hepatotoxicity, hypertension,|
03944|016|E|hypokalemia, and hemorrhagic events.(1)|
03944|017|B||
03944|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03944|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03944|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03944|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03944|022|P|female gender, or advanced age.(2)|
03944|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03944|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03944|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03944|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03944|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03944|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03944|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03944|030|B||
03944|031|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
03944|032|M|levoketoconazole is contraindicated with other agents that prolong the QT|
03944|033|M|interval. Avoid the use of strong CYP3A4 inhibitors two weeks before and|
03944|034|M|during levoketoconazole treatment.|
03944|035|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
03944|036|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
03944|037|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
03944|038|M|syndrome (including first-degree family history).|
03944|039|M|   Use caution in patients with other risk factors for QT prolongation|
03944|040|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
03944|041|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
03944|042|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03944|043|M|hypokalemia or hypomagnesemia.|
03944|044|M|   If a patient develops QT prolongation with a QTc interval greater than|
03944|045|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03944|046|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03944|047|M|QTc interval prolongation recurs, permanently discontinue|
03944|048|M|levoketoconazole.(1)|
03944|049|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03944|050|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03944|051|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03944|052|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03944|053|B||
03944|054|D|DISCUSSION:  The US manufacturer of levoketoconazole states levoketoconazole|
03944|055|D|is both an inhibitor and substrate of CYP3A4.(1)|
03944|056|D|   During phase 1 and 2 studies, which excluded patients with baseline QTcF|
03944|057|D|interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500|
03944|058|D|msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60|
03944|059|D|msec.(1)|
03944|060|D|   Agents that are linked to this monograph may have varying degrees of|
03944|061|D|potential to prolong the QTc interval but are generally accepted to have a|
03944|062|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03944|063|D|been shown to prolong the QTc interval either through their mechanism of|
03944|064|D|action, through studies on their effects on the QTc interval, or through|
03944|065|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03944|066|D|and/or post-marketing reports.(3)|
03944|067|D|   Strong CYP3A4 inhibitors linked to this monograph include: ceritinib,|
03944|068|D|clarithromycin, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir,|
03944|069|D|telithromycin, and voriconazole.(4)|
03944|070|B||
03944|071|R|REFERENCES:|
03944|072|B||
03944|073|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03944|074|R|  Pharmaceuticals, Inc. June, 2023.|1
03944|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03944|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03944|077|R|  settings: a scientific statement from the American Heart Association and|6
03944|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03944|079|R|  2;55(9):934-47.|6
03944|080|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03944|081|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03944|082|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03944|083|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03944|084|R|4.This information is based on an extract from the Certara Drug Interaction|6
03944|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03945|001|T|MONOGRAPH TITLE:  Levoketoconazole/Strong CYP3A4 Inhibitors|
03945|002|B||
03945|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03945|004|L|of severe adverse interaction.|
03945|005|B||
03945|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03945|007|A|levoketoconazole.(1)|
03945|008|B||
03945|009|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03945|010|E|may result in elevated levels of and toxicity from levoketoconazole.(1)|
03945|011|E|Elevated levels of levoketoconazole may increase the risk of QTc|
03945|012|E|prolongation and potentially life-threatening cardiac arrhythmias, including|
03945|013|E|torsades de pointes, hepatotoxicity, hypertension, hypokalemia, and|
03945|014|E|hemorrhagic events.(1)|
03945|015|B||
03945|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03945|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03945|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03945|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03945|020|P|female gender, or advanced age.(2)|
03945|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03945|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03945|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03945|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03945|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03945|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03945|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03945|028|B||
03945|029|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states to avoid|
03945|030|M|the use of strong CYP3A4 inhibitors two weeks before and during|
03945|031|M|levoketoconazole treatment.(1)|
03945|032|M|   Levoketoconazole is contraindicated in patients with a concurrent QT|
03945|033|M|prolonging agents, prolonged QTcF interval of greater than 470 msec at|
03945|034|M|baseline, history of torsades de pointes, ventricular tachycardia,|
03945|035|M|ventricular fibrillation, or long QT syndrome (including first-degree family|
03945|036|M|history).|
03945|037|M|   Use caution in patients with other risk factors for QT prolongation|
03945|038|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
03945|039|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
03945|040|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03945|041|M|hypokalemia or hypomagnesemia.|
03945|042|M|   If a patient develops QT prolongation with a QTc interval greater than|
03945|043|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03945|044|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03945|045|M|QTc interval prolongation recurs, permanently discontinue|
03945|046|M|levoketoconazole.(1)|
03945|047|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03945|048|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03945|049|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03945|050|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03945|051|B||
03945|052|D|DISCUSSION:  The US manufacturer of levoketoconazole states levoketoconazole|
03945|053|D|is both an inhibitor and substrate of CYP3A4.(1)|
03945|054|D|   During phase 1 and 2 studies, which excluded patients with baseline QTcF|
03945|055|D|interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500|
03945|056|D|msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60|
03945|057|D|msec.(1)|
03945|058|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
03945|059|D|cobicistat, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
03945|060|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03945|061|D|tipranavir, troleandomycin, and tucatinib.(3,4)|
03945|062|B||
03945|063|R|REFERENCES:|
03945|064|B||
03945|065|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03945|066|R|  Pharmaceuticals, Inc. June, 2023.|1
03945|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03945|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03945|069|R|  settings: a scientific statement from the American Heart Association and|6
03945|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03945|071|R|  2;55(9):934-47.|6
03945|072|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03945|073|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03945|074|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03945|075|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03945|076|R|4.This information is based on an extract from the Certara Drug Interaction|6
03945|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03946|001|T|MONOGRAPH TITLE:  Levoketoconazole/Apalutamide|
03946|002|B||
03946|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03946|004|L|of severe adverse interaction.|
03946|005|B||
03946|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03946|007|A|levoketoconazole.(1)  Apalutamide is a strong CYP3A4 inducer.(2,3)|
03946|008|B||
03946|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may reduce the|
03946|010|E|clinical effectiveness of levoketoconazole.(1)|
03946|011|B||
03946|012|P|PREDISPOSING FACTORS:  None determined.|
03946|013|B||
03946|014|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
03946|015|M|concurrent use with strong CYP3A4 inducers is not recommended.  Avoid use|
03946|016|M|during and two weeks before treatment with levoketoconazole.(1)|
03946|017|B||
03946|018|D|DISCUSSION:  The US manufacturer of levoketoconazole states that|
03946|019|D|levoketoconazole is a substrate of CYP3A4.(1)|
03946|020|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide.(2,3)|
03946|021|B||
03946|022|R|REFERENCES:|
03946|023|B||
03946|024|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03946|025|R|  Pharmaceuticals, Inc. June, 2023.|1
03946|026|R|2.This information is based on an extract from the Certara Drug Interaction|6
03946|027|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03946|028|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03946|029|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03946|030|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03946|031|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03946|032|R|  11/14/2017.|1
03947|001|T|MONOGRAPH TITLE:  Atorvastatin/Levoketoconazole|
03947|002|B||
03947|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03947|004|L|take action as needed.|
03947|005|B||
03947|006|A|MECHANISM OF ACTION:  Levoketoconazole may inhibit the metabolism of|
03947|007|A|atorvastatin by CYP3A4.(1)|
03947|008|B||
03947|009|E|CLINICAL EFFECTS:  Concurrent use of levoketoconazole may result in elevated|
03947|010|E|levels of atorvastatin and increase the risk of myopathy and|
03947|011|E|rhabdomyolysis.(1,2)|
03947|012|B||
03947|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
03947|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
03947|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
03947|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
03947|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
03947|018|P|transporter OATP1B1 may have increased statin concentrations and be|
03947|019|P|predisposed to myopathy or rhabdomyolysis.|
03947|020|B||
03947|021|M|PATIENT MANAGEMENT:  Concurrent use of levoketoconazole with atorvastatin|
03947|022|M|may require a dose reduction.  Use the lowest dose possible of atorvastatin|
03947|023|M|and monitor for adverse reactions, especially if the atorvastatin dose|
03947|024|M|exceeds 20 mg.  Patients should be instructed to report any signs of|
03947|025|M|myopathy.(1,2)|
03947|026|M|   Fluvastatin, pitavastatin and pravastatin, HMG-CoA reductase inhibitors|
03947|027|M|that are not metabolized by CYP3A4, may be alternatives to atorvastatin in|
03947|028|M|patients receiving levoketoconazole.|
03947|029|B||
03947|030|D|DISCUSSION:  In a drug interaction study with 23 healthy subjects,|
03947|031|D|levoketoconazole (400 mg daily) increased the area-under-curve (AUC) and|
03947|032|D|maximum concentration (Cmax) of atorvastatin by 317.6% and 96.7%,|
03947|033|D|respectively.(1)|
03947|034|B||
03947|035|R|REFERENCES:|
03947|036|B||
03947|037|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03947|038|R|  Pharmaceuticals, Inc. June, 2023.|1
03947|039|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
03947|040|R|  2020.|1
03948|001|T|MONOGRAPH TITLE:  Slt HMG-CoA Reductase Inhibitors/Levoketoconazole|
03948|002|B||
03948|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03948|004|L|is contraindicated and generally should not be dispensed or administered to|
03948|005|L|the same patient.|
03948|006|B||
03948|007|A|MECHANISM OF ACTION:  Levoketoconazole(1) may inhibit the metabolism of|
03948|008|A|cerivastatin(2), lovastatin(3) or simvastatin(4) by CYP3A4.|
03948|009|B||
03948|010|E|CLINICAL EFFECTS:  Concurrent administration of levoketoconazole may result|
03948|011|E|in increased levels of cerivastatin, lovastatin or simvastatin, which may|
03948|012|E|result in an increased risk of rhabdomyolysis.(1-4)|
03948|013|B||
03948|014|P|PREDISPOSING FACTORS:  The risk of myopathy or rhabdomyolysis may be greater|
03948|015|P|in patients 65 years and older, inadequately treated hypothyroidism, renal|
03948|016|P|impairment, carnitine deficiency, malignant hyperthermia, or in patients|
03948|017|P|with a history of myopathy or rhabdomyolysis.  Patients with a SLCOB1|
03948|018|P|polymorphism that leads to decreased function of the hepatic uptake|
03948|019|P|transporter OATP1B1 may have increased statin concentrations and be|
03948|020|P|predisposed to myopathy or rhabdomyolysis.|
03948|021|B||
03948|022|M|PATIENT MANAGEMENT:  Strong CYP3A4 inhibitors such as levoketoconazole are|
03948|023|M|contraindicated with cerivastatin, lovastatin and simvastatin.(1-4)|
03948|024|B||
03948|025|D|DISCUSSION:  There are multiple studies and case reports showing increased|
03948|026|D|levels and cases of rhabdomyolysis with other strong CYP3A4 inhibitors (e.g.|
03948|027|D|itraconazole, posaconazole, and ketoconazole).|
03948|028|D|   In a double-blind cross-over study in 12 healthy subjects, administration|
03948|029|D|of lovastatin (40 mg single dose) after 4 days of itraconazole (200 mg|
03948|030|D|daily) increased lovastatin maximum concentration (Cmax) by more than|
03948|031|D|20-fold.  Lovastatin area-under-curve (AUC) and half-life (T1/2) increased|
03948|032|D|from undetectable levels in all but 3 subjects during placebo phase to 546|
03948|033|D|ng/ml and 3.6+/-1 hours, respectively, during itraconazole coadministration.|
03948|034|D|The lovastatin acid Cmax and AUC increased 13-fold and 23-fold,|
03948|035|D|respectively, during concurrent itraconazole.  The T1/2 of lovastatin acid|
03948|036|D|increased from undetectable levels in the placebo phase to 6+/-1.1 hours in|
03948|037|D|the itraconazole phase.(5)|
03948|038|D|   In a double-blind cross-over study in 10 subjects, administration of|
03948|039|D|lovastatin (40 mg single dose) after 4 days of itraconazole (100 mg daily)|
03948|040|D|increased lovastatin Cmax and AUC by about 15-fold.  The lovastatin Cmax and|
03948|041|D|AUC increased 12-fold and 15-fold, respectively, during itraconazole.  The|
03948|042|D|lovastatin and lovastatin acid T1/2 increased from undetectable levels to|
03948|043|D|3.7+/-3.8 hours and 4.7+/-4.0 hours, respectively, during itraconazole.(6)|
03948|044|D|   In a randomized, fixed-sequence, parallel-group, single-center,|
03948|045|D|open-label study, administration of different strengths of posaconazole (50,|
03948|046|D|100, or 200 mg) were evaluated with regards to its effects on simvastatin|
03948|047|D|concentration.  The regimen consisted of midazolam 2 mg orally 9 days prior|
03948|048|D|to the initiation of posaconazole and simvastatin 40 mg orally 6 days prior|
03948|049|D|to initiation of posaconazole.  Posaconazole was then given alone on days|
03948|050|D|1-7 once daily followed by coadministration with midazolam on day 8 and then|
03948|051|D|posaconazole again alone on days 9-10.  On day 11 simvastatin was given with|
03948|052|D|posaconazole followed by posaconazole alone on days 12-13. Results showed a|
03948|053|D|significant increase in the Cmax and AUC of simvastatin when given with|
03948|054|D|posaconazole vs. given alone.(7)|
03948|055|D|   Administration of cerivastatin (0.3 mg) with itraconazole (200 mg daily X|
03948|056|D|10 days) increased cerivastatin AUC and Cmax 38% and 12%, respectively.|
03948|057|D|There was no effect on itraconazole pharmacokinetics. Administration of|
03948|058|D|cerivastatin (0.8 mg single dose) with itraconazole increased cerivastatin|
03948|059|D|AUC and Cmax by 27% and 25%, respectively.(8)|
03948|060|D|   In a randomized, double-blind, cross-over study in 10 healthy subjects,|
03948|061|D|the administration of cerivastatin (0.3 mg single dose) on day 4 of|
03948|062|D|itraconazole (200 mg) increased cerivastatin parent compound AUC 15%.|
03948|063|D|Cerivastatin lactone AUC, Cmax, and T1/2 increased 2.6-fold, 1.8-fold, and|
03948|064|D|3.2-fold, respectively.  The M-23 active metabolite AUC increased 36%.  The|
03948|065|D|AUC and T1/2 of all active cerivastatin derivatives increased 27% and 40%,|
03948|066|D|respectively.(9)|
03948|067|D|   There are case reports of rhabdomyolysis with concurrent itraconazole and|
03948|068|D|lovastatin(10-12) and with concurrent itraconazole(13-17) or|
03948|069|D|ketoconazole(18-20) and simvastatin.|
03948|070|B||
03948|071|R|REFERENCES:|
03948|072|B||
03948|073|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03948|074|R|  Pharmaceuticals, Inc. June, 2023.|1
03948|075|R|2.Baycol (cerivastatin) US prescribing information. Bayer Corporation|1
03948|076|R|  December, 2000.|1
03948|077|R|3.Mevacor (lovastatin) US prescribing information. Merck & Co., Inc.|1
03948|078|R|  February, 2014.|1
03948|079|R|4.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
03948|080|R|  2023.|1
03948|081|R|5.Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma|2
03948|082|R|  concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996|2
03948|083|R|  Jul;60(1):54-61.|2
03948|084|R|6.Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on|2
03948|085|R|  the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol|2
03948|086|R|  1998 Jul;46(1):49-53.|2
03948|087|R|7.Krishna G, Ma L, Prasad P, Moton A, Martinho M, O'Mara E. Effect of|2
03948|088|R|  posaconazole on the pharmacokinetics of simvastatin and midazolam in|2
03948|089|R|  healthy volunteers. Expert Opin Drug Metab Toxicol 2012 Jan;8(1):1-10.|2
03948|090|R|8.Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on cerivastatin|2
03948|091|R|  pharmacokinetics. Eur J Clin Pharmacol 1999 Jan;54(11):851-5.|2
03948|092|R|9.Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P.|2
03948|093|R|  Itraconazole alters the pharmacokinetics of atorvastatin to a greater|2
03948|094|R|  extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000|2
03948|095|R|  Oct;68(4):391-400.|2
03948|096|R|10.Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin|3
03948|097|R|   and the antifungal agent itraconazole. N Engl J Med 1995 Sep 7;|3
03948|098|R|   333(10):664-5.|3
03948|099|R|11.Horn M. Coadministration of itraconazole with hypolipidemic agents may|3
03948|100|R|   induce rhabdomyolysis in healthy individuals. Arch Dermatol 1996 Oct;|3
03948|101|R|   132(10):1254.|3
03948|102|R|12.Segaert MF, De Soete C, Vandewiele I, Verbanck J.|3
03948|103|R|   Drug-interaction-induced rhabdomyolysis. Nephrol Dial Transplant 1996|3
03948|104|R|   Sep;11(9):1846-7.|3
03948|105|R|13.Roques S, Lytrivi M, Rusu D, Devriendt J, De Bels D.|3
03948|106|R|   Rhabdomyolysis-induced acute renal failure due to itraconazole and|3
03948|107|R|   simvastatin association. Drug Metabol Drug Interact 2011;26(2):79-80.|3
03948|108|R|14.Tiessen RG, Lagerwey HJ, Jager GJ, Sprenger HG. Drug interaction caused|3
03948|109|R|   by communication problems. Rhabdomyolysis due to a combination of|3
03948|110|R|   itraconazole and simvastatin. Ned Tijdschr Geneeskd 2010;154:A762.|3
03948|111|R|15.Saliba WR, Elias M. Severe myopathy induced by the co-administration of|3
03948|112|R|   simvastatin and itraconazole. Eur J Intern Med 2005 Aug;16(4):305.|3
03948|113|R|16.Vlahakos DV, Manginas A, Chilidou D, Zamanika C, Alivizatos PA.|3
03948|114|R|   Itraconazole-induced rhabdomyolysis and acute renal failure in a heart|3
03948|115|R|   transplant recipient treated with simvastatin and cyclosporine.|3
03948|116|R|   Transplantation 2002 Jun 27;73(12):1962-4.|3
03948|117|R|17.Maxa JL, Melton LB, Ogu CC, Sills MN, Limanni A. Rhabdomyolysis after|3
03948|118|R|   concomitant use of cyclosporine, simvastatin, gemfibrozil, and|3
03948|119|R|   itraconazole. Ann Pharmacother 2002 May;36(5):820-3.|3
03948|120|R|18.Gilad R, Lampl Y. Rhabdomyolysis induced by simvastatin and ketoconazole|3
03948|121|R|   treatment. Clin Neuropharmacol 1999 Sep-Oct;22(5):295-7.|3
03948|122|R|19.Watkins JL, Atkinson BJ, Pagliaro LC. Rhabdomyolysis in a Prostate Cancer|3
03948|123|R|   Patient Taking Ketoconazole and Simvastatin:  Case Report and Review of|3
03948|124|R|   the Literature (February). Ann Pharmacother 2011 Feb 8.|3
03948|125|R|20.Itakura H, Vaughn D, Haller DG, O'Dwyer PJ. Rhabdomyolysis from|3
03948|126|R|   cytochrome p-450 interaction of ketoconazole and simvastatin  in prostate|3
03948|127|R|   cancer. J Urol 2003 Feb;169(2):613.|3
03949|001|T|MONOGRAPH TITLE:  Levoketoconazole/H2 Antagonists; Proton Pump Inhibitors|
03949|002|B||
03949|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03949|004|L|of severe adverse interaction.|
03949|005|B||
03949|006|A|MECHANISM OF ACTION:  The aqueous solubility of levoketoconazole is pH|
03949|007|A|dependent.  Higher gastric pH leads to lower solubility.  H2-receptor|
03949|008|A|antagonists (H2RAs) and proton pump inhibitors (PPIs) increase gastric pH|
03949|009|A|and may decrease the absorption of levoketoconazole.(1)|
03949|010|B||
03949|011|E|CLINICAL EFFECTS:  Coadministration of H2RAs or PPIs may reduce the|
03949|012|E|bioavailability of levoketoconazole, leading to decreased systemic levels|
03949|013|E|and effectiveness.(1)|
03949|014|B||
03949|015|P|PREDISPOSING FACTORS:  None determined.|
03949|016|B||
03949|017|M|PATIENT MANAGEMENT:  Coadministration of levoketoconazole with PPIs and|
03949|018|M|H2RAs should be avoided.(1)|
03949|019|B||
03949|020|D|DISCUSSION:  Levoketoconazole is very slightly soluble in water but soluble|
03949|021|D|below pH 2.  H2RAs and PPIs raise gastric pH and may impair dissolution and|
03949|022|D|absorption of levoketoconazole.(1)|
03949|023|B||
03949|024|R|REFERENCE:|
03949|025|B||
03949|026|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03949|027|R|  Pharmaceuticals, Inc. June, 2023.|1
03950|001|T|MONOGRAPH TITLE:  Levoketoconazole/Strong CYP3A4 Inducers|
03950|002|B||
03950|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03950|004|L|of severe adverse interaction.|
03950|005|B||
03950|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
03950|007|A|levoketoconazole.(1)|
03950|008|B||
03950|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may reduce the|
03950|010|E|clinical effectiveness of levoketoconazole.(1)|
03950|011|B||
03950|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03950|013|P|of the inducer for longer than 1-2 weeks.|
03950|014|B||
03950|015|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
03950|016|M|concurrent use with strong CYP3A4 inducers is not recommended.  Avoid use|
03950|017|M|during and two weeks before treatment with levoketoconazole.(1)|
03950|018|B||
03950|019|D|DISCUSSION:  The US manufacturer of levoketoconazole states that|
03950|020|D|levoketoconazole is a substrate of CYP3A4.(1)|
03950|021|D|   Strong CYP3A4 inducers linked to this monograph are: barbiturates,|
03950|022|D|carbamazepine, enzalutamide, fosphenytoin, mitotane, phenobarbital,|
03950|023|D|phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(3,4)|
03950|024|B||
03950|025|R|REFERENCES:|
03950|026|B||
03950|027|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03950|028|R|  Pharmaceuticals, Inc. June, 2023.|1
03950|029|R|2.This information is based on an extract from the Certara Drug Interaction|6
03950|030|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03950|031|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03950|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03950|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03950|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03950|035|R|  11/14/2017.|1
03951|001|T|MONOGRAPH TITLE:  Levoketoconazole/Sucralfate|
03951|002|B||
03951|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03951|004|L|of severe adverse interaction.|
03951|005|B||
03951|006|A|MECHANISM OF ACTION:  Sucralfate may decrease the absorption of|
03951|007|A|levoketoconazole.(1)|
03951|008|B||
03951|009|E|CLINICAL EFFECTS:  The concurrent use of sucralfate and levoketoconazole may|
03951|010|E|decrease the absorption of levoketoconazole, which may result in therapeutic|
03951|011|E|failure.(1)|
03951|012|B||
03951|013|P|PREDISPOSING FACTORS:  None determined.|
03951|014|B||
03951|015|M|PATIENT MANAGEMENT:  Coadministration of levoketoconazole with sucralfate|
03951|016|M|should be avoided.(1)|
03951|017|B||
03951|018|D|DISCUSSION:  Sucralfate may impair absorption of levoketoconazole and should|
03951|019|D|be avoided.(1)|
03951|020|B||
03951|021|R|REFERENCE:|
03951|022|B||
03951|023|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03951|024|R|  Pharmaceuticals, Inc. June, 2023.|1
03952|001|T|MONOGRAPH TITLE:  Levoketoconazole/Antacids|
03952|002|B||
03952|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03952|004|L|take action as needed.|
03952|005|B||
03952|006|A|MECHANISM OF ACTION:  The aqueous solubility of levoketoconazole is pH|
03952|007|A|dependent.  Higher gastric pH leads to lower solubility.  Antacids increase|
03952|008|A|gastric pH and may decrease the absorption of levoketoconazole.(1)|
03952|009|B||
03952|010|E|CLINICAL EFFECTS:  Coadministration of antacids may reduce the|
03952|011|E|bioavailability of levoketoconazole, leading to decreased systemic levels|
03952|012|E|and effectiveness.(1)|
03952|013|B||
03952|014|P|PREDISPOSING FACTORS:  None determined.|
03952|015|B||
03952|016|M|PATIENT MANAGEMENT:  Coadministration of levoketoconazole with proton pump|
03952|017|M|inhibitors and H2 antagonists should be avoided.  If coadministration with|
03952|018|M|an acid-reducing agent is unavoidable, take the antacid 2 hours before|
03952|019|M|levoketoconazole.(1)|
03952|020|B||
03952|021|D|DISCUSSION:  Levoketoconazole is very slightly soluble in water but soluble|
03952|022|D|below pH 2.  Antacids raise gastric pH and may impair dissolution and|
03952|023|D|absorption of levoketoconazole.(1)|
03952|024|B||
03952|025|R|REFERENCE:|
03952|026|B||
03952|027|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03952|028|R|  Pharmaceuticals, Inc. June, 2023.|1
03953|001|T|MONOGRAPH TITLE:  Levoketoconazole/Slt Strong CYP3A4 Inducers that Prolong|
03953|002|T|QT|
03953|003|B||
03953|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03953|005|L|is contraindicated and generally should not be dispensed or administered to|
03953|006|L|the same patient.|
03953|007|B||
03953|008|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 that prolong the QTc|
03953|009|A|interval may induce the metabolism of levoketoconazole and result in|
03953|010|A|additive risk of QT prolongation.(1-3)|
03953|011|B||
03953|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
03953|013|E|may reduce the clinical effectiveness of levoketoconazole and may cause|
03953|014|E|additive effects on the QTc interval, which may result in life-threatening|
03953|015|E|cardiac arrhythmias including torsades de pointes.(1-3)|
03953|016|B||
03953|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03953|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03953|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03953|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03953|021|P|female gender, or advanced age.(3)|
03953|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03953|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03953|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03953|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03953|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03953|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03953|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03953|029|P|   Induction effects may be more likely with regular use of the inducer for|
03953|030|P|longer than 1-2 weeks.|
03953|031|B||
03953|032|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
03953|033|M|levoketoconazole is contraindicated with other agents that prolong the QT|
03953|034|M|interval. Avoid the use of strong CYP3A4 inducers two weeks before and|
03953|035|M|during levoketoconazole treatment.(1)|
03953|036|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
03953|037|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
03953|038|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
03953|039|M|syndrome (including first-degree family history).|
03953|040|M|   Use caution in patients with other risk factors for QT prolongation|
03953|041|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
03953|042|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
03953|043|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03953|044|M|hypokalemia or hypomagnesemia.|
03953|045|M|   If a patient develops QT prolongation with a QTc interval greater than|
03953|046|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03953|047|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03953|048|M|QTc interval prolongation recurs, permanently discontinue|
03953|049|M|levoketoconazole.(1)|
03953|050|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03953|051|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03953|052|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03953|053|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03953|054|B||
03953|055|D|DISCUSSION:  The US manufacturer of levoketoconazole states levoketoconazole|
03953|056|D|is both an inhibitor and substrate of CYP3A4.(1)|
03953|057|D|   During phase 1 and 2 studies, which excluded patients with baseline QTcF|
03953|058|D|interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500|
03953|059|D|msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60|
03953|060|D|msec.(1)|
03953|061|D|   Agents that are linked to this monograph may have varying degrees of|
03953|062|D|potential to prolong the QTc interval but are generally accepted to have a|
03953|063|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03953|064|D|been shown to prolong the QTc interval either through their mechanism of|
03953|065|D|action, through studies on their effects on the QTc interval, or through|
03953|066|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03953|067|D|and/or post-marketing reports.(3)|
03953|068|D|   Strong CYP3A4 inducers linked to this monograph are: encorafenib,|
03953|069|D|thioridazine.(3,4)|
03953|070|B||
03953|071|R|REFERENCES:|
03953|072|B||
03953|073|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03953|074|R|  Pharmaceuticals, Inc. June, 2023.|1
03953|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03953|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03953|077|R|  settings: a scientific statement from the American Heart Association and|6
03953|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03953|079|R|  2;55(9):934-47.|6
03953|080|R|3.This information is based on an extract from the Certara Drug Interaction|6
03953|081|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03953|082|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03953|083|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03953|084|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03953|085|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03953|086|R|  11/14/2017.|1
03954|001|T|MONOGRAPH TITLE:  Midostaurin/Slt Strong CYP3A4 Inhibitors that Prolong QT|
03954|002|B||
03954|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03954|004|L|of severe adverse interaction.|
03954|005|B||
03954|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03954|007|A|interval may inhibit the metabolism of midostaurin and result in additive|
03954|008|A|risk of QT prolongation.(1) Levoketoconazole can also prolong the QTc|
03954|009|A|interval.(2)|
03954|010|B||
03954|011|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03954|012|E|prolong QT may result in elevated levels of and toxicity from midostaurin,|
03954|013|E|including additive QTc prolongation, which may result in potentially|
03954|014|E|life-threatening cardiac arrhythmias, including torsades de pointes|
03954|015|E|(TdP).(1)|
03954|016|B||
03954|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03954|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
03954|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03954|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03954|021|P|female gender, or advanced age.(3)|
03954|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03954|023|P|higher systemic concentrations of either QT prolonging drug are additional|
03954|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03954|025|P|drug concentrations include rapid infusion of an intravenous dose or|
03954|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03954|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03954|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03954|029|B||
03954|030|M|PATIENT MANAGEMENT:  The manufacturer of midostaurin states to consider|
03954|031|M|alternative therapies that do not inhibit CYP3A4 whenever possible.|
03954|032|M|Consider interval assessments of QT by electrocardiogram (ECG) if taken|
03954|033|M|concurrently with medications that can prolong the QT interval.(1)|
03954|034|M|   Monitor patient for signs of midostaurin toxicity with concurrent use,|
03954|035|M|especially during the first week of concurrent therapy in advanced systemic|
03954|036|M|mastocytosis (SM) population and during the first week of each cycle of|
03954|037|M|chemotherapy in acute myeloid leukemia (AML) population.(1)|
03954|038|M|   The US manufacturer of adagrasib states that adagrasib should be avoided|
03954|039|M|with other agents that prolong the QT interval.(4)|
03954|040|M|   The US manufacturer of levoketoconazole states that levoketoconazole is|
03954|041|M|contraindicated with other agents that prolong the QT interval.(2)|
03954|042|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
03954|043|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
03954|044|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
03954|045|M|syndrome (including first-degree family history).  Use caution in patients|
03954|046|M|with other risk factors for QT prolongation including congestive heart|
03954|047|M|failure, bradyarrhythmias, and uncorrected electrolyte abnormalities.|
03954|048|M|Consider more frequent ECG monitoring.(2)|
03954|049|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03954|050|M|hypokalemia or hypomagnesemia.|
03954|051|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03954|052|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03954|053|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03954|054|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03954|055|B||
03954|056|D|DISCUSSION:  Midostaurin is a substrate of CYP3A4.(1)|
03954|057|D|   Concurrent administration of ketoconazole (400 mg daily for 10 days, a|
03954|058|D|strong CYP3A4 inhibitor) with a single 50 mg dose of midostaurin on day 6|
03954|059|D|increased the area-under-curve (AUC) of midostaurin and the active|
03954|060|D|metabolite, CGP62221, 10.4-fold and 3.5-fold, respectively.  The AUC over|
03954|061|D|time to last measurable concentration of CGP62221 increased by 1.2-fold|
03954|062|D|compared to midostaurin alone.(1)|
03954|063|D|   Concurrent administration of itraconazole (100 mg twice daily on days|
03954|064|D|22-28 for 13 doses, a strong CYP3A4 inhibitor) with multiple doses of|
03954|065|D|midostaurin (100 mg twice daily on days 1-2 and 50 mg twice daily on days|
03954|066|D|3-28) increased day 28 minimum concentration (Cmin) of midostaurin, CGP62221|
03954|067|D|and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, compared to|
03954|068|D|day 21 Cmin concentrations with midostaurin alone.(1)|
03954|069|D|   During phase 1 and 2 studies of levoketoconazole, which excluded patients|
03954|070|D|with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients|
03954|071|D|experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
03954|072|D|change-from-baseline QTcF > 60 msec.(2)|
03954|073|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
03954|074|D|lonafarnib, and levoketoconazole.(2,5-6)|
03954|075|B||
03954|076|R|REFERENCES:|
03954|077|B||
03954|078|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
03954|079|R|  Corporation November, 2021.|1
03954|080|R|2.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03954|081|R|  Pharmaceuticals, Inc. June, 2023.|1
03954|082|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03954|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03954|084|R|  settings: a scientific statement from the American Heart Association and|6
03954|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03954|086|R|  2;55(9):934-47.|6
03954|087|R|4.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
03954|088|R|  December 2022.|1
03954|089|R|5.This information is based on an extract from the Certara Drug Interaction|6
03954|090|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03954|091|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
03954|092|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03954|093|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03954|094|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03954|095|R|  11/14/2017.|1
03955|001|T|MONOGRAPH TITLE:  Eletriptan/Levoketoconazole|
03955|002|B||
03955|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03955|004|L|is contraindicated and generally should not be dispensed or administered to|
03955|005|L|the same patient.|
03955|006|B||
03955|007|A|MECHANISM OF ACTION:  Levoketoconazole is a strong inhibitor of CYP3A4 and|
03955|008|A|may inhibit the metabolism of eletriptan via this pathway.(1-3)|
03955|009|B||
03955|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
03955|011|E|adverse effects from eletriptan.(1,2)|
03955|012|B||
03955|013|P|PREDISPOSING FACTORS:  None determined.|
03955|014|B||
03955|015|M|PATIENT MANAGEMENT:  The US manufacturer of eletriptan states that|
03955|016|M|eletriptan should not be used within at least 72 hours of administration of|
03955|017|M|a strong CYP3A4 inhibitor.(2)|
03955|018|B||
03955|019|D|DISCUSSION:  In clinical studies, ketoconazole (400 mg), a strong CYP3A4|
03955|020|D|inhibitor, increased the eletriptan maximum concentration (Cmax) and|
03955|021|D|area-under-curve (AUC) by 2.7-fold and 5.9-fold, respectively.  The|
03955|022|D|half-life of eletriptan increased from 4.8 hours to 8.3 hours.(1)  The time|
03955|023|D|to Cmax (Tmax) increased from 2.8 hours to 5.4 hours.(2)|
03955|024|B||
03955|025|R|REFERENCES:|
03955|026|B||
03955|027|R|1.Relpax (eletriptan hydrobromide) UK summary of product characteristics.|1
03955|028|R|  Pfizer Limited September, 2013.|1
03955|029|R|2.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
03955|030|R|  March, 2020.|1
03955|031|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03955|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03955|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03955|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03955|035|R|  11/14/2017.|1
03955|036|R|4.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03955|037|R|  Pharmaceuticals, Inc. June, 2023.|1
03956|001|T|MONOGRAPH TITLE:  Iloperidone/Slt Strong CYP3A4 Inhibitors that Prolong QT|
03956|002|B||
03956|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03956|004|L|of severe adverse interaction.|
03956|005|B||
03956|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03956|007|A|iloperidone and result in additive risk of QT prolongation.(1)|
03956|008|B||
03956|009|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
03956|010|E|may result in elevated levels of and toxicity from iloperidone.(1)  Elevated|
03956|011|E|levels of iloperidone and concurrent use with agents that prolong the QTc|
03956|012|E|interval may increase the risk of QTc prolongation.(1)|
03956|013|B||
03956|014|P|PREDISPOSING FACTORS:  With iloperidone, the risk of QT prolongation or|
03956|015|P|torsades de pointes may be increased in patients with cardiovascular disease|
03956|016|P|(e.g. heart failure, myocardial infarction, history of torsades de pointes,|
03956|017|P|congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
03956|018|P|bradycardia, female gender, or advanced age.  Concurrent use of more than|
03956|019|P|one drug known to cause QT prolongation or higher systemic concentrations of|
03956|020|P|either QT prolonging drug are additional risk factors for torsades de|
03956|021|P|pointes.  Factors which may increase systemic drug concentrations include|
03956|022|P|rapid infusion of an intravenous dose or impaired metabolism or elimination|
03956|023|P|of the drug (e.g. coadministration with an agent which inhibits its|
03956|024|P|metabolism or elimination, genetic impairment in drug metabolism or|
03956|025|P|elimination, and/or renal/hepatic dysfunction).(1,2)|
03956|026|B||
03956|027|M|PATIENT MANAGEMENT:  The US manufacturer of iloperidone states that the dose|
03956|028|M|of iloperidone should be reduced to one-half of its normal dose when strong|
03956|029|M|CYP3A inhibitors are coadministered.  If the patient is also receiving a|
03956|030|M|CYP2D6 inhibitor, iloperidone should be reduced to one-half of its normal|
03956|031|M|dose but no additional dose reduction is required with both a CYP2D6|
03956|032|M|inhibitor and CYP3A4 inhibitor.  When the inhibitor is discontinued, the|
03956|033|M|dose of iloperidone should be increased.(1)|
03956|034|M|   The US manufacturer of levoketoconazole states that levoketoconazole is|
03956|035|M|contraindicated with other agents that prolong the QT interval.(2)|
03956|036|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
03956|037|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
03956|038|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
03956|039|M|syndrome (including first-degree family history).  Use caution in patients|
03956|040|M|with other risk factors for QT prolongation including congestive heart|
03956|041|M|failure, bradyarrhythmias, and uncorrected electrolyte abnormalities.|
03956|042|M|Consider more frequent ECG monitoring.(2)|
03956|043|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03956|044|M|hypokalemia or hypomagnesemia.|
03956|045|M|   If a patient develops QT prolongation with a QTc interval greater than|
03956|046|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03956|047|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03956|048|M|QTc interval prolongation recurs, permanently discontinue|
03956|049|M|levoketoconazole.(1)|
03956|050|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
03956|051|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03956|052|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03956|053|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03956|054|B||
03956|055|D|DISCUSSION:  Coadministration of ketoconazole (200 mg twice daily for 4|
03956|056|D|days) increased the AUC of iloperidone (3 mg single dose) and its P88 and|
03956|057|D|P95 metabolites by 57%, 55%, and 35%, respectively.(1)|
03956|058|D|   Coadministration of ketoconazole (200 mg twice daily) and iloperidone (12|
03956|059|D|mg twice daily) was associated with a mean QTcF increase of 19 msec from|
03956|060|D|baseline, compared with an increase of 9 msec with iloperidone alone.(1)|
03956|061|D|   Coadministration of ketoconazole and paroxetine (a CYP2D6 inhibitor) did|
03956|062|D|not increase the effects on iloperidone compared with either agent alone.(1)|
03956|063|D|   During phase 1 and 2 studies of levoketoconazole, which excluded patients|
03956|064|D|with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients|
03956|065|D|experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
03956|066|D|change-from-baseline QTcF > 60 msec.(1)|
03956|067|D|   Strong CYP3A4 inhibitors that prolong QT linked to this monograph|
03956|068|D|include: adagrasib, levoketoconazole, and lonafarnib.(4)|
03956|069|B||
03956|070|R|REFERENCES:|
03956|071|B||
03956|072|R|1.Fanapt (iloperidone) US prescribing information. Novartis Pharmaceuticals|1
03956|073|R|  Inc May, 2016.|1
03956|074|R|2.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03956|075|R|  Pharmaceuticals, Inc. June, 2023.|1
03956|076|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03956|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03956|078|R|  settings: a scientific statement from the American Heart Association and|6
03956|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03956|080|R|  2;55(9):934-47.|6
03956|081|R|4.This information is based on an extract from the Certara Drug Interaction|6
03956|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03957|001|T|MONOGRAPH TITLE:  Artemether;Lumefantrine/Strong CYP3A4 Inhib that Prolong|
03957|002|T|QT|
03957|003|B||
03957|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03957|005|L|is contraindicated and generally should not be dispensed or administered to|
03957|006|L|the same patient.|
03957|007|B||
03957|008|A|MECHANISM OF ACTION:  Potent inhibitors of CYP3A4 that prolong the QTc|
03957|009|A|interval may inhibit the metabolism of artemether and lumefantrine and|
03957|010|A|result in additive effects on the QTc interval.(1)|
03957|011|B||
03957|012|E|CLINICAL EFFECTS:  Concurrent use of potent CYP3A4 inhibitors that prolong|
03957|013|E|the QTc interval with artemether-lumefantrine may result in elevated levels|
03957|014|E|of the antimalarial agents and increased risk of toxicities, including|
03957|015|E|additive prolongation of the QTc interval, which may result in life|
03957|016|E|threatening arrhythmia and death.(1)|
03957|017|B||
03957|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03957|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03957|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03957|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03957|022|P|female gender, or advanced age.(2)|
03957|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03957|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03957|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03957|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03957|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03957|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03957|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03957|030|B||
03957|031|M|PATIENT MANAGEMENT:  The US manufacturer of artemether-lumefantrine states|
03957|032|M|that the use of artemether-lumefantrine should be avoided in patients taking|
03957|033|M|drugs that are known to prolong the QTc interval.  Concurrent use with|
03957|034|M|potent CYP3A4 inhibitors should be approached with caution.(1)|
03957|035|M|   The US manufacturer of adagrasib states that it should be avoided with|
03957|036|M|sensitive CYP3A4 substrates and with other drugs known to prolong the QTc|
03957|037|M|interval.(3)|
03957|038|M|   The US manufacturer of levoketoconazole states that levoketoconazole is|
03957|039|M|contraindicated with other agents that prolong the QT interval. Avoid the|
03957|040|M|use of strong CYP3A4 inhibitors two weeks before and during levoketoconazole|
03957|041|M|treatment.(4)|
03957|042|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
03957|043|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
03957|044|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
03957|045|M|syndrome (including first-degree family history).  Use caution in patients|
03957|046|M|with other risk factors for QT prolongation including congestive heart|
03957|047|M|failure, bradyarrhythmias, and uncorrected electrolyte abnormalities.|
03957|048|M|Consider more frequent ECG monitoring.(4)|
03957|049|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03957|050|M|hypokalemia or hypomagnesemia.|
03957|051|M|   If a patient develops QT prolongation with a QTc interval greater than|
03957|052|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03957|053|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03957|054|M|QTc interval prolongation recurs, permanently discontinue|
03957|055|M|levoketoconazole.(4)|
03957|056|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03957|057|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03957|058|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03957|059|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03957|060|B||
03957|061|D|DISCUSSION:  In a study in 13 healthy subjects, administration of|
03957|062|D|ketoconazole (400 mg Day 1, 200 mg Days 2-5, a potent inhibitor of CYP3A4)|
03957|063|D|with a single dose of artemether-lumefantrine (20 mg/120 mg) increased the|
03957|064|D|area-under-curve (AUC) of artemether and lumefantrine by 2.3-fold and|
03957|065|D|1.6-fold, respectively.(1)|
03957|066|D|   Agents that are linked to this monograph may have varying degrees of|
03957|067|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03957|068|D|been shown to prolong the QTc interval either through their mechanism of|
03957|069|D|action, through studies on their effects on the QTc interval, or through|
03957|070|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03957|071|D|and/or postmarketing reports.(5)|
03957|072|D|   During phase 1 and 2 studies of levoketoconazole, which excluded patients|
03957|073|D|with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients|
03957|074|D|experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
03957|075|D|change-from-baseline QTcF > 60 msec.(4)|
03957|076|D|    Strong CYP3A4 inhibitors that prolong the QTc interval linked to this|
03957|077|D|monograph include: adagrasib, levoketoconazole, and lonafarnib.(6,7)|
03957|078|B||
03957|079|R|REFERENCES:|
03957|080|B||
03957|081|R|1.Coartem (artemether/lumefantrine) US prescribing information. Novartis|1
03957|082|R|  Pharmaceuticals Corporation August, 2019.|1
03957|083|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03957|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03957|085|R|  settings: a scientific statement from the American Heart Association and|6
03957|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03957|087|R|  2;55(9):934-47.|6
03957|088|R|3.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03957|089|R|  Pharmaceuticals, Inc. June, 2023.|1
03957|090|R|4.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
03957|091|R|  December 2022.|1
03957|092|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03957|093|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03957|094|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03957|095|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03957|096|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
03957|097|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03957|098|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03957|099|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03957|100|R|  11/14/2017.|1
03957|101|R|7.This information is based on an extract from the Certara Drug Interaction|6
03957|102|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03958|001|T|MONOGRAPH TITLE:  Mobocertinib/Strong CYP3A4 Inhibitors that Prolong QT|
03958|002|B||
03958|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03958|004|L|is contraindicated and generally should not be dispensed or administered to|
03958|005|L|the same patient.|
03958|006|B||
03958|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
03958|008|A|interval may inhibit the metabolism of mobocertinib and result in additive|
03958|009|A|risk of QT prolongation.(1)|
03958|010|B||
03958|011|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 that|
03958|012|E|prolong QT may result in elevated levels of and toxicity from mobocertinib|
03958|013|E|including additive QTc prolongation, which may result in potentially|
03958|014|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
03958|015|B||
03958|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03958|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03958|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03958|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03958|020|P|female gender, or advanced age.(2)|
03958|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03958|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03958|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03958|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03958|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03958|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03958|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03958|028|B||
03958|029|M|PATIENT MANAGEMENT:  The manufacturer of levoketoconazole states that|
03958|030|M|concurrent use of agents known to prolong the QT interval is|
03958|031|M|contraindicated.(3)  The manufacturer of mobocertinib states that the use of|
03958|032|M|strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with|
03958|033|M|mobocertinib should be avoided.(1)|
03958|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03958|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03958|036|M|regular intervals.  Correct any electrolyte abnormalities.|
03958|037|M|   Increase the frequency of ECG monitoring in patients with risk factors|
03958|038|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
03958|039|M|or electrolyte abnormalities.|
03958|040|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
03958|041|M|fainting.|
03958|042|M|   If patients develop QTc prolongation during mobocertinib therapy, dose|
03958|043|M|modifications are recommended:|
03958|044|M|   - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold|
03958|045|M|mobocertinib until QTc returns to <= Grade 1 or baseline.  Upon recovery,|
03958|046|M|resume mobocertinib at the same dose.|
03958|047|M|   - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <=|
03958|048|M|Grade 1 or baseline.  Upon recovery, resume mobocertinib at the next lower|
03958|049|M|dose or permanently discontinue.|
03958|050|M|   - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60|
03958|051|M|msec from baseline) and first occurrence: hold mobocertinib until QTc|
03958|052|M|returns to <= Grade 1 or baseline.  Upon recovery, resume mobocertinib at|
03958|053|M|the next lower dose or permanently discontinue.|
03958|054|M|   - If Grade 3 and recurrence: permanently discontinue mobocertinib.|
03958|055|M|   - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia;|
03958|056|M|signs/symptoms of serious arrhythmia): permanently discontinue|
03958|057|M|mobocertinib.(1)|
03958|058|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
03958|059|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
03958|060|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
03958|061|M|syndrome (including first-degree family history).  Use caution in patients|
03958|062|M|with other risk factors for QT prolongation including congestive heart|
03958|063|M|failure, bradyarrhythmias, and uncorrected electrolyte abnormalities.|
03958|064|M|Consider more frequent ECG monitoring.|
03958|065|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03958|066|M|hypokalemia or hypomagnesemia.|
03958|067|M|   If a patient develops QT prolongation with a QTc interval greater than|
03958|068|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03958|069|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03958|070|M|QTc interval prolongation recurs, permanently discontinue|
03958|071|M|levoketoconazole.(3)|
03958|072|B||
03958|073|D|DISCUSSION:  Coadministration of mobocertinib with multiple doses of|
03958|074|D|itraconazole or ketoconazole (strong CYP3A inhibitors) is predicted to|
03958|075|D|increase the steady-state combined molar area-under curve (AUC) of|
03958|076|D|mobocertinib and its active metabolites by 374 to 419%.(1)|
03958|077|D|   In a clinical study, mobocertinib 160 mg once daily was associated with a|
03958|078|D|concentration-dependent increase in QTc, with the largest mean increase in|
03958|079|D|QTc of 23 msec.(1)|
03958|080|D|   In clinical studies, patients were excluded if baseline QTc was greater|
03958|081|D|than 470 msec.  In a subset of 250 patient with scheduled and unscheduled|
03958|082|D|electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and|
03958|083|D|11% of patients had a change-from-baseline QTc interval >60 msec.  Grade 4|
03958|084|D|Torsades de Pointes occurred in 1 patient (0.4%).(1)|
03958|085|D|   During phase 1 and 2 studies of levoketoconazole, which excluded patients|
03958|086|D|with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients|
03958|087|D|experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
03958|088|D|change-from-baseline QTcF > 60 msec.(3)|
03958|089|D|   Strong inhibitors of CYP3A4 that prolong QT include:|
03958|090|D|levoketoconazole.(3-5)|
03958|091|B||
03958|092|R|REFERENCES:|
03958|093|B||
03958|094|R|1.Exkivity (mobocertinib) US prescribing information. Takeda Pharmaceuticals|1
03958|095|R|  America, Inc. September, 2021.|1
03958|096|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03958|097|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03958|098|R|  settings: a scientific statement from the American Heart Association and|6
03958|099|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03958|100|R|  2;55(9):934-47.|6
03958|101|R|3.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03958|102|R|  Pharmaceuticals, Inc. June, 2023.|1
03958|103|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03958|104|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03958|105|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03958|106|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03958|107|R|  11/14/2017.|1
03958|108|R|5.This information is based on an extract from the Certara Drug Interaction|6
03958|109|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03959|001|T|MONOGRAPH TITLE:  Levoketoconazole/Idelalisib|
03959|002|B||
03959|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03959|004|L|of severe adverse interaction.|
03959|005|B||
03959|006|A|MECHANISM OF ACTION:  Levoketoconazole and idelalisib are both agents that|
03959|007|A|inhibit the CYP3A4 isoenzyme and are substrates of CYP3A4.(1,2)|
03959|008|B||
03959|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03959|010|E|levels of and effects from both levoketoconazole and idelalisib.(1,2)|
03959|011|E|   Elevated levels of levoketoconazole may increase the risk of QTc|
03959|012|E|prolongation and potentially life-threatening cardiac arrhythmias, including|
03959|013|E|torsades de pointes, hepatotoxicity, hypertension, hypokalemia, and|
03959|014|E|hemorrhagic events.(1)|
03959|015|E|   Elevated levels of idelalisib may result in hepatotoxicity, diarrhea,|
03959|016|E|colitis, pneumonitis, neutropenia or interstitial pneumonitis.(2)|
03959|017|B||
03959|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03959|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
03959|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03959|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03959|022|P|female gender, or advanced age.(3)|
03959|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03959|024|P|higher systemic concentrations of either QT prolonging drug are additional|
03959|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03959|026|P|drug concentrations include rapid infusion of an intravenous dose or|
03959|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03959|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03959|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03959|030|B||
03959|031|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states to avoid|
03959|032|M|the use of strong CYP3A4 inhibitors two weeks before and during|
03959|033|M|levoketoconazole treatment.(1)|
03959|034|M|   The US manufacturer of idelalisib states to avoid the use of strong|
03959|035|M|CYP3A4 inhibitors in patients undergoing therapy with idelalisib.(2)|
03959|036|M|Consider alternatives with no or minimal enzyme inhibition.|
03959|037|M|   Levoketoconazole is contraindicated in patients with a concurrent QT|
03959|038|M|prolonging agents, prolonged QTcF interval of greater than 470 msec at|
03959|039|M|baseline, history of torsades de pointes, ventricular tachycardia,|
03959|040|M|ventricular fibrillation, or long QT syndrome (including first-degree family|
03959|041|M|history).|
03959|042|M|   Use caution in patients with other risk factors for QT prolongation|
03959|043|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
03959|044|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
03959|045|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03959|046|M|hypokalemia or hypomagnesemia.|
03959|047|M|   If a patient develops QT prolongation with a QTc interval greater than|
03959|048|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03959|049|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03959|050|M|QTc interval prolongation recurs, permanently discontinue|
03959|051|M|levoketoconazole.(1)|
03959|052|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03959|053|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03959|054|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03959|055|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03959|056|M|   If concurrent use with idelalisib is warranted, monitor patients for|
03959|057|M|toxicity and follow toxicity dose modification guidelines.(2)|
03959|058|B||
03959|059|D|DISCUSSION:  The US manufacturer of levoketoconazole states levoketoconazole|
03959|060|D|is both an inhibitor and substrate of CYP3A4.(1)|
03959|061|D|   During phase 1 and 2 studies, which excluded patients with baseline QTcF|
03959|062|D|interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500|
03959|063|D|msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60|
03959|064|D|msec.(1)|
03959|065|D|   In a study in healthy subjects, the strong CYP3A4 inhibitor ketoconazole|
03959|066|D|(400 mg daily for 4 days) increased the AUC of idelalisib (400 mg single|
03959|067|D|dose) by 1.8-fold.(2)|
03959|068|B||
03959|069|R|REFERENCES:|
03959|070|B||
03959|071|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03959|072|R|  Pharmaceuticals, Inc. June, 2023.|1
03959|073|R|2.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
03959|074|R|  October, 2020.|1
03959|075|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03959|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03959|077|R|  settings: a scientific statement from the American Heart Association and|6
03959|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03959|079|R|  2;55(9):934-47.|6
03959|080|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03959|081|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03959|082|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03959|083|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03959|084|R|5.This information is based on an extract from the Certara Drug Interaction|6
03959|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03960|001|T|MONOGRAPH TITLE:  Levoketoconazole/Mifepristone|
03960|002|B||
03960|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03960|004|L|of severe adverse interaction.|
03960|005|B||
03960|006|A|MECHANISM OF ACTION:  Levoketoconazole and mifepristone are both agents that|
03960|007|A|inhibit the CYP3A4 isoenzyme and are substrates of CYP3A4.(1,2)|
03960|008|B||
03960|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03960|010|E|levels of and effects from both levoketoconazole and mifepristone.(1,2)|
03960|011|E|   Elevated levels of levoketoconazole may increase the risk of QTc|
03960|012|E|prolongation and potentially life-threatening cardiac arrhythmias, including|
03960|013|E|torsades de pointes, hepatotoxicity, hypertension, hypokalemia, and|
03960|014|E|hemorrhagic events.(1)|
03960|015|E|   Concurrent use of mifepristone with a strong CYP3A4 inhibitor may result|
03960|016|E|in a 5-fold increase in area-under-the-curve (AUC) or 80 percent decrease in|
03960|017|E|mifepristone clearance, leading to toxicity such as adrenal insufficiency,|
03960|018|E|or hypokalemia.(2)|
03960|019|B||
03960|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03960|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
03960|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03960|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03960|024|P|female gender, or advanced age.(3)|
03960|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03960|026|P|higher systemic concentrations of either QT prolonging drug are additional|
03960|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03960|028|P|drug concentrations include rapid infusion of an intravenous dose or|
03960|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03960|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03960|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03960|032|B||
03960|033|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states to avoid|
03960|034|M|the use of strong CYP3A4 inhibitors two weeks before and during|
03960|035|M|levoketoconazole treatment.(1)|
03960|036|M|   Levoketoconazole is contraindicated in patients with a concurrent QT|
03960|037|M|prolonging agents, prolonged QTcF interval of greater than 470 msec at|
03960|038|M|baseline, history of torsades de pointes, ventricular tachycardia,|
03960|039|M|ventricular fibrillation, or long QT syndrome (including first-degree family|
03960|040|M|history).|
03960|041|M|   Use caution in patients with other risk factors for QT prolongation|
03960|042|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
03960|043|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
03960|044|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03960|045|M|hypokalemia or hypomagnesemia.|
03960|046|M|   If a patient develops QT prolongation with a QTc interval greater than|
03960|047|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03960|048|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03960|049|M|QTc interval prolongation recurs, permanently discontinue|
03960|050|M|levoketoconazole.(1)|
03960|051|M|   The manufacturer of mifepristone for use in patients with endogenous|
03960|052|M|Cushing's syndrome states the benefit of the CYP3A4 inhibitor must be|
03960|053|M|carefully weighed against the potential risks and concurrent use should only|
03960|054|M|occur when necessary.(1)|
03960|055|M|   If starting mifepristone in a patient already taking a strong CYP3A4|
03960|056|M|inhibitor, initiate mifepristone at 300 mg and titrate if clinically|
03960|057|M|indicated to a maximum dose of 900 mg.(1)|
03960|058|M|   If a strong CYP3A4 inhibitor is started in a patient already taking|
03960|059|M|mifepristone, the following dose adjustments are recommended:|
03960|060|M| - If current mifepristone dose is 300 mg, no dose change warranted;|
03960|061|M| - If current mifepristone dose is 600 mg, reduce dose to 300 mg and titrate|
03960|062|M|if clinically indicated to a maximum dose of 600 mg;|
03960|063|M| - If current mifepristone dose is 900 mg, reduce dose to 600 mg and titrate|
03960|064|M|if clinically indicated to a maximum dose of 900 mg; and|
03960|065|M| - If current mifepristone dose if 1200 mg, reduce dose to 900 mg.(2)|
03960|066|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03960|067|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03960|068|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03960|069|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03960|070|B||
03960|071|D|DISCUSSION:  The US manufacturer of levoketoconazole states levoketoconazole|
03960|072|D|is both an inhibitor and substrate of CYP3A4.(1)|
03960|073|D|   During phase 1 and 2 studies, which excluded patients with baseline QTcF|
03960|074|D|interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500|
03960|075|D|msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60|
03960|076|D|msec.(1)|
03960|077|D|   A drug interaction study examined mifepristone 600 mg daily with|
03960|078|D|concurrent ketoconazole 200 mg twice daily on days 13-17. Concurrent|
03960|079|D|administration increased mifepristone AUC and maximum concentration (Cmax)|
03960|080|D|by 1.38-fold and 1.28-fld, respectively.(2)|
03960|081|D|   A drug interaction study of 33 healthy subjects on itraconazole 200 mg|
03960|082|D|daily coadministered with mifepristone 900 mg daily for 14 days found that|
03960|083|D|itraconazole increased the Cmax and AUC of mifepristone by 1.1-fold and|
03960|084|D|1.2-fold, respectively.(2)|
03960|085|B||
03960|086|R|REFERENCES:|
03960|087|B||
03960|088|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03960|089|R|  Pharmaceuticals, Inc. June, 2023.|1
03960|090|R|2.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
03960|091|R|  November, 2019.|1
03960|092|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03960|093|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03960|094|R|  settings: a scientific statement from the American Heart Association and|6
03960|095|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03960|096|R|  2;55(9):934-47.|6
03960|097|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03960|098|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03960|099|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03960|100|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03960|101|R|5.This information is based on an extract from the Certara Drug Interaction|6
03960|102|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03961|001|T|MONOGRAPH TITLE:  Levoketoconazole/Lonafarnib|
03961|002|B||
03961|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03961|004|L|is contraindicated and generally should not be dispensed or administered to|
03961|005|L|the same patient.|
03961|006|B||
03961|007|A|MECHANISM OF ACTION:  Levoketoconazole and lonafarnib are both agents that|
03961|008|A|inhibit the CYP3A4 isoenzyme and are substrates of CYP3A4.(1,2) Lonafarnib|
03961|009|A|is a sensitive CYP3A4 substrate.(2)|
03961|010|A|   Both agents have been shown to prolong the QTc interval.(1,2)|
03961|011|B||
03961|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
03961|013|E|levels of and effects from both levoketoconazole and lonafarnib, including|
03961|014|E|additive QTc prolongation and potentially life-threatening cardiac|
03961|015|E|arrhythmias including torsades de pointes (TdP) and hepatotoxicity.(1,2)|
03961|016|E|   Elevated levels of levoketoconazole may also increase the risk of|
03961|017|E|hypertension, hypokalemia, and hemorrhagic events.(1)|
03961|018|E|   Elevated levels of lonafarnib may also increase the risk of nausea and|
03961|019|E|vomiting, myelosuppression, and hypertension.(2)|
03961|020|B||
03961|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03961|022|P|may be increased in patients with cardiovascular disease (e.g. heart|
03961|023|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03961|024|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03961|025|P|female gender, or advanced age.(3)|
03961|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03961|027|P|higher systemic concentrations of either QT prolonging drug are additional|
03961|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03961|029|P|drug concentrations include rapid infusion of an intravenous dose or|
03961|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03961|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03961|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03961|033|B||
03961|034|M|PATIENT MANAGEMENT:  The use of lonafarnib with strong CYP3A4 inhibitors is|
03961|035|M|contraindicated.(2)|
03961|036|M|   The US manufacturer of levoketoconazole states to avoid the use of strong|
03961|037|M|CYP3A4 inhibitors two weeks before and during levoketoconazole treatment.(1)|
03961|038|M|   Levoketoconazole is contraindicated in patients taking a concurrent QT|
03961|039|M|prolonging agent, prolonged QTcF interval of greater than 470 msec at|
03961|040|M|baseline, history of torsades de pointes, ventricular tachycardia,|
03961|041|M|ventricular fibrillation, or long QT syndrome (including first-degree family|
03961|042|M|history).|
03961|043|M|   Use caution in patients with other risk factors for QT prolongation|
03961|044|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
03961|045|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
03961|046|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03961|047|M|hypokalemia or hypomagnesemia.|
03961|048|M|   If a patient develops QT prolongation with a QTc interval greater than|
03961|049|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03961|050|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03961|051|M|QTc interval prolongation recurs, permanently discontinue|
03961|052|M|levoketoconazole.(1)|
03961|053|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03961|054|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03961|055|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03961|056|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03961|057|B||
03961|058|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg of|
03961|059|D|lonafarnib following 200 mg ketoconazole (a strong CYP3A4 inhibitor), once|
03961|060|D|daily for 5 days, the area-under-the-curve (AUC) and maximum concentration|
03961|061|D|(Cmax) were increased by 425% and 270%, respectively.(1)|
03961|062|D|   The US manufacturer of levoketoconazole states levoketoconazole is both|
03961|063|D|an inhibitor and substrate of CYP3A4.(1)|
03961|064|D|   During phase 1 and 2 studies with levoketoconazole, which excluded|
03961|065|D|patients with baseline QTcF interval greater than 470 msec, 4 (2.4%)|
03961|066|D|patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
03961|067|D|change-from-baseline QTcF > 60 msec.(1)|
03961|068|B||
03961|069|R|REFERENCES:|
03961|070|B||
03961|071|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03961|072|R|  Pharmaceuticals, Inc. June, 2023.|1
03961|073|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
03961|074|R|  Inc. November, 2020.|1
03961|075|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03961|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03961|077|R|  settings: a scientific statement from the American Heart Association and|6
03961|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03961|079|R|  2;55(9):934-47.|6
03961|080|R|4.This information is based on an extract from the Certara Drug Interaction|6
03961|081|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03961|082|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03961|083|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03961|084|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03961|085|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03961|086|R|  11/14/2017.|1
03962|001|T|MONOGRAPH TITLE:  Levoketoconazole/Ivosidenib|
03962|002|B||
03962|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03962|004|L|of severe adverse interaction.|
03962|005|B||
03962|006|A|MECHANISM OF ACTION:  Ivosidenib, a strong inducer of CYP3A4 that prolongs|
03962|007|A|the QTc interval, may induce the metabolism of levoketoconazole and result|
03962|008|A|in additive risk of QT prolongation.(1-4)|
03962|009|A|   Levoketoconazole, a strong CYP3A4 inhibitor, may inhibit the metabolism|
03962|010|A|of ivosidenib.(1,2)|
03962|011|B||
03962|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
03962|013|E|may reduce the clinical effectiveness of levoketoconazole and may cause|
03962|014|E|additive effects on the QTc interval, which may result in life-threatening|
03962|015|E|cardiac arrhythmias including torsades de pointes.(1-4)|
03962|016|E|   Concurrent use of strong CYP3A4 inhibitors may increase systemic exposure|
03962|017|E|and the risk for ivosidenib toxicities such as QT prolongation.(2)|
03962|018|B||
03962|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03962|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
03962|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03962|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03962|023|P|female gender, or advanced age.(3)|
03962|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03962|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03962|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03962|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03962|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03962|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03962|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03962|031|B||
03962|032|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
03962|033|M|levoketoconazole is contraindicated with other agents that prolong the QT|
03962|034|M|interval. Avoid the use of strong CYP3A4 inducers two weeks before and|
03962|035|M|during levoketoconazole treatment.(1)|
03962|036|M|   The US manufacturer of ivosidenib recommends considering an alternative|
03962|037|M|concomitant medication with less potential for CYP3A4 inhibition.(2)|
03962|038|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
03962|039|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
03962|040|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
03962|041|M|syndrome (including first-degree family history).|
03962|042|M|   Use caution in patients with other risk factors for QT prolongation|
03962|043|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
03962|044|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
03962|045|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
03962|046|M|hypokalemia or hypomagnesemia.|
03962|047|M|   If a patient develops QT prolongation with a QTc interval greater than|
03962|048|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
03962|049|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
03962|050|M|QTc interval prolongation recurs, permanently discontinue|
03962|051|M|levoketoconazole.(1)|
03962|052|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03962|053|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03962|054|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03962|055|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03962|056|B||
03962|057|D|DISCUSSION:  The US manufacturer of levoketoconazole states levoketoconazole|
03962|058|D|is both an inhibitor and substrate of CYP3A4.(1)|
03962|059|D|   During phase 1 and 2 studies with levoketoconazole, which excluded|
03962|060|D|patients with baseline QTcF interval greater than 470 msec, 4 (2.4%)|
03962|061|D|patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
03962|062|D|change-from-baseline QTcF > 60 msec.(1)|
03962|063|D|   In a drug interaction study in healthy subjects, coadministration of|
03962|064|D|itraconazole (200 mg once daily for 18 days) with a single dose of|
03962|065|D|ivosidenib (250 mg) increased ivosidenib area-under-the-curve (AUC) by 269%.|
03962|066|D|No change was seen in ivosidenib's maximum concentration (Cmax).(2)|
03962|067|B||
03962|068|R|REFERENCES:|
03962|069|B||
03962|070|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03962|071|R|  Pharmaceuticals, Inc. June, 2023.|1
03962|072|R|2.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
03962|073|R|  Inc. August, 2021.|1
03962|074|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03962|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03962|076|R|  settings: a scientific statement from the American Heart Association and|6
03962|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03962|078|R|  2;55(9):934-47.|6
03962|079|R|4.This information is based on an extract from the Certara Drug Interaction|6
03962|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03962|081|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03962|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03962|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03962|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03962|085|R|  11/14/2017.|1
03963|001|T|MONOGRAPH TITLE:  Panobinostat/QT Prolonging Agents|
03963|002|B||
03963|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03963|004|L|of severe adverse interaction.|
03963|005|B||
03963|006|A|MECHANISM OF ACTION:  Panobinostat has been observed to prolong the QTc|
03963|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
03963|008|A|may result in additive effects on the QTc interval.(1)|
03963|009|B||
03963|010|E|CLINICAL EFFECTS:  The concurrent use of panobinostat with other agents that|
03963|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03963|012|E|arrhythmias, including torsades de pointes.(1)|
03963|013|B||
03963|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03963|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03963|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03963|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03963|018|P|female gender, or advanced age.(2)|
03963|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03963|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03963|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03963|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03963|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03963|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03963|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03963|026|B||
03963|027|M|PATIENT MANAGEMENT:  The manufacturer of panobinostat states concurrent use|
03963|028|M|agents known to prolong the QT interval are not recommended.|
03963|029|M|   Panobinostat should not be started in patients with a QTcF > 450 msec or|
03963|030|M|clinically significant baseline ST-segment or T-wave abnormalities.|
03963|031|M|   If during panobinostat therapy the QTcF increases to > 480 msec,|
03963|032|M|interrupt treatment and correct any electrolyte abnormalities.  If QT|
03963|033|M|prolongation does not resolve, permanently discontinue treatment with|
03963|034|M|panobinostat.(1)|
03963|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03963|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03963|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03963|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03963|039|B||
03963|040|D|DISCUSSION:  In the randomized multiple myeloma trial, QTc prolongation with|
03963|041|D|values between 451 msec to 480 msec occurred in 10.8% of panobinostat|
03963|042|D|treated patients and patients with values of 481 msec to 500 msec occurred|
03963|043|D|in 1.3% of patients.  A maximum QTcF increase from baseline of between 31|
03963|044|D|msec and 60 msec was reported in 14.5% of patients and a maximum QTcF|
03963|045|D|increase from baseline of >60 msec was reported in 0.8% of patients.(1)|
03963|046|D|   Pooled clinical data from over 500 patients treated with single agent|
03963|047|D|panobinostat in multiple indications and at different dose levels has shown|
03963|048|D|that the incidence of CTC Grade 3 QTc prolongation (QTcF >500 msec) was|
03963|049|D|approximately 1% overall and 5% or more at a dose of 60 mg or higher.(1)|
03963|050|D|   Agents that are linked to this monograph may have varying degrees of|
03963|051|D|potential to prolong the QTc interval but are generally accepted to have a|
03963|052|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03963|053|D|been shown to prolong the QTc interval either through their mechanism of|
03963|054|D|action, through studies on their effects on the QTc interval, or through|
03963|055|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03963|056|D|and/or post-marketing reports.(3)|
03963|057|B||
03963|058|R|REFERENCES:|
03963|059|B||
03963|060|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
03963|061|R|  Pharmaceuticals Corporation June, 2016.|1
03963|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03963|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03963|064|R|  settings: a scientific statement from the American Heart Association and|6
03963|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03963|066|R|  2;55(9):934-47.|6
03963|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03963|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03963|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03963|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03964|001|T|MONOGRAPH TITLE:  Panobinostat/Possible QT Prolonging Agents|
03964|002|B||
03964|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03964|004|L|take action as needed.|
03964|005|B||
03964|006|A|MECHANISM OF ACTION:  Panobinostat has been observed to prolong the QTc|
03964|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
03964|008|A|may result in additive effects on the QTc interval.(1)|
03964|009|B||
03964|010|E|CLINICAL EFFECTS:  The concurrent use of panobinostat with other agents that|
03964|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03964|012|E|arrhythmias, including torsades de pointes.(1)|
03964|013|B||
03964|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03964|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
03964|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03964|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03964|018|P|female gender, or advanced age.(2)|
03964|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03964|020|P|higher systemic concentrations of either QT prolonging drug are additional|
03964|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03964|022|P|drug concentrations include rapid infusion of an intravenous dose or|
03964|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03964|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03964|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03964|026|B||
03964|027|M|PATIENT MANAGEMENT:  The manufacturer of panobinostat states concurrent use|
03964|028|M|agents known to prolong the QT interval are not recommended.|
03964|029|M|   Panobinostat should not be started in patients with a QTcF > 450 msec or|
03964|030|M|clinically significant baseline ST-segment or T-wave abnormalities.|
03964|031|M|   If during panobinostat therapy the QTcF increases to > 480 msec,|
03964|032|M|interrupt treatment and correct any electrolyte abnormalities.  If QT|
03964|033|M|prolongation does not resolve, permanently discontinue treatment with|
03964|034|M|panobinostat.(1)|
03964|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03964|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03964|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03964|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03964|039|B||
03964|040|D|DISCUSSION:  In the randomized multiple myeloma trial, QTc prolongation with|
03964|041|D|values between 451 msec to 480 msec occurred in 10.8% of panobinostat|
03964|042|D|treated patients and patients with values of 481 msec to 500 msec occurred|
03964|043|D|in 1.3% of patients.  A maximum QTcF increase from baseline of between 31|
03964|044|D|msec and 60 msec was reported in 14.5% of patients and a maximum QTcF|
03964|045|D|increase from baseline of >60 msec was reported in 0.8% of patients.(1)|
03964|046|D|   Pooled clinical data from over 500 patients treated with single agent|
03964|047|D|panobinostat in multiple indications and at different dose levels has shown|
03964|048|D|that the incidence of CTC Grade 3 QTc prolongation (QTcF >500 msec) was|
03964|049|D|approximately 1% overall and 5% or more at a dose of 60 mg or higher.(1)|
03964|050|D|   Agents that are linked to this monograph may have varying degrees of|
03964|051|D|potential to prolong the QTc interval but are generally accepted to have a|
03964|052|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03964|053|D|been shown to prolong the QTc interval either through their mechanism of|
03964|054|D|action, through studies on their effects on the QTc interval, or through|
03964|055|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03964|056|D|and/or post-marketing reports.(3)|
03964|057|B||
03964|058|R|REFERENCES:|
03964|059|B||
03964|060|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
03964|061|R|  Pharmaceuticals Corporation June, 2016.|1
03964|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03964|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03964|064|R|  settings: a scientific statement from the American Heart Association and|6
03964|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03964|066|R|  2;55(9):934-47.|6
03964|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
03964|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03964|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03964|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03965|001|T|MONOGRAPH TITLE:  Tolterodine/QT Prolonging Agents|
03965|002|B||
03965|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03965|004|L|take action as needed.|
03965|005|B||
03965|006|A|MECHANISM OF ACTION:  Tolterodine has been observed to prolong the QTc|
03965|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
03965|008|A|may result in additive effects on the QTc interval.(1,2)|
03965|009|B||
03965|010|E|CLINICAL EFFECTS:  The concurrent use of tolterodine with other agents that|
03965|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
03965|012|E|arrhythmias, including torsades de pointes.(1,2)|
03965|013|B||
03965|014|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers may be at|
03965|015|P|increased risk.(1,2)|
03965|016|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03965|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03965|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03965|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03965|020|P|advanced age.(3)|
03965|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03965|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03965|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03965|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03965|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03965|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03965|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03965|028|B||
03965|029|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine states concurrent use|
03965|030|M|agents known to prolong the QT interval should be used with caution.|
03965|031|M|Consider close observation in patients with a known history of QT|
03965|032|M|prolongation or patients taking antiarrhythmic medications.(1,2)|
03965|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03965|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03965|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03965|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03965|037|B||
03965|038|D|DISCUSSION:  In a study of the effect of tolterodine immediate release|
03965|039|D|tablets, the effect on the QT interval appeared greater for 8 mg/day (two|
03965|040|D|times the therapeutic dose) compared to 4 mg/day.  Tolterodine 2 mg BID and|
03965|041|D|tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and|
03965|042|D|11.84 msec (7.11-16.58 msec), respectively.  The change in QT interval was|
03965|043|D|more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers|
03965|044|D|(EMs).(1,2)|
03965|045|D|   Agents that are linked to this monograph may have varying degrees of|
03965|046|D|potential to prolong the QTc interval but are generally accepted to have a|
03965|047|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
03965|048|D|been shown to prolong the QTc interval either through their mechanism of|
03965|049|D|action, through studies on their effects on the QTc interval, or through|
03965|050|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
03965|051|D|and/or post-marketing reports.(4)|
03965|052|B||
03965|053|R|REFERENCES:|
03965|054|B||
03965|055|R|1.Detrol (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03965|056|R|  August, 2012.|1
03965|057|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03965|058|R|  July, 2018.|1
03965|059|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03965|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03965|061|R|  settings: a scientific statement from the American Heart Association and|6
03965|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03965|063|R|  2;55(9):934-47.|6
03965|064|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03965|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03965|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03965|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03966|001|T|MONOGRAPH TITLE:  Ethyl Alcohol/Levoketoconazole; Ketoconazole|
03966|002|B||
03966|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03966|004|L|take action as needed.|
03966|005|B||
03966|006|A|MECHANISM OF ACTION:  The exact mechanism of action of this reaction is|
03966|007|A|unknown.  Like metronidazole, ketoconazole contains a methylated imidazole|
03966|008|A|ring.  Due to their structural similarity, it has been suggested that|
03966|009|A|alcohol dehydrogenase inhibition like that caused by metronidazole may|
03966|010|A|occur.(1)|
03966|011|A|   Levoketoconazole is an enantiomer of ketoconazole.(2)|
03966|012|B||
03966|013|E|CLINICAL EFFECTS:  Concurrent use of ketoconazole with alcohol has been|
03966|014|E|associated with a disulfiram-like reaction resulting in symptoms of|
03966|015|E|flushing, rash, peripheral edema, nausea, and headache.  Symptoms generally|
03966|016|E|resolve within a few hours.(2,3)|
03966|017|B||
03966|018|P|PREDISPOSING FACTORS:  None determined.|
03966|019|B||
03966|020|M|PATIENT MANAGEMENT:  Patients receiving levoketoconazole or ketoconazole|
03966|021|M|should be instructed to use caution if drinking alcohol and to avoid|
03966|022|M|excessive alcohol while taking levoketoconazole or ketoconazole.(2,3)|
03966|023|M|   Patients should be advised of the possible affects that may result from|
03966|024|M|ingestion or application of products that contain alcohol while taking|
03966|025|M|levoketoconazole or ketoconazole.|
03966|026|M|   Caution is also warranted when using intravenous preparations containing|
03966|027|M|alcohol solvents in patients receiving levoketoconazole or ketoconazole.|
03966|028|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
03966|029|M|   - The quantity of alcohol in paclitaxel injection formulations|
03966|030|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
03966|031|M|dose contains approximately 13 grams of alcohol.|
03966|032|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
03966|033|M|3-fold depending upon the manufacturer. FDA data on alcohol content (4):|
03966|034|M|   Product                      Manufacturer           Alcohol/200 mg dose|
03966|035|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
03966|036|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
03966|037|M|   Docetaxel Inj.               Accord                  4.0 grams|
03966|038|M|   Taxotere-one vial            Sanofi                  4.0 grams|
03966|039|M|    formulation|
03966|040|M|   Docetaxel Inj.               Hospira                 3.7 grams|
03966|041|M|   Docefrez                     Sun Pharma              2.9 grams|
03966|042|M|   Taxotere-two vial            Sanofi                  2.0 grams|
03966|043|M|    formulation|
03966|044|B||
03966|045|D|DISCUSSION:  Ketoconazole has been associated with disulfiram-like reactions|
03966|046|D|in patients who used alcohol.  An 82-year old male with a history of alcohol|
03966|047|D|abuse received a 1-week course of ketoconazole for esophageal candidiasis|
03966|048|D|and had symptoms of nausea, vomiting and facial flushing.  These symptoms|
03966|049|D|were assumed to be due to alcohol ingestion.(1)|
03966|050|B||
03966|051|R|REFERENCES:|
03966|052|B||
03966|053|R|1.Fazio RA, Wickremesinghe PC, Arsura EL. Ketoconazole treatment of Candida|3
03966|054|R|  esophagitis--a prospective study of 12 cases. Am J Gastroenterol 1983 May;|3
03966|055|R|  78(5):261-4.|3
03966|056|R|2.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03966|057|R|  Pharmaceuticals, Inc. June, 2023.|1
03966|058|R|3.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
03966|059|R|  Pharmaceuticals February, 2014.|1
03966|060|R|4.USFood and Drug Administration (FDA). Docetaxel: Drug Safety Communication|1
03966|061|R|  - May Cause Symptoms of Alcohol Intoxication. available at:|1
03966|062|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com|1
03966|063|R|  munication-fda-warns-cancer-drug-docetaxel-may-cause-symptoms-alcohol June|1
03966|064|R|  20, 2014.|1
03967|001|T|MONOGRAPH TITLE:  Levoketoconazole/Nevirapine|
03967|002|B||
03967|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03967|004|L|of severe adverse interaction.|
03967|005|B||
03967|006|A|MECHANISM OF ACTION:  Nevirapine may induce the metabolism of|
03967|007|A|levoketoconazole by CYP3A4.(1)|
03967|008|B||
03967|009|E|CLINICAL EFFECTS:  The concurrent administration of nevirapine and|
03967|010|E|levoketoconazole may result in decreased levels of levoketoconazole,|
03967|011|E|resulting in a loss of efficacy.(1)|
03967|012|B||
03967|013|P|PREDISPOSING FACTORS:  None determined.|
03967|014|B||
03967|015|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
03967|016|M|concurrent administration with CYP3A4 inducers should be used with|
03967|017|M|caution.(1)|
03967|018|B||
03967|019|D|DISCUSSION:  In a study in 21 HIV-infected patients, the concurrent|
03967|020|D|administration of nevirapine (200 mg twice daily) and ketoconazole (400 mg|
03967|021|D|once daily) resulted in decreases in the area-under-curve (AUC) and maximum|
03967|022|D|concentration (Cmax) of ketoconazole by 72% and 44%, respectively.(2)|
03967|023|B||
03967|024|R|REFERENCES:|
03967|025|B||
03967|026|R|1.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03967|027|R|  Pharmaceuticals, Inc. June, 2023.|1
03967|028|R|2.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
03967|029|R|  Pharmaceuticals February, 2014.|1
03967|030|R|3.Department of Health and Human Services. Table 15b. Drug Interactions|1
03967|031|R|  between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs.|1
03967|032|R|  Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults|1
03967|033|R|  and Adolescents 02/12/2013.|1
03968|001|T|MONOGRAPH TITLE:  Daridorexant/Strong CYP3A4 Inhibitors|
03968|002|B||
03968|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03968|004|L|is contraindicated and generally should not be dispensed or administered to|
03968|005|L|the same patient.|
03968|006|B||
03968|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03968|008|A|of daridorexant.(1)|
03968|009|B||
03968|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
03968|011|E|in increased levels of and effects from daridorexant including somnolence,|
03968|012|E|fatigue, CNS depressant effects, daytime impairment, or headache.(1)|
03968|013|B||
03968|014|P|PREDISPOSING FACTORS:  None determined.|
03968|015|B||
03968|016|M|PATIENT MANAGEMENT:  The Canadian and UK manufacturers of daridorexant state|
03968|017|M|that concurrent use of strong CYP3A4 inhibitors is contraindicated.(2-3)|
03968|018|M|   The US manufacturer of daridorexant states that concurrent use of strong|
03968|019|M|CYP3A4 inhibitors with daridorexant should be avoided.(1)|
03968|020|B||
03968|021|D|DISCUSSION:  Daridorexant is a CYP3A4 substrate.  In a PKPB model,|
03968|022|D|concurrent use of daridorexant with itraconazole, a strong CYP3A4 inhibitor,|
03968|023|D|increased daridorexant area-under-curve (AUC) by 400%.(1)|
03968|024|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
03968|025|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03968|026|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
03968|027|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
03968|028|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03968|029|D|troleandomycin, tucatinib, and voriconazole.(4)|
03968|030|B||
03968|031|R|REFERENCES:|
03968|032|B||
03968|033|R|1.Quvivig (daridorexant) US prescribing information. Idorsia Pharmaceuticals|1
03968|034|R|  Ltd October, 2023.|1
03968|035|R|2.Quviviq (daridorexant) UK Summary of Product Characteristics. Idorsia|1
03968|036|R|  Pharmaceuticals Deutschland GmbH October, 2023.|1
03968|037|R|3.Quviviq (daridorexant) Canadian Product Monograph. Idorsia Pharmaceuticals|1
03968|038|R|  Ltd January, 2024.|1
03968|039|R|4.This information is based on an extract from the Certara Drug Interaction|6
03968|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03969|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Levoketoconazole|
03969|002|B||
03969|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03969|004|L|of severe adverse interaction.|
03969|005|B||
03969|006|A|MECHANISM OF ACTION:  The metabolism of cyclosporine, sirolimus, and|
03969|007|A|temsirolimus by CYP3A4 may be inhibited by levoketoconazole.|
03969|008|B||
03969|009|E|CLINICAL EFFECTS:  Concurrent administration of levoketoconazole may result|
03969|010|E|in elevated levels of and toxicity from cyclosporine, sirolimus, or|
03969|011|E|temsirolimus.|
03969|012|B||
03969|013|P|PREDISPOSING FACTORS:  None determined.|
03969|014|B||
03969|015|M|PATIENT MANAGEMENT:  Cyclosporine, sirolimus, or temsirolimus levels and|
03969|016|M|renal function should be monitored if levoketoconazole is initiated or|
03969|017|M|discontinued from concurrent therapy.  The dosage of cyclosporine,|
03969|018|M|sirolimus, or temsirolimus may need to be adjusted.|
03969|019|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
03969|020|M|with strong CYP3A4 inhibitors such as levoketoconazole be avoided.  If|
03969|021|M|concurrent use is warranted, a dosage reduction to 12.5 mg/week of|
03969|022|M|temsirolimus should be considered.  If levoketoconazole is discontinued, a|
03969|023|M|washout period of 1 week should be allowed before adjusting the dosage of|
03969|024|M|temsirolimus to previous levels.|
03969|025|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
03969|026|M|concurrent use with strong CYP3A4 inhibitors should be avoided.|
03969|027|M|   The US manufacturer of levoketoconazole states concurrent use with|
03969|028|M|sensitive CYP3A4 substrates should be avoided.|
03969|029|B||
03969|030|D|DISCUSSION:  Ketoconazole has been reported to increase cyclosporine|
03969|031|D|concentrations . Exercise caution when stopping levoketoconazole as|
03969|032|D|cyclosporine concentration may decrease.|
03969|033|D|   In a multiple-dose study, concomitant administration of ketoconazole with|
03969|034|D|sirolimus oral solution increased the sirolimus Cmax, time to Cmax (Tmax),|
03969|035|D|and AUC by 4.3-fold, 38%, and 10.9-fold, respectively.  Single-dose|
03969|036|D|sirolimus did not affect steady-state 12-hour plasma ketoconazole|
03969|037|D|concentrations.|
03969|038|D|   In a study in 6 patients, ketoconazole was successfully used to augment|
03969|039|D|sirolimus levels.  Patients were able to receive one-eight to one-fourth|
03969|040|D|(0.25 - 0.50 mg daily) of the usual sirolimus dose while taking 100 to 200|
03969|041|D|mg of ketoconazole daily.|
03969|042|D|   Concurrent administration of ketoconazole had no effects on temsirolimus|
03969|043|D|AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and|
03969|044|D|2.2-fold, respectively.  Dosage adjustment of temsirolimus to 12.5 mg/week|
03969|045|D|in the presence of strong CYP3A4 inhibitors is expected to adjust levels to|
03969|046|D|the range observed without inhibitors; however, there are no data available|
03969|047|D|with this dose adjustment.|
03969|048|B||
03969|049|R|REFERENCES:|
03969|050|B||
03969|051|R|1.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
03969|052|R|  Inc. March, 2018.|1
03969|053|R|2.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
03969|054|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
03969|055|R|3.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
03969|056|R|  Aug, 2022.|1
03969|057|R|4.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03969|058|R|  Pharmaceuticals, Inc. June, 2023.|1
03969|059|R|5.Ferguson RM, Sutherland DE, Simmons RL, Najarian JS. Ketoconazole,|3
03969|060|R|  cyclosporin metabolism, and renal transplantation. Lancet 1982 Oct 16;|3
03969|061|R|  2(8303):882-3.|3
03969|062|R|6.Daneshmend TK. Ketoconazole-cyclosporin interaction. Lancet 1982 Dec 11;|3
03969|063|R|  2(8311):1342-3.|3
03969|064|R|7.Smith JM, Hows JM, Gordon-Smith EC, Baughan A, Goldman JM. Interaction of|4
03969|065|R|  CyA and ketoconazole. Clin Sci 1983;64(2):67P.|4
03969|066|R|8.Shepard JH, Canafax DM, Simmons RL, Najarian JS.|3
03969|067|R|  Cyclosporine-ketoconazole: a potentially dangerous drug-drug interaction.|3
03969|068|R|  Clin Pharm 1986 Jun;5(6):468.|3
03969|069|R|9.Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin|6
03969|070|R|  Pharmacokinet 1988 Jan;14(1):13-34.|6
03969|071|R|10.Charles BG, Ravenscroft PJ, Rigby RJ. The ketoconazole-cyclosporin|3
03969|072|R|   interaction in an elderly renal transplant patient. Aust N Z J Med 1989|3
03969|073|R|   Jun;19(3):292-3.|3
03969|074|R|11.Baciewicz AM, Baciewicz FA Jr. Cyclosporine pharmacokinetic drug|6
03969|075|R|   interactions. Am J Surg 1989 Feb;157(2):264-71.|6
03969|076|R|12.First MR, Schroeder TJ, Weiskittel P, Myre SA, Alexander JW, Pesce AJ.|2
03969|077|R|   Concomitant administration of cyclosporin and ketoconazole in renal|2
03969|078|R|   transplant recipients. Lancet 1989 Nov 18;2(8673):1198-201.|2
03969|079|R|13.Frey FJ. Concomitant cyclosporin and ketoconazole. Lancet 1990 Jan 13;|6
03969|080|R|   335(8681):109-10.|6
03969|081|R|14.Ah-Sing E, Poole TW, Ioannides C, King LJ. Mechanism of the|5
03969|082|R|   ketoconazole-cyclosporin interaction. Arch Toxicol 1990;64(6):511-3.|5
03969|083|R|15.Katzir D, Balschke TF. The cyclosporine-ketoconazole interaction. Hosp|3
03969|084|R|   Ther 1990 Jan;15:99-112.|3
03969|085|R|16.First MR, Schroeder TJ, Alexander JW, Stephens GW, Weiskittel P, Myre SA,|2
03969|086|R|   Pesce AJ. Cyclosporine dose reduction by ketoconazole administration in|2
03969|087|R|   renal transplant recipients. Transplantation 1991 Feb;51(2):365-70.|2
03969|088|R|17.Albengres E, Tillement JP. Cyclosporin and ketoconazole, drug interaction|6
03969|089|R|   or therapeutic association?. Int J Clin Pharmacol Ther Toxicol 1992 Dec;|6
03969|090|R|   30(12):555-70.|6
03969|091|R|18.First MR, Schroeder TJ, Michael A, Hariharan S, Weiskittel P, Alexander|2
03969|092|R|   JW. Cyclosporine-ketoconazole interaction. Long-term follow-up and|2
03969|093|R|   preliminary results of a randomized trial. Transplantation 1993 May;|2
03969|094|R|   55(5):1000-4.|2
03969|095|R|19.Sadaba B, Campanero MA, Quetglas EG, Azanza JR. Clinical relevance of|3
03969|096|R|   sirolimus drug interactions in transplant patients. Transplant Proc 2004|3
03969|097|R|   Dec;36(10):3226-8.|3
03969|098|R|20.Thomas PP, Manivannan J, John GT, Jacob CK. Sirolimus and ketoconazole|2
03969|099|R|   co-prescription in renal transplant recipients. Transplantation 2004 Feb|2
03969|100|R|   15;77(3):474-5.|2
03970|001|T|MONOGRAPH TITLE:  Daridorexant (Less Than or Equal To 25 mg)/Moderate CYP3A4|
03970|002|T|Inhibitors|
03970|003|B||
03970|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03970|005|L|take action as needed.|
03970|006|B||
03970|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
03970|008|A|metabolism of daridorexant.(1)|
03970|009|B||
03970|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
03970|011|E|result in increased levels of and effects from daridorexant including|
03970|012|E|somnolence, fatigue, CNS depressant effects, daytime impairment, or|
03970|013|E|headache.(1)|
03970|014|B||
03970|015|P|PREDISPOSING FACTORS:  None determined.|
03970|016|B||
03970|017|M|PATIENT MANAGEMENT:  The dose of daridorexant should be limited to 25 mg|
03970|018|M|daily when used with a moderate CYP3A4 inhibitor.(1)|
03970|019|B||
03970|020|D|DISCUSSION:  Daridorexant is a CYP3A4 substrate.  In a PKPB model,|
03970|021|D|concurrent use of daridorexant with diltiazem, a moderate CYP3A4 inhibitor,|
03970|022|D|increased daridorexant area-under-curve (AUC) and maximum concentration|
03970|023|D|(Cmax) by 2.4-fold and 1.4-fold, respectively.(1)|
03970|024|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
03970|025|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
03970|026|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
03970|027|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
03970|028|D|lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib,|
03970|029|D|schisandra, stiripentol, treosulfan, and verapamil.(2)|
03970|030|B||
03970|031|R|REFERENCES:|
03970|032|B||
03970|033|R|1.Quvivig (daridorexant) US prescribing information. Idorsia Pharmaceuticals|1
03970|034|R|  Ltd October, 2023.|1
03970|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
03970|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03971|001|T|MONOGRAPH TITLE:  Selected Corticosteroids/Levoketoconazole|
03971|002|B||
03971|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03971|004|L|take action as needed.|
03971|005|B||
03971|006|A|MECHANISM OF ACTION:  Levoketoconazole may inhibit the CYP3A4 mediated|
03971|007|A|metabolism of some corticosteroids, resulting in increased systemic|
03971|008|A|exposure.  Levoketoconazole may also suppress endogenous cortisol output.|
03971|009|A|Levoketoconazole is the enantiomer of ketoconazole.|
03971|010|B||
03971|011|E|CLINICAL EFFECTS:  Concurrent use of levoketoconazole may result in elevated|
03971|012|E|levels of and effects from the corticosteroid, including Cushing syndrome.|
03971|013|E|These effects have been seen with systemic as well as inhaled|
03971|014|E|corticosteroids.|
03971|015|B||
03971|016|P|PREDISPOSING FACTORS:  None determined.|
03971|017|B||
03971|018|M|PATIENT MANAGEMENT:  Patients should be carefully monitored with concurrent|
03971|019|M|administration of these agents, or when levoketoconazole is added to|
03971|020|M|corticosteroid therapy.  The dose of the corticosteroid may need to be|
03971|021|M|adjusted or alternative therapy considered.|
03971|022|B||
03971|023|D|DISCUSSION:  The concurrent use of ketoconazole has been shown to increase|
03971|024|D|budesonide area-under-curve (AUC) by eight-fold.|
03971|025|D|   In a study in eight healthy subjects, the simultaneous administration of|
03971|026|D|ketoconazole increased budesonide AUC by 6.5-fold.  Administering the two|
03971|027|D|agents 12 hours apart increased budesonide AUC by 3.8-fold.|
03971|028|D|   In a study in 6 healthy subjects, pretreatment with ketoconazole (200 mg|
03971|029|D|daily) increased the AUC of a single intravenous dose of methylprednisolone|
03971|030|D|(20 mg) by 135% and decreased its clearance by 60%.  Concurrent ketoconazole|
03971|031|D|also increased the reduction in 24-hour cortisol AUC and suppressed morning|
03971|032|D|cortisol concentrations.|
03971|033|D|   In a study in 8 healthy subjects, ketoconazole decreased the clearance of|
03971|034|D|methylprednisolone by 46% and increased mean residence time by 37%.|
03971|035|D|   In a randomized, cross-over study in 6 healthy subjects, pretreatment|
03971|036|D|with ketoconazole (200 mg daily for 6 days) had no effect on the|
03971|037|D|pharmacokinetics of a single intravenous dose of prednisolone (14.8 mg).|
03971|038|D|   In a study, concurrent oral ketoconazole increased the AUC of|
03971|039|D|des-ciclesonide from orally inhaled ciclesonide by 3.6-fold.  There were no|
03971|040|D|changes in ciclesonide levels.|
03971|041|D|   In a study in 24 healthy subjects, subjects were randomized to receive|
03971|042|D|either ketoconazole (200 mg BID) or placebo on Days 4-9 of a a 9 day course|
03971|043|D|of mometasone (400 mcg BID).  No subject had mometasone levels greater than|
03971|044|D|150 pcg/ml on Day 3.  Four of 12 subjects who received ketoconazole had|
03971|045|D|mometasone Cmax levels greater than 200 mcg/ml on Day 9.  Plasma cortisol|
03971|046|D|levels appeared to decrease as well.|
03971|047|D|   In a cross-over study in 15 healthy subjects, subjects were randomized to|
03971|048|D|receive fluticasone furoate and vilanterol on days 5-11 with either|
03971|049|D|ketoconazole (200mg once daily) or placebo for days 1-11 with a washout|
03971|050|D|period of 7-14 days.  Fluticasone furoate AUC was increased by 36%, Cmax was|
03971|051|D|increased by 33%, and decreased systemic cortisol levels by 27%.  There were|
03971|052|D|no effects on heart rate and blood potassium levels.  There was a small|
03971|053|D|increase in QTc which was 7.6ms greater when compared to placebo; however,|
03971|054|D|ketoconazole has been reported to increase QTc by 5-6ms.  Vilanterol AUC was|
03971|055|D|increased by 65% and Cmax was increased by 22%.  There were no effects on|
03971|056|D|heart rate and blood potassium levels.  No serious adverse events occurred|
03971|057|D|and no subjects withdrew from the study due to adverse events.  The most|
03971|058|D|common adverse event reported was headache.|
03971|059|D|   Coadministration of orally inhaled fluticasone (1000 mcg) and|
03971|060|D|ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma|
03971|061|D|fluticasone exposure and a 45% decrease in plasma cortisol AUC.|
03971|062|B||
03971|063|R|REFERENCES:|
03971|064|B||
03971|065|R|1.Main KM, Skov M, Sillesen IB, Dige-Petersen H, Muller J, Koch C, Lanng S.|3
03971|066|R|  Cushing's syndrome due to pharmacological interaction in a cystic fibrosis|3
03971|067|R|  patient. Acta Paediatr 2002;91(9):1008-11.|3
03971|068|R|2.De Wachter E, Malfroot A, De Schutter I, Vanbesien J, De Schepper J.|3
03971|069|R|  Inhaled budesonide induced Cushing's syndrome in cystic fibrosis patients,|3
03971|070|R|  due to drug inhibition of cytochrome P450. J Cyst Fibros 2003 Jun;|3
03971|071|R|  2(2):72-5.|3
03971|072|R|3.Seidegard J. Reduction of the inhibitory effect of ketoconazole on|2
03971|073|R|  budesonide pharmacokinetics by separation of their time of administration.|2
03971|074|R|  Clin Pharmacol Ther 2000 Jul;68(1):13-7.|2
03971|075|R|4.Woods DR, Arun CS, Corris PA, Perros P. Cushing's syndrome without excess|3
03971|076|R|  cortisol. BMJ 2006 Feb 25;332(7539):469-70.|3
03971|077|R|5.Glynn AM, Slaughter RL, Brass C, D'Ambrosio R, Jusko WJ. Effects of|2
03971|078|R|  ketoconazole on methylprednisolone pharmacokinetics and cortisol|2
03971|079|R|  secretion. Clin Pharmacol Ther 1986 Jun;39(6):654-9.|2
03971|080|R|6.Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ. Ketoconazole effects on|2
03971|081|R|  methylprednisolone disposition and their joint suppression of endogenous|2
03971|082|R|  cortisol. Clin Pharmacol Ther 1987 Oct;42(4):465-70.|2
03971|083|R|7.Yamashita SK, Ludwig EA, Middleton E Jr, Jusko WJ. Lack of pharmacokinetic|2
03971|084|R|  and pharmacodynamic interactions between ketoconazole and prednisolone.|2
03971|085|R|  Clin Pharmacol Ther 1991 May;49(5):558-70.|2
03971|086|R|8.Omnaris (ciclesonide) US prescribing information. Nycomed US Inc. November|1
03971|087|R|  20, 2007.|1
03971|088|R|9.Dulera (mometasone furoate/formoterol) US prescribing information. Merck &|1
03971|089|R|  Co., Inc. August, 2019.|1
03971|090|R|10.Kempsford R, Allen A, Bal J, Rubin D, Tombs L. The effect of ketoconazole|2
03971|091|R|   on the pharmacokinetics and pharmacodynamics of inhaled fluticasone|2
03971|092|R|   furoate and vilanterol trifenatate in healthy subjects. Br J Clin|2
03971|093|R|   Pharmacol 2013 Jun;75(6):1478-87.|2
03971|094|R|11.Flovent Diskus (fluticasone propionate) US prescribing information.|1
03971|095|R|   GlaxoSmithKline January, 2019.|1
03971|096|R|12.Recorlev (levoketoconazole) US prescribing information. Xeris|1
03971|097|R|   Pharmaceuticals, Inc. June, 2023.|1
03972|001|T|MONOGRAPH TITLE:  Rifabutin/Nirmatrelvir-Ritonavir|
03972|002|B||
03972|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03972|004|L|of severe adverse interaction.|
03972|005|B||
03972|006|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the metabolism of|
03972|007|A|rifabutin by CYP3A4.(1,2)|
03972|008|B||
03972|009|E|CLINICAL EFFECTS:  The concurrent use of nirmatrelvir-ritonavir with|
03972|010|E|rifabutin may result in increased levels, clinical effects, and side effects|
03972|011|E|(including neutropenia, lymphopenia, and influenza-like illness) of|
03972|012|E|rifabutin.(1,2)|
03972|013|B||
03972|014|P|PREDISPOSING FACTORS:  None determined.|
03972|015|B||
03972|016|M|PATIENT MANAGEMENT:  Concurrent use of nirmatrelvir with rifabutin may|
03972|017|M|require a dose adjustment of rifabutin.  The US manufacturer of rifabutin|
03972|018|M|recommends a rifabutin dose reduction of 75% (to a maximum of 150 mg every|
03972|019|M|other day or 3 times weekly) with concomitant ritonavir-boosted protease|
03972|020|M|inhibitors.(1,2)  In the HIV setting, subtherapeutic rifabutin levels have|
03972|021|M|been observed with a 75% dose reduction.(3-8)  Given the risk of rifamycin|
03972|022|M|resistance, the Department of Health and Human Services (DHHS) Guidelines|
03972|023|M|for the Use of Antiretroviral Agents(9) and the CDC's guidelines on managing|
03972|024|M|drug interactions in HIV-related tuberculosis (TB)(10) both recommend that|
03972|025|M|the dose of rifabutin be reduced to 150 mg once daily, or 300 mg three times|
03972|026|M|weekly (a 50% reduction), when used with protease inhibitors.  Clinicians|
03972|027|M|should recognize that there are limited safety data with this dose and|
03972|028|M|patients need to be closely monitored for rifabutin-related toxicities.|
03972|029|M|   Consider increased monitoring for increased side effects of rifabutin|
03972|030|M|including uveitis, thrombocytopenia, and neutropenia, and consider|
03972|031|M|monitoring rifabutin concentrations.(2)|
03972|032|B||
03972|033|D|DISCUSSION:  Nirmatrelvir-ritonavir is a strong CYP3A4 inhibitor.(1)|
03972|034|B||
03972|035|R|REFERENCES:|
03972|036|B||
03972|037|R|1.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
03972|038|R|  2021.|1
03972|039|R|2.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
03972|040|R|  information. Pfizer Inc. February, 2025.|1
03972|041|R|3.Naiker S, Connolly C, Wiesner L, Kellerman T, Reddy T, Harries A,|2
03972|042|R|  McIlleron H, Lienhardt C, Pym A. Randomized pharmacokinetic evaluation of|2
03972|043|R|  different rifabutin doses in African HIV- infected tuberculosis patients|2
03972|044|R|  on lopinavir/ritonavir-based antiretroviral therapy. BMC Pharmacol Toxicol|2
03972|045|R|  2014 Nov 19;15:61.|2
03972|046|R|4.Lan NT, Thu NT, Barrail-Tran A, Duc NH, Lan NN, Laureillard D, Lien TT,|2
03972|047|R|  Borand L, Quillet C, Connolly C, Lagarde D, Pym A, Lienhardt C, Dung NH,|2
03972|048|R|  Taburet AM, Harries AD. Randomised pharmacokinetic trial of rifabutin with|2
03972|049|R|  lopinavir/ritonavir-antiretroviral therapy in patients with HIV-associated|2
03972|050|R|  tuberculosis in Vietnam. PLoS One 2014;9(1):e84866.|2
03972|051|R|5.Boulanger C, Hollender E, Farrell K, Stambaugh JJ, Maasen D, Ashkin D,|2
03972|052|R|  Symes S, Espinoza LA, Rivero RO, Graham JJ, Peloquin CA. Pharmacokinetic|2
03972|053|R|  evaluation of rifabutin in combination with lopinavir-ritonavir in|2
03972|054|R|  patients with HIV infection and active tuberculosis. Clin Infect Dis 2009|2
03972|055|R|  Nov 1;49(9):1305-11.|2
03972|056|R|6.Khachi H, O'Connell R, Ladenheim D, Orkin C. Pharmacokinetic interactions|3
03972|057|R|  between rifabutin and lopinavir/ritonavir in HIV-infected patients with|3
03972|058|R|  mycobacterial co-infection. J Antimicrob Chemother 2009 Oct;64(4):871-3.|3
03972|059|R|7.Ramachandran G, Bhavani PK, Hemanth Kumar AK, Srinivasan R, Raja K, Sudha|2
03972|060|R|  V, Venkatesh S, Chandrasekaran C, Swaminathan S. Pharmacokinetics of|2
03972|061|R|  rifabutin during atazanavir/ritonavir co-administration in HIV-infected TB|2
03972|062|R|  patients in India. Int J Tuberc Lung Dis 2013 Dec;17(12):1564-8.|2
03972|063|R|8.Tanuma J, Sano K, Teruya K, Watanabe K, Aoki T, Honda H, Yazaki H, Tsukada|2
03972|064|R|  K, Gatanaga H, Kikuchi Y, Oka S. Pharmacokinetics of rifabutin in Japanese|2
03972|065|R|  HIV-infected patients with or without antiretroviral therapy. PLoS One|2
03972|066|R|  2013;8(8):e70611.|2
03972|067|R|9.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
03972|068|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
03972|069|R|  HIV. Department of Health and Human Services. Available at|6
03972|070|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
03972|071|R|  new-guidelines June 13, 2021.|6
03972|072|R|10.CDC. Managing Drug Interactions in the Treatment of HIV-Related|6
03972|073|R|   Tuberculosis online. Available at|6
03972|074|R|   https://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/introduction.|6
03972|075|R|   htm June, 2013.|6
03973|001|T|MONOGRAPH TITLE:  Amiodarone/Strong CYP3A4 Inhibitors that Prolong QT|
03973|002|B||
03973|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03973|004|L|of severe adverse interaction.|
03973|005|B||
03973|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
03973|007|A|may inhibit the metabolism of amiodarone and result in additive risk of QT|
03973|008|A|prolongation.  Amiodarone is a CYP3A4 substrate.(1)|
03973|009|B||
03973|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
03973|011|E|QT may increase the levels and effects of amiodarone including additive QTc|
03973|012|E|prolongation, which may result in potentially life-threatening cardiac|
03973|013|E|arrhythmias like torsades de pointes (TdP).(1)|
03973|014|B||
03973|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03973|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03973|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03973|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03973|019|P|female gender, or advanced age.(2)|
03973|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03973|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03973|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03973|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03973|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03973|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03973|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03973|027|B||
03973|028|M|PATIENT MANAGEMENT:  The US manufacturer of amiodarone states that the|
03973|029|M|concurrent use of QT prolonging agents should be avoided and that the need|
03973|030|M|to co-administer amiodarone with any other drug known to prolong the QTc|
03973|031|M|interval must be based on a careful assessment of the potential risks and|
03973|032|M|benefits of doing so for each patient.  Concurrent use with CYP3A4|
03973|033|M|inhibitors should also be avoided.(1)|
03973|034|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
03973|035|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
03973|036|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
03973|037|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
03973|038|B||
03973|039|D|DISCUSSION:  QTc prolongation has been reported during concurrent amiodarone|
03973|040|D|and azole antifungals, fluoroquinolones, and macrolide antibiotics.(1)|
03973|041|D|   A retrospective review of patients who received concurrent amiodarone and|
03973|042|D|haloperidol over a 24 month period found 49 patients who received concurrent|
03973|043|D|therapy for 381 exposures.  The mean increase in QTc interval was 9.8 msec;|
03973|044|D|the average change in QTc interval per patient was 23.6 msec.(3)|
03973|045|D|   Agents that are linked to this monograph may have varying degrees of|
03973|046|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
03973|047|D|been shown to prolong the QTc interval either through their mechanism of|
03973|048|D|action, through studies on their effects on the QTc interval, or through|
03973|049|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
03973|050|D|and/or postmarketing reports.(4)|
03973|051|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
03973|052|D|ceritinib, clarithromycin, lonafarnib, ribociclib, telithromycin, and|
03973|053|D|voriconazole.(5,6)|
03973|054|B||
03973|055|R|REFERENCES:|
03973|056|B||
03973|057|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
03973|058|R|  Pharmaceuticals October, 2018.|1
03973|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03973|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03973|061|R|  settings: a scientific statement from the American Heart Association and|6
03973|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03973|063|R|  2;55(9):934-47.|6
03973|064|R|3.Bush SE, Hatton RC, Winterstein AG, Thomson MR, Woo GW. Effects of|3
03973|065|R|  concomitant amiodarone and haloperidol on Q-Tc interval prolongation. Am J|3
03973|066|R|  Health Syst Pharm 2008 Dec 1;65(23):2232-6.|3
03973|067|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
03973|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03973|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03973|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03973|071|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03973|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03973|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03973|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03973|075|R|  11/14/2017.|1
03973|076|R|6.This information is based on an extract from the Certara Drug Interaction|6
03973|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03974|001|T|MONOGRAPH TITLE:  Slt Serotonergic Opioids (Extended Release)/Metaxalone|
03974|002|B||
03974|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03974|004|L|is contraindicated and generally should not be dispensed or administered to|
03974|005|L|the same patient.|
03974|006|B||
03974|007|A|MECHANISM OF ACTION:  Concurrent use of serotonergic opioids and metaxalone,|
03974|008|A|a weak monoamine oxidase (MAO) inhibitor, may result in additive CNS|
03974|009|A|depression and additive serotonergic effects.(1-3)|
03974|010|B||
03974|011|E|CLINICAL EFFECTS:  Concurrent use of opioids and metaxalone may result in|
03974|012|E|profound sedation, respiratory depression, coma, and/or death.(1-3)|
03974|013|E|   The concurrent use of some opioids with serotonergic properties with|
03974|014|E|metaxalone may result in serotonin syndrome.  Symptoms of serotonin syndrome|
03974|015|E|may include tremor, agitation, diaphoresis, hyperreflexia, clonus,|
03974|016|E|tachycardia, hyperthermia, and muscle rigidity.(1)|
03974|017|B||
03974|018|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03974|019|P|may increase the risk of adverse effects.|
03974|020|P|   Treatment with multiple medications which increase serotonin levels or|
03974|021|P|inhibit the metabolism of serotonin are risk factors for serotonin syndrome.|
03974|022|P|   Higher opioid concentrations, as may occur due to inhibition of opioid|
03974|023|P|clearance, patient specific genomic factors (e.g. poor metabolizer status|
03974|024|P|for a P450 enzyme), or high opioid dosage may increase the risk for an|
03974|025|P|interaction.|
03974|026|B||
03974|027|M|PATIENT MANAGEMENT:  Use an alternative analgesic when possible.  If|
03974|028|M|concurrent therapy is unavoidable, patients should be monitored for signs|
03974|029|M|and symptoms of serotonin syndrome.  Instruct patients to report muscle|
03974|030|M|twitching, tremors, shivering and stiffness, fever, heavy sweating, heart|
03974|031|M|palpitations, restlessness, confusion, agitation, trouble with coordination,|
03974|032|M|or severe diarrhea.|
03974|033|M|   If concurrent use is necessary, limit the dosages and duration of each|
03974|034|M|drug to the minimum possible while achieving the desired clinical effect.|
03974|035|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03974|036|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03974|037|M|indicated in the absence of an opioid and titrate based upon clinical|
03974|038|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03974|039|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03974|040|M|clinical response.(1,3)|
03974|041|M|   Respiratory depression can occur at any time during opioid therapy,|
03974|042|M|especially during therapy initiation and following dosage increases.  The|
03974|043|M|risk of opioid-related overdose or overdose-related death is increased with|
03974|044|M|higher opioid doses, and this risk persists over the course of therapy.|
03974|045|M|Consider these risks when using concurrently with other agents that may|
03974|046|M|cause CNS depression.(4)|
03974|047|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03974|048|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03974|049|M|unresponsiveness.(1,3)|
03974|050|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03974|051|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03974|052|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03974|053|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03974|054|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03974|055|M|as those taking CNS depressants) and when a patient has household|
03974|056|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03974|057|M|for obtaining an opioid reversal agent (e.g., prescription,|
03974|058|M|over-the-counter, or as part of a community-based program).(5)|
03974|059|B||
03974|060|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03974|061|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03974|062|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03974|063|D|million to 30 million patients.  During this time, the proportion of|
03974|064|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03974|065|D|million patients.(6)|
03974|066|D|   A retrospective cohort study compared the risk of opioid overdose|
03974|067|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03974|068|D|versus opioid use alone. The study examined two types of opioid users (naive|
03974|069|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03974|070|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03974|071|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03974|072|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03974|073|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03974|074|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03974|075|D|respectively).  Elevated risk was associated with concomitant users with|
03974|076|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03974|077|D|1.39, respectively).(7)|
03974|078|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03974|079|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03974|080|D|per 100,000 and drug overdose deaths involving both opioids and|
03974|081|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03974|082|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03974|083|D|increased from 18% to 31% during this time.(8)|
03974|084|D|   A prospective observational cohort study in North Carolina found that the|
03974|085|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03974|086|D|benzodiazepines were 10 times higher than patients receiving opioid|
03974|087|D|analgesics alone.(9)|
03974|088|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03974|089|D|death from overdose increased with concomitant opioid analgesics and|
03974|090|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03974|091|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03974|092|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03974|093|D|increased risk of fatal overdose.(10)|
03974|094|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03974|095|D|which benzodiazepines were determined to be a cause of death and that|
03974|096|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03974|097|D|determined to be a cause of death.  This study also found that other CNS|
03974|098|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03974|099|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03974|100|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03974|101|D|where opioid analgesics were also implicated.(11)|
03974|102|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03974|103|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03974|104|D|deaths.(12)|
03974|105|D|   Although documentation is lacking for some opioids, the FDA recommends|
03974|106|D|health professionals monitor and advise patients to report symptoms of|
03974|107|D|serotonin syndrome in patients receiving analgesic opioids and serotonergic|
03974|108|D|agents.(3)|
03974|109|D|   Metaxalone is a weak inhibitor of MAO.(2,13)|
03974|110|B||
03974|111|R|REFERENCES:|
03974|112|B||
03974|113|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03974|114|R|  warns about serious risks and death when combining opioid pain or cough|1
03974|115|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03974|116|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03974|117|R|2.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03974|118|R|  Pfizer Inc. January, 2024.|1
03974|119|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03974|120|R|  warns about several safety issues with opioid pain medicines; requires|1
03974|121|R|  label changes. available at:|1
03974|122|R|  http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
03974|123|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03974|124|R|  prescribing information for all opioid pain medicines to provide|1
03974|125|R|  additional guidance for safe use. Available at:|1
03974|126|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03974|127|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03974|128|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03974|129|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03974|130|R|  recommends health care professionals discuss naloxone with all patients|1
03974|131|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03974|132|R|  disorder. Available at:|1
03974|133|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03974|134|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03974|135|R|  d-pain July 23, 2020.|1
03974|136|R|6.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03974|137|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03974|138|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03974|139|R|7.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
03974|140|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
03974|141|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
03974|142|R|  Ther 2020 Jul;108(1):81-88.|2
03974|143|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03974|144|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03974|145|R|  49(4):493-501.|2
03974|146|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03974|147|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03974|148|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03974|149|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03974|150|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03974|151|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03974|152|R|   350:h2698.|2
03974|153|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03974|154|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03974|155|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03974|156|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03974|157|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03974|158|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03974|159|R|13.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03974|160|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03974|161|R|   Feb;34(2):346.e5-6.|3
03975|001|T|MONOGRAPH TITLE:  Abrocitinib/Strong CYP2C9 or CYP2C19 Inducers|
03975|002|B||
03975|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03975|004|L|of severe adverse interaction.|
03975|005|B||
03975|006|A|MECHANISM OF ACTION:  Abrocitinib is primarily metabolized by CYP2C9 and|
03975|007|A|CYP2C19.  Strong inducers of CYP2C9 or CYP2C19 may accelerate the metabolism|
03975|008|A|of abrocitinib.(1)|
03975|009|B||
03975|010|E|CLINICAL EFFECTS:  Concurrent use of abrocitinib with a strong CYP2C9 or|
03975|011|E|CYP2C19 inducer may result in decreased levels and effectiveness of|
03975|012|E|abrocitinib and its active metabolites, M1 and M2.(1)|
03975|013|B||
03975|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03975|015|P|of the inducer for longer than 1-2 weeks.|
03975|016|B||
03975|017|M|PATIENT MANAGEMENT:  The manufacturer of abrocitinib states that the|
03975|018|M|combination of abrocitinib with a strong CYP2C9 or CYP2C19 inducer should be|
03975|019|M|avoided.(1)|
03975|020|B||
03975|021|D|DISCUSSION:  In a study, rifampin (600 mg daily for 8 days), a strong|
03975|022|D|CYP2C19 and moderate CYP2C9 inducer, decreased the maximum concentration|
03975|023|D|(Cmax) and area-under-curve (AUC) of abrocitinib (200 mg) by 31% and 56%,|
03975|024|D|respectively.(1)|
03975|025|D|   Drugs that are strong CYP2C19 inducers linked to this monograph include:|
03975|026|D|apalutamide and rifampin.(2-3)|
03975|027|B||
03975|028|R|REFERENCES:|
03975|029|B||
03975|030|R|1.Cibinqo (abrocitinib) US prescribing information. Pfizer Labs January,|1
03975|031|R|  2022.|1
03975|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
03975|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03975|034|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03975|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03975|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03975|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03975|038|R|  11/14/2017.|1
03976|001|T|MONOGRAPH TITLE:  Abrocitinib/Selected Strong CYP2C19 Inhibitors|
03976|002|B||
03976|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03976|004|L|take action as needed.|
03976|005|B||
03976|006|A|MECHANISM OF ACTION:  Abrocitinib is primarily metabolized by CYP2C19 and|
03976|007|A|CYP2C9.  Agents that are inhibitors of CYP2C19 may inhibit the metabolism of|
03976|008|A|abrocitinib.(1)|
03976|009|B||
03976|010|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of CYP2C19 increases|
03976|011|E|plasma exposure of abrocitinib which may increase the incidence and severity|
03976|012|E|of adverse reactions of abrocitinib.  This may increase the risk of|
03976|013|E|infections, major adverse cardiovascular events, or thrombosis.(1)|
03976|014|B||
03976|015|P|PREDISPOSING FACTORS:  None determined.|
03976|016|B||
03976|017|M|PATIENT MANAGEMENT:  The manufacturer of abrocitinib states that the dose of|
03976|018|M|abrocitinib in patients who are taking strong CYP2C19 inhibitors should be|
03976|019|M|reduced to 50 mg once daily.  If an adequate response is not achieved after|
03976|020|M|12 weeks, consider increasing the dose to 100 mg once daily.  If the|
03976|021|M|response remains inadequate, discontinue therapy with abrocitinib.(1)|
03976|022|B||
03976|023|D|DISCUSSION:  In a study, fluvoxamine (50 mg daily for 9 days), a strong|
03976|024|D|CYP2C19 inhibitor, increased the maximum concentration (Cmax) and|
03976|025|D|area-under-curve (AUC) of abrocitinib (100 mg) by 1.33-fold and 1.91-fold,|
03976|026|D|respectively.(1)|
03976|027|D|   Strong CYP2C19 inhibitors linked to this monograph include: fluoxetine|
03976|028|D|and fluvoxamine.(2,3)|
03976|029|B||
03976|030|R|REFERENCES:|
03976|031|B||
03976|032|R|1.Cibinqo (abrocitinib) US prescribing information. Pfizer Labs January,|1
03976|033|R|  2022.|1
03976|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
03976|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03976|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03976|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03976|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03976|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03976|040|R|  11/14/2017.|1
03977|001|T|MONOGRAPH TITLE:  Abrocitinib/Dual Moderate to Strong CYP2C9 and CYP2C19|
03977|002|T|Inhibitors|
03977|003|B||
03977|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03977|005|L|of severe adverse interaction.|
03977|006|B||
03977|007|A|MECHANISM OF ACTION:  Abrocitinib is primarily metabolized by CYP2C9 and|
03977|008|A|CYP2C19.  Agents that are inhibitors of both CYP2C9 and CYP2C19 may decrease|
03977|009|A|the metabolism of abrocitinib.(1)|
03977|010|B||
03977|011|E|CLINICAL EFFECTS:  Concurrent use of a dual inhibitor of CY2C9 and CYP2C19|
03977|012|E|increases plasma exposure of abrocitinib which may increase the incidence|
03977|013|E|and severity of adverse reactions of abrocitinib.  This may increase the|
03977|014|E|risk of infections, major adverse cardiovascular events, or thrombosis.(1)|
03977|015|B||
03977|016|P|PREDISPOSING FACTORS:  None determined.|
03977|017|B||
03977|018|M|PATIENT MANAGEMENT:  The US manufacturer of abrocitinib states that the use|
03977|019|M|of abrocitinib with a moderate to strong dual inhibitor of CYP2C9 and|
03977|020|M|CYP2C19 should be avoided.(1)|
03977|021|M|   The Australian and UK manufacturers of abrocitinib do not provide|
03977|022|M|recommendations specifically for dual inhibitors of CYP2C9 and CYP2C19.|
03977|023|M|They recommend that patients receiving concomitant strong CYP2C19|
03977|024|M|inhibitors, including fluconazole, have their dose of abrocitinib decreased|
03977|025|M|by half.(2,3)  The Australian manufacturer further states that the 100 mg|
03977|026|M|daily dose of abrocitinib should be reserved for patients not responding to|
03977|027|M|12 weeks of treatment with 50 mg daily.(2)|
03977|028|B||
03977|029|D|DISCUSSION:  In a study, fluconazole (400 mg on Day 1 and 200 mg daily on|
03977|030|D|Days 2-7), a strong CYP2C19 and moderate CYP2C9 inhibitor, increased the|
03977|031|D|maximum concentration (Cmax) and area-under-curve (AUC) of abrocitinib (100|
03977|032|D|mg) by 1.23-fold and 2.55-fold, respectively.(1)|
03977|033|D|   Moderate to strong dual inhibitors of CYP2C9 and CYP2C19 includes:|
03977|034|D|fluconazole.(2,3)|
03977|035|B||
03977|036|R|REFERENCES:|
03977|037|B||
03977|038|R|1.Cibinqo (abrocitinib) US prescribing information. Pfizer Labs January,|1
03977|039|R|  2022.|1
03977|040|R|2.Cibinqo (abrocitinib) Australian Product Information. Pfizer Australia Pty|1
03977|041|R|  Ltd April 2024.|1
03977|042|R|3.Cibinqo (abrocitinib) UK Summary of Prescribing Information. Pfizer|1
03977|043|R|  Limited September 2024.|1
03977|044|R|4.This information is based on an extract from the Certara Drug Interaction|6
03977|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03977|046|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
03977|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03977|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03977|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03977|050|R|  11/14/2017.|1
03978|001|T|MONOGRAPH TITLE:  Abrocitinib/Antiplatelets; Aspirin (Greater Than 100 mg)|
03978|002|B||
03978|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03978|004|L|of severe adverse interaction.|
03978|005|B||
03978|006|A|MECHANISM OF ACTION:  Abrocitinib has been associated with transient,|
03978|007|A|dose-dependent thrombocytopenia.  The nadir platelet count occurs at a|
03978|008|A|median of 24 days after receiving abrocitinib 200 mg once daily and a 40%|
03978|009|A|recovery occurs by 12 weeks.  Concurrent use with agents that affect|
03978|010|A|platelet aggregation may result in an additive risk of bleeding.(1)|
03978|011|B||
03978|012|E|CLINICAL EFFECTS:  Concurrent use of abrocitinib with antiplatelet agents|
03978|013|E|may increase the risk of bleeding.(1)|
03978|014|B||
03978|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03978|016|P|patients with disease-associated factors (e.g. pre-existing|
03978|017|P|thrombocytopenia).  Abrocitinib is not recommended for patients with a|
03978|018|P|platelet count less than 150,000/mm3.(1)|
03978|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
03978|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03978|021|P|risk for bleeding.|
03978|022|B||
03978|023|M|PATIENT MANAGEMENT:  The concurrent use of abrocitinib with antiplatelet|
03978|024|M|agents (except aspirin < or = 81 mg daily) is contraindicated during the|
03978|025|M|first 3 months of abrocitinib therapy.|
03978|026|M|   Prior to starting abrocitinib therapy, obtain a complete blood count and|
03978|027|M|recheck at 4 weeks after initiation and 4 weeks after a dose increase.|
03978|028|M|Discontinuation of abrocitinib is required if platelets drop below|
03978|029|M|50,000/mm3.(1)|
03978|030|M|   If concurrent therapy is warranted after the first 3 months of|
03978|031|M|abrocitinib therapy, monitor patients receiving concurrent therapy for signs|
03978|032|M|of blood loss, including decreased hemoglobin, hematocrit, fecal occult|
03978|033|M|blood, and/or decreased blood pressure and promptly evaluate patients with|
03978|034|M|any symptoms.|
03978|035|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03978|036|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03978|037|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03978|038|M|and/or swelling.|
03978|039|B||
03978|040|D|DISCUSSION:  Abrocitinib has been associated with transient, dose-dependent|
03978|041|D|thrombocytopenia and is more severe with lower baseline platelet counts. At|
03978|042|D|baseline platelet counts of 170,000/mm3, 220,000/m3 and 270,000/mm3, the|
03978|043|D|nadirs were -41.2%, -33.4%, and -26.5%, respectively.  Recovery of platelet|
03978|044|D|count (about 40% recovery by 12 weeks) occurred without discontinuation of|
03978|045|D|the treatment.(1)|
03978|046|B||
03978|047|R|REFERENCE:|
03978|048|B||
03978|049|R|1.Cibinqo (abrocitinib) US prescribing information. Pfizer Labs January,|1
03978|050|R|  2022.|1
03979|001|T|MONOGRAPH TITLE:  Selected P-glycoprotein (P-gp) Substrates/Abrocitinib|
03979|002|T|(mono deleted 11/05/2025)|
03979|003|B||
03979|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03979|005|L|take action as needed.|
03979|006|B||
03979|007|A|MECHANISM OF ACTION:  Abrocitinib inhibits the P-glycoprotein (P-gp)|
03979|008|A|transporter and may increase absorption of P-gp substrates.(1)|
03979|009|B||
03979|010|E|CLINICAL EFFECTS:  Concurrent use of abrocitinib with narrow therapeutic|
03979|011|E|index P-gp substrates may result in elevated levels and toxicities of the|
03979|012|E|substrate.(1)|
03979|013|B||
03979|014|P|PREDISPOSING FACTORS:  None determined.|
03979|015|B||
03979|016|M|PATIENT MANAGEMENT:  When co-administered with abrocitinib, P-gp substrates|
03979|017|M|for which small concentration changes may result in serious or|
03979|018|M|life-threatening toxicities should be closely monitored.  Dose reduction of|
03979|019|M|the P-gp substrate may be necessary.(1)|
03979|020|B||
03979|021|D|DISCUSSION:  In a clinical study, single-dose abrocitinib (200 mg) increased|
03979|022|D|the area-under-curve (AUC) and maximum concentration (Cmax) of dabigatran, a|
03979|023|D|P-gp substrate, by approximately 53% and 40%, respectively.|
03979|024|D|   Selected P-gp substrates with narrow therapeutic index linked to this|
03979|025|D|monograph include: cyclosporine, digoxin, quinidine, sirolimus, and|
03979|026|D|tacrolimus.|
03979|027|B||
03979|028|R|REFERENCES:|
03979|029|B||
03979|030|R|1.Cibinqo (abrocitinib) US prescribing information. Pfizer Labs January,|1
03979|031|R|  2022.|1
03979|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
03979|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03980|001|T|MONOGRAPH TITLE:  Rivoceranib/Strong CYP3A4 Inhibitors|
03980|002|B||
03980|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03980|004|L|of severe adverse interaction.|
03980|005|B||
03980|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
03980|007|A|of rivoceranib.(1)|
03980|008|B||
03980|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
03980|010|E|elevated levels of and toxicity from rivoceranib, including increased risk|
03980|011|E|of hypertension, proteinuria, leukopenia, thrombocytopenia, neutropenia,|
03980|012|E|hyperbilirubinemia, anemia, and hepatotoxicity.(1)|
03980|013|B||
03980|014|P|PREDISPOSING FACTORS:  None determined.|
03980|015|B||
03980|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
03980|017|M|undergoing therapy with rivoceranib.  Consider alternatives with minimal or|
03980|018|M|little enzyme inhibition.  If concurrent use is necessary, closely monitor|
03980|019|M|for adverse effects.(1)|
03980|020|B||
03980|021|D|DISCUSSION:  In vitro data shows that rivoceranib is metabolized by|
03980|022|D|CYP3A4.(1)|
03980|023|D|   A study with rivoceranib showed that itraconazole reduced the clearance|
03980|024|D|of rivoceranib by 40% and increased the area-under-curve (AUC) by 75%.(1)|
03980|025|D|   In an animal study, rivoceranib levels were significantly increased when|
03980|026|D|coadministered with ketoconazole and voriconazole.(2)|
03980|027|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
03980|028|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
03980|029|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
03980|030|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
03980|031|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
03980|032|D|troleandomycin, tucatinib, and voriconazole.(3-5)|
03980|033|B||
03980|034|R|REFERENCES:|
03980|035|B||
03980|036|R|1.Aitan (rivoceranib (apatinib)) Hong Kong prescribing information. Jiangsu|1
03980|037|R|  Hengrui Pharmaceutical Co., Ltd. December, 2014.|1
03980|038|R|2.Lou D, Cui X, Bao SS, Sun W, Pan WH, Chen MC, Dong YY, Hu GX, Chen RJ,|5
03980|039|R|  Wang Z. Effects of ketoconazole, voriconazole, and itraconazole on the|5
03980|040|R|  pharmacokinetics of  apatinib in rats. Drug Dev Ind Pharm 2019 Apr;|5
03980|041|R|  45(4):689-693.|5
03980|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03980|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03980|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03980|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03980|046|R|  11/14/2017.|1
03980|047|R|4.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
03980|048|R|  Indiana University School of Medicine.  Available at:|1
03980|049|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
03980|050|R|5.This information is based on an extract from the Certara Drug Interaction|6
03980|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03981|001|T|MONOGRAPH TITLE:  Rivoceranib/Strong CYP3A4 Inducers|
03981|002|B||
03981|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03981|004|L|of severe adverse interaction.|
03981|005|B||
03981|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may accelerate the|
03981|007|A|metabolism of rivoceranib.(1)|
03981|008|B||
03981|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03981|010|E|may result in decreased levels and effectiveness of rivoceranib.(1)|
03981|011|B||
03981|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
03981|013|P|of the inducer for longer than 1-2 weeks.|
03981|014|B||
03981|015|M|PATIENT MANAGEMENT:  The manufacturer of rivoceranib states that concurrent|
03981|016|M|use with strong CYP3A4 inducers should be avoided.  If concurrent use is|
03981|017|M|necessary, closely monitor for treatment response.(1)|
03981|018|B||
03981|019|D|DISCUSSION:  In vitro data shows that rivoceranib is metabolized by|
03981|020|D|CYP3A4.(1)|
03981|021|D|   In a study with rifampin, rivoceranib levels decreased by 5.6-fold in|
03981|022|D|plasma clearance (CL/F) and 83% in plasma area-under-curve (AUC).(1)|
03981|023|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
03981|024|D|carbamazepine, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane,|
03981|025|D|phenobarbital, primidone, rifampin, rifapentine, and St. John's wort.(2-3)|
03981|026|B||
03981|027|R|REFERENCES:|
03981|028|B||
03981|029|R|1.Aitan (rivoceranib (apatinib)) Hong Kong prescribing information. Jiangsu|1
03981|030|R|  Hengrui Pharmaceutical Co., Ltd. December, 2014.|1
03981|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
03981|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03981|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03981|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03981|035|R|  11/14/2017.|1
03981|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
03981|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03982|001|T|MONOGRAPH TITLE:  Warfarin/Rivoceranib|
03982|002|B||
03982|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03982|004|L|take action as needed.|
03982|005|B||
03982|006|A|MECHANISM OF ACTION:  Rivoceranib is a CYP2C9 inhibitor(1) which may|
03982|007|A|decrease the metabolism of the S-enantiomer of warfarin.(2)|
03982|008|B||
03982|009|E|CLINICAL EFFECTS:  Concurrent use of rivoceranib may result in elevated|
03982|010|E|levels of warfarin and increased INR.(1)|
03982|011|B||
03982|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
03982|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
03982|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
03982|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03982|016|P|risk for bleeding (e.g. NSAIDs).|
03982|017|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
03982|018|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
03982|019|P|are expected to be more susceptible to this interaction.|
03982|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
03982|021|P|are expected to be less susceptible to effects from this drug combination,|
03982|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
03982|023|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
03982|024|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
03982|025|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
03982|026|P|and safe anticoagulation than patients without these CYP2C9 variants.|
03982|027|B||
03982|028|M|PATIENT MANAGEMENT:  Monitor INRs more frequently until stable in patients|
03982|029|M|who start rivoceranib therapy, or have the warfarin dose adjusted as|
03982|030|M|indicated.(1)|
03982|031|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
03982|032|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
03982|033|M|and/or decreased blood pressure and promptly evaluate patients with any|
03982|034|M|symptoms.|
03982|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03982|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03982|037|M|anticoagulation in patients with active pathologic bleeding.|
03982|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03982|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03982|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03982|041|M|and/or swelling.|
03982|042|M|   The time of highest risk for a coumarin-type drug interaction is when the|
03982|043|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
03982|044|M|before initiating, altering the dose or discontinuing either drug.|
03982|045|B||
03982|046|D|DISCUSSION:  In a clinical study, coadministration with rivoceranib|
03982|047|D|increased the area-under-curve (AUC) and concentration maximum (Cmax) of|
03982|048|D|S-warfarin by 92% (90% CI 1.68-2.18) and 24% (90% CI 1.10-1.39),|
03982|049|D|respectively.(5)|
03982|050|B||
03982|051|R|REFERENCES:|
03982|052|B||
03982|053|R|1.Aitan (rivoceranib (apatinib)) Hong Kong prescribing information. Jiangsu|1
03982|054|R|  Hengrui Pharmaceutical Co., Ltd. December, 2014.|1
03982|055|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
03982|056|R|  Squibb Company September, 2016.|1
03982|057|R|3.This information is based on an extract from the Certara Drug Interaction|6
03982|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03982|059|R|4.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
03982|060|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
03982|061|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
03982|062|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
03982|063|R|  Oct;90(4):625-9.|6
03982|064|R|5.Zhu YT, Teng Z, Zhang YF, Li W, Guo LX, Liu YP, Qu XJ, Wang QR, Mao SY,|2
03982|065|R|  Chen XY, Zhong DF. Effects of Apatinib on the Pharmacokinetics of|2
03982|066|R|  Nifedipine and Warfarin in Patients  with Advanced Solid Tumors. Drug Des|2
03982|067|R|  Devel Ther 2020;14:1963-1970.|2
03983|001|T|MONOGRAPH TITLE:  Rivoceranib/Fosphenytoin; Phenytoin|
03983|002|B||
03983|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03983|004|L|of severe adverse interaction.|
03983|005|B||
03983|006|A|MECHANISM OF ACTION:  Fosphenytoin and phenytoin, strong inducers of CYP3A4,|
03983|007|A|may accelerate the metabolism of rivoceranib.(1)|
03983|008|A|   Also, rivoceranib is a CYP2C9 inhibitor which may decrease the metabolism|
03983|009|A|of fosphenytoin and phenytoin.(1,2)|
03983|010|B||
03983|011|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
03983|012|E|may result in decreased levels and effectiveness of rivoceranib.(1)|
03983|013|E|  Also, concurrent use of rivoceranib may result in elevated levels of|
03983|014|E|fosphenytoin and phenytoin, resulting in phenytoin toxicity.  Phenytoin has|
03983|015|E|a narrow therapeutic range.  Early symptoms of phenytoin toxicity may|
03983|016|E|include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy,|
03983|017|E|slurred speech, blurred vision, nausea, and vomiting.  Severe toxicity may|
03983|018|E|produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction|
03983|019|E|and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may|
03983|020|E|be fatal.(2)|
03983|021|B||
03983|022|P|PREDISPOSING FACTORS:  Renal impairment, hepatic impairment, or|
03983|023|P|hypoalbuminemia.|
03983|024|B||
03983|025|M|PATIENT MANAGEMENT:  The manufacturer of rivoceranib states that concurrent|
03983|026|M|use with strong CYP3A4 inducers should be avoided.  If concurrent use is|
03983|027|M|necessary, closely monitor for treatment response.(1)|
03983|028|M|   Patients maintained on phenytoin should be carefully monitored if|
03983|029|M|rivoceranib is initiated or discontinued.(2)|
03983|030|M|   Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus,|
03983|031|M|ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred|
03983|032|M|vision, nausea, and vomiting).|
03983|033|B||
03983|034|D|DISCUSSION:  In vitro data shows that rivoceranib is metabolized by|
03983|035|D|CYP3A4.(1)|
03983|036|D|   In a study with rifampin, rivoceranib levels decreased by 5.6-fold in|
03983|037|D|plasma clearance (CL/F) and 83% in plasma area-under-curve (AUC).(1)|
03983|038|D|   In a clinical study, coadministration with rivoceranib increased the|
03983|039|D|area-under-curve (AUC) and concentration maximum (Cmax) of S-warfarin, a|
03983|040|D|CYP2C9 substrate, by 92% (90% CI 1.68-2.18) and 24% (90% CI 1.10-1.39),|
03983|041|D|respectively.(5)|
03983|042|B||
03983|043|R|REFERENCES:|
03983|044|B||
03983|045|R|1.Aitan (rivoceranib (apatinib)) Hong Kong prescribing information. Jiangsu|1
03983|046|R|  Hengrui Pharmaceutical Co., Ltd. December, 2014.|1
03983|047|R|2.Dilantin (phenytoin sodium) US prescribing information. Pfizer, Inc.|1
03983|048|R|  March, 2022.|1
03983|049|R|3.Zhu YT, Teng Z, Zhang YF, Li W, Guo LX, Liu YP, Qu XJ, Wang QR, Mao SY,|2
03983|050|R|  Chen XY, Zhong DF. Effects of Apatinib on the Pharmacokinetics of|2
03983|051|R|  Nifedipine and Warfarin in Patients  with Advanced Solid Tumors. Drug Des|2
03983|052|R|  Devel Ther 2020;14:1963-1970.|2
03983|053|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
03983|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03983|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03983|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03983|057|R|  11/14/2017.|1
03983|058|R|5.This information is based on an extract from the Certara Drug Interaction|6
03983|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03984|001|T|MONOGRAPH TITLE:  Slt Serotonergic Opioids (Immediate Release)/Metaxalone|
03984|002|B||
03984|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03984|004|L|is contraindicated and generally should not be dispensed or administered to|
03984|005|L|the same patient.|
03984|006|B||
03984|007|A|MECHANISM OF ACTION:  Concurrent use of serotonergic opioids and metaxalone,|
03984|008|A|a weak monoamine oxidase (MAO) inhibitor, may result in additive CNS|
03984|009|A|depression and additive serotonergic effects.(1,2)|
03984|010|B||
03984|011|E|CLINICAL EFFECTS:  Concurrent use of opioids and metaxalone may result in|
03984|012|E|profound sedation, respiratory depression, coma, and/or death.(2)|
03984|013|E|   The concurrent use of some opioids with serotonergic properties with|
03984|014|E|metaxalone may result in serotonin syndrome.  Symptoms of serotonin syndrome|
03984|015|E|may include tremor, agitation, diaphoresis, hyperreflexia, clonus,|
03984|016|E|tachycardia, hyperthermia, and muscle rigidity.(2)|
03984|017|B||
03984|018|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03984|019|P|may increase the risk of adverse effects.|
03984|020|P|   Treatment with multiple medications which increase serotonin levels or|
03984|021|P|inhibit the metabolism of serotonin are risk factors for serotonin syndrome.|
03984|022|P|   Higher opioid concentrations, as may occur due to inhibition of opioid|
03984|023|P|clearance, patient specific genomic factors (e.g. poor metabolizer status|
03984|024|P|for a P450 enzyme), or high opioid dosage may increase the risk for an|
03984|025|P|interaction.|
03984|026|B||
03984|027|M|PATIENT MANAGEMENT:  Use an alternative analgesic when possible.  If|
03984|028|M|concurrent therapy is unavoidable, patients should be monitored for signs|
03984|029|M|and symptoms of serotonin syndrome.  Instruct patients to report muscle|
03984|030|M|twitching, tremors, shivering and stiffness, fever, heavy sweating, heart|
03984|031|M|palpitations, restlessness, confusion, agitation, trouble with coordination,|
03984|032|M|or severe diarrhea.|
03984|033|M|   If concurrent use is necessary, limit the dosages and duration of each|
03984|034|M|drug to the minimum possible while achieving the desired clinical effect.|
03984|035|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03984|036|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03984|037|M|indicated in the absence of an opioid and titrate based upon clinical|
03984|038|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03984|039|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03984|040|M|clinical response.(2)|
03984|041|M|   Respiratory depression can occur at any time during opioid therapy,|
03984|042|M|especially during therapy initiation and following dosage increases.  The|
03984|043|M|risk of opioid-related overdose or overdose-related death is increased with|
03984|044|M|higher opioid doses, and this risk persists over the course of therapy.|
03984|045|M|Consider these risks when using concurrently with other agents that may|
03984|046|M|cause CNS depression.(3)|
03984|047|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03984|048|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03984|049|M|unresponsiveness.(2)|
03984|050|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03984|051|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03984|052|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03984|053|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03984|054|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03984|055|M|as those taking CNS depressants) and when a patient has household|
03984|056|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03984|057|M|for obtaining an opioid reversal agent (e.g., prescription,|
03984|058|M|over-the-counter, or as part of a community-based program).(4)|
03984|059|B||
03984|060|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03984|061|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03984|062|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03984|063|D|million to 30 million patients.  During this time, the proportion of|
03984|064|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03984|065|D|million patients.(5)|
03984|066|D|   A retrospective cohort study compared the risk of opioid overdose|
03984|067|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03984|068|D|versus opioid use alone. The study examined two types of opioid users (naive|
03984|069|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03984|070|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03984|071|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03984|072|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03984|073|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03984|074|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03984|075|D|respectively).  Elevated risk was associated with concomitant users with|
03984|076|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03984|077|D|1.39, respectively).(6)|
03984|078|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03984|079|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03984|080|D|per 100,000 and drug overdose deaths involving both opioids and|
03984|081|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03984|082|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03984|083|D|increased from 18% to 31% during this time.(7)|
03984|084|D|   A prospective observational cohort study in North Carolina found that the|
03984|085|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03984|086|D|benzodiazepines were 10 times higher than patients receiving opioid|
03984|087|D|analgesics alone.(8)|
03984|088|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03984|089|D|death from overdose increased with concomitant opioid analgesics and|
03984|090|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03984|091|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03984|092|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03984|093|D|increased risk of fatal overdose.(9)|
03984|094|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03984|095|D|which benzodiazepines were determined to be a cause of death and that|
03984|096|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03984|097|D|determined to be a cause of death.  This study also found that other CNS|
03984|098|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03984|099|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03984|100|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03984|101|D|where opioid analgesics were also implicated.(10)|
03984|102|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03984|103|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03984|104|D|deaths.(11)|
03984|105|D|   Although documentation is lacking for some opioids, the FDA recommends|
03984|106|D|health professionals monitor and advise patients to report symptoms of|
03984|107|D|serotonin syndrome in patients receiving analgesic opioids and serotonergic|
03984|108|D|agents.(12)|
03984|109|D|   The interaction between meperidine and MAOIs has been well documented.|
03984|110|D|There are two reports of potential interactions between MAOIs and|
03984|111|D|dextromethorphan.(13,14) In another case report, the concurrent use of|
03984|112|D|propoxyphene and phenylzine resulted in sedation and somnolence. The patient|
03984|113|D|had previously taken both agents alone with no adverse effects.(15)|
03984|114|D|   Although some studies have shown that morphine does not interact with|
03984|115|D|MAOIs,(16,17) other data indicates that MAOIs markedly potentiate the effect|
03984|116|D|of morphine.(18)|
03984|117|D|   Metaxalone is a weak inhibitor of MAO.(1,19)|
03984|118|B||
03984|119|R|REFERENCES:|
03984|120|B||
03984|121|R|1.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03984|122|R|  Pfizer Inc. January, 2024.|1
03984|123|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03984|124|R|  warns about serious risks and death when combining opioid pain or cough|1
03984|125|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03984|126|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03984|127|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03984|128|R|  prescribing information for all opioid pain medicines to provide|1
03984|129|R|  additional guidance for safe use. Available at:|1
03984|130|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03984|131|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03984|132|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03984|133|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03984|134|R|  recommends health care professionals discuss naloxone with all patients|1
03984|135|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03984|136|R|  disorder. Available at:|1
03984|137|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03984|138|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03984|139|R|  d-pain July 23, 2020.|1
03984|140|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03984|141|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03984|142|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03984|143|R|6.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
03984|144|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
03984|145|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
03984|146|R|  Ther 2020 Jul;108(1):81-88.|2
03984|147|R|7.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03984|148|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03984|149|R|  49(4):493-501.|2
03984|150|R|8.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03984|151|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03984|152|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03984|153|R|9.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03984|154|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03984|155|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03984|156|R|10.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03984|157|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03984|158|R|11.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03984|159|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03984|160|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03984|161|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03984|162|R|12.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03984|163|R|   warns about several safety issues with opioid pain medicines; requires|1
03984|164|R|   label changes. available at:|1
03984|165|R|   http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
03984|166|R|13.Rivers N, Horner B. Possible lethal reaction between Nardil and|3
03984|167|R|   dextromethorphan. Can Med Assoc J 1970 Jul;103:85.|3
03984|168|R|14.Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine|3
03984|169|R|   oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988 Dec 22;|3
03984|170|R|   319(25):1671.|3
03984|171|R|15.Garbutt JC. Potentiation of propoxyphene by phenelzine. Am J Psychiatry|3
03984|172|R|   1987 Feb;144(2):251-2.|3
03984|173|R|16.Evans-Prosser CD. The use of pethidine and morphine in the presence of|2
03984|174|R|   monoamine oxidase inhibitors. Br J Anaesth 1968 Apr;40(4):279-82.|2
03984|175|R|17.Carlsson A, Lindqvist M. Central and peripheral monoaminergic|2
03984|176|R|   membrane-pump blockade by some addictive analgesics and antihistamines. J|2
03984|177|R|   Pharm Pharmacol 1969 Jul;21(7):460-4.|2
03984|178|R|18.Avinza (morphine extended-release capsules) US prescribing information.|1
03984|179|R|   Ligand Pharmaceuticals Incorporated April, 2014.|1
03984|180|R|19.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03984|181|R|   therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03984|182|R|   Feb;34(2):346.e5-6.|3
03985|001|T|MONOGRAPH TITLE:  Methadone (Immediate Release)/Metaxalone|
03985|002|B||
03985|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03985|004|L|is contraindicated and generally should not be dispensed or administered to|
03985|005|L|the same patient.|
03985|006|B||
03985|007|A|MECHANISM OF ACTION:  Methadone may inhibit neural reuptake of|
03985|008|A|serotonin.(1-4)  Metaxalone is a weak inhibitor of monoamine oxidase|
03985|009|A|(MAO).(5,6)  MAOIs increase neuronal serotonin concentrations via inhibition|
03985|010|A|of MAO-A.  Concurrent use of methadone and metaxalone may result in additive|
03985|011|A|serotonergic effects(1-6) and additive CNS depression.(7,8)|
03985|012|B||
03985|013|E|CLINICAL EFFECTS:  The concurrent use of methadone with MAOIs like|
03985|014|E|metaxalone has been associated with serotonin syndrome.(1-6)  Symptoms of|
03985|015|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
03985|016|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(9)|
03985|017|E|   Concurrent use of methadone and metaxalone may also result in profound|
03985|018|E|sedation, respiratory depression, coma, and/or death.(7,8)|
03985|019|B||
03985|020|P|PREDISPOSING FACTORS:  Treatment with multiple medications which increase|
03985|021|P|serotonin levels or inhibit the metabolism of serotonin are risk factors for|
03985|022|P|serotonin syndrome.|
03985|023|P|   Higher opioid concentrations as may occur due to high opioid dosage or|
03985|024|P|inhibition of opioid clearance, patient specific genomic factors (e.g. poor|
03985|025|P|metabolizer status for a specific P450 enzyme), and concurrent use of|
03985|026|P|alcohol or other CNS depressants may increase the risk for a severe|
03985|027|P|interaction.|
03985|028|B||
03985|029|M|PATIENT MANAGEMENT:  When possible, avoid concomitant use of methadone and|
03985|030|M|metaxalone.|
03985|031|M|   The US manufacturer of methadone states that methadone is not recommended|
03985|032|M|during and within 14 days of therapy with MAOIs.(1,2)|
03985|033|M|   The Australian manufacturer of methadone states that methadone should not|
03985|034|M|be administered to patients receiving MAOIs.(3)|
03985|035|M|   The UK manufacturer of methadone states that concurrent use and use|
03985|036|M|within 2 weeks of discontinuation of MAOIs is contraindicated.(4)|
03985|037|M|   Use an alternative analgesic when possible.  If concurrent therapy is|
03985|038|M|unavoidable, patients should be monitored closely for signs and symptoms of|
03985|039|M|serotonin syndrome and respiratory depression.  Instruct patients to report|
03985|040|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03985|041|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03985|042|M|coordination, or severe diarrhea.|
03985|043|M|   Limit prescribing methadone with CNS depressants such as muscle relaxants|
03985|044|M|to patients for whom alternatives are ineffective, not tolerated, or would|
03985|045|M|be otherwise inadequate to provide sufficient management of pain.(7,8)|
03985|046|M|   If concurrent use is necessary, limit the dosages and duration of each|
03985|047|M|drug to the minimum possible while achieving the desired clinical effect.|
03985|048|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03985|049|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03985|050|M|indicated in the absence of an opioid and titrate based upon clinical|
03985|051|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03985|052|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03985|053|M|clinical response.(7,8)|
03985|054|M|   Respiratory depression can occur at any time during opioid therapy,|
03985|055|M|especially during therapy initiation and following dosage increases.  The|
03985|056|M|risk of opioid-related overdose or overdose-related death is increased with|
03985|057|M|higher opioid doses, and this risk persists over the course of therapy.|
03985|058|M|Consider these risks when using concurrently with other agents that may|
03985|059|M|cause CNS depression.(10)|
03985|060|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03985|061|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03985|062|M|unresponsiveness.(7,8)|
03985|063|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03985|064|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03985|065|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03985|066|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03985|067|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03985|068|M|as those taking CNS depressants) and when a patient has household|
03985|069|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03985|070|M|for obtaining an opioid reversal agent (e.g., prescription,|
03985|071|M|over-the-counter, or as part of a community-based program).(11)|
03985|072|B||
03985|073|D|DISCUSSION:  FDA performed a search of its adverse event database for cases|
03985|074|D|of serotonin syndrome with selected opiates for the period of January 1,|
03985|075|D|1969 to June 12, 2013; 5 cases were associated with methadone use during|
03985|076|D|this 43 year period.(8)|
03985|077|D|   Metaxalone is a weak MAO inhibitor.(5,6)|
03985|078|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03985|079|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03985|080|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03985|081|D|to 30 million patients.  During this time, the proportion of patients|
03985|082|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03985|083|D|patients.(12)|
03985|084|D|   A retrospective cohort study compared the risk of opioid overdose|
03985|085|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03985|086|D|versus opioid use alone. The study examined two types of opioid users (naive|
03985|087|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03985|088|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03985|089|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03985|090|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03985|091|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03985|092|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03985|093|D|respectively).  Elevated risk was associated with concomitant users with|
03985|094|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03985|095|D|1.39, respectively).(13)|
03985|096|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03985|097|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03985|098|D|per 100,000 and drug overdose deaths involving both opioids and|
03985|099|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03985|100|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03985|101|D|increased from 18% to 31% during this time.(14)|
03985|102|D|   A prospective observational cohort study in North Carolina found that the|
03985|103|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03985|104|D|benzodiazepines were 10 times higher than patients receiving opioid|
03985|105|D|analgesics alone.(15)|
03985|106|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03985|107|D|death from overdose increased with concomitant opioid analgesics and|
03985|108|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03985|109|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03985|110|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03985|111|D|increased risk of fatal overdose.(16)|
03985|112|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03985|113|D|which benzodiazepines were determined to be a cause of death and that|
03985|114|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03985|115|D|determined to be a cause of death.  This study also found that other CNS|
03985|116|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03985|117|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03985|118|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03985|119|D|where opioid analgesics were also implicated.(17)|
03985|120|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03985|121|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03985|122|D|deaths.(18)|
03985|123|B||
03985|124|R|REFERENCES:|
03985|125|B||
03985|126|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03985|127|R|  Pharmaceuticals Corp. June, 2021.|1
03985|128|R|2.Diskets Dispersible (methadone hydrochloride) US prescribing information.|1
03985|129|R|  Cebert Pharmaceuticals, Inc. August, 2007.|1
03985|130|R|3.Diamorphine hydrochloride Australian prescribing information. Auralis|1
03985|131|R|  March 13, 2008.|1
03985|132|R|4.Metharose (methadone hydrochloride) UK summary of product characteristics.|1
03985|133|R|  Rosemone Pharmaceuticals Limited January 9, 2008.|1
03985|134|R|5.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03985|135|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03985|136|R|  Feb;34(2):346.e5-6.|3
03985|137|R|6.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03985|138|R|  Pfizer Inc. January, 2024.|1
03985|139|R|7.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03985|140|R|  warns about serious risks and death when combining opioid pain or cough|1
03985|141|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03985|142|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03985|143|R|8.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03985|144|R|  warns about several safety issues with opioid pain medicines; requires|1
03985|145|R|  label changes. available at:|1
03985|146|R|  http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
03985|147|R|9.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03985|148|R|  352(11):1112-20.|6
03985|149|R|10.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03985|150|R|   updates prescribing information for all opioid pain medicines to provide|1
03985|151|R|   additional guidance for safe use. Available at:|1
03985|152|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescr|1
03985|153|R|   ibing-information-all-opioid-pain-medicines-provide-additional-guidance-s|1
03985|154|R|   afe-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03985|155|R|11.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03985|156|R|   recommends health care professionals discuss naloxone with all patients|1
03985|157|R|   when prescribing opioid pain relievers or medicines to treat opioid use|1
03985|158|R|   disorder. Available at:|1
03985|159|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-hea|1
03985|160|R|   lth-care-professionals-discuss-naloxone-all-patients-when-prescribing-opi|1
03985|161|R|   oid-pain July 23, 2020.|1
03985|162|R|12.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03985|163|R|   in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03985|164|R|   Am J Prev Med 2016 Aug;51(2):151-60.|2
03985|165|R|13.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein|2
03985|166|R|   AG. Risk of opioid overdose associated with concomitant use of opioids|2
03985|167|R|   and sekeltal muscle relaxants: A population-based cohort study. Clin|2
03985|168|R|   Pharmacol Ther 2020 Jul;108(1):81-88.|2
03985|169|R|14.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03985|170|R|   From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015|2
03985|171|R|   Oct;49(4):493-501.|2
03985|172|R|15.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03985|173|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03985|174|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03985|175|R|16.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03985|176|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03985|177|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03985|178|R|   350:h2698.|2
03985|179|R|17.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03985|180|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03985|181|R|18.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03985|182|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03985|183|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03985|184|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03986|001|T|MONOGRAPH TITLE:  Selected Opioids for MAT/Metaxalone|
03986|002|B||
03986|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03986|004|L|is contraindicated and generally should not be dispensed or administered to|
03986|005|L|the same patient.|
03986|006|B||
03986|007|A|MECHANISM OF ACTION:  Serotonergic opioids such as diacetylmorphine and|
03986|008|A|methadone may inhibit neural reuptake of serotonin.(1-5)  Metaxalone is a|
03986|009|A|weak inhibitor of monoamine oxidase (MAO).(6,7)  MAOIs increase neuronal|
03986|010|A|serotonin concentrations via inhibition of MAO-A.  Concurrent use of|
03986|011|A|methadone and metaxalone may result in additive serotonergic effects(1-7)|
03986|012|A|and additive CNS depression.(8,9)|
03986|013|A|   Levomethadone is an enantiomer of methadone.(10)|
03986|014|B||
03986|015|E|CLINICAL EFFECTS:  The concurrent use of serotoninergic opioids such as|
03986|016|E|diacetylmorphine or methadone with MAOIs like metaxalone has been associated|
03986|017|E|with serotonin syndrome.(1-7)  Symptoms of serotonin syndrome may include|
03986|018|E|tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
03986|019|E|hyperthermia, and muscle rigidity.(11)|
03986|020|E|   Concurrent use of methadone and metaxalone may also result in profound|
03986|021|E|sedation, respiratory depression, coma, and/or death.(8,9)|
03986|022|B||
03986|023|P|PREDISPOSING FACTORS:  Treatment with multiple medications which increase|
03986|024|P|serotonin levels or inhibit the metabolism of serotonin are risk factors for|
03986|025|P|serotonin syndrome.|
03986|026|P|   Higher opioid concentrations as may occur due to high opioid dosage or|
03986|027|P|inhibition of opioid clearance, patient specific genomic factors (e.g. poor|
03986|028|P|metabolizer status for a specific P450 enzyme), and concurrent use of|
03986|029|P|alcohol or other CNS depressants may increase the risk for a severe|
03986|030|P|interaction.|
03986|031|B||
03986|032|M|PATIENT MANAGEMENT:  When possible, avoid concomitant use of|
03986|033|M|diacetylmorphine or methadone and metaxalone.|
03986|034|M|   The US manufacturer of methadone states that methadone is not recommended|
03986|035|M|during and within 14 days of therapy with MAOIs.(1,2)|
03986|036|M|   The Australian manufacturer of methadone states that methadone should not|
03986|037|M|be administered to patients receiving MAOIs.(3)|
03986|038|M|   The UK manufacturer of methadone states that concurrent use and use|
03986|039|M|within 2 weeks of discontinuation of MAOIs is contraindicated.(4)|
03986|040|M|   The Canadian manufacturer of diacetylmorphine states that concurrent use|
03986|041|M|and use within 2 weeks of discontinuation of MAOIs is contraindicated.(5)|
03986|042|M|   Use an alternative analgesic when possible.  If concurrent therapy is|
03986|043|M|unavoidable, patients should be monitored closely for signs and symptoms of|
03986|044|M|serotonin syndrome and respiratory depression.  Instruct patients to report|
03986|045|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03986|046|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03986|047|M|coordination, or severe diarrhea.|
03986|048|M|   For patients on medication assisted treatment (MAT) with methadone,|
03986|049|M|discontinuation of metaxalone is preferred in most cases.  In some cases,|
03986|050|M|monitoring at a higher level of care for tapering may be appropriate.  In|
03986|051|M|others, gradual tapering or decreasing to the lowest effective dose of the|
03986|052|M|CNS depressant is appropriate.  Ensure that other health care providers|
03986|053|M|prescribing other CNS depressants are aware of the patient's methadone|
03986|054|M|treatment.(12)|
03986|055|M|   Respiratory depression can occur at any time during opioid therapy,|
03986|056|M|especially during therapy initiation and following dosage increases.  The|
03986|057|M|risk of opioid-related overdose or overdose-related death is increased with|
03986|058|M|higher opioid doses, and this risk persists over the course of therapy.|
03986|059|M|Consider these risks when using concurrently with other agents that may|
03986|060|M|cause CNS depression.(13)|
03986|061|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03986|062|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03986|063|M|unresponsiveness.(8,9)|
03986|064|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03986|065|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03986|066|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03986|067|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03986|068|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03986|069|M|as those taking CNS depressants) and when a patient has household|
03986|070|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03986|071|M|for obtaining an opioid reversal agent (e.g., prescription,|
03986|072|M|over-the-counter, or as part of a community-based program).(14)|
03986|073|B||
03986|074|D|DISCUSSION:  FDA performed a search of its adverse event database for cases|
03986|075|D|of serotonin syndrome with selected opiates for the period of January 1,|
03986|076|D|1969 to June 12, 2013; 5 cases were associated with methadone use during|
03986|077|D|this 43 year period.(9)|
03986|078|D|   Metaxalone is a weak MAO inhibitor.(6,7)|
03986|079|D|   Between 2002 and 2014, the number of patients receiving an opioid|
03986|080|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
03986|081|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
03986|082|D|to 30 million patients.  During this time, the proportion of patients|
03986|083|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
03986|084|D|patients.(15)|
03986|085|D|   A retrospective cohort study compared the risk of opioid overdose|
03986|086|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03986|087|D|versus opioid use alone. The study examined two types of opioid users (naive|
03986|088|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03986|089|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03986|090|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03986|091|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03986|092|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03986|093|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03986|094|D|respectively).  Elevated risk was associated with concomitant users with|
03986|095|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03986|096|D|1.39, respectively).(16)|
03986|097|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03986|098|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03986|099|D|per 100,000 and drug overdose deaths involving both opioids and|
03986|100|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03986|101|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03986|102|D|increased from 18% to 31% during this time.(17)|
03986|103|D|   A prospective observational cohort study in North Carolina found that the|
03986|104|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03986|105|D|benzodiazepines were 10 times higher than patients receiving opioid|
03986|106|D|analgesics alone.(18)|
03986|107|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03986|108|D|death from overdose increased with concomitant opioid analgesics and|
03986|109|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03986|110|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03986|111|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03986|112|D|increased risk of fatal overdose.(19)|
03986|113|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03986|114|D|which benzodiazepines were determined to be a cause of death and that|
03986|115|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03986|116|D|determined to be a cause of death.  This study also found that other CNS|
03986|117|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03986|118|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03986|119|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03986|120|D|where opioid analgesics were also implicated.(20)|
03986|121|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03986|122|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03986|123|D|deaths.(21)|
03986|124|B||
03986|125|R|REFERENCES:|
03986|126|B||
03986|127|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03986|128|R|  Pharmaceuticals Corp. June, 2021.|1
03986|129|R|2.Diskets Dispersible (methadone hydrochloride) US prescribing information.|1
03986|130|R|  Cebert Pharmaceuticals, Inc. August, 2007.|1
03986|131|R|3.Diamorphine hydrochloride Australian prescribing information. Auralis|1
03986|132|R|  March 13, 2008.|1
03986|133|R|4.Metharose (methadone hydrochloride) UK summary of product characteristics.|1
03986|134|R|  Rosemone Pharmaceuticals Limited January 9, 2008.|1
03986|135|R|5.Diacetylmorphine Canadian prescribing information. Pharmascience Inc.|1
03986|136|R|  February, 2022.|1
03986|137|R|6.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03986|138|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03986|139|R|  Feb;34(2):346.e5-6.|3
03986|140|R|7.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03986|141|R|  Pfizer Inc. January, 2024.|1
03986|142|R|8.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03986|143|R|  warns about serious risks and death when combining opioid pain or cough|1
03986|144|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03986|145|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03986|146|R|9.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03986|147|R|  warns about several safety issues with opioid pain medicines; requires|1
03986|148|R|  label changes. available at:|1
03986|149|R|  http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
03986|150|R|10.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
03986|151|R|   Pharma AS November 30, 2018.|1
03986|152|R|11.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03986|153|R|   352(11):1112-20.|6
03986|154|R|12.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03986|155|R|   urges caution about withholding opioid addiction medications from|1
03986|156|R|   patients taking benzodiazepines or CNS depressants: careful medication|1
03986|157|R|   management can reduce risks. available at:|1
03986|158|R|   https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
03986|159|R|13.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03986|160|R|   updates prescribing information for all opioid pain medicines to provide|1
03986|161|R|   additional guidance for safe use. Available at:|1
03986|162|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescr|1
03986|163|R|   ibing-information-all-opioid-pain-medicines-provide-additional-guidance-s|1
03986|164|R|   afe-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03986|165|R|14.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03986|166|R|   recommends health care professionals discuss naloxone with all patients|1
03986|167|R|   when prescribing opioid pain relievers or medicines to treat opioid use|1
03986|168|R|   disorder. Available at:|1
03986|169|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-hea|1
03986|170|R|   lth-care-professionals-discuss-naloxone-all-patients-when-prescribing-opi|1
03986|171|R|   oid-pain July 23, 2020.|1
03986|172|R|15.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03986|173|R|   in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03986|174|R|   Am J Prev Med 2016 Aug;51(2):151-60.|2
03986|175|R|16.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein|2
03986|176|R|   AG. Risk of opioid overdose associated with concomitant use of opioids|2
03986|177|R|   and sekeltal muscle relaxants: A population-based cohort study. Clin|2
03986|178|R|   Pharmacol Ther 2020 Jul;108(1):81-88.|2
03986|179|R|17.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03986|180|R|   From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015|2
03986|181|R|   Oct;49(4):493-501.|2
03986|182|R|18.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03986|183|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03986|184|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03986|185|R|19.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03986|186|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03986|187|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03986|188|R|   350:h2698.|2
03986|189|R|20.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03986|190|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03986|191|R|21.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03986|192|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03986|193|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03986|194|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03987|001|T|MONOGRAPH TITLE:  Methadone (Cough and Cold)/Metaxalone|
03987|002|B||
03987|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03987|004|L|is contraindicated and generally should not be dispensed or administered to|
03987|005|L|the same patient.|
03987|006|B||
03987|007|A|MECHANISM OF ACTION:  Methadone may inhibit neural reuptake of|
03987|008|A|serotonin.(1-4)  Metaxalone is a weak inhibitor of monoamine oxidase|
03987|009|A|(MAO).(5,6)  MAOIs increase neuronal serotonin concentrations via inhibition|
03987|010|A|of MAO-A.  Concurrent use of methadone and metaxalone may result in additive|
03987|011|A|serotonergic effects(1-6) and additive CNS depression.(7,8)|
03987|012|B||
03987|013|E|CLINICAL EFFECTS:  The concurrent use of methadone with MAOIs like|
03987|014|E|metaxalone has been associated with serotonin syndrome.(1-6)  Symptoms of|
03987|015|E|serotonin syndrome may include tremor, agitation, diaphoresis,|
03987|016|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(9)|
03987|017|E|   Concurrent use of methadone and metaxalone may also result in profound|
03987|018|E|sedation, respiratory depression, coma, and/or death.(7,8)|
03987|019|B||
03987|020|P|PREDISPOSING FACTORS:  Treatment with multiple medications which increase|
03987|021|P|serotonin levels or inhibit the metabolism of serotonin are risk factors for|
03987|022|P|serotonin syndrome.|
03987|023|P|   Higher opioid concentrations as may occur due to high opioid dosage or|
03987|024|P|inhibition of opioid clearance, patient specific genomic factors (e.g. poor|
03987|025|P|metabolizer status for a specific P450 enzyme), and concurrent use of|
03987|026|P|alcohol or other CNS depressants may increase the risk for a severe|
03987|027|P|interaction.|
03987|028|B||
03987|029|M|PATIENT MANAGEMENT:  When possible, avoid prescribing methadone-containing|
03987|030|M|cough and cold medications for patients taking CNS depressants such as|
03987|031|M|muscle relaxants.(7)|
03987|032|M|   The US manufacturer of methadone states that methadone is not recommended|
03987|033|M|during and within 14 days of therapy with MAOIs.(1,2)|
03987|034|M|   The Australian manufacturer of methadone states that methadone should not|
03987|035|M|be administered to patients receiving MAOIs.(3)|
03987|036|M|   The UK manufacturer of methadone states that concurrent use and use|
03987|037|M|within 2 weeks of discontinuation of MAOIs is contraindicated.(4)|
03987|038|M|   Use an alternative analgesic when possible.  If concurrent therapy is|
03987|039|M|unavoidable, patients should be monitored closely for signs and symptoms of|
03987|040|M|serotonin syndrome and respiratory depression.  Instruct patients to report|
03987|041|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
03987|042|M|heart palpitations, restlessness, confusion, agitation, trouble with|
03987|043|M|coordination, or severe diarrhea.|
03987|044|M|   Respiratory depression can occur at any time during opioid therapy,|
03987|045|M|especially during therapy initiation and following dosage increases.  The|
03987|046|M|risk of opioid-related overdose or overdose-related death is increased with|
03987|047|M|higher opioid doses, and this risk persists over the course of therapy.|
03987|048|M|Consider these risks when using concurrently with other agents that may|
03987|049|M|cause CNS depression.(10)|
03987|050|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
03987|051|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03987|052|M|unresponsiveness.(7)|
03987|053|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03987|054|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03987|055|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03987|056|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03987|057|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03987|058|M|as those taking CNS depressants) and when a patient has household|
03987|059|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03987|060|M|for obtaining an opioid reversal agent (e.g., prescription,|
03987|061|M|over-the-counter, or as part of a community-based program).(11)|
03987|062|B||
03987|063|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03987|064|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03987|065|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03987|066|D|million to 30 million patients.  During this time, the proportion of|
03987|067|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03987|068|D|million patients.(12)|
03987|069|D|   A retrospective cohort study compared the risk of opioid overdose|
03987|070|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03987|071|D|versus opioid use alone. The study examined two types of opioid users (naive|
03987|072|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03987|073|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03987|074|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03987|075|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03987|076|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03987|077|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03987|078|D|respectively).  Elevated risk was associated with concomitant users with|
03987|079|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03987|080|D|1.39, respectively).(13)|
03987|081|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03987|082|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03987|083|D|per 100,000 and drug overdose deaths involving both opioids and|
03987|084|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03987|085|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03987|086|D|increased from 18% to 31% during this time.(14)|
03987|087|D|   A prospective observational cohort study in North Carolina found that the|
03987|088|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03987|089|D|benzodiazepines were 10 times higher than patients receiving opioid|
03987|090|D|analgesics alone.(15)|
03987|091|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03987|092|D|death from overdose increased with concomitant opioid analgesics and|
03987|093|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03987|094|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03987|095|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03987|096|D|increased risk of fatal overdose.(16)|
03987|097|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03987|098|D|which benzodiazepines were determined to be a cause of death and that|
03987|099|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03987|100|D|determined to be a cause of death.  This study also found that other CNS|
03987|101|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03987|102|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03987|103|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03987|104|D|where opioid analgesics were also implicated.(17)|
03987|105|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03987|106|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03987|107|D|deaths.(18)|
03987|108|B||
03987|109|R|REFERENCES:|
03987|110|B||
03987|111|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
03987|112|R|  Pharmaceuticals Corp. June, 2021.|1
03987|113|R|2.Diskets Dispersible (methadone hydrochloride) US prescribing information.|1
03987|114|R|  Cebert Pharmaceuticals, Inc. August, 2007.|1
03987|115|R|3.Diamorphine hydrochloride Australian prescribing information. Auralis|1
03987|116|R|  March 13, 2008.|1
03987|117|R|4.Metharose (methadone hydrochloride) UK summary of product characteristics.|1
03987|118|R|  Rosemone Pharmaceuticals Limited January 9, 2008.|1
03987|119|R|5.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03987|120|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03987|121|R|  Feb;34(2):346.e5-6.|3
03987|122|R|6.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03987|123|R|  Pfizer Inc. January, 2024.|1
03987|124|R|7.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03987|125|R|  warns about serious risks and death when combining opioid pain or cough|1
03987|126|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03987|127|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03987|128|R|8.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03987|129|R|  warns about several safety issues with opioid pain medicines; requires|1
03987|130|R|  label changes. available at:|1
03987|131|R|  http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
03987|132|R|9.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03987|133|R|  352(11):1112-20.|6
03987|134|R|10.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03987|135|R|   updates prescribing information for all opioid pain medicines to provide|1
03987|136|R|   additional guidance for safe use. Available at:|1
03987|137|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescr|1
03987|138|R|   ibing-information-all-opioid-pain-medicines-provide-additional-guidance-s|1
03987|139|R|   afe-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03987|140|R|11.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03987|141|R|   recommends health care professionals discuss naloxone with all patients|1
03987|142|R|   when prescribing opioid pain relievers or medicines to treat opioid use|1
03987|143|R|   disorder. Available at:|1
03987|144|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-hea|1
03987|145|R|   lth-care-professionals-discuss-naloxone-all-patients-when-prescribing-opi|1
03987|146|R|   oid-pain July 23, 2020.|1
03987|147|R|12.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03987|148|R|   in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03987|149|R|   Am J Prev Med 2016 Aug;51(2):151-60.|2
03987|150|R|13.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein|2
03987|151|R|   AG. Risk of opioid overdose associated with concomitant use of opioids|2
03987|152|R|   and sekeltal muscle relaxants: A population-based cohort study. Clin|2
03987|153|R|   Pharmacol Ther 2020 Jul;108(1):81-88.|2
03987|154|R|14.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03987|155|R|   From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015|2
03987|156|R|   Oct;49(4):493-501.|2
03987|157|R|15.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03987|158|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03987|159|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03987|160|R|16.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03987|161|R|   prescribing patterns and deaths from drug overdose among US veterans|2
03987|162|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
03987|163|R|   350:h2698.|2
03987|164|R|17.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03987|165|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03987|166|R|18.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03987|167|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03987|168|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03987|169|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03988|001|T|MONOGRAPH TITLE:  Selected Serotonergic Opioids/Metaxalone|
03988|002|B||
03988|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03988|004|L|of severe adverse interaction.|
03988|005|B||
03988|006|A|MECHANISM OF ACTION:  Concurrent use of serotonergic opioids and metaxalone,|
03988|007|A|a weak monoamine oxidase (MAO) inhibitor, may result in additive CNS|
03988|008|A|depression and additive serotonergic effects.(1-4)|
03988|009|B||
03988|010|E|CLINICAL EFFECTS:  Concurrent use of opioids and metaxalone may result in|
03988|011|E|profound sedation, respiratory depression, coma, and/or death.(3,4)|
03988|012|E|   The concurrent use of some opioids with serotonergic properties with|
03988|013|E|metaxalone may result in serotonin syndrome.  Symptoms of serotonin syndrome|
03988|014|E|may include tremor, agitation, diaphoresis, hyperreflexia, clonus,|
03988|015|E|tachycardia, hyperthermia, and muscle rigidity.(1-2,5)|
03988|016|B||
03988|017|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03988|018|P|may increase the risk of adverse effects.|
03988|019|P|   Treatment with multiple medications which increase serotonin levels or|
03988|020|P|inhibit the metabolism of serotonin are risk factors for serotonin syndrome.|
03988|021|P|   Higher opioid concentrations, as may occur due to inhibition of opioid|
03988|022|P|clearance, patient specific genomic factors (e.g. poor metabolizer status|
03988|023|P|for a P450 enzyme), or high opioid dosage may increase the risk for an|
03988|024|P|interaction.|
03988|025|B||
03988|026|M|PATIENT MANAGEMENT:  Use an alternative analgesic when possible.  If|
03988|027|M|concurrent therapy is warranted, patients should be monitored for signs and|
03988|028|M|symptoms of serotonin syndrome.  Instruct patients to report muscle|
03988|029|M|twitching, tremors, shivering and stiffness, fever, heavy sweating, heart|
03988|030|M|palpitations, restlessness, confusion, agitation, trouble with coordination,|
03988|031|M|or severe diarrhea.|
03988|032|M|   If concurrent use is necessary, limit the dosages and duration of each|
03988|033|M|drug to the minimum possible while achieving the desired clinical effect.|
03988|034|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03988|035|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03988|036|M|indicated in the absence of an opioid and titrate based upon clinical|
03988|037|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03988|038|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03988|039|M|clinical response.(3,4)|
03988|040|M|   Respiratory depression can occur at any time during opioid therapy,|
03988|041|M|especially during therapy initiation and following dosage increases.  The|
03988|042|M|risk of opioid-related overdose or overdose-related death is increased with|
03988|043|M|higher opioid doses, and this risk persists over the course of therapy.|
03988|044|M|Consider these risks when using concurrently with other agents that may|
03988|045|M|cause CNS depression.(6)|
03988|046|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03988|047|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03988|048|M|unresponsiveness.(3,4)|
03988|049|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03988|050|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03988|051|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03988|052|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03988|053|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03988|054|M|as those taking CNS depressants) and when a patient has household|
03988|055|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03988|056|M|for obtaining an opioid reversal agent (e.g., prescription,|
03988|057|M|over-the-counter, or as part of a community-based program).(7)|
03988|058|B||
03988|059|D|DISCUSSION:  Although documentation is lacking for some opioids, the FDA|
03988|060|D|recommends health professionals monitor and advise patients to report|
03988|061|D|symptoms of serotonin syndrome in patients receiving analgesic opioids and|
03988|062|D|serotonergic agents.(4)|
03988|063|D|   In a case report, the concurrent use of propoxyphene and phenelzine|
03988|064|D|resulted in sedation and somnolence. The patient had previously taken both|
03988|065|D|agents alone with no adverse effects.(8)|
03988|066|D|   Metaxalone is a weak inhibitor of MAO.(1,2)|
03988|067|B||
03988|068|R|REFERENCES:|
03988|069|B||
03988|070|R|1.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03988|071|R|  Pfizer Inc. January, 2024.|1
03988|072|R|2.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03988|073|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03988|074|R|  Feb;34(2):346.e5-6.|3
03988|075|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03988|076|R|  warns about serious risks and death when combining opioid pain or cough|1
03988|077|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03988|078|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03988|079|R|4.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03988|080|R|  warns about several safety issues with opioid pain medicines; requires|1
03988|081|R|  label changes. available at:|1
03988|082|R|  http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm March 22, 2016.|1
03988|083|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
03988|084|R|  352(11):1112-20.|6
03988|085|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03988|086|R|  prescribing information for all opioid pain medicines to provide|1
03988|087|R|  additional guidance for safe use. Available at:|1
03988|088|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03988|089|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03988|090|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03988|091|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03988|092|R|  recommends health care professionals discuss naloxone with all patients|1
03988|093|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03988|094|R|  disorder. Available at:|1
03988|095|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03988|096|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03988|097|R|  d-pain July 23, 2020.|1
03988|098|R|8.Garbutt JC. Potentiation of propoxyphene by phenelzine. Am J Psychiatry|3
03988|099|R|  1987 Feb;144(2):251-2.|3
03989|001|T|MONOGRAPH TITLE:  Selected Opioids (Extended Release)/Metaxalone|
03989|002|B||
03989|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03989|004|L|take action as needed.|
03989|005|B||
03989|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and metaxalone may result in|
03989|007|A|additive CNS depression.(1)|
03989|008|B||
03989|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
03989|010|E|as the muscle relaxant metaxalone, may result in profound sedation,|
03989|011|E|respiratory depression, coma, and/or death.(1)|
03989|012|B||
03989|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03989|014|P|may increase the risk of adverse effects.|
03989|015|B||
03989|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
03989|017|M|depressants such as the muscle relaxant metaxalone to patients for whom|
03989|018|M|alternatives are ineffective, not tolerated, or would be otherwise|
03989|019|M|inadequate to provide sufficient management of pain.(1)|
03989|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
03989|021|M|drug to the minimum possible while achieving the desired clinical effect.|
03989|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03989|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03989|024|M|indicated in the absence of an opioid and titrate based upon clinical|
03989|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03989|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03989|027|M|clinical response.(1)|
03989|028|M|   Respiratory depression can occur at any time during opioid therapy,|
03989|029|M|especially during therapy initiation and following dosage increases.  The|
03989|030|M|risk of opioid-related overdose or overdose-related death is increased with|
03989|031|M|higher opioid doses, and this risk persists over the course of therapy.|
03989|032|M|Consider these risks when using concurrently with other agents that may|
03989|033|M|cause CNS depression.(2)|
03989|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03989|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03989|036|M|unresponsiveness.(1)|
03989|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03989|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03989|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03989|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03989|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03989|042|M|as those taking CNS depressants) and when a patient has household|
03989|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03989|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
03989|045|M|over-the-counter, or as part of a community-based program).(3)|
03989|046|B||
03989|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03989|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03989|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03989|050|D|million to 30 million patients.  During this time, the proportion of|
03989|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03989|052|D|million patients.(4)|
03989|053|D|   A retrospective cohort study compared the risk of opioid overdose|
03989|054|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03989|055|D|versus opioid use alone. The study examined two types of opioid users (naive|
03989|056|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03989|057|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03989|058|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03989|059|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03989|060|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03989|061|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03989|062|D|respectively).  Elevated risk was associated with concomitant users with|
03989|063|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03989|064|D|1.39, respectively).(5)|
03989|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03989|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03989|067|D|per 100,000 and drug overdose deaths involving both opioids and|
03989|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03989|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03989|070|D|increased from 18% to 31% during this time.(6)|
03989|071|D|   A prospective observational cohort study in North Carolina found that the|
03989|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03989|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
03989|074|D|analgesics alone.(7)|
03989|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03989|076|D|death from overdose increased with concomitant opioid analgesics and|
03989|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03989|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03989|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03989|080|D|increased risk of fatal overdose.(8)|
03989|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03989|082|D|which benzodiazepines were determined to be a cause of death and that|
03989|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03989|084|D|determined to be a cause of death.  This study also found that other CNS|
03989|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03989|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03989|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03989|088|D|where opioid analgesics were also implicated.(9)|
03989|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03989|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03989|091|D|deaths.(10)|
03989|092|B||
03989|093|R|REFERENCES:|
03989|094|B||
03989|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03989|096|R|  warns about serious risks and death when combining opioid pain or cough|1
03989|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03989|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03989|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03989|100|R|  prescribing information for all opioid pain medicines to provide|1
03989|101|R|  additional guidance for safe use. Available at:|1
03989|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03989|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03989|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03989|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03989|106|R|  recommends health care professionals discuss naloxone with all patients|1
03989|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03989|108|R|  disorder. Available at:|1
03989|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03989|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03989|111|R|  d-pain July 23, 2020.|1
03989|112|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03989|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03989|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03989|115|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
03989|116|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
03989|117|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
03989|118|R|  Ther 2020 Jul;108(1):81-88.|2
03989|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03989|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03989|121|R|  49(4):493-501.|2
03989|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03989|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03989|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03989|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03989|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03989|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03989|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03989|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03989|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03989|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03989|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03989|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03990|001|T|MONOGRAPH TITLE:  Selected Opioids (Immediate Release)/Metaxalone|
03990|002|B||
03990|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03990|004|L|take action as needed.|
03990|005|B||
03990|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and metaxalone may result in|
03990|007|A|additive CNS depression.(1)|
03990|008|B||
03990|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
03990|010|E|as the muscle relaxant metaxalone, may result in profound sedation,|
03990|011|E|respiratory depression, coma, and/or death.(1)|
03990|012|B||
03990|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
03990|014|P|may increase the risk of adverse effects.|
03990|015|B||
03990|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
03990|017|M|depressants such as the muscle relaxant metaxalone to patients for whom|
03990|018|M|alternatives are ineffective, not tolerated, or would be otherwise|
03990|019|M|inadequate to provide sufficient management of pain.(1)|
03990|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
03990|021|M|drug to the minimum possible while achieving the desired clinical effect.|
03990|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
03990|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
03990|024|M|indicated in the absence of an opioid and titrate based upon clinical|
03990|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
03990|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
03990|027|M|clinical response.(1)|
03990|028|M|   Respiratory depression can occur at any time during opioid therapy,|
03990|029|M|especially during therapy initiation and following dosage increases.  The|
03990|030|M|risk of opioid-related overdose or overdose-related death is increased with|
03990|031|M|higher opioid doses, and this risk persists over the course of therapy.|
03990|032|M|Consider these risks when using concurrently with other agents that may|
03990|033|M|cause CNS depression.(2)|
03990|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
03990|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
03990|036|M|unresponsiveness.(1)|
03990|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
03990|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
03990|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
03990|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
03990|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
03990|042|M|as those taking CNS depressants) and when a patient has household|
03990|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
03990|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
03990|045|M|over-the-counter, or as part of a community-based program).(3)|
03990|046|B||
03990|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
03990|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
03990|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
03990|050|D|million to 30 million patients.  During this time, the proportion of|
03990|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
03990|052|D|million patients.(4)|
03990|053|D|   A retrospective cohort study compared the risk of opioid overdose|
03990|054|D|associated with concomitant use of opioids and skeletal muscle relaxants|
03990|055|D|versus opioid use alone. The study examined two types of opioid users (naive|
03990|056|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
03990|057|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
03990|058|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
03990|059|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
03990|060|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
03990|061|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
03990|062|D|respectively).  Elevated risk was associated with concomitant users with|
03990|063|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
03990|064|D|1.39, respectively).(5)|
03990|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
03990|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
03990|067|D|per 100,000 and drug overdose deaths involving both opioids and|
03990|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
03990|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
03990|070|D|increased from 18% to 31% during this time.(6)|
03990|071|D|   A prospective observational cohort study in North Carolina found that the|
03990|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
03990|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
03990|074|D|analgesics alone.(7)|
03990|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
03990|076|D|death from overdose increased with concomitant opioid analgesics and|
03990|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
03990|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
03990|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
03990|080|D|increased risk of fatal overdose.(8)|
03990|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
03990|082|D|which benzodiazepines were determined to be a cause of death and that|
03990|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
03990|084|D|determined to be a cause of death.  This study also found that other CNS|
03990|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
03990|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
03990|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
03990|088|D|where opioid analgesics were also implicated.(9)|
03990|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
03990|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
03990|091|D|deaths.(10)|
03990|092|B||
03990|093|R|REFERENCES:|
03990|094|B||
03990|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
03990|096|R|  warns about serious risks and death when combining opioid pain or cough|1
03990|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
03990|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
03990|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
03990|100|R|  prescribing information for all opioid pain medicines to provide|1
03990|101|R|  additional guidance for safe use. Available at:|1
03990|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
03990|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
03990|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
03990|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
03990|106|R|  recommends health care professionals discuss naloxone with all patients|1
03990|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
03990|108|R|  disorder. Available at:|1
03990|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
03990|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
03990|111|R|  d-pain July 23, 2020.|1
03990|112|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
03990|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
03990|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
03990|115|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
03990|116|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
03990|117|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
03990|118|R|  Ther 2020 Jul;108(1):81-88.|2
03990|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
03990|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
03990|121|R|  49(4):493-501.|2
03990|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
03990|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
03990|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
03990|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
03990|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
03990|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
03990|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
03990|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
03990|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
03990|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
03990|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
03990|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
03991|001|T|MONOGRAPH TITLE:  Dextromethorphan/Metaxalone|
03991|002|B||
03991|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03991|004|L|is contraindicated and generally should not be dispensed or administered to|
03991|005|L|the same patient.|
03991|006|B||
03991|007|A|MECHANISM OF ACTION:  Dextromethorphan inhibits neural reuptake of|
03991|008|A|serotonin.  Metaxalone, a weak inhibitor of MAO, may increase neuronal|
03991|009|A|serotonin concentrations.(1)|
03991|010|B||
03991|011|E|CLINICAL EFFECTS:  The concurrent use of dextromethorphan with MAOIs may|
03991|012|E|result in hypotension, hyperpyrexia, sedation, somnolence, and death.|
03991|013|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
03991|014|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
03991|015|E|rigidity.(1)|
03991|016|B||
03991|017|P|PREDISPOSING FACTORS:  Higher opioid concentrations as may occur due to|
03991|018|P|inhibition of opioid  clearance, patient specific genomic factors (e.g. poor|
03991|019|P|metabolizer status for a P450 enzyme), or high opioid dosage may increase|
03991|020|P|the risk for a severe interaction.|
03991|021|B||
03991|022|M|PATIENT MANAGEMENT:  Dextromethorphan should not be used in patients taking|
03991|023|M|MAOIs such as metaxalone.  Use alternative agents for cough.|
03991|024|M|   The US manufacturer of Nuedexta (dextromethorphan-quinidine) states|
03991|025|M|Nuedexta is contraindicated within 14 days of MAOI administration.(1)|
03991|026|M|Quinidine increases systemic dextromethorphan concentrations 10 to 20-fold.|
03991|027|B||
03991|028|D|DISCUSSION:  Metaxalone is a weak inhibitor of MAO.(2,3)|
03991|029|D|   There are at least two reports of potential interactions between MAOIs|
03991|030|D|and dextromethorphan.  Concomitant use of quinidine, a strong CYP2D6|
03991|031|D|inhibitor, increases systemic dextromethorphan concentrations 10 to 20-fold.|
03991|032|D|Other strong CYP2D6 inhibitors such as bupropion, fluoxetine and paroxetine|
03991|033|D|could similarly increase dextromethorphan levels and risk for serotonin|
03991|034|D|toxicity in patients also receiving MAOIs.(4,5)|
03991|035|B||
03991|036|R|REFERENCES:|
03991|037|B||
03991|038|R|1.Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) US|1
03991|039|R|  prescribing information. Avanir  Pharmaceuticals June, 2019.|1
03991|040|R|2.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
03991|041|R|  Pfizer Inc. January, 2024.|1
03991|042|R|3.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
03991|043|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
03991|044|R|  Feb;34(2):346.e5-6.|3
03991|045|R|4.Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine|3
03991|046|R|  oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988 Dec 22;|3
03991|047|R|  319(25):1671.|3
03991|048|R|5.Rivers N, Horner B. Possible lethal reaction between Nardil and|3
03991|049|R|  dextromethorphan. Can Med Assoc J 1970 Jul;103:85.|3
03992|001|T|MONOGRAPH TITLE:  Panobinostat (Greater Than 10 mg)/Strong CYP3A4 Inhibitors|
03992|002|T|that Prolong QT|
03992|003|B||
03992|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
03992|005|L|is contraindicated and generally should not be dispensed or administered to|
03992|006|L|the same patient.|
03992|007|B||
03992|008|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03992|009|A|panobinostat.|
03992|010|B||
03992|011|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
03992|012|E|in elevated levels of and toxicity from panobinostat,(1) including increased|
03992|013|E|risk of bleeding and prolongation of the QT interval which may result in|
03992|014|E|life-threatening arrhythmia and death.|
03992|015|B||
03992|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03992|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
03992|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03992|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03992|020|P|female gender, or advanced age.(2)|
03992|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03992|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03992|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03992|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03992|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03992|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03992|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03992|028|P|   The risk for bleeding episodes may be greater in patients with|
03992|029|P|disease-associated factors (e.g. thrombocytopenia).|
03992|030|P|   Drug associated risk factors include concurrent use of multiple drugs|
03992|031|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03992|032|P|risk for bleeding (e.g. NSAIDs).|
03992|033|B||
03992|034|M|PATIENT MANAGEMENT:  Reduce the dose of panobinostat to 10 mg when|
03992|035|M|coadministered with strong CYP3A4 inhibitors.  Limit the starting dose of|
03992|036|M|panobinostat to 10 mg in patients taking strong CYP3A4 inhibitors.(1)|
03992|037|M|   If concurrent therapy is warranted, continue standard monitoring of|
03992|038|M|complete blood counts, ECG, and serum electrolytes.  Instruct patients to|
03992|039|M|report any irregular heartbeat, dizziness, or fainting; nausea, vomiting, or|
03992|040|M|diarrhea; unusual tiredness, shortness of breath, paleness; unusual or|
03992|041|M|unexplained bleeding or bruising; signs of infection such as fever, cough,|
03992|042|M|or flu-like symptoms.  If panobinostat toxicity occurs, panobinostat or the|
03992|043|M|CYP3A4 inhibitor may need to be discontinued.(1)|
03992|044|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
03992|045|M|including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
03992|046|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03992|047|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03992|048|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03992|049|M|anticoagulation in patients with active pathologic bleeding.|
03992|050|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03992|051|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03992|052|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03992|053|M|and/or swelling.|
03992|054|B||
03992|055|D|DISCUSSION:  In 14 patients with advanced cancer, ketoconazole (a strong|
03992|056|D|CYP3A4 inhibitor, 200 mg twice daily for 14 days) increased the maximum|
03992|057|D|concentration (Cmax) and area-under-curve (AUC) of panobinostat by 62% and|
03992|058|D|73%, respectively.(1)|
03992|059|D|   Strong inhibitors of CYP3A4 include:  adagrasib, ceritinib,|
03992|060|D|clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole,|
03992|061|D|ribociclib, saquinavir, telithromycin, and voriconazole.(1,3-4)|
03992|062|B||
03992|063|R|REFERENCES:|
03992|064|B||
03992|065|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
03992|066|R|  Pharmaceuticals Corporation June, 2016.|1
03992|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03992|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03992|069|R|  settings: a scientific statement from the American Heart Association and|6
03992|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03992|071|R|  2;55(9):934-47.|6
03992|072|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03992|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03992|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03992|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03992|076|R|  11/14/2017.|1
03992|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
03992|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03993|001|T|MONOGRAPH TITLE:  Panobinostat (Less than or Equal To 10 mg)/Strong CYP3A4|
03993|002|T|Inhibitors that Prolong QT|
03993|003|B||
03993|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03993|005|L|of severe adverse interaction.|
03993|006|B||
03993|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03993|008|A|panobinostat.(1)|
03993|009|B||
03993|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
03993|011|E|in elevated levels of and toxicity from panobinostat, including increased|
03993|012|E|risk of bleeding and prolongation of the QT interval which may result in|
03993|013|E|life-threatening arrhythmia and death.(1)|
03993|014|B||
03993|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
03993|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
03993|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
03993|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
03993|019|P|female gender, or advanced age.(2)|
03993|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03993|021|P|higher systemic concentrations of either QT prolonging drug are additional|
03993|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03993|023|P|drug concentrations include rapid infusion of an intravenous dose or|
03993|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03993|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03993|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
03993|027|P|   The risk for bleeding episodes may be greater in patients with|
03993|028|P|disease-associated factors (e.g. thrombocytopenia).|
03993|029|P|   Drug associated risk factors include concurrent use of multiple drugs|
03993|030|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
03993|031|P|risk for bleeding (e.g. NSAIDs).|
03993|032|B||
03993|033|M|PATIENT MANAGEMENT:  Reduce the dose of panobinostat to 10 mg when|
03993|034|M|coadministered with strong CYP3A4 inhibitors.  Limit the starting dose of|
03993|035|M|panobinostat to 10 mg in patients taking strong CYP3A4 inhibitors.(1)|
03993|036|M|   If concurrent therapy is warranted, continue standard monitoring of|
03993|037|M|complete blood counts, ECG, and serum electrolytes.  Instruct patients to|
03993|038|M|report any irregular heartbeat, dizziness, or fainting; nausea, vomiting, or|
03993|039|M|diarrhea; unusual tiredness, shortness of breath, paleness; unusual or|
03993|040|M|unexplained bleeding or bruising; signs of infection such as fever, cough,|
03993|041|M|or flu-like symptoms.  If panobinostat toxicity occurs, panobinostat or the|
03993|042|M|CYP3A4 inhibitor may need to be discontinued.(1)|
03993|043|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
03993|044|M|including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
03993|045|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
03993|046|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
03993|047|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
03993|048|M|anticoagulation in patients with active pathologic bleeding.|
03993|049|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
03993|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
03993|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
03993|052|M|and/or swelling.|
03993|053|B||
03993|054|D|DISCUSSION:  In 14 patients with advanced cancer, ketoconazole (a strong|
03993|055|D|CYP3A4 inhibitor, 200 mg twice daily for 14 days) increased the maximum|
03993|056|D|concentration (Cmax) and area-under-curve (AUC) of panobinostat by 62% and|
03993|057|D|73%, respectively.(1)|
03993|058|D|   Strong inhibitors of CYP3A4 include:  clarithromycin, levoketoconazole|
03993|059|D|and lonafarnib.(3,4)|
03993|060|B||
03993|061|R|REFERENCES:|
03993|062|B||
03993|063|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
03993|064|R|  Pharmaceuticals Corporation June, 2016.|1
03993|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03993|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03993|067|R|  settings: a scientific statement from the American Heart Association and|6
03993|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03993|069|R|  2;55(9):934-47.|6
03993|070|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
03993|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03993|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03993|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03993|074|R|  11/14/2017.|1
03993|075|R|4.This information is based on an extract from the Certara Drug Interaction|6
03993|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03994|001|T|MONOGRAPH TITLE:  Tramadol/Tricyclic Compounds; Carbamazepine|
03994|002|B||
03994|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03994|004|L|of severe adverse interaction.|
03994|005|B||
03994|006|A|MECHANISM OF ACTION:  Tramadol and tricyclic compounds may lower the seizure|
03994|007|A|threshold.(1)|
03994|008|A|   Tramadol inhibits the reuptake of serotonin and norepinephrine but has|
03994|009|A|weak opioid effects.  M1, tramadol's active metabolite, is a stronger opioid|
03994|010|A|and up to 6 times more potent than tramadol in producing analgesia.(1)|
03994|011|A|Carbamazepine induces the metabolism of this tramadol opioid metabolite.|
03994|012|B||
03994|013|E|CLINICAL EFFECTS:  Concurrent use of tramadol and a tricyclic compound may|
03994|014|E|result in seizures or serotonin syndrome and may increase the risk of|
03994|015|E|suicide.(1)|
03994|016|E|   Concurrent use of tramadol and carbamazepine may significantly reduce the|
03994|017|E|analgesic effect of tramadol.(1)|
03994|018|E|   Although not used therapeutically as an antidepressant, carbamazepine is|
03994|019|E|a tricyclic compound.|
03994|020|B||
03994|021|P|PREDISPOSING FACTORS:  Risk of seizures may be increased in patients with|
03994|022|P|epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol|
03994|023|P|or drug withdrawal, or infections of the central nervous system.(1)|
03994|024|B||
03994|025|M|PATIENT MANAGEMENT:  Tramadol should be used with caution in patients taking|
03994|026|M|tricyclic compounds.(1)|
03994|027|M|   The use of tramadol and carbamazepine is not recommended.(1)|
03994|028|M|Carbamazepine induces metabolism (glucuronidation) of the tramadol opioid|
03994|029|M|metabolite (M1).  In patients on long-term carbamazepine when tramadol is|
03994|030|M|started, achieving adequate analgesia may be difficult.  Prescribing higher|
03994|031|M|tramadol doses would be associated with higher parent drug levels which may|
03994|032|M|result in serotonin and norepinephrine associated adverse effects.|
03994|033|M|   In patients receiving chronic tramadol treatment when carbamazepine is|
03994|034|M|started, anticipate a reduction in analgesic effects.  The maximal effects|
03994|035|M|of carbamazepine on tramadol efficacy may not be seen for 2 or more weeks.|
03994|036|M|Monitor for decreased tramadol efficacy, including symptoms of opioid|
03994|037|M|withdrawal, after carbamazepine is initiated or when carbamazepine dosage is|
03994|038|M|increased.|
03994|039|M|   If carbamazepine is to be discontinued in patients stabilized on the|
03994|040|M|combination of tramadol and carbamazepine, gradually decrease the|
03994|041|M|carbamazepine dose to decrease the risk of withdrawal seizures. As|
03994|042|M|carbamazepine induction wanes, systemic tramadol metabolite concentrations|
03994|043|M|will rise. The tramadol dose may need to be decreased to prevent tramadol|
03994|044|M|toxicity.|
03994|045|B||
03994|046|D|DISCUSSION:  The use of tramadol in patients treated with tricyclic|
03994|047|D|compounds may increase the risk of seizures.(1)  A review of 124 reports of|
03994|048|D|seizures following tramadol therapy received by the FDA through July 31,|
03994|049|D|1996 revealed that 23% of the patients were also taking tricyclic|
03994|050|D|antidepressants.(2)  Therefore, the manufacturer of tramadol states that|
03994|051|D|tramadol should be used with caution in patients treated with tricyclic|
03994|052|D|compounds.(1)  The manufacturer of tramadol also states that the use of|
03994|053|D|tramadol with carbamazepine is not recommended.(1)|
03994|054|D|   In a case report, a 79 year-old female developed serotonin syndrome three|
03994|055|D|days after the addition of tramadol to amitriptyline therapy. Over the next|
03994|056|D|four days, her condition deteriorated and she died.(3)|
03994|057|B||
03994|058|R|REFERENCES:|
03994|059|B||
03994|060|R|1.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
03994|061|R|  October, 2019.|1
03994|062|R|2.Kahn LH, Alderfer RJ, Graham DJ. Seizures reported with tramadol. JAMA|3
03994|063|R|  1997 Nov 26;278(20):1661.|3
03994|064|R|3.Kitson R, Carr B. Tramadol and severe serotonin syndrome. Anaesthesia 2005|3
03994|065|R|  Sep;60(9):934-5.|3
03995|001|T|MONOGRAPH TITLE:  Tolterodine (Less Than or Equal to 1 mg or Less Than or|
03995|002|T|Equal to 2 mg ER)/Strong CYP3A4 Inhibitors|
03995|003|B||
03995|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03995|005|L|take action as needed.|
03995|006|B||
03995|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03995|008|A|tolterodine by CYP3A4.(1,2)|
03995|009|B||
03995|010|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with strong|
03995|011|E|CYP3A4 inhibitors may result in elevated levels of tolterodine and signs of|
03995|012|E|toxicity.(1,2)|
03995|013|B||
03995|014|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers may be at|
03995|015|P|increased risk.(1,2)|
03995|016|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03995|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03995|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03995|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03995|020|P|advanced age.(3)|
03995|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03995|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03995|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03995|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03995|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03995|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03995|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03995|028|P|   The risk of anticholinergic toxicities including cognitive decline,|
03995|029|P|delirium, falls and fractures is increased in geriatric patients using more|
03995|030|P|than one medicine with anticholinergic properties.(4)|
03995|031|B||
03995|032|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
03995|033|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
03995|034|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
03995|035|M|used in patients receiving concurrent therapy with strong CYP3A4 inhibitors.|
03995|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03995|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03995|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03995|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03995|040|B||
03995|041|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP2D6, the|
03995|042|D|concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg|
03995|043|D|once daily for four days), another inhibitor of CYP3A4, resulted in a 60%|
03995|044|D|decrease in tolterodine clearance.(6)  Tolterodine AUC and Cmax increased|
03995|045|D|2.5-fold and 2-fold, respectively.(2)|
03995|046|D|   In a study of the effect of tolterodine immediate release tablets, the|
03995|047|D|effect on the QT interval appeared greater for 8 mg/day (two times the|
03995|048|D|therapeutic dose) compared to 4 mg/day.  Tolterodine 2 mg BID and|
03995|049|D|tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and|
03995|050|D|11.84 msec (7.11-16.58 msec), respectively.  The change in QT interval was|
03995|051|D|more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers|
03995|052|D|(EMs).(1,2)|
03995|053|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, idelalisib,|
03995|054|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03995|055|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03995|056|D|tipranavir, troleandomycin, and tucatinib.(7,8)|
03995|057|B||
03995|058|R|REFERENCES:|
03995|059|B||
03995|060|R|1.Detrol (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03995|061|R|  August, 2012.|1
03995|062|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03995|063|R|  July, 2018.|1
03995|064|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03995|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03995|066|R|  settings: a scientific statement from the American Heart Association and|6
03995|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03995|068|R|  2;55(9):934-47.|6
03995|069|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03995|070|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03995|071|R|  Soc 2023 Jul;71(7):2052-2081.|6
03995|072|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03995|073|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03995|074|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03995|075|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03995|076|R|6.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
03995|077|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
03995|078|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
03995|079|R|7.This information is based on an extract from the Certara Drug Interaction|6
03995|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03995|081|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
03995|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03995|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03995|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03995|085|R|  11/14/2017.|1
03996|001|T|MONOGRAPH TITLE:  Tolterodine (Greater Than 1 mg IR or Greater Than 2 mg|
03996|002|T|ER)/Strong CYP3A4 Inhibitor|
03996|003|B||
03996|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03996|005|L|of severe adverse interaction.|
03996|006|B||
03996|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03996|008|A|tolterodine by CYP3A4.(1,2)|
03996|009|B||
03996|010|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with strong|
03996|011|E|CYP3A4 inhibitors may result in elevated levels of tolterodine and signs of|
03996|012|E|toxicity.(1,2)|
03996|013|B||
03996|014|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers may be at|
03996|015|P|increased risk.(1,2)|
03996|016|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03996|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03996|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03996|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03996|020|P|advanced age.(3)|
03996|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03996|022|P|higher systemic concentrations of either QT prolonging drug are additional|
03996|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03996|024|P|drug concentrations include rapid infusion of an intravenous dose or|
03996|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03996|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03996|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03996|028|P|   The risk of anticholinergic toxicities including cognitive decline,|
03996|029|P|delirium, falls and fractures is increased in geriatric patients using more|
03996|030|P|than one medicine with anticholinergic properties.(4)|
03996|031|B||
03996|032|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
03996|033|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
03996|034|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
03996|035|M|used in patients receiving concurrent therapy with strong CYP3A4 inhibitors.|
03996|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03996|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03996|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03996|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03996|040|B||
03996|041|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP2D6, the|
03996|042|D|concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg|
03996|043|D|once daily for four days), another inhibitor of CYP3A4, resulted in a 60%|
03996|044|D|decrease in tolterodine clearance.(6)  Tolterodine AUC and Cmax increased|
03996|045|D|2.5-fold and 2-fold, respectively.(2)|
03996|046|D|   In a study of the effect of tolterodine immediate release tablets, the|
03996|047|D|effect on the QT interval appeared greater for 8 mg/day (two times the|
03996|048|D|therapeutic dose) compared to 4 mg/day.  Tolterodine 2 mg BID and|
03996|049|D|tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and|
03996|050|D|11.84 msec (7.11-16.58 msec), respectively.  The change in QT interval was|
03996|051|D|more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers|
03996|052|D|(EMs).(1,2)|
03996|053|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, idelalisib,|
03996|054|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
03996|055|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
03996|056|D|tipranavir, troleandomycin, and tucatinib.(7,8)|
03996|057|B||
03996|058|R|REFERENCES:|
03996|059|B||
03996|060|R|1.Detrol (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03996|061|R|  August, 2012.|1
03996|062|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03996|063|R|  July, 2018.|1
03996|064|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03996|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03996|066|R|  settings: a scientific statement from the American Heart Association and|6
03996|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03996|068|R|  2;55(9):934-47.|6
03996|069|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03996|070|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03996|071|R|  Soc 2023 Jul;71(7):2052-2081.|6
03996|072|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03996|073|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03996|074|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03996|075|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03996|076|R|6.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
03996|077|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
03996|078|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
03996|079|R|7.This information is based on an extract from the Certara Drug Interaction|6
03996|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03996|081|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
03996|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03996|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03996|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03996|085|R|  11/14/2017.|1
03997|001|T|MONOGRAPH TITLE:  Tolterodine (Greater Than 1 mg IR or Greater Than 2 mg|
03997|002|T|ER)/Strong CYP3A4 Inhibitors that Prolong QT|
03997|003|B||
03997|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03997|005|L|of severe adverse interaction.|
03997|006|B||
03997|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03997|008|A|tolterodine by CYP3A4.(1,2)|
03997|009|A|   Tolterodine has been observed to prolong the QTc interval.  Concurrent|
03997|010|A|use with other agents that prolong the QTc interval may result in additive|
03997|011|A|effects on the QTc interval.(1,2)|
03997|012|B||
03997|013|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with strong|
03997|014|E|CYP3A4 inhibitors may result in elevated levels of tolterodine and signs of|
03997|015|E|toxicity, including potentially life-threatening arrhythmias.(1,2)|
03997|016|B||
03997|017|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers may be at|
03997|018|P|increased risk.(1,2)|
03997|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03997|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03997|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03997|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03997|023|P|advanced age.(3)|
03997|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03997|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03997|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03997|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03997|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03997|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03997|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03997|031|P|   The risk of anticholinergic toxicities including cognitive decline,|
03997|032|P|delirium, falls and fractures is increased in geriatric patients using more|
03997|033|P|than one medicine with anticholinergic properties.(4)|
03997|034|B||
03997|035|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
03997|036|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
03997|037|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
03997|038|M|used in patients receiving concurrent therapy with strong CYP3A4 inhibitors.|
03997|039|M|   The manufacturer of tolterodine states concurrent use agents known to|
03997|040|M|prolong the QT interval should be used with caution.  Consider close|
03997|041|M|observation in patients with a known history of QT prolongation or patients|
03997|042|M|taking antiarrhythmic medications.(1,2)|
03997|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03997|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03997|045|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03997|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03997|047|B||
03997|048|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP2D6, the|
03997|049|D|concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg|
03997|050|D|once daily for four days), another inhibitor of CYP3A4, resulted in a 60%|
03997|051|D|decrease in tolterodine clearance.(6)  Tolterodine AUC and Cmax increased|
03997|052|D|2.5-fold and 2-fold, respectively.(2)|
03997|053|D|   In a study of the effect of tolterodine immediate release tablets, the|
03997|054|D|effect on the QT interval appeared greater for 8 mg/day (two times the|
03997|055|D|therapeutic dose) compared to 4 mg/day.  Tolterodine 2 mg BID and|
03997|056|D|tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and|
03997|057|D|11.84 msec (7.11-16.58 msec), respectively.  The change in QT interval was|
03997|058|D|more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers|
03997|059|D|(EMs).(1,2)|
03997|060|D|   Strong inhibitors of CYP3A4 include:  adagrasib, ceritinib,|
03997|061|D|clarithromycin, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir,|
03997|062|D|telithromycin, and voriconazole.(1,7,8)|
03997|063|B||
03997|064|R|REFERENCES:|
03997|065|B||
03997|066|R|1.Detrol (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03997|067|R|  August, 2012.|1
03997|068|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03997|069|R|  July, 2018.|1
03997|070|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03997|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03997|072|R|  settings: a scientific statement from the American Heart Association and|6
03997|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03997|074|R|  2;55(9):934-47.|6
03997|075|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03997|076|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03997|077|R|  Soc 2023 Jul;71(7):2052-2081.|6
03997|078|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03997|079|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03997|080|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03997|081|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03997|082|R|6.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
03997|083|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
03997|084|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
03997|085|R|7.This information is based on an extract from the Certara Drug Interaction|6
03997|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03997|087|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
03997|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03997|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03997|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03997|091|R|  11/14/2017.|1
03998|001|T|MONOGRAPH TITLE:  Tolterodine (Less Than or Equal to 1 mg or Less Than or|
03998|002|T|Equal to 2 mg ER)/Strong CYP3A4 Inhibitors that Prolong QT|
03998|003|B||
03998|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
03998|005|L|take action as needed.|
03998|006|B||
03998|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
03998|008|A|tolterodine by CYP3A4.(1,2)|
03998|009|A|   Tolterodine has been observed to prolong the QTc interval.  Concurrent|
03998|010|A|use with other agents that prolong the QTc interval may result in additive|
03998|011|A|effects on the QTc interval.(1,2)|
03998|012|B||
03998|013|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with strong|
03998|014|E|CYP3A4 inhibitors may result in elevated levels of tolterodine and signs of|
03998|015|E|toxicity, including potentially life-threatening cardiac arrhythmias.(1,2)|
03998|016|B||
03998|017|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers may be at|
03998|018|P|increased risk.(1,2)|
03998|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03998|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03998|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03998|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03998|023|P|advanced age.(3)|
03998|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03998|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03998|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03998|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03998|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03998|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03998|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03998|031|P|   The risk of anticholinergic toxicities including cognitive decline,|
03998|032|P|delirium, falls and fractures is increased in geriatric patients using more|
03998|033|P|than one medicine with anticholinergic properties.(4)|
03998|034|B||
03998|035|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
03998|036|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
03998|037|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
03998|038|M|used in patients receiving concurrent therapy with strong CYP3A4 inhibitors.|
03998|039|M|   The manufacturer of tolterodine states concurrent use agents known to|
03998|040|M|prolong the QT interval should be used with caution.  Consider close|
03998|041|M|observation in patients with a known history of QT prolongation or patients|
03998|042|M|taking antiarrhythmic medications.(1,2)|
03998|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03998|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03998|045|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03998|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03998|047|B||
03998|048|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP2D6, the|
03998|049|D|concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg|
03998|050|D|once daily for four days), another inhibitor of CYP3A4, resulted in a 60%|
03998|051|D|decrease in tolterodine clearance.(6)  Tolterodine AUC and Cmax increased|
03998|052|D|2.5-fold and 2-fold, respectively.(2)|
03998|053|D|   In a study of the effect of tolterodine immediate release tablets, the|
03998|054|D|effect on the QT interval appeared greater for 8 mg/day (two times the|
03998|055|D|therapeutic dose) compared to 4 mg/day.  Tolterodine 2 mg BID and|
03998|056|D|tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and|
03998|057|D|11.84 msec (7.11-16.58 msec), respectively.  The change in QT interval was|
03998|058|D|more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers|
03998|059|D|(EMs).(1,2)|
03998|060|D|   Strong inhibitors of CYP3A4 include:  adagrasib, ceritinib,|
03998|061|D|clarithromycin, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir,|
03998|062|D|telithromycin, and voriconazole.(1,7,8)|
03998|063|B||
03998|064|R|REFERENCES:|
03998|065|B||
03998|066|R|1.Detrol (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03998|067|R|  August, 2012.|1
03998|068|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03998|069|R|  July, 2018.|1
03998|070|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03998|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03998|072|R|  settings: a scientific statement from the American Heart Association and|6
03998|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03998|074|R|  2;55(9):934-47.|6
03998|075|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03998|076|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03998|077|R|  Soc 2023 Jul;71(7):2052-2081.|6
03998|078|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03998|079|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03998|080|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03998|081|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03998|082|R|6.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
03998|083|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
03998|084|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
03998|085|R|7.This information is based on an extract from the Certara Drug Interaction|6
03998|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03998|087|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
03998|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03998|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03998|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03998|091|R|  11/14/2017.|1
03999|001|T|MONOGRAPH TITLE:  Tolterodine (Less Than or Equal to 1 mg or Less Than or|
03999|002|T|Equal to 2 mg ER)/Levoketoconazole|
03999|003|B||
03999|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
03999|005|L|of severe adverse interaction.|
03999|006|B||
03999|007|A|MECHANISM OF ACTION:  Levoketoconazole, a strong CYP3A4 inhibitor, may|
03999|008|A|inhibit the metabolism of tolterodine by CYP3A4.(1,2)|
03999|009|A|   Tolterodine has been observed to prolong the QTc interval.  Concurrent|
03999|010|A|use with other agents that prolong the QTc interval may result in additive|
03999|011|A|effects on the QTc interval.(1,2)|
03999|012|B||
03999|013|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with|
03999|014|E|levoketoconazole may result in elevated levels of tolterodine and signs of|
03999|015|E|toxicity, including potentially life-threatening cardiac arrhythmias.(1,2)|
03999|016|B||
03999|017|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers may be at|
03999|018|P|increased risk.(1,2)|
03999|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
03999|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
03999|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
03999|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
03999|023|P|advanced age.(3)|
03999|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
03999|025|P|higher systemic concentrations of either QT prolonging drug are additional|
03999|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
03999|027|P|drug concentrations include rapid infusion of an intravenous dose or|
03999|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
03999|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
03999|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
03999|031|P|   The risk of anticholinergic toxicities including cognitive decline,|
03999|032|P|delirium, falls and fractures is increased in geriatric patients using more|
03999|033|P|than one medicine with anticholinergic properties.(4)|
03999|034|B||
03999|035|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
03999|036|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
03999|037|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
03999|038|M|used in patients receiving concurrent therapy with strong CYP3A4 inhibitors.|
03999|039|M|   The manufacturer of tolterodine states concurrent use agents known to|
03999|040|M|prolong the QT interval should be used with caution.  Consider close|
03999|041|M|observation in patients with a known history of QT prolongation or patients|
03999|042|M|taking antiarrhythmic medications.(1,2)|
03999|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
03999|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
03999|045|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
03999|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
03999|047|B||
03999|048|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP2D6, the|
03999|049|D|concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg|
03999|050|D|once daily for four days), another inhibitor of CYP3A4, resulted in a 60%|
03999|051|D|decrease in tolterodine clearance.(6)  Tolterodine AUC and Cmax increased|
03999|052|D|2.5-fold and 2-fold, respectively.(2)|
03999|053|D|   In a study of the effect of tolterodine immediate release tablets, the|
03999|054|D|effect on the QT interval appeared greater for 8 mg/day (two times the|
03999|055|D|therapeutic dose) compared to 4 mg/day.  Tolterodine 2 mg BID and|
03999|056|D|tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and|
03999|057|D|11.84 msec (7.11-16.58 msec), respectively.  The change in QT interval was|
03999|058|D|more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers|
03999|059|D|(EMs).(7,8)|
03999|060|B||
03999|061|R|REFERENCES:|
03999|062|B||
03999|063|R|1.Detrol (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03999|064|R|  August, 2012.|1
03999|065|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
03999|066|R|  July, 2018.|1
03999|067|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
03999|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
03999|069|R|  settings: a scientific statement from the American Heart Association and|6
03999|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
03999|071|R|  2;55(9):934-47.|6
03999|072|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
03999|073|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
03999|074|R|  Soc 2023 Jul;71(7):2052-2081.|6
03999|075|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
03999|076|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
03999|077|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
03999|078|R|  https://www.fda.gov/media/71372/download October, 2005.|1
03999|079|R|6.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
03999|080|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
03999|081|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
03999|082|R|7.This information is based on an extract from the Certara Drug Interaction|6
03999|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
03999|084|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
03999|085|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
03999|086|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
03999|087|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
03999|088|R|  11/14/2017.|1
04000|001|T|MONOGRAPH TITLE:  Selected Opioids (Cough and Cold)/Metaxalone|
04000|002|B||
04000|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04000|004|L|of severe adverse interaction.|
04000|005|B||
04000|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and muscle relaxants may|
04000|007|A|result in additive CNS depression.(1)|
04000|008|B||
04000|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
04000|010|E|as muscle relaxants, may result in profound sedation, respiratory|
04000|011|E|depression, coma, and/or death.(1)|
04000|012|B||
04000|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04000|014|P|may increase the risk of adverse effects.|
04000|015|B||
04000|016|M|PATIENT MANAGEMENT:  Avoid prescribing opioid-including cough medications|
04000|017|M|for patients taking CNS depressants such as muscle relaxants.(1)|
04000|018|M|   Respiratory depression can occur at any time during opioid therapy,|
04000|019|M|especially during therapy initiation and following dosage increases.  The|
04000|020|M|risk of opioid-related overdose or overdose-related death is increased with|
04000|021|M|higher opioid doses, and this risk persists over the course of therapy.|
04000|022|M|Consider these risks when using concurrently with other agents that may|
04000|023|M|cause CNS depression.(2)|
04000|024|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
04000|025|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04000|026|M|unresponsiveness.(1)|
04000|027|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04000|028|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04000|029|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04000|030|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04000|031|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04000|032|M|as those taking CNS depressants) and when a patient has household|
04000|033|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04000|034|M|for obtaining an opioid reversal agent (e.g., prescription,|
04000|035|M|over-the-counter, or as part of a community-based program).(3)|
04000|036|B||
04000|037|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04000|038|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04000|039|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04000|040|D|million to 30 million patients.  During this time, the proportion of|
04000|041|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04000|042|D|million patients.(4)|
04000|043|D|   A retrospective cohort study compared the risk of opioid overdose|
04000|044|D|associated with concomitant use of opioids and skeletal muscle relaxants|
04000|045|D|versus opioid use alone. The study examined two types of opioid users (naive|
04000|046|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
04000|047|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
04000|048|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
04000|049|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
04000|050|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
04000|051|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
04000|052|D|respectively).  Elevated risk was associated with concomitant users with|
04000|053|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
04000|054|D|1.39, respectively).(5)|
04000|055|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04000|056|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04000|057|D|per 100,000 and drug overdose deaths involving both opioids and|
04000|058|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04000|059|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04000|060|D|increased from 18% to 31% during this time.(6)|
04000|061|D|   A prospective observational cohort study in North Carolina found that the|
04000|062|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04000|063|D|benzodiazepines were 10 times higher than patients receiving opioid|
04000|064|D|analgesics alone.(7)|
04000|065|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04000|066|D|death from overdose increased with concomitant opioid analgesics and|
04000|067|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04000|068|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04000|069|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04000|070|D|increased risk of fatal overdose.(8)|
04000|071|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04000|072|D|which benzodiazepines were determined to be a cause of death and that|
04000|073|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04000|074|D|determined to be a cause of death.  This study also found that other CNS|
04000|075|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04000|076|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04000|077|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04000|078|D|where opioid analgesics were also implicated.(9)|
04000|079|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04000|080|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04000|081|D|deaths.(10)|
04000|082|B||
04000|083|R|REFERENCES:|
04000|084|B||
04000|085|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04000|086|R|  warns about serious risks and death when combining opioid pain or cough|1
04000|087|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04000|088|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04000|089|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04000|090|R|  prescribing information for all opioid pain medicines to provide|1
04000|091|R|  additional guidance for safe use. Available at:|1
04000|092|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04000|093|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04000|094|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04000|095|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04000|096|R|  recommends health care professionals discuss naloxone with all patients|1
04000|097|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04000|098|R|  disorder. Available at:|1
04000|099|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04000|100|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04000|101|R|  d-pain July 23, 2020.|1
04000|102|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04000|103|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04000|104|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04000|105|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
04000|106|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
04000|107|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
04000|108|R|  Ther 2020 Jul;108(1):81-88.|2
04000|109|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04000|110|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04000|111|R|  49(4):493-501.|2
04000|112|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04000|113|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04000|114|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04000|115|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04000|116|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04000|117|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04000|118|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04000|119|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04000|120|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04000|121|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04000|122|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04000|123|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04001|001|T|MONOGRAPH TITLE:  Cyclophosphamide/Strong CYP3A4 Inducers|
04001|002|B||
04001|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04001|004|L|take action as needed.|
04001|005|B||
04001|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04001|007|A|cyclophosphamide, resulting in increased formation of the active and toxic|
04001|008|A|metabolites.(1)|
04001|009|B||
04001|010|E|CLINICAL EFFECTS:  The concurrent administration of cyclophosphamide and|
04001|011|E|strong CYP3A4 inducers may result in increased levels and toxicity of|
04001|012|E|cyclophosphamide metabolites.(1)|
04001|013|B||
04001|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04001|015|P|of the inducer for longer than 1-2 weeks.|
04001|016|B||
04001|017|M|PATIENT MANAGEMENT:  Patients receiving both of these medications should be|
04001|018|M|alerted to the possibility of increased toxicity from cyclophosphamide.(1)|
04001|019|M|Monitor closely for signs of toxicity during concurrent therapy.  The dosage|
04001|020|M|of cyclophosphamide may need to be adjusted.|
04001|021|B||
04001|022|D|DISCUSSION:  A case report of a breast cancer patient who received three|
04001|023|D|cycles of high-dose chemotherapy including cyclophosphamide (1,000 mg/m2)|
04001|024|D|over 4 days with concomitant carbamazepine resulted in increased exposure to|
04001|025|D|cyclophosphamide active metabolite 4-hydroxycyclophosphamide by 58% and|
04001|026|D|decreased exposure to cyclophosphamide by 40%.(2)|
04001|027|D|   A case report of a 42-year-old patient with relapsing germ-cell cancer|
04001|028|D|taking high-dose chemotherapy including cyclophosphamide (1,500 mg/m2) with|
04001|029|D|concomitant phenytoin resulted in increased exposure to|
04001|030|D|4-hydroxycyclophosphamide by 51% and decreased exposure to cyclophosphamide|
04001|031|D|by 67%.(3)|
04001|032|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
04001|033|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04001|034|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04001|035|D|rifampin, and rifapentine.(4,5)|
04001|036|B||
04001|037|R|REFERENCES:|
04001|038|B||
04001|039|R|1.Procytox (cyclophosphamide) Canadian prescribing information. Baxter|1
04001|040|R|  Corporation September 7, 2012.|1
04001|041|R|2.Ekhart C,  Rodenhuis S,  Beijnen JH,  Huitema ADR. Carbamazepine induces|3
04001|042|R|  bioactivation of cyclophosphamide and thiotepa. Cancer Chemother Pharmacol|3
04001|043|R|  2009;63:543-547.|3
04001|044|R|3.de Jonge ME,  Huitema ADR,  van Dam SM,  Beijnen JH,  Rodenhuis S.|3
04001|045|R|  Significant induction of cyclophosphamide and thiotepa metabolism by|3
04001|046|R|  phenytoin. Cancer Chemother Pharmacol 2005;55:507-510.|3
04001|047|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04001|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04001|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04001|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04001|051|R|  11/14/2017.|1
04001|052|R|5.This information is based on an extract from the Certara Drug Interaction|6
04001|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04002|001|T|MONOGRAPH TITLE:  Oral Midazolam/Macrolide Antibiotics|
04002|002|B||
04002|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04002|004|L|of severe adverse interaction.|
04002|005|B||
04002|006|A|MECHANISM OF ACTION:  Macrolides may inhibit the metabolism and first-pass|
04002|007|A|clearance of oral midazolam through inhibition of CYP3A4.(1)|
04002|008|B||
04002|009|E|CLINICAL EFFECTS:  Serum concentrations of midazolam may be increased,|
04002|010|E|enhancing its pharmacological effects.  Toxic effects of increased midazolam|
04002|011|E|levels include profound sedation, respiratory depression, coma, and/or|
04002|012|E|death.(1)|
04002|013|B||
04002|014|P|PREDISPOSING FACTORS:  None determined.|
04002|015|B||
04002|016|M|PATIENT MANAGEMENT:  Recommendations for concurrent use of oral midazolam|
04002|017|M|with macrolide antibiotics vary between products and between regions.|
04002|018|M|   The Australian, Canadian, and UK manufacturers of clarithromycin state|
04002|019|M|that concurrent use of oral midazolam is contraindicated.(2-4)|
04002|020|M|   The US manufacturers of clarithromycin, midazolam, and telithromycin|
04002|021|M|advise caution when using oral midazolam with CYP3A4 inhibitors.  Patients|
04002|022|M|should be counseled about possible increased sedation and observed for this|
04002|023|M|side effect.  Decreasing the dose of midazolam may be necessary.(1,5,6)|
04002|024|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
04002|025|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04002|026|M|unresponsiveness.|
04002|027|B||
04002|028|D|DISCUSSION:  In a study of 12 healthy volunteers, clarithromycin (250 mg|
04002|029|D|twice daily for 5 days) increased the area-under-curve (AUC) of oral|
04002|030|D|midazolam (15 mg) by 3.57-fold.(7)|
04002|031|D|   Sixteen elderly volunteers who received clarithromycin pre-treatment (500|
04002|032|D|mg twice daily for 7 days) had increases in the AUC of oral midazolam of|
04002|033|D|8-fold and of IV midazolam of 3.2-fold.(8)|
04002|034|D|   In a study involving 12 healthy volunteers, oral erythromycin (500 mg|
04002|035|D|three times daily for 7 days) was followed by a single oral 15 mg midazolam|
04002|036|D|dose.  Concomitant administration of erythromycin and oral midazolam|
04002|037|D|produced a decrease in midazolam clearance and an increase in the half-life|
04002|038|D|and serum concentration of midazolam, with an AUC increase of 4.4-fold.|
04002|039|D|Sedation produced by midazolam was pronounced and long-lasting.  When|
04002|040|D|midazolam was given IV, first-pass metabolism was avoided and the effects of|
04002|041|D|the interaction were less profound.  A single IV dose of 0.15 mg/kg|
04002|042|D|midazolam given after 1 week of erythromycin 500 mg three times daily|
04002|043|D|resulted in a 54% decrease in midazolam clearance.(9)|
04002|044|D|   Oral use of midazolam and IV erythromycin has been associated with|
04002|045|D|unconsciousness in an 8-year-old boy.(10,11)|
04002|046|D|   In a study of 10 healthy volunteers, roxithromycin (300 mg daily for 6|
04002|047|D|days) increased the AUC of oral midazolam (15 mg) by 1.5-fold.(12)|
04002|048|D|   Concurrent administration of telithromycin increased the AUC of IV and|
04002|049|D|oral midazolam by 2-fold and 6-fold, respectively.(6)|
04002|050|B||
04002|051|R|REFERENCES:|
04002|052|B||
04002|053|R|1.Midazolam Hydrochloride Syrup US Prescribing Information. Padagis US LLC|1
04002|054|R|  December 11, 2021.|1
04002|055|R|2.Clairthro (clarithromycin) Australian Product Information. Apotex Pty Ltd|1
04002|056|R|  May 24, 2021.|1
04002|057|R|3.Biaxin (clarithromycin) Canadian prescribing information. Abbott|1
04002|058|R|  Laboratories, Limited October 25, 2021.|1
04002|059|R|4.Clarithromycin UK Summary of Product Characteristics. Ranbaxy (UK) Limited|1
04002|060|R|  January 26, 2022.|1
04002|061|R|5.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
04002|062|R|  September, 2019.|1
04002|063|R|6.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
04002|064|R|  November, 2015.|1
04002|065|R|7.Yeates RA, Laufen H, Zimmermann T. Interaction between midazolam and|2
04002|066|R|  clarithromycin: comparison with azithromycin. Int J Clin Pharmacol Ther|2
04002|067|R|  1996 Sep;34(9):400-5.|2
04002|068|R|8.Quinney SK, Haehner BD, Rhoades MB, Lin Z, Gorski JC, Hall SD. Interaction|2
04002|069|R|  between midazolam and clarithromycin in the elderly. Br J Clin Pharmacol|2
04002|070|R|  2008 Jan;65(1):98-109.|2
04002|071|R|9.Olkkola KT, Aranko K, Luurila H, Hiller A, Saarnivaara L, Himberg JJ,|2
04002|072|R|  Neuvonen PJ. A potentially hazardous interaction between erythromycin and|2
04002|073|R|  midazolam. Clin Pharmacol Ther 1993 Mar;53(3):298-305.|2
04002|074|R|10.Hiller A, Olkkola KT, Isohanni P, Saarnivaara L. Unconsciousness|3
04002|075|R|   associated with midazolam and erythromycin. Br J Anaesth 1990 Dec;|3
04002|076|R|   65(6):826-8.|3
04002|077|R|11.Wood M. Midazolam and erythromycin. Br J Anaesth 1991 Jul;67(1):131.|6
04002|078|R|12.Backman JT, Aranko K, Himberg JJ, Olkkola KT. A pharmacokinetic|2
04002|079|R|   interaction between roxithromycin and midazolam. Eur J Clin Pharmacol|2
04002|080|R|   1994;46(6):551-5.|2
04003|001|T|MONOGRAPH TITLE:  Panobinostat (Less than or Equal To 10 mg)/Strong CYP3A4|
04003|002|T|Inhibitors that Prolong QT|
04003|003|B||
04003|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04003|005|L|take action as needed.|
04003|006|B||
04003|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04003|008|A|panobinostat.(1)|
04003|009|B||
04003|010|E|CLINICAL EFFECTS:  Concurrent use of strong inhibitors of CYP3A4 may result|
04003|011|E|in elevated levels of and toxicity from panobinostat, including increased|
04003|012|E|risk of bleeding and prolongation of the QT interval which may result in|
04003|013|E|life-threatening arrhythmia and death.(1)|
04003|014|B||
04003|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04003|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04003|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04003|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04003|019|P|female gender, or advanced age.(2)|
04003|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04003|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04003|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04003|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04003|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04003|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04003|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04003|027|P|   The risk for bleeding episodes may be greater in patients with|
04003|028|P|disease-associated factors (e.g. thrombocytopenia).|
04003|029|P|   Drug associated risk factors include concurrent use of multiple drugs|
04003|030|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04003|031|P|risk for bleeding (e.g. NSAIDs).|
04003|032|B||
04003|033|M|PATIENT MANAGEMENT:  Reduce the dose of panobinostat to 10 mg when|
04003|034|M|coadministered with strong CYP3A4 inhibitors.  Limit the starting dose of|
04003|035|M|panobinostat to 10 mg in patients taking strong CYP3A4 inhibitors.(1)|
04003|036|M|   If concurrent therapy is warranted, continue standard monitoring of|
04003|037|M|complete blood counts, ECG, and serum electrolytes.  Instruct patients to|
04003|038|M|report any irregular heartbeat, dizziness, or fainting; nausea, vomiting, or|
04003|039|M|diarrhea; unusual tiredness, shortness of breath, paleness; unusual or|
04003|040|M|unexplained bleeding or bruising; signs of infection such as fever, cough,|
04003|041|M|or flu-like symptoms.  If panobinostat toxicity occurs, panobinostat or the|
04003|042|M|CYP3A4 inhibitor may need to be discontinued.(1)|
04003|043|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
04003|044|M|including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
04003|045|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
04003|046|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04003|047|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04003|048|M|anticoagulation in patients with active pathologic bleeding.|
04003|049|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04003|050|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04003|051|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04003|052|M|and/or swelling.|
04003|053|B||
04003|054|D|DISCUSSION:  In 14 patients with advanced cancer, ketoconazole (a strong|
04003|055|D|CYP3A4 inhibitor, 200 mg twice daily for 14 days) increased the maximum|
04003|056|D|concentration (Cmax) and area-under-curve (AUC) of panobinostat by 62% and|
04003|057|D|73%, respectively.(1)|
04003|058|D|   Strong inhibitors of CYP3A4 include:  adagrasib, ceritinib,|
04003|059|D|lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin,|
04003|060|D|and voriconazole.(3,4)|
04003|061|B||
04003|062|R|REFERENCES:|
04003|063|B||
04003|064|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
04003|065|R|  Pharmaceuticals Corporation June, 2016.|1
04003|066|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04003|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04003|068|R|  settings: a scientific statement from the American Heart Association and|6
04003|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04003|070|R|  2;55(9):934-47.|6
04003|071|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04003|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04003|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04003|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04003|075|R|  11/14/2017.|1
04003|076|R|4.This information is based on an extract from the Certara Drug Interaction|6
04003|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04004|001|T|MONOGRAPH TITLE:  Mitapivat/Strong CYP3A4 Inhibitors|
04004|002|B||
04004|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04004|004|L|of severe adverse interaction.|
04004|005|B||
04004|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04004|007|A|of mitapivat.(1)|
04004|008|B||
04004|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04004|010|E|in increased levels of and effects from mitapivat including decreased|
04004|011|E|estrone and estradiol levels in males, increased urate, back pain, and|
04004|012|E|arthralgias.(1)|
04004|013|B||
04004|014|P|PREDISPOSING FACTORS:  None determined.|
04004|015|B||
04004|016|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04004|017|M|mitapivat should be avoided.(1)|
04004|018|B||
04004|019|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04004|020|D|with mitapivat 20 mg single dose, itraconazole increased mitapivat|
04004|021|D|area-under-curve (AUC) and concentration maximum (Cmax) by 4.9-fold and|
04004|022|D|1.7-fold, respectively.  In a pharmacokinetic study with mitapivat 50 mg|
04004|023|D|twice daily, itraconazole increased mitapivat AUC and Cmax by 3.6-fold and|
04004|024|D|2.2-fold, respectively.  With ketoconazole, mitapivat doses of 5, 20, or 50|
04004|025|D|mg twice daily had an AUC and Cmax increased by 3.9-fold and 2.4-fold,|
04004|026|D|respectively.(1)|
04004|027|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
04004|028|D|clarithromycin, cobicistat, indinavir, itraconazole, josamycin,|
04004|029|D|ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone,|
04004|030|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
04004|031|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04004|032|D|troleandomycin, tucatinib, and voriconazole.(2)|
04004|033|B||
04004|034|R|REFERENCES:|
04004|035|B||
04004|036|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04004|037|R|  February, 2022.|1
04004|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
04004|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04005|001|T|MONOGRAPH TITLE:  Mitapivat (Less Than or Equal To 20 mg BID)/Moderate|
04005|002|T|CYP3A4 Inhibitors|
04005|003|B||
04005|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04005|005|L|take action as needed.|
04005|006|B||
04005|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04005|008|A|metabolism of mitapivat.(1)|
04005|009|B||
04005|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04005|011|E|result in increased levels of and effects from mitapivat including decreased|
04005|012|E|estrone and estradiol levels in males, increased urate, back pain, and|
04005|013|E|arthralgias.(1)|
04005|014|B||
04005|015|P|PREDISPOSING FACTORS:  None determined.|
04005|016|B||
04005|017|M|PATIENT MANAGEMENT:  The concurrent use of moderate CYP3A4 inhibitors with|
04005|018|M|mitapivat should be monitored closely for increased risk of adverse|
04005|019|M|reactions.  Mitapivat dose should not exceed 20 mg twice daily with|
04005|020|M|concurrent moderate CYP3A4 inhibitors.(1)|
04005|021|B||
04005|022|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04005|023|D|with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased|
04005|024|D|mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by|
04005|025|D|2.6-fold and 1.6-fold, respectively.(1)|
04005|026|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
04005|027|D|atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem,|
04005|028|D|dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir,|
04005|029|D|fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib,|
04005|030|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and|
04005|031|D|verapamil.(2)(2)|
04005|032|B||
04005|033|R|REFERENCES:|
04005|034|B||
04005|035|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04005|036|R|  February, 2022.|1
04005|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
04005|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04006|001|T|MONOGRAPH TITLE:  Mitapivat/Strong CYP3A4 Inducers|
04006|002|B||
04006|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04006|004|L|of severe adverse interaction.|
04006|005|B||
04006|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may decrease the metabolism|
04006|007|A|of mitapivat.(1)|
04006|008|B||
04006|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inducer may result in|
04006|010|E|decreased levels and effectiveness of mitapivat.(1)|
04006|011|B||
04006|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04006|013|P|of the inducer for longer than 1-2 weeks.|
04006|014|B||
04006|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of mitapivat with medications|
04006|016|M|that are strong CYP3A4 inducers.(1)|
04006|017|B||
04006|018|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04006|019|D|with a single 50 mg dose of mitapivat, rifampin decreased area-under-curve|
04006|020|D|(AUC) and concentration maximum (Cmax) by 91% and 77%, respectively.  After|
04006|021|D|mitapivat doses of 5, 20, or 50 mg twice daily, rifampin decreased AUC and|
04006|022|D|Cmax by 95% and 85%, respectively.(1)|
04006|023|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04006|024|D|carbamazepine, encorafenib, fosphenytoin, ivosidenib, lumacaftor, mitotane,|
04006|025|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
04006|026|D|wort.(2,3)|
04006|027|B||
04006|028|R|REFERENCES:|
04006|029|B||
04006|030|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04006|031|R|  February, 2022.|1
04006|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04006|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04006|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04006|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04006|036|R|  11/14/2017.|1
04006|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04006|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04007|001|T|MONOGRAPH TITLE:  Mitapivat/Moderate CYP3A4 Inducers|
04007|002|B||
04007|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04007|004|L|of severe adverse interaction.|
04007|005|B||
04007|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may increase the|
04007|007|A|metabolism of mitapivat.(1)|
04007|008|B||
04007|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inducer may result in|
04007|010|E|decreased levels and effectiveness of mitapivat.(1)|
04007|011|B||
04007|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04007|013|P|of the inducer for longer than 1-2 weeks.|
04007|014|B||
04007|015|M|PATIENT MANAGEMENT:  Consider alternative therapies that are not moderate|
04007|016|M|CYP3A4 inducers in patients who are on mitapivat.  If concurrent use is|
04007|017|M|necessary, monitor hemoglobin closely and titrate mitapivat dose, not to|
04007|018|M|exceed a maximum dose of 100 mg twice daily.(1)|
04007|019|B||
04007|020|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04007|021|D|with 5 or 20 mg twice daily of mitapivat, efavirenz decreased|
04007|022|D|area-under-curve (AUC) and concentration maximum (Cmax) by 60% and 30%,|
04007|023|D|respectively.  After mitapivat doses of 50 mg twice daily, efavirenz|
04007|024|D|decreased AUC and Cmax by 55% and 24%, respectively.(1)|
04007|025|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04007|026|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, modafinil,|
04007|027|D|nafcillin, pacritinib, pexidartinib, rifabutin, sotorasib, telotristat|
04007|028|D|ethyl, thioridazine, and tovorafenib.(2,3)|
04007|029|B||
04007|030|R|REFERENCES:|
04007|031|B||
04007|032|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04007|033|R|  February, 2022.|1
04007|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04007|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04007|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04007|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04007|038|R|  11/14/2017.|1
04007|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
04007|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04008|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Mitapivat|
04008|002|B||
04008|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04008|004|L|of severe adverse interaction.|
04008|005|B||
04008|006|A|MECHANISM OF ACTION:  Mitapivat is a moderate CYP3A4 inducer.|
04008|007|A|Coadministration of mitapivat with hormonal contraceptives may lead to|
04008|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
04008|009|A|decreased hormonal concentrations.(1)|
04008|010|B||
04008|011|E|CLINICAL EFFECTS:  Concurrent use of mitapivat can lead to ineffective|
04008|012|E|hormonal contraceptive and cause unintended pregnancy.(1)|
04008|013|B||
04008|014|P|PREDISPOSING FACTORS:  None determined.|
04008|015|B||
04008|016|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
04008|017|M|rely on hormonal contraceptives (including oral contraceptives, patches,|
04008|018|M|implants, and/or IUDs) for contraception.  Pregnant women and females of|
04008|019|M|reproductive potential should be counseled on the potential risk to the|
04008|020|M|fetus.(1)|
04008|021|M|   Advise females of reproductive potential to use effective non-hormonal|
04008|022|M|contraception during treatment with mitapivat.(1)|
04008|023|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04008|024|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04008|025|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04008|026|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
04008|027|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
04008|028|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
04008|029|M|and to seek medical advice if they do become pregnant.(2)|
04008|030|B||
04008|031|D|DISCUSSION:  Mitapivat is a moderate CYP3A4 inducer.  Mitapivat has not been|
04008|032|D|studied with hormonal contraceptives.  It can render some hormonal|
04008|033|D|contraceptives ineffective and may cause unintended pregnancy.  Women should|
04008|034|D|use non-hormonal contraception during therapy.(1)|
04008|035|D|   In an animal reproduction study, oral administration of mitapivat to|
04008|036|D|pregnant rats and rabbits during the period of organogenesis was not|
04008|037|D|teratogenic at doses up to 13 and 3 times the maximum recommended ose.(1)|
04008|038|B||
04008|039|R|REFERENCES:|
04008|040|B||
04008|041|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04008|042|R|  February, 2022.|1
04008|043|R|2.Medicines and Healthcare products Regulatory Agency.|1
04008|044|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04008|045|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04008|046|R|  available at:|1
04008|047|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04008|048|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04008|049|R|  -and-contraceptive-efficacy September 15, 2016..|1
04009|001|T|MONOGRAPH TITLE:  Selected CYP3A4 Substrates/Mitapivat|
04009|002|B||
04009|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04009|004|L|of severe adverse interaction.|
04009|005|B||
04009|006|A|MECHANISM OF ACTION:  Mitapivat is a moderate inducer of CYP3A4 and may|
04009|007|A|increase the metabolism of drugs metabolized by the CYP3A4 enzyme.|
04009|008|B||
04009|009|E|CLINICAL EFFECTS:  Concurrent use of mitapivat may lead to decreased serum|
04009|010|E|levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)|
04009|011|B||
04009|012|P|PREDISPOSING FACTORS:  None determined.|
04009|013|B||
04009|014|M|PATIENT MANAGEMENT:  The manufacturer of mitapivat states that|
04009|015|M|co-administration of CYP3A4 substrates for which minimal concentration|
04009|016|M|decreases may lead to serious therapeutic failure should be monitored for|
04009|017|M|loss of efficacy. If concomitant use is unavoidable, increase the dose of|
04009|018|M|the CYP3A4 substrate in accordance with approved product labeling.(1)|
04009|019|B||
04009|020|D|DISCUSSION:  In a clinical study, coadministration of mobocertinib 160 mg|
04009|021|D|once daily with oral or intravenous midazolam, a sensitive CYP3A4 substrate,|
04009|022|D|decreased midazolam area-under-curve (AUC) by 32% and 16%, respectively.(1)|
04009|023|D|   CYP3A4 substrates with a narrow therapeutic index linked to this|
04009|024|D|monograph include: cyclosporine, everolimus, sirolimus, tacrolimus, and|
04009|025|D|temsirolimus.(2-4)|
04009|026|B||
04009|027|R|REFERENCES:|
04009|028|B||
04009|029|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04009|030|R|  February, 2022.|1
04009|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04009|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04009|033|R|3.Sandimmune (cyclosporine) US prescribing information. Novartis|1
04009|034|R|  Pharmaceuticals Corporation September 2023.|1
04009|035|R|4.Afinitor (everolimus) US prescribing information. Novartaris|1
04009|036|R|  Pharmaceuticals Corporation February, 2020.|1
04009|037|R|5.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
04009|038|R|  Aug, 2022.|1
04009|039|R|6.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04009|040|R|  August, 2023.|1
04009|041|R|7.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
04009|042|R|  Inc. March, 2018.|1
04010|001|T|MONOGRAPH TITLE:  Mitapivat/Idelalisib|
04010|002|B||
04010|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04010|004|L|of severe adverse interaction.|
04010|005|B||
04010|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04010|007|A|of mitapivat.(1)  Idelalisib is a strong CYP3A4 inhibitor.|
04010|008|A|   Agents that induce CYP3A4 may induce the metabolism of idelalisib.(2)|
04010|009|A|Mitapivat is a moderate CYP3A4 inducer.|
04010|010|B||
04010|011|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04010|012|E|in increased levels of and effects from mitapivat including decreased|
04010|013|E|estrone and estradiol levels in males, increased urate, back pain, and|
04010|014|E|arthralgias.(1)|
04010|015|E|   Concurrent use of moderate CYP3A4 inducers may decrease the levels and|
04010|016|E|effectiveness of idelalisib.(2)|
04010|017|B||
04010|018|P|PREDISPOSING FACTORS:  None determined.|
04010|019|B||
04010|020|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04010|021|M|mitapivat should be avoided.(1)|
04010|022|M|   Avoid the concurrent use of moderate CYP3A4 inducers in patients|
04010|023|M|receiving therapy with idelalisib.(1)  Consider the use of alternative|
04010|024|M|agents with less enzyme induction potential.(2)|
04010|025|B||
04010|026|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04010|027|D|with mitapivat 20 mg single dose, itraconazole increased mitapivat|
04010|028|D|area-under-curve (AUC) and concentration maximum (Cmax) by 4.9-fold and|
04010|029|D|1.7-fold, respectively.  In a pharmacokinetic study with mitapivat 50 mg|
04010|030|D|twice daily, itraconazole increased mitapivat AUC and Cmax by 3.6-fold and|
04010|031|D|2.2-fold, respectively.  With ketoconazole, mitapivat doses of 5, 20, or 50|
04010|032|D|mg twice daily had an AUC and Cmax increased by 3.9-fold and 2.4-fold,|
04010|033|D|respectively.(1)|
04010|034|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
04010|035|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
04010|036|D|75%, respectively.(2)|
04010|037|B||
04010|038|R|REFERENCES:|
04010|039|B||
04010|040|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04010|041|R|  February, 2022.|1
04010|042|R|2.Zydelig (idelalisib) UK Summary of Product Characteristics. Gilead|1
04010|043|R|  Sciences Ltd December 17, 2019.|1
04010|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
04010|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04011|001|T|MONOGRAPH TITLE:  Mitapivat/Lonafarnib|
04011|002|B||
04011|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04011|004|L|is contraindicated and generally should not be dispensed or administered to|
04011|005|L|the same patient.|
04011|006|B||
04011|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04011|008|A|of mitapivat.(1)  Lonafarnib is a strong CYP3A4 inhibitor.|
04011|009|A|   Strong and moderate CYP3A4 inducers may increase the metabolism of|
04011|010|A|lonafarnib.(2)  Mitapivat is a moderate CYP3A4 inducer.|
04011|011|B||
04011|012|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04011|013|E|in increased levels of and effects from mitapivat including decreased|
04011|014|E|estrone and estradiol levels in males, increased urate, back pain, and|
04011|015|E|arthralgias.(1)|
04011|016|E|   Concurrent use of strong and moderate CYP3A4 inducers may decrease the|
04011|017|E|serum levels and effectiveness of lonafarnib.(2)|
04011|018|B||
04011|019|P|PREDISPOSING FACTORS:  None determined.|
04011|020|B||
04011|021|M|PATIENT MANAGEMENT:  The use of strong or moderate CYP3A4 inducers with|
04011|022|M|lonafarnib is contraindicated.(2)|
04011|023|M|   The concurrent use of strong CYP3A4 inhibitors with mitapivat should be|
04011|024|M|avoided.(1)|
04011|025|B||
04011|026|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04011|027|D|with mitapivat 20 mg single dose, itraconazole increased mitapivat|
04011|028|D|area-under-curve (AUC) and concentration maximum (Cmax) by 4.9-fold and|
04011|029|D|1.7-fold, respectively.  In a pharmacokinetic study with mitapivat 50 mg|
04011|030|D|twice daily, itraconazole increased mitapivat AUC and Cmax by 3.6-fold and|
04011|031|D|2.2-fold, respectively.  With ketoconazole, mitapivat doses of 5, 20, or 50|
04011|032|D|mg twice daily had an AUC and Cmax increased by 3.9-fold and 2.4-fold,|
04011|033|D|respectively.(1)|
04011|034|D|   With coadministration of a single oral dose of 50 mg lonafarnib (combined|
04011|035|D|with a single oral dose of 100 mg ritonavir) following 600 mg rifampin (a|
04011|036|D|strong CYP3A4 inducer) for 8 days, the AUC was reduced by 98% and the Cmax|
04011|037|D|was reduced by 92%.(2)|
04011|038|B||
04011|039|R|REFERENCES:|
04011|040|B||
04011|041|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04011|042|R|  February, 2022.|1
04011|043|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04011|044|R|  Inc. November, 2020.|1
04011|045|R|3.This information is based on an extract from the Certara Drug Interaction|6
04011|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04012|001|T|MONOGRAPH TITLE:  Mitapivat/Crizotinib|
04012|002|B||
04012|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04012|004|L|of severe adverse interaction.|
04012|005|B||
04012|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04012|007|A|metabolism of mitapivat.(1,2)  Crizotinib is a moderate CYP3A4 inhibitor.|
04012|008|A|   Agents that induce the CYP3A4 isoenzyme may induce the metabolism of|
04012|009|A|crizotinib.(3)  Mitapivat is a moderate CYP3A4 inducer.|
04012|010|B||
04012|011|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04012|012|E|result in increased levels of and effects from mitapivat including decreased|
04012|013|E|estrone and estradiol levels in males, increased urate, back pain, and|
04012|014|E|arthralgias.(1,2)|
04012|015|E|   Concurrent use of moderate CYP3A4 inducers may decrease the levels and|
04012|016|E|effectiveness of crizotinib.(3)|
04012|017|B||
04012|018|P|PREDISPOSING FACTORS:  None determined.|
04012|019|B||
04012|020|M|PATIENT MANAGEMENT:  Avoid the concurrent use of moderate CYP3A4 inducers in|
04012|021|M|patients receiving therapy with crizotinib.  Consider the use of alternative|
04012|022|M|agents with less enzyme induction potential.(3)|
04012|023|M|   The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be|
04012|024|M|monitored closely for increased risk of adverse reactions.  The US|
04012|025|M|manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg|
04012|026|M|twice daily with concurrent moderate CYP3A4 inhibitors.(1)  The Middle|
04012|027|M|Eastern manufacturer of mitapivat states that alternative agents that do not|
04012|028|M|inhibit CYP3A4 should be considered.  If concomitant use of a moderate|
04012|029|M|CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100|
04012|030|M|mg once daily.(2)|
04012|031|B||
04012|032|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04012|033|D|with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased|
04012|034|D|mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by|
04012|035|D|2.6-fold and 1.6-fold, respectively.(1)|
04012|036|D|   Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the Cmax and|
04012|037|D|AUC of a single dose of crizotinib (250 mg) by 69% and 82%, respectively.(3)|
04012|038|B||
04012|039|R|REFERENCES:|
04012|040|B||
04012|041|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04012|042|R|  February, 2022.|1
04012|043|R|2.Pyrukynd (mitapivat) Middle East Prescribing Information. Agios|1
04012|044|R|  Pharmaceuticals, Inc. July, 2025.|1
04012|045|R|3.Xalkori (crizotinib) UK Summary of Product Characteristics. Pfizer Limited|1
04012|046|R|  July, 2021.|1
04012|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
04012|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04013|001|T|MONOGRAPH TITLE:  Mitapivat/Duvelisib|
04013|002|B||
04013|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04013|004|L|of severe adverse interaction.|
04013|005|B||
04013|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04013|007|A|metabolism of mitapivat.(1,2)  Duvelisib is a moderate CYP3A4 inhibitor.|
04013|008|A|   Moderate inducers of CYP3A4 may accelerate the metabolism of|
04013|009|A|duvelisib.(3)  Mitapivat is a moderate CYP3A4 inducer.|
04013|010|B||
04013|011|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04013|012|E|result in increased levels of and effects from mitapivat including decreased|
04013|013|E|estrone and estradiol levels in males, increased urate, back pain, and|
04013|014|E|arthralgias.(1,2)|
04013|015|E|   Concurrent or recent use of moderate CYP3A4 inducers may alter the|
04013|016|E|clinical effectiveness of duvelisib.(3)|
04013|017|B||
04013|018|P|PREDISPOSING FACTORS:  None determined.|
04013|019|B||
04013|020|M|PATIENT MANAGEMENT:  Avoid the concurrent use of duvelisib with moderate|
04013|021|M|CYP3A4 inducers.(3)  When possible, select alternative agents in place of|
04013|022|M|the moderate CYP3A4 inducer.|
04013|023|M|   If the moderate CYP3A4 inducer cannot be avoided, increase the dose of|
04013|024|M|duvelisib on day 12 of concurrent therapy as follows:|
04013|025|M|   - If the initial dose of duvelisib is 25 mg twice daily, increase the|
04013|026|M|duvelisib dose to 40 mg twice daily.|
04013|027|M|   - If the initial dose of duvelisib is 15 mg twice daily, increase the|
04013|028|M|duvelisib dose to 25 mg twice daily.|
04013|029|M|   Monitor patients receiving concurrent therapy for reduced efficacy.(3)|
04013|030|M|   If the moderate CYP3A4 inducer is discontinued, reduce the dose of|
04013|031|M|duvelisib back to the initial dose 14 days after discontinuation of the|
04013|032|M|moderate CYP3A4 inducer.(3)|
04013|033|M|   The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be|
04013|034|M|monitored closely for increased risk of adverse reactions.  The US|
04013|035|M|manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg|
04013|036|M|twice daily with concurrent moderate CYP3A4 inhibitors.(1)  The Middle|
04013|037|M|Eastern manufacturer of mitapivat states that alternative agents that do not|
04013|038|M|inhibit CYP3A4 should be considered.  If concomitant use of a moderate|
04013|039|M|CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100|
04013|040|M|mg once daily.(2)|
04013|041|B||
04013|042|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04013|043|D|with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased|
04013|044|D|mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by|
04013|045|D|2.6-fold and 1.6-fold, respectively.(1)|
04013|046|D|   In an interaction study, etravirine (a moderate CYP3A inducer) 200 mg|
04013|047|D|twice daily decreased the Cmax and AUC of single dose duvelisib 25 mg by 16%|
04013|048|D|and 35%, respectively.(3)|
04013|049|B||
04013|050|R|REFERENCES:|
04013|051|B||
04013|052|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04013|053|R|  February, 2022.|1
04013|054|R|2.Pyrukynd (mitapivat) Middle East Prescribing Information. Agios|1
04013|055|R|  Pharmaceuticals, Inc. July, 2025.|1
04013|056|R|3.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
04013|057|R|  2021.|1
04013|058|R|4.This information is based on an extract from the Certara Drug Interaction|6
04013|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04014|001|T|MONOGRAPH TITLE:  Mitapivat/Enzalutamide|
04014|002|B||
04014|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04014|004|L|of severe adverse interaction.|
04014|005|B||
04014|006|A|MECHANISM OF ACTION:  Both mitapivat and enzalutamide are CYP3A4 substrates|
04014|007|A|and inducers.|
04014|008|A|   Strong inducers of CYP3A4 may increase the metabolism of mitapivat.(1)|
04014|009|A|Enzalutamide is a strong CYP3A4 inducer.|
04014|010|A|   Moderate inducers of CYP3A4 may increase the metabolism of|
04014|011|A|enzalutamide.(2)  Mitapivat is a moderate CYP3A4 inducer.|
04014|012|B||
04014|013|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
04014|014|E|effectiveness of both mitapivat and enzalutamide.(1)|
04014|015|B||
04014|016|P|PREDISPOSING FACTORS:  None determined.|
04014|017|B||
04014|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of mitapivat with|
04014|019|M|enzalutamide.(1,2)|
04014|020|B||
04014|021|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04014|022|D|with a single 50 mg dose of mitapivat, rifampin decreased area-under-curve|
04014|023|D|(AUC) and concentration maximum (Cmax) by 91% and 77%, respectively.  After|
04014|024|D|mitapivat doses of 5, 20, or 50 mg twice daily, rifampin decreased AUC and|
04014|025|D|Cmax by 95% and 85%, respectively.(1)|
04014|026|D|   Coadministration of rifampin (strong CYP3A4 inducer and moderate CYP2C8|
04014|027|D|inducer) decreased the composite AUC of enzalutamide and its active|
04014|028|D|metabolite by 37%.(2)|
04014|029|B||
04014|030|R|REFERENCES:|
04014|031|B||
04014|032|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04014|033|R|  February, 2022.|1
04014|034|R|2.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
04014|035|R|  September, 2022.|1
04014|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04014|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04014|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04014|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04014|040|R|  11/14/2017.|1
04014|041|R|4.This information is based on an extract from the Certara Drug Interaction|6
04014|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04015|001|T|MONOGRAPH TITLE:  Mitapivat/Lorlatinib|
04015|002|B||
04015|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04015|004|L|of severe adverse interaction.|
04015|005|B||
04015|006|A|MECHANISM OF ACTION:  Mitapivat and lorlatinib are both CYP3A4 substrates|
04015|007|A|and inducers.|
04015|008|A|   Moderate inducers of CYP3A4 may increase the metabolism of mitapivat.(1)|
04015|009|A|Lorlatinib is a moderate CYP3A4 inducer.|
04015|010|A|   Moderate inducers of CYP3A4 are expected to increase the metabolism of|
04015|011|A|lorlatinib.(2)  Mitapivat is a moderate CYP3A4 inducer.|
04015|012|B||
04015|013|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
04015|014|E|effectiveness of both mitapivat and lorlatinib.(1,2)|
04015|015|B||
04015|016|P|PREDISPOSING FACTORS:  None determined.|
04015|017|B||
04015|018|M|PATIENT MANAGEMENT:  Avoid concurrent administration of moderate inducers of|
04015|019|M|CYP3A4 with lorlatinib.(2)|
04015|020|M|   If concurrent use of lorlatinib and moderate CYP3A4 inducers cannot be|
04015|021|M|avoided, increase the dose of lorlatinib to 125 mg daily.(2)|
04015|022|M|   Concurrent use of mitapivat with medications that are moderate CYP3A4|
04015|023|M|inducers should be monitored closely.  Mitapivat dose should not exceed a|
04015|024|M|maximum dose of 100 mg twice daily with concurrent moderate CYP3A4|
04015|025|M|inducers.(1)|
04015|026|B||
04015|027|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04015|028|D|with 5 or 20 mg twice daily of mitapivat, efavirenz decreased|
04015|029|D|area-under-curve (AUC) and concentration maximum (Cmax) by 60% and 30%,|
04015|030|D|respectively.  After mitapivat doses of 50 mg twice daily, efavirenz|
04015|031|D|decreased AUC and Cmax by 55% and 24%, respectively.(1)|
04015|032|D|   Modafinil (a moderate CYP3A4 inducer) decreased the AUC and Cmax of a|
04015|033|D|single 100 mg dose of lorlatinib by 23% and 22%, respectively.(2)|
04015|034|B||
04015|035|R|REFERENCES:|
04015|036|B||
04015|037|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04015|038|R|  February, 2022.|1
04015|039|R|2.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
04015|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04015|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04015|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04015|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04015|044|R|  11/14/2017.|1
04015|045|R|4.This information is based on an extract from the Certara Drug Interaction|6
04015|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04016|001|T|MONOGRAPH TITLE:  Pacritinib/QT Prolonging Agents|
04016|002|B||
04016|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04016|004|L|of severe adverse interaction.|
04016|005|B||
04016|006|A|MECHANISM OF ACTION:  Pacritinib has been observed to prolong the QTc|
04016|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04016|008|A|may result in additive effects on the QTc interval.(1)|
04016|009|B||
04016|010|E|CLINICAL EFFECTS:  The concurrent use of pacritinib with other agents that|
04016|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04016|012|E|arrhythmias, including torsades de pointes.(1)|
04016|013|B||
04016|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04016|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04016|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04016|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04016|018|P|female gender, or advanced age.(2)|
04016|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04016|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04016|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04016|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04016|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04016|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04016|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04016|026|B||
04016|027|M|PATIENT MANAGEMENT:  The manufacturer of pacritinib states concurrent use|
04016|028|M|with agents known to prolong the QT interval should be avoided.  Avoid the|
04016|029|M|use of pacritinib in patients with a baseline QTc > 480 msec.  Correct|
04016|030|M|hypokalemia prior to initiation and during therapy with pacritinib.(1)|
04016|031|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04016|032|M|hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline|
04016|033|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04016|034|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04016|035|M|dose.(1)|
04016|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04016|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04016|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04016|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04016|040|B||
04016|041|D|DISCUSSION:  In a 24 week clinical study, patients treatment with pacritinib|
04016|042|D|200 mg twice daily had a change in QTc from baseline of 11 msec (90% CI:|
04016|043|D|5-17).(1)|
04016|044|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04016|045|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04016|046|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04016|047|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04016|048|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04016|049|D|adverse reactions were higher in the treatment arm than the control group|
04016|050|D|(3.8% vs 2%, respectively).(1)|
04016|051|D|   Agents that are linked to this monograph may have varying degrees of|
04016|052|D|potential to prolong the QTc interval but are generally accepted to have a|
04016|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04016|054|D|been shown to prolong the QTc interval either through their mechanism of|
04016|055|D|action, through studies on their effects on the QTc interval, or through|
04016|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04016|057|D|and/or post-marketing reports.(3)|
04016|058|B||
04016|059|R|REFERENCES:|
04016|060|B||
04016|061|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04016|062|R|  2024.|1
04016|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04016|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04016|065|R|  settings: a scientific statement from the American Heart Association and|6
04016|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04016|067|R|  2;55(9):934-47.|6
04016|068|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04016|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04016|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04016|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04017|001|T|MONOGRAPH TITLE:  Pacritinib/Possible QT Prolonging Agents|
04017|002|B||
04017|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04017|004|L|take action as needed.|
04017|005|B||
04017|006|A|MECHANISM OF ACTION:  Pacritinib has been observed to prolong the QTc|
04017|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04017|008|A|may result in additive effects on the QTc interval.(1)|
04017|009|B||
04017|010|E|CLINICAL EFFECTS:  The concurrent use of pacritinib with other agents that|
04017|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04017|012|E|arrhythmias, including torsades de pointes.(1)|
04017|013|B||
04017|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04017|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04017|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04017|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04017|018|P|female gender, or advanced age.(2)|
04017|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04017|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04017|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04017|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04017|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04017|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04017|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04017|026|B||
04017|027|M|PATIENT MANAGEMENT:  The manufacturer of pacritinib states concurrent use|
04017|028|M|with agents known to prolong the QT interval should be avoided.  Avoid the|
04017|029|M|use of pacritinib in patients with a baseline QTc > 480 msec.  Correct|
04017|030|M|hypokalemia prior to initiation and during therapy with pacritinib.(1)|
04017|031|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04017|032|M|hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline|
04017|033|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04017|034|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04017|035|M|dose.(1)|
04017|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04017|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04017|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04017|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04017|040|B||
04017|041|D|DISCUSSION:  In a 24 week clinical study, patients treatment with pacritinib|
04017|042|D|200 mg twice daily had a change in QTc from baseline of 11 msec (90% CI:|
04017|043|D|5-17).(1)|
04017|044|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04017|045|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04017|046|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04017|047|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04017|048|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04017|049|D|adverse reactions were higher in the treatment arm than the control group|
04017|050|D|(3.8% vs 2%, respectively).(1)|
04017|051|D|   Agents that are linked to this monograph may have varying degrees of|
04017|052|D|potential to prolong the QTc interval but are generally accepted to have a|
04017|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04017|054|D|been shown to prolong the QTc interval either through their mechanism of|
04017|055|D|action, through studies on their effects on the QTc interval, or through|
04017|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04017|057|D|and/or post-marketing reports.(3)|
04017|058|B||
04017|059|R|REFERENCES:|
04017|060|B||
04017|061|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04017|062|R|  2024.|1
04017|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04017|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04017|065|R|  settings: a scientific statement from the American Heart Association and|6
04017|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04017|067|R|  2;55(9):934-47.|6
04017|068|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04017|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04017|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04017|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04018|001|T|MONOGRAPH TITLE:  Pacritinib/Strong CYP3A4 Inhibitors|
04018|002|B||
04018|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04018|004|L|is contraindicated and generally should not be dispensed or administered to|
04018|005|L|the same patient.|
04018|006|B||
04018|007|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
04018|008|A|the metabolism of pacritinib.(1)|
04018|009|B||
04018|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04018|011|E|the levels and effects of pacritinib.(1)|
04018|012|E|    Elevated levels of pacritinib may result in QTc prolongation, which may|
04018|013|E|result in potentially life-threatening cardiac arrhythmias, including|
04018|014|E|torsades de pointes (TdP).  Other toxicities include bleeding, diarrhea,|
04018|015|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
04018|016|E|infection.(1)|
04018|017|B||
04018|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04018|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04018|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04018|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04018|022|P|female gender, or advanced age.(2)|
04018|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04018|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04018|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04018|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04018|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04018|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04018|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04018|030|B||
04018|031|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inhibitors is contraindicated|
04018|032|M|in patients undergoing therapy with pacritinib.(1)  Consider alternatives|
04018|033|M|with no or minimal enzyme inhibition.|
04018|034|M|   If coadministration with a strong CYP3A4 inhibitor is unavoidable,|
04018|035|M|monitor for prolongation of the QTc interval.(1)  When concurrent therapy is|
04018|036|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
04018|037|M|and monitoring EKG at baseline and regular intervals. Correct any|
04018|038|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04018|039|M|heartbeat, dizziness, or fainting.|
04018|040|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04018|041|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04018|042|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04018|043|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04018|044|M|dose according to labeling.(1)|
04018|045|B||
04018|046|D|DISCUSSION:  Clarithromycin (500 mg twice daily for 5 days) increased|
04018|047|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04018|048|D|pacritinib (400 mg) by 30% and 80%, respectively.(1)|
04018|049|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04018|050|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1)|
04018|051|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04018|052|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04018|053|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04018|054|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04018|055|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04018|056|D|adverse reactions were higher in the treatment arm than the control group|
04018|057|D|(3.8% vs 2%, respectively).(1)|
04018|058|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, indinavir,|
04018|059|D|itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone,|
04018|060|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir,|
04018|061|D|troleandomycin, and tucatinib.(3,4)|
04018|062|B||
04018|063|R|REFERENCES:|
04018|064|B||
04018|065|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04018|066|R|  2024.|1
04018|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04018|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04018|069|R|  settings: a scientific statement from the American Heart Association and|6
04018|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04018|071|R|  2;55(9):934-47.|6
04018|072|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04018|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04018|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04018|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04018|076|R|  11/14/2017.|1
04018|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
04018|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04019|001|T|MONOGRAPH TITLE:  Pacritinib/Strong CYP3A4 Inhibitors that Prolong QT|
04019|002|B||
04019|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04019|004|L|is contraindicated and generally should not be dispensed or administered to|
04019|005|L|the same patient.|
04019|006|B||
04019|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04019|008|A|interval may inhibit the metabolism of pacritinib and result in additive|
04019|009|A|risk of QT prolongation.(1)|
04019|010|B||
04019|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04019|012|E|the QTc interval may increase the levels and effects of pacritinib,|
04019|013|E|including additive QTc prolongation, which may result in potentially|
04019|014|E|life-threatening cardiac arrhythmias, including torsades de pointes|
04019|015|E|(TdP).(1)|
04019|016|E|   Other toxicities include bleeding, diarrhea, thrombocytopenia, major|
04019|017|E|adverse cardiovascular events, thrombosis, and infection.(1)|
04019|018|B||
04019|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04019|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04019|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04019|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04019|023|P|female gender, or advanced age.(2)|
04019|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04019|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04019|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04019|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04019|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04019|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04019|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04019|031|B||
04019|032|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inhibitors that prolong the|
04019|033|M|QTc interval is contraindicated in patients undergoing therapy with|
04019|034|M|pacritinib.(1)  Consider alternatives with no or minimal enzyme inhibition|
04019|035|M|and with no effect on the QTc interval.|
04019|036|M|   If coadministration is unavoidable, monitor for prolongation of the QTc|
04019|037|M|interval.(1)  When concurrent therapy is warranted: consider obtaining serum|
04019|038|M|calcium, magnesium, and potassium levels and monitoring EKG at baseline and|
04019|039|M|regular intervals. Correct any electrolyte abnormalities.  Instruct patients|
04019|040|M|to report any irregular heartbeat, dizziness, or fainting.|
04019|041|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04019|042|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04019|043|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04019|044|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04019|045|M|dose according to labeling.(1)|
04019|046|B||
04019|047|D|DISCUSSION:  Clarithromycin (500 mg twice daily for 5 days) increased|
04019|048|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04019|049|D|pacritinib (400 mg) by 30% and 80%, respectively.(1)|
04019|050|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04019|051|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1)|
04019|052|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04019|053|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04019|054|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04019|055|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04019|056|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04019|057|D|adverse reactions were higher in the treatment arm than the control group|
04019|058|D|(3.8% vs 2%, respectively).(1)|
04019|059|D|   Agents that are linked to this monograph may have varying degrees of|
04019|060|D|potential to prolong the QTc interval but are generally accepted to have a|
04019|061|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04019|062|D|been shown to prolong the QTc interval either through their mechanism of|
04019|063|D|action, through studies on their effects on the QTc interval, or through|
04019|064|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04019|065|D|and/or post-marketing reports.(5)|
04019|066|D|   Strong inhibitors of CYP3A4 that prolong QT include:  adagrasib,|
04019|067|D|ceritinib, clarithromycin, levoketoconazole, lopinavir, posaconazole,|
04019|068|D|ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)|
04019|069|B||
04019|070|R|REFERENCES:|
04019|071|B||
04019|072|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04019|073|R|  2024.|1
04019|074|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04019|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04019|076|R|  settings: a scientific statement from the American Heart Association and|6
04019|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04019|078|R|  2;55(9):934-47.|6
04019|079|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04019|080|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04019|081|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04019|082|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04019|083|R|  11/14/2017.|1
04019|084|R|4.This information is based on an extract from the Certara Drug Interaction|6
04019|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04019|086|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04019|087|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04019|088|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04019|089|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04020|001|T|MONOGRAPH TITLE:  Pacritinib/Moderate CYP3A4 Inhibitors|
04020|002|B||
04020|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04020|004|L|take action as needed.|
04020|005|B||
04020|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
04020|007|A|the metabolism of pacritinib.(1)|
04020|008|B||
04020|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04020|010|E|levels of and effects from pacritinib.(1)|
04020|011|E|    Elevated levels of pacritinib may result in QTc prolongation, which may|
04020|012|E|result in potentially life-threatening cardiac arrhythmias, including|
04020|013|E|torsades de pointes (TdP).  Other toxicities include bleeding, diarrhea,|
04020|014|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
04020|015|E|infection.(1)|
04020|016|B||
04020|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04020|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04020|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04020|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04020|021|P|female gender, or advanced age.(2)|
04020|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04020|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04020|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04020|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04020|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04020|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04020|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04020|029|B||
04020|030|M|PATIENT MANAGEMENT:  The manufacturer of pacritinib recommends monitoring|
04020|031|M|patients concomitantly receiving moderate CYP3A4 inhibitors (e.g.,|
04020|032|M|fluconazole) for increased adverse reactions and considering pacritinib dose|
04020|033|M|modifications based on safety.(1)|
04020|034|M|   When concurrent therapy is warranted monitor for prolongation of the QTc|
04020|035|M|interval.(1)  Consider obtaining serum calcium, magnesium, and potassium|
04020|036|M|levels and monitoring EKG at baseline and regular intervals. Correct any|
04020|037|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04020|038|M|heartbeat, dizziness, or fainting.|
04020|039|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04020|040|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04020|041|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04020|042|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04020|043|M|dose according to labeling.(1)|
04020|044|B||
04020|045|D|DISCUSSION:  Fluconazole (200 mg once daily for 7 days, a moderate CYP3A4|
04020|046|D|inhibitor) increased maximum concentration (Cmax) and area-under-curve (AUC)|
04020|047|D|of pacritinib (200 mg twice daily at steady state) by 41% and 45%,|
04020|048|D|respectively.(1)  Concomitant use of pacritinib with doses of fluconazole|
04020|049|D|greater than 200 mg once daily have not been studied.(1)|
04020|050|D|   Clarithromycin (500 mg twice daily for 5 days, a strong CYP3A4 inhibitor)|
04020|051|D|increased maximum concentration (Cmax) and area-under-curve (AUC) of a|
04020|052|D|single dose of pacritinib (400 mg) by 80% and 30%, respectively.(1)|
04020|053|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04020|054|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1)|
04020|055|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04020|056|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04020|057|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04020|058|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04020|059|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04020|060|D|adverse reactions were higher in the treatment arm than the control group|
04020|061|D|(3.8% vs 2%, respectively).(1)|
04020|062|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04020|063|D|atazanavir, berotralstat, conivaptan, darunavir, diltiazem, fluvoxamine,|
04020|064|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir,|
04020|065|D|netupitant, schisandra, stiripentol, tofisopam, treosulfan, verapamil and|
04020|066|D|voxelotor.(3,4)|
04020|067|B||
04020|068|R|REFERENCES:|
04020|069|B||
04020|070|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04020|071|R|  2024.|1
04020|072|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04020|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04020|074|R|  settings: a scientific statement from the American Heart Association and|6
04020|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04020|076|R|  2;55(9):934-47.|6
04020|077|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04020|078|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04020|079|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04020|080|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04020|081|R|  11/14/2017.|1
04020|082|R|4.This information is based on an extract from the Certara Drug Interaction|6
04020|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04021|001|T|MONOGRAPH TITLE:  Pacritinib/Moderate CYP3A4 Inhibitors that Prolong QT|
04021|002|B||
04021|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04021|004|L|take action as needed.|
04021|005|B||
04021|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong the QTc|
04021|007|A|interval may inhibit the metabolism of pacritinib and result in additive|
04021|008|A|risk of QT prolongation.(1)|
04021|009|B||
04021|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
04021|011|E|QT may increase the levels and effects of pacritinib, including additive QTc|
04021|012|E|prolongation, which may result in potentially life-threatening cardiac|
04021|013|E|arrhythmias, including torsades de pointes (TdP).(1)|
04021|014|E|   Other toxicities include bleeding, diarrhea, thrombocytopenia, major|
04021|015|E|adverse cardiovascular events, thrombosis, and infection.(1)|
04021|016|B||
04021|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04021|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04021|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04021|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04021|021|P|female gender, or advanced age.(2)|
04021|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04021|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04021|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04021|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04021|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04021|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04021|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04021|029|B||
04021|030|M|PATIENT MANAGEMENT:  The manufacturer of pacritinib recommends monitoring|
04021|031|M|patients concomitantly receiving moderate CYP3A4 inhibitors (e.g.,|
04021|032|M|fluconazole) for increased adverse reactions and considering pacritinib dose|
04021|033|M|modifications based on safety.(1)|
04021|034|M|   When concurrent therapy is warranted monitor for prolongation of the QTc|
04021|035|M|interval.(1) Consider obtaining serum calcium, magnesium, and potassium|
04021|036|M|levels and monitoring EKG at baseline and regular intervals. Correct any|
04021|037|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04021|038|M|heartbeat, dizziness, or fainting.|
04021|039|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04021|040|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04021|041|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04021|042|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04021|043|M|dose according to labeling.(1)|
04021|044|B||
04021|045|D|DISCUSSION:  Fluconazole (200 mg once daily for 7 days, a moderate CYP3A4|
04021|046|D|inhibitor) increased maximum concentration (Cmax) and area-under-curve (AUC)|
04021|047|D|of pacritinib (200 mg twice daily at steady state) by 41% and 45%,|
04021|048|D|respectively.(1)  Concomitant use of pacritinib with doses of fluconazole|
04021|049|D|greater than 200 mg once daily have not been studied.(1)|
04021|050|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04021|051|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1)|
04021|052|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04021|053|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04021|054|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04021|055|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04021|056|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04021|057|D|adverse reactions were higher in the treatment arm than the control group|
04021|058|D|(3.8% vs 2%, respectively).(1)|
04021|059|D|   Agents that are linked to this monograph may have varying degrees of|
04021|060|D|potential to prolong the QTc interval but are generally accepted to have a|
04021|061|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04021|062|D|been shown to prolong the QTc interval either through their mechanism of|
04021|063|D|action, through studies on their effects on the QTc interval, or through|
04021|064|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04021|065|D|and/or post-marketing reports.(5)|
04021|066|D|   Moderate inhibitors of CYP3A4 that prolong QT include: dronedarone,|
04021|067|D|erythromycin, fluconazole, and nilotinib.(3,4)|
04021|068|B||
04021|069|R|REFERENCES:|
04021|070|B||
04021|071|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04021|072|R|  2024.|1
04021|073|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04021|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04021|075|R|  settings: a scientific statement from the American Heart Association and|6
04021|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04021|077|R|  2;55(9):934-47.|6
04021|078|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04021|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04021|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04021|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04021|082|R|  11/14/2017.|1
04021|083|R|4.This information is based on an extract from the Certara Drug Interaction|6
04021|084|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04021|085|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04021|086|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04021|087|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04021|088|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04022|001|T|MONOGRAPH TITLE:  Pacritinib/Moderate CYP3A4 Inducers (mono deleted|
04022|002|T|11/19/2024)|
04022|003|B||
04022|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04022|005|L|of severe adverse interaction.|
04022|006|B||
04022|007|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04022|008|A|metabolism of pacritinib.(1)|
04022|009|B||
04022|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inducers may decrease|
04022|011|E|the levels and effectiveness of pacritinib.(1)|
04022|012|B||
04022|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04022|014|P|of the inducer for longer than 1-2 weeks.|
04022|015|B||
04022|016|M|PATIENT MANAGEMENT:  Avoid the concurrent use of moderate CYP3A4 inducers in|
04022|017|M|patients receiving therapy with pacritinib.(1)|
04022|018|M|   Consider the use of alternative agents with less enzyme induction|
04022|019|M|potential.(1)|
04022|020|B||
04022|021|D|DISCUSSION:  The impact of moderate CYP3A4 inducers on the pharmacokinetics|
04022|022|D|of pacritinib has not been investigated in clinical studies.(1)|
04022|023|D|   Rifampin (600 mg daily for 10 days), a strong CYP3A4 inducer, decreased|
04022|024|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
04022|025|D|of pacritinib (400 mg) by 51% and 87%, respectively.(1)|
04022|026|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
04022|027|D|bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad,|
04022|028|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib,|
04022|029|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04022|030|D|tipranavir/ritonavir, and tovorafenib.(2)|
04022|031|B||
04022|032|R|REFERENCES:|
04022|033|B||
04022|034|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04022|035|R|  2024.|1
04022|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04022|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04022|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04022|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04022|040|R|  11/14/2017.|1
04022|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
04022|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04023|001|T|MONOGRAPH TITLE:  Pacritinib/Moderate CYP3A4 Inducers that Prolong QT (mono|
04023|002|T|deleted 11/19/2024)|
04023|003|B||
04023|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04023|005|L|of severe adverse interaction.|
04023|006|B||
04023|007|A|MECHANISM OF ACTION:  Efavirenz and thioridazine, moderate CYP3A4 inducers,|
04023|008|A|may induce the metabolism of pacritinib and result in additive risk of QT|
04023|009|A|prolongation.(1)|
04023|010|B||
04023|011|E|CLINICAL EFFECTS:  Concurrent use of efavirenz and thioridazine may decrease|
04023|012|E|the levels and effectiveness of pacritinib and increase the risk of|
04023|013|E|potentially life-threatening arrhythmia, including torsade de pointes.(1)|
04023|014|B||
04023|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04023|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04023|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04023|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04023|019|P|female gender, or advanced age.(2)|
04023|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04023|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04023|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04023|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04023|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04023|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04023|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04023|027|P|   Induction effects may be more likely with regular use of the inducer for|
04023|028|P|longer than 1-2 weeks.|
04023|029|B||
04023|030|M|PATIENT MANAGEMENT:  Avoid the concurrent use of moderate CYP3A4 inducers|
04023|031|M|that prolong QT in patients receiving therapy with pacritinib.(1)|
04023|032|M|   Consider the use of alternative agents with less enzyme induction|
04023|033|M|potential.(1)|
04023|034|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04023|035|M|hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline|
04023|036|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04023|037|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04023|038|M|dose.(1)|
04023|039|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04023|040|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04023|041|M|baseline and regular intervals.(1)  Correct any electrolyte abnormalities.|
04023|042|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04023|043|B||
04023|044|D|DISCUSSION:  The impact of moderate CYP3A4 inducers has not been|
04023|045|D|investigated in clinical studies.(1)|
04023|046|D|   Rifampin (600 mg daily for 10 days), a strong CYP3A4 inducer, decreased|
04023|047|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
04023|048|D|of pacritinib (400 mg) by 51% and 87%, respectively.(1)|
04023|049|D|   In a 24 week clinical study, patients treatment with pacritinib 200 mg|
04023|050|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1)|
04023|051|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04023|052|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04023|053|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04023|054|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04023|055|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04023|056|D|adverse reactions were higher in the treatment arm than the control group|
04023|057|D|(3.8% vs 2%, respectively).(1)|
04023|058|D|   Agents that are linked to this monograph may have varying degrees of|
04023|059|D|potential to prolong the QTc interval but are generally accepted to have a|
04023|060|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04023|061|D|been shown to prolong the QTc interval either through their mechanism of|
04023|062|D|action, through studies on their effects on the QTc interval, or through|
04023|063|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04023|064|D|and/or post-marketing reports.(5)|
04023|065|D|   Moderate CYP3A4 inducers that prolong QT linked to this monograph|
04023|066|D|include: efavirenz and thioridazine.(3,4)|
04023|067|B||
04023|068|R|REFERENCES:|
04023|069|B||
04023|070|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04023|071|R|  2024.|1
04023|072|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04023|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04023|074|R|  settings: a scientific statement from the American Heart Association and|6
04023|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04023|076|R|  2;55(9):934-47.|6
04023|077|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04023|078|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04023|079|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04023|080|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04023|081|R|  11/14/2017.|1
04023|082|R|4.This information is based on an extract from the Certara Drug Interaction|6
04023|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04023|084|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04023|085|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04023|086|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04023|087|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04024|001|T|MONOGRAPH TITLE:  Pacritinib/Strong CYP3A4 Inducers|
04024|002|B||
04024|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04024|004|L|is contraindicated and generally should not be dispensed or administered to|
04024|005|L|the same patient.|
04024|006|B||
04024|007|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04024|008|A|metabolism of pacritinib.(1)|
04024|009|B||
04024|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04024|011|E|levels and effectiveness of pacritinib.(1)|
04024|012|B||
04024|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04024|014|P|of the inducer for longer than 1-2 weeks.|
04024|015|B||
04024|016|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers in patients receiving|
04024|017|M|therapy with pacritinib is contraindicated.(1)|
04024|018|M|   Consider the use of alternative agents with less enzyme induction|
04024|019|M|potential.(1)|
04024|020|B||
04024|021|D|DISCUSSION:  Rifampin (600 mg daily for 10 days), a strong CYP3A4 inducer,|
04024|022|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
04024|023|D|single dose of pacritinib (400 mg) by 51% and 87%, respectively.(1)|
04024|024|D|    Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04024|025|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04024|026|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
04024|027|D|St. John's wort.(2)|
04024|028|B||
04024|029|R|REFERENCES:|
04024|030|B||
04024|031|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04024|032|R|  2024.|1
04024|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04024|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04024|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04024|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04024|037|R|  11/14/2017.|1
04024|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
04024|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04025|001|T|MONOGRAPH TITLE:  Pacritinib/Strong CYP3A4 Inducers that Prolong QT|
04025|002|B||
04025|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04025|004|L|is contraindicated and generally should not be dispensed or administered to|
04025|005|L|the same patient.|
04025|006|B||
04025|007|A|MECHANISM OF ACTION:  Apalutamide and ivosidenib may induce the metabolism|
04025|008|A|of pacritinib and result in additive risk of QT prolongation.(1)|
04025|009|B||
04025|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
04025|011|E|may decrease the levels and effectiveness of pacritinib and increase the|
04025|012|E|risk of potentially life-threatening arrhythmia, including torsade de|
04025|013|E|pointes.(1)|
04025|014|B||
04025|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04025|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04025|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04025|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04025|019|P|female gender, or advanced age.(2)|
04025|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04025|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04025|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04025|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04025|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04025|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04025|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04025|027|P|   Induction effects may be more likely with regular use of the inducer for|
04025|028|P|longer than 1-2 weeks.|
04025|029|B||
04025|030|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers that prolong QT in|
04025|031|M|patients receiving therapy with pacritinib is contraindicated.(1)|
04025|032|M|   Consider the use of alternative agents with less enzyme induction|
04025|033|M|potential.(1)|
04025|034|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04025|035|M|hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline|
04025|036|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04025|037|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04025|038|M|dose.(1)|
04025|039|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04025|040|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04025|041|M|baseline and regular intervals.(1)  Correct any electrolyte abnormalities.|
04025|042|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04025|043|B||
04025|044|D|DISCUSSION:  Rifampin (600 mg daily for 10 days), a strong CYP3A4 inducer,|
04025|045|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
04025|046|D|single dose of pacritinib (400 mg) by 51% and 87%, respectively.(1)|
04025|047|D|   In a 24 week clinical study, patients treatment with pacritinib 200 mg|
04025|048|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1)|
04025|049|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04025|050|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04025|051|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04025|052|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04025|053|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04025|054|D|adverse reactions were higher in the treatment arm than the control group|
04025|055|D|(3.8% vs 2%, respectively).(1)|
04025|056|D|   Agents that are linked to this monograph may have varying degrees of|
04025|057|D|potential to prolong the QTc interval but are generally accepted to have a|
04025|058|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04025|059|D|been shown to prolong the QTc interval either through their mechanism of|
04025|060|D|action, through studies on their effects on the QTc interval, or through|
04025|061|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04025|062|D|and/or post-marketing reports.(4)|
04025|063|D|    Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04025|064|D|encorafenib and ivosidenib.(2)|
04025|065|B||
04025|066|R|REFERENCES:|
04025|067|B||
04025|068|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04025|069|R|  2024.|1
04025|070|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04025|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04025|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04025|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04025|074|R|  11/14/2017.|1
04025|075|R|3.This information is based on an extract from the Certara Drug Interaction|6
04025|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04025|077|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04025|078|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04025|079|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04025|080|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04026|001|T|MONOGRAPH TITLE:  Ranolazine (Extended Release Granules)/Alcohol|
04026|002|B||
04026|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04026|004|L|of severe adverse interaction.|
04026|005|B||
04026|006|A|MECHANISM OF ACTION:  Concomitant use of alcohol with ranolazine|
04026|007|A|extended-release granules may cause a rapid release of ranolazine.(1)|
04026|008|B||
04026|009|E|CLINICAL EFFECTS:  Rapid release of ranolazine may result in increased|
04026|010|E|systemic concentrations and toxicities, including QTc prolongation and|
04026|011|E|life-threatening cardiac arrhythmia like torsades de pointes.(1)|
04026|012|B||
04026|013|P|PREDISPOSING FACTORS:  The increased rate of release may be alcohol|
04026|014|P|concentration-dependent.|
04026|015|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04026|016|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04026|017|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04026|018|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04026|019|P|advanced age.(2)|
04026|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04026|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04026|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04026|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04026|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04026|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04026|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04026|027|B||
04026|028|M|PATIENT MANAGEMENT:  Patients are advised to avoid alcohol while taking|
04026|029|M|ranolazine extended-release granules.  Avoid the use of elixirs containing a|
04026|030|M|high-percentage of alcohol in patients taking these products.(1)|
04026|031|B||
04026|032|D|DISCUSSION:  An in-vitro dissolution study was conducted to evaluate the|
04026|033|D|impact of alcohol on extended-release characteristics of ranolazine|
04026|034|D|granules.  The in-vitro study showed that alcohol causes a rapid release of|
04026|035|D|ranolazine from the extended-release granules that may increase the risk of|
04026|036|D|adverse events associated with ranolazine.(1)|
04026|037|B||
04026|038|R|REFERENCES:|
04026|039|B||
04026|040|R|1.Aspruzyo Sprinkle (ranolazine) US prescribining information. Sun|1
04026|041|R|  Pharmaceutical Industries, Inc. February, 2022.|1
04026|042|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04026|043|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04026|044|R|  settings: a scientific statement from the American Heart Association and|6
04026|045|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04026|046|R|  2;55(9):934-47.|6
04027|001|T|MONOGRAPH TITLE:  Ganaxolone/Strong or Moderate CYP3A4 Inducers|
04027|002|B||
04027|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04027|004|L|of severe adverse interaction.|
04027|005|B||
04027|006|A|MECHANISM OF ACTION:  Ganaxolone is a substrate of CYP3A4.  Strong or|
04027|007|A|moderate inducers of CYP3A4 may induce the metabolism of ganaxolone.(1)|
04027|008|B||
04027|009|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
04027|010|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
04027|011|E|ganaxolone.(1)|
04027|012|B||
04027|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04027|014|P|of the inducer for longer than 1-2 weeks.|
04027|015|B||
04027|016|M|PATIENT MANAGEMENT:  The manufacturer of ganaxolone states that concurrent|
04027|017|M|use with strong or moderate CYP3A4 inducers should be avoided.  If|
04027|018|M|concurrent use is unavoidable, consider increasing the dose of ganaxolone.|
04027|019|M|Do not exceed the recommended maximum daily dose.(1)|
04027|020|M|   In patients who are stable on ganaxolone and are initiated on|
04027|021|M|anticonvulsants that are CYP3A4 inducers, consider increasing the dose of|
04027|022|M|ganaxolone.  Do not exceed the recommended maximum daily dose.(1)|
04027|023|B||
04027|024|D|DISCUSSION:  Co-administration of rifampin, a strong CYP3A4 inducer,|
04027|025|D|decreased the ganaxolone concentration maximum (Cmax) by 57% and|
04027|026|D|area-under-curve (AUC) by 68%.(1)|
04027|027|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04027|028|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04027|029|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04027|030|D|rifapentine, and St. John's wort.|
04027|031|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04027|032|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04027|033|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04027|034|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04027|035|D|thioridazine, and tovorafenib.(2-3)|
04027|036|B||
04027|037|R|REFERENCES:|
04027|038|B||
04027|039|R|1.Ztalmy (ganaxolone) US prescribing information. Marinus Pharmaceuticals,|1
04027|040|R|  Inc. March, 2022.|1
04027|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04027|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04027|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04027|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04027|045|R|  11/14/2017.|1
04027|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
04027|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04028|001|T|MONOGRAPH TITLE:  Selected Calcium Channel Blockers/Nirmatrelvir-Ritonavir|
04028|002|B||
04028|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04028|004|L|take action as needed.|
04028|005|B||
04028|006|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the metabolism of|
04028|007|A|calcium channel blockers by CYP3A4.(1,2)|
04028|008|B||
04028|009|E|CLINICAL EFFECTS:  Concurrent use of nirmatrelvir-ritonavir may result in|
04028|010|E|elevated levels of and toxicity from calcium channel blockers.|
04028|011|B||
04028|012|P|PREDISPOSING FACTORS:  None determined.|
04028|013|B||
04028|014|M|PATIENT MANAGEMENT:  Concurrent use of nirmatrelvir-ritonavir and selected|
04028|015|M|calcium channel blockers should be approached with caution.|
04028|016|M|   Monitor patients receiving concurrent therapy with nirmatrelvir-ritonavir|
04028|017|M|and either amlodipine, diltiazem, felodipine, nicardipine, nifedipine, or|
04028|018|M|verapamil for increased calcium channel blocker effects.  The dosage of the|
04028|019|M|calcium channel blocker may need to be adjusted.(1,2)|
04028|020|M|   The Journal of American College of Cardiology recommends a 50% reduction|
04028|021|M|in the dose amlodipine for 8 days with the initiation of|
04028|022|M|nirmatrelvir-ritonavir.  Close monitoring of blood pressure and dose|
04028|023|M|reduction or temporary discontinuation of calcium channel blockers may be|
04028|024|M|needed.  Resume calcium channel blockers 3 days after the last dose of|
04028|025|M|nirmatrelvir-ritonavir.(3)|
04028|026|B||
04028|027|D|DISCUSSION:  Nirmatrelvir-ritonavir is a strong CYP3A4 inhibitor and may|
04028|028|D|increase the levels of calcium channel blockers that are CYP3A4|
04028|029|D|substrates.(1,2)|
04028|030|D|   In a case report of a 80-year old female on verapamil, on day 2 of|
04028|031|D|concurrent nirmatrelvir-ritonavir the patient presented to the hospital with|
04028|032|D|symptomatic bradycardia (heart rate of 28 beats per minute and blood|
04028|033|D|pressure of 58/35 mmHg) requiring hospitalization, medical management, and a|
04028|034|D|temporary transvenous pacer.(4)|
04028|035|B||
04028|036|R|REFERENCES:|
04028|037|B||
04028|038|R|1.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04028|039|R|  information. Pfizer Inc. February, 2025.|1
04028|040|R|2.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
04028|041|R|  Monograph. Pfizer Canada ULC October, 2023.|1
04028|042|R|3.Abraham S Nohria A Neilan TG Asnani A Saji AM Shah J Lech T Grossman J|6
04028|043|R|  Abraham GM McQuillen DP Martin DT Sax PE Dani SS Ganatra S. Cardiovascular|6
04028|044|R|  Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19:|6
04028|045|R|  JACC Review Topic of the Week. J Am Coll Cardiol 2022 Oct 6.|6
04028|046|R|4.Haque OI, Mahar S, Hussain S, Sloane P. Pharmacokinetic interaction|3
04028|047|R|  between verapamil and ritonavir-boosted nirmatrelvir:  implications for|3
04028|048|R|  the management of COVID-19 in patients with hypertension. BMJ Case Rep|3
04028|049|R|  2023 Jan 13;16(1):.|3
04029|001|T|MONOGRAPH TITLE:  Erythromycin/Nirmatrelvir-Ritonavir|
04029|002|B||
04029|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04029|004|L|take action as needed.|
04029|005|B||
04029|006|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the metabolism of|
04029|007|A|erythromycin by CYP3A4.(1)|
04029|008|B||
04029|009|E|CLINICAL EFFECTS:  Concurrent use of erythromycin with strong CYP3A4|
04029|010|E|inhibitors such as nirmatrelvir-ritonavir may result in elevated levels of|
04029|011|E|erythromycin and risk of QT prolongation or torsades de pointes leading to|
04029|012|E|sudden death from cardiac causes.(1-3)|
04029|013|B||
04029|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04029|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04029|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04029|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04029|018|P|female gender, or advanced age.(3)|
04029|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04029|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04029|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04029|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04029|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04029|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04029|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04029|026|B||
04029|027|M|PATIENT MANAGEMENT:  The concurrent use of erythromycin with|
04029|028|M|nirmatrelvir-ritonavir should be used with caution.(1)|
04029|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04029|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04029|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04029|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04029|033|B||
04029|034|D|DISCUSSION:  Nirmatrelvir-ritonavir is a strong CYP3A4 inhibitor and may|
04029|035|D|increase the levels of erythromycin, a CYP3A4 substrate.(1)|
04029|036|B||
04029|037|R|REFERENCES:|
04029|038|B||
04029|039|R|1.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04029|040|R|  information. Pfizer Inc. February, 2025.|1
04029|041|R|2.Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral|2
04029|042|R|  erythromycin and the risk of sudden death from cardiac causes. N Engl J|2
04029|043|R|  Med 2004 Sep 9;351(11):1089-96.|2
04029|044|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04029|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04029|046|R|  settings: a scientific statement from the American Heart Association and|6
04029|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04029|048|R|  2;55(9):934-47.|6
04030|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors/Nirmatrelvir-Ritonavir|
04030|002|B||
04030|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04030|004|L|take action as needed.|
04030|005|B||
04030|006|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the metabolism of|
04030|007|A|amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir,|
04030|008|A|nelfinavir, saquinavir, and tipranavir.(1-11)|
04030|009|B||
04030|010|E|CLINICAL EFFECTS:  Concurrent administration of nirmatrelvir-ritonavir with|
04030|011|E|amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir,|
04030|012|E|nelfinavir, saquinavir, and tipranavir may increase levels and toxicity of|
04030|013|E|the protease inhibitors.(1-11)|
04030|014|B||
04030|015|P|PREDISPOSING FACTORS:  None determined.|
04030|016|B||
04030|017|M|PATIENT MANAGEMENT:  The manufacturer of nirmatrelvir-ritonavir states that|
04030|018|M|no dose adjustment is needed when coadministered with other ritonavir- or|
04030|019|M|cobicistat-containing products.  Patients on ritonavir-boosted or|
04030|020|M|cobicistat-boosted HIV regimens should continue their HIV therapy while on|
04030|021|M|nirmatrelvir-ritonavir.  Monitor patients closely for adverse effects.(1,2)|
04030|022|B||
04030|023|D|DISCUSSION:  Nirmatrelvir-ritonavir is a strong CYP3A4 inhibitor and may|
04030|024|D|increase the levels of CYP3A4 substrates, including amprenavir, atazanavir,|
04030|025|D|darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, and|
04030|026|D|tipranavir.(1-11)|
04030|027|B||
04030|028|R|REFERENCES:|
04030|029|B||
04030|030|R|1.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04030|031|R|  information. Pfizer Inc. February, 2025.|1
04030|032|R|2.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
04030|033|R|  Monograph. Pfizer Canada ULC October, 2023.|1
04030|034|R|3.Agenerase (amprenavir) Capsules US prescribing information.|1
04030|035|R|  GlaxoSmithKline May, 2005.|1
04030|036|R|4.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04030|037|R|  Squibb Company December, 2024.|1
04030|038|R|5.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04030|039|R|  March, 2023.|1
04030|040|R|6.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
04030|041|R|  March, 2019.|1
04030|042|R|7.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
04030|043|R|  September, 2016.|1
04030|044|R|8.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04030|045|R|  Laboratories December, 2019.|1
04030|046|R|9.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
04030|047|R|  Pharmaceuticals, Inc. September, 2016.|1
04030|048|R|10.Invirase (saquinavir mesylate) US prescribing information. Roche|1
04030|049|R|   Laboratories, Inc. March, 2019.|1
04030|050|R|11.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04030|051|R|   Pharmaceuticals, Inc. April, 2024.|1
04031|001|T|MONOGRAPH TITLE:  Gilteritinib/Strong CYP3A4 Inhibitors|
04031|002|B||
04031|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04031|004|L|take action as needed.|
04031|005|B||
04031|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
04031|007|A|the metabolism of gilteritinib.(1)|
04031|008|B||
04031|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04031|010|E|the levels and effects of gilteritinib.(1)|
04031|011|E|   Elevated levels of gilteritinib may result in QTc prolongation, which may|
04031|012|E|result in potentially life-threatening cardiac arrhythmias, including|
04031|013|E|torsades de pointes (TdP).(1)|
04031|014|B||
04031|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04031|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04031|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04031|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04031|019|P|female gender, or advanced age.(2)|
04031|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04031|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04031|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04031|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04031|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04031|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04031|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04031|027|B||
04031|028|M|PATIENT MANAGEMENT:  The use of gilteritinib with strong CYP3A4 inhibitors|
04031|029|M|should be used with caution.  Consider alternatives with no or minimal|
04031|030|M|enzyme inhibition.  If concurrent use is warranted, monitor patients more|
04031|031|M|frequently for adverse reactions.  Interrupt and reduce gilteritinib dose if|
04031|032|M|toxicities occur.(1)|
04031|033|M|   If coadministration with a strong CYP3A4 inhibitor is unavoidable,|
04031|034|M|monitor for prolongation of the QTc interval.  When concurrent therapy is|
04031|035|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
04031|036|M|and monitoring EKG at baseline and regular intervals. Correct any|
04031|037|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04031|038|M|heartbeat, dizziness, or fainting.|
04031|039|B||
04031|040|D|DISCUSSION:  Itraconazole (a strong CYP3A4 inhibitor) increased maximum|
04031|041|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04031|042|D|gilteritinib by 20% and 1200%, respectively.(1)|
04031|043|D|   In the gilteritinib clinical trial, 1.4% of patients developed a QTc|
04031|044|D|interval greater than 500 msec and 7% of patients had an increase QTc|
04031|045|D|greater than 60 msec.(1)|
04031|046|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
04031|047|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
04031|048|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
04031|049|D|tipranavir, troleandomycin, and tucatinib.(3,4)|
04031|050|B||
04031|051|R|REFERENCES:|
04031|052|B||
04031|053|R|1.Xospata (gilteritinib) US Prescribing Information. Astellas Pharma US,|1
04031|054|R|  Inc. January, 2022.|1
04031|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04031|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04031|057|R|  settings: a scientific statement from the American Heart Association and|6
04031|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04031|059|R|  2;55(9):934-47.|6
04031|060|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04031|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04031|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04031|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04031|064|R|  11/14/2017.|1
04031|065|R|4.This information is based on an extract from the Certara Drug Interaction|6
04031|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04032|001|T|MONOGRAPH TITLE:  Gilteritinib/Strong CYP3A4 Inhibitors that Prolong QT|
04032|002|B||
04032|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04032|004|L|take action as needed.|
04032|005|B||
04032|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04032|007|A|interval may inhibit the metabolism of gilteritinib and result in additive|
04032|008|A|risk of QT prolongation.(1)|
04032|009|B||
04032|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04032|011|E|the QTc interval may increase the levels and effects of gilteritinib,|
04032|012|E|including additive QTc prolongation, which may result in potentially|
04032|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
04032|014|E|(TdP).(1)|
04032|015|B||
04032|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04032|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04032|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04032|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04032|020|P|female gender, or advanced age.(2)|
04032|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04032|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04032|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04032|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04032|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04032|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04032|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04032|028|B||
04032|029|M|PATIENT MANAGEMENT:  The use of gilteritinib with strong CYP3A4 inhibitors|
04032|030|M|should be used with caution.  Consider alternatives with no or minimal|
04032|031|M|enzyme inhibition.  If concurrent use is warranted, monitor patients more|
04032|032|M|frequently for adverse reactions.  Interrupt and reduce gilteritinib dose if|
04032|033|M|toxicities occur.(1)|
04032|034|M|   If coadministration with a strong CYP3A4 inhibitor is unavoidable,|
04032|035|M|monitor for prolongation of the QTc interval.  When concurrent therapy is|
04032|036|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
04032|037|M|and monitoring EKG at baseline and regular intervals. Correct any|
04032|038|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04032|039|M|heartbeat, dizziness, or fainting.|
04032|040|M|   Prior to initiation of therapy with gilteritinib, obtain baseline ECG and|
04032|041|M|on days 8 and 15 of cycle 1, and prior to the start of the next two|
04032|042|M|subsequent cycles.|
04032|043|M|   If QTc prolongation develops:|
04032|044|M|   ---Monitor and supplement electrolytes as clinically indicated|
04032|045|M|   ---Review and adjust concomitant QT prolonging medications|
04032|046|M|   For a QTc interval greater than 500 msec:|
04032|047|M|   ---Interrupt gilteritinib therapy|
04032|048|M|   ---Resume gilteritinib therapy at 80 mg when the QTc interval returns to|
04032|049|M|within 30 msec of baseline or <= 480 msec.|
04032|050|M|   For QTc interval increased by > 30 msec on ECG on Day 8 of cycle 1:|
04032|051|M|   ---Confirm with ECG on Day 9|
04032|052|M|   ---If confirmed, consider dose reduction to 80 mg.(1)|
04032|053|B||
04032|054|D|DISCUSSION:  Itraconazole (a strong CYP3A4 inhibitor) increased maximum|
04032|055|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04032|056|D|gilteritinib by 20% and 1200%, respectively.(1)|
04032|057|D|   In the gilteritinib clinical trial, 1.4% of patients developed a QTc|
04032|058|D|interval greater than 500 msec and 7% of patients had an increase QTc|
04032|059|D|greater than 60 msec.(1)|
04032|060|D|   Agents that are linked to this monograph may have varying degrees of|
04032|061|D|potential to prolong the QTc interval but are generally accepted to have a|
04032|062|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04032|063|D|been shown to prolong the QTc interval either through their mechanism of|
04032|064|D|action, through studies on their effects on the QTc interval, or through|
04032|065|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04032|066|D|and/or post-marketing reports.(5)|
04032|067|D|   Strong inhibitors of CYP3A4 that prolong QT include: ceritinib,|
04032|068|D|clarithromycin, lonafarnib, lopinavir, ribociclib, saquinavir,|
04032|069|D|telithromycin, and voriconazole.(3,4)|
04032|070|B||
04032|071|R|REFERENCES:|
04032|072|B||
04032|073|R|1.Xospata (gilteritinib) US Prescribing Information. Astellas Pharma US,|1
04032|074|R|  Inc. January, 2022.|1
04032|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04032|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04032|077|R|  settings: a scientific statement from the American Heart Association and|6
04032|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04032|079|R|  2;55(9):934-47.|6
04032|080|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04032|081|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04032|082|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04032|083|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04032|084|R|  11/14/2017.|1
04032|085|R|4.This information is based on an extract from the Certara Drug Interaction|6
04032|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04032|087|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04032|088|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04032|089|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04032|090|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04033|001|T|MONOGRAPH TITLE:  Gilteritinib/Slt Strong CYP3A4 Inhibitors that Prolong QT|
04033|002|B||
04033|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04033|004|L|of severe adverse interaction.|
04033|005|B||
04033|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04033|007|A|interval may inhibit the metabolism of gilteritinib and result in additive|
04033|008|A|risk of QT prolongation.(1)|
04033|009|B||
04033|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04033|011|E|the QTc interval may increase the levels and effects of gilteritinib,|
04033|012|E|including additive QTc prolongation, which may result in potentially|
04033|013|E|life-threatening cardiac arrhythmias, including torsades de pointes|
04033|014|E|(TdP).(1)|
04033|015|B||
04033|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04033|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04033|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04033|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04033|020|P|female gender, or advanced age.(2)|
04033|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04033|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04033|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04033|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04033|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04033|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04033|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04033|028|B||
04033|029|M|PATIENT MANAGEMENT:  The use of gilteritinib with strong CYP3A4 inhibitors|
04033|030|M|should be used with caution.  Consider alternatives with no or minimal|
04033|031|M|enzyme inhibition.  If concurrent use is warranted, monitor patients more|
04033|032|M|frequently for adverse reactions.  Interrupt and reduce gilteritinib dose if|
04033|033|M|toxicities occur.(1)|
04033|034|M|   If coadministration with a strong CYP3A4 inhibitor is unavoidable,|
04033|035|M|monitor for prolongation of the QTc interval.  When concurrent therapy is|
04033|036|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
04033|037|M|and monitoring EKG at baseline and regular intervals. Correct any|
04033|038|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04033|039|M|heartbeat, dizziness, or fainting.|
04033|040|M|   Prior to initiation of therapy with gilteritinib, obtain baseline ECG and|
04033|041|M|on days 8 and 15 of cycle 1, and prior to the start of the next two|
04033|042|M|subsequent cycles.|
04033|043|M|   If QTc prolongation develops:|
04033|044|M|   ---Monitor and supplement electrolytes as clinically indicated|
04033|045|M|   ---Review and adjust concomitant QT prolonging medications|
04033|046|M|   For a QTc interval greater than 500 msec:|
04033|047|M|   ---Interrupt gilteritinib therapy|
04033|048|M|   ---Resume gilteritinib therapy at 80 mg when the QTc interval returns to|
04033|049|M|within 30 msec of baseline or <= 480 msec.|
04033|050|M|   For QTc interval increased by > 30 msec on ECG on Day 8 of cycle 1:|
04033|051|M|   ---Confirm with ECG on Day 9|
04033|052|M|   ---If confirmed, consider dose reduction to 80 mg.(1)|
04033|053|B||
04033|054|D|DISCUSSION:  Itraconazole (a strong CYP3A4 inhibitor) increased maximum|
04033|055|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04033|056|D|gilteritinib by 20% and 1200%, respectively.(1)|
04033|057|D|   In the gilteritinib clinical trial, 1.4% of patients developed a QTc|
04033|058|D|interval greater than 500 msec and 7% of patients had an increase QTc|
04033|059|D|greater than 60 msec.(1)|
04033|060|D|   Agents that are linked to this monograph may have varying degrees of|
04033|061|D|potential to prolong the QTc interval but are generally accepted to have a|
04033|062|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04033|063|D|been shown to prolong the QTc interval either through their mechanism of|
04033|064|D|action, through studies on their effects on the QTc interval, or through|
04033|065|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04033|066|D|and/or post-marketing reports.(5)|
04033|067|D|   Strong inhibitors of CYP3A4 that prolong QT include:  adagrasib,|
04033|068|D|levoketoconazole, and posaconazole.(3,4)|
04033|069|B||
04033|070|R|REFERENCES:|
04033|071|B||
04033|072|R|1.Xospata (gilteritinib) US Prescribing Information. Astellas Pharma US,|1
04033|073|R|  Inc. January, 2022.|1
04033|074|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04033|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04033|076|R|  settings: a scientific statement from the American Heart Association and|6
04033|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04033|078|R|  2;55(9):934-47.|6
04033|079|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04033|080|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04033|081|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04033|082|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04033|083|R|  11/14/2017.|1
04033|084|R|4.This information is based on an extract from the Certara Drug Interaction|6
04033|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04033|086|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04033|087|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04033|088|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04033|089|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04034|001|T|MONOGRAPH TITLE:  Pramlintide/Gastric Stimulants|
04034|002|B||
04034|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04034|004|L|is contraindicated and generally should not be dispensed or administered to|
04034|005|L|the same patient.|
04034|006|B||
04034|007|A|MECHANISM OF ACTION:  Pramlintide slows gastric emptying. Gastric stimulants|
04034|008|A|may result in decreased effects.(1)|
04034|009|B||
04034|010|E|CLINICAL EFFECTS:  Concurrent use of pramlintide and use of gastric|
04034|011|E|stimulants may result in decreased effects of both agents.(1)|
04034|012|B||
04034|013|P|PREDISPOSING FACTORS:  None determined.|
04034|014|B||
04034|015|M|PATIENT MANAGEMENT:  The manufacturer of pramlintide states that pramlintide|
04034|016|M|therapy should not be considered in patients requiring the use of drugs that|
04034|017|M|stimulate gastrointestinal motility.(1)|
04034|018|B||
04034|019|D|DISCUSSION:  Patients using drugs that alter gastrointestinal motility have|
04034|020|D|not been studied in clinical trials for pramlintide.(1)|
04034|021|B||
04034|022|R|REFERENCE:|
04034|023|B||
04034|024|R|1.Symlin (pramlintide acetate) US prescribing information. Amylin|1
04034|025|R|  Pharmaceuticals Inc. March, 2005.|1
04035|001|T|MONOGRAPH TITLE:  Etravirine/Tipranavir|
04035|002|B||
04035|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04035|004|L|is contraindicated and generally should not be dispensed or administered to|
04035|005|L|the same patient.|
04035|006|B||
04035|007|A|MECHANISM OF ACTION:  Tipranavir may induce the CYP2C19 and CYP3A4|
04035|008|A|metabolism of etravirine.(1)|
04035|009|B||
04035|010|E|CLINICAL EFFECTS:  Concurrent use of tipranavir may decrease etravirine|
04035|011|E|levels and result in sub-therapeutic levels of etravirine and the|
04035|012|E|development of resistance to etravirine.(1)|
04035|013|B||
04035|014|P|PREDISPOSING FACTORS:  None determined.|
04035|015|B||
04035|016|M|PATIENT MANAGEMENT:  The US manufacturer of etravirine states that it should|
04035|017|M|not be coadministered with tipranavir/ritonavir.(1)|
04035|018|B||
04035|019|D|DISCUSSION:  In a study in 19 subjects, concurrent tipranavir/ritonavir|
04035|020|D|(500/200 mg twice daily) decreased etravirine concentration maximum (Cmax),|
04035|021|D|area-under-curve (AUC), and concentration minimum (Cmin) by 71%, 76%, and|
04035|022|D|82%, respectively.  Tipranavir Cmax, AUC, and Cmin increased by 14%, 18%,|
04035|023|D|and 24%, respectively.(1)|
04035|024|B||
04035|025|R|REFERENCE:|
04035|026|B||
04035|027|R|1.Intelence (etravirine) US prescribing information. Janssen Pharmaceuticals|1
04035|028|R|  August, 2014.|1
04036|001|T|MONOGRAPH TITLE:  Selected Steroids/Selected Strong CYP3A4 Inhibitors|
04036|002|B||
04036|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04036|004|L|of severe adverse interaction.|
04036|005|B||
04036|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04036|007|A|corticosteroids metabolized by CYP3A4.|
04036|008|B||
04036|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04036|010|E|increased systemic exposure to and effects from corticosteroids metabolized|
04036|011|E|by CYP3A4, including Cushing's syndrome and adrenal suppression.|
04036|012|B||
04036|013|P|PREDISPOSING FACTORS:  None determined.|
04036|014|B||
04036|015|M|PATIENT MANAGEMENT:  If possible, avoid concurrent therapy between|
04036|016|M|betamethasone, budesonide, ciclesonide, fluticasone, dexamethasone,|
04036|017|M|methylprednisolone, or triamcinolone and strong CYP3A4 inhibitors.|
04036|018|M|Alternative corticosteroids that are less affected by CYP3A4 inhibitors|
04036|019|M|should be considered, like beclomethasone, prednisone, and prednisolone.  If|
04036|020|M|concurrent therapy is warranted, patients should be closely monitored for|
04036|021|M|systemic effects.  The corticosteroid may need to be discontinued.|
04036|022|B||
04036|023|D|DISCUSSION:  In a study, boceprevir (800 mg TID for 7 days) increased the|
04036|024|D|area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%.  The|
04036|025|D|maximum concentration (Cmax) and AUC of prednisolone increased by 16% and|
04036|026|D|37%, respectively.(3)|
04036|027|D|   A study of 14 healthy adults found that concurrent use of ketoconazole|
04036|028|D|with ciclesonide increased the AUC of ciclesonide's active metabolite,|
04036|029|D|des-ciclesonide, by approximately 3.6-fold at steady state, while levels of|
04036|030|D|ciclesonide remained unchanged.  However, the study concluded that no dosage|
04036|031|D|adjustments were required because ciclesonide has a very low potential to|
04036|032|D|cause side effects.(4)|
04036|033|D|   A study in 18 healthy subjects examined the effects of ritonavir (100 mg|
04036|034|D|twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects,|
04036|035|D|fluticasone was undetectable (<10 pg/ml) when administered alone.  In|
04036|036|D|subjects in whom fluticasone was detectable when given alone, Cmax and|
04036|037|D|area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively.|
04036|038|D|With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml|
04036|039|D|and 3102.6 pg x hr/ml, respectively.(6-8) This reflects increases in Cmax|
04036|040|D|and AUC by 25-fold and 350-fold, respectively.(6)  The cortisol AUC|
04036|041|D|decreased by 86%.(10-13)|
04036|042|D|   In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4|
04036|043|D|and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold|
04036|044|D|and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(14)|
04036|045|D|   There have been several case reports of Cushing's syndrome in patients|
04036|046|D|treated concurrently with ritonavir and inhaled budesonide,(15-16)|
04036|047|D|dexamethasone,(17) injectable triamcinolone,(18-21) nasal|
04036|048|D|fluticasone.(23-41)  Hepatitis has also been reported with concurrent|
04036|049|D|budesonide and ritonavir.(42)|
04036|050|D|   In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3|
04036|051|D|days) increased the AUC, Cmax, and elimination half-life of|
04036|052|D|methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(43)|
04036|053|D|   In a study in 8 healthy subjects, following nefazodone administration the|
04036|054|D|following changes were seen with methylprednisolone: mean (+/-SD) area under|
04036|055|D|the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966|
04036|056|D|+/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs.|
04036|057|D|14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was|
04036|058|D|longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(44)|
04036|059|D|   Selected steroids linked to this monograph include: betamethasone,|
04036|060|D|budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, and|
04036|061|D|triamcinolone.(45)|
04036|062|D|   Selected CYP3A4 inhibitors linked to this monograph include: adagrasib,|
04036|063|D|boceprevir, ceritinib, lonafarnib, mibefradil, nefazodone, ribociclib,|
04036|064|D|paritaprevir, telaprevir, and tucatinib.(1-2,45)|
04036|065|B||
04036|066|R|REFERENCES:|
04036|067|B||
04036|068|R|1.Serzone (nefazodone hydrochloride) US prescribing information.|1
04036|069|R|  Bristol-Myers Squibb Company January, 2005.|1
04036|070|R|2.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
04036|071|R|  Corporation September, 2024.|1
04036|072|R|3.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
04036|073|R|  January, 2017.|1
04036|074|R|4.Bohmer GM, Drollmann A, Gleiter CH, Nave R. Effect of coadministered|2
04036|075|R|  ketoconazole, a strong cytochrome P450 3A4 enzyme inhibitor, on the|2
04036|076|R|  pharmacokinetics of ciclesonide and its active metabolite|2
04036|077|R|  desisobutyryl-ciclesonide. Clin Pharmacokinet 2008;47(5):343-9.|2
04036|078|R|5.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
04036|079|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
04036|080|R|6.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04036|081|R|  Laboratories December, 2019.|1
04036|082|R|7.Invirase (saquinavir mesylate) US prescribing information. Roche|1
04036|083|R|  Laboratories, Inc. March, 2019.|1
04036|084|R|8.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04036|085|R|  Pharmaceuticals, Inc. April, 2024.|1
04036|086|R|9.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
04036|087|R|  September, 2016.|1
04036|088|R|10.Flovent HFA inhalation (fluticasone propionate) US prescribing|1
04036|089|R|   information. GlaxoSmithKline January, 2019.|1
04036|090|R|11.Flovent Rotadisk (fluticasone propionate) US prescribing information.|1
04036|091|R|   GlaxoSmithKline March, 2004.|1
04036|092|R|12.Flonase Nasal Spray (fluticasone propionate) US prescribing information.|1
04036|093|R|   GlaxoSmithKline January, 2019.|1
04036|094|R|13.Flovent Diskus (fluticasone propionate) US prescribing information.|1
04036|095|R|   GlaxoSmithKline January, 2019.|1
04036|096|R|14.Penzak SR, Formentini E, Alfaro RM, Long M, Natarajan V, Kovacs J.|2
04036|097|R|   Prednisolone pharmacokinetics in the presence and absence of ritonavir|2
04036|098|R|   after oral prednisone administration to healthy volunteers. J Acquir|2
04036|099|R|   Immune Defic Syndr 2005 Dec 15;40(5):573-80.|2
04036|100|R|15.Kedem E, Shahar E, Hassoun G, Pollack S. Iatrogenic Cushing's syndrome|3
04036|101|R|   due to coadministration of ritonavir and inhaled budesonide in an|3
04036|102|R|   asthmatic human immunodeficiency virus infected patient. J Asthma 2010|3
04036|103|R|   Sep;47(7):830-1.|3
04036|104|R|16.Gray D, Roux P, Carrihill M, Klein M. Adrenal suppression and Cushing's|3
04036|105|R|   syndrome secondary to ritonavir and budesonide. S Afr Med J 2010 May;|3
04036|106|R|   100(5):296-7.|3
04036|107|R|17.Ebright JR, Stellini MA, Tselis AC. Spinal epidural lipomatosis in a|3
04036|108|R|   human immunodeficiency virus-positive patient receiving steroids and|3
04036|109|R|   protease inhibitor therapy. Clin Infect Dis 2001 Mar 1;32(5):E90-1.|3
04036|110|R|18.Herold MA, Gunthard HF. Cushing syndrome after steroid-infiltration in|3
04036|111|R|   two HIV-patients with antiretroviral therapy. Praxis (Bern 1994) 2010 Jul|3
04036|112|R|   7;99(14):863-5.|3
04036|113|R|19.Danaher PJ, Salsbury TL, Delmar JA. Metabolic derangement after injection|3
04036|114|R|   of triamcinolone into the hip of an HIV-infected patient receiving|3
04036|115|R|   ritonavir. Orthopedics 2009 Jun;32(6):450.|3
04036|116|R|20.Dort K, Padia S, Wispelwey B, Moore CC. Adrenal suppression due to an|3
04036|117|R|   interaction between ritonavir and injected triamcinolone: a case report.|3
04036|118|R|   AIDS Res Ther 2009;6:10.|3
04036|119|R|21.Ramanathan R, Pau AK, Busse KH, Zemskova M, Nieman L, Kwan R, Hammer JH,|3
04036|120|R|   Mican JM, Maldarelli F. Iatrogenic Cushing syndrome after epidural|3
04036|121|R|   triamcinolone injections in an HIV type 1-infected patient receiving|3
04036|122|R|   therapy with ritonavir-lopinavir. Clin Infect Dis 2008 Dec 15;|3
04036|123|R|   47(12):e97-9.|3
04036|124|R|22.Yombi JC, Maiter D, Belkhir L, Nzeusseu A, Vandercam B. Iatrogenic|3
04036|125|R|   Cushing's syndrome and secondary adrenal insufficiency after a single|3
04036|126|R|   intra-articular administration of triamcinolone acetonide in HIV-infected|3
04036|127|R|   patients treated with ritonavir. Clin Rheumatol 2008 Dec;27 Suppl|3
04036|128|R|   2:S79-82.|3
04036|129|R|23.Rouanet I, Peyriere H, Mauboussin JM, Vincent D. Cushing's syndrome in a|3
04036|130|R|   patient treated by ritonavir/lopinavir and inhaled fluticasone. HIV Med|3
04036|131|R|   2003 Apr;4(2):149-50.|3
04036|132|R|24.Clevenbergh P, Corcostegui M, Gerard D, Hieronimus S, Mondain V,|3
04036|133|R|   Chichmanian RM, Sadoul JL, Dellamonica P. Iatrogenic Cushing's syndrome|3
04036|134|R|   in an HIV-infected patient treated with inhaled corticosteroids|3
04036|135|R|   (fluticasone propionate) and low dose ritonavir enhanced PI containing|3
04036|136|R|   regimen. J Infect 2002 Apr;44(3):194-5.|3
04036|137|R|25.Chen F, Kearney T, Robinson S, Daley-Yates PT, Waldron S, Churchill DR.|3
04036|138|R|   Cushing's syndrome and severe adrenal suppression in patients treated|3
04036|139|R|   with ritonavir and inhaled nasal fluticasone. Sex Transm Infect 1999 Aug;|3
04036|140|R|   75(4):274.|3
04036|141|R|26.Hillebrand-Haverkort ME, Prummel MF, ten Veen JH. Ritonavir-induced|3
04036|142|R|   Cushing's syndrome in a patient treated with nasal fluticasone. AIDS 1999|3
04036|143|R|   Sep 10;13(13):1803.|3
04036|144|R|27.Dupont C, Giraud V, Leporrier J, Greffe S, Rouveix E, Chinet T. Cushing's|3
04036|145|R|   syndrome induced by combined treatment with inhaled fluticasone and oral|3
04036|146|R|   ritonavir. Rev Mal Respir 2009 Sep;26(7):779-82.|3
04036|147|R|28.Collet-Gaudillat C, Roussin-Bretagne S, Desforges-Bullet V, Petit-Aubert|3
04036|148|R|   G, Doll J, Beressi JP. Iatrogenic Cushing's syndrome, diabetes mellitus|3
04036|149|R|   and secondary adrenal failure in a human immunodeficiency virus patient|3
04036|150|R|   treated with ritonavir boosted atazanavir and fluticasone. Ann Endocrinol|3
04036|151|R|   (Paris) 2009 Sep;70(4):252-5.|3
04036|152|R|29.Valin N, De Castro N, Garrait V, Bergeron A, Bouche C, Molina JM.|3
04036|153|R|   Iatrogenic Cushing's syndrome in HIV-infected patients receiving|3
04036|154|R|   ritonavir and inhaled fluticasone: description of 4 new cases and review|3
04036|155|R|   of the literature. J Int Assoc Physicians AIDS Care (Chic) 2009 Mar-Apr;|3
04036|156|R|   8(2):113-21.|3
04036|157|R|30.Bouldouyre MA, Moachon L, Guillevin L, Launay O. Iatrogenic Cushing|3
04036|158|R|   syndrome in an HIV-infected female patient: be careful about interaction|3
04036|159|R|   inhaled corticosteroids-ritonavir!. Presse Med 2008 Dec;37(12):1834-5.|3
04036|160|R|31.Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and|3
04036|161|R|   Cushing's syndrome secondary to an interaction between ritonavir and|3
04036|162|R|   fluticasone: a review of the literature. HIV Med 2008 Jul;9(6):389-96.|3
04036|163|R|32.Jinno S, Goshima C. Progression of Kaposi sarcoma associated with|3
04036|164|R|   iatrogenic Cushing syndrome in a person with HIV/AIDS. AIDS Read 2008|3
04036|165|R|   Feb;18(2):100-4.|3
04036|166|R|33.St Germain RM, Yigit S, Wells L, Girotto JE, Salazar JC. Cushing syndrome|3
04036|167|R|   and severe adrenal suppression caused by fluticasone and protease|3
04036|168|R|   inhibitor combination in an HIV-infected adolescent. AIDS Patient Care|3
04036|169|R|   STDS 2007 Jun;21(6):373-7.|3
04036|170|R|34.Bhumbra NA, Sahloff EG, Oehrtman SJ, Horner JM. Exogenous Cushing|3
04036|171|R|   syndrome with inhaled fluticasone in a child receiving|3
04036|172|R|   lopinavir/ritonavir. Ann Pharmacother 2007 Jul;41(7):1306-9.|3
04036|173|R|35.Pessanha TM, Campos JM, Barros AC, Pone MV, Garrido JR, Pone SM.|3
04036|174|R|   Iatrogenic Cushing's syndrome in a adolescent with AIDSs on ritonavir and|3
04036|175|R|   inhaled fluticasone. Case report and literature review. AIDS 2007 Feb 19;|3
04036|176|R|   21(4):529-32.|3
04036|177|R|36.Arrington-Sanders R, Hutton N, Siberry GK. Ritonavir-fluticasone|3
04036|178|R|   interaction causing Cushing syndrome in HIV-infected children and|3
04036|179|R|   adolescents. Pediatr Infect Dis J 2006 Nov;25(11):1044-8.|3
04036|180|R|37.Johnson SR, Marion AA, Vrchoticky T, Emmanuel PJ, Lujan-Zilbermann J.|3
04036|181|R|   Cushing syndrome with secondary adrenal insufficiency from concomitant|3
04036|182|R|   therapy with ritonavir and fluticasone. J Pediatr 2006 Mar;148(3):386-8.|3
04036|183|R|38.Gillett MJ, Cameron PU, Nguyen HV, Hurley DM, Mallal SA. Iatrogenic|3
04036|184|R|   Cushing's syndrome in an HIV-infected patient treated with ritonavir and|3
04036|185|R|   inhaled fluticasone. AIDS 2005 Apr 29;19(7):740-1.|3
04036|186|R|39.Samaras K, Pett S, Gowers A, McMurchie M, Cooper DA. Iatrogenic Cushing's|3
04036|187|R|   syndrome with osteoporosis and secondary adrenal failure in human|3
04036|188|R|   immunodeficiency virus-infected patients receiving inhaled|3
04036|189|R|   corticosteroids and ritonavir-boosted protease inhibitors: six cases. J|3
04036|190|R|   Clin Endocrinol Metab 2005 Jul;90(7):4394-8.|3
04036|191|R|40.Soldatos G, Sztal-Mazer S, Woolley I, Stockigt J. Exogenous|3
04036|192|R|   glucocorticoid excess as a result of ritonavir-fluticasone interaction.|3
04036|193|R|   Intern Med J 2005 Jan;35(1):67-8.|3
04036|194|R|41.Gupta SK, Dube MP. Exogenous cushing syndrome mimicking human|3
04036|195|R|   immunodeficiency virus lipodystrophy. Clin Infect Dis 2002 Sep 15;|3
04036|196|R|   35(6):E69-71.|3
04036|197|R|42.Sagir A, Wettstein M, Oette M, Erhardt A, Haussinger D.|3
04036|198|R|   Budesonide-induced acute hepatitis in an HIV-positive patient with|3
04036|199|R|   ritonavir as a co-medication. AIDS 2002 May 24;16(8):1191-2.|3
04036|200|R|43.Varis T, Backman JT, Kivisto KT, Neuvonen PJ. Diltiazem and mibefradil|2
04036|201|R|   increase the plasma concentrations and greatly enhance the|2
04036|202|R|   adrenal-suppressant effect of oral methylprednisolone. Clin Pharmacol|2
04036|203|R|   Ther 2000 Mar;67(3):215-21.|2
04036|204|R|44.Kotlyar M, Brewer ER, Golding M, Carson SW. Nefazodone inhibits|2
04036|205|R|   methylprednisolone disposition and enhances its adrenal-suppressant|2
04036|206|R|   effect. J Clin Psychopharmacol 2003 Dec;23(6):652-6.|2
04036|207|R|45.This information is based on an extract from the Certara Drug Interaction|6
04036|208|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04037|001|T|MONOGRAPH TITLE:  Caplacizumab/Anticoagulants; Antiplatelets|
04037|002|B||
04037|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04037|004|L|of severe adverse interaction.|
04037|005|B||
04037|006|A|MECHANISM OF ACTION:  Bleeding has been reported with the use of|
04037|007|A|caplacizumab.(1)|
04037|008|B||
04037|009|E|CLINICAL EFFECTS:  Concurrent use of caplacizumab with either anticoagulants|
04037|010|E|or antiplatelets may increase the risk of hemorrhage.(1)|
04037|011|B||
04037|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04037|013|P|patients with disease-associated factors (e.g. hemophilia, coagulation|
04037|014|P|factor deficiencies).|
04037|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
04037|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04037|017|P|risk for bleeding (e.g. NSAIDs).|
04037|018|B||
04037|019|M|PATIENT MANAGEMENT:  Avoid the use of caplacizumab with anticoagulants and|
04037|020|M|antiplatelets.  Interrupt caplacizumab therapy if clinically significant|
04037|021|M|bleeding occurs.  Patients may require von Willebrand factor concentrate to|
04037|022|M|rapidly correct hemostasis.  If caplacizumab is restarted, closely monitor|
04037|023|M|for signs of bleeding.(1)|
04037|024|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04037|025|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04037|026|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04037|027|M|patients with any symptoms.|
04037|028|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
04037|029|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04037|030|M|anticoagulation in patients with active pathologic bleeding.|
04037|031|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04037|032|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04037|033|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04037|034|M|and/or swelling.|
04037|035|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04037|036|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
04037|037|M|before initiating, altering the dose or discontinuing either drug.|
04037|038|B||
04037|039|D|DISCUSSION:  Bleeding has been reported with caplacizumab.  In clinical|
04037|040|D|studies, severe bleeding adverse reactions of epistaxis, gingival bleeding,|
04037|041|D|upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1%|
04037|042|D|of patients.  Overall, bleeding events occurred in approximately 58% of|
04037|043|D|patients on caplacizumab versus 43% of patients on placebo.(1)|
04037|044|D|   In post-marketing reports, cases of life-threatening and fatal bleeding|
04037|045|D|were reported with caplacizumab.(1)|
04037|046|B||
04037|047|R|REFERENCE:|
04037|048|B||
04037|049|R|1.Cablivi (caplacizumab) US prescribing information. Genzyme Corporation|1
04037|050|R|  February, 2022.|1
04038|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP2B6 Substrates/Lemborexant|
04038|002|B||
04038|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04038|004|L|take action as needed.|
04038|005|B||
04038|006|A|MECHANISM OF ACTION:  Lemborexant may induce the metabolism of CYP2B6|
04038|007|A|substrates.(1)|
04038|008|B||
04038|009|E|CLINICAL EFFECTS:  Concurrent lemborexant may result in decreased levels of|
04038|010|E|sensitive CYP2B6 substrates, which may result in a decrease in or failure of|
04038|011|E|clinical response.(1,2)|
04038|012|B||
04038|013|P|PREDISPOSING FACTORS:  None determined.|
04038|014|B||
04038|015|M|PATIENT MANAGEMENT:  The US manufacturer of lemborexant recommends close|
04038|016|M|monitoring of patients who receive lemborexant with CYP2B6 substrates.|
04038|017|M|Monitor patients receiving concurrent lemborexant for an adequate clinical|
04038|018|M|response.  The dosage of the CYP2B6 substrate may need to be adjusted.(1,2)|
04038|019|M|An alternative agent may need to be selected.|
04038|020|B||
04038|021|D|DISCUSSION:  In a study, lemborexant (10 mg dose) decreased the|
04038|022|D|concentration maximum (Cmax) and area-under-curve (AUC) of a S-bupropion by|
04038|023|D|49.9% and 45.5%, respectively.(1)|
04038|024|D|   Sensitive CYP2B6 substrates linked to this monograph include: bupropion|
04038|025|D|and esketamine.(3,4)|
04038|026|B||
04038|027|R|REFERENCES:|
04038|028|B||
04038|029|R|1.Dayvigo (lemborexant) US prescribing information. Eisai Inc. March, 2022.|1
04038|030|R|2.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
04038|031|R|  GlaxoSmithKline November, 2019.|1
04038|032|R|3.This information is based on an extract from the Certara Drug Interaction|6
04038|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04038|034|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04038|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04038|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04038|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04038|038|R|  11/14/2017.|1
04039|001|T|MONOGRAPH TITLE:  Triclabendazole/QT Prolonging Agents|
04039|002|B||
04039|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04039|004|L|take action as needed.|
04039|005|B||
04039|006|A|MECHANISM OF ACTION:  Triclabendazole has been observed to prolong the QTc|
04039|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04039|008|A|may result in additive effects on the QTc interval.(1) Triclabendazole is|
04039|009|A|partially metabolized by CYP1A2. Ciprofloxacin, propafenone, and vemurafenib|
04039|010|A|are CYP1A2 inhibitors and may inhibit the CYP1A2 mediated metabolism of|
04039|011|A|triclabendazole.|
04039|012|B||
04039|013|E|CLINICAL EFFECTS:  The concurrent use of triclabendazole with other agents|
04039|014|E|that prolong the QTc interval may result in potentially life-threatening|
04039|015|E|cardiac arrhythmias, including torsades de pointes.(1)|
04039|016|B||
04039|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04039|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04039|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04039|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04039|021|P|female gender, or advanced age.(2)|
04039|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04039|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04039|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04039|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04039|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04039|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04039|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04039|029|P|Hepatic impairment and concurrent use of CYP1A2 inhibitors may raise|
04039|030|P|triclabendazole levels and increase the risk of QT prolongation.(1)|
04039|031|B||
04039|032|M|PATIENT MANAGEMENT:  The manufacturer of triclabendazole states concurrent|
04039|033|M|use with agents known to prolong the QT interval should be used with|
04039|034|M|caution.  Monitor ECG in patients with a history of QTc prolongation,|
04039|035|M|symptoms of long QT interval, electrolyte imbalances, concurrent CYP1A2|
04039|036|M|inhibitors, or hepatic impairment.  If signs of a cardiac arrhythmia|
04039|037|M|develop, stop treatment with triclabendazole and monitor ECG.(1)|
04039|038|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04039|039|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04039|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04039|041|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04039|042|B||
04039|043|D|DISCUSSION:  In a thorough QT study, a dose-dependent prolongation in the|
04039|044|D|QTc interval was observed with triclabendazole. The largest|
04039|045|D|placebo-corrected mean increase in QTc was 9.2 msec (upper limit of|
04039|046|D|confidence interval (UCI): 12.2 msec) following oral administration of 10|
04039|047|D|mg/kg triclabendazole twice daily (at the recommended dose), and the largest|
04039|048|D|placebo-corrected mean increase in QTc was 21.7 msec (UCI: 24.7 msec)|
04039|049|D|following oral administration of 10 mg/kg triclabendazole twice daily for 3|
04039|050|D|days (3 times the approved recommended dosing duration).(1)|
04039|051|D|   Agents that are linked to this monograph may have varying degrees of|
04039|052|D|potential to prolong the QTc interval but are generally accepted to have a|
04039|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04039|054|D|been shown to prolong the QTc interval either through their mechanism of|
04039|055|D|action, through studies on their effects on the QTc interval, or through|
04039|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04039|057|D|and/or post-marketing reports.(3)|
04039|058|B||
04039|059|R|REFERENCES:|
04039|060|B||
04039|061|R|1.Egaten (triclabendazole) US precribing information. Novartis Feburary,|1
04039|062|R|  2022.|1
04039|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04039|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04039|065|R|  settings: a scientific statement from the American Heart Association and|6
04039|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04039|067|R|  2;55(9):934-47.|6
04039|068|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04039|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04039|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04039|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04040|001|T|MONOGRAPH TITLE:  Alpelisib/Strong CYP3A4 Inducers|
04040|002|B||
04040|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04040|004|L|of severe adverse interaction.|
04040|005|B||
04040|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04040|007|A|metabolism of alpelisib.(1,2)|
04040|008|B||
04040|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04040|010|E|levels and effectiveness of alpelisib.(1,2)|
04040|011|B||
04040|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04040|013|P|of the inducer for longer than 1-2 weeks.|
04040|014|B||
04040|015|M|PATIENT MANAGEMENT:  The manufacturer of alpelisib states the use of strong|
04040|016|M|CYP3A4 inducers in patients receiving therapy with alpelisib should be|
04040|017|M|avoided.  Consider the use of alternative agents with less enzyme induction|
04040|018|M|potential.(1,2)|
04040|019|B||
04040|020|D|DISCUSSION:  In a study, rifampin, a strong CYP3A4 inducer, decreased the|
04040|021|D|maximum concentration (Cmax) and area-under-curve (AUC) of single-dose|
04040|022|D|alpelisib (300 mg) by 38% and 57%, respectively, and of multiple doses of|
04040|023|D|alpelisib (300 mg) by 59% and 74%, respectively.(1)|
04040|024|D|    Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04040|025|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04040|026|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04040|027|D|rifampin, rifapentine, and St. John's wort.(3,4)|
04040|028|B||
04040|029|R|REFERENCES:|
04040|030|B||
04040|031|R|1.Piqray (alpelisib) US prescribing information. Novartis Pharmaceuticals|1
04040|032|R|  Corporation January, 2024.|1
04040|033|R|2.Vijoice (alpelisib) US prescribing information. Novartis Pharmaceuticals|1
04040|034|R|  Corporation April, 2022.|1
04040|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04040|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04040|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04040|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04040|039|R|  11/14/2017.|1
04040|040|R|4.This information is based on an extract from the Certara Drug Interaction|6
04040|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04041|001|T|MONOGRAPH TITLE:  Dofetilide/Cephalexin|
04041|002|B||
04041|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04041|004|L|is contraindicated and generally should not be dispensed or administered to|
04041|005|L|the same patient.|
04041|006|B||
04041|007|A|MECHANISM OF ACTION:  Dofetilide is primarily excreted in the urine via both|
04041|008|A|glomerular filtration and active tubular secretion via the cation transport|
04041|009|A|system.  Cephalexin may inhibit the excretion of dofetilide by the renal|
04041|010|A|cation transport system.(1)|
04041|011|B||
04041|012|E|CLINICAL EFFECTS:  Concurrent use of dofetilide with cephalexin may result|
04041|013|E|in increased levels of and toxicities of dofetilide, including potentially|
04041|014|E|life-threatening cardiac arrhythmias, like torsades de pointes (TdP).(1,2)|
04041|015|B||
04041|016|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
04041|017|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
04041|018|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
04041|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
04041|020|P|concurrent use of agents known to cause QT prolongation.(2)|
04041|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04041|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04041|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04041|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04041|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04041|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04041|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04041|028|P|   Renal impairment may increase risk for excessive QTc prolongation as|
04041|029|P|dofetilide is primarily renally eliminated. To prevent increased serum|
04041|030|P|levels and risk for ventricular arrhythmias, dofetilide must be dose|
04041|031|P|adjusted for creatinine clearance < or = to 60 mL/min.(1)|
04041|032|B||
04041|033|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that all renal|
04041|034|M|cation transport inhibitors are contraindicated.(1)   If dofetilide is to be|
04041|035|M|discontinued, a washout of at least 2 days is recommended prior to starting|
04041|036|M|cephalexin.(1)|
04041|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04041|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04041|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04041|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04041|041|B||
04041|042|D|DISCUSSION:  While the combination of dofetilide and cephalexin has not been|
04041|043|D|studied, clinical data is available for the combination of dofetilide with|
04041|044|D|other renal transport inhibitors, and for cephalexin with other renal|
04041|045|D|transport substrates.|
04041|046|D|   In a study, cephalexin 500 mg with metformin 500 mg increased the mean|
04041|047|D|metformin concentration maximum (Cmax) and area-under-curve (AUC) by an|
04041|048|D|average of 34% and 24%, respectively, and metformin mean renal clearance|
04041|049|D|decreased by 14%.  Metformin is a MATE and OCT2 substrate.(3)|
04041|050|D|   Dofetilide is primarily excreted in the urine via both glomerular|
04041|051|D|filtration and active tubular secretion via the cation transport system.|
04041|052|D|The concurrent administration of dofetilide (500 mcg twice daily) with|
04041|053|D|cimetidine (a MATE and OCT2 inhibitor)(400 mg twice daily) resulted in an|
04041|054|D|increase in dofetilide plasma levels by 58%.  The concurrent administration|
04041|055|D|of dofetilide (500 mcg single dose) with cimetidine (100 mg twice daily)|
04041|056|D|resulted in an increase in dofetilide plasma levels by 13%.(1)|
04041|057|B||
04041|058|R|REFERENCES:|
04041|059|B||
04041|060|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
04041|061|R|  2013.|1
04041|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04041|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04041|064|R|  settings: a scientific statement from the American Heart Association and|6
04041|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04041|066|R|  2;55(9):934-47.|6
04041|067|R|3.Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C,|2
04041|068|R|  Madhusudan Rao Y. Effect of cephalexin on the pharmacokinetics of|2
04041|069|R|  metformin in healthy human  volunteers. Drug Metabol Drug Interact 2002;|2
04041|070|R|  19(1):41-8.|2
04042|001|T|MONOGRAPH TITLE:  Sarilumab/Immunosuppressives; Immunomodulators|
04042|002|B||
04042|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04042|004|L|take action as needed.|
04042|005|B||
04042|006|A|MECHANISM OF ACTION:  Sarilumab, immunosuppressives, and immunomodulators|
04042|007|A|all suppress the immune system.(1)|
04042|008|B||
04042|009|E|CLINICAL EFFECTS:  Concurrent use of sarilumab with immunosuppressive or|
04042|010|E|immunomodulating agents may result in an increased risk for serious|
04042|011|E|infections.(1)|
04042|012|B||
04042|013|P|PREDISPOSING FACTORS:  None determined.|
04042|014|B||
04042|015|M|PATIENT MANAGEMENT:  The US manufacturer of sarilumab recommends caution|
04042|016|M|because the concurrent use of sarilumab with immunosuppressive agents may|
04042|017|M|increase the risk of infection.  If concurrent therapy is warranted,|
04042|018|M|consider the risk of additive immune suppression and monitor based on|
04042|019|M|prescribing information for both agents.(1)|
04042|020|B||
04042|021|D|DISCUSSION:  Sarilumab was studied as monotherapy and in combination with|
04042|022|D|methotrexate or conventional disease modifying antirheumatic drugs (DMARDs)|
04042|023|D|in rheumatoid arthritis studies.  Sarilumab has not been studied with|
04042|024|D|biological DMARDs and concurrent use should be avoided.  If concurrent|
04042|025|D|therapy is warranted, consider the potential for increased immunosuppressive|
04042|026|D|risks from both agents.(1)|
04042|027|D|   The most common infections reported by sarilumab treated patients in the|
04042|028|D|clinical trial periods included pneumonia and cellulitis.  Serious|
04042|029|D|bacterial, mycobacterial, fungal, and viral infections were observed in|
04042|030|D|patients receiving sarilumab.  Cases of tuberculosis, candidiasis, and|
04042|031|D|pneumocystis with sarilumab have been reported.(1)|
04042|032|B||
04042|033|R|REFERENCE:|
04042|034|B||
04042|035|R|1.Kevzara (sarilumab) US prescribing information. Sanofi-Aventis U.S. LLC|1
04042|036|R|  April, 2018.|1
04043|001|T|MONOGRAPH TITLE:  Tapentadol/Cyclobenzaprine|
04043|002|B||
04043|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04043|004|L|of severe adverse interaction.|
04043|005|B||
04043|006|A|MECHANISM OF ACTION:  Tapentadol and cyclobenzaprine, a tricyclic compound,|
04043|007|A|both may lower the seizure threshold, have additive effects on serotonin|
04043|008|A|levels,(1) and cause additive CNS depression.(3)|
04043|009|B||
04043|010|E|CLINICAL EFFECTS:  Concurrent use of tapentadol and cyclobenzaprine may|
04043|011|E|result in increased risk of seizures, serotonin syndrome, suicide,(1)|
04043|012|E|profound sedation, respiratory depression, coma, and/or death.(3)|
04043|013|B||
04043|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04043|015|P|may increase the risk of adverse effects.  Risk of seizures may be increased|
04043|016|P|in patients with epilepsy, a history of seizures, head trauma, metabolic|
04043|017|P|disorders, alcohol or drug withdrawal, or infections of the central nervous|
04043|018|P|system.(1)|
04043|019|B||
04043|020|M|PATIENT MANAGEMENT:  Tapentadol should be used with caution in patients|
04043|021|M|taking tricyclic compounds, including cyclobenzaprine.  Monitor patients|
04043|022|M|closely for serotonin syndrome.(1)|
04043|023|M|   Limit prescribing opioid analgesics with CNS depressants such as|
04043|024|M|cyclobenzaprine to patients for whom alternatives are ineffective, not|
04043|025|M|tolerated, or would be otherwise inadequate to provide sufficient management|
04043|026|M|of pain.(3)|
04043|027|M|   If concurrent use is necessary, limit the dosages and duration of each|
04043|028|M|drug to the minimum possible while achieving the desired clinical effect.|
04043|029|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04043|030|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04043|031|M|indicated in the absence of an opioid and titrate based upon clinical|
04043|032|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04043|033|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04043|034|M|clinical response.(3)|
04043|035|M|   Respiratory depression can occur at any time during opioid therapy,|
04043|036|M|especially during therapy initiation and following dosage increases.  The|
04043|037|M|risk of opioid-related overdose or overdose-related death is increased with|
04043|038|M|higher opioid doses, and this risk persists over the course of therapy.|
04043|039|M|Consider these risks when using concurrently with other agents that may|
04043|040|M|cause CNS depression.(4)|
04043|041|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04043|042|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04043|043|M|unresponsiveness.(3)|
04043|044|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04043|045|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04043|046|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04043|047|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04043|048|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04043|049|M|as those taking CNS depressants) and when a patient has household|
04043|050|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04043|051|M|for obtaining an opioid reversal agent (e.g., prescription,|
04043|052|M|over-the-counter, or as part of a community-based program).(5)|
04043|053|B||
04043|054|D|DISCUSSION:  Concurrent use of tapentadol with tricyclic compounds may|
04043|055|D|result in additive blockage of serotonin reuptake, leading to central|
04043|056|D|serotonergic hyperstimulation.  Cases of serotonin syndrome have been|
04043|057|D|reported with tapentadol in combination with other serotonergic drugs.(1)|
04043|058|D|   Use of tapentadol has been associated with increased seizure frequency in|
04043|059|D|patients with seizure disorders.(1)|
04043|060|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04043|061|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04043|062|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04043|063|D|to 30 million patients.  During this time, the proportion of patients|
04043|064|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04043|065|D|patients.(6)|
04043|066|D|   A retrospective cohort study compared the risk of opioid overdose|
04043|067|D|associated with concomitant use of opioids and skeletal muscle relaxants|
04043|068|D|versus opioid use alone. The study examined two types of opioid users (naive|
04043|069|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
04043|070|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
04043|071|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
04043|072|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
04043|073|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
04043|074|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
04043|075|D|respectively).  Elevated risk was associated with concomitant users with|
04043|076|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
04043|077|D|1.39, respectively).(7)|
04043|078|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04043|079|D|which benzodiazepines were determined to be a cause of death and that|
04043|080|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04043|081|D|determined to be a cause of death.  This study also found that other CNS|
04043|082|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04043|083|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04043|084|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04043|085|D|where opioid analgesics were also implicated.(8)|
04043|086|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04043|087|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04043|088|D|deaths.(9)|
04043|089|B||
04043|090|R|REFERENCES:|
04043|091|B||
04043|092|R|1.Nucynta ER (tapentadol) US prescribing information. Janssen|1
04043|093|R|  Pharmaceuticals December, 2023.|1
04043|094|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04043|095|R|  352(11):1112-20.|6
04043|096|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04043|097|R|  warns about serious risks and death when combining opioid pain or cough|1
04043|098|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04043|099|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04043|100|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04043|101|R|  prescribing information for all opioid pain medicines to provide|1
04043|102|R|  additional guidance for safe use. Available at:|1
04043|103|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04043|104|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04043|105|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04043|106|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04043|107|R|  recommends health care professionals discuss naloxone with all patients|1
04043|108|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04043|109|R|  disorder. Available at:|1
04043|110|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04043|111|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04043|112|R|  d-pain July 23, 2020.|1
04043|113|R|6.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04043|114|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04043|115|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04043|116|R|7.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
04043|117|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
04043|118|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
04043|119|R|  Ther 2020 Jul;108(1):81-88.|2
04043|120|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04043|121|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04043|122|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04043|123|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
04043|124|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
04043|125|R|  2014 Oct 10;63(40):881-5.|2
04044|001|T|MONOGRAPH TITLE:  Citalopram (Greater Than 20 mg)/Select CYP2C19 Inhibitors|
04044|002|T|that Prolong QT|
04044|003|B||
04044|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04044|005|L|of severe adverse interaction.|
04044|006|B||
04044|007|A|MECHANISM OF ACTION:  Citalopram is primarily metabolized by the CYP2C19|
04044|008|A|isoenzyme.(1)|
04044|009|B||
04044|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that inhibits CYP2C19 may|
04044|011|E|result in elevated levels of and toxicity from citalopram, including|
04044|012|E|including risks for serotonin syndrome or prolongation of the QTc|
04044|013|E|interval.(1-5)|
04044|014|E|   Prolongation of the QT interval may result in life-threatening|
04044|015|E|arrhythmias, including torsades de pointes.(2)|
04044|016|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
04044|017|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04044|018|E|rigidity.(5)|
04044|019|B||
04044|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04044|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
04044|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04044|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04044|024|P|female gender, advanced age, poor metabolizer status at CYP2C19, or higher|
04044|025|P|blood concentrations of citalopram.(2)|
04044|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04044|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04044|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04044|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04044|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04044|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04044|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04044|033|P|   Predisposing factors for serotonin-related adverse effects include use in|
04044|034|P|the elderly, in patients with hepatic impairment, and in patients receiving|
04044|035|P|multiple agents which increase central serotonin levels.(1,5)|
04044|036|P|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04044|037|P|magnesium, and potassium levels and monitoring ECG at baseline and at|
04044|038|P|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04044|039|P|patients to report any irregular heartbeat, dizziness, or fainting.|
04044|040|B||
04044|041|M|PATIENT MANAGEMENT:  The dose of citalopram should be limited to 20 mg in|
04044|042|M|patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4)|
04044|043|M|Concurrent use of citalopram with agents known to prolong the QT interval|
04044|044|M|should be avoided.(1)|
04044|045|M|   Evaluate the patient for other drugs, diseases and conditions which|
04044|046|M|increase risk for QT prolongation and correct risk factors (e.g. correct|
04044|047|M|hypokalemia, discontinue other QT prolonging drugs) when possible.(1,2)|
04044|048|M|Weigh the specific benefits versus risks for each patient.|
04044|049|M|   The US manufacturer recommends ECG monitoring for citalopram patients|
04044|050|M|with congestive heart failure, bradyarrhythmias, taking concomitant QT|
04044|051|M|prolonging medications or receiving concurrent therapy.(4)  Citalopram|
04044|052|M|should be discontinued in patients with persistent QTc measurements greater|
04044|053|M|than 500 ms.(2)|
04044|054|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04044|055|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04044|056|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04044|057|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04044|058|M|   If concurrent therapy is warranted, patients should be monitored for|
04044|059|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
04044|060|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
04044|061|M|heart palpitations, restlessness, confusion, agitation, trouble with|
04044|062|M|coordination, or severe diarrhea.|
04044|063|B||
04044|064|D|DISCUSSION:  Concurrent use of citalopram (40 mg daily) and cimetidine (400|
04044|065|D|mg twice daily) for 8 days increased the maximum concentration (Cmax) and|
04044|066|D|area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1)|
04044|067|D|   Inhibitors of CYP2C19 include:  lonafarnib, osilodrostat, rucaparib,|
04044|068|D|triclabendazole and voriconazole.(7,8)|
04044|069|B||
04044|070|R|REFERENCES:|
04044|071|B||
04044|072|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
04044|073|R|  Laboratories Inc. August, 2023.|1
04044|074|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04044|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04044|076|R|  settings: a scientific statement from the American Heart Association and|6
04044|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04044|078|R|  2;55(9):934-47.|6
04044|079|R|3.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
04044|080|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
04044|081|R|  and antidepressant use: a cross sectional study of electronic health|2
04044|082|R|  records. BMJ 2013;346:f288.|2
04044|083|R|4.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
04044|084|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
04044|085|R|  Lundbeck Canada January 25, 2012.|1
04044|086|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04044|087|R|  352(11):1112-20.|6
04044|088|R|6.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
04044|089|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
04044|090|R|  potential risk of abnormal heart rhythms with high doses. available at:|1
04044|091|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
04044|092|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04044|093|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04044|094|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04044|095|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04044|096|R|  11/14/2017.|1
04044|097|R|8.This information is based on an extract from the Certara Drug Interaction|6
04044|098|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04045|001|T|MONOGRAPH TITLE:  Tramadol/Cyclobenzaprine|
04045|002|B||
04045|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04045|004|L|of severe adverse interaction.|
04045|005|B||
04045|006|A|MECHANISM OF ACTION:  Tramadol and cyclobenzaprine, a tricyclic compound,|
04045|007|A|both may lower the seizure threshold, have additive effects on serotonin|
04045|008|A|levels,(1) and cause additive CNS depression.(3)|
04045|009|B||
04045|010|E|CLINICAL EFFECTS:  Concurrent use of tramadol and cyclobenzaprine may result|
04045|011|E|in increased risk of seizures, serotonin syndrome, suicide,(1) profound|
04045|012|E|sedation, respiratory depression, coma, and/or death.(3)|
04045|013|B||
04045|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04045|015|P|may increase the risk of adverse effects.  Risk of seizures may be increased|
04045|016|P|in patients with epilepsy, a history of seizures, head trauma, metabolic|
04045|017|P|disorders, alcohol or drug withdrawal, or infections of the central nervous|
04045|018|P|system.(1)|
04045|019|B||
04045|020|M|PATIENT MANAGEMENT:  Tramadol should be used with caution in patients taking|
04045|021|M|tricyclic compounds, including cyclobenzaprine.  Monitor patients closely|
04045|022|M|for serotonin syndrome.(1)|
04045|023|M|   Limit prescribing opioid analgesics with CNS depressants such as|
04045|024|M|cyclobenzaprine to patients for whom alternatives are ineffective, not|
04045|025|M|tolerated, or would be otherwise inadequate to provide sufficient management|
04045|026|M|of pain.(3)|
04045|027|M|   If concurrent use is necessary, limit the dosages and duration of each|
04045|028|M|drug to the minimum possible while achieving the desired clinical effect.|
04045|029|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04045|030|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04045|031|M|indicated in the absence of an opioid and titrate based upon clinical|
04045|032|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04045|033|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04045|034|M|clinical response.(3)|
04045|035|M|   Respiratory depression can occur at any time during opioid therapy,|
04045|036|M|especially during therapy initiation and following dosage increases.  The|
04045|037|M|risk of opioid-related overdose or overdose-related death is increased with|
04045|038|M|higher opioid doses, and this risk persists over the course of therapy.|
04045|039|M|Consider these risks when using concurrently with other agents that may|
04045|040|M|cause CNS depression.(4)|
04045|041|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04045|042|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04045|043|M|unresponsiveness.(3)|
04045|044|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04045|045|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04045|046|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04045|047|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04045|048|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04045|049|M|as those taking CNS depressants) and when a patient has household|
04045|050|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04045|051|M|for obtaining an opioid reversal agent (e.g., prescription,|
04045|052|M|over-the-counter, or as part of a community-based program).(5)|
04045|053|B||
04045|054|D|DISCUSSION:  The use of tramadol in patients treated with tricyclic|
04045|055|D|compounds may increase the risk of seizures.(1)  A review of 124 reports of|
04045|056|D|seizures following tramadol therapy received by the FDA through July 31,|
04045|057|D|1996 revealed that 23% of the patients were also taking tricyclic|
04045|058|D|antidepressants.(2)  Therefore, the manufacturer of tramadol states that|
04045|059|D|tramadol should be used with caution in patients treated with tricyclic|
04045|060|D|compounds.(1)|
04045|061|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04045|062|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04045|063|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04045|064|D|to 30 million patients.  During this time, the proportion of patients|
04045|065|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04045|066|D|patients.(6)|
04045|067|D|   A retrospective cohort study compared the risk of opioid overdose|
04045|068|D|associated with concomitant use of opioids and skeletal muscle relaxants|
04045|069|D|versus opioid use alone. The study examined two types of opioid users (naive|
04045|070|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
04045|071|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
04045|072|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
04045|073|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
04045|074|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
04045|075|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
04045|076|D|respectively).  Elevated risk was associated with concomitant users with|
04045|077|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
04045|078|D|1.39, respectively).(7)|
04045|079|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04045|080|D|which benzodiazepines were determined to be a cause of death and that|
04045|081|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04045|082|D|determined to be a cause of death.  This study also found that other CNS|
04045|083|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04045|084|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04045|085|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04045|086|D|where opioid analgesics were also implicated.(8)|
04045|087|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04045|088|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04045|089|D|deaths.(9)|
04045|090|B||
04045|091|R|REFERENCES:|
04045|092|B||
04045|093|R|1.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
04045|094|R|  October, 2019.|1
04045|095|R|2.Kahn LH, Alderfer RJ, Graham DJ. Seizures reported with tramadol. JAMA|3
04045|096|R|  1997 Nov 26;278(20):1661.|3
04045|097|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04045|098|R|  warns about serious risks and death when combining opioid pain or cough|1
04045|099|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04045|100|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04045|101|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04045|102|R|  prescribing information for all opioid pain medicines to provide|1
04045|103|R|  additional guidance for safe use. Available at:|1
04045|104|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04045|105|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04045|106|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04045|107|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04045|108|R|  recommends health care professionals discuss naloxone with all patients|1
04045|109|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04045|110|R|  disorder. Available at:|1
04045|111|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04045|112|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04045|113|R|  d-pain July 23, 2020.|1
04045|114|R|6.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04045|115|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04045|116|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04045|117|R|7.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
04045|118|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
04045|119|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
04045|120|R|  Ther 2020 Jul;108(1):81-88.|2
04045|121|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04045|122|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04045|123|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04045|124|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
04045|125|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
04045|126|R|  2014 Oct 10;63(40):881-5.|2
04046|001|T|MONOGRAPH TITLE:  Citalopram (Less than or Equal to 20 mg)/Selected CYP2C19|
04046|002|T|Inhibitors that Prolong QT|
04046|003|B||
04046|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04046|005|L|take action as needed.|
04046|006|B||
04046|007|A|MECHANISM OF ACTION:  Citalopram is primarily metabolized by the CYP2C19|
04046|008|A|isoenzyme.(1)|
04046|009|B||
04046|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that inhibits CYP2C19 may|
04046|011|E|result in elevated levels of and toxicity from citalopram, including|
04046|012|E|including risks for serotonin syndrome or prolongation of the QTc|
04046|013|E|interval.(1-5)|
04046|014|E|   Prolongation of the QT interval may result in life-threatening|
04046|015|E|arrhythmias, including torsades de pointes.(2)|
04046|016|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
04046|017|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04046|018|E|rigidity.(5)|
04046|019|B||
04046|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04046|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
04046|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04046|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04046|024|P|female gender, advanced age, poor metabolizer status at CYP2C19, or higher|
04046|025|P|blood concentrations of citalopram.(2)|
04046|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04046|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04046|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04046|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04046|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04046|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04046|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04046|033|P|   Predisposing factors for serotonin-related adverse effects include use in|
04046|034|P|the elderly, in patients with hepatic impairment, and in patients receiving|
04046|035|P|multiple agents which increase central serotonin levels.(1,5)|
04046|036|P|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04046|037|P|magnesium, and potassium levels and monitoring ECG at baseline and at|
04046|038|P|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04046|039|P|patients to report any irregular heartbeat, dizziness, or fainting.|
04046|040|B||
04046|041|M|PATIENT MANAGEMENT:  The dose of citalopram should be limited to 20 mg in|
04046|042|M|patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4)|
04046|043|M|Concurrent use of citalopram with agents known to prolong the QT interval|
04046|044|M|should be avoided.(1)|
04046|045|M|   Evaluate the patient for other drugs, diseases and conditions which|
04046|046|M|increase risk for QT prolongation and correct risk factors (e.g. correct|
04046|047|M|hypokalemia, hypocalcemia, hypomagnesemia, discontinue other QT prolonging|
04046|048|M|drugs) when possible.(1,2)  Weigh the specific benefits versus risks for|
04046|049|M|each patient.|
04046|050|M|   The US manufacturer recommends ECG monitoring for citalopram patients|
04046|051|M|with congestive heart failure, bradyarrhythmias, taking concomitant QT|
04046|052|M|prolonging medications or receiving concurrent therapy.(4)  Citalopram|
04046|053|M|should be discontinued in patients with persistent QTc measurements greater|
04046|054|M|than 500 ms.(2)|
04046|055|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04046|056|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04046|057|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04046|058|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04046|059|M|   If concurrent therapy is warranted, patients should be monitored for|
04046|060|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
04046|061|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
04046|062|M|heart palpitations, restlessness, confusion, agitation, trouble with|
04046|063|M|coordination, or severe diarrhea.|
04046|064|B||
04046|065|D|DISCUSSION:  Concurrent use of citalopram (40 mg daily) and cimetidine (400|
04046|066|D|mg twice daily) for 8 days increased the maximum concentration (Cmax) and|
04046|067|D|area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1)|
04046|068|D|   Inhibitors of CYP2C19 include:  lonafarnib, osilodrostat, rucaparib,|
04046|069|D|triclabendazole and voriconazole.(7,8)|
04046|070|B||
04046|071|R|REFERENCES:|
04046|072|B||
04046|073|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
04046|074|R|  Laboratories Inc. August, 2023.|1
04046|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04046|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04046|077|R|  settings: a scientific statement from the American Heart Association and|6
04046|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04046|079|R|  2;55(9):934-47.|6
04046|080|R|3.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
04046|081|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
04046|082|R|  and antidepressant use: a cross sectional study of electronic health|2
04046|083|R|  records. BMJ 2013;346:f288.|2
04046|084|R|4.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
04046|085|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
04046|086|R|  Lundbeck Canada January 25, 2012.|1
04046|087|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04046|088|R|  352(11):1112-20.|6
04046|089|R|6.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
04046|090|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
04046|091|R|  potential risk of abnormal heart rhythms with high doses. available at:|1
04046|092|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
04046|093|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04046|094|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04046|095|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04046|096|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04046|097|R|  11/14/2017.|1
04046|098|R|8.This information is based on an extract from the Certara Drug Interaction|6
04046|099|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04047|001|T|MONOGRAPH TITLE:  Escitalopram (Greater Than 15 mg)/Selected CYP2C19|
04047|002|T|Inhibitors that Prolong QT|
04047|003|B||
04047|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04047|005|L|take action as needed.|
04047|006|B||
04047|007|A|MECHANISM OF ACTION:  At lower systemic concentrations, escitalopram is|
04047|008|A|primarily metabolized by CYP2C19; at higher concentrations is also|
04047|009|A|metabolized by CYP3A4.(1)|
04047|010|B||
04047|011|E|CLINICAL EFFECTS:  Concurrent use of an agent which significantly inhibits|
04047|012|E|CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated|
04047|013|E|concentrations and toxicity from escitalopram, including risks for serotonin|
04047|014|E|syndrome or prolongation of the QTc interval.(1,5)  Prolongation of the QT|
04047|015|E|interval may result in life-threatening arrhythmias, including torsades de|
04047|016|E|pointes.(2)  Symptoms of serotonin syndrome may include tremor, agitation,|
04047|017|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04047|018|E|rigidity.(3)|
04047|019|B||
04047|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased in|
04047|021|P|patients with congenital long QT syndrome, cardiovascular disease (e.g.|
04047|022|P|heart failure, myocardial infarction), hypokalemia, hypomagnesemia,|
04047|023|P|hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status|
04047|024|P|at CYP2C19, concurrent use of more than one agent known to cause QT|
04047|025|P|prolongation, or with higher blood concentrations of escitalopram.(2)|
04047|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04047|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04047|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04047|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04047|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04047|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04047|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04047|033|P|   Predisposing factors for serotonin-related adverse effects include use in|
04047|034|P|the elderly, in patients with hepatic impairment, and in patients receiving|
04047|035|P|multiple agents which increase central serotonin levels.(1,3)|
04047|036|P|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04047|037|P|magnesium, and potassium levels and monitoring ECG at baseline and at|
04047|038|P|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04047|039|P|patients to report any irregular heartbeat, dizziness, or fainting.|
04047|040|B||
04047|041|M|PATIENT MANAGEMENT:  Evaluate patient for other drugs, diseases and|
04047|042|M|conditions which may further increase risk for QT prolongation and correct|
04047|043|M|risk factors (e.g. correct hypokalemia, discontinue other QT prolonging|
04047|044|M|drugs) when possible.(2,3)  It would be prudent to limit the escitalopram|
04047|045|M|dose to 10 mg daily in patients with QT prolonging risk factors who also|
04047|046|M|receive concurrent therapy with selected CYP2C19 inhibitors.(5)  Weigh the|
04047|047|M|specific benefits versus risks for each patient.|
04047|048|M|   If concurrent therapy is warranted, patients should be monitored for|
04047|049|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
04047|050|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
04047|051|M|heart palpitations, restlessness, confusion, agitation, trouble with|
04047|052|M|coordination, or severe diarrhea.|
04047|053|B||
04047|054|D|DISCUSSION:  A thorough QT study evaluating escitalopram 10 mg or 30 mg once|
04047|055|D|daily was conducted; a change of 10 msec for upper bound of the 95%|
04047|056|D|confidence level is the threshold for regulatory concern.  In this study,|
04047|057|D|changes to the upper bound of the 95% confidence interval were 6.4 msec and|
04047|058|D|12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The|
04047|059|D|Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended|
04047|060|D|escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar|
04047|061|D|to expected steady state concentrations in 2C19 poor metabolizers following|
04047|062|D|a 20 mg escitalopram dose.(1)|
04047|063|D|  In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of|
04047|064|D|CYP2C19 was administered daily for 6 days. On day 5 a single dose of|
04047|065|D|escitalopram 20 mg was also administered; the area-under-curve (AUC) of|
04047|066|D|escitalopram was increased by 50%. Manufacturer prescribing information|
04047|067|D|recommends a maximum citalopram dose of 20mg daily in patients receiving|
04047|068|D|CYP2C19 inhibitors.(1)|
04047|069|D|   Inhibitors of CYP2C19 include:  lonafarnib, osilodrostat, rucaparib,|
04047|070|D|triclabendazole and voriconazole.(4)|
04047|071|B||
04047|072|R|REFERENCES:|
04047|073|B||
04047|074|R|1.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
04047|075|R|  Pharmaceuticals Inc. May, 2023.|1
04047|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04047|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04047|078|R|  settings: a scientific statement from the American Heart Association and|6
04047|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04047|080|R|  2;55(9):934-47.|6
04047|081|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04047|082|R|  352(11):1112-20.|6
04047|083|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04047|084|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04047|085|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04047|086|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04047|087|R|  11/14/2017.|1
04047|088|R|5.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
04047|089|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
04047|090|R|  and antidepressant use: a cross sectional study of electronic health|2
04047|091|R|  records. BMJ 2013;346:f288.|2
04048|001|T|MONOGRAPH TITLE:  Opioids (Extended Release)/Cyclobenzaprine|
04048|002|B||
04048|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04048|004|L|take action as needed.|
04048|005|B||
04048|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and cyclobenzaprine may|
04048|007|A|result in additive CNS depression.(1)|
04048|008|B||
04048|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
04048|010|E|as cyclobenzaprine, may result in profound sedation, respiratory depression,|
04048|011|E|coma, and/or death.(1)|
04048|012|B||
04048|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04048|014|P|may increase the risk of adverse effects.|
04048|015|B||
04048|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
04048|017|M|depressants such as muscle relaxants to patients for whom alternatives are|
04048|018|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
04048|019|M|sufficient management of pain.(1)|
04048|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
04048|021|M|drug to the minimum possible while achieving the desired clinical effect.|
04048|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04048|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04048|024|M|indicated in the absence of an opioid and titrate based upon clinical|
04048|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04048|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04048|027|M|clinical response.(1)|
04048|028|M|   Respiratory depression can occur at any time during opioid therapy,|
04048|029|M|especially during therapy initiation and following dosage increases.  The|
04048|030|M|risk of opioid-related overdose or overdose-related death is increased with|
04048|031|M|higher opioid doses, and this risk persists over the course of therapy.|
04048|032|M|Consider these risks when using concurrently with other agents that may|
04048|033|M|cause CNS depression.(2)|
04048|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04048|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04048|036|M|unresponsiveness.(1)|
04048|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04048|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04048|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04048|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04048|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04048|042|M|as those taking CNS depressants) and when a patient has household|
04048|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04048|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
04048|045|M|over-the-counter, or as part of a community-based program).(3)|
04048|046|B||
04048|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04048|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04048|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04048|050|D|million to 30 million patients.  During this time, the proportion of|
04048|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04048|052|D|million patients.(4)|
04048|053|D|   A retrospective cohort study compared the risk of opioid overdose|
04048|054|D|associated with concomitant use of opioids and skeletal muscle relaxants|
04048|055|D|versus opioid use alone. The study examined two types of opioid users (naive|
04048|056|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
04048|057|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
04048|058|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
04048|059|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
04048|060|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
04048|061|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
04048|062|D|respectively).  Elevated risk was associated with concomitant users with|
04048|063|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
04048|064|D|1.39, respectively).(5)|
04048|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04048|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04048|067|D|per 100,000 and drug overdose deaths involving both opioids and|
04048|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04048|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04048|070|D|increased from 18% to 31% during this time.(6)|
04048|071|D|   A prospective observational cohort study in North Carolina found that the|
04048|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04048|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
04048|074|D|analgesics alone.(7)|
04048|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04048|076|D|death from overdose increased with concomitant opioid analgesics and|
04048|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04048|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04048|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04048|080|D|increased risk of fatal overdose.(8)|
04048|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04048|082|D|which benzodiazepines were determined to be a cause of death and that|
04048|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04048|084|D|determined to be a cause of death.  This study also found that other CNS|
04048|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04048|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04048|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04048|088|D|where opioid analgesics were also implicated.(9)|
04048|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04048|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04048|091|D|deaths.(10)|
04048|092|B||
04048|093|R|REFERENCES:|
04048|094|B||
04048|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04048|096|R|  warns about serious risks and death when combining opioid pain or cough|1
04048|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04048|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04048|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04048|100|R|  prescribing information for all opioid pain medicines to provide|1
04048|101|R|  additional guidance for safe use. Available at:|1
04048|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04048|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04048|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04048|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04048|106|R|  recommends health care professionals discuss naloxone with all patients|1
04048|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04048|108|R|  disorder. Available at:|1
04048|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04048|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04048|111|R|  d-pain July 23, 2020.|1
04048|112|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04048|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04048|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04048|115|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
04048|116|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
04048|117|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
04048|118|R|  Ther 2020 Jul;108(1):81-88.|2
04048|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04048|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04048|121|R|  49(4):493-501.|2
04048|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04048|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04048|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04048|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04048|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04048|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04048|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04048|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04048|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04048|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04048|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04048|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04049|001|T|MONOGRAPH TITLE:  Escitalopram (Less Than or Equal To 15 mg)/Selected|
04049|002|T|CYP2C19 Inhibitors that Prolong QT|
04049|003|B||
04049|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04049|005|L|take action as needed.|
04049|006|B||
04049|007|A|MECHANISM OF ACTION:  At lower systemic concentrations, escitalopram is|
04049|008|A|primarily metabolized by CYP2C19; at higher concentrations is also|
04049|009|A|metabolized by CYP3A4.(1)|
04049|010|B||
04049|011|E|CLINICAL EFFECTS:  Concurrent use of an agent which significantly inhibits|
04049|012|E|CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated|
04049|013|E|concentrations and toxicity from escitalopram, including risks for serotonin|
04049|014|E|syndrome or prolongation of the QTc interval.(1,5)  Prolongation of the QT|
04049|015|E|interval may result in life-threatening arrhythmias, including torsades de|
04049|016|E|pointes.(2)  Symptoms of serotonin syndrome may include tremor, agitation,|
04049|017|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04049|018|E|rigidity.(3)|
04049|019|B||
04049|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased in|
04049|021|P|patients with congenital long QT syndrome, cardiovascular disease (e.g.|
04049|022|P|heart failure, myocardial infarction), hypokalemia, hypomagnesemia,|
04049|023|P|hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status|
04049|024|P|at CYP2C19, concurrent use of more than one agent known to cause QT|
04049|025|P|prolongation, or with higher blood concentrations of escitalopram.(2)|
04049|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04049|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04049|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04049|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04049|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04049|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04049|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04049|033|P|   Predisposing factors for serotonin-related adverse effects include use in|
04049|034|P|the elderly, in patients with hepatic impairment, and in patients receiving|
04049|035|P|multiple agents which increase central serotonin levels.(1,3)|
04049|036|P|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04049|037|P|magnesium, and potassium levels and monitoring ECG at baseline and at|
04049|038|P|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04049|039|P|patients to report any irregular heartbeat, dizziness, or fainting.|
04049|040|B||
04049|041|M|PATIENT MANAGEMENT:  Evaluate patient for other drugs, diseases and|
04049|042|M|conditions which may further increase risk for QT prolongation and correct|
04049|043|M|risk factors (e.g. correct hypokalemia, discontinue other QT prolonging|
04049|044|M|drugs) when possible.(2,3)  It would be prudent to limit the escitalopram|
04049|045|M|dose to 10 mg daily in patients with QT prolonging risk factors who also|
04049|046|M|receive concurrent therapy with selected CYP2C19 inhibitors.(5)  Weigh the|
04049|047|M|specific benefits versus risks for each patient.|
04049|048|M|   If concurrent therapy is warranted, patients should be monitored for|
04049|049|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
04049|050|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
04049|051|M|heart palpitations, restlessness, confusion, agitation, trouble with|
04049|052|M|coordination, or severe diarrhea.|
04049|053|B||
04049|054|D|DISCUSSION:  A thorough QT study evaluating escitalopram 10 mg or 30 mg once|
04049|055|D|daily was conducted; a change of 10 msec for upper bound of the 95%|
04049|056|D|confidence level is the threshold for regulatory concern.  In this study,|
04049|057|D|changes to the upper bound of the 95% confidence interval were 6.4 msec and|
04049|058|D|12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The|
04049|059|D|Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended|
04049|060|D|escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar|
04049|061|D|to expected steady state concentrations in 2C19 poor metabolizers following|
04049|062|D|a 20 mg escitalopram dose.(1)|
04049|063|D|  In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of|
04049|064|D|CYP2C19 was administered daily for 6 days. On day 5 a single dose of|
04049|065|D|escitalopram 20 mg was also administered; the area-under-curve (AUC) of|
04049|066|D|escitalopram was increased by 50%. Manufacturer prescribing information|
04049|067|D|recommends a maximum citalopram dose of 20mg daily in patients receiving|
04049|068|D|CYP2C19 inhibitors.(1)|
04049|069|D|   Inhibitors of CYP2C19 include:  lonafarnib, osilodrostat, rucaparib,|
04049|070|D|triclabendazole, and voriconazole.(4)|
04049|071|B||
04049|072|R|REFERENCES:|
04049|073|B||
04049|074|R|1.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
04049|075|R|  Pharmaceuticals Inc. May, 2023.|1
04049|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04049|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04049|078|R|  settings: a scientific statement from the American Heart Association and|6
04049|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04049|080|R|  2;55(9):934-47.|6
04049|081|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04049|082|R|  352(11):1112-20.|6
04049|083|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04049|084|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04049|085|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04049|086|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04049|087|R|  11/14/2017.|1
04049|088|R|5.Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL,|2
04049|089|R|  Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH. QT interval|2
04049|090|R|  and antidepressant use: a cross sectional study of electronic health|2
04049|091|R|  records. BMJ 2013;346:f288.|2
04050|001|T|MONOGRAPH TITLE:  Opioids (Immediate Release)/Cyclobenzaprine|
04050|002|B||
04050|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04050|004|L|take action as needed.|
04050|005|B||
04050|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and cyclobenzaprine may|
04050|007|A|result in additive CNS depression.(1)|
04050|008|B||
04050|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
04050|010|E|as cyclobenzaprine, may result in profound sedation, respiratory depression,|
04050|011|E|coma, and/or death.(1)|
04050|012|B||
04050|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04050|014|P|may increase the risk of adverse effects.|
04050|015|B||
04050|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
04050|017|M|depressants such as muscle relaxants to patients for whom alternatives are|
04050|018|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
04050|019|M|sufficient management of pain.(1)|
04050|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
04050|021|M|drug to the minimum possible while achieving the desired clinical effect.|
04050|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04050|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04050|024|M|indicated in the absence of an opioid and titrate based upon clinical|
04050|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04050|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04050|027|M|clinical response.(1)|
04050|028|M|   Respiratory depression can occur at any time during opioid therapy,|
04050|029|M|especially during therapy initiation and following dosage increases.  The|
04050|030|M|risk of opioid-related overdose or overdose-related death is increased with|
04050|031|M|higher opioid doses, and this risk persists over the course of therapy.|
04050|032|M|Consider these risks when using concurrently with other agents that may|
04050|033|M|cause CNS depression.(2)|
04050|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04050|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04050|036|M|unresponsiveness.(1)|
04050|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04050|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04050|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04050|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04050|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04050|042|M|as those taking CNS depressants) and when a patient has household|
04050|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04050|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
04050|045|M|over-the-counter, or as part of a community-based program).(3)|
04050|046|B||
04050|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04050|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04050|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04050|050|D|million to 30 million patients.  During this time, the proportion of|
04050|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04050|052|D|million patients.(4)|
04050|053|D|   A retrospective cohort study compared the risk of opioid overdose|
04050|054|D|associated with concomitant use of opioids and skeletal muscle relaxants|
04050|055|D|versus opioid use alone. The study examined two types of opioid users (naive|
04050|056|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
04050|057|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
04050|058|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
04050|059|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
04050|060|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
04050|061|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
04050|062|D|respectively).  Elevated risk was associated with concomitant users with|
04050|063|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
04050|064|D|1.39, respectively).(5)|
04050|065|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04050|066|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04050|067|D|per 100,000 and drug overdose deaths involving both opioids and|
04050|068|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04050|069|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04050|070|D|increased from 18% to 31% during this time.(6)|
04050|071|D|   A prospective observational cohort study in North Carolina found that the|
04050|072|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04050|073|D|benzodiazepines were 10 times higher than patients receiving opioid|
04050|074|D|analgesics alone.(7)|
04050|075|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04050|076|D|death from overdose increased with concomitant opioid analgesics and|
04050|077|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04050|078|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04050|079|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04050|080|D|increased risk of fatal overdose.(8)|
04050|081|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04050|082|D|which benzodiazepines were determined to be a cause of death and that|
04050|083|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04050|084|D|determined to be a cause of death.  This study also found that other CNS|
04050|085|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04050|086|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04050|087|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04050|088|D|where opioid analgesics were also implicated.(9)|
04050|089|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04050|090|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04050|091|D|deaths.(10)|
04050|092|B||
04050|093|R|REFERENCES:|
04050|094|B||
04050|095|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04050|096|R|  warns about serious risks and death when combining opioid pain or cough|1
04050|097|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04050|098|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04050|099|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04050|100|R|  prescribing information for all opioid pain medicines to provide|1
04050|101|R|  additional guidance for safe use. Available at:|1
04050|102|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04050|103|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04050|104|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04050|105|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04050|106|R|  recommends health care professionals discuss naloxone with all patients|1
04050|107|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04050|108|R|  disorder. Available at:|1
04050|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04050|110|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04050|111|R|  d-pain July 23, 2020.|1
04050|112|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04050|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04050|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04050|115|R|5.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
04050|116|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
04050|117|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
04050|118|R|  Ther 2020 Jul;108(1):81-88.|2
04050|119|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04050|120|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04050|121|R|  49(4):493-501.|2
04050|122|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04050|123|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04050|124|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04050|125|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04050|126|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04050|127|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04050|128|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04050|129|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04050|130|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04050|131|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04050|132|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04050|133|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04051|001|T|MONOGRAPH TITLE:  Sirolimus Protein-Bound/Selected Macrolides|
04051|002|B||
04051|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04051|004|L|of severe adverse interaction.|
04051|005|B||
04051|006|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
04051|007|A|sirolimus by CYP3A4.(1)|
04051|008|B||
04051|009|E|CLINICAL EFFECTS:  Concurrent use of macrolide antibiotics may result in|
04051|010|E|elevated levels of and side effects from sirolimus.(1)|
04051|011|B||
04051|012|P|PREDISPOSING FACTORS:  None determined.|
04051|013|B||
04051|014|M|PATIENT MANAGEMENT:  Concurrent use with strong CYP3A4 inhibitors should be|
04051|015|M|avoided.(1)|
04051|016|M|   If concurrent therapy is warranted, sirolimus levels should be carefully|
04051|017|M|monitored in patients receiving concurrent therapy with macrolide|
04051|018|M|antibiotics.  The dosage of sirolimus may need to be adjusted during and/or|
04051|019|M|after macrolide therapy or the macrolide may need to be discontinued.  The|
04051|020|M|dosage of the macrolide antibiotic may need to be adjusted.|
04051|021|M|   Guidelines from the American Society of Transplantation state that|
04051|022|M|clarithromycin and erythromycin are contraindicated with sirolimus (although|
04051|023|M|product labels do not contraindicate these combinations).  If the|
04051|024|M|combination must be used, lower the dose of the immunosuppressant by up to|
04051|025|M|50 % upon initiation of the antibiotic and monitor levels every 3rd day with|
04051|026|M|sirolimus.(3)|
04051|027|B||
04051|028|D|DISCUSSION:  In an open, randomized, cross-over trial in 18 healthy|
04051|029|D|subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10|
04051|030|D|mg) increased sirolimus area-under-curve (AUC) and maximum concentration|
04051|031|D|(Cmax) by 60% and by 43%, respectively.  Sirolimus apparent oral clearance|
04051|032|D|and volume of distribution decreased by 38% and 45%, respectively.  There|
04051|033|D|were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2)|
04051|034|D|   In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with|
04051|035|D|verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold|
04051|036|D|and 2.3-fold, respectively.  The AUC and Cmax of the active S-enantiomer of|
04051|037|D|verapamil each increased by 1.5-fold.  Verapamil time to Cmax (Tmax) was|
04051|038|D|increased by 1.2 hours.(2)|
04051|039|D|   In a study in 24 healthy subjects, concurrent sirolimus (2 mg daily) and|
04051|040|D|erythromycin ethylsuccinate (800 mg 3 times daily) increased sirolimus Cmax,|
04051|041|D|AUC, and time to Cmax (Tmax) by 4.4-fold, 4.2-fold, and 0.4 hours,|
04051|042|D|respectively.  Erythromycin Cmax, AUC, and Tmax were increased by 1.6-fold,|
04051|043|D|1.7-fold, and 0.3 hours, respectively.(2)  There are case reports of|
04051|044|D|toxicity with concurrent sirolimus and erythromycin.(4)|
04051|045|B||
04051|046|R|REFERENCES:|
04051|047|B||
04051|048|R|1.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
04051|049|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
04051|050|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
04051|051|R|  Aug, 2022.|1
04051|052|R|3.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
04051|053|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
04051|054|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
04051|055|R|  e13510.|6
04051|056|R|4.Claesson K, Brattstrom C, Burke JT. Sirolimus and erythromycin|3
04051|057|R|  interaction: two cases. Transplant Proc 2001 May;33(3):2136.|3
04051|058|R|5.This information is based on an extract from the Certara Drug Interaction|6
04051|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04051|060|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04051|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04051|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04051|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04051|064|R|  11/14/2017.|1
04052|001|T|MONOGRAPH TITLE:  Sirolimus/Sotorasib|
04052|002|B||
04052|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04052|004|L|of severe adverse interaction.|
04052|005|B||
04052|006|A|MECHANISM OF ACTION:  Sotorasib is a moderate inducer of CYP3A4 and may|
04052|007|A|increase the metabolism of sirolimus.(1,2)|
04052|008|A|   Sotorasib is also an inhibitor of the P-glycoprotein (P-gp) system.  P-gp|
04052|009|A|substrates with a narrow therapeutic index such as sirolimus may be|
04052|010|A|increased.(1,2)|
04052|011|B||
04052|012|E|CLINICAL EFFECTS:  Concurrent use of sotorasib may lead to increased or|
04052|013|E|decreased serum levels and effectiveness of sirolimus.(1)|
04052|014|B||
04052|015|P|PREDISPOSING FACTORS:  None determined.|
04052|016|B||
04052|017|M|PATIENT MANAGEMENT:  Avoid concurrent use with sotorasib and sirolimus.(1)|
04052|018|M|   If concurrent use cannot be avoided, use caution and monitor sirolimus|
04052|019|M|serum concentrations.  The dose of sirolimus may need to be adjusted.(2)|
04052|020|B||
04052|021|D|DISCUSSION:  Coadministration of sotorasib with midazolam, a sensitive|
04052|022|D|CYP3A4 substrate, decreased midazolam area-under-curve (AUC) by 53% and|
04052|023|D|maximum concentration (Cmax) by 48%.(1)|
04052|024|D|   In a study, sotorasib increased the AUC of digoxin, a P-gp substrate, by|
04052|025|D|21% and Cmax by 91%.(1)|
04052|026|B||
04052|027|R|REFERENCES:|
04052|028|B||
04052|029|R|1.Lumakras (sotorasib) US prescribing information. Amgen Inc November, 2022.|1
04052|030|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
04052|031|R|  Aug, 2022.|1
04052|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04052|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04052|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04052|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04052|036|R|  11/14/2017.|1
04052|037|R|4.This information is based on an extract from the Certara Drug Interaction|6
04052|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04053|001|T|MONOGRAPH TITLE:  Abrocitinib/Ticlopidine|
04053|002|B||
04053|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04053|004|L|of severe adverse interaction.|
04053|005|B||
04053|006|A|MECHANISM OF ACTION:  Abrocitinib is primarily metabolized by CYP2C19 and|
04053|007|A|CYP2C9.  Ticlopidine is a strong inhibitor of CYP2C19 and may inhibit the|
04053|008|A|metabolism of abrocitinib.(1-3)|
04053|009|A|   Abrocitinib has been associated with transient, dose-dependent|
04053|010|A|thrombocytopenia.  The nadir platelet count occurs at a median of 24 days|
04053|011|A|after receiving abrocitinib 200 mg once daily and a 40% recovery occurs by|
04053|012|A|12 weeks.  Concurrent use with agents that affect platelet aggregation may|
04053|013|A|result in an additive risk of bleeding.(1)|
04053|014|B||
04053|015|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of CYP2C19 increases|
04053|016|E|plasma exposure of abrocitinib which may increase the incidence and severity|
04053|017|E|of adverse reactions of abrocitinib.  This may increase the risk of|
04053|018|E|infections, major adverse cardiovascular events, or thrombosis.(1)|
04053|019|E|   Concurrent use of abrocitinib with ticlopidine may also increase the risk|
04053|020|E|of bleeding.(1)|
04053|021|B||
04053|022|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04053|023|P|patients with disease-associated factors (e.g. pre-existing|
04053|024|P|thrombocytopenia).  Abrocitinib is not recommended for patients with a|
04053|025|P|platelet count less than 150,000/mm3.(1)|
04053|026|P|   Drug associated risk factors include concurrent use of multiple drugs|
04053|027|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04053|028|P|risk for bleeding.|
04053|029|B||
04053|030|M|PATIENT MANAGEMENT:  The concurrent use of abrocitinib with antiplatelet|
04053|031|M|agents (except aspirin <81 mg daily) is contraindicated during the first 3|
04053|032|M|months of abrocitinib therapy.|
04053|033|M|   Prior to starting abrocitinib therapy, obtain a complete blood count and|
04053|034|M|recheck at 4 weeks after initiation and 4 weeks after a dose increase.|
04053|035|M|Discontinuation of abrocitinib is required if platelets drop below|
04053|036|M|50,000/mm3.(1)|
04053|037|M|   If concurrent therapy is warranted after the first 3 months of|
04053|038|M|abrocitinib therapy, monitor patients receiving concurrent therapy for signs|
04053|039|M|of blood loss, including decreased hemoglobin, hematocrit, fecal occult|
04053|040|M|blood, and/or decreased blood pressure and promptly evaluate patients with|
04053|041|M|any symptoms.|
04053|042|M|   The manufacturer of abrocitinib states that the dose of abrocitinib in|
04053|043|M|patients who are taking strong CYP2C19 inhibitors should be reduced to 50 mg|
04053|044|M|once daily.  If an adequate response is not achieved after 12 weeks,|
04053|045|M|consider increasing the dose to 100 mg once daily.  If the response remains|
04053|046|M|inadequate, discontinue therapy with abrocitinib.(1)|
04053|047|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04053|048|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04053|049|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04053|050|M|and/or swelling.|
04053|051|B||
04053|052|D|DISCUSSION:  In a study, fluvoxamine (50 mg daily for 9 days), a strong|
04053|053|D|CYP2C19 inhibitor, increased the maximum concentration (Cmax) and|
04053|054|D|area-under-curve (AUC) of abrocitinib (100 mg) by 1.33-fold and 1.91-fold,|
04053|055|D|respectively.(1)|
04053|056|D|   Abrocitinib has been associated with transient, dose-dependent|
04053|057|D|thrombocytopenia and is more severe with lower baseline platelet counts. At|
04053|058|D|baseline platelet counts of 170,000/mm3, 220,000/m3 and 270,000/mm3, the|
04053|059|D|nadirs were -41.2%, -33.4%, and -26.5%, respectively.  Recovery of platelet|
04053|060|D|count (about 40% recovery by 12 weeks) occurred without discontinuation of|
04053|061|D|the treatment.(1)|
04053|062|B||
04053|063|R|REFERENCES:|
04053|064|B||
04053|065|R|1.Cibinqo (abrocitinib) US prescribing information. Pfizer Labs January,|1
04053|066|R|  2022.|1
04053|067|R|2.This information is based on an extract from the Certara Drug Interaction|6
04053|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04053|069|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04053|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04053|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04053|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04053|073|R|  11/14/2017.|1
04054|001|T|MONOGRAPH TITLE:  Eliglustat/Dual CYP3A4 & Weak CYP2D6 Inhibitors|
04054|002|B||
04054|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04054|004|L|of severe adverse interaction.|
04054|005|B||
04054|006|A|MECHANISM OF ACTION:  Dual strong or moderate CYP3A4 and weak CYP2D6|
04054|007|A|inhibitors may inhibit the metabolism of eliglustat.(1)|
04054|008|B||
04054|009|E|CLINICAL EFFECTS:  Concurrent use of an agent that is a dual strong or|
04054|010|E|moderate CYP3A4 and weak CYP2D6 inhibitor may result in elevated levels of|
04054|011|E|and clinical effects of eliglustat, including prolongation of the PR, QTc,|
04054|012|E|and/or QRS intervals, which may result in life-threatening cardiac|
04054|013|E|arrhythmias.(1)|
04054|014|B||
04054|015|P|PREDISPOSING FACTORS:  If the patient has liver disease, is also taking an|
04054|016|P|inhibitor of CYP2D6 and/or is an intermediate or poor metabolizer of CYP2D6,|
04054|017|P|eliglustat metabolism can be further inhibited.(1)|
04054|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04054|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04054|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04054|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04054|022|P|advanced age.(2)|
04054|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04054|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04054|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04054|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04054|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04054|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04054|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04054|030|B||
04054|031|M|PATIENT MANAGEMENT:  Prescribing information has no specific recommendation|
04054|032|M|on the use of eliglustat with drugs that are dual strong or moderate CYP3A4|
04054|033|M|and weak CYP2D6 inhibitors.|
04054|034|M|   The concurrent use of eliglustat with strong or moderate inhibitors of|
04054|035|M|CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in both|
04054|036|M|extensive and intermediate CYP2D6 metabolizers is contraindicated.(1)|
04054|037|M|   The concurrent use of eliglustat with strong inhibitors of CYP3A4 in|
04054|038|M|intermediate and poor CYP2D6 metabolizers is contraindicated.(1)|
04054|039|M|   The concurrent use of eliglustat with moderate inhibitors of CYP3A4 in|
04054|040|M|intermediate and poor CYP2D6 metabolizers should be avoided.(1)|
04054|041|M|   The dosage of eliglustat with strong or moderate inhibitors of CYP3A4 in|
04054|042|M|extensive CYP2D6 metabolizers should be limited to 84 mg daily.(1)|
04054|043|M|   The concurrent use of eliglustat with strong inhibitors of CYP3A4|
04054|044|M|concomitantly with strong or moderate inhibitors of CYP2D6 is|
04054|045|M|contraindicated.(1)|
04054|046|M|   The concurrent use of eliglustat with moderate inhibitors of CYP3A4|
04054|047|M|concomitantly with strong or moderate inhibitors of CYP2D6 in poor|
04054|048|M|metabolizers of CYP2D6 should be avoided and is contraindicated in extensive|
04054|049|M|and intermediate CYP2D6 metabolizers.(1)|
04054|050|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04054|051|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04054|052|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04054|053|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04054|054|B||
04054|055|D|DISCUSSION:  Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4,|
04054|056|D|increased eliglustat (84 mg BID) maximum concentration (Cmax) and|
04054|057|D|area-under-curve (AUC) by  4-fold and 4.4-fold, respectively, in extensive|
04054|058|D|metabolizers.  Physiologically-based pharmacokinetic (PKPB) models suggested|
04054|059|D|ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and|
04054|060|D|5.4-fold, respectively, in intermediate metabolizers.  PKPB models suggested|
04054|061|D|ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily)  by|
04054|062|D|4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1)|
04054|063|D|   PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would|
04054|064|D|increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in|
04054|065|D|extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in|
04054|066|D|intermediate metabolizers.|
04054|067|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a|
04054|068|D|strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax|
04054|069|D|and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers.|
04054|070|D|In intermediate metabolizers, eliglustat Cmax and AUC would be expected to|
04054|071|D|increase 7.5-fold and 9.8-fold, respectively.(1)|
04054|072|D|   PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine|
04054|073|D|(a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat|
04054|074|D|Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive|
04054|075|D|metabolizers.  In intermediate metabolizers, eliglustat Cmax and AUC would|
04054|076|D|be expected to increase 4.2-fold and 5-fold, respectively.(1)|
04054|077|D|   Dual strong CYP3A4 and weak CYP2D6 inhibitors include: cobicistat.(1,3,4)|
04054|078|D|   Dual moderate CYP3A4 and weak CYP2D6 inhibitors include: diltiazem,|
04054|079|D|fedratinib, fluvoxamine, imatinib, and verapamil.(1,3,4)|
04054|080|B||
04054|081|R|REFERENCES:|
04054|082|B||
04054|083|R|1.Cerdelga (eliglustat) US prescribing information. Genzyme Ireland, Ltd.|1
04054|084|R|  August, 2018.|1
04054|085|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04054|086|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04054|087|R|  settings: a scientific statement from the American Heart Association and|6
04054|088|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04054|089|R|  2;55(9):934-47.|6
04054|090|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04054|091|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04054|092|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04054|093|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04054|094|R|  11/14/2017.|1
04054|095|R|4.This information is based on an extract from the Certara Drug Interaction|6
04054|096|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04055|001|T|MONOGRAPH TITLE:  Ubrogepant/Ginkgo Biloba|
04055|002|B||
04055|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04055|004|L|of severe adverse interaction.|
04055|005|B||
04055|006|A|MECHANISM OF ACTION:  Ubrogepant is a CYP3A4 substrate.(1)  Ginkgo biloba is|
04055|007|A|both a weak CYP3A4 inhibitor and inducer.(2,3)|
04055|008|B||
04055|009|E|CLINICAL EFFECTS:  Concurrent use of ubrogepant with ginkgo biloba may lead|
04055|010|E|to increased or decreased levels and effectiveness of ubrogepant.(1)  The|
04055|011|E|net effect of ginkgo biloba on ubrogepant is unknown.|
04055|012|B||
04055|013|P|PREDISPOSING FACTORS:  None determined.|
04055|014|B||
04055|015|M|PATIENT MANAGEMENT:  The manufacturer of ubrogepant does not have|
04055|016|M|recommendations for concurrent use with agents that are both weak CYP3A4|
04055|017|M|inducers and inhibitors.  Concurrent use should be avoided.(1)|
04055|018|M|   For concurrent use with weak CYP3A4 inhibitors: The manufacturer|
04055|019|M|recommends a dosage adjustment of ubrogepant.  Initial dose of ubrogepant|
04055|020|M|should not exceed 50 mg when used concomitantly with weak inhibitors of|
04055|021|M|CYP3A4.  A second dose may be given within 24 hours but should not exceed 50|
04055|022|M|mg when used concurrently with weak CYP3A4 inhibitors.(1)|
04055|023|M|   For concurrent use with moderate or weak CYP3A4 inducers: The|
04055|024|M|manufacturer recommends a dosage adjustment of ubrogepant.  Initial dose of|
04055|025|M|ubrogepant should be 100 mg.  If a second dose is needed, the the dose of|
04055|026|M|ubrogepant should be 100 mg.(1)|
04055|027|B||
04055|028|D|DISCUSSION:  Coadministration of ubrogepant with verapamil, a moderate|
04055|029|D|CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in|
04055|030|D|area-under-curve (AUC) and concentration maximum (Cmax), respectively.  No|
04055|031|D|dedicated drug interaction study was conducted to assess concomitant use|
04055|032|D|with weak CYP3A4 inhibitors.  The conservative prediction of the maximal|
04055|033|D|potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not|
04055|034|D|expected to be more than 2-fold.(1)|
04055|035|D|   Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer,|
04055|036|D|resulted in an 80% reduction in ubrogepant exposure.  No dedicated drug|
04055|037|D|interaction studies were conducted to assess concomitant use with moderate|
04055|038|D|or weak CYP3A4 inducers.  Dose adjustment for concomitant use of ubrogepant|
04055|039|D|with moderate or weak CYP3A4 inducers is recommended based on a conservative|
04055|040|D|prediction of 50% reduction in exposure of ubrogepant.(1)|
04055|041|B||
04055|042|R|REFERENCES:|
04055|043|B||
04055|044|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
04055|045|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04055|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04055|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04055|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04055|049|R|  11/14/2017.|1
04055|050|R|3.This information is based on an extract from the Certara Drug Interaction|6
04055|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04056|001|T|MONOGRAPH TITLE:  Ubrogepant/Sotorasib|
04056|002|B||
04056|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04056|004|L|of severe adverse interaction.|
04056|005|B||
04056|006|A|MECHANISM OF ACTION:  Ubrogepant is a CYP3A4 and P-gp substrate.(1)|
04056|007|A|Sotorasib is a moderate CYP3A4 inducer and a P-glycoprotein (P-gp)|
04056|008|A|inhibitor.(2,3)|
04056|009|B||
04056|010|E|CLINICAL EFFECTS:  Concurrent use of ubrogepant with sotorasib may lead to|
04056|011|E|increased or decreased levels and effectiveness of ubrogepant.(1)  The net|
04056|012|E|effect of sotorasib on ubrogepant is unknown.|
04056|013|B||
04056|014|P|PREDISPOSING FACTORS:  None determined.|
04056|015|B||
04056|016|M|PATIENT MANAGEMENT:  The manufacturer of ubrogepant does not have|
04056|017|M|recommendations for concurrent use with agents that are both moderate CYP3A4|
04056|018|M|inducers and P-gp inhibitors.  Concurrent use should be avoided.(1)|
04056|019|M|   For concurrent use of ubrogepant with moderate CYP3A4 inducers: The|
04056|020|M|manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant.|
04056|021|M|Initial dose of ubrogepant should be 100 mg.  If a second dose is needed,|
04056|022|M|the dose of ubrogepant should be 100 mg.(1)|
04056|023|M|   For concurrent use of ubrogepant with P-gp inhibitors: The manufacturer|
04056|024|M|recommends a dosage adjustment of ubrogepant.  The dose of ubrogepant should|
04056|025|M|not exceed 50 mg for initial dose.  If a second dose of ubrogepant is|
04056|026|M|needed, the dose should not exceed 50 mg.(1)|
04056|027|M|   For concurrent use of sotorasib with P-gp substrates: The US manufacturer|
04056|028|M|of sotorasib states that the concurrent use of narrow therapeutic index P-gp|
04056|029|M|substrates should be avoided.  If concurrent therapy cannot be avoided, the|
04056|030|M|dosage of the narrow therapeutic index P-gp substrate should be decreased|
04056|031|M|according to the substrate prescribing information.(2)|
04056|032|B||
04056|033|D|DISCUSSION:  Coadministration of ubrogepant with rifampin, a strong CYP3A4|
04056|034|D|inducer, resulted in an 80% reduction in ubrogepant exposure.  No dedicated|
04056|035|D|drug interaction studies were conducted to assess concomitant use with|
04056|036|D|moderate or weak CYP3A4 inducers.  Dose adjustment for concomitant use of|
04056|037|D|ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a|
04056|038|D|conservative prediction of 50% reduction in exposure of ubrogepant.(1)|
04056|039|D|   In a study, sotorasib increased digoxin's area-under-curve (AUC) by 21%|
04056|040|D|and maximum concentration (Cmax) by 91%.(2)|
04056|041|B||
04056|042|R|REFERENCES:|
04056|043|B||
04056|044|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
04056|045|R|2.Lumakras (sotorasib) US prescribing information. Amgen Inc November, 2022.|1
04056|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
04056|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04057|001|T|MONOGRAPH TITLE:  Ubrogepant/Darolutamide|
04057|002|B||
04057|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04057|004|L|of severe adverse interaction.|
04057|005|B||
04057|006|A|MECHANISM OF ACTION:  Ubrogepant is a CYP3A4 and BCRP substrate.(1)|
04057|007|A|Darolutamide is a weak CYP3A4 inducer and BCRP inhibitor.(2)|
04057|008|B||
04057|009|E|CLINICAL EFFECTS:  Concurrent use of ubrogepant with darolutamide may lead|
04057|010|E|to increased or decreased levels and effectiveness of ubrogepant.(1)  The|
04057|011|E|net effect of darolutamide on ubrogepant is unknown.|
04057|012|B||
04057|013|P|PREDISPOSING FACTORS:  None determined.|
04057|014|B||
04057|015|M|PATIENT MANAGEMENT:  The manufacturer of ubrogepant does not have|
04057|016|M|recommendations for concurrent use with agents that are both weak CYP3A4|
04057|017|M|inducers and BCRP inhibitors.  Concurrent use should be avoided.(1)|
04057|018|M|   For concurrent use of ubrogepant with weak CYP3A4 inducers: The|
04057|019|M|manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant.|
04057|020|M|Initial dose of ubrogepant should be 100 mg.  If a second dose is needed,|
04057|021|M|the the dose of ubrogepant should be 100 mg.(1)|
04057|022|M|   For concurrent use of ubrogepant with BCRP inhibitors: The manufacturer|
04057|023|M|of ubrogepant recommends a dosage adjustment of ubrogepant.  The dose of|
04057|024|M|ubrogepant should not exceed 50 mg for initial dose.  If a second dose of|
04057|025|M|ubrogepant is needed, the dose should not exceed 50 mg.(1)|
04057|026|M|   For concurrent use of darolutamide with BCRP substrates: The manufacturer|
04057|027|M|of darolutamide states that concurrent use of BCRP substrates should be|
04057|028|M|avoided.  If concurrent use cannot be avoided, monitor for adverse events|
04057|029|M|more frequently and consider dose reduction of the BCRP substrate.(2)|
04057|030|B||
04057|031|D|DISCUSSION:  Ubrogepant is a substrate of CYP3A4 and the BCRP|
04057|032|D|transporter.(1)|
04057|033|D|   Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer,|
04057|034|D|resulted in an 80% reduction in ubrogepant exposure.  No dedicated drug|
04057|035|D|interaction studies were conducted to assess concomitant use with moderate|
04057|036|D|or weak CYP3A4 inducers.  Dose adjustment for concomitant use of ubrogepant|
04057|037|D|with moderate or weak CYP3A4 inducers is recommended based on a conservative|
04057|038|D|prediction of 50% reduction in exposure of ubrogepant.(1)|
04057|039|D|   Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant.|
04057|040|D|Clinical drug interaction studies with inhibitors of these transporters were|
04057|041|D|not conducted.  The US manufacturer of ubrogepant recommends dose adjustment|
04057|042|D|if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1)|
04057|043|B||
04057|044|R|REFERENCES:|
04057|045|B||
04057|046|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
04057|047|R|2.Nubeqa (darolutamide) US prescribing information. Bayer Healthcare|1
04057|048|R|  Pharmaceuticals, Inc. August, 2022.|1
04057|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
04057|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04058|001|T|MONOGRAPH TITLE:  Diacetylmorphine for MAT/Tizanidine|
04058|002|B||
04058|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04058|004|L|take action as needed.|
04058|005|B||
04058|006|A|MECHANISM OF ACTION:  Concurrent use of diacetylmorphine and muscle|
04058|007|A|relaxants may result in additive CNS depression.(1-3)|
04058|008|B||
04058|009|E|CLINICAL EFFECTS:  Concurrent use of diacetylmorphine and other CNS|
04058|010|E|depressants, such as muscle relaxants, may result in profound sedation,|
04058|011|E|respiratory depression, coma, and/or death.(1-3)|
04058|012|B||
04058|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04058|014|P|may increase the risk of adverse effects.|
04058|015|B||
04058|016|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with|
04058|017|M|diacetylmorphine is not contraindicated in patients taking CNS depressants;|
04058|018|M|however, discontinuation of CNS depressants is preferred in most cases.  In|
04058|019|M|some cases, monitoring at a higher level of care for tapering may be|
04058|020|M|appropriate.  In others, gradual tapering or decreasing to the lowest|
04058|021|M|effective dose of the CNS depressant is appropriate.  Ensure that other|
04058|022|M|health care providers prescribing other CNS depressants are aware of the|
04058|023|M|patient's diacetylmorphine treatment.(2)|
04058|024|M|   Respiratory depression can occur at any time during opioid therapy,|
04058|025|M|especially during therapy initiation and following dosage increases.  The|
04058|026|M|risk of opioid-related overdose or overdose-related death is increased with|
04058|027|M|higher opioid doses, and this risk persists over the course of therapy.|
04058|028|M|Consider these risks when using concurrently with other agents that may|
04058|029|M|cause CNS depression.(4)|
04058|030|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04058|031|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04058|032|M|unresponsiveness.(1)|
04058|033|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04058|034|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04058|035|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04058|036|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04058|037|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04058|038|M|as those taking CNS depressants) and when a patient has household|
04058|039|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04058|040|M|for obtaining an opioid reversal agent (e.g., prescription,|
04058|041|M|over-the-counter, or as part of a community-based program).(5)|
04058|042|B||
04058|043|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04058|044|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04058|045|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04058|046|D|million to 30 million patients.  During this time, the proportion of|
04058|047|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04058|048|D|million patients.(6)|
04058|049|D|   A retrospective cohort study compared the risk of opioid overdose|
04058|050|D|associated with concomitant use of opioids and skeletal muscle relaxants|
04058|051|D|versus opioid use alone. The study examined two types of opioid users (naive|
04058|052|D|opioid use and prevalent opioid use) with and without exposure to skeletal|
04058|053|D|muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the|
04058|054|D|naive and prevalent opioid user cohorts, respectively, generating a combined|
04058|055|D|estimate of 1.21.  The risk increased with treatment duration (less than or|
04058|056|D|equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80)|
04058|057|D|and for the use of baclofen and carisoprodol (HR 1.83 and 1.84,|
04058|058|D|respectively).  Elevated risk was associated with concomitant users with|
04058|059|D|daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and|
04058|060|D|1.39, respectively).(7)|
04058|061|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04058|062|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04058|063|D|per 100,000 and drug overdose deaths involving both opioids and|
04058|064|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04058|065|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04058|066|D|increased from 18% to 31% during this time.(8)|
04058|067|D|   A prospective observational cohort study in North Carolina found that the|
04058|068|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04058|069|D|benzodiazepines were 10 times higher than patients receiving opioid|
04058|070|D|analgesics alone.(9)|
04058|071|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04058|072|D|death from overdose increased with concomitant opioid analgesics and|
04058|073|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04058|074|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04058|075|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04058|076|D|increased risk of fatal overdose.(10)|
04058|077|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04058|078|D|which benzodiazepines were determined to be a cause of death and that|
04058|079|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04058|080|D|determined to be a cause of death.  This study also found that other CNS|
04058|081|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04058|082|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04058|083|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04058|084|D|where opioid analgesics were also implicated.(11)|
04058|085|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04058|086|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04058|087|D|deaths.(12)|
04058|088|D|   While concomitant use of MAT with CNS depressants increases the risk of|
04058|089|D|adverse reactions, barriers to MAT can pose a greater risk of morbidity and|
04058|090|D|mortality due to opioid use disorder.(2)|
04058|091|B||
04058|092|R|REFERENCES:|
04058|093|B||
04058|094|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04058|095|R|  warns about serious risks and death when combining opioid pain or cough|1
04058|096|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04058|097|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04058|098|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04058|099|R|  urges caution about withholding opioid addiction medications from patients|1
04058|100|R|  taking benzodiazepines or CNS depressants: careful medication management|1
04058|101|R|  can reduce risks. available at:|1
04058|102|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
04058|103|R|3.Diacetylmorphine Canadian prescribing information. Pharmascience Inc.|1
04058|104|R|  February, 2022.|1
04058|105|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04058|106|R|  prescribing information for all opioid pain medicines to provide|1
04058|107|R|  additional guidance for safe use. Available at:|1
04058|108|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04058|109|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04058|110|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04058|111|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04058|112|R|  recommends health care professionals discuss naloxone with all patients|1
04058|113|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04058|114|R|  disorder. Available at:|1
04058|115|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04058|116|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04058|117|R|  d-pain July 23, 2020.|1
04058|118|R|6.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04058|119|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04058|120|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04058|121|R|7.Li Y, Delcher C, Wei YJJ, Reisfield GM, Brown JD, Tighe P, Winterstein AG.|2
04058|122|R|  Risk of opioid overdose associated with concomitant use of opioids and|2
04058|123|R|  sekeltal muscle relaxants: A population-based cohort study. Clin Pharmacol|2
04058|124|R|  Ther 2020 Jul;108(1):81-88.|2
04058|125|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04058|126|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04058|127|R|  49(4):493-501.|2
04058|128|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04058|129|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04058|130|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04058|131|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04058|132|R|   prescribing patterns and deaths from drug overdose among US veterans|2
04058|133|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
04058|134|R|   350:h2698.|2
04058|135|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04058|136|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04058|137|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04058|138|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04058|139|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04058|140|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04059|001|T|MONOGRAPH TITLE:  Citalopram; Escitalopram/Fluconazole|
04059|002|B||
04059|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04059|004|L|of severe adverse interaction.|
04059|005|B||
04059|006|A|MECHANISM OF ACTION:  Citalopram is primarily metabolized by the CYP2C19|
04059|007|A|isoenzyme.(1)|
04059|008|A|   At lower systemic concentrations, escitalopram is primarily metabolized|
04059|009|A|by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(2)|
04059|010|A|   Concurrent use with other agents that prolong the QTc interval may result|
04059|011|A|in additive effects on the QTc interval.(1-4)|
04059|012|A|   Fluconazole is a strong CYP2C19 inhibitor and has been shown to prolong|
04059|013|A|the QTc interval.|
04059|014|B||
04059|015|E|CLINICAL EFFECTS:  Concurrent use of an agent which significantly inhibits|
04059|016|E|CYP2C19 may result in elevated concentrations and toxicity from citalopram|
04059|017|E|and escitalopram, including risks for serotonin syndrome or prolongation of|
04059|018|E|the QTc interval.(1,2)|
04059|019|E|   Prolongation of the QT interval may result in life-threatening|
04059|020|E|arrhythmias, including torsades de pointes.(5)|
04059|021|E|   Symptoms of serotonin syndrome may include tremor, agitation,|
04059|022|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04059|023|E|rigidity.(6)|
04059|024|B||
04059|025|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased in|
04059|026|P|patients with congenital long QT syndrome, cardiovascular disease (e.g.|
04059|027|P|heart failure, myocardial infarction), hypokalemia, hypomagnesemia,|
04059|028|P|hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status|
04059|029|P|at CYP2C19, concurrent use of more than one agent known to cause QT|
04059|030|P|prolongation, or with higher blood concentrations of escitalopram.(5)|
04059|031|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04059|032|P|higher systemic concentrations of either QT prolonging drug are additional|
04059|033|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04059|034|P|drug concentrations include rapid infusion of an intravenous dose or|
04059|035|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04059|036|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04059|037|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
04059|038|P|   Predisposing factors for serotonin-related adverse effects include use in|
04059|039|P|the elderly, in patients with hepatic impairment, and in patients receiving|
04059|040|P|multiple agents which increase central serotonin levels.(1,6)|
04059|041|P|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04059|042|P|magnesium, and potassium levels and monitoring ECG at baseline and at|
04059|043|P|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04059|044|P|patients to report any irregular heartbeat, dizziness, or fainting.|
04059|045|B||
04059|046|M|PATIENT MANAGEMENT:  Concurrent use of citalopram or escitalopram with|
04059|047|M|fluconazole should be avoided.(1,2)|
04059|048|M|   Due to the risk of QT prolongation, citalopram doses greater than 40 mg|
04059|049|M|once daily are not recommended.  Citalopram doses should be limited to 20 mg|
04059|050|M|once daily in patients who are CYP2C19 poor metabolizers or patients|
04059|051|M|receiving CYP2C19 inhibitors.(1)|
04059|052|M|   If patients have a persistent QTc measurement > 500 ms, discontinue|
04059|053|M|citalopram.  If a patient develops symptoms including dizziness,|
04059|054|M|palpitations, or syncope, further evaluation is warranted included cardiac|
04059|055|M|monitoring.(1)|
04059|056|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04059|057|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04059|058|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04059|059|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04059|060|M|   If concurrent therapy is warranted, patients should be monitored for|
04059|061|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
04059|062|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
04059|063|M|heart palpitations, restlessness, confusion, agitation, trouble with|
04059|064|M|coordination, or severe diarrhea.|
04059|065|B||
04059|066|D|DISCUSSION:  Concurrent use of citalopram (40 mg daily) and cimetidine (400|
04059|067|D|mg twice daily) for 8 days increased the maximum concentration (Cmax) and|
04059|068|D|area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1)|
04059|069|D|   Citalopram has been associated with dose-depended increases in the QTc|
04059|070|D|interval.  In healthy subjects, the maximum mean difference in QTc interval|
04059|071|D|seen with 20 mg of citalopram and 60 mg of citalopram were 8.5 msec (90% CI|
04059|072|D|= 6.2-10.8 msec) and 18.5 msec (90% CI = 16.0-21.0 msec), respectively.|
04059|073|D|Based on extrapolation, a 40 mg dose of citalopram is expected to produce a|
04059|074|D|mean increase in the QTc interval of 12.6 msec (90% CI = 10.9-14.3 msec).(1)|
04059|075|D|   In a clinical trial of use of citalopram for agitation in Alzheimer's|
04059|076|D|disease, citalopram (30 mg daily) was associated with a mean increase in QTc|
04059|077|D|of 18.1 msec.(7)|
04059|078|D|   A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was|
04059|079|D|conducted; a change of 10 msec for upper bound of the 95% confidence level|
04059|080|D|is the threshold for regulatory concern.  In this study, changes to the|
04059|081|D|upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for|
04059|082|D|the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg|
04059|083|D|was 1.7-fold higher than the Cmax for the maximum recommended escitalopram|
04059|084|D|dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected|
04059|085|D|steady state concentrations in 2C19 poor metabolizers following a 20 mg|
04059|086|D|escitalopram dose.(2)|
04059|087|D|  In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of|
04059|088|D|CYP2C19 was administered daily for 6 days. On day 5 a single dose of|
04059|089|D|escitalopram 20 mg was also administered; the area-under-curve (AUC) of|
04059|090|D|escitalopram was increased by 50%. Manufacturer prescribing information|
04059|091|D|recommends a maximum citalopram dose of 20mg daily in patients receiving|
04059|092|D|CYP2C19 inhibitors.(2)|
04059|093|D|      Fluconazole is a strong CYP2C19 inhibitor.(9)|
04059|094|B||
04059|095|R|REFERENCES:|
04059|096|B||
04059|097|R|1.Celexa (citalopram hydrobromide) US prescribing information. Forest|1
04059|098|R|  Laboratories Inc. August, 2023.|1
04059|099|R|2.Lexapro (escitalopram oxalate) US prescribing information. Forest|1
04059|100|R|  Pharmaceuticals Inc. May, 2023.|1
04059|101|R|3.Gagne M. Dear Canadian Healthcare Professional:  Subject: Association of|1
04059|102|R|  CELEXA (citalopram hydrobromide) with Dose - Dependent QT Prolongation.|1
04059|103|R|  Lundbeck Canada January 25, 2012.|1
04059|104|R|4.USFood and Drug Administration. FDA Drug Safety Communication: Revised|1
04059|105|R|  recommendations for Celexa (citalopram hydrobromide) related to a|1
04059|106|R|  potential risk of abnormal heart rhythms with high doses. available at:|1
04059|107|R|  http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm March 28, 2012.|1
04059|108|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04059|109|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04059|110|R|  settings: a scientific statement from the American Heart Association and|6
04059|111|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04059|112|R|  2;55(9):934-47.|6
04059|113|R|6.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04059|114|R|  352(11):1112-20.|6
04059|115|R|7.Drye LT, et al. Changes in QTc interval in the citalopram for agitation in|2
04059|116|R|  Alzheimer's disease (CitAD) randomized trial. PLoS One 2014;9(6):e98426.|2
04059|117|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
04059|118|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04059|119|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04059|120|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04059|121|R|9.This information is based on an extract from the Certara Drug Interaction|6
04059|122|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04060|001|T|MONOGRAPH TITLE:  Mavacamten/Strong CYP2C19 Inhibitors|
04060|002|B||
04060|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04060|004|L|is contraindicated and generally should not be dispensed or administered to|
04060|005|L|the same patient.|
04060|006|B||
04060|007|A|MECHANISM OF ACTION:  Strong CYP2C19 inhibitors may decrease the metabolism|
04060|008|A|of mavacamten.(1-3)|
04060|009|B||
04060|010|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of CYP2C19 increases|
04060|011|E|plasma exposure of mavacamten which may increase the incidence and severity|
04060|012|E|of adverse reactions of mavacamten.(1-3)|
04060|013|B||
04060|014|P|PREDISPOSING FACTORS:  CYP2C19 rapid and ultrarapid metabolizers may|
04060|015|P|experience an increased incidence or severity of adverse effects.(1-3)|
04060|016|B||
04060|017|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers of mavacamten state|
04060|018|M|concomitant use with a strong CYP2C19 inhibitor is contraindicated.(1,2)|
04060|019|M|   The UK manufacturer of mavacamten states concomitant use with strong|
04060|020|M|CYP2C19 inhibitors is dependent on CYP2C19 phenotype.|
04060|021|M|   Labeling recommends:|
04060|022|M|   -In patients who are CYP2C19 poor metabolizers, strong CYP2C19 inhibitors|
04060|023|M|may be used concurrently without dose adjustment of mavacamten.  Monitor|
04060|024|M|left ventricular ejection fraction (LVEF) in 4 weeks then resume usual|
04060|025|M|monitoring schedule.|
04060|026|M|   -In patient who are CYP2C19 intermediate, normal, rapid, or ultrarapid|
04060|027|M|metabolizers:|
04060|028|M|   When used concurrently with strong CYP2C19 inhibitors, initiate|
04060|029|M|mavacamten at 2.5 mg daily. If starting a strong CYP2C19 inhibitor, reduce|
04060|030|M|mavacamten dose from 15 mg to 5 mg, 10 mg to 2.5 mg, 5 mg to 2.5 mg, or|
04060|031|M|discontinue 2.5 mg.  Monitor LVEF in 4 weeks then resume usual monitoring|
04060|032|M|schedule.|
04060|033|M|   -If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of|
04060|034|M|2.5 mg daily.  If starting a strong CYP2C19 inhibitor, reduce mavacamten|
04060|035|M|dose from 5 mg to 2.5 mg or discontinue mavacamten if on 2.5 mg. Monitor|
04060|036|M|LVEF in 4 weeks then resume usual monitoring schedule.(3)|
04060|037|B||
04060|038|D|DISCUSSION:  Concomitant use of mavacamten (15 mg) with omeprazole (20 mg),|
04060|039|D|a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve|
04060|040|D|(AUC) by 48% with no effect on maximum concentration (Cmax) in healthy|
04060|041|D|CYP2C19 normal metabolizers and rapid metabolizers.(1)|
04060|042|D|   Strong CYP2C19 inhibitors linked to this monograph include: fluoxetine|
04060|043|D|and ticlopidine.(4,5)|
04060|044|B||
04060|045|R|REFERENCES:|
04060|046|B||
04060|047|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04060|048|R|  April, 2025.|1
04060|049|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04060|050|R|  Canada February, 2024.|1
04060|051|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04060|052|R|  Squibb July, 2023.|1
04060|053|R|4.This information is based on an extract from the Certara Drug Interaction|6
04060|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04060|055|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04060|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04060|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04060|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04060|059|R|  11/14/2017.|1
04061|001|T|MONOGRAPH TITLE:  Mavacamten/Strong CYP3A4 Inhibitors|
04061|002|B||
04061|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04061|004|L|of severe adverse interaction.|
04061|005|B||
04061|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04061|007|A|mavacamten.(1-3)|
04061|008|B||
04061|009|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of CYP3A4 increases plasma|
04061|010|E|exposure of mavacamten which may increase the incidence and severity of|
04061|011|E|adverse reactions of mavacamten.(1-3)|
04061|012|B||
04061|013|P|PREDISPOSING FACTORS:  CYP2C19 poor metabolizers may experience an increased|
04061|014|P|incidence or severity of adverse effects.(1-3)|
04061|015|B||
04061|016|M|PATIENT MANAGEMENT:  The US manufacturer of mavacamten recommends initiating|
04061|017|M|mavacamten at the recommended starting dosage of 2.5 mg orally once daily in|
04061|018|M|patients who are on stable therapy with a moderate CYP3A4 inhibitor.  Reduce|
04061|019|M|dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in|
04061|020|M|patients who are on mavacamten treatment and intend to initiate a strong|
04061|021|M|CYP3A4 inhibitor.  Schedule clinical and echocardiographic assessment 4|
04061|022|M|weeks after inhibitor initiation, and do not up-titrate mavacamten until 12|
04061|023|M|weeks after inhibitor initiation.(1)|
04061|024|M|   Avoid initiation of concomitant strong CYP3A4 inhibitors in patients who|
04061|025|M|are on stable treatment with 2.5 mg of mavacamten because a lower dose is|
04061|026|M|not available.(1)|
04061|027|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04061|028|M|duration of the strong CYP3A4 inhibitor.  After therapy with the strong|
04061|029|M|CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the|
04061|030|M|previous dose immediately upon discontinuation.(1)|
04061|031|M|   The Canadian manufacturers of mavacamten state concomitant use with|
04061|032|M|strong CYP3A4 inhibitors is contraindicated.(2)|
04061|033|M|   The UK manufacturer of mavacamten states concomitant use with strong|
04061|034|M|CYP3A4 inhibitors is dependent on CYP2C19 phenotype.  In patients who are|
04061|035|M|CYP2C19 poor metabolizers, concurrent use of strong CYP3A4 inhibitors is|
04061|036|M|contraindicated.  In patient who are CYP2C19 intermediate, normal, rapid, or|
04061|037|M|ultrarapid metabolizers, strong CYP3A4 inhibitors may be used concurrently|
04061|038|M|without dose adjustment of mavacamten.  Monitor left ventricular ejection|
04061|039|M|fraction (LVEF) in 4 weeks then resume usual monitoring schedule.(3)|
04061|040|B||
04061|041|D|DISCUSSION:  Concomitant use of mavacamten (15 mg) with ketoconazole 400 mg,|
04061|042|D|a strong CYP3A4 inhibitor, once daily is predicted to increase mavacamten|
04061|043|D|area-under-curve (AUC) and maximum concentration (Cmax) up to 130% and 90%,|
04061|044|D|respectively.(1)|
04061|045|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
04061|046|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04061|047|D|ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone,|
04061|048|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
04061|049|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, and|
04061|050|D|tucatinib.(4,5)|
04061|051|B||
04061|052|R|REFERENCES:|
04061|053|B||
04061|054|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04061|055|R|  April, 2025.|1
04061|056|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04061|057|R|  Canada February, 2024.|1
04061|058|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04061|059|R|  Squibb July, 2023.|1
04061|060|R|4.This information is based on an extract from the Certara Drug Interaction|6
04061|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04061|062|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04061|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04061|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04061|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04061|066|R|  11/14/2017.|1
04062|001|T|MONOGRAPH TITLE:  Mavacamten/Strong & Moderate CYP2C19 Inducers|
04062|002|B||
04062|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04062|004|L|is contraindicated and generally should not be dispensed or administered to|
04062|005|L|the same patient.|
04062|006|B||
04062|007|A|MECHANISM OF ACTION:  Strong and moderate inducers of CYP2C19 may increase|
04062|008|A|the metabolism of mavacamten.(1-3)|
04062|009|B||
04062|010|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP2C19 inducers|
04062|011|E|with mavacamten may decrease the levels and effectiveness of|
04062|012|E|mavacamten.(1-3)|
04062|013|B||
04062|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04062|015|P|of the inducer for longer than 1-2 weeks.|
04062|016|B||
04062|017|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers of mavacamten state|
04062|018|M|concomitant use of strong or moderate inducers of CYP2C19 is|
04062|019|M|contraindicated.(1,2)|
04062|020|M|   The UK manufacturer of mavacamten states concomitant use with strong or|
04062|021|M|moderate CYP2C19 inducers is dependent on CYP2C19 phenotype.  Labeling|
04062|022|M|recommends:|
04062|023|M|   -When initiating or increasing the dose of a strong inducer in patients|
04062|024|M|who are CYP2C19 poor metabolizers, monitor patients closely and adjust|
04062|025|M|mavacamten dose based on clinical response.  The maximum recommended dose of|
04062|026|M|mavacamten is 5 mg daily.|
04062|027|M|   -When initiating or increasing the dose a strong or moderate inducer in|
04062|028|M|patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid|
04062|029|M|metabolizers, monitor patients closely and adjust mavacamten dose based on|
04062|030|M|clinical response.|
04062|031|M|   -When discontinuing or decreasing the dose of a strong inducer in|
04062|032|M|patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten|
04062|033|M|from 5 mg to 2.5 mg, or pause therapy if dose is 2.5 mg.|
04062|034|M|   -When discontinuing or decreasing the dose of a strong or moderate|
04062|035|M|inducer in patients who are CYP2C19 intermediate, normal, rapid, or|
04062|036|M|ultrarapid metabolizers, decrease the dose of mavacamten by one dose level|
04062|037|M|when on doses of 5 mg or higher.  Maintain mavacamten dose when on 2.5 mg.|
04062|038|M|   -No dose adjustment is warranted with moderate inducers in patients who|
04062|039|M|are CYP2C19 poor metabolizers.(3)|
04062|040|B||
04062|041|D|DISCUSSION:  Concomitant use of mavacamten (a single 15 mg dose) with a|
04062|042|D|strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted|
04062|043|D|to decrease mavacamten area-under-curve (AUC) and maximum concentration|
04062|044|D|(Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by|
04062|045|D|69% and 4%, respectively, in CYP2C19 poor metabolizers.|
04062|046|D|   Moderate CYP2C19 inducers linked to this monograph include:|
04062|047|D|dicloxacillin.(4,5)|
04062|048|B||
04062|049|R|REFERENCES:|
04062|050|B||
04062|051|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04062|052|R|  April, 2025.|1
04062|053|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04062|054|R|  Canada February, 2024.|1
04062|055|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04062|056|R|  Squibb July, 2023.|1
04062|057|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04062|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04062|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04062|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04062|061|R|  11/14/2017.|1
04062|062|R|5.This information is based on an extract from the Certara Drug Interaction|6
04062|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04063|001|T|MONOGRAPH TITLE:  Fenfluramine/Strong CYP1A2 or CYP2D6 Inhibitors|
04063|002|B||
04063|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04063|004|L|take action as needed.|
04063|005|B||
04063|006|A|MECHANISM OF ACTION:  Strong CYP1A2 or CYP2D6 inhibitors may decrease the|
04063|007|A|metabolism of fenfluramine.(1)|
04063|008|A|   Over 75% of fenfluramine is metabolized to norfenfluramine prior to|
04063|009|A|elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.(1)|
04063|010|B||
04063|011|E|CLINICAL EFFECTS:  Concurrent use of agents that are strong CYP1A2 or CYP2D6|
04063|012|E|inhibitors may result in elevated levels of and toxicity from|
04063|013|E|fenfluramine.(1)|
04063|014|B||
04063|015|P|PREDISPOSING FACTORS:  None determined.|
04063|016|B||
04063|017|M|PATIENT MANAGEMENT:  The US manufacturer of fenfluramine states that the|
04063|018|M|maximum daily dosage of fenfluramine with a strong CYP1A2 or CYP2D6|
04063|019|M|inhibitor in patients not on stiripentol is 20 mg.  In patients on|
04063|020|M|concomitant stiripentol and clobazam, the maximum fenfluramine dosage with|
04063|021|M|strong CYP1A2 or CYP2D6 inhibitors is 17 mg.(1)|
04063|022|M|   If the strong CYP1A2 or CYP2D6 inhibitors is discontinued, consider|
04063|023|M|gradually increasing the fenfluramine dosage to the usual recommended dose|
04063|024|M|without the inhibitor.(1)|
04063|025|B||
04063|026|D|DISCUSSION:  In a study of healthy volunteers, fluvoxamine 50 mg daily (a|
04063|027|D|strong CYP1A2 inhibitor) increased the area-under-curve (AUC) and maximum|
04063|028|D|concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 102% and 22%,|
04063|029|D|respectively, and decreased the AUC and Cmax of norfenfluramine by 22% and|
04063|030|D|44%, respectively.(1)|
04063|031|D|   In a study of healthy volunteers, paroxetine 30 mg daily (a strong CYP2D6|
04063|032|D|inhibitor) increased the AUC and Cmax of single-dose fenfluramine 0.4 mg/kg|
04063|033|D|by 81% and 13%, respectively, and decreased the AUC and Cmax of|
04063|034|D|norfenfluramine by 13% and 29%, respectively.(1)|
04063|035|D|   Strong CYP1A2 inhibitors linked to this monograph include: Angelica root,|
04063|036|D|ciprofloxacin, enasidenib, vemurafenib, and viloxazine.|
04063|037|D|   Strong CYP2D6 inhibitors linked to this monograph include: bupropion,|
04063|038|D|dacomitinib, hydroquinidine, and quinidine.(1-4)|
04063|039|B||
04063|040|R|REFERENCES:|
04063|041|B||
04063|042|R|1.Fintepla (fenfluramine) US prescribing information. Zogenix Inc. January|1
04063|043|R|  2023.|1
04063|044|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04063|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04063|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04063|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04063|048|R|  11/14/2017.|1
04063|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
04063|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04064|001|T|MONOGRAPH TITLE:  Selected Anticoagulants/Thyroid|
04064|002|B||
04064|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04064|004|L|take action as needed.|
04064|005|B||
04064|006|A|MECHANISM OF ACTION:  Unknown. However, thyroid hormones may influence|
04064|007|A|concentrations of vitamin K-dependent clotting factors.|
04064|008|B||
04064|009|E|CLINICAL EFFECTS:  Concurrent use of vitamin K antagonists and thyroid|
04064|010|E|hormones may increase the risk for bleeding.  Hypothyroidism may increase|
04064|011|E|the oral anticoagulant requirements.  Administration of thyroid hormones or|
04064|012|E|hyperthyroidism may decrease oral anticoagulant requirements.|
04064|013|B||
04064|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04064|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04064|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
04064|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04064|018|P|risk for bleeding (e.g. NSAIDs).|
04064|019|B||
04064|020|M|PATIENT MANAGEMENT:  Monitor prothrombin activity and adjust the|
04064|021|M|anticoagulant dosage accordingly during initiation of warfarin therapy in|
04064|022|M|patients receiving thyroid replacement therapy, during the initiation or|
04064|023|M|titration of thyroid replacement therapy in patients receiving warfarin, or|
04064|024|M|if any changes in thyroid function occur.|
04064|025|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04064|026|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04064|027|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04064|028|M|patients with any symptoms.|
04064|029|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04064|030|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04064|031|M|anticoagulation in patients with active pathologic bleeding.|
04064|032|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04064|033|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04064|034|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04064|035|M|and/or swelling.|
04064|036|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04064|037|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04064|038|M|initiating, altering the dose or discontinuing either drug.|
04064|039|B||
04064|040|D|DISCUSSION:  Any change in thyroid status in patients stabilized on warfarin|
04064|041|D|may necessitate a change in warfarin dosage requirements.  Initiation of|
04064|042|D|thyroid replacement therapy in patients stabilized on warfarin may result in|
04064|043|D|increases in the effects of warfarin.  A decrease in the dose of warfarin|
04064|044|D|usually becomes necessary within one to four weeks after starting therapy|
04064|045|D|with thyroid compounds.  Warfarin therapy should be initiated in low doses|
04064|046|D|in patients who are hyperthyroid.|
04064|047|D|   In a 16 year population based nested matched case control study, 10,532|
04064|048|D|hospitalizations for hemorrhage were evaluated and matched to 40,595|
04064|049|D|controls.  The primary analysis showed no increase in risk of hemorrhage in|
04064|050|D|older patients on warfarin initiated on levothyroxine in previous 30 days|
04064|051|D|(OR 1.11, 95% CI 0.67-1.86).  When patients were matched up to 90 days prior|
04064|052|D|to the hemorrhage event, there was no significant association with|
04064|053|D|levothyroxine 31-60 days prior to index date (OR 0.75 95% CI 0.26-2.25) or|
04064|054|D|61-90 days prior to index date (OR 0.67 95% CI 0.15-3.01).|
04064|055|D|   A retrospective, self-controlled study of 102 patients on chronic|
04064|056|D|warfarin therapy were included if the patient had INR results 90 days before|
04064|057|D|and after starting levothyroxine.  The mean warfarin dose/INR ratio in the|
04064|058|D|pre-period and post-period had no significant change (p=0.825).  In patients|
04064|059|D|who achieved euthyroid during post-period, warfarin dose/INR ratio was|
04064|060|D|numerically lower in the post-period but not statistically significant|
04064|061|D|(13.42 versus 12.7, respectively; p=0.338).  In patients initiated on|
04064|062|D|levothyroxine doses greater than 50 mcg, pre-period and post-period warfarin|
04064|063|D|dose/INR ratio also had no significant difference (p>0.2).|
04064|064|B||
04064|065|R|REFERENCES:|
04064|066|B||
04064|067|R|1.Walters MB. The relationship between thyroid function and anticoagulant|3
04064|068|R|  therapy. Am J Cardiol 1963 Jan;11:112-4.|3
04064|069|R|2.Schrogie JJ, Solomon HM. The anticoagulant response to bishydroxycoumarin.|2
04064|070|R|  II. The effect of D- thyroxine, clofibrate, and norethandrolone. Clin|2
04064|071|R|  Pharmacol Ther 1967 Jan-Feb;8(1):70-7.|2
04064|072|R|3.Kimberg DV. The liver. In:  Werner SC, Ingbar SH, ed. Werner and Ingbar's|6
04064|073|R|  The thyroid. New York: Harper & Row; 1971: 569..|6
04064|074|R|4.Feely J, Stevenson IH, Crooks J. Altered plasma protein binding of drugs|5
04064|075|R|  in thyroid disease. Clin Pharmacokinet 1981 Jul-Aug;6(4):298-305.|5
04064|076|R|5.Weintraub M, Breckenridge RT, Griner PF. The effects of dextrothyroxine on|5
04064|077|R|  the kinetics of prothrombin activity: proposed mechanism of the|5
04064|078|R|  potentiation of warfarin by D-thyroxine. J Lab Clin Med 1973 Feb;|5
04064|079|R|  81(2):273-9.|5
04064|080|R|6.Owens JC, Neely WB, Owen WR. Effect of sodium dextrothyroxine in patients|2
04064|081|R|  receiving anticoagulants. N Engl J Med 1962 Jan 11;266(2):76-9.|2
04064|082|R|7.Self T, Weisburst M, Wooten E, Straughn A, Oliver J. Warfarin-induced|3
04064|083|R|  hypoprothrombinemia. Potentiation by hyperthyroidism. JAMA 1975 Mar 17;|3
04064|084|R|  231(11):1165-6.|3
04064|085|R|8.Rice AJ, McIntosh TJ, Fouts JR, Brunk SF, Wilson WR. Decreased sensitivity|2
04064|086|R|  to warfarin in patients with myxedema. Am J Med Sci 1971 Oct;262(4):211-5.|2
04064|087|R|9.Vagenakis AG, Cote R, Miller ME, Braverman LE, Stohlman F Jr. Enhancement|3
04064|088|R|  of warfarin-induced hypoprothrombinemia by thyrotoxicosis. Johns Hopkins|3
04064|089|R|  Med J 1972 Jul;131(1):69-73.|3
04064|090|R|10.Gotta AW, Sullivan CA, Seaman J, Jean-Gilles B. Prolonged intraoperative|3
04064|091|R|   bleeding caused by propylthiouracil-induced hypoprothrombinemia.|3
04064|092|R|   Anesthesiology 1972 Nov;37(5):562-3.|3
04064|093|R|11.Costigan DC, Freedman MH, Ehrlich RM. Potentiation of oral anticoagulant|3
04064|094|R|   effect by L-thyroxine. Clin Pediatr (Phila) 1984 Mar;23(3):172-4.|3
04064|095|R|12.Wood MD, Delate T, Clark M, Clark N, Horn JR, Witt DM. An evaluation of|2
04064|096|R|   the potential drug interaction between warfarin and levothyroxine. J|2
04064|097|R|   Thromb Haemost 2014 Aug;12(8):1313-9.|2
04064|098|R|13.Pincus D, Gomes T, Hellings C, Zheng H, Paterson JM, Mamdani MM, Juurlink|2
04064|099|R|   DN. A population-based assessment of the drug interaction between|2
04064|100|R|   levothyroxine and warfarin. Clin Pharmacol Ther 2012 Dec;92(6):766-70.|2
04065|001|T|MONOGRAPH TITLE:  Selected Anticoagulants/Antithyroid Drugs|
04065|002|B||
04065|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04065|004|L|take action as needed.|
04065|005|B||
04065|006|A|MECHANISM OF ACTION:  Antithyroid drugs may decrease breakdown of vitamin-K|
04065|007|A|dependent clotting factors, thus increasing the amount of clotting factors|
04065|008|A|available for use.|
04065|009|B||
04065|010|E|CLINICAL EFFECTS:  Decreased clearance of vitamin K dependent clotting|
04065|011|E|factors by antithyroid drugs may result in decreased therapeutic effects of|
04065|012|E|anticoagulants.  However, if thioamide-induced hypothrombinemia occurs, the|
04065|013|E|activity of the anticoagulant may be increased.|
04065|014|B||
04065|015|P|PREDISPOSING FACTORS:  None determined.|
04065|016|B||
04065|017|M|PATIENT MANAGEMENT:  If antithyroid treatment is started or discontinued in|
04065|018|M|patients stabilized on anticoagulant therapy, INRs should be closely|
04065|019|M|monitored and the anticoagulant dose should be adjusted as needed.  Some|
04065|020|M|patients may require alternative hyperthyroid medication in order to achieve|
04065|021|M|therapeutic anticoagulation.|
04065|022|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04065|023|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04065|024|M|initiating, altering the dose or discontinuing either drug.|
04065|025|B||
04065|026|D|DISCUSSION:  Caution should be used when this drug combination if given. In|
04065|027|D|the clinically hyperthyroid patient, the breakdown of the vitamin|
04065|028|D|k-dependent clotting factors is increased resulting in quicker and greater|
04065|029|D|response to the anticoagulant. When antithyroid drugs are administered to|
04065|030|D|correct this, the response to the anticoagulant may decrease. An increase in|
04065|031|D|the anticoagulant dosage may be required.|
04065|032|D|   There are several reports of decreased anticoagulant effects in patients|
04065|033|D|receiving antithyroid agents.  There has been one case reported where the|
04065|034|D|patient experienced an increased response to warfarin when propylthiouracil|
04065|035|D|was added to the patient's drug regimen.|
04065|036|B||
04065|037|R|REFERENCES:|
04065|038|B||
04065|039|R|1.Greenstein RH. Hypoprothrombinemia due to propylthiouracil therapy. JAMA|3
04065|040|R|  1960 Jul 2;173(9):1014-5.|3
04065|041|R|2.Naeye RL, Terrien CM. Hemorrhagic state after therapy with|3
04065|042|R|  propylthiouracil. Am J Clin Pathol 1960 Sep;34(3):254-7.|3
04065|043|R|3.Walters MB. The relationship between thyroid function and anticoagulant|3
04065|044|R|  therapy. Am J Cardiol 1963 Jan;11:112-4.|3
04065|045|R|4.Loeliger EA, van der Esch B, Mattern MJ, Hemker HC. The biological|2
04065|046|R|  disappearance rate of prothrombin, factors VII, IX and X from plasma in|2
04065|047|R|  hypothyoidism, hyperthyroidism, and during fever. Thrombos Diathes|2
04065|048|R|  Haemorrh 1963;10:267-77.|2
04065|049|R|5.Gilbert DK. Hypoprothrombinemia as a complication of propylthiouracil.|3
04065|050|R|  JAMA 1964 Sep;189(11):855.|3
04065|051|R|6.Rice AJ, McIntosh TJ, Fouts JR, Brunk SF, Wilson WR. Decreased sensitivity|2
04065|052|R|  to warfarin in patients with myxedema. Am J Med Sci 1971 Oct;262(4):211-5.|2
04065|053|R|7.Gotta AW, Sullivan CA, Seaman J, Jean-Gilles B. Prolonged intraoperative|3
04065|054|R|  bleeding caused by propylthiouracil-induced hypoprothrombinemia.|3
04065|055|R|  Anesthesiology 1972 Nov;37(5):562-3.|3
04065|056|R|8.Vagenakis AG, Cote R, Miller ME, Braverman LE, Stohlman F Jr. Enhancement|3
04065|057|R|  of warfarin-induced hypoprothrombinemia by thyrotoxicosis. Johns Hopkins|3
04065|058|R|  Med J 1972 Jul;131(1):69-73.|3
04065|059|R|9.Self T, Weisburst M, Wooten E, Straughn A, Oliver J. Warfarin-induced|3
04065|060|R|  hypoprothrombinemia. Potentiation by hyperthyroidism. JAMA 1975 Mar 17;|3
04065|061|R|  231(11):1165-6.|3
04065|062|R|10.Hansten PD. Drug interactions update. Oral anticoagulants and drugs which|6
04065|063|R|   alter thyroid function. Drug Intell Clin Pharm 1980 May;14(5):331-4.|6
04065|064|R|11.Costigan DC, Freedman MH, Ehrlich RM. Potentiation of oral anticoagulant|3
04065|065|R|   effect by L-thyroxine. Clin Pediatr (Phila) 1984 Mar;23(3):172-4.|3
04065|066|R|12.Akin F, Yaylali GF, Bastemir M, Yapar B. Effect of methimazole on|3
04065|067|R|   warfarin anticoagulation in a case of Graves' disease. Blood Coagul|3
04065|068|R|   Fibrinolysis 2008 Jan;19(1):89-91.|3
04065|069|R|13.Squizzato A, Vitale J, Gerdes VE, Romualdi E, Buller HR, Ageno W.|3
04065|070|R|   Recurrent deep venous thrombosis during optimal anticoagulation and overt|3
04065|071|R|   hyperthyroidism: a case report. Blood Coagul Fibrinolysis 2007 Dec;|3
04065|072|R|   18(8):801-3.|3
04065|073|R|14.Busenbark LA, Cushnie SA. Effect of Graves' disease and methimazole on|3
04065|074|R|   warfarin anticoagulation. Ann Pharmacother 2006 Jun;40(6):1200-3.|3
04066|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Mavacamten|
04066|002|B||
04066|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04066|004|L|of severe adverse interaction.|
04066|005|B||
04066|006|A|MECHANISM OF ACTION:  Mavacamten is a moderate CYP3A4 inducer.|
04066|007|A|Coadministration of mavacamten with hormonal contraceptives may lead to|
04066|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
04066|009|A|decreased hormonal concentrations.(1)|
04066|010|B||
04066|011|E|CLINICAL EFFECTS:  Concurrent use of mavacamten can lead to ineffective|
04066|012|E|hormonal contraceptive and cause unintended pregnancy.  Mavacamten may cause|
04066|013|E|fetal harm when administered to a pregnant woman.(1)|
04066|014|B||
04066|015|P|PREDISPOSING FACTORS:  None determined.|
04066|016|B||
04066|017|M|PATIENT MANAGEMENT:  Avoid concomitant use of hormonal contraceptives with|
04066|018|M|mavacamten.  Advise females of reproductive potential to use effective|
04066|019|M|non-hormonal contraception during treatment with mavacamten and for 4 months|
04066|020|M|after the last dose.(1)|
04066|021|M|   Hormonal contraceptives containing a combination of ethinyl estradiol and|
04066|022|M|norethindrone may be used with mavacamten.(1)|
04066|023|M|   Women of reproductive age should be counseled not to rely on hormonal|
04066|024|M|contraceptives (including oral contraceptives, patches, implants, and/or|
04066|025|M|IUDs) for contraception.  Pregnant women and females of reproductive|
04066|026|M|potential should be counseled on the potential risk to the fetus.(1)|
04066|027|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04066|028|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04066|029|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04066|030|M|contraceptive (i.e., a copper IUD).  If a non-hormonal emergency|
04066|031|M|contraceptive is not an option, double the usual dose of levonorgestrel from|
04066|032|M|1.5 to 3 mg.  Advise the patient to have a pregnancy test to exclude|
04066|033|M|pregnancy after use and to seek medical advice if she does become|
04066|034|M|pregnant.(3)|
04066|035|B||
04066|036|D|DISCUSSION:  Mavacamten is a moderate CYP3A4 inducer.(1)|
04066|037|D|   Concurrent use of a 16-day course of mavacamten (25 mg on days 1 and 2,|
04066|038|D|followed by 15 mg for 14 days) resulted in a decrease in midazolam|
04066|039|D|area-under-curve (AUC) and concentration maximum (Cmax) by 13% and 7%,|
04066|040|D|respectively, in healthy CYP2C19 normal metabolizers.  Concurrent use of|
04066|041|D|mavacamten once daily in patients with hypertrophic cardiomyopathy,|
04066|042|D|midazolam AUC and Cmax are predicted to decrease by 21 to 64% and 13 to 48%,|
04066|043|D|respectively, depending on the dose of mavacamten and CYP2C19 phenotype.(1)|
04066|044|D|   Mavacamten has not been studied with hormonal contraceptives.  It can|
04066|045|D|render some hormonal contraceptives ineffective and may cause unintended|
04066|046|D|pregnancy.  Women should use non-hormonal contraception during therapy.(1)|
04066|047|D|   In an animal reproduction study, mavacamten administration resulted in|
04066|048|D|decreases in mean fetal body weight, reductions in fetal ossification of|
04066|049|D|bones, and increases in post-implantation loss as well as increases in|
04066|050|D|skeletal malformations at doses similar to maximum recommended human|
04066|051|D|doses.(1)|
04066|052|B||
04066|053|R|REFERENCES:|
04066|054|B||
04066|055|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04066|056|R|  April, 2025.|1
04066|057|R|2.This information is based on an extract from the Certara Drug Interaction|6
04066|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04066|059|R|3.Medicines and Healthcare products Regulatory Agency.|1
04066|060|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04066|061|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04066|062|R|  available at:|1
04066|063|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04066|064|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04066|065|R|  -and-contraceptive-efficacy September 15, 2016..|1
04067|001|T|MONOGRAPH TITLE:  Mavacamten/Strong CYP3A4 Inducers|
04067|002|B||
04067|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04067|004|L|is contraindicated and generally should not be dispensed or administered to|
04067|005|L|the same patient.|
04067|006|B||
04067|007|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may increase|
04067|008|A|the metabolism of mavacamten.(1-3)|
04067|009|B||
04067|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04067|011|E|levels and effectiveness of mavacamten.(1-3)|
04067|012|B||
04067|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04067|014|P|of the inducer for longer than 1-2 weeks.|
04067|015|B||
04067|016|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers of mavacamten state|
04067|017|M|concurrent use of mavacamten with strong CYP3A4 inducers is|
04067|018|M|contraindicated.(1,2)|
04067|019|M|   The UK manufacturer of mavacamten states concomitant use with strong|
04067|020|M|CYP3A4 inducers is dependent on CYP2C19 phenotype.  Labeling recommends:|
04067|021|M|   -When initiating or increasing the dose of a strong inducer in patients|
04067|022|M|who are CYP2C19 poor metabolizers, monitor patients closely and adjust|
04067|023|M|mavacamten dose based on clinical response.  The maximum recommended dose of|
04067|024|M|mavacamten is 5 mg daily.|
04067|025|M|   -When initiating or increasing the dose a strong inducer in patients who|
04067|026|M|are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers, monitor|
04067|027|M|patients closely and adjust mavacamten dose based on clinical response.|
04067|028|M|   -When discontinuing or decreasing the dose of a strong inducer in|
04067|029|M|patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten|
04067|030|M|from 5 mg to 2.5 mg, or pause therapy if dose is 2.5 mg.|
04067|031|M|   -When discontinuing or decreasing the dose of a strong inducer in|
04067|032|M|patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid|
04067|033|M|metabolizers, decrease the dose of mavacamten by one dose level when on|
04067|034|M|doses of 5 mg or higher.  Maintain mavacamten dose when on 2.5 mg.(3)|
04067|035|B||
04067|036|D|DISCUSSION:  Concomitant use of mavacamten (a single 15 mg dose) with a|
04067|037|D|strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted|
04067|038|D|to decrease mavacamten area-under-curve (AUC) and maximum concentration|
04067|039|D|(Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by|
04067|040|D|69% and 4%, respectively, in CYP2C19 poor metabolizers.(1)|
04067|041|D|    Strong CYP3A4 inducers linked to this monograph include: barbiturates,|
04067|042|D|carbamazepine, encorafenib, ivosidenib, lumacaftor, mitotane, phenobarbital,|
04067|043|D|primidone, rifapentine, and St. John's wort.(4,5)|
04067|044|B||
04067|045|R|REFERENCES:|
04067|046|B||
04067|047|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04067|048|R|  April, 2025.|1
04067|049|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04067|050|R|  Canada February, 2024.|1
04067|051|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04067|052|R|  Squibb July, 2023.|1
04067|053|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04067|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04067|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04067|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04067|057|R|  11/14/2017.|1
04067|058|R|5.This information is based on an extract from the Certara Drug Interaction|6
04067|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04068|001|T|MONOGRAPH TITLE:  Mavacamten/Dual Strong or Moderate CYP2C19 & CYP3A4|
04068|002|T|Inducers|
04068|003|B||
04068|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04068|005|L|is contraindicated and generally should not be dispensed or administered to|
04068|006|L|the same patient.|
04068|007|B||
04068|008|A|MECHANISM OF ACTION:  Strong and moderate inducers of CYP2C19 or CYP3A4 may|
04068|009|A|increase the metabolism of mavacamten.(1-3)|
04068|010|B||
04068|011|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP2C19 or CYP3A4|
04068|012|E|inducers with mavacamten may decrease the levels of and effectiveness of|
04068|013|E|mavacamten.(1-3)|
04068|014|B||
04068|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04068|016|P|of the inducer for longer than 1-2 weeks.|
04068|017|B||
04068|018|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers of mavacamten state|
04068|019|M|concurrent use of strong or moderate inducers of CYP2C19 or CYP3A4 is|
04068|020|M|contraindicated.(1,2)|
04068|021|M|   The UK manufacturer of mavacamten states concomitant use with strong or|
04068|022|M|moderate CYP2C19 or CYP3A4 inducers is dependent on CYP2C19 phenotype.|
04068|023|M|Labeling recommends:|
04068|024|M|   -When initiating or increasing the dose of a strong CYP2C19 or CYP3A4|
04068|025|M|inducer in patients who are CYP2C19 poor metabolizers, monitor patients|
04068|026|M|closely and adjust mavacamten dose based on clinical response.  The maximum|
04068|027|M|recommended dose of mavacamten is 5 mg daily.|
04068|028|M|   -When initiating or increasing the dose of a moderate CYP3A4 inducer in|
04068|029|M|patients who are CYP2C19 poor metabolizers, monitor patients closely and|
04068|030|M|adjust mavacamten dose based on clinical response.|
04068|031|M|   -When initiating or increasing the dose a strong or moderate CYP2C19 or|
04068|032|M|strong CYP3A4 inducer in patients who are CYP2C19 intermediate, normal,|
04068|033|M|rapid, or ultrarapid metabolizers, monitor patients closely and adjust|
04068|034|M|mavacamten dose based on clinical response.|
04068|035|M|   -When discontinuing or decreasing the dose of a strong CYP2C19 or a|
04068|036|M|strong or moderate CYP3A4 inducer in patients who are CYP2C19 poor|
04068|037|M|metabolizers, decrease the dose of mavacamten from 5 mg to 2.5 mg, or pause|
04068|038|M|therapy if dose is 2.5 mg.|
04068|039|M|   -When discontinuing or decreasing the dose of a strong CYP2C19 or CYP3A4|
04068|040|M|inducer in patients who are CYP2C19 intermediate, normal, rapid, or|
04068|041|M|ultrarapid metabolizers, decrease the dose of mavacamten by one dose level|
04068|042|M|when on doses of 5 mg or higher.  Maintain mavacamten dose when on 2.5 mg.|
04068|043|M|   -When discontinuing or decreasing the dose of a moderate CYP2C19 inducer|
04068|044|M|in patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid|
04068|045|M|metabolizers, no dose adjustment is warranted.  Monitor patients closely and|
04068|046|M|adjust mavacamten dose based on clinical response.|
04068|047|M|   -No dose adjustment is warranted with moderate CYP2C19 inducers in|
04068|048|M|patients who are CYP2C19 poor metabolizers.|
04068|049|M|   -No dose adjustment is warranted with moderate CYP3A4 inducers in|
04068|050|M|patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid|
04068|051|M|metabolizers.(3)|
04068|052|B||
04068|053|D|DISCUSSION:  Concomitant use of mavacamten (a single 15 mg dose) with a|
04068|054|D|strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted|
04068|055|D|to decrease mavacamten area-under-curve (AUC) and maximum concentration|
04068|056|D|(Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by|
04068|057|D|69% and 4%, respectively, in CYP2C19 poor metabolizers.|
04068|058|D|   Drugs that induce both CYP2C19 and CYP3A4 linked to this monograph|
04068|059|D|include: apalutamide, asunaprevir, dipyrone, enzalutamide, fosphenytoin,|
04068|060|D|pacritinib, phenytoin, and rifampin.(4,5)|
04068|061|B||
04068|062|R|REFERENCES:|
04068|063|B||
04068|064|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04068|065|R|  April, 2025.|1
04068|066|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04068|067|R|  Canada February, 2024.|1
04068|068|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04068|069|R|  Squibb July, 2023.|1
04068|070|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04068|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04068|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04068|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04068|074|R|  11/14/2017.|1
04068|075|R|5.This information is based on an extract from the Certara Drug Interaction|6
04068|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04069|001|T|MONOGRAPH TITLE:  Mavacamten/Dual Strong or Moderate CYP2C19 & 3A4|
04069|002|T|Inhibitors|
04069|003|B||
04069|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04069|005|L|is contraindicated and generally should not be dispensed or administered to|
04069|006|L|the same patient.|
04069|007|B||
04069|008|A|MECHANISM OF ACTION:  Strong or moderate inhibitors of CYP2C19 or CYP3A4 may|
04069|009|A|decrease the metabolism of mavacamten.(1-3)|
04069|010|B||
04069|011|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP2C19 or CYP3A4|
04069|012|E|inhibitors increases plasma exposure of mavacamten, which may increase the|
04069|013|E|incidence and severity of adverse reactions of mavacamten.(1-3)|
04069|014|B||
04069|015|P|PREDISPOSING FACTORS:  None determined.|
04069|016|B||
04069|017|M|PATIENT MANAGEMENT:  The US and Canadian manufacturer of mavacamten state|
04069|018|M|concomitant use of strong or moderate inhibitors of CYP2C19 or CYP3A4 is|
04069|019|M|contraindicated.(1,2)|
04069|020|M|   The UK manufacturer of mavacamten states combined use of a strong CYP2C19|
04069|021|M|inhibitor and a strong CYP3A4 inhibitor (e.g., fluconazole, voriconazole) is|
04069|022|M|contraindicated.  The UK manufacturer does not provide recommendations for|
04069|023|M|combined use of a dual moderate CYP2C9 inhibitor and CYP3A4 inhibitor (e.g.,|
04069|024|M|fedratinib).(3)|
04069|025|B||
04069|026|D|DISCUSSION:  Concomitant use of mavacamten (15 mg) with omeprazole (20 mg),|
04069|027|D|a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve|
04069|028|D|(AUC) by 48% with no effect on maximum concentration (Cmax) in healthy|
04069|029|D|CYP2C19 normal metabolizers and rapid metabolizers.(1)|
04069|030|D|   Concomitant use of mavacamten (15 mg) with ketoconazole 400 mg, a strong|
04069|031|D|CYP3A4 inhibitor, once daily is predicted to increase mavacamten AUC and|
04069|032|D|Cmax up to 130% and 90%, respectively.(1)|
04069|033|D|   Drugs that inhibit both CYP2C19 and CYP3A4 linked to this monograph|
04069|034|D|include: fedratinib, fluconazole, fluvoxamine, and voriconazole.(4,5)|
04069|035|B||
04069|036|R|REFERENCES:|
04069|037|B||
04069|038|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04069|039|R|  April, 2025.|1
04069|040|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04069|041|R|  Canada February, 2024.|1
04069|042|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04069|043|R|  Squibb July, 2023.|1
04069|044|R|4.This information is based on an extract from the Certara Drug Interaction|6
04069|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04069|046|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04069|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04069|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04069|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04069|050|R|  11/14/2017.|1
04070|001|T|MONOGRAPH TITLE:  Mavacamten/Dual Weak CYP2C19 & Moderate CYP3A4 Inhibitors|
04070|002|B||
04070|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04070|004|L|of severe adverse interaction.|
04070|005|B||
04070|006|A|MECHANISM OF ACTION:  Weak CYP2C19 or moderate CYP3A4 inhibitors may inhibit|
04070|007|A|the metabolism of mavacamten.(1-3)|
04070|008|B||
04070|009|E|CLINICAL EFFECTS:  Concurrent use of weak CYP2C19 or moderate CYP3A4|
04070|010|E|inhibitors increases plasma exposure of mavacamten which may increase the|
04070|011|E|incidence and severity of adverse reactions of mavacamten.(1-3)|
04070|012|B||
04070|013|P|PREDISPOSING FACTORS:  None determined.|
04070|014|B||
04070|015|M|PATIENT MANAGEMENT:  The US manufacturer of mavacamten recommends to|
04070|016|M|initiate mavacamten at the recommended starting dosage of 5 mg orally once|
04070|017|M|daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or|
04070|018|M|a moderate CYP3A4 inhibitor.  Reduce dose by one level (i.e., 15 to 10 mg,|
04070|019|M|10 to 5 mg, or 5 to 2.5 mg) in patients who are on mavacamten treatment and|
04070|020|M|intend to initiate a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor.|
04070|021|M|Schedule clinical and echocardiographic assessment 4 weeks after inhibitor|
04070|022|M|initiation, and do not up-titrate mavacamten until 12 weeks after inhibitor|
04070|023|M|initiation.(1)|
04070|024|M|   Avoid initiation of concomitant weak CYP2C19 and moderate CYP3A4|
04070|025|M|inhibitors in patients who are on stable treatment with 2.5 mg of mavacamten|
04070|026|M|because a lower dose is not available.(1)|
04070|027|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04070|028|M|duration of the weak CYP2C19 and moderate CYP3A4 inhibitor.  After therapy|
04070|029|M|with the inhibitor is discontinued, mavacamten may be reinitiated at the|
04070|030|M|previous dose immediately upon discontinuation.(1)|
04070|031|M|   The Canadian manufacturer of mavacamten recommends additional monitoring|
04070|032|M|when concurrent use of weak CYP2C19 or moderate CYP3A4 inhibitors is|
04070|033|M|warranted.  Adjust the dose of mavacamten based on clinical assessment.(2)|
04070|034|M|   The UK manufacturer of mavacamten states no dose adjustment is necessary|
04070|035|M|with weak CYP2C19 or moderate CYP3A4 inhibitors.(3)  If CYP2C19 phenotype is|
04070|036|M|unknown, consider a starting dose of mavacamten of 2.5 mg daily with|
04070|037|M|moderate CYP3A4 inhibitors.(3)|
04070|038|B||
04070|039|D|DISCUSSION:  Concomitant use of mavacamten (15 mg) with omeprazole (20 mg),|
04070|040|D|a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve|
04070|041|D|(AUC) by 48% with no effect on maximum concentration (Cmax) in healthy|
04070|042|D|CYP2C19 normal metabolizers and rapid metabolizers.(1)|
04070|043|D|   Concomitant use of mavacamten (25 mg) with verapamil sustained release|
04070|044|D|(240 mg), a moderate CYP3A4 inhibitor, increased mavacamten AUC by 15% and|
04070|045|D|Cmax by 52% in intermediate metabolizers and normal metabolizers of|
04070|046|D|CYP2C19.(1)|
04070|047|D|   Concomitant use of mavacamten with diltiazem, a moderate CYP3A4|
04070|048|D|inhibitor, in CYP2C19 poor metabolizers is predicted to increase mavacamten|
04070|049|D|AUC and Cmax up to 55% and 42%, respectively.(1)|
04070|050|D|   Drugs that are weak CYP2C19 and moderate CYP3A4 inhibitors include:|
04070|051|D|berotralstat and treosulfan.(4,5)|
04070|052|B||
04070|053|R|REFERENCES:|
04070|054|B||
04070|055|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04070|056|R|  April, 2025.|1
04070|057|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04070|058|R|  Canada February, 2024.|1
04070|059|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04070|060|R|  Squibb July, 2023.|1
04070|061|R|4.This information is based on an extract from the Certara Drug Interaction|6
04070|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04070|063|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04070|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04070|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04070|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04070|067|R|  11/14/2017.|1
04071|001|T|MONOGRAPH TITLE:  Mavacamten/Weak CYP2C19 Inhibitors|
04071|002|B||
04071|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04071|004|L|of severe adverse interaction.|
04071|005|B||
04071|006|A|MECHANISM OF ACTION:  Weak CYP2C19 inhibitors may inhibit the metabolism of|
04071|007|A|mavacamten.(1-3)|
04071|008|B||
04071|009|E|CLINICAL EFFECTS:  Concurrent use of weak CYP2C19 inhibitors increases|
04071|010|E|plasma exposure of mavacamten which may increase the incidence and severity|
04071|011|E|of adverse reactions of mavacamten.(1-3)|
04071|012|B||
04071|013|P|PREDISPOSING FACTORS:  CYP2C19 rapid and ultrarapid metabolizers may|
04071|014|P|experience an increased incidence or severity of adverse effects.(1-3)|
04071|015|B||
04071|016|M|PATIENT MANAGEMENT:  The US manufacturer of mavacamten recommends to|
04071|017|M|initiate mavacamten at the recommended starting dosage of 5 mg orally once|
04071|018|M|daily in patients who are on stable therapy with a weak CYP2C19 inhibitor.|
04071|019|M|Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in|
04071|020|M|patients who are on mavacamten treatment and intend to initiate a weak|
04071|021|M|CYP2C19 inhibitor.  Schedule clinical and an echocardiographic assessment 4|
04071|022|M|weeks after inhibitor initiation, and do not up-titrate mavacamten until 12|
04071|023|M|weeks after inhibitor initiation.(1)|
04071|024|M|   Avoid initiation of concomitant weak CYP2C19 inhibitors in patients who|
04071|025|M|are on stable treatment with 2.5 mg of mavacamten because a lower dose is|
04071|026|M|not available.(1)|
04071|027|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04071|028|M|duration of the weak CYP2C19 inhibitor.  After therapy with the weak CYP2C19|
04071|029|M|inhibitor is discontinued, mavacamten may be reinitiated at the previous|
04071|030|M|dose immediately upon discontinuation.(1)|
04071|031|M|   The Canadian manufacturer of mavacamten recommends additional monitoring|
04071|032|M|when concurrent use of weak CYP2C19 inhibitors is warranted.  Adjust the|
04071|033|M|dose of mavacamten based on clinical assessment.(2)|
04071|034|M|   The UK manufacturer of mavacamten states no dose adjustment is necessary|
04071|035|M|with weak CYP2C19 inhibitors.  Monitor left ventricular ejection fraction|
04071|036|M|(LVEF) in 4 weeks then resume usual monitoring schedule.(3)|
04071|037|B||
04071|038|D|DISCUSSION:  Concomitant use of mavacamten (15 mg) with omeprazole (20 mg),|
04071|039|D|a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve|
04071|040|D|(AUC) by 48% with no effect on maximum concentration (Cmax) in healthy|
04071|041|D|CYP2C19 normal metabolizers and rapid metabolizers.(1)|
04071|042|D|   Weak CYP2C19 inhibitors include: armodafinil, cimetidine, enasidenib,|
04071|043|D|eslicarbazepine, felbamate, givosiran, isoniazid, obeticholic acid,|
04071|044|D|osilodrostat, piperine, rucaparib, tecovirimat.(4,5)|
04071|045|B||
04071|046|R|REFERENCES:|
04071|047|B||
04071|048|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04071|049|R|  April, 2025.|1
04071|050|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04071|051|R|  Canada February, 2024.|1
04071|052|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04071|053|R|  Squibb July, 2023.|1
04071|054|R|4.This information is based on an extract from the Certara Drug Interaction|6
04071|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04071|056|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04071|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04071|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04071|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04071|060|R|  11/14/2017.|1
04072|001|T|MONOGRAPH TITLE:  Mavacamten/Moderate CYP3A4 Inhibitors|
04072|002|B||
04072|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04072|004|L|of severe adverse interaction.|
04072|005|B||
04072|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may decrease the metabolism|
04072|007|A|of mavacamten.(1-3)|
04072|008|B||
04072|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04072|010|E|the plasma levels and the incidence and severity of adverse reactions of|
04072|011|E|mavacamten.(1-3)|
04072|012|B||
04072|013|P|PREDISPOSING FACTORS:  CYP2C19 poor metabolizers may experience an increased|
04072|014|P|incidence or severity of adverse effects.(1-3)|
04072|015|B||
04072|016|M|PATIENT MANAGEMENT:  The US manufacturer of mavacamten recommend initiating|
04072|017|M|mavacamten at the recommended starting dosage of 5 mg orally once daily in|
04072|018|M|patients who are on stable therapy with a moderate CYP3A4 inhibitor.  Reduce|
04072|019|M|dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in|
04072|020|M|patients who are on mavacamten treatment and intend to initiate a moderate|
04072|021|M|CYP3A4 inhibitor.  Schedule clinical and echocardiographic assessment 4|
04072|022|M|weeks after inhibitor initiation, and do not up-titrate mavacamten until 12|
04072|023|M|weeks after inhibitor initiation.(1)|
04072|024|M|   Avoid initiation of concomitant moderate CYP3A4 inhibitors in patients|
04072|025|M|who are on stable treatment with 2.5 mg of mavacamten because a lower dose|
04072|026|M|is not available.(1)|
04072|027|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04072|028|M|duration of the strong CYP3A4 inhibitor.  After therapy with the strong|
04072|029|M|CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the|
04072|030|M|previous dose immediately upon discontinuation.(1)|
04072|031|M|   The Canadian manufacturer of mavacamten recommends additional monitoring|
04072|032|M|when concurrent use of moderate CYP3A4 inhibitors is warranted.  Adjust the|
04072|033|M|dose of mavacamten based on clinical assessment.(2)|
04072|034|M|   The UK manufacturer of mavacamten states no dose adjustment is necessary|
04072|035|M|when starting mavacamten in patients on moderate CYP3A4 inhibitors or in|
04072|036|M|intermediate, normal, rapid, or ultra-rapid CYP2C19 metabolizers already on|
04072|037|M|mavacamten and starting a moderate CYP3A4 inhibitor.  If starting a moderate|
04072|038|M|CYP3A4 inhibitor in a patient who is a poor CYP2C19 metabolizer, reduce|
04072|039|M|mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks.|
04072|040|M|Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume|
04072|041|M|usual monitoring schedule.(3)|
04072|042|B||
04072|043|D|DISCUSSION:  Concomitant use of mavacamten (25 mg) with verapamil sustained|
04072|044|D|release (240 mg), a moderate CYP3A4 inhibitor, increased mavacamten|
04072|045|D|area-under-curve (AUC) by 15% and maximum concentration (Cmax) by 52% in|
04072|046|D|intermediate metabolizers and normal metabolizers of CYP2C19.(1)|
04072|047|D|   Concomitant use of mavacamten with diltiazem, a moderate CYP3A4|
04072|048|D|inhibitor, in CYP2C19 poor metabolizers is predicted to increase mavacamten|
04072|049|D|AUC and Cmax up to 55% and 42%, respectively.(1)|
04072|050|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04072|051|D|atazanavir, clofazimine, conivaptan, darunavir, dronedarone, erythromycin,|
04072|052|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir,|
04072|053|D|letermovir, netupitant, nilotinib, schisandra, tofisopam, and|
04072|054|D|treosulfan.(4,5)|
04072|055|B||
04072|056|R|REFERENCES:|
04072|057|B||
04072|058|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04072|059|R|  April, 2025.|1
04072|060|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04072|061|R|  Canada February, 2024.|1
04072|062|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04072|063|R|  Squibb July, 2023.|1
04072|064|R|4.This information is based on an extract from the Certara Drug Interaction|6
04072|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04072|066|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04072|067|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04072|068|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04072|069|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04072|070|R|  11/14/2017.|1
04073|001|T|MONOGRAPH TITLE:  Selected BCRP Substrates/Oteseconazole|
04073|002|B||
04073|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04073|004|L|of severe adverse interaction.|
04073|005|B||
04073|006|A|MECHANISM OF ACTION:  Oteseconazole is an inhibitor of the BCRP transporter,|
04073|007|A|which may result in increased absorption of BCRP substrates.(1)|
04073|008|B||
04073|009|E|CLINICAL EFFECTS:  Administration of oteseconazole with BCRP substrates may|
04073|010|E|result in elevated levels of and toxicity of the BCRP substrates.(1)|
04073|011|B||
04073|012|P|PREDISPOSING FACTORS:  None determined.|
04073|013|B||
04073|014|M|PATIENT MANAGEMENT:  The US manufacturer of oteseconazole states that the|
04073|015|M|lowest possible starting dose of the BCRP substrate should be used and to|
04073|016|M|consider reducing the dose of the substrate drug according to the product|
04073|017|M|labeling and monitor for adverse reactions.(1)|
04073|018|B||
04073|019|D|DISCUSSION:  Oteseconazole increased the area-under-curve (AUC) and maximum|
04073|020|D|concentration (Cmax) of rosuvastatin, a BCRP substrate, by 118% and 114%,|
04073|021|D|respectively.(1)|
04073|022|D|   BCRP substrates linked to this monograph include:  ciprofloxacin,|
04073|023|D|diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate,|
04073|024|D|mitoxantrone, rosuvastatin, and sulfasalazine.(1-2)|
04073|025|B||
04073|026|R|REFERENCES:|
04073|027|B||
04073|028|R|1.Vivjoa (oteseconazole) US prescribing information. Mycovia|1
04073|029|R|  Pharmaceuticals, Inc April, 2022.|1
04073|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04073|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04074|001|T|MONOGRAPH TITLE:  Mavacamten/Disopyramide; Ranolazine|
04074|002|B||
04074|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04074|004|L|of severe adverse interaction.|
04074|005|B||
04074|006|A|MECHANISM OF ACTION:  Mavacamten has been associated with left ventricular|
04074|007|A|systolic dysfunction and worsening heart failure symptoms in patients with|
04074|008|A|obstructive hypertrophic cardiomyopathy.  Concurrent use with disopyramide|
04074|009|A|and ranolazine may have additive negative inotropic effects.(1)|
04074|010|B||
04074|011|E|CLINICAL EFFECTS:  The concurrent use of mavacamten with other agents that|
04074|012|E|have negative inotropic effects may result in left ventricular systolic|
04074|013|E|dysfunction and worsening heart failure symptoms.(1)|
04074|014|B||
04074|015|P|PREDISPOSING FACTORS:  None determined.|
04074|016|B||
04074|017|M|PATIENT MANAGEMENT:  The US manufacturer of mavacamten states that the|
04074|018|M|concurrent use with disopyramide or ranolazine should be avoided.(1)|
04074|019|B||
04074|020|D|DISCUSSION:  Concurrent use of mavacamten with disopyramide or ranolazine|
04074|021|D|has not been studied.  Patients on monotherapy with disopyramide or|
04074|022|D|ranolazine were excluded from clinical trials.(1)|
04074|023|B||
04074|024|R|REFERENCE:|
04074|025|B||
04074|026|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04074|027|R|  April, 2025.|1
04075|001|T|MONOGRAPH TITLE:  Duvelisib/Mavacamten|
04075|002|B||
04075|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04075|004|L|of severe adverse interaction.|
04075|005|B||
04075|006|A|MECHANISM OF ACTION:  Duvelisib and mavacamten are both metabolized by|
04075|007|A|CYP3A4.  Mavacamten is a moderate CYP3A4 inducer while duvelisib is a|
04075|008|A|moderate CYP3A4 inhibitor.(1-2)|
04075|009|B||
04075|010|E|CLINICAL EFFECTS:  The net effect of coadministration of duvelisib and|
04075|011|E|mavacamten on CYP3A4 enzyme activity is unknown.  Concurrent or recent use|
04075|012|E|of mavacamten may either decrease the clinical effectiveness of duvelisib(1)|
04075|013|E|or increase the levels and toxicities of mavacamten.(2)|
04075|014|B||
04075|015|P|PREDISPOSING FACTORS:  None determined.|
04075|016|B||
04075|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04075|018|M|duvelisib with mavacamten. Concurrent therapy should be avoided.  If use of|
04075|019|M|this combination is necessary, the patient should be closely monitored for|
04075|020|M|duvelisib efficacy and mavacamten toxicity.|
04075|021|M|   The manufacturer of duvelisib makes the recommendations below for|
04075|022|M|concurrent use with CYP3A4 inducers:|
04075|023|M|   Avoid the concurrent use of duvelisib with moderate CYP3A4 inducers.(1)|
04075|024|M|When possible, select alternative agents in place of the moderate CYP3A4|
04075|025|M|inducer.|
04075|026|M|   If the moderate CYP3A4 inducer cannot be avoided, increase the dose of|
04075|027|M|duvelisib on day 12 of concurrent therapy as follows:|
04075|028|M|   - If the initial dose of duvelisib is 25 mg twice daily, increase the|
04075|029|M|duvelisib dose to 40 mg twice daily.|
04075|030|M|   - If the initial dose of duvelisib is 15 mg twice daily, increase the|
04075|031|M|duvelisib dose to 25 mg twice daily.|
04075|032|M|   If the moderate CYP3A4 inducer is discontinued, reduce the dose of|
04075|033|M|duvelisib back to the initial dose 14 days after discontinuation of the|
04075|034|M|moderate CYP3A4 inducer.(1)|
04075|035|M|   The manufacturer of mavacamten makes the recommendations below for|
04075|036|M|concurrent use with CYP3A4 inhibitors:|
04075|037|M|   Initiate mavacamten at the recommended starting dosage of 5 mg orally|
04075|038|M|once daily in patients who are on stable therapy with a moderate CYP3A4|
04075|039|M|inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to|
04075|040|M|2.5 mg) in patients who are on mavacamten treatment and intend to initiate a|
04075|041|M|moderate CYP3A4 inhibitor.  Schedule clinical and echocardiographic|
04075|042|M|assessment 4 weeks after inhibitor initiation, and do not up-titrate|
04075|043|M|mavacamten until 12 weeks after inhibitor initiation.(2)|
04075|044|M|   Avoid initiation of concomitant moderate CYP3A4 inhibitors in patients|
04075|045|M|who are on stable treatment with 2.5 mg of mavacamten because a lower dose|
04075|046|M|is not available.(2)|
04075|047|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04075|048|M|duration of the moderate CYP3A4 inhibitor.  After therapy with the moderate|
04075|049|M|CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the|
04075|050|M|previous dose immediately upon discontinuation.(2)|
04075|051|B||
04075|052|D|DISCUSSION:  In an interaction study, etravirine (a moderate CYP3A inducer)|
04075|053|D|200 mg twice daily decreased the maximum concentration (Cmax) and|
04075|054|D|area-under-curve (AUC) of single dose duvelisib 25 mg by 16% and 35%,|
04075|055|D|respectively.(1)|
04075|056|D|   Concomitant use of mavacamten (25 mg) with verapamil sustained release|
04075|057|D|(240 mg), a moderate CYP3A4 inhibitor, increased mavacamten AUC by 15% and|
04075|058|D|Cmax by 52% in intermediate metabolizers and normal metabolizers of|
04075|059|D|CYP2C19.(2)|
04075|060|D|   Concomitant use of mavacamten with diltiazem, a moderate CYP3A4|
04075|061|D|inhibitor, in CYP2C19 poor metabolizers is predicted to increase mavacamten|
04075|062|D|AUC and Cmax up to 55% and 42%, respectively.(2)|
04075|063|B||
04075|064|R|REFERENCES:|
04075|065|B||
04075|066|R|1.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
04075|067|R|  2021.|1
04075|068|R|2.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04075|069|R|  April, 2025.|1
04075|070|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04075|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04075|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04075|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04075|074|R|  11/14/2017.|1
04075|075|R|4.This information is based on an extract from the Certara Drug Interaction|6
04075|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04076|001|T|MONOGRAPH TITLE:  Rolapitant/Mavacamten|
04076|002|B||
04076|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04076|004|L|of severe adverse interaction.|
04076|005|B||
04076|006|A|MECHANISM OF ACTION:  Rolapitant is metabolized by CYP3A4.  Mavacamten is|
04076|007|A|metabolized by CYP2C19.  Mavacamten is a moderate CYP3A4 inducer while|
04076|008|A|rolapitant is a weak CYP2C19 inhibitor.(1-2)|
04076|009|B||
04076|010|E|CLINICAL EFFECTS:  The net effect of coadministration of rolapitant and|
04076|011|E|mavacamten is unknown.  Concurrent use may either decrease the clinical|
04076|012|E|effectiveness of rolapitant(1) or increase the levels and toxicities of|
04076|013|E|mavacamten.(2)|
04076|014|B||
04076|015|P|PREDISPOSING FACTORS:  None determined.|
04076|016|B||
04076|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04076|018|M|rolapitant with mavacamten.  Concurrent therapy should be avoided.  If use|
04076|019|M|of this combination is necessary, the patient should be closely monitored|
04076|020|M|for rolapitant efficacy and mavacamten toxicity.|
04076|021|M|   The manufacturer of rolapitant makes the recommendations below for|
04076|022|M|concurrent use with CYP3A4 inducers:|
04076|023|M|   The UK manufacturer of rolapitant states that rolapitant is not|
04076|024|M|recommended in patients already taking moderate CYP3A4 inducers.(1)|
04076|025|M|   If concomitant use is warranted, monitor the patient for decreased|
04076|026|M|antiemetic efficacy.  When possible and clinically appropriate, consider use|
04076|027|M|of an alternative antiemetic or alternatives to the moderate CYP3A4 inducer.|
04076|028|M|   The manufacturer of mavacamten makes the recommendations below for|
04076|029|M|concurrent use with CYP2C19 inhibitors:|
04076|030|M|   Initiate mavacamten at the recommended starting dosage of 5 mg orally|
04076|031|M|once daily in patients who are on stable therapy with a weak CYP2C19|
04076|032|M|inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to|
04076|033|M|2.5 mg) in patients who are on mavacamten treatment and intend to initiate a|
04076|034|M|weak CYP2C19 inhibitor.  Schedule clinical and echocardiographic assessment|
04076|035|M|4 weeks after inhibitor initiation, and do not up-titrate mavacamten until|
04076|036|M|12 weeks after inhibitor initiation.(2)|
04076|037|M|   Avoid initiation of concomitant weak CYP2C19 inhibitors in patients who|
04076|038|M|are on stable treatment with 2.5 mg of mavacamten because a lower dose is|
04076|039|M|not available.(2)|
04076|040|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04076|041|M|duration of the weak CYP2C19 inhibitor.  After therapy with the weak CYP2C19|
04076|042|M|inhibitor is discontinued, mavacamten may be reinitiated at the previous|
04076|043|M|dose immediately upon discontinuation.(2)|
04076|044|B||
04076|045|D|DISCUSSION:  The effect of moderate CYP3A4 inducers on rolapitant has not|
04076|046|D|been studied.  The UK manufacturer of rolapitant does not recommend the|
04076|047|D|concurrent use of rolapitant with moderate CYP3A4 inducers.|
04076|048|D|   Rifampin (600 mg daily for 14 days), a strong CYP3A4 inducer, decreased|
04076|049|D|the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose|
04076|050|D|of rolapitant (180 mg on Day 7) by 30% and 85%, respectively.  The half-life|
04076|051|D|of rolapitant decreased from 176 hours to 41 hours.(3)|
04076|052|D|   Concomitant use of mavacamten (15 mg) with omeprazole (20 mg), a weak|
04076|053|D|CYP2C19 inhibitor, once daily increased mavacamten AUC by 48% with no effect|
04076|054|D|on Cmax in healthy CYP2C19 normal metabolizers and rapid metabolizers.(2)|
04076|055|B||
04076|056|R|REFERENCES:|
04076|057|B||
04076|058|R|1.Varuby (rolapitant) UK Summary of Product Characteristics. Tesaro UK|1
04076|059|R|  Limited March 15, 2019.|1
04076|060|R|2.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04076|061|R|  April, 2025.|1
04076|062|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04076|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04076|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04076|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04076|066|R|  11/14/2017.|1
04076|067|R|4.This information is based on an extract from the Certara Drug Interaction|6
04076|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04077|001|T|MONOGRAPH TITLE:  Voxelotor/Mavacamten|
04077|002|B||
04077|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04077|004|L|of severe adverse interaction.|
04077|005|B||
04077|006|A|MECHANISM OF ACTION:  Voxelotor and mavacamten are both metabolized by|
04077|007|A|CYP3A4.  Mavacamten is a moderate CYP3A4 inducer while voxelotor is a|
04077|008|A|moderate CYP3A4 inhibitor.(1-2)|
04077|009|B||
04077|010|E|CLINICAL EFFECTS:  The net effect of coadministration of voxelotor and|
04077|011|E|mavacamten on CYP3A4 enzyme activity is unknown.  Concurrent use may either|
04077|012|E|decrease the clinical effectiveness of voxelotor(1) or increase the levels|
04077|013|E|and toxicities of mavacamten.(2)|
04077|014|B||
04077|015|P|PREDISPOSING FACTORS:  None determined.|
04077|016|B||
04077|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04077|018|M|voxelotor with mavacamten.  Concurrent therapy should be avoided.  If use of|
04077|019|M|this combination is necessary, the patient should be closely monitored for|
04077|020|M|voxelotor efficacy and mavacamten toxicity.|
04077|021|M|   The manufacturer of voxelotor makes the recommendations below for|
04077|022|M|concurrent use with CYP3A4 inducers:|
04077|023|M|   The manufacturer of voxelotor states that concurrent use with moderate|
04077|024|M|CYP3A4 inducers should be avoided.  If concomitant use is unavoidable,|
04077|025|M|increase the dose of voxelotor as follows:|
04077|026|M|   Patients 12 years and older on concurrent strong CYP3A4 inducers:|
04077|027|M|increase voxelotor dose to 2,500 mg daily.|
04077|028|M|   Patients 12 years and older on concurrent moderate CYP3A4 inducers:|
04077|029|M|increase voxelotor dose to 2,000 mg daily.|
04077|030|M|   Patients 4 years to less than 12 years on concurrent strong or moderate|
04077|031|M|CYP3A4 inducers: refer to prescribing information for recommended|
04077|032|M|weight-based dosage adjustments.(1)|
04077|033|M|   The manufacturer of mavacamten makes the recommendations below for|
04077|034|M|concurrent use with CYP3A4 inhibitors:|
04077|035|M|   Initiate mavacamten at the recommended starting dosage of 5 mg orally|
04077|036|M|once daily in patients who are on stable therapy with a moderate CYP3A4|
04077|037|M|inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to|
04077|038|M|2.5 mg) in patients who are on mavacamten treatment and intend to initiate a|
04077|039|M|moderate CYP3A4 inhibitor.  Schedule clinical and echocardiographic|
04077|040|M|assessment 4 weeks after inhibitor initiation, and do not up-titrate|
04077|041|M|mavacamten until 12 weeks after inhibitor initiation.(2)|
04077|042|M|   Avoid initiation of concomitant moderate CYP3A4 inhibitors in patients|
04077|043|M|who are on stable treatment with 2.5 mg of mavacamten because a lower dose|
04077|044|M|is not available.(2)|
04077|045|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04077|046|M|duration of the moderate CYP3A4 inhibitor.  After therapy with the moderate|
04077|047|M|CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the|
04077|048|M|previous dose immediately upon discontinuation.(2)|
04077|049|B||
04077|050|D|DISCUSSION:  Co-administration of voxelotor with efavirenz, a moderate|
04077|051|D|CYP3A4 inducer, is predicted to decrease the area-under-curve (AUC) of|
04077|052|D|voxelotor by 24%.(1)|
04077|053|D|   Concomitant use of mavacamten (25 mg) with verapamil sustained release|
04077|054|D|(240 mg), a moderate CYP3A4 inhibitor, increased mavacamten AUC by 15% and|
04077|055|D|concentration maximum (Cmax) by 52% in intermediate metabolizers and normal|
04077|056|D|metabolizers of CYP2C19.(2)|
04077|057|D|   Concomitant use of mavacamten with diltiazem, a moderate CYP3A4|
04077|058|D|inhibitor, in CYP2C19 poor metabolizers is predicted to increase mavacamten|
04077|059|D|AUC and Cmax up to 55% and 42%, respectively.(2)|
04077|060|B||
04077|061|R|REFERENCES:|
04077|062|B||
04077|063|R|1.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
04077|064|R|  Inc. December, 2021.|1
04077|065|R|2.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04077|066|R|  April, 2025.|1
04077|067|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04077|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04077|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04077|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04077|071|R|  11/14/2017.|1
04077|072|R|4.This information is based on an extract from the Certara Drug Interaction|6
04077|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04078|001|T|MONOGRAPH TITLE:  Crizotinib/Mavacamten|
04078|002|B||
04078|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04078|004|L|of severe adverse interaction.|
04078|005|B||
04078|006|A|MECHANISM OF ACTION:  Crizotinib and mavacamten are both metabolized by|
04078|007|A|CYP3A4.  Mavacamten is a moderate CYP3A4 inducer while crizotinib is a|
04078|008|A|moderate CYP3A4 inhibitor.(1-2)|
04078|009|B||
04078|010|E|CLINICAL EFFECTS:  The net effect of coadministration of crizotinib and|
04078|011|E|mavacamten on CYP3A4 enzyme activity is unknown.  Concurrent use may either|
04078|012|E|decrease the clinical effectiveness of crizotinib(1) or increase the levels|
04078|013|E|and toxicities of mavacamten.(2)|
04078|014|B||
04078|015|P|PREDISPOSING FACTORS:  None determined.|
04078|016|B||
04078|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04078|018|M|crizotinib with mavacamten.  Concurrent therapy should be avoided.  If use|
04078|019|M|of this combination is necessary, the patient should be closely monitored|
04078|020|M|for crizotinib efficacy and mavacamten toxicity.|
04078|021|M|   The manufacturer of crizotinib makes the recommendations below for|
04078|022|M|concurrent use with CYP3A4 inducers:|
04078|023|M|   Avoid the concurrent use of moderate CYP3A4 inducers in patients|
04078|024|M|receiving therapy with crizotinib.(1)|
04078|025|M|   Consider the use of alternative agents with less enzyme induction|
04078|026|M|potential.(1)|
04078|027|M|   The manufacturer of mavacamten makes the recommendations below for|
04078|028|M|concurrent use with CYP3A4 inhibitors:|
04078|029|M|   Initiate mavacamten at the recommended starting dosage of 5 mg orally|
04078|030|M|once daily in patients who are on stable therapy with a moderate CYP3A4|
04078|031|M|inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to|
04078|032|M|2.5 mg) in patients who are on mavacamten treatment and intend to initiate a|
04078|033|M|moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic|
04078|034|M|assessment 4 weeks after inhibitor initiation, and do not up-titrate|
04078|035|M|mavacamten until 12 weeks after inhibitor initiation.(2)|
04078|036|M|   Avoid initiation of concomitant moderate CYP3A4 inhibitors in patients|
04078|037|M|who are on stable treatment with 2.5 mg of mavacamten because a lower dose|
04078|038|M|is not available.(2)|
04078|039|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04078|040|M|duration of the moderate CYP3A4 inhibitor.  After therapy with the moderate|
04078|041|M|CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the|
04078|042|M|previous dose immediately upon discontinuation.(2)|
04078|043|B||
04078|044|D|DISCUSSION:  Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the|
04078|045|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04078|046|D|crizotinib (250 mg) by 69% and 82%, respectively.(1)|
04078|047|D|   Concomitant use of mavacamten (25 mg) with verapamil sustained release|
04078|048|D|(240 mg), a moderate CYP3A4 inhibitor, increased mavacamten AUC by 15% and|
04078|049|D|Cmax by 52% in intermediate metabolizers and normal metabolizers of|
04078|050|D|CYP2C19.(2)|
04078|051|D|   Concomitant use of mavacamten with diltiazem, a moderate CYP3A4|
04078|052|D|inhibitor, in CYP2C19 poor metabolizers is predicted to increase mavacamten|
04078|053|D|AUC and Cmax up to 55% and 42%, respectively.(2)|
04078|054|B||
04078|055|R|REFERENCES:|
04078|056|B||
04078|057|R|1.Xalkori (crizotinib) UK Summary of Product Characteristics. Pfizer Limited|1
04078|058|R|  July, 2021.|1
04078|059|R|2.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04078|060|R|  April, 2025.|1
04078|061|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04078|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04078|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04078|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04078|065|R|  11/14/2017.|1
04078|066|R|4.This information is based on an extract from the Certara Drug Interaction|6
04078|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04079|001|T|MONOGRAPH TITLE:  Lefamulin/Mavacamten|
04079|002|B||
04079|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04079|004|L|of severe adverse interaction.|
04079|005|B||
04079|006|A|MECHANISM OF ACTION:  Lefamulin and mavacamten are both metabolized by|
04079|007|A|CYP3A4.  Mavacamten is a moderate CYP3A4 inducer while oral lefamulin is a|
04079|008|A|moderate CYP3A4 inhibitor.(1-2)|
04079|009|B||
04079|010|E|CLINICAL EFFECTS:  The net effect of coadministration of lefamulin and|
04079|011|E|mavacamten on CYP3A4 enzyme activity is unknown.  Concurrent or recent use|
04079|012|E|of mavacamten may either decrease the clinical effectiveness of lefamulin(1)|
04079|013|E|or increase the levels and toxicities of mavacamten.(2)|
04079|014|B||
04079|015|P|PREDISPOSING FACTORS:  None determined.|
04079|016|B||
04079|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04079|018|M|lefamulin with mavacamten. Concurrent therapy should be avoided.  If use of|
04079|019|M|this combination is necessary, the patient should be closely monitored for|
04079|020|M|lefamulin efficacy and mavacamten toxicity.|
04079|021|M|   The manufacturer of lefamulin makes the recommendation below for|
04079|022|M|concurrent use with CYP3A4 inducers:|
04079|023|M|    Avoid the concurrent use of moderate CYP3A4 inducers in patients|
04079|024|M|receiving therapy with lefamulin.(1)|
04079|025|M|   The manufacturer of mavacamten makes the recommendations below for|
04079|026|M|concurrent use with CYP3A4 inhibitors like oral lefamulin:|
04079|027|M|   Initiate mavacamten at the recommended starting dosage of 5 mg orally|
04079|028|M|once daily in patients who are on stable therapy with a moderate CYP3A4|
04079|029|M|inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to|
04079|030|M|2.5 mg) in patients who are on mavacamten treatment and intend to initiate a|
04079|031|M|moderate CYP3A4 inhibitor.  Schedule clinical and echocardiographic|
04079|032|M|assessment 4 weeks after inhibitor initiation, and do not up-titrate|
04079|033|M|mavacamten until 12 weeks after inhibitor initiation.(2)|
04079|034|M|   Avoid initiation of concomitant moderate CYP3A4 inhibitors in patients|
04079|035|M|who are on stable treatment with 2.5 mg of mavacamten because a lower dose|
04079|036|M|is not available.(2)|
04079|037|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04079|038|M|duration of the moderate CYP3A4 inhibitor.  After therapy with the moderate|
04079|039|M|CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the|
04079|040|M|previous dose immediately upon discontinuation.(2)|
04079|041|B||
04079|042|D|DISCUSSION:  In a study, concurrent administration of rifampin (a strong|
04079|043|D|inducer) with lefamulin injection decreased lefamulin area-under-the-curve|
04079|044|D|(AUC) and maximum concentration (Cmax) by 28% and 8%.(1)|
04079|045|D|   In a study, concurrent administration of rifampin (a strong inducer) with|
04079|046|D|oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1)|
04079|047|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
04079|048|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the|
04079|049|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200%|
04079|050|D|and 100%, respectively.  No clinically significant effect on midazolam|
04079|051|D|pharmacokinetics was observed when co-administered with lefamulin|
04079|052|D|injection.(1)|
04079|053|D|   Concomitant use of mavacamten (25 mg) with verapamil sustained release|
04079|054|D|(240 mg), a moderate CYP3A4 inhibitor, increased mavacamten AUC by 15% and|
04079|055|D|Cmax by 52% in intermediate metabolizers and normal metabolizers of|
04079|056|D|CYP2C19.(2)|
04079|057|D|   Concomitant use of mavacamten with diltiazem, a moderate CYP3A4|
04079|058|D|inhibitor, in CYP2C19 poor metabolizers is predicted to increase mavacamten|
04079|059|D|AUC and Cmax up to 55% and 42%, respectively.(2)|
04079|060|B||
04079|061|R|REFERENCES:|
04079|062|B||
04079|063|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04079|064|R|  Inc August 2019.|1
04079|065|R|2.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04079|066|R|  April, 2025.|1
04079|067|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04079|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04079|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04079|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04079|071|R|  11/14/2017.|1
04079|072|R|4.This information is based on an extract from the Certara Drug Interaction|6
04079|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04080|001|T|MONOGRAPH TITLE:  Vonoprazan/Strong or Moderate CYP3A4 Inducers|
04080|002|B||
04080|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04080|004|L|of severe adverse interaction.|
04080|005|B||
04080|006|A|MECHANISM OF ACTION:  Vonoprazan is a substrate of CYP3A4.  Strong or|
04080|007|A|moderate inducers of CYP3A4 may increase the metabolism of vonoprazan.(1)|
04080|008|B||
04080|009|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
04080|010|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
04080|011|E|vonoprazan.(1)|
04080|012|B||
04080|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04080|014|P|of the inducer for longer than 1-2 weeks.|
04080|015|B||
04080|016|M|PATIENT MANAGEMENT:  The manufacturer of vonoprazan states that concurrent|
04080|017|M|use with strong or moderate CYP3A4 inducers should be avoided.(1)|
04080|018|B||
04080|019|D|DISCUSSION:  Strong CYP3A4 inducers like rifampin are predicted to decrease|
04080|020|D|the area-under-curve (AUC) of vonoprazan by 80%, and moderate CYP3A4|
04080|021|D|inducers like efavirenz are predicted to decrease vonoprazan AUC by 50%.(1)|
04080|022|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04080|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04080|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04080|025|D|rifapentine, and St. John's wort.|
04080|026|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04080|027|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04080|028|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04080|029|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and|
04080|030|D|tovorafenib.(2-3)|
04080|031|B||
04080|032|R|REFERENCES:|
04080|033|B||
04080|034|R|1.Voquezna (vonoprazan-amoxicillin and|1
04080|035|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04080|036|R|  Pharmaceuticals, Inc. November, 2023.|1
04080|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04080|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04080|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04080|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04080|041|R|  11/14/2017.|1
04080|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
04080|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04081|001|T|MONOGRAPH TITLE:  Vonoprazan-Clarithromycin-Amoxicillin/Strong or Moderate|
04081|002|T|CYP3A4 Inducers|
04081|003|B||
04081|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04081|005|L|of severe adverse interaction.|
04081|006|B||
04081|007|A|MECHANISM OF ACTION:  Vonoprazan and clarithromycin are substrates of|
04081|008|A|CYP3A4.  Strong or moderate inducers of CYP3A4 may increase the metabolism|
04081|009|A|of vonoprazan and clarithromycin.(1)|
04081|010|B||
04081|011|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
04081|012|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
04081|013|E|vonoprazan and clarithromycin.(1)|
04081|014|B||
04081|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04081|016|P|of the inducer for longer than 1-2 weeks.|
04081|017|B||
04081|018|M|PATIENT MANAGEMENT:  The manufacturer of vonoprazan states that concurrent|
04081|019|M|use with strong or moderate CYP3A4 inducers should be avoided.(1)|
04081|020|B||
04081|021|D|DISCUSSION:  Vonoprazan and clarithromycin are CYP3A4 substrates.  Strong|
04081|022|D|CYP3A4 inducers like rifampin are predicted to decrease the area-under-curve|
04081|023|D|(AUC) of vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are|
04081|024|D|predicted to decrease vonoprazan AUC by 50%.(1)|
04081|025|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04081|026|D|enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone,|
04081|027|D|rifampin, rifapentine, and St. John's wort.|
04081|028|D|   Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dipyrone,|
04081|029|D|etravirine, lesinurad, modafinil, nafcillin, telotristat ethyl, and|
04081|030|D|tovorafenib.(2-3)|
04081|031|B||
04081|032|R|REFERENCES:|
04081|033|B||
04081|034|R|1.Voquezna (vonoprazan-amoxicillin and|1
04081|035|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04081|036|R|  Pharmaceuticals, Inc. November, 2023.|1
04081|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04081|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04081|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04081|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04081|041|R|  11/14/2017.|1
04081|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
04081|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04082|001|T|MONOGRAPH TITLE:  Vonoprazan-Clarithromycin-Amoxicillin/Strong or Moderate|
04082|002|T|CYP3A4 Inducers that Prolong QT|
04082|003|B||
04082|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04082|005|L|of severe adverse interaction.|
04082|006|B||
04082|007|A|MECHANISM OF ACTION:  Strong or moderate inducers of CYP3A4 that prolong the|
04082|008|A|QTc interval may accelerate the metabolism of vonoprazan and|
04082|009|A|clarithromycin.(1)|
04082|010|A|   Clarithromycin prolongs the QTc interval.(1)  Some CYP3A4 inducers (e.g.,|
04082|011|A|efavirenz, thioridazine) can also prolong the QTc interval.(2)|
04082|012|B||
04082|013|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
04082|014|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
04082|015|E|vonoprazan and clarithromycin.(1)|
04082|016|E|   Additive QTc prolongation may occur and result in potentially|
04082|017|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
04082|018|B||
04082|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04082|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04082|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04082|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04082|023|P|female gender, or advanced age.(3)|
04082|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04082|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04082|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04082|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04082|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04082|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04082|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04082|031|P|   Induction effects may be more likely with regular use of the inducer for|
04082|032|P|longer than 1-2 weeks.|
04082|033|B||
04082|034|M|PATIENT MANAGEMENT:  The manufacturer of vonoprazan states that concurrent|
04082|035|M|use with strong or moderate CYP3A4 inducers should be avoided.(1)|
04082|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04082|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04082|038|M|regular intervals.  Correct any electrolyte abnormalities.|
04082|039|M|   Increase the frequency of ECG monitoring in patients with risk factors|
04082|040|M|for QTc prolongation, including congenital long QT syndrome, heart disease,|
04082|041|M|or electrolyte abnormalities.|
04082|042|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
04082|043|M|fainting.|
04082|044|B||
04082|045|D|DISCUSSION:  Vonoprazan and clarithromycin are CYP3A4 substrates.  Strong|
04082|046|D|CYP3A4 inducers like rifampin are predicted to decrease the area-under-curve|
04082|047|D|(AUC) of vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are|
04082|048|D|predicted to decrease vonoprazan AUC by 50%.(1)|
04082|049|D|   Agents that are linked to this monograph may have varying degrees of|
04082|050|D|potential to prolong the QTc interval but are generally accepted to have a|
04082|051|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04082|052|D|been shown to prolong the QTc interval either through their mechanism of|
04082|053|D|action, through studies on their effects on the QTc interval, or through|
04082|054|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04082|055|D|and/or post-marketing reports.(2)|
04082|056|D|   Strong or moderate inducers of CYP3A4 that prolong the QTc interval|
04082|057|D|include: efavirenz and thioridazine.(4,5)|
04082|058|B||
04082|059|R|REFERENCES:|
04082|060|B||
04082|061|R|1.Voquezna (vonoprazan-amoxicillin and|1
04082|062|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04082|063|R|  Pharmaceuticals, Inc. November, 2023.|1
04082|064|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
04082|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04082|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04082|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04082|068|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04082|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04082|070|R|  settings: a scientific statement from the American Heart Association and|6
04082|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04082|072|R|  2;55(9):934-47.|6
04082|073|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04082|074|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04082|075|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04082|076|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04082|077|R|  11/14/2017.|1
04082|078|R|5.This information is based on an extract from the Certara Drug Interaction|6
04082|079|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04083|001|T|MONOGRAPH TITLE:  Vonoprazan-Clarithromycin-Amoxicillin/Strong or Moderate|
04083|002|T|CYP3A4 Inducer & Substrate|
04083|003|B||
04083|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04083|005|L|of severe adverse interaction.|
04083|006|B||
04083|007|A|MECHANISM OF ACTION:  Bosentan, carbamazepine, dabrafenib, elagolix,|
04083|008|A|ivosidenib, lorlatinib, lumacaftor, and mitapivat are both moderate to|
04083|009|A|strong inducers and substrates of CYP3A4.(1,2)|
04083|010|A|   Moderate and strong inducers of CYP3A4 may increase the CYP3A4-mediated|
04083|011|A|metabolism of vonoprazan and clarithromycin.(3)|
04083|012|A|   Clarithromycin is a strong inhibitor of CYP3A4 and may decrease the|
04083|013|A|metabolism of CYP3A4 substrates.(3)|
04083|014|B||
04083|015|E|CLINICAL EFFECTS:  Concurrent use of moderate to strong CYP3A4 inducers may|
04083|016|E|result in decreased levels and effectiveness of vonoprazan and|
04083|017|E|clarithromycin.(3)  Concurrent use of CYP3A4 substrates with clarithromycin|
04083|018|E|may result in elevated levels of and toxicity from the substrate.(3)|
04083|019|B||
04083|020|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04083|021|P|of the inducer for longer than 1-2 weeks.|
04083|022|B||
04083|023|M|PATIENT MANAGEMENT:  The manufacturer of vonoprazan states that concurrent|
04083|024|M|use with strong or moderate CYP3A4 inducers should be avoided.(3)|
04083|025|B||
04083|026|D|DISCUSSION:  Vonoprazan and clarithromycin are CYP3A4 substrates.  Strong|
04083|027|D|CYP3A4 inducers like rifampin are predicted to decrease the area-under-curve|
04083|028|D|(AUC) of vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are|
04083|029|D|predicted to decrease vonoprazan AUC by 50%.(1)|
04083|030|D|   Strong inducers of CYP3A4 that are CYP3A4 substrates include:|
04083|031|D|carbamazepine, ivosidenib, and lumacaftor.|
04083|032|D|   Moderate inducers of CYP3A4 that are CYP3A4 substrates include: bosentan,|
04083|033|D|dabrafenib, elagolix, lorlatinib, mitapivat, and rifabutin.(2-3)|
04083|034|B||
04083|035|R|REFERENCES:|
04083|036|B||
04083|037|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
04083|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04083|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04083|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04083|041|R|  11/14/2017.|1
04083|042|R|2.This information is based on an extract from the Certara Drug Interaction|6
04083|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04083|044|R|3.Voquezna (vonoprazan-amoxicillin and|1
04083|045|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04083|046|R|  Pharmaceuticals, Inc. November, 2023.|1
04084|001|T|MONOGRAPH TITLE:  Atazanavir; Nelfinavir/Vonoprazan|
04084|002|B||
04084|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04084|004|L|of severe adverse interaction.|
04084|005|B||
04084|006|A|MECHANISM OF ACTION:  Proton pump inhibitors increase gastric pH.|
04084|007|A|Vonoprazan is a gastric proton pump inhibitor.  As gastric pH increases, the|
04084|008|A|solubility of atazanavir and nelfinavir decreases.(1-4)|
04084|009|B||
04084|010|E|CLINICAL EFFECTS:  Concurrent use of atazanavir(2,3) or nelfinavir(4) and a|
04084|011|E|proton pump inhibitor may result in decreased levels and effectiveness of|
04084|012|E|atazanavir or nelfinavir.|
04084|013|B||
04084|014|P|PREDISPOSING FACTORS:  None determined.|
04084|015|B||
04084|016|M|PATIENT MANAGEMENT:  The manufacturer of vonoprazan states concurrent use|
04084|017|M|with atazanavir or nelfinavir should be avoided.(1)|
04084|018|B||
04084|019|D|DISCUSSION:  Vonoprazan decreases gastric acidity by suppressing gastric|
04084|020|D|acid secretion and is characterized as a type of gastric proton-pump|
04084|021|D|inhibitor.(1)|
04084|022|D|   In a pharmacodynamic study, a single 20 mg dose of vonoprazan, elevated|
04084|023|D|the intragastric pH compared to placebo and was sustained for over 24-hours|
04084|024|D|after dosing.  The inhibitory effect of vonoprazan on acid secretion|
04084|025|D|increased with repeated daily dosing and antisecretory effect reached steady|
04084|026|D|state by Day 4 with a mean 24-hour intragastric pH of 6.0 following 20 mg|
04084|027|D|once daily dose.(1)|
04084|028|D|   In a study of 16 subjects, atazanavir (400 mg daily) area-under-curve|
04084|029|D|(AUC), maximum concentration (Cmax) and minimum concentration (Cmin)|
04084|030|D|decreased 94%, 96% and 95% respectively, when given with omeprazole (40 mg|
04084|031|D|daily).  Omeprazole AUC and Cmax increased 145% and 124% respectively.(2)|
04084|032|D|   In a study of 15 subjects, atazanavir AUC, Cmax and Cmin decreased 76%,|
04084|033|D|72% and 78% respectively, when given with omeprazole (40 mg daily) and|
04084|034|D|ritonavir (100 mg daily).(2)|
04084|035|D|   In a study in 13 subjects, administration of omeprazole (20 mg daily) 12|
04084|036|D|hours before atazanavir/ritonavir (300/100 mg daily) decreased atazanavir|
04084|037|D|Cmax, AUC, and Cmin by 39%, 42%, and 46%, respectively; however, the|
04084|038|D|atazanavir AUC and Cmin were 10% and 2.4-fold higher than average levels|
04084|039|D|seen with atazanavir 400 mg alone.(2)|
04084|040|D|   In a study in 14 subjects, administration of omeprazole (20 mg daily) 1|
04084|041|D|hour before atazanavir/ritonavir (400/100 mg daily) decreased atazanavir|
04084|042|D|Cmax, AUC, and Cmin by 31%, 30%, and 31%, respectively; however, the|
04084|043|D|atazanavir AUC and Cmin were 32% and 3.3-fold higher than average levels|
04084|044|D|seen with atazanavir 400 mg alone.(2)|
04084|045|B||
04084|046|R|REFERENCES:|
04084|047|B||
04084|048|R|1.Voquezna (vonoprazan-amoxicillin and|1
04084|049|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04084|050|R|  Pharmaceuticals, Inc. November, 2023.|1
04084|051|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04084|052|R|  Squibb Company December, 2024.|1
04084|053|R|3.Reyataz (atazanavir sulfate) Australian product information. Bristol-Myers|1
04084|054|R|  Squibb Pharmaceuticals October 25, 2023.|1
04084|055|R|4.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
04084|056|R|  Pharmaceuticals, Inc. September, 2016.|1
04085|001|T|MONOGRAPH TITLE:  Vonoprazan-Clarithromycin/Slt Protease|
04085|002|T|Inhibitors;Cobicistat|
04085|003|B||
04085|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04085|005|L|of severe adverse interaction.|
04085|006|B||
04085|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
04085|008|A|clarithromycin.(1,2)|
04085|009|B||
04085|010|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
04085|011|E|of clarithromycin(1-10), reduced levels of 14-OH-clarithromycin,(1-4) and|
04085|012|E|QTc prolongation.(1,2)|
04085|013|B||
04085|014|P|PREDISPOSING FACTORS:  Patients with decreased renal function (as shown by a|
04085|015|P|creatinine clearance (CrCL) of 60 ml/min or less are more susceptible to|
04085|016|P|effects of the interaction.(1-10)|
04085|017|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04085|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04085|019|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04085|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04085|021|P|advanced age.(11)|
04085|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04085|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04085|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04085|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04085|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04085|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04085|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(11)|
04085|029|B||
04085|030|M|PATIENT MANAGEMENT:  The manufacturer of clarithromycin-vonoprazan states|
04085|031|M|concurrent use with ritonavir is not recommended in patients with decreased|
04085|032|M|renal function.(1)|
04085|033|M|   The manufacturer of clarithromycin states that in patients receiving|
04085|034|M|ritonavir, the dose of clarithromycin be reduced by 50% in patients with a|
04085|035|M|CrCl of 30 ml/min to 60 ml/min. For patients with a CrCl of less than 30|
04085|036|M|ml/min, the dose of clarithromycin should be reduced by 75%. No dosage|
04085|037|M|adjustment is necessary in patients with normal renal function.(2)|
04085|038|M|   The manufacturers of darunavir,(5) the combination of lopinavir and|
04085|039|M|ritonavir,(6) ritonavir,(3) and tipranavir coadministered with ritonavir(4)|
04085|040|M|recommend that the dose of clarithromycin be reduced by 50% in patients with|
04085|041|M|a CrCl of 30 ml/min to 60 ml/min.  For patients with a CrCl of less than 30|
04085|042|M|ml/min, the dose of clarithromycin should be reduced by 75%. No adjustment|
04085|043|M|is necessary in patients with normal renal function.|
04085|044|M|   The manufacturer of the combination of elvitegravir, cobicistat,|
04085|045|M|emtricitabine, and tenofovir disoproxil states that no adjustment is|
04085|046|M|necessary in patients with a CrCl greater than or equal to 60 ml/min.  In|
04085|047|M|patients with a CrCl of 50 ml/min to 60 ml/min, the dose of clarithromycin|
04085|048|M|should be reduced by 50%.(7)|
04085|049|M|   Dosages of clarithromycin in excess of 1000 mg per day should not be used|
04085|050|M|in patients taking protease inhibitors.(1)|
04085|051|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04085|052|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04085|053|M|regular intervals.  Correct any electrolyte abnormalities.|
04085|054|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
04085|055|M|fainting.|
04085|056|B||
04085|057|D|DISCUSSION:  In a study in 17 subjects, concurrent clarithromycin (500 mg|
04085|058|D|twice daily) and darunavir/ritonavir (400/100 mg twice daily) decreased the|
04085|059|D|Cmax and AUC of darunavir by 17%, 13%, respectively.  Clarithromycin Cmax,|
04085|060|D|AUC, and Cmin increased by 1.26-fold, 1.57-fold, and 2.74-fold,|
04085|061|D|respectively.(5)|
04085|062|D|   In a study in 22 subjects, concurrent clarithromycin and ritonavir|
04085|063|D|increased clarithromycin AUC,(1,3) Cmax,(3) and Cmin(3) by 77%, 31%, and|
04085|064|D|2.8-fold, respectively.  The AUC,(1) Cmax,(1) and Cmin(1) of|
04085|065|D|14-OH-clarithromycin decreased by 100%, 99%, and 100%, respectively.|
04085|066|D|Ritonavir AUC, Cmax, Cmin increased by 12%, 15%, 14%, respectively.(3)|
04085|067|D|   In a study in 24 subjects, concurrent clarithromycin (500 mg twice daily)|
04085|068|D|and tipranavir/ritonavir (500/200 mg twice daily) increased tipranavir Cmax,|
04085|069|D|AUC, and Cmin by 1.40-fold, 1.66-fold, 2.00-fold, respectively.  The AUC and|
04085|070|D|Cmin of clarithromycin increased 1.19-fold and 1.68-fold, respectively.  The|
04085|071|D|Cmax, AUC, and Cmin of 14-OH-clarithromycin decreased by 97%, 97%, and 95%,|
04085|072|D|respectively.(4)|
04085|073|D|   In a controlled study in 21 healthy volunteers the use of|
04085|074|D|tipranavir/ritonavir (500/200 for 7 days) concurrently with clarithromycin|
04085|075|D|(500mg twice daily for 14 days) led to increased TPV/r Cmax, AUC, and Cp12h|
04085|076|D|by 40%, 66%, and 100% respectively.  The formation of the active metabolite|
04085|077|D|14-OH-CLR was decreased by 95%, and both AUC and Cmax of 14-OH-CLR were|
04085|078|D|decreased by 97% in the presence of tipranavir.  Single dose|
04085|079|D|tipranavir/ritonavir result in no statistical change in clarithromycin AUC|
04085|080|D|or Cmax, but a 50% increase in Cp12h was identified.  Multiple dose|
04085|081|D|tipranavir/ritonavir showed a 19% increase in clarithromycin AUC, no change|
04085|082|D|in Cmax, and a 68% increase in Cp12h versus clarithromycin alone.(12)|
04085|083|D|   Selected protease inhibitors linked to this monograph include:|
04085|084|D|boceprevir, cobicistat, darunavir, lopinavir, ritonavir, telaprevir, and|
04085|085|D|tipranavir.|
04085|086|B||
04085|087|R|REFERENCES:|
04085|088|B||
04085|089|R|1.Voquezna (vonoprazan-amoxicillin and|1
04085|090|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04085|091|R|  Pharmaceuticals, Inc. November, 2023.|1
04085|092|R|2.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
04085|093|R|  September, 2019.|1
04085|094|R|3.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
04085|095|R|  December, 2019.|1
04085|096|R|4.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04085|097|R|  Pharmaceuticals, Inc. April, 2024.|1
04085|098|R|5.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04085|099|R|  March, 2023.|1
04085|100|R|6.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04085|101|R|  Laboratories December, 2019.|1
04085|102|R|7.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
04085|103|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
04085|104|R|8.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
04085|105|R|  June, 2025.|1
04085|106|R|9.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
04085|107|R|  Incorporated October, 2013.|1
04085|108|R|10.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
04085|109|R|   January, 2017.|1
04085|110|R|11.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
04085|111|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
04085|112|R|   hospital settings: a scientific statement from the American Heart|6
04085|113|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
04085|114|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
04085|115|R|12.la Porte CJ, Sabo JP, Elgadi M, Cameron DW. Interaction studies of|2
04085|116|R|   tipranavir-ritonavir with clarithromycin, fluconazole, and rifabutin in|2
04085|117|R|   healthy volunteers. Antimicrob Agents Chemother 2009 Jan;53(1):162-73.|2
04086|001|T|MONOGRAPH TITLE:  Bosutinib/Vonoprazan-Clarithromycin|
04086|002|B||
04086|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04086|004|L|of severe adverse interaction.|
04086|005|B||
04086|006|A|MECHANISM OF ACTION:  The solubility of bosutinib is pH dependent.  Changes|
04086|007|A|in gastric pH from proton pump inhibitors (PPIs) may decrease the absorption|
04086|008|A|of bosutinib.  Vonoprazan is a PPI.(1)|
04086|009|A|   If bosutinib is absorbed, strong inhibitors of CYP3A4 that prolong the|
04086|010|A|QTc interval may inhibit the metabolism of bosutinib and result in additive|
04086|011|A|risk of QT prolongation.  Clarithromycin is a strong CYP3A4 inhibitor.(1)|
04086|012|B||
04086|013|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
04086|014|E|levels and effectiveness of bosutinib.(1)|
04086|015|E|   If bosutinib is absorbed, concurrent use of strong inhibitors of CYP3A4|
04086|016|E|that prolong QT may result in elevated levels of and toxicity from|
04086|017|E|bosutinib, including additive QTc prolongation, which may result in|
04086|018|E|potentially life-threatening cardiac arrhythmias, including torsades de|
04086|019|E|pointes (TdP).(1)|
04086|020|E|   Other toxicities include nausea, vomiting, diarrhea, abdominal pain,|
04086|021|E|myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1)|
04086|022|B||
04086|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04086|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
04086|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04086|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04086|027|P|female gender, or advanced age.(2)|
04086|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04086|029|P|higher systemic concentrations of either QT prolonging drug are additional|
04086|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04086|031|P|drug concentrations include rapid infusion of an intravenous dose or|
04086|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04086|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04086|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04086|035|B||
04086|036|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs) in|
04086|037|M|patients receiving treatment with bosutinib.(1)|
04086|038|M|   Consider the use of short-acting antacids in these patients.  If antacids|
04086|039|M|are used, separate the administration times by at least 2 hours for|
04086|040|M|bosutinib.(1)|
04086|041|M|   The manufacturer of bosutinib also recommends avoiding the use of strong|
04086|042|M|CYP3A4 inhibitors that prolong QT in patients undergoing therapy with|
04086|043|M|bosutinib.(1)  Consider alternatives with no or minimal enzyme inhibition|
04086|044|M|and with no effect on the QTc interval.|
04086|045|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
04086|046|M|bosutinib should be monitored for prolongation of the QTc interval.  When|
04086|047|M|concurrent therapy is warranted: consider obtaining serum calcium,|
04086|048|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04086|049|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
04086|050|M|report any irregular heartbeat, dizziness, or fainting.|
04086|051|B||
04086|052|D|DISCUSSION:  In a randomized, phase I, double-blind, placebo-controlled,|
04086|053|D|sequential group study, 48 healthy adults received a single dose of|
04086|054|D|bosutinib 100, 200, 300, 400, 500, or 600 mg with ketoconazole 400 mg days|
04086|055|D|-1 and days 1-4. Bosutinib area-under-curve (AUC) and maximum concentration|
04086|056|D|(Cmax) increased 7.3-fold and 7.7-fold.(3)|
04086|057|D|   In an open-label, randomized, 2-period, crossover study, healthy subjects|
04086|058|D|received a single dose of bosutinib 100 mg alone and with multiple doses of|
04086|059|D|ketoconazole 400 mg.  Bosutinib Cmax and AUC increased 5.2-fold and|
04086|060|D|8.6-fold, respectively.(4)|
04086|061|D|   A retrospective review of 618 cancer patients treated with 902|
04086|062|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
04086|063|D|incidence of QTc prolongation.  In patients who received bosutinib, QTc|
04086|064|D|prolongation was identified in 8 patients(38.1%), with 5 patients (62.5%)|
04086|065|D|having Grade 1 (QTc 450-480 ms) and 3 patients(37.5%) having Grade 2 (QTc|
04086|066|D|480-500 ms) events.  Grade 3 events occurred in 1 (12.5%) patient having QTc|
04086|067|D|greater than or equal to 500 ms.  No patients had a QTc change greater than|
04086|068|D|or equal to 60 ms, ventricular tachycardia (VT), sudden cardiac death (SCD),|
04086|069|D|or TdP.(5)|
04086|070|D|   Agents that are linked to this monograph may have varying degrees of|
04086|071|D|potential to prolong the QTc interval but are generally accepted to have a|
04086|072|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04086|073|D|been shown to prolong the QTc interval either through their mechanism of|
04086|074|D|action, through studies on their effects on the QTc interval, or through|
04086|075|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04086|076|D|and/or post-marketing reports.(6)|
04086|077|D|   Strong inhibitors of CYP3A4 that prolong QT include: clarithromycin.(7,8)|
04086|078|B||
04086|079|R|REFERENCES:|
04086|080|B||
04086|081|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
04086|082|R|  2023.|1
04086|083|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04086|084|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04086|085|R|  settings: a scientific statement from the American Heart Association and|6
04086|086|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04086|087|R|  2;55(9):934-47.|6
04086|088|R|3.Abbas R, Leister C, El Gaaloul M, Chalon S, Sonnichsen D. Ascending|2
04086|089|R|  single-dose study of the safety profile, tolerability, and|2
04086|090|R|  pharmacokinetics of bosutinib coadministered with ketoconazole to healthy|2
04086|091|R|  adult subjects. Clin Ther 2012 Sep;34(9):2011-9.e1.|2
04086|092|R|4.Abbas R, Hug BA, Leister C, Burns J, Sonnichsen D. Effect of ketoconazole|2
04086|093|R|  on the pharmacokinetics of oral bosutinib in healthy subjects. J Clin|2
04086|094|R|  Pharmacol 2011 Dec;51(12):1721-7.|2
04086|095|R|5.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
04086|096|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
04086|097|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
04086|098|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
04086|099|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04086|100|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04086|101|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04086|102|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04086|103|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04086|104|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04086|105|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04086|106|R|  11/14/2017.|1
04086|107|R|8.This information is based on an extract from the Certara Drug Interaction|6
04086|108|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04087|001|T|MONOGRAPH TITLE:  Dasatinib/Vonoprazan-Clarithromycin|
04087|002|B||
04087|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04087|004|L|of severe adverse interaction.|
04087|005|B||
04087|006|A|MECHANISM OF ACTION:  The solubility of dasatinib is pH dependent.  Changes|
04087|007|A|in gastric pH from proton pump inhibitors (PPIs) may decrease the absorption|
04087|008|A|of dasatinib.  Vonoprazan is a PPI.(1)|
04087|009|A|   If dasatinib is absorbed, strong inhibitors of CYP3A4 that prolong the|
04087|010|A|QTc interval may inhibit the metabolism of dasatinib and result in additive|
04087|011|A|risk of QT prolongation.  Clarithromycin is a strong CYP3A4 inhibitor.(1)|
04087|012|B||
04087|013|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
04087|014|E|levels and effectiveness of dasatinib.(1)|
04087|015|E|   If dasatinib is absorbed, concurrent use of strong inhibitors of CYP3A4|
04087|016|E|that prolong QT may result in elevated levels of and toxicity from|
04087|017|E|dasatinib, including additive QTc prolongation, which may result in|
04087|018|E|potentially life-threatening cardiac arrhythmias, including torsades de|
04087|019|E|pointes (TdP).(1)|
04087|020|E|   Other toxicities include myelosuppression, serious hemorrhages, fluid|
04087|021|E|retention, pulmonary hypertension, cardiac ischemia, transient ischemic|
04087|022|E|attacks, and severe dermatological reactions.(1)|
04087|023|B||
04087|024|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04087|025|P|may be increased in patients with cardiovascular disease (e.g. heart|
04087|026|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04087|027|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04087|028|P|female gender, or advanced age.(2)|
04087|029|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04087|030|P|higher systemic concentrations of either QT prolonging drug are additional|
04087|031|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04087|032|P|drug concentrations include rapid infusion of an intravenous dose or|
04087|033|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04087|034|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04087|035|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04087|036|B||
04087|037|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs) in|
04087|038|M|patients receiving treatment with dasatinib.(1)|
04087|039|M|   Consider the use of short-acting antacids in these patients.  If antacids|
04087|040|M|are used, separate the administration times by at least 2 hours for|
04087|041|M|dasatinib.(1)|
04087|042|M|   The manufacturer of dasatinib also recommends avoiding the use of strong|
04087|043|M|CYP3A4 inhibitors that prolong QT in patients undergoing therapy with|
04087|044|M|dasatinib.(1)  Consider alternatives with no or minimal enzyme inhibition|
04087|045|M|and with no effect on the QTc interval.|
04087|046|M|   If concurrent use with dasatinib and a strong inhibitor of CYP3A4 is|
04087|047|M|warranted, consider decreasing the dose of dasatinib to 20 mg daily in|
04087|048|M|patients taking dasatinib 70 mg daily, 20 mg daily in patients taking|
04087|049|M|dasatinib 100 mg daily, and to 40 mg daily in patients taking dasatinib 140|
04087|050|M|mg daily.  If this dose is not tolerated, either the strong CYP3A4 inhibitor|
04087|051|M|must be discontinued or dasatinib should be stopped until therapy with the|
04087|052|M|CYP3A4 inhibitor has been completed.  When the CYP3A4 inhibitor has been|
04087|053|M|discontinued, a one-week washout period should be allowed before the dosage|
04087|054|M|of dasatinib is increased.  For patients taking 60 mg or 40 mg daily, stop|
04087|055|M|dasatinib until the inhibitor is discontinued.  Allow a washout period of|
04087|056|M|approximately one week after the inhibitor is stopped before reinitiating|
04087|057|M|dasatinib.(1)|
04087|058|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
04087|059|M|dasatinib should be monitored for prolongation of the QTc interval.  When|
04087|060|M|concurrent therapy is warranted: consider obtaining serum calcium,|
04087|061|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04087|062|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
04087|063|M|report any irregular heartbeat, dizziness, or fainting.|
04087|064|M|   The manufacturer of Phyrago states that it can be administered with|
04087|065|M|gastric acid reducing agents. Administration times should be separated with|
04087|066|M|antacids.(7)|
04087|067|B||
04087|068|D|DISCUSSION:  In a study in 24 healthy subjects, administration of a single|
04087|069|D|dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib|
04087|070|D|area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%,|
04087|071|D|respectively.(1)|
04087|072|D|   In a study in 14 healthy subjects, administration of a single dose of|
04087|073|D|dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state)|
04087|074|D|decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(1)|
04087|075|D|   In a study in 24 healthy subjects, simultaneous administration of|
04087|076|D|dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml)|
04087|077|D|decreased dasatinib AUC and Cmax by 55% and 58%, respectively.  In the same|
04087|078|D|subjects, administration of the antacid 2 hours before dasatinib decreased|
04087|079|D|dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(1)|
04087|080|D|   In a study in healthy subjects, concurrent ketoconazole (200 mg twice|
04087|081|D|daily) with dasatinib (20 mg) increased dasatinib maximum concentration|
04087|082|D|(Cmax) and area-under-curve (AUC) by 4-fold and 5-fold, respectively.|
04087|083|D|Recommended dosage adjustments are expected to adjust the dasatinib AUC to|
04087|084|D|ranges observed without CYP3A4 inhibitors; however, there are no clinical|
04087|085|D|data available.(1)|
04087|086|D|   A retrospective review of 618 cancer patients treated with 902|
04087|087|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
04087|088|D|incidence of QTc prolongation.  In patients who received dasatinib, QTc|
04087|089|D|prolongation was identified in 48 patients(41.7%) with 8 patients(16.7%)|
04087|090|D|having Grade 1 and 15 patients(31.3%) having Grade 2 events.  Grade 3 events|
04087|091|D|occurred in 8 patients(16.7%) having QTc greater than or equal to 500 ms and|
04087|092|D|14 patients (29.2%) having QTc change greater than or equal to 60 ms.  VT|
04087|093|D|was seen in 2 (4.2%) patients and 1 (2.1%) patient experienced TdP.(3)|
04087|094|D|   Agents that are linked to this monograph may have varying degrees of|
04087|095|D|potential to prolong the QTc interval but are generally accepted to have a|
04087|096|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04087|097|D|been shown to prolong the QTc interval either through their mechanism of|
04087|098|D|action, through studies on their effects on the QTc interval, or through|
04087|099|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04087|100|D|and/or post-marketing reports.(4)|
04087|101|D|   Phyrago is not sensitive to increased gastric pH due to its polymer|
04087|102|D|formulation. No clinically significant dasatinib pharmacokinetic changes|
04087|103|D|were seen with concurrent administration of Phyrago with omeprazole (proton|
04087|104|D|pump inhibitor) or famotidine (H2 receptor antagonist).(7)|
04087|105|D|   Strong inhibitors of CYP3A4 that prolong QT include: clarithromycin.(5,6)|
04087|106|B||
04087|107|R|REFERENCES:|
04087|108|B||
04087|109|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
04087|110|R|  Company February, 2023.|1
04087|111|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04087|112|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04087|113|R|  settings: a scientific statement from the American Heart Association and|6
04087|114|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04087|115|R|  2;55(9):934-47.|6
04087|116|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
04087|117|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
04087|118|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
04087|119|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04087|120|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04087|121|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04087|122|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04087|123|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04087|124|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04087|125|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04087|126|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04087|127|R|  11/14/2017.|1
04087|128|R|6.This information is based on an extract from the Certara Drug Interaction|6
04087|129|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04087|130|R|7.Phyrago (dasatinib) US Prescribing Information. Nanocopoeia, LLC December|1
04087|131|R|  2024.|1
04088|001|T|MONOGRAPH TITLE:  Nilotinib/Vonoprazan-Clarithromycin|
04088|002|B||
04088|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04088|004|L|of severe adverse interaction.|
04088|005|B||
04088|006|A|MECHANISM OF ACTION:  The solubility of nilotinib is pH dependent.  Changes|
04088|007|A|in gastric pH from proton pump inhibitors (PPIs) may decrease the absorption|
04088|008|A|of nilotinib.  Vonoprazan is a PPI.(1)|
04088|009|A|   If nilotinib is absorbed, agents that inhibit the CYP3A4 isoenzyme may|
04088|010|A|inhibit the metabolism of nilotinib.  Clarithromycin is a strong CYP3A4|
04088|011|A|inhibitor.(1)|
04088|012|B||
04088|013|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
04088|014|E|levels and effectiveness of nilotinib.(1)|
04088|015|E|   If nilotinib is absorbed, concurrent use of strong inhibitors of CYP3A4|
04088|016|E|that prolong QT may result in elevated levels of and toxicity from|
04088|017|E|nilotinib, including additive QTc prolongation, which may result in|
04088|018|E|potentially life-threatening cardiac arrhythmias, including torsades de|
04088|019|E|pointes (TdP).(1)|
04088|020|E|   Other toxicities include myelosuppression, severe hemorrhage, vascular|
04088|021|E|occlusive events, hepatotoxicity, pancreatitis, and fluid retention.(1)|
04088|022|B||
04088|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04088|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
04088|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04088|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04088|027|P|female gender, or advanced age.(2)|
04088|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04088|029|P|higher systemic concentrations of either QT prolonging drug are additional|
04088|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04088|031|P|drug concentrations include rapid infusion of an intravenous dose or|
04088|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04088|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04088|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04088|035|B||
04088|036|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs) in|
04088|037|M|patients receiving treatment with nilotinib.(1)|
04088|038|M|   Consider the use of short-acting antacids in these patients.  If antacids|
04088|039|M|are used, separate the administration times by at least 2 hours for|
04088|040|M|nilotinib.(1)|
04088|041|M|   If H2 antagonist therapy is required, nilotinib must be given 10 hours|
04088|042|M|after the H2 blocker and at least 2 hours before the next dose of the H2|
04088|043|M|blocker.(1)|
04088|044|M|   The manufacturer of nilotinib also recommends avoiding the use of strong|
04088|045|M|CYP3A4 inhibitors that prolong QT in patients undergoing therapy with|
04088|046|M|nilotinib.(1)  Consider alternatives with no or minimal enzyme inhibition|
04088|047|M|and with no effect on the QTc interval.|
04088|048|M|   Consider interrupting nilotinib therapy if a strong CYP3A4 inhibitor is|
04088|049|M|needed.  If concurrent use is warranted, a dose reduction to 300 mg once|
04088|050|M|daily in patients with resistant or intolerant Ph+CML or to 200 mg once|
04088|051|M|daily in patients with newly diagnosed Ph+CML-CP should be considered.  If|
04088|052|M|the 3A4 inhibitor is discontinued, a washout period should occur before the|
04088|053|M|nilotinib dose is adjusted upward.(6)|
04088|054|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
04088|055|M|nilotinib should be monitored for prolongation of the QTc interval.  When|
04088|056|M|concurrent therapy is warranted: consider obtaining serum calcium,|
04088|057|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04088|058|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
04088|059|M|report any irregular heartbeat, dizziness, or fainting.|
04088|060|B||
04088|061|D|DISCUSSION:  In a study in 22 healthy subjects, pretreatment with|
04088|062|D|esomeprazole (40 mg daily), decreased the Cmax and AUC of a single dose of|
04088|063|D|nilotinib (400 mg) by 27% and 34%, respectively.(1)  Increasing the dosage|
04088|064|D|of nilotinib or separating the administration time of nilotinib and the|
04088|065|D|proton pump inhibitor is not expected to eliminate the interaction.(1)|
04088|066|D|   There were no significant changes in nilotinib pharmacokinetics when|
04088|067|D|famotidine was administered 10 hours before or 2 hours after nilotinib.(1)|
04088|068|D|   There were no significant changes in nilotinib pharmacokinetics when an|
04088|069|D|antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was|
04088|070|D|administered 2 hours before or after nilotinib.(1)|
04088|071|D|   In a study in healthy subjects, concurrent ketoconazole (400 mg daily)|
04088|072|D|increased nilotinib area-under-curve (AUC) by 3-fold.(1)|
04088|073|D|   A retrospective review of 618 cancer patients treated with 902|
04088|074|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
04088|075|D|incidence of QTc prolongation.  In patients who received nilotinib, QTc|
04088|076|D|prolongation was identified in 29 patients (38.7%) with 1 patient(3.5%)|
04088|077|D|having Grade 1 and 2 patients(7%) having Grade 2 events.  Grade 3 events|
04088|078|D|occurred in 9 patients (31%) having QTc greater than or equal to 500 ms and|
04088|079|D|17 patients(58.6%) having QTc change greater than or equal to 60 ms.  No|
04088|080|D|patients developed VT, SCD, or TdP.(3)|
04088|081|D|   Agents that are linked to this monograph may have varying degrees of|
04088|082|D|potential to prolong the QTc interval but are generally accepted to have a|
04088|083|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04088|084|D|been shown to prolong the QTc interval either through their mechanism of|
04088|085|D|action, through studies on their effects on the QTc interval, or through|
04088|086|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04088|087|D|and/or post-marketing reports.(4)|
04088|088|D|   Strong inhibitors of CYP3A4 that prolong QT include: clarithromycin.(5,6)|
04088|089|B||
04088|090|R|REFERENCES:|
04088|091|B||
04088|092|R|1.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
04088|093|R|  Corporation September, 2021.|1
04088|094|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04088|095|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04088|096|R|  settings: a scientific statement from the American Heart Association and|6
04088|097|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04088|098|R|  2;55(9):934-47.|6
04088|099|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
04088|100|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
04088|101|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
04088|102|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04088|103|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04088|104|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04088|105|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04088|106|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04088|107|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04088|108|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04088|109|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04088|110|R|  11/14/2017.|1
04088|111|R|6.This information is based on an extract from the Certara Drug Interaction|6
04088|112|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04089|001|T|MONOGRAPH TITLE:  Pazopanib/Vonoprazan-Clarithromycin|
04089|002|B||
04089|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04089|004|L|of severe adverse interaction.|
04089|005|B||
04089|006|A|MECHANISM OF ACTION:  The solubility of pazopanib is pH dependent.  Changes|
04089|007|A|in gastric pH from proton pump inhibitors (PPIs) may decrease the absorption|
04089|008|A|of pazopanib.  Vonoprazan is a PPI.(1)|
04089|009|A|   If pazopanib is absorbed, strong inhibitors of CYP3A4 that prolong the|
04089|010|A|QTc interval may inhibit the metabolism of pazopanib and result in additive|
04089|011|A|risk of QT prolongation.(1)|
04089|012|B||
04089|013|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
04089|014|E|levels and effectiveness of pazopanib.(1)|
04089|015|E|   If pazopanib is absorbed, concurrent use of strong inhibitors of CYP3A4|
04089|016|E|that prolong QT may result in elevated levels of and toxicity from|
04089|017|E|pazopanib, including additive QTc prolongation, which may result in|
04089|018|E|potentially life-threatening cardiac arrhythmias, including torsades de|
04089|019|E|pointes (TdP).(1)|
04089|020|E|   Other toxicities include hepatotoxicity, cardiac dysfunction, serious|
04089|021|E|hemorrhage, arterial and venous thrombosis, thrombotic microangiopathy,|
04089|022|E|gastrointestinal perforation and fistula, hypertension, hypothyroidism,|
04089|023|E|interstitial lung disease, and proteinuria.(1)|
04089|024|B||
04089|025|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04089|026|P|may be increased in patients with cardiovascular disease (e.g. heart|
04089|027|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04089|028|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04089|029|P|female gender, or advanced age.(2)|
04089|030|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04089|031|P|higher systemic concentrations of either QT prolonging drug are additional|
04089|032|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04089|033|P|drug concentrations include rapid infusion of an intravenous dose or|
04089|034|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04089|035|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04089|036|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04089|037|B||
04089|038|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs) in|
04089|039|M|patients receiving treatment with pazopanib.(1)|
04089|040|M|   Consider the use of short-acting antacids in these patients.  If antacids|
04089|041|M|are used, separate the administration times by several hours for|
04089|042|M|pazopanib.(1)|
04089|043|M|   The manufacturer of pazopanib also recommends avoiding the use of strong|
04089|044|M|CYP3A4 inhibitors in patients undergoing therapy with pazopanib.(1)|
04089|045|M|Consider alternatives with no or minimal enzyme inhibition.|
04089|046|M|   If concurrent administration with pazopanib is warranted, the dosage of|
04089|047|M|pazopanib should be reduced to 400 mg.  Additional dosage reductions may be|
04089|048|M|required if adverse events occur.(1)|
04089|049|M|   Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and|
04089|050|M|pazopanib should be monitored for prolongation of the QTc interval.  When|
04089|051|M|concurrent therapy is warranted: consider obtaining serum calcium,|
04089|052|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04089|053|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
04089|054|M|report any irregular heartbeat, dizziness, or fainting.|
04089|055|B||
04089|056|D|DISCUSSION:  In a study in 13 patients, esomeprazole (40 mg daily for 5|
04089|057|D|days) decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%,|
04089|058|D|respectively, when compared to the administration of pazopanib alone.(1)|
04089|059|D|   Administration of multiple doses of oral pazopanib (400 mg) with multiple|
04089|060|D|doses of oral ketoconazole (400 mg) increased the area-under-curve (AUC) and|
04089|061|D|maximum concentration (Cmax) of pazopanib by 1.7-fold and 1.5-fold,|
04089|062|D|respectively.  Administration of a single dose of pazopanib ophthalmic drops|
04089|063|D|and ketoconazole, an inhibitor of CYP3A4 and P-gp, increased the AUC and|
04089|064|D|Cmax of pazopanib by 220% and 150%, respectively.  Administration of|
04089|065|D|lapatinib (1500 mg), a weak inhibitor of CYP3A4, P-gp, and BCRP, increased|
04089|066|D|the AUC and Cmax of pazopanib (800 mg) by 50% and 60%, respectively.|
04089|067|D|Decreasing the dosage of pazopanib to 400 mg in patients receiving strong|
04089|068|D|CYP3A4 inhibitors is expected to adjust the AUC of pazopanib to the normal|
04089|069|D|range; however, there are no clinical data available to support this.(1)|
04089|070|D|   A retrospective review of 618 cancer patients treated with 902|
04089|071|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
04089|072|D|incidence of QTc prolongation.  In patients who received pazopanib, QTc|
04089|073|D|prolongation was identified in 32 patients (19.4%) with 18 patients (56.3%)|
04089|074|D|having Grade 1 and 4 patients (12.5%) having Grade 2 events.  Grade 3 events|
04089|075|D|occurred in 3 patients (9.3%) having QTc greater than or equal to 500 ms and|
04089|076|D|4 patients (12.5%) having QTc change greater than or equal to 60 ms.  VT was|
04089|077|D|seen in 2 (6.3%) patients and 1 (3.1%) patient experienced SCD.(3)|
04089|078|D|   Agents that are linked to this monograph may have varying degrees of|
04089|079|D|potential to prolong the QTc interval but are generally accepted to have a|
04089|080|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04089|081|D|been shown to prolong the QTc interval either through their mechanism of|
04089|082|D|action, through studies on their effects on the QTc interval, or through|
04089|083|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04089|084|D|and/or post-marketing reports.(4)|
04089|085|D|   Strong inhibitors of CYP3A4 that prolong QT include: clarithromycin.(5,6)|
04089|086|B||
04089|087|R|REFERENCES:|
04089|088|B||
04089|089|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
04089|090|R|  2020.|1
04089|091|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04089|092|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04089|093|R|  settings: a scientific statement from the American Heart Association and|6
04089|094|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04089|095|R|  2;55(9):934-47.|6
04089|096|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
04089|097|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
04089|098|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
04089|099|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04089|100|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04089|101|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04089|102|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04089|103|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04089|104|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04089|105|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04089|106|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04089|107|R|  11/14/2017.|1
04089|108|R|6.This information is based on an extract from the Certara Drug Interaction|6
04089|109|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04090|001|T|MONOGRAPH TITLE:  Selected Kinase Inhibitors/Vonoprazan-Clarithromycin|
04090|002|B||
04090|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04090|004|L|of severe adverse interaction.|
04090|005|B||
04090|006|A|MECHANISM OF ACTION:  The solubility of dacomitinib(1) and gefitinib(2) is|
04090|007|A|pH dependent.  Changes in gastric pH from proton pump inhibitors may|
04090|008|A|decrease the absorption of dacomitinib(1) and gefitinib.(2)|
04090|009|B||
04090|010|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
04090|011|E|levels and effectiveness of dacomitinib(1) and gefitinib.(2)|
04090|012|B||
04090|013|P|PREDISPOSING FACTORS:  None determined.|
04090|014|B||
04090|015|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs) in|
04090|016|M|patients receiving treatment with dacomitinib(1) and gefitinib.(2)|
04090|017|M|   Consider the use of short-acting antacids in these patients.(1,2)  If|
04090|018|M|antacids are used, separate the administration times by several hours(1,2)|
04090|019|M|but at least 6 hours for gefitinib.(2)|
04090|020|M|   If H2 antagonist therapy is required with dacomitinib, dacomitinib must|
04090|021|M|be given once daily 10 hours after the H2 blocker and 6 hours before the|
04090|022|M|next dose of the H2 blocker.(1)|
04090|023|M|   If PPIs are required with gefitinib, administer gefitinib 12 hours after|
04090|024|M|the last dose or 12 hours before the next dose of the PPI.  Administer|
04090|025|M|gefitinib 6 hours before or after H2-antagonists or antacids.(2)|
04090|026|B||
04090|027|D|DISCUSSION:  In a study in healthy subjects, high dose ranitidine with|
04090|028|D|sodium carbonate was administered to maintain gastric pH above 5.0 and|
04090|029|D|gefitinib AUC decreased 47%.(2)|
04090|030|B||
04090|031|R|REFERENCES:|
04090|032|B||
04090|033|R|1.Vizimpro (dacomitinib) US prescribing information. Pfizer, Inc. September,|1
04090|034|R|  2018.|1
04090|035|R|2.Iressa (gefitinib) US prescribing information. AstraZeneca March 6, 2012.|1
04091|001|T|MONOGRAPH TITLE:  Erlotinib/Vonoprazan-Clarithromycin|
04091|002|B||
04091|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04091|004|L|of severe adverse interaction.|
04091|005|B||
04091|006|A|MECHANISM OF ACTION:  The solubility of erlotinib is pH dependent.  Changes|
04091|007|A|in gastric pH from proton pump inhibitors (PPIs) may decrease the absorption|
04091|008|A|of erlotinib.  Vonoprazan is a PPI.(1)|
04091|009|A|   If erlotinib is absorbed, agents that inhibit the CYP3A4 isoenzyme may|
04091|010|A|inhibit the metabolism of erlotinib.  Clarithromycin is a strong CYP3A4|
04091|011|A|inhibitor.(1)|
04091|012|B||
04091|013|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
04091|014|E|levels and effectiveness of erlotinib.(1)|
04091|015|E|   If erlotinib is absorbed, concurrent use of strong CYP3A4 inhibitors may|
04091|016|E|increase levels of and effects from erlotinib, including interstitial lung|
04091|017|E|disease, renal failure, hepatotoxicity, gastrointestinal perforation, skin|
04091|018|E|disorders, ocular disorders, or cerebrovascular events.(1)|
04091|019|B||
04091|020|P|PREDISPOSING FACTORS:  None determined.|
04091|021|B||
04091|022|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs) in|
04091|023|M|patients receiving treatment with erlotinib.(1)|
04091|024|M|   Consider the use of short-acting antacids in these patients.  If antacids|
04091|025|M|are used, separate the administration times by at least several hours for|
04091|026|M|erlotinib.(1)|
04091|027|M|   If H2 antagonist therapy is required, erlotinib must be given 10 hours|
04091|028|M|after the H2 blocker and at least 2 hours before the next dose of the H2|
04091|029|M|blocker.(1)|
04091|030|M|   The manufacturer of erlotinib also recommends avoiding the use of strong|
04091|031|M|CYP3A4 inhibitors in patients undergoing therapy with erlotinib.(1)|
04091|032|M|Consider alternatives with no or minimal enzyme inhibition.|
04091|033|M|   If concurrent therapy with erlotinib is required, decrease the dose of|
04091|034|M|erlotinib by 50 mg decrements.(1)|
04091|035|B||
04091|036|D|DISCUSSION:  In a study, concurrent omeprazole decreased the AUC and Cmax of|
04091|037|D|erlotinib by 46% and 61%, respectively.(1)|
04091|038|D|   In a study, administration of erlotinib two hours after a dose of|
04091|039|D|ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%,|
04091|040|D|respectively.  Administration of erlotinib 10 hours after and two hours|
04091|041|D|before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by|
04091|042|D|15% and 17%, respectively.(1)|
04091|043|D|   Co-administration of erlotinib with a strong CYP3A4 inhibitor,|
04091|044|D|ketoconazole, increased erlotinib area-under-curve (AUC) by 67%.(1)|
04091|045|D|   In a study, 24 healthy subjects received a single erlotinib 100 mg dose|
04091|046|D|alone or after ketoconazole 200 mg twice daily for 5 days. Mean AUC and|
04091|047|D|concentration maximum (Cmax) increased by approximately 2-fold.(2)|
04091|048|D|   Strong inhibitors of CYP3A4 include:  clarithromycin.(3,4)|
04091|049|B||
04091|050|R|REFERENCES:|
04091|051|B||
04091|052|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
04091|053|R|  2016.|1
04091|054|R|2.Rakhit A, Pantze MP, Fettner S, Jones HM, Charoin JE, Riek M, Lum BL,|2
04091|055|R|  Hamilton M. The effects of CYP3A4 inhibition on erlotinib|2
04091|056|R|  pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo|2
04091|057|R|  metabolic inhibition. Eur J Clin Pharmacol 2008 Jan;64(1):31-41.|2
04091|058|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04091|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04091|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04091|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04091|062|R|  11/14/2017.|1
04091|063|R|4.This information is based on an extract from the Certara Drug Interaction|6
04091|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04092|001|T|MONOGRAPH TITLE:  Neratinib/Vonoprazan-Clarithromycin|
04092|002|B||
04092|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04092|004|L|of severe adverse interaction.|
04092|005|B||
04092|006|A|MECHANISM OF ACTION:  The solubility of neratinib is pH dependent.  Changes|
04092|007|A|in gastric pH from proton pump inhibitors (PPIs) may decrease the absorption|
04092|008|A|of neratinib.  Vonoprazan is a PPI.(1)|
04092|009|A|   If neratinib is absorbed, inhibitors of CYP3A4 may inhibit the metabolism|
04092|010|A|of neratinib.  Clarithromycin is a strong CYP3A4 inhibitor.(1)|
04092|011|B||
04092|012|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
04092|013|E|levels and effectiveness of neratinib.(1)|
04092|014|E|   If neratinib is absorbed, concurrent use of strong CYP3A4 inhibitors may|
04092|015|E|result in increased systemic exposure to and effects from neratinib.(1)|
04092|016|B||
04092|017|P|PREDISPOSING FACTORS:  None determined.|
04092|018|B||
04092|019|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs) in|
04092|020|M|patients receiving treatment with neratinib.(1)|
04092|021|M|   Consider the use of short-acting antacids in these patients.  If antacids|
04092|022|M|are used, separate the administration times by at least 3 hours for|
04092|023|M|neratinib.(1)|
04092|024|M|   If H2 antagonist therapy is required, neratinib must be given 10 hours|
04092|025|M|after the H2 blocker and at least 2 hours before the next dose of the H2|
04092|026|M|blocker.(1)|
04092|027|M|   The manufacturer of neratinib also recommends avoiding the concurrent use|
04092|028|M|of neratinib with strong CYP3A4 inhibitors or moderate CYP3A4 and P-gp dual|
04092|029|M|inhibitors.(1)|
04092|030|M|   If concurrent use is warranted, monitor patients closely for increased|
04092|031|M|incidence and severity of diarrhea, abdominal pain, nausea, vomiting, and|
04092|032|M|dehydration.|
04092|033|B||
04092|034|D|DISCUSSION:  In a study in 15 healthy subjects, lansoprazole (30 mg at|
04092|035|D|steady state) decreased the Cmax and AUC of a single dose of neratinib (240|
04092|036|D|mg) by 71% and 65%, respectively.(1)|
04092|037|D|   Ketoconazole (400 mg daily for 5 days), a strong CYP3A4 inhibitor,|
04092|038|D|increased maximum concentration (Cmax) and area-under-curve (AUC) of a|
04092|039|D|single dose of neratinib by 221% and 381%, respectively.(1)|
04092|040|D|   Pharmacokinetic models predicted that verapamil, a moderate CYP3A4 and|
04092|041|D|P-gp dual inhibitor, would increase the Cmax and AUC of neratinib by 203%|
04092|042|D|and 299%, respectively.  Fluconazole, a moderate CYP3A4 inhibitor, is not|
04092|043|D|expected to have a significant interaction with neratinib.(1)|
04092|044|D|   Strong CYP3A4 inhibitors include:  clarithromycin.(1,3)|
04092|045|B||
04092|046|R|REFERENCES:|
04092|047|B||
04092|048|R|1.Nerlynx (neratinib) US prescribing information. Puma Biotechnology, Inc.|1
04092|049|R|  June, 2021.|1
04092|050|R|2.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
04092|051|R|  Monograph. Pfizer Canada ULC October, 2023.|1
04092|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
04092|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04093|001|T|MONOGRAPH TITLE:  Pexidartinib/Vonoprazan|
04093|002|B||
04093|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04093|004|L|of severe adverse interaction.|
04093|005|B||
04093|006|A|MECHANISM OF ACTION:  Multiple mechanisms are involved in this interaction.|
04093|007|A|With concurrent use of pexidartinib and vonoprazan:|
04093|008|A|   1. The solubility of pexidartinib is pH dependent.  Changes in gastric pH|
04093|009|A|from proton pump inhibitors (PPIs) may decrease the absorption of|
04093|010|A|pexidartinib.(1)  Vonoprazan is a PPI.(2)|
04093|011|A|   2. Pexidartinib is a moderate CYP3A4 inducer.  If pexidartinib is|
04093|012|A|absorbed, it may increase the CYP3A4-mediated metabolism of vonoprazan.(1,2)|
04093|013|A|   The triple pak formulation of vonoprazan-clarithromycin-amoxicillin is|
04093|014|A|also affected by the mechanisms above when used with pexidartinib.  In|
04093|015|A|addition, if pexidartinib is absorbed, CYP3A4 induction by pexidartinib may|
04093|016|A|increase the metabolism of clarithromycin, and clarithromycin, a strong|
04093|017|A|CYP3A4 inhibitor, may decrease the metabolism of pexidartinib.(1,2)|
04093|018|B||
04093|019|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
04093|020|E|levels and effectiveness of pexidartinib.(1)|
04093|021|E|   If pexidartinib is absorbed, it may decrease the levels and effectiveness|
04093|022|E|of vonoprazan and clarithromycin.  In addition, concurrent use of a strong|
04093|023|E|CYP3A4 inhibitor may increase the levels and toxicities of pexidartinib,|
04093|024|E|such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting,|
04093|025|E|jaundice, dark urine, abdominal pain, and unexplained fatigue. The net|
04093|026|E|effect of vonoprazan-clarithromycin on pexidartinib levels is unknown.|
04093|027|B||
04093|028|P|PREDISPOSING FACTORS:  None determined.|
04093|029|B||
04093|030|M|PATIENT MANAGEMENT:  Avoid the use of vonoprazan, vonoprazan-amoxicillin and|
04093|031|M|vonoprazan-clarithromycin-amoxicillin in patients receiving treatment with|
04093|032|M|pexidartinib.(1,2)|
04093|033|M|   Consider the use of short-acting antacids.  If antacids are used,|
04093|034|M|separate the administration times by at least 2 hours for pexidartinib.(1)|
04093|035|M|   If H2 antagonist therapy is required, pexidartinib must be given 10 hours|
04093|036|M|after the H2 blocker and at least 2 hours before the next dose of the H2|
04093|037|M|blocker.(1)|
04093|038|B||
04093|039|D|DISCUSSION:  Coadministration of esomeprazole decreased pexidartinib maximum|
04093|040|D|concentration (Cmax) and area-under-the-curve (AUC) by 55% and 50%.(1)|
04093|041|D|   Vonoprazan and clarithromycin are CYP3A4 substrates.  Strong CYP3A4|
04093|042|D|inducers like rifampin are predicted to decrease the AUC of vonoprazan by|
04093|043|D|80%, and moderate CYP3A4 inducers like efavirenz are predicted to decrease|
04093|044|D|vonoprazan AUC by 50%.(1)  Pexidartinib is a moderate CYP3A4 inducer.(2-3)|
04093|045|D|   Coadministration of itraconazole (strong CYP3A4 inhibitor) increased|
04093|046|D|pexidartinib Cmax and AUC by 48% and 70%.(1)|
04093|047|B||
04093|048|R|REFERENCES:|
04093|049|B||
04093|050|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04093|051|R|  November, 2023.|1
04093|052|R|2.Voquezna (vonoprazan-amoxicillin and|1
04093|053|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04093|054|R|  Pharmaceuticals, Inc. November, 2023.|1
04093|055|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04093|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04093|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04093|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04093|059|R|  11/14/2017.|1
04093|060|R|4.This information is based on an extract from the Certara Drug Interaction|6
04093|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04094|001|T|MONOGRAPH TITLE:  Infigratinib/Vonoprazan-Clarithromycin|
04094|002|B||
04094|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04094|004|L|of severe adverse interaction.|
04094|005|B||
04094|006|A|MECHANISM OF ACTION:  The aqueous solubility of infigratinib is pH|
04094|007|A|dependent.  Higher gastric pH leads to lower solubility which may reduce|
04094|008|A|infigratinib absorption.  Vonoprazan is a proton pump inhibitor (PPI).(1)|
04094|009|A|   If infigratinib is absorbed, strong inhibitors of CYP3A4 may inhibit the|
04094|010|A|metabolism of infigratinib.  Clarithromycin is a strong CYP3A4 inhibitor.(1)|
04094|011|B||
04094|012|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) may|
04094|013|E|reduce the bioavailability of infigratinib, leading to decreased systemic|
04094|014|E|levels and effectiveness.(1)|
04094|015|E|   If infigratinib is absorbed, concomitant use of a strong or moderate|
04094|016|E|CYP3A4 inhibitor increases infigratinib plasma concentrations, which may|
04094|017|E|increase the incidence and severity of adverse reactions.(1)|
04094|018|B||
04094|019|P|PREDISPOSING FACTORS:  None determined.|
04094|020|B||
04094|021|M|PATIENT MANAGEMENT:  Avoid the use of PPIs, H2 antagonists, and locally|
04094|022|M|acting antacids in patients receiving treatment with infigratinib.(1)|
04094|023|M|   If coadministration cannot be avoided and the PPI is replaced with a H2|
04094|024|M|antagonist, take infigratinib 2 hours before or 10 hours after the H2|
04094|025|M|antagonist.(1)|
04094|026|M|   If coadministration cannot be avoided and the PPI is replaced with an|
04094|027|M|antacid, take infigratinib 2 hours before or 2 hours after the antacid.(1)|
04094|028|M|   The manufacturer of infigratinib also recommends avoiding concomitant use|
04094|029|M|of strong or moderate CYP3A4 inhibitors with infigratinib.(1)|
04094|030|B||
04094|031|D|DISCUSSION:  Infigratinib is practically insoluble at pH 6.8.(1)|
04094|032|D|   In a clinical study, lansoprazole decreased the area-under-curve (AUC)|
04094|033|D|and maximum concentration (Cmax) of infigratinib by 45% and 49%,|
04094|034|D|respectively.  The AUC and Cmax of the active metabolite BHS697 were|
04094|035|D|decreased by 32% and 44%, respectively, and the active metabolite CQM157's|
04094|036|D|AUC and Cmax were decreased by 72% and 55%, respectively.(1)|
04094|037|D|   Coadministration of multiple doses of itraconazole (a strong CYP3A4|
04094|038|D|inhibitor) increased infigratinib area-under-curve (AUC) and maximum|
04094|039|D|concentration (Cmax) by 622% and 164%, respectively.(1)|
04094|040|B||
04094|041|R|REFERENCE:|
04094|042|B||
04094|043|R|1.Truseltiq (infigratinib) US prescribing information. QED Therapeutics,|1
04094|044|R|  Inc. May, 2021.|1
04095|001|T|MONOGRAPH TITLE:  Sotorasib/Vonoprazan|
04095|002|B||
04095|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04095|004|L|of severe adverse interaction.|
04095|005|B||
04095|006|A|MECHANISM OF ACTION:  The aqueous solubility of sotorasib is pH dependent.|
04095|007|A|Higher gastric pH leads to lower solubility which may reduce sotorasib|
04095|008|A|absorption.  Vonoprazan is a proton pump inhibitor (PPI).(1)|
04095|009|A|   If sotorasib is absorbed, it may increase the CYP3A4 metabolism of|
04095|010|A|vonoprazan and clarithromycin.(2)|
04095|011|B||
04095|012|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) or H2|
04095|013|E|antagonists may reduce the bioavailability of sotorasib, leading to|
04095|014|E|decreased systemic levels and effectiveness.(1)|
04095|015|E|   Also, the concurrent administration of strong or moderate CYP3A4|
04095|016|E|inducers, such as sotorasib, may result in decreased levels and|
04095|017|E|effectiveness of vonoprazan and clarithromycin.(2)|
04095|018|B||
04095|019|P|PREDISPOSING FACTORS:  None determined.|
04095|020|B||
04095|021|M|PATIENT MANAGEMENT:  Coadministration of sotorasib with proton pump|
04095|022|M|inhibitors, H2 antagonists, and antacids should be avoided.|
04095|023|M|   If coadministration with an acid-reducing agent is unavoidable, take|
04095|024|M|sotorasib 4 hours before or 10 hours after a locally acting antacid.(1)|
04095|025|M|   The UK manufacturer of sotorasib states if co-administration with an|
04095|026|M|acid-reducing agent (such as a PPI or an H2 antagonist) is required,|
04095|027|M|sotorasib should be taken with an acidic beverage (such as cola).|
04095|028|M|Alternatively, sotorasib should be taken 4 hours before or 10 hours after|
04095|029|M|administration of a local antacid.(3)|
04095|030|M|   The manufacturer of vonoprazan states that concurrent use with strong or|
04095|031|M|moderate CYP3A4 inducers should be avoided.(2)|
04095|032|B||
04095|033|D|DISCUSSION:  The solubility of sotorasib in the aqueous media decreases over|
04095|034|D|the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL.|
04095|035|D|   In an interaction study, coadministration of repeat doses of omeprazole|
04095|036|D|with a single dose of sotorasib decreased sotorasib maximum concentration|
04095|037|D|(Cmax) by 65% and area-under-curve (AUC) by 57% under fed conditions, and|
04095|038|D|decreased sotorasib Cmax by 57% and AUC by 42% under fasted conditions.|
04095|039|D|Under fasted conditions, co-administration of repeat doses of omeprazole|
04095|040|D|with a single dose of sotorasib and 240ml of an acidic beverage (non-diet|
04095|041|D|cola) decreased sotorasib Cmax by 32% and AUC by 23%.  The UK manufacturer|
04095|042|D|of sotorasib states the clinical relevance of the decreased sotorasib|
04095|043|D|exposure when co-administered with omeprazole and cola is unclear and|
04095|044|D|sotorasib efficacy might be reduced.(3)|
04095|045|D|   Coadministration of a single dose of famotidine given 10 hours prior to|
04095|046|D|and 2 hours after a single dose of sotorasib under fed conditions decreased|
04095|047|D|sotorasib Cmax by 35% and AUC by 38%.(1)|
04095|048|D|   Vonoprazan and clarithromycin are CYP3A4 substrates.  Strong CYP3A4|
04095|049|D|inducers like rifampin are predicted to decrease the AUC of vonoprazan by|
04095|050|D|80%, and moderate CYP3A4 inducers like efavirenz are predicted to decrease|
04095|051|D|vonoprazan AUC by 50%.(2)|
04095|052|B||
04095|053|R|REFERENCES:|
04095|054|B||
04095|055|R|1.Lumakras (sotorasib) US prescribing information. Amgen Inc November, 2022.|1
04095|056|R|2.Voquezna (vonoprazan-amoxicillin and|1
04095|057|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04095|058|R|  Pharmaceuticals, Inc. November, 2023.|1
04095|059|R|3.Lumykras (sotorasib) UK Prescribing Information. Amgen Ltd May 2024.|1
04096|001|T|MONOGRAPH TITLE:  Acalabrutinib/Vonoprazan-Clarithromycin|
04096|002|B||
04096|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04096|004|L|of severe adverse interaction.|
04096|005|B||
04096|006|A|MECHANISM OF ACTION:  The aqueous solubility of acalabrutinib capsules is pH|
04096|007|A|dependent.  Higher gastric pH leads to lower solubility which may reduce|
04096|008|A|acalabrutinib capsule absorption.  Vonoprazan is a proton pump inhibitor|
04096|009|A|(PPI).(1,2)|
04096|010|A|   If acalabrutinib is absorbed, strong inhibitors of CYP3A4 may inhibit the|
04096|011|A|metabolism of acalabrutinib.  Acalabrutinib capsules and tablets are CYP3A4|
04096|012|A|substrates.  Clarithromycin is a strong CYP3A4 inhibitor.(1,2)|
04096|013|B||
04096|014|E|CLINICAL EFFECTS:  Coadministration of PPIs may reduce the bioavailability|
04096|015|E|of acalabrutinib capsules, leading to decreased systemic levels and|
04096|016|E|effectiveness.(1)|
04096|017|E|   If acalabrutinib is absorbed, concurrent use of strong CYP3A4 inhibitors|
04096|018|E|may increase systemic exposure and the risk for acalabrutinib toxicities|
04096|019|E|such as neutropenia, anemia, or thrombocytopenia.(1)|
04096|020|B||
04096|021|P|PREDISPOSING FACTORS:  None determined.|
04096|022|B||
04096|023|M|PATIENT MANAGEMENT:  Coadministration of PPIs is not recommended with|
04096|024|M|acalabrutinib capsules.  Separation of doses may not eliminate the|
04096|025|M|interaction with acalabrutinib.(1)|
04096|026|M|   Acalabrutinib tablets are not affected by coadministration with proton|
04096|027|M|pump inhibitors and may be used concurrently.(1)|
04096|028|M|   The manufacturer of acalabrutinib capsules and tablets also recommends|
04096|029|M|avoiding concomitant use of acalabrutinib and strong CYP3A inhibitors.|
04096|030|M|Consider an alternative concomitant medication with less potential for|
04096|031|M|CYP3A4 inhibition.|
04096|032|M|   If a CYP3A inhibitor will be used short-term (such as anti-infective for|
04096|033|M|up to 7 days), interrupt acalabrutinib therapy.(1)|
04096|034|B||
04096|035|D|DISCUSSION:  In an interaction study, omeprazole (40 mg for 5 days) given|
04096|036|D|simultaneously with acalabrutinib, decreased acalabrutinib|
04096|037|D|area-under-the-curve (AUC) by 43%(1)|
04096|038|D|   In a drug interaction study in healthy subjects, coadministration of|
04096|039|D|itraconazole (200mg once daily for 5 days) with acalabrutinib increased|
04096|040|D|acalabrutinib maximum concentration (Cmax) and area-under-the-curve (AUC) by|
04096|041|D|3.9 and 5.1-fold, respectively.(1)|
04096|042|B||
04096|043|R|REFERENCES:|
04096|044|B||
04096|045|R|1.Calquence (acalabrutinib) US prescribing information. AstraZeneca|1
04096|046|R|  Pharmaceuticals LP August, 2022.|1
04096|047|R|2.Voquezna (vonoprazan-amoxicillin and|1
04096|048|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04096|049|R|  Pharmaceuticals, Inc. November, 2023.|1
04097|001|T|MONOGRAPH TITLE:  Indinavir/Vonoprazan-Clarithromycin|
04097|002|B||
04097|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04097|004|L|of severe adverse interaction.|
04097|005|B||
04097|006|A|MECHANISM OF ACTION:  The aqueous solubility of indinavir is pH dependent.|
04097|007|A|Higher gastric pH leads to lower solubility which may reduce indinavir|
04097|008|A|absorption.(1-2)|
04097|009|A|   If indinavir is absorbed, indinavir, an inhibitor of CYP3A4, may inhibit|
04097|010|A|the metabolism of clarithromycin.(1-4)|
04097|011|B||
04097|012|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors may reduce the|
04097|013|E|bioavailability of indinavir, leading to decreased systemic levels and|
04097|014|E|effectiveness.(1-3)|
04097|015|E|   If indinavir is absorbed, concurrent administration may result in|
04097|016|E|elevated levels of clarithromycin, reduced levels of 14-OH-clarithromycin,|
04097|017|E|and QTc prolongation.(4)|
04097|018|B||
04097|019|P|PREDISPOSING FACTORS:  Patients with decreased renal function (as shown by a|
04097|020|P|creatinine clearance (CrCL) of 60 ml/min or less are more susceptible to|
04097|021|P|effects of the interaction.(4)|
04097|022|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04097|023|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04097|024|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04097|025|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04097|026|P|advanced age.(5)|
04097|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04097|028|P|higher systemic concentrations of either QT prolonging drug are additional|
04097|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04097|030|P|drug concentrations include rapid infusion of an intravenous dose or|
04097|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04097|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04097|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
04097|034|B||
04097|035|M|PATIENT MANAGEMENT:  Concomitant administration of indinavir and proton pump|
04097|036|M|inhibitors is not recommended unless indinavir is accompanied by ritonavir,|
04097|037|M|typically dosed as indinavir 800 mg twice daily with ritonavir 100 mg twice|
04097|038|M|daily.  Monitor patients receiving concurrent therapy for changes in|
04097|039|M|indinavir effectiveness.(1)|
04097|040|M|   The manufacturer of vonoprazan-clarithromycin states concurrent use with|
04097|041|M|ritonavir is not recommended in patients with decreased renal function.(4)|
04097|042|B||
04097|043|D|DISCUSSION:  A retrospective analysis in 9 HIV+ patients found that|
04097|044|D|indinavir administration with omeprazole (20 mg) decreased the maximum|
04097|045|D|concentration (Cmax) of indinavir by 29%. Indinavir administration with|
04097|046|D|omeprazole (40 mg) decreased the Cmax of indinavir by 41%.(1)|
04097|047|D|   In a crossover study in 16 healthy volunteers, concurrent administration|
04097|048|D|of omeprazole (20 mg to 40 mg for 7 days) decreased the indinavir (800 mg|
04097|049|D|single dose) Cmax and area-under-the-curve (AUC) by 29-41% and 34-47%,|
04097|050|D|respectively.(2)|
04097|051|D|   Coadministration of omeprazole (40 mg) and indinavir (800 mg single dose)|
04097|052|D|to 14 HIV+ subjects resulted in a 47% decrease in indinavir AUC and a 55%|
04097|053|D|decrease in minimum concentration (Cmin). The addition of ritonavir (200 mg|
04097|054|D|single dose) reversed the effects of omeprazole.(3)|
04097|055|D|   In a crossover study in 5 healthy volunteers, concurrent administration|
04097|056|D|of indinavir (400 mg single dose) with a proton pump inhibitor resulted in|
04097|057|D|increased gastric pH and a smaller fraction of indinavir being dissolved and|
04097|058|D|lower intestinal concentrations.(6)|
04097|059|D|   In an animal study investigating the solubility of indinavir, solubility|
04097|060|D|of indinavir in aqueous media decreased from more than 100 mg/mL at pH 3 to|
04097|061|D|less than 0.1 mg/mL at pH 5 or above.(7)|
04097|062|B||
04097|063|R|REFERENCES:|
04097|064|B||
04097|065|R|1.Tappouni HL, Rublein JC, Donovan BJ, Hollowell SB, Tien HC, Min SS,|2
04097|066|R|  Theodore D, Rezk NL, Smith PC, Tallman MN, Raasch RH, Kashuba AD. Effect|2
04097|067|R|  of omeprazole on the plasma concentrations of indinavir when administered|2
04097|068|R|  alone and in combination with ritonavir. Am J Health Syst Pharm 2008 Mar|2
04097|069|R|  1;65(5):422-8.|2
04097|070|R|2.Burger DM, Hugen PW, Kroon FP, Groeneveld P, Brinkman K, Foudraine NA,|6
04097|071|R|  Sprenger H, Koopmans PP, Hekster YA. Pharmacokinetic interaction between|6
04097|072|R|  the proton pump inhibitor omeprazole and the HIV protease inhibitor|6
04097|073|R|  indinavir. AIDS 1998 Oct 22;12(15):2080-2.|6
04097|074|R|3.Rublein JC, Donovan BJ, Hollowell SB. Effects of omeprazole on the plasma|4
04097|075|R|  concentrations of indinavir in HIV-negative subjects. 43rd ICAAC 2003 Sep;|4
04097|076|R|  A-1611.|4
04097|077|R|4.Voquezna (vonoprazan-amoxicillin and|1
04097|078|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04097|079|R|  Pharmaceuticals, Inc. November, 2023.|1
04097|080|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04097|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04097|082|R|  settings: a scientific statement from the American Heart Association and|6
04097|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04097|084|R|  2;55(9):934-47.|6
04097|085|R|6.Rubbens J, Brouwers J, Tack J, Augustijns P. Gastrointestinal dissolution,|2
04097|086|R|  supersaturation and precipitation of the weak base  indinavir in healthy|2
04097|087|R|  volunteers. Eur J Pharm Biopharm 2016 Dec;109:122-129.|2
04097|088|R|7.Lin JH, Chen IW, Vastag KJ, Ostovic D. pH-dependent oral absorption of|5
04097|089|R|  L-735,524, a potent HIV protease inhibitor, in rats and dogs. Drug Metab|5
04097|090|R|  Dispos 1995 Jul;23(7):730-5.|5
04098|001|T|MONOGRAPH TITLE:  Selpercatinib/Vonoprazan-Clarithromycin|
04098|002|B||
04098|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04098|004|L|of severe adverse interaction.|
04098|005|B||
04098|006|A|MECHANISM OF ACTION:  The solubility of selpercatinib is pH dependent.|
04098|007|A|Increase in gastric pH from proton pump inhibitors (PPIs) may decrease the|
04098|008|A|solubility and absorption of selpercatinib.(1)  Vonoprazan is a PPI.(2)|
04098|009|A|   If selpercatinib is absorbed, strong CYP3A4 inhibitors that prolong the|
04098|010|A|QT interval may inhibit the metabolism of selpercatinib and result in|
04098|011|A|additive effects on the QT interval.(1)  Clarithromycin is a strong CYP3A4|
04098|012|A|inhibitor that prolongs the QT interval.(2)|
04098|013|B||
04098|014|E|CLINICAL EFFECTS:  Use of proton pump inhibitors may result in decreased|
04098|015|E|levels and effectiveness of selpercatinib.(1)|
04098|016|E|   If selpercatinib is absorbed, concurrent administration of a strong|
04098|017|E|CYP3A4 inhibitor that prolongs the QT interval may result in elevated levels|
04098|018|E|of and toxicity from selpercatinib.(1)  Elevated levels of selpercatinib may|
04098|019|E|increase the risk of QTc prolongation and potentially life-threatening|
04098|020|E|cardiac arrhythmias, including torsades de pointes, hepatotoxicity,|
04098|021|E|hypertension, and severe or life-threatening hemorrhagic events.(1)|
04098|022|B||
04098|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04098|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
04098|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04098|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04098|027|P|female gender, or advanced age.(3)|
04098|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04098|029|P|higher systemic concentrations of either QT prolonging drug are additional|
04098|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04098|031|P|drug concentrations include rapid infusion of an intravenous dose or|
04098|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04098|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04098|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04098|035|B||
04098|036|M|PATIENT MANAGEMENT:  Avoid the use of proton pump inhibitors (PPIs) in|
04098|037|M|patients receiving treatment with selpercatinib.  If coadministration with|
04098|038|M|PPIs cannot be avoided, take selpercatinib with food.(1)|
04098|039|M|   If the PPI is replaced with a H2 antagonist, take selpercatinib 2 hours|
04098|040|M|before or 10 hours after the H2 antagonist.(1)|
04098|041|M|   If the PPI is replaced with an antacid, take selpercatinib 2 hours before|
04098|042|M|or 2 hours after the antacid.(1)|
04098|043|M|   The manufacturer of selpercatinib also recommends avoiding concomitant|
04098|044|M|use of strong CYP3A4 inhibitors with selpercatinib.  If concomitant use|
04098|045|M|cannot be avoided, monitor the QTc interval more frequently and reduce the|
04098|046|M|dose of selpercatinib as follows:|
04098|047|M|   - If the current dose of selpercatinib is 160 mg twice daily, decrease|
04098|048|M|the dose to 80 mg twice daily.|
04098|049|M|   - If the current dose of selpercatinib is 120 mg twice daily, decrease|
04098|050|M|the dose to 40 mg twice daily.(1)|
04098|051|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
04098|052|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04098|053|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04098|054|M|patients to report any irregular heartbeat, dizziness, or fainting.(2)|
04098|055|M|   If grade 3 QT interval prolongation occurs, withhold selpercatinib until|
04098|056|M|recovery to baseline or Grades 0 or 1, then resume selpercatinib at a|
04098|057|M|reduced dose.  If grade 4 QT interval prolongation occurs, discontinue|
04098|058|M|selpercatinib.(1)|
04098|059|M|   After the CYP3A4 inhibitor has been discontinued for 3 to 5 elimination|
04098|060|M|half-lives, resume selpercatinib at the dose taken prior to initiating the|
04098|061|M|CYP3A inhibitor.(1)|
04098|062|B||
04098|063|D|DISCUSSION:  In a study, omeprazole decreased the area-under-curve (AUC) and|
04098|064|D|maximum concentration (Cmax) of selpercatinib (administered fasting) by 69%|
04098|065|D|and 88%, respectively.  When selpercatinib was administered with food,|
04098|066|D|omeprazole did not significantly affect selpercatinib levels.(1)|
04098|067|D|   In a thorough QT study, selpercatinib 160 mg twice daily increased QTc by|
04098|068|D|a mean of 10.6 msec (upper 90% confidence interval: 12.1 msec).  An increase|
04098|069|D|in QTcF interval to greater than 500 msec was measured in 6% of patients and|
04098|070|D|an increase in the QTcF interval of at least 60 msec over baseline was|
04098|071|D|measured in 15% of patients.(1)|
04098|072|D|   In a study, itraconazole (a strong CYP3A inhibitor) increased the|
04098|073|D|area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib by|
04098|074|D|133% and 30%, respectively.(1)|
04098|075|D|   Agents that are linked to this monograph may have varying degrees of|
04098|076|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04098|077|D|been shown to prolong the QTc interval either through their mechanism of|
04098|078|D|action, through studies on their effects on the QTc interval, or through|
04098|079|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04098|080|D|and/or postmarketing reports.(4)|
04098|081|B||
04098|082|R|REFERENCES:|
04098|083|B||
04098|084|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
04098|085|R|  2024.|1
04098|086|R|2.Voquezna (vonoprazan-amoxicillin and|1
04098|087|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04098|088|R|  Pharmaceuticals, Inc. November, 2023.|1
04098|089|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04098|090|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04098|091|R|  settings: a scientific statement from the American Heart Association and|6
04098|092|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04098|093|R|  2;55(9):934-47.|6
04098|094|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04098|095|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04098|096|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04098|097|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04099|001|T|MONOGRAPH TITLE:  Oral Contraceptives/Tirzepatide|
04099|002|B||
04099|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04099|004|L|of severe adverse interaction.|
04099|005|B||
04099|006|A|MECHANISM OF ACTION:  Tirzepatide delays gastric emptying, which may result|
04099|007|A|in decreased oral contraceptive absorption.(1,2)|
04099|008|B||
04099|009|E|CLINICAL EFFECTS:  Tirzepatide may result in decreased levels and|
04099|010|E|effectiveness of oral contraceptives.(1,2)|
04099|011|B||
04099|012|P|PREDISPOSING FACTORS:  None determined.|
04099|013|B||
04099|014|M|PATIENT MANAGEMENT:  The manufacturer of tirzepatide states patients should|
04099|015|M|be advised to switch from oral hormonal contraceptives to a non-oral|
04099|016|M|contraceptive method or to add a barrier method of contraception.  Patients|
04099|017|M|should use a non-oral contraceptive or barrier method of contraception for 4|
04099|018|M|weeks after starting tirzepatide and for 4 weeks after each dose escalation|
04099|019|M|of tirzepatide.(1,2)|
04099|020|M|   Hormonal contraceptives that are not administered orally are not expected|
04099|021|M|to be affected by tirzepatide.(1)|
04099|022|B||
04099|023|D|DISCUSSION:  In a pharmacokinetic study, a single dose of tirzepatide 5 mg|
04099|024|D|with combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg|
04099|025|D|norgestimate) decreased the mean concentration maximum (Cmax) of ethinyl|
04099|026|D|estradiol, norgestimate, and norelgestromin by 59%, 66%, and 55%,|
04099|027|D|respectively, while mean area-under-curve (AUC) was reduced by 20%, 21%, and|
04099|028|D|23%, respectively.(1,2)|
04099|029|D|   A study in pregnant rats, tirzepatide caused fetal growth restrictions|
04099|030|D|and fetal abnormalities at clinical exposure.  A study in pregnant rabbits,|
04099|031|D|tirzepatide caused fetal growth restrictions at clinically relevant|
04099|032|D|exposures.(1)|
04099|033|B||
04099|034|R|REFERENCES:|
04099|035|B||
04099|036|R|1.Mounjaro (tirzepatide) US prescribing information. Eli Lilly and Company|1
04099|037|R|  May, 2022.|1
04099|038|R|2.Mounjaro (tirzepatide) UK summary of product characteristics. Eli Lilly|1
04099|039|R|  and Company Limited February, 2024.|1
04100|001|T|MONOGRAPH TITLE:  Savolitinib/QT Prolonging Agents|
04100|002|B||
04100|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04100|004|L|take action as needed.|
04100|005|B||
04100|006|A|MECHANISM OF ACTION:  Savolitinib has been observed to prolong the QTc|
04100|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04100|008|A|may result in additive effects on the QTc interval.(1)|
04100|009|B||
04100|010|E|CLINICAL EFFECTS:  The concurrent use of savolitinib with other agents that|
04100|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04100|012|E|arrhythmias, including torsades de pointes.(1)|
04100|013|B||
04100|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04100|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04100|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04100|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04100|018|P|female gender, or advanced age.(2)|
04100|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04100|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04100|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04100|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04100|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04100|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04100|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04100|026|B||
04100|027|M|PATIENT MANAGEMENT:  The manufacturer of savolitinib states concurrent use|
04100|028|M|with agents known to prolong the QT interval should be used with caution.(1)|
04100|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04100|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04100|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04100|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04100|033|B||
04100|034|D|DISCUSSION:  In a thorough QT study, patients treatment with savolitinib 600|
04100|035|D|mg had a mean change in QTc from baseline of 11.93 msec at 3-6 hours|
04100|036|D|postdose.(3)|
04100|037|D|   Agents that are linked to this monograph may have varying degrees of|
04100|038|D|potential to prolong the QTc interval but are generally accepted to have a|
04100|039|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04100|040|D|been shown to prolong the QTc interval either through their mechanism of|
04100|041|D|action, through studies on their effects on the QTc interval, or through|
04100|042|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04100|043|D|and/or post-marketing reports.(4)|
04100|044|B||
04100|045|R|REFERENCES:|
04100|046|B||
04100|047|R|1.Orpathys (savolitinib) Hong Kong prescribing information. Shanghai Hequan|1
04100|048|R|  Pharmaceutical Co., Ltd. March, 2022.|1
04100|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04100|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04100|051|R|  settings: a scientific statement from the American Heart Association and|6
04100|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04100|053|R|  2;55(9):934-47.|6
04100|054|R|3.Sahota T, Dota CD, Vik T, Yan W, Verheijen RB, Walker S, Li Y, Goldwater|2
04100|055|R|  R, Ghiorghiu D, Mellemgaard A, Ahmed GF. A Randomized, Double-Blind,|2
04100|056|R|  Placebo- and Positive-Controlled, Three-Way Crossover  Study in Healthy|2
04100|057|R|  Participants to Investigate the Effect of Savolitinib on the QTc|2
04100|058|R|  Interval. Clin Pharmacol Drug Dev 2021 May;10(5):521-534.|2
04100|059|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04100|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04100|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04100|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04101|001|T|MONOGRAPH TITLE:  Savolitinib/Strong CYP3A4 Inducers that Prolong QT|
04101|002|B||
04101|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04101|004|L|of severe adverse interaction.|
04101|005|B||
04101|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04101|007|A|savolitinib and result in additive risk of QT prolongation.(1)|
04101|008|B||
04101|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
04101|010|E|may decrease the levels and effectiveness of savolitinib and increase the|
04101|011|E|risk of potentially life-threatening arrhythmia, including torsade de|
04101|012|E|pointes.(1)|
04101|013|B||
04101|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04101|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04101|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04101|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04101|018|P|female gender, or advanced age.(2)|
04101|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04101|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04101|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04101|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04101|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04101|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04101|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04101|026|P|   Induction effects may be more likely with regular use of the inducer for|
04101|027|P|longer than 1-2 weeks.|
04101|028|B||
04101|029|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers that prolong QT in|
04101|030|M|patients receiving therapy with savolitinib should be avoided.(1)|
04101|031|M|   Consider the use of alternative agents with less enzyme induction|
04101|032|M|potential.(1)|
04101|033|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04101|034|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04101|035|M|baseline and regular intervals.(1)  Correct any electrolyte abnormalities.|
04101|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04101|037|B||
04101|038|D|DISCUSSION:  Rifampin decreased the maximum concentration (Cmax) and|
04101|039|D|area-under-curve (AUC) of savolitinib by 55% and 61%, respectively.(1)|
04101|040|D|   In a thorough QT study, patients treatment with savolitinib 600 mg had a|
04101|041|D|mean change in QTc from baseline of 11.93 msec at 3-6 hours postdose.(3)|
04101|042|D|   Agents that are linked to this monograph may have varying degrees of|
04101|043|D|potential to prolong the QTc interval but are generally accepted to have a|
04101|044|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04101|045|D|been shown to prolong the QTc interval either through their mechanism of|
04101|046|D|action, through studies on their effects on the QTc interval, or through|
04101|047|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04101|048|D|and/or post-marketing reports.(4)|
04101|049|D|    Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04101|050|D|encorafenib and ivosidenib.(5,6)|
04101|051|B||
04101|052|R|REFERENCES:|
04101|053|B||
04101|054|R|1.Orpathys (savolitinib) Hong Kong prescribing information. Shanghai Hequan|1
04101|055|R|  Pharmaceutical Co., Ltd. March, 2022.|1
04101|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04101|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04101|058|R|  settings: a scientific statement from the American Heart Association and|6
04101|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04101|060|R|  2;55(9):934-47.|6
04101|061|R|3.Sahota T, Dota CD, Vik T, Yan W, Verheijen RB, Walker S, Li Y, Goldwater|2
04101|062|R|  R, Ghiorghiu D, Mellemgaard A, Ahmed GF. A Randomized, Double-Blind,|2
04101|063|R|  Placebo- and Positive-Controlled, Three-Way Crossover  Study in Healthy|2
04101|064|R|  Participants to Investigate the Effect of Savolitinib on the QTc|2
04101|065|R|  Interval. Clin Pharmacol Drug Dev 2021 May;10(5):521-534.|2
04101|066|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04101|067|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04101|068|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04101|069|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04101|070|R|5.This information is based on an extract from the Certara Drug Interaction|6
04101|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04101|072|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04101|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04101|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04101|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04101|076|R|  11/14/2017.|1
04102|001|T|MONOGRAPH TITLE:  Savolitinib/Strong CYP3A4 Inducers|
04102|002|B||
04102|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04102|004|L|of severe adverse interaction.|
04102|005|B||
04102|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04102|007|A|metabolism of savolitinib.(1)|
04102|008|B||
04102|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04102|010|E|levels and effectiveness of savolitinib.(1)|
04102|011|B||
04102|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04102|013|P|of the inducer for longer than 1-2 weeks.|
04102|014|B||
04102|015|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers in patients receiving|
04102|016|M|therapy with savolitinib should be avoided.(1)|
04102|017|M|   Consider the use of alternative agents with less enzyme induction|
04102|018|M|potential.(1)|
04102|019|B||
04102|020|D|DISCUSSION:  Rifampin decreased the maximum concentration (Cmax) and|
04102|021|D|area-under-curve (AUC) of savolitinib by 55% and 61%, respectively.(1)|
04102|022|D|    Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04102|023|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04102|024|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
04102|025|D|St. John's wort.(2)|
04102|026|B||
04102|027|R|REFERENCES:|
04102|028|B||
04102|029|R|1.Orpathys (savolitinib) Hong Kong prescribing information. Shanghai Hequan|1
04102|030|R|  Pharmaceutical Co., Ltd. March, 2022.|1
04102|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04102|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04102|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04102|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04102|035|R|  11/14/2017.|1
04102|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
04102|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04103|001|T|MONOGRAPH TITLE:  Selected Kinase Inhibitors/Vonoprazan|
04103|002|B||
04103|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04103|004|L|of severe adverse interaction.|
04103|005|B||
04103|006|A|MECHANISM OF ACTION:  The solubility of bosutinib,(1) dacomitinib,(2)|
04103|007|A|dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and|
04103|008|A|pazopanib(8) is pH dependent.  Changes in gastric pH from vonoprazan(9) may|
04103|009|A|decrease the absorption of bosutinib,(1) dacomitinib,(2) dasatinib,(3)|
04103|010|A|erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib.(8)|
04103|011|B||
04103|012|E|CLINICAL EFFECTS:  Use of vonoprazan may result in decreased levels and|
04103|013|E|effectiveness of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4)|
04103|014|E|gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib.(8)|
04103|015|B||
04103|016|P|PREDISPOSING FACTORS:  None determined.|
04103|017|B||
04103|018|M|PATIENT MANAGEMENT:  Avoid the use of vonoprazan(9) in patients receiving|
04103|019|M|treatment with bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4)|
04103|020|M|gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib.(8)|
04103|021|M|   Consider the use of short-acting antacids in these patients.(1-8)  If|
04103|022|M|antacids are used, separate the administration times by several hours(1-8)|
04103|023|M|but at least 2 hours for bosutinib,(1) dasatinib,(3) and nilotinib,(7) 6|
04103|024|M|hours for gefitinib,(5) and 3 hours for neratinib.(6)|
04103|025|M|   If H2 antagonist therapy is required with dacomitinib, dacomitinib must|
04103|026|M|be given once daily 10 hours after the H2 blocker and 6 hours before the|
04103|027|M|next dose of the H2 blocker.(2)|
04103|028|M|   If H2 antagonist therapy is required with gefitinib, administer gefitinib|
04103|029|M|6 hours before or after H2-antagonists or antacids.(5)|
04103|030|M|   If H2 antagonist therapy is required with erlotinib, neratinib, or|
04103|031|M|nilotinib, the kinase inhibitor must be given 10 hours after the H2 blocker|
04103|032|M|and at least 2 hours before the next dose of the H2 blocker.(4,6,7)|
04103|033|M|   The manufacturer of Phyrago states that it can be administered with|
04103|034|M|gastric acid reducing agents. Administration times should be separated with|
04103|035|M|antacids.(14)|
04103|036|B||
04103|037|D|DISCUSSION:  Vonoprazan decreases gastric acidity by suppressing gastric|
04103|038|D|acid secretion and is characterized as a type of gastric proton-pump|
04103|039|D|inhibitor.(9)|
04103|040|D|   In a pharmacodynamic study, a single 20 mg dose of vonoprazan, elevated|
04103|041|D|the intragastric pH compared to placebo and was sustained for over 24-hours|
04103|042|D|after dosing.  The inhibitory effect of vonoprazan on acid secretion|
04103|043|D|increased with repeated daily dosing and antisecretory effect reached steady|
04103|044|D|state by Day 4 with a mean 24-hour intragastric pH of 6.0 following 20 mg|
04103|045|D|once daily dose.(9)|
04103|046|D|   In a study, concurrent rabeprazole decreased the Cmax and AUC of|
04103|047|D|dacomitinib by 51% and 39%, respectively.(2)|
04103|048|D|   In a study in 24 healthy subjects, administration of a single dose of|
04103|049|D|dasatinib (50 mg) 10 hours after famotidine decreased dasatinib|
04103|050|D|area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%,|
04103|051|D|respectively.(3)|
04103|052|D|   In a study in 14 healthy subjects, administration of a single dose of|
04103|053|D|dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state)|
04103|054|D|decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(3)|
04103|055|D|   In a study in 24 healthy subjects, simultaneous administration of|
04103|056|D|dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml)|
04103|057|D|decreased dasatinib AUC and Cmax by 55% and 58%, respectively.  In the same|
04103|058|D|subjects, administration of the antacid 2 hours before dasatinib decreased|
04103|059|D|dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(3)|
04103|060|D|   In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib|
04103|061|D|by 46% and 61%, respectively.(4)|
04103|062|D|   In a study, administration of erlotinib two hours after a dose of|
04103|063|D|ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%,|
04103|064|D|respectively.  Administration of erlotinib 10 hours after and two hours|
04103|065|D|before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by|
04103|066|D|15% and 17%, respectively.(4)|
04103|067|D|   In a case report, a patient that was given erlotinib (150 mg daily,) with|
04103|068|D|algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before|
04103|069|D|or 2 hours after erlotinib) did not see a significant reduction in serum|
04103|070|D|trough concentrations of erlotinib.  When the patient was switched to|
04103|071|D|intravenous pantoprazole via continuous infusion (8 mg per hour), serum|
04103|072|D|erlotinib levels decreased significantly below minimal trough concentrations|
04103|073|D|for effective tyrosine kinase inhibition.  When the patient was switched to|
04103|074|D|oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib|
04103|075|D|returned to therapeutic levels.(10)|
04103|076|D|   In a study in healthy subjects, high dose ranitidine with sodium|
04103|077|D|carbonate was administered to maintain gastric pH above 5.0 and gefitinib|
04103|078|D|AUC decreased 47%.(5)|
04103|079|D|   In a study in 15 healthy subjects, lansoprazole (30 mg at steady state)|
04103|080|D|decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and|
04103|081|D|65%, respectively.(6)|
04103|082|D|   In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg|
04103|083|D|daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by|
04103|084|D|27% and 34%, respectively.(7,11)  Increasing the dosage of nilotinib or|
04103|085|D|separating the administration time of nilotinib and the proton pump|
04103|086|D|inhibitor is not expected to eliminate the interaction.(7)|
04103|087|D|   There were no significant changes in nilotinib pharmacokinetics when|
04103|088|D|famotidine was administered 10 hours before or 2 hours after nilotinib.(7)|
04103|089|D|   There were no significant changes in nilotinib pharmacokinetics when an|
04103|090|D|antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was|
04103|091|D|administered 2 hours before or after nilotinib.(7)|
04103|092|D|   In a study in 13 patients, esomeprazole (40 mg daily for 5 days)|
04103|093|D|decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%,|
04103|094|D|respectively, when compared to the administration of pazopanib alone.(12)|
04103|095|D|   In an open-label, crossover study in 17 evaluable patients, omeprazole|
04103|096|D|(40 mg daily) had no significant effects on the pharmacokinetics,|
04103|097|D|pharmacodynamics, or safety of bortezomib (1.3 mg/m2).(13)|
04103|098|D|   Phyrago is not sensitive to increased gastric pH due to its polymer|
04103|099|D|formulation. No clinically significant pharmacokinetic changes were seen|
04103|100|D|with concurrent administration of Phyrago with omeprazole (proton pump|
04103|101|D|inhibitor) or famotidine (H2 receptor antagonist).(14)|
04103|102|B||
04103|103|R|REFERENCES:|
04103|104|B||
04103|105|R|1.Bosulif (bosutinib) US prescribing information. Pfizer Inc. September,|1
04103|106|R|  2023.|1
04103|107|R|2.Vizimpro (dacomitinib) US prescribing information. Pfizer, Inc. September,|1
04103|108|R|  2018.|1
04103|109|R|3.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
04103|110|R|  Company February, 2023.|1
04103|111|R|4.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
04103|112|R|  2016.|1
04103|113|R|5.Iressa (gefitinib) US prescribing information. AstraZeneca March 6, 2012.|1
04103|114|R|6.Nerlynx (neratinib) US prescribing information. Puma Biotechnology, Inc.|1
04103|115|R|  June, 2021.|1
04103|116|R|7.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
04103|117|R|  Corporation September, 2021.|1
04103|118|R|8.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
04103|119|R|  2020.|1
04103|120|R|9.Voquezna (vonoprazan-amoxicillin and|1
04103|121|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04103|122|R|  Pharmaceuticals, Inc. November, 2023.|1
04103|123|R|10.Ter Heine R, Fanggiday JC, Lankheet NA, Beijnen JH, Van Der Westerlaken|3
04103|124|R|   MM, Staaks GH, Malingre MM. Erlotinib and pantoprazole: a relevant|3
04103|125|R|   interaction or not?. Br J Clin Pharmacol 2010 Dec;70(6):908-11.|3
04103|126|R|11.Yin OQ, Gallagher N, Fischer D, Demirhan E, Zhou W, Golor G, Schran H.|2
04103|127|R|   Effect of the Proton Pump Inhibitor Esomeprazole on the Oral Absorption|2
04103|128|R|   and Pharmacokinetics of Nilotinib. J Clin Pharmacol 2010 May 24.|2
04103|129|R|12.Tan AR, Gibbon DG, Stein MN, Lindquist D, Edenfield JW, Martin JC,|2
04103|130|R|   Gregory C, Suttle AB, Tada H, Botbyl J, Stephenson JJ. Effects of|2
04103|131|R|   ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in|2
04103|132|R|   patients with solid tumors. Cancer Chemother Pharmacol 2013 Jun;|2
04103|133|R|   71(6):1635-43.|2
04103|134|R|13.Quinn DI, Nemunaitis J, Fuloria J, Britten CD, Gabrail N, Yee L, Acharya|2
04103|135|R|   M, Chan K, Cohen N, Dudov A. Effect of the cytochrome P450 2C19 inhibitor|2
04103|136|R|   omeprazole on the pharmacokinetics and safety profile of bortezomib in|2
04103|137|R|   patients with advanced solid tumours, non-Hodgkin's lymphoma or multiple|2
04103|138|R|   myeloma. Clin Pharmacokinet 2009;48(3):199-209.|2
04103|139|R|14.Phyrago (dasatinib) US Prescribing Information. Nanocopoeia, LLC December|1
04103|140|R|   2024.|1
04104|001|T|MONOGRAPH TITLE:  Selected Benzodiazepines/Fluconazole; Voriconazole|
04104|002|B||
04104|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04104|004|L|take action as needed.|
04104|005|B||
04104|006|A|MECHANISM OF ACTION:  Fluconazole and voriconazole may inhibit the|
04104|007|A|metabolism of benzodiazepines by CYP3A4.|
04104|008|B||
04104|009|E|CLINICAL EFFECTS:  The concurrent administration of fluconazole or|
04104|010|E|voriconazole with benzodiazepines metabolized by CYP3A4 may result in|
04104|011|E|elevated levels of and increased clinical effects from the benzodiazepines.|
04104|012|E|Toxic effects of increased levels of benzodiazepines include profound|
04104|013|E|sedation, respiratory depression, coma, and/or death.|
04104|014|B||
04104|015|P|PREDISPOSING FACTORS:  None determined.|
04104|016|B||
04104|017|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with fluconazole|
04104|018|M|or voriconazole should be monitored for increased benzodiazepine effects.|
04104|019|M|The dosage of the benzodiazepine may need to be decreased or the|
04104|020|M|benzodiazepine may need to be discontinued.|
04104|021|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
04104|022|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04104|023|M|unresponsiveness.|
04104|024|B||
04104|025|D|DISCUSSION:  In a study in 12 healthy subjects, pretreatment with|
04104|026|D|fluconazole (400 mg twice daily Day 1, 200 mg twice daily Day 2) increased|
04104|027|D|the area-under-curve (AUC) and half-life of a single dose of diazepam (5 mg)|
04104|028|D|by 2.5-fold and 1.4-fold, respectively.  Pharmacodynamic effects were|
04104|029|D|increased slightly.(1)|
04104|030|D|   In a study in 12 healthy subjects, pretreatment with voriconazole (400 mg|
04104|031|D|twice daily Day 1, 200 mg twice daily Day 2) increased the AUC and half-life|
04104|032|D|of a single dose of diazepam (5 mg) by 2.2-fold and 100%, respectively.|
04104|033|D|Pharmacodynamic effects were increased slightly.(1)|
04104|034|D|   A study in 10 patients showed that fluconazole (400 mg initially, then|
04104|035|D|200 mg intravenously) increased intravenous midazolam concentrations by|
04104|036|D|0-4-fold.(2)  A study in nine subjects showed that fluconazole (400 mg)|
04104|037|D|increased the midazolam AUC, maximum concentration (Cmax), and half-life by|
04104|038|D|2-3 fold, 2-2.5-fold, and 2.5-fold, respectively.  The pharmacokinetic|
04104|039|D|changes were larger when fluconazole was given orally when compared to|
04104|040|D|intravenous fluconazole. Both oral and intravenous fluconazole increased the|
04104|041|D|pharmacodynamic effects.(3)  A study in 12 subjects showed that the AUC of|
04104|042|D|oral midazolam increased 3.6-fold during fluconazole therapy.(4)  One study|
04104|043|D|found that a single, 150 mg dose of fluconazole did not significantly effect|
04104|044|D|midazolam pharmacokinetics.(5)   Fluconazole has also been shown to inhibit|
04104|045|D|the metabolism of midazolam in vitro.(6)|
04104|046|D|   In a randomized, cross-over study in 10 healthy male volunteers,|
04104|047|D|voriconazole (400 mg twice daily on the first day and 200 mg twice daily on|
04104|048|D|the second day) reduced the clearance on intravenous midazolam (0.05 mg/kg)|
04104|049|D|by 72% and increased its elimination half-life by 3-fold.  Voriconazole|
04104|050|D|increased the mean Cmax and the AUC of oral midazolam (7.5 mg) by 3.8 and|
04104|051|D|10.3-fold, respectively.  Voriconazole also prolonged the half-life of oral|
04104|052|D|midazolam by 3.5-fold, and increased the oral bioavailability of midazolam|
04104|053|D|by 2.7-fold.  Voriconazole profoundly increased the psychomotor effects of|
04104|054|D|oral midazolam but only weakly increased the effects of intravenous|
04104|055|D|midazolam.(7)|
04104|056|D|   In a study in 12 healthy subjects, fluconazole had no significant effects|
04104|057|D|on the pharmacokinetics or pharmacodynamics of oral or rectal bromazepam.(8)|
04104|058|B||
04104|059|R|REFERENCES:|
04104|060|B||
04104|061|R|1.Saari TI, Laine K, Bertilsson L, Neuvonen PJ, Olkkola KT. Voriconazole and|2
04104|062|R|  fluconazole increase the exposure to oral diazepam. Eur J Clin Pharmacol|2
04104|063|R|  2007 Oct;63(10):941-9.|2
04104|064|R|2.Ahonen J, Olkkola KT, Takala A, Neuvonen PJ. Interaction between|2
04104|065|R|  fluconazole and midazolam in intensive care patients. Acta Anaesthesiol|2
04104|066|R|  Scand 1999 May;43(5):509-14.|2
04104|067|R|3.Ahonen J, Olkkola KT, Neuvonen PJ. Effect of route of administration of|2
04104|068|R|  fluconazole on the interaction between fluconazole and midazolam. Eur J|2
04104|069|R|  Clin Pharmacol 1997;51(5):415-9.|2
04104|070|R|4.Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic|2
04104|071|R|  antimycotics, itraconazole and fluconazole, on the pharmacokinetics and|2
04104|072|R|  pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996 Mar;|2
04104|073|R|  82(3):511-6.|2
04104|074|R|5.Vanakoski J, Mattila MJ, Vainio P, Idanpaan-Heikkila JJ, Tornwall M. 150|2
04104|075|R|  mg fluconazole does not substantially increase the effects of 10 mg|2
04104|076|R|  midazolam or the plasma midazolam concentrations in healthy subjects. Int|2
04104|077|R|  J Clin Pharmacol Ther 1995 Sep;33(9):518-23.|2
04104|078|R|6.von Moltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS,|5
04104|079|R|  Shader RI. Midazolam hydroxylation by human liver microsomes in vitro:|5
04104|080|R|  inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents. J|5
04104|081|R|  Clin Pharmacol 1996 Sep;36(9):783-91.|5
04104|082|R|7.Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT. Effect of|2
04104|083|R|  voriconazole on the pharmacokinetics and pharmacodynamics of intravenous|2
04104|084|R|  and oral midazolam. Clin Pharmacol Ther 2006 Apr;79(4):362-70.|2
04104|085|R|8.Ohtani Y, Kotegawa T, Tsutsumi K, Morimoto T, Hirose Y, Nakano S. Effect|2
04104|086|R|  of fluconazole on the pharmacokinetics and pharmacodynamics of oral and|2
04104|087|R|  rectal bromazepam: an application of electroencephalography as the|2
04104|088|R|  pharmacodynamic method. J Clin Pharmacol 2002 Feb;42(2):183-91.|2
04104|089|R|9.US Food and Drug Administration (FDA). Drug Development and Drug|1
04104|090|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04104|091|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04104|092|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04104|093|R|  11/14/2017.|1
04105|001|T|MONOGRAPH TITLE:  Diazepam/Fluconazole; Voriconazole|
04105|002|B||
04105|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04105|004|L|of severe adverse interaction.|
04105|005|B||
04105|006|A|MECHANISM OF ACTION:  Fluconazole and voriconazole may inhibit CYP2C19 and|
04105|007|A|CYP3A4, both major pathways of diazepam metabolism.(1-4)|
04105|008|B||
04105|009|E|CLINICAL EFFECTS:  The concurrent administration of fluconazole or|
04105|010|E|voriconazole with diazepam may result in elevated levels of and increased|
04105|011|E|clinical effects from diazepam. Toxic effects include profound sedation,|
04105|012|E|respiratory depression, coma, and/or death.|
04105|013|B||
04105|014|P|PREDISPOSING FACTORS:  None determined.|
04105|015|B||
04105|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with fluconazole|
04105|017|M|or voriconazole should be monitored for increased diazepam effects.  The|
04105|018|M|dosage of diazepam may need to be decreased or diazepam may need to be|
04105|019|M|discontinued.|
04105|020|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
04105|021|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04105|022|M|unresponsiveness.|
04105|023|B||
04105|024|D|DISCUSSION:  In a study in 12 healthy subjects, pretreatment with|
04105|025|D|fluconazole (400 mg twice daily Day 1, 200 mg twice daily Day 2) increased|
04105|026|D|the area-under-curve (AUC) and half-life of a single dose of diazepam (5 mg)|
04105|027|D|by 2.5-fold and 1.4-fold, respectively.  Pharmacodynamic effects were|
04105|028|D|increased slightly.(1)|
04105|029|D|   In a study in 12 healthy subjects, pretreatment with voriconazole (400 mg|
04105|030|D|twice daily Day 1, 200 mg twice daily Day 2) increased the AUC and half-life|
04105|031|D|of a single dose of diazepam (5 mg) by 2.2-fold and 100%, respectively.|
04105|032|D|Pharmacodynamic effects were increased slightly.(1)|
04105|033|D|   A study in 10 patients showed that fluconazole (400 mg initially, then|
04105|034|D|200 mg intravenously) increased intravenous midazolam concentrations by|
04105|035|D|0-4-fold.(5)  A study in nine subjects showed that fluconazole (400 mg)|
04105|036|D|increased the midazolam AUC, maximum concentration (Cmax), and half-life by|
04105|037|D|2-3 fold, 2-2.5-fold, and 2.5-fold, respectively.  The pharmacokinetic|
04105|038|D|changes were larger when fluconazole was given orally when compared to|
04105|039|D|intravenous fluconazole. Both oral and intravenous fluconazole increased the|
04105|040|D|pharmacodynamic effects.(6)  A study in 12 subjects showed that the AUC of|
04105|041|D|oral midazolam increased 3.6-fold during fluconazole therapy.(7)  One study|
04105|042|D|found that a single, 150 mg dose of fluconazole did not significantly effect|
04105|043|D|midazolam pharmacokinetics.(8)   Fluconazole has also been shown to inhibit|
04105|044|D|the metabolism of midazolam in vitro.(9)|
04105|045|D|   In a randomized, cross-over study in 10 healthy male volunteers,|
04105|046|D|voriconazole (400 mg twice daily on the first day and 200 mg twice daily on|
04105|047|D|the second day) reduced the clearance on intravenous midazolam (0.05 mg/kg)|
04105|048|D|by 72% and increased its elimination half-life by 3-fold.  Voriconazole|
04105|049|D|increased the mean Cmax and the AUC of oral midazolam (7.5 mg) by 3.8 and|
04105|050|D|10.3-fold, respectively.  Voriconazole also prolonged the half-life of oral|
04105|051|D|midazolam by 3.5-fold, and increased the oral bioavailability of midazolam|
04105|052|D|by 2.7-fold.  Voriconazole profoundly increased the psychomotor effects of|
04105|053|D|oral midazolam but only weakly increased the effects of intravenous|
04105|054|D|midazolam.(10)|
04105|055|B||
04105|056|R|REFERENCES:|
04105|057|B||
04105|058|R|1.Saari TI, Laine K, Bertilsson L, Neuvonen PJ, Olkkola KT. Voriconazole and|2
04105|059|R|  fluconazole increase the exposure to oral diazepam. Eur J Clin Pharmacol|2
04105|060|R|  2007 Oct;63(10):941-9.|2
04105|061|R|2.Valium (diazepam) US prescribing information. Roche Products Inc December,|1
04105|062|R|  2016.|1
04105|063|R|3.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
04105|064|R|  2024.|1
04105|065|R|4.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
04105|066|R|5.Ahonen J, Olkkola KT, Takala A, Neuvonen PJ. Interaction between|2
04105|067|R|  fluconazole and midazolam in intensive care patients. Acta Anaesthesiol|2
04105|068|R|  Scand 1999 May;43(5):509-14.|2
04105|069|R|6.Ahonen J, Olkkola KT, Neuvonen PJ. Effect of route of administration of|2
04105|070|R|  fluconazole on the interaction between fluconazole and midazolam. Eur J|2
04105|071|R|  Clin Pharmacol 1997;51(5):415-9.|2
04105|072|R|7.Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic|2
04105|073|R|  antimycotics, itraconazole and fluconazole, on the pharmacokinetics and|2
04105|074|R|  pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996 Mar;|2
04105|075|R|  82(3):511-6.|2
04105|076|R|8.Vanakoski J, Mattila MJ, Vainio P, Idanpaan-Heikkila JJ, Tornwall M. 150|2
04105|077|R|  mg fluconazole does not substantially increase the effects of 10 mg|2
04105|078|R|  midazolam or the plasma midazolam concentrations in healthy subjects. Int|2
04105|079|R|  J Clin Pharmacol Ther 1995 Sep;33(9):518-23.|2
04105|080|R|9.von Moltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS,|5
04105|081|R|  Shader RI. Midazolam hydroxylation by human liver microsomes in vitro:|5
04105|082|R|  inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents. J|5
04105|083|R|  Clin Pharmacol 1996 Sep;36(9):783-91.|5
04105|084|R|10.Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT. Effect|2
04105|085|R|   of voriconazole on the pharmacokinetics and pharmacodynamics of|2
04105|086|R|   intravenous and oral midazolam. Clin Pharmacol Ther 2006 Apr;|2
04105|087|R|   79(4):362-70.|2
04105|088|R|11.US Food and Drug Administration (FDA). Drug Development and Drug|1
04105|089|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
04105|090|R|   at:|1
04105|091|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
04105|092|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04105|093|R|   11/14/2017.|1
04106|001|T|MONOGRAPH TITLE:  Dronedarone/Selected Strong CYP3A4 Inducers|
04106|002|B||
04106|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04106|004|L|of severe adverse interaction.|
04106|005|B||
04106|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04106|007|A|dronedarone by CYP3A4.(1)|
04106|008|A|   Dronedarone may inhibit the metabolism of carbamazepine.(2)|
04106|009|B||
04106|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04106|011|E|decreased levels and effectiveness of dronedarone.(1)|
04106|012|E|   Concurrent use of dronedarone and carbamazepine may also result in|
04106|013|E|elevated levels of and toxicity from carbamazepine.(2)|
04106|014|B||
04106|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04106|016|P|of the inducer for longer than 1-2 weeks.|
04106|017|B||
04106|018|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that|
04106|019|M|concurrent use of strong CYP3A4 inducers should be avoided.(1)|
04106|020|M|   The US manufacturer of carbamazepine states CYP3A4 inhibitors may|
04106|021|M|increase plasma carbamazepine levels.  If concurrent use is warranted,|
04106|022|M|closely monitor carbamazepine levels and observe the patient for signs of|
04106|023|M|toxicity (dizziness, ataxia, blurred vision, or SIADH).  The dosage of|
04106|024|M|carbamazepine may need to be adjusted or carbamazepine may need to be|
04106|025|M|discontinued.(2)|
04106|026|B||
04106|027|D|DISCUSSION:  Concurrent use of rifampin and dronedarone (exact dosages not|
04106|028|D|stated) decreased dronedarone exposure by 80%.(1)|
04106|029|D|   Carbamazepine is almost completely metabolized to|
04106|030|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
04106|031|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
04106|032|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
04106|033|D|CYP3A5.(2,3)|
04106|034|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04106|035|D|barbiturates, carbamazepine, enzalutamide, lumacaftor, mitotane,|
04106|036|D|phenobarbital, phenytoin or primidone.(4)|
04106|037|B||
04106|038|R|REFERENCES:|
04106|039|B||
04106|040|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
04106|041|R|  November, 2020.|1
04106|042|R|2.Tegretol (carbamazepine) US prescribing information. Novartis|1
04106|043|R|  Pharmaceuticals Corporation September, 2023.|1
04106|044|R|3.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
04106|045|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
04106|046|R|  Dec;21(12):906-10.|6
04106|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
04106|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04107|001|T|MONOGRAPH TITLE:  Fenfluramine/St. John's Wort|
04107|002|B||
04107|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04107|004|L|of severe adverse interaction.|
04107|005|B||
04107|006|A|MECHANISM OF ACTION:  St. John's wort, a strong CYP3A4 inducer, may increase|
04107|007|A|the metabolism of fenfluramine.(1)|
04107|008|A|   Over 75% of fenfluramine is metabolized to norfenfluramine prior to|
04107|009|A|elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.  CYP2C9, CYP2C19, and|
04107|010|A|CYP3A4 play a minor role in fenfluramine metabolism.(1)|
04107|011|A|   Concurrent administration may result in additive effects on serotonin,|
04107|012|A|resulting in serotonin syndrome.|
04107|013|B||
04107|014|E|CLINICAL EFFECTS:  Concurrent use with St. John's wort may result in|
04107|015|E|decreased levels and effectiveness of fenfluramine.(1)|
04107|016|E|   May result in serotonin syndrome, a potentially life-threatening syndrome|
04107|017|E|which may include one or more of the following symptoms: tremor, agitation,|
04107|018|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04107|019|E|rigidity.(3)|
04107|020|B||
04107|021|P|PREDISPOSING FACTORS:  None determined.|
04107|022|B||
04107|023|M|PATIENT MANAGEMENT:  The manufacturer of fenfluramine recommends avoiding|
04107|024|M|coadministration with strong CYP3A4 inducers.  Patients who must receive|
04107|025|M|concurrent therapy should be monitored for decreased efficacy.(1)|
04107|026|M|   Fenfluramine should not be administered with other serotonergic agents|
04107|027|M|such as the selective serotonin reuptake inhibitors, sumatriptan, or|
04107|028|M|dihydroergotamine.|
04107|029|M|   If concurrent therapy is warranted, patients should be monitored for|
04107|030|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
04107|031|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
04107|032|M|heart palpitations, restlessness, confusion, agitation, trouble with|
04107|033|M|coordination, or severe diarrhea.|
04107|034|B||
04107|035|D|DISCUSSION:  In a study with healthy volunteers, steady-state rifampin (a|
04107|036|D|CYP1A2, CYP2B6, and CYP3A4 inducer) 600 mg daily decreased the area-under|
04107|037|D|curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4|
04107|038|D|mg/kg by 58% and 40%, respectively, and increased the AUC and Cmax of|
04107|039|D|norfenfluramine by 50% and 13%, respectively.(1)|
04107|040|D|   The serotonin syndrome interaction is based on FDA mandated class|
04107|041|D|labeling for these agents. Although there is no clinical documentation for|
04107|042|D|an interaction between dexfenfluramine or fenfluramine and either the|
04107|043|D|selective serotonin reuptake inhibitors, sumatriptan, or dihydroergotamine,|
04107|044|D|caution is still warranted.  This syndrome has been reported with the|
04107|045|D|selective serotonin reuptake inhibitors and other serotonergic agents,|
04107|046|D|including sumatriptan and dihydroergotamine.|
04107|047|B||
04107|048|R|REFERENCES:|
04107|049|B||
04107|050|R|1.Fintepla (fenfluramine) US prescribing information. Zogenix Inc. January|1
04107|051|R|  2023.|1
04107|052|R|2.Personal Communication. Wyeth Labs Inc. July 1996.|1
04107|053|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04107|054|R|  352(11):1112-20.|6
04107|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
04107|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04107|057|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04107|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04107|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04107|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04107|061|R|  11/14/2017.|1
04108|001|T|MONOGRAPH TITLE:  Selected Antidiabetics/Safinamide|
04108|002|B||
04108|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04108|004|L|take action as needed.|
04108|005|B||
04108|006|A|MECHANISM OF ACTION:  The exact mechanism by which MAO inhibitors such as|
04108|007|A|safinamide affect carbohydrate metabolism and subsequent enhancement of the|
04108|008|A|hypoglycemic action of insulin is not clear.  The adrenergic response to|
04108|009|A|hypoglycemia may be blocked by insulin release caused by MAOI's.  In vitro|
04108|010|A|studies have shown that MAO inhibitors are capable of both potentiating and|
04108|011|A|inhibiting insulin release, depending on their concentrations.  Stimulation|
04108|012|A|of glucose-mediated insulin secretion is believed to be related to the MAO|
04108|013|A|inhibitory effects of the drugs.|
04108|014|B||
04108|015|E|CLINICAL EFFECTS:  The hypoglycemic response to both insulin and glucose|
04108|016|E|lowering agents including alpha glucosidase inhibitors, meglitinides, and|
04108|017|E|sulfonylurea may be increased.|
04108|018|B||
04108|019|P|PREDISPOSING FACTORS:  None determined.|
04108|020|B||
04108|021|M|PATIENT MANAGEMENT:  Concurrent MAO inhibitor therapy for depression in a|
04108|022|M|diabetic patient will often require reduction in dosage of the hypoglycemic|
04108|023|M|agent because of enhanced hypoglycemic effects.  Since the extent of the|
04108|024|M|reaction is highly unpredictable, any diabetic patients receiving MAO|
04108|025|M|inhibitors should be monitored for possible excessive hypoglycemia.|
04108|026|B||
04108|027|D|DISCUSSION:  This interaction is likely to occur.  The interaction between|
04108|028|D|MAOIs and insulin is well documented.  Additional documentation is necessary|
04108|029|D|to confirm the potential interaction of MAOI's with other glucose lowering|
04108|030|D|agents including alpha glucosidase inhibitors, meglitinides, and|
04108|031|D|sulfonylureas but is expected to occur based on pharmacologic similarity.|
04108|032|D|   It may take several weeks for the full hypoglycemic effect of the MAOI to|
04108|033|D|occur.  Conversely, it may take several weeks for the effect to dissipate|
04108|034|D|after stopping the MAOI.|
04108|035|B||
04108|036|R|REFERENCES:|
04108|037|B||
04108|038|R|1.Xadago (safinamide) US prescribing information. US WorldMeds, LLC August,|1
04108|039|R|  2021.|1
04108|040|R|2.Cooper AJ, Keddie KMG. Hypotensive collapse and hypoglycaemia after|3
04108|041|R|  mebanazine -- a monoamine-oxidase inhibitor. Lancet 1964 May 23;1:1133-5.|3
04108|042|R|3.Cooper AJ, Ashcroft G. Potentiation of insulin hypoglycaemia by M.A.O.I.|5
04108|043|R|  antidepressant drugs. Lancet 1966 Feb 19;1(7434):407-9.|5
04108|044|R|4.Cooper AJ. The action of mebanazine, a mono amine oxidase inhibitor|3
04108|045|R|  antidepressant drug in diabetes. II. Int J Neuropsychiatry 1966 Aug;|3
04108|046|R|  2(4):342-5.|3
04108|047|R|5.Cooper AJ, Ashcroft G. Modification of insulin and sulfonylurea|6
04108|048|R|  hypoglycemia by monoamine- oxidase inhibitor drugs. Diabetes 1967 Apr;|6
04108|049|R|  16(4):272-4.|6
04108|050|R|6.Adnitt PI. Hypoglycemic action of monoamineoxidase inhibitors (MAOI'S).|2
04108|051|R|  Diabetes 1968 Oct;17(10):628-33.|2
04108|052|R|7.Absher JR, Black DW. Tranylcypromine withdrawal delirium. J Clin|3
04108|053|R|  Psychopharmacol 1988 Oct;8(5):379-80.|3
04108|054|R|8.Aleyassine H, Gardiner RJ. Dual action of antidepressant drugs (MAO|2
04108|055|R|  inhibitors) on insulin release. Endocrinology 1975 Mar;96(3):702-10.|2
04108|056|R|9.Aleyassine H, Lee SH. Inhibition of insulin release by substrates and|2
04108|057|R|  inhibitors of monoamine oxidase. Am J Physiol 1972 Mar;222(3):565-9.|2
04109|001|T|MONOGRAPH TITLE:  Glyburide/Safinamide|
04109|002|B||
04109|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04109|004|L|take action as needed.|
04109|005|B||
04109|006|A|MECHANISM OF ACTION:  Safinamide transiently inhibits BCRP in the small|
04109|007|A|intestine, which may result in increased absorption of BCRP substrates such|
04109|008|A|as glyburide.(1)|
04109|009|A|   The exact mechanism by which MAO inhibitors such as safinamide affect|
04109|010|A|carbohydrate metabolism and subsequent enhancement of the hypoglycemic|
04109|011|A|action of insulin is not clear.  The adrenergic response to hypoglycemia may|
04109|012|A|be blocked by insulin release caused by MAOI's.  In vitro studies have shown|
04109|013|A|that MAO inhibitors are capable of both potentiating and inhibiting insulin|
04109|014|A|release, depending on their concentrations.  Stimulation of glucose-mediated|
04109|015|A|insulin secretion is believed to be related to the MAO inhibitory effects of|
04109|016|A|the drugs.|
04109|017|B||
04109|018|E|CLINICAL EFFECTS:  Administration of safinamide with glyburide may result in|
04109|019|E|elevated levels of and toxicity from glyburide, including additive|
04109|020|E|hypoglycemia.(1)|
04109|021|B||
04109|022|P|PREDISPOSING FACTORS:  None determined.|
04109|023|B||
04109|024|M|PATIENT MANAGEMENT:  The EMA and UK manufacturer of safinamide recommend|
04109|025|M|monitoring patients who are on concomitant drugs that are substrates of|
04109|026|M|BCRP, including glyburide.  Dose adjustment of glyburide should be performed|
04109|027|M|according to the prescribing information for glyburide.(1)|
04109|028|M|   Concurrent MAO inhibitor therapy for depression in a diabetic patient|
04109|029|M|will often require reduction in dosage of the hypoglycemic agent because of|
04109|030|M|enhanced hypoglycemic effects.  Since the extent of the reaction is highly|
04109|031|M|unpredictable, any diabetic patients receiving MAO inhibitors should be|
04109|032|M|monitored for possible excessive hypoglycemia.(1)|
04109|033|B||
04109|034|D|DISCUSSION:  Safinamide transiently inhibits BCRP in the small intestine,|
04109|035|D|which may result in increased absorption of BCRP substrates.(1)|
04109|036|D|   In a clinical study, safinamide increased the AUC of rosuvastatin, a BCRP|
04109|037|D|substrate, by 1.25- to 2-fold.(1,3)|
04109|038|B||
04109|039|R|REFERENCES:|
04109|040|B||
04109|041|R|1.Xadago (safinamide) EMA summary of product characteristics. Zambon S.p.A.|1
04109|042|R|  October 30, 2019.|1
04109|043|R|2.Xadago (safinamide) US prescribing information. US WorldMeds, LLC August,|1
04109|044|R|  2021.|1
04109|045|R|3.European Medicines Agency (EMA). Xadago: EPAR - Procedural steps taken and|1
04109|046|R|  scientific information after the authorisation. Accessed at:|1
04109|047|R|  https://www.ema.europa.eu/en/documents/procedural-steps-after/xadago-epar-|1
04109|048|R|  procedural-steps-taken-scientific-information-after-authorisation_en.pdf|1
04109|049|R|  October 30, 2019.|1
04110|001|T|MONOGRAPH TITLE:  Mometasone/Selected CYP3A4 Inhibitors|
04110|002|B||
04110|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04110|004|L|take action as needed.|
04110|005|B||
04110|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04110|007|A|mometasone.(1-14,17)|
04110|008|B||
04110|009|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
04110|010|E|increased systemic exposure to and effects from mometasone, including|
04110|011|E|Cushing's syndrome and adrenal suppression.(1-14,17)|
04110|012|B||
04110|013|P|PREDISPOSING FACTORS:  None determined.|
04110|014|B||
04110|015|M|PATIENT MANAGEMENT:  Use caution when using concurrent therapy with|
04110|016|M|mometasone and CYP3A4 inhibitors.  Alternative corticosteroids that are less|
04110|017|M|affected by CYP3A4 inhibitors should be considered, like beclomethasone and|
04110|018|M|prednisolone.(14)|
04110|019|M|   If concurrent therapy is warranted, patients should be closely monitored|
04110|020|M|for systemic effects.  The corticosteroid may need to be discontinued.|
04110|021|B||
04110|022|D|DISCUSSION:  In a study in 24 healthy subjects, inhaled mometasone furoate|
04110|023|D|(400 mcg delivered by a dry powder inhaler twice daily for 9 days) with|
04110|024|D|ketoconazole (200 mg on Days 4 to 9) increased systemic mometasone furoate|
04110|025|D|concentrations from <150 pg/mL on Day 3 prior to coadministration of|
04110|026|D|ketoconazole to a peak plasma concentrations of mometasone furoate >200|
04110|027|D|pg/mL on Day 9 (211-324 pg/mL).(14)|
04110|028|D|   There have been several case reports of Cushing's syndrome in patients|
04110|029|D|treated concurrently with ritonavir and nasal fluticasone and|
04110|030|D|mometasone.(15)|
04110|031|D|   A review of corticosteroid use patients on protease inhibitors detailed|
04110|032|D|the interactions that can result in accumulation of corticosteroids, leading|
04110|033|D|to adrenal suppression and Cushing's syndrome.(16)|
04110|034|D|   Selected CYP3A4 inhibitors linked to this monograph include: atazanavir,|
04110|035|D|boceprevir, ceritinib, cobicistat, darunavir, fosamprenavir, idelalisib,|
04110|036|D|indinavir, lenacapavir, lonafarnib, lopinavir, mibefradil, nelfinavir,|
04110|037|D|nirmatrelvir, paritaprevir, saquinavir, telaprevir, tipranavir, and|
04110|038|D|tucatinib.(17)|
04110|039|B||
04110|040|R|REFERENCES:|
04110|041|B||
04110|042|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04110|043|R|  Squibb Company December, 2024.|1
04110|044|R|2.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
04110|045|R|  January, 2017.|1
04110|046|R|3.Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) US|1
04110|047|R|  prescribing information. Gilead Sciences, Inc. September, 2021.|1
04110|048|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04110|049|R|  March, 2023.|1
04110|050|R|5.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
04110|051|R|  March, 2019.|1
04110|052|R|6.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
04110|053|R|  September, 2016.|1
04110|054|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04110|055|R|  Laboratories December, 2019.|1
04110|056|R|8.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
04110|057|R|  Pharmaceuticals, Inc. September, 2016.|1
04110|058|R|9.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04110|059|R|  information. Pfizer Inc. February, 2025.|1
04110|060|R|10.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
04110|061|R|   December, 2019.|1
04110|062|R|11.Invirase (saquinavir mesylate) US prescribing information. Roche|1
04110|063|R|   Laboratories, Inc. March, 2019.|1
04110|064|R|12.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
04110|065|R|   Incorporated October, 2013.|1
04110|066|R|13.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04110|067|R|   Pharmaceuticals, Inc. April, 2024.|1
04110|068|R|14.Asmanex (mometasone furoate) US prescribing information. Organon LLC|1
04110|069|R|   June, 2022.|1
04110|070|R|15.Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and|3
04110|071|R|   Cushing's syndrome secondary to an interaction between ritonavir and|3
04110|072|R|   fluticasone: a review of the literature. HIV Med 2008 Jul;9(6):389-96.|3
04110|073|R|16.Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in|6
04110|074|R|   HIV-positive individuals taking protease  inhibitors: a review of|6
04110|075|R|   pharmacokinetics, case reports and clinical management. HIV Med 2013 Oct;|6
04110|076|R|   14(9):519-29.|6
04110|077|R|17.This information is based on an extract from the Certara Drug Interaction|6
04110|078|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04111|001|T|MONOGRAPH TITLE:  Letermovir (Greater Than 240 mg)/Cyclosporine|
04111|002|B||
04111|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04111|004|L|is contraindicated and generally should not be dispensed or administered to|
04111|005|L|the same patient.|
04111|006|B||
04111|007|A|MECHANISM OF ACTION:  Cyclosporine, an OATP1B1/3 inhibitor, may inhibit the|
04111|008|A|metabolism of letermovir. Letermovir, a moderate CYP3A4 inhibitor, may|
04111|009|A|inhibit the metabolism of cyclosporine.(1)|
04111|010|B||
04111|011|E|CLINICAL EFFECTS:  The concurrent administration of cyclosporine and|
04111|012|E|letermovir may result in elevated levels of letermovir and/or|
04111|013|E|cyclosporine.(1)|
04111|014|B||
04111|015|P|PREDISPOSING FACTORS:  None determined.|
04111|016|B||
04111|017|M|PATIENT MANAGEMENT:  The manufacturer of letermovir states that if oral or|
04111|018|M|intravenous letermovir is coadministered with cyclosporine, the dosage of|
04111|019|M|letermovir should be decreased to 240 mg once daily in adult and pediatric|
04111|020|M|patients 12 years of age or older in the following populations:|
04111|021|M|   - Hematopoietic stem cell transplantation (HSCT) recipients weighing at|
04111|022|M|least 30 kg, or|
04111|023|M|   - Kidney transplant recipients weighing at least 40 kg.(1)|
04111|024|M|   If cyclosporine is initiated after starting letermovir, the next dose of|
04111|025|M|letermovir should be decreased to 240 mg once daily.(1)|
04111|026|M|   If cyclosporine is discontinued after starting letermovir, the next dose|
04111|027|M|of letermovir should be increased to 480 mg once daily.(1)|
04111|028|M|   If cyclosporine dosing is interrupted due to high cyclosporine levels, no|
04111|029|M|dose adjustment of letermovir is needed.(1)|
04111|030|M|   The manufacturer of letermovir states that if oral or intravenous|
04111|031|M|letermovir is coadministered with cyclosporine in pediatric HSCT recipients|
04111|032|M|6 months to less than 12 years of age, or 12 years of age and weighing less|
04111|033|M|than 30 kg, the dosage of letermovir may require adjustment as outlined:|
04111|034|M|   - 30 kg and above: Daily dose of letermovir = 240 mg|
04111|035|M|   - 15 kg to less than 30 kg: Daily dose of letermovir = 120 mg|
04111|036|M|   - 7.5 kg to less than 15 kg: Daily dose of letermovir = 60 mg|
04111|037|M|   - 6 kg to less than 7.5 kg: Daily dose of letermovir = 40 mg|
04111|038|M|   If cyclosporine is initiated after starting letermovir, the next dose of|
04111|039|M|letermovir should be the daily oral or intravenous dose co-administered with|
04111|040|M|cyclosporine.(1)|
04111|041|M|   If cyclosporine is discontinued after starting letermovir, the next dose|
04111|042|M|of letermovir should be the daily oral or intravenous dose administered|
04111|043|M|without cyclosporine.(1)|
04111|044|M|   If cyclosporine dosing is interrupted due to high cyclosporine levels, no|
04111|045|M|dose adjustment of letermovir is needed.(1)|
04111|046|M|   Refer to letermovir prescribing information for dosing recommendations|
04111|047|M|based on patient age and weight.(1)|
04111|048|M|   Frequently monitor cyclosporine whole blood concentrations during|
04111|049|M|treatment and after discontinuation of letermovir and adjust the dose of|
04111|050|M|cyclosporine accordingly.(1)|
04111|051|B||
04111|052|D|DISCUSSION:  In a study, concurrent administration of cyclosporine (200 mg|
04111|053|D|single dose, oral) with letermovir (240 mg once daily, oral) increased|
04111|054|D|letermovir's area-under-the-curve (AUC), maximum concentration (Cmax), and|
04111|055|D|trough concentration (C24hr) by 2.11-fold, 1.48-fold, and 2.06-fold.(1)|
04111|056|D|   In a study, concurrent administration of cyclosporine (50 mg single dose,|
04111|057|D|oral) with letermovir (240 mg once daily, oral) increased cyclosporine's AUC|
04111|058|D|and C24hr by 1.66-fold and 2.19-fold.(1)|
04111|059|B||
04111|060|R|REFERENCES:|
04111|061|B||
04111|062|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
04111|063|R|  2024.|1
04111|064|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04111|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04111|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04111|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04111|068|R|  11/14/2017.|1
04111|069|R|3.This information is based on an extract from the Certara Drug Interaction|6
04111|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04112|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Maribavir|
04112|002|B||
04112|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04112|004|L|take action as needed.|
04112|005|B||
04112|006|A|MECHANISM OF ACTION:  The metabolism of cyclosporine, everolimus, sirolimus,|
04112|007|A|tacrolimus and temsirolimus by CYP3A4 may be inhibited by maribavir.|
04112|008|B||
04112|009|E|CLINICAL EFFECTS:  Concurrent administration of maribavir may result in|
04112|010|E|elevated levels of and toxicity from cyclosporine, everolimus, sirolimus,|
04112|011|E|tacrolimus or temsirolimus.|
04112|012|B||
04112|013|P|PREDISPOSING FACTORS:  None determined.|
04112|014|B||
04112|015|M|PATIENT MANAGEMENT:  Cyclosporine, everolimus, sirolimus, tacrolimus or|
04112|016|M|temsirolimus levels and renal function should be monitored frequently during|
04112|017|M|therapy with maribavir.  Monitor immunosuppressant levels closely during|
04112|018|M|initiation and after discontinuation of maribavir.  The dosage of|
04112|019|M|cyclosporine, everolimus, sirolimus, tacrolimus or temsirolimus may need to|
04112|020|M|be adjusted.|
04112|021|B||
04112|022|D|DISCUSSION:  In a study in 20 patients, maribavir increased the|
04112|023|D|area-under-curve (AUC), concentration maximum (Cmax), and Ctau of tacrolimus|
04112|024|D|by 51%, 38%, and 57%, respectively.|
04112|025|D|   In a multiple-dose study, concomitant administration of ketoconazole with|
04112|026|D|sirolimus oral solution increased the sirolimus Cmax, time to Cmax (Tmax),|
04112|027|D|and AUC by 4.3-fold, 38%, and 10.9-fold, respectively.  Single-dose|
04112|028|D|sirolimus did not affect steady-state 12-hour plasma ketoconazole|
04112|029|D|concentrations.|
04112|030|D|   In a study in 6 patients, ketoconazole was successfully used to augment|
04112|031|D|sirolimus levels.  Patients were able to receive one-eight to one-fourth|
04112|032|D|(0.25 - 0.50 mg daily) of the usual sirolimus dose while taking 100 to 200|
04112|033|D|mg of ketoconazole daily.|
04112|034|D|   Concurrent administration of ketoconazole had no effects on temsirolimus|
04112|035|D|AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and|
04112|036|D|2.2-fold, respectively.  Dosage adjustment of temsirolimus to 12.5 mg/week|
04112|037|D|in the presence of strong CYP3A4 inhibitors is expected to adjust levels to|
04112|038|D|the range observed without inhibitors; however, there are no data available|
04112|039|D|with this dose adjustment.|
04112|040|B||
04112|041|R|REFERENCES:|
04112|042|B||
04112|043|R|1.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
04112|044|R|  Inc. March, 2018.|1
04112|045|R|2.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
04112|046|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
04112|047|R|3.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
04112|048|R|  Aug, 2022.|1
04112|049|R|4.Livtencity (maribavir) US prescribing information. Takeda Pharmaceuticals|1
04112|050|R|  America, Inc. November, 2021.|1
04112|051|R|5.Ferguson RM, Sutherland DE, Simmons RL, Najarian JS. Ketoconazole,|3
04112|052|R|  cyclosporin metabolism, and renal transplantation. Lancet 1982 Oct 16;|3
04112|053|R|  2(8303):882-3.|3
04112|054|R|6.Daneshmend TK. Ketoconazole-cyclosporin interaction. Lancet 1982 Dec 11;|3
04112|055|R|  2(8311):1342-3.|3
04112|056|R|7.Smith JM, Hows JM, Gordon-Smith EC, Baughan A, Goldman JM. Interaction of|4
04112|057|R|  CyA and ketoconazole. Clin Sci 1983;64(2):67P.|4
04112|058|R|8.Shepard JH, Canafax DM, Simmons RL, Najarian JS.|3
04112|059|R|  Cyclosporine-ketoconazole: a potentially dangerous drug-drug interaction.|3
04112|060|R|  Clin Pharm 1986 Jun;5(6):468.|3
04112|061|R|9.Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin|6
04112|062|R|  Pharmacokinet 1988 Jan;14(1):13-34.|6
04112|063|R|10.Charles BG, Ravenscroft PJ, Rigby RJ. The ketoconazole-cyclosporin|3
04112|064|R|   interaction in an elderly renal transplant patient. Aust N Z J Med 1989|3
04112|065|R|   Jun;19(3):292-3.|3
04112|066|R|11.Baciewicz AM, Baciewicz FA Jr. Cyclosporine pharmacokinetic drug|6
04112|067|R|   interactions. Am J Surg 1989 Feb;157(2):264-71.|6
04112|068|R|12.First MR, Schroeder TJ, Weiskittel P, Myre SA, Alexander JW, Pesce AJ.|2
04112|069|R|   Concomitant administration of cyclosporin and ketoconazole in renal|2
04112|070|R|   transplant recipients. Lancet 1989 Nov 18;2(8673):1198-201.|2
04112|071|R|13.Frey FJ. Concomitant cyclosporin and ketoconazole. Lancet 1990 Jan 13;|6
04112|072|R|   335(8681):109-10.|6
04112|073|R|14.Ah-Sing E, Poole TW, Ioannides C, King LJ. Mechanism of the|5
04112|074|R|   ketoconazole-cyclosporin interaction. Arch Toxicol 1990;64(6):511-3.|5
04112|075|R|15.Katzir D, Balschke TF. The cyclosporine-ketoconazole interaction. Hosp|3
04112|076|R|   Ther 1990 Jan;15:99-112.|3
04112|077|R|16.First MR, Schroeder TJ, Alexander JW, Stephens GW, Weiskittel P, Myre SA,|2
04112|078|R|   Pesce AJ. Cyclosporine dose reduction by ketoconazole administration in|2
04112|079|R|   renal transplant recipients. Transplantation 1991 Feb;51(2):365-70.|2
04112|080|R|17.Albengres E, Tillement JP. Cyclosporin and ketoconazole, drug interaction|6
04112|081|R|   or therapeutic association?. Int J Clin Pharmacol Ther Toxicol 1992 Dec;|6
04112|082|R|   30(12):555-70.|6
04112|083|R|18.First MR, Schroeder TJ, Michael A, Hariharan S, Weiskittel P, Alexander|2
04112|084|R|   JW. Cyclosporine-ketoconazole interaction. Long-term follow-up and|2
04112|085|R|   preliminary results of a randomized trial. Transplantation 1993 May;|2
04112|086|R|   55(5):1000-4.|2
04112|087|R|19.Sadaba B, Campanero MA, Quetglas EG, Azanza JR. Clinical relevance of|3
04112|088|R|   sirolimus drug interactions in transplant patients. Transplant Proc 2004|3
04112|089|R|   Dec;36(10):3226-8.|3
04112|090|R|20.Thomas PP, Manivannan J, John GT, Jacob CK. Sirolimus and ketoconazole|2
04112|091|R|   co-prescription in renal transplant recipients. Transplantation 2004 Feb|2
04112|092|R|   15;77(3):474-5.|2
04113|001|T|MONOGRAPH TITLE:  Tacrolimus/Moderate and Weak CYP3A4 Inducers|
04113|002|B||
04113|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04113|004|L|take action as needed.|
04113|005|B||
04113|006|A|MECHANISM OF ACTION:  Moderate or weak CYP3A4 inducers may accelerate the|
04113|007|A|metabolism of tacrolimus.(1)|
04113|008|B||
04113|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate or weak CYP3A4 inducer may|
04113|010|E|result in decreased levels and effectiveness of tacrolimus.(1)|
04113|011|B||
04113|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04113|013|P|of the inducer for longer than 1-2 weeks.|
04113|014|B||
04113|015|M|PATIENT MANAGEMENT:  The manufacturer of tacrolimus recommends monitoring|
04113|016|M|tacrolimus whole blood trough concentrations and adjusting tacrolimus dose|
04113|017|M|if needed.  Monitor clinical response closely.(1)|
04113|018|B||
04113|019|D|DISCUSSION:  A 13-year-old cystic fibrosis patient with a history of liver|
04113|020|D|transplant on stable doses of tacrolimus underwent 2 separate courses of|
04113|021|D|nafcillin therapy (a moderate CYP3A4 inducer).  During the 1st course of|
04113|022|D|nafcillin, his tacrolimus levels started to fall 3 days after starting|
04113|023|D|nafcillin, became undetectable at day 8, and recovered to therapeutic levels|
04113|024|D|without a change in tacrolimus dose 5 days after discontinuation of|
04113|025|D|nafcillin.  During the 2nd course of nafcillin, tacrolimus level became|
04113|026|D|undetectable 4 days after starting nafcillin and recovered 3 days after|
04113|027|D|stopping nafcillin.(2)|
04113|028|D|   Moderate inducers of CYP3A4 would be expected to decrease the AUC of a|
04113|029|D|sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan,|
04113|030|D|cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib,|
04113|031|D|mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and|
04113|032|D|tovorafenib.(3,4)|
04113|033|D|   Weak inducers of CYP3A4 would be expected to decrease the AUC of a|
04113|034|D|sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene,|
04113|035|D|brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone,|
04113|036|D|dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine,|
04113|037|D|floxacillin, garlic, genistein, ginseng, glycyrrhizin,|
04113|038|D|meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone,|
04113|039|D|oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone,|
04113|040|D|sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine,|
04113|041|D|ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)|
04113|042|B||
04113|043|R|REFERENCES:|
04113|044|B||
04113|045|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04113|046|R|  August, 2023.|1
04113|047|R|2.Wungwattana M, Savic M. Tacrolimus interaction with nafcillin resulting in|3
04113|048|R|  significant decreases in  tacrolimus concentrations: A case report.|3
04113|049|R|  Transpl Infect Dis 2017 Apr;19(2):.|3
04113|050|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04113|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04113|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04113|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04113|054|R|  11/14/2017.|1
04113|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
04113|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04114|001|T|MONOGRAPH TITLE:  Tacrolimus/Selected Strong CYP3A4 Inhibitors|
04114|002|B||
04114|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04114|004|L|of severe adverse interaction.|
04114|005|B||
04114|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04114|007|A|tacrolimus CYP3A4.(1,2)|
04114|008|B||
04114|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04114|010|E|increased levels of tacrolimus, including QT prolongation, nephrotoxicity,|
04114|011|E|neurotoxicity, cardiovascular toxicity, hypertension, anemia, and increased|
04114|012|E|risk of serious infections.(1,2)|
04114|013|B||
04114|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04114|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04114|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04114|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04114|018|P|female gender, or advanced age.(3)|
04114|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04114|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04114|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04114|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04114|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04114|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04114|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04114|026|B||
04114|027|M|PATIENT MANAGEMENT:  The US manufacturer of tacrolimus states that|
04114|028|M|concurrent use with strong CYP3A4 inhibitors may result in a rapid and sharp|
04114|029|M|rise in tacrolimus concentration despite immediate tacrolimus dose|
04114|030|M|reduction.  Frequent monitoring of tacrolimus levels should start within 1-3|
04114|031|M|days of initiation of concurrent therapy and continue as necessary.(2)|
04114|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04114|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04114|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04114|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04114|036|B||
04114|037|D|DISCUSSION:  In a study of 6 normal volunteers, a significant increase in|
04114|038|D|tacrolimus oral bioavailability (14% versus 30%) was observed with|
04114|039|D|concomitant ketoconazole, another inhibitor of CYP3A4, administration (200|
04114|040|D|mg).  The apparent oral clearance of tacrolimus during ketoconazole|
04114|041|D|administration was significantly decreased compared to tacrolimus alone|
04114|042|D|(0.430 L/hr/kg versus 0.148 L/hr/kg).  Overall, IV clearance of tacrolimus|
04114|043|D|was not significantly changed by ketoconazole coadministration, although it|
04114|044|D|was highly variable between patients.(2)|
04114|045|D|   Strong CYP3A4 inhibitors linked to this monograph include: grapefruit,|
04114|046|D|idelalisib and nefazodone.|
04114|047|B||
04114|048|R|REFERENCES:|
04114|049|B||
04114|050|R|1.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
04114|051|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
04114|052|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
04114|053|R|  e13510.|6
04114|054|R|2.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04114|055|R|  August, 2023.|1
04114|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04114|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04114|058|R|  settings: a scientific statement from the American Heart Association and|6
04114|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04114|060|R|  2;55(9):934-47.|6
04115|001|T|MONOGRAPH TITLE:  Tacrolimus/QT Prolonging Agents|
04115|002|B||
04115|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04115|004|L|take action as needed.|
04115|005|B||
04115|006|A|MECHANISM OF ACTION:  Tacrolimus has been observed to prolong the QTc|
04115|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04115|008|A|may result in additive effects on the QTc interval.(1)|
04115|009|B||
04115|010|E|CLINICAL EFFECTS:  The concurrent use of tacrolimus with other agents that|
04115|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04115|012|E|arrhythmias, including torsades de pointes.(1)|
04115|013|B||
04115|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04115|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04115|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04115|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04115|018|P|female gender, or advanced age.(2)|
04115|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04115|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04115|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04115|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04115|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04115|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04115|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04115|026|B||
04115|027|M|PATIENT MANAGEMENT:  The manufacturer of tacrolimus states concurrent use|
04115|028|M|with agents known to prolong the QT interval should be used with caution and|
04115|029|M|monitoring for QT prolongation is recommended.(1)|
04115|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04115|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04115|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04115|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04115|034|B||
04115|035|D|DISCUSSION:  Tacrolimus has been associated with QT prolongation.(1)|
04115|036|D|   In a kidney transplant population, 98 patients received immunosuppressive|
04115|037|D|management with tacrolimus, cyclosporine, everolimus, or azathioprine.  All|
04115|038|D|patients post-transplant had significantly prolonged QTc interval compared|
04115|039|D|to pre-transplant in all groups.(3)|
04115|040|D|   Agents that are linked to this monograph may have varying degrees of|
04115|041|D|potential to prolong the QTc interval but are generally accepted to have a|
04115|042|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04115|043|D|been shown to prolong the QTc interval either through their mechanism of|
04115|044|D|action, through studies on their effects on the QTc interval, or through|
04115|045|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04115|046|D|and/or post-marketing reports.(4)|
04115|047|B||
04115|048|R|REFERENCES:|
04115|049|B||
04115|050|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04115|051|R|  August, 2023.|1
04115|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04115|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04115|054|R|  settings: a scientific statement from the American Heart Association and|6
04115|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04115|056|R|  2;55(9):934-47.|6
04115|057|R|3.Ikitimur B, Cosansu K, Karadag B, Cakmak HA, Avci BK, Erturk E, Seyahi N,|2
04115|058|R|  Ongen Z. Long-Term Impact of Different Immunosuppressive Drugs on QT and|2
04115|059|R|  PR Intervals in  Renal Transplant Patients. Ann Noninvasive Electrocardiol|2
04115|060|R|  2015 Sep;20(5):426-32.|2
04115|061|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04115|062|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04115|063|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04115|064|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04116|001|T|MONOGRAPH TITLE:  Tacrolimus/Selected Strong CYP3A4 Inhibitors that Prolong|
04116|002|T|QT|
04116|003|B||
04116|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04116|005|L|of severe adverse interaction.|
04116|006|B||
04116|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04116|008|A|tacrolimus CYP3A4.(1,2)|
04116|009|B||
04116|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04116|011|E|increased levels of tacrolimus, including QT prolongation, nephrotoxicity,|
04116|012|E|neurotoxicity, cardiovascular toxicity, hypertension, anemia, and increased|
04116|013|E|risk of serious infections.(1,2)|
04116|014|B||
04116|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04116|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04116|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04116|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04116|019|P|female gender, or advanced age.(3)|
04116|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04116|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04116|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04116|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04116|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04116|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04116|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04116|027|B||
04116|028|M|PATIENT MANAGEMENT:  The US manufacturer of tacrolimus states that|
04116|029|M|concurrent use with strong CYP3A4 inhibitors may result in a rapid and sharp|
04116|030|M|rise in tacrolimus concentration despite immediate tacrolimus dose|
04116|031|M|reduction.  Frequent monitoring of tacrolimus levels should start within 1-3|
04116|032|M|days of initiation of concurrent therapy and continue as necessary.(2)|
04116|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04116|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04116|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04116|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04116|037|B||
04116|038|D|DISCUSSION:  In a study of 6 normal volunteers, a significant increase in|
04116|039|D|tacrolimus oral bioavailability (14% versus 30%) was observed with|
04116|040|D|concomitant ketoconazole, another inhibitor of CYP3A4, administration (200|
04116|041|D|mg).  The apparent oral clearance of tacrolimus during ketoconazole|
04116|042|D|administration was significantly decreased compared to tacrolimus alone|
04116|043|D|(0.430 L/hr/kg versus 0.148 L/hr/kg).  Overall, IV clearance of tacrolimus|
04116|044|D|was not significantly changed by ketoconazole coadministration, although it|
04116|045|D|was highly variable between patients.(2)|
04116|046|D|   Tacrolimus has been associated with QT prolongation.(1)|
04116|047|D|   In a kidney transplant population, 98 patients received immunosuppressive|
04116|048|D|management with tacrolimus, cyclosporine, everolimus, or azathioprine.  All|
04116|049|D|patients post-transplant had significantly prolonged QTc interval compared|
04116|050|D|to pre-transplant in all groups.(4)|
04116|051|D|   Strong CYP3A4 inhibitors that prolong QT linked to this monograph|
04116|052|D|include:  adagrasib, ceritinib, levoketoconazole, and lonafarnib.|
04116|053|B||
04116|054|R|REFERENCES:|
04116|055|B||
04116|056|R|1.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
04116|057|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
04116|058|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
04116|059|R|  e13510.|6
04116|060|R|2.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04116|061|R|  August, 2023.|1
04116|062|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04116|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04116|064|R|  settings: a scientific statement from the American Heart Association and|6
04116|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04116|066|R|  2;55(9):934-47.|6
04116|067|R|4.Ikitimur B, Cosansu K, Karadag B, Cakmak HA, Avci BK, Erturk E, Seyahi N,|2
04116|068|R|  Ongen Z. Long-Term Impact of Different Immunosuppressive Drugs on QT and|2
04116|069|R|  PR Intervals in  Renal Transplant Patients. Ann Noninvasive Electrocardiol|2
04116|070|R|  2015 Sep;20(5):426-32.|2
04117|001|T|MONOGRAPH TITLE:  Tacrolimus/Protease Inhibitors; Cobicistat|
04117|002|B||
04117|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04117|004|L|of severe adverse interaction.|
04117|005|B||
04117|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04117|007|A|tacrolimus CYP3A4.(1,2)  HIV and HCV protease inhibitors as well as|
04117|008|A|cobicistat are CYP3A4 inhibitors.(1-17)|
04117|009|B||
04117|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04117|011|E|increased levels of tacrolimus, including QT prolongation, nephrotoxicity,|
04117|012|E|neurotoxicity, cardiovascular toxicity, hypertension, anemia, and increased|
04117|013|E|risk of serious infections.(1,2)|
04117|014|B||
04117|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04117|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04117|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04117|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04117|019|P|female gender, or advanced age.(2)|
04117|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04117|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04117|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04117|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04117|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04117|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04117|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04117|027|B||
04117|028|M|PATIENT MANAGEMENT:  The US manufacturer of tacrolimus states that|
04117|029|M|concurrent use with strong CYP3A4 inhibitors may result in a rapid and sharp|
04117|030|M|rise in tacrolimus concentration despite immediate tacrolimus dose|
04117|031|M|reduction.  Frequent monitoring of tacrolimus levels should start within 1-3|
04117|032|M|days of initiation of concurrent therapy and continue as necessary.(2)|
04117|033|M|   For patients concurrently taking tacrolimus and either a HIV or HCV|
04117|034|M|protease inhibitor or cobicistat, therapeutic concentration monitoring of|
04117|035|M|the immunosuppressant is recommended.  Depending upon the agents involved,|
04117|036|M|dose decreases of the immunosuppressant agent may be required.(1-17)|
04117|037|M|   Guidelines from the American Society of Transplantation recommend|
04117|038|M|avoiding the use of ritonavir- or cobicistat-based HIV or HCV antiviral|
04117|039|M|regimens with tacrolimus due to an increased risk of graft loss and death,|
04117|040|M|as well as the availability of HIV integrase inhibitors that avoid|
04117|041|M|interactions with immunosuppressants.  If the combination must be used,|
04117|042|M|lower the dose of tacrolimus to 1 mg once or twice a week.  Monitor drug|
04117|043|M|concentrations closely.(1)|
04117|044|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04117|045|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04117|046|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04117|047|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04117|048|M|   The protease inhibitors linked to this monograph include: amprenavir,|
04117|049|M|atazanavir, boceprevir, cobicistat, darunavir, fosamprenavir, indinavir,|
04117|050|M|lopinavir, nelfinavir, telaprevir, and tipranavir.|
04117|051|B||
04117|052|D|DISCUSSION:  A retrospective study of 42 HIV+ kidney transplant recipients|
04117|053|D|examined rejection rates in patients on ritonavir-boosted protease inhibitor|
04117|054|D|(PI) antiretroviral regimens compared to patients on other antiretroviral|
04117|055|D|regimens.  Immunosuppression therapy consisted of cyclosporine in 7 patients|
04117|056|D|(17%) and tacrolimus in 32 patients (76%).  The remaining 3 patients were|
04117|057|D|transitioning between drugs.  Over 3 years, 65% of patients on PI-based|
04117|058|D|antiretroviral therapy experienced rejection, compared with 36% of patients|
04117|059|D|on other antiretroviral therapies (p<0.001).  There was no difference in|
04117|060|D|patient or graft survival at 3 years.(18)|
04117|061|D|   Boceprevir (800 mg TID for 11 days) increased the Cmax and AUC of|
04117|062|D|tacrolimus (0.5 mg single dose) by 9.90-fold and 17.1-fold, respectively.|
04117|063|D|There were no significant effects on boceprevir pharmacokinetics.(4)|
04117|064|D|   In a case report, tacrolimus levels in a 50 year-old male kidney|
04117|065|D|transplant recipient increased from 7.5 ng/ml to 111.2 ng/ml one week after|
04117|066|D|initiation of an HIV regimen including elvitegravir 150 mg, cobicistat 150|
04117|067|D|mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg once|
04117|068|D|daily.  The patient experienced headache, insomnia, stomachache,|
04117|069|D|hyperkalemia, and increased SCr at which time the HIV regimen was stopped.|
04117|070|D|On day 15 the patient's tacrolimus level returned to 4.0 ng/ml at which time|
04117|071|D|the patient resumed tacrolimus at previous stable dose and the HIV regimen|
04117|072|D|was changed to abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg|
04117|073|D|daily without any further increase in tacrolimus levels.(19)|
04117|074|D|   In a case report, tacrolimus levels in a 41 year-old male kidney|
04117|075|D|transplant recipient increased from 8.7 ng/ml to 106 ng/ml within 3 days of|
04117|076|D|the addition of tenofovir and darunavir/ritonavir therapy, despite the|
04117|077|D|patient's tacrolimus dosage being decreased 12%.  Concurrent therapy was|
04117|078|D|eventually titrated to 0.5 mg of tacrolimus given once weekly.(20)|
04117|079|D|   There are several case reports of decreased tacrolimus requirements|
04117|080|D|and/or toxicity during concurrent indinavir,(21) lopinavir/ritonavir,(22-24)|
04117|081|D|and nelfinavir.(25)  In a study in 5 HIV+ liver transplant patients,|
04117|082|D|tacrolimus needs were 38 times lower with concurrent nelfinavir.(23)|
04117|083|D|   A case report describes a 52 year-old male with HIV and hepatitis C who|
04117|084|D|experienced severe tacrolimus toxicity after the addition of an HIV regimen|
04117|085|D|including nelfinavir (750 mg three times daily) following his liver|
04117|086|D|transplantation.  The HIV regimen was temporarily stopped until the|
04117|087|D|tacrolimus levels normalized at which time the medications were restarted|
04117|088|D|having replaced nelfinavir with saquinavir (400 mg twice/day) and ritonavir|
04117|089|D|(400 mg twice/day).  The patient again experienced neurological symptoms|
04117|090|D|associated with tacrolimus toxicity and was found to have a tacrolimus level|
04117|091|D|over 120 ng/ml.  The medications were held allowing for a long recovery. The|
04117|092|D|HIV regimen was rechallenged a third time using the original combination|
04117|093|D|which included nelfinavir.  The dose of tacrolimus was dramatically|
04117|094|D|decreased and the schedule changed until the tacrolimus levels finally|
04117|095|D|stabilized.(26)|
04117|096|D|   In a study in 9 subjects, the concurrent administration of telaprevir|
04117|097|D|(750 mg TID) decreased the Cmax and AUC of a single dose of tacrolimus (0.5|
04117|098|D|mg) by 2.34-fold and 17.6-fold, respectively, when compared to levels|
04117|099|D|achieved with a single 2 mg dose of tacrolimus.  Extrapolated to level|
04117|100|D|expected with the 2 mg dose, tacrolimus Cmax and AUC would have increased by|
04117|101|D|9.35-fold% and 70.3-fold, respectively.(5)|
04117|102|D|   The protease inhibitors linked to this monograph include: amprenavir,|
04117|103|D|atazanavir, boceprevir, cobicistat, darunavir, fosamprenavir, indinavir,|
04117|104|D|lopinavir, nelfinavir, telaprevir, and tipranavir.|
04117|105|B||
04117|106|R|REFERENCES:|
04117|107|B||
04117|108|R|1.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
04117|109|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
04117|110|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
04117|111|R|  e13510.|6
04117|112|R|2.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04117|113|R|  August, 2023.|1
04117|114|R|3.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
04117|115|R|  Inc. March, 2018.|1
04117|116|R|4.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
04117|117|R|  January, 2017.|1
04117|118|R|5.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
04117|119|R|  Incorporated October, 2013.|1
04117|120|R|6.Agenerase (amprenavir) Capsules US prescribing information.|1
04117|121|R|  GlaxoSmithKline May, 2005.|1
04117|122|R|7.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04117|123|R|  Squibb Company December, 2024.|1
04117|124|R|8.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
04117|125|R|  June, 2025.|1
04117|126|R|9.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04117|127|R|  March, 2023.|1
04117|128|R|10.Lexiva (fosamprenavir calcium) US prescribing information.|1
04117|129|R|   GlaxoSmithKline March, 2019.|1
04117|130|R|11.Crixivan (indinavir sulfate) US prescribing information. Merck & Co.,|1
04117|131|R|   Inc. September, 2016.|1
04117|132|R|12.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04117|133|R|   Laboratories December, 2019.|1
04117|134|R|13.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
04117|135|R|   Pharmaceuticals, Inc. September, 2016.|1
04117|136|R|14.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
04117|137|R|   December, 2019.|1
04117|138|R|15.Invirase (saquinavir mesylate) US prescribing information. Roche|1
04117|139|R|   Laboratories, Inc. March, 2019.|1
04117|140|R|16.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04117|141|R|   Pharmaceuticals, Inc. April, 2024.|1
04117|142|R|17.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
04117|143|R|   prescribing information. Aadi Bioscience, Inc. November, 2021.|1
04117|144|R|18.Rollins B, Farouk S, DeBoccardo G, Lerner S, Rana M, Huprikar S, Miko L,|2
04117|145|R|   Delaney V, Florman S, Shapiro R. Higher rates of rejection in|2
04117|146|R|   HIV-infected kidney transplant recipients on ritonavir-boosted protease|2
04117|147|R|   inhibitors: 3-year follow-up study. Clin Transplant 2019 Jun;|2
04117|148|R|   33(6):e13534.|2
04117|149|R|19.Han Z, Kane BM, Petty LA, Josephson MA, Sutor J, Pursell KJ. Cobicistat|3
04117|150|R|   Significantly Increases Tacrolimus Serum Concentrations in a Renal|3
04117|151|R|   Transplant Recipient with Human Immunodeficiency Virus Infection.|3
04117|152|R|   Pharmacotherapy 2016 Jun;36(6):e50-e53.|3
04117|153|R|20.Mertz D, Battegay M, Marzolini C, Mayr M. Drug-drug interaction in a|3
04117|154|R|   kidney transplant recipient receiving HIV salvage therapy and tacrolimus.|3
04117|155|R|   Am J Kidney Dis 2009 Jul;54(1):e1-4.|3
04117|156|R|21.Jain AK, Venkataramanan R, Shapiro R, Scantlebury VP, Potdar S, Bonham|2
04117|157|R|   CA, Ragni M, Fung JJ. The interaction between antiretroviral agents and|2
04117|158|R|   tacrolimus in liver and kidney transplant patients. Liver Transpl 2002|2
04117|159|R|   Sep;8(9):841-5.|2
04117|160|R|22.Schonder KS, Shullo MA, Okusanya O. Tacrolimus and lopinavir/ritonavir|3
04117|161|R|   interaction in liver transplantation. Ann Pharmacother 2003 Dec;|3
04117|162|R|   37(12):1793-6.|3
04117|163|R|23.Jain AB, Venkataramanan R, Eghtesad B, Marcos A, Ragni M, Shapiro R,|3
04117|164|R|   Rafail AB, Fung JJ. Effect of coadministered lopinavir and ritonavir|3
04117|165|R|   (Kaletra) on tacrolimus blood concentration in liver transplantation|3
04117|166|R|   patients. Liver Transpl 2003 Sep;9(9):954-60.|3
04117|167|R|24.Guaraldi G, Cocchi S, Codeluppi M, Di Benedetto F, Bonora S, Pecorari M,|3
04117|168|R|   Gennari W, Cautero N, Pinna AD, Gerunda GE, Esposito R. Role of|3
04117|169|R|   therapeutic drug monitoring in a patient with human immunodeficiency|3
04117|170|R|   virus infection and end-stage liver disease undergoing orthotopic liver|3
04117|171|R|   transplantation. Transplant Proc 2005 Jul-Aug;37(6):2609-10.|3
04117|172|R|25.Schvarcz R, Rudbeck G, Soderdahl G, Stahle L. Interaction between|3
04117|173|R|   nelfinavir and tacrolimus after orthoptic liver transplantation in a|3
04117|174|R|   patient coinfected with HIV and hepatitis C virus (HCV). Transplantation|3
04117|175|R|   2000 May 27;69(10):2194-5.|3
04117|176|R|26.Sheikh AM, Wolf DC, Lebovics E, Goldberg R, Horowitz HW. Concomitant|3
04117|177|R|   human immunodeficiency virus protease inhibitor therapy markedly reduces|3
04117|178|R|   tacrolimus metabolism and increases blood levels. Transplantation 1999|3
04117|179|R|   Jul 27;68(2):307-9.|3
04118|001|T|MONOGRAPH TITLE:  Tacrolimus/Selected Azole Antifungal Agents|
04118|002|B||
04118|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04118|004|L|of severe adverse interaction.|
04118|005|B||
04118|006|A|MECHANISM OF ACTION:  The metabolism of tacrolimus by CYP3A4 may be|
04118|007|A|inhibited by clotrimazole, itraconazole, and ketoconazole.|
04118|008|B||
04118|009|E|CLINICAL EFFECTS:  Concurrent administration of an azole antifungal may|
04118|010|E|result in elevated levels of and toxicity from tacrolimus, including QT|
04118|011|E|prolongation, nephrotoxicity, neurotoxicity, cardiovascular toxicity,|
04118|012|E|hypertension, anemia, and increased risk of serious infections.|
04118|013|B||
04118|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04118|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04118|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04118|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04118|018|P|female gender, or advanced age.|
04118|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04118|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04118|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04118|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04118|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04118|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04118|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).|
04118|026|B||
04118|027|M|PATIENT MANAGEMENT:  Tacrolimus levels and renal function should be|
04118|028|M|monitored if an azole antifungal is initiated or discontinued from|
04118|029|M|concurrent therapy.  The dosage of tacrolimus may need to be adjusted.|
04118|030|M|   Guidelines from the American Society of Transplantation recommend|
04118|031|M|avoiding concurrent use of tacrolimus with itraconazole or ketoconazole.  If|
04118|032|M|the combination must be used, lower the dose of the immunosuppressant by at|
04118|033|M|least 50% and monitor levels closely.|
04118|034|M|   The US manufacturer of tacrolimus states that coadministration with|
04118|035|M|strong CYP3A4 inhibitors may result in a rapid and sharp rise in tacrolimus|
04118|036|M|concentration despite immediate tacrolimus dose reduction.  Frequent|
04118|037|M|monitoring of tacrolimus levels should start within 1-3 days of initiation|
04118|038|M|of concurrent therapy and continue as necessary.|
04118|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04118|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04118|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04118|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04118|043|B||
04118|044|D|DISCUSSION:  The interaction between fluconazole and tacrolimus is|
04118|045|D|dose-dependent.  In a study in 20 patients, the addition of fluconazole to|
04118|046|D|tacrolimus therapy resulted in the need for a 56% dosage reduction in|
04118|047|D|tacrolimus.  Patients on fluconazole 100 mg/day experienced a 1.4-fold|
04118|048|D|increase in tacrolimus trough level and those on fluconazole 200 mg/day had|
04118|049|D|a 3.1-fold increase in tacrolimus troughs.  Acute renal dysfunction was seen|
04118|050|D|in three patients and acute mental status changes were seen in two subjects.|
04118|051|D|Another study found a 16% increase in tacrolimus levels with concurrent|
04118|052|D|fluconazole.  In a case report of a patient who is homozygous for a|
04118|053|D|loss-of-function allele for CYP3A5, fluconazole increased tacrolimus levels|
04118|054|D|by 9.13-fold and required an 87% reduction in tacrolimus dose.|
04118|055|D|   In a study in six subjects, the administration of ketoconazole ten hours|
04118|056|D|before tacrolimus did not significantly affect the clearance, volume of|
04118|057|D|distribution, or hepatic bioavailability of tacrolimus. However, there was|
04118|058|D|100% increase in oral bioavailability of tacrolimus when administered ten|
04118|059|D|hours after ketoconazole.|
04118|060|D|   In a study in six subjects, concurrent administration of ketoconazole|
04118|061|D|(200 mg) increased tacrolimus oral bioavailability by 114%.  Oral tacrolimus|
04118|062|D|clearance decreased by 65.6%. There was no significant effect on the|
04118|063|D|clearance of intravenous tacrolimus.|
04118|064|D|   In a retrospective study of lung transplant patients, those who had|
04118|065|D|itraconazole discontinued while on tacrolimus required a 76% increase in|
04118|066|D|dose to maintain therapeutic levels, (p < 0.0001).|
04118|067|D|   There have been several case reports of increased tacrolimus levels|
04118|068|D|during the concurrent administration of clotrimazole, itraconazole, and|
04118|069|D|ketoconazole.|
04118|070|B||
04118|071|R|REFERENCES:|
04118|072|B||
04118|073|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04118|074|R|  August, 2023.|1
04118|075|R|2.Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin|6
04118|076|R|  Pharmacokinet 1988 Jan;14(1):13-34.|6
04118|077|R|3.Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis|6
04118|078|R|  1990 Mar-Apr;12 Suppl 3:S327-33.|6
04118|079|R|4.Osowski CL, Dix SP, Lin LS, Mullins RE, Geller RB, Wingard JR. Evaluation|2
04118|080|R|  of the drug interaction between intravenous high-dose fluconazole and|2
04118|081|R|  cyclosporine or tacrolimus in bone marrow transplant patients.|2
04118|082|R|  Transplantation 1996 Apr 27;61(8):1268-72.|2
04118|083|R|5.Capone D, Gentile A, Imperatore P, Palmiero G, Basile V. Effects of|3
04118|084|R|  itraconazole on tacrolimus blood concentrations in a renal transplant|3
04118|085|R|  recipient. Ann Pharmacother 1999 Oct;33(10):1124-5.|3
04118|086|R|6.Billaud EM, Guillemain R, Tacco F, Chevalier P. Evidence for a|3
04118|087|R|  pharmacokinetic interaction between itraconazole and tacrolimus in organ|3
04118|088|R|  transplant patients. Br J Clin Pharmacol 1998 Sep;46(3):271-2.|3
04118|089|R|7.Furlan V, Parquin F, Penaud JF, Cerrina J, Ladurie FL, Dartevelle P,|3
04118|090|R|  Taburet AM. Interaction between tacrolimus and itraconazole in a|3
04118|091|R|  heart-lung transplant recipient. Transplant Proc 1998 Feb;30(1):187-8.|3
04118|092|R|8.Kramer MR, Merin G, Rudis E, Bar I, Nesher T, Bublil M, Milgalter E. Dose|3
04118|093|R|  adjustment and cost of itraconazole prophylaxis in lung transplant|3
04118|094|R|  recipients receiving cyclosporine and tacrolimus (FK 506). Transplant Proc|3
04118|095|R|  1997 Sep;29(6):2657-9.|3
04118|096|R|9.Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C, Gritsch|3
04118|097|R|  A, McCauley J, Starzl T, Demetris AJ, Randhawa PS. Clinical features of|3
04118|098|R|  acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant|3
04118|099|R|  recipients. Clin Transplant 1997 Jun;11(3):237-42.|3
04118|100|R|10.Floren LC, Bekersky I, Benet LZ, Mekki Q, Dressler D, Lee JW, Roberts JP,|2
04118|101|R|   Hebert MF. Tacrolimus oral bioavailability doubles with coadministration|2
04118|102|R|   of ketoconazole. Clin Pharmacol Ther 1997 Jul;62(1):41-9.|2
04118|103|R|11.Assan R, Fredj G, Larger E, Feutren G, Bismuth H. FK 506/fluconazole|3
04118|104|R|   interaction enhances FK 506 nephrotoxicity. Diabete Metab 1994 Jan-Feb;|3
04118|105|R|   20(1):49-52.|3
04118|106|R|12.Mieles L, Venkataramanan R, Yokoyama I, Warty VJ, Starzl TE. Interaction|3
04118|107|R|   between FK506 and clotrimazole in a liver transplant recipient.|3
04118|108|R|   Transplantation 1991 Dec;52(6):1086-7.|3
04118|109|R|13.Viesselmann CW, Descourouez JL, Jorgenson MR, Radke NA, Odorico JS.|2
04118|110|R|   Clinically Significant Drug Interaction Between Clotrimazole and|2
04118|111|R|   Tacrolimus in Pancreas Transplant Recipients and Associated Risk of|2
04118|112|R|   Allograft Rejection. Pharmacotherapy 2016 Mar;36(3):335-41.|2
04118|113|R|14.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
04118|114|R|   Products, L.P. February, 2024.|1
04118|115|R|15.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
04118|116|R|   immunosuppressants-Guidelines from the American Society of|6
04118|117|R|   Transplantation Infectious Diseases Community of Practice. Clin|6
04118|118|R|   Transplant 2019 Feb 28;e13510.|6
04118|119|R|16.He J, Yu Y, Yin C, Liu H, Zou H, Ma J, Yang W, Liu Y, Zhong L, Chen X.|3
04118|120|R|   Clinically significant drug-drug interaction between tacrolimus and|3
04118|121|R|   fluconazole in stable renal transplant recipient and literature review. J|3
04118|122|R|   Clin Pharm Ther 2020 Apr;45(2):264-269.|3
04118|123|R|17.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
04118|124|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
04118|125|R|   hospital settings: a scientific statement from the American Heart|6
04118|126|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
04118|127|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
04119|001|T|MONOGRAPH TITLE:  Tacrolimus/Selected Macrolides|
04119|002|B||
04119|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04119|004|L|of severe adverse interaction.|
04119|005|B||
04119|006|A|MECHANISM OF ACTION:  Macrolide antibiotics may inhibit the metabolism of|
04119|007|A|tacrolimus by CYP3A4.|
04119|008|B||
04119|009|E|CLINICAL EFFECTS:  The concurrent administration of tacrolimus with a|
04119|010|E|macrolide that inhibits CYP3A4 may result in elevated levels of tacrolimus|
04119|011|E|and possible toxicity, including QT prolongation, nephrotoxicity,|
04119|012|E|neurotoxicity, cardiovascular toxicity, hypertension, anemia, and increased|
04119|013|E|risk of serious infections.|
04119|014|E|   The levels of the macrolide may also be elevated and result in toxicity.|
04119|015|B||
04119|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04119|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04119|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04119|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04119|020|P|female gender, or advanced age.|
04119|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04119|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04119|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04119|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04119|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04119|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04119|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).|
04119|028|B||
04119|029|M|PATIENT MANAGEMENT:  Tacrolimus levels should be carefully monitored in|
04119|030|M|patients receiving concurrent therapy with macrolide antibiotics.  The|
04119|031|M|dosage of tacrolimus may need to be adjusted during and/or after macrolide|
04119|032|M|therapy or the macrolide may need to be discontinued.  The dosage of the|
04119|033|M|macrolide antibiotic may need to be adjusted.|
04119|034|M|   Guidelines from the American Society of Transplantation state that the|
04119|035|M|use of clarithromycin or erythromycin with tacrolimus should be avoided.  If|
04119|036|M|the combination must be used, lower the dose of the immunosuppressant by up|
04119|037|M|to 50 % upon initiation of the antibiotic and monitor levels daily with|
04119|038|M|tacrolimus.|
04119|039|M|   The US manufacturer of tacrolimus states that coadministration with a|
04119|040|M|strong CYP3A4 inhibitor may result in a rapid and sharp rise in tacrolimus|
04119|041|M|concentration despite immediate tacrolimus dose reduction.  Frequent|
04119|042|M|monitoring of tacrolimus levels should start within 1-3 days of initiation|
04119|043|M|of concurrent therapy and continue as necessary.|
04119|044|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04119|045|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04119|046|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04119|047|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04119|048|B||
04119|049|D|DISCUSSION:  In a study of 6 normal volunteers, a significant increase in|
04119|050|D|tacrolimus oral bioavailability (14% versus 30%) was observed with|
04119|051|D|concomitant ketoconazole, another inhibitor of CYP3A4, administration (200|
04119|052|D|mg).  The apparent oral clearance of tacrolimus during ketoconazole|
04119|053|D|administration was significantly decreased compared to tacrolimus alone|
04119|054|D|(0.430 L/hr/kg versus 0.148 L/hr/kg).  Overall, IV clearance of tacrolimus|
04119|055|D|was not significantly changed by ketoconazole coadministration, although it|
04119|056|D|was highly variable between patients.|
04119|057|D|   Several case reports have documented elevated tacrolimus levels and a|
04119|058|D|decrease in renal function following the addition of erythromycin to|
04119|059|D|tacrolimus therapy.|
04119|060|D|   There have been two reports of elevated tacrolimus levels and decreased|
04119|061|D|renal function following the addition of clarithromycin to tacrolimus|
04119|062|D|therapy.|
04119|063|D|   In vitro studies have shown that the metabolism of tacrolimus is|
04119|064|D|inhibited by erythromycin, josamycin, and troleandomycin.|
04119|065|D|   Azithromycin, a weak CYP3A4 inhibitor, and spiramycin, which does not|
04119|066|D|inhibit the CYP P-450 system, would not be expected to interact with|
04119|067|D|tacrolimus.|
04119|068|B||
04119|069|R|REFERENCES:|
04119|070|B||
04119|071|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04119|072|R|  August, 2023.|1
04119|073|R|2.Padhi ID, Long P, Basha M, Anandan JV. Interaction between tacrolimus and|3
04119|074|R|  erythromycin. Ther Drug Monit 1997 Feb;19(1):120-2.|3
04119|075|R|3.Jensen C, Jordan M, Shapiro R, Scantlebury V, Hakala T, Fung J, Starzl T,|3
04119|076|R|  Venkataramanan R. Interaction between tacrolimus and erythromycin. Lancet|3
04119|077|R|  1994 Sep 17;344(8925):825.|3
04119|078|R|4.Shaeffer MS, Collier D, Sorrell MF. Interaction between FK506 and|3
04119|079|R|  erythromycin. Ann Pharmacother 1994 Feb;28(2):280-1.|3
04119|080|R|5.Furlan V, Perello L, Jacquemin E, Debray D, Taburet AM. Interactions|3
04119|081|R|  between FK506 and rifampicin or erythromycin in pediatric liver|3
04119|082|R|  recipients. Transplantation 1995 Apr 27;59(8):1217-8.|3
04119|083|R|6.Wolter K, Wagner K, Philipp T, Fritschka E. Interaction between FK 506 and|3
04119|084|R|  clarithromycin in a renal transplant patient. Eur J Clin Pharmacol 1994;|3
04119|085|R|  47(2):207-8.|3
04119|086|R|7.Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C, Gritsch|3
04119|087|R|  A, McCauley J, Starzl T, Demetris AJ, Randhawa PS. Clinical features of|3
04119|088|R|  acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant|3
04119|089|R|  recipients. Clin Transplant 1997 Jun;11(3):237-42.|3
04119|090|R|8.Christians U, Schmidt G, Bader A, Lampen A, Schottmann R, Linck A, Sewing|5
04119|091|R|  KF. Identification of drugs inhibiting the in vitro metabolism of|5
04119|092|R|  tacrolimus by human liver microsomes. Br J Clin Pharmacol 1996 Mar;|5
04119|093|R|  41(3):187-90.|5
04119|094|R|9.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
04119|095|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
04119|096|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
04119|097|R|  e13510.|6
04119|098|R|10.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V,|6
04119|099|R|   Philippides GJ, Roden DM, Zareba W. Prevention of torsade de pointes in|6
04119|100|R|   hospital settings: a scientific statement from the American Heart|6
04119|101|R|   Association and the American College of Cardiology Foundation. J Am Coll|6
04119|102|R|   Cardiol 2010 Mar 2;55(9):934-47.|6
04120|001|T|MONOGRAPH TITLE:  Tacrolimus/Posaconazole; Voriconazole|
04120|002|B||
04120|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04120|004|L|of severe adverse interaction.|
04120|005|B||
04120|006|A|MECHANISM OF ACTION:  The metabolism of tacrolimus by CYP3A4 may be|
04120|007|A|inhibited by posaconazole and voriconazole.(1-4)|
04120|008|B||
04120|009|E|CLINICAL EFFECTS:  Concurrent administration of posaconazole or voriconazole|
04120|010|E|may result in elevated levels of and toxicity from tacrolimus, including QT|
04120|011|E|prolongation, nephrotoxicity, neurotoxicity, cardiovascular toxicity,|
04120|012|E|hypertension, anemia, and increased risk of serious infections.(1-4)|
04120|013|B||
04120|014|P|PREDISPOSING FACTORS:  Concurrent use of voriconazole in patients who are|
04120|015|P|poor or intermediate CYP2C19 metabolizers may necessitate larger|
04120|016|P|immunosuppressant dose adjustments than in patients who are extensive|
04120|017|P|CYP2C19 metabolizers.(5)|
04120|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04120|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04120|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04120|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04120|022|P|advanced age.(6)|
04120|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04120|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04120|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04120|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04120|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04120|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04120|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)|
04120|030|B||
04120|031|M|PATIENT MANAGEMENT:  Tacrolimus levels and renal function should be|
04120|032|M|monitored if posaconazole or voriconazole is initiated or discontinued from|
04120|033|M|concurrent therapy.  The dosage of tacrolimus may need to be adjusted.(1-4)|
04120|034|M|Posaconazole tablets have improved bioavailability and higher concentrations|
04120|035|M|per dose than posaconazole suspension.  A greater dose reduction of the|
04120|036|M|immunosuppressant may be necessary when posaconazole tablets are used.(7-9)|
04120|037|M|   The manufacturers of posaconazole(1,2), tacrolimus(4), and|
04120|038|M|voriconazole(3) recommend that the dose of tacrolimus be reduced to about|
04120|039|M|one-third its original dose when posaconazole or voriconazole is initiated.|
04120|040|M|A rapid and sharp rise in tacrolimus concentration may occur despite|
04120|041|M|immediate tacrolimus dose reduction.  Frequent monitoring of tacrolimus|
04120|042|M|levels should start within 1-3 days of initiation of concurrent therapy and|
04120|043|M|continue as necessary during and after azole therapy.(4)  The dosage of|
04120|044|M|tacrolimus may need to be adjusted following azole therapy.|
04120|045|B||
04120|046|D|DISCUSSION:  One study looked at the effects of posaconazole on the|
04120|047|D|metabolism of tacrolimus when both medications were administered|
04120|048|D|concurrently in healthy individuals.  The coadministration resulted in an|
04120|049|D|increase in both the AUC and the maximum concentration (Cmax) of tacrolimus|
04120|050|D|by 358% and 121%, respectively, as well as an increase in the elimination|
04120|051|D|half-life and a decrease in total body clearance.  The changes in the|
04120|052|D|pharmacokinetics of the drug led to an increased incidence of adverse|
04120|053|D|reactions associated with the elevated levels of tacrolimus.  The occurrence|
04120|054|D|of adverse reactions was 83% for patients taking the combination compared to|
04120|055|D|39% and 67% for patients taking either tacrolimus or posaconazole alone,|
04120|056|D|respectively.  In efficacy studies, clinically significant interactions|
04120|057|D|resulting in hospitalization and/or posaconazole discontinuation were|
04120|058|D|reported.|
04120|059|D|   Three studies have compared the effects of posaconazole tablets versus|
04120|060|D|posaconazole suspension on the dose-normalized concentration of tacrolimus|
04120|061|D|(C/D ratio). The C/D ratio with posaconazole tablets was 1.6 to 2 times|
04120|062|D|higher than the C/D ratio with posaconazole suspension.(7-9)  In one study,|
04120|063|D|the daily dose of tacrolimus required to achieve therapeutic concentration|
04120|064|D|was 1.08 mg with posaconazole tablets and 2.32 mg with posaconazole|
04120|065|D|suspension (p<0.0001).(8)|
04120|066|D|   In healthy subjects, voriconazole (400 mg every 12 hours Day 1, 200 mg|
04120|067|D|every 12 hours Days 2-7) increased tacrolimus (0.1 mg/kg single dose) Cmax|
04120|068|D|and AUC by 2-fold and 3-fold, respectively.|
04120|069|D|   In a retrospective study of lung transplant patients, those who had|
04120|070|D|voriconazole discontinued while on tacrolimus required a 64% increase in|
04120|071|D|dose to maintain therapeutic levels, (p = 0.002).  Patients who had|
04120|072|D|itraconazole discontinued while on tacrolimus required a 76% increase in|
04120|073|D|dose to maintain therapeutic levels, (p < 0.0001).|
04120|074|D|   In a trial involving bone marrow transplant patients, those who were|
04120|075|D|given voriconazole while on a stable dose of tacrolimus had their median|
04120|076|D|concentration/dose (C/D) ratio of tacrolimus increase by as much as 116%, (p|
04120|077|D|< 0.001).|
04120|078|D|   There have been several case reports of increased tacrolimus levels|
04120|079|D|during the concurrent administration of clotrimazole, itraconazole,|
04120|080|D|ketoconazole, and voriconazole.|
04120|081|B||
04120|082|R|REFERENCES:|
04120|083|B||
04120|084|R|1.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
04120|085|R|  January, 2022.|1
04120|086|R|2.Noxafil (posaconazole) UK summary of product characteristics.|1
04120|087|R|  Schering-Plough Ltd. January, 2022.|1
04120|088|R|3.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
04120|089|R|4.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04120|090|R|  August, 2023.|1
04120|091|R|5.Huang X, Zhou Y, Zhang J, Xiang H, Mei H, Liu L, Tong L, Zeng F, Huang Y,|2
04120|092|R|  Zhou H, Zhang Y. The importance of CYP2C19 genotype in tacrolimus dose|2
04120|093|R|  optimization when  concomitant with voriconazole in heart transplant|2
04120|094|R|  recipients. Br J Clin Pharmacol 2022 May 4.|2
04120|095|R|6.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04120|096|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04120|097|R|  settings: a scientific statement from the American Heart Association and|6
04120|098|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04120|099|R|  2;55(9):934-47.|6
04120|100|R|7.Stelzer D, Weber A, Ihle F, Matthes S, Ceelen F, Zimmermann G, Kneidinger|2
04120|101|R|  N, Schramm R, Winter H, Zoller M, Vogeser M, Behr J, Neurohr C.|2
04120|102|R|  Posaconazole liquid vs tablet formulation in lung transplant recipients.|2
04120|103|R|  Mycoses 2018 Mar;61(3):186-194.|2
04120|104|R|8.Chanoine S, Gautier-Veyret E, Pluchart H, Tonini J, Fonrose X, Claustre J,|2
04120|105|R|  Bedouch P, Stanke-Labesque F. Tablets or oral suspension for posaconazole|2
04120|106|R|  in lung transplant recipients?  Consequences for trough concentrations of|2
04120|107|R|  tacrolimus and everolimus. Br J Clin Pharmacol 2020 May 29.|2
04120|108|R|9.Launay M, Roux A, Beaumont L, Douvry B, Lecuyer L, Douez E, Picard C,|2
04120|109|R|  Grenet D, Jullien V, Boussaud V, Guillemain R, Billaud EM. Posaconazole|2
04120|110|R|  Tablets in Real-Life Lung Transplantation: Impact on Exposure,  Drug-Drug|2
04120|111|R|  Interactions, and Drug Management in Lung Transplant Patients, Including|2
04120|112|R|  Those with Cystic Fibrosis. Antimicrob Agents Chemother 2018 Mar;62(3):.|2
04120|113|R|10.Sansone-Parsons A, Krishna G, Martinho M, Kantesaria B, Gelone S, Mant|2
04120|114|R|   TG. Effect of oral posaconazole on the pharmacokinetics of cyclosporine|2
04120|115|R|   and tacrolimus. Pharmacotherapy 2007 Jun;27(6):825-34.|2
04120|116|R|11.Romero AJ, Pogamp PL, Nilsson LG, Wood N. Effect of voriconazole on the|2
04120|117|R|   pharmacokinetics of cyclosporine in renal transplant patients. Clin|2
04120|118|R|   Pharmacol Ther 2002 Apr;71(4):226-34.|2
04120|119|R|12.Sadaba B, Campanero MA, Quetglas EG, Azanza JR. Clinical relevance of|3
04120|120|R|   sirolimus drug interactions in transplant patients. Transplant Proc 2004|3
04120|121|R|   Dec;36(10):3226-8.|3
04120|122|R|13.Capone D, Tarantino G, Gentile A, Sabbatini M, Polichetti G, Santangelo|3
04120|123|R|   M, Nappi R, Ciotola A, D'Alessandro V, Renda A, Basile V, Federico S.|3
04120|124|R|   Effects of voriconazole on tacrolimus metabolism in a kidney transplant|3
04120|125|R|   recipient. J Clin Pharm Ther 2010 Feb;35(1):121-4.|3
04120|126|R|14.Kramer MR, Amital A, Fuks L, Shitrit D. Voriconazole and itraconazole in|2
04120|127|R|   lung transplant recipients receiving tacrolimus (FK 506): efficacy and|2
04120|128|R|   drug interaction. Clin Transplant 2010 Dec 16.|2
04120|129|R|15.Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S. Drug interaction|2
04120|130|R|   between voriconazole and calcineurin inhibitors in allogeneic|2
04120|131|R|   hematopoietic stem cell transplant recipients. Bone Marrow Transplant|2
04120|132|R|   2009 Sep;44(6):371-4.|2
04121|001|T|MONOGRAPH TITLE:  Tacrolimus/Pazopanib|
04121|002|B||
04121|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04121|004|L|of severe adverse interaction.|
04121|005|B||
04121|006|A|MECHANISM OF ACTION:  Inhibitors of P-gp or BCRP may result in increased|
04121|007|A|absorption and higher levels of pazopanib.(1)  Tacrolimus is a P-gp|
04121|008|A|inhibitor.|
04121|009|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus.(2)|
04121|010|A|Pazopanib is a weak CYP3A4 inhibitor.|
04121|011|A|   In addition, concurrent use of pazopanib and tacrolimus may result in|
04121|012|A|additive or synergistic effects on the QTc interval.(1,2)|
04121|013|B||
04121|014|E|CLINICAL EFFECTS:  Concurrent use of pazopanib and tacrolimus may result in|
04121|015|E|elevated levels of and toxicity from both pazopanib and tacrolimus.(1,2)|
04121|016|E|   In addition, concurrent administration of pazopanib and tacrolimus may|
04121|017|E|result in additive prolongation of the QTc interval and life-threatening|
04121|018|E|cardiac arrhythmias, including torsades de pointes.|
04121|019|B||
04121|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04121|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04121|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04121|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04121|024|P|gender, or advanced age.(3)|
04121|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04121|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04121|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04121|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04121|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04121|030|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04121|031|P|dysfunction).(3)|
04121|032|B||
04121|033|M|PATIENT MANAGEMENT:  The US manufacturer of pazopanib states concurrent use|
04121|034|M|of strong P-gp or BCRP inhibitors should be avoided.  Use caution when|
04121|035|M|pazopanib is coadministered with other drugs known to prolong the QTc|
04121|036|M|interval.(1)|
04121|037|M|   The US manufacturer of tacrolimus recommends frequently monitoring|
04121|038|M|tacrolimus whole blood trough concentrations and reducing tacrolimus dose if|
04121|039|M|needed.(2)|
04121|040|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
04121|041|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04121|042|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04121|043|M|heartbeat, dizziness, or fainting.|
04121|044|B||
04121|045|D|DISCUSSION:  Administration of 1,500 mg lapatinib, a substrate and weak|
04121|046|D|inhibitor of CYP3A4, P-gp, and BCRP, with 800 mg pazopanib resulted in an|
04121|047|D|approximately 50% to 60% increase in mean pazopanib area-under-curve (AUC)|
04121|048|D|and maximum concentration (Cmax) compared with administration of 800 mg|
04121|049|D|pazopanib alone.(1)|
04121|050|D|   In clinical studies, 2% (11/558) of patients receiving pazopanib|
04121|051|D|experienced QT prolongation.  Torsades de pointes occurred in less than 1%|
04121|052|D|(2/977) of patients who received pazopanib in monotherapy studies.  In a|
04121|053|D|randomized clinical trial, 3 of 290 patients who received pazopanib had|
04121|054|D|post-baseline QTc values between 500 and  549 msec.  None of the patients|
04121|055|D|receiving placebo had post-baseline QTc values greater than or equal to 500|
04121|056|D|msec.(1)|
04121|057|D|   The coadministration of amiodarone and tacrolimus was described in a case|
04121|058|D|report of a 73-year-old kidney transplant recipient with normal renal|
04121|059|D|function who was on amiodarone for years.  Tacrolimus 7 mg per day was|
04121|060|D|started and after 3 months, the patient was found to have a tacrolimus level|
04121|061|D|of 63 ng/mL.  The dose of tacrolimus was lowered to 2 mg per day, and|
04121|062|D|tacrolimus levels dropped to 12.9 ng/mL.(4)|
04121|063|D|   In another case report, a 65-year-old man on amiodarone for 5 years|
04121|064|D|started tacrolimus 3 mg twice daily status-post renal transplant.  After one|
04121|065|D|day, QTc was prolonged from a baseline of 440 ms to 535 ms.  QTc dropped to|
04121|066|D|493 ms three days after discontinuation of amiodarone and dose reduction of|
04121|067|D|tacrolimus.(5)|
04121|068|D|   A case report describes the interaction between azithromycin and|
04121|069|D|tacrolimus in a 27-year old woman with acute myelogenous leukemia who had a|
04121|070|D|bone marrow transplant.  On tacrolimus 0.02 mg/kg/day IV, the patient had|
04121|071|D|stable tacrolimus levels of 15.8 to 17.5 ng/mL.  Three days after initiation|
04121|072|D|of azithromycin 500 mg daily, tacrolimus levels rose to over 30 ng/mL.(6)|
04121|073|D|   In a case report, a 64-year-old kidney transplant recipient on a stable|
04121|074|D|dose of tacrolimus 10 mg twice daily for 5 months was started on ranolazine|
04121|075|D|500 mg twice daily for angina.  Tacrolimus levels rose from the patient's|
04121|076|D|stable levels of 7 to 10 ng/mL in the previous 5 months to 17.8 ng/mL after|
04121|077|D|1 day.(7)|
04121|078|D|   Another case report describes a 54-year-old kidney transplant recipient|
04121|079|D|on tacrolimus 3 mg twice daily with trough levels of 4.5 to 7.4 ng/mL for|
04121|080|D|the previous 4 years.  After he was started on ranolazine 375 mg twice|
04121|081|D|daily, tacrolimus levels rose to 10.9 ng/mL and serum creatinine (Scr) rose|
04121|082|D|from 1.2 to 2 mg/dL.  Ranolazine was discontinued after one month, and|
04121|083|D|tacrolimus levels dropped to 3.6 ng/mL, with complete reversal of renal|
04121|084|D|failure.(8)|
04121|085|D|   A 62-year-old kidney transplant recipient on a stable dose of tacrolimus|
04121|086|D|for years was started on ranolazine and titrated to 1,000 mg twice daily|
04121|087|D|over one month.  After 2 weeks, he experienced renal failure with Scr rising|
04121|088|D|from 1.5 to 2.4 mg/dL, and tacrolimus level was elevated at 14 ng/mL.|
04121|089|D|Ranolazine was discontinued and tacrolimus levels decreased to 7 ng/mL after|
04121|090|D|3 days, with Scr returning to baseline.(9)|
04121|091|B||
04121|092|R|REFERENCES:|
04121|093|B||
04121|094|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
04121|095|R|  2020.|1
04121|096|R|2.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04121|097|R|  August, 2023.|1
04121|098|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04121|099|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04121|100|R|  settings: a scientific statement from the American Heart Association and|6
04121|101|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04121|102|R|  2;55(9):934-47.|6
04121|103|R|4.Kisters K, Cziborra M, Funke C, Brylak S, Hausberg M.|3
04121|104|R|  Amiodarone-tacrolimus interaction in kidney transplantation. Clin Nephrol|3
04121|105|R|  2008 Dec;70(6):563.|3
04121|106|R|5.Burger CI, Clase CM, Gangji AS. Case report: drug interaction between|3
04121|107|R|  tacrolimus and amiodarone with QT prolongation. Transplantation 2010 May|3
04121|108|R|  15;89(9):1166-7.|3
04121|109|R|6.Mori T, Aisa Y, Nakazato T, Yamazaki R, Ikeda Y, Okamoto S.|3
04121|110|R|  Tacrolimus-azithromycin interaction in a recipient of allogeneic bone|3
04121|111|R|  marrow transplantation. Transpl Int 2005 Jun;18(6):757-8.|3
04121|112|R|7.Pierce Dwayne A, Reeves-Daniel Amber M. Ranolazine-tacrolimus interaction.|3
04121|113|R|  Ann Pharmacother 2010 Nov;44(11):1844-1849.|3
04121|114|R|8.Seck Sidy, Bellantoni Marianna, Zoccali Carmine, Enia Giuseppe. Ranolazine|3
04121|115|R|  can markedly increase tacrolimus blood levels. NDT Plus 2011 Feb;|3
04121|116|R|  4(1):44-45.|3
04121|117|R|9.Patni Hitesh, Gitman Michael, Hazzan Azzour, Jhaveri Kenar D. Ranolazine,|3
04121|118|R|  tacrolimus, and diltiazem might be a hazardous combination in a transplant|3
04121|119|R|  patient. Ren Fail 2012 Jan;34(2):251-253.|3
04121|120|R|10.This information is based on an extract from the Certara Drug Interaction|6
04121|121|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04122|001|T|MONOGRAPH TITLE:  Tacrolimus/Moderate and Weak CYP3A4 Inducers that Prolong|
04122|002|T|QT|
04122|003|B||
04122|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04122|005|L|take action as needed.|
04122|006|B||
04122|007|A|MECHANISM OF ACTION:  Moderate or weak CYP3A4 inducers may accelerate the|
04122|008|A|metabolism of tacrolimus.(1)|
04122|009|A|   In addition, concurrent use of tacrolimus and other agents that prolong|
04122|010|A|the QT interval may result in additive or synergistic effects on the QTc|
04122|011|A|interval.(1)|
04122|012|B||
04122|013|E|CLINICAL EFFECTS:  Concurrent use of a moderate or weak CYP3A4 inducer may|
04122|014|E|result in decreased levels and effectiveness of tacrolimus.(1)|
04122|015|E|   In addition, concurrent administration of QT prolonging agents and|
04122|016|E|tacrolimus may result in additive prolongation of the QTc interval and|
04122|017|E|life-threatening cardiac arrhythmias, including torsades de pointes.|
04122|018|B||
04122|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04122|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04122|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04122|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04122|023|P|gender, or advanced age.(2)|
04122|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04122|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04122|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04122|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04122|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04122|029|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04122|030|P|dysfunction).(2)|
04122|031|P|   Induction effects may be more likely with regular use of the inducer for|
04122|032|P|longer than 1-2 weeks.|
04122|033|B||
04122|034|M|PATIENT MANAGEMENT:  The manufacturer of tacrolimus recommends monitoring|
04122|035|M|tacrolimus whole blood trough concentrations and adjusting tacrolimus dose|
04122|036|M|if needed.  Monitor clinical response closely.(1)|
04122|037|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
04122|038|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04122|039|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04122|040|M|heartbeat, dizziness, or fainting.|
04122|041|B||
04122|042|D|DISCUSSION:  A 13-year-old cystic fibrosis patient with a history of liver|
04122|043|D|transplant on stable doses of tacrolimus underwent 2 separate courses of|
04122|044|D|nafcillin therapy (a moderate CYP3A4 inducer).  During the 1st course of|
04122|045|D|nafcillin, his tacrolimus levels started to fall 3 days after starting|
04122|046|D|nafcillin, became undetectable at day 8, and recovered to therapeutic levels|
04122|047|D|without a change in tacrolimus dose 5 days after discontinuation of|
04122|048|D|nafcillin.  During the 2nd course of nafcillin, tacrolimus level became|
04122|049|D|undetectable 4 days after starting nafcillin and recovered 3 days after|
04122|050|D|stopping nafcillin.(3)|
04122|051|D|   Tacrolimus has been associated with QT prolongation.(1)|
04122|052|D|   In a kidney transplant population, 98 patients received immunosuppressive|
04122|053|D|management with tacrolimus, cyclosporine, everolimus, or azathioprine.  All|
04122|054|D|patients post-transplant had significantly prolonged QTc interval compared|
04122|055|D|to pre-transplant in all groups.(4)|
04122|056|D|   Agents that are linked to this monograph may have varying degrees of|
04122|057|D|potential to prolong the QTc interval but are generally accepted to have a|
04122|058|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04122|059|D|been shown to prolong the QTc interval either through their mechanism of|
04122|060|D|action, through studies on their effects on the QTc interval, or through|
04122|061|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04122|062|D|and/or post-marketing reports.(5)|
04122|063|D|   Moderate inducers of CYP3A4 that prolong QT include: efavirenz,|
04122|064|D|pacritinib, and thioridazine.(6,7)|
04122|065|D|   Weak inducers of CYP3A4 that prolong QT include: pitolisant and|
04122|066|D|vemurafenib.(6,7)|
04122|067|B||
04122|068|R|REFERENCES:|
04122|069|B||
04122|070|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04122|071|R|  August, 2023.|1
04122|072|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04122|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04122|074|R|  settings: a scientific statement from the American Heart Association and|6
04122|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04122|076|R|  2;55(9):934-47.|6
04122|077|R|3.Wungwattana M, Savic M. Tacrolimus interaction with nafcillin resulting in|3
04122|078|R|  significant decreases in  tacrolimus concentrations: A case report.|3
04122|079|R|  Transpl Infect Dis 2017 Apr;19(2):.|3
04122|080|R|4.Ikitimur B, Cosansu K, Karadag B, Cakmak HA, Avci BK, Erturk E, Seyahi N,|2
04122|081|R|  Ongen Z. Long-Term Impact of Different Immunosuppressive Drugs on QT and|2
04122|082|R|  PR Intervals in  Renal Transplant Patients. Ann Noninvasive Electrocardiol|2
04122|083|R|  2015 Sep;20(5):426-32.|2
04122|084|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04122|085|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04122|086|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04122|087|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04122|088|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04122|089|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04122|090|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04122|091|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04122|092|R|  11/14/2017.|1
04122|093|R|7.This information is based on an extract from the Certara Drug Interaction|6
04122|094|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04123|001|T|MONOGRAPH TITLE:  Slt Immunosuppressants;Temsirolimus/Nirmatrelvir-Ritonavir|
04123|002|B||
04123|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04123|004|L|is contraindicated and generally should not be dispensed or administered to|
04123|005|L|the same patient.|
04123|006|B||
04123|007|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the metabolism of|
04123|008|A|cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus by|
04123|009|A|CYP3A4.(1-7)|
04123|010|B||
04123|011|E|CLINICAL EFFECTS:  Concurrent use of nirmatrelvir-ritonavir may result in|
04123|012|E|increased levels of and risk of toxicity from cyclosporine, everolimus,|
04123|013|E|sirolimus, tacrolimus, or temsirolimus.(1-7)|
04123|014|B||
04123|015|P|PREDISPOSING FACTORS:  None determined.|
04123|016|B||
04123|017|M|PATIENT MANAGEMENT:  The American Society of Transplantation (AST) Statement|
04123|018|M|on Oral Antiviral Therapy for COVID-19 for Organ Transplant Recipients|
04123|019|M|states use of nirmatrelvir-ritonavir will be challenging in transplant|
04123|020|M|patients due to significant drug interactions and difficulty with|
04123|021|M|therapeutic drug monitoring in outpatients with active Covid-19 infections.|
04123|022|M|Alternatives such as early use of either an appropriate monoclonal antibody|
04123|023|M|or outpatient intravenous remdesivir may be preferred as first line therapy|
04123|024|M|in transplant patients to prevent progression.(8)|
04123|025|M|   The US manufacturer of nirmatrelvir-ritonavir states concurrent use with|
04123|026|M|immunosuppressants should not be used if close monitoring is not|
04123|027|M|feasible.(6)|
04123|028|M|   Specific immunosuppressant recommendations:|
04123|029|M|   -Cyclosporine: For therapy with nirmatrelvir-ritonavir in patients on|
04123|030|M|cyclosporine, some experts recommend lowering the cyclosporine dose by 80%.|
04123|031|M|   -Tacrolimus: For therapy with nirmatrelvir-ritonavir in patients on|
04123|032|M|tacrolimus, experts recommend holding tacrolimus for the 5-day duration of|
04123|033|M|nirmatrelvir-ritonavir therapy.  Tacrolimus level is recommended on day 3 to|
04123|034|M|assess the need for a one-time dose of tacrolimus during|
04123|035|M|nirmatrelvir-ritonavir therapy.|
04123|036|M|   -As soon as possible after nirmatrelvir-ritonavir therapy, cyclosporine|
04123|037|M|or tacrolimus levels should be checked, and every 2-4 days thereafter until|
04123|038|M|stable, to determine when to increase cyclosporine doses or resume|
04123|039|M|tacrolimus.(7)|
04123|040|M|   -Everolimus: For therapy with nirmatrelvir-ritonavir in patients on|
04123|041|M|everolimus, AST states CYP3A4 inhibitors, such as clarithromycin,|
04123|042|M|ketoconazole, voriconazole, and HIV protease inhibitors, are contraindicated|
04123|043|M|with everolimus. The US manufacturer of everolimus states concurrent use|
04123|044|M|should be avoided with strong CYP3A4 inhibitors.|
04123|045|M|   -Sirolimus: The US manufacturer of nirmatrelvir-ritonavir(6) and|
04123|046|M|sirolimus protein-bound injection (Fyarro)(9) state concurrent use should be|
04123|047|M|avoided.|
04123|048|M|   -Temsirolimus: The US manufacturer of temsirolimus recommends that|
04123|049|M|concurrent therapy with strong CYP3A4 inhibitors such as|
04123|050|M|nirmatrelvir-ritonavir be avoided. If concurrent use is warranted, a dosage|
04123|051|M|reduction to 12.5 mg/week of temsirolimus should be considered.  If|
04123|052|M|nirmatrelvir-ritonavir is discontinued, a washout period of 1 week should be|
04123|053|M|allowed before adjusting the dosage of temsirolimus to previous levels.(2)|
04123|054|M|   For patients concurrently taking cyclosporine, everolimus, sirolimus,|
04123|055|M|tacrolimus, or temsirolimus with nirmatrelvir, therapeutic concentration|
04123|056|M|monitoring of the immunosuppressant is recommended.|
04123|057|B||
04123|058|D|DISCUSSION:  A retrospective study evaluated the interaction between|
04123|059|D|cyclosporine or tacrolimus and nirmatrelvir/ritonavir in 25 solid-organ|
04123|060|D|transplant recipients.  Upon nirmatrelvir/ritonavir initiation, cyclosporine|
04123|061|D|doses were decreased by 80% and tacrolimus was held for the duration of|
04123|062|D|nirmatrelvir/ritonavir therapy.  No patients had acute rejection in the 30|
04123|063|D|days following nirmatrelvir/ritonavir.  In 21 patients on tacrolimus, the|
04123|064|D|median tacrolimus trough concentration before and after|
04123|065|D|nirmatrelvir/ritonavir therapy was 7.4 ng/mL (IQR, 6.6-8.6) and 5.2 ng/mL|
04123|066|D|(IQR, 3.6-8.7), respectively.  Four patients had supratherapeutic tacrolimus|
04123|067|D|troughs after restarting tacrolimus.  In these patients, tacrolimus was|
04123|068|D|resumed at either reduced dose or at pre-nirmatrelvir/ritonavir dose 2-5|
04123|069|D|days after completion of nirmatrelvir/ritonavir therapy.(5)|
04123|070|D|   Concurrent use of nirmatrelvir/ritonavir with tacrolimus resulted in|
04123|071|D|elevated tacrolimus levels, treatment interruption, and acute kidney|
04123|072|D|injury.(11)|
04123|073|D|   In a case series, 12 bilateral lung transplant recipients with COVID-19|
04123|074|D|were started on nirmatrelvir/ritonavir.  All patients were on|
04123|075|D|immediate-release tacrolimus and prednisone, and all except one were also on|
04123|076|D|mycophenolate.  Patients stopped tacrolimus 10-14 hours before starting|
04123|077|D|nirmatrelvir-ritonavir and had tacrolimus levels checked between days 3-5 of|
04123|078|D|therapy.  One patient required a supplemental 0.5 mg dose of tacrolimus|
04123|079|D|during nirmatrelvir-ritonavir therapy.  Six patients had trough levels|
04123|080|D|within goal, and 3 patients had troughs below goal but at adequate|
04123|081|D|immunosuppression level based on the clinicians' judgement.  Ten of the|
04123|082|D|patients resumed tacrolimus at 25% of their baseline dose at day 8, and 9 of|
04123|083|D|them resumed full dose tacrolimus by day 10.  One patient was hospitalized|
04123|084|D|for worsening COVID-19.  No patients experienced tacrolimus side effects or|
04123|085|D|acute rejection.(12)|
04123|086|D|   In a case series of 3 renal transplant recipients, tacrolimus was held 1|
04123|087|D|day before patients started nirmatrelvir-ritonavir therapy.  Two patients|
04123|088|D|resumed previous doses of tacrolimus one day after finishing|
04123|089|D|nirmatrelvir/ritonavir; one had stable tacrolimus levels and the other was|
04123|090|D|supratherapeutic.  The 3rd patient received a supplemental dose of|
04123|091|D|tacrolimus on day 4 of therapy and resumed his previous dose starting on day|
04123|092|D|5, and was supratherapeutic on day 6.  No patients experienced adverse|
04123|093|D|effects or graft rejection.  The authors state that nirmatrelvir/ritonavir|
04123|094|D|is not contraindicated and tacrolimus levels can be closely monitored for|
04123|095|D|patients on tacrolimus.(13)|
04123|096|D|   In a case report of a 67-year old patient on chronic tacrolimus therapy,|
04123|097|D|after 4 days of nirmatrelvir-ritonavir she presented to the emergency|
04123|098|D|department with slowed speech, fatigue, weakness, and loss of appetite.  The|
04123|099|D|patient's tacrolimus level was 176.4 ng/mL (normal range is 5-20 ng/mL).(14)|
04123|100|D|   In a case series of 4 renal transplant recipients, tacrolimus was paused|
04123|101|D|during nirmatrelvir-ritonavir therapy, which resulted in stable therapeutic|
04123|102|D|levels.  In one patient, tacrolimus was resumed immediately and resulted in|
04123|103|D|a toxic tacrolimus level.  In three patients, tacrolimus was resumed at a|
04123|104|D|reduced dose 24 hours after nirmatrelvir-ritonavir was stopped and resulted|
04123|105|D|in therapeutic to supratherapeutic tacrolimus levels.(15)|
04123|106|D|   In a case report of a 39-year-old female, the patient developed a sudden|
04123|107|D|increase in tacrolimus levels after starting nirmatrelvir-ritonavir.(16)|
04123|108|D|   In a PKPB model, tacrolimus clearance decreased to 35% and|
04123|109|D|bioavailability increased by 18.7-fold after the coadministration of|
04123|110|D|nirmatrelvir/ritonavir, compared with tacrolimus alone.(17)|
04123|111|D|   The selected immunosuppressants linked to this monograph include:|
04123|112|D|cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.|
04123|113|B||
04123|114|R|REFERENCES:|
04123|115|B||
04123|116|R|1.Sandimmune (cyclosporine) US prescribing information. Novartis|1
04123|117|R|  Pharmaceuticals Corporation September 2023.|1
04123|118|R|2.Afinitor (everolimus) US prescribing information. Novartaris|1
04123|119|R|  Pharmaceuticals Corporation February, 2020.|1
04123|120|R|3.Zortress (everolimus) US prescribing information. Novartis Pharmaceuticals|1
04123|121|R|  Corporation Sept, 2023.|1
04123|122|R|4.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
04123|123|R|  Inc. March, 2018.|1
04123|124|R|5.Prograf (tacrolimus) US prescribing information. Fujisawa Healthcare, Inc.|1
04123|125|R|  November, 2022.|1
04123|126|R|6.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04123|127|R|  information. Pfizer Inc. February, 2025.|1
04123|128|R|7.Lange NW, Salerno DM, Jennings DL, Choe J, Hedvat J, Kovac DB, Scheffert|6
04123|129|R|  J, Shertel T, Ratner LE, Brown RS Jr, Pereira MR. Nirmatrelvir/ritonavir|6
04123|130|R|  use: Managing clinically significant drug-drug interactions  with|6
04123|131|R|  transplant immunosuppressants. Am J Transplant 2022 Jan 11.|6
04123|132|R|8.DKumar AHumar MGIson DKaul EBlumberg NTheodoropoulos LDanziger-Isakov|6
04123|133|R|  MMichaels SAitken. AST Statement on Oral Antiviral Therapy for COVID-19|6
04123|134|R|  for Organ Transplant Recipients..|6
04123|135|R|9.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
04123|136|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
04123|137|R|10.Salerno DM, Jennings DL, Lange NW, Bley Kovac D, Shertel T, Chen JK,|2
04123|138|R|   Hedvat J, Scheffert J, Brown RS Jr, Pereira MR. Early clinical experience|2
04123|139|R|   with nirmatrelvir/ritonavir for treatment of COVID-19 in  solid organ|2
04123|140|R|   transplant recipients. Am J Transplant 2022 Mar 12.|2
04123|141|R|11.Prikis M, Cameron A. Paxlovid (Nirmatelvir/Ritonavir) and Tacrolimus|3
04123|142|R|   Drug-Drug Interaction in a Kidney  Transplant Patient with SARS-2-CoV|3
04123|143|R|   infection: A Case Report. Transplant Proc 2022 May 19.|3
04123|144|R|12.Guzman Cordero C, Saez-Torres de Vicente M. Management of|3
04123|145|R|   nirmatrelvir/ritonavir and tacrolimus interaction in kidney  transplant|3
04123|146|R|   recipients infected by COVID-19: a three-case series. Eur J Hosp Pharm|3
04123|147|R|   2022 Dec 19.|3
04123|148|R|13.Dewey KW, Yen B, Lazo J, Seijo L, Jariwala R, Shah RJ, Quan D, Carpenter|3
04123|149|R|   B, Paul Singer J, Breen K, Hays S, Florez R. Nirmatrelvir/ritonavir Use|3
04123|150|R|   With Tacrolimus in Lung Transplant Recipients: A  Single-center Case|3
04123|151|R|   Series. Transplantation 2022 Oct 28.|3
04123|152|R|14.Sindelar M, McCabe D, Carroll E. Tacrolimus Drug-Drug Interaction with|3
04123|153|R|   Nirmatrelvir/Ritonavir (Paxlovid) Managed  with Phenytoin. J Med Toxicol|3
04123|154|R|   2023 Jan;19(1):45-48.|3
04123|155|R|15.Schneider J, Wobser R, Kahn W, Wagner D, Tanriver Y, Walz G.|3
04123|156|R|   Nirmatrelvir/ritonavir treatment in SARS-CoV-2 positive kidney transplant|3
04123|157|R|   recipients - a case series with four patients. BMC Nephrol 2023 Apr 15;|3
04123|158|R|   24(1):99.|3
04123|159|R|16.Chen Y, Wan W, Yao X, Guan Y. Drug-drug interaction between paxlovid and|3
04123|160|R|   tacrolimus in a patient with  myasthenia gravis and SARS-CoV-2 infection.|3
04123|161|R|   J Neuroimmunol 2023 Dec 15;385:578245.|3
04123|162|R|17.Tomida T, Itohara K, Yamamoto K, Kimura T, Fujita K, Uda A, Kitahiro Y,|5
04123|163|R|   Yokoyama N, Hyodo Y, Omura T, Yano I. A model-based pharmacokinetic|5
04123|164|R|   assessment of drug-drug interaction between  tacrolimus and|5
04123|165|R|   nirmatrelvir/ritonavir in a kidney transplant patient with  COVID-19.|5
04123|166|R|   Drug Metab Pharmacokinet 2023 Dec;53:100529.|5
04124|001|T|MONOGRAPH TITLE:  Cannabidiol/Ritonavir|
04124|002|B||
04124|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04124|004|L|take action as needed.|
04124|005|B||
04124|006|A|MECHANISM OF ACTION:  Cannabidiol (CBD) is a substrate of CYP2C19 and|
04124|007|A|CYP3A4.  The primary metabolic pathway of cannabidiol is via CYP2C19 to two|
04124|008|A|major metabolites, 7-hydroxycannabidiol (7-OH-CBD) and|
04124|009|A|6alpha-hydroxycannabidiol.  Cannabidiol has a minor pathway via CYP3A4 to|
04124|010|A|6beta-hydroxycannabidiol and 4-hydroxycannabidiol.(1,2)|
04124|011|A|   Ritonavir is both a strong inducer of CYP2C19 and a strong inhibitor of|
04124|012|A|CYP3A4.(3,4)|
04124|013|B||
04124|014|E|CLINICAL EFFECTS:  The concurrent administration of cannabidiol with|
04124|015|E|ritonavir may result in decreased or increased levels of CBD.(1-3)|
04124|016|B||
04124|017|P|PREDISPOSING FACTORS:  None determined.|
04124|018|B||
04124|019|M|PATIENT MANAGEMENT:  The overall effect of ritonavir on cannabidiol|
04124|020|M|concentrations may be an increase or decrease and should be monitored|
04124|021|M|closely.(1,2)|
04124|022|M|   The US manufacturer of CBD solution recommends considering increasing|
04124|023|M|cannabidiol dosage by up to 2-fold, based on the patient's clinical response|
04124|024|M|and tolerance, when used concurrently with a strong CYP3A4 inducer and/or|
04124|025|M|CYP2C19 inducer.  The manufacturer does not have recommendations for|
04124|026|M|concurrent use with CYP3A4 inhibitors.(1)|
04124|027|M|   The Canadian manufacturer of CBD-THC spray states that concurrent use|
04124|028|M|with strong CYP3A4 inhibitors may require a dose titration.  The|
04124|029|M|manufacturer does not have recommendations for concurrent use with CYP2C19|
04124|030|M|inducers.(2)|
04124|031|B||
04124|032|D|DISCUSSION:  In a study with itraconazole (a strong CYP3A4 inhibitor),|
04124|033|D|cannabidiol exposure increased <10% and the 7-OH-CBD metabolite exposure|
04124|034|D|increased <20%.(1)|
04124|035|D|   In a study of 12 healthy volunteers, rifampin 600 mg (a strong CYP2C19|
04124|036|D|and CYP3A4 inducer) decreased the maximum concentration (Cmax) and|
04124|037|D|area-under-curve (AUC) of CBD by 52% and 58%, respectively, of THC by 39%|
04124|038|D|and 24%, respectively, and of 11-hydroxy-THC (a primary metabolite of THC)|
04124|039|D|by 86% and 87%, respectively.(5)|
04124|040|D|   In a study in 16 healthy volunteers, a single dose of cannabidiol with|
04124|041|D|steady state rifampin decreased the Cmax and AUC of CBD by 34% and 32%,|
04124|042|D|respectively, of 7-hydroxy-CBD by 67% and 63%, and 7-carboxy-CBD by 3% and|
04124|043|D|44%.(6)|
04124|044|D|   In a study in healthy volunteers, ritonavir (400 mg twice daily for 9|
04124|045|D|days) decreased the AUC and Cmax by 82% and 66%, receptively, of|
04124|046|D|voriconazole (a CYP2C19 substrate).  In a second study, ritonavir (100 mg|
04124|047|D|twice daily for 9 days) decreased the AUC and Cmax by 39% and 24%,|
04124|048|D|respectively, of voriconazole.(3)|
04124|049|B||
04124|050|R|REFERENCES:|
04124|051|B||
04124|052|R|1.Epidiolex (cannabidiol) US prescribing information. Greenwich Biosciences,|1
04124|053|R|  Inc. June, 2025.|1
04124|054|R|2.Sativex (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD))|1
04124|055|R|  Canadian prescribing information. GW Pharma Ltd. December 11, 2019.|1
04124|056|R|3.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
04124|057|R|  December, 2019.|1
04124|058|R|4.This information is based on an extract from the Certara Drug Interaction|6
04124|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04124|060|R|5.Stott C, White L, Wright S, Wilbraham D, Guy G. A Phase I, open-label,|2
04124|061|R|  randomized, crossover study in three parallel groups to evaluate the|2
04124|062|R|  effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics|2
04124|063|R|  of THC/CBD oromucosal spray in healthy volunteers. Springerplus 2013 Dec;|2
04124|064|R|  2(1):236.|2
04124|065|R|6.Patsalos PN, Szaflarski JP, Gidal B, VanLandingham K, Critchley D,|6
04124|066|R|  Morrison G. Clinical implications of trials investigating drug-drug|6
04124|067|R|  interactions between cannabidiol and enzyme inducers or inhibitors or|6
04124|068|R|  common antiseizure drugs. Epilepsia 2020 Sep 12.|6
04125|001|T|MONOGRAPH TITLE:  Mitapivat (50 mg BID)/Moderate CYP3A4 Inhibitors|
04125|002|B||
04125|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04125|004|L|is contraindicated and generally should not be dispensed or administered to|
04125|005|L|the same patient.|
04125|006|B||
04125|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04125|008|A|metabolism of mitapivat.(1)|
04125|009|B||
04125|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04125|011|E|result in increased levels of and effects from mitapivat including decreased|
04125|012|E|estrone and estradiol levels in males, increased urate, back pain, and|
04125|013|E|arthralgias.(1)|
04125|014|B||
04125|015|P|PREDISPOSING FACTORS:  None determined.|
04125|016|B||
04125|017|M|PATIENT MANAGEMENT:  The concurrent use of moderate CYP3A4 inhibitors with|
04125|018|M|mitapivat should be monitored closely for increased risk of adverse|
04125|019|M|reactions.  Mitapivat dose should not exceed 20 mg twice daily with|
04125|020|M|concurrent moderate CYP3A4 inhibitors.(1)|
04125|021|B||
04125|022|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04125|023|D|with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased|
04125|024|D|mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by|
04125|025|D|2.6-fold and 1.6-fold, respectively.(1)|
04125|026|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04125|027|D|atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem,|
04125|028|D|dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir,|
04125|029|D|fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib,|
04125|030|D|schisandra, stiripentol, treosulfan, tofisopam, and verapamil.(2)|
04125|031|B||
04125|032|R|REFERENCES:|
04125|033|B||
04125|034|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04125|035|R|  February, 2022.|1
04125|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
04125|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04126|001|T|MONOGRAPH TITLE:  Epinephrine/Cardioselective Beta-Blockers|
04126|002|B||
04126|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04126|004|L|take action as needed.|
04126|005|B||
04126|006|A|MECHANISM OF ACTION:  Concurrent use of beta-blockers also block the beta|
04126|007|A|effects of epinephrine, which results in predomination of alpha effects.|
04126|008|A|The plasma clearance of epinephrine is decreased.|
04126|009|B||
04126|010|E|CLINICAL EFFECTS:  Concurrent use of epinephrine with beta-blockers may|
04126|011|E|result in hypertension with reflex bradycardia.  Epinephrine resistance in|
04126|012|E|patients with anaphylaxis has been reported.|
04126|013|B||
04126|014|P|PREDISPOSING FACTORS:  None determined.|
04126|015|B||
04126|016|M|PATIENT MANAGEMENT:  Hypertension and bradycardia are less likely to occur|
04126|017|M|with cardioselective beta-blockers.  If both drugs are administered, monitor|
04126|018|M|blood pressure carefully.  Use caution when treating anaphylaxis with|
04126|019|M|epinephrine since response may be poor.|
04126|020|B||
04126|021|D|DISCUSSION:  A 29-year-old male undergoing elective nasal septoplasty|
04126|022|D|developed severe hypertension with a blood pressure of 207/123 mmHg after|
04126|023|D|topical epinephrine (1:1000) was applied to the nasal mucosa. Intravenous|
04126|024|D|metoprolol was administered but the patient went into cardiogenic shock|
04126|025|D|thought to be a result of unopposed alpha stimulation by the combination of|
04126|026|D|epinephrine and metoprolol.(1)|
04126|027|D|   A study observed the differences in cardiovascular responses to|
04126|028|D|subcutaneous epinephrine (given to provide hemostasis during scalp incision|
04126|029|D|for craniotomy) between patients who received propranolol vs. metoprolol vs.|
04126|030|D|no pretreatment. While metoprolol prevented the cardiovascular effects of|
04126|031|D|epinephrine infiltration, propranolol pretreatment was associated with a|
04126|032|D|highly significant increase (P less than 0.01) in mean arterial pressure and|
04126|033|D|a significant decrease (P less than 0.05) in heart rate.(2)|
04126|034|D|   A double-blind cross-over trial studied the effects of epinephrine|
04126|035|D|infusion during treatment with propranolol vs. metoprolol in 8 hypertensive|
04126|036|D|patients.  Patients on propranolol experienced significant increases in|
04126|037|D|blood pressure and systemic vascular resistance (SVR), whereas patients on|
04126|038|D|metoprolol had less increase in systolic blood pressure while the diastolic|
04126|039|D|pressure remained unchanged and SVR decreased.(3)|
04126|040|D|   In spontaneously hypertensive rats, epinephrine in combination with|
04126|041|D|pindolol induced remarkable hemodynamic changes (in particular, increase in|
04126|042|D|diastolic blood pressure), which were prevented by phentolamine|
04126|043|D|pretreatment, whereas epinephrine with acebutolol pretreatment induced no|
04126|044|D|significant hemodynamic changes.(4)|
04126|045|B||
04126|046|R|REFERENCES:|
04126|047|B||
04126|048|R|1.Schwalm JD, Hamstra J, Mulji A, Velianou JL. Cardiogenic shock following|3
04126|049|R|  nasal septoplasty: a case report and review of the  literature. Can J|3
04126|050|R|  Anaesth 2008 Jun;55(6):376-9.|3
04126|051|R|2.Muralidhar K, Bhanumurthy S. Attenuation of the cardiovascular responses|2
04126|052|R|  to subcutaneous adrenaline in  neurosurgical patients. Br J Anaesth 1992|2
04126|053|R|  Mar;68(3):264-7.|2
04126|054|R|3.van Herwaarden CL, Fennis JF, Binkhorst RA, van't Laar A. Haemodynamic|2
04126|055|R|  effects of adrenaline during treatment of hypertensive patients with|2
04126|056|R|  propranolol and metoprolol. Eur J Clin Pharmacol 1977 Dec 28;|2
04126|057|R|  12(6):397-402.|2
04126|058|R|4.Kim Y. Interaction between beta blockers and epinephrine on hemodynamics|5
04126|059|R|  of  spontaneously hypertensive rats. Res Commun Chem Pathol Pharmacol 1993|5
04126|060|R|  Apr;80(1):3-19.|5
04127|001|T|MONOGRAPH TITLE:  Nirmatrelvir-Ritonavir/Strong CYP3A4 Inducers|
04127|002|B||
04127|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04127|004|L|is contraindicated and generally should not be dispensed or administered to|
04127|005|L|the same patient.|
04127|006|B||
04127|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 are expected to increase the|
04127|008|A|metabolism of nirmatrelvir.(1)|
04127|009|B||
04127|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong inducers of CYP3A4 may|
04127|011|E|result in decreased levels and effectiveness of nirmatrelvir.(1)|
04127|012|B||
04127|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04127|014|P|of the inducer for longer than 1-2 weeks.|
04127|015|B||
04127|016|M|PATIENT MANAGEMENT:  Concurrent administration of strong CYP3A4 inducers|
04127|017|M|with nirmatrelvir is contraindicated.(1)|
04127|018|B||
04127|019|D|DISCUSSION:  In a study of 12 healthy volunteers, carbamazepine was titrated|
04127|020|D|to 300 mg every 12 hours and then coadministered with nirmatrelvir/ritonavir|
04127|021|D|300 mg/100 mg on day 15 of carbamazepine.  Carbamazepine decreased|
04127|022|D|nirmatrelvir AUC and Cmax by 55% and 43%, respectively, and decreased|
04127|023|D|ritonavir AUC and Cmax both by about 74%.(2)|
04127|024|D|   Strong inducers of CYP3A4 include apalutamide, barbiturates,|
04127|025|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04127|026|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04127|027|D|rifapentine, and St. John's wort.(8,9)|
04127|028|B||
04127|029|R|REFERENCES:|
04127|030|B||
04127|031|R|1.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04127|032|R|  information. Pfizer Inc. February, 2025.|1
04127|033|R|2.Cox DS, Van Eyck L, Pawlak S, Beckerman B, Linn C, Ginman K, Cha YT,|2
04127|034|R|  LaBadie RR, Shi H, Damle B. Effects of itraconazole and carbamazepine on|2
04127|035|R|  the pharmacokinetics of  nirmatrelvir/ritonavir in healthy adults. Br J|2
04127|036|R|  Clin Pharmacol 2023 May 15.|2
04127|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04127|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04127|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04127|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04127|041|R|  11/14/2017.|1
04127|042|R|4.This information is based on an extract from the Certara Drug Interaction|6
04127|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04128|001|T|MONOGRAPH TITLE:  Pimavanserin (Greater Than 10 mg)/Strong CYP3A4|
04128|002|T|Inhibitors; Protease Inhibitors|
04128|003|B||
04128|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04128|005|L|is contraindicated and generally should not be dispensed or administered to|
04128|006|L|the same patient.|
04128|007|B||
04128|008|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
04128|009|A|metabolism of pimavanserin.(1)|
04128|010|B||
04128|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors or HIV|
04128|012|E|protease inhibitors may increase systemic exposure and the risk for|
04128|013|E|pimavanserin toxicities such as peripheral edema, confusion, or QT|
04128|014|E|prolongation.(1,2)|
04128|015|B||
04128|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04128|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04128|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04128|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04128|020|P|gender, or advanced age.(3)|
04128|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04128|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04128|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04128|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04128|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04128|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04128|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04128|028|B||
04128|029|M|PATIENT MANAGEMENT:  When concomitant use of pimavanserin and a strong|
04128|030|M|CYP3A4 inhibitor or HIV protease inhibitor is needed, the pimavanserin dose|
04128|031|M|should be reduced to 10 mg once daily.(1,2)|
04128|032|M|   With unboosted atazanavir, consider using alternative antipsychotic|
04128|033|M|agents.(2)|
04128|034|M|   During concomitant therapy with a strong CYP3A4 inhibitor or HIV protease|
04128|035|M|inhibitor, monitor patients closely for prolongation of the QT interval.|
04128|036|M|Obtain serum calcium, magnesium, and potassium levels and monitor ECG at|
04128|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04128|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04128|039|B||
04128|040|D|DISCUSSION:  In a drug interaction study, ketoconazole increased|
04128|041|D|pimavanserin maximum concentration (Cmax) 1.5-fold and area-under-curve(AUC)|
04128|042|D|3-fold.|
04128|043|D|   A thorough QTc study performed in 252 subjects found a mean maximum|
04128|044|D|change from baseline of 13.5 msec (upper bound of the 90% confidence|
04128|045|D|interval was 16.6 msec) at twice the therapeutic dose.(1) Thus,|
04128|046|D|coadministration of pimavanserin and a QT prolonging agent, even at a|
04128|047|D|reduced dose, may increase the risk for significant QT prolongation.|
04128|048|D|   CYP3A4 inhibitors linked to this monograph include: atazanavir,|
04128|049|D|boceprevir, cobicistat, darunavir, fosamprenavir, idelalisib, indinavir,|
04128|050|D|itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone,|
04128|051|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir,|
04128|052|D|troleandomycin, and tucatinib.(4)|
04128|053|B||
04128|054|R|REFERENCES:|
04128|055|B||
04128|056|R|1.Nuplazid (pimavanserin) US prescribing information. ACADIA Pharmaceuticals|1
04128|057|R|  Inc. May, 2019.|1
04128|058|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04128|059|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04128|060|R|  HIV. Department of Health and Human Services. Available at:|6
04128|061|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
04128|062|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
04128|063|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04128|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04128|065|R|  settings: a scientific statement from the American Heart Association and|6
04128|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04128|067|R|  2;55(9):934-47.|6
04128|068|R|4.This information is based on an extract from the Certara Drug Interaction|6
04128|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04129|001|T|MONOGRAPH TITLE:  Pimavanserin (Greater Than 10 mg)/Strong CYP3A4 Inhibitors|
04129|002|T|that Prolong QT|
04129|003|B||
04129|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04129|005|L|is contraindicated and generally should not be dispensed or administered to|
04129|006|L|the same patient.|
04129|007|B||
04129|008|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04129|009|A|interval may inhibit the metabolism of pimavanserin and result in additive|
04129|010|A|effects on the QTc interval.(1)|
04129|011|B||
04129|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04129|013|E|the QTc interval may increase systemic exposure and the risk for|
04129|014|E|pimavanserin toxicities such as peripheral edema, confusion, or additive QTc|
04129|015|E|prolongation and life-threatening cardiac arrhythmias like torsades de|
04129|016|E|pointes.(1)|
04129|017|B||
04129|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04129|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04129|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04129|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04129|022|P|gender, or advanced age.(2)|
04129|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04129|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04129|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04129|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04129|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04129|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04129|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04129|030|B||
04129|031|M|PATIENT MANAGEMENT:  The manufacturer of pimavanserin recommends avoiding|
04129|032|M|use with agents that prolong the QTc interval.(1)  The US Department of|
04129|033|M|Health and Human Services HIV guidelines state that pimavanserin should not|
04129|034|M|be coadministered with saquinavir or lopinavir due to the risk of QTc|
04129|035|M|prolongation.(3)|
04129|036|M|   If concomitant use of pimavanserin and a strong CYP3A4 inhibitor is|
04129|037|M|needed, the pimavanserin dose should be reduced to 10 mg once daily.(1)|
04129|038|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
04129|039|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
04129|040|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
04129|041|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
04129|042|M|irregular heartbeat, dizziness, or fainting.|
04129|043|B||
04129|044|D|DISCUSSION:  In a drug interaction study, ketoconazole increased|
04129|045|D|pimavanserin maximum concentration (Cmax) 1.5-fold and area-under-curve(AUC)|
04129|046|D|3-fold.|
04129|047|D|   A thorough QTc study performed in 252 subjects found a mean maximum|
04129|048|D|change from baseline of 13.5 msec (upper bound of the 90% confidence|
04129|049|D|interval was 16.6 msec) at twice the therapeutic dose.(1) Thus,|
04129|050|D|coadministration of pimavanserin and a QT prolonging agent, even at a|
04129|051|D|reduced dose, may increase the risk for significant QT prolongation.|
04129|052|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
04129|053|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
04129|054|D|posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(4)|
04129|055|B||
04129|056|R|REFERENCES:|
04129|057|B||
04129|058|R|1.Nuplazid (pimavanserin) US prescribing information. ACADIA Pharmaceuticals|1
04129|059|R|  Inc. May, 2019.|1
04129|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04129|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04129|062|R|  settings: a scientific statement from the American Heart Association and|6
04129|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04129|064|R|  2;55(9):934-47.|6
04129|065|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04129|066|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04129|067|R|  HIV. Department of Health and Human Services. Available at:|6
04129|068|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
04129|069|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
04129|070|R|4.This information is based on an extract from the Certara Drug Interaction|6
04129|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04130|001|T|MONOGRAPH TITLE:  Lumateperone (Greater Than 21 mg)/Moderate CYP3A4|
04130|002|T|Inhibitors|
04130|003|B||
04130|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04130|005|L|is contraindicated and generally should not be dispensed or administered to|
04130|006|L|the same patient.|
04130|007|B||
04130|008|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04130|009|A|metabolism of lumateperone.(1)|
04130|010|B||
04130|011|E|CLINICAL EFFECTS:  Concurrent use of lumateperone with moderate CYP3A4|
04130|012|E|inhibitors increases lumateperone exposure, which may increase the risk of|
04130|013|E|adverse reactions.(1)|
04130|014|B||
04130|015|P|PREDISPOSING FACTORS:  Patients with moderate or severe hepatic impairment|
04130|016|P|(Child-Pugh class B or C) may be at higher risk of increased lumateperone|
04130|017|P|exposure.(1)|
04130|018|B||
04130|019|M|PATIENT MANAGEMENT:  The manufacturer of lumateperone recommends decreasing|
04130|020|M|the dosage of lumateperone to 21 mg once daily in patients receiving|
04130|021|M|moderate CYP3A4 inhibitors.(1)|
04130|022|B||
04130|023|D|DISCUSSION:  Coadministration of lumateperone with itraconazole, a strong|
04130|024|D|CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in|
04130|025|D|area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1)|
04130|026|D|   Coadministration of lumateperone with diltiazem, a moderate CYP3A4|
04130|027|D|inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax,|
04130|028|D|respectively.(1)|
04130|029|D|   Moderate inhibitors of CYP3A4 include:  aprepitant, avacopan,|
04130|030|D|berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone,|
04130|031|D|duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine,|
04130|032|D|fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir,|
04130|033|D|letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol,|
04130|034|D|tofisopam, verapamil, treosulfan, and voxelotor.(2,3)|
04130|035|B||
04130|036|R|REFERENCES:|
04130|037|B||
04130|038|R|1.Caplyta (lumateperone) US prescribing information. Intra-Cellular|1
04130|039|R|  Therapies, Inc. November, 2025.|1
04130|040|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04130|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04130|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04130|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04130|044|R|  11/14/2017.|1
04130|045|R|3.This information is based on an extract from the Certara Drug Interaction|6
04130|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04131|001|T|MONOGRAPH TITLE:  Lumateperone (<=10.5 mg)/Strong CYP3A4 Inhib; Protease|
04131|002|T|Inhib|
04131|003|B||
04131|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04131|005|L|take action as needed.|
04131|006|B||
04131|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 and protease inhibitors|
04131|008|A|may inhibit the metabolism of lumateperone.(1,2)|
04131|009|B||
04131|010|E|CLINICAL EFFECTS:  Concurrent use of lumateperone with strong CYP3A4|
04131|011|E|inhibitors or protease inhibitors increases lumateperone exposure, which may|
04131|012|E|increase the risk of adverse reactions.(1,2)|
04131|013|B||
04131|014|P|PREDISPOSING FACTORS:  Patients with moderate or severe hepatic impairment|
04131|015|P|(Child-Pugh class B or C) may be at higher risk of increased lumateperone|
04131|016|P|exposure.(1)|
04131|017|B||
04131|018|M|PATIENT MANAGEMENT:  The manufacturer of lumateperone recommends decreasing|
04131|019|M|the dosage of lumateperone to 10.5 mg once daily in patients receiving|
04131|020|M|strong CYP3A4 inhibitors.(1)|
04131|021|M|   The US Department of Health and Human Services HIV guidelines state that|
04131|022|M|protease inhibitors should not be coadministered with lumateperone.(2)|
04131|023|B||
04131|024|D|DISCUSSION:  Coadministration of lumateperone with itraconazole, a strong|
04131|025|D|CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in|
04131|026|D|area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1)|
04131|027|D|   Coadministration of lumateperone with diltiazem, a moderate CYP3A4|
04131|028|D|inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax,|
04131|029|D|respectively.(1)|
04131|030|D|   Strong inhibitors of CYP3A4 include:  adagrasib, amprenavir, atazanavir,|
04131|031|D|boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, fosamprenavir,|
04131|032|D|grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
04131|033|D|levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone,|
04131|034|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole,|
04131|035|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04131|036|D|troleandomycin, tucatinib, and voriconazole.(2-4)|
04131|037|B||
04131|038|R|REFERENCES:|
04131|039|B||
04131|040|R|1.Caplyta (lumateperone) US prescribing information. Intra-Cellular|1
04131|041|R|  Therapies, Inc. November, 2025.|1
04131|042|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04131|043|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04131|044|R|  HIV. Department of Health and Human Services. Available at:|6
04131|045|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
04131|046|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
04131|047|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04131|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04131|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04131|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04131|051|R|  11/14/2017.|1
04131|052|R|4.This information is based on an extract from the Certara Drug Interaction|6
04131|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04132|001|T|MONOGRAPH TITLE:  Lumateperone (Less Than or Equal To 21 mg)/Moderate CYP3A4|
04132|002|T|Inhibitors|
04132|003|B||
04132|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04132|005|L|take action as needed.|
04132|006|B||
04132|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04132|008|A|metabolism of lumateperone.(1)|
04132|009|B||
04132|010|E|CLINICAL EFFECTS:  Concurrent use of lumateperone with moderate CYP3A4|
04132|011|E|inhibitors increases lumateperone exposure, which may increase the risk of|
04132|012|E|adverse reactions.(1)|
04132|013|B||
04132|014|P|PREDISPOSING FACTORS:  Patients with moderate or severe hepatic impairment|
04132|015|P|(Child-Pugh class B or C) may be at higher risk of increased lumateperone|
04132|016|P|exposure.(1)|
04132|017|B||
04132|018|M|PATIENT MANAGEMENT:  The manufacturer of lumateperone recommends decreasing|
04132|019|M|the dosage of lumateperone to 21 mg once daily in patients receiving|
04132|020|M|moderate CYP3A4 inhibitors.(1)|
04132|021|B||
04132|022|D|DISCUSSION:  Coadministration of lumateperone with itraconazole, a strong|
04132|023|D|CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in|
04132|024|D|area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1)|
04132|025|D|   Coadministration of lumateperone with diltiazem, a moderate CYP3A4|
04132|026|D|inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax,|
04132|027|D|respectively.(1)|
04132|028|D|   Moderate inhibitors of CYP3A4 include: aprepitant, avacopan,|
04132|029|D|berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone,|
04132|030|D|duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine,|
04132|031|D|fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir,|
04132|032|D|letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol,|
04132|033|D|tofisopam, treosulfan, verapamil, and voxelotor.(2,3)|
04132|034|B||
04132|035|R|REFERENCES:|
04132|036|B||
04132|037|R|1.Caplyta (lumateperone) US prescribing information. Intra-Cellular|1
04132|038|R|  Therapies, Inc. November, 2025.|1
04132|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04132|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04132|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04132|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04132|043|R|  11/14/2017.|1
04132|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
04132|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04133|001|T|MONOGRAPH TITLE:  Rosuvastatin/Selected BCRP Inhibitors|
04133|002|B||
04133|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04133|004|L|take action as needed.|
04133|005|B||
04133|006|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate of the BCRP|
04133|007|A|transporter.(1,2)|
04133|008|A|   Inhibitors of this transporter may increase intestinal absorption and|
04133|009|A|hepatic uptake of BCRP substrates rosuvastatin.(1-8)|
04133|010|B||
04133|011|E|CLINICAL EFFECTS:  Simultaneous use of BCRP inhibitors may result in|
04133|012|E|increased levels and side effects from rosuvastatin, including|
04133|013|E|rhabdomyolysis.(2,4)|
04133|014|B||
04133|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04133|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04133|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04133|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04133|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04133|020|P|transporter OATP1B1 may have increased statin concentrations and be|
04133|021|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04133|022|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04133|023|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04133|024|B||
04133|025|M|PATIENT MANAGEMENT:  Concurrent use of rosuvastatin with BCRP inhibitors may|
04133|026|M|result in increased risk of side effects associated with rosuvastatin.  If|
04133|027|M|concurrent therapy is warranted, close monitoring would be prudent for|
04133|028|M|statin related side effects including rhabdomyolysis.|
04133|029|M|   The Canadian manufacturer of clopidogrel states that the dose of|
04133|030|M|rosuvastatin should not exceed 20 mg daily when used concomitantly with|
04133|031|M|clopidogrel.(5)  There is no recommendation for rosuvastatin dose|
04133|032|M|adjustments from the Australian and US manufacturers of clopidogrel.(6,7)|
04133|033|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
04133|034|M|of rosuvastatin should not exceed 5 mg daily when used with agents that|
04133|035|M|increase rosuvastatin exposure by 2-fold or more (e.g., clopidogrel,|
04133|036|M|lopinavir-ritonavir, roxadustat).  The maximum daily dose should be adjusted|
04133|037|M|so that the expected rosuvastatin exposure does not exceed that obtained|
04133|038|M|with the usual maximum daily dose.(8)|
04133|039|M|   Educate the patient of signs and symptoms of rhabdomyolysis.|
04133|040|B||
04133|041|D|DISCUSSION:  Rosuvastatin is a BCRP substrate.(1,2)|
04133|042|D|   In a clinical study of 20 patients with stable coronary heart disease,|
04133|043|D|single-dose clopidogrel 300 mg (a BCRP inhibitor) increased the|
04133|044|D|area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin by|
04133|045|D|2-fold and 1.3-fold, respectively.  Multiple doses of clopidogrel 75 mg|
04133|046|D|daily for 7 days increased rosuvastatin AUC by 1.4-fold but did not affect|
04133|047|D|the Cmax.(4)|
04133|048|D|   In a pharmacokinetic study, concomitant use of lazertinib increased|
04133|049|D|rosuvastatin Cmax by 2.2-fold and AUC by 2-fold.(3)|
04133|050|D|   BCRP inhibitors linked to this monograph include:  clopidogrel, curcumin,|
04133|051|D|encorafenib, lazertinib, pantoprazole, ritonavir, rolapitant, roxadustat,|
04133|052|D|tolvaptan, turmeric, and zongertinib.(2-9)|
04133|053|B||
04133|054|R|REFERENCES:|
04133|055|B||
04133|056|R|1.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04133|057|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04133|058|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04133|059|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04133|060|R|  44(3):398-408.|5
04133|061|R|2.Ning C, Su S, Li J, Kong D, Cai H, Qin Z, Xing H, Chen X, He J. Evaluation|5
04133|062|R|  of a Clinically Relevant Drug-Drug Interaction Between Rosuvastatin  and|5
04133|063|R|  Clopidogrel and the Risk of Hepatotoxicity. Front Pharmacol 2021;|5
04133|064|R|  12:715577.|5
04133|065|R|3.Lazcluze (lazertinib) US Prescribing Information. Janssen Biotech, Inc.|1
04133|066|R|  August 2024.|1
04133|067|R|4.Pinheiro LF, Franca CN, Izar MC, Barbosa SP, Bianco HT, Kasmas SH, Mendes|2
04133|068|R|  GD, Povoa RM, Fonseca FA. Pharmacokinetic interactions between clopidogrel|2
04133|069|R|  and rosuvastatin: effects on  vascular protection in subjects with|2
04133|070|R|  coronary heart disease. Int J Cardiol 2012 Jun 28;158(1):125-9.|2
04133|071|R|5.Plavix (clopidogrel) Canadian Product Monograph. sanofi-aventis Canada|1
04133|072|R|  Inc. February, 2022.|1
04133|073|R|6.Plavix (clopidogrel hydrogen sulfate) Australian prescribing information.|1
04133|074|R|  Sanofi-Synthelabo Australia Pty Limited May, 2022.|1
04133|075|R|7.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
04133|076|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
04133|077|R|8.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
04133|078|R|  Australia Pty Ltd July 8, 2024.|1
04133|079|R|9.This information is based on an extract from the Certara Drug Interaction|6
04133|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04135|001|T|MONOGRAPH TITLE:  Lemborexant (Greater Than 5 mg)/Weak CYP3A4 Inhibitors|
04135|002|B||
04135|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04135|004|L|is contraindicated and generally should not be dispensed or administered to|
04135|005|L|the same patient.|
04135|006|B||
04135|007|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
04135|008|A|lemborexant.(1)|
04135|009|B||
04135|010|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of CYP3A4 may result in|
04135|011|E|increased levels of and effects from lemborexant, including somnolence,|
04135|012|E|fatigue, CNS depressant effects, daytime impairment, headache, and nightmare|
04135|013|E|or abnormal dreams.(1)|
04135|014|B||
04135|015|P|PREDISPOSING FACTORS:  None determined.|
04135|016|B||
04135|017|M|PATIENT MANAGEMENT:  The maximum recommended dose of lemborexant with|
04135|018|M|concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per|
04135|019|M|dose.(1)|
04135|020|B||
04135|021|D|DISCUSSION:  Lemborexant is a CYP3A4 substrate.  In a PKPB model, concurrent|
04135|022|D|use of lemborexant with itraconazole increased area-under-curve (AUC) and|
04135|023|D|concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively.|
04135|024|D|Concurrent use of lemborexant with fluconazole increased AUC and Cmax by|
04135|025|D|4.25-fold and 1.75-fold, respectively.(1)|
04135|026|D|   Weak inhibitors of CYP3A4 include:  alprazolam, amiodarone, amlodipine,|
04135|027|D|anamorelin, asciminib, azithromycin, Baikal skullcap, belumosudil,|
04135|028|D|berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib,|
04135|029|D|chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole,|
04135|030|D|cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine,|
04135|031|D|dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin,|
04135|032|D|fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat,|
04135|033|D|glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid,|
04135|034|D|istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib,|
04135|035|D|leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone,|
04135|036|D|mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil,|
04135|037|D|piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir,|
04135|038|D|resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir,|
04135|039|D|sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan,|
04135|040|D|trofinetide, viloxazine, vonoprazan, and ziftomenib.(1,2)|
04135|041|B||
04135|042|R|REFERENCES:|
04135|043|B||
04135|044|R|1.Dayvigo (lemborexant) US prescribing information. Eisai Inc. March, 2022.|1
04135|045|R|2.This information is based on an extract from the Certara Drug Interaction|6
04135|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04136|001|T|MONOGRAPH TITLE:  Tacrolimus/Nicardipine|
04136|002|B||
04136|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04136|004|L|of severe adverse interaction.|
04136|005|B||
04136|006|A|MECHANISM OF ACTION:  Nicardipine may inhibit the metabolism of tacrolimus|
04136|007|A|by CYP3A4.(1-7)|
04136|008|B||
04136|009|E|CLINICAL EFFECTS:  Concurrent use of nicardipine may result in elevated|
04136|010|E|levels of and side effects from tacrolimus, including nephrotoxicity,|
04136|011|E|prolongation of the QTc interval and life-threatening cardiac arrhythmias,|
04136|012|E|torsades de pointes, graft dysfunction, and increased risk of|
04136|013|E|infections.(1-7)|
04136|014|B||
04136|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04136|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04136|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04136|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04136|019|P|gender, or advanced age.|
04136|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04136|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04136|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04136|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04136|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04136|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04136|026|P|dysfunction).|
04136|027|B||
04136|028|M|PATIENT MANAGEMENT:  Patients maintained on tacrolimus should be closely|
04136|029|M|monitored if nicardipine is initiated or discontinued.  The dosage of|
04136|030|M|tacrolimus may need to be adjusted or nicardipine may need to be|
04136|031|M|discontinued.  Consider an alternative antihypertensive agent, such as|
04136|032|M|labetalol.|
04136|033|M|   When concurrent therapy of nicardipine and tacrolimus is warranted,|
04136|034|M|consider obtaining serum calcium, magnesium, and potassium levels and|
04136|035|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04136|036|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04136|037|M|heartbeat, dizziness, or fainting.|
04136|038|B||
04136|039|D|DISCUSSION:  In a clinical study, eight patients who were CYP3A5|
04136|040|D|non-expressors had a higher median concentration maximum (Cmax) than both|
04136|041|D|four patients CYP3A5 expressors and controls (24.3 ng/ml, 13.9 ng/mL, and|
04136|042|D|14.6 ng/ml, respectively). Compared to the other two groups, CYP3A5|
04136|043|D|non-expressors had higher dose adjusted Cmax, less time to Cmax, and more|
04136|044|D|scheduled tacrolimus doses held per patient. Six of eight CYP3A5|
04136|045|D|non-expressors had potentially toxic Cmax levels (> 20 ng/ml) compared with|
04136|046|D|none of four CYP3A5 expressors and 11.25% of control group.(5)|
04136|047|D|   A case report of a 20-year-old kidney transplant patient on tacrolimus 5|
04136|048|D|mg twice daily, mycophenolate mofetil, and prednisone was started on|
04136|049|D|intravenous nicardipine. Twelve hours after starting nicardipine, the|
04136|050|D|tacrolimus trough level was 16.3 ng/mL (target range 12-18 ng/mL).|
04136|051|D|Tacrolimus dose was reduced.(6)|
04136|052|B||
04136|053|R|REFERENCES:|
04136|054|B||
04136|055|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04136|056|R|  August, 2023.|1
04136|057|R|2.Cardene (nicardipine) US prescribing information. EKR Therapeutics, Inc.|1
04136|058|R|  August, 2016.|1
04136|059|R|3.Christians U, Schmidt G, Bader A, Lampen A, Schottmann R, Linck A, Sewing|5
04136|060|R|  KF. Identification of drugs inhibiting the in vitro metabolism of|5
04136|061|R|  tacrolimus by human liver microsomes. Br J Clin Pharmacol 1996 Mar;|5
04136|062|R|  41(3):187-90.|5
04136|063|R|4.Lampen A, Christians U, Guengerich FP, Watkins PB, Kolars JC, Bader A,|5
04136|064|R|  Gonschior AK, Dralle H, Hackbarth I, Sewing KF. Metabolism of the|5
04136|065|R|  immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug|5
04136|066|R|  interactions, and interindividual variability. Drug Metab Dispos 1995 Dec;|5
04136|067|R|  23(12):1315-24.|5
04136|068|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04136|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04136|070|R|  settings: a scientific statement from the American Heart Association and|6
04136|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04136|072|R|  2;55(9):934-47.|6
04136|073|R|6.Hooper DK, Fukuda T, Gardiner R, Logan B, Roy-Chaudhury A, Kirby CL, Vinks|2
04136|074|R|  AA, Goebel J. Risk of tacrolimus toxicity in CYP3A5 nonexpressors treated|2
04136|075|R|  with intravenous  nicardipine after kidney transplantation.|2
04136|076|R|  Transplantation 2012 Apr 27;93(8):806-12.|2
04136|077|R|7.Hooper DK, Carle AC, Schuchter J, Goebel J. Interaction between tacrolimus|3
04136|078|R|  and intravenous nicardipine in the treatment of  post-kidney transplant|3
04136|079|R|  hypertension at pediatric hospitals. Pediatr Transplant 2011 Feb;|3
04136|080|R|  15(1):88-95.|3
04137|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Tecovirimat|
04137|002|B||
04137|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04137|004|L|take action as needed.|
04137|005|B||
04137|006|A|MECHANISM OF ACTION:  Tecovirimat may induce the CYP3A4-mediated metabolism|
04137|007|A|of hormonal contraceptives.(1,2)|
04137|008|B||
04137|009|E|CLINICAL EFFECTS:  Concurrent use of tecovirimat may reduce the|
04137|010|E|effectiveness of hormonal contraceptives.(1,2)|
04137|011|B||
04137|012|P|PREDISPOSING FACTORS:  None determined.|
04137|013|B||
04137|014|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
04137|015|M|rely on hormonal contraception (including oral contraceptives, patches,|
04137|016|M|implants, and/or IUDs) for contraception.  Women should use an effective|
04137|017|M|non-hormonal method of contraception or a back-up method of birth control|
04137|018|M|during and for 28 days after tecovirimat therapy.(1,2)|
04137|019|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04137|020|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04137|021|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04137|022|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
04137|023|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
04137|024|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
04137|025|M|and to seek medical advice if they do become pregnant.(3)|
04137|026|B||
04137|027|D|DISCUSSION:  In a pharmacokinetic study, tecovirimat decreased the|
04137|028|D|concentration maximum (Cmax) and area-under-curve (AUC) of midazolam (a|
04137|029|D|CYP3A4 substrate) by 39% and 32%, respectively.  The effectiveness of|
04137|030|D|hormonal contraceptives, including oral contraceptives, patches, implants,|
04137|031|D|and/or IUDs may be decreased.  Women should use a back-up method of birth|
04137|032|D|control during and for 28 days after tecovirimat therapy.(1)|
04137|033|B||
04137|034|R|REFERENCES:|
04137|035|B||
04137|036|R|1.Tpoxx (tecovirimat) US prescribing information. SIGA Technologies, Inc.|1
04137|037|R|  May, 2022.|1
04137|038|R|2.Tecovirimat UK summary of product characteristics. SIGA Technologies inc.|1
04137|039|R|  June, 2022..|1
04137|040|R|3.Medicines and Healthcare products Regulatory Agency.|1
04137|041|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04137|042|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04137|043|R|  available at:|1
04137|044|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04137|045|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04137|046|R|  -and-contraceptive-efficacy September 15, 2016..|1
04138|001|T|MONOGRAPH TITLE:  Doravirine/Tecovirimat|
04138|002|B||
04138|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04138|004|L|take action as needed.|
04138|005|B||
04138|006|A|MECHANISM OF ACTION:  Tecovirimat may induce the metabolism of doravirine|
04138|007|A|via CYP3A4.(1-4)|
04138|008|B||
04138|009|E|CLINICAL EFFECTS:  Concurrent or recent use of tecovirimat may result in|
04138|010|E|decreased levels and effectiveness of doravirine, as well as the development|
04138|011|E|of resistance.(1-4)|
04138|012|B||
04138|013|P|PREDISPOSING FACTORS:  None determined.|
04138|014|B||
04138|015|M|PATIENT MANAGEMENT:  Coadministration of doravirine with tecovirimat should|
04138|016|M|be approached with caution.  Some experts state that dose adjustment of|
04138|017|M|either drug is not necessary while others suggest the following dosage|
04138|018|M|change:  For adult and pediatric patients weighing at least 35 kg, consider|
04138|019|M|increasing doravirine to 100 mg twice daily during treatment with|
04138|020|M|tecovirimat and for approximately 2 weeks after the end of treatment.(1-4)|
04138|021|B||
04138|022|D|DISCUSSION:  In a study in 17 healthy subjects, coadministration of|
04138|023|D|efavirenz (600 mg daily) with a single dose of doravirine (100 mg) decreased|
04138|024|D|doravirine's area-under-curve (AUC), maximum concentration (Cmax), and 24|
04138|025|D|hour concentration (C24) by 62%, 35%, and 85%, respectively.(1)|
04138|026|D|   In a pharmacokinetic study, tecovirimat decreased the Cmax and AUC of|
04138|027|D|midazolam by 39% and 32%, respectively.(2-3)|
04138|028|B||
04138|029|R|REFERENCES:|
04138|030|B||
04138|031|R|1.Pifeltro (doravirine) US prescribing information. Merck & Co. Inc.|1
04138|032|R|  September, 2019.|1
04138|033|R|2.Tpoxx (tecovirimat) US prescribing information. SIGA Technologies, Inc.|1
04138|034|R|  May, 2022.|1
04138|035|R|3.Tecovirimat UK summary of product characteristics. SIGA Technologies inc.|1
04138|036|R|  June, 2022..|1
04138|037|R|4.Joseph PMcGowan MD FACP FIDSA; Steven MFine MD PhD; Rona Vail MD; Samuel|6
04138|038|R|  TMerrick MD; Asa Radix MD MPH PhD; Christopher JHoffmann MD MPH; Charles|6
04138|039|R|  JGonzalez MD. Drug-Drug Interactions Between Antiretroviral Medications|6
04138|040|R|  and Medications for Treatment of Severe Monkeypox. Clinical Guidelines|6
04138|041|R|  Program August 4, 2022.|6
04139|001|T|MONOGRAPH TITLE:  Rilpivirine/Tecovirimat|
04139|002|B||
04139|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04139|004|L|take action as needed.|
04139|005|B||
04139|006|A|MECHANISM OF ACTION:  Tecovirimat may induce the metabolism of rilpivirine|
04139|007|A|by CYP3A4.(1-4)|
04139|008|B||
04139|009|E|CLINICAL EFFECTS:  Concurrent or recent use of tecovirimat may result in|
04139|010|E|decreased levels and effectiveness of rilpivirine, as well as the|
04139|011|E|development of resistance.(1-4)|
04139|012|B||
04139|013|P|PREDISPOSING FACTORS:  None determined.|
04139|014|B||
04139|015|M|PATIENT MANAGEMENT:  Coadministration of rilpivirine with tecovirimat should|
04139|016|M|be approached with caution. Consider increasing rilpivirine to 50 mg daily|
04139|017|M|during treatment with tecovirimat and for approximately 2 weeks after the|
04139|018|M|end of treatment.(1-4)|
04139|019|B||
04139|020|D|DISCUSSION:  In a study in 18 subjects, rifabutin (300 mg daily), a moderate|
04139|021|D|CYP3A4 inducer, decreased the maximum concentration (Cmax), area-under-curve|
04139|022|D|(AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily)|
04139|023|D|by 31%, 42%, and 48%, respectively.(1)|
04139|024|D|   A study in 18 subjects compared rilpivirine administered alone (25 mg|
04139|025|D|orally daily) to coadministration with rifabutin (300 mg daily) and|
04139|026|D|rilpivirine (50 mg orally daily). A significant difference was not found|
04139|027|D|with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine.(1)|
04139|028|D|   In a pharmacokinetic study, tecovirimat decreased the Cmax and AUC of|
04139|029|D|midazolam by 39% and 32%, respectively.(2-3)|
04139|030|B||
04139|031|R|REFERENCES:|
04139|032|B||
04139|033|R|1.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
04139|034|R|  March, 2024.|1
04139|035|R|2.Tpoxx (tecovirimat) US prescribing information. SIGA Technologies, Inc.|1
04139|036|R|  May, 2022.|1
04139|037|R|3.Tecovirimat UK summary of product characteristics. SIGA Technologies inc.|1
04139|038|R|  June, 2022..|1
04139|039|R|4.Joseph PMcGowan MD FACP FIDSA; Steven MFine MD PhD; Rona Vail MD; Samuel|6
04139|040|R|  TMerrick MD; Asa Radix MD MPH PhD; Christopher JHoffmann MD MPH; Charles|6
04139|041|R|  JGonzalez MD. Drug-Drug Interactions Between Antiretroviral Medications|6
04139|042|R|  and Medications for Treatment of Severe Monkeypox. Clinical Guidelines|6
04139|043|R|  Program August 4, 2022.|6
04140|001|T|MONOGRAPH TITLE:  Maraviroc/Tecovirimat|
04140|002|B||
04140|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04140|004|L|take action as needed.|
04140|005|B||
04140|006|A|MECHANISM OF ACTION:  Tecovirimat may induce the metabolism of maraviroc by|
04140|007|A|CYP34.(1-4)|
04140|008|B||
04140|009|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inducers in the absence of an|
04140|010|E|inhibitor of CYP3A4 and without a dosage adjustment of maraviroc may result|
04140|011|E|in decreased levels and effectiveness of maraviroc.(1)|
04140|012|B||
04140|013|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
04140|014|P|renal impairment.(1)|
04140|015|B||
04140|016|M|PATIENT MANAGEMENT:  Coadministration of maraviroc with tecovirimat should|
04140|017|M|be approached with caution.|
04140|018|M|   In adults, consider increasing maraviroc to 600 mg twice daily when|
04140|019|M|coadministered with tecovirimat in the absence of a protease inhibitor or|
04140|020|M|other strong CYP3A4 inhibitors.  When coadministered with tecovirimat in|
04140|021|M|presence of a protease inhibitor or strong CYP3A4 inhibitor, consider|
04140|022|M|decreasing maraviroc to 150 mg twice daily. These dose adjustments should be|
04140|023|M|considered during and for approximately 2 weeks after the end of tecovirimat|
04140|024|M|treatment.(1-4)|
04140|025|M|   In adults, maraviroc should not be used with a strong CYP3A4 inducer in|
04140|026|M|patients with a creatinine clearance less than 30 ml/min or end-stage renal|
04140|027|M|disease.(1)|
04140|028|M|   In children aged 2 years and older weighing at least 10 kg, patients|
04140|029|M|receiving therapy with strong CYP3A4 inducers who are not also receiving an|
04140|030|M|inhibitor of CYP3A4 is not recommended.(1)|
04140|031|M|   In children aged 2 years and older weighing at least 10 kg, patients|
04140|032|M|receiving therapy with a strong CYP3A4 inducer and a strong CYP3A4 inhibitor|
04140|033|M|should receive the following maraviroc dose based on tablet or oral solution|
04140|034|M|(20 mg/ml):|
04140|035|M|- 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily|
04140|036|M|- 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily|
04140|037|M|- 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily|
04140|038|M|- >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily|
04140|039|M|   In pediatric patients aged 2 years and older weighing at least 10 kg, no|
04140|040|M|dose recommendations are available with mild to moderate renal impairment.|
04140|041|M|Maraviroc is contraindicated in pediatric patients with severe renal|
04140|042|M|impairment or end-stage renal disease who are on concurrent therapy with|
04140|043|M|strong CYP3A4 inhibitors.(1)|
04140|044|B||
04140|045|D|DISCUSSION:  In a study in 12 subjects, concurrent efavirenz (600 mg daily)|
04140|046|D|decreased the minimum concentration (Cmin), area-under-curve (AUC), and|
04140|047|D|maximum concentration (Cmax) of maraviroc (100 mg twice daily) by 45%,|
04140|048|D|44.8%, and 51.4%, respectively.(1)|
04140|049|D|   In a study in 12 subjects, concurrent efavirenz (600 mg daily) increased|
04140|050|D|the Cmin, AUC, and Cmax of maraviroc (200 mg twice daily) by 9%, 15%, and|
04140|051|D|16%, respectively, when compared to the administration of maraviroc (100 mg|
04140|052|D|twice daily) alone.(1)|
04140|053|D|   In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased|
04140|054|D|the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 78%, 63%, and|
04140|055|D|66%, respectively.(1)|
04140|056|D|   In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased|
04140|057|D|the Cmin and Cmax of maraviroc (200 mg twice daily) by 34% and 4%,|
04140|058|D|respectively, when compared to the administration of maraviroc (100 mg twice|
04140|059|D|daily) alone.  The AUC of maraviroc increased by 3%.(1)|
04140|060|D|   In a pharmacokinetic study, tecovirimat decreased the Cmax and AUC of|
04140|061|D|midazolam by 39% and 32%, respectively.(2-3)|
04140|062|B||
04140|063|R|REFERENCES:|
04140|064|B||
04140|065|R|1.Selzentry (maraviroc) US prescribing information. Pfizer Inc. October,|1
04140|066|R|  2020.|1
04140|067|R|2.Tpoxx (tecovirimat) US prescribing information. SIGA Technologies, Inc.|1
04140|068|R|  May, 2022.|1
04140|069|R|3.Tecovirimat UK summary of product characteristics. SIGA Technologies inc.|1
04140|070|R|  June, 2022..|1
04140|071|R|4.Joseph PMcGowan MD FACP FIDSA; Steven MFine MD PhD; Rona Vail MD; Samuel|6
04140|072|R|  TMerrick MD; Asa Radix MD MPH PhD; Christopher JHoffmann MD MPH; Charles|6
04140|073|R|  JGonzalez MD. Drug-Drug Interactions Between Antiretroviral Medications|6
04140|074|R|  and Medications for Treatment of Severe Monkeypox. Clinical Guidelines|6
04140|075|R|  Program August 4, 2022.|6
04141|001|T|MONOGRAPH TITLE:  Thiotepa/Strong CYP3A4 Inducers|
04141|002|B||
04141|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04141|004|L|of severe adverse interaction.|
04141|005|B||
04141|006|A|MECHANISM OF ACTION:  Thiotepa is a prodrug and is converted to its active|
04141|007|A|metabolite via CYP3A4.  Strong CYP3A4 inducers may increase the conversion|
04141|008|A|of thiotepa to its active metabolite, TEPA.(1-3)|
04141|009|B||
04141|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may increase the|
04141|011|E|levels of the active metabolite TEPA and increase the risk of toxicity,|
04141|012|E|including bone marrow suppression, CNS effects (including headache, apathy,|
04141|013|E|confusion, or seizures), and exfoliative dermatitis.(1)|
04141|014|B||
04141|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04141|016|P|of the inducer for longer than 1-2 weeks.|
04141|017|B||
04141|018|M|PATIENT MANAGEMENT:  The manufacturer of thiotepa states concurrent use of|
04141|019|M|strong CYP3A4 inducers in patients receiving therapy with thiotepa should be|
04141|020|M|avoided.  Consider the use of alternative agents with less enzyme induction|
04141|021|M|potential.(1)|
04141|022|M|   If concomitant use of strong CYP3A4 inducer cannot be avoided, closely|
04141|023|M|monitor for signs of toxicity.  A dose reduction of thiotepa may be required|
04141|024|M|based on plasma levels of TEPA.(1)|
04141|025|B||
04141|026|D|DISCUSSION:  Thiotepa is converted to its active metabolite primarily|
04141|027|D|through the CYP3A4 and CYP2B6 enzymes.(2)|
04141|028|D|   A case report demonstrated the effects of phenytoin on thiotepa|
04141|029|D|metabolism.  When phenytoin was co-administered with thiotepa, the|
04141|030|D|area-under-the curve (AUC) of TEPA increased 115%.(3)|
04141|031|D|   Strong CYP3A4 inducers linked to this monograph include:  apalutamide,|
04141|032|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04141|033|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04141|034|D|rifapentine, and St. John's wort.(1,4-5)|
04141|035|B||
04141|036|R|REFERENCES:|
04141|037|B||
04141|038|R|1.Tepadina (thiotepa) US prescribing information. Adienne SA January, 2017.|1
04141|039|R|2.Jacobson PA, Green K, Birnbaum A, Remmel RP. Cytochrome P450 isozymes 3A4|5
04141|040|R|  and 2B6 are involved in the in vitro human  metabolism of thiotepa to|5
04141|041|R|  TEPA. Cancer Chemother Pharmacol 2002 Jun;49(6):461-7.|5
04141|042|R|3.de Jonge ME, Huitema AD, van Dam SM, Beijnen JH, Rodenhuis S. Significant|3
04141|043|R|  induction of cyclophosphamide and thiotepa metabolism by phenytoin. Cancer|3
04141|044|R|  Chemother Pharmacol 2005 May;55(5):507-10.|3
04141|045|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04141|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04141|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04141|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04141|049|R|  11/14/2017.|1
04141|050|R|5.This information is based on an extract from the Certara Drug Interaction|6
04141|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04142|001|T|MONOGRAPH TITLE:  Betibeglogene Autotemcel/Anti-Retrovirals; Hydroxyurea|
04142|002|B||
04142|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04142|004|L|of severe adverse interaction.|
04142|005|B||
04142|006|A|MECHANISM OF ACTION:  Betibeglogene autotemcel is prepared from apheresed|
04142|007|A|cells that are transduced with a replication defective, self-inactivating|
04142|008|A|lentiviral vector.  Antiretrovirals may interfere with the manufacturing of|
04142|009|A|apheresed cells.  Hydroxyurea may interfere with hematopoietic stem cell|
04142|010|A|(HSC) mobilization of CD34+ cells.(1)|
04142|011|B||
04142|012|E|CLINICAL EFFECTS:  Use of hydroxyurea before mobilization may result in|
04142|013|E|unsuccessful stem cell mobilization.  Use of antiretrovirals before|
04142|014|E|mobilization and apheresis may interfere with the production of|
04142|015|E|betibeglogene autotemcel.|
04142|016|B||
04142|017|P|PREDISPOSING FACTORS:  None determined.|
04142|018|B||
04142|019|M|PATIENT MANAGEMENT:  Discontinue antiretrovirals and hydroxyurea for at|
04142|020|M|least one month prior to mobilization and until all cycles of apheresis are|
04142|021|M|completed.|
04142|022|M|   If a patient requires antiretrovirals for HIV prophylaxis, then confirm a|
04142|023|M|negative HIV test before beginning mobilization and apheresis of CD34+|
04142|024|M|cells.|
04142|025|B||
04142|026|D|DISCUSSION:  Antiretroviral medications and hydroxyurea may interfere with|
04142|027|D|the manufacturing of betibeglogene autotemcel therapy.(1)|
04142|028|B||
04142|029|R|REFERENCE:|
04142|030|B||
04142|031|R|1.Zyntelgo (betibeglogene autotemcel) US prescribing information. bluebird|1
04142|032|R|  bio August 2022.|1
04143|001|T|MONOGRAPH TITLE:  Bromocriptine; Cabergoline/Selected Macrolide Antibiotics|
04143|002|B||
04143|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04143|004|L|of severe adverse interaction.|
04143|005|B||
04143|006|A|MECHANISM OF ACTION:  Selected macrolide antibiotics that are strong CYP3A4|
04143|007|A|inhibitors may inhibit the metabolism of bromocriptine and cabergoline.(1-3)|
04143|008|B||
04143|009|E|CLINICAL EFFECTS:  Concurrent use of selected macrolide antibiotics may|
04143|010|E|result in increased levels of bromocriptine and cabergoline, which may|
04143|011|E|result in increased side effects of these agents.(1-3)|
04143|012|B||
04143|013|P|PREDISPOSING FACTORS:  None determined.|
04143|014|B||
04143|015|M|PATIENT MANAGEMENT:  Use caution with concurrent therapy with bromocriptine|
04143|016|M|and cabergoline with selected macrolide antibiotics.(1-3)|
04143|017|M|   The US manufacturer of bromocriptine states use caution when|
04143|018|M|co-administering drugs that are inhibitors of CYP3A4.  Concomitant use of|
04143|019|M|strong CYP3A4 inhibitors should be avoided.  Ensure adequate washout of|
04143|020|M|strong CYP3A4 inhibitor drug before initiating bromocriptine.(2)|
04143|021|B||
04143|022|D|DISCUSSION:  Concurrent administration of selected macrolide antibiotics|
04143|023|D|with bromocriptine or cabergoline may increase the side effects of these|
04143|024|D|agents.  Clarithromycin, josamycin, telithromycin and troleandomycin are|
04143|025|D|strong CYP3A4 inhibitors.(4)|
04143|026|D|   Itraconazole has been shown to increase cabergoline concentrations with|
04143|027|D|concurrent use.  A case report including 2 patients with concurrent therapy|
04143|028|D|of cabergoline and itraconazole noted plasma levels of cabergoline to be|
04143|029|D|increased by 300% in one of the patients. This increase in cabergoline|
04143|030|D|concentrations was noted to increase clinical improvement.(6)|
04143|031|D|   A study compared ten healthy male volunteers taking cabergoline (1|
04143|032|D|mg/day) alone for 6 days or a single oral dose of cabergoline plus|
04143|033|D|clarithromycin (400 mg/day) for 6 days.  Mean plasma cabergoline|
04143|034|D|concentrations increased 2.6-fold with clarithromycin coadministration.  The|
04143|035|D|study also compared seven patients with Parkinson's disease receiving stable|
04143|036|D|doses of cabergoline alone and with the addition of clarithromycin (400|
04143|037|D|mg/day for 6 days).  Cabergoline plasma concentrations increased 1.7-fold|
04143|038|D|during clarithromycin coadministration.(7)|
04143|039|D|   A study in five healthy subjects found that concurrent administration of|
04143|040|D|erythromycin, a moderate CYP3A4 inhibitor, and bromocriptine resulted in a|
04143|041|D|268% increase in area-under-curve (AUC) for bromocriptine and a 4.6-fold|
04143|042|D|increase in bromocriptine maximum concentration (Cmax).(8)|
04143|043|B||
04143|044|R|REFERENCES:|
04143|045|B||
04143|046|R|1.Cycloset (bromocriptine mesylate) tablets, US prescribing information.|1
04143|047|R|  Veroscience LLC February 2, 2016.|1
04143|048|R|2.Dostinex (cabergoline) US prescribing information. Pfizer April, 2025.|1
04143|049|R|3.Lu WJ, Huang K, Lai ML, Huang JD. Erythromycin alters the pharmacokinetics|6
04143|050|R|  of bromocriptine by inhibition of organic anion transporting polypeptide|6
04143|051|R|  C-mediated uptake. Clin Pharmacol Ther 2006 Oct;80(4):421-2.|6
04143|052|R|4.This information is based on an extract from the Certara Drug Interaction|6
04143|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04143|054|R|5.Christensen J, Dupont E, OStergaard K. Cabergoline plasma concentration is|3
04143|055|R|  increased during concomitant treatment with itraconazole. Mov Disord 2002|3
04143|056|R|  Nov;17(6):1360-2.|3
04143|057|R|6.Nakatsuka A,  Nagai M,  Yabe H,  Nishikawa N,  Nomura T,  Moritoyo H,|2
04143|058|R|  Moritoyo T,  Nomoto M. Effect of clarithromycin on the pharmacokinetics of|2
04143|059|R|  cabergoline in healthy controls and in patients with Parkinson's disease.|2
04143|060|R|  J Pharmacol Sci 2006 Jan;100(1):59-64.|2
04143|061|R|7.Nelson MV, Berchou RC, Kareti D, LeWitt PA. Pharmacokinetic evaluation of|2
04143|062|R|  erythromycin and caffeine administered with bromocriptine. Clin Pharmacol|2
04143|063|R|  Ther 1990 Jun;47(6):694-7.|2
04144|001|T|MONOGRAPH TITLE:  Betibeglogene Autotemcel/Myelosuppressive Iron Chelators|
04144|002|B||
04144|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04144|004|L|of severe adverse interaction.|
04144|005|B||
04144|006|A|MECHANISM OF ACTION:  Treatment with betibeglogene autotemcel requires|
04144|007|A|hematopoietic stem cell (HSC) mobilization which can suppress the immune|
04144|008|A|system.|
04144|009|B||
04144|010|E|CLINICAL EFFECTS:  Myelosuppressive iron chelators may result in increased|
04144|011|E|risk of serious infections.|
04144|012|B||
04144|013|P|PREDISPOSING FACTORS:  None determined.|
04144|014|B||
04144|015|M|PATIENT MANAGEMENT:  Avoid myelosuppressive iron chelators for six months|
04144|016|M|after betibeglogene autotemcel infusion.  If iron chelation is needed,|
04144|017|M|consider administration of non-myelosuppressive iron chelators.(1)|
04144|018|B||
04144|019|D|DISCUSSION:  In clinical trials, 100% of 41 patients experienced Grade 3 or|
04144|020|D|4 neutropenia from Day 1 to Month 24.(1)|
04144|021|B||
04144|022|R|REFERENCE:|
04144|023|B||
04144|024|R|1.Zyntelgo (betibeglogene autotemcel) US prescribing information. bluebird|1
04144|025|R|  bio August 2022.|1
04145|001|T|MONOGRAPH TITLE:  Clozapine/Selected Strong CYP3A4 Inhibitors|
04145|002|B||
04145|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04145|004|L|of severe adverse interaction.|
04145|005|B||
04145|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04145|007|A|clozapine.(1,2)|
04145|008|B||
04145|009|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with CYP3A4|
04145|010|E|inhibitors may result in elevated levels of clozapine and an increase in|
04145|011|E|clozapine related side effects such as orthostatic hypotension, syncope, QT|
04145|012|E|prolongation, profound sedation and seizures.(1)|
04145|013|B||
04145|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04145|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04145|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04145|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04145|018|P|female gender, or advanced age.(3)|
04145|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04145|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04145|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04145|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04145|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04145|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04145|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04145|026|P|   The risk of anticholinergic toxicities including cognitive decline,|
04145|027|P|delirium, falls and fractures is increased in geriatric patients using more|
04145|028|P|than one medicine with anticholinergic properties.(4)|
04145|029|B||
04145|030|M|PATIENT MANAGEMENT:  Clozapine levels should be monitored in patients|
04145|031|M|receiving concurrent therapy with strong CYP3A4 inhibitors.  Patients should|
04145|032|M|be monitored for signs of clozapine toxicity.  The dosage of clozapine may|
04145|033|M|need to be adjusted, or one or both agents may need to be discontinued.|
04145|034|M|Clozapine levels should also be monitored following the discontinuation of|
04145|035|M|of the CYP3A4 inhibitor from concurrent therapy.(1)|
04145|036|M|   The Australian manufacturer of nirmatrelvir/ritonavir contraindicates|
04145|037|M|co-administration with clozapine.(5)|
04145|038|M|   If concurrent therapy is warranted in patients receiving clozapine,|
04145|039|M|consider obtaining serum calcium, magnesium, and potassium levels and|
04145|040|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04145|041|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04145|042|M|heartbeat, dizziness, or fainting.|
04145|043|B||
04145|044|D|DISCUSSION:  In a study in 92 psychiatric patients maintained on clozapine,|
04145|045|D|the ratio of clozapine levels/dose was found to correlate with expression of|
04145|046|D|CYP3A4.(1)|
04145|047|D|   Clozapine is a substrate of CYP1A2, CYP2D6, and CYP3AA4.(2)|
04145|048|B||
04145|049|R|REFERENCES:|
04145|050|B||
04145|051|R|1.Clozaril (clozapine) prescribing information. Novartis Pharmaceuticals|1
04145|052|R|  Corporation July, 2002.|1
04145|053|R|2.Toth K, Csukly G, Sirok D, Belic A, Kiss A, Hafra E, Deri M , Menus A,|2
04145|054|R|  BitterI, MonostoryK. Potential Role of Patients' CYP3A-Status in Clozapine|2
04145|055|R|  Pharmacokinetics. Int J Neuropsychopharmacol 2017 Jul 1;20(7):529-537.|2
04145|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04145|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04145|058|R|  settings: a scientific statement from the American Heart Association and|6
04145|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04145|060|R|  2;55(9):934-47.|6
04145|061|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04145|062|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04145|063|R|  Soc 2023 Jul;71(7):2052-2081.|6
04145|064|R|5.Paxlovid (nirmatrelvir-ritonavir) Australian Product Information. Pfizer|1
04145|065|R|  Australia Pty Ltd February 28, 2025.|1
04146|001|T|MONOGRAPH TITLE:  Clozapine/Strong CYP3A4 Inhibitors that Prolong QT|
04146|002|B||
04146|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04146|004|L|of severe adverse interaction.|
04146|005|B||
04146|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04146|007|A|clozapine.(1,2)|
04146|008|A|   Concurrent use of clozapine with agents that prolong the QTc interval may|
04146|009|A|result in additive effects on the QTc interval.(1)|
04146|010|B||
04146|011|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with CYP3A4|
04146|012|E|inhibitors may result in elevated levels of clozapine and an increase in|
04146|013|E|clozapine related side effects such as orthostatic hypotension, syncope, QT|
04146|014|E|prolongation, profound sedation and seizures.(1)|
04146|015|E|   The use of clozapine in patients maintained on agents that prolong the|
04146|016|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
04146|017|E|including torsades de pointes.(1)|
04146|018|B||
04146|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04146|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04146|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04146|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04146|023|P|female gender, or advanced age.(3)|
04146|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04146|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04146|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04146|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04146|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04146|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04146|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04146|031|P|   The risk of anticholinergic toxicities including cognitive decline,|
04146|032|P|delirium, falls and fractures is increased in geriatric patients using more|
04146|033|P|than one medicine with anticholinergic properties.(4)|
04146|034|B||
04146|035|M|PATIENT MANAGEMENT:  Clozapine levels should be monitored in patients|
04146|036|M|receiving concurrent therapy with strong CYP3A4 inhibitors.  Patients should|
04146|037|M|be monitored for signs of clozapine toxicity, including QT prolongation.|
04146|038|M|The dosage of clozapine may need to be adjusted, or one or both agents may|
04146|039|M|need to be discontinued.  Clozapine levels should also be monitored|
04146|040|M|following the discontinuation of of the CYP3A4 inhibitor from concurrent|
04146|041|M|therapy.(1)|
04146|042|M|   If concurrent therapy is warranted in patients receiving clozapine,|
04146|043|M|consider obtaining serum calcium, magnesium, and potassium levels and|
04146|044|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04146|045|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04146|046|M|heartbeat, dizziness, or fainting.|
04146|047|B||
04146|048|D|DISCUSSION:  In a study in 92 psychiatric patients maintained on clozapine,|
04146|049|D|the ratio of clozapine levels/dose was found to correlate with expression of|
04146|050|D|CYP3A4.(1)|
04146|051|D|   Clozapine is a substrate of CYP1A2, CYP2D6, and CYP3AA4.(2)|
04146|052|B||
04146|053|R|REFERENCES:|
04146|054|B||
04146|055|R|1.Clozaril (clozapine) prescribing information. Novartis Pharmaceuticals|1
04146|056|R|  Corporation July, 2002.|1
04146|057|R|2.Toth K, Csukly G, Sirok D, Belic A, Kiss A, Hafra E, Deri M , Menus A,|2
04146|058|R|  BitterI, MonostoryK. Potential Role of Patients' CYP3A-Status in Clozapine|2
04146|059|R|  Pharmacokinetics. Int J Neuropsychopharmacol 2017 Jul 1;20(7):529-537.|2
04146|060|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04146|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04146|062|R|  settings: a scientific statement from the American Heart Association and|6
04146|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04146|064|R|  2;55(9):934-47.|6
04146|065|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04146|066|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04146|067|R|  Soc 2023 Jul;71(7):2052-2081.|6
04147|001|T|MONOGRAPH TITLE:  Acalabrutinib Tablets/Cimetidine (mono deleted 12/06/2023)|
04147|002|B||
04147|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04147|004|L|take action as needed.|
04147|005|B||
04147|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
04147|007|A|the metabolism of acalabrutinib.(1)|
04147|008|B||
04147|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04147|010|E|levels of and effects from acalabrutinib.(1)|
04147|011|B||
04147|012|P|PREDISPOSING FACTORS:  None determined.|
04147|013|B||
04147|014|M|PATIENT MANAGEMENT:  Recommendations for management of this interaction vary|
04147|015|M|in different regions.|
04147|016|M|   The US manufacturer of acalabrutinib states that the concurrent chronic|
04147|017|M|use of strong CYP3A4 inhibitors with acalabrutinib is not recommended.  For|
04147|018|M|short-term use of strong CYP3A4 inhibitors, such as 7 days or less of|
04147|019|M|antibiotics/antifungals, consider interruption of acalabrutinib therapy.  If|
04147|020|M|a moderate CYP3A4 inhibitor is required, reduce the dose of acalabrutinib to|
04147|021|M|100 mg once daily.(1)|
04147|022|M|   The UK manufacturer of acalabrutinib makes the same recommendation|
04147|023|M|regarding strong CYP3A4 inhibitors, but states that no dose adjustment is|
04147|024|M|needed for concurrent use of acalabrutinib with moderate CYP3A4 inhibitors.|
04147|025|M|Patients should be monitored closely for adverse effects.(2)|
04147|026|B||
04147|027|D|DISCUSSION:  In a study with healthy volunteers, single-dose fluconazole 400|
04147|028|D|mg and isavuconazole 200 mg daily for 5 days (both moderate CYP3A4|
04147|029|D|inhibitors) increased the maximum concentration (Cmax) and area-under-curve|
04147|030|D|(AUC) of acalabrutinib by 1.4- to 2-fold.  The Cmax and AUC of the active|
04147|031|D|metabolite ACP-5862 was decreased by 0.65- to 0.88-fold.(2)|
04147|032|D|   A physiologically based pharmacokinetic simulation with acalabrutinib and|
04147|033|D|moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) predicted|
04147|034|D|that coadministration increases acalabrutinib Cmax and AUC by 2- to almost|
04147|035|D|3-fold.(1)|
04147|036|D|   In a study in healthy subjects, itraconazole (200mg once daily for 5|
04147|037|D|days, a strong inhibitor) increased the Cmax and AUC of acalabrutinib by|
04147|038|D|3.9-fold and 5.1-fold, respectively.(1)|
04147|039|B||
04147|040|R|REFERENCES:|
04147|041|B||
04147|042|R|1.Calquence (acalabrutinib) US prescribing information. AstraZeneca|1
04147|043|R|  Pharmaceuticals LP August, 2022.|1
04147|044|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04147|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04147|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04147|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04147|048|R|  11/14/2017.|1
04147|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
04147|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04148|001|T|MONOGRAPH TITLE:  Clozapine/Myelosuppressive Strong CYP3A4 Inhibitors|
04148|002|B||
04148|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04148|004|L|of severe adverse interaction.|
04148|005|B||
04148|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04148|007|A|clozapine.(1,2)|
04148|008|A|   Clozapine and concurrent use with other myelosuppressive agents may be|
04148|009|A|associated with additive risk of neutropenia or agranulocytosis.(1)|
04148|010|B||
04148|011|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with CYP3A4|
04148|012|E|inhibitors may result in elevated levels of clozapine and an increase in|
04148|013|E|clozapine related side effects such as orthostatic hypotension, syncope, QT|
04148|014|E|prolongation, profound sedation and seizures.(1)|
04148|015|E|   Moderate neutropenia, even if due to combination therapy, may require|
04148|016|E|abrupt discontinuation of clozapine resulting in decompensation of the|
04148|017|E|patient's psychiatric disorder (e.g. schizophrenia).  The disease treated by|
04148|018|E|the myelosuppressive agent may be compromised if myelosuppression requires|
04148|019|E|dose reduction, delay, or discontinuation of the myelosuppressive agent.|
04148|020|E|Undetected severe neutropenia or agranulocytosis may be fatal.|
04148|021|B||
04148|022|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04148|023|P|may be increased in patients with cardiovascular disease (e.g. heart|
04148|024|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04148|025|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04148|026|P|female gender, or advanced age.(2)|
04148|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04148|028|P|higher systemic concentrations of either QT prolonging drug are additional|
04148|029|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04148|030|P|drug concentrations include rapid infusion of an intravenous dose or|
04148|031|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04148|032|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04148|033|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04148|034|P|   Low white blood counts prior to initiation of the myelosuppressive agent|
04148|035|P|may increase risk for clinically significant neutropenia.|
04148|036|B||
04148|037|M|PATIENT MANAGEMENT:  Clozapine levels should be monitored in patients|
04148|038|M|receiving concurrent therapy with strong CYP3A4 inhibitors.  Patients should|
04148|039|M|be monitored for signs of clozapine toxicity, including QT prolongation and|
04148|040|M|myelosuppression.  The dosage of clozapine may need to be adjusted, or one|
04148|041|M|or both agents may need to be discontinued.  Clozapine levels should also be|
04148|042|M|monitored following the discontinuation of of the CYP3A4 inhibitor from|
04148|043|M|concurrent therapy.(1)|
04148|044|M|   If a patient stabilized on clozapine therapy requires treatment with a|
04148|045|M|myelosuppressive agent, the clozapine prescriber should consult with|
04148|046|M|prescriber of the myelosuppressive agent (e.g. oncologist) to discuss|
04148|047|M|treatment and monitoring options.(2)  More frequent ANC monitoring or|
04148|048|M|treatment alternatives secondary to neutropenic episodes may need to be|
04148|049|M|considered.|
04148|050|M|   Clozapine is only available through a restricted  distribution system|
04148|051|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
04148|052|M|dispensing.(1-2)  For most clozapine patients, clozapine treatment must be|
04148|053|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
04148|054|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
04148|055|M|interrupted for suspected clozapine-induced neutropenia < 500|
04148|056|M|cells/microliter.(2)|
04148|057|M|   If concurrent therapy is warranted in patients receiving clozapine,|
04148|058|M|consider obtaining serum calcium, magnesium, and potassium levels and|
04148|059|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04148|060|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04148|061|M|heartbeat, dizziness, or fainting.|
04148|062|B||
04148|063|D|DISCUSSION:  In a study in 92 psychiatric patients maintained on clozapine,|
04148|064|D|the ratio of clozapine levels/dose was found to correlate with expression of|
04148|065|D|CYP3A4.(1) Clozapine is a substrate of CYP1A2, CYP2D6, and CYP3AA4.(2)|
04148|066|D|   Clozapine is only available through a restricted  distribution system|
04148|067|D|which requires documentation of the ANC prior to dispensing.(1)|
04148|068|B||
04148|069|R|REFERENCES:|
04148|070|B||
04148|071|R|1.Clozaril (clozapine) prescribing information. Novartis Pharmaceuticals|1
04148|072|R|  Corporation July, 2002.|1
04148|073|R|2.Toth K, Csukly G, Sirok D, Belic A, Kiss A, Hafra E, Deri M , Menus A,|2
04148|074|R|  BitterI, MonostoryK. Potential Role of Patients' CYP3A-Status in Clozapine|2
04148|075|R|  Pharmacokinetics. Int J Neuropsychopharmacol 2017 Jul 1;20(7):529-537.|2
04149|001|T|MONOGRAPH TITLE:  Clozapine/Myelosuppressive CYP3A4 Inhibitors that Prolong|
04149|002|T|QT|
04149|003|B||
04149|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04149|005|L|of severe adverse interaction.|
04149|006|B||
04149|007|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04149|008|A|clozapine.(1,2)|
04149|009|A|   Concurrent use of clozapine with agents that prolong the QTc interval and|
04149|010|A|cause myelosuppression may result in additive effects on both the QTc|
04149|011|A|interval and blood counts.(1)|
04149|012|B||
04149|013|E|CLINICAL EFFECTS:  The concurrent administration of clozapine with CYP3A4|
04149|014|E|inhibitors may result in elevated levels of clozapine and an increase in|
04149|015|E|clozapine related side effects such as orthostatic hypotension, syncope, QT|
04149|016|E|prolongation, profound sedation and seizures.(1)|
04149|017|E|   The use of clozapine in patients maintained on agents that prolong the|
04149|018|E|QTc interval may result in potentially life-threatening cardiac arrhythmias,|
04149|019|E|including torsades de pointes.(1)|
04149|020|E|   Moderate neutropenia, even if due to combination therapy, may require|
04149|021|E|abrupt discontinuation of clozapine resulting in decompensation of the|
04149|022|E|patient's psychiatric disorder (e.g. schizophrenia).  The disease treated by|
04149|023|E|the myelosuppressive agent may be compromised if myelosuppression requires|
04149|024|E|dose reduction, delay, or discontinuation of the myelosuppressive agent.|
04149|025|E|Undetected severe neutropenia or agranulocytosis may be fatal.|
04149|026|B||
04149|027|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04149|028|P|may be increased in patients with cardiovascular disease (e.g. heart|
04149|029|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04149|030|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04149|031|P|female gender, or advanced age.(2)|
04149|032|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04149|033|P|higher systemic concentrations of either QT prolonging drug are additional|
04149|034|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04149|035|P|drug concentrations include rapid infusion of an intravenous dose or|
04149|036|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04149|037|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04149|038|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04149|039|P|   Low white blood counts prior to initiation of the myelosuppressive agent|
04149|040|P|may increase risk for clinically significant neutropenia.|
04149|041|B||
04149|042|M|PATIENT MANAGEMENT:  Clozapine levels should be monitored in patients|
04149|043|M|receiving concurrent therapy with strong CYP3A4 inhibitors.  Patients should|
04149|044|M|be monitored for signs of clozapine toxicity, including QT prolongation and|
04149|045|M|myelosuppression.  The dosage of clozapine may need to be adjusted, or one|
04149|046|M|or both agents may need to be discontinued.  Clozapine levels should also be|
04149|047|M|monitored following the discontinuation of of the CYP3A4 inhibitor from|
04149|048|M|concurrent therapy.(1)|
04149|049|M|   If a patient stabilized on clozapine therapy requires treatment with a|
04149|050|M|myelosuppressive agent, the clozapine prescriber should consult with|
04149|051|M|prescriber of the myelosuppressive agent (e.g. oncologist) to discuss|
04149|052|M|treatment and monitoring options.(2)  More frequent ANC monitoring or|
04149|053|M|treatment alternatives secondary to neutropenic episodes may need to be|
04149|054|M|considered.|
04149|055|M|   Clozapine is only available through a restricted  distribution system|
04149|056|M|which requires documentation of the absolute neutrophil count (ANC) prior to|
04149|057|M|dispensing.(1-2)  For most clozapine patients, clozapine treatment must be|
04149|058|M|interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter.|
04149|059|M|For patients with benign ethnic neutropenia (BEN), treatment must be|
04149|060|M|interrupted for suspected clozapine-induced neutropenia < 500|
04149|061|M|cells/microliter.(2)|
04149|062|M|   If concurrent therapy is warranted in patients receiving clozapine,|
04149|063|M|consider obtaining serum calcium, magnesium, and potassium levels and|
04149|064|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04149|065|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04149|066|M|heartbeat, dizziness, or fainting.|
04149|067|B||
04149|068|D|DISCUSSION:  In a study in 92 psychiatric patients maintained on clozapine,|
04149|069|D|the ratio of clozapine levels/dose was found to correlate with expression of|
04149|070|D|CYP3A4.(1) Clozapine is a substrate of CYP1A2, CYP2D6, and CYP3AA4.(2)|
04149|071|D|   Clozapine is only available through a restricted  distribution system|
04149|072|D|which requires documentation of the ANC prior to dispensing.(1)|
04149|073|D|   Myelosuppressive CYP3A4 inhibitors that prolong QT linked to this|
04149|074|D|monograph include: adagrasib, lonafarnib, and ribociclib.|
04149|075|B||
04149|076|R|REFERENCES:|
04149|077|B||
04149|078|R|1.Clozaril (clozapine) prescribing information. Novartis Pharmaceuticals|1
04149|079|R|  Corporation July, 2002.|1
04149|080|R|2.Toth K, Csukly G, Sirok D, Belic A, Kiss A, Hafra E, Deri M , Menus A,|2
04149|081|R|  BitterI, MonostoryK. Potential Role of Patients' CYP3A-Status in Clozapine|2
04149|082|R|  Pharmacokinetics. Int J Neuropsychopharmacol 2017 Jul 1;20(7):529-537.|2
04150|001|T|MONOGRAPH TITLE:  Selected Bowel Preparations/Stimulant Laxatives|
04150|002|B||
04150|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04150|004|L|of severe adverse interaction.|
04150|005|B||
04150|006|A|MECHANISM OF ACTION:  Osmotic laxatives and stimulant laxatives may have|
04150|007|A|additive adverse effects.(1)|
04150|008|B||
04150|009|E|CLINICAL EFFECTS:  Concurrent use of stimulant laxatives and Sutab tablets|
04150|010|E|(sodium sulfate, magnesium sulfate, and potassium chloride) may increase the|
04150|011|E|risk of mucosal ulceration, ischemic colitis, gastric ulcerations, or|
04150|012|E|gastritis.(1)|
04150|013|B||
04150|014|P|PREDISPOSING FACTORS:  None determined.|
04150|015|B||
04150|016|M|PATIENT MANAGEMENT:  The manufacturer of Sutab tablets (sodium sulfate,|
04150|017|M|magnesium sulfate and potassium chloride) recommends avoiding the use of|
04150|018|M|stimulant laxatives while using this bowel preparation product.(1)|
04150|019|B||
04150|020|D|DISCUSSION:  Osmotic laxative products may produce colonic mucosal aphthous|
04150|021|D|ulcerations which reports have shown can lead to ischemic colitis requiring|
04150|022|D|hospitalization.  Using stimulant laxatives in addition may increase this|
04150|023|D|risk.(1)|
04150|024|B||
04150|025|R|REFERENCE:|
04150|026|B||
04150|027|R|1.Sutab (sodium sulfate, magnesium sulfate, and potassium chloride tablets)|1
04150|028|R|  US prescribing information. Braintree Laboratories, Inc. February, 2022.|1
04164|001|T|MONOGRAPH TITLE:  Lomitapide (Greater Than 40 mg)/Hormonal Contraceptives|
04164|002|B||
04164|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04164|004|L|is contraindicated and generally should not be dispensed or administered to|
04164|005|L|the same patient.|
04164|006|B||
04164|007|A|MECHANISM OF ACTION:  Hormonal contraceptives are weak inhibitors of CYP3A4|
04164|008|A|and may inhibit the metabolism of lomitapide.(1)|
04164|009|A|   Lomitapide is very susceptible to CYP3A4 inhibition.  For example, in an|
04164|010|A|interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide|
04164|011|A|exposure was increased 27-fold.(2)  Thus even weak CYP3A4 inhibitors may|
04164|012|A|affect lomitapide exposure (AUC, area-under-curve).|
04164|013|B||
04164|014|E|CLINICAL EFFECTS:  Concurrent use of a weak inhibitor of CYP3A4 may result|
04164|015|E|in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)|
04164|016|B||
04164|017|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
04164|018|P|hepatic impairment or with end-stage renal disease.(1)|
04164|019|B||
04164|020|M|PATIENT MANAGEMENT:  The maximum lomitapide dose should be 40 mg daily for|
04164|021|M|patients taking hormonal contraceptives.  Due to lomitapide's long|
04164|022|M|half-life, it may take 1 to 2 weeks to see the full effect of this|
04164|023|M|interaction.|
04164|024|M|   When initiating a hormonal contraceptive in patients taking lomitapide 10|
04164|025|M|mg daily or more, decrease the dose of lomitapide by 50%.  In patients|
04164|026|M|taking lomitapide 5 mg daily, continue current dose.|
04164|027|B||
04164|028|D|DISCUSSION:  Lomitapide is very susceptible to CYP3A4 inhibition.  For|
04164|029|D|example, in an interaction study with a strong CYP3A4 inhibitor|
04164|030|D|(ketoconazole) lomitapide exposure was increased 27-fold.(2)  Based upon|
04164|031|D|interactions with stronger inhibitors, weak inhibitors of CYP3A4 are|
04164|032|D|predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1)|
04164|033|B||
04164|034|R|REFERENCE:|
04164|035|B||
04164|036|R|1.Juxtapid (lomitapide) US prescribing information. Aegerion|1
04164|037|R|  Pharmaceuticals, Inc. May, 2016.|1
04165|001|T|MONOGRAPH TITLE:  Saccharomyces Boulardii/Antifungals|
04165|002|B||
04165|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
04165|004|L|Assess the risk to the patient and take action as needed.|
04165|005|B||
04165|006|A|MECHANISM OF ACTION:  The mechanism of action is unknown but may be due to|
04165|007|A|inactivation of Saccharomyces boulardii by the antifungal therapy.(1)|
04165|008|B||
04165|009|E|CLINICAL EFFECTS:  Concurrent use of antifungals may result in decreased|
04165|010|E|effectiveness of Saccharomyces boulardii.(1)|
04165|011|B||
04165|012|P|PREDISPOSING FACTORS:  None determined.|
04165|013|B||
04165|014|M|PATIENT MANAGEMENT:  Patients taking antifungals should be alerted to the|
04165|015|M|possibility of probiotics containing Saccharomyces boulardii may be|
04165|016|M|inactivated. Consider holding probiotics containing Saccharomyces boulardii|
04165|017|M|during therapy with antifungals.|
04165|018|B||
04165|019|D|DISCUSSION:  Antifungals are known to have activity against Saccharomyces|
04165|020|D|boulardii and a possible interaction is expected.|
04165|021|B||
04165|022|R|REFERENCE:|
04165|023|B||
04165|024|R|1.Florastor Daily Probiotic Supplement US prescribing information. Biocodex|1
04165|025|R|  North America November, 2021.|1
04166|001|T|MONOGRAPH TITLE:  Bupropion/Strong CYP2B6 Inducers|
04166|002|B||
04166|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04166|004|L|of severe adverse interaction.|
04166|005|B||
04166|006|A|MECHANISM OF ACTION:  Strong CYP2B6 inducers may induce the metabolism of|
04166|007|A|bupropion.(1)|
04166|008|B||
04166|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP2B6 inducers may|
04166|010|E|decrease the effectiveness of bupropion.(1)|
04166|011|B||
04166|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04166|013|P|of the inducer for longer than 1-2 weeks.|
04166|014|B||
04166|015|M|PATIENT MANAGEMENT:  Concurrent use of bupropion and strong CYP2B6 inducers|
04166|016|M|should be avoided.  Consider the use of alternative agents in patients|
04166|017|M|maintained on bupropion for psychiatric indications and inform patients that|
04166|018|M|bupropion may not be effective for smoking cessation during concurrent|
04166|019|M|therapy with strong CYP2B6 inducers.|
04166|020|M|   If concurrent use is warranted, monitor patients for decreased levels and|
04166|021|M|effectiveness if strong CYP2B6 inducers are initiated.  The dosage of|
04166|022|M|bupropion may need to be increased; however, the maximum recommended dose of|
04166|023|M|bupropion should not be exceed.(2)|
04166|024|B||
04166|025|D|DISCUSSION:  In a study in 16 healthy subjects, rifampin (600 mg/day, a|
04166|026|D|moderate CYP2B6 inducer) increased bupropion (150 mg single dose) apparent|
04166|027|D|clearance 2-fold and decreased the bupropion half-life by 48%.  In addition,|
04166|028|D|concurrent rifampin increased the maximum concentration (Cmax) of|
04166|029|D|hydroxybupropion by 43% and decreased the hydroxybupropion area-under-curve|
04166|030|D|(AUC) by 38%.(2)|
04166|031|D|   In a study with 34 subjects, the effects of 150 mg of bupropion alone and|
04166|032|D|150 mg of bupropion with carbamazepine (a strong CYP2B6 inducer) were|
04166|033|D|compared. Carbamazepine decreased bupropion AUC by 90% and peak Cmax by 87%.|
04166|034|D|In addition, hydroxybupropion peak concentration Cmax by 71% and AUC by|
04166|035|D|50%.(3)|
04166|036|D|   Strong CYP2B6 inducers linked include: carbamazepine.(4,5)|
04166|037|B||
04166|038|R|REFERENCES:|
04166|039|B||
04166|040|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
04166|041|R|  GlaxoSmithKline November, 2019.|1
04166|042|R|2.Loboz KK, Gross AS, Williams KM, Liauw WS, Day RO, Blievernicht JK, Zanger|2
04166|043|R|  UM, McLachlan AJ. Cytochrome P450 2B6 activity as measured by bupropion|2
04166|044|R|  hydroxylation: effect of induction by rifampin and ethnicity. Clin|2
04166|045|R|  Pharmacol Ther 2006 Jul;80(1):75-84.|2
04166|046|R|3.Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George|2
04166|047|R|  MS, Callahan AM, Hinton ML, Chao J, Post RM. Carbamazepine but not|2
04166|048|R|  valproate induces bupropion metabolism. J Clin Psychopharmacol 1995 Oct;|2
04166|049|R|  15(5):327-33.|2
04166|050|R|4.This information is based on an extract from the Certara Drug Interaction|6
04166|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04166|052|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04166|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04166|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04166|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04166|056|R|  11/14/2017.|1
04167|001|T|MONOGRAPH TITLE:  Bupropion Combinations/Strong CYP2B6 Inducers|
04167|002|B||
04167|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04167|004|L|of severe adverse interaction.|
04167|005|B||
04167|006|A|MECHANISM OF ACTION:  Strong CYP2B6 inducers may induce the metabolism of|
04167|007|A|bupropion.(1,2)  For the dextromethorphan/bupropion combination, the|
04167|008|A|metabolism of dextromethorphan may also be increased.(1)|
04167|009|B||
04167|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP2B6 inducers may|
04167|011|E|decrease the effectiveness of bupropion.(1,2)  For the|
04167|012|E|dextromethorphan/bupropion combination, the levels and effectiveness of|
04167|013|E|dextromethorphan may also be decreased.(1)|
04167|014|B||
04167|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04167|016|P|of the inducer for longer than 1-2 weeks.|
04167|017|B||
04167|018|M|PATIENT MANAGEMENT:  The manufacturers of dextromethorphan/bupropion and|
04167|019|M|naltrexone/bupropion state concurrent use with strong CYP2B6 inducers should|
04167|020|M|be avoided.(1,2)|
04167|021|B||
04167|022|D|DISCUSSION:  In a clinical study, carbamazepine 200 mg decreased the maximum|
04167|023|D|concentration (Cmax) and area-under-curve (AUC) of bupropion by 74% and 76%,|
04167|024|D|respectively, and decreased the Cmax and AUC of dextromethorphan by 59% and|
04167|025|D|64%, respectively.(1)|
04167|026|D|   In a study with 34 subjects, the effects of 150 mg of bupropion alone and|
04167|027|D|150 mg of bupropion with carbamazepine (a strong CYP2B6 inducer) were|
04167|028|D|compared. Carbamazepine decreased bupropion AUC by 90% and peak Cmax by 87%.|
04167|029|D|In addition, hydroxybupropion peak concentration Cmax by 71% and AUC by|
04167|030|D|50%.(3)|
04167|031|D|   In a study in 16 healthy subjects, rifampin (600 mg/day, a moderate|
04167|032|D|CYP2B6 inducer) increased bupropion (150 mg single dose) apparent clearance|
04167|033|D|2-fold and decreased the bupropion half-life by 48%.  In addition,|
04167|034|D|concurrent rifampin increased the Cmax of hydroxybupropion by 43% and|
04167|035|D|decreased the hydroxybupropion AUC by 38%.(4)|
04167|036|D|   Strong CYP2B6 inducers linked include: carbamazepine.(5,6)|
04167|037|B||
04167|038|R|REFERENCES:|
04167|039|B||
04167|040|R|1.Auvelity (dextromethorphan and bupropion) US prescribing information.|1
04167|041|R|  Axsome Therapeutics, Inc. September, 2022.|1
04167|042|R|2.Contrave (naltrexone and bupropion) US prescribing infromation. Nalpropion|1
04167|043|R|  Pharmaceuticals LLC May, 2024.|1
04167|044|R|3.Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George|2
04167|045|R|  MS, Callahan AM, Hinton ML, Chao J, Post RM. Carbamazepine but not|2
04167|046|R|  valproate induces bupropion metabolism. J Clin Psychopharmacol 1995 Oct;|2
04167|047|R|  15(5):327-33.|2
04167|048|R|4.Loboz KK, Gross AS, Williams KM, Liauw WS, Day RO, Blievernicht JK, Zanger|2
04167|049|R|  UM, McLachlan AJ. Cytochrome P450 2B6 activity as measured by bupropion|2
04167|050|R|  hydroxylation: effect of induction by rifampin and ethnicity. Clin|2
04167|051|R|  Pharmacol Ther 2006 Jul;80(1):75-84.|2
04167|052|R|5.This information is based on an extract from the Certara Drug Interaction|6
04167|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04167|054|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04167|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04167|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04167|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04167|058|R|  11/14/2017.|1
04168|001|T|MONOGRAPH TITLE:  Bupropion Combinations/Moderate CYP2B6 Inducers|
04168|002|B||
04168|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04168|004|L|take action as needed.|
04168|005|B||
04168|006|A|MECHANISM OF ACTION:  Moderate CYP2B6 inducers may induce the metabolism of|
04168|007|A|bupropion.(1,2)  For the dextromethorphan/bupropion combination, the|
04168|008|A|metabolism of dextromethorphan may also be increased.(1)|
04168|009|B||
04168|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP2B6 inducers may decrease|
04168|011|E|the effectiveness of bupropion.(1,2)  For the dextromethorphan/bupropion|
04168|012|E|combination, the levels and effectiveness of dextromethorphan may also be|
04168|013|E|decreased.(1)|
04168|014|B||
04168|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04168|016|P|of the inducer for longer than 1-2 weeks.|
04168|017|B||
04168|018|M|PATIENT MANAGEMENT:  Consider the use of alternative agents in patients|
04168|019|M|maintained on bupropion for psychiatric indications and inform patients that|
04168|020|M|bupropion may not be effective for smoking cessation during concurrent|
04168|021|M|moderate CYP2B6 inducers.|
04168|022|M|   If concurrent use is warranted, monitor patients for decreased levels and|
04168|023|M|effectiveness if moderate CYP2B6 inducers are initiated.  The dosage of|
04168|024|M|bupropion may need to be increased; however, the maximum recommended dose of|
04168|025|M|bupropion should not be exceed.(2)|
04168|026|B||
04168|027|D|DISCUSSION:  In a clinical study, carbamazepine 200 mg decreased the maximum|
04168|028|D|concentration (Cmax) and area-under-curve (AUC) of bupropion by 74% and 76%,|
04168|029|D|respectively, and decreased the Cmax and AUC of dextromethorphan by 59% and|
04168|030|D|64%, respectively.(1)|
04168|031|D|   In a study with 34 subjects, the effects of 150 mg of bupropion alone and|
04168|032|D|150 mg of bupropion with carbamazepine (a strong CYP2B6 inducer) were|
04168|033|D|compared. Carbamazepine decreased bupropion AUC by 90% and peak Cmax by 87%.|
04168|034|D|In addition, carbamazepine increased hydroxybupropion Cmax by 71% and AUC|
04168|035|D|by 50%.(3)|
04168|036|D|   In a study in 16 healthy subjects, rifampin (600 mg/day, a moderate|
04168|037|D|CYP2B6 inducer) increased bupropion (150 mg single dose) apparent clearance|
04168|038|D|2-fold and decreased the bupropion half-life by 48%.  In addition,|
04168|039|D|concurrent rifampin increased the Cmax of hydroxybupropion by 43% and|
04168|040|D|decreased the hydroxybupropion AUC by 38%.(4)|
04168|041|D|   Moderate CYP2B6 inducers linked include: dipyrone, efavirenz, rifampin,|
04168|042|D|and ritonavir.(4,5)|
04168|043|B||
04168|044|R|REFERENCES:|
04168|045|B||
04168|046|R|1.Auvelity (dextromethorphan and bupropion) US prescribing information.|1
04168|047|R|  Axsome Therapeutics, Inc. September, 2022.|1
04168|048|R|2.Contrave (naltrexone and bupropion) US prescribing infromation. Nalpropion|1
04168|049|R|  Pharmaceuticals LLC May, 2024.|1
04168|050|R|3.Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George|2
04168|051|R|  MS, Callahan AM, Hinton ML, Chao J, Post RM. Carbamazepine but not|2
04168|052|R|  valproate induces bupropion metabolism. J Clin Psychopharmacol 1995 Oct;|2
04168|053|R|  15(5):327-33.|2
04168|054|R|4.Loboz KK, Gross AS, Williams KM, Liauw WS, Day RO, Blievernicht JK, Zanger|2
04168|055|R|  UM, McLachlan AJ. Cytochrome P450 2B6 activity as measured by bupropion|2
04168|056|R|  hydroxylation: effect of induction by rifampin and ethnicity. Clin|2
04168|057|R|  Pharmacol Ther 2006 Jul;80(1):75-84.|2
04168|058|R|5.This information is based on an extract from the Certara Drug Interaction|6
04168|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04168|060|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04168|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04168|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04168|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04168|064|R|  11/14/2017.|1
04169|001|T|MONOGRAPH TITLE:  Erythromycin/Atazanavir|
04169|002|B||
04169|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04169|004|L|of severe adverse interaction.|
04169|005|B||
04169|006|A|MECHANISM OF ACTION:  Atazanavir may inhibit the metabolism of erythromycin|
04169|007|A|by CYP3A4.(3)  Erythromycin has been shown to prolong the QTc interval,|
04169|008|A|which may result in torsades de pointes.(1)|
04169|009|A|   In addition, atazanavir has been shown to prolong the PR interval which|
04169|010|A|may have additional effects on the risk of arrhythmias.(2)|
04169|011|B||
04169|012|E|CLINICAL EFFECTS:  Concurrent use of erythromycin with potent inhibitors of|
04169|013|E|CYP3A4 such as atazanavir may result in elevated levels of erythromycin and|
04169|014|E|risk of QT prolongation or torsades de pointes leading to sudden death from|
04169|015|E|cardiac causes.(1)|
04169|016|B||
04169|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04169|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04169|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04169|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04169|021|P|female gender, or advanced age.(3)|
04169|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04169|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04169|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04169|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04169|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04169|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04169|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04169|029|B||
04169|030|M|PATIENT MANAGEMENT:  It has been suggested that the concurrent use of|
04169|031|M|erythromycin with strong CYP3A4 inhibitors should be avoided.(1)|
04169|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04169|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04169|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04169|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04169|036|B||
04169|037|D|DISCUSSION:  A retrospective review examined sudden cardiac death in|
04169|038|D|Tennessee Medicaid patients.  Erythromycin use increased the risk of sudden|
04169|039|D|cardiac death by 1.79-fold.  Concurrent use of erythromycin with a potent|
04169|040|D|inhibitor of CYP3A4 (diltiazem, fluconazole, itraconazole, ketoconazole,|
04169|041|D|troleandomycin, or verapamil) increased the risk of sudden cardiac death by|
04169|042|D|5.35-fold when compared to patients receiving no antibiotic therapy.  There|
04169|043|D|was one death in 106 person-years among concurrent users of diltiazem and|
04169|044|D|erythromycin.  There were two deaths in 78 person-years among concurrent|
04169|045|D|users of verapamil and erythromycin.  There were no sudden cardiac deaths|
04169|046|D|among concurrent users of erythromycin and other calcium channel blockers|
04169|047|D|that do not inhibit CYP3A4.(1)|
04169|048|B||
04169|049|R|REFERENCES:|
04169|050|B||
04169|051|R|1.Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral|2
04169|052|R|  erythromycin and the risk of sudden death from cardiac causes. N Engl J|2
04169|053|R|  Med 2004 Sep 9;351(11):1089-96.|2
04169|054|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04169|055|R|  Squibb Company December, 2024.|1
04169|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04169|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04169|058|R|  settings: a scientific statement from the American Heart Association and|6
04169|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04169|060|R|  2;55(9):934-47.|6
04170|001|T|MONOGRAPH TITLE:  Elivaldogene Autotemcel/Anti-Retrovirals|
04170|002|B||
04170|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04170|004|L|of severe adverse interaction.|
04170|005|B||
04170|006|A|MECHANISM OF ACTION:  Elivaldogene autotemcel is prepared from apheresed|
04170|007|A|cells that are transduced with a replication defective, self-inactivating|
04170|008|A|lentiviral vector.  Antiretrovirals may interfere with the manufacturing of|
04170|009|A|apheresed cells.|
04170|010|B||
04170|011|E|CLINICAL EFFECTS:  Use of antiretrovirals before mobilization and apheresis|
04170|012|E|may interfere with the production of elivaldogene autotemcel.|
04170|013|B||
04170|014|P|PREDISPOSING FACTORS:  None determined.|
04170|015|B||
04170|016|M|PATIENT MANAGEMENT:  Discontinue antiretrovirals for at least one month|
04170|017|M|prior to mobilization and until all cycles of apheresis are completed.|
04170|018|M|   If a patient requires antiretrovirals for HIV prophylaxis, then confirm a|
04170|019|M|negative HIV test before beginning mobilization and apheresis of CD34+|
04170|020|M|cells.|
04170|021|B||
04170|022|D|DISCUSSION:  Antiretroviral medications may interfere with the manufacturing|
04170|023|D|of elivaldogene autotemcel therapy.(1)|
04170|024|B||
04170|025|R|REFERENCE:|
04170|026|B||
04170|027|R|1.Skysona (elivaldogene autotemcel) US prescribing information. bluebird bio|1
04170|028|R|  September 2022.|1
04171|001|T|MONOGRAPH TITLE:  Zolmitriptan (Less Than or Equal To 2.5 mg)/Cimetidine|
04171|002|B||
04171|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04171|004|L|take action as needed.|
04171|005|B||
04171|006|A|MECHANISM OF ACTION:  Cimetidine inhibits the CYP1A2 mediated metabolism of|
04171|007|A|zolmitriptan and its active N-desmethyl metabolite.(1,2)|
04171|008|B||
04171|009|E|CLINICAL EFFECTS:  Increased concentrations of zolmitriptan and its active|
04171|010|E|N-desmethyl metabolite may increase the risk for adverse effects such as|
04171|011|E|paresthesia, dizziness, or sensation of heaviness or tightness in the|
04171|012|E|neck/throat/jaw, or chest.(1)|
04171|013|B||
04171|014|P|PREDISPOSING FACTORS:  Due to the extended half-life associated with|
04171|015|P|concurrent cimetidine use, multiple doses of zolmitriptan within a 24-hour|
04171|016|P|period may lead to accumulation, increasing the risk for adverse|
04171|017|P|effects.(1,2)|
04171|018|B||
04171|019|M|PATIENT MANAGEMENT:  The manufacturer of zolmitriptan recommends the maximum|
04171|020|M|single dose be reduced to 2.5 mg, not to exceed 5 mg in any 24-hour|
04171|021|M|period.(1)|
04171|022|M|   When possible, consider use of an alternative acid reducing agent.|
04171|023|B||
04171|024|D|DISCUSSION:  Zolmitriptan is converted to several metabolites, but only the|
04171|025|D|N-desmethyl metabolite is active.  Although plasma concentrations are about|
04171|026|D|2/3 of the parent drug, the N-desmethyl metabolite is 2 to 6 times more|
04171|027|D|potent at 5-HT1B/1D receptors than zolmitriptan and may contribute|
04171|028|D|substantially to its pharmacologic effect.(1)|
04171|029|D|   Zolmitriptan added to therapeutic doses of cimetidine 400 mg three times|
04171|030|D|a day increased the area-under-curve(AUC) for zolmitriptan and its active|
04171|031|D|N-desmethyl metabolite of approximately 1.5 fold and 2 fold|
04171|032|D|respectively.(1,2)|
04171|033|D|   An open 2 period crossover study in 16 volunteer subjects evaluated the|
04171|034|D|pharmacokinetics of zolmitriptan and the N-desmethyl metabolite with or|
04171|035|D|without cimetidine 400mg every 8 hours for 2 days.  After cimetidine|
04171|036|D|treatment, the AUC of zolmitriptan and the N-desmethyl metabolite increased|
04171|037|D|1.48 and 2.05 fold respectively.  The half-life of zolmitriptan increased|
04171|038|D|from 4.99 to 7.19 hours, while the active metabolite half-life increased|
04171|039|D|from 3.81 to 8.00 hours after treatment with cimetidine.(2)|
04171|040|B||
04171|041|R|REFERENCES:|
04171|042|B||
04171|043|R|1.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
04171|044|R|  Pharmaceuticals LP September, 2012.|1
04171|045|R|2.Dixon R, French S, Kemp J, Sellers M, Yates R. The metabolism of|2
04171|046|R|  zolmitriptan: effects of an inducer and an inhibitor of cytochrome p450 on|2
04171|047|R|  its pharmacokinetics in healthy volunteers. Clin Drug Investig 1998;|2
04171|048|R|  15(6):515-22.|2
04172|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 20 mg)/Tafamidis|
04172|002|B||
04172|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04172|004|L|is contraindicated and generally should not be dispensed or administered to|
04172|005|L|the same patient.|
04172|006|B||
04172|007|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate of the BCRP|
04172|008|A|transporter.(1,2)  Tafamidis has been shown to inhibit this transporter and|
04172|009|A|may increase intestinal absorption and decrease hepatic uptake of|
04172|010|A|rosuvastatin.(1-3)|
04172|011|B||
04172|012|E|CLINICAL EFFECTS:  Concurrent use of tafamidis may result in increased|
04172|013|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1,2)|
04172|014|B||
04172|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04172|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04172|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04172|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04172|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04172|020|P|transporter OATP1B1 may have increased statin concentrations and be|
04172|021|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04172|022|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04172|023|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04172|024|B||
04172|025|M|PATIENT MANAGEMENT:  Avoid concomitant use of tafamidis with rosuvastatin.|
04172|026|M|If used concomitantly, initiate rosuvastatin at 5 mg once daily and do not|
04172|027|M|exceed a dose of rosuvastatin 20 mg once daily.|
04172|028|M|   Monitor patients closely for signs and symptoms of toxicity from|
04172|029|M|increased rosuvastatin concentrations.(1)|
04172|030|B||
04172|031|D|DISCUSSION:  In a clinical study of healthy subjects, tafamidis (multiple|
04172|032|D|doses of 61 mg daily) increased the area-under-curve (AUC) and concentration|
04172|033|D|maximum (Cmax) of rosuvastatin by 96.75% and 85.59%, respectively.(3)|
04172|034|B||
04172|035|R|REFERENCES:|
04172|036|B||
04172|037|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04172|038|R|  Pharmaceuticals LP July, 2024.|1
04172|039|R|2.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04172|040|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04172|041|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04172|042|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04172|043|R|  44(3):398-408.|5
04172|044|R|3.Vyndamax (tafamidis) US prescribing information. Pfizer, Inc. June, 2021.|1
04173|001|T|MONOGRAPH TITLE:  Tucidinostat/QT Prolonging Agents|
04173|002|B||
04173|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04173|004|L|take action as needed.|
04173|005|B||
04173|006|A|MECHANISM OF ACTION:  Concurrent use of tucidinostat with other agents that|
04173|007|A|prolong the QTc interval may result in additive effects on the QTc|
04173|008|A|interval.(1)|
04173|009|B||
04173|010|E|CLINICAL EFFECTS:  The use of tucidinostat in patients maintained on agents|
04173|011|E|that prolong the QTc interval may result in potentially life-threatening|
04173|012|E|cardiac arrhythmias, including torsades de pointes.(1)|
04173|013|B||
04173|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04173|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04173|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04173|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04173|018|P|gender, or advanced age.(2)|
04173|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04173|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04173|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04173|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04173|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04173|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04173|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04173|026|B||
04173|027|M|PATIENT MANAGEMENT:  Concurrent use of tucidinostat and other agents that|
04173|028|M|are known to prolong the QTc interval should be used with caution.  The|
04173|029|M|manufacturer of tucidinostat recommends monitoring ECG and electrolytes|
04173|030|M|every three weeks.(1)|
04173|031|M|   If the QTc interval exceeds 500 ms, tucidinostat should be suspended and|
04173|032|M|the ECG should be monitored more frequently.  After the QTc interval|
04173|033|M|prolongation has resolved, tucidinostat may be restarted at a reduced|
04173|034|M|dose.(1)|
04173|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04173|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04173|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04173|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04173|039|B||
04173|040|D|DISCUSSION:  Agents that are linked to this monograph may have varying|
04173|041|D|degrees of potential to prolong the QTc interval but are generally accepted|
04173|042|D|to have a risk of causing Torsades de Pointes.  Agents linked to this|
04173|043|D|monograph have been shown to prolong the QTc interval either through their|
04173|044|D|mechanism of action, through studies on their effects on the QTc interval,|
04173|045|D|or through reports of QTc prolongation and/or Torsades de Pointes in|
04173|046|D|clinical trials and/or post-marketing reports.(3)|
04173|047|B||
04173|048|R|REFERENCES:|
04173|049|B||
04173|050|R|1.Epidaza (tucidinostat) Hong Kong prescribing information. Shenzhen|1
04173|051|R|  Chipscreen Biosciences Co., Ltd. November 2019.|1
04173|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04173|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04173|054|R|  settings: a scientific statement from the American Heart Association and|6
04173|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04173|056|R|  2;55(9):934-47.|6
04173|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04173|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04173|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04173|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04174|001|T|MONOGRAPH TITLE:  Futibatinib/Strong CYP3A4 Inducers|
04174|002|B||
04174|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04174|004|L|of severe adverse interaction.|
04174|005|B||
04174|006|A|MECHANISM OF ACTION:  Futibatinib is primarily metabolized by CYP3A4.|
04174|007|A|Agents that induce CYP3A4 may reduce the plasma levels of futibatinib.(1)|
04174|008|B||
04174|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
04174|010|E|result in decreased levels and effectiveness of futibatinib.(1)|
04174|011|B||
04174|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04174|013|P|of the inducer for longer than 1-2 weeks.|
04174|014|B||
04174|015|M|PATIENT MANAGEMENT:  The manufacturer of futibatinib states concurrent use|
04174|016|M|with strong CYP3A4 inducers should be avoided.(1)|
04174|017|B||
04174|018|D|DISCUSSION:  Coadministration with rifampin (strong CYP3A4 inducer)|
04174|019|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of|
04174|020|D|futibatinib by 53% and 64%, respectively.(1)|
04174|021|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04174|022|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04174|023|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04174|024|D|rifampin, rifapentine, and St. John's wort.(2,3)|
04174|025|B||
04174|026|R|REFERENCES:|
04174|027|B||
04174|028|R|1.Lytgobi (futibatinib) US prescribing information. Taiho Oncology Inc.|1
04174|029|R|  October, 2025.|1
04174|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04174|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04174|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04174|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04174|034|R|  11/14/2017.|1
04174|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04174|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04175|001|T|MONOGRAPH TITLE:  Futibatinib/Strong CYP3A4 Inhibitors|
04175|002|B||
04175|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04175|004|L|of severe adverse interaction.|
04175|005|B||
04175|006|A|MECHANISM OF ACTION:  Futibatinib is primarily metabolized by CYP3A4. Agents|
04175|007|A|that are strong CYP3A4 inhibitors may inhibit the metabolism of|
04175|008|A|futibatinib.(1)|
04175|009|B||
04175|010|E|CLINICAL EFFECTS:  Concurrent use with inhibitors of CYP3A4 may result in|
04175|011|E|elevated systemic levels and toxicity from futibatinib including|
04175|012|E|hyperphosphatemia, retinal pigment epithelial detachment and elevated liver|
04175|013|E|enzymes.(1)|
04175|014|B||
04175|015|P|PREDISPOSING FACTORS:  None determined.|
04175|016|B||
04175|017|M|PATIENT MANAGEMENT:  The manufacturer of futibatinib states concurrent use|
04175|018|M|with strong CYP3A4 inhibitors should be avoided.(1)|
04175|019|B||
04175|020|D|DISCUSSION:  In an interaction study, multiple doses of itraconazole (an|
04175|021|D|inhibitor of CYP3A4) increased the mean maximum concentration (Cmax) and|
04175|022|D|area-under-curve (AUC) of futibatinib by 51% and 41%, respectively.(1)|
04175|023|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
04175|024|D|boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib,|
04175|025|D|indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole,|
04175|026|D|lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
04175|027|D|nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir,|
04175|028|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
04175|029|D|voriconazole.(2,3)|
04175|030|B||
04175|031|R|REFERENCES:|
04175|032|B||
04175|033|R|1.Lytgobi (futibatinib) US prescribing information. Taiho Oncology Inc.|1
04175|034|R|  October, 2025.|1
04175|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04175|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04175|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04175|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04175|039|R|  11/14/2017.|1
04175|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04175|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04176|001|T|MONOGRAPH TITLE:  Sodium Phenylbutyrate-Taurursodiol/Aluminum-Based|
04176|002|T|Antacids; Bile Acid Sequestrants|
04176|003|B||
04176|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04176|005|L|of severe adverse interaction.|
04176|006|B||
04176|007|A|MECHANISM OF ACTION:  Aluminum-based antacids and bile acid sequestrants|
04176|008|A|(including cholestyramine, colestipol, and colesevelam) may bind to sodium|
04176|009|A|phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine),|
04176|010|A|which may decrease gastrointestinal absorption and impair enterohepatic|
04176|011|A|recirculation of sodium phenylbutyrate-taurursodiol.(1)|
04176|012|B||
04176|013|E|CLINICAL EFFECTS:  Simultaneous administration of an aluminum-based antacid|
04176|014|E|or bile acid sequestrants (including cholestyramine, colestipol, or|
04176|015|E|colesevelam) may result in decreased absorption and effectiveness of sodium|
04176|016|E|phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine).(1)|
04176|017|B||
04176|018|P|PREDISPOSING FACTORS:  None determined.|
04176|019|B||
04176|020|M|PATIENT MANAGEMENT:  The US manufacturer of sodium|
04176|021|M|phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine)|
04176|022|M|states that concurrent therapy with aluminum-based antacids or bile acid|
04176|023|M|sequestrants should be avoided.  Consider alternative acid lowering agents|
04176|024|M|or cholesterol lowering agents in patients taking sodium|
04176|025|M|phenylbutyrate-taurursodiol.(1)|
04176|026|M|   The Canadian manufacturer of sodium phenylbutyrate-taurursodiol|
04176|027|M|recommends not using bile acid sequestrants with sodium|
04176|028|M|phenylbutyrate-taurursodiol.(2)|
04176|029|M|   The Canadian manufacturer of sodium phenylbutyrate-taurursodiol states|
04176|030|M|that if aluminum-based antacids are required, administer antacids at least 2|
04176|031|M|hours prior to or 2 hours after the administration of sodium|
04176|032|M|phenylbutyrate-taurursodiol.(2)|
04176|033|B||
04176|034|D|DISCUSSION:  Aluminum-based antacids have been shown to adsorb bile acids in|
04176|035|D|vitro.  Bile acid sequestrants (including cholestyramine, colestipol, or|
04176|036|D|colesevelam) reduce bile acid absorption.(1)|
04176|037|B||
04176|038|R|REFERENCES:|
04176|039|B||
04176|040|R|1.Relyvrio (sodium phenylbutyrate and taurursodiol) US prescribing|1
04176|041|R|  information. Amylyx Pharmaceuticals, Inc. September, 2022.|1
04176|042|R|2.Albrioza (sodium phenylbutyrate and ursodoxicoltaurine) Canadian product|1
04176|043|R|  monograph. Amylyx Pharmaceuticals Inc. June, 2022.|1
04177|001|T|MONOGRAPH TITLE:  Sodium Phenylbutyrate-Taurursodiol/HDAC Inhibitors|
04177|002|B||
04177|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04177|004|L|of severe adverse interaction.|
04177|005|B||
04177|006|A|MECHANISM OF ACTION:  The mechanism of the increased gastrointestinal (GI)|
04177|007|A|adverse effects with concurrent sodium phenylbutyrate-taurursodiol (sodium|
04177|008|A|phenylbutyrate-ursodoxicoltaurine) and other HDAC inhibitors is not known.|
04177|009|A|Phenylbutyrate is a pan-histone deacetylase (HDAC) inhibitor.(1,2)|
04177|010|B||
04177|011|E|CLINICAL EFFECTS:  Concurrent use of sodium phenylbutyrate-taurursodiol|
04177|012|E|(sodium phenylbutyrate-ursodoxicoltaurine) and another HDAC inhibitor may|
04177|013|E|result in GI adverse effects including nausea and vomiting.|
04177|014|B||
04177|015|P|PREDISPOSING FACTORS:  None determined.|
04177|016|B||
04177|017|M|PATIENT MANAGEMENT:  The US manufacturer recommends avoiding use of other|
04177|018|M|HDAC inhibitors in patients taking sodium phenylbutyrate-taurursodiol|
04177|019|M|(sodium phenylbutyrate-ursodoxicoltaurine).(1)|
04177|020|M|   The CA manufacturer states sodium phenylbutyrate-taurursodiol should not|
04177|021|M|be coadministered wiht other HDAC inhibitors.(2)|
04177|022|B||
04177|023|D|DISCUSSION:  Concurrent use of sodium phenylbutyrate-taurursodiol (sodium|
04177|024|D|phenylbutyrate-ursodoxicoltaurine) and another HDAC inhibitor may result in|
04177|025|D|increased GI adverse effects.(1,2)|
04177|026|D|   HDAC inhibitors include: belinostat, panobinostat, phenylbutyrate,|
04177|027|D|romidepsin, sodium butyrate, and valproic acid.|
04177|028|B||
04177|029|R|REFERENCES:|
04177|030|B||
04177|031|R|1.Relyvrio (sodium phenylbutyrate and taurursodiol) US prescribing|1
04177|032|R|  information. Amylyx Pharmaceuticals, Inc. September, 2022.|1
04177|033|R|2.Albrioza (sodium phenylbutyrate and ursodoxicoltaurine) Canadian product|1
04177|034|R|  monograph. Amylyx Pharmaceuticals Inc. June, 2022.|1
04178|001|T|MONOGRAPH TITLE:  Sodium Phenylbutyrate-Taurursodiol/OAT3 Inhibitors|
04178|002|B||
04178|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04178|004|L|of severe adverse interaction.|
04178|005|B||
04178|006|A|MECHANISM OF ACTION:  Inhibitors of organic anion transporter 3 (OAT3) may|
04178|007|A|inhibit the renal elimination of conjugated sodium phenylbutyrate and sodium|
04178|008|A|phenylbutyrate metabolites.(1,2)|
04178|009|B||
04178|010|E|CLINICAL EFFECTS:  Concurrent use of organic anion transporter 3 (OAT3)|
04178|011|E|inhibitors may result in an increase in both the therapeutic and toxic|
04178|012|E|effects of sodium phenylbutyrate.(1,2)|
04178|013|B||
04178|014|P|PREDISPOSING FACTORS:  None determined.|
04178|015|B||
04178|016|M|PATIENT MANAGEMENT:  The US manufacturer of sodium|
04178|017|M|phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine)|
04178|018|M|states that concurrent use with organic anion transporter 3 (OAT3)|
04178|019|M|inhibitors should be avoided.(1)|
04178|020|M|   The Canadian manufacturer of sodium phenylbutyrate-taurursodiol states|
04178|021|M|that OAT3 inhibitors should not be used with sodium|
04178|022|M|phenylbutyrate-taurursodiol.(2)|
04178|023|B||
04178|024|D|DISCUSSION:  Probenecid may inhibit the renal elimination of conjugated|
04178|025|D|sodium phenylbutyrate and sodium phenylbutyrate metabolites.(1,2)|
04178|026|D|   OAT3 inhibitors linked to this monograph include:  cabotegravir,|
04178|027|D|leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(3)|
04178|028|B||
04178|029|R|REFERENCES:|
04178|030|B||
04178|031|R|1.Relyvrio (sodium phenylbutyrate and taurursodiol) US prescribing|1
04178|032|R|  information. Amylyx Pharmaceuticals, Inc. September, 2022.|1
04178|033|R|2.Albrioza (sodium phenylbutyrate and ursodoxicoltaurine) Canadian product|1
04178|034|R|  monograph. Amylyx Pharmaceuticals Inc. June, 2022.|1
04178|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04178|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04179|001|T|MONOGRAPH TITLE:  Selected Opioids (Cough and Cold)/Selected Tranquilizers|
04179|002|B||
04179|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04179|004|L|of severe adverse interaction.|
04179|005|B||
04179|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and tranquilizers may result|
04179|007|A|in additive CNS depression.(1)|
04179|008|B||
04179|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants such|
04179|010|E|as tranquilizers may result in profound sedation, respiratory depression,|
04179|011|E|coma, and/or death.(1)|
04179|012|B||
04179|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04179|014|P|may increase the risk of adverse effects.|
04179|015|B||
04179|016|M|PATIENT MANAGEMENT:  Avoid prescribing opioid-including cough medications|
04179|017|M|for patients taking CNS depressants such tranquilizers.(1)|
04179|018|M|   Respiratory depression can occur at any time during opioid therapy,|
04179|019|M|especially during therapy initiation and following dosage increases.  The|
04179|020|M|risk of opioid-related overdose or overdose-related death is increased with|
04179|021|M|higher opioid doses, and this risk persists over the course of therapy.|
04179|022|M|Consider these risks when using concurrently with other agents that may|
04179|023|M|cause CNS depression.(2)|
04179|024|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
04179|025|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04179|026|M|unresponsiveness.(1)|
04179|027|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04179|028|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04179|029|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04179|030|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04179|031|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04179|032|M|as those taking CNS depressants) and when a patient has household|
04179|033|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04179|034|M|for obtaining an opioid reversal agent (e.g., prescription,|
04179|035|M|over-the-counter, or as part of a community-based program).(3)|
04179|036|B||
04179|037|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04179|038|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04179|039|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04179|040|D|million to 30 million patients.  During this time, the proportion of|
04179|041|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04179|042|D|million patients.(4)|
04179|043|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04179|044|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04179|045|D|per 100,000 and drug overdose deaths involving both opioids and|
04179|046|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04179|047|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04179|048|D|increased from 18% to 31% during this time.(5)|
04179|049|D|   A prospective observational cohort study in North Carolina found that the|
04179|050|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04179|051|D|benzodiazepines were 10 times higher than patients receiving opioid|
04179|052|D|analgesics alone.(6)|
04179|053|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04179|054|D|death from overdose increased with concomitant opioid analgesics and|
04179|055|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04179|056|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04179|057|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04179|058|D|increased risk of fatal overdose.(7)|
04179|059|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04179|060|D|which benzodiazepines were determined to be a cause of death and that|
04179|061|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04179|062|D|determined to be a cause of death.  This study also found that other CNS|
04179|063|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04179|064|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04179|065|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04179|066|D|where opioid analgesics were also implicated.(8)|
04179|067|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04179|068|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04179|069|D|deaths.(9)|
04179|070|B||
04179|071|R|REFERENCES:|
04179|072|B||
04179|073|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04179|074|R|  warns about serious risks and death when combining opioid pain or cough|1
04179|075|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04179|076|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04179|077|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04179|078|R|  prescribing information for all opioid pain medicines to provide|1
04179|079|R|  additional guidance for safe use. Available at:|1
04179|080|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04179|081|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04179|082|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04179|083|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04179|084|R|  recommends health care professionals discuss naloxone with all patients|1
04179|085|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04179|086|R|  disorder. Available at:|1
04179|087|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04179|088|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04179|089|R|  d-pain July 23, 2020.|1
04179|090|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04179|091|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04179|092|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04179|093|R|5.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04179|094|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04179|095|R|  49(4):493-501.|2
04179|096|R|6.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04179|097|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04179|098|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04179|099|R|7.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04179|100|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04179|101|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04179|102|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04179|103|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04179|104|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04179|105|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
04179|106|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
04179|107|R|  2014 Oct 10;63(40):881-5.|2
04180|001|T|MONOGRAPH TITLE:  Select Opioids (Extended Release)/Select Tranquilizers|
04180|002|B||
04180|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04180|004|L|take action as needed.|
04180|005|B||
04180|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and sleep drugs or|
04180|007|A|tranquilizers may result in additive CNS depression.(1)|
04180|008|B||
04180|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants such|
04180|010|E|as tranquilizers may result in profound sedation, respiratory depression,|
04180|011|E|coma, and/or death.(1)|
04180|012|B||
04180|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04180|014|P|may increase the risk of adverse effects.|
04180|015|B||
04180|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
04180|017|M|depressants such as tranquilizers to patients for whom alternatives are|
04180|018|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
04180|019|M|sufficient management of pain.(1)|
04180|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
04180|021|M|drug to the minimum possible while achieving the desired clinical effect.|
04180|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04180|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04180|024|M|indicated in the absence of an opioid and titrate based upon clinical|
04180|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04180|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04180|027|M|clinical response.(1)|
04180|028|M|   Respiratory depression can occur at any time during opioid therapy,|
04180|029|M|especially during therapy initiation and following dosage increases.  The|
04180|030|M|risk of opioid-related overdose or overdose-related death is increased with|
04180|031|M|higher opioid doses, and this risk persists over the course of therapy.|
04180|032|M|Consider these risks when using concurrently with other agents that may|
04180|033|M|cause CNS depression.(2)|
04180|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04180|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04180|036|M|unresponsiveness.(1)|
04180|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04180|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04180|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04180|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04180|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04180|042|M|as those taking CNS depressants) and when a patient has household|
04180|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04180|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
04180|045|M|over-the-counter, or as part of a community-based program).(3)|
04180|046|B||
04180|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04180|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04180|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04180|050|D|million to 30 million patients.  During this time, the proportion of|
04180|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04180|052|D|million patients.(4)|
04180|053|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04180|054|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04180|055|D|per 100,000 and drug overdose deaths involving both opioids and|
04180|056|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04180|057|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04180|058|D|increased from 18% to 31% during this time.(5)|
04180|059|D|   A prospective observational cohort study in North Carolina found that the|
04180|060|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04180|061|D|benzodiazepines were 10 times higher than patients receiving opioid|
04180|062|D|analgesics alone.(6)|
04180|063|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04180|064|D|death from overdose increased with concomitant opioid analgesics and|
04180|065|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04180|066|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04180|067|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04180|068|D|increased risk of fatal overdose.(7)|
04180|069|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04180|070|D|which benzodiazepines were determined to be a cause of death and that|
04180|071|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04180|072|D|determined to be a cause of death.  This study also found that other CNS|
04180|073|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04180|074|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04180|075|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04180|076|D|where opioid analgesics were also implicated.(8)|
04180|077|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04180|078|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04180|079|D|deaths.(9)|
04180|080|B||
04180|081|R|REFERENCES:|
04180|082|B||
04180|083|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04180|084|R|  warns about serious risks and death when combining opioid pain or cough|1
04180|085|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04180|086|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04180|087|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04180|088|R|  prescribing information for all opioid pain medicines to provide|1
04180|089|R|  additional guidance for safe use. Available at:|1
04180|090|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04180|091|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04180|092|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04180|093|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04180|094|R|  recommends health care professionals discuss naloxone with all patients|1
04180|095|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04180|096|R|  disorder. Available at:|1
04180|097|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04180|098|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04180|099|R|  d-pain July 23, 2020.|1
04180|100|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04180|101|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04180|102|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04180|103|R|5.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04180|104|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04180|105|R|  49(4):493-501.|2
04180|106|R|6.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04180|107|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04180|108|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04180|109|R|7.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04180|110|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04180|111|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04180|112|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04180|113|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04180|114|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04180|115|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
04180|116|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
04180|117|R|  2014 Oct 10;63(40):881-5.|2
04181|001|T|MONOGRAPH TITLE:  Select Opioids (Immediate Release)/Select Tranquilizers|
04181|002|B||
04181|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04181|004|L|take action as needed.|
04181|005|B||
04181|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and tranquilizers may result|
04181|007|A|in additive CNS depression.(1)|
04181|008|B||
04181|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants such|
04181|010|E|as tranquilizers may result in profound sedation, respiratory depression,|
04181|011|E|coma, and/or death.(1)|
04181|012|B||
04181|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04181|014|P|may increase the risk of adverse effects.|
04181|015|B||
04181|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
04181|017|M|depressants such as tranquilizers to patients for whom alternatives are|
04181|018|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
04181|019|M|sufficient management of pain.(1)|
04181|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
04181|021|M|drug to the minimum possible while achieving the desired clinical effect.|
04181|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04181|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04181|024|M|indicated in the absence of an opioid and titrate based upon clinical|
04181|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04181|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04181|027|M|clinical response.(1)|
04181|028|M|   Respiratory depression can occur at any time during opioid therapy,|
04181|029|M|especially during therapy initiation and following dosage increases.  The|
04181|030|M|risk of opioid-related overdose or overdose-related death is increased with|
04181|031|M|higher opioid doses, and this risk persists over the course of therapy.|
04181|032|M|Consider these risks when using concurrently with other agents that may|
04181|033|M|cause CNS depression.(2)|
04181|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04181|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04181|036|M|unresponsiveness.(1)|
04181|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04181|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04181|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04181|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04181|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04181|042|M|as those taking CNS depressants) and when a patient has household|
04181|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04181|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
04181|045|M|over-the-counter, or as part of a community-based program).(3)|
04181|046|B||
04181|047|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04181|048|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04181|049|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04181|050|D|million to 30 million patients.  During this time, the proportion of|
04181|051|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04181|052|D|million patients.(4)|
04181|053|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04181|054|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04181|055|D|per 100,000 and drug overdose deaths involving both opioids and|
04181|056|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04181|057|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04181|058|D|increased from 18% to 31% during this time.(5)|
04181|059|D|   A prospective observational cohort study in North Carolina found that the|
04181|060|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04181|061|D|benzodiazepines were 10 times higher than patients receiving opioid|
04181|062|D|analgesics alone.(6)|
04181|063|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04181|064|D|death from overdose increased with concomitant opioid analgesics and|
04181|065|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04181|066|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04181|067|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04181|068|D|increased risk of fatal overdose.(7)|
04181|069|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04181|070|D|which benzodiazepines were determined to be a cause of death and that|
04181|071|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04181|072|D|determined to be a cause of death.  This study also found that other CNS|
04181|073|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04181|074|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04181|075|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04181|076|D|where opioid analgesics were also implicated.(8)|
04181|077|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04181|078|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04181|079|D|deaths.(9)|
04181|080|B||
04181|081|R|REFERENCES:|
04181|082|B||
04181|083|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04181|084|R|  warns about serious risks and death when combining opioid pain or cough|1
04181|085|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04181|086|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04181|087|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04181|088|R|  prescribing information for all opioid pain medicines to provide|1
04181|089|R|  additional guidance for safe use. Available at:|1
04181|090|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04181|091|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04181|092|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04181|093|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04181|094|R|  recommends health care professionals discuss naloxone with all patients|1
04181|095|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04181|096|R|  disorder. Available at:|1
04181|097|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04181|098|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04181|099|R|  d-pain July 23, 2020.|1
04181|100|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04181|101|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04181|102|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04181|103|R|5.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04181|104|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04181|105|R|  49(4):493-501.|2
04181|106|R|6.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04181|107|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04181|108|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04181|109|R|7.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04181|110|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04181|111|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04181|112|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04181|113|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04181|114|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04181|115|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
04181|116|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
04181|117|R|  2014 Oct 10;63(40):881-5.|2
04182|001|T|MONOGRAPH TITLE:  Selected Opioids for MAT/Select Tranquilizers|
04182|002|B||
04182|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04182|004|L|take action as needed.|
04182|005|B||
04182|006|A|MECHANISM OF ACTION:  Concurrent use of diacetylmorphine and tranquilizers|
04182|007|A|may result in additive CNS depression.(1-3)|
04182|008|B||
04182|009|E|CLINICAL EFFECTS:  Concurrent use of diacetylmorphine and other CNS|
04182|010|E|depressants such as tranquilizers may result in profound sedation,|
04182|011|E|respiratory depression, coma, and/or death.(1-3)|
04182|012|B||
04182|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04182|014|P|may increase the risk of adverse effects.|
04182|015|B||
04182|016|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with|
04182|017|M|diacetylmorphine is not contraindicated in patients taking CNS depressants;|
04182|018|M|however, discontinuation of CNS depressants is preferred in most cases.  In|
04182|019|M|some cases, monitoring at a higher level of care may be appropriate.  In|
04182|020|M|others, gradual tapering or decreasing to the lowest effective dose of the|
04182|021|M|CNS depressant is appropriate.  Consider other medications and|
04182|022|M|nonpharmacologic treatments to address anxiety or insomnia.  Ensure that|
04182|023|M|other health care providers prescribing other CNS depressants are aware of|
04182|024|M|the patient's methadone treatment.(2)|
04182|025|M|   Respiratory depression can occur at any time during opioid therapy,|
04182|026|M|especially during therapy initiation and following dosage increases.  The|
04182|027|M|risk of opioid-related overdose or overdose-related death is increased with|
04182|028|M|higher opioid doses, and this risk persists over the course of therapy.|
04182|029|M|Consider these risks when using concurrently with other agents that may|
04182|030|M|cause CNS depression.(4)|
04182|031|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04182|032|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04182|033|M|unresponsiveness.(1)|
04182|034|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04182|035|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04182|036|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04182|037|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04182|038|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04182|039|M|as those taking CNS depressants) and when a patient has household|
04182|040|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04182|041|M|for obtaining an opioid reversal agent (e.g., prescription,|
04182|042|M|over-the-counter, or as part of a community-based program).(5)|
04182|043|B||
04182|044|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04182|045|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04182|046|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04182|047|D|million to 30 million patients.  During this time, the proportion of|
04182|048|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04182|049|D|million patients.(6)|
04182|050|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04182|051|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04182|052|D|per 100,000 and drug overdose deaths involving both opioids and|
04182|053|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04182|054|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04182|055|D|increased from 18% to 31% during this time.(7)|
04182|056|D|   A prospective observational cohort study in North Carolina found that the|
04182|057|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04182|058|D|benzodiazepines were 10 times higher than patients receiving opioid|
04182|059|D|analgesics alone.(8)|
04182|060|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04182|061|D|death from overdose increased with concomitant opioid analgesics and|
04182|062|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04182|063|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04182|064|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04182|065|D|increased risk of fatal overdose.(9)|
04182|066|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04182|067|D|which benzodiazepines were determined to be a cause of death and that|
04182|068|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04182|069|D|determined to be a cause of death.  This study also found that other CNS|
04182|070|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04182|071|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04182|072|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04182|073|D|where opioid analgesics were also implicated.(10)|
04182|074|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04182|075|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04182|076|D|deaths.(11)|
04182|077|D|   While concomitant use of MAT with CNS depressants increases the risk of|
04182|078|D|adverse reactions, barriers to MAT can pose a greater risk of morbidity and|
04182|079|D|mortality due to opioid use disorder.(2)|
04182|080|B||
04182|081|R|REFERENCES:|
04182|082|B||
04182|083|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04182|084|R|  warns about serious risks and death when combining opioid pain or cough|1
04182|085|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04182|086|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04182|087|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04182|088|R|  urges caution about withholding opioid addiction medications from patients|1
04182|089|R|  taking benzodiazepines or CNS depressants: careful medication management|1
04182|090|R|  can reduce risks. available at:|1
04182|091|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
04182|092|R|3.Diacetylmorphine Canadian prescribing information. Pharmascience Inc.|1
04182|093|R|  February, 2022.|1
04182|094|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04182|095|R|  prescribing information for all opioid pain medicines to provide|1
04182|096|R|  additional guidance for safe use. Available at:|1
04182|097|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04182|098|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04182|099|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04182|100|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04182|101|R|  recommends health care professionals discuss naloxone with all patients|1
04182|102|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04182|103|R|  disorder. Available at:|1
04182|104|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04182|105|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04182|106|R|  d-pain July 23, 2020.|1
04182|107|R|6.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04182|108|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04182|109|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04182|110|R|7.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04182|111|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04182|112|R|  49(4):493-501.|2
04182|113|R|8.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04182|114|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04182|115|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04182|116|R|9.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04182|117|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04182|118|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04182|119|R|10.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04182|120|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04182|121|R|11.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04182|122|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04182|123|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04182|124|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04183|001|T|MONOGRAPH TITLE:  Methadone (Cough and Cold)/Sleep Drugs; Tranquilizers|
04183|002|B||
04183|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04183|004|L|of severe adverse interaction.|
04183|005|B||
04183|006|A|MECHANISM OF ACTION:  Concurrent use of methadone and sleep drugs or|
04183|007|A|tranquilizers may result in additive CNS depression and sleep-related|
04183|008|A|disorders.(1)|
04183|009|B||
04183|010|E|CLINICAL EFFECTS:  Concurrent use of methadone and other CNS depressants,|
04183|011|E|such as sleep drugs or tranquilizers, may result in profound sedation,|
04183|012|E|respiratory depression, coma, and/or death.(1)|
04183|013|E|   Concurrent use of methadone with eszopiclone, zaleplon, or zolpidem may|
04183|014|E|increase the risk of sleep-related disorders including central sleep apnea|
04183|015|E|and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking,|
04183|016|E|sleep driving, and other activities while not fully awake.  Rarely, serious|
04183|017|E|injuries or death have resulted from complex sleep behaviors.(2)|
04183|018|B||
04183|019|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04183|020|P|may increase the risk of adverse effects.|
04183|021|B||
04183|022|M|PATIENT MANAGEMENT:  Avoid prescribing opioid-including cough medications|
04183|023|M|for patients taking CNS depressants such as sleep drugs or tranquilizers.(1)|
04183|024|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
04183|025|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04183|026|M|unresponsiveness.(1)|
04183|027|M|   Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who|
04183|028|M|have had a previous episode of complex sleep behavior.(2)|
04183|029|M|   Respiratory depression can occur at any time during opioid therapy,|
04183|030|M|especially during therapy initiation and following dosage increases.  The|
04183|031|M|risk of opioid-related overdose or overdose-related death is increased with|
04183|032|M|higher opioid doses, and this risk persists over the course of therapy.|
04183|033|M|Consider these risks when using concurrently with other agents that may|
04183|034|M|cause CNS depression.|
04183|035|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04183|036|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04183|037|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04183|038|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04183|039|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04183|040|M|as those taking CNS depressants) and when a patient has household|
04183|041|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04183|042|M|for obtaining an opioid reversal agent (e.g., prescription,|
04183|043|M|over-the-counter, or as part of a community-based program).(3)|
04183|044|B||
04183|045|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04183|046|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04183|047|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04183|048|D|million to 30 million patients.  During this time, the proportion of|
04183|049|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04183|050|D|million patients.(4)|
04183|051|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04183|052|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04183|053|D|per 100,000 and drug overdose deaths involving both opioids and|
04183|054|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04183|055|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04183|056|D|increased from 18% to 31% during this time.(5)|
04183|057|D|   A prospective observational cohort study in North Carolina found that the|
04183|058|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04183|059|D|benzodiazepines were 10 times higher than patients receiving opioid|
04183|060|D|analgesics alone.(6)|
04183|061|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04183|062|D|death from overdose increased with concomitant opioid analgesics and|
04183|063|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04183|064|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04183|065|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04183|066|D|increased risk of fatal overdose.(7)|
04183|067|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04183|068|D|which benzodiazepines were determined to be a cause of death and that|
04183|069|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04183|070|D|determined to be a cause of death.  This study also found that other CNS|
04183|071|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04183|072|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04183|073|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04183|074|D|where opioid analgesics were also implicated.(8)|
04183|075|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04183|076|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04183|077|D|deaths.(9)|
04183|078|D|   As of April 2019, the FDA had identified 66 cases of complex sleep|
04183|079|D|behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases|
04183|080|D|resulted in death and the remainder resulted in serious injuries.  It was|
04183|081|D|not reported how many of the cases involved concomitant use of other CNS|
04183|082|D|depressants.(2)|
04183|083|B||
04183|084|R|REFERENCES:|
04183|085|B||
04183|086|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04183|087|R|  warns about serious risks and death when combining opioid pain or cough|1
04183|088|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04183|089|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04183|090|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA adds|1
04183|091|R|  Boxed Warning for risk of serious injuries caused by sleepwalking with|1
04183|092|R|  certain prescription insomnia medicines. Available at:|1
04183|093|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warn|1
04183|094|R|  ing-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomni|1
04183|095|R|  a April 30, 2019.|1
04183|096|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04183|097|R|  recommends health care professionals discuss naloxone with all patients|1
04183|098|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04183|099|R|  disorder. Available at:|1
04183|100|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04183|101|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04183|102|R|  d-pain July 23, 2020.|1
04183|103|R|4.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04183|104|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04183|105|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04183|106|R|5.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04183|107|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04183|108|R|  49(4):493-501.|2
04183|109|R|6.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04183|110|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04183|111|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04183|112|R|7.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04183|113|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04183|114|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04183|115|R|8.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04183|116|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04183|117|R|9.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04183|118|R|  reliever and benzodiazepine drug abuse-related emergency department visits|2
04183|119|R|  and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep|2
04183|120|R|  2014 Oct 10;63(40):881-5.|2
04184|001|T|MONOGRAPH TITLE:  Levomethadone;Methadone (Immediate Release)/Sleep Drugs;|
04184|002|T|Tranquilizers|
04184|003|B||
04184|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04184|005|L|take action as needed.|
04184|006|B||
04184|007|A|MECHANISM OF ACTION:  Concurrent use of methadone and sleep drugs or|
04184|008|A|tranquilizers may result in additive CNS depression and sleep-related|
04184|009|A|disorders.(1)|
04184|010|A|   Levomethadone is an enantiomer of methadone.(2)|
04184|011|B||
04184|012|E|CLINICAL EFFECTS:  Concurrent use of methadone and other CNS depressants,|
04184|013|E|such as sleep drugs or tranquilizers, may result in profound sedation,|
04184|014|E|respiratory depression, coma, and/or death.(1)|
04184|015|E|   Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may|
04184|016|E|increase the risk of sleep-related disorders including central sleep apnea|
04184|017|E|and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking,|
04184|018|E|sleep driving, and other activities while not fully awake.  Rarely, serious|
04184|019|E|injuries or death have resulted from complex sleep behaviors.(3)|
04184|020|B||
04184|021|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04184|022|P|may increase the risk of adverse effects.|
04184|023|B||
04184|024|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
04184|025|M|depressants such as sleep drugs or tranquilizers to patients for whom|
04184|026|M|alternatives are ineffective, not tolerated, or would be otherwise|
04184|027|M|inadequate to provide sufficient management of pain.(1)|
04184|028|M|   If concurrent use is necessary, limit the dosages and duration of each|
04184|029|M|drug to the minimum possible while achieving the desired clinical effect.|
04184|030|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04184|031|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04184|032|M|indicated in the absence of an opioid and titrate based upon clinical|
04184|033|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04184|034|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04184|035|M|clinical response.(1)|
04184|036|M|   Respiratory depression can occur at any time during opioid therapy,|
04184|037|M|especially during therapy initiation and following dosage increases.  The|
04184|038|M|risk of opioid-related overdose or overdose-related death is increased with|
04184|039|M|higher opioid doses, and this risk persists over the course of therapy.|
04184|040|M|Consider these risks when using concurrently with other agents that may|
04184|041|M|cause CNS depression.(4)|
04184|042|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04184|043|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04184|044|M|unresponsiveness.(1)|
04184|045|M|   Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who|
04184|046|M|have had a previous episode of complex sleep behavior.(3)|
04184|047|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04184|048|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04184|049|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04184|050|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04184|051|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04184|052|M|as those taking CNS depressants) and when a patient has household|
04184|053|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04184|054|M|for obtaining an opioid reversal agent (e.g., prescription,|
04184|055|M|over-the-counter, or as part of a community-based program).(5)|
04184|056|B||
04184|057|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04184|058|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04184|059|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04184|060|D|million to 30 million patients.  During this time, the proportion of|
04184|061|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04184|062|D|million patients.(6)|
04184|063|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04184|064|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04184|065|D|per 100,000 and drug overdose deaths involving both opioids and|
04184|066|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04184|067|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04184|068|D|increased from 18% to 31% during this time.(7)|
04184|069|D|   A prospective observational cohort study in North Carolina found that the|
04184|070|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04184|071|D|benzodiazepines were 10 times higher than patients receiving opioid|
04184|072|D|analgesics alone.(8)|
04184|073|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04184|074|D|death from overdose increased with concomitant opioid analgesics and|
04184|075|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04184|076|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04184|077|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04184|078|D|increased risk of fatal overdose.(9)|
04184|079|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04184|080|D|which benzodiazepines were determined to be a cause of death and that|
04184|081|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04184|082|D|determined to be a cause of death.  This study also found that other CNS|
04184|083|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04184|084|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04184|085|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04184|086|D|where opioid analgesics were also implicated.(10)|
04184|087|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04184|088|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04184|089|D|deaths.(11)|
04184|090|D|   As of April 2019, the FDA had identified 66 cases of complex sleep|
04184|091|D|behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases|
04184|092|D|resulted in death and the remainder resulted in serious injuries.  It was|
04184|093|D|not reported how many of the cases involved concomitant use of other CNS|
04184|094|D|depressants.(2)|
04184|095|B||
04184|096|R|REFERENCES:|
04184|097|B||
04184|098|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04184|099|R|  warns about serious risks and death when combining opioid pain or cough|1
04184|100|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04184|101|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04184|102|R|2.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
04184|103|R|  Pharma AS November 30, 2018.|1
04184|104|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA adds|1
04184|105|R|  Boxed Warning for risk of serious injuries caused by sleepwalking with|1
04184|106|R|  certain prescription insomnia medicines. Available at:|1
04184|107|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warn|1
04184|108|R|  ing-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomni|1
04184|109|R|  a April 30, 2019.|1
04184|110|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04184|111|R|  prescribing information for all opioid pain medicines to provide|1
04184|112|R|  additional guidance for safe use. Available at:|1
04184|113|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04184|114|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04184|115|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04184|116|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04184|117|R|  recommends health care professionals discuss naloxone with all patients|1
04184|118|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04184|119|R|  disorder. Available at:|1
04184|120|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04184|121|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04184|122|R|  d-pain July 23, 2020.|1
04184|123|R|6.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04184|124|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04184|125|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04184|126|R|7.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04184|127|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04184|128|R|  49(4):493-501.|2
04184|129|R|8.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04184|130|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04184|131|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04184|132|R|9.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04184|133|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04184|134|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04184|135|R|10.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04184|136|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04184|137|R|11.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04184|138|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04184|139|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04184|140|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04185|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone for MAT/Sleep Drugs;|
04185|002|T|Tranquilizers|
04185|003|B||
04185|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04185|005|L|take action as needed.|
04185|006|B||
04185|007|A|MECHANISM OF ACTION:  Concurrent use of methadone and sleep drugs or|
04185|008|A|tranquilizers may result in additive CNS depression and sleep-related|
04185|009|A|disorders.(1,2)|
04185|010|A|   Levomethadone is an enantiomer of methadone.(3)|
04185|011|B||
04185|012|E|CLINICAL EFFECTS:  Concurrent use of methadone and other CNS depressants,|
04185|013|E|such as sleep drugs or tranquilizers, may result in profound sedation,|
04185|014|E|respiratory depression, coma, and/or death.(1,2)|
04185|015|E|   Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may|
04185|016|E|increase the risk of sleep-related disorders including central sleep apnea|
04185|017|E|and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking,|
04185|018|E|sleep driving, and other activities while not fully awake.  Rarely, serious|
04185|019|E|injuries or death have resulted from complex sleep behaviors.(4)|
04185|020|B||
04185|021|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04185|022|P|may increase the risk of adverse effects.|
04185|023|B||
04185|024|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with methadone is|
04185|025|M|not contraindicated in patients taking CNS depressants; however,|
04185|026|M|discontinuation of CNS depressants is preferred in most cases.  In some|
04185|027|M|cases, monitoring at a higher level of care may be appropriate.  In others,|
04185|028|M|gradual tapering or decreasing to the lowest effective dose of the CNS|
04185|029|M|depressant is appropriate.  Consider other medications and nonpharmacologic|
04185|030|M|treatments to address anxiety or insomnia.  Ensure that other health care|
04185|031|M|providers prescribing other CNS depressants are aware of the patient's|
04185|032|M|buprenorphine or methadone treatment.(2)|
04185|033|M|   Respiratory depression can occur at any time during opioid therapy,|
04185|034|M|especially during therapy initiation and following dosage increases.  The|
04185|035|M|risk of opioid-related overdose or overdose-related death is increased with|
04185|036|M|higher opioid doses, and this risk persists over the course of therapy.|
04185|037|M|Consider these risks when using concurrently with other agents that may|
04185|038|M|cause CNS depression.|
04185|039|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04185|040|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04185|041|M|unresponsiveness.(1)|
04185|042|M|   Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who|
04185|043|M|have had a previous episode of complex sleep behavior.(4)|
04185|044|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04185|045|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04185|046|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04185|047|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04185|048|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04185|049|M|as those taking CNS depressants) and when a patient has household|
04185|050|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04185|051|M|for obtaining an opioid reversal agent (e.g., prescription,|
04185|052|M|over-the-counter, or as part of a community-based program).(5)|
04185|053|B||
04185|054|D|DISCUSSION:  Between 2002 and 2014, the number of patients receiving an|
04185|055|D|opioid analgesic increased 8%, from 75 million to 81 million patients, and|
04185|056|D|the number of patients receiving a benzodiazepine increased 31%, from 23|
04185|057|D|million to 30 million patients.  During this time, the proportion of|
04185|058|D|patients receiving concurrent therapy increased 31%, from 23 million to 30|
04185|059|D|million patients.(6)|
04185|060|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04185|061|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04185|062|D|per 100,000 and drug overdose deaths involving both opioids and|
04185|063|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04185|064|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04185|065|D|increased from 18% to 31% during this time.(7)|
04185|066|D|   A prospective observational cohort study in North Carolina found that the|
04185|067|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04185|068|D|benzodiazepines were 10 times higher than patients receiving opioid|
04185|069|D|analgesics alone.(8)|
04185|070|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04185|071|D|death from overdose increased with concomitant opioid analgesics and|
04185|072|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04185|073|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04185|074|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04185|075|D|increased risk of fatal overdose.(9)|
04185|076|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04185|077|D|which benzodiazepines were determined to be a cause of death and that|
04185|078|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04185|079|D|determined to be a cause of death.  This study also found that other CNS|
04185|080|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04185|081|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04185|082|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04185|083|D|where opioid analgesics were also implicated.(10)|
04185|084|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04185|085|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04185|086|D|deaths.(11)|
04185|087|D|   While concomitant use of MAT with CNS depressants increases the risk of|
04185|088|D|adverse reactions, barriers to MAT can pose a greater risk of morbidity and|
04185|089|D|mortality due to opioid use disorder.(2)|
04185|090|D|   As of April 2019, the FDA had identified 66 cases of complex sleep|
04185|091|D|behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases|
04185|092|D|resulted in death and the remainder resulted in serious injuries.  It was|
04185|093|D|not reported how many of the cases involved concomitant use of other CNS|
04185|094|D|depressants.(4)|
04185|095|B||
04185|096|R|REFERENCES:|
04185|097|B||
04185|098|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04185|099|R|  warns about serious risks and death when combining opioid pain or cough|1
04185|100|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04185|101|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04185|102|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04185|103|R|  urges caution about withholding opioid addiction medications from patients|1
04185|104|R|  taking benzodiazepines or CNS depressants: careful medication management|1
04185|105|R|  can reduce risks. available at:|1
04185|106|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
04185|107|R|3.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
04185|108|R|  Pharma AS November 30, 2018.|1
04185|109|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA adds|1
04185|110|R|  Boxed Warning for risk of serious injuries caused by sleepwalking with|1
04185|111|R|  certain prescription insomnia medicines. Available at:|1
04185|112|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warn|1
04185|113|R|  ing-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomni|1
04185|114|R|  a April 30, 2019.|1
04185|115|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04185|116|R|  recommends health care professionals discuss naloxone with all patients|1
04185|117|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04185|118|R|  disorder. Available at:|1
04185|119|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04185|120|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04185|121|R|  d-pain July 23, 2020.|1
04185|122|R|6.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04185|123|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04185|124|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04185|125|R|7.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04185|126|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04185|127|R|  49(4):493-501.|2
04185|128|R|8.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04185|129|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04185|130|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04185|131|R|9.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04185|132|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04185|133|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04185|134|R|10.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04185|135|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04185|136|R|11.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04185|137|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04185|138|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04185|139|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04186|001|T|MONOGRAPH TITLE:  Methadone (Cough and Cold)/Lemborexant|
04186|002|B||
04186|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04186|004|L|of severe adverse interaction.|
04186|005|B||
04186|006|A|MECHANISM OF ACTION:  Lemborexant may induce the metabolism of CYP2B6|
04186|007|A|substrates such as methadone.  Additionally, concurrent use of lemborexant|
04186|008|A|and methadone may result in additive CNS depression.(1,2)|
04186|009|B||
04186|010|E|CLINICAL EFFECTS:  Concomitant use of methadone with CYP2B6 inducers such as|
04186|011|E|lemborexant can decrease the plasma concentration of methadone, resulting in|
04186|012|E|decreased efficacy or onset of withdrawal symptoms in patients physically|
04186|013|E|dependent on methadone.(1,2)|
04186|014|E|   Concurrent use of lemborexant and other CNS depressants, such as|
04186|015|E|methadone, may impair daytime wakefulness.(1,2)|
04186|016|B||
04186|017|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04186|018|P|may increase the risk of adverse effects.|
04186|019|B||
04186|020|M|PATIENT MANAGEMENT:  Avoid prescribing methadone-containing cough|
04186|021|M|medications for patients taking CNS depressants such as lemborexant.(3)|
04186|022|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
04186|023|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04186|024|M|unresponsiveness.(2) Monitor for signs of opioid withdrawal in patients|
04186|025|M|physically dependent on methadone.(1,2)|
04186|026|M|   Discuss naloxone with all patients when prescribing or renewing an opioid|
04186|027|M|analgesic or medicine to treat opioid use disorder (OUD).  Consider|
04186|028|M|prescribing naloxone to patients prescribed medicines to treat OUD or opioid|
04186|029|M|analgesics who are at increased risk of opioid overdose (such as those|
04186|030|M|taking CNS depressants) and when a patient has household members/close|
04186|031|M|contacts at risk for accidental overdose.(3)|
04186|032|B||
04186|033|D|DISCUSSION:  In a study, lemborexant (10 mg dose) decreased the|
04186|034|D|concentration maximum (Cmax) and area-under-curve (AUC) of a S-bupropion (a|
04186|035|D|CYP2D6 substrate) by 49.9% and 45.5%, respectively.(1)|
04186|036|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04186|037|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04186|038|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04186|039|D|to 30 million patients.  During this time, the proportion of patients|
04186|040|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04186|041|D|patients.(4)|
04186|042|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04186|043|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04186|044|D|per 100,000 and drug overdose deaths involving both opioids and|
04186|045|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04186|046|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04186|047|D|increased from 18% to 31% during this time.(5)|
04186|048|D|   A prospective observational cohort study in North Carolina found that the|
04186|049|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04186|050|D|benzodiazepines were 10 times higher than patients receiving opioid|
04186|051|D|analgesics alone.(6)|
04186|052|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04186|053|D|death from overdose increased with concomitant opioid analgesics and|
04186|054|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04186|055|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04186|056|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04186|057|D|increased risk of fatal overdose.(7)|
04186|058|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04186|059|D|which benzodiazepines were determined to be a cause of death and that|
04186|060|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04186|061|D|determined to be a cause of death.  This study also found that other CNS|
04186|062|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04186|063|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04186|064|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04186|065|D|where opioid analgesics were also implicated.(8)|
04186|066|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04186|067|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04186|068|D|deaths.(9)|
04186|069|B||
04186|070|R|REFERENCES:|
04186|071|B||
04186|072|R|1.Dayvigo (lemborexant) US prescribing information. Eisai Inc. March, 2022.|1
04186|073|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
04186|074|R|  Pharmaceuticals Corp. June, 2021.|1
04186|075|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04186|076|R|  warns about serious risks and death when combining opioid pain or cough|1
04186|077|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04186|078|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04186|079|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04186|080|R|  recommends health care professionals discuss naloxone with all patients|1
04186|081|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04186|082|R|  disorder. Available at:|1
04186|083|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04186|084|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04186|085|R|  d-pain July 23, 2020.|1
04186|086|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04186|087|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04186|088|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04186|089|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04186|090|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04186|091|R|  49(4):493-501.|2
04186|092|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04186|093|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04186|094|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04186|095|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04186|096|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04186|097|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04186|098|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04186|099|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04186|100|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04186|101|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04186|102|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04186|103|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04187|001|T|MONOGRAPH TITLE:  Levomethadone;Methadone (Immediate Release)/Lemborexant|
04187|002|B||
04187|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04187|004|L|take action as needed.|
04187|005|B||
04187|006|A|MECHANISM OF ACTION:  Lemborexant may induce the metabolism of CYP2B6|
04187|007|A|substrates such as methadone.  Additionally, concurrent use of lemborexant|
04187|008|A|and methadone may result in additive CNS depression.(1-3)|
04187|009|A|   Levomethadone is the active (R)-enantiomer of methadone.(3)|
04187|010|B||
04187|011|E|CLINICAL EFFECTS:  Concomitant use of methadone with CYP2B6 inducers such as|
04187|012|E|lemborexant can decrease the plasma concentration of methadone, resulting in|
04187|013|E|decreased efficacy or onset of withdrawal symptoms in patients physically|
04187|014|E|dependent on methadone.(1-3)|
04187|015|E|   Concurrent use of lemborexant and other CNS depressants, such as|
04187|016|E|methadone, may impair daytime wakefulness.(1-3)|
04187|017|B||
04187|018|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04187|019|P|may increase the risk of adverse effects.|
04187|020|B||
04187|021|M|PATIENT MANAGEMENT:  Limit prescribing methadone with CNS depressants such|
04187|022|M|as lemborexant to patients for whom alternatives are inadequate.(4)|
04187|023|M|   Respiratory depression can occur at any time during opioid therapy,|
04187|024|M|especially during therapy initiation and following dosage increases.|
04187|025|M|Consider this risk when using concurrently with other agents that may cause|
04187|026|M|CNS depression.(5)|
04187|027|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
04187|028|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04187|029|M|unresponsiveness.(4)  Monitor for signs of opioid withdrawal in patients|
04187|030|M|physically dependent on methadone.(1-3)|
04187|031|M|   Discuss naloxone with all patients when prescribing or renewing an opioid|
04187|032|M|analgesic or medicine to treat opioid use disorder (OUD).  Consider|
04187|033|M|prescribing naloxone to patients prescribed medicines to treat OUD or opioid|
04187|034|M|analgesics who are at increased risk of opioid overdose (such as those|
04187|035|M|taking CNS depressants) and when a patient has household members/close|
04187|036|M|contacts at risk for accidental overdose.(6)|
04187|037|B||
04187|038|D|DISCUSSION:  In a study, lemborexant (10 mg dose) decreased the|
04187|039|D|concentration maximum (Cmax) and area-under-curve (AUC) of a S-bupropion by|
04187|040|D|49.9% and 45.5%, respectively.(1)|
04187|041|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04187|042|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04187|043|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04187|044|D|to 30 million patients.  During this time, the proportion of patients|
04187|045|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04187|046|D|patients.(7)|
04187|047|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04187|048|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04187|049|D|per 100,000 and drug overdose deaths involving both opioids and|
04187|050|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04187|051|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04187|052|D|increased from 18% to 31% during this time.(8)|
04187|053|D|   A prospective observational cohort study in North Carolina found that the|
04187|054|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04187|055|D|benzodiazepines were 10 times higher than patients receiving opioid|
04187|056|D|analgesics alone.(9)|
04187|057|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04187|058|D|death from overdose increased with concomitant opioid analgesics and|
04187|059|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04187|060|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04187|061|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04187|062|D|increased risk of fatal overdose.(10)|
04187|063|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04187|064|D|which benzodiazepines were determined to be a cause of death and that|
04187|065|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04187|066|D|determined to be a cause of death.  This study also found that other CNS|
04187|067|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04187|068|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04187|069|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04187|070|D|where opioid analgesics were also implicated.(11)|
04187|071|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04187|072|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04187|073|D|deaths.(12)|
04187|074|B||
04187|075|R|REFERENCES:|
04187|076|B||
04187|077|R|1.Dayvigo (lemborexant) US prescribing information. Eisai Inc. March, 2022.|1
04187|078|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
04187|079|R|  Pharmaceuticals Corp. June, 2021.|1
04187|080|R|3.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
04187|081|R|  Pharma AS November 30, 2018.|1
04187|082|R|4.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04187|083|R|  warns about serious risks and death when combining opioid pain or cough|1
04187|084|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04187|085|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04187|086|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04187|087|R|  prescribing information for all opioid pain medicines to provide|1
04187|088|R|  additional guidance for safe use. Available at:|1
04187|089|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04187|090|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04187|091|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04187|092|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04187|093|R|  recommends health care professionals discuss naloxone with all patients|1
04187|094|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04187|095|R|  disorder. Available at:|1
04187|096|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04187|097|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04187|098|R|  d-pain July 23, 2020.|1
04187|099|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04187|100|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04187|101|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04187|102|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04187|103|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04187|104|R|  49(4):493-501.|2
04187|105|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04187|106|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04187|107|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04187|108|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04187|109|R|   prescribing patterns and deaths from drug overdose among US veterans|2
04187|110|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
04187|111|R|   350:h2698.|2
04187|112|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04187|113|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04187|114|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04187|115|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04187|116|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04187|117|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04188|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone for MAT/Lemborexant|
04188|002|B||
04188|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04188|004|L|take action as needed.|
04188|005|B||
04188|006|A|MECHANISM OF ACTION:  Lemborexant may induce the metabolism of CYP2B6|
04188|007|A|substrates such as methadone.  Additionally, concurrent use of lemborexant|
04188|008|A|and methadone may result in additive CNS depression.(1-3)|
04188|009|A|   Levomethadone is the active (R)-enantiomer of methadone.(3)|
04188|010|B||
04188|011|E|CLINICAL EFFECTS:  Concomitant use of methadone with CYP2B6 inducers such as|
04188|012|E|lemborexant can decrease the plasma concentration of methadone, resulting in|
04188|013|E|decreased efficacy or onset of withdrawal symptoms in patients physically|
04188|014|E|dependent on methadone.(1-3)|
04188|015|E|   Concurrent use of lemborexant and other CNS depressants, such as|
04188|016|E|methadone, may impair daytime wakefulness.(1-3)|
04188|017|B||
04188|018|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04188|019|P|may increase the risk of adverse effects.|
04188|020|B||
04188|021|M|PATIENT MANAGEMENT:  Medication assisted treatment (MAT) with methadone is|
04188|022|M|not contraindicated in patients taking CNS depressants; however,|
04188|023|M|discontinuation of CNS depressants is preferred in most cases.  In some|
04188|024|M|cases, monitoring at a higher level of care may be appropriate.  In others,|
04188|025|M|gradual tapering or decreasing to the lowest effective dose of the CNS|
04188|026|M|depressant is appropriate.  Consider other medications and nonpharmacologic|
04188|027|M|treatments to address anxiety or insomnia.  Ensure that other health care|
04188|028|M|providers prescribing other CNS depressants are aware of the patient's|
04188|029|M|methadone treatment.(5)|
04188|030|M|   Respiratory depression can occur at any time during opioid therapy,|
04188|031|M|especially during therapy initiation and following dosage increases.  The|
04188|032|M|risk of opioid-related overdose or overdose-related death is increased with|
04188|033|M|higher opioid doses, and this risk persists over the course of therapy.|
04188|034|M|Consider these risks when using concurrently with other agents that may|
04188|035|M|cause CNS depression.(6)|
04188|036|M|   If concurrent use is necessary, monitor patients for unusual dizziness or|
04188|037|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04188|038|M|unresponsiveness.(4)  Monitor for signs of opioid withdrawal in patients|
04188|039|M|physically dependent on methadone.(1-3)|
04188|040|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04188|041|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04188|042|M|treat opioid use disorder (OUD).  Consider prescribing opioid reversal|
04188|043|M|agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04188|044|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04188|045|M|as those taking CNS depressants) and when a patient has household|
04188|046|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04188|047|M|for obtaining an opioid reversal agent (e.g., prescription,|
04188|048|M|over-the-counter, or as part of a community-based program).(7)|
04188|049|B||
04188|050|D|DISCUSSION:  In a study, lemborexant (10 mg dose) decreased the|
04188|051|D|concentration maximum (Cmax) and area-under-curve (AUC) of a S-bupropion by|
04188|052|D|49.9% and 45.5%, respectively.(1)|
04188|053|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04188|054|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04188|055|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04188|056|D|to 30 million patients.  During this time, the proportion of patients|
04188|057|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04188|058|D|patients.(8)|
04188|059|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04188|060|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04188|061|D|per 100,000 and drug overdose deaths involving both opioids and|
04188|062|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04188|063|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04188|064|D|increased from 18% to 31% during this time.(9)|
04188|065|D|   A prospective observational cohort study in North Carolina found that the|
04188|066|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04188|067|D|benzodiazepines were 10 times higher than patients receiving opioid|
04188|068|D|analgesics alone.(10)|
04188|069|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04188|070|D|death from overdose increased with concomitant opioid analgesics and|
04188|071|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04188|072|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04188|073|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04188|074|D|increased risk of fatal overdose.(11)|
04188|075|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04188|076|D|which benzodiazepines were determined to be a cause of death and that|
04188|077|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04188|078|D|determined to be a cause of death.  This study also found that other CNS|
04188|079|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04188|080|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04188|081|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04188|082|D|where opioid analgesics were also implicated.(12)|
04188|083|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04188|084|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04188|085|D|deaths.(13)|
04188|086|D|   While concomitant use of MAT with CNS depressants increases the risk of|
04188|087|D|adverse reactions, barriers to MAT can pose a greater risk of morbidity and|
04188|088|D|mortality due to opioid use disorder.(5)|
04188|089|B||
04188|090|R|REFERENCES:|
04188|091|B||
04188|092|R|1.Dayvigo (lemborexant) US prescribing information. Eisai Inc. March, 2022.|1
04188|093|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
04188|094|R|  Pharmaceuticals Corp. June, 2021.|1
04188|095|R|3.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
04188|096|R|  Pharma AS November 30, 2018.|1
04188|097|R|4.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04188|098|R|  warns about serious risks and death when combining opioid pain or cough|1
04188|099|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04188|100|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04188|101|R|5.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04188|102|R|  urges caution about withholding opioid addiction medications from patients|1
04188|103|R|  taking benzodiazepines or CNS depressants: careful medication management|1
04188|104|R|  can reduce risks. available at:|1
04188|105|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
04188|106|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04188|107|R|  prescribing information for all opioid pain medicines to provide|1
04188|108|R|  additional guidance for safe use. Available at:|1
04188|109|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04188|110|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04188|111|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04188|112|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04188|113|R|  recommends health care professionals discuss naloxone with all patients|1
04188|114|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04188|115|R|  disorder. Available at:|1
04188|116|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04188|117|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04188|118|R|  d-pain July 23, 2020.|1
04188|119|R|8.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04188|120|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04188|121|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04188|122|R|9.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04188|123|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04188|124|R|  49(4):493-501.|2
04188|125|R|10.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04188|126|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04188|127|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04188|128|R|11.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04188|129|R|   prescribing patterns and deaths from drug overdose among US veterans|2
04188|130|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
04188|131|R|   350:h2698.|2
04188|132|R|12.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04188|133|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04188|134|R|13.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04188|135|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04188|136|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04188|137|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04189|001|T|MONOGRAPH TITLE:  Selected P-glycoprotein (P-gp) Substrates/Selpercatinib|
04189|002|T|(mono deleted 11/05/2025)|
04189|003|B||
04189|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04189|005|L|of severe adverse interaction.|
04189|006|B||
04189|007|A|MECHANISM OF ACTION:  Selpercatinib is an inhibitor of the P-glycoprotein|
04189|008|A|(P-gp) transporter and may increase the plasma concentrations of P-gp|
04189|009|A|substrates.(1)|
04189|010|B||
04189|011|E|CLINICAL EFFECTS:  Concurrent use of selpercatinib with P-gp substrates may|
04189|012|E|result in elevated levels of the substrate, increasing the risk for adverse|
04189|013|E|effects.(1)|
04189|014|B||
04189|015|P|PREDISPOSING FACTORS:  None determined.|
04189|016|B||
04189|017|M|PATIENT MANAGEMENT:  The US manufacturer of selpercatinib states that the|
04189|018|M|concurrent use of narrow therapeutic index P-gp substrates should be|
04189|019|M|avoided.  If concurrent therapy cannot be avoided, follow recommendations|
04189|020|M|for the narrow therapeutic index P-gp substrate according to the substrate's|
04189|021|M|prescribing information.(1)|
04189|022|B||
04189|023|D|DISCUSSION:  In a study, selpercatinib increased dabigatran's|
04189|024|D|area-under-curve (AUC) by 38% and maximum concentration (Cmax) by 43%.(1)|
04189|025|D|   Selected narrow therapeutic index P-gp substrates include: afatinib,|
04189|026|D|betrixaban, bilastine, dabigatran, digoxin, edoxaban, etoposide, everolimus,|
04189|027|D|loperamide, rimegepant, rivaroxaban, sirolimus, and ubrogepant.(1,2)|
04189|028|B||
04189|029|R|REFERENCES:|
04189|030|B||
04189|031|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
04189|032|R|  2024.|1
04189|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
04189|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04190|001|T|MONOGRAPH TITLE:  Valbenazine (Less Than or Equal to 40 mg)/Strong CYP3A4|
04190|002|T|Inhibitors|
04190|003|B||
04190|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04190|005|L|take action as needed.|
04190|006|B||
04190|007|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
04190|008|A|metabolism of valbenazine.(1)|
04190|009|B||
04190|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04190|011|E|systemic exposure and the risk for valbenazine toxicities such as QT|
04190|012|E|prolongation.(1)|
04190|013|B||
04190|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04190|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04190|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04190|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04190|018|P|gender, or advanced age.(2)|
04190|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04190|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04190|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04190|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04190|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04190|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04190|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04190|026|P|   Concurrent use of strong CYP2D6 inhibitors may further increase levels of|
04190|027|P|valbenazine.(1)|
04190|028|B||
04190|029|M|PATIENT MANAGEMENT:  Reduce the valbenazine dose to 40 mg once daily when|
04190|030|M|valbenazine is coadministered with a strong CYP3A4 inhibitor.(1)|
04190|031|M|   During concomitant therapy with a strong CYP3A4 inhibitor, monitor|
04190|032|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
04190|033|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
04190|034|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
04190|035|M|irregular heartbeat, dizziness, or fainting.|
04190|036|B||
04190|037|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
04190|038|D|coadministration of ketoconazole with valbenazine increased valbenazine|
04190|039|D|maximum concentration (Cmax) and area-under-the-curve (AUC) by 2 and|
04190|040|D|1.5-fold, respectively. Cmax and AUC for the active metabolite of|
04190|041|D|valbenazine (alpha-HTBZ) increased by approximately 2 and 1.6-fold,|
04190|042|D|respectively.|
04190|043|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
04190|044|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir,|
04190|045|D|itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil,|
04190|046|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
04190|047|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04190|048|D|troleandomycin, tucatinib, and voriconazole.(3)|
04190|049|B||
04190|050|R|REFERENCES:|
04190|051|B||
04190|052|R|1.Ingrezza (valbenazine) US prescribing information. Neurocrine Biosciences,|1
04190|053|R|  Inc. April, 2020.|1
04190|054|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04190|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04190|056|R|  settings: a scientific statement from the American Heart Association and|6
04190|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04190|058|R|  2;55(9):934-47.|6
04190|059|R|3.This information is based on an extract from the Certara Drug Interaction|6
04190|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04191|001|T|MONOGRAPH TITLE:  Rivaroxaban/Nirmatrelvir-Ritonavir|
04191|002|B||
04191|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04191|004|L|is contraindicated and generally should not be dispensed or administered to|
04191|005|L|the same patient.|
04191|006|B||
04191|007|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the metabolism of|
04191|008|A|rivaroxaban by CYP3A4 and by P-glycoprotein.(1-5)|
04191|009|B||
04191|010|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
04191|011|E|P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and|
04191|012|E|clinical effects of rivaroxaban,(1-3) including an increased risk of|
04191|013|E|bleeding.|
04191|014|B||
04191|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04191|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04191|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
04191|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04191|019|P|risk for bleeding (e.g. NSAIDs).|
04191|020|B||
04191|021|M|PATIENT MANAGEMENT:  The US manufacturer of nirmatrelvir-ritonavir states|
04191|022|M|concurrent use with rivaroxaban should be avoided.(4)|
04191|023|M|   The Canadian manufacturer of nirmatrelvir-ritonavir states use with|
04191|024|M|rivaroxaban should not be used concomitantly.(5)|
04191|025|M|   The Journal of American College of Cardiology states use of|
04191|026|M|nirmatrelvir-ritonavir with rivaroxaban should be avoided.  Use of|
04191|027|M|rivaroxaban cannot be safely adjusted or interrupted.  If|
04191|028|M|nirmatrelvir-ritonavir is deemed necessary, withhold rivaroxaban for 24-36|
04191|029|M|hours before starting nirmatrelvir-ritonavir.  Use of an alternative|
04191|030|M|anticoagulant is recommended for a total of 8 days.  Rivaroxaban may be|
04191|031|M|restarted on day 9.(6)|
04191|032|M|   If concurrent therapy is deemed medically necessary, monitor patients|
04191|033|M|receiving concurrent therapy for signs of blood loss, including decreased|
04191|034|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
04191|035|M|and promptly evaluate patients with any symptoms.|
04191|036|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04191|037|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04191|038|M|anticoagulation in patients with active pathologic bleeding.|
04191|039|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04191|040|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04191|041|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04191|042|M|and/or swelling.|
04191|043|B||
04191|044|D|DISCUSSION:  Concurrent use of rivaroxaban with ketoconazole (400 mg daily)|
04191|045|D|increased rivaroxaban AUC and Cmax by 2.6-fold and 1.7-fold, respectively.|
04191|046|D|There were also significant increases in pharmacodynamic effects.(1-3)|
04191|047|D|   Clarithromycin increased the Cmax and AUC of a single dose of rivaroxaban|
04191|048|D|by 40% and 50%, respectively and is not expected to affect bleeding risk.(2)|
04191|049|D|   Agents that are not strong inhibitors of both CYP3A4 and P-glycoprotein,|
04191|050|D|including fluconazole, are expected to increase rivaroxaban levels to a|
04191|051|D|lesser extent and can be used with rivaroxaban with caution(2) in patients|
04191|052|D|with normal renal function.(3)|
04191|053|B||
04191|054|R|REFERENCES:|
04191|055|B||
04191|056|R|1.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
04191|057|R|  2015.|1
04191|058|R|2.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
04191|059|R|  Inc. March, 2020.|1
04191|060|R|3.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
04191|061|R|  August, 2021.|1
04191|062|R|4.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04191|063|R|  information. Pfizer Inc. February, 2025.|1
04191|064|R|5.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
04191|065|R|  Monograph. Pfizer Canada ULC October, 2023.|1
04191|066|R|6.Abraham S Nohria A Neilan TG Asnani A Saji AM Shah J Lech T Grossman J|6
04191|067|R|  Abraham GM McQuillen DP Martin DT Sax PE Dani SS Ganatra S. Cardiovascular|6
04191|068|R|  Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19:|6
04191|069|R|  JACC Review Topic of the Week. J Am Coll Cardiol 2022 Oct 6.|6
04192|001|T|MONOGRAPH TITLE:  Clopidogrel/Nirmatrelvir-Ritonavir|
04192|002|B||
04192|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04192|004|L|of severe adverse interaction.|
04192|005|B||
04192|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
04192|007|A|active metabolite via a 2 step process.  The first conversion step is|
04192|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
04192|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
04192|010|A|thought to be the more important enzyme involved in formation of the|
04192|011|A|pharmacologically active metabolite.(1)|
04192|012|A|   CYP3A4 is responsible for 39.8% of the second step of metabolism.|
04192|013|A|Protease inhibitors that are strong CYP3A4 inhibitors may inhibit the|
04192|014|A|metabolism of clopidogrel to its active form by CYP3A4.(1,2)|
04192|015|B||
04192|016|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors that are strong|
04192|017|E|CYP3A4 inhibitors may result in decreased clopidogrel effectiveness,|
04192|018|E|resulting in increased risk of adverse cardiac events.(1)|
04192|019|B||
04192|020|P|PREDISPOSING FACTORS:  None determined.|
04192|021|B||
04192|022|M|PATIENT MANAGEMENT:  The US manufacturer of clopidogrel as well as the US|
04192|023|M|and Canadian manufacturers of nirmatrelvir-ritonavir do not make specific|
04192|024|M|recommendations for concurrent use of clopidogrel and|
04192|025|M|nirmatrelvir-ritonavir.  Patient monitoring for adequate inhibition of|
04192|026|M|platelet reactivity with clopidogrel is warranted.(1,4-5)|
04192|027|M|   The Australian manufacturer of nirmatrelvir-ritonavir states that|
04192|028|M|concomitant use of clopidogrel should be avoided.(6)|
04192|029|M|   The Journal of American College of Cardiology (JACC) states use of|
04192|030|M|nirmatrelvir-ritonavir with clopidogrel should be avoided in patients with a|
04192|031|M|recent percutaneous coronary intervention (PCI) (at least within previous 6|
04192|032|M|weeks) or history of high-risk PCI.  If use of nirmatrelvir-ritonavir is|
04192|033|M|deemed necessary, consider switching to prasugrel with a loading dose while|
04192|034|M|on nirmatrelvir-ritonavir.(7)|
04192|035|M|   The JACC states concurrent use of nirmatrelvir-ritonavir with clopidogrel|
04192|036|M|is considered safe to co-administer in other low-risk patients.(7)|
04192|037|M|   HIV treatment guidelines from the US Department of Health and Human|
04192|038|M|Services and the European AIDS Clinical Society, and the University of|
04192|039|M|Liverpool HIV Drug Interactions database all recommend not to coadminister|
04192|040|M|clopidogrel with any protease inhibitor or cobicistat.(8-10)|
04192|041|M|   Consider alternatives to protease inhibitors that are strong CYP3A4|
04192|042|M|inhibitors in patients stabilized on clopidogrel and alternatives to|
04192|043|M|clopidogrel in patients stabilized on protease inhibitors that are strong|
04192|044|M|CYP3A4 inhibitors.  If concurrent therapy is warranted, consider appropriate|
04192|045|M|testing to assure adequate inhibition of platelet reactivity.|
04192|046|B||
04192|047|D|DISCUSSION:  In a randomized, cross-over study in healthy subjects,|
04192|048|D|ketoconazole (400 mg daily) decreased the maximum concentration (Cmax) of|
04192|049|D|the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg|
04192|050|D|daily) by 61%.  The area-under-curve (AUC) of the active metabolite of|
04192|051|D|clopidogrel was decreased by 22% following the loading dose and by 29%|
04192|052|D|during maintenance dosing.  Clopidogrel-induced inhibition of platelet|
04192|053|D|aggregation was decreased by 28% following the loading dose and by 33%|
04192|054|D|during the maintenance dose.(11)|
04192|055|D|   A randomized cross over study in 12 healthy volunteers and 9 HIV-infected|
04192|056|D|patients evaluated the impact of boosted antiretroviral therapy (ARV) on the|
04192|057|D|pharmacokinetics and efficacy of clopidogrel.  Healthy patients had 3.2-fold|
04192|058|D|lower AUC (p=0.02) and Cmax of clopidogrel active metabolite (p=0.03) than|
04192|059|D|HIV patients.  Platelet reactivity was also 35% lower in health patients|
04192|060|D|compared to HIV patients (p=0.04).  All healthy patients had a platelet|
04192|061|D|reactivity below the cut-off value at 4 hours after clopidogrel dose, while|
04192|062|D|44% of HIV patients were above the cut-off value of 206.(12)|
04192|063|D|   A cross-sectional study in 240 post acute coronary syndrome (ACS)|
04192|064|D|patients compared platelet reactivity under aspirin and P2Y12 inhibitor|
04192|065|D|therapy between HIV and non-HIV patients with first episode ACS on dual|
04192|066|D|antiplatelet therapy.  Study evaluated residual platelet aggregation (RPA),|
04192|067|D|P2Y12 assay (PRU), and VASP platelet reactivity index (VASP-PRI).  HIV|
04192|068|D|patients were all on ARV therapy, most commonly with protease inhibitors|
04192|069|D|(darunavir, lopinavir, atazanavir, and indinavir in combination with|
04192|070|D|ritonavir in all but two patients).  Patients on ARV containing protease|
04192|071|D|inhibitors compared to other combinations had increased platelet reactivity|
04192|072|D|to P2Y12 inhibitors and higher prevalence of high residual platelet|
04192|073|D|reactivity (HPR) (OR 4.4 (95%CI 1.1-18.1) with RPA, P = 0.04; OR 3.1 (95%CI|
04192|074|D|= 0.84-11.5) with VASP-PRI; P = 0.09, and OR 4.3 (95%CI 1.02-18.1) with PRU,|
04192|075|D|P = 0.047).  Patients with CD4 T cell count lower than 350/mm3 also had|
04192|076|D|consistently increased platelet reactivity to P2Y12 inhibitors and higher|
04192|077|D|prevalence of HPR (OR 3.41 (95%CI 0.60-19.4) with RPA, P = 0.17; OR 7.1|
04192|078|D|(95%CI 0.94-54.2) with VASP-PRI, P = 0.06; and OR 7.9 (95%CI 1.42-44.8) with|
04192|079|D|PRU, P = 0.002), although this association was not significant for all three|
04192|080|D|tests.(13)|
04192|081|B||
04192|082|R|REFERENCES:|
04192|083|B||
04192|084|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
04192|085|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
04192|086|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
04192|087|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
04192|088|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
04192|089|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
04192|090|R|  38(1):92-9.|5
04192|091|R|3.Wang ZY, Chen M, Zhu LL, Yu LS, Zeng S, Xiang MX, Zhou Q. Pharmacokinetic|6
04192|092|R|  drug interactions with clopidogrel: updated review and risk management in|6
04192|093|R|  combination therapy. Ther Clin Risk Manag 2015;11:449-67.|6
04192|094|R|4.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04192|095|R|  information. Pfizer Inc. February, 2025.|1
04192|096|R|5.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
04192|097|R|  Monograph. Pfizer Canada ULC October, 2023.|1
04192|098|R|6.Paxlovid (nirmatrelvir-ritonavir) Australian Product Information. Pfizer|1
04192|099|R|  Australia Pty Ltd February 28, 2025.|1
04192|100|R|7.Abraham S Nohria A Neilan TG Asnani A Saji AM Shah J Lech T Grossman J|6
04192|101|R|  Abraham GM McQuillen DP Martin DT Sax PE Dani SS Ganatra S. Cardiovascular|6
04192|102|R|  Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19:|6
04192|103|R|  JACC Review Topic of the Week. J Am Coll Cardiol 2022 Oct 6.|6
04192|104|R|8.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04192|105|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04192|106|R|  HIV. Department of Health and Human Services. Available at|6
04192|107|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
04192|108|R|  new-guidelines June 13, 2021.|6
04192|109|R|9.European AIDS Clinical Society. EACS Guidelines version 10.0. Available|6
04192|110|R|  at: https://eacs.sanfordguide.com/ November 2019.|6
04192|111|R|10.Liverpool Drug Interactions Group. HIV Drug Interactions. Available at:|6
04192|112|R|   https://hiv-druginteractions.org/.|6
04192|113|R|11.Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT,|2
04192|114|R|   Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by|2
04192|115|R|   ketoconazole affects prasugrel and clopidogrel pharmacokinetics and|2
04192|116|R|   pharmacodynamics differently. Clin Pharmacol Ther 2007 May;81(5):735-41.|2
04192|117|R|12.Hauguel-Moreau M, Boccara F, Boyd A, Salem JE, Brugier D, Curjol A, Hulot|2
04192|118|R|   JS, Kerneis M, Galier S, Cohen A, Montalescot G, Collet JP, Silvain J.|2
04192|119|R|   Platelet reactivity in human immunodeficiency virus infected patients on|2
04192|120|R|   dual antiplatelet therapy for an acute coronary syndrome: the|2
04192|121|R|   EVERE2ST-HIV study. Eur Heart J 2017 Jun 1;38(21):1676-1686.|2
04192|122|R|13.Marsousi N, Daali Y, Fontana P, Reny JL, Ancrenaz-Sirot V, Calmy A, Rudaz|2
04192|123|R|   S, Desmeules JA, Samer CF. Impact of Boosted Antiretroviral Therapy on|2
04192|124|R|   the Pharmacokinetics and Efficacy of  Clopidogrel and Prasugrel Active|2
04192|125|R|   Metabolites. Clin Pharmacokinet 2018 Oct;57(10):1347-1354.|2
04193|001|T|MONOGRAPH TITLE:  Apixaban/Nirmatrelvir-Ritonavir|
04193|002|B||
04193|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04193|004|L|of severe adverse interaction.|
04193|005|B||
04193|006|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the metabolism of|
04193|007|A|apixaban by CYP3A4 and by P-glycoprotein (P-gp).(1-4)|
04193|008|B||
04193|009|E|CLINICAL EFFECTS:  Concurrent use of an agent that is both an inhibitor of|
04193|010|E|P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and|
04193|011|E|clinical effects of apixaban, including an increased risk of bleeding.(1-4)|
04193|012|B||
04193|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04193|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04193|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
04193|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04193|017|P|risk for bleeding (e.g. NSAIDs).|
04193|018|B||
04193|019|M|PATIENT MANAGEMENT:  The US manufacturer of nirmatrelvir-ritonavir states|
04193|020|M|concurrent use with apixaban may require a dose adjustment based on apixaban|
04193|021|M|indication.(5)|
04193|022|M|   The Journal of American College of Cardiology states use of|
04193|023|M|nirmatrelvir-ritonavir with apixaban should be avoided.  Use of|
04193|024|M|apixaban cannot be safely adjusted or interrupted in patients on dialysis.|
04193|025|M|If nirmatrelvir-ritonavir is deemed necessary, dose adjustment|
04193|026|M|recommendations based on apixaban indication are recommended.(6)|
04193|027|M|   For AF:|
04193|028|M|   -If on 5 mg apixaban twice daily: Start nirmatrelvir-ritonavir and|
04193|029|M|decrease dose to 2.5 mg twice daily for a total of 8 days and then resume|
04193|030|M|apixaban at the previous dose.|
04193|031|M|   -If on 2.5 mg apixaban twice daily: Avoid nirmatrelvir-ritonavir or|
04193|032|M|withhold apixaban for 12-24 hours before starting nirmatrelvir-ritonavir|
04193|033|M|along with an alternative anticoagulant for a total of 8 days and then|
04193|034|M|resume apixaban at the previous dose.|
04193|035|M|   For VTE:|
04193|036|M|   -If on 10 mg apixaban twice daily: Start nirmatrelvir-ritonavir and|
04193|037|M|decrease apixaban to 5 mg twice daily for a total of 8 days and then resume|
04193|038|M|apixaban at the previous dose.|
04193|039|M|   -If on 5 mg apixaban twice daily: Start nirmatrelvir-ritonavir and|
04193|040|M|decrease apixaban to 2.5 mg twice daily for a total of 8 days and then|
04193|041|M|resume apixaban at the previous dose.|
04193|042|M|   -If on 2.5 mg apixaban twice daily for VTE prophylaxis: Can continue the|
04193|043|M|same dose while on nirmatrelvir-ritonavir (will likely achieve therapeutic|
04193|044|M|levels).|
04193|045|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04193|046|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04193|047|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04193|048|M|patients with any symptoms.|
04193|049|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04193|050|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04193|051|M|anticoagulation in patients with active pathologic bleeding.|
04193|052|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04193|053|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04193|054|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04193|055|M|and/or swelling.|
04193|056|B||
04193|057|D|DISCUSSION:  Concurrent ketoconazole (400 mg daily) increased the|
04193|058|D|area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by|
04193|059|D|2-fold and 1.6-fold, respectively.(1)|
04193|060|B||
04193|061|R|REFERENCES:|
04193|062|B||
04193|063|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04193|064|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04193|065|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04193|066|R|  Squibb-Pfizer January, 2025.|1
04193|067|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04193|068|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04193|069|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04193|070|R|  Company April, 2025.|1
04193|071|R|5.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04193|072|R|  information. Pfizer Inc. February, 2025.|1
04193|073|R|6.Abraham S Nohria A Neilan TG Asnani A Saji AM Shah J Lech T Grossman J|6
04193|074|R|  Abraham GM McQuillen DP Martin DT Sax PE Dani SS Ganatra S. Cardiovascular|6
04193|075|R|  Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19:|6
04193|076|R|  JACC Review Topic of the Week. J Am Coll Cardiol 2022 Oct 6.|6
04194|001|T|MONOGRAPH TITLE:  Dabigatran/Nirmatrelvir-Ritonavir|
04194|002|B||
04194|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04194|004|L|of severe adverse interaction.|
04194|005|B||
04194|006|A|MECHANISM OF ACTION:  Dabigatran etexilate is a substrate for the|
04194|007|A|P-glycoprotein (P-gp) system.  Inhibition of intestinal P-gp leads to|
04194|008|A|increased absorption of dabigatran.(1-3)|
04194|009|B||
04194|010|E|CLINICAL EFFECTS:  The concurrent use dabigatran with P-gp inhibitors may|
04194|011|E|lead to elevated plasma levels of dabigatran, increasing the risk for|
04194|012|E|bleeding.|
04194|013|B||
04194|014|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
04194|015|P|bleeding include renal impairment, concomitant use of P-gp inhibitors,|
04194|016|P|patient age >74 years, coexisting conditions (e.g. recent trauma) or use of|
04194|017|P|drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50|
04194|018|P|kg.(1-4)|
04194|019|B||
04194|020|M|PATIENT MANAGEMENT:  The US manufacturer of nirmatrelvir-ritonavir states|
04194|021|M|concurrent use with dabigatran should be avoided or may require a dose|
04194|022|M|adjustment based on dabigatran indication and renal function.(5)|
04194|023|M|   The Journal of American College of Cardiology states use of|
04194|024|M|nirmatrelvir-ritonavir with dabigatran should be avoided.  Use of|
04194|025|M|dabigatran cannot be safely adjusted or interrupted.  If|
04194|026|M|nirmatrelvir-ritonavir is deemed necessary, dose adjustment is recommended|
04194|027|M|based on the dabigatran indication.(6)|
04194|028|M|   For AF:|
04194|029|M|   -If CrCl > 50 mL/min: Decrease dose to 110 mg twice daily for 8 days from|
04194|030|M|the start of nirmatrelvir-ritonavir and then resume dabigatran at the|
04194|031|M|previous dose (this dosage is not available in the United States).|
04194|032|M|   -If CrCl 30-5 0mL/min: Decrease dose to 75 mg twice daily for 8 days from|
04194|033|M|the start of nirmatrelvir-ritonavir and then resume dabigatran at the|
04194|034|M|previous dose.|
04194|035|M|   -If CrCl < 30 mL/min: Avoid co-administration of nirmatrelvir-ritonavir|
04194|036|M|with dabigatran; consider switching to an alternative anticoagulant.|
04194|037|M|   For VTE:|
04194|038|M|   -If on 150 mg dabigatran twice daily: Co-administration with|
04194|039|M|nirmatrelvir-ritonavir is not recommended.  Withhold dabigatran for 12-24|
04194|040|M|hours and then start nirmatrelvir-ritonavir with an alternative|
04194|041|M|anticoagulant (eg, enoxaparin) for a total of 8 days, and then resume|
04194|042|M|dabigatran at previous dose.|
04194|043|M|   Assess renal function and evaluate patient for other pre-existing risk|
04194|044|M|factors for bleeding prior to initiating concurrent therapy.|
04194|045|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
04194|046|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
04194|047|M|and/or decreased blood pressure and promptly evaluate patients with any|
04194|048|M|symptoms.  Consider regular monitoring of hemoglobin, platelet levels,|
04194|049|M|and/or activated partial thromboplastin time (aPTT) or ecarin clotting time|
04194|050|M|(ECT).|
04194|051|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04194|052|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04194|053|M|anticoagulation in patients with active pathologic bleeding.|
04194|054|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04194|055|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04194|056|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04194|057|M|and/or swelling.|
04194|058|B||
04194|059|D|DISCUSSION:  When dabigatran was co-administered with amiodarone, the extent|
04194|060|D|and rate of absorption of amiodarone and its active metabolite DEA were|
04194|061|D|essentially unchanged. The dabigatran area-under-curve (AUC) and maximum|
04194|062|D|concentration (Cmax) were increased by about 60% and 50%, respectively;(1,2)|
04194|063|D|however, dabigatran clearance was increased by 65%.(1)|
04194|064|D|   Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000|
04194|065|D|mg) increased the AUC and Cmax of dabigatran by 53% and 56%,|
04194|066|D|respectively.(1,2)|
04194|067|D|   Chronic administration of immediate release verapamil one hour prior to|
04194|068|D|dabigatran dose increased dabigatran AUC by 154%.(4)  Administration of|
04194|069|D|dabigatran two hours before verapamil results in a negligible increase in|
04194|070|D|dabigatran AUC.(1)|
04194|071|D|   Administration of sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg|
04194|072|D|daily) increased the Cmax and AUC of a single dose of dabigatran (75 mg) by|
04194|073|D|2.87-fold and 2.61-fold, respectively.(7)|
04194|074|D|   Simultaneous administration of glecaprevir-pibrentasvir (300/120 mg|
04194|075|D|daily) with a single dose of dabigatran (150 mg) increased the Cmax and AUC|
04194|076|D|by 2.05-fold and 2.38-fold, respectively.(8)|
04194|077|D|   A retrospective comparative effectiveness cohort study including data|
04194|078|D|from 9,886 individuals evaluated adverse bleeding rates with standard doses|
04194|079|D|of oral anticoagulants with concurrent verapamil or diltiazem in patients|
04194|080|D|with nonvalvular atrial fibrillation and normal kidney function.  The study|
04194|081|D|compared rates of bleeding following co-administration of either dabigatran,|
04194|082|D|rivaroxaban, or apixaban with verapamil or diltiazem, compared to|
04194|083|D|co-administration with amlodipine or metoprolol.  Results of the study found|
04194|084|D|that concomitant dabigatran use with verapamil or diltiazem was associated|
04194|085|D|with increased overall bleeding (hazard ratio (HR) 1.52; 95% confidence|
04194|086|D|interval (CI), 1.05-2.20, p<0.05) and increased overall GI bleeding (HR|
04194|087|D|2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine.  When compared|
04194|088|D|to metoprolol, concomitant dabigatran use with verapamil or diltiazem was|
04194|089|D|also associated with increased overall bleeding (HR, 1.43; 95% CI,|
04194|090|D|1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI,|
04194|091|D|1.42-3.79, p<0.05).  No association was found between increased bleeding of|
04194|092|D|any kind and concurrent use of rivaroxaban or apixaban with verapamil or|
04194|093|D|diltiazem.(9)|
04194|094|D|   A summary of pharmacokinetic interactions with dabigatran and amiodarone|
04194|095|D|or verapamil concluded that concurrent use is considered safe if CrCl is|
04194|096|D|greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min|
04194|097|D|in VTE and less than 30 ml/min for NVAF.  Concurrent use with diltiazem was|
04194|098|D|considered safe.(10)|
04194|099|D|   In a pharmacokinetic study in 12 healthy subjects, concurrent use of|
04194|100|D|dabigatran with nirmatrelvir-ritonavir increased the geometric mean AUC and|
04194|101|D|Cmax by 1.9-fold and 2.3-fold, respectively.  Concurrent use of dabigatran|
04194|102|D|with ritonavir alone increased the mean AUC and Cmax by 1.7-fold and|
04194|103|D|1.7-fold, respectively.(11)|
04194|104|B||
04194|105|R|REFERENCES:|
04194|106|B||
04194|107|R|1.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
04194|108|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
04194|109|R|2.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
04194|110|R|  Boehringer Ingelheim March, 23 2020.|1
04194|111|R|3.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
04194|112|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
04194|113|R|4.Anonymous. FDA Dabigatran background package for Cardio-Renal Advisory|1
04194|114|R|  Committee. available at|1
04194|115|R|  http://wayback.archive-it.org/7993/20170405212218/https://www.fda.gov/down|1
04194|116|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascularan|1
04194|117|R|  dRenalDrugsAdvisoryCommittee/UCM247244.pdf September 20, 2010.|1
04194|118|R|5.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04194|119|R|  information. Pfizer Inc. February, 2025.|1
04194|120|R|6.Abraham S Nohria A Neilan TG Asnani A Saji AM Shah J Lech T Grossman J|6
04194|121|R|  Abraham GM McQuillen DP Martin DT Sax PE Dani SS Ganatra S. Cardiovascular|6
04194|122|R|  Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19:|6
04194|123|R|  JACC Review Topic of the Week. J Am Coll Cardiol 2022 Oct 6.|6
04194|124|R|7.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
04194|125|R|  Gilead Sciences, Inc. September, 2019.|1
04194|126|R|8.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
04194|127|R|  Inc. October, 2023.|1
04194|128|R|9.Pham P, Schmidt S, Lesko L, Lip GYH, Brown JD. Association of Oral|2
04194|129|R|  Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding  Events in|2
04194|130|R|  Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function.|2
04194|131|R|  JAMA Netw Open;3(4)(2574-3805 (Electronic). 2574-3805 (Linking)):.|2
04194|132|R|10.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
04194|133|R|   Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
04194|134|R|   of  the Week..|6
04194|135|R|11.Cox DS, Rehman M, Khan T, Ginman K, Salageanu J, LaBadie RR, Wan K, Damle|2
04194|136|R|   B. Effects of Nirmatrelvir/Ritonavir on Midazolam and Dabigatran|2
04194|137|R|   Pharmacokinetics in  Healthy Participants. Br J Clin Pharmacol 2023 Jun|2
04194|138|R|   24.|2
04195|001|T|MONOGRAPH TITLE:  Edoxaban/Nirmatrelvir-Ritonavir|
04195|002|B||
04195|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04195|004|L|of severe adverse interaction.|
04195|005|B||
04195|006|A|MECHANISM OF ACTION:  Edoxaban is a substrate for P-glycoprotein (P-gp).|
04195|007|A|Inhibitors of P-gp may increase intestinal absorption and decrease renal|
04195|008|A|tubular elimination of edoxaban.(1-4)|
04195|009|B||
04195|010|E|CLINICAL EFFECTS:  Concurrent use with P-gp inhibitors may result in higher|
04195|011|E|systemic concentrations of edoxaban which may increase the risk for|
04195|012|E|bleeding.(1-4)|
04195|013|B||
04195|014|P|PREDISPOSING FACTORS:  Bleeding risk may be increased in patients with|
04195|015|P|creatinine clearance below 50 mL per minute and in patients greater than 75|
04195|016|P|years of age.(1-2).|
04195|017|P|   Use of multiple agents which increase edoxaban exposure or affect|
04195|018|P|hemostasis would be expected to increase the risk for bleeding.|
04195|019|P|   The risk for bleeding episodes may be greater in patients with|
04195|020|P|disease-associated factors (e.g. thrombocytopenia).|
04195|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
04195|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04195|023|P|risk for bleeding (e.g. NSAIDs).|
04195|024|B||
04195|025|M|PATIENT MANAGEMENT:  The Journal of American College of Cardiology states|
04195|026|M|concurrent use of nirmatrelvir-ritonavir with edoxaban should be avoided.|
04195|027|M|Use of edoxaban cannot be safely adjusted or interrupted.  If|
04195|028|M|nirmatrelvir-ritonavir is deemed necessary, dose adjustment recommendations|
04195|029|M|based on edoxaban dose are recommended.(5)|
04195|030|M|   -If on 60 mg edoxaban daily: Decrease dose of edoxaban by 50% for a total|
04195|031|M|of 8 days from the start of nirmatrelvir-ritonavir and then resume edoxaban|
04195|032|M|at the previous dose.|
04195|033|M|   -If on 30 mg edoxaban daily: Withhold edoxaban when starting|
04195|034|M|nirmatrelvir-ritonavir.  Use an alternative anticoagulant (eg, enoxaparin)|
04195|035|M|for 8 days and then resume edoxaban.|
04195|036|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
04195|037|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
04195|038|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
04195|039|M|   When applicable, perform agent-specific laboratory test (e.g. anti Factor|
04195|040|M|Xa inhibition) to monitor efficacy and safety of anticoagulation.|
04195|041|M|Discontinue anticoagulation in patients with active pathologic bleeding.|
04195|042|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04195|043|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04195|044|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04195|045|M|and/or swelling.|
04195|046|M|   Discontinue edoxaban in patients with active bleeding.|
04195|047|B||
04195|048|D|DISCUSSION:  Edoxaban interaction studies have not been performed for|
04195|049|D|nirmatrelvir-ritonavir(1) and so the magnitude of any interaction with these|
04195|050|D|agents is not known.|
04195|051|B||
04195|052|R|REFERENCES:|
04195|053|B||
04195|054|R|1.FDA Center for Drug Evaluation and Research (CDER). Application number|1
04195|055|R|  206316 Savaysa (edoxaban tosylate) Clinical Pharmacology and|1
04195|056|R|  Biopharmaceutics Review. available at:|1
04195|057|R|  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s00|1
04195|058|R|  0ClinPharmR.pdf January 8, 2015.|1
04195|059|R|2.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
04195|060|R|  2019.|1
04195|061|R|3.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04195|062|R|  information. Pfizer Inc. February, 2025.|1
04195|063|R|4.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
04195|064|R|  Monograph. Pfizer Canada ULC October, 2023.|1
04195|065|R|5.Abraham S Nohria A Neilan TG Asnani A Saji AM Shah J Lech T Grossman J|6
04195|066|R|  Abraham GM McQuillen DP Martin DT Sax PE Dani SS Ganatra S. Cardiovascular|6
04195|067|R|  Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19:|6
04195|068|R|  JACC Review Topic of the Week. J Am Coll Cardiol 2022 Oct 6.|6
04196|001|T|MONOGRAPH TITLE:  Selpercatinib/Berotralstat (mono deleted 02/15/2024)|
04196|002|B||
04196|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04196|004|L|of severe adverse interaction.|
04196|005|B||
04196|006|A|MECHANISM OF ACTION:  Berotralstat is a moderate CYP3A4 inhibitor and may|
04196|007|A|inhibit the metabolism of selpercatinib.(1)|
04196|008|A|   Selpercatinib is a P-glycoprotein (P-gp) inhibitor and may increase the|
04196|009|A|absorption of berotralstat.(2)|
04196|010|B||
04196|011|E|CLINICAL EFFECTS:  Concurrent administration of selpercatinib and|
04196|012|E|berotralstat may result in elevated levels of and toxicity from both|
04196|013|E|agents.(1,2)  Elevated levels of selpercatinib may increase the risk of QTc|
04196|014|E|prolongation and potentially life-threatening arrhythmias including torsades|
04196|015|E|de pointes, hepatotoxicity, hypertension, and severe or life-threatening|
04196|016|E|hemorrhagic events.(1)|
04196|017|B||
04196|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04196|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04196|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04196|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04196|022|P|female gender, or advanced age.(3)|
04196|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04196|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04196|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04196|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04196|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04196|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04196|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04196|030|B||
04196|031|M|PATIENT MANAGEMENT:  The US manufacturer of selpercatinib recommends|
04196|032|M|avoiding concomitant use of moderate CYP3A4 inhibitors and avoiding|
04196|033|M|concomitant use of P-gp substrates where minimal concentration changes may|
04196|034|M|lead to increased adverse reactions.(1)  If concomitant use cannot be|
04196|035|M|avoided, a berotralstat dose of 110 mg daily is recommended,(2) and reduce|
04196|036|M|the dose of selpercatinib as follows:|
04196|037|M|   - If the current dose of selpercatinib is 160 mg twice daily, decrease|
04196|038|M|the dose to 120 mg twice daily.|
04196|039|M|   - If the current dose of selpercatinib is 120 mg twice daily, decrease|
04196|040|M|the dose to 80 mg twice daily.|
04196|041|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
04196|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04196|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04196|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04196|045|M|   If grade 3 QT interval prolongation occurs, withhold selpercatinib until|
04196|046|M|recovery to baseline or Grades 0 or 1, then resume selpercatinib at a|
04196|047|M|reduced dose.  If grade 4 QT interval prolongation occurs, discontinue|
04196|048|M|selpercatinib.(1)|
04196|049|M|   After the inhibitor has been discontinued for 3 to 5 elimination|
04196|050|M|half-lives, resume selpercatinib at the dose taken prior to initiating the|
04196|051|M|CYP3A inhibitor.(1)|
04196|052|B||
04196|053|D|DISCUSSION:  Coadministration of diltiazem, fluconazole, or verapamil|
04196|054|D|(moderate CYP3A inhibitors) is predicted to increase the area-under-curve|
04196|055|D|(AUC) and maximum concentration (Cmax) of selpercatinib by 60-99% and|
04196|056|D|46-76%, respectively.(1)|
04196|057|D|   In a thorough QT study, selpercatinib 160 mg twice daily increased QTc by|
04196|058|D|a mean of 10.6 msec (upper 90% confidence interval: 12.1 msec).  An increase|
04196|059|D|in QTcF interval to greater than 500 msec was measured in 6% of patients and|
04196|060|D|an increase in the QTcF interval of at least 60 msec over baseline was|
04196|061|D|measured in 15% of patients.(1)|
04196|062|D|   Administration of cyclosporine, a P-gp and BCRP inhibitor, with|
04196|063|D|berotralstat, increased berotralstat maximum concentration (Cmax) and|
04196|064|D|area-under-the-curve(0-last) (AUC 0-last), area-under-the-curve(0-inf) (AUC|
04196|065|D|0-inf) by 25%, 55%, and 69%.(2)|
04196|066|B||
04196|067|R|REFERENCES:|
04196|068|B||
04196|069|R|1.Retevmo (selpercatinib) US prescribing information. Eli Lilly April, 2024.|1
04196|070|R|2.Orladeyo (berotralstat) US prescribing information. BioCryst|1
04196|071|R|  Pharmaceuticals, Inc. November 2023.|1
04196|072|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04196|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04196|074|R|  settings: a scientific statement from the American Heart Association and|6
04196|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04196|076|R|  2;55(9):934-47.|6
04197|001|T|MONOGRAPH TITLE:  Tadalafil (PAH)/Select Protease Inhibitors; Cobicistat|
04197|002|B||
04197|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04197|004|L|take action as needed.|
04197|005|B||
04197|006|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
04197|007|A|tadalafil.(1-10)|
04197|008|B||
04197|009|E|CLINICAL EFFECTS:  The concurrent administration of a protease inhibitor may|
04197|010|E|result in elevated levels of tadalafil, which may result in increased|
04197|011|E|adverse effects such as hypotension, visual changes, and priapism.(1-10)|
04197|012|B||
04197|013|P|PREDISPOSING FACTORS:  None determined.|
04197|014|B||
04197|015|M|PATIENT MANAGEMENT:  The US manufacturers of the protease inhibitors state|
04197|016|M|that in patients who have received a protease inhibitor for at least one|
04197|017|M|week, the initial dosage of tadalafil for the treatment of primary pulmonary|
04197|018|M|hypertension should be 20 mg daily.  The dosage may be increased to 40 mg|
04197|019|M|daily based upon tolerability.(2-10)|
04197|020|M|   The US manufacturers of the protease inhibitors state that in patients|
04197|021|M|who have been receiving tadalafil for the treatment of primary pulmonary|
04197|022|M|hypertension, tadalafil should be discontinued for 24 hours before beginning|
04197|023|M|protease inhibitor therapy other than nelfinavir without concurrent|
04197|024|M|ritonavir.  After one week, tadalafil may be resumed at a dosage of 20 mg|
04197|025|M|daily.  The dosage may be increased to 40 mg daily based upon|
04197|026|M|tolerability.(2-10)|
04197|027|M|   In patients who have been receiving tadalafil for the treatment of|
04197|028|M|primary pulmonary hypertension, tadalafil should be adjusted to 20 mg daily|
04197|029|M|prior to beginning therapy with nelfinavir without concurrent ritonavir.|
04197|030|M|The dosage may be increased to 40 mg daily based upon tolerability.(7)|
04197|031|M|   In patients who have been receiving tadalafil for the treatment of|
04197|032|M|primary pulmonary hypertension, maintain tadalafil dose when switching from|
04197|033|M|darunavir/ritonavir to darunavir/cobicistat.(11)|
04197|034|M|   The US manufacturers of tadalafil(1) and the protease inhibitors(2-10)|
04197|035|M|state that the recommended dose of as needed tadalafil for the treatment of|
04197|036|M|erectile dysfunction is 10 mg of tadalafil every 72 hours in patients|
04197|037|M|receiving concurrent therapy.|
04197|038|M|   The US manufacturer of tadalafil states that the recommended dose of|
04197|039|M|daily tadalafil for the treatment of erectile dysfunction in patients taking|
04197|040|M|potent inhibitors of CYP3A4 is 2.5 mg.(1)|
04197|041|M|   Patients should be counseled that they are at an increased risk of|
04197|042|M|tadalafil adverse effects, including hypotension, syncope, visual changes,|
04197|043|M|and priapism.  Patients experiencing these effects should report them|
04197|044|M|promptly to their physician.|
04197|045|B||
04197|046|D|DISCUSSION:  Concurrent administration of a single dose of tadalafil (20 mg)|
04197|047|D|with ritonavir (500 mg or 600 mg twice daily) increased tadalafil|
04197|048|D|area-under-curve (AUC) by 32% and decreased tadalafil concentration maximum|
04197|049|D|(Cmax) by 30%.|
04197|050|D|   Concurrent administration of tipranavir/ritonavir (500/200 mg twice daily|
04197|051|D|for 17 doses) had no significant effects on the AUC of a single dose of|
04197|052|D|tadalafil (10 mg).  Tadalafil Cmax decreased 30%.  Tipranavir Cmax, AUC, and|
04197|053|D|concentration minimum (Cmin) decreased by 10%, 15%, and 19%, respectively.|
04197|054|D|Administration of a single dose of tipranavir/ritonavir (500/200 mg)|
04197|055|D|increased the AUC of a single dose of tadalafil (10 mg) by 2.33-fold.|
04197|056|D|Tadalafil Cmax decreased 22%.|
04197|057|D|   Concurrent administration of a single dose of tadalafil (20 mg) with|
04197|058|D|ritonavir (200 mg twice daily) increased tadalafil AUC by 124%.|
04197|059|B||
04197|060|R|REFERENCES:|
04197|061|B||
04197|062|R|1.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
04197|063|R|  February, 2018.|1
04197|064|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04197|065|R|  Squibb Company December, 2024.|1
04197|066|R|3.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04197|067|R|  March, 2023.|1
04197|068|R|4.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
04197|069|R|  March, 2019.|1
04197|070|R|5.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
04197|071|R|  September, 2016.|1
04197|072|R|6.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04197|073|R|  Laboratories December, 2019.|1
04197|074|R|7.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
04197|075|R|  Pharmaceuticals, Inc. September, 2016.|1
04197|076|R|8.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
04197|077|R|  December, 2019.|1
04197|078|R|9.Invirase (saquinavir mesylate) US prescribing information. Roche|1
04197|079|R|  Laboratories, Inc. March, 2019.|1
04197|080|R|10.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04197|081|R|   Pharmaceuticals, Inc. April, 2024.|1
04197|082|R|11.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
04197|083|R|   Pharmaceuticals, Inc. March, 2025.|1
04198|001|T|MONOGRAPH TITLE:  Tadalafil (PAH)/Nirmatrelvir-Ritonavir|
04198|002|B||
04198|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04198|004|L|of severe adverse interaction.|
04198|005|B||
04198|006|A|MECHANISM OF ACTION:  The nirmatrelvir-ritonavir may inhibit the metabolism|
04198|007|A|of tadalafil by CYP3A4.(1-2)|
04198|008|B||
04198|009|E|CLINICAL EFFECTS:  The concurrent administration of nirmatrelvir-ritonavir|
04198|010|E|may result in elevated levels of tadalafil, which may result in increased|
04198|011|E|adverse effects such as hypotension, visual changes, and priapism.(1,2)|
04198|012|B||
04198|013|P|PREDISPOSING FACTORS:  None determined.|
04198|014|B||
04198|015|M|PATIENT MANAGEMENT:  The US manufacturer of nirmatrelvir-ritonavir states|
04198|016|M|the concurrent use of tadalafil for pulmonary arterial hypertension (PAH)|
04198|017|M|should be avoided.(2)|
04198|018|M|   The US manufacturers of the protease inhibitors state that in patients|
04198|019|M|who have received a protease inhibitor for at least one week, the initial|
04198|020|M|dosage of tadalafil for the treatment of primary pulmonary hypertension|
04198|021|M|should be 20 mg daily.  The dosage may be increased to 40 mg daily based|
04198|022|M|upon tolerability.(3-11)|
04198|023|M|   The US manufacturers of the protease inhibitors state that in patients|
04198|024|M|who have been receiving tadalafil for the treatment of primary pulmonary|
04198|025|M|hypertension, tadalafil should be discontinued for 24 hours before beginning|
04198|026|M|protease inhibitor therapy other than nelfinavir without concurrent|
04198|027|M|ritonavir.  After one week, tadalafil may be resumed at a dosage of 20 mg|
04198|028|M|daily.  The dosage may be increased to 40 mg daily based upon|
04198|029|M|tolerability.(3-11)|
04198|030|M|   In patients who have been receiving tadalafil for the treatment of|
04198|031|M|primary pulmonary hypertension, tadalafil should be adjusted to 20 mg daily|
04198|032|M|prior to beginning therapy with nelfinavir without concurrent ritonavir.|
04198|033|M|The dosage may be increased to 40 mg daily based upon tolerability.(5)|
04198|034|M|   The US manufacturer of tadalafil states that the recommended dose of as|
04198|035|M|needed tadalafil for the treatment of erectile dysfunction is 10 mg of|
04198|036|M|tadalafil every 72 hours in patients receiving concurrent strong CYP3A4|
04198|037|M|inhibitors.(1)|
04198|038|M|   The US manufacturer of tadalafil states that the recommended dose of|
04198|039|M|daily tadalafil for the treatment of erectile dysfunction in patients taking|
04198|040|M|strong CYP3A4 inhibitors is 2.5 mg.(1)|
04198|041|M|   Patients should be counseled that they are at an increased risk of|
04198|042|M|tadalafil adverse effects, including hypotension, syncope, visual changes,|
04198|043|M|and priapism.  Patients experiencing these effects should report them|
04198|044|M|promptly to their physician.|
04198|045|B||
04198|046|D|DISCUSSION:  Concurrent administration of a single dose of tadalafil (20 mg)|
04198|047|D|with ritonavir (500 mg or 600 mg twice daily) increased tadalafil|
04198|048|D|area-under-curve (AUC) by 32% and decreased tadalafil concentration maximum|
04198|049|D|(Cmax) by 30%.|
04198|050|D|   Concurrent administration of tipranavir/ritonavir (500/200 mg twice daily|
04198|051|D|for 17 doses) had no significant effects on the AUC of a single dose of|
04198|052|D|tadalafil (10 mg).  Tadalafil Cmax decreased 30%.  Tipranavir Cmax, AUC, and|
04198|053|D|concentration minimum (Cmin) decreased by 10%, 15%, and 19%, respectively.|
04198|054|D|Administration of a single dose of tipranavir/ritonavir (500/200 mg)|
04198|055|D|increased the AUC of a single dose of tadalafil (10 mg) by 2.33-fold.|
04198|056|D|Tadalafil Cmax decreased 22%.|
04198|057|D|   Concurrent administration of a single dose of tadalafil (20 mg) with|
04198|058|D|ritonavir (200 mg twice daily) increased tadalafil AUC by 124%.|
04198|059|B||
04198|060|R|REFERENCES:|
04198|061|B||
04198|062|R|1.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
04198|063|R|  February, 2018.|1
04198|064|R|2.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04198|065|R|  information. Pfizer Inc. February, 2025.|1
04198|066|R|3.Invirase (saquinavir mesylate) US prescribing information. Roche|1
04198|067|R|  Laboratories, Inc. March, 2019.|1
04198|068|R|4.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04198|069|R|  Squibb Company December, 2024.|1
04198|070|R|5.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
04198|071|R|  Pharmaceuticals, Inc. September, 2016.|1
04198|072|R|6.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04198|073|R|  Pharmaceuticals, Inc. April, 2024.|1
04198|074|R|7.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04198|075|R|  March, 2023.|1
04198|076|R|8.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
04198|077|R|  March, 2019.|1
04198|078|R|9.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
04198|079|R|  September, 2016.|1
04198|080|R|10.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04198|081|R|   Laboratories December, 2019.|1
04198|082|R|11.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
04198|083|R|   December, 2019.|1
04199|001|T|MONOGRAPH TITLE:  Daridorexant (Greater Than 25 mg)/Moderate CYP3A4|
04199|002|T|Inhibitors|
04199|003|B||
04199|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04199|005|L|is contraindicated and generally should not be dispensed or administered to|
04199|006|L|the same patient.|
04199|007|B||
04199|008|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04199|009|A|metabolism of daridorexant.(1)|
04199|010|B||
04199|011|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04199|012|E|result in increased levels of and effects from daridorexant including|
04199|013|E|somnolence, fatigue, CNS depressant effects, daytime impairment, or|
04199|014|E|headache.(1)|
04199|015|B||
04199|016|P|PREDISPOSING FACTORS:  None determined.|
04199|017|B||
04199|018|M|PATIENT MANAGEMENT:  The dose of daridorexant should be limited to 25 mg|
04199|019|M|daily when used with a moderate CYP3A4 inhibitor.(1)|
04199|020|B||
04199|021|D|DISCUSSION:  Daridorexant is a CYP3A4 substrate.  In a PKPB model,|
04199|022|D|concurrent use of daridorexant with diltiazem, a moderate CYP3A4 inhibitor,|
04199|023|D|increased daridorexant area-under-curve (AUC) and maximum concentration|
04199|024|D|(Cmax) by 2.4-fold and 1.4-fold, respectively.(1)|
04199|025|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
04199|026|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
04199|027|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
04199|028|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
04199|029|D|lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib,|
04199|030|D|schisandra, stiripentol, treosulfan and verapamil.(2)|
04199|031|B||
04199|032|R|REFERENCES:|
04199|033|B||
04199|034|R|1.Quvivig (daridorexant) US prescribing information. Idorsia Pharmaceuticals|1
04199|035|R|  Ltd October, 2023.|1
04199|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
04199|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04200|001|T|MONOGRAPH TITLE:  Duvelisib/Pexidartinib (125 mg)|
04200|002|B||
04200|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04200|004|L|of severe adverse interaction.|
04200|005|B||
04200|006|A|MECHANISM OF ACTION:  Duvelisib and pexidartinib are both metabolized by|
04200|007|A|CYP3A4.  Pexidartinib is a moderate CYP3A4 inducer while duvelisib is a|
04200|008|A|moderate CYP3A4 inhibitor.(1-2)|
04200|009|B||
04200|010|E|CLINICAL EFFECTS:  The net effect of coadministration of duvelisib and|
04200|011|E|pexidartinib on CYP3A4 enzyme activity is unknown.  Concurrent or recent use|
04200|012|E|of pexidartinib may either decrease the clinical effectiveness of|
04200|013|E|duvelisib(1) or increase the levels and toxicities of pexidartinib.(2)|
04200|014|B||
04200|015|P|PREDISPOSING FACTORS:  None determined.|
04200|016|B||
04200|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04200|018|M|duvelisib with pexidartinib.  Concurrent therapy should be avoided.  If use|
04200|019|M|of this combination is necessary, the patient should be closely monitored|
04200|020|M|for duvelisib efficacy and pexidartinib toxicity.|
04200|021|M|   The manufacturer of duvelisib makes the recommendations below for|
04200|022|M|concurrent use with CYP3A4 inducers.|
04200|023|M|   Avoid the concurrent use of duvelisib with moderate CYP3A4 inducers.(1)|
04200|024|M|When possible, select alternative agents in place of the moderate CYP3A4|
04200|025|M|inducer.|
04200|026|M|   If the moderate CYP3A4 inducer cannot be avoided, increase the dose of|
04200|027|M|duvelisib on day 12 of concurrent therapy as follows:|
04200|028|M|   - If the initial dose of duvelisib is 25 mg twice daily, increase the|
04200|029|M|duvelisib dose to 40 mg twice daily.|
04200|030|M|   - If the initial dose of duvelisib is 15 mg twice daily, increase the|
04200|031|M|duvelisib dose to 25 mg twice daily.|
04200|032|M|   If the moderate CYP3A4 inducer is discontinued, reduce the dose of|
04200|033|M|duvelisib back to the initial dose 14 days after discontinuation of the|
04200|034|M|moderate CYP3A4 inducer.(1)|
04200|035|M|   The manufacturer of pexidartinib makes the recommendations below for|
04200|036|M|concurrent use with CYP3A4 inhibitors.|
04200|037|M|   Coadministration with moderate inhibitors of CYP3A4 should be avoided.(2)|
04200|038|M|If coadministration with a moderate CYP3A4 inhibitor cannot be avoided,|
04200|039|M|reduce the pexidartinib dose according to the following recommendations.|
04200|040|M|   If the planned total daily dose is currently 500 mg, modify the total|
04200|041|M|daily dose to 250 mg by administering 125 mg twice daily.|
04200|042|M|   If the planned total daily dose is currently 375 mg, modify the total|
04200|043|M|daily dose to 250 mg by administering 125 mg twice daily.|
04200|044|M|   If the planned total daily dose is currently 250 mg, modify the total|
04200|045|M|daily dose to 125 mg by administering 125 mg once daily.|
04200|046|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
04200|047|M|increase the pexidartinib dose to the dose that was used before starting the|
04200|048|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
04200|049|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04200|050|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04200|051|M|recommendations in the Turalio package insert.  Advise patients to|
04200|052|M|immediately report any symptoms of hepatotoxicity.|
04200|053|B||
04200|054|D|DISCUSSION:  In an interaction study, etravirine (a moderate CYP3A inducer)|
04200|055|D|200 mg twice daily decreased the maximum concentration (Cmax) and|
04200|056|D|area-under-curve (AUC) of single dose duvelisib 25 mg by 16% and 35%,|
04200|057|D|respectively.(1)|
04200|058|D|   Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased|
04200|059|D|pexidartinib Cmax and AUC by 41% and 67%, respectively.(2)|
04200|060|B||
04200|061|R|REFERENCES:|
04200|062|B||
04200|063|R|1.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
04200|064|R|  2021.|1
04200|065|R|2.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04200|066|R|  November, 2023.|1
04200|067|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04200|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04200|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04200|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04200|071|R|  11/14/2017.|1
04200|072|R|4.This information is based on an extract from the Certara Drug Interaction|6
04200|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04201|001|T|MONOGRAPH TITLE:  Pexidartinib/Cimetidine (mono deleted 12/06/2023)|
04201|002|B||
04201|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04201|004|L|of severe adverse interaction.|
04201|005|B||
04201|006|A|MECHANISM OF ACTION:  Cimetidine, a moderate inhibitor of CYP3A4, may|
04201|007|A|inhibit the metabolism of pexidartinib.(1,2)|
04201|008|A|   The solubility of pexidartinib is pH dependent.  Changes in gastric pH|
04201|009|A|from H2 antagonists may decrease the absorption of pexidartinib.(1)|
04201|010|B||
04201|011|E|CLINICAL EFFECTS:  The net effect of the concurrent administration of|
04201|012|E|cimetidine and pexidartinib is unknown.  Cimetidine may either increase or|
04201|013|E|decrease plasma levels of pexidartinib.  CYP3A4 inhibition by cimetidine may|
04201|014|E|result in elevated levels and increased effects of pexidartinib, such as|
04201|015|E|hepatotoxicity.(1,2)  Symptoms can include nausea, vomiting, jaundice, dark|
04201|016|E|urine, abdominal pain, and unexplained fatigue.|
04201|017|E|   The H2-receptor blocking effect of cimetidine may result in decreased|
04201|018|E|absorption and decreased levels and effectiveness of pexidartinib.(1)|
04201|019|B||
04201|020|P|PREDISPOSING FACTORS:  None determined.|
04201|021|B||
04201|022|M|PATIENT MANAGEMENT:  The optimal administration schedule and dosing of|
04201|023|M|pexidartinib and cimetidine when used in combination is unknown.|
04201|024|M|Manufacturers provide recommendations for dose modification of pexidartinib|
04201|025|M|when used with a moderate CYP3A4 inhibitor, but the recommendations may not|
04201|026|M|apply when opposing mechanisms are involved.  Dose modifications mentioned|
04201|027|M|below are informational only.|
04201|028|M|   Consider the use of short-acting antacids in patients taking|
04201|029|M|pexidartinib.  If antacids are used, separate the administration times by at|
04201|030|M|least 2 hours.|
04201|031|M|   If H2 antagonist therapy is required, the pexidartinib must be given 10|
04201|032|M|hours after the H2 blocker and at least 2 hours before the next dose of the|
04201|033|M|H2 blocker.|
04201|034|M|   The US manufacturer of pexidartinib states that pexidartinib|
04201|035|M|coadministration with moderate inhibitors of CYP3A4 should be avoided.  If|
04201|036|M|coadministration of pexidartinib with moderate CYP3A4 inhibitors cannot be|
04201|037|M|avoided, reduce the pexidartinib dose according to the following|
04201|038|M|recommendations.(1)|
04201|039|M|   If the planned total daily dose is currently 500 mg, modify the total|
04201|040|M|daily dose to 250 mg by administering 125 mg twice daily.|
04201|041|M|   If the planned total daily dose is currently 375 mg, modify the total|
04201|042|M|daily dose to 250 mg by administering 125 mg twice daily.|
04201|043|M|   If the planned total daily dose is currently 250 mg, modify the total|
04201|044|M|daily dose to 125 mg by administering 125 mg once daily.|
04201|045|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
04201|046|M|increase the pexidartinib dose to the dose that was used before starting the|
04201|047|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
04201|048|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04201|049|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04201|050|M|recommendations in the Turalio package insert. Advise patients to|
04201|051|M|immediately report any symptoms of hepatotoxicity.|
04201|052|B||
04201|053|D|DISCUSSION:  Coadministration of fluconazole (a moderate CYP3A4 inhibitor)|
04201|054|D|increased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
04201|055|D|(AUC) by 41% and 67%.(1)|
04201|056|D|   Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by|
04201|057|D|55% and 50%.(1)|
04201|058|B||
04201|059|R|REFERENCES:|
04201|060|B||
04201|061|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04201|062|R|  November, 2023.|1
04201|063|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04201|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04201|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04201|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04201|067|R|  11/14/2017.|1
04201|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
04201|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04202|001|T|MONOGRAPH TITLE:  Pexidartinib/Dronedarone|
04202|002|B||
04202|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04202|004|L|of severe adverse interaction.|
04202|005|B||
04202|006|A|MECHANISM OF ACTION:  Dronedarone may moderately inhibit the CYP3A4|
04202|007|A|metabolism of pexidartinib.(1,2)|
04202|008|A|   Pexidartinib is a moderate inducer of CYP3A4 and may increase the|
04202|009|A|metabolism of dronedarone.(1)|
04202|010|B||
04202|011|E|CLINICAL EFFECTS:  Concurrent use of dronedarone may result in elevated|
04202|012|E|levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2)|
04202|013|E|Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain,|
04202|014|E|and unexplained fatigue.|
04202|015|E|   Concurrent use of dronedarone may also result in decreased serum levels|
04202|016|E|and effectiveness of dronedarone.(1)|
04202|017|B||
04202|018|P|PREDISPOSING FACTORS:  None determined.|
04202|019|B||
04202|020|M|PATIENT MANAGEMENT:  The US manufacturer of pexidartinib states that|
04202|021|M|co-administration of CYP3A4 substrates with a narrow therapeutic window,|
04202|022|M|like dronedarone, should be avoided.  Pexidartinib coadministration with|
04202|023|M|moderate inhibitors of CYP3A4 should also be avoided.(1)|
04202|024|M|   The optimal dosing of pexidartinib and dronedarone when used in|
04202|025|M|combination is unknown.  Manufacturers provide recommendations for dose|
04202|026|M|modification of pexidartinib when used with a moderate CYP3A4 inhibitor, but|
04202|027|M|the recommendations may not apply when there is a multi-directional|
04202|028|M|interaction.  Dose modifications mentioned below are informational only.|
04202|029|M|   If coadministration of pexidartinib with moderate CYP3A4 inhibitors|
04202|030|M|cannot be avoided, reduce the pexidartinib dose according to the following|
04202|031|M|recommendations.|
04202|032|M|   If the planned total daily dose is currently 500 mg, modify the total|
04202|033|M|daily dose to 250 mg by administering 125 mg twice daily.|
04202|034|M|   If the planned total daily dose is currently 375 mg, modify the total|
04202|035|M|daily dose to 250 mg by administering 125 mg twice daily.|
04202|036|M|   If the planned total daily dose is currently 250 mg, modify the total|
04202|037|M|daily dose to 125 mg by administering 125 mg once daily.|
04202|038|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
04202|039|M|increase the pexidartinib dose to the dose that was used before starting the|
04202|040|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
04202|041|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04202|042|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04202|043|M|recommendations in the Turalio package insert. Advise patients to|
04202|044|M|immediately report any symptoms of hepatotoxicity.|
04202|045|M|   There are no recommendations to guide dosing of dronedarone in the|
04202|046|M|presence of a moderate CYP3A4 inducer.|
04202|047|B||
04202|048|D|DISCUSSION:  Coadministration of fluconazole (a moderate CYP3A4 inhibitor)|
04202|049|D|increased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
04202|050|D|(AUC) by 41% and 67%.(1)|
04202|051|D|   Coadministration of pexidartinib 400 mg twice daily with oral midazolam,|
04202|052|D|a sensitive CYP3A4 substrate, in patients decreased midazolam|
04202|053|D|area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1)|
04202|054|B||
04202|055|R|REFERENCES:|
04202|056|B||
04202|057|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04202|058|R|  November, 2023.|1
04202|059|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04202|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04202|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04202|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04202|063|R|  11/14/2017.|1
04202|064|R|3.This information is based on an extract from the Certara Drug Interaction|6
04202|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04203|001|T|MONOGRAPH TITLE:  Pexidartinib/Idelalisib|
04203|002|B||
04203|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04203|004|L|of severe adverse interaction.|
04203|005|B||
04203|006|A|MECHANISM OF ACTION:  Idelalisib is both a substrate and a strong inhibitor|
04203|007|A|of the CYP3A4 isoenzyme.(1)  Pexidartinib is both a substrate and a moderate|
04203|008|A|inducer of CYP3A4.(2)  Concurrent use of pexidartinib and idelalisib may|
04203|009|A|alter exposure to one or both agents.|
04203|010|B||
04203|011|E|CLINICAL EFFECTS:  Concurrent use of pexidartinib and idelalisib may result|
04203|012|E|in elevated levels of and toxicity from pexidartinib(2) and decreased levels|
04203|013|E|and efficacy of idelalisib.(1)  The net effect and magnitude of the two-way|
04203|014|E|interaction between pexidartinib and idelalisib is unknown.|
04203|015|B||
04203|016|P|PREDISPOSING FACTORS:  None determined.|
04203|017|B||
04203|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pexidartinib and|
04203|019|M|idelalisib.(2,3)  Consider alternatives with no or minimal effect on the|
04203|020|M|CYP3A4 isoenzyme.|
04203|021|M|   The optimal dosing of pexidartinib and idelalisib when used in|
04203|022|M|combination is unknown.  Manufacturers provide recommendations for dose|
04203|023|M|modification of pexidartinib when used with a strong CYP3A4 inhibitor, but|
04203|024|M|the recommendations may not apply when there is a multi-directional|
04203|025|M|interaction.  Dose modifications mentioned below are informational only.|
04203|026|M|   If coadministration of pexidartinib with a strong CYP3A4 inhibitor cannot|
04203|027|M|be avoided, reduce the pexidartinib dose according to the following|
04203|028|M|recommendations.|
04203|029|M|   If the planned total daily dose is currently 500 mg, modify the total|
04203|030|M|daily dose to 250 mg by administering 125 mg twice daily.|
04203|031|M|   If the planned total daily dose is currently 375 mg, modify the total|
04203|032|M|daily dose to 250 mg by administering 125 mg twice daily.|
04203|033|M|   If the planned total daily dose is currently 250 mg, modify the total|
04203|034|M|daily dose to 125 mg by administering 125 mg once daily.|
04203|035|M|   If concomitant use of a strong CYP3A4 inhibitor is discontinued, increase|
04203|036|M|the pexidartinib dose to the dose that was used before starting the|
04203|037|M|inhibitor after three plasma half-lives of the strong CYP3A4 inhibitor.|
04203|038|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04203|039|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04203|040|M|recommendations in the Turalio package insert. Advise patients to|
04203|041|M|immediately report any symptoms of hepatotoxicity.|
04203|042|M|   Patients receiving concurrent therapy with pexidartinib and idelalisib|
04203|043|M|should be monitored closely for efficacy and signs of toxicities.(1,2)|
04203|044|B||
04203|045|D|DISCUSSION:  Coadministration of itraconazole, a strong CYP3A inhibitor,|
04203|046|D|increased pexidartinib area-under curve (AUC) by 70% and maximum|
04203|047|D|concentration (Cmax) by 48%.(2)|
04203|048|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
04203|049|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
04203|050|D|75%, respectively.(3)|
04203|051|B||
04203|052|R|REFERENCES:|
04203|053|B||
04203|054|R|1.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
04203|055|R|  October, 2020.|1
04203|056|R|2.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04203|057|R|  November, 2023.|1
04203|058|R|3.Zydelig (idelalisib) UK Summary of Product Characteristics. Gilead|1
04203|059|R|  Sciences Ltd December 17, 2019.|1
04203|060|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04203|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04203|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04203|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04203|064|R|  11/14/2017.|1
04203|065|R|5.This information is based on an extract from the Certara Drug Interaction|6
04203|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04204|001|T|MONOGRAPH TITLE:  Pexidartinib/Moderate CYP3A4 Inhibitors|
04204|002|B||
04204|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04204|004|L|of severe adverse interaction.|
04204|005|B||
04204|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04204|007|A|metabolism of pexidartinib.(1,2)|
04204|008|B||
04204|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04204|010|E|result in elevated levels and increased effects of pexidartinib, such as|
04204|011|E|hepatotoxicity.(1,2)  Symptoms can include nausea, vomiting, jaundice, dark|
04204|012|E|urine, abdominal pain, and unexplained fatigue.|
04204|013|B||
04204|014|P|PREDISPOSING FACTORS:  None determined.|
04204|015|B||
04204|016|M|PATIENT MANAGEMENT:  The US manufacturer of pexidartinib states that|
04204|017|M|pexidartinib coadministration with moderate inhibitors of CYP3A4 should be|
04204|018|M|avoided.(1)|
04204|019|M|   If coadministration with a moderate CYP3A4 inhibitor cannot be avoided,|
04204|020|M|reduce the pexidartinib dose according to the following recommendations.|
04204|021|M|   If the planned total daily dose is currently 500 mg, modify the total|
04204|022|M|daily dose to 250 mg by administering 125 mg twice daily.|
04204|023|M|   If the planned total daily dose is currently 375 mg, modify the total|
04204|024|M|daily dose to 250 mg by administering 125 mg twice daily.|
04204|025|M|   If the planned total daily dose is currently 250 mg, modify the total|
04204|026|M|daily dose to 125 mg by administering 125 mg once daily.|
04204|027|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
04204|028|M|increase the pexidartinib dose to the dose that was used before starting the|
04204|029|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
04204|030|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04204|031|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04204|032|M|recommendations in the Turalio package insert. Advise patients to|
04204|033|M|immediately report any symptoms of hepatotoxicity.|
04204|034|B||
04204|035|D|DISCUSSION:  Coadministration of fluconazole (a moderate CYP3A4 inhibitor)|
04204|036|D|increased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
04204|037|D|(AUC) by 41% and 67%.(1)|
04204|038|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04204|039|D|atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem,|
04204|040|D|erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
04204|041|D|imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra,|
04204|042|D|stiripentol, tofisopam, treosulfan, and verapamil.(1,3)|
04204|043|B||
04204|044|R|REFERENCES:|
04204|045|B||
04204|046|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04204|047|R|  November, 2023.|1
04204|048|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04204|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04204|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04204|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04204|052|R|  11/14/2017.|1
04204|053|R|3.This information is based on an extract from the Certara Drug Interaction|6
04204|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04205|001|T|MONOGRAPH TITLE:  Pexidartinib/UGT1A4 Inhibitors|
04205|002|B||
04205|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04205|004|L|of severe adverse interaction.|
04205|005|B||
04205|006|A|MECHANISM OF ACTION:  Inhibitors of UGT1A4 may inhibit the metabolism of|
04205|007|A|pexidartinib.(1)|
04205|008|B||
04205|009|E|CLINICAL EFFECTS:  Concurrent use of a inhibitors of UGT1A4 may result in|
04205|010|E|elevated levels and increased effects of pexidartinib, such as|
04205|011|E|hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark|
04205|012|E|urine, abdominal pain, and unexplained fatigue.|
04205|013|B||
04205|014|P|PREDISPOSING FACTORS:  None determined.|
04205|015|B||
04205|016|M|PATIENT MANAGEMENT:  The US manufacturer of pexidartinib states that|
04205|017|M|pexidartinib coadministration with inhibitors of UGT1A4 should be|
04205|018|M|avoided.(1)|
04205|019|M|   If coadministration with a UGT1A4 inhibitor cannot be avoided, reduce the|
04205|020|M|pexidartinib dose according to the following recommendations.|
04205|021|M|   If the planned total daily dose is currently 500 mg, modify the total|
04205|022|M|daily dose to 250 mg by administering 125 mg twice daily.|
04205|023|M|   If the planned total daily dose is currently 375 mg, modify the total|
04205|024|M|daily dose to 250 mg by administering 125 mg twice daily.|
04205|025|M|   If the planned total daily dose is currently 250 mg, modify the total|
04205|026|M|daily dose to 125 mg by administering 125 mg once daily.|
04205|027|M|   If concomitant use of a UGT1A4 inhibitor is discontinued, increase the|
04205|028|M|pexidartinib dose to the dose that was used before starting the inhibitor|
04205|029|M|after three plasma half-lives of the UGT1A4 inhibitor.|
04205|030|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04205|031|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04205|032|M|recommendations in the Turalio package insert. Advise patients to|
04205|033|M|immediately report any symptoms of hepatotoxicity.|
04205|034|B||
04205|035|D|DISCUSSION:  Coadministration of probenecid (UGT1A4 inhibitor) increased|
04205|036|D|pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by|
04205|037|D|5% and 60%.(1)|
04205|038|D|   Inhibitors of UGT1A4 linked to this monograph include:  probenecid.(1,2)|
04205|039|B||
04205|040|R|REFERENCES:|
04205|041|B||
04205|042|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04205|043|R|  November, 2023.|1
04205|044|R|2.This information is based on an extract from the Certara Drug Interaction|6
04205|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04206|001|T|MONOGRAPH TITLE:  Pexidartinib/Strong CYP3A4 Inhibitors|
04206|002|B||
04206|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04206|004|L|of severe adverse interaction.|
04206|005|B||
04206|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04206|007|A|of pexidartinib.(1,2)|
04206|008|B||
04206|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04206|010|E|in elevated levels and increased effects of pexidartinib, such as|
04206|011|E|hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark|
04206|012|E|urine, abdominal pain, and unexplained fatigue.|
04206|013|B||
04206|014|P|PREDISPOSING FACTORS:  None determined.|
04206|015|B||
04206|016|M|PATIENT MANAGEMENT:  The US manufacturer of pexidartinib states that|
04206|017|M|pexidartinib coadministration with strong inhibitors of CYP3A4 should be|
04206|018|M|avoided.(1)|
04206|019|M|   If coadministration with a strong CYP3A4 inhibitor cannot be avoided,|
04206|020|M|reduce the pexidartinib dose according to the following recommendations.|
04206|021|M|   If the planned total daily dose is currently 500 mg, modify the total|
04206|022|M|daily dose to 250 mg by administering 125 mg twice daily.|
04206|023|M|   If the planned total daily dose is currently 375 mg, modify the total|
04206|024|M|daily dose to 250 mg by administering 125 mg twice daily.|
04206|025|M|   If the planned total daily dose is currently 250 mg, modify the total|
04206|026|M|daily dose to 125 mg by administering 125 mg once daily.|
04206|027|M|   If concomitant use of a strong CYP3A4 inhibitor is discontinued, increase|
04206|028|M|the pexidartinib dose to the dose that was used before starting the|
04206|029|M|inhibitor after three plasma half-lives of the strong CYP3A4 inhibitor.|
04206|030|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04206|031|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04206|032|M|recommendations in the Turalio package insert. Advise patients to|
04206|033|M|immediately report any symptoms of hepatotoxicity.|
04206|034|B||
04206|035|D|DISCUSSION:  Coadministration of itraconazole (strong CYP3A4 inhibitor)|
04206|036|D|increased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
04206|037|D|(AUC) by 48% and 70%.(1)|
04206|038|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
04206|039|D|clarithromycin, cobicistat, indinavir, itraconazole, josamycin,|
04206|040|D|ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone,|
04206|041|D|nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir,|
04206|042|D|saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(1,3)|
04206|043|B||
04206|044|R|REFERENCES:|
04206|045|B||
04206|046|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04206|047|R|  November, 2023.|1
04206|048|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04206|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04206|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04206|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04206|052|R|  11/14/2017.|1
04206|053|R|3.This information is based on an extract from the Certara Drug Interaction|6
04206|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04207|001|T|MONOGRAPH TITLE:  Verapamil/Selected Strong CYP3A4 Inducers|
04207|002|B||
04207|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04207|004|L|of severe adverse interaction.|
04207|005|B||
04207|006|A|MECHANISM OF ACTION:  Concurrent use of strong CYP3A4 inducers may|
04207|007|A|accelerate the CYP3A4-mediated metabolism of verapamil.(1,2)|
04207|008|B||
04207|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease|
04207|010|E|levels and effectiveness of verapamil.(1,2)|
04207|011|B||
04207|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04207|013|P|of the inducer for longer than 1-2 weeks.|
04207|014|B||
04207|015|M|PATIENT MANAGEMENT:  The manufacturer of verapamil states concurrent use of|
04207|016|M|CYP3A4 inducers may result in significantly decreased verapamil levels.(1)|
04207|017|M|   Observe the patient for a decrease in the therapeutic effects of|
04207|018|M|verapamil if a strong CYP3A4 inducer is initiated.  The dose of verapamil|
04207|019|M|may need to be adjusted if a strong CYP3A4 inducer is initiated or|
04207|020|M|discontinued.(1)|
04207|021|B||
04207|022|D|DISCUSSION:  In healthy subjects, verapamil concentrations were evaluated|
04207|023|D|after 21 days of phenobarbital treatment.  After a single dose of verapamil,|
04207|024|D|mean total apparent oral clearance was increased after phenobarbital|
04207|025|D|treatment (75.1 vs. 376.2 ml/min/kg).  Clearance of verapamil free drug was|
04207|026|D|also increased.  Mean total verapamil systemic clearance was increased (9.95|
04207|027|D|vs. 18.9 ml/min/kg).  After multiple oral administration, total verapamil|
04207|028|D|apparent oral clearance was increased after phenobarbital pretreatment (21.2|
04207|029|D|vs. 91.2 ml/min/kg). Free drug clearance was also increased.(2)|
04207|030|D|   A study in six subjects examined the effects of pretreatment with|
04207|031|D|rifampin (600 mg daily for 15 days), a CYP3A4 inducer, on single doses of|
04207|032|D|verapamil (10 mg intravenously or 120 mg orally).  Rifampin significantly|
04207|033|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of|
04207|034|D|oral verapamil and resulted in no changes in the P-R interval.  There were|
04207|035|D|small decreases in the AUC of intravenous verapamil.(3)|
04207|036|D|   In a study in 8 male subjects, pretreatment with rifampin (600 mg daily|
04207|037|D|for 15 days) increased the systemic clearance of S-verapamil by 1.3-fold and|
04207|038|D|the apparent oral-clearance of S-verapamil by 32-fold.  The bioavailability|
04207|039|D|of S-verapamil decreased 25-fold.  The effect of oral verapamil on AV|
04207|040|D|conduction was almost abolished.  No significant changes were noted for|
04207|041|D|intravenous administration of verapamil.(4)|
04207|042|D|   There have been case reports of decreased effectiveness of verapamil|
04207|043|D|during concurrent rifampin therapy.(5,6)|
04207|044|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04207|045|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin,|
04207|046|D|and primidone.(7,8)|
04207|047|B||
04207|048|R|REFERENCES:|
04207|049|B||
04207|050|R|1.Calan (verapamil hydrochloride) US prescribing information. Pfizer, Inc.|1
04207|051|R|  August, 2016.|1
04207|052|R|2.Rutledge DR, Pieper JA, Mirvis DM. Effects of chronic phenobarbital on|2
04207|053|R|  verapamil disposition in humans. J Pharmacol Exp Ther 1988 Jul;|2
04207|054|R|  246(1):7-13.|2
04207|055|R|3.Barbarash RA, Bauman JL, Fischer JH, Kondos GT, Batenhorst RL. Near-total|2
04207|056|R|  reduction in verapamil bioavailability by rifampin. Electrocardiographic|2
04207|057|R|  correlates. Chest 1988 Nov;94(5):954-9.|2
04207|058|R|4.Fromm MF, Busse D, Kroemer HK, Eichelbaum M. Differential induction of|2
04207|059|R|  prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology|2
04207|060|R|  1996 Oct;24(4):796-801.|2
04207|061|R|5.Rahn KH, Mooy J, Bohm R, vd Vet A. Reduction of bioavailability of|3
04207|062|R|  verapamil by rifampin. N Engl J Med 1985 Apr 4;312(14):920-1.|3
04207|063|R|6.Barbarash RA. Verapamil-rifampin interaction. Drug Intell Clin Pharm 1985|3
04207|064|R|  Jul-Aug;19(7-8):559-60.|3
04207|065|R|7.This information is based on an extract from the Certara Drug Interaction|6
04207|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04207|067|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
04207|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04207|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04207|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04207|071|R|  11/14/2017.|1
04208|001|T|MONOGRAPH TITLE:  Tadalafil (BPH)/Select Protease Inhibitors; Cobicistat|
04208|002|B||
04208|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04208|004|L|of severe adverse interaction.|
04208|005|B||
04208|006|A|MECHANISM OF ACTION:  The protease inhibitors may inhibit the metabolism of|
04208|007|A|tadalafil.(1-11)|
04208|008|B||
04208|009|E|CLINICAL EFFECTS:  The concurrent administration of a protease inhibitor may|
04208|010|E|result in elevated levels of tadalafil, which may result in increased|
04208|011|E|adverse effects such as hypotension, visual changes, and priapism.(1-11)|
04208|012|B||
04208|013|P|PREDISPOSING FACTORS:  None determined.|
04208|014|B||
04208|015|M|PATIENT MANAGEMENT:  The US manufacturer of tadalafil states that tadalafil|
04208|016|M|for benign prostatic hyperplasia (BPH) is not recommended with strong CYP3A4|
04208|017|M|inhibitors.(1)  The HIV guidelines state that the recommended daily dose of|
04208|018|M|tadalafil for BPH should be 2.5 mg daily in patients receiving concurrent|
04208|019|M|therapy.(12)|
04208|020|M|   The US manufacturers of tadalafil(2) and the protease inhibitors(3-11)|
04208|021|M|state that the recommended dose of as needed tadalafil for the treatment of|
04208|022|M|erectile dysfunction is 10 mg of tadalafil every 72 hours in patients|
04208|023|M|receiving concurrent therapy.|
04208|024|M|   The US manufacturer of tadalafil states that the recommended dose of|
04208|025|M|daily tadalafil for the treatment of erectile dysfunction in patients taking|
04208|026|M|potent inhibitors of CYP3A4 is 2.5 mg.(2)|
04208|027|M|   The US manufacturers of the protease inhibitors state that in patients|
04208|028|M|who have received a protease inhibitor for at least one week, the initial|
04208|029|M|dosage of tadalafil for the treatment of primary pulmonary hypertension|
04208|030|M|should be 20 mg daily.  The dosage may be increased to 40 mg daily based|
04208|031|M|upon tolerability.(3-11)|
04208|032|M|   The US manufacturers of the protease inhibitors state that in patients|
04208|033|M|who have been receiving tadalafil for the treatment of primary pulmonary|
04208|034|M|hypertension, tadalafil should be discontinued for 24 hours before beginning|
04208|035|M|protease inhibitor therapy other than nelfinavir without concurrent|
04208|036|M|ritonavir.  After one week, tadalafil may be resumed at a dosage of 20 mg|
04208|037|M|daily.  The dosage may be increased to 40 mg daily based upon|
04208|038|M|tolerability.(3-11)|
04208|039|M|   In patients who have been receiving tadalafil for the treatment of|
04208|040|M|primary pulmonary hypertension, tadalafil should be adjusted to 20 mg daily|
04208|041|M|prior to beginning therapy with nelfinavir without concurrent ritonavir.|
04208|042|M|The dosage may be increased to 40 mg daily based upon tolerability.(8)|
04208|043|M|   In patients who have been receiving tadalafil for the treatment of|
04208|044|M|primary pulmonary hypertension, maintain tadalafil dose when switching from|
04208|045|M|darunavir/ritonavir to darunavir/cobicistat.(13)|
04208|046|M|   Patients should be counseled that they are at an increased risk of|
04208|047|M|tadalafil adverse effects, including hypotension, syncope, visual changes,|
04208|048|M|and priapism.  Patients experiencing these effects should report them|
04208|049|M|promptly to their physician.|
04208|050|B||
04208|051|D|DISCUSSION:  Concurrent administration of a single dose of tadalafil (20 mg)|
04208|052|D|with ritonavir (500 mg or 600 mg twice daily) increased tadalafil|
04208|053|D|area-under-curve (AUC) by 32% and decreased tadalafil concentration maximum|
04208|054|D|(Cmax) by 30%.|
04208|055|D|   Concurrent administration of tipranavir/ritonavir (500/200 mg twice daily|
04208|056|D|for 17 doses) had no significant effects on the AUC of a single dose of|
04208|057|D|tadalafil (10 mg).  Tadalafil Cmax decreased 30%.  Tipranavir Cmax, AUC, and|
04208|058|D|concentration minimum (Cmin) decreased by 10%, 15%, and 19%, respectively.|
04208|059|D|Administration of a single dose of tipranavir/ritonavir (500/200 mg)|
04208|060|D|increased the AUC of a single dose of tadalafil (10 mg) by 2.33-fold.|
04208|061|D|Tadalafil Cmax decreased 22%.|
04208|062|D|   Concurrent administration of a single dose of tadalafil (20 mg) with|
04208|063|D|ritonavir (200 mg twice daily) increased tadalafil AUC by 124%.|
04208|064|B||
04208|065|R|REFERENCES:|
04208|066|B||
04208|067|R|1.Entadfi (finasteride and tadalafil) US prescribing information. Veru Inc.|1
04208|068|R|  December, 2021.|1
04208|069|R|2.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
04208|070|R|  February, 2018.|1
04208|071|R|3.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04208|072|R|  Squibb Company December, 2024.|1
04208|073|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04208|074|R|  March, 2023.|1
04208|075|R|5.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
04208|076|R|  March, 2019.|1
04208|077|R|6.Crixivan (indinavir sulfate) US prescribing information. Merck & Co., Inc.|1
04208|078|R|  September, 2016.|1
04208|079|R|7.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04208|080|R|  Laboratories December, 2019.|1
04208|081|R|8.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
04208|082|R|  Pharmaceuticals, Inc. September, 2016.|1
04208|083|R|9.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
04208|084|R|  December, 2019.|1
04208|085|R|10.Invirase (saquinavir mesylate) US prescribing information. Roche|1
04208|086|R|   Laboratories, Inc. March, 2019.|1
04208|087|R|11.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04208|088|R|   Pharmaceuticals, Inc. April, 2024.|1
04208|089|R|12.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04208|090|R|   for the use of antiretroviral agents in adults and adolescents Living|6
04208|091|R|   with HIV. Department of Health and Human Services. Available at|6
04208|092|R|   https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats|6
04208|093|R|   -new-guidelines June 13, 2021.|6
04208|094|R|13.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
04208|095|R|   Pharmaceuticals, Inc. March, 2025.|1
04212|001|T|MONOGRAPH TITLE:  Ombitasvir-Paritaprevir-Ritonavir/Nirmatrelvir-Ritonavir|
04212|002|B||
04212|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04212|004|L|take action as needed.|
04212|005|B||
04212|006|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the metabolism of|
04212|007|A|paritaprevir-ritonavir by CYP3A4.(1-3)|
04212|008|B||
04212|009|E|CLINICAL EFFECTS:  Concurrent administration of nirmatrelvir-ritonavir with|
04212|010|E|paritaprevir-ritonavir may increase levels and toxicity of|
04212|011|E|paritaprevir-ritonavir.(1-3)|
04212|012|B||
04212|013|P|PREDISPOSING FACTORS:  None determined.|
04212|014|B||
04212|015|M|PATIENT MANAGEMENT:  The manufacturer of nirmatrelvir-ritonavir states that|
04212|016|M|no dose adjustment is needed when coadministered with other|
04212|017|M|ritonavir-containing products.  Patients on|
04212|018|M|ombitasvir-paritaprevir-ritonavir hepatitis C regimens should continue their|
04212|019|M|hepatitis C therapy while on nirmatrelvir-ritonavir.  Monitor patients|
04212|020|M|closely for adverse effects.(1,2)|
04212|021|B||
04212|022|D|DISCUSSION:  Nirmatrelvir-ritonavir is a strong CYP3A4 inhibitor and may|
04212|023|D|increase the levels of CYP3A4 substrates, including|
04212|024|D|ombitasvir-paritaprevir-ritonavir.(1-3)|
04212|025|B||
04212|026|R|REFERENCES:|
04212|027|B||
04212|028|R|1.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04212|029|R|  information. Pfizer Inc. February, 2025.|1
04212|030|R|2.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
04212|031|R|  Monograph. Pfizer Canada ULC October, 2023.|1
04212|032|R|3.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
04212|033|R|  prescribing information. AbbVie Inc. December, 2019.|1
04213|001|T|MONOGRAPH TITLE:  Sofosbuvir-Velpatasvir-Voxilaprevir/Nirmatrelvir-Ritonavir|
04213|002|B||
04213|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04213|004|L|take action as needed.|
04213|005|B||
04213|006|A|MECHANISM OF ACTION:  Nirmatrelvir-ritonavir may inhibit the hepatic uptake|
04213|007|A|and elimination of voxilaprevir by OATP1B1 and OATP1B3.(1-6)|
04213|008|B||
04213|009|E|CLINICAL EFFECTS:  Concurrent administration of nirmatrelvir-ritonavir with|
04213|010|E|sofosbuvir-velpatasvir-voxilaprevir may increase levels and toxicity of|
04213|011|E|voxilaprevir.(1-6)|
04213|012|B||
04213|013|P|PREDISPOSING FACTORS:  None determined.|
04213|014|B||
04213|015|M|PATIENT MANAGEMENT:  There are no recommendations to guide coadministration|
04213|016|M|of nirmatrelvir-ritonavir with sofosbuvir-velpatasvir-voxilaprevir.  If|
04213|017|M|coadministration is warranted, monitor patients closely for adverse|
04213|018|M|effects.(1,2)|
04213|019|B||
04213|020|D|DISCUSSION:  Nirmatrelvir-ritonavir is an OATP1B1/3 inhibitor and may|
04213|021|D|increase the levels of OATP substrates, including voxilaprevir.(1-6)  While|
04213|022|D|there are no specific recommendations regarding coadministration of|
04213|023|D|nirmatrelvir-ritonavir with sofosbuvir-velpatasvir-voxilaprevir, the US|
04213|024|D|manufacturer of sofosbuvir-velpatasvir-voxilaprevir does have the following|
04213|025|D|recommendations for other protease inhibitors: there are no clinically|
04213|026|D|significant interactions with ritonavir or darunavir.  Atazanavir and|
04213|027|D|lopinavir are not recommended due to the risk of increased voxilaprevir|
04213|028|D|levels.(6)  How nirmatrelvir affects the OATP transporters and the clinical|
04213|029|D|relevance of any interaction with sofosbuvir-velpatasvir-voxilaprevir is|
04213|030|D|unknown.|
04213|031|B||
04213|032|R|REFERENCES:|
04213|033|B||
04213|034|R|1.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04213|035|R|  information. Pfizer Inc. February, 2025.|1
04213|036|R|2.Paxlovid (nirmatrelvir tablets and ritonavir tablets) Canadian Product|1
04213|037|R|  Monograph. Pfizer Canada ULC October, 2023.|1
04213|038|R|3.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) Australian product|1
04213|039|R|  information. Gilead Sciences Pty Ltd June 21, 2019.|1
04213|040|R|4.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) Canadian prescribing|1
04213|041|R|  information. Gilead Sciences Canada, Inc. June 26, 2019.|1
04213|042|R|5.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) UK Summary of Product|1
04213|043|R|  Characteristics. Gilead Sciences Ltd September 3, 2019.|1
04213|044|R|6.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
04213|045|R|  Gilead Sciences, Inc. September, 2019.|1
04214|001|T|MONOGRAPH TITLE:  Levomethadone; Methadone/Cannabidiol|
04214|002|B||
04214|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04214|004|L|take action as needed.|
04214|005|B||
04214|006|A|MECHANISM OF ACTION:  Methadone is metabolized primarily by CYP2B6.|
04214|007|A|Inhibitors or inducers of CYP2B6 may alter the metabolism of methadone.(1-3)|
04214|008|A|Cannabidiol may have both inhibiting and inducing effects on CYP2B6.(4-7)|
04214|009|A|   Levomethadone is the active (R)-enantiomer of methadone.(8)|
04214|010|B||
04214|011|E|CLINICAL EFFECTS:  Concurrent administration of cannabidiol, a CYP2B6|
04214|012|E|inhibitor and inducer, may result in either decreased levels and clinical|
04214|013|E|effects of levomethadone or methadone, which may result in decreased|
04214|014|E|efficacy; or increased levels which may result in QTc prolongation and|
04214|015|E|life-threatening arrhythmias.  Elevated levels can also cause profound|
04214|016|E|sedation, respiratory depression, coma, and/or death.|
04214|017|E|   The discontinuation of CYP2B6 inhibitors in patients maintained on|
04214|018|E|levomethadone or methadone may result in symptoms of opioid withdrawal.|
04214|019|E|   Levomethadone and methadone have been associated with serotonin syndrome.|
04214|020|E|Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis,|
04214|021|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)|
04214|022|B||
04214|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04214|024|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04214|025|P|myocardial infarction, history of torsades de pointes, congenital long QT|
04214|026|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04214|027|P|gender, or advanced age.(9)|
04214|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04214|029|P|higher systemic concentrations of either QT prolonging drug are additional|
04214|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04214|031|P|drug concentrations include rapid infusion of an intravenous dose or|
04214|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04214|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04214|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(9)|
04214|035|B||
04214|036|M|PATIENT MANAGEMENT:  If concomitant use of levomethadone or methadone with|
04214|037|M|cannabidiol (a CYP2B6 inhibitor and inducer) is necessary, closely monitor|
04214|038|M|the patient when cannabidiol is initiated or withdrawn.  Patients should be|
04214|039|M|monitored for signs of both opioid toxicity and opioid withdrawal.  The|
04214|040|M|dosage of levomethadone or methadone may need to be adjusted.(3)|
04214|041|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
04214|042|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
04214|043|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
04214|044|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04214|045|M|   Respiratory depression can occur at any time during opioid therapy,|
04214|046|M|especially during therapy initiation and following dosage increases.  The|
04214|047|M|risk of opioid-related overdose or overdose-related death is increased with|
04214|048|M|higher opioid doses, and this risk persists over the course of therapy.|
04214|049|M|Consider these risks when using concurrently with agents that may increase|
04214|050|M|opioid drug levels.(10)|
04214|051|M|   Monitor patients for unusual dizziness or lightheadedness, extreme|
04214|052|M|sleepiness, slowed or difficult breathing, or unresponsiveness.|
04214|053|M|   Patients should also be monitored for signs and symptoms of serotonin|
04214|054|M|syndrome.  Instruct patients to report muscle twitching, tremors, shivering|
04214|055|M|and stiffness, fever, heavy sweating, heart palpitations, restlessness,|
04214|056|M|confusion, agitation, trouble with coordination, or severe diarrhea.|
04214|057|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04214|058|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04214|059|M|treat opioid use disorder (OUD).  Consider prescribing opioid reversal|
04214|060|M|agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04214|061|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04214|062|M|as those taking CNS depressants) and when a patient has household|
04214|063|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04214|064|M|for obtaining an opioid reversal agent (e.g., prescription,|
04214|065|M|over-the-counter, or as part of a community-based program).(11)|
04214|066|B||
04214|067|D|DISCUSSION:  In a case report, a 13 year old girl on concurrent methadone|
04214|068|D|7.5 mg twice daily and cannabidiol 375 mg/day for 2 months had her|
04214|069|D|cannabidiol dose increased 4-fold.  After 2 weeks, methadone levels|
04214|070|D|increased and patient reported sleepiness and fatigue.  Cannabidiol was|
04214|071|D|discontinued and methadone levels decreased 14 days after discontinuation,|
04214|072|D|with improvement in sleepiness and fatigue.(6)|
04214|073|D|   Some in vitro data suggests cannabidiol is a weak CYP2B6 inhibitor at|
04214|074|D|clinically relevant doses(7) while other in vitro data state that CYP2B6|
04214|075|D|inhibition occurs at concentrations greatly exceeding clinical doses.(5)|
04214|076|D|   In a clinical study, oral voriconazole (400 mg every 12 hours for 1 day,|
04214|077|D|then 200 mg every 12 hours for 4 days, a CYP2B6 inhibitor) increased the|
04214|078|D|maximum concentration (Cmax) and area-under-curve (AUC) of (R)-methadone by|
04214|079|D|31% and 47%, respectively, in subjects receiving a methadone maintenance|
04214|080|D|dose of 30 mg to 100 mg daily. The Cmax and AUC of (S)-methadone increased|
04214|081|D|by 65% and 103%, respectively.(3)|
04214|082|D|   In healthy subjects, ticlopidine (250 mg twice daily for 4 days, a CYP2B6|
04214|083|D|inhibitor) increased the dose-adjusted AUC of (R)-methadone and|
04214|084|D|(S)-methadone by about 20% and 60%, respectively.(12)|
04214|085|B||
04214|086|R|REFERENCES:|
04214|087|B||
04214|088|R|1.Kharasch ED. Current Concepts in Methadone Metabolism and Transport. Clin|6
04214|089|R|  Pharmacol Drug Dev 2017 Mar;6(2):125-134.|6
04214|090|R|2.Younis IR, Lakota EA, Volpe DA, Patel V, Xu Y, Sahajwalla CG. Drug-Drug|6
04214|091|R|  Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned. J|6
04214|092|R|  Clin Pharmacol 2019 Aug;59(8):1035-1043.|6
04214|093|R|3.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
04214|094|R|  Pharmaceuticals Corp. June, 2021.|1
04214|095|R|4.Epidiolex (cannabidiol) US prescribing information. Greenwich Biosciences,|1
04214|096|R|  Inc. June, 2025.|1
04214|097|R|5.Sativex (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD))|1
04214|098|R|  Canadian prescribing information. GW Pharma Ltd. December 11, 2019.|1
04214|099|R|6.Madden K, Tanco K, Bruera E. Clinically Significant Drug-Drug Interaction|3
04214|100|R|  Between Methadone and Cannabidiol. Pediatrics 2020 Jun;145(6):.|3
04214|101|R|7.Bansal S, Paine MF, Unadkat JD. Comprehensive Predictions of Cytochrome|5
04214|102|R|  P450 (P450)-Mediated In Vivo  Cannabinoid-Drug Interactions Based on|5
04214|103|R|  Reversible and Time-Dependent P450  Inhibition in Human Liver Microsomes.|5
04214|104|R|  Drug Metab Dispos 2022 Apr;50(4):351-360.|5
04214|105|R|8.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
04214|106|R|  Pharma AS November 30, 2018.|1
04214|107|R|9.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04214|108|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04214|109|R|  settings: a scientific statement from the American Heart Association and|6
04214|110|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04214|111|R|  2;55(9):934-47.|6
04214|112|R|10.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04214|113|R|   updates prescribing information for all opioid pain medicines to provide|1
04214|114|R|   additional guidance for safe use. Available at:|1
04214|115|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescr|1
04214|116|R|   ibing-information-all-opioid-pain-medicines-provide-additional-guidance-s|1
04214|117|R|   afe-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04214|118|R|11.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04214|119|R|   recommends health care professionals discuss naloxone with all patients|1
04214|120|R|   when prescribing opioid pain relievers or medicines to treat opioid use|1
04214|121|R|   disorder. Available at:|1
04214|122|R|   https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-hea|1
04214|123|R|   lth-care-professionals-discuss-naloxone-all-patients-when-prescribing-opi|1
04214|124|R|   oid-pain July 23, 2020.|1
04214|125|R|12.Kharasch ED, Stubbert K. Role of cytochrome P4502B6 in methadone|2
04214|126|R|   metabolism and clearance. J Clin Pharmacol 2013 Mar;53(3):305-13.|2
04215|001|T|MONOGRAPH TITLE:  Non-Live or Non-Replicating Vaccines/Teplizumab|
04215|002|B||
04215|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04215|004|L|of severe adverse interaction.|
04215|005|B||
04215|006|A|MECHANISM OF ACTION:  Teplizumab may cause lymphopenia and alter the immune|
04215|007|A|system's response to vaccines.(1)|
04215|008|B||
04215|009|E|CLINICAL EFFECTS:  Administration of a non-live vaccine within the 2 weeks|
04215|010|E|prior to, during, or for 6 weeks following teplizumab therapy may result in|
04215|011|E|decreased effectiveness of the vaccine.(1)|
04215|012|B||
04215|013|P|PREDISPOSING FACTORS:  None determined.|
04215|014|B||
04215|015|M|PATIENT MANAGEMENT:  Ideally, administer vaccines prior to initiating|
04215|016|M|teplizumab therapy.|
04215|017|M|   The manufacturer of teplizumab states that non-live vaccines (e.g.,|
04215|018|M|inactivated or mRNA vaccines) are not recommended within the 2 weeks prior|
04215|019|M|to, during, or for 6 weeks after stopping teplizumab therapy.(1)  The immune|
04215|020|M|response to non-live vaccines should be monitored in patients who receive|
04215|021|M|teplizumab within these time frames.|
04215|022|M|   The Centers for Disease Control's (CDC) Advisory Committee on|
04215|023|M|Immunization Practices (ACIP) states that non-live vaccines should be used|
04215|024|M|with caution in patients who are severely immunosuppressed.  Patients who|
04215|025|M|are vaccinated within the 14 days prior to initiating immunosuppressive|
04215|026|M|therapy should be considered unvaccinated and should be revaccinated at|
04215|027|M|least 3 months after immunosuppressive therapy is discontinued when immune|
04215|028|M|competence is restored.(2)|
04215|029|M|   For COVID-19 vaccines, the CDC advises planning for vaccination at least|
04215|030|M|2 weeks before starting or resuming immunosuppressive therapy.  Patients|
04215|031|M|should be offered and given a COVID-19 vaccine even if the use and timing of|
04215|032|M|immunosuppressive agents cannot be adjusted.  The CDC states that an|
04215|033|M|age-appropriate mRNA COVID-19 vaccine is preferred over the Janssen COVID-19|
04215|034|M|vaccine for the primary and booster doses for immunocompromised patients.|
04215|035|M|All immunocompromised patients over 5 years of age should receive at least 1|
04215|036|M|booster dose if eligible.  See the CDC's Interim Clinical Considerations for|
04215|037|M|Use of COVID-19 Vaccines for age- and product-specific recommendations.(3)|
04215|038|B||
04215|039|D|DISCUSSION:  Vaccinations may be less effective if administered within 2|
04215|040|D|weeks before, during, and for 6 weeks following teplizumab therapy.(1)|
04215|041|B||
04215|042|R|REFERENCES:|
04215|043|B||
04215|044|R|1.Tzield (teplizumab-mzwv) US prescribing information. Provention Bio, Inc.|1
04215|045|R|  November, 2022.|1
04215|046|R|2.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
04215|047|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
04215|048|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
04215|049|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
04215|050|R|  recs.pdf February 10, 2023;1-197.|6
04215|051|R|3.Centers for Disease Control and Prevention (CDC). Interim Clinical|6
04215|052|R|  Considerations for Use of COVID-19 Vaccines Currently Approved or|6
04215|053|R|  Authorized in the United States. Accessed at:|6
04215|054|R|  https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vac|6
04215|055|R|  cines-us.html Last updated: September 15, 2023.|6
04215|056|R|4.Curtis JR, Johnson SR, Anthony DD, Arasaratnam RJ, Baden LR, Bass AR,|6
04215|057|R|  etal. American College of Rheumatology COVID-19 Vaccine Clinical Guidance|6
04215|058|R|  Summary for Patients with Rheumatic and Musucloskeletal Diseases - Version|6
04215|059|R|  5. Arthritis and Rheumatology. Available at:|6
04215|060|R|  https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Gui|6
04215|061|R|  dance-Rheumatic-Diseases-Summary.pdf February 2, 2022.|6
04216|001|T|MONOGRAPH TITLE:  Live Vaccines; Live BCG/Teplizumab|
04216|002|B||
04216|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04216|004|L|of severe adverse interaction.|
04216|005|B||
04216|006|A|MECHANISM OF ACTION:  Teplizumab may cause lymphopenia and suppress the|
04216|007|A|immune system.  Immunocompromised patients may be at increased risk for|
04216|008|A|uninhibited replication after administration of live, attenuated vaccines or|
04216|009|A|intravesicular BCG.|
04216|010|A|   Immune response to vaccines may be decreased during periods of|
04216|011|A|immunocompromise.(1,2)|
04216|012|B||
04216|013|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained.|
04216|014|E|The vaccine may result in illness.(1,2)|
04216|015|E|   After instillation of intravesicular BCG, immunosuppression may interfere|
04216|016|E|with local immune response, or increase the severity of mycobacterial|
04216|017|E|infection following inadvertent systemic exposure.(3)|
04216|018|B||
04216|019|P|PREDISPOSING FACTORS:  Immunosuppressive diseases (e.g. hematologic|
04216|020|P|malignancies, HIV disease), treatments (e.g. radiation) and drugs may all|
04216|021|P|increase the magnitude of immunodeficiency.|
04216|022|B||
04216|023|M|PATIENT MANAGEMENT:  The Centers for Disease Control (CDC) Advisory|
04216|024|M|Committee on Immunization Practices (ACIP) states that live-virus and|
04216|025|M|live-attenuated vaccines should not be administered to patients who are|
04216|026|M|immunocompromised.  The magnitude of immunocompromise and associated risks|
04216|027|M|should be determined by a physician.(1)|
04216|028|M|   Vaccination should ideally precede the initiation of teplizumab therapy|
04216|029|M|by 8 weeks.  Live vaccines are not recommended within the 8 weeks prior to,|
04216|030|M|during, or for 52 weeks after stopping teplizumab therapy.(2)|
04216|031|B||
04216|032|D|DISCUSSION:  Vaccinations may be less effective if administered within 8|
04216|033|D|weeks before, during, and for 52 weeks following teplizumab therapy.(2)|
04216|034|D|   Killed or inactivated vaccines do not pose a danger to immunocompromised|
04216|035|D|patients.(1)|
04216|036|B||
04216|037|R|REFERENCES:|
04216|038|B||
04216|039|R|1.Centers for Disease Control and Prevention. General Recommendations on|1
04216|040|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
04216|041|R|  Practices (ACIP). MMWR.  Available at:|1
04216|042|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
04216|043|R|  February 17, 2022;60(RR No.2):1-68.|1
04216|044|R|2.Tzield (teplizumab-mzwv) US prescribing information. Provention Bio, Inc.|1
04216|045|R|  November, 2022.|1
04216|046|R|3.TICE BCG (BCG live, for intravesical use) prescribing information. Organon|1
04216|047|R|  USA Inc. October, 2010.|1
04217|001|T|MONOGRAPH TITLE:  Sensitive CYP3A4 Substrates that Prolong QT/Oral Lefamulin|
04217|002|B||
04217|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04217|004|L|is contraindicated and generally should not be dispensed or administered to|
04217|005|L|the same patient.|
04217|006|B||
04217|007|A|MECHANISM OF ACTION:  Oral lefamulin is a moderate CYP3A4 inhibitor and may|
04217|008|A|inhibit the metabolism of CYP3A4 substrates.  Also, concurrent use of|
04217|009|A|lefamulin with agents that prolong the QTc interval may result in additive|
04217|010|A|effects on the QTc interval.(1)|
04217|011|B||
04217|012|E|CLINICAL EFFECTS:  Concurrent use of oral lefamulin with drugs sensitive to|
04217|013|E|inhibition of the CYP3A4 pathway may lead to increased serum levels and|
04217|014|E|adverse effects, including potentially life-threatening cardiac arrhythmias|
04217|015|E|like torsades de pointes.(1)|
04217|016|B||
04217|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04217|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04217|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04217|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04217|021|P|female gender, or advanced age.(2)|
04217|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04217|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04217|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04217|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04217|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04217|027|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04217|028|P|dysfunction).(2)|
04217|029|P|   With pimozide, the risk of anticholinergic toxicities including cognitive|
04217|030|P|decline, delirium, falls and fractures is increased in geriatric patients|
04217|031|P|using more than one medicine with anticholinergic properties.(3)|
04217|032|B||
04217|033|M|PATIENT MANAGEMENT:  The combination of oral lefamulin with sensitive CYP3A4|
04217|034|M|substrates that prolong the QTc interval is contraindicated.(1)|
04217|035|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
04217|036|M|values (serum calcium, magnesium, and potassium) prior to the start of|
04217|037|M|treatment, after initiation of any drug known to prolong the QT interval,|
04217|038|M|and periodically monitor during therapy.  Correct any electrolyte|
04217|039|M|abnormalities.(1)|
04217|040|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
04217|041|M|fainting.|
04217|042|B||
04217|043|D|DISCUSSION:  In a thorough QT study, intravenous lefamulin increased the|
04217|044|D|QTcF 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF by|
04217|045|D|9.3 msec (90% CI = 10.9 msec).(1)|
04217|046|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
04217|047|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the|
04217|048|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200%|
04217|049|D|and 100%, respectively.  No clinically significant effect on midazolam|
04217|050|D|pharmacokinetics was observed when co-administered with lefamulin|
04217|051|D|injection.(1)|
04217|052|D|   Sensitive CYP3A4 substrates that prolong the QTc interval linked to this|
04217|053|D|monograph include: bosutinib, dasatinib, dronedarone, eliglustat,|
04217|054|D|entrectinib, gepirone, ivabradine, levomethadyl, lumefantrine, midostaurin,|
04217|055|D|mobocertinib, pimozide, quetiapine, saquinavir, tacrolimus, and|
04217|056|D|terfenadine.(4-6)|
04217|057|D|   Agents that are linked to this monograph may have varying degrees of|
04217|058|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04217|059|D|been shown to prolong the QTc interval either through their mechanism of|
04217|060|D|action, through studies on their effects on the QTc interval, or through|
04217|061|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04217|062|D|and/or postmarketing reports.(6)|
04217|063|B||
04217|064|R|REFERENCES:|
04217|065|B||
04217|066|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04217|067|R|  Inc August 2019.|1
04217|068|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04217|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04217|070|R|  settings: a scientific statement from the American Heart Association and|6
04217|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04217|072|R|  2;55(9):934-47.|6
04217|073|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04217|074|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04217|075|R|  Soc 2023 Jul;71(7):2052-2081.|6
04217|076|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04217|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04217|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04217|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04217|080|R|  11/14/2017.|1
04217|081|R|5.This information is based on an extract from the Certara Drug Interaction|6
04217|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04217|083|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
04217|084|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04217|085|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04217|086|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04218|001|T|MONOGRAPH TITLE:  Larotrectinib/Moderate CYP3A4 Inducers|
04218|002|B||
04218|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04218|004|L|take action as needed.|
04218|005|B||
04218|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may increase the|
04218|007|A|metabolism of larotrectinib.(1)|
04218|008|B||
04218|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
04218|010|E|in decreased levels and effectiveness of larotrectinib.(1)|
04218|011|B||
04218|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04218|013|P|of the inducer for longer than 1-2 weeks.|
04218|014|B||
04218|015|M|PATIENT MANAGEMENT:  The manufacturer of larotrectinib states that the|
04218|016|M|concurrent use of moderate CYP3A4 inducers requires a dose modification.|
04218|017|M|Double the dose of larotrectinib when coadministered with moderate CYP3A4|
04218|018|M|inducers.  After the moderate CYP3A4 inducer has been discontinued for 3 to|
04218|019|M|5 elimination half-lives, resume the larotrectinib dose at the dose taken|
04218|020|M|prior to initiating the CYP3A4 inducer.(1)|
04218|021|B||
04218|022|D|DISCUSSION:  In a study, efavirenz (a moderate CYP3A4 inducer) was predicted|
04218|023|D|to decrease area-under-curve (AUC) and maximum concentration (Cmax) by 72%|
04218|024|D|and 60%, respectively, compared to larotrectinib administered alone.(1)|
04218|025|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04218|026|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04218|027|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04218|028|D|pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine, and|
04218|029|D|tovorafenib.(3-4)|
04218|030|B||
04218|031|R|REFERENCES:|
04218|032|B||
04218|033|R|1.Vitrakvi (larotrectinib) US prescribing information. Loxo Oncology, Inc.|1
04218|034|R|  November, 2022.|1
04218|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04218|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04218|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04218|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04218|039|R|  11/14/2017.|1
04218|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04218|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04219|001|T|MONOGRAPH TITLE:  Olutasidenib/Strong and Moderate CYP3A4 Inducers|
04219|002|B||
04219|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04219|004|L|of severe adverse interaction.|
04219|005|B||
04219|006|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inducers may increase the|
04219|007|A|metabolism of olutasidenib by CYP3A4.(1)|
04219|008|B||
04219|009|E|CLINICAL EFFECTS:  The concurrent use of strong and moderate CYP3A4 inducers|
04219|010|E|and olutasidenib may result in decreased levels and clinical effectiveness|
04219|011|E|of olutasidenib.(1)|
04219|012|B||
04219|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04219|014|P|of the inducer for longer than 1-2 weeks.|
04219|015|B||
04219|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong and moderate CYP3A4|
04219|017|M|inducers with olutasidenib.(1)|
04219|018|B||
04219|019|D|DISCUSSION:  Coadministration of multiple doses of rifampin (a strong CYP3A4|
04219|020|D|inducer) decreased olutasidenib area-under-curve (AUC) and maximum|
04219|021|D|concentration (Cmax) by 80% and 43%, respectively.(1)|
04219|022|D|   Strong and moderate CYP3A4 inducers linked to this monograph include:|
04219|023|D|apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate,|
04219|024|D|dabrafenib, dipyrone, efavirenz, elagolix, encorafenib, enzalutamide,|
04219|025|D|etravirine, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor,|
04219|026|D|mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib,|
04219|027|D|pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin,|
04219|028|D|rifampin, rifapentine, St. John's wort, sotorasib, telotristat,|
04219|029|D|thioridazine, and tovorafenib.(2)|
04219|030|B||
04219|031|R|REFERENCES:|
04219|032|B||
04219|033|R|1.Rezlidhia (olutasidenib) US prescribing information. Rigel|1
04219|034|R|  Pharmaceuticals, Inc. December 2022..|1
04219|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
04219|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04220|001|T|MONOGRAPH TITLE:  Larotrectinib/Moderate CYP3A4 Inhibitors|
04220|002|B||
04220|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04220|004|L|take action as needed.|
04220|005|B||
04220|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
04220|007|A|metabolism of larotrectinib.(1)|
04220|008|B||
04220|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04220|010|E|systemic exposure and the risk for larotrectinib toxicities such as|
04220|011|E|neurotoxicity or hepatotoxicity.(1)|
04220|012|B||
04220|013|P|PREDISPOSING FACTORS:  None determined.|
04220|014|B||
04220|015|M|PATIENT MANAGEMENT:  Patients receiving a moderate CYP3A4 inhibitor|
04220|016|M|concurrently with larotrectinib should be monitored for adverse effects more|
04220|017|M|frequently.  A dose reduction may be needed based on the severity of adverse|
04220|018|M|effects.  Refer to prescribing information for dosage modifications.|
04220|019|B||
04220|020|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
04220|021|D|coadministration of itraconazole (a strong CYP3A4 inhibitor) with a single|
04220|022|D|dose of larotrectinib (100 mg) increased larotrectinib maximum concentration|
04220|023|D|(Cmax) and area-under-the-curve (AUC) by 2.8 and 4.3-fold, respectively.(1)|
04220|024|D|   Fluconazole (a moderate CYP3A4 inhibitor) is predicted to increase the|
04220|025|D|AUC and Cmax of larotrectinib by 2.7-fold and 1.9-fold, respectively.(1)|
04220|026|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
04220|027|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir,|
04220|028|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
04220|029|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral|
04220|030|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib,|
04220|031|D|schisandra, stiripentol, tofisopam, treosulfan, verapamil, and|
04220|032|D|voxelotor.(2,3)|
04220|033|B||
04220|034|R|REFERENCES:|
04220|035|B||
04220|036|R|1.Vitrakvi (larotrectinib) US prescribing information. Loxo Oncology, Inc.|1
04220|037|R|  November, 2022.|1
04220|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04220|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04220|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04220|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04220|042|R|  11/14/2017.|1
04220|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
04220|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04221|001|T|MONOGRAPH TITLE:  Lithium/Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors|
04221|002|B||
04221|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04221|004|L|take action as needed.|
04221|005|B||
04221|006|A|MECHANISM OF ACTION:  Sodium-glucose cotransporter 2 (SGLT2) inhibitors may|
04221|007|A|increase the renal excretion of lithium by impairing the proximal tubular|
04221|008|A|reabsorption of lithium.(1,2)|
04221|009|B||
04221|010|E|CLINICAL EFFECTS:  Concurrent use of SGLT2 inhibitors may result in|
04221|011|E|decreased levels and clinical effectiveness of lithium.(1-6)|
04221|012|B||
04221|013|P|PREDISPOSING FACTORS:  None determined.|
04221|014|B||
04221|015|M|PATIENT MANAGEMENT:  Lithium levels should be monitored more frequently when|
04221|016|M|starting or changing the dose of SGLT2 inhibitors.  The dose of lithium may|
04221|017|M|need to be adjusted.(3-6)|
04221|018|B||
04221|019|D|DISCUSSION:  A 29 year old patient stabilized on lithium with good|
04221|020|D|therapeutic response was started on empagliflozin on day 10 of lithium|
04221|021|D|therapy.  Three days later, lithium level was subtherapeutic.  Empagliflozin|
04221|022|D|was stopped.  After 1 week, lithium levels returned to therapeutic range.|
04221|023|D|Two days later, the patient had another trial of empagliflozin and again|
04221|024|D|developed subtherapeutic lithium levels.(1)|
04221|025|D|   A post hoc analysis of 2 dapagliflozin trials (IMPROVE and DapKid)|
04221|026|D|examined the effects of dapagliflozin on volume status in diabetic patients|
04221|027|D|with albuminuric kidney disease.  Lithium excretion, which served as a|
04221|028|D|marker of proximal tubular sodium excretion, was found to increase by 19.6%|
04221|029|D|(p < 0.01).(2)|
04221|030|B||
04221|031|R|REFERENCES:|
04221|032|B||
04221|033|R|1.Armstrong GP. Empagliflozin-Mediated Lithium Excretion: A Case Study and|3
04221|034|R|  Clinical Applications. Am J Case Rep 2020 Jun 10;21:e923311.|3
04221|035|R|2.Eickhoff MK, Dekkers CCJ, Kramers BJ, Laverman GD, Frimodt-Moller M,|2
04221|036|R|  Jorgensen NR, Faber J, Danser AHJ, Gansevoort RT, Rossing P, Persson F,|2
04221|037|R|  Heerspink HJL. Effects of Dapagliflozin on Volume Status When Added to|2
04221|038|R|  Renin-Angiotensin System  Inhibitors. J Clin Med 2019 May 31;8(6):.|2
04221|039|R|3.Steglatro (ertugliflozin) US prescribing information. Merck & Co. October|1
04221|040|R|  2022.|1
04221|041|R|4.Jardiance (empagliflozin) US prescribing information. Boehringer Ingelheim|1
04221|042|R|  Pharmaceuticals, Inc. June, 2023.|1
04221|043|R|5.Invokana (canagliflozin) US prescribing information. Janssen|1
04221|044|R|  Pharmaceuticals, Inc. October, 2022.|1
04221|045|R|6.Lithobid (lithium carbonate) US prescribing information. ANI|1
04221|046|R|  Pharmaceuticals, Inc. May, 2018.|1
04221|047|R|7.Horowitz LC, Fisher GU. Acute lithium toxicity. N Engl J Med 1969 Dec 11;|3
04221|048|R|  281(24):1369.|3
04221|049|R|8.Thomsen K, Schou M. Renal lithium excretion in man. Am J Physiol 1968 Oct;|2
04221|050|R|  215(4):823-7.|2
04222|001|T|MONOGRAPH TITLE:  Apixaban/Levetiracetam|
04222|002|B||
04222|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04222|004|L|take action as needed.|
04222|005|B||
04222|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown.|
04222|007|A|Levetiracetam may decrease the efficacy of apixaban.|
04222|008|B||
04222|009|E|CLINICAL EFFECTS:  Concurrent use of levetiracetam may result in decreased|
04222|010|E|effectiveness of apixaban.|
04222|011|B||
04222|012|P|PREDISPOSING FACTORS:  None determined.|
04222|013|B||
04222|014|M|PATIENT MANAGEMENT:  Concurrent use of levetiracetam in patients receiving|
04222|015|M|apixaban should be approached with caution.  Consider alternative|
04222|016|M|anticonvulsants in patients maintained on apixaban.|
04222|017|M|   If concurrent use is warranted, monitor patients closely for decreased|
04222|018|M|response to apixaban.|
04222|019|B||
04222|020|D|DISCUSSION:  A nested case-control study of 100,168 patients on apixaban,|
04222|021|D|dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic|
04222|022|D|emboli in patients with atrial fibrillation or recurrent thromboembolism in|
04222|023|D|patients with thromboembolism.  The primary outcome of CVA/systemic embolism|
04222|024|D|with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of|
04222|025|D|2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26|
04222|026|D|(1.13-4.54) compared to controls.(5)|
04222|027|D|   A population-based retrospective cohort study of 8746 patients on|
04222|028|D|apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence|
04222|029|D|of first ischemic stroke with concurrent antiseizure medications.|
04222|030|D|Antiseizure medications that induce CYP3A4 or P-gp were associated with an|
04222|031|D|increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%,|
04222|032|D|adjusted hazard ratio 1.28).  The annual incidence rates of ischemic stroke|
04222|033|D|(valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous|
04222|034|D|thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were|
04222|035|D|higher among valproate and levetiracetam users but were not statistically|
04222|036|D|different from controls.(6)|
04222|037|D|   In a case report, a 54 year old man with a complicated medical history|
04222|038|D|including paroxysmal atrial fibrillation, heart failure, and epilepsy who|
04222|039|D|was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg|
04222|040|D|twice daily, taken simultaneously with levetiracetam.  On day 10 of|
04222|041|D|dabigatran, trough levels were normal but Cmax was subtherapeutic.|
04222|042|D|Separation of dabigatran administration to 4 hours before levetiracetam|
04222|043|D|resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL.  Over 32 months|
04222|044|D|of follow-up, no hemorrhagic or ischemic events occurred.(7)|
04222|045|D|   A retrospective study of 320 patients with atrial fibrillation on DOAC|
04222|046|D|therapy for secondary stroke prevention compared the incidence of ischemic|
04222|047|D|stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing|
04222|048|D|medications (n=43), P-gp inducing medications (n=13), or no interacting|
04222|049|D|medications (n=264).  Twenty of the patients were on levetiracetam.  There|
04222|050|D|was no statistically significant difference between any of the groups.(8)|
04222|051|D|   A small prospective cohort study of 19 patients on the combination of|
04222|052|D|levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4|
04222|053|D|patients on rivaroxaban) did not find a significant correlation between|
04222|054|D|levetiracetam and DOAC concentrations.  One patient who was on low-dose|
04222|055|D|apixaban had low apixaban levels, and there were no thromboembolic events in|
04222|056|D|the 1388 +/- 994 days of follow-up.(9)|
04222|057|B||
04222|058|R|REFERENCES:|
04222|059|B||
04222|060|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04222|061|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04222|062|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04222|063|R|  Squibb-Pfizer January, 2025.|1
04222|064|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04222|065|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04222|066|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04222|067|R|  Company April, 2025.|1
04222|068|R|5.Gronich N, Stein N, Muszkat M. Association Between Use of|2
04222|069|R|  Pharmacokinetic-Interacting Drugs and Effectiveness  and Safety of Direct|2
04222|070|R|  Acting Oral Anticoagulants: Nested Case-Control Study. Clin Pharmacol Ther|2
04222|071|R|  2021 Dec;110(6):1526-1536.|2
04222|072|R|6.Ip BY, Ko H, Wong GL, Yip TC, Lau LH, Lau AY, Leng X, Leung H, Chan HH,|2
04222|073|R|  Chan HY, Mok VC, Soo YO, Leung TW. Thromboembolic Risks with Concurrent|2
04222|074|R|  Direct Oral Anticoagulants and Antiseizure  Medications: A|2
04222|075|R|  Population-Based Analysis. CNS Drugs 2022 Dec;36(12):1313-1324.|2
04222|076|R|7.Menichelli D, Pastori D, Pignatelli P, Pani A. Minimizing drug-drug|3
04222|077|R|  interactions between dabigatran and levetiracetam through  clinical|3
04222|078|R|  management: a case report. Eur Heart J Case Rep 2023 Jan;7(1):ytad006.|3
04222|079|R|8.Ho CJ, Chen SH, Lin CH, Lu YT, Hsu CW, Tsai MH. Non-vitamin K Oral|2
04222|080|R|  Anticoagulants and Anti-seizure Medications: A Retrospective  Cohort|2
04222|081|R|  Study. Front Neurol 2020;11:588053.|2
04222|082|R|9.Mavri A, Ilc S. The efficacy of direct oral anticoagulants in patients on|2
04222|083|R|  concomitant treatment  with levetiracetam. Sci Rep 2023 Jun 7;13(1):9257.|2
04223|001|T|MONOGRAPH TITLE:  Adagrasib/Strong CYP3A4 Inducers|
04223|002|B||
04223|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04223|004|L|of severe adverse interaction.|
04223|005|B||
04223|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may increase the metabolism|
04223|007|A|of adagrasib.(1)|
04223|008|B||
04223|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
04223|010|E|in decreased levels and effectiveness of adagrasib.(1)|
04223|011|B||
04223|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04223|013|P|of the inducer for longer than 1-2 weeks.|
04223|014|B||
04223|015|M|PATIENT MANAGEMENT:  The manufacturer of adagrasib states that the|
04223|016|M|concurrent use of strong CYP3A4 inducers should be avoided, and that|
04223|017|M|alternative treatments with less CYP3A4 induction should be considered.(1)|
04223|018|B||
04223|019|D|DISCUSSION:  In a study with healthy subjects, co-administration of rifampin|
04223|020|D|(strong 3A4 inducer) with a single dose of adagrasib (600 mg), decreased|
04223|021|D|adagrasib area-under-curve (AUC) by 95% and maximum concentration (Cmax) by|
04223|022|D|88%.(1) Co-administration of rifampin (strong 3A4 inducer) with multiple|
04223|023|D|doses of adagrasib (600 mg) is predicted to decrease adagrasib AUC by|
04223|024|D|greater than 61% and Cmax by greater than 66%.|
04223|025|D|   Strong inducers of CYP3A4 linked to this monograph include: apalutamide,|
04223|026|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04223|027|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
04223|028|D|St. John's wort.(3-4)|
04223|029|B||
04223|030|R|REFERENCES:|
04223|031|B||
04223|032|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04223|033|R|  December 2022.|1
04223|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04223|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04223|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04223|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04223|038|R|  11/14/2017.|1
04223|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
04223|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04224|001|T|MONOGRAPH TITLE:  Adagrasib/Ivosidenib|
04224|002|B||
04224|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04224|004|L|of severe adverse interaction.|
04224|005|B||
04224|006|A|MECHANISM OF ACTION:  Ivosidenib, a strong CYP3A4 inducer(1), may induce the|
04224|007|A|CYP3A4 isoenzyme and increase the metabolism of adagrasib.(2)|
04224|008|A|   Strong inhibitors of the CYP3A4 enzyme may inhibit the metabolism of|
04224|009|A|ivosidenib.(3)  Adagrasib is a strong CYP3A4 inhibitor.(1)|
04224|010|A|   Concurrent use of adagrasib and ivosidenib may also result in additive|
04224|011|A|effects on the QTc interval.|
04224|012|B||
04224|013|E|CLINICAL EFFECTS:  Concurrent use of adagrasib with ivosidenib, a strong|
04224|014|E|CYP3A4 inducer, may decrease the levels and effectiveness of adagrasib and|
04224|015|E|may cause additive effects on the QTc interval, which may result in|
04224|016|E|life-threatening cardiac arrhythmias including torsades de pointes.(2)  In|
04224|017|E|addition, systemic exposure to ivosidenib may increase and elevate the risk|
04224|018|E|for ivosidenib toxicities such as QT prolongation.(3)|
04224|019|B||
04224|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04224|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
04224|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04224|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04224|024|P|female gender, or advanced age.(3)|
04224|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04224|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04224|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04224|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04224|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04224|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04224|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04224|032|B||
04224|033|M|PATIENT MANAGEMENT:  The manufacturer of adagrasib states that the|
04224|034|M|concurrent use of strong CYP3A4 inducers should be avoided, and that|
04224|035|M|alternative treatments with less CYP3A4 induction should be considered.(2)|
04224|036|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04224|037|M|withhold adagrasib until QTc interval less than 481 msec or QTc interval|
04224|038|M|returns to baseline. Resume adagrasib at the next lower dose level. If|
04224|039|M|patients develop torsade de pointes, polymorphic ventricular tachycardia, or|
04224|040|M|signs and symptoms of serious or life-threatening arrhythmia, permanently|
04224|041|M|discontinue adagrasib.(2)|
04224|042|M|   Avoid the concurrent use of strong CYP3A4 inducers like ivosidenib in|
04224|043|M|patients receiving therapy with adagrasib.  Consider the use of alternative|
04224|044|M|agents with less enzyme induction potential and less potential to affect the|
04224|045|M|QTc interval.(3)|
04224|046|M|   The US manufacturer of ivosidenib recommends considering an alternative|
04224|047|M|concomitant medication with less potential for CYP3A4 inhibition.(3)|
04224|048|M|   Although the manufacturer of ivosidenib provides recommendations for dose|
04224|049|M|modification of ivosidenib when used with strong CYP3A4 inhibitors, it has|
04224|050|M|not been studied in dual-directional interactions such as with adagrasib.|
04224|051|M|Thus, this dose modification recommendation is for information only.  The US|
04224|052|M|manufacturer of ivosidenib states when concomitant use of ivosidenib and a|
04224|053|M|strong CYP3A4 inhibitor is needed, the ivosidenib dose should be reduced to|
04224|054|M|250 mg once daily.  If the strong CYP3A4 inhibitor is discontinued, increase|
04224|055|M|the ivosidenib dose to the recommended dose of 500 mg once daily after at|
04224|056|M|least 5 half-lives of the strong 3A4 inhibitor.(3)|
04224|057|M|   If concurrent therapy is warranted, monitor patients closely for|
04224|058|M|prolongation of the QT interval.  Obtain serum calcium, magnesium, and|
04224|059|M|potassium levels and monitor ECG at regular intervals.  Correct any|
04224|060|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04224|061|M|heartbeat, dizziness, or fainting.|
04224|062|B||
04224|063|D|DISCUSSION:  In a study with healthy subjects, co-administration of rifampin|
04224|064|D|(strong 3A4 inducer) with a single dose of adagrasib (600 mg), decreased|
04224|065|D|adagrasib area-under-curve (AUC) by 95% and maximum concentration (Cmax) by|
04224|066|D|88%.(2)  Co-administration of rifampin (strong 3A4 inducer) with multiple|
04224|067|D|doses of adagrasib (600 mg) is predicted to decrease adagrasib AUC by|
04224|068|D|greater than 61% and Cmax by greater than 66%.(2)|
04224|069|D|   Adagrasib has been associated with QTc interval prolongation.  Adagrasib|
04224|070|D|increased QTc in a concentration-dependent manner. In patients administered|
04224|071|D|adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18|
04224|072|D|msec.  In the pooled safety population, 6% of 366 patients with at least one|
04224|073|D|post-baseline ECG had an average QTc greater than 501 msec and 11% of|
04224|074|D|patients had a increase from baseline QTc greater than 60 msec.(2)|
04224|075|D|   In a drug interaction study in healthy subjects, coadministration of|
04224|076|D|itraconazole (200 mg once daily for 18 days) with a single dose of|
04224|077|D|ivosidenib (250 mg) increased ivosidenib AUC by 269%.  No change was seen in|
04224|078|D|ivosidenib's Cmax.(3)|
04224|079|B||
04224|080|R|REFERENCES:|
04224|081|B||
04224|082|R|1.This information is based on an extract from the Certara Drug Interaction|6
04224|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04224|084|R|2.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04224|085|R|  December 2022.|1
04224|086|R|3.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04224|087|R|  Inc. August, 2021.|1
04224|088|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04224|089|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04224|090|R|  settings: a scientific statement from the American Heart Association and|6
04224|091|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04224|092|R|  2;55(9):934-47.|6
04225|001|T|MONOGRAPH TITLE:  Adagrasib/Strong CYP3A4 Inhibitors|
04225|002|B||
04225|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04225|004|L|of severe adverse interaction.|
04225|005|B||
04225|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04225|007|A|of adagrasib.(1,2)|
04225|008|B||
04225|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04225|010|E|in elevated levels and increased effects of adagrasib, such as|
04225|011|E|hepatotoxicity, intersitial lung disease or pneumonitis, or gastrointestinal|
04225|012|E|adverse reactions.(1,2) Symptoms can include nausea, vomiting, jaundice,|
04225|013|E|dark urine, abdominal pain, and unexplained fatigue.|
04225|014|E|   Concurrent use may also result in increased risk of QTc prolongation,|
04225|015|E|which may lead to life-threatening cardiac arrhythmias like torsades de|
04225|016|E|pointes.(1)|
04225|017|B||
04225|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04225|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04225|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04225|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04225|022|P|gender, or advanced age.(4)|
04225|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04225|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04225|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04225|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04225|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04225|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04225|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04225|030|B||
04225|031|M|PATIENT MANAGEMENT:  The US manufacturer of adagrasib states that adagrasib|
04225|032|M|coadministration with strong inhibitors of CYP3A4 should be avoided until|
04225|033|M|adagrasib concentrations have reached steady state (approximately 8|
04225|034|M|days).(1)|
04225|035|M|   Monitor liver tests, including AST, ALT, total bilirubin, according to|
04225|036|M|the recommendations in the Krazati package insert. Advise patients to|
04225|037|M|immediately report any symptoms of hepatotoxicity.|
04225|038|M|   Monitor for new or worsening respiratory symptoms indicative of|
04225|039|M|interstitial lung disease or pneumonitis.|
04225|040|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04225|041|M|withhold adagrasib until QTc interval less than 481 msec or QTc interval|
04225|042|M|returns to baseline. Resume adagrasib at the next lower dose level. If|
04225|043|M|patients develop torsade de pointes, polymorphic ventricular tachycardia, or|
04225|044|M|signs and symptoms of serious or life-threatening arrhythmia, permanently|
04225|045|M|discontinue adagrasib.(1)|
04225|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04225|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04225|048|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04225|049|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04225|050|B||
04225|051|D|DISCUSSION:  Coadministration of itraconazole (a strong CYP3A4 inhibitor)|
04225|052|D|increased adagrasib (single dose 200 mg) maximum concentration (Cmax) and|
04225|053|D|area-under-the-curve (AUC) by 2.4-fold and 4-fold. No clinically significant|
04225|054|D|differences in the pharmacokinetics of adagrasib at steady state were|
04225|055|D|predicted when used concomitantly with itraconazole.(1)|
04225|056|D|    Adagrasib has been associated with QTc interval prolongation. Adagrasib|
04225|057|D|increased QTc in a concentration-dependent manner. In patients administered|
04225|058|D|adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18|
04225|059|D|msec. In the pooled safety population, 6% of 366 patients with at least one|
04225|060|D|post-baseline ECG had an average QTc greater than 501 msec and 11% of|
04225|061|D|patients had a increase from baseline QTc greater than 60 msec.(1)|
04225|062|D|   Strong inhibitors of CYP3A4 linked to this monograph include: boceprevir,|
04225|063|D|cobicistat, itraconazole, josamycin, ketoconazole, mibefradil, nefazodone,|
04225|064|D|nelfinavir, nirmatrelvir/ritonavir, telaprevir, and tucatinib.(1,3)|
04225|065|B||
04225|066|R|REFERENCES:|
04225|067|B||
04225|068|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04225|069|R|  December 2022.|1
04225|070|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04225|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04225|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04225|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04225|074|R|  11/14/2017.|1
04225|075|R|3.This information is based on an extract from the Certara Drug Interaction|6
04225|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04225|077|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04225|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04225|079|R|  settings: a scientific statement from the American Heart Association and|6
04225|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04225|081|R|  2;55(9):934-47.|6
04226|001|T|MONOGRAPH TITLE:  Adagrasib/Strong CYP3A4 Inhibitors that Prolong QT|
04226|002|B||
04226|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04226|004|L|of severe adverse interaction.|
04226|005|B||
04226|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04226|007|A|interval may inhibit the metabolism of adagrasib and result in additive|
04226|008|A|effects on the QTc interval.(1,2)|
04226|009|B||
04226|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 that|
04226|011|E|prolongs the QTc interval may result in elevated levels and increased|
04226|012|E|effects of adagrasib, such as hepatotoxicity, intersitial lung disease or|
04226|013|E|pneumonitis, or gastrointestinal adverse reactions.(1,2) Symptoms can|
04226|014|E|include nausea, vomiting, jaundice, dark urine, abdominal pain, and|
04226|015|E|unexplained fatigue.|
04226|016|E|   Concurrent use may also result in additive QTc prolongation, which may|
04226|017|E|lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)|
04226|018|B||
04226|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04226|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04226|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04226|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04226|023|P|gender, or advanced age.(4)|
04226|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04226|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04226|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04226|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04226|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04226|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04226|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04226|031|B||
04226|032|M|PATIENT MANAGEMENT:  The US manufacturer of adagrasib states that the|
04226|033|M|concurrent use of QT prolonging agents should be avoided.(1)|
04226|034|M|   The US manufacturer of adagrasib states that adagrasib coadministration|
04226|035|M|with strong inhibitors of CYP3A4 should be avoided until adagrasib|
04226|036|M|concentrations have reached steady state (approximately 8 days).(1)|
04226|037|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
04226|038|M|values (serum calcium, magnesium, and potassium) prior to the start of|
04226|039|M|treatment, after initiation of any drug known to prolong the QT interval,|
04226|040|M|and periodically monitor during therapy.  Correct any electrolyte|
04226|041|M|abnormalities. Instruct patients to report any irregular heartbeat,|
04226|042|M|dizziness, or fainting.|
04226|043|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04226|044|M|withhold adagrasib until QTc interval less than 481 msec or QTc interval|
04226|045|M|returns to baseline. Resume adagrasib at the next lower dose level. If|
04226|046|M|patients develop torsade de pointes, polymorphic ventricular tachycardia, or|
04226|047|M|signs and symptoms of serious or life-threatening arrhythmia, permanently|
04226|048|M|discontinue adagrasib.(1)|
04226|049|M|   Monitor liver tests, including AST, ALT, total bilirubin, according to|
04226|050|M|the recommendations in the Krazati package insert. Advise patients to|
04226|051|M|immediately report any symptoms of hepatotoxicity.|
04226|052|M|   Monitor for new or worsening respiratory symptoms indicative of|
04226|053|M|interstitial lung disease or pneumonitis.|
04226|054|B||
04226|055|D|DISCUSSION:  Coadministration of itraconazole (strong CYP3A4 inhibitor)|
04226|056|D|increased adagrasib (single dose 200 mg) maximum concentration (Cmax) and|
04226|057|D|area-under-the-curve (AUC) by 2.4-fold and 4-fold. No clinically significant|
04226|058|D|differences in the pharmacokinetics of adagrasib at steady state were|
04226|059|D|predicted when used concomitantly with itraconazole.(1)|
04226|060|D|    Adagrasib has been associated with QTc interval prolongation. Adagrasib|
04226|061|D|increased QTc in a concentration-dependent manner. In patients administered|
04226|062|D|adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18|
04226|063|D|msec. In the pooled safety population, 6% of 366 patients with at least one|
04226|064|D|post-baseline ECG had an average QTc greater than 501 msec and 11% of|
04226|065|D|patients had a increase from baseline QTc greater than 60 msec.(1)|
04226|066|D|   Agents that are linked to this monograph may have varying degrees of|
04226|067|D|potential to prolong the QTc interval but are generally accepted to have a|
04226|068|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04226|069|D|been shown to prolong the QTc interval either through their mechanism of|
04226|070|D|action, through studies on their effects on the QTc interval, or through|
04226|071|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04226|072|D|and/or post-marketing reports.(4)|
04226|073|D|   Strong inhibitors of CYP3A4 linked to this monograph include:|
04226|074|D|clarithromycin, telithromycin, and voriconazole.(1,3)|
04226|075|B||
04226|076|R|REFERENCES:|
04226|077|B||
04226|078|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04226|079|R|  December 2022.|1
04226|080|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04226|081|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04226|082|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04226|083|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04226|084|R|  11/14/2017.|1
04226|085|R|3.This information is based on an extract from the Certara Drug Interaction|6
04226|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04226|087|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04226|088|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04226|089|R|  settings: a scientific statement from the American Heart Association and|6
04226|090|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04226|091|R|  2;55(9):934-47.|6
04227|001|T|MONOGRAPH TITLE:  Adagrasib/QT Prolonging Agents|
04227|002|B||
04227|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04227|004|L|of severe adverse interaction.|
04227|005|B||
04227|006|A|MECHANISM OF ACTION:  Adagrasib has been shown to prolong the QTc interval.|
04227|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
04227|008|A|additive effects on the QTc interval.(1-3)|
04227|009|B||
04227|010|E|CLINICAL EFFECTS:  The concurrent use of adagrasib with other agents that|
04227|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04227|012|E|arrhythmias, including torsades de pointes.(1-3)|
04227|013|B||
04227|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04227|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04227|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04227|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04227|018|P|gender, or advanced age.(2)|
04227|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04227|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04227|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04227|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04227|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04227|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04227|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04227|026|B||
04227|027|M|PATIENT MANAGEMENT:  The US manufacturer of adagrasib states that the|
04227|028|M|concurrent use of QT prolonging agents should be avoided.(1)|
04227|029|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
04227|030|M|values (serum calcium, magnesium, and potassium) prior to the start of|
04227|031|M|treatment, after initiation of any drug known to prolong the QT interval,|
04227|032|M|and periodically monitor during therapy.  Correct any electrolyte|
04227|033|M|abnormalities. Instruct patients to report any irregular heartbeat,|
04227|034|M|dizziness, or fainting.|
04227|035|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04227|036|M|withhold adagrasib until QTc interval less than 481 msec or QTc interval|
04227|037|M|returns to baseline. Resume adagrasib at the next lower dose level. If|
04227|038|M|patients develop torsade de pointes, polymorphic ventricular tachycardia, or|
04227|039|M|signs and symptoms of serious or life-threatening arrhythmia, permanently|
04227|040|M|discontinue adagrasib.(1)|
04227|041|B||
04227|042|D|DISCUSSION:  Adagrasib has been associated with QTc interval prolongation.|
04227|043|D|Adagrasib increased QTc in a concentration-dependent manner. In patients|
04227|044|D|administered adagrasib 600 mg twice daily, the mean QTcF change from|
04227|045|D|baseline was 18 msec. In the pooled safety population, 6% of 366 patients|
04227|046|D|with at least one post-baseline ECG had an average QTc greater than 501 msec|
04227|047|D|and 11% of patients had a increase from baseline QTc greater than 60|
04227|048|D|msec.(1)|
04227|049|D|   Agents that are linked to this monograph may have varying degrees of|
04227|050|D|potential to prolong the QTc interval but are generally accepted to have a|
04227|051|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04227|052|D|been shown to prolong the QTc interval either through their mechanism of|
04227|053|D|action, through studies on their effects on the QTc interval, or through|
04227|054|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04227|055|D|and/or postmarketing reports.(3)|
04227|056|B||
04227|057|R|REFERENCES:|
04227|058|B||
04227|059|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04227|060|R|  December 2022.|1
04227|061|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04227|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04227|063|R|  settings: a scientific statement from the American Heart Association and|6
04227|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04227|065|R|  2;55(9):934-47.|6
04227|066|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04227|067|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04227|068|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04227|069|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04228|001|T|MONOGRAPH TITLE:  Adagrasib/Possible QT Prolonging Agents|
04228|002|B||
04228|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04228|004|L|take action as needed.|
04228|005|B||
04228|006|A|MECHANISM OF ACTION:  Adagrasib has been shown to prolong the QTc interval.|
04228|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
04228|008|A|additive effects on the QTc interval.(1-3)|
04228|009|B||
04228|010|E|CLINICAL EFFECTS:  The concurrent use of adagrasib with other agents that|
04228|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04228|012|E|arrhythmias, including torsades de pointes.(1-3)|
04228|013|B||
04228|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04228|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04228|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04228|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04228|018|P|gender, or advanced age.(2)|
04228|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04228|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04228|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04228|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04228|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04228|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04228|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04228|026|B||
04228|027|M|PATIENT MANAGEMENT:  The US manufacturer of adagrasib states that the|
04228|028|M|concurrent use of QT prolonging agents should be avoided.(1)|
04228|029|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
04228|030|M|values (serum calcium, magnesium, and potassium) prior to the start of|
04228|031|M|treatment, after initiation of any drug known to prolong the QT interval,|
04228|032|M|and periodically monitor during therapy.  Correct any electrolyte|
04228|033|M|abnormalities. Instruct patients to report any irregular heartbeat,|
04228|034|M|dizziness, or fainting.|
04228|035|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04228|036|M|withhold adagrasib until QTc interval less than 481 msec or QTc interval|
04228|037|M|returns to baseline. Resume adagrasib at the next lower dose level. If|
04228|038|M|patients develop torsade de pointes, polymorphic ventricular tachycardia, or|
04228|039|M|signs and symptoms of serious or life-threatening arrhythmia, permanently|
04228|040|M|discontinue adagrasib.(1)|
04228|041|B||
04228|042|D|DISCUSSION:  Adagrasib has been associated with QTc interval prolongation.|
04228|043|D|Adagrasib increased QTc in a concentration-dependent manner. In patients|
04228|044|D|administered adagrasib 600 mg twice daily, the mean QTcF change from|
04228|045|D|baseline was 18 msec. In the pooled safety population, 6% of 366 patients|
04228|046|D|with at least one post-baseline ECG had an average QTc greater than 501 msec|
04228|047|D|and 11% of patients had a increase from baseline QTc greater than 60|
04228|048|D|msec.(1)|
04228|049|D|   Agents that are linked to this monograph may have been associated with|
04228|050|D|Torsade de Pointes and/or QT prolongation but at this time lack substantial|
04228|051|D|evidence for causing Torsade de Pointes.(3)|
04228|052|B||
04228|053|R|REFERENCES:|
04228|054|B||
04228|055|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04228|056|R|  December 2022.|1
04228|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04228|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04228|059|R|  settings: a scientific statement from the American Heart Association and|6
04228|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04228|061|R|  2;55(9):934-47.|6
04228|062|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04228|063|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04228|064|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04228|065|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04229|001|T|MONOGRAPH TITLE:  Haloperidol/Adagrasib|
04229|002|B||
04229|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04229|004|L|of severe adverse interaction.|
04229|005|B||
04229|006|A|MECHANISM OF ACTION:  Haloperidol is metabolized via many metabolic|
04229|007|A|pathways. The contributions of CYP2D6, CYP3A4 and possibly CYP1A2 pathways|
04229|008|A|are most clearly defined.  Concomitant use of haloperidol with inhibitors of|
04229|009|A|one or more of these pathways may lead to clinically significant increases|
04229|010|A|in haloperidol levels and result in additive QT effects of the QTc interval.|
04229|011|A|Adagrasib is a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor.(1,2)|
04229|012|B||
04229|013|E|CLINICAL EFFECTS:  The concurrent administration of adagrasib may result in|
04229|014|E|elevated levels of haloperidol and lead to toxicities such as orthostatic|
04229|015|E|hypotension, akathisia, acute dystonia, or Parkinsonism.|
04229|016|E|   Concurrent use may also result in additive QTc prolongation, which may|
04229|017|E|lead to life-threatening cardiac arrhythmias like torsade de pointes.(1,2)|
04229|018|B||
04229|019|P|PREDISPOSING FACTORS:  Elderly patients, particularly those with a history|
04229|020|P|of falls or swallowing disorders, and patients with Parkinson Disease, Lewy|
04229|021|P|Body Disease, or other dementias are more sensitive to antipsychotics and|
04229|022|P|have a greater risk for adverse effects.|
04229|023|P|   Younger patients, patients on low doses of haloperidol, or on a dose|
04229|024|P|targeted to lower-therapeutic serum levels, have a lower interaction risk.|
04229|025|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04229|026|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04229|027|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
04229|028|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04229|029|P|advanced age.(3)|
04229|030|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04229|031|P|higher systemic concentrations of either QT prolonging drug are additional|
04229|032|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04229|033|P|drug concentrations include rapid infusion of an intravenous dose or|
04229|034|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04229|035|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04229|036|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04229|037|P|   The risk of anticholinergic toxicities including cognitive decline,|
04229|038|P|delirium, falls and fractures is increased in geriatric patients using more|
04229|039|P|than one medicine with anticholinergic properties.(4)|
04229|040|B||
04229|041|M|PATIENT MANAGEMENT:  The manufacturer of adagrasib states that concurrent|
04229|042|M|use with QT prolonging agents, sensitive CYP2D6 substrates with a narrow|
04229|043|M|therapeutic window, or sensitive CYP3A4 substrates should be avoided.(2)|
04229|044|M|   Monitor patient for extrapyramidal side effects and orthostatic|
04229|045|M|hypotension if adagrasib is added to haloperidol therapy and lower|
04229|046|M|haloperidol dose if needed.(1)|
04229|047|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
04229|048|M|values (serum calcium, magnesium, and potassium) prior to the start of|
04229|049|M|treatment, after initiation of any drug known to prolong the QT interval,|
04229|050|M|and periodically monitor during therapy.  Correct any electrolyte|
04229|051|M|abnormalities. Instruct patients to report any irregular heartbeat,|
04229|052|M|dizziness, or fainting.|
04229|053|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04229|054|M|withhold adagrasib until QTc interval less than 481 msec or QTc interval|
04229|055|M|returns to baseline. Resume adagrasib at the next lower dose level. If|
04229|056|M|patients develop torsade de pointes, polymorphic ventricular tachycardia, or|
04229|057|M|signs and symptoms of serious or life-threatening arrhythmia, permanently|
04229|058|M|discontinue adagrasib.(1)|
04229|059|B||
04229|060|D|DISCUSSION:  Although it is an older agent, the complex pharmacokinetics of|
04229|061|D|haloperidol are not yet fully understood.|
04229|062|D|   Adagrasib has been associated with QTc interval prolongation. Adagrasib|
04229|063|D|increased QTc in a concentration-dependent manner. In patients administered|
04229|064|D|adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18|
04229|065|D|msec. In the pooled safety population, 6% of 366 patients with at least one|
04229|066|D|post-baseline ECG had an average QTc greater than 501 msec and 11% of|
04229|067|D|patients had a increase from baseline QTc greater than 60 msec.(1)|
04229|068|B||
04229|069|R|REFERENCES:|
04229|070|B||
04229|071|R|1.Haldol injection (haloperidol) US prescribing information. Janssen|1
04229|072|R|  Pharmaceuticals, Inc. October, 2025.|1
04229|073|R|2.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04229|074|R|  December 2022.|1
04229|075|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04229|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04229|077|R|  settings: a scientific statement from the American Heart Association and|6
04229|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04229|079|R|  2;55(9):934-47.|6
04229|080|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04229|081|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04229|082|R|  Soc 2023 Jul;71(7):2052-2081.|6
04230|001|T|MONOGRAPH TITLE:  Adagrasib/Levoketoconazole|
04230|002|B||
04230|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04230|004|L|is contraindicated and generally should not be dispensed or administered to|
04230|005|L|the same patient.|
04230|006|B||
04230|007|A|MECHANISM OF ACTION:  Levoketoconazole is a strong inhibitor of CYP3A4 that|
04230|008|A|prolongs the QTc interval and may inhibit the CYP3A4 metabolism of|
04230|009|A|adagrasib.  This combination may also have additive effects on the QTc|
04230|010|A|interval.(1,2)|
04230|011|B||
04230|012|E|CLINICAL EFFECTS:  Concurrent use of levoketoconazole, a strong inhibitor of|
04230|013|E|CYP3A4 that prolongs the QTc interval, may result in elevated levels and|
04230|014|E|increased effects of adagrasib, such as hepatotoxicity, intersitial lung|
04230|015|E|disease or pneumonitis, or gastrointestinal adverse reactions.(1,2) Symptoms|
04230|016|E|can include nausea, vomiting, jaundice, dark urine, abdominal pain, and|
04230|017|E|unexplained fatigue.|
04230|018|E|   Concurrent use may also result in additive QTc prolongation, which may|
04230|019|E|lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)|
04230|020|B||
04230|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04230|022|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04230|023|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04230|024|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04230|025|P|gender, or advanced age.(4)|
04230|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04230|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04230|028|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04230|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04230|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04230|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04230|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)|
04230|033|B||
04230|034|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
04230|035|M|levoketoconazole is contraindicated with other agents that prolong the QT|
04230|036|M|interval.(2)|
04230|037|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
04230|038|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
04230|039|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
04230|040|M|syndrome (including first-degree family history).|
04230|041|M|   Use caution in patients with other risk factors for QT prolongation|
04230|042|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
04230|043|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
04230|044|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
04230|045|M|hypokalemia or hypomagnesemia.|
04230|046|M|   If a patient develops QT prolongation with a QTc interval greater than|
04230|047|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
04230|048|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
04230|049|M|QTc interval prolongation recurs, permanently discontinue|
04230|050|M|levoketoconazole.(1)|
04230|051|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04230|052|M|withhold adagrasib until QTc interval less than 481 msec or QTc interval|
04230|053|M|returns to baseline. Resume adagrasib at the next lower dose level. If|
04230|054|M|patients develop torsade de pointes, polymorphic ventricular tachycardia, or|
04230|055|M|signs and symptoms of serious or life-threatening arrhythmia, permanently|
04230|056|M|discontinue adagrasib.(1)|
04230|057|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04230|058|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04230|059|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04230|060|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04230|061|M|   Monitor liver tests, including AST, ALT, total bilirubin, according to|
04230|062|M|the recommendations in the adagrasib package insert. Advise patients to|
04230|063|M|immediately report any symptoms of hepatotoxicity.|
04230|064|M|   Monitor for new or worsening respiratory symptoms indicative of|
04230|065|M|interstitial lung disease or pneumonitis.|
04230|066|B||
04230|067|D|DISCUSSION:  Coadministration of itraconazole (strong CYP3A4 inhibitor)|
04230|068|D|increased adagrasib (single dose 200 mg) maximum concentration (Cmax) and|
04230|069|D|area-under-the-curve (AUC) by 2.4-fold and 4-fold. No clinically significant|
04230|070|D|differences in the pharmacokinetics of adagrasib at steady state were|
04230|071|D|predicted when used concomitantly with itraconazole.(1)|
04230|072|D|    Adagrasib has been associated with QTc interval prolongation. Adagrasib|
04230|073|D|increased QTc in a concentration-dependent manner. In patients administered|
04230|074|D|adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18|
04230|075|D|msec. In the pooled safety population, 6% of 366 patients with at least one|
04230|076|D|post-baseline ECG had an average QTc greater than 501 msec and 11% of|
04230|077|D|patients had a increase from baseline QTc greater than 60 msec.(1)|
04230|078|D|   During phase 1 and 2 studies with levoketoconazole, which excluded|
04230|079|D|patients with baseline QTcF interval greater than 470 msec, 4 (2.4%)|
04230|080|D|patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
04230|081|D|change-from-baseline QTcF > 60 msec.(2)|
04230|082|D|   Agents that are linked to this monograph may have varying degrees of|
04230|083|D|potential to prolong the QTc interval but are generally accepted to have a|
04230|084|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04230|085|D|been shown to prolong the QTc interval either through their mechanism of|
04230|086|D|action, through studies on their effects on the QTc interval, or through|
04230|087|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04230|088|D|and/or post-marketing reports.(5)|
04230|089|B||
04230|090|R|REFERENCES:|
04230|091|B||
04230|092|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04230|093|R|  December 2022.|1
04230|094|R|2.Recorlev (levoketoconazole) US prescribing information. Xeris|1
04230|095|R|  Pharmaceuticals, Inc. June, 2023.|1
04230|096|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04230|097|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04230|098|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04230|099|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04230|100|R|  11/14/2017.|1
04230|101|R|4.This information is based on an extract from the Certara Drug Interaction|6
04230|102|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04230|103|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04230|104|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04230|105|R|  settings: a scientific statement from the American Heart Association and|6
04230|106|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04230|107|R|  2;55(9):934-47.|6
04231|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP3A4 Substrates/Adagrasib|
04231|002|B||
04231|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04231|004|L|of severe adverse interaction.|
04231|005|B||
04231|006|A|MECHANISM OF ACTION:  Adagrasib is a strong inhibitor of CYP3A4 and may|
04231|007|A|decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.(1)|
04231|008|B||
04231|009|E|CLINICAL EFFECTS:  Concurrent use of adagrasib may lead to increased serum|
04231|010|E|levels and adverse effects of drugs sensitive to inhibition of the CYP3A4|
04231|011|E|pathway.(1)|
04231|012|B||
04231|013|P|PREDISPOSING FACTORS:  None determined.|
04231|014|B||
04231|015|M|PATIENT MANAGEMENT:  The manufacturer of adagrasib states that|
04231|016|M|coadministration of CYP3A4 substrates should be avoided.(1)|
04231|017|B||
04231|018|D|DISCUSSION:  In a study, adagrasib (400 mg twice daily) increased the|
04231|019|D|area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose|
04231|020|D|of midazolam by 21-fold and 4.8-fold, respectively. In a study, adagrasib|
04231|021|D|(600 mg twice daily) increased the AUC and Cmax of a single dose of|
04231|022|D|midazolam by 31-fold and 3.1-fold, respectively.(1)|
04231|023|D|   CYP3A4 substrates with a narrow therapeutic index linked to this|
04231|024|D|monograph include: atazanavir, atorvastatin, brotizolam, darunavir,|
04231|025|D|ebastine, eletriptan, indinavir, nisoldipine, paritaprevir, and|
04231|026|D|tipranavir.(1-3)|
04231|027|B||
04231|028|R|REFERENCES:|
04231|029|B||
04231|030|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04231|031|R|  December 2022.|1
04231|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04231|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04231|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04231|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04231|036|R|  11/14/2017.|1
04231|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04231|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04232|001|T|MONOGRAPH TITLE:  Select Sensitive 3A4 Substrates that Prolong QT/Adagrasib|
04232|002|B||
04232|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04232|004|L|of severe adverse interaction.|
04232|005|B||
04232|006|A|MECHANISM OF ACTION:  Adagrasib is a strong inhibitor of CYP3A4 and may|
04232|007|A|decrease the metabolism of drugs metabolized by the CYP3A4 enzyme and result|
04232|008|A|in additive effects on the QTc interval.(1)|
04232|009|B||
04232|010|E|CLINICAL EFFECTS:  Concurrent use of adagrasib may lead to increased serum|
04232|011|E|levels and adverse effects of drugs sensitive to inhibition of the CYP3A4|
04232|012|E|pathway.(1)|
04232|013|E|   Concurrent use may also result in additive QTc prolongation, which may|
04232|014|E|lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)|
04232|015|B||
04232|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04232|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04232|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04232|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04232|020|P|gender, or advanced age.(2)|
04232|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04232|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04232|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04232|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04232|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04232|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04232|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04232|028|B||
04232|029|M|PATIENT MANAGEMENT:  The manufacturer of adagrasib states that|
04232|030|M|coadministration of CYP3A4 substrates should be avoided.(1)|
04232|031|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04232|032|M|withhold adagrasib until QTc interval is less than 481 msec or QTc interval|
04232|033|M|returns to baseline. Resume adagrasib at the next lower dose level. If|
04232|034|M|patients develop torsade de pointes, polymorphic ventricular tachycardia, or|
04232|035|M|signs and symptoms of serious or life-threatening arrhythmia, permanently|
04232|036|M|discontinue adagrasib.(1)|
04232|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04232|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04232|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04232|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04232|041|B||
04232|042|D|DISCUSSION:  In a study, adagrasib (400 mg twice daily) increased the|
04232|043|D|area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose|
04232|044|D|of midazolam by 21-fold and 4.8-fold, respectively. In a study, adagrasib|
04232|045|D|(600 mg twice daily) increased the AUC and Cmax of a single dose of|
04232|046|D|midazolam by 31-fold and 3.1-fold, respectively.(1)|
04232|047|D|   Adagrasib has been associated with QTc interval prolongation. Adagrasib|
04232|048|D|increased QTc in a concentration-dependent manner. In patients administered|
04232|049|D|adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18|
04232|050|D|msec. In the pooled safety population, 6% of 366 patients with at least one|
04232|051|D|post-baseline ECG had an average QTc greater than 501 msec and 11% of|
04232|052|D|patients had a increase from baseline QTc greater than 60 msec.(1)|
04232|053|D|   Agents that are linked to this monograph may have varying degrees of|
04232|054|D|potential to prolong the QTc interval but are generally accepted to have a|
04232|055|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04232|056|D|been shown to prolong the QTc interval either through their mechanism of|
04232|057|D|action, through studies on their effects on the QTc interval, or through|
04232|058|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04232|059|D|and/or post-marketing reports.(4)|
04232|060|D|   CYP3A4 substrates with a narrow therapeutic index linked to this|
04232|061|D|monograph include: lopinavir, saquinavir, and terfenadine.(1,3-4)|
04232|062|B||
04232|063|R|REFERENCES:|
04232|064|B||
04232|065|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04232|066|R|  December 2022.|1
04232|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04232|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04232|069|R|  settings: a scientific statement from the American Heart Association and|6
04232|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04232|071|R|  2;55(9):934-47.|6
04232|072|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04232|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04232|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04232|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04232|076|R|  11/14/2017.|1
04232|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
04232|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04233|001|T|MONOGRAPH TITLE:  Warfarin/Adagrasib|
04233|002|B||
04233|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04233|004|L|of severe adverse interaction.|
04233|005|B||
04233|006|A|MECHANISM OF ACTION:  Adagrasib is a moderate CYP2C9 inhibitor(1) which may|
04233|007|A|decrease the metabolism of the S-enantiomer of warfarin.(1,2)|
04233|008|B||
04233|009|E|CLINICAL EFFECTS:  Concurrent use of adagrasib may result in elevated levels|
04233|010|E|of warfarin and increased INR.(1)|
04233|011|B||
04233|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04233|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04233|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
04233|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04233|016|P|risk for bleeding (e.g. NSAIDs).|
04233|017|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
04233|018|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
04233|019|P|are expected to be more susceptible to this interaction.|
04233|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
04233|021|P|are expected to be less susceptible to effects from this drug combination,|
04233|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
04233|023|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
04233|024|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
04233|025|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
04233|026|P|and safe anticoagulation than patients without these CYP2C9 variants.|
04233|027|B||
04233|028|M|PATIENT MANAGEMENT:  The US manufacturer of adagrasib states that concurrent|
04233|029|M|administration with sensitive CYP2C9 substrates should be avoided.(1)|
04233|030|M|   Monitor INRs more frequently until stable in patients who start adagrasib|
04233|031|M|therapy.(1,2)|
04233|032|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04233|033|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
04233|034|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
04233|035|M|evaluate patients with any symptoms.|
04233|036|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04233|037|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04233|038|M|anticoagulation in patients with active pathologic bleeding.|
04233|039|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04233|040|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04233|041|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04233|042|M|and/or swelling.|
04233|043|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04233|044|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04233|045|M|initiating, altering the dose or discontinuing either drug.|
04233|046|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
04233|047|B||
04233|048|D|DISCUSSION:  In clinical studies, coadministration of adagrasib 600 mg twice|
04233|049|D|daily increased the area-under-the-curve (AUC) and maximum concentration|
04233|050|D|(Cmax) of S-warfarin by 2.9-fold and 1.1-fold, respectively.(1)|
04233|051|B||
04233|052|R|REFERENCES:|
04233|053|B||
04233|054|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04233|055|R|  December 2022.|1
04233|056|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
04233|057|R|  Squibb Company September, 2016.|1
04233|058|R|3.This information is based on an extract from the Certara Drug Interaction|6
04233|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04233|060|R|4.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
04233|061|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
04233|062|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
04233|063|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
04233|064|R|  Oct;90(4):625-9.|6
04234|001|T|MONOGRAPH TITLE:  Desipramine; Imipramine/Adagrasib|
04234|002|B||
04234|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04234|004|L|of severe adverse interaction.|
04234|005|B||
04234|006|A|MECHANISM OF ACTION:  Adagrasib is a moderate inhibitor of CYP2D6 and is|
04234|007|A|expected to inhibit the metabolism of agents through this pathway.(1)|
04234|008|B||
04234|009|E|CLINICAL EFFECTS:  Concurrent use of adagrasib may result in elevated levels|
04234|010|E|of and toxicity from agents metabolized by CYP2D6.(1)|
04234|011|B||
04234|012|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
04234|013|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
04234|014|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
04234|015|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
04234|016|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
04234|017|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
04234|018|P|systemic steroids).|
04234|019|P|   The risk of anticholinergic toxicities including cognitive decline,|
04234|020|P|delirium, falls and fractures is increased in geriatric patients using more|
04234|021|P|than one medicine with anticholinergic properties.(2)|
04234|022|B||
04234|023|M|PATIENT MANAGEMENT:  Avoid the concurrent use of adagrasib with CYP2D6|
04234|024|M|substrates with a narrow therapeutic index (e.g. desipramine, imipramine).|
04234|025|M|If concurrent use is warranted, monitor patients for toxicity.(1)|
04234|026|B||
04234|027|D|DISCUSSION:  In a study, adagrasib (400 mg twice daily) increased the|
04234|028|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04234|029|D|dextromethorphan (a sensitive CYP2D6 substrate) by 1.9-fold and 1.8-fold,|
04234|030|D|respectively. Adagrasib (600 mg twice daily) is predicted to increase the|
04234|031|D|Cmax and AUC of a single dose of dextromethorphan by 1.7-fold and 2.4-fold,|
04234|032|D|respectively.(1)|
04234|033|B||
04234|034|R|REFERENCES:|
04234|035|B||
04234|036|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04234|037|R|  December 2022.|1
04234|038|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04234|039|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04234|040|R|  Soc 2023 Jul;71(7):2052-2081.|6
04234|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04234|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04234|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04234|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04234|045|R|  11/14/2017.|1
04235|001|T|MONOGRAPH TITLE:  Digoxin; Etoposide/Adagrasib|
04235|002|B||
04235|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04235|004|L|of severe adverse interaction.|
04235|005|B||
04235|006|A|MECHANISM OF ACTION:  Adagrasib may increase the absorption of digoxin and|
04235|007|A|etoposide by inhibiting P-glycoprotein (P-gp).(1)|
04235|008|B||
04235|009|E|CLINICAL EFFECTS:  Concurrent use of adagrasib may result in elevated levels|
04235|010|E|of and toxicity from digoxin and etoposide.(1)|
04235|011|E|   Symptoms of digoxin toxicity can include anorexia, nausea, vomiting,|
04235|012|E|headache, fatigue, malaise, drowsiness, generalized muscle weakness,|
04235|013|E|disorientation, hallucinations, visual disturbances, and arrhythmias.|
04235|014|E|   Etoposide toxicity may include hematologic and gastrointestinal|
04235|015|E|toxicities.|
04235|016|B||
04235|017|P|PREDISPOSING FACTORS:  The interaction magnitude may be greater in patients|
04235|018|P|receiving oral etoposide, or with impaired renal or hepatic function.|
04235|019|B||
04235|020|M|PATIENT MANAGEMENT:  The US manufacturer of adagrasib states that concurrent|
04235|021|M|administration of sensitive narrow therapeutic index P-glycoprotein|
04235|022|M|substrates (e.g. digoxin, etoposide) with adagrasib should be avoided.(1)|
04235|023|B||
04235|024|D|DISCUSSION:  Concurrent adagrasib (600 mg twice daily) increased the|
04235|025|D|area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by|
04235|026|D|1.5-fold and 1.9-fold, respectively.(1)|
04235|027|B||
04235|028|R|REFERENCES:|
04235|029|B||
04235|030|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04235|031|R|  December 2022.|1
04235|032|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
04235|033|R|  Pharmaceuticals, Inc. August, 2018.|1
04235|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04235|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04236|001|T|MONOGRAPH TITLE:  Cyclosporine; Sirolimus/Adagrasib|
04236|002|B||
04236|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04236|004|L|of severe adverse interaction.|
04236|005|B||
04236|006|A|MECHANISM OF ACTION:  Adagrasib may decrease the metabolism and increase the|
04236|007|A|absorption of cyclosporine and sirolimus by inhibiting CYP3A4 and|
04236|008|A|P-glycoprotein (P-gp).(1)|
04236|009|B||
04236|010|E|CLINICAL EFFECTS:  Concurrent use of adagrasib may result in elevated levels|
04236|011|E|of and toxicity from cyclosporine and sirolimus.(1)|
04236|012|B||
04236|013|P|PREDISPOSING FACTORS:  None determined.|
04236|014|B||
04236|015|M|PATIENT MANAGEMENT:  The US manufacturer of adagrasib states that concurrent|
04236|016|M|administration of sensitive narrow therapeutic index P-glycoprotein|
04236|017|M|substrates or sensitive CYP3A4 substrates (e.g. cyclosporine, sirolimus)|
04236|018|M|with adagrasib should be avoided.(1)|
04236|019|B||
04236|020|D|DISCUSSION:  Concurrent adagrasib (600 mg twice daily) increased the|
04236|021|D|area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by|
04236|022|D|1.5-fold and 1.9-fold, respectively.(1)|
04236|023|D|   In a study, adagrasib (400 mg twice daily) increased the AUC and Cmax of|
04236|024|D|a single dose of midazolam by 21-fold and 4.8-fold, respectively.  In a|
04236|025|D|study, adagrasib (600 mg twice daily) increased the AUC and Cmax of a single|
04236|026|D|dose of midazolam by 31-fold and 3.1-fold, respectively.(1)|
04236|027|B||
04236|028|R|REFERENCES:|
04236|029|B||
04236|030|R|1.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04236|031|R|  December 2022.|1
04236|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
04236|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04237|001|T|MONOGRAPH TITLE:  Alprostadil/Acetaminophen; NSAIDs|
04237|002|B||
04237|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04237|004|L|of severe adverse interaction.|
04237|005|B||
04237|006|A|MECHANISM OF ACTION:  Alprostadil is a prostaglandin E1 product used to|
04237|007|A|maintain patency of a patent ductus arteriosus (PDA).(1)   Acetaminophen and|
04237|008|A|nonsteroidal anti-inflammatory (NSAID) agents inhibit prostaglandins and may|
04237|009|A|be used for PDA closure in addition to pain/fever management.(2-4)|
04237|010|B||
04237|011|E|CLINICAL EFFECTS:  Simultaneous administration of acetaminophen or NSAIDs|
04237|012|E|may result in decreased clinical effects from alprostadil, including|
04237|013|E|reduction in PDA.(1)|
04237|014|B||
04237|015|P|PREDISPOSING FACTORS:  None determined.|
04237|016|B||
04237|017|M|PATIENT MANAGEMENT:  Avoid concurrent administration of acetaminophen or|
04237|018|M|NSAIDs in patients on alprostadil for maintaining patency of a patent ductus|
04237|019|M|arteriosus (PDA).(1)|
04237|020|B||
04237|021|D|DISCUSSION:  NSAIDs and acetaminophen are used as management for patent|
04237|022|D|ductus arteriosus (PDA) closure.(2-4)  Alprostadil is used to maintain|
04237|023|D|patency of a PDA.(1)|
04237|024|D|   In a case report, a 37-week gestational age neonate with cardiac defects|
04237|025|D|required alprostadil therapy for PDA patency.  After multiple doses of|
04237|026|D|acetaminophen for pain, an echocardiogram showed reduction of the PDA|
04237|027|D|requiring increased doses of alprostadil.  Additional acetaminophen was|
04237|028|D|discontinued.  Follow up echocardiogram showed successful reversal of PDA|
04237|029|D|reduction and alprostadil dose was reduced.(5)|
04237|030|B||
04237|031|R|REFERENCES:|
04237|032|B||
04237|033|R|1.Prostin VR Pediatric (alprostadil injection) US prescribing information.|1
04237|034|R|  Pharmacia and Upjohn Company LLC May, 2020.|1
04237|035|R|2.Schindler T, Smyth J, Bolisetty S, Michalowski J, Mallitt KA, Singla A,|2
04237|036|R|  Lui K. Early PARacetamol (EPAR) Trial: A Randomized Controlled Trial of|2
04237|037|R|  Early  Paracetamol to Promote Closure of the Ductus Arteriosus in Preterm|2
04237|038|R|  Infants. Neonatology 2021;118(3):274-281.|2
04237|039|R|3.Bahrami R, Ezzatabadi A, Mehdizadegan N, Mohammadi H, Amoozgar H, Edraki|2
04237|040|R|  M. Does high dose intravenous acetaminophen affect liver function for PDA|2
04237|041|R|  closure in  premature neonate?. Ital J Pediatr 2021 Feb 18;47(1):37.|2
04237|042|R|4.Luecke CM, Liviskie CJ, Zeller BN, Vesoulis ZA, McPherson C. Acetaminophen|2
04237|043|R|  for Patent Ductus Arteriosus in Extremely Low-Birth-Weight  Neonates. J|2
04237|044|R|  Pediatr Pharmacol Ther 2017 Nov-Dec;22(6):461-466.|2
04237|045|R|5.Jennifer MRyder PharmD; Esther Bae PharmD. Increasing Alprostadil|3
04237|046|R|  Requirements in a Neonate With Cardiac Anomalies and Co-administration of|3
04237|047|R|  Rectal and Oral Acetaminophen. J Pediatr Pharmacol Ther 2022 Aug 19;|3
04237|048|R|  27(6):573-7.|3
04238|001|T|MONOGRAPH TITLE:  Dabigatran/Levetiracetam|
04238|002|B||
04238|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04238|004|L|take action as needed.|
04238|005|B||
04238|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown.|
04238|007|A|Levetiracetam may decrease the efficacy of dabigatran.|
04238|008|B||
04238|009|E|CLINICAL EFFECTS:  Concurrent use of levetiracetam may result in decreased|
04238|010|E|effectiveness of dabigatran.|
04238|011|B||
04238|012|P|PREDISPOSING FACTORS:  None determined.|
04238|013|B||
04238|014|M|PATIENT MANAGEMENT:  Concurrent use of levetiracetam in patients receiving|
04238|015|M|dabigatran should be approached with caution.  Consider alternative|
04238|016|M|anticonvulsants in patients maintained on dabigatran.|
04238|017|M|   If concurrent use is warranted, monitor patients closely for decreased|
04238|018|M|response to dabigatran.|
04238|019|B||
04238|020|D|DISCUSSION:  A nested case-control study of 100,168 patients on apixaban,|
04238|021|D|dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic|
04238|022|D|emboli in patients with atrial fibrillation or recurrent thromboembolism in|
04238|023|D|patients with thromboembolism.  The primary outcome of CVA/systemic embolism|
04238|024|D|with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of|
04238|025|D|2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26|
04238|026|D|(1.13-4.54) compared to controls.(4)|
04238|027|D|   A population-based retrospective cohort study of 8746 patients on|
04238|028|D|apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence|
04238|029|D|of first ischemic stroke with concurrent antiseizure medications.|
04238|030|D|Antiseizure medications that induce CYP3A4 or P-gp were associated with an|
04238|031|D|increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%,|
04238|032|D|adjusted hazard ratio 1.28).  The annual incidence rates of ischemic stroke|
04238|033|D|(valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous|
04238|034|D|thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were|
04238|035|D|higher among valproate and levetiracetam users but were not statistically|
04238|036|D|different from controls.(5)|
04238|037|D|   In a case report, a 54 year old man with a complicated medical history|
04238|038|D|including paroxysmal atrial fibrillation, heart failure, and epilepsy who|
04238|039|D|was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg|
04238|040|D|twice daily, taken simultaneously with levetiracetam.  On day 10 of|
04238|041|D|dabigatran, trough levels were normal but Cmax was subtherapeutic.|
04238|042|D|Separation of dabigatran administration to 4 hours before levetiracetam|
04238|043|D|resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL.  Over 32 months|
04238|044|D|of follow-up, no hemorrhagic or ischemic events occurred.(6)|
04238|045|D|   A retrospective study of 320 patients with atrial fibrillation on DOAC|
04238|046|D|therapy for secondary stroke prevention compared the incidence of ischemic|
04238|047|D|stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing|
04238|048|D|medications (n=43), P-gp inducing medications (n=13), or no interacting|
04238|049|D|medications (n=264).  Twenty of the patients were on levetiracetam.  There|
04238|050|D|was no statistically significant difference between any of the groups.(7)|
04238|051|D|   A small prospective cohort study of 19 patients on the combination of|
04238|052|D|levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4|
04238|053|D|patients on rivaroxaban) did not find a significant correlation between|
04238|054|D|levetiracetam and DOAC concentrations.  One patient who was on low-dose|
04238|055|D|apixaban had low apixaban levels, and there were no thromboembolic events in|
04238|056|D|the 1388 +/- 994 days of follow-up.(8)|
04238|057|B||
04238|058|R|REFERENCES:|
04238|059|B||
04238|060|R|1.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
04238|061|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
04238|062|R|2.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
04238|063|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
04238|064|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
04238|065|R|  Boehringer Ingelheim March, 23 2020.|1
04238|066|R|4.Gronich N, Stein N, Muszkat M. Association Between Use of|2
04238|067|R|  Pharmacokinetic-Interacting Drugs and Effectiveness  and Safety of Direct|2
04238|068|R|  Acting Oral Anticoagulants: Nested Case-Control Study. Clin Pharmacol Ther|2
04238|069|R|  2021 Dec;110(6):1526-1536.|2
04238|070|R|5.Ip BY, Ko H, Wong GL, Yip TC, Lau LH, Lau AY, Leng X, Leung H, Chan HH,|2
04238|071|R|  Chan HY, Mok VC, Soo YO, Leung TW. Thromboembolic Risks with Concurrent|2
04238|072|R|  Direct Oral Anticoagulants and Antiseizure  Medications: A|2
04238|073|R|  Population-Based Analysis. CNS Drugs 2022 Dec;36(12):1313-1324.|2
04238|074|R|6.Menichelli D, Pastori D, Pignatelli P, Pani A. Minimizing drug-drug|3
04238|075|R|  interactions between dabigatran and levetiracetam through  clinical|3
04238|076|R|  management: a case report. Eur Heart J Case Rep 2023 Jan;7(1):ytad006.|3
04238|077|R|7.Ho CJ, Chen SH, Lin CH, Lu YT, Hsu CW, Tsai MH. Non-vitamin K Oral|2
04238|078|R|  Anticoagulants and Anti-seizure Medications: A Retrospective  Cohort|2
04238|079|R|  Study. Front Neurol 2020;11:588053.|2
04238|080|R|8.Mavri A, Ilc S. The efficacy of direct oral anticoagulants in patients on|2
04238|081|R|  concomitant treatment  with levetiracetam. Sci Rep 2023 Jun 7;13(1):9257.|2
04239|001|T|MONOGRAPH TITLE:  Edoxaban/Levetiracetam|
04239|002|B||
04239|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04239|004|L|take action as needed.|
04239|005|B||
04239|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown.|
04239|007|A|Levetiracetam may decrease the efficacy of edoxaban.|
04239|008|B||
04239|009|E|CLINICAL EFFECTS:  Concurrent use of levetiracetam may result in decreased|
04239|010|E|effectiveness of edoxaban.|
04239|011|B||
04239|012|P|PREDISPOSING FACTORS:  None determined.|
04239|013|B||
04239|014|M|PATIENT MANAGEMENT:  Concurrent use of levetiracetam in patients receiving|
04239|015|M|edoxaban should be approached with caution.  Consider alternative|
04239|016|M|anticonvulsants in patients maintained on edoxaban.|
04239|017|M|   If concurrent use is warranted, monitor patients closely for decreased|
04239|018|M|response to edoxaban.|
04239|019|B||
04239|020|D|DISCUSSION:  A nested case-control study of 100,168 patients on apixaban,|
04239|021|D|dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic|
04239|022|D|emboli in patients with atrial fibrillation or recurrent thromboembolism in|
04239|023|D|patients with thromboembolism.  The primary outcome of CVA/systemic embolism|
04239|024|D|with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of|
04239|025|D|2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26|
04239|026|D|(1.13-4.54) compared to controls.(4)|
04239|027|D|   A population-based retrospective cohort study of 8746 patients on|
04239|028|D|apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence|
04239|029|D|of first ischemic stroke with concurrent antiseizure medications.|
04239|030|D|Antiseizure medications that induce CYP3A4 or P-gp were associated with an|
04239|031|D|increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%,|
04239|032|D|adjusted hazard ratio 1.28).  The annual incidence rates of ischemic stroke|
04239|033|D|(valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous|
04239|034|D|thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were|
04239|035|D|higher among valproate and levetiracetam users but were not statistically|
04239|036|D|different from controls.(5)|
04239|037|D|   In a case report, a 54 year old man with a complicated medical history|
04239|038|D|including paroxysmal atrial fibrillation, heart failure, and epilepsy who|
04239|039|D|was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg|
04239|040|D|twice daily, taken simultaneously with levetiracetam.  On day 10 of|
04239|041|D|dabigatran, trough levels were normal but Cmax was subtherapeutic.|
04239|042|D|Separation of dabigatran administration to 4 hours before levetiracetam|
04239|043|D|resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL.  Over 32 months|
04239|044|D|of follow-up, no hemorrhagic or ischemic events occurred.(6)|
04239|045|D|   A retrospective study of 320 patients with atrial fibrillation on DOAC|
04239|046|D|therapy for secondary stroke prevention compared the incidence of ischemic|
04239|047|D|stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing|
04239|048|D|medications (n=43), P-gp inducing medications (n=13), or no interacting|
04239|049|D|medications (n=264).  Twenty of the patients were on levetiracetam.  There|
04239|050|D|was no statistically significant difference between any of the groups.(7)|
04239|051|D|   A small prospective cohort study of 19 patients on the combination of|
04239|052|D|levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4|
04239|053|D|patients on rivaroxaban) did not find a significant correlation between|
04239|054|D|levetiracetam and DOAC concentrations.  One patient who was on low-dose|
04239|055|D|apixaban had low apixaban levels, and there were no thromboembolic events in|
04239|056|D|the 1388 +/- 994 days of follow-up.(8)|
04239|057|B||
04239|058|R|REFERENCES:|
04239|059|B||
04239|060|R|1.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
04239|061|R|  2019.|1
04239|062|R|2.Lixiana (edoxaban) Canadian product monograph. Servier Canada Inc.|1
04239|063|R|  February, 2023.|1
04239|064|R|3.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
04239|065|R|  Sankyo UK Limited July 2, 2015.|1
04239|066|R|4.Gronich N, Stein N, Muszkat M. Association Between Use of|2
04239|067|R|  Pharmacokinetic-Interacting Drugs and Effectiveness  and Safety of Direct|2
04239|068|R|  Acting Oral Anticoagulants: Nested Case-Control Study. Clin Pharmacol Ther|2
04239|069|R|  2021 Dec;110(6):1526-1536.|2
04239|070|R|5.Ip BY, Ko H, Wong GL, Yip TC, Lau LH, Lau AY, Leng X, Leung H, Chan HH,|2
04239|071|R|  Chan HY, Mok VC, Soo YO, Leung TW. Thromboembolic Risks with Concurrent|2
04239|072|R|  Direct Oral Anticoagulants and Antiseizure  Medications: A|2
04239|073|R|  Population-Based Analysis. CNS Drugs 2022 Dec;36(12):1313-1324.|2
04239|074|R|6.Menichelli D, Pastori D, Pignatelli P, Pani A. Minimizing drug-drug|3
04239|075|R|  interactions between dabigatran and levetiracetam through  clinical|3
04239|076|R|  management: a case report. Eur Heart J Case Rep 2023 Jan;7(1):ytad006.|3
04239|077|R|7.Ho CJ, Chen SH, Lin CH, Lu YT, Hsu CW, Tsai MH. Non-vitamin K Oral|2
04239|078|R|  Anticoagulants and Anti-seizure Medications: A Retrospective  Cohort|2
04239|079|R|  Study. Front Neurol 2020;11:588053.|2
04239|080|R|8.Mavri A, Ilc S. The efficacy of direct oral anticoagulants in patients on|2
04239|081|R|  concomitant treatment  with levetiracetam. Sci Rep 2023 Jun 7;13(1):9257.|2
04240|001|T|MONOGRAPH TITLE:  Rivaroxaban/Levetiracetam|
04240|002|B||
04240|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04240|004|L|take action as needed.|
04240|005|B||
04240|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown.|
04240|007|A|Levetiracetam may decrease the efficacy of rivaroxaban.|
04240|008|B||
04240|009|E|CLINICAL EFFECTS:  Concurrent use of levetiracetam may result in decreased|
04240|010|E|effectiveness of rivaroxaban.|
04240|011|B||
04240|012|P|PREDISPOSING FACTORS:  None determined.|
04240|013|B||
04240|014|M|PATIENT MANAGEMENT:  Concurrent use of levetiracetam in patients receiving|
04240|015|M|rivaroxaban should be approached with caution.  Consider alternative|
04240|016|M|anticonvulsants in patients maintained on rivaroxaban.|
04240|017|M|   If concurrent use is warranted, monitor patients closely for decreased|
04240|018|M|response to rivaroxaban.|
04240|019|B||
04240|020|D|DISCUSSION:  A nested case-control study of 100,168 patients on apixaban,|
04240|021|D|dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic|
04240|022|D|emboli in patients with atrial fibrillation or recurrent thromboembolism in|
04240|023|D|patients with thromboembolism.  The primary outcome of CVA/systemic embolism|
04240|024|D|with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of|
04240|025|D|2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26|
04240|026|D|(1.13-4.54) compared to controls.(4)|
04240|027|D|   A population-based retrospective cohort study of 8746 patients on|
04240|028|D|apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence|
04240|029|D|of first ischemic stroke with concurrent antiseizure medications.|
04240|030|D|Antiseizure medications that induce CYP3A4 or P-gp were associated with an|
04240|031|D|increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%,|
04240|032|D|adjusted hazard ratio 1.28).  The annual incidence rates of ischemic stroke|
04240|033|D|(valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous|
04240|034|D|thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were|
04240|035|D|higher among valproate and levetiracetam users but were not statistically|
04240|036|D|different from controls.(5)|
04240|037|D|   In a case report, a 69-year-old male on rivaroxaban for nonvalvular|
04240|038|D|atrial fibrillation experienced transient ischemic attacks while on|
04240|039|D|concurrent levetiracetam.  During concurrent use of levetiracetam,|
04240|040|D|rivaroxaban levels were subtherapeutic.  After tapering off levetiracetam,|
04240|041|D|rivaroxaban levels were within therapeutic range and the transient ischemic|
04240|042|D|attacks resolved.(6)|
04240|043|D|   In a case report, a 54 year old man with a complicated medical history|
04240|044|D|including paroxysmal atrial fibrillation, heart failure, and epilepsy who|
04240|045|D|was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg|
04240|046|D|twice daily, taken simultaneously with levetiracetam.  On day 10 of|
04240|047|D|dabigatran, trough levels were normal but Cmax was subtherapeutic.|
04240|048|D|Separation of dabigatran administration to 4 hours before levetiracetam|
04240|049|D|resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL.  Over 32 months|
04240|050|D|of follow-up, no hemorrhagic or ischemic events occurred.(7)|
04240|051|D|   A retrospective study of 320 patients with atrial fibrillation on DOAC|
04240|052|D|therapy for secondary stroke prevention compared the incidence of ischemic|
04240|053|D|stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing|
04240|054|D|medications (n=43), P-gp inducing medications (n=13), or no interacting|
04240|055|D|medications (n=264).  Twenty of the patients were on levetiracetam.  There|
04240|056|D|was no statistically significant difference between any of the groups.(8)|
04240|057|D|   A small prospective cohort study of 19 patients on the combination of|
04240|058|D|levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4|
04240|059|D|patients on rivaroxaban) did not find a significant correlation between|
04240|060|D|levetiracetam and DOAC concentrations.  One patient who was on low-dose|
04240|061|D|apixaban had low apixaban levels, and there were no thromboembolic events in|
04240|062|D|the 1388 +/- 994 days of follow-up.(9)|
04240|063|B||
04240|064|R|REFERENCES:|
04240|065|B||
04240|066|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
04240|067|R|  Inc. March, 2020.|1
04240|068|R|2.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
04240|069|R|  August, 2021.|1
04240|070|R|3.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
04240|071|R|  2015.|1
04240|072|R|4.Gronich N, Stein N, Muszkat M. Association Between Use of|2
04240|073|R|  Pharmacokinetic-Interacting Drugs and Effectiveness  and Safety of Direct|2
04240|074|R|  Acting Oral Anticoagulants: Nested Case-Control Study. Clin Pharmacol Ther|2
04240|075|R|  2021 Dec;110(6):1526-1536.|2
04240|076|R|5.Ip BY, Ko H, Wong GL, Yip TC, Lau LH, Lau AY, Leng X, Leung H, Chan HH,|2
04240|077|R|  Chan HY, Mok VC, Soo YO, Leung TW. Thromboembolic Risks with Concurrent|2
04240|078|R|  Direct Oral Anticoagulants and Antiseizure  Medications: A|2
04240|079|R|  Population-Based Analysis. CNS Drugs 2022 Dec;36(12):1313-1324.|2
04240|080|R|6.Paciullo F, Costa C, Gresele P. Rivaroxaban Plasma Levels and|3
04240|081|R|  Levetiracetam: A Case Report. Ann Intern Med 2020 Jul 7;173(1):71-72.|3
04240|082|R|7.Menichelli D, Pastori D, Pignatelli P, Pani A. Minimizing drug-drug|3
04240|083|R|  interactions between dabigatran and levetiracetam through  clinical|3
04240|084|R|  management: a case report. Eur Heart J Case Rep 2023 Jan;7(1):ytad006.|3
04240|085|R|8.Ho CJ, Chen SH, Lin CH, Lu YT, Hsu CW, Tsai MH. Non-vitamin K Oral|2
04240|086|R|  Anticoagulants and Anti-seizure Medications: A Retrospective  Cohort|2
04240|087|R|  Study. Front Neurol 2020;11:588053.|2
04240|088|R|9.Mavri A, Ilc S. The efficacy of direct oral anticoagulants in patients on|2
04240|089|R|  concomitant treatment  with levetiracetam. Sci Rep 2023 Jun 7;13(1):9257.|2
04241|001|T|MONOGRAPH TITLE:  Apixaban/Valproate Derivatives|
04241|002|B||
04241|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04241|004|L|take action as needed.|
04241|005|B||
04241|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown.|
04241|007|A|Valproate derivatives may decrease the efficacy of apixaban.|
04241|008|B||
04241|009|E|CLINICAL EFFECTS:  Concurrent use of valproate derivatives may result in|
04241|010|E|decreased effectiveness of apixaban.|
04241|011|B||
04241|012|P|PREDISPOSING FACTORS:  None determined.|
04241|013|B||
04241|014|M|PATIENT MANAGEMENT:  Concurrent use of valproate derivatives in patients|
04241|015|M|receiving apixaban should be approached with caution.  Consider alternative|
04241|016|M|anticonvulsants in patients maintained on apixaban.|
04241|017|M|   If concurrent use is warranted, monitor patients closely for decreased|
04241|018|M|response to apixaban.|
04241|019|B||
04241|020|D|DISCUSSION:  A nested case-control study of 100,168 patients on apixaban,|
04241|021|D|dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic|
04241|022|D|emboli in patients with atrial fibrillation or recurrent thromboembolism in|
04241|023|D|patients with thromboembolism.  The primary outcome of CVA/systemic embolism|
04241|024|D|with concurrent use of valproic acid resulted in an odds ratio (95% CI) of|
04241|025|D|2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38|
04241|026|D|(1.37-4.12) compared to controls.(5)|
04241|027|D|   A population-based retrospective cohort study of 8746 patients on|
04241|028|D|apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence|
04241|029|D|of first ischemic stroke with concurrent antiseizure medications.|
04241|030|D|Antiseizure medications that induce CYP3A4 or P-gp were associated with an|
04241|031|D|increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%,|
04241|032|D|adjusted hazard ratio 1.28).  The annual incidence rates of ischemic stroke|
04241|033|D|(valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous|
04241|034|D|thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were|
04241|035|D|higher among valproate and levetiracetam users but were not statistically|
04241|036|D|different from controls.(6)|
04241|037|B||
04241|038|R|REFERENCES:|
04241|039|B||
04241|040|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04241|041|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04241|042|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04241|043|R|  Squibb-Pfizer January, 2025.|1
04241|044|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04241|045|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04241|046|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04241|047|R|  Company April, 2025.|1
04241|048|R|5.Gronich N, Stein N, Muszkat M. Association Between Use of|2
04241|049|R|  Pharmacokinetic-Interacting Drugs and Effectiveness  and Safety of Direct|2
04241|050|R|  Acting Oral Anticoagulants: Nested Case-Control Study. Clin Pharmacol Ther|2
04241|051|R|  2021 Dec;110(6):1526-1536.|2
04241|052|R|6.Ip BY, Ko H, Wong GL, Yip TC, Lau LH, Lau AY, Leng X, Leung H, Chan HH,|2
04241|053|R|  Chan HY, Mok VC, Soo YO, Leung TW. Thromboembolic Risks with Concurrent|2
04241|054|R|  Direct Oral Anticoagulants and Antiseizure  Medications: A|2
04241|055|R|  Population-Based Analysis. CNS Drugs 2022 Dec;36(12):1313-1324.|2
04242|001|T|MONOGRAPH TITLE:  Dabigatran/Valproate Derivatives|
04242|002|B||
04242|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04242|004|L|take action as needed.|
04242|005|B||
04242|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown.|
04242|007|A|Valproate derivatives may decrease the efficacy of dabigatran.|
04242|008|B||
04242|009|E|CLINICAL EFFECTS:  Concurrent use of valproate derivatives may result in|
04242|010|E|decreased effectiveness of dabigatran.|
04242|011|B||
04242|012|P|PREDISPOSING FACTORS:  None determined.|
04242|013|B||
04242|014|M|PATIENT MANAGEMENT:  Concurrent use of valproate derivatives in patients|
04242|015|M|receiving dabigatran should be approached with caution.  Consider|
04242|016|M|alternative anticonvulsants in patients maintained on dabigatran.|
04242|017|M|   If concurrent use is warranted, monitor patients closely for decreased|
04242|018|M|response to dabigatran.|
04242|019|B||
04242|020|D|DISCUSSION:  A nested case-control study of 100,168 patients on apixaban,|
04242|021|D|dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic|
04242|022|D|emboli in patients with atrial fibrillation or recurrent thromboembolism in|
04242|023|D|patients with thromboembolism.  The primary outcome of CVA/systemic embolism|
04242|024|D|with concurrent use of valproic acid resulted in an odds ratio (95% CI) of|
04242|025|D|2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38|
04242|026|D|(1.37-4.12) compared to controls.(4)|
04242|027|D|   A population-based retrospective cohort study of 8746 patients on|
04242|028|D|apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence|
04242|029|D|of first ischemic stroke with concurrent antiseizure medications.|
04242|030|D|Antiseizure medications that induce CYP3A4 or P-gp were associated with an|
04242|031|D|increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%,|
04242|032|D|adjusted hazard ratio 1.28).  The annual incidence rates of ischemic stroke|
04242|033|D|(valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous|
04242|034|D|thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were|
04242|035|D|higher among valproate and levetiracetam users but were not statistically|
04242|036|D|different from controls.(5)|
04242|037|B||
04242|038|R|REFERENCES:|
04242|039|B||
04242|040|R|1.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
04242|041|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
04242|042|R|2.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
04242|043|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
04242|044|R|3.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
04242|045|R|  Boehringer Ingelheim March, 23 2020.|1
04242|046|R|4.Gronich N, Stein N, Muszkat M. Association Between Use of|2
04242|047|R|  Pharmacokinetic-Interacting Drugs and Effectiveness  and Safety of Direct|2
04242|048|R|  Acting Oral Anticoagulants: Nested Case-Control Study. Clin Pharmacol Ther|2
04242|049|R|  2021 Dec;110(6):1526-1536.|2
04242|050|R|5.Ip BY, Ko H, Wong GL, Yip TC, Lau LH, Lau AY, Leng X, Leung H, Chan HH,|2
04242|051|R|  Chan HY, Mok VC, Soo YO, Leung TW. Thromboembolic Risks with Concurrent|2
04242|052|R|  Direct Oral Anticoagulants and Antiseizure  Medications: A|2
04242|053|R|  Population-Based Analysis. CNS Drugs 2022 Dec;36(12):1313-1324.|2
04243|001|T|MONOGRAPH TITLE:  Edoxaban/Valproate Derivatives|
04243|002|B||
04243|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04243|004|L|take action as needed.|
04243|005|B||
04243|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown.|
04243|007|A|Valproate derivatives may decrease the efficacy of edoxaban.|
04243|008|B||
04243|009|E|CLINICAL EFFECTS:  Concurrent use of valproate derivatives may result in|
04243|010|E|decreased effectiveness of edoxaban.|
04243|011|B||
04243|012|P|PREDISPOSING FACTORS:  None determined.|
04243|013|B||
04243|014|M|PATIENT MANAGEMENT:  Concurrent use of valproate derivatives in patients|
04243|015|M|receiving edoxaban should be approached with caution.  Consider alternative|
04243|016|M|anticonvulsants in patients maintained on edoxaban.|
04243|017|M|   If concurrent use is warranted, monitor patients closely for decreased|
04243|018|M|response to edoxaban.|
04243|019|B||
04243|020|D|DISCUSSION:  A nested case-control study of 100,168 patients on apixaban,|
04243|021|D|dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic|
04243|022|D|emboli in patients with atrial fibrillation or recurrent thromboembolism in|
04243|023|D|patients with thromboembolism.  The primary outcome of CVA/systemic embolism|
04243|024|D|with concurrent use of valproic acid resulted in an odds ratio (95% CI) of|
04243|025|D|2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38|
04243|026|D|(1.37-4.12) compared to controls.(4)|
04243|027|D|   A population-based retrospective cohort study of 8746 patients on|
04243|028|D|apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence|
04243|029|D|of first ischemic stroke with concurrent antiseizure medications.|
04243|030|D|Antiseizure medications that induce CYP3A4 or P-gp were associated with an|
04243|031|D|increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%,|
04243|032|D|adjusted hazard ratio 1.28).  The annual incidence rates of ischemic stroke|
04243|033|D|(valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous|
04243|034|D|thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were|
04243|035|D|higher among valproate and levetiracetam users but were not statistically|
04243|036|D|different from controls.(5)|
04243|037|B||
04243|038|R|REFERENCES:|
04243|039|B||
04243|040|R|1.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
04243|041|R|  2019.|1
04243|042|R|2.Lixiana (edoxaban) Canadian product monograph. Servier Canada Inc.|1
04243|043|R|  February, 2023.|1
04243|044|R|3.Lixiana (edoxaban tosilate) UK summary of product characteristics. Daiichi|1
04243|045|R|  Sankyo UK Limited July 2, 2015.|1
04243|046|R|4.Gronich N, Stein N, Muszkat M. Association Between Use of|2
04243|047|R|  Pharmacokinetic-Interacting Drugs and Effectiveness  and Safety of Direct|2
04243|048|R|  Acting Oral Anticoagulants: Nested Case-Control Study. Clin Pharmacol Ther|2
04243|049|R|  2021 Dec;110(6):1526-1536.|2
04243|050|R|5.Ip BY, Ko H, Wong GL, Yip TC, Lau LH, Lau AY, Leng X, Leung H, Chan HH,|2
04243|051|R|  Chan HY, Mok VC, Soo YO, Leung TW. Thromboembolic Risks with Concurrent|2
04243|052|R|  Direct Oral Anticoagulants and Antiseizure  Medications: A|2
04243|053|R|  Population-Based Analysis. CNS Drugs 2022 Dec;36(12):1313-1324.|2
04244|001|T|MONOGRAPH TITLE:  Rivaroxaban/Valproate Derivatives|
04244|002|B||
04244|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04244|004|L|take action as needed.|
04244|005|B||
04244|006|A|MECHANISM OF ACTION:  The mechanism of the interaction is unknown.|
04244|007|A|Valproate derivatives may decrease the efficacy of rivaroxaban.|
04244|008|B||
04244|009|E|CLINICAL EFFECTS:  Concurrent use of valproate derivatives may result in|
04244|010|E|decreased effectiveness of rivaroxaban.|
04244|011|B||
04244|012|P|PREDISPOSING FACTORS:  None determined.|
04244|013|B||
04244|014|M|PATIENT MANAGEMENT:  Concurrent use of valproate derivatives in patients|
04244|015|M|receiving rivaroxaban should be approached with caution.  Consider|
04244|016|M|alternative anticonvulsants in patients maintained on rivaroxaban.|
04244|017|M|   If concurrent use is warranted, monitor patients closely for decreased|
04244|018|M|response to rivaroxaban.|
04244|019|B||
04244|020|D|DISCUSSION:  A nested case-control study of 100,168 patients on apixaban,|
04244|021|D|dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic|
04244|022|D|emboli in patients with atrial fibrillation or recurrent thromboembolism in|
04244|023|D|patients with thromboembolism.  The primary outcome of CVA/systemic embolism|
04244|024|D|with concurrent use of valproic acid resulted in an odds ratio (95% CI) of|
04244|025|D|2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38|
04244|026|D|(1.37-4.12) compared to controls.(4)|
04244|027|D|   A population-based retrospective cohort study of 8746 patients on|
04244|028|D|apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence|
04244|029|D|of first ischemic stroke with concurrent antiseizure medications.|
04244|030|D|Antiseizure medications that induce CYP3A4 or P-gp were associated with an|
04244|031|D|increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%,|
04244|032|D|adjusted hazard ratio 1.28).  The annual incidence rates of ischemic stroke|
04244|033|D|(valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous|
04244|034|D|thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were|
04244|035|D|higher among valproate and levetiracetam users but were not statistically|
04244|036|D|different from controls.(5)|
04244|037|D|   In a case report, a 30-year-old male with a history of deep vein|
04244|038|D|thrombosis (DVT) developed recurrent DVTs on rivaroxaban.  The patient was|
04244|039|D|on concurrent valproic acid and lamotrigine for seizures.  During concurrent|
04244|040|D|use with valproic acid, rivaroxaban levels were below the 5th percentile.|
04244|041|D|Valproic acid was gradually tapered off and rivaroxaban levels increased|
04244|042|D|significantly.(6)|
04244|043|B||
04244|044|R|REFERENCES:|
04244|045|B||
04244|046|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
04244|047|R|  Inc. March, 2020.|1
04244|048|R|2.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
04244|049|R|  2015.|1
04244|050|R|3.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
04244|051|R|  August, 2021.|1
04244|052|R|4.Gronich N, Stein N, Muszkat M. Association Between Use of|2
04244|053|R|  Pharmacokinetic-Interacting Drugs and Effectiveness  and Safety of Direct|2
04244|054|R|  Acting Oral Anticoagulants: Nested Case-Control Study. Clin Pharmacol Ther|2
04244|055|R|  2021 Dec;110(6):1526-1536.|2
04244|056|R|5.Ip BY, Ko H, Wong GL, Yip TC, Lau LH, Lau AY, Leng X, Leung H, Chan HH,|2
04244|057|R|  Chan HY, Mok VC, Soo YO, Leung TW. Thromboembolic Risks with Concurrent|2
04244|058|R|  Direct Oral Anticoagulants and Antiseizure  Medications: A|2
04244|059|R|  Population-Based Analysis. CNS Drugs 2022 Dec;36(12):1313-1324.|2
04244|060|R|6.Langenbruch L, Meuth SG, Wiendl H, Mesters R, MAddel G. Clinically|3
04244|061|R|  relevant interaction of rivaroxaban and valproic acid - A case report.|3
04244|062|R|  Seizure 2020 Aug;80:46-47.|3
04245|001|T|MONOGRAPH TITLE:  Nadofaragene Firadenovec/Selected Immunosuppressants|
04245|002|B||
04245|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04245|004|L|is contraindicated and generally should not be dispensed or administered to|
04245|005|L|the same patient.|
04245|006|B||
04245|007|A|MECHANISM OF ACTION:  Nadofaragene firadenovec may contain low levels of|
04245|008|A|replication-competent adenovirus.(1)|
04245|009|B||
04245|010|E|CLINICAL EFFECTS:  Concurrent use of nadofaragene firadenovec in patients|
04245|011|E|receiving immunosuppressive therapy may cause disseminated adenovirus|
04245|012|E|infection.(1)|
04245|013|B||
04245|014|P|PREDISPOSING FACTORS:  None determined.|
04245|015|B||
04245|016|M|PATIENT MANAGEMENT:  Individuals who are immunosuppressed or|
04245|017|M|immune-deficient should not receive nadofaragene firadenovec.(1)|
04245|018|B||
04245|019|D|DISCUSSION:  Nadofaragene firadenovec is a non-replicating adenoviral|
04245|020|D|vector-based gene therapy but may contain low levels of|
04245|021|D|replication-competent adenovirus.  Immunocompromised persons, including|
04245|022|D|those receiving immunosuppressant therapy, may be at risk for disseminated|
04245|023|D|adenovirus infection.(1)|
04245|024|B||
04245|025|R|REFERENCE:|
04245|026|B||
04245|027|R|1.Adstiladrin (nadofaragene firadenovec-vncg ) US prescribing information.|1
04245|028|R|  Ferring Pharmaceuticals December 2022.|1
04246|001|T|MONOGRAPH TITLE:  Dabigatran/Diltiazem|
04246|002|B||
04246|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04246|004|L|take action as needed.|
04246|005|B||
04246|006|A|MECHANISM OF ACTION:  Dabigatran etexilate is a substrate for the|
04246|007|A|P-glycoprotein (P-gp) system.  Diltiazem is a P-gp inhibitor.  Inhibition of|
04246|008|A|intestinal P-gp leads to increased absorption of dabigatran.(1-3)|
04246|009|B||
04246|010|E|CLINICAL EFFECTS:  The concurrent use dabigatran with diltiazem may lead to|
04246|011|E|elevated plasma levels of dabigatran, increasing the risk for bleeding.|
04246|012|B||
04246|013|P|PREDISPOSING FACTORS:  Factors associated with an increased risk for|
04246|014|P|bleeding include renal impairment, concomitant use of P-gp inhibitors,|
04246|015|P|patient age >74 years, coexisting conditions (e.g. recent trauma) or use of|
04246|016|P|drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50|
04246|017|P|kg.(1-4)|
04246|018|B||
04246|019|M|PATIENT MANAGEMENT:  Assess renal function and evaluate patient for other|
04246|020|M|pre-existing risk factors for bleeding prior to initiating concurrent|
04246|021|M|therapy.  Caution and close monitoring is warranted with concurrent use of|
04246|022|M|dabigatran and diltiazem.|
04246|023|M|   The US manufacturer of dabigatran states that the concurrent use of|
04246|024|M|dabigatran and P-gp inhibitors should be avoided in atrial fibrillation|
04246|025|M|patients with severe renal impairment (CrCl less than 30 ml/min) and in|
04246|026|M|patients with moderate renal impairment (CrCl less than 50 ml/min) being|
04246|027|M|treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or|
04246|028|M|pulmonary embolism (PE).  The interaction with P-gp inhibitors can be|
04246|029|M|minimized by taking dabigatran several hours apart from the P-gp inhibitor|
04246|030|M|dose.(1)|
04246|031|M|   The concomitant use of dabigatran with P-gp inhibitors has not been|
04246|032|M|studied in pediatric patients but may increase exposure to dabigatran.(1)|
04246|033|M|   While the US manufacturer of dabigatran states that no dosage adjustment|
04246|034|M|is necessary in other patients,(1) the Canadian manufacturer of dabigatran|
04246|035|M|states that concomitant use of strong P-gp inhibitors such as but not|
04246|036|M|limited to cyclosporine, itraconazole, nelfinavir, posaconazole, ritonavir,|
04246|037|M|saquinavir, tacrolimus and tipranavir may be expected to increase systemic|
04246|038|M|exposure to dabigatran and should be used with caution.(2)|
04246|039|M|   The UK manufacturer of dabigatran also states when dabigatran is used in|
04246|040|M|atrial fibrillation patients and for treatment of DVT and PE concurrently|
04246|041|M|with mild to moderate P-gp inhibitors, the dose of dabigatran should be|
04246|042|M|reduced from 150 mg twice daily to 110 mg twice daily, taken simultaneously|
04246|043|M|with the P-gp inhibitor.  When used for VTE prophylaxis after orthopedic|
04246|044|M|surgery concurrently with amiodarone, quinidine, or verapamil, the|
04246|045|M|dabigatran loading dose should be reduced from 110 mg to 75 mg, and the|
04246|046|M|maintenance dose should be reduced from 220 mg daily to 150 mg daily, taken|
04246|047|M|simultaneously with the P-gp inhibitor.  For patients with CLcr 30-50 mL/min|
04246|048|M|on concurrent verapamil or other moderate P-gp inhibitor, consider further|
04246|049|M|lowering the dabigatran dose to 75 mg daily.(3)|
04246|050|M|   Concomitant administration of P-gp inhibitors is expected to result in|
04246|051|M|increased dabigatran plasma concentrations. If not otherwise specifically|
04246|052|M|described, close clinical surveillance is required when dabigatran is|
04246|053|M|co-administered with strong P-gp inhibitors. Dose reductions may be required|
04246|054|M|in combination with some P-gp inhibitors.(3)|
04246|055|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
04246|056|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
04246|057|M|and/or decreased blood pressure and promptly evaluate patients with any|
04246|058|M|symptoms.  Consider regular monitoring of hemoglobin, platelet levels,|
04246|059|M|and/or activated partial thromboplastin time (aPTT) or ecarin clotting time|
04246|060|M|(ECT).|
04246|061|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04246|062|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04246|063|M|anticoagulation in patients with active pathologic bleeding.|
04246|064|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04246|065|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04246|066|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04246|067|M|and/or swelling.|
04246|068|B||
04246|069|D|DISCUSSION:  A retrospective cohort study included data from 9,886|
04246|070|D|individuals evaluating rates of adverse bleeding with standard doses of oral|
04246|071|D|anticoagulants with concurrent verapamil or diltiazem in patients with|
04246|072|D|nonvalvular atrial fibrillation and normal kidney function. Concurrent|
04246|073|D|dabigatran use with verapamil or diltiazem was associated with increased|
04246|074|D|overall bleeding (hazard ratio (HR) 1.52; 95% confidence interval (CI),|
04246|075|D|1.05-2.20, p<0.05) and increased overall gastrointestinal (GI) bleeding (HR|
04246|076|D|2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine.  When compared|
04246|077|D|to metoprolol, concomitant dabigatran use with verapamil or diltiazem was|
04246|078|D|also associated with increased overall bleeding (HR, 1.43; 95% CI,|
04246|079|D|1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI,|
04246|080|D|1.42-3.79, p<0.05).  No association was found between increased bleeding of|
04246|081|D|any kind and concurrent use of rivaroxaban or apixaban with verapamil or|
04246|082|D|diltiazem.(5)|
04246|083|D|   A summary of pharmacokinetic interactions with dabigatran and amiodarone|
04246|084|D|or verapamil concluded that concurrent use is considered safe if CrCl is|
04246|085|D|greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min|
04246|086|D|in VTE and less than 30 ml/min for NVAF.  Concurrent use with diltiazem was|
04246|087|D|considered safe.(6)|
04246|088|D|   In a study of 4,544 patients with atrial fibrillation, the association|
04246|089|D|between the concomitant use of diltiazem and direct oral anticoagulants|
04246|090|D|(DOACs) (rivaroxaban, apixaban, and dabigatran) with bleeding was evaluated.|
04246|091|D|The study reported that DOAC patients taking diltiazem were associated with|
04246|092|D|a higher risk of any bleeding-related hospitalizations (unadjusted risk|
04246|093|D|difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted HR,|
04246|094|D|1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk|
04246|095|D|difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted HR,|
04246|096|D|1.84 [95% CI, 1.18-2.85]). Increased risk of bleeding with diltiazem was|
04246|097|D|observed in both patients with and without chronic kidney disease (estimated|
04246|098|D|glomerular filtration rate <60 mL/min per 1.73 m2).(7)|
04246|099|D|   In a retrospective cohort study, the association of novel oral|
04246|100|D|anticoagulants (NOACs) with or without concomitant medication with risk of|
04246|101|D|major bleeding was assessed in 91,330 patients with nonvalvular atrial|
04246|102|D|fibrillation.  Concurrent use of amiodarone, fluconazole, rifampin, and|
04246|103|D|phenytoin with NOACs had a significant increase in adjusted incidence rates|
04246|104|D|per 1000 person-years of major bleeding than NOACs alone.  Compared with|
04246|105|D|NOAC use alone, the adjusted incidence rate for major bleeding was|
04246|106|D|significantly lower for concurrent use of atorvastatin, digoxin, and|
04246|107|D|erythromycin or clarithromycin and was not significantly different for|
04246|108|D|concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole,|
04246|109|D|itraconazole, voriconazole, or posaconazole; and dronedarone.(8)|
04246|110|D|   A retrospective cohort study included patients taking DOACs (dabigatran,|
04246|111|D|apixaban, rivaroxaban) who were prescribed amiodarone, verapamil, or|
04246|112|D|diltiazem compared to amlodipine or metoprolol.  The study evaluated the|
04246|113|D|association between hospitalization or emergency room visit due to major|
04246|114|D|hemorrhage and concomitant administration of DOACs with either a moderate|
04246|115|D|P-gp inhibitor or agents with no P-gp activity.  Results of the study show|
04246|116|D|the weighted risk of major hemorrhage was not increased with amiodarone,|
04246|117|D|verapamil, or diltiazem initiation in DOAC users, compared to metoprolol or|
04246|118|D|amlodipine, during the full follow-up period (HR; 95% confidence interval]:|
04246|119|D|amiodarone HR 0.77 [0.61-0.97]; verapamil HR 1.32 [0.88-1.98]; diltiazem HR|
04246|120|D|0.99 [0.85-1.15], respectively).(9)|
04246|121|B||
04246|122|R|REFERENCES:|
04246|123|B||
04246|124|R|1.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
04246|125|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
04246|126|R|2.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
04246|127|R|  Boehringer Ingelheim March, 23 2020.|1
04246|128|R|3.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
04246|129|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
04246|130|R|4.Anonymous. FDA Dabigatran background package for Cardio-Renal Advisory|1
04246|131|R|  Committee. available at|1
04246|132|R|  http://wayback.archive-it.org/7993/20170405212218/https://www.fda.gov/down|1
04246|133|R|  loads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascularan|1
04246|134|R|  dRenalDrugsAdvisoryCommittee/UCM247244.pdf September 20, 2010.|1
04246|135|R|5.Pham P, Schmidt S, Lesko L, Lip GYH, Brown JD. Association of Oral|2
04246|136|R|  Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding  Events in|2
04246|137|R|  Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function.|2
04246|138|R|  JAMA Netw Open;3(4)(2574-3805 (Electronic). 2574-3805 (Linking)):.|2
04246|139|R|6.Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select|6
04246|140|R|  Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic|6
04246|141|R|  of  the Week..|6
04246|142|R|7.Xu Y, Chang AR, Inker LA, McAdams-DeMarco M, Grams ME, Shin JI.|2
04246|143|R|  Concomitant Use of Diltiazem With Direct Oral Anticoagulants and Bleeding|2
04246|144|R|  Risk in  Atrial Fibrillation. J Am Heart Assoc 2022 Jul 19;11(14):e025723.|2
04246|145|R|8.Chang SH, Chou IJ, Yeh YH, Chiou MJ, Wen MS, Kuo CT, See LC, Kuo CF.|2
04246|146|R|  Association Between Use of Non-Vitamin K Oral Anticoagulants With and|2
04246|147|R|  Without  Concurrent Medications and Risk of Major Bleeding in Nonvalvular|2
04246|148|R|  Atrial  Fibrillation. JAMA 2017 Oct 3;318(13):1250-1259.|2
04246|149|R|9.Hill K, Sucha E, Rhodes E, Bota S, Hundemer GL, Clark EG, Canney M, Harel|2
04246|150|R|  Z, Wang TF, Carrier M, Wijeysundera HC, Knoll G, Sood MM. Amiodarone,|2
04246|151|R|  Verapamil, or Diltiazem Use With Direct Oral Anticoagulants and the  Risk|2
04246|152|R|  of Hemorrhage in Older Adults. CJC Open 2022 Mar;4(3):315-323.|2
04246|153|R|10.This information is based on an extract from the Certara Drug Interaction|6
04246|154|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04247|001|T|MONOGRAPH TITLE:  Lenacapavir/Strong CYP3A4 Inducers|
04247|002|B||
04247|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04247|004|L|is contraindicated and generally should not be dispensed or administered to|
04247|005|L|the same patient.|
04247|006|B||
04247|007|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may accelerate|
04247|008|A|the metabolism of lenacapavir.(1-3)|
04247|009|B||
04247|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04247|011|E|levels and effectiveness of lenacapavir.(1-3)|
04247|012|B||
04247|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04247|014|P|of the inducer for longer than 1-2 weeks.|
04247|015|B||
04247|016|M|PATIENT MANAGEMENT:  The manufacturer of lenacapavir states that concurrent|
04247|017|M|use of strong CYP3A4 inducers is contraindicated.(1-3)|
04247|018|B||
04247|019|D|DISCUSSION:  In a study, rifampin 600 mg once daily (inducer of CYP3A4|
04247|020|D|[strong], P-glycoprotein, and UGT1A1) decreased the maximum concentration|
04247|021|D|(Cmax) and area-under-curve (AUC) of lenacapavir by 55% and 84%,|
04247|022|D|respectively.(1)|
04247|023|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04247|024|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04247|025|D|lumacaftor, mitotane, phenytoin, rifampin, rifapentine, and St. John's|
04247|026|D|wort.(4,5)|
04247|027|B||
04247|028|R|REFERENCES:|
04247|029|B||
04247|030|R|1.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04247|031|R|  Sciences Ireland UC August, 2022.|1
04247|032|R|2.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04247|033|R|  November 2024.|1
04247|034|R|3.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04247|035|R|  Inc. November, 2022.|1
04247|036|R|4.This information is based on an extract from the Certara Drug Interaction|6
04247|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04247|038|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04247|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04247|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04247|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04247|042|R|  11/14/2017.|1
04248|001|T|MONOGRAPH TITLE:  Lenacapavir/Moderate CYP3A4 Inducers|
04248|002|B||
04248|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04248|004|L|of severe adverse interaction.|
04248|005|B||
04248|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may accelerate|
04248|007|A|the metabolism of lenacapavir.(1-3)|
04248|008|B||
04248|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inducers may decrease|
04248|010|E|the levels and effectiveness of lenacapavir.(1-3)|
04248|011|B||
04248|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04248|013|P|of the inducer for longer than 1-2 weeks.|
04248|014|B||
04248|015|M|PATIENT MANAGEMENT:  The manufacturer of lenacapavir states that concurrent|
04248|016|M|use of moderate CYP3A4 inducers is not recommended.(1-3)|
04248|017|B||
04248|018|D|DISCUSSION:  In a study, efavirenz 600 mg once daily (inducer of CYP3A4|
04248|019|D|[moderate] and P-glycoprotein) decreased the maximum concentration (Cmax)|
04248|020|D|and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1)|
04248|021|D|   Moderate CYP3A4 inducers linked to this monograph include:  barbiturates,|
04248|022|D|cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
04248|023|D|lesinurad, lorlatinib, modafinil, nafcillin, nevirapine, oxcarbazepine,|
04248|024|D|phenobarbital, primidone, rifabutin, sotorasib, telotristat ethyl,|
04248|025|D|thioridazine, tipranavir-ritonavir, and tovorafenib.(4,5)|
04248|026|B||
04248|027|R|REFERENCES:|
04248|028|B||
04248|029|R|1.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04248|030|R|  Sciences Ireland UC August, 2022.|1
04248|031|R|2.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04248|032|R|  November 2024.|1
04248|033|R|3.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04248|034|R|  Inc. November, 2022.|1
04248|035|R|4.This information is based on an extract from the Certara Drug Interaction|6
04248|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04248|037|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04248|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04248|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04248|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04248|041|R|  11/14/2017.|1
04249|001|T|MONOGRAPH TITLE:  Lenacapavir/Strong CYP3A4 & P-gp & UGT1A1 Inhibitors|
04249|002|B||
04249|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04249|004|L|of severe adverse interaction.|
04249|005|B||
04249|006|A|MECHANISM OF ACTION:  Lenacapavir is metabolized by CYP3A4 and UGT1A1 and is|
04249|007|A|a substrate of the P-glycoprotein (P-gp) efflux transport protein.(1)|
04249|008|A|   Combined inhibitors of CYP3A4, P-gp, and UGT1A1 may increase absorption|
04249|009|A|and inhibit metabolism and elimination of lenacapavir.(1-3)|
04249|010|B||
04249|011|E|CLINICAL EFFECTS:  Concurrent use with combined inhibitors of CYP3A4, P-gp,|
04249|012|E|and UGT1A1 may result in elevated systemic levels and toxicity from|
04249|013|E|lenacapavir.(1-3)|
04249|014|B||
04249|015|P|PREDISPOSING FACTORS:  None determined.|
04249|016|B||
04249|017|M|PATIENT MANAGEMENT:  The US, Canadian, and UK manufacturers of lenacapavir|
04249|018|M|state concurrent use with combined CYP3A4, P-gp, and UGT1A1 inhibitors is|
04249|019|M|not recommended.(1-3)|
04249|020|B||
04249|021|D|DISCUSSION:  In an interaction study, atazanavir/cobicistat (inhibitor of|
04249|022|D|CYP3A4, P-gp, and UGT1A1) at a dose of 300 mg/150 mg daily increased the|
04249|023|D|maximum concentration (Cmax) and area-under-curve (AUC) of lenacapavir by|
04249|024|D|6.6-fold and 4.21-fold, respectively.(1)|
04249|025|D|   Combined CYP3A4, P-gp, and UGT1A1 inhibitors linked to this monograph|
04249|026|D|include: atazanavir/cobicistat and indinavir.(4,5)|
04249|027|B||
04249|028|R|REFERENCES:|
04249|029|B||
04249|030|R|1.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04249|031|R|  November 2024.|1
04249|032|R|2.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04249|033|R|  Sciences Ireland UC August, 2022.|1
04249|034|R|3.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04249|035|R|  Inc. November, 2022.|1
04249|036|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04249|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04249|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04249|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04249|040|R|  11/14/2017.|1
04249|041|R|5.This information is based on an extract from the Certara Drug Interaction|6
04249|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04250|001|T|MONOGRAPH TITLE:  Tadalafil (PAH)/Lenacapavir|
04250|002|B||
04250|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04250|004|L|of severe adverse interaction.|
04250|005|B||
04250|006|A|MECHANISM OF ACTION:  Lenacapavir may inhibit the metabolism of tadalafil by|
04250|007|A|CYP3A4.(1-4)|
04250|008|B||
04250|009|E|CLINICAL EFFECTS:  The concurrent administration of lenacapavir may result|
04250|010|E|in elevated levels of tadalafil, which may result in increased adverse|
04250|011|E|effects such as hypotension, visual changes, and priapism.(1-4)|
04250|012|B||
04250|013|P|PREDISPOSING FACTORS:  None determined.|
04250|014|B||
04250|015|M|PATIENT MANAGEMENT:  The manufacturer of lenacapavir states the concurrent|
04250|016|M|use of tadalafil for pulmonary arterial hypertension (PAH) is not|
04250|017|M|recommended.(2-4)|
04250|018|M|   The US manufacturer of tadalafil and the UK and Canadian manufacturers of|
04250|019|M|lenacapavir state that the recommended dose of as needed tadalafil for the|
04250|020|M|treatment of erectile dysfunction is 10 mg of tadalafil every 72 hours in|
04250|021|M|patients receiving concomitant therapy.(1,3-4)|
04250|022|M|   The US manufacturer of tadalafil and the UK and Canadian manufacturers of|
04250|023|M|lenacapavir state that the recommended dose of daily tadalafil is 2.5 mg for|
04250|024|M|the treatment of erectile dysfunction in patients receiving concomitant|
04250|025|M|therapy.(1,3-4)|
04250|026|M|   Patients should be counseled that they are at an increased risk of|
04250|027|M|tadalafil adverse effects, including hypotension, syncope, visual changes,|
04250|028|M|and priapism.  Patients experiencing these effects should report them|
04250|029|M|promptly to their physician.|
04250|030|B||
04250|031|D|DISCUSSION:  Concurrent administration of lenacapavir 600 mg with a single|
04250|032|D|2.5 mg dose of midazolam (a CYP3A4 substrate) increased midazolam maximum|
04250|033|D|concentration (Cmax) and area-under-curve (AUC) by 1.94-fold and 3.59-fold,|
04250|034|D|respectively.(2-4)|
04250|035|D|   Concurrent administration of a single 20 mg dose of tadalafil with|
04250|036|D|ketoconazole (400 mg daily) increased tadalafil AUC and maximum|
04250|037|D|concentration (Cmax) by 312% and 22%, respectively.  Concurrent|
04250|038|D|administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg|
04250|039|D|daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(1)|
04250|040|B||
04250|041|R|REFERENCES:|
04250|042|B||
04250|043|R|1.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
04250|044|R|  February, 2018.|1
04250|045|R|2.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04250|046|R|  November 2024.|1
04250|047|R|3.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04250|048|R|  Sciences Ireland UC August, 2022.|1
04250|049|R|4.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04250|050|R|  Inc. November, 2022.|1
04251|001|T|MONOGRAPH TITLE:  Sildenafil (ED);Tadalafil (ED)/Lenacapavir|
04251|002|B||
04251|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04251|004|L|of severe adverse interaction.|
04251|005|B||
04251|006|A|MECHANISM OF ACTION:  Lenacapavir may inhibit the metabolism of sildenafil|
04251|007|A|and tadalafil by CYP3A4.(1-4)|
04251|008|B||
04251|009|E|CLINICAL EFFECTS:  The concurrent administration of lenacapavir may result|
04251|010|E|in elevated levels of sildenafil and tadalafil, which may result in|
04251|011|E|increased adverse effects such as hypotension, visual changes, and|
04251|012|E|priapism.(1-4)|
04251|013|B||
04251|014|P|PREDISPOSING FACTORS:  None determined.|
04251|015|B||
04251|016|M|PATIENT MANAGEMENT:  The US manufacturer of sildenafil and the UK and|
04251|017|M|Canadian manufacturers of lenacapavir recommend a starting dose of 25 mg of|
04251|018|M|sildenafil for erectile dysfunction in patients receiving concomitant|
04251|019|M|therapy.(1, 3-5)|
04251|020|M|   The US manufacturer of tadalafil and the UK and Canadian manufacturers of|
04251|021|M|lenacapavir state that the recommended dose of as needed tadalafil for the|
04251|022|M|treatment of erectile dysfunction is 10 mg of tadalafil every 72 hours in|
04251|023|M|patients receiving concomitant therapy.(2-5)|
04251|024|M|   The US manufacturer of tadalafil and the UK and Canadian manufacturers of|
04251|025|M|lenacapavir state that the recommended dose of daily tadalafil for the|
04251|026|M|treatment of erectile dysfunction is 2.5 mg in patients receiving|
04251|027|M|concomitant therapy.(2-5)|
04251|028|M|   The US manufacturer of tadalafil chewable tablets (Chewtadzy) states the|
04251|029|M|maximum recommended dose of as needed tadalafil for erectile dysfunction in|
04251|030|M|patients taking strong CYP3A4 inhibitors is 10 mg every 72 hours.  The use|
04251|031|M|of tadalafil chewable tablets (Chewtazdy) for once daily use for erectile|
04251|032|M|dysfunction or benign prostatic hyperplasia (BPH) is not recommended in|
04251|033|M|patients taking strong CYP3A4 inhibitors due to the lack of a 2.5 mg tablet|
04251|034|M|strength.(6)|
04251|035|M|   The manufacturer of lenacapavir states the concurrent use of tadalafil|
04251|036|M|for pulmonary arterial hypertension (PAH) is not recommended.(3-5)|
04251|037|M|   Patients should be counseled that they are at an increased risk of|
04251|038|M|tadalafil adverse effects, including hypotension, syncope, visual changes,|
04251|039|M|and priapism.  Patients experiencing these effects should report them|
04251|040|M|promptly to their physician.|
04251|041|B||
04251|042|D|DISCUSSION:  Concurrent administration of a single 100 mg dose of sildenafil|
04251|043|D|with erythromycin (500 mg twice daily for five days) resulted in an increase|
04251|044|D|of sildenafil area-under-curve (AUC) by 182%.  Therefore, the manufacturer|
04251|045|D|of sildenafil recommends a starting dose of 25 mg of sildenafil in patients|
04251|046|D|receiving concomitant therapy with other strong CYP3A4 inhibitors such as|
04251|047|D|itraconazole or ketoconazole.(1)|
04251|048|D|   Concurrent administration of a single 20 mg dose of tadalafil with|
04251|049|D|ketoconazole (400 mg daily) increased tadalafil AUC and maximum|
04251|050|D|concentration (Cmax) by 312% and 22%, respectively.  Concurrent|
04251|051|D|administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg|
04251|052|D|daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(2)|
04251|053|D|   Concurrent administration of lenacapavir 600 mg with a single 2.5 mg dose|
04251|054|D|of midazolam (a CYP3A4 substrate) increased midazolam maximum concentration|
04251|055|D|(Cmax) and area-under-curve (AUC) by 1.94-fold and 3.59-fold,|
04251|056|D|respectively.(3-5)|
04251|057|B||
04251|058|R|REFERENCES:|
04251|059|B||
04251|060|R|1.Viagra (sildenafil) US prescribing information. Pfizer Inc. December 14,|1
04251|061|R|  2017.|1
04251|062|R|2.Cialis (tadalafil) US prescribing information. Eli Lilly and Company|1
04251|063|R|  February, 2018.|1
04251|064|R|3.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04251|065|R|  November 2024.|1
04251|066|R|4.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04251|067|R|  Sciences Ireland UC August, 2022.|1
04251|068|R|5.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04251|069|R|  Inc. November, 2022.|1
04251|070|R|6.Chewtadzy (tadalafil chewable tablets) US prescribing information. ANI|1
04251|071|R|  Pharmaceuticals, Inc. June, 2024.|1
04252|001|T|MONOGRAPH TITLE:  Cyclosporine/Lenacapavir|
04252|002|B||
04252|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04252|004|L|take action as needed.|
04252|005|B||
04252|006|A|MECHANISM OF ACTION:  Lenacapavir may inhibit the metabolism of cyclosporine|
04252|007|A|by CYP3A4.|
04252|008|B||
04252|009|E|CLINICAL EFFECTS:  Concurrent use of lenacapavir may result in elevated|
04252|010|E|levels of and toxicity from cyclosporine.|
04252|011|B||
04252|012|P|PREDISPOSING FACTORS:  None determined.|
04252|013|B||
04252|014|M|PATIENT MANAGEMENT:  Monitor cyclosporine levels and kidney function in|
04252|015|M|patients in whom lenacapavir is initiated, adjusted, or discontinued.  The|
04252|016|M|dosage of cyclosporine may need to be adjusted or lenacapavir may need to be|
04252|017|M|discontinued.|
04252|018|B||
04252|019|D|DISCUSSION:  In a study, simultaneous administration of midazolam (2.5 mg|
04252|020|D|single dose) with lenacapavir resulted in an increase in the maximum|
04252|021|D|concentration (Cmax) and area-under-the-curve (AUC) of midazolam by|
04252|022|D|1.94-fold and 3.59 fold and 1-hydroxymidazolam of 0.54-fold and 0.76-fold.|
04252|023|D|Administration of midazolam (2.5 mg single dose) one day after lenacapavir|
04252|024|D|resulted in an increase in Cmax and AUC of 2.16-fold and 4.08 fold and|
04252|025|D|1-hydroxymidazolam of 0.52-fold and 0.84-fold.|
04252|026|B||
04252|027|R|REFERENCES:|
04252|028|B||
04252|029|R|1.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04252|030|R|  November 2024.|1
04252|031|R|2.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04252|032|R|  Sciences Ireland UC August, 2022.|1
04252|033|R|3.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04252|034|R|  Inc. November, 2022.|1
04252|035|R|4.This information is based on an extract from the Certara Drug Interaction|6
04252|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04253|001|T|MONOGRAPH TITLE:  Lovastatin; Simvastatin/Lenacapavir|
04253|002|B||
04253|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04253|004|L|take action as needed.|
04253|005|B||
04253|006|A|MECHANISM OF ACTION:  Lenacapavir may inhibit the metabolism of lovastatin|
04253|007|A|and simvastatin by CYP3A4.(1)|
04253|008|B||
04253|009|E|CLINICAL EFFECTS:  Concurrent use of lenacapavir may result in elevated|
04253|010|E|levels and side effects of lovastatin or simvastatin, including|
04253|011|E|rhabdomyolysis.(1,2)|
04253|012|B||
04253|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04253|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04253|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04253|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04253|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04253|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04253|019|P|predisposed to myopathy or rhabdomyolysis.|
04253|020|B||
04253|021|M|PATIENT MANAGEMENT:  The manufacturer of lenacapavir recommends initiating|
04253|022|M|lovastatin or simvastatin with the lowest starting dose and titrating|
04253|023|M|carefully.(1-3) Patients receiving concurrent therapy with lenacapavir and|
04253|024|M|lovastatin or simvastatin should be carefully monitored for adverse effects,|
04253|025|M|including rhabdomyolysis.|
04253|026|B||
04253|027|D|DISCUSSION:  Concurrent administration of lenacapavir 600 mg with a single|
04253|028|D|2.5 mg dose of midazolam (a CYP3A4 substrate) increased midazolam maximum|
04253|029|D|concentration (Cmax) and area-under-curve (AUC) by 1.94-fold and 3.59-fold,|
04253|030|D|respectively.(1-3)|
04253|031|B||
04253|032|R|REFERENCES:|
04253|033|B||
04253|034|R|1.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04253|035|R|  November 2024.|1
04253|036|R|2.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04253|037|R|  Sciences Ireland UC August, 2022.|1
04253|038|R|3.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04253|039|R|  Inc. November, 2022.|1
04253|040|R|4.O'Brien SG, Meinhardt P, Bond E, Beck J, Peng B, Dutreix C, Mehring G,|2
04253|041|R|  Milosavljev S, Huber C, Capdeville R, Fischer T. Effects of imatinib|2
04253|042|R|  mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a|2
04253|043|R|  cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia.|2
04253|044|R|  Br J Cancer 2003 Nov 17;89(10):1855-9.|2
04254|001|T|MONOGRAPH TITLE:  Midazolam; Triazolam/Lenacapavir|
04254|002|B||
04254|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04254|004|L|take action as needed.|
04254|005|B||
04254|006|A|MECHANISM OF ACTION:  Lenacapavir is a moderate inhibitor of CYP3A4 and may|
04254|007|A|decrease metabolism of midazolam and triazolam.(1-3)|
04254|008|B||
04254|009|E|CLINICAL EFFECTS:  Concurrent administration of lenacapavir and midazolam or|
04254|010|E|triazolam may result in increased clinical effects (e.g. profound sedation,|
04254|011|E|respiratory depression, coma, and/or death) of midazolam or triazolam.(1-3)|
04254|012|E|   CYP3A4 is the major or only hepatic metabolism pathway for the phase I|
04254|013|E|elimination of midazolam.|
04254|014|B||
04254|015|P|PREDISPOSING FACTORS:  None determined.|
04254|016|B||
04254|017|M|PATIENT MANAGEMENT:  The manufacturer of lenacapavir states concurrent use|
04254|018|M|with midazolam or triazolam should be approached with caution.(1-3)|
04254|019|M|   Monitor patients for unusual dizziness or lightheadedness, extreme|
04254|020|M|sleepiness, slowed or difficult breathing, or unresponsiveness.|
04254|021|B||
04254|022|D|DISCUSSION:  Concurrent administration of lenacapavir 600 mg with a single|
04254|023|D|2.5 mg dose of midazolam increased midazolam maximum concentration (Cmax)|
04254|024|D|and area-under-curve (AUC) by 1.94-fold and 3.59-fold, respectively.(1-3)|
04254|025|B||
04254|026|R|REFERENCES:|
04254|027|B||
04254|028|R|1.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04254|029|R|  November 2024.|1
04254|030|R|2.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04254|031|R|  Sciences Ireland UC August, 2022.|1
04254|032|R|3.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04254|033|R|  Inc. November, 2022.|1
04254|034|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04254|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04254|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04254|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04254|038|R|  11/14/2017.|1
04254|039|R|5.This information is based on an extract from the Certara Drug Interaction|6
04254|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04255|001|T|MONOGRAPH TITLE:  Lenacapavir/Pexidartinib|
04255|002|B||
04255|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04255|004|L|of severe adverse interaction.|
04255|005|B||
04255|006|A|MECHANISM OF ACTION:  Lenacapavir and pexidartinib are both metabolized by|
04255|007|A|CYP3A4.  Pexidartinib is a moderate CYP3A4 inducer while lenacapavir is a|
04255|008|A|moderate CYP3A4 inhibitor.(1-4)|
04255|009|B||
04255|010|E|CLINICAL EFFECTS:  The net effect of coadministration of lenacapavir and|
04255|011|E|pexidartinib on CYP3A4 enzyme activity is unknown.  Concurrent or recent use|
04255|012|E|of pexidartinib may either decrease the clinical effectiveness of|
04255|013|E|lenacapavir or increase the levels and toxicities of pexidartinib.(1-4)|
04255|014|B||
04255|015|P|PREDISPOSING FACTORS:  None determined.|
04255|016|B||
04255|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04255|018|M|lenacapavir with pexidartinib.  Concurrent therapy is not recommended.  If|
04255|019|M|use of this combination is necessary, the patient should be closely|
04255|020|M|monitored for lenacapavir efficacy and pexidartinib toxicity.|
04255|021|M|   The manufacturer of lenacapavir states concurrent use with moderate|
04255|022|M|CYP3A4 inducers is not recommended.(1-3)|
04255|023|M|   Lenacapavir has a long half-life and may increase the levels of CYP3A4|
04255|024|M|substrates initiated within 9 months after the last dose of subcutaneous|
04255|025|M|lenacapavir.(1-3)|
04255|026|M|   The manufacturer of pexidartinib makes the recommendations below for|
04255|027|M|concurrent use with moderate CYP3A4 inhibitors.|
04255|028|M|   Coadministration with moderate inhibitors of CYP3A4 should be avoided.(4)|
04255|029|M|If coadministration with a moderate CYP3A4 inhibitor cannot be avoided,|
04255|030|M|reduce the pexidartinib dose according to the following recommendations.|
04255|031|M|   If the planned total daily dose is currently 800 mg, modify the total|
04255|032|M|daily dose to 400 mg by administering 200 mg twice daily.|
04255|033|M|   If the planned total daily dose is currently 600 mg, modify the total|
04255|034|M|daily dose to 400 mg by administering 200 mg twice daily.|
04255|035|M|   If the planned total daily dose is currently 400 mg, modify the total|
04255|036|M|daily dose to 200 mg by administering 200 mg once daily.|
04255|037|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
04255|038|M|increase the pexidartinib dose to the dose that was used before starting the|
04255|039|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
04255|040|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04255|041|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04255|042|M|recommendations in the Turalio package insert.  Advise patients to|
04255|043|M|immediately report any symptoms of hepatotoxicity.|
04255|044|B||
04255|045|D|DISCUSSION:  In a study, efavirenz 600 mg once daily (inducer of CYP3A4|
04255|046|D|[moderate] and P-glycoprotein) decreased the maximum concentration (Cmax)|
04255|047|D|and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1)|
04255|048|D|   Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased|
04255|049|D|pexidartinib Cmax and AUC by 41% and 67%, respectively.(4)|
04255|050|B||
04255|051|R|REFERENCES:|
04255|052|B||
04255|053|R|1.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04255|054|R|  November 2024.|1
04255|055|R|2.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04255|056|R|  Sciences Ireland UC August, 2022.|1
04255|057|R|3.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04255|058|R|  Inc. November, 2022.|1
04255|059|R|4.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04255|060|R|  November, 2023.|1
04255|061|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04255|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04255|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04255|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04255|065|R|  11/14/2017.|1
04255|066|R|6.This information is based on an extract from the Certara Drug Interaction|6
04255|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04256|001|T|MONOGRAPH TITLE:  Lenacapavir/Pexidartinib (125 mg)|
04256|002|B||
04256|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04256|004|L|of severe adverse interaction.|
04256|005|B||
04256|006|A|MECHANISM OF ACTION:  Lenacapavir and pexidartinib are both metabolized by|
04256|007|A|CYP3A4.  Pexidartinib is a moderate CYP3A4 inducer while lenacapavir is a|
04256|008|A|moderate CYP3A4 inhibitor.(1-4)|
04256|009|B||
04256|010|E|CLINICAL EFFECTS:  The net effect of coadministration of lenacapavir and|
04256|011|E|pexidartinib on CYP3A4 enzyme activity is unknown.  Concurrent or recent use|
04256|012|E|of pexidartinib may either decrease the clinical effectiveness of|
04256|013|E|lenacapavir or increase the levels and toxicities of pexidartinib.(1-4|
04256|014|B||
04256|015|P|PREDISPOSING FACTORS:  None determined.|
04256|016|B||
04256|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04256|018|M|lenacapavir with pexidartinib.  Concurrent therapy is not recommended.  If|
04256|019|M|use of this combination is necessary, the patient should be closely|
04256|020|M|monitored for lenacapavir efficacy and pexidartinib toxicity.|
04256|021|M|   The manufacturer of lenacapavir states concurrent use with moderate|
04256|022|M|CYP3A4 inducers is not recommended.(1-3)|
04256|023|M|   Lenacapavir has a long half-life and may increase the levels of CYP3A4|
04256|024|M|substrates initiated within 9 months after the last dose of subcutaneous|
04256|025|M|lenacapavir.(1-3)|
04256|026|M|   The manufacturer of pexidartinib makes the recommendations below for|
04256|027|M|concurrent use with CYP3A4 inhibitors.|
04256|028|M|   Coadministration with moderate inhibitors of CYP3A4 should be avoided.(4)|
04256|029|M|If coadministration with a moderate CYP3A4 inhibitor cannot be avoided,|
04256|030|M|reduce the pexidartinib dose according to the following recommendations.|
04256|031|M|   If the planned total daily dose is currently 500 mg, modify the total|
04256|032|M|daily dose to 250 mg by administering 125 mg twice daily.|
04256|033|M|   If the planned total daily dose is currently 375 mg, modify the total|
04256|034|M|daily dose to 250 mg by administering 125 mg twice daily.|
04256|035|M|   If the planned total daily dose is currently 250 mg, modify the total|
04256|036|M|daily dose to 125 mg by administering 125 mg once daily.|
04256|037|M|   If concomitant use of a moderate CYP3A4 inhibitor is discontinued,|
04256|038|M|increase the pexidartinib dose to the dose that was used before starting the|
04256|039|M|inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor.|
04256|040|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04256|041|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04256|042|M|recommendations in the Turalio package insert.  Advise patients to|
04256|043|M|immediately report any symptoms of hepatotoxicity.|
04256|044|B||
04256|045|D|DISCUSSION:  In a study, efavirenz 600 mg once daily (inducer of CYP3A4|
04256|046|D|[moderate] and P-glycoprotein) decreased the maximum concentration (Cmax)|
04256|047|D|and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1)|
04256|048|D|   Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased|
04256|049|D|pexidartinib Cmax and AUC by 41% and 67%, respectively.(4)|
04256|050|B||
04256|051|R|REFERENCES:|
04256|052|B||
04256|053|R|1.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04256|054|R|  November 2024.|1
04256|055|R|2.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04256|056|R|  Sciences Ireland UC August, 2022.|1
04256|057|R|3.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04256|058|R|  Inc. November, 2022.|1
04256|059|R|4.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04256|060|R|  November, 2023.|1
04256|061|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04256|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04256|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04256|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04256|065|R|  11/14/2017.|1
04256|066|R|6.This information is based on an extract from the Certara Drug Interaction|6
04256|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04257|001|T|MONOGRAPH TITLE:  Lenacapavir/Bosentan|
04257|002|B||
04257|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04257|004|L|of severe adverse interaction.|
04257|005|B||
04257|006|A|MECHANISM OF ACTION:  Lenacapavir and bosentan are both metabolized by|
04257|007|A|CYP3A4.  Bosentan is a moderate CYP3A4 inducer while lenacapavir is a|
04257|008|A|moderate CYP3A4 inhibitor.(1-4)|
04257|009|B||
04257|010|E|CLINICAL EFFECTS:  The net effect of coadministration of lenacapavir and|
04257|011|E|bosentan on CYP3A4 enzyme activity is unknown.  Concurrent or recent use of|
04257|012|E|lenacapavir may either decrease the clinical effectiveness of|
04257|013|E|lenacapavir(1-3) or increase the levels and toxicities of bosentan.(4)|
04257|014|B||
04257|015|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, lenacapavir, and a CYP2C9|
04257|016|P|inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
04257|017|P|sulfinpyrazone, or phenylbutazone)(6) could lead to blockade of both major|
04257|018|P|metabolic pathways for bosentan, resulting in large increases in bosentan|
04257|019|P|plasma concentrations.(4)|
04257|020|B||
04257|021|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04257|022|M|lenacapavir with bosentan.  Concurrent therapy is not recommended.  If use|
04257|023|M|of this combination is necessary, the patient should be closely monitored|
04257|024|M|for lenacapavir efficacy and bosentan toxicity.|
04257|025|M|   The manufacturer of lenacapavir states that concurrent use with moderate|
04257|026|M|CYP3A4 inducers is not recommended.(1-3)|
04257|027|M|   Lenacapavir has a long half-life and may increase the levels of CYP3A4|
04257|028|M|substrates initiated within 9 months after the last dose of subcutaneous|
04257|029|M|lenacapavir.(1-3)|
04257|030|M|   The manufacturer of bosentan makes the recommendations below for|
04257|031|M|concurrent use with CYP3A4 inhibitors.|
04257|032|M|   Review medication list to see if patient is also receiving a CYP2C9|
04257|033|M|inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
04257|034|M|sulfinpyrazone, or phenylbutazone).|
04257|035|M|   Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended|
04257|036|M|by the manufacturer as the combination may lead to large increases in|
04257|037|M|bosentan plasma concentrations.(4)|
04257|038|M|   For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated,|
04257|039|M|monitor tolerance to concomitant therapy and adjust bosentan dose if needed.|
04257|040|B||
04257|041|D|DISCUSSION:  In a study, efavirenz 600 mg once daily (inducer of CYP3A4|
04257|042|D|[moderate] and P-glycoprotein) decreased the maximum concentration (Cmax)|
04257|043|D|and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1-3)|
04257|044|D|   In a study in healthy subjects, concurrent bosentan and ketoconazole (a|
04257|045|D|strong CYP3A4 inhibitor) administration increased bosentan steady-state Cmax|
04257|046|D|and AUC by 2.1-fold and 2.3-fold, respectively.(4)|
04257|047|B||
04257|048|R|REFERENCES:|
04257|049|B||
04257|050|R|1.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04257|051|R|  November 2024.|1
04257|052|R|2.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04257|053|R|  Inc. November, 2022.|1
04257|054|R|3.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04257|055|R|  Sciences Ireland UC August, 2022.|1
04257|056|R|4.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
04257|057|R|  US, Inc. September 5, 2017.|1
04257|058|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04257|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04257|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04257|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04257|062|R|  11/14/2017.|1
04257|063|R|6.This information is based on an extract from the Certara Drug Interaction|6
04257|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04258|001|T|MONOGRAPH TITLE:  Lenacapavir/Mitapivat|
04258|002|B||
04258|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04258|004|L|of severe adverse interaction.|
04258|005|B||
04258|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may accelerate the|
04258|007|A|metabolism of lenacapavir.(1-3)  Mitapivat is a moderate CYP3A4 inducer.|
04258|008|A|   Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(4)|
04258|009|A|Lenacapavir is a moderate CYP3A4 inhibitor.|
04258|010|B||
04258|011|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
04258|012|E|alter the clinical effectiveness of lenacapavir.(1-3)|
04258|013|E|   Concurrent use of a moderate inhibitor of CYP3A4 may result in increased|
04258|014|E|levels of and effects from mitapivat including decreased estrone and|
04258|015|E|estradiol levels in males, increased urate, back pain, and arthralgias.(4)|
04258|016|B||
04258|017|P|PREDISPOSING FACTORS:  None determined.|
04258|018|B||
04258|019|M|PATIENT MANAGEMENT:  The concurrent use of lenacapavir with moderate CYP3A4|
04258|020|M|inducers is not recommended.(1-3)|
04258|021|M|   Lenacapavir has a long half-life and may increase the levels of CYP3A4|
04258|022|M|substrates initiated within 9 months after the last dose of subcutaneous|
04258|023|M|lenacapavir.(1-3)|
04258|024|M|   The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be|
04258|025|M|monitored closely for increased risk of adverse reactions.  The US|
04258|026|M|manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg|
04258|027|M|twice daily with concurrent moderate CYP3A4 inhibitors.(4)  The Middle|
04258|028|M|Eastern manufacturer of mitapivat states that alternative agents that do not|
04258|029|M|inhibit CYP3A4 should be considered.  If concomitant use of a moderate|
04258|030|M|CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100|
04258|031|M|mg once daily.(5)|
04258|032|B||
04258|033|D|DISCUSSION:  In a study, efavirenz 600 mg once daily (inducer of CYP3A4|
04258|034|D|[moderate] and P-glycoprotein) decreased the maximum concentration (Cmax)|
04258|035|D|and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1)|
04258|036|D|   Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study with|
04258|037|D|mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole (a moderate CYP3A4|
04258|038|D|inhibitor) increased mitapivat AUC and Cmax by 2.6-fold and 1.6-fold,|
04258|039|D|respectively.(4)|
04258|040|B||
04258|041|R|REFERENCES:|
04258|042|B||
04258|043|R|1.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04258|044|R|  Sciences Ireland UC August, 2022.|1
04258|045|R|2.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04258|046|R|  November 2024.|1
04258|047|R|3.Sunlenca (lenacapavir) Canadian Product Monograph. Gilead Sciences Canada,|1
04258|048|R|  Inc. November, 2022.|1
04258|049|R|4.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04258|050|R|  February, 2022.|1
04258|051|R|5.Pyrukynd (mitapivat) Middle East Prescribing Information. Agios|1
04258|052|R|  Pharmaceuticals, Inc. July, 2025.|1
04258|053|R|6.This information is based on an extract from the Certara Drug Interaction|6
04258|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04259|001|T|MONOGRAPH TITLE:  Non-Live or Non-Replicating Vaccines/Ublituximab|
04259|002|B||
04259|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04259|004|L|take action as needed.|
04259|005|B||
04259|006|A|MECHANISM OF ACTION:  Ublituximab is an immunosuppressant and may alter the|
04259|007|A|immune system's response to vaccines.(1)|
04259|008|B||
04259|009|E|CLINICAL EFFECTS:  Administration of a non-live vaccine within 2 weeks|
04259|010|E|before or during ublituximab therapy may result in decreased effectiveness|
04259|011|E|of the vaccine.  If possible, non-live vaccines should be administered at|
04259|012|E|least two weeks prior to initiating ublituximab therapy.(1)|
04259|013|B||
04259|014|P|PREDISPOSING FACTORS:  None determined.|
04259|015|B||
04259|016|M|PATIENT MANAGEMENT:  Ideally, administer non-live vaccines at least two|
04259|017|M|weeks prior to initiating ublituximab therapy.|
04259|018|M|   The immune response to non-live vaccines should be monitored in patients|
04259|019|M|receiving ublituximab.  Vaccinations given during ublituximab therapy may|
04259|020|M|need to be repeated.(1)|
04259|021|M|   Patients who are vaccinated within the 14 days prior to initiating|
04259|022|M|immunosuppressive therapy should be considered unvaccinated and should be|
04259|023|M|revaccinated at least 3 months after immunosuppressive therapy is|
04259|024|M|discontinued when immune competence is restored.(2)|
04259|025|B||
04259|026|D|DISCUSSION:  Vaccinations may be less effective if administered within 2|
04259|027|D|weeks before or during ublituximab treatment.(1)|
04259|028|B||
04259|029|R|REFERENCES:|
04259|030|B||
04259|031|R|1.Briumvi (ublituximab-xiiy) US prescribing information. TG Therapeutics|1
04259|032|R|  December, 2022.|1
04259|033|R|2.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
04259|034|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
04259|035|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
04259|036|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
04259|037|R|  recs.pdf February 10, 2023;1-197.|6
04260|001|T|MONOGRAPH TITLE:  Ublituximab/Immunosuppressives; Immunomodulators|
04260|002|B||
04260|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04260|004|L|take action as needed.|
04260|005|B||
04260|006|A|MECHANISM OF ACTION:  Ublituximab, immunosuppressives, and immunomodulators|
04260|007|A|all suppress the immune system.(1)|
04260|008|B||
04260|009|E|CLINICAL EFFECTS:  Concurrent use of ublituximab with immunosuppressive or|
04260|010|E|immunomodulating agents may result in an increased risk for serious|
04260|011|E|infections.(1)|
04260|012|B||
04260|013|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
04260|014|P|immunosuppressive or immune-modulating medications.|
04260|015|B||
04260|016|M|PATIENT MANAGEMENT:  The US manufacturer of ublituximab recommends caution|
04260|017|M|because the concurrent use of ublituximab with immunomodulating or|
04260|018|M|immunosuppressive agents, including immunosuppressant doses of|
04260|019|M|corticosteroids, may increase the risk of infection.(1)|
04260|020|M|   If concurrent therapy is warranted, consider the risk of additive immune|
04260|021|M|suppression and monitor based on prescribing information for both agents.|
04260|022|M|   When switching from agents with immune effects, the half-life and|
04260|023|M|mechanism of action of these drugs must be taken into consideration in order|
04260|024|M|to prevent additive immunosuppressive effects.(1)|
04260|025|B||
04260|026|D|DISCUSSION:  The most common infections reported by ublituximab-treated|
04260|027|D|patients in the clinical trial periods included upper respiratory tract|
04260|028|D|infections and urinary tract infections.  Serious, including|
04260|029|D|life-threatening or fatal, bacterial and viral infections were observed in|
04260|030|D|patients receiving ublituximab.(1)|
04260|031|D|   Serious and/or fatal bacterial, fungal, and new or reactivated viral|
04260|032|D|infections have been associated with other anti-CD20 B-cell depleting|
04260|033|D|therapies.  There were no cases of progressive multifocal|
04260|034|D|leukoencephalopathy (PML) reported during the clinical trials; however,|
04260|035|D|there have been reports of PML during or following completion of other|
04260|036|D|anti-CD20 B-cell depleting therapies.(1)|
04260|037|B||
04260|038|R|REFERENCE:|
04260|039|B||
04260|040|R|1.Briumvi (ublituximab-xiiy) US prescribing information. TG Therapeutics|1
04260|041|R|  December, 2022.|1
04261|001|T|MONOGRAPH TITLE:  Dextromethorphan/Selected Serotonergic Agents|
04261|002|B||
04261|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04261|004|L|take action as needed.|
04261|005|B||
04261|006|A|MECHANISM OF ACTION:  Dextromethorphan inhibits neuronal reuptake of|
04261|007|A|serotonin.  Concurrent administration with one or more serotonergic agents|
04261|008|A|may increase serotonin effects, leading to serotonin toxicity.(1-11)|
04261|009|B||
04261|010|E|CLINICAL EFFECTS:  The concurrent use of dextromethorphan with serotonergic|
04261|011|E|agents may increase the risk for serotonin syndrome.  Serotonin syndrome|
04261|012|E|constitutes a range of toxicities from mild to life threatening.(3)|
04261|013|E|   Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis,|
04261|014|E|intermittent tremor, and/or myoclonus.(3)|
04261|015|E|   Moderate serotonin symptoms may include: tachycardia, hypertension,|
04261|016|E|hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds,|
04261|017|E|hyperreflexia, and/OR clonus.(3)|
04261|018|E|   Severe serotonin symptoms may include: severe hypertension and|
04261|019|E|tachycardia, shock, agitated delirium, muscular rigidity, and/or|
04261|020|E|hypertonicity.(3)|
04261|021|B||
04261|022|P|PREDISPOSING FACTORS:  Concurrent use of additional drugs which increase CNS|
04261|023|P|serotonin levels would be expected to further increase risk for serotonin|
04261|024|P|syndrome.(1-11)|
04261|025|B||
04261|026|M|PATIENT MANAGEMENT:  Monitor patients on multiple serotonergic agents for|
04261|027|M|symptoms of serotonin toxicity.  Patients in whom serotonin syndrome is|
04261|028|M|suspected should receive immediate medical attention.  If the interacting|
04261|029|M|agents are prescribed by different providers, it would be prudent to assure|
04261|030|M|that both are aware of concomitant therapy and monitoring the patient for|
04261|031|M|serotonin toxicities.  Advise patients not to exceed recommended dosages of|
04261|032|M|dextromethorphan.|
04261|033|M|   If concurrent therapy is warranted, patients should be monitored for|
04261|034|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
04261|035|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
04261|036|M|heart palpitations, restlessness, confusion, agitation, trouble with|
04261|037|M|coordination, or severe diarrhea.|
04261|038|B||
04261|039|D|DISCUSSION:  Dextromethorphan inhibits neuronal reuptake of serotonin and|
04261|040|D|may potentially precipitate dose-dependant serotonin toxicity in conjunction|
04261|041|D|with other serotonergic agents.(4,5)|
04261|042|D|   Serotonin syndrome has been reported in patients following the addition|
04261|043|D|of dextromethorphan containing cough syrups to duloxetine,(6)|
04261|044|D|escitalopram,(7) fluoxetine,(8,9) paroxetine,(10) and sertraline.(11)|
04261|045|D|   Selected serotonergic agents linked to this monograph include:|
04261|046|D|citalopram, clomipramine, duloxetine, escitalopram, fluvoxamine, imipramine,|
04261|047|D|levomilnacipran, milnacipran, sertraline, venlafaxine, vilazodone and|
04261|048|D|vortioxetine.|
04261|049|B||
04261|050|R|REFERENCES:|
04261|051|B||
04261|052|R|1.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
04261|053|R|  Technologies January, 2017.|1
04261|054|R|2.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
04261|055|R|  and Company August, 2023.|1
04261|056|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04261|057|R|  352(11):1112-20.|6
04261|058|R|4.Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin|6
04261|059|R|  toxicity. Br J Anaesth 2005 Oct;95(4):434-41.|6
04261|060|R|5.Schwartz AR, Pizon AF, Brooks DE. Dextromethorphan-induced serotonin|3
04261|061|R|  syndrome. Clin Toxicol (Phila) 2008 Sep;46(8):771-3.|3
04261|062|R|6.Hardy M, Panikkar G. A Case of Serotonin Syndrome in the Setting of|3
04261|063|R|  Dextromethorphan-Based Cough  Medicine, Tramadol, and Multiple|3
04261|064|R|  Antidepressants. Prim Care Companion CNS Disord 2020 Mar 5;22(2):.|3
04261|065|R|7.Dy P, Arcega V, Ghali W, Wolfe W. Serotonin syndrome caused by drug to|3
04261|066|R|  drug interaction between escitalopram and  dextromethorphan. BMJ Case Rep|3
04261|067|R|  2017 Aug 7;2017:.|3
04261|068|R|8.Navarro A, Perry C, Bobo WV. A case of serotonin syndrome precipitated by|3
04261|069|R|  abuse of the anticough remedy dextromethorphan in a bipolar patient|3
04261|070|R|  treated with fluoxetine and lithium. Gen Hosp Psychiatry 2006 Jan-Feb;|3
04261|071|R|  28(1):78-80.|3
04261|072|R|9.Achamallah NS. Visual hallucinations after combining fluoxetine and|3
04261|073|R|  dextromethorphan. Am J Psychiatry 1992 Oct;149(10):1406.|3
04261|074|R|10.Skop BP, Finkelstein JA, Mareth TR, Magoon MR, Brown TM. The serotonin|3
04261|075|R|   syndrome associated with paroxetine, an over-the-counter cold remedy, and|3
04261|076|R|   vascular disease. Am J Emerg Med 1994 Nov;12(6):642-4.|3
04261|077|R|11.Sethi R, Kablinger AS, Kavuru B. Serotonin Syndrome in a|3
04261|078|R|   Sertraline-Treated Man Taking NyQuil Containing  Dextromethorphan for|3
04261|079|R|   Cold. Prim Care Companion CNS Disord 2012;14(6):.|3
04262|001|T|MONOGRAPH TITLE:  Abiraterone/Spironolactone|
04262|002|B||
04262|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04262|004|L|of severe adverse interaction.|
04262|005|B||
04262|006|A|MECHANISM OF ACTION:  When used in an androgen-deprived environment created|
04262|007|A|by abiraterone, spironolactone binds to the androgen receptor and acts as an|
04262|008|A|androgen agonist.|
04262|009|B||
04262|010|E|CLINICAL EFFECTS:  Spironolactone may increase prostate-specific antigen|
04262|011|E|(PSA) levels in metastatic prostate cancer patients on abiraterone.|
04262|012|B||
04262|013|P|PREDISPOSING FACTORS:  None determined.|
04262|014|B||
04262|015|M|PATIENT MANAGEMENT:  Concurrent use of spironolactone and abiraterone is not|
04262|016|M|recommended.|
04262|017|B||
04262|018|D|DISCUSSION:  In a case report, a 67-year-old man with metastatic|
04262|019|D|castration-resistant prostate cancer (mCRPC) on abiraterone for 6 months|
04262|020|D|with good response started spironolactone for heart failure.  His PSA rose|
04262|021|D|from 0.004 ng/mL prior to starting spironolactone to 0.93 ng/mL.  After|
04262|022|D|spironolactone discontinuation, PSA dropped to 0.38 ng/mL, but subsequently|
04262|023|D|rose again due to disease progression.(3)|
04262|024|D|   A 67-year-old man on spironolactone 25 mg daily and a history of prostate|
04262|025|D|cancer experienced bone progression and a rise in PSA.  He was started on|
04262|026|D|abiraterone 1,000 mg daily and prednisone 5 mg twice daily, but PSA|
04262|027|D|continued to rise 5 months after starting abiraterone.(3)|
04262|028|D|   In a case report, an 86-year-old man on abiraterone for mCRPC started|
04262|029|D|spironolactone and experienced biochemical and radiologic disease|
04262|030|D|progression with PSA rising from 278.7 ng/mL to 792.7 ng/mL.  After|
04262|031|D|spironolactone was discontinued, PSA dropped to 334.2 ng/mL.(4)|
04262|032|D|   A 57-year-old man with mCRPC on spironolactone failed to respond to|
04262|033|D|abiraterone and prednisone, with PSA rising from 5.97 ng/mL to 8.08 ng/mL.|
04262|034|D|Spironolactone was discontinued and PSA dropped to 2.8 ng/mL after 2 weeks|
04262|035|D|and 0.45 ng/mL after 2 months.  After 10 months on abiraterone, the patient|
04262|036|D|experienced disease progression and was switched to enzalutamide.  Eight|
04262|037|D|months later, his PSA rose slightly to 0.2 ng/mL.  He revealed that he had|
04262|038|D|been taking spironolactone for 3 weeks.  Spironolactone was stopped and PSA|
04262|039|D|dropped to 0.14 ng/mL.(5)|
04262|040|B||
04262|041|R|REFERENCES:|
04262|042|B||
04262|043|R|1.Aldactone (spironolactone) US prescribing information. Pfizer November,|1
04262|044|R|  2025.|1
04262|045|R|2.Zytiga (abiraterone) EMA Summary of Product Characteristics. Janssen-Cilag|1
04262|046|R|  International NV May, 2016.|1
04262|047|R|3.Vicente-Valor J, Escudero-Vilaplana V, Collado-Borrell R, Lopez-Lopez C,|3
04262|048|R|  Villanueva-Bueno C, Revuelta-Herrero JL, Ruiz-Briones P, Somoza-Fernandez|3
04262|049|R|  B, Herranz A, Sanjurjo M. Potential negative pharmacodynamic interaction|3
04262|050|R|  of spironolactone and abiraterone  in two prostate cancer patients. J|3
04262|051|R|  Oncol Pharm Pract 2022 Jan 17;10781552221074621.|3
04262|052|R|4.Dhondt B, Buelens S, Van Besien J, Beysens M, De Bleser E, Ost P, Lumen N.|3
04262|053|R|  Abiraterone and spironolactone in prostate cancer: a combination to avoid.|3
04262|054|R|  Acta Clin Belg 2019 Dec;74(6):439-444.|3
04262|055|R|5.Flynn T, Guancial EA, Kilari M, Kilari D. Case Report: Spironolactone|3
04262|056|R|  Withdrawal Associated With a Dramatic Response in a  Patient With|3
04262|057|R|  Metastatic Castrate-Resistant Prostate Cancer. Clin Genitourin Cancer 2017|3
04262|058|R|  Feb;15(1):e95-e97.|3
04263|001|T|MONOGRAPH TITLE:  Tacrolimus (Extended Release)/Alcohol|
04263|002|B||
04263|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04263|004|L|of severe adverse interaction.|
04263|005|B||
04263|006|A|MECHANISM OF ACTION:  Concomitant use of alcohol with tacrolimus extended|
04263|007|A|release formulations may result in increased tacrolimus levels in the blood|
04263|008|A|due to a rapid release of tacrolimus.(1-5)|
04263|009|B||
04263|010|E|CLINICAL EFFECTS:  Concurrent use of alcohol may result in a faster release|
04263|011|E|of tacrolimus and interfere with the extended release characteristics of the|
04263|012|E|formulation, potentially increasing absorption and blood levels of|
04263|013|E|tacrolimus.  Increased levels of tacrolimus may increase the risk of|
04263|014|E|toxicities, including nephrotoxicity, neurotoxicity, and QT prolongation.(1)|
04263|015|B||
04263|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04263|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04263|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04263|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04263|020|P|gender, or advanced age.|
04263|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04263|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04263|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04263|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04263|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04263|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04263|027|P|dysfunction).|
04263|028|B||
04263|029|M|PATIENT MANAGEMENT:  The manufacturers of tacrolimus extended release|
04263|030|M|formulations state that the concurrent use of alcohol is not|
04263|031|M|recommended.(1-4)|
04263|032|M|   Patients are advised to avoid alcohol while taking this product.|
04263|033|B||
04263|034|D|DISCUSSION:  In vitro dissolution studies evaluated the potential for|
04263|035|D|alcohol-induced dose-dumping with extended release tacrolimus products in|
04263|036|D|the presence of alcohol at varying alcohol concentrations (5, 10, 20, and|
04263|037|D|40%).(3-5)|
04263|038|D|   Data from the manufacturer of tacrolimus extended release tablets show|
04263|039|D|there is no alcohol-induced dose-dumping in the various alcohol|
04263|040|D|concentrations.  However, the rate of drug release was increased by 10% (5%|
04263|041|D|to 15%) at 2.5 hours in the presence of roughly 40% alcohol at pH 1.2 for|
04263|042|D|the 0.75 mg, 1 mg, and 4 mg tablet.(4)|
04263|043|D|   Data from in vitro studies regarding tacrolimus extended release capsules|
04263|044|D|found an average of 35% and 25% of the dose was released at 0.5 hour for the|
04263|045|D|0.5 mg and 5 mg strengths respectively at a pH of 1.2 in an alcohol|
04263|046|D|concentration of 20%.  At an alcohol concentration of 40%, the amount of the|
04263|047|D|dose released at 0.5 hour was 89% and 54% for the 0.5 mg and 5 mg|
04263|048|D|strengths.(3,5)|
04263|049|B||
04263|050|R|REFERENCES:|
04263|051|B||
04263|052|R|1.Astagraf XL (tacrolimus extended-release capsules) US prescribing|1
04263|053|R|  information. Astellas Pharma US, Inc. August, 2023.|1
04263|054|R|2.Envarsus XR (tarolimus extended-release tablets) US prescribing|1
04263|055|R|  information. Veloxis Pharmaceuticals September, 2023.|1
04263|056|R|3.US Food and Drug Administration (FDA). Drug Approval Package Astagraf XL|1
04263|057|R|  (tacrolimus extended-release capsules) Application No.: 204096. Accessed|1
04263|058|R|  at:|1
04263|059|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204096Orig1s000Cli|1
04263|060|R|  nPharmR.pdf July 19, 2013.|1
04263|061|R|4.US Food and Drug Administration (FDA). Drug Approval Package Envarsus XR|1
04263|062|R|  (tacrolimus extended-release tablets) Application No.: 206406Orig1.|1
04263|063|R|  Accessed at:|1
04263|064|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206406Orig1s000Cli|1
04263|065|R|  nPharmR.pdf July 10, 2015.|1
04263|066|R|5.Tanzi MG, Undre N, Keirns J, Fitzsimmons WE, Brown M, First MR.|6
04263|067|R|  Pharmacokinetics of prolonged-release tacrolimus and implications for use|6
04263|068|R|  in  solid organ transplant recipients. Clin Transplant 2016 Aug;|6
04263|069|R|  30(8):901-11.|6
04264|001|T|MONOGRAPH TITLE:  Pemetrexed/Proton Pump Inhibitors|
04264|002|B||
04264|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04264|004|L|of severe adverse interaction.|
04264|005|B||
04264|006|A|MECHANISM OF ACTION:  Proton pump inhibitors may inhibit the active|
04264|007|A|secretion of pemetrexed from the kidney via the organic anion transporter 3|
04264|008|A|(OAT3).(1,2,3)|
04264|009|B||
04264|010|E|CLINICAL EFFECTS:  The concurrent use of pemetrexed and proton pump|
04264|011|E|inhibitors may result in increased levels and toxicities of pemetrexed,|
04264|012|E|including severe neurotoxicity, stomatitis, and myelosuppression, including|
04264|013|E|neutropenia.|
04264|014|B||
04264|015|P|PREDISPOSING FACTORS:  Risk factors for pemetrexed toxicity include|
04264|016|P|high-dose oncology regimens, impaired renal function, and concurrent use of|
04264|017|P|nephrotoxic medications.|
04264|018|B||
04264|019|M|PATIENT MANAGEMENT:  For patients receiving pemetrexed, consider|
04264|020|M|discontinuation of proton pump inhibitors for the duration of pemetrexed|
04264|021|M|therapy.  If concurrent use cannot be avoided, monitor closely for elevated|
04264|022|M|pemetrexed levels and toxicity.|
04264|023|B||
04264|024|D|DISCUSSION:  A prospective observational study of 156 patients receiving|
04264|025|D|pemetrexed-based therapy found that severe hematological toxicity, namely|
04264|026|D|neutropenia and anemia, occurred in 34/55 patients (61.8%) taking concurrent|
04264|027|D|proton pump inhibitors (PPIs) and in 36/101 patients (35.6%) who did not|
04264|028|D|consume PPIs.  In Cox regression multivariable analysis, the hazard ratio|
04264|029|D|for severe hematological toxicity with PPI use was 2.51 (95% CI =|
04264|030|D|1.47-4.26).  Esomeprazole, pantoprazole, and lansoprazole were the most|
04264|031|D|consumed PPIs in the study, but no correlation was investigated.(1)|
04264|032|D|   A retrospective review of 61 patients investigated medication-related|
04264|033|D|causes of severe hematological toxicity in patients on|
04264|034|D|pemetrexed/carboplatin chemotherapy.  Twenty-three patients took PPIs:|
04264|035|D|lansoprazole (n=16), esomeprazole (n=5), omeprazole (n=1), and rabeprazole|
04264|036|D|(n=1).  In a multiple logistic regression analysis, use of PPIs in patients|
04264|037|D|receiving pemetrexed/carboplatin combination chemotherapy was associated|
04264|038|D|severe hematotoxicity (odds ratio: 5.34, 95% CI: 1.06-26.94, P = 0.042).(2)|
04264|039|D|   In an in vitro analysis and retrospective study, lansoprazole,|
04264|040|D|rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan were|
04264|041|D|shown to inhibit OAT3-mediated uptake of pemetrexed, with lansoprazole|
04264|042|D|having the greatest inhibitory effect.  In the multivariate analysis of 108|
04264|043|D|patients, concurrent use of lansoprazole (but not other PPIs) and|
04264|044|D|pemetrexed/carboplatin was a significant risk factor for the development of|
04264|045|D|hematological toxicity (odds ratio: 10.004, P = 0.005).(3)|
04264|046|D|   In a retrospective study of 74 patients who received pemetrexed, 24|
04264|047|D|patients (32%) were on concomitant PPIs.  Pemetrexed toxicity was associated|
04264|048|D|with cystatin clearance (p=0.0135), albumin level (p=0.0333), and proton|
04264|049|D|pump inhibitors (p=0.035) on multivariate analysis.  Most patients (n=14)|
04264|050|D|took esomeprazole or omeprazole, with the remainder taking lansoprazole|
04264|051|D|(n=5), pantoprazole (n=4) or an unspecified agent.(4)|
04264|052|B||
04264|053|R|REFERENCES:|
04264|054|B||
04264|055|R|1.Slimano F, Le Bozec A, Cransac A, Foucher P, Lesauvage F, Delclaux B, Dory|2
04264|056|R|  A, Mennecier B, Bertrand B, Gubeno-Dumon MC, Dukic S, Mongaret C, Bouche|2
04264|057|R|  O, Hettler D, Boulin M, Dewolf M, Kanagaratnam L. Association between|2
04264|058|R|  proton pump inhibitors and severe hematological toxicity in  patients|2
04264|059|R|  receiving pemetrexed-based anticancer treatment: The prospective IPPEM|2
04264|060|R|  study. Lung Cancer 2022 Apr;166:114-121.|2
04264|061|R|2.Araki R, Keira T, Masuda Y, Tanaka T, Yamada H, Hamamoto T. Effects of|2
04264|062|R|  proton pump inhibitors on severe haematotoxicity induced after first|2
04264|063|R|  course of pemetrexed/carboplatin combination chemotherapy. J Clin Pharm|2
04264|064|R|  Ther 2019 Apr;44(2):276-284.|2
04264|065|R|3.Ikemura K, Hamada Y, Kaya C, Enokiya T, Muraki Y, Nakahara H, Fujimoto H,|2
04264|066|R|  Kobayashi T, Iwamoto T, Okuda M. Lansoprazole Exacerbates|2
04264|067|R|  Pemetrexed-Mediated Hematologic Toxicity by Competitive  Inhibition of|2
04264|068|R|  Renal Basolateral Human Organic Anion Transporter 3. Drug Metab Dispos|2
04264|069|R|  2016 Oct;44(10):1543-9.|2
04264|070|R|4.Bonnet M, Jouinot A, Boudou-Rouquette P, Seif V, Villeminey C, Arrondeau|2
04264|071|R|  J, Vidal M, Batista R, Wislez M, Blanchet B, Goldwasser F,|2
04264|072|R|  Thomas-Schoemann A. Predictive factors associated with pemetrexed acute|2
04264|073|R|  toxicity. Eur J Clin Pharmacol 2023 May;79(5):635-641.|2
04265|001|T|MONOGRAPH TITLE:  Pirtobrutinib/Strong CYP3A4 Inhibitors|
04265|002|B||
04265|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04265|004|L|of severe adverse interaction.|
04265|005|B||
04265|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04265|007|A|of pirtobrutinib.(1)|
04265|008|B||
04265|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04265|010|E|in increased levels of and effects from pirtobrutinib including hemorrhage|
04265|011|E|and cytopenias such as neutropenia, anemia, and thrombocytopenia.(1)|
04265|012|B||
04265|013|P|PREDISPOSING FACTORS:  None determined.|
04265|014|B||
04265|015|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04265|016|M|pirtobrutinib should be avoided.  If concurrent use cannot be avoided,|
04265|017|M|reduce the dose of pirtobrutinib by 50 mg.  If the current pirtobrutinib|
04265|018|M|dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the|
04265|019|M|duration of strong CYP3A4 inhibitor use.(1)|
04265|020|M|   After discontinuation of a strong CYP3A4 inhibitor for 5 half-lives,|
04265|021|M|resume the previous pirtobrutinib dose.(1)|
04265|022|B||
04265|023|D|DISCUSSION:  Co-administration of a single 200 mg dose of pirtobrutinib with|
04265|024|D|itraconazole (a strong CYP3A4 inhibitor) increased area-under-curve (AUC) of|
04265|025|D|pirtobrutinib by 49%.(1)|
04265|026|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04265|027|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04265|028|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
04265|029|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04265|030|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04265|031|D|troleandomycin, tucatinib, and voriconazole.(2)|
04265|032|B||
04265|033|R|REFERENCES:|
04265|034|B||
04265|035|R|1.Jaypirca (pirtobrutinib) US prescribing information. Eli Lilly January|1
04265|036|R|  2023.|1
04265|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
04265|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04266|001|T|MONOGRAPH TITLE:  Cariprazine/Strong and Moderate CYP3A4 Inducers|
04266|002|B||
04266|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04266|004|L|of severe adverse interaction.|
04266|005|B||
04266|006|A|MECHANISM OF ACTION:  Cariprazine and its major active metabolite DDCAR are|
04266|007|A|metabolized by CYP3A4.  Strong and moderate inducers of CYP3A4 may|
04266|008|A|accelerate the metabolism of cariprazine.(1-4)|
04266|009|B||
04266|010|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
04266|011|E|may result in decreased levels and effectiveness of cariprazine.(1-4)|
04266|012|B||
04266|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04266|014|P|of the inducer for longer than 1-2 weeks.|
04266|015|B||
04266|016|M|PATIENT MANAGEMENT:  The US manufacturer of cariprazine does not recommend|
04266|017|M|concurrent use of strong CYP3A4 inducers.(1)|
04266|018|M|   The Australian, Canadian, and UK manufacturers of cariprazine state that|
04266|019|M|concurrent use of strong and moderate CYP3A4 inducers is|
04266|020|M|contraindicated.(2-4)|
04266|021|B||
04266|022|D|DISCUSSION:  Cariprazine and its active metabolites are primarily|
04266|023|D|metabolized by CYP3A4.  Coadministration with CYP3A4 inducers has not been|
04266|024|D|studied and the net effect is unclear.  Due to the long half life of the|
04266|025|D|active metabolites, it takes several weeks for cariprazine to reach steady|
04266|026|D|state after dosage changes.(1)|
04266|027|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04266|028|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04266|029|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04266|030|D|rifapentine, and St. John's wort.(5-6)|
04266|031|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04266|032|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04266|033|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04266|034|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
04266|035|D|thioridazine, and tovorafenib.(5-6)|
04266|036|B||
04266|037|R|REFERENCES:|
04266|038|B||
04266|039|R|1.Vraylar (cariprazine) US prescribing information. Forest Laboratories LLC|1
04266|040|R|  November, 2024.|1
04266|041|R|2.Reagila (capriprazine) Australian Product Information. Gedeon Richter|1
04266|042|R|  Australia Pty Ltd January, 2024.|1
04266|043|R|3.Vraylar (cariprazine) Canadian Product Monograph. AbbVie Corporation March|1
04266|044|R|  6, 2024.|1
04266|045|R|4.Reagila (cariprazine) UK Summary of Product Characteristics. Recordati|1
04266|046|R|  Pharmaceuticals Limited March, 2024.|1
04266|047|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04266|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04266|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04266|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04266|051|R|  11/14/2017.|1
04266|052|R|6.This information is based on an extract from the Certara Drug Interaction|6
04266|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04267|001|T|MONOGRAPH TITLE:  Pirtobrutinib/Strong CYP3A4 Inducers|
04267|002|B||
04267|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04267|004|L|of severe adverse interaction.|
04267|005|B||
04267|006|A|MECHANISM OF ACTION:  Pirtobrutinib is metabolized by CYP3A4.  Strong|
04267|007|A|inducers of CYP3A4 may increase the metabolism of pirtobrutinib.(1)|
04267|008|B||
04267|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
04267|010|E|in decreased levels and effectiveness of pirtobrutinib.(1)|
04267|011|B||
04267|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04267|013|P|of the inducer for longer than 1-2 weeks.|
04267|014|B||
04267|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of pirtobrutinib with strong|
04267|016|M|CYP3A4 inducers.(1)|
04267|017|B||
04267|018|D|DISCUSSION:  Coadministration of a single 200 mg dose of pirtobrutinib with|
04267|019|D|rifampin (a strong CYP3A inducer) decreased the area-under-curve (AUC) of|
04267|020|D|pirtobrutinib by 71%.(1)|
04267|021|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04267|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04267|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04267|024|D|rifapentine, and St. John's wort.(2,3)|
04267|025|B||
04267|026|R|REFERENCES:|
04267|027|B||
04267|028|R|1.Jaypirca (pirtobrutinib) US prescribing information. Eli Lilly January|1
04267|029|R|  2023.|1
04267|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04267|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04267|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04267|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04267|034|R|  11/14/2017.|1
04267|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04267|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04268|001|T|MONOGRAPH TITLE:  Elacestrant/Strong and Moderate CYP3A4 Inducers|
04268|002|B||
04268|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04268|004|L|of severe adverse interaction.|
04268|005|B||
04268|006|A|MECHANISM OF ACTION:  Elacestrant is metabolized by CYP3A4.  Strong and|
04268|007|A|moderate inducers of CYP3A4 may increase the metabolism of elacestrant.(1)|
04268|008|B||
04268|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
04268|010|E|may result in decreased levels and effectiveness of elacestrant.(1)|
04268|011|B||
04268|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04268|013|P|of the inducer for longer than 1-2 weeks.|
04268|014|B||
04268|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of elacestrant with strong or|
04268|016|M|moderate CYP3A4 inducers.(1)|
04268|017|B||
04268|018|D|DISCUSSION:  Coadministration of 200 mg dose of elacestrant with rifampin (a|
04268|019|D|strong CYP3A inducer) decreased the maximum concentration (Cmax) and|
04268|020|D|area-under-curve (AUC) of elacestrant by 73% and 86%, respectively.(1)|
04268|021|D|   Efavirenz is predicted to decrease the Cmax and AUC of elacestrant by 44|
04268|022|D|to 63% and 55% to 73%, respectively.(1)|
04268|023|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04268|024|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04268|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04268|026|D|rifapentine, and St. John's wort.(2,3)|
04268|027|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04268|028|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04268|029|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04268|030|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
04268|031|D|thioridazine, and tovorafenib.(2,3)|
04268|032|B||
04268|033|R|REFERENCES:|
04268|034|B||
04268|035|R|1.Orserdu (elacestrant) US prescribing information. Stemline Therapeutics,|1
04268|036|R|  Inc. January 2023.|1
04268|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04268|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04268|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04268|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04268|041|R|  11/14/2017.|1
04268|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
04268|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04269|001|T|MONOGRAPH TITLE:  Elacestrant/Strong and Moderate CYP3A4 Inhibitors|
04269|002|B||
04269|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04269|004|L|of severe adverse interaction.|
04269|005|B||
04269|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
04269|007|A|elacestrant.(1)|
04269|008|B||
04269|009|E|CLINICAL EFFECTS:  Concomitant use of a strong or moderate CYP3A4 inhibitor|
04269|010|E|increases elacestrant plasma concentrations, which may increase the|
04269|011|E|incidence and severity of adverse reactions.(1)|
04269|012|B||
04269|013|P|PREDISPOSING FACTORS:  None determined.|
04269|014|B||
04269|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong or moderate CYP3A4|
04269|016|M|inhibitors with elacestrant.(1)|
04269|017|B||
04269|018|D|DISCUSSION:  Coadministration of itraconazole (a strong CYP3A4 inhibitor)|
04269|019|D|increased elacestrant area-under-curve (AUC) and maximum concentration|
04269|020|D|(Cmax) by 5.3-fold and 4.4-fold, respectively.(1)|
04269|021|D|   Coadministration of fluconazole (a moderate CYP3A4 inhibitor) is|
04269|022|D|predicted to increase elacestrant AUC and Cmax by 2.3-fold and 1.6-fold,|
04269|023|D|respectively.(1)|
04269|024|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
04269|025|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04269|026|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
04269|027|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04269|028|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04269|029|D|troleandomycin, tucatinib, and voriconazole.(2)|
04269|030|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
04269|031|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
04269|032|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
04269|033|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral|
04269|034|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
04269|035|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil,|
04269|036|D|and voxelotor.(2)|
04269|037|B||
04269|038|R|REFERENCES:|
04269|039|B||
04269|040|R|1.Orserdu (elacestrant) US prescribing information. Stemline Therapeutics,|1
04269|041|R|  Inc. January 2023.|1
04269|042|R|2.This information is based on an extract from the Certara Drug Interaction|6
04269|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04270|001|T|MONOGRAPH TITLE:  Digoxin/Pirtobrutinib|
04270|002|B||
04270|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04270|004|L|take action as needed.|
04270|005|B||
04270|006|A|MECHANISM OF ACTION:  Pirtobrutinib may increase the absorption of digoxin|
04270|007|A|by inhibiting P-glycoprotein (P-gp).(1)|
04270|008|B||
04270|009|E|CLINICAL EFFECTS:  Concurrent use of pirtobrutinib may result in elevated|
04270|010|E|levels of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can|
04270|011|E|include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
04270|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
04270|013|E|disturbances, and arrhythmias.|
04270|014|B||
04270|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
04270|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
04270|017|P|risk of digoxin toxicity.|
04270|018|B||
04270|019|M|PATIENT MANAGEMENT:  Monitor digoxin concentrations before and during the|
04270|020|M|administration of pirtobrutinib.  The manufacturer of digoxin recommends|
04270|021|M|decreasing the dose of digoxin by approximately 15-30% or by modifying the|
04270|022|M|dosing frequency to reduce digoxin concentrations.(2)|
04270|023|B||
04270|024|D|DISCUSSION:  A single 200 mg dose of pirtobrutinib increased the|
04270|025|D|area-under-curve (AUC) and maximum concentration (Cmax) of digoxin|
04270|026|D|(sensitive P-gp substrate) by 17% and 51%, respectively.  Multiple doses of|
04270|027|D|pirtobrutinib (200 mg daily) further increased the AUC and Cmax of digoxin|
04270|028|D|(sensitive P-gp substrate) up to 35% and 55%, respectively.(1)|
04270|029|B||
04270|030|R|REFERENCES:|
04270|031|B||
04270|032|R|1.Jaypirca (pirtobrutinib) US prescribing information. Eli Lilly January|1
04270|033|R|  2023.|1
04270|034|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
04270|035|R|  Pharmaceuticals, Inc. August, 2018.|1
04271|001|T|MONOGRAPH TITLE:  Lonafarnib/Pirtobrutinib (mono deleted 05/28/2024)|
04271|002|B||
04271|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04271|004|L|of severe adverse interaction.|
04271|005|B||
04271|006|A|MECHANISM OF ACTION:  Lonafarnib and pirtobrutinib are both CYP3A4|
04271|007|A|substrates and inhibitors.(1,2) Lonafarnib is a sensitive CYP3A4|
04271|008|A|substrate.(2)|
04271|009|B||
04271|010|E|CLINICAL EFFECTS:  Concurrent use of lonafarnib with weak CYP3A4 inhibitors|
04271|011|E|such as pirtobrutinib may increase the risk of adverse reactions of|
04271|012|E|lonafarnib including nausea and vomiting, increased liver enzymes,|
04271|013|E|myelosuppression, and hypertension.(1)|
04271|014|E|   Concurrent use of pirtobrutinib with strong CYP3A4 inhibitors such as|
04271|015|E|lonafarnib may increase levels of and effects from pirtobrutinib.(2)|
04271|016|B||
04271|017|P|PREDISPOSING FACTORS:  None determined.|
04271|018|B||
04271|019|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pirtobrutinib and|
04271|020|M|lonafarnib (1,2).|
04271|021|M|   The effect of the two-way inhibition of pirtobrutinib and lonafarnib|
04271|022|M|metabolism is unknown.  The optimal doses of pirtobrutinib and lonafarnib|
04271|023|M|when used concurrently have not been determined.  Manufacturers provide|
04271|024|M|recommendations for dose modification of pirtobrutinib and lonafarnib when|
04271|025|M|each is used with a CYP3A4 inhibitor, but the recommendations may not apply|
04271|026|M|when there is a two-way inhibition.  Dose modifications mentioned below are|
04271|027|M|informational only.|
04271|028|M|   If concurrent administration of a weak CYP3A4 inhibitor with lonafarnib|
04271|029|M|is unavoidable, reduce the dose of lonafarnib to 115 mg/m2 or continue at|
04271|030|M|115 mg/m2 without further dosage increases.(1)|
04271|031|M|   Closely monitor patients for arrhythmias and events such as syncope and|
04271|032|M|heart palpitations because lonafarnib exposures may be increased despite the|
04271|033|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
04271|034|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
04271|035|M|inhibitor.(1)|
04271|036|M|   If concurrent administration of a strong CYP3A4 inhibitor with|
04271|037|M|pirtobrutinib is unavoidable, reduce the dose of pirtobrutinib by 50 mg.  If|
04271|038|M|the current pirtobrutinib dosage is 50 mg once daily, interrupt|
04271|039|M|pirtobrutinib treatment for the duration of strong CYP3A4 inhibitor use.|
04271|040|M|After discontinuation of a strong CYP3A4 inhibitor for 5 half-lives, resume|
04271|041|M|the previous pirtobrutinib dose.(2)|
04271|042|B||
04271|043|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg lonafarnib|
04271|044|D|following 200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5|
04271|045|D|days, the area-under-curve (AUC) and maximum concentration (Cmax) were|
04271|046|D|increased by 425% and 270%, respectively.(1)|
04271|047|D|   Coadministration of a single 200 mg dose of pirtobrutinib with|
04271|048|D|itraconazole (a strong CYP3A4 inhibitor) increased AUC of pirtobrutinib by|
04271|049|D|49%.(2)|
04271|050|B||
04271|051|R|REFERENCES:|
04271|052|B||
04271|053|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04271|054|R|  Inc. November, 2020.|1
04271|055|R|2.Jaypirca (pirtobrutinib) US prescribing information. Eli Lilly January|1
04271|056|R|  2023.|1
04271|057|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04271|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04271|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04271|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04271|061|R|  11/14/2017.|1
04271|062|R|4.This information is based on an extract from the Certara Drug Interaction|6
04271|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04272|001|T|MONOGRAPH TITLE:  Pirtobrutinib/Moderate CYP3A4 Inducers|
04272|002|B||
04272|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04272|004|L|of severe adverse interaction.|
04272|005|B||
04272|006|A|MECHANISM OF ACTION:  Pirtobrutinib is metabolized by CYP3A4.  Moderate|
04272|007|A|inducers of CYP3A4 may increase the metabolism of pirtobrutinib.(1)|
04272|008|B||
04272|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
04272|010|E|in decreased levels and effectiveness of pirtobrutinib.(1)|
04272|011|B||
04272|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04272|013|P|of the inducer for longer than 1-2 weeks.|
04272|014|B||
04272|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of pirtobrutinib with moderate|
04272|016|M|CYP3A4 inducers.(1)|
04272|017|M|   If concomitant use of moderate CYP3A4 inducers is unavoidable, and the|
04272|018|M|current dose of pirtobrutinib is 200 mg daily, increase the dose to 300 mg|
04272|019|M|daily.  If the current pirtobrutinib dosage is 50 mg or 100 mg once daily,|
04272|020|M|increase the dose by 50 mg.(1)|
04272|021|B||
04272|022|D|DISCUSSION:  Efavirenz and bosentan (moderate CYP3A inducers) are predicted|
04272|023|D|to decrease the area-under-curve (AUC) of pirtobrutinib by 49% and 27%,|
04272|024|D|respectively.(1)|
04272|025|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04272|026|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04272|027|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04272|028|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and|
04272|029|D|thioridazine.(2,3)|
04272|030|B||
04272|031|R|REFERENCES:|
04272|032|B||
04272|033|R|1.Jaypirca (pirtobrutinib) US prescribing information. Eli Lilly January|1
04272|034|R|  2023.|1
04272|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04272|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04272|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04272|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04272|039|R|  11/14/2017.|1
04272|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04272|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04273|001|T|MONOGRAPH TITLE:  Methotrexate (Oncology-Injection)/Dasatinib; Imatinib|
04273|002|B||
04273|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04273|004|L|take action as needed.|
04273|005|B||
04273|006|A|MECHANISM OF ACTION:  The exact mechanism of the interaction is unknown.|
04273|007|A|Methotrexate is a substrate of the OAT3, BCRP, and OATP transporters.(1)  In|
04273|008|A|vitro, dasatinib inhibits OATP1B1/3 and imatinib inhibits BCRP.(2)  In|
04273|009|A|addition, dasatinib and imatinib can both cause peripheral edema and|
04273|010|A|ascites, which may increase methotrexate volume of distribution and result|
04273|011|A|in drug accumulation.(3,4)|
04273|012|B||
04273|013|E|CLINICAL EFFECTS:  The concurrent use of methotrexate with dasatinib or|
04273|014|E|imatinib may result in decreased methotrexate elimination and elevated|
04273|015|E|levels and toxicities of methotrexate, including an increased risk of severe|
04273|016|E|neurotoxicity, stomatitis, and myelosuppression/neutropenia.|
04273|017|B||
04273|018|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
04273|019|P|high-dose oncology regimens, impaired renal function, ascites, or pleural|
04273|020|P|effusions.|
04273|021|B||
04273|022|M|PATIENT MANAGEMENT:  Patients receiving concurrent high-dose methotrexate|
04273|023|M|and dasatinib or imatinib should be monitored closely for elevated|
04273|024|M|methotrexate levels and methotrexate toxicity.  Consideration may be given|
04273|025|M|to holding therapy with dasatinib at least 24 hours before or holding|
04273|026|M|imatinib at least 48 hours before starting methotrexate, and resuming|
04273|027|M|dasatinib or imatinib after methotrexate has cleared.(3,5,6)|
04273|028|B||
04273|029|D|DISCUSSION:  In a case series, 4 pediatric patients with Philadelphia|
04273|030|D|chromosome-positive B-cell acute lymphoblastic leukemia (ALL) had delayed|
04273|031|D|methotrexate clearance during their first cycle of high-dose methotrexate|
04273|032|D|and imatinib, resulting in acute kidney injury, delays in subsequent|
04273|033|D|methotrexate cycles, and prolonged hospitalization.  Imatinib was withheld|
04273|034|D|for subsequent methotrexate cycles, and patients had increased methotrexate|
04273|035|D|clearance and decreased toxicities.(3)|
04273|036|D|   A 48-year-old female with ALL treated with imatinib 600 mg daily,|
04273|037|D|intravenous cytarabine, etoposide, and high-dose methotrexate with folinic|
04273|038|D|acid developed peripheral edema, ascites, and pleural effusions.  She was|
04273|039|D|found to have delayed methotrexate elimination.  Imatinib was stopped on day|
04273|040|D|13 of her chemotherapy cycle and methotrexate disappeared from plasma at day|
04273|041|D|20.(4)|
04273|042|D|   Three pediatric ALL patients developed high methotrexate levels after|
04273|043|D|receiving concurrent imatinib with high-dose methotrexate.  One patient did|
04273|044|D|not experience toxicities.  One patient developed nausea, epigastric pain,|
04273|045|D|and mucositis, which recurred when the patient was given concurrent therapy|
04273|046|D|during the next treatment cycle.  The last patient developed acute renal|
04273|047|D|failure and cytolysis.  She held imatinib for her subsequent cycle of|
04273|048|D|methotrexate and did not experience elevated methotrexate levels or|
04273|049|D|toxicities.(5)|
04273|050|D|   A retrospective study of 121 ALL patients treated with high-dose|
04273|051|D|methotrexate found that 7 patients who received dasatinib and methotrexate|
04273|052|D|had significantly slower methotrexate clearance than patients who did not|
04273|053|D|receive a tyrosine kinase inhibitor (TKI) agent.(6)|
04273|054|B||
04273|055|R|REFERENCES:|
04273|056|B||
04273|057|R|1.Mikkelsen TS, Thorn CF, Yang JJ, Ulrich CM, French D, Zaza G, Dunnenberger|6
04273|058|R|  HM, Marsh S, McLeod HL, Giacomini K, Becker ML, Gaedigk R, Leeder JS,|6
04273|059|R|  Kager L, Relling MV, Evans W, Klein TE. PharmGKB summary: methotrexate|6
04273|060|R|  pathway. Pharmacogenet Genomics 2011 Oct;21(10):679-86.|6
04273|061|R|2.This information is based on an extract from the Certara Drug Interaction|6
04273|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04273|063|R|3.Pommert L, Liberio N, Ng JS, Egelund TA, Siver MJ, Katzenstein HM, Burke|3
04273|064|R|  MJ. Concurrent Imatinib Dosing With High-dose Methotrexate Leads to Acute|3
04273|065|R|  Kidney  Injury and Delayed Methotrexate Clearance in Pediatric Patients|3
04273|066|R|  With Philadelphia  Chromosome-positive B-Cell Acute Lymphoblastic|3
04273|067|R|  Leukemia. J Pediatr Hematol Oncol 2021 Mar 1;43(2):e296-e300.|3
04273|068|R|4.Van Hest RM, Schnog JB, Van't Veer MB, Cornelissen JJ. Extremely slow|3
04273|069|R|  methotrexate elimination in a patient with t(9;22) positive acute|3
04273|070|R|  lymphoblastic leukemia treated with imatinib. Am J Hematol 2008 Sep;|3
04273|071|R|  83(9):757-8.|3
04273|072|R|5.Loue C, Garnier N, Bertrand Y, Bleyzac N. High methotrexate exposure and|3
04273|073|R|  toxicity in children with t(9;22) positive acute  lymphoblastic leukaemia|3
04273|074|R|  treated with imatinib. J Clin Pharm Ther 2015 Oct;40(5):599-600.|3
04273|075|R|6.Ramsey LB, Mizuno T, Vinks AA, O'Brien MM. Delayed methotrexate clearance|2
04273|076|R|  in patients with acute lymphoblastic leukemia  concurrently receiving|2
04273|077|R|  dasatinib. Pediatr Blood Cancer 2019 May;66(5):e27618.|2
04274|001|T|MONOGRAPH TITLE:  Fenfluramine/Selected SSRIs that Inhibit CYP1A2 or CYP2D6|
04274|002|B||
04274|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04274|004|L|take action as needed.|
04274|005|B||
04274|006|A|MECHANISM OF ACTION:  Strong CYP1A2 or CYP2D6 inhibitors may decrease the|
04274|007|A|metabolism of fenfluramine.(1)|
04274|008|A|   Over 75% of fenfluramine is metabolized to norfenfluramine prior to|
04274|009|A|elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.(1)|
04274|010|A|   Concurrent administration may also result in additive effects on|
04274|011|A|serotonin, resulting in serotonin syndrome.|
04274|012|B||
04274|013|E|CLINICAL EFFECTS:  Concurrent use of agents that are strong CYP1A2 or CYP2D6|
04274|014|E|inhibitors may result in elevated levels of and toxicity from fenfluramine,|
04274|015|E|including CNS depression, hypertension, and serotonin syndrome.(1)|
04274|016|E|   Serotonin syndrome is a potentially life-threatening syndrome which may|
04274|017|E|include one or more of the following symptoms: tremor, agitation,|
04274|018|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04274|019|E|rigidity.(2)|
04274|020|B||
04274|021|P|PREDISPOSING FACTORS:  None determined.|
04274|022|B||
04274|023|M|PATIENT MANAGEMENT:  The US manufacturer of fenfluramine states that the|
04274|024|M|maximum daily dosage of fenfluramine with a strong CYP1A2 or CYP2D6|
04274|025|M|inhibitor in patients not on stiripentol is 20 mg.  In patients on|
04274|026|M|concomitant stiripentol and clobazam, the maximum fenfluramine dosage with|
04274|027|M|strong CYP1A2 or CYP2D6 inhibitors is 17 mg.(1)|
04274|028|M|   If the strong CYP1A2 or CYP2D6 inhibitor is discontinued, consider|
04274|029|M|gradually increasing the fenfluramine dosage to the usual recommended dose|
04274|030|M|without the inhibitor.(1)|
04274|031|M|   The manufacturer of fenfluramine states that fenfluramine should be used|
04274|032|M|with caution with other serotonergic agents such as selective serotonin|
04274|033|M|reuptake inhibitors.|
04274|034|M|   If concurrent therapy is warranted, patients should be monitored for|
04274|035|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
04274|036|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
04274|037|M|heart palpitations, restlessness, confusion, agitation, trouble with|
04274|038|M|coordination, or severe diarrhea.|
04274|039|B||
04274|040|D|DISCUSSION:  In a study of healthy volunteers, fluvoxamine 50 mg daily (a|
04274|041|D|strong CYP1A2 inhibitor) increased the area-under-curve (AUC) and maximum|
04274|042|D|concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 102% and 22%,|
04274|043|D|respectively, and decreased the AUC and Cmax of norfenfluramine by 22% and|
04274|044|D|44%, respectively.(1)|
04274|045|D|   In a study of healthy volunteers, paroxetine 30 mg daily (a strong CYP2D6|
04274|046|D|inhibitor) increased the AUC and Cmax of single-dose fenfluramine 0.4 mg/kg|
04274|047|D|by 81% and 13%, respectively, and decreased the AUC and Cmax of|
04274|048|D|norfenfluramine by 13% and 29%, respectively.(1)|
04274|049|D|   Strong CYP1A2 inhibitors linked to this monograph include:|
04274|050|D|fluvoxamine.(3,4)|
04274|051|D|   Strong CYP2D6 inhibitors linked to this monograph include: fluoxetine and|
04274|052|D|paroxetine.(3,4)|
04274|053|B||
04274|054|R|REFERENCES:|
04274|055|B||
04274|056|R|1.Fintepla (fenfluramine) US prescribing information. Zogenix Inc. January|1
04274|057|R|  2023.|1
04274|058|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04274|059|R|  352(11):1112-20.|6
04274|060|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04274|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04274|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04274|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04274|064|R|  11/14/2017.|1
04274|065|R|4.This information is based on an extract from the Certara Drug Interaction|6
04274|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04275|001|T|MONOGRAPH TITLE:  Crizotinib/Sotalol|
04275|002|B||
04275|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04275|004|L|of severe adverse interaction.|
04275|005|B||
04275|006|A|MECHANISM OF ACTION:  Concurrent use of crizotinib and sotalol may result in|
04275|007|A|symptomatic bradycardia and additive effects on the QTc interval.(1)|
04275|008|B||
04275|009|E|CLINICAL EFFECTS:  Bradycardia may be associated with an increase in the QTc|
04275|010|E|interval. The use of crizotinib and sotalol may result in potentially|
04275|011|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
04275|012|B||
04275|013|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04275|014|P|may be increased in patients with cardiovascular disease (e.g. heart|
04275|015|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04275|016|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04275|017|P|female gender, or advanced age.(2)|
04275|018|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04275|019|P|higher systemic concentrations of either QT prolonging drug are additional|
04275|020|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04275|021|P|drug concentrations include rapid infusion of an intravenous dose or|
04275|022|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04275|023|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04275|024|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04275|025|B||
04275|026|M|PATIENT MANAGEMENT:  The manufacturer of crizotinib recommends avoiding|
04275|027|M|concurrent use of crizotinib and other agents known to cause bradycardia to|
04275|028|M|the extent possible.(1)|
04275|029|M|   If combination therapy is required, monitor heart rate and blood pressure|
04275|030|M|regularly.  If bradycardia occurs, withhold crizotinib until heart rate|
04275|031|M|recovers to 60 bpm or above, or patient is asymptomatic.  Re-evaluate the|
04275|032|M|use of the concomitant medication.  If the concomitant medication is|
04275|033|M|discontinued or its dose is reduced, resume crizotinib at the previous dose|
04275|034|M|upon patient's recovery.  If the concomitant medication is not discontinued|
04275|035|M|or dose adjusted, resume crizotinib at a reduced dose upon patient's|
04275|036|M|recovery.|
04275|037|M|   If life-threatening bradycardia occurs, discontinue or reduce the dose of|
04275|038|M|the concomitant medication.  Upon the patient's recovery, lower the dose of|
04275|039|M|crizotinib to 250 mg daily.  Monitor blood pressure and heart rate|
04275|040|M|frequently.(1)|
04275|041|M|   Consider periodic electrocardiogram (ECG) and electrolyte monitoring|
04275|042|M|(calcium, magnesium, and potassium levels at baseline and regular intervals)|
04275|043|M|in patients receiving concurrent therapy with crizotinib and another agent|
04275|044|M|that prolongs the QTc interval.(1)|
04275|045|M|   In patients who develop a QTc greater than 500 ms on at least 2 separate|
04275|046|M|ECGs, withhold crizotinib until recovery to baseline or to a QTc less than|
04275|047|M|481 ms, then resume crizotinib at reduced dose.(1)|
04275|048|M|   In patients who develop a QTc greater than 500 ms or greater than or|
04275|049|M|equal to 60 ms change from baseline with Torsade de pointes or polymorphic|
04275|050|M|ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently|
04275|051|M|discontinue crizotinib.(1)|
04275|052|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
04275|053|M|fainting.|
04275|054|B||
04275|055|D|DISCUSSION:  Crizotinib is associated with concentration-dependent QTc|
04275|056|D|interval prolongation.  In a clinical trial 2.1% of patients were found to|
04275|057|D|have a QTcF greater than or equal to 500 msec and 5% of patients had an|
04275|058|D|increase in QTcF by greater than or equal to 60 msec.(1)|
04275|059|D|   A retrospective review of 618 cancer patients treated with 902|
04275|060|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
04275|061|D|incidence of QTc prolongation.  In patients who received crizotinib, QTc|
04275|062|D|prolongation was identified in 1 (50%) with 1 (100%) having Grade 1 (QTc|
04275|063|D|450-480 ms).  No patients had a QTc change greater than or equal to 60 ms,|
04275|064|D|ventricular tachycardia, sudden cardiac death, or TdP.(3)|
04275|065|D|   Across clinical trials, bradycardia occurred in 13% of patients on|
04275|066|D|crizotinib, and grade 3 syncope occurred in 2.4% of patients on crizotinib|
04275|067|D|compared with 0.6% on chemotherapy.(1)|
04275|068|B||
04275|069|R|REFERENCES:|
04275|070|B||
04275|071|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
04275|072|R|  2023.|1
04275|073|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04275|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04275|075|R|  settings: a scientific statement from the American Heart Association and|6
04275|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04275|077|R|  2;55(9):934-47.|6
04275|078|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
04275|079|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
04275|080|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
04275|081|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04275|082|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04275|083|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04275|084|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04276|001|T|MONOGRAPH TITLE:  Apomorphine/Sotalol|
04276|002|B||
04276|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04276|004|L|take action as needed.|
04276|005|B||
04276|006|A|MECHANISM OF ACTION:  Apomorphine has been shown to prolong the QTc|
04276|007|A|interval.  Apomorphine also causes dose-dependent decreases in blood|
04276|008|A|pressure.  Concurrent use with other agents that lower blood pressure and|
04276|009|A|prolong the QTc interval may result in additive effects on both blood|
04276|010|A|pressure and the QTc interval.(1)|
04276|011|B||
04276|012|E|CLINICAL EFFECTS:  The concurrent use of apomorphine with other agents that|
04276|013|E|lower blood pressure and prolong the QTc interval may result in orthostatic|
04276|014|E|hypotension with or without dizziness, nausea, or syncope, and potentially|
04276|015|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
04276|016|B||
04276|017|P|PREDISPOSING FACTORS:  The risk of orthostatic hypotension may be increased|
04276|018|P|during dose escalation of apomorphine and in patients with renal or hepatic|
04276|019|P|impairment.(1)|
04276|020|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04276|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04276|022|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
04276|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04276|024|P|advanced age.(3)|
04276|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04276|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04276|027|P|factors for torsade de pointes.  Factors which may increase systemic drug|
04276|028|P|concentrations include rapid infusion of an intravenous dose or impaired|
04276|029|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
04276|030|P|which inhibits its metabolism or elimination, genetic impairment in drug|
04276|031|P|metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04276|032|B||
04276|033|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with sotalol|
04276|034|M|should be monitored for hypotension.  Counsel patients about the risk of|
04276|035|M|orthostatic hypotension.(1)|
04276|036|M|   The manufacturer of apomorphine states that the use of apomorphine with|
04276|037|M|other agents known to prolong the QT interval should be done with|
04276|038|M|caution.(1)|
04276|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04276|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04276|041|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04276|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04276|043|B||
04276|044|D|DISCUSSION:  In a thorough QT study at exposures similar to those achieved|
04276|045|D|with the recommended dosing, apomorphine resulted in a prolongation of QTcF|
04276|046|D|of 10 msec (90% upper confidence interval of 16 msec). The thorough QT study|
04276|047|D|also identified a significant exposure-response relationship between|
04276|048|D|apomorphine concentration and QTcF.(1)|
04276|049|D|   Healthy volunteers who took sublingual nitroglycerin (0.4 mg)|
04276|050|D|concomitantly with apomorphine experienced a mean largest decrease in supine|
04276|051|D|systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood|
04276|052|D|pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and|
04276|053|D|DBP of 14.3 mm Hg and 13.5 mm Hg, respectively.  The maximum decrease in SBP|
04276|054|D|and DBP was 65 mm Hg and 43 mm Hg, respectively.  When apomorphine was taken|
04276|055|D|alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3|
04276|056|D|mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm|
04276|057|D|Hg, respectively.(1)|
04276|058|B||
04276|059|R|REFERENCES:|
04276|060|B||
04276|061|R|1.Apokyn (apomorphine hydrochloride) US prescribing information. Tercica,|1
04276|062|R|  Inc. May, 2019.|1
04276|063|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
04276|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04276|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04276|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04276|067|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04276|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04276|069|R|  settings: a scientific statement from the American Heart Association and|6
04276|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04276|071|R|  2;55(9):934-47.|6
04277|001|T|MONOGRAPH TITLE:  Daprodustat/Strong CYP2C8 Inhibitors|
04277|002|B||
04277|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04277|004|L|is contraindicated and generally should not be dispensed or administered to|
04277|005|L|the same patient.|
04277|006|B||
04277|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2C8 may impair the|
04277|008|A|CYP2C8-mediated metabolism of daprodustat.(1)|
04277|009|B||
04277|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP2C8 may result|
04277|011|E|in elevated levels of and clinical effects of daprodustat, including the|
04277|012|E|risk for thromboembolic events and hypertension.|
04277|013|B||
04277|014|P|PREDISPOSING FACTORS:  Patients with a history of myocardial infarction,|
04277|015|P|cerebrovascular event, or acute coronary syndrome within the past 3 months|
04277|016|P|may be at increased risk of thromboembolic events.  Other risk factors for|
04277|017|P|thromboembolic events include thrombophilia, malignancy, hyperlipidemia,|
04277|018|P|hypertension, heart failure, diabetes mellitus, chronic kidney disease,|
04277|019|P|COPD, obesity, tobacco smoking, major surgery with prolonged post-operative|
04277|020|P|immobilization, and being bed-ridden.|
04277|021|B||
04277|022|M|PATIENT MANAGEMENT:  The manufacturer of daprodustat states that concomitant|
04277|023|M|administration of strong CYP2C8 inhibitors is contraindicated.(1)|
04277|024|B||
04277|025|D|DISCUSSION:  In an interaction study, gemfibrozil 600 mg twice daily for 5|
04277|026|D|days increased the area-under-curve (AUC) and maximum concentration (Cmax)|
04277|027|D|of daprodustat (single 100 mg dose) by 18.6-fold and 3.9-fold|
04277|028|D|respectively.(1)|
04277|029|D|   Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)|
04277|030|B||
04277|031|R|REFERENCES:|
04277|032|B||
04277|033|R|1.Jesduvroq (daprodustat) US Prescribing Information. GlaxoSmithKline Feb,|1
04277|034|R|  2023.|1
04277|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04277|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04277|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04277|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04277|039|R|  11/14/2017.|1
04277|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04277|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04278|001|T|MONOGRAPH TITLE:  Daprodustat/Moderate CYP2C8 Inhibitors|
04278|002|B||
04278|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04278|004|L|take action as needed.|
04278|005|B||
04278|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP2C8 may impair the|
04278|007|A|CYP2C8-mediated metabolism of daprodustat.(1)|
04278|008|B||
04278|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP2C8 may|
04278|010|E|result in elevated levels of and clinical effects of daprodustat, including|
04278|011|E|the risk for thromboembolic events and hypertension.|
04278|012|B||
04278|013|P|PREDISPOSING FACTORS:  Patients with a history of myocardial infarction,|
04278|014|P|cerebrovascular event, or acute coronary syndrome within the past 3 months|
04278|015|P|may be at increased risk of thromboembolic events.  Other risk factors for|
04278|016|P|thromboembolic events include thrombophilia, malignancy, hyperlipidemia,|
04278|017|P|hypertension, heart failure, diabetes mellitus, chronic kidney disease,|
04278|018|P|COPD, obesity, tobacco smoking, major surgery with prolonged post-operative|
04278|019|P|immobilization, and being bed-ridden.|
04278|020|B||
04278|021|M|PATIENT MANAGEMENT:  The manufacturer of daprodustat states that the|
04278|022|M|starting dose of daprodustat should be reduced by half when initiating|
04278|023|M|treatment in patients on clopidogrel or moderate CYP2C8 inhibitors except in|
04278|024|M|patients who starting dose is already 1 mg.(1)|
04278|025|M|   Monitor hemoglobin and adjust the dose of daprodustat when initiating or|
04278|026|M|stopping therapy with clopidogrel or moderate CYP2C8 inhibitors.(1)|
04278|027|B||
04278|028|D|DISCUSSION:  In an interaction study, gemfibrozil 600 mg twice daily for 5|
04278|029|D|days increased the area-under-curve (AUC) and maximum concentration (Cmax)|
04278|030|D|of daprodustat (single 100 mg dose) by 18.6-fold and 3.9-fold|
04278|031|D|respectively.(1)|
04278|032|D|   Concomitant administration of daprodustat with clopidogrel 75 mg once|
04278|033|D|daily is expected to increase daprodustat AUC and Cmax by at least 4-fold|
04278|034|D|and 3-fold, respectively.(1)|
04278|035|D|   Moderate inhibitors of CYP2C8 include deferasirox, leflunomide,|
04278|036|D|letermovir, mifepristone (chronic therapy), pirtobrutinib, selpercatinib,|
04278|037|D|and teriflunomide.(2,3)|
04278|038|B||
04278|039|R|REFERENCES:|
04278|040|B||
04278|041|R|1.Jesduvroq (daprodustat) US Prescribing Information. GlaxoSmithKline Feb,|1
04278|042|R|  2023.|1
04278|043|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04278|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04278|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04278|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04278|047|R|  11/14/2017.|1
04278|048|R|3.This information is based on an extract from the Certara Drug Interaction|6
04278|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04279|001|T|MONOGRAPH TITLE:  Daprodustat; Roxadustat; Vadadustat/Lenalidomide|
04279|002|B||
04279|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04279|004|L|of severe adverse interaction.|
04279|005|B||
04279|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.|
04279|007|B||
04279|008|E|CLINICAL EFFECTS:  Concurrent use of daprodustat, roxadustat, or vadadustat|
04279|009|E|with lenalidomide may increase the risk of thrombosis.(1-5)|
04279|010|B||
04279|011|P|PREDISPOSING FACTORS:  Predisposing factors include a history of|
04279|012|P|thromboembolic disorder, thrombophilia, malignancy, hyperlipidemia,|
04279|013|P|hypertension, heart failure, diabetes mellitus, chronic kidney disease,|
04279|014|P|COPD, obesity, tobacco smoking, major surgery with prolonged post-operative|
04279|015|P|immobilization, and being bed-ridden.|
04279|016|B||
04279|017|M|PATIENT MANAGEMENT:  The US manufacturer of lenalidomide states the risk of|
04279|018|M|venous thromboembolism (VTE) may be increased when patients are taking|
04279|019|M|concomitant therapy with erythropoietin stimulating agents.  Use caution|
04279|020|M|with concomitant use after a patient-specific risk-benefit assessment has|
04279|021|M|been completed.  Observe patients for signs and symptoms of VTE and instruct|
04279|022|M|patients to seek medical care if they develop symptoms such as shortness of|
04279|023|M|breath, chest pain, or arm or leg swelling.(1)|
04279|024|M|   The National Comprehensive Cancer Network (NCCN) Guidelines include use|
04279|025|M|of erythropoietic stimulating agents as a high risk factor for venous|
04279|026|M|thromboembolism (VTE).  Other risk factors include: active cancer, advanced|
04279|027|M|stage cancer, certain cancer types, regional bulky lymphadenopathy, familial|
04279|028|M|and/or acquired hypercoagulability, medical comorbidities, poor performance|
04279|029|M|status, older age, major surgery, central venous catheter, chemotherapy|
04279|030|M|including lenalidomide plus high-dose dexamethasone, hormone replacement|
04279|031|M|therapy, contraceptives, tamoxifen/raloxifene, diethylstilbestrol, smoking,|
04279|032|M|obesity, or activity level/exercise.(6)|
04279|033|M|   The NCCN Guidelines utilize a Risk Assessment Model to determine|
04279|034|M|chemoprophylaxis.  In patients with 0-1 risk factors, consider VTE|
04279|035|M|chemoprophylaxis with aspirin 81-325 mg once daily.  In patients with >/= 2|
04279|036|M|risk factors, consider VTE chemoprophylaxis with low-molecular weight|
04279|037|M|heparin (LMWH) with a dose equivalent to enoxaparin 40 mg once daily or|
04279|038|M|full-dose warfarin with a dose to maintain a target international normalized|
04279|039|M|ratio (INR) 2-3.(6)|
04279|040|B||
04279|041|D|DISCUSSION:  Daprodustat, roxadustat, and vadadustat increase endogenous|
04279|042|D|erythropoietin by increasing transcription of the HIF-responsive genes.(2-5)|
04279|043|D|   The National Comprehensive Cancer Network (NCCN) Guidelines include use|
04279|044|D|of erythropoietin as an individual risk factor for venous thromboembolism|
04279|045|D|(VTE).  Patients should be assessed for total risk based on NCCN guidelines|
04279|046|D|and recommended for the appropriate VTE chemoprophylaxis agent based on risk|
04279|047|D|category.(6)|
04279|048|D|   A pooled analysis of two placebo-controlled trials in multiple myeloma|
04279|049|D|noted an incidence rate for VTE of 23% in patients receiving lenalidomide,|
04279|050|D|dexamethasone and erythropoietic therapy versus 5% in patients without|
04279|051|D|erythropoietic therapy.  A multivariate analysis indicated an independent|
04279|052|D|correlation between thrombosis and patients with concomitant erythropoietin|
04279|053|D|therapy.(7)|
04279|054|D|   A pooled analysis of 125 patients from 3 trials with multiple myeloma on|
04279|055|D|lenalidomide therapy noted a 17% incidence of VTE in patients on|
04279|056|D|lenalidomide with concurrent erythropoietin therapy.(8)|
04279|057|D|   Several studies have evaluated the optimal VTE prophylaxis agent with|
04279|058|D|lenalidomide-treated patients.  Patients receiving|
04279|059|D|lenalidomide/dexamethasone and no chemoprophylaxis had a VTE incidence of|
04279|060|D|11-75%, 26% with the use of aspirin, 17% with the use of|
04279|061|D|aspirin/LMWH/warfarin combination therapy, and 2-15% with the use of|
04279|062|D|LMWH.(9)|
04279|063|B||
04279|064|R|REFERENCES:|
04279|065|B||
04279|066|R|1.Revlimid (lenalidomide) US prescribing information. Celgene Corporation|1
04279|067|R|  May 2019.|1
04279|068|R|2.Jesduvroq (daprodustat) US Prescribing Information. GlaxoSmithKline Feb,|1
04279|069|R|  2023.|1
04279|070|R|3.Evrenzo (roxadustat) UK summary of product characteristics. Atellas Pharma|1
04279|071|R|  Europe B.V. November, 2021.|1
04279|072|R|4.Vafseo (vadadustat) Australian prescribing information. Akebia|1
04279|073|R|  Therapeutics, Inc. October, 2023.|1
04279|074|R|5.Vafseo (vadadustat) UK Summary of Product Characteristics. Akebia Europe|1
04279|075|R|  Limited May, 2023.|1
04279|076|R|6.Streiff M, Holmstrom B, Ashrani Aetal. Cancer-associated venous|6
04279|077|R|  thromboembolic disease.  NCCN Clinical Practice Guidelines in Oncology.|6
04279|078|R|  Available at www.nccn.org/professionals/physician_gls/f_guidelines.asp|6
04279|079|R|  January, 2015.|6
04279|080|R|7.Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple|2
04279|081|R|  myeloma. N Engl J Med 2006 May 11;354(19):2079-80.|2
04279|082|R|8.Menon SP, Rajkumar SV, Lacy M, Falco P, Palumbo A. Thromboembolic events|2
04279|083|R|  with lenalidomide-based therapy for multiple myeloma. Cancer 2008 Apr 1;|2
04279|084|R|  112(7):1522-8.|2
04279|085|R|9.Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J,|6
04279|086|R|  Barlogie B, Harousseau J, Zonder JA, Cavo M, Zangari M, Attal M, Belch A,|6
04279|087|R|  Knop S, etal. Prevention of thalidomide- and lenalidomide-associated|6
04279|088|R|  thrombosis in myeloma. Leukemia 2008 Feb;22(2):414-23.|6
04280|001|T|MONOGRAPH TITLE:  Apixaban/HIV Protease Inhibitors; Cobicistat|
04280|002|B||
04280|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04280|004|L|of severe adverse interaction.|
04280|005|B||
04280|006|A|MECHANISM OF ACTION:  Apixaban is metabolized by CYP3A4 and is a substrate|
04280|007|A|of the P-glycoprotein (P-gp) efflux transport protein.(1-4)|
04280|008|A|   HIV protease inhibitors are CYP3A4 and P-gp inhibitors and may increase|
04280|009|A|the absorption and decrease the elimination of apixaban.(1-5)|
04280|010|B||
04280|011|E|CLINICAL EFFECTS:  Concurrent use of protease inhibitors may result in|
04280|012|E|elevated levels and clinical effects of apixaban, including an increased|
04280|013|E|risk of bleeding.(1-5)|
04280|014|B||
04280|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04280|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04280|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
04280|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04280|019|P|risk for bleeding (e.g. NSAIDs).|
04280|020|B||
04280|021|M|PATIENT MANAGEMENT:  Recommendations for concurrent use of apixaban and HIV|
04280|022|M|protease inhibitors vary in different regions.|
04280|023|M|   The Australian(1) and Canadian(2) manufacturers of apixaban state that|
04280|024|M|the concurrent use of agents that are strong inhibitors of both P-gp and|
04280|025|M|CYP3A4 with apixaban is contraindicated.  The UK manufacturer of apixaban|
04280|026|M|states that concurrent use of these agents is not recommended.(3)  The US|
04280|027|M|manufacturer of apixaban states that if concurrent use cannot be avoided,|
04280|028|M|the dosage of apixaban should be reduced by 50% except in patients already|
04280|029|M|receiving apixaban 2.5 mg twice daily, for whom concurrent use should be|
04280|030|M|avoided.(4)|
04280|031|M|   The US manufacturer of atazanavir states that coadministration of|
04280|032|M|unboosted atazanavir should be closely monitored.(5)|
04280|033|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
04280|034|M|loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or|
04280|035|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
04280|036|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04280|037|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04280|038|M|anticoagulation in patients with active pathologic bleeding.|
04280|039|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04280|040|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04280|041|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04280|042|M|and/or swelling.|
04280|043|B||
04280|044|D|DISCUSSION:  Concurrent ketoconazole (400 mg daily), a strong CYP3A4 and|
04280|045|D|P-gp inhibitor, increased the area-under-curve (AUC) and maximum|
04280|046|D|concentration (Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1)|
04280|047|D|   HIV protease inhibitors linked to this monograph are: atazanavir,|
04280|048|D|cobicistat, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir,|
04280|049|D|ritonavir, saquinavir, and tipranavir.|
04280|050|B||
04280|051|R|REFERENCES:|
04280|052|B||
04280|053|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04280|054|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04280|055|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04280|056|R|  Squibb-Pfizer January, 2025.|1
04280|057|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04280|058|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04280|059|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04280|060|R|  Company April, 2025.|1
04280|061|R|5.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04280|062|R|  Squibb Company December, 2024.|1
04281|001|T|MONOGRAPH TITLE:  Sparsentan/Strong CYP3A4 Inhibitors|
04281|002|B||
04281|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04281|004|L|of severe adverse interaction.|
04281|005|B||
04281|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04281|007|A|of sparsentan.(1)|
04281|008|B||
04281|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04281|010|E|in increased levels of and effects from sparsentan including hepatotoxicity,|
04281|011|E|hypotension, hyperkalemia, and renal impairment.(1)|
04281|012|B||
04281|013|P|PREDISPOSING FACTORS:  None determined.|
04281|014|B||
04281|015|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04281|016|M|sparsentan should be avoided.  If concurrent use cannot be avoided,|
04281|017|M|interrupt therapy with sparsentan.  When resuming sparsentan, consider dose|
04281|018|M|titration.(1)|
04281|019|B||
04281|020|D|DISCUSSION:  Co-administration of a single dose of sparsentan with|
04281|021|D|itraconazole (a strong CYP3A4 inhibitor) increased concentration maximum|
04281|022|D|(Cmax) and area-under-curve (AUC) of sparsentan by 25% and 174%,|
04281|023|D|respectively.(1)|
04281|024|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04281|025|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04281|026|D|ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone,|
04281|027|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
04281|028|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04281|029|D|troleandomycin, tucatinib, and voriconazole.(2)|
04281|030|B||
04281|031|R|REFERENCES:|
04281|032|B||
04281|033|R|1.Filspari (sparsentan) US prescribing information. Travere Therapeutics|1
04281|034|R|  February, 2023.|1
04281|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
04281|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04282|001|T|MONOGRAPH TITLE:  Sparsentan/Strong CYP3A4 Inducers|
04282|002|B||
04282|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04282|004|L|of severe adverse interaction.|
04282|005|B||
04282|006|A|MECHANISM OF ACTION:  Sparsentan is metabolized by CYP3A4.  Strong inducers|
04282|007|A|of CYP3A4 may increase the metabolism of sparsentan.(1)|
04282|008|B||
04282|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
04282|010|E|in decreased levels and effectiveness of sparsentan.(1)|
04282|011|B||
04282|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04282|013|P|of the inducer for longer than 1-2 weeks.|
04282|014|B||
04282|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of sparsentan with strong CYP3A4|
04282|016|M|inducers.(1)|
04282|017|B||
04282|018|D|DISCUSSION:  Coadministration of a single dose of sparsentan with rifampin|
04282|019|D|(a strong CYP3A inducer) is predicted to decrease the concentration maximum|
04282|020|D|(Cmax) and area-under-curve (AUC) of sparsentan by 23% and 47%,|
04282|021|D|respectively.(1)|
04282|022|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04282|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04282|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04282|025|D|rifapentine, and St. John's wort.(2,3)|
04282|026|B||
04282|027|R|REFERENCES:|
04282|028|B||
04282|029|R|1.Filspari (sparsentan) US prescribing information. Travere Therapeutics|1
04282|030|R|  February, 2023.|1
04282|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04282|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04282|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04282|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04282|035|R|  11/14/2017.|1
04282|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
04282|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04283|001|T|MONOGRAPH TITLE:  Sparsentan/H2 Antagonists; Proton Pump Inhibitors|
04283|002|B||
04283|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04283|004|L|of severe adverse interaction.|
04283|005|B||
04283|006|A|MECHANISM OF ACTION:  The aqueous solubility of sparsentan is pH dependent.|
04283|007|A|Higher gastric pH leads to lower solubility.  H2-receptor antagonists|
04283|008|A|(H2RAs) and proton pump inhibitors (PPIs) increase gastric pH and may|
04283|009|A|decrease the absorption of sparsentan.(1)|
04283|010|B||
04283|011|E|CLINICAL EFFECTS:  Coadministration of H2RAs or PPIs may reduce the|
04283|012|E|bioavailability of sparsentan, leading to decreased systemic levels and|
04283|013|E|effectiveness.(1)|
04283|014|B||
04283|015|P|PREDISPOSING FACTORS:  None determined.|
04283|016|B||
04283|017|M|PATIENT MANAGEMENT:  Coadministration of sparsentan with PPIs and H2RAs|
04283|018|M|should be avoided.(1)|
04283|019|B||
04283|020|D|DISCUSSION:  Sparsentan is practically insoluble in water but has intrinsic|
04283|021|D|solubility of 1.48 mg/mL and 0.055 mg/mL below pH 1.2 and 6.8, respectively.|
04283|022|D|H2RAs and PPIs raise gastric pH and may impair dissolution and absorption|
04283|023|D|of sparsentan.(1)|
04283|024|B||
04283|025|R|REFERENCE:|
04283|026|B||
04283|027|R|1.Filspari (sparsentan) US prescribing information. Travere Therapeutics|1
04283|028|R|  February, 2023.|1
04284|001|T|MONOGRAPH TITLE:  Sparsentan/Antacids|
04284|002|B||
04284|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04284|004|L|take action as needed.|
04284|005|B||
04284|006|A|MECHANISM OF ACTION:  The aqueous solubility of sparsentan is pH dependent.|
04284|007|A|Higher gastric pH leads to lower solubility.  Antacids increase gastric pH|
04284|008|A|and may decrease the absorption of sparsentan.(1)|
04284|009|B||
04284|010|E|CLINICAL EFFECTS:  Coadministration of antacids may reduce the|
04284|011|E|bioavailability of sparsentan, leading to decreased systemic levels and|
04284|012|E|effectiveness.(1)|
04284|013|B||
04284|014|P|PREDISPOSING FACTORS:  None determined.|
04284|015|B||
04284|016|M|PATIENT MANAGEMENT:  If coadministration with an acid-reducing agent is|
04284|017|M|unavoidable, take an antacid 2 hours before or 2 hours after sparsentan.|
04284|018|M|   Coadministration of sparsentan with proton pump inhibitors and H2|
04284|019|M|antagonists should be avoided.(1)|
04284|020|B||
04284|021|D|DISCUSSION:  Sparsentan is practically insoluble in water but has intrinsic|
04284|022|D|solubility of 1.48 mg/mL and 0.055 mg/mL below pH 1.2 and 6.8, respectively.|
04284|023|D|Antacids raise gastric pH and may impair dissolution and absorption of|
04284|024|D|sparsentan.(1)|
04284|025|B||
04284|026|R|REFERENCE:|
04284|027|B||
04284|028|R|1.Filspari (sparsentan) US prescribing information. Travere Therapeutics|1
04284|029|R|  February, 2023.|1
04285|001|T|MONOGRAPH TITLE:  Dextromethorphan/Selected Strong CYP2D6 Inhibitors|
04285|002|B||
04285|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04285|004|L|take action as needed.|
04285|005|B||
04285|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2D6 may inhibit the metabolism|
04285|007|A|of dextromethorphan.(1-4)|
04285|008|B||
04285|009|E|CLINICAL EFFECTS:  Patients may experience increased adverse effects of|
04285|010|E|dextromethorphan due to elevated systemic concentrations.|
04285|011|E|   Elevated levels of dextromethorphan or concomitant use of two or more|
04285|012|E|serotonergic agents increases the risk for serotonin syndrome.  Serotonin|
04285|013|E|syndrome constitutes a range of toxicities from mild to life threatening.(5)|
04285|014|E|   Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis,|
04285|015|E|intermittent tremor, and/or myoclonus.(5)|
04285|016|E|   Moderate serotonin symptoms may include: tachycardia, hypertension,|
04285|017|E|hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds,|
04285|018|E|hyperreflexia, and/OR clonus.(5)|
04285|019|E|   Severe serotonin symptoms may include: severe hypertension and|
04285|020|E|tachycardia, shock, agitated delirium, muscular rigidity, and/or|
04285|021|E|hypertonicity.(5)|
04285|022|B||
04285|023|P|PREDISPOSING FACTORS:  Concurrent use of additional drugs which increase CNS|
04285|024|P|serotonin levels would be expected to further increase risk for serotonin|
04285|025|P|syndrome.(5)|
04285|026|B||
04285|027|M|PATIENT MANAGEMENT:  Monitor patients for elevated dextromethorphan levels|
04285|028|M|or on multiple serotonergic agents for symptoms of serotonin toxicity.|
04285|029|M|Patients in whom serotonin syndrome is suspected should receive immediate|
04285|030|M|medical attention.  If the interacting agents are prescribed by different|
04285|031|M|providers, it would be prudent to assure that both are aware of concomitant|
04285|032|M|therapy and monitoring the patient for serotonin toxicities.  Advise|
04285|033|M|patients not to exceed recommended dosages of dextromethorphan.|
04285|034|M|   If concurrent therapy is warranted, patients should be monitored for|
04285|035|M|signs and symptoms of serotonin syndrome.  Instruct patients to report|
04285|036|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
04285|037|M|heart palpitations, restlessness, confusion, agitation, trouble with|
04285|038|M|coordination, or severe diarrhea.|
04285|039|B||
04285|040|D|DISCUSSION:  An open label parallel group trial evaluated the interaction|
04285|041|D|between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed|
04285|042|D|strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with|
04285|043|D|a mean age of 33.6 years.  Subjects were randomly divided into 2 groups:|
04285|044|D|  - Group 1 received paroxetine 20 mg once daily for 12 days, followed by|
04285|045|D|the addition of dextromethorphan-quinidine twice daily for 8 days.|
04285|046|D|  - Group 2 received dextromethorphan-quinidine twice daily for 8 days,|
04285|047|D|followed by paroxetine 20 mg daily for 12 days.|
04285|048|D|Results: overall, adverse effects were reported in 19 of 26 subjects who|
04285|049|D|received combination therapy (73%) and 15 of 27 subjects who received|
04285|050|D|monotherapy (56%). Adverse effects from the combination differed somewhat|
04285|051|D|between groups and were more closely associated with the second drug product|
04285|052|D|administered. Group 1 reported dizziness, headache, somnolence, euphoria,|
04285|053|D|nausea, and vomiting after the addition of dextromethorphan-quinidine to|
04285|054|D|paroxetine.  Group 2 adverse events were dizziness, headache, nausea,|
04285|055|D|vomiting, insomnia, anxiety, and hyperhidrosis after the addition of|
04285|056|D|paroxetine to dextromethorphan.(1)|
04285|057|D|   Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of|
04285|058|D|dextromethorphan by 27-fold.(4)|
04285|059|D|   Serotonin syndrome has been reported in patients following the addition|
04285|060|D|of dextromethorphan containing cough syrups to fluoxetine(6,7) and|
04285|061|D|paroxetine.(8)|
04285|062|D|   Selected strong CYP2D6 inhibitors linked to this monograph include:|
04285|063|D|bupropion, dacomitinib, hydroquinidine, quinidine, and terbinafine.(8)|
04285|064|B||
04285|065|R|REFERENCES:|
04285|066|B||
04285|067|R|1.Schoedel KA, Pope LE, Sellers EM. Randomized open-label drug-drug|2
04285|068|R|  interaction trial of dextromethorphan/quinidine and paroxetine in healthy|2
04285|069|R|  volunteers. Clin Drug Investig 2012 Mar 1;32(3):157-69.|2
04285|070|R|2.Paxil (paroxetine hydrochloride) US prescribing information. Apotex|1
04285|071|R|  Technologies January, 2017.|1
04285|072|R|3.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
04285|073|R|  and Company August, 2023.|1
04285|074|R|4.Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. Fluoxetine-|2
04285|075|R|  and norfluoxetine-mediated complex drug-drug interactions: in vitro to in|2
04285|076|R|  vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol|2
04285|077|R|  Ther 2014 Jun;95(6):653-62.|2
04285|078|R|5.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04285|079|R|  352(11):1112-20.|6
04285|080|R|6.Navarro A, Perry C, Bobo WV. A case of serotonin syndrome precipitated by|3
04285|081|R|  abuse of the anticough remedy dextromethorphan in a bipolar patient|3
04285|082|R|  treated with fluoxetine and lithium. Gen Hosp Psychiatry 2006 Jan-Feb;|3
04285|083|R|  28(1):78-80.|3
04285|084|R|7.Achamallah NS. Visual hallucinations after combining fluoxetine and|3
04285|085|R|  dextromethorphan. Am J Psychiatry 1992 Oct;149(10):1406.|3
04285|086|R|8.Skop BP, Finkelstein JA, Mareth TR, Magoon MR, Brown TM. The serotonin|3
04285|087|R|  syndrome associated with paroxetine, an over-the-counter cold remedy, and|3
04285|088|R|  vascular disease. Am J Emerg Med 1994 Nov;12(6):642-4.|3
04285|089|R|9.This information is based on an extract from the Certara Drug Interaction|6
04285|090|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04286|001|T|MONOGRAPH TITLE:  Sildenafil (PAH)/Strong and Moderate CYP3A4 Inducers|
04286|002|B||
04286|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04286|004|L|take action as needed.|
04286|005|B||
04286|006|A|MECHANISM OF ACTION:  Sildenafil is metabolized by CYP3A4.  Strong and|
04286|007|A|moderate inducers of CYP3A4 may increase the metabolism of sildenafil.(1)|
04286|008|B||
04286|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
04286|010|E|may result in substantially decreased levels and effectiveness of|
04286|011|E|sildenafil.(1)|
04286|012|B||
04286|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04286|014|P|of the inducer for longer than 1-2 weeks.|
04286|015|B||
04286|016|M|PATIENT MANAGEMENT:  Concomitant use of sildenafil with strong or moderate|
04286|017|M|CYP3A4 inducers should be monitored closely.  An increased dosage of|
04286|018|M|sildenafil may be needed.  Reduce sildenafil dose to 20 mg three times daily|
04286|019|M|when discontinuing treatment with strong and moderate CYP3A4 inducers.(1)|
04286|020|B||
04286|021|D|DISCUSSION:  Population pharmacokinetic analysis of data from patients in|
04286|022|D|clinical trials found that sildenafil clearance increased about 3-fold when|
04286|023|D|coadministered with mild CYP3A4 inducers.(1)|
04286|024|D|   A randomized, double-blind, placebo-controlled, parallel-group study of|
04286|025|D|55 healthy volunteers found that 10 days of bosentan (125 mg twice daily), a|
04286|026|D|moderate CYP3A4 inducer, decreased the maximum concentration (Cmax) and|
04286|027|D|area-under-curve (AUC) of sildenafil by 55.4% and 62.6%, respectively.|
04286|028|D|Sildenafil increased bosentan Cmax and AUC by 42% and 49.8%, respectively.|
04286|029|D|The combination was well tolerated without serious adverse events.(2)|
04286|030|D|   In a study of 15 HIV-negative subjects, etravirine (800 mg twice daily|
04286|031|D|for 14 days), a moderate CYP3A4 inducer, decreased the Cmax and AUC of|
04286|032|D|sildenafil by 45% and 57%, respectively.(3)|
04286|033|D|   The authors of a review article on drug interactions in pulmonary|
04286|034|D|arterial hypertension therapy state that phenytoin and rifampin (strong|
04286|035|D|CYP3A4 inducers) are not recommended with sildenafil due to an expected|
04286|036|D|near-complete clearance of sildenafil.(4)|
04286|037|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04286|038|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04286|039|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04286|040|D|rifapentine, and St. John's wort.(5,6)|
04286|041|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04286|042|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04286|043|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04286|044|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
04286|045|D|thioridazine, and tovorafenib.(5,6)|
04286|046|B||
04286|047|R|REFERENCES:|
04286|048|B||
04286|049|R|1.Revatio (sildenafil citrate) US prescribing information. Viatris January,|1
04286|050|R|  2023.|1
04286|051|R|2.Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic|2
04286|052|R|  interactions between steady-state bosentan and sildenafil. Eur J Clin|2
04286|053|R|  Pharmacol 2008 Jan;64(1):43-50.|2
04286|054|R|3.Scholler-Gyure M, Debroye C, Vyncke V, et al. Effect of TMC125 on|4
04286|055|R|  sildenafil pharmacokinetics poster no.45. 7th International Workshop of|4
04286|056|R|  Clinical Pharmacology of HIV Therapy. Lisbon, Portugal 2006 Apr 20-22.|4
04286|057|R|4.Wu S, Hoang HB, Yang JZ, Papamatheakis DG, Poch DS, Alotaibi M, Lombardi|6
04286|058|R|  S, Rodriguez C, Kim NH, Fernandes TM. Drug-Drug Interactions in the|6
04286|059|R|  Management of Patients With Pulmonary Arterial  Hypertension. Chest 2022|6
04286|060|R|  Dec;162(6):1360-1372.|6
04286|061|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04286|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04286|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04286|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04286|065|R|  11/14/2017.|1
04286|066|R|6.This information is based on an extract from the Certara Drug Interaction|6
04286|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04287|001|T|MONOGRAPH TITLE:  Sparsentan/Angiotensin II Receptor Blockers; Endothelin|
04287|002|T|Receptor Antagonists; Aliskiren|
04287|003|B||
04287|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04287|005|L|is contraindicated and generally should not be dispensed or administered to|
04287|006|L|the same patient.|
04287|007|B||
04287|008|A|MECHANISM OF ACTION:  Sparsentan is an antagonist of the endothelin type A|
04287|009|A|receptor and the angiotensin II type 1 receptor which are thought to|
04287|010|A|contribute to the pathogenesis of IgA nephropathy.(1)  Coadministration with|
04287|011|A|angiotensin II receptor blockers (ARBs), endothelin receptor antagonists|
04287|012|A|(ERAs), or aliskiren may result in additive inhibition of angiotensin.|
04287|013|B||
04287|014|E|CLINICAL EFFECTS:  Concurrent use of sparsentan with ARBs, ERAs, or|
04287|015|E|aliskiren may result in hypotension, syncope, hyperkalemia, and changes in|
04287|016|E|renal function (including renal failure).(1)|
04287|017|B||
04287|018|P|PREDISPOSING FACTORS:  Patients with renal artery stenosis, chronic kidney|
04287|019|P|disease, severe congestive heart failure, or volume depletion may be at risk|
04287|020|P|of developing acute kidney injury on sparsentan.(1)|
04287|021|P|   Patients with advanced kidney disease or taking concomitant|
04287|022|P|potassium-increasing drugs (e.g., potassium supplements, potassium-sparing|
04287|023|P|diuretics), or using potassium-containing salt substitutes are at increased|
04287|024|P|risk for developing hyperkalemia.(1)|
04287|025|B||
04287|026|M|PATIENT MANAGEMENT:  Do not coadminister sparsentan with ARBs, ERAs, or|
04287|027|M|aliskiren.  Prior to initiating treatment with sparsentan, discontinue use|
04287|028|M|of ARBs, ERAs, and aliskiren.(1)|
04287|029|B||
04287|030|D|DISCUSSION:  The US manufacturer of sparsentan states that concomitant use|
04287|031|D|of sparsentan with ARBs, ERAs, or aliskiren is contraindicated.(1)|
04287|032|B||
04287|033|R|REFERENCE:|
04287|034|B||
04287|035|R|1.Filspari (sparsentan) US prescribing information. Travere Therapeutics|1
04287|036|R|  February, 2023.|1
04288|001|T|MONOGRAPH TITLE:  Sparsentan/NSAIDs; Salicylates|
04288|002|B||
04288|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04288|004|L|take action as needed.|
04288|005|B||
04288|006|A|MECHANISM OF ACTION:  Sparsentan is an endothelin and angiotensin II|
04288|007|A|receptor antagonist.(1)  Angiotensin II receptor blockers can cause|
04288|008|A|vasodilation of the efferent renal arteriole which may result in decreased|
04288|009|A|glomerular filtration rate.  NSAIDs inhibit prostaglandin synthesis which|
04288|010|A|can lead to afferent arteriolar vasoconstriction.|
04288|011|B||
04288|012|E|CLINICAL EFFECTS:  Concurrent use of sparsentan with NSAIDs (including|
04288|013|E|selective COX-2 inhibitors) may result in renal hypoperfusion and|
04288|014|E|deterioration of renal clearance, including possible acute kidney injury|
04288|015|E|(AKI).  These effects are usually reversible.(1)|
04288|016|B||
04288|017|P|PREDISPOSING FACTORS:  Patients older than 75 years old, with renal artery|
04288|018|P|stenosis, chronic kidney disease, severe congestive heart failure, or volume|
04288|019|P|depletion (including from diuretic use and dehydration) may be at greater|
04288|020|P|risk for AKI.(1-3)|
04288|021|B||
04288|022|M|PATIENT MANAGEMENT:  Monitor for signs of worsening renal function if an|
04288|023|M|NSAID (including selective COX-2 inhibitors) is used concurrently with|
04288|024|M|sparsentan.  If renal function deteriorates, the NSAID may need to be|
04288|025|M|discontinued.(1)|
04288|026|B||
04288|027|D|DISCUSSION:  In a computational study, the risk of AKI using triple therapy|
04288|028|D|with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was|
04288|029|D|assessed.  The study found the following factors may increase an|
04288|030|D|individual's susceptibility to AKI: low water intake, drug sensitivity,|
04288|031|D|greater than 75 years of age, and renal impairment.(2,3)|
04288|032|D|    In an observational study, current use of a triple therapy combination|
04288|033|D|was associated with an increased rate of acute kidney injury (rate ratio|
04288|034|D|(RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI|
04288|035|D|associated with triple therapy were observed in the first 30 days of use (RR|
04288|036|D|1.82, CI 1.35-2.46).(4)|
04288|037|B||
04288|038|R|REFERENCES:|
04288|039|B||
04288|040|R|1.Filspari (sparsentan) US prescribing information. Travere Therapeutics|1
04288|041|R|  February, 2023.|1
04288|042|R|2.Leete J,  Wang C,  Lopez-Hernandez FJ,  Layton AT. Determining risk|6
04288|043|R|  factors for triple whammy acute kidney injury. Math Biosci 2022 Apr 4.|6
04288|044|R|3.Dreischulte T,  Morales DR,  Bell S,  Guthrie B. Combined use of|2
04288|045|R|  nonsteroidal anti-inflammatory drugs with diuretics and/or|2
04288|046|R|  renin-angiotensin system inhibitors in the community increases the risk of|2
04288|047|R|  acute kidney injury. Kidney Int 2015 Aug;88(2):396-403.|2
04288|048|R|4.Lapi F,  Azoulay L,  Yin H,  Nessim SJ,  Suissa S. Concurrent use of|2
04288|049|R|  diuretics, angiotensin converting enzyme inhibitors, and angiotensin|2
04288|050|R|  receptor blockers with non-steroidal anti-inflammatory drugs and risk of|2
04288|051|R|  acute kidney injury: nested case-control study. BMJ 2013 Jan;8(346):.|2
04289|001|T|MONOGRAPH TITLE:  Warfarin/Norethindrone (Greater Than or Equal To 5 mg)|
04289|002|B||
04289|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04289|004|L|take action as needed.|
04289|005|B||
04289|006|A|MECHANISM OF ACTION:  Norethindrone is a weak CYP2C9 inhibitor(1) which may|
04289|007|A|decrease the metabolism of the S-enantiomer of warfarin.(1,2)|
04289|008|B||
04289|009|E|CLINICAL EFFECTS:  Concurrent use of norethindrone may result in elevated|
04289|010|E|levels of warfarin and increased INR.(1-3)|
04289|011|B||
04289|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04289|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04289|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
04289|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04289|016|P|risk for bleeding (e.g. NSAIDs).|
04289|017|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
04289|018|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
04289|019|P|are expected to be more susceptible to this interaction.|
04289|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
04289|021|P|are expected to be less susceptible to effects from this drug combination,|
04289|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
04289|023|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
04289|024|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
04289|025|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
04289|026|P|and safe anticoagulation than patients without these CYP2C9 variants.|
04289|027|B||
04289|028|M|PATIENT MANAGEMENT:  Monitor INRs more frequently until stable in patients|
04289|029|M|who start norethindrone therapy.(2,3)|
04289|030|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
04289|031|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
04289|032|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
04289|033|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04289|034|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04289|035|M|anticoagulation in patients with active pathologic bleeding.|
04289|036|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04289|037|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04289|038|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04289|039|M|and/or swelling.|
04289|040|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04289|041|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04289|042|M|initiating, altering the dose or discontinuing either drug.|
04289|043|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
04289|044|B||
04289|045|D|DISCUSSION:  A case series of 3 adolescent females with a history of|
04289|046|D|mechanical mitral valve replacement who developed heavy menstrual bleeding|
04289|047|D|(HMB) found that starting norethindrone in combination with warfarin|
04289|048|D|resulted in increased INRs.(3)|
04289|049|D|   -Patient 1, a 12-year-old female, who was stable on 42 mg warfarin|
04289|050|D|weekly, started norethindrone 10 mg daily for HMB.  The patient's INR became|
04289|051|D|supratherapeutic (INR 4-6) and required a decrease in warfarin dose to 21 mg|
04289|052|D|weekly (50% reduction).(3)|
04289|053|D|   -Patient 2, a 14-year-old female, who was stable on 35 mg warfarin|
04289|054|D|weekly, started norethindrone for HMB (10 mg four times daily for 4 days|
04289|055|D|followed by a maintenance dose of 15 mg daily).  The patient required a 43%|
04289|056|D|dose reduction of warfarin to 28 mg weekly.(3)|
04289|057|D|   -Patient 3, a 15-year-old female, was stable on 24.5 mg of warfarin|
04289|058|D|weekly.  After starting norethindrone 5 mg for 1 month and increasing|
04289|059|D|norethindrone to 10 mg daily, the patient's warfarin requirement decreased|
04289|060|D|to 17.5 mg weekly and eventually stabilized at 19 mg weekly (29% dose|
04289|061|D|reduction).  One year later, an intrauterine device was placed and|
04289|062|D|norethindrone was tapered and discontinued over 2 months.  The patient's|
04289|063|D|warfarin requirement increased to 28 mg weekly once norethindrone was|
04289|064|D|discontinued (47% increase).(3)|
04289|065|B||
04289|066|R|REFERENCES:|
04289|067|B||
04289|068|R|1.Korhonen T,  Turpeinen M,  Tolonen A,  Laine K,  Pelkonen O.|5
04289|069|R|  Identification of the human cytochrome P450 enzymes involved in the in|5
04289|070|R|  vitro biotransformation of lynestrenol and norethindrone. J Steroid|5
04289|071|R|  Biochem Mol Biol May 2008;110(1-2):56-66.|5
04289|072|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
04289|073|R|  Squibb Company September, 2016.|1
04289|074|R|3.Grapsy J,  Hoang A,  Ying L,  Zia A. Potential drug-drug interaction|3
04289|075|R|  between warfarin and norethindrone in adolescent females: A case series.|3
04289|076|R|  Am J Health-Syst Pharm February 2023;80(3):124-129.|3
04289|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
04289|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04289|079|R|5.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
04289|080|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
04289|081|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
04289|082|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
04289|083|R|  Oct;90(4):625-9.|6
04290|001|T|MONOGRAPH TITLE:  Fedratinib/Mitapivat|
04290|002|B||
04290|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04290|004|L|of severe adverse interaction.|
04290|005|B||
04290|006|A|MECHANISM OF ACTION:  Fedratinib and mitapivat are substrates of|
04290|007|A|CYP3A4.(1-3)|
04290|008|A|   Fedratinib, a moderate CYP3A4 inhibitor, may inhibit the metabolism of|
04290|009|A|mitapivat.(1)  Mitapivat, a moderate CYP3A4 inducer, may induce the|
04290|010|A|metabolism of fedratinib.(2,3)|
04290|011|B||
04290|012|E|CLINICAL EFFECTS:  Concurrent use of fedratinib with moderate CYP3A4|
04290|013|E|inducers such as mitapivat may result in decreased levels and effectiveness|
04290|014|E|of fedratinib.(1)|
04290|015|E|   Concurrent use of mitapivat with moderate CYP3A4 inhibitors such as|
04290|016|E|fedratinib may result in increased levels of and effects from mitapivat|
04290|017|E|including decreased estrone and estradiol levels in males, increased urate,|
04290|018|E|back pain, and arthralgias.(2,3)|
04290|019|B||
04290|020|P|PREDISPOSING FACTORS:  None determined.|
04290|021|B||
04290|022|M|PATIENT MANAGEMENT:  Avoid the concurrent use of fedratinib and|
04290|023|M|mitapivat.(1-3)|
04290|024|M|  The effect of the two-way inhibition and induction of fedratinib and|
04290|025|M|mitapivat metabolism is unknown. The optimal doses of fedratinib and|
04290|026|M|mitapivat when used concurrently have not been determined. Dose|
04290|027|M|modifications mentioned below are informational only.|
04290|028|M|   The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be|
04290|029|M|monitored closely for increased risk of adverse reactions.  The US|
04290|030|M|manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg|
04290|031|M|twice daily with concurrent moderate CYP3A4 inhibitors.(2)  The Middle|
04290|032|M|Eastern manufacturer of mitapivat states that alternative agents that do not|
04290|033|M|inhibit CYP3A4 should be considered.  If concomitant use of a moderate|
04290|034|M|CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100|
04290|035|M|mg once daily.(3)|
04290|036|B||
04290|037|D|DISCUSSION:  The effect of CYP3A4 inducers has not been studied. Fedratinib|
04290|038|D|is metabolized by CYP3A4.(1)|
04290|039|D|   Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study with|
04290|040|D|mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased|
04290|041|D|mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by|
04290|042|D|2.6-fold and 1.6-fold, respectively.(2)|
04290|043|B||
04290|044|R|REFERENCES:|
04290|045|B||
04290|046|R|1.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
04290|047|R|  May, 2023.|1
04290|048|R|2.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04290|049|R|  February, 2022.|1
04290|050|R|3.Pyrukynd (mitapivat) Middle East Prescribing Information. Agios|1
04290|051|R|  Pharmaceuticals, Inc. July, 2025.|1
04290|052|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04290|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04290|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04290|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04290|056|R|  11/14/2017.|1
04290|057|R|5.This information is based on an extract from the Certara Drug Interaction|6
04290|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04291|001|T|MONOGRAPH TITLE:  Lonafarnib/Oral Lefamulin|
04291|002|B||
04291|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04291|004|L|is contraindicated and generally should not be dispensed or administered to|
04291|005|L|the same patient.|
04291|006|B||
04291|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors such as lonafarnib may|
04291|008|A|inhibit the metabolism of lefamulin.(1)|
04291|009|A|   Both agents have been shown to prolong the QTc interval.(1,2)|
04291|010|B||
04291|011|E|CLINICAL EFFECTS:  Concurrent use lonafarnib may increase the levels of and|
04291|012|E|adverse reactions of lefamulin, including additive QTc prolongation which|
04291|013|E|may lead to potentially life-threatening arrhythmias like torsades de|
04291|014|E|pointes (TdP).(1,2)|
04291|015|B||
04291|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04291|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04291|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04291|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04291|020|P|gender, or advanced age.(3)|
04291|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04291|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04291|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04291|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04291|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04291|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04291|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04291|028|B||
04291|029|M|PATIENT MANAGEMENT:  The manufacturer of lefamulin states that the|
04291|030|M|concurrent use of CYP3A4 substrates known to prolong the QTc interval, like|
04291|031|M|lonafarnib, is contraindicated.(1)|
04291|032|M|   If concomitant therapy is necessary, monitor patients closely for|
04291|033|M|prolongation of the QT interval.  Obtain serum calcium, magnesium, and|
04291|034|M|potassium levels and monitor ECG at regular intervals.  Correct any|
04291|035|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04291|036|M|heartbeat, dizziness, or fainting.|
04291|037|B||
04291|038|D|DISCUSSION:  Coadministration of ketoconazole (a strong CYP3A4 inhibitor)|
04291|039|D|with lefamulin tablets increased lefamulin AUC and Cmax by 165% and 58%.(1)|
04291|040|D|   In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5|
04291|041|D|days) increased the area-under-the-curve (AUC) and maximum concentration|
04291|042|D|(Cmax) of a single dose of midazolam (3 mg), a sensitive CYP3A4 substrate,|
04291|043|D|by 639% and 180%, respectively.(2)|
04291|044|D|   In a thorough QT study of adult pneumonia patients, intravenous lefamulin|
04291|045|D|150 mg twice daily caused a mean QTcF increase of 13.6 msec (90% upper CI =|
04291|046|D|15.5 msec) and oral lefamulin 600 mg twice daily caused a mean QTcF increase|
04291|047|D|of 9.3 msec (90% upper CI = 10.9 msec).(1)|
04291|048|D|   In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive|
04291|049|D|days and a single 200 mg dose on day 10 increased the mean QTc interval by|
04291|050|D|19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48|
04291|051|D|hours after administration of the morning dose of lonafarnib 200 mg.  The|
04291|052|D|maximum concentration (Cmax) on Day 10 was 2233 ng/ml, which is similar to|
04291|053|D|the mean Cmax of 2695 ng/ml observed in the Hutchinson-Gilford Progeria|
04291|054|D|Syndrome patient population.(2)|
04291|055|B||
04291|056|R|REFERENCES:|
04291|057|B||
04291|058|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04291|059|R|  Inc August 2019.|1
04291|060|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04291|061|R|  Inc. November, 2020.|1
04291|062|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04291|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04291|064|R|  settings: a scientific statement from the American Heart Association and|6
04291|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04291|066|R|  2;55(9):934-47.|6
04291|067|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04291|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04291|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04291|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04291|071|R|  11/14/2017.|1
04291|072|R|5.This information is based on an extract from the Certara Drug Interaction|6
04291|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04292|001|T|MONOGRAPH TITLE:  Bosentan/Fedratinib|
04292|002|B||
04292|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04292|004|L|of severe adverse interaction.|
04292|005|B||
04292|006|A|MECHANISM OF ACTION:  Bosentan is metabolized by CYP2C9 and CYP3A4.  It is|
04292|007|A|also an inducer of these enzymes.  With regular dosing bosentan auto-induces|
04292|008|A|its own metabolism.(1)  Moderate CYP3A4 inhibitors such as fedratinib may|
04292|009|A|inhibit the CYP3A4 mediated metabolism of bosentan.(1,2)|
04292|010|A|   Fedratinib is a substrate of CYP3A4.  Moderate CYP3A4 inducers such as|
04292|011|A|bosentan may induce the metabolism of fedratinib.(2)|
04292|012|B||
04292|013|E|CLINICAL EFFECTS:  Concurrent use of bosentan with an inhibitor of CYP3A4|
04292|014|E|such as fedratinib may result in elevated levels of and toxicity from|
04292|015|E|bosentan.(1)|
04292|016|E|   The concurrent use of fedratinib with a moderate CYP3A4 inducer such as|
04292|017|E|bosentan may result in decreased levels and effectiveness of fedratinib.(2)|
04292|018|B||
04292|019|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, a CYP3A4 inhibitor and a|
04292|020|P|CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
04292|021|P|sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major|
04292|022|P|metabolic pathways for bosentan, resulting in large increases in bosentan|
04292|023|P|plasma concentrations.(1,3)|
04292|024|B||
04292|025|M|PATIENT MANAGEMENT:  The effect of the two-way inhibition and induction of|
04292|026|M|fedratinib and bosentan metabolism is unknown.  The optimal doses of|
04292|027|M|fedratinib and bosentan when used concurrently have not been determined.|
04292|028|M|Concurrent use should be avoided.  Dose modifications mentioned below are|
04292|029|M|informational only.|
04292|030|M|   The manufacturer of fedratinib states that concurrent use with moderate|
04292|031|M|CYP3A4 inducers should be avoided.(2)|
04292|032|M|   In patients receiving bosentan, review medication list to see if patient|
04292|033|M|is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole,|
04292|034|M|miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone).|
04292|035|M|   Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended|
04292|036|M|by the manufacturer of bosentan as the combination may lead to large|
04292|037|M|increases in bosentan plasma concentrations.(1)|
04292|038|M|   For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated,|
04292|039|M|monitor tolerance to concomitant therapy and adjust bosentan dose if needed.|
04292|040|M|   In patients who have been receiving a strong CYP3A4 inhibitor for at|
04292|041|M|least 10 days, start bosentan at 62.5 mg once daily or every other day based|
04292|042|M|upon individual tolerability.|
04292|043|M|   Discontinue use of bosentan at least 36 hours prior to initiation of a|
04292|044|M|strong CYP3A4 inhibitor.|
04292|045|M|   After at least 10 days following the initiation of a strong CYP3A4|
04292|046|M|inhibitor, resume bosentan at 62.5 mg once daily or every other day based|
04292|047|M|upon individual tolerability.|
04292|048|B||
04292|049|D|DISCUSSION:  In a study in healthy subjects, concurrent bosentan and|
04292|050|D|ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan|
04292|051|D|steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by|
04292|052|D|2.1-fold and 2.3-fold, respectively.(1)|
04292|053|D|   The effect of CYP3A4 inducers has not been studied. Fedratinib is|
04292|054|D|metabolized by CYP3A4.(2)|
04292|055|B||
04292|056|R|REFERENCES:|
04292|057|B||
04292|058|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
04292|059|R|  US, Inc. September 5, 2017.|1
04292|060|R|2.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
04292|061|R|  May, 2023.|1
04292|062|R|3.This information is based on an extract from the Certara Drug Interaction|6
04292|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04293|001|T|MONOGRAPH TITLE:  Omaveloxolone/Strong CYP3A4 Inhibitors|
04293|002|B||
04293|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04293|004|L|of severe adverse interaction.|
04293|005|B||
04293|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04293|007|A|of omaveloxolone.(1)|
04293|008|B||
04293|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04293|010|E|in increased levels of and effects from omaveloxolone including|
04293|011|E|hepatotoxicity and hyperlipidemia.(1)|
04293|012|B||
04293|013|P|PREDISPOSING FACTORS:  None determined.|
04293|014|B||
04293|015|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04293|016|M|omaveloxolone should be avoided.|
04293|017|M|   If concurrent use cannot be avoided, reduce the omaveloxolone dosage to|
04293|018|M|50 mg daily and monitor closely.  If adverse reactions emerge,|
04293|019|M|coadministration with strong CYP3A4 inhibitors should be discontinued.(1)|
04293|020|B||
04293|021|D|DISCUSSION:  Coadministration of omaveloxolone with itraconazole (a strong|
04293|022|D|CYP3A4 inhibitor) increased the concentration maximum (Cmax) and|
04293|023|D|area-under-curve (AUC) of omaveloxolone by 3-fold and 4-fold,|
04293|024|D|respectively.(1)|
04293|025|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04293|026|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04293|027|D|ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone,|
04293|028|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
04293|029|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04293|030|D|troleandomycin, tucatinib, and voriconazole.(2)|
04293|031|B||
04293|032|R|REFERENCES:|
04293|033|B||
04293|034|R|1.Skyclarys (omaveloxolone) US prescribing information. Reata|1
04293|035|R|  Pharmaceuticals, Inc. December 2024.|1
04293|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
04293|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04294|001|T|MONOGRAPH TITLE:  Omaveloxolone/Moderate CYP3A4 Inhibitors|
04294|002|B||
04294|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04294|004|L|of severe adverse interaction.|
04294|005|B||
04294|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
04294|007|A|metabolism of omaveloxolone.(1)|
04294|008|B||
04294|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04294|010|E|result in increased levels of and effects from omaveloxolone including|
04294|011|E|hepatotoxicity and hyperlipidemia.(1)|
04294|012|B||
04294|013|P|PREDISPOSING FACTORS:  None determined.|
04294|014|B||
04294|015|M|PATIENT MANAGEMENT:  The concurrent use of moderate CYP3A4 inhibitors with|
04294|016|M|omaveloxolone should be avoided.|
04294|017|M|   If concurrent use cannot be avoided, reduce the omaveloxolone dosage to|
04294|018|M|100 mg daily and monitor closely.  If adverse reactions emerge, reduce the|
04294|019|M|dose to 50 mg once daily.(1)|
04294|020|B||
04294|021|D|DISCUSSION:  Coadministration of omaveloxolone with verapamil (a moderate|
04294|022|D|CYP3A4 inhibitor) increased both the concentration maximum (Cmax) and|
04294|023|D|area-under-curve (AUC) of omaveloxolone by 1.25-fold.(1)|
04294|024|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04294|025|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
04294|026|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
04294|027|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
04294|028|D|isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant,|
04294|029|D|nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
04294|030|D|verapamil, and voxelotor.(2,3)|
04294|031|B||
04294|032|R|REFERENCES:|
04294|033|B||
04294|034|R|1.Skyclarys (omaveloxolone) US prescribing information. Reata|1
04294|035|R|  Pharmaceuticals, Inc. December 2024.|1
04294|036|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04294|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04294|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04294|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04294|040|R|  11/14/2017.|1
04294|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
04294|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04295|001|T|MONOGRAPH TITLE:  Omaveloxolone/Strong and Moderate CYP3A4 Inducers|
04295|002|B||
04295|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04295|004|L|of severe adverse interaction.|
04295|005|B||
04295|006|A|MECHANISM OF ACTION:  Omaveloxolone is metabolized by CYP3A4.  Strong and|
04295|007|A|moderate inducers of CYP3A4 may increase the metabolism of omaveloxolone.(1)|
04295|008|B||
04295|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
04295|010|E|may result in decreased levels and effectiveness of omaveloxolone.(1)|
04295|011|B||
04295|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04295|013|P|of the inducer for longer than 1-2 weeks.|
04295|014|B||
04295|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of omaveloxolone with strong or|
04295|016|M|moderate CYP3A4 inducers.(1)|
04295|017|B||
04295|018|D|DISCUSSION:  Omaveloxolone is a substrate of CYP3A4. The effect of|
04295|019|D|concomitant use with strong CYP3A4 inducers is unknown.  Concurrent|
04295|020|D|administration of a single dose of efavirenz (moderate CYP3A4 inducer) with|
04295|021|D|omaveloxolone decreased the maximum concentration (Cmax) and|
04295|022|D|area-under-the-curve (AUC) of omaveloxolone by 38% and 48%.(1)|
04295|023|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04295|024|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04295|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04295|026|D|rifapentine, and St. John's wort.(2,3)|
04295|027|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04295|028|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04295|029|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04295|030|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
04295|031|D|thioridazine, and tovorafenib.(2,3)|
04295|032|B||
04295|033|R|REFERENCES:|
04295|034|B||
04295|035|R|1.Skyclarys (omaveloxolone) US prescribing information. Reata|1
04295|036|R|  Pharmaceuticals, Inc. December 2024.|1
04295|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04295|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04295|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04295|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04295|041|R|  11/14/2017.|1
04295|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
04295|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04296|001|T|MONOGRAPH TITLE:  Amphetamines/Antacids; Urinary Alkalinizers|
04296|002|B||
04296|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04296|004|L|take action as needed.|
04296|005|B||
04296|006|A|MECHANISM OF ACTION:  Antacids and urinary alkalinizers increase the|
04296|007|A|absorption of amphetamines.|
04296|008|B||
04296|009|E|CLINICAL EFFECTS:  Concurrent use of amphetamines and antacids or urinary|
04296|010|E|alkalinizers may result in increased amphetamine levels and side effects.|
04296|011|B||
04296|012|P|PREDISPOSING FACTORS:  None determined.|
04296|013|B||
04296|014|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers state that|
04296|015|M|coadministration of alkalinizing agents with amphetamines should be|
04296|016|M|avoided.(1-3)|
04296|017|M|   The Canadian manufacturer states that concurrent use of proton pump|
04296|018|M|inhibitors and amphetamines should be avoided.(3)  The US manufacturer|
04296|019|M|states that patients receiving concurrent therapy should be monitored for|
04296|020|M|changes in clinical effects.(1)|
04296|021|M|   Monitor patients receiving concurrent therapy for changes in amphetamine|
04296|022|M|effectiveness and side effects.  If concurrent use cannot be avoided,|
04296|023|M|separate the administration times of amphetamines and antacids.|
04296|024|M|   Some vitamin preparations may contain sufficient quantities of calcium|
04296|025|M|and/or magnesium salts with antacid properties to interact as well.|
04296|026|B||
04296|027|D|DISCUSSION:  Concurrent use of alkalinizing agents with amphetamines|
04296|028|D|increase the absorption of amphetamines.  Co-administration of these should|
04296|029|D|be avoided because of the potential of increased actions of the|
04296|030|D|amphetamines.(1,2)|
04296|031|B||
04296|032|R|REFERENCES:|
04296|033|B||
04296|034|R|1.Adderall XR (amphetamine) US prescribing information. Shire US Inc. April,|1
04296|035|R|  2015.|1
04296|036|R|2.Adderall (amphetmine) US prescribing information. Barr Laboratories, Inc.|1
04296|037|R|  January, 2017.|1
04296|038|R|3.Adderall XR (amphetamine) Canadian prescribing information. Shire Canada|1
04296|039|R|  Inc. September 30, 2009.|1
04297|001|T|MONOGRAPH TITLE:  Oral Contraceptives/Exenatide Microsphere|
04297|002|B||
04297|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04297|004|L|of severe adverse interaction.|
04297|005|B||
04297|006|A|MECHANISM OF ACTION:  Exenatide delays gastric emptying, which may result in|
04297|007|A|decreased oral contraceptive absorption.(1,2)|
04297|008|B||
04297|009|E|CLINICAL EFFECTS:  Exenatide may result in decreased levels and|
04297|010|E|effectiveness of oral contraceptives.(1,2)|
04297|011|B||
04297|012|P|PREDISPOSING FACTORS:  None determined.|
04297|013|B||
04297|014|M|PATIENT MANAGEMENT:  Concurrent use of oral contraceptives with|
04297|015|M|extended-release exenatide is not recommended.  No recommendations are|
04297|016|M|available for the timing of administration of extended-release exenatide and|
04297|017|M|oral contraceptives.(1)|
04297|018|M|   Consider using non-sustained release exenatide.  If using non-sustained|
04297|019|M|release exenatide, oral contraceptives should be taken one hour before|
04297|020|M|administering exenatide non-sustained release.(2)|
04297|021|B||
04297|022|D|DISCUSSION:  In a study in 32 healthy females, administration of an oral|
04297|023|D|contraceptive 30 minutes after exenatide (5 mcg BID) decreased the maximum|
04297|024|D|concentration (Cmax) of ethinyl estradiol and levonorgestrel by 45% and 27%,|
04297|025|D|respectively.  Time to Cmax (Tmax) of ethinyl estradiol and levonorgestrel|
04297|026|D|increased by 3 hours and 3.5 hours, respectively.  Administering the oral|
04297|027|D|contraceptive one hour before exenatide decreased the Cmax of ethinyl|
04297|028|D|estradiol by 15%, but there was no effect on levonorgestrel.  There was no|
04297|029|D|significant effect on bioavailability with either regimen.(1-3)|
04297|030|B||
04297|031|R|REFERENCES:|
04297|032|B||
04297|033|R|1.Bydureon (exenatide) US prescribing information. AstraZeneca|1
04297|034|R|  Pharmaceuticals LP October, 2017.|1
04297|035|R|2.Byetta (exenatide) US prescribing information. AstraZeneca Pharmaceuticals|1
04297|036|R|  LP November, 2021.|1
04297|037|R|3.Kothare PA, Seger ME, Northrup J, Mace K, Mitchell MI, Linnebjerg H.|2
04297|038|R|  Effect of exenatide on the pharmacokinetics of a combination oral|2
04297|039|R|  contraceptive in healthy women: an open-label, randomised, crossover|2
04297|040|R|  trial. BMC Clin Pharmacol 2012;12:8.|2
04298|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Omaveloxolone|
04298|002|B||
04298|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04298|004|L|of severe adverse interaction.|
04298|005|B||
04298|006|A|MECHANISM OF ACTION:  Omaveloxolone is a weak CYP3A4 inducer.|
04298|007|A|Coadministration of omaveloxolone with hormonal contraceptives may lead to|
04298|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
04298|009|A|decreased hormonal concentrations.(1)|
04298|010|B||
04298|011|E|CLINICAL EFFECTS:  Concurrent use of omaveloxolone may reduce the|
04298|012|E|effectiveness of hormonal contraceptives.(1)|
04298|013|B||
04298|014|P|PREDISPOSING FACTORS:  None determined.|
04298|015|B||
04298|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of hormonal contraceptives with|
04298|017|M|omaveloxolone.  Advise females of reproductive potential to use effective|
04298|018|M|non-hormonal contraception (e.g., non-hormonal intrauterine system) or|
04298|019|M|additional non-hormonal contraceptive (e.g., condoms) during treatment with|
04298|020|M|omaveloxolone and for 28 days after the last dose.|
04298|021|M|   Women of reproductive age should be counseled not to rely on hormonal|
04298|022|M|contraceptives (including oral contraceptives, patches, implants, and/or|
04298|023|M|IUDs) for contraception.(1)|
04298|024|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04298|025|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04298|026|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04298|027|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
04298|028|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
04298|029|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
04298|030|M|and to seek medical advice if she does become pregnant.(2)|
04298|031|B||
04298|032|D|DISCUSSION:  Coadministration of omaveloxolone with midazolam (a CYP3A|
04298|033|D|substrate) decreased the area-under-curve (AUC) of midazolam by 45%.(1)|
04298|034|B||
04298|035|R|REFERENCES:|
04298|036|B||
04298|037|R|1.Skyclarys (omaveloxolone) US prescribing information. Reata|1
04298|038|R|  Pharmaceuticals, Inc. December 2024.|1
04298|039|R|2.Medicines and Healthcare products Regulatory Agency.|1
04298|040|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04298|041|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04298|042|R|  available at:|1
04298|043|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04298|044|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04298|045|R|  -and-contraceptive-efficacy September 15, 2016..|1
04299|001|T|MONOGRAPH TITLE:  Trofinetide/Laxatives|
04299|002|B||
04299|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04299|004|L|of severe adverse interaction.|
04299|005|B||
04299|006|A|MECHANISM OF ACTION:  Trofinetide commonly causes diarrhea of mild to|
04299|007|A|moderate severity.  Laxatives may increase the incidence or severity of|
04299|008|A|diarrhea.(1)|
04299|009|B||
04299|010|E|CLINICAL EFFECTS:  Concurrent use of laxatives with trofinetide may increase|
04299|011|E|the risk of severe diarrhea.(1)|
04299|012|B||
04299|013|P|PREDISPOSING FACTORS:  None determined.|
04299|014|B||
04299|015|M|PATIENT MANAGEMENT:  Patients should stop laxatives before starting|
04299|016|M|trofinetide.  If diarrhea occurs, consider anti-diarrheal treatment and|
04299|017|M|monitor hydration status.  If severe diarrhea or dehydration occurs,|
04299|018|M|interrupt, reduce dose, or discontinue trofinetide.(1)|
04299|019|B||
04299|020|D|DISCUSSION:  In clinical trials, 85% of patients on trofinetide developed|
04299|021|D|diarrhea.  Concurrent use of laxatives may increase this risk.(1)|
04299|022|B||
04299|023|R|REFERENCE:|
04299|024|B||
04299|025|R|1.Daybue (trofinetide) US presribing information. Acadia Pharmaceuticals|1
04299|026|R|  Inc. March, 2023.|1
04300|001|T|MONOGRAPH TITLE:  Zavegepant/OATP1B3 Inhibitors|
04300|002|B||
04300|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04300|004|L|of severe adverse interaction.|
04300|005|B||
04300|006|A|MECHANISM OF ACTION:  Zavegepant is a substrate of the organic anion|
04300|007|A|transporting polypeptide 1B3 (OATP1B3) transporter.  Inhibitors of OATP1B3|
04300|008|A|may increase zavegepant exposure.(1)|
04300|009|B||
04300|010|E|CLINICAL EFFECTS:  Concurrent use of OATP1B3 inhibitors may result in|
04300|011|E|increased levels of and toxicity from zavegepant.(1)|
04300|012|B||
04300|013|P|PREDISPOSING FACTORS:  None determined.|
04300|014|B||
04300|015|M|PATIENT MANAGEMENT:  Concurrent administration of zavegepant with OATP1B3|
04300|016|M|inhibitors should be avoided.(1)|
04300|017|B||
04300|018|D|DISCUSSION:  In a study, rifampin (an OATP1B3 and NTCP inhibitor) at steady|
04300|019|D|state increased the area-under-curve (AUC) and maximum concentration (Cmax)|
04300|020|D|of zavegepant by 2.3-fold and 2.2-fold.  Since rifampin is also a CYP3A4|
04300|021|D|inducer and zavegepant is metabolized by CYP3A4, concurrent use of|
04300|022|D|zavegepant with other OATP1B3 inhibitors that are not CYP3A4 inducers may|
04300|023|D|have an even more significant effect on zavegepant exposure.(1)|
04300|024|D|   OATP1B3 inhibitors include: atazanavir, belumosudil, cobicistat,|
04300|025|D|cyclosporine, darolutamide, enasidenib, encorafenib, fostemsavir,|
04300|026|D|glecaprevir/pibrentasvir, leflunomide, leniolisib, letermovir,|
04300|027|D|lopinavir/ritonavir, paritaprevir, resmetirom, rifampin, ritonavir,|
04300|028|D|teriflunomide, velpatasvir, voclosporin, and voxilaprevir.(2-9)|
04300|029|B||
04300|030|R|REFERENCES:|
04300|031|B||
04300|032|R|1.Zavzpret (zavegepant) US prescribing information. Pfizer Inc. March, 2023.|1
04300|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04300|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04300|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04300|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04300|037|R|  11/14/2017.|1
04300|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
04300|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04300|040|R|4.Nubeqa (darolutamide) US prescribing information. Bayer Healthcare|1
04300|041|R|  Pharmaceuticals, Inc. August, 2022.|1
04300|042|R|5.Braftovi (encorafenib) capsules US prescribing information. Array|1
04300|043|R|  BioPharma December, 2024.|1
04300|044|R|6.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
04300|045|R|  Inc. October, 2023.|1
04300|046|R|7.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
04300|047|R|  prescribing information. AbbVie Inc. December, 2019.|1
04300|048|R|8.Aubagio (teriflunomide) US prescribing information. Genzyme Corporation|1
04300|049|R|  November, 2020.|1
04300|050|R|9.McFeely SJ, Ritchie TK, Yu J, Nordmark A, Berglund EG, Levy RH,|6
04300|051|R|  Ragueneau-Majlessi I. Inhibitors of Organic Anion-Transporting|6
04300|052|R|  Polypeptides 1B1 and 1B3: Clinical  Relevance and Regulatory Perspective.|6
04300|053|R|  J Clin Pharmacol 2020 Aug;60(8):1087-1098.|6
04301|001|T|MONOGRAPH TITLE:  Zavegepant/Intranasal Decongestants|
04301|002|B||
04301|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04301|004|L|take action as needed.|
04301|005|B||
04301|006|A|MECHANISM OF ACTION:  Intranasal decongestants may decrease the absorption|
04301|007|A|of zavegepant.(1)|
04301|008|B||
04301|009|E|CLINICAL EFFECTS:  Concurrent administration of intranasal decongestants may|
04301|010|E|result in decreased systemic exposure and effectiveness of zavegepant.(1)|
04301|011|B||
04301|012|P|PREDISPOSING FACTORS:  None determined.|
04301|013|B||
04301|014|M|PATIENT MANAGEMENT:  Avoid concurrent use of intranasal decongestants with|
04301|015|M|zavegepant.  If concurrent use is unavoidable, use the decongestant at least|
04301|016|M|1 hour after zavegepant.(1)|
04301|017|B||
04301|018|D|DISCUSSION:  Intranasal decongestants may lower absorption of zavegepant.|
04301|019|D|This effect has not been clinically evaluated.(1)|
04301|020|B||
04301|021|R|REFERENCE:|
04301|022|B||
04301|023|R|1.Zavzpret (zavegepant) US prescribing information. Pfizer Inc. March, 2023.|1
04302|001|T|MONOGRAPH TITLE:  Fluorouracil & Fluorouracil Prodrugs/Allopurinol|
04302|002|B||
04302|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04302|004|L|of severe adverse interaction.|
04302|005|B||
04302|006|A|MECHANISM OF ACTION:  Allopurinol may decrease conversion of fluorouracil to|
04302|007|A|its active metabolites, FdUMP and FUTP.(1-4)|
04302|008|A|   Capecitabine and tegafur are prodrugs of fluorouracil.|
04302|009|B||
04302|010|E|CLINICAL EFFECTS:  Concurrent use of allopurinol with fluorouracil or|
04302|011|E|fluorouracil prodrugs (e.g., capecitabine, tegafur) may result in decreased|
04302|012|E|levels of the active metabolites of fluorouracil and loss of efficacy.|
04302|013|B||
04302|014|P|PREDISPOSING FACTORS:  None determined.|
04302|015|B||
04302|016|M|PATIENT MANAGEMENT:  The concurrent use of fluorouracil or fluorouracil|
04302|017|M|prodrugs with allopurinol should be avoided.(1-4)|
04302|018|B||
04302|019|D|DISCUSSION:  This is a theoretical interaction based on non-clinical data.|
04302|020|D|   Allopurinol may decrease the levels of the active metabolites of|
04302|021|D|fluorouracil, FdUMP and FUTP.  Capecitabine and tegafur are prodrugs of|
04302|022|D|fluorouracil.(1-4)|
04302|023|B||
04302|024|R|REFERENCES:|
04302|025|B||
04302|026|R|1.Xeloda (capecitabine) US prescribing information. Roche Pharmaceuticals|1
04302|027|R|  October, 2025.|1
04302|028|R|2.Xeloda (capecitabine) UK Summary of Product Characteristics. Roche|1
04302|029|R|  Products Limited April, 2019.|1
04302|030|R|3.Teysuno (tegafur/gimeracil/oteracil) UK summary of product|1
04302|031|R|  characteristics. Nordic Group B.V. February, 2022.|1
04302|032|R|4.Uftoral (tegafur/uracil) UK summary of product characteristics. Merck|1
04302|033|R|  Pharmaceuticals March 9, 2006.|1
04303|001|T|MONOGRAPH TITLE:  Ganciclovir; Valganciclovir/Maribavir|
04303|002|B||
04303|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04303|004|L|of severe adverse interaction.|
04303|005|B||
04303|006|A|MECHANISM OF ACTION:  Maribavir may inhibit pUL97 protein kinase which|
04303|007|A|catalyzes the phosphorylation step required for activation of ganciclovir or|
04303|008|A|valganciclovir.(1)|
04303|009|B||
04303|010|E|CLINICAL EFFECTS:  Concurrent administration of maribavir with ganciclovir|
04303|011|E|or valganciclovir may antagonize the antiviral activity of ganciclovir or|
04303|012|E|valganciclovir, resulting in decreased clinical efficacy and/or virological|
04303|013|E|failure of ganciclovir and valganciclovir.(1)|
04303|014|B||
04303|015|P|PREDISPOSING FACTORS:  None determined.|
04303|016|B||
04303|017|M|PATIENT MANAGEMENT:  The manufacturer of maribavir states that the|
04303|018|M|concurrent use of maribavir with ganciclovir or valganciclovir is not|
04303|019|M|recommended.(1)|
04303|020|B||
04303|021|D|DISCUSSION:  Ganciclovir and valganciclovir require activation via|
04303|022|D|phosphorylation to the active form by human CMV pUL97 protein kinase.(2,3)|
04303|023|D|   The antiviral activity of maribavir is mediated by competitive inhibition|
04303|024|D|of the protein kinase activity of pUL97 and may antagonize the antiviral|
04303|025|D|activity of ganciclovir or valganciclovir.(1)|
04303|026|D|   In the setting of combination therapy, in vitro data suggests|
04303|027|D|antagonistic activity when maribavir is coadministered with ganciclovir or|
04303|028|D|valganciclovir.(4-7)|
04303|029|B||
04303|030|R|REFERENCES:|
04303|031|B||
04303|032|R|1.Livtencity (maribavir) US prescribing information. Takeda Pharmaceuticals|1
04303|033|R|  America, Inc. November, 2021.|1
04303|034|R|2.Cytovene IV (ganciclovir) US prescribing information. Genentech Inc.|1
04303|035|R|  August, 2018.|1
04303|036|R|3.Valcyte (valganciclovir) US prescribing information. Genentech June, 2017.|1
04303|037|R|4.Gandhi RG, Kotton CN. Evaluating the Safety of Maribavir for the Treatment|6
04303|038|R|  of Cytomegalovirus. Ther Clin Risk Manag 2022;18:223-232.|6
04303|039|R|5.Kleiboeker HL, Descourouez JL, Schulz LT, Mandelbrot DA, Odorico JS, Rice|6
04303|040|R|  JP, Saddler CM, Smith JA, Jorgenson MR. Maribavir for the Management of|6
04303|041|R|  Cytomegalovirus in Adult Transplant Recipients: A  Review of the|6
04303|042|R|  Literature and Practical Considerations. Ann Pharmacother 2022 Aug 24;|6
04303|043|R|  10600280221118959.|6
04303|044|R|6.Chou S, Ercolani RJ, Derakhchan K. Antiviral activity of maribavir in|5
04303|045|R|  combination with other drugs active against  human cytomegalovirus.|5
04303|046|R|  Antiviral Res 2018 Sep;157:128-133.|5
04303|047|R|7.Chou S. Cytomegalovirus UL97 mutations in the era of ganciclovir and|6
04303|048|R|  maribavir. Rev Med Virol 2008 Jul-Aug;18(4):233-46.|6
04304|001|T|MONOGRAPH TITLE:  Selected Steroids/Nirmatrelvir-Ritonavir|
04304|002|B||
04304|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04304|004|L|take action as needed.|
04304|005|B||
04304|006|A|MECHANISM OF ACTION:  Nirmatrelvir/ritonavir may inhibit the metabolism of|
04304|007|A|corticosteroids metabolized by CYP3A4.(1)|
04304|008|B||
04304|009|E|CLINICAL EFFECTS:  Nirmatrelvir/ritonavir may result in increased systemic|
04304|010|E|exposure to and effects from corticosteroids metabolized by CYP3A4.(1)|
04304|011|B||
04304|012|P|PREDISPOSING FACTORS:  None determined.|
04304|013|B||
04304|014|M|PATIENT MANAGEMENT:  Coadministration with corticosteroids of all routes of|
04304|015|M|administration of which exposures are significantly increased by strong|
04304|016|M|CYP3A4 inhibitors can increase the risk of Cushing's syndrome and adrenal|
04304|017|M|suppression.  However, the risk of Cushing's syndrome and adrenal|
04304|018|M|suppression associated with short-term use of a strong CYP3A4 inhibitor is|
04304|019|M|low.(1)|
04304|020|M|   The manufacturer of nirmatrelvir/ritonavir recommends considering|
04304|021|M|alternative corticosteroids including beclomethasone, prednisone, and|
04304|022|M|prednisolone.(1)|
04304|023|B||
04304|024|D|DISCUSSION:  Concurrent use of a single dose of midazolam 2 mg, a CYP3A4|
04304|025|D|substrate, with nirmatrelvir-ritonavir (300 mg/100 mg twice daily for nine|
04304|026|D|doses) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
04304|027|D|of midazolam by 37% and 143%, respectively.(1)|
04304|028|D|   A study in 18 healthy subjects examined the effects of ritonavir (100 mg|
04304|029|D|twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects,|
04304|030|D|fluticasone was undetectable (<10 pg/ml) when administered alone.  In|
04304|031|D|subjects in whom fluticasone was detectable when given alone, Cmax and|
04304|032|D|area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively.|
04304|033|D|With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml|
04304|034|D|and 3102.6 pg x hr/ml, respectively.(7,11,13) This reflects increases in|
04304|035|D|Cmax and AUC by 25-fold and 350-fold, respectively.(3)  The cortisol AUC|
04304|036|D|decreased by 86%.(3-6)|
04304|037|D|   In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4|
04304|038|D|and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold|
04304|039|D|and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(7)|
04304|040|D|   Selected steroids linked to this monograph include: budesonide,|
04304|041|D|ciclesonide, dexamethasone, fluticasone, methylprednisolone, and|
04304|042|D|triamcinolone.(8)|
04304|043|B||
04304|044|R|REFERENCES:|
04304|045|B||
04304|046|R|1.Paxlovid (nirmatrelvir tablets and ritonavir tablets) US prescribing|1
04304|047|R|  information. Pfizer Inc. February, 2025.|1
04304|048|R|2.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
04304|049|R|  December, 2019.|1
04304|050|R|3.Flovent HFA inhalation (fluticasone propionate) US prescribing|1
04304|051|R|  information. GlaxoSmithKline January, 2019.|1
04304|052|R|4.Flovent Rotadisk (fluticasone propionate) US prescribing information.|1
04304|053|R|  GlaxoSmithKline March, 2004.|1
04304|054|R|5.Flonase Nasal Spray (fluticasone propionate) US prescribing information.|1
04304|055|R|  GlaxoSmithKline January, 2019.|1
04304|056|R|6.Flovent Diskus (fluticasone propionate) US prescribing information.|1
04304|057|R|  GlaxoSmithKline January, 2019.|1
04304|058|R|7.Penzak SR, Formentini E, Alfaro RM, Long M, Natarajan V, Kovacs J.|2
04304|059|R|  Prednisolone pharmacokinetics in the presence and absence of ritonavir|2
04304|060|R|  after oral prednisone administration to healthy volunteers. J Acquir|2
04304|061|R|  Immune Defic Syndr 2005 Dec 15;40(5):573-80.|2
04304|062|R|8.This information is based on an extract from the Certara Drug Interaction|6
04304|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04305|001|T|MONOGRAPH TITLE:  Valproate/Methotrexate|
04305|002|B||
04305|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04305|004|L|take action as needed.|
04305|005|B||
04305|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Methotrexate may|
04305|007|A|compete with valproate for binding to albumin and displace valproate.|
04305|008|A|Unbound valproate may be rapidly metabolized.(1-3)|
04305|009|B||
04305|010|E|CLINICAL EFFECTS:  Concurrent use of methotrexate with valproate may|
04305|011|E|decrease the levels and effectiveness of valproate.(1)|
04305|012|B||
04305|013|P|PREDISPOSING FACTORS:  None determined.|
04305|014|B||
04305|015|M|PATIENT MANAGEMENT:  Monitor valproate levels and clinical response when|
04305|016|M|starting or stopping methotrexate therapy.  Valproate dosage adjustments may|
04305|017|M|be necessary.(1)|
04305|018|B||
04305|019|D|DISCUSSION:  A 6-year-old male with acute lymphoblastic leukemia who|
04305|020|D|developed epileptic symptoms during chemotherapy was maintained on valproate|
04305|021|D|30 mg/kg/day.  Upon receipt of methotrexate-containing chemotherapy (5|
04305|022|D|gram/m2), the patient developed a focal epileptic attack that became|
04305|023|D|generalized.  Serum valproate levels were found to have dropped from 800|
04305|024|D|mmol/L before methotrexate to 196 mmol/L after methotrexate.  Before the|
04305|025|D|next dose of methotrexate, valproate dosage was increased and clonazepam was|
04305|026|D|added.  Valproate levels again dropped from 660 mmol/L to 172 mmol/L, but no|
04305|027|D|seizures developed.(2)|
04305|028|D|   In another case report, a 21-year-old male who was seizure-free for 5|
04305|029|D|years on valproic acid 600 mg/day for juvenile Absence Epilepsy started|
04305|030|D|methotrexate 15 mg/week for psoriasis.  His absence seizures relapsed and|
04305|031|D|serum valproate levels was found to have dropped from 92 mcg/mL before|
04305|032|D|methotrexate administration to 18 mcg/mL after methotrexate.(3)|
04305|033|B||
04305|034|R|REFERENCES:|
04305|035|B||
04305|036|R|1.Depakote (divalproex sodium) US prescribing information. AbbVie Inc.|1
04305|037|R|  February, 2023.|1
04305|038|R|2.Schroder H, Ostergaard JR. Interference of high-dose methotrexate in the|3
04305|039|R|  metabolism of valproate?. Pediatr Hematol Oncol 1994 Jul-Aug;11(4):445-9.|3
04305|040|R|3.Cherian A, Shetty SC, Divya KP, Pavuluri H. Weekly methotrexate may reduce|3
04305|041|R|  valproate levels causing relapse of genetic  generalized epilepsy.|3
04305|042|R|  Epilepsy Behav Rep 2021;16:100457.|3
04306|001|T|MONOGRAPH TITLE:  Live Vaccines/Leniolisib|
04306|002|B||
04306|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04306|004|L|of severe adverse interaction.|
04306|005|B||
04306|006|A|MECHANISM OF ACTION:  Leniolisib modifies the immune system.  Immune|
04306|007|A|response to live vaccines may be decreased during treatment with|
04306|008|A|leniolisib.(1)|
04306|009|B||
04306|010|E|CLINICAL EFFECTS:  The expected serum antibody response may not be|
04306|011|E|obtained.(1)|
04306|012|B||
04306|013|P|PREDISPOSING FACTORS:  Immunosuppressive diseases (e.g. hematologic|
04306|014|P|malignancies, HIV disease), treatments (e.g. radiation) and drugs may all|
04306|015|P|increase the magnitude of immunodeficiency.|
04306|016|B||
04306|017|M|PATIENT MANAGEMENT:  The manufacturer of leniolisib states live, attenuated|
04306|018|M|vaccinations may be less effective if administered during leniolisib|
04306|019|M|treatment.(1)|
04306|020|B||
04306|021|D|DISCUSSION:  Killed or inactivated vaccines do not pose a danger to|
04306|022|D|immunocompromised patients.(1)|
04306|023|B||
04306|024|R|REFERENCES:|
04306|025|B||
04306|026|R|1.Joenja (leniolisib) US prescribing information. Pharming Healthcare Inc.|1
04306|027|R|  May, 2025.|1
04306|028|R|2.Centers for Disease Control and Prevention. General Recommendations on|1
04306|029|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
04306|030|R|  Practices (ACIP). MMWR.  Available at:|1
04306|031|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
04306|032|R|  February 17, 2022;60(RR No.2):1-68.|1
04307|001|T|MONOGRAPH TITLE:  Leniolisib/Strong CYP3A4 Inhibitors|
04307|002|B||
04307|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04307|004|L|of severe adverse interaction.|
04307|005|B||
04307|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04307|007|A|of leniolisib.(1)|
04307|008|B||
04307|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04307|010|E|in increased levels of and effects from leniolisib including neutropenia.(1)|
04307|011|E|Common side effects may also include sinusitis.(1)|
04307|012|B||
04307|013|P|PREDISPOSING FACTORS:  None determined.|
04307|014|B||
04307|015|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04307|016|M|leniolisib should be avoided.(1)|
04307|017|B||
04307|018|D|DISCUSSION:  Leniolisib exposure was increased 2-fold when coadministered|
04307|019|D|with itraconazole, a strong CYP3A4 inhibitor.(1)|
04307|020|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04307|021|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04307|022|D|ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone,|
04307|023|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
04307|024|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04307|025|D|troleandomycin, tucatinib, and voriconazole.(2)|
04307|026|B||
04307|027|R|REFERENCES:|
04307|028|B||
04307|029|R|1.Joenja (leniolisib) US prescribing information. Pharming Healthcare Inc.|1
04307|030|R|  May, 2025.|1
04307|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04307|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04308|001|T|MONOGRAPH TITLE:  Leniolisib/Strong and Moderate CYP3A4 Inducers|
04308|002|B||
04308|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04308|004|L|of severe adverse interaction.|
04308|005|B||
04308|006|A|MECHANISM OF ACTION:  Leniolisib is metabolized by CYP3A4.  Strong and|
04308|007|A|moderate inducers of CYP3A4 may increase the metabolism of leniolisib.(1)|
04308|008|B||
04308|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
04308|010|E|may result in decreased levels and effectiveness of leniolisib.(1)|
04308|011|B||
04308|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04308|013|P|of the inducer for longer than 1-2 weeks.|
04308|014|B||
04308|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of leniolisib with strong or|
04308|016|M|moderate CYP3A4 inducers.(1)|
04308|017|B||
04308|018|D|DISCUSSION:  PBPK model-based simulations predicted a maximum decrease of|
04308|019|D|78% and 58% in leniolisib area-under-curve (AUC) with rifampin (strong|
04308|020|D|CYP3A4 inducer) and efavirenz (moderate CYP3A4 inducer), respectively.(1)|
04308|021|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04308|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04308|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04308|024|D|rifapentine, and St. John's wort.(2,3)|
04308|025|D|   Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dabrafenib,|
04308|026|D|dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib,|
04308|027|D|mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib,|
04308|028|D|repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and|
04308|029|D|tovorafenib.(2,3)|
04308|030|B||
04308|031|R|REFERENCES:|
04308|032|B||
04308|033|R|1.Joenja (leniolisib) US prescribing information. Pharming Healthcare Inc.|1
04308|034|R|  May, 2025.|1
04308|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04308|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04308|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04308|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04308|039|R|  11/14/2017.|1
04308|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04308|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04309|001|T|MONOGRAPH TITLE:  Patiromer/Telmisartan|
04309|002|B||
04309|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04309|004|L|take action as needed.|
04309|005|B||
04309|006|A|MECHANISM OF ACTION:  Patiromer may bind to telmisartan.(1)|
04309|007|B||
04309|008|E|CLINICAL EFFECTS:  Concurrent use may result in decreased gastrointestinal|
04309|009|E|absorption and loss of efficacy of telmisartan.(1)|
04309|010|B||
04309|011|P|PREDISPOSING FACTORS:  None determined.|
04309|012|B||
04309|013|M|PATIENT MANAGEMENT:  The US manufacturer of patiromer recommends|
04309|014|M|administering patiromer at least 3 hours before or 3 hours after|
04309|015|M|telmisartan.(1)|
04309|016|B||
04309|017|D|DISCUSSION:  An in vitro binding study found potentially clinically|
04309|018|D|significant binding of telmisartan by patiromer.  It is recommended to take|
04309|019|D|these drugs 3 hours apart.(1)|
04309|020|B||
04309|021|R|REFERENCE:|
04309|022|B||
04309|023|R|1.Veltassa (patiromer) US prescribing information. Relypasa, Inc. October,|1
04309|024|R|  2023.|1
04310|001|T|MONOGRAPH TITLE:  Patiromer/Bisoprolol; Carvedilol; Nebivolol|
04310|002|B||
04310|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04310|004|L|take action as needed.|
04310|005|B||
04310|006|A|MECHANISM OF ACTION:  Patiromer may bind to bisoprolol, carvedilol, and|
04310|007|A|nebivolol.(1)|
04310|008|B||
04310|009|E|CLINICAL EFFECTS:  Concurrent use may result in decreased gastrointestinal|
04310|010|E|absorption and loss of efficacy of bisoprolol, carvedilol, and nebivolol.(1)|
04310|011|B||
04310|012|P|PREDISPOSING FACTORS:  None determined.|
04310|013|B||
04310|014|M|PATIENT MANAGEMENT:  The US manufacturer of patiromer recommends|
04310|015|M|administering patiromer at least 3 hours before or 3 hours after bisoprolol,|
04310|016|M|carvedilol, or nebivolol.(1)|
04310|017|B||
04310|018|D|DISCUSSION:  An in vitro binding study found potentially clinically|
04310|019|D|significant binding of bisoprolol, carvedilol, and nebivolol by patiromer.|
04310|020|D|It is recommended to take these drugs 3 hours apart.(1)|
04310|021|B||
04310|022|R|REFERENCE:|
04310|023|B||
04310|024|R|1.Veltassa (patiromer) US prescribing information. Relypasa, Inc. October,|1
04310|025|R|  2023.|1
04311|001|T|MONOGRAPH TITLE:  Patiromer/Mycophenolate|
04311|002|B||
04311|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04311|004|L|take action as needed.|
04311|005|B||
04311|006|A|MECHANISM OF ACTION:  Patiromer may bind to mycophenolate.(1)|
04311|007|B||
04311|008|E|CLINICAL EFFECTS:  Concurrent use may result in decreased gastrointestinal|
04311|009|E|absorption and loss of efficacy of mycophenolate.(1)|
04311|010|B||
04311|011|P|PREDISPOSING FACTORS:  None determined.|
04311|012|B||
04311|013|M|PATIENT MANAGEMENT:  The US manufacturer of patiromer recommends|
04311|014|M|administering patiromer at least 3 hours before or 3 hours after|
04311|015|M|mycophenolate.(1)|
04311|016|B||
04311|017|D|DISCUSSION:  An in vitro binding study found potentially clinically|
04311|018|D|significant binding of mycophenolate by patiromer.  It is recommended to|
04311|019|D|take these drugs 3 hours apart.(1)|
04311|020|B||
04311|021|R|REFERENCE:|
04311|022|B||
04311|023|R|1.Veltassa (patiromer) US prescribing information. Relypasa, Inc. October,|1
04311|024|R|  2023.|1
04312|001|T|MONOGRAPH TITLE:  Patiromer/Quinidine|
04312|002|B||
04312|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04312|004|L|take action as needed.|
04312|005|B||
04312|006|A|MECHANISM OF ACTION:  Patiromer may bind to quinidine.(1)|
04312|007|B||
04312|008|E|CLINICAL EFFECTS:  Concurrent use may result in decreased gastrointestinal|
04312|009|E|absorption and loss of efficacy of quinidine.(1)|
04312|010|B||
04312|011|P|PREDISPOSING FACTORS:  None determined.|
04312|012|B||
04312|013|M|PATIENT MANAGEMENT:  The US manufacturer of patiromer recommends|
04312|014|M|administering patiromer at least 3 hours before or 3 hours after|
04312|015|M|quinidine.(1)|
04312|016|B||
04312|017|D|DISCUSSION:  An in vitro binding study found potentially clinically|
04312|018|D|significant binding of quinidine by patiromer.  It is recommended to take|
04312|019|D|these drugs 3 hours apart.(1)|
04312|020|B||
04312|021|R|REFERENCE:|
04312|022|B||
04312|023|R|1.Veltassa (patiromer) US prescribing information. Relypasa, Inc. October,|1
04312|024|R|  2023.|1
04313|001|T|MONOGRAPH TITLE:  Patiromer/Thiamine|
04313|002|B||
04313|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04313|004|L|take action as needed.|
04313|005|B||
04313|006|A|MECHANISM OF ACTION:  Patiromer may bind to thiamine.(1)|
04313|007|B||
04313|008|E|CLINICAL EFFECTS:  Concurrent use may result in decreased gastrointestinal|
04313|009|E|absorption and loss of efficacy of thiamine.(1)|
04313|010|B||
04313|011|P|PREDISPOSING FACTORS:  None determined.|
04313|012|B||
04313|013|M|PATIENT MANAGEMENT:  The US manufacturer of patiromer recommends|
04313|014|M|administering patiromer at least 3 hours before or 3 hours after|
04313|015|M|thiamine.(1)|
04313|016|B||
04313|017|D|DISCUSSION:  An in vitro binding study found potentially clinically|
04313|018|D|significant binding of thiamine by patiromer.  It is recommended to take|
04313|019|D|these drugs 3 hours apart.(1)|
04313|020|B||
04313|021|R|REFERENCE:|
04313|022|B||
04313|023|R|1.Veltassa (patiromer) US prescribing information. Relypasa, Inc. October,|1
04313|024|R|  2023.|1
04314|001|T|MONOGRAPH TITLE:  Zanubrutinib/Moderate CYP3A4 Inducers|
04314|002|B||
04314|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04314|004|L|of severe adverse interaction.|
04314|005|B||
04314|006|A|MECHANISM OF ACTION:  Zanubrutinib is a substrate of CYP3A4.  Moderate|
04314|007|A|inducers of CYP3A4 may induce the metabolism of zanubrutinib.(1)|
04314|008|B||
04314|009|E|CLINICAL EFFECTS:  The concurrent administration of moderate CYP3A4 inducers|
04314|010|E|may result in decreased levels and effectiveness of zanubrutinib.(1)|
04314|011|B||
04314|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04314|013|P|of the inducer for longer than 1-2 weeks.|
04314|014|B||
04314|015|M|PATIENT MANAGEMENT:  The manufacturer of zanubrutinib states that concurrent|
04314|016|M|use with moderate CYP3A4 inducers should be avoided.  If concurrent use|
04314|017|M|cannot be avoided, increase zanubrutinib dosage to 320 mg twice daily.(1)|
04314|018|B||
04314|019|D|DISCUSSION:  Co-administration of multiple doses of efavirenz, a moderate|
04314|020|D|CYP3A4 inducer, is predicted to decrease zanubrutinib Cmax by 58% and AUC by|
04314|021|D|60%.(1)|
04314|022|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04314|023|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04314|024|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04314|025|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04314|026|D|thioridazine, and tovorafenib.(2-3)|
04314|027|B||
04314|028|R|REFERENCES:|
04314|029|B||
04314|030|R|1.Brukinsa (zanubrutinib) US prescribing information. BeiGene June, 2025.|1
04314|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04314|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04314|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04314|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04314|035|R|  11/14/2017.|1
04314|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
04314|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04315|001|T|MONOGRAPH TITLE:  Methoxsalen/Selected Photosensitizers|
04315|002|B||
04315|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04315|004|L|of severe adverse interaction.|
04315|005|B||
04315|006|A|MECHANISM OF ACTION:  Methoxsalen causes photosensitivity due to residual|
04315|007|A|drug which is present in all parts of the skin from photopheresis.|
04315|008|A|Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic|
04315|009|A|staining dyes (such as methylene blue, rose bengal, or toluidine blue),|
04315|010|A|phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone,|
04315|011|A|naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort,|
04315|012|A|sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known|
04315|013|A|photosensitizers.(1)|
04315|014|B||
04315|015|E|CLINICAL EFFECTS:  Concurrent use of methoxsalen in patients taking|
04315|016|E|anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic|
04315|017|E|staining dyes (such as methylene blue, rose bengal, or toluidine blue),|
04315|018|E|phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone,|
04315|019|E|naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort,|
04315|020|E|sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the|
04315|021|E|risk of phototoxicity.(1)|
04315|022|B||
04315|023|P|PREDISPOSING FACTORS:  None determined.|
04315|024|B||
04315|025|M|PATIENT MANAGEMENT:  The US manufacturer of methoxsalen states that|
04315|026|M|concurrent use of methoxsalen with anthralin, coal tar and derivatives,|
04315|027|M|fluoroquinolones, griseofulvin, organic staining dyes (such as methylene|
04315|028|M|blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such|
04315|029|M|as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic|
04315|030|M|acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas,|
04315|031|M|tetracyclines, and thiazides should be avoided.(1)|
04315|032|B||
04315|033|D|DISCUSSION:  All patients who have received methoxsalen become|
04315|034|D|photosensitive.  It is unknown what the risk of photosensitivity reactions|
04315|035|D|is when methoxsalen is used concurrently with other photosensitizing|
04315|036|D|agents.(1)|
04315|037|B||
04315|038|R|REFERENCE:|
04315|039|B||
04315|040|R|1.Uvadex (methoxsalen) US prescribing information. Therakos, Inc. May, 2021.|1
04316|001|T|MONOGRAPH TITLE:  Bortezomib/Strong CYP3A4 Inhibitors|
04316|002|B||
04316|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04316|004|L|take action as needed.|
04316|005|B||
04316|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04316|007|A|of bortezomib.(1)|
04316|008|B||
04316|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 may result|
04316|010|E|in increased levels of and effects from bortezomib including peripheral|
04316|011|E|neuropathy, thrombocytopenia, and neutropenia.(1)|
04316|012|B||
04316|013|P|PREDISPOSING FACTORS:  Patients with moderate to severe hepatic impairment|
04316|014|P|have increased exposure to bortezomib.|
04316|015|B||
04316|016|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04316|017|M|bortezomib should be approached with caution.  If concurrent use is|
04316|018|M|necessary, monitor patients for signs of bortezomib toxicity and consider a|
04316|019|M|dose reduction of bortezomib.(1)|
04316|020|B||
04316|021|D|DISCUSSION:  In a 2-way crossover study, 12 patients were randomized to|
04316|022|D|receive concomitant ketoconazole (a strong CYP3A4 inhibitor) during one of|
04316|023|D|either 2 cycles of bortezomib.  Ketoconazole 400 mg daily for 4 days|
04316|024|D|increased the AUC of bortezomib by 35% and increased blood proteasome|
04316|025|D|inhibitory effect by 24-46%.  However, the frequency and grade of adverse|
04316|026|D|events were not increased by ketoconazole.(2)|
04316|027|D|   In a retrospective review, 6 patients with relapsed multiple myeloma|
04316|028|D|received bortezomib; 2 patients were also on itraconazole (a strong CYP3A4|
04316|029|D|inhibitor), 1 patient was on lansoprazole (a CYP2C19 inhibitor), and 1|
04316|030|D|patient was on itraconazole and lansoprazole.  New or worsening peripheral|
04316|031|D|neuropathy and grade 4 thrombocytopenia occurred in all 3 patients on|
04316|032|D|itraconazole, and grade 3 neutropenia occurred in 2 of the patients,|
04316|033|D|compared to none of the patients not on itraconazole.(3)|
04316|034|D|   In a case report, two patient with refractory multiple myeloma started on|
04316|035|D|bortezomib with itraconazole or voriconazole and developed paralytic ileus|
04316|036|D|12 and 15 days later.  The authors suggest that these were cases of|
04316|037|D|autonomic neuropathy caused by concomitant use of itraconazole or|
04316|038|D|voriconazole with bortezomib.(4)|
04316|039|D|   In a retrospective study of 48 patients with relapsed or refractory|
04316|040|D|multiple myeloma on bortezomib, concomitant use of itraconazole was a risk|
04316|041|D|factor for developing early-onset peripheral neuropathy [OR 19.0|
04316|042|D|(1.89-190.96, p=0.01)] on multivariate logistic regression analysis.(5)|
04316|043|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04316|044|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04316|045|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
04316|046|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04316|047|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04316|048|D|troleandomycin, tucatinib, and voriconazole.(6)|
04316|049|B||
04316|050|R|REFERENCES:|
04316|051|B||
04316|052|R|1.Velcade (bortezomib) US prescribing information. Mellennium|1
04316|053|R|  Pharmaceuticals, Inc. October, 2021.|1
04316|054|R|2.Venkatakrishnan K, Rader M, Ramanathan RK, Ramalingam S, Chen E, Riordan|2
04316|055|R|  W, Trepicchio W, Cooper M, Karol M, von Moltke L, Neuwirth R, Egorin M,|2
04316|056|R|  Chatta G. Effect of the CYP3A inhibitor ketoconazole on the|2
04316|057|R|  pharmacokinetics and  pharmacodynamics of bortezomib in patients with|2
04316|058|R|  advanced solid tumors: a  prospective, multicenter, open-label,|2
04316|059|R|  randomized, two-way crossover drug-drug  interaction study. Clin Ther|2
04316|060|R|  2009;31 Pt 2:2444-58.|2
04316|061|R|3.Iwamoto T, Ishibashi M, Fujieda A, Masuya M, Katayama N, Okuda M. Drug|2
04316|062|R|  interaction between itraconazole and bortezomib: exacerbation of|2
04316|063|R|  peripheral  neuropathy and thrombocytopenia induced by bortezomib.|2
04316|064|R|  Pharmacotherapy 2010 Jul;30(7):661-5.|2
04316|065|R|4.Koda Y, Mori T, Shimizu T, Kato J, Yamane A, Sadahira K, Tsukada Y,|3
04316|066|R|  Yokoyama K, Hashimoto N, Hattori Y, Okamoto S. Early onset of paralytic|3
04316|067|R|  ileus caused by simultaneous administration of  bortezomib and azole|3
04316|068|R|  antifungals in multiple myeloma patients. Rinsho Ketsueki 2012 Aug;|3
04316|069|R|  53(8):760-4.|3
04316|070|R|5.Hashimoto N, Yokoyama K, Sadahira K, Ueda T, Tsukada Y, Okamoto S.|2
04316|071|R|  Itraconazole may increase the risk of early-onset bortezomib-induced|2
04316|072|R|  peripheral  neuropathy. Int J Hematol 2012 Dec;96(6):758-63.|2
04316|073|R|6.This information is based on an extract from the Certara Drug Interaction|6
04316|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04317|001|T|MONOGRAPH TITLE:  Pexidartinib/Moderate CYP3A4 Inhibitors & Substrates|
04317|002|B||
04317|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04317|004|L|of severe adverse interaction.|
04317|005|B||
04317|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04317|007|A|metabolism of pexidartinib.(1,2)  Fedratinib,(2) oral lefamulin,(3)|
04317|008|A|rilzabrutinib,(4)and voxelotor(5) are moderate CYP3A4 inhibitors.|
04317|009|A|   Moderate inducers of CYP3A4 may induce the metabolism of fedratinib,(2)|
04317|010|A|lefamulin,(3) rilzabrutinib,(4) and voxelotor.(5)  Pexidartinib is a|
04317|011|A|moderate CYP3A4 inducer.(1)|
04317|012|B||
04317|013|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04317|014|E|result in elevated levels and increased effects of pexidartinib, such as|
04317|015|E|hepatotoxicity.(1,2)  Symptoms can include nausea, vomiting, jaundice, dark|
04317|016|E|urine, abdominal pain, and unexplained fatigue.|
04317|017|E|   The concurrent use of a moderate CYP3A4 inducer may result in decreased|
04317|018|E|levels and effectiveness of fedratinib,(2) lefamulin,(3) rilzabrutinib,(4)|
04317|019|E|and voxelotor.(5)|
04317|020|B||
04317|021|P|PREDISPOSING FACTORS:  None determined.|
04317|022|B||
04317|023|M|PATIENT MANAGEMENT:  The US manufacturer of pexidartinib states that|
04317|024|M|pexidartinib coadministration with moderate inhibitors of CYP3A4 should be|
04317|025|M|avoided.(1)|
04317|026|M|   The US manufacturers of fedratinib states that concurrent use with|
04317|027|M|moderate CYP3A4 inducers should be avoided.(2)|
04317|028|M|   The US manufacturers of lefamulin states that concurrent use with|
04317|029|M|moderate CYP3A4 inducers should be avoided.(3)|
04317|030|M|   The US manufacturer of rilzabrutinib states that concurrent use with|
04317|031|M|moderate CYP3A4 inducers should be avoided.(4)|
04317|032|M|   The US manufacturers of voxelotor states that concurrent use with|
04317|033|M|moderate CYP3A4 inducers should be avoided.(5)|
04317|034|B||
04317|035|D|DISCUSSION:  Coadministration of fluconazole (a moderate CYP3A4 inhibitor)|
04317|036|D|increased pexidartinib maximum concentration (Cmax) and area-under-the-curve|
04317|037|D|(AUC) by 41% and 67%.(1)|
04317|038|D|   The effect of CYP3A4 inducers has not been studied. Fedratinib is|
04317|039|D|metabolized by CYP3A4.(2)|
04317|040|D|   In a study, concurrent administration of rifampin (a strong inducer) with|
04317|041|D|lefamulin injection decreased lefamulin AUC and Cmax by 28% and 8%.(3)|
04317|042|D|   In a study, concurrent administration of rifampin (a strong inducer) with|
04317|043|D|oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(3)|
04317|044|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
04317|045|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the AUC|
04317|046|D|and Cmax of midazolam by 200% and 100%, respectively.  No clinically|
04317|047|D|significant effect on midazolam pharmacokinetics was observed when|
04317|048|D|co-administered with lefamulin injection.(3)|
04317|049|D|   Concomitant administration of rilzabrutinib with efavirenz or rifabutin|
04317|050|D|(moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib AUC and|
04317|051|D|Cmax by up to 70% at steady state.(4)|
04317|052|D|   A pharmacokinetic model predicted that co-administration of rifampin, a|
04317|053|D|strong CYP3A4 inducer, would decrease the area-under-curve (AUC) of|
04317|054|D|voxelotor by 40%.(5)|
04317|055|D|   Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted|
04317|056|D|to decrease the AUC of voxelotor by 24%.(5)|
04317|057|D|   Drugs that are both moderate inhibitors and substrates of CYP3A4 include:|
04317|058|D|fedratinib, oral lefamulin, rilzabrutinib, and voxelotor.(2-7)|
04317|059|B||
04317|060|R|REFERENCES:|
04317|061|B||
04317|062|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04317|063|R|  November, 2023.|1
04317|064|R|2.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
04317|065|R|  May, 2023.|1
04317|066|R|3.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04317|067|R|  Inc August 2019.|1
04317|068|R|4.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
04317|069|R|  August, 2025.|1
04317|070|R|5.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
04317|071|R|  Inc. December, 2021.|1
04317|072|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04317|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04317|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04317|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04317|076|R|  11/14/2017.|1
04317|077|R|7.This information is based on an extract from the Certara Drug Interaction|6
04317|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04318|001|T|MONOGRAPH TITLE:  Belimumab/Biologic Therapies|
04318|002|B||
04318|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04318|004|L|take action as needed.|
04318|005|B||
04318|006|A|MECHANISM OF ACTION:  Concurrent use of belimumab with other biologic|
04318|007|A|therapies may result in additive or synergistic effects on the immune|
04318|008|A|system.(1)|
04318|009|B||
04318|010|E|CLINICAL EFFECTS:  Concurrent use of belimumab with other biologic therapies|
04318|011|E|may increase the risk of serious infections.(1)|
04318|012|B||
04318|013|P|PREDISPOSING FACTORS:  None determined.|
04318|014|B||
04318|015|M|PATIENT MANAGEMENT:  The concurrent use of belimumab with other biologic|
04318|016|M|therapies should be approached with caution.(1)|
04318|017|B||
04318|018|D|DISCUSSION:  In a randomized, double-blind, placebo-controlled trial, more|
04318|019|D|patients who received belimumab and rituximab experienced serious adverse|
04318|020|D|events, serious infections, and post-injection systemic reactions (22.2%,|
04318|021|D|9%, and 13.2%, respectively) than patients who received belimumab with|
04318|022|D|placebo (13.9%, 2.8%, 9.7%) or standard therapy (19.7%, 5.3%, 5.3%).(1)|
04318|023|D|   The combination of belimumab with other biologic therapies has not been|
04318|024|D|studied and should be used cautiously.(1)|
04318|025|B||
04318|026|R|REFERENCE:|
04318|027|B||
04318|028|R|1.Benlysta (belimumab) US prescribing information. GlaxoSmithKline December,|1
04318|029|R|  2020.|1
04319|001|T|MONOGRAPH TITLE:  Anifrolumab/Biologic Therapies|
04319|002|B||
04319|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04319|004|L|of severe adverse interaction.|
04319|005|B||
04319|006|A|MECHANISM OF ACTION:  Concurrent use of anifrolumab with other biologic|
04319|007|A|therapies may result in additive or synergistic effects on the immune|
04319|008|A|system.(1)|
04319|009|B||
04319|010|E|CLINICAL EFFECTS:  Concurrent use of anifrolumab with other biologic|
04319|011|E|therapies may increase the risk of serious infections.(1)|
04319|012|B||
04319|013|P|PREDISPOSING FACTORS:  None determined.|
04319|014|B||
04319|015|M|PATIENT MANAGEMENT:  The concurrent use of anifrolumab with other biologic|
04319|016|M|therapies is not recommended.(1)|
04319|017|B||
04319|018|D|DISCUSSION:  The combination of anifrolumab with other biologic therapies|
04319|019|D|has not been studied and is not recommended.(1)|
04319|020|B||
04319|021|R|REFERENCE:|
04319|022|B||
04319|023|R|1.Saphnelo (anifrolumab-fnia) US Prescribing Information. AstraZeneca AB|1
04319|024|R|  Sodertalje July, 2021.|1
04320|001|T|MONOGRAPH TITLE:  Levomilnacipran (Extended Release)/Alcohol|
04320|002|B||
04320|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04320|004|L|of severe adverse interaction.|
04320|005|B||
04320|006|A|MECHANISM OF ACTION:  Concomitant use of alcohol with extended-release|
04320|007|A|levomilnacipran may cause a rapid release of levomilnacipran.(1)|
04320|008|B||
04320|009|E|CLINICAL EFFECTS:  Rapid release of levomilnacipran may result in increased|
04320|010|E|systemic concentrations and toxicities, including bleeding, seizures,|
04320|011|E|hypertension, tachycardia, and serotonin syndrome.(1) Symptoms of serotonin|
04320|012|E|syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus,|
04320|013|E|tachycardia, hyperthermia, and muscle rigidity.|
04320|014|B||
04320|015|P|PREDISPOSING FACTORS:  The increased rate of release may be alcohol|
04320|016|P|concentration-dependent.|
04320|017|B||
04320|018|M|PATIENT MANAGEMENT:  Patients are advised to avoid alcohol while taking|
04320|019|M|extended-release levomilnacipran.  Avoid the use of elixirs containing a|
04320|020|M|high-percentage of alcohol in patients taking these products.(1)|
04320|021|B||
04320|022|D|DISCUSSION:  An in-vitro dissolution study found that alcohol (5%, 20%, and|
04320|023|D|40% (v/v)) increases levomilnacipran release from extended-release capsules|
04320|024|D|by 9.5%, 23%, and 56% at 2 hours.  Alcohol 40% resulted in nearly complete|
04320|025|D|drug release in 4 hours.(1)|
04320|026|B||
04320|027|R|REFERENCE:|
04320|028|B||
04320|029|R|1.Fetzima (levomilnacipran) US prescribing information. Forest|1
04320|030|R|  Pharmaceuticals, Inc. October, 2023.|1
04321|001|T|MONOGRAPH TITLE:  Aripiprazole Lauroxil (Aristada)/Strong CYP3A4 Inhibitors;|
04321|002|T|Atazanavir; Darunavir|
04321|003|B||
04321|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04321|005|L|take action as needed.|
04321|006|B||
04321|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04321|008|A|aripiprazole.(1)|
04321|009|B||
04321|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
04321|011|E|may result in elevated levels of and toxicity from aripiprazole.(1)|
04321|012|B||
04321|013|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04321|014|P|patients who are CYP2D6 poor metabolizers, or who receive concomitant|
04321|015|P|treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine,|
04321|016|P|paroxetine, quinidine) in addition to treatment with a strong CYP3A4|
04321|017|P|inhibitor.(1)|
04321|018|B||
04321|019|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole lauroxil|
04321|020|M|extended-release injection (Aristada) recommends the following dose|
04321|021|M|adjustments for patients who receive a strong CYP3A4 inhibitor for greater|
04321|022|M|than 14 days:(1)|
04321|023|M|   - in patients already receiving aripiprazole lauroxil, reduce dose to the|
04321|024|M|next lower strength.  For patients receiving 441 mg, no further dose|
04321|025|M|reduction is necessary, if tolerated.|
04321|026|M|   - for patients who are known to be poor CYP2D6 metabolizers and are|
04321|027|M|taking a strong CYP3A4 inhibitor for greater than 14 days, reduce dose to|
04321|028|M|441 mg per month. For patients receiving 441 mg, no further dose reduction|
04321|029|M|is necessary, if tolerated.|
04321|030|M|   - for patients taking both a strong CYP2D6 and CYP3A4 inhibitor for|
04321|031|M|greater than 14 days, avoid 662 mg, 882 mg, and 1,064 mg doses. No dose|
04321|032|M|adjustment is necessary in patients taking the 441 mg dose, if tolerated.|
04321|033|B||
04321|034|D|DISCUSSION:  The coadministration of ketoconazole (200 mg daily for 14 days)|
04321|035|D|with a single oral dose of aripiprazole (15 mg) resulted in increases in the|
04321|036|D|area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and|
04321|037|D|77%, respectively.  In simulations, the combination of strong CYP2D6 and|
04321|038|D|CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by|
04321|039|D|4.5-fold.  The concurrent use of strong CYP3A4 inhibitors in poor CYP2D6|
04321|040|D|metabolizers is predicted to increase aripiprazole Cmax and AUC by|
04321|041|D|3-fold.(1)|
04321|042|D|   CYP3A4 inhibitors linked to this monograph include: adagrasib,|
04321|043|D|atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir,|
04321|044|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
04321|045|D|levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone,|
04321|046|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
04321|047|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04321|048|D|troleandomycin, tucatinib, and voriconazole.(2)|
04321|049|B||
04321|050|R|REFERENCES:|
04321|051|B||
04321|052|R|1.Aristada (aripiprazole lauroxil) extended-release injectable US|1
04321|053|R|  prescribing information. Alkermes Inc. November, 2018.|1
04321|054|R|2.This information is based on an extract from the Certara Drug Interaction|6
04321|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04322|001|T|MONOGRAPH TITLE:  Aripiprazole Lauroxil (Aristada)/Select Strong CYP2D6|
04322|002|T|Inhibitors|
04322|003|B||
04322|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04322|005|L|take action as needed.|
04322|006|B||
04322|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
04322|008|A|aripiprazole.(1)|
04322|009|B||
04322|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
04322|011|E|with aripiprazole may result in elevated levels of and toxicity from|
04322|012|E|aripiprazole.(1)|
04322|013|B||
04322|014|P|PREDISPOSING FACTORS:  The interaction is expected to be more severe in|
04322|015|P|patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6|
04322|016|P|inhibitor.  Poor metabolizers of CYP2D6 are not expected to be affected by|
04322|017|P|this interaction.(1)|
04322|018|B||
04322|019|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole lauroxil|
04322|020|M|extended-release injection (Aristada) recommends the following dose|
04322|021|M|adjustments for patients who receive a strong CYP2D6 inhibitor for greater|
04322|022|M|than 14 days:(1)|
04322|023|M|   - Reduce the dose of aripiprazole lauroxil to the next lower strength.|
04322|024|M|No dosage adjustment is necessary in patient taking the 441 mg dose, if|
04322|025|M|tolerated.|
04322|026|M|   - For patients taking both a strong CYP2D6 and CYP3A4 inhibitor, avoid|
04322|027|M|662 mg, 882 mg, and 1,064 mg doses. No dose adjustment is necessary in|
04322|028|M|patients taking the 441 mg dose, if tolerated.|
04322|029|M|   If the patient is a poor metabolizer of CYP2D6, no dose adjusment is|
04322|030|M|required.(1)|
04322|031|B||
04322|032|D|DISCUSSION:  The administration of quinidine (166 mg daily for 13 days, a|
04322|033|D|strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg)|
04322|034|D|resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole|
04322|035|D|and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite|
04322|036|D|of aripiprazole.  In simulations, the combination of strong CYP2D6 and|
04322|037|D|CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by|
04322|038|D|4.5-fold. (1)|
04322|039|D|   Strong CYP2D6 inhibitors linked to this monograph are dacomitinib,|
04322|040|D|fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)|
04322|041|B||
04322|042|R|REFERENCES:|
04322|043|B||
04322|044|R|1.Aristada (aripiprazole lauroxil) extended-release injectable US|1
04322|045|R|  prescribing information. Alkermes Inc. November, 2018.|1
04322|046|R|2.This information is based on an extract from the Certara Drug Interaction|6
04322|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04322|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04322|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04322|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04322|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04322|052|R|  11/14/2017.|1
04324|001|T|MONOGRAPH TITLE:  Aripiprazole Lauroxil (Aristada)/Bupropion|
04324|002|B||
04324|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04324|004|L|take action as needed.|
04324|005|B||
04324|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors such as bupropion may inhibit|
04324|007|A|the metabolism of aripiprazole.  Both agents are also known to lower the|
04324|008|A|seizure threshold.(1-3)|
04324|009|B||
04324|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
04324|011|E|with aripiprazole may result in elevated levels of and toxicity from|
04324|012|E|aripiprazole.  Concurrent use may also result in additive effects on the|
04324|013|E|seizure threshold, increasing the risk of seizures.(1-3)|
04324|014|B||
04324|015|P|PREDISPOSING FACTORS:  The pharmacokinetic interaction is expected to be|
04324|016|P|more severe in patients taking both a strong CYP3A4 inhibitor and a strong|
04324|017|P|CYP2D6 inhibitor.  Poor metabolizers of CYP2D6 are not expected to|
04324|018|P|experience increased aripiprazole exposure.(1)|
04324|019|P|   The risk of seizures may be increased in patients with a history of head|
04324|020|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
04324|021|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
04324|022|P|of over-the-counter stimulants an anorectics; a total daily dose of|
04324|023|P|bupropion greater than 450 mg or single doses greater than 150 mg; rapid|
04324|024|P|escalation of bupropion dosage; diabetics treated with oral hypoglycemics or|
04324|025|P|insulin; or with concomitant medications known to lower seizure threshold|
04324|026|P|(antidepressants, theophylline, systemic steroids).(2-3)|
04324|027|B||
04324|028|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics such|
04324|029|M|as aripiprazole should be undertaken only with extreme caution and with low|
04324|030|M|initial bupropion dosing, small gradual dosage increases of bupropion,(2-3)|
04324|031|M|and reduced dosages of aripiprazole.(1)  Single doses of bupropion should|
04324|032|M|not exceed 150 mg.(2-3)  The maximum daily dose of bupropion should not|
04324|033|M|exceed 300 mg for smoking cessation(3) or 450 mg for depression.(2)|
04324|034|M|   The US manufacturer of aripiprazole lauroxil extended-release injection|
04324|035|M|(Aristada) recommends the following dose adjustments for patients who|
04324|036|M|receive a strong CYP2D6 inhibitor for greater than 14 days:(1)|
04324|037|M|   - Reduce the dose of aripiprazole lauroxil to the next lower strength.|
04324|038|M|No dosage adjustment is necessary in patient taking the 441 mg dose, if|
04324|039|M|tolerated.|
04324|040|M|   - For patients taking both a strong CYP2D6 and CYP3A4 inhibitor, avoid|
04324|041|M|662 mg, 882 mg, and 1,064 mg doses. No dose adjustment is necessary in|
04324|042|M|patients taking the 441 mg dose, if it is tolerated.|
04324|043|M|   If the patient is a poor metabolizer of CYP2D6, no dose adjustment is|
04324|044|M|required.(1)|
04324|045|B||
04324|046|D|DISCUSSION:  The administration of quinidine (166 mg daily for 13 days, a|
04324|047|D|strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg)|
04324|048|D|resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole|
04324|049|D|and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite|
04324|050|D|of aripiprazole.  In simulations, the combination of strong CYP2D6 and|
04324|051|D|CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by|
04324|052|D|4.5-fold.(1)|
04324|053|B||
04324|054|R|REFERENCES:|
04324|055|B||
04324|056|R|1.Aristada (aripiprazole lauroxil) extended-release injectable US|1
04324|057|R|  prescribing information. Alkermes Inc. November, 2018.|1
04324|058|R|2.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
04324|059|R|  GlaxoSmithKline November, 2019.|1
04324|060|R|3.Zyban (bupropion hydrochloride) US prescribing information.|1
04324|061|R|  GlaxoSmithKline July, 2019.|1
04324|062|R|4.This information is based on an extract from the Certara Drug Interaction|6
04324|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04325|001|T|MONOGRAPH TITLE:  Fecal Microbiota Spores/Antibiotics|
04325|002|B||
04325|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04325|004|L|of severe adverse interaction.|
04325|005|B||
04325|006|A|MECHANISM OF ACTION:  Fecal microbiota spores is a suspension of live|
04325|007|A|bacterial spores, which may be compromised by concurrent use of|
04325|008|A|antibiotics.(1)|
04325|009|B||
04325|010|E|CLINICAL EFFECTS:  Antibiotics may decrease the effectiveness of fecal|
04325|011|E|microbiota spores.(1)|
04325|012|B||
04325|013|P|PREDISPOSING FACTORS:  None determined.|
04325|014|B||
04325|015|M|PATIENT MANAGEMENT:  Antibiotics should not be used concurrently with fecal|
04325|016|M|microbiota spores.  Antibacterial treatment should be completed for 2 to 4|
04325|017|M|days before initiating treatment with fecal microbiota spores.(1)|
04325|018|B||
04325|019|D|DISCUSSION:  Antibiotics may compromise the effectiveness of fecal|
04325|020|D|microbiota spores.|
04325|021|B||
04325|022|R|REFERENCE:|
04325|023|B||
04325|024|R|1.Vowst (fecal microbiota spores, live-brpk) US prescribing information.|1
04325|025|R|  Seres Therapeutics, Inc. April, 2023.|1
04327|001|T|MONOGRAPH TITLE:  Selected Retinoids (Systemic)/Growth Hormone|
04327|002|B||
04327|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04327|004|L|of severe adverse interaction.|
04327|005|B||
04327|006|A|MECHANISM OF ACTION:  Both systemic retinoids(1-8,11) and growth|
04327|007|A|hormones(9-11) have been independently associated with medication-induced|
04327|008|A|intracranial hypertension.|
04327|009|B||
04327|010|E|CLINICAL EFFECTS:  The concurrent use of oral retinoids(1-8) with growth|
04327|011|E|hormones(9-10) may increase the risk of intracranial hypertension|
04327|012|E|(pseudotumor cerebri).  Early signs of intracranial hypertension include|
04327|013|E|papilledema (inflammation of the optic nerve), headache, nausea, vomiting,|
04327|014|E|and visual disturbances such as blurred vision, double vision, and loss of|
04327|015|E|vision.(12)|
04327|016|B||
04327|017|P|PREDISPOSING FACTORS:  Women of childbearing age with high body mass may|
04327|018|P|have a higher risk of developing intracranial hypertension.(8)|
04327|019|B||
04327|020|M|PATIENT MANAGEMENT:  The US manufacturer of tretinoin advises avoiding|
04327|021|M|concomitant use of other products that can cause intracranial|
04327|022|M|hypertension.(1)|
04327|023|M|   Patients who present with symptoms of intracranial hypertension should be|
04327|024|M|screened for papilledema.  If papilledema is present, they should|
04327|025|M|discontinue the drug and be referred to a neurologist for further|
04327|026|M|treatment.(1-8)|
04327|027|B||
04327|028|D|DISCUSSION:  Vitamin A derivatives and growth hormone have both been|
04327|029|D|strongly associated with intracranial hypertension.|
04327|030|D|   A review of ocular side effects from the National Registry of|
04327|031|D|Drug-Induced Ocular Side Effects, the World Health Organization, the Food|
04327|032|D|and Drug Administration, and medical journals from 1979 to 2003 found 21|
04327|033|D|patients who developed intracranial hypertension while taking tretinoin,|
04327|034|D|acitretin, or etretinate at prescribed doses.  Symptom onset occurred at an|
04327|035|D|average of 2-3 months after starting retinoid therapy and all except 3 cases|
04327|036|D|resolved within a few months after discontinuing therapy.(8)|
04327|037|D|   In a systematic review of 580 reported cases of medication-induced|
04327|038|D|intracranial hypertension between January 1900 and June 2019 found in|
04327|039|D|MEDLINE, EMBASE, and Cochrane Review Databases, there were 259 verifiable|
04327|040|D|cases of intracranial hypertension.  Vitamin A derivatives were implicated|
04327|041|D|in 84 cases, though 25 cases occurred with excessive vitamin A|
04327|042|D|supplementation.  Growth hormone was implicated in 24 cases, all of which|
04327|043|D|occurred in pediatric patients and involved frequent or higher doses of|
04327|044|D|growth hormone.(12)|
04327|045|B||
04327|046|R|REFERENCES:|
04327|047|B||
04327|048|R|1.Vesanoid (tretinoin) US prescribing information. Roche Laboratories, Inc.|1
04327|049|R|  February, 2023.|1
04327|050|R|2.Vesanoid (tretinoin) UK summary of product characteristics. Roche Products|1
04327|051|R|  Limited March 20, 2006.|1
04327|052|R|3.Neotigason (acitretin) UK summary of product characteristics. Roche|1
04327|053|R|  Products Limited April 5, 2006.|1
04327|054|R|4.Soriatane (acitretin) US prescribing information. Roche Pharmaceuticals|1
04327|055|R|  February, 2014.|1
04327|056|R|5.Roaccutane (isotretinoin) UK summary of product characteristics. Roche|1
04327|057|R|  Products Limited February 14, 2006.|1
04327|058|R|6.Accutane (isotretinoin) US prescribing information. Roche Laboratories,|1
04327|059|R|  Inc. January, 2010.|1
04327|060|R|7.Toctino (alitretinoin) UK summary of product characteristics. Basilea|1
04327|061|R|  Pharmaceuticals Ltd September 19, 2008.|1
04327|062|R|8.Fraunfelder FW, Fraunfelder FT. Evidence for a probable causal|3
04327|063|R|  relationship between tretinoin, acitretin, and etretinate and intracranial|3
04327|064|R|  hypertension. J Neuroophthalmol 2004 Sep;24(3):214-6.|3
04327|065|R|9.Nutropin AQ Nuspin (somatropin) US prescribing information. Genentech,|1
04327|066|R|  Inc. December, 2021.|1
04327|067|R|10.Skytrofa (lonapegsomatropin-tcgd) US prescribing information. Ascendis|1
04327|068|R|   Pharma Endocrinology, Inc. July, 2025.|1
04327|069|R|11.Xu C, Zhang J, Zhang Y, Sun Q, Yang X, Fang W. Drug-Induced Intracranial|6
04327|070|R|   Pressure Increase: Disproportionality Analysis of the Public Version of|6
04327|071|R|   the FDA Event Reporting System. Acta Neurologica Scandinavica September|6
04327|072|R|   2024.|6
04327|073|R|12.Tan MG, Worley B, Kim WB, Ten Hove M, Beecker J. Drug-Induced|6
04327|074|R|   Intracranial Hypertension: A Systematic Review and Critical  Assessment|6
04327|075|R|   of Drug-Induced Causes. Am J Clin Dermatol 2020 Apr;21(2):163-172.|6
04328|001|T|MONOGRAPH TITLE:  Selected Retinoids (Systemic)/Lithium|
04328|002|B||
04328|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04328|004|L|of severe adverse interaction.|
04328|005|B||
04328|006|A|MECHANISM OF ACTION:  Both systemic retinoids(1-7) and lithium(8-9) have|
04328|007|A|been independently associated with medication-induced intracranial|
04328|008|A|hypertension.|
04328|009|B||
04328|010|E|CLINICAL EFFECTS:  The concurrent use of oral retinoids(1-7) with|
04328|011|E|lithium(8-9) may increase the risk of intracranial hypertension (pseudotumor|
04328|012|E|cerebri).  Early signs of intracranial hypertension include papilledema|
04328|013|E|(inflammation of the optic nerve), headache, nausea, vomiting, and visual|
04328|014|E|disturbances such as blurred vision, double vision, and loss of vision.(10)|
04328|015|B||
04328|016|P|PREDISPOSING FACTORS:  Women of childbearing age who are overweight or have|
04328|017|P|a previous history of intracranial hypertension are at a greater risk of|
04328|018|P|developing intracranial hypertension.(10)|
04328|019|B||
04328|020|M|PATIENT MANAGEMENT:  The US manufacturer of tretinoin advises avoiding|
04328|021|M|concomitant use of other products that can cause intracranial|
04328|022|M|hypertension.(1)|
04328|023|M|   Patients who present with symptoms of intracranial hypertension should be|
04328|024|M|screened for papilledema.  If papilledema is present, they should|
04328|025|M|discontinue the drug and be referred to a neurologist for further|
04328|026|M|treatment.(1-7)|
04328|027|B||
04328|028|D|DISCUSSION:  Vitamin A derivatives and lithium have both been strongly|
04328|029|D|associated with intracranial hypertension.  In a systematic review of 580|
04328|030|D|reported cases of medication-induced intracranial hypertension between|
04328|031|D|January 1900 and June 2019 found in MEDLINE, EMBASE, and Cochrane Review|
04328|032|D|Databases, there were 259 verifiable cases of intracranial hypertension.|
04328|033|D|Vitamin A derivatives were implicated in 84 cases, though 25 cases occurred|
04328|034|D|with excessive vitamin A supplementation.  Lithium was implicated in 17|
04328|035|D|cases with lithium levels in therapeutic range.(10)|
04328|036|B||
04328|037|R|REFERENCES:|
04328|038|B||
04328|039|R|1.Vesanoid (tretinoin) US prescribing information. Roche Laboratories, Inc.|1
04328|040|R|  February, 2023.|1
04328|041|R|2.Vesanoid (tretinoin) UK summary of product characteristics. Roche Products|1
04328|042|R|  Limited March 20, 2006.|1
04328|043|R|3.Neotigason (acitretin) UK summary of product characteristics. Roche|1
04328|044|R|  Products Limited April 5, 2006.|1
04328|045|R|4.Soriatane (acitretin) US prescribing information. Roche Pharmaceuticals|1
04328|046|R|  February, 2014.|1
04328|047|R|5.Roaccutane (isotretinoin) UK summary of product characteristics. Roche|1
04328|048|R|  Products Limited February 14, 2006.|1
04328|049|R|6.Accutane (isotretinoin) US prescribing information. Roche Laboratories,|1
04328|050|R|  Inc. January, 2010.|1
04328|051|R|7.Toctino (alitretinoin) UK summary of product characteristics. Basilea|1
04328|052|R|  Pharmaceuticals Ltd September 19, 2008.|1
04328|053|R|8.Lithium carbonate US prescribing information. West-Ward Pharmaceuticals|1
04328|054|R|  Corp. October, 2022.|1
04328|055|R|9.Tan MG, Worley B, Kim WB, Ten Hove M, Beecker J. Drug-Induced Intracranial|6
04328|056|R|  Hypertension: A Systematic Review and Critical  Assessment of Drug-Induced|6
04328|057|R|  Causes. Am J Clin Dermatol 2020 Apr;21(2):163-172.|6
04328|058|R|10.Fraunfelder FW, Fraunfelder FT. Evidence for a probable causal|3
04328|059|R|   relationship between tretinoin, acitretin, and etretinate and|3
04328|060|R|   intracranial hypertension. J Neuroophthalmol 2004 Sep;24(3):214-6.|3
04329|001|T|MONOGRAPH TITLE:  Tretinoin/Strong CYP3A4 Inhibitors|
04329|002|B||
04329|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04329|004|L|of severe adverse interaction.|
04329|005|B||
04329|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04329|007|A|of tretinoin.(1)|
04329|008|B||
04329|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
04329|010|E|increased levels of and effects from tretinoin including hepatotoxicity and|
04329|011|E|hyperlipidemia.(1)|
04329|012|E|   Retinoids, including tretinoin, have been associated with intracranial|
04329|013|E|hypertension, especially in pediatric patients. Early signs and symptoms|
04329|014|E|include papilledema, headache, nausea, vomiting, and visual disturbances.(1)|
04329|015|B||
04329|016|P|PREDISPOSING FACTORS:  None determined.|
04329|017|B||
04329|018|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04329|019|M|tretinoin should be avoided.  If concurrent use cannot be avoided, monitor|
04329|020|M|patients more frequently for adverse reactions.(1)|
04329|021|M|   Evaluate patients with symptoms for intracranial hypertension (such as|
04329|022|M|papilledema, headache, nausea, vomiting, and visual disturbances), and, if|
04329|023|M|present, institute care in concert with neurological assessment. Consider|
04329|024|M|interruption, dose reduction, or discontinuation of tretinoin as|
04329|025|M|appropriate.(1)|
04329|026|B||
04329|027|D|DISCUSSION:  In 13 patients on tretinoin for 4 weeks, single-dose|
04329|028|D|ketoconazole (400 to 1200 mg) increased tretinoin area-under-curve (AUC) by|
04329|029|D|72%.(1)|
04329|030|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04329|031|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04329|032|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
04329|033|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04329|034|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04329|035|D|troleandomycin, tucatinib, and voriconazole.(2)|
04329|036|B||
04329|037|R|REFERENCES:|
04329|038|B||
04329|039|R|1.Vesanoid (tretinoin) US prescribing information. Roche Laboratories, Inc.|1
04329|040|R|  February, 2023.|1
04329|041|R|2.This information is based on an extract from the Certara Drug Interaction|6
04329|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04330|001|T|MONOGRAPH TITLE:  Tretinoin/Strong CYP3A4 Inducers|
04330|002|B||
04330|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04330|004|L|of severe adverse interaction.|
04330|005|B||
04330|006|A|MECHANISM OF ACTION:  Tretinoin is metabolized by CYP3A4.  Strong inducers|
04330|007|A|of CYP3A4 may increase the metabolism of tretinoin.(1)|
04330|008|B||
04330|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
04330|010|E|in decreased levels and effectiveness of tretinoin.(1)|
04330|011|B||
04330|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04330|013|P|of the inducer for longer than 1-2 weeks.|
04330|014|B||
04330|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of tretinoin with strong CYP3A4|
04330|016|M|inducers.(1)|
04330|017|B||
04330|018|D|DISCUSSION:  The coadministration of tretinoin with strong CYP3A4 inducers|
04330|019|D|has not been studied.  Tretinoin is metabolized by CYP3A4, CYP2C8, and|
04330|020|D|CYP2E, and undergoes glucuronidation.(1)|
04330|021|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04330|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04330|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04330|024|D|rifapentine, and St. John's wort.(2)|
04330|025|B||
04330|026|R|REFERENCES:|
04330|027|B||
04330|028|R|1.Vesanoid (tretinoin) US prescribing information. Roche Laboratories, Inc.|1
04330|029|R|  February, 2023.|1
04330|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04330|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04331|001|T|MONOGRAPH TITLE:  Fezolinetant/CYP1A2 Inhibitors|
04331|002|B||
04331|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04331|004|L|is contraindicated and generally should not be dispensed or administered to|
04331|005|L|the same patient.|
04331|006|B||
04331|007|A|MECHANISM OF ACTION:  Inhibitors of CYP1A2 may inhibit the metabolism of|
04331|008|A|fezolinetant.(1-4)|
04331|009|B||
04331|010|E|CLINICAL EFFECTS:  Concurrent use of a CYP1A2 inhibitor may increase levels|
04331|011|E|of and adverse effects from fezolinetant.(1-4)|
04331|012|B||
04331|013|P|PREDISPOSING FACTORS:  None determined.|
04331|014|B||
04331|015|M|PATIENT MANAGEMENT:  Recommendations for concurrent use of fezolinetant with|
04331|016|M|CYP1A2 inhibitors differ in different regions.|
04331|017|M|   The US manufacturer of fezolinetant states that concurrent use with|
04331|018|M|strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1)|
04331|019|M|   The Australian, Canadian, and UK manufacturers of fezolinetant state that|
04331|020|M|concurrent use with strong and moderate CYP1A2 inhibitors is|
04331|021|M|contraindicated, while weak CYP1A2 inhibitors are not predicted to cause|
04331|022|M|clinically relevant changes in fezolinetant exposure.(2-4)|
04331|023|B||
04331|024|D|DISCUSSION:  In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased|
04331|025|D|fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80%|
04331|026|D|and 840%, respectively.  Mexiletine (400 mg every 8 hours), a moderate|
04331|027|D|CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%,|
04331|028|D|respectively.  Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor,|
04331|029|D|increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1)|
04331|030|D|   Strong CYP1A2 inhibitors linked to this monograph include angelica root,|
04331|031|D|ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib.|
04331|032|D|   Moderate CYP1A2 inhibitors linked to this monograph include capmatinib,|
04331|033|D|dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen,|
04331|034|D|mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib,|
04331|035|D|troleandomycin, vemurafenib, and viloxazine.|
04331|036|D|   Weak CYP1A2 inhibitors linked to this monograph include allopurinol,|
04331|037|D|artemisinin, caffeine, cannabidiol, cimetidine, curcumin, dan-shen,|
04331|038|D|deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin,|
04331|039|D|obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib,|
04331|040|D|simeprevir, thiabendazole, ticlopidine, triclabendazole, verapamil,|
04331|041|D|zileuton.(5-7)|
04331|042|B||
04331|043|R|REFERENCES:|
04331|044|B||
04331|045|R|1.Veozah (fezolinetant) US prescribing information. Astellas Pharma US, Inc.|1
04331|046|R|  May, 2023.|1
04331|047|R|2.Veoza (fezolinetant) Australian product information. Astellas Pharma|1
04331|048|R|  Australia Pty Ltd July, 2024.|1
04331|049|R|3.Veozah (fezolinetant) Canadian Product Monograph. Astellas Pharma Canada,|1
04331|050|R|  Inc. December, 2024.|1
04331|051|R|4.Veoza (fezolinetant) UK summary of product characteristics. Astellas|1
04331|052|R|  Pharma Ltd. April, 2025.|1
04331|053|R|5.This information is based on an extract from the Certara Drug Interaction|6
04331|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04331|055|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04331|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04331|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04331|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04331|059|R|  11/14/2017.|1
04331|060|R|7.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
04331|061|R|  Indiana University School of Medicine.  Available at:|1
04331|062|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
04332|001|T|MONOGRAPH TITLE:  Procainamide/Tafenoquine|
04332|002|B||
04332|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04332|004|L|of severe adverse interaction.|
04332|005|B||
04332|006|A|MECHANISM OF ACTION:  The active tubular secretion of procainamide and|
04332|007|A|N-acetylprocainamide via organic cation transporter 2 (OCT2) may be|
04332|008|A|inhibited by tafenoquine.(1)|
04332|009|B||
04332|010|E|CLINICAL EFFECTS:  The concurrent administration of procainamide with|
04332|011|E|tafenoquine may result in elevated levels and increased toxicities of|
04332|012|E|procainamide, including torsades de pointes.(1)|
04332|013|B||
04332|014|P|PREDISPOSING FACTORS:  Renal impairment may increase risk for excessive QTc|
04332|015|P|prolongation as procainamide is primarily renally eliminated.|
04332|016|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04332|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04332|018|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
04332|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04332|020|P|advanced age.(2)|
04332|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04332|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04332|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04332|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04332|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04332|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04332|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04332|028|B||
04332|029|M|PATIENT MANAGEMENT:  The manufacturer of tafenoquine states the concurrent|
04332|030|M|administration of tafenoquine with organic cation transporter 2 (OCT2)|
04332|031|M|substrates with a narrow therapeutic index, such as procainamide, should be|
04332|032|M|avoided.(1,2)|
04332|033|M|   If concurrent use cannot be avoided, monitor patient for signs and|
04332|034|M|symptoms of procainamide toxicity.  Procainamide and N-acetylprocainamide|
04332|035|M|levels should be checked.  Elderly patients and those with impaired renal|
04332|036|M|function are especially at risk.|
04332|037|B||
04332|038|D|DISCUSSION:  Procainamide and its metabolite N-acetylprocainamide are|
04332|039|D|primarily excreted in the urine by both glomerular filtration and active|
04332|040|D|tubular secretion via the cation transport system.  Tafenoquine is believed|
04332|041|D|to inhibit the cation transport system (OCT2).(1-3)|
04332|042|D|   Signs and symptoms of procainamide toxicity include widening of the QRS|
04332|043|D|complex, tachycardia, intraventricular conduction delay, hypotension,|
04332|044|D|oliguria, lethargy, confusion, nausea and vomiting.|
04332|045|B||
04332|046|R|REFERENCES:|
04332|047|B||
04332|048|R|1.Kozenis (tafenoquine) AU prescribing information. GlaxoSmithKline|1
04332|049|R|  Australia Pty Ltd March 9, 2022.|1
04332|050|R|2.Krintafel (tafenoquine) tablets US prescribing information.|1
04332|051|R|  GlaxoSmithKline November, 2020.|1
04332|052|R|3.Procainamide US prescribing information. Hospira, Inc. March, 2017.|1
04332|053|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04332|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04332|055|R|  settings: a scientific statement from the American Heart Association and|6
04332|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04332|057|R|  2;55(9):934-47.|6
04333|001|T|MONOGRAPH TITLE:  Mixed & Indirect Sympathomimetics; Oral|
04333|002|T|Phenylephrine/Rasagiline|
04333|003|B||
04333|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04333|005|L|of severe adverse interaction.|
04333|006|B||
04333|007|A|MECHANISM OF ACTION:  Catecholamine stores increased by MAOIs can be|
04333|008|A|released by indirect acting sympathomimetics such as ephedrine and|
04333|009|A|amphetamine.  MAO inhibitors also interfere with gut and liver metabolism of|
04333|010|A|direct acting sympathomimetics (e.g oral phenylephrine).|
04333|011|B||
04333|012|E|CLINICAL EFFECTS:  Concurrent use of MAOIs may result in potentiation of|
04333|013|E|sympathomimetic effects, which may result in headaches, hypertensive crisis,|
04333|014|E|toxic neurological effects, and malignant hyperpyrexia.  Hypertensive crisis|
04333|015|E|has been reported in patients taking recommended doses of rasagiline with|
04333|016|E|sympathomimetic agents.|
04333|017|B||
04333|018|P|PREDISPOSING FACTORS:  None determined.|
04333|019|B||
04333|020|M|PATIENT MANAGEMENT:  At recommended dosages, rasagiline is selective for|
04333|021|M|MAO-B; however, at higher dosages it has been shown to lose its selectivity.|
04333|022|M|Patients receiving higher dosages of rasagiline should be considered|
04333|023|M|susceptive to this interaction.  Concurrent use should be approached with|
04333|024|M|caution.|
04333|025|B||
04333|026|D|DISCUSSION:  Indirect acting sympathomimetic amines may cause abrupt|
04333|027|D|elevation of blood pressure when administered to patients taking monoamine|
04333|028|D|oxidase inhibitors, resulting in a potentially fatal hypertensive crisis.|
04333|029|D|   Mixed (direct and indirect) acting sympathomimetics have also been shown|
04333|030|D|to interact with monoamine oxidase inhibitors depending on their degree of|
04333|031|D|indirect action.  The direct-acting sympathomimetics have not been reported|
04333|032|D|to interact.  Dopamine is metabolized by monoamine oxidase, and its pressor|
04333|033|D|effect is enhanced by monoamine oxidase inhibitors.|
04333|034|B||
04333|035|R|REFERENCES:|
04333|036|B||
04333|037|R|1.Goldberg LI. Monoamine oxidase inhibitors. Adverse reactions and possible|6
04333|038|R|  mechanisms. JAMA 1964 Nov 2;190(5):456-62.|6
04333|039|R|2.Adderall XR (amphetamine) US prescribing information. Shire US Inc. April,|1
04333|040|R|  2015.|1
04333|041|R|3.Ritalin LA (methylphenidate hydrochloride) US prescribing information.|1
04333|042|R|  Novartis Pharmaceuticals Corporation June, 2021.|1
04333|043|R|4.Focalin (dexmethylphenidate hydrochloride) US prescribing information.|1
04333|044|R|  Novartis Pharmaceuticals Corporation June, 2021.|1
04333|045|R|5.Parnate (tranylcypromine sulfate) US prescribing information.|1
04333|046|R|  GlaxoSmithKline January 4, 2018.|1
04333|047|R|6.Cuthbert MF, Greenberg MP, Morley SW. Cough and cold remedies: a potential|2
04333|048|R|  danger to patients on monoamine oxidase inhibitors. Br Med J 1969 Feb 15;|2
04333|049|R|  1(5641):404-6.|2
04333|050|R|7.Smookler S, Bermudez AJ. Hypertensive crisis resulting from an MAO|3
04333|051|R|  inhibitor and an over-the-counter appetite suppressant. Ann Emerg Med 1982|3
04333|052|R|  Sep;11(9):482-4U.|3
04333|053|R|8.Mason AM, Buckle RM. "Cold" cures and monoamine-oxidase inhibitors. Br Med|3
04333|054|R|  J 1969 Mar 29;1(5647):845-6.|3
04333|055|R|9.Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN.|2
04333|056|R|  Interactions between sympathomimetic amines and antidepressant agents in|2
04333|057|R|  man. Br Med J 1973 Feb 10;1(5849):311-5.|2
04333|058|R|10.Elis J, Laurence DR, Mattie H, Prichard BN. Modification by monoamine|2
04333|059|R|   oxidase inhibitors of the effect of some sympathomimetics on blood|2
04333|060|R|   pressure. Br Med J 1967 Apr 8;2(5544):75-8.|2
04333|061|R|11.HORWITZ D, GOLDBERG LI, SJOERDSMA A. Increased blood pressure responses|2
04333|062|R|   to dopamine and norepinephrine produced by monoamine oxidase inhibitors|2
04333|063|R|   in man. J Lab Clin Med 1960 Nov;56:747-53.|2
04333|064|R|12.Cuthbert MF, Vere DW. Potentiation of the cardiovascular effects of some|2
04333|065|R|   catecholamines by a monoamine oxidase inhibitor. Br J Pharmacol 1971 Oct;|2
04333|066|R|   43(2):471P-472P.|2
04333|067|R|13.Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function.|5
04333|068|R|   Pharmacol Rev 1966 Jun;18(2):925-64.|5
04333|069|R|14.GOLDBERG LI. MONOAMINE OXIDASE INHIBITORS. ADVERSE REACTIONS AND POSSIBLE|6
04333|070|R|   MECHANISMS. JAMA 1964 Nov 2;190:456-62.|6
04333|071|R|15.Kopin IJ. Biochemical aspects of release of norepinephrine and other|5
04333|072|R|   amines from sympathetic nerve endings. Pharmacol Rev 1966 Mar;|5
04333|073|R|   18(1):513-23.|5
04333|074|R|16.BETHUNE HC, BURRELL RH, CULPAN RH, OGG GJ. VASCULAR CRISES ASSOCIATED|6
04333|075|R|   WITH MONOAMINE-OXIDASE INHIBITORS. Am J Psychiatry 1964 Sep;121:245-8.|6
04333|076|R|17.O'Dea K, Rand MJ. Interaction between amphetamine and monoamine oxidase|5
04333|077|R|   inhibitors. Eur J Pharmacol 1969 May;6(2):115-20.|5
04333|078|R|18.Azilect (rasagiline) US prescribing information. Teva Neurosciences Inc.|1
04333|079|R|   June, 2020.|1
04334|001|T|MONOGRAPH TITLE:  Imatinib/Strong CYP3A4 Inducers|
04334|002|B||
04334|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04334|004|L|of severe adverse interaction.|
04334|005|B||
04334|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04334|007|A|metabolism of imatinib.(1)|
04334|008|B||
04334|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04334|010|E|levels and effectiveness of imatinib.(1)|
04334|011|B||
04334|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04334|013|P|of the inducer for longer than 1-2 weeks.|
04334|014|B||
04334|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04334|016|M|patients receiving therapy with antineoplastic enzyme inhibitors.  Consider|
04334|017|M|the use of alternative agents with less enzyme induction potential.(1)|
04334|018|M|   The dose of imatinib should be increased by at least 50% and clinical|
04334|019|M|response should be carefully monitored.  Dosages up to 1,200 mg daily (600|
04334|020|M|mg twice daily) have been used in patients receiving concurrent therapy with|
04334|021|M|strong CYP3A4 inducers.(1)|
04334|022|B||
04334|023|D|DISCUSSION:  Pretreatment of 14 healthy subjects with rifampin (600 mg daily|
04334|024|D|for 10 days) increased the clearance of a single dose of imatinib (400 mg)|
04334|025|D|by 3.8-fold.  The area-under-curve (AUC) and maximum concentration (Cmax)|
04334|026|D|decreased by 74% and 54%, respectively.(1,2)  The Cmax of the CGP74588|
04334|027|D|metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(2)|
04334|028|D|   Strong inducers of CYP3A4 include:  barbiturates, dexamethasone,|
04334|029|D|enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone,|
04334|030|D|rifampin, and rifapentine.(3,4)|
04334|031|B||
04334|032|R|REFERENCES:|
04334|033|B||
04334|034|R|1.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
04334|035|R|  Pharmaceuticals Corporation August, 2022.|1
04334|036|R|2.Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U,|2
04334|037|R|  Seiberling M. Effect of rifampicin on the pharmacokinetics of imatinib|2
04334|038|R|  mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol|2
04334|039|R|  2004 Feb;53(2):102-6.|2
04334|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04334|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04334|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04334|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04334|044|R|  11/14/2017.|1
04334|045|R|4.This information is based on an extract from the Certara Drug Interaction|6
04334|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04335|001|T|MONOGRAPH TITLE:  Lapatinib/Strong CYP3A4 Inducers|
04335|002|B||
04335|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04335|004|L|of severe adverse interaction.|
04335|005|B||
04335|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04335|007|A|metabolism of lapatinib.(1)|
04335|008|B||
04335|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04335|010|E|levels and effectiveness of lapatinib.(1)|
04335|011|B||
04335|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04335|013|P|of the inducer for longer than 1-2 weeks.|
04335|014|B||
04335|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04335|016|M|patients receiving therapy with lapatinib.  Consider the use of alternative|
04335|017|M|agents with less enzyme induction potential.(1)|
04335|018|M|   The dose of lapatinib should be gradually titrated from 1,250 mg/day up|
04335|019|M|to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from|
04335|020|M|1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive|
04335|021|M|breast cancer indication) based on patient tolerability.  If the inducer is|
04335|022|M|discontinued, the dose of lapatinib should be adjusted to the normal|
04335|023|M|dose.(1)|
04335|024|B||
04335|025|D|DISCUSSION:  In healthy subjects, carbamazepine (100 mg twice daily for 3|
04335|026|D|days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased|
04335|027|D|the area-under-curve (AUC) of lapatinib by 72%.  The dose adjustment|
04335|028|D|recommendations are based on pharmacokinetic studies and are predicted to|
04335|029|D|adjust lapatinib AUC to the range observed without concurrent CYP3A4|
04335|030|D|inducers; however, there are no clinical data with these doses in patients|
04335|031|D|receiving strong CYP3A4 inducers.(1)|
04335|032|D|   Strong inducers of CYP3A4 include:  barbiturates, dexamethasone,|
04335|033|D|enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone,|
04335|034|D|rifampin, and rifapentine.(2,3)|
04335|035|B||
04335|036|R|REFERENCES:|
04335|037|B||
04335|038|R|1.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
04335|039|R|  2018.|1
04335|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
04335|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04335|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04335|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04335|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04335|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04335|046|R|  11/14/2017.|1
04336|001|T|MONOGRAPH TITLE:  Axitinib/Strong & Moderate CYP3A4 Inducers|
04336|002|B||
04336|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04336|004|L|of severe adverse interaction.|
04336|005|B||
04336|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04336|007|A|metabolism of axitinib.(1)|
04336|008|B||
04336|009|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
04336|010|E|decrease the levels and effectiveness of axitinib.(1)|
04336|011|B||
04336|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04336|013|P|of the inducer for longer than 1-2 weeks.|
04336|014|B||
04336|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong or moderate CYP3A4|
04336|016|M|inducers in patients receiving therapy with axitinib.(1)  Consider the use|
04336|017|M|of alternatives with little to no induction potential.(1)|
04336|018|B||
04336|019|D|DISCUSSION:  Rifampin (600 mg daily for 9 days), a strong CYP3A4 inducer,|
04336|020|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of|
04336|021|D|axitinib to less than half and less than 25% of levels seen without|
04336|022|D|concurrent rifampin.(1)|
04336|023|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04336|024|D|carbamazepine, dexamethasone, encorafenib, enzalutamide, ivosidenib,|
04336|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin,|
04336|026|D|rifampin, rifapentine, and St. John's wort.|
04336|027|D|   Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib,|
04336|028|D|efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten,|
04336|029|D|mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib,|
04336|030|D|sotorasib, telotristat ethyl, thioridazine and tovorafenib.(1-3)|
04336|031|B||
04336|032|R|REFERENCES:|
04336|033|B||
04336|034|R|1.Inlyta (axitinib) US prescribing information. Pfizer Inc. September, 2022.|1
04336|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04336|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04336|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04336|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04336|039|R|  11/14/2017.|1
04336|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04336|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04337|001|T|MONOGRAPH TITLE:  Systemic Corticosteroids; Corticotropin/Non-Live or|
04337|002|T|Non-Replicating Vaccines|
04337|003|B||
04337|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04337|005|L|take action as needed.|
04337|006|B||
04337|007|A|MECHANISM OF ACTION:  Corticosteroids and corticotropin suppress the immune|
04337|008|A|system and may alter the immune system's response to vaccines.(1)|
04337|009|B||
04337|010|E|CLINICAL EFFECTS:  Vaccines administered during or within 2 weeks prior to|
04337|011|E|therapy with corticosteroids or corticotropin may result in decreased|
04337|012|E|effectiveness of the vaccine.(1)|
04337|013|B||
04337|014|P|PREDISPOSING FACTORS:  Patients receiving immunosuppressive doses of|
04337|015|P|corticosteroids or corticotropin for equal to or greater than 14 consecutive|
04337|016|P|days.(1)|
04337|017|B||
04337|018|M|PATIENT MANAGEMENT:  The Centers for Disease Control's (CDC) Advisory|
04337|019|M|Committee on Immunization Practices (ACIP) states that non-live vaccines|
04337|020|M|should be used with caution in patients who are severely immunosuppressed,|
04337|021|M|including those who are receiving or have received high-dose, systemic|
04337|022|M|steroids for greater than or equal to 14 consecutive days.  When initiating|
04337|023|M|immunosuppressives doses of corticosteroids, wait 2 weeks after a non-live|
04337|024|M|vaccines is administered.  However, if patients require therapy for chronic|
04337|025|M|inflammatory conditions, do not delay therapy due to past vaccines.(1)|
04337|026|M|   The immune response to non-live vaccines should be monitored in patients|
04337|027|M|receiving corticosteroids.  Vaccinations given during corticosteroid therapy|
04337|028|M|may need to be repeated.(1)  Patients who are vaccinated within the 14 days|
04337|029|M|prior to initiating immunosuppressive therapy should be considered|
04337|030|M|unvaccinated and should be revaccinated at least 3 months after|
04337|031|M|immunosuppressive therapy is discontinued when immune competence is|
04337|032|M|restored.(1)|
04337|033|B||
04337|034|D|DISCUSSION:  Vaccinations given during and within 2 weeks prior to|
04337|035|D|corticosteroid therapy may be less effective.  However they are considered|
04337|036|D|safe to administer.(1)|
04337|037|D|   Many clinicians consider a dose equivalent to either 2 mg/kg of body|
04337|038|D|weight or a total of 20 mg/day of prednisone as sufficiently|
04337|039|D|immunosuppressive to raise safety concerns about live-virus vaccines.(1)|
04337|040|D|   Immunization procedures may be undertaken in patients receiving|
04337|041|D|corticosteroids when the therapy is short term (less than 2 weeks); low to|
04337|042|D|moderate dose; long-term, alternate-day treatment with short-acting|
04337|043|D|preparations; maintenance physiologic doses (replacement therapy); or|
04337|044|D|administered topically (skin or eyes), by aerosol, or by intra-articular,|
04337|045|D|bursal, or tendon injection.(1)|
04337|046|B||
04337|047|R|REFERENCE:|
04337|048|B||
04337|049|R|1.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
04337|050|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
04337|051|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
04337|052|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
04337|053|R|  recs.pdf February 10, 2023;1-197.|6
04338|001|T|MONOGRAPH TITLE:  Ritlecitinib/Immunosuppressives; Immunomodulators|
04338|002|B||
04338|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04338|004|L|of severe adverse interaction.|
04338|005|B||
04338|006|A|MECHANISM OF ACTION:  Ritlecitinib, immunosuppressives, and immunomodulators|
04338|007|A|all suppress the immune system.|
04338|008|B||
04338|009|E|CLINICAL EFFECTS:  Concurrent use of ritlecitinib with immunosuppressives or|
04338|010|E|immunomodulators may result in an increased risk of serious infections.|
04338|011|B||
04338|012|P|PREDISPOSING FACTORS:  None determined.|
04338|013|B||
04338|014|M|PATIENT MANAGEMENT:  The US manufacturer of ritlecitinib states that|
04338|015|M|concurrent use of ritlecitinib with other JAK inhibitors, biologic|
04338|016|M|immunomodulators, cyclosporine or other potent immunosuppressants is not|
04338|017|M|recommended.(1)|
04338|018|B||
04338|019|D|DISCUSSION:  Serious infections have been reported in patients receiving|
04338|020|D|ritlecitinib.  Reported infections included appendicitis, COVID-19 infection|
04338|021|D|(including pneumonia), and sepsis.  Reports of viral reactivation, including|
04338|022|D|herpes virus reactivation was reported in clinical studies with|
04338|023|D|ritlecitinib.(1)|
04338|024|B||
04338|025|R|REFERENCE:|
04338|026|B||
04338|027|R|1.Litfulo (ritlecitinib) US prescribing information. Pfizer Inc. June 2023.|1
04339|001|T|MONOGRAPH TITLE:  Ritlecitinib/Strong CYP3A4 Inducers|
04339|002|B||
04339|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04339|004|L|of severe adverse interaction.|
04339|005|B||
04339|006|A|MECHANISM OF ACTION:  Ritlecitinib is a substrate of CYP3A4.  Strong|
04339|007|A|inducers of CYP3A4 may induce the metabolism of ritlecitinib.(1)|
04339|008|B||
04339|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
04339|010|E|in decreased levels and effectiveness of ritlecitinib.(1)|
04339|011|B||
04339|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04339|013|P|of the inducer for longer than 1-2 weeks.|
04339|014|B||
04339|015|M|PATIENT MANAGEMENT:  The manufacturer of ritlecitinib states concurrent|
04339|016|M|administration with strong CYP3A4 inducers is not recommended.(1)|
04339|017|B||
04339|018|D|DISCUSSION:  Ritlecitinib is a substrate of CYP3A4.(1)|
04339|019|D|   Concurrent administration of rifampin (600 mg once daily for 8 days, a|
04339|020|D|strong CYP3A4 inducer) with a single 50 mg dose of ritlecitinib decreased|
04339|021|D|the area-under-curve (AUC) and maximum concentration (Cmax) of ritlecitinib|
04339|022|D|by 44% and 25%, respectively, in healthy subjects.(1)|
04339|023|D|   Strong CYP3A4 inducers linked to this monograph include:  apalutamide,|
04339|024|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib,|
04339|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04339|026|D|rifapentine, and St. John's wort.(2-3)|
04339|027|B||
04339|028|R|REFERENCES:|
04339|029|B||
04339|030|R|1.Litfulo (ritlecitinib) US prescribing information. Pfizer Inc. June 2023.|1
04339|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04339|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04339|033|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04339|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04339|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04339|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04339|037|R|  11/14/2017.|1
04340|001|T|MONOGRAPH TITLE:  IgG Antibodies and Derivatives/Rozanolixizumab-noli|
04340|002|B||
04340|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04340|004|L|take action as needed.|
04340|005|B||
04340|006|A|MECHANISM OF ACTION:  The neonatal Fc receptor (FcRn) prevents catabolism|
04340|007|A|and mediates recycling of IgG and albumin, which leads to their long|
04340|008|A|persistence in the body.(1,2)  Rozanolixizumab-noli binds to FcRn and may|
04340|009|A|decrease systemic exposure of other ligands of FcRn, like immunoglobulins|
04340|010|A|and IgG-based antibodies.(3)|
04340|011|B||
04340|012|E|CLINICAL EFFECTS:  The effectiveness of medications that bind to FcRn may be|
04340|013|E|decreased.(3)|
04340|014|B||
04340|015|P|PREDISPOSING FACTORS:  None determined.|
04340|016|B||
04340|017|M|PATIENT MANAGEMENT:  The manufacturer of rozanolixizumab-noli states that|
04340|018|M|concurrent use with medications that bind to the human neonatal Fc receptor|
04340|019|M|(FcRn) should be closely monitored for reduced effectiveness of these|
04340|020|M|medications.  If long-term use of such medications is essential for the|
04340|021|M|patient, consider discontinuing rozanolixizumab-noli and use alternative|
04340|022|M|therapies.(3)|
04340|023|B||
04340|024|D|DISCUSSION:  Clinical drug interaction studies with rozanolixizumab-noli|
04340|025|D|have not been performed.  Rozanolixizumab-noli may decrease concentrations|
04340|026|D|of compounds that bind to the human FcRn.(3)|
04340|027|B||
04340|028|R|REFERENCES:|
04340|029|B||
04340|030|R|1.Sockolosky JT, Szoka FC. The neonatal Fc receptor, FcRn, as a target for|6
04340|031|R|  drug delivery and therapy. Adv Drug Deliv Rev 2015 Aug 30;91:109-24.|6
04340|032|R|2.Kuo TT, Aveson VG. Neonatal Fc receptor and IgG-based therapeutics. MAbs|6
04340|033|R|  2011 Sep-Oct;3(5):422-30.|6
04340|034|R|3.Rystiggo (rozanolixizumab-noli) US prescribing information. UCB, Inc. June|1
04340|035|R|  2023.|1
04341|001|T|MONOGRAPH TITLE:  Lapatinib/Strong CYP3A4 Inducers that Prolong QT|
04341|002|B||
04341|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04341|004|L|of severe adverse interaction.|
04341|005|B||
04341|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04341|007|A|metabolism of lapatinib. Also, an additive risk of QT prolongation may|
04341|008|A|result from concurrent use of two agents that prolong the QT interval.(1)|
04341|009|B||
04341|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 that|
04341|011|E|prolongs QT may result in decreased levels and effectiveness of lapatinib|
04341|012|E|and increase the risk of potentially life-threatening arrhythmia, including|
04341|013|E|torsade de pointes.(1)|
04341|014|B||
04341|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04341|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04341|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04341|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04341|019|P|female gender, or advanced age.(2)|
04341|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04341|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04341|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04341|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04341|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04341|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04341|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04341|027|P|   Induction effects may be more likely with regular use of the inducer for|
04341|028|P|longer than 1-2 weeks.|
04341|029|B||
04341|030|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04341|031|M|patients receiving therapy with lapatinib.  Consider the use of alternative|
04341|032|M|agents with less enzyme induction potential.(1)|
04341|033|M|   If concurrent use is necessary, the dose of lapatinib should be gradually|
04341|034|M|titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic|
04341|035|M|breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone|
04341|036|M|receptor positive, HER2 positive breast cancer indication) based on patient|
04341|037|M|tolerability.  If the inducer is discontinued, the dose of lapatinib should|
04341|038|M|be adjusted to the normal dose.(1)|
04341|039|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04341|040|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04341|041|M|baseline and regular intervals.(1)  Correct any electrolyte abnormalities.|
04341|042|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04341|043|B||
04341|044|D|DISCUSSION:  In healthy subjects, carbamazepine (100 mg twice daily for 3|
04341|045|D|days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased|
04341|046|D|the area-under-curve (AUC) of lapatinib by 72%.  The dose adjustment|
04341|047|D|recommendations are based on pharmacokinetic studies and are predicted to|
04341|048|D|adjust lapatinib AUC to the range observed without concurrent CYP3A4|
04341|049|D|inducers; however, there are no clinical data with these doses in patients|
04341|050|D|receiving strong CYP3A4 inducers.(1)|
04341|051|D|   Agents that are linked to this monograph may have varying degrees of|
04341|052|D|potential to prolong the QTc interval but are generally accepted to have a|
04341|053|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04341|054|D|been shown to prolong the QTc interval either through their mechanism of|
04341|055|D|action, through studies on their effects on the QTc interval, or through|
04341|056|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04341|057|D|and/or post-marketing reports.(3)|
04341|058|D|   Strong CYP3A4 inducers that prolong QT include:  encorafenib and|
04341|059|D|ivosidenib.(4,5)|
04341|060|B||
04341|061|R|REFERENCES:|
04341|062|B||
04341|063|R|1.Tykerb (lapatinib) US prescribing information. GlaxoSmithKline December,|1
04341|064|R|  2018.|1
04341|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04341|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04341|067|R|  settings: a scientific statement from the American Heart Association and|6
04341|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04341|069|R|  2;55(9):934-47.|6
04341|070|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04341|071|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04341|072|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04341|073|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04341|074|R|4.This information is based on an extract from the Certara Drug Interaction|6
04341|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04341|076|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04341|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04341|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04341|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04341|080|R|  11/14/2017.|1
04342|001|T|MONOGRAPH TITLE:  Ivosidenib/Imatinib|
04342|002|B||
04342|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04342|004|L|of severe adverse interaction.|
04342|005|B||
04342|006|A|MECHANISM OF ACTION:  Ivosidenib, a strong CYP3A4 inducer(1), may induce the|
04342|007|A|CYP3A4 isoenzyme and increase the metabolism of imatinib.(2)|
04342|008|A|   Moderate inhibitors of the CYP3A4 enzyme may inhibit the metabolism of|
04342|009|A|ivosidenib.(3)  Imatinib is a moderate CYP3A4 inhibitor.(1)|
04342|010|A|   Concurrent use of imatinib and ivosidenib may also result in additive|
04342|011|A|effects on the QTc interval.|
04342|012|B||
04342|013|E|CLINICAL EFFECTS:  Concurrent use of imatinib with ivosidenib, a strong|
04342|014|E|CYP3A4 inducer, may decrease the levels and effectiveness of imatinib and|
04342|015|E|may cause additive effects on the QTc interval, which may result in|
04342|016|E|life-threatening cardiac arrhythmias including torsades de pointes.(2)|
04342|017|E|   Concurrent use of moderate CYP3A4 inhibitors may also increase systemic|
04342|018|E|exposure and the risk for ivosidenib toxicities such as QT prolongation.(3)|
04342|019|B||
04342|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04342|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04342|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04342|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04342|024|P|gender, or advanced age.(4)|
04342|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04342|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04342|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04342|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04342|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04342|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04342|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04342|032|B||
04342|033|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers like|
04342|034|M|ivosidenib in patients receiving therapy with imatinib.  Consider the use of|
04342|035|M|alternative agents with less enzyme induction potential and less potential|
04342|036|M|to affect the QTc interval.(2)|
04342|037|M|   Although the manufacturer of imatinib provides recommendations for dose|
04342|038|M|modification of imatinib when used with strong CYP3A4 inducers, it has not|
04342|039|M|been studied in dual-directional interactions such as with ivosidenib.|
04342|040|M|Thus, this dose modification recommendation is for information only.  If|
04342|041|M|concurrent therapy with strong CYP3A4 inducers is required, the dose of|
04342|042|M|imatinib should be increased by at least 50% and clinical response should be|
04342|043|M|carefully monitored.  Dosages up to 1,200 mg daily (600 mg twice daily) have|
04342|044|M|been used in patients receiving concurrent therapy with strong CYP3A4|
04342|045|M|inducers.(2)|
04342|046|M|   The US manufacturer of ivosidenib recommends considering an alternative|
04342|047|M|concomitant medication with less potential for CYP3A4 inhibition.(3)|
04342|048|M|   If concurrent therapy is warranted, monitor patients closely for|
04342|049|M|prolongation of the QT interval.  Obtain serum calcium, magnesium, and|
04342|050|M|potassium levels and monitor ECG at regular intervals.  Correct any|
04342|051|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04342|052|M|heartbeat, dizziness, or fainting.|
04342|053|B||
04342|054|D|DISCUSSION:  Pretreatment of 14 healthy subjects with rifampin (600 mg daily|
04342|055|D|for 10 days) increased the clearance of a single dose of imatinib (400 mg)|
04342|056|D|by 3.8-fold.  The area-under-the-curve (AUC) and maximum concentration|
04342|057|D|(Cmax) decreased by 74% and 54%, respectively.(2)  The Cmax of the CGP74588|
04342|058|D|metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(2)|
04342|059|D|   In a drug interaction study in healthy subjects, coadministration of|
04342|060|D|itraconazole (200 mg once daily for 18 days) with a single dose of|
04342|061|D|ivosidenib (250 mg) increased ivosidenib AUC by 269%. No change was seen in|
04342|062|D|ivosidenib's Cmax.(3)|
04342|063|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
04342|064|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
04342|065|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
04342|066|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
04342|067|D|190%, respectively.(3)|
04342|068|B||
04342|069|R|REFERENCES:|
04342|070|B||
04342|071|R|1.This information is based on an extract from the Certara Drug Interaction|6
04342|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04342|073|R|2.Gleevec (imatinib mesylate) US prescribing information. Novartis|1
04342|074|R|  Pharmaceuticals Corporation August, 2022.|1
04342|075|R|3.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04342|076|R|  Inc. August, 2021.|1
04342|077|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04342|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04342|079|R|  settings: a scientific statement from the American Heart Association and|6
04342|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04342|081|R|  2;55(9):934-47.|6
04343|001|T|MONOGRAPH TITLE:  Palovarotene/Strong and Moderate CYP3A4 Inducers|
04343|002|B||
04343|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04343|004|L|of severe adverse interaction.|
04343|005|B||
04343|006|A|MECHANISM OF ACTION:  Palovarotene is extensively metabolized by CYP3A4.|
04343|007|A|Strong and moderate inducers of CYP3A4 may increase the metabolism of|
04343|008|A|palovarotene.(1)|
04343|009|B||
04343|010|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
04343|011|E|may result in decreased levels and effectiveness of palovarotene.(1)|
04343|012|B||
04343|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04343|014|P|of the inducer for longer than 1-2 weeks.|
04343|015|B||
04343|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of palovarotene with strong and|
04343|017|M|moderate CYP3A4 inducers.(1)|
04343|018|B||
04343|019|D|DISCUSSION:  In a clinical trial, rifampin, a strong CYP3A4 inducer,|
04343|020|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of|
04343|021|D|palovarotene by 81% and 89%, respectively.(1)|
04343|022|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04343|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04343|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04343|025|D|rifapentine, and St. John's wort.(2)|
04343|026|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04343|027|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04343|028|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04343|029|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04343|030|D|thioridazine, and tovorafenib.(2)|
04343|031|B||
04343|032|R|REFERENCES:|
04343|033|B||
04343|034|R|1.Sohonos (palovarotene) US prescribing information. Ipsen|1
04343|035|R|  Biopharmaceuticals, Inc. August 2023.|1
04343|036|R|2.Sohonos (palovarotene) Canadian Product Monograph. Ipsen|1
04343|037|R|  Biopharmaceuticals Canada Inc. January, 2022.|1
04343|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
04343|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04344|001|T|MONOGRAPH TITLE:  Palovarotene/Strong CYP3A4 Inhibitors|
04344|002|B||
04344|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04344|004|L|of severe adverse interaction.|
04344|005|B||
04344|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04344|007|A|of palovarotene.(1,2)|
04344|008|B||
04344|009|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
04344|010|E|increased levels of and effects from palovarotene including rash, alopecia,|
04344|011|E|skin exfoliation, photosensitivity, reduction in bone mass, hyperostosis,|
04344|012|E|and night blindness.(1,2)|
04344|013|B||
04344|014|P|PREDISPOSING FACTORS:  None determined.|
04344|015|B||
04344|016|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04344|017|M|palovarotene should be avoided.(1,2)|
04344|018|B||
04344|019|D|DISCUSSION:  In a clinical trial, ketoconazole, a strong CYP3A4 inhibitor,|
04344|020|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
04344|021|D|palovarotene by 121% and 212%, respectively.(1,2)|
04344|022|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04344|023|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
04344|024|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir,|
04344|025|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir,|
04344|026|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
04344|027|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)|
04344|028|B||
04344|029|R|REFERENCES:|
04344|030|B||
04344|031|R|1.Sohonos (palovarotene) Canadian Product Monograph. Ipsen|1
04344|032|R|  Biopharmaceuticals Canada Inc. January, 2022.|1
04344|033|R|2.Sohonos (palovarotene) US prescribing information. Ipsen|1
04344|034|R|  Biopharmaceuticals, Inc. August 2023.|1
04344|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04344|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04345|001|T|MONOGRAPH TITLE:  Colchicine (for Cardioprotection)/P-glycoprotein (P-gp)|
04345|002|T|Inhibitors|
04345|003|B||
04345|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04345|005|L|is contraindicated and generally should not be dispensed or administered to|
04345|006|L|the same patient.|
04345|007|B||
04345|008|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors may affect the|
04345|009|A|transport of colchicine, a P-gp substrate.(1,2)|
04345|010|B||
04345|011|E|CLINICAL EFFECTS:  Concurrent use of a P-gp inhibitor may result in elevated|
04345|012|E|levels of and toxicity from colchicine.  Symptoms of colchicine toxicity|
04345|013|E|include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness|
04345|014|E|or pain; numbness or tingling in the fingers or toes; myelosuppression;|
04345|015|E|feeling weak or tired; increased infections; and pale or gray color of the|
04345|016|E|lips, tongue, or palms of hands.(1,2)|
04345|017|B||
04345|018|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04345|019|P|patients with renal or hepatic impairment.(1,2)|
04345|020|B||
04345|021|M|PATIENT MANAGEMENT:  The manufacturer of colchicine used for cardiovascular|
04345|022|M|risk reduction states that concurrent use of colchicine with P-gp inhibitors|
04345|023|M|is contraindicated.(1)|
04345|024|B||
04345|025|D|DISCUSSION:  There are several reports of colchicine toxicity(3-5) and|
04345|026|D|death(6,7) following the addition of clarithromycin to therapy.  In a|
04345|027|D|retrospective review of 116 patients who received clarithromycin and|
04345|028|D|colchicine during the same hospitalization, 10.2% (9/88) of patients who|
04345|029|D|received simultaneous therapy died, compared to 3.6% (1/28) of patients who|
04345|030|D|received sequential therapy.(8)|
04345|031|D|   An FDA review of 117 colchicine-related deaths that were not attributable|
04345|032|D|to overdose found that 60 deaths (51%) involved concurrent use of|
04345|033|D|clarithromycin.(2)|
04345|034|D|   There is one case report of colchicine toxicity with concurrent|
04345|035|D|erythromycin.(9)|
04345|036|D|   In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for|
04345|037|D|7 days) increased the maximum concentration (Cmax) and area-under-curve|
04345|038|D|(AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to|
04345|039|D|318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1)|
04345|040|D|   In a study in 24 subjects, pretreatment with verapamil (240 mg twice|
04345|041|D|daily for 7 days) increased the Cmax and AUC of a single dose of colchicine|
04345|042|D|(0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to|
04345|043|D|217.2%), respectively.(1)|
04345|044|D|   Colchicine toxicity has been reported with concurrent use of CYP3A4 and|
04345|045|D|P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem,|
04345|046|D|erythromycin, and verapamil.(1,2)|
04345|047|D|   P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir,|
04345|048|D|azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine,|
04345|049|D|danicopan, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone,|
04345|050|D|erythromycin, flibanserin, fluvoxamine, fostamatinib,|
04345|051|D|glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, ledipasvir,|
04345|052|D|mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine,|
04345|053|D|ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, valbenazine,|
04345|054|D|velpatasvir, vemurafenib, venetoclax, verapamil, vimseltinib, and|
04345|055|D|voclosporin.(1,10,11)|
04345|056|B||
04345|057|R|REFERENCES:|
04345|058|B||
04345|059|R|1.Lodoco (colchicine) US prescribing information. AGEPHA Pharma USA, LLC|1
04345|060|R|  June, 2023.|1
04345|061|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
04345|062|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
04345|063|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
04345|064|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
04345|065|R|3.van der Velden W, Huussen J, Ter Laak H, de Sevaux R. Colchicine-induced|3
04345|066|R|  neuromyopathy in a patient with chronic renal failure: the role of|3
04345|067|R|  clarithromycin. Neth J Med 2008 May;66(5):204-6.|3
04345|068|R|4.Akdag I, Ersoy A, Kahvecioglu S, Gullulu M, Dilek K. Acute colchicine|3
04345|069|R|  intoxication during clarithromycin administration in patients with chronic|3
04345|070|R|  renal failure. J Nephrol 2006 Jul-Aug;19(4):515-7.|3
04345|071|R|5.Rollot F, Pajot O, Chauvelot-Moachon L, Nazal EM, Kelaidi C, Blanche P.|3
04345|072|R|  Acute colchicine intoxication during clarithromycin administration. Ann|3
04345|073|R|  Pharmacother 2004 Dec;38(12):2074-7.|3
04345|074|R|6.Cheng VC, Ho PL, Yuen KY. Two probable cases of serious drug interaction|3
04345|075|R|  between clarithromycin and colchicine. South Med J 2005 Aug;98(8):811-3.|3
04345|076|R|7.Dogukan A, Oymak FS, Taskapan H, Guven M, Tokgoz B, Utas C. Acute fatal|3
04345|077|R|  colchicine intoxication in a patient on continuous ambulatory peritoneal|3
04345|078|R|  dialysis (CAPD). Possible role of clarithromycin administration. Clin|3
04345|079|R|  Nephrol 2001 Feb;55(2):181-2.|3
04345|080|R|8.Hung IF, Wu AK, Cheng VC, Tang BS, To KW, Yeung CK, Woo PC, Lau SK, Cheung|2
04345|081|R|  BM, Yuen KY. Fatal interaction between clarithromycin and colchicine in|2
04345|082|R|  patients with renal insufficiency: a retrospective study. Clin Infect Dis|2
04345|083|R|  2005 Aug 1;41(3):291-300.|2
04345|084|R|9.Caraco Y, Putterman C, Rahamimov R, Ben-Chetrit E. Acute colchicine|3
04345|085|R|  intoxication--possible role of erythromycin administration. J Rheumatol|3
04345|086|R|  1992 Mar;19(3):494-6.|3
04345|087|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
04345|088|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
04345|089|R|   at:|1
04345|090|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
04345|091|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04345|092|R|   11/14/2017.|1
04345|093|R|11.This information is based on an extract from the Certara Drug Interaction|6
04345|094|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04346|001|T|MONOGRAPH TITLE:  Colchicine (for Cardioprotection)/Strong CYP3A4|
04346|002|T|Inhibitors;Atazanavir;Darunavir|
04346|003|B||
04346|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04346|005|L|is contraindicated and generally should not be dispensed or administered to|
04346|006|L|the same patient.|
04346|007|B||
04346|008|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04346|009|A|colchicine.(1,2)|
04346|010|B||
04346|011|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
04346|012|E|elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
04346|013|E|toxicity include muscle weakness or pain; numbness or tingling in the|
04346|014|E|fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea|
04346|015|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
04346|016|E|color of the lips, tongue, or palms of hands.(1,2)|
04346|017|B||
04346|018|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04346|019|P|patients with renal or hepatic impairment.(1,2)|
04346|020|B||
04346|021|M|PATIENT MANAGEMENT:  The manufacturer of colchicine used for cardiovascular|
04346|022|M|risk reduction states that concurrent use of colchicine with strong CYP3A4|
04346|023|M|inhibitors is contraindicated.(1)|
04346|024|B||
04346|025|D|DISCUSSION:  There are several reports of colchicine toxicity(4-6) and|
04346|026|D|death(7,8) following the addition of clarithromycin to therapy.  In a|
04346|027|D|retrospective review of 116 patients who received clarithromycin and|
04346|028|D|colchicine during the same hospitalization, 10.2% (9/88) of patients who|
04346|029|D|received simultaneous therapy died, compared to 3.6% (1/28) of patients who|
04346|030|D|received sequential therapy.(9)|
04346|031|D|   An FDA review of 117 colchicine-related deaths that were not attributable|
04346|032|D|to overdose found that 60 deaths (51%) involved concurrent use of|
04346|033|D|clarithromycin.(2)|
04346|034|D|   In a study in 23 subjects, pretreatment with clarithromycin (250 mg twice|
04346|035|D|daily for 7 days) increased the maximum concentration (Cmax) and|
04346|036|D|area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 227.2%|
04346|037|D|(range 65.7% to 591.1%) and by 281.5% (range 88.7% to 851.6%),|
04346|038|D|respectively.(1)|
04346|039|D|   In a study in 24 subjects, pretreatment with ketoconazole (200 mg twice|
04346|040|D|daily for 5 days) increased the Cmax and AUC of a single dose of colchicine|
04346|041|D|(0.6 mg) by 101.7% (range 19.6% to 219%) and by 212.2% (range 76.7% to|
04346|042|D|419.6%), respectively.(1)|
04346|043|D|   In a study in 18 subjects, pretreatment with ritonavir (100 mg twice|
04346|044|D|daily for 5 days) increased the Cmax and AUC of a single dose of colchicine|
04346|045|D|(0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to|
04346|046|D|924.4%), respectively.(1)|
04346|047|D|   Colchicine toxicity has been reported with concurrent use of CYP3A4 and|
04346|048|D|P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem,|
04346|049|D|erythromycin, and verapamil.(1,2)|
04346|050|D|   Strong inhibitors of CYP3A4 include: adagrasib, atazanavir, boceprevir,|
04346|051|D|ceritinib, clarithromycin, cobicistat, darunavir, idelalisib, indinavir,|
04346|052|D|itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib,|
04346|053|D|lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
04346|054|D|nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir,|
04346|055|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
04346|056|D|voriconazole.(1,10)|
04346|057|B||
04346|058|R|REFERENCES:|
04346|059|B||
04346|060|R|1.Lodoco (colchicine) US prescribing information. AGEPHA Pharma USA, LLC|1
04346|061|R|  June, 2023.|1
04346|062|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
04346|063|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
04346|064|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
04346|065|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
04346|066|R|3.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
04346|067|R|  November, 2015.|1
04346|068|R|4.van der Velden W, Huussen J, Ter Laak H, de Sevaux R. Colchicine-induced|3
04346|069|R|  neuromyopathy in a patient with chronic renal failure: the role of|3
04346|070|R|  clarithromycin. Neth J Med 2008 May;66(5):204-6.|3
04346|071|R|5.Akdag I, Ersoy A, Kahvecioglu S, Gullulu M, Dilek K. Acute colchicine|3
04346|072|R|  intoxication during clarithromycin administration in patients with chronic|3
04346|073|R|  renal failure. J Nephrol 2006 Jul-Aug;19(4):515-7.|3
04346|074|R|6.Rollot F, Pajot O, Chauvelot-Moachon L, Nazal EM, Kelaidi C, Blanche P.|3
04346|075|R|  Acute colchicine intoxication during clarithromycin administration. Ann|3
04346|076|R|  Pharmacother 2004 Dec;38(12):2074-7.|3
04346|077|R|7.Cheng VC, Ho PL, Yuen KY. Two probable cases of serious drug interaction|3
04346|078|R|  between clarithromycin and colchicine. South Med J 2005 Aug;98(8):811-3.|3
04346|079|R|8.Dogukan A, Oymak FS, Taskapan H, Guven M, Tokgoz B, Utas C. Acute fatal|3
04346|080|R|  colchicine intoxication in a patient on continuous ambulatory peritoneal|3
04346|081|R|  dialysis (CAPD). Possible role of clarithromycin administration. Clin|3
04346|082|R|  Nephrol 2001 Feb;55(2):181-2.|3
04346|083|R|9.Hung IF, Wu AK, Cheng VC, Tang BS, To KW, Yeung CK, Woo PC, Lau SK, Cheung|2
04346|084|R|  BM, Yuen KY. Fatal interaction between clarithromycin and colchicine in|2
04346|085|R|  patients with renal insufficiency: a retrospective study. Clin Infect Dis|2
04346|086|R|  2005 Aug 1;41(3):291-300.|2
04346|087|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
04346|088|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
04346|089|R|   at:|1
04346|090|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
04346|091|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04346|092|R|   11/14/2017.|1
04346|093|R|11.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04346|094|R|   Squibb Company December, 2024.|1
04346|095|R|12.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04346|096|R|   March, 2023.|1
04346|097|R|13.Crixivan (indinavir sulfate) US prescribing information. Merck & Co.,|1
04346|098|R|   Inc. September, 2016.|1
04346|099|R|14.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04346|100|R|   Laboratories December, 2019.|1
04346|101|R|15.Viracept (nelfinavir mesylate) US prescribing information. Agouron|1
04346|102|R|   Pharmaceuticals, Inc. September, 2016.|1
04346|103|R|16.Norvir (ritonavir) US prescribing information. Abbott Laboratories|1
04346|104|R|   December, 2019.|1
04346|105|R|17.Invirase (saquinavir mesylate) US prescribing information. Roche|1
04346|106|R|   Laboratories, Inc. March, 2019.|1
04346|107|R|18.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04346|108|R|   Pharmaceuticals, Inc. April, 2024.|1
04346|109|R|19.Victrelis (boceprevir) US prescribing information. Schering Corporation|1
04346|110|R|   January, 2017.|1
04346|111|R|20.Incivek (telaprevir) US prescribing information. Vertex Pharmaceuticals|1
04346|112|R|   Incorporated October, 2013.|1
04347|001|T|MONOGRAPH TITLE:  Colchicine (for Cardioprotection)/Moderate CYP3A4|
04347|002|T|Inhibitors|
04347|003|B||
04347|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04347|005|L|of severe adverse interaction.|
04347|006|B||
04347|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04347|008|A|of colchicine.(1,2)|
04347|009|B||
04347|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
04347|011|E|in elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
04347|012|E|toxicity include muscle weakness or pain; numbness or tingling in the|
04347|013|E|fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea|
04347|014|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
04347|015|E|color of the lips, tongue, or palms of hands.(1,2)|
04347|016|B||
04347|017|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04347|018|P|patients with renal and/or hepatic impairment.(1,2)|
04347|019|B||
04347|020|M|PATIENT MANAGEMENT:  Monitor patients receiving moderate CYP3A4 inhibitors|
04347|021|M|for signs of colchicine toxicity.  Avoid concurrent use in patients with|
04347|022|M|existing renal or hepatic impairment.(1)|
04347|023|M|   Patients should be instructed to immediately report any signs of|
04347|024|M|colchicine toxicity, such as muscle weakness/pain, numbness/tingling in|
04347|025|M|fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness,|
04347|026|M|pale/gray color of the lips/tongue/palms of hands, and/or severe|
04347|027|M|diarrhea/vomiting.|
04347|028|B||
04347|029|D|DISCUSSION:  There is one case report of colchicine toxicity with concurrent|
04347|030|D|erythromycin.(4)|
04347|031|D|   In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for|
04347|032|D|7 days) increased the maximum concentration (Cmax) and area-under-curve|
04347|033|D|(AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to|
04347|034|D|318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1)|
04347|035|D|   In a study in 18 subjects, pretreatment with ritonavir (100 mg twice|
04347|036|D|daily for 5 days) increased the Cmax and AUC of a single dose of colchicine|
04347|037|D|(0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to|
04347|038|D|924.4%), respectively.(1)|
04347|039|D|   In a study in 24 subjects, pretreatment with verapamil (240 mg twice|
04347|040|D|daily for 7 days) increased the Cmax and AUC of a single dose of colchicine|
04347|041|D|(0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to|
04347|042|D|217.2%), respectively.(1)|
04347|043|D|   Colchicine toxicity has been reported with concurrent use of CYP3A4|
04347|044|D|inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin,|
04347|045|D|and verapamil.(1,2)|
04347|046|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant, avacopan,|
04347|047|D|clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole,|
04347|048|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir,|
04347|049|D|letermovir, netupitant, nilotinib, rilzabrutinib, sevabertinib, stiripentol,|
04347|050|D|and treosulfan.(1,5,6)|
04347|051|B||
04347|052|R|REFERENCES:|
04347|053|B||
04347|054|R|1.Lodoco (colchicine) US prescribing information. AGEPHA Pharma USA, LLC|1
04347|055|R|  June, 2023.|1
04347|056|R|2.Anonymous. Information for Healthcare Professionals: New Safety|1
04347|057|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
04347|058|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
04347|059|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
04347|060|R|3.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
04347|061|R|  March, 2019.|1
04347|062|R|4.Caraco Y, Putterman C, Rahamimov R, Ben-Chetrit E. Acute colchicine|3
04347|063|R|  intoxication--possible role of erythromycin administration. J Rheumatol|3
04347|064|R|  1992 Mar;19(3):494-6.|3
04347|065|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04347|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04347|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04347|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04347|069|R|  11/14/2017.|1
04347|070|R|6.This information is based on an extract from the Certara Drug Interaction|6
04347|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04348|001|T|MONOGRAPH TITLE:  Cabozantinib/Strong CYP3A4 Inducers|
04348|002|B||
04348|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04348|004|L|of severe adverse interaction.|
04348|005|B||
04348|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04348|007|A|cabozantinib.(1,2)|
04348|008|B||
04348|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04348|010|E|may result in decreased levels and effectiveness of cabozantinib.(1,2)|
04348|011|B||
04348|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04348|013|P|of the inducer for longer than 1-2 weeks.|
04348|014|B||
04348|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04348|016|M|patients receiving therapy with cabozantinib.  Consider the use of|
04348|017|M|alternative agents with less enzyme induction potential.(1,2)|
04348|018|M|   If concurrent use of a CYP3A4 inducer cannot be avoided, increase the|
04348|019|M|daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily)|
04348|020|M|as tolerated. The daily dose should not exceed 80 mg.  Resume the dose that|
04348|021|M|was used prior to initiating the CYP3A4 inducer 2 to 3 days after|
04348|022|M|discontinuation of the strong inducer.(1)|
04348|023|M|   Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to|
04348|024|M|180 mg daily or from 100 mg to 140 mg daily) as tolerated.  The daily dose|
04348|025|M|of cabozantinib should not exceed 180 mg.  If the CYP3A4 inducer is|
04348|026|M|discontinued, reduce the dosage of cabozantinib to the dose used prior to|
04348|027|M|initiation of the inducer 2 to 3 days after discontinuation of the strong|
04348|028|M|inducer.(2)|
04348|029|B||
04348|030|D|DISCUSSION:  In a study in healthy subjects, rifampin (600 mg daily for 31|
04348|031|D|days) decreased the AUC of a single dose of cabozantinib by 77%.(1,2)|
04348|032|D|   Strong inducers of CYP3A4 include:  barbiturates, encorafenib,|
04348|033|D|enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin,|
04348|034|D|primidone, rifampin, and rifapentine.(3,4)|
04348|035|B||
04348|036|R|REFERENCES:|
04348|037|B||
04348|038|R|1.Cabometyx (cabozantinib) tablets, US prescribing information. Exelixis|1
04348|039|R|  Inc. January, 2021.|1
04348|040|R|2.Cometriq (cabozantinib) US prescribing information. Exelixix, Inc.|1
04348|041|R|  January, 2020.|1
04348|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
04348|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04348|044|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04348|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04348|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04348|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04348|048|R|  11/14/2017.|1
04349|001|T|MONOGRAPH TITLE:  Ceritinib/Strong CYP3A4 Inducers|
04349|002|B||
04349|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04349|004|L|of severe adverse interaction.|
04349|005|B||
04349|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04349|007|A|ceritinib.(1)|
04349|008|B||
04349|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04349|010|E|may result in decreased levels and effectiveness of ceritinib.(1)|
04349|011|B||
04349|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04349|013|P|of the inducer for longer than 1-2 weeks.|
04349|014|B||
04349|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04349|016|M|patients receiving therapy with ceritinib.  Consider the use of alternative|
04349|017|M|agents with less enzyme induction potential.(1)|
04349|018|B||
04349|019|D|DISCUSSION:  In a study in 19 healthy subjects, rifampin (600 mg daily for|
04349|020|D|14 days) decreased the maximum concentration (Cmax) and area-under-curve|
04349|021|D|(AUC) of a single dose of ceritinib by 44% and 70%, respectively.(1)|
04349|022|D|   Strong inducers of CYP3A4 include:  barbiturates, enzalutamide,|
04349|023|D|fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04349|024|D|rifapentine.(2,3)|
04349|025|B||
04349|026|R|REFERENCES:|
04349|027|B||
04349|028|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
04349|029|R|  Corporation August, 2021.|1
04349|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04349|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04349|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04349|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04349|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04349|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04349|036|R|  11/14/2017.|1
04350|001|T|MONOGRAPH TITLE:  Crizotinib/Strong CYP3A4 Inducers|
04350|002|B||
04350|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04350|004|L|of severe adverse interaction.|
04350|005|B||
04350|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04350|007|A|crizotinib.(1)|
04350|008|B||
04350|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04350|010|E|may result in decreased levels and effectiveness of crizotinib.(1)|
04350|011|B||
04350|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04350|013|P|of the inducer for longer than 1-2 weeks.|
04350|014|B||
04350|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04350|016|M|patients receiving therapy with crizotinib.  Consider the use of alternative|
04350|017|M|agents with less enzyme induction potential.(1)|
04350|018|B||
04350|019|D|DISCUSSION:  Rifampin (600 mg daily) decreased the maximum concentration|
04350|020|D|(Cmax) and area-under-curve (AUC) of a single dose of crizotinib (250 mg) by|
04350|021|D|69% and 82%, respectively.(1)|
04350|022|D|   Strong inducers of CYP3A4 include:  barbiturates, enzalutamide,|
04350|023|D|fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04350|024|D|rifapentine.(2,3)|
04350|025|B||
04350|026|R|REFERENCES:|
04350|027|B||
04350|028|R|1.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
04350|029|R|  2023.|1
04350|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04350|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04350|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04350|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04350|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04350|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04350|036|R|  11/14/2017.|1
04351|001|T|MONOGRAPH TITLE:  Dasatinib/Strong CYP3A4 Inducers|
04351|002|B||
04351|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04351|004|L|of severe adverse interaction.|
04351|005|B||
04351|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04351|007|A|dasatinib.(1)|
04351|008|B||
04351|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04351|010|E|may result in decreased levels and effectiveness of dasatinib.(1)|
04351|011|B||
04351|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04351|013|P|of the inducer for longer than 1-2 weeks.|
04351|014|B||
04351|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04351|016|M|patients receiving therapy with dasatinib.  Consider the use of alternative|
04351|017|M|agents with less enzyme induction potential.(1)|
04351|018|M|   If concurrent use is necessary, consider increasing the dose of|
04351|019|M|dasatinib.(1)|
04351|020|B||
04351|021|D|DISCUSSION:  In a study in healthy subjects, concurrent rifampin (600 mg|
04351|022|D|daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC)|
04351|023|D|of a single dose of dasatinib by 81% and 82%, respectively.(1)|
04351|024|D|   Strong inducers of CYP3A4 include:  barbiturates, enzalutamide,|
04351|025|D|fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04351|026|D|rifapentine.(2,3)|
04351|027|B||
04351|028|R|REFERENCES:|
04351|029|B||
04351|030|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
04351|031|R|  Company February, 2023.|1
04351|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
04351|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04351|034|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04351|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04351|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04351|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04351|038|R|  11/14/2017.|1
04352|001|T|MONOGRAPH TITLE:  Erlotinib/CYP3A4 Inducers|
04352|002|B||
04352|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04352|004|L|of severe adverse interaction.|
04352|005|B||
04352|006|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
04352|007|A|erlotinib.(1)|
04352|008|B||
04352|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a CYP3A4 inducer may result|
04352|010|E|in decreased levels and effectiveness of erlotinib.(1)|
04352|011|B||
04352|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04352|013|P|of the inducer for longer than 1-2 weeks.|
04352|014|B||
04352|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of CYP3A4 inducers in patients|
04352|016|M|receiving therapy with erlotinib.  Consider the use of alternative agents|
04352|017|M|with less enzyme induction potential.(1)|
04352|018|M|   Consider increasing the dosage of erlotinib by 50 mg increments as|
04352|019|M|tolerated at two week intervals (to a maximum of 450 mg) while closely|
04352|020|M|monitoring the patient.  The highest dosage studied with concurrent rifampin|
04352|021|M|is 450 mg.  If the dosage of erlotinib is increased, it will need to be|
04352|022|M|decreased when the inducer is discontinued.(1)|
04352|023|B||
04352|024|D|DISCUSSION:  Pretreatment and concurrent therapy with rifampin increased|
04352|025|D|erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve|
04352|026|D|(AUC) by 66% to 80%.  This is equivalent to a dose of about 30 mg to 50 mg|
04352|027|D|in NSCLC.(1)|
04352|028|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
04352|029|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
04352|030|D|150 mg dose of erlotinib.(1)|
04352|031|D|   In a case report, coadministration of phenytoin (180mg daily) and|
04352|032|D|erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml|
04352|033|D|to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from|
04352|034|D|1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold|
04352|035|D|(from 3.53 L/h to 41.7 L/h).(2)|
04352|036|D|   In a study, concurrent use of sorafenib (400 mg twice daily) and|
04352|037|D|erlotinib (150 mg daily) decreased the concentration minimum (Cmin),|
04352|038|D|concentration maximum (Cmax), and AUC of erlotinib.(3)|
04352|039|D|   In an animal study, concurrent use of dexamethasone and erlotinib|
04352|040|D|decreased the AUC of erlotinib by 0.6-fold.(4)|
04352|041|D|   Strong inducers of CYP3A4 include:  barbiturates, encorafenib,|
04352|042|D|enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin,|
04352|043|D|primidone, rifampin, and rifapentine.(5,6)|
04352|044|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04352|045|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04352|046|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04352|047|D|pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and|
04352|048|D|tovorafenib.(5,6)|
04352|049|D|   Weak inducers of CYP3A4 include: amprenavir, armodafinil, bexarotene,|
04352|050|D|brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin,|
04352|051|D|echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo,|
04352|052|D|ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin,|
04352|053|D|oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide,|
04352|054|D|sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat,|
04352|055|D|terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib,|
04352|056|D|vinblastine, and zanubrutinib.(5,6)|
04352|057|B||
04352|058|R|REFERENCES:|
04352|059|B||
04352|060|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
04352|061|R|  2016.|1
04352|062|R|2.Ohgami M, Kaburagi T, Kurosawa A, Homma M. Drug interaction between|3
04352|063|R|  erlotinib and phenytoin for brain metastases in a patient with nonsmall|3
04352|064|R|  cell lung cancer. Lung Cancer 2016 Nov;101:9-10.|3
04352|065|R|3.Peereboom DM, Ahluwalia MS, Ye X, Supko JG, Hilderbrand SL, Phuphanich S,|2
04352|066|R|  Nabors LB, Rosenfeld MR, Mikkelsen T, Grossman SA. NABTT 0502: a phase II|2
04352|067|R|  and pharmacokinetic study of erlotinib and sorafenib for  patients with|2
04352|068|R|  progressive or recurrent glioblastoma multiforme. Neuro Oncol 2013 Apr;|2
04352|069|R|  15(4):490-6.|2
04352|070|R|4.Deeken JF, Beumer JH, Anders NM, Wanjiku T, Rusnak M, Rudek MA.|5
04352|071|R|  Preclinical assessment of the interactions between the antiretroviral|5
04352|072|R|  drugs,  ritonavir and efavirenz, and the tyrosine kinase inhibitor|5
04352|073|R|  erlotinib. Cancer Chemother Pharmacol 2015 Oct;76(4):813-9.|5
04352|074|R|5.This information is based on an extract from the Certara Drug Interaction|6
04352|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04352|076|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04352|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04352|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04352|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04352|080|R|  11/14/2017.|1
04353|001|T|MONOGRAPH TITLE:  Gefitinib/Strong CYP3A4 Inducers|
04353|002|B||
04353|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04353|004|L|of severe adverse interaction.|
04353|005|B||
04353|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04353|007|A|gefitinib.(1)|
04353|008|B||
04353|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04353|010|E|may result in decreased levels and effectiveness of gefitinib.(1)|
04353|011|B||
04353|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04353|013|P|of the inducer for longer than 1-2 weeks.|
04353|014|B||
04353|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04353|016|M|patients receiving therapy with gefitinib.  Consider the use of alternative|
04353|017|M|agents with less enzyme induction potential.(1)|
04353|018|M|   If concurrent use of a CYP3A4 inducer cannot be avoided, consider a dose|
04353|019|M|increase to 500 mg daily of gefitinib in the absence of severe adverse drug|
04353|020|M|reaction.  Clinical response and adverse events should be closely|
04353|021|M|monitored.(1)|
04353|022|B||
04353|023|D|DISCUSSION:  In a study in healthy male volunteers, rifampicin decreased|
04353|024|D|area-under-curve (AUC) of gefitinib by 85%.(1)|
04353|025|D|   Strong inducers of CYP3A4 include:  barbiturates, encorafenib,|
04353|026|D|enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin,|
04353|027|D|primidone, rifampin, and rifapentine.(2,3)|
04353|028|B||
04353|029|R|REFERENCES:|
04353|030|B||
04353|031|R|1.Iressa (gefitinib tablets) US prescribing information. AstraZeneca|1
04353|032|R|  Pharmaceuticals LP April 7, 2004.|1
04353|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
04353|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04353|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04353|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04353|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04353|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04353|039|R|  11/14/2017.|1
04354|001|T|MONOGRAPH TITLE:  Ibrutinib/Strong CYP3A4 Inducers|
04354|002|B||
04354|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04354|004|L|of severe adverse interaction.|
04354|005|B||
04354|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04354|007|A|ibrutinib.(1)|
04354|008|B||
04354|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04354|010|E|may result in decreased levels and effectiveness of ibrutinib.(1)|
04354|011|B||
04354|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04354|013|P|of the inducer for longer than 1-2 weeks.|
04354|014|B||
04354|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04354|016|M|patients receiving therapy with ibrutinib.  Consider the use of alternative|
04354|017|M|agents with less enzyme induction potential.(1)|
04354|018|B||
04354|019|D|DISCUSSION:  The coadministration of rifampin decreased the maximum|
04354|020|D|concentration (Cmax) and area-under-curve (AUC) of ibrutinib by more than|
04354|021|D|13-fold and 10-fold.(1)|
04354|022|D|   Strong inducers of CYP3A4 include:  barbiturates, encorafenib,|
04354|023|D|enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin,|
04354|024|D|primidone, rifampin, and rifapentine.(2,3)|
04354|025|B||
04354|026|R|REFERENCES:|
04354|027|B||
04354|028|R|1.Imbruvica (ibrutinib) US Prescribing information. Pharmacyclics, Inc.|1
04354|029|R|  August, 2022.|1
04354|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04354|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04354|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04354|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04354|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04354|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04354|036|R|  11/14/2017.|1
04355|001|T|MONOGRAPH TITLE:  Idelalisib/Strong CYP3A4 Inducers|
04355|002|B||
04355|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04355|004|L|of severe adverse interaction.|
04355|005|B||
04355|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04355|007|A|idelalisib.(1)|
04355|008|B||
04355|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04355|010|E|may result in decreased levels and effectiveness of idelalisib.(1)|
04355|011|B||
04355|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04355|013|P|of the inducer for longer than 1-2 weeks.|
04355|014|B||
04355|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04355|016|M|patients receiving therapy with idelalisib.  Consider the use of alternative|
04355|017|M|agents with less enzyme induction potential.(1)|
04355|018|B||
04355|019|D|DISCUSSION:  In a study in healthy subjects, rifampin (600 mg daily for 8|
04355|020|D|days) decreased the maximum concentration (Cmax) and area-under-curve (AUC)|
04355|021|D|of idelalisib (150 mg single dose) by 58% and 75%, respectively.(1)|
04355|022|D|   Strong inducers of CYP3A4 include:  barbiturates, enzalutamide,|
04355|023|D|fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04355|024|D|rifapentine.(2,3)|
04355|025|B||
04355|026|R|REFERENCES:|
04355|027|B||
04355|028|R|1.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
04355|029|R|  October, 2020.|1
04355|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04355|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04355|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04355|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04355|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04355|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04355|036|R|  11/14/2017.|1
04356|001|T|MONOGRAPH TITLE:  Nilotinib/Strong CYP3A4 Inducers|
04356|002|B||
04356|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04356|004|L|of severe adverse interaction.|
04356|005|B||
04356|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04356|007|A|nilotinib.(1)|
04356|008|B||
04356|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04356|010|E|may result in decreased levels and effectiveness of nilotinib.(1)|
04356|011|B||
04356|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04356|013|P|of the inducer for longer than 1-2 weeks.|
04356|014|B||
04356|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04356|016|M|patients receiving therapy with nilotinib.  Consider the use of alternative|
04356|017|M|agents with less enzyme induction potential.(1)|
04356|018|M|   Because of the nonlinear pharmacokinetic profile of nilotinib, increasing|
04356|019|M|its dose is unlikely to compensate for enzyme induction.(1)|
04356|020|B||
04356|021|D|DISCUSSION:  In a study in healthy subjects, concurrent rifampin (600 mg|
04356|022|D|daily for 12 days) decreased nilotinib area-under-curve (AUC) by 80%.(1)|
04356|023|D|   Strong inducers of CYP3A4 include:  barbiturates, enzalutamide,|
04356|024|D|fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04356|025|D|rifapentine.(2,3)|
04356|026|B||
04356|027|R|REFERENCES:|
04356|028|B||
04356|029|R|1.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
04356|030|R|  Corporation September, 2021.|1
04356|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04356|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04356|033|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04356|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04356|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04356|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04356|037|R|  11/14/2017.|1
04357|001|T|MONOGRAPH TITLE:  Pazopanib/Strong CYP3A4 Inducers|
04357|002|B||
04357|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04357|004|L|of severe adverse interaction.|
04357|005|B||
04357|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04357|007|A|pazopanib.(1)|
04357|008|B||
04357|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04357|010|E|may result in decreased levels and effectiveness of pazopanib.(1)|
04357|011|B||
04357|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04357|013|P|of the inducer for longer than 1-2 weeks.|
04357|014|B||
04357|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04357|016|M|patients receiving therapy with pazopanib.  Consider the use of alternative|
04357|017|M|agents with less enzyme induction potential.(1)|
04357|018|M|   Pazopanib should not be administered to patients who cannot avoid chronic|
04357|019|M|use of strong CYP3A4 inducers.(1)|
04357|020|B||
04357|021|D|DISCUSSION:  Pazopanib is primarily metabolized by CYP3A4.(1)|
04357|022|D|   Strong inducers of CYP3A4 include:  barbiturates, enzalutamide,|
04357|023|D|fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04357|024|D|rifapentine.(2,3)|
04357|025|B||
04357|026|R|REFERENCES:|
04357|027|B||
04357|028|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
04357|029|R|  2020.|1
04357|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04357|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04357|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04357|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04357|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04357|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04357|036|R|  11/14/2017.|1
04358|001|T|MONOGRAPH TITLE:  Sorafenib/Strong CYP3A4 Inducers|
04358|002|B||
04358|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04358|004|L|of severe adverse interaction.|
04358|005|B||
04358|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04358|007|A|sorafenib.(1)|
04358|008|B||
04358|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04358|010|E|may result in decreased levels and effectiveness of sorafenib.(1)|
04358|011|B||
04358|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04358|013|P|of the inducer for longer than 1-2 weeks.|
04358|014|B||
04358|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04358|016|M|patients receiving therapy with sorafenib.  Consider the use of alternative|
04358|017|M|agents with less enzyme induction potential.(1)|
04358|018|B||
04358|019|D|DISCUSSION:  Concurrent rifampin (600 mg daily for 5 days) decreased the|
04358|020|D|area-under-curve (AUC) of a single dose of sorafenib (400 mg) by 37%.(1)|
04358|021|D|   Strong inducers of CYP3A4 include:  barbiturates, enzalutamide,|
04358|022|D|fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04358|023|D|rifapentine.(2,3)|
04358|024|B||
04358|025|R|REFERENCES:|
04358|026|B||
04358|027|R|1.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
04358|028|R|  Corporation July, 2020.|1
04358|029|R|2.This information is based on an extract from the Certara Drug Interaction|6
04358|030|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04358|031|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04358|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04358|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04358|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04358|035|R|  11/14/2017.|1
04359|001|T|MONOGRAPH TITLE:  Sunitinib/Strong CYP3A4 Inducers|
04359|002|B||
04359|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04359|004|L|of severe adverse interaction.|
04359|005|B||
04359|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04359|007|A|sunitinib.(1)|
04359|008|B||
04359|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04359|010|E|may result in decreased levels and effectiveness of sunitinib.(1)|
04359|011|B||
04359|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04359|013|P|of the inducer for longer than 1-2 weeks.|
04359|014|B||
04359|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04359|016|M|patients receiving therapy with sunitinib.  Consider the use of alternative|
04359|017|M|agents with less enzyme induction potential.(1)|
04359|018|M|   A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients|
04359|019|M|with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma|
04359|020|M|(RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine|
04359|021|M|tumors (pNET) should be considered.(1)|
04359|022|B||
04359|023|D|DISCUSSION:  In a study with healthy subjects, concurrent rifampin decreased|
04359|024|D|the combined sunitinib plus primary active metabolite maximum concentration|
04359|025|D|(Cmax) and area-under-curve (AUC) by 23% and 46%, respectively, of a single|
04359|026|D|dose of sunitinib.(1)|
04359|027|D|   Strong inducers of CYP3A4 include:  barbiturates, enzalutamide,|
04359|028|D|fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04359|029|D|rifapentine.(2,3)|
04359|030|B||
04359|031|R|REFERENCES:|
04359|032|B||
04359|033|R|1.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
04359|034|R|  2021.|1
04359|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
04359|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04359|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04359|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04359|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04359|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04359|041|R|  11/14/2017.|1
04360|001|T|MONOGRAPH TITLE:  Vandetanib/Strong CYP3A4 Inducers|
04360|002|B||
04360|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04360|004|L|of severe adverse interaction.|
04360|005|B||
04360|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04360|007|A|vandetanib.(1)|
04360|008|B||
04360|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04360|010|E|may result in decreased levels and effectiveness of vandetanib.(1)|
04360|011|B||
04360|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04360|013|P|of the inducer for longer than 1-2 weeks.|
04360|014|B||
04360|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04360|016|M|patients receiving therapy with vandetanib.  Consider the use of alternative|
04360|017|M|agents with less enzyme induction potential.(1)|
04360|018|B||
04360|019|D|DISCUSSION:  In healthy volunteers, rifampin 600 mg daily (a strong CYP3A4|
04360|020|D|inducer) for 31 days decreased the area-under-curve (AUC) of vandetanib by|
04360|021|D|40% on day 10.  There was no change in vandetanib maximum concentration|
04360|022|D|(Cmax).  The AUC and Cmax of N-desmethylvandetanib increased by 266% and|
04360|023|D|414%, respectively.(1)|
04360|024|D|   Strong inducers of CYP3A4 include:  barbiturates, enzalutamide,|
04360|025|D|fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04360|026|D|rifapentine.(2,3)|
04360|027|B||
04360|028|R|REFERENCES:|
04360|029|B||
04360|030|R|1.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
04360|031|R|  Pharmaceuticals LP October, 2018.|1
04360|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
04360|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04360|034|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04360|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04360|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04360|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04360|038|R|  11/14/2017.|1
04361|001|T|MONOGRAPH TITLE:  Vandetanib/Strong CYP3A4 Inducers that Prolong QT|
04361|002|B||
04361|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04361|004|L|of severe adverse interaction.|
04361|005|B||
04361|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04361|007|A|metabolism of vandetanib.  Also, an additive risk of QT prolongation may|
04361|008|A|result from concurrent use of two agents that prolong the QT interval.(1)|
04361|009|B||
04361|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 that|
04361|011|E|prolongs QT may result in decreased levels and effectiveness of vandetanib|
04361|012|E|and increase the risk of potentially life-threatening arrhythmia, including|
04361|013|E|torsade de pointes.(1)|
04361|014|B||
04361|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04361|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04361|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04361|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04361|019|P|female gender, or advanced age.(2)|
04361|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04361|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04361|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04361|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04361|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04361|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04361|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04361|027|P|   Induction effects may be more likely with regular use of the inducer for|
04361|028|P|longer than 1-2 weeks.|
04361|029|B||
04361|030|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04361|031|M|patients receiving therapy with vandetanib.  Consider the use of alternative|
04361|032|M|agents with less enzyme induction potential.(1)|
04361|033|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04361|034|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04361|035|M|baseline and regular intervals.(1)  Correct any electrolyte abnormalities.|
04361|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04361|037|B||
04361|038|D|DISCUSSION:  In healthy volunteers, rifampin 600 mg daily (a strong CYP3A4|
04361|039|D|inducer) for 31 days decreased the area-under-curve (AUC) of vandetanib by|
04361|040|D|40% on day 10.  There was no change in vandetanib maximum concentration|
04361|041|D|(Cmax).  The AUC and Cmax of N-desmethylvandetanib increased by 266% and|
04361|042|D|414%, respectively.(1)|
04361|043|D|   Agents that are linked to this monograph may have varying degrees of|
04361|044|D|potential to prolong the QTc interval but are generally accepted to have a|
04361|045|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04361|046|D|been shown to prolong the QTc interval either through their mechanism of|
04361|047|D|action, through studies on their effects on the QTc interval, or through|
04361|048|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04361|049|D|and/or post-marketing reports.(3)|
04361|050|D|   Strong CYP3A4 inducers that prolong QT include:  encorafenib and|
04361|051|D|ivosidenib.(4,5)|
04361|052|B||
04361|053|R|REFERENCES:|
04361|054|B||
04361|055|R|1.Caprelsa (vandetanib) US prescribing information. AstraZeneca|1
04361|056|R|  Pharmaceuticals LP June, 2020.|1
04361|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04361|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04361|059|R|  settings: a scientific statement from the American Heart Association and|6
04361|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04361|061|R|  2;55(9):934-47.|6
04361|062|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04361|063|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04361|064|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04361|065|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04361|066|R|4.This information is based on an extract from the Certara Drug Interaction|6
04361|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04361|068|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04361|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04361|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04361|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04361|072|R|  11/14/2017.|1
04362|001|T|MONOGRAPH TITLE:  Dasatinib/Strong CYP3A4 Inducers that Prolong QT|
04362|002|B||
04362|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04362|004|L|of severe adverse interaction.|
04362|005|B||
04362|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04362|007|A|metabolism of dasatinib. Also, an additive risk of QT prolongation may|
04362|008|A|result from concurrent use of two agents that prolong the QT interval.(1)|
04362|009|B||
04362|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 that|
04362|011|E|prolongs QT may result in decreased levels and effectiveness of dasatinib|
04362|012|E|and increase the risk of potentially life-threatening arrhythmia, including|
04362|013|E|torsade de pointes.(1)|
04362|014|B||
04362|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04362|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04362|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04362|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04362|019|P|female gender, or advanced age.(2)|
04362|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04362|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04362|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04362|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04362|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04362|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04362|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04362|027|P|   Induction effects may be more likely with regular use of the inducer for|
04362|028|P|longer than 1-2 weeks.|
04362|029|B||
04362|030|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04362|031|M|patients receiving therapy with dasatinib.  Consider the use of alternative|
04362|032|M|agents with less enzyme induction potential.(1)|
04362|033|M|   If concurrent use is necessary, consider increasing the dose of|
04362|034|M|dasatinib.(1)|
04362|035|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04362|036|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04362|037|M|baseline and regular intervals.  Correct any electrolyte abnormalities.|
04362|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04362|039|B||
04362|040|D|DISCUSSION:  In a study in healthy subjects, concurrent rifampin (600 mg|
04362|041|D|daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC)|
04362|042|D|of a single dose of dasatinib by 81% and 82%, respectively.(1)|
04362|043|D|   Agents that are linked to this monograph may have varying degrees of|
04362|044|D|potential to prolong the QTc interval but are generally accepted to have a|
04362|045|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04362|046|D|been shown to prolong the QTc interval either through their mechanism of|
04362|047|D|action, through studies on their effects on the QTc interval, or through|
04362|048|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04362|049|D|and/or post-marketing reports.(3)|
04362|050|D|   Strong CYP3A4 inducers that prolong QT include:  encorafenib and|
04362|051|D|ivosidenib.(4,5)|
04362|052|B||
04362|053|R|REFERENCES:|
04362|054|B||
04362|055|R|1.Sprycel (dasatinib) US prescribing information. Bristol-Myers Squibb|1
04362|056|R|  Company February, 2023.|1
04362|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04362|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04362|059|R|  settings: a scientific statement from the American Heart Association and|6
04362|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04362|061|R|  2;55(9):934-47.|6
04362|062|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04362|063|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04362|064|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04362|065|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04362|066|R|4.This information is based on an extract from the Certara Drug Interaction|6
04362|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04362|068|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04362|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04362|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04362|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04362|072|R|  11/14/2017.|1
04363|001|T|MONOGRAPH TITLE:  Pazopanib/Strong CYP3A4 Inducers that Prolong QT|
04363|002|B||
04363|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04363|004|L|of severe adverse interaction.|
04363|005|B||
04363|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04363|007|A|metabolism of pazopanib.  Also, an additive risk of QT prolongation may|
04363|008|A|result from concurrent use of two agents that prolong the QT interval.(1)|
04363|009|B||
04363|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 that|
04363|011|E|prolongs QT may result in decreased levels and effectiveness of pazopanib|
04363|012|E|and increase the risk of potentially life-threatening arrhythmia, including|
04363|013|E|torsade de pointes.(1)|
04363|014|B||
04363|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04363|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04363|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04363|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04363|019|P|female gender, or advanced age.(2)|
04363|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04363|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04363|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04363|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04363|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04363|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04363|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04363|027|P|   Induction effects may be more likely with regular use of the inducer for|
04363|028|P|longer than 1-2 weeks.|
04363|029|B||
04363|030|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04363|031|M|patients receiving therapy with pazopanib.  Consider the use of alternative|
04363|032|M|agents with less enzyme induction potential.(1)|
04363|033|M|   Pazopanib should not be administered to patients who cannot avoid chronic|
04363|034|M|use of strong CYP3A4 inducers.(1)|
04363|035|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04363|036|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04363|037|M|baseline and regular intervals.  Correct any electrolyte abnormalities.|
04363|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04363|039|B||
04363|040|D|DISCUSSION:  Pazopanib is primarily metabolized by CYP3A4.(1)|
04363|041|D|   Agents that are linked to this monograph may have varying degrees of|
04363|042|D|potential to prolong the QTc interval but are generally accepted to have a|
04363|043|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04363|044|D|been shown to prolong the QTc interval either through their mechanism of|
04363|045|D|action, through studies on their effects on the QTc interval, or through|
04363|046|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04363|047|D|and/or post-marketing reports.(3)|
04363|048|D|   Strong CYP3A4 inducers that prolong QT include: ivosidenib.(4,5)|
04363|049|B||
04363|050|R|REFERENCES:|
04363|051|B||
04363|052|R|1.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
04363|053|R|  2020.|1
04363|054|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04363|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04363|056|R|  settings: a scientific statement from the American Heart Association and|6
04363|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04363|058|R|  2;55(9):934-47.|6
04363|059|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04363|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04363|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04363|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04363|063|R|4.This information is based on an extract from the Certara Drug Interaction|6
04363|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04363|065|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04363|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04363|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04363|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04363|069|R|  11/14/2017.|1
04364|001|T|MONOGRAPH TITLE:  Sorafenib/Strong CYP3A4 Inducers that Prolong QT|
04364|002|B||
04364|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04364|004|L|of severe adverse interaction.|
04364|005|B||
04364|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04364|007|A|metabolism of sorafenib.  Also, an additive risk of QT prolongation may|
04364|008|A|result from concurrent use of two agents that prolong the QT interval.(1)|
04364|009|B||
04364|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 that|
04364|011|E|prolongs QT may result in decreased levels and effectiveness of sorafenib|
04364|012|E|and increase the risk of potentially life-threatening arrhythmia, including|
04364|013|E|torsade de pointes.(1)|
04364|014|B||
04364|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04364|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04364|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04364|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04364|019|P|female gender, or advanced age.(2)|
04364|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04364|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04364|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04364|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04364|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04364|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04364|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04364|027|P|   Induction effects may be more likely with regular use of the inducer for|
04364|028|P|longer than 1-2 weeks.|
04364|029|B||
04364|030|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04364|031|M|patients receiving therapy with sorafenib.  Consider the use of alternative|
04364|032|M|agents with less enzyme induction potential.(1)|
04364|033|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04364|034|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04364|035|M|baseline and regular intervals.(1)  Correct any electrolyte abnormalities.|
04364|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04364|037|B||
04364|038|D|DISCUSSION:  Concurrent rifampin (600 mg daily for 5 days) decreased the|
04364|039|D|area-under-curve (AUC) of a single dose of sorafenib (400 mg) by 37%.(1)|
04364|040|D|   Agents that are linked to this monograph may have varying degrees of|
04364|041|D|potential to prolong the QTc interval but are generally accepted to have a|
04364|042|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04364|043|D|been shown to prolong the QTc interval either through their mechanism of|
04364|044|D|action, through studies on their effects on the QTc interval, or through|
04364|045|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04364|046|D|and/or post-marketing reports.(3)|
04364|047|D|   Strong CYP3A4 inducers that prolong QT include: encorafenib,|
04364|048|D|ivosidenib.(4,5)|
04364|049|B||
04364|050|R|REFERENCES:|
04364|051|B||
04364|052|R|1.Nexavar (sorafenib) US prescribing information. Bayer Pharmaceuticals|1
04364|053|R|  Corporation July, 2020.|1
04364|054|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04364|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04364|056|R|  settings: a scientific statement from the American Heart Association and|6
04364|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04364|058|R|  2;55(9):934-47.|6
04364|059|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04364|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04364|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04364|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04364|063|R|4.This information is based on an extract from the Certara Drug Interaction|6
04364|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04364|065|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04364|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04364|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04364|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04364|069|R|  11/14/2017.|1
04365|001|T|MONOGRAPH TITLE:  Sunitinib/Strong CYP3A4 Inducers that Prolong QT|
04365|002|B||
04365|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04365|004|L|of severe adverse interaction.|
04365|005|B||
04365|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04365|007|A|metabolism of sunitinib.  Also, an additive risk of QT prolongation may|
04365|008|A|result from concurrent use of two agents that prolong the QT interval.(1)|
04365|009|B||
04365|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 that|
04365|011|E|prolongs QT may result in decreased levels and effectiveness of sunitinib|
04365|012|E|and increase the risk of potentially life-threatening arrhythmia, including|
04365|013|E|torsade de pointes.(1)|
04365|014|B||
04365|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04365|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04365|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04365|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04365|019|P|female gender, or advanced age.(2)|
04365|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04365|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04365|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04365|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04365|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04365|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04365|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04365|027|P|   Induction effects may be more likely with regular use of the inducer for|
04365|028|P|longer than 1-2 weeks.|
04365|029|B||
04365|030|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04365|031|M|patients receiving therapy with sunitinib.  Consider the use of alternative|
04365|032|M|agents with less enzyme induction potential.(1)|
04365|033|M|   A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients|
04365|034|M|with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma|
04365|035|M|(RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine|
04365|036|M|tumors (pNET) should be considered.(1)|
04365|037|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04365|038|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04365|039|M|baseline and regular intervals.(1)  Correct any electrolyte abnormalities.|
04365|040|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04365|041|B||
04365|042|D|DISCUSSION:  In a study with healthy subjects, concurrent rifampin decreased|
04365|043|D|the combined (sunitinib plus primary active metabolite) maximum|
04365|044|D|concentration (Cmax) and area-under-curve (AUC) by 23% and 46%,|
04365|045|D|respectively, of a single dose of sunitinib.(1)|
04365|046|D|   Agents that are linked to this monograph may have varying degrees of|
04365|047|D|potential to prolong the QTc interval but are generally accepted to have a|
04365|048|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04365|049|D|been shown to prolong the QTc interval either through their mechanism of|
04365|050|D|action, through studies on their effects on the QTc interval, or through|
04365|051|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04365|052|D|and/or post-marketing reports.(3)|
04365|053|D|   Strong CYP3A4 inducers that prolong QT include:  encorafenib and|
04365|054|D|ivosidenib.(4,5)|
04365|055|B||
04365|056|R|REFERENCES:|
04365|057|B||
04365|058|R|1.Sutent (sunitinib malate) US prescribing information. Pfizer Inc. August,|1
04365|059|R|  2021.|1
04365|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04365|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04365|062|R|  settings: a scientific statement from the American Heart Association and|6
04365|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04365|064|R|  2;55(9):934-47.|6
04365|065|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04365|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04365|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04365|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04365|069|R|4.This information is based on an extract from the Certara Drug Interaction|6
04365|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04365|071|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04365|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04365|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04365|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04365|075|R|  11/14/2017.|1
04366|001|T|MONOGRAPH TITLE:  Olaparib/Strong & Moderate CYP3A4 Inducers|
04366|002|B||
04366|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04366|004|L|of severe adverse interaction.|
04366|005|B||
04366|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04366|007|A|metabolism of olaparib.(1)|
04366|008|B||
04366|009|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
04366|010|E|decrease the levels and effectiveness of olaparib.(1)|
04366|011|B||
04366|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04366|013|P|of the inducer for longer than 1-2 weeks.|
04366|014|B||
04366|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong or moderate CYP3A4|
04366|016|M|inducers in patients receiving therapy with olaparib.(1)  Consider the use|
04366|017|M|of alternatives with little to no induction potential.|
04366|018|B||
04366|019|D|DISCUSSION:  In a drug interaction trial, olaparib area-under-curve (AUC)|
04366|020|D|and maximum concentration (Cmax) decreased 87% and 71% respectively when|
04366|021|D|olaparib was administered with rifampin.  Based upon simulated models, a|
04366|022|D|moderate CYP3A4 inducer is predicted to decrease olaparib AUC by 50-60% and|
04366|023|D|Cmax by 20-30%.(1-3)|
04366|024|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04366|025|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04366|026|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04366|027|D|rifapentine, and St. John's wort.|
04366|028|D|   Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib,|
04366|029|D|efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten,|
04366|030|D|mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib,|
04366|031|D|rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4-5)|
04366|032|B||
04366|033|R|REFERENCES:|
04366|034|B||
04366|035|R|1.Lynparza (olaparib) capsules US prescribing information. AstraZenica|1
04366|036|R|  Pharmaceuticals October 23, 2017.|1
04366|037|R|2.Lynparza (olaparib) tablets US prescribing information. AstraZenica|1
04366|038|R|  Pharmaceuticals March, 2021.|1
04366|039|R|3.Dirix L, Swaisland H, Verheul HM. Effect of Itraconazole and Rifampin on|2
04366|040|R|  the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors:|2
04366|041|R|  Results of Two Phase I Open-label Studies. Clin Ther 2016 Oct;|2
04366|042|R|  38(10):2286-2299.|2
04366|043|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04366|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04366|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04366|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04366|047|R|  11/14/2017.|1
04366|048|R|5.This information is based on an extract from the Certara Drug Interaction|6
04366|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04367|001|T|MONOGRAPH TITLE:  Palbociclib/Strong & Moderate CYP3A4 Inducers|
04367|002|B||
04367|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04367|004|L|of severe adverse interaction.|
04367|005|B||
04367|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04367|007|A|metabolism of palbociclib.(1)|
04367|008|B||
04367|009|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
04367|010|E|decrease the levels and effectiveness of palbociclib.(1)|
04367|011|B||
04367|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04367|013|P|of the inducer for longer than 1-2 weeks.|
04367|014|B||
04367|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong or moderate CYP3A4|
04367|016|M|inducers in patients receiving therapy with palbociclib.(1)  Consider the|
04367|017|M|use of alternatives with little to no induction potential.|
04367|018|B||
04367|019|D|DISCUSSION:  In a study in 14 healthy subjects, rifampin (600 mg daily)|
04367|020|D|decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a|
04367|021|D|single dose of palbociclib by 70% and 85%, respectively.(1)|
04367|022|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04367|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04367|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04367|025|D|rifapentine, and St. John's wort.|
04367|026|D|   Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib,|
04367|027|D|efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten,|
04367|028|D|mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib,|
04367|029|D|rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)|
04367|030|B||
04367|031|R|REFERENCES:|
04367|032|B||
04367|033|R|1.Ibrance (palbociclib) US prescribing information. Pfizer Labs September,|1
04367|034|R|  2023.|1
04367|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04367|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04367|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04367|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04367|039|R|  11/14/2017.|1
04367|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04367|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04368|001|T|MONOGRAPH TITLE:  Sonidegib/Strong & Moderate CYP3A4 Inducers|
04368|002|B||
04368|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04368|004|L|of severe adverse interaction.|
04368|005|B||
04368|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04368|007|A|metabolism of sonidegib.(1)|
04368|008|B||
04368|009|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
04368|010|E|decrease the levels and effectiveness of sonidegib.(1)|
04368|011|B||
04368|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04368|013|P|of the inducer for longer than 1-2 weeks.|
04368|014|B||
04368|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong or moderate CYP3A4|
04368|016|M|inducers in patients receiving therapy with sonidegib.(1)  Consider the use|
04368|017|M|of alternatives with little to no induction potential.|
04368|018|B||
04368|019|D|DISCUSSION:  In an interaction study, 16 healthy subjects received a single|
04368|020|D|dose of sonidegib 800mg alone or 5 days after receiving rifampin 600 mg|
04368|021|D|daily for 14 days. Mean sonidegib area-under-curve (AUC) was decreased by|
04368|022|D|75% and maximum concentration (Cmax) decreased 54% when taken with rifampin.|
04368|023|D|Based upon population based pharmacokinetic (PBPK) simulations, a moderate|
04368|024|D|CYP3A4 inducer such as efavirenz given for 14 days is predicted to decrease|
04368|025|D|sonidegib AUC 56% in cancer patients taking sonidegib 200 mg daily.|
04368|026|D|Coadministration with a moderate CYP3A4 inducer for 4 months is predicted to|
04368|027|D|decrease sonidegib exposure (AUC) by 69%.(1)|
04368|028|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04368|029|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04368|030|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04368|031|D|rifapentine, and St. John's wort.|
04368|032|D|   Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib,|
04368|033|D|efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten,|
04368|034|D|mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib,|
04368|035|D|rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)|
04368|036|B||
04368|037|R|REFERENCES:|
04368|038|B||
04368|039|R|1.Odomzo (sonidegib) US prescribing information. Novartis Pharmaceuticals|1
04368|040|R|  May, 2019.|1
04368|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04368|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04368|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04368|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04368|045|R|  11/14/2017.|1
04368|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
04368|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04369|001|T|MONOGRAPH TITLE:  Cabazitaxel/Strong CYP3A4 Inducers|
04369|002|B||
04369|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04369|004|L|of severe adverse interaction.|
04369|005|B||
04369|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04369|007|A|cabazitaxel.(1-3)|
04369|008|B||
04369|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04369|010|E|may result in decreased levels and effectiveness of cabazitaxel.(1,2)|
04369|011|B||
04369|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04369|013|P|of the inducer for longer than 1-2 weeks.|
04369|014|B||
04369|015|M|PATIENT MANAGEMENT:  The UK and Canadian prescribing information recommends|
04369|016|M|avoiding concurrent use of strong inducers of CYP3A4 with cabazitaxel.(1,2)|
04369|017|M|Consider the use of agents with no or minimal induction potential if|
04369|018|M|possible.  Monitor patients for decreased response to therapy.|
04369|019|M|   The US prescribing information does not make a recommendation for|
04369|020|M|concurrent use of cabazitaxel with strong CYP3A4 inducers.(3)|
04369|021|B||
04369|022|D|DISCUSSION:  Cabazitaxel is metabolized by CYP3A4 and strong inducers of|
04369|023|D|this isoenzyme are expected to decrease levels of cabazitaxel.(1-3)|
04369|024|D|   In a study in 21 advanced cancer patients, rifampin (600mg) decreased the|
04369|025|D|exposure to cabazitaxel (15mg/m2) by 17%.(1-3)|
04369|026|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
04369|027|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04369|028|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04369|029|D|rifapentine, and St. John's wort.(4,5)|
04369|030|B||
04369|031|R|REFERENCES:|
04369|032|B||
04369|033|R|1.Jevtana (cabazitaxel) Canadian product monograph. Sandoz Canada inc|1
04369|034|R|  November, 2023.|1
04369|035|R|2.Jevtana (cabazitaxel) UK Summary of Product Characteristics. Sanofi|1
04369|036|R|  Genzyme February, 2024.|1
04369|037|R|3.Jevtana (cabazitaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
04369|038|R|  July, 2023.|1
04369|039|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04369|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04369|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04369|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04369|043|R|  11/14/2017.|1
04369|044|R|5.This information is based on an extract from the Certara Drug Interaction|6
04369|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04370|001|T|MONOGRAPH TITLE:  Docetaxel/Strong CYP3A4 Inducers|
04370|002|B||
04370|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04370|004|L|of severe adverse interaction.|
04370|005|B||
04370|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04370|007|A|docetaxel.(1)|
04370|008|B||
04370|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04370|010|E|may result in decreased levels and effectiveness of docetaxel.(1)|
04370|011|B||
04370|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04370|013|P|of the inducer for longer than 1-2 weeks.|
04370|014|B||
04370|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
04370|016|M|docetaxel.(1)  Consider the use of agents with no or minimal induction|
04370|017|M|potential if possible.  Monitor patients for decreased response to therapy.|
04370|018|B||
04370|019|D|DISCUSSION:  Docetaxel is metabolized by CYP3A4 and strong inducers of this|
04370|020|D|isoenzyme are expected to decrease levels of docetaxel.(1)|
04370|021|D|   In a study in 10 cancer patients, St. John's wort decreased the|
04370|022|D|area-under-curve (AUC) of docetaxel by 11.6%.  There were no significant|
04370|023|D|decreases in docetaxel maximum concentration (Cmax) or half-life.|
04370|024|D|Docetaxel-related toxicities were lower during St. John's wort.(2)|
04370|025|D|   In an in vitro study, hyperforin, a constituent of St. John's wort,|
04370|026|D|induced the metabolism of docetaxel in a dose-dependent fashion with|
04370|027|D|induction ranged from 2.6-fold to 7-fold greater than controls.  In this|
04370|028|D|same experiment, rifampin induced docetaxel metabolism 6.8-fold to|
04370|029|D|32-fold.(3)|
04370|030|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
04370|031|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04370|032|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04370|033|D|rifapentine, and St. John's wort.(4-5)|
04370|034|B||
04370|035|R|REFERENCES:|
04370|036|B||
04370|037|R|1.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
04370|038|R|  January, 2023.|1
04370|039|R|2.Goey AK, Meijerman I, Rosing H, Marchetti S, Mergui-Roelvink M, Keessen M,|2
04370|040|R|  Burgers JA, Beijnen JH, Schellens JH. The Effect of St John's Wort on the|2
04370|041|R|  Pharmacokinetics of Docetaxel. Clin Pharmacokinet 2014 Jan;53(1):103-10.|2
04370|042|R|3.Komoroski BJ, Parise RA, Egorin MJ, Strom SC, Venkataramanan R. Effect of|5
04370|043|R|  the St. John's wort constituent hyperforin on docetaxel metabolism by|5
04370|044|R|  human hepatocyte cultures. Clin Cancer Res 2005 Oct 1;11(19 Pt 1):6972-9.|5
04370|045|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04370|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04370|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04370|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04370|049|R|  11/14/2017.|1
04370|050|R|5.This information is based on an extract from the Certara Drug Interaction|6
04370|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04371|001|T|MONOGRAPH TITLE:  Doxorubicin/Strong CYP3A4 Inducers|
04371|002|B||
04371|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04371|004|L|of severe adverse interaction.|
04371|005|B||
04371|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04371|007|A|doxorubicin.(1)|
04371|008|B||
04371|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04371|010|E|may result in decreased levels and effectiveness of doxorubicin.(1)|
04371|011|B||
04371|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04371|013|P|of the inducer for longer than 1-2 weeks.|
04371|014|B||
04371|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
04371|016|M|doxorubicin.(1)  Consider the use of agents with no or minimal induction|
04371|017|M|potential if possible.  Monitor patients for decreased response to therapy.|
04371|018|B||
04371|019|D|DISCUSSION:  Doxorubicin is metabolized by CYP3A4 and strong inducers of|
04371|020|D|this isoenzyme are expected to decrease levels of doxorubicin.(1)|
04371|021|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
04371|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04371|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04371|024|D|rifapentine, and St. John's wort.(2,3)|
04371|025|B||
04371|026|R|REFERENCES:|
04371|027|B||
04371|028|R|1.Doxorubicin US prescribing information. Pfizer Labs August, 2019.|1
04371|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04371|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04371|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04371|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04371|033|R|  11/14/2017.|1
04371|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04371|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04372|001|T|MONOGRAPH TITLE:  Paclitaxel/Strong CYP3A4 Inducers|
04372|002|B||
04372|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04372|004|L|of severe adverse interaction.|
04372|005|B||
04372|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04372|007|A|paclitaxel.(1)|
04372|008|B||
04372|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04372|010|E|may result in decreased levels and effectiveness of paclitaxel.(1)|
04372|011|B||
04372|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04372|013|P|of the inducer for longer than 1-2 weeks.|
04372|014|B||
04372|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
04372|016|M|paclitaxel.(1)  Consider the use of agents with no or minimal induction|
04372|017|M|potential if possible.  Monitor patients for decreased response to therapy.|
04372|018|B||
04372|019|D|DISCUSSION:  Paclitaxel is metabolized by CYP3A4 and strong inducers of this|
04372|020|D|isoenzyme are expected to decrease levels of paclitaxel.(1)|
04372|021|D|   In a Phase 2 study of paclitaxel, none of the subjects taking phenytoin|
04372|022|D|experienced a partial or complete response to paclitaxel.  Paclitaxel levels|
04372|023|D|were 70% lower in these patients than in patients not receiving|
04372|024|D|phenytoin.(2)|
04372|025|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
04372|026|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04372|027|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04372|028|D|rifapentine, and St. John's wort.(3,4)|
04372|029|B||
04372|030|R|REFERENCES:|
04372|031|B||
04372|032|R|1.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
04372|033|R|  Company August, 2010.|1
04372|034|R|2.Fetell MR, Grossman SA, Fisher JD, Erlanger B, Rowinsky E, Stockel J,|2
04372|035|R|  Piantadosi S. Preirradiation paclitaxel in glioblastoma multiforme:|2
04372|036|R|  efficacy, pharmacology, and drug interactions. New Approaches to Brain|2
04372|037|R|  Tumor Therapy Central Nervous System Consortium. J Clin Oncol 1997 Sep;|2
04372|038|R|  15(9):3121-8.|2
04372|039|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04372|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04372|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04372|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04372|043|R|  11/14/2017.|1
04372|044|R|4.This information is based on an extract from the Certara Drug Interaction|6
04372|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04373|001|T|MONOGRAPH TITLE:  Panobinostat/Strong CYP3A4 Inducers|
04373|002|B||
04373|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04373|004|L|of severe adverse interaction.|
04373|005|B||
04373|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04373|007|A|panobinostat.(1)|
04373|008|B||
04373|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04373|010|E|may result in decreased levels and effectiveness of panobinostat.(1)|
04373|011|B||
04373|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04373|013|P|of the inducer for longer than 1-2 weeks.|
04373|014|B||
04373|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
04373|016|M|panobinostat.(1)  Consider the use of agents with no or minimal induction|
04373|017|M|potential if possible.  Monitor patients for decreased response to therapy.|
04373|018|B||
04373|019|D|DISCUSSION:  Panobinostat is metabolized by CYP3A4 and strong inducers of|
04373|020|D|this isoenzyme are expected to decrease levels of panobinostat.(1)|
04373|021|D|   Physiologically-based pharmacokinetic (PBPK) models predict a 70%|
04373|022|D|decrease in exposure of panobinostat with strong inducers of CYP3A4.(1)|
04373|023|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
04373|024|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
04373|025|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
04373|026|D|wort.(2,3)|
04373|027|B||
04373|028|R|REFERENCES:|
04373|029|B||
04373|030|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
04373|031|R|  Pharmaceuticals Corporation June, 2016.|1
04373|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04373|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04373|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04373|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04373|036|R|  11/14/2017.|1
04373|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04373|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04374|001|T|MONOGRAPH TITLE:  Vincristine/Strong CYP3A4 Inducers|
04374|002|B||
04374|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04374|004|L|of severe adverse interaction.|
04374|005|B||
04374|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04374|007|A|vincristine.(1)|
04374|008|B||
04374|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04374|010|E|may result in decreased levels and effectiveness of vincristine.(1)|
04374|011|B||
04374|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04374|013|P|of the inducer for longer than 1-2 weeks.|
04374|014|B||
04374|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
04374|016|M|vincristine.(1)  Consider the use of agents with no or minimal induction|
04374|017|M|potential if possible.  Monitor patients for decreased response to therapy.|
04374|018|B||
04374|019|D|DISCUSSION:  Vincristine is metabolized by CYP3A4 and strong inducers of|
04374|020|D|this isoenzyme are expected to decrease levels of vincristine.(1)|
04374|021|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
04374|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04374|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04374|024|D|rifapentine, and St. John's wort.(2,3)|
04374|025|B||
04374|026|R|REFERENCES:|
04374|027|B||
04374|028|R|1.Marqibo (vincristine sulfate) US prescribing information. Talon|1
04374|029|R|  Therapeutics, Inc July, 2020.|1
04374|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04374|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04374|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04374|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04374|034|R|  11/14/2017.|1
04374|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04374|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04375|001|T|MONOGRAPH TITLE:  Ivosidenib/Ceritinib|
04375|002|B||
04375|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04375|004|L|of severe adverse interaction.|
04375|005|B||
04375|006|A|MECHANISM OF ACTION:  Ivosidenib, a strong CYP3A4 inducer(1), may induce the|
04375|007|A|CYP3A4 isoenzyme and increase the metabolism of ceritinib.(2)|
04375|008|A|   Strong inhibitors of the CYP3A4 enzyme may inhibit the metabolism of|
04375|009|A|ivosidenib.(3)  Ceritinib is a strong CYP3A4 inhibitor.(1)|
04375|010|A|   Concurrent use of ceritinib and ivosidenib may also result in additive|
04375|011|A|effects on the QTc interval.|
04375|012|B||
04375|013|E|CLINICAL EFFECTS:  Concurrent use of ceritinib with ivosidenib, a strong|
04375|014|E|CYP3A4 inducer, may decrease the levels and effectiveness of ceritinib and|
04375|015|E|may cause additive effects on the QTc interval, which may result in|
04375|016|E|life-threatening cardiac arrhythmias including torsades de pointes.(2)  In|
04375|017|E|addition, systemic exposure to ivosidenib may increase and elevate the risk|
04375|018|E|for ivosidenib toxicities such as QT prolongation.(3)|
04375|019|B||
04375|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04375|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04375|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04375|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04375|024|P|gender, or advanced age.(4)|
04375|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04375|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04375|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04375|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04375|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04375|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04375|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04375|032|B||
04375|033|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers like|
04375|034|M|ivosidenib in patients receiving therapy with ceritinib.  Consider the use|
04375|035|M|of alternative agents with less enzyme induction potential and less|
04375|036|M|potential to affect the QTc interval.(2)|
04375|037|M|   The US manufacturer of ivosidenib recommends considering an alternative|
04375|038|M|concomitant medication with less potential for CYP3A4 inhibition.(3)|
04375|039|M|   Although the manufacturer of ivosidenib provides recommendations for dose|
04375|040|M|modification of ivosidenib when used with strong CYP3A4 inhibitors, it has|
04375|041|M|not been studied in dual-directional interactions such as with ceritinib.|
04375|042|M|Thus, this dose modification recommendation is for information only.  The US|
04375|043|M|manufacturer of ivosidenib states when concomitant use of ivosidenib and a|
04375|044|M|strong CYP3A4 inhibitor is needed, the ivosidenib dose should be reduced to|
04375|045|M|250 mg once daily.  If the strong CYP3A4 inhibitor is discontinued, increase|
04375|046|M|the ivosidenib dose to the recommended dose of 500 mg once daily after at|
04375|047|M|least 5 half-lives of the strong 3A4 inhibitor.(3)|
04375|048|M|   If concurrent therapy is warranted, monitor patients closely for|
04375|049|M|prolongation of the QT interval.  Obtain serum calcium, magnesium, and|
04375|050|M|potassium levels and monitor ECG at regular intervals.  Correct any|
04375|051|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04375|052|M|heartbeat, dizziness, or fainting.|
04375|053|B||
04375|054|D|DISCUSSION:  In a study in 19 healthy subjects, rifampin (600 mg daily for|
04375|055|D|14 days) decreased the maximum concentration (Cmax) and area-under-curve|
04375|056|D|(AUC) of a single dose of ceritinib by 44% and 70%, respectively.(2)|
04375|057|D|   In a drug interaction study in healthy subjects, coadministration of|
04375|058|D|itraconazole (200 mg once daily for 18 days) with a single dose of|
04375|059|D|ivosidenib (250 mg) increased ivosidenib AUC by 269%. No change was seen in|
04375|060|D|ivosidenib's Cmax.(3)|
04375|061|B||
04375|062|R|REFERENCES:|
04375|063|B||
04375|064|R|1.This information is based on an extract from the Certara Drug Interaction|6
04375|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04375|066|R|2.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
04375|067|R|  Corporation August, 2021.|1
04375|068|R|3.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04375|069|R|  Inc. August, 2021.|1
04375|070|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04375|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04375|072|R|  settings: a scientific statement from the American Heart Association and|6
04375|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04375|074|R|  2;55(9):934-47.|6
04376|001|T|MONOGRAPH TITLE:  Ivosidenib/Idelalisib|
04376|002|B||
04376|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04376|004|L|of severe adverse interaction.|
04376|005|B||
04376|006|A|MECHANISM OF ACTION:  Ivosidenib, a strong CYP3A4 inducer(1), may induce the|
04376|007|A|CYP3A4 isoenzyme and increase the metabolism of idelalisib.(2)|
04376|008|A|   Strong inhibitors of the CYP3A4 enzyme may inhibit the metabolism of|
04376|009|A|ivosidenib.(3)  Idelalisib is a strong CYP3A4 inhibitor.(1)|
04376|010|B||
04376|011|E|CLINICAL EFFECTS:  Concurrent use of idelalisib with ivosidenib, a strong|
04376|012|E|CYP3A4 inducer, may decrease the levels and effectiveness of idelalisib.(2)|
04376|013|E|In addition, systemic exposure of ivosidenib may increase and elevate the|
04376|014|E|risk for ivosidenib toxicities such as QT prolongation.(3)|
04376|015|B||
04376|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04376|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04376|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04376|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04376|020|P|gender, or advanced age.(4)|
04376|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04376|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04376|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04376|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04376|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04376|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04376|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04376|028|B||
04376|029|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers like|
04376|030|M|ivosidenib in patients receiving therapy with idelalisib.  Consider the use|
04376|031|M|of alternative agents with less enzyme induction potential.(2)|
04376|032|M|   The US manufacturer of ivosidenib recommends considering an alternative|
04376|033|M|concomitant medication with less potential for CYP3A4 inhibition.(3)|
04376|034|M|   Although the manufacturer of ivosidenib provides recommendations for dose|
04376|035|M|modification of ivosidenib when used with strong CYP3A4 inhibitors, it has|
04376|036|M|not been studied in dual-directional interactions such as with idelalisib.|
04376|037|M|Thus, this dose modification recommendation is for information only.  The US|
04376|038|M|manufacturer of ivosidenib states when concomitant use of ivosidenib and a|
04376|039|M|strong CYP3A4 inhibitor is needed, the ivosidenib dose should be reduced to|
04376|040|M|250 mg once daily.  If the strong CYP3A4 inhibitor is discontinued, increase|
04376|041|M|the ivosidenib dose to the recommended dose of 500 mg once daily after at|
04376|042|M|least 5 half-lives of the strong 3A4 inhibitor.(3)|
04376|043|M|   If concurrent therapy is warranted, monitor patients closely for|
04376|044|M|prolongation of the QT interval.  Obtain serum calcium, magnesium, and|
04376|045|M|potassium levels and monitor ECG at regular intervals.  Correct any|
04376|046|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04376|047|M|heartbeat, dizziness, or fainting.|
04376|048|B||
04376|049|D|DISCUSSION:  In a study in healthy subjects, rifampin (600 mg daily for 8|
04376|050|D|days) decreased the maximum concentration (Cmax) and area-under-curve (AUC)|
04376|051|D|of idelalisib (150 mg single dose) by 58% and 75%, respectively.(2)|
04376|052|D|   In a drug interaction study in healthy subjects, coadministration of|
04376|053|D|itraconazole (200 mg once daily for 18 days) with a single dose of|
04376|054|D|ivosidenib (250 mg) increased ivosidenib AUC by 269%. No change was seen in|
04376|055|D|ivosidenib's Cmax.(3)|
04376|056|B||
04376|057|R|REFERENCES:|
04376|058|B||
04376|059|R|1.This information is based on an extract from the Certara Drug Interaction|6
04376|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04376|061|R|2.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
04376|062|R|  October, 2020.|1
04376|063|R|3.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04376|064|R|  Inc. August, 2021.|1
04376|065|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04376|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04376|067|R|  settings: a scientific statement from the American Heart Association and|6
04376|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04376|069|R|  2;55(9):934-47.|6
04377|001|T|MONOGRAPH TITLE:  Ivosidenib/Nilotinib|
04377|002|B||
04377|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04377|004|L|of severe adverse interaction.|
04377|005|B||
04377|006|A|MECHANISM OF ACTION:  Ivosidenib, a strong CYP3A4 inducer(1), may induce the|
04377|007|A|CYP3A4 isoenzyme and increase the metabolism of nilotinib.(2)|
04377|008|A|   Moderate inhibitors of the CYP3A4 enzyme may inhibit the metabolism of|
04377|009|A|ivosidenib.(3)  Nilotinib is a moderate CYP3A4 inhibitor.(1)|
04377|010|A|   Concurrent use of nilotinib and ivosidenib may also result in additive|
04377|011|A|effects on the QTc interval.|
04377|012|B||
04377|013|E|CLINICAL EFFECTS:  Concurrent use of nilotinib with ivosidenib, a strong|
04377|014|E|CYP3A4 inducer, may decrease the levels and effectiveness of nilotinib and|
04377|015|E|may cause additive effects on the QTc interval, which may result in|
04377|016|E|life-threatening cardiac arrhythmias including torsades de pointes.(2)  In|
04377|017|E|addition, systemic exposure of ivosidenib may increase and elevate the risk|
04377|018|E|for toxicities such as QT prolongation.(3)|
04377|019|B||
04377|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04377|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04377|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04377|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04377|024|P|gender, or advanced age.(4)|
04377|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04377|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04377|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04377|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04377|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04377|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04377|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04377|032|B||
04377|033|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers like|
04377|034|M|ivosidenib in patients receiving therapy with nilotinib.  Consider the use|
04377|035|M|of alternative agents with less enzyme induction potential and less|
04377|036|M|potential to affect the QTc interval.(2)|
04377|037|M|   The US manufacturer of ivosidenib recommends considering an alternative|
04377|038|M|concomitant medication with less potential for CYP3A4 inhibition.(3)|
04377|039|M|   If concurrent therapy is warranted, monitor patients closely for|
04377|040|M|prolongation of the QT interval.  Obtain serum calcium, magnesium, and|
04377|041|M|potassium levels and monitor ECG at regular intervals.  Correct any|
04377|042|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04377|043|M|heartbeat, dizziness, or fainting.|
04377|044|B||
04377|045|D|DISCUSSION:  In a study in healthy subjects, concurrent rifampin (600 mg|
04377|046|D|daily for 12 days) decreased nilotinib area-under-curve (AUC) by 80%.(2)|
04377|047|D|   In a drug interaction study in healthy subjects, coadministration of|
04377|048|D|itraconazole (200 mg once daily for 18 days) with a single dose of|
04377|049|D|ivosidenib (250 mg) increased ivosidenib AUC by 269%. No change was seen in|
04377|050|D|ivosidenib's maximum concentration (Cmax).(3)|
04377|051|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
04377|052|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
04377|053|D|by 173%.  In regards to multiple-dosing, coadministration of ivosidenib with|
04377|054|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
04377|055|D|190%, respectively.(3)|
04377|056|B||
04377|057|R|REFERENCES:|
04377|058|B||
04377|059|R|1.This information is based on an extract from the Certara Drug Interaction|6
04377|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04377|061|R|2.Tasigna (nilotinib) US prescribing information. Novartis Pharmaceuticals|1
04377|062|R|  Corporation September, 2014.|1
04377|063|R|3.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04377|064|R|  Inc. August, 2021.|1
04377|065|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04377|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04377|067|R|  settings: a scientific statement from the American Heart Association and|6
04377|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04377|069|R|  2;55(9):934-47.|6
04378|001|T|MONOGRAPH TITLE:  Panobinostat/Strong CYP3A4 Inducers that Prolong QT|
04378|002|B||
04378|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04378|004|L|of severe adverse interaction.|
04378|005|B||
04378|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04378|007|A|metabolism of panobinostat.  Also, an additive risk of QT prolongation may|
04378|008|A|result from concurrent use of two agents that prolong the QT interval.(1)|
04378|009|B||
04378|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 that|
04378|011|E|prolongs QT may result in decreased levels and effectiveness of panobinostat|
04378|012|E|and increase the risk of potentially life-threatening arrhythmia, including|
04378|013|E|torsade de pointes.(1)|
04378|014|B||
04378|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04378|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04378|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04378|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04378|019|P|female gender, or advanced age.(2)|
04378|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04378|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04378|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04378|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04378|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04378|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04378|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04378|027|P|   Induction effects may be more likely with regular use of the inducer for|
04378|028|P|longer than 1-2 weeks.|
04378|029|B||
04378|030|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong CYP3A4 inducers in|
04378|031|M|patients receiving therapy with panobinostat.  Consider the use of|
04378|032|M|alternative agents with less enzyme induction potential.(1)|
04378|033|M|   If concurrent use is necessary, consider electrocardiogram (ECG) and|
04378|034|M|electrolyte monitoring (calcium, magnesium, and potassium levels) at|
04378|035|M|baseline and regular intervals.(1)  Correct any electrolyte abnormalities.|
04378|036|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04378|037|B||
04378|038|D|DISCUSSION:  Panobinostat is metabolized by CYP3A4 and strong inducers of|
04378|039|D|this isoenzyme are expected to decrease levels of panobinostat.(1)|
04378|040|D|   Physiologically-based pharmacokinetic (PBPK) models predict a 70%|
04378|041|D|decrease in exposure of panobinostat with strong inducers of CYP3A4.(1)|
04378|042|D|   Agents that are linked to this monograph may have varying degrees of|
04378|043|D|potential to prolong the QTc interval but are generally accepted to have a|
04378|044|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04378|045|D|been shown to prolong the QTc interval either through their mechanism of|
04378|046|D|action, through studies on their effects on the QTc interval, or through|
04378|047|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04378|048|D|and/or post-marketing reports.(3)|
04378|049|D|   Strong CYP3A4 inducers that prolong QT include:  encorafenib and|
04378|050|D|ivosidenib.(4,5)|
04378|051|B||
04378|052|R|REFERENCES:|
04378|053|B||
04378|054|R|1.Farydak (panobinostat) US prescribing information. Novartis|1
04378|055|R|  Pharmaceuticals Corporation June, 2016.|1
04378|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04378|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04378|058|R|  settings: a scientific statement from the American Heart Association and|6
04378|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04378|060|R|  2;55(9):934-47.|6
04378|061|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04378|062|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04378|063|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04378|064|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04378|065|R|4.This information is based on an extract from the Certara Drug Interaction|6
04378|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04378|067|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04378|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04378|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04378|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04378|071|R|  11/14/2017.|1
04379|001|T|MONOGRAPH TITLE:  Valoctocogene Roxaparvovec/Efavirenz|
04379|002|B||
04379|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04379|004|L|of severe adverse interaction.|
04379|005|B||
04379|006|A|MECHANISM OF ACTION:  The mechanism of this interaction has not been|
04379|007|A|established.(1)|
04379|008|B||
04379|009|E|CLINICAL EFFECTS:  Co-administration of valoctocogene roxaparvovec with|
04379|010|E|efavirenz was poorly tolerated and resulted in elevations of liver enzymes|
04379|011|E|with subsequent decreased factor VIII levels and increased risk of|
04379|012|E|bleeding.(1)|
04379|013|B||
04379|014|P|PREDISPOSING FACTORS:  None determined.|
04379|015|B||
04379|016|M|PATIENT MANAGEMENT:  The manufacturer of valoctocogene roxaparvovec states|
04379|017|M|that co-administration with efavirenz is not recommended.(1)|
04379|018|B||
04379|019|D|DISCUSSION:  In an HIV positive patient who had been stable on his|
04379|020|D|antiretroviral regimen for over 10 years, treatment with valoctocogene|
04379|021|D|roxaparvovec and the antiretroviral regimen of efavirenz, lamivudine, and|
04379|022|D|tenofovir resulted in elevations of liver enzymes.  The patient developed|
04379|023|D|asymptomatic elevations in ALT, AST, and GGT (> 5 x ULN (upper limit of|
04379|024|D|normal)) and serum bilirubin (> ULN and up to 1.5 x ULN).  The liver enzyme|
04379|025|D|elevations resolved after efavirenz was stopped, worsened with rechallenge|
04379|026|D|of efavirenz, and resolved again after replacing efavirenz with raltegravir.|
04379|027|D|In addition, the patient did not maintain detectable FVIII levels after|
04379|028|D|gene therapy, experiencing 21 bleeding events and eventually reverting to|
04379|029|D|prophylactic FVIII therapy.(1,2)|
04379|030|D|   In vitro studies indicate efavirenz suppresses factor VIII transcription|
04379|031|D|independent of hepatotoxicity, and expression was not restored upon|
04379|032|D|discontinuation.(1)|
04379|033|D|   In efavirenz HIV trials, 20% of hepatitis B or C coinfected patients who|
04379|034|D|received efavirenz had ALT elevations > 5 times the upper limit of normal|
04379|035|D|versus 7% of patients in the control arm.(3)|
04379|036|B||
04379|037|R|REFERENCES:|
04379|038|B||
04379|039|R|1.Roctavian (valoctocogene roxaparvovec-rvox) US prescribing information.|1
04379|040|R|  BioMarin Pharmaceutical Inc. June, 2023.|1
04379|041|R|2.Ragni MV, Majerus E, Fong S, Yates B, Scheeler S, Razon L, Yu H, Reddy DB,|3
04379|042|R|  Robinson TM. Valoctocogene roxaparvovec gene transfer in participants with|3
04379|043|R|  HIV. Blood Adv 2023 Apr 25;7(8):1525-1530.|3
04379|044|R|3.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
04379|045|R|  Company November, 2023.|1
04380|001|T|MONOGRAPH TITLE:  Valoctocogene Roxaparvovec/Isotretinoin|
04380|002|B||
04380|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04380|004|L|of severe adverse interaction.|
04380|005|B||
04380|006|A|MECHANISM OF ACTION:  The mechanism of this interaction has not been|
04380|007|A|established.(1)|
04380|008|B||
04380|009|E|CLINICAL EFFECTS:  Co-administration of valoctocogene roxaparvovec with|
04380|010|E|isotretinoin resulted in decreased factor VIII activity, which may result in|
04380|011|E|increased risk of bleeding.(1)|
04380|012|B||
04380|013|P|PREDISPOSING FACTORS:  None determined.|
04380|014|B||
04380|015|M|PATIENT MANAGEMENT:  The manufacturer of valoctocogene roxaparvovec states|
04380|016|M|that co-administration with isotretinoin is not recommended in patients who|
04380|017|M|are benefiting from valoctocogene roxaparvovec.(1)|
04380|018|B||
04380|019|D|DISCUSSION:  In a patient treated with valoctocogene roxaparvovec and|
04380|020|D|isotretinoin, decreased factor VIII activity without ALT elevation was noted|
04380|021|D|after starting isotretinoin.  The factor VIII activity recovered after|
04380|022|D|isotretinoin was stopped.(1)|
04380|023|D|   In vitro studies indicate isotretinoin suppresses factor VIII|
04380|024|D|transcription independent of hepatotoxicity, without impact of ALT, and|
04380|025|D|expression was partially restored upon discontinuation.(1)|
04380|026|B||
04380|027|R|REFERENCE:|
04380|028|B||
04380|029|R|1.Roctavian (valoctocogene roxaparvovec-rvox) US prescribing information.|1
04380|030|R|  BioMarin Pharmaceutical Inc. June, 2023.|1
04381|001|T|MONOGRAPH TITLE:  Lecanemab/Antiplatelets|
04381|002|B||
04381|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04381|004|L|take action as needed.|
04381|005|B||
04381|006|A|MECHANISM OF ACTION:  Microhemorrhage has been reported with the use of|
04381|007|A|lecanemab.  Radiographic changes on brain MRI have been noted as amyloid|
04381|008|A|related imaging abnormalities-hemosiderin deposition (ARIA-H) which included|
04381|009|A|microhemorrhage.  In addition, intracerebral hemorrhages (ICH) greater than|
04381|010|A|1 cm in diameter have occurred in patients treated with lecanemab.(1)|
04381|011|B||
04381|012|E|CLINICAL EFFECTS:  Concurrent use of lecanemab with antiplatelets may|
04381|013|E|increase the risk of hemorrhage.(1)|
04381|014|B||
04381|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04381|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04381|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
04381|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04381|019|P|risk for bleeding (e.g. NSAIDs).|
04381|020|B||
04381|021|M|PATIENT MANAGEMENT:  Lecanemab should be used with extreme caution in|
04381|022|M|patients treated with antiplatelets.  Evaluate the risks and benefits of|
04381|023|M|concurrent use of lecanemab with antiplatelets.(1)|
04381|024|M|   Appropriate use recommendations for lecanemab state antiplatelets may be|
04381|025|M|used at standard doses if patients meet other criteria for lecanemab|
04381|026|M|therapy.  Use of antiplatelet agents in patients who are homozygous for the|
04381|027|M|APOE4 gene may have an increased risk of ARIA with lecanemab therapy.(2)|
04381|028|M|   Patients receiving concurrent therapy with lecanemab and antiplatelets|
04381|029|M|should be closely monitored for signs and symptoms of bleeding and changes|
04381|030|M|in platelet count or International Normalized Ratio (INR).(1)|
04381|031|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04381|032|M|therapy for signs of microhemorrhage, including headache, nausea/vomiting,|
04381|033|M|confusion, dizziness, visual disturbance, gait difficulties, and loss of|
04381|034|M|coordination.  General signs of blood loss include decreased hemoglobin,|
04381|035|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
04381|036|M|evaluate patients with any symptoms.|
04381|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04381|038|M|confusion, headache, dizziness, nausea, visual changes, unusual bleeding|
04381|039|M|from the gums or nose; unusual bruising; red or black, tarry stools; red,|
04381|040|M|pink or dark brown urine; acute abdominal or joint pain and/or swelling.|
04381|041|B||
04381|042|D|DISCUSSION:  In clinical studies, lecanemab was observed to increase ARIA-H,|
04381|043|D|including microhemorrhage and intracerebral hemorrhage.  Radiographic|
04381|044|D|changes were classified as mild (<=4 new incidences), moderate (5 to 9 new|
04381|045|D|incidences), or severe (10 or more new incidences.  Patients were excluded|
04381|046|D|from clinical trials if taking concurrent anticoagulants or|
04381|047|D|anti-platelets.(1)|
04381|048|D|   In Studies 1 and 2, the maximum severity of ARIA-H microhemorrhage was|
04381|049|D|mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of|
04381|050|D|patients.  Intracerebral hemorrhage greater than 1 cm in diameter was|
04381|051|D|reported in 0.7% (6/898) of patients in Study 2 after treatment with|
04381|052|D|lecanemab compared to 0.1% (1/897) on placebo. Fatal events of intracerebral|
04381|053|D|hemorrhage in patients taking lecanemab have been observed.(1)|
04381|054|D|   In Study 2, baseline use of antithrombotic medications (aspirin, other|
04381|055|D|antiplatelets, or anticoagulants) were allowed if patient was on a stable|
04381|056|D|dose.  Aspirin was the most common antithrombotic agent.  The incidence of|
04381|057|D|ICH was 0.9% (3/328 patients) in patients taking lecanemab with a|
04381|058|D|concomitant antithrombotic medication at the time of the event compared to|
04381|059|D|0.6% (3/545 patients) in those who did not receive an antithrombotic.|
04381|060|D|Patients taking lecanemab with an anticoagulant alone or combined with an|
04381|061|D|antiplatelet medication or aspirin had an incidence of intracerebral|
04381|062|D|hemorrhage of 2.5% (2/79 patients) compared to none in patients who received|
04381|063|D|placebo.|
04381|064|B||
04381|065|R|REFERENCES:|
04381|066|B||
04381|067|R|1.Leqembi (lecanemab-irmb) US prescribing information. Eisai Inc July, 2023.|1
04381|068|R|2.Cummings J, Apostolova L, Rabinovici GD, Atri A, Aisen P, Greenberg S,|6
04381|069|R|  Hendrix S, Selkoe D, Weiner M, Petersen RC, Salloway S. Lecanemab:|6
04381|070|R|  Appropriate Use Recommendations. J Prev Alzheimers Dis 2023;10(3):362-377.|6
04382|001|T|MONOGRAPH TITLE:  Selected P-glycoprotein (P-gp) Substrates/Quercetin|
04382|002|B||
04382|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
04382|004|L|Assess the risk to the patient and take action as needed.|
04382|005|B||
04382|006|A|MECHANISM OF ACTION:  Quercetin inhibits the P-glycoprotein (P-gp)|
04382|007|A|transporter and may increase absorption of P-gp substrates.(1)|
04382|008|B||
04382|009|E|CLINICAL EFFECTS:  Concurrent use of quercetin with P-gp substrates may|
04382|010|E|result in elevated levels and toxicities of the substrate.(1)|
04382|011|B||
04382|012|P|PREDISPOSING FACTORS:  None determined.|
04382|013|B||
04382|014|M|PATIENT MANAGEMENT:  Concurrent use of quercetin with P-gp substrates is not|
04382|015|M|recommended.  Consider stopping quercetin or quercetin containing|
04382|016|M|products.(1)|
04382|017|B||
04382|018|D|DISCUSSION:  In a clinical study, quercetin (500 mg for 7 days) increased|
04382|019|D|the area-under-curve (AUC) and maximum concentration (Cmax) of fexofenadine,|
04382|020|D|a P-gp substrate, by approximately 55% and 68%, respectively.(1)|
04382|021|D|   Quercetin has increased the levels of several P-gp substrates.(2-6)|
04382|022|D|   Selected P-gp substrates linked to this monograph include: afatinib,|
04382|023|D|aliskiren, berotralstat, betrixaban, bilastine, colchicine, cyclosporine,|
04382|024|D|dabigatran, digoxin, doxorubicin, edoxaban, etoposide, everolimus, oral|
04382|025|D|lefamulin, loperamide, pazopanib, quinidine, relugolix, rimegepant,|
04382|026|D|rivaroxaban, sirolimus, tacrolimus, talazoparib, topotecan, ubrogepant, and|
04382|027|D|venetoclax.(7)|
04382|028|B||
04382|029|R|REFERENCES:|
04382|030|B||
04382|031|R|1.Kim KA, Park PW, Park JY. Short-term effect of quercetin on the|2
04382|032|R|  pharmacokinetics of fexofenadine, a  substrate of P-glycoprotein, in|2
04382|033|R|  healthy volunteers. Eur J Clin Pharmacol 2009 Jun;65(6):609-14.|2
04382|034|R|2.Stockton (CA): Therapeutic Research Faculty; 1995-2021[Cited 12 July|6
04382|035|R|  2023]. Quercetin.  In: Natural Medicines Comprehensive Database database|6
04382|036|R|  on the internet. Available from:|6
04382|037|R|  https://naturalmedicines.therapeuticresearch.com. Subscription required to|6
04382|038|R|  view.|6
04382|039|R|3.Choi JS, Choi BC, Choi KE. Effect of quercetin on the pharmacokinetics of|2
04382|040|R|  oral cyclosporine. Am J Health Syst Pharm 2004 Nov 15;61(22):2406-9.|2
04382|041|R|4.Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-herbal interactions. Life|6
04382|042|R|  Sci 2006 Mar 27;78(18):2131-45.|6
04382|043|R|5.Choi JS, Jo BW, Kim YC. Enhanced paclitaxel bioavailability after oral|5
04382|044|R|  administration of paclitaxel or  prodrug to rats pretreated with|5
04382|045|R|  quercetin. Eur J Pharm Biopharm 2004 Mar;57(2):313-8.|5
04382|046|R|6.Qamar Z, Ashhar MU, Annu, Qizilibash FF, Sahoo PK, Ali A, Ali J, Baboota|5
04382|047|R|  S. Lipid nanocarrier of selegiline augmented anti-Parkinson's effect via|5
04382|048|R|  P-gp  modulation using quercetin. Int J Pharm 2021 Nov 20;609:121131.|5
04382|049|R|7.This information is based on an extract from the Certara Drug Interaction|6
04382|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04383|001|T|MONOGRAPH TITLE:  Rosuvastatin/Pirtobrutinib|
04383|002|B||
04383|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04383|004|L|take action as needed.|
04383|005|B||
04383|006|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate of the BCRP|
04383|007|A|transporter.(1,2)  Pirtobrutinib has been shown to inhibit this transporter|
04383|008|A|and may increase intestinal absorption and hepatic uptake of|
04383|009|A|rosuvastatin.(1-3)|
04383|010|B||
04383|011|E|CLINICAL EFFECTS:  Simultaneous use of pirtobrutinib may result in increased|
04383|012|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1,2)|
04383|013|B||
04383|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04383|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04383|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04383|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04383|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04383|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04383|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04383|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04383|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04383|023|B||
04383|024|M|PATIENT MANAGEMENT:  Concurrent use may result in increased risk of side|
04383|025|M|effects associated with rosuvastatin.  If concurrent therapy is warranted,|
04383|026|M|close monitoring would be prudent for statin related side effects including|
04383|027|M|rhabdomyolysis.|
04383|028|M|   Educate the patient on signs and symptoms of rhabdomyolysis.|
04383|029|B||
04383|030|D|DISCUSSION:  In a clinical study of healthy subjects, pirtobrutinib|
04383|031|D|(multiple doses of 200 mg daily) increased the area-under-curve (AUC) and|
04383|032|D|concentration maximum (Cmax) of rosuvastatin by 140% and 146%,|
04383|033|D|respectively.(3)|
04383|034|B||
04383|035|R|REFERENCES:|
04383|036|B||
04383|037|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04383|038|R|  Pharmaceuticals LP July, 2024.|1
04383|039|R|2.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04383|040|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04383|041|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04383|042|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04383|043|R|  44(3):398-408.|5
04383|044|R|3.Jaypirca (pirtobrutinib) US prescribing information. Eli Lilly January|1
04383|045|R|  2023.|1
04384|001|T|MONOGRAPH TITLE:  Quizartinib/QT Prolonging Agents|
04384|002|B||
04384|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04384|004|L|of severe adverse interaction.|
04384|005|B||
04384|006|A|MECHANISM OF ACTION:  Quizartinib has been shown to prolong the QTc interval|
04384|007|A|in a dose- and concentration dependent manner.  Concurrent use with other|
04384|008|A|agents that prolong the QTc interval may result in additive effects on the|
04384|009|A|QTc interval.(1-3)|
04384|010|B||
04384|011|E|CLINICAL EFFECTS:  The concurrent use of quizartinib with other agents that|
04384|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04384|013|E|arrhythmias, including torsades de pointes.(1-3)|
04384|014|B||
04384|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04384|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04384|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04384|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04384|019|P|gender, or advanced age.(2)|
04384|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04384|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04384|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04384|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04384|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04384|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04384|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04384|027|B||
04384|028|M|PATIENT MANAGEMENT:  The US manufacturer of quizartinib states that the|
04384|029|M|concurrent use of QT prolonging agents should be avoided.(1)|
04384|030|M|   Quizartinib is only available through a restricted REMS program due to|
04384|031|M|the serious risk of QT prolongation, torsades de pointes, and cardiac|
04384|032|M|arrest.|
04384|033|M|   The manufacturer recommends monitoring as follows:|
04384|034|M|   -Initiate quizartinib only if the QTcF is less than or equal to 450 ms.|
04384|035|M|   -During induction and consolidation, monitor ECGs prior to initiation and|
04384|036|M|then at minimum once weekly during treatment.|
04384|037|M|   -During maintenance, monitor ECGs prior to initiation and then at minimum|
04384|038|M|once weekly for the first month following dose initiation and escalation and|
04384|039|M|clinically therafter.  Dose escalation may occur only if the QTcF is less|
04384|040|M|than or equal to 450 ms.|
04384|041|M|   The manufacturer recommends the following dose modifications for adverse|
04384|042|M|reactions:|
04384|043|M|   -If the QTcF is 450 ms to 480 ms (Grade 1) - Continue quizartinib dose.|
04384|044|M|   -If the QTcF is 481 ms to 500 ms (Grade 2) - Reduce the dose of|
04384|045|M|quizartinib without interruption based on prescribing information.  Resume|
04384|046|M|the previous dose in the next cycle if the QTcF has decreased to less than|
04384|047|M|450 ms.|
04384|048|M|   -If the QTcF is greater than 500 ms (Grade 3) - Interrupt quizartinib.|
04384|049|M|Resume at a reduced dose based on prescribing information when the QTcF is|
04384|050|M|less than 450 ms.  Maintain the dose of 26.5 mg once daily during|
04384|051|M|maintenance if the QTcF is greater than 500 ms during induction or|
04384|052|M|consolidation.|
04384|053|M|   -If recurrent QTcF is greater than 500 ms (Grade 3) - Permanently|
04384|054|M|discontinue quizartinib if QTcF is greater than 500 ms despite dose|
04384|055|M|reduction and correction/elimination of other risk factors.|
04384|056|M|   -If TdP, polymorphic ventricular tachycardia, or signs/symptoms of|
04384|057|M|life-threatening arrhythmia occur (Grade 4) - Permanently discontinue|
04384|058|M|quizartinib.|
04384|059|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
04384|060|M|values (serum calcium, magnesium, and potassium) prior to the start of|
04384|061|M|treatment, after initiation of any drug known to prolong the QT interval,|
04384|062|M|and periodically monitor during therapy.  Correct any electrolyte|
04384|063|M|abnormalities. Instruct patients to report any irregular heartbeat,|
04384|064|M|dizziness, or fainting.|
04384|065|B||
04384|066|D|DISCUSSION:  Quizartinib has been associated with QTc interval prolongation,|
04384|067|D|Torsades de Pointes, ventricular arrhythmias, cardiac arrest, and sudden|
04384|068|D|death.  Quizartinib increased QTc in a dose- and concentration-dependent|
04384|069|D|manner.(1)|
04384|070|D|   In an exposure-response analysis, quizartinib had a predicted|
04384|071|D|concentration-dependent QTc prolongation of 18 to 24 ms (upper bound of|
04384|072|D|2-sided 90% CI: 21 and 27 ms) at a median steady-state Cmax dose of 26.5 mg|
04384|073|D|and 53 mg during maintenance therapy.(1)|
04384|074|D|   In patients administered quizartinib, 2.3% of 265 patients had a QTcF|
04384|075|D|greater than 500 msec and 10% of patients had a increase from baseline QTcF|
04384|076|D|greater than 60 msec.(1)|
04384|077|D|   In patients administered quizartinib during the induction phase, torsades|
04384|078|D|de pointes occurred in approximately 0.2% of patients, cardiac arrest|
04384|079|D|occurred in 0.6%, including 0.4% with a fatal outcome, and 0.1% of patients|
04384|080|D|experienced ventricular fibrillation.(1)|
04384|081|D|   Agents that are linked to this monograph may have varying degrees of|
04384|082|D|potential to prolong the QTc interval but are generally accepted to have a|
04384|083|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04384|084|D|been shown to prolong the QTc interval either through their mechanism of|
04384|085|D|action, through studies on their effects on the QTc interval, or through|
04384|086|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04384|087|D|and/or postmarketing reports.(3)|
04384|088|B||
04384|089|R|REFERENCES:|
04384|090|B||
04384|091|R|1.Vanflyta (quizartinib) US prescribing infromation. Daiichi Sankyo, Inc|1
04384|092|R|  July, 2023.|1
04384|093|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04384|094|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04384|095|R|  settings: a scientific statement from the American Heart Association and|6
04384|096|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04384|097|R|  2;55(9):934-47.|6
04384|098|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04384|099|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04384|100|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04384|101|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04385|001|T|MONOGRAPH TITLE:  Quizartinib/Strong CYP3A4 Inhibitors|
04385|002|B||
04385|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04385|004|L|take action as needed.|
04385|005|B||
04385|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04385|007|A|of quizartinib.(1)|
04385|008|B||
04385|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04385|010|E|the levels and effects of quizartinib.(1)|
04385|011|E|    Elevated levels of quizartinib may result in QTc prolongation, which may|
04385|012|E|result in potentially life-threatening cardiac arrhythmias, including|
04385|013|E|torsades de pointes (TdP).  Other toxicities include neutropenia.(1)|
04385|014|B||
04385|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04385|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04385|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04385|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04385|019|P|female gender, or advanced age.(2)|
04385|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04385|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04385|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04385|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04385|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04385|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04385|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04385|027|B||
04385|028|M|PATIENT MANAGEMENT:  The US manufacturer of quizartinib recommends reducing|
04385|029|M|the dosage of quizartinib when used concomitantly with strong CYP3A4|
04385|030|M|inhibitors.(1)|
04385|031|M|   The manufacturer recommends the following dose reduction:|
04385|032|M|   -If the patient is taking 53 mg once daily, reduce the dose to 26.5 mg|
04385|033|M|once daily.|
04385|034|M|   -If the patient is taking 35.4 mg once daily, reduce the dose to 17.7 mg|
04385|035|M|once daily.|
04385|036|M|   -If the patient is taking 26.5 mg once daily, reduce the dose to 17.7 mg|
04385|037|M|once daily.|
04385|038|M|   -If the patient is taking 17.7 mg once daily, interrupt treatment with|
04385|039|M|quizartinib for the duration of strong CYP3A4 inhibitor use.|
04385|040|M|   After discontinuation of a strong CYP3A4 inhibitor for 5 half-lives,|
04385|041|M|resume the quizartinib dose that was taken before initiating the strong|
04385|042|M|inhibitor.|
04385|043|M|   Quizartinib is only available through a restricted REMS program due to|
04385|044|M|the serious risk of QT prolongation, torsades de pointes (TdP), and cardiac|
04385|045|M|arrest.|
04385|046|M|   The manufacturer recommends monitoring as follows:|
04385|047|M|   -Initiate quizartinib only if the QTcF is less than or equal to 450 ms.|
04385|048|M|   -During induction and consolidation, monitor ECGs prior to initiation and|
04385|049|M|then at minimum once weekly during treatment.|
04385|050|M|   -During maintenance, monitor ECGs prior to initiation and then at minimum|
04385|051|M|once weekly for the first month following dose initiation and escalation and|
04385|052|M|clinically therafter.  Dose escalation may occur only if the QTcF is less|
04385|053|M|than or equal to 450 ms.|
04385|054|M|   The manufacturer recommends the following dose modifications for adverse|
04385|055|M|reactions:|
04385|056|M|   -If the QTcF is 450 ms to 480 ms (Grade 1) - Continue quizartinib dose.|
04385|057|M|   -If the QTcF is 481 ms to 500 ms (Grade 2) - Reduce the dose of|
04385|058|M|quizartinib without interruption based on prescribing information.  Resume|
04385|059|M|the previous dose in the next cycle if the QTcF has decreased to less than|
04385|060|M|450 ms.|
04385|061|M|   -If the QTcF is greater than 500 ms (Grade 3) - Interrupt quizartinib.|
04385|062|M|Resume at a reduced dose based on prescribing information when the QTcF is|
04385|063|M|less than 450 ms.  Maintain the dose of 26.5 mg once daily during|
04385|064|M|maintenance if the QTcF is greater than 500 ms during induction or|
04385|065|M|consolidation.|
04385|066|M|   -If recurrent QTcF is greater than 500 ms (Grade 3) - Permanently|
04385|067|M|discontinue quizartinib if QTcF is greater than 500 ms despite dose|
04385|068|M|reduction and correction/elimination of other risk factors.|
04385|069|M|   -If TdP, polymorphic ventricular tachycardia, or signs/symptoms of|
04385|070|M|life-threatening arrhythmia occur (Grade 4) - Permanently discontinue|
04385|071|M|quizartinib.|
04385|072|M|   Obtain ECGs and electrolyte values (serum calcium, magnesium, and|
04385|073|M|potassium) prior to the start of treatment, after initiation of any drug|
04385|074|M|known to prolong the QT interval, and periodically monitor during therapy.|
04385|075|M|Correct any electrolyte abnormalities. Instruct patients to report any|
04385|076|M|irregular heartbeat, dizziness, or fainting.|
04385|077|B||
04385|078|D|DISCUSSION:  The area-under-curve (AUC) of quizartinib increased by 94% and|
04385|079|D|the maximum concentration (Cmax) by 17% following coadministration of a|
04385|080|D|single 53 mg quizartinib dose with ketoconazole (a strong CYP3A4 inhibitor).|
04385|081|D|The AUC of active metabolite AC886 decreased by 94% and decreased Cmax by|
04385|082|D|60%.(1)|
04385|083|D|   Quizartinib has been associated with QTc interval prolongation, torsades|
04385|084|D|de pointes, ventricular arrhythmias, cardiac arrest, and sudden death.|
04385|085|D|Quizartinib increased QTc in a dose- and concentration-dependent manner.(1)|
04385|086|D|   In an exposure-response analysis, quizartinib had a predicted|
04385|087|D|concentration-dependent QTc prolongation of 18 to 24 ms (upper bound of|
04385|088|D|2-sided 90% CI: 21 and 27 ms) at a median steady-state Cmax dose of 26.5 mg|
04385|089|D|and 53 mg during maintenance therapy.(1)|
04385|090|D|   In patients administered quizartinib, 2.3% of 265 patients had a QTcF|
04385|091|D|greater than 500 msec and 10% of patients had a increase from baseline QTcF|
04385|092|D|greater than 60 msec.(1)|
04385|093|D|   In patients administered quizartinib during the induction phase, torsades|
04385|094|D|de pointes occurred in approximately 0.2% of patients, cardiac arrest|
04385|095|D|occurred in 0.6%, including 0.4% with a fatal outcome, and 0.1% of patients|
04385|096|D|experienced ventricular fibrillation.(1)|
04385|097|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
04385|098|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
04385|099|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
04385|100|D|tipranavir, troleandomycin, and tucatinib.(3,4)|
04385|101|B||
04385|102|R|REFERENCES:|
04385|103|B||
04385|104|R|1.Vanflyta (quizartinib) US prescribing infromation. Daiichi Sankyo, Inc|1
04385|105|R|  July, 2023.|1
04385|106|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04385|107|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04385|108|R|  settings: a scientific statement from the American Heart Association and|6
04385|109|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04385|110|R|  2;55(9):934-47.|6
04385|111|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04385|112|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04385|113|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04385|114|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04385|115|R|  11/14/2017.|1
04385|116|R|4.This information is based on an extract from the Certara Drug Interaction|6
04385|117|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04386|001|T|MONOGRAPH TITLE:  Quizartinib/Levoketoconazole|
04386|002|B||
04386|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04386|004|L|is contraindicated and generally should not be dispensed or administered to|
04386|005|L|the same patient.|
04386|006|B||
04386|007|A|MECHANISM OF ACTION:  Levoketoconazole is a strong inhibitor of CYP3A4 that|
04386|008|A|prolongs the QTc interval and may inhibit the CYP3A4 metabolism of|
04386|009|A|quizartinib.  This combination may also have additive effects on the QTc|
04386|010|A|interval.(1,2)|
04386|011|B||
04386|012|E|CLINICAL EFFECTS:  Concurrent use of levoketoconazole may result in elevated|
04386|013|E|levels and increased effects of quizartinib such as neutropenia.|
04386|014|E|   Concurrent use may also result in additive QTc prolongation, which may|
04386|015|E|lead to life-threatening cardiac arrhythmias like torsade de pointes.(1,2)|
04386|016|B||
04386|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04386|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04386|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04386|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04386|021|P|female gender, or advanced age.(3)|
04386|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04386|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04386|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04386|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04386|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04386|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04386|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04386|029|B||
04386|030|M|PATIENT MANAGEMENT:  The US manufacturer of levoketoconazole states that|
04386|031|M|levoketoconazole is contraindicated with other agents that prolong the QT|
04386|032|M|interval.(2)|
04386|033|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
04386|034|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
04386|035|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
04386|036|M|syndrome (including first-degree family history).|
04386|037|M|   If concurrent therapy is unavoidable, prior to starting levoketoconazole,|
04386|038|M|obtain a baseline ECG and correct hypokalemia or hypomagnesemia.|
04386|039|M|   If a patient develops QT prolongation with a QTc interval greater than|
04386|040|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
04386|041|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
04386|042|M|QTc interval prolongation recurs, permanently discontinue|
04386|043|M|levoketoconazole.(2)|
04386|044|M|   If concurrent therapy is unavoidable, reduce the dosage of quizartinib|
04386|045|M|when used concomitantly with strong CYP3A inhibitors.(1)|
04386|046|M|   If the patient is taking 53 mg once daily, reduce the dose to 26.5 mg|
04386|047|M|once daily.  If the patient is taking 35.4 mg once daily, reduce the dose to|
04386|048|M|17.7 mg once daily.  If the patient is taking 26.5 mg once daily, reduce the|
04386|049|M|dose to 17.7 mg once daily.  If the patient is taking 17.7 mg once daily,|
04386|050|M|interrupt quizartinib therapy.(1)|
04386|051|M|   If patients develop QTc prolongation between 481 ms and 500 ms, reduce|
04386|052|M|the dose of quizartinib without interruption. Resume quizartinib at the|
04386|053|M|previous dose in the next cycle if QTcF has decreased to less than 450 ms.|
04386|054|M|   If patients develop QTc prolongation >500 ms, interrupt quizartinib|
04386|055|M|therapy. Resume quizartinib when QTcF returns to <450 ms.|
04386|056|M|   For recurrent QTcF >500 ms, torsades de pointes or other signs/symptoms|
04386|057|M|of life-threatening arrhythmia, permanently discontinue quizartinib.(1)|
04386|058|M|   Monitor for prolongation of the QTc interval.  Consider obtaining serum|
04386|059|M|calcium, magnesium, and potassium levels and monitoring EKG at baseline and|
04386|060|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04386|061|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04386|062|B||
04386|063|D|DISCUSSION:  The area-under-curve (AUC) of quizartinib increased by 94% and|
04386|064|D|the maximum concentration (Cmax) by 17% following coadministration of a|
04386|065|D|single 53 mg quizartinib dose with ketoconazole (a strong CYP3A4 inhibitor).|
04386|066|D|The AUC of active metabolite AC886 decreased by 94% and decreased Cmax by|
04386|067|D|60%.(1)|
04386|068|D|   Quizartinib has been associated with QTc interval prolongation, torsades|
04386|069|D|de pointes, ventricular arrhythmias, cardiac arrest, and sudden death.|
04386|070|D|Quizartinib increased QTc in a dose- and concentration-dependent manner.(1)|
04386|071|D|   In an exposure-response analysis, quizartinib had a predicted|
04386|072|D|concentration-dependent QTc prolongation of 18 to 24 ms (upper bound of|
04386|073|D|2-sided 90% CI: 21 and 27 ms) at a median steady-state Cmax dose of 26.5 mg|
04386|074|D|and 53 mg during maintenance therapy.(1)|
04386|075|D|   In patients administered quizartinib, 2.3% of 265 patients had a QTcF|
04386|076|D|greater than 500 msec and 10% of patients had a increase from baseline QTcF|
04386|077|D|greater than 60 msec.(1)|
04386|078|D|   In patients administered quizartinib during the induction phase, torsades|
04386|079|D|de pointes occurred in approximately 0.2% of patients, cardiac arrest|
04386|080|D|occurred in 0.6%, including 0.4% with a fatal outcome, and 0.1% of patients|
04386|081|D|experienced ventricular fibrillation.(1)|
04386|082|D|   During phase 1 and 2 studies with levoketoconazole, which excluded|
04386|083|D|patients with baseline QTcF interval greater than 470 msec, 4 (2.4%)|
04386|084|D|patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
04386|085|D|change-from-baseline QTcF > 60 msec.(2)|
04386|086|B||
04386|087|R|REFERENCES:|
04386|088|B||
04386|089|R|1.Vanflyta (quizartinib) US prescribing infromation. Daiichi Sankyo, Inc|1
04386|090|R|  July, 2023.|1
04386|091|R|2.Recorlev (levoketoconazole) US prescribing information. Xeris|1
04386|092|R|  Pharmaceuticals, Inc. June, 2023.|1
04386|093|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04386|094|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04386|095|R|  settings: a scientific statement from the American Heart Association and|6
04386|096|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04386|097|R|  2;55(9):934-47.|6
04386|098|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04386|099|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04386|100|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04386|101|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04386|102|R|  11/14/2017.|1
04386|103|R|5.This information is based on an extract from the Certara Drug Interaction|6
04386|104|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04387|001|T|MONOGRAPH TITLE:  Quizartinib/Strong CYP3A4 Inhibitors that Prolong QT|
04387|002|B||
04387|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04387|004|L|of severe adverse interaction.|
04387|005|B||
04387|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04387|007|A|interval may inhibit the metabolism of quizartinib and result in additive|
04387|008|A|effects on the QTc interval.(1)|
04387|009|B||
04387|010|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP3A4 that|
04387|011|E|prolongs the QTc interval may result in elevated levels and increased|
04387|012|E|effects of quizartinib such as neutropenia.(1)|
04387|013|E|   Concurrent use may also result in additive QTc prolongation, which may|
04387|014|E|lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)|
04387|015|B||
04387|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04387|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04387|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04387|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04387|020|P|female gender, or advanced age.(2)|
04387|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04387|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04387|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04387|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04387|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04387|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04387|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04387|028|B||
04387|029|M|PATIENT MANAGEMENT:  The US manufacturer of quizartinib recommends reducing|
04387|030|M|the dosage of quizartinib when used concomitantly with strong CYP3A|
04387|031|M|inhibitors.(1)|
04387|032|M|   The manufacturer recommends the following dose reduction:|
04387|033|M|   -If the patient is taking 53 mg once daily, reduce the dose to 26.5 mg|
04387|034|M|once daily.|
04387|035|M|   -If the patient is taking 35.4 mg once daily, reduce the dose to 17.7 mg|
04387|036|M|once daily.|
04387|037|M|   -If the patient is taking 26.5 mg once daily, reduce the dose to 17.7 mg|
04387|038|M|once daily.|
04387|039|M|   -If the patient is taking 17.7 mg once daily, interrupt treatment with|
04387|040|M|quizartinib for the duration of strong CYP3A4 inhibitor use.|
04387|041|M|   After discontinuation of a strong CYP3A4 inhibitor for 5 half-lives,|
04387|042|M|resume the quizartinib dose that was taken before initiating the strong|
04387|043|M|inhibitor.|
04387|044|M|   Quizartinib is only available through a restricted REMS program due to|
04387|045|M|the serious risk of QT prolongation, torsades de pointes (TdP), and cardiac|
04387|046|M|arrest.|
04387|047|M|   The manufacturer recommends monitoring as follows:|
04387|048|M|   -Initiate quizartinib only if the QTcF is less than or equal to 450 ms.|
04387|049|M|   -During induction and consolidation, monitor ECGs prior to initiation and|
04387|050|M|then at minimum once weekly during treatment.|
04387|051|M|   -During maintenance, monitor ECGs prior to initiation and then at minimum|
04387|052|M|once weekly for the first month following dose initiation and escalation and|
04387|053|M|clinically therafter.  Dose escalation may occur only if the QTcF is less|
04387|054|M|than or equal to 450 ms.|
04387|055|M|   The manufacturer recommends the following dose modifications for adverse|
04387|056|M|reactions:|
04387|057|M|   -If the QTcF is 450 ms to 480 ms (Grade 1) - Continue quizartinib dose.|
04387|058|M|   -If the QTcF is 481 ms to 500 ms (Grade 2) - Reduce the dose of|
04387|059|M|quizartinib without interruption based on prescribing information.  Resume|
04387|060|M|the previous dose in the next cycle if the QTcF has decreased to less than|
04387|061|M|450 ms.|
04387|062|M|   -If the QTcF is greater than 500 ms (Grade 3) - Interrupt quizartinib.|
04387|063|M|Resume at a reduced dose based on prescribing information when the QTcF is|
04387|064|M|less than 450 ms.  Maintain the dose of 26.5 mg once daily during|
04387|065|M|maintenance if the QTcF is greater than 500 ms during induction or|
04387|066|M|consolidation.|
04387|067|M|   -If recurrent QTcF is greater than 500 ms (Grade 3) - Permanently|
04387|068|M|discontinue quizartinib if QTcF is greater than 500 ms despite dose|
04387|069|M|reduction and correction/elimination of other risk factors.|
04387|070|M|   -If TdP, polymorphic ventricular tachycardia, or signs/symptoms of|
04387|071|M|life-threatening arrhythmia occur (Grade 4) - Permanently discontinue|
04387|072|M|quizartinib.|
04387|073|M|   Obtain ECGs and electrolyte values (serum calcium, magnesium, and|
04387|074|M|potassium) prior to the start of treatment, after initiation of any drug|
04387|075|M|known to prolong the QT interval, and periodically monitor during therapy.|
04387|076|M|Correct any electrolyte abnormalities. Instruct patients to report any|
04387|077|M|irregular heartbeat, dizziness, or fainting.|
04387|078|B||
04387|079|D|DISCUSSION:  The area-under-curve (AUC) of quizartinib increased by 94% and|
04387|080|D|the maximum concentration (Cmax) by 17% following coadministration of a|
04387|081|D|single 53 mg quizartinib dose with ketoconazole (a strong CYP3A4 inhibitor).|
04387|082|D|The AUC of active metabolite AC886 decreased by 94% and decreased Cmax by|
04387|083|D|60%.(1)|
04387|084|D|   Quizartinib has been associated with QTc interval prolongation, torsades|
04387|085|D|de pointes, ventricular arrhythmias, cardiac arrest, and sudden death.|
04387|086|D|Quizartinib increased QTc in a dose- and concentration-dependent manner.(1)|
04387|087|D|   In an exposure-response analysis, quizartinib had a predicted|
04387|088|D|concentration-dependent QTc prolongation of 18 to 24 ms (upper bound of|
04387|089|D|2-sided 90% CI: 21 and 27 ms) at a median steady-state Cmax dose of 26.5 mg|
04387|090|D|and 53 mg during maintenance therapy.(1)|
04387|091|D|   In patients administered quizartinib, 2.3% of 265 patients had a QTcF|
04387|092|D|greater than 500 msec and 10% of patients had a increase from baseline QTcF|
04387|093|D|greater than 60 msec.(1)|
04387|094|D|   In patients administered quizartinib during the induction phase, torsades|
04387|095|D|de pointes occurred in approximately 0.2% of patients, cardiac arrest|
04387|096|D|occurred in 0.6%, including 0.4% with a fatal outcome, and 0.1% of patients|
04387|097|D|experienced ventricular fibrillation.(1)|
04387|098|D|   Agents that are linked to this monograph may have varying degrees of|
04387|099|D|potential to prolong the QTc interval but are generally accepted to have a|
04387|100|D|risk of causing torsades de pointes.  Agents linked to this monograph have|
04387|101|D|been shown to prolong the QTc interval either through their mechanism of|
04387|102|D|action, through studies on their effects on the QTc interval, or through|
04387|103|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04387|104|D|and/or postmarketing reports.(3)|
04387|105|D|   Strong inhibitors of CYP3A4 include: adagrasib, ceritinib,|
04387|106|D|clarithromycin, lonafarnib, lopinavir, ribociclib, saquinavir,|
04387|107|D|telithromycin, and voriconazole.(4,5)|
04387|108|B||
04387|109|R|REFERENCES:|
04387|110|B||
04387|111|R|1.Vanflyta (quizartinib) US prescribing infromation. Daiichi Sankyo, Inc|1
04387|112|R|  July, 2023.|1
04387|113|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04387|114|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04387|115|R|  settings: a scientific statement from the American Heart Association and|6
04387|116|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04387|117|R|  2;55(9):934-47.|6
04387|118|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04387|119|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04387|120|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04387|121|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04387|122|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04387|123|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04387|124|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04387|125|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04387|126|R|  11/14/2017.|1
04387|127|R|5.This information is based on an extract from the Certara Drug Interaction|6
04387|128|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04388|001|T|MONOGRAPH TITLE:  Quizartinib/Possible QT Prolonging Agents|
04388|002|B||
04388|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04388|004|L|take action as needed.|
04388|005|B||
04388|006|A|MECHANISM OF ACTION:  Quizartinib has been shown to prolong the QTc interval|
04388|007|A|in a dose- and concentration dependent manner.  Concurrent use with other|
04388|008|A|agents that prolong the QTc interval may result in additive effects on the|
04388|009|A|QTc interval.(1-3)|
04388|010|B||
04388|011|E|CLINICAL EFFECTS:  The concurrent use of quizartinib with other agents that|
04388|012|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04388|013|E|arrhythmias, including torsades de pointes.(1-3)|
04388|014|B||
04388|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04388|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04388|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04388|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04388|019|P|gender, or advanced age.(2)|
04388|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04388|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04388|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04388|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04388|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04388|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04388|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04388|027|B||
04388|028|M|PATIENT MANAGEMENT:  The US manufacturer of quizartinib states that the|
04388|029|M|concurrent use of QT prolonging agents should be avoided.(1)|
04388|030|M|   Quizartinib is only available through a restricted REMS program due to|
04388|031|M|the serious risk of QT prolongation, torsades de pointes, and cardiac|
04388|032|M|arrest.|
04388|033|M|   The manufacturer recommends monitoring as follows:|
04388|034|M|   -Initiate quizartinib only if the QTcF is less than or equal to 450 ms.|
04388|035|M|   -During induction and consolidation, monitor ECGs prior to initiation and|
04388|036|M|then at minimum once weekly during treatment.|
04388|037|M|   -During maintenance, monitor ECGs prior to initiation and then at minimum|
04388|038|M|once weekly for the first month following dose initiation and escalation and|
04388|039|M|clinically therafter.  Dose escalation may occur only if the QTcF is less|
04388|040|M|than or equal to 450 ms.|
04388|041|M|   The manufacturer recommends the following dose modifications for adverse|
04388|042|M|reactions:|
04388|043|M|   -If the QTcF is 450 ms to 480 ms (Grade 1) - Continue quizartinib dose.|
04388|044|M|   -If the QTcF is 481 ms to 500 ms (Grade 2) - Reduce the dose of|
04388|045|M|quizartinib without interruption based on prescribing information.  Resume|
04388|046|M|the previous dose in the next cycle if the QTcF has decreased to less than|
04388|047|M|450 ms.|
04388|048|M|   -If the QTcF is greater than 500 ms (Grade 3) - Interrupt quizartinib.|
04388|049|M|Resume at a reduced dose based on prescribing information when the QTcF is|
04388|050|M|less than 450 ms.  Maintain the dose of 26.5 mg once daily during|
04388|051|M|maintenance if the QTcF is greater than 500 ms during induction or|
04388|052|M|consolidation.|
04388|053|M|   -If recurrent QTcF is greater than 500 ms (Grade 3) - Permanently|
04388|054|M|discontinue quizartinib if QTcF is greater than 500 ms despite dose|
04388|055|M|reduction and correction/elimination of other risk factors.|
04388|056|M|   -If TdP, polymorphic ventricular tachycardia, or signs/symptoms of|
04388|057|M|life-threatening arrhythmia occur (Grade 4) - Permanently discontinue|
04388|058|M|quizartinib.|
04388|059|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
04388|060|M|values (serum calcium, magnesium, and potassium) prior to the start of|
04388|061|M|treatment, after initiation of any drug known to prolong the QT interval,|
04388|062|M|and periodically monitor during therapy.  Correct any electrolyte|
04388|063|M|abnormalities. Instruct patients to report any irregular heartbeat,|
04388|064|M|dizziness, or fainting.|
04388|065|B||
04388|066|D|DISCUSSION:  Quizartinib has been associated with QTc interval prolongation,|
04388|067|D|Torsades de Pointes, ventricular arrhythmias, cardiac arrest, and sudden|
04388|068|D|death.  Quizartinib increased QTc in a dose- and concentration-dependent|
04388|069|D|manner.(1)|
04388|070|D|   In an exposure-response analysis, quizartinib had a predicted|
04388|071|D|concentration-dependent QTc prolongation of 18 to 24 ms (upper bound of|
04388|072|D|2-sided 90% CI: 21 and 27 ms) at a median steady-state Cmax dose of 26.5 mg|
04388|073|D|and 53 mg during maintenance therapy.(1)|
04388|074|D|   In patients administered quizartinib, 2.3% of 265 patients had a QTcF|
04388|075|D|greater than 500 msec and 10% of patients had a increase from baseline QTcF|
04388|076|D|greater than 60 msec.(1)|
04388|077|D|   In patients administered quizartinib during the induction phase, torsades|
04388|078|D|de pointes occurred in approximately 0.2% of patients, cardiac arrest|
04388|079|D|occurred in 0.6%, including 0.4% with a fatal outcome, and 0.1% of patients|
04388|080|D|experienced ventricular fibrillation.(1)|
04388|081|D|   Agents that are linked to this monograph may have varying degrees of|
04388|082|D|potential to prolong the QTc interval but are generally accepted to have a|
04388|083|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04388|084|D|been shown to prolong the QTc interval either through their mechanism of|
04388|085|D|action, through studies on their effects on the QTc interval, or through|
04388|086|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04388|087|D|and/or postmarketing reports.(3)|
04388|088|B||
04388|089|R|REFERENCES:|
04388|090|B||
04388|091|R|1.Vanflyta (quizartinib) US prescribing infromation. Daiichi Sankyo, Inc|1
04388|092|R|  July, 2023.|1
04388|093|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04388|094|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04388|095|R|  settings: a scientific statement from the American Heart Association and|6
04388|096|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04388|097|R|  2;55(9):934-47.|6
04388|098|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04388|099|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04388|100|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04388|101|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04389|001|T|MONOGRAPH TITLE:  Quizartinib/Strong & Moderate CYP3A4 Inducers|
04389|002|B||
04389|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04389|004|L|of severe adverse interaction.|
04389|005|B||
04389|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may induce the|
04389|007|A|metabolism of quizartinib.(1)|
04389|008|B||
04389|009|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
04389|010|E|decrease the levels and effectiveness of quizartinib.(1)|
04389|011|B||
04389|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04389|013|P|of the inducer for longer than 1-2 weeks.|
04389|014|B||
04389|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of strong or moderate CYP3A4|
04389|016|M|inducers in patients receiving therapy with quizartinib.(1)|
04389|017|B||
04389|018|D|DISCUSSION:  The area-under-curve (AUC) of quizartinib decreased by 90% and|
04389|019|D|maximum concentration (Cmax) by 45% following concomitant use of a single 53|
04389|020|D|mg dose of quizartinib with efavirenz (a moderate CYP3A inducer).  The AUC|
04389|021|D|of active metabolite AC886 decreased by 96% and the Cmax by 68%.  The effect|
04389|022|D|of concomitant use with a strong CYP3A inducer may result in even greater|
04389|023|D|effect on quizartinib pharmacokinetics based on mechanistic understanding of|
04389|024|D|the drugs involved.|
04389|025|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04389|026|D|carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane,|
04389|027|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
04389|028|D|wort.|
04389|029|D|   Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib,|
04389|030|D|elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat,|
04389|031|D|modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib,|
04389|032|D|telotristat ethyl, and tovorafenib.(2-3)|
04389|033|B||
04389|034|R|REFERENCES:|
04389|035|B||
04389|036|R|1.Vanflyta (quizartinib) US prescribing infromation. Daiichi Sankyo, Inc|1
04389|037|R|  July, 2023.|1
04389|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04389|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04389|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04389|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04389|042|R|  11/14/2017.|1
04389|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
04389|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04390|001|T|MONOGRAPH TITLE:  Quizartinib/Strong & Moderate CYP3A4 Inducers that Prolong|
04390|002|T|QT|
04390|003|B||
04390|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04390|005|L|of severe adverse interaction.|
04390|006|B||
04390|007|A|MECHANISM OF ACTION:  Strong or moderate inducers of CYP3A4 that prolong the|
04390|008|A|QTc interval may accelerate the metabolism of quizartinib.(1)|
04390|009|A|   Quizartinib prolongs the QTc interval.(1)  Some CYP3A4 inducers (e.g.,|
04390|010|A|efavirenz, thioridazine) can also prolong the QTc interval.(3,4)|
04390|011|B||
04390|012|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
04390|013|E|decrease the levels and effectiveness of quizartinib.(1)|
04390|014|E|   Additive QTc prolongation may occur and result in potentially|
04390|015|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
04390|016|B||
04390|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04390|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04390|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04390|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04390|021|P|female gender, or advanced age.(2)|
04390|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04390|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04390|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04390|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04390|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04390|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04390|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04390|029|P|   Induction effects may be more likely with regular use of the inducer for|
04390|030|P|longer than 1-2 weeks.|
04390|031|B||
04390|032|M|PATIENT MANAGEMENT:  The US manufacturer of quizartinib states that the|
04390|033|M|concurrent use of QT prolonging agents should be avoided.(1)  Avoid the|
04390|034|M|concurrent use of strong or moderate CYP3A4 inducers in patients receiving|
04390|035|M|therapy with quizartinib.(1)|
04390|036|M|   Quizartinib is only available through a restricted REMS program due to|
04390|037|M|the serious risk of QT prolongation, torsades de pointes, and cardiac|
04390|038|M|arrest.|
04390|039|M|   The manufacturer recommends monitoring as follows:|
04390|040|M|   -Initiate quizartinib only if the QTcF is less than or equal to 450 ms.|
04390|041|M|   -During induction and consolidation, monitor ECGs prior to initiation and|
04390|042|M|then at minimum once weekly during treatment.|
04390|043|M|   -During maintenance, monitor ECGs prior to initiation and then at minimum|
04390|044|M|once weekly for the first month following dose initiation and escalation and|
04390|045|M|clinically therafter.  Dose escalation may occur only if the QTcF is less|
04390|046|M|than or equal to 450 ms.|
04390|047|M|   The manufacturer recommends the following dose modifications for adverse|
04390|048|M|reactions:|
04390|049|M|   -If the QTcF is 450 ms to 480 ms (Grade 1) - Continue quizartinib dose.|
04390|050|M|   -If the QTcF is 481 ms to 500 ms (Grade 2) - Reduce the dose of|
04390|051|M|quizartinib without interruption based on prescribing information.  Resume|
04390|052|M|the previous dose in the next cycle if the QTcF has decreased to less than|
04390|053|M|450 ms.|
04390|054|M|   -If the QTcF is greater than 500 ms (Grade 3) - Interrupt quizartinib.|
04390|055|M|Resume at a reduced dose based on prescribing information when the QTcF is|
04390|056|M|less than 450 ms.  Maintain the dose of 26.5 mg once daily during|
04390|057|M|maintenance if the QTcF is greater than 500 ms during induction or|
04390|058|M|consolidation.|
04390|059|M|   -If recurrent QTcF is greater than 500 ms (Grade 3) - Permanently|
04390|060|M|discontinue quizartinib if QTcF is greater than 500 ms despite dose|
04390|061|M|reduction and correction/elimination of other risk factors.|
04390|062|M|   -If TdP, polymorphic ventricular tachycardia, or signs/symptoms of|
04390|063|M|life-threatening arrhythmia occur (Grade 4) - Permanently discontinue|
04390|064|M|quizartinib.|
04390|065|M|   When concurrent therapy cannot be avoided, obtain ECGs and electrolyte|
04390|066|M|values (serum calcium, magnesium, and potassium) prior to the start of|
04390|067|M|treatment, after initiation of any drug known to prolong the QT interval,|
04390|068|M|and periodically monitor during therapy.  Correct any electrolyte|
04390|069|M|abnormalities. Instruct patients to report any irregular heartbeat,|
04390|070|M|dizziness, or fainting.|
04390|071|B||
04390|072|D|DISCUSSION:  The area-under-curve (AUC) of quizartinib decreased by 90% and|
04390|073|D|maximum concentration (Cmax) by 45% following concomitant use of a single 53|
04390|074|D|mg dose of quizartinib with efavirenz (a moderate CYP3A inducer).  The AUC|
04390|075|D|of active metabolite AC886 decreased by 96% and the Cmax by 68%.  The effect|
04390|076|D|of concomitant use with a strong CYP3A inducer may result in even greater|
04390|077|D|effect on quizartinib pharmacokinetics based on mechanistic understanding of|
04390|078|D|the drugs involved.(1)|
04390|079|D|   Quizartinib has been associated with QTc interval prolongation, Torsades|
04390|080|D|de Pointes, ventricular arrhythmias, cardiac arrest, and sudden death.|
04390|081|D|Quizartinib increased QTc in a dose- and concentration-dependent manner.(1)|
04390|082|D|   In an exposure-response analysis, quizartinib had a predicted|
04390|083|D|concentration-dependent QTc prolongation of 18 to 24 ms (upper bound of|
04390|084|D|2-sided 90% CI: 21 and 27 ms) at a median steady-state Cmax dose of 26.5 mg|
04390|085|D|and 53 mg during maintenance therapy.(1)|
04390|086|D|   In patients administered quizartinib, 2.3% of 265 patients had a QTcF|
04390|087|D|greater than 500 msec and 10% of patients had a increase from baseline QTcF|
04390|088|D|greater than 60 msec.(1)|
04390|089|D|   In patients administered quizartinib during the induction phase, torsades|
04390|090|D|de pointes occurred in approximately 0.2% of patients, cardiac arrest|
04390|091|D|occurred in 0.6%, including 0.4% with a fatal outcome, and 0.1% of patients|
04390|092|D|experienced ventricular fibrillation.(1)|
04390|093|D|   Agents that are linked to this monograph may have varying degrees of|
04390|094|D|potential to prolong the QTc interval but are generally accepted to have a|
04390|095|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04390|096|D|been shown to prolong the QTc interval either through their mechanism of|
04390|097|D|action, through studies on their effects on the QTc interval, or through|
04390|098|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04390|099|D|and/or postmarketing reports.(2)|
04390|100|D|   Strong inducers of CYP3A4 include:  encorafenib and ivosidenib.|
04390|101|D|   Moderate inducers of CYP3A4 include:  efavirenz, pacritinib, and|
04390|102|D|thioridazine.(3,4)|
04390|103|B||
04390|104|R|REFERENCES:|
04390|105|B||
04390|106|R|1.Vanflyta (quizartinib) US prescribing infromation. Daiichi Sankyo, Inc|1
04390|107|R|  July, 2023.|1
04390|108|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04390|109|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04390|110|R|  settings: a scientific statement from the American Heart Association and|6
04390|111|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04390|112|R|  2;55(9):934-47.|6
04390|113|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04390|114|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04390|115|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04390|116|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04390|117|R|  11/14/2017.|1
04390|118|R|4.This information is based on an extract from the Certara Drug Interaction|6
04390|119|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04391|001|T|MONOGRAPH TITLE:  Domperidone/Selected Moderate CYP3A4 Inhibitors|
04391|002|B||
04391|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04391|004|L|of severe adverse interaction.|
04391|005|B||
04391|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors impair the CYP3A4 mediated|
04391|007|A|metabolism of domperidone.(1)|
04391|008|B||
04391|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
04391|010|E|in elevated levels of and toxicity from domperidone, including|
04391|011|E|life-threatening cardiac arrhythmias such as torsades de pointes.(1)|
04391|012|B||
04391|013|P|PREDISPOSING FACTORS:  In epidemiologic studies and post-market safety data,|
04391|014|P|domperidone was associated with an increased risk for serious ventricular|
04391|015|P|arrhythmias in patients > 60 years of age, using more than 30 mg of|
04391|016|P|domperidone daily, and having other risk factors for QT prolongation.(1)|
04391|017|P|   In general, the risk of QT prolongation or torsades de pointes may be|
04391|018|P|increased in patients with cardiovascular disease (e.g. heart failure,|
04391|019|P|myocardial infarction, history of torsades de pointes, congenital long QT|
04391|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04391|021|P|gender, or advanced age.(2)|
04391|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04391|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04391|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04391|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04391|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04391|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04391|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04391|029|B||
04391|030|M|PATIENT MANAGEMENT:  Concurrent use of moderate CYP3A4 inhibitors with|
04391|031|M|domperidone is not recommended.  Use alternative antiemetics, or an|
04391|032|M|alternative to the moderate CYP3A4 inhibitor, whichever is more clinically|
04391|033|M|appropriate.|
04391|034|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
04391|035|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
04391|036|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
04391|037|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04391|038|B||
04391|039|D|DISCUSSION:  In a study in 24 healthy subjects, ketoconazole (200 mg twice|
04391|040|D|daily) tripled plasma levels of domperidone (10 mg four times daily).  In|
04391|041|D|male subjects, the combination significantly increased QTc interval greater|
04391|042|D|than either agent alone.  In females, there were no significant changes in|
04391|043|D|QTc intervals, but QTc intervals were correlated with domperidone levels.(3)|
04391|044|D|   Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant,|
04391|045|D|avacopan, berotralstat, conivaptan, crizotinib, diltiazem, duvelisib,|
04391|046|D|fedratinib, fluvoxamine, imatinib, isavuconazole, oral lefamulin,|
04391|047|D|lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra,|
04391|048|D|stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4-5)|
04391|049|B||
04391|050|R|REFERENCES:|
04391|051|B||
04391|052|R|1.Health Canada. Domperidone Maleate - Association with Serious Abnormal|1
04391|053|R|  Heart Rhythms and Sudden Death (Cardiac Arrest). available at:|1
04391|054|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/43423a-e|1
04391|055|R|  ng.php January 20, 2015.|1
04391|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04391|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04391|058|R|  settings: a scientific statement from the American Heart Association and|6
04391|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04391|060|R|  2;55(9):934-47.|6
04391|061|R|3.Boyce MJ, Baisley KJ, Warrington SJ. Pharmacokinetic interaction between|2
04391|062|R|  domperidone and ketoconazole leads to QT prolongation in healthy|2
04391|063|R|  volunteers: a randomized, placebo-controlled, double-blind, crossover|2
04391|064|R|  study. Br J Clin Pharmacol 2012 Mar;73(3):411-21.|2
04391|065|R|4.This information is based on an extract from the Certara Drug Interaction|6
04391|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04391|067|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04391|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04391|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04391|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04391|071|R|  11/14/2017.|1
04392|001|T|MONOGRAPH TITLE:  Cisapride/Selected Strong and Moderate CYP3A4 Inhibitors|
04392|002|B||
04392|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04392|004|L|is contraindicated and generally should not be dispensed or administered to|
04392|005|L|the same patient.|
04392|006|B||
04392|007|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inhibitors impair the|
04392|008|A|CYP3A4 mediated metabolism of cisapride.(1)|
04392|009|B||
04392|010|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inhibitors|
04392|011|E|may result in elevated levels of and toxicity from cisapride, including|
04392|012|E|life-threatening cardiac arrhythmias such as torsades de pointes.(1-2)|
04392|013|B||
04392|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsades|
04392|015|P|de pointes may be increased in patients with cardiovascular disease (e.g.|
04392|016|P|heart failure, myocardial infarction, history of torsades de pointes,|
04392|017|P|congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia,|
04392|018|P|bradycardia, female gender, or advanced age.(3)|
04392|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04392|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04392|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04392|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04392|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04392|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04392|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04392|026|B||
04392|027|M|PATIENT MANAGEMENT:  Concurrent use of strong or moderate CYP3A4 inhibitors|
04392|028|M|with cisapride is contraindicated.  Use alternative antiemetics, or an|
04392|029|M|alternative to the strong or moderate CYP3A4 inhibitor, whichever is more|
04392|030|M|clinically appropriate.|
04392|031|M|   The US manufacturer of itraconazole states that concurrent administration|
04392|032|M|with cisapride is contraindicated during and two weeks after itraconazole|
04392|033|M|treatment.(4)|
04392|034|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
04392|035|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
04392|036|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
04392|037|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04392|038|B||
04392|039|D|DISCUSSION:  Strong CYP3A4 inhibitors linked to this monograph include:|
04392|040|D|adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib,|
04392|041|D|indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole,|
04392|042|D|lonafarnib, lopinavir, mifepristone, nefazodone, nelfinavir, nirmatrelvir,|
04392|043|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
04392|044|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(5)|
04392|045|D|   Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir,|
04392|046|D|atazanavir, avacopan, ciprofloxacin, clofazimine, conivaptan, darunavir,|
04392|047|D|erythromycin, fosamprenavir, rilzabrutinib, sevabertinib, and treosulfan.(5)|
04392|048|B||
04392|049|R|REFERENCES:|
04392|050|B||
04392|051|R|1.Health Canada. Domperidone Maleate - Association with Serious Abnormal|1
04392|052|R|  Heart Rhythms and Sudden Death (Cardiac Arrest). available at:|1
04392|053|R|  http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/43423a-e|1
04392|054|R|  ng.php January 20, 2015.|1
04392|055|R|2.Prepulsid (cisapride) US prescribing information. Janssen Pharmaceutica|1
04392|056|R|  Products, L.P. January, 2000.|1
04392|057|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04392|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04392|059|R|  settings: a scientific statement from the American Heart Association and|6
04392|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04392|061|R|  2;55(9):934-47.|6
04392|062|R|4.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
04392|063|R|  Products, L.P. February, 2024.|1
04392|064|R|5.This information is based on an extract from the Certara Drug Interaction|6
04392|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04393|001|T|MONOGRAPH TITLE:  Allopurinol/Amoxicillin, Ampicillin, Bendamustine|
04393|002|B||
04393|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04393|004|L|take action as needed.|
04393|005|B||
04393|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Allopurinol,|
04393|007|A|amoxicillin, ampicillin, and bendamustine have been documented to cause|
04393|008|A|cases of Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN),|
04393|009|A|and Drug reaction with eosinophilia and systemic symptoms (DRESS).(1)|
04393|010|B||
04393|011|E|CLINICAL EFFECTS:  Concurrent administration of allopurinol with|
04393|012|E|amoxicillin, ampicillin or bendamustine may result in an increased incidence|
04393|013|E|of rash which may be severe.|
04393|014|B||
04393|015|P|PREDISPOSING FACTORS:  Patients who are HLA-B*58:01 positive may be at|
04393|016|P|increased risk.|
04393|017|B||
04393|018|M|PATIENT MANAGEMENT:  Consider an alternative to amoxicillin, ampicillin, or|
04393|019|M|bendamustine in patients with a history of serious skin rashes, such as SJS,|
04393|020|M|TEN, or DRESS.  Discontinue allopurinol at the first appearance of skin rash|
04393|021|M|or other signs which may indicate a hypersensitivity reaction when used with|
04393|022|M|amoxicillin or ampicillin or bendamustine.  Instruct patients to seek|
04393|023|M|medical attention for any peeling skin rash or blisters.(1)|
04393|024|B||
04393|025|D|DISCUSSION:  In the Boston Collaborative Drug Surveillance Program, drug|
04393|026|D|rash was seen in 22.4% of 67 hospitalized patients (relative risk 3.0)|
04393|027|D|receiving concurrent allopurinol and ampicillin compared to 7.5% of 1257|
04393|028|D|patients receiving only ampicillin and 2.1% of 283 patients rceiving only|
04393|029|D|allopurinol.(4)|
04393|030|D|   A hospital drug monitoring program found the observed risk of developing|
04393|031|D|an exanthema with concurrent use is as follows: aminopenicillin without|
04393|032|D|allopurinol 10.1%, aminopenicillin combined with allopurinol 7.2%,|
04393|033|D|allopurinol without aminopenicillin 3.0%, or neither of the two drugs|
04393|034|D|1.5%.(6)|
04393|035|D|   A case-control study did not find a statistically significant increased|
04393|036|D|risk of SJS with concurrent use of allopurinol and amoxicillin or ampicillin|
04393|037|D|(allopurinol alone 4.4% vs. with amoxicillin 6.8%; allopurinol alone 0.1%|
04393|038|D|vs. with ampicillin 2.7% at 1 month)(allopurinol alone 4.4% vs. with|
04393|039|D|amoxicillin 5.7% or allopurinol alone 0.2% vs. with ampicillin 2.9% at 3|
04393|040|D|months).(8)|
04393|041|D|   In a retrospective study looking at mortality data, records were screened|
04393|042|D|for administration of high risk drugs associated with SJS. Allopurinol and|
04393|043|D|ampicillin was one of the drug combinations listed as contributing to|
04393|044|D|mortality in patients (p = 0.049).(9)|
04393|045|B||
04393|046|R|REFERENCES:|
04393|047|B||
04393|048|R|1.Aloprim (allopurinol) US prescribing information. Mylan Institutional LLC|1
04393|049|R|  February 17, 2002.|1
04393|050|R|2.Turney R, Skittrall JP, Donovan J, Agranoff D. Drug Reaction, Eosinophilia|3
04393|051|R|  and Systemic Symptoms (DRESS) syndrome secondary to  allopurinol with|3
04393|052|R|  early lymphadenopathy and symptom relapse. BMJ Case Rep 2015 Oct 5;2015:.|3
04393|053|R|3.Murphy TF. Ampicillin rash and hyperuricemia. Ann Intern Med 1979 Aug;|6
04393|054|R|  91(2):324.|6
04393|055|R|4.Excess of ampicillin rashes associated with allopurinol or hyperuricemia.|2
04393|056|R|  A  report from the Boston Collaborative Drug Surveillance Program, Boston|2
04393|057|R|  University  Medical Center. N Engl J Med 1972 Mar 9;286(10):505-7.|2
04393|058|R|5.Perez A, Cabrerizo S, de Barrio M, Diaz MP, Herrero T, Tornero P, Baeza|3
04393|059|R|  ML. Erythema-multiforme-like eruption from amoxycillin and allopurinol.|3
04393|060|R|  Contact Dermatitis 2001 Feb;44(2):113-4.|3
04393|061|R|6.Sonntag MR, Zoppi M, Fritschy D, Maibach R, Stocker F, Sollberger J,|6
04393|062|R|  Buchli W, Hess T, Hoigne R. Exanthema during frequent use of antibiotics|6
04393|063|R|  and antibacterial drugs  (penicillin, especially aminopenicillin,|6
04393|064|R|  cephalosporin and cotrimoxazole) as well  as allopurinol. Results of The|6
04393|065|R|  Berne Comprehensive Hospital Drug Monitoring  Program. Schweiz Med|6
04393|066|R|  Wochenschr 1986 Feb 1;116(5):142-5.|6
04393|067|R|7.Wang F, Ma Z, Wu X, Liu L. Allopurinol-induced toxic epidermal necrolysis|3
04393|068|R|  featuring almost 60% skin  detachment. Medicine (Baltimore) 2019 Jun;|3
04393|069|R|  98(25):e16078.|3
04393|070|R|8.Syu FK, Pan HY, Chuang PC, Huang YS, Cheng CY, Cheng FJ. Incidence of|2
04393|071|R|  Stevens-Johnson syndrome following combination drug use of  allopurinol,|2
04393|072|R|  carbamazepine and phenytoin in Taiwan: A case-control study. J Dermatol|2
04393|073|R|  2018 Sep;45(9):1080-1087.|2
04393|074|R|9.Cheng FJ, Syu FK, Lee KH, Chen FC, Wu CH, Chen CC. Correlation between|6
04393|075|R|  drug-drug interaction-induced Stevens-Johnson syndrome and  related deaths|6
04393|076|R|  in Taiwan. J Food Drug Anal 2016 Apr;24(2):427-432.|6
04394|001|T|MONOGRAPH TITLE:  Allopurinol/Thiazide Diuretics|
04394|002|B||
04394|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04394|004|L|take action as needed.|
04394|005|B||
04394|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Allopurinol has been|
04394|007|A|documented to cause Stevens-Johnson syndrome (SJS), Toxic epidermal|
04394|008|A|necrolysis (TEN), and Drug reaction with eosinophilia and systemic symptoms|
04394|009|A|(DRESS).(1)|
04394|010|B||
04394|011|E|CLINICAL EFFECTS:  Concurrent administration of allopurinol with thiazides|
04394|012|E|may result in an increased incidence of rash which may be severe.|
04394|013|B||
04394|014|P|PREDISPOSING FACTORS:  Patients who are HLA-B*58:01 positive or have|
04394|015|P|impaired renal function may be at increased risk.|
04394|016|B||
04394|017|M|PATIENT MANAGEMENT:  The manufacturer of allopurinol recommends monitoring|
04394|018|M|renal function and reducing the dose of allopurinol in patients with|
04394|019|M|concomitant thiazide diuretic use and impaired renal function.  Discontinue|
04394|020|M|allopurinol at the first appearance of skin rash or other signs which may|
04394|021|M|indicate a hypersensitivity reaction when used with thiazide diuretics.|
04394|022|M|Instruct patients to seek medical attention for any peeling skin rash or|
04394|023|M|blisters.(1)|
04394|024|B||
04394|025|D|DISCUSSION:  There are case reports of patients on concurrent thiazide|
04394|026|D|diuretics and allopurinol developing SJS, TEN, or DRESS.(1,2)|
04394|027|B||
04394|028|R|REFERENCES:|
04394|029|B||
04394|030|R|1.Aloprim (allopurinol) US prescribing information. Mylan Institutional LLC|1
04394|031|R|  February 17, 2002.|1
04394|032|R|2.Cardoso CS, Vieira AM, Oliveira AP. DRESS syndrome: a case report and|3
04394|033|R|  literature review. BMJ Case Rep 2011 Jun 3;2011:.|3
04395|001|T|MONOGRAPH TITLE:  Disopyramide/Strong CYP3A4 Inhibitors that Prolong QT|
04395|002|B||
04395|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04395|004|L|is contraindicated and generally should not be dispensed or administered to|
04395|005|L|the same patient.|
04395|006|B||
04395|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
04395|008|A|may inhibit the metabolism of disopyramide and result in additive effects on|
04395|009|A|the QTc interval.(1,2)|
04395|010|B||
04395|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04395|012|E|the QT interval with disopyramide may result in elevated levels of|
04395|013|E|disopyramide and serious and/or life-threatening effects, including QT|
04395|014|E|prolongation.(1,2)|
04395|015|B||
04395|016|P|PREDISPOSING FACTORS:  Renal and hepatic impairment may increase risk for|
04395|017|P|excessive QTc prolongation as disopyramide is eliminated renally and|
04395|018|P|hepatically. To prevent increased serum levels and risk for ventricular|
04395|019|P|arrhythmias, disopyramide must be dose adjusted in renal and hepatic|
04395|020|P|insufficiency.|
04395|021|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04395|022|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04395|023|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04395|024|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04395|025|P|advanced age.(3)|
04395|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04395|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04395|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04395|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04395|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04395|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04395|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04395|033|B||
04395|034|M|PATIENT MANAGEMENT:  The US labeling states coadministration of disopyramide|
04395|035|M|with QT prolonging agents is not advised and coadministration of strong|
04395|036|M|CYP3A4 inhibitors that prolong the QT interval with disopyramide should be|
04395|037|M|avoided.  If use of the combination is warranted, clinical monitoring is|
04395|038|M|recommended.(1)|
04395|039|M|   The Australian manufacturer of disopyramide states that concurrent use|
04395|040|M|with agents liable to produce torsades de pointes is contraindicated.(2)|
04395|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04395|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04395|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04395|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04395|045|B||
04395|046|D|DISCUSSION:  Strong CYP3A4 inhibitors may inhibit the metabolism and|
04395|047|D|increase levels of disopyramide by inhibition of CYP3A4.(1,2)|
04395|048|D|   Selected CYP3A4 inhibitors that prolong QT linked to this monograph|
04395|049|D|include:  adagrasib, clarithromycin, levoketoconazole and lonafarnib.(4,5)|
04395|050|B||
04395|051|R|REFERENCES:|
04395|052|B||
04395|053|R|1.Norpace (disopyramide phosphate) US prescribing information. Pfizer Inc.|1
04395|054|R|  December, 2020.|1
04395|055|R|2.Rythmodan (disopyramide) Australian prescribing information. Aventis|1
04395|056|R|  Pharma Pty Ltd. September 22, 2000.|1
04395|057|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04395|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04395|059|R|  settings: a scientific statement from the American Heart Association and|6
04395|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04395|061|R|  2;55(9):934-47.|6
04395|062|R|4.This information is based on an extract from the Certara Drug Interaction|6
04395|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04395|064|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04395|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04395|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04395|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04395|068|R|  11/14/2017.|1
04397|001|T|MONOGRAPH TITLE:  Pralsetinib/P-glycoprotein (P-gp) Inhibitors|
04397|002|B||
04397|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04397|004|L|of severe adverse interaction.|
04397|005|B||
04397|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors may inhibit cellular|
04397|007|A|efflux of pralsetinib.(1)|
04397|008|B||
04397|009|E|CLINICAL EFFECTS:  Concurrent administration of a P-gp inhibitor may result|
04397|010|E|in elevated levels of and toxicity from pralsetinib, including hemorrhagic|
04397|011|E|events, pneumonitis, hepatotoxicity, hypertension, and QTc prolongation,|
04397|012|E|which may result in potentially life-threatening cardiac arrhythmias like|
04397|013|E|torsades de pointes (TdP).(1-3)|
04397|014|B||
04397|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04397|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04397|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04397|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04397|019|P|female gender, or advanced age.(4)|
04397|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04397|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04397|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04397|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04397|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04397|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04397|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04397|027|B||
04397|028|M|PATIENT MANAGEMENT:  Coadministration of pralsetinib with a P-gp inhibitor|
04397|029|M|should be avoided.(1)|
04397|030|M|   If coadministration with a P-gp inhibitor cannot be avoided, use with|
04397|031|M|caution and reduce the dose of pralsetinib as follows:|
04397|032|M|   -If the current dose is 400 mg once daily, decrease the dose to 300 mg|
04397|033|M|daily.|
04397|034|M|   -If the current dose is 300 mg once daily, decrease the dose to 200 mg|
04397|035|M|daily.|
04397|036|M|   -If the current dose is 200 mg once daily, decrease the dose to 100 mg|
04397|037|M|daily.|
04397|038|M|   After the inhibitor is discontinued for three to five half-lives, resume|
04397|039|M|the dose of pralsetinib at the dose taken prior to initiation of the|
04397|040|M|inhibitor.(1)|
04397|041|M|   The manufacturer of venetoclax states that if concurrent use with a P-gp|
04397|042|M|substrate cannot be avoided, take pralsetinib at least 6 hours before|
04397|043|M|venetoclax.(5)|
04397|044|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04397|045|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04397|046|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04397|047|M|report any irregular heartbeat, dizziness, or fainting.|
04397|048|M|   If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until|
04397|049|M|QTc is <470 ms.  Resume pralsetinib at the same dose if risk factors that|
04397|050|M|cause QT prolongation an are identified and corrected.  If risk factors that|
04397|051|M|cause QT prolongation are not identified, resume pralsetinib at a reduced|
04397|052|M|dose.  Permanently discontinue pralsetinib if the patient develops|
04397|053|M|life-threatening arrhythmia.(3)|
04397|054|B||
04397|055|D|DISCUSSION:  Coadministration of a single dose of cyclosporine 600 mg (a|
04397|056|D|P-gp inhibitor) with a single pralsetinib 200 mg dose increased pralsetinib|
04397|057|D|concentration maximum (Cmax) by 48% and area-under-curve (AUC) by 81%.(1)|
04397|058|D|   P-glycoprotein inhibitors linked to this monograph include:  asunaprevir,|
04397|059|D|belumosudil, carvedilol, cyclosporine, danicopan, daridorexant,|
04397|060|D|deutivacaftor, diosmin, flibanserin, fostamatinib, ginseng,|
04397|061|D|glecaprevir/pibrentasvir, ivacaftor, ledipasvir, neratinib,|
04397|062|D|sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, venetoclax,|
04397|063|D|vimseltinib, and voclosporin.(6,7)|
04397|064|B||
04397|065|R|REFERENCES:|
04397|066|B||
04397|067|R|1.Gavreto (pralsetinib) US prescribing information. Rigel Pharmaceuticals,|1
04397|068|R|  Inc. June, 2024.|1
04397|069|R|2.EMA Committee for Medicinal Products for Human Use (CHMP). Gavreto|1
04397|070|R|  (pralsetinib) European Medicines Agency Assessment Report|1
04397|071|R|  EMA/CHMP/41191/2021. Roche Registration GmbH. September 12, 2021.|1
04397|072|R|3.Gavreto (pralsetinib) Canadian Product Monograph. Hoffmann-La Roche|1
04397|073|R|  Limited May, 2024.|1
04397|074|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04397|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04397|076|R|  settings: a scientific statement from the American Heart Association and|6
04397|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04397|078|R|  2;55(9):934-47.|6
04397|079|R|5.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
04397|080|R|  2021.|1
04397|081|R|6.This information is based on an extract from the Certara Drug Interaction|6
04397|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04397|083|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04397|084|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04397|085|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04397|086|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04397|087|R|  11/14/2017.|1
04398|001|T|MONOGRAPH TITLE:  Pralsetinib/Moderate CYP3A4 Inducers|
04398|002|B||
04398|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04398|004|L|of severe adverse interaction.|
04398|005|B||
04398|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04398|007|A|of pralsetinib.(1)|
04398|008|B||
04398|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inducer may result in|
04398|010|E|a loss of pralsetinib efficacy.(1)|
04398|011|B||
04398|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04398|013|P|of the inducer for longer than 1-2 weeks.|
04398|014|B||
04398|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pralsetinib with moderate|
04398|016|M|CYP3A4 inducers.(1)|
04398|017|M|  If coadministration with a moderate CYP3A4 inducer cannot be avoided,|
04398|018|M|increase the dose of pralsetinib on day 7 of coadministration with|
04398|019|M|pralsetinib as follows:|
04398|020|M|   -If the current dose is 400 mg once daily, increase the dose to 600 mg|
04398|021|M|daily.|
04398|022|M|   -If the current dose is 300 mg once daily, increase the dose to 500 mg|
04398|023|M|daily.|
04398|024|M|   -If the current dose is 200 mg once daily, increase the dose to 300 mg|
04398|025|M|daily.|
04398|026|M|After discontinuation of a moderate CYP3A4 inducer for at least 14 days,|
04398|027|M|resume the previous pralsetinib dose prior to initiating the moderate CYP3A4|
04398|028|M|inducer.(1)|
04398|029|M|   Monitor patients receiving concurrent therapy for reduced efficacy.|
04398|030|B||
04398|031|D|DISCUSSION:  Coadministration of efavirenz 600 mg once daily is expected to|
04398|032|D|decrease pralsetinib concentration maximum (Cmax) by 18% and|
04398|033|D|area-under-curve (AUC) by 45%.(1)|
04398|034|D|     Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04398|035|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04398|036|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04398|037|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04398|038|D|thioridazine, and tovorafenib.(2-3)|
04398|039|B||
04398|040|R|REFERENCES:|
04398|041|B||
04398|042|R|1.Gavreto (pralsetinib) US prescribing information. Rigel Pharmaceuticals,|1
04398|043|R|  Inc. June, 2024.|1
04398|044|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04398|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04398|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04398|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04398|048|R|  11/14/2017.|1
04398|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
04398|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04399|001|T|MONOGRAPH TITLE:  Zuranolone/Strong CYP3A4 Inhibitors|
04399|002|B||
04399|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04399|004|L|take action as needed.|
04399|005|B||
04399|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04399|007|A|of zuranolone.(1)|
04399|008|B||
04399|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04399|010|E|the levels and effects of zuranolone, including somnolence and CNS|
04399|011|E|depression.(1)|
04399|012|B||
04399|013|P|PREDISPOSING FACTORS:  None determined.|
04399|014|B||
04399|015|M|PATIENT MANAGEMENT:  The US prescribing information recommends dose|
04399|016|M|adjustment if zuranolone is to be given with a strong CYP3A4 inhibitor.|
04399|017|M|Reduce the zuranolone dose to 30 mg orally once daily in the evening for 14|
04399|018|M|days when used concurrently with strong CYP3A4 inhibitors.(1)|
04399|019|B||
04399|020|D|DISCUSSION:  Coadministration of zuranolone with itraconazole (a strong|
04399|021|D|CYP3A4 inhibitor) increased the maximum concentration (Cmax) by 25% and|
04399|022|D|area-under-curve (AUC) by 62%.(1)|
04399|023|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04399|024|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04399|025|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
04399|026|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04399|027|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04399|028|D|troleandomycin, tucatinib, and voriconazole.(2,3)|
04399|029|B||
04399|030|R|REFERENCES:|
04399|031|B||
04399|032|R|1.Zurzuvae (zuranolone) US prescribing information. Sage Therapeutics, Inc.|1
04399|033|R|  August, 2023.|1
04399|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
04399|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04399|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04399|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04399|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04399|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04399|040|R|  11/14/2017.|1
04400|001|T|MONOGRAPH TITLE:  Zuranolone/CYP3A4 Inducers|
04400|002|B||
04400|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04400|004|L|of severe adverse interaction.|
04400|005|B||
04400|006|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
04400|007|A|zuranolone.(1)|
04400|008|B||
04400|009|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inducer may result in a loss|
04400|010|E|of zuranolone efficacy.(1)|
04400|011|B||
04400|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04400|013|P|of the inducer for longer than 1-2 weeks.|
04400|014|B||
04400|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of zuranolone with CYP3A4|
04400|016|M|inducers.(1)|
04400|017|B||
04400|018|D|DISCUSSION:  Coadministration of zuranolone with rifampin decreased the|
04400|019|D|maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by|
04400|020|D|0.15-fold.(1)|
04400|021|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04400|022|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04400|023|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04400|024|D|rifampin, rifapentine, and St. John's wort.|
04400|025|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
04400|026|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
04400|027|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
04400|028|D|pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat|
04400|029|D|ethyl, thioridazine, and tovorafenib.|
04400|030|D|   Weak CYP3A4 inducers linked to this monograph include:  armodafinil,|
04400|031|D|bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide,|
04400|032|D|dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin,|
04400|033|D|garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib,|
04400|034|D|nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone,|
04400|035|D|pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone,|
04400|036|D|sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine,|
04400|037|D|topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)|
04400|038|B||
04400|039|R|REFERENCES:|
04400|040|B||
04400|041|R|1.Zurzuvae (zuranolone) US prescribing information. Sage Therapeutics, Inc.|1
04400|042|R|  August, 2023.|1
04400|043|R|2.This information is based on an extract from the Certara Drug Interaction|6
04400|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04400|045|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04400|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04400|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04400|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04400|049|R|  11/14/2017.|1
04401|001|T|MONOGRAPH TITLE:  Palovarotene/Moderate CYP3A4 Inhibitors|
04401|002|B||
04401|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04401|004|L|take action as needed.|
04401|005|B||
04401|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04401|007|A|of palovarotene.(1)|
04401|008|B||
04401|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
04401|010|E|in elevated levels of and toxicity from palovarotene, including rash,|
04401|011|E|alopecia, skin exfoliation, photosensitivity, reduction in bone mass,|
04401|012|E|hyperostosis, and night blindness.(1,2)|
04401|013|B||
04401|014|P|PREDISPOSING FACTORS:  None determined.|
04401|015|B||
04401|016|M|PATIENT MANAGEMENT:  The concurrent use of moderate CYP3A4 inhibitors with|
04401|017|M|palovarotene should be avoided.  If concurrent use cannot be avoided, reduce|
04401|018|M|the dose of palovarotene by half, according to the US prescribing|
04401|019|M|information.(1)|
04401|020|B||
04401|021|D|DISCUSSION:  In a clinical trial, erythromycin, a moderate CYP3A4 inhibitor,|
04401|022|D|increased the maximum concentration (Cmax) and area-under-curve (AUC) of|
04401|023|D|palovarotene by 1.6- and 2.5-fold, respectively.(1)|
04401|024|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
04401|025|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
04401|026|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
04401|027|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
04401|028|D|isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib,|
04401|029|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil,|
04401|030|D|and voxelotor.(3,4)|
04401|031|B||
04401|032|R|REFERENCES:|
04401|033|B||
04401|034|R|1.Sohonos (palovarotene) US prescribing information. Ipsen|1
04401|035|R|  Biopharmaceuticals, Inc. August 2023.|1
04401|036|R|2.Sohonos (palovarotene) Canadian Product Monograph. Ipsen|1
04401|037|R|  Biopharmaceuticals Canada Inc. January, 2022.|1
04401|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04401|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04401|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04401|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04401|042|R|  11/14/2017.|1
04401|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
04401|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04402|001|T|MONOGRAPH TITLE:  Pozelimab/Intravenous Immunoglobulin|
04402|002|B||
04402|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04402|004|L|of severe adverse interaction.|
04402|005|B||
04402|006|A|MECHANISM OF ACTION:  The neonatal Fc receptor (FcRn) prevents catabolism|
04402|007|A|and mediates recycling of IgG and albumin, which leads to their long|
04402|008|A|persistence in the body.(1,2)  Pozelimab is an IgG4P antibody.  Concurrent|
04402|009|A|use of intravenous immunoglobulin which binds to FcRn may interfere with the|
04402|010|A|FcRn recycling mechanism of pozelimab and decrease systemic exposure of|
04402|011|A|pozelimab.(3)|
04402|012|B||
04402|013|E|CLINICAL EFFECTS:  The levels and effectiveness of pozelimab may be|
04402|014|E|decreased.(3)|
04402|015|B||
04402|016|P|PREDISPOSING FACTORS:  None determined.|
04402|017|B||
04402|018|M|PATIENT MANAGEMENT:  The manufacturer of pozelimab states that concomitant|
04402|019|M|use of intravenous immunoglobulin should avoided with pozelimab.  If|
04402|020|M|concomitant use cannot be avoided, monitor patients for worsening signs and|
04402|021|M|symptoms of CD55-deficient protein-losing enteropathy.(3)|
04402|022|B||
04402|023|D|DISCUSSION:  Clinical drug interaction studies with pozelimab have not been|
04402|024|D|performed.  Immunoglobulins may interfere with the endosomal FcRn recycling|
04402|025|D|mechanism of monoclonal antibodies like pozelimab and decrease|
04402|026|D|concentrations of pozelimab.(3)|
04402|027|B||
04402|028|R|REFERENCES:|
04402|029|B||
04402|030|R|1.Sockolosky JT, Szoka FC. The neonatal Fc receptor, FcRn, as a target for|6
04402|031|R|  drug delivery and therapy. Adv Drug Deliv Rev 2015 Aug 30;91:109-24.|6
04402|032|R|2.Kuo TT, Aveson VG. Neonatal Fc receptor and IgG-based therapeutics. MAbs|6
04402|033|R|  2011 Sep-Oct;3(5):422-30.|6
04402|034|R|3.Veopoz (pozelimab-bbfg) US prescribing information. Regeneron|1
04402|035|R|  Pharmaceuticals, Inc., August 2023.|1
04403|001|T|MONOGRAPH TITLE:  Lurbinectedin/Moderate CYP3A4 Inhibitors|
04403|002|B||
04403|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04403|004|L|of severe adverse interaction.|
04403|005|B||
04403|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04403|007|A|of lurbinectedin.(1)|
04403|008|B||
04403|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors with|
04403|010|E|lurbinectedin may increase systemic exposure and the risk for toxicities|
04403|011|E|such as myelosuppression, hepatotoxicity, neuropathy, fatigue, nausea, and|
04403|012|E|musculoskeletal pain.(1)|
04403|013|B||
04403|014|P|PREDISPOSING FACTORS:  None determined.|
04403|015|B||
04403|016|M|PATIENT MANAGEMENT:  The US manufacturer of lurbinectedin states that the|
04403|017|M|concurrent use of lurbinectedin with moderate CYP3A4 inhibitors should be|
04403|018|M|avoided.  If the use of a moderate CYP3A4 inhibitor cannot be avoided,|
04403|019|M|reduce the dose of lurbinectedin by 50%.  After discontinuation of the|
04403|020|M|moderate CYP3A4 inhibitor for 5 half-lives of the inhibitor, resume the|
04403|021|M|lurbinectedin dose used before starting the inhibitor.(1)|
04403|022|B||
04403|023|D|DISCUSSION:  Itraconazole (a strong CYP3A4 inhibitor) increased the|
04403|024|D|area-under-curve (AUC) of total lurbinectedin by 2.7-fold and unbound|
04403|025|D|lurbinectedin by 2.4-fold.(1)|
04403|026|D|   In a study including data from 443 patients with solid and hematologic|
04403|027|D|malignancies treated in six phase I and three phase II trials with|
04403|028|D|lurbinectedin as a single agent or combined with other agents, lurbinectedin|
04403|029|D|clearance decreased by 30%, area-under-curve (AUC) increased by 42%, and|
04403|030|D|concentration maximum (Cmax) increased by 7% when coadministered with a|
04403|031|D|CYP3A inhibitor.(2)|
04403|032|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
04403|033|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
04403|034|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
04403|035|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral|
04403|036|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib,|
04403|037|D|schisandra, stiripentol, tofisopam, treosulfan, verapamil, and|
04403|038|D|voxelotor.(3,4)|
04403|039|B||
04403|040|R|REFERENCES:|
04403|041|B||
04403|042|R|1.Zepzelca (lurbinectedin) US prescribing information. Pharma Mar USA Inc.|1
04403|043|R|  April, 2024.|1
04403|044|R|2.Fernandez-Teruel C, Gonzalez I, Troconiz IF, Lubomirov R, Soto A, Fudio S.|2
04403|045|R|  Population-Pharmacokinetic and Covariate Analysis of Lurbinectedin|2
04403|046|R|  (PM01183), a New  RNA Polymerase II Inhibitor, in Pooled Phase I/II Trials|2
04403|047|R|  in Patients with Cancer. Clinical Pharmacokinetics August 09, 2018.;|2
04403|048|R|  58(1179-1926):363-374.|2
04403|049|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04403|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04403|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04403|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04403|053|R|  11/14/2017.|1
04403|054|R|4.This information is based on an extract from the Certara Drug Interaction|6
04403|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04404|001|T|MONOGRAPH TITLE:  Dextroamphetamine Transdermal/Urinary Alkalinizers|
04404|002|B||
04404|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04404|004|L|of severe adverse interaction.|
04404|005|B||
04404|006|A|MECHANISM OF ACTION:  Urinary alkalinizers decrease the renal elimination of|
04404|007|A|dextroamphetamine.(1)|
04404|008|B||
04404|009|E|CLINICAL EFFECTS:  Concurrent use of dextroamphetamine and urinary|
04404|010|E|alkalinizers may result in increased dextroamphetamine levels and side|
04404|011|E|effects.|
04404|012|B||
04404|013|P|PREDISPOSING FACTORS:  None determined.|
04404|014|B||
04404|015|M|PATIENT MANAGEMENT:  Coadministration of dextroamphetamine with urinary|
04404|016|M|alkalinizing agents should be avoided.(1)|
04404|017|B||
04404|018|D|DISCUSSION:  Concurrent use of alkalinizing agents with dextroamphetamine|
04404|019|D|decreases the renal elimination of dextroamphetamine.  Co-administration of|
04404|020|D|these should be avoided because of the potential of increased actions of|
04404|021|D|dextroamphetamine.(1)|
04404|022|B||
04404|023|R|REFERENCE:|
04404|024|B||
04404|025|R|1.Xelstrym (dextroamphetamine) US prescribing information. Noven|1
04404|026|R|  Therapeutics, LLC March 2022.|1
04405|001|T|MONOGRAPH TITLE:  Cilostazol (Greater Than 50 mg BID)/Strong CYP2C19|
04405|002|T|Inhibitors that Cause Bleeding|
04405|003|B||
04405|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04405|005|L|is contraindicated and generally should not be dispensed or administered to|
04405|006|L|the same patient.|
04405|007|B||
04405|008|A|MECHANISM OF ACTION:  Fluoxetine and fluvoxamine are strong CYP2C19|
04405|009|A|inhibitors. Strong CYP2C19 inhibitors may inhibit the metabolism of|
04405|010|A|cilostazol.(1-3)|
04405|011|A|   In addition, serotonin release by platelets plays a role in|
04405|012|A|hemostasis.(2,3)  This may result in an increased risk of bleeding due to a|
04405|013|A|decrease in serotonin reuptake by platelets.|
04405|014|B||
04405|015|E|CLINICAL EFFECTS:  Concurrent use of cilostazol and strong CYP2C19|
04405|016|E|inhibitors may result in elevated levels and increased effects of|
04405|017|E|cilostazol.(1)|
04405|018|E|   Concurrent use of a selective serotonin reuptake inhibitor(2,3) and|
04405|019|E|cilostazol may result in bleeding.|
04405|020|B||
04405|021|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04405|022|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
04405|023|P|impairment has been associated with an elevated risk of GI bleed in patients|
04405|024|P|on SSRIs.(5)|
04405|025|P|   Drug associated risk factors include concurrent use of multiple drugs|
04405|026|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04405|027|P|risk for bleeding (e.g. NSAIDs).|
04405|028|B||
04405|029|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
04405|030|M|daily in patients receiving concurrent therapy with strong CYP2C19|
04405|031|M|inhibitors.(1)|
04405|032|M|   Selective serotonin reuptake inhibitors and agents that affect|
04405|033|M|coagulation should be used concurrently with caution.|
04405|034|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04405|035|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04405|036|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04405|037|M|patients with any symptoms.|
04405|038|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04405|039|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04405|040|M|anticoagulation in patients with active pathologic bleeding.|
04405|041|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04405|042|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04405|043|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04405|044|M|and/or swelling.|
04405|045|B||
04405|046|D|DISCUSSION:  A study in 20 subjects examined the effects of omeprazole (40|
04405|047|D|mg daily) on a single dose of cilostazol (100 mg).  Concurrent omeprazole|
04405|048|D|increased the cilostazol maximum concentration (Cmax) and area-under-curve|
04405|049|D|(AUC) by 18% and 26%, respectively.  The Cmax and AUC of the|
04405|050|D|3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%,|
04405|051|D|respectively.  The Cmax and AUC of the OPC-13213 metabolite of cilostazol|
04405|052|D|decreased by 22% and 31%, respectively.(4)|
04405|053|D|   In a retrospective review of 5 years of data from the|
04405|054|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
04405|055|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
04405|056|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
04405|057|D|only based on an observed-expected ration was 4.5 and in a patient using|
04405|058|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
04405|059|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
04405|060|D|bleeding to 12.2 and 5.2, respectively.(5)|
04405|061|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
04405|062|D|in patients receiving concurrent therapy with selective serotonin reuptake|
04405|063|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
04405|064|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
04405|065|D|respectively.(6)|
04405|066|D|   In a case-control study conducted in users of acenocoumarol or|
04405|067|D|phenprocoumon, 1848 patients who had been hospitalized with abnormal|
04405|068|D|bleeding were each matched to 4 control patients.  When patients took both a|
04405|069|D|SSRI and a coumarin, an increased risk of hospitalization due to major|
04405|070|D|non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to|
04405|071|D|gastrointestinal bleeding (adjusted OR 0.8).(7)|
04405|072|D|   A retrospective review examined patients discharged from a hospital with|
04405|073|D|antiplatelet therapy following a myocardial infarction.  When compared to|
04405|074|D|aspirin therapy alone, both aspirin therapy with a SSRI and aspirin,|
04405|075|D|clopidogrel, and SSRI therapy were associated with an increased risk of|
04405|076|D|bleeding (hazard ratios 1.42 and 2.35, respectively.)  Compared with dual|
04405|077|D|antiplatelet therapy (aspirin and clopidogrel), use of aspirin and|
04405|078|D|clopidogrel and a SSRI was also associated with increased risk of bleeding|
04405|079|D|(hazard ration 1.57).(8)|
04405|080|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
04405|081|D|anticoagulation (hazard ratio 2.63).  Paroxetine was not associated with an|
04405|082|D|increased risk.  There were insufficient numbers of patients taking other|
04405|083|D|SSRIs to assess increased risk.(9)|
04405|084|B||
04405|085|R|REFERENCES:|
04405|086|B||
04405|087|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
04405|088|R|  Pharmaceutical, Inc. January, 2015.|1
04405|089|R|2.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
04405|090|R|  and Company August, 2023.|1
04405|091|R|3.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
04405|092|R|  Pharmaceuticals, Inc. August, 2023.|1
04405|093|R|4.Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol.|2
04405|094|R|  Clin Pharmacokinet 1999;37 Suppl 2:53-9.|2
04405|095|R|5.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
04405|096|R|  Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
04405|097|R|  by level of kidney function: A population-based cohort study. Br J Clin|2
04405|098|R|  Pharmacol 2018 Sep;84(9):2142-2151.|2
04405|099|R|6.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
04405|100|R|  serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
04405|101|R|  population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
04405|102|R|7.Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding risk|2
04405|103|R|  with concurrent use of selective serotonin reuptake inhibitors and|2
04405|104|R|  coumarins. Arch Intern Med 2008 Jan 28;168(2):180-5.|2
04405|105|R|8.Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding|2
04405|106|R|  associated with combined use of selective serotonin reuptake inhibitors|2
04405|107|R|  and antiplatelet therapy following acute myocardial infarction. CMAJ 2011|2
04405|108|R|  Nov 8;183(16):1835-43.|2
04405|109|R|9.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
04405|110|R|  Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
04405|111|R|  antidepressants and the risk of overanticoagulation during acenocoumarol|2
04405|112|R|  maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
04406|001|T|MONOGRAPH TITLE:  Cilostazol (Less Than or Equal to 50 mg BID)/Strong|
04406|002|T|CYP2C19 Inhibitors that Cause Bleeding|
04406|003|B||
04406|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04406|005|L|take action as needed.|
04406|006|B||
04406|007|A|MECHANISM OF ACTION:  Fluoxetine and fluvoxamine are strong CYP2C19|
04406|008|A|inhibitors. Strong CYP2C19 inhibitors may inhibit the metabolism of|
04406|009|A|cilostazol.(1-3)|
04406|010|A|   In addition, serotonin release by platelets plays a role in|
04406|011|A|hemostasis.(2,3)  This may result in an increased risk of bleeding due to a|
04406|012|A|decrease in serotonin reuptake by platelets.|
04406|013|B||
04406|014|E|CLINICAL EFFECTS:  Concurrent use of cilostazol and strong CYP2C19|
04406|015|E|inhibitors may result in elevated levels and increased effects of|
04406|016|E|cilostazol.(1)|
04406|017|E|   Concurrent use of a selective serotonin reuptake inhibitor(2,3) and|
04406|018|E|cilostazol may result in bleeding.|
04406|019|B||
04406|020|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04406|021|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
04406|022|P|impairment has been associated with an elevated risk of GI bleed in patients|
04406|023|P|on SSRIs.(5)|
04406|024|P|   Drug associated risk factors include concurrent use of multiple drugs|
04406|025|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04406|026|P|risk for bleeding (e.g. NSAIDs).|
04406|027|B||
04406|028|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
04406|029|M|daily in patients receiving concurrent therapy with strong CYP2C19|
04406|030|M|inhibitors.(1)|
04406|031|M|   Selective serotonin reuptake inhibitors and agents that affect|
04406|032|M|coagulation should be used concurrently with caution.|
04406|033|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04406|034|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04406|035|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04406|036|M|patients with any symptoms.|
04406|037|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04406|038|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04406|039|M|anticoagulation in patients with active pathologic bleeding.|
04406|040|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04406|041|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04406|042|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04406|043|M|and/or swelling.|
04406|044|B||
04406|045|D|DISCUSSION:  A study in 20 subjects examined the effects of omeprazole (40|
04406|046|D|mg daily) on a single dose of cilostazol (100 mg).  Concurrent omeprazole|
04406|047|D|increased the cilostazol maximum concentration (Cmax) and area-under-curve|
04406|048|D|(AUC) by 18% and 26%, respectively.  The Cmax and AUC of the|
04406|049|D|3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%,|
04406|050|D|respectively.  The Cmax and AUC of the OPC-13213 metabolite of cilostazol|
04406|051|D|decreased by 22% and 31%, respectively.(4)|
04406|052|D|   In a retrospective review of 5 years of data from the|
04406|053|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
04406|054|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
04406|055|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
04406|056|D|only based on an observed-expected ration was 4.5 and in a patient using|
04406|057|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
04406|058|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
04406|059|D|bleeding to 12.2 and 5.2, respectively.(5)|
04406|060|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
04406|061|D|in patients receiving concurrent therapy with selective serotonin reuptake|
04406|062|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
04406|063|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
04406|064|D|respectively.(6)|
04406|065|D|   In a case-control study conducted in users of acenocoumarol or|
04406|066|D|phenprocoumon, 1848 patients who had been hospitalized with abnormal|
04406|067|D|bleeding were each matched to 4 control patients.  When patients took both a|
04406|068|D|SSRI and a coumarin, an increased risk of hospitalization due to major|
04406|069|D|non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to|
04406|070|D|gastrointestinal bleeding (adjusted OR 0.8).(7)|
04406|071|D|   A retrospective review examined patients discharged from a hospital with|
04406|072|D|antiplatelet therapy following a myocardial infarction.  When compared to|
04406|073|D|aspirin therapy alone, both aspirin therapy with a SSRI and aspirin,|
04406|074|D|clopidogrel, and SSRI therapy were associated with an increased risk of|
04406|075|D|bleeding (hazard ratios 1.42 and 2.35, respectively.)  Compared with dual|
04406|076|D|antiplatelet therapy (aspirin and clopidogrel), use of aspirin and|
04406|077|D|clopidogrel and a SSRI was also associated with increased risk of bleeding|
04406|078|D|(hazard ration 1.57).(8)|
04406|079|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
04406|080|D|anticoagulation (hazard ratio 2.63).  Paroxetine was not associated with an|
04406|081|D|increased risk.  There were insufficient numbers of patients taking other|
04406|082|D|SSRIs to assess increased risk.(9)|
04406|083|B||
04406|084|R|REFERENCES:|
04406|085|B||
04406|086|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
04406|087|R|  Pharmaceutical, Inc. January, 2015.|1
04406|088|R|2.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
04406|089|R|  and Company August, 2023.|1
04406|090|R|3.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
04406|091|R|  Pharmaceuticals, Inc. August, 2023.|1
04406|092|R|4.Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol.|2
04406|093|R|  Clin Pharmacokinet 1999;37 Suppl 2:53-9.|2
04406|094|R|5.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
04406|095|R|  Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
04406|096|R|  by level of kidney function: A population-based cohort study. Br J Clin|2
04406|097|R|  Pharmacol 2018 Sep;84(9):2142-2151.|2
04406|098|R|6.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
04406|099|R|  serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
04406|100|R|  population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
04406|101|R|7.Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding risk|2
04406|102|R|  with concurrent use of selective serotonin reuptake inhibitors and|2
04406|103|R|  coumarins. Arch Intern Med 2008 Jan 28;168(2):180-5.|2
04406|104|R|8.Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding|2
04406|105|R|  associated with combined use of selective serotonin reuptake inhibitors|2
04406|106|R|  and antiplatelet therapy following acute myocardial infarction. CMAJ 2011|2
04406|107|R|  Nov 8;183(16):1835-43.|2
04406|108|R|9.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
04406|109|R|  Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
04406|110|R|  antidepressants and the risk of overanticoagulation during acenocoumarol|2
04406|111|R|  maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
04407|001|T|MONOGRAPH TITLE:  Fluoxetine; Fluvoxamine/Ticlopidine|
04407|002|B||
04407|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04407|004|L|take action as needed.|
04407|005|B||
04407|006|A|MECHANISM OF ACTION:  Serotonin release by platelets plays a role in|
04407|007|A|hemostasis.(1,2)  The increased risk of bleeding may be a result of a|
04407|008|A|decrease in serotonin reuptake by platelets.|
04407|009|B||
04407|010|E|CLINICAL EFFECTS:  Concurrent use of a selective serotonin reuptake|
04407|011|E|inhibitor and ticlopidine may result in bleeding.|
04407|012|B||
04407|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04407|014|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
04407|015|P|impairment has been associated with an elevated risk of GI bleed in patients|
04407|016|P|on SSRIs.(3)|
04407|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
04407|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04407|019|P|risk for bleeding (e.g. NSAIDs).|
04407|020|B||
04407|021|M|PATIENT MANAGEMENT:  Selective serotonin reuptake inhibitors and agents that|
04407|022|M|affect coagulation should be used concurrently with caution.|
04407|023|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04407|024|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04407|025|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04407|026|M|patients with any symptoms.|
04407|027|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04407|028|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04407|029|M|anticoagulation in patients with active pathologic bleeding.|
04407|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04407|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04407|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04407|033|M|and/or swelling.|
04407|034|B||
04407|035|D|DISCUSSION:  In a retrospective review of 5 years of data from the|
04407|036|D|Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper|
04407|037|D|gastro-intestinal bleeding in antidepressant users were compared to those in|
04407|038|D|non-antidepressant users.  The risk of a bleed in a patient using an NSAID|
04407|039|D|only based on an observed-expected ration was 4.5 and in a patient using|
04407|040|D|low-dose aspirin only was 2.5.  Concurrent use of a selective serotonin|
04407|041|D|reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of|
04407|042|D|bleeding to 12.2 and 5.2, respectively.(4)|
04407|043|D|   In another study, there were 16 cases of upper gastrointestinal bleeding|
04407|044|D|in patients receiving concurrent therapy with selective serotonin reuptake|
04407|045|D|inhibitors and NSAIDs.  Adjusted relative risk of bleeding with NSAIDs,|
04407|046|D|selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6,|
04407|047|D|respectively.(5)|
04407|048|D|   In a case-control study conducted in users of acenocoumarol or|
04407|049|D|phenprocoumon, 1848 patients who had been hospitalized with abnormal|
04407|050|D|bleeding were each matched to 4 control patients.  When patients took both a|
04407|051|D|SSRI and a coumarin, an increased risk of hospitalization due to major|
04407|052|D|non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to|
04407|053|D|gastrointestinal bleeding (adjusted OR 0.8).(6)|
04407|054|D|   A retrospective review examined patients discharged from a hospital with|
04407|055|D|antiplatelet therapy following a myocardial infarction.  When compared to|
04407|056|D|aspirin therapy alone, both aspirin therapy with a SSRI and aspirin,|
04407|057|D|clopidogrel, and SSRI therapy were associated with an increased risk of|
04407|058|D|bleeding (hazard ratios 1.42 and 2.35, respectively.)  Compared with dual|
04407|059|D|antiplatelet therapy (aspirin and clopidogrel), use of aspirin and|
04407|060|D|clopidogrel and a SSRI was also associated with increased risk of bleeding|
04407|061|D|(hazard ration 1.57).(7)|
04407|062|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
04407|063|D|anticoagulation (hazard ratio 2.63).  Paroxetine was not associated with an|
04407|064|D|increased risk.  There were insufficient numbers of patients taking other|
04407|065|D|SSRIs to assess increased risk.(8)|
04407|066|B||
04407|067|R|REFERENCES:|
04407|068|B||
04407|069|R|1.Prozac (fluoxetine hydrochloride) US prescribing information. Eli Lilly|1
04407|070|R|  and Company August, 2023.|1
04407|071|R|2.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
04407|072|R|  Pharmaceuticals, Inc. August, 2023.|1
04407|073|R|3.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
04407|074|R|  Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
04407|075|R|  by level of kidney function: A population-based cohort study. Br J Clin|2
04407|076|R|  Pharmacol 2018 Sep;84(9):2142-2151.|2
04407|077|R|4.Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH.|2
04407|078|R|  Use of selective serotonin reuptake inhibitors and risk of upper|2
04407|079|R|  gastrointestinal tract bleeding: a population-based cohort study. Arch|2
04407|080|R|  Intern Med 2003 Jan 13;163(1):59-64.|2
04407|081|R|5.de Abajo FJ, Rodriguez LA, Montero D. Association between selective|2
04407|082|R|  serotonin reuptake inhibitors and upper gastrointestinal bleeding:|2
04407|083|R|  population based case-control study. BMJ 1999 Oct 23;319(7217):1106-9.|2
04407|084|R|6.Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding risk|2
04407|085|R|  with concurrent use of selective serotonin reuptake inhibitors and|2
04407|086|R|  coumarins. Arch Intern Med 2008 Jan 28;168(2):180-5.|2
04407|087|R|7.Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding|2
04407|088|R|  associated with combined use of selective serotonin reuptake inhibitors|2
04407|089|R|  and antiplatelet therapy following acute myocardial infarction. CMAJ 2011|2
04407|090|R|  Nov 8;183(16):1835-43.|2
04407|091|R|8.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
04407|092|R|  Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
04407|093|R|  antidepressants and the risk of overanticoagulation during acenocoumarol|2
04407|094|R|  maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
04408|001|T|MONOGRAPH TITLE:  Amlodipine; Levamlodipine/Slt Strong CYP3A4 Inhibit|
04408|002|B||
04408|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04408|004|L|take action as needed.|
04408|005|B||
04408|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the first-pass|
04408|007|A|and elimination metabolism of calcium channel blockers by CYP3A4.|
04408|008|B||
04408|009|E|CLINICAL EFFECTS:  The concurrent use of strong CYP3A4 inhibitors with|
04408|010|E|calcium channel blockers metabolized by CYP3A4 may result in elevated levels|
04408|011|E|of the calcium channel blocker and risk of adverse effects, including|
04408|012|E|hypotension and bradycardia.|
04408|013|B||
04408|014|P|PREDISPOSING FACTORS:  None determined.|
04408|015|B||
04408|016|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inhibitors with|
04408|017|M|calcium channel blockers should be approached with caution.  When these|
04408|018|M|agents are used concurrently, the dose of the calcium channel blocker may|
04408|019|M|need to be adjusted or an alternative agent considered.  Monitor patients|
04408|020|M|for increased calcium channel blocker effects.|
04408|021|M|   If the strong CYP3A4 inhibitor is discontinued, the dose of the calcium|
04408|022|M|channel blocker may need to be increased and patients should be observed for|
04408|023|M|decreased effects.|
04408|024|B||
04408|025|D|DISCUSSION:  Coadministration of a 180 mg dose of diltiazem (moderate CYP3A4|
04408|026|D|inhibitor) with 5 mg amlodipine resulted in a 60% increase in amlodipine|
04408|027|D|systemic exposure.  Strong inhibitor of CYP3A4 may increase plasma|
04408|028|D|concentrations of amlodipine to a greater extent.(1)|
04408|029|D|   In a study in 19 healthy subjects, telaprevir (750 mg every 8 hours for 7|
04408|030|D|days) increased the maximum concentration (Cmax) and area-under-curve (AUC)|
04408|031|D|of a single dose of amlodipine (5mg) by 1.27-fold and 2.79-fold,|
04408|032|D|respectively.(3)|
04408|033|D|   Strong CYP3A4 inhibitors include: adagrasib, ceritinib, clarithromycin,|
04408|034|D|cobicistat, fluconazole, idelalisib, indinavir, itraconazole, josamycin,|
04408|035|D|ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone,|
04408|036|D|nefazodone, nelfinavir, posaconazole, ribociclib, saquinavir, telithromycin,|
04408|037|D|tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5)|
04408|038|B||
04408|039|R|REFERENCES:|
04408|040|B||
04408|041|R|1.Norvasc (amlodipine) US Prescribing Information. Pfizer Labs October,|1
04408|042|R|  2017.|1
04408|043|R|2.Conjupri (levamlodipine) US prescribing information. CSPC Ouyi|1
04408|044|R|  Pharmaceutical Co., Ltd. December, 2019.|1
04408|045|R|3.Lee JE, van Heeswijk R, Alves K, Smith F, Garg V. Effect of the hepatitis|2
04408|046|R|  C virus protease inhibitor telaprevir on the pharmacokinetics of|2
04408|047|R|  amlodipine and atorvastatin. Antimicrob Agents Chemother 2011 Oct;|2
04408|048|R|  55(10):4569-74.|2
04408|049|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04408|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04408|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04408|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04408|053|R|  11/14/2017.|1
04408|054|R|5.This information is based on an extract from the Certara Drug Interaction|6
04408|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04409|001|T|MONOGRAPH TITLE:  Sotalol/Salmeterol|
04409|002|B||
04409|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04409|004|L|of severe adverse interaction.|
04409|005|B||
04409|006|A|MECHANISM OF ACTION:  Sotalol and salmeterol have been shown to prolong the|
04409|007|A|QTc interval. Concurrent use may result in additive effects on the QTc|
04409|008|A|interval.(1)|
04409|009|A|   Non-cardioselective beta-blockers and beta-2 agonists may antagonize the|
04409|010|A|effects of each other.|
04409|011|B||
04409|012|E|CLINICAL EFFECTS:  The concurrent use may result in potentially|
04409|013|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
04409|014|E|   Additionally, there may be diminished response to either the|
04409|015|E|beta-agonist, beta-blocker, or both may occur.  Beta-blockers may also|
04409|016|E|induce bronchospasm.|
04409|017|B||
04409|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation may be increased by|
04409|019|P|reduced creatinine clearance, female gender, larger doses of sotalol, and a|
04409|020|P|history of cardiomegaly or congestive heart failure.(1)  Risk may also be|
04409|021|P|increased in patients with cardiovascular disease (e.g. myocardial|
04409|022|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04409|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, or advanced age.(2)|
04409|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04409|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04409|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04409|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04409|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04409|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04409|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04409|031|P|   Patients receiving beta-2 agonists for the treatment of asthma may be|
04409|032|P|more at risk for bronchospasm.|
04409|033|B||
04409|034|M|PATIENT MANAGEMENT:  The manufacturer of sotalol states that concurrent use|
04409|035|M|with other agents known to prolong the QT interval is not recommended.(1)|
04409|036|M|   If possible, avoid beta-blocker therapy in asthmatic patients requiring|
04409|037|M|beta-2 agonist therapy.  If beta-blocker therapy is required, use a|
04409|038|M|cardio-selective beta-blocker.|
04409|039|M|   Monitor patients for decreased effects of either agent, such as increased|
04409|040|M|need for/use of beta-2 agonists or increased heart rate or blood pressure.|
04409|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04409|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04409|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04409|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04409|045|B||
04409|046|D|DISCUSSION:  Many patients with asymptomatic or mild reactive airways|
04409|047|D|disease tolerate beta-blockers well.  Most patients with COPD do not have|
04409|048|D|bronchospastic component to their illness and may be given beta-blockers.|
04409|049|D|Heart failure treatment guidelines recommend beta-blockers in the presence|
04409|050|D|of COPD.|
04409|051|D|   Non-selective beta-blockers have been shown to have a negative effect on|
04409|052|D|lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with|
04409|053|D|asthma and COPD.(3)|
04409|054|D|   An open-label study using the nonselective beta blocker nadolol showed no|
04409|055|D|effect on salbutamol in 10 patients with mild asthma not on controller|
04409|056|D|therapy.(4)|
04409|057|D|   A study in 8 healthy men showed that long acting propranolol (160 mg)|
04409|058|D|only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg|
04409|059|D|and 1600 mcg dose were unaffected. However, penbutolol prevented any|
04409|060|D|significant airway dilation with all doses of salbutamol.(5)|
04409|061|D|   In a double blind, three-way, crossover study, 44% (7/16 patients) of|
04409|062|D|patients taking metoprolol showed a greater than 20% decrease in FEV1|
04409|063|D|compared to 19% (3 patients) after dilevalol and 6% (1 patient) after|
04409|064|D|placebo. Dilevalol and metoprolol significantly inhibited isoproterenol|
04409|065|D|response compared to placebo.(6)|
04409|066|D|   A double-blind, randomized, crossover study in 10 asthmatic patients|
04409|067|D|showed that intravenous propranolol produced marked symptomatic|
04409|068|D|bronchoconstriction. Only a slight but significant inhibition of|
04409|069|D|bronchomotor sensitivity to isoproterenol was noted during esmolol|
04409|070|D|infusion.(7)|
04409|071|D|   In 18 patients with reversible bronchial asthma, labetalol caused a|
04409|072|D|significant increase in FEV1 and metoprolol caused a significant decrease in|
04409|073|D|FEV1. Concurrent administration of isoproterenol and labetalol caused a|
04409|074|D|further increase in FEV1. The effect of isoproterenol was decreased by|
04409|075|D|metoprolol (100, 200mg).(8)|
04409|076|D|   In one study propranolol (0.06mg/kg IV) was shown to almost completely|
04409|077|D|block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV)|
04409|078|D|did not affect isoproterenol.(9)|
04409|079|D|   Studies have shown that cardioselective beta-blockers are safe for|
04409|080|D|patients with asthma and COPD.(10,11,12)|
04409|081|D|   Nebivolol and celiprolol significantly decreased FEV1. Inhalation of|
04409|082|D|albuterol (up to 800mcg) significantly improved FEV1, but the values after|
04409|083|D|nebivolol and celiprolol administration were lower than the initial|
04409|084|D|values.(13)|
04409|085|D|   Administration of metoprolol did not cause any respiratory problems in 9|
04409|086|D|asthmatic patients. There was no significant difference between the|
04409|087|D|metoprolol and placebo groups in the respiratory response to an|
04409|088|D|isoproterenol aerosol in 24 asthmatic patients.(14)|
04409|089|D|   Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg|
04409|090|D|bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused|
04409|091|D|bronchoconstriction measured by a significant fall in PEFR (peak expiratory|
04409|092|D|flow rate).  Terbutaline was able to reverse bronchoconstriction in all|
04409|093|D|patients.(15)|
04409|094|D|   A double blind, placebo-controlled study analyzed the use of atenolol|
04409|095|D|100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before|
04409|096|D|and after exercise. All three drugs reduced significantly FEV1 and PEFR.|
04409|097|D|Administration of terbutaline improved all respiratory indices.(16)|
04409|098|D|   A double-blind crossover trial in 10 asthmatic patients showed that a|
04409|099|D|single IV dose of atenolol 3mg caused slight impairment of ventilatory|
04409|100|D|function.  A dose of salbutamol by inhalation was able to reverse the|
04409|101|D|bronchial effect of atenolol.(17)|
04409|102|D|   Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and|
04409|103|D|celiprolol 200mg/day were given to 10 asthmatic patients in a randomized,|
04409|104|D|crossover design with a two week washout period between each drug.  The|
04409|105|D|non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a|
04409|106|D|significant reduction in FEV1 and inhibited the bronchodilator response to|
04409|107|D|inhaled salbutamol.  Atenolol and celiprolol (beta1 selective beta blockers)|
04409|108|D|did not significantly affect respiratory function or antagonize salbutamol|
04409|109|D|effects.(18)|
04409|110|D|   A double blind, randomized, within patient, placebo-controlled study|
04409|111|D|compared the cardioselective beta-blocker atenolol to the non-selective|
04409|112|D|propranolol. Atenolol caused a significantly less drop in FEV1 compared to|
04409|113|D|propranolol. The effect of isoprenaline plus the beta blockers were also|
04409|114|D|studied. Both atenolol and propranolol effected isoprenaline FEV1 dose|
04409|115|D|response curves but the greatest displacement was seen with propranolol.(19)|
04409|116|D|   The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol|
04409|117|D|40mg, atenolol 100 mg were evaluated in 34 asthmatic patients.  Propranolol|
04409|118|D|and atenolol caused significant reductions in pulmonary function.|
04409|119|D|Propranolol pretreatment caused a significant reduction in the effect of the|
04409|120|D|bronchodilator. Celiprolol did not antagonize the bronchodilators.(20)|
04409|121|D|   A double-blind, placebo controlled, randomized, crossover design study|
04409|122|D|studied the effects of propranolol 80mg or celiprolol 200 or 400mg on|
04409|123|D|pulmonary function.  Propranolol produced a significant decrease in FEV1 and|
04409|124|D|FVC. Celiprolol and placebo had similar results. The effect of aerosolized|
04409|125|D|terbutaline was also measured.  Even at supratherapeutic doses, terbutaline|
04409|126|D|was unable to restore pulmonary function parameters to baseline levels after|
04409|127|D|treatment with propranolol.  Terbutaline caused further bronchodilation|
04409|128|D|after administration of celiprolol.(21)|
04409|129|D|   Eleven asthmatic patients showed significant bronchoconstriction in small|
04409|130|D|airways after propranolol 40mg and pindolol 2.5mg in a double blind,|
04409|131|D|randomized trial. Large airways only showed bronchoconstriction with|
04409|132|D|propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment|
04409|133|D|with propranolol and pindolol. The bronchodilator effect of terbutaline on|
04409|134|D|large airways was diminished after both propranolol and timolol.(22)|
04409|135|B||
04409|136|R|REFERENCES:|
04409|137|B||
04409|138|R|1.Betapace (sotalol hydrochloride) US prescribing information. Bayer|1
04409|139|R|  Healthcare Inc. June, 2021.|1
04409|140|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04409|141|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04409|142|R|  settings: a scientific statement from the American Heart Association and|6
04409|143|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04409|144|R|  2;55(9):934-47.|6
04409|145|R|3.van der Woude HJ, Zaagsma J, Postma DS, Winter TH, van Hulst M, Aalbers R.|6
04409|146|R|  Detrimental effects of beta-blockers in COPD: a concern for nonselective|6
04409|147|R|  beta-blockers. Chest 2005 Mar;127(3):818-24.|6
04409|148|R|4.Hanania NA, Mannava B, Franklin AE, Lipworth BJ, Williamson PA, Garner WJ,|2
04409|149|R|  Dickey BF, Bond RA. Response to salbutamol in patients with mild asthma|2
04409|150|R|  treated with nadolol. Eur Respir J 2010 Oct;36(4):963-5.|2
04409|151|R|5.Warren JB, Monaghan AT, Clark TJ. Effect of penbutolol and propranolol on|2
04409|152|R|  normal airway response to salbutamol. Clin Pharmacol Ther 1984 Jul;|2
04409|153|R|  36(1):47-50.|2
04409|154|R|6.Chodosh S, Tuck J, Blasucci DJ. The effects of dilevalol, metoprolol, and|2
04409|155|R|  placebo on ventilatory function in asthmatics. J Cardiovasc Pharmacol|2
04409|156|R|  1988;11 Suppl 2:S18-24.|2
04409|157|R|7.Sheppard D, DiStefano S, Byrd RC, Eschenbacher WL, Bell V, Steck J, Laddu|2
04409|158|R|  A. Effects of esmolol on airway function in patients with asthma. J Clin|2
04409|159|R|  Pharmacol 1986 Mar;26(3):169-74.|2
04409|160|R|8.Falliers CJ, Vincent ME, Medakovic M. Effect of single doses of labetalol,|2
04409|161|R|  metoprolol, and placebo on ventilatory function in patients with bronchial|2
04409|162|R|  asthma: interaction with isoproterenol. J Asthma 1986;23(5):251-60.|2
04409|163|R|9.Johnsson G, Svedmyr N, Thiringer G. Effects of intravenous propranolol and|2
04409|164|R|  metoprolol and their interaction with isoprenaline on pulmonary function,|2
04409|165|R|  heart rate and blood pressure in asthmatics. Eur J Clin Pharmacol 1975 Apr|2
04409|166|R|  4;8(3-4):175-80.|2
04409|167|R|10.Tafreshi MJ, Weinacker AB. Beta-adrenergic-blocking agents in|6
04409|168|R|   bronchospastic diseases: a therapeutic dilemma. Pharmacotherapy 1999 Aug;|6
04409|169|R|   19(8):974-8.|6
04409|170|R|11.Chafin CC, Soberman JE, Demirkan K, Self T. Beta-blockers after|6
04409|171|R|   myocardial infarction: do benefits ever outweigh risks in asthma?.|6
04409|172|R|   Cardiology 1999;92(2):99-105.|6
04409|173|R|12.Salpeter SR, Ormiston TM, Salpeter EE, Poole PJ, Cates CJ.|6
04409|174|R|   Cardioselective beta-blockers for chronic obstructive pulmonary disease:|6
04409|175|R|   a meta-analysis. Respir Med 2003 Oct;97(10):1094-101.|6
04409|176|R|13.Cazzola M, Noschese P, D'Amato M, D'Amato G. Comparison of the effects of|2
04409|177|R|   single oral doses of nebivolol and celiprolol on airways in patients with|2
04409|178|R|   mild asthma. Chest 2000 Nov;118(5):1322-6.|2
04409|179|R|14.Mue S, Sasaki T, Shibahara S, Takahashi M, Ohmi T, Yamauchi K, Suzuki S,|2
04409|180|R|   Hida W, Takishima T. Influence of metoprolol on hemodynamics and|2
04409|181|R|   respiratory function in asthmatic patients. Int J Clin Pharmacol Biopharm|2
04409|182|R|   1979 Aug;17(8):346-50.|2
04409|183|R|15.Lammers JW, Folgering HT, van Herwaarden CL. Respiratory tolerance of|2
04409|184|R|   bisoprolol and metoprolol in asthmatic patients. J Cardiovasc Pharmacol|2
04409|185|R|   1986;8 Suppl 11:S69-73.|2
04409|186|R|16.Greefhorst AP, van Herwaarden CL. Comparative study of the ventilatory|2
04409|187|R|   effects of three beta 1-selective blocking agents in asthmatic patients.|2
04409|188|R|   Eur J Clin Pharmacol 1981;20(6):417-21.|2
04409|189|R|17.Boye NP, Vale JR. Effect in bronchial asthma of a new beta-adrenergic|2
04409|190|R|   blocking drug atenolol (ICI 66, 082). Eur J Clin Pharmacol 1977;|2
04409|191|R|   11(1):11-4.|2
04409|192|R|18.Fogari R, Zoppi A, Tettamanti F, Poletti L, Rizzardi G, Fiocchi G.|2
04409|193|R|   Comparative effects of celiprolol, propranolol, oxprenolol, and atenolol|2
04409|194|R|   on respiratory function in hypertensive patients with chronic obstructive|2
04409|195|R|   lung disease. Cardiovasc Drugs Ther 1990 Aug;4(4):1145-9.|2
04409|196|R|19.Ellis ME, Sahay JN, Chatterjee SS, Cruickshank JM, Ellis SH.|2
04409|197|R|   Cardioselectivity of atenolol in asthmatic patients. Eur J Clin Pharmacol|2
04409|198|R|   1981;21(3):173-6.|2
04409|199|R|20.Doshan HD, Rosenthal RR, Brown R, Slutsky A, Applin WJ, Caruso FS.|2
04409|200|R|   Celiprolol, atenolol and propranolol: a comparison of pulmonary effects|2
04409|201|R|   in asthmatic patients. J Cardiovasc Pharmacol 1986;8 Suppl 4:S105-8.|2
04409|202|R|21.Matthys H, Doshan HD, Ruhle KH, Braig H, Pohl M, Applin WJ, Caruso FS,|2
04409|203|R|   Neiss ES. The bronchosparing effect of celiprolol, a new beta 1- alpha|2
04409|204|R|   2-receptor antagonist on pulmonary function of propranolol-sensitive|2
04409|205|R|   asthmatics. J Clin Pharmacol 1985 Jul-Aug;25(5):354-9.|2
04409|206|R|22.Brooks TW, Creekmore FM, Young DC, Asche CV, Oberg B, Samuelson WM. Rates|2
04409|207|R|   of hospitalizations and emergency department visits in patients with|2
04409|208|R|   asthma and chronic obstructive pulmonary disease taking beta-blockers.|2
04409|209|R|   Pharmacotherapy 2007 May;27(5):684-90.|2
04409|210|R|23.Boskabady MH, Snashall PD. Bronchial responsiveness to beta-adrenergic|2
04409|211|R|   stimulation and enhanced beta-blockade in asthma. Respirology 2000 Jun;|2
04409|212|R|   5(2):111-8.|2
04409|213|R|24.Patakas D, Argiropoulou V, Louridas G, Tsara V. Beta-blockers in|2
04409|214|R|   bronchial asthma: effect of propranolol and pindolol on large and small|2
04409|215|R|   airways. Thorax 1983 Feb;38(2):108-12.|2
04410|001|T|MONOGRAPH TITLE:  Salmeterol/Non-Cardioselective Beta-Blockers|
04410|002|B||
04410|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04410|004|L|of severe adverse interaction.|
04410|005|B||
04410|006|A|MECHANISM OF ACTION:  Non-cardioselective beta-blockers and beta-2 agonists|
04410|007|A|may antagonize the effects of each other.|
04410|008|B||
04410|009|E|CLINICAL EFFECTS:  Diminished response to either the beta-agonist,|
04410|010|E|beta-blocker, or both may occur.  Beta-blockers may also induce|
04410|011|E|bronchospasm.|
04410|012|B||
04410|013|P|PREDISPOSING FACTORS:  Patients receiving beta-2 agonists for the treatment|
04410|014|P|of asthma may be more at risk for bronchospasm.|
04410|015|B||
04410|016|M|PATIENT MANAGEMENT:  If possible, avoid beta-blocker therapy in asthmatic|
04410|017|M|patients requiring beta-2 agonist therapy.  If beta-blocker therapy is|
04410|018|M|required, use a cardio-selective beta-blocker.|
04410|019|M|   Monitor patients for decreased effects of either agent, such as increased|
04410|020|M|need for/use of beta-2 agonists or increased heart rate or blood pressure.|
04410|021|B||
04410|022|D|DISCUSSION:  Many patients with asymptomatic or mild reactive airways|
04410|023|D|disease tolerate beta-blockers well.  Most patients with COPD do not have|
04410|024|D|bronchospastic component to their illness and may be given beta-blockers.|
04410|025|D|Heart failure treatment guidelines recommend beta-blockers in the presence|
04410|026|D|of COPD.|
04410|027|D|   Non-selective beta-blockers have been shown to have a negative effect on|
04410|028|D|lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with|
04410|029|D|asthma and COPD.(1)|
04410|030|D|   An open-label study using the nonselective beta blocker nadolol showed no|
04410|031|D|effect on salbutamol in 10 patients with mild asthma not on controller|
04410|032|D|therapy.(2)|
04410|033|D|   A study in 8 healthy men showed that long acting propranolol (160 mg)|
04410|034|D|only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg|
04410|035|D|and 1600 mcg dose were unaffected. However, penbutolol prevented any|
04410|036|D|significant airway dilation with all doses of salbutamol.(3)|
04410|037|D|   In a double blind, three-way, crossover study, 44% (7/16 patients) of|
04410|038|D|patients taking metoprolol showed a greater than 20% decrease in FEV1|
04410|039|D|compared to 19% (3 patients) after dilevalol and 6% (1 patient) after|
04410|040|D|placebo. Dilevalol and metoprolol significantly inhibited isoproterenol|
04410|041|D|response compared to placebo.(4)|
04410|042|D|   A double-blind, randomized, crossover study in 10 asthmatic patients|
04410|043|D|showed that intravenous propranolol produced marked symptomatic|
04410|044|D|bronchoconstriction. Only a slight but significant inhibition of|
04410|045|D|bronchomotor sensitivity to isoproterenol was noted during esmolol|
04410|046|D|infusion.(5)|
04410|047|D|   In 18 patients with reversible bronchial asthma, labetalol caused a|
04410|048|D|significant increase in FEV1 and metoprolol caused a significant decrease in|
04410|049|D|FEV1. Concurrent administration of isoproterenol and labetalol caused a|
04410|050|D|further increase in FEV1. The effect of isoproterenol was decreased by|
04410|051|D|metoprolol (100, 200mg).(6)|
04410|052|D|   In one study propranolol (0.06mg/kg IV) was shown to almost completely|
04410|053|D|block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV)|
04410|054|D|did not affect isoproterenol.(7)|
04410|055|D|   Studies have shown that cardioselective beta-blockers are safe for|
04410|056|D|patients with asthma and COPD.(8,9,10)|
04410|057|D|   Nebivolol and celiprolol significantly decreased FEV1. Inhalation of|
04410|058|D|albuterol (up to 800mcg) significantly improved FEV1, but the values after|
04410|059|D|nebivolol and celiprolol administration were lower than the initial|
04410|060|D|values.(11)|
04410|061|D|   Administration of metoprolol did not cause any respiratory problems in 9|
04410|062|D|asthmatic patients. There was no significant difference between the|
04410|063|D|metoprolol and placebo groups in the respiratory response to an|
04410|064|D|isoproterenol aerosol in 24 asthmatic patients.(12)|
04410|065|D|   Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg|
04410|066|D|bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused|
04410|067|D|bronchoconstriction measured by a significant fall in PEFR (peak expiratory|
04410|068|D|flow rate).  Terbutaline was able to reverse bronchoconstriction in all|
04410|069|D|patients.(13)|
04410|070|D|   A double blind, placebo-controlled study analyzed the use of atenolol|
04410|071|D|100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before|
04410|072|D|and after exercise. All three drugs reduced significantly FEV1 and PEFR.|
04410|073|D|Administration of terbutaline improved all respiratory indices.(14)|
04410|074|D|   A double-blind crossover trial in 10 asthmatic patients showed that a|
04410|075|D|single IV dose of atenolol 3mg caused slight impairment of ventilatory|
04410|076|D|function.  A dose of salbutamol by inhalation was able to reverse the|
04410|077|D|bronchial effect of atenolol.(15)|
04410|078|D|   Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and|
04410|079|D|celiprolol 200mg/day were given to 10 asthmatic patients in a randomized,|
04410|080|D|crossover design with a two week washout period between each drug.  The|
04410|081|D|non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a|
04410|082|D|significant reduction in FEV1 and inhibited the bronchodilator response to|
04410|083|D|inhaled salbutamol.  Atenolol and celiprolol (beta1 selective beta blockers)|
04410|084|D|did not significantly affect respiratory function or antagonize salbutamol|
04410|085|D|effects.(16)|
04410|086|D|   A double blind, randomized, within patient, placebo-controlled study|
04410|087|D|compared the cardioselective beta-blocker atenolol to the non-selective|
04410|088|D|propranolol. Atenolol caused a significantly less drop in FEV1 compared to|
04410|089|D|propranolol. The effect of isoprenaline plus the beta blockers were also|
04410|090|D|studied. Both atenolol and propranolol effected isoprenaline FEV1 dose|
04410|091|D|response curves but the greatest displacement was seen with propranolol.(17)|
04410|092|D|   The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol|
04410|093|D|40mg, atenolol 100 mg were evaluated in 34 asthmatic patients.  Propranolol|
04410|094|D|and atenolol caused significant reductions in pulmonary function.|
04410|095|D|Propranolol pretreatment caused a significant reduction in the effect of the|
04410|096|D|bronchodilator. Celiprolol did not antagonize the bronchodilators.(18)|
04410|097|D|   A double-blind, placebo controlled, randomized, crossover design study|
04410|098|D|studied the effects of propranolol 80mg or celiprolol 200 or 400mg on|
04410|099|D|pulmonary function.  Propranolol produced a significant decrease in FEV1 and|
04410|100|D|FVC. Celiprolol and placebo had similar results. The effect of aerosolized|
04410|101|D|terbutaline was also measured.  Even at supratherapeutic doses, terbutaline|
04410|102|D|was unable to restore pulmonary function parameters to baseline levels after|
04410|103|D|treatment with propranolol.  Terbutaline caused further bronchodilation|
04410|104|D|after administration of celiprolol.(19)|
04410|105|D|   Eleven asthmatic patients showed significant bronchoconstriction in small|
04410|106|D|airways after propranolol 40mg and pindolol 2.5mg in a double blind,|
04410|107|D|randomized trial. Large airways only showed bronchoconstriction with|
04410|108|D|propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment|
04410|109|D|with propranolol and pindolol. The bronchodilator effect of terbutaline on|
04410|110|D|large airways was diminished after both propranolol and timolol.(20)|
04410|111|B||
04410|112|R|REFERENCES:|
04410|113|B||
04410|114|R|1.van der Woude HJ, Zaagsma J, Postma DS, Winter TH, van Hulst M, Aalbers R.|6
04410|115|R|  Detrimental effects of beta-blockers in COPD: a concern for nonselective|6
04410|116|R|  beta-blockers. Chest 2005 Mar;127(3):818-24.|6
04410|117|R|2.Hanania NA, Mannava B, Franklin AE, Lipworth BJ, Williamson PA, Garner WJ,|2
04410|118|R|  Dickey BF, Bond RA. Response to salbutamol in patients with mild asthma|2
04410|119|R|  treated with nadolol. Eur Respir J 2010 Oct;36(4):963-5.|2
04410|120|R|3.Warren JB, Monaghan AT, Clark TJ. Effect of penbutolol and propranolol on|2
04410|121|R|  normal airway response to salbutamol. Clin Pharmacol Ther 1984 Jul;|2
04410|122|R|  36(1):47-50.|2
04410|123|R|4.Chodosh S, Tuck J, Blasucci DJ. The effects of dilevalol, metoprolol, and|2
04410|124|R|  placebo on ventilatory function in asthmatics. J Cardiovasc Pharmacol|2
04410|125|R|  1988;11 Suppl 2:S18-24.|2
04410|126|R|5.Sheppard D, DiStefano S, Byrd RC, Eschenbacher WL, Bell V, Steck J, Laddu|2
04410|127|R|  A. Effects of esmolol on airway function in patients with asthma. J Clin|2
04410|128|R|  Pharmacol 1986 Mar;26(3):169-74.|2
04410|129|R|6.Falliers CJ, Vincent ME, Medakovic M. Effect of single doses of labetalol,|2
04410|130|R|  metoprolol, and placebo on ventilatory function in patients with bronchial|2
04410|131|R|  asthma: interaction with isoproterenol. J Asthma 1986;23(5):251-60.|2
04410|132|R|7.Johnsson G, Svedmyr N, Thiringer G. Effects of intravenous propranolol and|2
04410|133|R|  metoprolol and their interaction with isoprenaline on pulmonary function,|2
04410|134|R|  heart rate and blood pressure in asthmatics. Eur J Clin Pharmacol 1975 Apr|2
04410|135|R|  4;8(3-4):175-80.|2
04410|136|R|8.Tafreshi MJ, Weinacker AB. Beta-adrenergic-blocking agents in|6
04410|137|R|  bronchospastic diseases: a therapeutic dilemma. Pharmacotherapy 1999 Aug;|6
04410|138|R|  19(8):974-8.|6
04410|139|R|9.Chafin CC, Soberman JE, Demirkan K, Self T. Beta-blockers after myocardial|6
04410|140|R|  infarction: do benefits ever outweigh risks in asthma?. Cardiology 1999;|6
04410|141|R|  92(2):99-105.|6
04410|142|R|10.Salpeter SR, Ormiston TM, Salpeter EE, Poole PJ, Cates CJ.|6
04410|143|R|   Cardioselective beta-blockers for chronic obstructive pulmonary disease:|6
04410|144|R|   a meta-analysis. Respir Med 2003 Oct;97(10):1094-101.|6
04410|145|R|11.Cazzola M, Noschese P, D'Amato M, D'Amato G. Comparison of the effects of|2
04410|146|R|   single oral doses of nebivolol and celiprolol on airways in patients with|2
04410|147|R|   mild asthma. Chest 2000 Nov;118(5):1322-6.|2
04410|148|R|12.Mue S, Sasaki T, Shibahara S, Takahashi M, Ohmi T, Yamauchi K, Suzuki S,|2
04410|149|R|   Hida W, Takishima T. Influence of metoprolol on hemodynamics and|2
04410|150|R|   respiratory function in asthmatic patients. Int J Clin Pharmacol Biopharm|2
04410|151|R|   1979 Aug;17(8):346-50.|2
04410|152|R|13.Lammers JW, Folgering HT, van Herwaarden CL. Respiratory tolerance of|2
04410|153|R|   bisoprolol and metoprolol in asthmatic patients. J Cardiovasc Pharmacol|2
04410|154|R|   1986;8 Suppl 11:S69-73.|2
04410|155|R|14.Greefhorst AP, van Herwaarden CL. Comparative study of the ventilatory|2
04410|156|R|   effects of three beta 1-selective blocking agents in asthmatic patients.|2
04410|157|R|   Eur J Clin Pharmacol 1981;20(6):417-21.|2
04410|158|R|15.Boye NP, Vale JR. Effect in bronchial asthma of a new beta-adrenergic|2
04410|159|R|   blocking drug atenolol (ICI 66, 082). Eur J Clin Pharmacol 1977;|2
04410|160|R|   11(1):11-4.|2
04410|161|R|16.Fogari R, Zoppi A, Tettamanti F, Poletti L, Rizzardi G, Fiocchi G.|2
04410|162|R|   Comparative effects of celiprolol, propranolol, oxprenolol, and atenolol|2
04410|163|R|   on respiratory function in hypertensive patients with chronic obstructive|2
04410|164|R|   lung disease. Cardiovasc Drugs Ther 1990 Aug;4(4):1145-9.|2
04410|165|R|17.Ellis ME, Sahay JN, Chatterjee SS, Cruickshank JM, Ellis SH.|2
04410|166|R|   Cardioselectivity of atenolol in asthmatic patients. Eur J Clin Pharmacol|2
04410|167|R|   1981;21(3):173-6.|2
04410|168|R|18.Doshan HD, Rosenthal RR, Brown R, Slutsky A, Applin WJ, Caruso FS.|2
04410|169|R|   Celiprolol, atenolol and propranolol: a comparison of pulmonary effects|2
04410|170|R|   in asthmatic patients. J Cardiovasc Pharmacol 1986;8 Suppl 4:S105-8.|2
04410|171|R|19.Matthys H, Doshan HD, Ruhle KH, Braig H, Pohl M, Applin WJ, Caruso FS,|2
04410|172|R|   Neiss ES. The bronchosparing effect of celiprolol, a new beta 1- alpha|2
04410|173|R|   2-receptor antagonist on pulmonary function of propranolol-sensitive|2
04410|174|R|   asthmatics. J Clin Pharmacol 1985 Jul-Aug;25(5):354-9.|2
04410|175|R|20.Brooks TW, Creekmore FM, Young DC, Asche CV, Oberg B, Samuelson WM. Rates|2
04410|176|R|   of hospitalizations and emergency department visits in patients with|2
04410|177|R|   asthma and chronic obstructive pulmonary disease taking beta-blockers.|2
04410|178|R|   Pharmacotherapy 2007 May;27(5):684-90.|2
04410|179|R|21.Boskabady MH, Snashall PD. Bronchial responsiveness to beta-adrenergic|2
04410|180|R|   stimulation and enhanced beta-blockade in asthma. Respirology 2000 Jun;|2
04410|181|R|   5(2):111-8.|2
04410|182|R|22.Patakas D, Argiropoulou V, Louridas G, Tsara V. Beta-blockers in|2
04410|183|R|   bronchial asthma: effect of propranolol and pindolol on large and small|2
04410|184|R|   airways. Thorax 1983 Feb;38(2):108-12.|2
04411|001|T|MONOGRAPH TITLE:  Meperidine/Selected CYP3A4 Inhibitors|
04411|002|B||
04411|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04411|004|L|of severe adverse interaction.|
04411|005|B||
04411|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04411|007|A|meperidine.|
04411|008|B||
04411|009|E|CLINICAL EFFECTS:  The concurrent administration of a CYP3A4 inhibitor may|
04411|010|E|result in elevated levels of and toxicity from meperidine, including|
04411|011|E|profound sedation, respiratory depression, coma, and/or death.|
04411|012|B||
04411|013|P|PREDISPOSING FACTORS:  None determined.|
04411|014|B||
04411|015|M|PATIENT MANAGEMENT:  If concomitant use is necessary, consider dose|
04411|016|M|reduction of meperidine until stable drug effects are achieved. Monitor|
04411|017|M|patients for respiratory depression and sedation at frequent intervals.(1)|
04411|018|M|   If the CYP3A4 inhibitor is discontinued, consider increasing the|
04411|019|M|meperidine dose until stable drug effects are achieved.  Monitor for signs|
04411|020|M|of opioid withdrawal.(1)|
04411|021|M|   The Australian manufacturer of nirmatrelvir/ritonavir contraindicates|
04411|022|M|co-administration with meperidine.(2)|
04411|023|M|    Respiratory depression can occur at any time during opioid therapy,|
04411|024|M|especially during therapy initiation and following dosage increases.  The|
04411|025|M|risk of opioid-related overdose or overdose-related death is increased with|
04411|026|M|higher opioid doses, and this risk persists over the course of therapy.|
04411|027|M|Consider these risks when using concurrently with other agents that may|
04411|028|M|cause CNS depression.(3)|
04411|029|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04411|030|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04411|031|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04411|032|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04411|033|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04411|034|M|as those taking CNS depressants) and when a patient has household|
04411|035|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04411|036|M|for obtaining an opioid reversal agent (e.g., prescription,|
04411|037|M|over-the-counter, or as part of a community-based program).(4)|
04411|038|B||
04411|039|D|DISCUSSION:  Plasma concentrations of the active metabolite normeperidine|
04411|040|D|may be increased by ritonavir (strong CYP3A4 inhibitor).(1)|
04411|041|D|   Strong CYP3A4 inhibitors that would be expected to interact with|
04411|042|D|meperidine include:  boceprevir, clarithromycin, cobicistat, elvitegravir,|
04411|043|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib,|
04411|044|D|lopinavir, mibefradil, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
04411|045|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04411|046|D|troleandomycin, tucatinib, voriconazole.(5)|
04411|047|D|   Moderate CYP3A4 inhibitors include:  erythromycin and fluconazole.(5)|
04411|048|B||
04411|049|R|REFERENCES:|
04411|050|B||
04411|051|R|1.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
04411|052|R|  Pharmaceuticals LLC. December, 2023.|1
04411|053|R|2.Paxlovid (nirmatrelvir-ritonavir) Australian Product Information. Pfizer|1
04411|054|R|  Australia Pty Ltd February 28, 2025.|1
04411|055|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04411|056|R|  prescribing information for all opioid pain medicines to provide|1
04411|057|R|  additional guidance for safe use. Available at:|1
04411|058|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04411|059|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04411|060|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04411|061|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04411|062|R|  recommends health care professionals discuss naloxone with all patients|1
04411|063|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04411|064|R|  disorder. Available at:|1
04411|065|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04411|066|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04411|067|R|  d-pain July 23, 2020.|1
04411|068|R|5.This information is based on an extract from the Certara Drug Interaction|6
04411|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04412|001|T|MONOGRAPH TITLE:  Nefazodone/Tramadol|
04412|002|B||
04412|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04412|004|L|take action as needed.|
04412|005|B||
04412|006|A|MECHANISM OF ACTION:  Tramadol inhibits the reuptake of serotonin.(1)|
04412|007|A|Metabolism of nefazodone leads to formation of a common active metabolite,|
04412|008|A|m-chlorophenylpiperazine (mCPP) which is an agonist at a variety of|
04412|009|A|serotonin receptors.(2-3)|
04412|010|A|   Both tramadol and mCPP are metabolized by CYP2D6.(1,3-5)|
04412|011|B||
04412|012|E|CLINICAL EFFECTS:  Concurrent administration could increase the risk for|
04412|013|E|serotonin syndrome.  Symptoms of serotonin syndrome may include tremor,|
04412|014|E|agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia,|
04412|015|E|and muscle rigidity.(6)|
04412|016|B||
04412|017|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04412|018|P|systemic concentrations of tramadol or mCPP would be predicted to increase|
04412|019|P|risk for serotonin toxicity.  Concomitant therapy with other agents which|
04412|020|P|increase brain serotonin concentrations may also increase risk.(1,2,6)|
04412|021|P|   Renal dysfunction and chronic use of meperidine would be expected to|
04412|022|P|increase the risk for serotonin toxicity due to meperidine.|
04412|023|P|   Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion,|
04412|024|P|cinacalcet, duloxetine, fluoxetine, paroxetine, quinidine, or systemic|
04412|025|P|terbinafine) may also increase mCPP and tramadol concentrations, increasing|
04412|026|P|risk for serotonin toxicity.|
04412|027|P|   Patients who are poor metabolizers at CYP2D6 would be expected to have|
04412|028|P|higher tramadol and mCPP concentrations compared with extensive|
04412|029|P|metabolizers.(1)|
04412|030|B||
04412|031|M|PATIENT MANAGEMENT:  Assess patient for predisposing risk factors and|
04412|032|M|monitor accordingly.  The manufacturer of tramadol recommends careful|
04412|033|M|monitoring for signs and symptoms of serotonin syndrome when a metabolic|
04412|034|M|inhibitor or another serotoninergic agent is started, or when the dose of|
04412|035|M|either agent is increased.(1)|
04412|036|B||
04412|037|D|DISCUSSION:  Nefazodone and tramadol have each been associated with|
04412|038|D|serotonin syndrome when given concurrently with one or more serotoninergic|
04412|039|D|agents.(1-2)|
04412|040|D|   MCPP has been associated with serotonin syndrome when used as a probe of|
04412|041|D|central serotonin function in human investigational studies.(7)|
04412|042|D|   Nefazodone has several active metabolites, including mCCP. Although|
04412|043|D|systemic mCPP concentrations are low relative to nefazodone concentrations,|
04412|044|D|in animal studies the ratio of brain:blood concentrations for mCPP to|
04412|045|D|nefazodone were 47:1 and 10:1 in the mouse and rat respectively.(3)|
04412|046|B||
04412|047|R|REFERENCES:|
04412|048|B||
04412|049|R|1.Ultram (tramadol) US prescribing information. Janssen Pharmaceutical, Inc.|1
04412|050|R|  October, 2019.|1
04412|051|R|2.Serzone (nefazodone hydrochloride) US prescribing information.|1
04412|052|R|  Bristol-Myers Squibb Company January, 2005.|1
04412|053|R|3.Schatzberg Alan F and Nemeroff  Charles B (editors). Chapter 19 Trazodone|6
04412|054|R|  and Nefazodone. American Psychiatric Press Textbook of Psychopharmacology,|6
04412|055|R|  3rd ed. 2004.|6
04412|056|R|4.Wen B, Ma L, Rodrigues AD, Zhu M. Detection of novel reactive metabolites|5
04412|057|R|  of trazodone: evidence for CYP2D6-mediated bioactivation of|5
04412|058|R|  m-chlorophenylpiperazine. Drug Metab Dispos 2008 May;36(5):841-50.|5
04412|059|R|5.Kast RE. Trazodone generates m-CPP: in 2008 risks from m-CPP might|6
04412|060|R|  outweigh benefits of trazodone. World J Biol Psychiatry 2009;10(4 Pt|6
04412|061|R|  2):682-5.|6
04412|062|R|6.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04412|063|R|  352(11):1112-20.|6
04412|064|R|7.Kovaleva J, Devuyst E, De Paepe P, Verstraete A. Acute|3
04412|065|R|  chlorophenylpiperazine overdose: a case report and review of the|3
04412|066|R|  literature. Ther Drug Monit 2008 Jun;30(3):394-8.|3
04413|001|T|MONOGRAPH TITLE:  Meperidine/Serotonergic CYP3A4 Inhibitors|
04413|002|B||
04413|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04413|004|L|of severe adverse interaction.|
04413|005|B||
04413|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors such as fluvoxamine and nefazodone|
04413|007|A|may inhibit the metabolism of meperidine.(1-3)|
04413|008|A|   Meperidine inhibits the reuptake of serotonin.(1)  Fluvoxamine and|
04413|009|A|nefazodone also inhibit the reuptake of serotonin.(2,3)|
04413|010|B||
04413|011|E|CLINICAL EFFECTS:  Concurrent administration may result in elevated levels|
04413|012|E|of and toxicity from meperidine.(1)|
04413|013|E|   Concurrent administration could also increase the risk for serotonin|
04413|014|E|syndrome.  Symptoms of serotonin syndrome may include tremor, agitation,|
04413|015|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04413|016|E|rigidity.(4)|
04413|017|B||
04413|018|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04413|019|P|systemic concentrations of meperidine would be predicted to increase risk|
04413|020|P|for serotonin toxicity.  Concomitant therapy with other agents which|
04413|021|P|increase brain serotonin concentrations may also increase risk.(1-4)|
04413|022|P|   Renal dysfunction and chronic use of meperidine would be expected to|
04413|023|P|increase the risk for serotonin toxicity due to meperidine.(1)|
04413|024|B||
04413|025|M|PATIENT MANAGEMENT:  If concomitant use is necessary, consider dose|
04413|026|M|reduction of meperidine until stable drug effects are achieved. Monitor|
04413|027|M|patients for respiratory depression and sedation at frequent intervals.(1)|
04413|028|M|   If the CYP3A4 inhibitor is discontinued, consider increasing the|
04413|029|M|meperidine dose until stable drug effects are achieved.  Monitor for signs|
04413|030|M|of opioid withdrawal.(1)|
04413|031|M|   Respiratory depression can occur at any time during opioid therapy,|
04413|032|M|especially during therapy initiation and following dosage increases.  The|
04413|033|M|risk of opioid-related overdose or overdose-related death is increased with|
04413|034|M|higher opioid doses, and this risk persists over the course of therapy.|
04413|035|M|Consider these risks when using concurrently with other agents that may|
04413|036|M|cause CNS depression.(5)|
04413|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04413|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04413|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04413|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04413|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04413|042|M|as those taking CNS depressants) and when a patient has household|
04413|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04413|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
04413|045|M|over-the-counter, or as part of a community-based program).(6)|
04413|046|M|   Assess patient for predisposing risk factors of serotonin syndrome and|
04413|047|M|monitor accordingly.  The manufacturer of meperidine recommends careful|
04413|048|M|monitoring for signs and symptoms of serotonin syndrome when a metabolic|
04413|049|M|inhibitor or another serotoninergic agent is started, or when the dose of|
04413|050|M|either agent is increased.(1-4)|
04413|051|B||
04413|052|D|DISCUSSION:  Plasma concentrations of the active metabolite normeperidine|
04413|053|D|may be increased by ritonavir (strong CYP3A4 inhibitor).(1)|
04413|054|B||
04413|055|R|REFERENCES:|
04413|056|B||
04413|057|R|1.Demerol (meperidine hydrochloride) US prescribing information. Validus|1
04413|058|R|  Pharmaceuticals LLC. December, 2023.|1
04413|059|R|2.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
04413|060|R|  Pharmaceuticals, Inc. August, 2023.|1
04413|061|R|3.Serzone (nefazodone hydrochloride) US prescribing information.|1
04413|062|R|  Bristol-Myers Squibb Company January, 2005.|1
04413|063|R|4.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04413|064|R|  352(11):1112-20.|6
04413|065|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04413|066|R|  prescribing information for all opioid pain medicines to provide|1
04413|067|R|  additional guidance for safe use. Available at:|1
04413|068|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04413|069|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04413|070|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04413|071|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04413|072|R|  recommends health care professionals discuss naloxone with all patients|1
04413|073|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04413|074|R|  disorder. Available at:|1
04413|075|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04413|076|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04413|077|R|  d-pain July 23, 2020.|1
04414|001|T|MONOGRAPH TITLE:  Berotralstat/Voclosporin (mono deleted 02/15/2024)|
04414|002|B||
04414|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04414|004|L|of severe adverse interaction.|
04414|005|B||
04414|006|A|MECHANISM OF ACTION:  Berotralstat, a moderate CYP3A4 inhibitor, may inhibit|
04414|007|A|the metabolism of voclosporin.(1)  Voclosporin, a P-gp inhibitor, may|
04414|008|A|increase the absorption of berotralstat.(2)|
04414|009|B||
04414|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04414|011|E|levels of and effects from voclosporin, including infection, neurotoxicity,|
04414|012|E|nephrotoxicity, hypertension, or hyperkalemia.(1)|
04414|013|E|   The concurrent administration of berotralstat with an inhibitor of|
04414|014|E|P-glycoprotein may result in elevated levels of berotralstat.(2)|
04414|015|B||
04414|016|P|PREDISPOSING FACTORS:  None determined.|
04414|017|B||
04414|018|M|PATIENT MANAGEMENT:  The magnitude of effect of the two-way inhibition of|
04414|019|M|the metabolism of voclosporin and berotralstat is unknown.  The optimal|
04414|020|M|doses of voclosporin and berotralstat when used concurrently have not been|
04414|021|M|determined.  Manufacturers provide recommendations for dose modification of|
04414|022|M|voclosporin when used with a moderate CYP3A4 inhibitor and berotralstat when|
04414|023|M|used with a P-gp inhibitor, but the recommendations may not apply when there|
04414|024|M|is a two-way inhibition.  Dose modifications mentioned below are|
04414|025|M|informational only.|
04414|026|M|   The prescribing information for voclosporin states the use of moderate|
04414|027|M|CYP3A4 inhibitors in patients undergoing therapy with voclosporin requires a|
04414|028|M|dose adjustment.  Voclosporin dose should be reduced to 15.8 mg in the|
04414|029|M|morning and 7.9 mg in the evening.(1)  Consider alternatives with no or|
04414|030|M|minimal enzyme inhibition.|
04414|031|M|   The manufacturer of berotralstat recommends a dose of 110 mg once daily|
04414|032|M|of berotralstat when coadministered chronically with P-gp inhibitors.(2)|
04414|033|B||
04414|034|D|DISCUSSION:  Concurrent use of voclosporin and ketoconazole 400 mg daily|
04414|035|D|(strong CYP3A4 inhibitor) for 9 days increased the concentration maximum|
04414|036|D|(Cmax) and area-under-curve (AUC) by 6.45-fold and 18.55-fold,|
04414|037|D|respectively.(1)|
04414|038|D|   Concurrent use of voclosporin and verapamil 80 mg three times a day for|
04414|039|D|10 days (moderate CYP3A4 inhibitor and P-gp inhibitor) increased Cmax and|
04414|040|D|AUC by 2.08-fold and 2.71-fold, respectively.(1)|
04414|041|D|   Berotralstat is a substrate of P-gp and BCRP transporters.  Use of P-gp|
04414|042|D|or BCRP inhibitors may increase the exposure of berotralstat. The US|
04414|043|D|manufacturer of berotralstat recommends dose adjustment if berotralstat is|
04414|044|D|coadministered with P-gp or BCRP inhibitors.(2)|
04414|045|D|   Administration of cyclosporine, a P-gp and BCRP inhibitor, with|
04414|046|D|berotralstat, increased berotralstat Cmax and area-under-the-curve(0-last)|
04414|047|D|(AUC 0-last), area-under-the-curve(0-inf) (AUC 0-inf) by 25%, 55%, and|
04414|048|D|69%.(2)|
04414|049|B||
04414|050|R|REFERENCES:|
04414|051|B||
04414|052|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
04414|053|R|  April, 2024.|1
04414|054|R|2.Orladeyo (berotralstat) US prescribing information. BioCryst|1
04414|055|R|  Pharmaceuticals, Inc. November 2023.|1
04414|056|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04414|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04414|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04414|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04414|060|R|  11/14/2017.|1
04414|061|R|4.This information is based on an extract from the Certara Drug Interaction|6
04414|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04415|001|T|MONOGRAPH TITLE:  Pazopanib/Encorafenib|
04415|002|B||
04415|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04415|004|L|of severe adverse interaction.|
04415|005|B||
04415|006|A|MECHANISM OF ACTION:  Encorafenib is a strong CYP3A4 inducer and a BCRP|
04415|007|A|inhibitor.(1)  Pazopanib is a CYP3A4 and BCRP substrate.(2)  Encorafenib may|
04415|008|A|induce the metabolism and increase the absorption of pazopanib.  Also, an|
04415|009|A|additive risk of QT prolongation may result from concurrent use of two|
04415|010|A|agents that prolong the QT interval.(1,2)|
04415|011|B||
04415|012|E|CLINICAL EFFECTS:  The net effect of this interaction is unknown.|
04415|013|E|Concurrent use of strong CYP3A4 inducers with pazopanib may result in|
04415|014|E|decreased levels and effectiveness of pazopanib while concurrent use of|
04415|015|E|other agents that prolong the QTc interval and inhibit BCRP may result in|
04415|016|E|elevated levels of pazopanib, signs of toxicity, and potentially|
04415|017|E|life-threatening cardiac arrhythmias, including torsades de pointes.(2)|
04415|018|B||
04415|019|P|PREDISPOSING FACTORS:  CYP3A4 induction effects may be more likely with|
04415|020|P|regular use of the inducer for longer than 1-2 weeks.|
04415|021|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04415|022|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04415|023|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
04415|024|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04415|025|P|advanced age.(3)|
04415|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04415|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04415|028|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04415|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04415|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04415|031|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04415|032|P|dysfunction).(3)|
04415|033|B||
04415|034|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pazopanib and|
04415|035|M|encorafenib.(1,2)|
04415|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04415|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04415|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04415|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04415|040|B||
04415|041|D|DISCUSSION:  Encorafenib 450 mg daily decreased the area-under-curve (AUC)|
04415|042|D|and maximum concentration (Cmax) of midazolam 2 mg, a sensitive CYP3A4|
04415|043|D|substrate, by 82% and 74%, respectively.(1)|
04415|044|D|   Encorafenib 450 mg daily increased the AUC and Cmax of single-dose|
04415|045|D|rosuvastatin, a BCRP substrate, by 1.6-fold and 2.7-fold, respectively.(1)|
04415|046|D|   Administration of 1,500 mg lapatinib, a substrate and weak inhibitor of|
04415|047|D|CYP3A4, P-gp, and BCRP, with 800 mg pazopanib resulted in an approximately|
04415|048|D|50% to 60% increase in mean pazopanib AUC and Cmax compared with|
04415|049|D|administration of 800 mg pazopanib alone.(2)|
04415|050|D|   In a study of adult patients with melanoma who received the recommended|
04415|051|D|dose of encorafenib in combination with binimetinib, the largest mean QTcF|
04415|052|D|change (90% CI) from baseline was 18 (14 to 22) ms.(1)|
04415|053|D|   In clinical studies, 2% (11/558) of patients receiving pazopanib|
04415|054|D|experienced QT prolongation.  Torsades de pointes occurred in less than 1%|
04415|055|D|(2/977) of patients who received pazopanib in monotherapy studies.  In a|
04415|056|D|randomized clinical trial, 3 of 290 patients who received pazopanib had|
04415|057|D|post-baseline QTc values between 500 and 549 msec.  None of the patients|
04415|058|D|receiving placebo had post-baseline QTc values greater than or equal to 500|
04415|059|D|msec.(2)|
04415|060|D|   A retrospective review of 618 cancer patients treated with 902|
04415|061|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
04415|062|D|incidence of QTc prolongation.  In patients who received pazopanib, QTc|
04415|063|D|prolongation was identified in 32 patients (19.4%) with 18 patients (56.3%)|
04415|064|D|having Grade 1 (QTc 450-480 ms) and 4 patients (12.5%) having Grade 2 (QTc|
04415|065|D|480-500 ms) events.  Grade 3 events occurred in 3 patients (9.3%) having QTc|
04415|066|D|greater than or equal to 500 ms and 4 patients (12.5%) having QTc changes|
04415|067|D|greater than or equal to 60 ms.  Ventricular tachycardia was seen in 2|
04415|068|D|patients (6.3%) and 1 patient (3.1%) experienced sudden cardiac death.(4)|
04415|069|B||
04415|070|R|REFERENCES:|
04415|071|B||
04415|072|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
04415|073|R|  BioPharma December, 2024.|1
04415|074|R|2.Votrient (pazopanib) US prescribing information. GlaxoSmithKline August,|1
04415|075|R|  2020.|1
04415|076|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04415|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04415|078|R|  settings: a scientific statement from the American Heart Association and|6
04415|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04415|080|R|  2;55(9):934-47.|6
04415|081|R|4.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
04415|082|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
04415|083|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
04416|001|T|MONOGRAPH TITLE:  Reboxetine/Strong CYP3A4 Inhibitors|
04416|002|B||
04416|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04416|004|L|of severe adverse interaction.|
04416|005|B||
04416|006|A|MECHANISM OF ACTION:  Reboxetine is primarily metabolized by CYP3A4.  Strong|
04416|007|A|inhibitors of CYP3A4 may inhibit the metabolism of reboxetine.(1,2)|
04416|008|B||
04416|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04416|010|E|the levels and effects of reboxetine, including hypertension, tachycardia,|
04416|011|E|orthostasis, and urinary retention.(1,2)|
04416|012|B||
04416|013|P|PREDISPOSING FACTORS:  None determined.|
04416|014|B||
04416|015|M|PATIENT MANAGEMENT:  The UK prescribing information states that reboxetine|
04416|016|M|should not be given with drugs known to inhibit CYP3A4.(1)|
04416|017|B||
04416|018|D|DISCUSSION:  In healthy volunteers, ketoconazole 200 mg daily with single|
04416|019|D|dose reboxetine 4 mg increased R,R(-)-reboxetine and S,S(+)-reboxetine|
04416|020|D|area-under-curve (AUC) by 58% and 43%, respectively.  Half life increased|
04416|021|D|significantly but maximum concentration (Cmax) did not change, which the|
04416|022|D|authors postulated was the reason for lack of increased side effects. The|
04416|023|D|authors recommended caution and considering reboxetine dose reduction.(3)|
04416|024|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04416|025|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04416|026|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
04416|027|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04416|028|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04416|029|D|troleandomycin, tucatinib, and voriconazole.(4,5)|
04416|030|B||
04416|031|R|REFERENCES:|
04416|032|B||
04416|033|R|1.Edronax (reboxetine) UK Summary of Product Characteristics. Pfizer Limited|1
04416|034|R|  February 24, 2022.|1
04416|035|R|2.Edronax (reboxetine mesylate) Australian prescribing information. Pfizer|1
04416|036|R|  Australia Pty Ltd. November 8, 2022.|1
04416|037|R|3.Herman BD, Fleishaker JC, Brown MT. Ketoconazole inhibits the clearance of|2
04416|038|R|  the enantiomers of the antidepressant  reboxetine in humans. Clin|2
04416|039|R|  Pharmacol Ther 1999 Oct;66(4):374-9.|2
04416|040|R|4.This information is based on an extract from the Certara Drug Interaction|6
04416|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04416|042|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04416|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04416|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04416|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04416|046|R|  11/14/2017.|1
04417|001|T|MONOGRAPH TITLE:  Ofloxacin/QT Prolonging Agents|
04417|002|B||
04417|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04417|004|L|take action as needed.|
04417|005|B||
04417|006|A|MECHANISM OF ACTION:  Ofloxacin has been shown to prolong the QTc interval.|
04417|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
04417|008|A|additive effects on the QTc interval.(1,2)|
04417|009|B||
04417|010|E|CLINICAL EFFECTS:  The concurrent use of ofloxacin with other agents that|
04417|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04417|012|E|arrhythmias, including torsades de pointes.(1,2)|
04417|013|B||
04417|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04417|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04417|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04417|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04417|018|P|gender, or advanced age.(3)|
04417|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04417|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04417|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04417|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04417|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04417|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04417|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04417|026|B||
04417|027|M|PATIENT MANAGEMENT:  The manufacturer of ofloxacin states that ofloxacin|
04417|028|M|should be used with caution when given with other agents known to prolong|
04417|029|M|the QT interval.(1,2)|
04417|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04417|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04417|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04417|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04417|034|B||
04417|035|D|DISCUSSION:  A retrospective database analysis identified case reports of|
04417|036|D|torsades de pointes with ofloxacin.(4)|
04417|037|D|   Clinical practice guidelines on the use of systemic fluoroquinolones|
04417|038|D|categorize agents into three groups based on the associated risk of QT|
04417|039|D|prolongation.  Ofloxacin is included in group 2: fluoroquinolones associated|
04417|040|D|with a low risk of QT prolongation.  Other fluoroquinolones in group 2|
04417|041|D|include levofloxacin and norfloxacin.(5)|
04417|042|D|   Agents that are linked to this monograph may have varying degrees of|
04417|043|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04417|044|D|been shown to prolong the QTc interval either through their mechanism of|
04417|045|D|action, through studies on their effects on the QTc interval, or through|
04417|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04417|047|D|and/or postmarketing reports.(6)|
04417|048|B||
04417|049|R|REFERENCES:|
04417|050|B||
04417|051|R|1.Ofloxacin US prescribing information. Nivagen Pharmaceuticals, Inc. July,|1
04417|052|R|  2023.|1
04417|053|R|2.Ofloxacin tablets UK summary of product characteristics. Mylan December,|1
04417|054|R|  2022.|1
04417|055|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04417|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04417|057|R|  settings: a scientific statement from the American Heart Association and|6
04417|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04417|059|R|  2;55(9):934-47.|6
04417|060|R|4.Frothingham R. Rates of torsades de pointes associated with ciprofloxacin,|2
04417|061|R|  ofloxacin,  levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy|2
04417|062|R|  2001 Dec;21(12):1468-72.|2
04417|063|R|5.Chidiac C. Update on a proper use of systemic fluoroquinolones in adult|6
04417|064|R|  patients  (ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin,|6
04417|065|R|  ofloxacin, pefloxacin.  SPILF.). Med Mal Infect 2015 Sep;45(9):348-73.|6
04417|066|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
04417|067|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04417|068|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04417|069|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04419|001|T|MONOGRAPH TITLE:  Migalastat/Caffeine-Containing Products|
04419|002|B||
04419|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04419|004|L|take action as needed.|
04419|005|B||
04419|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is unknown.|
04419|007|B||
04419|008|E|CLINICAL EFFECTS:  Concurrent use of a caffeine-containing product may|
04419|009|E|result in decreased levels and effectiveness of migalastat.(1)|
04419|010|B||
04419|011|P|PREDISPOSING FACTORS:  None determined.|
04419|012|B||
04419|013|M|PATIENT MANAGEMENT:  Avoid coadministration of migalastat with|
04419|014|M|caffeine-containing products.  Do not administer caffeine-containing|
04419|015|M|products within 2 hours before and 2 hours after taking migalastat.(1)|
04419|016|B||
04419|017|D|DISCUSSION:  Coadministration of migalastat with caffeine 190 mg decreased|
04419|018|D|the migalastat maximum concentration (Cmax) by 60% and area-under-curve|
04419|019|D|(AUC) by 55%.(1)|
04419|020|B||
04419|021|R|REFERENCE:|
04419|022|B||
04419|023|R|1.Galafold (migalastat) US prescribing information. Amicus Therapeutics US,|1
04419|024|R|  LLC June, 2023.|1
04420|001|T|MONOGRAPH TITLE:  Erdafitinib/Strong CYP3A4 or Moderate CYP2C9 Inhibitors|
04420|002|B||
04420|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04420|004|L|of severe adverse interaction.|
04420|005|B||
04420|006|A|MECHANISM OF ACTION:  Erdafitinib is metabolized by CYP3A4 and CYP2C9.|
04420|007|A|Strong inhibitors of CYP3A4 or moderate inhibitors of CYP2C9 may inhibit the|
04420|008|A|metabolism of erdafitinib.(1)|
04420|009|B||
04420|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 or moderate CYP2C9|
04420|011|E|inhibitors may increase the levels and effects of erdafitinib, including|
04420|012|E|retinopathy and hyperphosphatemia.(1)|
04420|013|B||
04420|014|P|PREDISPOSING FACTORS:  None determined.|
04420|015|B||
04420|016|M|PATIENT MANAGEMENT:  The US prescribing information states that concurrent|
04420|017|M|use of erdafitinib with strong CYP3A4 inhibitors or moderate CYPC9|
04420|018|M|inhibitors should be avoided.  If concurrent use cannot be avoided, monitor|
04420|019|M|closely for adverse reactions and consider a dose modification based on|
04420|020|M|prescribing information.  If the strong CYP3A4 or moderate CYP2C9 inhibitor|
04420|021|M|is discontinued, consider increasing the erdafitinib dose if patient does|
04420|022|M|not have any drug-related toxicity.(1)|
04420|023|M|    If concurrent use with nitisinone cannot be avoided, the manufacturer of|
04420|024|M|nitisinone recommends reducing the dosage of a CYP2C9 substrate like|
04420|025|M|erdafitinib by one-half.(2)|
04420|026|B||
04420|027|D|DISCUSSION:  In PKPB models, concurrent use of fluconazole (a moderate|
04420|028|D|CYP2C9 and CYP3A4 inhibitor) resulted in erdafitinib mean ratios for|
04420|029|D|concentration maximum (Cmax) and area-under-curve (AUC) of 121% and 148% ,|
04420|030|D|respectively, compared to erdafitinib alone.(1)|
04420|031|D|   In PKPB models, concurrent use of itraconazole (a strong CYP3A4 inhibitor|
04420|032|D|and P-gp inhibitor) resulted in erdafitinib mean ratios for Cmax and AUC of|
04420|033|D|105% and 134%, respectively, compared to erdafitinib alone.(1)|
04420|034|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
04420|035|D|clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin,|
04420|036|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
04420|037|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04420|038|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04420|039|D|troleandomycin, tucatinib, and voriconazole.(3,4)|
04420|040|D|   Moderate inhibitors of CYP2C9 include: adagrasib, amiodarone, apazone,|
04420|041|D|asciminib, benzbromarone, fluconazole, miconazole, mifepristone, milk|
04420|042|D|thistle, nitisinone, oxandrolone, phenylbutazone, and sulfaphenazole.(2,3)|
04420|043|B||
04420|044|R|REFERENCES:|
04420|045|B||
04420|046|R|1.Balversa (erdafitinib) US prescribing information. Janssen|1
04420|047|R|  Pharmaceuticals, Inc. January, 2024.|1
04420|048|R|2.Harliku (nitisinone) US prescribing information. Cycle Pharmaceuticals Ltd|1
04420|049|R|  June, 2025.|1
04420|050|R|3.This information is based on an extract from the Certara Drug Interaction|6
04420|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04420|052|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04420|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04420|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04420|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04420|056|R|  11/14/2017.|1
04421|001|T|MONOGRAPH TITLE:  Warfarin/Rucaparib|
04421|002|B||
04421|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04421|004|L|of severe adverse interaction.|
04421|005|B||
04421|006|A|MECHANISM OF ACTION:  Rucaparib is a weak CYP2C9 inhibitor which may|
04421|007|A|decrease the metabolism of the S-enantiomer of warfarin.(1-3)|
04421|008|B||
04421|009|E|CLINICAL EFFECTS:  Concurrent use of rucaparib may result in elevated levels|
04421|010|E|of warfarin and increased INR.(1,2)|
04421|011|B||
04421|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04421|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04421|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
04421|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04421|016|P|risk for bleeding (e.g. NSAIDs).|
04421|017|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
04421|018|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
04421|019|P|are expected to be more susceptible to this interaction.|
04421|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
04421|021|P|are expected to be less susceptible to effects from this drug combination,|
04421|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
04421|023|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
04421|024|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
04421|025|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
04421|026|P|and safe anticoagulation than patients without these CYP2C9 variants.|
04421|027|B||
04421|028|M|PATIENT MANAGEMENT:  The US manufacturer of rucaparib states that concurrent|
04421|029|M|administration with sensitive CYP2C9 substrates should be avoided.(1)|
04421|030|M|   If concurrent use cannot be avoided, monitor INRs more frequently until|
04421|031|M|stable in patients who start rucaparib therapy.(1,2)|
04421|032|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04421|033|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
04421|034|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
04421|035|M|evaluate patients with any symptoms.|
04421|036|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04421|037|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04421|038|M|anticoagulation in patients with active pathologic bleeding.|
04421|039|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04421|040|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04421|041|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04421|042|M|and/or swelling.|
04421|043|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04421|044|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04421|045|M|initiating, altering the dose or discontinuing either drug.|
04421|046|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
04421|047|B||
04421|048|D|DISCUSSION:  In clinical studies, coadministration of rucaparib increased|
04421|049|D|the area-under-the-curve (AUC) and maximum concentration (Cmax) of|
04421|050|D|S-warfarin by 1.5-fold and <1.1-fold, respectively.(1)|
04421|051|B||
04421|052|R|REFERENCES:|
04421|053|B||
04421|054|R|1.Rubraca (rucaparib) US prescribing information. Clovis Oncology, Inc.|1
04421|055|R|  December, 2022.|1
04421|056|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
04421|057|R|  Squibb Company September, 2016.|1
04421|058|R|3.This information is based on an extract from the Certara Drug Interaction|6
04421|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04421|060|R|4.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
04421|061|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
04421|062|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
04421|063|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
04421|064|R|  Oct;90(4):625-9.|6
04422|001|T|MONOGRAPH TITLE:  Warfarin/Alpelisib (mono deleted 03/16/2024)|
04422|002|B||
04422|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04422|004|L|take action as needed.|
04422|005|B||
04422|006|A|MECHANISM OF ACTION:  Alpelisib may induce the metabolism of S-warfarin by|
04422|007|A|CYP2C9.(1,2)|
04422|008|B||
04422|009|E|CLINICAL EFFECTS:  Concurrent use of alpelisib may result in decreased|
04422|010|E|levels and effectiveness of warfarin, which may increase the risk of|
04422|011|E|clotting.(1,2)|
04422|012|B||
04422|013|P|PREDISPOSING FACTORS:  None determined.|
04422|014|B||
04422|015|M|PATIENT MANAGEMENT:  Monitor INR response closely in patients maintained on|
04422|016|M|warfarin when initiating, titrating, and discontinuing alpelisib.  Patients|
04422|017|M|maintained on alpelisib may require higher dosages of warfarin.|
04422|018|B||
04422|019|D|DISCUSSION:  Alpelisib is an inducer of CYP2C9.(1,2)|
04422|020|B||
04422|021|R|REFERENCES:|
04422|022|B||
04422|023|R|1.Piqray (alpelisib) US prescribing information. Novartis Pharmaceuticals|1
04422|024|R|  Corporation January, 2024.|1
04422|025|R|2.Vijoice (alpelisib) US prescribing information. Novartis Pharmaceuticals|1
04422|026|R|  Corporation April, 2022.|1
04423|001|T|MONOGRAPH TITLE:  Warfarin/Etoposide|
04423|002|B||
04423|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04423|004|L|take action as needed.|
04423|005|B||
04423|006|A|MECHANISM OF ACTION:  Etoposide is a CYP2C9 inhibitor which may decrease the|
04423|007|A|metabolism of the S-enantiomer of warfarin.(1-3)|
04423|008|B||
04423|009|E|CLINICAL EFFECTS:  Concurrent use of etoposide may result in elevated levels|
04423|010|E|of warfarin and increased INR.(1,2)|
04423|011|B||
04423|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04423|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04423|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
04423|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04423|016|P|risk for bleeding (e.g. NSAIDs).|
04423|017|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
04423|018|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
04423|019|P|are expected to be more susceptible to this interaction.|
04423|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
04423|021|P|are expected to be less susceptible to effects from this drug combination,|
04423|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
04423|023|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
04423|024|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
04423|025|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
04423|026|P|and safe anticoagulation than patients without these CYP2C9 variants.|
04423|027|B||
04423|028|M|PATIENT MANAGEMENT:  Monitor INR closely in patients maintained on warfarin|
04423|029|M|when initiating, titrating, and discontinuing etoposide.  Patients|
04423|030|M|maintained on etoposide may require lower dosages of warfarin.(1,2)|
04423|031|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04423|032|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
04423|033|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
04423|034|M|evaluate patients with any symptoms.|
04423|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04423|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04423|037|M|anticoagulation in patients with active pathologic bleeding.|
04423|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04423|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04423|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04423|041|M|and/or swelling.|
04423|042|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04423|043|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04423|044|M|initiating, altering the dose or discontinuing either drug.|
04423|045|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
04423|046|B||
04423|047|D|DISCUSSION:  In case reports, patients maintained on warfarin had increased|
04423|048|D|INR levels with concurrent etoposide chemotherapy regimens.(5-7)|
04423|049|B||
04423|050|R|REFERENCES:|
04423|051|B||
04423|052|R|1.Etopophos (etoposide) US prescribing information. H2-Pharma, LLC November,|1
04423|053|R|  2022.|1
04423|054|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
04423|055|R|  Squibb Company September, 2016.|1
04423|056|R|3.This information is based on an extract from the Certara Drug Interaction|6
04423|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04423|058|R|4.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
04423|059|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
04423|060|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
04423|061|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
04423|062|R|  Oct;90(4):625-9.|6
04423|063|R|5.Le AT, Hasson NK, Lum BL. Enhancement of warfarin response in a patient|3
04423|064|R|  receiving etoposide and carboplatin  chemotherapy. Ann Pharmacother 1997|3
04423|065|R|  Sep;31(9):1006-8.|3
04423|066|R|6.Okada N, Watanabe H, Kagami S, Ishizawa K. Ifosfamide and etoposide|3
04423|067|R|  chemotherapy may interact with warfarin, enhancing the  warfarin induced|3
04423|068|R|  anticoagulant response. Int J Clin Pharmacol Ther 2016 Jan;54(1):58-61.|3
04423|069|R|7.Suzuki T, Koga H, Yamazaki S, Saeki H, Tanaka H, Nishimura M, Nakaseko C,|3
04423|070|R|  Nakasa H, Nakamura H, Ariyoshi N, Kitada M. Probable interaction between|3
04423|071|R|  warfarin and antitumor agents used in R-ESHAP  chemotherapy. Clin Ther|3
04423|072|R|  2008 Jun;30(6):1155-9.|3
04424|001|T|MONOGRAPH TITLE:  Tricyclic Antidepressants; Mianserin/Carbamazepine;|
04424|002|T|Phenobarbital|
04424|003|B||
04424|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04424|005|L|take action as needed.|
04424|006|B||
04424|007|A|MECHANISM OF ACTION:  Carbamazepine and phenobarbital may induce the|
04424|008|A|metabolism of tricyclic antidepressants (TCAs) and mianserin by the CYP P450|
04424|009|A|isoenzyme system.(1,2)|
04424|010|B||
04424|011|E|CLINICAL EFFECTS:  The concurrent administration of TCAs or mianserin with|
04424|012|E|carbamazepine or phenobarbital may result in decreased levels and clinical|
04424|013|E|effects of the TCA or mianserin.(1,2)|
04424|014|B||
04424|015|P|PREDISPOSING FACTORS:  None determined.|
04424|016|B||
04424|017|M|PATIENT MANAGEMENT:  Patients receiving both of these medications should be|
04424|018|M|alerted to the possibility of decreased effects of the TCA or|
04424|019|M|mianserin.(1,2)  Observe the patient for loss of the therapeutic effect of|
04424|020|M|the TCA or mianserin and consider monitoring TCA or mianserin levels during|
04424|021|M|concurrent therapy.(3,4)  Consider dose adjustment of the TCA or mianserin|
04424|022|M|if carbamazepine or phenobarbital is added to or discontinued from|
04424|023|M|concurrent therapy.(2,4)|
04424|024|B||
04424|025|D|DISCUSSION:  A study of 22 psychiatric patients examined the effects of|
04424|026|D|carbamazepine on serum levels of several antidepressants.  Carbamazepine|
04424|027|D|lowered amitriptyline levels by 60%, doxepin levels by 55%, and mianserin|
04424|028|D|levels by 70%.  The authors recommended carefully monitoring antidepressant|
04424|029|D|drug levels when carbamazepine is coadministered.(3)|
04424|030|D|   A large retrospective study found that patients on carbamazepine with|
04424|031|D|amitriptyline or nortriptyline had concentration/dose (C/D) ratios for the|
04424|032|D|antidepressants that were about 50% lower than the C/D ratios for patients|
04424|033|D|not on carbamazepine.  The authors suggest that therapeutic drug monitoring|
04424|034|D|is valuable for managing drug interactions.(4)|
04424|035|D|   In healthy volunteers, carbamazepine 200 mg twice daily for 28 days|
04424|036|D|increased desipramine clearance by 31%.(6)|
04424|037|D|   In a study of 13 patients with depression, carbamazepine 400 mg per day|
04424|038|D|decreased total imipramine levels by 39.5% and desipramine levels by 24.5%|
04424|039|D|but levels of the pharmacologically active free drugs were not affected.|
04424|040|D|The authors suggested that dose adjustment of imipramine may not be|
04424|041|D|necessary.(7)|
04424|042|D|   A pharmacokinetic study found that carbamazepine 400 mg per daily for 4|
04424|043|D|weeks decreased plasma concentrations of mianserin by 34-45%.  A doubling of|
04424|044|D|the mianserin dose was proposed when coadministered with carbamazepine.(5)|
04424|045|B||
04424|046|R|REFERENCES:|
04424|047|B||
04424|048|R|1.Tegretol (carbamazepine) US prescribing information. Novartis|1
04424|049|R|  Pharmaceuticals Corporation September, 2023.|1
04424|050|R|2.Lumin (mianserin) Australian prescribing information. Alphapharm Pty Ltd|1
04424|051|R|  December, 2019.|1
04424|052|R|3.Leinonen E, Lillsunde P, Laukkanen V, Ylitalo P. Effects of carbamazepine|2
04424|053|R|  on serum antidepressant concentrations in psychiatric  patients. J Clin|2
04424|054|R|  Psychopharmacol 1991 Oct;11(5):313-8.|2
04424|055|R|4.Jerling M, Bertilsson L, Sjoqvist F. The use of therapeutic drug|2
04424|056|R|  monitoring data to document kinetic drug  interactions: an example with|2
04424|057|R|  amitriptyline and nortriptyline. Ther Drug Monit 1994 Feb;16(1):1-12.|2
04424|058|R|5.Eap CB, Yasui N, Kaneko S, Baumann P, Powell K, Otani K. Effects of|2
04424|059|R|  carbamazepine coadministration on plasma concentrations of the|2
04424|060|R|  enantiomers of mianserin and of its metabolites. Ther Drug Monit 1999 Apr;|2
04424|061|R|  21(2):166-70.|2
04424|062|R|6.Spina E, Avenoso A, Campo GM, Caputi AP, Perucca E. The effect of|2
04424|063|R|  carbamazepine on the 2-hydroxylation of desipramine. Psychopharmacology|2
04424|064|R|  (Berl) 1995 Feb;117(4):413-6.|2
04424|065|R|7.Szymura-Oleksiak J, Wyska E, Wasieczko A. Pharmacokinetic interaction|2
04424|066|R|  between imipramine and carbamazepine in patients with  major depression.|2
04424|067|R|  Psychopharmacology (Berl) 2001 Feb;154(1):38-42.|2
04425|001|T|MONOGRAPH TITLE:  Erlotinib/Corticosteroids that Induce CYP3A4|
04425|002|B||
04425|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04425|004|L|of severe adverse interaction.|
04425|005|B||
04425|006|A|MECHANISM OF ACTION:  Inducers of CYP3A4 may induce the metabolism of|
04425|007|A|erlotinib.(1)|
04425|008|B||
04425|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a CYP3A4 inducer may result|
04425|010|E|in decreased levels and effectiveness of erlotinib.(1)|
04425|011|E|   In addition, concurrent use of corticosteroids may increase the risk of|
04425|012|E|gastrointestinal perforation in patients receiving erlotinib.  Fatalities|
04425|013|E|have been reported.(1)|
04425|014|B||
04425|015|P|PREDISPOSING FACTORS:  Patients with a history of peptic ulceration or|
04425|016|P|diverticular disease or who are receiving concomitant anti-angiogenic,|
04425|017|P|NSAIDs, and/or taxane-based chemotherapy may be an increased risk of|
04425|018|P|gastrointestinal perforation.(1)|
04425|019|P|   Induction effects may be more likely with regular use of the inducer for|
04425|020|P|longer than 1-2 weeks.|
04425|021|B||
04425|022|M|PATIENT MANAGEMENT:  Avoid the concurrent use of CYP3A4 inducers in patients|
04425|023|M|receiving therapy with erlotinib.  Consider the use of alternative agents|
04425|024|M|with less enzyme induction potential.(1)|
04425|025|M|   Consider increasing the dosage of erlotinib by 50 mg increments as|
04425|026|M|tolerated at two week intervals (to a maximum of 450 mg) while closely|
04425|027|M|monitoring the patient.  The highest dosage studied with concurrent rifampin|
04425|028|M|is 450 mg.  If the dosage of erlotinib is increased, it will need to be|
04425|029|M|decreased when the inducer is discontinued.(1)|
04425|030|M|   Monitor patients receiving concurrent therapy for signs of|
04425|031|M|gastrointestinal perforation.  Discontinue erlotinib in patients who develop|
04425|032|M|gastrointestinal perforation.(1)|
04425|033|B||
04425|034|D|DISCUSSION:  Pretreatment and concurrent therapy with rifampin increased|
04425|035|D|erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve|
04425|036|D|(AUC) by 66% to 80%.  This is equivalent to a dose of about 30 mg to 50 mg|
04425|037|D|in NSCLC.(1)|
04425|038|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
04425|039|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
04425|040|D|150 mg dose of erlotinib.(1)|
04425|041|D|   In a case report, coadministration of phenytoin (180mg daily) and|
04425|042|D|erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml|
04425|043|D|to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from|
04425|044|D|1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold|
04425|045|D|(from 3.53 L/h to 41.7 L/h).(2)|
04425|046|D|   In a study, concurrent use of sorafenib (400 mg twice daily) and|
04425|047|D|erlotinib (150 mg daily) decreased the concentration minimum (Cmin),|
04425|048|D|concentration maximum (Cmax), and AUC of erlotinib.(3)|
04425|049|D|   In an animal study, concurrent use of dexamethasone and erlotinib|
04425|050|D|decreased the AUC of erlotinib by 0.6-fold.(4)|
04425|051|D|   In a phase II trial of concurrent bevacizumab plus erlotinib, 2 of 13|
04425|052|D|patients suffered fatal gastrointestinal perforations.(5)|
04425|053|D|   In another phase II trial of concurrent bevacizumab with erlotinib, 1 of|
04425|054|D|104 patients died of gastrointestinal perforation.(6)|
04425|055|D|   Two patients developed gastrointestinal perforations while taking|
04425|056|D|erlotinib, corticosteroids, and ciprofloxacin.(7)|
04425|057|D|   Corticosteroids that induce CYP3A4 include: dexamethasone and|
04425|058|D|methylprednisolone.(8,9)|
04425|059|B||
04425|060|R|REFERENCES:|
04425|061|B||
04425|062|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
04425|063|R|  2016.|1
04425|064|R|2.Ohgami M, Kaburagi T, Kurosawa A, Homma M. Drug interaction between|3
04425|065|R|  erlotinib and phenytoin for brain metastases in a patient with nonsmall|3
04425|066|R|  cell lung cancer. Lung Cancer 2016 Nov;101:9-10.|3
04425|067|R|3.Peereboom DM, Ahluwalia MS, Ye X, Supko JG, Hilderbrand SL, Phuphanich S,|2
04425|068|R|  Nabors LB, Rosenfeld MR, Mikkelsen T, Grossman SA. NABTT 0502: a phase II|2
04425|069|R|  and pharmacokinetic study of erlotinib and sorafenib for  patients with|2
04425|070|R|  progressive or recurrent glioblastoma multiforme. Neuro Oncol 2013 Apr;|2
04425|071|R|  15(4):490-6.|2
04425|072|R|4.Deeken JF, Beumer JH, Anders NM, Wanjiku T, Rusnak M, Rudek MA.|5
04425|073|R|  Preclinical assessment of the interactions between the antiretroviral|5
04425|074|R|  drugs,  ritonavir and efavirenz, and the tyrosine kinase inhibitor|5
04425|075|R|  erlotinib. Cancer Chemother Pharmacol 2015 Oct;76(4):813-9.|5
04425|076|R|5.Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, Salgia R,|2
04425|077|R|  Stadler WM, Vokes EE, Fleming GF. Efficacy and safety of bevacizumab plus|2
04425|078|R|  erlotinib for patients with recurrent ovarian, primary peritoneal, and|2
04425|079|R|  fallopian tube cancer: a trial of the Chicago, PMH, and California Phase|2
04425|080|R|  II Consortia. Gynecol Oncol 2008 Jul;110(1):49-55.|2
04425|081|R|6.Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S,|2
04425|082|R|  Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA,|2
04425|083|R|  McDermott D. Randomized phase II study of erlotinib combined with|2
04425|084|R|  bevacizumab compared with bevacizumab alone in metastatic renal cell|2
04425|085|R|  cancer. J Clin Oncol 2007 Oct 10;25(29):4536-41.|2
04425|086|R|7.Gass-Jegu F, Gschwend A, Gairard-Dory AC, Mennecier B, Tebacher-Alt M,|3
04425|087|R|  Gourieux B, Quoix E. Gastrointestinal perforations in patients treated|3
04425|088|R|  with erlotinib: A report of two cases with fatal outcome and literature|3
04425|089|R|  review. Lung Cancer 2016 Sep;99:76-8.|3
04425|090|R|8.This information is based on an extract from the Certara Drug Interaction|6
04425|091|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04425|092|R|9.US Food and Drug Administration (FDA). Drug Development and Drug|1
04425|093|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04425|094|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04425|095|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04425|096|R|  11/14/2017.|1
04426|001|T|MONOGRAPH TITLE:  Tocilizumab/Immunosuppressives; Immunomodulators|
04426|002|B||
04426|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04426|004|L|take action as needed.|
04426|005|B||
04426|006|A|MECHANISM OF ACTION:  Tocilizumab, immunosuppressives, and immunomodulators|
04426|007|A|all suppress the immune system.(1)|
04426|008|B||
04426|009|E|CLINICAL EFFECTS:  Concurrent use of tocilizumab with immunosuppressive or|
04426|010|E|immunomodulating agents may result in an increased risk for serious|
04426|011|E|infections.(1)|
04426|012|B||
04426|013|P|PREDISPOSING FACTORS:  None determined.|
04426|014|B||
04426|015|M|PATIENT MANAGEMENT:  The US manufacturer of tocilizumab recommends caution|
04426|016|M|because the concurrent use of tocilizumab with immunosuppressive agents may|
04426|017|M|increase the risk of infection.  If concurrent therapy is warranted,|
04426|018|M|consider the risk of additive immune suppression and monitor based on|
04426|019|M|prescribing information for both agents.(1)|
04426|020|B||
04426|021|D|DISCUSSION:  Tocilizumab was studied as monotherapy and in combination with|
04426|022|D|methotrexate, non-biologic DMARDs or corticosteroids, depending on the|
04426|023|D|indication.  Tocilizumab has not been studied with biological DMARDs and|
04426|024|D|concurrent use should be avoided.  If concurrent therapy is warranted,|
04426|025|D|consider the potential for increased immunosuppressive risks from both|
04426|026|D|agents.(1)|
04426|027|D|   The most common infections reported by tocilizumab treated patients in|
04426|028|D|the clinical trial periods included pneumonia, urinary tract infection,|
04426|029|D|cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and|
04426|030|D|bacterial arthritis.  Serious bacterial, mycobacterial, fungal, and viral|
04426|031|D|infections were observed in patients receiving tocilizumab.  Cases of|
04426|032|D|tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis|
04426|033|D|have been reported.(1)|
04426|034|B||
04426|035|R|REFERENCE:|
04426|036|B||
04426|037|R|1.Actemra (tocilizumab) US prescribing information. Genentech, Inc. June,|1
04426|038|R|  2019.|1
04427|001|T|MONOGRAPH TITLE:  Pexidartinib (200 mg)/Erlotinib (mono deleted 02/04/2025)|
04427|002|B||
04427|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04427|004|L|of severe adverse interaction.|
04427|005|B||
04427|006|A|MECHANISM OF ACTION:  Inhibitors of UGT may inhibit the metabolism of|
04427|007|A|pexidartinib.(1)  Erlotinib is a UGT inhibitor.|
04427|008|A|   Inducers of CYP3A4 may induce the metabolism of erlotinib.(2)|
04427|009|A|Pexidartinib is a CYP3A4 inducer.|
04427|010|A|   Concurrent use of pexidartinib and erlotinib may alter exposure to one or|
04427|011|A|both agents.|
04427|012|B||
04427|013|E|CLINICAL EFFECTS:  Concurrent use of a UGT inhibitor such as erlotinib may|
04427|014|E|result in elevated levels and increased effects of pexidartinib, such as|
04427|015|E|hepatotoxicity.(1,2)  Symptoms can include nausea, vomiting, jaundice, dark|
04427|016|E|urine, abdominal pain, and unexplained fatigue.|
04427|017|E|   Concurrent or recent use of a CYP3A4 inducer such as pexidartinib may|
04427|018|E|result in decreased levels and effectiveness of erlotinib.(1,2)|
04427|019|B||
04427|020|P|PREDISPOSING FACTORS:  None determined.|
04427|021|B||
04427|022|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pexidartinib and erlotinib.|
04427|023|M|   The US manufacturer of pexidartinib states that pexidartinib|
04427|024|M|coadministration with inhibitors of UGT should be avoided.(1)|
04427|025|M|   If coadministration with a UGT1A4 inhibitor cannot be avoided, reduce the|
04427|026|M|pexidartinib dose according to the following recommendations.|
04427|027|M|   If the planned total daily dose is currently 800 mg, modify the total|
04427|028|M|daily dose to 400 mg by administering 200 mg twice daily.|
04427|029|M|   If the planned total daily dose is currently 600 mg, modify the total|
04427|030|M|daily dose to 400 mg by administering 200 mg twice daily.|
04427|031|M|   If the planned total daily dose is currently 400 mg, modify the total|
04427|032|M|daily dose to 200 mg by administering 200 mg once daily.|
04427|033|M|   If concomitant use of a UGT inhibitor is discontinued, increase the|
04427|034|M|pexidartinib dose to the dose that was used before starting the inhibitor|
04427|035|M|after three plasma half-lives of the UGT inhibitor.|
04427|036|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04427|037|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04427|038|M|recommendations in the Turalio package insert. Advise patients to|
04427|039|M|immediately report any symptoms of hepatotoxicity.|
04427|040|M|   The US manufacturer of erlotinib states to avoid the concurrent use of|
04427|041|M|CYP3A4 inducers in patients receiving therapy with erlotinib.  Consider the|
04427|042|M|use of alternative agents with less enzyme induction potential.(2)|
04427|043|M|   Consider increasing the dosage of erlotinib by 50 mg increments as|
04427|044|M|tolerated at two week intervals (to a maximum of 450 mg) while closely|
04427|045|M|monitoring the patient.  The highest dosage studied with concurrent rifampin|
04427|046|M|is 450 mg.  If the dosage of erlotinib is increased, it will need to be|
04427|047|M|decreased when the inducer is discontinued.(2)|
04427|048|M|   Patient receiving concurrent therapy with pexidartinib and erlotinib|
04427|049|M|should be monitored closely for efficacy and signs or toxicities.(1,2)|
04427|050|B||
04427|051|D|DISCUSSION:  Coadministration of probenecid (UGT inhibitor) increased|
04427|052|D|pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by|
04427|053|D|5% and 60%.(1)|
04427|054|D|   Pretreatment and concurrent therapy with rifampin increased erlotinib|
04427|055|D|clearance by 3-fold and decreased the erlotinib AUC by 66% to 80%.  This is|
04427|056|D|equivalent to a dose of about 30 mg to 50 mg in NSCLC.(2)|
04427|057|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
04427|058|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
04427|059|D|150 mg dose of erlotinib.(2)|
04427|060|B||
04427|061|R|REFERENCES:|
04427|062|B||
04427|063|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04427|064|R|  November, 2023.|1
04427|065|R|2.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
04427|066|R|  2016.|1
04428|001|T|MONOGRAPH TITLE:  Pexidartinib/Erlotinib (mono deleted 02/04/2025)|
04428|002|B||
04428|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04428|004|L|of severe adverse interaction.|
04428|005|B||
04428|006|A|MECHANISM OF ACTION:  Inhibitors of UGT may inhibit the metabolism of|
04428|007|A|pexidartinib.(1)  Erlotinib is a UGT inhibitor.|
04428|008|A|   Inducers of CYP3A4 may induce the metabolism of erlotinib.(2)|
04428|009|A|Pexidartinib is a CYP3A4 inducer.|
04428|010|A|   Concurrent use of pexidartinib and erlotinib may alter exposure to one or|
04428|011|A|both agents.|
04428|012|B||
04428|013|E|CLINICAL EFFECTS:  Concurrent use of a UGT inhibitor such as erlotinib may|
04428|014|E|result in elevated levels and increased effects of pexidartinib, such as|
04428|015|E|hepatotoxicity.(1,2)  Symptoms can include nausea, vomiting, jaundice, dark|
04428|016|E|urine, abdominal pain, and unexplained fatigue.|
04428|017|E|   Concurrent or recent use of a CYP3A4 inducer such as pexidartinib may|
04428|018|E|result in decreased levels and effectiveness of erlotinib.(1,2)|
04428|019|B||
04428|020|P|PREDISPOSING FACTORS:  None determined.|
04428|021|B||
04428|022|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pexidartinib and erlotinib.|
04428|023|M|   The US manufacturer of pexidartinib states that pexidartinib|
04428|024|M|coadministration with inhibitors of UGT should be avoided.(1)|
04428|025|M|   If coadministration with a UGT1A4 inhibitor cannot be avoided, reduce the|
04428|026|M|pexidartinib dose according to the following recommendations.|
04428|027|M|   If the planned total daily dose is currently 500 mg, modify the total|
04428|028|M|daily dose to 250 mg by administering 125 mg twice daily.|
04428|029|M|   If the planned total daily dose is currently 375 mg, modify the total|
04428|030|M|daily dose to 250 mg by administering 125 mg twice daily.|
04428|031|M|   If the planned total daily dose is currently 250 mg, modify the total|
04428|032|M|daily dose to 125 mg by administering 125 mg once daily.|
04428|033|M|   If concomitant use of a UGT inhibitor is discontinued, increase the|
04428|034|M|pexidartinib dose to the dose that was used before starting the inhibitor|
04428|035|M|after three plasma half-lives of the UGT inhibitor.|
04428|036|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04428|037|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04428|038|M|recommendations in the Turalio package insert. Advise patients to|
04428|039|M|immediately report any symptoms of hepatotoxicity.|
04428|040|M|   The US manufacturer of erlotinib states to avoid the concurrent use of|
04428|041|M|CYP3A4 inducers in patients receiving therapy with erlotinib.  Consider the|
04428|042|M|use of alternative agents with less enzyme induction potential.(2)|
04428|043|M|   Consider increasing the dosage of erlotinib by 50 mg increments as|
04428|044|M|tolerated at two week intervals (to a maximum of 450 mg) while closely|
04428|045|M|monitoring the patient.  The highest dosage studied with concurrent rifampin|
04428|046|M|is 450 mg.  If the dosage of erlotinib is increased, it will need to be|
04428|047|M|decreased when the inducer is discontinued.(2)|
04428|048|M|   Patient receiving concurrent therapy with pexidartinib and erlotinib|
04428|049|M|should be monitored closely for efficacy and signs or toxicities.(1,2)|
04428|050|B||
04428|051|D|DISCUSSION:  Coadministration of probenecid (UGT inhibitor) increased|
04428|052|D|pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by|
04428|053|D|5% and 60%.(1)|
04428|054|D|   Pretreatment and concurrent therapy with rifampin increased erlotinib|
04428|055|D|clearance by 3-fold and decreased the erlotinib AUC by 66% to 80%.  This is|
04428|056|D|equivalent to a dose of about 30 mg to 50 mg in NSCLC.(2)|
04428|057|D|   In a study, pretreatment with rifampin for 11 days decreased the AUC of a|
04428|058|D|single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single|
04428|059|D|150 mg dose of erlotinib.(2)|
04428|060|B||
04428|061|R|REFERENCES:|
04428|062|B||
04428|063|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04428|064|R|  November, 2023.|1
04428|065|R|2.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
04428|066|R|  2016.|1
04429|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal to 10 mg)/Enasidenib|
04429|002|B||
04429|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04429|004|L|take action as needed.|
04429|005|B||
04429|006|A|MECHANISM OF ACTION:  Enasidenib is an inhibitor of the BCRP and OATP1B1|
04429|007|A|transporters and may increase the absorption and/or decrease the elimination|
04429|008|A|of rosuvastatin.(1,3)|
04429|009|B||
04429|010|E|CLINICAL EFFECTS:  Concurrent use of enasidenib may result in increased|
04429|011|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1)|
04429|012|B||
04429|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04429|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04429|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04429|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04429|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04429|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04429|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04429|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04429|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04429|022|B||
04429|023|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
04429|024|M|dose of rosuvastatin should not exceed 10 mg daily when used concurrently|
04429|025|M|with enasidenib.  Monitor patients closely for signs and symptoms of|
04429|026|M|toxicity from increased rosuvastatin concentrations.(1)|
04429|027|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
04429|028|M|of rosuvastatin should not exceed 5 mg daily when used with enasidenib.(2)|
04429|029|B||
04429|030|D|DISCUSSION:  In a study, enasidenib 100 mg daily increased the maximum|
04429|031|D|concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by|
04429|032|D|366% and 244%, respectively.(1)|
04429|033|B||
04429|034|R|REFERENCES:|
04429|035|B||
04429|036|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04429|037|R|  Pharmaceuticals LP July, 2024.|1
04429|038|R|2.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
04429|039|R|  Australia Pty Ltd July 8, 2024.|1
04429|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04429|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04430|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 10 mg)/Enasidenib|
04430|002|B||
04430|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04430|004|L|is contraindicated and generally should not be dispensed or administered to|
04430|005|L|the same patient.|
04430|006|B||
04430|007|A|MECHANISM OF ACTION:  Enasidenib is an inhibitor of the BCRP and OATP1B1|
04430|008|A|transporters and may increase the absorption and/or decrease the elimination|
04430|009|A|of rosuvastatin.(1)|
04430|010|B||
04430|011|E|CLINICAL EFFECTS:  Concurrent use of enasidenib may result in increased|
04430|012|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1)|
04430|013|B||
04430|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04430|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04430|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04430|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04430|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04430|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04430|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04430|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04430|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04430|023|B||
04430|024|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
04430|025|M|dose of rosuvastatin should not exceed 10 mg daily when used concurrently|
04430|026|M|with enasidenib.  Monitor patients closely for signs and symptoms of|
04430|027|M|toxicity from increased rosuvastatin concentrations.(1)|
04430|028|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
04430|029|M|of rosuvastatin should not exceed 5 mg daily when used with enasidenib.(2)|
04430|030|B||
04430|031|D|DISCUSSION:  In a study, enasidenib 100 mg daily increased the maximum|
04430|032|D|concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by|
04430|033|D|366% and 244%, respectively.(1)|
04430|034|B||
04430|035|R|REFERENCES:|
04430|036|B||
04430|037|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04430|038|R|  Pharmaceuticals LP July, 2024.|1
04430|039|R|2.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
04430|040|R|  Australia Pty Ltd July 8, 2024.|1
04430|041|R|3.This information is based on an extract from the Certara Drug Interaction|6
04430|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04431|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal to 10 mg)/Capmatinib|
04431|002|B||
04431|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04431|004|L|take action as needed.|
04431|005|B||
04431|006|A|MECHANISM OF ACTION:  Capmatinib inhibits BCRP, which may result in|
04431|007|A|increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)|
04431|008|B||
04431|009|E|CLINICAL EFFECTS:  Concurrent use of capmatinib with rosuvastatin may result|
04431|010|E|in increased levels and side effects from rosuvastatin, including|
04431|011|E|rhabdomyolysis.(1,2)|
04431|012|B||
04431|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04431|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04431|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04431|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04431|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04431|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04431|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04431|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04431|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04431|022|B||
04431|023|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
04431|024|M|dose of rosuvastatin should not exceed 10 mg daily when used concurrently|
04431|025|M|with capmatinib.(1)|
04431|026|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
04431|027|M|of rosuvastatin should not exceed 5 mg daily when used with capmatinib.(3)|
04431|028|M|   Monitor patients closely for signs and symptoms of toxicity from|
04431|029|M|increased rosuvastatin concentrations.(1)|
04431|030|B||
04431|031|D|DISCUSSION:  In a study, capmatinib increased rosuvastatin (a BCRP|
04431|032|D|substrate) area-under-curve (AUC) by 108% and maximum concentration (Cmax)|
04431|033|D|by 204%.(1)|
04431|034|B||
04431|035|R|REFERENCES:|
04431|036|B||
04431|037|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04431|038|R|  Pharmaceuticals LP July, 2024.|1
04431|039|R|2.Tabrecta (capmatinib) US prescribing information. Novartis Pharmaceuticals|1
04431|040|R|  Corporation May, 2020.|1
04431|041|R|3.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
04431|042|R|  Australia Pty Ltd July 8, 2024.|1
04431|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
04431|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04432|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 10 mg)/Capmatinib|
04432|002|B||
04432|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04432|004|L|is contraindicated and generally should not be dispensed or administered to|
04432|005|L|the same patient.|
04432|006|B||
04432|007|A|MECHANISM OF ACTION:  Capmatinib inhibits BCRP, which may result in|
04432|008|A|increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)|
04432|009|B||
04432|010|E|CLINICAL EFFECTS:  Concurrent use of capmatinib with rosuvastatin may result|
04432|011|E|in increased levels and side effects from rosuvastatin, including|
04432|012|E|rhabdomyolysis.(1,2)|
04432|013|B||
04432|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04432|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04432|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04432|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04432|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04432|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04432|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04432|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04432|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04432|023|B||
04432|024|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
04432|025|M|dose of rosuvastatin should not exceed 10 mg daily when used concurrently|
04432|026|M|with capmatinib.(1)|
04432|027|M|   The Australian manufacturer of rosuvastatin states that the starting dose|
04432|028|M|of rosuvastatin should not exceed 5 mg daily when used with capmatinib.(3)|
04432|029|M|   Monitor patients closely for signs and symptoms of toxicity from|
04432|030|M|increased rosuvastatin concentrations.(1)|
04432|031|B||
04432|032|D|DISCUSSION:  In a study, capmatinib increased rosuvastatin (a BCRP|
04432|033|D|substrate) area-under-curve (AUC) by 108% and maximum concentration (Cmax)|
04432|034|D|by 204%.(1)|
04432|035|B||
04432|036|R|REFERENCES:|
04432|037|B||
04432|038|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04432|039|R|  Pharmaceuticals LP July, 2024.|1
04432|040|R|2.Tabrecta (capmatinib) US prescribing information. Novartis Pharmaceuticals|1
04432|041|R|  Corporation May, 2020.|1
04432|042|R|3.Crestor (rosuvastatin calcium) Australian Product Information. A. Menarini|1
04432|043|R|  Australia Pty Ltd July 8, 2024.|1
04432|044|R|4.This information is based on an extract from the Certara Drug Interaction|6
04432|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04433|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal to 20 mg)/Fostamatinib|
04433|002|B||
04433|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04433|004|L|take action as needed.|
04433|005|B||
04433|006|A|MECHANISM OF ACTION:  Fostamatinib inhibits BCRP, which may result in|
04433|007|A|increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)|
04433|008|B||
04433|009|E|CLINICAL EFFECTS:  Concurrent use of fostamatinib may result in increased|
04433|010|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1,2)|
04433|011|B||
04433|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04433|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04433|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04433|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04433|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04433|017|P|transporter OATP1B1 may have increased statin concentrations and be|
04433|018|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04433|019|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04433|020|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04433|021|B||
04433|022|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
04433|023|M|dose of rosuvastatin should not exceed 20 mg daily when used concurrently|
04433|024|M|with fostamatinib.(1)|
04433|025|M|   Monitor patients closely for signs and symptoms of toxicity from|
04433|026|M|increased rosuvastatin concentrations.(1)|
04433|027|B||
04433|028|D|DISCUSSION:  In a study, fostamatinib increased rosuvastatin (a BCRP|
04433|029|D|substrate) area-under-curve (AUC) by 95% and maximum concentration (Cmax) by|
04433|030|D|88%.(1)|
04433|031|B||
04433|032|R|REFERENCES:|
04433|033|B||
04433|034|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04433|035|R|  Pharmaceuticals LP July, 2024.|1
04433|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
04433|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04434|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 20 mg)/Fostamatinib|
04434|002|B||
04434|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04434|004|L|is contraindicated and generally should not be dispensed or administered to|
04434|005|L|the same patient.|
04434|006|B||
04434|007|A|MECHANISM OF ACTION:  Fostamatinib inhibits BCRP, which may result in|
04434|008|A|increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)|
04434|009|B||
04434|010|E|CLINICAL EFFECTS:  Concurrent use of fostamatinib may result in increased|
04434|011|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1,2)|
04434|012|B||
04434|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04434|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04434|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04434|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04434|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04434|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04434|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04434|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04434|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04434|022|B||
04434|023|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
04434|024|M|dose of rosuvastatin should not exceed 20 mg daily when used concurrently|
04434|025|M|with fostamatinib.(1)|
04434|026|M|   Monitor patients closely for signs and symptoms of toxicity from|
04434|027|M|increased rosuvastatin concentrations.(1)|
04434|028|B||
04434|029|D|DISCUSSION:  In a study, fostamatinib increased rosuvastatin (a BCRP|
04434|030|D|substrate) area-under-curve (AUC) by 95% and maximum concentration (Cmax) by|
04434|031|D|88%.(1)|
04434|032|B||
04434|033|R|REFERENCES:|
04434|034|B||
04434|035|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04434|036|R|  Pharmaceuticals LP July, 2024.|1
04434|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
04434|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04435|001|T|MONOGRAPH TITLE:  COVID-19 Vaccines/Orthopoxvirus Vaccines|
04435|002|B||
04435|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04435|004|L|take action as needed.|
04435|005|B||
04435|006|A|MECHANISM OF ACTION:  Both the COVID-19 vaccines and orthopoxvirus vaccines|
04435|007|A|have been reported to cause myocarditis and pericarditis.(1,2)|
04435|008|B||
04435|009|E|CLINICAL EFFECTS:  Concurrent use of COVID-19 vaccines and orthopoxvirus|
04435|010|E|vaccines may increase the risk of myocarditis and pericarditis.(1,2)|
04435|011|B||
04435|012|P|PREDISPOSING FACTORS:  Myocarditis and pericarditis have been reported more|
04435|013|P|frequently in adolescent and young adult males after the 2nd dose of|
04435|014|P|COVID-19 vaccines and within a week of vaccination.(1)|
04435|015|P|   Patients with pre-existing heart disease or 3 or more cardiac risk|
04435|016|P|factors (hypertension, diabetes, hypercholesterolemia, family history of|
04435|017|P|heart disease, and smoking) have a theoretical risk for myopericarditis with|
04435|018|P|the smallpox-mpox vaccine.(2)|
04435|019|B||
04435|020|M|PATIENT MANAGEMENT:  While there is no required minimum interval between|
04435|021|M|receiving the COVID-19 vaccine and the smallpox or smallpox-mpox vaccine,|
04435|022|M|patients who are predisposed to developing myocarditis or pericarditis may|
04435|023|M|consider waiting 4 weeks between vaccines.  However, if an orthopoxvirus|
04435|024|M|vaccine is recommended in the setting of an outbreak, or a patient's risk|
04435|025|M|for severe COVID-19 disease is high, administration of both vaccines should|
04435|026|M|not be delayed.  The smallpox-mpox vaccine is preferred over the smallpox|
04435|027|M|vaccine when coadministering with a COVID-19 vaccine.(1,2)|
04435|028|B||
04435|029|D|DISCUSSION:  Myocarditis and pericarditis have been reported rarely after|
04435|030|D|COVID-19 vaccination in the United States, but available evidence both in|
04435|031|D|the US and internationally supports a causal relationship.(1)|
04435|032|D|   After primary vaccination with the smallpox vaccine, there is an|
04435|033|D|estimated rate of myocarditis of 5.7 per 1,000 patients.  Myocarditis has|
04435|034|D|not been reported with the smallpox-mpox vaccine, but since the mechanism|
04435|035|D|for myocarditis with the smallpox vaccine is believed to be immune-mediated,|
04435|036|D|there is a possibility that antigens in the smallpox-mpox vaccine may|
04435|037|D|precipitate myopericarditis.(2)|
04435|038|B||
04435|039|R|REFERENCES:|
04435|040|B||
04435|041|R|1.Centers for Disease Control and Prevention (CDC). Interim Clinical|6
04435|042|R|  Considerations for Use of COVID-19 Vaccines Currently Approved or|6
04435|043|R|  Authorized in the United States. Accessed at:|6
04435|044|R|  https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vac|6
04435|045|R|  cines-us.html Last updated: September 15, 2023.|6
04435|046|R|2.Rao AK, Petersen BW, Whitehill F, Razeq JH, Isaacs SN, Merchlinsky MJ,|6
04435|047|R|  Campos-Outcalt D, Morgan RL, Damon I, Sanchez PJ, Bell BP. Use of JYNNEOS|6
04435|048|R|  (Smallpox and Monkeypox Vaccine, Live, Nonreplicating) for  Preexposure|6
04435|049|R|  Vaccination of Persons at Risk for Occupational Exposure to|6
04435|050|R|  Orthopoxviruses: Recommendations of the Advisory Committee on Immunization|6
04435|051|R|  Practices - United States, 2022. MMWR Morb Mortal Wkly Rep 2022 Jun 3;|6
04435|052|R|  71(22):734-742.|6
04436|001|T|MONOGRAPH TITLE:  Tiagabine/Selected Anticonvulsants; Barbiturates|
04436|002|B||
04436|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04436|004|L|take action as needed.|
04436|005|B||
04436|006|A|MECHANISM OF ACTION:  Barbiturates, carbamazepine, phenobarbital, phenytoin,|
04436|007|A|and primidone may induce the metabolism of tiagabine by CYP3A4.(1)|
04436|008|B||
04436|009|E|CLINICAL EFFECTS:  Concurrent use of barbiturates, carbamazepine,|
04436|010|E|phenobarbital, phenytoin, or primidone with tiagabine may result in|
04436|011|E|decreased levels and clinical effectiveness of tiagabine.(1)|
04436|012|B||
04436|013|P|PREDISPOSING FACTORS:  None determined.|
04436|014|B||
04436|015|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with tiagabine|
04436|016|M|and barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone|
04436|017|M|should be observed for decreased tiagabine levels and clinical|
04436|018|M|effectiveness.  The dose of tiagabine should be adjusted accordingly when|
04436|019|M|coadministered with enzyme-inducing antiepileptic drugs.|
04436|020|M|   The US manufacturer of tiagabine provides dosing titration|
04436|021|M|recommendations for tiagabine when used concurrently with enzyme-inducing|
04436|022|M|antiepileptic drugs.  In patients 12-18 years old, tiagabine should be|
04436|023|M|initiated at 4 mg daily and increased by 4 mg weekly until clinical response|
04436|024|M|is achieved, to a maximum of 32 mg/day.  In adults, tiagabine should be|
04436|025|M|initiated at 4 mg daily and increased by 4-8 mg weekly until clinical|
04436|026|M|response is achieved, to a maximum of 56 mg/day.|
04436|027|M|   The dose of tiagabine may need to be adjusted if these agents are added|
04436|028|M|to or removed from tiagabine therapy.  It may be useful to obtain plasma|
04436|029|M|levels of tiagabine before and after changes are made in the therapeutic|
04436|030|M|regimen.(1)|
04436|031|B||
04436|032|D|DISCUSSION:  Population pharmacokinetic studies have shown that tiagabine|
04436|033|D|clearance is 60% greater in patients taking carbamazepine, phenytoin,|
04436|034|D|phenobarbital, or primidone than in patients not on an enzyme inducer.(1)|
04436|035|B||
04436|036|R|REFERENCE:|
04436|037|B||
04436|038|R|1.Gabitril (tiagabine) US prescribing information. Cephalon, LLC September,|1
04436|039|R|  2021.|1
04437|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 20 mg)/Tafamidis|
04437|002|B||
04437|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04437|004|L|of severe adverse interaction.|
04437|005|B||
04437|006|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate of the BCRP|
04437|007|A|transporter.(1,2)  Tafamidis has been shown to inhibit this transporter and|
04437|008|A|may increase intestinal absorption and decrease hepatic uptake of|
04437|009|A|rosuvastatin.(1-3)|
04437|010|B||
04437|011|E|CLINICAL EFFECTS:  Concurrent use of tafamidis may result in increased|
04437|012|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1,2)|
04437|013|B||
04437|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04437|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04437|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04437|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04437|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04437|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04437|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04437|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04437|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04437|023|B||
04437|024|M|PATIENT MANAGEMENT:  Avoid concomitant use of tafamidis with rosuvastatin.|
04437|025|M|If used concomitantly, initiate rosuvastatin at 5 mg once daily and do not|
04437|026|M|exceed a dose of rosuvastatin 20 mg once daily.|
04437|027|M|   Monitor patients closely for signs and symptoms of toxicity from|
04437|028|M|increased rosuvastatin concentrations.(1)|
04437|029|B||
04437|030|D|DISCUSSION:  In a clinical study of healthy subjects, tafamidis (multiple|
04437|031|D|doses of 61 mg daily) increased the area-under-curve (AUC) and concentration|
04437|032|D|maximum (Cmax) of rosuvastatin by 96.75% and 85.59%, respectively.(3)|
04437|033|B||
04437|034|R|REFERENCES:|
04437|035|B||
04437|036|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04437|037|R|  Pharmaceuticals LP July, 2024.|1
04437|038|R|2.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04437|039|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04437|040|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04437|041|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04437|042|R|  44(3):398-408.|5
04437|043|R|3.Vyndamax (tafamidis) US prescribing information. Pfizer, Inc. June, 2021.|1
04438|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 10 mg)/Momelotinib|
04438|002|B||
04438|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04438|004|L|is contraindicated and generally should not be dispensed or administered to|
04438|005|L|the same patient.|
04438|006|B||
04438|007|A|MECHANISM OF ACTION:  Momelotinib inhibits BCRP, which may result in|
04438|008|A|increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)|
04438|009|B||
04438|010|E|CLINICAL EFFECTS:  Concurrent use of momelotinib with rosuvastatin may|
04438|011|E|result in increased levels and side effects from rosuvastatin, including|
04438|012|E|rhabdomyolysis.(1,2)|
04438|013|B||
04438|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04438|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04438|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04438|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04438|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04438|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04438|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04438|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04438|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04438|023|B||
04438|024|M|PATIENT MANAGEMENT:  The US manufacturer of momelotinib recommends|
04438|025|M|initiating rosuvastatin at 5 mg and not to increase dose to more than 10 mg|
04438|026|M|once daily.(2)|
04438|027|M|   Monitor patients closely for signs and symptoms of toxicity from|
04438|028|M|increased rosuvastatin concentrations.(1)|
04438|029|B||
04438|030|D|DISCUSSION:  In a study, momelotinib 200 mg daily increased single-dose|
04438|031|D|rosuvastatin 10 mg (a BCRP substrate) area-under-curve (AUC) by 170% and|
04438|032|D|maximum concentration (Cmax) by 220%.(2)|
04438|033|B||
04438|034|R|REFERENCES:|
04438|035|B||
04438|036|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04438|037|R|  Pharmaceuticals LP July, 2024.|1
04438|038|R|2.Ojjaara (momelotinib) US prescribing information. GlaxoSmithKline|1
04438|039|R|  September, 2023.|1
04438|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04438|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04439|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal to 10 mg)/Momelotinib|
04439|002|B||
04439|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04439|004|L|take action as needed.|
04439|005|B||
04439|006|A|MECHANISM OF ACTION:  Momelotinib inhibits BCRP, which may result in|
04439|007|A|increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)|
04439|008|B||
04439|009|E|CLINICAL EFFECTS:  Concurrent use of momelotinib with rosuvastatin may|
04439|010|E|result in increased levels and side effects from rosuvastatin, including|
04439|011|E|rhabdomyolysis.(1,2)|
04439|012|B||
04439|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04439|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04439|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04439|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04439|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04439|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04439|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04439|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04439|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04439|022|B||
04439|023|M|PATIENT MANAGEMENT:  The US manufacturer of momelotinib recommends|
04439|024|M|initiating rosuvastatin at 5 mg and not to increase dose to more than 10 mg|
04439|025|M|once daily.(2)|
04439|026|M|   Monitor patients closely for signs and symptoms of toxicity from|
04439|027|M|increased rosuvastatin concentrations.(1)|
04439|028|B||
04439|029|D|DISCUSSION:  In a study, momelotinib 200 mg daily increased single-dose|
04439|030|D|rosuvastatin 10 mg (a BCRP substrate) area-under-curve (AUC) by 170% and|
04439|031|D|maximum concentration (Cmax) by 220%.(2)|
04439|032|B||
04439|033|R|REFERENCES:|
04439|034|B||
04439|035|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04439|036|R|  Pharmaceuticals LP July, 2024.|1
04439|037|R|2.Ojjaara (momelotinib) US prescribing information. GlaxoSmithKline|1
04439|038|R|  September, 2023.|1
04439|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
04439|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04440|001|T|MONOGRAPH TITLE:  Selected BCRP Substrates/Momelotinib|
04440|002|B||
04440|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04440|004|L|take action as needed.|
04440|005|B||
04440|006|A|MECHANISM OF ACTION:  Momelotinib is an inhibitor of the BCRP transporter,|
04440|007|A|which may result in increased absorption and decreased hepatic uptake of|
04440|008|A|BCRP substrates.(1)|
04440|009|B||
04440|010|E|CLINICAL EFFECTS:  Administration of momelotinib with BCRP substrates may|
04440|011|E|result in elevated levels of and toxicity of the BCRP substrates.(1)|
04440|012|B||
04440|013|P|PREDISPOSING FACTORS:  None determined.|
04440|014|B||
04440|015|M|PATIENT MANAGEMENT:  The US manufacturer of momelotinib states concurrent|
04440|016|M|use with BCRP substrates should be approached with caution.  If concurrent|
04440|017|M|use is warranted, consider reducing the dose of the substrate drug according|
04440|018|M|to the product labeling and monitor for adverse reactions.(1)|
04440|019|B||
04440|020|D|DISCUSSION:  Momelotinib increased the area-under-curve (AUC) and maximum|
04440|021|D|concentration (Cmax) of rosuvastatin, a BCRP substrate, by 220% and 170%,|
04440|022|D|respectively.(1)|
04440|023|D|   BCRP substrates linked to this monograph include: ciprofloxacin,|
04440|024|D|glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and|
04440|025|D|sulfasalazine.(1-2)|
04440|026|B||
04440|027|R|REFERENCES:|
04440|028|B||
04440|029|R|1.Ojjaara (momelotinib) US prescribing information. GlaxoSmithKline|1
04440|030|R|  September, 2023.|1
04440|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04440|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04441|001|T|MONOGRAPH TITLE:  Momelotinib/OATP1B1-3 Inhibitors|
04441|002|B||
04441|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04441|004|L|take action as needed.|
04441|005|B||
04441|006|A|MECHANISM OF ACTION:  OATP1B1 and 1B3 inhibitors may decrease the hepatic|
04441|007|A|uptake of momelotinib.(1)|
04441|008|B||
04441|009|E|CLINICAL EFFECTS:  Concurrent use of OATP1B1 and 1B3 inhibitors may result|
04441|010|E|in elevated levels of and side effects from momelotinib, including|
04441|011|E|myelosuppression and hepatotoxicity.(1)|
04441|012|B||
04441|013|P|PREDISPOSING FACTORS:  None determined.|
04441|014|B||
04441|015|M|PATIENT MANAGEMENT:  Concurrent use of momelotinib with OATP1B1 and 1B3|
04441|016|M|inhibitors should be approached with caution.  Monitor patients closely for|
04441|017|M|adverse reactions and consider dose modifications per momelotinib|
04441|018|M|prescribing recommendations.(1)|
04441|019|B||
04441|020|D|DISCUSSION:  Concurrent administration of a single dose rifampin, an|
04441|021|D|OATP1B1/1B3 inhibitor, increased the maximum concentration (Cmax) and|
04441|022|D|area-under-curve (AUC) of a single dose of momelotinib by 40% and 57%,|
04441|023|D|respectively.  The M21 metabolite Cmax increased 6% and AUC increased|
04441|024|D|12%.(1)|
04441|025|D|   OATP1B1 inhibitors include: atazanavir, belumosudil, boceprevir,|
04441|026|D|cobicistat, cyclosporine, darolutamide, darunavir, eltrombopag, enasidenib,|
04441|027|D|encorafenib, erythromycin, fostemsavir, gemfibrozil,|
04441|028|D|glecaprevir-pibrentasvir, ledipasvir, letermovir, lopinavir, nirmatrelvir,|
04441|029|D|paritaprevir, resmetirom, rifampin, roxadustat, saquinavir, simeprevir,|
04441|030|D|telaprevir, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)|
04441|031|B||
04441|032|R|REFERENCES:|
04441|033|B||
04441|034|R|1.Ojjaara (momelotinib) US prescribing information. GlaxoSmithKline|1
04441|035|R|  September, 2023.|1
04441|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
04441|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04442|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 20 mg)/Febuxostat|
04442|002|B||
04442|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04442|004|L|is contraindicated and generally should not be dispensed or administered to|
04442|005|L|the same patient.|
04442|006|B||
04442|007|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate of the BCRP|
04442|008|A|transporter.(1,2)  Febuxostat has been shown to inhibit this transporter and|
04442|009|A|may increase intestinal absorption and decrease hepatic uptake of|
04442|010|A|rosuvastatin.(1-2)|
04442|011|B||
04442|012|E|CLINICAL EFFECTS:  Concurrent use of febuxostat may result in increased|
04442|013|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1,2)|
04442|014|B||
04442|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04442|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04442|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04442|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04442|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04442|020|P|transporter OATP1B1 may have increased statin concentrations and be|
04442|021|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04442|022|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04442|023|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04442|024|B||
04442|025|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
04442|026|M|dose of rosuvastatin should not exceed 20 mg daily when used concurrently|
04442|027|M|with febuxostat.(1)|
04442|028|M|   Monitor patients closely for signs and symptoms of toxicity from|
04442|029|M|increased rosuvastatin concentrations.(1)|
04442|030|B||
04442|031|D|DISCUSSION:  In a study, febuxostat 120 mg daily for 4 days increased the|
04442|032|D|area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
04442|033|D|rosuvastatin 10 mg by 1.9-fold and 2.1-fold, respectively.(1)|
04442|034|B||
04442|035|R|REFERENCES:|
04442|036|B||
04442|037|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04442|038|R|  Pharmaceuticals LP July, 2024.|1
04442|039|R|2.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04442|040|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04442|041|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04442|042|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04442|043|R|  44(3):398-408.|5
04443|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 20 mg)/Febuxostat|
04443|002|B||
04443|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04443|004|L|take action as needed.|
04443|005|B||
04443|006|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate of the BCRP|
04443|007|A|transporter.(1,2)  Febuxostat has been shown to inhibit this transporter and|
04443|008|A|may increase intestinal absorption and decrease hepatic uptake of|
04443|009|A|rosuvastatin.(1-2)|
04443|010|B||
04443|011|E|CLINICAL EFFECTS:  Concurrent use of febuxostat may result in increased|
04443|012|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1,2)|
04443|013|B||
04443|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04443|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04443|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04443|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04443|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04443|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04443|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04443|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04443|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04443|023|B||
04443|024|M|PATIENT MANAGEMENT:  The US manufacturer of rosuvastatin states that the|
04443|025|M|dose of rosuvastatin should not exceed 20 mg daily when used concurrently|
04443|026|M|with febuxostat.(1)|
04443|027|M|   Monitor patients closely for signs and symptoms of toxicity from|
04443|028|M|increased rosuvastatin concentrations.(1)|
04443|029|B||
04443|030|D|DISCUSSION:  In a study, febuxostat 120 mg daily for 4 days increased the|
04443|031|D|area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
04443|032|D|rosuvastatin 10 mg by 1.9-fold and 2.1-fold, respectively.(1)|
04443|033|B||
04443|034|R|REFERENCES:|
04443|035|B||
04443|036|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04443|037|R|  Pharmaceuticals LP July, 2024.|1
04443|038|R|2.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04443|039|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04443|040|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04443|041|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04443|042|R|  44(3):398-408.|5
04444|001|T|MONOGRAPH TITLE:  Anesthesia Agents/GLP-1 Receptor Agonists|
04444|002|B||
04444|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04444|004|L|take action as needed.|
04444|005|B||
04444|006|A|MECHANISM OF ACTION:  GLP-1 receptor agonists can cause delayed gastric|
04444|007|A|emptying.(1,2)|
04444|008|B||
04444|009|E|CLINICAL EFFECTS:  Gastric contents may remain in the stomach after|
04444|010|E|preoperative fasting, which could increase the risk of regurgitation and|
04444|011|E|aspiration.(1,2)|
04444|012|B||
04444|013|P|PREDISPOSING FACTORS:  None determined.|
04444|014|B||
04444|015|M|PATIENT MANAGEMENT:  The American Society of Anesthesiologists (ASA)|
04444|016|M|recommends the following for patients receiving elective procedures:|
04444|017|M|   - For patients on daily dosing, consider holding GLP-1 agonists on the|
04444|018|M|day of the procedure.  For patients on weekly dosing, consider holding GLP-1|
04444|019|M|agonists a week prior to the procedure.|
04444|020|M|   - Consult an endocrinologist for patients taking GLP-1 agonists for|
04444|021|M|diabetes management if the GLP-1 agonist is held longer than the dosing|
04444|022|M|schedule to avoid hyperglycemia.|
04444|023|M|   - For patients requiring urgent or emergent procedures, proceed and treat|
04444|024|M|the patient as 'full stomach.'(3)|
04444|025|B||
04444|026|D|DISCUSSION:  In one case report, a 31-year-old patient taking semaglutide|
04444|027|D|followed preoperative fasting guidelines but food residue was discovered|
04444|028|D|upon endoscopy, leading to cancellation of the surgical procedure.(4)|
04444|029|D|   In a case report, a semaglutide-treated patient experienced regurgitation|
04444|030|D|upon induction of general anesthesia despite a 20 hour preoperative fasting|
04444|031|D|period.  The patient received semaglutide two days before the scheduled|
04444|032|D|procedure.(5)|
04444|033|D|   A case report of a 42-year-old patient after fasting for 18 hours showed|
04444|034|D|substantial gastric content upon endoscopy. The patient experienced|
04444|035|D|intraoperative pulmonary aspiration of gastric contents which were suctioned|
04444|036|D|from the trachea and bronchi using bronchoscopy.(6)|
04444|037|B||
04444|038|R|REFERENCES:|
04444|039|B||
04444|040|R|1.Kobori T, Onishi Y, Yoshida Y, Tahara T, Kikuchi T, Kubota T, Iwamoto M,|2
04444|041|R|  Sawada T, Kobayashi R, Fujiwara H Kasuga M. Association of glucagon-like|2
04444|042|R|  peptide-1 receptor agonist treatment with gastric residue in an|2
04444|043|R|  esophagogastroduodenoscopy. J Diabetes Investig 2023 Jun;14(6):767-773.|2
04444|044|R|2.ISMP Canada Safety Bulletin. Glucagon-like peptide-1 (GLP-1) receptor|6
04444|045|R|  agonists: risk of aspiration during anesthesia. 2023 Sept;23(9):1-7.|6
04444|046|R|3.American Society of Anesthesiologists (ASA). Consensus-Based Guidance on|6
04444|047|R|  Preoperative Management of Patients (Adults and Children) on Glucagon-Like|6
04444|048|R|  Peptide-1 (GLP-1) Receptor Agonists. 2023 Jun.|6
04444|049|R|4.Gulak MA, Murphy P. Regurgitation under anesthesia in a fasted patient|3
04444|050|R|  prescribed semaglutide for weight loss: a case report. Can J Anaesth 2023|3
04444|051|R|  Aug;70(8):1397-1400.|3
04444|052|R|5.Silveira SQ, da Silva LM, de Campos Vieira Abib A, de Moura DTH, de Moura|6
04444|053|R|  EGH, Santos LB, Ho AM, Nersessian RSF, Lima FLM, Silva MV, Mizubuti GB.|6
04444|054|R|  Relationship between perioperative semaglutide use and residual gastric|6
04444|055|R|  content: A retrospective analysis of patients undergoing elective upper|6
04444|056|R|  endoscopy. J Clin Anesth 2023 Aug;87(111091):.|6
04444|057|R|6.Klein SR, Hobai IA. Semaglutide, delayed gastric emptying, and|3
04444|058|R|  intraoperative pulmonary aspiration: a case report. Can J Anaesth 2023|3
04444|059|R|  Aug;70(8):1394-1396.|3
04445|001|T|MONOGRAPH TITLE:  NSAIDs; Aspirin (Non-Cardioprotective)/Metoprolol|
04445|002|B||
04445|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04445|004|L|take action as needed.|
04445|005|B||
04445|006|A|MECHANISM OF ACTION:  Unknown; however, possibly related to inhibition of|
04445|007|A|prostaglandin by NSAIDs.|
04445|008|B||
04445|009|E|CLINICAL EFFECTS:  The antihypertensive action of metoprolol may be|
04445|010|E|decreased.|
04445|011|B||
04445|012|P|PREDISPOSING FACTORS:  None determined.|
04445|013|B||
04445|014|M|PATIENT MANAGEMENT:  Monitor patient's blood pressure and adjust the dose of|
04445|015|M|metoprolol as needed.|
04445|016|B||
04445|017|D|DISCUSSION:  Concurrent administration of metoprolol and NSAIDs has been|
04445|018|D|associated with a clinically significant loss in antihypertensive response.|
04445|019|D|The magnitude of the effect of NSAIDs on control of blood pressure by|
04445|020|D|beta-blockers needs to be determined for each anti-inflammatory agent.|
04445|021|D|   One or more of the drug pairs linked to this monograph have been included|
04445|022|D|in a list of interactions that could be considered for classification as|
04445|023|D|"non-interruptive" in EHR systems.  This DDI subset was vetted by an expert|
04445|024|D|panel commissioned by the U.S. Office of the National Coordinator (ONC) for|
04445|025|D|Health Information Technology.|
04445|026|B||
04445|027|R|REFERENCES:|
04445|028|B||
04445|029|R|1.Durao V, Prata MM, Goncalves LM. Modification of antihypertensive effect|2
04445|030|R|  of beta-adrenoceptor-blocking agents by inhibition of endogenous|2
04445|031|R|  prostaglandin synthesis. Lancet 1977 Nov 12;2(8046):1005-7.|2
04445|032|R|2.Lopez-Ovejero JA, Weber MA, Drayer JIM, Sealey JE, Laragh JH. Effects of|2
04445|033|R|  indomethacin alone and during diuretic or B-adrenoreceptor-blockade|2
04445|034|R|  therapy on blood pressure and the renin system in essential hypertension.|2
04445|035|R|  Clin Sci Mol Med 1978;55:203s-5s.|2
04445|036|R|3.Watkins J, Abbott EC, Hensby CN, Webster J, Dollery CT. Attenuation of|2
04445|037|R|  hypotensive effect of propranolol and thiazide diuretics by indomethacin.|2
04445|038|R|  Br Med J 1980 Sep 13;281(6242):702-5.|2
04445|039|R|4.Salvetti A, Arzilli F, Pedrinelli R, Beggi P, Motolese M. Interaction|2
04445|040|R|  between oxprenolol and indomethacin on blood pressure in essential|2
04445|041|R|  hypertensive patients. Eur J Clin Pharmacol 1982;22(3):197-201.|2
04445|042|R|5.Salvetti A, Pedrinelli R, Alberici P, Magagna A, Abdel-Haq B. The|2
04445|043|R|  influence of indomethacin and sulindac on some pharmacological actions of|2
04445|044|R|  atenolol in hypertensive patients. Br J Clin Pharmacol 1984;17 Suppl|2
04445|045|R|  1:108S-111S.|2
04445|046|R|6.Rodriquez Alvarez C, Baez MA, Weidler DJ. Effect of sulindac and piroxicam|4
04445|047|R|  administration on the antihypertensive effect of propranolol. J Clin|4
04445|048|R|  Pharmacol 1986;26:544.|4
04445|049|R|7.Radack KL, Deck CC, Bloomfield SS. Ibuprofen interferes with the efficacy|2
04445|050|R|  of antihypertensive drugs. A randomized, double-blind, placebo-controlled|2
04445|051|R|  trial of ibuprofen compared with acetaminophen. Ann Intern Med 1987 Nov;|2
04445|052|R|  107(5):628-35.|2
04445|053|R|8.Schoenfeld A, Freedman S, Hod M, Ovadia Y. Antagonism of antihypertensive|3
04445|054|R|  drug therapy in pregnancy by indomethacin?. Am J Obstet Gynecol 1989 Nov;|3
04445|055|R|  161(5):1204-5.|3
04445|056|R|9.Abate MA, Layne RD, Neely JL, D'Alessandri R. Effect of naproxen and|2
04445|057|R|  sulindac on blood pressure response to atenolol. DICP 1990 Sep;|2
04445|058|R|  24(9):810-3.|2
04445|059|R|10.Abate MA, Neely JL, Layne RD, D'Alessandri R. Interaction of indomethacin|2
04445|060|R|   and sulindac with labetalol. Br J Clin Pharmacol 1991 Mar;31(3):363-6.|2
04445|061|R|11.Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of|6
04445|062|R|   nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med|6
04445|063|R|   1993 Feb 22;153(4):477-84.|6
04445|064|R|12.Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, Teich JM,|6
04445|065|R|   Middleton B, Bates DW. Drug-drug interactions that should be|6
04445|066|R|   non-interruptive in order to reduce alert fatigue in electronic health|6
04445|067|R|   records. J Am Med Inform Assoc 2012 Sep 25.|6
04446|001|T|MONOGRAPH TITLE:  Gepirone/Moderate CYP3A4 Inhibitors|
04446|002|B||
04446|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04446|004|L|take action as needed.|
04446|005|B||
04446|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
04446|007|A|the metabolism of gepirone.(1)|
04446|008|B||
04446|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04446|010|E|the levels of and effects from gepirone, including QTc prolongation, which|
04446|011|E|may result in potentially life-threatening cardiac arrhythmias, including|
04446|012|E|torsades de pointes (TdP).|
04446|013|E|   Serotonin syndrome may also result. Symptoms of serotonin syndrome may|
04446|014|E|include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
04446|015|E|hyperthermia, and muscle rigidity.(1)|
04446|016|B||
04446|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04446|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04446|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04446|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04446|021|P|female gender, or advanced age.(2)|
04446|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04446|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04446|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04446|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04446|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04446|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04446|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04446|029|B||
04446|030|M|PATIENT MANAGEMENT:  If gepirone is used concurrently with a moderate CYP3A4|
04446|031|M|inhibitor, reduce the dose of gepirone by 50%.(1)|
04446|032|M|   Monitor for prolongation of the QTc interval.(1)  When concurrent therapy|
04446|033|M|is warranted: consider obtaining serum calcium, magnesium, and potassium|
04446|034|M|levels and monitoring EKG at baseline and regular intervals. Correct any|
04446|035|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04446|036|M|heartbeat, dizziness, or fainting.|
04446|037|M|   If QTcF is > 450 msec at baseline, do not initiate gepirone.  If QTc|
04446|038|M|increases to > 450 msec during treatment, monitor ECGs more frequently and|
04446|039|M|do not increase the dose of gepirone.(1)|
04446|040|B||
04446|041|D|DISCUSSION:  In a study, verapamil (80 mg 3 times daily), a moderate CYP3A4|
04446|042|D|inhibitor, increased both the maximum concentration (Cmax) and|
04446|043|D|area-under-curve (AUC) of gepirone 18.2 mg by about 2.75-fold.(1)|
04446|044|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
04446|045|D|atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem,|
04446|046|D|duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib,|
04446|047|D|isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib,|
04446|048|D|schisandra, stiripentol, tofisopam, treosulfan, verapamil, and|
04446|049|D|voxelotor.(3,4)|
04446|050|B||
04446|051|R|REFERENCES:|
04446|052|B||
04446|053|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04446|054|R|  Inc. September, 2023.|1
04446|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04446|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04446|057|R|  settings: a scientific statement from the American Heart Association and|6
04446|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04446|059|R|  2;55(9):934-47.|6
04446|060|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04446|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04446|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04446|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04446|064|R|  11/14/2017.|1
04446|065|R|4.This information is based on an extract from the Certara Drug Interaction|6
04446|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04447|001|T|MONOGRAPH TITLE:  Gepirone/Moderate CYP3A4 Inhibitors that Prolong QT|
04447|002|B||
04447|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04447|004|L|take action as needed.|
04447|005|B||
04447|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong the QTc|
04447|007|A|interval may inhibit the metabolism of gepirone and result in additive risk|
04447|008|A|of QT prolongation.(1)|
04447|009|B||
04447|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
04447|011|E|QT may increase the levels and effects of gepirone including additive QTc|
04447|012|E|prolongation, which may result in potentially life-threatening cardiac|
04447|013|E|arrhythmias, including torsades de pointes (TdP).(1)|
04447|014|E|   Serotonin syndrome may also result.  Symptoms of serotonin syndrome may|
04447|015|E|include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
04447|016|E|hyperthermia, and muscle rigidity.(1)|
04447|017|B||
04447|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04447|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04447|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04447|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04447|022|P|female gender, or advanced age.(2)|
04447|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04447|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04447|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04447|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04447|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04447|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04447|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04447|030|B||
04447|031|M|PATIENT MANAGEMENT:  If gepirone is used concurrently with a moderate CYP3A4|
04447|032|M|inhibitor that prolongs the QTc interval, reduce the dose of gepirone by|
04447|033|M|50%.(1)|
04447|034|M|   Monitor for prolongation of the QTc interval more frequently.(1)  When|
04447|035|M|concurrent therapy is warranted: consider obtaining serum calcium,|
04447|036|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04447|037|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04447|038|M|report any irregular heartbeat, dizziness, or fainting.|
04447|039|M|   If QTcF is > 450 msec at baseline, do not initiate gepirone.  If QTc|
04447|040|M|increases to > 450 msec during treatment, monitor ECGs more frequently and|
04447|041|M|do not increase the dose of gepirone.(1)|
04447|042|B||
04447|043|D|DISCUSSION:  In a study, verapamil (80 mg 3 times daily), a moderate CYP3A4|
04447|044|D|inhibitor, increased both the maximum concentration (Cmax) and|
04447|045|D|area-under-curve (AUC) of gepirone 18.2 mg by about 2.75-fold.(1)|
04447|046|D|   In a thorough QT study, 100 mg per day of immediate-release gepirone|
04447|047|D|increased the mean QTc by 18.4 msec (upper 90% CI = 22.7 msec) on day 1 and|
04447|048|D|16.1 msec (upper 90% CI = 20.7) on day 7.  The dose of gepirone was 2-fold|
04447|049|D|the exposure of the recommended maximum daily dose.(1)|
04447|050|D|   Agents that are linked to this monograph may have varying degrees of|
04447|051|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04447|052|D|been shown to prolong the QTc interval either through their mechanism of|
04447|053|D|action, through studies on their effects on the QTc interval, or through|
04447|054|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04447|055|D|and/or postmarketing reports.(3)|
04447|056|D|   Moderate inhibitors of CYP3A4 that prolong QT include:  clofazimine,|
04447|057|D|crizotinib, erythromycin, fluconazole, and nilotinib.(4,5)|
04447|058|B||
04447|059|R|REFERENCES:|
04447|060|B||
04447|061|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04447|062|R|  Inc. September, 2023.|1
04447|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04447|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04447|065|R|  settings: a scientific statement from the American Heart Association and|6
04447|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04447|067|R|  2;55(9):934-47.|6
04447|068|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04447|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04447|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04447|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04447|072|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04447|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04447|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04447|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04447|076|R|  11/14/2017.|1
04447|077|R|5.This information is based on an extract from the Certara Drug Interaction|6
04447|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04448|001|T|MONOGRAPH TITLE:  Gepirone/Strong CYP3A4 Inhibitors|
04448|002|B||
04448|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04448|004|L|is contraindicated and generally should not be dispensed or administered to|
04448|005|L|the same patient.|
04448|006|B||
04448|007|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
04448|008|A|the metabolism of gepirone.(1)|
04448|009|B||
04448|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04448|011|E|the levels of and effects from gepirone including QTc prolongation, which|
04448|012|E|may result in potentially life-threatening cardiac arrhythmias, including|
04448|013|E|torsades de pointes (TdP).(1)|
04448|014|E|   Serotonin syndrome may also result.  Symptoms of serotonin syndrome may|
04448|015|E|include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
04448|016|E|hyperthermia, and muscle rigidity.(1)|
04448|017|B||
04448|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04448|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04448|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04448|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04448|022|P|female gender, or advanced age.(2)|
04448|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04448|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04448|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04448|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04448|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04448|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04448|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04448|030|B||
04448|031|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inhibitors is contraindicated|
04448|032|M|in patients undergoing therapy with gepirone.(1)|
04448|033|M|   If coadministration with a strong CYP3A4 inhibitor is unavoidable,|
04448|034|M|monitor for prolongation of the QTc interval.(1)  When concurrent therapy is|
04448|035|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
04448|036|M|and monitoring EKG at baseline and regular intervals. Correct any|
04448|037|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04448|038|M|heartbeat, dizziness, or fainting.|
04448|039|M|   If QTcF is > 450 msec at baseline, do not initiate gepirone.  If QTc|
04448|040|M|increases to > 450 msec during treatment, monitor ECGs more frequently and|
04448|041|M|do not increase the dose of gepirone.(1)|
04448|042|B||
04448|043|D|DISCUSSION:  In a study, ketoconazole (200 mg twice daily), a strong CYP3A4|
04448|044|D|inhibitor, increased the maximum concentration (Cmax) and area-under-curve|
04448|045|D|(AUC) of gepirone 36.3 mg by about 5.25-fold and 5.5-fold, respectively.(1)|
04448|046|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib,|
04448|047|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone,|
04448|048|D|nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir,|
04448|049|D|tipranavir, troleandomycin, and tucatinib.(3,4)|
04448|050|B||
04448|051|R|REFERENCES:|
04448|052|B||
04448|053|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04448|054|R|  Inc. September, 2023.|1
04448|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04448|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04448|057|R|  settings: a scientific statement from the American Heart Association and|6
04448|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04448|059|R|  2;55(9):934-47.|6
04448|060|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04448|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04448|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04448|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04448|064|R|  11/14/2017.|1
04448|065|R|4.This information is based on an extract from the Certara Drug Interaction|6
04448|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04449|001|T|MONOGRAPH TITLE:  Gepirone/Strong CYP3A4 Inhibitors that Prolong QT|
04449|002|B||
04449|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04449|004|L|is contraindicated and generally should not be dispensed or administered to|
04449|005|L|the same patient.|
04449|006|B||
04449|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04449|008|A|interval may inhibit the metabolism of gepirone and result in additive risk|
04449|009|A|of QT prolongation.(1)|
04449|010|B||
04449|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04449|012|E|QT may increase the levels and effects of gepirone including additive QTc|
04449|013|E|prolongation, which may result in potentially life-threatening cardiac|
04449|014|E|arrhythmias, including torsades de pointes (TdP).(1)|
04449|015|E|   Serotonin syndrome may also result.  Symptoms of serotonin syndrome may|
04449|016|E|include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
04449|017|E|hyperthermia, and muscle rigidity.(1)|
04449|018|B||
04449|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04449|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04449|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04449|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04449|023|P|female gender, or advanced age.(2)|
04449|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04449|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04449|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04449|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04449|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04449|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04449|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04449|031|B||
04449|032|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inhibitors is contraindicated|
04449|033|M|in patients undergoing therapy with gepirone.(1)|
04449|034|M|   If coadministration with a strong CYP3A4 inhibitor is unavoidable,|
04449|035|M|monitor for prolongation of the QTc interval more frequently.(1)  When|
04449|036|M|concurrent therapy is warranted: consider obtaining serum calcium,|
04449|037|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04449|038|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
04449|039|M|report any irregular heartbeat, dizziness, or fainting.|
04449|040|M|   If QTcF is > 450 msec at baseline, do not initiate gepirone.  If QTc|
04449|041|M|increases to > 450 msec during treatment, monitor ECGs more frequently and|
04449|042|M|do not increase the dose of gepirone.(1)|
04449|043|B||
04449|044|D|DISCUSSION:  In a study, ketoconazole (200 mg twice daily), a strong CYP3A4|
04449|045|D|inhibitor, increased the maximum concentration (Cmax) and area-under-curve|
04449|046|D|(AUC) of gepirone 36.3 mg by about 5.25-fold and 5.5-fold, respectively.(1)|
04449|047|D|   In a thorough QT study, 100 mg per day of immediate-release gepirone|
04449|048|D|increased the mean QTc by 18.4 msec (upper 90% CI = 22.7 msec) on day 1 and|
04449|049|D|16.1 msec (upper 90% CI = 20.7) on day 7.  The dose of gepirone was 2-fold|
04449|050|D|the exposure of the recommended maximum daily dose.(1)|
04449|051|D|   Agents that are linked to this monograph may have varying degrees of|
04449|052|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04449|053|D|been shown to prolong the QTc interval either through their mechanism of|
04449|054|D|action, through studies on their effects on the QTc interval, or through|
04449|055|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04449|056|D|and/or postmarketing reports.(3)|
04449|057|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
04449|058|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir,|
04449|059|D|posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(4,5)|
04449|060|B||
04449|061|R|REFERENCES:|
04449|062|B||
04449|063|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04449|064|R|  Inc. September, 2023.|1
04449|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04449|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04449|067|R|  settings: a scientific statement from the American Heart Association and|6
04449|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04449|069|R|  2;55(9):934-47.|6
04449|070|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04449|071|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04449|072|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04449|073|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04449|074|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04449|075|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04449|076|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04449|077|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04449|078|R|  11/14/2017.|1
04449|079|R|5.This information is based on an extract from the Certara Drug Interaction|6
04449|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04450|001|T|MONOGRAPH TITLE:  Gepirone/Strong CYP3A4 Inducers|
04450|002|B||
04450|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04450|004|L|of severe adverse interaction.|
04450|005|B||
04450|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may accelerate|
04450|007|A|the metabolism of gepirone.(1)|
04450|008|B||
04450|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04450|010|E|levels and effectiveness of gepirone.(1)|
04450|011|B||
04450|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04450|013|P|of the inducer for longer than 1-2 weeks.|
04450|014|B||
04450|015|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers in patients receiving|
04450|016|M|therapy with gepirone should be avoided.(1)|
04450|017|M|   Consider the use of alternative agents with less enzyme induction|
04450|018|M|potential.(1)|
04450|019|B||
04450|020|D|DISCUSSION:  In a study, rifampin 600 mg daily decrease the maximum|
04450|021|D|concentration (Cmax) and area-under-curve (AUC) of gepirone by 20-fold and|
04450|022|D|29-fold, respectively.  The Cmax and AUC of the active metabolite, 3'-OH|
04450|023|D|gepirone, also decreased by 2.5-fold and 3-fold, respectively.(1)|
04450|024|D|    Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04450|025|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04450|026|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2)|
04450|027|B||
04450|028|R|REFERENCES:|
04450|029|B||
04450|030|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04450|031|R|  Inc. September, 2023.|1
04450|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04450|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04450|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04450|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04450|036|R|  11/14/2017.|1
04450|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04450|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04451|001|T|MONOGRAPH TITLE:  Gepirone/Strong CYP3A4 Inducers that Prolong QT|
04451|002|B||
04451|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04451|004|L|of severe adverse interaction.|
04451|005|B||
04451|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 that prolong the QTc|
04451|007|A|interval may induce the metabolism of gepirone and result in additive risk|
04451|008|A|of QT prolongation.(1)|
04451|009|B||
04451|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
04451|011|E|may decrease the levels and effectiveness of gepirone and cause additive|
04451|012|E|effects of the QTc interval, which may result in potentially|
04451|013|E|life-threatening arrhythmias, including torsades de pointes.(1)|
04451|014|B||
04451|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04451|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04451|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04451|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04451|019|P|female gender, or advanced age.(2)|
04451|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04451|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04451|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04451|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04451|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04451|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04451|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04451|027|P|   Induction effects may be more likely with regular use of the inducer for|
04451|028|P|longer than 1-2 weeks.|
04451|029|B||
04451|030|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers that prolong QT in|
04451|031|M|patients receiving therapy with gepirone should be avoided.(1)|
04451|032|M|   Consider the use of alternative agents with less enzyme induction|
04451|033|M|potential.(1)|
04451|034|M|   If concurrent use is warranted, monitor for prolongation of the QTc|
04451|035|M|interval more frequently.(1)  When concurrent therapy is warranted: consider|
04451|036|M|obtaining serum calcium, magnesium, and potassium levels and monitoring EKG|
04451|037|M|at baseline and regular intervals.  Correct any electrolyte abnormalities.|
04451|038|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04451|039|M|   If QTcF is > 450 msec at baseline, do not initiate gepirone.  If QTc|
04451|040|M|increases to > 450 msec during treatment, monitor ECGs more frequently and|
04451|041|M|do not increase the dose of gepirone.(1)|
04451|042|B||
04451|043|D|DISCUSSION:  In a study, rifampin 600 mg daily decreased the maximum|
04451|044|D|concentration (Cmax) and area-under-curve (AUC) of gepirone by 20-fold and|
04451|045|D|29-fold, respectively.  The Cmax and AUC of the active metabolite, 3'-OH|
04451|046|D|gepirone, also decreased by 2.5-fold and 3-fold, respectively.(1)|
04451|047|D|   In a thorough QT study, 100 mg per day of immediate-release gepirone|
04451|048|D|increased the mean QTc by 18.4 msec (upper 90% CI = 22.7 msec) on day 1 and|
04451|049|D|16.1 msec (upper 90% CI = 20.7) on day 7.  The dose of gepirone was 2-fold|
04451|050|D|the exposure of the recommended maximum daily dose.(1)|
04451|051|D|   Agents that are linked to this monograph may have varying degrees of|
04451|052|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04451|053|D|been shown to prolong the QTc interval either through their mechanism of|
04451|054|D|action, through studies on their effects on the QTc interval, or through|
04451|055|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04451|056|D|and/or postmarketing reports.(3)|
04451|057|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04451|058|D|encorafenib and ivosidenib.(4)|
04451|059|B||
04451|060|R|REFERENCES:|
04451|061|B||
04451|062|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04451|063|R|  Inc. September, 2023.|1
04451|064|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04451|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04451|066|R|  settings: a scientific statement from the American Heart Association and|6
04451|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04451|068|R|  2;55(9):934-47.|6
04451|069|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04451|070|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04451|071|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04451|072|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04451|073|R|4.This information is based on an extract from the Certara Drug Interaction|6
04451|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04452|001|T|MONOGRAPH TITLE:  Gepirone/MAOIs|
04452|002|B||
04452|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04452|004|L|is contraindicated and generally should not be dispensed or administered to|
04452|005|L|the same patient.|
04452|006|B||
04452|007|A|MECHANISM OF ACTION:  Combination of MAOIs, which decrease the breakdown of|
04452|008|A|serotonin, and gepirone, a selective 5-HT1A agonist, may cause an increase|
04452|009|A|in endogenous serotonin, which could lead to hypertensive crisis and|
04452|010|A|serotonin syndrome.(1)|
04452|011|B||
04452|012|E|CLINICAL EFFECTS:  Concurrent use of gepirone and MAOIs may result in|
04452|013|E|hypertensive crisis and serotonin syndrome, a potentially life-threatening|
04452|014|E|condition with symptoms including altered mental status, hypertension,|
04452|015|E|restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis,|
04452|016|E|shivering, and tremor.(1)|
04452|017|B||
04452|018|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04452|019|P|systemic concentrations of either drug would be predicted to increase risk|
04452|020|P|for serotonin toxicity.(2)|
04452|021|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04452|022|P|concentrations may also increase risk for serotonin syndrome.(2)|
04452|023|B||
04452|024|M|PATIENT MANAGEMENT:  The concurrent use of gepirone with MAOIs is|
04452|025|M|contraindicated.(1)  At least 14 days must elapse between discontinuation of|
04452|026|M|an MAOI intended to treat depression and initiation of therapy with|
04452|027|M|gepirone. Conversely, at least 14 days must be allowed after stopping|
04452|028|M|gepirone before starting an MAOI antidepressant.(1)|
04452|029|M|   Do not initiate gepirone in a patient treated with an MAOI such as|
04452|030|M|linezolid or intravenous methylene blue, or until 24 hours after the last|
04452|031|M|dose of linezolid or methylene blue.(1,3)  If it is necessary to initiate|
04452|032|M|treatment with an MAOI such as linezolid or intravenous methylene blue in a|
04452|033|M|patient taking gepirone, discontinue gepirone before initiating the MAOI|
04452|034|M|treatment.(1,3)|
04452|035|M|    In emergency situations in patients maintained on gepirone, weigh the|
04452|036|M|availability and safety of alternatives to linezolid or methylene blue|
04452|037|M|against the risk of hypertensive crisis.  If linezolid or methylene blue|
04452|038|M|therapy is required, the patient's gepirone should be immediately|
04452|039|M|discontinued.  Patients should be monitored for hypertensive crisis for 2|
04452|040|M|weeks or until 24 hours after the last dose of linezolid or methylene blue,|
04452|041|M|whichever comes first.(3)|
04452|042|M|   In non-emergency situations in patients maintained on gepirone when|
04452|043|M|linezolid or methylene blue therapy is planned, discontinue the patient's|
04452|044|M|gepirone at least 2 weeks in advance of linezolid or methylene blue therapy.|
04452|045|M|The patient's gepirone therapy may be resumed 24 hours after the last dose|
04452|046|M|of linezolid or methylene blue.(1)|
04452|047|B||
04452|048|D|DISCUSSION:  Gepirone and its 3'-OH metabolite act as agonists at 5HT1A|
04452|049|D|receptors.  Gepirone is contraindicated in patients taking, or within 14|
04452|050|D|days of stopping, MAOIs due to the risk of serious and possibly fatal drug|
04452|051|D|interactions, including hypertensive crisis and serotonin syndrome.(1)|
04452|052|D|   Methylene blue, when administered intravenously, has been shown to reach|
04452|053|D|sufficient concentrations to be a potent inhibitor of MAO-A.(4,5)|
04452|054|D|   Metaxalone is a weak inhibitor of MAO.(6,7)|
04452|055|B||
04452|056|R|REFERENCES:|
04452|057|B||
04452|058|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04452|059|R|  Inc. September, 2023.|1
04452|060|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04452|061|R|  352(11):1112-20.|6
04452|062|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
04452|063|R|  information about the drug interaction between methylene blue|1
04452|064|R|  (methylthioninium chloride) and serotonergic psychiatric medications.|1
04452|065|R|  available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
04452|066|R|  21, 2011.|1
04452|067|R|4.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
04452|068|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
04452|069|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
04452|070|R|5.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
04452|071|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
04452|072|R|  2000 Jun;56(3):247-50.|2
04452|073|R|6.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
04452|074|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
04452|075|R|  Feb;34(2):346.e5-6.|3
04452|076|R|7.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
04452|077|R|  Pfizer Inc. January, 2024.|1
04453|001|T|MONOGRAPH TITLE:  Gepirone/QT Prolonging Agents|
04453|002|B||
04453|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04453|004|L|take action as needed.|
04453|005|B||
04453|006|A|MECHANISM OF ACTION:  Gepirone has been shown to prolong the QTc interval.|
04453|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
04453|008|A|additive effects on the QTc interval.(1)|
04453|009|B||
04453|010|E|CLINICAL EFFECTS:  The concurrent use of gepirone with other agents that|
04453|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04453|012|E|arrhythmias, including torsades de pointes.(1)|
04453|013|B||
04453|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04453|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04453|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04453|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04453|018|P|gender, or advanced age.(2)|
04453|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04453|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04453|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04453|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04453|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04453|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04453|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04453|026|B||
04453|027|M|PATIENT MANAGEMENT:  The manufacturer of gepirone states that gepirone|
04453|028|M|should be used with caution and ECGs should be monitored more frequently|
04453|029|M|when used with other agents known to prolong the QTc interval.(1)|
04453|030|M|   If QTcF is > 450 msec at baseline, do not initiate gepirone.  If QTc|
04453|031|M|increases to > 450 msec during treatment, monitor ECGs more frequently and|
04453|032|M|do not increase the dose of gepirone.(1)|
04453|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04453|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04453|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04453|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04453|037|B||
04453|038|D|DISCUSSION:  In a thorough QT study, 100 mg per day of immediate-release|
04453|039|D|gepirone increased the mean QTc 18.4 msec (upper 90% CI = 22.7 msec) on day|
04453|040|D|1 and 16.1 msec (upper 90% CI = 20.7) on day 7.  The dose of gepirone was|
04453|041|D|2-fold the exposure of the recommended maximum daily dose.(1)|
04453|042|D|   Agents that are linked to this monograph may have varying degrees of|
04453|043|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04453|044|D|been shown to prolong the QTc interval either through their mechanism of|
04453|045|D|action, through studies on their effects on the QTc interval, or through|
04453|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04453|047|D|and/or postmarketing reports.(3)|
04453|048|B||
04453|049|R|REFERENCES:|
04453|050|B||
04453|051|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04453|052|R|  Inc. September, 2023.|1
04453|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04453|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04453|055|R|  settings: a scientific statement from the American Heart Association and|6
04453|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04453|057|R|  2;55(9):934-47.|6
04453|058|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04453|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04453|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04453|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04454|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Pegaspargase|
04454|002|B||
04454|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04454|004|L|of severe adverse interaction.|
04454|005|B||
04454|006|A|MECHANISM OF ACTION:  An indirect interaction may occur due to pegaspargase|
04454|007|A|hepatotoxicity resulting in decreased hepatic clearance of hormonal|
04454|008|A|contraceptives.(1,2)  Both medicines may also cause thromboembolic events.|
04454|009|B||
04454|010|E|CLINICAL EFFECTS:  Concurrent use of pegaspargase may result in increased|
04454|011|E|levels and effects of hormonal contraceptives and increase the risk of|
04454|012|E|venous thromboembolism.(3)|
04454|013|B||
04454|014|P|PREDISPOSING FACTORS:  Patients with risk factors for thrombosis include|
04454|015|P|those with advanced age, obesity (BMI >30), smoking, prolonged|
04454|016|P|immobilization, heart failure, hypercoagulable states, history of venous|
04454|017|P|thromboembolism, malignancy, and major surgery.|
04454|018|B||
04454|019|M|PATIENT MANAGEMENT:  The Australian and UK manufacturers of pegaspargase|
04454|020|M|state that hormonal contraceptives are not considered to be sufficiently|
04454|021|M|safe in patients on pegaspargase.  Concurrent use of hormonal contraceptives|
04454|022|M|and pegaspargase is not recommended.(1,2)|
04454|023|M|   The US manufacturer of pegaspargase states that females of reproductive|
04454|024|M|potential should be counseled to use an effective non-hormonal contraceptive|
04454|025|M|method during and for 3 months after therapy with pegaspargase.(4)  The UK|
04454|026|M|manufacturer of pegaspargase recommends using non-oral contraceptives during|
04454|027|M|and for 6 months after therapy with pegaspargase.(2)|
04454|028|B||
04454|029|D|DISCUSSION:  Hepatotoxicity caused by pegaspargase may result in increased|
04454|030|D|exposure to hormonal contraceptives and increase the risk of|
04454|031|D|thromboembolism.  Concurrent use of hormonal contraceptives is not|
04454|032|D|recommended.(1-4)|
04454|033|B||
04454|034|R|REFERENCES:|
04454|035|B||
04454|036|R|1.Oncaspar (pegaspargase) Australian product information. Servier|1
04454|037|R|  Laboratories (Aust.) Pty. Ltd. May, 2023.|1
04454|038|R|2.Oncaspar (pegaspargase) UK Summary of Product Characteristics. Les|1
04454|039|R|  Laboratoires Servier March, 2023.|1
04454|040|R|3.Beavers CJ, Rodgers JE, Bagnola AJ, Beckie TM, Campia U, Di Palo KE,|6
04454|041|R|  Okwuosa TM, Przespolewski ER, Dent S. Cardio-Oncology Drug Interactions: A|6
04454|042|R|  Scientific Statement From the American Heart  Association. Circulation|6
04454|043|R|  2022 Apr 12;145(15):e811-e838.|6
04454|044|R|4.Oncaspar (pegaspargase) US prescribing information. Servier|1
04454|045|R|  Pharmaceuticals LLC December, 2022.|1
04455|001|T|MONOGRAPH TITLE:  Rifabutin/Telithromycin|
04455|002|B||
04455|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04455|004|L|of severe adverse interaction.|
04455|005|B||
04455|006|A|MECHANISM OF ACTION:  Rifabutin may induce the metabolism of telithromycin|
04455|007|A|by CYP3A4.(1-3)  Additionally, telithromycin may inhibit the metabolism of|
04455|008|A|rifabutin by CYP3A4.(1-3)|
04455|009|B||
04455|010|E|CLINICAL EFFECTS:  Concurrent use of rifabutin may result in decreased|
04455|011|E|levels and effectiveness of telithromycin.(1-3)  Concurrent use may also|
04455|012|E|result in increased levels of and side effects from rifabutin.(1-3)|
04455|013|B||
04455|014|P|PREDISPOSING FACTORS:  None determined.|
04455|015|B||
04455|016|M|PATIENT MANAGEMENT:  The UK manufacturer of telithromycin states that|
04455|017|M|treatment with CYP3A4 inducers should be avoided during and for two weeks|
04455|018|M|after treatment with the CYP3A4 inducer.(2)|
04455|019|M|   The US manufacturer of telithromycin states that concurrent treatment|
04455|020|M|with CYP3A4 inducers should be avoided.(3)  Monitor patients receiving|
04455|021|M|concurrent therapy for decrease antibiotic efficacy.|
04455|022|B||
04455|023|D|DISCUSSION:  Concurrent use of telithromycin with rifampin (strong CYP3A4|
04455|024|D|inducer) decreased the maximum concentration (Cmax) and area-under-curve|
04455|025|D|(AUC) of telithromycin by 79% and by 86%, respectively.(2)|
04455|026|D|   The induction effect decreases during the two weeks following the|
04455|027|D|discontinuation of the inducer.(2)|
04455|028|B||
04455|029|R|REFERENCES:|
04455|030|B||
04455|031|R|1.Mycobutin (rifabutin) US prescribing information. Pfizer Inc. September,|1
04455|032|R|  2021.|1
04455|033|R|2.Ketek (telithromycin) UK summary of product characteristics.|1
04455|034|R|  Sanofi-Aventis June 2, 2009.|1
04455|035|R|3.Ketek (telithromycin) US prescribing information. Sanofi-Aventis U.S. LLC|1
04455|036|R|  November, 2015.|1
04456|001|T|MONOGRAPH TITLE:  Gepirone/Moderate CYP3A4 Inhibitors that Prolong QT|
04456|002|B||
04456|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04456|004|L|of severe adverse interaction.|
04456|005|B||
04456|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong the QTc|
04456|007|A|interval may inhibit the metabolism of gepirone and result in additive risk|
04456|008|A|of QT prolongation.(1,2)|
04456|009|B||
04456|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
04456|011|E|QT may increase the levels and effects of gepirone including additive QTc|
04456|012|E|prolongation, which may result in potentially life-threatening cardiac|
04456|013|E|arrhythmias, including torsades de pointes (TdP).(1,2)|
04456|014|E|   Serotonin syndrome may also result.  Symptoms of serotonin syndrome may|
04456|015|E|include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia,|
04456|016|E|hyperthermia, and muscle rigidity.|
04456|017|B||
04456|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04456|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04456|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04456|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04456|022|P|female gender, or advanced age.(3)|
04456|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04456|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04456|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04456|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04456|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04456|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04456|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04456|030|B||
04456|031|M|PATIENT MANAGEMENT:  The US manufacturer of gepirone states if gepirone is|
04456|032|M|used concurrently with a moderate CYP3A4 inhibitor that prolongs the QTc|
04456|033|M|interval, reduce the dose of gepirone by 50%.(1)|
04456|034|M|   The US manufacturer of dronedarone states that the use of drugs that are|
04456|035|M|known to prolong the QTc interval is contraindicated.  These agents include|
04456|036|M|phenothiazine anti-psychotics, tricyclic antidepressants, certain oral|
04456|037|M|macrolide antibiotics, and Class IA and III antiarrhythmics.(2)|
04456|038|M|   If concurrent use is unavoidable, monitor for prolongation of the QTc|
04456|039|M|interval more frequently.(1)  When concurrent therapy is warranted: consider|
04456|040|M|obtaining serum calcium, magnesium, and potassium levels and monitoring EKG|
04456|041|M|at baseline and regular intervals.  Correct any electrolyte abnormalities.|
04456|042|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04456|043|M|   If QTcF is > 450 msec at baseline, do not initiate gepirone.  If QTc|
04456|044|M|increases to > 450 msec during treatment, monitor ECGs more frequently and|
04456|045|M|do not increase the dose of gepirone.(1)|
04456|046|B||
04456|047|D|DISCUSSION:  In a study, verapamil (80 mg 3 times daily), a moderate CYP3A4|
04456|048|D|inhibitor, increased both the maximum concentration (Cmax) and|
04456|049|D|area-under-curve (AUC) of gepirone 18.2 mg by about 2.75-fold.(1)|
04456|050|D|   In a thorough QT study, 100 mg per day of immediate-release gepirone|
04456|051|D|increased the mean QTc by 18.4 msec (upper 90% CI = 22.7 msec) on day 1 and|
04456|052|D|16.1 msec (upper 90% CI = 20.7) on day 7.  The dose of gepirone was 2-fold|
04456|053|D|the exposure of the recommended maximum daily dose.(1)|
04456|054|D|   Agents that are linked to this monograph may have varying degrees of|
04456|055|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04456|056|D|been shown to prolong the QTc interval either through their mechanism of|
04456|057|D|action, through studies on their effects on the QTc interval, or through|
04456|058|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04456|059|D|and/or postmarketing reports.(4)|
04456|060|D|   Moderate inhibitors of CYP3A4 that prolong QT include: dronedarone.(5,6)|
04456|061|B||
04456|062|R|REFERENCES:|
04456|063|B||
04456|064|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04456|065|R|  Inc. September, 2023.|1
04456|066|R|2.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
04456|067|R|  November, 2020.|1
04456|068|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04456|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04456|070|R|  settings: a scientific statement from the American Heart Association and|6
04456|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04456|072|R|  2;55(9):934-47.|6
04456|073|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04456|074|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04456|075|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04456|076|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04456|077|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04456|078|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04456|079|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04456|080|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04456|081|R|  11/14/2017.|1
04456|082|R|6.This information is based on an extract from the Certara Drug Interaction|6
04456|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04457|001|T|MONOGRAPH TITLE:  Gepirone/Serotoninergic Agents|
04457|002|B||
04457|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04457|004|L|take action as needed.|
04457|005|B||
04457|006|A|MECHANISM OF ACTION:  Gepirone is a serotonin receptor agonist.  Concurrent|
04457|007|A|administration with one or more serotonergic agents may increase serotonin|
04457|008|A|effects, resulting in serotonin toxicity.(1,2)|
04457|009|B||
04457|010|E|CLINICAL EFFECTS:  Concurrent use of gepirone with other serotonergic agents|
04457|011|E|may increase the risk of hypertensive crisis and serotonin syndrome, a|
04457|012|E|potentially life-threatening syndrome which may include one or more of the|
04457|013|E|following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus,|
04457|014|E|tachycardia, hyperthermia, and muscle rigidity.(1)|
04457|015|B||
04457|016|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04457|017|P|systemic concentrations of either drug would be predicted to increase risk|
04457|018|P|for serotonin toxicity.(2)|
04457|019|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04457|020|P|concentrations may also increase risk for serotonin syndrome.(2)|
04457|021|B||
04457|022|M|PATIENT MANAGEMENT:  If concurrent use of gepirone with other serotonergic|
04457|023|M|agents is clinically warranted, counsel the patient on the increased risk of|
04457|024|M|serotonin syndrome and monitor for symptoms.  If symptoms of serotonin|
04457|025|M|syndrome develop, discontinue gepirone and/or the other serotonergic agents|
04457|026|M|immediately and initiate supportive measures.(1)|
04457|027|B||
04457|028|D|DISCUSSION:  Gepirone and its 3'-OH metabolite act as agonists at 5HT1A|
04457|029|D|receptors.  Use with other agents that also increase serotonin in the body|
04457|030|D|must be undertaken with caution and monitored closely due to the risk of|
04457|031|D|serotonin syndrome.(1)|
04457|032|B||
04457|033|R|REFERENCES:|
04457|034|B||
04457|035|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04457|036|R|  Inc. September, 2023.|1
04457|037|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04457|038|R|  352(11):1112-20.|6
04458|001|T|MONOGRAPH TITLE:  Gepirone/Serotoninergic Agents that Prolong QT|
04458|002|B||
04458|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04458|004|L|take action as needed.|
04458|005|B||
04458|006|A|MECHANISM OF ACTION:  Gepirone is a serotonin receptor agonist.  Concurrent|
04458|007|A|use with one or more serotonergic agents that prolong the QTc interval may|
04458|008|A|increase serotonin effects.  Concurrent use may also result in additive|
04458|009|A|effects on the QTc interval.(1,2)|
04458|010|B||
04458|011|E|CLINICAL EFFECTS:  Concurrent use of gepirone with other serotonergic agents|
04458|012|E|that prolong the QTc interval may increase the risk of hypertensive crisis|
04458|013|E|and serotonin syndrome, a potentially life-threatening syndrome which may|
04458|014|E|include one or more of the following symptoms: tremor, agitation,|
04458|015|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04458|016|E|rigidity.(1)|
04458|017|E|   Additive QTc prolongation may also occur, resulting in potentially|
04458|018|E|life-threatening arrhythmias like torsades de pointes.(1)|
04458|019|B||
04458|020|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04458|021|P|systemic concentrations of either drug would be predicted to increase risk|
04458|022|P|for serotonin toxicity.(2)|
04458|023|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04458|024|P|concentrations may also increase risk for serotonin syndrome.(2)|
04458|025|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04458|026|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04458|027|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04458|028|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04458|029|P|advanced age.(3)|
04458|030|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04458|031|P|higher systemic concentrations of either QT prolonging drug are additional|
04458|032|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04458|033|P|drug concentrations include rapid infusion of an intravenous dose or|
04458|034|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04458|035|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04458|036|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04458|037|B||
04458|038|M|PATIENT MANAGEMENT:  If concurrent use of gepirone with other serotonergic|
04458|039|M|agents is clinically warranted, counsel the patient on the increased risk of|
04458|040|M|serotonin syndrome and monitor for symptoms.  If symptoms of serotonin|
04458|041|M|syndrome develop, discontinue gepirone and/or the other serotonergic agents|
04458|042|M|immediately and initiate supportive measures.(1)|
04458|043|M|   Gepirone should be used with caution and ECGs should be monitored more|
04458|044|M|frequently when used with other agents known to prolong the QTc interval.(1)|
04458|045|M|   If QTcF is > 450 msec at baseline, do not initiate gepirone.  If QTc|
04458|046|M|increases to > 450 msec during treatment, monitor ECGs more frequently and|
04458|047|M|do not increase the dose of gepirone.(1)|
04458|048|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04458|049|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04458|050|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04458|051|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04458|052|B||
04458|053|D|DISCUSSION:  Gepirone and its 3'-OH metabolite act as agonists at 5HT1A|
04458|054|D|receptors.  Use with other agents that also increase serotonin in the body|
04458|055|D|must be undertaken with caution and monitored closely due to the risk of|
04458|056|D|serotonin syndrome.(1)|
04458|057|D|   In a thorough QT study, 100 mg per day of immediate-release gepirone|
04458|058|D|increased the mean QTc 18.4 msec (upper 90% CI = 22.7 msec) on day 1 and|
04458|059|D|16.1 msec (upper 90% CI = 20.7) on day 7.  The dose of gepirone was 2-fold|
04458|060|D|the exposure of the recommended maximum daily dose.(1)|
04458|061|D|   Agents that are linked to this monograph may have varying degrees of|
04458|062|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04458|063|D|been shown to prolong the QTc interval either through their mechanism of|
04458|064|D|action, through studies on their effects on the QTc interval, or through|
04458|065|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04458|066|D|and/or postmarketing reports.(4)|
04458|067|B||
04458|068|R|REFERENCES:|
04458|069|B||
04458|070|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04458|071|R|  Inc. September, 2023.|1
04458|072|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04458|073|R|  352(11):1112-20.|6
04458|074|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04458|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04458|076|R|  settings: a scientific statement from the American Heart Association and|6
04458|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04458|078|R|  2;55(9):934-47.|6
04458|079|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04458|080|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04458|081|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04458|082|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04459|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Meropenem-Vaborbactam|
04459|002|B||
04459|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04459|004|L|take action as needed.|
04459|005|B||
04459|006|A|MECHANISM OF ACTION:  Meropenem-vaborbactam may induce the CYP3A4-mediated|
04459|007|A|metabolism of hormonal contraceptives.(1,2)|
04459|008|B||
04459|009|E|CLINICAL EFFECTS:  Concurrent use of meropenem-vaborbactam may reduce the|
04459|010|E|blood concentrations and  effectiveness of hormonal contraceptives.(1,2)|
04459|011|B||
04459|012|P|PREDISPOSING FACTORS:  None determined.|
04459|013|B||
04459|014|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled not to|
04459|015|M|rely on hormonal contraception (including oral contraceptives, patches,|
04459|016|M|implants, and/or IUDs) for contraception.  Women should use an effective|
04459|017|M|non-hormonal method of contraception or an additional method of birth|
04459|018|M|control during and for 28 days after meropenem-vaborbactam therapy.(1,2)|
04459|019|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04459|020|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04459|021|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04459|022|M|contraceptive (i.e., a copper IUD).  If a non-hormonal emergency|
04459|023|M|contraceptive is not an option, double the usual dose of levonorgestrel from|
04459|024|M|1.5 to 3 mg.  Advise the patient to have a pregnancy test to exclude|
04459|025|M|pregnancy after use and to seek medical advice if they do become|
04459|026|M|pregnant.(2)|
04459|027|B||
04459|028|D|DISCUSSION:  There have been no studies evaluating the potential of|
04459|029|D|meropenem-vaborbactam to interact with other drugs.  In vitro data suggest|
04459|030|D|that both meropenem and vaborbactam are weak CYP3A4 inducers.(1,2)|
04459|031|B||
04459|032|R|REFERENCES:|
04459|033|B||
04459|034|R|1.Vabomere (meropenem vaborbactam) US prescribing information. September,|1
04459|035|R|  2023 Melinta Therapeutics, LLC.|1
04459|036|R|2.Vaborem (meropenem-vaborbactam) UK Summary of Product Characteristics.|1
04459|037|R|  Menarini International Operations Luxembourg S.A. March, 2023.|1
04459|038|R|3.Medicines and Healthcare products Regulatory Agency.|1
04459|039|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04459|040|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04459|041|R|  available at:|1
04459|042|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04459|043|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04459|044|R|  -and-contraceptive-efficacy September 15, 2016..|1
04460|001|T|MONOGRAPH TITLE:  Etrasimod/Dual CYP2C9 and CYP3A4 Inhibitors that Prolong|
04460|002|T|QT|
04460|003|B||
04460|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04460|005|L|of severe adverse interaction.|
04460|006|B||
04460|007|A|MECHANISM OF ACTION:  Dual moderate to strong inhibitors of CYP2C9 and|
04460|008|A|CYP3A4 that prolong the QTc interval may inhibit the metabolism of|
04460|009|A|etrasimod.  Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)|
04460|010|A|   Initiation of etrasimod has a negative chronotropic effect, which may|
04460|011|A|increase the risk of developing QT prolongation.(1)|
04460|012|B||
04460|013|E|CLINICAL EFFECTS:  Concurrent use of a dual moderate or strong inhibitor of|
04460|014|E|CYP2C9 and CYP3A4 may result in elevated levels and increased effects of|
04460|015|E|etrasimod.(1)|
04460|016|E|   Initiation of etrasimod may result in a transient decrease in heart rate.|
04460|017|E|A mean decrease in heart rate of 7.2 (8.98) beats per minute was seen 2 to|
04460|018|E|3 hours after the first dose.  The first dose has also been associated with|
04460|019|E|heart block. Symptomatic bradycardia has been observed.  Bradycardia may be|
04460|020|E|associated with an increase in the QTc interval, increasing the risk for|
04460|021|E|torsades de pointes.(1)|
04460|022|B||
04460|023|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
04460|024|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
04460|025|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
04460|026|P|prolonged QTc interval prior to etrasimod initiation, factors associated|
04460|027|P|with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant|
04460|028|P|treatment with QT prolonging agents may increase risk for cardiovascular|
04460|029|P|toxicity due to etrasimod.|
04460|030|P|   The risk of QT prolongation or torsades de pointes may also be increased|
04460|031|P|in patients with a history of torsades de pointes, hypocalcemia,|
04460|032|P|bradycardia, female gender, or advanced age.(2)|
04460|033|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04460|034|P|higher systemic concentrations of the QT prolonging drug are additional risk|
04460|035|P|factors for torsades de pointes.  Factors which may increase systemic drug|
04460|036|P|concentrations include rapid infusion of an intravenous dose or impaired|
04460|037|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
04460|038|P|which inhibits its metabolism or elimination, genetic impairment in drug|
04460|039|P|metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04460|040|B||
04460|041|M|PATIENT MANAGEMENT:  Concomitant use of etrasimod with dual moderate to|
04460|042|M|strong inhibitors of CYP2C9 and CYP3A4 is not recommended.(1)|
04460|043|M|   If concurrent therapy is unavoidable, obtain an ECG to determine if|
04460|044|M|preexisting conduction abnormalities are present prior to initiation of|
04460|045|M|etrasimod.(1)|
04460|046|M|   Advice from a cardiologist is recommended in patients with preexisting|
04460|047|M|heart and cerebrovascular conditions, prolonged QTc interval, risk factors|
04460|048|M|for QT prolongation, concurrent therapy with QT prolonging drugs or drugs|
04460|049|M|that slow the heart rate or AV conduction.(1)|
04460|050|M|   Monitor blood pressure during treatment.(1)|
04460|051|B||
04460|052|D|DISCUSSION:  Initiation of etrasimod may result in a transient decrease in|
04460|053|D|heart rate or transient AV conduction delays.(1)|
04460|054|D|   A transient decrease in heart rate was observed during the initial dosing|
04460|055|D|phase of etrasimod and bradyarrhythmic events (AV blocks) were detected at a|
04460|056|D|higher incidence under etrasimod treatment than placebo.(1)|
04460|057|D|   Concomitant use of etrasimod with steady-state fluconazole (moderate|
04460|058|D|CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by|
04460|059|D|84%.(1)|
04460|060|D|   Dual inhibitors of CYP2C9 and CYP3A4 include: adagrasib and|
04460|061|D|fluconazole.(3)|
04460|062|B||
04460|063|R|REFERENCES:|
04460|064|B||
04460|065|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04460|066|R|  2023.|1
04460|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04460|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04460|069|R|  settings: a scientific statement from the American Heart Association and|6
04460|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04460|071|R|  2;55(9):934-47.|6
04460|072|R|3.This information is based on an extract from the Certara Drug Interaction|6
04460|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04461|001|T|MONOGRAPH TITLE:  Etrasimod/Strong and Moderate CYP2C8 Inhibitors|
04461|002|B||
04461|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04461|004|L|take action as needed.|
04461|005|B||
04461|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP2C8 may impair|
04461|007|A|the CYP2C8-mediated metabolism of etrasimod.(1)|
04461|008|A|   Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)|
04461|009|B||
04461|010|E|CLINICAL EFFECTS:  In patients who are poor metabolizers of CYP2C9,|
04461|011|E|concurrent use of a strong or moderate inhibitor of CYP2C8 may result in|
04461|012|E|elevated levels of and clinical effects from etrasimod including|
04461|013|E|immunosuppression, decreased lung function, bradycardia, and AV conduction|
04461|014|E|delays.|
04461|015|B||
04461|016|P|PREDISPOSING FACTORS:  CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may|
04461|017|P|have decreased clearance of etrasimod when etrasimod is used concomitantly|
04461|018|P|with strong or moderate inhibitors of CYP2C8.(1)|
04461|019|B||
04461|020|M|PATIENT MANAGEMENT:  Concomitant use of etrasimod with strong or moderate|
04461|021|M|CYP2C8 inhibitors in patients who are CYP2C9 poor metabolizers is not|
04461|022|M|recommended.(1)|
04461|023|B||
04461|024|D|DISCUSSION:  CYP2C9 activity is decreased in individuals with genetic|
04461|025|D|variants such as CYP2C9*2 and CYP2C9*3 alleles.  The impact of CYP2C9|
04461|026|D|genetic variants on the pharmacokinetics of etrasimod has not been directly|
04461|027|D|evaluated.  Increased exposure of etrasimod in patients who are CYP2C9 poor|
04461|028|D|metabolizers is expected with concomitant use of strong or moderate|
04461|029|D|inhibitors of CYP2C8.(1)|
04461|030|D|   Concomitant use of etrasimod with steady-state fluconazole (a moderate|
04461|031|D|CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by|
04461|032|D|84%.(1)|
04461|033|D|   Strong inhibitors of CYP2C8 include: clopidogrel and gemfibrozil.(2,3)|
04461|034|D|   Moderate inhibitors of CYP2C8 include: deferasirox.(2,3)|
04461|035|B||
04461|036|R|REFERENCES:|
04461|037|B||
04461|038|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04461|039|R|  2023.|1
04461|040|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04461|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04461|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04461|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04461|044|R|  11/14/2017.|1
04461|045|R|3.This information is based on an extract from the Certara Drug Interaction|6
04461|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04462|001|T|MONOGRAPH TITLE:  Etrasimod/QT Prolonging Agents|
04462|002|B||
04462|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04462|004|L|take action as needed.|
04462|005|B||
04462|006|A|MECHANISM OF ACTION:  Etrasimod is a sphingosine-1-phosphate (S1P) receptor|
04462|007|A|modulator.  Initiation of etrasimod has a negative chronotropic effect,|
04462|008|A|which may increase the risk of developing QT prolongation.|
04462|009|B||
04462|010|E|CLINICAL EFFECTS:  Initiation of etrasimod may result in a transient|
04462|011|E|decrease in heart rate. A mean decrease in heart rate of 7.2 (8.98) beats|
04462|012|E|per minute was seen 2 to 3 hours after the first dose.  The first dose has|
04462|013|E|also been associated with heart block. Symptomatic bradycardia has been|
04462|014|E|observed.  Bradycardia may be associated with an increase in the QTc|
04462|015|E|interval, increasing the risk for torsades de pointes.(1)|
04462|016|B||
04462|017|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
04462|018|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
04462|019|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
04462|020|P|prolonged QTc interval prior to etrasimod initiation, factors associated|
04462|021|P|with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant|
04462|022|P|treatment with QT prolonging agents may increase risk for cardiovascular|
04462|023|P|toxicity due to etrasimod.|
04462|024|P|   The risk of QT prolongation or torsades de pointes may also be increased|
04462|025|P|in patients with a history of torsades de pointes, hypocalcemia,|
04462|026|P|bradycardia, female gender, or advanced age.(2)|
04462|027|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04462|028|P|higher systemic concentrations of the QT prolonging drug are additional risk|
04462|029|P|factors for torsades de pointes.  Factors which may increase systemic drug|
04462|030|P|concentrations include rapid infusion of an intravenous dose or impaired|
04462|031|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
04462|032|P|which inhibits its metabolism or elimination, genetic impairment in drug|
04462|033|P|metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04462|034|B||
04462|035|M|PATIENT MANAGEMENT:  Prior to initiation of etrasimod, obtain an ECG to|
04462|036|M|determine if preexisting conduction abnormalities are present.(1)|
04462|037|M|   Advice from a cardiologist is recommended in patients with preexisting|
04462|038|M|heart and cerebrovascular conditions, prolonged QTc interval, risk factors|
04462|039|M|for QT prolongation, concurrent therapy with QT prolonging drugs or drugs|
04462|040|M|that slow the heart rate or AV conduction.(1)|
04462|041|M|   Monitor blood pressure during treatment.(1)|
04462|042|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04462|043|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04462|044|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04462|045|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04462|046|B||
04462|047|D|DISCUSSION:  Initiation of etrasimod may result in a transient decrease in|
04462|048|D|heart rate or transient AV conduction delays.(1)|
04462|049|D|   A transient decrease in heart rate was observed during the initial dosing|
04462|050|D|phase of etrasimod and bradyarrhythmic events (AV blocks) were detected at a|
04462|051|D|higher incidence under etrasimod treatment than placebo.(1)|
04462|052|B||
04462|053|R|REFERENCES:|
04462|054|B||
04462|055|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04462|056|R|  2023.|1
04462|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04462|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04462|059|R|  settings: a scientific statement from the American Heart Association and|6
04462|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04462|061|R|  2;55(9):934-47.|6
04463|001|T|MONOGRAPH TITLE:  Etrasimod/Agents That Cause Bradycardia|
04463|002|B||
04463|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04463|004|L|of severe adverse interaction.|
04463|005|B||
04463|006|A|MECHANISM OF ACTION:  Initiation of etrasimod has caused transient decreases|
04463|007|A|in heart rate and atrioventricular conduction delays after the first dose.|
04463|008|A|The first dose has also been associated with heart block.  Additional agents|
04463|009|A|that cause bradycardia further increase the risk for symptomatic|
04463|010|A|bradycardia.(1)|
04463|011|B||
04463|012|E|CLINICAL EFFECTS:  The heart rate lowering effect of etrasimod is transient|
04463|013|E|and is usually seen with the first dose.  Bradycardia may be associated with|
04463|014|E|an increase in the QTc interval, increasing the risk for torsade de|
04463|015|E|pointes.(1)|
04463|016|B||
04463|017|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular disease (e.g. heart|
04463|018|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
04463|019|P|history of torsades de pointes, or heart block), severe untreated sleep|
04463|020|P|apnea, a prolonged QTc interval prior to etrasimod initiation, or factors|
04463|021|P|associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia,|
04463|022|P|bradycardia, female gender, or advanced age) may increase risk for|
04463|023|P|cardiovascular toxicity due to etrasimod.(2)|
04463|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04463|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04463|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04463|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04463|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04463|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04463|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04463|031|B||
04463|032|M|PATIENT MANAGEMENT:  The prescribing information for etrasimod treatment|
04463|033|M|states that advice from a cardiologist should be sought before initiating|
04463|034|M|etrasimod treatment in patients currently taking additional agents that|
04463|035|M|cause bradycardia or in patients with preexisting heart and cerebrovascular|
04463|036|M|conditions, with resting heart rate of less than 50 bpm, history of|
04463|037|M|symptomatic bradycardia, recurrent cardiogenic syncope, severe untreated|
04463|038|M|sleep apnea, or history of Mobitz type 1 second-degree AV block (unless has|
04463|039|M|functioning pacemaker).(1)|
04463|040|M|   Monitor blood pressure during treatment.(1)|
04463|041|B||
04463|042|D|DISCUSSION:  Initiation of etrasimod treatment has been associated with|
04463|043|D|transient atrioventricular (AV) conduction delays. The AV conduction delays|
04463|044|D|manifested  as first or second degree AV block (prolonged PR interval on|
04463|045|D|ECG), which occurred in 0.7% of etrasimod treated patients in UC-1 and in|
04463|046|D|0.8% of patients in UC-2 and UC-3 compared to 0% for placebo in all|
04463|047|D|studies.(1)|
04463|048|B||
04463|049|R|REFERENCES:|
04463|050|B||
04463|051|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04463|052|R|  2023.|1
04463|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04463|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04463|055|R|  settings: a scientific statement from the American Heart Association and|6
04463|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04463|057|R|  2;55(9):934-47.|6
04464|001|T|MONOGRAPH TITLE:  Etrasimod/Beta-Blockers|
04464|002|B||
04464|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04464|004|L|of severe adverse interaction.|
04464|005|B||
04464|006|A|MECHANISM OF ACTION:  Initiation of etrasimod has caused transient decreases|
04464|007|A|in heart rate and atrioventricular conduction delays after the first dose.|
04464|008|A|The first dose has also been associated with heart block.  Beta-blockers|
04464|009|A|further increase the risk for symptomatic bradycardia or heart block.(1)|
04464|010|B||
04464|011|E|CLINICAL EFFECTS:  The heart rate lowering effect of etrasimod is transient|
04464|012|E|and is usually seen with the first dose.  Bradycardia may be associated with|
04464|013|E|an increase in the QTc interval, increasing the risk for torsade de|
04464|014|E|pointes.(1)|
04464|015|B||
04464|016|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular disease (e.g. heart|
04464|017|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
04464|018|P|history of torsades de pointes, or heart block), severe untreated sleep|
04464|019|P|apnea, a prolonged QTc interval prior to etrasimod initiation, or factors|
04464|020|P|associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia,|
04464|021|P|bradycardia, female gender, or advanced age) may increase risk for|
04464|022|P|cardiovascular toxicity due to etrasimod.|
04464|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04464|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04464|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04464|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04464|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04464|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04464|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04464|030|B||
04464|031|M|PATIENT MANAGEMENT:  The prescribing information states etrasimod therapy|
04464|032|M|can be initiated in patients receiving stable doses of beta blocker therapy.|
04464|033|M|Cardiology consultation is recommended before initiating a beta blocker in a|
04464|034|M|patient receiving stable etrasimod treatment.(1)|
04464|035|B||
04464|036|D|DISCUSSION:  Initiation of etrasimod may result in a transient decrease in|
04464|037|D|heart rate and AV conduction delays.|
04464|038|D|   In two studies, after the first dose of etrasimod 2 mg, ulcerative|
04464|039|D|colitis patients saw a mean decrease from baseline in heart rate of 7.2 bpm|
04464|040|D|at hour 3 in UC-1 an hour 2 in UC-2.(1)|
04464|041|D|   In UC-1, bradycardia was reported on Day 1 in 1% of etrasimod patients,|
04464|042|D|0.3% on Day 2 compared to no patients receiving placebo.In UC-2 and UC-3,|
04464|043|D|bradycardia was reported on Day 1 in 2.9% of etrasimod patients, 0.3% on Day|
04464|044|D|2 compared to no patients receiving placebo. Patients experiencing|
04464|045|D|bradycardia were generally asymptomatic. The few patients with symptomatic|
04464|046|D|bradycardia reported dizziness that resolved without intervention.(1)|
04464|047|D|   Beta-Blockers linked to this monograph are: atenolol, betaxolol,|
04464|048|D|bisoprolol, carvedilol, esmolol, labetalol, landiolol, metoprolol, nadolol,|
04464|049|D|nebivolol, propranolol and timolol.|
04464|050|B||
04464|051|R|REFERENCES:|
04464|052|B||
04464|053|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04464|054|R|  2023.|1
04464|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04464|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04464|057|R|  settings: a scientific statement from the American Heart Association and|6
04464|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04464|059|R|  2;55(9):934-47.|6
04465|001|T|MONOGRAPH TITLE:  Etrasimod/CYP2C8 Inhibitors that Prolong QT|
04465|002|B||
04465|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04465|004|L|take action as needed.|
04465|005|B||
04465|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2C8 that prolong the QTc interval may|
04465|007|A|inhibit the metabolism of etrasimod.  Etrasimod is metabolized by CYP2C8,|
04465|008|A|CYP2C9, and CYP3A4.(1)|
04465|009|A|   Initiation of etrasimod has a negative chronotropic effect, which may|
04465|010|A|increase the risk of developing QT prolongation.(1)|
04465|011|B||
04465|012|E|CLINICAL EFFECTS:  In patients who are poor metabolizers of CYP2C9,|
04465|013|E|concurrent use of an inhibitor of CYP2C8 may result in elevated levels and|
04465|014|E|increased effects of etrasimod.(1)|
04465|015|E|   Initiation of etrasimod may result in a transient decrease in heart rate.|
04465|016|E|A mean decrease in heart rate of 7.2 (8.98) beats per minute was seen 2 to|
04465|017|E|3 hours after the first dose.  The first dose has also been associated with|
04465|018|E|heart block. Symptomatic bradycardia has been observed.  Bradycardia may be|
04465|019|E|associated with an increase in the QTc interval, increasing the risk for|
04465|020|E|torsades de pointes.(1)|
04465|021|B||
04465|022|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
04465|023|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
04465|024|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
04465|025|P|prolonged QTc interval prior to etrasimod initiation, factors associated|
04465|026|P|with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant|
04465|027|P|treatment with QT prolonging agents may increase risk for cardiovascular|
04465|028|P|toxicity due to etrasimod.|
04465|029|P|   The risk of QT prolongation or torsades de pointes may also be increased|
04465|030|P|in patients with a history of torsades de pointes, hypocalcemia,|
04465|031|P|bradycardia, female gender, or advanced age.(2)|
04465|032|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04465|033|P|higher systemic concentrations of the QT prolonging drug are additional risk|
04465|034|P|factors for torsades de pointes.  Factors which may increase systemic drug|
04465|035|P|concentrations include rapid infusion of an intravenous dose or impaired|
04465|036|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
04465|037|P|which inhibits its metabolism or elimination, genetic impairment in drug|
04465|038|P|metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04465|039|P|   CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased|
04465|040|P|clearance of etrasimod when etrasimod is used concomitantly with strong or|
04465|041|P|moderate inhibitors of CYP2C8.(1)|
04465|042|B||
04465|043|M|PATIENT MANAGEMENT:  Concomitant use of etrasimod with strong or moderate|
04465|044|M|CYP2C8 inhibitors in patients who are CYP2C9 poor metabolizers is not|
04465|045|M|recommended.(1)|
04465|046|M|   If concurrent therapy is unavoidable, obtain an ECG to determine if|
04465|047|M|preexisting conduction abnormalities are present prior to initiation of|
04465|048|M|etrasimod.(1)|
04465|049|M|   Advice from a cardiologist is recommended in patients with preexisting|
04465|050|M|heart and cerebrovascular conditions, prolonged QTc interval, risk factors|
04465|051|M|for QT prolongation, concurrent therapy with QT prolonging drugs or drugs|
04465|052|M|that slow the heart rate or AV conduction.(1)|
04465|053|M|   Monitor blood pressure during treatment.(1)|
04465|054|B||
04465|055|D|DISCUSSION:  Initiation of etrasimod may result in a transient decrease in|
04465|056|D|heart rate or transient AV conduction delays.(1)|
04465|057|D|   A transient decrease in heart rate was observed during the initial dosing|
04465|058|D|phase of etrasimod and bradyarrhythmic events (AV blocks) were detected at a|
04465|059|D|higher incidence under etrasimod treatment than placebo.(1)|
04465|060|D|   CYP2C9 activity is decreased in individuals with genetic variants such as|
04465|061|D|CYP2C9*2 and CYP2C9*3 alleles.  The impact of CYP2C9 genetic variants on the|
04465|062|D|pharmacokinetics of etrasimod has not been directly evaluated.  Increased|
04465|063|D|exposure of etrasimod in patients who are CYP2C9 poor metabolizers is|
04465|064|D|expected with concomitant use of moderate to strong inhibitors of CYP2C8.(1)|
04465|065|D|   Concomitant use of etrasimod with steady-state fluconazole (a moderate|
04465|066|D|CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by|
04465|067|D|84%.(1)|
04465|068|D|   Moderate inhibitors of CYP2C8 include: selpercatinib.(3)|
04465|069|B||
04465|070|R|REFERENCES:|
04465|071|B||
04465|072|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04465|073|R|  2023.|1
04465|074|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04465|075|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04465|076|R|  settings: a scientific statement from the American Heart Association and|6
04465|077|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04465|078|R|  2;55(9):934-47.|6
04465|079|R|3.This information is based on an extract from the Certara Drug Interaction|6
04465|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04466|001|T|MONOGRAPH TITLE:  Etrasimod/Strong and Moderate CYP3A4 Inhibitors|
04466|002|B||
04466|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04466|004|L|take action as needed.|
04466|005|B||
04466|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may impair|
04466|007|A|the CYP3A4-mediated metabolism of etrasimod.(1)|
04466|008|A|   Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)|
04466|009|B||
04466|010|E|CLINICAL EFFECTS:  In patients who are poor metabolizers of CYP2C9 or are|
04466|011|E|also taking a strong or moderate CYP2C9 inhibitor, concurrent use of a|
04466|012|E|strong or moderate inhibitor of CYP3A4 may result in elevated levels of and|
04466|013|E|clinical effects from etrasimod including immunosuppression, decreased lung|
04466|014|E|function, bradycardia, and AV conduction delays.|
04466|015|B||
04466|016|P|PREDISPOSING FACTORS:  CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may|
04466|017|P|have decreased clearance of etrasimod when etrasimod is used concomitantly|
04466|018|P|with strong or moderate inhibitors of CYP3A4.  Patients who are also taking|
04466|019|P|a strong or moderate CYP2C9 inhibitor may also have decreased etrasimod|
04466|020|P|clearance.(1)|
04466|021|B||
04466|022|M|PATIENT MANAGEMENT:  Concomitant use of etrasimod with strong or moderate|
04466|023|M|CYP3A4 inhibitors in patients who are CYP2C9 poor metabolizers is not|
04466|024|M|recommended.(1)|
04466|025|M|   Concomitant use with strong or moderate CYP3A4 inhibitors in patients who|
04466|026|M|are also taking a strong or moderate CYP2C9 inhibitor is not recommended.|
04466|027|M|(1)|
04466|028|B||
04466|029|D|DISCUSSION:  CYP2C9 activity is decreased in individuals with genetic|
04466|030|D|variants such as CYP2C9*2 and CYP2C9*3 alleles.  The impact of CYP2C9|
04466|031|D|genetic variants on the pharmacokinetics of etrasimod has not been directly|
04466|032|D|evaluated.  Increased exposure of etrasimod in patients who are CYP2C9 poor|
04466|033|D|metabolizers is expected with concomitant use of moderate to strong|
04466|034|D|inhibitors of CYP3A4.(1)|
04466|035|D|   Concomitant use of etrasimod with steady-state fluconazole (a moderate|
04466|036|D|CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by|
04466|037|D|84%.(1)|
04466|038|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, grapefruit,|
04466|039|D|indinavir, itraconazole, josamycin, ketoconazole, mibefradil, nefazodone,|
04466|040|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir,|
04466|041|D|troleandomycin, and tucatinib.(2,3)|
04466|042|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
04466|043|D|atazanavir, avacopan, berotralstat, conivaptan, darunavir, fluvoxamine,|
04466|044|D|fosamprenavir, fosnetupitant, isavuconazonium, letermovir, lenacapavir,|
04466|045|D|netupitant, schisandra, stiripentol, tofisopam, and voxelotor.(2,3)|
04466|046|B||
04466|047|R|REFERENCES:|
04466|048|B||
04466|049|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04466|050|R|  2023.|1
04466|051|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04466|052|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04466|053|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04466|054|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04466|055|R|  11/14/2017.|1
04466|056|R|3.This information is based on an extract from the Certara Drug Interaction|6
04466|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04467|001|T|MONOGRAPH TITLE:  Clozapine/Etrasimod|
04467|002|B||
04467|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04467|004|L|of severe adverse interaction.|
04467|005|B||
04467|006|A|MECHANISM OF ACTION:  Concurrent use of clozapine with other agents that|
04467|007|A|prolong the QTc interval may result in additive effects on the QTc|
04467|008|A|interval.(1)  Initiation of etrasimod has a negative chronotropic effect|
04467|009|A|leading to a mean decrease in heart rate of 7 beats per minute (bpm) after|
04467|010|A|the first dose.(1)  This may increase the risk of QT prolongation.(1-4)|
04467|011|A|   Etrasimod causes reversible sequestration of lymphocytes in lymphoid|
04467|012|A|tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte|
04467|013|A|count at 52 weeks.(1)  Clozapine may be associated with additive risk of|
04467|014|A|neutropenia or agranulocytosis.|
04467|015|B||
04467|016|E|CLINICAL EFFECTS:  Concurrent use of clozapine with agents that prolong the|
04467|017|E|QTc interval may result in life-threatening cardiac arrhythmias.(2)|
04467|018|E|   Initiation of etrasimod may result in a transient decrease in heart rate.|
04467|019|E|A mean decrease in heart rate of 7.2 beats per minute was seen 2 to 3 hours|
04467|020|E|after the first dose. The first dose has also been associated with heart|
04467|021|E|block. Symptomatic bradycardia has been observed. Bradycardia may be|
04467|022|E|associated with an increase in the QTc interval, increasing the risk for|
04467|023|E|torsades des pointes.(1,3,4)|
04467|024|E|   Concurrent use of etrasimod and clozapine may result in an increased risk|
04467|025|E|of fatal infections, such as disseminated herpetic infection, cryptococcal|
04467|026|E|infection, or progressive multifocal leukoencephalopathy (PML).(1,2)|
04467|027|B||
04467|028|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04467|029|P|may be increased in patients with cardiovascular disease (e.g. heart|
04467|030|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04467|031|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04467|032|P|female gender, or advanced age.(4)|
04467|033|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04467|034|P|higher systemic concentrations of the QT prolonging drug are additional risk|
04467|035|P|factors for torsades de pointes.  Factors which may increase systemic drug|
04467|036|P|concentrations include rapid infusion of an intravenous dose or impaired|
04467|037|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
04467|038|P|which inhibits its metabolism or elimination, genetic impairment in drug|
04467|039|P|metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04467|040|P|   Incomplete washout of previously prescribed immunosuppressive or|
04467|041|P|immune-modulating medications may increase the risk from this|
04467|042|P|interaction.(1)|
04467|043|B||
04467|044|M|PATIENT MANAGEMENT:  Approach the concurrent use of clozapine and other|
04467|045|M|agents that prolong the QTc interval with caution.(2) Prior to initiation of|
04467|046|M|etrasimod, obtain an ECG to determine if preexisting conduction|
04467|047|M|abnormalities are present.(1)|
04467|048|M|   The prescribing information for etrasimod treatment states that advice|
04467|049|M|from a cardiologist should be sought before initiating etrasimod treatment|
04467|050|M|in patients currently taking additional agents that cause bradycardia, such|
04467|051|M|as clozapine, or in patients with preexisting heart and cerebrovascular|
04467|052|M|conditions, with resting heart rate of less than 50 bpm, history of|
04467|053|M|symptomatic bradycardia, recurrent cardiogenic syncope, severe untreated|
04467|054|M|sleep apnea, or history of Mobitz type 1 second-degree AV block (unless has|
04467|055|M|functioning pacemaker).(1)|
04467|056|M|   If concurrent therapy is unavoidable, obtain an ECG to determine if|
04467|057|M|preexisting conduction abnormalities are present prior to initiation of|
04467|058|M|etrasimod.  Instruct patients to report any irregular heartbeat, dizziness,|
04467|059|M|or fainting.|
04467|060|M|   The etrasimod US prescribing information states etrasimod has not been|
04467|061|M|studied in combination with anti-neoplastic, immune-modulating, or|
04467|062|M|immunosuppressive therapies.  Concomitant administration of these therapies|
04467|063|M|with etrasimod should be avoided because of the risk of additive immune|
04467|064|M|effects during therapy and in the weeks following administration.|
04467|065|M|Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks|
04467|066|M|after discontinuation.(1)|
04467|067|M|   When switching from drugs with prolonged immune effects, the half-life|
04467|068|M|and mode of action of these drugs must be considered in order to avoid|
04467|069|M|unintended additive immunosuppressive effects.(1)|
04467|070|B||
04467|071|D|DISCUSSION:  Treatment with clozapine has been associated with QT|
04467|072|D|prolongation as well as ventricular arrhythmia, torsades de pointes, cardiac|
04467|073|D|arrest, and sudden death.(2)|
04467|074|D|   Initiation of etrasimod may result in a transient decrease in heart rate|
04467|075|D|or transient AV conduction delays.(1)|
04467|076|D|   Initiation of etrasimod treatment has been associated with transient|
04467|077|D|atrioventricular (AV) conduction delays. The AV conduction delays manifested|
04467|078|D|as first or second degree AV block (prolonged PR interval on ECG), which|
04467|079|D|occurred in 0.7% of etrasimod treated patients in UC-1 and in 0.8% of|
04467|080|D|patients in UC-2 and UC-3 compared to 0% for placebo in all studies.(1)|
04467|081|D|   Fatal disseminated herpes zoster and herpes simplex infections,|
04467|082|D|cryptococcal meningitis, disseminated cryptococcal infections, and cases of|
04467|083|D|progressive multifocal leukoencephalopathy (PML) have been reported in|
04467|084|D|patients treated with other sphingosine-1 phosphate receptor modulators.(1)|
04467|085|B||
04467|086|R|REFERENCES:|
04467|087|B||
04467|088|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04467|089|R|  2023.|1
04467|090|R|2.Clozaril (clozapine tablets) US prescribing information. Novartis|1
04467|091|R|  Pharmaceuticals Corporation April, 2020.|1
04467|092|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04467|093|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04467|094|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04467|095|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04467|096|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04467|097|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04467|098|R|  settings: a scientific statement from the American Heart Association and|6
04467|099|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04467|100|R|  2;55(9):934-47.|6
04468|001|T|MONOGRAPH TITLE:  Etrasimod/Strong and Moderate 3A4 Inhibitors that Prolong|
04468|002|T|QT|
04468|003|B||
04468|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04468|005|L|take action as needed.|
04468|006|B||
04468|007|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may impair|
04468|008|A|the CYP3A4-mediated metabolism of etrasimod.  Etrasimod is metabolized by|
04468|009|A|CYP2C8, CYP2C9, and CYP3A4.(1)|
04468|010|A|   Initiation of etrasimod has a negative chronotropic effect, which may|
04468|011|A|increase the risk of developing QT prolongation.(1)|
04468|012|B||
04468|013|E|CLINICAL EFFECTS:  In patients who are poor metabolizers of CYP2C9 or are|
04468|014|E|also taking a strong or moderate CYP2C9 inhibitor, concurrent use of a|
04468|015|E|strong or moderate inhibitor of CYP3A4 may result in elevated levels of and|
04468|016|E|clinical effects from etrasimod including immunosuppression, decreased lung|
04468|017|E|function, bradycardia, and AV conduction delays.|
04468|018|E|   Initiation of etrasimod may result in a transient decrease in heart rate.|
04468|019|E|A mean decrease in heart rate of 7.2 (8.98) beats per minute was seen 2 to|
04468|020|E|3 hours after the first dose.  The first dose has also been associated with|
04468|021|E|heart block. Symptomatic bradycardia has been observed.  Bradycardia may be|
04468|022|E|associated with an increase in the QTc interval, increasing the risk for|
04468|023|E|torsades de pointes.(1)|
04468|024|B||
04468|025|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
04468|026|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
04468|027|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
04468|028|P|prolonged QTc interval prior to etrasimod initiation, factors associated|
04468|029|P|with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant|
04468|030|P|treatment with QT prolonging agents may increase risk for cardiovascular|
04468|031|P|toxicity due to etrasimod.|
04468|032|P|   The risk of QT prolongation or torsades de pointes may also be increased|
04468|033|P|in patients with a history of torsades de pointes, hypocalcemia,|
04468|034|P|bradycardia, female gender, or advanced age.(2)|
04468|035|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04468|036|P|higher systemic concentrations of the QT prolonging drug are additional risk|
04468|037|P|factors for torsades de pointes.  Factors which may increase systemic drug|
04468|038|P|concentrations include rapid infusion of an intravenous dose or impaired|
04468|039|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
04468|040|P|which inhibits its metabolism or elimination, genetic impairment in drug|
04468|041|P|metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04468|042|P|   CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased|
04468|043|P|clearance of etrasimod when etrasimod is used concomitantly with strong or|
04468|044|P|moderate inhibitors of CYP3A4.  Patients who are also taking a strong or|
04468|045|P|moderate CYP2C9 inhibitor may also have decreased etrasimod clearance.(1)|
04468|046|B||
04468|047|M|PATIENT MANAGEMENT:  Concomitant use of etrasimod with strong or moderate|
04468|048|M|CYP3A4 inhibitors in patients who are CYP2C9 poor metabolizers is not|
04468|049|M|recommended.(1)|
04468|050|M|   Concomitant use of etrasimod with strong or moderate CYP3A4 inhibitors in|
04468|051|M|patients who are also taking a strong or moderate CYP2C9 inhibitor is not|
04468|052|M|recommended. (1)|
04468|053|M|   If concurrent therapy is unavoidable, obtain an ECG to determine if|
04468|054|M|preexisting conduction abnormalities are present prior to initiation of|
04468|055|M|etrasimod.(1)|
04468|056|M|   Advice from a cardiologist is recommended in patients with preexisting|
04468|057|M|heart and cerebrovascular conditions, prolonged QTc interval, risk factors|
04468|058|M|for QT prolongation, concurrent therapy with QT prolonging drugs or drugs|
04468|059|M|that slow the heart rate or AV conduction.(1)|
04468|060|M|   Monitor blood pressure during treatment.(1)|
04468|061|B||
04468|062|D|DISCUSSION:  Initiation of etrasimod may result in a transient decrease in|
04468|063|D|heart rate or transient AV conduction delays.(1)|
04468|064|D|   A transient decrease in heart rate was observed during the initial dosing|
04468|065|D|phase of etrasimod and bradyarrhythmic events (AV blocks) were detected at a|
04468|066|D|higher incidence under etrasimod treatment than placebo.(1)|
04468|067|D|   CYP2C9 activity is decreased in individuals with genetic variants such as|
04468|068|D|CYP2C9*2 and CYP2C9*3 alleles.  The impact of CYP2C9 genetic variants on the|
04468|069|D|pharmacokinetics of etrasimod has not been directly evaluated.  Increased|
04468|070|D|exposure of etrasimod in patients who are CYP2C9 poor metabolizers is|
04468|071|D|expected with concomitant use of moderate to strong inhibitors of CYP3A4.(1)|
04468|072|D|   Concomitant use of etrasimod with steady-state fluconazole (a moderate|
04468|073|D|CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by|
04468|074|D|84%.(1)|
04468|075|D|   Strong CYP3A4 inhibitors include: ceritinib, clarithromycin,|
04468|076|D|levoketoconazole, lopinavir/ritonavir, posaconazole, saquinavir,|
04468|077|D|telithromycin, and voriconazole.(2,3)|
04468|078|D|   Moderate CYP3A4 inhibitors include: clofazimine, dronedarone,|
04468|079|D|erythromycin, and oral lefamulin.(2,3)|
04468|080|B||
04468|081|R|REFERENCES:|
04468|082|B||
04468|083|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04468|084|R|  2023.|1
04468|085|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04468|086|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04468|087|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04468|088|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04468|089|R|  11/14/2017.|1
04468|090|R|3.This information is based on an extract from the Certara Drug Interaction|6
04468|091|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04469|001|T|MONOGRAPH TITLE:  Etrasimod/Immunosuppressives; Immunomodulators|
04469|002|B||
04469|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04469|004|L|of severe adverse interaction.|
04469|005|B||
04469|006|A|MECHANISM OF ACTION:  Etrasimod causes reversible sequestration of|
04469|007|A|lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in|
04469|008|A|peripheral blood lymphocyte count at 52 weeks.(1)  Other immunosuppressives|
04469|009|A|and immune-modulators also suppress the immune system.|
04469|010|B||
04469|011|E|CLINICAL EFFECTS:  Concurrent use of etrasimod with immunosuppressive or|
04469|012|E|immune-modulating agents may result in an increased risk of serious and|
04469|013|E|fatal infections, such as disseminated herpetic infection, cryptococcal|
04469|014|E|infection, or progressive multifocal leukoencephalopathy (PML).(1)|
04469|015|B||
04469|016|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
04469|017|P|immunosuppressive or immune-modulating medications increases the risk of|
04469|018|P|adverse effects.|
04469|019|B||
04469|020|M|PATIENT MANAGEMENT:  The etrasimod US prescribing information states|
04469|021|M|etrasimod has not been studied in combination with anti-neoplastic,|
04469|022|M|immune-modulating, or immunosuppressive therapies.  Concomitant|
04469|023|M|administration of these therapies with etrasimod should be avoided because|
04469|024|M|of the risk of additive immune effects during therapy and in the weeks|
04469|025|M|following administration.  Etrasimod's effect on peripheral lymphocytes may|
04469|026|M|persist for up to 5 weeks after discontinuation.(1)|
04469|027|M|   When switching from drugs with prolonged immune effects, the half-life|
04469|028|M|and mode of action of these drugs must be considered in order to avoid|
04469|029|M|unintended additive immunosuppressive effects.(1)|
04469|030|B||
04469|031|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections,|
04469|032|D|cryptococcal meningitis, disseminated cryptococcal infections, and cases of|
04469|033|D|progressive multifocal leukoencephalopathy (PML) have been reported in|
04469|034|D|patients treated with other sphingosine-1 phosphate receptor modulators.(1)|
04469|035|B||
04469|036|R|REFERENCE:|
04469|037|B||
04469|038|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04469|039|R|  2023.|1
04470|001|T|MONOGRAPH TITLE:  Etrasimod/Immunosuppressive CYP2C8 Inhibitors|
04470|002|B||
04470|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04470|004|L|of severe adverse interaction.|
04470|005|B||
04470|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP2C8 may impair|
04470|007|A|the CYP2C8-mediated metabolism of etrasimod.  Etrasimod is metabolized by|
04470|008|A|CYP2C8, CYP2C9, and CYP3A4.(1)|
04470|009|A|   Etrasimod causes reversible sequestration of lymphocytes in lymphoid|
04470|010|A|tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte|
04470|011|A|count at 52 weeks.(1)  Other immunosuppressives and immune-modulators also|
04470|012|A|suppress the immune system.|
04470|013|B||
04470|014|E|CLINICAL EFFECTS:  In patients who are poor metabolizers of CYP2C9,|
04470|015|E|concurrent use of a strong or moderate inhibitor of CYP2C8 may result in|
04470|016|E|elevated levels of and clinical effects from etrasimod including|
04470|017|E|immunosuppression, decreased lung function, bradycardia, and AV conduction|
04470|018|E|delays.|
04470|019|E|   Concurrent use of etrasimod with immunosuppressive or immune-modulating|
04470|020|E|agents may result in an increased risk of serious and fatal infections, such|
04470|021|E|as disseminated herpetic infection, cryptococcal infection, or progressive|
04470|022|E|multifocal leukoencephalopathy (PML).(1)|
04470|023|B||
04470|024|P|PREDISPOSING FACTORS:  CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may|
04470|025|P|have decreased clearance of etrasimod when etrasimod is used concomitantly|
04470|026|P|with strong or moderate inhibitors of CYP2C8.(1)|
04470|027|P|   Incomplete washout of previously prescribed immunosuppressive or|
04470|028|P|immune-modulating medications increases the risk of adverse effects.|
04470|029|B||
04470|030|M|PATIENT MANAGEMENT:  The etrasimod US prescribing information states|
04470|031|M|etrasimod has not been studied in combination with anti-neoplastic,|
04470|032|M|immune-modulating, or immunosuppressive therapies.  Concomitant|
04470|033|M|administration of these therapies with etrasimod should be avoided because|
04470|034|M|of the risk of additive immune effects during therapy and in the weeks|
04470|035|M|following administration.  Etrasimod's effect on peripheral lymphocytes may|
04470|036|M|persist for up to 5 weeks after discontinuation.(1)|
04470|037|M|   When switching from drugs with prolonged immune effects, the half-life|
04470|038|M|and mode of action of these drugs must be considered in order to avoid|
04470|039|M|unintended additive immunosuppressive effects.(1)|
04470|040|M|   In addition, concomitant use with strong to moderate CYP2C8 inhibitors in|
04470|041|M|patients who are CYP2C9 poor metabolizers is not recommended.(1)|
04470|042|B||
04470|043|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections,|
04470|044|D|cryptococcal meningitis, disseminated cryptococcal infections, and cases of|
04470|045|D|progressive multifocal leukoencephalopathy (PML) have been reported in|
04470|046|D|patients treated with other sphingosine-1 phosphate receptor modulators.(1)|
04470|047|D|   CYP2C9 activity is decreased in individuals with genetic variants such as|
04470|048|D|CYP2C9*2 and CYP2C9*3 alleles.  The impact of CYP2C9 genetic variants on the|
04470|049|D|pharmacokinetics of etrasimod has not been directly evaluated.  Increased|
04470|050|D|exposure of etrasimod in patients who are CYP2C9 poor metabolizers is|
04470|051|D|expected with concomitant use of moderate to strong inhibitors of CYP2C8 or|
04470|052|D|CYP3A4.(1)|
04470|053|D|   Concomitant use of etrasimod with steady-state fluconazole (a moderate|
04470|054|D|CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by|
04470|055|D|84%.(1)|
04470|056|D|   Moderate inhibitors of CYP2C8 include: leflunomide, pirtobrutinib, and|
04470|057|D|teriflunomide.(2,3)|
04470|058|B||
04470|059|R|REFERENCES:|
04470|060|B||
04470|061|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04470|062|R|  2023.|1
04470|063|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04470|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04470|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04470|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04470|067|R|  11/14/2017.|1
04470|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
04470|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04471|001|T|MONOGRAPH TITLE:  Selected CYP2D6 Substrates/Desvenlafaxine (Greater Than or|
04471|002|T|Equal To 400 mg)|
04471|003|B||
04471|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04471|005|L|of severe adverse interaction.|
04471|006|B||
04471|007|A|MECHANISM OF ACTION:  Desvenlafaxine is considered a weak inhibitor of|
04471|008|A|CYP2D6.(1)|
04471|009|B||
04471|010|E|CLINICAL EFFECTS:  Concurrent use of desvenlafaxine may lead to increased|
04471|011|E|serum levels and adverse effects of drugs sensitive to inhibition of the|
04471|012|E|CYP2D6 pathway.(1)  Agents linked to this monograph are: atomoxetine,|
04471|013|E|dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol,|
04471|014|E|perphenazine, tolterodine, and yohimbine.|
04471|015|B||
04471|016|P|PREDISPOSING FACTORS:  With perphenazine and tolterodine, the risk of|
04471|017|P|anticholinergic toxicities including cognitive decline, delirium, falls and|
04471|018|P|fractures is increased in geriatric patients using more than one medicine|
04471|019|P|with anticholinergic properties.(2)|
04471|020|B||
04471|021|M|PATIENT MANAGEMENT:  Reduce the dose of CYP2D6 substrates by up to one-half|
04471|022|M|when coadministered with desvenlafaxine 400 mg.(1)|
04471|023|M|   Studies have shown that desvenlafaxine does not have a clinically|
04471|024|M|relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. CYP2D6|
04471|025|M|substrates should be dosed at the original level when coadministered with|
04471|026|M|desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued.(1)|
04471|027|B||
04471|028|D|DISCUSSION:  In a study, coadministration of desvenlafaxine 100 mg daily|
04471|029|D|with desipramine (single dose 50 mg) increased desipramine's maximum|
04471|030|D|concentration (Cmax) and area-under-the-curve (AUC)by 25% and 17%.(1)|
04471|031|D|   In a study, coadministration of desvenlafaxine 400 mg daily with|
04471|032|D|desipramine (single dose 50 mg) increased desipramine's maximum|
04471|033|D|concentration (Cmax) and area-under-the-curve (AUC)by 50% and 90%.(1)|
04471|034|D|   Selected CYP2D6 substrates linked to this monograph are: atomoxetine,|
04471|035|D|dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol,|
04471|036|D|perphenazine, tolterodine, and yohimbine.|
04471|037|B||
04471|038|R|REFERENCES:|
04471|039|B||
04471|040|R|1.Pristiq (desvenlafaxine succinate) US prescribing information. Wyeth|1
04471|041|R|  Pharmaceuticals, Inc. August, 2023.|1
04471|042|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04471|043|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04471|044|R|  Soc 2023 Jul;71(7):2052-2081.|6
04471|045|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04471|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04471|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04471|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04471|049|R|  11/14/2017.|1
04472|001|T|MONOGRAPH TITLE:  Etrasimod/Immunosuppressive 3A4 Inhibitors that Prolong QT|
04472|002|B||
04472|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04472|004|L|of severe adverse interaction.|
04472|005|B||
04472|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may impair|
04472|007|A|the CYP3A4-mediated metabolism of etrasimod.  Etrasimod is metabolized by|
04472|008|A|CYP2C8, CYP2C9, and CYP3A4.(1)|
04472|009|A|   Initiation of etrasimod has a negative chronotropic effect, which may|
04472|010|A|increase the risk of developing QT prolongation.(1)  Etrasimod causes|
04472|011|A|reversible sequestration of lymphocytes in lymphoid tissues, resulting in a|
04472|012|A|mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1)|
04472|013|A|Other immunosuppressives and immune-modulators also suppress the immune|
04472|014|A|system.|
04472|015|B||
04472|016|E|CLINICAL EFFECTS:  In patients who are poor metabolizers of CYP2C9 or who|
04472|017|E|are also taking a strong or moderate CYP2C9 inhibitor, concurrent use of a|
04472|018|E|strong or moderate CYP3A4 inhibitor may result in elevated levels of and|
04472|019|E|clinical effects from etrasimod including immunosuppression, decreased lung|
04472|020|E|function, bradycardia, and AV conduction delays.|
04472|021|E|   Initiation of etrasimod may result in a transient decrease in heart rate.|
04472|022|E|A mean decrease in heart rate of 7.2 (8.98) beats per minute was seen 2 to|
04472|023|E|3 hours after the first dose.  The first dose has also been associated with|
04472|024|E|heart block. Symptomatic bradycardia has been observed.  Bradycardia may be|
04472|025|E|associated with an increase in the QTc interval, increasing the risk for|
04472|026|E|torsades de pointes.(1)|
04472|027|E|   Concurrent use of etrasimod with immunosuppressive or immune-modulating|
04472|028|E|agents may result in an increased risk of serious and fatal infections such|
04472|029|E|as disseminated herpes infection, cryptococcal infection, or progressive|
04472|030|E|multifocal leukoencephalopathy.(1)|
04472|031|B||
04472|032|P|PREDISPOSING FACTORS:  Pre-existing cardiovascular or cerebrovascular|
04472|033|P|disease (e.g. heart failure, ischemic heart disease, history of myocardial|
04472|034|P|infarction, stroke, or heart block), severe untreated sleep apnea, a|
04472|035|P|prolonged QTc interval prior to etrasimod initiation, factors associated|
04472|036|P|with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant|
04472|037|P|treatment with QT prolonging agents may increase risk for cardiovascular|
04472|038|P|toxicity due to etrasimod.|
04472|039|P|   The risk of QT prolongation or torsades de pointes may also be increased|
04472|040|P|in patients with a history of torsades de pointes, hypocalcemia,|
04472|041|P|bradycardia, female gender, or advanced age.(2)|
04472|042|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04472|043|P|higher systemic concentrations of the QT prolonging drug are additional risk|
04472|044|P|factors for torsades de pointes.  Factors which may increase systemic drug|
04472|045|P|concentrations include rapid infusion of an intravenous dose or impaired|
04472|046|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
04472|047|P|which inhibits its metabolism or elimination, genetic impairment in drug|
04472|048|P|metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04472|049|P|   CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased|
04472|050|P|clearance of etrasimod when etrasimod is used concomitantly with strong or|
04472|051|P|moderate inhibitors of CYP3A4.(1)|
04472|052|P|   Additionally, incomplete washout of previously prescribed|
04472|053|P|immunosuppressive or immune-modulating medications increases the risk of|
04472|054|P|adverse effects.|
04472|055|B||
04472|056|M|PATIENT MANAGEMENT:  The etrasimod US prescribing information states|
04472|057|M|etrasimod has not been studied in combination with anti-neoplastic,|
04472|058|M|immune-modulating, or immunosuppressive therapies.  Concomitant|
04472|059|M|administration of these therapies with etrasimod should be avoided because|
04472|060|M|of the risk of additive immune effects during therapy and in the weeks|
04472|061|M|following administration.  Etrasimod's effect on peripheral lymphocytes may|
04472|062|M|persist for up to 5 weeks after discontinuation.(1)|
04472|063|M|   When switching from drugs with prolonged immune effects, the half-life|
04472|064|M|and mode of action of these drugs must be considered in order to avoid|
04472|065|M|unintended additive immunosuppressive effects.(1)|
04472|066|M|   In addition, concomitant use with strong or moderate CYP3A4 inhibitors in|
04472|067|M|patients who are CYP2C9 poor metabolizers or who are also taking a strong or|
04472|068|M|moderate CYP2C9 inhibitor is not recommended.(1)|
04472|069|M|   If concurrent therapy is unavoidable, obtain an ECG to determine if|
04472|070|M|preexisting conduction abnormalities are present prior to initiation of|
04472|071|M|etrasimod.(1)|
04472|072|M|   Advice from a cardiologist is recommended in patients with preexisting|
04472|073|M|heart and cerebrovascular conditions, prolonged QTc interval, risk factors|
04472|074|M|for QT prolongation, concurrent therapy with QT prolonging drugs or drugs|
04472|075|M|that slow the heart rate or AV conduction.(1)  Monitor blood pressure during|
04472|076|M|treatment.(1)|
04472|077|B||
04472|078|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections,|
04472|079|D|cryptococcal meningitis, disseminated cryptococcal infections, and cases of|
04472|080|D|progressive multifocal leukoencephalopathy (PML) have been reported in|
04472|081|D|patients treated with other sphingosine-1 phosphate receptor modulators.(1)|
04472|082|D|   Initiation of etrasimod may result in a transient decrease in heart rate|
04472|083|D|or transient AV conduction delays.(1)|
04472|084|D|   A transient decrease in heart rate was observed during the initial dosing|
04472|085|D|phase of etrasimod and bradyarrhythmic events (AV blocks) were detected at a|
04472|086|D|higher incidence under etrasimod treatment than placebo.(1)|
04472|087|D|   CYP2C9 activity is decreased in individuals with genetic variants such as|
04472|088|D|CYP2C9*2 and CYP2C9*3 alleles.  The impact of CYP2C9 genetic variants on the|
04472|089|D|pharmacokinetics of etrasimod has not been directly evaluated.  Increased|
04472|090|D|exposure of etrasimod in patients who are CYP2C9 poor metabolizers is|
04472|091|D|expected with concomitant use of strong or moderate inhibitors of CYP3A4.(1)|
04472|092|D|   Concomitant use of etrasimod with steady-state fluconazole (a moderate|
04472|093|D|CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by|
04472|094|D|84%.(1)|
04472|095|D|   CYP3A4 inhibitors linked to this monograph include: crizotinib,|
04472|096|D|lonafarnib, nilotinib and ribociclib.(3)|
04472|097|B||
04472|098|R|REFERENCES:|
04472|099|B||
04472|100|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04472|101|R|  2023.|1
04472|102|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04472|103|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04472|104|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04472|105|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04472|106|R|  11/14/2017.|1
04472|107|R|3.This information is based on an extract from the Certara Drug Interaction|6
04472|108|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04473|001|T|MONOGRAPH TITLE:  Etrasimod/Immunosuppressives; Immunomodulators that|
04473|002|T|Prolong QT|
04473|003|B||
04473|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04473|005|L|of severe adverse interaction.|
04473|006|B||
04473|007|A|MECHANISM OF ACTION:  Etrasimod causes reversible sequestration of|
04473|008|A|lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in|
04473|009|A|peripheral blood lymphocyte count at 52 weeks.(1)  Other immunosuppressives|
04473|010|A|and immune-modulators also suppress the immune system.|
04473|011|A|   Initiation of etrasimod has a negative chronotropic effect leading to a|
04473|012|A|mean decrease in heart rate of 7 beats per minute (bpm) after the first|
04473|013|A|dose.(1)  This may increase the risk of QT prolongation.|
04473|014|B||
04473|015|E|CLINICAL EFFECTS:  Concurrent use of etrasimod with immunosuppressive or|
04473|016|E|immune-modulating agents may result in an increased risk of serious and|
04473|017|E|fatal infections, such as disseminated herpetic infection, cryptococcal|
04473|018|E|infection, or progressive multifocal leukoencephalopathy (PML).(1)|
04473|019|E|   Initiation of etrasimod may result in a transient decrease in heart rate.|
04473|020|E|A mean decrease in heart rate of 7.2 (8.98) beats per minute was seen 2 to|
04473|021|E|3 hours after the first dose.  The first dose has also been associated with|
04473|022|E|heart block.  Symptomatic bradycardia has been observed.  Bradycardia may be|
04473|023|E|associated with an increase in the QTc interval, increasing the risk for|
04473|024|E|torsades de pointes.(1)|
04473|025|B||
04473|026|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
04473|027|P|immunosuppressive or immune-modulating medications may increase the risk of|
04473|028|P|infection.|
04473|029|P|   Pre-existing cardiovascular or cerebrovascular disease (e.g. heart|
04473|030|P|failure, ischemic heart disease, history of myocardial infarction, stroke,|
04473|031|P|or heart block), severe untreated sleep apnea, a prolonged QTc interval|
04473|032|P|prior to etrasimod initiation, factors associated with QTc prolongation, or|
04473|033|P|concomitant treatment with QT prolonging agents may increase risk for|
04473|034|P|cardiovascular toxicity due to etrasimod.(1)|
04473|035|P|   The risk of QT prolongation or torsades de pointes may also be increased|
04473|036|P|in patients with a history of torsades de pointes, hypocalcemia,|
04473|037|P|bradycardia, female gender, or advanced age.(2)|
04473|038|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04473|039|P|higher systemic concentrations of the QT prolonging drug are additional risk|
04473|040|P|factors for torsades de pointes.  Factors which may increase systemic drug|
04473|041|P|concentrations include rapid infusion of an intravenous dose or impaired|
04473|042|P|metabolism or elimination of the drug (e.g. coadministration with an agent|
04473|043|P|which inhibits its metabolism or elimination, genetic impairment in drug|
04473|044|P|metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04473|045|B||
04473|046|M|PATIENT MANAGEMENT:  The etrasimod US prescribing information states|
04473|047|M|etrasimod has not been studied in combination with anti-neoplastic,|
04473|048|M|immune-modulating, or immunosuppressive therapies.  Concomitant|
04473|049|M|administration of these therapies with etrasimod should be avoided because|
04473|050|M|of the risk of additive immune effects during therapy and in the weeks|
04473|051|M|following administration.  Etrasimod's effect on peripheral lymphocytes may|
04473|052|M|persist for up to 5 weeks after discontinuation.(1)|
04473|053|M|   When switching from drugs with prolonged immune effects, the half-life|
04473|054|M|and mode of action of these drugs must be considered in order to avoid|
04473|055|M|unintended additive immunosuppressive effects.(1)|
04473|056|M|   If concurrent therapy is unavoidable, obtain an ECG to determine if|
04473|057|M|preexisting conduction abnormalities are present prior to initiation of|
04473|058|M|etrasimod.(1)|
04473|059|M|   Advice from a cardiologist is recommended in patients with preexisting|
04473|060|M|heart and cerebrovascular conditions, prolonged QTc interval, risk factors|
04473|061|M|for QT prolongation, concurrent therapy with QT prolonging drugs or drugs|
04473|062|M|that slow the heart rate or AV conduction.(1)|
04473|063|M|   Monitor blood pressure during treatment.(1)|
04473|064|B||
04473|065|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections,|
04473|066|D|cryptococcal meningitis, disseminated cryptococcal infections, and cases of|
04473|067|D|progressive multifocal leukoencephalopathy (PML) have been reported in|
04473|068|D|patients treated with other sphingosine-1 phosphate receptor modulators.(1)|
04473|069|D|   Initiation of etrasimod may result in a transient decrease in heart rate|
04473|070|D|or transient AV conduction delays.(1)|
04473|071|D|   A transient decrease in heart rate was observed during the initial dosing|
04473|072|D|phase of etrasimod and bradyarrhythmic events (AV blocks) were detected at a|
04473|073|D|higher incidence under etrasimod treatment than placebo.(1)|
04473|074|B||
04473|075|R|REFERENCES:|
04473|076|B||
04473|077|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04473|078|R|  2023.|1
04473|079|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04473|080|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04473|081|R|  settings: a scientific statement from the American Heart Association and|6
04473|082|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04473|083|R|  2;55(9):934-47.|6
04474|001|T|MONOGRAPH TITLE:  Etrasimod/Immunosuppressive CYP3A4 Inhibitors|
04474|002|B||
04474|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04474|004|L|of severe adverse interaction.|
04474|005|B||
04474|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP3A4 may impair|
04474|007|A|the CYP3A4-mediated metabolism of etrasimod.  Etrasimod is metabolized by|
04474|008|A|CYP2C8, CYP2C9, and CYP3A4.(1)|
04474|009|A|   Etrasimod causes reversible sequestration of lymphocytes in lymphoid|
04474|010|A|tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte|
04474|011|A|count at 52 weeks.(1)  Other immunosuppressives and immune-modulators also|
04474|012|A|suppress the immune system.|
04474|013|B||
04474|014|E|CLINICAL EFFECTS:  In patients who are poor metabolizers of CYP2C9,|
04474|015|E|concurrent use of a strong or moderate inhibitor of CYP3A4 may result in|
04474|016|E|elevated levels of and clinical effects from etrasimod including|
04474|017|E|immunosuppression, decreased lung function, bradycardia, and AV conduction|
04474|018|E|delays.|
04474|019|E|   Concurrent use of etrasimod with immunosuppressive or immune-modulating|
04474|020|E|agents may result in an increased risk of serious and fatal infections, such|
04474|021|E|as disseminated herpetic infection, cryptococcal infection, or progressive|
04474|022|E|multifocal leukoencephalopathy (PML).(1)|
04474|023|B||
04474|024|P|PREDISPOSING FACTORS:  CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may|
04474|025|P|have decreased clearance of etrasimod when etrasimod is used concomitantly|
04474|026|P|with strong or moderate inhibitors of CYP3A4.(1)|
04474|027|P|   Additionally, incomplete washout of previously prescribed|
04474|028|P|immunosuppressive or immune-modulating medications increases the risk of|
04474|029|P|adverse events.|
04474|030|B||
04474|031|M|PATIENT MANAGEMENT:  The etrasimod US prescribing information states|
04474|032|M|etrasimod has not been studied in combination with anti-neoplastic,|
04474|033|M|immune-modulating, or immunosuppressive therapies.  Concomitant|
04474|034|M|administration of these therapies with etrasimod should be avoided because|
04474|035|M|of the risk of additive immune effects during therapy and in the weeks|
04474|036|M|following administration.  Etrasimod's effect on peripheral lymphocytes may|
04474|037|M|persist for up to 5 weeks after discontinuation.(1)|
04474|038|M|   When switching from drugs with prolonged immune effects, the half-life|
04474|039|M|and mode of action of these drugs must be considered in order to avoid|
04474|040|M|unintended additive immunosuppressive effects.(1)|
04474|041|M|   In addition, concomitant use with strong or moderate CYP3A4 inhibitors in|
04474|042|M|patients who are CYP2C9 poor metabolizers is not recommended.(1)|
04474|043|B||
04474|044|D|DISCUSSION:  Fatal disseminated herpes zoster and herpes simplex infections,|
04474|045|D|cryptococcal meningitis, disseminated cryptococcal infections, and cases of|
04474|046|D|progressive multifocal leukoencephalopathy (PML) have been reported in|
04474|047|D|patients treated with other sphingosine-1 phosphate receptor modulators.(1)|
04474|048|D|   CYP2C9 activity is decreased in individuals with genetic variants such as|
04474|049|D|CYP2C9*2 and CYP2C9*3 alleles.  The impact of CYP2C9 genetic variants on the|
04474|050|D|pharmacokinetics of etrasimod has not been directly evaluated.  Increased|
04474|051|D|exposure of etrasimod in patients who are CYP2C9 poor metabolizers is|
04474|052|D|expected with concomitant use of strong or moderate inhibitors of CYP3A4.(1)|
04474|053|D|   Concomitant use of etrasimod with steady-state fluconazole (a moderate|
04474|054|D|CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by|
04474|055|D|84%.(1)|
04474|056|D|   CYP3A4 inhibitors linked to this monograph include: duvelisib,|
04474|057|D|fedratinib, idelalisib, imatinib, rilzabrutinib, and treosulfan.(3)|
04474|058|B||
04474|059|R|REFERENCES:|
04474|060|B||
04474|061|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04474|062|R|  2023.|1
04474|063|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04474|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04474|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04474|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04474|067|R|  11/14/2017.|1
04474|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
04474|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04475|001|T|MONOGRAPH TITLE:  Etrasimod/Combined CYP2C8; CYP2C9; CYP3A4 Inhibitors|
04475|002|B||
04475|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04475|004|L|of severe adverse interaction.|
04475|005|B||
04475|006|A|MECHANISM OF ACTION:  Inhibitors of CYP2C8, CYP2C9, and CYP3A4 may impair|
04475|007|A|the metabolism of etrasimod.(1)|
04475|008|A|   Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)|
04475|009|B||
04475|010|E|CLINICAL EFFECTS:  Concurrent use of a combined inhibitor of CYP2C8, CYP2C9,|
04475|011|E|and CYP3A4 may result in elevated levels of and clinical effects from|
04475|012|E|etrasimod including immunosuppression, decreased lung function, bradycardia,|
04475|013|E|and AV conduction delays.|
04475|014|B||
04475|015|P|PREDISPOSING FACTORS:  None determined.|
04475|016|B||
04475|017|M|PATIENT MANAGEMENT:  Concomitant use of etrasimod with combined inhibitors|
04475|018|M|of CYP2C8, CYP2C9, and CYP3A4 is not recommended.|
04475|019|B||
04475|020|D|DISCUSSION:  Concomitant use of etrasimod with steady-state fluconazole (a|
04475|021|D|moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve|
04475|022|D|(AUC) by 84%.(1)|
04475|023|D|   Combined CYP2C8, CYP2C9, CYP3A4 inhibitors include: mifepristone.(2,3)|
04475|024|B||
04475|025|R|REFERENCES:|
04475|026|B||
04475|027|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04475|028|R|  2023.|1
04475|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04475|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04475|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04475|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04475|033|R|  11/14/2017.|1
04475|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04475|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04476|001|T|MONOGRAPH TITLE:  Etrasimod/Combined CYP2C8; CYP2C9; CYP3A4 Inducers|
04476|002|B||
04476|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04476|004|L|of severe adverse interaction.|
04476|005|B||
04476|006|A|MECHANISM OF ACTION:  Inducers of CYP2C8, CYP2C9, and CYP3A4 may increase|
04476|007|A|the metabolism of etrasimod.(1)|
04476|008|A|   Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)|
04476|009|B||
04476|010|E|CLINICAL EFFECTS:  Concurrent use of a combined inducer of CYP2C8, CYP2C9,|
04476|011|E|and CYP3A4 may result in decreased levels and effectiveness of etrasimod.(1)|
04476|012|B||
04476|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04476|014|P|of the inducer for longer than 1-2 weeks.|
04476|015|B||
04476|016|M|PATIENT MANAGEMENT:  Concomitant use of etrasimod with combined inducers of|
04476|017|M|CYP2C8, CYP2C9, and CYP3A4 is not recommended.(1)|
04476|018|B||
04476|019|D|DISCUSSION:  Concomitant use of etrasimod with rifampin (strong CYP3A4,|
04476|020|D|moderate CYP2C8, and CYP2C9 inducer) decreased etrasimod area-under-curve|
04476|021|D|(AUC) by 49%.(1)|
04476|022|D|   Combined inducers of CYP2C8, CYP2C9, and CYP3A4 include: carbamazepine|
04476|023|D|and rifampin.(2,3)|
04476|024|B||
04476|025|R|REFERENCES:|
04476|026|B||
04476|027|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04476|028|R|  2023.|1
04476|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04476|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04476|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04476|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04476|033|R|  11/14/2017.|1
04476|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04476|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04477|001|T|MONOGRAPH TITLE:  Non-Live or Non-Replicating Vaccines/Etrasimod|
04477|002|B||
04477|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04477|004|L|take action as needed.|
04477|005|B||
04477|006|A|MECHANISM OF ACTION:  Etrasimod is an immunosuppressant and may alter the|
04477|007|A|immune system's response to vaccines.(1)|
04477|008|B||
04477|009|E|CLINICAL EFFECTS:  Administration of a vaccine during and for up to 5 weeks|
04477|010|E|after discontinuation of etrasimod therapy may result in decreased|
04477|011|E|effectiveness of the vaccine.  Etrasimod treatment should be paused 5 weeks|
04477|012|E|prior and for 4 weeks after vaccination.(1)|
04477|013|B||
04477|014|P|PREDISPOSING FACTORS:  None determined.|
04477|015|B||
04477|016|M|PATIENT MANAGEMENT:  Ideally, administer vaccines prior to initiating|
04477|017|M|etrasimod therapy.|
04477|018|M|   The immune response to non-live vaccines should be monitored in patients|
04477|019|M|receiving etrasimod or who have received etrasimod in the previous 5 weeks.|
04477|020|M|Vaccinations given during and for up to 5 weeks after discontinuation of|
04477|021|M|etrasimod therapy may need to be repeated.(1)|
04477|022|M|   The Centers for Disease Control's (CDC) Advisory Committee on|
04477|023|M|Immunization Practices (ACIP) states that non-live vaccines should be used|
04477|024|M|with caution in patients who are severely immunosuppressed.  Patients who|
04477|025|M|are vaccinated within the 14 days prior to initiating immunosuppressive|
04477|026|M|therapy should be considered unvaccinated and should be revaccinated at|
04477|027|M|least 3 months after immunosuppressive therapy is discontinued when immune|
04477|028|M|competence is restored.(2)|
04477|029|B||
04477|030|D|DISCUSSION:  Vaccinations may be less effective if administered during and|
04477|031|D|for up to 5 weeks after etrasimod treatment.(1)  However they are considered|
04477|032|D|safe to administer.|
04477|033|B||
04477|034|R|REFERENCES:|
04477|035|B||
04477|036|R|1.Velsipity (etrasimod) US prescribing information. Pfizer Inc. October|1
04477|037|R|  2023.|1
04477|038|R|2.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
04477|039|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
04477|040|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
04477|041|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
04477|042|R|  recs.pdf February 10, 2023;1-197.|6
04478|001|T|MONOGRAPH TITLE:  Non-Live or Non-Replicating Vaccines/Ozanimod|
04478|002|B||
04478|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04478|004|L|take action as needed.|
04478|005|B||
04478|006|A|MECHANISM OF ACTION:  Ozanimod is an immunosuppressant and may alter the|
04478|007|A|immune system's response to vaccines.(1)|
04478|008|B||
04478|009|E|CLINICAL EFFECTS:  Administration of a vaccine during and for up to 3 months|
04478|010|E|after discontinuation of ozanimod therapy may result in decreased|
04478|011|E|effectiveness of the vaccine.  Ozanimod treatment should be paused 3 months|
04478|012|E|prior and for 1 month after vaccination.(1)|
04478|013|B||
04478|014|P|PREDISPOSING FACTORS:  None determined.|
04478|015|B||
04478|016|M|PATIENT MANAGEMENT:  Ideally, administer vaccines prior to initiating|
04478|017|M|ozanimod therapy.|
04478|018|M|   The immune response to non-live vaccines should be monitored in patients|
04478|019|M|receiving ozanimod or who have received ozanimod in the previous 3 months.|
04478|020|M|Vaccinations given during and for up to 3 months after discontinuation of|
04478|021|M|ozanimod therapy may need to be repeated.(1)|
04478|022|M|   The Centers for Disease Control's (CDC) Advisory Committee on|
04478|023|M|Immunization Practices (ACIP) states that non-live vaccines should be used|
04478|024|M|with caution in patients who are severely immunosuppressed.  Patients who|
04478|025|M|are vaccinated within the 14 days prior to initiating immunosuppressive|
04478|026|M|therapy should be considered unvaccinated and should be revaccinated at|
04478|027|M|least 3 months after immunosuppressive therapy is discontinued when immune|
04478|028|M|competence is restored.(2)|
04478|029|B||
04478|030|D|DISCUSSION:  Vaccinations may be less effective if administered during and|
04478|031|D|for up to 3 months after ozanimod treatment.(1)  However they are considered|
04478|032|D|safe to administer.|
04478|033|B||
04478|034|R|REFERENCES:|
04478|035|B||
04478|036|R|1.Zeposia (ozanimod) US prescribing information. Celgene Corporation August,|1
04478|037|R|  2024.|1
04478|038|R|2.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
04478|039|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
04478|040|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
04478|041|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
04478|042|R|  recs.pdf February 10, 2023;1-197.|6
04479|001|T|MONOGRAPH TITLE:  Non-Live or Non-Replicating Vaccines/Ponesimod|
04479|002|B||
04479|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04479|004|L|take action as needed.|
04479|005|B||
04479|006|A|MECHANISM OF ACTION:  Ponesimod is an immunosuppressant and may alter the|
04479|007|A|immune system's response to vaccines.(1)|
04479|008|B||
04479|009|E|CLINICAL EFFECTS:  Administration of a vaccine during and for up to 2 weeks|
04479|010|E|after discontinuation of ponesimod therapy may result in decreased|
04479|011|E|effectiveness of the vaccine.  Ponesimod treatment should be paused 1-2|
04479|012|E|weeks prior and for 4 weeks after vaccination.(1)|
04479|013|B||
04479|014|P|PREDISPOSING FACTORS:  None determined.|
04479|015|B||
04479|016|M|PATIENT MANAGEMENT:  Ideally, administer vaccines prior to initiating|
04479|017|M|ponesimod therapy.|
04479|018|M|   The immune response to non-live vaccines should be monitored in patients|
04479|019|M|receiving ponesimod or who have received ponesimod in the previous 2 weeks.|
04479|020|M|Vaccinations given during and for up to 2 weeks after discontinuation of|
04479|021|M|ponesimod therapy may need to be repeated.(1)|
04479|022|M|   The Centers for Disease Control's (CDC) Advisory Committee on|
04479|023|M|Immunization Practices (ACIP) states that non-live vaccines should be used|
04479|024|M|with caution in patients who are severely immunosuppressed.  Patients who|
04479|025|M|are vaccinated within the 14 days prior to initiating immunosuppressive|
04479|026|M|therapy should be considered unvaccinated and should be revaccinated at|
04479|027|M|least 3 months after immunosuppressive therapy is discontinued when immune|
04479|028|M|competence is restored.(2)|
04479|029|B||
04479|030|D|DISCUSSION:  Vaccinations may be less effective if administered during and|
04479|031|D|for up to 2 weeks after ponesimod treatment.(1)  However they are considered|
04479|032|D|safe to administer.|
04479|033|B||
04479|034|R|REFERENCES:|
04479|035|B||
04479|036|R|1.Ponvory (ponesimod) US prescribing information. Janssen Pharmaceuticals,|1
04479|037|R|  Inc. March, 2021.|1
04479|038|R|2.Kroger A Bahta L Long S Sanchez P. General Best Practice Guideline for|6
04479|039|R|  Immunization. Best Practices Guidance of the Advisory Committee on|6
04479|040|R|  Immunzation Practices (ACIP). MMWR. Available at:|6
04479|041|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-|6
04479|042|R|  recs.pdf February 10, 2023;1-197.|6
04480|001|T|MONOGRAPH TITLE:  Tenapanor/Laxatives; Stool Softeners|
04480|002|B||
04480|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04480|004|L|of severe adverse interaction.|
04480|005|B||
04480|006|A|MECHANISM OF ACTION:  Tenapanor commonly causes diarrhea of mild to moderate|
04480|007|A|severity.  Laxatives and stool softeners may increase the incidence or|
04480|008|A|severity of diarrhea.(1)|
04480|009|B||
04480|010|E|CLINICAL EFFECTS:  Concurrent use of laxatives or stool softeners with|
04480|011|E|tenapanor may increase the risk of severe diarrhea.(1)|
04480|012|B||
04480|013|P|PREDISPOSING FACTORS:  None determined.|
04480|014|B||
04480|015|M|PATIENT MANAGEMENT:  The US manufacturer of tenapanor states that patients|
04480|016|M|should be instructed to avoid stool softeners and laxatives with tenapanor.|
04480|017|M|If severe diarrhea occurs, tenapanor should be discontinued.(1)|
04480|018|B||
04480|019|D|DISCUSSION:  In clinical trials, 43-53% of CKD patients on dialysis treated|
04480|020|D|with tenapanor developed diarrhea.  Diarrhea usually occurred soon after|
04480|021|D|treatment initiation and was severe in 5% of patients.(1)|
04480|022|B||
04480|023|R|REFERENCE:|
04480|024|B||
04480|025|R|1.Xphozah (tenapanor) US prescribing information. Ardelyx, Inc. October|1
04480|026|R|  2023.|1
04481|001|T|MONOGRAPH TITLE:  Vamorolone/Strong CYP3A4 Inhibitors|
04481|002|B||
04481|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04481|004|L|take action as needed.|
04481|005|B||
04481|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04481|007|A|vamorolone which is metabolized by CYP3A4.(1)|
04481|008|B||
04481|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04481|010|E|increased systemic exposure to and effects from vamorolone, including|
04481|011|E|Cushing's syndrome and adrenal suppression.|
04481|012|B||
04481|013|P|PREDISPOSING FACTORS:  None determined.|
04481|014|B||
04481|015|M|PATIENT MANAGEMENT:  If vamorolone is used concurrently with a strong CYP3A4|
04481|016|M|inhibitor, reduce the dose of vamorolone to 4 mg/kg once daily.  No dose|
04481|017|M|adjustment is needed with moderate or weak CYP3A4 inhibitors.(1)|
04481|018|B||
04481|019|D|DISCUSSION:  In a study, multiple doses of itraconazole (a strong CYP3A4|
04481|020|D|inhibitor) increased vamorolone concentration maximum (Cmax) and|
04481|021|D|area-under-curve (AUC) by 8% and 44%, respectively.(1)|
04481|022|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
04481|023|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir,|
04481|024|D|itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib,|
04481|025|D|lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04481|026|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04481|027|D|troleandomycin, tucatinib, and voriconazole.(2)|
04481|028|B||
04481|029|R|REFERENCES:|
04481|030|B||
04481|031|R|1.Agamree (vamorolone) US prescribing information. Santhera Pharmaceuticals|1
04481|032|R|  (Switzerland) Ltd. October, 2023.|1
04481|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
04481|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04482|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 10 mg)/Ticagrelor|
04482|002|B||
04482|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04482|004|L|of severe adverse interaction.|
04482|005|B||
04482|006|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate of the BCRP|
04482|007|A|transporter.(1,2)  Ticagrelor may inhibit this transporter and may result in|
04482|008|A|increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)|
04482|009|B||
04482|010|E|CLINICAL EFFECTS:  Concurrent use of ticagrelor with rosuvastatin may result|
04482|011|E|in increased levels and side effects from rosuvastatin, including|
04482|012|E|rhabdomyolysis.(1,2)|
04482|013|B||
04482|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04482|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04482|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04482|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04482|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04482|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04482|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04482|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04482|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04482|023|B||
04482|024|M|PATIENT MANAGEMENT:  Monitor patients closely for signs and symptoms of|
04482|025|M|toxicity from increased rosuvastatin concentrations.  Consider alternative|
04482|026|M|statin therapy. (1,2)|
04482|027|B||
04482|028|D|DISCUSSION:  In a study, ticagrelor increased rosuvastatin area-under-curve|
04482|029|D|(AUC) and peak plasma concentration 2.6-fold and prolonged its half-life|
04482|030|D|from 3.1 to 6.6 hours.  Ticagrelor also decreased the renal clearance of|
04482|031|D|rosuvastatin by 11%.(3)|
04482|032|D|   In a study, reports of rhabdomyolysis with combined administration of|
04482|033|D|ticagrelor and rosuvastatin had a reporting odds ratio of 1.9 compared to|
04482|034|D|rosuvastatin alone.(4)|
04482|035|B||
04482|036|R|REFERENCES:|
04482|037|B||
04482|038|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04482|039|R|  Pharmaceuticals LP July, 2024.|1
04482|040|R|2.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04482|041|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04482|042|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04482|043|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04482|044|R|  44(3):398-408.|5
04482|045|R|3.Lehtisalo M, Kiander W, Filppula AM, Deng F, Kidron H, Korhonen M, Sinkko|2
04482|046|R|  J, Koivula K, Niemi M. Rhabdomyolysis during concomitant ticagrelor and|2
04482|047|R|  rosuvastatin: A breast cancer  resistance protein-mediated drug|2
04482|048|R|  interaction?. Br J Clin Pharmacol 2023 Jul;89(7):2309-2315.|2
04482|049|R|4.Roule V, Alexandre J, Lemaitre A, Chretien B, Sassier M, Fedrizzi S,|6
04482|050|R|  Beygui F, Dolladille C. Rhabdomyolysis with Co-Administration of Statins|6
04482|051|R|  and Antiplatelet  Therapies-Analysis of the WHO Pharmacovigilance|6
04482|052|R|  Database. Cardiovasc Drugs Ther 2023 Apr 28.|6
04483|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal To 10 mg)/Ticagrelor|
04483|002|B||
04483|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04483|004|L|take action as needed.|
04483|005|B||
04483|006|A|MECHANISM OF ACTION:  Rosuvastatin is a substrate of the BCRP|
04483|007|A|transporter.(1,2)  Ticagrelor may inhibit this transporter and may result in|
04483|008|A|increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)|
04483|009|B||
04483|010|E|CLINICAL EFFECTS:  Concurrent use of ticagrelor with rosuvastatin may result|
04483|011|E|in increased levels and side effects from rosuvastatin, including|
04483|012|E|rhabdomyolysis.(1,2)|
04483|013|B||
04483|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04483|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04483|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04483|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04483|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04483|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04483|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04483|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04483|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04483|023|B||
04483|024|M|PATIENT MANAGEMENT:  Monitor patients closely for signs and symptoms of|
04483|025|M|toxicity from increased rosuvastatin concentrations.  Consider alternative|
04483|026|M|statin therapy.(1,2)|
04483|027|B||
04483|028|D|DISCUSSION:  In a study, ticagrelor increased rosuvastatin area-under-curve|
04483|029|D|(AUC) and peak plasma concentration 2.6-fold and prolonged its half-life|
04483|030|D|from 3.1 to 6.6 hours.  Ticagrelor also decreased the renal clearance of|
04483|031|D|rosuvastatin by 11%.(3)|
04483|032|D|   In a study, reports of rhabdomyolysis with combined administration of|
04483|033|D|ticagrelor and rosuvastatin had a reporting odds ratio of 1.9 compared to|
04483|034|D|rosuvastatin alone.(4)|
04483|035|B||
04483|036|R|REFERENCES:|
04483|037|B||
04483|038|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04483|039|R|  Pharmaceuticals LP July, 2024.|1
04483|040|R|2.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04483|041|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04483|042|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04483|043|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04483|044|R|  44(3):398-408.|5
04483|045|R|3.Lehtisalo M, Kiander W, Filppula AM, Deng F, Kidron H, Korhonen M, Sinkko|2
04483|046|R|  J, Koivula K, Niemi M. Rhabdomyolysis during concomitant ticagrelor and|2
04483|047|R|  rosuvastatin: A breast cancer  resistance protein-mediated drug|2
04483|048|R|  interaction?. Br J Clin Pharmacol 2023 Jul;89(7):2309-2315.|2
04483|049|R|4.Roule V, Alexandre J, Lemaitre A, Chretien B, Sassier M, Fedrizzi S,|6
04483|050|R|  Beygui F, Dolladille C. Rhabdomyolysis with Co-Administration of Statins|6
04483|051|R|  and Antiplatelet  Therapies-Analysis of the WHO Pharmacovigilance|6
04483|052|R|  Database. Cardiovasc Drugs Ther 2023 Apr 28.|6
04484|001|T|MONOGRAPH TITLE:  Ethinyl Estradiol (Less Than or Equal To 20|
04484|002|T|mcg)/Glecaprevir-Pibrentasvir|
04484|003|B||
04484|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04484|005|L|of severe adverse interaction.|
04484|006|B||
04484|007|A|MECHANISM OF ACTION:  The mechanism of action has not been described.|
04484|008|B||
04484|009|E|CLINICAL EFFECTS:  Coadministration of greater than 20 mcg of ethinyl|
04484|010|E|estradiol with glecaprevir-pibrentasvir may increase the risk of ALT|
04484|011|E|elevations.(1)|
04484|012|B||
04484|013|P|PREDISPOSING FACTORS:  None determined.|
04484|014|B||
04484|015|M|PATIENT MANAGEMENT:  Due to the added risk for ALT elevations, the US|
04484|016|M|manufacturer of glecaprevir-pibrentasvir states that medications which|
04484|017|M|contain more than 20 mcg of ethinyl estradiol such as oral contraceptives|
04484|018|M|are not recommended to be administered with glecaprevir-pibrentasvir.  No|
04484|019|M|dose adjustment is required when glecaprevir-pibrentasvir is coadministered|
04484|020|M|with products containing 20 mcg or less of ethinyl estradiol.(1)|
04484|021|M|   The Canadian and UK manufacturers of glecaprevir-pibrentasvir state that|
04484|022|M|ethinyl estradiol-containing products are contraindicated.(2,3)|
04484|023|M|   Alternative methods of contraception, such as progestin only or|
04484|024|M|non-hormonal methods may be recommended during glecaprevir-pibrentasvir|
04484|025|M|therapy.|
04484|026|B||
04484|027|D|DISCUSSION:  Simultaneous administration of glecaprevir-pibrentasvir may|
04484|028|D|increase the risk of ALT elevations.(1)|
04484|029|B||
04484|030|R|REFERENCES:|
04484|031|B||
04484|032|R|1.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
04484|033|R|  Inc. October, 2023.|1
04484|034|R|2.Maviret (glecaprevir and pibrentasvir) UK Summary of Product|1
04484|035|R|  Characteristics. AbbVie Ltd. August, 2021.|1
04484|036|R|3.Maviret (glecaprevir and pibrentasvir) CA prescribing information. AbbVie|1
04484|037|R|  Corporation November 28, 2018.|1
04485|001|T|MONOGRAPH TITLE:  Cyclosporine/Selected Moderate CYP3A4 Inhibitors|
04485|002|B||
04485|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04485|004|L|take action as needed.|
04485|005|B||
04485|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04485|007|A|of cyclosporine.(1)|
04485|008|B||
04485|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
04485|010|E|in elevated levels of and toxicity from cyclosporine, including serious|
04485|011|E|infections, nephrotoxicity, and hepatotoxicity.(1)|
04485|012|B||
04485|013|P|PREDISPOSING FACTORS:  None determined.|
04485|014|B||
04485|015|M|PATIENT MANAGEMENT:  If cyclosporine is used with a moderate CYP3A4|
04485|016|M|inhibitor, dose adjustment of cyclosporine may be necessary to achieve the|
04485|017|M|desired cyclosporine concentration.(1)|
04485|018|B||
04485|019|D|DISCUSSION:  In a study, renal and cardiac patients required a cyclosporine|
04485|020|D|dose reduction of 15% to 48% when diltiazem was co-administered to maintain|
04485|021|D|a cyclosporine trough similar to cyclosporine alone.(2)|
04485|022|D|   In a study, cyclosporine required a 25% dose reduction when|
04485|023|D|co-administered with fluconazole to maintain a goal serum concentration|
04485|024|D|similar to cyclosporine alone.(3)|
04485|025|D|   Moderate inhibitors of CYP3A4 include: aprepitant, avacopan,|
04485|026|D|berotralstat, clofazimine, duvelisib, fedratinib, fluvoxamine, oral|
04485|027|D|lefamulin, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra,|
04485|028|D|stiripentol, tofisopam, and treosulfan.(4,5)|
04485|029|B||
04485|030|R|REFERENCES:|
04485|031|B||
04485|032|R|1.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
04485|033|R|  Corporation September, 2023.|1
04485|034|R|2.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
04485|035|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
04485|036|R|3.Gu TM, Lewis JS 2nd, Le H, Bubalo JS. Comparative effects of fluconazole,|2
04485|037|R|  posaconazole, and isavuconazole upon  tacrolimus and cyclosporine serum|2
04485|038|R|  concentrations. J Oncol Pharm Pract 2022 Sep;28(6):1357-1362.|2
04485|039|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04485|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04485|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04485|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04485|043|R|  11/14/2017.|1
04485|044|R|5.This information is based on an extract from the Certara Drug Interaction|6
04485|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04486|001|T|MONOGRAPH TITLE:  Cyclosporine/Aminoglycosides|
04486|002|B||
04486|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04486|004|L|of severe adverse interaction.|
04486|005|B||
04486|006|A|MECHANISM OF ACTION:  Cyclosporine and aminoglycosides can both cause|
04486|007|A|nephrotoxicity.  Concurrent administration may result in an additive or|
04486|008|A|synergistic risk of nephrotoxicity.(1-3)|
04486|009|B||
04486|010|E|CLINICAL EFFECTS:  Concurrent use of cyclosporine with aminoglycosides may|
04486|011|E|result in a higher risk of renal dysfunction, including structural kidney|
04486|012|E|damage.(1-3)|
04486|013|B||
04486|014|P|PREDISPOSING FACTORS:  Factors predisposing to nephrotoxicity include|
04486|015|P|pre-existing renal impairment, older age, higher doses or longer treatment|
04486|016|P|duration of either drug, and dehydration.(1-3)|
04486|017|B||
04486|018|M|PATIENT MANAGEMENT:  Avoid the concurrent use of cyclosporine and|
04486|019|M|aminoglycosides whenever possible.(2,3)  If concurrent use cannot be|
04486|020|M|avoided, it should be undertaken with great caution.  Minimize the|
04486|021|M|cyclosporine dose and monitor renal function carefully.  Frequent dose|
04486|022|M|adjustment may be indicated.  If renal function deteriorates, the|
04486|023|M|aminoglycoside may need to be decreased or discontinued.(1-4)|
04486|024|B||
04486|025|D|DISCUSSION:  Coadministration of cyclosporine with other drugs that may|
04486|026|D|impair renal function, like aminoglycosides, may cause additive or|
04486|027|D|synergistic impairment of renal function.|
04486|028|D|   A meta-analysis of 30 studies that evaluated the correlation and risk|
04486|029|D|factors between cyclosporine and kidney injury in allogeneic hematopoietic|
04486|030|D|stem cell transplant (allo-HSCT) patients included 7 studies that examined|
04486|031|D|the role of the combination with other drugs in the development of|
04486|032|D|nephrotoxicity.  Coadministration of aminoglycosides and amphotericin B were|
04486|033|D|independent risk factors for acute or chronic kidney diseases related to|
04486|034|D|cyclosporine in allo-HSCT patients.(5)|
04486|035|B||
04486|036|R|REFERENCES:|
04486|037|B||
04486|038|R|1.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
04486|039|R|  Corporation September, 2023.|1
04486|040|R|2.Gentamicin injection US prescribing information,. Fresenius Kabi USA, LLC.|1
04486|041|R|  October, 2015,.|1
04486|042|R|3.Tobramycin US prescribing information. X-GEN Pharmaceuticals, Inc.|1
04486|043|R|  September, 2011.|1
04486|044|R|4.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
04486|045|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
04486|046|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
04486|047|R|  e13510.|6
04486|048|R|5.Lu R, Shi Y, Yang M, Yang N, He S, Xin L, Qin Y, Li H, Zeng L, Zou K, Yang|6
04486|049|R|  C, Huang L, Shi W, Qiu X, Lu X, Zhang L. Occurrence and influencing|6
04486|050|R|  factors of cyclosporine A on the kidney injury  following allogeneic|6
04486|051|R|  hematopoietic stem cell transplantation: A systematic review  and|6
04486|052|R|  meta-analysis. Int Immunopharmacol 2023 Sep;122:110633.|6
04487|001|T|MONOGRAPH TITLE:  Fruquintinib/Strong CYP3A4 Inducers|
04487|002|B||
04487|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04487|004|L|of severe adverse interaction.|
04487|005|B||
04487|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04487|007|A|fruquintinib.(1)|
04487|008|B||
04487|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04487|010|E|may result in decreased levels and effectiveness of fruquintinib.(1)|
04487|011|B||
04487|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04487|013|P|of the inducer for longer than 1-2 weeks.|
04487|014|B||
04487|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
04487|016|M|fruquintinib.(1)|
04487|017|B||
04487|018|D|DISCUSSION:  Concomitant use with rifampin (strong CYP3A4 inducer) decreased|
04487|019|D|the fruquintinib maximum concentration (Cmax) by 12% and the|
04487|020|D|area-under-curve (AUC) by 65%.(1)|
04487|021|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04487|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04487|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04487|024|D|rifapentine, and St. John's wort.(2,3)|
04487|025|B||
04487|026|R|REFERENCES:|
04487|027|B||
04487|028|R|1.Fruzaqla (fruquintinib) US prescribing information. Takeda Pharmaceuticals|1
04487|029|R|  America, Inc. November 2023.|1
04487|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04487|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04487|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04487|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04487|034|R|  11/14/2017.|1
04487|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04487|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04488|001|T|MONOGRAPH TITLE:  Fruquintinib/Moderate CYP3A4 Inducers|
04488|002|B||
04488|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04488|004|L|of severe adverse interaction.|
04488|005|B||
04488|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04488|007|A|of fruquintinib.(1)|
04488|008|B||
04488|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate inducer of CYP3A4|
04488|010|E|may result in decreased levels and effectiveness of fruquintinib.(1)|
04488|011|B||
04488|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04488|013|P|of the inducer for longer than 1-2 weeks.|
04488|014|B||
04488|015|M|PATIENT MANAGEMENT:  If possible, avoid concurrent use of moderate inducers|
04488|016|M|of CYP3A4 with fruquintinib.  If concurrent use cannot be avoided, continue|
04488|017|M|to administer fruquintinib at the recommended dosage.(1)|
04488|018|B||
04488|019|D|DISCUSSION:  Concomitant use with efavirenz (moderate CYP3A4 inducer) is|
04488|020|D|predicted to decrease the fruquintinib maximum concentration (Cmax) by 4%|
04488|021|D|and the area-under-curve (AUC) by 32%.(1)|
04488|022|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04488|023|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04488|024|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04488|025|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04488|026|D|thioridazine, and tovorafenib.(2,3)|
04488|027|B||
04488|028|R|REFERENCES:|
04488|029|B||
04488|030|R|1.Fruzaqla (fruquintinib) US prescribing information. Takeda Pharmaceuticals|1
04488|031|R|  America, Inc. November 2023.|1
04488|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04488|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04488|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04488|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04488|036|R|  11/14/2017.|1
04488|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04488|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04489|001|T|MONOGRAPH TITLE:  Clopidogrel/Vonoprazan|
04489|002|B||
04489|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04489|004|L|of severe adverse interaction.|
04489|005|B||
04489|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
04489|007|A|active metabolite via a 2 step process.  The first conversion step is|
04489|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
04489|009|A|CYP3A4, CYP2B6 and CYP2C19.(1,2)  CYP2C19 contributes to both steps and is|
04489|010|A|thought to be the more important enzyme involved in formation of the|
04489|011|A|pharmacologically active metabolite.(1)|
04489|012|A|   Vonoprazan may inhibit CYP2C19 mediated conversion to the active|
04489|013|A|metabolite of clopidogrel.(7-10)|
04489|014|B||
04489|015|E|CLINICAL EFFECTS:  Concurrent use of vonoprazan may result in decreased|
04489|016|E|clopidogrel effectiveness, resulting in increased risk of adverse cardiac|
04489|017|E|events.|
04489|018|B||
04489|019|P|PREDISPOSING FACTORS:  None determined.|
04489|020|B||
04489|021|M|PATIENT MANAGEMENT:  The US manufacturer of vonoprazan states concurrent use|
04489|022|M|should be carefully monitored.  Monitor patients closely for clopidogrel|
04489|023|M|efficacy and consider alternative antiplatelet agents.(7,8)|
04489|024|M|   Evaluate patient risk for gastrointestinal (GI) bleeding.  When PPIs are|
04489|025|M|needed, use dexlansoprazole, lansoprazole, pantoprazole or rabeprazole as|
04489|026|M|they have a lower interaction risk.(1,11)  Consider the use of H2 blockers|
04489|027|M|(such as famotidine, nizatidine, or ranitidine) in patients with a low|
04489|028|M|bleeding risk and reserve the use of PPIs for patients at higher risk of GI|
04489|029|M|bleeding.|
04489|030|M|   The US manufacturer of clopidogrel states that alternatives to|
04489|031|M|clopidogrel should be considered in patients who are poor metabolizers of|
04489|032|M|CYP2C19.(1)  It would be prudent to assume that patients taking strong|
04489|033|M|inhibitors of CYP2C19 are poor metabolizers of this isoenzyme.  Moderate|
04489|034|M|CYP2C19 inhibitors, such as omeprazole, and weak CYP2C19 inhibitors, such as|
04489|035|M|cimetidine, may also affect this interaction.|
04489|036|M|   Consider alternatives to vonoprazan in patients stabilized on clopidogrel|
04489|037|M|and alternatives to clopidogrel in patients stabilized on vonoprazan.  If|
04489|038|M|concurrent therapy is warranted, consider appropriate testing to assure|
04489|039|M|adequate inhibition of platelet reactivity.|
04489|040|B||
04489|041|D|DISCUSSION:  In a study in 7 healthy subjects, concurrent use of vonoprazan|
04489|042|D|resulted in an increase and decrease in the area under the plasma|
04489|043|D|concentration-time curve (AUC) of proguanil and cycloguanil, respectively.|
04489|044|D|The AUC ratio of cycloguanil/proguanil was reduced to 0.507-fold (95% CI|
04489|045|D|0.409-0.605) with concurrent vonoprazan.(9)|
04489|046|D|   In a study in 12 healthy subjects, the inhibition of platelet aggregation|
04489|047|D|was decreased with daily and every other day use of vonoprazan with|
04489|048|D|clopidogrel (21.8% and 25%, respectively) compared to clopidogrel alone|
04489|049|D|(40.8%).(10)|
04489|050|B||
04489|051|R|REFERENCES:|
04489|052|B||
04489|053|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
04489|054|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
04489|055|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
04489|056|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
04489|057|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
04489|058|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
04489|059|R|  38(1):92-9.|5
04489|060|R|3.US Food and Drug Association. Information on Clopidogrel Bisulfate|1
04489|061|R|  (marketed as Plavix). Available at:|1
04489|062|R|  http://wayback.archive-it.org/7993/20170111075953/http:/www.fda.gov/Drugs/|1
04489|063|R|  DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm19083|1
04489|064|R|  6.htm October 27, 2010.|1
04489|065|R|4.Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati|2
04489|066|R|  J, Mottier D, Abgrall JF, Boschat J. Influence of omeprazole on the|2
04489|067|R|  antiplatelet action of clopidogrel associated with aspirin: the|2
04489|068|R|  randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am|2
04489|069|R|  Coll Cardiol 2008 Jan 22;51(3):256-60.|2
04489|070|R|5.Yun KH, Rhee SJ, Park HY, Yoo NJ, Kim NH, Oh SK, Jeong JW. Effects of|2
04489|071|R|  omeprazole on the antiplatelet activity of clopidogrel. Int Heart J 2010|2
04489|072|R|  Jan;51(1):13-6.|2
04489|073|R|6.Stockl KM, Le L, Zakharyan A, Harada AS, Solow BK, Addiego JE, Ramsey S.|2
04489|074|R|  Risk of rehospitalization for patients using clopidogrel with a proton|2
04489|075|R|  pump inhibitor. Arch Intern Med 2010 Apr 26;170(8):704-10.|2
04489|076|R|7.Voquezna (vonoprazan-amoxicillin and|1
04489|077|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04489|078|R|  Pharmaceuticals, Inc. November, 2023.|1
04489|079|R|8.Voquezna (vonoprazan) US prescribing information. Phathom Pharmaceuticals,|1
04489|080|R|  Inc. November, 2023.|1
04489|081|R|9.Funakoshi R, Tomoda Y, Kudo T, Furihata K, Kusuhara H, Ito K. Effects of|2
04489|082|R|  proton pump inhibitors, esomeprazole and vonoprazan, on the  disposition|2
04489|083|R|  of proguanil, a CYP2C19 substrate, in healthy volunteers. Br J Clin|2
04489|084|R|  Pharmacol 2019 Jul;85(7):1454-1463.|2
04489|085|R|10.Higuchi T, Yamade M, Takahashi S, Tamura S, Tani S, Kagami T, Uotani T,|2
04489|086|R|   Hamaya Y, Iwaizumi M, Osawa S, Sugimoto K, Furuta T. Influence of daily|2
04489|087|R|   versus alternate-day dosing of vonoprazan on intragastric pH,  serum|2
04489|088|R|   gastrin, and the antiplatelet function of clopidogrel : Influence of|2
04489|089|R|   alternate-day dosing of vonoprazan. Eur J Clin Pharmacol 2022 Jun;|2
04489|090|R|   78(6):955-963.|2
04489|091|R|11.Aciphex (rabeprazole) prescribing information. Eisai Inc. June, 2018.|1
04490|001|T|MONOGRAPH TITLE:  Nevirapine/Selected Strong CYP3A4 Inducers|
04490|002|B||
04490|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04490|004|L|of severe adverse interaction.|
04490|005|B||
04490|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may accelerate the metabolism|
04490|007|A|of nevirapine.(1)|
04490|008|B||
04490|009|E|CLINICAL EFFECTS:  Concurrent use of nevirapine with strong CYP3A4 inducers|
04490|010|E|may result in sub-therapeutic levels of nevirapine and the development of|
04490|011|E|resistance to non-nucleoside reverse transcriptase inhibitor (NNRTIs).|
04490|012|B||
04490|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04490|014|P|of the inducer for longer than 1-2 weeks.|
04490|015|B||
04490|016|M|PATIENT MANAGEMENT:  The University of Liverpool's HIV Drug Interactions|
04490|017|M|database advises not coadministering most strong CYP3A4 inducers with|
04490|018|M|nevirapine, except for carbamazepine and phenytoin, which should be used|
04490|019|M|with caution and monitored for virologic response and drug levels.(2)|
04490|020|M|   The US Department of Health and Human Services HIV guidelines recommend|
04490|021|M|considering alternative therapies to carbamazepine, phenytoin, and|
04490|022|M|phenobarbital for patients on nevirapine.  If concurrent use is necessary,|
04490|023|M|monitor nevirapine levels and virologic response.(3)|
04490|024|M|   The US manufacturer of nevirapine states that concurrent use of|
04490|025|M|carbamazepine (a strong CYP3A4 inducer) should be approached with caution|
04490|026|M|and monitored for virologic response and anticonvulsant levels.(1)|
04490|027|B||
04490|028|D|DISCUSSION:  In a study in 14 subjects, concurrent nevirapine and rifampin|
04490|029|D|decreased nevirapine area-under-curve (AUC), maximum concentration (Cmax),|
04490|030|D|and minimum concentration (Cmin) of nevirapine by 58%, 50%, and 68%,|
04490|031|D|respectively.  There were no significant changes to rifampin Cmax or AUC.(1)|
04490|032|D|   In a study in 10 HIV-positive tuberculosis patients, concurrent rifampin|
04490|033|D|and nevirapine decreased nevirapine AUC and Cmax by 31% and by 36%,|
04490|034|D|respectively.  There was a non-statistically significant decrease in|
04490|035|D|nevirapine Cmin by 21%.(4)|
04490|036|D|   In an open label pharmacokinetic study of 36 healthy, HIV-negative women,|
04490|037|D|the effects of several CYP3A4 inducers on plasma nevirapine levels after a|
04490|038|D|single-dose of nevirapine 200 mg was determined.  Phenobarbital 200 mg did|
04490|039|D|not produce therapeutic levels and did not have an effect on nevirapine|
04490|040|D|levels.  Carbamazepine 400 mg and phenytoin 184 mg for 3 days and for 7 days|
04490|041|D|lowered nevirapine half-life from 46.3 hours to 33.8 hours, 27.1 hours, and|
04490|042|D|34.5 hours, respectively.  Time to undetectable nevirapine levels decreased|
04490|043|D|from 14 days to 12 days with carbamazepine and 8.5 days with both phenytoin|
04490|044|D|regimens.(5)|
04490|045|D|   A study in 158 HIV+ pregnant women examined the effect of single-dose|
04490|046|D|carbamazepine 400 mg on plasma concentrations of nevirapine and development|
04490|047|D|of nevirapine resistance mutations after single-dose nevirapine 200 mg|
04490|048|D|administered at delivery.  Nevirapine levels at 1 week post-partum were 36%|
04490|049|D|lower in the patients who received carbamazepine, and there was a trend|
04490|050|D|towards fewer nevirapine resistance mutations.(6)|
04490|051|D|   A pharmacokinetic study in 73 HIV+ pregnant women confirmed that|
04490|052|D|phenytoin 184 mg for 7 days decreases the half-life of single-dose|
04490|053|D|nevirapine.  Nevirapine half-life was 25.5 hours in the phenytoin group and|
04490|054|D|63.2 hours in the control group.(7)|
04490|055|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04490|056|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04490|057|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and|
04490|058|D|primidone.(8)|
04490|059|B||
04490|060|R|REFERENCES:|
04490|061|B||
04490|062|R|1.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim|1
04490|063|R|  Pharmaceuticals, Inc. June, 2022.|1
04490|064|R|2.Liverpool Drug Interactions Group. HIV Drug Interactions. Available at:|6
04490|065|R|  https://hiv-druginteractions.org/.|6
04490|066|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04490|067|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04490|068|R|  HIV. Department of Health and Human Services. Available at:|6
04490|069|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
04490|070|R|  nd-adolescent-arv/whats-new March 23, 2023.|6
04490|071|R|4.Ribera E, Pou L, Lopez RM, Crespo M, Falco V, Ocana I, Ruiz I, Pahissa A.|2
04490|072|R|  Pharmacokinetic interaction between nevirapine and rifampicin in|2
04490|073|R|  HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr 2001|2
04490|074|R|  Dec 15;28(5):450-3.|2
04490|075|R|5.L'homme RF, Dijkema T, van der Ven AJ, Burger DM. Brief report: enzyme|2
04490|076|R|  inducers reduce elimination half-life after a single dose of  nevirapine|2
04490|077|R|  in healthy women. J Acquir Immune Defic Syndr 2006 Oct 1;43(2):193-6.|2
04490|078|R|6.Muro EP, Fillekes Q, Kisanga ER, L'homme R, Aitken SC, Mariki G, Van der|2
04490|079|R|  Ven AJ, Dolmans W, Schuurman R, Walker AS, Gibb DM, Burger DM. Intrapartum|2
04490|080|R|  single-dose carbamazepine reduces nevirapine levels faster and may|2
04490|081|R|  decrease resistance after a single dose of nevirapine for perinatal HIV|2
04490|082|R|  prevention. J Acquir Immune Defic Syndr 2012 Mar 1;59(3):266-73.|2
04490|083|R|7.Fillekes Q, Muro EP, Chunda C, Aitken S, Kisanga ER, Kankasa C, Thomason|2
04490|084|R|  MJ, Gibb DM, Walker AS, Burger DM. Effect of 7 days of phenytoin on the|2
04490|085|R|  pharmacokinetics of and the development of  resistance to single-dose|2
04490|086|R|  nevirapine for perinatal HIV prevention: a randomized  pilot trial. J|2
04490|087|R|  Antimicrob Chemother 2013 Nov;68(11):2609-15.|2
04490|088|R|8.This information is based on an extract from the Certara Drug Interaction|6
04490|089|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04491|001|T|MONOGRAPH TITLE:  Repotrectinib/Strong and Moderate CYP3A4 Inhibitors|
04491|002|B||
04491|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04491|004|L|of severe adverse interaction.|
04491|005|B||
04491|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
04491|007|A|repotrectinib.(1)|
04491|008|B||
04491|009|E|CLINICAL EFFECTS:  Concomitant use of a strong or moderate CYP3A4 inhibitor|
04491|010|E|increases repotrectinib plasma concentrations, which may increase the|
04491|011|E|incidence and severity of adverse reactions, including CNS effects|
04491|012|E|(dizziness, ataxia, cognitive disorders), interstitial lung|
04491|013|E|disease/pneumonitis, hepatotoxicity, and myalgia.(1)|
04491|014|B||
04491|015|P|PREDISPOSING FACTORS:  None determined.|
04491|016|B||
04491|017|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong or moderate CYP3A4|
04491|018|M|inhibitors with repotrectinib.  Discontinue CYP3A4 inhibitors for 3 to 5|
04491|019|M|half lives of the inhibitor prior to initiating repotrectinib.(1)|
04491|020|B||
04491|021|D|DISCUSSION:  In a study, itraconazole (a strong CYP3A4 and P-gp inhibitor)|
04491|022|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
04491|023|D|repotrectinib by 5.9-fold and 1.7-fold, respectively.(1)|
04491|024|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
04491|025|D|clarithromycin, cobicistat, grapefruit, indinavir, itraconazole, josamycin,|
04491|026|D|ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone,|
04491|027|D|nefazodone, nelfinavir, nirmatrelvir, posaconazole, ribociclib, saquinavir,|
04491|028|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
04491|029|D|voriconazole.(2)|
04491|030|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
04491|031|D|berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone,|
04491|032|D|erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
04491|033|D|imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra,|
04491|034|D|stiripentol, tofisopam, treosulfan, and verapamil.(2)|
04491|035|B||
04491|036|R|REFERENCES:|
04491|037|B||
04491|038|R|1.Augtyro (repotrectinib) US prescribing information. Bristol-Myers Squibb|1
04491|039|R|  Company November, 2023.|1
04491|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
04491|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04492|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Repotrectinib|
04492|002|B||
04492|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04492|004|L|of severe adverse interaction.|
04492|005|B||
04492|006|A|MECHANISM OF ACTION:  Repotrectinib may induce the CYP3A4-mediated|
04492|007|A|metabolism of hormonal contraceptives.(1)|
04492|008|B||
04492|009|E|CLINICAL EFFECTS:  Concurrent use of repotrectinib may reduce the blood|
04492|010|E|concentrations and effectiveness of hormonal contraceptives.  Repotrectinib|
04492|011|E|may cause fetal harm when administered to pregnant women.(1)|
04492|012|B||
04492|013|P|PREDISPOSING FACTORS:  None determined.|
04492|014|B||
04492|015|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled to avoid|
04492|016|M|hormonal contraception (including oral contraceptives, patches, implants,|
04492|017|M|and/or IUDs) due to the risk of contraceptive failure.  Women should use an|
04492|018|M|effective non-hormonal method of contraception during and for 2 months after|
04492|019|M|repotrectinib therapy.(1)|
04492|020|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04492|021|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04492|022|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04492|023|M|contraceptive (i.e., a copper IUD).  If a non-hormonal emergency|
04492|024|M|contraceptive is not an option, double the usual dose of levonorgestrel from|
04492|025|M|1.5 to 3 mg.  Advise the patient to have a pregnancy test to exclude|
04492|026|M|pregnancy after use and to seek medical advice if they do become|
04492|027|M|pregnant.(2)|
04492|028|B||
04492|029|D|DISCUSSION:  Repotrectinib is a moderate CYP3A4 inducer.  In a study,|
04492|030|D|repotrectinib decreased the area-under-curve (AUC) and maximum concentration|
04492|031|D|(Cmax) of midazolam (a sensitive CYP3A4 substrate) by 69% and 48%,|
04492|032|D|respectively.  It may also decrease estrogen or progestin concentrations and|
04492|033|D|reduce the effectiveness of hormonal contraceptives.  Repotrectinib may|
04492|034|D|cause fetal harm when administered to pregnant women.(1)|
04492|035|B||
04492|036|R|REFERENCES:|
04492|037|B||
04492|038|R|1.Augtyro (repotrectinib) US prescribing information. Bristol-Myers Squibb|1
04492|039|R|  Company November, 2023.|1
04492|040|R|2.Medicines and Healthcare products Regulatory Agency.|1
04492|041|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04492|042|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04492|043|R|  available at:|1
04492|044|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04492|045|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04492|046|R|  -and-contraceptive-efficacy September 15, 2016..|1
04493|001|T|MONOGRAPH TITLE:  Capivasertib/Strong CYP3A4 Inhibitors|
04493|002|B||
04493|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04493|004|L|of severe adverse interaction.|
04493|005|B||
04493|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the CYP3A4|
04493|007|A|metabolism of capivasertib.(1)|
04493|008|B||
04493|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04493|010|E|increased systemic exposure to and effects from capivasertib, hyperglycemia,|
04493|011|E|severe diarrhea, and cutaneous adverse reactions.(1)|
04493|012|B||
04493|013|P|PREDISPOSING FACTORS:  None determined.|
04493|014|B||
04493|015|M|PATIENT MANAGEMENT:  Avoid concomitant use with strong CYP3A4 inhibitors.|
04493|016|M|If concomitant use cannot be avoided, reduce the capivasertib dose to 320 mg|
04493|017|M|twice daily for 4 days followed by 3 days off.(1)|
04493|018|M|   After discontinuation of the strong CYP3A4 inhibitor for 3 to 5|
04493|019|M|half-lives of the inhibitor, resume the capivasertib dosage that was taken|
04493|020|M|prior to initiating the strong CYP3A4 inhibitor.(1)|
04493|021|B||
04493|022|D|DISCUSSION:  Itraconazole (strong CYP3A4 inhibitor) is predicted to increase|
04493|023|D|capivasertib area-under-curve (AUC) by up to 1.7-fold and maximum|
04493|024|D|concentration (Cmax) by up to 1.4-fold.(1)|
04493|025|D|   Strong CYP3A4 inhibitors linked to this monograph include: adagrasib,|
04493|026|D|boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib,|
04493|027|D|indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole,|
04493|028|D|lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
04493|029|D|nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir,|
04493|030|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
04493|031|D|voriconazole.(2,3)|
04493|032|B||
04493|033|R|REFERENCES:|
04493|034|B||
04493|035|R|1.Truqap (capivasertib) US prescribing information. AstraZeneca|1
04493|036|R|  Pharmaceuticals LP November, 2023.|1
04493|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04493|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04493|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04493|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04493|041|R|  11/14/2017.|1
04493|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
04493|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04494|001|T|MONOGRAPH TITLE:  Capivasertib/Moderate CYP3A4 Inhibitors|
04494|002|B||
04494|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04494|004|L|take action as needed.|
04494|005|B||
04494|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the CYP3A4|
04494|007|A|metabolism of capivasertib.(1)|
04494|008|B||
04494|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
04494|010|E|in increased systemic exposure to and effects from capivasertib,|
04494|011|E|hyperglycemia, severe diarrhea, and cutaneous adverse reactions.(1)|
04494|012|B||
04494|013|P|PREDISPOSING FACTORS:  None determined.|
04494|014|B||
04494|015|M|PATIENT MANAGEMENT:  Concomitant use of capivasertib with moderate CYP3A4|
04494|016|M|inhibitors requires a dose reduction of capivasertib.  Reduce the|
04494|017|M|capivasertib dose to 320 mg twice daily for 4 days followed by 3 days|
04494|018|M|off.(1)|
04494|019|M|   After discontinuation of the strong CYP3A4 inhibitor for 3 to 5|
04494|020|M|half-lives of the inhibitor, resume the capivasertib dosage that was taken|
04494|021|M|prior to initiating the strong CYP3A4 inhibitor.(1)|
04494|022|B||
04494|023|D|DISCUSSION:  Itraconazole (strong CYP3A4 inhibitor) is predicted to increase|
04494|024|D|capivasertib area-under-curve (AUC) by up to 1.7-fold and maximum|
04494|025|D|concentration (Cmax) by up to 1.4-fold.(1)|
04494|026|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
04494|027|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
04494|028|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
04494|029|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
04494|030|D|isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant,|
04494|031|D|nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
04494|032|D|verapamil, and voxelotor.(2,3)|
04494|033|B||
04494|034|R|REFERENCES:|
04494|035|B||
04494|036|R|1.Truqap (capivasertib) US prescribing information. AstraZeneca|1
04494|037|R|  Pharmaceuticals LP November, 2023.|1
04494|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04494|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04494|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04494|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04494|042|R|  11/14/2017.|1
04494|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
04494|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04495|001|T|MONOGRAPH TITLE:  Capivasertib/Corticosteroids|
04495|002|B||
04495|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04495|004|L|take action as needed.|
04495|005|B||
04495|006|A|MECHANISM OF ACTION:  Capivasertib may cause severe hyperglycemia.|
04495|007|A|Corticosteroids also cause hyperglycemia.(1)|
04495|008|B||
04495|009|E|CLINICAL EFFECTS:  Concurrent use of capivasertib with corticosteroids may|
04495|010|E|cause severe hyperglycemia.(1)|
04495|011|B||
04495|012|P|PREDISPOSING FACTORS:  Patients with a medical history of diabetes mellitus|
04495|013|P|and in patients with risk factors for hyperglycemia, such as obesity (BMI >=|
04495|014|P|30), elevated fasting glucose of > 160 mg/dL, HbA1c at or above the upper|
04495|015|P|limit of normal, or intercurrent infections, may be at increased risk for|
04495|016|P|hyperglycemia.(1)|
04495|017|B||
04495|018|M|PATIENT MANAGEMENT:  The US manufacturer of capivasertib recommends|
04495|019|M|monitoring fasting blood glucose more frequently in patients on concomitant|
04495|020|M|systemic corticosteroids.(1)|
04495|021|M|   If hyperglycemia occurs after starting capivasertib, monitor fasting|
04495|022|M|glucose as clinically indicated and at least twice weekly until fasting|
04495|023|M|glucose returns to normal.(1)|
04495|024|B||
04495|025|D|DISCUSSION:  Because capivasertib has been associated with severe|
04495|026|D|hyperglycemia, fasting blood glucose should be monitored closely during the|
04495|027|D|concurrent use of corticosteroids with capivasertib therapy.(1)|
04495|028|D|   In clinical studies, hyperglycemia occurred in 18% of patients treated|
04495|029|D|with capivasertib.  Grade 3 (insulin therapy initiated; hospitalization|
04495|030|D|indicated) or Grade 4 (life-threatening consequences; urgent intervention|
04495|031|D|indicated) hyperglycemia occurred in 2.8% of patients.  Diabetic|
04495|032|D|ketoacidosis occurred in 0.3% of patients and diabetic metabolic|
04495|033|D|decompensation in 0.6% of patients.  Dose reduction for hyperglycemia was|
04495|034|D|required in 0.6% of patients and permanent discontinuation was required in|
04495|035|D|0.6% of patients.  The median time to first occurrence of hyperglycemia was|
04495|036|D|15 days (range: 1 to 367).(1)|
04495|037|D|   In the 65 patients with hyperglycemia, 45% required treatment with|
04495|038|D|anti-hyperglycemic medication (insulin in 15%, and metformin in 29%).  Of|
04495|039|D|the 29 patients who required anti-hyperglycemic medication during treatment|
04495|040|D|with capivasertib, 66% (19/29) remained on these medications at treatment|
04495|041|D|discontinuation or last follow up.(1)|
04495|042|B||
04495|043|R|REFERENCE:|
04495|044|B||
04495|045|R|1.Truqap (capivasertib) US prescribing information. AstraZeneca|1
04495|046|R|  Pharmaceuticals LP November, 2023.|1
04496|001|T|MONOGRAPH TITLE:  Siponimod/Immunosuppressive Moderate and Strong CYP3A4|
04496|002|T|Inducers|
04496|003|B||
04496|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04496|005|L|of severe adverse interaction.|
04496|006|B||
04496|007|A|MECHANISM OF ACTION:  Drugs that are moderate or strong inducers of CYP3A4|
04496|008|A|may increase the metabolism of siponimod.(1)  Patients with a CYP2C9*1/*3 or|
04496|009|A|*2/*3 genotype who are more dependent on CYP3A4 for the metabolism of|
04496|010|A|siponimod would experience a greater effect of CYP3A4 induction.|
04496|011|A|   Siponimod in combination with immunosuppressives and immune-modulators|
04496|012|A|all suppress the immune system.(1)|
04496|013|A|   Repotrectinib is an immunosuppressive agent that is also a moderate|
04496|014|A|CYP3A4 inducer.(2)|
04496|015|B||
04496|016|E|CLINICAL EFFECTS:  Concurrent use of a siponimod with a moderate or strong|
04496|017|E|CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype may result|
04496|018|E|in decreased levels and effectiveness of siponimod.(1)|
04496|019|E|   Concurrent use of siponimod with immunosuppressive or immune-modulating|
04496|020|E|agents may result in an increased risk of serious infections, such as|
04496|021|E|disseminated herpetic infection or progressive multifocal|
04496|022|E|leukoencephalopathy (PML), an opportunistic infection caused by the JC virus|
04496|023|E|(JCV).(1)|
04496|024|B||
04496|025|P|PREDISPOSING FACTORS:  Patients with a CYP2C9*1/*3 or *2/*3 genotype who are|
04496|026|P|more dependent on CYP3A4 for the metabolism of siponimod would experience a|
04496|027|P|greater effect of CYP3A4 induction.|
04496|028|P|   Incomplete washout of previously prescribed immunosuppressive or|
04496|029|P|immune-modulating medications.|
04496|030|P|   Induction effects may be more likely with regular use of the inducer for|
04496|031|P|longer than 1-2 weeks.|
04496|032|B||
04496|033|M|PATIENT MANAGEMENT:  The manufacturer of siponimod says that the combination|
04496|034|M|of siponimod with a moderate or strong CYP3A4 inducer is not recommended for|
04496|035|M|patients with a CYP2C9*1/*3 or *2/*3 genotype.(1)|
04496|036|M|   Agents that are both moderate CYP3A4 inducers and moderate CYP2C9|
04496|037|M|inducers (e.g., lorlatinib) should be used with caution regardless of the|
04496|038|M|patient's CYP2C9 genotype.(1)|
04496|039|M|   The siponimod US prescribing information states this information|
04496|040|M|regarding immunosuppression:|
04496|041|M|   -Siponimod has not been studied in combination with anti-neoplastic,|
04496|042|M|immune-modulating, or immunosuppressive therapies.  Caution should be used|
04496|043|M|during concomitant administration because of the risk of additive immune|
04496|044|M|effects during therapy and in the week following administration.  When|
04496|045|M|switching from drugs with prolonged immune effects, the half-life and mode|
04496|046|M|of action of these drugs must be considered in order to avoid unintended|
04496|047|M|additive immunosuppressive effects.  Initiating treatment with siponimod|
04496|048|M|after alemtuzumab is not recommended.  However, siponimod can generally be|
04496|049|M|started immediately after discontinuation of beta interferon or glatiramer|
04496|050|M|acetate.(1)|
04496|051|B||
04496|052|D|DISCUSSION:  In a study, efavirenz (a moderate CYP3A4 inducer) decreased the|
04496|053|D|area-under-curve (AUC) of siponimod by up to 52% across CYP2C9 genotypes.|
04496|054|D|   Fatal disseminated herpes zoster and herpes simplex infections and cases|
04496|055|D|of progressive multifocal leukoencephalopathy (PML) have been reported in|
04496|056|D|patients who previously received immunomodulators or immunosuppressants.(1)|
04496|057|D|   Drugs that are immunosuppressive moderate or strong CYP3A4 inducers|
04496|058|D|linked to this monograph include: encorafenib and repotrectinib.(2-4)|
04496|059|B||
04496|060|R|REFERENCES:|
04496|061|B||
04496|062|R|1.Mayzent (siponimod) US prescribing information. Novartis Pharmaceuticals|1
04496|063|R|  Corporation August, 2025.|1
04496|064|R|2.Augtyro (repotrectinib) US prescribing information. Bristol-Myers Squibb|1
04496|065|R|  Company November, 2023.|1
04496|066|R|3.This information is based on an extract from the Certara Drug Interaction|6
04496|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04496|068|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04496|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04496|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04496|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04496|072|R|  11/14/2017.|1
04497|001|T|MONOGRAPH TITLE:  Capivasertib/Strong and Moderate CYP3A4 Inducers|
04497|002|B||
04497|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04497|004|L|of severe adverse interaction.|
04497|005|B||
04497|006|A|MECHANISM OF ACTION:  Strong and moderate inducers of CYP3A4 may increase|
04497|007|A|the metabolism of capivasertib.(1)|
04497|008|B||
04497|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP3A4|
04497|010|E|may result in decreased levels and effectiveness of capivasertib.(1)|
04497|011|B||
04497|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04497|013|P|of the inducer for longer than 1-2 weeks.|
04497|014|B||
04497|015|M|PATIENT MANAGEMENT:  Avoid concomitant use of capivasertib with strong and|
04497|016|M|moderate CYP3A4 inducers.(1)|
04497|017|B||
04497|018|D|DISCUSSION:  Rifampin (strong CYP3A4 inducer) is predicted to decrease|
04497|019|D|capivasertib area-under-curve (AUC) by 70% and maximum concentration (Cmax)|
04497|020|D|by 60%.(1)|
04497|021|D|   Efavirenz (moderate CYP3A4 inducer) is predicted to decrease capivasertib|
04497|022|D|AUC by 60% and Cmax by 50%.(1)|
04497|023|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04497|024|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04497|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04497|026|D|rifapentine, and St. John's wort.(2,3)|
04497|027|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04497|028|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04497|029|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04497|030|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and|
04497|031|D|tovorafenib.(2,3)|
04497|032|B||
04497|033|R|REFERENCES:|
04497|034|B||
04497|035|R|1.Truqap (capivasertib) US prescribing information. AstraZeneca|1
04497|036|R|  Pharmaceuticals LP November, 2023.|1
04497|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04497|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04497|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04497|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04497|041|R|  11/14/2017.|1
04497|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
04497|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04498|001|T|MONOGRAPH TITLE:  Capivasertib/Lonafarnib (mono deleted 05/28/2024)|
04498|002|B||
04498|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04498|004|L|of severe adverse interaction.|
04498|005|B||
04498|006|A|MECHANISM OF ACTION:  Capivasertib and lonafarnib are both CYP3A4 substrates|
04498|007|A|and inhibitors.(1,2) Lonafarnib is a sensitive CYP3A4 substrate.(2)|
04498|008|B||
04498|009|E|CLINICAL EFFECTS:  Concurrent use of capivasertib with strong CYP3A4|
04498|010|E|inhibitors such as lonafarnib may increase levels of and effects from|
04498|011|E|capivasertib including hyperglycemia, sever diarrhea, and cutaneous adverse|
04498|012|E|reactions.(1)|
04498|013|E|   Concurrent use of lonafarnib with weak CYP3A4 inhibitors such as|
04498|014|E|capivasertib may increase the risk of adverse reactions of lonafarnib|
04498|015|E|including nausea and vomiting, increased liver enzymes, myelosuppression,|
04498|016|E|and hypertension.(2)|
04498|017|B||
04498|018|P|PREDISPOSING FACTORS:  None determined.|
04498|019|B||
04498|020|M|PATIENT MANAGEMENT:  Avoid the concurrent use of capivasertib and|
04498|021|M|lonafarnib.(1,2)|
04498|022|M|   The effect of the two-way inhibition of capivasertib and lonafarnib|
04498|023|M|metabolism is unknown.  The optimal doses of capivasertib and lonafarnib|
04498|024|M|when used concurrently have not been determined.  Manufacturers provide|
04498|025|M|recommendations for dose modification of capivasertib and lonafarnib when|
04498|026|M|each is used with a CYP3A4 inhibitor, but the recommendations may not apply|
04498|027|M|when there is a two-way inhibition.  Dose modifications mentioned below are|
04498|028|M|informational only.|
04498|029|M|   Avoid concomitant use of capivasertib with strong CYP3A4 inhibitors.  If|
04498|030|M|concomitant use cannot be avoided, reduce the capivasertib dose to 320 mg|
04498|031|M|twice daily for 4 days followed by 3 days off.(1)|
04498|032|M|   After discontinuation of the strong CYP3A4 inhibitor, resume the|
04498|033|M|capivasertib dosage (after 3 to 5 half-lives of the inhibitor) that was|
04498|034|M|taken prior to initiating the strong CYP3A4 inhibitor.(1)|
04498|035|M|   If concurrent administration of a weak CYP3A4 inhibitor with lonafarnib|
04498|036|M|is unavoidable, reduce the dose of lonafarnib to 115 mg/m2 or continue at|
04498|037|M|115 mg/m2 without further dosage increases.(2)|
04498|038|M|   Closely monitor patients for arrhythmias and events such as syncope and|
04498|039|M|heart palpitations because lonafarnib exposures may be increased despite the|
04498|040|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
04498|041|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
04498|042|M|inhibitor.(2)|
04498|043|B||
04498|044|D|DISCUSSION:  Itraconazole (strong CYP3A4 inhibitor) is predicted to increase|
04498|045|D|capivasertib area-under-curve (AUC) by up to 1.7-fold and maximum|
04498|046|D|concentration (Cmax) by up to 1.4-fold.(1)|
04498|047|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
04498|048|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
04498|049|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
04498|050|B||
04498|051|R|REFERENCES:|
04498|052|B||
04498|053|R|1.Truqap (capivasertib) US prescribing information. AstraZeneca|1
04498|054|R|  Pharmaceuticals LP November, 2023.|1
04498|055|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04498|056|R|  Inc. November, 2020.|1
04498|057|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04498|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04498|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04498|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04498|061|R|  11/14/2017.|1
04498|062|R|4.This information is based on an extract from the Certara Drug Interaction|6
04498|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04499|001|T|MONOGRAPH TITLE:  Pexidartinib/Capivasertib (mono deleted 02/04/2025)|
04499|002|B||
04499|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04499|004|L|of severe adverse interaction.|
04499|005|B||
04499|006|A|MECHANISM OF ACTION:  Inhibitors of UGT may inhibit the metabolism of|
04499|007|A|pexidartinib.(1)  Capivasertib is a UGT inhibitor.|
04499|008|A|   Inducers of CYP3A4 may induce the metabolism of capivasertib.(2)|
04499|009|A|Pexidartinib is a CYP3A4 inducer.|
04499|010|A|   Concurrent use of pexidartinib and capivasertib may alter exposure to one|
04499|011|A|or both agents.|
04499|012|B||
04499|013|E|CLINICAL EFFECTS:  Concurrent use of a UGT inhibitor such as capivasertib|
04499|014|E|may result in elevated levels and increased effects of pexidartinib, such as|
04499|015|E|hepatotoxicity.(1,2)  Symptoms can include nausea, vomiting, jaundice, dark|
04499|016|E|urine, abdominal pain, and unexplained fatigue.|
04499|017|E|   Concurrent or recent use of a CYP3A4 inducer such as pexidartinib may|
04499|018|E|result in decreased levels and effectiveness of capivasertib.(1,2)|
04499|019|B||
04499|020|P|PREDISPOSING FACTORS:  None determined.|
04499|021|B||
04499|022|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pexidartinib and|
04499|023|M|capivasertib.|
04499|024|M|   The US manufacturer of pexidartinib states that pexidartinib|
04499|025|M|coadministration with inhibitors of UGT should be avoided.(1)|
04499|026|M|   If coadministration with a UGT1A4 inhibitor cannot be avoided, reduce the|
04499|027|M|pexidartinib dose according to the following recommendations.|
04499|028|M|   If the planned total daily dose is currently 500 mg, modify the total|
04499|029|M|daily dose to 250 mg by administering 125 mg twice daily.|
04499|030|M|   If the planned total daily dose is currently 375 mg, modify the total|
04499|031|M|daily dose to 250 mg by administering 125 mg twice daily.|
04499|032|M|   If the planned total daily dose is currently 250 mg, modify the total|
04499|033|M|daily dose to 125 mg by administering 125 mg once daily.|
04499|034|M|   If concomitant use of a UGT inhibitor is discontinued, increase the|
04499|035|M|pexidartinib dose to the dose that was used before starting the inhibitor|
04499|036|M|after three plasma half-lives of the UGT inhibitor.|
04499|037|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04499|038|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04499|039|M|recommendations in the Turalio package insert. Advise patients to|
04499|040|M|immediately report any symptoms of hepatotoxicity.|
04499|041|M|   The US manufacturer of capivasertib states to avoid the concurrent use of|
04499|042|M|CYP3A4 inducers in patients receiving therapy with capivasertib.(2)|
04499|043|M|   Patients receiving concurrent therapy with pexidartinib and capivasertib|
04499|044|M|should be monitored closely for efficacy and signs of toxicities.(1,2)|
04499|045|B||
04499|046|D|DISCUSSION:  Coadministration of probenecid (UGT inhibitor) increased|
04499|047|D|pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by|
04499|048|D|5% and 60%.(1)|
04499|049|D|   Efavirenz (moderate CYP3A4 inducer) is predicted to decrease capivasertib|
04499|050|D|AUC by 60% and Cmax by 50%.(2)|
04499|051|B||
04499|052|R|REFERENCES:|
04499|053|B||
04499|054|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04499|055|R|  November, 2023.|1
04499|056|R|2.Truqap (capivasertib) US prescribing information. AstraZeneca|1
04499|057|R|  Pharmaceuticals LP November, 2023.|1
04500|001|T|MONOGRAPH TITLE:  Pexidartinib (200 mg)/Capivasertib (mono deleted|
04500|002|T|02/04/2025)|
04500|003|B||
04500|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04500|005|L|of severe adverse interaction.|
04500|006|B||
04500|007|A|MECHANISM OF ACTION:  Inhibitors of UGT may inhibit the metabolism of|
04500|008|A|pexidartinib.(1)  Capivasertib is a UGT inhibitor.|
04500|009|A|   Inducers of CYP3A4 may induce the metabolism of capivasertib.(2)|
04500|010|A|Pexidartinib is a CYP3A4 inducer.|
04500|011|A|   Concurrent use of pexidartinib and capivasertib may alter exposure to one|
04500|012|A|or both agents.|
04500|013|B||
04500|014|E|CLINICAL EFFECTS:  Concurrent use of a UGT inhibitor such as capivasertib|
04500|015|E|may result in elevated levels and increased effects of pexidartinib, such as|
04500|016|E|hepatotoxicity.(1,2)  Symptoms can include nausea, vomiting, jaundice, dark|
04500|017|E|urine, abdominal pain, and unexplained fatigue.|
04500|018|E|   Concurrent or recent use of a CYP3A4 inducer such as pexidartinib may|
04500|019|E|result in decreased levels and effectiveness of capivasertib.(1,2)|
04500|020|B||
04500|021|P|PREDISPOSING FACTORS:  None determined.|
04500|022|B||
04500|023|M|PATIENT MANAGEMENT:  Avoid the concurrent use of pexidartinib and|
04500|024|M|capivasertib.|
04500|025|M|   The US manufacturer of pexidartinib states that pexidartinib|
04500|026|M|coadministration with inhibitors of UGT should be avoided.(1)|
04500|027|M|   If coadministration with a UGT1A4 inhibitor cannot be avoided, reduce the|
04500|028|M|pexidartinib dose according to the following recommendations.|
04500|029|M|   If the planned total daily dose is currently 800 mg, modify the total|
04500|030|M|daily dose to 400 mg by administering 200 mg twice daily.|
04500|031|M|   If the planned total daily dose is currently 600 mg, modify the total|
04500|032|M|daily dose to 400 mg by administering 200 mg twice daily.|
04500|033|M|   If the planned total daily dose is currently 400 mg, modify the total|
04500|034|M|daily dose to 200 mg by administering 200 mg once daily.|
04500|035|M|   If concomitant use of a UGT inhibitor is discontinued, increase the|
04500|036|M|pexidartinib dose to the dose that was used before starting the inhibitor|
04500|037|M|after three plasma half-lives of the UGT inhibitor.|
04500|038|M|   Monitor liver tests, including AST, ALT, total bilirubin, direct|
04500|039|M|bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the|
04500|040|M|recommendations in the Turalio package insert. Advise patients to|
04500|041|M|immediately report any symptoms of hepatotoxicity.|
04500|042|M|   The US manufacturer of capivasertib states to avoid the concurrent use of|
04500|043|M|CYP3A4 inducers in patients receiving therapy with capivasertib.(2)|
04500|044|M|   Patients receiving concurrent therapy with pexidartinib and erlotinib|
04500|045|M|should be monitored closely for efficacy and signs or toxicities.(1,2)|
04500|046|B||
04500|047|D|DISCUSSION:  Coadministration of probenecid (UGT inhibitor) increased|
04500|048|D|pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by|
04500|049|D|5% and 60%.(1)|
04500|050|D|   Efavirenz (moderate CYP3A4 inducer) is predicted to decrease capivasertib|
04500|051|D|AUC by 60% and Cmax by 50%.(2)|
04500|052|B||
04500|053|R|REFERENCES:|
04500|054|B||
04500|055|R|1.Turalio (pexidartinib) US prescribing information. Daiichi Sankyo, Inc.|1
04500|056|R|  November, 2023.|1
04500|057|R|2.Truqap (capivasertib) US prescribing information. AstraZeneca|1
04500|058|R|  Pharmaceuticals LP November, 2023.|1
04501|001|T|MONOGRAPH TITLE:  Repotrectinib/Strong or Moderate CYP3A4 Inducers|
04501|002|B||
04501|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04501|004|L|of severe adverse interaction.|
04501|005|B||
04501|006|A|MECHANISM OF ACTION:  Strong or moderate CYP3A4 inducers may induce the|
04501|007|A|metabolism of repotrectinib.(1)|
04501|008|B||
04501|009|E|CLINICAL EFFECTS:  Coadministration of repotrectinib with a strong or|
04501|010|E|moderate CYP3A4 inducer decreases repotrectinib plasma concentrations, which|
04501|011|E|may decrease efficacy of repotrectinib.(1)|
04501|012|B||
04501|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04501|014|P|of the inducer for longer than 1-2 weeks.|
04501|015|B||
04501|016|M|PATIENT MANAGEMENT:  The manufacturer of repotrectinib states that|
04501|017|M|concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)|
04501|018|B||
04501|019|D|DISCUSSION:  Coadministration of repotrectinib with rifampin, a strong|
04501|020|D|CYP3A4 and P-glycoprotein inducer, decreased concentration maximum (Cmax) by|
04501|021|D|79% and area-under-curve (AUC) by 92%.(1)|
04501|022|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04501|023|D|carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane,|
04501|024|D|phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's|
04501|025|D|wort.(2,3)|
04501|026|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04501|027|D|dabrafenib, dipyrone, efavirenz, elagolix, encorafenib, etravirine,|
04501|028|D|lesinurad, modafinil, nafcillin, pacritinib, pexidartinib, rifabutin,|
04501|029|D|sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)|
04501|030|B||
04501|031|R|REFERENCES:|
04501|032|B||
04501|033|R|1.Augtyro (repotrectinib) US prescribing information. Bristol-Myers Squibb|1
04501|034|R|  Company November, 2023.|1
04501|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04501|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04501|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04501|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04501|039|R|  11/14/2017.|1
04501|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04501|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04502|001|T|MONOGRAPH TITLE:  Repotrectinib/CYP3A4 Inhibitors and Substrates|
04502|002|B||
04502|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04502|004|L|of severe adverse interaction.|
04502|005|B||
04502|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
04502|007|A|repotrectinib.(1)  Clarithromycin(2) and idelalisib(3) are strong CYP3A4|
04502|008|A|inhibitors, and crizotinib,(4) duvelisib,(5) fedratinib,(6) oral|
04502|009|A|lefamulin,(7) lenacapavir,(8) and voxelotor(9) are moderate CYP3A4|
04502|010|A|inhibitors.|
04502|011|A|   Moderate inducers of CYP3A4 may induce the metabolism of crizotinib,(4)|
04502|012|A|duvelisib,(5) fedratinib,(6) idelalisib,(3) oral lefamulin,(7)|
04502|013|A|lenacapavir,(8) vonoprazan,(2) and voxelotor.(9)  Repotrectinib is a|
04502|014|A|moderate CYP3A4 inducer.(1)|
04502|015|B||
04502|016|E|CLINICAL EFFECTS:  Concomitant use of a strong or moderate CYP3A4 inhibitor|
04502|017|E|increases repotrectinib plasma concentrations, which may increase the|
04502|018|E|incidence and severity of adverse reactions, including CNS effects|
04502|019|E|(dizziness, ataxia, cognitive disorders), interstitial lung|
04502|020|E|disease/pneumonitis, hepatotoxicity, and myalgia.(1)|
04502|021|E|   The concurrent use of a moderate CYP3A4 inducer may result in decreased|
04502|022|E|levels and effectiveness of crizotinib,(4) duvelisib,(5) fedratinib,(6)|
04502|023|E|idelalisib,(3) oral lefamulin,(7) lenacapavir,(8) vonoprazan,(2) and|
04502|024|E|voxelotor.(9)|
04502|025|B||
04502|026|P|PREDISPOSING FACTORS:  None determined.|
04502|027|B||
04502|028|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong or moderate CYP3A4|
04502|029|M|inhibitors that are also CYP3A4 substrates with repotrectinib.(1)|
04502|030|B||
04502|031|D|DISCUSSION:  In a study, itraconazole (a strong CYP3A4 and P-gp inhibitor)|
04502|032|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
04502|033|D|repotrectinib by 5.9-fold and 1.7-fold, respectively.(1)|
04502|034|D|   Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the Cmax and|
04502|035|D|AUC of a single dose of crizotinib (250 mg) by 69% and 82%, respectively.(4)|
04502|036|D|   In an interaction study, etravirine (a moderate CYP3A inducer) 200 mg|
04502|037|D|twice daily decreased the Cmax and AUC of single dose duvelisib 25 mg by 16%|
04502|038|D|and 35%, respectively.(5)|
04502|039|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
04502|040|D|decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and|
04502|041|D|75%, respectively.(3)|
04502|042|D|   In a study, concurrent administration of rifampin (a strong inducer) with|
04502|043|D|oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(7)|
04502|044|D|   In a study, efavirenz 600 mg once daily (inducer of CYP3A4 [moderate] and|
04502|045|D|P-glycoprotein) decreased the Cmax and AUC of lenacapavir by 36% and 56%,|
04502|046|D|respectively.(8)|
04502|047|D|   Strong CYP3A4 inducers like rifampin are predicted to decrease the AUC of|
04502|048|D|vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are predicted|
04502|049|D|to decrease vonoprazan AUC by 50%.(2)|
04502|050|D|   Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted|
04502|051|D|to decrease the AUC of voxelotor by 24%.(9)|
04502|052|D|   Agents linked to this monograph include: crizotinib, duvelisib,|
04502|053|D|fedratinib, idelalisib, oral lefamulin, lenacapavir, rilzabrutinib,|
04502|054|D|vonoprazan-amoxicillin-clarithromycin, and voxelotor.|
04502|055|B||
04502|056|R|REFERENCES:|
04502|057|B||
04502|058|R|1.Augtyro (repotrectinib) US prescribing information. Bristol-Myers Squibb|1
04502|059|R|  Company November, 2023.|1
04502|060|R|2.Voquezna (vonoprazan-amoxicillin and|1
04502|061|R|  vonoprazan-amoxicillin-clarithromycin) US prescribing information. Phathom|1
04502|062|R|  Pharmaceuticals, Inc. November, 2023.|1
04502|063|R|3.Zydelig (idelalisib) US prescribing information. Gilead Sciences, Inc.|1
04502|064|R|  October, 2020.|1
04502|065|R|4.Xalkori (crizotinib) US prescribing information. Pfizer Inc. September,|1
04502|066|R|  2023.|1
04502|067|R|5.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
04502|068|R|  2021.|1
04502|069|R|6.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
04502|070|R|  May, 2023.|1
04502|071|R|7.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04502|072|R|  Inc August 2019.|1
04502|073|R|8.Sunlenca (lenacapavir) US prescribing information. Gilead Sciences, Inc.|1
04502|074|R|  November 2024.|1
04502|075|R|9.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
04502|076|R|  Inc. December, 2021.|1
04502|077|R|10.This information is based on an extract from the Certara Drug Interaction|6
04502|078|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04503|001|T|MONOGRAPH TITLE:  Repotrectinib/Strong and Moderate 3A4 Inducers &|
04503|002|T|Substrates|
04503|003|B||
04503|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04503|005|L|of severe adverse interaction.|
04503|006|B||
04503|007|A|MECHANISM OF ACTION:  Repotrectinib,(1) lorlatinib,(2) and mitapivat(3) are|
04503|008|A|all CYP3A4 substrates and moderate CYP3A4 inducers.|
04503|009|A|   CYP3A4 inducers may induce the metabolism of repotrectinib.(1)|
04503|010|A|   Repotrectinib may induce the metabolism of CYP3A4 substrates, such as|
04503|011|A|lorlatinib and mitapivat.(1)|
04503|012|B||
04503|013|E|CLINICAL EFFECTS:  Coadministration of repotrectinib with a CYP3A4 inducer|
04503|014|E|decreases repotrectinib plasma concentrations, which may decrease efficacy|
04503|015|E|of repotrectinib.(1)|
04503|016|E|   Coadministration of repotrectinib with a CYP3A4 substrate decreases the|
04503|017|E|CYP3A4 substrate plasma concentrations, which may decrease efficacy of the|
04503|018|E|CYP3A4 substrate.(1)|
04503|019|B||
04503|020|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04503|021|P|of the inducer for longer than 1-2 weeks.|
04503|022|B||
04503|023|M|PATIENT MANAGEMENT:  Concurrent use should be avoided.|
04503|024|M|   The manufacturer of repotrectinib states that concurrent use with strong|
04503|025|M|or moderate CYP3A4 inducers should be avoided.(1)|
04503|026|M|   The manufacturer of repotrectinib states to avoid concomitant use with|
04503|027|M|CYP3A4 substrates where minimal concentration changes can cause reduced|
04503|028|M|efficacy unless otherwise recommended in the prescribing information for the|
04503|029|M|CYP3A4 substrate.  If concomitant use is unavoidable, increase the CYP3A4|
04503|030|M|substrate dosage in accordance with approved product labeling.(1)|
04503|031|M|   The manufacturer of lorlatinib states that concurrent use with moderate|
04503|032|M|CYP3A4 inducers, such as repotrectinib, should be avoided.  If concurrent|
04503|033|M|use of lorlatinib cannot be avoided, increase the dose of lorlatinib to 125|
04503|034|M|mg daily.(2)|
04503|035|M|   The manufacturer of mitapivat states that alternative therapies should be|
04503|036|M|considered that are not moderate CYP3A4 inducers in patients who are on|
04503|037|M|mitapivat.  If concurrent use is necessary, monitor hemoglobin closely and|
04503|038|M|titrate mitapivat dose, not to exceed a maximum dose of 100 mg twice|
04503|039|M|daily.(3)|
04503|040|B||
04503|041|D|DISCUSSION:  Coadministration of repotrectinib with rifampin, a strong|
04503|042|D|CYP3A4 and P-glycoprotein inducer, decreased the maximum concentration|
04503|043|D|(Cmax) of repotrectinib by 79% and area-under-curve (AUC) by 92%.(1)|
04503|044|D|   Coadministration of repotrectinib once daily for 14 days followed by 160|
04503|045|D|mg twice daily for 7 days with midazolam (a sensitive CYP3A4 substrate)|
04503|046|D|decreased midazolam AUC and Cmax by 69% and 48%, respectively.(1)|
04503|047|D|   Modafinil (a moderate CYP3A4 inducer) decreased the AUC and Cmax of a|
04503|048|D|single 100 mg dose of lorlatinib by 23% and 22%, respectively.(2)|
04503|049|D|   In a pharmacokinetic study with 5 or 20 mg twice daily of mitapivat,|
04503|050|D|efavirenz (a moderate CYP3A4 inducer) decreased the AUC and Cmax of|
04503|051|D|mitapivat by 60% and 30%, respectively. After mitapivat doses of 50 mg twice|
04503|052|D|daily, efavirenz decreased mitapivat AUC and Cmax by 55% and 24%,|
04503|053|D|respectively.(3)|
04503|054|B||
04503|055|R|REFERENCES:|
04503|056|B||
04503|057|R|1.Augtyro (repotrectinib) US prescribing information. Bristol-Myers Squibb|1
04503|058|R|  Company November, 2023.|1
04503|059|R|2.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
04503|060|R|3.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04503|061|R|  February, 2022.|1
04503|062|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04503|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04503|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04503|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04503|066|R|  11/14/2017.|1
04503|067|R|5.This information is based on an extract from the Certara Drug Interaction|6
04503|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04504|001|T|MONOGRAPH TITLE:  Gepirone/St. John's Wort|
04504|002|B||
04504|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04504|004|L|of severe adverse interaction.|
04504|005|B||
04504|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may accelerate|
04504|007|A|the metabolism of gepirone.(1)  St. John's wort is a strong CYP3A4|
04504|008|A|inducer.(2,3)|
04504|009|A|   Gepirone is a serotonin receptor agonist.  Concurrent administration with|
04504|010|A|one or more serotonergic agents, such as St. John's wort, may increase|
04504|011|A|serotonin effects, resulting in serotonin toxicity.(1,4)|
04504|012|B||
04504|013|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04504|014|E|levels and effectiveness of gepirone.(1)|
04504|015|E|   Concurrent use of gepirone with other serotonergic agents such as St.|
04504|016|E|John's wort may increase the risk of hypertensive crisis and serotonin|
04504|017|E|syndrome, a potentially life-threatening syndrome which may include one or|
04504|018|E|more of the following symptoms: tremor, agitation, diaphoresis,|
04504|019|E|hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)|
04504|020|B||
04504|021|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04504|022|P|systemic concentrations of either drug would be predicted to increase risk|
04504|023|P|for serotonin toxicity.(4)|
04504|024|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04504|025|P|concentrations may also increase risk for serotonin syndrome.(4)|
04504|026|P|   Induction effects may be more likely with regular use of the inducer for|
04504|027|P|longer than 1-2 weeks.|
04504|028|B||
04504|029|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers in patients receiving|
04504|030|M|therapy with gepirone should be avoided.(1)|
04504|031|M|   Consider the use of alternative agents with less enzyme induction|
04504|032|M|potential.(1)|
04504|033|M|   If concurrent use of gepirone with other serotonergic agents is|
04504|034|M|clinically warranted, counsel the patient on the increased risk of serotonin|
04504|035|M|syndrome and monitor for symptoms.  If symptoms of serotonin syndrome|
04504|036|M|develop, discontinue gepirone and/or the other serotonergic agents|
04504|037|M|immediately and initiate supportive measures.(1)|
04504|038|B||
04504|039|D|DISCUSSION:  In a study, rifampin 600 mg daily decrease the maximum|
04504|040|D|concentration (Cmax) and area-under-curve (AUC) of gepirone by 20-fold and|
04504|041|D|29-fold, respectively.  The Cmax and AUC of the active metabolite, 3'-OH|
04504|042|D|gepirone, also decreased by 2.5-fold and 3-fold, respectively.(1)|
04504|043|D|   Gepirone and its 3'-OH metabolite act as agonists at 5HT1A receptors.|
04504|044|D|Use with other agents that also increase serotonin in the body must be|
04504|045|D|undertaken with caution and monitored closely due to the risk of serotonin|
04504|046|D|syndrome.(1)|
04504|047|B||
04504|048|R|REFERENCES:|
04504|049|B||
04504|050|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04504|051|R|  Inc. September, 2023.|1
04504|052|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04504|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04504|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04504|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04504|056|R|  11/14/2017.|1
04504|057|R|3.This information is based on an extract from the Certara Drug Interaction|6
04504|058|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04504|059|R|4.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04504|060|R|  352(11):1112-20.|6
04505|001|T|MONOGRAPH TITLE:  Nirogacestat/Strong and Moderate CYP3A4 Inhibitors|
04505|002|B||
04505|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04505|004|L|of severe adverse interaction.|
04505|005|B||
04505|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
04505|007|A|nirogacestat.(1)|
04505|008|B||
04505|009|E|CLINICAL EFFECTS:  Concomitant use of a strong or moderate CYP3A4 inhibitor|
04505|010|E|increases nirogacestat plasma concentrations, which may increase the|
04505|011|E|incidence and severity of adverse reactions, including hepatotoxicity,|
04505|012|E|diarrhea, hypokalemia, and hypophosphatemia.(1)|
04505|013|B||
04505|014|P|PREDISPOSING FACTORS:  None determined.|
04505|015|B||
04505|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of strong or moderate CYP3A4|
04505|017|M|inhibitors with nirogacestat.(1)|
04505|018|B||
04505|019|D|DISCUSSION:  In a study, itraconazole (a strong CYP3A4 inhibitor) increased|
04505|020|D|the area-under-curve (AUC) and maximum concentration (Cmax) of nirogacestat|
04505|021|D|by 8.2-fold and 2.5-fold, respectively, following a single 100 mg dose of|
04505|022|D|nirogacestat.  In a PKPB model, nirogacestat AUC was predicted to increase|
04505|023|D|by 6.33-, 5.19-, and 3.46-fold following coadministration of multiple doses|
04505|024|D|of nirogacestat (150 mg BID) with itraconazole, ketoconazole and|
04505|025|D|clarithromycin (strong CYP3A inhibitors), respectively.(1)|
04505|026|D|   In a PKPB model, nirogacestat AUC was predicted to increase 2.73-and|
04505|027|D|3.18-fold following coadministration of multiple doses of nirogacestat (150|
04505|028|D|mg BID) with erythromycin (moderate CYP3A inhibitor) and fluconazole|
04505|029|D|(moderate CYP3A inhibitor), respectively.(1)|
04505|030|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
04505|031|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
04505|032|D|josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil,|
04505|033|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04505|034|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04505|035|D|troleandomycin, tucatinib, and voriconazole.(2)|
04505|036|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
04505|037|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
04505|038|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
04505|039|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral|
04505|040|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, schisandra,|
04505|041|D|stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2)|
04505|042|B||
04505|043|R|REFERENCES:|
04505|044|B||
04505|045|R|1.Ogsiveo (nirogacestat) US prescribing information. SpringWorks|1
04505|046|R|  Therapeutics Inc. April, 2024.|1
04505|047|R|2.This information is based on an extract from the Certara Drug Interaction|6
04505|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04506|001|T|MONOGRAPH TITLE:  Nirogacestat/Strong and Moderate CYP3A4 Inducers|
04506|002|B||
04506|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04506|004|L|of severe adverse interaction.|
04506|005|B||
04506|006|A|MECHANISM OF ACTION:  Strong or moderate CYP3A4 inducers may induce the|
04506|007|A|metabolism of nirogacestat.(1)|
04506|008|B||
04506|009|E|CLINICAL EFFECTS:  Coadministration of nirogacestat with a strong or|
04506|010|E|moderate CYP3A4 inducer decreases nirogacestat plasma concentrations, which|
04506|011|E|may decrease efficacy of nirogacestat.(1)|
04506|012|B||
04506|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04506|014|P|of the inducer for longer than 1-2 weeks.|
04506|015|B||
04506|016|M|PATIENT MANAGEMENT:  The manufacturer of nirogacestat states that concurrent|
04506|017|M|use with strong or moderate CYP3A4 inducers should be avoided.(1)|
04506|018|B||
04506|019|D|DISCUSSION:  In a PKPB model, coadministration of rifampin, a strong CYP3A4|
04506|020|D|inducer, following multiple doses of nirogacestat (150 mg BID) is predicted|
04506|021|D|to decrease the area-under-curve (AUC) of nirogacestat by 85%.(1)|
04506|022|D|   In a PKPB model, coadministration of efavirenz, a moderate CYP3A4|
04506|023|D|inducer, following multiple doses of nirogacestat (150 mg BID) is predicted|
04506|024|D|to decrease the AUC of nirogacestat by 67%.(1)|
04506|025|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04506|026|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04506|027|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04506|028|D|rifapentine, and St. John's wort.(2,3)|
04506|029|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04506|030|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04506|031|D|lorlatinib, mavacamten, modafinil, nafcillin, pacritinib, pexidartinib,|
04506|032|D|rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)|
04506|033|B||
04506|034|R|REFERENCES:|
04506|035|B||
04506|036|R|1.Ogsiveo (nirogacestat) US prescribing information. SpringWorks|1
04506|037|R|  Therapeutics Inc. April, 2024.|1
04506|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04506|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04506|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04506|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04506|042|R|  11/14/2017.|1
04506|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
04506|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04507|001|T|MONOGRAPH TITLE:  Intravenous Lefamulin/Moderate CYP3A4 Inducers|
04507|002|B||
04507|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04507|004|L|of severe adverse interaction.|
04507|005|B||
04507|006|A|MECHANISM OF ACTION:  Lefamulin is a substrate of CYP3A4.  Moderate inducers|
04507|007|A|of CYP3A4 may induce the metabolism of lefamulin.(1)|
04507|008|B||
04507|009|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
04507|010|E|inducer may result in decreased levels and effectiveness of lefamulin.(1)|
04507|011|B||
04507|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04507|013|P|of the inducer for longer than 1-2 weeks.|
04507|014|B||
04507|015|M|PATIENT MANAGEMENT:  The manufacturer of lefamulin states that concurrent|
04507|016|M|use with moderate CYP3A4 inducers should be avoided.(1)|
04507|017|B||
04507|018|D|DISCUSSION:  In a study, concurrent administration of rifampin (a strong|
04507|019|D|inducer) with lefamulin injection decreased lefamulin area-under-the-curve|
04507|020|D|(AUC) and maximum concentration (Cmax) by 28% and 8%.(1)|
04507|021|D|   Moderate inducers of CYP3A4 linked to this monograph include: mitapivat|
04507|022|D|and repotrectinib.(2-3)|
04507|023|B||
04507|024|R|REFERENCES:|
04507|025|B||
04507|026|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04507|027|R|  Inc August 2019.|1
04507|028|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04507|029|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04507|030|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04507|031|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04507|032|R|  11/14/2017.|1
04507|033|R|3.This information is based on an extract from the Certara Drug Interaction|6
04507|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04508|001|T|MONOGRAPH TITLE:  Nirogacestat/H2 Antagonists; Proton Pump Inhibitors|
04508|002|B||
04508|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04508|004|L|of severe adverse interaction.|
04508|005|B||
04508|006|A|MECHANISM OF ACTION:  The aqueous solubility of nirogacestat is pH|
04508|007|A|dependent.  Higher gastric pH leads to lower solubility which may reduce|
04508|008|A|nirogacestat absorption.(1)|
04508|009|B||
04508|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) or H2|
04508|011|E|antagonists may reduce the bioavailability of nirogacestat, leading to|
04508|012|E|decreased systemic levels and effectiveness.(1)|
04508|013|B||
04508|014|P|PREDISPOSING FACTORS:  None determined.|
04508|015|B||
04508|016|M|PATIENT MANAGEMENT:  Coadministration of nirogacestat with proton pump|
04508|017|M|inhibitors, H2 antagonists, and antacids should be avoided.|
04508|018|M|   If coadministration with an acid-reducing agent is unavoidable, take|
04508|019|M|nirogacestat 2 hours before or 2 hours after a locally acting antacid.(1)|
04508|020|B||
04508|021|D|DISCUSSION:  The solubility of nirogacestat is poor at a pH >= 6.(1)|
04508|022|D|   Concomitant use of proton pump inhibitors, H2 antagonists, or antacids|
04508|023|D|are expected to reduce concentrations of nirogacestat.(1)|
04508|024|B||
04508|025|R|REFERENCE:|
04508|026|B||
04508|027|R|1.Ogsiveo (nirogacestat) US prescribing information. SpringWorks|1
04508|028|R|  Therapeutics Inc. April, 2024.|1
04509|001|T|MONOGRAPH TITLE:  Nirogacestat/Antacids|
04509|002|B||
04509|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04509|004|L|take action as needed.|
04509|005|B||
04509|006|A|MECHANISM OF ACTION:  The aqueous solubility of nirogacestat is pH|
04509|007|A|dependent.  Higher gastric pH leads to lower solubility which may reduce|
04509|008|A|nirogacestat absorption.(1)|
04509|009|B||
04509|010|E|CLINICAL EFFECTS:  Coadministration of antacids may reduce the|
04509|011|E|bioavailability of nirogacestat, leading to decreased systemic levels and|
04509|012|E|effectiveness.(1)|
04509|013|B||
04509|014|P|PREDISPOSING FACTORS:  None determined.|
04509|015|B||
04509|016|M|PATIENT MANAGEMENT:  Coadministration of nirogacestat with proton pump|
04509|017|M|inhibitors, H2 antagonists, and antacids should be avoided.|
04509|018|M|   If coadministration with an acid-reducing agent is unavoidable, take|
04509|019|M|nirogacestat 2 hours before or 2 hours after a locally acting antacid.(1)|
04509|020|B||
04509|021|D|DISCUSSION:  The solubility of nirogacestat is poor at a pH >= 6.(1)|
04509|022|D|   Concomitant use of proton pump inhibitors, H2 antagonists, or antacids|
04509|023|D|are expected to reduce concentrations of nirogacestat.(1)|
04509|024|B||
04509|025|R|REFERENCE:|
04509|026|B||
04509|027|R|1.Ogsiveo (nirogacestat) US prescribing information. SpringWorks|1
04509|028|R|  Therapeutics Inc. April, 2024.|1
04510|001|T|MONOGRAPH TITLE:  Palbociclib/Proton Pump Inhibitors|
04510|002|B||
04510|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04510|004|L|take action as needed.|
04510|005|B||
04510|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is not fully|
04510|007|A|understood and may involve dysbiosis or gastric pH changes resulting from|
04510|008|A|proton pump inhibitors (PPIs).(1,2)  The aqueous solubility of palbociclib|
04510|009|A|is pH-dependent.  Higher gastric pH leads to lower solubility which may|
04510|010|A|reduce palbociclib absorption.(1)|
04510|011|B||
04510|012|E|CLINICAL EFFECTS:  Coadministration of PPIs may reduce the bioavailability|
04510|013|E|of palbociclib, leading to decreased systemic levels and effectiveness.(1)|
04510|014|E|Although administration of palbociclib with food minimizes the decrease in|
04510|015|E|absorption,(1) retrospective studies and a meta-analysis have found lower|
04510|016|E|survival rates among patients on concurrent PPIs.(2-7)|
04510|017|B||
04510|018|P|PREDISPOSING FACTORS:  None determined.|
04510|019|B||
04510|020|M|PATIENT MANAGEMENT:  The manufacturer of palbociclib capsules states that|
04510|021|M|palbociclib should be taken with food, whereas palbociclib tablets may be|
04510|022|M|taken with or without food.  There are no constraints on concurrent use of|
04510|023|M|proton pump inhibitors.(1)|
04510|024|M|   Given the decreased survival rates observed in patients who received PPIs|
04510|025|M|with palbociclib, the authors of some studies on concurrent use of these|
04510|026|M|agents have made various recommendations, including avoiding PPIs with|
04510|027|M|palbociclib, using ribociclib instead of palbociclib, using low strengths of|
04510|028|M|PPIs, or using H2-antagonists or antacids.(2-7)|
04510|029|B||
04510|030|D|DISCUSSION:  Palbociclib solubility decreases significantly above pH 4.(1)|
04510|031|D|   In a study with healthy volunteers, rabeprazole decreased the maximum|
04510|032|D|concentration (Cmax) and area-under-curve (AUC) of single-dose palbociclib|
04510|033|D|without food by 80% and 62%, respectively.  In another study of healthy|
04510|034|D|volunteers in a fed state, rabeprazole decreased Cmax and AUC of single-dose|
04510|035|D|palbociclib by 41% and 13%, respectively.(1)|
04510|036|D|   A systematic review and meta-analysis examined studies of HER2-negative,|
04510|037|D|hormone receptor-positive patients with metastatic breast cancer treated|
04510|038|D|with palbociclib or ribociclib with or without concomitant PPIs that|
04510|039|D|reported on survival outcomes.  Eight studies consisting of 2,584 patients|
04510|040|D|(830 on PPIs, 1754 not on PPIs) were included.  Patients on concurrent PPIs|
04510|041|D|had a significantly higher risk of all-cause mortality (HR, 2.03; 95% CI,|
04510|042|D|1.49 to 2.77) and disease progression (HR, 1.75; 95% CI, 1.26 to 2.43)|
04510|043|D|compared to patients not on PPIs, though there was a high degree of|
04510|044|D|heterogeneity in disease progression.(2)|
04510|045|D|   A retrospective cohort of patients with advanced or metastatic breast|
04510|046|D|cancer treated with palbociclib capsules (344 patients on PPIs, 966 patients|
04510|047|D|not on PPIs) revealed that patients on PPIs had shorter progression-free|
04510|048|D|survival (PFS) (HR 1.76 (95% CI, 1.46-2.13) and lower overall survival (HR,|
04510|049|D|2.71 [95% CI, 2.07-3.53]).(3)|
04510|050|D|   A post-hoc analysis of the phase 2 PARSIFAL trial evaluated PFS in|
04510|051|D|patients on palbociclib capsules. 326 patients were PPI-naive, 64 patients|
04510|052|D|were early users of PPIs (started on PPIs since starting palbociclib), and|
04510|053|D|91 patients were long-term users of PPIs.  PPI use was associated with a|
04510|054|D|shorter PFS (HR in early PPI users 1.5; 95% CI  1.1-2.2; HR in long-term PPI|
04510|055|D|users 1.4; 95% CI 1.1-1.9).(4)|
04510|056|D|   A retrospective study of 50 patients with metastatic breast cancer on|
04510|057|D|palbociclib found that concurrent PPI use was associated with a shorter|
04510|058|D|PFS.(5)|
04510|059|D|   In an observational study of patients with metastatic breast cancer on|
04510|060|D|palbociclib capsules, PFS was compared between 65 patients on PPIs and 40|
04510|061|D|patients not on PPIs.  On multivariate analysis, PPI usage was an|
04510|062|D|independent predictor of shorter PFS (HR 5.60; 95% confidence interval:|
04510|063|D|1.98-15.85).(6)|
04510|064|D|   A retrospective observational cohort of metastatic breast cancer patients|
04510|065|D|on palbociclib found that patients on concurrent PPIs had a shorter PFS than|
04510|066|D|those not on PPIs (14.0 versus 37.9 months, p < 0.0001).(7)|
04510|067|D|   In contrast to these findings, other studies have not found a detrimental|
04510|068|D|effect of PPIs on palbociclib efficacy.  A retrospective observational study|
04510|069|D|focused on 112 patients with endocrine-resistant metastatic breast cancer on|
04510|070|D|palbociclib capsules (n=58) and tablets (n=20).  There was no difference in|
04510|071|D|PFS in patients on concurrent PPIs compared to those not on PPIs.(8)  A|
04510|072|D|study looking at 82 patients with metastatic breast cancer treat 1st line|
04510|073|D|with palbociclib tablets(9) and a retrospective observational study on|
04510|074|D|metastatic breast cancer patients on palbociclib capsules(10) also did not|
04510|075|D|find a significantly different PFS between patients with and without|
04510|076|D|concurrent PPIs.|
04510|077|B||
04510|078|R|REFERENCES:|
04510|079|B||
04510|080|R|1.Ibrance (palbociclib) US prescribing information. Pfizer Labs September,|1
04510|081|R|  2023.|1
04510|082|R|2.Chang YC, Song J, Chang Y, Huang CH, Sudan A, Chen PC, Chi KY. The|6
04510|083|R|  Association between Proton Pump Inhibitors and the Effectiveness of CDK|6
04510|084|R|  Inhibitors in HR+ /HER- Advanced Breast Cancer Patients: A Systematic|6
04510|085|R|  Review and  Meta-Analysis. Cancers (Basel) 2023 Oct 25;15(21):.|6
04510|086|R|3.Lee JE, Kwon SH, Kwon S, Jung HI, Nam JH, Lee EK. Concomitant Use of|2
04510|087|R|  Proton Pump Inhibitors and Palbociclib Among Patients With  Breast Cancer.|2
04510|088|R|  JAMA Netw Open 2023 Jul 3;6(7):e2324852.|2
04510|089|R|4.Di Cosimo S, Perez-Garcia JM, Ezquerra MB, Dalenc F, Gil MG, Borrego MR,|2
04510|090|R|  Gavila J, Sampayo-Cordero M, Aguirre E, Schmid P, Marme F, Gligorov J,|2
04510|091|R|  Schneeweiss A, Albanell J, Zamora P, Wheatley D. Impact of Proton Pump|2
04510|092|R|  Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone|2
04510|093|R|  Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+ /HER2- ABC):|2
04510|094|R|  Exploratory Analysis of the PARSIFAL Trial abstract. Cancer Res 2023|2
04510|095|R|  March;83(5 Suppl):PD13-10.|2
04510|096|R|5.Caglayan D, Kocak MZ, Geredeli C, Tatli AM, Goksu SS, Eryilmaz MK, Araz M,|2
04510|097|R|  Artac M. The effect of concomitant use of proton pump inhibitors with CDK|2
04510|098|R|  4/6 inhibitors  on survival in metastatic breast cancer. Eur J Clin|2
04510|099|R|  Pharmacol 2023 Feb;79(2):243-248.|2
04510|100|R|6.Eser K, Onder AH, Sezer E, Cil T, Inal A, Ozturk B, Ercolak V, Duman BB,|2
04510|101|R|  Celik H, Koseci T, Kesen O. Proton pump inhibitors may reduce the efficacy|2
04510|102|R|  of ribociclib and palbociclib in metastatic breast cancer patients based|2
04510|103|R|  on an observational study. BMC Cancer 2022 May 7;22(1):516.|2
04510|104|R|7.Del Re M, Omarini C, Diodati L, Palleschi M, Meattini I, Crucitta S,|2
04510|105|R|  Lorenzini G, Isca C, Fontana A, Livi L, Piacentini F, Fogli S, De Giorgi|2
04510|106|R|  U, Danesi R. Drug-drug interactions between palbociclib and proton pump|2
04510|107|R|  inhibitors may  significantly affect clinical outcome of metastatic breast|2
04510|108|R|  cancer patients. ESMO Open 2021 Oct;6(5):100231.|2
04510|109|R|8.Takahashi K, Uozumi R, Mukohara T, Hayashida T, Iwabe M, Iihara H,|2
04510|110|R|  Kusuhara-Mamishin K, Kitagawa Y, Tsuchiya M, Kitahora M, Nagayama A,|2
04510|111|R|  Kosaka S, Asano-Niwa Y, . Proton Pump Inhibitors and Cyclin-Dependent|2
04510|112|R|  Kinase 4/6 Inhibitors in Patients  With Breast Cancer. Oncologist 2024 Feb|2
04510|113|R|  10.|2
04510|114|R|9.Schieber T, Steele S, Collins S, Berger M, Fleming M, McLaughlin E,|2
04510|115|R|  Sudheendra P, Vargo C. Effect of Concurrent Proton Pump Inhibitors With|2
04510|116|R|  Palbociclib Tablets for  Metastatic Breast Cancer. Clin Breast Cancer 2023|2
04510|117|R|  Aug;23(6):658-663.|2
04510|118|R|10.Odabas H, Dogan A, Ozcelik M, Yildirim S, Ozkerim U, Turan N, Yildirim|2
04510|119|R|   ME, Gumus M. Does Proton Pump Inhibitors Decrease the Efficacy of|2
04510|120|R|   Palbociclib and Ribociclib  in Patients with Metastatic Breast Cancer?.|2
04510|121|R|   Medicina (Kaunas) 2023 Mar 12;59(3):.|2
04511|001|T|MONOGRAPH TITLE:  Mitapivat/Nirogacestat|
04511|002|B||
04511|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04511|004|L|of severe adverse interaction.|
04511|005|B||
04511|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04511|007|A|metabolism of mitapivat.(1)  Nirogacestat is a moderate CYP3A4 inhibitor.|
04511|008|A|   Moderate inducers of CYP3A4 may accelerate the metabolism of|
04511|009|A|nirogacestat.(2)  Mitapivat is a moderate CYP3A4 inducer.|
04511|010|B||
04511|011|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04511|012|E|result in increased levels of and effects from mitapivat including decreased|
04511|013|E|estrone and estradiol levels in males, increased urate, back pain, and|
04511|014|E|arthralgias.(1)|
04511|015|E|   Concurrent or recent use of moderate CYP3A4 inducers may alter the|
04511|016|E|clinical effectiveness of nirogacestat.(2)|
04511|017|B||
04511|018|P|PREDISPOSING FACTORS:  None determined.|
04511|019|B||
04511|020|M|PATIENT MANAGEMENT:  The manufacturer of nirogacestat states that concurrent|
04511|021|M|use with strong or moderate CYP3A4 inducers should be avoided.(1)|
04511|022|M|   The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be|
04511|023|M|monitored closely for increased risk of adverse reactions.  The US|
04511|024|M|manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg|
04511|025|M|twice daily with concurrent moderate CYP3A4 inhibitors.(1)  The Middle|
04511|026|M|Eastern manufacturer of mitapivat states that alternative agents that do not|
04511|027|M|inhibit CYP3A4 should be considered.  If concomitant use of a moderate|
04511|028|M|CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100|
04511|029|M|mg once daily.(3)|
04511|030|B||
04511|031|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
04511|032|D|with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased|
04511|033|D|mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by|
04511|034|D|2.6-fold and 1.6-fold, respectively.(1)|
04511|035|D|   In a PKPB model, coadministration of rifampin, a strong CYP3A4 inducer,|
04511|036|D|following multiple doses of nirogacestat (150 mg BID) is predicted to|
04511|037|D|decrease the AUC of nirogacestat by 85%.(2)|
04511|038|D|   In a PKPB model, coadministration of efavirenz, a moderate CYP3A4|
04511|039|D|inducer, following multiple doses of nirogacestat (150 mg BID) is predicted|
04511|040|D|to decrease the AUC of nirogacestat by 67%.(2)|
04511|041|B||
04511|042|R|REFERENCES:|
04511|043|B||
04511|044|R|1.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04511|045|R|  February, 2022.|1
04511|046|R|2.Ogsiveo (nirogacestat) US prescribing information. SpringWorks|1
04511|047|R|  Therapeutics Inc. April, 2024.|1
04511|048|R|3.Pyrukynd (mitapivat) Middle East Prescribing Information. Agios|1
04511|049|R|  Pharmaceuticals, Inc. July, 2025.|1
04511|050|R|4.This information is based on an extract from the Certara Drug Interaction|6
04511|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04512|001|T|MONOGRAPH TITLE:  Selected Sensitive CYP3A4 Substrates/Nirogacestat|
04512|002|B||
04512|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04512|004|L|of severe adverse interaction.|
04512|005|B||
04512|006|A|MECHANISM OF ACTION:  Nirogacestat is a moderate inhibitor of CYP3A4 and may|
04512|007|A|decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.(1)|
04512|008|B||
04512|009|E|CLINICAL EFFECTS:  Concurrent use of nirogacestat may lead to increased|
04512|010|E|serum levels and adverse effects of drugs sensitive to inhibition of the|
04512|011|E|CYP3A4 pathway.(1-3)|
04512|012|B||
04512|013|P|PREDISPOSING FACTORS:  None determined.|
04512|014|B||
04512|015|M|PATIENT MANAGEMENT:  Avoid concomitant nirogacestat use with CYP3A4|
04512|016|M|substrates where minimal concentration changes may lead to serious adverse|
04512|017|M|reactions.(1)|
04512|018|M|   Concurrent use of nirogacestat with alfentanil should be avoided. If|
04512|019|M|concurrent use is warranted, limit the dosages and duration of alfentanil to|
04512|020|M|the minimum possible while achieving the desired clinical effect. If|
04512|021|M|starting a CYP3A4 inhibitor with an opioid, consider a dosage reduction of|
04512|022|M|the opioid. If an opioid is indicated in a patient already taking a CYP3A4|
04512|023|M|inhibitor, prescribe a lower dose of the opioid and titrate based upon|
04512|024|M|clinical response.(2)|
04512|025|M|   Concurrent use of nirogacestat with cobimetinib should be avoided. For|
04512|026|M|patients taking cobimetinib 60 mg daily, if concurrent short-term use (14|
04512|027|M|days or less) of a moderate CYP3A4 inhibitor cannot be avoided, reduce|
04512|028|M|cobimetinib dose to 20 mg daily. After discontinuation of the moderate|
04512|029|M|CYP3A4 inhibitor, resume the previous 60 mg dose. Patients who are taking|
04512|030|M|cobimetinib 40 mg or 20 mg daily should not receive a moderate or strong|
04512|031|M|CYP3A4 inhibitor.(3)|
04512|032|B||
04512|033|D|DISCUSSION:  Midazolam (CYP3A4 substrate) maximum concentration (Cmax) is|
04512|034|D|predicted to increase by 1.77-fold and area-under-curve (AUC) by 2.07-fold|
04512|035|D|following concomitant use with multiple doses of nirogacestat (150 mg twice|
04512|036|D|daily).(1)|
04512|037|D|   CYP3A4 sensitive substrates linked to this monograph include: alfentanil,|
04512|038|D|cobimetinib, fentanyl, lovastatin, and simvastatin.(4,5)|
04512|039|B||
04512|040|R|REFERENCES:|
04512|041|B||
04512|042|R|1.Ogsiveo (nirogacestat) US prescribing information. SpringWorks|1
04512|043|R|  Therapeutics Inc. April, 2024.|1
04512|044|R|2.Alfenta (alfentanil) US prescribing information. Akorn December, 2023.|1
04512|045|R|3.Cotellic (cobimetinib) US prescribing information. Genentech, Inc.|1
04512|046|R|  October, 2022.|1
04512|047|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04512|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04512|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04512|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04512|051|R|  11/14/2017.|1
04512|052|R|5.This information is based on an extract from the Certara Drug Interaction|6
04512|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04513|001|T|MONOGRAPH TITLE:  Dexmedetomidine Sublingual/QT Prolonging Agents|
04513|002|B||
04513|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04513|004|L|of severe adverse interaction.|
04513|005|B||
04513|006|A|MECHANISM OF ACTION:  Dexmedetomidine sublingual has been shown to prolong|
04513|007|A|the QTc interval.  Concurrent use with other agents that prolong the QTc|
04513|008|A|interval may result in additive effects on the QTc interval.(1)|
04513|009|B||
04513|010|E|CLINICAL EFFECTS:  The concurrent use of dexmedetomidine sublingual with|
04513|011|E|other agents that prolong the QTc interval may result in potentially|
04513|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
04513|013|B||
04513|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04513|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04513|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04513|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04513|018|P|gender, or advanced age.(2)|
04513|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04513|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04513|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04513|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04513|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04513|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04513|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04513|026|B||
04513|027|M|PATIENT MANAGEMENT:  The manufacturer of dexmedetomidine sublingual states|
04513|028|M|that concurrent use should be avoided with other agents known to prolong the|
04513|029|M|QTc interval.(1)|
04513|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04513|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04513|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04513|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04513|034|B||
04513|035|D|DISCUSSION:  In a QT study, dexmedetomidine sublingual had a concentration|
04513|036|D|dependent effect on the QT interval.  The mean QTc (95% confidence interval)|
04513|037|D|increased from baseline by 6 (7) msec with a 120 mcg single dose, 8 (9) msec|
04513|038|D|with 120 mcg followed by 2 additional doses of 60 mcg (total 3 doses), 8|
04513|039|D|(11) msec with a single 180 mcg dose, and 11 (14) msec with 180 mcg followed|
04513|040|D|by 2 additional doses of 90 mcg (total 3 doses), respectively.(1)|
04513|041|D|   Agents that are linked to this monograph may have varying degrees of|
04513|042|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04513|043|D|been shown to prolong the QTc interval either through their mechanism of|
04513|044|D|action, through studies on their effects on the QTc interval, or through|
04513|045|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04513|046|D|and/or postmarketing reports.(3)|
04513|047|B||
04513|048|R|REFERENCES:|
04513|049|B||
04513|050|R|1.Igalmi (dexmedetomidine film) US prescribing information. BioXcel|1
04513|051|R|  Therapeutics, Inc. December, 2022.|1
04513|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04513|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04513|054|R|  settings: a scientific statement from the American Heart Association and|6
04513|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04513|056|R|  2;55(9):934-47.|6
04513|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04513|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04513|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04513|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04514|001|T|MONOGRAPH TITLE:  Finerenone/Moderate CYP3A4 Inhibitors|
04514|002|B||
04514|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04514|004|L|take action as needed.|
04514|005|B||
04514|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04514|007|A|metabolism of finerenone.(1)|
04514|008|B||
04514|009|E|CLINICAL EFFECTS:  Concurrent use of finerenone with a moderate inhibitor of|
04514|010|E|CYP3A4 increases finerenone concentrations and may increase the risk of|
04514|011|E|toxicity (e.g., hyperkalemia, hypotension).(1)|
04514|012|B||
04514|013|P|PREDISPOSING FACTORS:  Severe renal disease and concurrent use of potassium|
04514|014|P|supplements increase the risk for hyperkalemia.|
04514|015|B||
04514|016|M|PATIENT MANAGEMENT:  The manufacturer of finerenone states that use with|
04514|017|M|moderate CYP3A4 inhibitors should be closely monitored.  Check serum|
04514|018|M|potassium during drug initiation or dosage adjustment of either finerenone|
04514|019|M|or the moderate CYP3A4 inhibitor.  Dose adjustment of finerenone may be|
04514|020|M|necessary.(1)|
04514|021|B||
04514|022|D|DISCUSSION:  Concurrent use of finerenone with erythromycin, a moderate|
04514|023|D|CYP3A4 inhibitor, increased finerenone area-under-curve (AUC) by 248% and|
04514|024|D|maximum concentration (Cmax) by 88%.(1)|
04514|025|D|   Concurrent use of finerenone with verapamil, a moderate CYP3A4 inhibitor,|
04514|026|D|increased finerenone AUC by 170% and Cmax by 122%.(1)|
04514|027|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  amprenavir,|
04514|028|D|aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan,|
04514|029|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
04514|030|D|fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
04514|031|D|imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir,|
04514|032|D|netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam,|
04514|033|D|treosulfan, verapamil, and voxelotor.(2,3)|
04514|034|B||
04514|035|R|REFERENCES:|
04514|036|B||
04514|037|R|1.KERENDIA (finerenone) US prescribing information. Bayer HealthCare|1
04514|038|R|  Pharmaceuticals Inc. July, 2025.|1
04514|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
04514|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04514|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04514|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04514|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04514|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04514|045|R|  11/14/2017.|1
04515|001|T|MONOGRAPH TITLE:  Macitentan/Moderate CYP3A4 Inhibitors|
04515|002|B||
04515|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04515|004|L|take action as needed.|
04515|005|B||
04515|006|A|MECHANISM OF ACTION:  Macitentan is primarily metabolized by CYP3A4, with|
04515|007|A|minor contributions from CYP2C8, CYP2C9, and CYP2C19.  Moderate inhibitors|
04515|008|A|of CYP3A4 may inhibit the metabolism of macitentan.(1)|
04515|009|B||
04515|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04515|011|E|result in elevated levels and increased effects of macitentan, including|
04515|012|E|hepatotoxicity and fluid retention.(1)|
04515|013|B||
04515|014|P|PREDISPOSING FACTORS:  Concomitant use of a moderate CYP2C9 inhibitor|
04515|015|P|increases the magnitude of this interaction and the risk of adverse events.|
04515|016|B||
04515|017|M|PATIENT MANAGEMENT:  The manufacturer of macitentan states that concurrent|
04515|018|M|use of both a moderate CYP2C9 inhibitor and a moderate CYP3A4 inhibitor|
04515|019|M|should be avoided.(1)|
04515|020|M|   While the manufacturer does not provide recommendations for concurrent|
04515|021|M|use of a moderate CYP3A4 inhibitor alone, it would be prudent to use caution|
04515|022|M|and monitor for adverse effects.|
04515|023|B||
04515|024|D|DISCUSSION:  Based on pharmacokinetic (PBPK) modeling, dual moderate|
04515|025|D|inhibitors of CYP2C9 and CYP3A4 such as fluconazole are predicted to|
04515|026|D|increase macitentan exposure by 4-fold.(1)|
04515|027|D|   Pretreatment with ketoconazole increased the area-under-curve (AUC) and|
04515|028|D|maximum concentration (Cmax) of macitentan by approximately 2.3 and|
04515|029|D|1.3-fold, respectively.(1)|
04515|030|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  amprenavir,|
04515|031|D|aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan,|
04515|032|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
04515|033|D|fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
04515|034|D|isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant,|
04515|035|D|nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
04515|036|D|verapamil, and voxelotor.(2)|
04515|037|B||
04515|038|R|REFERENCES:|
04515|039|B||
04515|040|R|1.Opsumit (macitentan) US prescribing information. Actelion Pharmaceuticals|1
04515|041|R|  US, Inc. October, 2021.|1
04515|042|R|2.This information is based on an extract from the Certara Drug Interaction|6
04515|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04516|001|T|MONOGRAPH TITLE:  Iptacopan/Strong CYP2C8 Inhibitors|
04516|002|B||
04516|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04516|004|L|of severe adverse interaction.|
04516|005|B||
04516|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2C8 may impair the|
04516|007|A|CYP2C8-mediated metabolism of iptacopan.(1)|
04516|008|B||
04516|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inhibitor of CYP2C8 may result|
04516|010|E|in elevated levels of and clinical effects of iptacopan, including the risk|
04516|011|E|of serious infections caused by encapsulated bacteria and hyperlipidemia.(1)|
04516|012|B||
04516|013|P|PREDISPOSING FACTORS:  None determined.|
04516|014|B||
04516|015|M|PATIENT MANAGEMENT:  The manufacturer of iptacopan states that concomitant|
04516|016|M|administration of strong CYP2C8 inhibitors is not recommended.(1)|
04516|017|B||
04516|018|D|DISCUSSION:  No studies have been done evaluating the effects of strong|
04516|019|D|CYP2C8 inhibitors on iptacopan.  A Phase 1 drug-drug interaction study with|
04516|020|D|clopidogrel 300 mg x 1 then 75 mg daily (moderate CYP2C8 inhibitor) in|
04516|021|D|healthy volunteers demonstrated no clinically relevant effects on the plasma|
04516|022|D|pharmacokinetics of iptacopan 100 mg daily. In the presence of clopidogrel,|
04516|023|D|the geometric mean maximum concentration (Cmax) of iptacopan increased by 5%|
04516|024|D|and the area-under-curve (AUC) increased by 36%.(2)|
04516|025|D|   Strong inhibitors of CYP2C8 include gemfibrozil.(3,4)|
04516|026|B||
04516|027|R|REFERENCES:|
04516|028|B||
04516|029|R|1.Fabhalta (iptacopan) US prescribing information. Novartis Pharmaceuticals|1
04516|030|R|  Corporation December 2023.|1
04516|031|R|2.Schmouder R,  Shah B,  Taylor A,  Nidamarthy PK,  Kulmatycki K. Assessment|4
04516|032|R|  of drug interactions with Iptacopan. Poster Presented at ISN World|4
04516|033|R|  Congress of Nephrology 2023 Bangkok// Thailand March 30-April 2//2023.|4
04516|034|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04516|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04516|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04516|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04516|038|R|  11/14/2017.|1
04516|039|R|4.This information is based on an extract from the Certara Drug Interaction|6
04516|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04517|001|T|MONOGRAPH TITLE:  Vadadustat/Polyvalent Cations and Phosphate Binders|
04517|002|B||
04517|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04517|004|L|take action as needed.|
04517|005|B||
04517|006|A|MECHANISM OF ACTION:  Vadadustat may form a chelate with iron supplements,|
04517|007|A|phosphate binders, and other medicinal products whose primary component|
04517|008|A|consists of polyvalent cations such as aluminum, calcium, magnesium,|
04517|009|A|selenium, and zinc.(1)|
04517|010|B||
04517|011|E|CLINICAL EFFECTS:  Simultaneous administration of vadadustat and polyvalent|
04517|012|E|cations and phosphate binders decreases the exposure and effectiveness of|
04517|013|E|vadadustat.(1)|
04517|014|B||
04517|015|P|PREDISPOSING FACTORS:  None determined.|
04517|016|B||
04517|017|M|PATIENT MANAGEMENT:  The manufacturer of vadadustat states that it should be|
04517|018|M|administered at least 1 hour before or 2 hours after any medications or|
04517|019|M|products whose primary component consists of iron, phosphate binders and|
04517|020|M|polyvalent cations.(1)|
04517|021|B||
04517|022|D|DISCUSSION:  Two studies evaluating the pharmacokinetics, safety, and|
04517|023|D|tolerability of a single oral dose of vadadustat coadministered with a|
04517|024|D|phosphate binder or iron supplement were conducted in healthy adult|
04517|025|D|participants.  Vadadustat exposure was reduced by coadministration with|
04517|026|D|sevelamer carbonate, calcium acetate, ferric citrate, and ferrous sulfate.|
04517|027|D|Geometric least squares mean ratios for area under the concentration-time|
04517|028|D|curve (AUC) were reduced 37% to 55% by phosphate binders and 46% by ferrous|
04517|029|D|sulfate.  However, when vadadustat was administered 1 hour before phosphate|
04517|030|D|binders, 90% confidence intervals for vadadustat exposure were within the|
04517|031|D|no-effect boundaries of +50% to -33%, indicating that drug-drug interactions|
04517|032|D|can be reduced by administering vadadustat 1 hour before phosphate|
04517|033|D|binders.(2)|
04517|034|B||
04517|035|R|REFERENCES:|
04517|036|B||
04517|037|R|1.Vafseo (vadadustat) Australian prescribing information. Akebia|1
04517|038|R|  Therapeutics, Inc. October, 2023.|1
04517|039|R|2.Paulson SK,  Martinez J,  Sawant R,  Burke SK,  Chavan A. Effect of|2
04517|040|R|  Phosphate Binders and a Dietary Iron Supplement on the Pharmacokinetics of|2
04517|041|R|  a Single Dose of Vadadustat in Healthy Adults. Clinical Pharmacology in|2
04517|042|R|  Drug Development 19 September 2021;11(4):475-485.|2
04518|001|T|MONOGRAPH TITLE:  Simvastatin (Greater Than 20 mg)/Vadadustat|
04518|002|B||
04518|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04518|004|L|is contraindicated and generally should not be dispensed or administered to|
04518|005|L|the same patient.|
04518|006|B||
04518|007|A|MECHANISM OF ACTION:  Vadadustat inhibits the BCRP transporter, which may|
04518|008|A|result in increased absorption and decreased hepatic uptake of|
04518|009|A|simvastatin.(1-4)|
04518|010|B||
04518|011|E|CLINICAL EFFECTS:  Concurrent vadadustat may result in elevated levels of|
04518|012|E|simvastatin, which may result in myopathy and rhabdomyolysis.(1-4)|
04518|013|B||
04518|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04518|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04518|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04518|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04518|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04518|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04518|020|P|predisposed to myopathy or rhabdomyolysis.|
04518|021|B||
04518|022|M|PATIENT MANAGEMENT:  Do not exceed a dosage of 20 mg daily of simvastatin in|
04518|023|M|patients receiving concurrent therapy with vadadustat.(1-4)|
04518|024|M|   The US manufacturer of vadadustat recommends a starting dose of|
04518|025|M|simvastatin 5 mg daily when receiving concurrent therapy.(4)|
04518|026|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04518|027|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04518|028|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04518|029|M|urine, and/or discolored urine.|
04518|030|B||
04518|031|D|DISCUSSION:  Concurrent use of vadadustat increased the area-under-curve|
04518|032|D|(AUC) of simvastatin by approximately 2-fold.(2-4)|
04518|033|B||
04518|034|R|REFERENCES:|
04518|035|B||
04518|036|R|1.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
04518|037|R|  2023.|1
04518|038|R|2.Vafseo (vadadustat) Australian prescribing information. Akebia|1
04518|039|R|  Therapeutics, Inc. October, 2023.|1
04518|040|R|3.Vafseo (vadadustat) UK Summary of Product Characteristics. Akebia Europe|1
04518|041|R|  Limited May, 2023.|1
04518|042|R|4.Vafseo (vadadustat) tablets US prescribing information. Akebia|1
04518|043|R|  Therapeutics, Inc March, 2024.|1
04519|001|T|MONOGRAPH TITLE:  Simvastatin (Less Than or Equal To 20 mg)/Vadadustat|
04519|002|B||
04519|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04519|004|L|take action as needed.|
04519|005|B||
04519|006|A|MECHANISM OF ACTION:  Vadadustat inhibits the BCRP transporter, which may|
04519|007|A|result in increased absorption and decreased hepatic uptake of|
04519|008|A|simvastatin.(1-4)|
04519|009|B||
04519|010|E|CLINICAL EFFECTS:  Concurrent vadadustat may result in elevated levels of|
04519|011|E|simvastatin, which may result in myopathy and rhabdomyolysis.(1-4)|
04519|012|B||
04519|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04519|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04519|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04519|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04519|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04519|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04519|019|P|predisposed to myopathy or rhabdomyolysis.|
04519|020|B||
04519|021|M|PATIENT MANAGEMENT:  Do not exceed a dosage of 20 mg daily of simvastatin in|
04519|022|M|patients receiving concurrent therapy with vadadustat.(1-4)|
04519|023|M|   The US manufacturer of vadadustat recommends a starting dose of|
04519|024|M|simvastatin 5 mg daily when receiving concurrent therapy.(4)|
04519|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04519|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04519|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04519|028|M|urine, and/or discolored urine.|
04519|029|B||
04519|030|D|DISCUSSION:  Concurrent use of vadadustat increased the area-under-curve|
04519|031|D|(AUC) of simvastatin by approximately 2-fold.(2-4)|
04519|032|B||
04519|033|R|REFERENCES:|
04519|034|B||
04519|035|R|1.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
04519|036|R|  2023.|1
04519|037|R|2.Vafseo (vadadustat) Australian prescribing information. Akebia|1
04519|038|R|  Therapeutics, Inc. October, 2023.|1
04519|039|R|3.Vafseo (vadadustat) UK Summary of Product Characteristics. Akebia Europe|1
04519|040|R|  Limited May, 2023.|1
04519|041|R|4.Vafseo (vadadustat) tablets US prescribing information. Akebia|1
04519|042|R|  Therapeutics, Inc March, 2024.|1
04520|001|T|MONOGRAPH TITLE:  Rosuvastatin (> 5 mg)/Vadadustat|
04520|002|B||
04520|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04520|004|L|is contraindicated and generally should not be dispensed or administered to|
04520|005|L|the same patient.|
04520|006|B||
04520|007|A|MECHANISM OF ACTION:  Vadadustat inhibits the BCRP transporter, which may|
04520|008|A|result in increased absorption and decreased hepatic uptake of|
04520|009|A|rosuvastatin.(1-4)|
04520|010|B||
04520|011|E|CLINICAL EFFECTS:  Concurrent use of vadadustat with rosuvastatin may result|
04520|012|E|in increased levels and side effects from rosuvastatin, including myopathy|
04520|013|E|and rhabdomyolysis.(1-4)|
04520|014|B||
04520|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04520|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04520|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04520|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04520|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04520|020|P|transporter OATP1B1 may have increased statin concentrations and be|
04520|021|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04520|022|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04520|023|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04520|024|B||
04520|025|M|PATIENT MANAGEMENT:  Labelling recommendations vary between countries.|
04520|026|M|   The US manufacturer of vadadustat recommends a maximum daily dose of 5 mg|
04520|027|M|of rosuvastatin in patients receiving concurrent therapy.(4)|
04520|028|M|   The UK and Australian manufacturers of vadadustat recommend a maximum|
04520|029|M|daily dose of 10 mg of rosuvastatin in patients receiving concurrent|
04520|030|M|therapy.(2,3)|
04520|031|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04520|032|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04520|033|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04520|034|M|urine, and/or discolored urine.|
04520|035|B||
04520|036|D|DISCUSSION:  Concurrent use of vadadustat increased the area-under-curve|
04520|037|D|(AUC) and maximum concentration (Cmax) of rosuvastatin by 2- to 3-fold.(2-4)|
04520|038|B||
04520|039|R|REFERENCES:|
04520|040|B||
04520|041|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04520|042|R|  Pharmaceuticals LP July, 2024.|1
04520|043|R|2.Vafseo (vadadustat) Australian prescribing information. Akebia|1
04520|044|R|  Therapeutics, Inc. October, 2023.|1
04520|045|R|3.Vafseo (vadadustat) UK Summary of Product Characteristics. Akebia Europe|1
04520|046|R|  Limited May, 2023.|1
04520|047|R|4.Vafseo (vadadustat) tablets US prescribing information. Akebia|1
04520|048|R|  Therapeutics, Inc March, 2024.|1
04521|001|T|MONOGRAPH TITLE:  Rosuvastatin (<= 5 mg)/Vadadustat|
04521|002|B||
04521|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04521|004|L|take action as needed.|
04521|005|B||
04521|006|A|MECHANISM OF ACTION:  Vadadustat inhibits the BCRP transporter, which may|
04521|007|A|result in increased absorption and decreased hepatic uptake of|
04521|008|A|rosuvastatin.(1-4)|
04521|009|B||
04521|010|E|CLINICAL EFFECTS:  Concurrent use of vadadustat with rosuvastatin may result|
04521|011|E|in increased levels and side effects from rosuvastatin, including myopathy|
04521|012|E|and rhabdomyolysis.(1-4)|
04521|013|B||
04521|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04521|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04521|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04521|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04521|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04521|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04521|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04521|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04521|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04521|023|B||
04521|024|M|PATIENT MANAGEMENT:  Labelling recommendations vary between countries.|
04521|025|M|   The US manufacturer of vadadustat recommends a maximum daily dose of 5 mg|
04521|026|M|of rosuvastatin in patients receiving concurrent therapy.(4)|
04521|027|M|   The UK and Australian manufacturers of vadadustat recommend a maximum|
04521|028|M|daily dose of 10 mg of rosuvastatin in patients receiving concurrent|
04521|029|M|therapy.(2,3)|
04521|030|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04521|031|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04521|032|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04521|033|M|urine, and/or discolored urine.|
04521|034|B||
04521|035|D|DISCUSSION:  Concurrent use of vadadustat increased the area-under-curve|
04521|036|D|(AUC) and maximum concentration (Cmax) of rosuvastatin by 2- to 3-fold.(2-4)|
04521|037|B||
04521|038|R|REFERENCES:|
04521|039|B||
04521|040|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04521|041|R|  Pharmaceuticals LP July, 2024.|1
04521|042|R|2.Vafseo (vadadustat) Australian prescribing information. Akebia|1
04521|043|R|  Therapeutics, Inc. October, 2023.|1
04521|044|R|3.Vafseo (vadadustat) UK Summary of Product Characteristics. Akebia Europe|1
04521|045|R|  Limited May, 2023.|1
04521|046|R|4.Vafseo (vadadustat) tablets US prescribing information. Akebia|1
04521|047|R|  Therapeutics, Inc March, 2024.|1
04524|001|T|MONOGRAPH TITLE:  Vadadustat/Erythropoietin Stimulating Agents|
04524|002|B||
04524|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04524|004|L|take action as needed.|
04524|005|B||
04524|006|A|MECHANISM OF ACTION:  Vadadustat and erythropoietin stimulating agents|
04524|007|A|(ESAs) both stimulate endogenous erythropoietin production, resulting in|
04524|008|A|increased red blood cell production.(1-2)|
04524|009|B||
04524|010|E|CLINICAL EFFECTS:  Concurrent use of vadadustat and erythropoietin|
04524|011|E|stimulating agents may increase the risk of thrombosis.|
04524|012|B||
04524|013|P|PREDISPOSING FACTORS:  Predisposing factors include a history of|
04524|014|P|thromboembolic disorder, thrombophilia, malignancy, hyperlipidemia,|
04524|015|P|hypertension, heart failure, diabetes mellitus, chronic kidney disease,|
04524|016|P|COPD, obesity, tobacco smoking, major surgery with prolonged post-operative|
04524|017|P|immobilization, and being bed-ridden.|
04524|018|B||
04524|019|M|PATIENT MANAGEMENT:  ESAs should be stopped before initiating vadadustat.(1)|
04524|020|M|   For patients receiving temporary ESA rescue treatment, vadadustat should|
04524|021|M|be held until hemoglobin levels are greater than or equal to 10 g/dL.  The|
04524|022|M|pause in vadadustat treatment should be extended to:|
04524|023|M|- 2 days after last dose of epoetin|
04524|024|M|- 7 days after last dose of darbepoetin alfa|
04524|025|M|- 14 days after last dose of methoxy polyethylene glycol-epoetin beta|
04524|026|M|Vadadustat should be resumed at the prior dose or one dose higher, with|
04524|027|M|subsequent titration according to the dose titration guidelines in the|
04524|028|M|vadadustat package insert.(1-2)|
04524|029|M|   Monitor hemoglobin levels every two weeks until stable, then monitor at|
04524|030|M|least monthly.(1-2)|
04524|031|M|   Observe patients for signs and symptoms of venous thromboembolism and|
04524|032|M|instruct patients to seek medical care if they develop symptoms such as|
04524|033|M|shortness of breath, chest pain, or arm or leg swelling.|
04524|034|B||
04524|035|D|DISCUSSION:  Vadadustat increases endogenous erythropoietin by decreasing|
04524|036|D|degradation of hypoxia-inducible factor (HIF), which increases transcription|
04524|037|D|of the HIF-responsive genes including EPO.  Thromboembolic events were|
04524|038|D|reported as very common (13.7%) in two active-controlled clinical trials in|
04524|039|D|chronic kidney disease.(1-2)|
04524|040|D|   Controlled clinical trials of patients showed that ESAs increased the|
04524|041|D|risk of death, myocardial infarction, stroke, congestive heart failure, and|
04524|042|D|other thromboembolic events with a higher target hemoglobin.(3)|
04524|043|B||
04524|044|R|REFERENCES:|
04524|045|B||
04524|046|R|1.Vafseo (vadadustat) Australian prescribing information. Akebia|1
04524|047|R|  Therapeutics, Inc. October, 2023.|1
04524|048|R|2.Vafseo (vadadustat) UK Summary of Product Characteristics. Akebia Europe|1
04524|049|R|  Limited May, 2023.|1
04524|050|R|3.Aranesp (darbepoetin alfa) US prescribing information. Amgen Inc April 13,|1
04524|051|R|  2017.|1
04525|001|T|MONOGRAPH TITLE:  Exagamglogene Autotemcel/Hydroxyurea|
04525|002|B||
04525|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04525|004|L|of severe adverse interaction.|
04525|005|B||
04525|006|A|MECHANISM OF ACTION:  Hydroxyurea may interfere with hematopoietic stem cell|
04525|007|A|(HSC) mobilization of CD34+ cells.(1)|
04525|008|B||
04525|009|E|CLINICAL EFFECTS:  Use of hydroxyurea before mobilization may result in|
04525|010|E|unsuccessful stem cell mobilization and interfere with lovotibeglogene|
04525|011|E|autotemcel therapy.|
04525|012|B||
04525|013|P|PREDISPOSING FACTORS:  None determined.|
04525|014|B||
04525|015|M|PATIENT MANAGEMENT:  Discontinue disease modifying therapies for sickle cell|
04525|016|M|disease (e.g., hydroxyurea) 8 weeks before each mobilization cycle.(1)|
04525|017|M|   It is recommended that patients be transfused at least 8 weeks prior to|
04525|018|M|the initiation of myeloablative conditioning.  At initiation of red blood|
04525|019|M|cell exchange or simple transfusions, discontinue disease modifying|
04525|020|M|therapies for sickle cell disease (e.g., hydroxyurea).(1)|
04525|021|B||
04525|022|D|DISCUSSION:  Hydroxyurea may interfere with the manufacturing and|
04525|023|D|effectiveness of exagamglogene autotemcel therapy.  There is no experience|
04525|024|D|with the use of hydroxyurea after exagamglogene autotemcel infusion.(1)|
04525|025|B||
04525|026|R|REFERENCE:|
04525|027|B||
04525|028|R|1.Casgevy (exagamglogene autotemcel) US prescribing information. Vertex|1
04525|029|R|  Pharmaceuticals Incorporated December, 2023.|1
04526|001|T|MONOGRAPH TITLE:  Lovotibeglogene Autotemcel/Anti-Retrovirals|
04526|002|B||
04526|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04526|004|L|of severe adverse interaction.|
04526|005|B||
04526|006|A|MECHANISM OF ACTION:  Lovotibeglogene autotemcel is prepared from apheresed|
04526|007|A|cells that are transduced with a replication defective, self-inactivating|
04526|008|A|lentiviral vector.  Antiretrovirals may interfere with the manufacturing of|
04526|009|A|apheresed cells.|
04526|010|B||
04526|011|E|CLINICAL EFFECTS:  Use of antiretrovirals before mobilization and apheresis|
04526|012|E|may interfere with the production of lovotibeglogene autotemcel.(1)|
04526|013|B||
04526|014|P|PREDISPOSING FACTORS:  None determined.|
04526|015|B||
04526|016|M|PATIENT MANAGEMENT:  Discontinue antiretrovirals for at least one month|
04526|017|M|prior to mobilization and until all cycles of apheresis are completed.(1)|
04526|018|M|There are some long-acting antiretroviral medications that may require a|
04526|019|M|longer duration of discontinuation for elimination of the medication.|
04526|020|M|   If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a|
04526|021|M|negative test for HIV before beginning mobilization and apheresis of CD34+|
04526|022|M|cells.(1)|
04526|023|B||
04526|024|D|DISCUSSION:  Antiretroviral medications may interfere with the manufacturing|
04526|025|D|of lovotibeglogene autotemcel therapy.(1)|
04526|026|B||
04526|027|R|REFERENCE:|
04526|028|B||
04526|029|R|1.Lyfgenia (lovotibeglogene autotemcel) US prescribing information. bluebird|1
04526|030|R|  bio, Inc. December, 2023.|1
04527|001|T|MONOGRAPH TITLE:  Lovotibeglogene Autotemcel/Myelosuppressive Iron Chelators|
04527|002|B||
04527|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04527|004|L|of severe adverse interaction.|
04527|005|B||
04527|006|A|MECHANISM OF ACTION:  Treatment with lovotibeglogene autotemcel requires|
04527|007|A|hematopoietic stem cell (HSC) mobilization which can suppress the immune|
04527|008|A|system.|
04527|009|B||
04527|010|E|CLINICAL EFFECTS:  Myelosuppressive iron chelators may result in increased|
04527|011|E|risk of serious infections.|
04527|012|B||
04527|013|P|PREDISPOSING FACTORS:  None determined.|
04527|014|B||
04527|015|M|PATIENT MANAGEMENT:  Iron chelators should be discontinued 7 days prior to|
04527|016|M|initiation of mobilization or conditioning.|
04527|017|M|   Avoid myelosuppressive iron chelators for six months after|
04527|018|M|lovotibeglogene autotemcel infusion.  Avoid non-myelosuppressive iron|
04527|019|M|chelators for three months after lovotibeglogene autotemcel infusion.|
04527|020|M|   If iron chelation is needed, consider phlebotomy in lieu of iron|
04527|021|M|chelation when appropriate.(1)|
04527|022|B||
04527|023|D|DISCUSSION:  In preparation for infusion of lovotibeglogene autotemcel, iron|
04527|024|D|chelation should be discontinued 7 days prior to initiation of mobilization|
04527|025|D|or conditioning.(1)|
04527|026|D|   In clinical trials, 60% of 45 patients experienced Grade 3 or 4|
04527|027|D|neutropenia from Day 1 to Month 24.(1)|
04527|028|B||
04527|029|R|REFERENCE:|
04527|030|B||
04527|031|R|1.Lyfgenia (lovotibeglogene autotemcel) US prescribing information. bluebird|1
04527|032|R|  bio, Inc. December, 2023.|1
04528|001|T|MONOGRAPH TITLE:  Exagamglogene Autotemcel/Myelosuppressive Iron Chelators|
04528|002|B||
04528|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04528|004|L|of severe adverse interaction.|
04528|005|B||
04528|006|A|MECHANISM OF ACTION:  Treatment with exagamglogene autotemcel requires|
04528|007|A|hematopoietic stem cell (HSC) mobilization which can suppress the immune|
04528|008|A|system.|
04528|009|B||
04528|010|E|CLINICAL EFFECTS:  Myelosuppressive iron chelators may result in increased|
04528|011|E|risk of serious infections.|
04528|012|B||
04528|013|P|PREDISPOSING FACTORS:  None determined.|
04528|014|B||
04528|015|M|PATIENT MANAGEMENT:  Iron chelators should be discontinued 7 days prior to|
04528|016|M|initiation of mobilization or conditioning.|
04528|017|M|   Avoid myelosuppressive iron chelators for six months after exagamglogene|
04528|018|M|autotemcel infusion.  Avoid non-myelosuppressive iron chelators for three|
04528|019|M|months after exagamglogene autotemcel infusion.|
04528|020|M|   If iron chelation is needed, consider phlebotomy in lieu of iron|
04528|021|M|chelation when appropriate.(1)|
04528|022|B||
04528|023|D|DISCUSSION:  In preparation for infusion of exagamglogene autotemcel, iron|
04528|024|D|chelation should be discontinued 7 days prior to initiation of mobilization|
04528|025|D|or conditioning.(1)|
04528|026|D|   In clinical trials, 100% of 44 patients experienced Grade 3 or 4|
04528|027|D|neutropenia from Day 1 to Month 24.(1)|
04528|028|B||
04528|029|R|REFERENCE:|
04528|030|B||
04528|031|R|1.Casgevy (exagamglogene autotemcel) US prescribing information. Vertex|1
04528|032|R|  Pharmaceuticals Incorporated December, 2023.|1
04529|001|T|MONOGRAPH TITLE:  Exagamglogene Autotemcel/Iron Chelators|
04529|002|B||
04529|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04529|004|L|of severe adverse interaction.|
04529|005|B||
04529|006|A|MECHANISM OF ACTION:  Treatment with exagamglogene autotemcel requires|
04529|007|A|hematopoietic stem cell (HSC) mobilization which can suppress the immune|
04529|008|A|system.|
04529|009|B||
04529|010|E|CLINICAL EFFECTS:  Iron chelators should be held prior to and after infusion|
04529|011|E|with exagamglogene autotemcel.|
04529|012|B||
04529|013|P|PREDISPOSING FACTORS:  None determined.|
04529|014|B||
04529|015|M|PATIENT MANAGEMENT:  Iron chelators should be discontinued 7 days prior to|
04529|016|M|initiation of mobilization or conditioning.|
04529|017|M|   Avoid myelosuppressive iron chelators for six months after exagamglogene|
04529|018|M|autotemcel infusion.  Avoid non-myelosuppressive iron chelators for three|
04529|019|M|months after exagamglogene autotemcel infusion.|
04529|020|M|   If iron chelation is needed, consider phlebotomy in lieu of iron|
04529|021|M|chelation when appropriate.(1)|
04529|022|B||
04529|023|D|DISCUSSION:  In preparation for infusion of exagamglogene autotemcel, iron|
04529|024|D|chelation should be discontinued 7 days prior to initiation of mobilization|
04529|025|D|or conditioning.(1)|
04529|026|B||
04529|027|R|REFERENCE:|
04529|028|B||
04529|029|R|1.Casgevy (exagamglogene autotemcel) US prescribing information. Vertex|1
04529|030|R|  Pharmaceuticals Incorporated December, 2023.|1
04530|001|T|MONOGRAPH TITLE:  Lovotibeglogene Autotemcel/Iron Chelators|
04530|002|B||
04530|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04530|004|L|take action as needed.|
04530|005|B||
04530|006|A|MECHANISM OF ACTION:  Treatment with lovotibeglogene autotemcel requires|
04530|007|A|hematopoietic stem cell (HSC) mobilization which can suppress the immune|
04530|008|A|system.|
04530|009|B||
04530|010|E|CLINICAL EFFECTS:  Iron chelators should be held prior to and after infusion|
04530|011|E|with lovotibeglogene autotemcel.|
04530|012|B||
04530|013|P|PREDISPOSING FACTORS:  None determined.|
04530|014|B||
04530|015|M|PATIENT MANAGEMENT:  Iron chelators should be discontinued 7 days prior to|
04530|016|M|initiation of mobilization or conditioning.|
04530|017|M|   Avoid myelosuppressive iron chelators for six months after|
04530|018|M|lovotibeglogene autotemcel infusion.  Avoid non-myelosuppressive iron|
04530|019|M|chelators for three months after lovotibeglogene autotemcel infusion.|
04530|020|M|   If iron chelation is needed, consider phlebotomy in lieu of iron|
04530|021|M|chelation when appropriate.(1)|
04530|022|B||
04530|023|D|DISCUSSION:  In preparation for infusion of lovotibeglogene autotemcel, iron|
04530|024|D|chelation should be discontinued 7 days prior to initiation of mobilization|
04530|025|D|or conditioning.(1)|
04530|026|B||
04530|027|R|REFERENCES:|
04530|028|B||
04530|029|R|1.Lyfgenia (lovotibeglogene autotemcel) US prescribing information. bluebird|1
04530|030|R|  bio, Inc. December, 2023.|1
04530|031|R|2.bluebird bio. Personal Communication - Lyfgenia. 20 December 2023.|1
04531|001|T|MONOGRAPH TITLE:  Exagamglogene Autotemcel/Disease Modifying Agents|
04531|002|B||
04531|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04531|004|L|of severe adverse interaction.|
04531|005|B||
04531|006|A|MECHANISM OF ACTION:  The interaction potential of disease modifying agents|
04531|007|A|with exagamglogene autotemcel is unknown.(1)|
04531|008|B||
04531|009|E|CLINICAL EFFECTS:  Disease modifying agents may interfere with exagamglogene|
04531|010|E|autotemcel therapy.(1)|
04531|011|B||
04531|012|P|PREDISPOSING FACTORS:  None determined.|
04531|013|B||
04531|014|M|PATIENT MANAGEMENT:  Discontinue disease modifying therapies for sickle cell|
04531|015|M|disease (e.g. voxelotor, crizanlizumab) at least 8 weeks prior to the start|
04531|016|M|of mobilization.(1)|
04531|017|M|   It is recommended that patients be transfused at least 8 weeks prior to|
04531|018|M|the initiation of myeloablative conditioning.  At initiation of red blood|
04531|019|M|cell exchange or simple transfusions, discontinue disease modifying|
04531|020|M|therapies for sickle cell disease (e.g. voxelotor, crizanlizumab).(1)|
04531|021|B||
04531|022|D|DISCUSSION:  There is no experience with the use of disease modifying agents|
04531|023|D|with exagamglogene autotemcel infusion.(1)|
04531|024|B||
04531|025|R|REFERENCE:|
04531|026|B||
04531|027|R|1.Casgevy (exagamglogene autotemcel) US prescribing information. Vertex|1
04531|028|R|  Pharmaceuticals Incorporated December, 2023.|1
04532|001|T|MONOGRAPH TITLE:  Lovotibeglogene Autotemcel/Hydroxyurea|
04532|002|B||
04532|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04532|004|L|of severe adverse interaction.|
04532|005|B||
04532|006|A|MECHANISM OF ACTION:  Hydroxyurea may interfere with hematopoietic stem cell|
04532|007|A|(HSC) mobilization of CD34+ cells.(1)|
04532|008|B||
04532|009|E|CLINICAL EFFECTS:  Use of hydroxyurea before mobilization may result in|
04532|010|E|unsuccessful stem cell mobilization and interfere with lovotibeglogene|
04532|011|E|autotemcel therapy.|
04532|012|B||
04532|013|P|PREDISPOSING FACTORS:  None determined.|
04532|014|B||
04532|015|M|PATIENT MANAGEMENT:  Discontinue hydroxyurea for at least 2 months prior to|
04532|016|M|mobilization and until all cycles of apheresis are completed, and 2 days|
04532|017|M|prior to conditioning.(1)|
04532|018|B||
04532|019|D|DISCUSSION:  Hydroxyurea may interfere with the manufacturing and|
04532|020|D|effectiveness of lovotibeglogene autotemcel therapy.(1)|
04532|021|B||
04532|022|R|REFERENCE:|
04532|023|B||
04532|024|R|1.Lyfgenia (lovotibeglogene autotemcel) US prescribing information. bluebird|1
04532|025|R|  bio, Inc. December, 2023.|1
04533|001|T|MONOGRAPH TITLE:  Busulfan/Phenytoin|
04533|002|B||
04533|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04533|004|L|of severe adverse interaction.|
04533|005|B||
04533|006|A|MECHANISM OF ACTION:  Phenytoin may increase the plasma concentrations of|
04533|007|A|busulfan.  The exact mechanism is unknown but may be due to induction of|
04533|008|A|glutathione-S-transferase.(1)|
04533|009|B||
04533|010|E|CLINICAL EFFECTS:  Concurrent use of phenytoin may result in elevated levels|
04533|011|E|of and toxicity from busulfan.(1-6)|
04533|012|B||
04533|013|P|PREDISPOSING FACTORS:  None determined.|
04533|014|B||
04533|015|M|PATIENT MANAGEMENT:  Consider alternative seizure prophylaxis in patients on|
04533|016|M|busulfan such as levetiracetam.(2-6)|
04533|017|M|   If concurrent therapy with phenytoin is warranted, patients should be|
04533|018|M|closely monitored for busulfan toxicity.(1)|
04533|019|B||
04533|020|D|DISCUSSION:  Clinical studies and guidelines support the use of alternative|
04533|021|D|seizure prophylaxis in patients on busulfan such as levetiracetam.(2-6)|
04533|022|D|   Phenytoin increased the clearance of busulfan by 15% or more.(1)|
04533|023|D|   In a cohort study of 2155 patients receiving allogenic hematopoietic cell|
04533|024|D|transplantation (HCT), 1460 patients received phenytoin and 695 received|
04533|025|D|alternative antiepileptic medications (AEMs).  The study found no|
04533|026|D|differences in decreased overall survival or relapse-free survival or|
04533|027|D|increased risks of relapse, nonrelapse mortality, acute or chronic|
04533|028|D|graft-versus-host disease, or regimen-related toxicity associated with the|
04533|029|D|use of alternative AEMs compared with phenytoin.(4)|
04533|030|D|   In a retrospective review of 36 HCT patients, levetiracetam was given as|
04533|031|D|an alternative antiseizure prophylaxis.  Patients receiving levetiracetam|
04533|032|D|1000 mg oral twice daily had no episodes of seizures and therapy was|
04533|033|D|well-tolerated.(5)|
04533|034|D|   In a retrospective review of 139 HCT patients, incidence of seizures was|
04533|035|D|evaluated in patients who received phenytoin and patients who did not.  Of|
04533|036|D|the 43 patients who received phenytoin prophylaxis, four patients (9.3%) had|
04533|037|D|a seizure during the conditioning regimen, of which two patients had|
04533|038|D|cerebral non-Hodgkin lymphoma, and all 4 patients had very high levels of|
04533|039|D|phenytoin (intoxication).  Of the 96 patients that did not receive phenytoin|
04533|040|D|prophylaxis, three patients (3.1%) had a seizure, and one of these patients|
04533|041|D|had an undefined cerebral lesion.(6)|
04533|042|B||
04533|043|R|REFERENCES:|
04533|044|B||
04533|045|R|1.Busulfex (busulfan) US prescribing information. Otsuka America|1
04533|046|R|  Pharmaceutical, Inc. November, 2022.|1
04533|047|R|2.Palmer J, McCune JS, Perales MA, Marks D, Bubalo J, Mohty M, Wingard JR,|6
04533|048|R|  Paci A, Hassan M, Bredeson C, Pidala J, Shah N, Shaughnessy P, Majhail N,|6
04533|049|R|  Schriber J, Savani BN, Carpenter PA. Personalizing busulfan-based|6
04533|050|R|  conditioning: considerations from the American Society for Blood and|6
04533|051|R|  Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow|6
04533|052|R|  Transplant 2016;1915-1925.|6
04533|053|R|3.Eberly AL, Anderson GD, Bubalo JS, McCune JS. Optimal prevention of|6
04533|054|R|  seizures induced by high-dose busulfan. Pharmacotherapy 2008 Dec;|6
04533|055|R|  28(12):1502-10.|6
04533|056|R|4.McCune JS, Wang T, BoSubait K, Aljurf M, Beitinjaneh A. Association of|2
04533|057|R|  Antiepileptic Medications with Outcomes after Allogeneic  Hematopoietic|2
04533|058|R|  Cell Transplantation with Busulfan Cyclophosphamide Conditioning. Biol|2
04533|059|R|  Blood Marrow Transplant 2019 Jul;25(7):1424-1431.|2
04533|060|R|5.Chaguaceda C, Aguilera-JimAnez V, Gutierrez G, Roura J, Riu G. Oral|2
04533|061|R|  levetiracetam for prevention of busulfan-induced seizures in adult|2
04533|062|R|  hematopoietic cell transplant. Int J Clin Pharm 2020 Apr;42(2):351-354.|2
04533|063|R|6.Germeraad RS, Demandt AMP, Rouhl RPW. Phenytoin as seizure prophylaxis in|2
04533|064|R|  hematopoietic stem cell transplantation with  busulfan conditioning. Front|2
04533|065|R|  Neurol 2022;13:928550.|2
04534|001|T|MONOGRAPH TITLE:  Lovotibeglogene Autotemcel/Erythropoietic agents|
04534|002|B||
04534|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04534|004|L|of severe adverse interaction.|
04534|005|B||
04534|006|A|MECHANISM OF ACTION:  Erythropoietic agents may interfere with hematopoietic|
04534|007|A|stem cell (HSC) mobilization of CD34+ cells.(1)|
04534|008|B||
04534|009|E|CLINICAL EFFECTS:  Use of erythropoietic agents before mobilization may|
04534|010|E|result in unsuccessful stem cell mobilization.(1)|
04534|011|B||
04534|012|P|PREDISPOSING FACTORS:  None determined.|
04534|013|B||
04534|014|M|PATIENT MANAGEMENT:  Discontinue erythropoietic agents at least 2 months|
04534|015|M|prior to mobilization.(1)|
04534|016|B||
04534|017|D|DISCUSSION:  Erythropoietic agents may interfere with the manufacturing of|
04534|018|D|lovotibeglogene autotemcel therapy.  There are no data regarding use of|
04534|019|D|erythropoietin between apheresis and conditioning or after lovotibeglogene|
04534|020|D|autotemcel therapy.(1)|
04534|021|B||
04534|022|R|REFERENCE:|
04534|023|B||
04534|024|R|1.Lyfgenia (lovotibeglogene autotemcel) US prescribing information. bluebird|1
04534|025|R|  bio, Inc. December, 2023.|1
04535|001|T|MONOGRAPH TITLE:  Lovotibeglogene Autotemcel/Disease Modifying Agents|
04535|002|B||
04535|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04535|004|L|of severe adverse interaction.|
04535|005|B||
04535|006|A|MECHANISM OF ACTION:  The interaction potential of disease modifying agents|
04535|007|A|with lovotibeglogene autotemcel is unknown.(1)|
04535|008|B||
04535|009|E|CLINICAL EFFECTS:  Disease modifying agents may interfere with|
04535|010|E|lovotibeglogene autotemcel therapy.(1)|
04535|011|B||
04535|012|P|PREDISPOSING FACTORS:  None determined.|
04535|013|B||
04535|014|M|PATIENT MANAGEMENT:  Discontinue disease modifying therapies (e.g.|
04535|015|M|voxelotor, crizanlizumab) for sickle cell disease at least 8 weeks prior to|
04535|016|M|start of mobilization and conditioning.(1)|
04535|017|B||
04535|018|D|DISCUSSION:  There is no experience with the use of disease modifying agents|
04535|019|D|with lovotibeglogene autotemcel infusion.(1)|
04535|020|B||
04535|021|R|REFERENCE:|
04535|022|B||
04535|023|R|1.Lyfgenia (lovotibeglogene autotemcel) US prescribing information. bluebird|1
04535|024|R|  bio, Inc. December, 2023.|1
04536|001|T|MONOGRAPH TITLE:  Belumosudil (400 mg)/Strong CYP3A4 Inducers|
04536|002|B||
04536|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04536|004|L|take action as needed.|
04536|005|B||
04536|006|A|MECHANISM OF ACTION:  Belumosudil is primarily metabolized by CYP3A4.(1)|
04536|007|B||
04536|008|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers and belumosudil|
04536|009|E|may result in decreased systemic concentrations of belumosudil, which may|
04536|010|E|decrease the efficacy of belumosudil.(1)|
04536|011|B||
04536|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04536|013|P|of the inducer for longer than 1-2 weeks.|
04536|014|B||
04536|015|M|PATIENT MANAGEMENT:  Increase the dosage of belumosudil to 200 mg twice|
04536|016|M|daily when coadministered with strong CYP3A inducers.(1)|
04536|017|B||
04536|018|D|DISCUSSION:  Coadministration of rifampin decreased belumosudil maximum|
04536|019|D|concentration (Cmax) by 59% and area-under-curve (AUC) by 72% in healthy|
04536|020|D|subjects.|
04536|021|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04536|022|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04536|023|D|ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone,|
04536|024|D|rifampin, rifapentine and St. John's Wort.(2,3)|
04536|025|B||
04536|026|R|REFERENCES:|
04536|027|B||
04536|028|R|1.Rezurock (belumosudil) US prescribing information. Kadmon Pharmaceuticals,|1
04536|029|R|  LLC April, 2024.|1
04536|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04536|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04536|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04536|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04536|034|R|  11/14/2017.|1
04536|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04536|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04537|001|T|MONOGRAPH TITLE:  Encorafenib/Atazanavir (mono deleted 04/09/2024)|
04537|002|B||
04537|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04537|004|L|is contraindicated and generally should not be dispensed or administered to|
04537|005|L|the same patient.|
04537|006|B||
04537|007|A|MECHANISM OF ACTION:  Atazanavir is a moderate inhibitor of CYP3A4 and may|
04537|008|A|inhibit the metabolism of encorafenib.(1-2)|
04537|009|B||
04537|010|E|CLINICAL EFFECTS:  Concurrent use of atazanavir with encorafenib may result|
04537|011|E|in elevated levels of and toxicity from encorafenib, including QT|
04537|012|E|prolongation.(1-2)|
04537|013|B||
04537|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04537|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04537|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04537|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04537|018|P|female gender, or advanced age.(3)|
04537|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04537|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04537|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04537|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04537|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04537|024|P|an agent which inhibits its metabolism or elimination, and/or renal/hepatic|
04537|025|P|dysfunction).(3)|
04537|026|B||
04537|027|M|PATIENT MANAGEMENT:  The US manufacturer of atazanavir states that|
04537|028|M|coadministration of encorafenib with atazanavir (with or without ritonavir)|
04537|029|M|is contraindicated due to the potential for the loss of virologic response|
04537|030|M|and risk of serious adverse events such as QT interval prolongation.(2)|
04537|031|B||
04537|032|D|DISCUSSION:  No studies have been done with encorafenib and atazanavir.|
04537|033|D|Coadministration of posaconazole (a strong CYP3A4 inhibitor) and diltiazem|
04537|034|D|(a moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) of|
04537|035|D|encorafenib by 3-fold and 2-fold, respectively, and increased the maximum|
04537|036|D|concentration (Cmax) by 68% and 45%, respectively, after a single dose of|
04537|037|D|encorafenib 50 mg (0.1 times the recommended dose).(1)|
04537|038|D|   Encorafenib has been associated with a dose-dependent QTc interval|
04537|039|D|prolongation.  Following administration of encorafenib in combination with|
04537|040|D|binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms|
04537|041|D|(14-22 ms), based on central tendency analysis.(1)|
04537|042|B||
04537|043|R|REFERENCES:|
04537|044|B||
04537|045|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
04537|046|R|  BioPharma October, 2023.|1
04537|047|R|2.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04537|048|R|  Squibb Company December, 2024.|1
04537|049|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04537|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04537|051|R|  settings: a scientific statement from the American Heart Association and|6
04537|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04537|053|R|  2;55(9):934-47.|6
04538|001|T|MONOGRAPH TITLE:  Encorafenib; Ivosidenib/Atazanavir|
04538|002|B||
04538|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04538|004|L|is contraindicated and generally should not be dispensed or administered to|
04538|005|L|the same patient.|
04538|006|B||
04538|007|A|MECHANISM OF ACTION:  Atazanavir is moderate inhibitor of CYP3A4 and may|
04538|008|A|inhibit the metabolism of encorafenib and ivosidenib.(1-3)  Encorafenib and|
04538|009|A|ivosidenib are strong CYP3A4 inducers and may accelerate the metabolism of|
04538|010|A|atazanavir.(3)|
04538|011|B||
04538|012|E|CLINICAL EFFECTS:  Concurrent use of atazanavir with encorafenib or|
04538|013|E|ivosidenib may result in elevated levels of and toxicity from encorafenib or|
04538|014|E|ivosidenib, including QT prolongation,(1,2) as well as decreased levels and|
04538|015|E|effectiveness of atazanavir.(3)|
04538|016|B||
04538|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04538|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04538|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04538|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04538|021|P|female gender, or advanced age.(4)|
04538|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04538|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04538|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04538|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04538|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04538|027|P|an agent which inhibits its metabolism or elimination, and/or renal/hepatic|
04538|028|P|dysfunction).(4)|
04538|029|B||
04538|030|M|PATIENT MANAGEMENT:  The US manufacturer of atazanavir states that|
04538|031|M|coadministration of encorafenib or ivosidenib with atazanavir (with or|
04538|032|M|without ritonavir) is contraindicated due to the potential for the loss of|
04538|033|M|virologic response and risk of serious adverse events such as QT interval|
04538|034|M|prolongation.(3)|
04538|035|B||
04538|036|D|DISCUSSION:  In a clinical study, encorafenib 450 mg daily with binimetinib|
04538|037|D|45 mg twice daily decreased the area-under-curve (AUC) and maximum|
04538|038|D|concentration (Cmax) of midazolam 2 mg by 82% and 74%, respectively.(1)|
04538|039|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
04538|040|D|moderate CYP3A4 inhibitor, may increase the AUC of single-dose ivosidenib|
04538|041|D|(500 mg)  by 173%.  In regards to multiple-dosing, coadministration of|
04538|042|D|ivosidenib with fluconazole is predicted to increase ivosidenib Cmax and AUC|
04538|043|D|by 152% and 190%, respectively.(2)|
04538|044|D|   In a study, rifampin (600 mg daily for 10 days), a strong CYP3A4 inducer,|
04538|045|D|decreased the AUC and Cmax of atazanavir 300 mg daily with ritonavir 100 mg|
04538|046|D|daily by 72% and 53%, respectively.(3)|
04538|047|B||
04538|048|R|REFERENCES:|
04538|049|B||
04538|050|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
04538|051|R|  BioPharma December, 2024.|1
04538|052|R|2.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04538|053|R|  Inc. August, 2021.|1
04538|054|R|3.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04538|055|R|  Squibb Company December, 2024.|1
04538|056|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04538|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04538|058|R|  settings: a scientific statement from the American Heart Association and|6
04538|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04538|060|R|  2;55(9):934-47.|6
04539|001|T|MONOGRAPH TITLE:  Dexmedetomidine Sublingual/Possible QT Prolonging Agents|
04539|002|B||
04539|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04539|004|L|take action as needed.|
04539|005|B||
04539|006|A|MECHANISM OF ACTION:  Dexmedetomidine sublingual has been shown to prolong|
04539|007|A|the QTc interval.  Concurrent use with other agents that prolong the QTc|
04539|008|A|interval may result in additive effects on the QTc interval.(1)|
04539|009|B||
04539|010|E|CLINICAL EFFECTS:  The concurrent use of dexmedetomidine sublingual with|
04539|011|E|other agents that prolong the QTc interval may result in potentially|
04539|012|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
04539|013|B||
04539|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04539|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04539|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04539|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04539|018|P|gender, or advanced age.(2)|
04539|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04539|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04539|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04539|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04539|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04539|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04539|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04539|026|B||
04539|027|M|PATIENT MANAGEMENT:  The manufacturer of dexmedetomidine sublingual states|
04539|028|M|that concurrent use should be avoided with other agents known to prolong the|
04539|029|M|QTc interval.(1)|
04539|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04539|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04539|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04539|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04539|034|B||
04539|035|D|DISCUSSION:  In a QT study, dexmedetomidine sublingual had a concentration|
04539|036|D|dependent effect on the QT interval.  The mean QTc (95% confidence interval)|
04539|037|D|increased from baseline by 6 (7) msec with a 120 mcg single dose, 8 (9) msec|
04539|038|D|with 120 mcg followed by 2 additional doses of 60 mcg (total 3 doses), 8|
04539|039|D|(11) msec with a single 180 mcg dose, and 11 (14) msec with 180 mcg followed|
04539|040|D|by 2 additional doses of 90 mcg (total 3 doses), respectively.(1)|
04539|041|D|   Agents that are linked to this monograph may have varying degrees of|
04539|042|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04539|043|D|been shown to prolong the QTc interval either through their mechanism of|
04539|044|D|action, through studies on their effects on the QTc interval, or through|
04539|045|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04539|046|D|and/or postmarketing reports.(3)|
04539|047|B||
04539|048|R|REFERENCES:|
04539|049|B||
04539|050|R|1.Igalmi (dexmedetomidine film) US prescribing information. BioXcel|1
04539|051|R|  Therapeutics, Inc. December, 2022.|1
04539|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04539|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04539|054|R|  settings: a scientific statement from the American Heart Association and|6
04539|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04539|056|R|  2;55(9):934-47.|6
04539|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04539|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04539|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04539|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04540|001|T|MONOGRAPH TITLE:  Belumosudil (400 mg)/Proton Pump Inhibitors|
04540|002|B||
04540|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04540|004|L|take action as needed.|
04540|005|B||
04540|006|A|MECHANISM OF ACTION:  Belumosudil is best absorbed in an acidic environment.|
04540|007|A|Proton pump inhibitors (PPIs) decrease gastric acidity and may decrease|
04540|008|A|belumosudil absorption and systemic concentrations.(1)|
04540|009|B||
04540|010|E|CLINICAL EFFECTS:  Coadministration of PPIs with belumosudil decreases|
04540|011|E|systemic concentrations of belumosudil, which may decrease the efficacy of|
04540|012|E|belumosudil.(1)|
04540|013|B||
04540|014|P|PREDISPOSING FACTORS:  None determined.|
04540|015|B||
04540|016|M|PATIENT MANAGEMENT:  Increase the dosage of belumosudil to 200 mg twice|
04540|017|M|daily when coadministered with PPIs.(1)|
04540|018|B||
04540|019|D|DISCUSSION:  Coadministration of rabeprazole decreased belumosudil maximum|
04540|020|D|concentration (Cmax) by 87% and area-under-curve (AUC) by 80%, and|
04540|021|D|omeprazole decreased belumosudil Cmax by 68% and AUC by 47% in healthy|
04540|022|D|subjects.(1)|
04540|023|B||
04540|024|R|REFERENCE:|
04540|025|B||
04540|026|R|1.Rezurock (belumosudil) US prescribing information. Kadmon Pharmaceuticals,|1
04540|027|R|  LLC April, 2024.|1
04541|001|T|MONOGRAPH TITLE:  Elagolix/Atazanavir|
04541|002|B||
04541|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04541|004|L|of severe adverse interaction.|
04541|005|B||
04541|006|A|MECHANISM OF ACTION:  Atazanavir, a moderate inhibitor of CYP3A4, may|
04541|007|A|decrease the metabolism of elagolix.(1)  Elagolix, a moderate CYP3A4|
04541|008|A|inducer, may increase the metabolism of atazanavir.(2)|
04541|009|B||
04541|010|E|CLINICAL EFFECTS:  Concurrent use of atazanavir with elagolix may result in|
04541|011|E|elevated levels of and side effects from elagolix, including bone loss and|
04541|012|E|increased risk of hepatic transaminase elevations,(1) as well as decreased|
04541|013|E|levels and effectiveness of atazanavir.(2)|
04541|014|B||
04541|015|P|PREDISPOSING FACTORS:  None determined.|
04541|016|B||
04541|017|M|PATIENT MANAGEMENT:  The US manufacturer of atazanavir states that|
04541|018|M|coadministration of elagolix and atazanavir (with or without ritonavir) is|
04541|019|M|not recommended due to the potential loss of virological response and the|
04541|020|M|potential risk of adverse events associated with elagolix.(1-2)|
04541|021|M|   Coadministration of atazanavir and cobicistat with elagolix may result in|
04541|022|M|decreased plasma concentrations of atazanavir and/or cobicistat.(3,4)|
04541|023|M|   If coadministration is necessary, limit concomitant use of elagolix 200|
04541|024|M|mg twice daily with atazanavir with or without ritonavir or cobicistat for|
04541|025|M|up to 1 month or limit concomitant use of elagolix 150 mg once daily with|
04541|026|M|atazanavir (with or without ritonavir or cobicistat) for up to 6 months.|
04541|027|M|Monitor virologic response.(1,3,4)|
04541|028|B||
04541|029|D|DISCUSSION:  No studies have been done with elagolix and atazanavir.|
04541|030|D|   A Phase 1 drug-drug interaction study with multiple doses of ketoconazole|
04541|031|D|(400mg once daily), a strong CYP3A4 inhibitor, and a single dose of elagolix|
04541|032|D|resulted in an elagolix increased maximum plasma concentration (Cmax) of|
04541|033|D|1.8-fold and an area-under-curve (AUC) increase of 2.2-fold, compared with|
04541|034|D|elagolix alone.(2,5)|
04541|035|D|   Elagolix (300 mg twice daily for 11 days) decreased the Cmax and AUC of|
04541|036|D|single-dose midazolam (2 mg), a sensitive CYP3A4 substrate, by 44% and 54%,|
04541|037|D|respectively.  Elagolix (150 mg once daily for 13 days) decreased the Cmax|
04541|038|D|and AUC of single-dose midazolam (2 mg) by 19% and 35%, respectively.(2)|
04541|039|B||
04541|040|R|REFERENCES:|
04541|041|B||
04541|042|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04541|043|R|  Squibb Company December, 2024.|1
04541|044|R|2.Orilissa (elagolix) US prescribing information. AbbVie Inc. February,|1
04541|045|R|  2021.|1
04541|046|R|3.Evotaz (atazanavir and cobicistat) US prescribing information.|1
04541|047|R|  Bristol-Myers-Squibb Company May, 2025.|1
04541|048|R|4.Evotaz (atazanavir and cobicistat) Australian prescribing information.|1
04541|049|R|  Bristol-Myers Squibb Australia Pty Ltd December, 2024.|1
04541|050|R|5.Polepally AR,  Ng JW,  Salem AH,  Dufek MB,  Parikh A,  Carter DC,|2
04541|051|R|  Kamradt K,  Mostafa NM,  Shebley M. Assessment of Clinical Drug-Drug|2
04541|052|R|  Interactions of Elagolix, a Gonadotropin-Releasing Hormone Receptor|2
04541|053|R|  Antagonist. American College of Clinical Pharmacology 2020;|2
04541|054|R|  60(12):1606-1616.|2
04542|001|T|MONOGRAPH TITLE:  Tacrolimus/Cannabidiol|
04542|002|B||
04542|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04542|004|L|take action as needed.|
04542|005|B||
04542|006|A|MECHANISM OF ACTION:  The mechanism of this interaction is not fully|
04542|007|A|understood, but may involve inhibition of CYP3A4 and of the P-glycoprotein|
04542|008|A|transporter by cannabidiol (CBD).(1-5)  Tacrolimus is a substrate of both|
04542|009|A|CYP3A4 and P-gp.(6)|
04542|010|B||
04542|011|E|CLINICAL EFFECTS:  Concurrent use of CBD may result in elevated levels of|
04542|012|E|and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and|
04542|013|E|prolongation of the QTc interval and life-threatening cardiac arrhythmias,|
04542|014|E|including torsades de pointes.(1,2)|
04542|015|B||
04542|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04542|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04542|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04542|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04542|020|P|gender, or advanced age.(7)|
04542|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04542|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04542|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04542|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04542|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04542|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04542|027|P|dysfunction).(7)|
04542|028|B||
04542|029|M|PATIENT MANAGEMENT:  The Canadian manufacturer of the combination of the|
04542|030|M|CBD-THC buccal spray advises caution when it is used concurrently with|
04542|031|M|CYP3A4 substrates.(4)  For patients concurrently taking tacrolimus,|
04542|032|M|therapeutic concentration monitoring of the immunosuppressant is|
04542|033|M|recommended.  Depending upon the agents involved, dose decreases of|
04542|034|M|tacrolimus may be required.(8)|
04542|035|M|   The US manufacturer of tacrolimus recommends closely monitoring|
04542|036|M|tacrolimus whole blood trough concentrations and reducing tacrolimus dose if|
04542|037|M|needed while taking cannabidiol.(1,2)|
04542|038|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
04542|039|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04542|040|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04542|041|M|heartbeat, dizziness, or fainting.|
04542|042|B||
04542|043|D|DISCUSSION:  A study of 22 healthy volunteers administered cannabidiol (2.5|
04542|044|D|mg/kg twice daily for 3 days then 5 mg/kg twice daily for 11 days) found|
04542|045|D|that cannabidiol increased the area under curve (AUC) and maximum|
04542|046|D|concentration (Cmax) of single-dose tacrolimus 5 mg by 3.07-fold and|
04542|047|D|4.18-fold, respectively.(9)|
04542|048|D|   Two case reports have described elevation of tacrolimus levels by|
04542|049|D|cannabinoids. In the first case, a 67-year-old man status-post allogenic|
04542|050|D|hematopoietic stem cell transplant was started on tacrolimus.  Tacrolimus|
04542|051|D|blood levels over the next month were erratic, rising to a peak of 45.8|
04542|052|D|ng/mL despite decreasing dose of tacrolimus.  This was attributed to both|
04542|053|D|edible marijuana gummies and inhaled marijuana.(4)  In the second case, a|
04542|054|D|32-year-old woman who was stable for a year on tacrolimus 5 mg twice daily|
04542|055|D|for interstitial nephritis was started on CBD for refractory epilepsy.|
04542|056|D|During the initial CBD dose titration as well as a dose titration 9 months|
04542|057|D|later, the patient had elevated tacrolimus levels and experienced tacrolimus|
04542|058|D|toxicity with elevated serum creatinine, ultimately requiring a 10-fold|
04542|059|D|reduction in tacrolimus dose.(8)|
04542|060|B||
04542|061|R|REFERENCES:|
04542|062|B||
04542|063|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04542|064|R|  August, 2023.|1
04542|065|R|2.Astagraf XL (tacrolimus extended-release capsules) US prescribing|1
04542|066|R|  information. Astellas Pharma US, Inc. August, 2023.|1
04542|067|R|3.Epidiolex (cannabidiol) US prescribing information. Greenwich Biosciences,|1
04542|068|R|  Inc. June, 2025.|1
04542|069|R|4.Sativex (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD))|1
04542|070|R|  Canadian prescribing information. GW Pharma Ltd. December 11, 2019.|1
04542|071|R|5.Hauser N, Sahai T, Richards R, Roberts T. High on Cannabis and Calcineurin|3
04542|072|R|  Inhibitors: A Word of Warning in an Era of Legalized Marijuana. Case Rep|3
04542|073|R|  Transplant 2016;2016:4028492.|3
04542|074|R|6.This information is based on an extract from the Certara Drug Interaction|6
04542|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04542|076|R|7.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04542|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04542|078|R|  settings: a scientific statement from the American Heart Association and|6
04542|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04542|080|R|  2;55(9):934-47.|6
04542|081|R|8.Leino AD, Emoto C, Fukuda T, Privitera M, Vinks AA, Alloway RR. Evidence|3
04542|082|R|  of a clinically significant drug-drug interaction between cannabidiol and|3
04542|083|R|  tacrolimus. Am J Transplant 2019 Oct;19(10):2944-2948.|3
04542|084|R|9.So GC, Lu JBL, Koyama S, Cheng YH, Gisch DL, McClara K, Dexter PR,|2
04542|085|R|  Sharfuddin AA, Etkins J, Tillman EM, Beamon TR, Cowsert Z, Stuart JS,|2
04542|086|R|  Desta Z, Eadon MT. A Phase I Trial of the Pharmacokinetic Interaction|2
04542|087|R|  Between Cannabidiol and  Tacrolimus. Clin Pharmacol Ther 2024 Nov 27.|2
04543|001|T|MONOGRAPH TITLE:  Tacrolimus/Myelosuppressive Mod-Weak CYP3A4 Inh|
04543|002|B||
04543|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04543|004|L|take action as needed.|
04543|005|B||
04543|006|A|MECHANISM OF ACTION:  Moderate and weak immunosuppressive inhibitors of|
04543|007|A|CYP3A4 may inhibit the metabolism of tacrolimus and increase the risk of|
04543|008|A|additive immunosuppression.(1)|
04543|009|B||
04543|010|E|CLINICAL EFFECTS:  Concurrent use of an immunosuppressive CYP3A4 inhibitor|
04543|011|E|may result in elevated levels of and toxicity from tacrolimus, including|
04543|012|E|nephrotoxicity, neurotoxicity, immunosuppression, and prolongation of the|
04543|013|E|QTc interval and life-threatening cardiac arrhythmias, including torsades de|
04543|014|E|pointes.(1)|
04543|015|B||
04543|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04543|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04543|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04543|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04543|020|P|gender, or advanced age.(2)|
04543|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04543|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04543|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04543|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04543|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04543|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04543|027|P|dysfunction).(2)|
04543|028|B||
04543|029|M|PATIENT MANAGEMENT:  The US manufacturer of tacrolimus recommends monitoring|
04543|030|M|tacrolimus whole blood trough concentrations and reducing tacrolimus dose if|
04543|031|M|needed.(1)|
04543|032|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
04543|033|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04543|034|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04543|035|M|heartbeat, dizziness, or fainting.|
04543|036|B||
04543|037|D|DISCUSSION:  In a study of 26 renal transplant recipients, conjugated|
04543|038|D|estrogens 3.75 mg daily increased the tacrolimus dose-corrected|
04543|039|D|concentration of tacrolimus by 85.6%.  Discontinuation of the conjugated|
04543|040|D|estrogens led to a decrease in tacrolimus concentration of 46.6%.(3)|
04543|041|D|   A case report describes a 65-year-old kidney transplant recipient who was|
04543|042|D|stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL.  Ten|
04543|043|D|days after starting on estradiol gel 0.5 mg per day, her tacrolimus level|
04543|044|D|rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at|
04543|045|D|baseline to 2 mg/dL.  Tacrolimus dose was reduced by 60%, and trough levels|
04543|046|D|and Scr normalized after two weeks.(4)|
04543|047|D|   A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir|
04543|048|D|200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%,|
04543|049|D|while the maximum concentration (Cmax) of tacrolimus was decreased by|
04543|050|D|40%.(5)|
04543|051|D|  An analysis of FAERS data from  2004-2017, found a significant assoc ation|
04543|052|D|between transplant rejection and concurrent use of tacrolimus and|
04543|053|D|clotrimazole (reporting odds ration 1.92, 95% CI). A retrospective study of|
04543|054|D|7 heart transplant patients on concurrent tacrolimus and clotrimazole troche|
04543|055|D|showed a significant correlation between tacrolimus trough concentration and|
04543|056|D|AUC after clotrimazole discontinuation. Tacrolimus clearance and|
04543|057|D|bioavailability after clotrimazole discontinuation was 2.2-fold greater|
04543|058|D|(0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL|
04543|059|D|at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7)|
04543|060|D|   A retrospective study of 26 heart transplant patients found that|
04543|061|D|discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5|
04543|062|D|expresser group had a 3.3-fold increase in apparent oral clearance and AUC|
04543|063|D|of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser|
04543|064|D|group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8)|
04543|065|D|   A study of 6 adult kidney transplant recipients found that clotrimazole|
04543|066|D|(5-day course) increased the tacrolimus AUC 250% and the blood trough|
04543|067|D|concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance|
04543|068|D|decreased 60% with coadministration of clotrimazole.(9)|
04543|069|D|   A case report describes a 23-year-old kidney transplant recipient who was|
04543|070|D|stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily,|
04543|071|D|prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche|
04543|072|D|10 mg four times daily. Discontinuation of clotrimazole resulted in a|
04543|073|D|decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a|
04543|074|D|period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting|
04543|075|D|in an increased tacrolimus level of 19.2 ng/ml.(10)|
04543|076|D|   A retrospective study in 95 heart transplant recipients on concurrent|
04543|077|D|clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7%|
04543|078|D|was required after clotrimazole discontinuation. Tacrolimus trough|
04543|079|D|concentration was found to have decreased 42.5% after clotrimazole|
04543|080|D|discontinuation.(11)|
04543|081|D|   A retrospective study in 65 pancreas transplant patients on concurrent|
04543|082|D|tacrolimus, clotrimazole, cyclosporine, and prednisone found that|
04543|083|D|clotrimazole discontinuation at 3 months after transplantation may cause|
04543|084|D|significant tacrolimus trough level reductions.(12)|
04543|085|D|   Moderate CYP3A4 inhibitors linked to this monograph include: duvelisib,|
04543|086|D|fedratinib, imatinib, rilzabrutinib, and treosulfan.(6)|
04543|087|D|   Weak CYP3A4 inhibitors linked to this monograph include: asciminib,|
04543|088|D|belumosudil, capivasertib, everolimus, larotrectinib, leflunomide, olaparib,|
04543|089|D|palbociclib, and teriflunomide.(6)|
04543|090|B||
04543|091|R|REFERENCES:|
04543|092|B||
04543|093|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04543|094|R|  August, 2023.|1
04543|095|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04543|096|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04543|097|R|  settings: a scientific statement from the American Heart Association and|6
04543|098|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04543|099|R|  2;55(9):934-47.|6
04543|100|R|3.Ghadimi M, Dashti-Khavidaki S, Shahali M, Gohari M, Khatami MR, Alamdari|2
04543|101|R|  A. Tacrolimus interaction with oral oestrogen in kidney transplant|2
04543|102|R|  recipients: A case-control study. J Clin Pharm Ther 2018 Aug;|2
04543|103|R|  43(4):513-518.|2
04543|104|R|4.Migali G, Tintillier M. Interaction between estradiol and tacrolimus in|3
04543|105|R|  kidney-transplanted menopausal women. NDT Plus 2008 Aug;1(4):277-8.|3
04543|106|R|5.Feng HP, Caro L, Fandozzi CM, Guo Z, Talaty J, Wolford D, Panebianco D,|2
04543|107|R|  Iwamoto M, Butterton JR, Yeh WW. Pharmacokinetic Interactions Between|2
04543|108|R|  Elbasvir/Grazoprevir and Immunosuppressant Drugs in Healthy Volunteers. J|2
04543|109|R|  Clin Pharmacol 2018 May;58(5):666-673.|2
04543|110|R|6.This information is based on an extract from the Certara Drug Interaction|6
04543|111|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04543|112|R|7.Uno T, Wada K, Hosomi K, Matsuda S, Ikura MM, Takenaka H, Terakawa N, Oita|2
04543|113|R|  A, Yokoyama S, Kawase A, Takada M. Drug interactions between tacrolimus|2
04543|114|R|  and clotrimazole troche: a data mining approach followed by a|2
04543|115|R|  pharmacokinetic study. Eur J Clin Pharmacol 2020 Jan;76(1):117-125.|2
04543|116|R|8.Uno T, Wada K, Matsuda S, Terada Y, Terakawa N, Oita A, Yokoyama S, Kawase|2
04543|117|R|  A, Hosomi K, Takada M. Effects of clotrimazole on tacrolimus|2
04543|118|R|  pharmacokinetics in patients with heart transplants with different CYP3A5|2
04543|119|R|  genotypes. Eur J Clin Pharmacol 2019 Jan;75(1):67-75.|2
04543|120|R|9.Vasquez EM, Shin GP, Sifontis N, Benedetti E. Concomitant clotrimazole|2
04543|121|R|  therapy more than doubles the relative oral bioavailability of tacrolimus.|2
04543|122|R|  Ther Drug Monit 2005 Oct;27(5):587-91.|2
04543|123|R|10.Choy M. Tacrolimus interaction with clotrimazole: a concise case report|3
04543|124|R|   and literature review. P T 2010 Oct;35(10):568-9.|3
04543|125|R|11.Laub MR, Crow SA, Personett HA, Dierkhising R, Boilson B, Razonable R.|2
04543|126|R|   Effects of clotrimazole troches on tacrolimus dosing in heart transplant|2
04543|127|R|   recipients. Transpl Infect Dis 2018 Dec;20(6):e12979.|2
04543|128|R|12.Viesselmann CW, Descourouez JL, Jorgenson MR, Radke NA, Odorico JS.|2
04543|129|R|   Clinically Significant Drug Interaction Between Clotrimazole and|2
04543|130|R|   Tacrolimus in Pancreas Transplant Recipients and Associated Risk of|2
04543|131|R|   Allograft Rejection. Pharmacotherapy 2016 Mar;36(3):335-41.|2
04544|001|T|MONOGRAPH TITLE:  Sirolimus Protein-Bound/Myelosuppressive Mod-Weak 3A4 Inh|
04544|002|B||
04544|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04544|004|L|of severe adverse interaction.|
04544|005|B||
04544|006|A|MECHANISM OF ACTION:  Moderate and weak immunosuppressive CYP3A4 inhibitors|
04544|007|A|may inhibit the metabolism of sirolimus by CYP3A4 and increase the risk of|
04544|008|A|additive immunosuppression.(1)|
04544|009|B||
04544|010|E|CLINICAL EFFECTS:  Concurrent use of moderate or weak CYP3A4 inhibitors may|
04544|011|E|result in elevated levels of and side effects from sirolimus including|
04544|012|E|immunosuppression.(1)|
04544|013|B||
04544|014|P|PREDISPOSING FACTORS:  None determined.|
04544|015|B||
04544|016|M|PATIENT MANAGEMENT:  The US manufacturer of sirolimus protein-bound|
04544|017|M|injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when|
04544|018|M|used concurrently with moderate or weak CYP3A4 inhibitors.  Concurrent use|
04544|019|M|with strong CYP3A4 inhibitors should be avoided.(1)|
04544|020|B||
04544|021|D|DISCUSSION:  In an open, randomized, cross-over trial in 18 healthy|
04544|022|D|subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10|
04544|023|D|mg) increased sirolimus area-under-curve (AUC) and maximum concentration|
04544|024|D|(Cmax) by 60% and by 43%, respectively.  Sirolimus apparent oral clearance|
04544|025|D|and volume of distribution decreased by 38% and 45%, respectively.  There|
04544|026|D|were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2)|
04544|027|D|   In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with|
04544|028|D|verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold|
04544|029|D|and 2.3-fold, respectively.  The AUC and Cmax of the active S-enantiomer of|
04544|030|D|verapamil each increased by 1.5-fold.  Verapamil time to Cmax (Tmax) was|
04544|031|D|increased by 1.2 hours.(2)|
04544|032|D|   Moderate CYP3A4 inhibitors linked to this monograph include: duvelisib,|
04544|033|D|fedratinib, imatinib, rilzabrutinib, and treosulfan.(3,4)|
04544|034|D|   Weak CYP3A4 inhibitors linked to this monograph include: asciminib,|
04544|035|D|belumosudil, capivasertib, everolimus, lapatinib, larotrectinib,|
04544|036|D|leflunomide, olaparib, palbociclib, teriflunomide, and ziftomenib.(3,4)|
04544|037|B||
04544|038|R|REFERENCES:|
04544|039|B||
04544|040|R|1.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
04544|041|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
04544|042|R|2.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
04544|043|R|  Aug, 2022.|1
04544|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
04544|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04544|046|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04544|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04544|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04544|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04544|050|R|  11/14/2017.|1
04545|001|T|MONOGRAPH TITLE:  Paclitaxel/Immunosuppressive CYP2C8 Inhibitors|
04545|002|B||
04545|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04545|004|L|of severe adverse interaction.|
04545|005|B||
04545|006|A|MECHANISM OF ACTION:  Immunosuppressive inhibitors of CYP2C8 may inhibit the|
04545|007|A|metabolism of paclitaxel and increase the risk of additive|
04545|008|A|immunosuppression.(1)  Leflunomide and teriflunomide are moderate CYP2C8|
04545|009|A|inhibitors.(3)|
04545|010|B||
04545|011|E|CLINICAL EFFECTS:  Concurrent use of immunosuppressive CYP2C8 inhibitors and|
04545|012|E|paclitaxel may result in elevated levels and clinical effects of paclitaxel,|
04545|013|E|including immunosuppression.(1,2)|
04545|014|B||
04545|015|P|PREDISPOSING FACTORS:  None determined.|
04545|016|B||
04545|017|M|PATIENT MANAGEMENT:  The US manufacturers of paclitaxel recommend|
04545|018|M|combination use CYP2C8 inhibitors with caution.  If concomitant use is|
04545|019|M|necessary, paclitaxel dose reduction may be required.(1,2)|
04545|020|B||
04545|021|D|DISCUSSION:  The US manufacturer of paclitaxel recommends use with CYP2C8|
04545|022|D|inhibitors with caution.(1,2)|
04545|023|B||
04545|024|R|REFERENCES:|
04545|025|B||
04545|026|R|1.Lopid (gemfibrozil) US prescribing information. Pfizer Pharmaceuticals,|1
04545|027|R|  Ltd. December, 2020.|1
04545|028|R|2.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
04545|029|R|  Company August, 2010.|1
04545|030|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04545|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04545|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04545|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04545|034|R|  11/14/2017.|1
04546|001|T|MONOGRAPH TITLE:  Cefpodoxime/Antacids|
04546|002|B||
04546|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04546|004|L|take action as needed.|
04546|005|B||
04546|006|A|MECHANISM OF ACTION:  Absorption of oral cefpodoxime may be reduced in|
04546|007|A|patients receiving concomitant treatment with acid reducing agents.(1-3)|
04546|008|B||
04546|009|E|CLINICAL EFFECTS:  Antibiotic efficacy against organisms with a high minimum|
04546|010|E|inhibitory concentration (MIC) to cefpodoxime could be decreased.|
04546|011|B||
04546|012|P|PREDISPOSING FACTORS:  Taking cefpodoxime on an empty stomach magnifies this|
04546|013|P|effect.|
04546|014|B||
04546|015|M|PATIENT MANAGEMENT:  Separate the administration of cefpodoxime by at least|
04546|016|M|1-2 hours after administration of antacids.  Some vitamin preparations may|
04546|017|M|contain sufficient quantities of calcium and/or magnesium salts with antacid|
04546|018|M|properties to interact as well.|
04546|019|M|   Since concurrent use of H2 antagonists and proton pump inhibitors (PPIs)|
04546|020|M|in patients taking cefpodoxime should be avoided, these would not be|
04546|021|M|alternatives to antacids in these patients.|
04546|022|B||
04546|023|D|DISCUSSION:  In a study of ten subjects, administration of cefpodoxime after|
04546|024|D|single dose famotidine 40 mg decreased both maximum concentration (Cmax) and|
04546|025|D|area-under-curve (AUC) by approximately 40% compared with administration of|
04546|026|D|cefpodoxime on an empty stomach.(2)|
04546|027|D|   In a study of 17 subjects, administration of cefpodoxime after single|
04546|028|D|dose ranitidine 150 mg decreased Cmax and AUC by approximately 40% compared|
04546|029|D|with administration of cefpodoxime on an empty stomach.(3)|
04546|030|B||
04546|031|R|REFERENCES:|
04546|032|B||
04546|033|R|1.Vantin (cefpodoxime proxetil) US prescribing information. Pharmacia &|1
04546|034|R|  Upjohn Company April, 2007.|1
04546|035|R|2.Saathoff N, Lode H, Neider K, Depperman KM, Borner K, Koeppe P.|2
04546|036|R|  Pharmacokinetics of cefpodoxime proxetil and interactions with an antacid|2
04546|037|R|  and an  H2 receptor antagonist. Antimicrob Agents Chemother 1992 Apr;|2
04546|038|R|  36(4):796-800.|2
04546|039|R|3.Hughes GS, Heald DL, Barker KB, Patel RK, Spillers CR, Watts KC, Batts DH,|2
04546|040|R|  Euler AR. The effects of gastric pH and food on the pharmacokinetics of a|2
04546|041|R|  new oral cephalosporin, cefpodoxime proxetil. Clin Pharmacol Ther 1989|2
04546|042|R|  Dec;46(6):674-85.|2
04547|001|T|MONOGRAPH TITLE:  NSAIDs; Salicylates/Minoxidil|
04547|002|B||
04547|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04547|004|L|take action as needed.|
04547|005|B||
04547|006|A|MECHANISM OF ACTION:  Oral minoxidil functions as a direct-acting peripheral|
04547|007|A|vasodilator, lowering elevated systolic and diastolic blood pressure by|
04547|008|A|reducing resistance in peripheral blood vessels.  This triggers a|
04547|009|A|compensatory increase in cardiac output and renin secretion and results in|
04547|010|A|sodium and water retention.  NSAIDs inhibit prostaglandin synthesis and also|
04547|011|A|result in sodium and water retention.(1,2)|
04547|012|B||
04547|013|E|CLINICAL EFFECTS:  The risk of heart failure may increase with oral|
04547|014|E|minoxidil and NSAIDs due to their combined effects on blood vessel dilation,|
04547|015|E|fluid retention, and altered sodium balance.  Minoxidil efficacy may be|
04547|016|E|compromised.(1,2)|
04547|017|B||
04547|018|P|PREDISPOSING FACTORS:  Higher doses of oral minoxidil have been associated|
04547|019|P|with serious adverse events, including hypotensive syncope, pericarditis,|
04547|020|P|pericardial effusion, and myocardial infarction.(1-5)|
04547|021|B||
04547|022|M|PATIENT MANAGEMENT:  Closely monitor body weight, fluid and electrolyte|
04547|023|M|balance, and blood pressure when using oral minoxidil and NSAIDs|
04547|024|M|concurrently.|
04547|025|M|   Minoxidil tablets should be co-administered with an appropriate diuretic|
04547|026|M|to prevent fluid retention and potential congestive heart failure.  A|
04547|027|M|high-ceiling (loop) diuretic is often necessary alongside vigilant|
04547|028|M|monitoring of body weight.  Without concurrent diuretic use, minoxidil may|
04547|029|M|lead to the retention of salt and water within a few days.(1,2)|
04547|030|B||
04547|031|D|DISCUSSION:  While the manufacturer of minoxidil does not provide specific|
04547|032|D|recommendations regarding NSAID co-administration, it emphasizes the|
04547|033|D|necessity of combining minoxidil with a beta-blocker to prevent tachycardia|
04547|034|D|and increased myocardial workload.  Additionally, concurrent use with a|
04547|035|D|diuretic is recommended to avert serious fluid accumulation and potential|
04547|036|D|congestive heart failure.|
04547|037|D|   NSAID labeling warns about fluid retention, edema, an elevated risk of|
04547|038|D|heart failure, and potential drug interactions with beta-blockers and|
04547|039|D|diuretics which can result in a blunting of the antihypertensive and|
04547|040|D|cardiovascular effects of these agents.(1-5)|
04547|041|B||
04547|042|R|REFERENCES:|
04547|043|B||
04547|044|R|1.Celebrex (celecoxib) US prescribing information. Pfizer Inc. May, 2019.|1
04547|045|R|2.Minoxidil US prescribing information. Actavis Pharma, Inc. December, 2021.|1
04547|046|R|3.Naprosyn (naproxen) US prescribing information. Atnahs Pharma May, 2021.|1
04547|047|R|4.Jimenez-Cauhe J, Pirmez R, Muller-Ramos P, Melo DF, Ortega-Quijano D,|2
04547|048|R|  Moreno-Arrones OM. Safety of Low-Dose Oral Minoxidil in Patients With|2
04547|049|R|  Hypertension and Arrhythmia: A  Multicenter Study of 264 Patients. Actas|2
04547|050|R|  Dermosifiliogr 2024 Jan;115(1):28-35.|2
04547|051|R|5.VanoGalvan S, Pirmez R, Hermosa-Gelbard A, Moreno-Arrones CM,|2
04547|052|R|  Saceda-Corralo D. Safety of low-dose oral minoxidil for hair loss: A|2
04547|053|R|  multicenter study of 1404  patients. J Am Acad Dermatol 2021 Jun;|2
04547|054|R|  84(6):1644-1651.|2
04548|001|T|MONOGRAPH TITLE:  Itraconazole/Selected Strong CYP3A4 Inducers|
04548|002|B||
04548|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04548|004|L|of severe adverse interaction.|
04548|005|B||
04548|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolism of|
04548|007|A|itraconazole via CYP3A4.(1)|
04548|008|B||
04548|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04548|010|E|decreased levels and effectiveness of itraconazole.(1)|
04548|011|B||
04548|012|P|PREDISPOSING FACTORS:  None determined.|
04548|013|B||
04548|014|M|PATIENT MANAGEMENT:  The US manufacturer of itraconazole states that|
04548|015|M|concurrent use with strong CYP3A4 inducers is not recommended two weeks|
04548|016|M|before and during itraconazole treatment.(1)|
04548|017|M|   Consider alternatives to itraconazole in patients receiving strong CYP3A4|
04548|018|M|inducers unless the benefits of therapy outweigh the risks.  If concurrent|
04548|019|M|therapy is necessary, monitor patients closely for decreased therapeutic|
04548|020|M|effects.|
04548|021|B||
04548|022|D|DISCUSSION:  Concurrent itraconazole (200 mg daily) with rifabutin (a CYP3A4|
04548|023|D|inducer) (300 mg daily) in six HIV-infected patients resulted in an|
04548|024|D|increased effect on rifabutin and a decrease in itraconazole's|
04548|025|D|area-under-curve (AUC) and concentration maximum (Cmax) by 70% and 75%,|
04548|026|D|respectively.(1)|
04548|027|D|   In a study in 18 subjects, concurrent efavirenz (a CYP3A4 inducer) (600|
04548|028|D|mg daily) decreased the Cmax, AUC, and minimum concentration (Cmin) of|
04548|029|D|itraconazole (200 mg twice daily) by 37%, 39%, and 44%, respectively.  The|
04548|030|D|Cmax, AUC, and Cmin of hydroxyitraconazole decreased by 35%, 37%, and 43%,|
04548|031|D|respectively.(2-4)|
04548|032|D|   Strong inducers of CYP3A4 include: apalutamide, enzalutamide, mitotane,|
04548|033|D|and St. John's wort.(5,6)|
04548|034|B||
04548|035|R|REFERENCES:|
04548|036|B||
04548|037|R|1.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
04548|038|R|  Products, L.P. February, 2024.|1
04548|039|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
04548|040|R|  Company November, 2023.|1
04548|041|R|3.Sustiva (efavirenz) Canadian prescribing information. Bristol-Myers Squibb|1
04548|042|R|  January 8, 2007.|1
04548|043|R|4.Sustiva (efavirenz) UK summary of product characteristics. Bristol-Myers|1
04548|044|R|  Squibb Pharmaceuticals Ltd January 26, 2007.|1
04548|045|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04548|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04548|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04548|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04548|049|R|  11/14/2017.|1
04548|050|R|6.This information is based on an extract from the Certara Drug Interaction|6
04548|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04549|001|T|MONOGRAPH TITLE:  Letermovir/Select OATP1B1-3 Inhibitors|
04549|002|B||
04549|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04549|004|L|take action as needed.|
04549|005|B||
04549|006|A|MECHANISM OF ACTION:  OATP1B1 and 1B3 inhibitors may decrease the hepatocyte|
04549|007|A|uptake and increase the plasma concentration of letermovir.(1)|
04549|008|B||
04549|009|E|CLINICAL EFFECTS:  Concurrent use of OATP1B1 and 1B3 inhibitors may result|
04549|010|E|in elevated levels of and side effects from letermovir, including diarrhea,|
04549|011|E|nausea, abdominal pain, and peripheral edema.(1)|
04549|012|B||
04549|013|P|PREDISPOSING FACTORS:  None determined.|
04549|014|B||
04549|015|M|PATIENT MANAGEMENT:  Concurrent use of letermovir with OATP1B1 and 1B3|
04549|016|M|inhibitors should be approached with caution. Monitor patients closely for|
04549|017|M|adverse reactions and consider dose modifications per prescribing|
04549|018|M|recommendations.(1)|
04549|019|B||
04549|020|D|DISCUSSION:  Letermovir is a substrate of OATP1B1 and 1B3. Co-administration|
04549|021|D|of letermovir with drugs that are inhibitors of OATP1B1 and 1B3 transporters|
04549|022|D|may result in increases in letermovir plasma concentrations.(1)|
04549|023|D|   OAT1B1 and 1B3 inhibitors include: belumosudil, enasidenib,|
04549|024|D|glecaprevir/pibrentasvir, paritaprevir, and vadadustat.(2-6)|
04549|025|B||
04549|026|R|REFERENCES:|
04549|027|B||
04549|028|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
04549|029|R|  2024.|1
04549|030|R|2.Idhifa (enasidenib) US prescribing information. Celgene Corporation|1
04549|031|R|  November, 2020.|1
04549|032|R|3.Mavyret (glecaprevir and pibrentasvir) US prescribing information. AbbVie|1
04549|033|R|  Inc. October, 2023.|1
04549|034|R|4.Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) US|1
04549|035|R|  prescribing information. AbbVie Inc. December, 2019.|1
04549|036|R|5.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
04549|037|R|  November, 2017.|1
04549|038|R|6.This information is based on an extract from the Certara Drug Interaction|6
04549|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04550|001|T|MONOGRAPH TITLE:  T Cell Immunotherapies/NSAIDs; Salicylates|
04550|002|B||
04550|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04550|004|L|take action as needed.|
04550|005|B||
04550|006|A|MECHANISM OF ACTION:  NSAIDs augment the immune system.  Concurrent use with|
04550|007|A|NSAIDs may interfere with the activity of CAR-T cell immunotherapies.(1)|
04550|008|B||
04550|009|E|CLINICAL EFFECTS:  NSAIDs may decrease the efficacy of CAR-T cell|
04550|010|E|immunotherapies.(1)|
04550|011|B||
04550|012|P|PREDISPOSING FACTORS:  None determined.|
04550|013|B||
04550|014|M|PATIENT MANAGEMENT:  NSAIDs should be used with caution with or after CAR-T|
04550|015|M|cell immunotherapy.(1)|
04550|016|B||
04550|017|D|DISCUSSION:  An in vitro study showed aspirin and celecoxib negatively|
04550|018|D|affected CD19.CAR-T cells through their effects on the induction of|
04550|019|D|apoptosis, reduction of activation, and impairment of proliferation.(1)|
04550|020|B||
04550|021|R|REFERENCE:|
04550|022|B||
04550|023|R|1.Yang M,  Wang L,  Ni M,  Neuber B,  Wang S,  Gong W,  Sauer T,  Schubert|5
04550|024|R|  ML,  Huckelhoven-Krauss A,  Xia R,  Ge J,  Kleist C,  Eckstein V,  Sellner|5
04550|025|R|  L,  Muller-Tidow C,  Dreger P,  Schmitt M,  Schmitt A. Dual effects of|5
04550|026|R|  cyclooxygenase inhibitors in combination with CD19.CAR-T cell|5
04550|027|R|  immunotherapy. Front Immunol 2021 May 26;12(670088):.|5
04551|001|T|MONOGRAPH TITLE:  Gepirone/Fluvoxamine|
04551|002|B||
04551|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04551|004|L|take action as needed.|
04551|005|B||
04551|006|A|MECHANISM OF ACTION:  Fluvoxamine is a moderate CYP3A4 inhibitor and may|
04551|007|A|inhibit the metabolism of gepirone.(1-2, 5-6)  Both fluvoxamine and gepirone|
04551|008|A|can increase serotonin effects, resulting in serotonin toxicity.|
04551|009|B||
04551|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04551|011|E|the levels of and effects from gepirone, including QTc prolongation, which|
04551|012|E|may result in potentially life-threatening cardiac arrhythmias, including|
04551|013|E|torsades de pointes (TdP).(1,2)|
04551|014|E|   Concurrent use of fluvoxamine and gepirone may also result in serotonin|
04551|015|E|syndrome. Symptoms of serotonin syndrome may include tremor, agitation,|
04551|016|E|diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle|
04551|017|E|rigidity.(1-3)|
04551|018|B||
04551|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04551|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04551|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04551|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04551|023|P|female gender, or advanced age.(4)|
04551|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04551|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04551|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04551|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04551|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04551|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04551|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04551|031|P|   Serotonin syndrome risk is dose-related.  Higher systemic concentrations|
04551|032|P|of either drug would be predicted to increase risk for serotonin|
04551|033|P|toxicity.(3)|
04551|034|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04551|035|P|concentrations may also increase risk for serotonin syndrome.(3)|
04551|036|B||
04551|037|M|PATIENT MANAGEMENT:  If gepirone is used concurrently with a moderate CYP3A4|
04551|038|M|inhibitor, reduce the dose of gepirone by 50%.(1)|
04551|039|M|   Monitor for prolongation of the QTc interval.(1)  When concurrent therapy|
04551|040|M|is warranted: consider obtaining serum calcium, magnesium, and potassium|
04551|041|M|levels and monitoring EKG at baseline and regular intervals. Correct any|
04551|042|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04551|043|M|heartbeat, dizziness, or fainting.|
04551|044|M|   If QTcF is > 450 msec at baseline, do not initiate gepirone.  If QTc|
04551|045|M|increases to > 450 msec during treatment, monitor ECGs more frequently and|
04551|046|M|do not increase the dose of gepirone.(1)|
04551|047|M|   If concurrent use of gepirone with other serotonergic agents is|
04551|048|M|clinically warranted, counsel the patient on the increased risk of serotonin|
04551|049|M|syndrome and monitor for symptoms.  If symptoms of serotonin syndrome|
04551|050|M|develop, discontinue gepirone and/or the other serotonergic agents|
04551|051|M|immediately and initiate supportive measures.(1)|
04551|052|B||
04551|053|D|DISCUSSION:  In a study, verapamil (80 mg 3 times daily), a moderate CYP3A4|
04551|054|D|inhibitor, increased both the maximum concentration (Cmax) and|
04551|055|D|area-under-curve (AUC) of gepirone 18.2 mg by about 2.75-fold.(1)|
04551|056|D|   Gepirone and its 3'-OH metabolite act as agonists at 5HT1A receptors.|
04551|057|D|Use with other agents that also increase serotonin in the body must be|
04551|058|D|undertaken with caution and monitored closely due to the risk of serotonin|
04551|059|D|syndrome.(1)|
04551|060|B||
04551|061|R|REFERENCES:|
04551|062|B||
04551|063|R|1.Exxua (gepirone) US prescribing information. Fabre-Kramer Pharmaceuticals,|1
04551|064|R|  Inc. September, 2023.|1
04551|065|R|2.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
04551|066|R|  Pharmaceuticals, Inc. August, 2023.|1
04551|067|R|3.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04551|068|R|  352(11):1112-20.|6
04551|069|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04551|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04551|071|R|  settings: a scientific statement from the American Heart Association and|6
04551|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04551|073|R|  2;55(9):934-47.|6
04551|074|R|5.This information is based on an extract from the Certara Drug Interaction|6
04551|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04551|076|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04551|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04551|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04551|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04551|080|R|  11/14/2017.|1
04552|001|T|MONOGRAPH TITLE:  Tizanidine/Strong CYP1A2 Inhibitors|
04552|002|B||
04552|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04552|004|L|is contraindicated and generally should not be dispensed or administered to|
04552|005|L|the same patient.|
04552|006|B||
04552|007|A|MECHANISM OF ACTION:  Strong CYP1A2 inhibitors may inhibit the metabolism of|
04552|008|A|tizanidine.|
04552|009|B||
04552|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP1A2 inhibitors may result in|
04552|011|E|elevated levels of and effects from tizanidine, including hypotension|
04552|012|E|(including decreases in both systolic and diastolic pressure), bradycardia,|
04552|013|E|drowsiness, sedation, and decreased psychomotor function.(1-5)|
04552|014|B||
04552|015|P|PREDISPOSING FACTORS:  The risk of anticholinergic toxicities including|
04552|016|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
04552|017|P|patients using more than one medicine with anticholinergic properties.(6)|
04552|018|B||
04552|019|M|PATIENT MANAGEMENT:  The US manufacturer for tizanidine states concurrent|
04552|020|M|use with strong CYP1A2 inhibitors is contraindicated.(1,3)|
04552|021|B||
04552|022|D|DISCUSSION:  In a double-blind, randomized, cross-over study in 10 healthy|
04552|023|D|subjects, pretreatment with ciprofloxacin (500 mg twice daily) for 3 days|
04552|024|D|increased the tizanidine area-under-curve (AUC) and maximum concentration|
04552|025|D|(Cmax) by 10-fold (range 6-fold to 24-fold) and 7-fold (range 4-fold to|
04552|026|D|21-fold), respectively, when compared to administration with placebo.|
04552|027|D|During the ciprofloxacin phase, tizanidine pharmacodynamic effects were also|
04552|028|D|increased; the mean decreases in systolic and diastolic blood pressure were|
04552|029|D|35 mmHg and 24 mmHg, respectively, and there were significant increases in|
04552|030|D|sedation as shown by the Digit Symbol Substitution Test, subjective drug|
04552|031|D|effect, and subjective drowsiness.  During the placebo phase, the mean|
04552|032|D|decreases in systolic and diastolic blood pressure were 15 mmHg and 11mm Hg,|
04552|033|D|respectively.(7)|
04552|034|D|   In a case report, a 45 year old woman on maintenance tizanidine therapy|
04552|035|D|was given ciprofloxacin which reduced her systolic and diastolic blood|
04552|036|D|pressure 22 and 14 mmHg, respectively, on the day of ciprofloxacin|
04552|037|D|administration. On day three the patient's blood pressure was reported low|
04552|038|D|at 92/54 mmHg. On days 5 and 6, her body temperature and urine volume|
04552|039|D|decreased 1.1 C and 496 mL/dL, respectively.  The patient's symptoms|
04552|040|D|improved immediately after ciprofloxacin was discontinued.(8)|
04552|041|D|   A retrospective study looked at adverse reaction case reports in the WHO|
04552|042|D|pharmacovigilance database with concurrent tizanidine and ciprofloxacin|
04552|043|D|administration and found that 57.1% of the adverse reactions were qualified|
04552|044|D|as serious because of hospitalization.  The most frequently observed|
04552|045|D|reactions included hypotension, somnolence, fatigue, and asthenia.(9)|
04552|046|D|   A retrospective cohort study assessed the impact of concurrent|
04552|047|D|administration of tizanidine and ciprofloxacin on outpatient physician|
04552|048|D|visits and hospitalizations and found a significant association between|
04552|049|D|exposure to tizanidine and ciprofloxacin and outpatient physician visits at|
04552|050|D|14 and 30 days (odds ratio (OR) = 1.61, (95% CI = 1.17-2.24)(p = 0.004); OR|
04552|051|D|= 1.59 (95% CI = 1.1-2.34)(p = 0.016)) and a trend for increased risk of|
04552|052|D|hospitalization for all evaluated time periods (OR = 1.68 (95% CI =|
04552|053|D|0.84-3.17), OR = 1.52 (95% CI = 0.63-3.33), OR = 2.19 (95% CI =|
04552|054|D|0.88-5.02).(10)|
04552|055|D|   Following multiple doses of enasidenib 100 mg, the AUC and Cmax of a|
04552|056|D|single dose of caffeine 100 mg (a sensitive CYP1A2 substrate) increased by|
04552|057|D| 655% and 18%, respectively.(3)|
04552|058|D|   In a study in 10 healthy subjects, pretreatment with fluvoxamine (100 mg|
04552|059|D|daily for 4 days) increased the AUC and Cmax of a single dose of tizanidine|
04552|060|D|(4 mg) by 33-fold (range: 14-fold to 103-fold) and by 12-fold (range 5-fold|
04552|061|D|to 33-fold), respectively.  Tizanidine half-life increased from 1.5 hours to|
04552|062|D|4.3 hours.  The mean decrease in systolic blood pressure was 35 mmHg.  The|
04552|063|D|mean decrease in diastolic blood pressure was 20 mmHg.  Heart rate decreased|
04552|064|D|by 4 beats/minute.  There were also significant effects on the Digit|
04552|065|D|Substitution Test, subjective drug effects, and drowsiness.(1,11)|
04552|066|D|   There is one case report of an interaction between tizanidine and|
04552|067|D|fluvoxamine.(12)|
04552|068|D|   In a study in human liver microsomes, fluvoxamine inhibited the|
04552|069|D|metabolism of tizanidine.(13)|
04552|070|D|   Concomitant use of viloxazine significantly increases the total exposure,|
04552|071|D|but not peak exposure, of sensitive CYP1A2 substrates, which may increase|
04552|072|D|the risk of adverse reactions associated with these CYP1A2 substrates.   In|
04552|073|D|a study, viloxazine increased the AUC of caffeine by almost 6-fold.(5)|
04552|074|D|   Strong CYP1A2 inhibitors linked to this monograph include: angelica root|
04552|075|D|(angelica dahurica radix), ciprofloxacin, enasidenib, enoxacin, fluvoxamine,|
04552|076|D|rofecoxib, and viloxazine.(3)|
04552|077|D|   One or more of the drug pairs linked to this monograph have been included|
04552|078|D|in a list of interactions that should be considered "high-priority" for|
04552|079|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
04552|080|D|vetted by an expert panel commissioned by the U.S. Office of the National|
04552|081|D|Coordinator (ONC) for Health Information Technology.|
04552|082|B||
04552|083|R|REFERENCES:|
04552|084|B||
04552|085|R|1.Zanaflex (tizanidine hydrochloride) US prescribing information. Legacy|1
04552|086|R|  Pharma Inc. November 22, 2024.|1
04552|087|R|2.Cipro (ciprofloxacin hydrochloride) US prescribing information. Bayer|1
04552|088|R|  Corporation March, 2022.|1
04552|089|R|3.Idhifa (enasidenib) US prescribing information. Celgene Corporation|1
04552|090|R|  November, 2020.|1
04552|091|R|4.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
04552|092|R|  Pharmaceuticals, Inc. August, 2023.|1
04552|093|R|5.Qelbree (viloxazine) US prescribing information. Catalent Pharma|1
04552|094|R|  Solutions, LLC April, 2021.|1
04552|095|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04552|096|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04552|097|R|  Soc 2023 Jul;71(7):2052-2081.|6
04552|098|R|7.Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ. Ciprofloxacin greatly|2
04552|099|R|  increases concentrations and hypotensive effect of tizanidine by|2
04552|100|R|  inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin|2
04552|101|R|  Pharmacol Ther 2004 Dec;76(6):598-606.|2
04552|102|R|8.Momo K, Homma M, Kohda Y, Ohkoshi N, Yoshizawa T, Tamaoka A. Drug|3
04552|103|R|  interaction of tizanidine and ciprofloxacin: case report. Clin Pharmacol|3
04552|104|R|  Ther 2006 Dec;80(6):717-9.|3
04552|105|R|9.Rudolph A, Dahmke H, Kupferschmidt H, Burden A, Weiler S. Coadministration|6
04552|106|R|  of tizanidine and ciprofloxacin: a retrospective analysis of the WHO|6
04552|107|R|  pharmacovigilance database. Eur J Clin Pharmacol 2021 Jun;77(6):895-902.|6
04552|108|R|10.Jodicke AM, Curkovic I, Zellweger U, Tomka IT, Neuer T, Kullak-Ublick GA,|6
04552|109|R|   Roos M, Egbring M. Analysis of Drug-Drug Interactions in Swiss Claims|6
04552|110|R|   Data Using Tizanidine and Ciprofloxacin as a Prototypical Contraindicated|6
04552|111|R|   Combination. Ann Pharmacother 2018 Oct;52(10):983-991.|6
04552|112|R|11.Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine|2
04552|113|R|   drastically increases concentrations and effects of tizanidine: a|2
04552|114|R|   potentially hazardous interaction. Clin Pharmacol Ther 2004 Apr;|2
04552|115|R|   75(4):331-41.|2
04552|116|R|12.Momo K, Doki K, Hosono H, Homma M, Kohda Y. Drug interaction of|3
04552|117|R|   tizanidine and fluvoxamine. Clin Pharmacol Ther 2004 Nov;76(5):509-10.|3
04552|118|R|13.Granfors MT, Backman JT, Laitila J, Neuvonen PJ. Tizanidine is mainly|5
04552|119|R|   metabolized by cytochrome p450 1A2 in vitro. Br J Clin Pharmacol 2004|5
04552|120|R|   Mar;57(3):349-53.|5
04552|121|R|14.This information is based on an extract from the Certara Drug Interaction|6
04552|122|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04552|123|R|15.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
04552|124|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
04552|125|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
04552|126|R|   19(5):735-43.|6
04553|001|T|MONOGRAPH TITLE:  Vincristine/P-glycoprotein (P-gp) Inducers|
04553|002|B||
04553|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04553|004|L|of severe adverse interaction.|
04553|005|B||
04553|006|A|MECHANISM OF ACTION:  Inducers of P-glycoprotein (P-gp) may reduce systemic|
04553|007|A|exposure to vincristine.(1)|
04553|008|B||
04553|009|E|CLINICAL EFFECTS:  Concurrent or recent use of P-gp inducers may result in|
04553|010|E|decreased effectiveness of vincristine.(1)|
04553|011|B||
04553|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04553|013|P|of the inducer for longer than 1-2 weeks.|
04553|014|B||
04553|015|M|PATIENT MANAGEMENT:  The US manufacturer of vincristine states that|
04553|016|M|concurrent use of P-gp inducers should be avoided.(1) Consider the use of|
04553|017|M|agents with no or minimal induction potential if possible. Monitor patients|
04553|018|M|for decreased response to therapy.|
04553|019|B||
04553|020|D|DISCUSSION:  Vincristine is transported by P-gp and inducers of this|
04553|021|D|transporter are expected to decrease levels of vincristine.(1)|
04553|022|D|   Inducers of P-gp include linked to this monograph include: efavirenz,|
04553|023|D|green tea, and lorlatinib.(2,3)|
04553|024|B||
04553|025|R|REFERENCES:|
04553|026|B||
04553|027|R|1.Marqibo (vincristine sulfate) US prescribing information. Talon|1
04553|028|R|  Therapeutics, Inc July, 2020.|1
04553|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04553|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04553|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04553|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04553|033|R|  11/14/2017.|1
04553|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04553|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04554|001|T|MONOGRAPH TITLE:  Vincristine/P-glycoprotein (P-gp) Inhibitors|
04554|002|B||
04554|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04554|004|L|of severe adverse interaction.|
04554|005|B||
04554|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors may inhibit cellular|
04554|007|A|efflux of vincristine.(1)|
04554|008|B||
04554|009|E|CLINICAL EFFECTS:  Concurrent administration of a P-gp inhibitor may result|
04554|010|E|in elevated levels of and toxicity from vincristine including|
04554|011|E|myelosuppression, neurologic toxicity, tumor lysis syndrome, hepatotoxicity,|
04554|012|E|constipation, or bowel obstruction.(1)|
04554|013|B||
04554|014|P|PREDISPOSING FACTORS:  None determined.|
04554|015|B||
04554|016|M|PATIENT MANAGEMENT:  Avoid the use of P-gp inhibitors in patients undergoing|
04554|017|M|therapy with vincristine.(1) Consider alternatives with no or minimal P-gp|
04554|018|M|inhibition.|
04554|019|M|   The manufacturer of vincristine states that concomitant use of P-gp|
04554|020|M|inhibitors should be avoided.(1)|
04554|021|M|   The manufacturer of lopinavir/ritonavir states that patients who develop|
04554|022|M|significant hematological or gastrointestinal toxicity on concomitant|
04554|023|M|vincristine should temporarily hold lopinavir/ritonavir, or use alternative|
04554|024|M|medications that do not inhibit CYP3A4 or P-gp.(2)|
04554|025|B||
04554|026|D|DISCUSSION:  Vincristine is a substrate of P-gp. Inhibitors of P-gp may|
04554|027|D|increase toxicity of vincristine.(1)|
04554|028|D|   There are several case reports of neurotoxicity with concurrent|
04554|029|D|administration of vincristine and itraconazole.(3-5)|
04554|030|D|   There is a case report of neurotoxicity with concurrent administration of|
04554|031|D|lopinavir-ritonavir with vincristine.(6)|
04554|032|D|   In a prospective study in 22 children receiving various chemotherapy with|
04554|033|D|prophylactic itraconazole oral solution (0.5 ml/kg per day), two children|
04554|034|D|receiving vincristine developed non-alcoholic steatohepatitis (NASH) and one|
04554|035|D|child developed syndrome of inappropriate anti-diuretic hormone secretion|
04554|036|D|(SIADH).(7)|
04554|037|D|   Inhibitors of P-gp linked to this monograph include:  abrocitinib,|
04554|038|D|amiodarone, Asian ginseng (Panax ginseng), asunaprevir, azithromycin,|
04554|039|D|belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan,|
04554|040|D|daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, elagolix,|
04554|041|D|eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo|
04554|042|D|biloba, glecaprevir and pibrentasvir, imlunestrant, isavuconazonium,|
04554|043|D|ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum),|
04554|044|D|neratinib, osimertinib, pirtobrutinib, propafenone, quercetin, quinidine,|
04554|045|D|ranolazine, rolapitant, Schisandra chinensis, selpercatinib, sofosbuvir,|
04554|046|D|sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib, venetoclax,|
04554|047|D|verapamil, vilazodone, vimseltinib, and voclosporin.(8,9)|
04554|048|B||
04554|049|R|REFERENCES:|
04554|050|B||
04554|051|R|1.Marqibo (vincristine sulfate) US prescribing information. Talon|1
04554|052|R|  Therapeutics, Inc July, 2020.|1
04554|053|R|2.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04554|054|R|  Laboratories December, 2019.|1
04554|055|R|3.Takahashi N, Kameoka Y, Yamanaka Y, Ubukawa K, Saito K, Fujishima M,|3
04554|056|R|  Fujishima N, Saito H, Hirokawa M, Scott SA, Sawada K. Itraconazole oral|3
04554|057|R|  solution enhanced vincristine neurotoxicity in five patients with|3
04554|058|R|  malignant lymphoma. Intern Med 2008;47(7):651-3.|3
04554|059|R|4.Pana ZD, Roilides E. Risk of azole-enhanced vincristine neurotoxicity in|6
04554|060|R|  pediatric patients with hematological malignancies: old problem - new|6
04554|061|R|  dilemma. Pediatr Blood Cancer 2011 Jul 15;57(1):30-5.|6
04554|062|R|5.Murphy JA, Ross LM, Gibson BE. Vincristine toxicity in five children with|3
04554|063|R|  acute lymphoblastic leukaemia. Lancet 1995 Aug 12;346(8972):443.|3
04554|064|R|6.Leveque D, Santucci R, Pavillet J, Herbrecht R, Bergerat JP. Paralytic|3
04554|065|R|  ileus possibly associated with interaction between ritonavir/lopinavir|3
04554|066|R|  and vincristine. Pharm World Sci 2009 Dec;31(6):619-21.|3
04554|067|R|7.Kobayashi R, Suzuki D, Yasuda K, Kobayashi K. Itraconazole for invasive|2
04554|068|R|  fungal infection with pediatric malignancies. Pediatr Int 2010 Oct;|2
04554|069|R|  52(5):707-10.|2
04554|070|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
04554|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04554|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04554|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04554|074|R|  11/14/2017.|1
04554|075|R|9.This information is based on an extract from the Certara Drug Interaction|6
04554|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04555|001|T|MONOGRAPH TITLE:  Lemborexant/Strong and Moderate CYP3A4 Inducers|
04555|002|B||
04555|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04555|004|L|of severe adverse interaction.|
04555|005|B||
04555|006|A|MECHANISM OF ACTION:  Lemborexant is a substrate of CYP3A4.  Strong or|
04555|007|A|moderate inducers of CYP3A4 may induce the metabolism of lemborexant.(1)|
04555|008|B||
04555|009|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
04555|010|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
04555|011|E|lemborexant.(1)|
04555|012|B||
04555|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04555|014|P|of the inducer for longer than 1-2 weeks.|
04555|015|B||
04555|016|M|PATIENT MANAGEMENT:  The manufacturer of lemborexant states that concurrent|
04555|017|M|use with strong or moderate CYP3A4 inducers should be avoided.(1)|
04555|018|B||
04555|019|D|DISCUSSION:  A pharmacokinetic model predicted that co-administration of|
04555|020|D|rifampin, a strong CYP3A4 inducer, would decrease the AUC of lemborexant by|
04555|021|D|90%.(1)|
04555|022|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04555|023|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04555|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04555|025|D|rifapentine, and St. John's wort.|
04555|026|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04555|027|D|dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib,|
04555|028|D|mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib,|
04555|029|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and|
04555|030|D|tovorafenib.(2,3)|
04555|031|B||
04555|032|R|REFERENCES:|
04555|033|B||
04555|034|R|1.Dayvigo (lemborexant) US prescribing information. Eisai Inc. March, 2022.|1
04555|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04555|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04555|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04555|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04555|039|R|  11/14/2017.|1
04555|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04555|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04556|001|T|MONOGRAPH TITLE:  Lemborexant/Efavirenz|
04556|002|B||
04556|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04556|004|L|of severe adverse interaction.|
04556|005|B||
04556|006|A|MECHANISM OF ACTION:  Lemborexant is a substrate of CYP3A4.  Efavirenz is a|
04556|007|A|moderate inducer of CYP3A4 and may increase the metabolism of|
04556|008|A|lemborexant.(1,2)|
04556|009|A|   Efavirenz is a substrate of CYP2B6. Lemborexant is an inducer of CYP2B6|
04556|010|A|and may increase the metabolism of efavirenz.(1,2)|
04556|011|B||
04556|012|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
04556|013|E|effectiveness of both lemborexant and efavirenz.(1,2)|
04556|014|B||
04556|015|P|PREDISPOSING FACTORS:  None determined.|
04556|016|B||
04556|017|M|PATIENT MANAGEMENT:  The manufacturer of lemborexant states that concurrent|
04556|018|M|use with moderate CYP3A4 inducers should be avoided.(1)|
04556|019|B||
04556|020|D|DISCUSSION:  A pharmacokinetic model predicted that co-administration of|
04556|021|D|rifampin, a strong CYP3A4 inducer, would decrease the AUC of lemborexant by|
04556|022|D|90%.(1)|
04556|023|D|   In a study, lemborexant (10 mg dose) decreased the concentration maximum|
04556|024|D|(Cmax) and area-under-curve (AUC) of a S-bupropion (a CYP2B6 substrate) by|
04556|025|D|49.9% and 45.5%, respectively.(1)|
04556|026|B||
04556|027|R|REFERENCES:|
04556|028|B||
04556|029|R|1.Dayvigo (lemborexant) US prescribing information. Eisai Inc. March, 2022.|1
04556|030|R|2.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
04556|031|R|  Company August, 2012.|1
04556|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04556|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04556|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04556|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04556|036|R|  11/14/2017.|1
04556|037|R|4.This information is based on an extract from the Certara Drug Interaction|6
04556|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04557|001|T|MONOGRAPH TITLE:  Efavirenz/Barbiturates|
04557|002|B||
04557|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04557|004|L|of severe adverse interaction.|
04557|005|B||
04557|006|A|MECHANISM OF ACTION:  Efavirenz may induce the metabolism of barbiturates|
04557|007|A|via CYP2C19.  Barbiturates may induce the metabolism of efavirenz by|
04557|008|A|CYP3A4.(1-2)|
04557|009|B||
04557|010|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
04557|011|E|effectiveness of both efavirenz and phenobarbital.(1-2)|
04557|012|B||
04557|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04557|014|P|of the inducer for longer than 1-2 weeks.|
04557|015|B||
04557|016|M|PATIENT MANAGEMENT:  The US HIV guidelines state an alternative|
04557|017|M|antiretroviral or anticonvulsant should be considered.  If coadministration|
04557|018|M|is necessary, monitor anticonvulsant and efavirenz concentrations.(2)|
04557|019|B||
04557|020|D|DISCUSSION:  No specific interaction studies have been performed.|
04557|021|D|   In a case report, an HIV+ patient stable on phenytoin (another strong|
04557|022|D|CYP3A4 inducer) (200 mg twice daily) was started on efavirenz (800 mg once|
04557|023|D|daily) and emtricitabine/tenofovir (200/300 mg once daily).  Efavirenz|
04557|024|D|concentrations at Day 5 and 15 were undetectable.  Efavirenz concentrations|
04557|025|D|increased after increasing the efavirenz dose (600 mg twice daily) and|
04557|026|D|stopping phenytoin.(3)|
04557|027|D|   In another case report, a man stable on phenytoin (300 mg twice daily)|
04557|028|D|was started on efavirenz (600 mg once daily).  One week later efavirenz|
04557|029|D|concentration (340 ng/ml) was found to be below the target concentration of|
04557|030|D|1000 ng/ml.  The phenytoin dosage was rapidly tapered and efavirenz dosage|
04557|031|D|was increased (800 mg once daily).  Eighteen days after initiating|
04557|032|D|efavirenz, the efavirenz concentration was still reduced.  Phenytoin|
04557|033|D|concentrations were also measured while receiving efavirenz (600 mg once|
04557|034|D|daily).  A gradual increase was seen over three weeks (11 mcg/ml to 23.5|
04557|035|D|mcg/ml).(4)|
04557|036|B||
04557|037|R|REFERENCES:|
04557|038|B||
04557|039|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
04557|040|R|  Company November, 2023.|1
04557|041|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04557|042|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04557|043|R|  HIV. Department of Health and Human Services. Available at|6
04557|044|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
04557|045|R|  new-guidelines June 13, 2021.|6
04557|046|R|3.Spak CW, Dhanireddy S, Kosel BW. Clinical interaction between efavirenz|3
04557|047|R|  and phenytoin. AIDS 2008 Jan 2;22(1):164-5.|3
04557|048|R|4.Robertson SM, Penzak SR, Lane J, Pau AK, Mican JM. A potentially|3
04557|049|R|  significant interaction between efavirenz and phenytoin: a case report and|3
04557|050|R|  review of the literature. Clin Infect Dis 2005 Jul 15;41(2):e15-8.|3
04558|001|T|MONOGRAPH TITLE:  Digoxin/Fostamatinib|
04558|002|B||
04558|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04558|004|L|take action as needed.|
04558|005|B||
04558|006|A|MECHANISM OF ACTION:  Fostamatinib may increase the absorption of digoxin by|
04558|007|A|inhibiting P-glycoprotein (P-gp).(1)|
04558|008|B||
04558|009|E|CLINICAL EFFECTS:  Concurrent use of fostamatinib may result in elevated|
04558|010|E|levels of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can|
04558|011|E|include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
04558|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
04558|013|E|disturbances, and arrhythmias.|
04558|014|B||
04558|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
04558|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
04558|017|P|risk of digoxin toxicity.|
04558|018|B||
04558|019|M|PATIENT MANAGEMENT:  Monitor digoxin concentrations before and during the|
04558|020|M|administration of fostamatinib. The manufacturer of digoxin recommends|
04558|021|M|decreasing the dose of digoxin by approximately 15-30% or by modifying the|
04558|022|M|dosing frequency to reduce digoxin concentrations.(2)|
04558|023|B||
04558|024|D|DISCUSSION:  A 100 mg twice daily dose of fostamatinib increased the|
04558|025|D|area-under-curve (AUC) and maximum concentration (Cmax) of digoxin (0.25 mg|
04558|026|D|once daily, sensitive P-gp substrate) by 37% and 70%, respectively.(1)|
04558|027|D|   In a clinical study, subjects received oral digoxin (loading dose of 0.25|
04558|028|D|mg twice daily on day 1 and 0.25 mg once daily on days 2 to 8) followed by|
04558|029|D|oral digoxin (0.25 mg once daily) with oral fostamatinib (100 mg twice|
04558|030|D|daily) on days 9 to 15.  Concurrent use with fostamatinib increased the Cmax|
04558|031|D|and AUC of digoxin by 1.7-fold and 1.27-fold, respectively.(3)|
04558|032|B||
04558|033|R|REFERENCES:|
04558|034|B||
04558|035|R|1.Tavalisse (fostamatinib) prescribing information. Rigel Pharmaceuticals,|1
04558|036|R|  Inc April 2018.|1
04558|037|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
04558|038|R|  Pharmaceuticals, Inc. August, 2018.|1
04558|039|R|3.Martin P, Gillen M, Millson D, Oliver S, Brealey C, Elsby R, Baluom M, Lau|2
04558|040|R|  D, Mant T. Effects of Fostamatinib on the Pharmacokinetics of Digoxin (a|2
04558|041|R|  P-Glycoprotein  Substrate): Results From in Vitro and Phase I Clinical|2
04558|042|R|  Studies. Clin Ther 2015 Dec 1;37(12):2811-22.|2
04559|001|T|MONOGRAPH TITLE:  Praziquantel/Moderate CYP3A4 Inducers|
04559|002|B||
04559|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04559|004|L|of severe adverse interaction.|
04559|005|B||
04559|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04559|007|A|of praziquantel.(1,2)|
04559|008|B||
04559|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate inducer of CYP3A4|
04559|010|E|may decrease the levels and effectiveness of praziquantel.(1,2)|
04559|011|B||
04559|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04559|013|P|of the inducer for longer than 1-2 weeks.|
04559|014|B||
04559|015|M|PATIENT MANAGEMENT:  The US manufacturer of praziquantel recommends avoiding|
04559|016|M|concomitant administration with moderate CYP3A4 inducers due to the risk of|
04559|017|M|a clinically significant decrease in praziquantel plasma concentration which|
04559|018|M|may lead to reduced therapeutic effect of praziquantel.(2)|
04559|019|M|   In patients receiving a clinically significant CYP3A4 inducer drug who|
04559|020|M|need immediate treatment for schistosomiasis, alternative agents for|
04559|021|M|schistosomiasis should be considered, where possible.  If praziquantel|
04559|022|M|treatment is necessary immediately, increase monitoring for reduced|
04559|023|M|anthelmintic efficacy associated with praziquantel,  when used in|
04559|024|M|combination with a moderate CYP3A4 inducer.(2)|
04559|025|M|   In patients receiving a clinically significant CYP3A4 inducer drug whose|
04559|026|M|treatment could be delayed, discontinue the CYP3A4 inducer drug at least 2|
04559|027|M|to 4 weeks before administration of praziquantel and, where possible,|
04559|028|M|consider starting alternative medications that are not CYP3A4 inducers.  The|
04559|029|M|CYP3A4 inducer drug can be restarted 1 day after completion of praziquantel|
04559|030|M|treatment, if needed.(2)|
04559|031|B||
04559|032|D|DISCUSSION:  In a crossover study, 20 healthy subjects ingested a single 40|
04559|033|D|mg/kg oral dose of praziquantel following pre-treatment with oral efavirenz|
04559|034|D|(400 mg daily for 13 days). Oral efavirenz reduced the mean praziquantel|
04559|035|D|area-under-curve (AUC) by 77% and maximum concentration (Cmax) by 79%, when|
04559|036|D|coadministered with praziquantel compared to praziquantel given alone.(2)|
04559|037|D|   Moderate CYP3A4 inducers include: belzutifan, bosentan, cenobamate,|
04559|038|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04559|039|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04559|040|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
04559|041|D|thioridazine, and tovorafenib.(3-4)|
04559|042|B||
04559|043|R|REFERENCES:|
04559|044|B||
04559|045|R|1.Sustiva (efavirenz) US prescribing information. Bristol-Myers Squibb|1
04559|046|R|  Company November, 2023.|1
04559|047|R|2.Biltricide (praziquantel) US prescribing information. Bayer HealthCare|1
04559|048|R|  Pharmaceuticals Inc. January, 2019.|1
04559|049|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04559|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04559|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04559|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04559|053|R|  11/14/2017.|1
04559|054|R|4.This information is based on an extract from the Certara Drug Interaction|6
04559|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04560|001|T|MONOGRAPH TITLE:  Clozapine/Marijuana Smoke|
04560|002|B||
04560|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04560|004|L|take action as needed.|
04560|005|B||
04560|006|A|MECHANISM OF ACTION:  Clozapine is primarily metabolized by CYP1A2 with|
04560|007|A|CYP3A4 playing a lesser role in clozapine clearance.(1)  Marijuana, when|
04560|008|A|consumed by smoking, has been shown to induce CYP1A2.(2)|
04560|009|B||
04560|010|E|CLINICAL EFFECTS:  Smoking marijuana may lower serum clozapine|
04560|011|E|concentrations resulting in reduced pharmacologic effects.|
04560|012|B||
04560|013|P|PREDISPOSING FACTORS:  Patients who smoke both marijuana and tobacco may|
04560|014|P|have larger increases in clozapine clearance.(3)|
04560|015|B||
04560|016|M|PATIENT MANAGEMENT:  Monitor clozapine efficacy closely and observe the|
04560|017|M|patient for a change in the therapeutic effects of clozapine if the patient|
04560|018|M|starts, alters, or discontinues marijuana use.  Monitor clozapine levels|
04560|019|M|closely and adjust clozapine dose accordingly.|
04560|020|B||
04560|021|D|DISCUSSION:  In a study in chronic marijuana users, users of both marijuana|
04560|022|D|and tobacco, and control subjects, theophylline (a CYP1A2 substrate)|
04560|023|D|clearance was 42% higher in marijuana users.  Theophylline clearance was|
04560|024|D|increased 79% in subjects who smoked both marijuana and tobacco.(3)|
04560|025|D|   Case reports have noted clinically significant changes in clozapine|
04560|026|D|levels in patient starting and stopping marijuana.(4,5)|
04560|027|B||
04560|028|R|REFERENCES:|
04560|029|B||
04560|030|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
04560|031|R|  Pharmaceuticals Corporation March, 2013.|1
04560|032|R|2.Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and|6
04560|033|R|  inducers of human drug metabolizing enzymes: a systematic review. Drug|6
04560|034|R|  Metab Rev 2014 Feb;46(1):86-95.|6
04560|035|R|3.Jusko WJ, Schentag JJ, Clark JH, Gardner M, Yurchak AM. Enhanced|2
04560|036|R|  biotransformation of theophylline in marihuana and tobacco smokers. Clin|2
04560|037|R|  Pharmacol Ther 1978 Oct;24(4):405-10.|2
04560|038|R|4.Zullino DF, Delessert D, Eap CB, Preisig M, Baumann P. Tobacco and|3
04560|039|R|  cannabis smoking cessation can lead to intoxication with clozapine or|3
04560|040|R|  olanzapine. Int Clin Psychopharmacol 2002 May;17(3):141-3.|3
04560|041|R|5.Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable|6
04560|042|R|  clozapine or olanzapine treatment. Ann Pharmacother 2010 Apr;44(4):727-32.|6
04561|001|T|MONOGRAPH TITLE:  Olanzapine/Marijuana Smoke|
04561|002|B||
04561|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04561|004|L|take action as needed.|
04561|005|B||
04561|006|A|MECHANISM OF ACTION:  Olanzapine is primarily metabolized by CYP1A2.(1)|
04561|007|A|Marijuana, when consumed by smoking, has been shown to induce CYP1A2.(2)|
04561|008|B||
04561|009|E|CLINICAL EFFECTS:  Smoking marijuana may lower serum olanzapine|
04561|010|E|concentrations resulting in reduced pharmacologic effects.|
04561|011|B||
04561|012|P|PREDISPOSING FACTORS:  Patients who smoke both marijuana and tobacco may|
04561|013|P|have larger increases in olanzapine clearance.(3)|
04561|014|B||
04561|015|M|PATIENT MANAGEMENT:  Monitor olanzapine efficacy closely and observe the|
04561|016|M|patient for a change in the therapeutic effects of olanzapine if the patient|
04561|017|M|starts, alters, or discontinues marijuana use.  Adjust olanzapine dose|
04561|018|M|accordingly.|
04561|019|B||
04561|020|D|DISCUSSION:  In a study in chronic marijuana users, users of both marijuana|
04561|021|D|and tobacco, and control subjects, theophylline (a CYP1A2 substrate)|
04561|022|D|clearance was 42% higher in marijuana users.  Theophylline clearance was|
04561|023|D|increased 79% in subjects who smoked both marijuana and tobacco.(3)|
04561|024|D|   Case reports have noted clinically significant changes in olanzapine|
04561|025|D|levels in patient starting and stopping marijuana.(4,5)|
04561|026|B||
04561|027|R|REFERENCES:|
04561|028|B||
04561|029|R|1.Zyprexa Relprevv (olanzapine ext-rel IM susp.) US prescribing information.|1
04561|030|R|  Eli Lilly and Company February, 2017.|1
04561|031|R|2.Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and|6
04561|032|R|  inducers of human drug metabolizing enzymes: a systematic review. Drug|6
04561|033|R|  Metab Rev 2014 Feb;46(1):86-95.|6
04561|034|R|3.Jusko WJ, Schentag JJ, Clark JH, Gardner M, Yurchak AM. Enhanced|2
04561|035|R|  biotransformation of theophylline in marihuana and tobacco smokers. Clin|2
04561|036|R|  Pharmacol Ther 1978 Oct;24(4):405-10.|2
04561|037|R|4.Zullino DF, Delessert D, Eap CB, Preisig M, Baumann P. Tobacco and|3
04561|038|R|  cannabis smoking cessation can lead to intoxication with clozapine or|3
04561|039|R|  olanzapine. Int Clin Psychopharmacol 2002 May;17(3):141-3.|3
04561|040|R|5.Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable|6
04561|041|R|  clozapine or olanzapine treatment. Ann Pharmacother 2010 Apr;44(4):727-32.|6
04562|001|T|MONOGRAPH TITLE:  Velpatasvir/Strong and Moderate CYP3A4 Inducers|
04562|002|B||
04562|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04562|004|L|of severe adverse interaction.|
04562|005|B||
04562|006|A|MECHANISM OF ACTION:  Strong or moderate CYP3A4 inducers may induce the|
04562|007|A|metabolism of velpatasvir via CYP3A4.(1,2)|
04562|008|B||
04562|009|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate CYP3A4 inducers may|
04562|010|E|result in decreased levels and effectiveness of velpatasvir.(1,2)|
04562|011|B||
04562|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04562|013|P|of the inducer for longer than 1-2 weeks.|
04562|014|B||
04562|015|M|PATIENT MANAGEMENT:  The concurrent use of velpatasvir with strong or|
04562|016|M|moderate CYP3A4 inducers is not recommended.(1,2)|
04562|017|B||
04562|018|D|DISCUSSION:  In an interaction study, efavirenz 600 mg daily (in combination|
04562|019|D|with emtricitabine-tenofovir DF) decreased velpatasvir concentration maximum|
04562|020|D|(Cmax) and area-under-curve (AUC) by 47% and 53%, respectively.(1)|
04562|021|D|   In an interaction study, rifampin 600 mg daily decreased velpatasvir Cmax|
04562|022|D|and AUC by 71% and 82%, respectively.(1)|
04562|023|D|   Strong and moderate CYP3A4 inducers include: belzutifan, bosentan,|
04562|024|D|cenobamate, dabrafenib, elagolix, enzalutamide, ivosidenib, lesinurad,|
04562|025|D|lumacaftor, mavacamten, methimazole, mitapivat, mitotane, modafinil,|
04562|026|D|nafcillin, pacritinib, pexidartinib, sotorasib, telotristat, thioridazine,|
04562|027|D|and tovorafenib.(3)|
04562|028|B||
04562|029|R|REFERENCES:|
04562|030|B||
04562|031|R|1.Epclusa (sofosbuvir and velpatasvir) US prescribing information. Gilead|1
04562|032|R|  Sciences, Inc. April, 2022.|1
04562|033|R|2.Vosevi (sofosbuvir/velpatasvir/voxilaprevir) US prescribing information.|1
04562|034|R|  Gilead Sciences, Inc. September, 2019.|1
04562|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04562|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04563|001|T|MONOGRAPH TITLE:  Lifileucel/Anticoagulants|
04563|002|B||
04563|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04563|004|L|take action as needed.|
04563|005|B||
04563|006|A|MECHANISM OF ACTION:  Internal organ hemorrhage, including intraabdominal|
04563|007|A|and intracranial hemorrhage, has been reported in the presence of persistent|
04563|008|A|or repeated thrombocytopenia following treatment with lifileucel.(1)|
04563|009|B||
04563|010|E|CLINICAL EFFECTS:  Concurrent use or recent therapy with lifileucel and an|
04563|011|E|anticoagulant may increase the risk of life-threatening hemorrhage,|
04563|012|E|including intraabdominal and intracranial hemorrhage.(1)|
04563|013|B||
04563|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04563|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04563|016|B||
04563|017|M|PATIENT MANAGEMENT:  The US manufacturer states patients with persistent or|
04563|018|M|repeated thrombocytopenia after receiving lifileucel should not use|
04563|019|M|anticoagulants.  If anticoagulation therapy is warranted, close monitoring|
04563|020|M|of patients must take place.(1)|
04563|021|M|   The US manufacturer recommends withholding or discontinuing lifileucel if|
04563|022|M|internal organ hemorrhage is indicated, or patient is ineligible for IL-2|
04563|023|M|(aldesleukin) infusion.(1)|
04563|024|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04563|025|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04563|026|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04563|027|M|patients with any symptoms.|
04563|028|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
04563|029|M|to monitor efficacy and safety of anticoagulation.|
04563|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04563|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04563|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04563|033|M|and/or swelling.|
04563|034|B||
04563|035|D|DISCUSSION:  In the open-label single-arm study of 156 adult patients, two|
04563|036|D|cases of internal organ hemorrhage (abdominal hemorrhage and intracranial|
04563|037|D|hemorrhage) leading to death were reported.(1)|
04563|038|D|   The incidence of grade 3 or 4 laboratory abnormalities occurring in|
04563|039|D|melanoma patients following treatment with lifileucel included|
04563|040|D|thrombocytopenia (78.2%), neutropenia (69.2%) and anemia (58.3%). Prolonged|
04563|041|D|thrombocytopenia occurred in 30.1% of patients.(1)|
04563|042|B||
04563|043|R|REFERENCE:|
04563|044|B||
04563|045|R|1.Amtagvi (lifileucel) US prescribing information. Iovance Biotherapeutics,|1
04563|046|R|  Inc. February, 2024.|1
04564|001|T|MONOGRAPH TITLE:  Clozapine/Bulk Forming Laxatives|
04564|002|B||
04564|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04564|004|L|take action as needed.|
04564|005|B||
04564|006|A|MECHANISM OF ACTION:  Clozapine has potent anticholinergic properties and|
04564|007|A|inhibits serotonin receptors, including 5-HT3.(1-4)  Both of these|
04564|008|A|properties may cause inhibition of gastrointestinal (GI) smooth muscle|
04564|009|A|contraction, resulting in decreased peristalsis.(3,4)|
04564|010|A|   If fluid intake is inadequate, bulk forming laxatives can increase the|
04564|011|A|risk of gastrointestinal obstruction.(1-6)|
04564|012|B||
04564|013|E|CLINICAL EFFECTS:  Concurrent use of clozapine and bulk forming laxatives|
04564|014|E|with inadequate fluid intake may increase the risk of constipation (common)|
04564|015|E|and serious bowel complications (uncommon), including complete bowel|
04564|016|E|obstruction, fecal impaction, paralytic ileus and intestinal ischemia or|
04564|017|E|infarction.(1-6)|
04564|018|B||
04564|019|P|PREDISPOSING FACTORS:  The risk for serious bowel complications is higher|
04564|020|P|with increasing age, higher frequency of constipation, and in patients on|
04564|021|P|higher doses of clozapine or multiple anticholinergic agents.(1,5)|
04564|022|B||
04564|023|M|PATIENT MANAGEMENT:  Concurrent use of bulk forming laxatives with clozapine|
04564|024|M|may be used with caution in patients who can maintain adequate fluid intake.|
04564|025|M|Evaluate the patient's bowel function regularly.|
04564|026|M|   If patient is unable to maintain adequate fluid intake and use bulk|
04564|027|M|forming laxatives as prescribed, avoid the use of bulk forming laxatives|
04564|028|M|with clozapine.(1-6)|
04564|029|M|   Monitor for symptoms of constipation and GI hypomotility, including|
04564|030|M|having bowel movements less than three times weekly or less than usual,|
04564|031|M|difficulty having a bowel movement or passing gas, nausea, vomiting, and|
04564|032|M|abdominal pain or distention.(2)|
04564|033|M|   Consider a prophylactic laxative in those with a history of constipation|
04564|034|M|or bowel obstruction.(2)  Review patient medication list for anticholinergic|
04564|035|M|agents which may have additive effects on decreased GI motility.  When|
04564|036|M|possible, decrease the dosage or number of prescribed anticholinergic|
04564|037|M|agents, particularly in the elderly.|
04564|038|M|   Counsel the patient about the importance of maintaining adequate|
04564|039|M|hydration.  Encourage regular exercise and eating a high-fiber diet.(2)|
04564|040|B||
04564|041|D|DISCUSSION:  The concurrent use of clozapine and bulk forming laxatives has|
04564|042|D|not been studied.  Use of bulk forming laxatives with inadequate fluid|
04564|043|D|intake has been associated with gastrointestinal obstruction.|
04564|044|B||
04564|045|R|REFERENCES:|
04564|046|B||
04564|047|R|1.Clozaril (clozapine tablets) US prescribing information. Novartis|1
04564|048|R|  Pharmaceuticals Corporation April, 2020.|1
04564|049|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA|6
04564|050|R|  strengthens warning that untreated constipation caused by schizophrenia|6
04564|051|R|  medicine clozapine (Clozaril) can lead to serious bowel problems.|6
04564|052|R|  Available at:|6
04564|053|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-strengthens-war|6
04564|054|R|  ning-untreated-constipation-caused-schizophrenia-medicine-clozapine-clozar|6
04564|055|R|  il-can February 18, 2020.|6
04564|056|R|3.Peyriere H, Roux C, Ferard C, Deleau N, Kreft-Jais C, Hillaire-Buys D,|6
04564|057|R|  Boulenger JP, Blayac JP. Antipsychotics-induced ischaemic colitis and|6
04564|058|R|  gastrointestinal necrosis: a review  of the French pharmacovigilance|6
04564|059|R|  database. Pharmacoepidemiol Drug Saf 2009 Oct;18(10):948-55.|6
04564|060|R|4.Hibbard KR, Propst A, Frank DE, Wyse J. Fatalities associated with|3
04564|061|R|  clozapine-related constipation and bowel obstruction:  a literature review|3
04564|062|R|  and two case reports. Psychosomatics 2009 Jul-Aug;50(4):416-9.|3
04564|063|R|5.Nielsen J, Meyer JM. Risk factors for ileus in patients with|2
04564|064|R|  schizophrenia. Schizophr Bull 2012 May;38(3):592-8.|2
04564|065|R|6.Chen HK, Hsieh CJ. Risk of gastrointestinal Hypomotility in schizophrenia|2
04564|066|R|  and schizoaffective disorder treated with antipsychotics: A retrospective|2
04564|067|R|  cohort study. Schizophr Res 2018 May;195:237-244.|2
04566|001|T|MONOGRAPH TITLE:  Selected Azole Antifungal CYP3A4 Substrates/Enasidenib|
04566|002|B||
04566|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04566|004|L|of severe adverse interaction.|
04566|005|B||
04566|006|A|MECHANISM OF ACTION:  Enasidenib is a weak CYP3A4 inducer and may induce the|
04566|007|A|metabolism of azole antifungal agents that are CYP3A4 substrates.(1-7)|
04566|008|B||
04566|009|E|CLINICAL EFFECTS:  The concurrent use of enasidenib, a weak CYP3A4 inducer,|
04566|010|E|with azole antifungal agents that are CYP3A4 substrates may result in|
04566|011|E|reduced levels of the azole antifungal and therapeutic failure.|
04566|012|B||
04566|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04566|014|P|of the inducer for longer than 1-2 weeks.|
04566|015|B||
04566|016|M|PATIENT MANAGEMENT:  Do not administer enasidenib with antifungal agents|
04566|017|M|that are substrates of CYP3A4.(1)|
04566|018|M|   Concurrent therapy should only be undertaken if benefits are considered|
04566|019|M|to outweigh risks.|
04566|020|M|   If concurrent therapy is necessary, observe the patient for a decrease in|
04566|021|M|the therapeutic effect of the antifungal agent.  It may be necessary to|
04566|022|M|increase the dose of the antifungal agent.(2-7)|
04566|023|B||
04566|024|D|DISCUSSION:  Intravenous midazolam (sensitive CYP3A4 substrate)|
04566|025|D|area-under-curve (AUC) and maximum concentration (Cmax) decreased by 43% and|
04566|026|D|23%, respectively, following concomitant use of multiple doses of enasidenib|
04566|027|D|100 mg.(1)|
04566|028|D|   Selected azole antifungals include: clotrimazole, econazole, fluconazole,|
04566|029|D|isavuconazonium, itraconazole, ketoconazole, miconazole, posaconazole, and|
04566|030|D|voriconazole.|
04566|031|B||
04566|032|R|REFERENCES:|
04566|033|B||
04566|034|R|1.Idhifa (enasidenib) US prescribing information. Celgene Corporation|1
04566|035|R|  November, 2020.|1
04566|036|R|2.Sporanox (itraconazole) US prescribing information. Janssen Pharmaceutica|1
04566|037|R|  Products, L.P. February, 2024.|1
04566|038|R|3.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
04566|039|R|  Pharmaceuticals February, 2014.|1
04566|040|R|4.Diflucan (fluconazole) US prescribing information. Pfizer Inc. February,|1
04566|041|R|  2024.|1
04566|042|R|5.Cresemba (isavuconazonium sulfate) US prescribing information. Astellas|1
04566|043|R|  Pharma US, Inc. May, 2021.|1
04566|044|R|6.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
04566|045|R|  January, 2022.|1
04566|046|R|7.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
04567|001|T|MONOGRAPH TITLE:  Ubrogepant/Encorafenib|
04567|002|B||
04567|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04567|004|L|of severe adverse interaction.|
04567|005|B||
04567|006|A|MECHANISM OF ACTION:  Encorafenib is a strong CYP3A4 inducer and a BCRP|
04567|007|A|inhibitor.(1)  Ubrogepant is a CYP3A4 and BCRP substrate.(2)  Encorafenib|
04567|008|A|may induce the metabolism and increase the absorption of ubrogepant.(1,2)|
04567|009|B||
04567|010|E|CLINICAL EFFECTS:  The net effect of this interaction is unknown.|
04567|011|E|Concurrent use of strong CYP3A4 inducers with ubrogepant may result in|
04567|012|E|decreased levels and effectiveness of ubrogepant while concurrent use of|
04567|013|E|agents that inhibit BCRP may result in elevated levels and side effects from|
04567|014|E|ubrogepant.(2)|
04567|015|B||
04567|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04567|017|P|of the inducer for longer than 1-2 weeks.|
04567|018|B||
04567|019|M|PATIENT MANAGEMENT:  The manufacturer of ubrogepant does not have|
04567|020|M|recommendations for concurrent use with agents that are both strong CYP3A4|
04567|021|M|inducers and BCRP inhibitors.  Concurrent use should be avoided.(2)|
04567|022|M|   For concurrent use of ubrogepant with strong CYP3A4 inducers, the|
04567|023|M|manufacturer of ubrogepant states that concurrent use should be avoided.(2)|
04567|024|M|   For concurrent use of ubrogepant with BCRP inhibitors, the manufacturer|
04567|025|M|of ubrogepant recommends a dosage adjustment of ubrogepant.  The dose of|
04567|026|M|ubrogepant should not exceed 50 mg for initial dose.  If a second dose of|
04567|027|M|ubrogepant is needed, the dose should not exceed 50 mg.(2)|
04567|028|B||
04567|029|D|DISCUSSION:  Ubrogepant is a substrate of CYP3A4 and the BCRP|
04567|030|D|transporter.(2)|
04567|031|D|   Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer,|
04567|032|D|resulted in an 80% reduction in ubrogepant exposure.(2)|
04567|033|D|   Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant.|
04567|034|D|Clinical drug interaction studies with inhibitors of these transporters were|
04567|035|D|not conducted.  The US manufacturer of ubrogepant recommends dose adjustment|
04567|036|D|if ubrogepant is coadministered with P-gp or BCRP inhibitors.(2)|
04567|037|B||
04567|038|R|REFERENCES:|
04567|039|B||
04567|040|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
04567|041|R|  BioPharma December, 2024.|1
04567|042|R|2.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
04568|001|T|MONOGRAPH TITLE:  Ritlecitinib/Immunosuppressive Strong CYP3A4 Inducers|
04568|002|B||
04568|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04568|004|L|of severe adverse interaction.|
04568|005|B||
04568|006|A|MECHANISM OF ACTION:  Ritlecitinib is a substrate of CYP3A4. Drugs that are|
04568|007|A|inducers of CYP3A4 may increase the metabolism of ritlecitinib.(1)|
04568|008|A|   Ritlecitinib and immunosuppressives both suppress the immune system.|
04568|009|B||
04568|010|E|CLINICAL EFFECTS:  Concurrent use of an immunosuppressive strong CYP3A4|
04568|011|E|inducer may result in decreased levels and effectiveness of ritlecitinib and|
04568|012|E|increased risk of serious infections.(1)|
04568|013|B||
04568|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04568|015|P|of the inducer for longer than 1-2 weeks.|
04568|016|B||
04568|017|M|PATIENT MANAGEMENT:  The US manufacturer of ritlecitinib states that|
04568|018|M|concurrent administration with strong CYP3A4 inducers or with other potent|
04568|019|M|immunosuppressants is not recommended.(1)|
04568|020|M|   The manufacturer of encorafenib states concurrent administration with|
04568|021|M|CYP3A4 substrates should be avoided.  If coadministration cannot be avoided,|
04568|022|M|refer to the CYP3A4 substrate product labeling for recommendations.(2)|
04568|023|B||
04568|024|D|DISCUSSION:  Concurrent administration of rifampin (600 mg once daily for 8|
04568|025|D|days, a strong CYP3A4 inducer) with a single 50 mg dose of ritlecitinib|
04568|026|D|decreased the area-under-curve (AUC) and maximum concentration (Cmax) of|
04568|027|D|ritlecitinib by 44% and 25%, respectively, in healthy subjects.(1,3,4)|
04568|028|D|   Serious infections have been reported in patients receiving ritlecitinib.|
04568|029|D|Reported infections included appendicitis, COVID-19 infection (including|
04568|030|D|pneumonia), and sepsis.  Reports of viral reactivation, including herpes|
04568|031|D|virus reactivation was reported in clinical studies with ritlecitinib.(1)|
04568|032|D|   Immunosuppressive strong CYP3A4 inducers linked to this monograph|
04568|033|D|include: encorafenib.(2,4)|
04568|034|B||
04568|035|R|REFERENCES:|
04568|036|B||
04568|037|R|1.Litfulo (ritlecitinib) US prescribing information. Pfizer Inc. June 2023.|1
04568|038|R|2.Braftovi (encorafenib) capsules US prescribing information. Array|1
04568|039|R|  BioPharma December, 2024.|1
04568|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04568|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04568|042|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04568|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04568|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04568|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04568|046|R|  11/14/2017.|1
04569|001|T|MONOGRAPH TITLE:  Rivaroxaban/Enzalutamide|
04569|002|B||
04569|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04569|004|L|of severe adverse interaction.|
04569|005|B||
04569|006|A|MECHANISM OF ACTION:  Enzalutamide may induce the metabolism of rivaroxaban|
04569|007|A|by CYP3A4, but increase rivaroxaban absorption by inhibiting P-glycoprotein|
04569|008|A|(P-gp).  The net result is an overall decrease in rivaroxaban levels.(1-4)|
04569|009|B||
04569|010|E|CLINICAL EFFECTS:  Concurrent or recent use of enzalutamide may result in|
04569|011|E|decreased levels and effectiveness of rivaroxaban.(1-4)|
04569|012|B||
04569|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04569|014|P|of the inducer for longer than 1-2 weeks.|
04569|015|B||
04569|016|M|PATIENT MANAGEMENT:  The manufacturer of rivaroxaban states to avoid the|
04569|017|M|concurrent use of agents that are combined P-gp and strong CYP3A4 inducers.|
04569|018|M|It would be prudent to follow the same recommendations with|
04569|019|M|enzalutamide.(1-4)|
04569|020|M|   Depending on indication and renal function, dabigatran, edoxaban, or|
04569|021|M|warfarin may be alternatives.|
04569|022|B||
04569|023|D|DISCUSSION:  In a clinical trial, rifampin (600 mg daily) decreased the|
04569|024|D|area-under-curve (AUC) and concentration maximum (Cmax) of a single dose of|
04569|025|D|rivaroxaban (20 mg with food) by 50% and 22%, respectively.  Similar|
04569|026|D|decreases in pharmacodynamic effects were seen.(1)|
04569|027|D|   In a clinical trial, enzalutamide (160 mg daily) increased digoxin AUC by|
04569|028|D|33% and Cmax by 17%.(4)|
04569|029|D|   Enzalutamide is a strong inducer of CYP3A4 and an inhibitor of P-gp.(2)|
04569|030|D|   A PBPK model evaluated the effects of enzalutamide as a strong CYP3A4|
04569|031|D|inducer and P-gp inhibitor on rivaroxaban.  The model predicted a decrease|
04569|032|D|in rivaroxaban AUC by 45% with a 25% decrease in Cmax.(5)|
04569|033|B||
04569|034|R|REFERENCES:|
04569|035|B||
04569|036|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
04569|037|R|  Inc. March, 2020.|1
04569|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
04569|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04569|040|R|3.Shatzel JJ, Daughety MM, Olson SR, Beer TM, DeLoughery TG. Management of|6
04569|041|R|  Anticoagulation in Patients With Prostate Cancer Receiving Enzalutamide. J|6
04569|042|R|  Oncol Pract 2017 Nov;13(11):720-727.|6
04569|043|R|4.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
04569|044|R|  September, 2022.|1
04569|045|R|5.Otsuka Y, Poondru S, Bonate PL, Rose RH, Jamei M, Ushigome F, Minematsu T.|5
04569|046|R|  Physiologically-based pharmacokinetic modeling to predict drug-drug|5
04569|047|R|  interaction  of enzalutamide with combined P-gp and CYP3A substrates. J|5
04569|048|R|  Pharmacokinet Pharmacodyn 2023 Oct;50(5):365-376.|5
04570|001|T|MONOGRAPH TITLE:  Upadacitinib/Immunosuppressive Strong CYP3A4 Inducers|
04570|002|B||
04570|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04570|004|L|of severe adverse interaction.|
04570|005|B||
04570|006|A|MECHANISM OF ACTION:  Upadacitinib is a substrate of CYP3A4.  Drugs that are|
04570|007|A|inducers of CYP3A4 may increase the metabolism of upadacitinib.(1)|
04570|008|A|   Ritlecitinib and immunosuppressives both suppress the immune system.|
04570|009|B||
04570|010|E|CLINICAL EFFECTS:  Concurrent use of an immunosuppressive strong CYP3A4|
04570|011|E|inducer may result in decreased levels and effectiveness of upadacitinib and|
04570|012|E|increased risk of serious infections.(1)|
04570|013|B||
04570|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04570|015|P|of the inducer for longer than 1-2 weeks.|
04570|016|B||
04570|017|M|PATIENT MANAGEMENT:  The US manufacturer of upadacitinib states that|
04570|018|M|concurrent administration with strong CYP3A4 inducers or with other potent|
04570|019|M|immunosuppressants is not recommended.(1)|
04570|020|M|   The manufacturer of encorafenib states concurrent administration with|
04570|021|M|CYP3A4 substrates should be avoided.  If coadministration cannot be avoided,|
04570|022|M|refer to the CYP3A4 substrate product labeling for recommendations.(2)|
04570|023|B||
04570|024|D|DISCUSSION:  Concomitant administration of rifampin (600 mg once daily for 9|
04570|025|D|days, strong CYP3A4 inducer) with upadacitinib decreased upadacitinib|
04570|026|D|maximum concentration (Cmax) and area-under-the-curve (AUC) by 51% and|
04570|027|D|61%.(1,3,4)|
04570|028|D|   Serious infections have been reported in patients receiving upadacitinib.|
04570|029|D|Reported infections included pneumonia, cellulitis, tuberculosis,|
04570|030|D|multidermatomal herpes zoster, oral/esophageal candidiasis, cryptococcosis.|
04570|031|D|Reports of viral reactivation, including herpes virus reactivation and|
04570|032|D|hepatitis B reactivation, were reported in clinical studies with|
04570|033|D|upadacitinib.(1)|
04570|034|D|   Immunosuppressive strong CYP3A4 inducers linked to this monograph|
04570|035|D|include: encorafenib.(2,4)|
04570|036|B||
04570|037|R|REFERENCES:|
04570|038|B||
04570|039|R|1.Rinvoq (upadacitinib) US prescribing information. AbbVie Inc April, 2025.|1
04570|040|R|2.Braftovi (encorafenib) capsules US prescribing information. Array|1
04570|041|R|  BioPharma December, 2024.|1
04570|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04570|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04570|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04570|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04570|046|R|  11/14/2017.|1
04570|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
04570|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04571|001|T|MONOGRAPH TITLE:  Quetiapine (Less Than or Equal To 150 mg)/Strong 3A4|
04571|002|T|Inducers that Prolong QT|
04571|003|B||
04571|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04571|005|L|take action as needed.|
04571|006|B||
04571|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
04571|008|A|clearance of quetiapine.(1)|
04571|009|A|   Quetiapine may prolong the QTc interval.  Concomitant use with other QT|
04571|010|A|prolonging agents may result in an additive risk of QT prolongation.(1)|
04571|011|B||
04571|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
04571|013|E|with quetiapine may decrease the levels and effectiveness of quetiapine and|
04571|014|E|cause additive effects on the QTc interval, which may result in|
04571|015|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
04571|016|B||
04571|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04571|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04571|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04571|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04571|021|P|female gender, or advanced age.(2)|
04571|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04571|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04571|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04571|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04571|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04571|027|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04571|028|P|dysfunction).(2)|
04571|029|P|   Induction effects may be more likely with regular use of the inducer for|
04571|030|P|longer than 1-2 weeks.|
04571|031|B||
04571|032|M|PATIENT MANAGEMENT:  In patients on quetiapine receiving chronic treatment|
04571|033|M|(i.e., greater than 7-14 days) of inducers of CYP3A4, titrate the dose of|
04571|034|M|quetiapine based on the patient's clinical response and tolerance, up to|
04571|035|M|5-fold of the original dose.  The onset of induction is gradual but may|
04571|036|M|begin within one week for potent agents (e.g. rifampin). The time to maximal|
04571|037|M|induction may be 2 or more weeks depending upon the half-life and dose of|
04571|038|M|the inducer. If the CYP3A4 inducer is discontinued, the dose of quetiapine|
04571|039|M|should be reduced to the original level within 7-14 days.(1)|
04571|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04571|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04571|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04571|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04571|044|B||
04571|045|D|DISCUSSION:  In an interaction study, 18 stable patients with schizophrenia,|
04571|046|D|schizoaffective or bipolar disorder started treatment with quetiapine,|
04571|047|D|achieving the target dose of 300 mg twice daily on day five.  On day 9|
04571|048|D|carbamazepine  was started, gradually increasing to the target dose of 200|
04571|049|D|mg three times a day on day 13.  Patients continued on the combination|
04571|050|D|through day 33 to assure maximal enzyme induction was achieved.|
04571|051|D|Carbamazepine decreased quetiapine AUC 87%, decreased steady-state maximum|
04571|052|D|concentration (Cmax) by 80%, and increased clearance approximately|
04571|053|D|7-fold.(3)|
04571|054|D|   In a review of 2111 quetiapine levels from 1179 patients, quetiapine|
04571|055|D|levels were 86% lower in patients receiving concurrent carbamazepine.(4)|
04571|056|D|   In a review of 62 psychiatric patients, patients receiving carbamazepine|
04571|057|D|had significantly lower quetiapine concentration-to-dose ratios.(5)|
04571|058|D|   A case report described a newly hospitalized patient admitted on|
04571|059|D|carbamazepine 600 mg daily and risperidone 8 mg daily for schizoaffective|
04571|060|D|disorder. She was then converted from risperidone to quetiapine. After 7|
04571|061|D|days of treatment at the target quetiapine dose of 700 mg daily, serum|
04571|062|D|quetiapine concentrations were undetectable.  A repeat level 7 days later|
04571|063|D|was also undetectable. The decision was then made to discontinue|
04571|064|D|carbamazepine and continue quetiapine without dose adjustment.  Quetiapine|
04571|065|D|concentrations increased over the following days to weeks and were|
04571|066|D|accompanied by clinical improvement sufficient for discharge.  The authors|
04571|067|D|also briefly described 2 additional patients, each receiving carbamazepine|
04571|068|D|for a seizure disorder who were subsequently treated with quetiapine 600 mg|
04571|069|D|or 700 mg daily for more than two weeks.  As with the first case, quetiapine|
04571|070|D|serum concentrations with concurrent carbamazepine therapy were below the|
04571|071|D|limit of detection for each patient (lower limit of detection was 25|
04571|072|D|mcg/mL).(6)|
04571|073|D|   Concurrent use of phenytoin (100 mg three times daily), a strong CYP3A4|
04571|074|D|inducer, and quetiapine increased oral clearance of quetiapine by 5-fold.(7)|
04571|075|D|   Agents that are linked to this monograph may have varying degrees of|
04571|076|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04571|077|D|been shown to prolong the QTc interval either through their mechanism of|
04571|078|D|action, through studies on their effects on the QTc interval, or through|
04571|079|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04571|080|D|and/or postmarketing reports.(8)|
04571|081|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04571|082|D|encorafenib and ivosidenib.(9)|
04571|083|B||
04571|084|R|REFERENCES:|
04571|085|B||
04571|086|R|1.Seroquel (quetiapine) US prescribing information. AstraZeneca|1
04571|087|R|  Pharmaceuticals LP September, 2020.|1
04571|088|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04571|089|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04571|090|R|  settings: a scientific statement from the American Heart Association and|6
04571|091|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04571|092|R|  2;55(9):934-47.|6
04571|093|R|3.Grimm SW, Richtand NM, Winter HR, Stams KR, Reele SB. Effects of|2
04571|094|R|  cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine|2
04571|095|R|  pharmacokinetics. Br J Clin Pharmacol 2006 Jan;61(1):58-69.|2
04571|096|R|4.Castberg I, Skogvoll E, Spigset O. Quetiapine and drug interactions:|2
04571|097|R|  evidence from a routine therapeutic drug monitoring service. J Clin|2
04571|098|R|  Psychiatry 2007 Oct;68(10):1540-5.|2
04571|099|R|5.Hasselstrom J, Linnet K. Quetiapine serum concentrations in psychiatric|2
04571|100|R|  patients: the influence of comedication. Ther Drug Monit 2004 Oct;|2
04571|101|R|  26(5):486-91.|2
04571|102|R|6.Nickl-Jockschat T, Paulzen M, Schneider F, Grozinger M. Drug interaction|3
04571|103|R|  can lead to undetectable serum concentrations of quetiapine in the|3
04571|104|R|  presence of carbamazepine. Clin Neuropharmacol 2009 Jan-Feb;32(1):55.|3
04571|105|R|7.Wong YW, Yeh C, Thyrum PT. The effects of concomitant phenytoin|2
04571|106|R|  administration on the steady-state pharmacokinetics of quetiapine. J Clin|2
04571|107|R|  Psychopharmacol 2001 Feb;21(1):89-93.|2
04571|108|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
04571|109|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04571|110|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04571|111|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04571|112|R|9.This information is based on an extract from the Certara Drug Interaction|6
04571|113|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04572|001|T|MONOGRAPH TITLE:  Enzalutamide/Strong CYP3A4 Inducers and Substrates|
04572|002|B||
04572|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04572|004|L|of severe adverse interaction.|
04572|005|B||
04572|006|A|MECHANISM OF ACTION:  Ivosidenib and encorafenib are both strong inducers|
04572|007|A|and substrates of CYP3A4.(1,2,4)|
04572|008|A|   Strong inducers of CYP3A4 may increase the metabolism of enzalutamide.(3)|
04572|009|A|   Enzalutamide is also a strong inducer of CYP3A4 and may increase the|
04572|010|A|metabolism of encorafenib and ivosidenib.(3,4)|
04572|011|B||
04572|012|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 may result in|
04572|013|E|decreased levels and effectiveness of enzalutamide.(1)  Concurrent use of|
04572|014|E|CYP3A4 substrates with enzalutamide may result in reduced levels and|
04572|015|E|therapeutic effect of the substrate.(3)|
04572|016|B||
04572|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04572|018|P|of the inducer for longer than 1-2 weeks.|
04572|019|B||
04572|020|M|PATIENT MANAGEMENT:  Avoid concurrent use of strong inducers of CYP3A4 with|
04572|021|M|enzalutamide.  Consider the use of agents with no or minimal induction|
04572|022|M|potential if possible.(3)|
04572|023|B||
04572|024|D|DISCUSSION:  Enzalutamide is primarily metabolized by CYP2C8 and CYP3A4.|
04572|025|D|CYP2C8 is responsible for metabolism of enzalutamide to the active|
04572|026|D|metabolite.(3)|
04572|027|D|   Coadministration of rifampin (strong CYP3A4 inducer and moderate CYP2C8|
04572|028|D|inducer) decreased the composite area-under-curve (AUC) of enzalutamide and|
04572|029|D|its active metabolite by 37% with no effect on concentration maximum|
04572|030|D|(Cmax).(3)|
04572|031|D|   Coadministration of enzalutamide with midazolam (sensitive CYP3A4|
04572|032|D|substrate) decreased the midazolam area-under-curve (AUC) by 86% and|
04572|033|D|concentration maximum (Cmax) by 77%.(3)|
04572|034|B||
04572|035|R|REFERENCES:|
04572|036|B||
04572|037|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04572|038|R|  Inc. August, 2021.|1
04572|039|R|2.Braftovi (encorafenib) capsules US prescribing information. Array|1
04572|040|R|  BioPharma December, 2024.|1
04572|041|R|3.Xtandi (enzalutamide) US prescribing information. Astellas Pharma US, Inc.|1
04572|042|R|  September, 2022.|1
04572|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
04572|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04573|001|T|MONOGRAPH TITLE:  Selected Nephrotoxic Agents/Polymyxin B|
04573|002|B||
04573|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04573|004|L|of severe adverse interaction.|
04573|005|B||
04573|006|A|MECHANISM OF ACTION:  Polymyxin B can cause nephrotoxicity with a slight|
04573|007|A|degree of tubular damage.  Concurrent administration of other nephrotoxic|
04573|008|A|agents may result in an increased risk of nephrotoxicity.(1)|
04573|009|B||
04573|010|E|CLINICAL EFFECTS:  Concurrent use of polymyxin B with other nephrotoxic|
04573|011|E|agents may result in additive nephrotoxic effects.  Polymyxin B|
04573|012|E|nephrotoxicity is characterized by albuminuria, cellular casts, azotemia,|
04573|013|E|diminished urine output, elevated BUN and rising blood levels usually after|
04573|014|E|about 4 days of therapy.(1,2)|
04573|015|B||
04573|016|P|PREDISPOSING FACTORS:  Factors predisposing to nephrotoxicity include higher|
04573|017|P|cumulative doses and longer duration of therapy of polymyxin B and exposure|
04573|018|P|to multiple nephrotoxins.(2)|
04573|019|B||
04573|020|M|PATIENT MANAGEMENT:  Concurrent or sequential use of potentially nephrotoxic|
04573|021|M|agents with polymyxin B should be avoided.  If concurrent use is necessary,|
04573|022|M|it should be undertaken with great caution.  Check renal function at|
04573|023|M|baseline and monitor renal function and polymyxin B blood levels frequently|
04573|024|M|during therapy.(1)|
04573|025|B||
04573|026|D|DISCUSSION:  Polymyxin B is associated with high rates of nephrotoxicity.|
04573|027|D|Concurrent use with other nephrotoxins may increase the risk of|
04573|028|D|nephrotoxicity.|
04573|029|B||
04573|030|R|REFERENCES:|
04573|031|B||
04573|032|R|1.Polymyxin B US prescribing information. Fresenius Kabi USA, LLC December,|1
04573|033|R|  2022.|1
04573|034|R|2.Pike M, Saltiel E. Colistin- and polymyxin-induced nephrotoxicity: focus|6
04573|035|R|  on literature utilizing the  RIFLE classification scheme of acute kidney|6
04573|036|R|  injury. J Pharm Pract 2014 Dec;27(6):554-61.|6
04574|001|T|MONOGRAPH TITLE:  Nisoldipine/Selected Strong CYP3A4 Inducers|
04574|002|B||
04574|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04574|004|L|is contraindicated and generally should not be dispensed or administered to|
04574|005|L|the same patient.|
04574|006|B||
04574|007|A|MECHANISM OF ACTION:  CYP3A4 inducers may induce the hepatic metabolism of|
04574|008|A|nisoldipine.(1)|
04574|009|B||
04574|010|E|CLINICAL EFFECTS:  Concurrent use of an inducer of CYP3A4 may decrease|
04574|011|E|levels and effectiveness of nisoldipine.(1)|
04574|012|B||
04574|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04574|014|P|of the inducer for longer than 1-2 weeks.|
04574|015|B||
04574|016|M|PATIENT MANAGEMENT:  The US manufacturer of nisoldipine states it should|
04574|017|M|generally not be coadministered with CYP3A4 inducers.(1)|
04574|018|B||
04574|019|D|DISCUSSION:  Concurrent administration of phenytoin with nisoldipine (40 mg)|
04574|020|D|decreased nisoldipine plasma concentrations below detectable levels.(1)|
04574|021|D|   In a study comparing patients receiving chronic phenytoin therapy to|
04574|022|D|healthy controls, phenytoin decreased the AUC of a single dose of|
04574|023|D|nisoldipine by 89%.(2)|
04574|024|D|   Selected CYP3A4 inducers linked to this monograph include apalutamide,|
04574|025|D|encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane and St. John's|
04574|026|D|Wort.(3,4)|
04574|027|B||
04574|028|R|REFERENCES:|
04574|029|B||
04574|030|R|1.Sular (nisoldipine) US prescribing information. Shionogi, Inc. June, 2017.|1
04574|031|R|2.Michelucci R, Cipolla G, Passarelli D, Gatti G, Ochan M, Heinig R,|2
04574|032|R|  Tassinari CA, Perucca E. Reduced plasma nisoldipine concentrations in|2
04574|033|R|  phenytoin-treated patients with epilepsy. Epilepsia 1996 Nov;|2
04574|034|R|  37(11):1107-10.|2
04574|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04574|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04574|037|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04574|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04574|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04574|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04574|041|R|  11/14/2017.|1
04575|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Selected Strong CYP3A4|
04575|002|T|Inducers|
04575|003|B||
04575|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04575|005|L|of severe adverse interaction.|
04575|006|B||
04575|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04575|008|A|cyclosporine, everolimus, sirolimus and temsirolimus.(1-5)|
04575|009|B||
04575|010|E|CLINICAL EFFECTS:  Concurrent use of strong inducers of CYP3A4 may result in|
04575|011|E|decreased levels and effectiveness of cyclosporine, everolimus, sirolimus|
04575|012|E|and temsirolimus.(1)|
04575|013|B||
04575|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04575|015|P|of the inducer for longer than 1-2 weeks.|
04575|016|B||
04575|017|M|PATIENT MANAGEMENT:  If possible, consider alternatives to strong CYP3A4|
04575|018|M|inducers in patients maintained on cyclosporine and sirolimus. If concurrent|
04575|019|M|therapy is warranted, monitor cyclosporine and sirolimus serum levels and|
04575|020|M|observe the patient for graft rejection. The dosage of cyclosporine and|
04575|021|M|sirolimus may need to be adjusted following the initiation or|
04575|022|M|discontinuation of these agents.|
04575|023|M|   The US manufacturer of everolimus states that concurrent use with strong|
04575|024|M|CYP3A4 inducers should be avoided.  If concurrent use is warranted, consider|
04575|025|M|increasing the dose of everolimus.  In patients with advanced hormone|
04575|026|M|receptor-positive, HER2-negative breast cancer (HR+BC); advanced pancreatic|
04575|027|M|neuroendocrine tumors (PNET); or advanced renal cell carcinoma; or renal|
04575|028|M|angiomyolipoma with TSC, double the daily dose of everolimus using 5 mg|
04575|029|M|increments or less.  If the inducer is discontinued, return the dose to that|
04575|030|M|used prior to inducer therapy once the inducer has been stopped for 5 days.|
04575|031|M|In patients with subependymal giant cell astrocytoma with TSC, double the|
04575|032|M|dose of everolimus using 5 mg increments or less.  Subsequent dosing should|
04575|033|M|be individualized based on therapeutic drug monitoring.  If the inducer is|
04575|034|M|discontinued, return the dose of everolimus to the dose used prior to the|
04575|035|M|inducer once the inducer has been stopped for 5 days, and assess everolimus|
04575|036|M|trough levels 2 weeks later.(1)|
04575|037|M|   The US manufacturer of temsirolimus states that concurrent use of strong|
04575|038|M|inducers of CYP3A4, such as carbamazepine, phenobarbital, phenytoin,|
04575|039|M|rifabutin, rifampicin, or rifampin should be avoided.  If concurrent therapy|
04575|040|M|is warranted, consider increasing the dosage of temsirolimus from 25 mg/week|
04575|041|M|to 50 mg/week.  If the inducer is discontinued, the dosage of temsirolimus|
04575|042|M|should be returned to the previous dose.(2)|
04575|043|M|   If possible, consider alternatives to strong CYP3A4 inducers in patients|
04575|044|M|maintained on cyclosporine and sirolimus.  If concurrent therapy is|
04575|045|M|warranted, monitor cyclosporine and sirolimus serum levels and observe the|
04575|046|M|patient for graft rejection.  The dosage of cyclosporine and sirolimus may|
04575|047|M|need to be adjusted following the initiation or discontinuation of these|
04575|048|M|agents.|
04575|049|B||
04575|050|D|DISCUSSION:  Encorafenib and ivosidenib are strong CYP3A4 inducers. Other|
04575|051|D|strong CYP3A4 inducers have been documented to decrease exposure to|
04575|052|D|cyclosporine, everolimus, sirolimus, and temsirolimus.|
04575|053|D|   In a study in 10 lung transplant patients, significantly higher doses of|
04575|054|D|cyclosporine were required during nafcillin therapy to maintain therapeutic|
04575|055|D|trough levels.  Patients also developed higher serum creatinine levels and|
04575|056|D|more renal dysfunction than patients not receiving nafcillin.  In a case|
04575|057|D|report, a patient experienced 70% and 85% drops in cyclosporine levels|
04575|058|D|during two separate courses of nafcillin therapy.|
04575|059|D|   Trough cyclosporine concentrations have been found to decrease within 48|
04575|060|D|hours after starting phenytoin even when the dose of cyclosporine is|
04575|061|D|increased. Conversely, cyclosporine concentrations may increase when the|
04575|062|D|hydantoin is discontinued. The effect of the hydantoin on cyclosporine may|
04575|063|D|reverse over a period of one to three weeks after stopping the hydantoin.|
04575|064|D|   Concurrent administration of cyclosporine and rifampin has been|
04575|065|D|associated with lowering of cyclosporine to undetectable serum levels.|
04575|066|D|Decreases in cyclosporine levels have been observed within 2 days of|
04575|067|D|concomitant therapy but will probably not be maximal for 1 week. The effects|
04575|068|D|of the interaction may persist for up to 3 weeks after rifampin is stopped.|
04575|069|D|   In an open-label study in 11 renal transplant patients, subjects received|
04575|070|D|St. John's wort (600 mg daily) for 14 days in addition to their normal|
04575|071|D|cyclosporine regimen.  After 14 days of St. John's wort, dose-corrected|
04575|072|D|cyclosporine area-under-curve (AUC), maximum concentration (Cmax), and|
04575|073|D|minimum concentration (Cmin) decreased by 46%, 42%, and 41%, respectively.|
04575|074|D|Mean cyclosporine dose increased from 2.7 mg/kg/day at 4.2 mg/kg/day at the|
04575|075|D|end of the study.  Subjects required their first cyclosporine dosage|
04575|076|D|adjustment at Day 3.|
04575|077|D|   There are several  case reports of decreased cyclosporine with concurrent|
04575|078|D|carbamazepine, phenobarbital, and St. John's wort.|
04575|079|D|   In healthy subjects, concurrent use of rifampin, a strong inducer of|
04575|080|D|CYP3A4, decreased everolimus AUC and Cmax by 64% and 58%, respectively.|
04575|081|D|   Increasing the dosage of everolimus to 20 mg daily in patients taking a|
04575|082|D|strong inducer of CYP3A4 is expected to increase the AUC of everolimus to|
04575|083|D|levels seen without a concurrent inducer; however, there are no clinical|
04575|084|D|data available with this dosage in patients receiving strong CYP3A4|
04575|085|D|inducers.|
04575|086|D|  In an open-label clinical trial, 10 male patients received ridaforolimus|
04575|087|D|(40 mg daily, days 1 and 14) and rifampin (600 mg daily, days 1-21).|
04575|088|D|Administration of rifampin resulted in a reduction in the mean whole-blood|
04575|089|D|concentration of ridaforolimus (AUC-GMR 0.57, Cmax- GMR 0.66).  The mean|
04575|090|D|whole-blood concentration of ridaforolimus increased 1.5-fold following|
04575|091|D|ketoconazole administration.|
04575|092|D|   In a study in 14 healthy subjects, pretreatment with rifampin (600 mg|
04575|093|D|daily for 14 days) decreased the AUC and Cmax of a single dose of sirolimus|
04575|094|D|(20 mg) by 82% and 71%, respectively.  The oral clearance of sirolimus|
04575|095|D|increased by 5.5-fold.|
04575|096|D|   There are case report of decreased sirolimus levels with concurrent|
04575|097|D|phenytoin and rifampin.|
04575|098|D|   Concurrent rifampin had no significant effects on the AUC or Cmax of|
04575|099|D|temsirolimus; however, sirolimus AUC and Cmax decreased by 56% and 65%,|
04575|100|D|respectively.  A dosage adjustment to 50 mg/week of temsirolimus in the|
04575|101|D|presence of strong CYP3A4 inducers is predicted to adjust levels to those|
04575|102|D|seen without inducers; however, there are no clinical data in patients using|
04575|103|D|this dose.|
04575|104|D|   There is a case report of decreased temsirolimus effectiveness with|
04575|105|D|concurrent rifampin.|
04575|106|B||
04575|107|R|REFERENCES:|
04575|108|B||
04575|109|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
04575|110|R|  BioPharma December, 2024.|1
04575|111|R|2.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04575|112|R|  Inc. August, 2021.|1
04575|113|R|3.Afinitor (everolimus) US prescribing information. Novartaris|1
04575|114|R|  Pharmaceuticals Corporation February, 2020.|1
04575|115|R|4.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
04575|116|R|  Aug, 2022.|1
04575|117|R|5.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
04575|118|R|  Inc. March, 2018.|1
04575|119|R|6.Langhoff E, Madsen S. Rapid metabolism of cyclosporin and prednisone in|3
04575|120|R|  kidney transplant patient receiving tuberculostatic treatment. Lancet 1983|3
04575|121|R|  Oct 29;2(8357):1031.|3
04575|122|R|7.Van Buren D, Wideman CA, Ried M, Gibbons S, Van Buren CT, Jarowenko M,|3
04575|123|R|  Flechner SM, Frazier OH, Cooley DA, Kahan BD. The antagonistic effect of|3
04575|124|R|  rifampin upon cyclosporine bioavailability. Transplant Proc 1984 Dec;|3
04575|125|R|  16(6):1642-5.|3
04575|126|R|8.Daniels NJ, Dover JS, Schachter RK. Interaction between cyclosporin and|3
04575|127|R|  rifampicin. Lancet 1984 Sep 15;2(8403):639.|3
04575|128|R|9.Allen RD, Hunnisett AG, Morris PJ. Cyclosporin and rifampicin in renal|3
04575|129|R|  transplantation. Lancet 1985 Apr 27;1(8435):980.|3
04575|130|R|10.Howard P, Bixler TJ, Gill B. Cyclosporine-rifampin drug interaction. Drug|3
04575|131|R|   Intell Clin Pharm 1985 Oct;19(10):763-4.|3
04575|132|R|11.Anonymous. Cyclosporin and antituberculous therapy. Lancet 1985 Jun 8;|3
04575|133|R|   1(8441):1342-3.|3
04575|134|R|12.Cassidy MJ, Van Zyl-Smit R, Pascoe MD, Swanepoel CR, Jacobson JE. Effect|3
04575|135|R|   of rifampicin on cyclosporin A blood levels in a renal transplant|3
04575|136|R|   recipient. Nephron 1985;41(2):207-8.|3
04575|137|R|13.Offermann G, Keller F, Molzahn M. Low cyclosporin A blood levels and|3
04575|138|R|   acute graft rejection in a renal transplant recipient during rifampin|3
04575|139|R|   treatment. Am J Nephrol 1985;5(5):385-7.|3
04575|140|R|14.al-Sulaiman MH, Dhar JM, al-Khader AA. Successful use of rifampicin in|2
04575|141|R|   the treatment of tuberculosis in renal transplant patients|2
04575|142|R|   immunosuppressed with cyclosporine. Transplantation 1990 Oct;50(4):597-8.|2
04575|143|R|15.Vandevelde C, Chang A, Andrews D, Riggs W, Jewesson P. Rifampin and|3
04575|144|R|   ansamycin interactions with cyclosporine after renal transplantation.|3
04575|145|R|   Pharmacotherapy 1991;11(1):88-9.|3
04575|146|R|16.Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of|2
04575|147|R|   cyclosporine with concomitant rifampin administration is markedly less|2
04575|148|R|   than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992 Nov;|2
04575|149|R|   52(5):453-7.|2
04575|150|R|17.Keown PA, Stiller CR, Laupacis AL, Howson W, Coles R, Stawecki M, Koegler|2
04575|151|R|   J, Carruthers G, McKenzie N, Sinclair NR. The effects and side effects of|2
04575|152|R|   cyclosporine: relationship to drug pharmacokinetics. Transplant Proc 1982|2
04575|153|R|   Dec;14(4):659-61.|2
04575|154|R|18.Freeman DJ, Laupacis A, Keown PA, Stiller CR, Carruthers SG. Evaluation|2
04575|155|R|   of cyclosporin-phenytoin interaction with observations on cyclosporin|2
04575|156|R|   metabolites. Br J Clin Pharmacol 1984 Dec;18(6):887-93.|2
04575|157|R|19.Keown PA, Laupacis A, Carruthers G, Stawecki M, Koegler J, McKenzie FN,|2
04575|158|R|   Wall W, Stiller CR. Interaction between phenytoin and cyclosporine|2
04575|159|R|   following organ transplantation. Transplantation 1984 Sep;38(3):304-6.|2
04575|160|R|20.Rowland M, Gupta SK. Cyclosporin-phenytoin interaction: re-evaluation|2
04575|161|R|   using metabolite data. Br J Clin Pharmacol 1987 Sep;24(3):329-34.|2
04575|162|R|21.Ptachcinski RJ, Venkataramanan R, Rosenthal JT, Burckart GJ, Taylor RJ,|2
04575|163|R|   Hakala TR. Cyclosporine kinetics in renal transplantation. Clin Pharmacol|2
04575|164|R|   Ther 1985 Sep;38(3):296-300.|2
04575|165|R|22.Carstensen H, Jacobsen N, Dieperink H. Interaction between cyclosporin A|3
04575|166|R|   and phenobarbitone. Br J Clin Pharmacol 1986 May;21(5):550-1.|3
04575|167|R|23.Noguchi M, Kiuchi C, Akiyama H, Sakamaki H, Onozawa Y. Interaction|3
04575|168|R|   between cyclosporin A and anticonvulsants. Bone Marrow Transplantation|3
04575|169|R|   Team. Bone Marrow Transplant 1992 May;9(5):391.|3
04575|170|R|24.Schofield OM, Camp RD, Levene GM. Cyclosporin A in psoriasis: interaction|3
04575|171|R|   with carbamazepine. Br J Dermatol 1990 Mar;122(3):425-6.|3
04575|172|R|25.Lele P, Peterson P, Yang S, Jarrell B, Burke JF Jr. Cyclosporine and|4
04575|173|R|   tegretrol -- another drug interaction. Kidney Int 1985;27(1):344.|4
04575|174|R|26.Soto Alvarez J, Sacristan Del Castillo JA, Alsar Ortiz MJ. Effect of|3
04575|175|R|   carbamazepine on cyclosporin blood level. Nephron 1991;58(2):235-6.|3
04575|176|R|27.Cooney GF, Mochon M, Kaiser B, Dunn SP, Goldsmith B. Effects of|2
04575|177|R|   carbamazepine on cyclosporine metabolism in pediatric renal transplant|2
04575|178|R|   recipients. Pharmacotherapy 1995 May-Jun;15(3):353-6.|2
04575|179|R|28.Kovarik JM, Hartmann S, Figueiredo J, Rouilly M, Port A, Rordorf C.|2
04575|180|R|   Effect of rifampin on apparent clearance of everolimus. Ann Pharmacother|2
04575|181|R|   2002 Jun;36(6):981-5.|2
04575|182|R|29.Ngo BT, Pascoe M, Kahn D. Drug interaction between rifampicin and|3
04575|183|R|   sirolimus in transplant patients. Saudi J Kidney Dis Transpl 2011|3
04575|184|R|   Jan-Feb;22(1):112-5.|3
04575|185|R|30.Stroh M, Palcza J, McCrea J, Marsilio S, Breidinger S, Panebianco D,|2
04575|186|R|   Johnson-Levonas A, Kraft WK, Orford K, Murphy G, Agrawal N, Trucksis M,|2
04575|187|R|   Wagner JA, Iwamoto M. The effect of multiple doses of rifampin and|2
04575|188|R|   ketoconazole on the single-dose pharmacokinetics of ridaforolimus. Cancer|2
04575|189|R|   Chemother Pharmacol 2012 May;69(5):1247-53.|2
04575|190|R|31.Lopez-Montes A, Gallego E, Lopez E, Perez J, Lorenzo I, Llamas F, Serrano|3
04575|191|R|   A, Andres E, Illescas L, Gomez C. Treatment of tuberculosis with|3
04575|192|R|   rifabutin in a renal transplant recipient. Am J Kidney Dis 2004 Oct;|3
04575|193|R|   44(4):e59-63.|3
04575|194|R|32.Bauer S, Stormer E, Johne A, Kruger H, Budde K, Neumayer HH, Roots I, Mai|2
04575|195|R|   I. Alterations in cyclosporin A pharmacokinetics and metabolism during|2
04575|196|R|   treatment with St John's wort in renal transplant patients. Br J Clin|2
04575|197|R|   Pharmacol 2003 Feb;55(2):203-11.|2
04575|198|R|33.Alscher DM, Klotz U. Drug interaction of herbal tea containing St. John's|3
04575|199|R|   wort with cyclosporine. Transpl Int 2003 Jul;16(7):543-4.|3
04575|200|R|34.Turton-Weeks SM, Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz|3
04575|201|R|   SR. St John's wort: a hidden risk for transplant patients. Prog|3
04575|202|R|   Transplant 2001 Jun;11(2):116-20.|3
04575|203|R|35.Moschella C, Jaber BL. Interaction between cyclosporine and Hypericum|3
04575|204|R|   perforatum (St. John's wort) after organ transplantation. Am J Kidney Dis|3
04575|205|R|   2001 Nov;38(5):1105-7.|3
04575|206|R|36.Beer AM, Ostermann T. St. John's wort: interaction with cyclosporine|3
04575|207|R|   increases risk of rejection for the kidney transplant and raises daily|3
04575|208|R|   cost of medication. Med Klin (Munich) 2001 Aug 15;96(8):480-3.|3
04575|209|R|37.Ahmed SM, Banner NR, Dubrey SW. Low cyclosporin-A level due to|3
04575|210|R|   Saint-John's-wort in heart transplant patients. J Heart Lung Transplant|3
04575|211|R|   2001 Jul;20(7):795.|3
04575|212|R|38.Karliova M, Treichel U, Malago M, Frilling A, Gerken G, Broelsch CE.|3
04575|213|R|   Interaction of Hypericum perforatum (St. John's wort) with cyclosporin A|3
04575|214|R|   metabolism in a patient after liver transplantation. J Hepatol 2000 Nov;|3
04575|215|R|   33(5):853-5.|3
04575|216|R|39.Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. Drug|3
04575|217|R|   interaction between St. John's wort and cyclosporine. Ann Pharmacother|3
04575|218|R|   2000 Sep;34(9):1013-6.|3
04575|219|R|40.Mandelbaum A, Pertzborn F, Martin-Facklam M, Wiesel M. Unexplained|3
04575|220|R|   decrease of cyclosporin trough levels in a compliant renal transplant|3
04575|221|R|   patient. Nephrol Dial Transplant 2000 Sep;15(9):1473-4.|3
04575|222|R|41.Breidenbach T, Kliem V, Burg M, Radermacher J, Hoffmann MW, Klempnauer J.|3
04575|223|R|   Profound drop of cyclosporin A whole blood trough levels caused by St.|3
04575|224|R|   John's wort (Hypericum perforatum). Transplantation 2000 May 27;|3
04575|225|R|   69(10):2229-30.|3
04575|226|R|42.Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G. Acute heart|3
04575|227|R|   transplant rejection due to Saint John's wort. Lancet 2000 Feb 12;|3
04575|228|R|   355(9203):548-9.|3
04575|229|R|43.Bolley R, Zulke C, Kammerl M, Fischereder M, Kramer BK.|3
04575|230|R|   Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4|3
04575|231|R|   system with St John's wort. Transplantation 2002 Mar 27;73(6):1009.|3
04575|232|R|44.Fridell JA, Jain AK, Patel K, Virji M, Rao KN, Fung JJ, Venkataramanan R.|3
04575|233|R|   Phenytoin decreases the blood concentrations of sirolimus in a liver|3
04575|234|R|   transplant recipient: a case report. Ther Drug Monit 2003 Feb;|3
04575|235|R|   25(1):117-9.|3
04575|236|R|45.Formea CM, Evans CG, Karlix JL. Altered cytochrome p450 metabolism of|3
04575|237|R|   calcineurin inhibitors: case report and review of the literature.|3
04575|238|R|   Pharmacotherapy 2005 Jul;25(7):1021-9.|3
04575|239|R|46.Bates D, Burak KW, Coffin CS, Ying T, Enns EM. Phenytoin-induced|3
04575|240|R|   reduction in sirolimus levels. Can J Hosp Pharm 2011 Jul;64(4):271-4.|3
04575|241|R|47.Coriat R, Mir O, Ropert S, Loulergue P, Billemont B, Goldwasser F.|3
04575|242|R|   Reactivation of tuberculosis during temsirolimus therapy. Invest New|3
04575|243|R|   Drugs 2011 Dec;29(6):1494-6.|3
04575|244|R|48.Veremis SA, Maddux MS, Pollak R, Mozes MF. Subtherapeutic cyclosporine|3
04575|245|R|   concentrations during nafcillin therapy. Transplantation 1987 Jun;|3
04575|246|R|   43(6):913-5.|3
04576|001|T|MONOGRAPH TITLE:  Glucagon (Diagnostic)/Anticholinergics|
04576|002|B||
04576|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04576|004|L|of severe adverse interaction.|
04576|005|B||
04576|006|A|MECHANISM OF ACTION:  Glucagon and anticholinergic agents may have additive|
04576|007|A|effects on inhibition of gastrointestinal motility.(1)|
04576|008|B||
04576|009|E|CLINICAL EFFECTS:  Concurrent use of glucagon with anticholinergic agents|
04576|010|E|may increase the risk of gastrointestinal hypomotility, including|
04576|011|E|constipation and bowel complications.(1)|
04576|012|B||
04576|013|P|PREDISPOSING FACTORS:  None determined.|
04576|014|B||
04576|015|M|PATIENT MANAGEMENT:  Concurrent use of glucagon as a diagnotic aid is not|
04576|016|M|recommended with the use of anticholinergic agents.(1)|
04576|017|M|   If concurrent use is necessary, evaluate the patient's bowel function.|
04576|018|M|Monitor for symptoms of constipation and gastrointestinal hypomotility.|
04576|019|B||
04576|020|D|DISCUSSION:  Both glucagon and anticholinergic agents may have additive|
04576|021|D|effects on inhibition of gastrointestinal motility and increase the risk of|
04576|022|D|gastrointestinal adverse effects.(1)|
04576|023|B||
04576|024|R|REFERENCE:|
04576|025|B||
04576|026|R|1.Glucagon injection (diagnostic) US prescribing information. Fresenius Kabi|1
04576|027|R|  USA, LLC April, 2022.|1
04577|001|T|MONOGRAPH TITLE:  Resmetirom/Strong CYP2C8 Inhibitors|
04577|002|B||
04577|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04577|004|L|of severe adverse interaction.|
04577|005|B||
04577|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2C8 may inhibit the metabolism|
04577|007|A|of resmetirom.(1)|
04577|008|B||
04577|009|E|CLINICAL EFFECTS:  Concomitant use of a strong CYP2C8 inhibitor may increase|
04577|010|E|resmetirom plasma concentrations, which may increase the risk of resmetirom|
04577|011|E|toxicity, including hepatotoxicity.(1)|
04577|012|B||
04577|013|P|PREDISPOSING FACTORS:  None determined.|
04577|014|B||
04577|015|M|PATIENT MANAGEMENT:  Concomitant use of resmetirom with strong CYP2C8|
04577|016|M|inhibitors is not recommended.(1)|
04577|017|B||
04577|018|D|DISCUSSION:  Multiple doses of resmetirom 100 mg daily were given with|
04577|019|D|clopidogrel, a moderate CYP2C8 inhibitor, and the resmetirom|
04577|020|D|area-under-curve (AUC) and maximum concentration (Cmax) increased 1.7-fold|
04577|021|D|and 1.3-fold, respectively.(1)|
04577|022|D|   Strong CYP2C8 inhibitors linked to this monograph include gemfibrozil.(2)|
04577|023|B||
04577|024|R|REFERENCES:|
04577|025|B||
04577|026|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04577|027|R|  Pharmaceuticals March, 2024.|1
04577|028|R|2.This information is based on an extract from the Certara Drug Interaction|6
04577|029|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04578|001|T|MONOGRAPH TITLE:  Resmetirom/Moderate CYP2C8 Inhibitors|
04578|002|B||
04578|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04578|004|L|take action as needed.|
04578|005|B||
04578|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP2C8 may inhibit the|
04578|007|A|metabolism of resmetirom.(1)|
04578|008|B||
04578|009|E|CLINICAL EFFECTS:  Concomitant use of a moderate CYP2C8 inhibitor may|
04578|010|E|increase resmetirom plasma concentrations, which may increase the risk of|
04578|011|E|resmetirom toxicity, including hepatotoxicity.(1)|
04578|012|B||
04578|013|P|PREDISPOSING FACTORS:  None determined.|
04578|014|B||
04578|015|M|PATIENT MANAGEMENT:  Concomitant use of resmetirom with moderate CYP2C8|
04578|016|M|inhibitors is not recommended.  If concurrent use is warranted, reduce the|
04578|017|M|dose of resmetirom based on the patient's weight.|
04578|018|M|   -If <100 kg, reduce the dose of resmetirom to 60 mg once daily;|
04578|019|M|   -If >=100 kg, reduce the dose of resmetirom to 80 mg once daily.(1)|
04578|020|B||
04578|021|D|DISCUSSION:  Multiple doses of resmetirom 100 mg daily were given with|
04578|022|D|clopidogrel, a moderate CYP2C8 inhibitor, and the resmetirom|
04578|023|D|area-under-curve (AUC) and maximum concentration (Cmax) increased 1.7-fold|
04578|024|D|and 1.3-fold, respectively.(1)|
04578|025|D|   Moderate CYP2C8 inhibitors linked to this monograph include:|
04578|026|D|clopidogrel, deferasirox, leflunomide, mifepristone (chronic therapy),|
04578|027|D|pirtobrutinib, selpercatinib, and teriflunomide.(2)|
04578|028|B||
04578|029|R|REFERENCES:|
04578|030|B||
04578|031|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04578|032|R|  Pharmaceuticals March, 2024.|1
04578|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
04578|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04579|001|T|MONOGRAPH TITLE:  Rosuvastatin (Greater Than 20 mg)/Resmetirom|
04579|002|B||
04579|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04579|004|L|is contraindicated and generally should not be dispensed or administered to|
04579|005|L|the same patient.|
04579|006|B||
04579|007|A|MECHANISM OF ACTION:  Resmetirom is an inhibitor of the BCRP, OATP1B1, and|
04579|008|A|OATP1B3 transporters and may increase the absorption and/or decrease the|
04579|009|A|elimination of rosuvastatin.(1-3)|
04579|010|B||
04579|011|E|CLINICAL EFFECTS:  Concurrent use of resmetirom may result in increased|
04579|012|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3)|
04579|013|B||
04579|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04579|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04579|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04579|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04579|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04579|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04579|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04579|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04579|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04579|023|B||
04579|024|M|PATIENT MANAGEMENT:  The US manufacturer of resmetirom states that the dose|
04579|025|M|of rosuvastatin should not exceed 20 mg daily when used concurrently with|
04579|026|M|resmetirom.(1)|
04579|027|M|   Monitor patients closely for signs and symptoms of toxicity from|
04579|028|M|increased rosuvastatin concentrations.(1,2)|
04579|029|B||
04579|030|D|DISCUSSION:  In a study, resmetirom (as steady state) increased the|
04579|031|D|area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
04579|032|D|rosuvastatin 10 mg by 1.8-fold and 2.9-fold, respectively.(1)|
04579|033|B||
04579|034|R|REFERENCES:|
04579|035|B||
04579|036|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04579|037|R|  Pharmaceuticals March, 2024.|1
04579|038|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04579|039|R|  Pharmaceuticals LP July, 2024.|1
04579|040|R|3.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04579|041|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04579|042|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04579|043|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04579|044|R|  44(3):398-408.|5
04580|001|T|MONOGRAPH TITLE:  Rosuvastatin (Less Than or Equal to 20 mg)/Resmetirom|
04580|002|B||
04580|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04580|004|L|take action as needed.|
04580|005|B||
04580|006|A|MECHANISM OF ACTION:  Resmetirom is an inhibitor of the BCRP, OATP1B1, and|
04580|007|A|OATP1B3 transporters and may increase the absorption and/or decrease the|
04580|008|A|elimination of rosuvastatin.(1-3)|
04580|009|B||
04580|010|E|CLINICAL EFFECTS:  Concurrent use of resmetirom may result in increased|
04580|011|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3)|
04580|012|B||
04580|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04580|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04580|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04580|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04580|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04580|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04580|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04580|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04580|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04580|022|B||
04580|023|M|PATIENT MANAGEMENT:  The US manufacturer of resmetirom states that the dose|
04580|024|M|of rosuvastatin should not exceed 20 mg daily when used concurrently with|
04580|025|M|resmetirom.(1)|
04580|026|M|   Monitor patients closely for signs and symptoms of toxicity from|
04580|027|M|increased rosuvastatin concentrations.(1,2)|
04580|028|B||
04580|029|D|DISCUSSION:  In a study, resmetirom (as steady state) increased the|
04580|030|D|area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
04580|031|D|rosuvastatin 10 mg by 1.8-fold and 2.9-fold, respectively.(1)|
04580|032|B||
04580|033|R|REFERENCES:|
04580|034|B||
04580|035|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04580|036|R|  Pharmaceuticals March, 2024.|1
04580|037|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04580|038|R|  Pharmaceuticals LP July, 2024.|1
04580|039|R|3.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04580|040|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04580|041|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04580|042|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04580|043|R|  44(3):398-408.|5
04581|001|T|MONOGRAPH TITLE:  Simvastatin (Greater Than 20 mg)/Resmetirom|
04581|002|B||
04581|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04581|004|L|is contraindicated and generally should not be dispensed or administered to|
04581|005|L|the same patient.|
04581|006|B||
04581|007|A|MECHANISM OF ACTION:  Resmetirom inhibits the BCRP, OATP1B1, and OATP1B3|
04581|008|A|transporters, which may result in increased absorption and decreased hepatic|
04581|009|A|uptake of simvastatin.(1,2)|
04581|010|B||
04581|011|E|CLINICAL EFFECTS:  Concurrent resmetirom may result in elevated levels of|
04581|012|E|simvastatin, which may result in myopathy and rhabdomyolysis.(1,2)|
04581|013|B||
04581|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04581|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04581|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04581|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04581|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04581|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04581|020|P|predisposed to myopathy or rhabdomyolysis.|
04581|021|B||
04581|022|M|PATIENT MANAGEMENT:  The US manufacturer of resmetirom states that the dose|
04581|023|M|of simvastatin should not exceed 20 mg daily when used concurrently with|
04581|024|M|resmetirom.(1)|
04581|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04581|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04581|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04581|028|M|urine, and/or discolored urine.|
04581|029|B||
04581|030|D|DISCUSSION:  Concurrent use of resmetirom increased the concentration|
04581|031|D|maximum (Cmax) and area-under-curve (AUC) of a 20 mg single dose of|
04581|032|D|simvastatin by 1.4-fold and 1.7-fold, respectively.(1)|
04581|033|B||
04581|034|R|REFERENCES:|
04581|035|B||
04581|036|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04581|037|R|  Pharmaceuticals March, 2024.|1
04581|038|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
04581|039|R|  2023.|1
04582|001|T|MONOGRAPH TITLE:  Simvastatin (Less Than or Equal to 20 mg)/Resmetirom|
04582|002|B||
04582|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04582|004|L|take action as needed.|
04582|005|B||
04582|006|A|MECHANISM OF ACTION:  Resmetirom inhibits the BCRP, OATP1B1, and OATP1B3|
04582|007|A|transporters, which may result in increased absorption and decreased hepatic|
04582|008|A|uptake of simvastatin.(1,2)|
04582|009|B||
04582|010|E|CLINICAL EFFECTS:  Concurrent resmetirom may result in elevated levels of|
04582|011|E|simvastatin, which may result in myopathy and rhabdomyolysis.(1,2)|
04582|012|B||
04582|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04582|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04582|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04582|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04582|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04582|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04582|019|P|predisposed to myopathy or rhabdomyolysis.|
04582|020|B||
04582|021|M|PATIENT MANAGEMENT:  The US manufacturer of resmetirom states that the dose|
04582|022|M|of simvastatin should not exceed 20 mg daily when used concurrently with|
04582|023|M|resmetirom.(1)|
04582|024|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04582|025|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04582|026|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04582|027|M|urine, and/or discolored urine.|
04582|028|B||
04582|029|D|DISCUSSION:  Concurrent use of resmetirom increased the concentration|
04582|030|D|maximum (Cmax) and area-under-curve (AUC) of a 20 mg single dose of|
04582|031|D|simvastatin by 1.4-fold and 1.7-fold, respectively.(1)|
04582|032|B||
04582|033|R|REFERENCES:|
04582|034|B||
04582|035|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04582|036|R|  Pharmaceuticals March, 2024.|1
04582|037|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
04582|038|R|  2023.|1
04583|001|T|MONOGRAPH TITLE:  Pravastatin (Greater Than 40 mg)/Resmetirom|
04583|002|B||
04583|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04583|004|L|is contraindicated and generally should not be dispensed or administered to|
04583|005|L|the same patient.|
04583|006|B||
04583|007|A|MECHANISM OF ACTION:  Resmetirom is an inhibitor of OATP1B1 and OATP1B3.(1)|
04583|008|A|Pravastatin is a substrate for OATP1B1 and OATP1B3 transport.(2)|
04583|009|B||
04583|010|E|CLINICAL EFFECTS:  Concurrent use of resmetirom may lead to higher systemic|
04583|011|E|concentrations of pravastatin, increasing the risk for statin-induced|
04583|012|E|myopathy or rhabdomyolysis.|
04583|013|B||
04583|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04583|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04583|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04583|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04583|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04583|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04583|020|P|predisposed to myopathy or rhabdomyolysis.|
04583|021|B||
04583|022|M|PATIENT MANAGEMENT:  The US manufacturer of resmetirom states that the dose|
04583|023|M|of pravastatin should not exceed 40 mg daily when used concurrently with|
04583|024|M|resmetirom.(1)|
04583|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04583|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04583|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04583|028|M|urine, and/or discolored urine.|
04583|029|B||
04583|030|D|DISCUSSION:  In an interaction study, resmetirom increased pravastatin (40|
04583|031|D|mg single dose) maximum concentration (Cmax) 1.3-fold and area-under-curve|
04583|032|D|(AUC) 1.4-fold. respectively.(1)|
04583|033|B||
04583|034|R|REFERENCES:|
04583|035|B||
04583|036|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04583|037|R|  Pharmaceuticals March, 2024.|1
04583|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
04583|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04584|001|T|MONOGRAPH TITLE:  Pravastatin (Less Than or Equal to 40 mg)/Resmetirom|
04584|002|B||
04584|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04584|004|L|take action as needed.|
04584|005|B||
04584|006|A|MECHANISM OF ACTION:  Resmetirom is an inhibitor of OATP1B1 and OATP1B3.(1)|
04584|007|A|Pravastatin is a substrate for OATP1B1 and OATP1B3 transport.(2)|
04584|008|B||
04584|009|E|CLINICAL EFFECTS:  Concurrent use of resmetirom may lead to higher systemic|
04584|010|E|concentrations of pravastatin, increasing the risk for statin-induced|
04584|011|E|myopathy or rhabdomyolysis.|
04584|012|B||
04584|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04584|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04584|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04584|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04584|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04584|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04584|019|P|predisposed to myopathy or rhabdomyolysis.|
04584|020|B||
04584|021|M|PATIENT MANAGEMENT:  The US manufacturer of resmetirom states that the dose|
04584|022|M|of pravastatin should not exceed 40 mg daily when used concurrently with|
04584|023|M|resmetirom.(1)|
04584|024|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04584|025|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04584|026|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04584|027|M|urine, and/or discolored urine.|
04584|028|B||
04584|029|D|DISCUSSION:  In an interaction study, resmetirom increased pravastatin (40|
04584|030|D|mg single dose) maximum concentration (Cmax) 1.3-fold and area-under-curve|
04584|031|D|(AUC) 1.4-fold. respectively.(1)|
04584|032|B||
04584|033|R|REFERENCES:|
04584|034|B||
04584|035|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04584|036|R|  Pharmaceuticals March, 2024.|1
04584|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
04584|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04585|001|T|MONOGRAPH TITLE:  Atorvastatin (Greater Than 40 mg)/Resmetirom|
04585|002|B||
04585|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04585|004|L|is contraindicated and generally should not be dispensed or administered to|
04585|005|L|the same patient.|
04585|006|B||
04585|007|A|MECHANISM OF ACTION:  Resmetirom is an inhibitor of the BCRP, OATP1B1, and|
04585|008|A|OATP1B3 transporters and may increase the absorption and/or decrease the|
04585|009|A|elimination of atorvastatin.(1,2)|
04585|010|B||
04585|011|E|CLINICAL EFFECTS:  Concurrent use of resmetirom may result in elevated|
04585|012|E|levels of atorvastatin, which could result in rhabdomyolysis.|
04585|013|B||
04585|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04585|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04585|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04585|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04585|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04585|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04585|020|P|predisposed to myopathy or rhabdomyolysis.|
04585|021|B||
04585|022|M|PATIENT MANAGEMENT:  The US manufacturer of resmetirom states that the dose|
04585|023|M|of atorvastatin should not exceed 40 mg daily when used concurrently with|
04585|024|M|resmetirom.(1)|
04585|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04585|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04585|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04585|028|M|urine, and/or discolored urine.|
04585|029|B||
04585|030|D|DISCUSSION:  In a study, resmetirom (100 mg daily) increased the|
04585|031|D|area-under-curve (AUC) of atorvastatin 20 mg by 1.4-fold, with no change in|
04585|032|D|the maximum concentration (Cmax).  Atorvastatin lactone Cmax and AUC|
04585|033|D|increased 2.0-fold and 1.8-fold, respectively.(1)|
04585|034|B||
04585|035|R|REFERENCES:|
04585|036|B||
04585|037|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04585|038|R|  Pharmaceuticals March, 2024.|1
04585|039|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
04585|040|R|  2020.|1
04586|001|T|MONOGRAPH TITLE:  Atorvastatin (Less Than or Equal to 40 mg)/Resmetirom|
04586|002|B||
04586|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04586|004|L|take action as needed.|
04586|005|B||
04586|006|A|MECHANISM OF ACTION:  Resmetirom is an inhibitor of the BCRP, OATP1B1, and|
04586|007|A|OATP1B3 transporters and may increase the absorption and/or decrease the|
04586|008|A|elimination of atorvastatin.(1,2)|
04586|009|B||
04586|010|E|CLINICAL EFFECTS:  Concurrent use of resmetirom may result in elevated|
04586|011|E|levels of atorvastatin, which could result in rhabdomyolysis.|
04586|012|B||
04586|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04586|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04586|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04586|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04586|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04586|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04586|019|P|predisposed to myopathy or rhabdomyolysis.|
04586|020|B||
04586|021|M|PATIENT MANAGEMENT:  The US manufacturer of resmetirom states that the dose|
04586|022|M|of atorvastatin should not exceed 40 mg daily when used concurrently with|
04586|023|M|resmetirom.(1)|
04586|024|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04586|025|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04586|026|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04586|027|M|urine, and/or discolored urine.|
04586|028|B||
04586|029|D|DISCUSSION:  In a study, resmetirom (100 mg daily) increased the|
04586|030|D|area-under-curve (AUC) of atorvastatin 20 mg by 1.4-fold, with no change in|
04586|031|D|the maximum concentration (Cmax).  Atorvastatin lactone Cmax and AUC|
04586|032|D|increased 2.0-fold and 1.8-fold, respectively.(1)|
04586|033|B||
04586|034|R|REFERENCES:|
04586|035|B||
04586|036|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04586|037|R|  Pharmaceuticals March, 2024.|1
04586|038|R|2.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
04586|039|R|  2020.|1
04587|001|T|MONOGRAPH TITLE:  Atidarsagene Autotemcel/Anti-Retrovirals|
04587|002|B||
04587|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04587|004|L|of severe adverse interaction.|
04587|005|B||
04587|006|A|MECHANISM OF ACTION:  Atidarsagene autotemcel is prepared from apheresed|
04587|007|A|cells that are transduced with a replication defective, self-inactivating|
04587|008|A|lentiviral vector.  Antiretrovirals may interfere with the manufacturing of|
04587|009|A|apheresed cells.|
04587|010|B||
04587|011|E|CLINICAL EFFECTS:  Use of antiretrovirals before mobilization and apheresis|
04587|012|E|may interfere with the production of atidarsagene autotemcel.|
04587|013|B||
04587|014|P|PREDISPOSING FACTORS:  None determined.|
04587|015|B||
04587|016|M|PATIENT MANAGEMENT:  Discontinue antiretrovirals for at least one month|
04587|017|M|prior to mobilization (or the expected duration of time needed for|
04587|018|M|elimination of the medication) until all cycles of apheresis are completed.|
04587|019|M|   If a patient requires antiretrovirals for HIV prophylaxis, then confirm a|
04587|020|M|negative HIV test before beginning mobilization and apheresis of CD34+|
04587|021|M|cells.|
04587|022|B||
04587|023|D|DISCUSSION:  Antiretroviral medications may interfere with the manufacturing|
04587|024|D|of atidarsagene autotemcel therapy.(1)|
04587|025|B||
04587|026|R|REFERENCE:|
04587|027|B||
04587|028|R|1.Lenmeldy (atidarsagene autotemcel) US prescribing information. Orchard|1
04587|029|R|  Therapeutics March, 2024.|1
04588|001|T|MONOGRAPH TITLE:  Metoprolol (Extended Release)/Alcohol|
04588|002|B||
04588|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04588|004|L|of severe adverse interaction.|
04588|005|B||
04588|006|A|MECHANISM OF ACTION:  Concomitant use of alcohol with metoprolol|
04588|007|A|extended-release capsules may cause a rapid release of metoprolol.(1)|
04588|008|B||
04588|009|E|CLINICAL EFFECTS:  Rapid release of metoprolol may result in increased|
04588|010|E|systemic concentrations and toxicities, including bradycardia and|
04588|011|E|hypotension.(1)|
04588|012|B||
04588|013|P|PREDISPOSING FACTORS:  None determined.|
04588|014|B||
04588|015|M|PATIENT MANAGEMENT:  The manufacturer of metoprolol extended release|
04588|016|M|capsules states that concurrent use with alcohol should be avoided.(1)|
04588|017|M|   Patients are advised to avoid alcohol and elixirs containing a|
04588|018|M|high-percentage of alcohol while taking this product.|
04588|019|B||
04588|020|D|DISCUSSION:  An in vitro dissolution study evaluated the potential for|
04588|021|D|alcohol-induced dose-dumping with metoprolol extended-release capsules in|
04588|022|D|the presence of varying alcohol concentrations (5, 10, 20, and 40%).  The|
04588|023|D|rate of drug release was increased.  The study showed that approximately 89%|
04588|024|D|of the total metoprolol dose was released at 2 hours at the 40% alcohol|
04588|025|D|level, and 17% of total drug was released at 2 hours with 5% alcohol.(1)|
04588|026|B||
04588|027|R|REFERENCE:|
04588|028|B||
04588|029|R|1.Kapspargo Sprinkle (metoprolol succinate) US prescribing information. Ohm|1
04588|030|R|  Laboratories, Inc. April, 2023.|1
04589|001|T|MONOGRAPH TITLE:  Digoxin/Osimertinib|
04589|002|B||
04589|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04589|004|L|take action as needed.|
04589|005|B||
04589|006|A|MECHANISM OF ACTION:  Osimertinib may increase the absorption of digoxin by|
04589|007|A|inhibiting P-glycoprotein (P-gp).(1)|
04589|008|B||
04589|009|E|CLINICAL EFFECTS:  Concurrent use of osimertinib may result in elevated|
04589|010|E|levels of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can|
04589|011|E|include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
04589|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
04589|013|E|disturbances, and arrhythmias.|
04589|014|B||
04589|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
04589|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
04589|017|P|risk of digoxin toxicity.|
04589|018|B||
04589|019|M|PATIENT MANAGEMENT:  Monitor digoxin concentrations before and during the|
04589|020|M|administration of osimertinib.  The manufacturer of digoxin recommends|
04589|021|M|decreasing the dose of digoxin by approximately 15-30% or by modifying the|
04589|022|M|dosing frequency to reduce digoxin concentrations.(2)|
04589|023|B||
04589|024|D|DISCUSSION:  Osimertinib increased the area-under-curve (AUC) and maximum|
04589|025|D|concentration (Cmax) of fexofenadine (a P-gp substrate) by 56% and 76% after|
04589|026|D|a single dose of osimertinib, respectively, and by 27% and 25% at|
04589|027|D|steady-state of osimertinib, respectively.(1)|
04589|028|B||
04589|029|R|REFERENCES:|
04589|030|B||
04589|031|R|1.Tagrisso (osimertinib) US prescribing information. AstraZeneca|1
04589|032|R|  Pharmaceuticals September, 2024.|1
04589|033|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
04589|034|R|  Pharmaceuticals, Inc. August, 2018.|1
04590|001|T|MONOGRAPH TITLE:  Direct Oral Anticoagulants/Anticoagulants (mono deleted|
04590|002|T|04/04/2024)|
04590|003|B||
04590|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04590|005|L|is contraindicated and generally should not be dispensed or administered to|
04590|006|L|the same patient.|
04590|007|B||
04590|008|A|MECHANISM OF ACTION:  Additive effects on hemostasis.(1-15)|
04590|009|B||
04590|010|E|CLINICAL EFFECTS:  Concurrent use of direct oral anticoagulants (DOACs) with|
04590|011|E|another anticoagulant may result in additive effects resulting in an|
04590|012|E|increased risk of bleeding.(1-15)|
04590|013|B||
04590|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04590|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04590|016|P|   Bleeding risk may be increased in patients with renal impairment and in|
04590|017|P|patients > 75 years of age.  Use of multiple agents which affect hemostasis|
04590|018|P|increases the risk for bleeding.|
04590|019|B||
04590|020|M|PATIENT MANAGEMENT:  The long-term use of concurrent therapy with direct|
04590|021|M|oral anticoagulants (DOACs) and other anticoagulants is generally considered|
04590|022|M|contraindicated.  However, overlap may be necessary when switching therapy|
04590|023|M|from one agent to another in order to prevent thrombotic events.|
04590|024|M|Manufacturer recommendations concerning overlap (if any) and timing of|
04590|025|M|discontinuation versus initiation vary depending upon which agent is being|
04590|026|M|discontinued and initiated.  Refer to current prescribing information for|
04590|027|M|both agents for additional details.(1-15)|
04590|028|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
04590|029|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
04590|030|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
04590|031|M|   Discontinue anticoagulants in patients with active bleeding.|
04590|032|M|   Specific recommendations for converting between anticoagulants:|
04590|033|M|-APIXABAN:(1-4)|
04590|034|M|   - When converting between apixaban and anticoagulants other than|
04590|035|M|warfarin, discontinue the current anticoagulant and begin the new one when|
04590|036|M|next dose is due.|
04590|037|M|-DABIGATRAN:(6-8)|
04590|038|M|   - When converting from parenteral anticoagulants to dabigatran,|
04590|039|M|administer dabigatran 0-2 hours before the next dose of the parenteral drug|
04590|040|M|is due.|
04590|041|M|   - When converting from dabigatran to a parenteral anticoagulant in|
04590|042|M|adults, begin parenteral anticoagulant:|
04590|043|M|   --12 hours after last dose of dabigatran in patients with CrCl greater|
04590|044|M|than or equal to 30 ml/min,|
04590|045|M|   --24 hours after last dose of dabigatran in patients with CrCl less than|
04590|046|M|30 ml/min.|
04590|047|M|   - When converting from dabigatran to a parenteral anticoagulant in|
04590|048|M|pedatrics, begin the parenteral anticoagulant 12 hours after the last dose|
04590|049|M|of dabigatran.|
04590|050|M|-EDOXABAN:(9-11)|
04590|051|M|   - When converting from other (non-vitamin K antagonist) oral|
04590|052|M|anticoagulants to edoxaban, discontinue current oral anticoagulant and start|
04590|053|M|edoxaban at the time of the next scheduled dose of the old oral|
04590|054|M|anticoagulant.|
04590|055|M|   - When converting from a low molecular weight heparin (LMWH) to edoxaban,|
04590|056|M|start edoxaban at the time of the next scheduled administration of LMWH.|
04590|057|M|   - When converting from unfractionated heparin to edoxaban, discontinue|
04590|058|M|the infusion and start edoxaban 4 hours later.|
04590|059|M|   - When converting from edoxaban to another DOAC, discontinue edoxaban and|
04590|060|M|begin the new oral anticoagulant at the time of the next scheduled dose of|
04590|061|M|edoxaban.|
04590|062|M|   - When converting from edoxaban to parenteral anticoagulation, start the|
04590|063|M|parenteral anticoagulant at the time of the next dose of edoxaban.|
04590|064|M|-RIVAROXABAN:(12-15)|
04590|065|M|   - When converting from rivaroxaban to anticoagulants other than warfarin|
04590|066|M|and switching to an anticoagulant with rapid onset, discontinue rivaroxaban|
04590|067|M|and begin new anticoagulant when next dose of rivaroxaban is due.|
04590|068|M|   - When converting from anticoagulants other than warfarin to rivaroxaban,|
04590|069|M|discontinue current anticoagulant and begin rivaroxaban between 0-2 hours|
04590|070|M|before next evening dose of the drug is due. For patients receiving|
04590|071|M|continuous infusion of unfractionated heparin, simultaneously stop the|
04590|072|M|infusion and administer rivaroxaban.|
04590|073|B||
04590|074|D|DISCUSSION:  Limited overlap of DOACs with other anticoagulants may be|
04590|075|D|required when initiating or discontinuing DOACs in order to prevent|
04590|076|D|thrombotic events.  However, long-term concomitant treatment is not|
04590|077|D|recommended because of increased risk of bleeding.(1-15)|
04590|078|B||
04590|079|R|REFERENCES:|
04590|080|B||
04590|081|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04590|082|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04590|083|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04590|084|R|  Squibb-Pfizer January, 2025.|1
04590|085|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04590|086|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04590|087|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04590|088|R|  Company September, 2021.|1
04590|089|R|5.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
04590|090|R|  Inc. July, 2019.|1
04590|091|R|6.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
04590|092|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
04590|093|R|7.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
04590|094|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
04590|095|R|8.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
04590|096|R|  Boehringer Ingelheim March, 23 2020.|1
04590|097|R|9.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
04590|098|R|  2019.|1
04590|099|R|10.Lixiana (edoxaban) Canadian product monograph. Servier Canada Inc.|1
04590|100|R|   February, 2023.|1
04590|101|R|11.Lixiana (edoxaban tosilate) UK summary of product characteristics.|1
04590|102|R|   Daiichi Sankyo UK Limited July 2, 2015.|1
04590|103|R|12.Xarelto (rivaroxaban) US prescribing information. Janssen|1
04590|104|R|   Pharmaceuticals, Inc. March, 2020.|1
04590|105|R|13.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
04590|106|R|   August, 2021.|1
04590|107|R|14.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
04590|108|R|   2015.|1
04590|109|R|15.Xarelto (rivaroxaban) Australian prescribing information. BAYER AUSTRALIA|1
04590|110|R|   LTD December, 2022.|1
04591|001|T|MONOGRAPH TITLE:  Direct Oral Anticoagulants/Selected Anticoagulants|
04591|002|T|(Vitamin K Antagonists) (mono deleted 04/04/2024)|
04591|003|B||
04591|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04591|005|L|is contraindicated and generally should not be dispensed or administered to|
04591|006|L|the same patient.|
04591|007|B||
04591|008|A|MECHANISM OF ACTION:  Additive effects on hemostasis.(1-15)|
04591|009|B||
04591|010|E|CLINICAL EFFECTS:  Concurrent use of direct oral anticoagulants (DOACs) with|
04591|011|E|warfarin may result in additive effects resulting in an increased risk of|
04591|012|E|bleeding.(1-15)|
04591|013|B||
04591|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04591|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04591|016|P|   Bleeding risk may be increased in patients with renal impairment and in|
04591|017|P|patients > 75 years of age.  Use of multiple agents which affect hemostasis|
04591|018|P|increases the risk for bleeding.|
04591|019|B||
04591|020|M|PATIENT MANAGEMENT:  The long-term use of concurrent therapy with direct|
04591|021|M|oral anticoagulants (DOACs) and other anticoagulants is generally considered|
04591|022|M|contraindicated.  However, overlap may be necessary when switching therapy|
04591|023|M|from one agent to another in order to prevent thrombotic events.|
04591|024|M|Manufacturer recommendations concerning overlap (if any) and timing of|
04591|025|M|discontinuation versus initiation vary depending upon which agent is being|
04591|026|M|discontinued and initiated.  Refer to current prescribing information for|
04591|027|M|both agents for additional details.(1-15)|
04591|028|M|   Monitor patients receiving concurrent therapy for signs of blood loss,|
04591|029|M|including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or|
04591|030|M|decreased blood pressure and promptly evaluate patients with any symptoms.|
04591|031|M|   Discontinue anticoagulants in patients with active bleeding.|
04591|032|M|   Specific recommendations for converting between oral anticoagulants:|
04591|033|M|-APIXABAN:(1-4)|
04591|034|M|   - When converting from warfarin to apixaban, discontinue warfarin and|
04591|035|M|begin apixaban when the international normalized ratio (INR) is below 2.0.|
04591|036|M|   - Apixaban affects INR.  Therefore concurrent administration with|
04591|037|M|warfarin when converting from apixaban to warfarin is not useful in|
04591|038|M|determining target warfarin dose.  If continuous anticoagulation is|
04591|039|M|warranted, discontinue apixaban and begin both warfarin and a parenteral|
04591|040|M|anticoagulant when next dose of apixaban is due.  Once INR is within range,|
04591|041|M|discontinue the parenteral anticoagulant.|
04591|042|M|-DABIGATRAN:(6-8)|
04591|043|M|   - When converting from warfarin to dabigatran, discontinue warfarin and|
04591|044|M|begin dabigatran when the patient's INR is below 2.0.|
04591|045|M|   - When converting from dabigatran to warfarin in adults, start warfarin:|
04591|046|M|   --3 days before discontinuing dabigatran in patients with CrCl greater|
04591|047|M|than 50 ml/min,|
04591|048|M|   --2 days before discontinuing dabigatran in patients with CrCl of 30|
04591|049|M|ml/min to 50 ml/min,|
04591|050|M|   --1 day before discontinuing dabigatran in patients with CrCl of 15|
04591|051|M|ml/min to 30 ml/min.|
04591|052|M|   --There is no recommendation available for converting dabigatran to|
04591|053|M|warfarin in patients with CrCl less than 15 ml/min.|
04591|054|M|   - When converting from dabigatran to warfarin in pediatrics, start|
04591|055|M|warfarin:|
04591|056|M|   --3 days before discontinuing dabigatran in patient with eGFR >= 50|
04591|057|M|ml/min/1.73 m2.|
04591|058|M|   --There is no data on using dabigatran in pediatric patients with eGFR <|
04591|059|M|50 ml/min/1.73 m2.|
04591|060|M|   - Dabigatran affects INR.  Therefore the INR will better reflect|
04591|061|M|warfarin's effect only after stopping dabigatran for at least 2 days.|
04591|062|M|-EDOXABAN:(9-11)|
04591|063|M|   - When converting from warfarin to edoxaban, discontinue warfarin and|
04591|064|M|start edoxaban when the INR is < or = to 2.5.|
04591|065|M|   - When converting from edoxaban to warfarin, for patients taking 60 mg of|
04591|066|M|edoxaban, reduce the dose to 30 mg and begin warfarin concomitantly.  For|
04591|067|M|patients receiving 30 mg of edoxaban, reduce the dose to 15 mg and begin|
04591|068|M|warfarin concomitantly.  INR must be measured at least weekly and just prior|
04591|069|M|to the daily dose of edoxaban to minimize the effects of edoxaban on INR|
04591|070|M|measurement.  Once a stable INR = or > 2.0 is achieved, edoxaban should be|
04591|071|M|discontinued and the warfarin continued.|
04591|072|M|   - A second edoxaban to warfarin conversion option:  Discontinue edoxaban|
04591|073|M|and administer a parenteral anticoagulant and warfarin at the time of the|
04591|074|M|next scheduled edoxaban dose. Once a stable INR = or > 2.0 is achieved, the|
04591|075|M|parenteral anticoagulant should be discontinued and the warfarin continued.|
04591|076|M|-RIVAROXABAN:(12-15)|
04591|077|M|   - When converting from warfarin to rivaroxaban, discontinue warfarin and|
04591|078|M|begin rivaroxaban once international normalized ratio (INR) is below 3.0 in|
04591|079|M|adults and below 2.5 in pediatric patients.|
04591|080|M|   - When converting from rivaroxaban to warfarin in adults, rivaroxaban|
04591|081|M|affects INR.  Therefore concurrent administration with warfarin is not|
04591|082|M|useful in determining target warfarin dose.  If continuous anticoagulation|
04591|083|M|is warranted, discontinue rivaroxaban and begin both warfarin and a|
04591|084|M|parenteral anticoagulant when the next dose of rivaroxaban is due.  Once INR|
04591|085|M|is within range, discontinue the parenteral anticoagulant.|
04591|086|M|   - When converting from rivaroxaban to warfarin in pediatrics, continue|
04591|087|M|rivaroxaban for at least 2 days after the first dose of warfarin.  After two|
04591|088|M|days, INR should be measured just prior to the next scheduled dose of|
04591|089|M|rivaroxaban.  Once a stable INR = or > 2.0 is achieved, rivaroxaban should|
04591|090|M|be discontinued and warfarin continued.|
04591|091|B||
04591|092|D|DISCUSSION:  Limited overlap of DOACs with warfarin may be required when|
04591|093|D|initiating or discontinuing DOACs in order to prevent thrombotic events.|
04591|094|D|However, long-term concomitant treatment is not recommended because of|
04591|095|D|increased risk of bleeding.(1-15)|
04591|096|B||
04591|097|R|REFERENCES:|
04591|098|B||
04591|099|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04591|100|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04591|101|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04591|102|R|  Squibb-Pfizer January, 2025.|1
04591|103|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04591|104|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04591|105|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04591|106|R|  Company September, 2021.|1
04591|107|R|5.Bevyxxa (betrixaban) US prescribing information. Portola Pharmaceuticals,|1
04591|108|R|  Inc. July, 2019.|1
04591|109|R|6.Pradaxa (dabigatran etexilate mesilate) UK summary of product|1
04591|110|R|  characteristics. Boehringer Ingelheim Limited January 10, 2020.|1
04591|111|R|7.Pradaxa (dabigatran etexilate mesylate) US prescribing information.|1
04591|112|R|  Boehringer Ingelheim Pharmaceuticals, Inc. June, 2021.|1
04591|113|R|8.Pradax (dabigatran etexilate mesilate) Canadian prescribing information.|1
04591|114|R|  Boehringer Ingelheim March, 23 2020.|1
04591|115|R|9.Savaysa (edoxaban) US prescribing information. Daiichi Sankyo, Inc August,|1
04591|116|R|  2019.|1
04591|117|R|10.Lixiana (edoxaban) Canadian product monograph. Servier Canada Inc.|1
04591|118|R|   February, 2023.|1
04591|119|R|11.Lixiana (edoxaban tosilate) UK summary of product characteristics.|1
04591|120|R|   Daiichi Sankyo UK Limited July 2, 2015.|1
04591|121|R|12.Xarelto (rivaroxaban) US prescribing information. Janssen|1
04591|122|R|   Pharmaceuticals, Inc. March, 2020.|1
04591|123|R|13.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
04591|124|R|   August, 2021.|1
04591|125|R|14.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
04591|126|R|   2015.|1
04591|127|R|15.Xarelto (rivaroxaban) Australian prescribing information. BAYER AUSTRALIA|1
04591|128|R|   LTD December, 2022.|1
04592|001|T|MONOGRAPH TITLE:  Mavacamten/Diltiazem; Verapamil|
04592|002|B||
04592|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04592|004|L|of severe adverse interaction.|
04592|005|B||
04592|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as diltiazem and|
04592|007|A|verapamil may decrease the metabolism of mavacamten.(1-3)|
04592|008|A|   The combination of mavacamten, diltiazem or verapamil, and a beta blocker|
04592|009|A|may result in an increased risk of additive negative inotropic effects.(1)|
04592|010|B||
04592|011|E|CLINICAL EFFECTS:  Concurrent use of diltiazem or verapamil may increase the|
04592|012|E|plasma levels and the incidence and severity of adverse reactions of|
04592|013|E|mavacamten.(1)|
04592|014|E|   Concurrent use of mavacamten and diltiazem or verapamil with a beta|
04592|015|E|blocker may increase the incidence and severity of heart failure.(1)|
04592|016|B||
04592|017|P|PREDISPOSING FACTORS:  CYP2C19 poor metabolizers may experience an increased|
04592|018|P|incidence or severity of adverse effects.(1)|
04592|019|P|   Patients established on treatment with a beta blocker may experience an|
04592|020|P|increased incidence or severity of heart failure symptoms.(1)|
04592|021|B||
04592|022|M|PATIENT MANAGEMENT:  The US manufacturer of mavacamten makes the|
04592|023|M|recommendations below for concurrent use with CYP3A4 inhibitors such as|
04592|024|M|diltiazem and verapamil:|
04592|025|M|   Initiate mavacamten at the recommended starting dosage of 5 mg orally|
04592|026|M|once daily in patients who are on stable therapy with a moderate CYP3A4|
04592|027|M|inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to|
04592|028|M|2.5 mg) in patients who are on mavacamten treatment and intend to initiate a|
04592|029|M|moderate CYP3A4 inhibitor.  Schedule clinical and echocardiographic|
04592|030|M|assessment 4 weeks after inhibitor initiation, and do not up-titrate|
04592|031|M|mavacamten until 12 weeks after inhibitor initiation.(1)|
04592|032|M|   Avoid initiation of concomitant moderate CYP3A4 inhibitors in patients|
04592|033|M|who are on stable treatment with 2.5 mg of mavacamten because a lower dose|
04592|034|M|is not available.(1)|
04592|035|M|   Avoid concomitant use of mavacamten in patients on verapamil with a beta|
04592|036|M|blocker, or diltiazem with a beta blocker as these medications and|
04592|037|M|combinations increase the risk of left ventricular systolic dysfunction and|
04592|038|M|heart failure symptoms and clinical experience is limited.(1)|
04592|039|M|   The Canadian manufacturer of mavacamten recommends additional monitoring|
04592|040|M|when concurrent use of moderate CYP3A4 inhibitors is warranted.  Adjust the|
04592|041|M|dose of mavacamten based on clinical assessment.(2)|
04592|042|M|   The UK manufacturer of mavacamten states no dose adjustment is necessary|
04592|043|M|when starting mavacamten in patients on moderate CYP3A4 inhibitors.  If|
04592|044|M|starting a moderate CYP3A4 inhibitor in a patient who is a poor CYP2C19|
04592|045|M|metabolizer, reduce mavacamten 5 mg to 2.5 mg.  If CYP2C19 phenotype is|
04592|046|M|unknown, consider a starting dose of mavacamten of 2.5 mg daily.(3)|
04592|047|B||
04592|048|D|DISCUSSION:  Concomitant use of mavacamten (25 mg) with verapamil sustained|
04592|049|D|release (240 mg) increased mavacamten area-under-curve (AUC) by 16% and|
04592|050|D|maximum concentration (Cmax) by 52% in intermediate metabolizers and normal|
04592|051|D|metabolizers of CYP2C19.(1)|
04592|052|D|   Concomitant use of mavacamten with diltiazem in CYP2C19 poor metabolizers|
04592|053|D|is predicted to increase mavacamten AUC and Cmax up to 55% and 42%,|
04592|054|D|respectively.(1)|
04592|055|B||
04592|056|R|REFERENCES:|
04592|057|B||
04592|058|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04592|059|R|  April, 2025.|1
04592|060|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04592|061|R|  Canada February, 2024.|1
04592|062|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04592|063|R|  Squibb July, 2023.|1
04592|064|R|4.This information is based on an extract from the Certara Drug Interaction|6
04592|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04592|066|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04592|067|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04592|068|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04592|069|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04592|070|R|  11/14/2017.|1
04593|001|T|MONOGRAPH TITLE:  Sotalol/Aluminium And Magnesium Antacids|
04593|002|B||
04593|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04593|004|L|take action as needed.|
04593|005|B||
04593|006|A|MECHANISM OF ACTION:  Aluminum- and magnesium-containing antacids may reduce|
04593|007|A|the absorption of sotalol.(1)|
04593|008|B||
04593|009|E|CLINICAL EFFECTS:  Simultaneous administration of sotalol with antacids|
04593|010|E|containing aluminum or magnesium may result in decreased levels and|
04593|011|E|effectiveness of sotalol.(1)|
04593|012|B||
04593|013|P|PREDISPOSING FACTORS:  None determined.|
04593|014|B||
04593|015|M|PATIENT MANAGEMENT:  If coadministration with an aluminum- or|
04593|016|M|magnesium-containing antacid agent is unavoidable, take the antacid 2 hours|
04593|017|M|before or 2 hours after sotalol.(1)|
04593|018|B||
04593|019|D|DISCUSSION:  In a study with 6 healthy volunteers, administration of oral|
04593|020|D|sotalol simultaneously with antacids reduced the maximum concentration|
04593|021|D|(Cmax) and area under the curve (AUC) of sotalol by 26% and 20%,|
04593|022|D|respectively, compared to sotalol alone.  There was a 25% reduction in the|
04593|023|D|bradycardic effect at rest.  Administration of the antacid two hours after|
04593|024|D|oral sotalol had no effect on the pharmacokinetics or pharmacodynamics of|
04593|025|D|sotalol.(1,2)|
04593|026|B||
04593|027|R|REFERENCES:|
04593|028|B||
04593|029|R|1.Sotylize (sotalol) oral solution, US prescribing information. Azurity|1
04593|030|R|  Pharmaceuticals, Inc. January, 2024.|1
04593|031|R|2.Laer S, Neumann J, Scholz H. Interaction between sotalol and an antacid|2
04593|032|R|  preparation. Br J Clin Pharmacol 1997;43:269-272.|2
04594|001|T|MONOGRAPH TITLE:  Encorafenib/CYP3A4 Inhibitors and Substrates|
04594|002|B||
04594|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04594|004|L|of severe adverse interaction.|
04594|005|B||
04594|006|A|MECHANISM OF ACTION:  Encorafenib is a CYP3A4 substrate and a strong CYP3A4|
04594|007|A|inducer.  Strong and moderate inhibitors of CYP3A4 may inhibit the|
04594|008|A|metabolism of encorafenib.  Also, the metabolism of sensitive substrates of|
04594|009|A|CYP3A4 may be induced by encorafenib.(1)|
04594|010|B||
04594|011|E|CLINICAL EFFECTS:  Concomitant use of encorafenib with agents that are both|
04594|012|E|strong or moderate CYP3A4 inhibitors and CYP3A4 substrates may result in|
04594|013|E|increased levels and effects from encorafenib including QT prolongation.|
04594|014|E|Concomitant use may also result in decreased levels and effectiveness of the|
04594|015|E|CYP3A4 substrate.(1)|
04594|016|B||
04594|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04594|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04594|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04594|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04594|021|P|female gender, or advanced age.(2)|
04594|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04594|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04594|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04594|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04594|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04594|027|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04594|028|P|dysfunction).(2)|
04594|029|P|   Induction effects may be more likely with regular use of the inducer for|
04594|030|P|longer than 1-2 weeks.|
04594|031|B||
04594|032|M|PATIENT MANAGEMENT:  Avoid concomitant use of encorafenib with strong or|
04594|033|M|moderate CYP3A4 inhibitors that are also CYP3A4 substrates.(1)|
04594|034|M|   The US manufacturer of encorafenib states that it should be avoided with|
04594|035|M|CYP3A4 substrates for which decreased plasma concentrations may result in|
04594|036|M|decreased therapeutic efficacy.  If coadministration cannot be avoided,|
04594|037|M|refer to the CYP3A4 substrate prescribing information for|
04594|038|M|recommendations.(1)|
04594|039|M|   In addition, concurrent use of strong or moderate CYP3A4 inhibitors with|
04594|040|M|encorafenib should be avoided.(1)|
04594|041|M|   The net effect of this two-way interaction is unknown and optimal doses|
04594|042|M|of the drugs when used concurrently have not been determined.  The|
04594|043|M|manufacturer provides recommendations for dose modification when encorafenib|
04594|044|M|is used with a CYP3A4 inhibitor, but the recommendations may not apply when|
04594|045|M|there is a two-way interaction.  Dose modifications mentioned below are|
04594|046|M|informational only.|
04594|047|M|  If concurrent use of strong or moderate CYP3A4 inhibitors with encorafenib|
04594|048|M|is unavoidable, reduce the encorafenib dose as follows:|
04594|049|M|   - If the current daily dose of encorafenib is 450 mg, reduce encorafenib|
04594|050|M|to 150 mg with strong CYP3A4 inhibitors, and 225 mg with moderate CYP3A4|
04594|051|M|inhibitors.|
04594|052|M|   - If the current daily dose of encorafenib is 300 mg, reduce encorafenib|
04594|053|M|to 75 mg with strong CYP3A4 inhibitors, and 150 mg with moderate CYP3A4|
04594|054|M|inhibitors.|
04594|055|M|   - If the current daily dose of encorafenib is 225 mg or 150 mg, reduce|
04594|056|M|encorafenib to 75 mg with both strong and moderate CYP3A4 inhibitors.|
04594|057|M|   - After the inhibitor has been discontinued for 3 to 5 half-lives, resume|
04594|058|M|encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor.(1)|
04594|059|M|   When concurrent therapy cannot be avoided, monitor patients closely for|
04594|060|M|prolongation of the QT interval.  Obtain ECGs and electrolyte values (serum|
04594|061|M|calcium, magnesium, and potassium) at regular intervals.  Correct any|
04594|062|M|electrolyte abnormalities.|
04594|063|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
04594|064|M|fainting.|
04594|065|M|   Recommended dosage modifications for encorafenib and QTc prolongation|
04594|066|M|adverse reactions include:|
04594|067|M|   - QTcF greater than 500 ms and less than or equal to 60 ms increase from|
04594|068|M|baseline: Withhold encorafenib until QTcF less than or equal to 500 ms.|
04594|069|M|Resume at reduced dose.  If more than one recurrence, permanently|
04594|070|M|discontinue encorafenib.|
04594|071|M|   - QTcF greater than 500 ms and greater than 60 ms increase from baseline:|
04594|072|M|Permanently discontinue encorafenib.(1)|
04594|073|M|   See encorafenib prescribing information for additional information|
04594|074|M|regarding dose reductions.(1)|
04594|075|B||
04594|076|D|DISCUSSION:  Coadministration of posaconazole (strong CYP3A4 inhibitor) or|
04594|077|D|diltiazem (moderate CYP3A4 inhibitor) increased the area-under-curve (AUC)|
04594|078|D|of encorafenib by 3-fold and 2-fold, respectively, and increased the maximum|
04594|079|D|concentration (Cmax) by 68% and 45%, respectively, after a single dose of|
04594|080|D|encorafenib 50 mg (0.1 times the recommended dose).(1)|
04594|081|D|   Encorafenib 450 mg daily with binimetinib 45 mg twice daily decreased the|
04594|082|D|AUC and Cmax of single dose of midazolam 2 mg, a sensitive CYP3A4 substrate,|
04594|083|D|by 82% and 74%, respectively, relative to midazolam 2 mg alone.(1)|
04594|084|D|   Encorafenib has been associated with a dose-dependent QTc interval|
04594|085|D|prolongation.  Following administration of encorafenib in combination with|
04594|086|D|binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms|
04594|087|D|(14-22 ms), based on central tendency analysis.(1)|
04594|088|D|   Agents that are both strong CYP3A4 inhibitors and CYP3A4 substrates|
04594|089|D|linked to this monograph include: idelalisib, itraconazole, mifepristone,|
04594|090|D|and tucatinib.(3)|
04594|091|D|   Agents that are both moderate CYP3A4 inhibitors and CYP3A4 substrates|
04594|092|D|linked to this monograph include: aprepitant, darunavir, diltiazem,|
04594|093|D|duvelisib, fedratinib, fosnetupitant, imatinib, netupitant, rilzabrutinib,|
04594|094|D|verapamil and voxelotor.(3)|
04594|095|B||
04594|096|R|REFERENCES:|
04594|097|B||
04594|098|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
04594|099|R|  BioPharma December, 2024.|1
04594|100|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04594|101|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04594|102|R|  settings: a scientific statement from the American Heart Association and|6
04594|103|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04594|104|R|  2;55(9):934-47.|6
04594|105|R|3.This information is based on an extract from the Certara Drug Interaction|6
04594|106|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04595|001|T|MONOGRAPH TITLE:  Rosuvastatin (> 10 mg)/Danicopan|
04595|002|B||
04595|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04595|004|L|is contraindicated and generally should not be dispensed or administered to|
04595|005|L|the same patient.|
04595|006|B||
04595|007|A|MECHANISM OF ACTION:  Danicopan is an inhibitor of the BCRP transporter and|
04595|008|A|may increase the absorption and/or decrease the elimination of|
04595|009|A|rosuvastatin.(1-3)|
04595|010|B||
04595|011|E|CLINICAL EFFECTS:  Concurrent use of danicopan may result in increased|
04595|012|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3)|
04595|013|B||
04595|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04595|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04595|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04595|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04595|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04595|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04595|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04595|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04595|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04595|023|B||
04595|024|M|PATIENT MANAGEMENT:  The US manufacturer of danicopan states that the dose|
04595|025|M|of rosuvastatin should not exceed 10 mg daily when used concurrently with|
04595|026|M|danicopan.(1)|
04595|027|M|   Monitor patients closely for signs and symptoms of toxicity from|
04595|028|M|increased rosuvastatin concentrations.(1,2)|
04595|029|B||
04595|030|D|DISCUSSION:  In a study, danicopan (at steady state) increased the|
04595|031|D|area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
04595|032|D|rosuvastatin 20 mg by 2.2-fold and 3.3-fold, respectively.(1)|
04595|033|B||
04595|034|R|REFERENCES:|
04595|035|B||
04595|036|R|1.Voydeya (danicopan) tablets, US prescribing information. Alexion|1
04595|037|R|  Pharmaceuticals, Inc March, 2024.|1
04595|038|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04595|039|R|  Pharmaceuticals LP July, 2024.|1
04595|040|R|3.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04595|041|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04595|042|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04595|043|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04595|044|R|  44(3):398-408.|5
04596|001|T|MONOGRAPH TITLE:  Rosuvastatin (<= 10 mg)/Danicopan|
04596|002|B||
04596|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04596|004|L|take action as needed.|
04596|005|B||
04596|006|A|MECHANISM OF ACTION:  Danicopan is an inhibitor of the BCRP transporter and|
04596|007|A|may increase the absorption and/or decrease the elimination of|
04596|008|A|rosuvastatin.(1-3)|
04596|009|B||
04596|010|E|CLINICAL EFFECTS:  Concurrent use of danicopan may result in increased|
04596|011|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3)|
04596|012|B||
04596|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04596|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04596|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04596|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04596|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04596|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04596|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04596|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04596|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04596|022|B||
04596|023|M|PATIENT MANAGEMENT:  The US manufacturer of danicopan states that the dose|
04596|024|M|of rosuvastatin should not exceed 10 mg daily when used concurrently with|
04596|025|M|danicopan.(1)|
04596|026|M|   Monitor patients closely for signs and symptoms of toxicity from|
04596|027|M|increased rosuvastatin concentrations.(1,2)|
04596|028|B||
04596|029|D|DISCUSSION:  In a study, danicopan (as steady state) increased the|
04596|030|D|area-under-curve (AUC) and maximum concentration (Cmax) of single-dose|
04596|031|D|rosuvastatin 20 mg by 2.2-fold and 3.3-fold, respectively.(1)|
04596|032|B||
04596|033|R|REFERENCES:|
04596|034|B||
04596|035|R|1.Voydeya (danicopan) tablets, US prescribing information. Alexion|1
04596|036|R|  Pharmaceuticals, Inc March, 2024.|1
04596|037|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04596|038|R|  Pharmaceuticals LP July, 2024.|1
04596|039|R|3.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04596|040|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04596|041|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04596|042|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04596|043|R|  44(3):398-408.|5
04597|001|T|MONOGRAPH TITLE:  Risperidone Intramuscular Monthly (Risvan)/Strong CYP3A4|
04597|002|T|Inducers|
04597|003|B||
04597|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04597|005|L|take action as needed.|
04597|006|B||
04597|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
04597|008|A|clearance of risperidone by CYP3A4.(1)|
04597|009|B||
04597|010|E|CLINICAL EFFECTS:  Strong CYP3A4 inducers may result in decreased levels and|
04597|011|E|effectiveness of risperidone.(1)|
04597|012|B||
04597|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04597|014|P|of the inducer for longer than 1-2 weeks.|
04597|015|B||
04597|016|M|PATIENT MANAGEMENT:  Patients receiving risperidone should be closely|
04597|017|M|monitored in the first 4-8 weeks of starting an inducer of CYP3A4.  The|
04597|018|M|dosage of risperidone may need to be adjusted.(1)|
04597|019|M|   The US manufacturer of risperidone for monthly intramuscular injections|
04597|020|M|(Risvan) states that patients on concurrent strong CYP3A4 inducers should|
04597|021|M|have their risperidone dosage increased as follows:|
04597|022|M|   - If patient is on risperidone 75 mg monthly, increase to 100 mg monthly.|
04597|023|M|   - If patient is on risperidone 100 mg monthly, consider additional oral|
04597|024|M|risperidone.|
04597|025|M|   If the CYP3A4 inducer is discontinued, reevaluate the risperidone dose|
04597|026|M|and lower it as needed.  In a patient taking 75 mg monthly, continue the 75|
04597|027|M|mg dose unless risperidone treatment interruption is judged to be|
04597|028|M|necessary.(1)|
04597|029|B||
04597|030|D|DISCUSSION:  In a clinical study, carbamazepine decreased the steady-state|
04597|031|D|plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%.|
04597|032|D|Plasma concentrations of carbamazepine were not significantly affected.(1)|
04597|033|D|   A study in 11 schizophrenic inpatients examined the effects of the|
04597|034|D|addition of carbamazepine (200 mg twice daily) for one week to risperidone|
04597|035|D|(3 mg twice daily).  Concurrent carbamazepine decreased plasma|
04597|036|D|concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by|
04597|037|D|50%, 44%, and 45%, respectively.(2)|
04597|038|D|   A study compared 23 patients receiving risperidone alone to 11 patients|
04597|039|D|receiving concurrent risperidone and carbamazepine.  The groups were matched|
04597|040|D|for sex, age, body weight, and risperidone dosage.  Plasma concentrations of|
04597|041|D|9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone|
04597|042|D|were significantly lower in patients receiving concurrent carbamazepine.|
04597|043|D|Five subjects received risperidone with and without carbamazepine.  In these|
04597|044|D|patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone|
04597|045|D|concentrations were lower during concurrent carbamazepine.(3)|
04597|046|D|   In a case report, a patient developed an exacerbation of psychotic|
04597|047|D|symptoms four weeks after the addition of carbamazepine (800 mg daily) to|
04597|048|D|his regimen.  Plasma levels of risperidone and 9-hydroxyrisperidone had|
04597|049|D|decreased by 77% and 63%, respectively.(4)|
04597|050|D|   In an open, randomized cross-over study in 10 healthy males, pretreatment|
04597|051|D|with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC)|
04597|052|D|and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg)|
04597|053|D|by 72% and 50%, respectively.(5)|
04597|054|D|   In a study in 10 healthy males, pretreatment with rifampin (600 mg daily|
04597|055|D|for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone|
04597|056|D|(1 mg) by 51% and 38%, respectively.  The AUC of 9-hydroxyrisperidone and|
04597|057|D|the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43%|
04597|058|D|and 45%, respectively.  The Cmax of 9-hydroxyrisperidone and the active|
04597|059|D|moieties decreased by 46% and 41%, respectively.(6)|
04597|060|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
04597|061|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04597|062|D|ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifampin,|
04597|063|D|rifapentine and St. John's Wort.(7,8)|
04597|064|B||
04597|065|R|REFERENCES:|
04597|066|B||
04597|067|R|1.Risvan (risperidone) US prescribing information. Laboratorios|1
04597|068|R|  Farmaceuticos Rovi S.A. Madrid, Spain March, 2024.|1
04597|069|R|2.Ono S, Mihara K, Suzuki A, Kondo T, Yasui-Furukori N, Furukori H, de Vries|2
04597|070|R|  R, Kaneko S. Significant pharmacokinetic interaction between risperidone|2
04597|071|R|  and carbamazepine: its relationship with CYP2D6 genotypes.|2
04597|072|R|  Psychopharmacology (Berl) 2002 Jun;162(1):50-4.|2
04597|073|R|3.Spina E, Avenoso A, Facciola G, Salemi M, Scordo MG, Giacobello T, Madia|2
04597|074|R|  AG, Perucca E. Plasma concentrations of risperidone and|2
04597|075|R|  9-hydroxyrisperidone: effect of comedication with carbamazepine or|2
04597|076|R|  valproate. Ther Drug Monit 2000 Aug;22(4):481-5.|2
04597|077|R|4.Spina E, Scordo MG, Avenoso A, Perucca E. Adverse drug interaction between|3
04597|078|R|  risperidone and carbamazepine in a patient with chronic schizophrenia and|3
04597|079|R|  deficient CYP2D6 activity. J Clin Psychopharmacol 2001 Feb;21(1):108-9.|3
04597|080|R|5.Mahatthanatrakul W, Nontaput T, Ridtitid W, Wongnawa M, Sunbhanich M.|2
04597|081|R|  Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of|2
04597|082|R|  antipsychotic risperidone in healthy volunteers. J Clin Pharm Ther 2007|2
04597|083|R|  Apr;32(2):161-7.|2
04597|084|R|6.Kim KA, Park PW, Liu KH, Kim KB, Lee HJ, Shin JG, Park JY. Effect of|2
04597|085|R|  rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics|2
04597|086|R|  of risperidone. J Clin Pharmacol 2008 Jan;48(1):66-72.|2
04597|087|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04597|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04597|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04597|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04597|091|R|  11/14/2017.|1
04597|092|R|8.This information is based on an extract from the Certara Drug Interaction|6
04597|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04598|001|T|MONOGRAPH TITLE:  Risperidone Intramuscular Monthly (Risvan)/Strong CYP2D6|
04598|002|T|Inhibitors|
04598|003|B||
04598|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04598|005|L|take action as needed.|
04598|006|B||
04598|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
04598|008|A|risperidone by CYP2D6.(1)|
04598|009|B||
04598|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2D6 inhibitors may result in|
04598|011|E|elevated levels of risperidone and an increase in risperidone side|
04598|012|E|effects.(1)|
04598|013|B||
04598|014|P|PREDISPOSING FACTORS:  None determined.|
04598|015|B||
04598|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with strong|
04598|017|M|CYP2D6 inhibitors with risperidone should be observed for increases in|
04598|018|M|risperidone side effects, including extrapyramidal and Parkinsonian|
04598|019|M|symptoms.|
04598|020|M|   The US manufacturer of risperidone for monthly intramuscular injection|
04598|021|M|(Risvan) makes the following recommendations for patients who receive a|
04598|022|M|strong CYP2D6 inhibitor:|
04598|023|M|   - Initiation of a CYP2D6 inhibitor: the recommended dose of risperidone|
04598|024|M|is 75 mg started at least 2 to 4 weeks prior to starting a strong CYP2D6|
04598|025|M|inhibitor to adjust for the expected increase in plasma concentrations of|
04598|026|M|risperidone.  When strong CYP2D6 inhibitors are initiated in patients|
04598|027|M|receiving risperidone 75 mg, it is recommended to continue treatment with 75|
04598|028|M|mg unless clinical judgment necessitates interruption of risperidone|
04598|029|M|treatment.|
04598|030|M|   - Discontinuation of a CYP2D6 inhibitor: the effects of discontinuation|
04598|031|M|of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and|
04598|032|M|9-hydroxyrisperidone (active metabolite) have not been studied.(1)|
04598|033|B||
04598|034|D|DISCUSSION:  A study in 10 patients examined the effects of fluoxetine (20|
04598|035|D|mg daily) on risperidone (4-6 mg/day).  One patient dropped out following|
04598|036|D|the development of severe akathisia after one week of fluoxetine.  Her|
04598|037|D|risperidone levels had increased 457%.  In the remaining patients,|
04598|038|D|fluoxetine increased risperidone levels by 308% at two weeks and by 733% at|
04598|039|D|four weeks.  Levels of the active moiety increased by 75% by four weeks.|
04598|040|D|During the second week of fluoxetine therapy, two patients developed|
04598|041|D|Parkinsonian symptoms.(2)|
04598|042|D|   A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers|
04598|043|D|examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg|
04598|044|D|daily). Concurrent fluoxetine increased the area-under-curve (AUC) of|
04598|045|D|risperidone and the active moiety by 29% and by 100%, respectively, in poor|
04598|046|D|metabolizers.  In extensive metabolizers, the AUC of risperidone and the|
04598|047|D|active moiety increased by 70% and 41%, respectively.(3)|
04598|048|D|   A study in 10 patients examined the effects of paroxetine (20 mg daily)|
04598|049|D|on risperidone (4-8 mg/day).  After two and four weeks of concurrent|
04598|050|D|therapy, risperidone concentrations increased 388% and 453%, respectively.|
04598|051|D|Plasma concentrations of the active moiety increased 39.4% and 44.5% after|
04598|052|D|two and four weeks of concurrent therapy, respectively.  No symptoms of|
04598|053|D|risperidone toxicity or change in extrapyramidal effects were noted.  One|
04598|054|D|patient developed Parkinsonism.(4)|
04598|055|D|   Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib,|
04598|056|D|fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)|
04598|057|B||
04598|058|R|REFERENCES:|
04598|059|B||
04598|060|R|1.Risvan (risperidone) US prescribing information. Laboratorios|1
04598|061|R|  Farmaceuticos Rovi S.A. Madrid, Spain March, 2024.|1
04598|062|R|2.Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E.|2
04598|063|R|  Inhibition of risperidone metabolism by fluoxetine in patients with|2
04598|064|R|  schizophrenia: a clinically relevant pharmacokinetic drug interaction. J|2
04598|065|R|  Clin Psychopharmacol 2002 Aug;22(4):419-23.|2
04598|066|R|3.Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The|2
04598|067|R|  effect of fluoxetine on the pharmacokinetics and safety of risperidone in|2
04598|068|R|  psychiatric patients. Pharmacopsychiatry 2002 Mar;35(2):50-6.|2
04598|069|R|4.Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A. Plasma|2
04598|070|R|  concentrations of risperidone and 9-hydroxyrisperidone during combined|2
04598|071|R|  treatment with paroxetine. Ther Drug Monit 2001 Jun;23(3):223-7.|2
04598|072|R|5.This information is based on an extract from the Certara Drug Interaction|6
04598|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04599|001|T|MONOGRAPH TITLE:  Risperidone Intramuscular Monthly/Bupropion|
04599|002|B||
04599|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04599|004|L|take action as needed.|
04599|005|B||
04599|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors such as bupropion may inhibit|
04599|007|A|the metabolism of risperidone.  Both agents are also known to lower the|
04599|008|A|seizure threshold.(1-3)|
04599|009|B||
04599|010|E|CLINICAL EFFECTS:  Concurrent administration of bupropion with risperidone|
04599|011|E|may result in elevated levels of and toxicity from risperidone.  Concurrent|
04599|012|E|use may also result in additive effects on the seizure threshold, increasing|
04599|013|E|the risk of seizures.(1-3)|
04599|014|B||
04599|015|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
04599|016|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
04599|017|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
04599|018|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics; a|
04599|019|P|total daily dose of bupropion greater than 450 mg or single doses greater|
04599|020|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
04599|021|P|oral hypoglycemics or insulin; or with concomitant medications known to|
04599|022|P|lower seizure threshold (antidepressants, theophylline, systemic|
04599|023|P|steroids).(1-2)|
04599|024|B||
04599|025|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and risperidone should|
04599|026|M|be undertaken only with extreme caution and with low initial bupropion|
04599|027|M|dosing, small gradual dosage increases of bupropion,(1-2) and reduced|
04599|028|M|dosages of risperidone.(3)  Single doses of bupropion should not exceed 150|
04599|029|M|mg.(1-2)  The maximum daily dose of bupropion should not exceed 300 mg for|
04599|030|M|smoking cessation(2) or 450 mg for depression.(1)|
04599|031|M|   The US manufacturer of risperidone for monthly intramuscular injection|
04599|032|M|(Risvan) makes the following recommendations for patients who receive a|
04599|033|M|strong CYP2D6 inhibitor, such as bupropion:|
04599|034|M|   - Initiation of a CYP2D6 inhibitor: the recommended dose of risperidone|
04599|035|M|is 75 mg started at least 2 to 4 weeks prior to starting a strong CYP2D6|
04599|036|M|inhibitor to adjust for the expected increase in plasma concentrations of|
04599|037|M|risperidone.  When strong CYP2D6 inhibitors are initiated in patients|
04599|038|M|receiving risperidone 75 mg, it is recommended to continue treatment with 75|
04599|039|M|mg unless clinical judgment necessitates interruption of risperidone|
04599|040|M|treatment.|
04599|041|M|   - Discontinuation of a CYP2D6 inhibitor: the effects of discontinuation|
04599|042|M|of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and|
04599|043|M|9-hydroxyrisperidone (active metabolite) have not been studied.(3)|
04599|044|B||
04599|045|D|DISCUSSION:  No specific drug interaction studies have been performed with|
04599|046|D|intramuscular risperidone extended-release formulation (Risvan) and|
04599|047|D|bupropion.|
04599|048|D|   The drug interaction data summarized is based on studies with oral|
04599|049|D|risperidone and other strong CYP2D6 inhibitors:|
04599|050|D|   A study in 10 patients examined the effects of fluoxetine (20 mg daily)|
04599|051|D|on risperidone (4-6 mg/day).  One patient dropped out following the|
04599|052|D|development of severe akathisia after one week of fluoxetine.  Her|
04599|053|D|risperidone levels had increased 457%.  In the remaining patients,|
04599|054|D|fluoxetine increased risperidone levels by 308% at two weeks and by 733% at|
04599|055|D|four weeks.  Levels of the active moiety increased by 75% by four weeks.|
04599|056|D|During the second week of fluoxetine therapy, two patients developed|
04599|057|D|Parkinsonian symptoms.(4)|
04599|058|D|   A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers|
04599|059|D|examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg|
04599|060|D|daily). Concurrent fluoxetine increased the area-under-curve (AUC) of|
04599|061|D|risperidone and the active moiety by 29% and by 100%, respectively, in poor|
04599|062|D|metabolizers.  In extensive metabolizers, the AUC of risperidone and the|
04599|063|D|active moiety increased by 70% and 41%, respectively.(5)|
04599|064|D|   A study in 10 patients examined the effects of paroxetine (20 mg daily)|
04599|065|D|on risperidone (4-8 mg/day).  After two and four weeks of concurrent|
04599|066|D|therapy, risperidone concentrations increased 388% and 453%, respectively.|
04599|067|D|Plasma concentrations of the active moiety increased 39.4% and 44.5% after|
04599|068|D|two and four weeks of concurrent therapy, respectively.  No symptoms of|
04599|069|D|risperidone toxicity or change in extrapyramidal effects were noted.  One|
04599|070|D|patient developed Parkinsonism.(6)|
04599|071|B||
04599|072|R|REFERENCES:|
04599|073|B||
04599|074|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
04599|075|R|  GlaxoSmithKline November, 2019.|1
04599|076|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
04599|077|R|  GlaxoSmithKline July, 2019.|1
04599|078|R|3.Risvan (risperidone) US prescribing information. Laboratorios|1
04599|079|R|  Farmaceuticos Rovi S.A. Madrid, Spain March, 2024.|1
04599|080|R|4.Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E.|2
04599|081|R|  Inhibition of risperidone metabolism by fluoxetine in patients with|2
04599|082|R|  schizophrenia: a clinically relevant pharmacokinetic drug interaction. J|2
04599|083|R|  Clin Psychopharmacol 2002 Aug;22(4):419-23.|2
04599|084|R|5.Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The|2
04599|085|R|  effect of fluoxetine on the pharmacokinetics and safety of risperidone in|2
04599|086|R|  psychiatric patients. Pharmacopsychiatry 2002 Mar;35(2):50-6.|2
04599|087|R|6.Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A. Plasma|2
04599|088|R|  concentrations of risperidone and 9-hydroxyrisperidone during combined|2
04599|089|R|  treatment with paroxetine. Ther Drug Monit 2001 Jun;23(3):223-7.|2
04600|001|T|MONOGRAPH TITLE:  Lecanemab/Anticoagulants|
04600|002|B||
04600|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04600|004|L|of severe adverse interaction.|
04600|005|B||
04600|006|A|MECHANISM OF ACTION:  Microhemorrhage has been reported with the use of|
04600|007|A|lecanemab.  Radiographic changes on brain MRI have been noted as amyloid|
04600|008|A|related imaging abnormalities-hemosiderin deposition (ARIA-H) which included|
04600|009|A|microhemorrhage.  In addition, intracerebral hemorrhages (ICH) greater than|
04600|010|A|1 cm in diameter have occurred in patients treated with lecanemab.(1)|
04600|011|B||
04600|012|E|CLINICAL EFFECTS:  Concurrent use of lecanemab with anticoagulants agents|
04600|013|E|may increase the risk of hemorrhage.(1)|
04600|014|B||
04600|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04600|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04600|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
04600|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04600|019|P|risk for bleeding (e.g. NSAIDs).|
04600|020|B||
04600|021|M|PATIENT MANAGEMENT:  The US manufacturer of lecanemab advises extreme|
04600|022|M|caution in patients treated with anticoagulants.  Evaluate the risks and|
04600|023|M|benefits of concurrent use of lecanemab with anticoagulants.(1)|
04600|024|M|   Appropriate use recommendations for lecanemab state patients on|
04600|025|M|anticoagulants should not receive lecanemab.(2)|
04600|026|M|   The UK manufacturer of lecanemab contraindicates initiation of lecanemab|
04600|027|M|in patients receiving ongoing anticoagulant therapy.  If anticoagulation is|
04600|028|M|necessary, then lecanemab should be paused.  Lecanemab can be reinstated if|
04600|029|M|anticoagulation is no longer medically indicated.(3)|
04600|030|M|   If concurrent therapy is warranted, patients should be closely monitored|
04600|031|M|for signs and symptoms of microhemorrhage, including headache,|
04600|032|M|nausea/vomiting, confusion, dizziness, visual disturbance, gait|
04600|033|M|difficulties, and loss of coordination, as well as other bleeding and|
04600|034|M|changes in platelet count or International Normalized Ratio (INR).(1)|
04600|035|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
04600|036|M|to monitor efficacy and safety of anticoagulation. Discontinue|
04600|037|M|anticoagulation in patients with active pathologic bleeding.|
04600|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04600|039|M|confusion, headache, dizziness, nausea, visual changes, unusual bleeding|
04600|040|M|from the gums or nose; unusual bruising; red or black, tarry stools; red,|
04600|041|M|pink or dark brown urine; acute abdominal or joint pain and/or swelling.|
04600|042|B||
04600|043|D|DISCUSSION:  In clinical studies, lecanemab was observed to increase ARIA-H,|
04600|044|D|including microhemorrhage and intracerebral hemorrhage.  Radiographic|
04600|045|D|changes were classified as mild (<=4 new incidences), moderate (5 to 9 new|
04600|046|D|incidences), or severe (10 or more new incidences.  Patients were excluded|
04600|047|D|from clinical trials if taking concurrent anticoagulants or|
04600|048|D|anti-platelets.(1)|
04600|049|D|   In Studies 1 and 2, the maximum severity of ARIA-H microhemorrhage was|
04600|050|D|mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of|
04600|051|D|patients.  Intracerebral hemorrhage greater than 1 cm in diameter was|
04600|052|D|reported in 0.7% (6/898) of patients in Study 2 after treatment with|
04600|053|D|lecanemab compared to 0.1% (1/897) on placebo. Fatal events of intracerebral|
04600|054|D|hemorrhage in patients taking lecanemab have been observed.(1)|
04600|055|D|   In Study 2, baseline use of antithrombotic medications (aspirin, other|
04600|056|D|antiplatelets, or anticoagulants) were allowed if patient was on a stable|
04600|057|D|dose.  Aspirin was the most common antithrombotic agent.  The incidence of|
04600|058|D|ICH was 0.9% (3/328 patients) in patients taking lecanemab with a|
04600|059|D|concomitant antithrombotic medication at the time of the event compared to|
04600|060|D|0.6% (3/545 patients) in those who did not receive an antithrombotic.|
04600|061|D|Patients taking lecanemab with an anticoagulant alone or combined with an|
04600|062|D|antiplatelet medication or aspirin had an incidence of intracerebral|
04600|063|D|hemorrhage of 2.5% (2/79 patients) compared to none in patients who received|
04600|064|D|placebo.|
04600|065|B||
04600|066|R|REFERENCES:|
04600|067|B||
04600|068|R|1.Leqembi (lecanemab-irmb) US prescribing information. Eisai Inc July, 2023.|1
04600|069|R|2.Cummings J, Apostolova L, Rabinovici GD, Atri A, Aisen P, Greenberg S,|6
04600|070|R|  Hendrix S, Selkoe D, Weiner M, Petersen RC, Salloway S. Lecanemab:|6
04600|071|R|  Appropriate Use Recommendations. J Prev Alzheimers Dis 2023;10(3):362-377.|6
04600|072|R|3.Leqembi (lecanemab) UK prescribing information. Eisai Ltd August 2024.|1
04601|001|T|MONOGRAPH TITLE:  Lecanemab/Thrombolytics|
04601|002|B||
04601|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04601|004|L|of severe adverse interaction.|
04601|005|B||
04601|006|A|MECHANISM OF ACTION:  Microhemorrhage has been reported with the use of|
04601|007|A|lecanemab.  Radiographic changes on brain MRI have been noted as amyloid|
04601|008|A|related imaging abnormalities-hemosiderin deposition (ARIA-H) which included|
04601|009|A|microhemorrhage.  In addition, intracerebral hemorrhages (ICH) greater than|
04601|010|A|1 cm in diameter have occurred in patients treated with lecanemab.(1)|
04601|011|B||
04601|012|E|CLINICAL EFFECTS:  Concurrent use of lecanemab with thrombolytic agents may|
04601|013|E|increase the risk of hemorrhage.(1)|
04601|014|B||
04601|015|P|PREDISPOSING FACTORS:  Patients with ongoing amyloid-related imaging|
04601|016|P|abnormalities (ARIA) may be at increased risk for post-thrombolytic|
04601|017|P|intracranial hemorrhage (ICH).|
04601|018|P|   The risk for bleeding episodes may be greater in patients with|
04601|019|P|disease-associated factors (e.g. thrombocytopenia).|
04601|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
04601|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04601|022|P|risk for bleeding (e.g. NSAIDs).|
04601|023|B||
04601|024|M|PATIENT MANAGEMENT:  Lecanemab should be used with extreme caution in|
04601|025|M|patients treated with thrombolytics.  Evaluate the risks and benefits of|
04601|026|M|concurrent use of lecanemab with thrombolytics.(1)|
04601|027|M|   Appropriate use recommendations for lecanemab state patients on lecanemab|
04601|028|M|should not receive thrombolytics.(2)|
04601|029|M|   If thrombolytics are warranted, patients receiving concurrent therapy|
04601|030|M|with lecanemab and thrombolytics should be closely monitored for signs and|
04601|031|M|symptoms of bleeding and changes in platelet count or symptoms associated|
04601|032|M|with ARIA-H.(1)|
04601|033|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04601|034|M|therapy for signs of microhemorrhage, including headache, nausea/vomiting,|
04601|035|M|confusion, dizziness, visual disturbance, gait difficulties, and loss of|
04601|036|M|coordination.  General signs of blood loss include decreased hemoglobin,|
04601|037|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
04601|038|M|evaluate patients with any symptoms.|
04601|039|M|   When applicable, perform computed tomography (CT) scans and magnetic|
04601|040|M|resonance imaging (MRIs) to monitor efficacy and safety of thrombolytic use|
04601|041|M|with lecanemab. Discontinue thrombolytics in patients with active pathologic|
04601|042|M|bleeding.(1)|
04601|043|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04601|044|M|confusion, headache, dizziness, nausea, visual changes, unusual bleeding|
04601|045|M|from the gums or nose; unusual bruising; red or black, tarry stools; red,|
04601|046|M|pink or dark brown urine; acute abdominal or joint pain and/or swelling.|
04601|047|B||
04601|048|D|DISCUSSION:  In a case report, a patient treated with thrombolytics for|
04601|049|D|acute stroke who had received lecanemab experienced severe, multi-focal|
04601|050|D|brain hemorrhages leading to death.(3)|
04601|051|D|   In clinical studies, lecanemab was observed to increase ARIA-H, including|
04601|052|D|microhemorrhage and intracerebral hemorrhage.  Radiographic changes were|
04601|053|D|classified as mild (<=4 new incidences), moderate (5 to 9 new incidences),|
04601|054|D|or severe (10 or more new incidences.  Patients were excluded from clinical|
04601|055|D|trials if taking concurrent anticoagulants or anti-platelets.(1)|
04601|056|D|   In Studies 1 and 2, the maximum severity of ARIA-H microhemorrhage was|
04601|057|D|mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of|
04601|058|D|patients.  Intracerebral hemorrhage greater than 1 cm in diameter was|
04601|059|D|reported in 0.7% (6/898) of patients in Study 2 after treatment with|
04601|060|D|lecanemab compared to 0.1% (1/897) on placebo. Fatal events of intracerebral|
04601|061|D|hemorrhage in patients taking lecanemab have been observed.(1)|
04601|062|B||
04601|063|R|REFERENCES:|
04601|064|B||
04601|065|R|1.Leqembi (lecanemab-irmb) US prescribing information. Eisai Inc July, 2023.|1
04601|066|R|2.Cummings J, Apostolova L, Rabinovici GD, Atri A, Aisen P, Greenberg S,|6
04601|067|R|  Hendrix S, Selkoe D, Weiner M, Petersen RC, Salloway S. Lecanemab:|6
04601|068|R|  Appropriate Use Recommendations. J Prev Alzheimers Dis 2023;10(3):362-377.|6
04601|069|R|3.Reish NJ, Jamshidi P, Stamm B, Flanagan ME, Sugg E, Tang M, Donohue KL,|3
04601|070|R|  McCord M, Krumpelman C, Mesulam MM, Castellani R, Chou SH. Multiple|3
04601|071|R|  Cerebral Hemorrhages in a Patient Receiving Lecanemab and Treated with|3
04601|072|R|  t-PA for Stroke. N Engl J Med 2023 Feb 2;388(5):478-479.|3
04601|073|R|4.Bilodeau PA, Dickson JR, Kozberg MG. The Impact of Anti-Amyloid|6
04601|074|R|  Immunotherapies on Stroke Care. J Clin Med 2024 Feb 22;13(5):.|6
04602|001|T|MONOGRAPH TITLE:  Encorafenib/CYP3A4 Inhibitors and Substrates that Prolong|
04602|002|T|QT|
04602|003|B||
04602|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04602|005|L|of severe adverse interaction.|
04602|006|B||
04602|007|A|MECHANISM OF ACTION:  Encorafenib is a CYP3A4 substrate and a strong CYP3A4|
04602|008|A|inducer.  Strong and moderate inhibitors of CYP3A4 may inhibit the|
04602|009|A|metabolism of encorafenib.  Also, the metabolism of sensitive substrates of|
04602|010|A|CYP3A4 may be induced by encorafenib.(1)|
04602|011|A|   Encorafenib may prolong the QTc interval.  Concomitant use with other QT|
04602|012|A|prolonging agents may result in an additive risk of QT prolongation.(1)|
04602|013|B||
04602|014|E|CLINICAL EFFECTS:  Concomitant use of encorafenib with agents that are both|
04602|015|E|strong or moderate CYP3A4 inhibitors and CYP3A4 substrates may result in|
04602|016|E|increased levels and effects from encorafenib including QT prolongation.|
04602|017|E|Concomitant use may also result in decreased levels and effectiveness of the|
04602|018|E|CYP3A4 substrate.(1)|
04602|019|B||
04602|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04602|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
04602|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04602|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04602|024|P|female gender, or advanced age.(2)|
04602|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04602|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04602|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04602|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04602|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04602|030|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04602|031|P|dysfunction).(2)|
04602|032|P|   Induction effects may be more likely with regular use of the inducer for|
04602|033|P|longer than 1-2 weeks.|
04602|034|B||
04602|035|M|PATIENT MANAGEMENT:  Avoid concomitant use of encorafenib with strong or|
04602|036|M|moderate CYP3A4 inhibitors that are also CYP3A4 substrates and prolong the|
04602|037|M|QTc interval.(1)|
04602|038|M|   The US manufacturer of encorafenib states that it should be avoided with|
04602|039|M|CYP3A4 substrates for which decreased plasma concentrations may result in|
04602|040|M|decreased therapeutic efficacy.  If coadministration cannot be avoided,|
04602|041|M|refer to the CYP3A4 substrate prescribing information for|
04602|042|M|recommendations.(1)|
04602|043|M|   In addition, concurrent use of strong or moderate CYP3A4 inhibitors or QT|
04602|044|M|prolonging medications with encorafenib should be avoided.(1)|
04602|045|M|   The net effect of this two-way interaction is unknown and optimal doses|
04602|046|M|of the drugs when used concurrently have not been determined.  The|
04602|047|M|manufacturer provides recommendations for dose modification when encorafenib|
04602|048|M|is used with a CYP3A4 inhibitor, but the recommendations may not apply when|
04602|049|M|there is a two-way interaction.  Dose modifications mentioned below are|
04602|050|M|informational only.|
04602|051|M|  If concurrent use of strong or moderate CYP3A4 inhibitors with encorafenib|
04602|052|M|is unavoidable, reduce the encorafenib dose as follows:|
04602|053|M|   - If the current daily dose of encorafenib is 450 mg, reduce encorafenib|
04602|054|M|to 150 mg with strong CYP3A4 inhibitors, and 225 mg with moderate CYP3A4|
04602|055|M|inhibitors.|
04602|056|M|   - If the current daily dose of encorafenib is 300 mg, reduce encorafenib|
04602|057|M|to 75 mg with strong CYP3A4 inhibitors, and 150 mg with moderate CYP3A4|
04602|058|M|inhibitors.|
04602|059|M|   - If the current daily dose of encorafenib is 225 mg or 150 mg, reduce|
04602|060|M|encorafenib to 75 mg with both strong and moderate CYP3A4 inhibitors.|
04602|061|M|   - After the inhibitor has been discontinued for 3 to 5 half-lives, resume|
04602|062|M|encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor.(1)|
04602|063|M|   When concurrent therapy cannot be avoided, monitor patients closely for|
04602|064|M|prolongation of the QT interval.  Obtain ECGs and electrolyte values (serum|
04602|065|M|calcium, magnesium, and potassium) at regular intervals.  Correct any|
04602|066|M|electrolyte abnormalities.|
04602|067|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
04602|068|M|fainting.|
04602|069|M|   Recommended dosage modifications for encorafenib and QTc prolongation|
04602|070|M|adverse reactions include:|
04602|071|M|   - QTcF greater than 500 ms and less than or equal to 60 ms increase from|
04602|072|M|baseline: Withhold encorafenib until QTcF less than or equal to 500 ms.|
04602|073|M|Resume at reduced dose.  If more than one recurrence, permanently|
04602|074|M|discontinue encorafenib.|
04602|075|M|   - QTcF greater than 500 ms and greater than 60 ms increase from baseline:|
04602|076|M|Permanently discontinue encorafenib.(1)|
04602|077|M|   See encorafenib prescribing information for additional information|
04602|078|M|regarding dose reductions.(1)|
04602|079|B||
04602|080|D|DISCUSSION:  Coadministration of posaconazole (strong CYP3A4 inhibitor) or|
04602|081|D|diltiazem (moderate CYP3A4 inhibitor) increased the area-under-curve (AUC)|
04602|082|D|of encorafenib by 3-fold and 2-fold, respectively, and increased the maximum|
04602|083|D|concentration (Cmax) by 68% and 45%, respectively, after a single dose of|
04602|084|D|encorafenib 50 mg (0.1 times the recommended dose).(1)|
04602|085|D|   Encorafenib 450 mg daily with binimetinib 45 mg twice daily decreased the|
04602|086|D|AUC and Cmax of single dose of midazolam 2 mg, a sensitive CYP3A4 substrate,|
04602|087|D|by 82% and 74%, respectively, relative to midazolam 2 mg alone.(1)|
04602|088|D|   Encorafenib has been associated with a dose-dependent QTc interval|
04602|089|D|prolongation.  Following administration of encorafenib in combination with|
04602|090|D|binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms|
04602|091|D|(14-22 ms), based on central tendency analysis.(1)|
04602|092|D|   Following administration of encorafenib in combination with cetuximab and|
04602|093|D|mFOLFOX6, an increase of QTcF >500 ms was measured in 3.6% (8/222) of|
04602|094|D|patients.(1)|
04602|095|D|   Agents that are linked to this monograph may have varying degrees of|
04602|096|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04602|097|D|been shown to prolong the QTc interval either through their mechanism of|
04602|098|D|action, through studies on their effects on the QTc interval, or through|
04602|099|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04602|100|D|and/or postmarketing reports.(3)|
04602|101|D|   Agents that are both strong CYP3A4 inhibitors and CYP3A4 substrates and|
04602|102|D|prolong the QTc interval linked to this monograph include: adagrasib,|
04602|103|D|ceritinib, clarithromycin, and ribociclib.(4)|
04602|104|D|   Agents that are both moderate CYP3A4 inhibitors and CYP3A4 substrates and|
04602|105|D|prolong the QTc interval linked to this monograph include: crizotinib,|
04602|106|D|dronedarone, erythromycin, oral lefamulin and nilotinib.(4)|
04602|107|B||
04602|108|R|REFERENCES:|
04602|109|B||
04602|110|R|1.Braftovi (encorafenib) capsules US prescribing information. Array|1
04602|111|R|  BioPharma December, 2024.|1
04602|112|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04602|113|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04602|114|R|  settings: a scientific statement from the American Heart Association and|6
04602|115|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04602|116|R|  2;55(9):934-47.|6
04602|117|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04602|118|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04602|119|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04602|120|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04602|121|R|4.This information is based on an extract from the Certara Drug Interaction|6
04602|122|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04603|001|T|MONOGRAPH TITLE:  Ivosidenib/CYP3A4 Inhibitors and Substrates|
04603|002|B||
04603|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04603|004|L|of severe adverse interaction.|
04603|005|B||
04603|006|A|MECHANISM OF ACTION:  Ivosidenib is a CYP3A4 substrate and a strong CYP3A4|
04603|007|A|inducer.  Strong and moderate inhibitors of CYP3A4 may inhibit the|
04603|008|A|metabolism of ivosidenib.  Also, the metabolism of sensitive substrates of|
04603|009|A|CYP3A4 may be induced by ivosidenib.(1)|
04603|010|B||
04603|011|E|CLINICAL EFFECTS:  Concomitant use of ivosidenib with agents that are both|
04603|012|E|strong or moderate CYP3A4 inhibitors and CYP3A4 substrates may result in|
04603|013|E|increased levels and effects from ivosidenib including QT prolongation.|
04603|014|E|Concomitant use may also result in decreased levels and effectiveness of the|
04603|015|E|CYP3A4 substrate.(1)|
04603|016|B||
04603|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04603|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04603|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04603|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04603|021|P|female gender, or advanced age.(2)|
04603|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04603|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04603|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04603|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04603|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04603|027|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04603|028|P|dysfunction).(2)|
04603|029|P|   Induction effects may be more likely with regular use of the inducer for|
04603|030|P|longer than 1-2 weeks.|
04603|031|B||
04603|032|M|PATIENT MANAGEMENT:  Avoid concomitant use of ivosidenib with strong or|
04603|033|M|moderate CYP3A4 inhibitors that are also CYP3A4 substrates.  Consider an|
04603|034|M|alternative concomitant medication with less potential for CYP3A4|
04603|035|M|interaction.(1)|
04603|036|M|   The US manufacturer of ivosidenib states that if coadministration with a|
04603|037|M|sensitive CYP3A4 substrate cannot be avoided, monitor patients for loss of|
04603|038|M|therapeutic effect of these drugs.(1)|
04603|039|M|   The net effect of this two-way interaction is unknown and optimal doses|
04603|040|M|of the drugs when used concurrently have not been determined.  The|
04603|041|M|manufacturer provides recommendations for dose modification when ivosidenib|
04603|042|M|is used with a CYP3A4 inhibitor, but the recommendations may not apply when|
04603|043|M|there is a two-way interaction.  Dose modifications mentioned below are|
04603|044|M|informational only.|
04603|045|M|   If coadministration of a strong CYP3A4 inhibitor cannot be avoided,|
04603|046|M|reduce ivosidenib dose to 250 mg once daily.  After the inhibitor has been|
04603|047|M|discontinued for at least 5 half-lives, resume the ivosidenib dose that was|
04603|048|M|taken prior initiating the CYP3A4 inhibitor (500 mg once daily).(1)|
04603|049|M|   No dose adjustment is recommended for ivosidenib when coadministered with|
04603|050|M|moderate CYP3A4 inhibitors.(1)|
04603|051|M|   When concurrent therapy cannot be avoided, monitor patients closely for|
04603|052|M|prolongation of the QT interval.  Obtain ECGs and electrolyte values (serum|
04603|053|M|calcium, magnesium, and potassium) at regular intervals.  Correct any|
04603|054|M|electrolyte abnormalities.|
04603|055|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
04603|056|M|fainting.|
04603|057|M|   Recommended dosage modifications for ivosidenib and QTc interval|
04603|058|M|prolongation adverse reactions include:|
04603|059|M|   - QTc interval greater than 480 msec (millisecond) and less than 500|
04603|060|M|msec: Monitor and supplement electrolyte levels as clinically indicated.|
04603|061|M|Review and adjust concomitant medications with known QTc interval-prolonging|
04603|062|M|effects.  Withhold ivosidenib until after the QT interval returns to less|
04603|063|M|than or equal to 480 msec.  Resume ivosidenib at a dose of 500 mg once|
04603|064|M|daily.  Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
04603|065|M|prolongation.|
04603|066|M|   - QTc interval greater than 500 msec: Monitor and supplement electrolyte|
04603|067|M|levels as clinically indicated.  Review and adjust concomitant medications|
04603|068|M|with known QTc interval-prolonging effects.   Withhold ivosidenib until|
04603|069|M|after the QT interval returns to within 30 msec of baseline or less than or|
04603|070|M|equal to 480 msec.  Resume ivosidenib at a reduced dose of 250 mg once|
04603|071|M|daily. Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
04603|072|M|prolongation. Consider re-escalating the dose of ivosidenib to 500 mg daily|
04603|073|M|if an alternative etiology for QTc prolongation can be identified.|
04603|074|M|   - QTc interval prolongation with signs/symptoms of life-threatening|
04603|075|M|arrhythmia: Permanently discontinue ivosidenib.(1)|
04603|076|M|   See ivosidenib prescribing information for additional information|
04603|077|M|regarding dose reductions.(1)|
04603|078|B||
04603|079|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
04603|080|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
04603|081|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
04603|082|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
04603|083|D|(Cmax).(1)|
04603|084|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
04603|085|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
04603|086|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
04603|087|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
04603|088|D|190%, respectively.(1)|
04603|089|D|   In a PBPK model, ivosidenib 500 mg for 15 days was predicted to decrease|
04603|090|D|the AUC and Cmax of midazolam 5 mg by 82% and 73%, respectively.(3)|
04603|091|D|   In clinical trials of ivosidenib, 9% of patients experienced a QTc|
04603|092|D|interval greater than 500 msec and 14% of patients had an increased from|
04603|093|D|baseline QTc interval of greater than 60 msec.  Patients with a baseline QTc|
04603|094|D|of equal to or greater than 450 msec without pre-existing bundle branch|
04603|095|D|block, or with a history of long QT syndrome were excluded from this|
04603|096|D|trial.(1)|
04603|097|D|   Agents that are both strong CYP3A4 inhibitors and CYP3A4 substrates|
04603|098|D|linked to this monograph include: mifepristone.(4)|
04603|099|D|   Agents that are both moderate CYP3A4 inhibitors and CYP3A4 substrates|
04603|100|D|linked to this monograph include: aprepitant, darunavir, diltiazem,|
04603|101|D|duvelisib, fosnetupitant, netupitant, rilzabrutinib, stiripentol, and|
04603|102|D|verapamil.(4)|
04603|103|B||
04603|104|R|REFERENCES:|
04603|105|B||
04603|106|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04603|107|R|  Inc. August, 2021.|1
04603|108|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04603|109|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04603|110|R|  settings: a scientific statement from the American Heart Association and|6
04603|111|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04603|112|R|  2;55(9):934-47.|6
04603|113|R|3.Bolleddula J, Ke A, Yang H, Prakash C. PBPK modeling to predict drug-drug|2
04603|114|R|  interactions of ivosidenib as a perpetrator in  cancer patients and|2
04603|115|R|  qualification of the Simcyp platform for CYP3A4 induction. CPT|2
04603|116|R|  Pharmacometrics Syst Pharmacol 2021 Jun;10(6):577-588.|2
04603|117|R|4.This information is based on an extract from the Certara Drug Interaction|6
04603|118|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04604|001|T|MONOGRAPH TITLE:  Ivosidenib/CYP3A4 Inhibitors and Substrates that Prolong|
04604|002|T|QT|
04604|003|B||
04604|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04604|005|L|of severe adverse interaction.|
04604|006|B||
04604|007|A|MECHANISM OF ACTION:  Ivosidenib is a CYP3A4 substrate and a strong CYP3A4|
04604|008|A|inducer.  Strong and moderate inhibitors of CYP3A4 may inhibit the|
04604|009|A|metabolism of ivosidenib.  Also, the metabolism of sensitive substrates of|
04604|010|A|CYP3A4 may be induced by ivosidenib.(1)|
04604|011|A|   Ivosidenib may prolong the QTc interval.  Concomitant use with other QT|
04604|012|A|prolonging agents may result in an additive risk of QT prolongation.(1)|
04604|013|B||
04604|014|E|CLINICAL EFFECTS:  Concomitant use of ivosidenib with agents that are both|
04604|015|E|strong or moderate CYP3A4 inhibitors and CYP3A4 substrates may result in|
04604|016|E|increased levels and effects from ivosidenib including QT prolongation.|
04604|017|E|Concomitant use may also result in decreased levels and effectiveness of the|
04604|018|E|CYP3A4 substrate.(1)|
04604|019|B||
04604|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04604|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
04604|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04604|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04604|024|P|female gender, or advanced age.(2)|
04604|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04604|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04604|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04604|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04604|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04604|030|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04604|031|P|dysfunction).(2)|
04604|032|P|   Induction effects may be more likely with regular use of the inducer for|
04604|033|P|longer than 1-2 weeks.|
04604|034|B||
04604|035|M|PATIENT MANAGEMENT:  Avoid concomitant use of ivosidenib with strong or|
04604|036|M|moderate CYP3A4 inhibitors that are also CYP3A4 substrates and prolong the|
04604|037|M|QTc interval.  Consider an alternative concomitant medication with less|
04604|038|M|potential for CYP3A4 interaction.(1)|
04604|039|M|   The US manufacturer of ivosidenib states that if coadministration with a|
04604|040|M|sensitive CYP3A4 substrate cannot be avoided, monitor patients for loss of|
04604|041|M|therapeutic effect of these drugs.(1)|
04604|042|M|   The net effect of this two-way interaction is unknown and optimal doses|
04604|043|M|of the drugs when used concurrently have not been determined.  The|
04604|044|M|manufacturer provides recommendations for dose modification when ivosidenib|
04604|045|M|is used with a CYP3A4 inhibitor, but the recommendations may not apply when|
04604|046|M|there is a two-way interaction.  Dose modifications mentioned below are|
04604|047|M|informational only.|
04604|048|M|   If coadministration of a strong CYP3A4 inhibitor cannot be avoided,|
04604|049|M|reduce ivosidenib dose to 250 mg once daily.  After the inhibitor has been|
04604|050|M|discontinued for at least 5 half-lives, resume the ivosidenib dose that was|
04604|051|M|taken prior initiating the CYP3A4 inhibitor (500 mg once daily).(1)|
04604|052|M|   No dose adjustment is recommended for ivosidenib when coadministered with|
04604|053|M|moderate CYP3A4 inhibitors.(1)|
04604|054|M|   When concurrent therapy cannot be avoided, monitor patients closely for|
04604|055|M|prolongation of the QT interval.  Obtain ECGs and electrolyte values (serum|
04604|056|M|calcium, magnesium, and potassium) at regular intervals.  Correct any|
04604|057|M|electrolyte abnormalities.(1)|
04604|058|M|   Instruct patients to report any irregular heartbeat, dizziness, or|
04604|059|M|fainting.|
04604|060|M|   Recommended dosage modifications for ivosidenib and QTc interval|
04604|061|M|prolongation adverse reactions include:|
04604|062|M|   - QTc interval greater than 480 msec (millisecond) and less than 500|
04604|063|M|msec: Monitor and supplement electrolyte levels as clinically indicated.|
04604|064|M|Review and adjust concomitant medications with known QTc interval-prolonging|
04604|065|M|effects.  Withhold ivosidenib until after the QT interval returns to less|
04604|066|M|than or equal to 480 msec.  Resume ivosidenib at a dose of 500 mg once|
04604|067|M|daily.  Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
04604|068|M|prolongation.|
04604|069|M|   - QTc interval greater than 500 msec: Monitor and supplement electrolyte|
04604|070|M|levels as clinically indicated.  Review and adjust concomitant medications|
04604|071|M|with known QTc interval-prolonging effects.   Withhold ivosidenib until|
04604|072|M|after the QT interval returns to within 30 msec of baseline or less than or|
04604|073|M|equal to 480 msec.  Resume ivosidenib at a reduced dose of 250 mg once|
04604|074|M|daily.  Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
04604|075|M|prolongation.  Consider re-escalating the dose of ivosidenib to 500 mg daily|
04604|076|M|if an alternative etiology for QTc prolongation can be identified.|
04604|077|M|   - QTc interval prolongation with signs/symptoms of life-threatening|
04604|078|M|arrhythmia: Permanently discontinue ivosidenib.(1)|
04604|079|M|   See ivosidenib prescribing information for additional information|
04604|080|M|regarding dose reductions.(1)|
04604|081|B||
04604|082|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
04604|083|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
04604|084|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
04604|085|D|(AUC) by 269%.  No change was seen in ivosidenib's maximum concentration|
04604|086|D|(Cmax).(1)|
04604|087|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
04604|088|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
04604|089|D|by 173%.  In regards to multiple-dosing, coadministration of ivosidenib with|
04604|090|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
04604|091|D|190%, respectively.(1)|
04604|092|D|   In a PBPK model, ivosidenib 500 mg for 15 days was predicted to decrease|
04604|093|D|the AUC and Cmax of midazolam 5 mg by 82% and 73%, respectively.(3)|
04604|094|D|   In clinical trials of ivosidenib, 9% of patients experienced a QTc|
04604|095|D|interval greater than 500 msec and 14% of patients had an increased from|
04604|096|D|baseline QTc interval of greater than 60 msec.  Patients with a baseline QTc|
04604|097|D|of equal to or greater than 450 msec without pre-existing bundle branch|
04604|098|D|block, or with a history of long QT syndrome were excluded from this|
04604|099|D|trial.(1)|
04604|100|D|   Agents that are linked to this monograph may have varying degrees of|
04604|101|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04604|102|D|been shown to prolong the QTc interval either through their mechanism of|
04604|103|D|action, through studies on their effects on the QTc interval, or through|
04604|104|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04604|105|D|and/or postmarketing reports.(3)|
04604|106|D|   Agents that are both strong CYP3A4 inhibitors and CYP3A4 substrates and|
04604|107|D|prolong the QTc interval linked to this monograph include: clarithromycin|
04604|108|D|and ribociclib.(4)|
04604|109|D|   Agents that are both moderate CYP3A4 inhibitors and CYP3A4 substrates and|
04604|110|D|prolong the QTc interval linked to this monograph include: erythromycin and|
04604|111|D|oral lefamulin.(4)|
04604|112|B||
04604|113|R|REFERENCES:|
04604|114|B||
04604|115|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
04604|116|R|  Inc. August, 2021.|1
04604|117|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04604|118|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04604|119|R|  settings: a scientific statement from the American Heart Association and|6
04604|120|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04604|121|R|  2;55(9):934-47.|6
04604|122|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04604|123|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04604|124|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04604|125|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04604|126|R|4.This information is based on an extract from the Certara Drug Interaction|6
04604|127|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04605|001|T|MONOGRAPH TITLE:  Lonafarnib/Moderate CYP3A4 Inhibitors|
04605|002|B||
04605|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04605|004|L|take action as needed.|
04605|005|B||
04605|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04605|007|A|of lonafarnib.(1)|
04605|008|B||
04605|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors with|
04605|010|E|lonafarnib may increase the risk of adverse reactions including QT|
04605|011|E|prolongation and potentially life-threatening cardiac arrhythmias like|
04605|012|E|torsades de pointes, nausea and vomiting, increased liver enzymes,|
04605|013|E|myelosuppression, and hypertension.(1)|
04605|014|B||
04605|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04605|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04605|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04605|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04605|019|P|female gender, or advanced age.(2)|
04605|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04605|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04605|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04605|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04605|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04605|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04605|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04605|027|B||
04605|028|M|PATIENT MANAGEMENT:  The use of lonafarnib with moderate CYP3A4 inhibitors|
04605|029|M|should be approached with caution.  No dose adjustment of lonafarnib is|
04605|030|M|recommended when moderate CYP3A4 inhibitors are added to steady-state|
04605|031|M|lonafarnib.  When initiating lonafarnib therapy in a patient already taking|
04605|032|M|a moderate CYP3A4 inhibitor, monitor the patient closely for the first 7|
04605|033|M|days of therapy.  If the patient does not tolerate lonafarnib, consider an|
04605|034|M|alternative that is not a moderate CYP3A4 inhibitor.(1)|
04605|035|M|   Lonafarnib dose modification recommendation: if the QTc interval is|
04605|036|M|greater than or equal to 500 msec, withhold lonafarnib until the QTc|
04605|037|M|interval is less than 470 msec, then resume lonafarnib at the same|
04605|038|M|dosage.(1)|
04605|039|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04605|040|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04605|041|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04605|042|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04605|043|B||
04605|044|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg lonafarnib|
04605|045|D|following 200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5|
04605|046|D|days, the area-under-curve (AUC) and maximum concentration (Cmax) were|
04605|047|D|increased by 425% and 270%, respectively.(1)|
04605|048|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
04605|049|D|berotralstat, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine,|
04605|050|D|fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir,|
04605|051|D|letermovir, netupitant, nirogacestat, schisandra, stiripentol, tofisopam,|
04605|052|D|treosulfan, verapamil, and voxelotor.(2,3)|
04605|053|B||
04605|054|R|REFERENCES:|
04605|055|B||
04605|056|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04605|057|R|  Inc. November, 2020.|1
04605|058|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
04605|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04605|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04605|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04605|062|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04605|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04605|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04605|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04605|066|R|  11/14/2017.|1
04605|067|R|4.This information is based on an extract from the Certara Drug Interaction|6
04605|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04606|001|T|MONOGRAPH TITLE:  Amiodarone/Strong CYP3A4 Inducers that Prolong QT|
04606|002|B||
04606|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04606|004|L|of severe adverse interaction.|
04606|005|B||
04606|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04606|007|A|amiodarone by CYP3A4.|
04606|008|A|   Concurrent use of agents that prolong the QTc interval may result in|
04606|009|A|additive effects on the QTc interval.(1-3)|
04606|010|B||
04606|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04606|012|E|decreased levels and effectiveness of amiodarone and increase the risk of|
04606|013|E|potentially life-threatening arrhythmias including torsades de pointes.(1-3)|
04606|014|B||
04606|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04606|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04606|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04606|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04606|019|P|female gender, or advanced age.(4)|
04606|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04606|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04606|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04606|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04606|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04606|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04606|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04606|027|P|   Induction effects may be more likely with regular use of the inducer for|
04606|028|P|longer than 1-2 weeks.|
04606|029|B||
04606|030|M|PATIENT MANAGEMENT:  The US manufacturer of amiodarone states that the|
04606|031|M|concurrent use of QT prolonging drugs should be avoided.  The need to|
04606|032|M|co-administer amiodarone with any other drug known to prolong the QTc|
04606|033|M|interval must be based on a careful assessment of the potential risks and|
04606|034|M|benefits of doing so for each patient.(1)|
04606|035|M|   The Australian(2) and UK(3) manufacturers of amiodarone states that|
04606|036|M|concurrent use of agents known to cause torsades de pointes is|
04606|037|M|contraindicated.|
04606|038|M|   The US manufacturer of amiodarone states concurrent use with CYP3A4|
04606|039|M|inducers may decrease amiodarone serum concentrations.  Consider monitoring|
04606|040|M|amiodarone serum concentrations during concurrent use.(1)|
04606|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04606|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04606|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04606|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04606|045|B||
04606|046|D|DISCUSSION:  Concurrent use of rifampin, another potent inducer of CYP3A4,|
04606|047|D|and amiodarone has been shown to decrease levels of amiodarone and|
04606|048|D|desethylamiodarone.(1)|
04606|049|D|   In a study in 5 healthy subjects, phenytoin (2-4 mg/kg/day) decreased|
04606|050|D|amiodarone levels (200 mg daily) by 32% to 49%.(5)|
04606|051|D|   Agents that are linked to this monograph may have varying degrees of|
04606|052|D|potential to prolong the QTc interval but are generally accepted to have a|
04606|053|D|risk of causing torsades de pointes.  Agents linked to this monograph have|
04606|054|D|been shown to prolong the QTc interval either through their mechanism of|
04606|055|D|action, through studies on their effects on the QTc interval, or through|
04606|056|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04606|057|D|and/or postmarketing reports.(6)|
04606|058|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04606|059|D|encorafenib and ivosidenib.(7)|
04606|060|B||
04606|061|R|REFERENCES:|
04606|062|B||
04606|063|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
04606|064|R|  Pharmaceuticals October, 2018.|1
04606|065|R|2.Cordarone X (amiodarone hydrochloride) Australian prescribing information.|1
04606|066|R|  Sanofi-Synthelabo Australia Pty Limited Augsut 15, 2007.|1
04606|067|R|3.Cordarone X (amiodarone hydrochloride) UK summary of product|1
04606|068|R|  characteristics. Sanofi-Aventis July 6, 2010.|1
04606|069|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04606|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04606|071|R|  settings: a scientific statement from the American Heart Association and|6
04606|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04606|073|R|  2;55(9):934-47.|6
04606|074|R|5.Nolan PE Jr, Marcus FI, Karol MD, Hoyer GL, Gear K. Effect of phenytoin on|2
04606|075|R|  the clinical pharmacokinetics of amiodarone. J Clin Pharmacol 1990 Dec;|2
04606|076|R|  30(12):1112-9.|2
04606|077|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
04606|078|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04606|079|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04606|080|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04606|081|R|7.This information is based on an extract from the Certara Drug Interaction|6
04606|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04607|001|T|MONOGRAPH TITLE:  Select Antimalarials/Strong CYP3A4 Inducers that Prolong|
04607|002|T|QT|
04607|003|B||
04607|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04607|005|L|of severe adverse interaction.|
04607|006|B||
04607|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04607|008|A|quinidine and quinine.(1-2)|
04607|009|A|   Concurrent use of agents that prolong the QTc interval may result in|
04607|010|A|additive effects on the QTc interval.(1-2)|
04607|011|B||
04607|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04607|013|E|decreased levels and effectiveness of quinidine and quinine, and increase|
04607|014|E|the risk of potentially life-threatening arrhythmias including torsades de|
04607|015|E|pointes.(1-2)|
04607|016|B||
04607|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04607|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04607|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04607|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04607|021|P|female gender, or advanced age.(3)|
04607|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04607|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04607|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04607|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04607|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04607|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04607|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04607|029|P|   Induction effects may be more likely with regular use of the inducer for|
04607|030|P|longer than 1-2 weeks.|
04607|031|B||
04607|032|M|PATIENT MANAGEMENT:  If possible, avoid the use of hydroquinidine or|
04607|033|M|quinidine with other agents known to prolong the QT interval.(1)|
04607|034|M|   The US manufacturer of quinine recommends avoiding the concurrent use of|
04607|035|M|strong CYP3A4 inducers because of the increased risk of malaria treatment|
04607|036|M|failure.(2)|
04607|037|M|   In patients receiving concurrent strong CYP3A4 inducers, monitor|
04607|038|M|quinidine or quinine serum levels and observe the patient for symptoms of|
04607|039|M|reduced efficacy.  Adjust the dosage accordingly.|
04607|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04607|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04607|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04607|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04607|044|B||
04607|045|D|DISCUSSION:  Several studies document the reduction in quinidine response in|
04607|046|D|patients receiving concurrent rifampin.  Decreased elimination half-life,|
04607|047|D|reduced area-under-curve (AUC), and low serum quinidine level were observed.|
04607|048|D|   In healthy volunteers, quinine AUC and maximum concentration (Cmax) were|
04607|049|D|reduced 85% and 55%, respectively, after a single dose of rifampin was added|
04607|050|D|after two weeks of quinine therapy.(1)|
04607|051|D|  In a randomized control trial of 59 male patients with Plasmodium|
04607|052|D|falciparum malaria, treatment with concomitant quinine and rifampin was|
04607|053|D|associated with a cure rate of only 35% compared to 88% in those treated|
04607|054|D|with quinine monotherapy.  The AUC of quinine during treatment days 3|
04607|055|D|through 7 was significantly reduced in the quinine plus rifampin group|
04607|056|D|compared to those treated with quinine alone (11.7 vs. 47.5 mcg/ml/day; p <|
04607|057|D|0.004).(4)|
04607|058|D|   In an open-label, cross-over study in 7 healthy subjects, concurrent|
04607|059|D|rifampin (600 mg daily) decreased the AUC and Cmax of a single dose of|
04607|060|D|mefloquine (500 mg) by 68% and 19%, respectively.(5)|
04607|061|D|   Agents that are linked to this monograph may have varying degrees of|
04607|062|D|potential to prolong the QTc interval but are generally accepted to have a|
04607|063|D|risk of causing torsades de pointes.  Agents linked to this monograph have|
04607|064|D|been shown to prolong the QTc interval either through their mechanism of|
04607|065|D|action, through studies on their effects on the QTc interval, or through|
04607|066|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04607|067|D|and/or postmarketing reports.(6)|
04607|068|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04607|069|D|encorafenib and ivosidenib.(7)|
04607|070|B||
04607|071|R|REFERENCES:|
04607|072|B||
04607|073|R|1.Quinidine sulfate US prescribing informaiton. Epic Pharma, LLC November,|1
04607|074|R|  2023.|1
04607|075|R|2.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
04607|076|R|  Industries, Inc. August, 2019.|1
04607|077|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04607|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04607|079|R|  settings: a scientific statement from the American Heart Association and|6
04607|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04607|081|R|  2;55(9):934-47.|6
04607|082|R|4.Pukrittayakamee S, Prakongpan S, Wanwimolruk S, Clemens R, Looareesuwan S,|2
04607|083|R|  White NJ. Adverse effect of rifampin on quinine efficacy in uncomplicated|2
04607|084|R|  falciparum malaria. Antimicrob Agents Chemother 2003 May;47(5):1509-13.|2
04607|085|R|5.Ridtitid W, Wongnawa M, Mahatthanatrakul W, Chaipol P, Sunbhanich M.|2
04607|086|R|  Effect of rifampin on plasma concentrations of mefloquine in healthy|2
04607|087|R|  volunteers. J Pharm Pharmacol 2000 Oct;52(10):1265-9.|2
04607|088|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
04607|089|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04607|090|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04607|091|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04607|092|R|7.This information is based on an extract from the Certara Drug Interaction|6
04607|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04608|001|T|MONOGRAPH TITLE:  Ivabradine/Strong CYP3A4 Inducers that Prolong QT|
04608|002|B||
04608|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04608|004|L|of severe adverse interaction.|
04608|005|B||
04608|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04608|007|A|ivabradine by CYP3A4.|
04608|008|A|   Concurrent use of agents that prolong the QTc interval may result in|
04608|009|A|additive effects on the QTc interval.(1)|
04608|010|B||
04608|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04608|012|E|decreased levels and effectiveness of ivabradine and increase the risk of|
04608|013|E|potentially life-threatening arrhythmias including torsades de pointes.(1)|
04608|014|B||
04608|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04608|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04608|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04608|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04608|019|P|female gender, or advanced age.(2)|
04608|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04608|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04608|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04608|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04608|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04608|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04608|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04608|027|P|   Induction effects may be more likely with regular use of the inducer for|
04608|028|P|longer than 1-2 weeks.|
04608|029|B||
04608|030|M|PATIENT MANAGEMENT:  The concurrent use of strong CYP3A4 inducers that|
04608|031|M|prolong QT should be avoided during ivabradine therapy.  If concurrent use|
04608|032|M|is necessary, monitor patients for signs and symptoms of worsening heart|
04608|033|M|failure and heart rate greater than 60 bpm.(1)|
04608|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04608|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04608|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04608|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04608|038|B||
04608|039|D|DISCUSSION:  Concurrent use of St. John's wort with ivabradine (10 mg twice|
04608|040|D|daily) decreased ivabradine area-under-curve (AUC) by 50%.(1)|
04608|041|D|   Agents that are linked to this monograph may have varying degrees of|
04608|042|D|potential to prolong the QTc interval but are generally accepted to have a|
04608|043|D|risk of causing torsades de pointes.  Agents linked to this monograph have|
04608|044|D|been shown to prolong the QTc interval either through their mechanism of|
04608|045|D|action, through studies on their effects on the QTc interval, or through|
04608|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04608|047|D|and/or postmarketing reports.(3)|
04608|048|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04608|049|D|encorafenib and ivosidenib.(4)|
04608|050|B||
04608|051|R|REFERENCES:|
04608|052|B||
04608|053|R|1.Corlanor (ivabradine) US prescribing information. Amgen, Inc. August,|1
04608|054|R|  2021.|1
04608|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04608|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04608|057|R|  settings: a scientific statement from the American Heart Association and|6
04608|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04608|059|R|  2;55(9):934-47.|6
04608|060|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04608|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04608|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04608|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04608|064|R|4.This information is based on an extract from the Certara Drug Interaction|6
04608|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04609|001|T|MONOGRAPH TITLE:  Macimorelin/Strong CYP3A4 Inducers that Prolong QT|
04609|002|B||
04609|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04609|004|L|of severe adverse interaction.|
04609|005|B||
04609|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04609|007|A|macimorelin by CYP3A4.|
04609|008|A|   Concurrent use of agents that prolong the QTc interval may result in|
04609|009|A|additive effects on the QTc interval.(1)|
04609|010|B||
04609|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04609|012|E|decreased levels and effectiveness of macimorelin and increase the risk of|
04609|013|E|potentially life-threatening arrhythmias including torsades de pointes.(1)|
04609|014|B||
04609|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04609|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04609|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04609|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04609|019|P|female gender, or advanced age.(2)|
04609|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04609|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04609|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04609|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04609|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04609|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04609|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04609|027|P|   Induction effects may be more likely with regular use of the inducer for|
04609|028|P|longer than 1-2 weeks.|
04609|029|B||
04609|030|M|PATIENT MANAGEMENT:  Avoid the concurrent use of macimorelin with strong|
04609|031|M|CYP3A4 inducers that prolong the QT interval.(1)|
04609|032|M|   The US manufacturer of macimorelin states concurrent use with a strong|
04609|033|M|CYP3A4 inducer may reduce the plasma macimorelin concentrations and may lead|
04609|034|M|to false positive test results.  Discontinue strong CYP3A4 inducers prior to|
04609|035|M|macimorelin use.  Sufficient washout time of strong CYP3A4 inducers prior to|
04609|036|M|administration of macimorelin is recommended.(1)|
04609|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04609|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04609|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04609|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04609|041|B||
04609|042|D|DISCUSSION:  In vitro data suggests CYP3A4 is the major metabolism pathway|
04609|043|D|for macimorelin.(1)|
04609|044|D|   In a thorough QT study in 60 healthy subjects, a supra-therapeutic dose|
04609|045|D|of macimorelin (2mg/kg, 4 times the recommended dosage) produced a mean|
04609|046|D|change in QTc of 9.6 msec (upper 95% CI of 11.4 msec).  Similar effects were|
04609|047|D|seen in a single-ascending dose study which examined dosages of 1.5 mg/kg, 1|
04609|048|D|mg/kg, and 2 mg/kg, suggesting an absence of dose-dependent changes.(1)|
04609|049|D|   Agents that are linked to this monograph may have varying degrees of|
04609|050|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04609|051|D|been shown to prolong the QTc interval either through their mechanism of|
04609|052|D|action, through studies on their effects on the QTc interval, or through|
04609|053|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04609|054|D|and/or postmarketing reports.(3)|
04609|055|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04609|056|D|encorafenib and ivosidenib.(4)|
04609|057|B||
04609|058|R|REFERENCES:|
04609|059|B||
04609|060|R|1.Macrilen (macimorelin) US prescribing information. Aeterna Zentaris GmbH|1
04609|061|R|  December, 2017.|1
04609|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04609|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04609|064|R|  settings: a scientific statement from the American Heart Association and|6
04609|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04609|066|R|  2;55(9):934-47.|6
04609|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04609|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04609|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04609|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04609|071|R|4.This information is based on an extract from the Certara Drug Interaction|6
04609|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04610|001|T|MONOGRAPH TITLE:  Midostaurin/Strong CYP3A4 Inducers that Prolong QT|
04610|002|B||
04610|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04610|004|L|of severe adverse interaction.|
04610|005|B||
04610|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04610|007|A|midostaurin by CYP3A4.|
04610|008|A|   Concurrent use of agents that prolong the QTc interval may result in|
04610|009|A|additive effects on the QTc interval.(1)|
04610|010|B||
04610|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04610|012|E|decreased levels and effectiveness of midostaurin and increase the risk of|
04610|013|E|potentially life-threatening arrhythmias including torsades de pointes.(1)|
04610|014|B||
04610|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04610|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04610|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04610|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04610|019|P|female gender, or advanced age.(2)|
04610|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04610|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04610|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04610|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04610|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04610|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04610|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04610|027|P|   Induction effects may be more likely with regular use of the inducer for|
04610|028|P|longer than 1-2 weeks.|
04610|029|B||
04610|030|M|PATIENT MANAGEMENT:  The manufacturer of midostaurin states to avoid|
04610|031|M|concurrent use with strong CYP3A4 inducers and recommends caution in|
04610|032|M|patients treated with drugs that affect the QTc interval.(1)|
04610|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04610|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04610|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04610|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04610|037|B||
04610|038|D|DISCUSSION:  Midostaurin is a substrate of CYP3A4.(1)|
04610|039|D|   Concurrent administration of rifampin (600 mg daily for 14 days, a strong|
04610|040|D|CYP3A4 inducer) with a single 50 mg dose of midostaurin on day 9 decreased|
04610|041|D|the area-under-curve (AUC) of midostaurin and CGP62221, the active|
04610|042|D|metabolite, by 96% and 92%, respectively.  The AUC over time to last|
04610|043|D|measurable concentration of CGP62221 decreased by 59%.(1)|
04610|044|D|   In a randomized study of midostaurin 75 mg twice daily for 3 days there|
04610|045|D|was no clinically significant prolongation of QTc interval or relationship|
04610|046|D|between changes in QTc and concentrations for midostaurin and its active|
04610|047|D|metabolites (CGP62221 and CGP52421).  However the study noted the duration|
04610|048|D|was not long enough to estimate the effects of the metabolite CGP52421 on|
04610|049|D|the QTc interval.(1)|
04610|050|D|   In a pooled analysis in patients with advanced systemic mastocytosis|
04610|051|D|(SM), 4.7% patients had a post-baseline QTcF > 480 ms, no patients had a|
04610|052|D|QTcF > 500 ms, and 6.3% patients had a QTcF > 60 ms compared to baseline.(2)|
04610|053|D|   In a randomized placebo-controlled study in patients with acute myeloid|
04610|054|D|leukemia (AML), the proportion of patients with QTc prolongation was higher|
04610|055|D|in the midostaurin group compared to placebo (QTcF > 480 ms: 10.1% vs 5.7%;|
04610|056|D|QTcF > 500 ms: 6.2% vs 2.6%; QTcF > 60 ms change from baseline: 18.4% vs|
04610|057|D|10.7%).(1)|
04610|058|D|   Agents that are linked to this monograph may have varying degrees of|
04610|059|D|potential to prolong the QTc interval but are generally accepted to have a|
04610|060|D|risk of causing torsades de pointes.  Agents linked to this monograph have|
04610|061|D|been shown to prolong the QTc interval either through their mechanism of|
04610|062|D|action, through studies on their effects on the QTc interval, or through|
04610|063|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04610|064|D|and/or postmarketing reports.(3)|
04610|065|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04610|066|D|encorafenib and ivosidenib.(4)|
04610|067|B||
04610|068|R|REFERENCES:|
04610|069|B||
04610|070|R|1.Rydapt (midostaurin) US prescribing information. Novartis Pharmaceuticals|1
04610|071|R|  Corporation November, 2021.|1
04610|072|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04610|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04610|074|R|  settings: a scientific statement from the American Heart Association and|6
04610|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04610|076|R|  2;55(9):934-47.|6
04610|077|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04610|078|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04610|079|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04610|080|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04610|081|R|4.This information is based on an extract from the Certara Drug Interaction|6
04610|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04611|001|T|MONOGRAPH TITLE:  Osimertinib/Strong CYP3A4 Inducers that Prolong QT|
04611|002|B||
04611|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04611|004|L|of severe adverse interaction.|
04611|005|B||
04611|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04611|007|A|osimertinib by CYP3A4.|
04611|008|A|   Concurrent use of agents that prolong the QTc interval may result in|
04611|009|A|additive effects on the QTc interval.(1)|
04611|010|B||
04611|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04611|012|E|decreased levels and effectiveness of osimertinib and increase the risk of|
04611|013|E|potentially life-threatening arrhythmias including torsades de pointes.(1)|
04611|014|B||
04611|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04611|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04611|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04611|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04611|019|P|female gender, or advanced age.(2)|
04611|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04611|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04611|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04611|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04611|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04611|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04611|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04611|027|P|   Induction effects may be more likely with regular use of the inducer for|
04611|028|P|longer than 1-2 weeks.|
04611|029|B||
04611|030|M|PATIENT MANAGEMENT:  The US manufacturer of osimertinib states that|
04611|031|M|concurrent use of CYP3A4 inducers that prolong QT should be avoided.  If|
04611|032|M|concurrent therapy cannot be avoided increase the osimertinib dose to 160 mg|
04611|033|M|daily.  Resume osimertinib at 80 mg three weeks after the discontinuation of|
04611|034|M|the strong CYP3A4 inducer.|
04611|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04611|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04611|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04611|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04611|039|M|   Dose adjustments for prolonged QTc interval(1):|
04611|040|M|    - If QTc is greater than 500 msec on at least 2 separate ECGs, withhold|
04611|041|M|osimertinib until QTc is < 481 msec or recovery to baseline (if baseline QTc|
04611|042|M|was greater than or equal to 481 msec), then resume osimertinib at 40 mg per|
04611|043|M|day.|
04611|044|M|    - For QTc prolongation with signs or symptoms of life threatening|
04611|045|M|arrhythmia, permanently discontinue osimertinib.(1)|
04611|046|B||
04611|047|D|DISCUSSION:  In a clinical pharmacokinetic study, the AUC of osimertinib was|
04611|048|D|reduced by 78% in patients when coadministered with rifampin (600 mg daily|
04611|049|D|for 21 days).(1)|
04611|050|D|   A retrospective review of 618 cancer patients treated with 902|
04611|051|D|administrations of tyrosine kinase inhibitors were evaluated for rate and|
04611|052|D|incidence of QTc prolongation.  In patients who received osimertinib, QTc|
04611|053|D|prolongation was identified in 4 (25%) with 1 (25%) having Grade 1 (QTc|
04611|054|D|450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms).  Grade 3 events|
04611|055|D|occurred in 1 (25%) having QTc greater than or equal to 500 ms and 1 (25%)|
04611|056|D|having QTc change greater than or equal to 60 ms.  No patients had|
04611|057|D|ventricular tachycardia, sudden cardiac death, or TdP.(3)|
04611|058|D|   In clinical studies of 1813 patients treated with osimertinib|
04611|059|D|monotherapy, 1.1% of patients were found to have a QTc interval greater than|
04611|060|D|500 ms and 4.3% of patients had an increase from baseline QTc > 60 ms.(1)|
04611|061|D|   Agents that are linked to this monograph may have varying degrees of|
04611|062|D|potential to prolong the QTc interval but are generally accepted to have a|
04611|063|D|risk of causing torsades de pointes.  Agents linked to this monograph have|
04611|064|D|been shown to prolong the QTc interval either through their mechanism of|
04611|065|D|action, through studies on their effects on the QTc interval, or through|
04611|066|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04611|067|D|and/or postmarketing reports.(4)|
04611|068|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04611|069|D|encorafenib and ivosidenib.(5)|
04611|070|B||
04611|071|R|REFERENCES:|
04611|072|B||
04611|073|R|1.Tagrisso (osimertinib) US prescribing information. AstraZeneca|1
04611|074|R|  Pharmaceuticals September, 2024.|1
04611|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04611|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04611|077|R|  settings: a scientific statement from the American Heart Association and|6
04611|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04611|079|R|  2;55(9):934-47.|6
04611|080|R|3.Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc|2
04611|081|R|  Prolongation Among Cancer Patients Treated with Tyrosine Kinase|2
04611|082|R|  Inhibitors. Int J Cancer. 2020 May 25.|2
04611|083|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04611|084|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04611|085|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04611|086|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04611|087|R|5.This information is based on an extract from the Certara Drug Interaction|6
04611|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04612|001|T|MONOGRAPH TITLE:  Tacrolimus/Strong CYP3A4 Inducers that Prolong QT|
04612|002|B||
04612|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04612|004|L|of severe adverse interaction.|
04612|005|B||
04612|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04612|007|A|tacrolimus by CYP3A4.|
04612|008|A|   Concurrent use of agents that prolong the QTc interval may result in|
04612|009|A|additive effects on the QTc interval.(1)|
04612|010|B||
04612|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04612|012|E|decreased levels and effectiveness of tacrolimus and increase the risk of|
04612|013|E|potentially life-threatening arrhythmias including torsades de pointes.(1)|
04612|014|B||
04612|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04612|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04612|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04612|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04612|019|P|female gender, or advanced age.(2)|
04612|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04612|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04612|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04612|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04612|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04612|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04612|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04612|027|P|   Induction effects may be more likely with regular use of the inducer for|
04612|028|P|longer than 1-2 weeks.|
04612|029|B||
04612|030|M|PATIENT MANAGEMENT:  If possible, consider alternatives to strong CYP3A4|
04612|031|M|inducers in patients maintained on tacrolimus.  If concurrent therapy is|
04612|032|M|warranted, monitor tacrolimus serum levels and observe the patient for graft|
04612|033|M|rejection.  The dosage of tacrolimus may need to be adjusted following the|
04612|034|M|initiation or discontinuation of these agents.(1)|
04612|035|M|   The American Society of Transplantation guidelines state that tacrolimus|
04612|036|M|should be avoided in combination with rifabutin and rifampin, other CYP3A4|
04612|037|M|inducers.  If concurrent therapy with rifampin is needed, increase the dose|
04612|038|M|of tacrolimus by 2-fold when the combination is initiated and monitor|
04612|039|M|tacrolimus concentrations frequently with rapid subsequent dose increases as|
04612|040|M|needed.  The reverse is recommended when rifampin is discontinued.(3)|
04612|041|M|   Concurrent use of tacrolimus with agents known to prolong the QT interval|
04612|042|M|should be approached with caution.  Monitoring for QT prolongation is|
04612|043|M|recommended.(1)|
04612|044|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04612|045|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04612|046|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04612|047|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04612|048|B||
04612|049|D|DISCUSSION:  A study in six healthy subjects examined the effects of|
04612|050|D|rifampin (a strong CYP3A4 inducer) on single doses of oral (0.1 mg/kg) and|
04612|051|D|intravenous (0.025 mg/kg/4 hours) tacrolimus.  Rifampin increased tacrolimus|
04612|052|D|clearance by 47% and decreased tacrolimus bioavailability by 51%.(4)|
04612|053|D|   In a study in 10 healthy subjects, pretreatment with St. John's wort (300|
04612|054|D|mg 3 times daily for 18 days), a strong CYP3A4 inducer, decreased the AUC of|
04612|055|D|a single dose of tacrolimus (0.1 mg/kg) by 35.3%.  Tacrolimus apparent oral|
04612|056|D|clearance and volume of distribution increased by 68% and 53%,|
04612|057|D|respectively.(5)|
04612|058|D|   In a study in 10 renal transplant patients, concurrent St. John's wort|
04612|059|D|(600 mg daily) for 2 weeks increased tacrolimus dose requirements from a|
04612|060|D|baseline of 4.5 mg/day to 8.0 mg/day.  Dose-correct tacrolimus AUC decreased|
04612|061|D|by 57.8%.(6)|
04612|062|D|   There have been several case reports of decreased tacrolimus levels with|
04612|063|D|other strong CYP3A4 inducers including carbamazepine, phenobarbital,|
04612|064|D|phenytoin, rifampin, and St. John's wort.(7-14)|
04612|065|D|   Phenobarbital and phenytoin have been used successfully to treat|
04612|066|D|tacrolimus overdose.(15-17)|
04612|067|D|   Tacrolimus has been associated with QT prolongation.(1)|
04612|068|D|   In a kidney transplant population, 98 patients received immunosuppressive|
04612|069|D|management with tacrolimus, cyclosporine, everolimus, or azathioprine.  All|
04612|070|D|patients post-transplant had significantly prolonged QTc interval compared|
04612|071|D|to pre-transplant in all groups.(18)|
04612|072|D|   Agents that are linked to this monograph may have varying degrees of|
04612|073|D|potential to prolong the QTc interval but are generally accepted to have a|
04612|074|D|risk of causing torsades de pointes.  Agents linked to this monograph have|
04612|075|D|been shown to prolong the QTc interval either through their mechanism of|
04612|076|D|action, through studies on their effects on the QTc interval, or through|
04612|077|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04612|078|D|and/or postmarketing reports.(19)|
04612|079|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04612|080|D|encorafenib and ivosidenib.(20)|
04612|081|B||
04612|082|R|REFERENCES:|
04612|083|B||
04612|084|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04612|085|R|  August, 2023.|1
04612|086|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04612|087|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04612|088|R|  settings: a scientific statement from the American Heart Association and|6
04612|089|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04612|090|R|  2;55(9):934-47.|6
04612|091|R|3.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
04612|092|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
04612|093|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
04612|094|R|  e13510.|6
04612|095|R|4.Hebert MF, Fisher RM, Marsh CL, Dressler D, Bekersky I. Effects of|2
04612|096|R|  rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin|2
04612|097|R|  Pharmacol 1999 Jan;39(1):91-6.|2
04612|098|R|5.Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John's|2
04612|099|R|  wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy|2
04612|100|R|  volunteers. J Clin Pharmacol 2004 Jan;44(1):89-94.|2
04612|101|R|6.Mai I, Stormer E, Bauer S, Kruger H, Budde K, Roots I. Impact of St John's|2
04612|102|R|  wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid|2
04612|103|R|  in renal transplant patients. Nephrol Dial Transplant 2003 Apr;|2
04612|104|R|  18(4):819-22.|2
04612|105|R|7.Wada K, Takada M, Sakai M, Ochi H, Kotake T, Okada H, Morishita H, Oda N,|3
04612|106|R|  Mano A, Kato TS, Komamura K, Nakatani T. Drug interaction between|3
04612|107|R|  tacrolimus and carbamazepine in a Japanese heart transplant recipient: a|3
04612|108|R|  case report. J Heart Lung Transplant 2009 Apr;28(4):409-11.|3
04612|109|R|8.Siddiqi N, Marfo K. Clinically significant drug-drug interaction between|3
04612|110|R|  tacrolimus and phenobarbital: the price we pay. J Pharm Pract 2010 Dec;|3
04612|111|R|  23(6):585-9.|3
04612|112|R|9.Wada K, Takada M, Ueda T, Ochi H, Kotake T, Morishita H, Hanatani A,|3
04612|113|R|  Nakatani T. Drug interactions between tacrolimus and phenytoin in Japanese|3
04612|114|R|  heart transplant recipients: 2 case reports. Int J Clin Pharmacol Ther|3
04612|115|R|  2007 Sep;45(9):524-8.|3
04612|116|R|10.Kiuchi T, Tanaka K, Inomata Y, Uemoto S, Satomura K, Egawa H, Uyama S,|3
04612|117|R|   Sano K, Okajima H, Yamaoka Y. Experience of tacrolimus-based|3
04612|118|R|   immunosuppression in living-related liver transplantation complicated|3
04612|119|R|   with graft tuberculosis: interaction with rifampicin and side effects.|3
04612|120|R|   Transplant Proc 1996 Dec;28(6):3171-2.|3
04612|121|R|11.Furlan V, Perello L, Jacquemin E, Debray D, Taburet AM. Interactions|3
04612|122|R|   between FK506 and rifampicin or erythromycin in pediatric liver|3
04612|123|R|   recipients. Transplantation 1995 Apr 27;59(8):1217-8.|3
04612|124|R|12.Bhaloo S, Prasad GV. Severe reduction in tacrolimus levels with rifampin|3
04612|125|R|   despite multiple cytochrome P450 inhibitors: a case report. Transplant|3
04612|126|R|   Proc 2003 Nov;35(7):2449-51.|3
04612|127|R|13.Chenhsu RY, Loong CC, Chou MH, Lin MF, Yang WC. Renal allograft|3
04612|128|R|   dysfunction associated with rifampin-tacrolimus interaction. Ann|3
04612|129|R|   Pharmacother 2000 Jan;34(1):27-31.|3
04612|130|R|14.Abdel Halim M, Al-Otaibi T, Gheith O, El-Kholy O, Abdel Tawab K, Said T,|3
04612|131|R|   Nair P, Nampoory MR. Toxic tacrolimus blood levels with rifampin|3
04612|132|R|   administration in a renal transplant  recipient. Ann Transplant 2010|3
04612|133|R|   Jan-Mar;15(1):57-60.|3
04612|134|R|15.Karasu Z, Gurakar A, Carlson J, Pennington S, Kerwin B, Wright H, Nour B,|3
04612|135|R|   Sebastian A. Acute tacrolimus overdose and treatment with phenytoin in|3
04612|136|R|   liver transplant recipients. J Okla State Med Assoc 2001 Apr;94(4):121-3.|3
04612|137|R|16.Quiros-Tejeira RE, Chang IF, Bristow LJ, Karpen SJ, Goss JA. Treatment of|3
04612|138|R|   acute tacrolimus whole-blood elevation with phenobarbital in the|3
04612|139|R|   pediatric liver transplant recipient. Pediatr Transplant 2005 Dec;|3
04612|140|R|   9(6):792-6.|3
04612|141|R|17.McLaughlin GE, Rossique-Gonzalez M, Gelman B, Kato T. Use of|3
04612|142|R|   phenobarbital in the management of acute tacrolimus toxicity: a case|3
04612|143|R|   report. Transplant Proc 2000 May;32(3):665-8.|3
04612|144|R|18.Ikitimur B, Cosansu K, Karadag B, Cakmak HA, Avci BK, Erturk E, Seyahi N,|2
04612|145|R|   Ongen Z. Long-Term Impact of Different Immunosuppressive Drugs on QT and|2
04612|146|R|   PR Intervals in  Renal Transplant Patients. Ann Noninvasive|2
04612|147|R|   Electrocardiol 2015 Sep;20(5):426-32.|2
04612|148|R|19.USDepartment of Health and Human Services Food and Drug Administration.|1
04612|149|R|   ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04612|150|R|   Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04612|151|R|   https://www.fda.gov/media/71372/download October, 2005.|1
04612|152|R|20.This information is based on an extract from the Certara Drug Interaction|6
04612|153|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04613|001|T|MONOGRAPH TITLE:  Toremifene/Strong CYP3A4 Inducers that Prolong QT|
04613|002|B||
04613|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04613|004|L|of severe adverse interaction.|
04613|005|B||
04613|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04613|007|A|toremifene by CYP3A4.|
04613|008|A|   Concurrent use of agents that prolong the QTc interval may result in|
04613|009|A|additive effects on the QTc interval.(1)|
04613|010|B||
04613|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04613|012|E|decreased levels and effectiveness of toremifene and increase the risk of|
04613|013|E|potentially life-threatening arrhythmias including torsades de pointes.(1)|
04613|014|B||
04613|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04613|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04613|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04613|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04613|019|P|female gender, or advanced age.(2)|
04613|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04613|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04613|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04613|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04613|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04613|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04613|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04613|027|P|   Induction effects may be more likely with regular use of the inducer for|
04613|028|P|longer than 1-2 weeks.|
04613|029|B||
04613|030|M|PATIENT MANAGEMENT:  The US manufacturer of toremifene states that|
04613|031|M|concurrent use with strong CYP3A4 inducers that prolong QT should be|
04613|032|M|avoided.  If treatment with an agent known to prolong the QT interval is|
04613|033|M|required, toremifene therapy should be interrupted.  If it is not possible|
04613|034|M|to interrupt toremifene therapy, electrocardiograms (ECGs) should be|
04613|035|M|obtained and patients should be closely monitored for QT prolongation.(1)|
04613|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04613|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04613|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04613|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04613|040|B||
04613|041|D|DISCUSSION:  In clinical trials, ten patients on anticonvulsants which|
04613|042|D|included carbamazepine, phenobarbital, and phenytoin experienced a 2-fold|
04613|043|D|increase in clearance and a decrease in the elimination half-life of|
04613|044|D|toremifene.(1,3)  The area-under-curve (AUC) and half-life of|
04613|045|D|N-demethyltoremifene, an active metabolite of toremifene, decreased by 61%|
04613|046|D|and 78%, respectively.(3)|
04613|047|D|   In a study in healthy males, rifampin (600 mg daily for 5 days) decreased|
04613|048|D|maximum concentration (Cmax) and AUC of a single dose of toremifene (120 mg)|
04613|049|D|by 55% and 87%, respectively.  The Cmax of N-demethyltoremifene increased|
04613|050|D|48% and the AUC of N-demethyltoremifene decreased by 80%.(4)|
04613|051|D|   Agents that are linked to this monograph may have varying degrees of|
04613|052|D|potential to prolong the QTc interval but are generally accepted to have a|
04613|053|D|risk of causing torsades de pointes.  Agents linked to this monograph have|
04613|054|D|been shown to prolong the QTc interval either through their mechanism of|
04613|055|D|action, through studies on their effects on the QTc interval, or through|
04613|056|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04613|057|D|and/or postmarketing reports.(5)|
04613|058|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04613|059|D|encorafenib and ivosidenib.(6)|
04613|060|B||
04613|061|R|REFERENCES:|
04613|062|B||
04613|063|R|1.Fareston (toremifene citrate) US prescribing information. GTx, Inc. March,|1
04613|064|R|  2011.|1
04613|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04613|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04613|067|R|  settings: a scientific statement from the American Heart Association and|6
04613|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04613|069|R|  2;55(9):934-47.|6
04613|070|R|3.Anttila M, Laakso S, Nylanden P, Sotaniemi EA. Pharmacokinetics of the|2
04613|071|R|  novel antiestrogenic agent toremifene in subjects with altered liver and|2
04613|072|R|  kidney function. Clin Pharmacol Ther 1995 Jun;57(6):628-35.|2
04613|073|R|4.Kivisto KT, Villikka K, Nyman L, Anttila M, Neuvonen PJ. Tamoxifen and|2
04613|074|R|  toremifene concentrations in plasma are greatly decreased by rifampin.|2
04613|075|R|  Clin Pharmacol Ther 1998 Dec;64(6):648-54.|2
04613|076|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04613|077|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04613|078|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04613|079|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04613|080|R|6.This information is based on an extract from the Certara Drug Interaction|6
04613|081|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04614|001|T|MONOGRAPH TITLE:  Vemurafenib/Strong CYP3A4 Inducers that Prolong QT|
04614|002|B||
04614|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04614|004|L|of severe adverse interaction.|
04614|005|B||
04614|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04614|007|A|vemurafenib by CYP3A4.|
04614|008|A|   Concurrent use of agents that prolong the QTc interval may result in|
04614|009|A|additive effects on the QTc interval.(1)|
04614|010|B||
04614|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04614|012|E|decreased levels and effectiveness of vemurafenib and increase the risk of|
04614|013|E|potentially life-threatening arrhythmias including torsades de pointes.(1)|
04614|014|B||
04614|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04614|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04614|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04614|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04614|019|P|female gender, or advanced age.(2)|
04614|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04614|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04614|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04614|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04614|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04614|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04614|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04614|027|P|   Induction effects may be more likely with regular use of the inducer for|
04614|028|P|longer than 1-2 weeks.|
04614|029|B||
04614|030|M|PATIENT MANAGEMENT:  Vemurafenib should not be initiated in patients taking|
04614|031|M|medications known to prolong the QT interval, patients with a baseline QTc|
04614|032|M|greater than 500 msec, uncorrectable electrolyte abnormalities, or known|
04614|033|M|long QT syndrome.(1)|
04614|034|M|   All patients receiving vemurafenib should undergo ECG testing at|
04614|035|M|baseline, after 15 days of treatment, monthly during the first 3 months of|
04614|036|M|treatment, and then every 3 months.  If a patient's QTc exceeds 500 msec|
04614|037|M|during treatment, vemurafenib should be discontinued and cardiac risk|
04614|038|M|factors for QT prolongation should be controlled.  Consider discontinuing|
04614|039|M|other medications known to prolong the QT interval at this time.  If the|
04614|040|M|patient's QTc decreases below 500 msec, vemurafenib may be introduced at a|
04614|041|M|lower dosage according to the current labeling recommendations.  If the|
04614|042|M|patient's QTc remains greater than 500 msec and increased >60 msec from|
04614|043|M|pre-treatment values after controlling cardiac risk factors for|
04614|044|M|prolongation, permanently discontinue vemurafenib.(1)|
04614|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04614|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04614|047|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04614|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04614|049|M|   The manufacturer of vemurafenib also states to avoid concurrent use with|
04614|050|M|strong CYP3A4 inducers and replace these drugs with alternative drugs when|
04614|051|M|possible.  If concurrent administration with a strong CYP3A4 inducer is|
04614|052|M|unavoidable, increase the dose of vemurafenib by 240 mg (one tablet) as|
04614|053|M|tolerated.(1)|
04614|054|M|   If concurrent use of a strong CYP3A4 inducer is discontinued, allow a 2|
04614|055|M|week period to lapse and then resume the dose of vemurafenib that was taken|
04614|056|M|prior to initiation of the strong CYP3A4 inducer.(1)|
04614|057|B||
04614|058|D|DISCUSSION:  In a study in healthy subjects, coadministration of single dose|
04614|059|D|vemurafenib 960 mg with rifampin (600 mg daily, a strong CYP3A inducer)|
04614|060|D|decreased vemurafenib area-under-curve (AUC) by 40% (90% CI: 24%, 53%) with|
04614|061|D|no effect on maximum concentration (Cmax), when compared to vemurafenib|
04614|062|D|alone.(1)|
04614|063|D|   Vemurafenib is associated with concentration-dependent QTc interval|
04614|064|D|prolongation.  In the first month of treatment, the largest mean QTc change|
04614|065|D|was 12.8 msec (upper boundary of 90% CI:  14.9 msec).  In the first 6 months|
04614|066|D|of treatment, the largest mean QTc change was 15.1 msec (upper boundary of|
04614|067|D|90% CI:  17.7 msec).(1)|
04614|068|D|   Agents that are linked to this monograph may have varying degrees of|
04614|069|D|potential to prolong the QTc interval but are generally accepted to have a|
04614|070|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04614|071|D|been shown to prolong the QTc interval either through their mechanism of|
04614|072|D|action, through studies on their effects on the QTc interval, or through|
04614|073|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04614|074|D|and/or post-marketing reports.(3)|
04614|075|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04614|076|D|encorafenib and ivosidenib.(4)|
04614|077|B||
04614|078|R|REFERENCES:|
04614|079|B||
04614|080|R|1.Zelboraf (vemurafenib) US Prescribing Information. Hoffman-La Roche|1
04614|081|R|  November, 2017.|1
04614|082|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04614|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04614|084|R|  settings: a scientific statement from the American Heart Association and|6
04614|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04614|086|R|  2;55(9):934-47.|6
04614|087|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04614|088|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04614|089|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04614|090|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04614|091|R|4.This information is based on an extract from the Certara Drug Interaction|6
04614|092|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04615|001|T|MONOGRAPH TITLE:  Quetiapine (Less Than or Equal To 150 mg)/Strong CYP3A4|
04615|002|T|Inducers|
04615|003|B||
04615|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04615|005|L|take action as needed.|
04615|006|B||
04615|007|A|MECHANISM OF ACTION:  Quetiapine and its active metabolite are metabolized|
04615|008|A|by CYP3A4.(1)  In addition, FDA describes quetiapine as a sensitive CYP3A4|
04615|009|A|substrate: a drug which can have large changes in systemic exposure due to|
04615|010|A|induction (or inhibition) of the CYP3A4 pathway.(2)|
04615|011|B||
04615|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers and quetiapine|
04615|013|E|will result in decreased systemic concentrations of quetiapine and may lead|
04615|014|E|to therapeutic failure.(1)|
04615|015|B||
04615|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04615|017|P|of the inducer for longer than 1-2 weeks.|
04615|018|B||
04615|019|M|PATIENT MANAGEMENT:  In patients on quetiapine receiving chronic treatment|
04615|020|M|(i.e., greater than 7-14 days) of inducers of CYP3A4, titrate the dose of|
04615|021|M|quetiapine based on the patient's clinical response and tolerance, up to|
04615|022|M|5-fold of the original dose.  The onset of induction is gradual but may|
04615|023|M|begin within one week for potent agents (e.g. rifampin). The time to maximal|
04615|024|M|induction may be 2 or more weeks depending upon the half-life and dose of|
04615|025|M|the inducer.|
04615|026|M|   If the CYP3A4 inducer is discontinued, the dose of quetiapine should be|
04615|027|M|reduced to the original level within 7-14 days.(1)|
04615|028|B||
04615|029|D|DISCUSSION:  In an interaction study, 18 stable patients with schizophrenia,|
04615|030|D|schizoaffective or bipolar disorder started treatment with quetiapine,|
04615|031|D|achieving the target dose of 300 mg twice daily on day five.  On day 9|
04615|032|D|carbamazepine  was started, gradually increasing to the target dose of 200|
04615|033|D|mg three times a day on day 13.  Patients continued on the combination|
04615|034|D|through day 33 to assure maximal enzyme induction was achieved.|
04615|035|D|Carbamazepine decreased quetiapine AUC 87%, decreased steady-state maximum|
04615|036|D|concentration (Cmax) by 80%, and increased clearance approximately|
04615|037|D|7-fold.(3)|
04615|038|D|   In a review of 2111 quetiapine levels from 1179 patients, quetiapine|
04615|039|D|levels were 86% lower in patients receiving concurrent carbamazepine.(4)|
04615|040|D|   In a review of 62 psychiatric patients, patients receiving carbamazepine|
04615|041|D|had significantly lower quetiapine concentration-to-dose ratios.(5)|
04615|042|D|   A case report described a newly hospitalized patient admitted on|
04615|043|D|carbamazepine 600 mg daily and risperidone 8 mg daily for schizoaffective|
04615|044|D|disorder. She was then converted from risperidone to quetiapine. After 7|
04615|045|D|days of treatment at the target quetiapine dose of 700 mg daily, serum|
04615|046|D|quetiapine concentrations were undetectable.  A repeat level 7 days later|
04615|047|D|was also undetectable. The decision was then made to discontinue|
04615|048|D|carbamazepine and continue quetiapine without dose adjustment.  Quetiapine|
04615|049|D|concentrations increased over the following days to weeks and were|
04615|050|D|accompanied by clinical improvement sufficient for discharge.  The authors|
04615|051|D|also briefly described 2 additional patients, each receiving carbamazepine|
04615|052|D|for a seizure disorder who were subsequently treated with quetiapine 600 mg|
04615|053|D|or 700 mg daily for more than two weeks.  As with the first case, quetiapine|
04615|054|D|serum concentrations with concurrent carbamazepine therapy were below the|
04615|055|D|limit of detection for each patient (lower limit of detection was 25|
04615|056|D|mcg/mL).(6)|
04615|057|D|   Concurrent use of phenytoin (100 mg three times daily), a strong CYP3A4|
04615|058|D|inducer, and quetiapine increased oral clearance of quetiapine by 5-fold.(7)|
04615|059|D|      FDA defines strong CYP inducers as agents which cause at least an 80%|
04615|060|D|decrease in systemic exposure (area-under-curve or AUC) of a drug|
04615|061|D|metabolized by a specific CYP enzyme.(2)  Strong CYP3A4 inducers linked to|
04615|062|D|this monograph include: apalutamide, barbiturates, carbamazepine,|
04615|063|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin,|
04615|064|D|primidone, rifampin, rifapentine and St. John's Wort.(8)|
04615|065|B||
04615|066|R|REFERENCES:|
04615|067|B||
04615|068|R|1.Seroquel (quetiapine) US prescribing information. AstraZeneca|1
04615|069|R|  Pharmaceuticals LP September, 2020.|1
04615|070|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04615|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04615|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04615|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04615|074|R|  11/14/2017.|1
04615|075|R|3.Grimm SW, Richtand NM, Winter HR, Stams KR, Reele SB. Effects of|2
04615|076|R|  cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine|2
04615|077|R|  pharmacokinetics. Br J Clin Pharmacol 2006 Jan;61(1):58-69.|2
04615|078|R|4.Castberg I, Skogvoll E, Spigset O. Quetiapine and drug interactions:|2
04615|079|R|  evidence from a routine therapeutic drug monitoring service. J Clin|2
04615|080|R|  Psychiatry 2007 Oct;68(10):1540-5.|2
04615|081|R|5.Hasselstrom J, Linnet K. Quetiapine serum concentrations in psychiatric|2
04615|082|R|  patients: the influence of comedication. Ther Drug Monit 2004 Oct;|2
04615|083|R|  26(5):486-91.|2
04615|084|R|6.Nickl-Jockschat T, Paulzen M, Schneider F, Grozinger M. Drug interaction|3
04615|085|R|  can lead to undetectable serum concentrations of quetiapine in the|3
04615|086|R|  presence of carbamazepine. Clin Neuropharmacol 2009 Jan-Feb;32(1):55.|3
04615|087|R|7.Wong YW, Yeh C, Thyrum PT. The effects of concomitant phenytoin|2
04615|088|R|  administration on the steady-state pharmacokinetics of quetiapine. J Clin|2
04615|089|R|  Psychopharmacol 2001 Feb;21(1):89-93.|2
04615|090|R|8.This information is based on an extract from the Certara Drug Interaction|6
04615|091|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04616|001|T|MONOGRAPH TITLE:  Selected Protease Inhibitors;|
04616|002|T|Cobicistat/Oxcarbazepine;Eslicarbazepine|
04616|003|B||
04616|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04616|005|L|take action as needed.|
04616|006|B||
04616|007|A|MECHANISM OF ACTION:  Oxcarbazepine and eslicarbazepine may induce the|
04616|008|A|metabolism of protease inhibitors and cobicistat via CYP3A4.(1-9)|
04616|009|A|Oxcarbazepine and eslicarbazepine are weak CYP3A4 inducers.(7-9)|
04616|010|A|   Selected protease inhibitors that are CYP3A4 substrates include|
04616|011|A|atazanavir, darunavir, and lopinavir.(1-6)|
04616|012|B||
04616|013|E|CLINICAL EFFECTS:  Concurrent use of selected protease inhibitors including|
04616|014|E|atazanavir, darunavir, or lopinavir, or cobicistat with oxcarbazepine or|
04616|015|E|eslicarbazepine may result decreased levels and/or suboptimal|
04616|016|E|pharmacokinetics of protease inhibitors and cobicistat, resulting in the|
04616|017|E|development of resistance.(1-8)|
04616|018|B||
04616|019|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04616|020|P|of the inducer for longer than 1-2 weeks.|
04616|021|B||
04616|022|M|PATIENT MANAGEMENT:  Concurrent use of protease inhibitors including|
04616|023|M|atazanavir, darunavir, or lopinavir, or cobicistat-containing HIV regimens|
04616|024|M|with oxcarbazepine should be approached with caution.(1-8,10,11)|
04616|025|M|   The manufacturer of darunavir-cobicistat states consider an alternative|
04616|026|M|anticonvulsant or antiretroviral therapy. If coadministration is necessary,|
04616|027|M|monitor for lack or loss of virologic response.(12)|
04616|028|M|   The Department of Health and Human Services (DHHS) Guidelines for the Use|
04616|029|M|of Antiretroviral Agents recommend the use of alternative anticonvulsants or|
04616|030|M|antiretroviral therapy.  If concurrent use is warranted, monitor patients|
04616|031|M|closely for virologic response.(10)|
04616|032|B||
04616|033|D|DISCUSSION:  Atazanavir, cobicistat, darunavir, and lopinavir are primarily|
04616|034|D|metabolized by CYP3A4.  Inducers of CYP3A4 are expected to reduce|
04616|035|D|atazanavir, cobicistat, darunavir, and lopinavir levels, which may lead to|
04616|036|D|loss of response.(1-6)|
04616|037|D|   Oxcarbazepine is a weak CYP3A4 inducer.(7-9)|
04616|038|D|   In a study in 27 subjects, the administration of atazanavir and efavirenz|
04616|039|D|without ritonavir decreased the atazanavir area-under-curve (AUC), maximum|
04616|040|D|concentration (Cmax), and minimum concentration (Cmin) by 74%, 59%, and 93%|
04616|041|D|respectively.(1)|
04616|042|D|   In a study in 13 subjects, concurrent atazanavir/ritonavir (300/100 mg|
04616|043|D|daily) with efavirenz (600 mg daily) increased atazanavir AUC, Cmax, and|
04616|044|D|Cmin by 39%, 14%, and 48%, when compared to atazanavir 400 mg daily|
04616|045|D|alone.(1)|
04616|046|D|   In a study in 14 subjects, concurrent atazanavir/ritonavir (400/100 mg|
04616|047|D|daily) with efavirenz (600 mg daily) increased atazanavir Cmax by 17%.|
04616|048|D|Atazanavir Cmin decreased by 42%.(1)|
04616|049|D|   In a study in 23 subjects, concurrent nevirapine (200 mg twice daily)|
04616|050|D|with atazanavir/ritonavir (300/100 mg daily) decreased atazanavir Cmax, AUC,|
04616|051|D|and Cmin by 28%, 42%, an 72%, respectively.(1,2)  Nevirapine Cmax, AUC, and|
04616|052|D|Cmin increased 17%, 25%, and 32%, respectively.(1)|
04616|053|D|   In a study in 23 subjects, concurrent nevirapine (200 mg twice daily)|
04616|054|D|with atazanavir/ritonavir (400/100 mg daily) decreased atazanavir AUC and|
04616|055|D|Cmin by 19% and 59%, respectively.(1,2)  Nevirapine Cmax, AUC, and Cmin|
04616|056|D|increased 21%, 26%, and 35%, respectively.(1)|
04616|057|D|   A study in 11 subjects examined the effects of concurrent administration|
04616|058|D|of efavirenz (600 mg daily) with lopinavir/ritonavir (400/100 mg twice|
04616|059|D|daily). When compared to 7 controls, concurrent administration resulted in|
04616|060|D|decreases in the AUC and and Cmin lopinavir by 19% and 39%, respectively.|
04616|061|D|Efavirenz AUC and Cmin decreased 16% and 16%, respectively.(6)|
04616|062|D|   In a study in 19 subjects, concurrent efavirenz (600 mg daily) with|
04616|063|D|lopinavir/ritonavir (500/125 mg twice daily) increased lopinavir Cmax) and|
04616|064|D|AUC by 12% and 6%, respectively, and decreased lopinavir Cmin by 10% when|
04616|065|D|compared to lopinavir/ritonavir 400/100 mg twice daily alone.(6)|
04616|066|D|   In a study in 23 subjects, concurrent efavirenz (600 mg daily) with|
04616|067|D|lopinavir/ritonavir (600/150 mg twice daily) increased lopinavir Cmax, AUC,|
04616|068|D|and Cmin by 36%, 36%, and 32%, respectively, when compared to|
04616|069|D|lopinavir/ritonavir (400/100 mg twice daily) without concurrent|
04616|070|D|efavirenz.(6)|
04616|071|D|   Another study compared 5 subjects taking concurrent nevirapine (200 mg|
04616|072|D|daily for 14 days, twice daily for 6 days) with 6 subjects taking|
04616|073|D|lopinavir/ritonavir alone. Concurrent therapy increased nevirapine Cmax,|
04616|074|D|AUC, and Cmin by 5%, 8%, and 15% respectively.(6)|
04616|075|B||
04616|076|R|REFERENCES:|
04616|077|B||
04616|078|R|1.Reyataz (atazanavir sulfate) US prescribing information. Bristol-Myers|1
04616|079|R|  Squibb Company December, 2024.|1
04616|080|R|2.Evotaz (atazanavir and cobicistat) US prescribing information.|1
04616|081|R|  Bristol-Myers-Squibb Company May, 2025.|1
04616|082|R|3.Tybost (cobicistat) US prescribing information. Gilead Sciences, Inc.|1
04616|083|R|  June, 2025.|1
04616|084|R|4.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04616|085|R|  March, 2023.|1
04616|086|R|5.Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) US|1
04616|087|R|  prescribing information. Janssen Pharmaceutical Companies April, 2022.|1
04616|088|R|6.Kaletra (lopinavir/ritonavir tablets) US prescribing information. Abbott|1
04616|089|R|  Laboratories December, 2019.|1
04616|090|R|7.Trileptal (oxcarbazepine) US prescribing information. Novartis|1
04616|091|R|  Pharmaceuticals Corporation November, 2017.|1
04616|092|R|8.Oxtellar XR (oxcarbazepine) extended-release US prescribing information.|1
04616|093|R|  Supernus, Inc. December, 2018.|1
04616|094|R|9.This information is based on an extract from the Certara Drug Interaction|6
04616|095|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04616|096|R|10.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04616|097|R|   for the use of antiretroviral agents in adults and adolescents Living|6
04616|098|R|   with HIV. Department of Health and Human Services. Available at:|6
04616|099|R|   https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-|6
04616|100|R|   and-adolescent-arv/whats-new March 23, 2023.|6
04616|101|R|11.Liverpool Drug Interactions Group. HIV Drug Interactions. Available at:|6
04616|102|R|   https://hiv-druginteractions.org/.|6
04616|103|R|12.Prezcobix (darunavir and cobicistat) US prescribing information. Janssen|1
04616|104|R|   Pharmaceuticals, Inc. March, 2025.|1
04617|001|T|MONOGRAPH TITLE:  Mifepristone/Carbamazepine|
04617|002|B||
04617|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04617|004|L|of severe adverse interaction.|
04617|005|B||
04617|006|A|MECHANISM OF ACTION:  Carbamazepine may induce the metabolism of|
04617|007|A|mifepristone.(1,2)  Mifepristone may inhibit the metabolism of|
04617|008|A|carbamazepine.(3)|
04617|009|B||
04617|010|E|CLINICAL EFFECTS:  Concurrent administration may result in decreased levels|
04617|011|E|and effectiveness of mifepristone(1,2) and elevated levels of|
04617|012|E|carbamazepine.(3)|
04617|013|B||
04617|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04617|015|P|of the inducer for longer than 1-2 weeks.|
04617|016|B||
04617|017|M|PATIENT MANAGEMENT:  The concurrent use of mifepristone with carbamazepine|
04617|018|M|should be avoided.(1,2)|
04617|019|M|   If mifepristone is used as a progestin antagonist and concurrent use|
04617|020|M|cannot be avoided, conduct post-treatment assessment as detailed in the|
04617|021|M|mifepristone prescribing information to verify treatment success.(1,2)|
04617|022|M|   The manufacturer of carbamazepine states that CYP3A4 inhibitors may|
04617|023|M|increase plasma carbamazepine levels.  If concurrent use is warranted, close|
04617|024|M|monitoring of carbamazepine levels is indicated and dosage adjustment may be|
04617|025|M|required.(3)|
04617|026|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
04617|027|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
04617|028|M|should be observed for signs of toxicity (dizziness, ataxia, blurred vision,|
04617|029|M|or SIADH).  The dosage of carbamazepine may need to be adjusted or|
04617|030|M|carbamazepine may need to be discontinued.(3)|
04617|031|B||
04617|032|D|DISCUSSION:  In a study, rifampin decreased mifepristone area-under-curve|
04617|033|D|(AUC) by 6.3-fold.  The AUC of mifepristone active metabolites|
04617|034|D|22-hydroxy-mifepristone and N-demethyl-mifepristone decreased by 20-fold and|
04617|035|D|5.9-fold, respectively.(4)|
04617|036|D|   Carbamazepine is almost completely metabolized to|
04617|037|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
04617|038|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
04617|039|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
04617|040|D|CYP3A5.(1,5)|
04617|041|D|   In a randomized, cross-over study of ten seizure patients, the effects of|
04617|042|D|grapefruit juice on the pharmacokinetics of carbamazepine were determined.|
04617|043|D|Results indicate a statistically significant increase in serum|
04617|044|D|concentrations and area under the concentration-time curve (AUC) in the|
04617|045|D|grapefruit juice arm.(6)|
04617|046|B||
04617|047|R|REFERENCES:|
04617|048|B||
04617|049|R|1.Mifeprex (mifepristone) US prescribing information. Danco Laboratories,|1
04617|050|R|  LLC January, 2023.|1
04617|051|R|2.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
04617|052|R|  November, 2019.|1
04617|053|R|3.Tegretol (carbamazepine) US prescribing information. Novartis|1
04617|054|R|  Pharmaceuticals Corporation September, 2023.|1
04617|055|R|4.Rifadin (rifampin) US prescribing information. Sanofi-Aventis U.S. LLC|1
04617|056|R|  October, 2024.|1
04617|057|R|5.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
04617|058|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
04617|059|R|  Dec;21(12):906-10.|6
04617|060|R|6.Garg SK, Kumar N, Bhargava VK, Prabhakar SK. Effect of grapefruit juice on|2
04617|061|R|  carbamazepine bioavailability in patients with epilepsy. Clin Pharmacol|2
04617|062|R|  Ther 1998 Sep;64(3):286-8.|2
04618|001|T|MONOGRAPH TITLE:  Vamorolone/Mifepristone|
04618|002|B||
04618|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04618|004|L|is contraindicated and generally should not be dispensed or administered to|
04618|005|L|the same patient.|
04618|006|B||
04618|007|A|MECHANISM OF ACTION:  Mifepristone is an antagonist of the progesterone and|
04618|008|A|glucocorticoid (GR-II) receptors, but has little effect at the|
04618|009|A|mineralocorticoid (GR-I) receptor.  Mifepristone has a higher affinity for|
04618|010|A|the glucocorticoid receptor than either dexamethasone or cortisol and will|
04618|011|A|displace both endogenous and exogenous glucocorticoids from their binding|
04618|012|A|sites.(1-2)|
04618|013|A|   Additionally, mifepristone is a strong CYP3A4 inhibitor and may inhibit|
04618|014|A|the metabolism of vamorolone.(3)|
04618|015|B||
04618|016|E|CLINICAL EFFECTS:  Although serum cortisol levels rise, antagonism of the|
04618|017|E|glucocorticoid receptor may lead to adrenal insufficiency and decreased|
04618|018|E|effectiveness of vamorolone.|
04618|019|E|   Concurrent use of strong CYP3A4 inhibitors may result in increased|
04618|020|E|systemic exposure to and effects from vamorolone, including Cushing's|
04618|021|E|syndrome and adrenal suppression.|
04618|022|B||
04618|023|P|PREDISPOSING FACTORS:  None determined.|
04618|024|B||
04618|025|M|PATIENT MANAGEMENT:  The manufacturers of mifepristone state that|
04618|026|M|mifepristone is contraindicated in patients receiving concurrent long-term|
04618|027|M|corticosteroid therapy like vamorolone.(1-2)  Due to its long mean half-life|
04618|028|M|of 85 hours(2), even short term mifepristone use may have an extended|
04618|029|M|duration of effect.|
04618|030|B||
04618|031|D|DISCUSSION:  The manufacturers of mifepristone states that mifepristone is|
04618|032|D|contraindicated in patients receiving concurrent long-term corticosteroid|
04618|033|D|therapy.(1-2)|
04618|034|D|   In a study, multiple doses of itraconazole (a strong CYP3A4 inhibitor)|
04618|035|D|increased vamorolone concentration maximum (Cmax) and area-under-curve (AUC)|
04618|036|D|by 8% and 44%, respectively.(3)|
04618|037|B||
04618|038|R|REFERENCES:|
04618|039|B||
04618|040|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
04618|041|R|  November, 2019.|1
04618|042|R|2.Mifeprex (mifepristone) US prescribing information. Danco Laboratories,|1
04618|043|R|  LLC January, 2023.|1
04618|044|R|3.Agamree (vamorolone) US prescribing information. Santhera Pharmaceuticals|1
04618|045|R|  (Switzerland) Ltd. October, 2023.|1
04619|001|T|MONOGRAPH TITLE:  Tofacitinib/Immunosuppressive Strong CYP3A4 Inducers|
04619|002|B||
04619|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04619|004|L|of severe adverse interaction.|
04619|005|B||
04619|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04619|007|A|tofacitinib.(1-3)|
04619|008|A|   Concurrent use of tofacitinib and potent immunosuppressants may result in|
04619|009|A|additive or synergistic effects on the immune system.(1)|
04619|010|B||
04619|011|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 may result|
04619|012|E|in decreased levels and effectiveness of tofacitinib.(1)  Concurrent use of|
04619|013|E|tofacitinib and potent immunosuppressants use may increase the risk of|
04619|014|E|serious infections.(1)|
04619|015|B||
04619|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04619|017|P|of the inducer for longer than 1-2 weeks.|
04619|018|B||
04619|019|M|PATIENT MANAGEMENT:  The US manufacturer of tofacitinib states that the|
04619|020|M|concurrent use of immunosuppressive CYP3A4 inducers is not recommended and|
04619|021|M|may result in loss of or reduced clinical response of tofacitinib and|
04619|022|M|increased risk of infections.(1)|
04619|023|M|   If concurrent use cannot be avoided, patient should be monitored for|
04619|024|M|decreases in lymphocytes and neutrophils.  Therapy should be adjusted based|
04619|025|M|on the indication.|
04619|026|M|- For all indications: If absolute neutrophil count (ANC) or lymphocyte|
04619|027|M|count is less than 500 cells/mm3, discontinue tofacitinib.|
04619|028|M|- For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil|
04619|029|M|count (ANC) 500 to 1000 cells/mm3: interrupt dosing.  When ANC is greater|
04619|030|M|than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg|
04619|031|M|once daily.|
04619|032|M|- For ulcerative colitis and ANC 500 to 1000 cells/mm3:|
04619|033|M|   -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily.  When|
04619|034|M|ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on|
04619|035|M|clinical response.|
04619|036|M|   -If taking Xeljanz 5 mg twice daily, interrupt dosing.  When ANC is|
04619|037|M|greater than 1000 cells/mm3, resume 5 mg twice daily.|
04619|038|M|   -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily.|
04619|039|M|When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based|
04619|040|M|on clinical response.|
04619|041|M|   -If taking Xeljanz XR 11 mg once daily, interrupt dosing.  When ANC is|
04619|042|M|greater than 1000 cells/mm3, resume 11 mg once daily.|
04619|043|M|- For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500|
04619|044|M|to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000|
04619|045|M|cells/mm3.(1)|
04619|046|B||
04619|047|D|DISCUSSION:  A study of 12 subjects received tofacitinib (30 mg) with|
04619|048|D|concurrent rifampin (600 mg daily), a strong inducer of CYP3A4, with a|
04619|049|D|decreased tofacitinib area-under-curve (AUC) by 84% and maximum|
04619|050|D|concentration (Cmax) by 74%.(4)|
04619|051|D|   Drugs that are immunosuppressive strong CYP3A4 inducers linked to this|
04619|052|D|monograph include: encorafenib.(2,3)|
04619|053|B||
04619|054|R|REFERENCES:|
04619|055|B||
04619|056|R|1.Xeljanz (tofacitinib) US prescribing information. Pfizer Inc. October,|1
04619|057|R|  2025.|1
04619|058|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04619|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04619|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04619|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04619|062|R|  11/14/2017.|1
04619|063|R|3.This information is based on an extract from the Certara Drug Interaction|6
04619|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04619|065|R|4.Pfizer Medical Information Department. Personal Communications:|1
04619|066|R|  Xeljanz/Xeljanz XR. Pfizer Medical Information March 31, 2016.|1
04620|001|T|MONOGRAPH TITLE:  Tovorafenib/Strong CYP2C8 Inhibitors|
04620|002|B||
04620|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04620|004|L|of severe adverse interaction.|
04620|005|B||
04620|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2C8 may inhibit the metabolism|
04620|007|A|of tovorafenib.(1)|
04620|008|B||
04620|009|E|CLINICAL EFFECTS:  Concomitant use of a strong CYP2C8 inhibitor may increase|
04620|010|E|tovorafenib plasma concentrations, which may increase the risk of|
04620|011|E|tovorafenib toxicity, including hepatotoxicity, bleeding, and|
04620|012|E|photosensitivity.(1)|
04620|013|B||
04620|014|P|PREDISPOSING FACTORS:  None determined.|
04620|015|B||
04620|016|M|PATIENT MANAGEMENT:  The manufacturer of tovorafenib recommends avoiding|
04620|017|M|concomitant use of tovorafenib with strong CYP2C8 inhibitors.(1)|
04620|018|B||
04620|019|D|DISCUSSION:  Strong CYP2C8 inhibitors are predicted to increase tovorafenib|
04620|020|D|exposure.(1)|
04620|021|D|   Strong CYP2C8 inhibitors linked to this monograph include gemfibrozil.(2)|
04620|022|B||
04620|023|R|REFERENCES:|
04620|024|B||
04620|025|R|1.Ojemda (tovorafenib) US prescribing information. Day One|1
04620|026|R|  Biopharmaceuticals Inc. April 2024.|1
04620|027|R|2.This information is based on an extract from the Certara Drug Interaction|6
04620|028|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04621|001|T|MONOGRAPH TITLE:  Tovorafenib/Moderate CYP2C8 Inhibitors|
04621|002|B||
04621|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04621|004|L|of severe adverse interaction.|
04621|005|B||
04621|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP2C8 may inhibit the|
04621|007|A|metabolism of tovorafenib.(1)|
04621|008|B||
04621|009|E|CLINICAL EFFECTS:  Concomitant use of a moderate CYP2C8 inhibitor may|
04621|010|E|increase tovorafenib plasma concentrations, which may increase the risk of|
04621|011|E|tovorafenib toxicity, including hepatotoxicity, bleeding, and|
04621|012|E|photosensitivity.(1)|
04621|013|B||
04621|014|P|PREDISPOSING FACTORS:  None determined.|
04621|015|B||
04621|016|M|PATIENT MANAGEMENT:  The manufacturer of tovorafenib recommends avoiding|
04621|017|M|concomitant use of tovorafenib with moderate CYP2C8 inhibitors.(1)|
04621|018|B||
04621|019|D|DISCUSSION:  Moderate CYP2C8 inhibitors are predicted to increase|
04621|020|D|tovorafenib exposure.(1)|
04621|021|D|   Moderate CYP2C8 inhibitors linked to this monograph include clopidogrel,|
04621|022|D|deferasirox, leflunomide, letermovir, mifepristone (chronic therapy), and|
04621|023|D|teriflunomide.(2)|
04621|024|B||
04621|025|R|REFERENCES:|
04621|026|B||
04621|027|R|1.Ojemda (tovorafenib) US prescribing information. Day One|1
04621|028|R|  Biopharmaceuticals Inc. April 2024.|1
04621|029|R|2.This information is based on an extract from the Certara Drug Interaction|6
04621|030|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04622|001|T|MONOGRAPH TITLE:  Tovorafenib/Strong and Moderate CYP2C8 Inducers|
04622|002|B||
04622|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04622|004|L|of severe adverse interaction.|
04622|005|B||
04622|006|A|MECHANISM OF ACTION:  Tovorafenib is a substrate of CYP2C8.  Strong and|
04622|007|A|moderate inducers of CYP2C8 may induce the metabolism of tovorafenib.(1)|
04622|008|B||
04622|009|E|CLINICAL EFFECTS:  Concurrent use of a strong or moderate inducer of CYP2C8|
04622|010|E|may result in decreased levels and effectiveness of tovorafenib.(1)|
04622|011|B||
04622|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04622|013|P|of the inducer for longer than 1-2 weeks.|
04622|014|B||
04622|015|M|PATIENT MANAGEMENT:  The manufacturer of tovorafenib states to avoid|
04622|016|M|concurrent administration with strong and moderate CYP2C8 inducers.(1)|
04622|017|B||
04622|018|D|DISCUSSION:  Strong and moderate CYP2C8 inducers are predicted to decrease|
04622|019|D|tovorafenib exposure.(1)|
04622|020|D|   Moderate CYP2C8 inducers linked to this monograph include: carbamazepine,|
04622|021|D|ivosidenib, and rifampin.(2-3)|
04622|022|B||
04622|023|R|REFERENCES:|
04622|024|B||
04622|025|R|1.Ojemda (tovorafenib) US prescribing information. Day One|1
04622|026|R|  Biopharmaceuticals Inc. April 2024.|1
04622|027|R|2.This information is based on an extract from the Certara Drug Interaction|6
04622|028|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04622|029|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04622|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04622|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04622|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04622|033|R|  11/14/2017.|1
04623|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Tovorafenib|
04623|002|B||
04623|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04623|004|L|of severe adverse interaction.|
04623|005|B||
04623|006|A|MECHANISM OF ACTION:  Tovorafenib may induce the CYP3A4-mediated metabolism|
04623|007|A|of hormonal contraceptives.(1)|
04623|008|B||
04623|009|E|CLINICAL EFFECTS:  Concurrent use of tovorafenib may reduce the blood|
04623|010|E|concentrations and effectiveness of hormonal contraceptives.  Tovorafenib|
04623|011|E|may cause fetal harm when administered to pregnant women.(1)|
04623|012|B||
04623|013|P|PREDISPOSING FACTORS:  None determined.|
04623|014|B||
04623|015|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled to avoid|
04623|016|M|hormonal contraception (including oral contraceptives, patches, implants,|
04623|017|M|and/or IUDs) due to the risk of contraceptive failure.  Women should use an|
04623|018|M|effective non-hormonal method of contraception during and for 28 days after|
04623|019|M|tovorafenib therapy.(1)|
04623|020|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04623|021|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04623|022|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04623|023|M|contraceptive (i.e., a copper IUD).  If a non-hormonal emergency|
04623|024|M|contraceptive is not an option, double the usual dose of levonorgestrel from|
04623|025|M|1.5 to 3 mg.  Advise the patient to have a pregnancy test to exclude|
04623|026|M|pregnancy after use and to seek medical advice if they do become|
04623|027|M|pregnant.(2)|
04623|028|B||
04623|029|D|DISCUSSION:  A pharmacokinetic model predicted tovorafenib to decrease|
04623|030|D|midazolam Cmax and AUC by at least 20%. Tovorafenib may also decrease|
04623|031|D|estrogen or progestin concentrations and reduce the effectiveness of|
04623|032|D|hormonal contraceptives and/or an increase in breakthrough bleeding.|
04623|033|D|Tovorafenib may cause fetal harm when administered to pregnant women.(1)|
04623|034|B||
04623|035|R|REFERENCES:|
04623|036|B||
04623|037|R|1.Ojemda (tovorafenib) US prescribing information. Day One|1
04623|038|R|  Biopharmaceuticals Inc. April 2024.|1
04623|039|R|2.Medicines and Healthcare products Regulatory Agency.|1
04623|040|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04623|041|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04623|042|R|  available at:|1
04623|043|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04623|044|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04623|045|R|  -and-contraceptive-efficacy September 15, 2016..|1
04624|001|T|MONOGRAPH TITLE:  Digoxin/Belumosudil|
04624|002|B||
04624|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04624|004|L|of severe adverse interaction.|
04624|005|B||
04624|006|A|MECHANISM OF ACTION:  Belumosudil may increase the absorption of digoxin by|
04624|007|A|inhibiting P-glycoprotein (P-gp).(1)|
04624|008|B||
04624|009|E|CLINICAL EFFECTS:  Concurrent use of belumosudil may result in elevated|
04624|010|E|levels of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can|
04624|011|E|include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
04624|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
04624|013|E|disturbances, and arrhythmias.|
04624|014|B||
04624|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
04624|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
04624|017|P|risk of digoxin toxicity.|
04624|018|B||
04624|019|M|PATIENT MANAGEMENT:  Avoid coadministration of belumosudil with P-gp|
04624|020|M|substrates such as digoxin.  If coadministration cannot be avoided, monitor|
04624|021|M|serum digoxin concentrations before initiating belumosudil.  When the|
04624|022|M|digoxin concentration is expected to be increased by greater than 50%, the|
04624|023|M|manufacturer of digoxin recommends decreasing the dose of digoxin by|
04624|024|M|approximately 15-30% or by modifying the dosing frequency to reduce digoxin|
04624|025|M|concentrations.  Continue monitoring and reduce digoxin dose as|
04624|026|M|necessary.(2)|
04624|027|B||
04624|028|D|DISCUSSION:  Coadministration of belumosudil increased dabigatran (P-gp|
04624|029|D|substrate) area-under-curve (AUC) and maximum concentration (Cmax) by|
04624|030|D|2-fold.(1)|
04624|031|B||
04624|032|R|REFERENCES:|
04624|033|B||
04624|034|R|1.Rezurock (belumosudil) US prescribing information. Kadmon Pharmaceuticals,|1
04624|035|R|  LLC April, 2024.|1
04624|036|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
04624|037|R|  Pharmaceuticals, Inc. August, 2018.|1
04625|001|T|MONOGRAPH TITLE:  HMG-CoA Reductase Inhibitors/Belumosudil|
04625|002|B||
04625|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04625|004|L|of severe adverse interaction.|
04625|005|B||
04625|006|A|MECHANISM OF ACTION:  HMG-CoA reductase inhibitors are substrates of the|
04625|007|A|BCRP and OATP1B1 transporters.(1-7)  Belumosudil may increase the absorption|
04625|008|A|and decrease the hepatic uptake and metabolism of HMG-CoA reductase|
04625|009|A|inhibitors by inhibiting OATP1B1 and BCRP transporters.(7,8)|
04625|010|B||
04625|011|E|CLINICAL EFFECTS:  Simultaneous use of belumosudil may result in increased|
04625|012|E|levels and side effects from HMG-CoA reductase inhibitors, including|
04625|013|E|rhabdomyolysis.(8)|
04625|014|B||
04625|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04625|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04625|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04625|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04625|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04625|020|P|transporter OATP1B1 may have increased statin concentrations and be|
04625|021|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04625|022|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04625|023|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04625|024|B||
04625|025|M|PATIENT MANAGEMENT:  The US and Australian manufacturers of belumosudil|
04625|026|M|state that concurrent use of BCRP and OATP1B1 substrates for which minimal|
04625|027|M|concentration changes may lead to serious toxicities should be avoided.(8-9)|
04625|028|M|If coadministration cannot be avoided, lower the dose of the HMG-CoA|
04625|029|M|reductase inhibitor according to its labeling recommendations.(9)|
04625|030|B||
04625|031|D|DISCUSSION:  Coadministration of belumosudil increased rosuvastatin (OATP1B1|
04625|032|D|and BCRP substrate) maximum concentration (Cmax) and area-under-curve (AUC)|
04625|033|D|by 3.6- and 4.6-fold, respectively.(8)|
04625|034|B||
04625|035|R|REFERENCES:|
04625|036|B||
04625|037|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04625|038|R|  Pharmaceuticals LP July, 2024.|1
04625|039|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
04625|040|R|  2023.|1
04625|041|R|3.Pravachol (pravastatin sodium) US prescribing information. Bristol-Myers|1
04625|042|R|  Squibb Company May, 2022.|1
04625|043|R|4.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
04625|044|R|  2020.|1
04625|045|R|5.This information is based on an extract from the Certara Drug Interaction|6
04625|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04625|047|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04625|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04625|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04625|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04625|051|R|  11/14/2017.|1
04625|052|R|7.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04625|053|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04625|054|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04625|055|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04625|056|R|  44(3):398-408.|5
04625|057|R|8.Rezurock (belumosudil) US prescribing information. Kadmon Pharmaceuticals,|1
04625|058|R|  LLC April, 2024.|1
04625|059|R|9.Rezurock (Belumosudil) Australian Product Information. Sanofi Aventis|1
04625|060|R|  September 2024.|1
04626|001|T|MONOGRAPH TITLE:  Paliperidone Intramuscular Injection/Strong CYP3A4|
04626|002|T|Inducers|
04626|003|B||
04626|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04626|005|L|of severe adverse interaction.|
04626|006|B||
04626|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
04626|008|A|clearance of paliperidone by CYP3A4.(1-3)|
04626|009|B||
04626|010|E|CLINICAL EFFECTS:  Strong CYP3A4 inducers may result in decreased levels and|
04626|011|E|effectiveness of paliperidone.(1-3)|
04626|012|B||
04626|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04626|014|P|of the inducer for longer than 1-2 weeks.|
04626|015|B||
04626|016|M|PATIENT MANAGEMENT:  The US manufacturer of extended release paliperidone|
04626|017|M|injections recommends avoiding concurrent use of CYP3A4 inducers during the|
04626|018|M|dosing interval.  If concurrent therapy with a strong CYP3A4 inducer is|
04626|019|M|necessary, consider managing the patient with paliperidone extended-release|
04626|020|M|oral tablets.(1-3)|
04626|021|B||
04626|022|D|DISCUSSION:  In a study in 6 schizophrenic patients, carbamazepine at doses|
04626|023|D|of 200 mg/day, 400 mg/day, and 600 mg/day decreased paliperidone|
04626|024|D|concentrations by 55.7%, 36.1%, and 33.6%, respectively.  Some patients|
04626|025|D|experienced worsening of psychotic symptoms during concurrent therapy.(4)|
04626|026|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
04626|027|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04626|028|D|mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St.|
04626|029|D|John's Wort.(5-6)|
04626|030|B||
04626|031|R|REFERENCES:|
04626|032|B||
04626|033|R|1.Invega Sustenna (paliperidone palmitate) US prescribing information.|1
04626|034|R|  Janssen Pharmaceuticals, Inc. December 20, 2017.|1
04626|035|R|2.Invega Trinza (paliperidone palmitate) US prescribing information. Janssen|1
04626|036|R|  Pharmaceuticals, Inc. August, 2021.|1
04626|037|R|3.Invega Hafyera (paliperidone palmitate) US prescribing information.|1
04626|038|R|  Janssen Pharmaceuticals, Inc October, 2021.|1
04626|039|R|4.Yasui-Furukori N, Kubo K, Ishioka M, Tsuchimine S, Inoue Y. Interaction|2
04626|040|R|  between paliperidone and carbamazepine. Ther Drug Monit 2013 Oct;|2
04626|041|R|  35(5):649-52.|2
04626|042|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04626|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04626|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04626|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04626|046|R|  11/14/2017.|1
04626|047|R|6.This information is based on an extract from the Certara Drug Interaction|6
04626|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04627|001|T|MONOGRAPH TITLE:  Risperidone Intramuscular Every 2 Weeks (Consta)/Strong|
04627|002|T|CYP3A4 Inducers|
04627|003|B||
04627|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04627|005|L|take action as needed.|
04627|006|B||
04627|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
04627|008|A|clearance of risperidone by CYP3A4.(1)  Risperidone may inhibit the|
04627|009|A|metabolism of carbamazepine.(2)|
04627|010|B||
04627|011|E|CLINICAL EFFECTS:  Strong CYP3A4 inducers may result in decreased levels and|
04627|012|E|effectiveness of risperidone.(1)|
04627|013|B||
04627|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04627|015|P|of the inducer for longer than 1-2 weeks.|
04627|016|B||
04627|017|M|PATIENT MANAGEMENT:  The US manufacturer of extended release risperidone|
04627|018|M|microspheres for injection (Risperdal Consta) recommends that patients|
04627|019|M|maintained on this product be closely monitored during the first 4-8 weeks|
04627|020|M|of concurrent therapy if an inducer of CYP3A4 is initiated.  Patients may|
04627|021|M|need a dosage increase of this product or additional oral risperidone.|
04627|022|M|   If the CYP3A4 inducer is discontinued, the manufacturer recommends that|
04627|023|M|the dosage of risperidone should be re-evaluated and, if necessary,|
04627|024|M|decreased. Patients may be placed on a lower dose between 2 to 4 weeks|
04627|025|M|before the planned discontinuation of strong CYP3A4 inducers to adjust for|
04627|026|M|the expected increase in risperidone concentrations.|
04627|027|M|   For patients treated with the recommended dose of 25 mg who are|
04627|028|M|discontinuing from CYP3A4 inducers, it is recommended to continue treatment|
04627|029|M|with the 25 mg dose unless clinical judgment necessitates lowering the dose|
04627|030|M|to 12.5 mg or necessitates interruption of risperidone treatment.  The|
04627|031|M|efficacy of the 12.5 mg dose has not been investigated in clinical trials.|
04627|032|M|   Patients receiving carbamazepine should be closely monitored if|
04627|033|M|risperidone is initiated or discontinued from concurrent therapy.  The|
04627|034|M|dosage of carbamazepine may need to be adjusted.(2)|
04627|035|B||
04627|036|D|DISCUSSION:  A study in 11 schizophrenic inpatients examined the effects of|
04627|037|D|the addition of carbamazepine (200 mg twice daily) for one week to|
04627|038|D|risperidone (3 mg twice daily).  Concurrent carbamazepine decreased plasma|
04627|039|D|concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by|
04627|040|D|50%, 44%, and 45%, respectively.(3)|
04627|041|D|   A study compared 23 patients receiving risperidone alone to 11 patients|
04627|042|D|receiving concurrent risperidone and carbamazepine.  The groups were matched|
04627|043|D|for sex, age, body weight, and risperidone dosage.  Plasma concentrations of|
04627|044|D|9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone|
04627|045|D|were significantly lower in patients receiving concurrent carbamazepine.|
04627|046|D|Five subjects received risperidone with and without carbamazepine.  In these|
04627|047|D|patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone|
04627|048|D|concentrations were lower during concurrent carbamazepine.(4)|
04627|049|D|   A study in eight patients examined the effects of the addition of|
04627|050|D|risperidone (1 mg daily) to carbamazepine (400 mg to 1200 mg daily).  After|
04627|051|D|two weeks of risperidone, carbamazepine levels increased 19%.(1)|
04627|052|D|   In a case report, a patient developed an exacerbation of psychotic|
04627|053|D|symptoms four weeks after the addition of carbamazepine (800 mg daily) to|
04627|054|D|his regimen.  Plasma levels of risperidone and 9-hydroxyrisperidone had|
04627|055|D|decreased by 77% and 63%, respectively.(5)|
04627|056|D|   In an open, randomized cross-over study in 10 healthy males, pretreatment|
04627|057|D|with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC)|
04627|058|D|and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg)|
04627|059|D|by 72% and 50%, respectively.(6)|
04627|060|D|   In a study in 10 healthy males, pretreatment with rifampin (600 mg daily|
04627|061|D|for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone|
04627|062|D|(1 mg) by 51% and 38%, respectively.  The AUC of 9-hydroxyrisperidone and|
04627|063|D|the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43%|
04627|064|D|and 45%, respectively.  The Cmax of 9-hydroxyrisperidone and the active|
04627|065|D|moieties decreased by 46% and 41%, respectively.(7)|
04627|066|D|   Strong CYP3A4 inducers linked to this monograph are:  apalutamide,|
04627|067|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04627|068|D|mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St.|
04627|069|D|John's Wort.(8,9)|
04627|070|B||
04627|071|R|REFERENCES:|
04627|072|B||
04627|073|R|1.Risperdal Consta (risperidone long acting injection) US prescribing|1
04627|074|R|  information. Janssen Pharmaceutical Ltd. September, 2011.|1
04627|075|R|2.Mula M, Monaco F. Carbamazepine-risperidone interactions in patients with|2
04627|076|R|  epilepsy. Clin Neuropharmacol 2002 Mar-Apr;25(2):97-100.|2
04627|077|R|3.Ono S, Mihara K, Suzuki A, Kondo T, Yasui-Furukori N, Furukori H, de Vries|2
04627|078|R|  R, Kaneko S. Significant pharmacokinetic interaction between risperidone|2
04627|079|R|  and carbamazepine: its relationship with CYP2D6 genotypes.|2
04627|080|R|  Psychopharmacology (Berl) 2002 Jun;162(1):50-4.|2
04627|081|R|4.Spina E, Avenoso A, Facciola G, Salemi M, Scordo MG, Giacobello T, Madia|2
04627|082|R|  AG, Perucca E. Plasma concentrations of risperidone and|2
04627|083|R|  9-hydroxyrisperidone: effect of comedication with carbamazepine or|2
04627|084|R|  valproate. Ther Drug Monit 2000 Aug;22(4):481-5.|2
04627|085|R|5.Spina E, Scordo MG, Avenoso A, Perucca E. Adverse drug interaction between|3
04627|086|R|  risperidone and carbamazepine in a patient with chronic schizophrenia and|3
04627|087|R|  deficient CYP2D6 activity. J Clin Psychopharmacol 2001 Feb;21(1):108-9.|3
04627|088|R|6.Mahatthanatrakul W, Nontaput T, Ridtitid W, Wongnawa M, Sunbhanich M.|2
04627|089|R|  Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of|2
04627|090|R|  antipsychotic risperidone in healthy volunteers. J Clin Pharm Ther 2007|2
04627|091|R|  Apr;32(2):161-7.|2
04627|092|R|7.Kim KA, Park PW, Liu KH, Kim KB, Lee HJ, Shin JG, Park JY. Effect of|2
04627|093|R|  rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics|2
04627|094|R|  of risperidone. J Clin Pharmacol 2008 Jan;48(1):66-72.|2
04627|095|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
04627|096|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04627|097|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04627|098|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04627|099|R|  11/14/2017.|1
04627|100|R|9.This information is based on an extract from the Certara Drug Interaction|6
04627|101|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04628|001|T|MONOGRAPH TITLE:  Paliperidone IM/Strong CYP3A4 Inducers that Prolong QT|
04628|002|B||
04628|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04628|004|L|of severe adverse interaction.|
04628|005|B||
04628|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04628|007|A|paliperidone by CYP3A4.|
04628|008|A|   Paliperidone may prolong the QTc interval. Concurrent use of agents that|
04628|009|A|prolong the QTc interval may result in additive effects on the QTc|
04628|010|A|interval.(1-3)|
04628|011|B||
04628|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
04628|013|E|may result in decreased levels and effectiveness of paliperidone and|
04628|014|E|increase the risk of potentially life-threatening arrhythmias including|
04628|015|E|torsades de pointes.(1-3)|
04628|016|B||
04628|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04628|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04628|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04628|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04628|021|P|female gender, or advanced age.(4)|
04628|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04628|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04628|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04628|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04628|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04628|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04628|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04628|029|P|   Induction effects may be more likely with regular use of the inducer for|
04628|030|P|longer than 1-2 weeks.|
04628|031|B||
04628|032|M|PATIENT MANAGEMENT:  The US manufacturer of extended release paliperidone|
04628|033|M|injections recommends avoiding concurrent use of CYP3A4 inducers during the|
04628|034|M|dosing interval.  Concurrent use of drugs that are known to prolong the QTc|
04628|035|M|interval should also be avoided.  If concurrent therapy with a strong CYP3A4|
04628|036|M|inducer is necessary, consider managing the patient with paliperidone|
04628|037|M|extended-release oral tablets.(1-3)|
04628|038|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04628|039|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04628|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04628|041|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04628|042|B||
04628|043|D|DISCUSSION:  In a study in 6 schizophrenic patients, carbamazepine at doses|
04628|044|D|of 200 mg/day, 400 mg/day, and 600 mg/day decreased paliperidone|
04628|045|D|concentrations by 55.7%, 36.1%, and 33.6%, respectively. Some patients|
04628|046|D|experienced worsening of psychotic symptoms during concurrent therapy.(5)|
04628|047|D|   Agents that are linked to this monograph may have varying degrees of|
04628|048|D|potential to prolong the QTc interval but are generally accepted to have a|
04628|049|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04628|050|D|been shown to prolong the QTc interval either through their mechanism of|
04628|051|D|action, through studies on their effects on the QTc interval, or through|
04628|052|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04628|053|D|and/or post-marketing reports.|
04628|054|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04628|055|D|encorafenib and ivosidenib.(6)|
04628|056|B||
04628|057|R|REFERENCES:|
04628|058|B||
04628|059|R|1.Invega Sustenna (paliperidone palmitate) US prescribing information.|1
04628|060|R|  Janssen Pharmaceuticals, Inc. December 20, 2017.|1
04628|061|R|2.Invega Trinza (paliperidone palmitate) US prescribing information. Janssen|1
04628|062|R|  Pharmaceuticals, Inc. August, 2021.|1
04628|063|R|3.Invega Hafyera (paliperidone palmitate) US prescribing information.|1
04628|064|R|  Janssen Pharmaceuticals, Inc October, 2021.|1
04628|065|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04628|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04628|067|R|  settings: a scientific statement from the American Heart Association and|6
04628|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04628|069|R|  2;55(9):934-47.|6
04628|070|R|5.Yasui-Furukori N, Kubo K, Ishioka M, Tsuchimine S, Inoue Y. Interaction|2
04628|071|R|  between paliperidone and carbamazepine. Ther Drug Monit 2013 Oct;|2
04628|072|R|  35(5):649-52.|2
04628|073|R|6.This information is based on an extract from the Certara Drug Interaction|6
04628|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04629|001|T|MONOGRAPH TITLE:  Risperidone Subcutaneous Every 1-2 Months (Uzedy)/Strong|
04629|002|T|CYP3A4 Inducers|
04629|003|B||
04629|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04629|005|L|take action as needed.|
04629|006|B||
04629|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
04629|008|A|clearance of risperidone by CYP3A4.(1)  Risperidone may inhibit the|
04629|009|A|metabolism of carbamazepine.(2)|
04629|010|B||
04629|011|E|CLINICAL EFFECTS:  Strong CYP3A4 inducers may result in decreased levels and|
04629|012|E|effectiveness of risperidone.(1)|
04629|013|B||
04629|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04629|015|P|of the inducer for longer than 1-2 weeks.|
04629|016|B||
04629|017|M|PATIENT MANAGEMENT:  The US manufacturer of extended release risperidone|
04629|018|M|injectable suspension (Uzedy) recommends that patients maintained on this|
04629|019|M|product be closely monitored during the first 4-8 weeks of concurrent|
04629|020|M|therapy if an inducer of CYP3A4 is initiated.|
04629|021|M|   In patients receiving Uzedy at a specific dose, consider increasing the|
04629|022|M|dose to the next highest dose.|
04629|023|M|   In patients receiving the 125 mg dose monthly or 250 mg once every 2|
04629|024|M|months, additional oral risperidone therapy may need to be considered.|
04629|025|M|   If the CYP3A4 inducer is discontinued, the dose of Uzedy or any|
04629|026|M|additional risperidone therapy should be re-evaluated and, if necessary,|
04629|027|M|decreased to adjust for the expected increase in plasma concentration of|
04629|028|M|risperidone.|
04629|029|M|   For patients treated with Uzedy 50 mg once monthly or Uzedy 100 mg once|
04629|030|M|every 2 months and discontinuing a strong CYP3A4 inducer, it is recommended|
04629|031|M|to continue treatment with the same dose unless clinical judgment|
04629|032|M|necessitates interruption of risperidone treatment.(1)|
04629|033|M|   Patients receiving carbamazepine should be closely monitored if|
04629|034|M|risperidone is initiated or discontinued from concurrent therapy.  The|
04629|035|M|dosage of carbamazepine may need to be adjusted.(2)|
04629|036|B||
04629|037|D|DISCUSSION:  A study in 11 schizophrenic inpatients examined the effects of|
04629|038|D|the addition of carbamazepine (200 mg twice daily) for one week to|
04629|039|D|risperidone (3 mg twice daily).  Concurrent carbamazepine decreased plasma|
04629|040|D|concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by|
04629|041|D|50%, 44%, and 45%, respectively.(3)|
04629|042|D|   A study compared 23 patients receiving risperidone alone to 11 patients|
04629|043|D|receiving concurrent risperidone and carbamazepine.  The groups were matched|
04629|044|D|for sex, age, body weight, and risperidone dosage.  Plasma concentrations of|
04629|045|D|9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone|
04629|046|D|were significantly lower in patients receiving concurrent carbamazepine.|
04629|047|D|Five subjects received risperidone with and without carbamazepine.  In these|
04629|048|D|patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone|
04629|049|D|concentrations were lower during concurrent carbamazepine.(4)|
04629|050|D|   A study in eight patients examined the effects of the addition of|
04629|051|D|risperidone (1 mg daily) to carbamazepine (400 mg to 1200 mg daily).  After|
04629|052|D|two weeks of risperidone, carbamazepine levels increased 19%.(1)|
04629|053|D|   In a case report, a patient developed an exacerbation of psychotic|
04629|054|D|symptoms four weeks after the addition of carbamazepine (800 mg daily) to|
04629|055|D|his regimen.  Plasma levels of risperidone and 9-hydroxyrisperidone had|
04629|056|D|decreased by 77% and 63%, respectively.(5)|
04629|057|D|   In an open, randomized cross-over study in 10 healthy males, pretreatment|
04629|058|D|with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC)|
04629|059|D|and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg)|
04629|060|D|by 72% and 50%, respectively.(6)|
04629|061|D|   In a study in 10 healthy males, pretreatment with rifampin (600 mg daily|
04629|062|D|for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone|
04629|063|D|(1 mg) by 51% and 38%, respectively.  The AUC of 9-hydroxyrisperidone and|
04629|064|D|the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43%|
04629|065|D|and 45%, respectively.  The Cmax of 9-hydroxyrisperidone and the active|
04629|066|D|moieties decreased by 46% and 41%, respectively.(7)|
04629|067|D|   Strong CYP3A4 inducers linked to this monograph are:  apalutamide,|
04629|068|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04629|069|D|mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St.|
04629|070|D|John's Wort.(8,9)|
04629|071|B||
04629|072|R|REFERENCES:|
04629|073|B||
04629|074|R|1.Uzedy (risperidone extended-release injectable suspension) US prescribing|1
04629|075|R|  information. Teva Pharmaceuticals April, 2023.|1
04629|076|R|2.Mula M, Monaco F. Carbamazepine-risperidone interactions in patients with|2
04629|077|R|  epilepsy. Clin Neuropharmacol 2002 Mar-Apr;25(2):97-100.|2
04629|078|R|3.Ono S, Mihara K, Suzuki A, Kondo T, Yasui-Furukori N, Furukori H, de Vries|2
04629|079|R|  R, Kaneko S. Significant pharmacokinetic interaction between risperidone|2
04629|080|R|  and carbamazepine: its relationship with CYP2D6 genotypes.|2
04629|081|R|  Psychopharmacology (Berl) 2002 Jun;162(1):50-4.|2
04629|082|R|4.Spina E, Avenoso A, Facciola G, Salemi M, Scordo MG, Giacobello T, Madia|2
04629|083|R|  AG, Perucca E. Plasma concentrations of risperidone and|2
04629|084|R|  9-hydroxyrisperidone: effect of comedication with carbamazepine or|2
04629|085|R|  valproate. Ther Drug Monit 2000 Aug;22(4):481-5.|2
04629|086|R|5.Spina E, Scordo MG, Avenoso A, Perucca E. Adverse drug interaction between|3
04629|087|R|  risperidone and carbamazepine in a patient with chronic schizophrenia and|3
04629|088|R|  deficient CYP2D6 activity. J Clin Psychopharmacol 2001 Feb;21(1):108-9.|3
04629|089|R|6.Mahatthanatrakul W, Nontaput T, Ridtitid W, Wongnawa M, Sunbhanich M.|2
04629|090|R|  Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of|2
04629|091|R|  antipsychotic risperidone in healthy volunteers. J Clin Pharm Ther 2007|2
04629|092|R|  Apr;32(2):161-7.|2
04629|093|R|7.Kim KA, Park PW, Liu KH, Kim KB, Lee HJ, Shin JG, Park JY. Effect of|2
04629|094|R|  rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics|2
04629|095|R|  of risperidone. J Clin Pharmacol 2008 Jan;48(1):66-72.|2
04629|096|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
04629|097|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04629|098|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04629|099|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04629|100|R|  11/14/2017.|1
04629|101|R|9.This information is based on an extract from the Certara Drug Interaction|6
04629|102|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04630|001|T|MONOGRAPH TITLE:  Risperidone Subcutaneous Monthly (Perseris)/Strong CYP3A4|
04630|002|T|Inducers|
04630|003|B||
04630|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04630|005|L|take action as needed.|
04630|006|B||
04630|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
04630|008|A|clearance of risperidone by CYP3A4.(1)  Risperidone may inhibit the|
04630|009|A|metabolism of carbamazepine.(2)|
04630|010|B||
04630|011|E|CLINICAL EFFECTS:  Strong CYP3A4 inducers may result in decreased levels and|
04630|012|E|effectiveness of risperidone.(1)|
04630|013|B||
04630|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04630|015|P|of the inducer for longer than 1-2 weeks.|
04630|016|B||
04630|017|M|PATIENT MANAGEMENT:  The US manufacturer of extended release risperidone|
04630|018|M|injectable suspension (Perseris) recommends that patients maintained on this|
04630|019|M|product be closely monitored during the first 4-8 weeks of concurrent|
04630|020|M|therapy if an inducer of CYP3A4 is initiated.|
04630|021|M|   In patients receiving Perseris 90 mg, consider increasing the dose to 120|
04630|022|M|mg.|
04630|023|M|   In patients receiving the 120 mg dose, additional oral risperidone|
04630|024|M|therapy may need to be considered.|
04630|025|M|   If the CYP3A4 inducer is discontinued, the dose of Perseris or any|
04630|026|M|additional risperidone therapy should be re-evaluated and, if necessary,|
04630|027|M|decreased to adjust for the expected increase in plasma concentration of|
04630|028|M|risperidone.|
04630|029|M|   For patients treated with Perseris 90 mg and discontinuing a strong|
04630|030|M|CYP3A4 inducer, it is recommended to continue treatment with the 90 mg dose|
04630|031|M|unless clinical judgment necessitates interruption of risperidone treatment.|
04630|032|M|   Patients receiving carbamazepine should be closely monitored if|
04630|033|M|risperidone is initiated or discontinued from concurrent therapy.  The|
04630|034|M|dosage of carbamazepine may need to be adjusted.(2)|
04630|035|B||
04630|036|D|DISCUSSION:  A study in 11 schizophrenic inpatients examined the effects of|
04630|037|D|the addition of carbamazepine (200 mg twice daily) for one week to|
04630|038|D|risperidone (3 mg twice daily).  Concurrent carbamazepine decreased plasma|
04630|039|D|concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by|
04630|040|D|50%, 44%, and 45%, respectively.(3)|
04630|041|D|   A study compared 23 patients receiving risperidone alone to 11 patients|
04630|042|D|receiving concurrent risperidone and carbamazepine.  The groups were matched|
04630|043|D|for sex, age, body weight, and risperidone dosage.  Plasma concentrations of|
04630|044|D|9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone|
04630|045|D|were significantly lower in patients receiving concurrent carbamazepine.|
04630|046|D|Five subjects received risperidone with and without carbamazepine.  In these|
04630|047|D|patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone|
04630|048|D|concentrations were lower during concurrent carbamazepine.(4)|
04630|049|D|   A study in eight patients examined the effects of the addition of|
04630|050|D|risperidone (1 mg daily) to carbamazepine (400 mg to 1200 mg daily).  After|
04630|051|D|two weeks of risperidone, carbamazepine levels increased 19%.(2)|
04630|052|D|   In a case report, a patient developed an exacerbation of psychotic|
04630|053|D|symptoms four weeks after the addition of carbamazepine (800 mg daily) to|
04630|054|D|his regimen.  Plasma levels of risperidone and 9-hydroxyrisperidone had|
04630|055|D|decreased by 77% and 63%, respectively.(5)|
04630|056|D|   In an open, randomized cross-over study in 10 healthy males, pretreatment|
04630|057|D|with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC)|
04630|058|D|and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg)|
04630|059|D|by 72% and 50%, respectively.(6)|
04630|060|D|   In a study in 10 healthy males, pretreatment with rifampin (600 mg daily|
04630|061|D|for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone|
04630|062|D|(1 mg) by 51% and 38%, respectively.  The AUC of 9-hydroxyrisperidone and|
04630|063|D|the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43%|
04630|064|D|and 45%, respectively.  The Cmax of 9-hydroxyrisperidone and the active|
04630|065|D|moieties decreased by 46% and 41%, respectively.(7)|
04630|066|D|   Strong CYP3A4 inducers linked to this monograph are:  apalutamide,|
04630|067|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04630|068|D|mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St.|
04630|069|D|John's Wort.(8,9)|
04630|070|B||
04630|071|R|REFERENCES:|
04630|072|B||
04630|073|R|1.Perseris (risperidone) extended-release injectable suspension US|1
04630|074|R|  prescribing information. Indivior Inc. July, 2018.|1
04630|075|R|2.Mula M, Monaco F. Carbamazepine-risperidone interactions in patients with|2
04630|076|R|  epilepsy. Clin Neuropharmacol 2002 Mar-Apr;25(2):97-100.|2
04630|077|R|3.Ono S, Mihara K, Suzuki A, Kondo T, Yasui-Furukori N, Furukori H, de Vries|2
04630|078|R|  R, Kaneko S. Significant pharmacokinetic interaction between risperidone|2
04630|079|R|  and carbamazepine: its relationship with CYP2D6 genotypes.|2
04630|080|R|  Psychopharmacology (Berl) 2002 Jun;162(1):50-4.|2
04630|081|R|4.Spina E, Avenoso A, Facciola G, Salemi M, Scordo MG, Giacobello T, Madia|2
04630|082|R|  AG, Perucca E. Plasma concentrations of risperidone and|2
04630|083|R|  9-hydroxyrisperidone: effect of comedication with carbamazepine or|2
04630|084|R|  valproate. Ther Drug Monit 2000 Aug;22(4):481-5.|2
04630|085|R|5.Spina E, Scordo MG, Avenoso A, Perucca E. Adverse drug interaction between|3
04630|086|R|  risperidone and carbamazepine in a patient with chronic schizophrenia and|3
04630|087|R|  deficient CYP2D6 activity. J Clin Psychopharmacol 2001 Feb;21(1):108-9.|3
04630|088|R|6.Mahatthanatrakul W, Nontaput T, Ridtitid W, Wongnawa M, Sunbhanich M.|2
04630|089|R|  Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of|2
04630|090|R|  antipsychotic risperidone in healthy volunteers. J Clin Pharm Ther 2007|2
04630|091|R|  Apr;32(2):161-7.|2
04630|092|R|7.Kim KA, Park PW, Liu KH, Kim KB, Lee HJ, Shin JG, Park JY. Effect of|2
04630|093|R|  rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics|2
04630|094|R|  of risperidone. J Clin Pharmacol 2008 Jan;48(1):66-72.|2
04630|095|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
04630|096|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04630|097|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04630|098|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04630|099|R|  11/14/2017.|1
04630|100|R|9.This information is based on an extract from the Certara Drug Interaction|6
04630|101|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04631|001|T|MONOGRAPH TITLE:  Mavorixafor/Strong CYP3A4 Inhibitors|
04631|002|B||
04631|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04631|004|L|take action as needed.|
04631|005|B||
04631|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04631|007|A|mavorixafor.(1)|
04631|008|A|   Mavorixafor is also a substrate of P-glycoprotein (P-gp).  P-gp|
04631|009|A|inhibitors may increase mavorixafor exposure.(1)  Many CYP3A4 inhibitors|
04631|010|A|also inhibit P-glycoprotein (P-gp), including boceprevir, cobicistat,|
04631|011|A|indinavir, itraconazole, josamycin, ketoconazole, mifepristone, nefazodone,|
04631|012|A|nelfinavir, nirmatrelvir/ritonavir, tipranavir, and tucatinib.(2)|
04631|013|B||
04631|014|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04631|015|E|the levels and effects of mavorixafor including QTc prolongation, which may|
04631|016|E|result in potentially life-threatening cardiac arrhythmias like torsades de|
04631|017|E|pointes (TdP).(1)|
04631|018|B||
04631|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04631|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04631|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04631|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04631|023|P|female gender, or advanced age.(3)|
04631|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04631|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04631|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04631|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04631|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04631|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04631|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04631|031|B||
04631|032|M|PATIENT MANAGEMENT:  Reduce the dose of mavorixafor to 200 mg once daily|
04631|033|M|when used concomitantly with strong CYP3A4 inhibitors.(1)|
04631|034|M|   If coadministration with a strong CYP3A4 inhibitor is necessary, monitor|
04631|035|M|more frequently for adverse effects of mavorixafor.(1)  When concurrent|
04631|036|M|therapy is warranted, consider obtaining serum calcium, magnesium, and|
04631|037|M|potassium levels and monitoring EKG at baseline and regular intervals.|
04631|038|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
04631|039|M|irregular heartbeat, dizziness, or fainting.|
04631|040|B||
04631|041|D|DISCUSSION:  In a study with healthy subjects, itraconazole 200 mg daily (a|
04631|042|D|strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose|
04631|043|D|mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg|
04631|044|D|alone.  This suggests that itraconazole increased mavorixafor exposure by|
04631|045|D|about 2-fold.(1)|
04631|046|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04631|047|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04631|048|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04631|049|D|60% and 39%, respectively.(4)|
04631|050|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, grapefruit,|
04631|051|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
04631|052|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
04631|053|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(2,5)|
04631|054|B||
04631|055|R|REFERENCES:|
04631|056|B||
04631|057|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04631|058|R|  Inc. April, 2024.|1
04631|059|R|2.This information is based on an extract from the Certara Drug Interaction|6
04631|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04631|061|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04631|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04631|063|R|  settings: a scientific statement from the American Heart Association and|6
04631|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04631|065|R|  2;55(9):934-47.|6
04631|066|R|4.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04631|067|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04631|068|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04631|069|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04631|070|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04631|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04631|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04631|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04631|074|R|  11/14/2017.|1
04632|001|T|MONOGRAPH TITLE:  Mavorixafor/Strong CYP3A4 Inhibitors that Prolong QT|
04632|002|B||
04632|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04632|004|L|take action as needed.|
04632|005|B||
04632|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
04632|007|A|may inhibit the metabolism of mavorixafor and result in additive risk of QT|
04632|008|A|prolongation.(1)|
04632|009|A|   Mavorixafor is also a substrate of P-glycoprotein (P-gp).  P-gp|
04632|010|A|inhibitors may increase mavorixafor exposure.(1)  Many CYP3A4 inhibitors|
04632|011|A|also inhibit P-glycoprotein (P-gp), including adagrasib, clarithromycin,|
04632|012|A|lopinavir/ritonavir, saquinavir, and telithromycin.(2)|
04632|013|B||
04632|014|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04632|015|E|QT may increase the levels and effects of mavorixafor including additive QTc|
04632|016|E|prolongation, which may result in potentially life-threatening cardiac|
04632|017|E|arrhythmias like torsades de pointes (TdP).(1)|
04632|018|B||
04632|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04632|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04632|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04632|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04632|023|P|female gender, or advanced age.(3)|
04632|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04632|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04632|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04632|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04632|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04632|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04632|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04632|031|B||
04632|032|M|PATIENT MANAGEMENT:  Reduce the dose of mavorixafor to 200 mg once daily|
04632|033|M|when used concomitantly with strong CYP3A4 inhibitors.(1)|
04632|034|M|   If concurrent use is warranted, monitor ECG prior to initiation, during|
04632|035|M|concurrent therapy, and as clinically indicated.(1)|
04632|036|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04632|037|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04632|038|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04632|039|M|report any irregular heartbeat, dizziness, or fainting.|
04632|040|M|   If QT prolongation occurs, a dose reduction or discontinuation of|
04632|041|M|mavorixafor may be required.(1)|
04632|042|B||
04632|043|D|DISCUSSION:  In a study with healthy subjects, itraconazole 200 mg daily (a|
04632|044|D|strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose|
04632|045|D|mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg|
04632|046|D|alone.  This suggests that itraconazole increased mavorixafor exposure by|
04632|047|D|about 2-fold.(1)|
04632|048|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04632|049|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04632|050|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04632|051|D|60% and 39%, respectively.(4)|
04632|052|D|   Agents that are linked to this monograph may have varying degrees of|
04632|053|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04632|054|D|been shown to prolong the QTc interval either through their mechanism of|
04632|055|D|action, through studies on their effects on the QTc interval, or through|
04632|056|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04632|057|D|and/or postmarketing reports.(5)|
04632|058|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
04632|059|D|ceritinib, clarithromycin, lonafarnib, lopinavir/ritonavir, posaconazole,|
04632|060|D|ribociclib, saquinavir, telithromycin, and voriconazole.(2,6)|
04632|061|B||
04632|062|R|REFERENCES:|
04632|063|B||
04632|064|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04632|065|R|  Inc. April, 2024.|1
04632|066|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04632|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04632|068|R|  settings: a scientific statement from the American Heart Association and|6
04632|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04632|070|R|  2;55(9):934-47.|6
04632|071|R|3.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04632|072|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04632|073|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04632|074|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04632|075|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04632|076|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04632|077|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04632|078|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04632|079|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04632|080|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04632|081|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04632|082|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04632|083|R|  11/14/2017.|1
04632|084|R|6.This information is based on an extract from the Certara Drug Interaction|6
04632|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04633|001|T|MONOGRAPH TITLE:  Mavorixafor/Moderate CYP3A4 Inhibitors that Prolong QT|
04633|002|B||
04633|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04633|004|L|take action as needed.|
04633|005|B||
04633|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong the QTc|
04633|007|A|interval may inhibit the metabolism of mavorixafor and result in additive|
04633|008|A|risk of QT prolongation.(1)|
04633|009|A|   Mavorixafor is also a substrate of P-glycoprotein (P-gp).  P-gp|
04633|010|A|inhibitors may increase mavorixafor exposure.(1)  Many CYP3A4 inhibitors|
04633|011|A|also inhibit P-glycoprotein (P-gp), including erythromycin.(2)|
04633|012|B||
04633|013|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
04633|014|E|QT may increase the levels and effects of mavorixafor including additive QTc|
04633|015|E|prolongation, which may result in potentially life-threatening cardiac|
04633|016|E|arrhythmias like torsades de pointes (TdP).(1)|
04633|017|B||
04633|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04633|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04633|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04633|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04633|022|P|female gender, or advanced age.(3)|
04633|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04633|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04633|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04633|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04633|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04633|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04633|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04633|030|B||
04633|031|M|PATIENT MANAGEMENT:  When used concomitantly with moderate CYP3A4|
04633|032|M|inhibitors, monitor more frequently for mavorixafor adverse effects and|
04633|033|M|reduce the dose in 100 mg increments, if necessary, but not to a dose less|
04633|034|M|than 200 mg.(1)|
04633|035|M|   If concurrent use is warranted, monitor ECG prior to initiation, during|
04633|036|M|concurrent therapy, and as clinically indicated.(1)|
04633|037|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04633|038|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04633|039|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04633|040|M|report any irregular heartbeat, dizziness, or fainting.|
04633|041|M|   If QT prolongation occurs, a dose reduction or discontinuation of|
04633|042|M|mavorixafor may be required.(1)|
04633|043|B||
04633|044|D|DISCUSSION:  There are no clinical studies for the combination of|
04633|045|D|mavorixafor and moderate CYP3A4 inhibitors.|
04633|046|D|   In a study with healthy subjects, itraconazole 200 mg daily (a strong|
04633|047|D|CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor|
04633|048|D|200 mg similar to that from single-dose mavorixafor 400 mg alone.  This|
04633|049|D|suggests that itraconazole increased mavorixafor exposure by about|
04633|050|D|2-fold.(1)|
04633|051|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04633|052|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04633|053|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04633|054|D|60% and 39%, respectively.(4)|
04633|055|D|   Agents that are linked to this monograph may have varying degrees of|
04633|056|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04633|057|D|been shown to prolong the QTc interval either through their mechanism of|
04633|058|D|action, through studies on their effects on the QTc interval, or through|
04633|059|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04633|060|D|and/or postmarketing reports.(5)|
04633|061|D|   Moderate inhibitors of CYP3A4 that prolong QT include:  clofazimine,|
04633|062|D|crizotinib, erythromycin, fluconazole, oral lefamulin and nilotinib.(2,6)|
04633|063|B||
04633|064|R|REFERENCES:|
04633|065|B||
04633|066|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04633|067|R|  Inc. April, 2024.|1
04633|068|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04633|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04633|070|R|  settings: a scientific statement from the American Heart Association and|6
04633|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04633|072|R|  2;55(9):934-47.|6
04633|073|R|3.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04633|074|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04633|075|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04633|076|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04633|077|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04633|078|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04633|079|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04633|080|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04633|081|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04633|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04633|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04633|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04633|085|R|  11/14/2017.|1
04633|086|R|6.This information is based on an extract from the Certara Drug Interaction|6
04633|087|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04634|001|T|MONOGRAPH TITLE:  Mavorixafor/Moderate CYP3A4 Inhibitors|
04634|002|B||
04634|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04634|004|L|take action as needed.|
04634|005|B||
04634|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04634|007|A|of mavorixafor.(1)|
04634|008|A|   Mavorixafor is also a substrate of P-glycoprotein (P-gp).  P-gp|
04634|009|A|inhibitors may increase mavorixafor exposure.(1)  Many CYP3A4 inhibitors|
04634|010|A|also inhibit P-glycoprotein (P-gp), including cimetidine, diltiazem,|
04634|011|A|fluvoxamine, isavuconazonium, schisandra, and verapamil.(2)|
04634|012|B||
04634|013|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04634|014|E|the levels and effects of mavorixafor, including thrombocytopenia and QTc|
04634|015|E|prolongation, which may result in potentially life-threatening cardiac|
04634|016|E|arrhythmias like torsades de pointes (TdP).(1)|
04634|017|B||
04634|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04634|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04634|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04634|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04634|022|P|female gender, or advanced age.(3)|
04634|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04634|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04634|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04634|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04634|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04634|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04634|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04634|030|B||
04634|031|M|PATIENT MANAGEMENT:  When used concomitantly with moderate CYP3A4|
04634|032|M|inhibitors, monitor more frequently for mavorixafor adverse effects and|
04634|033|M|reduce the dose in 100 mg increments, if necessary, but not to a dose less|
04634|034|M|than 200 mg.(1)|
04634|035|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
04634|036|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04634|037|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
04634|038|M|report any irregular heartbeat, dizziness, or fainting.|
04634|039|B||
04634|040|D|DISCUSSION:  There are no clinical studies for the combination of|
04634|041|D|mavorixafor and moderate CYP3A4 inhibitors.|
04634|042|D|   In a study with healthy subjects, itraconazole 200 mg daily (a strong|
04634|043|D|CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor|
04634|044|D|200 mg similar to that from single-dose mavorixafor 400 mg alone.  This|
04634|045|D|suggests that itraconazole increased mavorixafor exposure by about|
04634|046|D|2-fold.(1)|
04634|047|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04634|048|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04634|049|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04634|050|D|60% and 39%, respectively.(4)|
04634|051|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04634|052|D|atazanavir, avacopan, berotralstat, cimetidine, conivaptan, darunavir,|
04634|053|D|diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant,|
04634|054|D|imatinib, isavuconazonium, lenacapavir, letermovir, netupitant,|
04634|055|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil and|
04634|056|D|voxelotor.(2,5)|
04634|057|B||
04634|058|R|REFERENCES:|
04634|059|B||
04634|060|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04634|061|R|  Inc. April, 2024.|1
04634|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04634|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04634|064|R|  settings: a scientific statement from the American Heart Association and|6
04634|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04634|066|R|  2;55(9):934-47.|6
04634|067|R|3.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04634|068|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04634|069|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04634|070|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04634|071|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04634|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04634|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04634|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04634|075|R|  11/14/2017.|1
04634|076|R|5.This information is based on an extract from the Certara Drug Interaction|6
04634|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04635|001|T|MONOGRAPH TITLE:  Mavorixafor/Strong CYP3A4 Inducers|
04635|002|B||
04635|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04635|004|L|of severe adverse interaction.|
04635|005|B||
04635|006|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may accelerate|
04635|007|A|the metabolism of mavorixafor.(1)|
04635|008|B||
04635|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04635|010|E|levels and effectiveness of mavorixafor.(1)|
04635|011|B||
04635|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04635|013|P|of the inducer for longer than 1-2 weeks.|
04635|014|B||
04635|015|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers in patients receiving|
04635|016|M|therapy with mavorixafor should be avoided.(1)|
04635|017|M|   Consider the use of alternative agents with less enzyme induction|
04635|018|M|potential.(1)|
04635|019|B||
04635|020|D|DISCUSSION:  Mavorixafor is a CYP3A4 substrate.  Concurrent use with strong|
04635|021|D|CYP3A4 inducers is predicted to decrease the concentration maximum (Cmax)|
04635|022|D|and area-under-curve (AUC) of mavorixafor.(1)|
04635|023|D|    Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04635|024|D|barbiturates, carbamazepine, fosphenytoin, lumacaftor, mitotane,|
04635|025|D|phenobarbital, phenytoin, primidone, and rifapentine.(2)|
04635|026|B||
04635|027|R|REFERENCES:|
04635|028|B||
04635|029|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04635|030|R|  Inc. April, 2024.|1
04635|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04635|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04635|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04635|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04635|035|R|  11/14/2017.|1
04635|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
04635|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04636|001|T|MONOGRAPH TITLE:  Mavorixafor/Strong CYP3A4 Inducers that Prolong QT|
04636|002|B||
04636|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04636|004|L|of severe adverse interaction.|
04636|005|B||
04636|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 that prolong the QTc|
04636|007|A|interval may induce the metabolism of mavorixafor and result in additive|
04636|008|A|risk of QT prolongation.(1)|
04636|009|B||
04636|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
04636|011|E|may decrease the levels and effectiveness of mavorixafor and cause additive|
04636|012|E|effects of the QTc interval, which may result in potentially|
04636|013|E|life-threatening arrhythmias, including torsades de pointes.(1)|
04636|014|B||
04636|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04636|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04636|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04636|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04636|019|P|female gender, or advanced age.(2)|
04636|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04636|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04636|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04636|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04636|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04636|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04636|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04636|027|P|   Induction effects may be more likely with regular use of the inducer for|
04636|028|P|longer than 1-2 weeks.|
04636|029|B||
04636|030|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers that prolong QT in|
04636|031|M|patients receiving therapy with mavorixafor should be avoided.(1)  Consider|
04636|032|M|the use of alternative agents with less enzyme induction potential.(1)|
04636|033|M|   If concurrent use is warranted, monitor ECG prior to initiation, during|
04636|034|M|concurrent therapy, and as clinically indicated with other agents known to|
04636|035|M|prolong the QTc interval.(1)|
04636|036|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04636|037|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04636|038|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04636|039|M|report any irregular heartbeat, dizziness, or fainting.|
04636|040|M|   If QT prolongation occurs, a dose reduction or discontinuation of|
04636|041|M|mavorixafor may be required.(1)|
04636|042|B||
04636|043|D|DISCUSSION:  Mavorixafor is a CYP3A4 substrate.  Concurrent use with strong|
04636|044|D|CYP3A4 inducers is predicted to decrease the concentration maximum (Cmax)|
04636|045|D|and area-under-curve (AUC) of mavorixafor.(1)|
04636|046|D|   In a thorough QT study, a dose of mavorixafor 800 mg increased the mean|
04636|047|D|QTc 15.6 msec (upper 90% CI = 19.9 msec).  The dose of mavorixafor was 2|
04636|048|D|times the recommended maximum daily dose.(1)|
04636|049|D|   Agents that are linked to this monograph may have varying degrees of|
04636|050|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04636|051|D|been shown to prolong the QTc interval either through their mechanism of|
04636|052|D|action, through studies on their effects on the QTc interval, or through|
04636|053|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04636|054|D|and/or postmarketing reports.(3)|
04636|055|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04636|056|D|encorafenib and ivosidenib.(4)|
04636|057|B||
04636|058|R|REFERENCES:|
04636|059|B||
04636|060|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04636|061|R|  Inc. April, 2024.|1
04636|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04636|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04636|064|R|  settings: a scientific statement from the American Heart Association and|6
04636|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04636|066|R|  2;55(9):934-47.|6
04636|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04636|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04636|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04636|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04636|071|R|4.This information is based on an extract from the Certara Drug Interaction|6
04636|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04637|001|T|MONOGRAPH TITLE:  Mavorixafor/QT Prolonging Agents|
04637|002|B||
04637|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04637|004|L|take action as needed.|
04637|005|B||
04637|006|A|MECHANISM OF ACTION:  Mavorixafor has been shown to prolong the QTc|
04637|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04637|008|A|may result in additive effects on the QTc interval.(1)|
04637|009|B||
04637|010|E|CLINICAL EFFECTS:  The concurrent use of mavorixafor with other agents that|
04637|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04637|012|E|arrhythmias, including torsades de pointes.(1)|
04637|013|B||
04637|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04637|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04637|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04637|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04637|018|P|gender, or advanced age.(2)|
04637|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04637|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04637|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04637|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04637|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04637|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04637|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04637|026|B||
04637|027|M|PATIENT MANAGEMENT:  The manufacturer of mavorixafor states that concurrent|
04637|028|M|use of mavorixafor with other agents known to prolong the QTc interval|
04637|029|M|should be approached with caution.  ECG monitoring is recommended prior to|
04637|030|M|initiation, during concurrent therapy, and as clinically indicated with|
04637|031|M|other agents known to prolong the QTc interval.(1)|
04637|032|M|   If QT prolongation occurs, a dose reduction or discontinuation of|
04637|033|M|mavorixafor may be required.(1)|
04637|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04637|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04637|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04637|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04637|038|B||
04637|039|D|DISCUSSION:  In a thorough QT study, a dose of mavorixafor 800 mg increased|
04637|040|D|the mean QTc 15.6 msec (upper 90% CI = 19.9 msec).  The dose of mavorixafor|
04637|041|D|was 2 times the recommended maximum daily dose.(1)|
04637|042|D|   Agents that are linked to this monograph may have varying degrees of|
04637|043|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04637|044|D|been shown to prolong the QTc interval either through their mechanism of|
04637|045|D|action, through studies on their effects on the QTc interval, or through|
04637|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04637|047|D|and/or postmarketing reports.(3)|
04637|048|B||
04637|049|R|REFERENCES:|
04637|050|B||
04637|051|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04637|052|R|  Inc. April, 2024.|1
04637|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04637|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04637|055|R|  settings: a scientific statement from the American Heart Association and|6
04637|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04637|057|R|  2;55(9):934-47.|6
04638|001|T|MONOGRAPH TITLE:  Mavorixafor/Goldenseal|
04638|002|B||
04638|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04638|004|L|of severe adverse interaction.|
04638|005|B||
04638|006|A|MECHANISM OF ACTION:  Goldenseal may inhibit the metabolism of mavorixafor|
04638|007|A|by CYP3A4.(1)|
04638|008|B||
04638|009|E|CLINICAL EFFECTS:  Goldenseal may result in increased systemic exposure to|
04638|010|E|and effects from mavorixafor by CYP3A4 metabolism.(1)|
04638|011|B||
04638|012|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04638|013|P|may be increased in patients with cardiovascular disease (e.g. heart|
04638|014|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04638|015|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04638|016|P|female gender, or advanced age.(2)|
04638|017|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04638|018|P|higher systemic concentrations of either QT prolonging drug are additional|
04638|019|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04638|020|P|drug concentrations include rapid infusion of an intravenous dose or|
04638|021|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04638|022|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04638|023|P|dysfunction).(2)|
04638|024|B||
04638|025|M|PATIENT MANAGEMENT:  The US manufacturer of mavorixafor recommends avoiding|
04638|026|M|concomitant use with dietary supplements that include goldenseal, as it is a|
04638|027|M|CYP3A4 inhibitor and may increase risk of adverse reactions from|
04638|028|M|mavorixafor.(1)|
04638|029|B||
04638|030|D|DISCUSSION:  Concomitant use of goldenseal with midazolam increased|
04638|031|D|midazolam's area-under-curve (AUC) and maximum concentration (Cmax),|
04638|032|D|indicating significant inhibition of CYP3A4.(3-4)|
04638|033|B||
04638|034|R|REFERENCES:|
04638|035|B||
04638|036|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04638|037|R|  Inc. April, 2024.|1
04638|038|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04638|039|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04638|040|R|  settings: a scientific statement from the American Heart Association and|6
04638|041|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04638|042|R|  2;55(9):934-47.|6
04638|043|R|3.Gurley BJ, Swain A, Hubbard MA, Hartsfield F, Thaden J, Williams DK,|2
04638|044|R|  Gentry WB, Tong Y. Supplementation With Goldenseal (Hydrastis canadensis),|2
04638|045|R|  but not Kava Kava (Piper methysticum), Inhibits Human CYP3A Activity In|2
04638|046|R|  Vivo. Clinical Pharmacology & Therapeutics 09 May 2007;83(1):61-69.|2
04638|047|R|4.This information is based on an extract from the Certara Drug Interaction|6
04638|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04639|001|T|MONOGRAPH TITLE:  Digoxin/Mavorixafor|
04639|002|B||
04639|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04639|004|L|take action as needed.|
04639|005|B||
04639|006|A|MECHANISM OF ACTION:  Mavorixafor may increase the absorption of digoxin by|
04639|007|A|inhibiting P-glycoprotein (P-gp).(1)|
04639|008|B||
04639|009|E|CLINICAL EFFECTS:  Concurrent use of mavorixafor may result in elevated|
04639|010|E|levels of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can|
04639|011|E|include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
04639|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
04639|013|E|disturbances, and arrhythmias.|
04639|014|B||
04639|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
04639|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
04639|017|P|risk of digoxin toxicity.|
04639|018|B||
04639|019|M|PATIENT MANAGEMENT:  The manufacturer of mavorixafor recommends monitoring|
04639|020|M|digoxin concentrations before initiation of mavorixafor. Monitor digoxin|
04639|021|M|concentrations during concurrent use with mavorixafor as recommended by the|
04639|022|M|digoxin labeling.(1)|
04639|023|M|   The manufacturer of digoxin recommends decreasing the dose of digoxin by|
04639|024|M|approximately 15-30% or by modifying the dosing frequency to reduce digoxin|
04639|025|M|concentrations.(2)|
04639|026|B||
04639|027|D|DISCUSSION:  In a study in healthy subjects, concomitant use of a single|
04639|028|D|oral dose of 0.25 mg of digoxin with mavorixafor dosed to steady state (400|
04639|029|D|mg/day) increased the digoxin maximum concentration (Cmax) by 1.5-fold and|
04639|030|D|the area-under-curve (AUC) by 1.6-fold.(1)|
04639|031|B||
04639|032|R|REFERENCES:|
04639|033|B||
04639|034|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04639|035|R|  Inc. April, 2024.|1
04639|036|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
04639|037|R|  Pharmaceuticals, Inc. August, 2018.|1
04640|001|T|MONOGRAPH TITLE:  Mavorixafor/P-glycoprotein (P-gp) Inhibitors|
04640|002|B||
04640|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04640|004|L|take action as needed.|
04640|005|B||
04640|006|A|MECHANISM OF ACTION:  Mavorixafor is a substrate of the P-glycoprotein|
04640|007|A|(P-gp) transporter.  P-gp inhibitors may significantly increase the|
04640|008|A|absorption of mavorixafor.(1)|
04640|009|B||
04640|010|E|CLINICAL EFFECTS:  Concurrent administration of mavorixafor with an|
04640|011|E|inhibitor of P-glycoprotein may result in elevated levels of and effects|
04640|012|E|from mavorixafor, including potentially life-threatening cardiac|
04640|013|E|arrhythmias, torsades de pointes, and sudden death.(1)|
04640|014|B||
04640|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04640|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04640|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04640|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04640|019|P|female gender, or advanced age.(2)|
04640|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04640|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04640|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04640|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04640|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04640|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04640|026|P|dysfunction).(2)|
04640|027|B||
04640|028|M|PATIENT MANAGEMENT:  When used concomitantly with P-gp inhibitors, monitor|
04640|029|M|more frequently for mavorixafor adverse effects and reduce the dose in 100|
04640|030|M|mg increments, if necessary, but not to a dose less than 200 mg.(1)|
04640|031|M|   The manufacturer of vimseltinib states concurrent use with P-gp|
04640|032|M|substrates should be avoided. If concurrent use cannot be avoided, take|
04640|033|M|vimseltinib at least 4 hours prior to mavorixafor.(4)|
04640|034|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
04640|035|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04640|036|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04640|037|M|report any irregular heartbeat, dizziness, or fainting.|
04640|038|B||
04640|039|D|DISCUSSION:  In a study with healthy subjects, itraconazole 200 mg daily (a|
04640|040|D|strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose|
04640|041|D|mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg|
04640|042|D|alone. This suggests that itraconazole increased mavorixafor exposure by|
04640|043|D|about 2-fold.(1)|
04640|044|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04640|045|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04640|046|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04640|047|D|60% and 39%, respectively.(1)|
04640|048|D|   P-glycoprotein inhibitors linked to this monograph include: abrocitinib,|
04640|049|D|Asian ginseng, asunaprevir, capmatinib, carvedilol, cyclosporine, danicopan,|
04640|050|D|daridorexant, deutivacaftor, diosmin, elagolix, flibanserin, fostamatinib,|
04640|051|D|ginkgo biloba,  glecaprevir/pibrentasvir, ivacaftor, milk thistle,|
04640|052|D|neratinib, pirtobrutinib, quercetin, rolapitant,|
04640|053|D|sofosbuvir/velpatasvir/voxilaprevir, tepotinib, velpatasvir, vilazodone,|
04640|054|D|vimseltinib, and voclosporin.(1,4-6)|
04640|055|B||
04640|056|R|REFERENCES:|
04640|057|B||
04640|058|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04640|059|R|  Inc. April, 2024.|1
04640|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04640|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04640|062|R|  settings: a scientific statement from the American Heart Association and|6
04640|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04640|064|R|  2;55(9):934-47.|6
04640|065|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04640|066|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04640|067|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04640|068|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04640|069|R|4.Romvimza (vimseltinib) US prescribing information. Deciphera|1
04640|070|R|  Pharmaceuticals, LLC February, 2025.|1
04640|071|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04640|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04640|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04640|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04640|075|R|  11/14/2017.|1
04640|076|R|6.This information is based on an extract from the Certara Drug Interaction|6
04640|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04641|001|T|MONOGRAPH TITLE:  Mavorixafor/P-gp Inhibitors that Prolong QT|
04641|002|B||
04641|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04641|004|L|take action as needed.|
04641|005|B||
04641|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors that prolong the QT|
04641|007|A|interval may increase the absorption of mavorixafor and may result in|
04641|008|A|additive effects on the QTc interval.(1)|
04641|009|B||
04641|010|E|CLINICAL EFFECTS:  Concurrent use of P-gp inhibitors that prolong the QTc|
04641|011|E|interval may increase the levels and effects of mavorixafor including|
04641|012|E|additive QTc prolongation, which may result in potentially life-threatening|
04641|013|E|cardiac arrhythmias, including torsades de pointes, and sudden death.(1)|
04641|014|B||
04641|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04641|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04641|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04641|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04641|019|P|female gender, or advanced age.(2)|
04641|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04641|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04641|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04641|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04641|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04641|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04641|026|P|dysfunction).(2)|
04641|027|B||
04641|028|M|PATIENT MANAGEMENT:  When used concomitantly with P-gp inhibitors, monitor|
04641|029|M|more frequently for mavorixafor adverse effects and reduce the dose in 100|
04641|030|M|mg increments, if necessary, but not to a dose less than 200 mg.(1)|
04641|031|M|   The manufacturer of mavorixafor states the concurrent use of mavorixafor|
04641|032|M|should be used with caution with other agents known to prolong the QT|
04641|033|M|interval. ECG monitoring is recommended prior to initiation, during|
04641|034|M|concurrent therapy, and as clinically indicated with other agents known to|
04641|035|M|prolong the QTc interval.(1)|
04641|036|M|   If QT prolongation occurs, a dose reduction or discontinuation of|
04641|037|M|mavorixafor may be required.(1)|
04641|038|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04641|039|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04641|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04641|041|M|patients to report any irregular heartbeat, dizziness, or fainting.(1)|
04641|042|B||
04641|043|D|DISCUSSION:  In a thorough QT study, a dose of mavorixafor 800 mg increased|
04641|044|D|the mean QTc 15.6 msec (upper 90% confidence interval = 19.8 msec). The dose|
04641|045|D|of mavorixafor was 2 times the recommended maximum daily dose.(1)|
04641|046|D|   In a study with healthy subjects, itraconazole 200 mg daily (a strong|
04641|047|D|CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor|
04641|048|D|200 mg similar to that from single-dose mavorixafor 400 mg alone. This|
04641|049|D|suggests that itraconazole increased mavorixafor exposure by about|
04641|050|D|2-fold.(1)|
04641|051|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04641|052|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04641|053|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04641|054|D|60% and 39%, respectively.(3)|
04641|055|D|   Agents that are linked to this monograph may have varying degrees of|
04641|056|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04641|057|D|been shown to prolong the QTc interval either through their mechanism of|
04641|058|D|action, through studies on their effects on the QTc interval, or through|
04641|059|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04641|060|D|and/or postmarketing reports.(4)|
04641|061|D|   P-gp inhibitors linked to this monograph include: amiodarone,|
04641|062|D|azithromycin, hydroquinidine, lapatinib, osimertinib, quinidine, ranolazine,|
04641|063|D|vemurafenib and selpercatinib.(5)|
04641|064|B||
04641|065|R|REFERENCES:|
04641|066|B||
04641|067|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04641|068|R|  Inc. April, 2024.|1
04641|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04641|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04641|071|R|  settings: a scientific statement from the American Heart Association and|6
04641|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04641|073|R|  2;55(9):934-47.|6
04641|074|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04641|075|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04641|076|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04641|077|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04641|078|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04641|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04641|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04641|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04641|082|R|  11/14/2017.|1
04641|083|R|5.This information is based on an extract from the Certara Drug Interaction|6
04641|084|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04642|001|T|MONOGRAPH TITLE:  Selected CYP2D6 Substrates/Mavorixafor|
04642|002|B||
04642|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04642|004|L|is contraindicated and generally should not be dispensed or administered to|
04642|005|L|the same patient.|
04642|006|B||
04642|007|A|MECHANISM OF ACTION:  Mavorixafor is a strong inhibitor of CYP2D6 and is|
04642|008|A|expected to inhibit the metabolism of agents through this pathway.(1)|
04642|009|B||
04642|010|E|CLINICAL EFFECTS:  Concurrent use of mavorixafor may result in elevated|
04642|011|E|levels of and toxicity from agents metabolized by CYP2D6.(1)|
04642|012|B||
04642|013|P|PREDISPOSING FACTORS:  With tricyclic antidepressants, the risk of seizures|
04642|014|P|may be increased in patients with a history of head trauma or prior seizure;|
04642|015|P|CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives;|
04642|016|P|addiction to opiates, cocaine, or stimulants; use of over-the-counter|
04642|017|P|stimulants and anorectics; diabetics treated with oral hypoglycemics or|
04642|018|P|insulin; or with concomitant medications known to lower seizure threshold|
04642|019|P|(antipsychotics, theophylline, systemic steroids).|
04642|020|P|   With anticholinergic agents, the risk of anticholinergic toxicities|
04642|021|P|including cognitive decline, delirium, falls and fractures is increased in|
04642|022|P|geriatric patients using more than one medicine with anticholinergic|
04642|023|P|properties.(2)|
04642|024|B||
04642|025|M|PATIENT MANAGEMENT:  The US manufacturer of mavorixafor states concurrent|
04642|026|M|use with CYP2D6 substrate that are highly dependent on CYP2D6 metabolism is|
04642|027|M|contraindicated.(1)|
04642|028|M|   The US manufacturer of doxepin states if concurrent use of doxepin and|
04642|029|M|strong CYP2D6 inhibitors such as mavorixafor is warranted, monitor doxepin|
04642|030|M|plasma concentrations and reduce the doxepin dose based on doxepin plasma|
04642|031|M|concentrations.(5)|
04642|032|B||
04642|033|D|DISCUSSION:  Mavorixafor (400 mg) increased dextromethorphan (CYP2D6|
04642|034|D|substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold|
04642|035|D|and 9-fold, respectively.(1)|
04642|036|D|   Selected CYP2D6 substrates linked to this monograph include:|
04642|037|D|aripiprazole, atomoxetine, brexpiprazole, desipramine, deutetrabenazine,|
04642|038|D|dextromethorphan, doxepin, encainide, fenfluramine, metoclopramide,|
04642|039|D|methoxyphenamine, metoprolol, mexiletine, nebivolol, paroxetine,|
04642|040|D|perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and|
04642|041|D|yohimbine.|
04642|042|B||
04642|043|R|REFERENCES:|
04642|044|B||
04642|045|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04642|046|R|  Inc. April, 2024.|1
04642|047|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04642|048|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04642|049|R|  Soc 2023 Jul;71(7):2052-2081.|6
04642|050|R|3.This information is based on an extract from the Certara Drug Interaction|6
04642|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04642|052|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04642|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04642|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04642|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04642|056|R|  11/14/2017.|1
04642|057|R|5.Sinequan (doxepin) US prescribing information. Pfizer July, 2025.|1
04643|001|T|MONOGRAPH TITLE:  Selected CYP2D6 Substrates that Prolong QT/Mavorixafor|
04643|002|B||
04643|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04643|004|L|is contraindicated and generally should not be dispensed or administered to|
04643|005|L|the same patient.|
04643|006|B||
04643|007|A|MECHANISM OF ACTION:  Mavorixafor is an inhibitor of CYP2D6 and is expected|
04643|008|A|to inhibit the metabolism of substrates of this pathway.(1)|
04643|009|B||
04643|010|E|CLINICAL EFFECTS:  Concurrent use of mavorixafor may result in elevated|
04643|011|E|levels of and toxicity from agents metabolized by CYP2D6.(1)|
04643|012|E|  Higher systemic concentrations of QT prolonging drugs which are|
04643|013|E|metabolized by CYP2D6 may increase the risk for torsades de pointes.|
04643|014|B||
04643|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04643|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04643|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04643|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04643|019|P|gender, or advanced age.(2)|
04643|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04643|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04643|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04643|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04643|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04643|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04643|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04643|027|P|   With tolterodine, the risk of anticholinergic toxicities including|
04643|028|P|cognitive decline, delirium, falls and fractures is increased in geriatric|
04643|029|P|patients using more than one medicine with anticholinergic properties.(3)|
04643|030|B||
04643|031|M|PATIENT MANAGEMENT:  The US manufacturer of mavorixafor states concurrent|
04643|032|M|use with CYP2D6 substrates that are highly dependent on CYP2D6 metabolism is|
04643|033|M|contraindicated.(1)|
04643|034|B||
04643|035|D|DISCUSSION:  Mavorixafor (400 mg) increased dextromethorphan (CYP2D6|
04643|036|D|substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold|
04643|037|D|and 9-fold, respectively.(1)|
04643|038|D|   In a thorough QT study, a dose of mavorixafor 800 mg increased the mean|
04643|039|D|QTc 15.6 msec (upper 90% CI = 19.9 msec).  The dose of mavorixafor was 2|
04643|040|D|times the recommended maximum daily dose.(1)|
04643|041|D|   Agents that are linked to this monograph may have varying degrees of|
04643|042|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04643|043|D|been shown to prolong the QTc interval either through their mechanism of|
04643|044|D|action, through studies on their effects on the QTc interval, or through|
04643|045|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04643|046|D|and/or postmarketing reports.(4)|
04643|047|D|   CYP2D6 substrates that are QT prolonging drugs linked to this monograph|
04643|048|D|include:  eliglustat, flecainide, iloperidone, maprotiline, perhexiline,|
04643|049|D|pitolisant, prajmaline, propafenone, tolterodine, and zuclopenthixol.(5,6)|
04643|050|B||
04643|051|R|REFERENCES:|
04643|052|B||
04643|053|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04643|054|R|  Inc. April, 2024.|1
04643|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04643|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04643|057|R|  settings: a scientific statement from the American Heart Association and|6
04643|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04643|059|R|  2;55(9):934-47.|6
04643|060|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04643|061|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04643|062|R|  Soc 2023 Jul;71(7):2052-2081.|6
04643|063|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04643|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04643|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04643|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04643|067|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04643|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04643|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04643|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04643|071|R|  11/14/2017.|1
04643|072|R|6.This information is based on an extract from the Certara Drug Interaction|6
04643|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04644|001|T|MONOGRAPH TITLE:  Mavorixafor/Lonafarnib (mono deleted 05/28/2024)|
04644|002|B||
04644|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04644|004|L|of severe adverse interaction.|
04644|005|B||
04644|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04644|007|A|of mavorixafor.  Lonafarnib is a strong CYP3A4 inhibitor.(1)|
04644|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.|
04644|009|A|Mavorixafor is a weak CYP3A4 inhibitor.(2)|
04644|010|B||
04644|011|E|CLINICAL EFFECTS:  Concurrent use of mavorixafor with lonafarnib may result|
04644|012|E|in an increase in mavorixafor levels and clinical adverse effects including|
04644|013|E|QTc prolongation, which may result in potentially life-threatening cardiac|
04644|014|E|arrhythmias like torsades de pointes (TdP).(1)|
04644|015|E|   Concurrent use may also increase the risk of adverse reactions of|
04644|016|E|lonafarnib including nausea and vomiting, increased liver enzymes,|
04644|017|E|myelosuppression, and hypertension.(2)|
04644|018|B||
04644|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04644|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04644|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04644|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04644|023|P|female gender, or advanced age.(3)|
04644|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04644|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04644|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04644|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04644|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04644|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04644|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04644|031|B||
04644|032|M|PATIENT MANAGEMENT:  Avoid coadministration of mavorixafor and lonafarnib.|
04644|033|M|   If coadministration is unavoidable, reduce the dose of mavorixafor to 200|
04644|034|M|mg once daily.(1)|
04644|035|M|   If coadministration is unavoidable, reduce the dose of lonafarnib to 115|
04644|036|M|mg/m2 or continue 115 mg/m2 without further dose increases.(2)|
04644|037|M|   Patients should be counseled that concurrent use of lonafarnib with|
04644|038|M|mavorixafor may result in an increase in side effects.|
04644|039|M|   Closely monitor patients for arrhythmias and events such as syncope and|
04644|040|M|heart palpitations because lonafarnib exposures may be increased despite the|
04644|041|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
04644|042|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
04644|043|M|inhibitor.(2)|
04644|044|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
04644|045|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04644|046|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04644|047|M|report any irregular heartbeat, dizziness, or fainting.|
04644|048|B||
04644|049|D|DISCUSSION:  In a study with healthy subjects, itraconazole 200 mg daily (a|
04644|050|D|strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose|
04644|051|D|mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg|
04644|052|D|alone.  This suggests that itraconazole increased mavorixafor exposure by|
04644|053|D|about 2-fold.(1)|
04644|054|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04644|055|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04644|056|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04644|057|D|60% and 39%, respectively.(4)|
04644|058|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
04644|059|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
04644|060|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
04644|061|B||
04644|062|R|REFERENCES:|
04644|063|B||
04644|064|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04644|065|R|  Inc. April, 2024.|1
04644|066|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04644|067|R|  Inc. November, 2020.|1
04644|068|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04644|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04644|070|R|  settings: a scientific statement from the American Heart Association and|6
04644|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04644|072|R|  2;55(9):934-47.|6
04644|073|R|4.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04644|074|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04644|075|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04644|076|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04644|077|R|5.This information is based on an extract from the Certara Drug Interaction|6
04644|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04645|001|T|MONOGRAPH TITLE:  Mavorixafor (Greater Than 200 mg)/Strong CYP3A4 Inhibitors|
04645|002|T|that Prolong QT|
04645|003|B||
04645|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04645|005|L|is contraindicated and generally should not be dispensed or administered to|
04645|006|L|the same patient.|
04645|007|B||
04645|008|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
04645|009|A|may inhibit the metabolism of mavorixafor and result in additive risk of QT|
04645|010|A|prolongation.(1)|
04645|011|A|   Mavorixafor is also a substrate of P-glycoprotein (P-gp).  P-gp|
04645|012|A|inhibitors may increase mavorixafor exposure.(1)  Many CYP3A4 inhibitors|
04645|013|A|also inhibit P-glycoprotein (P-gp), including adagrasib, clarithromycin,|
04645|014|A|lopinavir/ritonavir, saquinavir, and telithromycin.(2)|
04645|015|B||
04645|016|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04645|017|E|QT may increase the levels and effects of mavorixafor including additive QTc|
04645|018|E|prolongation, which may result in potentially life-threatening cardiac|
04645|019|E|arrhythmias like torsades de pointes (TdP).(1)|
04645|020|B||
04645|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04645|022|P|may be increased in patients with cardiovascular disease (e.g. heart|
04645|023|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04645|024|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04645|025|P|female gender, or advanced age.(3)|
04645|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04645|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04645|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04645|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04645|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04645|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04645|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04645|033|B||
04645|034|M|PATIENT MANAGEMENT:  Reduce the dose of mavorixafor to 200 mg once daily|
04645|035|M|when used concomitantly with strong CYP3A4 inhibitors.(1)|
04645|036|M|   If concurrent use is warranted, monitor ECG prior to initiation, during|
04645|037|M|concurrent therapy, and as clinically indicated.(1)|
04645|038|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04645|039|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04645|040|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04645|041|M|report any irregular heartbeat, dizziness, or fainting.|
04645|042|M|   If QT prolongation occurs, a dose reduction or discontinuation of|
04645|043|M|mavorixafor may be required.(1)|
04645|044|B||
04645|045|D|DISCUSSION:  In a study with healthy subjects, itraconazole 200 mg daily (a|
04645|046|D|strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose|
04645|047|D|mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg|
04645|048|D|alone.  This suggests that itraconazole increased mavorixafor exposure by|
04645|049|D|about 2-fold.(1)|
04645|050|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04645|051|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04645|052|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04645|053|D|60% and 39%, respectively.(4)|
04645|054|D|   Agents that are linked to this monograph may have varying degrees of|
04645|055|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04645|056|D|been shown to prolong the QTc interval either through their mechanism of|
04645|057|D|action, through studies on their effects on the QTc interval, or through|
04645|058|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04645|059|D|and/or postmarketing reports.(5)|
04645|060|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
04645|061|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib,|
04645|062|D|lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin,|
04645|063|D|and voriconazole.(2,6)|
04645|064|B||
04645|065|R|REFERENCES:|
04645|066|B||
04645|067|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04645|068|R|  Inc. April, 2024.|1
04645|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04645|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04645|071|R|  settings: a scientific statement from the American Heart Association and|6
04645|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04645|073|R|  2;55(9):934-47.|6
04645|074|R|3.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04645|075|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04645|076|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04645|077|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04645|078|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04645|079|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04645|080|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04645|081|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04645|082|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04645|083|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04645|084|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04645|085|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04645|086|R|  11/14/2017.|1
04645|087|R|6.This information is based on an extract from the Certara Drug Interaction|6
04645|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04646|001|T|MONOGRAPH TITLE:  Mavorixafor (Greater Than 200 mg)/Strong CYP3A4 Inhibitors|
04646|002|B||
04646|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04646|004|L|is contraindicated and generally should not be dispensed or administered to|
04646|005|L|the same patient.|
04646|006|B||
04646|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04646|008|A|mavorixafor.(1)|
04646|009|A|   Mavorixafor is also a substrate of P-glycoprotein (P-gp).  P-gp|
04646|010|A|inhibitors may increase mavorixafor exposure.(1)  Many CYP3A4 inhibitors|
04646|011|A|also inhibit P-glycoprotein (P-gp), including boceprevir, cobicistat,|
04646|012|A|indinavir, itraconazole, josamycin, ketoconazole, mifepristone, nefazodone,|
04646|013|A|nelfinavir, nirmatrelvir/ritonavir, tipranavir, and tucatinib.(2)|
04646|014|B||
04646|015|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04646|016|E|the levels and effects of mavorixafor including QTc prolongation, which may|
04646|017|E|result in potentially life-threatening cardiac arrhythmias like torsades de|
04646|018|E|pointes (TdP).(1)|
04646|019|B||
04646|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04646|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
04646|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04646|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04646|024|P|female gender, or advanced age.(3)|
04646|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04646|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04646|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04646|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04646|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04646|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04646|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04646|032|B||
04646|033|M|PATIENT MANAGEMENT:  Reduce the dose of mavorixafor to 200 mg once daily|
04646|034|M|when used concomitantly with strong CYP3A4 inhibitors.(1)|
04646|035|M|   If coadministration with a strong CYP3A4 inhibitor is necessary, monitor|
04646|036|M|more frequently for adverse effects of mavorixafor.(1)  When concurrent|
04646|037|M|therapy is warranted, consider obtaining serum calcium, magnesium, and|
04646|038|M|potassium levels and monitoring EKG at baseline and regular intervals.|
04646|039|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
04646|040|M|irregular heartbeat, dizziness, or fainting.|
04646|041|B||
04646|042|D|DISCUSSION:  In a study with healthy subjects, itraconazole 200 mg daily (a|
04646|043|D|strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose|
04646|044|D|mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg|
04646|045|D|alone.  This suggests that itraconazole increased mavorixafor exposure by|
04646|046|D|about 2-fold.(1)|
04646|047|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04646|048|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04646|049|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04646|050|D|60% and 39%, respectively.(4)|
04646|051|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, grapefruit,|
04646|052|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
04646|053|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
04646|054|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(2,5)|
04646|055|B||
04646|056|R|REFERENCES:|
04646|057|B||
04646|058|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04646|059|R|  Inc. April, 2024.|1
04646|060|R|2.This information is based on an extract from the Certara Drug Interaction|6
04646|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04646|062|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04646|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04646|064|R|  settings: a scientific statement from the American Heart Association and|6
04646|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04646|066|R|  2;55(9):934-47.|6
04646|067|R|4.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04646|068|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04646|069|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04646|070|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04646|071|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04646|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04646|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04646|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04646|075|R|  11/14/2017.|1
04647|001|T|MONOGRAPH TITLE:  Mavorixafor/Strong CYP3A4 Inhibitors that Prolong QT|
04647|002|B||
04647|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04647|004|L|of severe adverse interaction.|
04647|005|B||
04647|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
04647|007|A|may inhibit the metabolism of mavorixafor and result in additive risk of QT|
04647|008|A|prolongation.(1)|
04647|009|A|   Mavorixafor is also a substrate of P-glycoprotein (P-gp).  P-gp|
04647|010|A|inhibitors may increase mavorixafor exposure.(1)  Many CYP3A4 inhibitors|
04647|011|A|also inhibit P-glycoprotein (P-gp), including levoketoconazole.(2)|
04647|012|B||
04647|013|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04647|014|E|QT may increase the levels and effects of mavorixafor including additive QTc|
04647|015|E|prolongation, which may result in potentially life-threatening cardiac|
04647|016|E|arrhythmias like torsades de pointes (TdP).(1)|
04647|017|B||
04647|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04647|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04647|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04647|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04647|022|P|female gender, or advanced age.(3)|
04647|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04647|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04647|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04647|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04647|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04647|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04647|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04647|030|B||
04647|031|M|PATIENT MANAGEMENT:  Reduce the dose of mavorixafor to 200 mg once daily|
04647|032|M|when used concomitantly with strong CYP3A4 inhibitors.(1)|
04647|033|M|   The US manufacturer of levoketoconazole states that levoketoconazole is|
04647|034|M|contraindicated with other agents that prolong the QT interval.(4)|
04647|035|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
04647|036|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
04647|037|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
04647|038|M|syndrome (including first-degree family history).  Use caution in patients|
04647|039|M|with other risk factors for QT prolongation including congestive heart|
04647|040|M|failure, bradyarrhythmias, and uncorrected electrolyte abnormalities.|
04647|041|M|Consider more frequent ECG monitoring.(4)|
04647|042|M|   If concurrent use is warranted, monitor ECG prior to initiation, during|
04647|043|M|concurrent therapy, and as clinically indicated.(1)|
04647|044|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04647|045|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04647|046|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04647|047|M|report any irregular heartbeat, dizziness, or fainting.|
04647|048|M|   If QT prolongation occurs, a dose reduction or discontinuation of|
04647|049|M|mavorixafor may be required.(1)|
04647|050|B||
04647|051|D|DISCUSSION:  In a study with healthy subjects, itraconazole 200 mg daily (a|
04647|052|D|strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose|
04647|053|D|mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg|
04647|054|D|alone.  This suggests that itraconazole increased mavorixafor exposure by|
04647|055|D|about 2-fold.(1)|
04647|056|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04647|057|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04647|058|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04647|059|D|60% and 39%, respectively.(5)|
04647|060|D|   Agents that are linked to this monograph may have varying degrees of|
04647|061|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04647|062|D|been shown to prolong the QTc interval either through their mechanism of|
04647|063|D|action, through studies on their effects on the QTc interval, or through|
04647|064|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04647|065|D|and/or postmarketing reports.(6)|
04647|066|D|   Strong inhibitors of CYP3A4 that prolong QT linked to this monograph|
04647|067|D|include: levoketoconazole.(2,7)|
04647|068|B||
04647|069|R|REFERENCES:|
04647|070|B||
04647|071|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04647|072|R|  Inc. April, 2024.|1
04647|073|R|2.This information is based on an extract from the Certara Drug Interaction|6
04647|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04647|075|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04647|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04647|077|R|  settings: a scientific statement from the American Heart Association and|6
04647|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04647|079|R|  2;55(9):934-47.|6
04647|080|R|4.Recorlev (levoketoconazole) US prescribing information. Xeris|1
04647|081|R|  Pharmaceuticals, Inc. June, 2023.|1
04647|082|R|5.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04647|083|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04647|084|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04647|085|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04647|086|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
04647|087|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04647|088|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04647|089|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04647|090|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04647|091|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04647|092|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04647|093|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04647|094|R|  11/14/2017.|1
04648|001|T|MONOGRAPH TITLE:  Mavorixafor/Moderate CYP3A4 Inhibitors that Prolong QT|
04648|002|B||
04648|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04648|004|L|of severe adverse interaction.|
04648|005|B||
04648|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong the QTc|
04648|007|A|interval may inhibit the metabolism of mavorixafor and result in additive|
04648|008|A|risk of QT prolongation.(1)|
04648|009|A|   Mavorixafor is also a substrate of P-glycoprotein (P-gp).  P-gp|
04648|010|A|inhibitors may increase mavorixafor exposure.(1)  Many CYP3A4 inhibitors|
04648|011|A|also inhibit P-glycoprotein (P-gp), including dronedarone.(2)|
04648|012|B||
04648|013|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
04648|014|E|QT may increase the levels and effects of mavorixafor including additive QTc|
04648|015|E|prolongation, which may result in potentially life-threatening cardiac|
04648|016|E|arrhythmias like torsades de pointes (TdP).(1)|
04648|017|B||
04648|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04648|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04648|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04648|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04648|022|P|female gender, or advanced age.(3)|
04648|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04648|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04648|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04648|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04648|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04648|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04648|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04648|030|B||
04648|031|M|PATIENT MANAGEMENT:  When used concomitantly with moderate CYP3A4|
04648|032|M|inhibitors, monitor more frequently for mavorixafor adverse effects and|
04648|033|M|reduce the dose in 100 mg increments, if necessary, but not to a dose less|
04648|034|M|than 200 mg.(1)|
04648|035|M|   The US manufacturer of dronedarone states that the use of drugs that are|
04648|036|M|known to prolong the QTc interval is contraindicated.(4)  When concurrent|
04648|037|M|therapy of possible QT prolonging agents such as mavorixafor is warranted,|
04648|038|M|monitor ECG prior to initiation, during concurrent therapy, and as|
04648|039|M|clinically indicated.(1)|
04648|040|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04648|041|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04648|042|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04648|043|M|report any irregular heartbeat, dizziness, or fainting.|
04648|044|M|   If QT prolongation occurs, a dose reduction or discontinuation of|
04648|045|M|mavorixafor may be required.(1)|
04648|046|B||
04648|047|D|DISCUSSION:  There are no clinical studies for the combination of|
04648|048|D|mavorixafor and moderate CYP3A4 inhibitors.|
04648|049|D|   In a study with healthy subjects, itraconazole 200 mg daily (a strong|
04648|050|D|CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor|
04648|051|D|200 mg similar to that from single-dose mavorixafor 400 mg alone.  This|
04648|052|D|suggests that itraconazole increased mavorixafor exposure by about|
04648|053|D|2-fold.(1)|
04648|054|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04648|055|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04648|056|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04648|057|D|60% and 39%, respectively.(5)|
04648|058|D|   Agents that are linked to this monograph may have varying degrees of|
04648|059|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04648|060|D|been shown to prolong the QTc interval either through their mechanism of|
04648|061|D|action, through studies on their effects on the QTc interval, or through|
04648|062|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04648|063|D|and/or postmarketing reports.(6)|
04648|064|D|   Moderate inhibitors of CYP3A4 that prolong QT linked to this monograph|
04648|065|D|include: dronedarone.(2,7)|
04648|066|B||
04648|067|R|REFERENCES:|
04648|068|B||
04648|069|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04648|070|R|  Inc. April, 2024.|1
04648|071|R|2.This information is based on an extract from the Certara Drug Interaction|6
04648|072|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04648|073|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04648|074|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04648|075|R|  settings: a scientific statement from the American Heart Association and|6
04648|076|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04648|077|R|  2;55(9):934-47.|6
04648|078|R|4.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
04648|079|R|  November, 2020.|1
04648|080|R|5.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04648|081|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04648|082|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04648|083|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04648|084|R|6.USDepartment of Health and Human Services Food and Drug Administration.|1
04648|085|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04648|086|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04648|087|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04648|088|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04648|089|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04648|090|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04648|091|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04648|092|R|  11/14/2017.|1
04649|001|T|MONOGRAPH TITLE:  Mavorixafor/Venetoclax|
04649|002|B||
04649|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04649|004|L|of severe adverse interaction.|
04649|005|B||
04649|006|A|MECHANISM OF ACTION:  Mavorixafor and venetoclax are both inhibitors and|
04649|007|A|substrates of the P-gp transporter.  Concurrent use may increase the|
04649|008|A|absorption of both drugs.(1-4)|
04649|009|B||
04649|010|E|CLINICAL EFFECTS:  Concurrent use of mavorixafor and venetoclax may result|
04649|011|E|in an increase in mavorixafor levels and clinical adverse effects including|
04649|012|E|QTc prolongation, which may result in potentially life-threatening cardiac|
04649|013|E|arrhythmias, including torsades de pointes (Tdp).(1)|
04649|014|E|   Concurrent use may also increase the risk of adverse reactions of|
04649|015|E|venetoclax including tumor lysis syndrome.(2)|
04649|016|B||
04649|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04649|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04649|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04649|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04649|021|P|female gender, or advanced age.(5)|
04649|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04649|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04649|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04649|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04649|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04649|027|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04649|028|P|dysfunction).(5)|
04649|029|P|   Risk factors for tumor lysis syndrome include(2):|
04649|030|P|- the ramp-up phase of venetoclax therapy when tumor burden is highest|
04649|031|P|- initial magnitude of tumor burden|
04649|032|P|- renal impairment|
04649|033|P|   The risk of venetoclax toxicities may be increased in patients with|
04649|034|P|severe hepatic impairment.(2)|
04649|035|B||
04649|036|M|PATIENT MANAGEMENT:  Avoid coadministration of mavorixafor and venetoclax.|
04649|037|M|   If coadministration is unavoidable, reduce the dose of mavorixafor to 200|
04649|038|M|mg once daily.(1)|
04649|039|M|   The manufacturer of venetoclax recommends avoiding P-gp inhibitors and|
04649|040|M|considering alternative treatment when possible.  If a P-gp inhibitor must|
04649|041|M|be used, reduce venetoclax dose by at least 50%.  Monitor more closely for|
04649|042|M|signs of toxicity such as tumor lysis syndrome, hematologic and|
04649|043|M|non-hematologic toxicities.(2)|
04649|044|M|   If the P-gp inhibitor is discontinued, the manufacturer of venetoclax|
04649|045|M|recommends resuming the prior (i.e. pre-inhibitor) dose of venetoclax 2 to 3|
04649|046|M|days after discontinuation of the P-gp inhibitor.(2)|
04649|047|B||
04649|048|D|DISCUSSION:  No interaction studies have been conducted between mavorixafor|
04649|049|D|and venetoclax.|
04649|050|D|   In a study with healthy subjects, itraconazole 200 mg daily (a strong|
04649|051|D|CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor|
04649|052|D|200 mg similar to that from single-dose mavorixafor 400 mg alone.  This|
04649|053|D|suggests that itraconazole increased mavorixafor exposure by about|
04649|054|D|2-fold.(1)|
04649|055|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04649|056|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04649|057|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04649|058|D|60% and 39%, respectively.(6)|
04649|059|D|     In 11 healthy subjects, a single dose of rifampin (a P-gp inhibitor)|
04649|060|D|increased venetoclax maximum concentration (Cmax) and area-under-curve (AUC)|
04649|061|D|by 106% and 78%, respectively.(2)|
04649|062|D|   In 11 previously treated NHL subjects, ketoconazole (a strong CYP3A4|
04649|063|D|inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days|
04649|064|D|increased the Cmax and AUC of venetoclax 2.3-fold and 6.4-fold|
04649|065|D|respectively.(2)|
04649|066|B||
04649|067|R|REFERENCES:|
04649|068|B||
04649|069|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04649|070|R|  Inc. April, 2024.|1
04649|071|R|2.Venclexta (venetoclax) US prescribing information. AbbVie Inc. October,|1
04649|072|R|  2021.|1
04649|073|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04649|074|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04649|075|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04649|076|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04649|077|R|  11/14/2017.|1
04649|078|R|4.This information is based on an extract from the Certara Drug Interaction|6
04649|079|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04649|080|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04649|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04649|082|R|  settings: a scientific statement from the American Heart Association and|6
04649|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04649|084|R|  2;55(9):934-47.|6
04649|085|R|6.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04649|086|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04649|087|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04649|088|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04650|001|T|MONOGRAPH TITLE:  Mavorixafor/Dual Strong CYP3A4 Inducers and P-gp|
04650|002|T|Inhibitors|
04650|003|B||
04650|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04650|005|L|of severe adverse interaction.|
04650|006|B||
04650|007|A|MECHANISM OF ACTION:  Mavorixafor is a substrate of CYP3A4 and of the|
04650|008|A|P-glycoprotein (P-gp) transporter.(1)  Agents that are both strong CYP3A4|
04650|009|A|inducers and P-gp inhibitors such as enzalutamide, rifampin and St. John's|
04650|010|A|Wort may induce the metabolism and increase the absorption of|
04650|011|A|mavorixafor.(2,3)|
04650|012|B||
04650|013|E|CLINICAL EFFECTS:  The net effect of this interaction is unknown.|
04650|014|E|Concurrent use of strong CYP3A4 inducers may result in decreased levels and|
04650|015|E|effectiveness of mavorixafor.  Concurrent use of P-gp inhibitors may result|
04650|016|E|in elevated levels and toxicities of mavorixafor including QTc prolongation,|
04650|017|E|which may result in potentially life-threatening cardiac arrhythmias like|
04650|018|E|torsades de pointes (TdP).(1)|
04650|019|B||
04650|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04650|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04650|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04650|023|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04650|024|P|gender, or advanced age.(4)|
04650|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04650|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04650|027|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04650|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04650|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04650|030|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04650|031|P|dysfunction).(4)|
04650|032|P|   CYP3A4 induction effects may be more likely with regular use of the|
04650|033|P|inducer for longer than 1-2 weeks.|
04650|034|B||
04650|035|M|PATIENT MANAGEMENT:  Coadministration of mavorixafor with combined strong|
04650|036|M|CYP3A4 inducers and P-gp inhibitors should be avoided.|
04650|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04650|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04650|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04650|040|M|patients to report any irregular heartbeat, dizziness, or fainting.(1)|
04650|041|B||
04650|042|D|DISCUSSION:  No interaction studies have been conducted between mavorixafor|
04650|043|D|and dual strong CYP3A4 inducers and P-gp inhibitors.|
04650|044|D|   Mavorixafor is a CYP3A4 substrate. Concurrent use with strong CYP3A4|
04650|045|D|inducers is predicted to decrease the maximum concentration (Cmax) and|
04650|046|D|area-under-curve (AUC) of mavorixafor.(1)|
04650|047|D|   Mavorixafor is also a P-gp substrate.  In a study with healthy subjects,|
04650|048|D|itraconazole 200 mg daily (a strong CYP3A4 and P-gp inhibitor) increased the|
04650|049|D|exposure to single-dose mavorixafor 200 mg similar to that from single-dose|
04650|050|D|mavorixafor 400 mg alone.  This suggests that itraconazole increased|
04650|051|D|mavorixafor exposure by about 2-fold.(1)|
04650|052|D|   A study in healthy volunteers found that ritonavir 100 mg twice daily (a|
04650|053|D|strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve|
04650|054|D|(AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by|
04650|055|D|60% and 39%, respectively.(5)|
04650|056|D|   Combined strong CYP3A4 inducers and P-gp inhibitors linked to this|
04650|057|D|monograph include: enzalutamide, rifampin and St. John's Wort.(2,3)|
04650|058|B||
04650|059|R|REFERENCES:|
04650|060|B||
04650|061|R|1.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04650|062|R|  Inc. April, 2024.|1
04650|063|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04650|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04650|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04650|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04650|067|R|  11/14/2017.|1
04650|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
04650|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04650|070|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04650|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04650|072|R|  settings: a scientific statement from the American Heart Association and|6
04650|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04650|074|R|  2;55(9):934-47.|6
04650|075|R|5.Cao YJ, Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,|2
04650|076|R|  Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW. Effect of|2
04650|077|R|  low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist  AMD070|2
04650|078|R|  in healthy volunteers. Antimicrob Agents Chemother 2008 May;52(5):1630-4.|2
04651|001|T|MONOGRAPH TITLE:  Valbenazine (Greater Than 40 mg)/Strong CYP2D6 Inhibitors|
04651|002|B||
04651|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04651|004|L|is contraindicated and generally should not be dispensed or administered to|
04651|005|L|the same patient.|
04651|006|B||
04651|007|A|MECHANISM OF ACTION:  Valbenazine's active metabolite (alpha-HTBZ) is|
04651|008|A|metabolized by CYP2D6 and CYP3A4.(1)|
04651|009|A|  Bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine|
04651|010|A|are strong inhibitors of CYP2D6.(2,3)|
04651|011|B||
04651|012|E|CLINICAL EFFECTS:  Concurrent use of bupropion, dacomitinib, fluoxetine,|
04651|013|E|paroxetine, quinidine or terbinafine may result in elevated levels and|
04651|014|E|adverse effects of valbenazine such as somnolence and QT prolongation.|
04651|015|B||
04651|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04651|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04651|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04651|019|P|syndrome, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04651|020|P|gender, or advanced age.(4)|
04651|021|P|   Concurrent use of more more than one drug known to cause QT prolongation|
04651|022|P|or higher systemic concentrations of either QT prolonging drug are|
04651|023|P|additional risk factors for torsade de pointes. Factors which may increase|
04651|024|P|systemic drug concentrations include rapid infusion of an intravenous dose|
04651|025|P|or impaired metabolism or elimination of the drug (e.g. coadministration|
04651|026|P|with an agent which inhibits its own metabolism or elimination, genetic|
04651|027|P|impairment in drug metabolism or elimination, and/or renal/hepatic|
04651|028|P|dysfunction.(2)|
04651|029|P|   Concurrent use of strong CYP3A4 inhibitors may further increase levels of|
04651|030|P|valbenazine.(1)|
04651|031|B||
04651|032|M|PATIENT MANAGEMENT:  Reduce the valbenazine dose to 40 mg once daily when|
04651|033|M|valbenazine is coadministered with a strong CYP2D6 inhibitor.(1)|
04651|034|M|   During concomitant therapy with a strong CYP2D6 inhibitor, monitor|
04651|035|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
04651|036|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
04651|037|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
04651|038|M|irregular heartbeat, dizziness, or fainting.|
04651|039|B||
04651|040|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
04651|041|D|coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine|
04651|042|D|did not affect valbenazine maximum concentration (Cmax) or|
04651|043|D|area-under-the-curve (AUC).  However, Cmax and AUC for the active metabolite|
04651|044|D|of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold,|
04651|045|D|respectively.|
04651|046|D|   Strong CYP2D6 inhibitors linked to this monograph include bupropion,|
04651|047|D|dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.|
04651|048|B||
04651|049|R|REFERENCES:|
04651|050|B||
04651|051|R|1.Ingrezza (valbenazine) US prescribing information. Neurocrine Biosciences,|1
04651|052|R|  Inc. April, 2020.|1
04651|053|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04651|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04651|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04651|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04651|057|R|  11/14/2017.|1
04651|058|R|3.This information is based on an extract from the Certara Drug Interaction|6
04651|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04651|060|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04651|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04651|062|R|  settings: a scientific statement from the American Heart Association and|6
04651|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04651|064|R|  2;55(9):934-47.|6
04652|001|T|MONOGRAPH TITLE:  Aripiprazole Lauroxil (Aristada)/Strong 3A4 Inducers|
04652|002|B||
04652|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04652|004|L|take action as needed.|
04652|005|B||
04652|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
04652|007|A|clearance of aripiprazole.(1,2)|
04652|008|B||
04652|009|E|CLINICAL EFFECTS:  Strong CYP3A4 inducers may result in decreased levels and|
04652|010|E|effectiveness of aripiprazole.(1)|
04652|011|B||
04652|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04652|013|P|of the inducer for longer than 1-2 weeks.|
04652|014|B||
04652|015|M|PATIENT MANAGEMENT:  For patients receiving the 441 mg dose of aripiprazole|
04652|016|M|lauroxil extended-release injection and concomitant treatment with a CYP3A4|
04652|017|M|inducer for greater than 14 days, increase the aripiprazole lauroxil to 662|
04652|018|M|mg.  No dose adjustment is needed for patients receiving the 662 mg, 882 mg,|
04652|019|M|or 1,064 mg doses.(2)|
04652|020|B||
04652|021|D|DISCUSSION:  The concurrent administration of carbamazepine (200 mg twice|
04652|022|D|daily) with aripiprazole (30 mg daily) resulted in 70% decreases in the|
04652|023|D|area-under-curve (AUC) and maximum concentration (Cmax) of both aripiprazole|
04652|024|D|and dehydro-aripiprazole, its active metabolite.(1)|
04652|025|D|   Strong CYP3A4 inducers linked to this monograph are:  apalutamide,|
04652|026|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04652|027|D|mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St.|
04652|028|D|John's Wort.(3,4)|
04652|029|B||
04652|030|R|REFERENCES:|
04652|031|B||
04652|032|R|1.Abilify (aripiprazole) US prescribing information. Otsuka America|1
04652|033|R|  Pharmaceutical, Inc. August, 2019.|1
04652|034|R|2.Aristada (aripiprazole lauroxil) extended-release injectable US|1
04652|035|R|  prescribing information. Alkermes Inc. November, 2018.|1
04652|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04652|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04652|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04652|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04652|040|R|  11/14/2017.|1
04652|041|R|4.This information is based on an extract from the Certara Drug Interaction|6
04652|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04653|001|T|MONOGRAPH TITLE:  Risperidone Intramuscular Every 2 Weeks (Consta)/Slt|
04653|002|T|Strong 2D6 Inhibitors|
04653|003|B||
04653|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04653|005|L|take action as needed.|
04653|006|B||
04653|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
04653|008|A|risperidone by CYP2D6.(1)|
04653|009|B||
04653|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2D6 inhibitors may result in|
04653|011|E|elevated levels of risperidone and an increase in risperidone side|
04653|012|E|effects.(1)|
04653|013|B||
04653|014|P|PREDISPOSING FACTORS:  None determined.|
04653|015|B||
04653|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with strong|
04653|017|M|CYP2D6 inhibitors with risperidone should be observed for increases in|
04653|018|M|risperidone side effects, including extrapyramidal and Parkinsonian|
04653|019|M|symptoms.  The dosage of risperidone should be re-evaluated.(1)|
04653|020|M|   The US manufacturer of extended release risperidone microspheres for|
04653|021|M|injection (Risperdal Consta) recommends that patients maintained on the 25|
04653|022|M|mg dose of this product continue to receive the 25 mg dose when either|
04653|023|M|fluoxetine or paroxetine (strong CYP2D6 inhibitors) is initiated, unless|
04653|024|M|clinical judgment necessitates lowering the dose or interrupting therapy.|
04653|025|M|If a decision is made to lower the dose, the dose may be lowered 2 to 4|
04653|026|M|weeks before the initiation of fluoxetine or paroxetine.(1)|
04653|027|M|   When initiating the product in patients maintained on fluoxetine or|
04653|028|M|paroxetine, a starting dose of 12.5 mg can be considered.  The efficacy of|
04653|029|M|this dose has not been confirmed in clinical trials.(1)|
04653|030|M|   One set of authors recommended a low initial dose of paroxetine of 10|
04653|031|M|mg/day to 20 mg/day in patients receiving risperidone.(2)|
04653|032|B||
04653|033|D|DISCUSSION:  A study in 10 patients examined the effects of fluoxetine (20|
04653|034|D|mg daily) on risperidone (4-6 mg/day).  One patient dropped out following|
04653|035|D|the development of severe akathisia after one week of fluoxetine.  Her|
04653|036|D|risperidone levels had increased 457%.  In the remaining patients,|
04653|037|D|fluoxetine increased risperidone levels by 308% at two weeks and by 733% at|
04653|038|D|four weeks.  Levels of the active moiety increased by 75% by four weeks.|
04653|039|D|During the second week of fluoxetine therapy, two patients developed|
04653|040|D|Parkinsonian symptoms.(3)|
04653|041|D|   Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone|
04653|042|D|plasma concentrations.(3)|
04653|043|D|   A study in 3 poor metabolizer and 8 extensive metabolizers examined the|
04653|044|D|effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily).|
04653|045|D|Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone|
04653|046|D|and the active moiety by 29% and by 100%, respectively, in poor|
04653|047|D|metabolizers.  In extensive metabolizers, the AUC of risperidone and the|
04653|048|D|active moiety increased by 70% and 41%, respectively.(4)|
04653|049|D|   A study in 10 patients examined the effects of paroxetine (20 mg daily)|
04653|050|D|on risperidone (4-8 mg/day).  After two and four weeks of concurrent|
04653|051|D|therapy, risperidone concentrations increased 388% and 453%, respectively.|
04653|052|D|Plasma concentrations of the active moiety increased 39.4% and 44.5% after|
04653|053|D|two and four weeks of concurrent therapy, respectively.  No symptoms of|
04653|054|D|risperidone toxicity or change in extrapyramidal effects were noted.  One|
04653|055|D|patient developed Parkinsonism.(2)|
04653|056|D|   Paroxetine has been shown to lower 9-hydroxyrisperidone plasma|
04653|057|D|concentrations by 10%.(2)|
04653|058|D|   Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib,|
04653|059|D|fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)|
04653|060|B||
04653|061|R|REFERENCES:|
04653|062|B||
04653|063|R|1.Risperdal Consta (risperidone long acting injection) US prescribing|1
04653|064|R|  information. Janssen Pharmaceutical Ltd. September, 2011.|1
04653|065|R|2.Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A. Plasma|2
04653|066|R|  concentrations of risperidone and 9-hydroxyrisperidone during combined|2
04653|067|R|  treatment with paroxetine. Ther Drug Monit 2001 Jun;23(3):223-7.|2
04653|068|R|3.Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E.|2
04653|069|R|  Inhibition of risperidone metabolism by fluoxetine in patients with|2
04653|070|R|  schizophrenia: a clinically relevant pharmacokinetic drug interaction. J|2
04653|071|R|  Clin Psychopharmacol 2002 Aug;22(4):419-23.|2
04653|072|R|4.Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The|2
04653|073|R|  effect of fluoxetine on the pharmacokinetics and safety of risperidone in|2
04653|074|R|  psychiatric patients. Pharmacopsychiatry 2002 Mar;35(2):50-6.|2
04653|075|R|5.This information is based on an extract from the Certara Drug Interaction|6
04653|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04654|001|T|MONOGRAPH TITLE:  Risperidone Subcutaneous Every 1-2 Months (Uzedy)/Slt|
04654|002|T|Strong 2D6 Inhibitors|
04654|003|B||
04654|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04654|005|L|take action as needed.|
04654|006|B||
04654|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
04654|008|A|risperidone by CYP2D6.(1)|
04654|009|B||
04654|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2D6 inhibitors may result in|
04654|011|E|elevated levels of risperidone and an increase in risperidone side|
04654|012|E|effects.(1)|
04654|013|B||
04654|014|P|PREDISPOSING FACTORS:  None determined.|
04654|015|B||
04654|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with strong|
04654|017|M|CYP2D6 inhibitors with risperidone should be observed for increases in|
04654|018|M|risperidone side effects, including extrapyramidal and Parkinsonian|
04654|019|M|symptoms.(2)|
04654|020|M|   The manufacturer of extended release risperidone injectable suspension|
04654|021|M|(Uzedy) recommends patients be placed on the lowest dose (50 mg monthly or|
04654|022|M|100 mg once every 2 months) of Uzedy before the planned start of strong|
04654|023|M|CYP2D6 inhibitor therapy to adjust for the expected increase in risperidone|
04654|024|M|plasma concentrations.  When strong CYP2D6 inhibitors are initiated in|
04654|025|M|patients receiving Uzedy 50 mg monthly or 100 mg once every 2 months, it is|
04654|026|M|recommended to continue treatment with the same dose unless clinical|
04654|027|M|judgment necessitates interruption of risperidone treatment.(1)|
04654|028|M|   One set of authors recommended a low initial dose of paroxetine of 10|
04654|029|M|mg/day to 20 mg/day in patients receiving risperidone.(3)|
04654|030|B||
04654|031|D|DISCUSSION:  In a study in 7 patients maintained on risperidone (doses|
04654|032|D|ranged from 2 mg daily to 4 mg daily), the addition of duloxetine (60 mg|
04654|033|D|daily) increased risperidone levels by 25%.  The mean plasma|
04654|034|D|risperidone/9-hydroxyrisperidone ratio increased 1.95-fold.  One patient|
04654|035|D|developed mild extrapyramidal symptoms.  His risperidone level at the time|
04654|036|D|was 72 ng/ml.(4)  In contrast, a retrospective chart review compared 7|
04654|037|D|patients receiving concurrent risperidone and duloxetine to control patients|
04654|038|D|receiving only risperidone and found no significant effect on risperidone|
04654|039|D|levels.(5)|
04654|040|D|   A study in 10 patients examined the effects of fluoxetine (20 mg daily)|
04654|041|D|on risperidone (4-6 mg/day).  One patient dropped out following the|
04654|042|D|development of severe akathisia after one week of fluoxetine.  Her|
04654|043|D|risperidone levels had increased 457%.  In the remaining patients,|
04654|044|D|fluoxetine increased risperidone levels by 308% at two weeks and by 733% at|
04654|045|D|four weeks.  Levels of the active moiety increased by 75% by four weeks.|
04654|046|D|During the second week of fluoxetine therapy, two patients developed|
04654|047|D|Parkinsonian symptoms.(6)|
04654|048|D|   Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone|
04654|049|D|plasma concentrations.(6)|
04654|050|D|   A study in 3 poor metabolizer and 8 extensive metabolizers examined the|
04654|051|D|effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily).|
04654|052|D|Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone|
04654|053|D|and the active moiety by 29% and by 100%, respectively, in poor|
04654|054|D|metabolizers.  In extensive metabolizers, the AUC of risperidone and the|
04654|055|D|active moiety increased by 70% and 41%, respectively.(7)|
04654|056|D|   A study in 10 patients examined the effects of paroxetine (20 mg daily)|
04654|057|D|on risperidone (4-8 mg/day).  After two and four weeks of concurrent|
04654|058|D|therapy, risperidone concentrations increased 388% and 453%, respectively.|
04654|059|D|Plasma concentrations of the active moiety increased 39.4% and 44.5% after|
04654|060|D|two and four weeks of concurrent therapy, respectively.  No symptoms of|
04654|061|D|risperidone toxicity or change in extrapyramidal effects were noted.  One|
04654|062|D|patient developed Parkinsonism.(3)|
04654|063|D|   Paroxetine has been shown to lower 9-hydroxyrisperidone plasma|
04654|064|D|concentrations by 10%.(3)|
04654|065|D|   Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib,|
04654|066|D|fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)|
04654|067|B||
04654|068|R|REFERENCES:|
04654|069|B||
04654|070|R|1.Uzedy (risperidone extended-release injectable suspension) US prescribing|1
04654|071|R|  information. Teva Pharmaceuticals April, 2023.|1
04654|072|R|2.Risperdal (risperidone) US prescribing information. Janssen Pharmaceutical|1
04654|073|R|  Ltd. February 2021.|1
04654|074|R|3.Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A. Plasma|2
04654|075|R|  concentrations of risperidone and 9-hydroxyrisperidone during combined|2
04654|076|R|  treatment with paroxetine. Ther Drug Monit 2001 Jun;23(3):223-7.|2
04654|077|R|4.Santoro V, D'Arrigo C, Spina E, Mico U, Muscatello MR, Zoccali R. Effect|2
04654|078|R|  of adjunctive duloxetine on the plasma concentrations of clozapine,|2
04654|079|R|  olanzapine, and risperidone in patients with psychotic disorders. J Clin|2
04654|080|R|  Psychopharmacol 2010 Oct;30(5):634-6.|2
04654|081|R|5.Hendset M, Molden E, Enoksen TB, Refsum H, Hermann M. The effect of|2
04654|082|R|  coadministration of duloxetine on steady-state serum concentration of|2
04654|083|R|  risperidone and aripiprazole: a study based on therapeutic drug monitoring|2
04654|084|R|  data. Ther Drug Monit 2010 Dec;32(6):787-90.|2
04654|085|R|6.Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E.|2
04654|086|R|  Inhibition of risperidone metabolism by fluoxetine in patients with|2
04654|087|R|  schizophrenia: a clinically relevant pharmacokinetic drug interaction. J|2
04654|088|R|  Clin Psychopharmacol 2002 Aug;22(4):419-23.|2
04654|089|R|7.Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The|2
04654|090|R|  effect of fluoxetine on the pharmacokinetics and safety of risperidone in|2
04654|091|R|  psychiatric patients. Pharmacopsychiatry 2002 Mar;35(2):50-6.|2
04654|092|R|8.This information is based on an extract from the Certara Drug Interaction|6
04654|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04655|001|T|MONOGRAPH TITLE:  Risperidone Subcutaneous Injection Monthly|
04655|002|T|(Perseris)/Strong CYP2D6 Inhibitors|
04655|003|B||
04655|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04655|005|L|take action as needed.|
04655|006|B||
04655|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
04655|008|A|risperidone by CYP2D6.(1)|
04655|009|B||
04655|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2D6 inhibitors may result in|
04655|011|E|elevated levels of risperidone and an increase in risperidone side|
04655|012|E|effects.(1)|
04655|013|B||
04655|014|P|PREDISPOSING FACTORS:  None determined.|
04655|015|B||
04655|016|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with strong|
04655|017|M|CYP2D6 inhibitors with risperidone should be observed for increases in|
04655|018|M|risperidone side effects, including extrapyramidal and Parkinsonian|
04655|019|M|symptoms.|
04655|020|M|   The manufacturer of extended release risperidone injectable suspension|
04655|021|M|(Perseris) recommends patients be placed on the lowest dose (90 mg) of|
04655|022|M|Perseris two to four weeks before the planned start of a strong CYP2D6|
04655|023|M|inhibitor to adjust for the expected increase in risperidone plasma|
04655|024|M|concentrations.  When a strong CYP2D6 inhibitor is initiated in patients|
04655|025|M|receiving Perseris 90 mg, it is recommended to continue treatment with 90 mg|
04655|026|M|unless clinical judgment necessitates interruption of risperidone|
04655|027|M|treatment.(1)|
04655|028|B||
04655|029|D|DISCUSSION:  A study in 10 patients examined the effects of fluoxetine (20|
04655|030|D|mg daily) on risperidone (4-6 mg/day).  One patient dropped out following|
04655|031|D|the development of severe akathisia after one week of fluoxetine.  Her|
04655|032|D|risperidone levels had increased 457%.  In the remaining patients,|
04655|033|D|fluoxetine increased risperidone levels by 308% at two weeks and by 733% at|
04655|034|D|four weeks.  Levels of the active moiety increased by 75% by four weeks.|
04655|035|D|During the second week of fluoxetine therapy, two patients developed|
04655|036|D|Parkinsonian symptoms.(2)|
04655|037|D|   A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers|
04655|038|D|examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg|
04655|039|D|daily). Concurrent fluoxetine increased the area-under-curve (AUC) of|
04655|040|D|risperidone and the active moiety by 29% and by 100%, respectively, in poor|
04655|041|D|metabolizers.  In extensive metabolizers, the AUC of risperidone and the|
04655|042|D|active moiety increased by 70% and 41%, respectively.(3)|
04655|043|D|   A study in 10 patients examined the effects of paroxetine (20 mg daily)|
04655|044|D|on risperidone (4-8 mg/day).  After two and four weeks of concurrent|
04655|045|D|therapy, risperidone concentrations increased 388% and 453%, respectively.|
04655|046|D|Plasma concentrations of the active moiety increased 39.4% and 44.5% after|
04655|047|D|two and four weeks of concurrent therapy, respectively.  No symptoms of|
04655|048|D|risperidone toxicity or change in extrapyramidal effects were noted.  One|
04655|049|D|patient developed Parkinsonism.(4)|
04655|050|D|   Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib,|
04655|051|D|fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)|
04655|052|B||
04655|053|R|REFERENCES:|
04655|054|B||
04655|055|R|1.Perseris (risperidone) extended-release injectable suspension US|1
04655|056|R|  prescribing information. Indivior Inc. July, 2018.|1
04655|057|R|2.Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E.|2
04655|058|R|  Inhibition of risperidone metabolism by fluoxetine in patients with|2
04655|059|R|  schizophrenia: a clinically relevant pharmacokinetic drug interaction. J|2
04655|060|R|  Clin Psychopharmacol 2002 Aug;22(4):419-23.|2
04655|061|R|3.Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The|2
04655|062|R|  effect of fluoxetine on the pharmacokinetics and safety of risperidone in|2
04655|063|R|  psychiatric patients. Pharmacopsychiatry 2002 Mar;35(2):50-6.|2
04655|064|R|4.Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A. Plasma|2
04655|065|R|  concentrations of risperidone and 9-hydroxyrisperidone during combined|2
04655|066|R|  treatment with paroxetine. Ther Drug Monit 2001 Jun;23(3):223-7.|2
04655|067|R|5.This information is based on an extract from the Certara Drug Interaction|6
04655|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04656|001|T|MONOGRAPH TITLE:  Risperidone Intramuscular Every 2 Weeks/Bupropion|
04656|002|B||
04656|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04656|004|L|take action as needed.|
04656|005|B||
04656|006|A|MECHANISM OF ACTION:  Bupropion is a strong CYP2D6 inhibitor and may inhibit|
04656|007|A|the metabolism of risperidone.(1-4) Both bupropion and risperidone are known|
04656|008|A|to lower the seizure threshold.(1-3)|
04656|009|B||
04656|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels and|
04656|011|E|increased side effects from risperidone. Concurrent use of bupropion and|
04656|012|E|risperidone may result in additive effects on the seizure threshold,|
04656|013|E|increasing the risk of seizures.(1-3)|
04656|014|B||
04656|015|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
04656|016|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
04656|017|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
04656|018|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
04656|019|P|total daily dose of bupropion greater than 450 mg or single doses greater|
04656|020|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
04656|021|P|oral hypoglycemics or insulin; or with concomitant medications known to|
04656|022|P|lower seizure threshold (antidepressants, theophylline, systemic|
04656|023|P|steroids).(1,2)|
04656|024|P|   The risk of anticholinergic toxicities including cognitive decline,|
04656|025|P|delirium, falls and fractures is increased in geriatric patients using more|
04656|026|P|than one medicine with anticholinergic properties.(6)|
04656|027|B||
04656|028|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics|
04656|029|M|should be undertaken only with extreme caution and with low initial|
04656|030|M|bupropion dosing and small gradual dosage increases.(1,2)  Single doses|
04656|031|M|should not exceed 150 mg.(1,2)  The maximum daily dose of bupropion should|
04656|032|M|not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)|
04656|033|M|   Patients receiving concurrent therapy with strong CYP2D6 inhibitors with|
04656|034|M|risperidone should be observed for increases in risperidone side effects,|
04656|035|M|including extrapyramidal and Parkinsonian symptoms.|
04656|036|M|   The US manufacturer of extended release risperidone microspheres for|
04656|037|M|injection (Risperdal Consta) recommends that patients maintained on the 25|
04656|038|M|mg dose of this product continue to receive the 25 mg dose when either|
04656|039|M|fluoxetine or paroxetine (strong CYP2D6 inhibitors) is initiated, unless|
04656|040|M|clinical judgment necessitates lowering the dose or interrupting therapy.|
04656|041|M|If a decision is made to lower the dose, the dose may be lowered 2 to 4|
04656|042|M|weeks before the initiation of fluoxetine or paroxetine.(3)|
04656|043|B||
04656|044|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
04656|045|D|other agents that lower seizure threshold, the manufacturer of bupropion|
04656|046|D|states that the concurrent use of bupropion and antipsychotics should be|
04656|047|D|undertaken only with extreme caution and with low initial bupropion dosing|
04656|048|D|and small gradual dosage increases.(1)|
04656|049|D|   In a study in 7 patients maintained on risperidone (doses ranged from 2|
04656|050|D|mg daily to 4 mg daily), the addition of duloxetine (60 mg daily) increased|
04656|051|D|risperidone levels by 25%.  The mean plasma risperidone/9-hydroxyrisperidone|
04656|052|D|ratio increased 1.95-fold.  One patient developed mild extrapyramidal|
04656|053|D|symptoms.  His risperidone level at the time was 72 ng/ml.(7)  In contrast,|
04656|054|D|a retrospective chart review compared 7 patients receiving concurrent|
04656|055|D|risperidone and duloxetine to control patients receiving only risperidone|
04656|056|D|and found no significant effect on risperidone levels.(8)|
04656|057|D|   A study in 10 patients examined the effects of fluoxetine (20 mg daily)|
04656|058|D|on risperidone (4-6 mg/day).  One patient dropped out following the|
04656|059|D|development of severe akathisia after one week of fluoxetine.  Her|
04656|060|D|risperidone levels had increased 457%.  In the remaining patients,|
04656|061|D|fluoxetine increased risperidone levels by 308% at two weeks and by 733% at|
04656|062|D|four weeks.  Levels of the active moiety increased by 75% by four weeks.|
04656|063|D|During the second week of fluoxetine therapy, two patients developed|
04656|064|D|Parkinsonian symptoms.(9)|
04656|065|D|   Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone|
04656|066|D|plasma concentrations.(9)|
04656|067|D|   A study in 3 poor metabolizer and 8 extensive metabolizers examined the|
04656|068|D|effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily).|
04656|069|D|Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone|
04656|070|D|and the active moiety by 29% and by 100%, respectively, in poor|
04656|071|D|metabolizers.  In extensive metabolizers, the AUC of risperidone and the|
04656|072|D|active moiety increased by 70% and 41%, respectively.(10)|
04656|073|D|   A study in 10 patients examined the effects of paroxetine (20 mg daily)|
04656|074|D|on risperidone (4-8 mg/day).  After two and four weeks of concurrent|
04656|075|D|therapy, risperidone concentrations increased 388% and 453%, respectively.|
04656|076|D|Plasma concentrations of the active moiety increased 39.4% and 44.5% after|
04656|077|D|two and four weeks of concurrent therapy, respectively.  No symptoms of|
04656|078|D|risperidone toxicity or change in extrapyramidal effects were noted.  One|
04656|079|D|patient developed Parkinsonism.(11)|
04656|080|D|   Paroxetine has been shown to lower 9-hydroxyrisperidone plasma|
04656|081|D|concentrations by 10%.(11)|
04656|082|B||
04656|083|R|REFERENCES:|
04656|084|B||
04656|085|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
04656|086|R|  GlaxoSmithKline November, 2019.|1
04656|087|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
04656|088|R|  GlaxoSmithKline July, 2019.|1
04656|089|R|3.Risperdal Consta (risperidone long acting injection) US prescribing|1
04656|090|R|  information. Janssen Pharmaceutical Ltd. September, 2011.|1
04656|091|R|4.This information is based on an extract from the Certara Drug Interaction|6
04656|092|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04656|093|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04656|094|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04656|095|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04656|096|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04656|097|R|  11/14/2017.|1
04656|098|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04656|099|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04656|100|R|  Soc 2023 Jul;71(7):2052-2081.|6
04656|101|R|7.Santoro V, D'Arrigo C, Spina E, Mico U, Muscatello MR, Zoccali R. Effect|2
04656|102|R|  of adjunctive duloxetine on the plasma concentrations of clozapine,|2
04656|103|R|  olanzapine, and risperidone in patients with psychotic disorders. J Clin|2
04656|104|R|  Psychopharmacol 2010 Oct;30(5):634-6.|2
04656|105|R|8.Hendset M, Molden E, Enoksen TB, Refsum H, Hermann M. The effect of|2
04656|106|R|  coadministration of duloxetine on steady-state serum concentration of|2
04656|107|R|  risperidone and aripiprazole: a study based on therapeutic drug monitoring|2
04656|108|R|  data. Ther Drug Monit 2010 Dec;32(6):787-90.|2
04656|109|R|9.Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E.|2
04656|110|R|  Inhibition of risperidone metabolism by fluoxetine in patients with|2
04656|111|R|  schizophrenia: a clinically relevant pharmacokinetic drug interaction. J|2
04656|112|R|  Clin Psychopharmacol 2002 Aug;22(4):419-23.|2
04656|113|R|10.Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The|2
04656|114|R|   effect of fluoxetine on the pharmacokinetics and safety of risperidone in|2
04656|115|R|   psychiatric patients. Pharmacopsychiatry 2002 Mar;35(2):50-6.|2
04656|116|R|11.Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A. Plasma|2
04656|117|R|   concentrations of risperidone and 9-hydroxyrisperidone during combined|2
04656|118|R|   treatment with paroxetine. Ther Drug Monit 2001 Jun;23(3):223-7.|2
04657|001|T|MONOGRAPH TITLE:  Risperidone Subcutaneous Every 1-2 Months|
04657|002|T|(Uzedy)/Bupropion|
04657|003|B||
04657|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04657|005|L|take action as needed.|
04657|006|B||
04657|007|A|MECHANISM OF ACTION:  Bupropion is a strong CYP2D6 inhibitor and may inhibit|
04657|008|A|the metabolism of risperidone.(1-4)  Both bupropion and risperidone are|
04657|009|A|known to lower the seizure threshold.(1-3)|
04657|010|B||
04657|011|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels and|
04657|012|E|increased side effects from risperidone.  Concurrent use of bupropion and|
04657|013|E|risperidone may result in additive effects on the seizure threshold,|
04657|014|E|increasing the risk of seizures.(1-3)|
04657|015|B||
04657|016|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
04657|017|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
04657|018|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
04657|019|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
04657|020|P|total daily dose of bupropion greater than 450 mg or single doses greater|
04657|021|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
04657|022|P|oral hypoglycemics or insulin; or with concomitant medications known to|
04657|023|P|lower seizure threshold (antidepressants, theophylline, systemic|
04657|024|P|steroids).(1,2)|
04657|025|P|   The risk of anticholinergic toxicities including cognitive decline,|
04657|026|P|delirium, falls and fractures is increased in geriatric patients using more|
04657|027|P|than one medicine with anticholinergic properties.(6)|
04657|028|B||
04657|029|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics|
04657|030|M|should be undertaken only with extreme caution and with low initial|
04657|031|M|bupropion dosing and small gradual dosage increases.(1,2)  Single doses|
04657|032|M|should not exceed 150 mg.(1,2)  The maximum daily dose of bupropion should|
04657|033|M|not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)|
04657|034|M|   Patients receiving concurrent therapy with strong CYP2D6 inhibitors with|
04657|035|M|risperidone should be observed for increases in risperidone side effects,|
04657|036|M|including extrapyramidal and Parkinsonian symptoms.|
04657|037|M|   The manufacturer of extended release risperidone injectable suspension|
04657|038|M|(Uzedy) recommends patients be placed on the lowest dose (50 mg monthly or|
04657|039|M|100 mg once every 2 months) of Uzedy before the planned start of strong|
04657|040|M|CYP2D6 inhibitor therapy to adjust for the expected increase in risperidone|
04657|041|M|plasma concentrations.  When strong CYP2D6 inhibitors are initiated in|
04657|042|M|patients receiving Uzedy 50 mg monthly or 100 mg once every 2 months, it is|
04657|043|M|recommended to continue treatment with the same dose unless clinical|
04657|044|M|judgment necessitates interruption of risperidone treatment.(3)|
04657|045|B||
04657|046|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
04657|047|D|other agents that lower seizure threshold, the manufacturer of bupropion|
04657|048|D|states that the concurrent use of bupropion and antipsychotics should be|
04657|049|D|undertaken only with extreme caution and with low initial bupropion dosing|
04657|050|D|and small gradual dosage increases.(1)|
04657|051|D|   In a study in 7 patients maintained on risperidone (doses ranged from 2|
04657|052|D|mg daily to 4 mg daily), the addition of duloxetine (60 mg daily) increased|
04657|053|D|risperidone levels by 25%.  The mean plasma risperidone/9-hydroxyrisperidone|
04657|054|D|ratio increased 1.95-fold.  One patient developed mild extrapyramidal|
04657|055|D|symptoms.  His risperidone level at the time was 72 ng/ml.(7)  In contrast,|
04657|056|D|a retrospective chart review compared 7 patients receiving concurrent|
04657|057|D|risperidone and duloxetine to control patients receiving only risperidone|
04657|058|D|and found no significant effect on risperidone levels.(8)|
04657|059|D|   A study in 10 patients examined the effects of fluoxetine (20 mg daily)|
04657|060|D|on risperidone (4-6 mg/day).  One patient dropped out following the|
04657|061|D|development of severe akathisia after one week of fluoxetine.  Her|
04657|062|D|risperidone levels had increased 457%.  In the remaining patients,|
04657|063|D|fluoxetine increased risperidone levels by 308% at two weeks and by 733% at|
04657|064|D|four weeks.  Levels of the active moiety increased by 75% by four weeks.|
04657|065|D|During the second week of fluoxetine therapy, two patients developed|
04657|066|D|Parkinsonian symptoms.(9)|
04657|067|D|   Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone|
04657|068|D|plasma concentrations.(9)|
04657|069|D|   A study in 3 poor metabolizer and 8 extensive metabolizers examined the|
04657|070|D|effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily).|
04657|071|D|Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone|
04657|072|D|and the active moiety by 29% and by 100%, respectively, in poor|
04657|073|D|metabolizers.  In extensive metabolizers, the AUC of risperidone and the|
04657|074|D|active moiety increased by 70% and 41%, respectively.(10)|
04657|075|D|   A study in 10 patients examined the effects of paroxetine (20 mg daily)|
04657|076|D|on risperidone (4-8 mg/day).  After two and four weeks of concurrent|
04657|077|D|therapy, risperidone concentrations increased 388% and 453%, respectively.|
04657|078|D|Plasma concentrations of the active moiety increased 39.4% and 44.5% after|
04657|079|D|two and four weeks of concurrent therapy, respectively.  No symptoms of|
04657|080|D|risperidone toxicity or change in extrapyramidal effects were noted.  One|
04657|081|D|patient developed Parkinsonism.(11)|
04657|082|D|   Paroxetine has been shown to lower 9-hydroxyrisperidone plasma|
04657|083|D|concentrations by 10%.(11)|
04657|084|B||
04657|085|R|REFERENCES:|
04657|086|B||
04657|087|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
04657|088|R|  GlaxoSmithKline November, 2019.|1
04657|089|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
04657|090|R|  GlaxoSmithKline July, 2019.|1
04657|091|R|3.Uzedy (risperidone extended-release injectable suspension) US prescribing|1
04657|092|R|  information. Teva Pharmaceuticals April, 2023.|1
04657|093|R|4.This information is based on an extract from the Certara Drug Interaction|6
04657|094|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04657|095|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04657|096|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04657|097|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04657|098|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04657|099|R|  11/14/2017.|1
04657|100|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04657|101|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04657|102|R|  Soc 2023 Jul;71(7):2052-2081.|6
04657|103|R|7.Santoro V, D'Arrigo C, Spina E, Mico U, Muscatello MR, Zoccali R. Effect|2
04657|104|R|  of adjunctive duloxetine on the plasma concentrations of clozapine,|2
04657|105|R|  olanzapine, and risperidone in patients with psychotic disorders. J Clin|2
04657|106|R|  Psychopharmacol 2010 Oct;30(5):634-6.|2
04657|107|R|8.Hendset M, Molden E, Enoksen TB, Refsum H, Hermann M. The effect of|2
04657|108|R|  coadministration of duloxetine on steady-state serum concentration of|2
04657|109|R|  risperidone and aripiprazole: a study based on therapeutic drug monitoring|2
04657|110|R|  data. Ther Drug Monit 2010 Dec;32(6):787-90.|2
04657|111|R|9.Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E.|2
04657|112|R|  Inhibition of risperidone metabolism by fluoxetine in patients with|2
04657|113|R|  schizophrenia: a clinically relevant pharmacokinetic drug interaction. J|2
04657|114|R|  Clin Psychopharmacol 2002 Aug;22(4):419-23.|2
04657|115|R|10.Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The|2
04657|116|R|   effect of fluoxetine on the pharmacokinetics and safety of risperidone in|2
04657|117|R|   psychiatric patients. Pharmacopsychiatry 2002 Mar;35(2):50-6.|2
04657|118|R|11.Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A. Plasma|2
04657|119|R|   concentrations of risperidone and 9-hydroxyrisperidone during combined|2
04657|120|R|   treatment with paroxetine. Ther Drug Monit 2001 Jun;23(3):223-7.|2
04658|001|T|MONOGRAPH TITLE:  Risperidone Subcutaneous Monthly (Perseris)/Bupropion|
04658|002|B||
04658|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04658|004|L|take action as needed.|
04658|005|B||
04658|006|A|MECHANISM OF ACTION:  Bupropion is a strong CYP2D6 inhibitor and may inhibit|
04658|007|A|the metabolism of risperidone.(1-4)  Both bupropion and risperidone are|
04658|008|A|known to lower the seizure threshold.(1-3)|
04658|009|B||
04658|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels and|
04658|011|E|increased side effects from risperidone.  Concurrent use of bupropion and|
04658|012|E|risperidone may result in additive effects on the seizure threshold,|
04658|013|E|increasing the risk of seizures.(1-3)|
04658|014|B||
04658|015|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
04658|016|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
04658|017|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
04658|018|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
04658|019|P|total daily dose of bupropion greater than 450 mg or single doses greater|
04658|020|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
04658|021|P|oral hypoglycemics or insulin; or with concomitant medications known to|
04658|022|P|lower seizure threshold (antidepressants, theophylline, systemic|
04658|023|P|steroids).(1,2)|
04658|024|P|   The risk of anticholinergic toxicities including cognitive decline,|
04658|025|P|delirium, falls and fractures is increased in geriatric patients using more|
04658|026|P|than one medicine with anticholinergic properties.(6)|
04658|027|B||
04658|028|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics|
04658|029|M|should be undertaken only with extreme caution and with low initial|
04658|030|M|bupropion dosing and small gradual dosage increases.(1,2)  Single doses|
04658|031|M|should not exceed 150 mg.(1,2)  The maximum daily dose of bupropion should|
04658|032|M|not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)|
04658|033|M|   Patients receiving concurrent therapy with strong CYP2D6 inhibitors with|
04658|034|M|risperidone should be observed for increases in risperidone side effects,|
04658|035|M|including extrapyramidal and Parkinsonian symptoms.|
04658|036|M|   The manufacturer of extended release risperidone injectable suspension|
04658|037|M|(Perseris) recommends patients be placed on the lowest dose (90 mg) of|
04658|038|M|Perseris two to four weeks before the planned start of a strong CYP2D6|
04658|039|M|inhibitor to adjust for the expected increase in risperidone plasma|
04658|040|M|concentrations. When a strong CYP2D6 inhibitor is initiated in patients|
04658|041|M|receiving Perseris 90 mg, it is recommended to continue treatment with 90 mg|
04658|042|M|unless clinical judgment necessitates interruption of risperidone|
04658|043|M|treatment.(1)|
04658|044|B||
04658|045|D|DISCUSSION:  Because of the risk of seizure from concurrent bupropion and|
04658|046|D|other agents that lower seizure threshold, the manufacturer of bupropion|
04658|047|D|states that the concurrent use of bupropion and antipsychotics should be|
04658|048|D|undertaken only with extreme caution and with low initial bupropion dosing|
04658|049|D|and small gradual dosage increases.(1)|
04658|050|D|   A study in 10 patients examined the effects of fluoxetine (20 mg daily)|
04658|051|D|on risperidone (4-6 mg/day).  One patient dropped out following the|
04658|052|D|development of severe akathisia after one week of fluoxetine.  Her|
04658|053|D|risperidone levels had increased 457%.  In the remaining patients,|
04658|054|D|fluoxetine increased risperidone levels by 308% at two weeks and by 733% at|
04658|055|D|four weeks.  Levels of the active moiety increased by 75% by four weeks.|
04658|056|D|During the second week of fluoxetine therapy, two patients developed|
04658|057|D|Parkinsonian symptoms.(7)|
04658|058|D|   A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers|
04658|059|D|examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg|
04658|060|D|daily). Concurrent fluoxetine increased the area-under-curve (AUC) of|
04658|061|D|risperidone and the active moiety by 29% and by 100%, respectively, in poor|
04658|062|D|metabolizers.  In extensive metabolizers, the AUC of risperidone and the|
04658|063|D|active moiety increased by 70% and 41%, respectively.(8)|
04658|064|D|   A study in 10 patients examined the effects of paroxetine (20 mg daily)|
04658|065|D|on risperidone (4-8 mg/day).  After two and four weeks of concurrent|
04658|066|D|therapy, risperidone concentrations increased 388% and 453%, respectively.|
04658|067|D|Plasma concentrations of the active moiety increased 39.4% and 44.5% after|
04658|068|D|two and four weeks of concurrent therapy, respectively.  No symptoms of|
04658|069|D|risperidone toxicity or change in extrapyramidal effects were noted.  One|
04658|070|D|patient developed Parkinsonism.(9)|
04658|071|B||
04658|072|R|REFERENCES:|
04658|073|B||
04658|074|R|1.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
04658|075|R|  GlaxoSmithKline November, 2019.|1
04658|076|R|2.Zyban (bupropion hydrochloride) US prescribing information.|1
04658|077|R|  GlaxoSmithKline July, 2019.|1
04658|078|R|3.Perseris (risperidone) extended-release injectable suspension US|1
04658|079|R|  prescribing information. Indivior Inc. July, 2018.|1
04658|080|R|4.This information is based on an extract from the Certara Drug Interaction|6
04658|081|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04658|082|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04658|083|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04658|084|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04658|085|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04658|086|R|  11/14/2017.|1
04658|087|R|6.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04658|088|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04658|089|R|  Soc 2023 Jul;71(7):2052-2081.|6
04658|090|R|7.Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E.|2
04658|091|R|  Inhibition of risperidone metabolism by fluoxetine in patients with|2
04658|092|R|  schizophrenia: a clinically relevant pharmacokinetic drug interaction. J|2
04658|093|R|  Clin Psychopharmacol 2002 Aug;22(4):419-23.|2
04658|094|R|8.Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The|2
04658|095|R|  effect of fluoxetine on the pharmacokinetics and safety of risperidone in|2
04658|096|R|  psychiatric patients. Pharmacopsychiatry 2002 Mar;35(2):50-6.|2
04658|097|R|9.Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A. Plasma|2
04658|098|R|  concentrations of risperidone and 9-hydroxyrisperidone during combined|2
04658|099|R|  treatment with paroxetine. Ther Drug Monit 2001 Jun;23(3):223-7.|2
04659|001|T|MONOGRAPH TITLE:  Intravenous Lefamulin/Strong CYP3A4 Inducers that Prolong|
04659|002|T|QT|
04659|003|B||
04659|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04659|005|L|of severe adverse interaction.|
04659|006|B||
04659|007|A|MECHANISM OF ACTION:  Lefamulin is a substrate of CYP3A4.  Strong CYP3A4|
04659|008|A|inducers that prolong the QTc interval may induce the metabolism of|
04659|009|A|lefamulin and result in additive risk of QT prolongation.(1)|
04659|010|B||
04659|011|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4 inducer|
04659|012|E|that prolongs QT may result in decreased levels and effectiveness of|
04659|013|E|lefamulin and may cause additive effects on the QTc interval, which may|
04659|014|E|result in life-threatening cardiac arrhythmias including torsades de|
04659|015|E|pointes.(1)|
04659|016|B||
04659|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04659|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04659|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04659|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04659|021|P|female gender, or advanced age.(2)|
04659|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04659|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04659|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04659|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04659|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04659|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04659|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04659|029|P|   Induction effects may be more likely with regular use of the inducer for|
04659|030|P|longer than 1-2 weeks.|
04659|031|B||
04659|032|M|PATIENT MANAGEMENT:  The manufacturer of lefamulin states that concurrent|
04659|033|M|use with strong CYP3A4 inducers should be avoided.(1)|
04659|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04659|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04659|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04659|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04659|038|B||
04659|039|D|DISCUSSION:  In a study, concurrent administration of rifampin (strong|
04659|040|D|CYP3A4inducer) with lefamulin injection decreased lefamulin|
04659|041|D|area-under-the-curve (AUC) and maximum concentration (Cmax) by 28% and|
04659|042|D|8%.(1)|
04659|043|D|   Strong inducers of CYP3A4 that prolong QT include: encorafenib and|
04659|044|D|ivosidenib.(3,4)|
04659|045|B||
04659|046|R|REFERENCES:|
04659|047|B||
04659|048|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04659|049|R|  Inc August 2019.|1
04659|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04659|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04659|052|R|  settings: a scientific statement from the American Heart Association and|6
04659|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04659|054|R|  2;55(9):934-47.|6
04659|055|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04659|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04659|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04659|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04659|059|R|  11/14/2017.|1
04659|060|R|4.This information is based on an extract from the Certara Drug Interaction|6
04659|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04660|001|T|MONOGRAPH TITLE:  Pegulicianine/Blue Dyes|
04660|002|B||
04660|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04660|004|L|of severe adverse interaction.|
04660|005|B||
04660|006|A|MECHANISM OF ACTION:  Pegulicianine produces a fluorescent signal in and|
04660|007|A|around tumor and tumor-associated cells.  Blue dyes also produce a|
04660|008|A|fluorescent signal and may affect the results of imaging with|
04660|009|A|pegulicianine.(1)|
04660|010|B||
04660|011|E|CLINICAL EFFECTS:  Fluorescence imaging with pegulicianine may not be|
04660|012|E|accurate in patients who receive blue dyes for sentinel lymph node|
04660|013|E|mapping.(1)|
04660|014|B||
04660|015|P|PREDISPOSING FACTORS:  None determined.|
04660|016|B||
04660|017|M|PATIENT MANAGEMENT:  Avoid administration of blue dyes for sentinel lymph|
04660|018|M|node mapping in patients planned for imaging with pegulicianine.(1)|
04660|019|B||
04660|020|D|DISCUSSION:  Blue dyes used for sentinel lymph node mapping produce a|
04660|021|D|fluorescent signal that interferes with the fluorescent signal from|
04660|022|D|pegulicianine.  The potential of other dyes to interfere with pegulicianine|
04660|023|D|imaging has not been evaluated.(1)|
04660|024|B||
04660|025|R|REFERENCE:|
04660|026|B||
04660|027|R|1.Lumisight (pegulicianine) US prescribing information. Lumicell, Inc.|1
04660|028|R|  April, 2024.|1
04661|001|T|MONOGRAPH TITLE:  Amiodarone/Strong CYP3A4 Inhibitors|
04661|002|B||
04661|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04661|004|L|of severe adverse interaction.|
04661|005|B||
04661|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04661|007|A|amiodarone.  Amiodarone is a CYP3A4 substrate.(1)|
04661|008|B||
04661|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04661|010|E|the levels and effects of amiodarone including QTc prolongation, which may|
04661|011|E|result in potentially life-threatening cardiac arrhythmias like torsades de|
04661|012|E|pointes (TdP).(1)|
04661|013|B||
04661|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04661|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04661|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04661|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04661|018|P|female gender, or advanced age.(2)|
04661|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04661|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04661|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04661|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04661|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04661|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04661|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04661|026|B||
04661|027|M|PATIENT MANAGEMENT:  The US manufacturer of amiodarone states concurrent use|
04661|028|M|with CYP3A4 inhibitors should be avoided.(1)|
04661|029|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
04661|030|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
04661|031|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
04661|032|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04661|033|B||
04661|034|D|DISCUSSION:  QTc prolongation has been reported during concurrent amiodarone|
04661|035|D|and azole antifungals, fluoroquinolones, and macrolide antibiotics.(1)|
04661|036|D|   A retrospective review of patients who received concurrent amiodarone and|
04661|037|D|haloperidol over a 24 month period found 49 patients who received concurrent|
04661|038|D|therapy for 381 exposures.  The mean increase in QTc interval was 9.8 msec;|
04661|039|D|the average change in QTc interval per patient was 23.6 msec.(3)|
04661|040|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, grapefruit,|
04661|041|D|idelalisib, itraconazole, josamycin, ketoconazole, mifepristone, nefazodone,|
04661|042|D|telaprevir, troleandomycin, and tucatinib.(4,5)|
04661|043|B||
04661|044|R|REFERENCES:|
04661|045|B||
04661|046|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
04661|047|R|  Pharmaceuticals October, 2018.|1
04661|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04661|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04661|050|R|  settings: a scientific statement from the American Heart Association and|6
04661|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04661|052|R|  2;55(9):934-47.|6
04661|053|R|3.Bush SE, Hatton RC, Winterstein AG, Thomson MR, Woo GW. Effects of|3
04661|054|R|  concomitant amiodarone and haloperidol on Q-Tc interval prolongation. Am J|3
04661|055|R|  Health Syst Pharm 2008 Dec 1;65(23):2232-6.|3
04661|056|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04661|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04661|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04661|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04661|060|R|  11/14/2017.|1
04661|061|R|5.This information is based on an extract from the Certara Drug Interaction|6
04661|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04662|001|T|MONOGRAPH TITLE:  Amiodarone/Strong CYP3A4 Inhibitors that Prolong QT|
04662|002|B||
04662|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04662|004|L|is contraindicated and generally should not be dispensed or administered to|
04662|005|L|the same patient.|
04662|006|B||
04662|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
04662|008|A|may inhibit the metabolism of amiodarone and result in additive risk of QT|
04662|009|A|prolongation.  Amiodarone is a CYP3A4 substrate.(1)|
04662|010|B||
04662|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04662|012|E|QT may increase the levels and effects of amiodarone including additive QTc|
04662|013|E|prolongation, which may result in potentially life-threatening cardiac|
04662|014|E|arrhythmias like torsades de pointes (TdP).(1)|
04662|015|B||
04662|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04662|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04662|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04662|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04662|020|P|female gender, or advanced age.(2)|
04662|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04662|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04662|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04662|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04662|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04662|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04662|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04662|028|B||
04662|029|M|PATIENT MANAGEMENT:  The US manufacturer of amiodarone states that the|
04662|030|M|concurrent use of QT prolonging agents should be avoided and that the need|
04662|031|M|to co-administer amiodarone with any other drug known to prolong the QTc|
04662|032|M|interval must be based on a careful assessment of the potential risks and|
04662|033|M|benefits of doing so for each patient.  Concurrent use with CYP3A4|
04662|034|M|inhibitors should also be avoided.(1)|
04662|035|M|   The US manufacturer of levoketoconazole states that levoketoconazole is|
04662|036|M|contraindicated with other agents that prolong the QT interval.(3)|
04662|037|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
04662|038|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
04662|039|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
04662|040|M|syndrome (including first-degree family history).|
04662|041|M|   Use caution in patients with other risk factors for QT prolongation|
04662|042|M|including congestive heart failure, bradyarrhythmias, and uncorrected|
04662|043|M|electrolyte abnormalities.  Consider more frequent ECG monitoring.|
04662|044|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
04662|045|M|hypokalemia or hypomagnesemia.|
04662|046|M|   If a patient develops QT prolongation with a QTc interval greater than|
04662|047|M|500 msec, temporarily discontinue levoketoconazole.  After resolution of|
04662|048|M|prolonged QTc interval, levoketoconazole may be resumed at a lower dose.  If|
04662|049|M|QTc interval prolongation recurs, permanently discontinue|
04662|050|M|levoketoconazole.(3)|
04662|051|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
04662|052|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
04662|053|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
04662|054|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04662|055|B||
04662|056|D|DISCUSSION:  QTc prolongation has been reported during concurrent amiodarone|
04662|057|D|and azole antifungals, fluoroquinolones, and macrolide antibiotics.(1)|
04662|058|D|   A retrospective review of patients who received concurrent amiodarone and|
04662|059|D|haloperidol over a 24 month period found 49 patients who received concurrent|
04662|060|D|therapy for 381 exposures.  The mean increase in QTc interval was 9.8 msec;|
04662|061|D|the average change in QTc interval per patient was 23.6 msec.(3)|
04662|062|D|   During phase 1 and 2 studies with levoketoconazole, which excluded|
04662|063|D|patients with baseline QTcF interval greater than 470 msec, 4 (2.4%)|
04662|064|D|patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
04662|065|D|change-from-baseline QTcF > 60 msec.(2)|
04662|066|D|   Agents that are linked to this monograph may have varying degrees of|
04662|067|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04662|068|D|been shown to prolong the QTc interval either through their mechanism of|
04662|069|D|action, through studies on their effects on the QTc interval, or through|
04662|070|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04662|071|D|and/or postmarketing reports.(4)|
04662|072|D|   Strong inhibitors of CYP3A4 that prolong QT include:|
04662|073|D|levoketoconazole.(6,7)|
04662|074|B||
04662|075|R|REFERENCES:|
04662|076|B||
04662|077|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
04662|078|R|  Pharmaceuticals October, 2018.|1
04662|079|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04662|080|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04662|081|R|  settings: a scientific statement from the American Heart Association and|6
04662|082|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04662|083|R|  2;55(9):934-47.|6
04662|084|R|3.Recorlev (levoketoconazole) US prescribing information. Xeris|1
04662|085|R|  Pharmaceuticals, Inc. June, 2023.|1
04662|086|R|4.Bush SE, Hatton RC, Winterstein AG, Thomson MR, Woo GW. Effects of|3
04662|087|R|  concomitant amiodarone and haloperidol on Q-Tc interval prolongation. Am J|3
04662|088|R|  Health Syst Pharm 2008 Dec 1;65(23):2232-6.|3
04662|089|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04662|090|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04662|091|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04662|092|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04662|093|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04662|094|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04662|095|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04662|096|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04662|097|R|  11/14/2017.|1
04662|098|R|7.This information is based on an extract from the Certara Drug Interaction|6
04662|099|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04663|001|T|MONOGRAPH TITLE:  Amiodarone/Lonafarnib (mono deleted 05/28/2024)|
04663|002|B||
04663|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04663|004|L|of severe adverse interaction.|
04663|005|B||
04663|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04663|007|A|amiodarone.  Lonafarnib is a strong CYP3A4 inhibitor.(1)|
04663|008|A|   Weak inhibitors of CYP3A4 may inhibit the metabolism of lonafarnib.|
04663|009|A|Amiodarone is a weak CYP3A4 inhibitor.(2)|
04663|010|B||
04663|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04663|012|E|the levels and effects of amiodarone including QTc prolongation, which may|
04663|013|E|result in potentially life-threatening cardiac arrhythmias like torsades de|
04663|014|E|pointes (TdP).(1)|
04663|015|E|   Concurrent use may also increase the risk of adverse reactions of|
04663|016|E|lonafarnib including nausea and vomiting, increased liver enzymes,|
04663|017|E|myelosuppression, and hypertension.(2)|
04663|018|B||
04663|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04663|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04663|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04663|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04663|023|P|female gender, or advanced age.(3)|
04663|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04663|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04663|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04663|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04663|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04663|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04663|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04663|031|B||
04663|032|M|PATIENT MANAGEMENT:  Avoid coadministration of amiodarone and lonafarnib.|
04663|033|M|   The US manufacturer of amiodarone states concurrent use with CYP3A4|
04663|034|M|inhibitors should be avoided.(1)|
04663|035|M|   If coadministration is unavoidable, reduce the dose of lonafarnib to 115|
04663|036|M|mg/m2 or continue 115 mg/m2 without further dose increases.(2)|
04663|037|M|   Patients should be counseled that concurrent use of lonafarnib with|
04663|038|M|amiodarone may result in an increase in side effects.|
04663|039|M|   Closely monitor patients for arrhythmias and events such as syncope and|
04663|040|M|heart palpitations because lonafarnib exposures may be increased despite the|
04663|041|M|dosage reduction and the effect on the QT interval is unknown.  Resume|
04663|042|M|previous lonafarnib dosage 14 days after discontinuing the weak CYP3A4|
04663|043|M|inhibitor.(2)|
04663|044|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
04663|045|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
04663|046|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
04663|047|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04663|048|B||
04663|049|D|DISCUSSION:  QTc prolongation has been reported during concurrent amiodarone|
04663|050|D|and azole antifungals, fluoroquinolones, and macrolide antibiotics.(1)|
04663|051|D|   A retrospective review of patients who received concurrent amiodarone and|
04663|052|D|haloperidol over a 24 month period found 49 patients who received concurrent|
04663|053|D|therapy for 381 exposures.  The mean increase in QTc interval was 9.8 msec;|
04663|054|D|the average change in QTc interval per patient was 23.6 msec.(4)|
04663|055|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
04663|056|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
04663|057|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
04663|058|B||
04663|059|R|REFERENCES:|
04663|060|B||
04663|061|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
04663|062|R|  Pharmaceuticals October, 2018.|1
04663|063|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04663|064|R|  Inc. November, 2020.|1
04663|065|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04663|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04663|067|R|  settings: a scientific statement from the American Heart Association and|6
04663|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04663|069|R|  2;55(9):934-47.|6
04663|070|R|4.Bush SE, Hatton RC, Winterstein AG, Thomson MR, Woo GW. Effects of|3
04663|071|R|  concomitant amiodarone and haloperidol on Q-Tc interval prolongation. Am J|3
04663|072|R|  Health Syst Pharm 2008 Dec 1;65(23):2232-6.|3
04663|073|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04663|074|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04663|075|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04663|076|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04663|077|R|  11/14/2017.|1
04663|078|R|6.This information is based on an extract from the Certara Drug Interaction|6
04663|079|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04664|001|T|MONOGRAPH TITLE:  Ropeginterferon alfa-2b/Select Immunosuppressives|
04664|002|B||
04664|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04664|004|L|is contraindicated and generally should not be dispensed or administered to|
04664|005|L|the same patient.|
04664|006|B||
04664|007|A|MECHANISM OF ACTION:  Ropeginterferon alfa-2b and immunosuppressives both|
04664|008|A|suppress the immune system.|
04664|009|B||
04664|010|E|CLINICAL EFFECTS:  Concurrent use of ropeginterferon alfa-2b with|
04664|011|E|immunosuppressives may result in an increased risk of serious infections.|
04664|012|B||
04664|013|P|PREDISPOSING FACTORS:  None determined.|
04664|014|B||
04664|015|M|PATIENT MANAGEMENT:  The US and UK manufacturers of ropeginterferon alfa-2b|
04664|016|M|state that concurrent use of ropeginterferon alfa-2b in transplant patients|
04664|017|M|receiving immunosuppressive agents is contraindicated.(1-2)|
04664|018|B||
04664|019|D|DISCUSSION:  In clinical trials, 20% of patients experienced leukopenia.|
04664|020|D|Interferon alfa products may cause fatal or life-threatening|
04664|021|D|infections.(1-2)|
04664|022|B||
04664|023|R|REFERENCES:|
04664|024|B||
04664|025|R|1.Besremi (ropeginterferon alfa-2b) US prescribing information.|1
04664|026|R|  PharmaEssentia April 2024.|1
04664|027|R|2.Besremi (ropeginterferon alfa-2b) UK prescribing information. AOP Orphan|1
04664|028|R|  Ltd February 2023.|1
04665|001|T|MONOGRAPH TITLE:  Ropeginterferon alfa-2b/Slt Immunosuppress;|
04665|002|T|Immunomodulator|
04665|003|B||
04665|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04665|005|L|of severe adverse interaction.|
04665|006|B||
04665|007|A|MECHANISM OF ACTION:  Ropeginterferon alfa-2b and immunosuppressives both|
04665|008|A|suppress the immune system.|
04665|009|B||
04665|010|E|CLINICAL EFFECTS:  Concurrent use of ropeginterferon alfa-2b with|
04665|011|E|immunosuppressives may result in an increased risk of serious infections.|
04665|012|B||
04665|013|P|PREDISPOSING FACTORS:  None determined.|
04665|014|B||
04665|015|M|PATIENT MANAGEMENT:  Avoid concurrent use of myelosuppressive agents.(1-2)|
04665|016|M|If concurrent use cannot be avoided, monitor for effects of excessive|
04665|017|M|immunosuppression.|
04665|018|B||
04665|019|D|DISCUSSION:  In clinical trials, 20% of patients experienced leukopenia.|
04665|020|D|Interferon alfa products may cause fatal or life-threatening|
04665|021|D|infections.(1-2)|
04665|022|B||
04665|023|R|REFERENCES:|
04665|024|B||
04665|025|R|1.Besremi (ropeginterferon alfa-2b) US prescribing information.|1
04665|026|R|  PharmaEssentia April 2024.|1
04665|027|R|2.Besremi (ropeginterferon alfa-2b) UK prescribing information. AOP Orphan|1
04665|028|R|  Ltd February 2023.|1
04666|001|T|MONOGRAPH TITLE:  Simvastatin (Greater Than 20 mg)/Voclosporin|
04666|002|B||
04666|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04666|004|L|is contraindicated and generally should not be dispensed or administered to|
04666|005|L|the same patient.|
04666|006|B||
04666|007|A|MECHANISM OF ACTION:  Voclosporin inhibits the OATP1B1 and OATP1B3|
04666|008|A|transporters, which may result in increased absorption and decreased hepatic|
04666|009|A|uptake of simvastatin.(1,2)|
04666|010|B||
04666|011|E|CLINICAL EFFECTS:  Concurrent voclosporin may result in elevated levels of|
04666|012|E|simvastatin, which may result in myopathy and rhabdomyolysis.(1,2)|
04666|013|B||
04666|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04666|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04666|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04666|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04666|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04666|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04666|020|P|predisposed to myopathy or rhabdomyolysis.|
04666|021|B||
04666|022|M|PATIENT MANAGEMENT:  The US manufacturer of voclosporin states that the dose|
04666|023|M|of simvastatin should not exceed 20 mg daily when used concurrently with|
04666|024|M|voclosporin.  In patients who have previously tolerated simvastatin 80 mg|
04666|025|M|daily for at least one year without muscle toxicity, limit the simvastatin|
04666|026|M|dose to 40 mg daily.(1)|
04666|027|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04666|028|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04666|029|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04666|030|M|urine, and/or discolored urine.|
04666|031|B||
04666|032|D|DISCUSSION:  Concurrent use of voclosporin (23.7 mg twice daily) increased|
04666|033|D|the concentration maximum (Cmax) and area-under-curve (AUC) of a 40 mg|
04666|034|D|single dose of simvastatin by 3.1-fold and 1.8-fold, respectively.(1)|
04666|035|B||
04666|036|R|REFERENCES:|
04666|037|B||
04666|038|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
04666|039|R|  April, 2024.|1
04666|040|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
04666|041|R|  2023.|1
04667|001|T|MONOGRAPH TITLE:  Simvastatin (Less Than or Equal to 20 mg)/Voclosporin|
04667|002|B||
04667|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04667|004|L|take action as needed.|
04667|005|B||
04667|006|A|MECHANISM OF ACTION:  Voclosporin inhibits the OATP1B1 and OATP1B3|
04667|007|A|transporters, which may result in increased absorption and decreased hepatic|
04667|008|A|uptake of simvastatin.(1,2)|
04667|009|B||
04667|010|E|CLINICAL EFFECTS:  Concurrent voclosporin may result in elevated levels of|
04667|011|E|simvastatin, which may result in myopathy and rhabdomyolysis.(1,2)|
04667|012|B||
04667|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04667|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04667|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04667|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04667|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04667|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04667|019|P|predisposed to myopathy or rhabdomyolysis.|
04667|020|B||
04667|021|M|PATIENT MANAGEMENT:  The US manufacturer of voclosporin states that the dose|
04667|022|M|of simvastatin should not exceed 20 mg daily when used concurrently with|
04667|023|M|voclosporin.  In patients who have previously tolerated simvastatin 80 mg|
04667|024|M|daily for at least one year without muscle toxicity, limit the simvastatin|
04667|025|M|dose to 40 mg daily.(1)|
04667|026|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04667|027|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04667|028|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04667|029|M|urine, and/or discolored urine.|
04667|030|B||
04667|031|D|DISCUSSION:  Concurrent use of voclosporin (23.7 mg twice daily) increased|
04667|032|D|the concentration maximum (Cmax) and area-under-curve (AUC) of a 40 mg|
04667|033|D|single dose of simvastatin by 3.1-fold and 1.8-fold, respectively.(1)|
04667|034|B||
04667|035|R|REFERENCES:|
04667|036|B||
04667|037|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
04667|038|R|  April, 2024.|1
04667|039|R|2.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
04667|040|R|  2023.|1
04668|001|T|MONOGRAPH TITLE:  Raltegravir (600 mg HD)/Tipranavir|
04668|002|B||
04668|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04668|004|L|of severe adverse interaction.|
04668|005|B||
04668|006|A|MECHANISM OF ACTION:  Raltegravir is a substrate of|
04668|007|A|UDP-glucuronosyltransferase 1A1 (UGT1A1).  Inducers of UGT1A1 such as|
04668|008|A|tipranavir may induce the metabolism of raltegravir.(1,2)|
04668|009|B||
04668|010|E|CLINICAL EFFECTS:  Tipranavir may reduce the levels and clinical|
04668|011|E|effectiveness of raltegravir.(1,2)|
04668|012|B||
04668|013|P|PREDISPOSING FACTORS:  None determined.|
04668|014|B||
04668|015|M|PATIENT MANAGEMENT:  The US manufacturer of raltegravir states that the|
04668|016|M|concurrent use of raltegravir HD (600 mg) is not recommended.(1)  No dose|
04668|017|M|adjustment is recommended when raltegravir is dosed at 400 mg twice|
04668|018|M|daily.(1,2)|
04668|019|B||
04668|020|D|DISCUSSION:  No clinical studies have been conducted to evaluate the drug|
04668|021|D|interaction between tipranavir/ritonavir with raltegravir 1,200 mg daily.|
04668|022|D|In a drug interaction study of 15 subjects, tipranavir/ritonavir (500 mg/200|
04668|023|D|mg twice daily) decreased the area-under-curve (AUC) and maximum|
04668|024|D|concentration (Cmax) of raltegravir 400 mg twice daily by 24% and 18%,|
04668|025|D|respectively.  This effect was not considered to be clinically|
04668|026|D|meaningful.(1)|
04668|027|B||
04668|028|R|REFERENCES:|
04668|029|B||
04668|030|R|1.Isentress (raltegravir) US prescribing information. Merck & CO., Inc. May,|1
04668|031|R|  2021.|1
04668|032|R|2.Aptivus (tipranavir) US prescribing information. Boehringer Ingelheim|1
04668|033|R|  Pharmaceuticals, Inc. April, 2024.|1
04669|001|T|MONOGRAPH TITLE:  Atorvastatin/Voclosporin|
04669|002|B||
04669|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04669|004|L|take action as needed.|
04669|005|B||
04669|006|A|MECHANISM OF ACTION:  Voclosporin is an inhibitor of the OATP1B1 and OATP1B3|
04669|007|A|transporters and may increase the absorption and/or decrease the elimination|
04669|008|A|of atorvastatin.(1,2)|
04669|009|B||
04669|010|E|CLINICAL EFFECTS:  Concurrent use of voclosporin may result in elevated|
04669|011|E|levels of atorvastatin, which could result in rhabdomyolysis.|
04669|012|B||
04669|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04669|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04669|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04669|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04669|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04669|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04669|019|P|predisposed to myopathy or rhabdomyolysis.|
04669|020|B||
04669|021|M|PATIENT MANAGEMENT:  The US manufacturer of voclosporin states that|
04669|022|M|atorvastatin should be monitored closely for adverse events including|
04669|023|M|myopathy and rhabdomyolysis.  Consider using the lowest effective dose of|
04669|024|M|atorvastatin.(1)|
04669|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04669|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04669|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04669|028|M|urine, and/or discolored urine.|
04669|029|B||
04669|030|D|DISCUSSION:  Concurrent use of voclosporin (23.7 mg twice daily) increased|
04669|031|D|the concentration maximum (Cmax) and area-under-curve (AUC) of a 40 mg|
04669|032|D|single dose of simvastatin (an OATP1B1 and OATP1B3 substrate) by 3.1-fold|
04669|033|D|and 1.8-fold, respectively.(1)|
04669|034|B||
04669|035|R|REFERENCES:|
04669|036|B||
04669|037|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
04669|038|R|  2020.|1
04669|039|R|2.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
04669|040|R|  April, 2024.|1
04670|001|T|MONOGRAPH TITLE:  Rosuvastatin/Voclosporin|
04670|002|B||
04670|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04670|004|L|take action as needed.|
04670|005|B||
04670|006|A|MECHANISM OF ACTION:  Voclosporin is an inhibitor of the OATP1B1 and OATP1B3|
04670|007|A|transporters and may increase the absorption and/or decrease the elimination|
04670|008|A|of rosuvastatin.(1-3)|
04670|009|B||
04670|010|E|CLINICAL EFFECTS:  Concurrent use of voclosporin may result in increased|
04670|011|E|levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3)|
04670|012|B||
04670|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04670|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04670|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04670|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04670|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04670|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04670|019|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04670|020|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04670|021|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04670|022|B||
04670|023|M|PATIENT MANAGEMENT:  The US manufacturer of voclosporin states that|
04670|024|M|rosuvastatin should be monitored closely for adverse events including|
04670|025|M|myopathy and rhabdomyolysis.  Consider using the lowest effective dose of|
04670|026|M|rosuvastatin.(1)|
04670|027|M|   Monitor patients closely for signs and symptoms of toxicity from|
04670|028|M|increased rosuvastatin concentrations.(1,2)|
04670|029|B||
04670|030|D|DISCUSSION:  Concurrent use of voclosporin (23.7 mg twice daily) increased|
04670|031|D|the concentration maximum (Cmax) and area-under-curve (AUC) of a 40 mg|
04670|032|D|single dose of simvastatin (an OATP1B1 and OATP1B3 substrate) by 3.1-fold|
04670|033|D|and 1.8-fold, respectively.(1)|
04670|034|B||
04670|035|R|REFERENCES:|
04670|036|B||
04670|037|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
04670|038|R|  April, 2024.|1
04670|039|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04670|040|R|  Pharmaceuticals LP July, 2024.|1
04670|041|R|3.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04670|042|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04670|043|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04670|044|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04670|045|R|  44(3):398-408.|5
04671|001|T|MONOGRAPH TITLE:  Pravastatin/Voclosporin|
04671|002|B||
04671|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04671|004|L|take action as needed.|
04671|005|B||
04671|006|A|MECHANISM OF ACTION:  Voclosporin is an inhibitor of OATP1B1 and OATP1B3.(1)|
04671|007|A|Pravastatin is a substrate for OATP1B1 and OATP1B3 transport.(2)|
04671|008|B||
04671|009|E|CLINICAL EFFECTS:  Concurrent use of voclosporin may lead to higher systemic|
04671|010|E|concentrations of pravastatin, increasing the risk for statin-induced|
04671|011|E|myopathy or rhabdomyolysis.|
04671|012|B||
04671|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04671|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04671|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04671|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04671|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04671|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04671|019|P|predisposed to myopathy or rhabdomyolysis.|
04671|020|B||
04671|021|M|PATIENT MANAGEMENT:  The US manufacturer of voclosporin states that|
04671|022|M|pravastatin should be monitored closely for adverse events including|
04671|023|M|myopathy and rhabdomyolysis.  Consider using the lowest effective dose of|
04671|024|M|pravastatin.(1)|
04671|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04671|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04671|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04671|028|M|urine, and/or discolored urine.|
04671|029|B||
04671|030|D|DISCUSSION:  Concurrent use of voclosporin (23.7 mg twice daily) increased|
04671|031|D|the concentration maximum (Cmax) and area-under-curve (AUC) of a 40 mg|
04671|032|D|single dose of simvastatin (an OATP1B1 and OATP1B3 substrate) by 3.1-fold|
04671|033|D|and 1.8-fold, respectively.(1)|
04671|034|B||
04671|035|R|REFERENCES:|
04671|036|B||
04671|037|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
04671|038|R|  April, 2024.|1
04671|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
04671|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04672|001|T|MONOGRAPH TITLE:  Fluoroestradiol F-18/Estrogen Receptor Blockers (ERBs)|
04672|002|B||
04672|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04672|004|L|of severe adverse interaction.|
04672|005|B||
04672|006|A|MECHANISM OF ACTION:  Drugs that bind to the estrogen receptor (ER) may|
04672|007|A|compete with the binding of radioactive diagnostic agent fluoroestradiol|
04672|008|A|F-18.(1)|
04672|009|B||
04672|010|E|CLINICAL EFFECTS:  Concurrent use of estrogen receptor blockers such as|
04672|011|E|selective estrogen receptor modulators (SERMs) and selective estrogen|
04672|012|E|receptor down-regulators (SERDs) may reduce the detection of ER-positive|
04672|013|E|lesions with fluoroestradiol F-18.(1)|
04672|014|B||
04672|015|P|PREDISPOSING FACTORS:  None determined.|
04672|016|B||
04672|017|M|PATIENT MANAGEMENT:  Before administering fluoroestradiol F-18, discontinue|
04672|018|M|drugs that bind to the ER, such as SERMs and SERDs, for at least 5|
04672|019|M|biological half-lives.(1)|
04672|020|M|   The following washout periods apply when discontinuing ERBs, prior to|
04672|021|M|fluoroestradiol F-18 administration:|
04672|022|M|- Bazedoxifene = 7 days|
04672|023|M|- Clomiphene = 25 days|
04672|024|M|- Elacestrant = 11 days|
04672|025|M|- Enclomiphene = 25 days|
04672|026|M|- Fulvestrant = 28 weeks|
04672|027|M|- Imlunestrant = 7 days|
04672|028|M|- Ospemifene = 5 days|
04672|029|M|- Raloxifene = 7 days|
04672|030|M|- Tamoxifen = 8 weeks|
04672|031|M|- Toremifene = 5 weeks|
04672|032|B||
04672|033|D|DISCUSSION:  The following ERBs are linked to this monograph:|
04672|034|D|   SERDs: elacestrant, imlunestrant, and fulvestrant.|
04672|035|D|   SERMs: bazedoxifene, clomiphene, enclomiphene, ospemifene, raloxifene,|
04672|036|D|tamoxifen and toremifene.|
04672|037|B||
04672|038|R|REFERENCE:|
04672|039|B||
04672|040|R|1.Cerianna (fluoroestradiol F 18) US Prescribing Information. GE Healthcare|1
04672|041|R|  05/2024.|1
04673|001|T|MONOGRAPH TITLE:  Celiprolol; Esmolol/Diltiazem; Verapamil|
04673|002|B||
04673|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04673|004|L|is contraindicated and generally should not be dispensed or administered to|
04673|005|L|the same patient.|
04673|006|B||
04673|007|A|MECHANISM OF ACTION:  Select beta blockers (celiprolol and esmolol) and|
04673|008|A|non-dihydropyridine calcium channel blockers, including diltiazem and|
04673|009|A|verapamil, have negative inotropic and chronotropic effects.(1-4)|
04673|010|B||
04673|011|E|CLINICAL EFFECTS:  Concurrent use of celiprolol or esmolol with intravenous|
04673|012|E|(IV) non-dihydropyridine calcium channel blockers, including diltiazem and|
04673|013|E|verapamil, may result in additive cardiovascular effects, including|
04673|014|E|hypotension, bradycardia, conduction abnormalities, cardiovascular collapse,|
04673|015|E|and fatal cardiac arrest.(1-2)|
04673|016|B||
04673|017|P|PREDISPOSING FACTORS:  Preexisting left ventricular dysfunction and high|
04673|018|P|doses of the beta-blocking agent may predispose patients to adverse|
04673|019|P|responses to this drug combination. Other possible factors include|
04673|020|P|parenteral administration and concurrent administration of other|
04673|021|P|cardio-depressant drugs such as antiarrhythmics.|
04673|022|B||
04673|023|M|PATIENT MANAGEMENT:  The concurrent use of esmolol and intravenous (IV)|
04673|024|M|non-dihydropyridine calcium channel blockers, including diltiazem and|
04673|025|M|verapamil, is contraindicated.(1)|
04673|026|M|   The Australian manufacturer of celiprolol states that intravenous|
04673|027|M|administration of calcium channel blockers such as verapamil and diltiazem|
04673|028|M|is contraindicated during treatment with celiprolol (exception: intensive|
04673|029|M|care).  Do not coadminister verapamil intravenously until 48 hours after|
04673|030|M|discontinuation of celiprolol.(2)|
04673|031|M|   The UK manufacturer of celiprolol states when changing from verapamil to|
04673|032|M|celiprolol, and vice versa, a period between stopping one and starting the|
04673|033|M|other is recommended.  Concomitant administration of both drugs is not|
04673|034|M|recommended and should only be initiated with both clinical signs and ECG|
04673|035|M|monitored carefully.  Patients with pre-existing conduction abnormalities|
04673|036|M|should not be given the two drugs together.(5)|
04673|037|B||
04673|038|D|DISCUSSION:  Coadministration of celiprolol or esmolol with intravenous (IV)|
04673|039|D|non-dihydropyridine calcium channel blockers, including diltiazem and|
04673|040|D|verapamil, may result in additive cardiovascular effects, including|
04673|041|D|hypotension, bradycardia, conduction abnormalities, cardiovascular collapse,|
04673|042|D|and fatal cardiac arrest.(1,2,5)|
04673|043|B||
04673|044|R|REFERENCES:|
04673|045|B||
04673|046|R|1.Esmolol Injection US prescribing information. WG Critical Care, LLC May,|1
04673|047|R|  2024.|1
04673|048|R|2.Celipro Lich (celiprolol hydrochloride) German prescribing information.|1
04673|049|R|  Zentiva Pharma GmbH July 2018.|1
04673|050|R|3.Covera-HS (verapamil hydrochloride) US prescribing information. G.D.|1
04673|051|R|  Searle LLC September, 2017.|1
04673|052|R|4.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
04673|053|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
04673|054|R|5.Celectol (celiprolol hydrochloride) UK summary of product characteristics.|1
04673|055|R|  Neon Healthcare Ltd July 2024.|1
04674|001|T|MONOGRAPH TITLE:  Erlotinib/Ropeginterferon alfa-2b|
04674|002|B||
04674|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04674|004|L|of severe adverse interaction.|
04674|005|B||
04674|006|A|MECHANISM OF ACTION:  Ropeginterferon alfa-2b and erlotinib both suppress|
04674|007|A|the immune system.  The exact mechanism of gastrointestinal perforation with|
04674|008|A|erlotinib is unknown.|
04674|009|B||
04674|010|E|CLINICAL EFFECTS:  Concurrent use of ropeginterferon alfa-2b with erlotinib|
04674|011|E|may result in an increased risk of serious infections and gastrointestinal|
04674|012|E|perforation.  Fatal cases of gastrointestinal perforation have been|
04674|013|E|reported.(1)|
04674|014|B||
04674|015|P|PREDISPOSING FACTORS:  Patients with a history of peptic ulceration or|
04674|016|P|diverticular disease or who are receiving concomitant corticosteroids,|
04674|017|P|NSAIDs, and/or taxane-based chemotherapy may be an increased risk of|
04674|018|P|gastrointestinal perforation.(1)|
04674|019|B||
04674|020|M|PATIENT MANAGEMENT:  Avoid concurrent use of ropeginterferon alfa-2b and|
04674|021|M|erlotinib.(1-2)|
04674|022|M|   If concurrent use cannot be avoided, monitor for effects of excessive|
04674|023|M|immunosuppression and gastrointestinal perforation.  Discontinue erlotinib|
04674|024|M|in patients who develop gastrointestinal perforation.(1)|
04674|025|B||
04674|026|D|DISCUSSION:  In a phase II trial of concurrent bevacizumab plus erlotinib, 2|
04674|027|D|of 13 patients suffered fatal gastrointestinal perforations.(3)|
04674|028|D|   In another phase II trial of concurrent bevacizumab with erlotinib, 1 of|
04674|029|D|104 patients died of gastrointestinal perforation.(4)|
04674|030|D|   In clinical trials of ropeginterferon alfa-2b, 20% of patients|
04674|031|D|experienced leukopenia.  Interferon alfa products may cause fatal or|
04674|032|D|life-threatening infections.(2)|
04674|033|B||
04674|034|R|REFERENCES:|
04674|035|B||
04674|036|R|1.Tarceva (erlotinib) US prescribing information. Genentech, Inc. October,|1
04674|037|R|  2016.|1
04674|038|R|2.Besremi (ropeginterferon alfa-2b) US prescribing information.|1
04674|039|R|  PharmaEssentia April 2024.|1
04674|040|R|3.Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, Salgia R,|2
04674|041|R|  Stadler WM, Vokes EE, Fleming GF. Efficacy and safety of bevacizumab plus|2
04674|042|R|  erlotinib for patients with recurrent ovarian, primary peritoneal, and|2
04674|043|R|  fallopian tube cancer: a trial of the Chicago, PMH, and California Phase|2
04674|044|R|  II Consortia. Gynecol Oncol 2008 Jul;110(1):49-55.|2
04674|045|R|4.Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S,|2
04674|046|R|  Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA,|2
04674|047|R|  McDermott D. Randomized phase II study of erlotinib combined with|2
04674|048|R|  bevacizumab compared with bevacizumab alone in metastatic renal cell|2
04674|049|R|  cancer. J Clin Oncol 2007 Oct 10;25(29):4536-41.|2
04675|001|T|MONOGRAPH TITLE:  Labetalol/Diltiazem; Verapamil|
04675|002|B||
04675|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04675|004|L|is contraindicated and generally should not be dispensed or administered to|
04675|005|L|the same patient.|
04675|006|B||
04675|007|A|MECHANISM OF ACTION:  Both labetalol and non-dihydropyridine calcium channel|
04675|008|A|blockers, including diltiazem and verapamil, have negative inotropic and|
04675|009|A|chronotropic effects.(1-4)|
04675|010|B||
04675|011|E|CLINICAL EFFECTS:  Concurrent use of labetalol with non-dihydropyridine|
04675|012|E|calcium channel blockers may result in additive cardiovascular effects,|
04675|013|E|including hypotension, bradycardia, congestive heart failure, conduction|
04675|014|E|abnormalities, and cardiovascular collapse.(1-4)|
04675|015|B||
04675|016|P|PREDISPOSING FACTORS:  Preexisting left ventricular dysfunction and high|
04675|017|P|doses of the beta-blocking agent may predispose patients to adverse|
04675|018|P|responses to this drug combination. Other possible factors include|
04675|019|P|parenteral administration and concurrent administration of other|
04675|020|P|cardio-depressant drugs such as antiarrhythmics.|
04675|021|B||
04675|022|M|PATIENT MANAGEMENT:  The concurrent use of labetalol with|
04675|023|M|non-dihydropyridine calcium channel blockers is contraindicated.(1,2)|
04675|024|B||
04675|025|D|DISCUSSION:  Concurrent use of labetalol with non-dihydropyridine calcium|
04675|026|D|channel blockers may result in hypotension, bradycardia, congestive heart|
04675|027|D|failure, conduction abnormalities, and cardiovascular collapse.(1-4)  Excess|
04675|028|D|bradycardia, AV block, and complete heart block have been reported.(3)|
04675|029|B||
04675|030|R|REFERENCES:|
04675|031|B||
04675|032|R|1.Labetalol Hydrochloride US prescribing information. Alvogen, Inc. April,|1
04675|033|R|  2024.|1
04675|034|R|2.Labetalol Hydrochloride Injection US prescribing information. Hikma|1
04675|035|R|  Pharmaceuticals USA Inc. June, 2023.|1
04675|036|R|3.Covera-HS (verapamil hydrochloride) US prescribing information. G.D.|1
04675|037|R|  Searle LLC September, 2017.|1
04675|038|R|4.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
04675|039|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
04676|001|T|MONOGRAPH TITLE:  Labetalol/Selected Calcium Channel Blockers|
04676|002|B||
04676|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04676|004|L|take action as needed.|
04676|005|B||
04676|006|A|MECHANISM OF ACTION:  Both labetalol and calcium channel blockers have|
04676|007|A|negative inotropic and chronotropic effects.|
04676|008|B||
04676|009|E|CLINICAL EFFECTS:  Concurrent use of labetalol with calcium channel blockers|
04676|010|E|may result in additive cardiovascular effects.|
04676|011|B||
04676|012|P|PREDISPOSING FACTORS:  Preexisting left ventricular dysfunction and high|
04676|013|P|doses of the beta-blocking agent may predispose patients to adverse|
04676|014|P|responses to this drug combination. Other possible factors include|
04676|015|P|parenteral administration and concurrent administration of other|
04676|016|P|cardio-depressant drugs such as antiarrhythmics.|
04676|017|B||
04676|018|M|PATIENT MANAGEMENT:  The concurrent use of labetalol and calcium channel|
04676|019|M|blockers should be monitored closely for signs of increased|
04676|020|M|cardio-depressant effects and hypotension.  Adjust the dose of one or both|
04676|021|M|medicines accordingly.|
04676|022|B||
04676|023|D|DISCUSSION:  Concurrent use of labetalol with calcium channel blockers may|
04676|024|D|result in additive cardiovascular effects.|
04676|025|D|   Coadministration of these classes of drugs may be effective in the|
04676|026|D|treatment of angina pectoris and hypertension. Patients should be screened|
04676|027|D|in order to determine who should receive this combination of agents.|
04676|028|B||
04676|029|R|REFERENCES:|
04676|030|B||
04676|031|R|1.Vinceneux P, Canal M, Domart Y, Roux A, Cascio B, Orofiamma B, Larribaud|2
04676|032|R|  J, Flouvat B, Carbon C. Pharmacokinetic and pharmacodynamic interactions|2
04676|033|R|  between nifedipine and propranolol or betaxolol. Int J Clin Pharmacol Ther|2
04676|034|R|  Toxicol 1986 Mar;24(3):153-8.|2
04676|035|R|2.Rosenkranz B, Ledermann H, Frolich JC. Interaction between nifedipine and|2
04676|036|R|  atenolol: pharmacokinetics and pharmacodynamics in normotensive|2
04676|037|R|  volunteers. J Cardiovasc Pharmacol 1986 Sep-Oct;8(5):943-9.|2
04676|038|R|3.Anastassiades CJ. Nifedipine and beta-blocker drugs. Br Med J 1980 Nov 8;|3
04676|039|R|  281(6250):1251-2.|3
04676|040|R|4.Staffurth JS, Emery P. Adverse interaction between nifedipine and|3
04676|041|R|  beta-blockade. Br Med J 1981 Jan 17;282:225.|3
04676|042|R|5.Joshi PI, Dalal JJ, Ruttley MS, Sheridan DJ, Henderson AH. Nifedipine and|2
04676|043|R|  left ventricular function in beta-blocked patients. Br Heart J 1981 Apr;|2
04676|044|R|  45(4):457-9.|2
04676|045|R|6.Winniford MD, Markham RV Jr, Firth BG, Nicod P, Hillis LD. Hemodynamic and|2
04676|046|R|  electrophysiologic effects of verapamil and nifedipine in patients on|2
04676|047|R|  propranolol. Am J Cardiol 1982 Oct;50(4):704-710.|2
04676|048|R|7.Packer M, Meller J, Medina N, Yushak M, Smith H, Holt J, Guererro J, Todd|2
04676|049|R|  GD, McAllister RG Jr, Gorlin R. Hemodynamic consequences of combined|2
04676|050|R|  beta-adrenergic and slow calcium channel blockade in man. Circulation 1982|2
04676|051|R|  Apr;65(4):660-8.|2
04676|052|R|8.Robson RH, Vishwanath MC. Nifedipine and beta-blockade as a cause of|3
04676|053|R|  cardiac failure. Br Med J (Clin Res Ed) 1982 Jan 9;284(6309):104.|3
04676|054|R|9.Anastassiades C. Nifedipine and beta-blockade as a cause of cardiac|3
04676|055|R|  failure. Br Med J (Clin Res Ed) 1982 Feb 13;284(6314):506.|3
04676|056|R|10.Vanhaleweyk GL, Serruys PW, Hugenholtz PG. Anti-anginal,|6
04676|057|R|   electrophysiologic and hemodynamic effects of combined|6
04676|058|R|   beta-blocker/calcium antagonist therapy. Eur Heart J 1983 Jul;4 Suppl|6
04676|059|R|   D:117-28.|6
04676|060|R|11.Sinclair NI, Benzie JL. Timolol eye drops and verapamil--a dangerous|3
04676|061|R|   combination. Med J Aust 1983 Jun 11;1(12):548.|3
04676|062|R|12.Eisenberg JN, Oakley GD. Probable adverse interaction between oral|3
04676|063|R|   metoprolol and verapamil. Postgrad Med J 1984 Oct;60(708):705-6.|3
04676|064|R|13.Findlay IN, McInnes GT, Dargie HJ. Beta blockers and verapamil: a|3
04676|065|R|   cautionary tale. Br Med J (Clin Res Ed) 1984 Oct 20;289(6451):1074.|3
04676|066|R|14.Zatuchni J. Bradycardia and hypotension after propranolol HCl and|3
04676|067|R|   verapamil. Heart Lung 1985 Jan;14(1):94-5.|3
04676|068|R|15.Winniford MD, Fulton KL, Hillis LD. Symptomatic sinus bradycardia during|2
04676|069|R|   concomitant propranolol-verapamil administration. Am Heart J 1985 Aug;|2
04676|070|R|   110(2):498.|2
04676|071|R|16.Lam YW, Giard MJ, Warren JB. Calcium channel blockers and treatment of|6
04676|072|R|   hypertension. Drug Intell Clin Pharm 1986 Mar;20(3):187-98.|6
04676|073|R|17.Opie LH, White DA. Adverse interaction between nifedipine and|2
04676|074|R|   beta-blockade. Br Med J 1980 Nov 29;281(6253):1462.|2
04676|075|R|18.Gangji D, Juvent M, Niset G, Wathieu M, Degreve M, Bellens R, Poortmans|2
04676|076|R|   J, Degre S, Fitzsimons TJ, Herchuelz A. Study of the influence of|2
04676|077|R|   nifedipine on the pharmacokinetics and pharmacodynamics of propranolol,|2
04676|078|R|   metoprolol and atenolol. Br J Clin Pharmacol 1984;17 Suppl 1:29S-35S.|2
04676|079|R|19.Kendall MJ, Jack DB, Laugher SJ, Lobo J, Rolf Smith S. Lack of a|2
04676|080|R|   pharmacokinetic interaction between nifedipine and the beta- adrenoceptor|2
04676|081|R|   blockers metoprolol and atenolol. Br J Clin Pharmacol 1984 Sep;|2
04676|082|R|   18(3):331-5.|2
04676|083|R|20.Leon MB, Rosing DR, Bonow RO, Epstein SE. Combination therapy with|6
04676|084|R|   calcium-channel blockers and beta blockers for chronic stable angina|6
04676|085|R|   pectoris. Am J Cardiol 1985 Jan 25;55(3):69B-80B.|6
04676|086|R|21.Vetrovec GW, Parker VE. Acute electrophysiologic, hemodynamic and left|2
04676|087|R|   ventricular effects of nifedipine and beta-blocker interactions.|2
04676|088|R|   Maintenance of global and regional left ventricular wall motion. Am J|2
04676|089|R|   Cardiol 1985 May 17;55(12):21E-26E.|2
04676|090|R|22.Hamann SR, Kaltenborn KE, McAllister RG Jr. Nifedipine-propranolol|5
04676|091|R|   interaction: dependence of cardiovascular effects on plasma drug|5
04676|092|R|   concentrations. J Cardiovasc Pharmacol 1987 Aug;10(2):182-9.|5
04676|093|R|23.Lubsen J, Tijssen JG. Efficacy of nifedipine and metoprolol in the early|2
04676|094|R|   treatment of unstable angina in the coronary care unit: findings from the|2
04676|095|R|   Holland Interuniversity Nifedipine/metoprolol Trial (HINT). Am J Cardiol|2
04676|096|R|   1987 Jul 15;60(2):18A-25A.|2
04676|097|R|24.Nayler WG. The potential for added benefits with beta-blockers and|6
04676|098|R|   calcium antagonists in treating cardiovascular disorders. Drugs 1988;35|6
04676|099|R|   Suppl 4:1-8.|6
04676|100|R|25.Anonymous. Nifedipine and atenolol singly and combined for treatment of|2
04676|101|R|   essential hypertension: comparative multicentre study in general practice|2
04676|102|R|   in the United Kingdom. Nifedipine-Atenolol Study Review Committee. Br Med|2
04676|103|R|   J (Clin Res Ed) 1988 Feb 13;296(6620):468-72.|2
04676|104|R|26.Maclean D, Mitchell ET, Coulson RR, Fitzsimons TJ, McDevitt DG.|2
04676|105|R|   Atenolol-nifedipine combinations compared to atenolol alone in|2
04676|106|R|   hypertension: efficacy and tolerability. Br J Clin Pharmacol 1988 Apr;|2
04676|107|R|   25(4):425-31.|2
04676|108|R|27.Stanley NN, Thirkettle JL, Varma MP, Larkin H, Heath ID. The efficacy and|2
04676|109|R|   tolerability of atenolol, nifedipine, and their combination in the|2
04676|110|R|   management of hypertension. Eur J Clin Pharmacol 1988;34(6):543-8.|2
04676|111|R|28.McCourty JC, Silas JH, Tucker GT, Lennard MS. The effect of combined|2
04676|112|R|   therapy on the pharmacokinetics and pharmacodynamics of verapamil and|2
04676|113|R|   propranolol in patients with angina pectoris. Br J Clin Pharmacol 1988|2
04676|114|R|   Mar;25(3):349-57.|2
04676|115|R|29.Keech AC, Harper RW, Harrison PM, Pitt A, McLean AJ. Extent and|2
04676|116|R|   pharmacokinetic mechanisms of oral atenolol-verapamil interaction in man.|2
04676|117|R|   Eur J Clin Pharmacol 1988;35(4):363-6.|2
04676|118|R|30.Carruthers SG, Freeman DJ, Bailey DG. Pharmacodynamic interaction between|4
04676|119|R|   beta-blockers and verapamil: possible relevance of ancillary properties.|4
04676|120|R|   Clin Pharmacol Ther 1989 Feb;45(2):170.|4
04676|121|R|31.Murdoch D, McInnes GI, Thomson GD, Murray GD, Brodie MJ. Pharmacodynamics|4
04676|122|R|   and pharmacokinetics of verapamil and propranolol after single and|4
04676|123|R|   repeated administration. Br J Clin Pharmacol 1989;28:233P-4P.|4
04676|124|R|32.Hunt BA, Bottorff MB, Herring VL, Self TH, Lalonde RL. Effects of calcium|2
04676|125|R|   channel blockers on the pharmacokinetics of propranolol stereoisomers.|2
04676|126|R|   Clin Pharmacol Ther 1990 May;47(5):584-91.|2
04676|127|R|33.Murdoch DL, Thomson GD, Thompson GG, Murray GD, Brodie MJ, McInnes GT.|2
04676|128|R|   Evaluation of potential pharmacodynamic and pharmacokinetic interactions|2
04676|129|R|   between verapamil and propranolol in normal subjects. Br J Clin Pharmacol|2
04676|130|R|   1991 Mar;31(3):323-32.|2
04676|131|R|34.Bailey DG, Carruthers SG. Interaction between oral verapamil and|2
04676|132|R|   beta-blockers during submaximal exercise: relevance of ancillary|2
04676|133|R|   properties. Clin Pharmacol Ther 1991 Apr;49(4):370-6.|2
04677|001|T|MONOGRAPH TITLE:  Lercanidipine/Strong CYP3A4 Inducers|
04677|002|B||
04677|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04677|004|L|of severe adverse interaction.|
04677|005|B||
04677|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04677|007|A|lercanidipine.(1)|
04677|008|B||
04677|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04677|010|E|may result in decreased levels and effectiveness of lercanidipine.(1)|
04677|011|B||
04677|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04677|013|P|of the inducer for longer than 1-2 weeks.|
04677|014|B||
04677|015|M|PATIENT MANAGEMENT:  Concurrent use of strong inducers of CYP3A4 with|
04677|016|M|lercanidipine is not recommended.  If concurrent use is warranted, blood|
04677|017|M|pressure should be monitored more frequently than usual.(1)|
04677|018|B||
04677|019|D|DISCUSSION:  Lercanidipine is extensively metabolized by CYP3A4, with no|
04677|020|D|parent drug found in urine or feces.(1)|
04677|021|D|   Strong inducers of CYP3A4 include: apalutamide, barbiturates,|
04677|022|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04677|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04677|024|D|rifapentine, and St. John's wort.(2,3)|
04677|025|B||
04677|026|R|REFERENCES:|
04677|027|B||
04677|028|R|1.Zanidip (lercanidipine) UK prescribing information. Recordati|1
04677|029|R|  Pharmaceuticals Limited October 4, 2019.|1
04677|030|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04677|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04677|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04677|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04677|034|R|  11/14/2017.|1
04677|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04677|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04678|001|T|MONOGRAPH TITLE:  Diltiazem/Selected Strong CYP3A4 Inducers|
04678|002|B||
04678|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04678|004|L|of severe adverse interaction.|
04678|005|B||
04678|006|A|MECHANISM OF ACTION:  Concurrent use of strong CYP3A4 inducers may|
04678|007|A|accelerate the CYP3A4-mediated metabolism of diltiazem.(1)|
04678|008|A|   Diltiazem is a CYP3A4 inhibitor and may inhibit the metabolism of|
04678|009|A|phenytoin.(2)|
04678|010|B||
04678|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may decrease the|
04678|012|E|levels and effectiveness of diltiazem.(1)|
04678|013|E|   If the patient is on phenytoin, concurrent use of diltiazem (especially|
04678|014|E|at high doses) may also result in elevated levels of and toxicity from|
04678|015|E|phenytoin.(2)|
04678|016|B||
04678|017|P|PREDISPOSING FACTORS:  Higher doses of diltiazem may increase the risk of|
04678|018|P|elevated phenytoin levels.|
04678|019|P|   Induction effects may be more likely with regular use of the inducer for|
04678|020|P|longer than 1-2 weeks.|
04678|021|B||
04678|022|M|PATIENT MANAGEMENT:  The manufacturer of diltiazem states that|
04678|023|M|coadministration of CYP3A4 inducers should be avoided.(1)|
04678|024|M|   Observe the patient for a decrease in the therapeutic effects of|
04678|025|M|diltiazem if a strong CYP3A4 inducer is initiated.  The dose of diltiazem|
04678|026|M|may need to be adjusted if an inducer is initiated or discontinued.|
04678|027|M|   Monitor phenytoin levels when initiating or discontinuing diltiazem in|
04678|028|M|patients maintained on phenytoin.(2)|
04678|029|B||
04678|030|D|DISCUSSION:  Concurrent administration of rifampin, a strong CYP3A4 inducer,|
04678|031|D|has been shown to lower diltiazem levels below detectable limits.(1)|
04678|032|D|   A study in six subjects examined the effects of pretreatment with|
04678|033|D|rifampin (600 mg daily for 15 days) on single doses of verapamil (10 mg|
04678|034|D|intravenously or 120 mg orally).  Rifampin significantly decreased the|
04678|035|D|maximum concentration (Cmax) and area-under-curve (AUC) of oral verapamil|
04678|036|D|and resulted in no changes in the P-R interval.  There were small decreases|
04678|037|D|in the AUC of intravenous verapamil.(3)|
04678|038|D|   In a study in 8 male subjects, pretreatment with rifampin (600 mg daily|
04678|039|D|for 15 days) increased the systemic clearance of S-verapamil by 1.3-fold and|
04678|040|D|the apparent oral-clearance of S-verapamil by 32-fold.  The bioavailability|
04678|041|D|of S-verapamil decreased 25-fold.  The effect of oral verapamil on AV|
04678|042|D|conduction was almost abolished.  No significant changes were noted with|
04678|043|D|intravenous administration of verapamil.(4)|
04678|044|D|   In one case report, a patient established on phenytoin treatment (250 mg|
04678|045|D|twice daily) experienced signs of phenytoin toxicity after initiating|
04678|046|D|high-dose diltiazem (90 mg every 2 hours for a total of 4 doses, then 120 mg|
04678|047|D|every 4 hours for a total of 4 doses and then 240 mg of sustained release|
04678|048|D|formulation every 8 hours).  Serum phenytoin concentration was raised at 41|
04678|049|D|mcg/ml and phenytoin was held and reloaded at a lower maintenance dose (150|
04678|050|D|mg twice daily), whilst the patient continued treatment on diltiazem.|
04678|051|D|Subsequent serum phenytoin concentrations were within range (17.1 and 14.8|
04678|052|D|mcg/ml).(2)|
04678|053|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04678|054|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin,|
04678|055|D|and primidone.(5,6)|
04678|056|B||
04678|057|R|REFERENCES:|
04678|058|B||
04678|059|R|1.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
04678|060|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
04678|061|R|2.Clarke WR, Horn JR, Kawabori I, Gurtel S. Potentially Serious Drug|3
04678|062|R|  Interactions Secondary to High-Dose Diltiazem Used in the Treatment of|3
04678|063|R|  Pulmonary Hypertension. Pharmacotherapy 1993;13(4):402-405.|3
04678|064|R|3.Barbarash RA, Bauman JL, Fischer JH, Kondos GT, Batenhorst RL. Near-total|2
04678|065|R|  reduction in verapamil bioavailability by rifampin. Electrocardiographic|2
04678|066|R|  correlates. Chest 1988 Nov;94(5):954-9.|2
04678|067|R|4.Fromm MF, Busse D, Kroemer HK, Eichelbaum M. Differential induction of|2
04678|068|R|  prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology|2
04678|069|R|  1996 Oct;24(4):796-801.|2
04678|070|R|5.This information is based on an extract from the Certara Drug Interaction|6
04678|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04678|072|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04678|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04678|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04678|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04678|076|R|  11/14/2017.|1
04679|001|T|MONOGRAPH TITLE:  Aripiprazole IM Monthly (Abilify Maintena)/Strong CYP3A4|
04679|002|T|Inhibitors; Atazanavir; Darunavir|
04679|003|B||
04679|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04679|005|L|take action as needed.|
04679|006|B||
04679|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04679|008|A|aripiprazole.(1)|
04679|009|B||
04679|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
04679|011|E|may result in elevated levels of and toxicity from aripiprazole.(1)|
04679|012|B||
04679|013|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04679|014|P|patients who are CYP2D6 poor metabolizers, or who receive concomitant|
04679|015|P|treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine,|
04679|016|P|paroxetine, quinidine) in addition to treatment with a strong CYP3A4|
04679|017|P|inhibitor.(1-2)|
04679|018|B||
04679|019|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole IM monthly|
04679|020|M|injection (Abilify Maintena) recommends the following dose adjustments for|
04679|021|M|patients who receive a strong CYP3A4 inhibitor for longer than 14 days:(1)|
04679|022|M|   - if the aripiprazole dose is 400 mg per month and a strong CYP3A4|
04679|023|M|inhibitor is started, then decrease aripiprazole dose to 300 mg per month.|
04679|024|M|   - if the aripiprazole dose is 400 mg per month and patient receives|
04679|025|M|concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6|
04679|026|M|inhibitor, then decrease dose to 200 mg per month.|
04679|027|M|   - if the aripiprazole dose is 300 mg per month and a strong CYP3A4|
04679|028|M|inhibitor is started, then decrease aripiprazole dose to 200 mg per month.|
04679|029|M|Patients who are CYP2D6 poor metabolizers and receive treatment with a|
04679|030|M|strong CYP3A inhibitor should also receive 200 mg per month.|
04679|031|M|   - if the aripiprazole dose is 300 mg per month and patient receives|
04679|032|M|concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6|
04679|033|M|inhibitor, then decrease dose to 160 mg per month.|
04679|034|M|   The monthly aripiprazole dose may need to be increased if long-term|
04679|035|M|CYP3A4 inhibitor treatment is discontinued.(1)|
04679|036|B||
04679|037|D|DISCUSSION:  There have been no specific drug-drug interaction studies with|
04679|038|D|aripiprazole long-acting injections.|
04679|039|D|   The coadministration of ketoconazole (200 mg daily for 14 days) with a|
04679|040|D|single oral dose of aripiprazole (15 mg) resulted in increases in the|
04679|041|D|area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and|
04679|042|D|77%, respectively.  In simulations, the combination of strong CYP2D6 and|
04679|043|D|CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by|
04679|044|D|4.5-fold.  The concurrent use of strong CYP3A4 inhibitors in poor CYP2D6|
04679|045|D|metabolizers is predicted to increase aripiprazole Cmax and AUC by|
04679|046|D|3-fold.(1)|
04679|047|D|   CYP3A4 inhibitors linked to this monograph include: adagrasib,|
04679|048|D|atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir,|
04679|049|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
04679|050|D|levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone,|
04679|051|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
04679|052|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04679|053|D|troleandomycin, tucatinib, and voriconazole.(2)|
04679|054|B||
04679|055|R|REFERENCES:|
04679|056|B||
04679|057|R|1.Abilify Maintena (aripiprazole ext-rel inj.) prescribing information.|1
04679|058|R|  Otsuka Pharmaceuticals January, 2016.|1
04679|059|R|2.This information is based on an extract from the Certara Drug Interaction|6
04679|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04680|001|T|MONOGRAPH TITLE:  Aripiprazole IM Monthly (Abilify Maintena)/Selected Strong|
04680|002|T|CYP2D6 Inhibitors|
04680|003|B||
04680|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04680|005|L|take action as needed.|
04680|006|B||
04680|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
04680|008|A|aripiprazole.(1)|
04680|009|B||
04680|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
04680|011|E|with aripiprazole may result in elevated levels of and toxicity from|
04680|012|E|aripiprazole.(1)|
04680|013|B||
04680|014|P|PREDISPOSING FACTORS:  The interaction is expected to be more severe in|
04680|015|P|patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6|
04680|016|P|inhibitor.(1)|
04680|017|B||
04680|018|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole IM monthly|
04680|019|M|injection (Abilify Maintena) recommends the following dose adjustments for|
04680|020|M|patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1)|
04680|021|M|   - if the aripiprazole dose is 400 mg per month and a strong CYP2D6|
04680|022|M|inhibitor is started, then decrease aripiprazole dose to 300 mg per month.|
04680|023|M|   - if the aripiprazole dose is 400 mg per month and patient receives|
04680|024|M|concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6|
04680|025|M|inhibitor, then decrease dose to 200 mg per month.|
04680|026|M|   - if the aripiprazole dose is 300 mg per month and a strong CYP2D6|
04680|027|M|inhibitor is started, then decrease aripiprazole dose to 200 mg per month.|
04680|028|M|   - if the aripiprazole dose is 300 mg per month and patient receives|
04680|029|M|concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6|
04680|030|M|inhibitor, then decrease dose to 160 mg per month.(1)|
04680|031|B||
04680|032|D|DISCUSSION:  There have been no drug-drug interaction studies with|
04680|033|D|aripiprazole long-acting injections.|
04680|034|D|   The administration of quinidine (166 mg daily for 13 days, a strong|
04680|035|D|inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in|
04680|036|D|a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35%|
04680|037|D|decrease in the AUC of dehydro-aripiprazole, the active metabolite of|
04680|038|D|aripiprazole.(1)|
04680|039|D|   Strong CYP2D6 inhibitors linked to this monograph are dacomitinib,|
04680|040|D|fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(3,4)|
04680|041|B||
04680|042|R|REFERENCES:|
04680|043|B||
04680|044|R|1.Abilify Maintena (aripiprazole ext-rel inj.) prescribing information.|1
04680|045|R|  Otsuka Pharmaceuticals January, 2016.|1
04680|046|R|2.This information is based on an extract from the Certara Drug Interaction|6
04680|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04680|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04680|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04680|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04680|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04680|052|R|  11/14/2017.|1
04681|001|T|MONOGRAPH TITLE:  Aripiprazole IM Monthly (Abilify Maintena)/Bupropion|
04681|002|B||
04681|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04681|004|L|take action as needed.|
04681|005|B||
04681|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors such as bupropion may inhibit|
04681|007|A|the metabolism of aripiprazole.(1-2)  Both agents are also known to lower|
04681|008|A|the seizure threshold.(1,3-4)|
04681|009|B||
04681|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
04681|011|E|with aripiprazole may result in elevated levels of and toxicity from|
04681|012|E|aripiprazole.(1)  Concurrent use may also result in additive effects on the|
04681|013|E|seizure threshold, increasing the risk of seizures.(1,3-4)|
04681|014|B||
04681|015|P|PREDISPOSING FACTORS:  The pharmacokinetic interaction is expected to be|
04681|016|P|more severe in patients taking both a strong CYP3A4 inhibitor and a strong|
04681|017|P|CYP2D6 inhibitor.(1)|
04681|018|P|   The risk of seizures may be increased in patients with a history of head|
04681|019|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
04681|020|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
04681|021|P|of over-the-counter stimulants an anorectics; a total daily dose of|
04681|022|P|bupropion greater than 450 mg or single doses greater than 150 mg; rapid|
04681|023|P|escalation of bupropion dosage; diabetics treated with oral hypoglycemics or|
04681|024|P|insulin; or with concomitant medications known to lower seizure threshold|
04681|025|P|(antidepressants, theophylline, systemic steroids).(3-4)|
04681|026|B||
04681|027|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics such|
04681|028|M|as aripiprazole should be undertaken only with extreme caution and with low|
04681|029|M|initial bupropion dosing, small gradual dosage increases of bupropion,(3-4)|
04681|030|M|and reduced dosages of aripiprazole.(1)  Single doses of bupropion should|
04681|031|M|not exceed 150 mg.(3-4)  The maximum daily dose of bupropion should not|
04681|032|M|exceed 300 mg for smoking cessation(4) or 450 mg for depression.(3)|
04681|033|M|   The US manufacturer of aripiprazole IM monthly injection (Abilify|
04681|034|M|Maintena) recommends the following dose adjustments for patients who receive|
04681|035|M|a strong CYP2D6 inhibitor for greater than 14 days:(1)|
04681|036|M|   - if the aripiprazole dose is 400 mg per month and a strong CYP2D6|
04681|037|M|inhibitor is started, then decrease aripiprazole dose to 300 mg per month.|
04681|038|M|   - if the aripiprazole dose is 400 mg per month and patient receives|
04681|039|M|concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6|
04681|040|M|inhibitor, then decrease dose to 200 mg per month.|
04681|041|M|   - if the aripiprazole dose is 300 mg per month and a strong CYP2D6|
04681|042|M|inhibitor is started, then decrease aripiprazole dose to 200 mg per month.|
04681|043|M|   - if the aripiprazole dose is 300 mg per month and patient receives|
04681|044|M|concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6|
04681|045|M|inhibitor, then decrease dose to 160 mg per month.(1)|
04681|046|B||
04681|047|D|DISCUSSION:  There have been no drug-drug interaction studies with|
04681|048|D|aripiprazole long-acting injections.|
04681|049|D|   The administration of quinidine (166 mg daily for 13 days, a strong|
04681|050|D|inhibitor of CYP2D6) with a single dose of oral aripiprazole (10 mg)|
04681|051|D|resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole|
04681|052|D|and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite|
04681|053|D|of aripiprazole.(1)|
04681|054|B||
04681|055|R|REFERENCES:|
04681|056|B||
04681|057|R|1.Abilify Maintena (aripiprazole ext-rel inj.) prescribing information.|1
04681|058|R|  Otsuka Pharmaceuticals January, 2016.|1
04681|059|R|2.This information is based on an extract from the Certara Drug Interaction|6
04681|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04681|061|R|3.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
04681|062|R|  GlaxoSmithKline November, 2019.|1
04681|063|R|4.Zyban (bupropion hydrochloride) US prescribing information.|1
04681|064|R|  GlaxoSmithKline July, 2019.|1
04682|001|T|MONOGRAPH TITLE:  Aripiprazole IM Every 2 Months (Abilify Asimtufii)/Strong|
04682|002|T|CYP3A4 Inhibitors; Atazanavir; Darunavir|
04682|003|B||
04682|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04682|005|L|take action as needed.|
04682|006|B||
04682|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04682|008|A|aripiprazole.(1)|
04682|009|B||
04682|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP3A4 inhibitor|
04682|011|E|may result in elevated levels of and toxicity from aripiprazole.(1)|
04682|012|B||
04682|013|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04682|014|P|patients who are CYP2D6 poor metabolizers, or who receive concomitant|
04682|015|P|treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine,|
04682|016|P|paroxetine, quinidine) in addition to treatment with a strong CYP3A4|
04682|017|P|inhibitor.(1)|
04682|018|B||
04682|019|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole IM every 2 months|
04682|020|M|injection (Abilify Asimtufii) makes the following recommendations for|
04682|021|M|patients who receive a strong CYP3A4 inhibitor for greater than 14 days:(1)|
04682|022|M|   - if the aripiprazole dose is 960 mg every 2 months and a strong CYP3A4|
04682|023|M|inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2|
04682|024|M|months.|
04682|025|M|   - if the patient is taking both a strong CYP3A4 inhibitor AND a strong|
04682|026|M|CYP2D6 inhibitor, avoid use of Abilify Asimtufii.|
04682|027|M|   - if the patient is a poor CYP2D6 metabolizer and receives treatment with|
04682|028|M|a strong CYP3A4 inhibitor, avoid use of Abilify Asimtufii.|
04682|029|B||
04682|030|D|DISCUSSION:  There have been no specific drug-drug interaction studies with|
04682|031|D|aripiprazole long-acting injections.|
04682|032|D|   The coadministration of ketoconazole (200 mg daily for 14 days) with a|
04682|033|D|single oral dose of aripiprazole (15 mg) resulted in increases in the|
04682|034|D|area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and|
04682|035|D|77%, respectively.  In simulations, the combination of strong CYP2D6 and|
04682|036|D|CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by|
04682|037|D|4.5-fold.  The concurrent use of strong CYP3A4 inhibitors in poor CYP2D6|
04682|038|D|metabolizers is predicted to increase aripiprazole Cmax and AUC by|
04682|039|D|3-fold.(1)|
04682|040|D|   CYP3A4 inhibitors linked to this monograph include: adagrasib,|
04682|041|D|atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir,|
04682|042|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole,|
04682|043|D|levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone,|
04682|044|D|nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole,|
04682|045|D|ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04682|046|D|troleandomycin, tucatinib, and voriconazole.(2)|
04682|047|B||
04682|048|R|REFERENCES:|
04682|049|B||
04682|050|R|1.Abilify Asimtufii (aripiprazole extended-release injectable) US|1
04682|051|R|  prescribing information. Otsuka Pharmaceutical Co., Ltd. April, 2023.|1
04682|052|R|2.This information is based on an extract from the Certara Drug Interaction|6
04682|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04683|001|T|MONOGRAPH TITLE:  Aripiprazole IM Every 2 Months (Abilify Asimtufii)/Slt|
04683|002|T|Strong CYP2D6 Inhibitors|
04683|003|B||
04683|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04683|005|L|take action as needed.|
04683|006|B||
04683|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
04683|008|A|aripiprazole.(1)|
04683|009|B||
04683|010|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
04683|011|E|with aripiprazole may result in elevated levels of and toxicity from|
04683|012|E|aripiprazole.(1)|
04683|013|B||
04683|014|P|PREDISPOSING FACTORS:  The interaction is expected to be more severe in|
04683|015|P|patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6|
04683|016|P|inhibitor.(1)|
04683|017|B||
04683|018|M|PATIENT MANAGEMENT:  The US manufacturer of aripiprazole IM every 2 months|
04683|019|M|injection (Abilify Asimtufii) makes the following recommendations for|
04683|020|M|patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1)|
04683|021|M|   - if the aripiprazole dose is 960 mg every 2 months and a strong CYP2D6|
04683|022|M|inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2|
04683|023|M|months.|
04683|024|M|   - if the patient is taking both a strong CYP2D6 inhibitor AND a strong|
04683|025|M|CYP3A4 inhibitor, avoid use of Abilify Asimtufii.|
04683|026|B||
04683|027|D|DISCUSSION:  There have been no specific drug-drug interaction studies with|
04683|028|D|aripiprazole long-acting injections.|
04683|029|D|   The administration of quinidine (166 mg daily for 13 days, a strong|
04683|030|D|inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in|
04683|031|D|a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35%|
04683|032|D|decrease in the AUC of dehydro-aripiprazole, the active metabolite of|
04683|033|D|aripiprazole.  In simulations, the combination of strong CYP2D6 and CYP3A4|
04683|034|D|inhibitors is predicted to increase aripiprazole Cmax and AUC by|
04683|035|D|4.5-fold.(1)|
04683|036|D|   Strong CYP2D6 inhibitors linked to this monograph are dacomitinib,|
04683|037|D|fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)|
04683|038|B||
04683|039|R|REFERENCES:|
04683|040|B||
04683|041|R|1.Abilify Asimtufii (aripiprazole extended-release injectable) US|1
04683|042|R|  prescribing information. Otsuka Pharmaceutical Co., Ltd. April, 2023.|1
04683|043|R|2.This information is based on an extract from the Certara Drug Interaction|6
04683|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04683|045|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04683|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04683|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04683|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04683|049|R|  11/14/2017.|1
04684|001|T|MONOGRAPH TITLE:  Aripiprazole IM Every 2 Months (Abilify|
04684|002|T|Asimtufii)/Bupropion|
04684|003|B||
04684|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04684|005|L|take action as needed.|
04684|006|B||
04684|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors such as bupropion may inhibit|
04684|008|A|the metabolism of aripiprazole.  Both agents are also known to lower the|
04684|009|A|seizure threshold.(1-3)|
04684|010|B||
04684|011|E|CLINICAL EFFECTS:  Concurrent administration of a strong CYP2D6 inhibitor|
04684|012|E|with aripiprazole may result in elevated levels of and toxicity from|
04684|013|E|aripiprazole.  Concurrent use may also result in additive effects on the|
04684|014|E|seizure threshold, increasing the risk of seizures.(1-3)|
04684|015|B||
04684|016|P|PREDISPOSING FACTORS:  The pharmacokinetic interaction is expected to be|
04684|017|P|more severe in patients taking both a strong CYP3A4 inhibitor and a strong|
04684|018|P|CYP2D6 inhibitor.(1)|
04684|019|P|   The risk of seizures may be increased in patients with a history of head|
04684|020|P|trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use|
04684|021|P|of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use|
04684|022|P|of over-the-counter stimulants an anorectics; a total daily dose of|
04684|023|P|bupropion greater than 450 mg or single doses greater than 150 mg; rapid|
04684|024|P|escalation of bupropion dosage; diabetics treated with oral hypoglycemics or|
04684|025|P|insulin; or with concomitant medications known to lower seizure threshold|
04684|026|P|(antidepressants, theophylline, systemic steroids).(2-3)|
04684|027|B||
04684|028|M|PATIENT MANAGEMENT:  The concurrent use of bupropion and antipsychotics such|
04684|029|M|as aripiprazole should be undertaken only with extreme caution and with low|
04684|030|M|initial bupropion dosing, small gradual dosage increases of bupropion,(2-3)|
04684|031|M|and reduced dosages of aripiprazole.(1)  Single doses of bupropion should|
04684|032|M|not exceed 150 mg.(2-3)  The maximum daily dose of bupropion should not|
04684|033|M|exceed 300 mg for smoking cessation(3) or 450 mg for depression.(2)|
04684|034|M|   The US manufacturer of aripiprazole IM every 2 months injection (Abilify|
04684|035|M|Asimtufii) makes the following recommendations for patients who receive a|
04684|036|M|strong CYP2D6 inhibitor for greater than 14 days:(1)|
04684|037|M|   - if the aripiprazole dose is 960 mg every 2 months and a strong CYP2D6|
04684|038|M|inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2|
04684|039|M|months.|
04684|040|M|   - if the patient is taking both a strong CYP2D6 inhibitor AND a strong|
04684|041|M|CYP3A4 inhibitor, avoid use of Abilify Asimtufii.|
04684|042|B||
04684|043|D|DISCUSSION:  There have been no specific drug-drug interaction studies with|
04684|044|D|aripiprazole long-acting injections.|
04684|045|D|   The administration of quinidine (166 mg daily for 13 days, a strong|
04684|046|D|inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in|
04684|047|D|a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35%|
04684|048|D|decrease in the AUC of dehydro-aripiprazole, the active metabolite of|
04684|049|D|aripiprazole.  In simulations, the combination of strong CYP2D6 and CYP3A4|
04684|050|D|inhibitors is predicted to increase aripiprazole Cmax and AUC by|
04684|051|D|4.5-fold.(1)|
04684|052|B||
04684|053|R|REFERENCES:|
04684|054|B||
04684|055|R|1.Abilify Asimtufii (aripiprazole extended-release injectable) US|1
04684|056|R|  prescribing information. Otsuka Pharmaceutical Co., Ltd. April, 2023.|1
04684|057|R|2.Wellbutrin (bupropion hydrochloride) US prescribing information.|1
04684|058|R|  GlaxoSmithKline November, 2019.|1
04684|059|R|3.Zyban (bupropion hydrochloride) US prescribing information.|1
04684|060|R|  GlaxoSmithKline July, 2019.|1
04685|001|T|MONOGRAPH TITLE:  Atorvastatin/Asciminib (mono deleted 10/08/2025)|
04685|002|B||
04685|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04685|004|L|of severe adverse interaction.|
04685|005|B||
04685|006|A|MECHANISM OF ACTION:  Asciminib is an inhibitor of the BCRP, OATP1B1, and|
04685|007|A|OATP1B3 transporters and may increase the absorption and/or decrease the|
04685|008|A|elimination of atorvastatin.(1-3)|
04685|009|B||
04685|010|E|CLINICAL EFFECTS:  Concurrent use of asciminib may result in elevated levels|
04685|011|E|of atorvastatin, which could result in rhabdomyolysis.|
04685|012|B||
04685|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04685|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04685|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04685|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04685|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04685|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04685|019|P|predisposed to myopathy or rhabdomyolysis.|
04685|020|B||
04685|021|M|PATIENT MANAGEMENT:  The manufacturer of asciminib states that concurrent|
04685|022|M|use with atorvastatin should be avoided.(1,2)|
04685|023|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04685|024|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04685|025|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04685|026|M|urine, and/or discolored urine.|
04685|027|B||
04685|028|D|DISCUSSION:  In a PKPB model, concurrent use of asciminib 40 mg twice daily,|
04685|029|D|80 mg daily, and 200 mg twice daily increased the concentration maximum|
04685|030|D|(Cmax) by 97%, 143% and 300%, respectively, and area-under-curve (AUC) by|
04685|031|D|81%, 122%, and 326%, respectively, of a single dose of atorvastatin (an|
04685|032|D|OATP1B1 and OATP1B3 substrate).(4)|
04685|033|D|   In a PKPB model, concurrent use of asciminib 40 mg twice daily, 80 mg|
04685|034|D|daily, and 200 mg twice daily increased the Cmax by 453%, 530% and 732%,|
04685|035|D|respectively, and AUC by 190%, 202%, and 311%, respectively, of a single|
04685|036|D|dose of rosuvastatin (an OATP1B1 and BCRP substrate).(4)|
04685|037|B||
04685|038|R|REFERENCES:|
04685|039|B||
04685|040|R|1.Scemblix (asciminib) US prescribing information. Novartis Pharmaceuticals|1
04685|041|R|  Corporation October, 2025.|1
04685|042|R|2.Scemblix (asciminib) Canadian product monograph. Novartis Pharmaceuticals|1
04685|043|R|  Canada Inc. July, 2024.|1
04685|044|R|3.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
04685|045|R|  2020.|1
04685|046|R|4.Novartis Medical Information Medical Response Resources, Scemblix - Drug|1
04685|047|R|  Interactions. Novartis Pharmaceuticals Corporation May 13, 2024.|1
04686|001|T|MONOGRAPH TITLE:  Rosuvastatin/Asciminib|
04686|002|B||
04686|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04686|004|L|of severe adverse interaction.|
04686|005|B||
04686|006|A|MECHANISM OF ACTION:  Asciminib is an inhibitor of the BCRP transporter and|
04686|007|A|may increase the absorption and/or decrease the elimination of|
04686|008|A|rosuvastatin.(1-3)|
04686|009|B||
04686|010|E|CLINICAL EFFECTS:  Concurrent use of asciminib may result in elevated levels|
04686|011|E|of rosuvastatin, which could result in rhabdomyolysis.|
04686|012|B||
04686|013|P|PREDISPOSING FACTORS:  Patients on rosuvastatin with ABCG2 polymorphisms|
04686|014|P|leading to decreased or poor BCRP transporter function may have increased|
04686|015|P|rosuvastatin concentrations and risk of myopathy.|
04686|016|B||
04686|017|M|PATIENT MANAGEMENT:  The manufacturer of asciminib states that concurrent|
04686|018|M|use with rosuvastatin should be avoided.(1,2)|
04686|019|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04686|020|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04686|021|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04686|022|M|urine, and/or discolored urine.|
04686|023|B||
04686|024|D|DISCUSSION:  In a PKPB model, concurrent use of asciminib 40 mg twice daily,|
04686|025|D|80 mg daily, and 200 mg twice daily increased the concentration maximum|
04686|026|D|(Cmax) by 453%, 530% and 732%, respectively, and area-under-curve (AUC) by|
04686|027|D|190%, 202%, and 311%, respectively, of a single dose of rosuvastatin (a BCRP|
04686|028|D|substrate).(4)|
04686|029|B||
04686|030|R|REFERENCES:|
04686|031|B||
04686|032|R|1.Scemblix (asciminib) US prescribing information. Novartis Pharmaceuticals|1
04686|033|R|  Corporation October, 2025.|1
04686|034|R|2.Scemblix (asciminib) Canadian product monograph. Novartis Pharmaceuticals|1
04686|035|R|  Canada Inc. July, 2024.|1
04686|036|R|3.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04686|037|R|  Pharmaceuticals LP July, 2024.|1
04686|038|R|4.Novartis Medical Information Medical Response Resources, Scemblix - Drug|1
04686|039|R|  Interactions. Novartis Pharmaceuticals Corporation May 13, 2024.|1
04687|001|T|MONOGRAPH TITLE:  Pravastatin/Asciminib (mono deleted 10/08/2025)|
04687|002|B||
04687|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04687|004|L|take action as needed.|
04687|005|B||
04687|006|A|MECHANISM OF ACTION:  Asciminib is an inhibitor of OATP1B1 and OATP1B3.(1-3)|
04687|007|A|Pravastatin is a substrate for OATP1B1 and OATP1B3 transport.(4)|
04687|008|B||
04687|009|E|CLINICAL EFFECTS:  Concurrent use of asciminib may lead to higher systemic|
04687|010|E|concentrations of pravastatin, increasing the risk for statin-induced|
04687|011|E|myopathy or rhabdomyolysis.|
04687|012|B||
04687|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04687|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04687|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04687|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04687|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04687|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04687|019|P|predisposed to myopathy or rhabdomyolysis.|
04687|020|B||
04687|021|M|PATIENT MANAGEMENT:  The manufacturer of asciminib states that pravastatin|
04687|022|M|should be used with caution and monitored closely for adverse events|
04687|023|M|including myopathy and rhabdomyolysis.  Consider using the lowest effective|
04687|024|M|dose of pravastatin.(1,2)|
04687|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04687|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04687|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04687|028|M|urine, and/or discolored urine.|
04687|029|B||
04687|030|D|DISCUSSION:  In a PKPB model, concurrent use of asciminib 40 mg twice daily,|
04687|031|D|80 mg daily, and 200 mg twice daily increased the maximum concentration|
04687|032|D|(Cmax) of a single dose of pravastatin (an OATP1B1 and OATP1B3 substrate) by|
04687|033|D|43%, 63% and 141%, respectively, and increased area-under-curve (AUC) by|
04687|034|D|37%, 51%, and 137%, respectively.(3)|
04687|035|D|   In a PKPB model, concurrent use of asciminib 40 mg twice daily, 80 mg|
04687|036|D|daily, and 200 mg twice daily increased the Cmax of a single dose of|
04687|037|D|atorvastatin (an OATP1B1 and OATP1B3 substrate) by 97%, 143% and 300%,|
04687|038|D|respectively, and increased AUC by 81%, 122%, and 326%, respectively.(3)|
04687|039|D|   In a PKPB model, concurrent use of asciminib 40 mg twice daily, 80 mg|
04687|040|D|daily, and 200 mg twice daily increased the Cmax of a single dose of|
04687|041|D|rosuvastatin (an OATP1B1 and BCRP substrate) by 453%, 530% and 732%,|
04687|042|D|respectively, and increased AUC by 190%, 202%, and 311%, respectively.(3)|
04687|043|B||
04687|044|R|REFERENCES:|
04687|045|B||
04687|046|R|1.Scemblix (asciminib) US prescribing information. Novartis Pharmaceuticals|1
04687|047|R|  Corporation October, 2025.|1
04687|048|R|2.Scemblix (asciminib) Canadian product monograph. Novartis Pharmaceuticals|1
04687|049|R|  Canada Inc. July, 2024.|1
04687|050|R|3.Novartis Medical Information Medical Response Resources, Scemblix - Drug|1
04687|051|R|  Interactions. Novartis Pharmaceuticals Corporation May 13, 2024.|1
04687|052|R|4.This information is based on an extract from the Certara Drug Interaction|6
04687|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04688|001|T|MONOGRAPH TITLE:  Simvastatin/Asciminib|
04688|002|B||
04688|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04688|004|L|take action as needed.|
04688|005|B||
04688|006|A|MECHANISM OF ACTION:  Asciminib is an inhibitor of the BCRP transporter and|
04688|007|A|may increase the absorption and/or decrease the elimination of|
04688|008|A|simvastatin.(1-3)|
04688|009|B||
04688|010|E|CLINICAL EFFECTS:  Concurrent asciminib may result in elevated levels of|
04688|011|E|simvastatin, which may result in myopathy and rhabdomyolysis.(1,2)|
04688|012|B||
04688|013|P|PREDISPOSING FACTORS:  None determined.|
04688|014|B||
04688|015|M|PATIENT MANAGEMENT:  The manufacturer of asciminib states that simvastatin|
04688|016|M|should be used with caution and monitored closely for adverse events|
04688|017|M|including myopathy and rhabdomyolysis.  Consider using the lowest effective|
04688|018|M|dose of simvastatin.(1,2)|
04688|019|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04688|020|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04688|021|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04688|022|M|urine, and/or discolored urine.|
04688|023|B||
04688|024|D|DISCUSSION:  In a PKPB model, concurrent use of asciminib 40 mg twice daily,|
04688|025|D|80 mg daily, and 200 mg twice daily increased the maximum concentration|
04688|026|D|(Cmax) of a single dose of pravastatin (an OATP1B1 and OATP1B3 substrate) by|
04688|027|D|43%, 63% and 141%, respectively, and increased area-under-curve (AUC) by|
04688|028|D|37%, 51%, and 137%, respectively.(3)|
04688|029|D|   In a PKPB model, concurrent use of asciminib 40 mg twice daily, 80 mg|
04688|030|D|daily, and 200 mg twice daily increased the Cmax of a single dose of|
04688|031|D|atorvastatin (an OATP1B1 and OATP1B3 substrate) by 97%, 143% and 300%,|
04688|032|D|respectively, and increased AUC by 81%, 122%, and 326%, respectively.(3)|
04688|033|D|   In a PKPB model, concurrent use of asciminib 40 mg twice daily, 80 mg|
04688|034|D|daily, and 200 mg twice daily increased the Cmax of a single dose of|
04688|035|D|rosuvastatin (an OATP1B1 and BCRP substrate) by 453%, 530% and 732%,|
04688|036|D|respectively, and increased AUC by 190%, 202%, and 311%, respectively.(3)|
04688|037|B||
04688|038|R|REFERENCES:|
04688|039|B||
04688|040|R|1.Scemblix (asciminib) US prescribing information. Novartis Pharmaceuticals|1
04688|041|R|  Corporation October, 2025.|1
04688|042|R|2.Scemblix (asciminib) Canadian product monograph. Novartis Pharmaceuticals|1
04688|043|R|  Canada Inc. July, 2024.|1
04688|044|R|3.Novartis Medical Information Medical Response Resources, Scemblix - Drug|1
04688|045|R|  Interactions. Novartis Pharmaceuticals Corporation May 13, 2024.|1
04688|046|R|4.Zocor (simvastatin) US prescribing information. Merck & Co., Inc. March,|1
04688|047|R|  2023.|1
04689|001|T|MONOGRAPH TITLE:  Mavacamten/Moderate CYP3A4 Inducers|
04689|002|B||
04689|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04689|004|L|is contraindicated and generally should not be dispensed or administered to|
04689|005|L|the same patient.|
04689|006|B||
04689|007|A|MECHANISM OF ACTION:  Agents that induce the CYP3A4 isoenzyme may increase|
04689|008|A|the metabolism of mavacamten.(1-3)|
04689|009|B||
04689|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inducers may decrease|
04689|011|E|the levels and effectiveness of mavacamten.(1-3)|
04689|012|B||
04689|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04689|014|P|of the inducer for longer than 1-2 weeks.|
04689|015|B||
04689|016|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers of mavacamten state|
04689|017|M|concurrent use of mavacamten with moderate CYP3A4 inducers is|
04689|018|M|contraindicated.(1,2)|
04689|019|M|   The UK manufacturer of mavacamten states that management of mavacamten|
04689|020|M|during concomitant use with moderate CYP3A4 inducers is dependent on CYP2C19|
04689|021|M|phenotype.  Labeling recommends:|
04689|022|M|   -When initiating or increasing the dose of a moderate inducer in patients|
04689|023|M|who are CYP2C19 poor metabolizers, monitor patients closely and adjust|
04689|024|M|mavacamten dose based on clinical response.|
04689|025|M|   -When discontinuing or decreasing the dose of a moderate inducer in|
04689|026|M|patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten|
04689|027|M|to 2.5 mg, or pause therapy if dose is 2.5 mg.|
04689|028|M|   -No dose adjustment is warranted with moderate inducers in patients who|
04689|029|M|are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers.(3)|
04689|030|B||
04689|031|D|DISCUSSION:  Concomitant use of mavacamten (a single 15 mg dose) with a|
04689|032|D|strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted|
04689|033|D|to decrease mavacamten area-under-curve (AUC) and maximum concentration|
04689|034|D|(Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by|
04689|035|D|69% and 4%, respectively, in CYP2C19 poor metabolizers.(1)|
04689|036|D|    Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
04689|037|D|bosentan, cenobamate, dabrafenib, elagolix, lesinurad, modafinil, nafcillin,|
04689|038|D|pexidartinib, rifabutin, sotorasib, telotristat, thioridazine, and|
04689|039|D|tovorafenib.(4,5)|
04689|040|B||
04689|041|R|REFERENCES:|
04689|042|B||
04689|043|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04689|044|R|  April, 2025.|1
04689|045|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04689|046|R|  Canada February, 2024.|1
04689|047|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04689|048|R|  Squibb July, 2023.|1
04689|049|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04689|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04689|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04689|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04689|053|R|  11/14/2017.|1
04689|054|R|5.This information is based on an extract from the Certara Drug Interaction|6
04689|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04690|001|T|MONOGRAPH TITLE:  Mavacamten/Lorlatinib|
04690|002|B||
04690|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04690|004|L|is contraindicated and generally should not be dispensed or administered to|
04690|005|L|the same patient.|
04690|006|B||
04690|007|A|MECHANISM OF ACTION:  Mavacamten and lorlatinib are both CYP3A4 substrates|
04690|008|A|and inducers.|
04690|009|A|   Moderate inducers of CYP3A4 may increase the metabolism of|
04690|010|A|mavacamten.(1-3)  Lorlatinib is a moderate CYP3A4 inducer.|
04690|011|A|   Moderate inducers of CYP3A4 are expected to increase the metabolism of|
04690|012|A|lorlatinib.(4)  Mavacamten is a moderate CYP3A4 inducer.|
04690|013|B||
04690|014|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
04690|015|E|effectiveness of both mavacamten and lorlatinib.(1-4)|
04690|016|B||
04690|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04690|018|P|of the inducer for longer than 1-2 weeks.|
04690|019|B||
04690|020|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers of mavacamten state|
04690|021|M|concurrent use of mavacamten with moderate CYP3A4 inducers is|
04690|022|M|contraindicated.(1,2)|
04690|023|M|   The UK manufacturer of mavacamten states that management of mavacamten|
04690|024|M|during concomitant use with moderate CYP3A4 inducers is dependent on CYP2C19|
04690|025|M|phenotype.  Labeling recommends:|
04690|026|M|   -When initiating or increasing the dose of a moderate inducer in patients|
04690|027|M|who are CYP2C19 poor metabolizers, monitor patients closely and adjust|
04690|028|M|mavacamten dose based on clinical response.|
04690|029|M|   -When discontinuing or decreasing the dose of a moderate inducer in|
04690|030|M|patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten|
04690|031|M|to 2.5 mg, or pause therapy if dose is 2.5 mg.|
04690|032|M|   -No dose adjustment is warranted with moderate inducers in patients who|
04690|033|M|are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers.(3)|
04690|034|M|   The manufacturer of lorlatinib recommends avoiding concurrent|
04690|035|M|administration of moderate inducers of CYP3A4 with lorlatinib.(4)|
04690|036|M|   If concurrent use of lorlatinib and moderate CYP3A4 inducers cannot be|
04690|037|M|avoided, increase the dose of lorlatinib to 125 mg daily.(4)|
04690|038|B||
04690|039|D|DISCUSSION:  Concomitant use of mavacamten (a single 15 mg dose) with a|
04690|040|D|strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted|
04690|041|D|to decrease mavacamten area-under-curve (AUC) and maximum concentration|
04690|042|D|(Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by|
04690|043|D|69% and 4%, respectively, in CYP2C19 poor metabolizers.(1)|
04690|044|D|   Modafinil (a moderate CYP3A4 inducer) decreased the AUC and Cmax of a|
04690|045|D|single 100 mg dose of lorlatinib by 23% and 22%, respectively.(4)|
04690|046|B||
04690|047|R|REFERENCES:|
04690|048|B||
04690|049|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04690|050|R|  April, 2025.|1
04690|051|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04690|052|R|  Canada February, 2024.|1
04690|053|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04690|054|R|  Squibb July, 2023.|1
04690|055|R|4.Lorbrena (lorlatinib) US prescribing information. Pfizer Inc. March, 2021.|1
04690|056|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04690|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04690|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04690|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04690|060|R|  11/14/2017.|1
04690|061|R|6.This information is based on an extract from the Certara Drug Interaction|6
04690|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04691|001|T|MONOGRAPH TITLE:  Mavacamten/Mitapivat|
04691|002|B||
04691|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04691|004|L|is contraindicated and generally should not be dispensed or administered to|
04691|005|L|the same patient.|
04691|006|B||
04691|007|A|MECHANISM OF ACTION:  Mavacamten and mitapivat are both CYP3A4 substrates|
04691|008|A|and inducers.|
04691|009|A|   Moderate inducers of CYP3A4 may increase the metabolism of|
04691|010|A|mavacamten.(1-3)  Mitapivat is a moderate CYP3A4 inducer.|
04691|011|A|   Moderate inducers of CYP3A4 are expected to increase the metabolism of|
04691|012|A|mitapivat.(4)  Mavacamten is a moderate CYP3A4 inducer.|
04691|013|B||
04691|014|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
04691|015|E|effectiveness of both mavacamten and mitapivat.(1-4)|
04691|016|B||
04691|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04691|018|P|of the inducer for longer than 1-2 weeks.|
04691|019|B||
04691|020|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers of mavacamten state|
04691|021|M|concurrent use of mavacamten with moderate CYP3A4 inducers is|
04691|022|M|contraindicated.(1,2)|
04691|023|M|   The UK manufacturer of mavacamten states that management of mavacamten|
04691|024|M|during concomitant use with moderate CYP3A4 inducers is dependent on CYP2C19|
04691|025|M|phenotype.  Labeling recommends:|
04691|026|M|   -When initiating or increasing the dose of a moderate inducer in patients|
04691|027|M|who are CYP2C19 poor metabolizers, monitor patients closely and adjust|
04691|028|M|mavacamten dose based on clinical response.|
04691|029|M|   -When discontinuing or decreasing the dose of a moderate inducer in|
04691|030|M|patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten|
04691|031|M|to 2.5 mg, or pause therapy if dose is 2.5 mg.|
04691|032|M|   -No dose adjustment is warranted with moderate inducers in patients who|
04691|033|M|are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers.(3)|
04691|034|M|   The manufacturer of mitapivat states that concurrent use of mitapivat|
04691|035|M|with medications that are moderate CYP3A4 inducers should be monitored|
04691|036|M|closely.  Mitapivat dose should not exceed a maximum dose of 100 mg twice|
04691|037|M|daily with concurrent moderate CYP3A4 inducers.(4)|
04691|038|B||
04691|039|D|DISCUSSION:  Concomitant use of mavacamten (a single 15 mg dose) with a|
04691|040|D|strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted|
04691|041|D|to decrease mavacamten area-under-curve (AUC) and maximum concentration|
04691|042|D|(Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by|
04691|043|D|69% and 4%, respectively, in CYP2C19 poor metabolizers.(1)|
04691|044|D|   Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study with 5 or 20|
04691|045|D|mg twice daily of mitapivat, efavirenz decreased AUC and Cmax by 60% and|
04691|046|D|30%, respectively.  After mitapivat doses of 50 mg twice daily, efavirenz|
04691|047|D|decreased AUC and Cmax by 55% and 24%, respectively.(4)|
04691|048|B||
04691|049|R|REFERENCES:|
04691|050|B||
04691|051|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04691|052|R|  April, 2025.|1
04691|053|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04691|054|R|  Canada February, 2024.|1
04691|055|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04691|056|R|  Squibb July, 2023.|1
04691|057|R|4.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04691|058|R|  February, 2022.|1
04691|059|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04691|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04691|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04691|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04691|063|R|  11/14/2017.|1
04691|064|R|6.This information is based on an extract from the Certara Drug Interaction|6
04691|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04692|001|T|MONOGRAPH TITLE:  Mavacamten/Repotrectinib|
04692|002|B||
04692|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04692|004|L|is contraindicated and generally should not be dispensed or administered to|
04692|005|L|the same patient.|
04692|006|B||
04692|007|A|MECHANISM OF ACTION:  Mavacamten and repotrectinib are both CYP3A4|
04692|008|A|substrates and inducers.|
04692|009|A|   Moderate inducers of CYP3A4 may increase the metabolism of|
04692|010|A|mavacamten.(1-3)  Repotrectinib is a moderate CYP3A4 inducer.|
04692|011|A|   Moderate inducers of CYP3A4 are expected to increase the metabolism of|
04692|012|A|repotrectinib.(4)  Mavacamten is a moderate CYP3A4 inducer.|
04692|013|B||
04692|014|E|CLINICAL EFFECTS:  Concurrent use may result in decreased levels and|
04692|015|E|effectiveness of both mavacamten and repotrectinib.(1-4)|
04692|016|B||
04692|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04692|018|P|of the inducer for longer than 1-2 weeks.|
04692|019|B||
04692|020|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers of mavacamten state|
04692|021|M|concurrent use of mavacamten with moderate CYP3A4 inducers is|
04692|022|M|contraindicated.(1,2)|
04692|023|M|   The UK manufacturer of mavacamten states that management of mavacamten|
04692|024|M|during concomitant use with moderate CYP3A4 inducers is dependent on CYP2C19|
04692|025|M|phenotype.  Labeling recommends:|
04692|026|M|   -When initiating or increasing the dose of a moderate inducer in patients|
04692|027|M|who are CYP2C19 poor metabolizers, monitor patients closely and adjust|
04692|028|M|mavacamten dose based on clinical response.|
04692|029|M|   -When discontinuing or decreasing the dose of a moderate inducer in|
04692|030|M|patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten|
04692|031|M|to 2.5 mg, or pause therapy if dose is 2.5 mg.|
04692|032|M|   -No dose adjustment is warranted with moderate inducers in patients who|
04692|033|M|are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers.(3)|
04692|034|M|   The manufacturer of repotrectinib states that concurrent use with strong|
04692|035|M|or moderate CYP3A4 inducers should be avoided.(4)|
04692|036|B||
04692|037|D|DISCUSSION:  Concomitant use of mavacamten (a single 15 mg dose) with a|
04692|038|D|strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted|
04692|039|D|to decrease mavacamten area-under-curve (AUC) and maximum concentration|
04692|040|D|(Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by|
04692|041|D|69% and 4%, respectively, in CYP2C19 poor metabolizers.(1)|
04692|042|D|   Coadministration of repotrectinib with rifampin, a strong CYP3A4 and|
04692|043|D|P-glycoprotein inducer, decreased repotrectinib Cmax by 79% and AUC by|
04692|044|D|92%.(4)|
04692|045|B||
04692|046|R|REFERENCES:|
04692|047|B||
04692|048|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04692|049|R|  April, 2025.|1
04692|050|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04692|051|R|  Canada February, 2024.|1
04692|052|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04692|053|R|  Squibb July, 2023.|1
04692|054|R|4.Augtyro (repotrectinib) US prescribing information. Bristol-Myers Squibb|1
04692|055|R|  Company November, 2023.|1
04692|056|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04692|057|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04692|058|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04692|059|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04692|060|R|  11/14/2017.|1
04692|061|R|6.This information is based on an extract from the Certara Drug Interaction|6
04692|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04693|001|T|MONOGRAPH TITLE:  Lonafarnib/QT Prolonging Agents|
04693|002|B||
04693|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04693|004|L|of severe adverse interaction.|
04693|005|B||
04693|006|A|MECHANISM OF ACTION:  Lonafarnib has been shown to prolong the QTc interval.|
04693|007|A|Concurrent use with other agents that prolong the QTc interval may result|
04693|008|A|in additive effects on the QTc interval.(1)|
04693|009|B||
04693|010|E|CLINICAL EFFECTS:  The concurrent use of lonafarnib with other agents that|
04693|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04693|012|E|arrhythmias, including torsades de pointes.(1)|
04693|013|B||
04693|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04693|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04693|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04693|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04693|018|P|gender, or advanced age.(2)|
04693|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04693|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04693|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04693|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04693|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04693|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04693|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04693|026|B||
04693|027|M|PATIENT MANAGEMENT:  The manufacturer of lonafarnib states that the|
04693|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
04693|029|M|cannot be avoided, obtain ECGs when initiating, during concurrent use, and|
04693|030|M|as clinically indicated.(1)|
04693|031|M|   Lonafarnib dose modification recommendation: if the QTc interval is|
04693|032|M|greater than or equal to 500 msec, withhold lonafarnib until the QTc|
04693|033|M|interval is less than 470 msec, then resume lonafarnib at the same|
04693|034|M|dosage.(1)|
04693|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04693|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04693|037|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04693|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04693|039|B||
04693|040|D|DISCUSSION:  In a thorough QT study, lonafarnib 200 mg twice daily for 9|
04693|041|D|consecutive days and a single 200 mg dose on day 10 increased the mean QTc|
04693|042|D|interval by 19 msec (upper bound of 90% confidence interval = 27 msec) on|
04693|043|D|day 10 at 48 hours after administration of the morning dose of lonafarnib|
04693|044|D|200 mg.  The maximum concentration (Cmax) on Day 10 was 2233 ng/ml, which is|
04693|045|D|similar to the mean Cmax of 2695 ng/ml observed in the Hutchinson-Gilford|
04693|046|D|Progeria Syndrome patient population.(1)|
04693|047|D|   Agents that are linked to this monograph may have varying degrees of|
04693|048|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04693|049|D|been shown to prolong the QTc interval either through their mechanism of|
04693|050|D|action, through studies on their effects on the QTc interval, or through|
04693|051|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04693|052|D|and/or postmarketing reports.(3)|
04693|053|B||
04693|054|R|REFERENCES:|
04693|055|B||
04693|056|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04693|057|R|  Inc. November, 2020.|1
04693|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04693|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04693|060|R|  settings: a scientific statement from the American Heart Association and|6
04693|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04693|062|R|  2;55(9):934-47.|6
04693|063|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04693|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04693|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04693|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04694|001|T|MONOGRAPH TITLE:  Lonafarnib/Possible QT Prolonging Agents|
04694|002|B||
04694|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04694|004|L|take action as needed.|
04694|005|B||
04694|006|A|MECHANISM OF ACTION:  Lonafarnib has been shown to prolong the QTc interval.|
04694|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
04694|008|A|additive effects on the QTc interval.(1)|
04694|009|B||
04694|010|E|CLINICAL EFFECTS:  The concurrent use of lonafarnib with other agents that|
04694|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04694|012|E|arrhythmias, including torsades de pointes.(1)|
04694|013|B||
04694|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04694|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04694|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04694|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04694|018|P|gender, or advanced age.(2)|
04694|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04694|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04694|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04694|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04694|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04694|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04694|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04694|026|B||
04694|027|M|PATIENT MANAGEMENT:  The manufacturer of lonafarnib states that the|
04694|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
04694|029|M|cannot be avoided, obtain ECGs when initiating, during concurrent use, and|
04694|030|M|as clinically indicated.(1)|
04694|031|M|   Lonafarnib dose modification recommendation: if the QTc interval is|
04694|032|M|greater than or equal to 500 msec, withhold lonafarnib until the QTc|
04694|033|M|interval is less than 470 msec, then resume lonafarnib at the same|
04694|034|M|dosage.(1)|
04694|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04694|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04694|037|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04694|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04694|039|B||
04694|040|D|DISCUSSION:  In a thorough QT study, lonafarnib 200 mg twice daily for 9|
04694|041|D|consecutive days and a single 200 mg dose on day 10 increased the mean QTc|
04694|042|D|interval by 19 msec (upper bound of 90% confidence interval = 27 msec) on|
04694|043|D|day 10 at 48 hours after administration of the morning dose of lonafarnib|
04694|044|D|200 mg.  The maximum concentration (Cmax) on Day 10 was 2233 ng/ml, which is|
04694|045|D|similar to the mean Cmax of 2695 ng/ml observed in the Hutchinson-Gilford|
04694|046|D|Progeria Syndrome patient population.(1)|
04694|047|D|   Agents that are linked to this monograph may have varying degrees of|
04694|048|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04694|049|D|been shown to prolong the QTc interval either through their mechanism of|
04694|050|D|action, through studies on their effects on the QTc interval, or through|
04694|051|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04694|052|D|and/or postmarketing reports.(3)|
04694|053|B||
04694|054|R|REFERENCES:|
04694|055|B||
04694|056|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04694|057|R|  Inc. November, 2020.|1
04694|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04694|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04694|060|R|  settings: a scientific statement from the American Heart Association and|6
04694|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04694|062|R|  2;55(9):934-47.|6
04694|063|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04694|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04694|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04694|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04695|001|T|MONOGRAPH TITLE:  Ceritinib/Lonafarnib|
04695|002|B||
04695|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04695|004|L|is contraindicated and generally should not be dispensed or administered to|
04695|005|L|the same patient.|
04695|006|B||
04695|007|A|MECHANISM OF ACTION:  Ceritinib and lonafarnib are both agents that inhibit|
04695|008|A|the CYP3A4 isoenzyme and are substrates of CYP3A4.(1,2) Lonafarnib is a|
04695|009|A|sensitive CYP3A4 substrate.(2)|
04695|010|A|   Both agents have been shown to prolong the QTc interval.(1,2)|
04695|011|B||
04695|012|E|CLINICAL EFFECTS:  Concurrent use of ceritinib and lonafarnib may increase|
04695|013|E|the levels of and effects from both agents, including additive QTc|
04695|014|E|prolongation and potentially life-threatening cardiac arrhythmias like|
04695|015|E|torsades de pointes, and hepatotoxicity.(1,2)|
04695|016|E|   Elevated levels of ceritinib may also increase the risk of bradycardia,|
04695|017|E|pancreatitis, hyperglycemia, and interstitial lung disease.(1)|
04695|018|E|   Elevated levels of lonafarnib may also increase the risk of nausea and|
04695|019|E|vomiting, myelosuppression, and hypertension.(2)|
04695|020|B||
04695|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04695|022|P|may be increased in patients with cardiovascular disease (e.g. heart|
04695|023|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04695|024|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04695|025|P|female gender, or advanced age.(3)|
04695|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04695|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04695|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04695|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04695|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04695|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04695|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04695|033|B||
04695|034|M|PATIENT MANAGEMENT:  The use of lonafarnib with strong CYP3A4 inhibitors|
04695|035|M|like ceritinib is contraindicated.(2)  Consider alternatives with no or|
04695|036|M|minimal enzyme inhibition and with no effect on the QTc interval.|
04695|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04695|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04695|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04695|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04695|041|B||
04695|042|D|DISCUSSION:  In a study in 19 healthy subjects, ketoconazole (200 mg twice|
04695|043|D|daily for 14 days) increased the maximum concentration (Cmax) and|
04695|044|D|area-under-curve (AUC) of a single dose of ceritinib (450 mg) by 22% and|
04695|045|D|2.9-fold, respectively.  The steady-state AUC of ceritinib at reduced doses|
04695|046|D|after concurrent ketoconazole was predicted by simulations to be similar to|
04695|047|D|the steady-state AUC of ceritinib alone.(1)|
04695|048|D|   In a clinical trial 3% of patients experienced a QTc interval increase|
04695|049|D|over baseline greater than 60 msec.  Less than 1% of patients (1 of 304)|
04695|050|D|treated with ceritinib was found to have a QTc greater than 500 msec.  The|
04695|051|D|upper limit of the 90% confidence interval for mean QTC increase was 16 msec|
04695|052|D|at ceritinib 750 mg.  Data suggested that ceritinib produces|
04695|053|D|concentration-dependent QTc interval prolongation.(1)|
04695|054|D|   With coadministration of a single oral dose of lonafarnib 50 mg following|
04695|055|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
04695|056|D|AUC and Cmax of lonafarnib were increased by 425% and 270%, respectively.(2)|
04695|057|D|   In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive|
04695|058|D|days and a single 200 mg dose on day 10 increased the mean QTc interval by|
04695|059|D|19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48|
04695|060|D|hours after administration of the morning dose of lonafarnib 200 mg.  The|
04695|061|D|Cmax on Day 10 was 2233 ng/ml, which is similar to the mean Cmax of 2695|
04695|062|D|ng/ml observed in the Hutchinson-Gilford Progeria Syndrome patient|
04695|063|D|population.(2)|
04695|064|B||
04695|065|R|REFERENCES:|
04695|066|B||
04695|067|R|1.Zykadia (ceritinib) US prescribing information. Novartis Pharmaceuticals|1
04695|068|R|  Corporation August, 2021.|1
04695|069|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04695|070|R|  Inc. November, 2020.|1
04695|071|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04695|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04695|073|R|  settings: a scientific statement from the American Heart Association and|6
04695|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04695|075|R|  2;55(9):934-47.|6
04695|076|R|4.This information is based on an extract from the Certara Drug Interaction|6
04695|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04695|078|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04695|079|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04695|080|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04695|081|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04695|082|R|  11/14/2017.|1
04696|001|T|MONOGRAPH TITLE:  Ribociclib/Lonafarnib|
04696|002|B||
04696|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04696|004|L|is contraindicated and generally should not be dispensed or administered to|
04696|005|L|the same patient.|
04696|006|B||
04696|007|A|MECHANISM OF ACTION:  Ribociclib and lonafarnib are both agents that inhibit|
04696|008|A|the CYP3A4 isoenzyme and are substrates of CYP3A4.(1,2) Lonafarnib is a|
04696|009|A|sensitive CYP3A4 substrate.(2)|
04696|010|A|   Both agents have been shown to prolong the QTc interval.(1,2)|
04696|011|B||
04696|012|E|CLINICAL EFFECTS:  Concurrent use of ribociclib and lonafarnib may increase|
04696|013|E|the levels of and effects from both agents, including additive QTc|
04696|014|E|prolongation and potentially life-threatening cardiac arrhythmias including|
04696|015|E|torsades de pointes, hepatotoxicity, and myelosuppression.(1,2)|
04696|016|E|   Elevated levels of ribociclib may also increase the risk of severe skin|
04696|017|E|reactions and interstitial lung disease.(1)|
04696|018|E|   Elevated levels of lonafarnib may also increase the risk of nausea and|
04696|019|E|vomiting and hypertension.(2)|
04696|020|B||
04696|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04696|022|P|may be increased in patients with cardiovascular disease (e.g. heart|
04696|023|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04696|024|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04696|025|P|female gender, or advanced age.(3)|
04696|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04696|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04696|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04696|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04696|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04696|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04696|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04696|033|B||
04696|034|M|PATIENT MANAGEMENT:  The use of lonafarnib with strong CYP3A4 inhibitors|
04696|035|M|like ribociclib is contraindicated.(2)  Consider alternatives with no or|
04696|036|M|minimal enzyme inhibition and with no effect on the QTc interval.|
04696|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04696|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04696|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04696|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04696|041|B||
04696|042|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
04696|043|D|coadministration of ritonavir (100 mg twice a day for 14 days) with a single|
04696|044|D|dose of ribociclib (400 mg) increased ribociclib maximum concentration|
04696|045|D|(Cmax) and area-under-curve (AUC) by 1.7 and 3.2-fold, respectively.  Cmax|
04696|046|D|and AUC for LEQ803 (ribociclib metabolite) decreased by 96% and 98%,|
04696|047|D|respectively.(1)|
04696|048|D|   Ribociclib has been shown to prolong the QTc interval in a|
04696|049|D|concentration-dependent manner.  At steady state, the mean increase in QTc|
04696|050|D|interval exceeded 20 msec.(1)|
04696|051|D|   With coadministration of a single oral dose of lonafarnib 50 mg following|
04696|052|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
04696|053|D|AUC and Cmax of lonafarnib were increased by 425% and 270%, respectively.(2)|
04696|054|D|   In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive|
04696|055|D|days and a single 200 mg dose on day 10 increased the mean QTc interval by|
04696|056|D|19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48|
04696|057|D|hours after administration of the morning dose of lonafarnib 200 mg.  The|
04696|058|D|Cmax on Day 10 was 2233 ng/ml, which is similar to the mean Cmax of 2695|
04696|059|D|ng/ml observed in the Hutchinson-Gilford Progeria Syndrome patient|
04696|060|D|population.(2)|
04696|061|B||
04696|062|R|REFERENCES:|
04696|063|B||
04696|064|R|1.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
04696|065|R|  Corporation September, 2024.|1
04696|066|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04696|067|R|  Inc. November, 2020.|1
04696|068|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04696|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04696|070|R|  settings: a scientific statement from the American Heart Association and|6
04696|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04696|072|R|  2;55(9):934-47.|6
04696|073|R|4.This information is based on an extract from the Certara Drug Interaction|6
04696|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04696|075|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04696|076|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04696|077|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04696|078|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04696|079|R|  11/14/2017.|1
04697|001|T|MONOGRAPH TITLE:  Dronedarone/Strong CYP3A4 Inhibitors that Prolong QT|
04697|002|B||
04697|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04697|004|L|is contraindicated and generally should not be dispensed or administered to|
04697|005|L|the same patient.|
04697|006|B||
04697|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
04697|008|A|may inhibit the metabolism of dronedarone and result in additive risk of QTc|
04697|009|A|prolongation.  Dronedarone is a CYP3A4 substrate.(1)|
04697|010|B||
04697|011|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor that prolongs|
04697|012|E|QT may increase the levels and effects of dronedarone, including additive|
04697|013|E|QTc prolongation, which may result in life-threatening cardiac arrhythmias|
04697|014|E|like torsades de pointes( TdP).(1)|
04697|015|B||
04697|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04697|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04697|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04697|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04697|020|P|gender, or advanced age.(2)|
04697|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04697|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04697|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04697|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04697|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04697|026|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04697|027|P|dysfunction).(2)|
04697|028|B||
04697|029|M|PATIENT MANAGEMENT:  The US manufacturer of dronedarone states that|
04697|030|M|concurrent administration of strong CYP3A4 inhibitors is contraindicated.|
04697|031|M|Concurrent use of drugs that prolong the QT interval is also|
04697|032|M|contraindicated.  Treatment with drugs that prolong QTc or are strong CYP3A4|
04697|033|M|inhibitors must be stopped before starting dronedarone.(1)|
04697|034|M|   If alternatives are not available and concurrent therapy is deemed|
04697|035|M|medically necessary, obtain serum calcium, magnesium, and potassium levels|
04697|036|M|and monitor ECG at baseline and at regular intervals.  Correct any|
04697|037|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04697|038|M|heartbeat, dizziness, or fainting.|
04697|039|M|   If the QTc interval is >500 msec, discontinue dronedarone.(1)|
04697|040|B||
04697|041|D|DISCUSSION:  Concurrent use of ketoconazole 200 mg once daily and|
04697|042|D|dronedarone (dosage not stated) increased the area-under-curve (AUC) and|
04697|043|D|maximum concentration (Cmax) of dronedarone by 17-fold and 9-fold,|
04697|044|D|respectively.(1)|
04697|045|D|   Dronedarone causes dose-dependent increases in QTc, with 400 mg twice|
04697|046|D|daily taken with food causing an estimated 15 msec increase in QTcF.(1)|
04697|047|D|   Strong CYP3A4 inhibitors that prolong QT linked to this monograph|
04697|048|D|include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib,|
04697|049|D|lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and|
04697|050|D|voriconazole.|
04697|051|B||
04697|052|R|REFERENCES:|
04697|053|B||
04697|054|R|1.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
04697|055|R|  November, 2020.|1
04697|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04697|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04697|058|R|  settings: a scientific statement from the American Heart Association and|6
04697|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04697|060|R|  2;55(9):934-47.|6
04698|001|T|MONOGRAPH TITLE:  Digoxin/Tepotinib|
04698|002|B||
04698|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04698|004|L|of severe adverse interaction.|
04698|005|B||
04698|006|A|MECHANISM OF ACTION:  Tepotinib may increase the absorption of digoxin by|
04698|007|A|inhibiting P-glycoprotein (P-gp).(1)|
04698|008|B||
04698|009|E|CLINICAL EFFECTS:  Concurrent use of tepotinib may result in elevated levels|
04698|010|E|of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can include|
04698|011|E|anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
04698|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
04698|013|E|disturbances, and arrhythmias.|
04698|014|B||
04698|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
04698|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
04698|017|P|risk of digoxin toxicity.|
04698|018|B||
04698|019|M|PATIENT MANAGEMENT:  Avoid coadministration of tepotinib with P-gp|
04698|020|M|substrates such as digoxin.(1)|
04698|021|M|   If coadministration cannot be avoided, monitor serum digoxin|
04698|022|M|concentrations before initiating tepotinib.  When the digoxin concentration|
04698|023|M|is expected to be increased by greater than 50%, the manufacturer of digoxin|
04698|024|M|recommends decreasing the dose of digoxin by approximately 15-30% or by|
04698|025|M|modifying the dosing frequency to reduce digoxin concentrations.  Continue|
04698|026|M|monitoring and reduce digoxin dose as necessary.(2)|
04698|027|B||
04698|028|D|DISCUSSION:  Coadministration of tepotinib increased dabigatran (P-gp|
04698|029|D|substrate) area-under-curve (AUC) and maximum concentration (Cmax) by 50%|
04698|030|D|and 40%, respectively.(1)|
04698|031|B||
04698|032|R|REFERENCES:|
04698|033|B||
04698|034|R|1.Tepmetko (tepotinib) US prescribing information. EMD Serono, Inc.|1
04698|035|R|  February, 2024.|1
04698|036|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
04698|037|R|  Pharmaceuticals, Inc. August, 2018.|1
04699|001|T|MONOGRAPH TITLE:  Lonafarnib/Strong CYP3A4 Inducers that Prolong QT|
04699|002|B||
04699|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04699|004|L|is contraindicated and generally should not be dispensed or administered to|
04699|005|L|the same patient.|
04699|006|B||
04699|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers that prolong the QTc interval|
04699|008|A|may increase the metabolism of lonafarnib.  Concurrent use may result in an|
04699|009|A|additive risk of QT prolongation.(1)|
04699|010|B||
04699|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
04699|012|E|may decrease the serum levels and effectiveness of lonafarnib and have|
04699|013|E|additive effects on the QTc interval, which may result in potentially|
04699|014|E|life-threatening arrhythmias including torsades de pointes.(1)|
04699|015|B||
04699|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04699|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04699|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04699|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04699|020|P|female gender, or advanced age.(2)|
04699|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04699|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04699|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04699|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04699|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04699|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04699|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04699|028|P|   Induction effects may be more likely with regular use of the inducer for|
04699|029|P|longer than 1-2 weeks.|
04699|030|B||
04699|031|M|PATIENT MANAGEMENT:  The use of strong CYP3A4 inducers with lonafarnib is|
04699|032|M|contraindicated.|
04699|033|M|   If concurrent use is warranted, monitor ECG prior to initiation, during|
04699|034|M|concurrent therapy, and as clinically indicated with other agents known to|
04699|035|M|prolong the QTc interval.(1)|
04699|036|B||
04699|037|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg lonafarnib|
04699|038|D|(combined with a single oral dose of 100 mg ritonavir) following 600 mg|
04699|039|D|rifampin (a strong CYP3A4 inducer) for 8 days, the area-under-curve (AUC)|
04699|040|D|was reduced by 98% and the maximum concentration (Cmax) was reduced by|
04699|041|D|92%.(1)|
04699|042|D|   In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive|
04699|043|D|days and a single 200 mg dose on day 10 increased the mean QTc interval by|
04699|044|D|19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48|
04699|045|D|hours after administration of the morning dose of lonafarnib 200 mg.  The|
04699|046|D|maximum concentration (Cmax) on Day 10 was 2233 ng/ml, which is similar to|
04699|047|D|the mean Cmax of 2695 ng/ml observed in the Hutchinson-Gilford Progeria|
04699|048|D|Syndrome patient population.(1)|
04699|049|D|   Strong inducers of CYP3A4 that prolong QT include: encorafenib and|
04699|050|D|ivosidenib.(3,4)|
04699|051|B||
04699|052|R|REFERENCES:|
04699|053|B||
04699|054|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04699|055|R|  Inc. November, 2020.|1
04699|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04699|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04699|058|R|  settings: a scientific statement from the American Heart Association and|6
04699|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04699|060|R|  2;55(9):934-47.|6
04699|061|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04699|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04699|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04699|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04699|065|R|  11/14/2017.|1
04699|066|R|4.This information is based on an extract from the Certara Drug Interaction|6
04699|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04700|001|T|MONOGRAPH TITLE:  Lonafarnib/Moderate CYP3A4 Inducers that Prolong QT|
04700|002|B||
04700|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04700|004|L|is contraindicated and generally should not be dispensed or administered to|
04700|005|L|the same patient.|
04700|006|B||
04700|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers that prolong the QTc interval|
04700|008|A|may increase the metabolism of lonafarnib.  Concurrent use may result in an|
04700|009|A|additive risk of QT prolongation.(1)|
04700|010|B||
04700|011|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inducers that prolong|
04700|012|E|QT may decrease the serum levels and effectiveness of lonafarnib and have|
04700|013|E|additive effects on the QTc interval, which may result in potentially|
04700|014|E|life-threatening arrhythmias including torsades de pointes.(1)|
04700|015|B||
04700|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04700|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04700|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04700|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04700|020|P|female gender, or advanced age.(2)|
04700|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04700|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04700|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04700|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04700|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04700|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04700|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04700|028|P|   Induction effects may be more likely with regular use of the inducer for|
04700|029|P|longer than 1-2 weeks.|
04700|030|B||
04700|031|M|PATIENT MANAGEMENT:  The use of moderate CYP3A4 inducers with lonafarnib is|
04700|032|M|contraindicated.|
04700|033|M|   If concurrent use is warranted, monitor ECG prior to initiation, during|
04700|034|M|concurrent therapy, and as clinically indicated with other agents known to|
04700|035|M|prolong the QTc interval.(1)|
04700|036|B||
04700|037|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg lonafarnib|
04700|038|D|(combined with a single oral dose of 100 mg ritonavir) following 600 mg|
04700|039|D|rifampin (a strong CYP3A4 inducer) for 8 days, the area-under-curve (AUC)|
04700|040|D|was reduced by 98% and the maximum concentration (Cmax) was reduced by|
04700|041|D|92%.(1)|
04700|042|D|   In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive|
04700|043|D|days and a single 200 mg dose on day 10 increased the mean QTc interval by|
04700|044|D|19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48|
04700|045|D|hours after administration of the morning dose of lonafarnib 200 mg.  The|
04700|046|D|maximum concentration (Cmax) on Day 10 was 2233 ng/ml, which is similar to|
04700|047|D|the mean Cmax of 2695 ng/ml observed in the Hutchinson-Gilford Progeria|
04700|048|D|Syndrome patient population.(1)|
04700|049|D|   Moderate inducers of CYP3A4 that prolong QT include: efavirenz and|
04700|050|D|thioridazine.(3,4)|
04700|051|B||
04700|052|R|REFERENCES:|
04700|053|B||
04700|054|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04700|055|R|  Inc. November, 2020.|1
04700|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04700|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04700|058|R|  settings: a scientific statement from the American Heart Association and|6
04700|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04700|060|R|  2;55(9):934-47.|6
04700|061|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04700|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04700|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04700|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04700|065|R|  11/14/2017.|1
04700|066|R|4.This information is based on an extract from the Certara Drug Interaction|6
04700|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04701|001|T|MONOGRAPH TITLE:  Lonafarnib/Strong CYP3A4 Inhibitors that Prolong QT|
04701|002|B||
04701|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04701|004|L|is contraindicated and generally should not be dispensed or administered to|
04701|005|L|the same patient.|
04701|006|B||
04701|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors that prolong the QTc interval|
04701|008|A|may inhibit the metabolism of lonafarnib and cause an additive risk of QTc|
04701|009|A|prolongation.(1)|
04701|010|B||
04701|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04701|012|E|QT may increase the levels and effects of lonafarnib including additive QTc|
04701|013|E|prolongation and potentially life-threatening cardiac arrhythmias like|
04701|014|E|torsades de pointes.  Concurrent use may also result in severe nausea and|
04701|015|E|vomiting, increased liver enzymes, myelosuppression, and hypertension.(1)|
04701|016|B||
04701|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04701|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04701|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04701|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04701|021|P|female gender, or advanced age.(2)|
04701|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04701|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04701|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04701|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04701|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04701|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04701|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04701|029|B||
04701|030|M|PATIENT MANAGEMENT:  The use of lonafarnib with strong CYP3A4 inhibitors is|
04701|031|M|contraindicated.(1)|
04701|032|M|   The manufacturer of lonafarnib states that the concurrent use of QT|
04701|033|M|prolonging agents should be avoided.  If concurrent use cannot be avoided,|
04701|034|M|obtain ECGs when initiating, during concurrent use, and as clinically|
04701|035|M|indicated.(1)|
04701|036|M|   Lonafarnib dose modification recommendation: if the QTc interval is|
04701|037|M|greater than or equal to 500 msec, withhold lonafarnib until the QTc|
04701|038|M|interval is less than 470 msec, then resume lonafarnib at the same|
04701|039|M|dosage.(1)|
04701|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04701|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04701|042|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04701|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04701|044|B||
04701|045|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg lonafarnib|
04701|046|D|following 200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5|
04701|047|D|days, the area-under-curve (AUC) and maximum concentration (Cmax) were|
04701|048|D|increased by 425% and 270%, respectively.(1)|
04701|049|D|   In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive|
04701|050|D|days and a single 200 mg dose on day 10 increased the mean QTc interval by|
04701|051|D|19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48|
04701|052|D|hours after administration of the morning dose of lonafarnib 200 mg.  The|
04701|053|D|Cmax on Day 10 was 2233 ng/ml, which is similar to the mean Cmax of 2695|
04701|054|D|ng/ml observed in the Hutchinson-Gilford Progeria Syndrome patient|
04701|055|D|population.(1)|
04701|056|D|   Strong inhibitors of CYP3A4 that prolong QT include: adagrasib,|
04701|057|D|clarithromycin, lopinavir/ritonavir, telithromycin, and voriconazole.(3)|
04701|058|B||
04701|059|R|REFERENCES:|
04701|060|B||
04701|061|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04701|062|R|  Inc. November, 2020.|1
04701|063|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
04701|064|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04701|065|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04701|066|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04701|067|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04701|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04701|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04701|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04701|071|R|  11/14/2017.|1
04701|072|R|4.This information is based on an extract from the Certara Drug Interaction|6
04701|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04702|001|T|MONOGRAPH TITLE:  Lonafarnib/Moderate CYP3A4 Inhibitors that Prolong QT|
04702|002|B||
04702|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04702|004|L|of severe adverse interaction.|
04702|005|B||
04702|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors that prolong the QTc|
04702|007|A|interval may inhibit the metabolism of lonafarnib and cause an additive risk|
04702|008|A|of QTc prolongation.(1)|
04702|009|B||
04702|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
04702|011|E|QT may increase the levels and effects of lonafarnib including additive QTc|
04702|012|E|prolongation and potentially life-threatening cardiac arrhythmias like|
04702|013|E|torsades de pointes.  Concurrent use may also result in severe nausea and|
04702|014|E|vomiting, increased liver enzymes, myelosuppression, and hypertension.(1)|
04702|015|B||
04702|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04702|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04702|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04702|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04702|020|P|female gender, or advanced age.(2)|
04702|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04702|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04702|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04702|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04702|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04702|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04702|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04702|028|B||
04702|029|M|PATIENT MANAGEMENT:  The use of lonafarnib with moderate CYP3A4 inhibitors|
04702|030|M|known to prolong the QTc interval should be avoided.(1)  If concurrent use|
04702|031|M|cannot be avoided, obtain ECGs when initiating, during concurrent use, and|
04702|032|M|as clinically indicated.  If the QTc interval is greater than or equal to|
04702|033|M|500 msec, withhold lonafarnib until the QTc interval is less than 470 msec,|
04702|034|M|then resume lonafarnib at the same dosage.(1)|
04702|035|M|   No dose adjustment of lonafarnib is recommended when moderate CYP3A4|
04702|036|M|inhibitors are added to steady-state lonafarnib.  When initiating lonafarnib|
04702|037|M|therapy in a patient already taking a moderate CYP3A4 inhibitor, monitor the|
04702|038|M|patient closely for the first 7 days of therapy.  If the patient does not|
04702|039|M|tolerate lonafarnib, consider an alternative that is not a moderate CYP3A4|
04702|040|M|inhibitor.(1)|
04702|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04702|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04702|043|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04702|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04702|045|B||
04702|046|D|DISCUSSION:  With coadministration of a single oral dose of 50 mg lonafarnib|
04702|047|D|following 200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5|
04702|048|D|days, the area-under-curve (AUC) and maximum concentration (Cmax) were|
04702|049|D|increased by 425% and 270%, respectively.(1)|
04702|050|D|   In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive|
04702|051|D|days and a single 200 mg dose on day 10 increased the mean QTc interval by|
04702|052|D|19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48|
04702|053|D|hours after administration of the morning dose of lonafarnib 200 mg.  The|
04702|054|D|Cmax on Day 10 was 2233 ng/ml, which is similar to the mean Cmax of 2695|
04702|055|D|ng/ml observed in the Hutchinson-Gilford Progeria Syndrome patient|
04702|056|D|population.(1)|
04702|057|D|   Moderate inhibitors of CYP3A4 that prolong QT include:  clofazimine,|
04702|058|D|erythromycin and fluconazole.(3,4)|
04702|059|B||
04702|060|R|REFERENCES:|
04702|061|B||
04702|062|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04702|063|R|  Inc. November, 2020.|1
04702|064|R|2.USDepartment of Health and Human Services Food and Drug Administration.|1
04702|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04702|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04702|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04702|068|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04702|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04702|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04702|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04702|072|R|  11/14/2017.|1
04702|073|R|4.This information is based on an extract from the Certara Drug Interaction|6
04702|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04703|001|T|MONOGRAPH TITLE:  Pimozide/Strong CYP2D6 Inhibitors that Prolong QT|
04703|002|B||
04703|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04703|004|L|is contraindicated and generally should not be dispensed or administered to|
04703|005|L|the same patient.|
04703|006|B||
04703|007|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors that prolong the QTc interval|
04703|008|A|may inhibit the metabolism of pimozide and cause an additive risk of QTc|
04703|009|A|prolongation.(1)|
04703|010|B||
04703|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2D6 inhibitors that prolong|
04703|012|E|QT may increase the levels and effects of pimozide including additive QTc|
04703|013|E|prolongation and potentially life-threatening cardiac arrhythmias like|
04703|014|E|torsades de pointes.|
04703|015|E|   Concurrent use may also result in extrapyramidal symptoms such as|
04703|016|E|akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and|
04703|017|E|oculogyric crisis.(2)|
04703|018|B||
04703|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04703|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04703|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04703|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04703|023|P|female gender, or advanced age.(2)|
04703|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04703|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04703|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04703|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04703|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04703|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04703|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04703|031|P|   The risk of anticholinergic toxicities including cognitive decline,|
04703|032|P|delirium, falls and fractures is increased in geriatric patients using more|
04703|033|P|than one medicine with anticholinergic properties.(3)|
04703|034|B||
04703|035|M|PATIENT MANAGEMENT:  The concurrent use of pimozide with strong inhibitors|
04703|036|M|of CYP2D6 is contraindicated.(1)|
04703|037|M|   If concurrent use cannot be avoided, then correct or minimize QT|
04703|038|M|prolonging risk factors, use the lowest effective dose of pimozide, and|
04703|039|M|discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if|
04703|040|M|possible.|
04703|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04703|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04703|043|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04703|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04703|045|B||
04703|046|D|DISCUSSION:  In a controlled study in healthy subjects, steady-state|
04703|047|D|paroxetine (60 mg daily, a strong inhibitor of CYP2D6) increased the AUC and|
04703|048|D|Cmax of a single dose of pimozide (2 mg) by 151% and 62%, respectively.(1)|
04703|049|D|   Strong CYP2D6 inhibitors that prolong QT linked include: hydroquinidine,|
04703|050|D|mavorixafor, and quinidine.(5,6)|
04703|051|D|   One or more of the drug pairs linked to this monograph have been included|
04703|052|D|in a list of interactions that should be considered "high-priority" for|
04703|053|D|inclusion and should not be inactivated in EHR systems.  This DDI subset was|
04703|054|D|vetted by an expert panel commissioned by the U.S. Office of the National|
04703|055|D|Coordinator (ONC) for Health Information Technology.|
04703|056|B||
04703|057|R|REFERENCES:|
04703|058|B||
04703|059|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
04703|060|R|  2011.|1
04703|061|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04703|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04703|063|R|  settings: a scientific statement from the American Heart Association and|6
04703|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04703|065|R|  2;55(9):934-47.|6
04703|066|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04703|067|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04703|068|R|  Soc 2023 Jul;71(7):2052-2081.|6
04703|069|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04703|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04703|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04703|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04703|073|R|  11/14/2017.|1
04703|074|R|5.This information is based on an extract from the Certara Drug Interaction|6
04703|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04703|076|R|6.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
04703|077|R|  Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
04703|078|R|  electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
04703|079|R|  19(5):735-43.|6
04704|001|T|MONOGRAPH TITLE:  Pimozide/Moderate CYP3A4 Inhibitors that Prolong QT|
04704|002|B||
04704|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04704|004|L|is contraindicated and generally should not be dispensed or administered to|
04704|005|L|the same patient.|
04704|006|B||
04704|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors that prolong the QTc|
04704|008|A|interval may inhibit the metabolism of pimozide and cause an additive risk|
04704|009|A|of QTc prolongation.(1)|
04704|010|B||
04704|011|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
04704|012|E|QT may increase the levels and effects of pimozide including additive QTc|
04704|013|E|prolongation and potentially life-threatening cardiac arrhythmias like|
04704|014|E|torsades de pointes.|
04704|015|E|   Concurrent use may also result in extrapyramidal symptoms such as|
04704|016|E|akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and|
04704|017|E|oculogyric crisis.(1)|
04704|018|B||
04704|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04704|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04704|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04704|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04704|023|P|female gender, or advanced age.(2)|
04704|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04704|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04704|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04704|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04704|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04704|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04704|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04704|031|P|   The risk of anticholinergic toxicities including cognitive decline,|
04704|032|P|delirium, falls and fractures is increased in geriatric patients using more|
04704|033|P|than one medicine with anticholinergic properties.(3)|
04704|034|B||
04704|035|M|PATIENT MANAGEMENT:  The use of pimozide with moderate CYP3A4 inhibitors|
04704|036|M|that prolong QT is contraindicated, especially when other risk factors for|
04704|037|M|QT prolongation are present.|
04704|038|M|   The manufacturer of pimozide states that concomitant treatment with|
04704|039|M|strong CYP3A4 inhibitors is contraindicated and treatment with less potent|
04704|040|M|inhibitors of CYP3A4 should also be avoided.(1)|
04704|041|M|   If concurrent use cannot be avoided, then correct or minimize QT|
04704|042|M|prolonging risk factors, use the lowest effective dose of pimozide, and|
04704|043|M|discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if|
04704|044|M|possible.|
04704|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04704|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04704|047|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04704|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04704|049|B||
04704|050|D|DISCUSSION:  Pimozide is metabolized at CYP3A.  Elevated levels of pimozide|
04704|051|D|may prolong the QTc interval resulting in life-threatening ventricular|
04704|052|D|arrhythmias.(1)|
04704|053|D|   Moderate inhibitors of CYP3A4 that prolong QT include:  clofazimine,|
04704|054|D|dronedarone, erythromycin, and fluconazole.(4,5)|
04704|055|B||
04704|056|R|REFERENCES:|
04704|057|B||
04704|058|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
04704|059|R|  2011.|1
04704|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04704|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04704|062|R|  settings: a scientific statement from the American Heart Association and|6
04704|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04704|064|R|  2;55(9):934-47.|6
04704|065|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04704|066|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04704|067|R|  Soc 2023 Jul;71(7):2052-2081.|6
04704|068|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04704|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04704|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04704|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04704|072|R|  11/14/2017.|1
04704|073|R|5.This information is based on an extract from the Certara Drug Interaction|6
04704|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04705|001|T|MONOGRAPH TITLE:  Quetiapine (Greater Than 150 mg)/Strong CYP3A4 Inducers|
04705|002|T|that Prolong QT|
04705|003|B||
04705|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04705|005|L|of severe adverse interaction.|
04705|006|B||
04705|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may increase the metabolic|
04705|008|A|clearance of quetiapine.(1)|
04705|009|A|   Quetiapine may prolong the QTc interval.  Concomitant use with other QT|
04705|010|A|prolonging agents may result in an additive risk of QT prolongation.(1)|
04705|011|B||
04705|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers that prolong QT|
04705|013|E|with quetiapine may decrease the levels and effectiveness of quetiapine and|
04705|014|E|cause additive effects on the QTc interval, which may result in|
04705|015|E|life-threatening cardiac arrhythmias, including torsades de pointes.(1)|
04705|016|B||
04705|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04705|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04705|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04705|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04705|021|P|female gender, or advanced age.(2)|
04705|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04705|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04705|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04705|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04705|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04705|027|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04705|028|P|dysfunction).(2)|
04705|029|P|   Induction effects may be more likely with regular use of the inducer for|
04705|030|P|longer than 1-2 weeks.|
04705|031|B||
04705|032|M|PATIENT MANAGEMENT:  In patients on quetiapine receiving chronic treatment|
04705|033|M|(i.e., greater than 7-14 days) of inducers of CYP3A4, titrate the dose of|
04705|034|M|quetiapine based on the patient's clinical response and tolerance, up to|
04705|035|M|5-fold of the original dose.  The onset of induction is gradual but may|
04705|036|M|begin within one week for potent agents (e.g. rifampin). The time to maximal|
04705|037|M|induction may be 2 or more weeks depending upon the half-life and dose of|
04705|038|M|the inducer.|
04705|039|M|   If the CYP3A4 inducer is discontinued, the dose of quetiapine should be|
04705|040|M|reduced to the original level within 7-14 days.(1)|
04705|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04705|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04705|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04705|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04705|045|B||
04705|046|D|DISCUSSION:  In an interaction study, 18 stable patients with schizophrenia,|
04705|047|D|schizoaffective or bipolar disorder started treatment with quetiapine,|
04705|048|D|achieving the target dose of 300 mg twice daily on day five.  On day 9|
04705|049|D|carbamazepine  was started, gradually increasing to the target dose of 200|
04705|050|D|mg three times a day on day 13.  Patients continued on the combination|
04705|051|D|through day 33 to assure maximal enzyme induction was achieved.|
04705|052|D|Carbamazepine decreased quetiapine AUC 87%, decreased steady-state maximum|
04705|053|D|concentration (Cmax) by 80%, and increased clearance approximately|
04705|054|D|7-fold.(3)|
04705|055|D|   In a review of 2111 quetiapine levels from 1179 patients, quetiapine|
04705|056|D|levels were 86% lower in patients receiving concurrent carbamazepine.(4)|
04705|057|D|   In a review of 62 psychiatric patients, patients receiving carbamazepine|
04705|058|D|had significantly lower quetiapine concentration-to-dose ratios.(5)|
04705|059|D|   A case report described a newly hospitalized patient admitted on|
04705|060|D|carbamazepine 600 mg daily and risperidone 8 mg daily for schizoaffective|
04705|061|D|disorder. She was then converted from risperidone to quetiapine. After 7|
04705|062|D|days of treatment at the target quetiapine dose of 700 mg daily, serum|
04705|063|D|quetiapine concentrations were undetectable.  A repeat level 7 days later|
04705|064|D|was also undetectable. The decision was then made to discontinue|
04705|065|D|carbamazepine and continue quetiapine without dose adjustment.  Quetiapine|
04705|066|D|concentrations increased over the following days to weeks and were|
04705|067|D|accompanied by clinical improvement sufficient for discharge.  The authors|
04705|068|D|also briefly described 2 additional patients, each receiving carbamazepine|
04705|069|D|for a seizure disorder who were subsequently treated with quetiapine 600 mg|
04705|070|D|or 700 mg daily for more than two weeks.  As with the first case, quetiapine|
04705|071|D|serum concentrations with concurrent carbamazepine therapy were below the|
04705|072|D|limit of detection for each patient (lower limit of detection was 25|
04705|073|D|mcg/mL).(6)|
04705|074|D|   Concurrent use of phenytoin (100 mg three times daily), a strong CYP3A4|
04705|075|D|inducer, and quetiapine increased oral clearance of quetiapine by 5-fold.(7)|
04705|076|D|   Agents that are linked to this monograph may have varying degrees of|
04705|077|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04705|078|D|been shown to prolong the QTc interval either through their mechanism of|
04705|079|D|action, through studies on their effects on the QTc interval, or through|
04705|080|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04705|081|D|and/or postmarketing reports.(8)|
04705|082|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04705|083|D|encorafenib and ivosidenib.(9)|
04705|084|B||
04705|085|R|REFERENCES:|
04705|086|B||
04705|087|R|1.Seroquel (quetiapine) US prescribing information. AstraZeneca|1
04705|088|R|  Pharmaceuticals LP September, 2020.|1
04705|089|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04705|090|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04705|091|R|  settings: a scientific statement from the American Heart Association and|6
04705|092|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04705|093|R|  2;55(9):934-47.|6
04705|094|R|3.Grimm SW, Richtand NM, Winter HR, Stams KR, Reele SB. Effects of|2
04705|095|R|  cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine|2
04705|096|R|  pharmacokinetics. Br J Clin Pharmacol 2006 Jan;61(1):58-69.|2
04705|097|R|4.Castberg I, Skogvoll E, Spigset O. Quetiapine and drug interactions:|2
04705|098|R|  evidence from a routine therapeutic drug monitoring service. J Clin|2
04705|099|R|  Psychiatry 2007 Oct;68(10):1540-5.|2
04705|100|R|5.Hasselstrom J, Linnet K. Quetiapine serum concentrations in psychiatric|2
04705|101|R|  patients: the influence of comedication. Ther Drug Monit 2004 Oct;|2
04705|102|R|  26(5):486-91.|2
04705|103|R|6.Nickl-Jockschat T, Paulzen M, Schneider F, Grozinger M. Drug interaction|3
04705|104|R|  can lead to undetectable serum concentrations of quetiapine in the|3
04705|105|R|  presence of carbamazepine. Clin Neuropharmacol 2009 Jan-Feb;32(1):55.|3
04705|106|R|7.Wong YW, Yeh C, Thyrum PT. The effects of concomitant phenytoin|2
04705|107|R|  administration on the steady-state pharmacokinetics of quetiapine. J Clin|2
04705|108|R|  Psychopharmacol 2001 Feb;21(1):89-93.|2
04705|109|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
04705|110|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04705|111|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04705|112|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04705|113|R|9.This information is based on an extract from the Certara Drug Interaction|6
04705|114|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04706|001|T|MONOGRAPH TITLE:  Tolterodine (>1 mg IR or >2 mg ER)/Levoketoconazole|
04706|002|B||
04706|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04706|004|L|of severe adverse interaction.|
04706|005|B||
04706|006|A|MECHANISM OF ACTION:  Levoketoconazole, a strong CYP3A4 inhibitor, may|
04706|007|A|inhibit the metabolism of tolterodine by CYP3A4.(1,2)|
04706|008|A|   Tolterodine has been observed to prolong the QTc interval.  Concurrent|
04706|009|A|use with other agents that prolong the QTc interval may result in additive|
04706|010|A|effects on the QTc interval.(1,2)|
04706|011|B||
04706|012|E|CLINICAL EFFECTS:  The concurrent administration of tolterodine with|
04706|013|E|levoketoconazole may result in elevated levels of tolterodine and signs of|
04706|014|E|toxicity, including potentially life-threatening cardiac arrhythmias.(1,2)|
04706|015|B||
04706|016|P|PREDISPOSING FACTORS:  Patients who are CYP2D6 poor metabolizers may be at|
04706|017|P|increased risk.(1,2)|
04706|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04706|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04706|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04706|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04706|022|P|advanced age.(3)|
04706|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04706|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04706|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04706|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04706|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04706|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04706|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04706|030|P|   The risk of anticholinergic toxicities including cognitive decline,|
04706|031|P|delirium, falls and fractures is increased in geriatric patients using more|
04706|032|P|than one medicine with anticholinergic properties.(4)|
04706|033|B||
04706|034|M|PATIENT MANAGEMENT:  The manufacturer of tolterodine recommends that a|
04706|035|M|maximum tolterodine dosage of 1 mg twice daily of the non extended release|
04706|036|M|dosage form(1) or 2 mg once daily of the extended release dosage form(2) be|
04706|037|M|used in patients receiving concurrent therapy with strong CYP3A4 inhibitors.|
04706|038|M|   The manufacturer of tolterodine states concurrent use agents known to|
04706|039|M|prolong the QT interval should be used with caution.  Consider close|
04706|040|M|observation in patients with a known history of QT prolongation or patients|
04706|041|M|taking antiarrhythmic medications.(1,2)|
04706|042|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04706|043|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04706|044|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04706|045|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04706|046|B||
04706|047|D|DISCUSSION:  In a study in eight subjects who were deficient in CYP2D6, the|
04706|048|D|concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg|
04706|049|D|once daily for four days), another inhibitor of CYP3A4, resulted in a 60%|
04706|050|D|decrease in tolterodine clearance.(6)  Tolterodine AUC and Cmax increased|
04706|051|D|2.5-fold and 2-fold, respectively.(2)|
04706|052|D|   In a study of the effect of tolterodine immediate release tablets, the|
04706|053|D|effect on the QT interval appeared greater for 8 mg/day (two times the|
04706|054|D|therapeutic dose) compared to 4 mg/day.  Tolterodine 2 mg BID and|
04706|055|D|tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and|
04706|056|D|11.84 msec (7.11-16.58 msec), respectively.  The change in QT interval was|
04706|057|D|more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers|
04706|058|D|(EMs).(7,8)|
04706|059|B||
04706|060|R|REFERENCES:|
04706|061|B||
04706|062|R|1.Detrol (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
04706|063|R|  August, 2012.|1
04706|064|R|2.Detrol LA (tolterodine tartrate) US prescribing information. Pfizer Inc.|1
04706|065|R|  July, 2018.|1
04706|066|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04706|067|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04706|068|R|  settings: a scientific statement from the American Heart Association and|6
04706|069|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04706|070|R|  2;55(9):934-47.|6
04706|071|R|4.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04706|072|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04706|073|R|  Soc 2023 Jul;71(7):2052-2081.|6
04706|074|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04706|075|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04706|076|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04706|077|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04706|078|R|6.Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole|2
04706|079|R|  inhibits the metabolism of tolterodine in subjects with deficient CYP2D6|2
04706|080|R|  activity. Br J Clin Pharmacol 1999 Oct;48(4):564-72.|2
04706|081|R|7.This information is based on an extract from the Certara Drug Interaction|6
04706|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04706|083|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
04706|084|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04706|085|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04706|086|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04706|087|R|  11/14/2017.|1
04707|001|T|MONOGRAPH TITLE:  Simvastatin (Greater Than 20 mg)/Avacopan|
04707|002|B||
04707|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04707|004|L|is contraindicated and generally should not be dispensed or administered to|
04707|005|L|the same patient.|
04707|006|B||
04707|007|A|MECHANISM OF ACTION:  Avacopan is a moderate CYP3A4 inhibitor and may|
04707|008|A|decrease the metabolism of simvastatin.(1)|
04707|009|B||
04707|010|E|CLINICAL EFFECTS:  Concurrent avacopan may result in elevated levels of|
04707|011|E|simvastatin, which may result in myopathy and rhabdomyolysis.(1)|
04707|012|B||
04707|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04707|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04707|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04707|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04707|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04707|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04707|019|P|predisposed to myopathy or rhabdomyolysis.|
04707|020|B||
04707|021|M|PATIENT MANAGEMENT:  When used concurrently with simvastatin, limit the dose|
04707|022|M|of simvastatin to 10 mg daily (or 20 mg daily for patients who have|
04707|023|M|previously tolerated simvastatin 80 mg daily for at least one year.)(1)|
04707|024|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04707|025|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04707|026|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04707|027|M|urine, and/or discolored urine.|
04707|028|B||
04707|029|D|DISCUSSION:  In a study, avacopan 60 mg twice daily with food was|
04707|030|D|administered for 7 days with simvastatin.  Since it takes 13 weeks to reach|
04707|031|D|steady state, this high dose of avacopan was used to achieve systemic levels|
04707|032|D|similar to those achieved at steady state with a dose of 30 mg twice daily|
04707|033|D|with food.  Avacopan increased the area-under-curve (AUC) and maximum|
04707|034|D|concentration (Cmax) of simvastatin by 3.53-fold and 3.20-fold,|
04707|035|D|respectively.(1)|
04707|036|B||
04707|037|R|REFERENCE:|
04707|038|B||
04707|039|R|1.Tavneos (avacopan) US prescribing information. ChemoCentryx, Inc. June,|1
04707|040|R|  2024.|1
04708|001|T|MONOGRAPH TITLE:  Simvastatin (Less Than or Equal To 20 mg)/Avacopan|
04708|002|B||
04708|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04708|004|L|take action as needed.|
04708|005|B||
04708|006|A|MECHANISM OF ACTION:  Avacopan is a moderate CYP3A4 inhibitor and may|
04708|007|A|decrease the metabolism of simvastatin.(1)|
04708|008|B||
04708|009|E|CLINICAL EFFECTS:  Concurrent avacopan may result in elevated levels of|
04708|010|E|simvastatin, which may result in myopathy and rhabdomyolysis.(1)|
04708|011|B||
04708|012|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04708|013|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04708|014|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04708|015|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04708|016|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04708|017|P|transporter OATP1B1 may have increased statin concentrations and be|
04708|018|P|predisposed to myopathy or rhabdomyolysis.|
04708|019|B||
04708|020|M|PATIENT MANAGEMENT:  When used concurrently with simvastatin, limit the dose|
04708|021|M|of simvastatin to 10 mg daily (or 20 mg daily for patients who have|
04708|022|M|previously tolerated simvastatin 80 mg daily for at least one year.)(1)|
04708|023|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04708|024|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04708|025|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04708|026|M|urine, and/or discolored urine.|
04708|027|B||
04708|028|D|DISCUSSION:  In a study, avacopan 60 mg twice daily with food was|
04708|029|D|administered for 7 days with simvastatin.  Since it takes 13 weeks to reach|
04708|030|D|steady state, this high dose of avacopan was used to achieve systemic levels|
04708|031|D|similar to those achieved at steady state with a dose of 30 mg twice daily|
04708|032|D|with food.  Avacopan increased the area-under-curve (AUC) and maximum|
04708|033|D|concentration (Cmax) of simvastatin by 3.53-fold and 3.20-fold,|
04708|034|D|respectively.(1)|
04708|035|B||
04708|036|R|REFERENCE:|
04708|037|B||
04708|038|R|1.Tavneos (avacopan) US prescribing information. ChemoCentryx, Inc. June,|1
04708|039|R|  2024.|1
04709|001|T|MONOGRAPH TITLE:  Elagolix/Voclosporin|
04709|002|B||
04709|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04709|004|L|is contraindicated and generally should not be dispensed or administered to|
04709|005|L|the same patient.|
04709|006|B||
04709|007|A|MECHANISM OF ACTION:  Strong inhibitors of OATP1B1 such as voclosporin may|
04709|008|A|decrease the hepatic uptake of elagolix.(1,2)  Moderate CYP3A4 inducers such|
04709|009|A|as elagolix may increase the metabolism of voclosporin.(3)|
04709|010|B||
04709|011|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of OATP1B1 may result in|
04709|012|E|elevated levels of and side effects from elagolix, including an increased|
04709|013|E|risk of ALT elevations.(1)  Concurrent use of a moderate CYP3A4 inducer may|
04709|014|E|decrease the serum levels and effectiveness of voclosporin.(3)|
04709|015|B||
04709|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04709|017|P|of the inducer for longer than 1-2 weeks.|
04709|018|B||
04709|019|M|PATIENT MANAGEMENT:  Concurrent use of elagolix and voclosporin is|
04709|020|M|contraindicated.(1)|
04709|021|B||
04709|022|D|DISCUSSION:  Single-dose rifampin 600 mg (an OATP1B1 inhibitor) increased|
04709|023|D|the maximum concentration (Cmax) and area-under-curve (AUC)of elagolix by|
04709|024|D|4.37-fold and 5.58-fold, respectively.(1)|
04709|025|D|   Concurrent use of voclosporin with rifampin 600 mg daily for 10 days|
04709|026|D|(strong CYP3A4 inducer) decreased the Cmax and AUC of voclosporin by 68% and|
04709|027|D|87%, respectively.(3)|
04709|028|B||
04709|029|R|REFERENCES:|
04709|030|B||
04709|031|R|1.Orilissa (elagolix) US prescribing information. AbbVie Inc. February,|1
04709|032|R|  2021.|1
04709|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04709|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04709|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04709|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04709|037|R|  11/14/2017.|1
04709|038|R|3.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
04709|039|R|  April, 2024.|1
04710|001|T|MONOGRAPH TITLE:  Voclosporin/Letermovir|
04710|002|B||
04710|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04710|004|L|of severe adverse interaction.|
04710|005|B||
04710|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors such as letermovir may|
04710|007|A|inhibit the metabolism of voclosporin.  OATP1B1-1B3 inhibitors such as|
04710|008|A|voclosporin may decrease hepatic uptake and increase the plasma|
04710|009|A|concentration of letermovir.(1,2)|
04710|010|B||
04710|011|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04710|012|E|levels of and effects from voclosporin, including infection, neurotoxicity,|
04710|013|E|nephrotoxicity, hypertension, or hyperkalemia.(1)|
04710|014|E|   Concurrent use of OATP1B1-1B3 inhibitors may result in elevated levels of|
04710|015|E|and side effects from letermovir, including diarrhea, nausea, abdominal|
04710|016|E|pain, and peripheral edema.(2)|
04710|017|B||
04710|018|P|PREDISPOSING FACTORS:  None determined.|
04710|019|B||
04710|020|M|PATIENT MANAGEMENT:  The prescribing information for voclosporin states the|
04710|021|M|use of moderate CYP3A4 inhibitors in patients undergoing therapy with|
04710|022|M|voclosporin requires a dose adjustment.  Voclosporin dose should be reduced|
04710|023|M|to 15.8 mg in the morning and 7.9 mg in the evening.(1)  Consider|
04710|024|M|alternatives with no or minimal enzyme inhibition.|
04710|025|M|   The prescribing information for letermovir states that concurrent|
04710|026|M|OATP1B1-1B3 inhibitors should be used with caution.  Monitor patients|
04710|027|M|closely for adverse reactions and consider dose modifications per|
04710|028|M|prescribing information.(2)|
04710|029|B||
04710|030|D|DISCUSSION:  Concurrent use of voclosporin and ketoconazole 400 mg daily|
04710|031|D|(strong CYP3A4 inhibitor) for 9 days increased the maximum concentration|
04710|032|D|(Cmax) and area-under-curve (AUC) of voclosporin by 6.45-fold and|
04710|033|D|18.55-fold, respectively.(1)|
04710|034|D|   Concurrent use of voclosporin and verapamil 80 mg three times a day for|
04710|035|D|10 days (moderate CYP3A4 inhibitor and P-gp inhibitor) increased Cmax and|
04710|036|D|AUC of voclosporin by 2.08-fold and 2.71-fold, respectively.(1)|
04710|037|D|   Letermovir is a substrate of OATP1B1 and 1B3. Co-administration of|
04710|038|D|letermovir with drugs that are inhibitors of OATP1B1-1B3 transporters may|
04710|039|D|result in increases in letermovir plasma concentrations.  Single-dose|
04710|040|D|rifampin 600 mg (an OATP1B1 inhibitor) increased the Cmax and AUC of|
04710|041|D|letermovir by 1.59-fold and 2.03-fold, respectively.(2)|
04710|042|B||
04710|043|R|REFERENCES:|
04710|044|B||
04710|045|R|1.Lupkynis (voclosporin) US prescribing information. Aurinia Pharmaceuticals|1
04710|046|R|  April, 2024.|1
04710|047|R|2.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
04710|048|R|  2024.|1
04710|049|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04710|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04710|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04710|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04710|053|R|  11/14/2017.|1
04710|054|R|4.This information is based on an extract from the Certara Drug Interaction|6
04710|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04711|001|T|MONOGRAPH TITLE:  Letermovir/Simeprevir|
04711|002|B||
04711|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04711|004|L|of severe adverse interaction.|
04711|005|B||
04711|006|A|MECHANISM OF ACTION:  OATP1B1 and 1B3 inhibitors such as simeprevir may|
04711|007|A|decrease the hepatic uptake and increase the plasma concentration of|
04711|008|A|letermovir.(1)  Moderate CYP3A4 inhibitors such as letermovir may slow down|
04711|009|A|the metabolism of simeprevir.(2)|
04711|010|B||
04711|011|E|CLINICAL EFFECTS:  Concurrent use of OATP1B1 and 1B3 inhibitors may result|
04711|012|E|in elevated levels of and side effects from letermovir, including diarrhea,|
04711|013|E|nausea, abdominal pain, and peripheral edema.(1)  Concurrent use of strong|
04711|014|E|or moderate CYP3A4 inhibitors may result in elevated levels of and toxicity|
04711|015|E|from simeprevir.(2)|
04711|016|B||
04711|017|P|PREDISPOSING FACTORS:  None determined.|
04711|018|B||
04711|019|M|PATIENT MANAGEMENT:  The US manufacturer of simeprevir states that|
04711|020|M|concurrent administration of strong or moderate inhibitors of CYP3A4 is not|
04711|021|M|recommended due to risk of toxicity.(2)|
04711|022|M|   Concurrent use of letermovir with OATP1B1 and 1B3 inhibitors should be|
04711|023|M|approached with caution.  Monitor patients closely for adverse reactions and|
04711|024|M|consider dose modifications per prescribing recommendations.(1)|
04711|025|B||
04711|026|D|DISCUSSION:  Letermovir is a substrate of OATP1B1 and 1B3. Co-administration|
04711|027|D|of letermovir with drugs that are inhibitors of OATP1B1-1B3 transporters may|
04711|028|D|result in increases in letermovir plasma concentrations.  Single-dose|
04711|029|D|rifampin 600 mg (an OATP1B1 inhibitor) increased the Cmax and AUC of|
04711|030|D|letermovir by 1.59-fold and 2.03-fold, respectively.(1)|
04711|031|D|   In a study in 24 subjects, erythromycin (500 mg TID for 7 days) increased|
04711|032|D|the maximum concentration (Cmax), area-under-curve (AUC) and Cmin of|
04711|033|D|simeprevir (150 mg daily for 7 days) by 4.53-fold, 7.47-fold, and|
04711|034|D|12.74-fold, respectively.  The Cmax and AUC of erythromycin increased by|
04711|035|D|1.59-fold and 1.39-fold, respectively.(2)|
04711|036|B||
04711|037|R|REFERENCES:|
04711|038|B||
04711|039|R|1.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
04711|040|R|  2024.|1
04711|041|R|2.Olysio (simeprevir) US prescribing information. Janssen Products, LP|1
04711|042|R|  November, 2017.|1
04711|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
04711|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04712|001|T|MONOGRAPH TITLE:  Tramadol/Methylphenidate|
04712|002|B||
04712|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04712|004|L|take action as needed.|
04712|005|B||
04712|006|A|MECHANISM OF ACTION:  Opioids and methylphenidate exhibit opposing effects|
04712|007|A|on the CNS.(1)|
04712|008|B||
04712|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and methylphenidate may have|
04712|010|E|unpredictable effects and may mask overdose symptoms of the opioid, such as|
04712|011|E|drowsiness and inability to focus.|
04712|012|B||
04712|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04712|014|P|may increase the risk of adverse effects.|
04712|015|B||
04712|016|M|PATIENT MANAGEMENT:  Limit prescribing tramadol with CNS stimulants such as|
04712|017|M|methylphenidate to patients for whom alternatives are ineffective, not|
04712|018|M|tolerated, or would be otherwise inadequate to provide sufficient management|
04712|019|M|of pain.  Concurrent use of methylphenidate with tramadol should be|
04712|020|M|approached with appropriate monitoring.|
04712|021|M|    If concurrent use is necessary, limit the dosages and duration of each|
04712|022|M|drug to the minimum possible while achieving the desired clinical effect.|
04712|023|M|   Respiratory depression can occur at any time during opioid therapy,|
04712|024|M|especially during therapy initiation and following dosage increases.  The|
04712|025|M|risk of opioid-related overdose or overdose-related death is increased with|
04712|026|M|higher opioid doses, and this risk persists over the course of therapy.|
04712|027|M|Consider these risks when using concurrently with other agents that may|
04712|028|M|cause CNS depression.(1)|
04712|029|M|   Monitor patients receiving concurrent therapy for signs of substance|
04712|030|M|abuse. Monitor patients receiving concurrent therapy for unusual dizziness|
04712|031|M|or lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04712|032|M|unresponsiveness.|
04712|033|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04712|034|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04712|035|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04712|036|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04712|037|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04712|038|M|as those taking CNS depressants) and when a patient has household|
04712|039|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04712|040|M|for obtaining an opioid reversal agent (e.g., prescription,|
04712|041|M|over-the-counter, or as part of a community-based program).|
04712|042|B||
04712|043|D|DISCUSSION:  A total of 70,237 persons died from drug overdoses in the|
04712|044|D|United States in 2017; approximately two thirds of these deaths involved an|
04712|045|D|opioid.(2).  The CDC analyzed 2016-2017 changes in age-adjusted death rates|
04712|046|D|involving cocaine and psychostimulants by demographic characteristics,|
04712|047|D|urbanization levels, U.S. Census region, 34 states, and the District of|
04712|048|D|Columbia (DC).  The CDC also examined trends in age-adjusted|
04712|049|D|cocaine-involved and psychostimulant-involved death rates from 2003 to 2017|
04712|050|D|overall, as well as with and without co-involvement of opioids.  Among all|
04712|051|D|2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333|
04712|052|D|(14.7%) involved psychostimulants.  Death rates increased from 2016 to 2017|
04712|053|D|for both drug categories across demographic characteristics, urbanization|
04712|054|D|levels, Census regions, and states.  In 2017, opioids were involved in 72.7%|
04712|055|D|and 50.4% of cocaine-involved and psychostimulant-involved overdoses,|
04712|056|D|respectively, and the data suggest that increases in cocaine-involved|
04712|057|D|overdose deaths from 2012 to 2017 were driven primarily by synthetic|
04712|058|D|opioids.(3)|
04712|059|D|   There was opioid co-involvement in 72.7 percent of cocaine and 50.4|
04712|060|D|percent of stimulant-involved overdose deaths.  This was largely driven by|
04712|061|D|synthetic opioids such as fentanyl. However, stimulant-involved overdose|
04712|062|D|without opioid co-involvement is also increasing.(2)|
04712|063|B||
04712|064|R|REFERENCES:|
04712|065|B||
04712|066|R|1.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04712|067|R|  prescribing information for all opioid pain medicines to provide|1
04712|068|R|  additional guidance for safe use. Available at:|1
04712|069|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04712|070|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04712|071|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04712|072|R|2.Seth P, Scholl L, Rudd RA, Bacon S. Overdose Deaths Involving Opioids,|6
04712|073|R|  Cocaine, and Psychostimulants - United States, 2015-2016. MMWR Morb Mortal|6
04712|074|R|  Wkly Rep 2018 Mar 30;67(12):349-358.|6
04712|075|R|3.Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved|6
04712|076|R|  Overdose Deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep 2018|6
04712|077|R|  Jan 4;67(5152):1419-1427.|6
04713|001|T|MONOGRAPH TITLE:  Procainamide/MATE Inhibitors that Prolong QT|
04713|002|B||
04713|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04713|004|L|take action as needed.|
04713|005|B||
04713|006|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
04713|007|A|protein transporters in the kidneys may interfere with the renal elimination|
04713|008|A|of procainamide and its active metabolite, N-acetylprocainamide (NAPA).|
04713|009|A|   MATE inhibitors that prolong the QTc interval may result in additive risk|
04713|010|A|of QT prolongation.|
04713|011|B||
04713|012|E|CLINICAL EFFECTS:  The pharmacological and toxic effects of procainamide and|
04713|013|E|NAPA may be increased, including potentially life-threatening cardiac|
04713|014|E|arrhythmias, like torsades de pointes (TdP).|
04713|015|B||
04713|016|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
04713|017|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
04713|018|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
04713|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
04713|020|P|concurrent use of agents known to cause QT prolongation.|
04713|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04713|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04713|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04713|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04713|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04713|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04713|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).|
04713|028|B||
04713|029|M|PATIENT MANAGEMENT:  Monitor serum procainamide and NAPA concentrations and|
04713|030|M|observe the patients for signs of toxicity.|
04713|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04713|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04713|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04713|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04713|035|B||
04713|036|D|DISCUSSION:  Administration of trimethoprim to patients receiving|
04713|037|D|procainamide produced an increase in the area under the concentration-time|
04713|038|D|curve and a decrease in the clearance of procainamide. At the same time,|
04713|039|D|serum NAPA concentrations and clearance were decreased.|
04713|040|D|   MATE inhibitors that prolong the QTc interval include: vandetanib.(4)|
04713|041|B||
04713|042|R|REFERENCES:|
04713|043|B||
04713|044|R|1.Kosoglou T, Rocci ML Jr, Vlasses PH. Trimethoprim alters the disposition|2
04713|045|R|  of procainamide and N- acetylprocainamide. Clin Pharmacol Ther 1988 Oct;|2
04713|046|R|  44(4):467-77.|2
04713|047|R|2.Vlasses PH, Kosoglou T, Chase SL, Greenspon AJ, Lottes S, Andress E,|2
04713|048|R|  Ferguson RK, Rocci ML Jr. Trimethoprim inhibition of the renal clearance|2
04713|049|R|  of procainamide and N- acetylprocainamide. Arch Intern Med 1989 Jun;|2
04713|050|R|  149(6):1350-3.|2
04713|051|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04713|052|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04713|053|R|  settings: a scientific statement from the American Heart Association and|6
04713|054|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04713|055|R|  2;55(9):934-47.|6
04713|056|R|4.This information is based on an extract from the Certara Drug Interaction|6
04713|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04714|001|T|MONOGRAPH TITLE:  Valbenazine (Greater Than 40 mg)/Mavorixafor|
04714|002|B||
04714|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04714|004|L|is contraindicated and generally should not be dispensed or administered to|
04714|005|L|the same patient.|
04714|006|B||
04714|007|A|MECHANISM OF ACTION:  Valbenazine's active metabolite (alpha-HTBZ) is|
04714|008|A|metabolized by CYP2D6 and CYP3A4.(1)  Mavorixafor is a strong CYP2D6|
04714|009|A|inhibitor.(2)|
04714|010|A|   Mavorixafor is a substrate of P-glycoprotein (P-gp).(2) Valbenazine is a|
04714|011|A|P-gp inhibitor.(1)|
04714|012|B||
04714|013|E|CLINICAL EFFECTS:  Concurrent use of valbenazine with a strong CYP2D6|
04714|014|E|inhibitor may result in elevated levels and adverse effects of valbenazine|
04714|015|E|such as somnolence and QT prolongation.(1)|
04714|016|E|   Concurrent use of mavorixafor with an inhibitor of P-glycoprotein may|
04714|017|E|result in elevated levels of and effects from mavorixafor, including|
04714|018|E|potentially life-threatening cardiac arrhythmias, torsades de pointes, and|
04714|019|E|sudden death.(1)|
04714|020|B||
04714|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04714|022|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04714|023|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04714|024|P|syndrome, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04714|025|P|gender, or advanced age.(5)|
04714|026|P|   Concurrent use of more more than one drug known to cause QT prolongation|
04714|027|P|or higher systemic concentrations of either QT prolonging drug are|
04714|028|P|additional risk factors for torsade de pointes. Factors which may increase|
04714|029|P|systemic drug concentrations include rapid infusion of an intravenous dose|
04714|030|P|or impaired metabolism or elimination of the drug (e.g. coadministration|
04714|031|P|with an agent which inhibits its own metabolism or elimination, genetic|
04714|032|P|impairment in drug metabolism or elimination, and/or renal/hepatic|
04714|033|P|dysfunction.(5)|
04714|034|P|   Concurrent use of strong CYP3A4 inhibitors may further increase levels of|
04714|035|P|valbenazine.(1)|
04714|036|B||
04714|037|M|PATIENT MANAGEMENT:  Reduce the valbenazine dose to 40 mg once daily when|
04714|038|M|valbenazine is coadministered with a strong CYP2D6 inhibitor.(1)|
04714|039|M|   When used mavorixafor is used concomitantly with P-gp inhibitors, monitor|
04714|040|M|more frequently for mavorixafor adverse effects and reduce the dose in 100|
04714|041|M|mg increments, if necessary, but not to a dose less than 200 mg.(2)|
04714|042|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
04714|043|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04714|044|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04714|045|M|report any irregular heartbeat, dizziness, or fainting.|
04714|046|B||
04714|047|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
04714|048|D|coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine|
04714|049|D|did not affect valbenazine maximum concentration (Cmax) or|
04714|050|D|area-under-the-curve (AUC).  However, Cmax and AUC for the active metabolite|
04714|051|D|of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold,|
04714|052|D|respectively.(1)|
04714|053|D|   In a study with healthy subjects, itraconazole 200 mg daily (a strong|
04714|054|D|CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor|
04714|055|D|200 mg similar to that from single-dose mavorixafor 400 mg alone. This|
04714|056|D|suggests that itraconazole increased mavorixafor exposure by about|
04714|057|D|2-fold.(1)|
04714|058|B||
04714|059|R|REFERENCES:|
04714|060|B||
04714|061|R|1.Ingrezza (valbenazine) US prescribing information. Neurocrine Biosciences,|1
04714|062|R|  Inc. April, 2020.|1
04714|063|R|2.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04714|064|R|  Inc. April, 2024.|1
04714|065|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04714|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04714|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04714|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04714|069|R|  11/14/2017.|1
04714|070|R|4.This information is based on an extract from the Certara Drug Interaction|6
04714|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04714|072|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04714|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04714|074|R|  settings: a scientific statement from the American Heart Association and|6
04714|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04714|076|R|  2;55(9):934-47.|6
04715|001|T|MONOGRAPH TITLE:  Valbenazine (Less Than or Equal to 40 mg)/Mavorixafor|
04715|002|B||
04715|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04715|004|L|take action as needed.|
04715|005|B||
04715|006|A|MECHANISM OF ACTION:  Valbenazine's active metabolite (alpha-HTBZ) is|
04715|007|A|metabolized by CYP2D6 and CYP3A4.(1)  Mavorixafor is a strong CYP2D6|
04715|008|A|inhibitor.(2)|
04715|009|A|   Mavorixafor is a substrate of P-glycoprotein (P-gp).(2) Valbenazine is a|
04715|010|A|P-gp inhibitor.(1)|
04715|011|B||
04715|012|E|CLINICAL EFFECTS:  Concurrent use of valbenazine with a strong CYP2D6|
04715|013|E|inhibitor may result in elevated levels and adverse effects of valbenazine|
04715|014|E|such as somnolence and QT prolongation.(1)|
04715|015|E|   Concurrent use of mavorixafor with an inhibitor of P-glycoprotein may|
04715|016|E|result in elevated levels of and effects from mavorixafor, including|
04715|017|E|potentially life-threatening cardiac arrhythmias, torsades de pointes, and|
04715|018|E|sudden death.(1)|
04715|019|B||
04715|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04715|021|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04715|022|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04715|023|P|syndrome, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04715|024|P|gender, or advanced age.(5)|
04715|025|P|   Concurrent use of more more than one drug known to cause QT prolongation|
04715|026|P|or higher systemic concentrations of either QT prolonging drug are|
04715|027|P|additional risk factors for torsade de pointes. Factors which may increase|
04715|028|P|systemic drug concentrations include rapid infusion of an intravenous dose|
04715|029|P|or impaired metabolism or elimination of the drug (e.g. coadministration|
04715|030|P|with an agent which inhibits its own metabolism or elimination, genetic|
04715|031|P|impairment in drug metabolism or elimination, and/or renal/hepatic|
04715|032|P|dysfunction.(5)|
04715|033|P|   Concurrent use of strong CYP3A4 inhibitors may further increase levels of|
04715|034|P|valbenazine.(1)|
04715|035|B||
04715|036|M|PATIENT MANAGEMENT:  Reduce the valbenazine dose to 40 mg once daily when|
04715|037|M|valbenazine is coadministered with a strong CYP2D6 inhibitor.(1)|
04715|038|M|   When used mavorixafor is used concomitantly with P-gp inhibitors, monitor|
04715|039|M|more frequently for mavorixafor adverse effects and reduce the dose in 100|
04715|040|M|mg increments, if necessary, but not to a dose less than 200 mg.(2)|
04715|041|M|   When concurrent therapy is warranted, consider obtaining serum calcium,|
04715|042|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04715|043|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04715|044|M|report any irregular heartbeat, dizziness, or fainting.|
04715|045|B||
04715|046|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
04715|047|D|coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine|
04715|048|D|did not affect valbenazine maximum concentration (Cmax) or|
04715|049|D|area-under-the-curve (AUC).  However, Cmax and AUC for the active metabolite|
04715|050|D|of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold,|
04715|051|D|respectively.(1)|
04715|052|D|   In a study with healthy subjects, itraconazole 200 mg daily (a strong|
04715|053|D|CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor|
04715|054|D|200 mg similar to that from single-dose mavorixafor 400 mg alone. This|
04715|055|D|suggests that itraconazole increased mavorixafor exposure by about|
04715|056|D|2-fold.(1)|
04715|057|B||
04715|058|R|REFERENCES:|
04715|059|B||
04715|060|R|1.Ingrezza (valbenazine) US prescribing information. Neurocrine Biosciences,|1
04715|061|R|  Inc. April, 2020.|1
04715|062|R|2.Xolremdi (mavorixafor) US prescribing information. X4 Pharmaceuticals,|1
04715|063|R|  Inc. April, 2024.|1
04715|064|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04715|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04715|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04715|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04715|068|R|  11/14/2017.|1
04715|069|R|4.This information is based on an extract from the Certara Drug Interaction|6
04715|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04715|071|R|5.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04715|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04715|073|R|  settings: a scientific statement from the American Heart Association and|6
04715|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04715|075|R|  2;55(9):934-47.|6
04716|001|T|MONOGRAPH TITLE:  Elafibranor/Bile Acid Sequestrants|
04716|002|B||
04716|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04716|004|L|take action as needed.|
04716|005|B||
04716|006|A|MECHANISM OF ACTION:  Bile acid sequestrants may bind to elafibranor in the|
04716|007|A|gut, resulting in decreased absorption of elafibranor.(1)|
04716|008|B||
04716|009|E|CLINICAL EFFECTS:  Coadministration of bile acid sequestrants with|
04716|010|E|elafibranor may cause reduced efficacy of elafibranor.(1)|
04716|011|B||
04716|012|P|PREDISPOSING FACTORS:  None determined.|
04716|013|B||
04716|014|M|PATIENT MANAGEMENT:  The US manufacturer states to administer bile acid|
04716|015|M|sequestrants (cholestyramine, colesevelam, and colestipol) at least 4 hours|
04716|016|M|before or 4 hours after administration of elafibranor, or at as great an|
04716|017|M|interval as possible.(1)|
04716|018|B||
04716|019|D|DISCUSSION:  Bile acid sequestrants are known to bind to drugs when given|
04716|020|D|concurrently.  Administration with elafibranor may result in decreased|
04716|021|D|systemic absorption.(1)|
04716|022|B||
04716|023|R|REFERENCE:|
04716|024|B||
04716|025|R|1.Iqirvo (elafibranor) US prescribing information. Ipsen Biopharmaceuticals,|1
04716|026|R|  Inc. June, 2024.|1
04717|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Elafibranor|
04717|002|B||
04717|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04717|004|L|of severe adverse interaction.|
04717|005|B||
04717|006|A|MECHANISM OF ACTION:  Elafibranor is a weak CYP3A4 inducer.|
04717|007|A|Coadministration of elafibranor with hormonal contraceptives may lead to|
04717|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
04717|009|A|decreased hormonal concentrations.(1)|
04717|010|B||
04717|011|E|CLINICAL EFFECTS:  Concurrent use of elafibranor may reduce the|
04717|012|E|effectiveness of hormonal contraceptives.(1)|
04717|013|B||
04717|014|P|PREDISPOSING FACTORS:  None determined.|
04717|015|B||
04717|016|M|PATIENT MANAGEMENT:  Avoid concomitant use of hormonal contraceptives with|
04717|017|M|elafibranor.  Advise females of reproductive potential to use effective|
04717|018|M|non-hormonal contraception (e.g., non-hormonal intrauterine system) or|
04717|019|M|additional non-hormonal contraceptive (e.g., condoms) during treatment with|
04717|020|M|elafibranor and for 21 days after the last dose.|
04717|021|M|   Women of reproductive age should be counseled not to rely on hormonal|
04717|022|M|contraceptives (including oral contraceptives, patches, implants, and/or|
04717|023|M|IUDs) for contraception.(1)|
04717|024|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04717|025|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04717|026|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04717|027|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
04717|028|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
04717|029|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
04717|030|M|and to seek medical advice if she does become pregnant.(2)|
04717|031|B||
04717|032|D|DISCUSSION:  Elafibranor is a weak CYP3A4 inducer.(1)|
04717|033|D|   Coadministration of elafibranor with simvastatin (a CYP3A, OATP1B1, and|
04717|034|D|OATP1B3 substrate) decreased the concentration maximum (Cmax) and|
04717|035|D|area-under-curve (AUC) of simvastatin beta-hydroxyacid by 26% and 32%,|
04717|036|D|respectively.(1)|
04717|037|B||
04717|038|R|REFERENCES:|
04717|039|B||
04717|040|R|1.Iqirvo (elafibranor) US prescribing information. Ipsen Biopharmaceuticals,|1
04717|041|R|  Inc. June, 2024.|1
04717|042|R|2.Medicines and Healthcare products Regulatory Agency.|1
04717|043|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04717|044|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04717|045|R|  available at:|1
04717|046|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04717|047|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04717|048|R|  -and-contraceptive-efficacy September 15, 2016..|1
04718|001|T|MONOGRAPH TITLE:  Crizotinib/OCT2 Inhibitors (mono deleted 08/06/2024)|
04718|002|B||
04718|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04718|004|L|take action as needed.|
04718|005|B||
04718|006|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
04718|007|A|(OCT2) may inhibit the excretion of crizotinib by OCT2 in the kidneys.(1)|
04718|008|B||
04718|009|E|CLINICAL EFFECTS:  Concurrent use of OCT2 renal transport inhibitors may|
04718|010|E|result in increased levels of and toxicity from crizotinib, including|
04718|011|E|myelosuppression and potentially life-threatening cardiac arrhythmias,|
04718|012|E|including torsades de pointes (TdP).(1,2)|
04718|013|B||
04718|014|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
04718|015|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
04718|016|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
04718|017|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
04718|018|P|concurrent use of agents known to cause QT prolongation.(2)|
04718|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04718|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04718|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04718|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04718|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04718|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04718|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04718|026|B||
04718|027|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
04718|028|M|concurrent use of crizotinib with OCT2 renal transport inhibitors.  If|
04718|029|M|concurrent use is appropriate, monitor for toxicities of crizotinib and|
04718|030|M|consider dosage reduction.(1)|
04718|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04718|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04718|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04718|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04718|035|B||
04718|036|D|DISCUSSION:  In a study, givinostat increased the levels of creatinine (OCT2|
04718|037|D|substrate) by 4.76 umol/L from baseline.(1)|
04718|038|D|   Selected OCT2 inhibitors linked include: givinostat.|
04718|039|B||
04718|040|R|REFERENCES:|
04718|041|B||
04718|042|R|1.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
04718|043|R|  March, 2024.|1
04718|044|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04718|045|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04718|046|R|  settings: a scientific statement from the American Heart Association and|6
04718|047|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04718|048|R|  2;55(9):934-47.|6
04719|001|T|MONOGRAPH TITLE:  Oxaliplatin/OCT2 Inhibitors|
04719|002|B||
04719|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04719|004|L|take action as needed.|
04719|005|B||
04719|006|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
04719|007|A|(OCT2) may inhibit the excretion of oxaliplatin by OCT2 in the kidneys.(1)|
04719|008|B||
04719|009|E|CLINICAL EFFECTS:  Concurrent use of OCT2 renal transport inhibitors may|
04719|010|E|result in increased levels of and toxicity from oxaliplatin, including|
04719|011|E|myelosuppression and potentially life-threatening cardiac arrhythmias,|
04719|012|E|including torsades de pointes (TdP).(1)|
04719|013|B||
04719|014|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
04719|015|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
04719|016|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
04719|017|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
04719|018|P|concurrent use of agents known to cause QT prolongation.(2)|
04719|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04719|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04719|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04719|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04719|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04719|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04719|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04719|026|B||
04719|027|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
04719|028|M|concurrent use of oxaliplatin with OCT2 renal transport inhibitors.  If|
04719|029|M|concurrent use is appropriate, monitor for toxicities of oxaliplatin and|
04719|030|M|consider dosage reduction.(1)|
04719|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04719|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04719|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04719|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04719|035|B||
04719|036|D|DISCUSSION:  In a study, givinostat increased the levels of creatinine (OCT2|
04719|037|D|substrate) by 4.76 umol/L from baseline.(3)|
04719|038|D|   In a study, trilaciclib increased the area-under-curve (AUC) and maximum|
04719|039|D|concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by|
04719|040|D|approximately 65% and 81%, respectively.  Renal clearance of metformin was|
04719|041|D|decreased by 37%.  Trilaciclib did not cause significant changes in the|
04719|042|D|pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4)|
04719|043|D|   OCT2 inhibitors linked to this monograph include:  arimoclomol,|
04719|044|D|dolutegravir, givinostat, trilaciclib, and vimseltinib.(5)|
04719|045|B||
04719|046|R|REFERENCES:|
04719|047|B||
04719|048|R|1.Eloxatin (oxaliplatin) US prescribing information. Sanofi-Aventis U.S. LLC|1
04719|049|R|  October, 2015.|1
04719|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04719|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04719|052|R|  settings: a scientific statement from the American Heart Association and|6
04719|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04719|054|R|  2;55(9):934-47.|6
04719|055|R|3.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
04719|056|R|  March, 2024.|1
04719|057|R|4.Cosela (trilaciclib) US prescribing information. G1 Therapeutics, Inc.|1
04719|058|R|  February, 2021.|1
04719|059|R|5.This information is based on an extract from the Certara Drug Interaction|6
04719|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04720|001|T|MONOGRAPH TITLE:  Sulfonylureas/Amiodarone|
04720|002|B||
04720|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04720|004|L|take action as needed.|
04720|005|B||
04720|006|A|MECHANISM OF ACTION:  Amiodarone may decrease the metabolism of|
04720|007|A|sulfonylureas by inhibiting CYP2C9.  Amiodarone is a moderate CYP2C9|
04720|008|A|inhibitor.(1-5)|
04720|009|B||
04720|010|E|CLINICAL EFFECTS:  Increased effectiveness of the sulfonylurea which may|
04720|011|E|result in clinical symptoms of hypoglycemia.|
04720|012|B||
04720|013|P|PREDISPOSING FACTORS:  This interaction may be more likely in patients using|
04720|014|P|higher doses of amiodarone and who use amiodarone for greater than 180|
04720|015|P|days.(6)|
04720|016|B||
04720|017|M|PATIENT MANAGEMENT:  Closely monitor blood glucose levels during concurrent|
04720|018|M|therapy.  The dose of the sulfonylurea may need to be adjusted when|
04720|019|M|initiating or discontinuing amiodarone therapy.|
04720|020|B||
04720|021|D|DISCUSSION:  In a nested case control study, concurrent use of amiodarone|
04720|022|D|and sulfonylureas increased the risk of severe hypoglycemia by 56% (95%|
04720|023|D|CI:0.98-2.46).  In patients on sulfonylureas, amiodarone use greater than|
04720|024|D|180 days and at higher daily doses was associated with a 2.08-fold and a|
04720|025|D|2.21-fold increase in severe hypoglycemia, respectively, which was|
04720|026|D|statistically significant.(6)|
04720|027|B||
04720|028|R|REFERENCES:|
04720|029|B||
04720|030|R|1.Amaryl (glimepiride) US prescribing information. Sanofi-Aventis U.S. LLC|1
04720|031|R|  October, 2013.|1
04720|032|R|2.Glucotrol (glipizide) US prescribing information. Pfizer August, 2016.|1
04720|033|R|3.Diabeta (glyburide) US prescribing information. Sanofi-Aventis U.S. LLC|1
04720|034|R|  October, 2013.|1
04720|035|R|4.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
04720|036|R|  Pharmaceuticals October, 2018.|1
04720|037|R|5.This information is based on an extract from the Certara Drug Interaction|6
04720|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04720|039|R|6.Lai JH, Wang MT, Wu CC, Huang YL, Lu CH, Liou JT. Risk of severe|2
04720|040|R|  hypoglycemic events from amiodarone-sulfonylureas interactions: A|2
04720|041|R|  population-based nested case-control study. Pharmacoepidemiol Drug Saf|2
04720|042|R|  2020 Aug;29(8):842-853.|2
04721|001|T|MONOGRAPH TITLE:  Stiripentol/Strong CYP3A4 or CYP2C19 Inducers|
04721|002|B||
04721|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04721|004|L|of severe adverse interaction.|
04721|005|B||
04721|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 or CYP2C19 may increase the|
04721|007|A|metabolism of stiripentol.(1)|
04721|008|B||
04721|009|E|CLINICAL EFFECTS:  Concurrent use of a strong inducer of CYP3A4 or CYP2C19|
04721|010|E|may result in decreased levels and effectiveness of stiripentol.(1)|
04721|011|B||
04721|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04721|013|P|of the inducer for longer than 1-2 weeks.|
04721|014|B||
04721|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of stiripentol with strong|
04721|016|M|CYP3A4 or strong CYP2C19 inducers.|
04721|017|M|   If concurrent therapy cannot be avoided, consider a dose adjustment of|
04721|018|M|stiripentol based on clinical monitoring and plasma levels.(1)|
04721|019|B||
04721|020|D|DISCUSSION:  Stiripentol is a substrate of CYP3A4 and CYP2C19.(1)|
04721|021|D|   Strong CYP3A4 or CYP2C19 inducers include:  apalutamide, barbiturates,|
04721|022|D|enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin,|
04721|023|D|primidone, rifampin, rifapentine, and St. John's wort.(1-3)|
04721|024|B||
04721|025|R|REFERENCES:|
04721|026|B||
04721|027|R|1.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
04721|028|R|  March, 2007.|1
04721|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04721|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04721|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04721|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04721|033|R|  11/14/2017.|1
04721|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04721|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04722|001|T|MONOGRAPH TITLE:  Atorvastatin/Selected BCRP Inhibitors|
04722|002|B||
04722|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04722|004|L|of severe adverse interaction.|
04722|005|B||
04722|006|A|MECHANISM OF ACTION:  BCRP inhibitors may result in increased absorption of|
04722|007|A|atorvastatin.(1)|
04722|008|B||
04722|009|E|CLINICAL EFFECTS:  Administration of atorvastatin with BCRP inhibitors may|
04722|010|E|result in elevated levels of atorvastatin, which could result in|
04722|011|E|rhabdomyolysis.(1)|
04722|012|B||
04722|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04722|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04722|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04722|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04722|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04722|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04722|019|P|predisposed to myopathy or rhabdomyolysis.|
04722|020|B||
04722|021|M|PATIENT MANAGEMENT:  Atorvastatin is a substrate of the efflux transporter|
04722|022|M|BCRP.(1)|
04722|023|M|   The US manufacturers of darolutamide and leniolisib recommend avoiding|
04722|024|M|concurrent use with BCRP substrates such as atorvastatin.(2,3)|
04722|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04722|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04722|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04722|028|M|urine, and/or discolored urine.(2)|
04722|029|B||
04722|030|D|DISCUSSION:  Concurrent administration of darolutamide with rosuvastatin|
04722|031|D|increased the mean area-under-the-curve (AUC) and maximum concentration|
04722|032|D|(Cmax) of rosuvastatin approximately 5-fold.(2)  The study authors found|
04722|033|D|that darolutamide has no effect on total or renal clearance of rosuvastatin|
04722|034|D|and thus no likely effect on OATP or OAT3, which suggests the increase in|
04722|035|D|rosuvastatin plasma concentrations is due to BCRP inhibition.(4)|
04722|036|D|   Concurrent administration of leniolisib with rosuvastatin increased the|
04722|037|D|systemic exposure of rosuvastatin by 2-fold.(3)|
04722|038|D|   BCRP inhibitors linked to this monograph include:  darolutamide and|
04722|039|D|leniolisib.(5,6)|
04722|040|B||
04722|041|R|REFERENCES:|
04722|042|B||
04722|043|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
04722|044|R|  2020.|1
04722|045|R|2.Nubeqa (darolutamide) US prescribing information. Bayer Healthcare|1
04722|046|R|  Pharmaceuticals, Inc. August, 2022.|1
04722|047|R|3.Joenja (leniolisib) US prescribing information. Pharming Healthcare Inc.|1
04722|048|R|  May, 2025.|1
04722|049|R|4.Zurth C,  Koskinen M,  Fricke R,  Prien O,  Korjamo T,  Graudenz K,|2
04722|050|R|  Denner K,  Bairlein M,  von Buhler CJ,  Wilkinson G,  Gieschen H.|2
04722|051|R|  Drug-drug interaction potential of darolutamide: in vitro and clinical|2
04722|052|R|  studies. Eur J Drug Metab Pharmacokinet Dec 2019;44(6):747-759.|2
04722|053|R|5.This information is based on an extract from the Certara Drug Interaction|6
04722|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04722|055|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04722|056|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04722|057|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04722|058|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04722|059|R|  11/14/2017.|1
04723|001|T|MONOGRAPH TITLE:  Ravidasvir/P-glycoprotein (P-gp) Inducers; Phenobarbital|
04723|002|B||
04723|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04723|004|L|is contraindicated and generally should not be dispensed or administered to|
04723|005|L|the same patient.|
04723|006|B||
04723|007|A|MECHANISM OF ACTION:  Inducers of P-glycoprotein (P-gp) may decrease the|
04723|008|A|absorption of ravidasvir.(1)|
04723|009|B||
04723|010|E|CLINICAL EFFECTS:  Concurrent or recent use of a P-gp inducer may result in|
04723|011|E|decreased levels and effectiveness of ravidasvir.(1)|
04723|012|B||
04723|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04723|014|P|of the inducer for longer than 1-2 weeks.|
04723|015|B||
04723|016|M|PATIENT MANAGEMENT:  The manufacturer of ravidasvir states concurrent use|
04723|017|M|with P-gp inducers is contraindicated.(1)|
04723|018|B||
04723|019|D|DISCUSSION:  Interaction studies with P-gp inducers have not been performed.|
04723|020|D|Co-administration with potent inducers of P-gp are expected to decrease|
04723|021|D|ravidasvir plasma concentrations and result in therapeutic failure.(1)|
04723|022|D|   Agents linked to this monograph include apalutamide, carbamazepine,|
04723|023|D|fosphenytoin, green tea, lorlatinib, phenobarbital, phenytoin, primidone,|
04723|024|D|quercetin, rifabutin, rifampin, and St. John's wort.(1-3)|
04723|025|B||
04723|026|R|REFERENCES:|
04723|027|B||
04723|028|R|1.Ravida (ravidasvir) Malaysia Prescribing Information. European Egyptian|1
04723|029|R|  Pharmaceutical Industries Co. Jan 20, 2024.|1
04723|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04723|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04723|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04723|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04723|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04723|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04723|036|R|  11/14/2017.|1
04724|001|T|MONOGRAPH TITLE:  Ravidasvir/Antacids|
04724|002|B||
04724|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04724|004|L|take action as needed.|
04724|005|B||
04724|006|A|MECHANISM OF ACTION:  Absorption of ravidasvir may be reduced in patients|
04724|007|A|receiving concomitant treatment with acid reducing agents.(1)|
04724|008|B||
04724|009|E|CLINICAL EFFECTS:  Administration of antacids may reduce the bioavailability|
04724|010|E|of ravidasvir, leading to decreased systemic levels and effectiveness.(1)|
04724|011|B||
04724|012|P|PREDISPOSING FACTORS:  None determined.|
04724|013|B||
04724|014|M|PATIENT MANAGEMENT:  In order to assure systemic absorption and maximal|
04724|015|M|effectiveness from use of this Hepatitis C treatment, counsel patient to|
04724|016|M|separate ravidasvir from antacid administration by 4 hours.(1)|
04724|017|M|   Some vitamin preparations may contain sufficient quantities of calcium|
04724|018|M|and/or magnesium salts with antacid properties to interact as well.|
04724|019|B||
04724|020|D|DISCUSSION:  Interaction studies with antacids have not been performed.|
04724|021|D|Co-administration with antacids are expected to decrease ravidasvir plasma|
04724|022|D|concentrations and potentially result in Hepatitis C treatment failure.(1)|
04724|023|B||
04724|024|R|REFERENCE:|
04724|025|B||
04724|026|R|1.Ravida (ravidasvir) Malaysia Prescribing Information. European Egyptian|1
04724|027|R|  Pharmaceutical Industries Co. Jan 20, 2024.|1
04725|001|T|MONOGRAPH TITLE:  Ravidasvir/H2 Antagonists|
04725|002|B||
04725|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04725|004|L|take action as needed.|
04725|005|B||
04725|006|A|MECHANISM OF ACTION:  Absorption of ravidasvir may be reduced in patients|
04725|007|A|receiving concomitant treatment with acid reducing agents.(1)|
04725|008|B||
04725|009|E|CLINICAL EFFECTS:  Administration of H2 antagonists may reduce the|
04725|010|E|bioavailability of ravidasvir, leading to decreased systemic levels and|
04725|011|E|effectiveness.(1)|
04725|012|B||
04725|013|P|PREDISPOSING FACTORS:  None determined.|
04725|014|B||
04725|015|M|PATIENT MANAGEMENT:  In order to assure systemic absorption and maximal|
04725|016|M|effectiveness from use of this Hepatitis C treatment, counsel patients to|
04725|017|M|administer H2 antagonists 4 hours after ravidasvir.(1)|
04725|018|B||
04725|019|D|DISCUSSION:  Interaction studies with antacids have not been performed.|
04725|020|D|Co-administration with H2 antagonists are expected to decrease ravidasvir|
04725|021|D|plasma concentrations and potentially result in Hepatitis C treatment|
04725|022|D|failure.(1)|
04725|023|B||
04725|024|R|REFERENCE:|
04725|025|B||
04725|026|R|1.Ravida (ravidasvir) Malaysia Prescribing Information. European Egyptian|1
04725|027|R|  Pharmaceutical Industries Co. Jan 20, 2024.|1
04726|001|T|MONOGRAPH TITLE:  Sofpironium/Strong CYP2D6 Inhibitors|
04726|002|B||
04726|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04726|004|L|of severe adverse interaction.|
04726|005|B||
04726|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP2D6 may inhibit the metabolism|
04726|007|A|of sofpironium.(1)|
04726|008|B||
04726|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP2D6 inhibitors may result in|
04726|010|E|elevated levels and adverse effects of sofpironium, including increased risk|
04726|011|E|of anticholinergic side effects.|
04726|012|B||
04726|013|P|PREDISPOSING FACTORS:  None determined.|
04726|014|B||
04726|015|M|PATIENT MANAGEMENT:  The concurrent use of sofpironium and strong CYP2D6|
04726|016|M|inhibitors should be avoided.(1)|
04726|017|M|   If concurrent therapy is warranted with a strong CYP2D6 inhibitor,|
04726|018|M|monitor patients closely for anticholinergic side effects.|
04726|019|B||
04726|020|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
04726|021|D|coadministration of paroxetine (a strong CYP2D6 inhibitor) with sofpironium|
04726|022|D|increased the maximum concentration (Cmax) and area-under-the-curve (AUC) by|
04726|023|D|approximately 2-fold compared to sofpironium administration alone.(1)|
04726|024|D|   Strong CYP2D6 inhibitors linked to this monograph include bupropion,|
04726|025|D|dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.(2,3)|
04726|026|B||
04726|027|R|REFERENCES:|
04726|028|B||
04726|029|R|1.Sofdra (sofpironium) US prescribing information. Botanix SB Inc. June,|1
04726|030|R|  2024.|1
04726|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04726|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04726|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04726|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04726|035|R|  11/14/2017.|1
04726|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
04726|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04727|001|T|MONOGRAPH TITLE:  Crovalimab/C5 Complement Inhibitors|
04727|002|B||
04727|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04727|004|L|of severe adverse interaction.|
04727|005|B||
04727|006|A|MECHANISM OF ACTION:  Crovalimab is a complement C5 inhibitor which binds to|
04727|007|A|epitopes on C5.  Other complement C5 inhibitors such as eculizumab and|
04727|008|A|ravulizumab bind to different epitopes on C5.  Use of multiple complement|
04727|009|A|inhibitors may lead to formation of drug-target-drug complexes (DTDCs) which|
04727|010|A|may increase the risk of serious type III hypersensitivity reactions.(1)|
04727|011|B||
04727|012|E|CLINICAL EFFECTS:  Use of multiple complement inhibitors may lead to|
04727|013|E|formation of drug-target-drug complexes (DTDCs) which may increase the risk|
04727|014|E|of serious type III hypersensitivity reactions.  Type III hypersensitivity|
04727|015|E|reactions can present as vasculitis, serum sickness, lymphadenopathy with|
04727|016|E|arthralgias, rheumatoid arthritis, or glomerulonephritis.(1)|
04727|017|B||
04727|018|P|PREDISPOSING FACTORS:  None determined.|
04727|019|B||
04727|020|M|PATIENT MANAGEMENT:  The manufacturer of crovalimab states caution is|
04727|021|M|advised when switching patients between other complement C5 inhibitors such|
04727|022|M|as eculizumab or ravulizumab.  The formation of drug-target-drug complexes|
04727|023|M|(DTDCs) can occur when switching therapies.  DTDCs are expected to be|
04727|024|M|cleared within approximately 8 weeks (with eculizumab) or longer (with|
04727|025|M|ravulizumab).  Consider the risks and benefits of the timing of switching|
04727|026|M|therapies with the risk of type III hypersensitivity reactions.(1)|
04727|027|M|   Monitor patients closely for signs of type III hypersensitivity|
04727|028|M|reactions.(1)|
04727|029|M|   If patients develop a hypersensitivity reaction, for mild or moderate|
04727|030|M|Type III hypersensitivity reactions, administer symptomatic treatment, such|
04727|031|M|as topical corticosteroids, antihistamines, antipyretics, and/or analgesics.|
04727|032|M|For severe reactions, initiate and taper oral or systemic corticosteroids|
04727|033|M|therapy as clinically indicated.(1)|
04727|034|B||
04727|035|D|DISCUSSION:  Clinical drug interaction studies with crovalimab have not been|
04727|036|D|performed.  Use of multiple complement inhibitors may lead to formation of|
04727|037|D|drug-target-drug complexes (DTDCs) which may increase the risk of serious|
04727|038|D|type III hypersensitivity reactions.(1)|
04727|039|D|   In clinical trials, type III hypersensitivity reactions were reported in|
04727|040|D|19% of patients who switched from eculizumab or ravulizumab to crovalimab.|
04727|041|D|Also, type III hypersensitivity reactions were documented in 25% of patients|
04727|042|D|who switched from crovalimab to either eculizumab or ravulizumab.(1)|
04727|043|B||
04727|044|R|REFERENCE:|
04727|045|B||
04727|046|R|1.Piasky (crovalimab-akkz) US prescribing information. Genentech June, 2024.|1
04728|001|T|MONOGRAPH TITLE:  Etonogestrel-Ethinyl Estradiol (Eluryng,|
04728|002|T|Nuvaring)/Oil-Based Vaginal Products|
04728|003|B||
04728|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04728|005|L|take action as needed.|
04728|006|B||
04728|007|A|MECHANISM OF ACTION:  The use of Eluryng or Nuvaring (etonogestrel-ethinyl|
04728|008|A|estradiol vaginal ring) with oil-based vaginal products has been associated|
04728|009|A|with ring breakage.(1,2)|
04728|010|B||
04728|011|E|CLINICAL EFFECTS:  Concurrent use of Eluryng or Nuvaring|
04728|012|E|(etonogestrel-ethinyl estradiol vaginal ring with oil-based vaginal products|
04728|013|E|has been associated with ring breakage.  Contraceptive efficacy is not|
04728|014|E|believed to be affected.  Vaginal injury including pain, discomfort, and|
04728|015|E|bleeding has been reported in association with ring breakage.(1,2)|
04728|016|B||
04728|017|P|PREDISPOSING FACTORS:  None determined.|
04728|018|B||
04728|019|M|PATIENT MANAGEMENT:  If the contraceptive ring breaks but stays in the|
04728|020|M|vagina, ring effectiveness should not be affected.  If a broken ring slips|
04728|021|M|out or is removed, it should not be reinserted.  Instead, it should be|
04728|022|M|discarded and replaced with a new ring.(1,2)|
04728|023|B||
04728|024|D|DISCUSSION:  A single-dose of an oil-based vaginal miconazole nitrate|
04728|025|D|capsule (1200 mg) increased etonogestrel levels by 17% and ethinyl estradiol|
04728|026|D|levels by 16%.(1)  These changes in serum levels are not expected to affect|
04728|027|D|efficacy.(3)|
04728|028|B||
04728|029|R|REFERENCES:|
04728|030|B||
04728|031|R|1.Eluryng (etonogestrel and ethinyl estradiol) US prescribing information.|1
04728|032|R|  Amneal Pharmaceuticals LLC May 19, 2022.|1
04728|033|R|2.Nuvaring (etonogestrel and ethinyl estradiol) US prescribing information.|1
04728|034|R|  Organon LLC June 1, 2024.|1
04728|035|R|3.Mulders TM. The combined contraceptive ring NuvaRing and spermicide|2
04728|036|R|  co-medication. Contraception 2003 Apr;67(4):271-2.|2
04730|001|T|MONOGRAPH TITLE:  Colchicine (for Gout & FMF)/Rifampin|
04730|002|B||
04730|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04730|004|L|of severe adverse interaction.|
04730|005|B||
04730|006|A|MECHANISM OF ACTION:  Colchicine is a substrate of CYP3A4 and P-glycoprotein|
04730|007|A|(P-gp).(1)  Rifampin is a P-gp inhibitor with short-term use (<7 days) and a|
04730|008|A|CYP3A4 and P-gp inducer with longer use.(2-5)|
04730|009|B||
04730|010|E|CLINICAL EFFECTS:  The exact course of this interaction is undefined.  The|
04730|011|E|addition of rifampin to existing colchicine therapy may initially increase|
04730|012|E|colchicine absorption, resulting in increased colchicine levels and side|
04730|013|E|effects including GI distress, neuropathy, myopathy, and|
04730|014|E|myelosuppression.(1,6)  Continued use will cause P-gp and CYP3A4 induction,|
04730|015|E|resulting in decreased colchicine levels and effectiveness.(1,2)|
04730|016|E|   The addition of colchicine to a patient already receiving rifampin or who|
04730|017|E|has recently discontinued rifampin may result in induction of colchicine|
04730|018|E|metabolism and decreased levels and efficacy of colchicine.(1,2)|
04730|019|B||
04730|020|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04730|021|P|patients with renal and/or hepatic impairment.(1,6)|
04730|022|B||
04730|023|M|PATIENT MANAGEMENT:  The use of colchicine in patients with renal or hepatic|
04730|024|M|impairment on P-gp inhibitors, including patients starting rifampin therapy,|
04730|025|M|is contraindicated.  Avoid concurrent use in other patients, if possible.|
04730|026|M|In patients without renal or hepatic impairment who are starting rifampin,|
04730|027|M|the dosage of colchicine should be reduced.|
04730|028|M|   For gout flares, the recommended dosage is 0.6 mg (1 tablet) for one|
04730|029|M|dose.  This dose should be repeated no earlier than in 3 days.|
04730|030|M|   For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use|
04730|031|M|0.3 mg daily.  If the original dosage was 0.6 mg daily, use 0.3 mg every|
04730|032|M|other day.|
04730|033|M|   For Familial Mediterranean fever (FMF), the recommended maximum daily|
04730|034|M|dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,6)|
04730|035|M|   Patients should be instructed to immediately report any signs of|
04730|036|M|colchicine toxicity, such as abdominal pain, nausea, significant diarrhea or|
04730|037|M|vomiting, muscle weakness or pain, numbness or tingling in the fingers or|
04730|038|M|toes, unusual bleeding or bruising, infections, weakness, tiredness, or pale|
04730|039|M|or gray color of the lips, tongue, or palms of hands.|
04730|040|M|   In patients who have been on rifampin for at least 1 week and require|
04730|041|M|colchicine therapy, monitor for decreased colchicine response.|
04730|042|B||
04730|043|D|DISCUSSION:  The combination of colchicine and rifampin has not been|
04730|044|D|studied.  Colchicine is a known P-gp and CYP3A4 substrate and concurrent|
04730|045|D|therapy with inhibitors of P-gp and/or CYP3A4 increases the risk for|
04730|046|D|colchicine toxicity, including death.(1)  An FDA review of 117|
04730|047|D|colchicine-related deaths that were not attributable to overdose found that|
04730|048|D|60 deaths (51%) involved concurrent use of clarithromycin (a P-gp and strong|
04730|049|D|CYP3A4 inhibitor).(2)|
04730|050|D|   In a study of 11 healthy volunteers, digoxin administered 1 hour after|
04730|051|D|the last dose of a 28-day course of rifampin increased the area-under-curve|
04730|052|D|(AUC(0-3h)) and maximum concentration (Cmax) of digoxin by 45% and 49%,|
04730|053|D|respectively, compared to digoxin administered in the absence of induction.|
04730|054|D|These digoxin levels represent both acute and chronic effects of rifampin on|
04730|055|D|digoxin disposition.  Digoxin AUC(0-3h) and Cmax at 1 week after rifampin|
04730|056|D|discontinuation were 68% and 69%, respectively, of the reference values,|
04730|057|D|demonstrating induction effects.(3)|
04730|058|D|   A study of 45 healthy volunteers investigated the effects of single-dose|
04730|059|D|rifampin on the pharmacokinetics of a probe-drug cocktail of digoxin,|
04730|060|D|furosemide, metformin, and rosuvastatin.  The AUC and Cmax of digoxin were|
04730|061|D|increased by 31% and 118%, respectively.(4)|
04730|062|D|   In a physiologically-based pharmacokinetic (PBPK) model, the effects of|
04730|063|D|rifampin on P-gp activity in the liver, intestine, and kidney were|
04730|064|D|predicted.  Single-dose rifampin 600 mg is expected to decrease P-gp|
04730|065|D|activity to 28% in the liver, <=5% in the intestine, and 44% in the kidney.|
04730|066|D|Rifampin 600 mg daily at steady state is predicted to increase P-gp activity|
04730|067|D|in the liver to 321%, in the intestine to 276%-284%, and in the kidney to|
04730|068|D|266%.(5)|
04730|069|B||
04730|070|R|REFERENCES:|
04730|071|B||
04730|072|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
04730|073|R|  2011.|1
04730|074|R|2.Rifadin (rifampin) US prescribing information. Sanofi-Aventis U.S. LLC|1
04730|075|R|  October, 2024.|1
04730|076|R|3.Reitman ML, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S, Stone|2
04730|077|R|  JA, Ding Y, Witter R, Gibson C, Roupe K, Evers R, Wagner JA, Stoch A.|2
04730|078|R|  Rifampin's acute inhibitory and chronic inductive drug interactions:|2
04730|079|R|  experimental  and model-based approaches to drug-drug interaction trial|2
04730|080|R|  design. Clin Pharmacol Ther 2011 Feb;89(2):234-42.|2
04730|081|R|4.Wiebe ST, Giessmann T, Hohl K, Schmidt-Gerets S, Hauel E, Jambrecina A,|2
04730|082|R|  Bader K, Ishiguro N, Taub ME, Sharma A, Ebner T, Mikus G, Fromm MF, Muller|2
04730|083|R|  F, Stopfer P. Validation of a Drug Transporter Probe Cocktail Using the|2
04730|084|R|  Prototypical Inhibitors  Rifampin, Probenecid, Verapamil, and Cimetidine.|2
04730|085|R|  Clin Pharmacokinet 2020 Dec;59(12):1627-1639.|2
04730|086|R|5.Asaumi R, Nunoya KI, Yamaura Y, Taskar KS, Sugiyama Y. Robust|5
04730|087|R|  physiologically based pharmacokinetic model of rifampicin for predicting|5
04730|088|R|  drug-drug interactions via P-glycoprotein induction and inhibition in the|5
04730|089|R|  intestine, liver, and kidney. CPT Pharmacometrics Syst Pharmacol 2022 Jul;|5
04730|090|R|  11(7):919-933.|5
04730|091|R|6.Anonymous. Information for Healthcare Professionals: New Safety|1
04730|092|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
04730|093|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
04730|094|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
04730|095|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04730|096|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04730|097|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04730|098|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04730|099|R|  11/14/2017.|1
04730|100|R|8.This information is based on an extract from the Certara Drug Interaction|6
04730|101|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04731|001|T|MONOGRAPH TITLE:  Colchicine (for Cardioprotection)/Rifampin|
04731|002|B||
04731|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04731|004|L|is contraindicated and generally should not be dispensed or administered to|
04731|005|L|the same patient.|
04731|006|B||
04731|007|A|MECHANISM OF ACTION:  Colchicine is a substrate of CYP3A4 and P-glycoprotein|
04731|008|A|(P-gp).(1)  Rifampin is a P-gp inhibitor with short-term use (<7 days) and a|
04731|009|A|CYP3A4 and P-gp inducer with longer use.(2-5)|
04731|010|B||
04731|011|E|CLINICAL EFFECTS:  The exact course of this interaction is undefined.  The|
04731|012|E|addition of rifampin to existing colchicine therapy may initially increase|
04731|013|E|colchicine absorption, resulting in increased colchicine levels and side|
04731|014|E|effects including GI distress, neuropathy, myopathy, and|
04731|015|E|myelosuppression.(1,6)  Continued use will cause P-gp and CYP3A4 induction,|
04731|016|E|resulting in decreased colchicine levels and effectiveness.(1,2)|
04731|017|E|   The addition of colchicine to a patient already receiving rifampin or who|
04731|018|E|has recently discontinued rifampin may result in induction of colchicine|
04731|019|E|metabolism and decreased levels and efficacy of colchicine.(1,2)|
04731|020|B||
04731|021|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04731|022|P|patients with renal or hepatic impairment.(1,6)|
04731|023|B||
04731|024|M|PATIENT MANAGEMENT:  The manufacturer of colchicine used for cardiovascular|
04731|025|M|risk reduction states that concurrent use of colchicine in patients on P-gp|
04731|026|M|inhibitors, including patients starting rifampin therapy, is|
04731|027|M|contraindicated.(1)|
04731|028|M|   In patients who have been on rifampin for at least 1 week and require|
04731|029|M|colchicine therapy, monitor for decreased colchicine response.|
04731|030|B||
04731|031|D|DISCUSSION:  The combination of colchicine and rifampin has not been|
04731|032|D|studied.  Colchicine is a known P-gp and CYP3A4 substrate and concurrent|
04731|033|D|therapy with inhibitors of P-gp and/or CYP3A4 increases the risk for|
04731|034|D|colchicine toxicity, including death.(1)  An FDA review of 117|
04731|035|D|colchicine-related deaths that were not attributable to overdose found that|
04731|036|D|60 deaths (51%) involved concurrent use of clarithromycin (a P-gp and strong|
04731|037|D|CYP3A4 inhibitor).(2)|
04731|038|D|   In a study of 11 healthy volunteers, digoxin administered 1 hour after|
04731|039|D|the last dose of a 28-day course of rifampin increased the area-under-curve|
04731|040|D|(AUC(0-3h)) and maximum concentration (Cmax) of digoxin by 45% and 49%,|
04731|041|D|respectively, compared to digoxin administered in the absence of induction.|
04731|042|D|These digoxin levels represent both acute and chronic effects of rifampin on|
04731|043|D|digoxin disposition.  Digoxin AUC(0-3h) and Cmax at 1 week after rifampin|
04731|044|D|discontinuation were 68% and 69%, respectively, of the reference values,|
04731|045|D|demonstrating induction effects.(3)|
04731|046|D|   A study of 45 healthy volunteers investigated the effects of single-dose|
04731|047|D|rifampin on the pharmacokinetics of a probe-drug cocktail of digoxin,|
04731|048|D|furosemide, metformin, and rosuvastatin.  The AUC and Cmax of digoxin were|
04731|049|D|increased by 31% and 118%, respectively.(4)|
04731|050|D|   In a physiologically-based pharmacokinetic (PBPK) model, the effects of|
04731|051|D|rifampin on P-gp activity in the liver, intestine, and kidney were|
04731|052|D|predicted.  Single-dose rifampin 600 mg is expected to decrease P-gp|
04731|053|D|activity to 28% in the liver, <=5% in the intestine, and 44% in the kidney.|
04731|054|D|Rifampin 600 mg daily at steady state is predicted to increase P-gp activity|
04731|055|D|in the liver to 321%, in the intestine to 276%-284%, and in the kidney to|
04731|056|D|266%.(5)|
04731|057|B||
04731|058|R|REFERENCES:|
04731|059|B||
04731|060|R|1.Lodoco (colchicine) US prescribing information. AGEPHA Pharma USA, LLC|1
04731|061|R|  June, 2023.|1
04731|062|R|2.Rifadin (rifampin) US prescribing information. Sanofi-Aventis U.S. LLC|1
04731|063|R|  October, 2024.|1
04731|064|R|3.Reitman ML, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S, Stone|2
04731|065|R|  JA, Ding Y, Witter R, Gibson C, Roupe K, Evers R, Wagner JA, Stoch A.|2
04731|066|R|  Rifampin's acute inhibitory and chronic inductive drug interactions:|2
04731|067|R|  experimental  and model-based approaches to drug-drug interaction trial|2
04731|068|R|  design. Clin Pharmacol Ther 2011 Feb;89(2):234-42.|2
04731|069|R|4.Wiebe ST, Giessmann T, Hohl K, Schmidt-Gerets S, Hauel E, Jambrecina A,|2
04731|070|R|  Bader K, Ishiguro N, Taub ME, Sharma A, Ebner T, Mikus G, Fromm MF, Muller|2
04731|071|R|  F, Stopfer P. Validation of a Drug Transporter Probe Cocktail Using the|2
04731|072|R|  Prototypical Inhibitors  Rifampin, Probenecid, Verapamil, and Cimetidine.|2
04731|073|R|  Clin Pharmacokinet 2020 Dec;59(12):1627-1639.|2
04731|074|R|5.Asaumi R, Nunoya KI, Yamaura Y, Taskar KS, Sugiyama Y. Robust|5
04731|075|R|  physiologically based pharmacokinetic model of rifampicin for predicting|5
04731|076|R|  drug-drug interactions via P-glycoprotein induction and inhibition in the|5
04731|077|R|  intestine, liver, and kidney. CPT Pharmacometrics Syst Pharmacol 2022 Jul;|5
04731|078|R|  11(7):919-933.|5
04731|079|R|6.Anonymous. Information for Healthcare Professionals: New Safety|1
04731|080|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
04731|081|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
04731|082|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
04731|083|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04731|084|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04731|085|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04731|086|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04731|087|R|  11/14/2017.|1
04731|088|R|8.This information is based on an extract from the Certara Drug Interaction|6
04731|089|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04732|001|T|MONOGRAPH TITLE:  Metformin/OCT2 Inhibitors|
04732|002|B||
04732|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04732|004|L|take action as needed.|
04732|005|B||
04732|006|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
04732|007|A|(OCT2) may inhibit the excretion of metformin by OCT2 in the kidneys.(1)|
04732|008|B||
04732|009|E|CLINICAL EFFECTS:  Concurrent use of OCT2 renal transport inhibitors may|
04732|010|E|result in increased levels of and toxicity from metformin.(1)|
04732|011|B||
04732|012|P|PREDISPOSING FACTORS:  Risk factors for metformin associated lactic acidosis|
04732|013|P|include renal impairment, sepsis, dehydration, excessive alcohol intake,|
04732|014|P|acute or chronic metabolic acidosis, hepatic insufficiency, acute heart|
04732|015|P|failure, metformin plasma levels higher than 5 micrograms/mL, and conditions|
04732|016|P|which may lead to tissue hypoxia.  Geriatric patients may also be at higher|
04732|017|P|risk due to slower metformin clearance and increased half-life in this|
04732|018|P|population.|
04732|019|B||
04732|020|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
04732|021|M|concurrent use of metformin with OCT2 renal transport inhibitors.  If|
04732|022|M|concurrent use is appropriate, monitor for toxicities of metformin and|
04732|023|M|consider dosage reduction of metformin.(1)|
04732|024|B||
04732|025|D|DISCUSSION:  In a study, givinostat increased the levels of creatinine (OCT2|
04732|026|D|substrate) by 4.76 umol/L from baseline.(1)|
04732|027|D|   OCT2 inhibitors linked to this monograph include:  arimoclomol,|
04732|028|D|givinostat, trilaciclib, and vimseltinib.(2)|
04732|029|B||
04732|030|R|REFERENCES:|
04732|031|B||
04732|032|R|1.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
04732|033|R|  March, 2024.|1
04732|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
04732|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04733|001|T|MONOGRAPH TITLE:  Pindolol/OCT2 Inhibitors|
04733|002|B||
04733|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04733|004|L|take action as needed.|
04733|005|B||
04733|006|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
04733|007|A|(OCT2) may inhibit the excretion of pindolol by OCT2 in the kidneys.(1,2)|
04733|008|B||
04733|009|E|CLINICAL EFFECTS:  Concurrent use of OCT2 renal transport inhibitors may|
04733|010|E|result in increased levels of and toxicity from pindolol.(1,2)|
04733|011|B||
04733|012|P|PREDISPOSING FACTORS:  None determined.|
04733|013|B||
04733|014|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
04733|015|M|concurrent use of pindolol with OCT2 renal transport inhibitors.  If|
04733|016|M|concurrent use is appropriate, monitor for toxicities of pindolol and|
04733|017|M|consider dosage reduction of pindolol.(1,2)|
04733|018|B||
04733|019|D|DISCUSSION:  In a study, givinostat increased the levels of creatinine (OCT2|
04733|020|D|substrate) by 4.76 umol/L from baseline.(1)|
04733|021|D|   In a study, trilaciclib increased the area-under-curve (AUC) and maximum|
04733|022|D|concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by|
04733|023|D|approximately 65% and 81%, respectively.  Renal clearance of metformin was|
04733|024|D|decreased by 37%.  Trilaciclib did not cause significant changes in the|
04733|025|D|pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2)|
04733|026|D|   OCT2 inhibitors linked to this monograph include:  arimoclomol,|
04733|027|D|cimetidine, dolutegravir, givinostat, and vimseltinib.(3)|
04733|028|B||
04733|029|R|REFERENCES:|
04733|030|B||
04733|031|R|1.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
04733|032|R|  March, 2024.|1
04733|033|R|2.Cosela (trilaciclib) US prescribing information. G1 Therapeutics, Inc.|1
04733|034|R|  February, 2021.|1
04733|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04733|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04735|001|T|MONOGRAPH TITLE:  Oliceridine/Moderate CYP2D6 Inhibitors|
04735|002|B||
04735|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04735|004|L|take action as needed.|
04735|005|B||
04735|006|A|MECHANISM OF ACTION:  Oliceridine is metabolized equally by CYP2D6 and|
04735|007|A|CYP3A4.  Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or|
04735|008|A|CYP3A4.(1)|
04735|009|B||
04735|010|E|CLINICAL EFFECTS:  The concurrent administration of a strong or moderate|
04735|011|E|CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels|
04735|012|E|of and toxicity from oliceridine including profound sedation, respiratory|
04735|013|E|depression, coma, and/or death.(1)|
04735|014|B||
04735|015|P|PREDISPOSING FACTORS:  Inhibition of both CYP2D6 and CYP3A4 pathways may|
04735|016|P|result in a greater increase in the levels of and toxcity of oliceridine.(1)|
04735|017|B||
04735|018|M|PATIENT MANAGEMENT:  Caution should be used when administering oliceridine|
04735|019|M|to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4.|
04735|020|M|Dosage adjustments should be made if warranted.  Closely monitor these|
04735|021|M|patients for respiratory depression and sedation at frequent intervals and|
04735|022|M|evaluate subsequent doses based on response.|
04735|023|M|   If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is|
04735|024|M|necessary, less frequent dosing of oliceridine may be required.|
04735|025|M|   If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued,|
04735|026|M|increase of the oliceridine dosage may be necessary.  Monitor for signs of|
04735|027|M|opioid withdrawal.|
04735|028|M|   Patients receiving concurrent therapy with both a strong or moderate|
04735|029|M|CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse|
04735|030|M|effects.|
04735|031|M|   Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and|
04735|032|M|a strong CYP3A4 inhibitor may require less frequent dosing of|
04735|033|M|oliceridine.(1)|
04735|034|M|   Respiratory depression can occur at any time during opioid therapy,|
04735|035|M|especially during therapy initiation and following dosage increases.  The|
04735|036|M|risk of opioid-related overdose or overdose-related death is increased with|
04735|037|M|higher opioid doses, and this risk persists over the course of therapy.|
04735|038|M|Consider these risks when using concurrently with other agents that may|
04735|039|M|cause CNS depression.(2)|
04735|040|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04735|041|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04735|042|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04735|043|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04735|044|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04735|045|M|as those taking CNS depressants) and when a patient has household|
04735|046|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04735|047|M|for obtaining an opioid reversal agent (e.g., prescription,|
04735|048|M|over-the-counter, or as part of a community-based program).(3)|
04735|049|B||
04735|050|D|DISCUSSION:  In a study of four healthy subjects who are CYP2D6 poor|
04735|051|D|metabolizers, itraconazole (200 mg daily for 5 days) increased the|
04735|052|D|area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1)|
04735|053|D|   In a study of subjects who were not CYP2D6 poor metabolizers,|
04735|054|D|ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the|
04735|055|D|pharmacokinetics of oliceridine.(1)|
04735|056|D|   Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir,|
04735|057|D|capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, lorcaserin,|
04735|058|D|mirabegron, moclobemide, and rolapitant.(4)|
04735|059|B||
04735|060|R|REFERENCES:|
04735|061|B||
04735|062|R|1.Olinvyk (oliceridine) US prescribing information. Trevena Inc December,|1
04735|063|R|  2023.|1
04735|064|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04735|065|R|  prescribing information for all opioid pain medicines to provide|1
04735|066|R|  additional guidance for safe use. Available at:|1
04735|067|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04735|068|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04735|069|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04735|070|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04735|071|R|  recommends health care professionals discuss naloxone with all patients|1
04735|072|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04735|073|R|  disorder. Available at:|1
04735|074|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04735|075|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04735|076|R|  d-pain July 23, 2020.|1
04735|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
04735|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04736|001|T|MONOGRAPH TITLE:  Oliceridine/Strong CYP3A4 Inhibitors|
04736|002|B||
04736|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04736|004|L|take action as needed.|
04736|005|B||
04736|006|A|MECHANISM OF ACTION:  Oliceridine is metabolized equally by CYP2D6 and|
04736|007|A|CYP3A4.  Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or|
04736|008|A|CYP3A4.(1)|
04736|009|B||
04736|010|E|CLINICAL EFFECTS:  The concurrent administration of a strong or moderate|
04736|011|E|CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels|
04736|012|E|of and toxicity from oliceridine including profound sedation, respiratory|
04736|013|E|depression, coma, and/or death.(1)|
04736|014|B||
04736|015|P|PREDISPOSING FACTORS:  Patients with CYP2D6 poor metabolizer phenotype may|
04736|016|P|be affected to a greater extent by CYP3A4 inhibitors.|
04736|017|P|   Inhibition of both CYP2D6 and CYP3A4 pathways may result in a greater|
04736|018|P|increase in the levels of and toxcity of oliceridine.(1)|
04736|019|B||
04736|020|M|PATIENT MANAGEMENT:  Caution should be used when administering oliceridine|
04736|021|M|to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4.|
04736|022|M|Dosage adjustments should be made if warranted.  Closely monitor these|
04736|023|M|patients for respiratory depression and sedation at frequent intervals and|
04736|024|M|evaluate subsequent doses based on response.|
04736|025|M|   If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is|
04736|026|M|necessary, less frequent dosing of oliceridine may be required.|
04736|027|M|   If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued,|
04736|028|M|increase of the oliceridine dosage may be necessary.  Monitor for signs of|
04736|029|M|opioid withdrawal.|
04736|030|M|   Patients receiving concurrent therapy with both a strong or moderate|
04736|031|M|CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse|
04736|032|M|effects.|
04736|033|M|   Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and|
04736|034|M|a strong CYP3A4 inhibitor may require less frequent dosing of|
04736|035|M|oliceridine.(1)|
04736|036|M|   Respiratory depression can occur at any time during opioid therapy,|
04736|037|M|especially during therapy initiation and following dosage increases.  The|
04736|038|M|risk of opioid-related overdose or overdose-related death is increased with|
04736|039|M|higher opioid doses, and this risk persists over the course of therapy.|
04736|040|M|Consider these risks when using concurrently with other agents that may|
04736|041|M|cause CNS depression.(2)|
04736|042|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04736|043|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04736|044|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04736|045|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04736|046|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04736|047|M|as those taking CNS depressants) and when a patient has household|
04736|048|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04736|049|M|for obtaining an opioid reversal agent (e.g., prescription,|
04736|050|M|over-the-counter, or as part of a community-based program).(3)|
04736|051|B||
04736|052|D|DISCUSSION:  In a study of four healthy subjects who are CYP2D6 poor|
04736|053|D|metabolizers, itraconazole (200 mg daily for 5 days) increased the|
04736|054|D|area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1)|
04736|055|D|   In a study of subjects who were not CYP2D6 poor metabolizers,|
04736|056|D|ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the|
04736|057|D|pharmacokinetics of oliceridine.(1)|
04736|058|D|   Strong CYP3A4 inhibitors include:  adagrasib, boceprevir, ceritinib,|
04736|059|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
04736|060|D|josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, mibefradil,|
04736|061|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
04736|062|D|posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir,|
04736|063|D|troleandomycin, tucatinib, and voriconazole.(4)|
04736|064|B||
04736|065|R|REFERENCES:|
04736|066|B||
04736|067|R|1.Olinvyk (oliceridine) US prescribing information. Trevena Inc December,|1
04736|068|R|  2023.|1
04736|069|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04736|070|R|  prescribing information for all opioid pain medicines to provide|1
04736|071|R|  additional guidance for safe use. Available at:|1
04736|072|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04736|073|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04736|074|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04736|075|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04736|076|R|  recommends health care professionals discuss naloxone with all patients|1
04736|077|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04736|078|R|  disorder. Available at:|1
04736|079|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04736|080|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04736|081|R|  d-pain July 23, 2020.|1
04736|082|R|4.This information is based on an extract from the Certara Drug Interaction|6
04736|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04737|001|T|MONOGRAPH TITLE:  Oliceridine/Moderate CYP3A4 Inhibitors|
04737|002|B||
04737|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04737|004|L|take action as needed.|
04737|005|B||
04737|006|A|MECHANISM OF ACTION:  Oliceridine is metabolized equally by CYP2D6 and|
04737|007|A|CYP3A4.  Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or|
04737|008|A|CYP3A4.(1)|
04737|009|B||
04737|010|E|CLINICAL EFFECTS:  The concurrent administration of a strong or moderate|
04737|011|E|CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels|
04737|012|E|of and toxicity from oliceridine including profound sedation, respiratory|
04737|013|E|depression, coma, and/or death.(1)|
04737|014|B||
04737|015|P|PREDISPOSING FACTORS:  Patients with CYP2D6 poor metabolizer phenotype may|
04737|016|P|be affected to a greater extent by CYP3A4 inhibitors.|
04737|017|P|   Inhibition of both CYP2D6 and CYP3A4 pathways may result in a greater|
04737|018|P|increase in the levels of and toxcity of oliceridine.(1)|
04737|019|B||
04737|020|M|PATIENT MANAGEMENT:  Caution should be used when administering oliceridine|
04737|021|M|to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4.|
04737|022|M|Dosage adjustments should be made if warranted.  Closely monitor these|
04737|023|M|patients for respiratory depression and sedation at frequent intervals and|
04737|024|M|evaluate subsequent doses based on response.|
04737|025|M|   If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is|
04737|026|M|necessary, less frequent dosing of oliceridine may be required.|
04737|027|M|   If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued,|
04737|028|M|increase of the oliceridine dosage may be necessary.  Monitor for signs of|
04737|029|M|opioid withdrawal.|
04737|030|M|   Patients receiving concurrent therapy with both a strong or moderate|
04737|031|M|CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse|
04737|032|M|effects.|
04737|033|M|   Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and|
04737|034|M|a strong CYP3A4 inhibitor may require less frequent dosing of|
04737|035|M|oliceridine.(1)|
04737|036|M|   Respiratory depression can occur at any time during opioid therapy,|
04737|037|M|especially during therapy initiation and following dosage increases.  The|
04737|038|M|risk of opioid-related overdose or overdose-related death is increased with|
04737|039|M|higher opioid doses, and this risk persists over the course of therapy.|
04737|040|M|Consider these risks when using concurrently with other agents that may|
04737|041|M|cause CNS depression.(2)|
04737|042|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04737|043|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04737|044|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04737|045|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04737|046|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04737|047|M|as those taking CNS depressants) and when a patient has household|
04737|048|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04737|049|M|for obtaining an opioid reversal agent (e.g., prescription,|
04737|050|M|over-the-counter, or as part of a community-based program).(3)|
04737|051|B||
04737|052|D|DISCUSSION:  In a study of four healthy subjects who are CYP2D6 poor|
04737|053|D|metabolizers, itraconazole (200 mg daily for 5 days) increased the|
04737|054|D|area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1)|
04737|055|D|   In a study of subjects who were not CYP2D6 poor metabolizers,|
04737|056|D|ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the|
04737|057|D|pharmacokinetics of oliceridine.(1)|
04737|058|D|   Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir,|
04737|059|D|avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir,|
04737|060|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
04737|061|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
04737|062|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
04737|063|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil,|
04737|064|D|and voxelotor.(4)|
04737|065|B||
04737|066|R|REFERENCES:|
04737|067|B||
04737|068|R|1.Olinvyk (oliceridine) US prescribing information. Trevena Inc December,|1
04737|069|R|  2023.|1
04737|070|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04737|071|R|  prescribing information for all opioid pain medicines to provide|1
04737|072|R|  additional guidance for safe use. Available at:|1
04737|073|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04737|074|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04737|075|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04737|076|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04737|077|R|  recommends health care professionals discuss naloxone with all patients|1
04737|078|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04737|079|R|  disorder. Available at:|1
04737|080|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04737|081|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04737|082|R|  d-pain July 23, 2020.|1
04737|083|R|4.This information is based on an extract from the Certara Drug Interaction|6
04737|084|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04738|001|T|MONOGRAPH TITLE:  Avacopan/Strong or Moderate CYP3A4 Inducer and Substrates|
04738|002|B||
04738|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04738|004|L|of severe adverse interaction.|
04738|005|B||
04738|006|A|MECHANISM OF ACTION:  Avacopan is moderate inhibitor and substrate of|
04738|007|A|CYP3A4.  Strong or moderate inducers of CYP3A4 may induce the metabolism of|
04738|008|A|avacopan.(1)  Avacopan may inhibit the metabolism of CYP3A4 substrates.(1)|
04738|009|B||
04738|010|E|CLINICAL EFFECTS:  The concurrent administration of strong or moderate|
04738|011|E|CYP3A4 inducers may result in decreased levels and effectiveness of|
04738|012|E|avacopan.(1)  Concurrent administration of avacopan with CYP3A4 substrates|
04738|013|E|may result in increased levels and side effects of the CYP3A4 substrate.(1)|
04738|014|B||
04738|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04738|016|P|of the inducer for longer than 1-2 weeks.|
04738|017|B||
04738|018|M|PATIENT MANAGEMENT:  The manufacturer of avacopan states that concurrent use|
04738|019|M|with strong or moderate CYP3A4 inducers should be avoided.(1)|
04738|020|M|   Consider dose reduction of CYP3A4 substrates when coadministering|
04738|021|M|avacopan with CYP3A4 substrates. Consult the concomitant CYP3A4 substrate|
04738|022|M|product information when considering administration with avacopan.(1)|
04738|023|B||
04738|024|D|DISCUSSION:  Co-administration of rifampin 600 mg once daily for 11 days, a|
04738|025|D|strong CYP3A4 inducer, decreased the avacopan maximum concentration (Cmax)|
04738|026|D|by 79% and area-under-curve (AUC) by 93%.(1)|
04738|027|D|   In a study, avacopan 60 mg twice daily with food was administered for 7|
04738|028|D|days with simvastatin.  Since it takes 13 weeks to reach steady state, this|
04738|029|D|high dose of avacopan was used to achieve systemic levels similar to those|
04738|030|D|achieved at steady state with a dose of 30 mg twice daily with food.|
04738|031|D|Avacopan increased the AUC and Cmax of simvastatin by 3.53-fold and|
04738|032|D|3.20-fold, respectively.(1)|
04738|033|D|   Moderate inducers and substrates of CYP3A4 include: bosentan,|
04738|034|D|encorafenib, ivosidenib, mavacamten, pacritinib, pexidartinib, and|
04738|035|D|repotrectinib.(2-3)|
04738|036|B||
04738|037|R|REFERENCES:|
04738|038|B||
04738|039|R|1.Tavneos (avacopan) US prescribing information. ChemoCentryx, Inc. June,|1
04738|040|R|  2024.|1
04738|041|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04738|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04738|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04738|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04738|045|R|  11/14/2017.|1
04738|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
04738|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04739|001|T|MONOGRAPH TITLE:  Methotrexate(Oncology-Inj)/OAT3 Inhibitors|
04739|002|B||
04739|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04739|004|L|of severe adverse interaction.|
04739|005|B||
04739|006|A|MECHANISM OF ACTION:  Inhibitors of organic anion transporter 3 (OAT3) may|
04739|007|A|inhibit the renal elimination of methotrexate.|
04739|008|B||
04739|009|E|CLINICAL EFFECTS:  Concurrent use of organic anion transporter 3 (OAT3)|
04739|010|E|inhibitors may result in an increase in both the therapeutic and toxic|
04739|011|E|effects of methotrexate, leading to increased risk of severe neurotoxicity,|
04739|012|E|stomatitis, and myelosuppression, including neutropenia.|
04739|013|B||
04739|014|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
04739|015|P|- High-dose oncology regimens|
04739|016|P|- Impaired renal function, ascites, or pleural effusions|
04739|017|B||
04739|018|M|PATIENT MANAGEMENT:  If coadministration cannot be avoided, monitor closely|
04739|019|M|for methotrexate adverse reactions.|
04739|020|B||
04739|021|D|DISCUSSION:  Concomitant administration of methotrexate and probenecid has|
04739|022|D|been shown to increase methotrexate plasma levels two to four times higher|
04739|023|D|than when methotrexate is administered alone.(2-5)|
04739|024|D|   OAT3 inhibitors linked to this monograph include:  cabotegravir,|
04739|025|D|nitisinone, probenecid and vadadustat.(7)|
04739|026|B||
04739|027|R|REFERENCES:|
04739|028|B||
04739|029|R|1.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
04739|030|R|  Inc. March, 2018.|1
04739|031|R|2.Israili ZH, Soliman AM, Cunningham RF, Plowden JF, Keller JW. The|4
04739|032|R|  interaction of methotrexate and probenecid in man and dog. Proc Am Assoc|4
04739|033|R|  Cancer Res 1978;19:194.|4
04739|034|R|3.Aherne GW, Piall E, Marks V, Mould G, White WF. Prolongation and|2
04739|035|R|  enhancement of serum methotrexate concentrations by probenecid. Br Med J|2
04739|036|R|  1978 Apr 29;1(6120):1097-9.|2
04739|037|R|4.Howell SB, Olshen RA, Rice JA. Effect of probenecid on cerebrospinal fluid|2
04739|038|R|  methotrexate kinetics. Clin Pharmacol Ther 1979 Nov;26(5):641-6.|2
04739|039|R|5.Lilly MB, Omura GA. Clinical pharmacology of oral intermediate-dose|2
04739|040|R|  methotrexate with or without probenecid. Cancer Chemother Pharmacol 1985;|2
04739|041|R|  15(3):220-2.|2
04739|042|R|6.Basin KS, Escalante A, Beardmore TD. Severe pancytopenia in a patient|3
04739|043|R|  taking low dose methotrexate and probenecid. J Rheumatol 1991 Apr;|3
04739|044|R|  18(4):609-10.|3
04739|045|R|7.This information is based on an extract from the Certara Drug Interaction|6
04739|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04740|001|T|MONOGRAPH TITLE:  Avacopan/Mitapivat|
04740|002|B||
04740|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04740|004|L|of severe adverse interaction.|
04740|005|B||
04740|006|A|MECHANISM OF ACTION:  Avacopan and mitapivat are both substrates of CYP3A4.|
04740|007|A|   Avacopan, a moderate CYP3A4 inhibitor, may inhibit the metabolism of|
04740|008|A|mitapivat.  Mitapivat, a moderate CYP3A4 inducer, may induce the metabolism|
04740|009|A|of avacopan.(1,2)|
04740|010|B||
04740|011|E|CLINICAL EFFECTS:  The concurrent use of avacopan with moderate CYP3A4|
04740|012|E|inducers may result in decreased levels and effectiveness of avacopan.(1)|
04740|013|E|   Concurrent use of mitapivat with moderate inhibitors of CYP3A4 may result|
04740|014|E|in increased levels of and effects from mitapivat including decreased|
04740|015|E|estrone and estradiol levels in males, increased urate, back pain, and|
04740|016|E|arthralgias.(2)|
04740|017|B||
04740|018|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04740|019|P|of the inducer for longer than 1-2 weeks.|
04740|020|B||
04740|021|M|PATIENT MANAGEMENT:  Avoid the concurrent use of avacopan and|
04740|022|M|mitapivat.(1,2)|
04740|023|M|   The effect of the two-way inhibition and induction of avacopan and|
04740|024|M|mitapivat metabolism is unknown.  The optimal doses of avacopan and|
04740|025|M|mitapivat when used concurrently have not been determined.  Dose|
04740|026|M|modifications mentioned below are informational only.|
04740|027|M|   If concurrent use is necessary, closely monitor for increased risk of|
04740|028|M|mitapivat adverse reactions.  The US manufacturer of mitapivat states that|
04740|029|M|mitapivat dose should not exceed 20 mg twice daily with concurrent moderate|
04740|030|M|CYP3A4 inhibitors.(2)  The Middle Eastern manufacturer of mitapivat states|
04740|031|M|that alternative agents that do not inhibit CYP3A4 should be considered.  If|
04740|032|M|concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of|
04740|033|M|mitapivat should not exceed 100 mg once daily.(3)|
04740|034|B||
04740|035|D|DISCUSSION:  Co-administration of rifampin 600 mg once daily for 11 days, a|
04740|036|D|strong CYP3A4 inducer, decreased the avacopan concentration maximum (Cmax)|
04740|037|D|by 79% and area-under-curve (AUC) by 93%.(1)|
04740|038|D|   In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily|
04740|039|D|dosing, fluconazole increased mitapivat AUC and Cmax by 2.6-fold and|
04740|040|D|1.6-fold, respectively.(2)|
04740|041|B||
04740|042|R|REFERENCES:|
04740|043|B||
04740|044|R|1.Tavneos (avacopan) US prescribing information. ChemoCentryx, Inc. June,|1
04740|045|R|  2024.|1
04740|046|R|2.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
04740|047|R|  February, 2022.|1
04740|048|R|3.Pyrukynd (mitapivat) Middle East Prescribing Information. Agios|1
04740|049|R|  Pharmaceuticals, Inc. July, 2025.|1
04741|001|T|MONOGRAPH TITLE:  Avacopan/Strong CYP3A4 Inhibitors and Substrates that|
04741|002|T|Prolong QT|
04741|003|B||
04741|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04741|005|L|of severe adverse interaction.|
04741|006|B||
04741|007|A|MECHANISM OF ACTION:  Avacopan is a moderate inhibitor and substrate of|
04741|008|A|CYP3A4.  Strong inhibitors of CYP3A4 may inhibit the metabolism of avacopan.|
04741|009|A|Avacopan may inhibit the metabolism of CYP3A4 substrates.(1)|
04741|010|A|   Some CYP3A4 substrates have the potential to prolong the QTc|
04741|011|A|interval.(2-3)|
04741|012|B||
04741|013|E|CLINICAL EFFECTS:  Concurrent use may increase the levels of and effects|
04741|014|E|from avacopan.(1)|
04741|015|E|   Concurrent use of avacopan with QT-prolonging CYP3A4 substrates may also|
04741|016|E|increase the risk of adverse reactions from the CYP3A4 substrate including|
04741|017|E|QT prolongation and potentially life-threatening cardiac arrhythmias such as|
04741|018|E|torsades de pointes.(2-3)|
04741|019|B||
04741|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04741|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
04741|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04741|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04741|024|P|female gender, or advanced age.(4)|
04741|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04741|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04741|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04741|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04741|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04741|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04741|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04741|032|B||
04741|033|M|PATIENT MANAGEMENT:  Reduce the dose of avacopan to 30 mg once daily when|
04741|034|M|coadministered with strong CYP3A4 inhibitors.(1)  Monitor liver tests,|
04741|035|M|including AST, ALT, alkaline phosphatase, and total bilirubin.  Advise|
04741|036|M|patients to report any symptoms of hepatotoxicity.|
04741|037|M|   If the patient is on lonafarnib, approach concurrent use with caution.|
04741|038|M|No dose adjustment of lonafarnib is recommended when moderate CYP3A4|
04741|039|M|inhibitors are added to steady-state lonafarnib.  When initiating lonafarnib|
04741|040|M|therapy in a patient already taking a moderate CYP3A4 inhibitor, monitor the|
04741|041|M|patient closely for the first 7 days of therapy.  If the patient does not|
04741|042|M|tolerate lonafarnib, consider an alternative that is not a moderate CYP3A4|
04741|043|M|inhibitor.(2)|
04741|044|M|   Lonafarnib dose modification recommendation: if the QTc interval is|
04741|045|M|greater than or equal to 500 msec, withhold lonafarnib until the QTc|
04741|046|M|interval is less than 470 msec, then resume lonafarnib at the same|
04741|047|M|dosage.(2)|
04741|048|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04741|049|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04741|050|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04741|051|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04741|052|M|   Australian and UK manufacturers of avacopan state coadministration with|
04741|053|M|strong CYP3A4 inhibitors should be used with caution.  Patients must be|
04741|054|M|monitored for potential increase of side effects due to the increased|
04741|055|M|exposure of avacopan.(5-6)|
04741|056|B||
04741|057|D|DISCUSSION:  In a study, administration of itraconazole 200 mg once daily|
04741|058|D|for 4 days (a strong CYP3A4 inhibitor) increased the maximum concentration|
04741|059|D|(Cmax) and area-under-curve (AUC) of avacopan by 1.87-fold and 2.19-fold.(1)|
04741|060|D|   Avacopan 60 mg twice daily for 7 days under fed conditions increased the|
04741|061|D|Cmax and AUC of simvastatin (a sensitive CYP3A4 substrate) by 3.2-fold and|
04741|062|D|3.53-fold, respectively.  This regimen of avacopan provided systemic levels|
04741|063|D|similar to exposure from avacopan 30 mg twice daily under fed conditions at|
04741|064|D|steady state.(1)|
04741|065|D|   Strong CYP3A4 inhibitors and substrates that prolong QT linked to this|
04741|066|D|monograph include: lonafarnib.(7-8)|
04741|067|B||
04741|068|R|REFERENCES:|
04741|069|B||
04741|070|R|1.Tavneos (avacopan) US prescribing information. ChemoCentryx, Inc. June,|1
04741|071|R|  2024.|1
04741|072|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04741|073|R|  Inc. November, 2020.|1
04741|074|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04741|075|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04741|076|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04741|077|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04741|078|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04741|079|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04741|080|R|  settings: a scientific statement from the American Heart Association and|6
04741|081|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04741|082|R|  2;55(9):934-47.|6
04741|083|R|5.Tavneos (avacopan) Australian prescribing information. Seqirus Pty Ltd Aug|1
04741|084|R|  13, 2024.|1
04741|085|R|6.Avacopan Vifor UK Summary of Product Characteristics. Vifor Fresenius|1
04741|086|R|  Medical Care Renal Pharma UK Ltd 12 May 2025.|1
04741|087|R|7.US Food and Drug Administration (FDA). Drug Development and Drug|1
04741|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04741|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04741|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04741|091|R|  11/14/2017.|1
04741|092|R|8.This information is based on an extract from the Certara Drug Interaction|6
04741|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04742|001|T|MONOGRAPH TITLE:  Donanemab/Antiplatelets|
04742|002|B||
04742|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04742|004|L|take action as needed.|
04742|005|B||
04742|006|A|MECHANISM OF ACTION:  Microhemorrhage has been reported with the use of|
04742|007|A|donanemab.  Radiographic changes on brain MRI have been noted as amyloid|
04742|008|A|related imaging abnormalities-hemosiderin deposition (ARIA-H) which included|
04742|009|A|microhemorrhage.  In addition, intracerebral hemorrhages (ICH) greater than|
04742|010|A|1 cm in diameter have occurred in patients treated with donanemab.(1)|
04742|011|B||
04742|012|E|CLINICAL EFFECTS:  Concurrent use of donanemab with antiplatelets may|
04742|013|E|increase the risk of hemorrhage.(1)|
04742|014|B||
04742|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04742|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04742|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
04742|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04742|019|P|risk for bleeding (e.g. NSAIDs).|
04742|020|B||
04742|021|M|PATIENT MANAGEMENT:  Donanemab should be used with extreme caution in|
04742|022|M|patients treated with antiplatelets.  Evaluate the risks and benefits of|
04742|023|M|concurrent use of donanemab with antiplatelets.(1)|
04742|024|M|   The manufacturer of donanemab recommends testing for AP0E4 status prior|
04742|025|M|to initiation of treatment.(1)  Use of antiplatelet agents in patients who|
04742|026|M|are homozygous for the APOE4 gene, may have an increased risk of ARIA with|
04742|027|M|donanemab therapy.(1-3)|
04742|028|M|   Patients receiving concurrent therapy with donanemab and antiplatelets|
04742|029|M|should be closely monitored for signs and symptoms of bleeding and changes|
04742|030|M|in platelet count.(1)|
04742|031|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04742|032|M|therapy for signs of microhemorrhage, including headache, nausea/vomiting,|
04742|033|M|confusion, dizziness, visual disturbance, gait difficulties, and loss of|
04742|034|M|coordination.  General signs of blood loss include decreased hemoglobin,|
04742|035|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
04742|036|M|evaluate patients with any symptoms.|
04742|037|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04742|038|M|confusion, headache, dizziness, nausea, visual changes, unusual bleeding|
04742|039|M|from the gums or nose; unusual bruising; red or black, tarry stools; red,|
04742|040|M|pink or dark brown urine; acute abdominal or joint pain and/or swelling.|
04742|041|B||
04742|042|D|DISCUSSION:  In a double-blind, placebo-controlled clinical study of 1736|
04742|043|D|participants randomized to receive donanemab (n = 860) or placebo (n = 876),|
04742|044|D|donanemab was observed to increase amyloid related imaging|
04742|045|D|abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and|
04742|046|D|intracerebral hemorrhage (ICH).  Radiographic changes were classified as|
04742|047|D|mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10|
04742|048|D|or more new incidences).  The maximum severity of ARIA-H microhemorrhage was|
04742|049|D|observed as mild in 17% (143/853), moderate in 4% (34/853), and severe in 5%|
04742|050|D|(40/853) of patients taking donanemab.(1)|
04742|051|D|   Baseline use of antithrombotic medications (aspirin, other antiplatelets,|
04742|052|D|or anticoagulants) was allowed.  The majority of exposures to antithrombotic|
04742|053|D|medications were to aspirin.  The incidence of ARIA-H was 30% (106/349) in|
04742|054|D|patients taking donanemab with a concomitant antithrombotic medication|
04742|055|D|within 30 days compared to 29% (148/504) who did not receive an|
04742|056|D|antithrombotic within 30 days of an ARIA-H event.(1)|
04742|057|D|   The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349|
04742|058|D|patients) in patients taking donanemab with a concomitant antithrombotic|
04742|059|D|medication compared to 0.4% (2/504) in those who did not receive an|
04742|060|D|antithrombotic.  One fatal ICH occurred in a patient taking donanemab in the|
04742|061|D|setting of focal neurologic symptoms of ARIA and the use of a thrombolytic|
04742|062|D|agent.(1)|
04742|063|B||
04742|064|R|REFERENCES:|
04742|065|B||
04742|066|R|1.Kisunla (donanemab-azbt) US prescribing information. Eli Lilly and Company|1
04742|067|R|  July, 2024.|1
04742|068|R|2.Doran SJ, Sawyer RP. Risk factors in developing amyloid related imaging|6
04742|069|R|  abnormalities (ARIA) and clinical implications. Frontiers in Neuroscience|6
04742|070|R|  19 January 2024;18:1326784:1-7.|6
04742|071|R|3.Couzin-Frankel J. New Alzheimer's drug clears FDA advisory vote despite|6
04742|072|R|  unknowns. SCIENCE 14 june 2024;384(6701):1164-1165.|6
04743|001|T|MONOGRAPH TITLE:  Donanemab/Anticoagulants|
04743|002|B||
04743|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04743|004|L|of severe adverse interaction.|
04743|005|B||
04743|006|A|MECHANISM OF ACTION:  Microhemorrhage has been reported with the use of|
04743|007|A|donanemab.  Radiographic changes on brain MRI have been noted as amyloid|
04743|008|A|related imaging abnormalities-hemosiderin deposition (ARIA-H) which included|
04743|009|A|microhemorrhage.  In addition, intracerebral hemorrhages (ICH) greater than|
04743|010|A|1 cm in diameter have occurred in patients treated with donanemab.(1)|
04743|011|B||
04743|012|E|CLINICAL EFFECTS:  Concurrent use of donanemab with anticoagulants agents|
04743|013|E|may increase the risk of hemorrhage.(1)|
04743|014|B||
04743|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04743|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04743|017|P|   Drug associated risk factors include concurrent use of multiple drugs|
04743|018|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04743|019|P|risk for bleeding (e.g. NSAIDs).|
04743|020|B||
04743|021|M|PATIENT MANAGEMENT:  Donanemab should be used with extreme caution in|
04743|022|M|patients treated with anticoagulants.  Evaluate the risks and benefits of|
04743|023|M|concurrent use of donanemab with anticoagulants.(1)|
04743|024|M|   The manufacturer of donanemab recommends testing for AP0E4 status prior|
04743|025|M|to initiation of treatment.(1)  Use of anticoagulant agents in patients who|
04743|026|M|are homozygous for the APOE4 gene, may have an increased risk of ARIA with|
04743|027|M|donanemab therapy.(1-3)|
04743|028|M|   If concurrent therapy is warranted, patients receiving concurrent therapy|
04743|029|M|with donanemab and anticoagulants should be closely monitored for signs and|
04743|030|M|symptoms of bleeding and changes in platelet count or International|
04743|031|M|Normalized Ratio (INR).(1)|
04743|032|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04743|033|M|therapy for signs of microhemorrhage, including headache, nausea/vomiting,|
04743|034|M|confusion, dizziness, visual disturbance, gait difficulties, and loss of|
04743|035|M|coordination.  General signs of blood loss include decreased hemoglobin,|
04743|036|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
04743|037|M|evaluate patients with any symptoms.|
04743|038|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
04743|039|M|to monitor efficacy and safety of anticoagulation. Discontinue|
04743|040|M|anticoagulation in patients with active pathologic bleeding.|
04743|041|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04743|042|M|confusion, headache, dizziness, nausea, visual changes, unusual bleeding|
04743|043|M|from the gums or nose; unusual bruising; red or black, tarry stools; red,|
04743|044|M|pink or dark brown urine; acute abdominal or joint pain and/or swelling.|
04743|045|B||
04743|046|D|DISCUSSION:  In a double-blind, placebo-controlled clinical study of 1736|
04743|047|D|participants randomized to receive donanemab (n = 860) or placebo (n = 876),|
04743|048|D|donanemab was observed to increase amyloid related imaging|
04743|049|D|abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and|
04743|050|D|intracerebral hemorrhage (ICH).  Radiographic changes were classified as|
04743|051|D|mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10|
04743|052|D|or more new incidences). The maximum severity of ARIA-H microhemorrhage was|
04743|053|D|observed as mild in 17% (143/853), moderate in 4% (34/853), and severe in 5%|
04743|054|D|(40/853) of patients taking donanemab.(1)|
04743|055|D|   Baseline use of antithrombotic medication (aspirin, other antiplatelets,|
04743|056|D|or anticoagulants) was allowed.  The majority of exposures to antithrombotic|
04743|057|D|medications were to aspirin.  The incidence of ARIA-H was 30% (106/349) in|
04743|058|D|patients taking donanemab with a concomitant antithrombotic medication|
04743|059|D|within 30 days compared to 29% (148/504) who did not receive an|
04743|060|D|antithrombotic within 30 days of an ARIA-H event.(1)|
04743|061|D|   The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349|
04743|062|D|patients) in patients taking donanemab with a concomitant antithrombotic|
04743|063|D|medication compared to 0.4% (2/504) in those who did not receive an|
04743|064|D|antithrombotic.  One fatal ICH occurred in a patient taking donanemab in the|
04743|065|D|setting of focal neurologic symptoms of ARIA and the use of a thrombolytic|
04743|066|D|agent.(1)|
04743|067|D|   The manufacturer of donanemab states the number of events and the limited|
04743|068|D|exposure to non-aspirin antithrombotic medications limit definitive|
04743|069|D|conclusions about the risk of ARIA or ICH in patients taking antithrombotic|
04743|070|D|medications concurrently with donanemab.  If concurrent therapy is|
04743|071|D|warranted, patients should be closely monitored for signs and symptoms of|
04743|072|D|bleeding and changes in platelet count or INR.(1)|
04743|073|B||
04743|074|R|REFERENCES:|
04743|075|B||
04743|076|R|1.Kisunla (donanemab-azbt) US prescribing information. Eli Lilly and Company|1
04743|077|R|  July, 2024.|1
04743|078|R|2.Doran SJ, Sawyer RP. Risk factors in developing amyloid related imaging|6
04743|079|R|  abnormalities (ARIA) and clinical implications. Frontiers in Neuroscience|6
04743|080|R|  19 January 2024;18:1326784:1-7.|6
04743|081|R|3.Couzin-Frankel J. New Alzheimer's drug clears FDA advisory vote despite|6
04743|082|R|  unknowns. SCIENCE 14 june 2024;384(6701):1164-1165.|6
04744|001|T|MONOGRAPH TITLE:  Donanemab/Thrombolytics|
04744|002|B||
04744|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04744|004|L|of severe adverse interaction.|
04744|005|B||
04744|006|A|MECHANISM OF ACTION:  Microhemorrhage has been reported with the use of|
04744|007|A|donanemab.  Radiographic changes on brain MRI have been noted as amyloid|
04744|008|A|related imaging abnormalities-hemosiderin deposition (ARIA-H) which included|
04744|009|A|microhemorrhage.  In addition, intracerebral hemorrhages (ICH) greater than|
04744|010|A|1 cm in diameter have occurred in patients treated with donanemab.(1)|
04744|011|B||
04744|012|E|CLINICAL EFFECTS:  Concurrent use of donanemab with thrombolytic agents may|
04744|013|E|increase the risk of hemorrhage.(1)|
04744|014|B||
04744|015|P|PREDISPOSING FACTORS:  Patients with ongoing amyloid-related imaging|
04744|016|P|abnormalities (ARIA) may be at increased risk for post-thrombolytic|
04744|017|P|intracranial hemorrhage (ICH).|
04744|018|P|   The risk for bleeding episodes may be greater in patients with|
04744|019|P|disease-associated factors (e.g. thrombocytopenia).|
04744|020|P|   Drug associated risk factors include concurrent use of multiple drugs|
04744|021|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04744|022|P|risk for bleeding (e.g. NSAIDs).|
04744|023|B||
04744|024|M|PATIENT MANAGEMENT:  Donanemab should be used with extreme caution in|
04744|025|M|patients treated with thrombolytics.  Evaluate the risks and benefits of|
04744|026|M|concurrent use of donanemab with thrombolytics.(1)|
04744|027|M|   The manufacturer of donanemab recommends testing for AP0E4 status prior|
04744|028|M|to initiation of treatment.(1)  Use of thrombolytics in patients who are|
04744|029|M|homozygous for the APOE4 gene, may have an increased risk of ARIA with|
04744|030|M|donanemab therapy.(1-3)|
04744|031|M|   If thrombolytics are warranted, patients receiving concurrent therapy|
04744|032|M|with donanemab and thrombolytics should be closely monitored for signs and|
04744|033|M|symptoms of bleeding and changes in platelet count or symptoms associated|
04744|034|M|with ARIA-H.(1)|
04744|035|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04744|036|M|therapy for signs of microhemorrhage, including headache, nausea/vomiting,|
04744|037|M|confusion, dizziness, visual disturbance, gait difficulties, and loss of|
04744|038|M|coordination.  General signs of blood loss include decreased hemoglobin,|
04744|039|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
04744|040|M|evaluate patients with any symptoms.|
04744|041|M|   When applicable, perform computed tomography (CT) scans and magnetic|
04744|042|M|resonance imaging (MRIs) to monitor efficacy and safety of thrombolytic use|
04744|043|M|with lecanemab. Discontinue thrombolytics in patients with active pathologic|
04744|044|M|bleeding.(1)|
04744|045|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04744|046|M|confusion, headache, dizziness, nausea, visual changes, unusual bleeding|
04744|047|M|from the gums or nose; unusual bruising; red or black, tarry stools; red,|
04744|048|M|pink or dark brown urine; acute abdominal or joint pain and/or swelling.|
04744|049|B||
04744|050|D|DISCUSSION:  In a double-blind, placebo-controlled clinical study of 1736|
04744|051|D|participants randomized to receive donanemab (n = 860) or placebo (n = 876),|
04744|052|D|donanemab was observed to increase amyloid related imaging|
04744|053|D|abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and|
04744|054|D|intracerebral hemorrhage (ICH).  One fatal ICH occurred in a patient taking|
04744|055|D|donanemab in the setting of focal neurologic symptoms of ARIA and the use of|
04744|056|D|a thrombolytic agent.(1)|
04744|057|D|   Radiographic changes were classified as mild (<=4 new incidences),|
04744|058|D|moderate (5 to 9 new incidences), or severe (10 or more new incidences). The|
04744|059|D|maximum severity of ARIA-H microhemorrhage was observed as mild in 17%|
04744|060|D|(143/853), moderate in 4% (34/853), and severe in 5% (40/853) of patients|
04744|061|D|taking donanemab.(1)|
04744|062|D|   Baseline use of antithrombotic medication (aspirin, other antiplatelets,|
04744|063|D|or anticoagulants) was allowed.  The majority of exposures to antithrombotic|
04744|064|D|medications were to aspirin.  The incidence of ARIA-H was 30% (106/349) in|
04744|065|D|patients taking donanemab with a concomitant antithrombotic medication|
04744|066|D|within 30 days compared to 29% (148/504) who did not receive an|
04744|067|D|antithrombotic within 30 days of an ARIA-H event.(1)|
04744|068|D|   The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349|
04744|069|D|patients) in patients taking donanemab with a concomitant antithrombotic|
04744|070|D|medication compared to 0.4% (2/504) in those who did not receive an|
04744|071|D|antithrombotic.(1)|
04744|072|D|   The manufacturer of donanemab states the number of events and the limited|
04744|073|D|exposure to non-aspirin antithrombotic medications limit definitive|
04744|074|D|conclusions about the risk of ARIA or ICH in patients taking antithrombotic|
04744|075|D|medications concurrently with donanemab.  If concurrent therapy is|
04744|076|D|warranted, patients should be closely monitored for signs and symptoms of|
04744|077|D|bleeding and changes in platelet count or INR.(1)|
04744|078|B||
04744|079|R|REFERENCES:|
04744|080|B||
04744|081|R|1.Kisunla (donanemab-azbt) US prescribing information. Eli Lilly and Company|1
04744|082|R|  July, 2024.|1
04744|083|R|2.Doran SJ, Sawyer RP. Risk factors in developing amyloid related imaging|6
04744|084|R|  abnormalities (ARIA) and clinical implications. Frontiers in Neuroscience|6
04744|085|R|  19 January 2024;18:1326784:1-7.|6
04744|086|R|3.Couzin-Frankel J. New Alzheimer's drug clears FDA advisory vote despite|6
04744|087|R|  unknowns. SCIENCE 14 june 2024;384(6701):1164-1165.|6
04744|088|R|4.Bilodeau PA, Dickson JR, Kozberg MG. The Impact of Anti-Amyloid|6
04744|089|R|  Immunotherapies on Stroke Care. J Clin Med 2024 Feb 22;13(5):.|6
04745|001|T|MONOGRAPH TITLE:  Selected Anticoagulants (Vitamin K antagonists)/Linezolid|
04745|002|B||
04745|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04745|004|L|take action as needed.|
04745|005|B||
04745|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Linezolid may|
04745|007|A|interfere with vitamin K-producing gut flora.|
04745|008|B||
04745|009|E|CLINICAL EFFECTS:  Concurrent use of linezolid may increase may result in|
04745|010|E|increased anticoagulant effects with possible bleeding.|
04745|011|B||
04745|012|P|PREDISPOSING FACTORS:  High anticoagulant doses, hepatic or renal|
04745|013|P|impairment, and poor nutrition may increase the risk of bleeding.|
04745|014|P|   The risk for bleeding episodes may be greater in patients with|
04745|015|P|disease-associated factors (e.g., thrombocytopenia).|
04745|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
04745|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04745|018|P|risk for bleeding (e.g., NSAIDs).|
04745|019|B||
04745|020|M|PATIENT MANAGEMENT:  Consider using an alternative antibiotic.|
04745|021|M|   If concurrent therapy is warranted, monitor prothrombin activity and|
04745|022|M|adjust the anticoagulant dosage accordingly.  Monitor patients for signs of|
04745|023|M|blood loss, including decreased hemoglobin, hematocrit, fecal occult blood,|
04745|024|M|and decreased blood pressure and promptly evaluate patients with any|
04745|025|M|symptoms.|
04745|026|M|   When applicable, perform agent-specific laboratory test (e.g., INR, aPTT)|
04745|027|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04745|028|M|anticoagulation in patients with active pathologic bleeding.|
04745|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04745|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04745|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04745|032|M|and/or swelling.|
04745|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04745|034|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
04745|035|M|before initiating, altering the dose or discontinuing either drug.|
04745|036|B||
04745|037|D|DISCUSSION:  A retrospective study examined 16 patients with left|
04745|038|D|ventricular assist system for severe heart failure taking warfarin (goal INR|
04745|039|D|3-4) and started on linezolid.  INR increased non-significantly (from 3.74|
04745|040|D|to 4.06) but warfarin dose decreased (3.23 mg/day to 2.69 mg/day (p=0.001))|
04745|041|D|and INR/warfarin dose ratio increased significantly.  Patients with fever|
04745|042|D|(temperature > 38 degrees C), potentially interacting medications, on liquid|
04745|043|D|diet or TPN or with decreased food intake were excluded.(1)|
04745|044|D|   A retrospective study of 6 patients on warfarin and linezolid after|
04745|045|D|cardiovascular surgery found that INR increased from 1.62 to 3 on day 4-5 of|
04745|046|D|concomitant therapy then decreased by day 10 after dose reduction or|
04745|047|D|withdrawal of warfarin.  Patients on potentially interacting medications|
04745|048|D|were excluded.(2)|
04745|049|D|   In a case series, 4 patients who were 2-5 days post aortic or mitral|
04745|050|D|valve replacement and started on acenocoumarol and linezolid all experienced|
04745|051|D|increased INR ranging from >5 to >10.(3)  A case report describes a patient|
04745|052|D|stable on acenocoumarol for a prosthetic aortic valve who developed INR of|
04745|053|D|5.6 three days after starting linezolid.(4)  Another case report describes a|
04745|054|D|patient who experienced INR of 5.2 three days after concomitant therapy with|
04745|055|D|acenocoumarol and linezolid.(5)|
04745|056|B||
04745|057|R|REFERENCES:|
04745|058|B||
04745|059|R|1.Kinoshita S, Wada K, Matsuda S, Kuwahara T, Sunami H, Sato T, Seguchi O,|2
04745|060|R|  Yanase M, Nakatani T, Takada M. Interaction between Warfarin and Linezolid|2
04745|061|R|  in Patients with Left Ventricular  Assist System in Japan. Intern Med|2
04745|062|R|  2016;55(7):719-24.|2
04745|063|R|2.Sakai Y, Naito T, Arima C, Miura M, Qin L, Hidaka H, Masunaga K, Kakuma T,|2
04745|064|R|  Watanabe H. Potential drug interaction between warfarin and linezolid.|2
04745|065|R|  Intern Med 2015;54(5):459-64.|2
04745|066|R|3.Sarma I, Sharma N, Das B, Kalita J. A Case Series on Acenocoumarol and|3
04745|067|R|  Linezolid Drug Interaction. Cureus 2024 Jan;16(1):e52753.|3
04745|068|R|4.Ghosh K, Ghosh K. Drug Interaction between Acenocoumarol and Linezolid. J|3
04745|069|R|  Assoc Physicians India 2017 Sep;65(9):107.|3
04745|070|R|5.Sarkar R, Paul R, Kole H, Das I, Chakraborty A. Drug Interaction between|3
04745|071|R|  Acenocoumarol and Linezolid: Report of a Case. J Assoc Physicians India|3
04745|072|R|  2016 Jul;64(7):107.|3
04746|001|T|MONOGRAPH TITLE:  Tacrolimus/Isavuconazonium|
04746|002|B||
04746|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04746|004|L|take action as needed.|
04746|005|B||
04746|006|A|MECHANISM OF ACTION:  The metabolism of tacrolimus by CYP3A4 may be|
04746|007|A|inhibited by isavuconazole.(1,2)|
04746|008|B||
04746|009|E|CLINICAL EFFECTS:  Concurrent administration of an azole antifungal may|
04746|010|E|result in elevated levels of and toxicity from tacrolimus, including QT|
04746|011|E|prolongation, nephrotoxicity, neurotoxicity, cardiovascular toxicity,|
04746|012|E|hypertension, anemia, and increased risk of serious infections.(1)|
04746|013|B||
04746|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04746|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04746|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04746|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04746|018|P|female gender, or advanced age.(3)|
04746|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04746|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04746|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04746|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04746|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04746|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04746|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04746|026|B||
04746|027|M|PATIENT MANAGEMENT:  Tacrolimus levels and renal function should be|
04746|028|M|monitored if an azole antifungal is initiated or discontinued from|
04746|029|M|concurrent therapy.  The dosage of tacrolimus may need to be adjusted.|
04746|030|M|   The manufacturers of tacrolimus and isavuconazonium recommend caution|
04746|031|M|with concurrent use of these agents.  Monitor tacrolimus whole blood trough|
04746|032|M|concentrations and adjust dose as needed.(1,2)|
04746|033|M|   Guidelines from the American Society of Transplantation state that while|
04746|034|M|isavuconazonium product labeling does not recommend a dose adjustment,|
04746|035|M|published literature has recommended empiric dose reduction of tacrolimus|
04746|036|M|ranging from 0-50% of the current dose with close therapeutic drug|
04746|037|M|monitoring.(4)|
04746|038|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04746|039|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04746|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04746|041|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04746|042|B||
04746|043|D|DISCUSSION:  Concurrent isavuconazonium increased the maximum concentration|
04746|044|D|(Cmax) and area-under-curve (AUC) of tacrolimus (5 mg) by approximately|
04746|045|D|1.4-fold and 2.25-fold, respectively.(2)|
04746|046|B||
04746|047|R|REFERENCES:|
04746|048|B||
04746|049|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04746|050|R|  August, 2023.|1
04746|051|R|2.Cresemba (isavuconazonium sulfate) US prescribing information. Astellas|1
04746|052|R|  Pharma US, Inc. May, 2021.|1
04746|053|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04746|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04746|055|R|  settings: a scientific statement from the American Heart Association and|6
04746|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04746|057|R|  2;55(9):934-47.|6
04746|058|R|4.Sparkes T, Lemonovich TL. Interactions between anti-infective agents and|6
04746|059|R|  immunosuppressants-Guidelines from the American Society of Transplantation|6
04746|060|R|  Infectious Diseases Community of Practice. Clin Transplant 2019 Feb 28;|6
04746|061|R|  e13510.|6
04747|001|T|MONOGRAPH TITLE:  Pentosan/Selected Anticoagulants|
04747|002|B||
04747|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04747|004|L|take action as needed.|
04747|005|B||
04747|006|A|MECHANISM OF ACTION:  Pentosan is a weak anticoagulant with 1/15 the|
04747|007|A|activity of heparin.  Concurrent use with anticoagulants may result in|
04747|008|A|additive effects.(1)|
04747|009|B||
04747|010|E|CLINICAL EFFECTS:  Concurrent use of pentosan and anticoagulants may|
04747|011|E|increase the risk of hemorrhage.(1)|
04747|012|B||
04747|013|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04747|014|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04747|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
04747|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04747|017|P|risk for bleeding (e.g. NSAIDs).|
04747|018|B||
04747|019|M|PATIENT MANAGEMENT:  Patients receiving concurrent therapy with pentosan and|
04747|020|M|anticoagulants should be evaluated for hemorrhage.(1)|
04747|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04747|022|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04747|023|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04747|024|M|patients with any symptoms.|
04747|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04747|026|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04747|027|M|anticoagulation in patients with active pathologic bleeding.|
04747|028|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04747|029|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04747|030|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04747|031|M|and/or swelling.|
04747|032|B||
04747|033|D|DISCUSSION:  Pentosan is a weak anticoagulant with 1/15 the activity of|
04747|034|D|heparin.(1)|
04747|035|D|   In a study in 41 patients with interstitial cystitis, the concurrent use|
04747|036|D|of pentosan and heparin (5000 units 3 times daily for 2 days, 5000 units 2|
04747|037|D|times daily for 12 days, then 5000 units daily as maintenance) resulted in|
04747|038|D|increased response rates at 3 and 9 months, compared with 17 controls|
04747|039|D|receiving pentosan alone.(2)|
04747|040|B||
04747|041|R|REFERENCES:|
04747|042|B||
04747|043|R|1.Elmiron (pentosan polysulfate sodium) US prescribing information.|1
04747|044|R|  Ortho-McNeil Pharmaceutical, Inc. March, 2021.|1
04747|045|R|2.van Ophoven A, Heinecke A, Hertle L. Safety and efficacy of concurrent|2
04747|046|R|  application of oral pentosan polysulfate and subcutaneous low-dose heparin|2
04747|047|R|  for patients with interstitial cystitis. Urology 2005 Oct;66(4):707-11.|2
04748|001|T|MONOGRAPH TITLE:  Pralsetinib/Strong and Moderate CYP3A4 Inhib that Prolong|
04748|002|T|QT|
04748|003|B||
04748|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04748|005|L|of severe adverse interaction.|
04748|006|B||
04748|007|A|MECHANISM OF ACTION:  Strong and moderate CYP3A4 inhibitors (including|
04748|008|A|combined moderate CYP3A4 and P-glycoprotein (P-gp) inhibitors) that prolong|
04748|009|A|the QTc interval may inhibit the metabolism of pralsetinib and result in|
04748|010|A|additive risk of QT prolongation.(1-3)|
04748|011|B||
04748|012|E|CLINICAL EFFECTS:  Concurrent administration of a strong or moderate CYP3A4|
04748|013|E|inhibitor (including combined moderate CYP3A4 and P-gp inhibitors) that|
04748|014|E|prolongs QT may result in elevated levels of and toxicity from pralsetinib,|
04748|015|E|including additive QTc prolongation, which may result in potentially|
04748|016|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1-3)|
04748|017|E|   Other toxicities include hemorrhagic events, pneumonitis, hepatotoxicity,|
04748|018|E|and hypertension.(1-3)|
04748|019|B||
04748|020|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04748|021|P|may be increased in patients with cardiovascular disease (e.g. heart|
04748|022|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04748|023|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04748|024|P|female gender, or advanced age.(4)|
04748|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04748|026|P|higher systemic concentrations of either QT prolonging drug are additional|
04748|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04748|028|P|drug concentrations include rapid infusion of an intravenous dose or|
04748|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04748|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04748|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04748|032|B||
04748|033|M|PATIENT MANAGEMENT:  Coadministration of pralsetinib with strong or moderate|
04748|034|M|CYP3A4 inhibitors (including combined moderate CYP3A4 and P-gp inhibitors)|
04748|035|M|that prolong QT should be avoided.(1-3)|
04748|036|M|   If coadministration with a strong or moderate CYP3A4 inhibitor that|
04748|037|M|prolongs QT cannot be avoided, use with caution and reduce the dose of|
04748|038|M|pralsetinib as follows:|
04748|039|M|   -If the current dose is 400 mg once daily, decrease the dose to 300 mg|
04748|040|M|daily.|
04748|041|M|   -If the current dose is 300 mg once daily, decrease the dose to 200 mg|
04748|042|M|daily.|
04748|043|M|   -If the current dose is 200 mg once daily, decrease the dose to 100 mg|
04748|044|M|daily.|
04748|045|M|   After the inhibitor is discontinued for three to five half-lives, resume|
04748|046|M|the dose of pralsetinib at the dose taken prior to initiation of the|
04748|047|M|inhibitor.(1)|
04748|048|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04748|049|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04748|050|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04748|051|M|report any irregular heartbeat, dizziness, or fainting.|
04748|052|M|   If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until|
04748|053|M|QTc is <470 ms.  Resume pralsetinib at the same dose if risk factors that|
04748|054|M|cause QT prolongation an are identified and corrected.  If risk factors that|
04748|055|M|cause QT prolongation are not identified, resume pralsetinib at a reduced|
04748|056|M|dose.  Permanently discontinue pralsetinib if the patient develops|
04748|057|M|life-threatening arrhythmia.(3)|
04748|058|B||
04748|059|D|DISCUSSION:  Coadministration of voriconazole 400 mg twice daily for 1 day|
04748|060|D|then 200 mg twice daily (a strong CYP3A inhibitor) resulted in 122% and 20%|
04748|061|D|increase in pralsetinib area-under-curve (AUC) and maximum concentration|
04748|062|D|(Cmax), respectively.(1)|
04748|063|D|   Fluconazole 400 mg daily (a moderate CYP3A4 inhibitor) increased|
04748|064|D|pralsetinib AUC and Cmax by 71% and 15%, respectively.(1)|
04748|065|D|   Verapamil 80 mg three times daily (a moderate CYP3A4 and P-glycoprotein|
04748|066|D|inhibitor) increased pralsetinib AUC and Cmax by 108% and 60%,|
04748|067|D|respectively.(1)|
04748|068|D|   In clinical trials, QTc prolongation developed in 5.1% of patients on|
04748|069|D|pralsetinib, with 2 patients (0.4%) having serious prolongation.  Two|
04748|070|D|patients required dose reductions or interruptions.  No patients required|
04748|071|D|permanent discontinuation of pralsetinib, and there was no life-threatening|
04748|072|D|or fatal QT prolongation.(2)|
04748|073|D|   In a secondary analysis of the phase II ARROW study, ECG and plasma|
04748|074|D|concentrations of 34 patients were examined.  At steady state, mean change|
04748|075|D|in QTc was 4.9-7.7 ms, with a greater QTc increase at higher concentrations,|
04748|076|D|especially above 3,000 ng/mL.  Although median minimum concentration (Cmin)|
04748|077|D|is 1,150 ng/mL, there is a large interindividual variation and|
04748|078|D|concentrations above 3,000 ng/mL may be expected in some patients.(2)|
04748|079|D|   Strong CYP3A4 inhibitors that prolong QT linked to this monograph|
04748|080|D|include: ceritinib, ribociclib, and voriconazole.(5,6)|
04748|081|D|   Moderate CYP3A4 inhibitors that prolong QT include: crizotinib,|
04748|082|D|fluconazole, oral lefamulin and nilotinib.(5,6)|
04748|083|D|   Dual moderate CYP3A4 and P-gp inhibitors that prolong QT include:|
04748|084|D|dronedarone and erythromycin.(5,6)|
04748|085|B||
04748|086|R|REFERENCES:|
04748|087|B||
04748|088|R|1.Gavreto (pralsetinib) US prescribing information. Rigel Pharmaceuticals,|1
04748|089|R|  Inc. June, 2024.|1
04748|090|R|2.EMA Committee for Medicinal Products for Human Use (CHMP). Gavreto|1
04748|091|R|  (pralsetinib) European Medicines Agency Assessment Report|1
04748|092|R|  EMA/CHMP/41191/2021. Roche Registration GmbH. September 12, 2021.|1
04748|093|R|3.Gavreto (pralsetinib) Canadian Product Monograph. Hoffmann-La Roche|1
04748|094|R|  Limited May, 2024.|1
04748|095|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04748|096|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04748|097|R|  settings: a scientific statement from the American Heart Association and|6
04748|098|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04748|099|R|  2;55(9):934-47.|6
04748|100|R|5.This information is based on an extract from the Certara Drug Interaction|6
04748|101|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04748|102|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04748|103|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04748|104|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04748|105|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04748|106|R|  11/14/2017.|1
04749|001|T|MONOGRAPH TITLE:  Pralsetinib/Dual Strong CYP3A4 and P-gp Inhibitors that|
04749|002|T|Prolong QT|
04749|003|B||
04749|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04749|005|L|of severe adverse interaction.|
04749|006|B||
04749|007|A|MECHANISM OF ACTION:  Combined strong CYP3A4 and P-glycoprotein (P-gp)|
04749|008|A|inhibitors that prolong the QTc interval may inhibit the metabolism of|
04749|009|A|pralsetinib and result in additive risk of QT prolongation.(1-3)|
04749|010|B||
04749|011|E|CLINICAL EFFECTS:  Concurrent administration of a combined strong CYP3A4 and|
04749|012|E|P-gp inhibitor that prolongs QT may result in elevated levels of and|
04749|013|E|toxicity from pralsetinib, including additive QTc prolongation, which may|
04749|014|E|result in potentially life-threatening cardiac arrhythmias like torsades de|
04749|015|E|pointes (TdP).(1-3)|
04749|016|E|   Other toxicities include hemorrhagic events, pneumonitis, hepatotoxicity,|
04749|017|E|and hypertension.(1-3)|
04749|018|B||
04749|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04749|020|P|may be increased in patients with cardiovascular disease (e.g. heart|
04749|021|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04749|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04749|023|P|female gender, or advanced age.(4)|
04749|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04749|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04749|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04749|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04749|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04749|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04749|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04749|031|B||
04749|032|M|PATIENT MANAGEMENT:  Coadministration of pralsetinib with combined strong|
04749|033|M|CYP3A4 and P-gp inhibitors that prolong QT should be avoided.|
04749|034|M|   If coadministration with a combined strong CYP3A4 and P-gp inhibitor that|
04749|035|M|prolongs QT cannot be avoided, use with caution reduce the dose of|
04749|036|M|pralsetinib as follows:|
04749|037|M|   -If the current dose is 400 mg once daily, decrease the dose to 200 mg|
04749|038|M|daily.|
04749|039|M|   -If the current dose is 300 mg once daily, decrease the dose to 200 mg|
04749|040|M|daily.|
04749|041|M|   -If the current dose is 200 mg once daily, decrease the dose to 100 mg|
04749|042|M|daily.|
04749|043|M|   After the inhibitor is discontinued for three to five half-lives, resume|
04749|044|M|the dose of pralsetinib at the dose taken prior to initiation of the|
04749|045|M|inhibitor.(1)|
04749|046|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04749|047|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04749|048|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04749|049|M|report any irregular heartbeat, dizziness, or fainting.|
04749|050|M|   If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until|
04749|051|M|QTc is <470 ms.  Resume pralsetinib at the same dose if risk factors that|
04749|052|M|cause QT prolongation an are identified and corrected.  If risk factors that|
04749|053|M|cause QT prolongation are not identified, resume pralsetinib at a reduced|
04749|054|M|dose.  Permanently discontinue pralsetinib if the patient develops|
04749|055|M|life-threatening arrhythmia.(3)|
04749|056|B||
04749|057|D|DISCUSSION:  Coadministration of itraconazole 200 mg once daily (a strong|
04749|058|D|CYP3A4 and P-gp inhibitor) with a single pralsetinib 200 mg dose increased|
04749|059|D|pralsetinib concentration maximum (Cmax) by 84% and area-under-curve (AUC)|
04749|060|D|by 251%.(1)|
04749|061|D|   In clinical trials, QTc prolongation developed in 5.1% of patients on|
04749|062|D|pralsetinib, with 2 patients (0.4%) having serious prolongation.  Two|
04749|063|D|patients required dose reductions or interruptions.  No patients required|
04749|064|D|permanent discontinuation of pralsetinib, and there was no life-threatening|
04749|065|D|or fatal QT prolongation.(2)|
04749|066|D|   In a secondary analysis of the phase II ARROW study, ECG and plasma|
04749|067|D|concentrations of 34 patients were examined.  At steady state, mean change|
04749|068|D|in QTc was 4.9-7.7 ms, with a greater QTc increase at higher concentrations,|
04749|069|D|especially above 3,000 ng/mL.  Although median minimum concentration (Cmin)|
04749|070|D|is 1,150 ng/mL, there is a large interindividual variation and|
04749|071|D|concentrations above 3,000 ng/mL may be expected in some patients.(2)|
04749|072|D|   Combined strong CYP3A4 and P-gp inhibitors linked to this monograph|
04749|073|D|include:  adagrasib, clarithromycin, levoketoconazole, lonafarnib,|
04749|074|D|lopinavir/ritonavir, posaconazole, saquinavir, and telithromycin.(5,6)|
04749|075|B||
04749|076|R|REFERENCES:|
04749|077|B||
04749|078|R|1.Gavreto (pralsetinib) US prescribing information. Rigel Pharmaceuticals,|1
04749|079|R|  Inc. June, 2024.|1
04749|080|R|2.EMA Committee for Medicinal Products for Human Use (CHMP). Gavreto|1
04749|081|R|  (pralsetinib) European Medicines Agency Assessment Report|1
04749|082|R|  EMA/CHMP/41191/2021. Roche Registration GmbH. September 12, 2021.|1
04749|083|R|3.Gavreto (pralsetinib) Canadian Product Monograph. Hoffmann-La Roche|1
04749|084|R|  Limited May, 2024.|1
04749|085|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04749|086|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04749|087|R|  settings: a scientific statement from the American Heart Association and|6
04749|088|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04749|089|R|  2;55(9):934-47.|6
04749|090|R|5.This information is based on an extract from the Certara Drug Interaction|6
04749|091|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04749|092|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04749|093|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04749|094|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04749|095|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04749|096|R|  11/14/2017.|1
04750|001|T|MONOGRAPH TITLE:  Pralsetinib/P-glycoprotein (P-gp) Inhibitors that Prolong|
04750|002|T|QT|
04750|003|B||
04750|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04750|005|L|of severe adverse interaction.|
04750|006|B||
04750|007|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors that prolong the QTc|
04750|008|A|interval may inhibit cellular efflux of pralsetinib and result in additive|
04750|009|A|risk of QT prolongation.(1-3)|
04750|010|B||
04750|011|E|CLINICAL EFFECTS:  Concurrent administration of a P-gp inhibitor that|
04750|012|E|prolongs QT may result in elevated levels of and toxicity from pralsetinib,|
04750|013|E|including additive QTc prolongation, which may result in potentially|
04750|014|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1-3)|
04750|015|E|   Other toxicities include hemorrhagic events, pneumonitis, hepatotoxicity,|
04750|016|E|and hypertension.(1-3)|
04750|017|B||
04750|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04750|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04750|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04750|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04750|022|P|female gender, or advanced age.(4)|
04750|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04750|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04750|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04750|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04750|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04750|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04750|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04750|030|B||
04750|031|M|PATIENT MANAGEMENT:  Coadministration of pralsetinib with a P-gp inhibitor|
04750|032|M|that prolongs QT should be avoided.(1-3)|
04750|033|M|   If coadministration with a P-gp inhibitor that prolongs QT cannot be|
04750|034|M|avoided, use with caution and reduce the dose of pralsetinib as follows:|
04750|035|M|   -If the current dose is 400 mg once daily, decrease the dose to 300 mg|
04750|036|M|daily.|
04750|037|M|   -If the current dose is 300 mg once daily, decrease the dose to 200 mg|
04750|038|M|daily.|
04750|039|M|   -If the current dose is 200 mg once daily, decrease the dose to 100 mg|
04750|040|M|daily.|
04750|041|M|   After the inhibitor is discontinued for three to five half-lives, resume|
04750|042|M|the dose of pralsetinib at the dose taken prior to initiation of the|
04750|043|M|inhibitor.(1)|
04750|044|M|   When concurrent therapy is warranted: consider obtaining serum calcium,|
04750|045|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04750|046|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04750|047|M|report any irregular heartbeat, dizziness, or fainting.|
04750|048|M|   If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until|
04750|049|M|QTc is <470 ms.  Resume pralsetinib at the same dose if risk factors that|
04750|050|M|cause QT prolongation an are identified and corrected.  If risk factors that|
04750|051|M|cause QT prolongation are not identified, resume pralsetinib at a reduced|
04750|052|M|dose.  Permanently discontinue pralsetinib if the patient develops|
04750|053|M|life-threatening arrhythmia.(3)|
04750|054|B||
04750|055|D|DISCUSSION:  Coadministration of a single dose of cyclosporine 600 mg (a|
04750|056|D|P-gp inhibitor) with a single pralsetinib 200 mg dose increased pralsetinib|
04750|057|D|concentration maximum (Cmax) by 48% and area-under-curve (AUC) by 81%.(1)|
04750|058|D|   In clinical trials, QTc prolongation developed in 5.1% of patients on|
04750|059|D|pralsetinib, with 2 patients (0.4%) having serious prolongation.  Two|
04750|060|D|patients required dose reductions or interruptions.  No patients required|
04750|061|D|permanent discontinuation of pralsetinib, and there was no life-threatening|
04750|062|D|or fatal QT prolongation.(2)|
04750|063|D|   In a secondary analysis of the phase II ARROW study, ECG and plasma|
04750|064|D|concentrations of 34 patients were examined.  At steady state, mean change|
04750|065|D|in QTc was 4.9-7.7 ms, with a greater QTc increase at higher concentrations,|
04750|066|D|especially above 3,000 ng/mL.  Although median minimum concentration (Cmin)|
04750|067|D|is 1,150 ng/mL, there is a large interindividual variation and|
04750|068|D|concentrations above 3,000 ng/mL may be expected in some patients.(2)|
04750|069|D|   P-glycoprotein inhibitors that prolong QT linked to this monograph|
04750|070|D|include:  amiodarone, azithromycin, hydroquinidine, lapatinib, mavorixafor,|
04750|071|D|osimertinib, propafenone, quinidine, ranolazine, and vemurafenib.(5,6)|
04750|072|B||
04750|073|R|REFERENCES:|
04750|074|B||
04750|075|R|1.Gavreto (pralsetinib) US prescribing information. Rigel Pharmaceuticals,|1
04750|076|R|  Inc. June, 2024.|1
04750|077|R|2.EMA Committee for Medicinal Products for Human Use (CHMP). Gavreto|1
04750|078|R|  (pralsetinib) European Medicines Agency Assessment Report|1
04750|079|R|  EMA/CHMP/41191/2021. Roche Registration GmbH. September 12, 2021.|1
04750|080|R|3.Gavreto (pralsetinib) Canadian Product Monograph. Hoffmann-La Roche|1
04750|081|R|  Limited May, 2024.|1
04750|082|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04750|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04750|084|R|  settings: a scientific statement from the American Heart Association and|6
04750|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04750|086|R|  2;55(9):934-47.|6
04750|087|R|5.This information is based on an extract from the Certara Drug Interaction|6
04750|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04750|089|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04750|090|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04750|091|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04750|092|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04750|093|R|  11/14/2017.|1
04751|001|T|MONOGRAPH TITLE:  Deuruxolitinib/Immunosuppressives; Immunomodulators|
04751|002|B||
04751|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04751|004|L|of severe adverse interaction.|
04751|005|B||
04751|006|A|MECHANISM OF ACTION:  Deuruxolitinib, immunosuppressives, and|
04751|007|A|immunomodulators all suppress the immune system.(1)|
04751|008|B||
04751|009|E|CLINICAL EFFECTS:  Concurrent use of deuruxolitinib and potent|
04751|010|E|immunosuppressants may increase the risk of serious infections.(1)|
04751|011|B||
04751|012|P|PREDISPOSING FACTORS:  None determined.|
04751|013|B||
04751|014|M|PATIENT MANAGEMENT:  The US manufacturer of deuruxolitinib states that|
04751|015|M|concurrent use of deuruxolitinib with other JAK inhibitors, biologic|
04751|016|M|immunomodulators, cyclosporine or other potent immunosuppressants is not|
04751|017|M|recommended.(1)|
04751|018|M|   If concurrent use cannot be avoided, patients should be monitored for|
04751|019|M|signs and symptoms of infection.  If a patient develops a serious or|
04751|020|M|opportunistic infection, interrupt deuruxolitinib treatment until the|
04751|021|M|infection is controlled.|
04751|022|B||
04751|023|D|DISCUSSION:  Serious infections have been reported in patients receiving|
04751|024|D|treatment with deuruxolitinib.(1)|
04751|025|B||
04751|026|R|REFERENCE:|
04751|027|B||
04751|028|R|1.Leqselvi (deuruxolitinib) tablets, US Prescribing Information. Sun|1
04751|029|R|  Pharmaceuticals Industries, Inc. July 2024.|1
04752|001|T|MONOGRAPH TITLE:  Deuruxolitinib/Strong & Moderate CYP2C9 Inducers|
04752|002|B||
04752|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04752|004|L|of severe adverse interaction.|
04752|005|B||
04752|006|A|MECHANISM OF ACTION:  Drugs that are strong or moderate inducers of CYP2C9|
04752|007|A|may increase the metabolism of deuruxolitinib.(1)|
04752|008|B||
04752|009|E|CLINICAL EFFECTS:  Concurrent use with a strong or moderate CYP2C9 inducer|
04752|010|E|may result in decreased levels and effectiveness of deuruxolitinib.(1)|
04752|011|B||
04752|012|P|PREDISPOSING FACTORS:  Concurrent use of a strong inducer of CYP3A4 may|
04752|013|P|magnify the effect of the CYP2C9 inducer on deuruxolitinib and further|
04752|014|P|decrease the levels of deuruxolitinib.|
04752|015|P|   Induction effects may be more likely with regular use of the inducer for|
04752|016|P|longer than 1-2 weeks.|
04752|017|B||
04752|018|M|PATIENT MANAGEMENT:  The manufacturer of deuruxolitinib states to avoid|
04752|019|M|concomitant use with strong or moderate CYP2C9 inducers.(1)|
04752|020|B||
04752|021|D|DISCUSSION:  No interactions studies have been conducted with strong or|
04752|022|D|moderate CYP2C9 inducers.|
04752|023|D|   In a study with rifampin (a strong CYP3A4 and moderate CYP2C9 inducer),|
04752|024|D|deuruxolitinib area-under-curve (AUC) decreased by 78% and maximum|
04752|025|D|concentration (Cmax) by 41% following concomitant use of multiple doses of|
04752|026|D|600 mg rifampin and a single dose of 12 mg deuruxolitinib (1.5 times the|
04752|027|D|licensed 8 mg dose).(1)|
04752|028|D|   Drugs that are moderate CYP2C9 inducers linked to this monograph include:|
04752|029|D|mavacamten.(2-3)|
04752|030|B||
04752|031|R|REFERENCES:|
04752|032|B||
04752|033|R|1.Leqselvi (deuruxolitinib) tablets, US Prescribing Information. Sun|1
04752|034|R|  Pharmaceuticals Industries, Inc. July 2024.|1
04752|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
04752|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04752|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04752|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04752|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04752|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04752|041|R|  11/14/2017.|1
04753|001|T|MONOGRAPH TITLE:  Deuruxolitinib/Strong & Moderate CYP2C9 Inhibitors|
04753|002|B||
04753|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04753|004|L|is contraindicated and generally should not be dispensed or administered to|
04753|005|L|the same patient.|
04753|006|B||
04753|007|A|MECHANISM OF ACTION:  Strong or moderate CYP2C9 inhibitors may inhibit the|
04753|008|A|metabolism of deuruxolitinib.(1)|
04753|009|B||
04753|010|E|CLINICAL EFFECTS:  Concurrent use of deuruxolitinib with a strong or|
04753|011|E|moderate inhibitor of CYP2C9 may result in elevated levels of and toxicity|
04753|012|E|from deuruxolitinib, including hematologic toxicities (neutropenia,|
04753|013|E|lymphopenia, anemia), lipid abnormalities, infection, and thrombosis.(1)|
04753|014|B||
04753|015|P|PREDISPOSING FACTORS:  None determined.|
04753|016|B||
04753|017|M|PATIENT MANAGEMENT:  The manufacturer of deuruxolitinib states that|
04753|018|M|concomitant treatment with a strong or moderate CYP2C9 inhibitor is|
04753|019|M|contraindicated.(1)|
04753|020|B||
04753|021|D|DISCUSSION:  Concurrent use with strong CYP2C9 inhibitors has not been|
04753|022|D|studied.|
04753|023|D|   Based on pharmacokinetic modelling, deuruxolitinib area-under-curve (AUC)|
04753|024|D|is predicted to be increased by 200% and maximum concentration (Cmax) by 25%|
04753|025|D|following concomitant use of multiple dosages of a strong CYP2C9 inhibitor|
04753|026|D|with a single dose of 12 mg deuruxolitinib (1.5 times the licensed 8 mg|
04753|027|D|dose).(1)|
04753|028|D|   Deuruxolitinib AUC increased by 140% and Cmax by 21% following|
04753|029|D|concomitant use of multiple dosages of 200 mg fluconazole (dual moderate|
04753|030|D|CYP3A4 and CYP2C9 inhibitor) with a single dose of 12 mg deuruxolitinib (1.5|
04753|031|D|times the licensed 8 mg dose).(1)|
04753|032|D|   Strong CYP2C9 inhibitors linked to this monograph include:|
04753|033|D|sulfaphenazole.(2-3)|
04753|034|D|   Moderate CY2C9 inhibitors linked to this monograph include: amiodarone,|
04753|035|D|apazone, benzbromarone, fluconazole, miconazole, mifepristone, milk thistle,|
04753|036|D|nitisinone, oxandrolone, phenylbutazone, and piperine.(2-3)|
04753|037|B||
04753|038|R|REFERENCES:|
04753|039|B||
04753|040|R|1.Leqselvi (deuruxolitinib) tablets, US Prescribing Information. Sun|1
04753|041|R|  Pharmaceuticals Industries, Inc. July 2024.|1
04753|042|R|2.This information is based on an extract from the Certara Drug Interaction|6
04753|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04753|044|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04753|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04753|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04753|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04753|048|R|  11/14/2017.|1
04754|001|T|MONOGRAPH TITLE:  Deuruxolitinib/Dual Inducers of CYP2C9 & CYP3A4|
04754|002|B||
04754|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04754|004|L|of severe adverse interaction.|
04754|005|B||
04754|006|A|MECHANISM OF ACTION:  Drugs that are both strong CYP3A4 and strong or|
04754|007|A|moderate inducers of CYP2C9 may increase the metabolism of|
04754|008|A|deuruxolitinib.(1)|
04754|009|B||
04754|010|E|CLINICAL EFFECTS:  Concurrent use with a strong CYP3A4 and strong or|
04754|011|E|moderate CYP2C9 dual inducer may result in decreased levels and|
04754|012|E|effectiveness of deuruxolitinib.(1)|
04754|013|B||
04754|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04754|015|P|of the inducer for longer than 1-2 weeks.|
04754|016|B||
04754|017|M|PATIENT MANAGEMENT:  The manufacturer of deuruxolitinib states to avoid|
04754|018|M|concomitant use with strong CYP3A4 and strong or moderate CYP2C9|
04754|019|M|inducers.(1)|
04754|020|B||
04754|021|D|DISCUSSION:  In a study with rifampin (a strong CYP3A4 and moderate CYP2C9|
04754|022|D|inducer), deuruxolitinib area-under-curve (AUC) decreased by 78% and maximum|
04754|023|D|concentration (Cmax) by 41% following concomitant use of multiple doses of|
04754|024|D|600 mg rifampin and a single dose of 12mg deuruxolitinib (1.5 times the|
04754|025|D|licensed 8 mg dose).(1)|
04754|026|D|   Drugs that are dual strong CYP3A4 and strong or moderate CYP2C9 inducers|
04754|027|D|linked to this monograph include: enzalutamide, rifampin and ritonavir.(2-3)|
04754|028|B||
04754|029|R|REFERENCES:|
04754|030|B||
04754|031|R|1.Leqselvi (deuruxolitinib) tablets, US Prescribing Information. Sun|1
04754|032|R|  Pharmaceuticals Industries, Inc. July 2024.|1
04754|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
04754|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04754|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04754|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04754|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04754|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04754|039|R|  11/14/2017.|1
04755|001|T|MONOGRAPH TITLE:  Benzgalantamine/Alcohol|
04755|002|B||
04755|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04755|004|L|of severe adverse interaction.|
04755|005|B||
04755|006|A|MECHANISM OF ACTION:  Concomitant use of alcohol with benzgalantamine may|
04755|007|A|cause a rapid release of benzgalantamine.(1)|
04755|008|B||
04755|009|E|CLINICAL EFFECTS:  Rapid release of benzgalantamine may result in increased|
04755|010|E|systemic concentrations and toxicities, including gastrointestinal bleeding,|
04755|011|E|seizures, bradycardia, AV block, and QT prolongation.|
04755|012|B||
04755|013|P|PREDISPOSING FACTORS:  The increased rate of release may be alcohol|
04755|014|P|concentration-dependent.|
04755|015|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04755|016|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04755|017|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
04755|018|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04755|019|P|advanced age.|
04755|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04755|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04755|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04755|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04755|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04755|025|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04755|026|P|dysfunction).|
04755|027|B||
04755|028|M|PATIENT MANAGEMENT:  The manufacturer of benzgalantamine states that|
04755|029|M|benzgalantamine should not be taken with alcohol.  Avoid the use of elixirs|
04755|030|M|containing a high-percentage of alcohol in patients taking these|
04755|031|M|products.(1)|
04755|032|M|   Patients are advised to avoid alcohol while taking this product.|
04755|033|B||
04755|034|D|DISCUSSION:  An in-vitro dissolution study found that alcohol (40% (v/v))|
04755|035|D|increases benzgalantamine release. Dose dumping was not observed in the|
04755|036|D|presence of lower alcohol concentrations.(1)|
04755|037|B||
04755|038|R|REFERENCE:|
04755|039|B||
04755|040|R|1.Zunveyl (benzgalantamine) US prescribing information. Alpha Cognition.|1
04755|041|R|  Inc. July, 2024.|1
04756|001|T|MONOGRAPH TITLE:  Deuruxolitinib/Immunosuppressive Strong & Mod 2C9|
04756|002|T|Inhibitors|
04756|003|B||
04756|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04756|005|L|is contraindicated and generally should not be dispensed or administered to|
04756|006|L|the same patient.|
04756|007|B||
04756|008|A|MECHANISM OF ACTION:  Immunosuppressive strong or moderate CYP2C9 inhibitors|
04756|009|A|may inhibit the metabolism of deuruxolitinib and increase the risk of|
04756|010|A|additive immunosuppression.(1)|
04756|011|B||
04756|012|E|CLINICAL EFFECTS:  Concurrent use of immunosuppressive strong or moderate|
04756|013|E|CYP2C9 inhibitors and deuruxolitinib may result in elevated levels and|
04756|014|E|clinical effects of deuruxolitinib, including hematologic toxicities|
04756|015|E|(neutropenia, lymphopenia, anemia), lipid abnormalities, infection, and|
04756|016|E|thrombosis.(1)|
04756|017|B||
04756|018|P|PREDISPOSING FACTORS:  None determined.|
04756|019|B||
04756|020|M|PATIENT MANAGEMENT:  The manufacturer of deuruxolitinib states that|
04756|021|M|concomitant treatment with a strong or moderate CYP2C9 inhibitor is|
04756|022|M|contraindicated.(1)|
04756|023|M|   The US manufacturer of deuruxolitinib states that concurrent use of|
04756|024|M|deuruxolitinib with other JAK inhibitors, biologic immunomodulators,|
04756|025|M|cyclosporine or other potent immunosuppressants is not recommended.(1)|
04756|026|B||
04756|027|D|DISCUSSION:  Serious infections have been reported in patients receiving|
04756|028|D|treatment with deuruxolitinib.(1)|
04756|029|D|   Concurrent use with strong CYP2C9 inhibitors has not been studied.|
04756|030|D|   Based on pharmacokinetic modeling, deuruxolitinib area-under-curve (AUC)|
04756|031|D|is predicted to be increased by 200% and maximum concentration (Cmax) by 25%|
04756|032|D|following concomitant use of multiple dosages of a strong CYP2C9 inhibitor|
04756|033|D|with a single dose of 12 mg deuruxolitinib (1.5 times the licensed 8 mg|
04756|034|D|dose).(1)|
04756|035|D|   Deuruxolitinib AUC increased by 140% and Cmax by 21% following|
04756|036|D|concomitant use of multiple dosages of 200 mg fluconazole (dual moderate|
04756|037|D|CYP3A4 and CYP2C9 inhibitor) with a single dose of 12 mg deuruxolitinib (1.5|
04756|038|D|times the licensed 8 mg dose).(1)|
04756|039|D|   Moderate immunosuppressive CYP2C9 inhibitors linked to this monograph|
04756|040|D|include: asciminib.(2-3)|
04756|041|B||
04756|042|R|REFERENCES:|
04756|043|B||
04756|044|R|1.Leqselvi (deuruxolitinib) tablets, US Prescribing Information. Sun|1
04756|045|R|  Pharmaceuticals Industries, Inc. July 2024.|1
04756|046|R|2.This information is based on an extract from the Certara Drug Interaction|6
04756|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04756|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04756|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04756|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04756|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04756|052|R|  11/14/2017.|1
04757|001|T|MONOGRAPH TITLE:  Lithium/Ringer's Solution, Lactated (mono deleted|
04757|002|T|09/04/2024)|
04757|003|B||
04757|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04757|005|L|take action as needed.|
04757|006|B||
04757|007|A|MECHANISM OF ACTION:  Lactated ringer's solution may increase the renal|
04757|008|A|excretion of lithium by alkalinization of the urine (formation of|
04757|009|A|bicarbonate).(1)|
04757|010|B||
04757|011|E|CLINICAL EFFECTS:  Concurrent use of lactated ringer's solution and lithium|
04757|012|E|may result in decreased levels and clinical effectiveness of lithium.(1)|
04757|013|B||
04757|014|P|PREDISPOSING FACTORS:  None determined.|
04757|015|B||
04757|016|M|PATIENT MANAGEMENT:  Concurrent use of lactated ringer's solution and|
04757|017|M|lithium should be avoided.  If concurrent use cannot be avoided, lithium|
04757|018|M|levels should be monitored during concurrent use or if lactated ringer's|
04757|019|M|solution is withdrawn from concurrent therapy.  The dose of lithium may need|
04757|020|M|to be adjusted.(1)|
04757|021|B||
04757|022|D|DISCUSSION:  Lactate is an alkalinizer (formation of bicarbonate).  Lactated|
04757|023|D|ringer's solution may interfere with the elimination of drugs, such as|
04757|024|D|lithium, with pH dependent renal elimination.(1)|
04757|025|B||
04757|026|R|REFERENCE:|
04757|027|B||
04757|028|R|1.Lactated Ringer's Injection, USP. Baxter Healthcare, Corporation July,|1
04757|029|R|  2024.|1
04758|001|T|MONOGRAPH TITLE:  Salicylates/Ringer's Solution, Lactated (mono deleted|
04758|002|T|09/04/2024)|
04758|003|B||
04758|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04758|005|L|take action as needed.|
04758|006|B||
04758|007|A|MECHANISM OF ACTION:  Lactated ringer's solution may increase the renal|
04758|008|A|excretion of salicylates by alkalinization of the urine (formation of|
04758|009|A|bicarbonate).(1)|
04758|010|B||
04758|011|E|CLINICAL EFFECTS:  Concurrent use of lactated ringer's solution and|
04758|012|E|salicylates may result in decreased levels and clinical effectiveness of|
04758|013|E|salicylates.(1)|
04758|014|B||
04758|015|P|PREDISPOSING FACTORS:  None determined.|
04758|016|B||
04758|017|M|PATIENT MANAGEMENT:  Concurrent use of lactated ringer's solution and|
04758|018|M|salicylates should be avoided.(1)|
04758|019|B||
04758|020|D|DISCUSSION:  Lactate is an alkalinizer (formation of bicarbonate).  Lactated|
04758|021|D|ringer's solution may interfere with the elimination of acidic drugs, such|
04758|022|D|as salicylates, with pH dependent renal elimination.(1)|
04758|023|B||
04758|024|R|REFERENCE:|
04758|025|B||
04758|026|R|1.Lactated Ringer's Injection, USP. Baxter Healthcare, Corporation July,|1
04758|027|R|  2024.|1
04759|001|T|MONOGRAPH TITLE:  Barbiturates/Ringer's Solution, Lactated (mono deleted|
04759|002|T|09/04/2024)|
04759|003|B||
04759|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04759|005|L|take action as needed.|
04759|006|B||
04759|007|A|MECHANISM OF ACTION:  Lactated ringer's solution may increase the renal|
04759|008|A|excretion of barbiturates by alkalinization of the urine (formation of|
04759|009|A|bicarbonate).(1)|
04759|010|B||
04759|011|E|CLINICAL EFFECTS:  Concurrent use of lactated ringer's solution and|
04759|012|E|barbiturates may result in decreased levels and clinical effectiveness of|
04759|013|E|barbiturates.(1)|
04759|014|B||
04759|015|P|PREDISPOSING FACTORS:  None determined.|
04759|016|B||
04759|017|M|PATIENT MANAGEMENT:  Concurrent use of lactated ringer's solution and|
04759|018|M|barbiturates should be avoided.(1)|
04759|019|B||
04759|020|D|DISCUSSION:  Lactate is an alkalinizer (formation of bicarbonate).  Lactated|
04759|021|D|ringer's solution may interfere with the elimination of acidic drugs, such|
04759|022|D|as barbiturates, with pH dependent renal elimination.(1)|
04759|023|B||
04759|024|R|REFERENCE:|
04759|025|B||
04759|026|R|1.Lactated Ringer's Injection, USP. Baxter Healthcare, Corporation July,|1
04759|027|R|  2024.|1
04760|001|T|MONOGRAPH TITLE:  Mifepristone (Chronic)/Str 3A4 Inducer & 2C8;2C9|
04760|002|T|Substrates|
04760|003|B||
04760|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04760|005|L|of severe adverse interaction.|
04760|006|B||
04760|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers such as enzalutamide,|
04760|008|A|fosphenytoin, or phenytoin may accelerate the metabolism of mifepristone by|
04760|009|A|CYP3A4.(1,2)  Mifepristone is a moderate inhibitor of CYP2C8 and CYP2C9.(1)|
04760|010|B||
04760|011|E|CLINICAL EFFECTS:  The concurrent use of mifepristone and strong CYP3A4|
04760|012|E|inducers may result in decreased levels and effectiveness of|
04760|013|E|mifepristone.(1,2)  Decreased clearance of drugs primarily metabolized by|
04760|014|E|CYP2C8 or CYP2C9 may increase systemic concentrations, leading to|
04760|015|E|toxicity.(1)|
04760|016|B||
04760|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04760|018|P|of the inducer for longer than 1-2 weeks.|
04760|019|B||
04760|020|M|PATIENT MANAGEMENT:  Avoid co-administration of mifepristone with strong|
04760|021|M|CYP3A4 inducers.(1-3)|
04760|022|M|   If mifepristone is used as a progestin antagonist and concurrent use|
04760|023|M|cannot be avoided, conduct post-treatment assessment as detailed in the|
04760|024|M|mifepristone prescribing information to verify treatment success.(1,3)|
04760|025|M|   If concurrent use cannot be avoided, closely monitor patients stable on|
04760|026|M|CYP2C8/2C9 substrates for increased therapeutic effect or toxicity when|
04760|027|M|chronic mifepristone therapy is started or adjusted.  Adjust dosage of the|
04760|028|M|2C8/2C9 substrate drug accordingly.  Because of the long half-life of|
04760|029|M|mifepristone, the effect of changes in mifepristone therapy may not be seen|
04760|030|M|for 2 weeks.|
04760|031|M|   For patients on chronic mifepristone and newly started on a CYP2C8/2C9|
04760|032|M|substrate, the smallest recommended dose of the CYP2C8/2C9 substrate is|
04760|033|M|suggested by the manufacturer of mifepristone.(1)|
04760|034|M|   If chronic mifepristone therapy is discontinued, the manufacturer of|
04760|035|M|mifepristone recommends waiting at least 2 weeks before increasing the dose|
04760|036|M|of a concomitant interacting medication.(1)|
04760|037|B||
04760|038|D|DISCUSSION:  In a study, rifampin decreased mifepristone area-under-curve|
04760|039|D|(AUC) by 6.3-fold.  The AUC of mifepristone active metabolites|
04760|040|D|22-hydroxy-mifepristone and N-demethyl-mifepristone decreased by 20-fold and|
04760|041|D|5.9-fold, respectively.(4)|
04760|042|D|   Mifepristone 1200 mg was given daily for 7 days, followed by a single|
04760|043|D|dose of fluvastatin (40 mg), a CYP 2C8/2C9.  The area-under-curve (AUC) of|
04760|044|D|fluvastatin was increased 3.57 fold. The manufacturer notes this result|
04760|045|D|could be representative of other oral drugs with CYP2C8/2C9 metabolism.(1)|
04760|046|D|   Mifepristone has a long elimination half-life of approximately 85 hours|
04760|047|D|and so full effects of a mifepristone dose change on CYP2C8/2C9 substrates|
04760|048|D|may not be seen for two weeks.  Extended monitoring for this interaction may|
04760|049|D|be required when mifepristone is started, stopped or if dose is changed.(1)|
04760|050|D|   Medications linked to this interaction are enzalutamide, fosphenytoin,|
04760|051|D|and phenytoin.  These drugs have a narrow therapeutic range or are|
04760|052|D|designated as CYP2C8 or CYP2C9 Sensitive Substrates(2,3), i.e. moderate|
04760|053|D|CYP2C8 or 2C9 inhibitors are expected to increase exposure (AUC) to these|
04760|054|D|agents by 2-fold to 5-fold.|
04760|055|B||
04760|056|R|REFERENCES:|
04760|057|B||
04760|058|R|1.Mifeprex (mifepristone) US prescribing information. Danco Laboratories,|1
04760|059|R|  LLC January, 2023.|1
04760|060|R|2.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
04760|061|R|  November, 2019.|1
04760|062|R|3.Rifadin (rifampin) US prescribing information. Sanofi-Aventis U.S. LLC|1
04760|063|R|  October, 2024.|1
04760|064|R|4.Rifadin (rifampin) UK Summary of Product Characteristics. Sanofi July 2,|1
04760|065|R|  2024.|1
04760|066|R|5.This information is based on an extract from the Certara Drug Interaction|6
04760|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04761|001|T|MONOGRAPH TITLE:  Meperidine/Methylphenidate|
04761|002|B||
04761|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04761|004|L|take action as needed.|
04761|005|B||
04761|006|A|MECHANISM OF ACTION:  Opioids and methylphenidate exhibit opposing effects|
04761|007|A|on the CNS.(1)|
04761|008|B||
04761|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and methylphenidate may have|
04761|010|E|unpredictable effects and may mask overdose symptoms of the opioid, such as|
04761|011|E|drowsiness and inability to focus.|
04761|012|B||
04761|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04761|014|P|may increase the risk of adverse effects.|
04761|015|B||
04761|016|M|PATIENT MANAGEMENT:  Limit prescribing meperidine with CNS stimulants such|
04761|017|M|as methylphenidate to patients for whom alternatives are ineffective, not|
04761|018|M|tolerated, or would be otherwise inadequate to provide sufficient management|
04761|019|M|of pain.|
04761|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
04761|021|M|drug to the minimum possible while achieving the desired clinical effect.|
04761|022|M|   Respiratory depression can occur at any time during opioid therapy,|
04761|023|M|especially during therapy initiation and following dosage increases.  The|
04761|024|M|risk of opioid-related overdose or overdose-related death is increased with|
04761|025|M|higher opioid doses, and this risk persists over the course of therapy.|
04761|026|M|Consider these risks when using concurrently with other agents that may|
04761|027|M|cause CNS depression.(1)|
04761|028|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04761|029|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04761|030|M|unresponsiveness.|
04761|031|M|  Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04761|032|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04761|033|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04761|034|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04761|035|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04761|036|M|as those taking CNS depressants) and when a patient has household|
04761|037|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04761|038|M|for obtaining an opioid reversal agent (e.g., prescription,|
04761|039|M|over-the-counter, or as part of a community-based program).|
04761|040|M|   Monitor patients receiving concurrent therapy for signs of substance|
04761|041|M|abuse.|
04761|042|B||
04761|043|D|DISCUSSION:  A total of 70,237 persons died from drug overdoses in the|
04761|044|D|United States in 2017; approximately two thirds of these deaths involved an|
04761|045|D|opioid.(2).  The CDC analyzed 2016-2017 changes in age-adjusted death rates|
04761|046|D|involving cocaine and psychostimulants by demographic characteristics,|
04761|047|D|urbanization levels, U.S. Census region, 34 states, and the District of|
04761|048|D|Columbia (DC).  The CDC also examined trends in age-adjusted|
04761|049|D|cocaine-involved and psychostimulant-involved death rates from 2003 to 2017|
04761|050|D|overall, as well as with and without co-involvement of opioids.  Among all|
04761|051|D|2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333|
04761|052|D|(14.7%) involved psychostimulants.  Death rates increased from 2016 to 2017|
04761|053|D|for both drug categories across demographic characteristics, urbanization|
04761|054|D|levels, Census regions, and states.  In 2017, opioids were involved in 72.7%|
04761|055|D|and 50.4% of cocaine-involved and psychostimulant-involved overdoses,|
04761|056|D|respectively, and the data suggest that increases in cocaine-involved|
04761|057|D|overdose deaths from 2012 to 2017 were driven primarily by synthetic|
04761|058|D|opioids.(3)|
04761|059|D|   There was opioid co-involvement in 72.7 percent of cocaine and 50.4|
04761|060|D|percent of stimulant-involved overdose deaths.  This was largely driven by|
04761|061|D|synthetic opioids such as fentanyl. However, stimulant-involved overdose|
04761|062|D|without opioid co-involvement is also increasing.(2)|
04761|063|B||
04761|064|R|REFERENCES:|
04761|065|B||
04761|066|R|1.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04761|067|R|  prescribing information for all opioid pain medicines to provide|1
04761|068|R|  additional guidance for safe use. Available at:|1
04761|069|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04761|070|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04761|071|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04761|072|R|2.Seth P, Scholl L, Rudd RA, Bacon S. Overdose Deaths Involving Opioids,|6
04761|073|R|  Cocaine, and Psychostimulants - United States, 2015-2016. MMWR Morb Mortal|6
04761|074|R|  Wkly Rep 2018 Mar 30;67(12):349-358.|6
04761|075|R|3.Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved|6
04761|076|R|  Overdose Deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep 2018|6
04761|077|R|  Jan 4;67(5152):1419-1427.|6
04762|001|T|MONOGRAPH TITLE:  Voriconazole/Flucloxacillin|
04762|002|B||
04762|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04762|004|L|take action as needed.|
04762|005|B||
04762|006|A|MECHANISM OF ACTION:  Flucloxacillin may induce the metabolism of|
04762|007|A|voriconazole by CYP3A4.(1-2)|
04762|008|B||
04762|009|E|CLINICAL EFFECTS:  Concurrent use of flucloxacillin and voriconazole may|
04762|010|E|result in decreased levels and therapeutic effect of voriconazole.(1-2)|
04762|011|B||
04762|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04762|013|P|of the inducer for longer than 1-2 weeks.|
04762|014|B||
04762|015|M|PATIENT MANAGEMENT:  The Australian and UK manufacturers of voriconazole|
04762|016|M|state that flucloxacillin has been reported to significantly decrease plasma|
04762|017|M|voriconazole concentrations.  If concomitant administration of voriconazole|
04762|018|M|with flucloxacillin cannot be avoided, monitor for potential loss of|
04762|019|M|voriconazole effectiveness and increase the dose of voriconazole if|
04762|020|M|needed.(1-2)|
04762|021|M|   The US manufacturer of voriconazole does not make any recommendations for|
04762|022|M|concurrent use with flucloxacillin.(3)|
04762|023|B||
04762|024|D|DISCUSSION:  No formal interaction studies have been done with|
04762|025|D|flucloxacillin and voriconazole.|
04762|026|D|   In a retrospective study of 33 patients treated with voriconazole with or|
04762|027|D|without flucloxacillin, subtherapeutic concentrations of voriconazole (<1|
04762|028|D|mg/L) were observed in 69% and 7% of the samples with flucloxacillin|
04762|029|D|co-treatment versus samples without flucloxacillin co-treatment,|
04762|030|D|respectively.(4)|
04762|031|D|   In a retrospective study of 20 patients receiving combination treatment|
04762|032|D|with voriconazole and flucloxacillin, subtherapeutic concentrations of|
04762|033|D|voriconazole (<1 mg/L) were observed in 11 of the 20 patients. In the|
04762|034|D|remaining 9 patients, little to no effect was found.(5)|
04762|035|D|   A retrospective study of 8 patients reported all patients exhibiting|
04762|036|D|subtherapeutic concentrations of voriconazole [median concentration 0.15|
04762|037|D|mg/L (interquartile range 0.10-0.28)] following initiation of|
04762|038|D|flucloxacillin.  In 5 patients, voriconazole concentrations remained|
04762|039|D|subtherapeutic despite dose increases, and treatment for 2 patients was|
04762|040|D|changed to alternative antifungal agents.(6)|
04762|041|B||
04762|042|R|REFERENCES:|
04762|043|B||
04762|044|R|1.Voriconazole (VFEND), Australian Product Information. Pfizer Australia Pty|1
04762|045|R|  Ltd October 2024.|1
04762|046|R|2.Vfend (voriconazole) UK summary of product characteristics. Pfizer Limited|1
04762|047|R|  March, 2022.|1
04762|048|R|3.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
04762|049|R|4.Daele RV, Wauters J, De Cock P, Buyle F, Leys J, Van Brantegem P, Gijsen|3
04762|050|R|  M, Annaert P, Debaveye Y, Lagrou K, Peetermans WE, Bruggemann RJ, Spriet|3
04762|051|R|  I. Concomitant Treatment with Voriconazole and Flucloxacillin: A|3
04762|052|R|  Combination to Avoid. antibiotics 15 September 2021;10(1112):1-9.|3
04762|053|R|5.Muilwijk EW, Dekkers BGJ, Henriet SSV, Verweij PE, Witjes B, Oude Lashof|3
04762|054|R|  AML, Groeneveld GH,  Van der Hoeven J, Alffenaar JWC, Russel FGM, Van der|3
04762|055|R|  Veerdonk F, Bruggemann RJM, . Flucloxacillin Results in Suboptimal Plasma|3
04762|056|R|  Voriconazole Concentrations. Antimicrobial Agents and Chemotherapy|3
04762|057|R|  September 2017;61(9):1-5.|3
04762|058|R|6.Burrows FS, Carlos LM, Stojanova J, Marriott DJE. It cuts both ways: A|3
04762|059|R|  single-center retrospective review describing a three-way interaction|3
04762|060|R|  between flucloxacillin, voriconazole and tacrolimus. International Journal|3
04762|061|R|  of Antimicrobial Agents September 2023;62(3):.|3
04763|001|T|MONOGRAPH TITLE:  Vorasidenib/Strong CYP1A2 Inhibitors|
04763|002|B||
04763|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04763|004|L|of severe adverse interaction.|
04763|005|B||
04763|006|A|MECHANISM OF ACTION:  Strong CYP1A2 inhibitors may inhibit the metabolism of|
04763|007|A|vorasidenib.(1)|
04763|008|B||
04763|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP1A2 inhibitors may result in|
04763|010|E|elevated levels of and effects from vorasidenib, including|
04763|011|E|hepatotoxicity.(1)|
04763|012|B||
04763|013|P|PREDISPOSING FACTORS:  None determined.|
04763|014|B||
04763|015|M|PATIENT MANAGEMENT:  The US manufacturer for vorasidenib states concurrent|
04763|016|M|use with strong CYP1A2 inhibitors should be avoided.(1)|
04763|017|B||
04763|018|D|DISCUSSION:  Vorasidenib is primarily metabolized by CYP1A2.(1)|
04763|019|D|   Concurrent use of vorasidenib and fluvoxamine (a strong CYP1A2 inhibitor)|
04763|020|D|is predicted to increase vorasidenib maximum concentration (Cmax) and|
04763|021|D|area-under-curve (AUC) by greater than 5-fold.(1)|
04763|022|D|   In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate|
04763|023|D|CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1)|
04763|024|D|   Strong CYP1A2 inhibitors linked to this monograph include: angelica root|
04763|025|D|(angelica dahurica radix), enasidenib, enoxacin, fluvoxamine, and|
04763|026|D|rofecoxib.(2)|
04763|027|B||
04763|028|R|REFERENCES:|
04763|029|B||
04763|030|R|1.Voranigo (vorasidenib) US prescribing information. Servier Pharmaceuticals|1
04763|031|R|  August, 2024.|1
04763|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
04763|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04764|001|T|MONOGRAPH TITLE:  Vorasidenib/Moderate CYP1A2 Inhibitors|
04764|002|B||
04764|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04764|004|L|of severe adverse interaction.|
04764|005|B||
04764|006|A|MECHANISM OF ACTION:  Moderate CYP1A2 inhibitors may inhibit the metabolism|
04764|007|A|of vorasidenib.(1)|
04764|008|B||
04764|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP1A2 inhibitors may result|
04764|010|E|in elevated levels of and effects from vorasidenib, including|
04764|011|E|hepatotoxicity.(1)|
04764|012|B||
04764|013|P|PREDISPOSING FACTORS:  None determined.|
04764|014|B||
04764|015|M|PATIENT MANAGEMENT:  The US manufacturer for vorasidenib states concurrent|
04764|016|M|use with moderate CYP1A2 inhibitors should be avoided.(1)|
04764|017|M|   If concurrent use of moderate CYP1A2 inhibitors cannot be avoided,|
04764|018|M|monitor for increased risk of adverse reactions and modify the dose of|
04764|019|M|vorasidenib as recommended in the prescribing information.(1)|
04764|020|B||
04764|021|D|DISCUSSION:  Vorasidenib is primarily metabolized by CYP1A2.(1)|
04764|022|D|   Concurrent use of vorasidenib and fluvoxamine (a strong CYP1A2 inhibitor)|
04764|023|D|is predicted to increase vorasidenib maximum concentration (Cmax) and|
04764|024|D|area-under-curve (AUC) by greater than 5-fold.(1)|
04764|025|D|   In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate|
04764|026|D|CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1)|
04764|027|D|   Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib,|
04764|028|D|ciprofloxacin, dipyrone, fexinidazole, genistein, methoxsalen, mexiletine,|
04764|029|D|osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib,|
04764|030|D|troleandomycin, vemurafenib, and viloxazine.(2)|
04764|031|B||
04764|032|R|REFERENCES:|
04764|033|B||
04764|034|R|1.Voranigo (vorasidenib) US prescribing information. Servier Pharmaceuticals|1
04764|035|R|  August, 2024.|1
04764|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
04764|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04765|001|T|MONOGRAPH TITLE:  Vorasidenib/Moderate CYP1A2 Inducers|
04765|002|B||
04765|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04765|004|L|of severe adverse interaction.|
04765|005|B||
04765|006|A|MECHANISM OF ACTION:  Moderate CYP1A2 inducers may increase the metabolism|
04765|007|A|of vorasidenib.(1)|
04765|008|B||
04765|009|E|CLINICAL EFFECTS:  Concurrent use of a CYP1A2 inducer may result in|
04765|010|E|decreased levels and effectiveness of vorasidenib.(1)|
04765|011|B||
04765|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04765|013|P|of the inducer for longer than 1-2 weeks.|
04765|014|B||
04765|015|M|PATIENT MANAGEMENT:  The US manufacturer of vorasidenib states concurrent|
04765|016|M|use with moderate CYP1A2 inducers should be avoided.(1)|
04765|017|B||
04765|018|D|DISCUSSION:  Vorasidenib is primarily metabolized by CYP1A2.(1)|
04765|019|D|   Concurrent use of vorasidenib with phenytoin or rifampin (moderate CYP1A2|
04765|020|D|inducers) is predicted to decrease vorasidenib concentration maximum (Cmax)|
04765|021|D|by 30% and area-under-curve (AUC) by 40%.(1)|
04765|022|D|   Moderate CYP1A2 inducers linked to this monograph include: fosphenytoin,|
04765|023|D|leflunomide, nelfinavir, phenytoin, rifampin, ritonavir, and|
04765|024|D|teriflunomide.(2)|
04765|025|B||
04765|026|R|REFERENCES:|
04765|027|B||
04765|028|R|1.Voranigo (vorasidenib) US prescribing information. Servier Pharmaceuticals|1
04765|029|R|  August, 2024.|1
04765|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04765|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04766|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Vorasidenib|
04766|002|B||
04766|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04766|004|L|of severe adverse interaction.|
04766|005|B||
04766|006|A|MECHANISM OF ACTION:  Vorasidenib may induce the CYP3A4-mediated metabolism|
04766|007|A|of hormonal contraceptives.(1)  Hormonal contraceptives may inhibit the|
04766|008|A|CYP1A2-mediated metabolism of vorasidenib.(1,2)|
04766|009|B||
04766|010|E|CLINICAL EFFECTS:  Concurrent use of vorasidenib may reduce the blood|
04766|011|E|concentrations and effectiveness of hormonal contraceptives.  Vorasidenib|
04766|012|E|may cause fetal harm when administered to pregnant women.(1)|
04766|013|E|   Concurrent use of moderate CYP1A2 inhibitors such as hormonal|
04766|014|E|contraceptives may result in elevated levels of and effects from|
04766|015|E|vorasidenib, including hepatotoxicity.(1)|
04766|016|B||
04766|017|P|PREDISPOSING FACTORS:  None determined.|
04766|018|B||
04766|019|M|PATIENT MANAGEMENT:  The US manufacturer of vorasidenib states that|
04766|020|M|concurrent use of moderate CYP1A2 inhibitors should be avoided.  If|
04766|021|M|concurrent use of moderate CYP1A2 inhibitors cannot be avoided, monitor for|
04766|022|M|increased risk of adverse reactions and modify the dose of vorasidenib as|
04766|023|M|recommended in the prescribing information.(1)|
04766|024|M|   Women of reproductive age should be counseled to avoid hormonal|
04766|025|M|contraception (including oral contraceptives, patches, implants, and/or|
04766|026|M|IUDs) due to the risk of contraceptive failure.  Women should use an|
04766|027|M|effective non-hormonal method of contraception during and for 3 months after|
04766|028|M|vorasidenib therapy.(1)|
04766|029|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04766|030|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04766|031|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04766|032|M|contraceptive (i.e., a copper IUD).  If a non-hormonal emergency|
04766|033|M|contraceptive is not an option, double the usual dose of levonorgestrel from|
04766|034|M|1.5 to 3 mg.  Advise the patient to have a pregnancy test to exclude|
04766|035|M|pregnancy after use and to seek medical advice if they do become|
04766|036|M|pregnant.(3)|
04766|037|B||
04766|038|D|DISCUSSION:  Vorasidenib is an inducer of CYP3A4 in vitro.  Concomitant use|
04766|039|D|of multiple doses of vorasidenib is predicted to decrease the concentration|
04766|040|D|of CYP3A4 substrates, including hormonal contraceptives.  Vorasidenib may|
04766|041|D|cause fetal harm when administered to pregnant women.(1)|
04766|042|D|   Vorasidenib is primarily metabolized by CYP1A2.  In a study, concurrent|
04766|043|D|use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased|
04766|044|D|vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1)|
04766|045|B||
04766|046|R|REFERENCES:|
04766|047|B||
04766|048|R|1.Voranigo (vorasidenib) US prescribing information. Servier Pharmaceuticals|1
04766|049|R|  August, 2024.|1
04766|050|R|2.This information is based on an extract from the Certara Drug Interaction|6
04766|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04766|052|R|3.Medicines and Healthcare products Regulatory Agency.|1
04766|053|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04766|054|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04766|055|R|  available at:|1
04766|056|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04766|057|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04766|058|R|  -and-contraceptive-efficacy September 15, 2016..|1
04767|001|T|MONOGRAPH TITLE:  Darunavir; Fosamprenavir/Lumacaftor|
04767|002|B||
04767|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04767|004|L|of severe adverse interaction.|
04767|005|B||
04767|006|A|MECHANISM OF ACTION:  Lumacaftor, a strong inducer of CYP3A4, may induce the|
04767|007|A|metabolism of darunavir and fosamprenavir.(1-3)|
04767|008|A|   Darunavir and fosamprenavir are designated as sensitive CYP3A4|
04767|009|A|substrates; strong inducers may decrease exposure by 80% or more.(4)|
04767|010|B||
04767|011|E|CLINICAL EFFECTS:  Concurrent use of lumacaftor may decrease the levels and|
04767|012|E|effectiveness of darunavir and fosamprenavir.(1-3)|
04767|013|B||
04767|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04767|015|P|of the inducer for longer than 1-2 weeks.|
04767|016|B||
04767|017|M|PATIENT MANAGEMENT:  The manufacturer of lumacaftor states concurrent use|
04767|018|M|with sensitive CYP3A4 substrates is not recommended.(1)|
04767|019|B||
04767|020|D|DISCUSSION:  In an interaction study lumacaftor reduced exposure to|
04767|021|D|ivacaftor, another CYP3A4 sensitive substrate, by 80%.(1)|
04767|022|B||
04767|023|R|REFERENCES:|
04767|024|B||
04767|025|R|1.Orkambi (lumacaftor, ivacaftor) US prescribing information. Vertex|1
04767|026|R|  Pharmaceuticals Inc. August, 2023.|1
04767|027|R|2.Prezista (darunavir) US prescribing information. Janssen Therapeutics|1
04767|028|R|  March, 2023.|1
04767|029|R|3.Lexiva (fosamprenavir calcium) US prescribing information. GlaxoSmithKline|1
04767|030|R|  March, 2019.|1
04767|031|R|4.This information is based on an extract from the Certara Drug Interaction|6
04767|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04767|033|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04767|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04767|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04767|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04767|037|R|  11/14/2017.|1
04768|001|T|MONOGRAPH TITLE:  Levodopa (Extended Release)/Alcohol|
04768|002|B||
04768|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04768|004|L|of severe adverse interaction.|
04768|005|B||
04768|006|A|MECHANISM OF ACTION:  Concomitant use of alcohol with extended release|
04768|007|A|levodopa may cause a rapid release of levodopa.(1)|
04768|008|B||
04768|009|E|CLINICAL EFFECTS:  Rapid release of levodopa may result in increased|
04768|010|E|systemic concentrations and effects of levodopa, including tremor,|
04768|011|E|hypertensive crisis, and postural hypotension.|
04768|012|B||
04768|013|P|PREDISPOSING FACTORS:  The increased rate of release may be alcohol|
04768|014|P|concentration-dependent.|
04768|015|B||
04768|016|M|PATIENT MANAGEMENT:  The manufacturer of Crexont (levodopa-carbidopa) states|
04768|017|M|that Crexont should not be taken with alcohol.  Avoid the use of elixirs|
04768|018|M|containing a high-percentage of alcohol in patients taking these|
04768|019|M|products.(1)|
04768|020|M|   Patients are advised to avoid alcohol while taking this product.|
04768|021|B||
04768|022|D|DISCUSSION:  An in-vitro dissolution study found that alcohol (40% (v/v))|
04768|023|D|increases levodopa release. Dose dumping was not observed in the presence of|
04768|024|D|lower alcohol concentrations.(1)|
04768|025|B||
04768|026|R|REFERENCE:|
04768|027|B||
04768|028|R|1.Crexont - carbidopa and levodopa capsule, extended release, US PI|1
04768|029|R|  Information. Amneal Pharmaceuticals LLC August 2024.|1
04769|001|T|MONOGRAPH TITLE:  Seladelpar/Bile Acid Sequestrants|
04769|002|B||
04769|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04769|004|L|take action as needed.|
04769|005|B||
04769|006|A|MECHANISM OF ACTION:  Bile acid sequestrants may bind to seladelpar in the|
04769|007|A|gut, resulting in decreased absorption of seladelpar.(1)|
04769|008|B||
04769|009|E|CLINICAL EFFECTS:  Coadministration of bile acid sequestrants with|
04769|010|E|seladelpar may result in reduced efficacy of seladelpar.(1)|
04769|011|B||
04769|012|P|PREDISPOSING FACTORS:  None determined.|
04769|013|B||
04769|014|M|PATIENT MANAGEMENT:  The US manufacturer of seladelpar states to administer|
04769|015|M|bile acid sequestrants (cholestyramine, colesevelam, and colestipol) at|
04769|016|M|least 4 hours before or 4 hours after administration of seladelpar, or at as|
04769|017|M|great an interval as possible.(1)|
04769|018|B||
04769|019|D|DISCUSSION:  Bile acid sequestrants are known to bind to drugs when given|
04769|020|D|concurrently.  Administration with seladelpar may result in decreased|
04769|021|D|systemic absorption.(1)|
04769|022|B||
04769|023|R|REFERENCE:|
04769|024|B||
04769|025|R|1.Livdelzi (seladelpar) US prescribing information. Gilead Sciences, Inc.|1
04769|026|R|  Aug, 2024.|1
04770|001|T|MONOGRAPH TITLE:  Seladelpar/Strong CYP2C9 Inhibitors|
04770|002|B||
04770|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04770|004|L|of severe adverse interaction.|
04770|005|B||
04770|006|A|MECHANISM OF ACTION:  Seladelpar is metabolized by CYP2C9, CYP3A4,and|
04770|007|A|CYP2C8.  Strong CYP2C9 inhibitors may inhibit the CYP2C9 mediated metabolism|
04770|008|A|of seladelpar.(1)|
04770|009|B||
04770|010|E|CLINICAL EFFECTS:  Concurrent use of seladelpar with a strong inhibitor of|
04770|011|E|CYP2C9 may result in elevated levels of and toxicity from seladelpar, such|
04770|012|E|as hepatotoxicity. Symptoms can include nausea, vomiting, jaundice, dark|
04770|013|E|urine, abdominal pain, and unexplained fatigue.(1)|
04770|014|B||
04770|015|P|PREDISPOSING FACTORS:  Concurrent use of seladelpar, a CYP2C9 inhibitor and|
04770|016|P|a CYP3A4 inhibitor (e.g. aprepitant, boceprevir, ceritinib, ciprofloxacin,|
04770|017|P|clarithromycin, conivaptan, crizotinib, cyclosporine, darunavir, diltiazem,|
04770|018|P|dronedarone, erythromycin, fluconazole, fosaprepitant, idelalisib, imatinib,|
04770|019|P|isavuconazole, itraconazole, ketoconazole, letermovir, mibefradil,|
04770|020|P|nefazodone, netupitant, nilotinib, posaconazole, ribociclib, telaprevir,|
04770|021|P|telithromycin, troleandomycin, verapamil, and voriconazole)(2) could lead to|
04770|022|P|blockade of both major metabolic pathways for seladelpar, resulting in large|
04770|023|P|increases in seladelpar plasma concentrations.(2)|
04770|024|P|   If a patient is a poor metabolizer of CYP2C9, seladelpar metabolism can|
04770|025|P|be further inhibited. The impact of CYP2C9 genetic variants on the|
04770|026|P|pharmacokinetics of seladelpar has not been directly evaluated. Based on|
04770|027|P|drug-drug interaction modeling data, CYP2C9 poor metabolizers may have up to|
04770|028|P|a 48% higher concentrations of seladelpar, when compared to normal|
04770|029|P|metabolizers.(1)|
04770|030|B||
04770|031|M|PATIENT MANAGEMENT:  Concomitant use of a strong CYP2C9 inhibitor with|
04770|032|M|seladelpar should be avoided as the combination may lead to elevated levels|
04770|033|M|in seladelpar plasma concentrations.(1)|
04770|034|B||
04770|035|D|DISCUSSION:  Concurrent seladelpar and sulfaphenazole, a strong CYP3A4|
04770|036|D|inhibitor, is predicted to increase seladelpar area-under-curve (AUC) by|
04770|037|D|3.7-fold.(1)|
04770|038|D|   In an in vitro study in healthy subjects, concurrent administration of|
04770|039|D|seladelpar (single 10 mg dose) and fluconazole, a moderate CYP2C9 and CYP3A4|
04770|040|D|inhibitor, increased seladelpar steady-state maximum concentrations (Cmax)|
04770|041|D|and area-under-curve (AUC) by 1.4-fold and 2.4-fold, respectively.(1)|
04770|042|D|   Strong CYP2C9 inhibitors linked to this monograph include:|
04770|043|D|sulfaphenazole.(1)|
04770|044|B||
04770|045|R|REFERENCES:|
04770|046|B||
04770|047|R|1.Livdelzi (seladelpar) US prescribing information. Gilead Sciences, Inc.|1
04770|048|R|  Aug, 2024.|1
04770|049|R|2.This information is based on an extract from the Certara Drug Interaction|6
04770|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04771|001|T|MONOGRAPH TITLE:  Seladelpar/OAT3 Inhibitors|
04771|002|B||
04771|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04771|004|L|of severe adverse interaction.|
04771|005|B||
04771|006|A|MECHANISM OF ACTION:  Inhibitors of organic anion transporter 3 (OAT3) may|
04771|007|A|inhibit the renal elimination of seladelpar.(1,2)|
04771|008|B||
04771|009|E|CLINICAL EFFECTS:  Concurrent use of organic anion transporter 3 (OAT3)|
04771|010|E|inhibitors may result in an increase in both the therapeutic and toxic|
04771|011|E|effects of seladelpar, such as hepatotoxicity.(1)  Symptoms can include|
04771|012|E|nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained|
04771|013|E|fatigue.|
04771|014|B||
04771|015|P|PREDISPOSING FACTORS:  None determined.|
04771|016|B||
04771|017|M|PATIENT MANAGEMENT:  The manufacturer of seladelpar states that concurrent|
04771|018|M|administration of seladelpar with organic anion transporter 3 (OAT3)|
04771|019|M|inhibitors should be avoided.(1)|
04771|020|B||
04771|021|D|DISCUSSION:  In a study in healthy subjects, concurrent administration of|
04771|022|D|seladelpar (single 10 mg dose) with probenecid (500 mg) resulted in|
04771|023|D|approximately a 2-fold increase in area-under-curve (AUC) and a 4.69-fold|
04771|024|D|increase in concentration maximum (Cmax) of seladelpar.(1)|
04771|025|D|   OAT3 inhibitors linked to this monograph include:  cabotegravir,|
04771|026|D|leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(1,2)|
04771|027|B||
04771|028|R|REFERENCES:|
04771|029|B||
04771|030|R|1.Livdelzi (seladelpar) US prescribing information. Gilead Sciences, Inc.|1
04771|031|R|  Aug, 2024.|1
04771|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
04771|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04772|001|T|MONOGRAPH TITLE:  Ketoconazole/Selected Strong CYP3A4 Inducers|
04772|002|B||
04772|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04772|004|L|of severe adverse interaction.|
04772|005|B||
04772|006|A|MECHANISM OF ACTION:  Ketoconazole is mainly metabolized by CYP3A4.|
04772|007|A|Concurrent use of strong CYP3A4 inducers may accelerate the metabolism of|
04772|008|A|ketoconazole.(1)|
04772|009|B||
04772|010|E|CLINICAL EFFECTS:  Serum levels and bioavailability of ketoconazole may be|
04772|011|E|decreased, resulting in decreased effectiveness of antifungal therapy.(1)|
04772|012|B||
04772|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04772|014|P|of the inducer for longer than 1-2 weeks.|
04772|015|B||
04772|016|M|PATIENT MANAGEMENT:  The US manufacturer of ketoconazole states that|
04772|017|M|coadministration of strong CYP3A4 inducers with ketoconazole is not|
04772|018|M|recommended.  These inducers should be avoided in the 2 weeks before and|
04772|019|M|during ketoconazole therapy unless benefits outweigh the risk of potentially|
04772|020|M|compromised ketoconazole efficacy.  If coadministration cannot be avoided,|
04772|021|M|monitor antifungal activity and increase ketoconazole dose as necessary.(1)|
04772|022|B||
04772|023|D|DISCUSSION:  In vitro studies have shown that CYP3A4 is the major enzyme|
04772|024|D|responsible for ketoconazole metabolism.(1)|
04772|025|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04772|026|D|enzalutamide, mitotane, and St. John's wort.(2,4)|
04772|027|B||
04772|028|R|REFERENCES:|
04772|029|B||
04772|030|R|1.Nizoral (ketoconazole oral) US prescribing information. Janssen|1
04772|031|R|  Pharmaceuticals February, 2014.|1
04772|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04772|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04772|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04772|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04772|036|R|  11/14/2017.|1
04772|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04772|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04773|001|T|MONOGRAPH TITLE:  Lazertinib/Strong CYP3A4 Inducers|
04773|002|B||
04773|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04773|004|L|of severe adverse interaction.|
04773|005|B||
04773|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04773|007|A|lazertinib.(1)|
04773|008|B||
04773|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
04773|010|E|reduce the clinical effectiveness of lazertinib.(1)|
04773|011|B||
04773|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04773|013|P|of the inducer for longer than 1-2 weeks.|
04773|014|B||
04773|015|M|PATIENT MANAGEMENT:  The US manufacturer of lazertinib states that|
04773|016|M|concurrent use of strong CYP3A4 inducers should be avoided.  Consider an|
04773|017|M|alternative concomitant medication with no potential to induce CYP3A4.(1)|
04773|018|B||
04773|019|D|DISCUSSION:  In a clinical pharmacokinetic study, concomitant use of|
04773|020|D|rifampin (strong CYP3A4 inducer) decreased lazertinib concentration maximum|
04773|021|D|(Cmax) by 72% and area-under-curve (AUC) by 83%.(1)|
04773|022|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
04773|023|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib,|
04773|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04773|025|D|rifapentine, and St. John's Wort.(2,3)|
04773|026|B||
04773|027|R|REFERENCES:|
04773|028|B||
04773|029|R|1.Lazcluze (lazertinib) US Prescribing Information. Janssen Biotech, Inc.|1
04773|030|R|  August 2024.|1
04773|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04773|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04773|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04773|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04773|035|R|  11/14/2017.|1
04773|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
04773|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04774|001|T|MONOGRAPH TITLE:  Lazertinib/Moderate CYP3A4 Inducers|
04774|002|B||
04774|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04774|004|L|of severe adverse interaction.|
04774|005|B||
04774|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04774|007|A|of lazertinib via this pathway.(1)|
04774|008|B||
04774|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
04774|010|E|reduce the clinical effectiveness of lazertinib.(1)|
04774|011|B||
04774|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04774|013|P|of the inducer for longer than 1-2 weeks.|
04774|014|B||
04774|015|M|PATIENT MANAGEMENT:  The US manufacturer of lazertinib states that|
04774|016|M|concurrent use of moderate CYP3A4 inducers should be avoided.  Consider an|
04774|017|M|alternative concomitant medication with no potential to induce CYP3A4.(1)|
04774|018|B||
04774|019|D|DISCUSSION:  In a pharmacokinetic modelling study, concomitant use of|
04774|020|D|efavirenz (moderate CYP3A4 inducer) is predicted to decrease lazertinib|
04774|021|D|steady state concentration maximum (Cmax) and area-under-curve (AUC) by at|
04774|022|D|least 32% and 44%, respectively.(1)|
04774|023|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04774|024|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04774|025|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04774|026|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04774|027|D|thioridazine, and tovorafenib.(2,3)|
04774|028|B||
04774|029|R|REFERENCES:|
04774|030|B||
04774|031|R|1.Lazcluze (lazertinib) US Prescribing Information. Janssen Biotech, Inc.|1
04774|032|R|  August 2024.|1
04774|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04774|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04774|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04774|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04774|037|R|  11/14/2017.|1
04774|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
04774|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04775|001|T|MONOGRAPH TITLE:  Amiodarone/Oxygen|
04775|002|B||
04775|003|L|SEVERITY LEVEL:  9-Undetermined Severity - Alternative Therapy Interaction:|
04775|004|L|Assess the risk to the patient and take action as needed.|
04775|005|B||
04775|006|A|MECHANISM OF ACTION:  Mechanism is unknown.  High-dose oxygen may enhance|
04775|007|A|the pulmonary toxicity of amiodarone.|
04775|008|B||
04775|009|E|CLINICAL EFFECTS:  Concurrent use of high-dose oxygen may increase the risk|
04775|010|E|of amiodarone-induced pulmonary toxicity, including acute respiratory|
04775|011|E|distress syndrome (ARDS).|
04775|012|B||
04775|013|P|PREDISPOSING FACTORS:  Patients may be at increased risk with high|
04775|014|P|concentrations of oxygen or during the acute post-op period after|
04775|015|P|cardiothoracic surgery.|
04775|016|B||
04775|017|M|PATIENT MANAGEMENT:  The concurrent use of high-dose oxygen in patients on|
04775|018|M|amiodarone should be monitored closely.|
04775|019|M|   Monitor patients for signs or symptoms of pulmonary toxicity, including|
04775|020|M|acute respiratory distress syndrome (ARDS).  If amiodarone-induced pulmonary|
04775|021|M|toxicity is suspected, discontinue amiodarone and provide supportive care.|
04775|022|B||
04775|023|D|DISCUSSION:  Mechanism has not been established.  Amiodarone has been|
04775|024|D|associated with pulmonary toxicity.|
04775|025|D|   Case reports of acute respiratory distress syndrome (ARDS) in acute|
04775|026|D|post-op cardiothoracic surgery patients receiving high-dose oxygen and|
04775|027|D|amiodarone have been reported.|
04775|028|B||
04775|029|R|REFERENCES:|
04775|030|B||
04775|031|R|1.Cordarone (amiodarone hydrochloride) US prescribing information. Wyeth|1
04775|032|R|  Pharmaceuticals October, 2018.|1
04775|033|R|2.Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity.|2
04775|034|R|  Br J Clin Pharmacol 2008 Jul;66(1):82-7.|2
04775|035|R|3.Papiris SA, Triantafillidou C, Kolilekas L, Markoulaki D, Manali ED.|6
04775|036|R|  Amiodarone: review of pulmonary effects and toxicity. Drug Saf 2010 Jul 1;|6
04775|037|R|  33(7):539-58.|6
04775|038|R|4.Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J 2009|6
04775|039|R|  Mar-Apr;16(2):43-8.|6
04775|040|R|5.Siddoway LA. Amiodarone: guidelines for use and monitoring. Am Fam|6
04775|041|R|  Physician 2003 Dec 1;68(11):2189-96.|6
04775|042|R|6.Feduska ET, Thoma BN, Torjman MC, Goldhammer JE. Acute Amiodarone|3
04775|043|R|  Pulmonary Toxicity. J Cardiothorac Vasc Anesth 2021 May;35(5):1485-1494.|3
04775|044|R|7.Lohiya RV, Pethe MP. Early Recognition of Acute Pneumonitis in Amiodarone|3
04775|045|R|  Treatment. Heart Views 2018 Jul-Sep;19(3):109-113.|3
04775|046|R|8.Baumann H, Fichtenkamm P, Schneider T, Biscoping J, Henrich M. Rapid onset|3
04775|047|R|  of amiodarone induced pulmonary toxicity after lung lobe resection -  A|3
04775|048|R|  case report and review of recent literature. Ann Med Surg (Lond) 2017 Sep;|3
04775|049|R|  21:53-57.|3
04775|050|R|9.Teerakanok J, Tantrachoti P, Chariyawong P, Nugent K. Acute Amiodarone|3
04775|051|R|  Pulmonary Toxicity After Surgical Procedures. Am J Med Sci 2016 Dec;|3
04775|052|R|  352(6):646-651.|3
04775|053|R|10.Benassi F, Molardi A, Righi E, Santangelo R, Meli M. ECMO for pulmonary|3
04775|054|R|   rescue in an adult with amiodarone-induced toxicity. Heart Vessels 2015|3
04775|055|R|   May;30(3):410-5.|3
04775|056|R|11.Fadahunsi O, Krol R. Acute amiodarone pulmonary toxicity following lung|3
04775|057|R|   resection. Int J Biomed Sci 2014 Sep;10(3):217-20.|3
04775|058|R|12.Nacca N, Bhamidipati CM, Yuhico LS, Pinnamaneni S, Szombathy T. Severe|3
04775|059|R|   amiodarone induced pulmonary toxicity. J Thorac Dis 2012 Dec;4(6):667-70.|3
04775|060|R|13.Handschin AE, Lardinois D, Schneiter D, Bloch K, Weder W. Acute|3
04775|061|R|   amiodarone-induced pulmonary toxicity following lung resection.|3
04775|062|R|   Respiration 2003 May-Jun;70(3):310-2.|3
04775|063|R|14.Donaldson L, Grant IS, Naysmith MR, Thomas JS. Acute amiodarone-induced|3
04775|064|R|   lung toxicity. Intensive Care Med 1998 Jun;24(6):626-30.|3
04775|065|R|15.Van Mieghem W, Coolen L, Malysse I, Lacquet LM, Deneffe GJ, Demedts MG.|3
04775|066|R|   Amiodarone and the development of ARDS after lung surgery. Chest 1994|3
04775|067|R|   Jun;105(6):1642-5.|3
04775|068|R|16.Saussine M, Colson P, Alauzen M, Mary H. Postoperative acute respiratory|3
04775|069|R|   distress syndrome. A complication of amiodarone  associated with 100|3
04775|070|R|   percent oxygen ventilation. Chest 1992 Sep;102(3):980-1.|3
04775|071|R|17.Greenspon AJ, Kidwell GA, Hurley W, Mannion J. Amiodarone-related|3
04775|072|R|   postoperative adult respiratory distress syndrome. Circulation 1991 Nov;|3
04775|073|R|   84(5 Suppl):III407-15.|3
04775|074|R|18.Tuzcu EM, Maloney JD, Sangani BH, Masterson ML, Hocevar KD, Golding LA,|3
04775|075|R|   Starr NJ, Golish JA, Castle LW, Morant VA. Cardiopulmonary effects of|3
04775|076|R|   chronic amiodarone therapy in the early postoperative  course of cardiac|3
04775|077|R|   surgery patients. Cleve Clin J Med 1987 Nov-Dec;54(6):491-7.|3
04776|001|T|MONOGRAPH TITLE:  Sodium Iodide I 131/Myelosuppressives that affect Iodide|
04776|002|B||
04776|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04776|004|L|of severe adverse interaction.|
04776|005|B||
04776|006|A|MECHANISM OF ACTION:  Sodium iodide I 131 can cause depression of the|
04776|007|A|hematopoetic system.  Myelosuppressives and immunomodulators also suppress|
04776|008|A|the immune system.(1)|
04776|009|A|   Many compounds can affect iodide protein binding and alter iodide|
04776|010|A|pharmacokinetics and pharmacodynamics.|
04776|011|B||
04776|012|E|CLINICAL EFFECTS:  Concurrent use of sodium iodide I 131 with agents that|
04776|013|E|cause bone marrow depression, including myelosuppressives or|
04776|014|E|immunomodulators, may result in an enhanced risk of hematologic disorders,|
04776|015|E|including anemia, blood dyscrasias, bone marrow depression, leukopenia, and|
04776|016|E|thrombocytopenia.  Bone marrow depression may increase the risk of serious|
04776|017|E|infections and bleeding.(1)|
04776|018|E|   Compounds that affect iodide pharmacokinetics and pharmacodynamics may|
04776|019|E|impact the effectiveness of radioactive iodide.(1,2)|
04776|020|B||
04776|021|P|PREDISPOSING FACTORS:  Compounds that affect iodide pharmacokinetics and|
04776|022|P|pharmacodynamics are expected to have the most impact during therapy using|
04776|023|P|radioactive iodide.  Diagnostic procedures would be expected to be impacted|
04776|024|P|less.|
04776|025|B||
04776|026|M|PATIENT MANAGEMENT:  The US manufacturer of sodium iodide I 131 states that|
04776|027|M|concurrent use with bone marrow depressants may enhance the depression of|
04776|028|M|the hematopoetic system caused by large doses of sodium iodide I 131.(1)|
04776|029|M|   Sodium iodide I 131 causes a dose-dependent bone marrow suppression,|
04776|030|M|including neutropenia or thrombocytopenia, in the 3 to 5 weeks following|
04776|031|M|administration.  Patients may be at increased risk of infections or bleeding|
04776|032|M|during this time.|
04776|033|M|   Monitor complete blood counts within one month of therapy.  If results|
04776|034|M|indicate leukopenia or thrombocytopenia, dosimetry should be used to|
04776|035|M|determine a safe sodium iodide I 131 activity.(1)|
04776|036|M|   Discuss the use of agents that affect iodide pharmacokinetics and|
04776|037|M|pharmacodynamics with the patient's oncologist.(1,2)|
04776|038|B||
04776|039|D|DISCUSSION:  Hematologic disorders including death have been reported with|
04776|040|D|sodium iodide I 131.  The most common hematologic disorders reported include|
04776|041|D|anemia, blood dyscrasias, bone marrow depression, leukopenia, and|
04776|042|D|thrombocytopenia.(1)|
04776|043|D|   Many agents interact with radioactive iodine.  The average duration of|
04776|044|D|effect is:|
04776|045|D|   anticoagulants - 1 week|
04776|046|D|   antihistamines - 1 week|
04776|047|D|   anti-thyroid drugs, e.g:|
04776|048|D|      carbimazole, methimazole, propylthiouracil - 3-5 days|
04776|049|D|   corticosteroids - 1 week|
04776|050|D|   iodide-containing medications, e.g:|
04776|051|D|      amiodarone - 1-6 months|
04776|052|D|      expectorants - 2 weeks|
04776|053|D|      Lugol solution - 3 weeks|
04776|054|D|      saturated solution of potassium iodine - 3 weeks|
04776|055|D|      vitamins - 10-14 days|
04776|056|D|   iodide-containing X-ray contrast agents - up to 1 year|
04776|057|D|   lithium - 4 weeks|
04776|058|D|   phenylbutazone - 1-2 weeks|
04776|059|D|   sulfonamides - 1 week|
04776|060|D|   thyroid hormones (natural or synthetic), e.g.:|
04776|061|D|      thyroxine - 4 weeks|
04776|062|D|      tri-iodothyronine - 2 weeks|
04776|063|D|   tolbutamide - 1 week|
04776|064|D|   topical iodide - 1-9 months (1,2)|
04776|065|B||
04776|066|R|REFERENCES:|
04776|067|B||
04776|068|R|1.Hicon (sodium iodide I-131) US prescribing information. Jubilant DraxImage|1
04776|069|R|  Inc June, 2021.|1
04776|070|R|2.Sodium Iodide I 131 Solution Therapeutic US prescribing information.|1
04776|071|R|  Mallinckrodt Inc. March, 2014.|1
04777|001|T|MONOGRAPH TITLE:  Sodium Iodide I 131/Agents that Affect Iodide|
04777|002|B||
04777|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04777|004|L|of severe adverse interaction.|
04777|005|B||
04777|006|A|MECHANISM OF ACTION:  Many compounds can affect iodide protein binding and|
04777|007|A|alter iodide pharmacokinetics and pharmacodynamics.(1,2)|
04777|008|B||
04777|009|E|CLINICAL EFFECTS:  Compounds that affect iodide pharmacokinetics and|
04777|010|E|pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2)|
04777|011|B||
04777|012|P|PREDISPOSING FACTORS:  Compounds that affect iodide pharmacokinetics and|
04777|013|P|pharmacodynamics are expected to have the most impact during therapy using|
04777|014|P|radioactive iodide.  Diagnostic procedures would be expected to be impacted|
04777|015|P|less.|
04777|016|B||
04777|017|M|PATIENT MANAGEMENT:  Discuss the use of agents that affect iodide|
04777|018|M|pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2)|
04777|019|M|   Because indocyanine green contains sodium iodide, the iodine-binding|
04777|020|M|capacity of thyroid tissue may be reduced for at least one week following|
04777|021|M|administration.  Do not perform radioactive iodine uptake studies for at|
04777|022|M|least one week following administration of indocyanine green.(3)|
04777|023|M|   The manufacturer of iopamidol states administration may interfere with|
04777|024|M|thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic|
04777|025|M|efficacy.  Avoid thyroid therapy or testing for up to 6 weeks post|
04777|026|M|administration of iopamidol.(4)|
04777|027|B||
04777|028|D|DISCUSSION:  Many agents interact with radioactive iodine.  The average|
04777|029|D|duration of effect is:|
04777|030|D|   anticoagulants - 1 week|
04777|031|D|   antihistamines - 1 week|
04777|032|D|   anti-thyroid drugs, e.g:|
04777|033|D|      carbimazole, methimazole, propylthiouracil - 3-5 days|
04777|034|D|   corticosteroids - 1 week|
04777|035|D|   iodide-containing medications, e.g:|
04777|036|D|      amiodarone - 1-6 months|
04777|037|D|      expectorants - 2 weeks|
04777|038|D|      Lugol solution - 3 weeks|
04777|039|D|      saturated solution of potassium iodine - 3 weeks|
04777|040|D|      vitamins - 10-14 days|
04777|041|D|   iodide-containing X-ray contrast agents - up to 1 year|
04777|042|D|   lithium - 4 weeks|
04777|043|D|   phenylbutazone - 1-2 weeks|
04777|044|D|   sulfonamides - 1 week|
04777|045|D|   thyroid hormones (natural or synthetic), e.g.:|
04777|046|D|      thyroxine - 4 weeks|
04777|047|D|      tri-iodothyronine - 2 weeks|
04777|048|D|   tolbutamide - 1 week|
04777|049|D|   topical iodide - 1-9 months (1,2)|
04777|050|B||
04777|051|R|REFERENCES:|
04777|052|B||
04777|053|R|1.Sodium Iodide I 131 Solution Therapeutic US prescribing information.|1
04777|054|R|  Mallinckrodt Inc. March, 2014.|1
04777|055|R|2.Hicon (sodium iodide I-131) US prescribing information. Jubilant DraxImage|1
04777|056|R|  Inc June, 2021.|1
04777|057|R|3.IC-GREEN (Indocyanine green for injection) US prescribing information.|1
04777|058|R|  Diagnostic Green LLC December 2024.|1
04777|059|R|4.ISOVUE (iopamidol) US Prescribing Information. Bracco Diagnostic Inc.|1
04777|060|R|  December 2024.|1
04778|001|T|MONOGRAPH TITLE:  Warfarin/Mifepristone (Chronic Therapy)|
04778|002|B||
04778|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04778|004|L|of severe adverse interaction.|
04778|005|B||
04778|006|A|MECHANISM OF ACTION:  Mifepristone is a moderate inhibitor of CYP2C9 and may|
04778|007|A|inhibit the CYP2C9-mediated metabolism of the S-enantiomer of warfarin.(2-4)|
04778|008|A|   Mifepristone is an antagonist at the progesterone receptor which can|
04778|009|A|result in endometrium thickening, cystic dilatation of endometrial glands,|
04778|010|A|or excessive vaginal bleeding.  Concurrent use with warfarin may further|
04778|011|A|increase risk.|
04778|012|B||
04778|013|E|CLINICAL EFFECTS:  Concurrent use of warfarin with mifepristone may result|
04778|014|E|in elevated levels and effects of warfarin, which may increase the risk of|
04778|015|E|bleeding.|
04778|016|E|   The concurrent use of mifepristone with anticoagulants such as warfarin|
04778|017|E|may result in endometrium thickening, cystic dilatation of endometrial|
04778|018|E|glands, or excessive vaginal bleeding.|
04778|019|B||
04778|020|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04778|021|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04778|022|P|   Drug associated risk factors include concurrent use of multiple drugs|
04778|023|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04778|024|P|risk for bleeding (e.g. NSAIDs).|
04778|025|B||
04778|026|M|PATIENT MANAGEMENT:  The manufacturer of mifepristone states that|
04778|027|M|mifepristone should be used with caution in patients receiving concurrent|
04778|028|M|anticoagulant therapy.(1)|
04778|029|M|   Monitor INR response closely in patients maintained on warfarin when|
04778|030|M|initiating, titrating, and discontinuing mifepristone.|
04778|031|M|   If concurrent therapy is deemed medically necessary, monitor patients|
04778|032|M|receiving concurrent therapy for signs of blood loss, including decreased|
04778|033|M|hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure|
04778|034|M|and promptly evaluate patients with any symptoms.|
04778|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04778|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04778|037|M|anticoagulation in patients with active pathologic bleeding.|
04778|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04778|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04778|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04778|041|M|and/or swelling.|
04778|042|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04778|043|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04778|044|M|initiating, altering the dose or discontinuing either drug.|
04778|045|M|   Women experiencing vaginal bleeding during concurrent use should be|
04778|046|M|referred to a gynecologist for further evaluation.|
04778|047|B||
04778|048|D|DISCUSSION:  The manufacturer of mifepristone states that mifepristone|
04778|049|D|should be used with caution in patients receiving concurrent anticoagulant|
04778|050|D|or antiplatelet therapy.(1)|
04778|051|D|   No formal interaction studies have been done with warfarin and|
04778|052|D|mifepristone.|
04778|053|D|   In clinical studies, coadministration of adagrasib 600 mg (moderate 2C9|
04778|054|D|inhibitor) twice daily increased the area-under-the-curve (AUC) and maximum|
04778|055|D|concentration (Cmax) of S-warfarin by 2.9-fold and 1.1-fold,|
04778|056|D|respectively.(5)|
04778|057|B||
04778|058|R|REFERENCES:|
04778|059|B||
04778|060|R|1.Korlym (mifepristone) US Prescribing Information. Corcept Therapeutics|1
04778|061|R|  November, 2019.|1
04778|062|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
04778|063|R|  Squibb Company September, 2016.|1
04778|064|R|3.This information is based on an extract from the Certara Drug Interaction|6
04778|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04778|066|R|4.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
04778|067|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
04778|068|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
04778|069|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
04778|070|R|  Oct;90(4):625-9.|6
04778|071|R|5.Krazati (adagrasib) US prescribing information. Mirati Therapeutics, Inc.|1
04778|072|R|  December 2022.|1
04779|001|T|MONOGRAPH TITLE:  Levacetylleucine/Acetylleucine|
04779|002|B||
04779|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04779|004|L|of severe adverse interaction.|
04779|005|B||
04779|006|A|MECHANISM OF ACTION:  The D-enantiomer (N-acetyl-D-leucine) portion of|
04779|007|A|racemic acetylleucine (or N-acetyl-DL-leucine) may compete with|
04779|008|A|levacetylleucine for monocarboxylate transporter uptake in the|
04779|009|A|intestines.(1,2)|
04779|010|B||
04779|011|E|CLINICAL EFFECTS:  Concurrent administration of N-acetyl-DL-leucine or|
04779|012|E|N-acetyl-D-leucine may result in decreased efficacy of levacetylleucine.(1)|
04779|013|B||
04779|014|P|PREDISPOSING FACTORS:  None determined.|
04779|015|B||
04779|016|M|PATIENT MANAGEMENT:  The manufacturer of levacetylleucine recommends that|
04779|017|M|the concomitant use of N-acetyl-DL-leucine or N-acetyl-D-leucine be|
04779|018|M|avoided.(1)|
04779|019|B||
04779|020|D|DISCUSSION:  In an animal model, administration of N-acetyl-DL-leucine|
04779|021|D|resulted in greater maximum concentration (Cmax) and area-under-curve (AUC)|
04779|022|D|of the D-enantiomer than the L-enantiomer, while elimination was similar for|
04779|023|D|both enantiomers.  Therefore, the D-enantiomer was thought to inhibit|
04779|024|D|intestinal uptake of the L-enantiomer.(2)|
04779|025|B||
04779|026|R|REFERENCES:|
04779|027|B||
04779|028|R|1.Aqneursa (levacetylleucine) US prescribing informatoin. IntraBio, Inc.|1
04779|029|R|  September, 2024.|1
04779|030|R|2.Churchill GC, Strupp M, Galione A, Platt FM. Unexpected differences in the|5
04779|031|R|  pharmacokinetics of N-acetyl-DL-leucine enantiomers  after oral dosing and|5
04779|032|R|  their clinical relevance. PLoS One 2020;15(2):e0229585.|5
04780|001|T|MONOGRAPH TITLE:  Bictegravir-Emtricitabine-Tenofovir Alafenamide/Selected|
04780|002|T|P-gp Inducers|
04780|003|B||
04780|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04780|005|L|take action as needed.|
04780|006|B||
04780|007|A|MECHANISM OF ACTION:  Tenofovir alafenamide (TAF) is a substrate of the|
04780|008|A|intestinal efflux transporter P-glycoprotein (P-gp).  Inducers of P-gp may|
04780|009|A|decrease systemic absorption of TAF.(1-2)|
04780|010|B||
04780|011|E|CLINICAL EFFECTS:  Concurrent or recent use of P-gp inducers may result in|
04780|012|E|decreased systemic levels and effectiveness of tenofovir alafenamide.(1-2)|
04780|013|B||
04780|014|P|PREDISPOSING FACTORS:  None determined.|
04780|015|B||
04780|016|M|PATIENT MANAGEMENT:  The manufacturer of bictegravir-emtricitabine-TAF|
04780|017|M|states that concurrent use with  rifabutin or rifapentine (P-gp inducers) is|
04780|018|M|not recommended.(1)  It may be prudent to use alternatives to other P-gp|
04780|019|M|inducers as well.|
04780|020|B||
04780|021|D|DISCUSSION:  When tenofovir alafenamide (TAF) was coadministered with|
04780|022|D|carbamazepine, the maximum concentration (Cmax) and area-under-curve (AUC)|
04780|023|D|were decreased 57% and 55%, respectively.(2)|
04780|024|D|   A subsequent study suggests that this interaction may not have clinically|
04780|025|D|significant effects on intracellular levels of tenofovir diphosphate, the|
04780|026|D|active metabolite of tenofovir alafenamide.  In a study of 23 healthy|
04780|027|D|volunteers, the intracellular Cmax and AUC of tenofovir diphosphate were 38%|
04780|028|D|and 36% lower, respectively, when tenofovir alafenamide was coadministered|
04780|029|D|with rifampin than without rifampin.  However, these levels of tenofovir|
04780|030|D|diphosphate were 4.4- and 4.21-fold higher, respectively, than levels|
04780|031|D|obtained from tenofovir disoproxil 300 mg daily without rifampin.(3)|
04780|032|D|   Selected P-gp inducers linked to this monograph include: lorlatinib.(4)|
04780|033|B||
04780|034|R|REFERENCES:|
04780|035|B||
04780|036|R|1.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
04780|037|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
04780|038|R|2.Descovy (emtricitabine and tenofovir alafenamide) US prescribing|1
04780|039|R|  information. Gilead Sciences, Inc. June, 2025.|1
04780|040|R|3.Cerrone Maddalena, Alfarisi Omamah, Neary Megan, Marzinke Mark A, Parsons|2
04780|041|R|  Teresa L, Owen Andrew, Maartens Gary, Pozniak Anton, Flexner Charles,|2
04780|042|R|  Boffito Marta. Rifampicin effect on intracellular and plasma|2
04780|043|R|  pharmacokinetics of tenofovir alafenamide. 2019 Jun;74(6):1670-1678.|2
04780|044|R|4.This information is based on an extract from the Certara Drug Interaction|6
04780|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04781|001|T|MONOGRAPH TITLE:  Bictegravir-Emtricitabine-Tenofovir Alafenamide/Strong|
04781|002|T|CYP3A4 and P-gp Inducers; Rifabutin|
04781|003|B||
04781|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04781|005|L|of severe adverse interaction.|
04781|006|B||
04781|007|A|MECHANISM OF ACTION:  Bictegravir is a CYP3A4 substrate and tenofovir|
04781|008|A|alafenamide (TAF) is a substrate of the intestinal efflux transporter|
04781|009|A|P-glycoprotein (P-gp).  Concurrent use of agents that are both CYP3A4 and|
04781|010|A|P-gp inducers may induce the metabolism of bictegravir and decrease systemic|
04781|011|A|absorption of TAF.(1)|
04781|012|A|   Phenobarbital may also induce the metabolism of TAF.(1)  Primidone is|
04781|013|A|metabolized to phenobarbital.|
04781|014|B||
04781|015|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 and P-gp|
04781|016|E|inducers, phenobarbital, primidone, or rifabutin may result in decreased|
04781|017|E|systemic levels of bictegravir and tenofovir alafenamide, virologic failure,|
04781|018|E|and development of resistance.(1)|
04781|019|B||
04781|020|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04781|021|P|of the inducer for longer than 1-2 weeks.|
04781|022|B||
04781|023|M|PATIENT MANAGEMENT:  The manufacturer of bictegravir recommends considering|
04781|024|M|alternatives to carbamazepine, phenobarbital, and phenytoin for patients on|
04781|025|M|bictegravir.(1)  The National Institute of Health HIV guidelines do not|
04781|026|M|recommend coadministration of carbamazepine, phenobarbital or phenytoin with|
04781|027|M|bictegravir.(2)  Fosphenytoin and primidone are metabolized to phenytoin and|
04781|028|M|phenobarbital, respectively.|
04781|029|M|   Other CYP3A4 inducers are not recommended to be coadministered with|
04781|030|M|bictegravir.(1,2)|
04781|031|B||
04781|032|D|DISCUSSION:  Coadministration of rifampin (600 mg daily, a strong CYP3A4|
04781|033|D|inducer) decreased bictegravir area-under-curve (AUC) by 75% and maximum|
04781|034|D|concentration (Cmax) by 28%.(1)  Although the other strong CYP3A4 inducers|
04781|035|D|linked to this monograph have not been studied with bictegravir, a similar|
04781|036|D|effect is expected.|
04781|037|D|   Coadministration of rifabutin (300 mg daily) with bictegravir decreased|
04781|038|D|bictegravir AUC and Cmax by 38% and 20%, respectively.(1)|
04781|039|D|   When tenofovir alafenamide (TAF) was coadministered with carbamazepine,|
04781|040|D|the maximum concentration (Cmax) and area-under-curve (AUC) were decreased|
04781|041|D|57% and 55%, respectively.(1-4)|
04781|042|D|   A subsequent study suggests that this interaction may not have clinically|
04781|043|D|significant effects on intracellular levels of tenofovir diphosphate, the|
04781|044|D|active metabolite of tenofovir alafenamide.  In a study of 23 healthy|
04781|045|D|volunteers, the intracellular Cmax and AUC of tenofovir diphosphate were 38%|
04781|046|D|and 36% lower, respectively, when tenofovir alafenamide was coadministered|
04781|047|D|with rifampin than without rifampin.  However, these levels of tenofovir|
04781|048|D|diphosphate were 4.4- and 4.21-fold higher, respectively, than levels|
04781|049|D|obtained from tenofovir disoproxil 300 mg daily without rifampin.(3)|
04781|050|D|   CYP3A4 and P-gp inducers linked to this monograph include: apalutamide,|
04781|051|D|carbamazepine, fosphenytoin, phenytoin, rifabutin, rifapentine, and St.|
04781|052|D|John's wort.(1,4)  Phenobarbital and primidone are known strong CYP3A4|
04781|053|D|inducers (4) and the manufacturer of bictegravir also classifies|
04781|054|D|phenobarbital as a P-gp inducer.(1)|
04781|055|B||
04781|056|R|REFERENCES:|
04781|057|B||
04781|058|R|1.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
04781|059|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
04781|060|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04781|061|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04781|062|R|  HIV. Department of Health and Human Services. Available at|6
04781|063|R|  https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-|6
04781|064|R|  new-guidelines June 13, 2021.|6
04781|065|R|3.Cerrone Maddalena, Alfarisi Omamah, Neary Megan, Marzinke Mark A, Parsons|2
04781|066|R|  Teresa L, Owen Andrew, Maartens Gary, Pozniak Anton, Flexner Charles,|2
04781|067|R|  Boffito Marta. Rifampicin effect on intracellular and plasma|2
04781|068|R|  pharmacokinetics of tenofovir alafenamide. 2019 Jun;74(6):1670-1678.|2
04781|069|R|4.This information is based on an extract from the Certara Drug Interaction|6
04781|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04782|001|T|MONOGRAPH TITLE:  Dofetilide/OCT2 Inhibitors that Prolong QT|
04782|002|B||
04782|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04782|004|L|is contraindicated and generally should not be dispensed or administered to|
04782|005|L|the same patient.|
04782|006|B||
04782|007|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
04782|008|A|(OCT2) that prolong the QT interval may inhibit the excretion of dofetilide|
04782|009|A|by OCT2 in the kidneys and result in additive risk of QT prolongation.(1)|
04782|010|B||
04782|011|E|CLINICAL EFFECTS:  Concurrent use of OCT2 inhibitors that prolong QT may|
04782|012|E|result in increased levels of and toxicities of dofetilide, including|
04782|013|E|additive potentially life-threatening cardiac arrhythmias, like torsades de|
04782|014|E|pointes (TdP).(1-3)|
04782|015|B||
04782|016|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
04782|017|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
04782|018|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
04782|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
04782|020|P|concurrent use of agents known to cause QT prolongation.(2)|
04782|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04782|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04782|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04782|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04782|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04782|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04782|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04782|028|P|   Renal impairment may increase risk for excessive QTc prolongation as|
04782|029|P|dofetilide is primarily renally eliminated. To prevent increased serum|
04782|030|P|levels and risk for ventricular arrhythmias, dofetilide must be dose|
04782|031|P|adjusted for creatinine clearance < or = to 60 mL/min.(1)|
04782|032|B||
04782|033|M|PATIENT MANAGEMENT:  The manufacturer of dofetilide states that all renal|
04782|034|M|cation transport inhibitors are contraindicated.   If dofetilide is to be|
04782|035|M|discontinued, a washout of at least 2 days is recommended prior to starting|
04782|036|M|OCT2 inhibitors.(1)|
04782|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04782|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04782|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04782|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04782|041|B||
04782|042|D|DISCUSSION:  Dofetilide is primarily excreted in the urine via both|
04782|043|D|glomerular filtration and active tubular secretion via the cation transport|
04782|044|D|system.  The concurrent administration of dofetilide (500 mcg twice daily)|
04782|045|D|with cimetidine (an OCT2 inhibitor)(400 mg twice daily) resulted in an|
04782|046|D|increase in dofetilide plasma levels by 58%.  The concurrent administration|
04782|047|D|of dofetilide (500 mcg single dose) with cimetidine (100 mg twice daily)|
04782|048|D|resulted in an increase in dofetilide plasma levels by 13%.(1)|
04782|049|D|   OCT2 inhibitors that prolong QT include: ranolazine.(3)|
04782|050|B||
04782|051|R|REFERENCES:|
04782|052|B||
04782|053|R|1.Tikosyn (dofetilide) US prescribing information. Pfizer Inc. December,|1
04782|054|R|  2013.|1
04782|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04782|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04782|057|R|  settings: a scientific statement from the American Heart Association and|6
04782|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04782|059|R|  2;55(9):934-47.|6
04782|060|R|3.This information is based on an extract from the Certara Drug Interaction|6
04782|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04783|001|T|MONOGRAPH TITLE:  Procainamide/OCT2 Inhibitors that Prolong QT|
04783|002|B||
04783|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04783|004|L|take action as needed.|
04783|005|B||
04783|006|A|MECHANISM OF ACTION:  Agents that inhibit the organic cation transporter 2|
04783|007|A|(OCT2) that prolong the QTc interval may inhibit the excretion of|
04783|008|A|procainamide by OCT2 in the kidneys and result in additive risk of QT|
04783|009|A|prolongation.|
04783|010|B||
04783|011|E|CLINICAL EFFECTS:  Concurrent use of OCT2 renal transport inhibitors that|
04783|012|E|prolong QT may result in increased levels of and toxicities of procainamide,|
04783|013|E|including additive potentially life-threatening cardiac arrhythmias, like|
04783|014|E|torsades de pointes (TdP).|
04783|015|B||
04783|016|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
04783|017|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
04783|018|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
04783|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
04783|020|P|concurrent use of agents known to cause QT prolongation.(3)|
04783|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04783|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04783|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04783|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04783|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04783|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04783|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04783|028|B||
04783|029|M|PATIENT MANAGEMENT:  Consider the potential benefits against the risks of|
04783|030|M|concurrent use of procainamide with OCT2 renal transport inhibitors.  If|
04783|031|M|concurrent use is appropriate, monitor for toxicities of procainamide and|
04783|032|M|consider dosage reduction of procainamide.(1)|
04783|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04783|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04783|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04783|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04783|037|B||
04783|038|D|DISCUSSION:  Administration of trimethoprim to patients receiving|
04783|039|D|procainamide produced an increase in the area under the concentration-time|
04783|040|D|curve and a decrease in the clearance of procainamide.  At the same time,|
04783|041|D|serum NAPA concentrations and clearance were decreased.|
04783|042|D|   OCT2 inhibitors that prolong QT include: ranolazine.(4)|
04783|043|B||
04783|044|R|REFERENCES:|
04783|045|B||
04783|046|R|1.Kosoglou T, Rocci ML Jr, Vlasses PH. Trimethoprim alters the disposition|2
04783|047|R|  of procainamide and N- acetylprocainamide. Clin Pharmacol Ther 1988 Oct;|2
04783|048|R|  44(4):467-77.|2
04783|049|R|2.Vlasses PH, Kosoglou T, Chase SL, Greenspon AJ, Lottes S, Andress E,|2
04783|050|R|  Ferguson RK, Rocci ML Jr. Trimethoprim inhibition of the renal clearance|2
04783|051|R|  of procainamide and N- acetylprocainamide. Arch Intern Med 1989 Jun;|2
04783|052|R|  149(6):1350-3.|2
04783|053|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04783|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04783|055|R|  settings: a scientific statement from the American Heart Association and|6
04783|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04783|057|R|  2;55(9):934-47.|6
04783|058|R|4.This information is based on an extract from the Certara Drug Interaction|6
04783|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04784|001|T|MONOGRAPH TITLE:  Chloroquine; Hydroxychloroquine/MATE Inhibit that Prolong|
04784|002|T|QT|
04784|003|B||
04784|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04784|005|L|of severe adverse interaction.|
04784|006|B||
04784|007|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
04784|008|A|protein transporters in the kidneys that prolong the QTc interval may|
04784|009|A|interfere with the renal elimination of chloroquine or hydroxychloroquine|
04784|010|A|via the MATE1 transporter and result in additive risk of QT|
04784|011|A|prolongation.(1,2)|
04784|012|B||
04784|013|E|CLINICAL EFFECTS:  Concurrent use of MATE renal transporter inhibitors that|
04784|014|E|prolong the QT interval may result in increased levels of and toxicity from|
04784|015|E|chloroquine or hydroxychloroquine, including irreversible retinopathy,|
04784|016|E|potentially life-threatening cardiac arrhythmias like torsades de pointes|
04784|017|E|(TdP), hypoglycemia, or myopathy.(1,2)|
04784|018|B||
04784|019|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
04784|020|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
04784|021|P|failure, myocardial infarction, history of torsade de pointes, congenital|
04784|022|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04784|023|P|female gender, or advanced age.(3)|
04784|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04784|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04784|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04784|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04784|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04784|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04784|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04784|031|B||
04784|032|M|PATIENT MANAGEMENT:  The manufacturers of chloroquine and hydroxychloroquine|
04784|033|M|state that concomitant use of MATE renal transporter inhibitors should be|
04784|034|M|avoided.(1,2)|
04784|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04784|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04784|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04784|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04784|039|B||
04784|040|D|DISCUSSION:  In a study of healthy volunteers, cimetidine (400 mg daily for|
04784|041|D|4 days) decreased the clearance of single-dose chloroquine (300 mg) by 53%|
04784|042|D|and half-life by 49%, compared to subjects not on cimetidine.(4)|
04784|043|D|   MATE inhibitors that prolong the QT include: ranolazine and|
04784|044|D|vandetanib.(5)|
04784|045|B||
04784|046|R|REFERENCES:|
04784|047|B||
04784|048|R|1.Aralen (chloroquine) US prescribing information. Sanofi-Aventis U.S. LLC|1
04784|049|R|  October, 2018.|1
04784|050|R|2.Plaquenil (hydroxychloroquine sulfate) US prescribing information.|1
04784|051|R|  Concordia Pharmaceuticals Inc. December, 2023.|1
04784|052|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04784|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04784|054|R|  settings: a scientific statement from the American Heart Association and|6
04784|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04784|056|R|  2;55(9):934-47.|6
04784|057|R|4.Ette EI, Brown-Awala EA, Essien EE. Chloroquine elimination in humans:|2
04784|058|R|  effect of low-dose cimetidine. J Clin Pharmacol 1987 Oct;27(10):813-6.|2
04784|059|R|5.This information is based on an extract from the Certara Drug Interaction|6
04784|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04785|001|T|MONOGRAPH TITLE:  Oxaliplatin/MATE Inhibitors that Prolong QT|
04785|002|B||
04785|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04785|004|L|take action as needed.|
04785|005|B||
04785|006|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
04785|007|A|protein transporters in the kidneys that prolong the QT interval may|
04785|008|A|interfere with the renal elimination of oxaliplatin and result in additive|
04785|009|A|risk of QT prolongation.(1)|
04785|010|A|   Oxaliplatin is a MATE substrate.(2,3)|
04785|011|B||
04785|012|E|CLINICAL EFFECTS:  Concurrent use of MATE renal transporter inhibitors may|
04785|013|E|result in increased levels of and toxicity from oxaliplatin.(1)|
04785|014|E|   The concurrent use of oxaliplatin and agents that prolong the QTc|
04785|015|E|interval may result in potentially life-threatening cardiac arrhythmias,|
04785|016|E|including torsades de pointes(TdP).(1)|
04785|017|B||
04785|018|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
04785|019|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
04785|020|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
04785|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
04785|022|P|concurrent use of agents known to cause QT prolongation.(4)|
04785|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04785|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04785|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04785|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04785|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04785|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04785|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04785|030|B||
04785|031|M|PATIENT MANAGEMENT:  Concurrent use of oxaliplatin with MATE renal|
04785|032|M|transporter inhibitors should be approached with caution and monitored|
04785|033|M|closely.  If concurrent use is warranted, monitor for toxicities of|
04785|034|M|oxaliplatin and consider dosage reduction based on toxicity dose|
04785|035|M|recommendations.(1)|
04785|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04785|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04785|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04785|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04785|040|B||
04785|041|D|DISCUSSION:  Oxaliplatin is a MATE substrate.(2,3)|
04785|042|D|   MATE inhibitors that prolong QT include: ranolazine and vandetanib.(6)|
04785|043|B||
04785|044|R|REFERENCES:|
04785|045|B||
04785|046|R|1.Eloxatin (oxaliplatin) US prescribing information. Sanofi-Aventis U.S. LLC|1
04785|047|R|  October, 2015.|1
04785|048|R|2.Yonezawa A, Inui K. Organic cation transporter OCT/SLC22A and H(+)/organic|2
04785|049|R|  cation antiporter  MATE/SLC47A are key molecules for nephrotoxicity of|2
04785|050|R|  platinum agents. Biochem Pharmacol 2011 Mar 1;81(5):563-8.|2
04785|051|R|3.Yokoo S, Yonezawa A, Masuda S, Fukatsu A, Katsura T, Inui K. Differential|2
04785|052|R|  contribution of organic cation transporters, OCT2 and MATE1, in  platinum|2
04785|053|R|  agent-induced nephrotoxicity. Biochem Pharmacol 2007 Aug 1;74(3):477-87.|2
04785|054|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04785|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04785|056|R|  settings: a scientific statement from the American Heart Association and|6
04785|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04785|058|R|  2;55(9):934-47.|6
04785|059|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
04785|060|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04785|061|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04785|062|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04785|063|R|6.This information is based on an extract from the Certara Drug Interaction|6
04785|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04786|001|T|MONOGRAPH TITLE:  Flecainide/MATE Inhibitors that Prolong QT|
04786|002|B||
04786|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04786|004|L|take action as needed.|
04786|005|B||
04786|006|A|MECHANISM OF ACTION:  Inhibitors of the Multidrug and Toxin Extrusion (MATE)|
04786|007|A|protein transporters in the kidneys that prolong the QT interval may|
04786|008|A|interfere with the renal elimination of flecainide and result in additive|
04786|009|A|risk of QT prolongation.(1)|
04786|010|B||
04786|011|E|CLINICAL EFFECTS:  Concurrent use of MATE renal transporter inhibitors may|
04786|012|E|result in increased levels of and toxicity from flecainide.(1)|
04786|013|E|   The concurrent use of flecainide and agents that prolong the QTc interval|
04786|014|E|may result in potentially life-threatening cardiac arrhythmias, including|
04786|015|E|torsades de pointes (TdP).(2)|
04786|016|B||
04786|017|P|PREDISPOSING FACTORS:  Risk factors for QT prolongation include:|
04786|018|P|cardiovascular disease (e.g. heart failure, recent myocardial infarction,|
04786|019|P|history of torsades de pointes, congenital long QT syndrome), female sex,|
04786|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and|
04786|021|P|concurrent use of agents known to cause QT prolongation.(2)|
04786|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04786|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04786|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04786|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04786|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04786|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04786|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04786|029|B||
04786|030|M|PATIENT MANAGEMENT:  Monitor serum flecainide concentrations and observe the|
04786|031|M|patients for signs of toxicity.|
04786|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04786|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04786|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04786|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04786|036|B||
04786|037|D|DISCUSSION:  In a pharmacokinetic study, concurrent use of cimetidine (1|
04786|038|D|gram daily, a MATE inhibitor) increased flecainide levels by 30% and|
04786|039|D|increased half-life by 10%.(1)|
04786|040|D|   MATE inhibitors that prolong QT include: ranolazine and vandetanib.(4)|
04786|041|B||
04786|042|R|REFERENCES:|
04786|043|B||
04786|044|R|1.Tambocor (flecainide) US prescribing information. Medicis December, 2011.|1
04786|045|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04786|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04786|047|R|  settings: a scientific statement from the American Heart Association and|6
04786|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04786|049|R|  2;55(9):934-47.|6
04786|050|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04786|051|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04786|052|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04786|053|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04786|054|R|4.This information is based on an extract from the Certara Drug Interaction|6
04786|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04787|001|T|MONOGRAPH TITLE:  Clopidogrel/Abrocitinib|
04787|002|B||
04787|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04787|004|L|of severe adverse interaction.|
04787|005|B||
04787|006|A|MECHANISM OF ACTION:  Clopidogrel is a prodrug and is converted to its|
04787|007|A|active metabolite via a 2-step process.  The first conversion step is|
04787|008|A|mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by|
04787|009|A|CYP3A4, CYP2B6 and CYP2C19.(1-3)  CYP2C19 contributes to both steps and is|
04787|010|A|thought to be the more important enzyme involved in formation of the|
04787|011|A|pharmacologically active metabolite.(1)|
04787|012|A|   Inhibitors of CYP2C19 may decrease the conversion of clopidogrel to its|
04787|013|A|active metabolite.(1)  Abrocitinib is a moderate CYP2C19 inhibitor.(4,5)|
04787|014|A|   Abrocitinib has been associated with transient, dose-dependent|
04787|015|A|thrombocytopenia.  The nadir platelet count occurs at a median of 24 days|
04787|016|A|after receiving abrocitinib 200 mg once daily and a 40% recovery occurs by|
04787|017|A|12 weeks.  Concurrent use with agents that affect platelet aggregation may|
04787|018|A|result in an additive risk of bleeding.(5)|
04787|019|B||
04787|020|E|CLINICAL EFFECTS:  Concurrent use of CYP2C19 inhibitors may result in|
04787|021|E|decreased clopidogrel effectiveness, resulting in increased risk of adverse|
04787|022|E|cardiac events.|
04787|023|E|   Concurrent use of abrocitinib with clopidogrel may increase the risk of|
04787|024|E|bleeding.(5)|
04787|025|B||
04787|026|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04787|027|P|patients with disease-associated factors (e.g. pre-existing|
04787|028|P|thrombocytopenia).  Abrocitinib is not recommended for patients with a|
04787|029|P|platelet count less than 150,000/mm3.(5)|
04787|030|P|   Drug associated risk factors include concurrent use of multiple drugs|
04787|031|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04787|032|P|risk for bleeding.|
04787|033|B||
04787|034|M|PATIENT MANAGEMENT:  Evaluate medication list or interaction alerts to|
04787|035|M|determine if patient is receiving additional drugs which may also inhibit|
04787|036|M|clopidogrel active metabolite formation.|
04787|037|M|   The US manufacturer of clopidogrel states that alternatives to|
04787|038|M|clopidogrel should be considered in patients who are poor metabolizers of|
04787|039|M|CYP2C19.(1)  It would be prudent to assume that patients taking strong|
04787|040|M|inhibitors of CYP2C19 are poor metabolizers of this isoenzyme.  Moderate or|
04787|041|M|weak inhibitors of CYP2C19 may have less of an effect on this interaction.|
04787|042|M|   Consider alternatives to CYP2C19 inhibitors in patients stabilized on|
04787|043|M|clopidogrel and alternatives to clopidogrel in patients stabilized on|
04787|044|M|CYP2C19 inhibitors.  If concurrent therapy is warranted, consider|
04787|045|M|appropriate testing to assure adequate inhibition of platelet reactivity.|
04787|046|M|   The concurrent use of abrocitinib with antiplatelet agents (except|
04787|047|M|aspirin < or = 81 mg daily) is contraindicated during the first 3 months of|
04787|048|M|abrocitinib therapy.(5)|
04787|049|M|   Prior to starting abrocitinib therapy, obtain a complete blood count and|
04787|050|M|recheck at 4 weeks after initiation and 4 weeks after a dose increase.|
04787|051|M|Discontinuation of abrocitinib is required if platelets drop below|
04787|052|M|50,000/mm3.(5)|
04787|053|M|   If concurrent therapy is warranted after the first 3 months of|
04787|054|M|abrocitinib therapy, monitor patients receiving concurrent therapy for signs|
04787|055|M|of blood loss, including decreased hemoglobin, hematocrit, fecal occult|
04787|056|M|blood, and/or decreased blood pressure and promptly evaluate patients with|
04787|057|M|any symptoms.(5)|
04787|058|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04787|059|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04787|060|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04787|061|M|and/or swelling.|
04787|062|B||
04787|063|D|DISCUSSION:  Clopidogrel is a prodrug and requires conversion to the active|
04787|064|D|metabolite by CYP2C19.|
04787|065|D|   Clopidogrel is not a sensitive substrate for CYP2C19 as CYP3A4, CYP2B6|
04787|066|D|and CYP1A2 also participate in active metabolite formation.  Studies have|
04787|067|D|not evaluated this specific drug combination; the actual magnitude of this|
04787|068|D|interaction is not known.  Given the possible consequences of clopidogrel|
04787|069|D|treatment failure, it would be prudent to avoid concomitant use of|
04787|070|D|clopidogrel and CYP2C19 inhibitors when possible.|
04787|071|D|   Abrocitinib has been associated with transient, dose-dependent|
04787|072|D|thrombocytopenia which is more severe with lower baseline platelet counts.|
04787|073|D|At baseline platelet counts of 170,000/mm3, 220,000/m3 and 270,000/mm3, the|
04787|074|D|nadirs were -41.2%, -33.4%, and -26.5%, respectively.  Recovery of platelet|
04787|075|D|count (about 40% recovery by 12 weeks) occurred without discontinuation of|
04787|076|D|the treatment.(5)|
04787|077|B||
04787|078|R|REFERENCES:|
04787|079|B||
04787|080|R|1.Plavix (clopidogrel bisulfate) US prescribing information. Bristol-Myers|1
04787|081|R|  Squibb/Sanofi Pharmaceuticals Partnership September, 2022.|1
04787|082|R|2.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T,|5
04787|083|R|  Kurihara A. Identification of the human cytochrome P450 enzymes involved|5
04787|084|R|  in the two oxidative steps in the bioactivation of clopidogrel to its|5
04787|085|R|  pharmacologically active metabolite. Drug Metab Dispos 2010 Jan;|5
04787|086|R|  38(1):92-9.|5
04787|087|R|3.US Food and Drug Association. Information on Clopidogrel Bisulfate|1
04787|088|R|  (marketed as Plavix). Available at:|1
04787|089|R|  http://wayback.archive-it.org/7993/20170111075953/http:/www.fda.gov/Drugs/|1
04787|090|R|  DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm19083|1
04787|091|R|  6.htm October 27, 2010.|1
04787|092|R|4.This information is based on an extract from the Certara Drug Interaction|6
04787|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04787|094|R|5.Cibinqo (abrocitinib) US prescribing information. Pfizer Labs January,|1
04787|095|R|  2022.|1
04788|001|T|MONOGRAPH TITLE:  Cilostazol (Less Than or Equal to 50 mg BID)/Abrocitinib|
04788|002|B||
04788|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04788|004|L|of severe adverse interaction.|
04788|005|B||
04788|006|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP2C19 may inhibit|
04788|007|A|the metabolism of cilostazol.(1-4)  Abrocitinib is a moderate CYP2C19|
04788|008|A|inhibitor.(5,6)|
04788|009|A|   Abrocitinib has been associated with transient, dose-dependent|
04788|010|A|thrombocytopenia.  The nadir platelet count occurs at a median of 24 days|
04788|011|A|after receiving abrocitinib 200 mg once daily and a 40% recovery occurs by|
04788|012|A|12 weeks.  Concurrent use with agents that affect platelet aggregation may|
04788|013|A|result in an additive risk of bleeding.(5)|
04788|014|B||
04788|015|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate inhibitors of|
04788|016|E|CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a|
04788|017|E|metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)|
04788|018|E|   Concurrent use of abrocitinib with antiplatelet agents such as cilostazol|
04788|019|E|may increase the risk of bleeding.(5)|
04788|020|B||
04788|021|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04788|022|P|patients with disease-associated factors (e.g. pre-existing|
04788|023|P|thrombocytopenia).  Abrocitinib is not recommended for patients with a|
04788|024|P|platelet count less than 150,000/mm3.(5)|
04788|025|P|   Drug associated risk factors include concurrent use of multiple drugs|
04788|026|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04788|027|P|risk for bleeding.|
04788|028|B||
04788|029|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
04788|030|M|daily in patients receiving concurrent therapy with strong and moderate|
04788|031|M|inhibitors of CYP2C19.(1)|
04788|032|M|   The concurrent use of abrocitinib with antiplatelet agents (except|
04788|033|M|aspirin < or = 81 mg daily) is contraindicated during the first 3 months of|
04788|034|M|abrocitinib therapy.(5)|
04788|035|M|   Prior to starting abrocitinib therapy, obtain a complete blood count and|
04788|036|M|recheck at 4 weeks after initiation and 4 weeks after a dose increase.|
04788|037|M|Discontinuation of abrocitinib is required if platelets drop below|
04788|038|M|50,000/mm3.(5)|
04788|039|M|   If concurrent therapy is warranted after the first 3 months of|
04788|040|M|abrocitinib therapy, monitor patients receiving concurrent therapy for signs|
04788|041|M|of blood loss, including decreased hemoglobin, hematocrit, fecal occult|
04788|042|M|blood, and/or decreased blood pressure and promptly evaluate patients with|
04788|043|M|any symptoms.(5)|
04788|044|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04788|045|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04788|046|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04788|047|M|and/or swelling.|
04788|048|B||
04788|049|D|DISCUSSION:  In a study in 20 subjects examined the effects of omeprazole (a|
04788|050|D|CYP2C19 inhibitor, 40 mg daily) on a single dose of cilostazol (100 mg).|
04788|051|D|Concurrent omeprazole increased the cilostazol maximum concentration (Cmax)|
04788|052|D|and area-under-curve (AUC) by 18% and 26%, respectively.  The Cmax and AUC|
04788|053|D|of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and|
04788|054|D|69%, respectively.  The Cmax and AUC of the OPC-13213 metabolite of|
04788|055|D|cilostazol decreased by 22% and 31%, respectively.(4)|
04788|056|D|   Abrocitinib has been associated with transient, dose-dependent|
04788|057|D|thrombocytopenia and is more severe with lower baseline platelet counts. At|
04788|058|D|baseline platelet counts of 170,000/mm3, 220,000/m3 and 270,000/mm3, the|
04788|059|D|nadirs were -41.2%, -33.4%, and -26.5%, respectively.  Recovery of platelet|
04788|060|D|count (about 40% recovery by 12 weeks) occurred without discontinuation of|
04788|061|D|the treatment.(5)|
04788|062|B||
04788|063|R|REFERENCES:|
04788|064|B||
04788|065|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
04788|066|R|  Pharmaceutical, Inc. January, 2015.|1
04788|067|R|2.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
04788|068|R|  Pharmaceuticals LP August, 2021.|1
04788|069|R|3.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
04788|070|R|  Pharmaceuticals LP June, 2018.|1
04788|071|R|4.Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol.|2
04788|072|R|  Clin Pharmacokinet 1999;37 Suppl 2:53-9.|2
04788|073|R|5.Cibinqo (abrocitinib) US prescribing information. Pfizer Labs January,|1
04788|074|R|  2022.|1
04788|075|R|6.This information is based on an extract from the Certara Drug Interaction|6
04788|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04789|001|T|MONOGRAPH TITLE:  Cilostazol (Greater Than 50 mg BID)/Abrocitinib|
04789|002|B||
04789|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04789|004|L|is contraindicated and generally should not be dispensed or administered to|
04789|005|L|the same patient.|
04789|006|B||
04789|007|A|MECHANISM OF ACTION:  Strong and moderate inhibitors of CYP2C19 may inhibit|
04789|008|A|the metabolism of cilostazol.(1-4)  Abrocitinib is a moderate CYP2C19|
04789|009|A|inhibitor.(5,6)|
04789|010|A|   Abrocitinib has been associated with transient, dose-dependent|
04789|011|A|thrombocytopenia.  The nadir platelet count occurs at a median of 24 days|
04789|012|A|after receiving abrocitinib 200 mg once daily and a 40% recovery occurs by|
04789|013|A|12 weeks.  Concurrent use with agents that affect platelet aggregation may|
04789|014|A|result in an additive risk of bleeding.(5)|
04789|015|B||
04789|016|E|CLINICAL EFFECTS:  Concurrent use of strong or moderate inhibitors of|
04789|017|E|CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a|
04789|018|E|metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)|
04789|019|E|   Concurrent use of abrocitinib with antiplatelet agents such as cilostazol|
04789|020|E|may increase the risk of bleeding.(5)|
04789|021|B||
04789|022|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04789|023|P|patients with disease-associated factors (e.g. pre-existing|
04789|024|P|thrombocytopenia).  Abrocitinib is not recommended for patients with a|
04789|025|P|platelet count less than 150,000/mm3.(5)|
04789|026|P|   Drug associated risk factors include concurrent use of multiple drugs|
04789|027|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04789|028|P|risk for bleeding.|
04789|029|B||
04789|030|M|PATIENT MANAGEMENT:  The dose of cilostazol should be limited to 50 mg twice|
04789|031|M|daily in patients receiving concurrent therapy with strong and moderate|
04789|032|M|inhibitors of CYP2C19.(1)|
04789|033|M|   The concurrent use of abrocitinib with antiplatelet agents (except|
04789|034|M|aspirin < or = 81 mg daily) is contraindicated during the first 3 months of|
04789|035|M|abrocitinib therapy.(5)|
04789|036|M|   Prior to starting abrocitinib therapy, obtain a complete blood count and|
04789|037|M|recheck at 4 weeks after initiation and 4 weeks after a dose increase.|
04789|038|M|Discontinuation of abrocitinib is required if platelets drop below|
04789|039|M|50,000/mm3.(5)|
04789|040|M|   If concurrent therapy is warranted after the first 3 months of|
04789|041|M|abrocitinib therapy, monitor patients receiving concurrent therapy for signs|
04789|042|M|of blood loss, including decreased hemoglobin, hematocrit, fecal occult|
04789|043|M|blood, and/or decreased blood pressure and promptly evaluate patients with|
04789|044|M|any symptoms.(5)|
04789|045|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04789|046|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04789|047|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04789|048|M|and/or swelling.|
04789|049|B||
04789|050|D|DISCUSSION:  In a study in 20 subjects examined the effects of omeprazole (a|
04789|051|D|CYP2C19 inhibitor, 40 mg daily) on a single dose of cilostazol (100 mg).|
04789|052|D|Concurrent omeprazole increased the cilostazol maximum concentration (Cmax)|
04789|053|D|and area-under-curve (AUC) by 18% and 26%, respectively.  The Cmax and AUC|
04789|054|D|of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and|
04789|055|D|69%, respectively.  The Cmax and AUC of the OPC-13213 metabolite of|
04789|056|D|cilostazol decreased by 22% and 31%, respectively.(4)|
04789|057|D|   Abrocitinib has been associated with transient, dose-dependent|
04789|058|D|thrombocytopenia and is more severe with lower baseline platelet counts. At|
04789|059|D|baseline platelet counts of 170,000/mm3, 220,000/m3 and 270,000/mm3, the|
04789|060|D|nadirs were -41.2%, -33.4%, and -26.5%, respectively.  Recovery of platelet|
04789|061|D|count (about 40% recovery by 12 weeks) occurred without discontinuation of|
04789|062|D|the treatment.(5)|
04789|063|B||
04789|064|R|REFERENCES:|
04789|065|B||
04789|066|R|1.Pletal (cilostazol) US prescribing information. Otsuka America|1
04789|067|R|  Pharmaceutical, Inc. January, 2015.|1
04789|068|R|2.Nexium (esomeprazole magnesium) US prescribing information. AstraZeneca|1
04789|069|R|  Pharmaceuticals LP August, 2021.|1
04789|070|R|3.Prilosec (omeprazole) US prescribing information. AstraZeneca|1
04789|071|R|  Pharmaceuticals LP June, 2018.|1
04789|072|R|4.Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol.|2
04789|073|R|  Clin Pharmacokinet 1999;37 Suppl 2:53-9.|2
04789|074|R|5.Cibinqo (abrocitinib) US prescribing information. Pfizer Labs January,|1
04789|075|R|  2022.|1
04789|076|R|6.This information is based on an extract from the Certara Drug Interaction|6
04789|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04790|001|T|MONOGRAPH TITLE:  Tovorafenib/Pirtobrutinib|
04790|002|B||
04790|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04790|004|L|of severe adverse interaction.|
04790|005|B||
04790|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP2C8 may inhibit the|
04790|007|A|metabolism of tovorafenib.(1)  Pirtobrutinib is a moderate CYP2C8|
04790|008|A|inhibitor.(3)|
04790|009|A|   Moderate inducers of CYP3A4 may increase the metabolism of|
04790|010|A|pirtobrutinib.(2)  Tovorafenib is a moderate CYP3A4 inducer.(3)|
04790|011|B||
04790|012|E|CLINICAL EFFECTS:  Concomitant use of a moderate CYP2C8 inhibitor may|
04790|013|E|increase tovorafenib plasma concentrations, which may increase the risk of|
04790|014|E|tovorafenib toxicity, including hepatotoxicity, bleeding, and|
04790|015|E|photosensitivity.(1)|
04790|016|E|   Concurrent use of a moderate inducer of CYP3A4 may result in decreased|
04790|017|E|levels and effectiveness of pirtobrutinib.(2)|
04790|018|B||
04790|019|P|PREDISPOSING FACTORS:  None determined.|
04790|020|B||
04790|021|M|PATIENT MANAGEMENT:  The manufacturer of tovorafenib recommends avoiding|
04790|022|M|concomitant use of tovorafenib with moderate CYP2C8 inhibitors.(1)|
04790|023|M|   The manufacturer of pirtobrutinib recommends avoiding concomitant use of|
04790|024|M|pirtobrutinib with moderate CYP3A4 inducers.(2)|
04790|025|M|   If concomitant use of moderate CYP3A4 inducers is unavoidable, and the|
04790|026|M|current dose of pirtobrutinib is 200 mg daily, increase the dose to 300 mg|
04790|027|M|daily.  If the current pirtobrutinib dosage is 50 mg or 100 mg once daily,|
04790|028|M|increase the dose by 50 mg.(2)|
04790|029|B||
04790|030|D|DISCUSSION:  No formal interaction studies have been done with tovorafenib|
04790|031|D|and pirtobrutinib.|
04790|032|D|   Moderate CYP2C8 inhibitors are predicted to increase tovorafenib|
04790|033|D|exposure.(1)|
04790|034|D|   Efavirenz and bosentan (moderate CYP3A inducers) are predicted to|
04790|035|D|decrease the area-under-curve (AUC) of pirtobrutinib by 49% and 27%,|
04790|036|D|respectively.(2)|
04790|037|B||
04790|038|R|REFERENCES:|
04790|039|B||
04790|040|R|1.Ojemda (tovorafenib) US prescribing information. Day One|1
04790|041|R|  Biopharmaceuticals Inc. April 2024.|1
04790|042|R|2.Jaypirca (pirtobrutinib) US prescribing information. Eli Lilly January|1
04790|043|R|  2023.|1
04790|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
04790|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04791|001|T|MONOGRAPH TITLE:  Tovorafenib/Selpercatinib|
04791|002|B||
04791|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04791|004|L|of severe adverse interaction.|
04791|005|B||
04791|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP2C8 may inhibit the|
04791|007|A|metabolism of tovorafenib.(1)  Selpercatinib is a moderate CYP2C8|
04791|008|A|inhibitor.(3)|
04791|009|A|   Strong and moderate CYP3A4 inducers may increase the metabolism of|
04791|010|A|selpercatinib.(2)  Tovorafenib is a moderate CYP3A4 inducer.(3)|
04791|011|B||
04791|012|E|CLINICAL EFFECTS:  Concomitant use of a moderate CYP2C8 inhibitor may|
04791|013|E|increase tovorafenib plasma concentrations, which may increase the risk of|
04791|014|E|tovorafenib toxicity, including hepatotoxicity, bleeding, and|
04791|015|E|photosensitivity.(1)|
04791|016|E|   Coadministration of selpercatinib with a strong or moderate CYP3A4|
04791|017|E|inducer decreases selpercatinib plasma concentrations, which may decrease|
04791|018|E|the efficacy of selpercatinib.(2)|
04791|019|B||
04791|020|P|PREDISPOSING FACTORS:  None determined.|
04791|021|B||
04791|022|M|PATIENT MANAGEMENT:  The manufacturer of tovorafenib recommends avoiding|
04791|023|M|concomitant use of tovorafenib with moderate CYP2C8 inhibitors.(1)|
04791|024|M|   The manufacturer of selpercatinib states that concurrent use with strong|
04791|025|M|and moderate CYP3A4 inducers should be avoided.(2)|
04791|026|B||
04791|027|D|DISCUSSION:  No formal interaction studies have been done with tovorafenib|
04791|028|D|and selpercatinib.|
04791|029|D|   Moderate CYP2C8 inhibitors are predicted to increase tovorafenib|
04791|030|D|exposure.(1)|
04791|031|D|   In a study, multiple doses of rifampin (a strong CYP3A inducer) decreased|
04791|032|D|the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib|
04791|033|D|by 87% and 70%, respectively.(2)|
04791|034|D|   Coadministration of multiple doses of bosentan or efavirenz (moderate|
04791|035|D|CYP3A inducers) is predicted to decrease the AUC and Cmax of selpercatinib|
04791|036|D|40-70% and 34-57%, respectively.(2)|
04791|037|B||
04791|038|R|REFERENCES:|
04791|039|B||
04791|040|R|1.Ojemda (tovorafenib) US prescribing information. Day One|1
04791|041|R|  Biopharmaceuticals Inc. April 2024.|1
04791|042|R|2.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
04791|043|R|  2024.|1
04791|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
04791|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04792|001|T|MONOGRAPH TITLE:  Phenobarbital; Primidone/Cenobamate|
04792|002|B||
04792|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04792|004|L|take action as needed.|
04792|005|B||
04792|006|A|MECHANISM OF ACTION:  Cenobamate may inhibit the CYP2C19-mediated metabolism|
04792|007|A|of phenobarbital and primidone.(1)|
04792|008|A|   Primidone is metabolized to phenobarbital.|
04792|009|B||
04792|010|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of and|
04792|011|E|toxicity from phenobarbital or primidone.(1)|
04792|012|E|   Symptoms of barbiturate toxicity may include drowsiness, dizziness,|
04792|013|E|ataxia, and respiratory depression.(2)|
04792|014|B||
04792|015|P|PREDISPOSING FACTORS:  None determined.|
04792|016|B||
04792|017|M|PATIENT MANAGEMENT:  The US and Canadian manufacturers of cenobamate state a|
04792|018|M|dose reduction of phenobarbital should be considered when used concomitantly|
04792|019|M|due to an increased risk of adverse reactions.  Patients maintained on|
04792|020|M|phenobarbital should be carefully monitored if cenobamate is initiated or|
04792|021|M|discontinued.(1,4)|
04792|022|M|   The UK manufacturer of cenobamate states that no dose adjustment of|
04792|023|M|cenobamate is required.  Concentrations of phenobarbital should be monitored|
04792|024|M|during cenobamate titration, and based on individual response, the dose of|
04792|025|M|phenobarbital may need to be reduced.(5-8)|
04792|026|M|   Monitor the patient for signs of barbiturate toxicity, such as|
04792|027|M|drowsiness, dizziness, ataxia, and respiratory depression.(2)|
04792|028|B||
04792|029|D|DISCUSSION:  In a study, concomitant administration of cenobamate 200 mg|
04792|030|D|daily and phenobarbital 90 mg daily did not cause clinically meaningful|
04792|031|D|changes in cenobamate exposure but led to increased phenobarbital exposures|
04792|032|D|(maximum concentration (Cmax) by 34% and area-under-curve (AUC) by|
04792|033|D|37%).(1,4,5)|
04792|034|B||
04792|035|R|REFERENCES:|
04792|036|B||
04792|037|R|1.Xcopri (cenobamate) US prescribing information. SK Life Science, Inc.|1
04792|038|R|  November, 2019.|1
04792|039|R|2.Sezaby (phenobarbital sodium)  US prescribing information. Sun|1
04792|040|R|  Pharmaceutical Industries, Inc. 11/2022.|1
04792|041|R|3.Center for Substance Abuse Treatment. Clinical Guidelines for the Use of|6
04792|042|R|  Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement|6
04792|043|R|  Protocol (TIP) Series 40. Substance Abuse and Mental Health Services|6
04792|044|R|  Administration (US) 2004.|6
04792|045|R|4.Xcopri (cenobamate) Canadian prescribing information. SK|1
04792|046|R|  Biopharmaceuticals Co., Ltd. May 15, 2024.|1
04792|047|R|5.Ontozry (cenobamate) UK prescribing information. Angelini Pharma UK-I|1
04792|048|R|  Limited April 2024.|1
04792|049|R|6.Carreno M, Gil-Nagel A, Serratosa JM, Toledo M, Rodriguez-Uranga JJ,|6
04792|050|R|  Villanueva V. Spanish consensus on the management of concomitant|6
04792|051|R|  antiseizure medications when using cenobamate in adults with|6
04792|052|R|  drug-resistant focal seizures. Epilepsia Open 24 March 2024;9:1051 - 1058.|6
04792|053|R|7.Villani F, Cianci V, Di Bonaventura C, Di Gennaro G, Galimberti CA,|6
04792|054|R|  Guerrini R, La Neve A, Mecarelli O, Pietrafusa N, Specchio N, Vigevano F,|6
04792|055|R|  Perucca E. Use of cenobamate for the treatment of focal epilepsy: an|6
04792|056|R|  Italian expert opinion paper. Expert Rev Neurother 24 Jan 2023;|6
04792|057|R|  22(11-12):935-940.|6
04792|058|R|8.Smith MC, Klein P, Krauss GL, Rashid S, Seiden LG, Stern JM, Rosenfeld WE.|6
04792|059|R|  Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate|6
04792|060|R|  Treatment: Expert Opinion Consensus Recommendations. Neurol Ther 3|6
04792|061|R|  September 2022;11:1705-1720.|6
04793|001|T|MONOGRAPH TITLE:  Tretinoin/Moderate CYP3A4 Inhibitors|
04793|002|B||
04793|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04793|004|L|take action as needed.|
04793|005|B||
04793|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04793|007|A|metabolism of tretinoin.(1)|
04793|008|B||
04793|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
04793|010|E|in increased levels of and effects from tretinoin including hepatotoxicity|
04793|011|E|and hyperlipidemia.(1)|
04793|012|E|   Retinoids, including tretinoin, have been associated with intracranial|
04793|013|E|hypertension, especially in pediatric patients. Early signs and symptoms|
04793|014|E|include papilledema, headache, nausea, vomiting, and visual disturbances.(1)|
04793|015|B||
04793|016|P|PREDISPOSING FACTORS:  None determined.|
04793|017|B||
04793|018|M|PATIENT MANAGEMENT:  The manufacturer of tretinoin recommends monitoring|
04793|019|M|patients taking a moderate CYP3A4 inhibitor in combination with tretinoin|
04793|020|M|more frequently for adverse reactions.(1)|
04793|021|M|   Evaluate patients with symptoms for intracranial hypertension (such as|
04793|022|M|papilledema, headache, nausea, vomiting, and visual disturbances), and, if|
04793|023|M|present, institute care in concert with neurological assessment. Consider|
04793|024|M|interruption, dose reduction, or discontinuation of tretinoin as|
04793|025|M|appropriate.(1)|
04793|026|B||
04793|027|D|DISCUSSION:  In 13 patients on tretinoin for 4 weeks, single-dose|
04793|028|D|ketoconazole (400 to 1200 mg) (strong CYP3A4 inhibitor) increased tretinoin|
04793|029|D|area-under-curve (AUC) by 72%.(1)|
04793|030|D|   There are no clinical pharmacokinetic studies on the combination of|
04793|031|D|tretinoin with a moderate CYP3A4 inhibitor.  The US manufacturer of|
04793|032|D|tretinoin states increased tretinoin toxicity following concomitant use of|
04793|033|D|tretinoin with certain antimycotics that are moderate CYP3A4 inhibitors has|
04793|034|D|been reported post-marketing.(1)|
04793|035|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04793|036|D|atazanavir, avacopan, clofazimine, conivaptan, crizotinib, darunavir,|
04793|037|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
04793|038|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium,|
04793|039|D|lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra,|
04793|040|D|stiripentol, tofisopam, and treosulfan.(2-3)|
04793|041|B||
04793|042|R|REFERENCES:|
04793|043|B||
04793|044|R|1.Vesanoid (tretinoin) US prescribing information. Roche Laboratories, Inc.|1
04793|045|R|  February, 2023.|1
04793|046|R|2.This information is based on an extract from the Certara Drug Interaction|6
04793|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04793|048|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04793|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04793|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04793|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04793|052|R|  11/14/2017.|1
04794|001|T|MONOGRAPH TITLE:  Coumarin Anticoagulants/Itraconazole; Posaconazole|
04794|002|B||
04794|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04794|004|L|take action as needed.|
04794|005|B||
04794|006|A|MECHANISM OF ACTION:  The more potent warfarin S-enantiomer is metabolized|
04794|007|A|by CYP2C9 while the weaker R-enantiomer is metabolized by CYP1A2 and|
04794|008|A|CYP3A4.(1)|
04794|009|A|   Itraconazole and posaconazole are strong inhibitors of CYP3A4.(2)|
04794|010|B||
04794|011|E|CLINICAL EFFECTS:  Concurrent use of select azole antifungals and coumarin|
04794|012|E|anticoagulants may increase the risk for bleeding.|
04794|013|B||
04794|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04794|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04794|016|P|   Additional drug associated risk factors include concurrent use of|
04794|017|P|multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or|
04794|018|P|have an inherent risk for bleeding (e.g. NSAIDs).|
04794|019|B||
04794|020|M|PATIENT MANAGEMENT:  In patients receiving warfarin when itraconazole or|
04794|021|M|posaconazole is started, closely monitor INR and reduce the dose of warfarin|
04794|022|M|as needed.(1,2)  After the azole therapy is discontinued, close monitoring|
04794|023|M|is again needed as the INR may fall after removal of the inhibitor.|
04794|024|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04794|025|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04794|026|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04794|027|M|patients with any symptoms.  Discontinue anticoagulation in patients with|
04794|028|M|active pathologic bleeding.|
04794|029|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04794|030|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04794|031|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04794|032|M|and/or swelling.|
04794|033|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04794|034|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04794|035|M|initiating, altering the dose or discontinuing either drug.|
04794|036|B||
04794|037|D|DISCUSSION:  In a case report, a 61 year old woman stable on warfarin for 12|
04794|038|D|months had recently started itraconazole 200 mg twice daily. She was|
04794|039|D|hospitalized for intractable bleeding and found to have an INR of 8.|
04794|040|D|Warfarin and itraconazole were stopped and patient was treated with fresh|
04794|041|D|frozen plasma, with a drop in INR to 2.4 after 2 days.(3)|
04794|042|D|   A prospective cohort study followed 1,172 patients on acenocoumarol who|
04794|043|D|started antimicrobials for risk of overanticoagulation (INR >6). Patients|
04794|044|D|who started itraconazole had an increased risk of overanticoagulation|
04794|045|D|compared to patients on amoxicillin-clavulanate (HR 4.11; 95% CI 1.79-9.45;|
04794|046|D|p = 0.001).(4)|
04794|047|D|   A retrospective review compared the changes in warfarin effects with|
04794|048|D|coadministration of fluconazole, itraconazole, or voriconazole in 18, 6, and|
04794|049|D|5 patients, respectively.  Mean INR increased slightly from 1.86 to 1.92 in|
04794|050|D|patients taking itraconazole (p=0.37) and did not increase >20% in any|
04794|051|D|patient.(5)|
04794|052|D|   A large systematic review was performed on 72 warfarin drug-drug|
04794|053|D|interactions studies that reported on bleeding, thromboembolic events, or|
04794|054|D|death.  Most studies were retrospective cohorts.  A meta-analysis of 11 of|
04794|055|D|those studies found a higher rate of clinically significant bleeding in|
04794|056|D|patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83).|
04794|057|D|Increased bleeding risk was also seen in subgroup analyses with azole|
04794|058|D|antifungals (OR=1.86; 95% CI 1.40-2.47).(6)|
04794|059|B||
04794|060|R|REFERENCES:|
04794|061|B||
04794|062|R|1.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
04794|063|R|  Squibb Company September, 2016.|1
04794|064|R|2.Noxafil (posaconazole) US prescribing information. Merck & Co. Inc|1
04794|065|R|  January, 2022.|1
04794|066|R|3.Yeh J, Soo SC, Summerton C, Richardson C. Potentiation of action of|3
04794|067|R|  warfarin by itraconazole. BMJ 1990 Sep 29;301(6753):669.|3
04794|068|R|4.Becker ML, van Uden  RCAE, Giezen TJ, Meijer K, Houtenbos I, van den Bemt|2
04794|069|R|  PMLA. Drug-drug interactions with metronidazole and itraconazole in|2
04794|070|R|  patients using  acenocoumarol. Eur J Clin Pharmacol 2020 Oct;|2
04794|071|R|  76(10):1457-1464.|2
04794|072|R|5.Yamamoto H, Habu Y, Yano I, Ozaki J, Kimura Y, Sato E, Shida A, Fukatsu S,|2
04794|073|R|  Matsubara K. Comparison of the effects of azole antifungal agents on the|2
04794|074|R|  anticoagulant activity of warfarin. Biol Pharm Bull 2014;37(12):1990-3.|2
04794|075|R|6.Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A,|6
04794|076|R|  Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug|6
04794|077|R|  interactions with warfarin: A systematic review and meta-analysis. Br J|6
04794|078|R|  Clin Pharmacol 2021 Nov;87(11):4051-4100.|6
04795|001|T|MONOGRAPH TITLE:  Foslevodopa; Levodopa/Isoniazid|
04795|002|B||
04795|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04795|004|L|take action as needed.|
04795|005|B||
04795|006|A|MECHANISM OF ACTION:  Isoniazid inhibits dopa decarboxylase, which is|
04795|007|A|responsible for the decarboxylation of levodopa to dopamine.(1)|
04795|008|A|   Foslevodopa is a prodrug of levodopa.(2,3)|
04795|009|B||
04795|010|E|CLINICAL EFFECTS:  Concurrent administration with isoniazid may result in|
04795|011|E|decreased dopamine and decreased effectiveness of levodopa.(1-2,4-5)|
04795|012|B||
04795|013|P|PREDISPOSING FACTORS:  None determined.|
04795|014|B||
04795|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
04795|016|M|isoniazid and levodopa or foslevodopa for worsening Parkinson's symptoms.(3)|
04795|017|M|The dose of levodopa may need to be increased.(1)|
04795|018|B||
04795|019|D|DISCUSSION:  In a case report, a 74-year-old woman with Lewy Body Dementia|
04795|020|D|stable on levodopa started rifampin 450 mg, ethambutol 500 mg, and isoniazid|
04795|021|D|300 mg daily for tubercular pleurisy and subsequently developed dysphagia,|
04795|022|D|which resolved after increasing her dose of levodopa.(1)|
04795|023|D|   In another case, a patient with idiopathic Parkinson's disease|
04795|024|D|deteriorated after starting rifampin and isoniazid for pulmonary|
04795|025|D|tuberculosis.  Motor function test found that the patient's "on" period was|
04795|026|D|75% longer after stopping antitubercular therapy and levodopa|
04795|027|D|area-under-curve (AUC) and maximum concentration (Cmax) were 37% and 33%|
04795|028|D|higher, respectively, compared to values obtained during TB therapy.(4)|
04795|029|D|   In a study of 20 patients, isoniazid 290 mg given to Parkinson's patients|
04795|030|D|on levodopa resulted in reduced levodopa-induced choreic dyskinesias but|
04795|031|D|intolerable worsening of Parkinson's symptoms.(5)|
04795|032|B||
04795|033|R|REFERENCES:|
04795|034|B||
04795|035|R|1.Ohki M, Tayama N. Dysphagia due to isoniazid therapy for tuberculosis in a|3
04795|036|R|  patient with Lewy body  dementia. Auris Nasus Larynx 2013 Jun;40(3):327-9.|3
04795|037|R|2.Vyalev (foscarbidopa and foslevodopa) US prescribing information. AbbVie|1
04795|038|R|  Inc. Oct 2024.|1
04795|039|R|3.Vyalev (foslevodopa/foscarbidopa) Canadian product monograph. AbbVie|1
04795|040|R|  Corporation May, 2023.|1
04795|041|R|4.Wenning GK, O'Connell MT, Patsalos PN, Quinn NP. A clinical and|3
04795|042|R|  pharmacokinetic case study of an interaction of levodopa and|3
04795|043|R|  antituberculous therapy in Parkinson's disease. Mov Disord 1995 Sep;|3
04795|044|R|  10(5):664-7.|3
04795|045|R|5.Gershanik OS, Luquin MR, Scipioni O, Obeso JA. Isoniazid therapy in|2
04795|046|R|  Parkinson's disease. Mov Disord 1988;3(2):133-9.|2
04796|001|T|MONOGRAPH TITLE:  Givinostat/QT Prolonging Agents|
04796|002|B||
04796|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04796|004|L|of severe adverse interaction.|
04796|005|B||
04796|006|A|MECHANISM OF ACTION:  Givinostat may prolong the QTc interval.  Concurrent|
04796|007|A|use with other agents that prolong the QTc interval may result in additive|
04796|008|A|effects on the QTc interval.(1)|
04796|009|B||
04796|010|E|CLINICAL EFFECTS:  The concurrent use of givinostat with other agents that|
04796|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04796|012|E|arrhythmias, including torsades de pointes.(1)|
04796|013|B||
04796|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04796|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04796|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04796|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04796|018|P|gender, or advanced age.(2)|
04796|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04796|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04796|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04796|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04796|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04796|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04796|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04796|026|B||
04796|027|M|PATIENT MANAGEMENT:  The manufacturer of givinostat states that the|
04796|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
04796|029|M|cannot be avoided, obtain ECGs prior to initiating givinostat, during|
04796|030|M|concomitant use, and as clinically indicated.(1)|
04796|031|M|   If the QTc interval is greater than 500 ms or the change from baseline is|
04796|032|M|greater than 60 ms, withhold givinostat therapy.(1)|
04796|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04796|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04796|035|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04796|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04796|037|B||
04796|038|D|DISCUSSION:  In a QT study, the largest mean increase in QTc interval of|
04796|039|D|13.6 ms (upper confidence interval of 17.1 ms) occurred 5 hours after|
04796|040|D|administration of givinostat 265.8 mg (approximately 5 times the recommended|
04796|041|D|53.2 mg dose in patients weighing 60 kg or more).(1)|
04796|042|D|   Agents that are linked to this monograph may have varying degrees of|
04796|043|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04796|044|D|been shown to prolong the QTc interval either through their mechanism of|
04796|045|D|action, through studies on their effects on the QTc interval, or through|
04796|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04796|047|D|and/or postmarketing reports.(3)|
04796|048|B||
04796|049|R|REFERENCES:|
04796|050|B||
04796|051|R|1.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
04796|052|R|  March, 2024.|1
04796|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04796|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04796|055|R|  settings: a scientific statement from the American Heart Association and|6
04796|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04796|057|R|  2;55(9):934-47.|6
04796|058|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04796|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04796|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04796|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04797|001|T|MONOGRAPH TITLE:  Givinostat/Possible QT Prolonging Agents|
04797|002|B||
04797|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04797|004|L|take action as needed.|
04797|005|B||
04797|006|A|MECHANISM OF ACTION:  Givinostat may prolong the QTc interval.  Concurrent|
04797|007|A|use with other agents that prolong the QTc interval may result in additive|
04797|008|A|effects on the QTc interval.(1)|
04797|009|B||
04797|010|E|CLINICAL EFFECTS:  The concurrent use of givinostat with other agents that|
04797|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04797|012|E|arrhythmias, including torsades de pointes.(1)|
04797|013|B||
04797|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04797|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04797|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04797|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04797|018|P|gender, or advanced age.(2)|
04797|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04797|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04797|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04797|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04797|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04797|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04797|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04797|026|B||
04797|027|M|PATIENT MANAGEMENT:  The manufacturer of givinostat states that the|
04797|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
04797|029|M|cannot be avoided, obtain ECGs prior to initiating givinostat, during|
04797|030|M|concomitant use, and as clinically indicated.(1)|
04797|031|M|   If the QTc interval is greater than 500 ms or the change from baseline is|
04797|032|M|greater than 60 ms, withhold givinostat therapy.(1)|
04797|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04797|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04797|035|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04797|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04797|037|B||
04797|038|D|DISCUSSION:  In a QT study, the largest mean increase in QTc interval of|
04797|039|D|13.6 ms (upper confidence interval of 17.1 ms) occurred 5 hours after|
04797|040|D|administration of givinostat 265.8 mg (approximately 5 times the recommended|
04797|041|D|53.2 mg dose in patients weighing 60 kg or more).(1)|
04797|042|D|   Agents that are linked to this monograph may have varying degrees of|
04797|043|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04797|044|D|been shown to prolong the QTc interval either through their mechanism of|
04797|045|D|action, through studies on their effects on the QTc interval, or through|
04797|046|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04797|047|D|and/or postmarketing reports.(3)|
04797|048|B||
04797|049|R|REFERENCES:|
04797|050|B||
04797|051|R|1.Duvyzat (givinostat) US prescribing information. ITF Therapeutics, LLC.|1
04797|052|R|  March, 2024.|1
04797|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04797|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04797|055|R|  settings: a scientific statement from the American Heart Association and|6
04797|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04797|057|R|  2;55(9):934-47.|6
04797|058|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04797|059|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04797|060|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04797|061|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04798|001|T|MONOGRAPH TITLE:  Ethinyl Estradiol (<= 20 mcg)/Avapritinib|
04798|002|B||
04798|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04798|004|L|take action as needed.|
04798|005|B||
04798|006|A|MECHANISM OF ACTION:  The mechanism of action has not been described.|
04798|007|B||
04798|008|E|CLINICAL EFFECTS:  Coadministration of ethinyl estradiol and avapritinib may|
04798|009|E|increase the plasma concentrations and toxicities of ethinyl estradiol.(1)|
04798|010|B||
04798|011|P|PREDISPOSING FACTORS:  Patients with risk factors for thrombosis may be at|
04798|012|P|higher risk of adverse events, including those with advanced age, obesity|
04798|013|P|(BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable|
04798|014|P|states, history of venous thromboembolism, malignancy, and major surgery.|
04798|015|B||
04798|016|M|PATIENT MANAGEMENT:  The manufacturer of avapritinib states that the daily|
04798|017|M|dose of ethinyl estradiol should not exceed 20 mcg unless a higher dose is|
04798|018|M|necessary.(1)|
04798|019|B||
04798|020|D|DISCUSSION:  In a study, coadministration of ethinyl estradiol 30|
04798|021|D|mcg/levonorgestrel 0.15 mg once daily and avapritinib 25 mg once daily|
04798|022|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
04798|023|D|ethinyl estradiol by 1.15-fold and 1.46-fold, respectively.(1)|
04798|024|B||
04798|025|R|REFERENCE:|
04798|026|B||
04798|027|R|1.Ayvakit (avapritinib) US prescribing information. Blueprint Medicines|1
04798|028|R|  Corporation June, 2021.|1
04799|001|T|MONOGRAPH TITLE:  Ethinyl Estradiol (> 20 mcg)/Avapritinib|
04799|002|B||
04799|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04799|004|L|of severe adverse interaction.|
04799|005|B||
04799|006|A|MECHANISM OF ACTION:  The mechanism of action has not been described.|
04799|007|B||
04799|008|E|CLINICAL EFFECTS:  Coadministration of ethinyl estradiol and avapritinib may|
04799|009|E|increase the plasma concentrations and toxicities of ethinyl estradiol.(1)|
04799|010|B||
04799|011|P|PREDISPOSING FACTORS:  Patients with risk factors for thrombosis may be at|
04799|012|P|higher risk of adverse events, including those with advanced age, obesity|
04799|013|P|(BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable|
04799|014|P|states, history of venous thromboembolism, malignancy, and major surgery.|
04799|015|B||
04799|016|M|PATIENT MANAGEMENT:  The manufacturer of avapritinib states that the daily|
04799|017|M|dose of ethinyl estradiol should not exceed 20 mcg unless a higher dose is|
04799|018|M|necessary.(1)|
04799|019|B||
04799|020|D|DISCUSSION:  In a study, coadministration of ethinyl estradiol 30|
04799|021|D|mcg/levonorgestrel 0.15 mg once daily and avapritinib 25 mg once daily|
04799|022|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
04799|023|D|ethinyl estradiol by 1.15-fold and 1.46-fold, respectively.(1)|
04799|024|B||
04799|025|R|REFERENCE:|
04799|026|B||
04799|027|R|1.Ayvakit (avapritinib) US prescribing information. Blueprint Medicines|1
04799|028|R|  Corporation June, 2021.|1
04800|001|T|MONOGRAPH TITLE:  Digoxin/Pacritinib|
04800|002|B||
04800|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04800|004|L|take action as needed.|
04800|005|B||
04800|006|A|MECHANISM OF ACTION:  Pacritinib may increase the absorption of digoxin by|
04800|007|A|inhibiting P-glycoprotein (P-gp).(1)|
04800|008|B||
04800|009|E|CLINICAL EFFECTS:  Concurrent use of Pacritinib may result in elevated|
04800|010|E|levels of and toxicity from digoxin.(1)  Symptoms of digoxin toxicity can|
04800|011|E|include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness,|
04800|012|E|generalized muscle weakness, disorientation, hallucinations, visual|
04800|013|E|disturbances, and arrhythmias.|
04800|014|B||
04800|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
04800|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
04800|017|P|risk of digoxin toxicity.|
04800|018|B||
04800|019|M|PATIENT MANAGEMENT:  Monitor digoxin concentrations before initiating|
04800|020|M|concomitant use with pacritinib and continue monitoring serum digoxin|
04800|021|M|concentrations as recommended in the prescribing information for|
04800|022|M|digoxin.(1-2)|
04800|023|M|   The manufacturer of digoxin recommends decreasing the dose of digoxin by|
04800|024|M|approximately 15-30% or by modifying the dosing frequency to reduce digoxin|
04800|025|M|concentrations.(2)|
04800|026|B||
04800|027|D|DISCUSSION:  Pacritinib (200 mg twice daily at steady state) increased|
04800|028|D|maximum concentration (Cmax) and are-under-curve (AUC) of a single dose of|
04800|029|D|digoxin (0.25 mg) by 29% and 15%, respectively.(1)|
04800|030|B||
04800|031|R|REFERENCES:|
04800|032|B||
04800|033|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04800|034|R|  2024.|1
04800|035|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
04800|036|R|  Pharmaceuticals, Inc. August, 2018.|1
04801|001|T|MONOGRAPH TITLE:  Rosuvastatin (<= 20 mg)/Pacritinib|
04801|002|B||
04801|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04801|004|L|take action as needed.|
04801|005|B||
04801|006|A|MECHANISM OF ACTION:  Pacritinib is an inhibitor of the BCRP transporter,|
04801|007|A|which may result in increased absorption and decreased hepatic uptake of|
04801|008|A|rosuvastatin.(1-3)|
04801|009|B||
04801|010|E|CLINICAL EFFECTS:  Concurrent use of pacritinib with rosuvastatin may result|
04801|011|E|in increased levels and side effects from rosuvastatin, including myopathy|
04801|012|E|and rhabdomyolysis.(1-2)|
04801|013|B||
04801|014|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04801|015|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04801|016|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04801|017|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04801|018|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04801|019|P|transporter OATP1B1 may have increased statin concentrations and be|
04801|020|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04801|021|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04801|022|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04801|023|B||
04801|024|M|PATIENT MANAGEMENT:  The manufacturer of pacritinib states that the dose of|
04801|025|M|rosuvastatin should not exceed 20 mg daily when used concurrently.(1)|
04801|026|M|   Monitor patients closely for signs and symptoms of toxicity from|
04801|027|M|increased rosuvastatin concentrations.(1,2)|
04801|028|B||
04801|029|D|DISCUSSION:  Concurrent use of pacritinib (200 mg twice daily at steady|
04801|030|D|state) increased the area-under-curve (AUC) and maximum concentration (Cmax)|
04801|031|D|of a single dose of rosuvastatin (5 mg) by 200% and 80%, respectively.(1)|
04801|032|B||
04801|033|R|REFERENCES:|
04801|034|B||
04801|035|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04801|036|R|  2024.|1
04801|037|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04801|038|R|  Pharmaceuticals LP July, 2024.|1
04801|039|R|3.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04801|040|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04801|041|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04801|042|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04801|043|R|  44(3):398-408.|5
04802|001|T|MONOGRAPH TITLE:  Rosuvastatin (> 20 mg)/Pacritinib|
04802|002|B||
04802|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04802|004|L|is contraindicated and generally should not be dispensed or administered to|
04802|005|L|the same patient.|
04802|006|B||
04802|007|A|MECHANISM OF ACTION:  Pacritinib is an inhibitor of the BCRP transporter,|
04802|008|A|which may result in increased absorption and decreased hepatic uptake of|
04802|009|A|rosuvastatin.(1-3)|
04802|010|B||
04802|011|E|CLINICAL EFFECTS:  Concurrent use of pacritinib with rosuvastatin may result|
04802|012|E|in increased levels and side effects from rosuvastatin, including myopathy|
04802|013|E|and rhabdomyolysis.(1-2)|
04802|014|B||
04802|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04802|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04802|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04802|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04802|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04802|020|P|transporter OATP1B1 may have increased statin concentrations and be|
04802|021|P|predisposed to myopathy or rhabdomyolysis.  Patients on rosuvastatin with|
04802|022|P|ABCG2 polymorphisms leading to decreased or poor BCRP transporter function|
04802|023|P|may have increased rosuvastatin concentrations and risk of myopathy.|
04802|024|B||
04802|025|M|PATIENT MANAGEMENT:  The manufacturer of pacritinib states that the dose of|
04802|026|M|rosuvastatin should not exceed 20 mg daily when used concurrently.(1)|
04802|027|M|   Monitor patients closely for signs and symptoms of toxicity from|
04802|028|M|increased rosuvastatin concentrations.(1,2)|
04802|029|B||
04802|030|D|DISCUSSION:  Concurrent use of pacritinib (200 mg twice daily at steady|
04802|031|D|state) increased the area-under-curve (AUC) and maximum concentration (Cmax)|
04802|032|D|of a single dose of rosuvastatin (5 mg) by 200% and 80%, respectively.(1)|
04802|033|B||
04802|034|R|REFERENCES:|
04802|035|B||
04802|036|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04802|037|R|  2024.|1
04802|038|R|2.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04802|039|R|  Pharmaceuticals LP July, 2024.|1
04802|040|R|3.Elsby R, Martin P, Surry D, Sharma P, Fenner K. Solitary Inhibition of the|5
04802|041|R|  Breast Cancer Resistance Protein Efflux Transporter  Results in a|5
04802|042|R|  Clinically Significant Drug-Drug Interaction with Rosuvastatin by  Causing|5
04802|043|R|  up to a 2-Fold Increase in Statin Exposure. Drug Metab Dispos 2016 Mar;|5
04802|044|R|  44(3):398-408.|5
04803|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Pacritinib|
04803|002|B||
04803|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04803|004|L|of severe adverse interaction.|
04803|005|B||
04803|006|A|MECHANISM OF ACTION:  Pacritinib is a moderate CYP3A4 inducer.|
04803|007|A|Coadministration of pacritinib with hormonal contraceptives may lead to|
04803|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
04803|009|A|decreased hormonal concentrations.(1)|
04803|010|B||
04803|011|E|CLINICAL EFFECTS:  Concurrent use of pacritinib may reduce the effectiveness|
04803|012|E|of hormonal contraceptives, except for intrauterine systems containing|
04803|013|E|levonorgestrel.(1)|
04803|014|B||
04803|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04803|016|P|of the inducer for longer than 1-2 weeks.|
04803|017|B||
04803|018|M|PATIENT MANAGEMENT:  The manufacturer of pacritinib states to avoid|
04803|019|M|concomitant use with hormonal contraceptives except for intrauterine systems|
04803|020|M|containing levonorgestrel.  If contraception is needed or desired, an|
04803|021|M|alternate contraceptive that is not affected by CYP3A4 inducers (e.g., an|
04803|022|M|intrauterine system) or additional non-hormonal contraceptives (e.g.,|
04803|023|M|condoms) should be used when treated concomitantly with pacritinib and for|
04803|024|M|30 days after the last dose of pacritinib.(1)|
04803|025|M|   Women of reproductive age should be counseled not to rely on hormonal|
04803|026|M|contraceptives (including oral contraceptives, patches, implants, and/or|
04803|027|M|IUDs) for contraception.(1)|
04803|028|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04803|029|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04803|030|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04803|031|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
04803|032|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
04803|033|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
04803|034|M|and to seek medical advice if she does become pregnant.(2)|
04803|035|B||
04803|036|D|DISCUSSION:  Pacritinib is a moderate CYP3A4 inducer.(1)|
04803|037|D|   Coadministration of pacritinib (200 mg twice daily at steady state) with|
04803|038|D|a single dose of oral midazolam (2 mg) (a CYP3A4 substrate) decreased the|
04803|039|D|concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 60%|
04803|040|D|and 60%, respectively.(1)|
04803|041|B||
04803|042|R|REFERENCES:|
04803|043|B||
04803|044|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04803|045|R|  2024.|1
04803|046|R|2.Medicines and Healthcare products Regulatory Agency.|1
04803|047|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04803|048|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04803|049|R|  available at:|1
04803|050|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04803|051|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04803|052|R|  -and-contraceptive-efficacy September 15, 2016..|1
04804|001|T|MONOGRAPH TITLE:  Revumenib/Strong CYP3A4 Inhibitors|
04804|002|B||
04804|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04804|004|L|take action as needed.|
04804|005|B||
04804|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
04804|007|A|the metabolism of revumenib.(1)|
04804|008|B||
04804|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04804|010|E|the levels of and effects from revumenib including QTc prolongation, which|
04804|011|E|may result in potentially life-threatening cardiac arrhythmias like torsades|
04804|012|E|de pointes (TdP).(1)|
04804|013|B||
04804|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04804|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04804|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04804|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04804|018|P|female gender, or advanced age.(2)|
04804|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04804|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04804|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04804|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04804|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04804|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04804|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04804|026|B||
04804|027|M|PATIENT MANAGEMENT:  The concomitant use of strong CYP3A4 inhibitors|
04804|028|M|requires dose reduction of revumenib.|
04804|029|M|   -For patients 1 year and older who weigh at least 40 kg, decrease the|
04804|030|M|dosage of revumenib to 160 mg twice daily.|
04804|031|M|   -For patients 1 year and older who weigh less than 40 kg, decrease the|
04804|032|M|dosage of revumenib to 95 mg/m2 twice daily.  Refer to the revumenib|
04804|033|M|prescribing information for total tablet dosage by body surface area.|
04804|034|M|   If the strong CYP3A4 inhibitor is discontinued, increase the dose of|
04804|035|M|revumenib to the recommended dose without strong CYP3A4 inhibitors after at|
04804|036|M|least 5 half-lives of the inhibitor.(1)|
04804|037|M|   If coadministration with a strong CYP3A4 inhibitor is unavoidable,|
04804|038|M|monitor for prolongation of the QTc interval.(1)  When concurrent therapy is|
04804|039|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
04804|040|M|and monitoring EKG at baseline and regular intervals. Correct any|
04804|041|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04804|042|M|heartbeat, dizziness, or fainting.|
04804|043|B||
04804|044|D|DISCUSSION:  In a study, azole antifungals that are strong CYP3A4 inhibitors|
04804|045|D|(i.e., posaconazole, itraconazole, and voriconazole) increased the|
04804|046|D|area-under-curve (AUC) and maximum concentration (Cmax) of revumenib by|
04804|047|D|2-fold.  Cobicistat (a strong CYP3A4 inhibitor) increased the AUC and Cmax|
04804|048|D|of revumenib by 2.5-fold.(1)|
04804|049|D|   Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, grapefruit,|
04804|050|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
04804|051|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04804|052|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(3,4)|
04804|053|B||
04804|054|R|REFERENCES:|
04804|055|B||
04804|056|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04804|057|R|  Inc November, 2024.|1
04804|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04804|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04804|060|R|  settings: a scientific statement from the American Heart Association and|6
04804|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04804|062|R|  2;55(9):934-47.|6
04804|063|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04804|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04804|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04804|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04804|067|R|  11/14/2017.|1
04804|068|R|4.This information is based on an extract from the Certara Drug Interaction|6
04804|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04805|001|T|MONOGRAPH TITLE:  Revumenib/Strong CYP3A4 Inhibitors that Prolong QT|
04805|002|B||
04805|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04805|004|L|of severe adverse interaction.|
04805|005|B||
04805|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04805|007|A|interval may inhibit the metabolism of revumenib and result in additive risk|
04805|008|A|of QT prolongation.(1)|
04805|009|B||
04805|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04805|011|E|the levels of and effects from revumenib including QTc prolongation, which|
04805|012|E|may result in potentially life-threatening cardiac arrhythmias like torsades|
04805|013|E|de pointes (TdP).(1)|
04805|014|B||
04805|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04805|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04805|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04805|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04805|019|P|female gender, or advanced age.(2)|
04805|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04805|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04805|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04805|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04805|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04805|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04805|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04805|027|B||
04805|028|M|PATIENT MANAGEMENT:  The manufacturer of revumenib states that concomitant|
04805|029|M|use of other drugs that may prolong the QTc interval should be avoided.  If|
04805|030|M|concurrent use cannot be avoided, obtain ECGs prior to initiating revumenib,|
04805|031|M|during concomitant use, and as clinically indicated.(1)|
04805|032|M|   If the QTc interval is greater than 480 ms, withhold revumenib therapy.|
04805|033|M|Resume revumenib after the QTc interval drops to 480 msec or less.(1)|
04805|034|M|   If concomitant use of strong CYP3A4 inhibitors is unavoidable, dose|
04805|035|M|reduction of revumenib is necessary.|
04805|036|M|   -For patients 1 year and older who weigh at least 40 kg, decrease the|
04805|037|M|dosage of revumenib to 160 mg twice daily.|
04805|038|M|   -For patients 1 year and older who weigh less than 40 kg, decrease the|
04805|039|M|dosage of revumenib to 95 mg/m2 twice daily.  Refer to the revumenib|
04805|040|M|prescribing information for total tablet dosage by body surface area.|
04805|041|M|   If the strong CYP3A4 inhibitor is discontinued, increase the dose of|
04805|042|M|revumenib to the recommended dose without strong CYP3A4 inhibitors after at|
04805|043|M|least 5 half-lives of the inhibitor.(1)|
04805|044|M|   If coadministration with a strong CYP3A4 inhibitor that prolongs QT is|
04805|045|M|unavoidable, monitor for prolongation of the QTc interval.(1)  When|
04805|046|M|concurrent therapy is warranted: consider obtaining serum calcium,|
04805|047|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04805|048|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
04805|049|M|report any irregular heartbeat, dizziness, or fainting.|
04805|050|B||
04805|051|D|DISCUSSION:  In a study, azole antifungals that are strong CYP3A4 inhibitors|
04805|052|D|(i.e., posaconazole, itraconazole, and voriconazole) increased the|
04805|053|D|area-under-curve (AUC) and maximum concentration (Cmax) of revumenib by|
04805|054|D|2-fold.  Cobicistat (a strong CYP3A4 inhibitor) increased the AUC and Cmax|
04805|055|D|of revumenib by 2.5-fold.(1)|
04805|056|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
04805|057|D|event in 29% of 135 patients treated with the recommended dosage of|
04805|058|D|revumenib; 12% of patients had Grade 3 QTc prolongation.  Revumenib|
04805|059|D|increased the QTc interval in a concentration-dependent manner.  At the mean|
04805|060|D|steady-state Cmax using the highest approved recommended dosage of revumenib|
04805|061|D|without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper|
04805|062|D|bound of 90% confidence interval = 30 msec).  At the steady-state Cmax using|
04805|063|D|the highest approved recommended dosage of revumenib with CYP3A4 inhibitors,|
04805|064|D|QTc increase was predicted to be 19 msec (upper bound of 90% confidence|
04805|065|D|interval = 22 msec).(1)|
04805|066|D|   Agents that are linked to this monograph may have varying degrees of|
04805|067|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04805|068|D|been shown to prolong the QTc interval either through their mechanism of|
04805|069|D|action, through studies on their effects on the QTc interval, or through|
04805|070|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04805|071|D|and/or postmarketing reports.(3)|
04805|072|D|   Strong inhibitors of CYP3A4 that prolong the QT interval include:|
04805|073|D|adagrasib, ceritinib, clarithromycin, lonafarnib, lopinavir, ribociclib,|
04805|074|D|saquinavir.(4,5)|
04805|075|B||
04805|076|R|REFERENCES:|
04805|077|B||
04805|078|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04805|079|R|  Inc November, 2024.|1
04805|080|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04805|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04805|082|R|  settings: a scientific statement from the American Heart Association and|6
04805|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04805|084|R|  2;55(9):934-47.|6
04805|085|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04805|086|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04805|087|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04805|088|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04805|089|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04805|090|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04805|091|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04805|092|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04805|093|R|  11/14/2017.|1
04805|094|R|5.This information is based on an extract from the Certara Drug Interaction|6
04805|095|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04806|001|T|MONOGRAPH TITLE:  Revumenib/Strong CYP3A4 Inhibitors that Prolong QT|
04806|002|B||
04806|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04806|004|L|take action as needed.|
04806|005|B||
04806|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04806|007|A|interval may inhibit the metabolism of revumenib and result in additive risk|
04806|008|A|of QT prolongation.(1)|
04806|009|B||
04806|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04806|011|E|the levels of and effects from revumenib including QTc prolongation, which|
04806|012|E|may result in potentially life-threatening cardiac arrhythmias like torsades|
04806|013|E|de pointes (TdP).(1)|
04806|014|B||
04806|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04806|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04806|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04806|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04806|019|P|female gender, or advanced age.(2)|
04806|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04806|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04806|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04806|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04806|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04806|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04806|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04806|027|B||
04806|028|M|PATIENT MANAGEMENT:  The manufacturer of revumenib states that concomitant|
04806|029|M|use of other drugs that may prolong the QTc interval should be avoided.  If|
04806|030|M|concurrent use cannot be avoided, obtain ECGs prior to initiating revumenib,|
04806|031|M|during concomitant use, and as clinically indicated.(1)|
04806|032|M|   If the QTc interval is greater than 480 ms, withhold revumenib therapy.|
04806|033|M|Resume revumenib after the QTc interval drops to 480 msec or less.(1)|
04806|034|M|   If concomitant use of strong CYP3A4 inhibitors is unavoidable, dose|
04806|035|M|reduction of revumenib is necessary.|
04806|036|M|   -For patients 1 year and older who weigh at least 40 kg, decrease the|
04806|037|M|dosage of revumenib to 160 mg twice daily.|
04806|038|M|   -For patients 1 year and older who weigh less than 40 kg, decrease the|
04806|039|M|dosage of revumenib to 95 mg/m2 twice daily.  Refer to the revumenib|
04806|040|M|prescribing information for total tablet dosage by body surface area.|
04806|041|M|   If the strong CYP3A4 inhibitor is discontinued, increase the dose of|
04806|042|M|revumenib to the recommended dose without strong CYP3A4 inhibitors after at|
04806|043|M|least 5 half-lives of the inhibitor.(1)|
04806|044|M|   If coadministration with a strong CYP3A4 inhibitor that prolongs QT is|
04806|045|M|unavoidable, monitor for prolongation of the QTc interval.(1)  When|
04806|046|M|concurrent therapy is warranted: consider obtaining serum calcium,|
04806|047|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04806|048|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
04806|049|M|report any irregular heartbeat, dizziness, or fainting.|
04806|050|B||
04806|051|D|DISCUSSION:  In a study, azole antifungals that are strong CYP3A4 inhibitors|
04806|052|D|(i.e., posaconazole, itraconazole, and voriconazole) increased the|
04806|053|D|area-under-curve (AUC) and maximum concentration (Cmax) of revumenib by|
04806|054|D|2-fold.  Cobicistat (a strong CYP3A4 inhibitor) increased the AUC and Cmax|
04806|055|D|of revumenib by 2.5-fold.(1)|
04806|056|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
04806|057|D|event in 29% of 135 patients treated with the recommended dosage of|
04806|058|D|revumenib; 12% of patients had Grade 3 QTc prolongation.  Revumenib|
04806|059|D|increased the QTc interval in a concentration-dependent manner.  At the mean|
04806|060|D|steady-state Cmax using the highest approved recommended dosage of revumenib|
04806|061|D|without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper|
04806|062|D|bound of 90% confidence interval = 30 msec).  At the steady-state Cmax using|
04806|063|D|the highest approved recommended dosage of revumenib with CYP3A4 inhibitors,|
04806|064|D|QTc increase was predicted to be 19 msec (upper bound of 90% confidence|
04806|065|D|interval = 22 msec).(1)|
04806|066|D|   Agents that are linked to this monograph may have varying degrees of|
04806|067|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04806|068|D|been shown to prolong the QTc interval either through their mechanism of|
04806|069|D|action, through studies on their effects on the QTc interval, or through|
04806|070|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04806|071|D|and/or postmarketing reports.(3)|
04806|072|D|   Strong inhibitors of CYP3A4 that prolong the QT interval include:|
04806|073|D|telithromycin and voriconazole.(4,5)|
04806|074|B||
04806|075|R|REFERENCES:|
04806|076|B||
04806|077|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04806|078|R|  Inc November, 2024.|1
04806|079|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04806|080|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04806|081|R|  settings: a scientific statement from the American Heart Association and|6
04806|082|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04806|083|R|  2;55(9):934-47.|6
04806|084|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04806|085|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04806|086|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04806|087|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04806|088|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04806|089|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04806|090|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04806|091|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04806|092|R|  11/14/2017.|1
04806|093|R|5.This information is based on an extract from the Certara Drug Interaction|6
04806|094|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04807|001|T|MONOGRAPH TITLE:  Revumenib/Strong CYP3A4 Inhibitors that Prolong QT|
04807|002|B||
04807|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04807|004|L|is contraindicated and generally should not be dispensed or administered to|
04807|005|L|the same patient.|
04807|006|B||
04807|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong the QTc|
04807|008|A|interval may inhibit the metabolism of revumenib and result in additive risk|
04807|009|A|of QT prolongation.(1)|
04807|010|B||
04807|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04807|012|E|the levels of and effects from revumenib including QTc prolongation, which|
04807|013|E|may result in potentially life-threatening cardiac arrhythmias like torsades|
04807|014|E|de pointes (TdP).(1)|
04807|015|B||
04807|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04807|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04807|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04807|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04807|020|P|female gender, or advanced age.(2)|
04807|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04807|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04807|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04807|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04807|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04807|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04807|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04807|028|B||
04807|029|M|PATIENT MANAGEMENT:  The manufacturer of revumenib states that concomitant|
04807|030|M|use of other drugs that may prolong the QTc interval should be avoided.  If|
04807|031|M|concurrent use cannot be avoided, obtain ECGs prior to initiating revumenib,|
04807|032|M|during concomitant use, and as clinically indicated.  If the QTc interval is|
04807|033|M|greater than 480 ms, withhold revumenib therapy.  Resume revumenib after the|
04807|034|M|QTc interval drops to 480 msec or less.(1)|
04807|035|M|   The manufacturer of levoketoconazole states that concomitant use of other|
04807|036|M|drugs that prolong the QTc interval is contraindicated.(3)|
04807|037|M|   If concomitant use of strong CYP3A4 inhibitors is unavoidable, dose|
04807|038|M|reduction of revumenib is necessary.|
04807|039|M|   -For patients 1 year and older who weigh at least 40 kg, decrease the|
04807|040|M|dosage of revumenib to 160 mg twice daily.|
04807|041|M|   -For patients 1 year and older who weigh less than 40 kg, decrease the|
04807|042|M|dosage of revumenib to 95 mg/m2 twice daily.  Refer to the revumenib|
04807|043|M|prescribing information for total tablet dosage by body surface area.|
04807|044|M|   If the strong CYP3A4 inhibitor is discontinued, increase the dose of|
04807|045|M|revumenib to the recommended dose without strong CYP3A4 inhibitors after at|
04807|046|M|least 5 half-lives of the inhibitor.(1)|
04807|047|M|   If coadministration with strong CYP3A4 inhibitors that prolong QT is|
04807|048|M|unavoidable, monitor for prolongation of the QTc interval.(1)  When|
04807|049|M|concurrent therapy is warranted: consider obtaining serum calcium,|
04807|050|M|magnesium, and potassium levels and monitoring EKG at baseline and regular|
04807|051|M|intervals. Correct any electrolyte abnormalities.  Instruct patients to|
04807|052|M|report any irregular heartbeat, dizziness, or fainting.|
04807|053|B||
04807|054|D|DISCUSSION:  In a study, azole antifungals that are strong CYP3A4 inhibitors|
04807|055|D|(i.e., posaconazole, itraconazole, and voriconazole) increased the|
04807|056|D|area-under-curve (AUC) and maximum concentration (Cmax) of revumenib by|
04807|057|D|2-fold.  Cobicistat (a strong CYP3A4 inhibitor) increased the AUC and Cmax|
04807|058|D|of revumenib by 2.5-fold.(1)|
04807|059|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
04807|060|D|event in 29% of 135 patients treated with the recommended dosage of|
04807|061|D|revumenib; 12% of patients had Grade 3 QTc prolongation.  Revumenib|
04807|062|D|increased the QTc interval in a concentration-dependent manner.  At the mean|
04807|063|D|steady-state Cmax using the highest approved recommended dosage of revumenib|
04807|064|D|without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper|
04807|065|D|bound of 90% confidence interval = 30 msec).  At the steady-state Cmax using|
04807|066|D|the highest approved recommended dosage of revumenib with CYP3A4 inhibitors,|
04807|067|D|QTc increase was predicted to be 19 msec (upper bound of 90% confidence|
04807|068|D|interval = 22 msec).(1)|
04807|069|D|   Agents that are linked to this monograph may have varying degrees of|
04807|070|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04807|071|D|been shown to prolong the QTc interval either through their mechanism of|
04807|072|D|action, through studies on their effects on the QTc interval, or through|
04807|073|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04807|074|D|and/or postmarketing reports.(4)|
04807|075|D|   Strong inhibitors of CYP3A4 that prolong the QT interval include:|
04807|076|D|levoketoconazole.(5,6)|
04807|077|B||
04807|078|R|REFERENCES:|
04807|079|B||
04807|080|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04807|081|R|  Inc November, 2024.|1
04807|082|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04807|083|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04807|084|R|  settings: a scientific statement from the American Heart Association and|6
04807|085|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04807|086|R|  2;55(9):934-47.|6
04807|087|R|3.Recorlev (levoketoconazole) US prescribing information. Xeris|1
04807|088|R|  Pharmaceuticals, Inc. June, 2023.|1
04807|089|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04807|090|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04807|091|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04807|092|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04807|093|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04807|094|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04807|095|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04807|096|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04807|097|R|  11/14/2017.|1
04807|098|R|6.This information is based on an extract from the Certara Drug Interaction|6
04807|099|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04808|001|T|MONOGRAPH TITLE:  Revumenib/Strong CYP3A4 Inducers that Prolong QT|
04808|002|B||
04808|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04808|004|L|of severe adverse interaction.|
04808|005|B||
04808|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04808|007|A|revumenib by CYP3A4 and increase formation of the M1 metabolite which|
04808|008|A|contributes to revumenib's effects on the QTc interval.(1)|
04808|009|A|   Concurrent use of agents that prolong the QTc interval may result in|
04808|010|A|additive effects on the QTc interval.(1)|
04808|011|B||
04808|012|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04808|013|E|decreased levels and effectiveness of revumenib and increased risk of QT|
04808|014|E|prolongation due to increased exposure to revumenib's M1 metabolite.  The|
04808|015|E|risk of potentially life-threatening arrhythmias including torsades de|
04808|016|E|pointes may be increased.(1)|
04808|017|B||
04808|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04808|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04808|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04808|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04808|022|P|female gender, or advanced age.(2)|
04808|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04808|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04808|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04808|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04808|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04808|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04808|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04808|030|P|   Induction effects may be more likely with regular use of the inducer for|
04808|031|P|longer than 1-2 weeks.|
04808|032|B||
04808|033|M|PATIENT MANAGEMENT:  The manufacturer of revumenib states that concomitant|
04808|034|M|use of other drugs that may prolong the QTc interval should be avoided.  In|
04808|035|M|addition, concomitant use of strong CYP3A4 inducers should be avoided.  If|
04808|036|M|concurrent use cannot be avoided, obtain ECGs prior to initiating revumenib,|
04808|037|M|during concomitant use, and as clinically indicated.(1)|
04808|038|M|   If the QTc interval is greater than 480 ms, withhold revumenib therapy.|
04808|039|M|Resume revumenib after the QTc interval drops to 480 msec or less.(1)|
04808|040|M|   If coadministration with another agent that prolongs QT is unavoidable,|
04808|041|M|monitor for prolongation of the QTc interval.(1)  When concurrent therapy is|
04808|042|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
04808|043|M|and monitoring EKG at baseline and regular intervals. Correct any|
04808|044|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04808|045|M|heartbeat, dizziness, or fainting.|
04808|046|B||
04808|047|D|DISCUSSION:  Revumenib is primarily metabolized by CYP3A4.  Concomitant use|
04808|048|D|of a strong CYP3A4 inducer may decrease revumenib concentrations and|
04808|049|D|increase M1 systemic exposure, resulting in decreased revumenib efficacy or|
04808|050|D|increased risk of QT prolongation.(1)|
04808|051|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
04808|052|D|event in 29% of 135 patients treated with the recommended dosage of|
04808|053|D|revumenib; 12% of patients had Grade 3 QTc prolongation.  Revumenib|
04808|054|D|increased the QTc interval in a concentration-dependent manner.  At the mean|
04808|055|D|steady-state Cmax using the highest approved recommended dosage of revumenib|
04808|056|D|without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper|
04808|057|D|bound of 90% confidence interval = 30 msec).  At the steady-state Cmax using|
04808|058|D|the highest approved recommended dosage of revumenib with CYP3A4 inhibitors,|
04808|059|D|QTc increase was predicted to be 19 msec (upper bound of 90% confidence|
04808|060|D|interval = 22 msec).(1)|
04808|061|D|   Agents that are linked to this monograph may have varying degrees of|
04808|062|D|potential to prolong the QTc interval but are generally accepted to have a|
04808|063|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04808|064|D|been shown to prolong the QTc interval either through their mechanism of|
04808|065|D|action, through studies on their effects on the QTc interval, or through|
04808|066|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04808|067|D|and/or post-marketing reports.(3)|
04808|068|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04808|069|D|encorafenib and ivosidenib.(4)|
04808|070|B||
04808|071|R|REFERENCES:|
04808|072|B||
04808|073|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04808|074|R|  Inc November, 2024.|1
04808|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04808|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04808|077|R|  settings: a scientific statement from the American Heart Association and|6
04808|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04808|079|R|  2;55(9):934-47.|6
04808|080|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04808|081|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04808|082|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04808|083|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04808|084|R|4.This information is based on an extract from the Certara Drug Interaction|6
04808|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04809|001|T|MONOGRAPH TITLE:  Revumenib/Strong CYP3A4 Inducers|
04809|002|B||
04809|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04809|004|L|of severe adverse interaction.|
04809|005|B||
04809|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04809|007|A|revumenib by CYP3A4 and increase formation of the M1 metabolite which|
04809|008|A|contributes to revumenib's effects on the QTc interval.(1)|
04809|009|B||
04809|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
04809|011|E|decreased levels and effectiveness of revumenib and increased risk of QT|
04809|012|E|prolongation due to increased exposure to revumenib's M1 metabolite.  The|
04809|013|E|risk of potentially life-threatening arrhythmias including torsades de|
04809|014|E|pointes may be increased.(1)|
04809|015|B||
04809|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04809|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04809|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04809|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04809|020|P|female gender, or advanced age.(2)|
04809|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04809|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04809|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04809|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04809|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04809|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04809|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04809|028|P|   Induction effects may be more likely with regular use of the inducer for|
04809|029|P|longer than 1-2 weeks.|
04809|030|B||
04809|031|M|PATIENT MANAGEMENT:  The manufacturer of revumenib states that concomitant|
04809|032|M|use of strong CYP3A4 inducers should be avoided.(1)|
04809|033|B||
04809|034|D|DISCUSSION:  Revumenib is primarily metabolized by CYP3A4.  Concomitant use|
04809|035|D|of a strong CYP3A4 inducer may decrease revumenib concentrations and|
04809|036|D|increase M1 systemic exposure, resulting in decreased revumenib efficacy or|
04809|037|D|increased risk of QT prolongation.(1)|
04809|038|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
04809|039|D|event in 29% of 135 patients treated with the recommended dosage of|
04809|040|D|revumenib; 12% of patients had Grade 3 QTc prolongation.  Revumenib|
04809|041|D|increased the QTc interval in a concentration-dependent manner.  At the mean|
04809|042|D|steady-state Cmax using the highest approved recommended dosage of revumenib|
04809|043|D|without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper|
04809|044|D|bound of 90% confidence interval = 30 msec).  At the steady-state Cmax using|
04809|045|D|the highest approved recommended dosage of revumenib with CYP3A4 inhibitors,|
04809|046|D|QTc increase was predicted to be 19 msec (upper bound of 90% confidence|
04809|047|D|interval = 22 msec).(1)|
04809|048|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04809|049|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04809|050|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
04809|051|D|St. John's wort.(3)|
04809|052|B||
04809|053|R|REFERENCES:|
04809|054|B||
04809|055|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04809|056|R|  Inc November, 2024.|1
04809|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04809|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04809|059|R|  settings: a scientific statement from the American Heart Association and|6
04809|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04809|061|R|  2;55(9):934-47.|6
04809|062|R|3.This information is based on an extract from the Certara Drug Interaction|6
04809|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04810|001|T|MONOGRAPH TITLE:  Ubrogepant/Pacritinib|
04810|002|B||
04810|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04810|004|L|of severe adverse interaction.|
04810|005|B||
04810|006|A|MECHANISM OF ACTION:  Pacritinib is a moderate CYP3A4 inducer and a BCRP|
04810|007|A|inhibitor.(1)  Ubrogepant is a CYP3A4 and BCRP substrate.(2,3)  Pacritinib|
04810|008|A|may induce the metabolism and increase the absorption of ubrogepant.(1,2)|
04810|009|B||
04810|010|E|CLINICAL EFFECTS:  The net effect of this interaction is unknown.|
04810|011|E|Concurrent use of moderate CYP3A4 inducers with ubrogepant may result in|
04810|012|E|decreased levels and effectiveness of ubrogepant while concurrent use of|
04810|013|E|agents that inhibit BCRP may result in elevated levels and side effects from|
04810|014|E|ubrogepant.(1,2)|
04810|015|B||
04810|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04810|017|P|of the inducer for longer than 1-2 weeks.|
04810|018|B||
04810|019|M|PATIENT MANAGEMENT:  The manufacturer of pacritinib states avoid|
04810|020|M|coadministration with drugs that are sensitive substrates of CYP3A4 such as|
04810|021|M|ubrogepant.(1,3)|
04810|022|M|   The manufacturer of ubrogepant does not have recommendations for|
04810|023|M|concurrent use with agents that are both moderate CYP3A4 inducers and BCRP|
04810|024|M|inhibitors.(2)|
04810|025|M|   If coadministration with moderate CYP3A4 inducers cannot be avoided, the|
04810|026|M|manufacturer of ubrogepant recommends a dose adjustment of ubrogepant.(1)|
04810|027|M|The dose of ubrogepant should not exceed 50 mg for initial dose.  If a|
04810|028|M|second dose of ubrogepant is needed, avoid within 24 hours.(1)|
04810|029|M|   If coadministration with BCRP inhibitors cannot be avoided, the|
04810|030|M|manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant.|
04810|031|M|The dose of ubrogepant should not exceed 50 mg for initial dose.  If a|
04810|032|M|second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1)|
04810|033|B||
04810|034|D|DISCUSSION:  Ubrogepant is a substrate of CYP3A4 and the BCRP|
04810|035|D|transporter.(2,3)|
04810|036|D|   The impact of moderate CYP3A4 inducers on the pharmacokinetics of|
04810|037|D|ubrogepant has not been investigated in clinical studies.  Coadministration|
04810|038|D|of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80%|
04810|039|D|reduction in ubrogepant exposure.(1)|
04810|040|D|   Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant.|
04810|041|D|Clinical drug interaction studies with inhibitors of these transporters were|
04810|042|D|not conducted.(2)|
04810|043|B||
04810|044|R|REFERENCES:|
04810|045|B||
04810|046|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04810|047|R|  2024.|1
04810|048|R|2.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
04810|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
04810|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04811|001|T|MONOGRAPH TITLE:  Revumenib/QT Prolonging Agents|
04811|002|B||
04811|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04811|004|L|of severe adverse interaction.|
04811|005|B||
04811|006|A|MECHANISM OF ACTION:  Revumenib may prolong the QTc interval.  Concurrent|
04811|007|A|use with other agents that prolong the QTc interval may result in additive|
04811|008|A|effects on the QTc interval.(1)|
04811|009|B||
04811|010|E|CLINICAL EFFECTS:  The concurrent use of revumenib with other agents that|
04811|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04811|012|E|arrhythmias, including torsades de pointes.(1)|
04811|013|B||
04811|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04811|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04811|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04811|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04811|018|P|gender, or advanced age.(2)|
04811|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04811|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04811|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04811|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04811|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04811|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04811|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04811|026|B||
04811|027|M|PATIENT MANAGEMENT:  The manufacturer of revumenib states that the|
04811|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
04811|029|M|cannot be avoided, obtain ECGs prior to initiating revumenib, during|
04811|030|M|concomitant use, and as clinically indicated.(1)|
04811|031|M|   If the QTc interval is greater than 480 ms, withhold revumenib therapy.|
04811|032|M|Resume revumenib after the QTc interval drops to 480 msec or less.(1)|
04811|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04811|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04811|035|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04811|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04811|037|B||
04811|038|D|DISCUSSION:  In clinical trials, QTc interval prolongation was reported as|
04811|039|D|an adverse event in 29% of 135 patients treated with the recommended dosage|
04811|040|D|of revumenib; 12% of patients had Grade 3 QTc prolongation.  Revumenib|
04811|041|D|increased the QTc interval in a concentration-dependent manner.  At the mean|
04811|042|D|steady-state Cmax using the highest approved recommended dosage of revumenib|
04811|043|D|without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper|
04811|044|D|bound of 90% confidence interval = 30 msec).  At the steady-state Cmax using|
04811|045|D|the highest approved recommended dosage of revumenib with CYP3A4 inhibitors,|
04811|046|D|QTc increase was predicted to be 19 msec (upper bound of 90% confidence|
04811|047|D|interval = 22 msec).(1)|
04811|048|D|   Agents that are linked to this monograph may have varying degrees of|
04811|049|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04811|050|D|been shown to prolong the QTc interval either through their mechanism of|
04811|051|D|action, through studies on their effects on the QTc interval, or through|
04811|052|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04811|053|D|and/or postmarketing reports.(3)|
04811|054|B||
04811|055|R|REFERENCES:|
04811|056|B||
04811|057|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04811|058|R|  Inc November, 2024.|1
04811|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04811|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04811|061|R|  settings: a scientific statement from the American Heart Association and|6
04811|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04811|063|R|  2;55(9):934-47.|6
04811|064|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04811|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04811|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04811|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04812|001|T|MONOGRAPH TITLE:  Revumenib/Possible QT Prolonging Agents|
04812|002|B||
04812|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04812|004|L|take action as needed.|
04812|005|B||
04812|006|A|MECHANISM OF ACTION:  Revumenib may prolong the QTc interval.  Concurrent|
04812|007|A|use with other agents that prolong the QTc interval may result in additive|
04812|008|A|effects on the QTc interval.(1)|
04812|009|B||
04812|010|E|CLINICAL EFFECTS:  The concurrent use of revumenib with other agents that|
04812|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04812|012|E|arrhythmias, including torsades de pointes.(1)|
04812|013|B||
04812|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04812|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04812|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04812|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04812|018|P|gender, or advanced age.(2)|
04812|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04812|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04812|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04812|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04812|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04812|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04812|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04812|026|B||
04812|027|M|PATIENT MANAGEMENT:  The manufacturer of revumenib states that the|
04812|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
04812|029|M|cannot be avoided, obtain ECGs prior to initiating revumenib, during|
04812|030|M|concomitant use, and as clinically indicated.(1)|
04812|031|M|   If the QTc interval is greater than 480 ms, withhold revumenib therapy.|
04812|032|M|Resume revumenib after the QTc interval drops to 480 msec or less.(1)|
04812|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04812|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04812|035|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04812|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04812|037|B||
04812|038|D|DISCUSSION:  In clinical trials, QTc interval prolongation was reported as|
04812|039|D|an adverse event in 29% of 135 patients treated with the recommended dosage|
04812|040|D|of revumenib; 12% of patients had Grade 3 QTc prolongation.  Revumenib|
04812|041|D|increased the QTc interval in a concentration-dependent manner.  At the mean|
04812|042|D|steady-state Cmax using the highest approved recommended dosage of revumenib|
04812|043|D|without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper|
04812|044|D|bound of 90% confidence interval = 30 msec).  At the steady-state Cmax using|
04812|045|D|the highest approved recommended dosage of revumenib with CYP3A4 inhibitors,|
04812|046|D|QTc increase was predicted to be 19 msec (upper bound of 90% confidence|
04812|047|D|interval = 22 msec).(1)|
04812|048|D|   Agents that are linked to this monograph may have varying degrees of|
04812|049|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04812|050|D|been shown to prolong the QTc interval either through their mechanism of|
04812|051|D|action, through studies on their effects on the QTc interval, or through|
04812|052|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04812|053|D|and/or postmarketing reports.(3)|
04812|054|B||
04812|055|R|REFERENCES:|
04812|056|B||
04812|057|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04812|058|R|  Inc November, 2024.|1
04812|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04812|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04812|061|R|  settings: a scientific statement from the American Heart Association and|6
04812|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04812|063|R|  2;55(9):934-47.|6
04812|064|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04812|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04812|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04812|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04813|001|T|MONOGRAPH TITLE:  Revumenib/Moderate CYP3A4 Inducers|
04813|002|B||
04813|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04813|004|L|of severe adverse interaction.|
04813|005|B||
04813|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
04813|007|A|revumenib by CYP3A4 and increase formation of the M1 metabolite which|
04813|008|A|contributes to revumenib's effects on the QTc interval.(1)|
04813|009|B||
04813|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inducers may result in|
04813|011|E|decreased levels and effectiveness of revumenib and increased risk of QT|
04813|012|E|prolongation due to increased exposure to revumenib's M1 metabolite.  The|
04813|013|E|risk of potentially life-threatening arrhythmias including torsades de|
04813|014|E|pointes may be increased.(1)|
04813|015|B||
04813|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04813|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04813|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04813|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04813|020|P|female gender, or advanced age.(2)|
04813|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04813|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04813|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04813|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04813|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04813|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04813|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04813|028|P|   Induction effects may be more likely with regular use of the inducer for|
04813|029|P|longer than 1-2 weeks.|
04813|030|B||
04813|031|M|PATIENT MANAGEMENT:  The manufacturer of revumenib states that concomitant|
04813|032|M|use of moderate CYP3A4 inducers should be avoided.(1)|
04813|033|B||
04813|034|D|DISCUSSION:  Revumenib is primarily metabolized by CYP3A4.  Concomitant use|
04813|035|D|of a moderate CYP3A4 inducer may decrease revumenib concentrations and|
04813|036|D|increase M1 systemic exposure, resulting in decreased revumenib efficacy or|
04813|037|D|increased risk of QT prolongation.(1)|
04813|038|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
04813|039|D|event in 29% of 135 patients treated with the recommended dosage of|
04813|040|D|revumenib; 12% of patients had Grade 3 QTc prolongation.  Revumenib|
04813|041|D|increased the QTc interval in a concentration-dependent manner.  At the mean|
04813|042|D|steady-state Cmax using the highest approved recommended dosage of revumenib|
04813|043|D|without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper|
04813|044|D|bound of 90% confidence interval = 30 msec).  At the steady-state Cmax using|
04813|045|D|the highest approved recommended dosage of revumenib with CYP3A4 inhibitors,|
04813|046|D|QTc increase was predicted to be 19 msec (upper bound of 90% confidence|
04813|047|D|interval = 22 msec).(1)|
04813|048|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
04813|049|D|bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad,|
04813|050|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib,|
04813|051|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(3)|
04813|052|B||
04813|053|R|REFERENCES:|
04813|054|B||
04813|055|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04813|056|R|  Inc November, 2024.|1
04813|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04813|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04813|059|R|  settings: a scientific statement from the American Heart Association and|6
04813|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04813|061|R|  2;55(9):934-47.|6
04813|062|R|3.This information is based on an extract from the Certara Drug Interaction|6
04813|063|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04814|001|T|MONOGRAPH TITLE:  Revumenib/Moderate CYP3A4 Inducers that Prolong QT|
04814|002|B||
04814|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04814|004|L|of severe adverse interaction.|
04814|005|B||
04814|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
04814|007|A|revumenib by CYP3A4 and increase formation of the M1 metabolite which|
04814|008|A|contributes to revumenib's effects on the QTc interval.(1)|
04814|009|A|   Concurrent use of agents that prolong the QTc interval may result in|
04814|010|A|additive effects on the QTc interval.(1)|
04814|011|B||
04814|012|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inducers may result in|
04814|013|E|decreased levels and effectiveness of revumenib and increased risk of QT|
04814|014|E|prolongation due to increased exposure to revumenib's M1 metabolite.  The|
04814|015|E|risk of potentially life-threatening arrhythmias including torsades de|
04814|016|E|pointes may be increased.(1)|
04814|017|B||
04814|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04814|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04814|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04814|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04814|022|P|female gender, or advanced age.(2)|
04814|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04814|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04814|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04814|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04814|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04814|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04814|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04814|030|P|   Induction effects may be more likely with regular use of the inducer for|
04814|031|P|longer than 1-2 weeks.|
04814|032|B||
04814|033|M|PATIENT MANAGEMENT:  The manufacturer of revumenib states that concomitant|
04814|034|M|use of other drugs that may prolong the QTc interval should be avoided.  In|
04814|035|M|addition, concomitant use of moderate CYP3A4 inducers should be avoided.  If|
04814|036|M|concurrent use cannot be avoided, obtain ECGs prior to initiating revumenib,|
04814|037|M|during concomitant use, and as clinically indicated.(1)|
04814|038|M|   If the QTc interval is greater than 480 ms, withhold revumenib therapy.|
04814|039|M|Resume revumenib after the QTc interval drops to 480 msec or less.(1)|
04814|040|M|   If coadministration with another agent that prolongs QT is unavoidable,|
04814|041|M|monitor for prolongation of the QTc interval.(1)  When concurrent therapy is|
04814|042|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
04814|043|M|and monitoring EKG at baseline and regular intervals. Correct any|
04814|044|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04814|045|M|heartbeat, dizziness, or fainting.|
04814|046|B||
04814|047|D|DISCUSSION:  Revumenib is primarily metabolized by CYP3A4.  Concomitant use|
04814|048|D|of a moderate CYP3A4 inducer may decrease revumenib concentrations and|
04814|049|D|increase M1 systemic exposure, resulting in decreased revumenib efficacy or|
04814|050|D|increased risk of QT prolongation.(1)|
04814|051|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
04814|052|D|event in 29% of 135 patients treated with the recommended dosage of|
04814|053|D|revumenib; 12% of patients had Grade 3 QTc prolongation.  Revumenib|
04814|054|D|increased the QTc interval in a concentration-dependent manner.  At the mean|
04814|055|D|steady-state Cmax using the highest approved recommended dosage of revumenib|
04814|056|D|without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper|
04814|057|D|bound of 90% confidence interval = 30 msec).  At the steady-state Cmax using|
04814|058|D|the highest approved recommended dosage of revumenib with CYP3A4 inhibitors,|
04814|059|D|QTc increase was predicted to be 19 msec (upper bound of 90% confidence|
04814|060|D|interval = 22 msec).(1)|
04814|061|D|   Agents that are linked to this monograph may have varying degrees of|
04814|062|D|potential to prolong the QTc interval but are generally accepted to have a|
04814|063|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04814|064|D|been shown to prolong the QTc interval either through their mechanism of|
04814|065|D|action, through studies on their effects on the QTc interval, or through|
04814|066|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04814|067|D|and/or post-marketing reports.(3)|
04814|068|D|   Moderate CYP3A4 inducers that prolong QT linked to this monograph|
04814|069|D|include: efavirenz, pacritinib, and thioridazine.(4)|
04814|070|B||
04814|071|R|REFERENCES:|
04814|072|B||
04814|073|R|1.Revuforj (revumenib) US prescribing information. Syndax Pharmaceuticals,|1
04814|074|R|  Inc November, 2024.|1
04814|075|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04814|076|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04814|077|R|  settings: a scientific statement from the American Heart Association and|6
04814|078|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04814|079|R|  2;55(9):934-47.|6
04814|080|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04814|081|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04814|082|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04814|083|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04814|084|R|4.This information is based on an extract from the Certara Drug Interaction|6
04814|085|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04815|001|T|MONOGRAPH TITLE:  Crizotinib/Pacritinib|
04815|002|B||
04815|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04815|004|L|of severe adverse interaction.|
04815|005|B||
04815|006|A|MECHANISM OF ACTION:  Crizotinib is a substrate and moderate inhibitor of|
04815|007|A|CYP3A4.(1)  Pacritinib is a substrate and moderate inducer of CYP3A4.(2)|
04815|008|A|   Agents that induce the CYP3A4 isoenzyme may induce the metabolism of|
04815|009|A|crizotinib.(1)|
04815|010|A|   Moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of|
04815|011|A|pacritinib.(2)|
04815|012|A|   Crizotinib and pacritinib have been observed to prolong the QTc interval.|
04815|013|A|Concurrent use of agents that prolong the QTc interval may result in|
04815|014|A|additive effects on the QTc interval.|
04815|015|B||
04815|016|E|CLINICAL EFFECTS:  Concurrent use of crizotinib and pacritinib may decrease|
04815|017|E|the levels and effectiveness of crizotinib(1) while increasing levels and|
04815|018|E|toxicity of pacritinib.(2)|
04815|019|E|   Concurrent use may result in additive QTc prolongation, which may result|
04815|020|E|in potentially life-threatening cardiac arrhythmias, including torsades de|
04815|021|E|pointes (TdP).(1)|
04815|022|E|   Other toxicities of pacritinib include bleeding, diarrhea,|
04815|023|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
04815|024|E|infection.(2)|
04815|025|B||
04815|026|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04815|027|P|may be increased in patients with cardiovascular disease (e.g. heart|
04815|028|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04815|029|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04815|030|P|female gender, or advanced age.(3)|
04815|031|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04815|032|P|higher systemic concentrations of either QT prolonging drug are additional|
04815|033|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04815|034|P|drug concentrations include rapid infusion of an intravenous dose or|
04815|035|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04815|036|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04815|037|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04815|038|P|   CYP2B6 genotype may also increase the risk of this interaction.  Patients|
04815|039|P|who are most susceptible to this interaction are patients who are CYP2B6|
04815|040|P|poor metabolizers with CYP2B6 *6/*6 allele.(4)|
04815|041|P|   Induction effects may be more likely with regular use of the inducer for|
04815|042|P|longer than 1-2 weeks.|
04815|043|B||
04815|044|M|PATIENT MANAGEMENT:  The concurrent use of crizotinib and pacritinib should|
04815|045|M|be avoided.(1)|
04815|046|M|   If concurrent use cannot be avoided, monitor patients for increased|
04815|047|M|adverse reactions from pacritinib and consider pacritinib dose modifications|
04815|048|M|based on safety.(2)|
04815|049|M|   If coadministration is unavoidable, monitor for prolongation of the QTc|
04815|050|M|interval.(1,2)  When concurrent therapy is warranted: consider obtaining|
04815|051|M|serum calcium, magnesium, and potassium levels and monitoring EKG at|
04815|052|M|baseline and regular intervals. Correct any electrolyte abnormalities.|
04815|053|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04815|054|M|   In patients who develop a QTc greater than 500 ms on at least 2 separate|
04815|055|M|ECGs, withhold crizotinib until recovery to baseline or to a QTc less than|
04815|056|M|481 ms, then resume crizotinib at reduced dose.(1)|
04815|057|M|   In patients who develop a QTc greater than 500 ms or greater than or|
04815|058|M|equal to 60 ms change from baseline with torsade de pointes or polymorphic|
04815|059|M|ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently|
04815|060|M|discontinue crizotinib.(1)|
04815|061|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04815|062|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04815|063|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04815|064|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04815|065|M|dose according to labeling.(2)|
04815|066|B||
04815|067|D|DISCUSSION:  Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the|
04815|068|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04815|069|D|crizotinib (250 mg) by 69% and 82%, respectively.(1)|
04815|070|D|   Clarithromycin (500 mg twice daily for 5 days, a strong CYP3A4 inhibitor)|
04815|071|D|increased Cmax and AUC of a single dose of pacritinib (400 mg) by 30% and|
04815|072|D|80%, respectively.(2)|
04815|073|D|    Crizotinib is associated with concentration-dependent QTc interval|
04815|074|D|prolongation.  In a clinical trial 2.1% of patients were found to have a|
04815|075|D|QTcF greater than or equal to 500 msec and 5% of patients had an increase in|
04815|076|D|QTcF by greater than or equal to 60 msec.(1)|
04815|077|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04815|078|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(2)|
04815|079|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04815|080|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04815|081|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04815|082|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04815|083|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04815|084|D|adverse reactions were higher in the treatment arm than the control group|
04815|085|D|(3.8% vs 2%, respectively).(2)|
04815|086|B||
04815|087|R|REFERENCES:|
04815|088|B||
04815|089|R|1.Xalkori (crizotinib) UK Summary of Product Characteristics. Pfizer Limited|1
04815|090|R|  July, 2021.|1
04815|091|R|2.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04815|092|R|  2024.|1
04815|093|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04815|094|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04815|095|R|  settings: a scientific statement from the American Heart Association and|6
04815|096|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04815|097|R|  2;55(9):934-47.|6
04815|098|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04815|099|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04815|100|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04815|101|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04815|102|R|  11/14/2017.|1
04815|103|R|5.This information is based on an extract from the Certara Drug Interaction|6
04815|104|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04816|001|T|MONOGRAPH TITLE:  Oral Lefamulin/Pacritinib|
04816|002|B||
04816|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04816|004|L|of severe adverse interaction.|
04816|005|B||
04816|006|A|MECHANISM OF ACTION:  Lefamulin and pacritinib are both metabolized by|
04816|007|A|CYP3A4.  Pacritinib is a moderate CYP3A4 inducer while oral lefamulin is a|
04816|008|A|moderate CYP3A4 inhibitor.(1-2)|
04816|009|B||
04816|010|E|CLINICAL EFFECTS:  The net effect of coadministration of lefamulin and|
04816|011|E|pacritinib on CYP3A4 enzyme activity is unknown.  Concurrent or recent use|
04816|012|E|of pacritinib may either decrease the clinical effectiveness of lefamulin(1)|
04816|013|E|or increase the levels and toxicities of pacritinib.(1,2)|
04816|014|E|   Concurrent use may result in additive QTc prolongation, which may result|
04816|015|E|in potentially life-threatening cardiac arrhythmias, including torsades de|
04816|016|E|pointes (TdP).(1,2)|
04816|017|E|   Other toxicities of pacritinib include bleeding, diarrhea,|
04816|018|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
04816|019|E|infection.(2)|
04816|020|B||
04816|021|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04816|022|P|may be increased in patients with cardiovascular disease (e.g. heart|
04816|023|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04816|024|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04816|025|P|female gender, or advanced age.(3)|
04816|026|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04816|027|P|higher systemic concentrations of either QT prolonging drug are additional|
04816|028|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04816|029|P|drug concentrations include rapid infusion of an intravenous dose or|
04816|030|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04816|031|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04816|032|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04816|033|P|   Induction effects may be more likely with regular use of the inducer for|
04816|034|P|longer than 1-2 weeks.|
04816|035|B||
04816|036|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
04816|037|M|lefamulin with pacritinib.|
04816|038|M|   Concurrent use of lefamulin with pacritinib should be avoided.(1)|
04816|039|M|   If concurrent use cannot be avoided, monitor patients for increased|
04816|040|M|adverse reactions from pacritinib and consider pacritinib dose modifications|
04816|041|M|based on safety.(2)|
04816|042|M|   If coadministration is unavoidable, monitor for prolongation of the QTc|
04816|043|M|interval.(1,2)  Consider obtaining serum calcium, magnesium, and potassium|
04816|044|M|levels and monitoring EKG at baseline and regular intervals. Correct any|
04816|045|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04816|046|M|heartbeat, dizziness, or fainting.|
04816|047|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04816|048|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04816|049|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04816|050|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04816|051|M|dose according to labeling.(2)|
04816|052|B||
04816|053|D|DISCUSSION:  In a study, concurrent administration of rifampin (a strong|
04816|054|D|CYP3A4 inducer) with oral lefamulin (tablets) decreased lefamulin|
04816|055|D|area-under-curve (AUC) and maximum concentration (Cmax) by 72% and 57%.(1)|
04816|056|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
04816|057|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the AUC|
04816|058|D|and Cmax of midazolam by 200% and 100%, respectively.  No clinically|
04816|059|D|significant effect on midazolam pharmacokinetics was observed when|
04816|060|D|co-administered with lefamulin injection.(1)|
04816|061|D|   Clarithromycin (500 mg twice daily for 5 days) increased maximum|
04816|062|D|concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04816|063|D|pacritinib (400 mg) by 30% and 80%, respectively.(2)|
04816|064|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04816|065|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(2)|
04816|066|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04816|067|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04816|068|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04816|069|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04816|070|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04816|071|D|adverse reactions were higher in the treatment arm than the control group|
04816|072|D|(3.8% vs 2%, respectively).(2)|
04816|073|B||
04816|074|R|REFERENCES:|
04816|075|B||
04816|076|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04816|077|R|  Inc August 2019.|1
04816|078|R|2.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04816|079|R|  2024.|1
04816|080|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04816|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04816|082|R|  settings: a scientific statement from the American Heart Association and|6
04816|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04816|084|R|  2;55(9):934-47.|6
04816|085|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04816|086|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04816|087|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04816|088|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04816|089|R|  11/14/2017.|1
04816|090|R|5.This information is based on an extract from the Certara Drug Interaction|6
04816|091|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04817|001|T|MONOGRAPH TITLE:  Lonafarnib/Pacritinib|
04817|002|B||
04817|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04817|004|L|is contraindicated and generally should not be dispensed or administered to|
04817|005|L|the same patient.|
04817|006|B||
04817|007|A|MECHANISM OF ACTION:  Lonafarnib is a substrate and strong inhibitor of|
04817|008|A|CYP3A4.(1)  Pacritinib is a substrate and moderate inducer of CYP3A4.(2)|
04817|009|A|   Agents that induce the CYP3A4 isoenzyme may induce the metabolism of|
04817|010|A|lonafarnib.(1)|
04817|011|A|   Strong CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of|
04817|012|A|pacritinib.(2)|
04817|013|A|   Lonafarnib and pacritinib have been observed to prolong the QTc interval.|
04817|014|A|Concurrent use of agents that prolong the QTc interval may result in|
04817|015|A|additive effects on the QTc interval.|
04817|016|B||
04817|017|E|CLINICAL EFFECTS:  Concurrent use of lonafarnib and pacritinib may decrease|
04817|018|E|the levels and effectiveness of lonafarnib(1) while increasing levels and|
04817|019|E|toxicity of pacritinib.(2)|
04817|020|E|   Concurrent use may result in additive QTc prolongation, which may result|
04817|021|E|in potentially life-threatening cardiac arrhythmias, including torsades de|
04817|022|E|pointes (TdP).(1)|
04817|023|E|   Other toxicities of pacritinib include bleeding, diarrhea,|
04817|024|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
04817|025|E|infection.(2)|
04817|026|B||
04817|027|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04817|028|P|may be increased in patients with cardiovascular disease (e.g. heart|
04817|029|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04817|030|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04817|031|P|female gender, or advanced age.(3)|
04817|032|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04817|033|P|higher systemic concentrations of either QT prolonging drug are additional|
04817|034|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04817|035|P|drug concentrations include rapid infusion of an intravenous dose or|
04817|036|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04817|037|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04817|038|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04817|039|P|   Induction effects may be more likely with regular use of the inducer for|
04817|040|P|longer than 1-2 weeks.|
04817|041|B||
04817|042|M|PATIENT MANAGEMENT:  The concurrent use of pacritinib with lonafarnib is|
04817|043|M|contraindicated.(2)|
04817|044|M|   If concurrent use is warranted, monitor ECG prior to initiation, during|
04817|045|M|concurrent therapy, and as clinically indicated.(1,2)|
04817|046|M|   If coadministration is unavoidable, monitor for prolongation of the QTc|
04817|047|M|interval.(1)  When concurrent therapy is warranted: consider obtaining serum|
04817|048|M|calcium, magnesium, and potassium levels and monitoring EKG at baseline and|
04817|049|M|regular intervals. Correct any electrolyte abnormalities.  Instruct patients|
04817|050|M|to report any irregular heartbeat, dizziness, or fainting.|
04817|051|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04817|052|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04817|053|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04817|054|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04817|055|M|dose according to labeling.(1)|
04817|056|B||
04817|057|D|DISCUSSION:  The combination of lonafarnib and pacritinib has not been|
04817|058|D|investigated in clinical studies.|
04817|059|D|   With coadministration of a single oral dose of 50 mg lonafarnib (combined|
04817|060|D|with a single oral dose of 100 mg ritonavir) following 600 mg rifampin (a|
04817|061|D|strong CYP3A4 inducer) for 8 days, the area-under-curve (AUC) was reduced by|
04817|062|D|98% and the maximum concentration (Cmax) was reduced by 92%.(1)|
04817|063|D|   Clarithromycin (500 mg twice daily for 5 days, strong CYP3A4 inhibitor)|
04817|064|D|increased Cmax and AUC of a single dose of pacritinib (400 mg) by 30% and|
04817|065|D|80%, respectively.(2)|
04817|066|D|    In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive|
04817|067|D|days and a single 200 mg dose on day 10 increased the mean QTc interval by|
04817|068|D|19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48|
04817|069|D|hours after administration of the morning dose of lonafarnib 200 mg.  The|
04817|070|D|maximum concentration (Cmax) on Day 10 was 2233 ng/ml, which is similar to|
04817|071|D|the mean Cmax of 2695 ng/ml observed in the Hutchinson-Gilford Progeria|
04817|072|D|Syndrome patient population.(1)|
04817|073|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04817|074|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04817|075|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04817|076|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04817|077|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04817|078|D|adverse reactions were higher in the treatment arm than the control group|
04817|079|D|(3.8% vs 2%, respectively).(2)|
04817|080|B||
04817|081|R|REFERENCES:|
04817|082|B||
04817|083|R|1.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
04817|084|R|  Inc. November, 2020.|1
04817|085|R|2.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04817|086|R|  2024.|1
04817|087|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04817|088|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04817|089|R|  settings: a scientific statement from the American Heart Association and|6
04817|090|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04817|091|R|  2;55(9):934-47.|6
04817|092|R|4.This information is based on an extract from the Certara Drug Interaction|6
04817|093|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04818|001|T|MONOGRAPH TITLE:  Intravenous Lefamulin/Moderate CYP3A4 Inducers that|
04818|002|T|Prolong QT|
04818|003|B||
04818|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04818|005|L|of severe adverse interaction.|
04818|006|B||
04818|007|A|MECHANISM OF ACTION:  Lefamulin is a substrate of CYP3A4.  Moderate inducers|
04818|008|A|of CYP3A4 may induce the metabolism of lefamulin.  Moderate CYP3A4 inducers|
04818|009|A|that prolong the QTc interval may result in additive risk of QT|
04818|010|A|prolongation.(1,2)|
04818|011|B||
04818|012|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
04818|013|E|inducer that prolongs QT may result in decreased levels and effectiveness of|
04818|014|E|lefamulin and cause additive effects on the QTc interval, which may result|
04818|015|E|in life-threatening cardiac arrhythmias including torsades de pointes.(1,2)|
04818|016|B||
04818|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04818|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04818|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04818|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04818|021|P|female gender, or advanced age.(2)|
04818|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04818|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04818|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04818|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04818|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04818|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04818|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04818|029|P|   Induction effects may be more likely with regular use of the inducer for|
04818|030|P|longer than 1-2 weeks.|
04818|031|B||
04818|032|M|PATIENT MANAGEMENT:  The manufacturer of lefamulin states that concurrent|
04818|033|M|use with moderate CYP3A4 inducers should be avoided.(1)|
04818|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04818|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04818|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04818|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04818|038|B||
04818|039|D|DISCUSSION:  In a study, concurrent administration of rifampin (strong|
04818|040|D|inducer) with lefamulin injection decreased lefamulin area-under-the-curve|
04818|041|D|(AUC) and maximum concentration (Cmax) by 28% and 8%.(1)|
04818|042|D|   Moderate inducers of CYP3A4 that prolong QT linked to this monograph|
04818|043|D|include:  pacritinib.|
04818|044|B||
04818|045|R|REFERENCES:|
04818|046|B||
04818|047|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04818|048|R|  Inc August 2019.|1
04818|049|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04818|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04818|051|R|  settings: a scientific statement from the American Heart Association and|6
04818|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04818|053|R|  2;55(9):934-47.|6
04818|054|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04818|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04818|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04818|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04818|058|R|  11/14/2017.|1
04818|059|R|4.This information is based on an extract from the Certara Drug Interaction|6
04818|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04819|001|T|MONOGRAPH TITLE:  Pacritinib/Idelalisib|
04819|002|B||
04819|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04819|004|L|is contraindicated and generally should not be dispensed or administered to|
04819|005|L|the same patient.|
04819|006|B||
04819|007|A|MECHANISM OF ACTION:  Pacritinib is a substrate of CYP3A4.(1) Strong CYP3A4|
04819|008|A|inhibitors such as idelalisib may inhibit the CYP3A4 mediated metabolism of|
04819|009|A|pacritinib.(1)|
04819|010|A|   Idelalisib is a substrate of CYP3A4. Moderate CYP3A4 inducers such as|
04819|011|A|pacritinib may induce the metabolism of idelalisib.(2)|
04819|012|B||
04819|013|E|CLINICAL EFFECTS:  Concurrent use of pacritinib with an inhibitor of CYP3A4|
04819|014|E|may result in elevated levels of and toxicity from pacritinib.(1)|
04819|015|E|    Elevated levels of pacritinib may result in QTc prolongation, which may|
04819|016|E|result in potentially life-threatening cardiac arrhythmias, including|
04819|017|E|torsades de pointes (TdP).  Other toxicities include bleeding, diarrhea,|
04819|018|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
04819|019|E|infection.(1)|
04819|020|E|   Concurrent use of moderate CYP3A4 inducers may decrease the levels and|
04819|021|E|effectiveness of idelalisib.(2)|
04819|022|B||
04819|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04819|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
04819|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04819|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04819|027|P|female gender, or advanced age.(3)|
04819|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04819|029|P|higher systemic concentrations of either QT prolonging drug are additional|
04819|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04819|031|P|drug concentrations include rapid infusion of an intravenous dose or|
04819|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04819|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04819|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04819|035|B||
04819|036|M|PATIENT MANAGEMENT:  The concurrent use of pacritinib with idelalisib is|
04819|037|M|contraindicated.(1)|
04819|038|M|   If concurrent use is warranted, monitor for prolongation of the QTc|
04819|039|M|interval.(1)  When concurrent therapy is warranted: consider obtaining serum|
04819|040|M|calcium, magnesium, and potassium levels and monitoring EKG at baseline and|
04819|041|M|regular intervals. Correct any electrolyte abnormalities.  Instruct patients|
04819|042|M|to report any irregular heartbeat, dizziness, or fainting.|
04819|043|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04819|044|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04819|045|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04819|046|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04819|047|M|dose according to labeling.(1)|
04819|048|B||
04819|049|D|DISCUSSION:  Clarithromycin (500 mg twice daily for 5 days) increased|
04819|050|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04819|051|D|pacritinib (400 mg) by 30% and 80%, respectively.(1)|
04819|052|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04819|053|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1)|
04819|054|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04819|055|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04819|056|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04819|057|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04819|058|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04819|059|D|adverse reactions were higher in the treatment arm than the control group|
04819|060|D|(3.8% vs 2%, respectively).(1)|
04819|061|D|   In a study in healthy subjects, rifampin (600 mg daily for 8 days)|
04819|062|D|decreased the concentration maximum (Cmax) and area-under-curve (AUC) of|
04819|063|D|idelalisib (150 mg single dose) by 58% and 75%, respectively.(3)|
04819|064|B||
04819|065|R|REFERENCES:|
04819|066|B||
04819|067|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04819|068|R|  2024.|1
04819|069|R|2.Zydelig (idelalisib) UK Summary of Product Characteristics. Gilead|1
04819|070|R|  Sciences Ltd December 17, 2019.|1
04819|071|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04819|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04819|073|R|  settings: a scientific statement from the American Heart Association and|6
04819|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04819|075|R|  2;55(9):934-47.|6
04819|076|R|4.This information is based on an extract from the Certara Drug Interaction|6
04819|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04820|001|T|MONOGRAPH TITLE:  Duvelisib/Pacritinib|
04820|002|B||
04820|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04820|004|L|of severe adverse interaction.|
04820|005|B||
04820|006|A|MECHANISM OF ACTION:  Duvelisib is a substrate and moderate inhibitor of|
04820|007|A|CYP3A4.(1)  Pacritinib is a substrate and moderate inducer of CYP3A4.(2)|
04820|008|A|   Agents that induce the CYP3A4 isoenzyme may induce the metabolism of|
04820|009|A|duvelisib.(1)|
04820|010|A|   Moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of|
04820|011|A|pacritinib.(2)|
04820|012|B||
04820|013|E|CLINICAL EFFECTS:  Concurrent use of duvelisib and pacritinib may decrease|
04820|014|E|the levels and effectiveness of duvelisib(1) while increasing levels and|
04820|015|E|toxicity of pacritinib.(2)|
04820|016|E|   Elevated levels of pacritinib may result in QTc prolongation, which may|
04820|017|E|result in potentially life-threatening cardiac arrhythmias, including|
04820|018|E|torsades de pointes (TdP).(2)|
04820|019|E|   Other toxicities of pacritinib include bleeding, diarrhea,|
04820|020|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
04820|021|E|infection.(2)|
04820|022|B||
04820|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04820|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
04820|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04820|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04820|027|P|female gender, or advanced age.(3)|
04820|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04820|029|P|higher systemic concentrations of either QT prolonging drug are additional|
04820|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04820|031|P|drug concentrations include rapid infusion of an intravenous dose or|
04820|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04820|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04820|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04820|035|P|   Induction effects may be more likely with regular use of the inducer for|
04820|036|P|longer than 1-2 weeks.|
04820|037|B||
04820|038|M|PATIENT MANAGEMENT:  The concurrent use of duvelisib and pacritinib should|
04820|039|M|be avoided.(1,2)|
04820|040|M|   The manufacturer recommendations for duvelisib are as follows:|
04820|041|M|   - If the moderate CYP3A4 inducer cannot be avoided, increase the dose of|
04820|042|M|duvelisib on day 12 of concurrent therapy as follows:|
04820|043|M|   - If the initial dose of duvelisib is 25 mg twice daily, increase the|
04820|044|M|duvelisib dose to 40 mg twice daily.|
04820|045|M|   - If the initial dose of duvelisib is 15 mg twice daily, increase the|
04820|046|M|duvelisib dose to 25 mg twice daily.|
04820|047|M|   - Monitor patients receiving concurrent therapy for reduced efficacy.(1)|
04820|048|M|  -  If the moderate CYP3A4 inducer is discontinued, reduce the dose of|
04820|049|M|duvelisib back to the initial dose 14 days after discontinuation of the|
04820|050|M|moderate CYP3A4 inducer.(1)|
04820|051|M|   The manufacturer recommendations for pacritinib are as follows:|
04820|052|M|   - If concurrent use cannot be avoided, monitor patients for increased|
04820|053|M|adverse reactions from pacritinib and consider pacritinib dose modifications|
04820|054|M|based on safety.(2)|
04820|055|M|   - If coadministration is unavoidable, monitor for prolongation of the QTc|
04820|056|M|interval.(1,2)  When concurrent therapy is warranted: consider obtaining|
04820|057|M|serum calcium, magnesium, and potassium levels and monitoring EKG at|
04820|058|M|baseline and regular intervals. Correct any electrolyte abnormalities.|
04820|059|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04820|060|M|   - If patients develop QTc prolongation >500 msec or >60 msec from|
04820|061|M|baseline, hold pacritinib.  If QTc prolongation resolves to <=480 msec or to|
04820|062|M|baseline within 1 week, resume pacritinib at the same dose.  If time to|
04820|063|M|resolution of the QTc interval takes greater than 1 week to resolve, reduce|
04820|064|M|the pacritinib dose according to labeling.(2)|
04820|065|B||
04820|066|D|DISCUSSION:  In an interaction study, etravirine (a moderate CYP3A inducer)|
04820|067|D|200 mg twice daily decreased the maximum concentration (Cmax) and|
04820|068|D|area-under-curve (AUC) of single dose duvelisib 25 mg by 16% and 35%,|
04820|069|D|respectively.(1)|
04820|070|D|   Clarithromycin (500 mg twice daily for 5 days, a strong CYP3A4 inhibitor)|
04820|071|D|increased Cmax and AUC of a single dose of pacritinib (400 mg) by 30% and|
04820|072|D|80%, respectively.(2)|
04820|073|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04820|074|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(2)|
04820|075|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04820|076|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04820|077|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04820|078|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04820|079|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04820|080|D|adverse reactions were higher in the treatment arm than the control group|
04820|081|D|(3.8% vs 2%, respectively).(2)|
04820|082|B||
04820|083|R|REFERENCES:|
04820|084|B||
04820|085|R|1.Copiktra (duvelisib) US prescribing information. Verastem, Inc. December,|1
04820|086|R|  2021.|1
04820|087|R|2.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04820|088|R|  2024.|1
04820|089|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04820|090|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04820|091|R|  settings: a scientific statement from the American Heart Association and|6
04820|092|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04820|093|R|  2;55(9):934-47.|6
04820|094|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04820|095|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04820|096|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04820|097|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04820|098|R|  11/14/2017.|1
04820|099|R|5.This information is based on an extract from the Certara Drug Interaction|6
04820|100|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04821|001|T|MONOGRAPH TITLE:  Lenacapavir/Pacritinib|
04821|002|B||
04821|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04821|004|L|of severe adverse interaction.|
04821|005|B||
04821|006|A|MECHANISM OF ACTION:  Lenacapavir is a substrate and moderate inhibitor of|
04821|007|A|CYP3A4.(1)  Pacritinib is a substrate and moderate inducer of CYP3A4.(2)|
04821|008|A|   Agents that induce the CYP3A4 isoenzyme may induce the metabolism of|
04821|009|A|lenacapavir.(1)|
04821|010|A|   Moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of|
04821|011|A|pacritinib.(2)|
04821|012|B||
04821|013|E|CLINICAL EFFECTS:  Concurrent use of lenacapavir and pacritinib may decrease|
04821|014|E|the levels and effectiveness of lenacapavir(1) while increasing levels and|
04821|015|E|toxicity of pacritinib.(2)|
04821|016|E|   Elevated levels of pacritinib may result in QTc prolongation, which may|
04821|017|E|result in potentially life-threatening cardiac arrhythmias, including|
04821|018|E|torsades de pointes (TdP).(2)|
04821|019|E|   Other toxicities of pacritinib include bleeding, diarrhea,|
04821|020|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
04821|021|E|infection.(2)|
04821|022|B||
04821|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04821|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
04821|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04821|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04821|027|P|female gender, or advanced age.(3)|
04821|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04821|029|P|higher systemic concentrations of either QT prolonging drug are additional|
04821|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04821|031|P|drug concentrations include rapid infusion of an intravenous dose or|
04821|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04821|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04821|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04821|035|P|   Induction effects may be more likely with regular use of the inducer for|
04821|036|P|longer than 1-2 weeks.|
04821|037|B||
04821|038|M|PATIENT MANAGEMENT:  The concurrent use of lenacapavir and pacritinib should|
04821|039|M|be avoided.(1,2)|
04821|040|M|   If concurrent use cannot be avoided, monitor patients for increased|
04821|041|M|adverse reactions from pacritinib and consider pacritinib dose modifications|
04821|042|M|based on safety.(2)|
04821|043|M|   If coadministration is unavoidable, monitor for prolongation of the QTc|
04821|044|M|interval.(1,2)  When concurrent therapy is warranted: consider obtaining|
04821|045|M|serum calcium, magnesium, and potassium levels and monitoring EKG at|
04821|046|M|baseline and regular intervals. Correct any electrolyte abnormalities.|
04821|047|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04821|048|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04821|049|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04821|050|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04821|051|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04821|052|M|dose according to labeling.(2)|
04821|053|B||
04821|054|D|DISCUSSION:  In a study, efavirenz 600 mg once daily (inducer of CYP3A4|
04821|055|D|[moderate]) decreased the maximum concentration (Cmax) and area-under-curve|
04821|056|D|(AUC) of lenacapavir by 36% and 56%, respectively.(1)|
04821|057|D|   Clarithromycin (500 mg twice daily for 5 days, a strong CYP3A4 inhibitor)|
04821|058|D|increased Cmax and AUC of a single dose of pacritinib (400 mg) by 30% and|
04821|059|D|80%, respectively.(2)|
04821|060|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04821|061|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(2)|
04821|062|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04821|063|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04821|064|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04821|065|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04821|066|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04821|067|D|adverse reactions were higher in the treatment arm than the control group|
04821|068|D|(3.8% vs 2%, respectively).(2)|
04821|069|B||
04821|070|R|REFERENCES:|
04821|071|B||
04821|072|R|1.Sunlenca (lenacapavir) EMA Summary of Product Characteristics. Gilead|1
04821|073|R|  Sciences Ireland UC August, 2022.|1
04821|074|R|2.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04821|075|R|  2024.|1
04821|076|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04821|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04821|078|R|  settings: a scientific statement from the American Heart Association and|6
04821|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04821|080|R|  2;55(9):934-47.|6
04821|081|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04821|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04821|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04821|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04821|085|R|  11/14/2017.|1
04821|086|R|5.This information is based on an extract from the Certara Drug Interaction|6
04821|087|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04822|001|T|MONOGRAPH TITLE:  Fedratinib/Pacritinib|
04822|002|B||
04822|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04822|004|L|of severe adverse interaction.|
04822|005|B||
04822|006|A|MECHANISM OF ACTION:  Fedratinib is a substrate and moderate inhibitor of|
04822|007|A|CYP3A4.(1)  Pacritinib is a substrate and moderate inducer of CYP3A4.(2)|
04822|008|A|   Agents that induce the CYP3A4 isoenzyme may induce the metabolism of|
04822|009|A|fedratinib.(1)|
04822|010|A|   Moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of|
04822|011|A|pacritinib.(2)|
04822|012|B||
04822|013|E|CLINICAL EFFECTS:  Concurrent use of fedratinib and pacritinib may decrease|
04822|014|E|the levels and effectiveness of fedratinib(1) while increasing levels and|
04822|015|E|toxicity of pacritinib.(2)|
04822|016|E|   Elevated levels of pacritinib may result in QTc prolongation, which may|
04822|017|E|result in potentially life-threatening cardiac arrhythmias, including|
04822|018|E|torsades de pointes (TdP).(2)|
04822|019|E|   Other toxicities of pacritinib include bleeding, diarrhea,|
04822|020|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
04822|021|E|infection.(2)|
04822|022|B||
04822|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04822|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
04822|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04822|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04822|027|P|female gender, or advanced age.(3)|
04822|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04822|029|P|higher systemic concentrations of either QT prolonging drug are additional|
04822|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04822|031|P|drug concentrations include rapid infusion of an intravenous dose or|
04822|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04822|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04822|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04822|035|P|   Induction effects may be more likely with regular use of the inducer for|
04822|036|P|longer than 1-2 weeks.|
04822|037|B||
04822|038|M|PATIENT MANAGEMENT:  The concurrent use of fedratinib and pacritinib should|
04822|039|M|be avoided.(1,2)|
04822|040|M|   If concurrent use cannot be avoided, monitor patients for increased|
04822|041|M|adverse reactions from pacritinib and consider pacritinib dose modifications|
04822|042|M|based on safety.(2)|
04822|043|M|   If coadministration is unavoidable, monitor for prolongation of the QTc|
04822|044|M|interval.(1,2)  When concurrent therapy is warranted: consider obtaining|
04822|045|M|serum calcium, magnesium, and potassium levels and monitoring EKG at|
04822|046|M|baseline and regular intervals. Correct any electrolyte abnormalities.|
04822|047|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04822|048|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
04822|049|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
04822|050|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
04822|051|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
04822|052|M|dose according to labeling.(2)|
04822|053|B||
04822|054|D|DISCUSSION:  Coadministration of efavirenz (moderate CYP3A4 inducer: 600 mg|
04822|055|D|once daily) with a single dose of fedratinib (500 mg; 1.25 times the|
04822|056|D|recommended dose) decreased the area-under-curve (AUC) of fedratinib by|
04822|057|D|approximately 47%.(1)|
04822|058|D|   Clarithromycin (500 mg twice daily for 5 days, a strong CYP3A4 inhibitor)|
04822|059|D|increased the maximum concentration (Cmax) and AUC of a single dose of|
04822|060|D|pacritinib (400 mg) by 30% and 80%, respectively.(2)|
04822|061|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
04822|062|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(2)|
04822|063|D|   Pacritinib has been associated with QTc interval prolongation.  In|
04822|064|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
04822|065|D|of patients in the treatment arm compared to 1% in the control arm.  The|
04822|066|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
04822|067|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
04822|068|D|adverse reactions were higher in the treatment arm than the control group|
04822|069|D|(3.8% vs 2%, respectively).(2)|
04822|070|B||
04822|071|R|REFERENCES:|
04822|072|B||
04822|073|R|1.Inrebic (fedratinib) US prescribing information. Impact Biomedicines, Inc|1
04822|074|R|  May, 2023.|1
04822|075|R|2.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
04822|076|R|  2024.|1
04822|077|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04822|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04822|079|R|  settings: a scientific statement from the American Heart Association and|6
04822|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04822|081|R|  2;55(9):934-47.|6
04822|082|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04822|083|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04822|084|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04822|085|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04822|086|R|  11/14/2017.|1
04822|087|R|5.This information is based on an extract from the Certara Drug Interaction|6
04822|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04823|001|T|MONOGRAPH TITLE:  Cariprazine/Moderate CYP3A4 Inhibitors|
04823|002|B||
04823|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04823|004|L|of severe adverse interaction.|
04823|005|B||
04823|006|A|MECHANISM OF ACTION:  Cariprazine and its major active metabolite DDCAR are|
04823|007|A|metabolized by CYP3A4.(1-4)|
04823|008|B||
04823|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
04823|010|E|in elevated levels of and toxicity from cariprazine.(1-4)|
04823|011|B||
04823|012|P|PREDISPOSING FACTORS:  None determined.|
04823|013|B||
04823|014|M|PATIENT MANAGEMENT:  When possible, avoid the use of moderate CYP3A4|
04823|015|M|inhibitors with cariprazine.|
04823|016|M|   The US manufacturer of cariprazine states that concurrent use of moderate|
04823|017|M|CYP3A4 inhibitors requires a dose adjustment.  If a moderate CYP3A4|
04823|018|M|inhibitor is initiated in a patient on a stable dose of cariprazine, the|
04823|019|M|following dose adjustments are recommended:|
04823|020|M|   -If current cariprazine dose is 1.5 or 3 mg daily - Decrease cariprazine|
04823|021|M|dose to 1.5 mg every other day.|
04823|022|M|   -If current cariprazine dose is 4.5 or 6 mg daily - Decrease cariprazine|
04823|023|M|dose to 1.5 mg daily.|
04823|024|M|   Cariprazine has two active metabolites, DCAR and DDCAR which have similar|
04823|025|M|in vitro activity and potency.  However, DDCAR has a longer half-life (1-3|
04823|026|M|weeks) than cariprazine (2-4 days), resulting in systemic DDCAR|
04823|027|M|concentrations that are about 4-fold higher than cariprazine.  Thus although|
04823|028|M|interaction onset may begin within a few days, the full effect of inhibition|
04823|029|M|may not be seen for 4 or more weeks.|
04823|030|M|   If a patient is already on a moderate CYP3A4 inhibitor when cariprazine|
04823|031|M|is started, the following dose adjustments are recommended:|
04823|032|M|   -For schizophrenia or bipolar mania - Start cariprazine dose at 1.5 mg|
04823|033|M|every other day; Increase to 1.5 mg daily, if needed.|
04823|034|M|   -For bipolar depression or adjunctive therapy for treatment of Major|
04823|035|M|Depressive Disorder (MDD) - Start cariprazine dose at 1.5 mg every other|
04823|036|M|day.(1)|
04823|037|M|   When the inhibitor is discontinued, cariprazine, DCAR and DDCAR will|
04823|038|M|begin to fall and the dosage may need be increased. Monitor for decreased|
04823|039|M|effectiveness for 4 or more weeks.|
04823|040|M|   The Australian, and Canadian manufacturers of cariprazine state that|
04823|041|M|concurrent use of moderate CYP3A4 inhibitors is contraindicated.(2,3)|
04823|042|M|   The UK manufacturer of cariprazine states that concurrent use of moderate|
04823|043|M|CYP3A4 inhibitors may require a dose adjustment.(4)|
04823|044|M|   The Canadian manufacturer of cariprazine states that concurrent use of|
04823|045|M|moderate CYP3A4 inhibitors is also contraindicated for at least 2 weeks|
04823|046|M|after cariprazine discontinuation.(3)|
04823|047|B||
04823|048|D|DISCUSSION:  In an interaction study, coadministration of ketoconazole 400|
04823|049|D|mg/day with cariprazine 0.5 mg/day increased cariprazine exposure (AUC,|
04823|050|D|area-under-curve) 4-fold and increased DDCAR AUC about 1.5-fold.(1)|
04823|051|D|   In a PKPB model, coadministration of ketoconazole 400 mg/day with|
04823|052|D|cariprazine 0.5 mg/day is predicted to increase cariprazine concentration|
04823|053|D|maximum (Cmax) and AUC by 5.5-fold and 6-fold, respectively.|
04823|054|D|Coadministration of fluconazole 200 mg/day with cariprazine 0.5 mg/day is|
04823|055|D|predicted to increased cariprazine Cmax and AUC by up to 3-fold.(1)|
04823|056|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  amprenavir,|
04823|057|D|aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
04823|058|D|diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole,|
04823|059|D|fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral|
04823|060|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
04823|061|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil,|
04823|062|D|and voxelotor.(5,6)|
04823|063|B||
04823|064|R|REFERENCES:|
04823|065|B||
04823|066|R|1.Vraylar (cariprazine) US prescribing information. Forest Laboratories LLC|1
04823|067|R|  November, 2024.|1
04823|068|R|2.Reagila (capriprazine) Australian Product Information. Gedeon Richter|1
04823|069|R|  Australia Pty Ltd January, 2024.|1
04823|070|R|3.Vraylar (cariprazine) Canadian Product Monograph. AbbVie Corporation March|1
04823|071|R|  6, 2024.|1
04823|072|R|4.Reagila (cariprazine) UK Summary of Product Characteristics. Recordati|1
04823|073|R|  Pharmaceuticals Limited March, 2024.|1
04823|074|R|5.This information is based on an extract from the Certara Drug Interaction|6
04823|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04823|076|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04823|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04823|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04823|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04823|080|R|  11/14/2017.|1
04824|001|T|MONOGRAPH TITLE:  Fludarabine/Pentostatin|
04824|002|B||
04824|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04824|004|L|of severe adverse interaction.|
04824|005|B||
04824|006|A|MECHANISM OF ACTION:  Mechanism is unknown.|
04824|007|B||
04824|008|E|CLINICAL EFFECTS:  Concurrent use of fludarabine and pentostatin may result|
04824|009|E|in an increased risk of pulmonary toxicity.(1,2)|
04824|010|B||
04824|011|P|PREDISPOSING FACTORS:  None determined.|
04824|012|B||
04824|013|M|PATIENT MANAGEMENT:  The concurrent use of fludarabine and pentostatin|
04824|014|M|should be avoided.(1,2)|
04824|015|B||
04824|016|D|DISCUSSION:  In a study of patients with refractory chronic lymphocytic|
04824|017|D|leukemia, the use of fludarabine combined with pentostatin resulted in|
04824|018|D|severe or fatal pulmonary toxicity in 4 of 6 patients.(1,2)|
04824|019|B||
04824|020|R|REFERENCES:|
04824|021|B||
04824|022|R|1.Nipent (pentostatin) US prescribing information. Hospira, Inc. September|1
04824|023|R|  2024.|1
04824|024|R|2.Fludara (fludarabine) US prescribing information. Genzyme Corporation|1
04824|025|R|  July, 2010.|1
04825|001|T|MONOGRAPH TITLE:  Acoramidis/UGT and Selected CYP3A4 Inducers|
04825|002|B||
04825|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04825|004|L|of severe adverse interaction.|
04825|005|B||
04825|006|A|MECHANISM OF ACTION:  UGT and selected CYP3A4 inducers may induce the|
04825|007|A|metabolism of acoramidis, which is glucuronidated by UGT1A9, UGT1A1, and|
04825|008|A|UGT2B7.(1)|
04825|009|B||
04825|010|E|CLINICAL EFFECTS:  Concurrent use of UGT and selected CYP3A4 inducers may|
04825|011|E|result in decreased levels and effectiveness of acoramidis.(1)|
04825|012|B||
04825|013|P|PREDISPOSING FACTORS:  None determined.|
04825|014|B||
04825|015|M|PATIENT MANAGEMENT:  The manufacturer of acoramidis states to avoid|
04825|016|M|concomitant use of acoramidis with UGT inducers and strong CYP3A|
04825|017|M|inducers.(1)|
04825|018|B||
04825|019|D|DISCUSSION:  UGT and selected CYP3A4 inducers linked to this monograph|
04825|020|D|include: carbamazepine, efavirenz, etravirine, fosphenytoin, phenobarbital,|
04825|021|D|phenytoin, primidone, rifampin, rifapentine, and ritonavir.|
04825|022|B||
04825|023|R|REFERENCE:|
04825|024|B||
04825|025|R|1.Attruby (acoramidis) US prescribing information. BridgeBio Pharma Inc.|1
04825|026|R|  November, 2024.|1
04826|001|T|MONOGRAPH TITLE:  Pralatrexate/Probenecid|
04826|002|B||
04826|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04826|004|L|of severe adverse interaction.|
04826|005|B||
04826|006|A|MECHANISM OF ACTION:  Inhibitors of multidrug resistance-associated protein|
04826|007|A|2 (MRP2) such as probenecid may inhibit the renal elimination of|
04826|008|A|pralatrexate.(1)|
04826|009|B||
04826|010|E|CLINICAL EFFECTS:  Concurrent use of probenecid with pralatrexate may result|
04826|011|E|in an increase in both the therapeutic and toxic effects of pralatrexate,|
04826|012|E|leading to increased risk of severe neurotoxicity, stomatitis, and|
04826|013|E|myelosuppression, including neutropenia.|
04826|014|B||
04826|015|P|PREDISPOSING FACTORS:  Patients with severe renal impairment (eGFR 15 to <|
04826|016|P|30 mL/min/1.73 m2) may be at greater risk for increased exposure and adverse|
04826|017|P|reactions.|
04826|018|B||
04826|019|M|PATIENT MANAGEMENT:  Administration of probenecid with pralatrexate should|
04826|020|M|be avoided.(1)|
04826|021|M|   If coadministration is unavoidable, monitor for increased risk of adverse|
04826|022|M|reactions.|
04826|023|B||
04826|024|D|DISCUSSION:  Concurrent administration of probenecid resulted in delayed|
04826|025|D|clearance of pralatrexate and increased pralatrexate exposure.(1)|
04826|026|B||
04826|027|R|REFERENCES:|
04826|028|B||
04826|029|R|1.Folotyn (pralatrexate) US prescribing information. Allos Therapeutics,|1
04826|030|R|  Inc. May, 2016.|1
04826|031|R|2.Fury MG, Krug LM, Azzoli CG, Sharma S, Kemeny N, Wu N, Kris MG, Rizvi NA.|2
04826|032|R|  A phase I clinical pharmacologic study of pralatrexate in combination with|2
04826|033|R|  probenecid in adults with advanced solid tumors. Cancer Chemother|2
04826|034|R|  Pharmacol 2006 May;57(5):671-7.|2
04826|035|R|3.This information is based on an extract from the Certara Drug Interaction|6
04826|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04827|001|T|MONOGRAPH TITLE:  Methotrexate(Oncology-Inj)/Immunosuppressive OAT3|
04827|002|T|Inhibitors|
04827|003|B||
04827|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04827|005|L|of severe adverse interaction.|
04827|006|B||
04827|007|A|MECHANISM OF ACTION:  Inhibitors of organic anion transporter 3 (OAT3) may|
04827|008|A|inhibit the renal elimination of methotrexate.|
04827|009|A|   Concurrent use of methotrexate with immunosuppressive agents may result|
04827|010|A|in additive or synergistic effects on the immune system.|
04827|011|B||
04827|012|E|CLINICAL EFFECTS:  Concurrent use of organic anion transporter 3 (OAT3)|
04827|013|E|inhibitors may result in an increase in both the therapeutic and toxic|
04827|014|E|effects of methotrexate, leading to increased risk of severe neurotoxicity,|
04827|015|E|stomatitis, and myelosuppression, including neutropenia.(1)  Concurrent use|
04827|016|E|of methotrexate with immunosuppressive agents may increase the risk of|
04827|017|E|serious infections.(1)|
04827|018|B||
04827|019|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
04827|020|P|- High-dose oncology regimens|
04827|021|P|- Impaired renal function, ascites, or pleural effusions|
04827|022|B||
04827|023|M|PATIENT MANAGEMENT:  If coadministration cannot be avoided, monitor closely|
04827|024|M|for methotrexate adverse reactions.(1)|
04827|025|B||
04827|026|D|DISCUSSION:  Concomitant administration of methotrexate and probenecid (OAT3|
04827|027|D|inhibitor) has been shown to increase methotrexate plasma levels two to four|
04827|028|D|times higher than when methotrexate is administered alone.(2-5)|
04827|029|D|   Methotrexate suppresses hematopoiesis and can cause severe and|
04827|030|D|life-threatening pancytopenia, anemia, aplastic anemia, leukopenia,|
04827|031|D|neutropenia, and thrombocytopenia.(1)|
04827|032|D|   Immunosuppressive OAT3 inhibitors linked to this monograph include:|
04827|033|D|leflunomide and teriflunomide.(7)|
04827|034|B||
04827|035|R|REFERENCES:|
04827|036|B||
04827|037|R|1.Methotrexate sodium Inj. US prescribing information. Hospira Worldwide,|1
04827|038|R|  Inc. March, 2018.|1
04827|039|R|2.Israili ZH, Soliman AM, Cunningham RF, Plowden JF, Keller JW. The|4
04827|040|R|  interaction of methotrexate and probenecid in man and dog. Proc Am Assoc|4
04827|041|R|  Cancer Res 1978;19:194.|4
04827|042|R|3.Aherne GW, Piall E, Marks V, Mould G, White WF. Prolongation and|2
04827|043|R|  enhancement of serum methotrexate concentrations by probenecid. Br Med J|2
04827|044|R|  1978 Apr 29;1(6120):1097-9.|2
04827|045|R|4.Howell SB, Olshen RA, Rice JA. Effect of probenecid on cerebrospinal fluid|2
04827|046|R|  methotrexate kinetics. Clin Pharmacol Ther 1979 Nov;26(5):641-6.|2
04827|047|R|5.Lilly MB, Omura GA. Clinical pharmacology of oral intermediate-dose|2
04827|048|R|  methotrexate with or without probenecid. Cancer Chemother Pharmacol 1985;|2
04827|049|R|  15(3):220-2.|2
04827|050|R|6.Basin KS, Escalante A, Beardmore TD. Severe pancytopenia in a patient|3
04827|051|R|  taking low dose methotrexate and probenecid. J Rheumatol 1991 Apr;|3
04827|052|R|  18(4):609-10.|3
04827|053|R|7.This information is based on an extract from the Certara Drug Interaction|6
04827|054|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04828|001|T|MONOGRAPH TITLE:  Allergen Immunotherapy/Ustekinumab|
04828|002|B||
04828|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04828|004|L|take action as needed.|
04828|005|B||
04828|006|A|MECHANISM OF ACTION:  Ustekinumab may decrease the protective effect of|
04828|007|A|allergen immunotherapy.|
04828|008|B||
04828|009|E|CLINICAL EFFECTS:  Ustekinumab may increase the risk of an allergic reaction|
04828|010|E|to allergen immunotherapy.|
04828|011|B||
04828|012|P|PREDISPOSING FACTORS:  None determined.|
04828|013|B||
04828|014|M|PATIENT MANAGEMENT:  Exercise caution in patients receiving or who have|
04828|015|M|received allergen immunotherapy. Counsel patients on the possible increased|
04828|016|M|risk of an allergic reaction.(1)|
04828|017|B||
04828|018|D|DISCUSSION:  Concurrent use of ustekinumab and allergen immunotherapy has|
04828|019|D|not been evaluated.(1)|
04828|020|B||
04828|021|R|REFERENCE:|
04828|022|B||
04828|023|R|1.Yesintek (ustekinumab-kfce) US prescribing information. Biocon Biologics,|1
04828|024|R|  Inc. December 2024.|1
04829|001|T|MONOGRAPH TITLE:  Crinecerfont/Strong CYP3A4 Inducers|
04829|002|B||
04829|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04829|004|L|take action as needed.|
04829|005|B||
04829|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04829|007|A|crinecerfont.(1)|
04829|008|B||
04829|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
04829|010|E|reduce the clinical effectiveness of crinecerfont.(1)|
04829|011|B||
04829|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04829|013|P|of the inducer for longer than 1-2 weeks.|
04829|014|B||
04829|015|M|PATIENT MANAGEMENT:  The US manufacturer of crinecerfont states that|
04829|016|M|concurrent use of strong CYP3A4 inducers requires a dose adjustment of|
04829|017|M|crinecerfont.  Increase the morning and evening doses of crinecerfont by|
04829|018|M|2-fold.|
04829|019|M|   In adults, increase the dosage of crinecerfont to 200 mg twice daily.|
04829|020|M|   In pediatric patients 4 years and older weighing:|
04829|021|M|   - 10 kg to <20 kg: increase the crinecerfont dosage to 50 mg twice daily,|
04829|022|M|   - 20 kg to <55 kg: increase the crinecerfont dosage to 100 mg twice|
04829|023|M|daily,|
04829|024|M|   - >=55 kg: increase the crinecerfont dosage to 200 mg twice daily.(1)|
04829|025|B||
04829|026|D|DISCUSSION:  In a study, concomitant use of rifampin (strong CYP3A4 inducer)|
04829|027|D|decreased crinecerfont maximum concentration (Cmax) by 23% and|
04829|028|D|area-under-curve (AUC) by 62%.(1)|
04829|029|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
04829|030|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04829|031|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04829|032|D|rifampin, rifapentine, and St. John's Wort.(2,3)|
04829|033|B||
04829|034|R|REFERENCES:|
04829|035|B||
04829|036|R|1.Crenessity (crinecerfont) US prrescribing information. Neurocrine|1
04829|037|R|  Biosciences, Inc. December 2024.|1
04829|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04829|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04829|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04829|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04829|042|R|  11/14/2017.|1
04829|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
04829|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04830|001|T|MONOGRAPH TITLE:  Crinecerfont/Moderate CYP3A4 Inducers|
04830|002|B||
04830|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04830|004|L|take action as needed.|
04830|005|B||
04830|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04830|007|A|of crinecerfont.(1)|
04830|008|B||
04830|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
04830|010|E|reduce the clinical effectiveness of crinecerfont.(1)|
04830|011|B||
04830|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04830|013|P|of the inducer for longer than 1-2 weeks.|
04830|014|B||
04830|015|M|PATIENT MANAGEMENT:  The US manufacturer of crinecerfont states that|
04830|016|M|concurrent use of moderate CYP3A4 inducers requires a dose adjustment of|
04830|017|M|crinecerfont.  Increase the evening dose of crinecerfont by 2-fold.  Do not|
04830|018|M|increase the morning dose.|
04830|019|M|   In adults, increase the dosage of crinecerfont to 100 mg in the morning|
04830|020|M|and 200 mg in the evening.|
04830|021|M|   In pediatric patients 4 years and older weighing:|
04830|022|M|   - 10 kg to <20 kg: increase the crinecerfont dosage to 25 mg in the|
04830|023|M|morning and 50 mg in the evening,|
04830|024|M|   - 20 kg to <55 kg: increase the crinecerfont dosage to 50 mg in the|
04830|025|M|morning and 100 mg in the evening,|
04830|026|M|   - >=55 kg: increase the crinecerfont dosage to 100 mg in the morning and|
04830|027|M|200 mg in the evening.(1)|
04830|028|B||
04830|029|D|DISCUSSION:  In a study, concomitant use of rifampin (strong CYP3A4 inducer)|
04830|030|D|decreased crinecerfont maximum concentration (Cmax) by 23% and|
04830|031|D|area-under-curve (AUC) by 62%.(1)|
04830|032|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04830|033|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04830|034|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04830|035|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04830|036|D|thioridazine, and tovorafenib.(2,3)|
04830|037|B||
04830|038|R|REFERENCES:|
04830|039|B||
04830|040|R|1.Crenessity (crinecerfont) US prrescribing information. Neurocrine|1
04830|041|R|  Biosciences, Inc. December 2024.|1
04830|042|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04830|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04830|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04830|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04830|046|R|  11/14/2017.|1
04830|047|R|3.This information is based on an extract from the Certara Drug Interaction|6
04830|048|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04831|001|T|MONOGRAPH TITLE:  Ensartinib/Selected Strong CYP3A4 Inducers|
04831|002|B||
04831|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04831|004|L|of severe adverse interaction.|
04831|005|B||
04831|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04831|007|A|ensartinib.(1)|
04831|008|B||
04831|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
04831|010|E|reduce the clinical effectiveness of ensartinib.(1)|
04831|011|B||
04831|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04831|013|P|of the inducer for longer than 1-2 weeks.|
04831|014|B||
04831|015|M|PATIENT MANAGEMENT:  The US manufacturer of ensartinib states that|
04831|016|M|concurrent use of strong CYP3A4 inducers should be avoided.(1)|
04831|017|B||
04831|018|D|DISCUSSION:  Ensartinib is predominately metabolized by CYP3A4.(1)|
04831|019|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
04831|020|D|barbiturates, carbamazepine, encorafenib, fosphenytoin, ivosidenib,|
04831|021|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, and|
04831|022|D|rifapentine.(2,3)|
04831|023|B||
04831|024|R|REFERENCES:|
04831|025|B||
04831|026|R|1.Ensacove (ensartinib) US prescribing information. Xcovery Holdings, Inc.|1
04831|027|R|  December, 2024.|1
04831|028|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04831|029|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04831|030|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04831|031|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04831|032|R|  11/14/2017.|1
04831|033|R|3.This information is based on an extract from the Certara Drug Interaction|6
04831|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04832|001|T|MONOGRAPH TITLE:  Ensartinib/Selected Moderate CYP3A4 Inducers|
04832|002|B||
04832|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04832|004|L|of severe adverse interaction.|
04832|005|B||
04832|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04832|007|A|of ensartinib.(1)|
04832|008|B||
04832|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
04832|010|E|reduce the clinical effectiveness of ensartinib.(1)|
04832|011|B||
04832|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04832|013|P|of the inducer for longer than 1-2 weeks.|
04832|014|B||
04832|015|M|PATIENT MANAGEMENT:  The US manufacturer of ensartinib states that|
04832|016|M|concurrent use of moderate CYP3A4 inducers should be avoided.(1)|
04832|017|B||
04832|018|D|DISCUSSION:  Ensartinib is predominately metabolized by CYP3A4.(1)|
04832|019|D|   Moderate CYP3A4 inducers linked to this monograph are: belzutifan,|
04832|020|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, etravirine,|
04832|021|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
04832|022|D|pexidartinib, pacritinib, repotrectinib, rifabutin, telotristat,|
04832|023|D|thioridazine, and tovorafenib.(2,3)|
04832|024|B||
04832|025|R|REFERENCES:|
04832|026|B||
04832|027|R|1.Ensacove (ensartinib) US prescribing information. Xcovery Holdings, Inc.|1
04832|028|R|  December, 2024.|1
04832|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04832|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04832|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04832|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04832|033|R|  11/14/2017.|1
04832|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04832|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04833|001|T|MONOGRAPH TITLE:  Ensartinib/Selected Strong CYP3A4 Inhibitors|
04833|002|B||
04833|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04833|004|L|of severe adverse interaction.|
04833|005|B||
04833|006|A|MECHANISM OF ACTION:  Ensartinib is primarily metabolized by CYP3A4.|
04833|007|A|Ensartinib metabolism may be inhibited by strong CYP3A4 inhibitors.(1)|
04833|008|B||
04833|009|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4|
04833|010|E|inhibitor may result in elevated levels of and toxicity from ensartinib.(1)|
04833|011|B||
04833|012|P|PREDISPOSING FACTORS:  None determined.|
04833|013|B||
04833|014|M|PATIENT MANAGEMENT:  The US manufacturer of ensartinib states that|
04833|015|M|concurrent use of strong CYP3A4 inhibitors should be avoided.(1)|
04833|016|B||
04833|017|D|DISCUSSION:  Ensartinib is predominately metabolized by CYP3A4.(1)|
04833|018|D|   Strong CYP3A4 inhibitors include:  adagrasib, ceritinib, grapefruit,|
04833|019|D|idelalisib, ribociclib, troleandomycin, and voriconazole.(2,3)|
04833|020|B||
04833|021|R|REFERENCES:|
04833|022|B||
04833|023|R|1.Ensacove (ensartinib) US prescribing information. Xcovery Holdings, Inc.|1
04833|024|R|  December, 2024.|1
04833|025|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04833|026|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04833|027|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04833|028|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04833|029|R|  11/14/2017.|1
04833|030|R|3.This information is based on an extract from the Certara Drug Interaction|6
04833|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04834|001|T|MONOGRAPH TITLE:  Ensartinib/Selected Moderate CYP3A4 Inhibitors|
04834|002|B||
04834|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04834|004|L|of severe adverse interaction.|
04834|005|B||
04834|006|A|MECHANISM OF ACTION:  Ensartinib is primarily metabolized by CYP3A4.|
04834|007|A|Ensartinib metabolism may be inhibited by moderate CYP3A4 inhibitors.(1)|
04834|008|B||
04834|009|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
04834|010|E|inhibitor may result in elevated levels of and toxicity from ensartinib.(1)|
04834|011|B||
04834|012|P|PREDISPOSING FACTORS:  None determined.|
04834|013|B||
04834|014|M|PATIENT MANAGEMENT:  The US manufacturer of ensartinib states that|
04834|015|M|concurrent use of moderate CYP3A4 inhibitors should be avoided.(1)|
04834|016|B||
04834|017|D|DISCUSSION:  Ensartinib is predominately metabolized by CYP3A4.(1)|
04834|018|D|   Moderate CYP3A4 inhibitors include:  amprenavir, aprepitant, atazanavir,|
04834|019|D|avacopan, berotralstat, clofazimine, crizotinib, darunavir, duvelisib,|
04834|020|D|fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, oral|
04834|021|D|lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat,|
04834|022|D|rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(2,3)|
04834|023|B||
04834|024|R|REFERENCES:|
04834|025|B||
04834|026|R|1.Ensacove (ensartinib) US prescribing information. Xcovery Holdings, Inc.|1
04834|027|R|  December, 2024.|1
04834|028|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04834|029|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04834|030|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04834|031|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04834|032|R|  11/14/2017.|1
04834|033|R|3.This information is based on an extract from the Certara Drug Interaction|6
04834|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04835|001|T|MONOGRAPH TITLE:  Ensartinib/Selected P-glycoprotein (P-gp) Inhibitors|
04835|002|B||
04835|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04835|004|L|of severe adverse interaction.|
04835|005|B||
04835|006|A|MECHANISM OF ACTION:  Ensartinib is a P-glycoprotein (P-gp) substrate.  P-gp|
04835|007|A|inhibitors may increase the levels of ensartinib.(1)|
04835|008|B||
04835|009|E|CLINICAL EFFECTS:  The concurrent administration of a P-glycoprotein (P-gp)|
04835|010|E|inhibitor may result in elevated levels of and toxicity from ensartinib.(1)|
04835|011|B||
04835|012|P|PREDISPOSING FACTORS:  None determined.|
04835|013|B||
04835|014|M|PATIENT MANAGEMENT:  The US manufacturer of ensartinib states that|
04835|015|M|concurrent use of P-glycoprotein (P-gp) inhibitors should be avoided.(1)|
04835|016|B||
04835|017|D|DISCUSSION:  Ensartinib is a substrate of P-gp. Inhibitors of P-gp may|
04835|018|D|increase toxicity of ensartinib.(1)|
04835|019|D|   Inhibitors of P-gp linked to this monograph include:  abrocitinib,|
04835|020|D|amiodarone, Asian ginseng (Panax ginseng), asunaprevir, azithromycin,|
04835|021|D|belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan,|
04835|022|D|daridorexant, diosmin, eliglustat, flibanserin, fostamatinib, ginkgo biloba,|
04835|023|D|glecaprevir and pibrentasvir, hydroquinidine, ivacaftor, lapatinib,|
04835|024|D|mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib,|
04835|025|D|propafenone, quercetin, quinidine, ranolazine, rolapitant, silibinin,|
04835|026|D|silymarin, sotagliflozin, tepotinib, tezacaftor, valbenazine, velpatasvir,|
04835|027|D|vemurafenib, venetoclax, vilazodone, vimseltinib, and voclosporin.(2,3)|
04835|028|B||
04835|029|R|REFERENCES:|
04835|030|B||
04835|031|R|1.Ensacove (ensartinib) US prescribing information. Xcovery Holdings, Inc.|1
04835|032|R|  December, 2024.|1
04835|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04835|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04835|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04835|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04835|037|R|  11/14/2017.|1
04835|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
04835|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04836|001|T|MONOGRAPH TITLE:  Ensartinib/Dual Strong CYP3A4 & P-gp Inhibitors|
04836|002|B||
04836|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04836|004|L|of severe adverse interaction.|
04836|005|B||
04836|006|A|MECHANISM OF ACTION:  Ensartinib is primarily metabolized by CYP3A4 and is|
04836|007|A|transported by P-glycoprotein (P-gp).(1)|
04836|008|A|   Inhibitors of CYP3A4 and P-gp may inhibit the absorption and metabolism|
04836|009|A|of ensartinib.(1)|
04836|010|B||
04836|011|E|CLINICAL EFFECTS:  Concurrent use with dual inhibitors of CYP3A4 and P-gp|
04836|012|E|may result in elevated systemic levels and toxicity from ensartinib.(1)|
04836|013|B||
04836|014|P|PREDISPOSING FACTORS:  None determined.|
04836|015|B||
04836|016|M|PATIENT MANAGEMENT:  The manufacturer of ensartinib states concurrent use|
04836|017|M|with both P-gp and strong CYP3A4 inhibitors should be avoided.(1)|
04836|018|B||
04836|019|D|DISCUSSION:  Ensartinib is predominately metabolized by CYP3A4 and is a P-gp|
04836|020|D|substrate.(1)|
04836|021|D|   Dual P-gp and strong CYP3A4 inhibitors linked to this monograph include:|
04836|022|D|boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, josamycin,|
04836|023|D|ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil,|
04836|024|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir,|
04836|025|D|posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir,|
04836|026|D|and tucatinib.(2,3)|
04836|027|B||
04836|028|R|REFERENCES:|
04836|029|B||
04836|030|R|1.Ensacove (ensartinib) US prescribing information. Xcovery Holdings, Inc.|1
04836|031|R|  December, 2024.|1
04836|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04836|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04836|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04836|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04836|036|R|  11/14/2017.|1
04836|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04836|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04837|001|T|MONOGRAPH TITLE:  Ensartinib/Dual Moderate CYP3A4 & P-gp Inhibitors|
04837|002|B||
04837|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04837|004|L|of severe adverse interaction.|
04837|005|B||
04837|006|A|MECHANISM OF ACTION:  Ensartinib is primarily metabolized by CYP3A4 and is|
04837|007|A|transported by P-glycoprotein (P-gp).(1)|
04837|008|A|   Inhibitors of CYP3A4 and P-gp may inhibit the absorption and metabolism|
04837|009|A|of ensartinib.(1)|
04837|010|B||
04837|011|E|CLINICAL EFFECTS:  Concurrent use with dual inhibitors of CYP3A4 and P-gp|
04837|012|E|may result in elevated systemic levels and toxicity from ensartinib.(1)|
04837|013|B||
04837|014|P|PREDISPOSING FACTORS:  None determined.|
04837|015|B||
04837|016|M|PATIENT MANAGEMENT:  The manufacturer of ensartinib states concurrent use|
04837|017|M|with both P-gp and moderate CYP3A4 inhibitors should be avoided.(1)|
04837|018|B||
04837|019|D|DISCUSSION:  Ensartinib is predominately metabolized by CYP3A4 and is a P-gp|
04837|020|D|substrate.(1)|
04837|021|D|   Dual P-gp and moderate CYP3A4 inhibitors linked to this monograph|
04837|022|D|include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine,|
04837|023|D|isavuconazonium, Schisandra, and verapamil.(2,3)|
04837|024|B||
04837|025|R|REFERENCES:|
04837|026|B||
04837|027|R|1.Ensacove (ensartinib) US prescribing information. Xcovery Holdings, Inc.|1
04837|028|R|  December, 2024.|1
04837|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04837|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04837|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04837|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04837|033|R|  11/14/2017.|1
04837|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04837|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04838|001|T|MONOGRAPH TITLE:  Rosuvastatin/Selected BCRP Inhibitors|
04838|002|B||
04838|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04838|004|L|of severe adverse interaction.|
04838|005|B||
04838|006|A|MECHANISM OF ACTION:  BCRP inhibitors may result in increased absorption of|
04838|007|A|rosuvastatin.(1-3)|
04838|008|B||
04838|009|E|CLINICAL EFFECTS:  Administration of rosuvastatin with BCRP inhibitors may|
04838|010|E|result in elevated levels of rosuvastatin, which could result in|
04838|011|E|rhabdomyolysis.(1)|
04838|012|B||
04838|013|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
04838|014|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
04838|015|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
04838|016|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
04838|017|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
04838|018|P|transporter OATP1B1 may have increased statin concentrations and be|
04838|019|P|predisposed to myopathy or rhabdomyolysis.|
04838|020|B||
04838|021|M|PATIENT MANAGEMENT:  Rosuvastatin is a substrate of the efflux transporter|
04838|022|M|BCRP.(1)|
04838|023|M|   The US manufacturers of leniolisib(2) and selpercatinib(3) recommend|
04838|024|M|avoiding concurrent use with BCRP substrates such as rosuvastatin.|
04838|025|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
04838|026|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
04838|027|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
04838|028|M|urine, and/or discolored urine.(1)|
04838|029|B||
04838|030|D|DISCUSSION:  Concurrent administration of leniolisib with rosuvastatin|
04838|031|D|increased the systemic exposure of rosuvastatin by 2-fold.(2)|
04838|032|D|   Concurrent administration of selpercatinib with rosuvastatin increased|
04838|033|D|the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of|
04838|034|D|rosuvastatin approximately 1.9-fold and 1.7-fold.(3)|
04838|035|D|   BCRP inhibitors linked to this monograph include: leniolisib and|
04838|036|D|selpercatinib.|
04838|037|B||
04838|038|R|REFERENCES:|
04838|039|B||
04838|040|R|1.Crestor (rosuvastatin calcium) US prescribing information. AstraZeneca|1
04838|041|R|  Pharmaceuticals LP July, 2024.|1
04838|042|R|2.Joenja (leniolisib) US prescribing information. Pharming Healthcare Inc.|1
04838|043|R|  May, 2025.|1
04838|044|R|3.Retevmo (selpercatinib) US prescribing information. Eli Lilly December,|1
04838|045|R|  2024.|1
04838|046|R|4.This information is based on an extract from the Certara Drug Interaction|6
04838|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04838|048|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04838|049|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04838|050|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04838|051|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04838|052|R|  11/14/2017.|1
04839|001|T|MONOGRAPH TITLE:  Ensartinib/Dual Moderate CYP3A4 Inducers & P-gp Inhibitors|
04839|002|B||
04839|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04839|004|L|of severe adverse interaction.|
04839|005|B||
04839|006|A|MECHANISM OF ACTION:  Ensartinib is primarily metabolized by CYP3A4 and is|
04839|007|A|transported by P-glycoprotein (P-gp).(1)|
04839|008|A|   Inducers of CYP3A4 may induce the metabolism of ensartinib while|
04839|009|A|inhibitors of P-gp may increase the absorption of ensartinib.(1)|
04839|010|B||
04839|011|E|CLINICAL EFFECTS:  The net effect of this interaction is unknown.|
04839|012|E|Concurrent use of ensartinib with CYP3A4 inducers may result in decreased|
04839|013|E|levels and effectiveness of ensartinib while concurrent use of P-gp|
04839|014|E|inhibitors may result in elevated systemic levels and toxicity from|
04839|015|E|ensartinib.(1)|
04839|016|B||
04839|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04839|018|P|of the inducer for longer than 1-2 weeks.|
04839|019|B||
04839|020|M|PATIENT MANAGEMENT:  The manufacturer of ensartinib states concurrent use|
04839|021|M|with both P-gp inhibitors and moderate CYP3A4 inducers should be avoided.(1)|
04839|022|B||
04839|023|D|DISCUSSION:  Ensartinib is predominately metabolized by CYP3A4 and is a P-gp|
04839|024|D|substrate.(1)|
04839|025|D|   Dual moderate CYP3A4 inducers and P-gp inhibitors linked to this|
04839|026|D|monograph include: elagolix and sotorasib.(2,3)|
04839|027|B||
04839|028|R|REFERENCES:|
04839|029|B||
04839|030|R|1.Ensacove (ensartinib) US prescribing information. Xcovery Holdings, Inc.|1
04839|031|R|  December, 2024.|1
04839|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04839|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04839|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04839|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04839|036|R|  11/14/2017.|1
04839|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04839|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04840|001|T|MONOGRAPH TITLE:  Ensartinib/Dual Strong CYP3A4 Inducers & P-gp Inhibitors|
04840|002|B||
04840|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04840|004|L|of severe adverse interaction.|
04840|005|B||
04840|006|A|MECHANISM OF ACTION:  Ensartinib is primarily metabolized by CYP3A4 and is|
04840|007|A|transported by P-glycoprotein (P-gp).(1)|
04840|008|A|   Inducers of CYP3A4 may induce the metabolism of ensartinib while|
04840|009|A|inhibitors of P-gp may increase the absorption of ensartinib.(1)|
04840|010|B||
04840|011|E|CLINICAL EFFECTS:  The net effect of this interaction is unknown.|
04840|012|E|Concurrent use of ensartinib with CYP3A4 inducers may result in decreased|
04840|013|E|levels and effectiveness of ensartinib while concurrent use of P-gp|
04840|014|E|inhibitors may result in elevated systemic levels and toxicity from|
04840|015|E|ensartinib.(1)|
04840|016|B||
04840|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04840|018|P|of the inducer for longer than 1-2 weeks.|
04840|019|B||
04840|020|M|PATIENT MANAGEMENT:  The manufacturer of ensartinib states concurrent use|
04840|021|M|with both P-gp inhibitors and strong CYP3A4 inducers should be avoided.(1)|
04840|022|B||
04840|023|D|DISCUSSION:  Ensartinib is predominately metabolized by CYP3A4 and is a P-gp|
04840|024|D|substrate.(1)|
04840|025|D|   Dual strong CYP3A4 inducers and P-gp inhibitors linked to this monograph|
04840|026|D|include: enzalutamide, lumacaftor-ivacaftor, and St. John's wort.(2,3)|
04840|027|B||
04840|028|R|REFERENCES:|
04840|029|B||
04840|030|R|1.Ensacove (ensartinib) US prescribing information. Xcovery Holdings, Inc.|1
04840|031|R|  December, 2024.|1
04840|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04840|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04840|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04840|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04840|036|R|  11/14/2017.|1
04840|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04840|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04841|001|T|MONOGRAPH TITLE:  Warfarin/Deutivacaftor|
04841|002|B||
04841|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04841|004|L|take action as needed.|
04841|005|B||
04841|006|A|MECHANISM OF ACTION:  Deutivacaftor is a CYP2C9 inhibitor(1) which may|
04841|007|A|decrease the metabolism of the S-enantiomer of warfarin.(2)|
04841|008|B||
04841|009|E|CLINICAL EFFECTS:  Concurrent use of deutivacaftor may result in elevated|
04841|010|E|levels of warfarin and increased INR.(1,2)|
04841|011|B||
04841|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04841|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04841|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
04841|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04841|016|P|risk for bleeding (e.g. NSAIDs).|
04841|017|P|   Pharmacogenomic information: patients with a CYP2C9 intermediate|
04841|018|P|metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene|
04841|019|P|are expected to be more susceptible to this interaction.|
04841|020|P|   Although patients with a pre-existing CYP2C9 poor metabolizer genotype|
04841|021|P|are expected to be less susceptible to effects from this drug combination,|
04841|022|P|their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and|
04841|023|P|*3/*3) result in an inherently higher warfarin half-life and risk for|
04841|024|P|warfarin-associated bleeding. CYP2C9 poor metabolizers generally require|
04841|025|P|lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective|
04841|026|P|and safe anticoagulation than patients without these CYP2C9 variants.|
04841|027|B||
04841|028|M|PATIENT MANAGEMENT:  Monitor INRs more frequently until stable in patients|
04841|029|M|who start deutivacaftor therapy, or have the warfarin dose adjusted as|
04841|030|M|indicated.(1)|
04841|031|M|   If concurrent therapy is warranted, monitor patients for signs of blood|
04841|032|M|loss, including decreased hemoglobin and/or hematocrit, fecal occult blood,|
04841|033|M|and/or decreased blood pressure and promptly evaluate patients with any|
04841|034|M|symptoms.|
04841|035|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04841|036|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04841|037|M|anticoagulation in patients with active pathologic bleeding.|
04841|038|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04841|039|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04841|040|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04841|041|M|and/or swelling.|
04841|042|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04841|043|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
04841|044|M|before initiating, altering the dose or discontinuing either drug.|
04841|045|B||
04841|046|D|DISCUSSION:  Deutivacaftor is a CYP2C9 inhibitor.(1)|
04841|047|B||
04841|048|R|REFERENCES:|
04841|049|B||
04841|050|R|1.Alyftrek (vanzacaftor, tezacaftor, and deutivacaftor) US prescribing|1
04841|051|R|  information. Vertex Pharmaceuticals Incorporated December, 2024.|1
04841|052|R|2.Coumadin (warfarin sodium) US prescribing information. Bristol-Myers|1
04841|053|R|  Squibb Company September, 2016.|1
04841|054|R|3.Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM,|6
04841|055|R|  Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman|6
04841|056|R|  RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for|6
04841|057|R|  CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011|6
04841|058|R|  Oct;90(4):625-9.|6
04842|001|T|MONOGRAPH TITLE:  Vanzacaftor-Tezacaftor-Deutivacaftor/Strong CYP3A4|
04842|002|T|Inducers|
04842|003|B||
04842|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04842|005|L|of severe adverse interaction.|
04842|006|B||
04842|007|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04842|008|A|vanzacaftor, tezacaftor, and deutivacaftor.(1)|
04842|009|B||
04842|010|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04842|011|E|may result in decreased levels and effectiveness of vanzacaftor, tezacaftor,|
04842|012|E|and deutivacaftor.(1)|
04842|013|B||
04842|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04842|015|P|of the inducer for longer than 1-2 weeks.|
04842|016|B||
04842|017|M|PATIENT MANAGEMENT:  Concurrent use of strong CYP3A4 inducers in patients|
04842|018|M|maintained on vanzacaftor- tezacaftor-deutivacaftor is not recommended.(1)|
04842|019|B||
04842|020|D|DISCUSSION:  Concurrent administration with rifampin (a strong inducer of|
04842|021|D|CYP3A4) is predicted to decrease vanzacaftor and deutivacaftor|
04842|022|D|area-under-curve (AUC) by 82% and 90%, respectively, and maximum|
04842|023|D|concentration (Cmax) by 78% and 80%, respectively.(1)|
04842|024|D|   Carbamazepine (a strong CYP3A4 inducer) is predicted to decrease|
04842|025|D|vanzacaftor and deutivacaftor AUC by 56% and 76%, respectively, and Cmax by|
04842|026|D|54% and 68%, respectively.(1)|
04842|027|D|   Strong inducers of CYP3A4 include:  apalutamide, barbiturates,|
04842|028|D|carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
04842|029|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
04842|030|D|rifapentine and St. John's wort.(2-3)|
04842|031|B||
04842|032|R|REFERENCES:|
04842|033|B||
04842|034|R|1.Alyftrek (vanzacaftor, tezacaftor, and deutivacaftor) US prescribing|1
04842|035|R|  information. Vertex Pharmaceuticals Incorporated December, 2024.|1
04842|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
04842|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04842|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04842|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04842|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04842|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04842|042|R|  11/14/2017.|1
04843|001|T|MONOGRAPH TITLE:  Vanzacaftor-Tezacaftor-Deutivacaftor/Moderate CYP3A4|
04843|002|T|Inducer|
04843|003|B||
04843|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04843|005|L|of severe adverse interaction.|
04843|006|B||
04843|007|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04843|008|A|of vanzacaftor, tezacaftor, and deutivacaftor.(1)|
04843|009|B||
04843|010|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate inducer of CYP3A4|
04843|011|E|may result in decreased levels and effectiveness of vanzacaftor, tezacaftor,|
04843|012|E|and deutivacaftor.(1)|
04843|013|B||
04843|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04843|015|P|of the inducer for longer than 1-2 weeks.|
04843|016|B||
04843|017|M|PATIENT MANAGEMENT:  Concurrent use of moderate CYP3A4 inducers in patients|
04843|018|M|maintained on vanzacaftor- tezacaftor-deutivacaftor is not recommended.(1)|
04843|019|B||
04843|020|D|DISCUSSION:  Concurrent administration with efavirenz (a moderate inducer of|
04843|021|D|CYP3A4) is predicted to decrease vanzacaftor and deutivacaftor|
04843|022|D|area-under-curve (AUC) by 69% and 73%, respectively, and maximum|
04843|023|D|concentration (Cmax) by 65% and 56%, respectively.(1)|
04843|024|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04843|025|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04843|026|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04843|027|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04843|028|D|thioridazine, and tovorafenib.(2,3)|
04843|029|B||
04843|030|R|REFERENCES:|
04843|031|B||
04843|032|R|1.Alyftrek (vanzacaftor, tezacaftor, and deutivacaftor) US prescribing|1
04843|033|R|  information. Vertex Pharmaceuticals Incorporated December, 2024.|1
04843|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
04843|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04843|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04843|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04843|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04843|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04843|040|R|  11/14/2017.|1
04844|001|T|MONOGRAPH TITLE:  Oral Lefamulin/Vanzacaftor-Tezacaftor-Deutivacaftor|
04844|002|B||
04844|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04844|004|L|of severe adverse interaction.|
04844|005|B||
04844|006|A|MECHANISM OF ACTION:  Inhibitors of P-glycoprotein (P-gp) may increase the|
04844|007|A|absorption of lefamulin.(1)  Tezacaftor-deutivacaftor is a P-gp|
04844|008|A|inhibitor.(2)|
04844|009|A|   Inhibitors of CYP3A4 may inhibit the metabolism of|
04844|010|A|vanzacaftor-tezacaftor-deutivacaftor.(2)  Oral lefamulin is a moderate|
04844|011|A|CYP3A4 inhibitor.(1)|
04844|012|B||
04844|013|E|CLINICAL EFFECTS:  The concurrent administration of lefamulin and|
04844|014|E|vanzacaftor-tezacaftor-deutivacaftor may result in elevated levels of|
04844|015|E|lefamulin and vanzacaftor-tezacaftor-deutivacaftor and signs of toxicity,|
04844|016|E|such as QT prolongation.|
04844|017|B||
04844|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04844|019|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04844|020|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04844|021|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04844|022|P|gender, or advanced age.(3)|
04844|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04844|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04844|025|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04844|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04844|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04844|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04844|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04844|030|B||
04844|031|M|PATIENT MANAGEMENT:  The US manufacturer of lefamulin states that oral|
04844|032|M|lefamulin tablet coadministration with P-gp inhibitors should be avoided.(1)|
04844|033|M|   The US manufacturer of vanzacaftor-tezacaftor-deutivacaftor states that|
04844|034|M|concurrent use with moderate CYP3A4 inhibitors requires a dose adjustment.|
04844|035|M|If concurrent use is warranted, the following dose adjustments are|
04844|036|M|recommended:|
04844|037|M|   -For age 6 to less than 12 years old AND less than 40 kg - Two tablets of|
04844|038|M|vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day;|
04844|039|M|   -For age 6 to less than 12 years old AND greater than or equal to 40 kg -|
04844|040|M|One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every|
04844|041|M|other day;|
04844|042|M|   -For age 12 years and older AND any weight - One tablet of vanzacaftor 10|
04844|043|M|mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.(2)|
04844|044|M|   If concomitant therapy of lefamulin with a P-gp inhibitor is necessary,|
04844|045|M|monitor patients closely for prolongation of the QT interval.  Obtain serum|
04844|046|M|calcium, magnesium, and potassium levels and monitor ECG at regular|
04844|047|M|intervals.  Correct any electrolyte abnormalities.  Instruct patients to|
04844|048|M|report any irregular heartbeat, dizziness, or fainting.|
04844|049|B||
04844|050|D|DISCUSSION:  Coadministration of ketoconazole (a strong CYP3A4 and P-gp|
04844|051|D|inhibitor) with lefamulin tablets increased lefamulin area-under-the-curve|
04844|052|D|(AUC) and maximum concentration (Cmax) by 165% and 58%.(1)|
04844|053|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
04844|054|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the AUC|
04844|055|D|and Cmax of midazolam by 200% and 100%, respectively.  No clinically|
04844|056|D|significant effect on midazolam pharmacokinetics was observed when|
04844|057|D|co-administered with lefamulin injection.(1)|
04844|058|D|   Concurrent administration with itraconazole (200 mg every 12 hours on Day|
04844|059|D|1, followed by 200 mg daily, a strong inhibitor of CYP3A4) with tezacaftor|
04844|060|D|(25 mg daily)-ivacaftor (50 mg daily) increased tezacaftor AUC and Cmax by|
04844|061|D|4-fold and 2.83-fold, respectively.(2)|
04844|062|D|   Concurrent administration with itraconazole (200 mg daily, a strong|
04844|063|D|inhibitor of CYP3A4) with single-dose elexacaftor 20 mg-tezacaftor 50|
04844|064|D|mg-deutivacaftor 50 mg increased tezacaftor AUC and Cmax by 4.51-fold and|
04844|065|D|1.48-fold and deutivacaftor AUC and Cmax by 11.1-fold and 1.96-fold.(2)|
04844|066|D|   Concurrent administration with itraconazole (200 mg daily, a strong|
04844|067|D|inhibitor of CYP3A4) with vanzacaftor (5 mg single dose) increased|
04844|068|D|vanzacaftor AUC and Cmax by 6.37-fold and 1.55-fold, respectively.(2)|
04844|069|D|   Concurrent administration with fluconazole (200 mg daily, a moderate|
04844|070|D|inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg|
04844|071|D|daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC|
04844|072|D|and Cmax by 2.55-fold and 2.48-fold and deutivacaftor by 3.13-fold and|
04844|073|D|2.27-fold, respectively.(2)|
04844|074|D|    Concurrent administration with erythromycin (500 mg four times daily, a|
04844|075|D|moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100|
04844|076|D|mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor|
04844|077|D|AUC and Cmax by 3.29-fold and 3.19-fold and deutivacaftor by 4.13-fold and|
04844|078|D|2.89-fold, respectively.(2)|
04844|079|D|   Concurrent administration with verapamil (80 mg three times daily, a|
04844|080|D|moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100|
04844|081|D|mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor|
04844|082|D|AUC and Cmax by 3.93-fold and 3.8-fold and deutivacaftor by 5.11-fold and|
04844|083|D|3.43-fold, respectively.(2)|
04844|084|B||
04844|085|R|REFERENCES:|
04844|086|B||
04844|087|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
04844|088|R|  Inc August 2019.|1
04844|089|R|2.Alyftrek (vanzacaftor, tezacaftor, and deutivacaftor) US prescribing|1
04844|090|R|  information. Vertex Pharmaceuticals Incorporated December, 2024.|1
04844|091|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04844|092|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04844|093|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04844|094|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04844|095|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04844|096|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04844|097|R|  settings: a scientific statement from the American Heart Association and|6
04844|098|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04844|099|R|  2;55(9):934-47.|6
04845|001|T|MONOGRAPH TITLE:  Vanzacaftor-Tezacaftor-Deutivacaftor/Strong CYP3A4|
04845|002|T|Inhibitors|
04845|003|B||
04845|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04845|005|L|take action as needed.|
04845|006|B||
04845|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 may inhibit the metabolism|
04845|008|A|of vanzacaftor-tezacaftor-deutivacaftor.  Vanzacaftor, tezacaftor, and|
04845|009|A|deutivacaftor are CYP3A4 substrates.(1)|
04845|010|B||
04845|011|E|CLINICAL EFFECTS:  Concurrent use of a strong CYP3A4 inhibitor may result in|
04845|012|E|elevated levels of and toxicity from vanzacaftor-tezacaftor-deutivacaftor,|
04845|013|E|such as hepatotoxicity.(1)|
04845|014|B||
04845|015|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
04845|016|P|hepatic impairment.(1)|
04845|017|B||
04845|018|M|PATIENT MANAGEMENT:  The US manufacturer of|
04845|019|M|vanzacaftor-tezacaftor-deutivacaftor states that concurrent use with strong|
04845|020|M|CYP3A4 inhibitors requires a dose adjustment.  If concurrent use is|
04845|021|M|warranted, the following dose adjustments are recommended:|
04845|022|M|   -For individuals 12 years and older AND any weight OR children 6 to less|
04845|023|M|than 12 years old AND weight greater than or equal to 40 kg - one tablet of|
04845|024|M|vanzacaftor 10mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week;|
04845|025|M|   -For children 6 to less than 12 years old AND weighing less than 40 kg -|
04845|026|M|two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once a|
04845|027|M|week.(1)|
04845|028|B||
04845|029|D|DISCUSSION:  Concurrent administration with itraconazole (200 mg every 12|
04845|030|D|hours on Day 1, followed by 200 mg daily, a strong inhibitor of CYP3A4) with|
04845|031|D|tezacaftor (25 mg daily)-ivacaftor (50 mg daily) increased tezacaftor|
04845|032|D|area-under-curve (AUC) and concentration maximum (Cmax) by 4-fold and|
04845|033|D|2.83-fold, respectively.(1)|
04845|034|D|   Concurrent administration with itraconazole (200 mg daily, a strong|
04845|035|D|inhibitor of CYP3A4) with single-dose elexacaftor 20 mg-tezacaftor 50|
04845|036|D|mg-deutivacaftor 50 mg increased tezacaftor AUC and Cmax by 4.51-fold and|
04845|037|D|1.48-fold and deutivacaftor AUC and Cmax by 11.1-fold and 1.96-fold.(1)|
04845|038|D|   Concurrent administration with itraconazole (200 mg daily, a strong|
04845|039|D|inhibitor of CYP3A4) with vanzacaftor (5 mg single dose) increased|
04845|040|D|vanzacaftor AUC and Cmax by 6.37-fold and 1.55-fold, respectively.(1)|
04845|041|D|   Concurrent administration with fluconazole (200 mg daily, a moderate|
04845|042|D|inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg|
04845|043|D|daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC|
04845|044|D|and Cmax by 2.55-fold and 2.48-fold and deutivacaftor by 3.13-fold and|
04845|045|D|2.27-fold, respectively.(1)|
04845|046|D|    Concurrent administration with erythromycin (500 mg four times daily, a|
04845|047|D|moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100|
04845|048|D|mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor|
04845|049|D|AUC and Cmax by 3.29-fold and 3.19-fold and deutivacaftor by 4.13-fold and|
04845|050|D|2.89-fold, respectively.(1)|
04845|051|D|   Concurrent administration with verapamil (80 mg three times daily, a|
04845|052|D|moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100|
04845|053|D|mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor|
04845|054|D|AUC and Cmax by 3.93-fold and 3.8-fold and deutivacaftor by 5.11-fold and|
04845|055|D|3.43-fold, respectively.(1)|
04845|056|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
04845|057|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
04845|058|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir,|
04845|059|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
04845|060|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
04845|061|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-4)|
04845|062|B||
04845|063|R|REFERENCES:|
04845|064|B||
04845|065|R|1.Alyftrek (vanzacaftor, tezacaftor, and deutivacaftor) US prescribing|1
04845|066|R|  information. Vertex Pharmaceuticals Incorporated December, 2024.|1
04845|067|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04845|068|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04845|069|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04845|070|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04845|071|R|  11/14/2017.|1
04845|072|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
04845|073|R|  Indiana University School of Medicine.  Available at:|1
04845|074|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
04845|075|R|4.This information is based on an extract from the Certara Drug Interaction|6
04845|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04846|001|T|MONOGRAPH TITLE:  Vanzacaftor-Tezacaftor-Deutivacaftor/Moderate CYP3A4|
04846|002|T|Inhibitors|
04846|003|B||
04846|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04846|005|L|take action as needed.|
04846|006|B||
04846|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
04846|008|A|metabolism of vanzacaftor-tezacaftor-deutivacaftor.  Vanzacaftor,|
04846|009|A|tezacaftor, and deutivacaftor are CYP3A substrates.(1)|
04846|010|B||
04846|011|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
04846|012|E|in elevated levels of and toxicity from|
04846|013|E|vanzacaftor-tezacaftor-deutivacaftor, such as hepatotoxicity.(1)|
04846|014|B||
04846|015|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
04846|016|P|hepatic impairment.(1)|
04846|017|B||
04846|018|M|PATIENT MANAGEMENT:  The US manufacturer of|
04846|019|M|vanzacaftor-tezacaftor-deutivacaftor states that concurrent use with|
04846|020|M|moderate CYP3A4 inhibitors requires a dose adjustment.  If concurrent use is|
04846|021|M|warranted, the following dose adjustments are recommended:|
04846|022|M|   -For age 6 to less than 12 years old AND less than 40 kg - Two tablets of|
04846|023|M|vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day;|
04846|024|M|   -For age 6 to less than 12 years old AND greater than or equal to 40 kg -|
04846|025|M|One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every|
04846|026|M|other day;|
04846|027|M|   -For age 12 years and older AND any weight - One tablet of vanzacaftor 10|
04846|028|M|mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.(1)|
04846|029|B||
04846|030|D|DISCUSSION:  Concurrent administration with itraconazole (200 mg every 12|
04846|031|D|hours on Day 1, followed by 200 mg daily, a strong inhibitor of CYP3A4) with|
04846|032|D|tezacaftor (25 mg daily)-ivacaftor (50 mg daily) increased tezacaftor|
04846|033|D|area-under-curve (AUC) and concentration maximum (Cmax) by 4-fold and|
04846|034|D|2.83-fold, respectively.(1)|
04846|035|D|   Concurrent administration with itraconazole (200 mg daily, a strong|
04846|036|D|inhibitor of CYP3A4) with single-dose elexacaftor 20 mg-tezacaftor 50|
04846|037|D|mg-deutivacaftor 50 mg increased tezacaftor AUC and Cmax by 4.51-fold and|
04846|038|D|1.48-fold and deutivacaftor AUC and Cmax by 11.1-fold and 1.96-fold.(1)|
04846|039|D|   Concurrent administration with itraconazole (200 mg daily, a strong|
04846|040|D|inhibitor of CYP3A4) with vanzacaftor (5 mg single dose) increased|
04846|041|D|vanzacaftor AUC and Cmax by 6.37-fold and 1.55-fold, respectively.(1)|
04846|042|D|   Concurrent administration with fluconazole (200 mg daily, a moderate|
04846|043|D|inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg|
04846|044|D|daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC|
04846|045|D|and Cmax by 2.55-fold and 2.48-fold and deutivacaftor by 3.13-fold and|
04846|046|D|2.27-fold, respectively.(1)|
04846|047|D|    Concurrent administration with erythromycin (500 mg four times daily, a|
04846|048|D|moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100|
04846|049|D|mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor|
04846|050|D|AUC and Cmax by 3.29-fold and 3.19-fold and deutivacaftor by 4.13-fold and|
04846|051|D|2.89-fold, respectively.(1)|
04846|052|D|   Concurrent administration with verapamil (80 mg three times daily, a|
04846|053|D|moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100|
04846|054|D|mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor|
04846|055|D|AUC and Cmax by 3.93-fold and 3.8-fold and deutivacaftor by 5.11-fold and|
04846|056|D|3.43-fold, respectively.(1)|
04846|057|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
04846|058|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
04846|059|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
04846|060|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
04846|061|D|isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
04846|062|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
04846|063|D|verapamil, and voxelotor.(2-4)|
04846|064|B||
04846|065|R|REFERENCES:|
04846|066|B||
04846|067|R|1.Alyftrek (vanzacaftor, tezacaftor, and deutivacaftor) US prescribing|1
04846|068|R|  information. Vertex Pharmaceuticals Incorporated December, 2024.|1
04846|069|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04846|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04846|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04846|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04846|073|R|  11/14/2017.|1
04846|074|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
04846|075|R|  Indiana University School of Medicine.  Available at:|1
04846|076|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
04846|077|R|4.This information is based on an extract from the Certara Drug Interaction|6
04846|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04847|001|T|MONOGRAPH TITLE:  Resmetirom/Letermovir|
04847|002|B||
04847|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04847|004|L|take action as needed.|
04847|005|B||
04847|006|A|MECHANISM OF ACTION:  Letermovir is a moderate CYP2C8 inhibitor and|
04847|007|A|substrate of OATP1B1 and 1B3.  Resmetirom is an inhibitor of OATP1B1 and a|
04847|008|A|substrate of CYP2C8.(1,2)|
04847|009|A|   Moderate inhibitors of CYP2C8 may inhibit the metabolism of|
04847|010|A|resmetirom.(1)|
04847|011|A|   OATP1B1 and 1B3 inhibitors may inhibit the metabolism of letermovir.(2)|
04847|012|B||
04847|013|E|CLINICAL EFFECTS:  Concomitant use of a moderate CYP2C8 inhibitor may|
04847|014|E|increase resmetirom plasma concentrations, which may increase the risk of|
04847|015|E|resmetirom toxicity, including hepatotoxicity.(1)|
04847|016|E|   Concurrent use of OATP1B1 and 1B3 inhibitors may result in elevated|
04847|017|E|levels of and side effects from letermovir, including diarrhea, nausea,|
04847|018|E|abdominal pain, and peripheral edema.(2)|
04847|019|B||
04847|020|P|PREDISPOSING FACTORS:  None determined.|
04847|021|B||
04847|022|M|PATIENT MANAGEMENT:  Concurrent use of letermovir with OATP1B1 and 1B3|
04847|023|M|inhibitors should be approached with caution. Monitor patients closely for|
04847|024|M|adverse reactions and consider dose modifications per prescribing|
04847|025|M|recommendations.(2)|
04847|026|M|   Concomitant use of resmetirom with moderate CYP2C8 inhibitors is not|
04847|027|M|recommended.  If concurrent use is warranted, reduce the dose of resmetirom|
04847|028|M|based on the patient's weight.|
04847|029|M|   -If <100 kg, reduce the dose of resmetirom to 60 mg once daily;|
04847|030|M|   -If >=100 kg, reduce the dose of resmetirom to 80 mg once daily.(1)|
04847|031|B||
04847|032|D|DISCUSSION:  Multiple doses of resmetirom 100 mg daily were given with|
04847|033|D|clopidogrel, a moderate CYP2C8 inhibitor, and the resmetirom|
04847|034|D|area-under-curve (AUC) and maximum concentration (Cmax) increased 1.7-fold|
04847|035|D|and 1.3-fold, respectively.(1)|
04847|036|D|   Letermovir is a substrate of OATP1B1 and 1B3. Co-administration of|
04847|037|D|letermovir with drugs that are inhibitors of OATP1B1 and 1B3 transporters|
04847|038|D|may result in increases in letermovir plasma concentrations.(2)|
04847|039|B||
04847|040|R|REFERENCES:|
04847|041|B||
04847|042|R|1.Rezdiffra (resmetirom) US prescribing information. Madrigal|1
04847|043|R|  Pharmaceuticals March, 2024.|1
04847|044|R|2.Prevymis (letermovir) US prescribing information. Merck & Co, Inc. August,|1
04847|045|R|  2024.|1
04847|046|R|3.This information is based on an extract from the Certara Drug Interaction|6
04847|047|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04848|001|T|MONOGRAPH TITLE:  Baricitinib/Immunosuppressive OAT3 Inhibitors|
04848|002|B||
04848|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04848|004|L|of severe adverse interaction.|
04848|005|B||
04848|006|A|MECHANISM OF ACTION:  Concurrent use of baricitinib with other potent|
04848|007|A|immunosuppressants may result in additive or synergistic effects on the|
04848|008|A|immune system.(1,2)|
04848|009|A|   Inhibitors of organic anion transporter 3 (OAT3) such as leflunomide and|
04848|010|A|teriflunomide(3) may inhibit the renal elimination of baricitinib.(1,2)|
04848|011|B||
04848|012|E|CLINICAL EFFECTS:  Concurrent use of organic anion transporter 3 (OAT3)|
04848|013|E|inhibitors may result in an increase in both the therapeutic and toxic|
04848|014|E|effects of baricitinib and may increase the risk of serious infections.(1,2)|
04848|015|B||
04848|016|P|PREDISPOSING FACTORS:  None determined.|
04848|017|B||
04848|018|M|PATIENT MANAGEMENT:  The US manufacturer of baricitinib states that|
04848|019|M|concurrent use of baricitinib with biologic DMARDs or potent|
04848|020|M|immunosuppressants is not recommended.(1)  If concurrent therapy with a|
04848|021|M|strong organic anion transporter 3 (OAT3) inhibitor is warranted, and the|
04848|022|M|recommended dosage is 4 mg once daily, reduce to 2 mg once daily.  If the|
04848|023|M|recommended dosage is 2 mg once daily, reduce dose to 1 mg once daily.  If|
04848|024|M|the recommended dosage is 1 mg once daily, consider discontinuing|
04848|025|M|probenecid.(2)|
04848|026|M|   OAT3 inhibitors with less inhibitor potency are not expected to cause a|
04848|027|M|clinically significant change in baricitinib levels.(1,2)|
04848|028|B||
04848|029|D|DISCUSSION:  In a clinical pharmacology study, dosing of probenecid (an OAT3|
04848|030|D|inhibitor with strong inhibition potential) resulted in approximately a|
04848|031|D|2-fold increase in area-under-curve (AUC) with no change in time maximum|
04848|032|D|(Tmax) or concentration maximum (Cmax) of baricitinib.(1,2)|
04848|033|D|   Most patients who developed serious infections while being treated with|
04848|034|D|baricitinib were on concomitant immunosuppressants like methotrexate and|
04848|035|D|corticosteroids.  The combination of baricitinib with other biologic DMARDs|
04848|036|D|has not been studied.(1)|
04848|037|B||
04848|038|R|REFERENCES:|
04848|039|B||
04848|040|R|1.Olumiant (baricitinib) UK summary of product characteristics. Eli Lilly|1
04848|041|R|  and Company August 26, 2019.|1
04848|042|R|2.Olumiant (baricitinib) US prescribing information. Eli Lilly and Company|1
04848|043|R|  June, 2022.|1
04848|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
04848|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04849|001|T|MONOGRAPH TITLE:  ACE Inhibitors/Dipeptidyl Peptidase-IV Inhibitors|
04849|002|B||
04849|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04849|004|L|take action as needed.|
04849|005|B||
04849|006|A|MECHANISM OF ACTION:  Bradykinin can cause vasodilation and increase|
04849|007|A|vascular permeability both directly and by stimulating release of substance|
04849|008|A|P, which also increases vascular permeability.(1)  Bradykinin is primarily|
04849|009|A|metabolized by angiotensin-1 converting enzyme (ACE).  If ACE is inhibited|
04849|010|A|by ACE inhibitors, other metabolic enzymes become more significant in|
04849|011|A|bradykinin metabolism, including dipeptidyl peptidase-IV (DPP-IV).  DPP-IV|
04849|012|A|inhibitors can inhibit both bradykinin and substance P metabolism.(2)|
04849|013|B||
04849|014|E|CLINICAL EFFECTS:  Concomitant therapy can increase the risk of vasodilation|
04849|015|E|leading to an increase in angioedema risk.(1-3)|
04849|016|B||
04849|017|P|PREDISPOSING FACTORS:  History of previous angioedema.|
04849|018|B||
04849|019|M|PATIENT MANAGEMENT:  Patients may be more susceptible to developing|
04849|020|M|angioedema if concomitantly taking an ACE inhibitor and DPP-IV inhibitor.|
04849|021|M|Consider switching the patient to an angiotensin receptor blocker or a|
04849|022|M|different anti-diabetic medication.|
04849|023|M|   Use caution in patients receiving concurrent therapy.(3)  Monitor closely|
04849|024|M|for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or|
04849|025|M|swollen throat, or trouble breathing).  Instruct patients to report|
04849|026|M|angioedema symptoms immediately.|
04849|027|B||
04849|028|D|DISCUSSION:  A pre-marketing surveillance compared incidence of angioedema|
04849|029|D|in patients on vildagliptin versus a comparator.  In all patients combined|
04849|030|D|regardless of ACE inhibitor therapy, there was no association between|
04849|031|D|vildagliptin and angioedema.  However among patients taking an ACE|
04849|032|D|inhibitor, vildagliptin was associated with an increased risk of angioedema|
04849|033|D|(odds ratio 9.29 (95% CI 1.22-70.70) from pooled data; odds ratio of 4.57|
04849|034|D|(95% CI 1.57-13.28) in the meta-analysis).  This interaction may be|
04849|035|D|dose-related.(4)|
04849|036|D|   In a pooled analysis of data from 19 clinical trials of patients on|
04849|037|D|sitagliptin versus a comparator, there was no difference in the incidence of|
04849|038|D|angioedema between patients on ACE inhibitors and sitagliptin compared to|
04849|039|D|patients on ACE inhibitors alone or patients not on ACE inhibitors.(5)|
04849|040|D|However, events were not adjudicated and encompassed urticaria, anaphylaxis,|
04849|041|D|and hypersensitivity reactions, which may have confounded the results.(6)|
04849|042|D|   A disproportionality analysis of the WHO pharmacovigilance database found|
04849|043|D|340,686 reports of bradykinin-mediated angioedema.  Of those, 345 reports|
04849|044|D|involved patients on concomitant ACE inhibitor and DPP-IV inhibitor, with a|
04849|045|D|reporting odds ratio of 42.77 (95% CI 36.93-49.53).  There was no|
04849|046|D|association between use of a DPP-IV inhibitor without an ACE inhibitor and|
04849|047|D|angioedema.(7)|
04849|048|B||
04849|049|R|REFERENCES:|
04849|050|B||
04849|051|R|1.Byrd JB, Woodard-Grice A, Stone E, Lucisano A, Schaefer H, Yu C, Eyler AE,|2
04849|052|R|  Salloum NE, Brown NJ. Association of angiotensin-converting enzyme|2
04849|053|R|  inhibitor-associated angioedema with  transplant and immunosuppressant|2
04849|054|R|  use. Allergy 2010 Nov;65(11):1381-7.|2
04849|055|R|2.Smolinska S, Antolin-Amerigo D, Popescu FD. Bradykinin Metabolism and|6
04849|056|R|  Drug-Induced Angioedema. Int J Mol Sci 2023 Jul 19;24(14):.|6
04849|057|R|3.Teva-Lisinopril Canadian Product Monograph. Teva Canada Limited August,|1
04849|058|R|  2024.|1
04849|059|R|4.Brown NJ, Byiers S, Carr D, Maldonado M, Warner BA. Dipeptidyl|2
04849|060|R|  peptidase-IV inhibitor use associated with increased risk of ACE|2
04849|061|R|  inhibitor-associated angioedema. Hypertension 2009 Sep;54(3):516-23.|2
04849|062|R|5.Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, Musser|2
04849|063|R|  BJ, Davies MJ, Kaufman KD, Goldstein BJ. Safety and tolerability of|2
04849|064|R|  sitagliptin in clinical studies: a pooled analysis of  data from 10,246|2
04849|065|R|  patients with type 2 diabetes. BMC Endocr Disord 2010 Apr 22;10:7.|2
04849|066|R|6.Cassano N, Nettis E, Di Leo E, Ambrogio F, Vena GA, Foti C. Angioedema|6
04849|067|R|  associated with dipeptidyl peptidase-IV inhibitors. Clin Mol Allergy 2021|6
04849|068|R|  Dec 6;19(1):24.|6
04849|069|R|7.Lepelley M, Khouri C, Lacroix C, Bouillet L. Angiotensin-converting enzyme|2
04849|070|R|  and dipeptidyl peptidase-4 inhibitor-induced  angioedema: A|2
04849|071|R|  disproportionality analysis of the WHO pharmacovigilance database. J|2
04849|072|R|  Allergy Clin Immunol Pract 2020 Jul-Aug;8(7):2406-2408.e1.|2
04850|001|T|MONOGRAPH TITLE:  Apixaban/Strong and Moderate CYP3A4 Inhibitors|
04850|002|B||
04850|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04850|004|L|take action as needed.|
04850|005|B||
04850|006|A|MECHANISM OF ACTION:  Apixaban is a substrate of CYP3A4 and P-glycoprotein|
04850|007|A|(P-gp).  It is about 20% metabolized, mainly by CYP3A4.(1-4)  Strong and|
04850|008|A|moderate CYP3A4 inhibitors may inhibit the metabolism of apixaban by CYP3A4.|
04850|009|B||
04850|010|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inhibitor may result in|
04850|011|E|elevated levels of and clinical effects of apixaban, including an increased|
04850|012|E|risk of bleeding, especially in the setting of concurrent therapy with an|
04850|013|E|agent that inhibits P-gp.(1-4)|
04850|014|B||
04850|015|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04850|016|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04850|017|P|   Drug-associated risk factors include concurrent use of P-gp inhibitors|
04850|018|P|and concurrent use of multiple drugs which inhibit|
04850|019|P|anticoagulant/antiplatelet metabolism or have an inherent risk for bleeding|
04850|020|P|(e.g. NSAIDs).|
04850|021|B||
04850|022|M|PATIENT MANAGEMENT:  The US manufacturer of apixaban provides|
04850|023|M|recommendations regarding concurrent use with strong inhibitors of both|
04850|024|M|CYP3A4 and P-gp, but does not provide guidance for concurrent use with|
04850|025|M|agents that inhibit CYP3A4 alone.(1)  The Australian, Canadian, and UK|
04850|026|M|labels for apixaban state that no dose adjustment for apixaban is required|
04850|027|M|when co-administered with agents that are not strong inhibitors of both|
04850|028|M|CYP3A4 and P-gp.(2-4)|
04850|029|M|   Expert opinion on the clinical significance of this interaction is varied|
04850|030|M|and depends on the inhibitor.  Some experts state that specific agents|
04850|031|M|(i.e., voriconazole, imatinib, and crizotinib) should be contraindicated.(5)|
04850|032|M|Others state that concurrent use is acceptable if there are no other|
04850|033|M|pharmacokinetic interactions; otherwise, a 50% dose reduction of apixaban is|
04850|034|M|suggested.(6)|
04850|035|M|   In patients who are also on concurrent P-gp inhibitors, consider the|
04850|036|M|manufacturer recommendations for use with dual CYP3A4 and P-gp inhibitors.|
04850|037|M|The US manufacturer of apixaban states that if concurrent use of strong|
04850|038|M|CYP3A4 and P-gp inhibitors cannot be avoided, the dosage of apixaban should|
04850|039|M|be reduced by 50%.  In patients already receiving apixaban 2.5 mg twice|
04850|040|M|daily, avoid the concurrent use of strong inhibitors of both P-gp and|
04850|041|M|CYP3A4.(1)  The Australian(2) and Canadian(3) manufacturers of apixaban|
04850|042|M|states that the concurrent use of agents that are strong inhibitors of both|
04850|043|M|P-gp and CYP3A4 with apixaban is contraindicated.  The UK manufacturer of|
04850|044|M|apixaban states that concurrent use of these agents is not recommended.(4)|
04850|045|M|Concurrent use of agents that are dual P-gp and moderate CYP3A4 inhibitors|
04850|046|M|are expected to increase apixaban levels to a lesser extent than agents that|
04850|047|M|are P-gp and strong CYP3A4 inhibitors.  No dose adjustment of apixaban is|
04850|048|M|necessary.  Use caution when administering apixaban with moderate inhibitors|
04850|049|M|of CYP3A4.|
04850|050|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04850|051|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04850|052|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04850|053|M|patients with any symptoms.|
04850|054|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04850|055|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04850|056|M|anticoagulation in patients with active pathologic bleeding.|
04850|057|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04850|058|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04850|059|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04850|060|M|and/or swelling.|
04850|061|B||
04850|062|D|DISCUSSION:  The US manufacturer of apixaban states that apixaban dose|
04850|063|D|reduction is recommended when apixaban exposure increases by more than 50%,|
04850|064|D|while efficacy is maintained when exposure is 25% lower.  Therefore, no dose|
04850|065|D|adjustment of apixaban is recommended for drug interactions that affect|
04850|066|D|apixaban exposure by 75% to 150%.(7)|
04850|067|D|   In a microdose cocktail study using apixaban 25 mcg, voriconazole 400 mg|
04850|068|D|every 12 hours for 2 doses then 200 mg every 12 hours (strong CYP3A4|
04850|069|D|inhibitor) had "only a minor interaction," increasing the AUC of apixaban by|
04850|070|D|1.33-fold (95% CI 1.01-1.75) while the Cmax and half-life remained|
04850|071|D|unchanged.(8)|
04850|072|D|   Another microdose cocktail study with apixaban 25 mcg and voriconazole|
04850|073|D|400 mg twice daily found that apixaban AUC increased by 1.24-fold with a|
04850|074|D|non-significant change in Cmax.(9)|
04850|075|D|   A retrospective cohort study of 50 oncology patients on apixaban|
04850|076|D|identified 14 patients on concurrent voriconazole, with 3 of those patients|
04850|077|D|receiving reduced-dose apixaban.  No bleeding or thrombosis occurred in any|
04850|078|D|of the patients on concurrent voriconazole.(10)|
04850|079|D|   An article evaluating the clinical significance of efflux transporters|
04850|080|D|like P-gp and BCRP in apixaban exposure analyzed pharmacokinetic data from|
04850|081|D|drug-drug interaction studies and concluded that all apixaban interactions|
04850|082|D|can be explained by inhibition of intestinal CYP3A4.  The authors explain|
04850|083|D|that apixaban is a highly permeable and soluble compound, so its ability to|
04850|084|D|undergo passive diffusion renders the role of membrane transporters|
04850|085|D|irrelevant, as evidenced by a lack of change in apixaban absorption rate in|
04850|086|D|the presence of drugs known to inhibit P-gp and BCRP.(11)|
04850|087|D|   A review article on DOAC drug-drug interactions suggests that the|
04850|088|D|combination of voriconazole, crizotinib or imatinib with apixaban or|
04850|089|D|rivaroxaban is contraindicated due to the potential for significant|
04850|090|D|increases in DOAC AUC.  The authors state that data with voriconazole is|
04850|091|D|missing and thus the interactions are unpredictable.(5)|
04850|092|D|   Another review article states that apixaban may be used with voriconazole|
04850|093|D|if no other pharmacokinetic inhibitor is present; otherwise, concurrent use|
04850|094|D|requires a 50% apixaban dose reduction.  No dose adjustment is recommended|
04850|095|D|with moderate CYP3A4 inhibitors.(6)|
04850|096|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
04850|097|D|ceritinib, idelalisib, mibefradil, nefazodone, ribociclib, troleandomycin,|
04850|098|D|and voriconazole.(12,13)|
04850|099|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  aprepitant,|
04850|100|D|avacopan, berotralstat, clofazimine, crizotinib, duvelisib, fedratinib,|
04850|101|D|fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir,|
04850|102|D|netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol,|
04850|103|D|tofisopam, treosulfan, and voxelotor.(12,13)|
04850|104|B||
04850|105|R|REFERENCES:|
04850|106|B||
04850|107|R|1.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04850|108|R|  Company April, 2025.|1
04850|109|R|2.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04850|110|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04850|111|R|3.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04850|112|R|  Squibb-Pfizer January, 2025.|1
04850|113|R|4.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04850|114|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04850|115|R|5.Ferri N, Colombo E, Tenconi M, Baldessin L, Corsini A. Drug-Drug|6
04850|116|R|  Interactions of Direct Oral Anticoagulants (DOACs): From  Pharmacological|6
04850|117|R|  to Clinical Practice. Pharmaceutics 2022 May 24;14(6):.|6
04850|118|R|6.Mar PL, Gopinathannair R, Gengler BE, Chung MK, Perez A, Dukes J,|6
04850|119|R|  Ezekowitz MD, Lakkireddy D, Lip GYH, Miletello M, Noseworthy PA, Reiffel|6
04850|120|R|  J, Tisdale JE, Olshansky B. Drug Interactions Affecting Oral Anticoagulant|6
04850|121|R|  Use. Circ Arrhythm Electrophysiol 2022 Jun;15(6):e007956.|6
04850|122|R|7.US Food and Drug Administration (FDA). Drug Approval Pacakge Eliquis|1
04850|123|R|  (apixaban) Application No.: 202155Orig1s000. Accessed at:|1
04850|124|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000Cli|1
04850|125|R|  nPharmR.pdf December, 2012.|1
04850|126|R|8.Mikus G, Foerster KI, Schaumaeker M, Lehmann ML, Burhenne J, Haefeli WE.|2
04850|127|R|  Application of a microdosed cocktail of 3 oral factor Xa inhibitors to|2
04850|128|R|  study  drug-drug interactions with different perpetrator drugs. Br J Clin|2
04850|129|R|  Pharmacol 2020 Aug;86(8):1632-1641.|2
04850|130|R|9.Rohr BS, Foerster KI, Blank A, Burhenne J, Mahmoudi M, Haefeli WE, Mikus|2
04850|131|R|  G. Perpetrator Characteristics of Azole Antifungal Drugs on Three Oral|2
04850|132|R|  Factor Xa  Inhibitors Administered as a Microdosed Cocktail. Clin|2
04850|133|R|  Pharmacokinet 2022 Jan;61(1):97-109.|2
04850|134|R|10.Bruner SA, DiPippo AJ, Rausch CR. Dose-adjusted direct oral|2
04850|135|R|   anticoagulants (DOACs) in patients with acute leukemia:  experience of a|2
04850|136|R|   tertiary cancer care center. Leuk Lymphoma 2025 Feb;66(2):352-354.|2
04850|137|R|11.Sodhi JK, Liu S, Benet LZ. Intestinal Efflux Transporters P-gp and BCRP|2
04850|138|R|   Are Not Clinically Relevant in  Apixaban Disposition. Pharm Res 2020 Sep|2
04850|139|R|   29;37(10):208.|2
04850|140|R|12.This information is based on an extract from the Certara Drug Interaction|6
04850|141|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04850|142|R|13.US Food and Drug Administration (FDA). Drug Development and Drug|1
04850|143|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
04850|144|R|   at:|1
04850|145|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
04850|146|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04850|147|R|   11/14/2017.|1
04851|001|T|MONOGRAPH TITLE:  Bictegravir/Efavirenz; Etravirine|
04851|002|B||
04851|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04851|004|L|of severe adverse interaction.|
04851|005|B||
04851|006|A|MECHANISM OF ACTION:  Efavirenz and etravirine may induce the metabolism of|
04851|007|A|bictegravir via CYP3A4 and UGT1A1.(1-3)|
04851|008|A|   Efavirenz and etravirine are moderate CYP3A4 and UGT1A1 inducers.(2)|
04851|009|B||
04851|010|E|CLINICAL EFFECTS:  The concurrent use of bictegravir and efavirenz or|
04851|011|E|etravirine may lead to decreased levels of bictegravir, which may result in|
04851|012|E|the loss of therapeutic effect and development of resistance to|
04851|013|E|bictegravir.(1-4)|
04851|014|B||
04851|015|P|PREDISPOSING FACTORS:  None determined.|
04851|016|B||
04851|017|M|PATIENT MANAGEMENT:  The HIV guidelines state that bictegravir and efavirenz|
04851|018|M|or etravirine should not be coadministered.(3)|
04851|019|B||
04851|020|D|DISCUSSION:  In a single dose study, rifampin (a strong CYP3A4 and UGT1A1|
04851|021|D|inducer) decreased the maximum concentration (Cmax) and area-under-curve|
04851|022|D|(AUC) levels of bictegravir by 28% and 75%, respectively.(1)|
04851|023|B||
04851|024|R|REFERENCES:|
04851|025|B||
04851|026|R|1.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
04851|027|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
04851|028|R|2.This information is based on an extract from the Certara Drug Interaction|6
04851|029|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04851|030|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04851|031|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04851|032|R|  HIV. Department of Health and Human Services. Available at:|6
04851|033|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
04851|034|R|  nd-adolescent-arv/whats-new?view=full September 12, 2024.|6
04852|001|T|MONOGRAPH TITLE:  Bictegravir/Atazanavir|
04852|002|B||
04852|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04852|004|L|of severe adverse interaction.|
04852|005|B||
04852|006|A|MECHANISM OF ACTION:  Atazanavir may inhibit the metabolism of bictegravir|
04852|007|A|via CYP3A4 and UGT1A1.(1,2)|
04852|008|B||
04852|009|E|CLINICAL EFFECTS:  The concurrent use of bictegravir and atazanavir may lead|
04852|010|E|to increased levels of bictegravir.(1)|
04852|011|B||
04852|012|P|PREDISPOSING FACTORS:  None determined.|
04852|013|B||
04852|014|M|PATIENT MANAGEMENT:  The HIV guidelines state that bictegravir and|
04852|015|M|atazanavir should not be coadministered.(3)|
04852|016|B||
04852|017|D|DISCUSSION:  In a pharmacokinetic study, atazanavir (400 mg daily for 8|
04852|018|D|days) increased the area-under-curve (AUC) of bictegravir by 4.15-fold.(1)|
04852|019|D|   In a pharmacokinetic study, atazanavir/cobicistat increased the AUC of|
04852|020|D|bictegravir by 306%.(3)|
04852|021|B||
04852|022|R|REFERENCES:|
04852|023|B||
04852|024|R|1.Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) US|1
04852|025|R|  prescribing information. Gilead Sciences, Inc. October, 2024.|1
04852|026|R|2.This information is based on an extract from the Certara Drug Interaction|6
04852|027|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04852|028|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04852|029|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04852|030|R|  HIV. Department of Health and Human Services. Available at:|6
04852|031|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
04852|032|R|  nd-adolescent-arv/whats-new?view=full September 12, 2024.|6
04853|001|T|MONOGRAPH TITLE:  Rivaroxaban/Strong and Moderate CYP3A4 Inhibitors|
04853|002|B||
04853|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04853|004|L|take action as needed.|
04853|005|B||
04853|006|A|MECHANISM OF ACTION:  Rivaroxaban is a substrate of CYP3A4 and|
04853|007|A|P-glycoprotein (P-gp).  It is about 18% metabolized, mainly by CYP3A4.(1-4)|
04853|008|A|Strong and moderate CYP3A4 inhibitors may inhibit the metabolism of|
04853|009|A|rivaroxaban by CYP3A4.|
04853|010|B||
04853|011|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inhibitor may result in|
04853|012|E|elevated levels of and clinical effects of rivaroxaban, including an|
04853|013|E|increased risk of bleeding, especially in the setting of concurrent therapy|
04853|014|E|with an agent that inhibits P-gp.(1-4)|
04853|015|B||
04853|016|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04853|017|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04853|018|P|   Patients with renal impairment may be at higher risk of elevated|
04853|019|P|rivaroxaban levels.|
04853|020|P|   Drug-associated risk factors include concurrent use of P-gp inhibitors|
04853|021|P|and concurrent use of multiple drugs which inhibit|
04853|022|P|anticoagulant/antiplatelet metabolism or have an inherent risk for bleeding|
04853|023|P|(e.g. NSAIDs).|
04853|024|B||
04853|025|M|PATIENT MANAGEMENT:  The US manufacturer of rivaroxaban provides|
04853|026|M|recommendations regarding concurrent use with strong and moderate inhibitors|
04853|027|M|of both CYP3A4 and P-gp, but does not provide guidance for concurrent use|
04853|028|M|with agents that inhibit CYP3A4 alone.(1)  The Canadian manufacturer of|
04853|029|M|rivaroxaban states that increases in rivaroxaban levels by drugs inhibiting|
04853|030|M|only CYP3A4 are expected to be less clinically relevant compared to drugs|
04853|031|M|inhibiting both CYP3A4 and P-gp.(2)  The UK manufacturer of rivaroxaban|
04853|032|M|states that drug interactions with agents that inhibit only CYP3A4 are|
04853|033|M|likely not clinically relevant in most patients but may be significant in|
04853|034|M|high-risk patients (e.g., renal impairment).(3)  The Australian manufacturer|
04853|035|M|of rivaroxaban states that drug interactions with drugs that inhibit only|
04853|036|M|CYP3A4 are not clinically relevant.(4)|
04853|037|M|   Expert opinion on the clinical significance of this interaction is varied|
04853|038|M|and depends on the inhibitor.  Some experts state that specific agents|
04853|039|M|(i.e., voriconazole, imatinib, and crizotinib) should be contraindicated.(5)|
04853|040|M|Others state that concurrent use is acceptable if there are no other|
04853|041|M|pharmacokinetic interactions; otherwise, the combination should be|
04853|042|M|avoided.(6)|
04853|043|M|   In patients who are also on concurrent P-gp inhibitors, consider the|
04853|044|M|manufacturer recommendations for use with dual CYP3A4 and P-gp inhibitors.|
04853|045|M|The Australian and Canadian manufacturers of rivaroxaban state that the|
04853|046|M|concurrent use of agents that are both an inhibitor of P-gp and a strong|
04853|047|M|inhibitor of CYP3A4 with rivaroxaban is contraindicated.(2,4)  The US|
04853|048|M|manufacturer states that concurrent use of strong CYP3A4 and P-gp inhibitors|
04853|049|M|should be avoided(1) while the UK manufacturer states that concurrent use is|
04853|050|M|not recommended.(3)  Agents that are not strong inhibitors of both CYP3A4|
04853|051|M|and P-gp, including fluconazole, are expected to increase rivaroxaban levels|
04853|052|M|to a lesser extent and can be used with rivaroxaban with caution in patients|
04853|053|M|with normal renal function; however, in patients with decreased renal|
04853|054|M|function (CrCL of 15 ml/min to 80 ml/min) these agents should only be used|
04853|055|M|if the benefits of concurrent therapy outweigh the increased risk of|
04853|056|M|bleeding.(1-4)|
04853|057|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04853|058|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04853|059|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04853|060|M|patients with any symptoms.|
04853|061|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04853|062|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04853|063|M|anticoagulation in patients with active pathologic bleeding.|
04853|064|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04853|065|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04853|066|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04853|067|M|and/or swelling.|
04853|068|B||
04853|069|D|DISCUSSION:  In a microdose cocktail study using rivaroxaban 25 mcg,|
04853|070|D|voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours|
04853|071|D|(strong CYP3A4 inhibitor) had "only a minor interaction," increasing the AUC|
04853|072|D|of rivaroxaban by 1.33-fold (p<0.05) while the Cmax and half-life remained|
04853|073|D|unchanged.(7)|
04853|074|D|   Another microdose cocktail study with rivaroxaban 25 mcg and voriconazole|
04853|075|D|400 mg twice daily found that rivaroxaban AUC increased by 1.16-fold with a|
04853|076|D|non-significant change in Cmax.(8)|
04853|077|D|   A review article on DOAC drug-drug interactions suggests that the|
04853|078|D|combination of voriconazole, crizotinib or imatinib with apixaban or|
04853|079|D|rivaroxaban is contraindicated due to the potential for significant|
04853|080|D|increases in DOAC AUC.  The authors state that data with voriconazole is|
04853|081|D|missing and thus the interactions are unpredictable.(5)|
04853|082|D|   Another review article states that rivaroxaban may be used with|
04853|083|D|voriconazole if no other pharmacokinetic inhibitor is present; otherwise,|
04853|084|D|concurrent use should be avoided.  No dose adjustment is recommended with|
04853|085|D|moderate CYP3A4 inhibitors.(6)|
04853|086|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
04853|087|D|ceritinib, idelalisib, mibefradil, nefazodone, ribociclib, troleandomycin,|
04853|088|D|and voriconazole.(9,10)|
04853|089|D|   Moderate CYP3A4 inhibitors linked to this monograph include:  aprepitant,|
04853|090|D|avacopan, berotralstat, clofazimine, crizotinib, duvelisib, fedratinib,|
04853|091|D|fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir,|
04853|092|D|netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam,|
04853|093|D|treosulfan, and voxelotor.(9,10)|
04853|094|B||
04853|095|R|REFERENCES:|
04853|096|B||
04853|097|R|1.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
04853|098|R|  Inc. March, 2020.|1
04853|099|R|2.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
04853|100|R|  2015.|1
04853|101|R|3.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
04853|102|R|  August, 2021.|1
04853|103|R|4.Xarelto (rivaroxaban) Australian prescribing information. BAYER AUSTRALIA|1
04853|104|R|  LTD December, 2022.|1
04853|105|R|5.Ferri N, Colombo E, Tenconi M, Baldessin L, Corsini A. Drug-Drug|6
04853|106|R|  Interactions of Direct Oral Anticoagulants (DOACs): From  Pharmacological|6
04853|107|R|  to Clinical Practice. Pharmaceutics 2022 May 24;14(6):.|6
04853|108|R|6.Mar PL, Gopinathannair R, Gengler BE, Chung MK, Perez A, Dukes J,|6
04853|109|R|  Ezekowitz MD, Lakkireddy D, Lip GYH, Miletello M, Noseworthy PA, Reiffel|6
04853|110|R|  J, Tisdale JE, Olshansky B. Drug Interactions Affecting Oral Anticoagulant|6
04853|111|R|  Use. Circ Arrhythm Electrophysiol 2022 Jun;15(6):e007956.|6
04853|112|R|7.Mikus G, Foerster KI, Schaumaeker M, Lehmann ML, Burhenne J, Haefeli WE.|2
04853|113|R|  Application of a microdosed cocktail of 3 oral factor Xa inhibitors to|2
04853|114|R|  study  drug-drug interactions with different perpetrator drugs. Br J Clin|2
04853|115|R|  Pharmacol 2020 Aug;86(8):1632-1641.|2
04853|116|R|8.Rohr BS, Foerster KI, Blank A, Burhenne J, Mahmoudi M, Haefeli WE, Mikus|2
04853|117|R|  G. Perpetrator Characteristics of Azole Antifungal Drugs on Three Oral|2
04853|118|R|  Factor Xa  Inhibitors Administered as a Microdosed Cocktail. Clin|2
04853|119|R|  Pharmacokinet 2022 Jan;61(1):97-109.|2
04853|120|R|9.This information is based on an extract from the Certara Drug Interaction|6
04853|121|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04853|122|R|10.US Food and Drug Administration (FDA). Drug Development and Drug|1
04853|123|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
04853|124|R|   at:|1
04853|125|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
04853|126|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04853|127|R|   11/14/2017.|1
04854|001|T|MONOGRAPH TITLE:  Propranolol/Selected CYP2D6 Inhibitors|
04854|002|B||
04854|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04854|004|L|take action as needed.|
04854|005|B||
04854|006|A|MECHANISM OF ACTION:  CYP2D6 inhibitors may inhibit the metabolism of|
04854|007|A|propranolol.(1)|
04854|008|B||
04854|009|E|CLINICAL EFFECTS:  Concurrent use of CYP2D6 inhibitors may result in|
04854|010|E|elevated levels of and toxicity from propranolol, including hypotension and|
04854|011|E|bradycardia.(1)|
04854|012|B||
04854|013|P|PREDISPOSING FACTORS:  None determined.|
04854|014|B||
04854|015|M|PATIENT MANAGEMENT:  Monitor patients receiving concurrent therapy with|
04854|016|M|propranolol and CYP2D6 inhibitors.  The dosage of propranolol may need to be|
04854|017|M|adjusted.(1)|
04854|018|B||
04854|019|D|DISCUSSION:  In a pharmacokinetic study in 16 healthy volunteers, concurrent|
04854|020|D|use of quinidine 200 mg (a CYP2D6 inhibitor) increased the area-under-curve|
04854|021|D|(AUC) of propranolol by 2.29-fold.(2)|
04854|022|D|   In a pharmacokinetic study in 6 healthy subjects, concurrent use of|
04854|023|D|quinidine increased propranolol AUC 2-fold.(3)|
04854|024|D|   A retrospective review of concurrent use of propranolol and|
04854|025|D|antidepressants evaluated the risk of hospitalization or emergency room|
04854|026|D|visit within 30 days of concurrent prescription.  In patients receiving|
04854|027|D|antidepressants with moderate to strong CYP2D6 inhibitory effects, patient|
04854|028|D|were an increased risk compared to patients receiving no antidepressants|
04854|029|D|(Hazard Ratio (HR) = 1.53; 95% CI 1.03-2.81 vs. HR = 1.24; 95% CI|
04854|030|D|0.82-1.88).(4)|
04854|031|D|   Case reports of bradycardia and cardiac adverse effects have been|
04854|032|D|reported with concurrent use of propranolol and the antidepressants|
04854|033|D|fluoxetine and paroxetine (strong CYP2D6 inhibitors).(5)|
04854|034|D|   Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine,|
04854|035|D|mavorixafor, and paroxetine.|
04854|036|D|   Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir,|
04854|037|D|berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat,|
04854|038|D|escitalopram, lorcaserin, mirabegron, moclobemide, quinine, ranolazine, and|
04854|039|D|rolapitant.|
04854|040|D|   Weak CYP2D6 inhibitors include: celecoxib, desvenlafaxine,|
04854|041|D|diphenhydramine, dimenhydrinate, dronabinol, fedratinib, hydroxychloroquine,|
04854|042|D|imatinib, osilodrostat, ranitidine, and sertraline.(6)|
04854|043|B||
04854|044|R|REFERENCES:|
04854|045|B||
04854|046|R|1.Inderal LA (propranolol) US prescribing information. ANI Pharmaceuticals,|1
04854|047|R|  Inc. August, 2024.|1
04854|048|R|2.Yasuhara M, Yatsuzuka A, Yamada K, Okumura K, Hori R, Sakurai T, Kawai C.|2
04854|049|R|  Alteration of propranolol pharmacokinetics and pharmacodynamics by|2
04854|050|R|  quinidine in  man. J Pharmacobiodyn 1990 Nov;13(11):681-7.|2
04854|051|R|3.Zhou HH, Anthony LB, Roden DM, Wood AJ. Quinidine reduces clearance of|2
04854|052|R|  (+)-propranolol more than (-)-propranolol through  marked reduction in|2
04854|053|R|  4-hydroxylation. Clin Pharmacol Ther 1990 Jun;47(6):686-93.|2
04854|054|R|4.Shin J, Hills NK, Finley PR. Combining Antidepressants with Beta-Blockers:|2
04854|055|R|  Evidence of a Clinically Significant  CYP2D6 Drug Interaction.|2
04854|056|R|  Pharmacotherapy 2020 Jun;40(6):507-516.|2
04854|057|R|5.Woron J, Siwek M, Gorostowicz A. Adverse effects of interactions between|6
04854|058|R|  antidepressants and medications used in  treatment of cardiovascular|6
04854|059|R|  disorders. Psychiatr Pol 2019 Oct 30;53(5):977-995.|6
04854|060|R|6.This information is based on an extract from the Certara Drug Interaction|6
04854|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04855|001|T|MONOGRAPH TITLE:  Dipyrone/Selected Myelosuppressive Agents|
04855|002|B||
04855|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04855|004|L|of severe adverse interaction.|
04855|005|B||
04855|006|A|MECHANISM OF ACTION:  Concurrent use of dipyrone with other drugs known to|
04855|007|A|be associated with neutropenia or agranulocytosis may increase the frequency|
04855|008|A|or risk for severe toxicity.(1-29)|
04855|009|B||
04855|010|E|CLINICAL EFFECTS:  Concurrent use of dipyrone with agents that cause bone|
04855|011|E|marrow depression, including myelosuppressives, may result in an enhanced|
04855|012|E|risk of hematologic disorders, including anemia, blood dyscrasias, bone|
04855|013|E|marrow depression, leukopenia, and thrombocytopenia.  Bone marrow depression|
04855|014|E|may increase the risk of serious infections and bleeding.  Undetected severe|
04855|015|E|neutropenia or agranulocytosis may be fatal.(1-29)|
04855|016|B||
04855|017|P|PREDISPOSING FACTORS:  None determined.|
04855|018|B||
04855|019|M|PATIENT MANAGEMENT:  Concurrent use of dipyrone and myelosuppressive agents|
04855|020|M|should be avoided.|
04855|021|M|   The European Medicines Agency states dipyrone is contraindicated in|
04855|022|M|patients with a prior medical history of dipyrone-induced agranulocytosis|
04855|023|M|(or from other pyrazolones/pyrazolidines), impaired bone marrow function or|
04855|024|M|diseases of the hematopoietic system.(3)|
04855|025|M|   International labeling for dipyrone and methotrexate state that|
04855|026|M|co-administration may increase the hematotoxicity of methotrexate,|
04855|027|M|especially in elderly patients, and therefore should be avoided.(1-2)|
04855|028|M|   The European Medicines Agency advises if agranulocytosis is suspected|
04855|029|M|with dipyrone, a complete blood count (including differential blood count)|
04855|030|M|should be performed immediately, and treatment must be stopped while waiting|
04855|031|M|for the results.  If confirmed, treatment must not be reintroduced.(1-3)|
04855|032|B||
04855|033|D|DISCUSSION:  A retrospective cohort study analyzed new users of dipyrone|
04855|034|D|(n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which|
04855|035|D|served as a reference cohort, and opioids-paracetamol (n=3,129,221) which|
04855|036|D|was the negative control.  During continuous treatment over a median of|
04855|037|D|37-40 days, 26 cases of hospitalized agranulocytosis occurred.  With the|
04855|038|D|assumption that agranulocytosis onset was 7 days prior to admission, the|
04855|039|D|hazard ratio of agranulocytosis associated with dipyrone was 4.40|
04855|040|D|[0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to|
04855|041|D|opioid-paracetamol.  HR of neutropenia from dipyrone was 2.98 [1.57-5.65]|
04855|042|D|compared to NSAIDs and not statistically significant compared to|
04855|043|D|opioids-paracetamol.  In a sensitivity analysis assuming that the onset of|
04855|044|D|agranulocytosis was the date of hospitalization, the HR of dipyrone-induced|
04855|045|D|agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to|
04855|046|D|NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol.|
04855|047|D|Agranulocytosis was very rare but more than 4 times more common with|
04855|048|D|dipyrone than other analgesics.(4)|
04855|049|D|   In a review of 1,448 reports of agranulocytosis attributed to dipyrone,|
04855|050|D|patients with fatal outcomes were older and more often had also received|
04855|051|D|methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18;|
04855|052|D|95% confidence interval: 3.06-8.78).(5)|
04855|053|D|   Agents linked to this interaction generally have > 5% risk for|
04855|054|D|neutropenia and/or warnings describing risk for myelosuppression in|
04855|055|D|manufacturer prescribing information.(2,6-26)|
04855|056|B||
04855|057|R|REFERENCES:|
04855|058|B||
04855|059|R|1.Optalgin (Dipyrone (Metamizole sodium)) Prescribing Information. Teva|1
04855|060|R|  Israel Ltd June 2022.|1
04855|061|R|2.Metoject (methotrexate) UK Prescribing Information. Medac Pharma LLP|1
04855|062|R|  October, 2024.|1
04855|063|R|3.EMA. EMA recommends measures to minimise serious outcomes of known side|6
04855|064|R|  effect with painkiller metamizole. 6 September 2024.|6
04855|065|R|4.Macia-Martinez MA, Castillo-Cano B, Garcia-Poza P, Martin-Merino E. Risk|3
04855|066|R|  of agranulocytosis with metamizole in comparison with alternative|3
04855|067|R|  medications based on health records in Spain. European Journal of Clinical|3
04855|068|R|  Pharmacology 22 June 2024;80(10):1503-1514.|3
04855|069|R|5.Hoffman F, Bantel C, Jobski K. Aganulocytosis attributed to metamizole: An|3
04855|070|R|  analysis of spontaneous reports in EudraVigilance 1985-2017. Basic &|3
04855|071|R|  Clinical Pharmacology & Toxicology 26 August 2019;126(2):116-125.|3
04855|072|R|6.Campath (alemtuzumab) US prescribing information. Genzyme Corporation|1
04855|073|R|  November 2, 2020.|1
04855|074|R|7.Tegretol (carbamazepine) US prescribing information. Novartis|1
04855|075|R|  Pharmaceuticals Corporation September, 2023.|1
04855|076|R|8.Vistide (cidofovir) US prescribing information. Gilead Sciences, Inc.|1
04855|077|R|  September, 2000.|1
04855|078|R|9.Taxotere (docetaxel) US prescribing information. Sanofi-Aventis U.S. LLC|1
04855|079|R|  May, 2010.|1
04855|080|R|10.Camptosar (irinotecan hydrochloride) US prescribing information.|1
04855|081|R|   Pharmacia & Upjohn Company January, 2020.|1
04855|082|R|11.Taxol (paclitaxel) US prescribing information. Bristol-Myers Squibb|1
04855|083|R|   Company August, 2010.|1
04855|084|R|12.Hycamtin Injection (topotecan hydrochloride) US prescribing information.|1
04855|085|R|   GlaxoSmithKline June, 2015.|1
04855|086|R|13.Hycamtin Oral (topotecan) US prescribing information. GlaxoSmithKline|1
04855|087|R|   September, 2018.|1
04855|088|R|14.Retrovir (zidovudine) US prescribing information. GlaxoSmithKline|1
04855|089|R|   September, 2018.|1
04855|090|R|15.Carbplatin Inj. US prescribing information. Teva October, 2011.|1
04855|091|R|16.Ridaura (auranofin) US prescribing information. Prometheus Laboratories|1
04855|092|R|   August, 2007.|1
04855|093|R|17.Leukeran (Chlorambucil) US prescribing information. GlaxoSmithKline|1
04855|094|R|   October, 2011.|1
04855|095|R|18.Cytovene IV (ganciclovir) US prescribing information. Genentech Inc.|1
04855|096|R|   August, 2018.|1
04855|097|R|19.Zevalin (ibritumomab) US prescribing information. Spectrum|1
04855|098|R|   Pharmaceuticals September, 2013.|1
04855|099|R|20.Revlimid (lenalidomide) US prescribing information. Celgene Corp.|1
04855|100|R|   January, 2019.|1
04855|101|R|21.Mitoxantrone Inj. US prescribing information. APP Pharmaceuticals July,|1
04855|102|R|   2010.|1
04855|103|R|22.Vumon (teniposide) US prescribing information. E.R. Squibb & Sons|1
04855|104|R|   October, 2011.|1
04855|105|R|23.Bexxar (tositumomab) US prescribing information. GlaxoSmithKline October,|1
04855|106|R|   2005.|1
04855|107|R|24.Valcyte (valganciclovir) US prescribing information. Genentech June,|1
04855|108|R|   2017.|1
04855|109|R|25.Kisqali (ribociclib) US prescribing information. Novartis Pharmaceuticals|1
04855|110|R|   Corporation September, 2024.|1
04855|111|R|26.Lartruvo (olaratumab) US prescribing information. Eli Lilly and Company|1
04855|112|R|   February, 2017.|1
04855|113|R|27.Bavencio (avelumab) US prescribing information. EMD Serono November,|1
04855|114|R|   2020.|1
04855|115|R|28.Zejula (niraparib) US prescribing information. Tesaro July, 2021.|1
04855|116|R|29.Aliqopa (copanlisib) US prescribing information. Bayer October, 2019.|1
04856|001|T|MONOGRAPH TITLE:  Apixaban; Rivaroxaban/Strong & Moderate CYP3A4 Inducers|
04856|002|B||
04856|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04856|004|L|take action as needed.|
04856|005|B||
04856|006|A|MECHANISM OF ACTION:  Apixaban and rivaroxaban are both substrates of CYP3A4|
04856|007|A|and P-glycoprotein (P-gp).  Apixaban is about 20% metabolized and|
04856|008|A|rivaroxaban is about 18% metabolized, mainly by CYP3A4.(1-8)  Strong and|
04856|009|A|moderate CYP3A4 inducers may induce the metabolism of apixaban and|
04856|010|A|rivaroxaban by CYP3A4.|
04856|011|B||
04856|012|E|CLINICAL EFFECTS:  Concurrent or recent use of a CYP3A4 inducer may result|
04856|013|E|in decreased levels and effectiveness of apixaban(1-4) or rivaroxaban,(5-8)|
04856|014|E|especially in the setting of concurrent therapy with an agent that induces|
04856|015|E|P-gp.|
04856|016|B||
04856|017|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04856|018|P|of the inducer for longer than 1-2 weeks.|
04856|019|P|   Drug-associated risk factors include concurrent use of P-gp inducers.|
04856|020|B||
04856|021|M|PATIENT MANAGEMENT:  The US, Australian, Canadian, and UK manufacturers of|
04856|022|M|apixaban provide recommendations regarding concurrent use with strong|
04856|023|M|inducers of both CYP3A4 and P-gp, but do not provide guidance for concurrent|
04856|024|M|use with agents that induce CYP3A4 alone.(1)|
04856|025|M|   The US manufacturer of rivaroxaban provides recommendations regarding|
04856|026|M|concurrent use with strong inducers of both CYP3A4 and P-gp, but does not|
04856|027|M|provide guidance for concurrent use with agents that induce CYP3A4 alone.(5)|
04856|028|M|The Australian manufacturer of rivaroxaban states that concurrent use of|
04856|029|M|strong CYP3A4 inducers should be approached with caution.(6)  The Canadian|
04856|030|M|and UK labels for rivaroxaban state that concurrent use of strong CYP3A4|
04856|031|M|inducers should be avoided.(7-8)|
04856|032|M|   When considering concurrent therapy with a strong or moderate CYP3A4|
04856|033|M|inducer with either apixaban or rivaroxaban, evaluate the patient's other|
04856|034|M|concurrent therapy for CYP3A4 and P-gp effects.|
04856|035|M|   In patients who are taking strong CYP3A4 inducers and are also on|
04856|036|M|concurrent P-gp inducers, consider the manufacturer recommendations for use|
04856|037|M|with dual CYP3A4 and P-gp inducers. The US manufacturers of apixaban and|
04856|038|M|rivaroxaban both state to avoid the concurrent use of agents that are|
04856|039|M|combined P-gp and strong CYP3A4 inducers in patients receiving apixaban or|
04856|040|M|rivaroxaban.(1-8)|
04856|041|M|   In patients who are taking moderate CYP3A4 inducers and are also on|
04856|042|M|concurrent P-gp inducers, It may be prudent to consider alternative therapy|
04856|043|M|or monitor the patient closely.|
04856|044|B||
04856|045|D|DISCUSSION:  The concurrent use of apixaban or rivaroxaban with strong|
04856|046|D|CYP3A4 inducers that are not also P-gp inducers has not been studied.|
04856|047|D|Apixaban and rivaroxaban are metabolized primarily by CYP3A4.  Strong CYP3A4|
04856|048|D|inducers may decrease the levels and effectiveness of apixaban and|
04856|049|D|rivaroxaban.|
04856|050|D|   The US manufacturer of apixaban states that apixaban dose reduction is|
04856|051|D|recommended when apixaban exposure increases by more than 50%, while|
04856|052|D|efficacy is maintained when exposure is 25% lower.  Therefore, no dose|
04856|053|D|adjustment of apixaban is recommended for drug interactions that affect|
04856|054|D|apixaban exposure by 75% to 150%.(9)|
04856|055|D|   An article evaluating the clinical significance of efflux transporters|
04856|056|D|like P-gp and BCRP in apixaban exposure analyzed pharmacokinetic data from|
04856|057|D|drug-drug interaction studies and concluded that all apixaban interactions|
04856|058|D|can be explained by inhibition of intestinal CYP3A4.  The authors explain|
04856|059|D|that apixaban is a highly permeable and soluble compound, so its ability to|
04856|060|D|undergo passive diffusion renders the role of membrane transporters|
04856|061|D|irrelevant, as evidenced by a lack of change in apixaban absorption rate in|
04856|062|D|the presence of drugs known to inhibit P-gp and BCRP.(10)|
04856|063|D|   Strong CYP3A4 inducers linked to this monograph include: barbiturates,|
04856|064|D|encorafenib, ivosidenib, lumacaftor, and mitotane.(11,12)|
04856|065|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
04856|066|D|bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad,|
04856|067|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04856|068|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04856|069|D|thioridazine, and tovorafenib.(11,12)|
04856|070|B||
04856|071|R|REFERENCES:|
04856|072|B||
04856|073|R|1.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04856|074|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04856|075|R|2.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04856|076|R|  Squibb-Pfizer January, 2025.|1
04856|077|R|3.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04856|078|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04856|079|R|4.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04856|080|R|  Company April, 2025.|1
04856|081|R|5.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
04856|082|R|  Inc. March, 2020.|1
04856|083|R|6.Xarelto (rivaroxaban) Australian prescribing information. BAYER AUSTRALIA|1
04856|084|R|  LTD December, 2022.|1
04856|085|R|7.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
04856|086|R|  2015.|1
04856|087|R|8.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
04856|088|R|  August, 2021.|1
04856|089|R|9.US Food and Drug Administration (FDA). Drug Approval Pacakge Eliquis|1
04856|090|R|  (apixaban) Application No.: 202155Orig1s000. Accessed at:|1
04856|091|R|  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000Cli|1
04856|092|R|  nPharmR.pdf December, 2012.|1
04856|093|R|10.Sodhi JK, Liu S, Benet LZ. Intestinal Efflux Transporters P-gp and BCRP|2
04856|094|R|   Are Not Clinically Relevant in  Apixaban Disposition. Pharm Res 2020 Sep|2
04856|095|R|   29;37(10):208.|2
04856|096|R|11.This information is based on an extract from the Certara Drug Interaction|6
04856|097|R|   Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04856|098|R|12.US Food and Drug Administration (FDA). Drug Development and Drug|1
04856|099|R|   Interactions: Table of Substrates, Inhibitors and Inducers.  Available|1
04856|100|R|   at:|1
04856|101|R|   https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and|1
04856|102|R|   -drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04856|103|R|   11/14/2017.|1
04857|001|T|MONOGRAPH TITLE:  Apixaban; Rivaroxaban/Fluvoxamine|
04857|002|B||
04857|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04857|004|L|take action as needed.|
04857|005|B||
04857|006|A|MECHANISM OF ACTION:  Apixaban and rivaroxaban are substrates of CYP3A4.|
04857|007|A|Apixaban is about 20% metabolized and rivaroxaban is about 18% metabolized,|
04857|008|A|mainly by CYP3A4.(1-8)  Fluvoxamine is a moderate CYP3A4 inhibitor and may|
04857|009|A|inhibit the metabolism of apixaban and rivaroxaban by CYP3A4.(9)|
04857|010|A|   Serotonin release by platelets plays a role in hemostasis.(9)|
04857|011|A|Fluvoxamine may cause a decrease in serotonin reuptake by platelets,|
04857|012|A|resulting in an additive risk of bleeding with anticoagulants.|
04857|013|B||
04857|014|E|CLINICAL EFFECTS:  Concurrent use of fluvoxamine and agents that affect|
04857|015|E|coagulation may result in bleeding.|
04857|016|B||
04857|017|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04857|018|P|patients with disease-associated factors (e.g. thrombocytopenia).  Renal|
04857|019|P|impairment has been associated with a higher risk of rivaroxaban levels and|
04857|020|P|an elevated risk of GI bleed in patients on SSRIs.(10)|
04857|021|P|   Drug associated risk factors include concurrent use of multiple drugs|
04857|022|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04857|023|P|risk for bleeding (e.g. NSAIDs).|
04857|024|B||
04857|025|M|PATIENT MANAGEMENT:  Concurrent therapy of fluvoxamine with apixaban or|
04857|026|M|rivaroxaban should be undertaken with caution.|
04857|027|M|   The manufacturers of apixaban and rivaroxaban do not provide guidance for|
04857|028|M|concurrent use with agents that inhibit CYP3A4 alone, while international|
04857|029|M|manufacturer recommendations vary but generally state that such interactions|
04857|030|M|are of low to no clinical significance.(1-8) Use caution with concurrent use|
04857|031|M|of moderate CYP3A4 inhibitors.|
04857|032|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04857|033|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04857|034|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04857|035|M|patients with any symptoms.|
04857|036|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT,|
04857|037|M|anti Factor Xa inhibition) to monitor efficacy and safety of|
04857|038|M|anticoagulation.  Discontinue anticoagulation in patients with active|
04857|039|M|pathologic bleeding.|
04857|040|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04857|041|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04857|042|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04857|043|M|and/or swelling.|
04857|044|B||
04857|045|D|DISCUSSION:  Fluvoxamine is a moderate CYP3A4 inhibitor and a serotonin|
04857|046|D|reuptake inhibitor.  Concurrent use with apixaban and rivaroxaban may|
04857|047|D|increase levels of the anticoagulants and result in an additive risk of|
04857|048|D|bleeding.  There are no studies or reports on the combination of apixaban|
04857|049|D|and rivaroxaban with moderate CYP3A4 inhibitors like fluvoxamine.|
04857|050|D|   In a microdose cocktail study using apixaban 25 mcg or rivaroxaban 25|
04857|051|D|mcg, voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12|
04857|052|D|hours (strong CYP3A4 inhibitor) had "only a minor interaction," increasing|
04857|053|D|the AUC of both apixaban and rivaroxaban by 1.33-fold (p<0.05) while the|
04857|054|D|Cmax and half-life remained unchanged.(11)|
04857|055|D|   Another microdose cocktail study with apixaban 25 mcg or rivaroxaban 25|
04857|056|D|mcg and voriconazole 400 mg twice daily found that apixaban AUC increased by|
04857|057|D|1.24-fold and rivaroxaban AUC increased by 1.16-fold with a non-significant|
04857|058|D|change in Cmax.(12)|
04857|059|D|   A review article on DOAC drug-drug interactions suggests that the|
04857|060|D|combination of voriconazole, crizotinib or imatinib with apixaban or|
04857|061|D|rivaroxaban is contraindicated due to the potential for significant|
04857|062|D|increases in DOAC AUC.  The authors state that data with voriconazole is|
04857|063|D|missing and thus the interactions are unpredictable.(13)|
04857|064|D|   Another review article states that apixaban and rivaroxaban may be used|
04857|065|D|with voriconazole if no other pharmacokinetic inhibitor is present.  No dose|
04857|066|D|adjustment is recommended with moderate CYP3A4 inhibitors.(14)|
04857|067|D|   A systemic review and meta-analysis evaluated the risk of bleeding|
04857|068|D|associated with the combination of SSRIs or SNRIs and DOACs.  Concurrent use|
04857|069|D|had a significantly higher risk of major bleeding than use of DOACs alone|
04857|070|D|(RR 1.25, 95% CI 1.07-1.47 among cohort studies; OR 1.4, 95% CI 1.24-1.66|
04857|071|D|for case-control studies).(15)|
04857|072|D|   In The Rotterdam Study, fluvoxamine increased the risk of over|
04857|073|D|anticoagulation (hazard ratio 2.63).  Paroxetine was not associated with an|
04857|074|D|increased risk.  There were insufficient numbers of patients taking other|
04857|075|D|SSRIs to assess increased risk.(16)|
04857|076|D|   A self-controlled case study of 1,622 oral anticoagulant-precipitant drug|
04857|077|D|pairs were reviewed and found 14% of drug pairs were associated with a|
04857|078|D|statistically significant elevated risk of thromboembolism.  Concurrent use|
04857|079|D|of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of|
04857|080|D|1.69 (1.11-2.57).(17)|
04857|081|B||
04857|082|R|REFERENCES:|
04857|083|B||
04857|084|R|1.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04857|085|R|  Company April, 2025.|1
04857|086|R|2.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04857|087|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04857|088|R|3.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04857|089|R|  Squibb-Pfizer January, 2025.|1
04857|090|R|4.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04857|091|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04857|092|R|5.Xarelto (rivaroxaban) US prescribing information. Janssen Pharmaceuticals,|1
04857|093|R|  Inc. March, 2020.|1
04857|094|R|6.Xarelto (rivaroxaban) Australian prescribing information. BAYER AUSTRALIA|1
04857|095|R|  LTD December, 2022.|1
04857|096|R|7.Xarelto (rivaroxaban) Canadian prescribing information. Bayer July 20,|1
04857|097|R|  2015.|1
04857|098|R|8.Xarelto (rivaroxaban) UK summary of product characteristics. Bayer plc|1
04857|099|R|  August, 2021.|1
04857|100|R|9.Luvox (fluvoxamine maleate) US prescribing information. Jazz|1
04857|101|R|  Pharmaceuticals, Inc. August, 2023.|1
04857|102|R|10.Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D.|2
04857|103|R|   Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors|2
04857|104|R|   by level of kidney function: A population-based cohort study. Br J Clin|2
04857|105|R|   Pharmacol 2018 Sep;84(9):2142-2151.|2
04857|106|R|11.Mikus G, Foerster KI, Schaumaeker M, Lehmann ML, Burhenne J, Haefeli WE.|2
04857|107|R|   Application of a microdosed cocktail of 3 oral factor Xa inhibitors to|2
04857|108|R|   study  drug-drug interactions with different perpetrator drugs. Br J Clin|2
04857|109|R|   Pharmacol 2020 Aug;86(8):1632-1641.|2
04857|110|R|12.Rohr BS, Foerster KI, Blank A, Burhenne J, Mahmoudi M, Haefeli WE, Mikus|2
04857|111|R|   G. Perpetrator Characteristics of Azole Antifungal Drugs on Three Oral|2
04857|112|R|   Factor Xa  Inhibitors Administered as a Microdosed Cocktail. Clin|2
04857|113|R|   Pharmacokinet 2022 Jan;61(1):97-109.|2
04857|114|R|13.Ferri N, Colombo E, Tenconi M, Baldessin L, Corsini A. Drug-Drug|6
04857|115|R|   Interactions of Direct Oral Anticoagulants (DOACs): From  Pharmacological|6
04857|116|R|   to Clinical Practice. Pharmaceutics 2022 May 24;14(6):.|6
04857|117|R|14.Mar PL, Gopinathannair R, Gengler BE, Chung MK, Perez A, Dukes J,|6
04857|118|R|   Ezekowitz MD, Lakkireddy D, Lip GYH, Miletello M, Noseworthy PA, Reiffel|6
04857|119|R|   J, Tisdale JE, Olshansky B. Drug Interactions Affecting Oral|6
04857|120|R|   Anticoagulant Use. Circ Arrhythm Electrophysiol 2022 Jun;15(6):e007956.|6
04857|121|R|15.Weng J, Lan R. Does Concomitant Use of Antidepressants and Direct Oral|2
04857|122|R|   Anticoagulants Increase  the Risk of Bleeding?: A Systematic Review and|2
04857|123|R|   Meta-Analysis. J Clin Psychopharmacol 2025 Mar-Apr 01;45(2):140-147.|2
04857|124|R|16.Teichert M, Visser LE, Uitterlinden AG, Hofman A, Buhre PJ, Straus S, De|2
04857|125|R|   Smet PA, Stricker BH. Selective serotonin reuptake inhibiting|2
04857|126|R|   antidepressants and the risk of overanticoagulation during acenocoumarol|2
04857|127|R|   maintenance treatment. Br J Clin Pharmacol 2011 May 4.|2
04857|128|R|17.Zhou M, Leonard CE, Brensinger CM, Bilker WB, Kimmel SE, Hecht TEH,|2
04857|129|R|   Hennessy S. Pharmacoepidemiologic Screening of Potential Oral|2
04857|130|R|   Anticoagulant Drug Interactions  Leading to Thromboembolic Events. Clin|2
04857|131|R|   Pharmacol Ther 2020 Aug;108(2):377-386.|2
04858|001|T|MONOGRAPH TITLE:  Suzetrigine/Strong CYP3A4 Inhibitors|
04858|002|B||
04858|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04858|004|L|is contraindicated and generally should not be dispensed or administered to|
04858|005|L|the same patient.|
04858|006|B||
04858|007|A|MECHANISM OF ACTION:  Suzetrigine and M6-SUZ (active metabolite of|
04858|008|A|suzetrigine) are CYP3A4 substrates.  Strong CYP3A4 inhibitors increase|
04858|009|A|suzetrigine and M6-SUZ exposures, which may cause suzetrigine adverse|
04858|010|A|reactions.(1)|
04858|011|B||
04858|012|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4|
04858|013|E|inhibitor may result in elevated levels of and toxicity from suzetrigine|
04858|014|E|including pruritis, muscle spasms, increased blood creatine phosphokinase,|
04858|015|E|and rash.(1)|
04858|016|B||
04858|017|P|PREDISPOSING FACTORS:  None determined.|
04858|018|B||
04858|019|M|PATIENT MANAGEMENT:  Concurrent use of suzetrigine and strong CYP3A4|
04858|020|M|inhibitors is contraindicated.(1)|
04858|021|B||
04858|022|D|DISCUSSION:  Concomitant administration of itraconazole (a strong CYP3A4|
04858|023|D|inhibitor) with a single dose of suzetrigine increased the area-under-curve|
04858|024|D|(AUC) of suzetrigine and active metabolite M6-SUZ by 4.8-fold and 4.4-fold,|
04858|025|D|respectively, while the maximum concentration (Cmax) of suzetrigine|
04858|026|D|increased by 1.5-fold and Cmax of M6-SUZ decreased by 32%.(1)|
04858|027|D|   Strong CYP3A4 inhibitors include:  adagrasib, boceprevir, ceritinib,|
04858|028|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
04858|029|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir,|
04858|030|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
04858|031|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
04858|032|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)|
04858|033|B||
04858|034|R|REFERENCES:|
04858|035|B||
04858|036|R|1.Journavx (suzetrigine) US prescribing information. Vertex Pharmaceuticals|1
04858|037|R|  Incorporated. January 2025.|1
04858|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
04858|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04858|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04858|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04858|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04858|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04858|044|R|  11/14/2017.|1
04859|001|T|MONOGRAPH TITLE:  Suzetrigine/Moderate CYP3A4 Inhibitors|
04859|002|B||
04859|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04859|004|L|take action as needed.|
04859|005|B||
04859|006|A|MECHANISM OF ACTION:  Suzetrigine and M6-SUZ (active metabolite of|
04859|007|A|suzetrigine) are CYP3A4 substrates.  Moderate CYP3A4 inhibitors increase|
04859|008|A|suzetrigine and M6-SUZ exposures, which may cause suzetrigine adverse|
04859|009|A|reactions.(1)|
04859|010|B||
04859|011|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
04859|012|E|inhibitor may result in elevated levels of and toxicity from suzetrigine|
04859|013|E|including pruritis, muscle spasms, increased blood creatine phosphokinase,|
04859|014|E|and rash.(1)|
04859|015|B||
04859|016|P|PREDISPOSING FACTORS:  None determined.|
04859|017|B||
04859|018|M|PATIENT MANAGEMENT:  When possible, avoid the use of moderate CYP3A4|
04859|019|M|inhibitors with suzetrigine.|
04859|020|M|   The US manufacturer of suzetrigine states when suzetrigine is|
04859|021|M|administered to patients taking moderate CYP3A4 inhibitors reduce the|
04859|022|M|suzetrigine dose as follows:|
04859|023|M|   -Dose 1: The recommended starting dose of suzetrigine is 100 mg orally.|
04859|024|M|   -Dose 2, 3, and 4: Starting 12 hours after the initial dose, take 50 mg|
04859|025|M|of suzetrigine orally every 12 hours.|
04859|026|M|   -Dose 5 and Subsequent Doses: Starting 12 hours after Dose 4, take 50 mg|
04859|027|M|of suzetrigine orally every 24 hours.(1)|
04859|028|B||
04859|029|D|DISCUSSION:  In a PKPB model, concomitant administration of fluconazole (a|
04859|030|D|moderate CYP3A4 inhibitor) with suzetrigine with the recommended dosage|
04859|031|D|modification is predicted to increase the area-under-curve (AUC) of|
04859|032|D|suzetrigine and active metabolite M6-SUZ by 1.5-fold and 1.2-fold,|
04859|033|D|respectively, while the maximum concentration (Cmax) of suzetrigine and|
04859|034|D|M6-SUZ by 1.4-fold and 1.1-fold, respectively, when compared to the regular|
04859|035|D|recommended dosage in the absence of fluconazole.(1)|
04859|036|D|   Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir,|
04859|037|D|aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan,|
04859|038|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
04859|039|D|fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
04859|040|D|imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir,|
04859|041|D|netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol,|
04859|042|D|tofisopam, treosulfan, verapamil, and voxelotor.(2-3)|
04859|043|B||
04859|044|R|REFERENCES:|
04859|045|B||
04859|046|R|1.Journavx (suzetrigine) US prescribing information. Vertex Pharmaceuticals|1
04859|047|R|  Incorporated. January 2025.|1
04859|048|R|2.This information is based on an extract from the Certara Drug Interaction|6
04859|049|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04859|050|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04859|051|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04859|052|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04859|053|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04859|054|R|  11/14/2017.|1
04860|001|T|MONOGRAPH TITLE:  Suzetrigine/Strong CYP3A4 Inducers|
04860|002|B||
04860|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04860|004|L|of severe adverse interaction.|
04860|005|B||
04860|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04860|007|A|suzetrigine.(1)|
04860|008|B||
04860|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
04860|010|E|reduce the clinical effectiveness of suzetrigine.(1)|
04860|011|B||
04860|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04860|013|P|of the inducer for longer than 1-2 weeks.|
04860|014|B||
04860|015|M|PATIENT MANAGEMENT:  The US manufacturer of suzetrigine states that|
04860|016|M|concurrent use of strong CYP3A4 inducers should be avoided.(1)|
04860|017|B||
04860|018|D|DISCUSSION:  In a study, concomitant use of rifampin (strong CYP3A4 inducer)|
04860|019|D|decreased suzetrigine maximum concentration (Cmax) by 80% and|
04860|020|D|area-under-curve (AUC) by 93%.  Active metabolite M6-SUZ AUC decreased by|
04860|021|D|85% and Cmax was increased by 1.3-fold.(1)|
04860|022|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
04860|023|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04860|024|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04860|025|D|rifampin, rifapentine, and St. John's Wort.(2,3)|
04860|026|B||
04860|027|R|REFERENCES:|
04860|028|B||
04860|029|R|1.Journavx (suzetrigine) US prescribing information. Vertex Pharmaceuticals|1
04860|030|R|  Incorporated. January 2025.|1
04860|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04860|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04860|033|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04860|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04860|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04860|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04860|037|R|  11/14/2017.|1
04861|001|T|MONOGRAPH TITLE:  Pirfenidone/Ciprofloxacin (Greater Than or Equal To 750 mg|
04861|002|T|BID)|
04861|003|B||
04861|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04861|005|L|of severe adverse interaction.|
04861|006|B||
04861|007|A|MECHANISM OF ACTION:  Pirfenidone is primarily metabolized by CYP1A2 which|
04861|008|A|is responsible for about 50% of its conversion to inactive drug.  CYP2C9,|
04861|009|A|2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone|
04861|010|A|metabolism.(1,2)|
04861|011|A|   Moderate inhibitors of CYP1A2 may inhibit the metabolism of|
04861|012|A|pirfenidone.(1,2)|
04861|013|A|   Ciprofloxacin is a moderate inhibitor of CYP1A2.(3,4)|
04861|014|B||
04861|015|E|CLINICAL EFFECTS:  Concurrent pirfenidone use with ciprofloxacin may lead to|
04861|016|E|increased systemic concentrations and toxicity from pirfenidone, including|
04861|017|E|serious liver injury.(1,2)|
04861|018|B||
04861|019|P|PREDISPOSING FACTORS:  A greater risk of adverse events may result from|
04861|020|P|concomitant treatment strong or moderate inhibitors of one or more other CYP|
04861|021|P|isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g.|
04861|022|P|amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine,|
04861|023|P|ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine).|
04861|024|P|   The magnitude of this interaction may be reduced in cigarette smokers.|
04861|025|P|Cigarette smoking induces production of CYP1A2 and, in the absence of a|
04861|026|P|CYP1A2 inhibitor, leads to decreased systemic concentrations of|
04861|027|P|pirfenidone.(1)|
04861|028|B||
04861|029|M|PATIENT MANAGEMENT:  The manufacturer of pirfenidone recommends avoiding|
04861|030|M|concurrent use of ciprofloxacin at doses of 750 mg twice daily or higher.|
04861|031|M|If concurrent use cannot be avoided, reduce pirfenidone dose to 534 mg three|
04861|032|M|times daily (total daily dose of 1,602 mg/day).  Monitor patients closely|
04861|033|M|when ciprofloxacin is used at a daily dosage of 250 mg to 1,000 mg.(1,2)|
04861|034|M|   Combinations of ciprofloxacin with strong or moderate CYP2C9, CYP2C19,|
04861|035|M|and/or CYP2D6 inhibitors should also be discontinued prior to and avoided|
04861|036|M|during pirfenidone treatment.(2)|
04861|037|B||
04861|038|D|DISCUSSION:  Pirfenidone is converted to inactive metabolites prior to|
04861|039|D|elimination.  CYP1A2 is responsible for approximately half of this|
04861|040|D|metabolism.|
04861|041|D|   In a single-dose study in 27 healthy subjects, coadministration of 801 mg|
04861|042|D|of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed|
04861|043|D|at 750 mg twice daily from Day 2 to Day 7) increased the exposure to|
04861|044|D|pirfenidone by 81%.(2)|
04861|045|B||
04861|046|R|REFERENCES:|
04861|047|B||
04861|048|R|1.Esbriet (pirfenidone) Canada prescribing information. InterMune Canada,|1
04861|049|R|  Inc. April, 2016.|1
04861|050|R|2.Esbriet (pirfenidone) US prescribing information. InterMune, Inc. October,|1
04861|051|R|  2014.|1
04862|001|T|MONOGRAPH TITLE:  Suzetrigine/Moderate CYP3A4 Inducers|
04862|002|B||
04862|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04862|004|L|of severe adverse interaction.|
04862|005|B||
04862|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04862|007|A|of suzetrigine.(1)|
04862|008|B||
04862|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
04862|010|E|reduce the clinical effectiveness of suzetrigine.(1)|
04862|011|B||
04862|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04862|013|P|of the inducer for longer than 1-2 weeks.|
04862|014|B||
04862|015|M|PATIENT MANAGEMENT:  The US manufacturer of suzetrigine states that|
04862|016|M|concurrent use of moderate CYP3A4 inducers should be avoided.(1)|
04862|017|B||
04862|018|D|DISCUSSION:  Concomitant administration of efavirenz (moderate CYP3A|
04862|019|D|inducer) with suzetrigine is predicted to decrease suzetrigine and active|
04862|020|D|metabolite M6-SUZ area-under-curve (AUC) by 63% and 60%, respectively, while|
04862|021|D|suzetrigine maximum concentration (Cmax) is predicted to decrease by 29% and|
04862|022|D|M6-SUZ Cmax is predicted to increase by 1.3-fold, respectively.(1)|
04862|023|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04862|024|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04862|025|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04862|026|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04862|027|D|thioridazine, and tovorafenib.(2,3)|
04862|028|B||
04862|029|R|REFERENCES:|
04862|030|B||
04862|031|R|1.Journavx (suzetrigine) US prescribing information. Vertex Pharmaceuticals|1
04862|032|R|  Incorporated. January 2025.|1
04862|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04862|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04862|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04862|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04862|037|R|  11/14/2017.|1
04862|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
04862|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04863|001|T|MONOGRAPH TITLE:  Selected Hormonal Contraceptives/Suzetrigine|
04863|002|B||
04863|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04863|004|L|of severe adverse interaction.|
04863|005|B||
04863|006|A|MECHANISM OF ACTION:  Suzetrigine may induce the metabolism of hormonal|
04863|007|A|contraceptives containing progestins other than levonorgestrel and|
04863|008|A|norethindrone.(1)|
04863|009|B||
04863|010|E|CLINICAL EFFECTS:  Concurrent use of suzetrigine and hormonal contraceptives|
04863|011|E|containing progestins other than levonorgestrel or norethindrone may result|
04863|012|E|in decreased levels and effectiveness of the contraceptive.(1)|
04863|013|B||
04863|014|P|PREDISPOSING FACTORS:  None determined.|
04863|015|B||
04863|016|M|PATIENT MANAGEMENT:  The manufacturer of suzetrigine advises that|
04863|017|M|suzetrigine-treated patients using hormonal contraceptives containing|
04863|018|M|progestins other than levonorgestrel and norethindrone should either:|
04863|019|M|   - Use additional non-hormonal contraceptives,|
04863|020|M|   - Use alternative contraceptives such as a combined oral contraceptive|
04863|021|M|containing ethinyl estradiol as the estrogen and levonorgestrel or|
04863|022|M|norethindrone as the progestin, or|
04863|023|M|   - Use an intrauterine system|
04863|024|M|   The alternative birth control method should be used during treatment with|
04863|025|M|suzetrigine and for 28 days after discontinuation of suzetrigine.(1)|
04863|026|B||
04863|027|D|DISCUSSION:  Suzetrigine did not result in clinically significant changes in|
04863|028|D|the pharmacokinetics of ethinyl estradiol and levonorgestrel when used|
04863|029|D|concomitantly with an oral contraceptive containing ethinyl estradiol and|
04863|030|D|levonorgestrel.(1)|
04863|031|D|   Suzetrigine administered 50 mg every 12 hours at steady state decreased|
04863|032|D|the area-under-curve (AUC) of midazolam (a CYP3A4 substrate) by 48% and|
04863|033|D|maximum concentration (Cmax) by 37%.(1)|
04863|034|B||
04863|035|R|REFERENCE:|
04863|036|B||
04863|037|R|1.Journavx (suzetrigine) US prescribing information. Vertex Pharmaceuticals|1
04863|038|R|  Incorporated. January 2025.|1
04864|001|T|MONOGRAPH TITLE:  Ziprasidone/MAOIs|
04864|002|B||
04864|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04864|004|L|is contraindicated and generally should not be dispensed or administered to|
04864|005|L|the same patient.|
04864|006|B||
04864|007|A|MECHANISM OF ACTION:  Combination of MAOIs, which decrease the breakdown of|
04864|008|A|serotonin, and ziprasidone, a 5-HT1A agonist and serotonin and|
04864|009|A|norepinephrine reuptake inhibitor, may cause an increase in endogenous|
04864|010|A|serotonin.(1-2)|
04864|011|B||
04864|012|E|CLINICAL EFFECTS:  Concurrent use of ziprasidone and MAOIs may result in|
04864|013|E|serotonin syndrome, a potentially life-threatening condition with symptoms|
04864|014|E|including altered mental status, hypertension, restlessness, myoclonus,|
04864|015|E|hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1)|
04864|016|B||
04864|017|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04864|018|P|systemic concentrations of either drug would be predicted to increase risk|
04864|019|P|for serotonin toxicity.(2)|
04864|020|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04864|021|P|concentrations may also increase risk for serotonin syndrome.(2)|
04864|022|B||
04864|023|M|PATIENT MANAGEMENT:  The concurrent use of ziprasidone with MAOIs is|
04864|024|M|contraindicated.  At least 14 days must elapse between discontinuation of an|
04864|025|M|MAOI and initiation of therapy with ziprasidone.  Conversely, at least 3|
04864|026|M|days must be allowed after stopping ziprasidone before starting an MAOI.(1)|
04864|027|M|   Do not initiate ziprasidone in a patient being treated with MAOIs such as|
04864|028|M|intravenous methylene blue.  If it is necessary to initiate treatment with|
04864|029|M|an MAOI such as intravenous methylene blue in a patient taking ziprasidone,|
04864|030|M|discontinue ziprasidone before initiating treatment with the MAOI.|
04864|031|B||
04864|032|D|DISCUSSION:  Several cases of serotonin syndrome have been reported in|
04864|033|D|patients receiving ziprasidone.(4-6)|
04864|034|D|   Methylene blue, when administered intravenously, has been shown to reach|
04864|035|D|sufficient concentrations to be a potent inhibitor of MAO-A.(7,8)|
04864|036|D|   Metaxalone is a weak inhibitor of MAO.(9,10)|
04864|037|B||
04864|038|R|REFERENCES:|
04864|039|B||
04864|040|R|1.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
04864|041|R|  May, 2021.|1
04864|042|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04864|043|R|  352(11):1112-20.|6
04864|044|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
04864|045|R|  information about the drug interaction between methylene blue|1
04864|046|R|  (methylthioninium chloride) and serotonergic psychiatric medications.|1
04864|047|R|  available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
04864|048|R|  21, 2011.|1
04864|049|R|4.Palekar N, Eisman J. Serotonin syndrome with ziprasidone and sertraline. J|3
04864|050|R|  Neuropsychiatry Clin Neurosci 2013 Spring;25(2):E1.|3
04864|051|R|5.Lin PY, Hong CJ, Tsai SJ. Serotonin syndrome caused by ziprasidone alone.|3
04864|052|R|  Psychiatry Clin Neurosci 2010 Jun;64(3):338-9.|3
04864|053|R|6.Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin|3
04864|054|R|  Syndrome in a Patient Taking Kratom and Multiple  Serotonergic Agents. J|3
04864|055|R|  Pharm Pract 2023 Dec;36(6):1523-1527.|3
04864|056|R|7.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity:|5
04864|057|R|  inhibition of monoamine oxidase A (MAO A) confirms a theoretical|5
04864|058|R|  prediction. Br J Pharmacol 2007 Nov;152(6):946-51.|5
04864|059|R|8.Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ|2
04864|060|R|  distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol|2
04864|061|R|  2000 Jun;56(3):247-50.|2
04864|062|R|9.Surmaitis RM, Nappe TM, Cook MD. Serotonin syndrome associated with|3
04864|063|R|  therapeutic metaxalone in a patient with  cirrhosis. Am J Emerg Med 2016|3
04864|064|R|  Feb;34(2):346.e5-6.|3
04864|065|R|10.Skelaxin (metaxalone) US prescribing information. Pfizer Laboratories Div|1
04864|066|R|   Pfizer Inc. January, 2024.|1
04865|001|T|MONOGRAPH TITLE:  Ziprasidone/Serotonergic Agents|
04865|002|B||
04865|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04865|004|L|take action as needed.|
04865|005|B||
04865|006|A|MECHANISM OF ACTION:  Ziprasidone is a 5-HT1A agonist and serotonin and|
04865|007|A|norepinephrine reuptake inhibitor.  Concurrent administration with one or|
04865|008|A|more serotonergic agents may increase serotonin effects, resulting in|
04865|009|A|serotonin toxicity.(1,2)|
04865|010|B||
04865|011|E|CLINICAL EFFECTS:  Concurrent use of ziprasidone and other serotonergic|
04865|012|E|agents may result in serotonin syndrome, a potentially life-threatening|
04865|013|E|condition with symptoms including altered mental status, hypertension,|
04865|014|E|restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis,|
04865|015|E|shivering, and tremor.(1)|
04865|016|B||
04865|017|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04865|018|P|systemic concentrations of either drug would be predicted to increase risk|
04865|019|P|for serotonin toxicity.(2)|
04865|020|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04865|021|P|concentrations may also increase risk for serotonin syndrome.(2)|
04865|022|B||
04865|023|M|PATIENT MANAGEMENT:  Caution patients about the risk of serotonin syndrome|
04865|024|M|with the concomitant use of ziprasidone with other serotonergic drugs.|
04865|025|M|Instruct patients to contact their healthcare provider, or report to the|
04865|026|M|emergency room, should they experience signs or symptoms of serotonin|
04865|027|M|syndrome.(1)|
04865|028|B||
04865|029|D|DISCUSSION:  Several cases of serotonin syndrome have been reported in|
04865|030|D|patients receiving ziprasidone.(4-6)|
04865|031|B||
04865|032|R|REFERENCES:|
04865|033|B||
04865|034|R|1.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
04865|035|R|  May, 2021.|1
04865|036|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04865|037|R|  352(11):1112-20.|6
04865|038|R|3.USFood and Drug Administration. FDA Drug Safety Communication: Updated|1
04865|039|R|  information about the drug interaction between methylene blue|1
04865|040|R|  (methylthioninium chloride) and serotonergic psychiatric medications.|1
04865|041|R|  available at:  http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm October|1
04865|042|R|  21, 2011.|1
04865|043|R|4.Palekar N, Eisman J. Serotonin syndrome with ziprasidone and sertraline. J|3
04865|044|R|  Neuropsychiatry Clin Neurosci 2013 Spring;25(2):E1.|3
04865|045|R|5.Lin PY, Hong CJ, Tsai SJ. Serotonin syndrome caused by ziprasidone alone.|3
04865|046|R|  Psychiatry Clin Neurosci 2010 Jun;64(3):338-9.|3
04865|047|R|6.Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin|3
04865|048|R|  Syndrome in a Patient Taking Kratom and Multiple  Serotonergic Agents. J|3
04865|049|R|  Pharm Pract 2023 Dec;36(6):1523-1527.|3
04866|001|T|MONOGRAPH TITLE:  Ziprasidone/Serotonergic Agents that Prolong QT|
04866|002|B||
04866|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04866|004|L|is contraindicated and generally should not be dispensed or administered to|
04866|005|L|the same patient.|
04866|006|B||
04866|007|A|MECHANISM OF ACTION:  Ziprasidone is a 5-HT1A agonist and serotonin and|
04866|008|A|norepinephrine reuptake inhibitor.  Concurrent administration with one or|
04866|009|A|more serotonergic agents may increase serotonin effects, resulting in|
04866|010|A|serotonin toxicity.  Current use may also result in additive effects on the|
04866|011|A|QTc interval.(1,2)|
04866|012|B||
04866|013|E|CLINICAL EFFECTS:  Concurrent use of ziprasidone and other serotonergic|
04866|014|E|agents may result in serotonin syndrome, a potentially life-threatening|
04866|015|E|condition with symptoms including altered mental status, hypertension,|
04866|016|E|restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis,|
04866|017|E|shivering, and tremor.(1)|
04866|018|E|   Additive QTc prolongation may also occur, resulting in potentially|
04866|019|E|life-threatening arrhythmias like torsades de pointes.(1)|
04866|020|B||
04866|021|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04866|022|P|systemic concentrations of either drug would be predicted to increase risk|
04866|023|P|for serotonin toxicity.(2)|
04866|024|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04866|025|P|concentrations may also increase risk for serotonin syndrome.(2)|
04866|026|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04866|027|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04866|028|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04866|029|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04866|030|P|advanced age.(3)|
04866|031|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04866|032|P|higher systemic concentrations of either QT prolonging drug are additional|
04866|033|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04866|034|P|drug concentrations include rapid infusion of an intravenous dose or|
04866|035|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04866|036|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04866|037|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04866|038|B||
04866|039|M|PATIENT MANAGEMENT:  Caution patients about the risk of serotonin syndrome|
04866|040|M|with the concomitant use of ziprasidone with other serotonergic drugs.|
04866|041|M|Instruct patients to contact their healthcare provider, or report to the|
04866|042|M|emergency room, should they experience signs or symptoms of serotonin|
04866|043|M|syndrome.(1)|
04866|044|M|   The manufacturer of ziprasidone states under contraindications that|
04866|045|M|ziprasidone should not be used with other drugs that prolong the QT interval|
04866|046|M|such as dofetilide, sotalol, quinidine, other Class Ia and III|
04866|047|M|anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol,|
04866|048|M|pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine,|
04866|049|M|mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron|
04866|050|M|mesylate, probucol or tacrolimus.(1)  It would be prudent to avoid the use|
04866|051|M|of ziprasidone with medicines suspected of prolonging the QT interval.|
04866|052|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
04866|053|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
04866|054|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
04866|055|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04866|056|B||
04866|057|D|DISCUSSION:  Several cases of serotonin syndrome have been reported in|
04866|058|D|patients receiving ziprasidone.(4-6)|
04866|059|D|   Agents that are linked to this monograph may have varying degrees of|
04866|060|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04866|061|D|been shown to prolong the QTc interval either through their mechanism of|
04866|062|D|action, through studies on their effects on the QTc interval, or through|
04866|063|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04866|064|D|and/or postmarketing reports.(7)|
04866|065|B||
04866|066|R|REFERENCES:|
04866|067|B||
04866|068|R|1.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
04866|069|R|  May, 2021.|1
04866|070|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04866|071|R|  352(11):1112-20.|6
04866|072|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04866|073|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04866|074|R|  settings: a scientific statement from the American Heart Association and|6
04866|075|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04866|076|R|  2;55(9):934-47.|6
04866|077|R|4.Palekar N, Eisman J. Serotonin syndrome with ziprasidone and sertraline. J|3
04866|078|R|  Neuropsychiatry Clin Neurosci 2013 Spring;25(2):E1.|3
04866|079|R|5.Lin PY, Hong CJ, Tsai SJ. Serotonin syndrome caused by ziprasidone alone.|3
04866|080|R|  Psychiatry Clin Neurosci 2010 Jun;64(3):338-9.|3
04866|081|R|6.Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin|3
04866|082|R|  Syndrome in a Patient Taking Kratom and Multiple  Serotonergic Agents. J|3
04866|083|R|  Pharm Pract 2023 Dec;36(6):1523-1527.|3
04866|084|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
04866|085|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04866|086|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04866|087|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04867|001|T|MONOGRAPH TITLE:  Ziprasidone/Serotonergic Agents that Prolong QT|
04867|002|B||
04867|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04867|004|L|of severe adverse interaction.|
04867|005|B||
04867|006|A|MECHANISM OF ACTION:  Ziprasidone is a 5-HT1A agonist and serotonin and|
04867|007|A|norepinephrine reuptake inhibitor.  Concurrent administration with one or|
04867|008|A|more serotonergic agents may increase serotonin effects, resulting in|
04867|009|A|serotonin toxicity.  Current use may also result in additive effects on the|
04867|010|A|QTc interval.(1,2)|
04867|011|B||
04867|012|E|CLINICAL EFFECTS:  Concurrent use of ziprasidone and other serotonergic|
04867|013|E|agents may result in serotonin syndrome, a potentially life-threatening|
04867|014|E|condition with symptoms including altered mental status, hypertension,|
04867|015|E|restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis,|
04867|016|E|shivering, and tremor.(1)|
04867|017|E|   Additive QTc prolongation may also occur, resulting in potentially|
04867|018|E|life-threatening arrhythmias like torsades de pointes.(1)|
04867|019|B||
04867|020|P|PREDISPOSING FACTORS:  Serotonin syndrome risk is dose-related.  Higher|
04867|021|P|systemic concentrations of either drug would be predicted to increase risk|
04867|022|P|for serotonin toxicity.(2)|
04867|023|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04867|024|P|concentrations may also increase risk for serotonin syndrome.(2)|
04867|025|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04867|026|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04867|027|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04867|028|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04867|029|P|advanced age.(3)|
04867|030|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04867|031|P|higher systemic concentrations of either QT prolonging drug are additional|
04867|032|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04867|033|P|drug concentrations include rapid infusion of an intravenous dose or|
04867|034|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04867|035|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04867|036|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04867|037|B||
04867|038|M|PATIENT MANAGEMENT:  Caution patients about the risk of serotonin syndrome|
04867|039|M|with the concomitant use of ziprasidone with other serotonergic drugs.|
04867|040|M|Instruct patients to contact their healthcare provider, or report to the|
04867|041|M|emergency room, should they experience signs or symptoms of serotonin|
04867|042|M|syndrome.(1)|
04867|043|M|   The manufacturer of ziprasidone states under contraindications that|
04867|044|M|ziprasidone should not be used with other drugs that prolong the QT interval|
04867|045|M|such as dofetilide, sotalol, quinidine, other Class Ia and III|
04867|046|M|anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol,|
04867|047|M|pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine,|
04867|048|M|mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron|
04867|049|M|mesylate, probucol or tacrolimus.(1)  It would be prudent to avoid the use|
04867|050|M|of ziprasidone with medicines suspected of prolonging the QT interval.|
04867|051|M|   If concurrent therapy is deemed medically necessary, consider obtaining|
04867|052|M|serum calcium, magnesium, and potassium levels and monitoring ECG at|
04867|053|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
04867|054|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
04867|055|B||
04867|056|D|DISCUSSION:  Several cases of serotonin syndrome have been reported in|
04867|057|D|patients receiving ziprasidone.(4-6)|
04867|058|D|   Agents that are linked to this monograph may have varying degrees of|
04867|059|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04867|060|D|been shown to prolong the QTc interval either through their mechanism of|
04867|061|D|action, through studies on their effects on the QTc interval, or through|
04867|062|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04867|063|D|and/or postmarketing reports.(7)|
04867|064|B||
04867|065|R|REFERENCES:|
04867|066|B||
04867|067|R|1.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer Inc.|1
04867|068|R|  May, 2021.|1
04867|069|R|2.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04867|070|R|  352(11):1112-20.|6
04867|071|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04867|072|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04867|073|R|  settings: a scientific statement from the American Heart Association and|6
04867|074|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04867|075|R|  2;55(9):934-47.|6
04867|076|R|4.Palekar N, Eisman J. Serotonin syndrome with ziprasidone and sertraline. J|3
04867|077|R|  Neuropsychiatry Clin Neurosci 2013 Spring;25(2):E1.|3
04867|078|R|5.Lin PY, Hong CJ, Tsai SJ. Serotonin syndrome caused by ziprasidone alone.|3
04867|079|R|  Psychiatry Clin Neurosci 2010 Jun;64(3):338-9.|3
04867|080|R|6.Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin|3
04867|081|R|  Syndrome in a Patient Taking Kratom and Multiple  Serotonergic Agents. J|3
04867|082|R|  Pharm Pract 2023 Dec;36(6):1523-1527.|3
04867|083|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
04867|084|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04867|085|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04867|086|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04868|001|T|MONOGRAPH TITLE:  Methadone for MAT/Ziprasidone|
04868|002|B||
04868|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04868|004|L|of severe adverse interaction.|
04868|005|B||
04868|006|A|MECHANISM OF ACTION:  Methadone has been shown to prolong the QTc interval.|
04868|007|A|Concurrent use with ziprasidone may result in additive effects on the QTc|
04868|008|A|interval.(1-3, 19)|
04868|009|A|   Concurrent use of methadone and ziprasidone may result in additive CNS|
04868|010|A|depression.(1-3,19)|
04868|011|A|   Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake|
04868|012|A|inhibitor.  Methadone may inhibit neural uptake of serotonin.  Concurrent|
04868|013|A|use may increase serotonin effects, resulting in serotonin toxicity.(19)|
04868|014|B||
04868|015|E|CLINICAL EFFECTS:  The concurrent use of methadone with other agents that|
04868|016|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04868|017|E|arrhythmias, including torsades de pointes.(1,2)|
04868|018|E|   Concurrent use of opioids and ziprasidone may result in profound|
04868|019|E|sedation, respiratory depression, coma, and/or death.(1-3)|
04868|020|E|   Concurrent use of ziprasidone and methadone may result in serotonin|
04868|021|E|syndrome, a potentially life-threatening condition with symptoms including|
04868|022|E|altered mental status, hypertension, restlessness, myoclonus, hyperthermia,|
04868|023|E|hyperreflexia, diaphoresis, shivering, and tremor.(15)|
04868|024|B||
04868|025|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04868|026|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04868|027|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04868|028|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04868|029|P|gender, or advanced age.(4)|
04868|030|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04868|031|P|higher systemic concentrations of either QT prolonging drug are additional|
04868|032|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04868|033|P|drug concentrations include rapid infusion of an intravenous dose or|
04868|034|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04868|035|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04868|036|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04868|037|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
04868|038|P|of adverse effects.|
04868|039|P|   Serotonin syndrome risk is dose-related.  Higher systemic concentrations|
04868|040|P|of either drug would be predicted to increase risk for serotonin|
04868|041|P|toxicity.(2)|
04868|042|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04868|043|P|concentrations may also increase risk for serotonin syndrome.(15)|
04868|044|B||
04868|045|M|PATIENT MANAGEMENT:  Concurrent use of methadone with other agents known to|
04868|046|M|prolong the QT interval should be approached with extreme caution.(1,2)|
04868|047|M|Limit prescribing methadone with CNS depressants such as antipsychotics to|
04868|048|M|patients for whom alternatives are ineffective, not tolerated, or would be|
04868|049|M|otherwise inadequate to provide sufficient management of pain.(3)|
04868|050|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04868|051|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04868|052|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04868|053|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04868|054|M|   Medication assisted treatment (MAT) with methadone is not contraindicated|
04868|055|M|in patients taking CNS depressants; however, gradual tapering or decreasing|
04868|056|M|to the lowest effective dose of antipsychotics may be appropriate.  Ensure|
04868|057|M|that other health care providers prescribing other CNS depressants are aware|
04868|058|M|of the patient's methadone treatment.(5)|
04868|059|M|   If concurrent use is necessary, limit the dosages and duration of each|
04868|060|M|drug to the minimum possible while achieving the desired clinical effect.|
04868|061|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04868|062|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04868|063|M|indicated in the absence of an opioid and titrate based upon clinical|
04868|064|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04868|065|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04868|066|M|clinical response.(3)|
04868|067|M|   Respiratory depression can occur at any time during opioid therapy,|
04868|068|M|especially during therapy initiation and following dosage increases.  The|
04868|069|M|risk of opioid-related overdose or overdose-related death is increased with|
04868|070|M|higher opioid doses, and this risk persists over the course of therapy.|
04868|071|M|Consider these risks when using concurrently with other agents that may|
04868|072|M|cause CNS depression.(6)|
04868|073|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04868|074|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04868|075|M|unresponsiveness.(3)|
04868|076|M|   Caution patients about the risk of serotonin syndrome with the|
04868|077|M|concomitant use of ziprasidone with other serotonergic drugs.  Instruct|
04868|078|M|patients to contact their healthcare provider, or report to the emergency|
04868|079|M|room, should they experience signs or symptoms of serotonin syndrome.(19)|
04868|080|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04868|081|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04868|082|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04868|083|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04868|084|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04868|085|M|as those taking CNS depressants) and when a patient has household|
04868|086|M|members/close contacts at risk for accidental overdose. Discuss the options|
04868|087|M|for obtaining an opioid reversal agent (e.g., prescription,|
04868|088|M|over-the-counter, or as part of a community-based program).(7)|
04868|089|B||
04868|090|D|DISCUSSION:  Most cases of methadone-induced QT prolongation are associated|
04868|091|D|with, but not limited to, higher dose treatment (greater than 200 mg daily)|
04868|092|D|and most involve patients being treated for pain with large, multiple daily|
04868|093|D|doses. Cases have been reported in patients treated with doses commonly used|
04868|094|D|for maintenance treatment of opioid addiction.(2)|
04868|095|D|   Levomethadone should be used with caution in patients with a history of|
04868|096|D|QT prolongation, advanced heart disease, concomitant CYP3A4 inhibitors, or|
04868|097|D|electrolyte abnormalities.  Cases of QT prolongation and torsades de pointes|
04868|098|D|have been reported, most commonly with high doses.(1)|
04868|099|D|   A nested case-control study looked at the relationship between|
04868|100|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
04868|101|D|antipsychotics was associated with a 2.33-fold increase in risk of|
04868|102|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
04868|103|D|significantly increased in patients with recent use of antipsychotics|
04868|104|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
04868|105|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
04868|106|D|of use.(8)|
04868|107|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04868|108|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04868|109|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04868|110|D|to 30 million patients.  During this time, the proportion of patients|
04868|111|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04868|112|D|patients.(9)|
04868|113|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04868|114|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04868|115|D|per 100,000 and drug overdose deaths involving both opioids and|
04868|116|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04868|117|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04868|118|D|increased from 18% to 31% during this time.(10)|
04868|119|D|   A prospective observational cohort study in North Carolina found that the|
04868|120|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04868|121|D|benzodiazepines were 10 times higher than patients receiving opioid|
04868|122|D|analgesics alone.(11)|
04868|123|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04868|124|D|death from overdose increased with concomitant opioid analgesics and|
04868|125|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04868|126|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04868|127|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04868|128|D|increased risk of fatal overdose.(12)|
04868|129|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04868|130|D|which benzodiazepines were determined to be a cause of death and that|
04868|131|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04868|132|D|determined to be a cause of death.  This study also found that other CNS|
04868|133|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04868|134|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04868|135|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04868|136|D|where opioid analgesics were also implicated.(13)|
04868|137|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04868|138|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04868|139|D|deaths.(14)|
04868|140|D|   Several cases of serotonin syndrome have been reported in patients|
04868|141|D|receiving ziprasidone.(16-18)|
04868|142|B||
04868|143|R|REFERENCES:|
04868|144|B||
04868|145|R|1.Levopidon (levomethadone) Swedish Summary of Product Characteristics. DNE|1
04868|146|R|  Pharma AS November 30, 2018.|1
04868|147|R|2.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
04868|148|R|  Pharmaceuticals Corp. June, 2021.|1
04868|149|R|3.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04868|150|R|  warns about serious risks and death when combining opioid pain or cough|1
04868|151|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04868|152|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04868|153|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04868|154|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04868|155|R|  settings: a scientific statement from the American Heart Association and|6
04868|156|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04868|157|R|  2;55(9):934-47.|6
04868|158|R|5.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04868|159|R|  urges caution about withholding opioid addiction medications from patients|1
04868|160|R|  taking benzodiazepines or CNS depressants: careful medication management|1
04868|161|R|  can reduce risks. available at:|1
04868|162|R|  https://www.fda.gov/drugs/drugsafety/ucm575307.htm September 20, 2017.|1
04868|163|R|6.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04868|164|R|  prescribing information for all opioid pain medicines to provide|1
04868|165|R|  additional guidance for safe use. Available at:|1
04868|166|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04868|167|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04868|168|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04868|169|R|7.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04868|170|R|  recommends health care professionals discuss naloxone with all patients|1
04868|171|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04868|172|R|  disorder. Available at:|1
04868|173|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04868|174|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04868|175|R|  d-pain July 23, 2020.|1
04868|176|R|8.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
04868|177|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
04868|178|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
04868|179|R|  Pharmacol 2020 Apr 26.|2
04868|180|R|9.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04868|181|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04868|182|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04868|183|R|10.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04868|184|R|   From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015|2
04868|185|R|   Oct;49(4):493-501.|2
04868|186|R|11.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04868|187|R|   Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04868|188|R|   Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04868|189|R|12.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04868|190|R|   prescribing patterns and deaths from drug overdose among US veterans|2
04868|191|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
04868|192|R|   350:h2698.|2
04868|193|R|13.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04868|194|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04868|195|R|14.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04868|196|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04868|197|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04868|198|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04868|199|R|15.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04868|200|R|   352(11):1112-20.|6
04868|201|R|16.Palekar N, Eisman J. Serotonin syndrome with ziprasidone and sertraline.|3
04868|202|R|   J Neuropsychiatry Clin Neurosci 2013 Spring;25(2):E1.|3
04868|203|R|17.Lin PY, Hong CJ, Tsai SJ. Serotonin syndrome caused by ziprasidone alone.|3
04868|204|R|   Psychiatry Clin Neurosci 2010 Jun;64(3):338-9.|3
04868|205|R|18.Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin|3
04868|206|R|   Syndrome in a Patient Taking Kratom and Multiple  Serotonergic Agents. J|3
04868|207|R|   Pharm Pract 2023 Dec;36(6):1523-1527.|3
04868|208|R|19.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer|1
04868|209|R|   Inc. May, 2021.|1
04869|001|T|MONOGRAPH TITLE:  Selected Serotonergic Opioids/Ziprasidone|
04869|002|B||
04869|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04869|004|L|take action as needed.|
04869|005|B||
04869|006|A|MECHANISM OF ACTION:  Concurrent use of serotonergic opioids such as|
04869|007|A|meperidine or tramadol and antipsychotics such as ziprasidone may result in|
04869|008|A|additive CNS depression or additive risk of serotonin syndrome.(1)|
04869|009|B||
04869|010|E|CLINICAL EFFECTS:  Concurrent use of serotonergic opioids such as meperidine|
04869|011|E|or tramadol and antipsychotics such as ziprasidone may result in profound|
04869|012|E|sedation, respiratory depression, coma, and/or death.(1)|
04869|013|B||
04869|014|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04869|015|P|may increase the risk of adverse effects.|
04869|016|P|   Serotonin syndrome risk is dose-related. Higher systemic concentrations|
04869|017|P|of either drug would be predicted to increase risk for serotonin toxicity.|
04869|018|P|Concomitant therapy with multiple agents which increase brain serotonin|
04869|019|P|concentrations may also increase risk for serotonin syndrome.(2)|
04869|020|B||
04869|021|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics such as meperidine|
04869|022|M|or tramadol with CNS depressants such as antipsychotics, including|
04869|023|M|ziprasidone, to patients for whom alternatives are ineffective, not|
04869|024|M|tolerated, or would be otherwise inadequate to provide sufficient management|
04869|025|M|of pain.(1)|
04869|026|M|   If concurrent use is necessary, limit the dosages and duration of each|
04869|027|M|drug to the minimum possible while achieving the desired clinical effect.|
04869|028|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04869|029|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04869|030|M|indicated in the absence of an opioid and titrate based upon clinical|
04869|031|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04869|032|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04869|033|M|clinical response.(1)|
04869|034|M|   Respiratory depression can occur at any time during opioid therapy,|
04869|035|M|especially during therapy initiation and following dosage increases.  The|
04869|036|M|risk of opioid-related overdose or overdose-related death is increased with|
04869|037|M|higher opioid doses, and this risk persists over the course of therapy.|
04869|038|M|Consider these risks when using concurrently with other agents that may|
04869|039|M|cause CNS depression.(2)|
04869|040|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04869|041|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04869|042|M|unresponsiveness,(1) as well as for signs of serotonin syndrome.|
04869|043|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04869|044|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04869|045|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04869|046|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04869|047|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04869|048|M|as those taking CNS depressants) and when a patient has household|
04869|049|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04869|050|M|for obtaining an opioid reversal agent (e.g., prescription,|
04869|051|M|over-the-counter, or as part of a community-based program).(3)|
04869|052|B||
04869|053|D|DISCUSSION:  A nested case-control study looked at the relationship between|
04869|054|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
04869|055|D|antipsychotics was associated with a 2.33-fold increase in risk of|
04869|056|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
04869|057|D|significantly increased in patients with recent use of antipsychotics|
04869|058|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
04869|059|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
04869|060|D|of use.(4)|
04869|061|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04869|062|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04869|063|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04869|064|D|to 30 million patients.  During this time, the proportion of patients|
04869|065|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04869|066|D|patients.(5)|
04869|067|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04869|068|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04869|069|D|per 100,000 and drug overdose deaths involving both opioids and|
04869|070|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04869|071|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04869|072|D|increased from 18% to 31% during this time.(6)|
04869|073|D|   A prospective observational cohort study in North Carolina found that the|
04869|074|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04869|075|D|benzodiazepines were 10 times higher than patients receiving opioid|
04869|076|D|analgesics alone.(7)|
04869|077|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04869|078|D|death from overdose increased with concomitant opioid analgesics and|
04869|079|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04869|080|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04869|081|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04869|082|D|increased risk of fatal overdose.(8)|
04869|083|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04869|084|D|which benzodiazepines were determined to be a cause of death and that|
04869|085|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04869|086|D|determined to be a cause of death.  This study also found that other CNS|
04869|087|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04869|088|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04869|089|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04869|090|D|where opioid analgesics were also implicated.(9)|
04869|091|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04869|092|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04869|093|D|deaths.(10)|
04869|094|D|   Several cases of serotonin syndrome have been reported in patients|
04869|095|D|receiving ziprasidone.(12-14)|
04869|096|B||
04869|097|R|REFERENCES:|
04869|098|B||
04869|099|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04869|100|R|  warns about serious risks and death when combining opioid pain or cough|1
04869|101|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04869|102|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04869|103|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04869|104|R|  prescribing information for all opioid pain medicines to provide|1
04869|105|R|  additional guidance for safe use. Available at:|1
04869|106|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04869|107|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04869|108|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04869|109|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04869|110|R|  recommends health care professionals discuss naloxone with all patients|1
04869|111|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04869|112|R|  disorder. Available at:|1
04869|113|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04869|114|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04869|115|R|  d-pain July 23, 2020.|1
04869|116|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
04869|117|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
04869|118|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
04869|119|R|  Pharmacol 2020 Apr 26.|2
04869|120|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04869|121|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04869|122|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04869|123|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04869|124|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04869|125|R|  49(4):493-501.|2
04869|126|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04869|127|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04869|128|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04869|129|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04869|130|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04869|131|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04869|132|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04869|133|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04869|134|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04869|135|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04869|136|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04869|137|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04869|138|R|11.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer|1
04869|139|R|   Inc. May, 2021.|1
04869|140|R|12.Palekar N, Eisman J. Serotonin syndrome with ziprasidone and sertraline.|3
04869|141|R|   J Neuropsychiatry Clin Neurosci 2013 Spring;25(2):E1.|3
04869|142|R|13.Lin PY, Hong CJ, Tsai SJ. Serotonin syndrome caused by ziprasidone alone.|3
04869|143|R|   Psychiatry Clin Neurosci 2010 Jun;64(3):338-9.|3
04869|144|R|14.Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin|3
04869|145|R|   Syndrome in a Patient Taking Kratom and Multiple  Serotonergic Agents. J|3
04869|146|R|   Pharm Pract 2023 Dec;36(6):1523-1527.|3
04870|001|T|MONOGRAPH TITLE:  Methadone (non MAT)/Ziprasidone|
04870|002|B||
04870|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04870|004|L|of severe adverse interaction.|
04870|005|B||
04870|006|A|MECHANISM OF ACTION:  Methadone has been shown to prolong the QTc interval.|
04870|007|A|Concurrent use with ziprasidone may result in additive effects on the QTc|
04870|008|A|interval.(1-3, 14)|
04870|009|A|   Concurrent use of methadone and ziprasidone may result in additive CNS|
04870|010|A|depression.(1-3,14)|
04870|011|A|   Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake|
04870|012|A|inhibitor.  Methadone may inhibit neural uptake of serotonin.  Concurrent|
04870|013|A|use may increase serotonin effects, resulting in serotonin toxicity.(14)|
04870|014|B||
04870|015|E|CLINICAL EFFECTS:  The concurrent use of methadone with other agents that|
04870|016|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04870|017|E|arrhythmias, including torsades de pointes.(1,2)|
04870|018|E|   Concurrent use of opioids and ziprasidone may result in profound|
04870|019|E|sedation, respiratory depression, coma, and/or death.(1-3)|
04870|020|E|   Concurrent use of ziprasidone and methadone may result in serotonin|
04870|021|E|syndrome, a potentially life-threatening condition with symptoms including|
04870|022|E|altered mental status, hypertension, restlessness, myoclonus, hyperthermia,|
04870|023|E|hyperreflexia, diaphoresis, shivering, and tremor.(13)|
04870|024|B||
04870|025|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04870|026|P|may be increased in patients with cardiovascular disease (e.g. heart|
04870|027|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04870|028|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04870|029|P|female gender, or advanced age.(3)|
04870|030|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04870|031|P|higher systemic concentrations of either QT prolonging drug are additional|
04870|032|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04870|033|P|drug concentrations include rapid infusion of an intravenous dose or|
04870|034|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04870|035|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04870|036|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04870|037|P|   Concurrent use of alcohol or other CNS depressants may increase the risk|
04870|038|P|of adverse effects.|
04870|039|P|   Concomitant therapy with multiple agents which increase brain serotonin|
04870|040|P|concentrations may also increase risk for serotonin syndrome.(13)|
04870|041|B||
04870|042|M|PATIENT MANAGEMENT:  Concurrent use of methadone with agents known to|
04870|043|M|prolong the QT interval should be approached with extreme caution.(1)  Limit|
04870|044|M|prescribing methadone with CNS depressants such as antipsychotics to|
04870|045|M|patients for whom alternatives are ineffective, not tolerated, or would be|
04870|046|M|otherwise inadequate to provide sufficient management of pain.(2)|
04870|047|M|   Caution patients about the risk of serotonin syndrome with the|
04870|048|M|concomitant use of ziprasidone with other serotonergic drugs.  Instruct|
04870|049|M|patients to contact their healthcare provider, or report to the emergency|
04870|050|M|room, should they experience signs or symptoms of serotonin syndrome.(14)|
04870|051|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04870|052|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04870|053|M|regular intervals.  Correct any electrolyte abnormalities. Instruct patients|
04870|054|M|to report any irregular heartbeat, dizziness, or fainting.|
04870|055|M|   If concurrent use is necessary, limit the dosages and duration of each|
04870|056|M|drug to the minimum possible while achieving the desired clinical effect.|
04870|057|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04870|058|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04870|059|M|indicated in the absence of an opioid and titrate based upon clinical|
04870|060|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04870|061|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04870|062|M|clinical response.(2)|
04870|063|M|   Respiratory depression can occur at any time during opioid therapy,|
04870|064|M|especially during therapy initiation and following dosage increases.  The|
04870|065|M|risk of opioid-related overdose or overdose-related death is increased with|
04870|066|M|higher opioid doses, and this risk persists over the course of therapy.|
04870|067|M|Consider these risks when using concurrently with other agents that may|
04870|068|M|cause CNS depression.(4)|
04870|069|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04870|070|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04870|071|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04870|072|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04870|073|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04870|074|M|as those taking CNS depressants) and when a patient has household|
04870|075|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04870|076|M|for obtaining an opioid reversal agent (e.g., prescription,|
04870|077|M|over-the-counter, or as part of a community-based program).(5)|
04870|078|B||
04870|079|D|DISCUSSION:  Most cases of methadone-induced QT prolongation are associated|
04870|080|D|with, but not limited to, higher dose treatment (greater than 200 mg daily)|
04870|081|D|and most involve patients being treated for pain with large, multiple daily|
04870|082|D|doses.  Cases have been reported in patients treated with doses commonly|
04870|083|D|used for maintenance treatment of opioid addiction.(1)|
04870|084|D|   A nested case-control study looked at the relationship between|
04870|085|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
04870|086|D|antipsychotics was associated with a 2.33-fold increase in risk of|
04870|087|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
04870|088|D|significantly increased in patients with recent use of antipsychotics|
04870|089|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
04870|090|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
04870|091|D|of use.(6)|
04870|092|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04870|093|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04870|094|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04870|095|D|to 30 million patients.  During this time, the proportion of patients|
04870|096|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04870|097|D|patients.(7)|
04870|098|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04870|099|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04870|100|D|per 100,000 and drug overdose deaths involving both opioids and|
04870|101|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04870|102|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04870|103|D|increased from 18% to 31% during this time.(8)|
04870|104|D|   A prospective observational cohort study in North Carolina found that the|
04870|105|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04870|106|D|benzodiazepines were 10 times higher than patients receiving opioid|
04870|107|D|analgesics alone.(9)|
04870|108|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04870|109|D|death from overdose increased with concomitant opioid analgesics and|
04870|110|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04870|111|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04870|112|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04870|113|D|increased risk of fatal overdose.(10)|
04870|114|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04870|115|D|which benzodiazepines were determined to be a cause of death and that|
04870|116|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04870|117|D|determined to be a cause of death.  This study also found that other CNS|
04870|118|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04870|119|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04870|120|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04870|121|D|where opioid analgesics were also implicated.(11)|
04870|122|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04870|123|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04870|124|D|deaths.(12)|
04870|125|D|   Several cases of serotonin syndrome have been reported in patients|
04870|126|D|receiving ziprasidone.(15-17)|
04870|127|B||
04870|128|R|REFERENCES:|
04870|129|B||
04870|130|R|1.Dolophine (methadone hydrochloride) US prescribing information. Wast-Ward|1
04870|131|R|  Pharmaceuticals Corp. June, 2021.|1
04870|132|R|2.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04870|133|R|  warns about serious risks and death when combining opioid pain or cough|1
04870|134|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04870|135|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04870|136|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04870|137|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04870|138|R|  settings: a scientific statement from the American Heart Association and|6
04870|139|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04870|140|R|  2;55(9):934-47.|6
04870|141|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04870|142|R|  prescribing information for all opioid pain medicines to provide|1
04870|143|R|  additional guidance for safe use. Available at:|1
04870|144|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04870|145|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04870|146|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04870|147|R|5.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04870|148|R|  recommends health care professionals discuss naloxone with all patients|1
04870|149|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04870|150|R|  disorder. Available at:|1
04870|151|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04870|152|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04870|153|R|  d-pain July 23, 2020.|1
04870|154|R|6.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
04870|155|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
04870|156|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
04870|157|R|  Pharmacol 2020 Apr 26.|2
04870|158|R|7.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04870|159|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04870|160|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04870|161|R|8.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04870|162|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04870|163|R|  49(4):493-501.|2
04870|164|R|9.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04870|165|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04870|166|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04870|167|R|10.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04870|168|R|   prescribing patterns and deaths from drug overdose among US veterans|2
04870|169|R|   receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;|2
04870|170|R|   350:h2698.|2
04870|171|R|11.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04870|172|R|   States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04870|173|R|12.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04870|174|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04870|175|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04870|176|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04870|177|R|13.Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005 Mar 17;|6
04870|178|R|   352(11):1112-20.|6
04870|179|R|14.Geodon (ziprasidone hydrochloride) US prescribing information. Pfizer|1
04870|180|R|   Inc. May, 2021.|1
04870|181|R|15.Palekar N, Eisman J. Serotonin syndrome with ziprasidone and sertraline.|3
04870|182|R|   J Neuropsychiatry Clin Neurosci 2013 Spring;25(2):E1.|3
04870|183|R|16.Lin PY, Hong CJ, Tsai SJ. Serotonin syndrome caused by ziprasidone alone.|3
04870|184|R|   Psychiatry Clin Neurosci 2010 Jun;64(3):338-9.|3
04870|185|R|17.Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin|3
04870|186|R|   Syndrome in a Patient Taking Kratom and Multiple  Serotonergic Agents. J|3
04870|187|R|   Pharm Pract 2023 Dec;36(6):1523-1527.|3
04871|001|T|MONOGRAPH TITLE:  Hymenoptera Venom Immunotherapy/ACE Inhibitors|
04871|002|B||
04871|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04871|004|L|take action as needed.|
04871|005|B||
04871|006|A|MECHANISM OF ACTION:  Angiotensin converting enzyme (ACE) inhibitors block|
04871|007|A|the conversion of angiotensin I to angiotensin II, resulting in vasodilation|
04871|008|A|and disrupting the compensatory response during anaphylaxis.|
04871|009|A|   Concurrent use of ACE inhibitors may increase the risk and severity of an|
04871|010|A|anaphylactoid reaction to Hymenoptera venom immunotherapy.(1-15)|
04871|011|B||
04871|012|E|CLINICAL EFFECTS:  Angiotensin converting enzyme (ACE) inhibitors may|
04871|013|E|increase the risk and severity of an anaphylactoid reaction to Hymenoptera|
04871|014|E|venom immunotherapy.(1-15)|
04871|015|B||
04871|016|P|PREDISPOSING FACTORS:  None determined.|
04871|017|B||
04871|018|M|PATIENT MANAGEMENT:  Administration of Hymenoptera venom immunotherapy in|
04871|019|M|patients on angiotensin converting enzyme (ACE) inhibitors should be|
04871|020|M|approached with caution.  In patients taking ACE inhibitors, consider|
04871|021|M|temporarily withholding ACE inhibitor therapy prior to each immunotherapy|
04871|022|M|procedure.|
04871|023|M|   If patients cannot safely discontinue ACE inhibitors, monitor patients|
04871|024|M|closely for signs of an anaphylactoid reaction.(1-15)|
04871|025|B||
04871|026|D|DISCUSSION:  Patients on angiotensin converting enzyme (ACE) inhibitors may|
04871|027|D|be at increased risk of an anaphylactoid reaction to Hymenoptera venom|
04871|028|D|immunotherapy.|
04871|029|D|   Clinical studies and guideline recommendations for concurrent use of ACE|
04871|030|D|inhibitors and Hymenoptera venom immunotherapy range from use with caution|
04871|031|D|to a relative contraindication.  Patients should be informed of the|
04871|032|D|potential risk of the possible interaction.(1-22)|
04871|033|B||
04871|034|R|REFERENCES:|
04871|035|B||
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04871|052|R|  clinical immunology/allergy specialists..|6
04871|053|R|10.Rueff F Bauer A Becker S Brehler R Brockow K Chaker AM Darsow U Fischer J|6
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04871|061|R|   Antolin-Amerigo D, Cichocka-Jarosz E, Gawlik R, Jakob T. EAACI guidelines|6
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04871|069|R|14.Slade CA, Douglass JA. Changing practice: no need to stop ACE inhibition|6
04871|070|R|   for venom immunotherapy. Clin Exp Allergy 2014;44(5):617-9.|6
04871|071|R|15.Pesek RD, Lockey RF. Treatment of Hymenoptera venom allergy: an update.|6
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04871|075|R|   inhibitors are not a risk factor for severe systemic sting  reactions and|2
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04871|079|R|   Angiotensin-converting enzyme inhibitors do not impair the safety of|2
04871|080|R|   Hymenoptera  venom immunotherapy build-up phase. Clin Exp Allergy 2014;|2
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04871|082|R|18.White KM, England RW. Safety of angiotensin-converting enzyme inhibitors|2
04871|083|R|   while receiving venom  immunotherapy. Ann Allergy Asthma Immunol 2008|2
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04871|087|R|   Allergy Clin Immunol 2024 Sep 2.|2
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04871|093|R|   anaphylactic reactions in patients with Hymenoptera  venom allergy:|2
04871|094|R|   importance of baseline serum tryptase. J Allergy Clin Immunol 2009 Nov;|2
04871|095|R|   124(5):1047-54.|2
04871|096|R|22.Francuzik W, Rueff F, Bauer A, Bilo MB, Cardona V, Christoff G,|2
04871|097|R|   Dolle-Bierke S, Ensina L, Fernandez Rivas M, Hawranek T. Phenotype and|2
04871|098|R|   risk factors of venom-induced anaphylaxis: A case-control study of the|2
04871|099|R|   European Anaphylaxis Registry. J Allergy Clin Immunol 2021 Feb;|2
04871|100|R|   147(2):653-622.|2
04872|001|T|MONOGRAPH TITLE:  Selected Immunosuppressants/Voriconazole|
04872|002|B||
04872|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04872|004|L|of severe adverse interaction.|
04872|005|B||
04872|006|A|MECHANISM OF ACTION:  The metabolism of cyclosporine and temsirolimus by|
04872|007|A|CYP3A4 may be inhibited by voriconazole.(1-2)|
04872|008|B||
04872|009|E|CLINICAL EFFECTS:  Concurrent administration of voriconazole may result in|
04872|010|E|elevated levels of and toxicity from cyclosporine or temsirolimus.(1-2)|
04872|011|B||
04872|012|P|PREDISPOSING FACTORS:  Concurrent use of voriconazole in patients who are|
04872|013|P|poor or intermediate CYP2C19 metabolizers may necessitate larger|
04872|014|P|immunosuppressant dose adjustments than in patients who are extensive|
04872|015|P|CYP2C19 metabolizers.(3)|
04872|016|B||
04872|017|M|PATIENT MANAGEMENT:  Cyclosporine or temsirolimus levels and renal function|
04872|018|M|should be monitored if voriconazole is initiated or discontinued from|
04872|019|M|concurrent therapy.(1-2)|
04872|020|M|   The manufacturer of voriconazole recommends that the dose of cyclosporine|
04872|021|M|be reduced by 50% when used with voriconazole.(1)  Cyclosporine levels|
04872|022|M|should be closely monitored during concurrent azole therapy.  The dosage of|
04872|023|M|cyclosporine may need adjusting when azole therapy has been completed.(1)|
04872|024|M|   The US manufacturer of temsirolimus recommends that concurrent therapy|
04872|025|M|with strong CYP3A4 inhibitors be avoided.  If concurrent use is warranted, a|
04872|026|M|dosage reduction to 12.5 mg/week of temsirolimus should be considered.  If|
04872|027|M|the azole is discontinued, a washout period of 1 week should be allowed|
04872|028|M|before adjusting the dosage of temsirolimus to previous levels.(2)|
04872|029|B||
04872|030|D|DISCUSSION:  In renal transplant recipients, voriconazole (200 mg orally|
04872|031|D|every 12 hours for 8 days) increased the maximum concentration (Cmax),|
04872|032|D|area-under-curve (AUC), and trough concentration (Cmin) of cyclosporine by|
04872|033|D|1.1-fold, 1.7-fold, and 2.48-fold, respectively.(4)|
04872|034|B||
04872|035|R|REFERENCES:|
04872|036|B||
04872|037|R|1.Vfend (voriconazole) US prescribing information. Pfizer Inc. March, 2025.|1
04872|038|R|2.Torisel (temsirolimus) US prescribing information. Wyeth Pharmaceuticals,|1
04872|039|R|  Inc. March, 2018.|1
04872|040|R|3.Huang X, Zhou Y, Zhang J, Xiang H, Mei H, Liu L, Tong L, Zeng F, Huang Y,|2
04872|041|R|  Zhou H, Zhang Y. The importance of CYP2C19 genotype in tacrolimus dose|2
04872|042|R|  optimization when  concomitant with voriconazole in heart transplant|2
04872|043|R|  recipients. Br J Clin Pharmacol 2022 May 4.|2
04872|044|R|4.Romero AJ, Pogamp PL, Nilsson LG, Wood N. Effect of voriconazole on the|2
04872|045|R|  pharmacokinetics of cyclosporine in renal transplant patients. Clin|2
04872|046|R|  Pharmacol Ther 2002 Apr;71(4):226-34.|2
04872|047|R|5.Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S. Drug interaction|2
04872|048|R|  between voriconazole and calcineurin inhibitors in allogeneic|2
04872|049|R|  hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2009|2
04872|050|R|  Sep;44(6):371-4.|2
04873|001|T|MONOGRAPH TITLE:  Foslevodopa; Levodopa/Linezolid|
04873|002|B||
04873|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04873|004|L|of severe adverse interaction.|
04873|005|B||
04873|006|A|MECHANISM OF ACTION:  Linezolid is a weak, nonselective monoamine oxidase|
04873|007|A|inhibitor (MAOI) that blocks the metabolism of dopamine and norepinephrine,|
04873|008|A|which are formed by levodopa. Also, storage and release of dopamine and|
04873|009|A|norepinephrine is increased.(1-2)|
04873|010|A|   Foslevodopa is a prodrug of levodopa.|
04873|011|B||
04873|012|E|CLINICAL EFFECTS:  Concurrent use of linezolid may result in increased|
04873|013|E|effects of levodopa, including tremor, hypertensive crisis, and postural|
04873|014|E|hypotension.|
04873|015|B||
04873|016|P|PREDISPOSING FACTORS:  None determined.|
04873|017|B||
04873|018|M|PATIENT MANAGEMENT:  The US manufacturer of carbidopa/levodopa states that|
04873|019|M|the concurrent use of nonselective MAO inhibitors is contraindicated.(1)|
04873|020|M|   The Canadian manufacturer of foslevodopa/foscarbidopa states that|
04873|021|M|concurrent use of nonselective MAO inhibitors and selective MAO type A|
04873|022|M|inhibitors is contraindicated.  MAO inhibitors should be stopped at least 2|
04873|023|M|weeks prior to initiation of foslevodopa/foscarbidopa therapy.(2)|
04873|024|M|   The manufacturer of linezolid does not contraindicate the use of|
04873|025|M|adrenergic agents but states that they should not be coadministered unless|
04873|026|M|the patient is closely monitored for potential increases in blood|
04873|027|M|pressure.(3)|
04873|028|M|   If concurrent therapy is warranted, patients should be monitored closely|
04873|029|M|for hypertensive crisis.|
04873|030|M|   The addition of a decarboxylase inhibitor to the combination of a|
04873|031|M|non-selective MAO inhibitor and levodopa may minimize risk of adverse|
04873|032|M|effects.  Phentolamine has been effective in treating hypertension caused by|
04873|033|M|this interaction.|
04873|034|B||
04873|035|D|DISCUSSION:  Hypertensive reactions, flushing, and palpitations have been|
04873|036|D|reported as a result of the interaction between levodopa and other MAO|
04873|037|D|inhibitors.|
04873|038|D|   In a case report, an 89-year-old female with COPD, sick sinus syndrome,|
04873|039|D|atrial fibrillation, hypertension, history of CVA, ischemic colitis, and|
04873|040|D|Parkinson's disease on many medications including carbidopa-levodopa for 6|
04873|041|D|years took linezolid for 8 days and developed seizure-like activity.  The|
04873|042|D|patient was afebrile and normotensive, but was tachycardic, lethargic,|
04873|043|D|agitated, and exhibited clonus on examination 2 days after linezolid was|
04873|044|D|discontinued.(4)|
04873|045|B||
04873|046|R|REFERENCES:|
04873|047|B||
04873|048|R|1.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
04873|049|R|  February, 2011.|1
04873|050|R|2.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
04873|051|R|3.Vyalev (foslevodopa/foscarbidopa) Canadian product monograph. AbbVie|1
04873|052|R|  Corporation May, 2023.|1
04873|053|R|4.Pettit NN, Alonso V, Wojcik E, Anyanwu EC, Ebara L, Benoit JL. Possible|3
04873|054|R|  serotonin syndrome with carbidopa-levodopa and linezolid. J Clin Pharm|3
04873|055|R|  Ther 2016 Feb;41(1):101-3.|3
04874|001|T|MONOGRAPH TITLE:  Carbidopa-Levodopa-Entacapone/Linezolid|
04874|002|B||
04874|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04874|004|L|of severe adverse interaction.|
04874|005|B||
04874|006|A|MECHANISM OF ACTION:  Since monoamine oxidase (MAO) and|
04874|007|A|catechol-O-methyltransferase (COMT) are the two major enzymes responsible|
04874|008|A|for the metabolism of catecholamines, the combination of|
04874|009|A|carbidopa-levodopa-entacapone and a non-selective MAOI may inhibit the|
04874|010|A|majority of catecholamine metabolism pathways.(1-5)|
04874|011|A|   Linezolid is a weak, nonselective monoamine oxidase inhibitor (MAOI).(6)|
04874|012|B||
04874|013|E|CLINICAL EFFECTS:  Concurrent administration of|
04874|014|E|carbidopa-levodopa-entacapone with linezolid may result in elevated levels|
04874|015|E|of catecholamines, which may result in elevated heart rate and blood|
04874|016|E|pressure.(1)|
04874|017|B||
04874|018|P|PREDISPOSING FACTORS:  None determined.|
04874|019|B||
04874|020|M|PATIENT MANAGEMENT:  The US manufacturer of carbidopa-levodopa-entacapone|
04874|021|M|states that concomitant use with a non-selective MAOI is contraindicated.|
04874|022|M|Nonselective MAOI should be discontinued at least 2 weeks prior to|
04874|023|M|initiating therapy with carbidopa-levodopa-entacapone.(1)|
04874|024|M|   The US manufacturer of carbidopa-levodopa states that the concurrent use|
04874|025|M|of nonselective MAO inhibitors is contraindicated.  Carbidopa-levodopa may|
04874|026|M|be administered with recommended dosages of selective MAO-B inhibitors.(2)|
04874|027|M|   The Canadian(5) and UK(3) manufacturers of entacapone state that|
04874|028|M|concomitant use of either a non-selective MAOI or a selective MAO-A|
04874|029|M|inhibitor with a selective MAO-B inhibitor with entacapone is|
04874|030|M|contraindicated.  Nonselective MAOI should be discontinued at least 2 weeks|
04874|031|M|prior to initiating entacapone therapy.|
04874|032|M|   The manufacturer of linezolid does not contraindicate the use of|
04874|033|M|adrenergic agents but states that they should not be coadministered unless|
04874|034|M|the patient is closely monitored for potential increases in blood|
04874|035|M|pressure.(6)|
04874|036|M|   If concurrent therapy is warranted, patients should be monitored closely|
04874|037|M|for hypertensive crisis.|
04874|038|M|   The addition of a decarboxylase inhibitor to the combination of a|
04874|039|M|non-selective MAO inhibitor and levodopa may minimize risk of adverse|
04874|040|M|effects.  Phentolamine has been effective in treating hypertension caused by|
04874|041|M|this interaction.|
04874|042|B||
04874|043|D|DISCUSSION:  Hypertensive reactions, flushing, and palpitations have been|
04874|044|D|reported as a result of the interaction between levodopa and other MAO|
04874|045|D|inhibitors.|
04874|046|D|   Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the|
04874|047|D|two major enzymes systems involved in the metabolism of catecholamines.|
04874|048|D|Therefore, theoretically, the combination of either entacapone, tolcapone,|
04874|049|D|or opicapone with a non-selective MAO inhibitor will result in inhibition of|
04874|050|D|the majority of catecholamine metabolism pathways.(1-5)|
04874|051|D|   In a case report, an 89-year-old female with COPD, sick sinus syndrome,|
04874|052|D|atrial fibrillation, hypertension, history of CVA, ischemic colitis, and|
04874|053|D|Parkinson's disease on many medications including carbidopa-levodopa for 6|
04874|054|D|years took linezolid for 8 days and developed seizure-like activity.  The|
04874|055|D|patient was afebrile and normotensive, but was tachycardic, lethargic,|
04874|056|D|agitated, and exhibited clonus on examination 2 days after linezolid was|
04874|057|D|discontinued.(7)|
04874|058|B||
04874|059|R|REFERENCES:|
04874|060|B||
04874|061|R|1.Stalveo (carbidopa; entacapone; levodopa) US Prescribing Information.|1
04874|062|R|  Orion/Novartis December, 2019.|1
04874|063|R|2.Sinemet (carbidopa/levodopa) US prescribing information. Merck & Co., Inc|1
04874|064|R|  February, 2011.|1
04874|065|R|3.Comtess (entacapone) UK summary of product characteristics. Orion Pharma,|1
04874|066|R|  UK September 16, 1998.|1
04874|067|R|4.Comtan (entacapone) US prescribing information. Orion Corporation|1
04874|068|R|  February, 2016.|1
04874|069|R|5.Comtan (entacapone) Canadian prescribing information. Novartis|1
04874|070|R|  Pharmaceuticals Canada Inc. March, 2006.|1
04874|071|R|6.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
04874|072|R|7.Pettit NN, Alonso V, Wojcik E, Anyanwu EC, Ebara L, Benoit JL. Possible|3
04874|073|R|  serotonin syndrome with carbidopa-levodopa and linezolid. J Clin Pharm|3
04874|074|R|  Ther 2016 Feb;41(1):101-3.|3
04875|001|T|MONOGRAPH TITLE:  Selected 5-HT1D Agonists/Linezolid|
04875|002|B||
04875|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04875|004|L|of severe adverse interaction.|
04875|005|B||
04875|006|A|MECHANISM OF ACTION:  Monoamine oxidase inhibitors (MAOIs) inhibit the|
04875|007|A|metabolism of rizatriptan,(1) sumatriptan,(2-9) and zolmitriptan.(10)|
04875|008|A|   Linezolid is a weak, reversible, nonselective MAOI.(12)|
04875|009|B||
04875|010|E|CLINICAL EFFECTS:  Concurrent use of linezolid may result in increased|
04875|011|E|levels and effects of rizatriptan, sumatriptan or zolmitriptan.(1-11)|
04875|012|B||
04875|013|P|PREDISPOSING FACTORS:  Patients with a history of cardiovascular disease,|
04875|014|P|e.g. coronary artery disease (CAD), transient ischemic attack (TIA), stroke,|
04875|015|P|cardiac conduction disorders or poorly controlled hypertension, are not|
04875|016|P|considered candidates for 5-HT1D agonist therapy and would be at greater|
04875|017|P|risk for toxicity due to this interaction.|
04875|018|B||
04875|019|M|PATIENT MANAGEMENT:  Concurrent administration of rizatriptan and a MAOI or|
04875|020|M|administration of rizatriptan within two weeks of the discontinuation of a|
04875|021|M|MAOI is contraindicated according to product labeling for rizatriptan.(1)|
04875|022|M|   Concurrent administration of sumatriptan and a MAOI within two weeks of|
04875|023|M|the discontinuation of a MAOI is contraindicated according to the|
04875|024|M|Australian, Canada, UK, and US product labeling for these agents.(2-9)|
04875|025|M|  Concurrent administration of zolmitriptan and a MAO-A Inhibitor or the|
04875|026|M|administration of zolmitriptan within two weeks of discontinuation of a|
04875|027|M|MAO-A Inhibitor is contraindicated according to US labeling.(10)  The UK|
04875|028|M|manufacturer states that a maximum of 7.5 mg of zolmitriptan should be|
04875|029|M|administered within 24 hours of a MAO-A inhibitor.(11)|
04875|030|M|   The manufacturer of linezolid does not contraindicated the use of 5-HT1D|
04875|031|M|agonists but states that they should not be coadministered unless clinically|
04875|032|M|appropriate and patients are carefully observed for signs and symptoms of|
04875|033|M|serotonin syndrome.(12)|
04875|034|M|  Eletriptan and frovatriptan are not metabolized by MAO-A(13,14) and may be|
04875|035|M|an alternative in patients who require treatment with linezolid.|
04875|036|B||
04875|037|D|DISCUSSION:  The combination of linezolid and 5-HT1D agonists has not been|
04875|038|D|studied.  Other MAOIs have been reported to interact with 5-HT1D agonists.|
04875|039|D|   Rizatriptan is metabolized by the 'A' subtype of monoamine oxidase.  In a|
04875|040|D|study with 12 subjects, the concurrent administration of rizatriptan (10 mg)|
04875|041|D|with moclobemide (450 mg daily, a selective, reversible MAO-A inhibitor)|
04875|042|D|resulted in increases in the rizatriptan area-under-curve (AUC) and maximum|
04875|043|D|concentration (Cmax) by 119% and 41%, respectively.  The AUC of the active|
04875|044|D|metabolite, N-monodesmethyl rizatriptan, increased over 400%.  Plasma|
04875|045|D|concentrations of rizatriptan may be increased by selective MAO-A inhibitors|
04875|046|D|or by nonselective MAO-A&B inhibitors, although the interaction is expected|
04875|047|D|to be greater with selective MAO-A inhibitors.  The manufacturer also states|
04875|048|D|that no interaction is expected with selective MAO-B inhibitors.(1)|
04875|049|D|   Sumatriptan oral bioavailability is approximately 15%, primarily due to|
04875|050|D|presystemic clearance by MAO-A in the gut and liver.  A small study found an|
04875|051|D|approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A|
04875|052|D|inhibitor was given prior to a 25 mg oral dose of sumatriptan.(4)|
04875|053|D|  In another study, pretreatment with an MAO-A inhibitor prior to|
04875|054|D|administration of injectable sumatriptan resulted in a 2-fold increase in|
04875|055|D|sumatriptan AUC and a 40% increase in elimination half-life.(8)|
04875|056|D|Pretreatment with a MAO-B inhibitor did not produce any significant changes|
04875|057|D|in sumatriptan pharmacokinetics.  The effect of a MAOI on nasal sumatriptan|
04875|058|D|systemic absorption is expected to be less than that seen with oral|
04875|059|D|sumatriptan but greater than that seen with injectable sumatriptan.(6)|
04875|060|D|  Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg|
04875|061|D|twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold|
04875|062|D|increase in Cmax and AUC for zolmitriptan's active N-desmethyl|
04875|063|D|metabolite.(10,11)|
04875|064|B||
04875|065|R|REFERENCES:|
04875|066|B||
04875|067|R|1.Maxalt (rizatriptan) US prescribing information. Merck & Co., Inc.|1
04875|068|R|  October, 2019.|1
04875|069|R|2.Imigran Tablets, Injection, and Nasal Spray (sumatriptan) Australian|1
04875|070|R|  prescribing information. GlaxoSmithKline February 11, 2002.|1
04875|071|R|3.Imigran Radis (sumaptriptan) UK summary of product characteristics.|1
04875|072|R|  GlaxoSmithKline UK June 8, 2004.|1
04875|073|R|4.Imitrex Tablets (sumatriptan) US prescribing information. GlaxoSmithKline|1
04875|074|R|  December 14, 2017.|1
04875|075|R|5.Imigran Nasal Spray (sumatriptan) UK summary of product characteristics.|1
04875|076|R|  GlaxoSmithKline UK July 8, 2004.|1
04875|077|R|6.Imitrex Nasal Spray (sumatriptan) US prescribing information.|1
04875|078|R|  GlaxoSmithKline December 14, 2017.|1
04875|079|R|7.Imigran Injection (sumatriptan) UK summary of product characteristics.|1
04875|080|R|  GlaxoSmithKline UK September 19, 2003.|1
04875|081|R|8.Imitrex Injection (sumatriptan) US prescribing information.|1
04875|082|R|  GlaxoSmithKline December 14, 2017.|1
04875|083|R|9.Imitrex (sumatriptan) CA prescribing information. GlaxoSmithKline Inc.|1
04875|084|R|  September 22, 2011.|1
04875|085|R|10.Zomig (zolmitriptan) US prescribing information. AstraZeneca|1
04875|086|R|   Pharmaceuticals LP September, 2012.|1
04875|087|R|11.Zomig (zolmitriptan) UK summary of product characteristics. Zeneca|1
04875|088|R|   Limited March, 1997.|1
04875|089|R|12.Zyvox (linezolid) US prescribing information. Pfizer Inc. November, 2021.|1
04875|090|R|13.Relpax (eletriptan hydrobromide) US prescribing information. Pfizer Inc.|1
04875|091|R|   March, 2020.|1
04875|092|R|14.Frova (frovatriptan) US prescribing information. Endo Pharmaceuticals|1
04875|093|R|   August, 2018.|1
04875|094|R|15.Eldepryl (selegiline) US prescribing information. Somerset|1
04875|095|R|   Pharmaceuticals February, 1997.|1
04875|096|R|16.Phansalkar S, Desai AA, Bell D, Yoshida E, Doole J, Czochanski M,|6
04875|097|R|   Middleton B, Bates DW. High-priority drug-drug interactions for use in|6
04875|098|R|   electronic health records. J Am Med Inform Assoc 2012 Sep-Oct;|6
04875|099|R|   19(5):735-43.|6
04876|001|T|MONOGRAPH TITLE:  Hemin/Anticoagulants|
04876|002|B||
04876|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04876|004|L|of severe adverse interaction.|
04876|005|B||
04876|006|A|MECHANISM OF ACTION:  Mild, transient anticoagulant effects has been|
04876|007|A|reported with the use of hemin.(1)|
04876|008|B||
04876|009|E|CLINICAL EFFECTS:  Concurrent use of hemin with anticoagulants may increase|
04876|010|E|the risk of bleeding.(1)|
04876|011|B||
04876|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04876|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04876|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
04876|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04876|016|P|risk for bleeding (e.g. NSAIDs).|
04876|017|B||
04876|018|M|PATIENT MANAGEMENT:  The manufacturer of hemin states concurrent use with|
04876|019|M|anticoagulant therapy should be avoided.(1)|
04876|020|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04876|021|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04876|022|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04876|023|M|patients with any symptoms.|
04876|024|M|   When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT)|
04876|025|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04876|026|M|anticoagulation in patients with active pathologic bleeding.|
04876|027|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04876|028|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04876|029|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04876|030|M|and/or swelling.|
04876|031|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04876|032|M|precipitant drug is initiated or discontinued.  Contact the prescriber|
04876|033|M|before initiating, altering the dose or discontinuing either drug.|
04876|034|B||
04876|035|D|DISCUSSION:  Mild, transient anticoagulant effects have been reported during|
04876|036|D|clinical studies with hemin.(1)|
04876|037|B||
04876|038|R|REFERENCE:|
04876|039|B||
04876|040|R|1.Panhematin (hemin) US prescribing information. Recordati Rare Diseases,|1
04876|041|R|  Inc. May, 2024.|1
04877|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Zanubrutinib|
04877|002|B||
04877|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04877|004|L|of severe adverse interaction.|
04877|005|B||
04877|006|A|MECHANISM OF ACTION:  Zanubrutinib is a weak CYP3A4 inducer.|
04877|007|A|Coadministration of zanubrutinib with hormonal contraceptives may lead to|
04877|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
04877|009|A|decreased hormonal concentrations.(1,2)|
04877|010|B||
04877|011|E|CLINICAL EFFECTS:  Concurrent use of zanubrutinib may reduce the|
04877|012|E|effectiveness of hormonal contraceptives.(1,2)|
04877|013|B||
04877|014|P|PREDISPOSING FACTORS:  None determined.|
04877|015|B||
04877|016|M|PATIENT MANAGEMENT:  Women of reproductive age should be counseled to use|
04877|017|M|highly effective contraception due to the risk of fetal harm with|
04877|018|M|zanubrutinib.  Women of reproductive age should not rely on hormonal|
04877|019|M|contraception (including oral contraceptives, patches, implants, and/or|
04877|020|M|IUDs) due to the risk of contraceptive failure.  Women who use hormonal|
04877|021|M|methods of birth control must add a barrier method.(1)|
04877|022|M|   Advise females of reproductive potential to use effective non-hormonal|
04877|023|M|contraception (e.g., non-hormonal intrauterine system) or additional|
04877|024|M|non-hormonal contraceptive (e.g., condoms) during treatment with|
04877|025|M|zanubrutinib and for 7 days after the last dose.(1,2)|
04877|026|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04877|027|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04877|028|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04877|029|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
04877|030|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
04877|031|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
04877|032|M|and to seek medical advice if she does become pregnant.(3)|
04877|033|B||
04877|034|D|DISCUSSION:  Zanubrutinib is a weak CYP3A4 inducer.(1,2)|
04877|035|D|   Coadministration of zanubrutinib with midazolam (a CYP3A substrate)|
04877|036|D|decreased the concentration maximum (Cmax) and area-under-curve (AUC) of|
04877|037|D|midazolam by 30% and 47%, respectively.(1,2)|
04877|038|B||
04877|039|R|REFERENCES:|
04877|040|B||
04877|041|R|1.Brukinsa (zanubrutinib) Canadian product monograph. BeiGene Switzerland|1
04877|042|R|  GmbH December, 2024.|1
04877|043|R|2.Brukinsa (zanubrutinib) US prescribing information. BeiGene June, 2025.|1
04877|044|R|3.Medicines and Healthcare products Regulatory Agency.|1
04877|045|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04877|046|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04877|047|R|  available at:|1
04877|048|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04877|049|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04877|050|R|  -and-contraceptive-efficacy September 15, 2016..|1
04878|001|T|MONOGRAPH TITLE:  Digoxin/Vimseltinib|
04878|002|B||
04878|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04878|004|L|of severe adverse interaction.|
04878|005|B||
04878|006|A|MECHANISM OF ACTION:  Vimseltinib may increase the absorption of digoxin by|
04878|007|A|inhibiting P-glycoprotein (P-gp).(1)|
04878|008|B||
04878|009|E|CLINICAL EFFECTS:  Concurrent use of vimseltinib may result in elevated|
04878|010|E|levels of and toxicity from digoxin.(1)|
04878|011|E|   Symptoms of digoxin toxicity can include anorexia, nausea, vomiting,|
04878|012|E|headache, fatigue, malaise, drowsiness, generalized muscle weakness,|
04878|013|E|disorientation, hallucinations, visual disturbances, and arrhythmias.|
04878|014|B||
04878|015|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
04878|016|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
04878|017|P|risk of digoxin toxicity.|
04878|018|B||
04878|019|M|PATIENT MANAGEMENT:  Monitor digoxin concentrations before initiating|
04878|020|M|concomitant use with vimseltinib and continue monitoring serum digoxin|
04878|021|M|concentrations as recommended in the prescribing information for|
04878|022|M|digoxin.(1-2)|
04878|023|M|   The manufacturer of digoxin recommends decreasing the dose of digoxin by|
04878|024|M|approximately 15-30% or by modifying the dosing frequency to reduce digoxin|
04878|025|M|concentrations.(2)|
04878|026|M|   The manufacturer of vimseltinib recommends avoiding concomitant use with|
04878|027|M|P-gp substrates.(1)|
04878|028|B||
04878|029|D|DISCUSSION:  In a clinical model, vimseltinib (30 mg twice weekly) increased|
04878|030|D|maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of|
04878|031|D|dabigatran (a P-gp substrate) by 2- to 3-fold.  Dabigatran Cmax and AUC are|
04878|032|D|predicted to increase up to 1.3-fold if administered 4 hours after|
04878|033|D|administration of vimseltinib 30 mg twice weekly.(1)|
04878|034|B||
04878|035|R|REFERENCES:|
04878|036|B||
04878|037|R|1.Romvimza (vimseltinib) US prescribing information. Deciphera|1
04878|038|R|  Pharmaceuticals, LLC February, 2025.|1
04878|039|R|2.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
04878|040|R|  Pharmaceuticals, Inc. August, 2018.|1
04879|001|T|MONOGRAPH TITLE:  Colchicine/Quinupristin-Dalfopristin, Pristinamycin|
04879|002|B||
04879|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04879|004|L|is contraindicated and generally should not be dispensed or administered to|
04879|005|L|the same patient.|
04879|006|B||
04879|007|A|MECHANISM OF ACTION:  Quinupristin-dalfopristin or pristinamycin may inhibit|
04879|008|A|the metabolism of colchicine by CYP3A4.(1)|
04879|009|B||
04879|010|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inhibitor may result in|
04879|011|E|elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
04879|012|E|toxicity include muscle weakness or pain; numbness or tingling in the|
04879|013|E|fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea|
04879|014|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
04879|015|E|color of the lips, tongue, or palms of hands.(1)|
04879|016|B||
04879|017|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04879|018|P|patients with renal or hepatic impairment.(1)|
04879|019|B||
04879|020|M|PATIENT MANAGEMENT:  The manufacturer of pristinamycin state that concurrent|
04879|021|M|use with colchicine is contraindicated.(1)|
04879|022|M|   The US manufacturer of quinupristin-dalfopristin recommends caution and|
04879|023|M|monitoring with narrow therapeutic index drugs including colchicine.(4)|
04879|024|B||
04879|025|D|DISCUSSION:  There are reports of colchicine toxicity(2) and death(3)|
04879|026|D|following the the concomitant administration of colchicine and|
04879|027|D|pristinamycin.|
04879|028|D|   In a study in 24 subjects, concurrent administration of|
04879|029|D|quinupristin-dalfopristin (7.5 mg/kg every 8 hours for 2 days) and|
04879|030|D|cyclosporine (300 mg on Day 3, CYP3A4 substrate) resulted in an increase in|
04879|031|D|cyclosporine's area-under-the-curve (AUC) and maximum concentration (Cmax)|
04879|032|D|of 63% and 30%, respectively. Cyclosporine half-life increased 77% while|
04879|033|D|clearance decreased 34%.(4)|
04879|034|D|   Concurrent administration of quinupristin-dalfopristin with nifedipine|
04879|035|D|(repeat oral doses, CYP3A4 substrate) in healthy volunteers increased the|
04879|036|D|Cmax and AUC by 18% and 44%. Concurrent midazolam (intravenous bolus dose,|
04879|037|D|CYP3A4 substrate) in healthy volunteers increased the Cmax and AUC by 14%|
04879|038|D|and 33%.(4)|
04879|039|D|   In a case report, concurrent administration of cyclosporine and|
04879|040|D|quinupristin-dalfopristin resulted in a 3-fold increase in cyclosporine|
04879|041|D|trough level which was managed by a 33% dose reduction in the cyclosporine|
04879|042|D|dose.(4) There are several other case reports of toxicity and increased|
04879|043|D|cyclosporine trough levels.(5,6)|
04879|044|D|   In a case report, concurrent administration of everolimus (CYP3A4|
04879|045|D|substrate) and pristinamycin resulted in a significant increase in|
04879|046|D|everolimus levels (increased to 33.5 mcg/L on Day 3 of pristinamycin) which|
04879|047|D|was managed by a 25% reduction in the everolimus dose.(7)|
04879|048|D|   In a case report, concurrent administration of tacrolimus (CYP3A4|
04879|049|D|substrate) and pristinamycin resulted in a 5-fold increase in tacrolimus|
04879|050|D|trough level.(8)|
04879|051|B||
04879|052|R|REFERENCES:|
04879|053|B||
04879|054|R|1.Pyostacin (pristinamycin) Australian product information. Sanofi Winthrop|1
04879|055|R|  Industrie Dec 2020.|1
04879|056|R|2.Nisse P, Arab T, Garat A, Descamps IM, Canevet C, Gressier B. Death|3
04879|057|R|  following administration of pristinamycine and colchicine. Presse Med 2012|3
04879|058|R|  Apr;41(4):441-2.|3
04879|059|R|3.Burns. Colchicine-pristinamycin co-prescription is dangerous. J Intern Med|3
04879|060|R|  2010;31(Suppl 1):S141.|3
04879|061|R|4.Synercid IV (quinupristin and dalfopristin for injection) US prescribing|1
04879|062|R|  information. Pfizer Inc March 2017.|1
04879|063|R|5.Gagnadoux MF, Loirat C, Pillion G, Bertheleme JP, Pouliquen M, Guest G,|3
04879|064|R|  Broyer M. Nephrotoxicity of pristinamycin-cyclosporin interaction in renal|3
04879|065|R|  transplant  patients. Presse Med 1987 Oct 24;16(35):1761.|3
04879|066|R|6.Herbrecht R, Garcia JJ, Bergerat JP, Oberling F. Effect of pristinamycin|3
04879|067|R|  on cyclosporin levels in bone marrow transplant  recipients. Bone Marrow|3
04879|068|R|  Transplant 1989 Jul;4(4):457-8.|3
04879|069|R|7.Lee LM Au Peh C. Interaction between everolimus and pristinamycin. NDT|3
04879|070|R|  Plus 2010;3:195-202.|3
04879|071|R|8.Belaiche S Logerol S Malvezzi P Qin W Tetaz R Zaoui P. Drug Interaction|3
04879|072|R|  with Pristinamycin in a Kidney and Pancrease Transplant Patient. J Nephrol|3
04879|073|R|  Therapeut 2012;S4:009.|3
04880|001|T|MONOGRAPH TITLE:  Slt Immunosuppressants/Quinupristin-Dalfopristin;|
04880|002|T|Pristinamycin|
04880|003|B||
04880|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04880|005|L|take action as needed.|
04880|006|B||
04880|007|A|MECHANISM OF ACTION:  The metabolism of immunosuppressants by CYP3A4 may be|
04880|008|A|inhibited by quinupristin-dalfopristin and pristinamycin.|
04880|009|B||
04880|010|E|CLINICAL EFFECTS:  Concurrent administration of quinupristin-dalfopristin or|
04880|011|E|pristinamycin may result in elevated levels of and toxicity from|
04880|012|E|immunosuppressants.|
04880|013|B||
04880|014|P|PREDISPOSING FACTORS:  None determined.|
04880|015|B||
04880|016|M|PATIENT MANAGEMENT:  Immunosuppressant levels and renal function should be|
04880|017|M|monitored if quinupristin-dalfopristin or pristinamycin is initiated or|
04880|018|M|discontinued from concurrent therapy.  The dosage of the immunosuppressant|
04880|019|M|may need to be adjusted.|
04880|020|M|   The US manufacturer of quinupristin-dalfopristin recommends caution and|
04880|021|M|monitoring with immunosuppressants.(1)|
04880|022|M|   The Australian manufacturer of pristinamycin recommends monitoring of|
04880|023|M|immunosuppressants levels, renal function, and adjustment of dose during|
04880|024|M|concomitant use and after discontinuation of the inhibitor.(2)|
04880|025|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
04880|026|M|a dose reduction to 56 mg/m2 is recommended when used concurrently moderate|
04880|027|M|or weak CYP3A4 inhibitors.(3)|
04880|028|B||
04880|029|D|DISCUSSION:  In a study in 24 subjects, concurrent administration of|
04880|030|D|quinupristin-dalfopristin (7.5 mg/kg every 8 hours for 2 days) and|
04880|031|D|cyclosporine (300 mg on Day 3, CYP3A4 substrate) resulted in an increase in|
04880|032|D|cyclosporine's area-under-the-curve (AUC) and maximum concentration (Cmax)|
04880|033|D|of 63% and 30%, respectively. Cyclosporine half-life increased 77% while|
04880|034|D|clearance decreased 34%.(1)|
04880|035|D|   Concurrent administration of quinupristin-dalfopristin with nifedipine|
04880|036|D|(repeat oral doses) in healthy volunteers increased the Cmax and AUC by 18%|
04880|037|D|and 44%. Concurrent midazolam (intravenous bolus dose) in healthy volunteers|
04880|038|D|increased the Cmax and AUC by 14% and 33%.(1)|
04880|039|D|   In a case report, concurrent administration of cyclosporine and|
04880|040|D|quinupristin-dalfopristin resulted in a 3-fold increase in cyclosporine|
04880|041|D|trough level which was managed by a 33% dose reduction in the cyclosporine|
04880|042|D|dose.(4) There are several other case reports of toxicity and increased|
04880|043|D|cyclosporine trough levels.(7,8)|
04880|044|D|   In a case report, concurrent administration of everolimus and|
04880|045|D|pristinamycin resulted in a significant increase in everolimus levels|
04880|046|D|(increased to 33.5 mcg/L on Day 3 of pristinamycin) which was managed by a|
04880|047|D|25% reduction in the everolimus dose.(5)|
04880|048|D|   In a case report, concurrent administration of tacrolimus and|
04880|049|D|pristinamycin resulted in a 5-fold increase in tacrolimus trough level.(6)|
04880|050|D|   Immunosuppressants linked to this monograph include sirolimus,|
04880|051|D|everolimus, temsirolimus, and tacrolimus.|
04880|052|B||
04880|053|R|REFERENCES:|
04880|054|B||
04880|055|R|1.Synercid IV (quinupristin and dalfopristin for injection) US prescribing|1
04880|056|R|  information. Pfizer Inc March 2017.|1
04880|057|R|2.Pyostacin (pristinamycin) Australian product information. SANOFI WINTHROP|1
04880|058|R|  INDUSTRIE May 5, 2010.|1
04880|059|R|3.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
04880|060|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
04880|061|R|4.Stamatakis MK, Richards JG. Interaction between quinupristin/dalfopristin|3
04880|062|R|  and cyclosporine. Ann Pharmacother 1997 May;31(5):576-8.|3
04880|063|R|5.Lee LM Au Peh C. Interaction between everolimus and pristinamycin. NDT|3
04880|064|R|  Plus 2010;3:195-202.|3
04880|065|R|6.Belaiche S Logerol S Malvezzi P Qin W Tetaz R Zaoui P. Drug Interaction|3
04880|066|R|  with Pristinamycin in a Kidney and Pancrease Transplant Patient. J Nephrol|3
04880|067|R|  Therapeut 2012;S4:009.|3
04880|068|R|7.Gagnadoux MF, Loirat C, Pillion G, Bertheleme JP, Pouliquen M, Guest G,|3
04880|069|R|  Broyer M. Nephrotoxicity of pristinamycin-cyclosporin interaction in renal|3
04880|070|R|  transplant  patients. Presse Med 1987 Oct 24;16(35):1761.|3
04880|071|R|8.Herbrecht R, Garcia JJ, Bergerat JP, Oberling F. Effect of pristinamycin|3
04880|072|R|  on cyclosporin levels in bone marrow transplant  recipients. Bone Marrow|3
04880|073|R|  Transplant 1989 Jul;4(4):457-8.|3
04881|001|T|MONOGRAPH TITLE:  Typhoid Vaccine Live Attenuated/Proguanil|
04881|002|B||
04881|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04881|004|L|take action as needed.|
04881|005|B||
04881|006|A|MECHANISM OF ACTION:  Proguanil may attenuate the immunization response to|
04881|007|A|oral typhoid Ty21a vaccines.(1)|
04881|008|B||
04881|009|E|CLINICAL EFFECTS:  Concurrent use may make the vaccine ineffective.(1)|
04881|010|B||
04881|011|P|PREDISPOSING FACTORS:  None determined.|
04881|012|B||
04881|013|M|PATIENT MANAGEMENT:  The manufacturer of oral typhoid Ty21a vaccine states|
04881|014|M|concomitant treatment with proguanil significantly reduced immune response|
04881|015|M|rate.  Proguanil should not be administered until 10 days or more after the|
04881|016|M|final dose of oral typhoid Ty21a vaccine.(1)|
04881|017|M|   To optimize vaccine effectiveness, the Centers for Disease Control (CDC)|
04881|018|M|recommends, when feasible, delay of antibacterial drug therapy for at least|
04881|019|M|3 days after the last dose of oral typhoid vaccine.(2)|
04881|020|M|   Fixed dose combination therapy atovaquone/proguanil for malaria|
04881|021|M|prophylaxis may be given concomitantly with oral typhoid Ty21a vaccine.(1)|
04881|022|B||
04881|023|D|DISCUSSION:  The manufacturer of oral typhoid Ty21a vaccine states|
04881|024|D|simultaneous administration of proguanil decreased the immune response rate|
04881|025|D|to the oral typhoid vaccine.  The manufacturer of oral typhoid Ty21a vaccine|
04881|026|D|states that vaccination should be completed ten days before the initiation|
04881|027|D|of proguanil.(1)|
04881|028|B||
04881|029|R|REFERENCES:|
04881|030|B||
04881|031|R|1.Vivotif (typhoid vaccine live attenuated) US prescribing information.|1
04881|032|R|  Berna Products August, 2006.|1
04881|033|R|2.Centers for Disease Control and Prevention. General Recommendations on|1
04881|034|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
04881|035|R|  Practices (ACIP). MMWR.  Available at:|1
04881|036|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
04881|037|R|  February 17, 2022;60(RR No.2):1-68.|1
04882|001|T|MONOGRAPH TITLE:  Opioids (Extended Release)/Ziprasidone|
04882|002|B||
04882|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04882|004|L|take action as needed.|
04882|005|B||
04882|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and ziprasidone may result|
04882|007|A|in additive CNS depression.(1)|
04882|008|B||
04882|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants, such|
04882|010|E|as ziprasidone, may result in profound sedation, respiratory depression,|
04882|011|E|coma, and/or death.(1)|
04882|012|B||
04882|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04882|014|P|may increase the risk of adverse effects.|
04882|015|B||
04882|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
04882|017|M|depressants such as ziprasidone to patients for whom alternatives are|
04882|018|M|ineffective, not tolerated, or would be otherwise inadequate to provide|
04882|019|M|sufficient management of pain.(1)|
04882|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
04882|021|M|drug to the minimum possible while achieving the desired clinical effect.|
04882|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04882|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04882|024|M|indicated in the absence of an opioid and titrate based upon clinical|
04882|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04882|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04882|027|M|clinical response.(1)|
04882|028|M|   Respiratory depression can occur at any time during opioid therapy,|
04882|029|M|especially during therapy initiation and following dosage increases.  The|
04882|030|M|risk of opioid-related overdose or overdose-related death is increased with|
04882|031|M|higher opioid doses, and this risk persists over the course of therapy.|
04882|032|M|Consider these risks when using concurrently with other agents that may|
04882|033|M|cause CNS depression.(2)|
04882|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04882|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04882|036|M|unresponsiveness.(1)|
04882|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04882|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04882|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04882|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04882|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04882|042|M|as those taking CNS depressants) and when a patient has household|
04882|043|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04882|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
04882|045|M|over-the-counter, or as part of a community-based program).(3)|
04882|046|B||
04882|047|D|DISCUSSION:  A nested case-control study looked at the relationship between|
04882|048|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
04882|049|D|antipsychotics was associated with a 2.33-fold increase in risk of|
04882|050|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
04882|051|D|significantly increased in patients with recent use of antipsychotics|
04882|052|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
04882|053|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
04882|054|D|of use.(4)|
04882|055|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04882|056|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04882|057|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04882|058|D|to 30 million patients.  During this time, the proportion of patients|
04882|059|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04882|060|D|patients.(5)|
04882|061|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04882|062|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04882|063|D|per 100,000 and drug overdose deaths involving both opioids and|
04882|064|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04882|065|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04882|066|D|increased from 18% to 31% during this time.(6)|
04882|067|D|   A prospective observational cohort study in North Carolina found that the|
04882|068|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04882|069|D|benzodiazepines were 10 times higher than patients receiving opioid|
04882|070|D|analgesics alone.(7)|
04882|071|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04882|072|D|death from overdose increased with concomitant opioid analgesics and|
04882|073|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04882|074|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04882|075|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04882|076|D|increased risk of fatal overdose.(8)|
04882|077|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04882|078|D|which benzodiazepines were determined to be a cause of death and that|
04882|079|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04882|080|D|determined to be a cause of death.  This study also found that other CNS|
04882|081|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04882|082|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04882|083|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04882|084|D|where opioid analgesics were also implicated.(9)|
04882|085|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04882|086|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04882|087|D|deaths.(10)|
04882|088|B||
04882|089|R|REFERENCES:|
04882|090|B||
04882|091|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04882|092|R|  warns about serious risks and death when combining opioid pain or cough|1
04882|093|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04882|094|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04882|095|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04882|096|R|  prescribing information for all opioid pain medicines to provide|1
04882|097|R|  additional guidance for safe use. Available at:|1
04882|098|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04882|099|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04882|100|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04882|101|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04882|102|R|  recommends health care professionals discuss naloxone with all patients|1
04882|103|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04882|104|R|  disorder. Available at:|1
04882|105|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04882|106|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04882|107|R|  d-pain July 23, 2020.|1
04882|108|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
04882|109|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
04882|110|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
04882|111|R|  Pharmacol 2020 Apr 26.|2
04882|112|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04882|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04882|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04882|115|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04882|116|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04882|117|R|  49(4):493-501.|2
04882|118|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04882|119|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04882|120|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04882|121|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04882|122|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04882|123|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04882|124|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04882|125|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04882|126|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04882|127|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04882|128|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04882|129|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04883|001|T|MONOGRAPH TITLE:  Slt Opioids (Immediate Release)/Ziprasidone|
04883|002|B||
04883|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04883|004|L|take action as needed.|
04883|005|B||
04883|006|A|MECHANISM OF ACTION:  Concurrent use of opioids and antipsychotics such as|
04883|007|A|ziprasidone may result in additive CNS depression.(1)|
04883|008|B||
04883|009|E|CLINICAL EFFECTS:  Concurrent use of opioids and other CNS depressants such|
04883|010|E|as ziprasidone may result in profound sedation, respiratory depression,|
04883|011|E|coma, and/or death.(1)|
04883|012|B||
04883|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04883|014|P|may increase the risk of adverse effects.|
04883|015|B||
04883|016|M|PATIENT MANAGEMENT:  Limit prescribing opioid analgesics with CNS|
04883|017|M|depressants such as antipsychotics, including ziprasidone, to patients for|
04883|018|M|whom alternatives are ineffective, not tolerated, or would be otherwise|
04883|019|M|inadequate to provide sufficient management of pain.(1)|
04883|020|M|   If concurrent use is necessary, limit the dosages and duration of each|
04883|021|M|drug to the minimum possible while achieving the desired clinical effect.|
04883|022|M|If starting a CNS depressant (for an indication other than epilepsy) with an|
04883|023|M|opioid analgesic, prescribe a lower initial dose of the CNS depressant than|
04883|024|M|indicated in the absence of an opioid and titrate based upon clinical|
04883|025|M|response.  If an opioid analgesic is indicated in a patient already taking a|
04883|026|M|CNS depressant, prescribe a lower dose of the opioid and titrate based upon|
04883|027|M|clinical response.(1)|
04883|028|M|   Respiratory depression can occur at any time during opioid therapy,|
04883|029|M|especially during therapy initiation and following dosage increases.  The|
04883|030|M|risk of opioid-related overdose or overdose-related death is increased with|
04883|031|M|higher opioid doses, and this risk persists over the course of therapy.|
04883|032|M|Consider these risks when using concurrently with other agents that may|
04883|033|M|cause CNS depression.(2)|
04883|034|M|   Monitor patients receiving concurrent therapy for unusual dizziness or|
04883|035|M|lightheadedness, extreme sleepiness, slowed or difficult breathing, or|
04883|036|M|unresponsiveness.(1)|
04883|037|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04883|038|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04883|039|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04883|040|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04883|041|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04883|042|M|as those taking CNS depressants) and when a patient has household|
04883|043|M|members/close contacts at risk for accidental overdose. Discuss the options|
04883|044|M|for obtaining an opioid reversal agent (e.g., prescription,|
04883|045|M|over-the-counter, or as part of a community-based program).(3)|
04883|046|B||
04883|047|D|DISCUSSION:  A nested case-control study looked at the relationship between|
04883|048|D|antipsychotic use and risk of acute respiratory failure.  Current use of|
04883|049|D|antipsychotics was associated with a 2.33-fold increase in risk of|
04883|050|D|respiratory failure compared to no use of antipsychotics.  The risk was also|
04883|051|D|significantly increased in patients with recent use of antipsychotics|
04883|052|D|(within the past 15-30 days, OR = 1.79) and recent past use (within 31-90|
04883|053|D|days OR = 1.41).  The risk increased with higher doses and longer duration|
04883|054|D|of use.(4)|
04883|055|D|   Between 2002 and 2014, the number of patients receiving an opioid|
04883|056|D|analgesic increased 8%, from 75 million to 81 million patients, and the|
04883|057|D|number of patients receiving a benzodiazepine increased 31%, from 23 million|
04883|058|D|to 30 million patients.  During this time, the proportion of patients|
04883|059|D|receiving concurrent therapy increased 31%, from 23 million to 30 million|
04883|060|D|patients.(5)|
04883|061|D|   From 2004 to 2011, the rate of nonmedical use-related emergency room|
04883|062|D|visits involving both opioids and benzodiazepines increased from 11 to 34.2|
04883|063|D|per 100,000 and drug overdose deaths involving both opioids and|
04883|064|D|benzodiazepines increased from 0.6 to 1.7 per 100,000.  The proportion of|
04883|065|D|prescription opioid analgesic deaths which also involved benzodiazepines|
04883|066|D|increased from 18% to 31% during this time.(6)|
04883|067|D|   A prospective observational cohort study in North Carolina found that the|
04883|068|D|rates of overdose death among patients co-dispensed opioid analgesics and|
04883|069|D|benzodiazepines were 10 times higher than patients receiving opioid|
04883|070|D|analgesics alone.(7)|
04883|071|D|   A case-cohort study of VA data from 2004-2009 found that the risk of|
04883|072|D|death from overdose increased with concomitant opioid analgesics and|
04883|073|D|benzodiazepines.  Compared to patients with no history of benzodiazepines,|
04883|074|D|patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and|
04883|075|D|patients with a current benzodiazepine prescription (HR=3.86) had an|
04883|076|D|increased risk of fatal overdose.(8)|
04883|077|D|   A study found that opioid analgesics contributed to 77% of deaths in|
04883|078|D|which benzodiazepines were determined to be a cause of death and that|
04883|079|D|benzodiazepines contributed to 30% of deaths in which opioid analgesics were|
04883|080|D|determined to be a cause of death.  This study also found that other CNS|
04883|081|D|depressants (including barbiturates, antipsychotic and neuroleptic drugs,|
04883|082|D|antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous|
04883|083|D|system drugs, and muscle relaxants) were contributory to death in many cases|
04883|084|D|where opioid analgesics were also implicated.(9)|
04883|085|D|   A study found that alcohol was involved in 18.5% of opioid analgesic|
04883|086|D|abuse-related ED visits and 22.1 percent of opioid analgesic-related|
04883|087|D|deaths.(10)|
04883|088|B||
04883|089|R|REFERENCES:|
04883|090|B||
04883|091|R|1.FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA|1
04883|092|R|  warns about serious risks and death when combining opioid pain or cough|1
04883|093|R|  medicines with benzodiazepines; requires its strongest warning. Available|1
04883|094|R|  at:  http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm August 31, 2016.|1
04883|095|R|2.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04883|096|R|  prescribing information for all opioid pain medicines to provide|1
04883|097|R|  additional guidance for safe use. Available at:|1
04883|098|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04883|099|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04883|100|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04883|101|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04883|102|R|  recommends health care professionals discuss naloxone with all patients|1
04883|103|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04883|104|R|  disorder. Available at:|1
04883|105|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04883|106|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04883|107|R|  d-pain July 23, 2020.|1
04883|108|R|4.Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use|2
04883|109|R|  of antipsychotics and the risk of acute respiratory failure among adults:|2
04883|110|R|  A  disease risk score-matched nested case-control study. Br J Clin|2
04883|111|R|  Pharmacol 2020 Apr 26.|2
04883|112|R|5.Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends|2
04883|113|R|  in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.|2
04883|114|R|  Am J Prev Med 2016 Aug;51(2):151-60.|2
04883|115|R|6.Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths|2
04883|116|R|  From Combined Use of Opioids and  Benzodiazepines. Am J Prev Med 2015 Oct;|2
04883|117|R|  49(4):493-501.|2
04883|118|R|7.Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S.|2
04883|119|R|  Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose|2
04883|120|R|  Mortality. Pain Med 2016 Jan;17(1):85-98.|2
04883|121|R|8.Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine|2
04883|122|R|  prescribing patterns and deaths from drug overdose among US veterans|2
04883|123|R|  receiving opioid analgesics: case-cohort study. BMJ 2015 Jun 10;350:h2698.|2
04883|124|R|9.Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United|2
04883|125|R|  States, 2010. JAMA 2013 Feb 20;309(7):657-9.|2
04883|126|R|10.Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain|2
04883|127|R|   reliever and benzodiazepine drug abuse-related emergency department|2
04883|128|R|   visits and drug-related deaths - United States, 2010. MMWR Morb Mortal|2
04883|129|R|   Wkly Rep 2014 Oct 10;63(40):881-5.|2
04884|001|T|MONOGRAPH TITLE:  Pirfenidone/Ciprofloxacin (Less Than 750 mg BID)|
04884|002|B||
04884|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04884|004|L|take action as needed.|
04884|005|B||
04884|006|A|MECHANISM OF ACTION:  Pirfenidone is primarily metabolized by CYP1A2 which|
04884|007|A|is responsible for about 50% of its conversion to inactive drug.  CYP2C9,|
04884|008|A|2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone|
04884|009|A|metabolism.(1,2)|
04884|010|A|   Moderate inhibitors of CYP1A2 may inhibit the metabolism of|
04884|011|A|pirfenidone.(1,2)|
04884|012|A|   Ciprofloxacin is a moderate inhibitor of CYP1A2.(3,4)|
04884|013|B||
04884|014|E|CLINICAL EFFECTS:  Concurrent pirfenidone use with ciprofloxacin may lead to|
04884|015|E|increased systemic concentrations and toxicity from pirfenidone, including|
04884|016|E|serious liver injury.(1,2)|
04884|017|B||
04884|018|P|PREDISPOSING FACTORS:  A greater risk of adverse events may result from|
04884|019|P|concomitant treatment strong or moderate inhibitors of one or more other CYP|
04884|020|P|isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g.|
04884|021|P|amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine,|
04884|022|P|ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine).|
04884|023|P|   The magnitude of this interaction may be reduced in cigarette smokers.|
04884|024|P|Cigarette smoking induces production of CYP1A2 and, in the absence of a|
04884|025|P|CYP1A2 inhibitor, leads to decreased systemic concentrations of|
04884|026|P|pirfenidone.(1)|
04884|027|B||
04884|028|M|PATIENT MANAGEMENT:  The manufacturer of pirfenidone recommends avoiding|
04884|029|M|concurrent use of ciprofloxacin at doses of 750 mg twice daily or higher.|
04884|030|M|If concurrent use cannot be avoided, reduce pirfenidone dose to 534 mg three|
04884|031|M|times daily (total daily dose of 1,602 mg/day).  Monitor patients closely|
04884|032|M|when ciprofloxacin is used at a daily dosage of 250 mg to 1,000 mg.(1,2)|
04884|033|M|   Combinations of ciprofloxacin with strong or moderate CYP2C9, CYP2C19,|
04884|034|M|and/or CYP2D6 inhibitors should also be discontinued prior to and avoided|
04884|035|M|during pirfenidone treatment.(2)|
04884|036|B||
04884|037|D|DISCUSSION:  Pirfenidone is converted to inactive metabolites prior to|
04884|038|D|elimination.  CYP1A2 is responsible for approximately half of this|
04884|039|D|metabolism.|
04884|040|D|   In a single-dose study in 27 healthy subjects, coadministration of 801 mg|
04884|041|D|of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed|
04884|042|D|at 750 mg twice daily from Day 2 to Day 7) increased the exposure to|
04884|043|D|pirfenidone by 81%.(2)|
04884|044|B||
04884|045|R|REFERENCES:|
04884|046|B||
04884|047|R|1.Esbriet (pirfenidone) Canada prescribing information. InterMune Canada,|1
04884|048|R|  Inc. April, 2016.|1
04884|049|R|2.Esbriet (pirfenidone) US prescribing information. InterMune, Inc. October,|1
04884|050|R|  2014.|1
04885|001|T|MONOGRAPH TITLE:  Ranolazine/Moderate CYP3A4 Inducers|
04885|002|B||
04885|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04885|004|L|of severe adverse interaction.|
04885|005|B||
04885|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04885|007|A|of ranolazine.(1,2)|
04885|008|B||
04885|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
04885|010|E|in decreased levels and effectiveness of ranolazine.(1,2)|
04885|011|B||
04885|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04885|013|P|of the inducer for longer than 1-2 weeks.|
04885|014|B||
04885|015|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
04885|016|M|concurrent use of CYP3A4 inducers such as rifampin, rifabutin, rifapentine,|
04885|017|M|phenobarbital, phenytoin, carbamazepine, and St. John's wort is|
04885|018|M|contraindicated.  Concurrent use of moderate CYP3A4 inducers should be|
04885|019|M|avoided.(1)|
04885|020|M|   The UK manufacturer of ranolazine states that ranolazine should not be|
04885|021|M|used in patients receiving CYP3A4 inducers.(2)|
04885|022|B||
04885|023|D|DISCUSSION:  Concurrent rifampin (600 mg daily), strong inducer of CYP3A4,|
04885|024|D|decreased ranolazine plasma concentrations by 95%.(1,2)  The effects of a|
04885|025|D|moderate CYP3A4 inducer on ranolazine concentrations has not been studied.|
04885|026|D|   Moderate inducers of CYP3A4 include:  belzutifan, bosentan, cenobamate,|
04885|027|D|dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib,|
04885|028|D|mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, sotorasib,|
04885|029|D|telotristat, and tovorafenib.(1-4)|
04885|030|B||
04885|031|R|REFERENCES:|
04885|032|B||
04885|033|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
04885|034|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
04885|035|R|  Pharma U.K. S.R.I. October 30, 2008.|1
04885|036|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04885|037|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04885|038|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04885|039|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04885|040|R|  11/14/2017.|1
04885|041|R|4.This information is based on an extract from the Certara Drug Interaction|6
04885|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04886|001|T|MONOGRAPH TITLE:  Ranolazine/Moderate CYP3A4 Inducers that Prolong QT|
04886|002|B||
04886|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04886|004|L|of severe adverse interaction.|
04886|005|B||
04886|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04886|007|A|of ranolazine.(1,2)|
04886|008|A|   Concurrent use of agents that prolong the QTc interval may result in|
04886|009|A|additive effects on the QTc interval.(1,2)|
04886|010|B||
04886|011|E|CLINICAL EFFECTS:  Concurrent use of a moderate inducer of CYP3A4 may result|
04886|012|E|in decreased levels and effectiveness of ranolazine and increased risk of QT|
04886|013|E|prolongation.  The risk of potentially life-threatening arrhythmias|
04886|014|E|including torsades de pointes may be increased.(1,2)|
04886|015|B||
04886|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04886|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04886|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04886|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04886|020|P|female gender, or advanced age.(3)|
04886|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04886|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04886|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04886|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04886|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04886|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04886|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04886|028|P|   Induction effects may be more likely with regular use of the inducer for|
04886|029|P|longer than 1-2 weeks.|
04886|030|B||
04886|031|M|PATIENT MANAGEMENT:  The US manufacturer of ranolazine states that the|
04886|032|M|concurrent use of CYP3A4 inducers such as rifampin, rifabutin, rifapentine,|
04886|033|M|phenobarbital, phenytoin, carbamazepine, and St. John's wort is|
04886|034|M|contraindicated.  Concurrent use of moderate CYP3A4 inducers should be|
04886|035|M|avoided.(1)|
04886|036|M|   The UK manufacturer of ranolazine states that ranolazine should not be|
04886|037|M|used in patients receiving CYP3A4 inducers.(2)|
04886|038|M|   If coadministration with another agent that prolongs QT is unavoidable,|
04886|039|M|monitor for prolongation of the QTc interval.  When concurrent therapy is|
04886|040|M|warranted: consider obtaining serum calcium, magnesium, and potassium levels|
04886|041|M|and monitoring EKG at baseline and regular intervals. Correct any|
04886|042|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04886|043|M|heartbeat, dizziness, or fainting.|
04886|044|B||
04886|045|D|DISCUSSION:  Concurrent rifampin (600 mg daily), strong inducer of CYP3A4,|
04886|046|D|decreased ranolazine plasma concentrations by 95%.(1,2)  The effects of a|
04886|047|D|moderate CYP3A4 inducer on ranolazine concentrations has not been studied.|
04886|048|D|   Agents that are linked to this monograph may have varying degrees of|
04886|049|D|potential to prolong the QTc interval but are generally accepted to have a|
04886|050|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04886|051|D|been shown to prolong the QTc interval either through their mechanism of|
04886|052|D|action, through studies on their effects on the QTc interval, or through|
04886|053|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04886|054|D|and/or post-marketing reports.(4)|
04886|055|D|   Moderate CYP3A4 inducers that prolong QT linked to this monograph|
04886|056|D|include: efavirenz, pacritinib, and thioridazine.(5,6)|
04886|057|B||
04886|058|R|REFERENCES:|
04886|059|B||
04886|060|R|1.Ranexa (ranolazine) US prescribing information. Gilead August, 2019.|1
04886|061|R|2.Ranexa (ranolazine) UK summary of product characteristics. A. Menarini|1
04886|062|R|  Pharma U.K. S.R.I. October 30, 2008.|1
04886|063|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04886|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04886|065|R|  settings: a scientific statement from the American Heart Association and|6
04886|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04886|067|R|  2;55(9):934-47.|6
04886|068|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04886|069|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04886|070|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04886|071|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04886|072|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04886|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04886|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04886|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04886|076|R|  11/14/2017.|1
04886|077|R|6.This information is based on an extract from the Certara Drug Interaction|6
04886|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04887|001|T|MONOGRAPH TITLE:  Clindamycin/Strong CYP3A4 Inducers|
04887|002|B||
04887|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04887|004|L|take action as needed.|
04887|005|B||
04887|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04887|007|A|clindamycin.|
04887|008|B||
04887|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong CYP3A4 inducer may|
04887|010|E|result in decreased antimicrobial activity of clindamycin.|
04887|011|B||
04887|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04887|013|P|of the inducer for longer than 1-2 weeks.|
04887|014|B||
04887|015|M|PATIENT MANAGEMENT:  Monitor the response to clindamycin.  Adjust the dose|
04887|016|M|of clindamycin or consider administration of a non-interacting antimicrobial|
04887|017|M|if necessary.|
04887|018|B||
04887|019|D|DISCUSSION:  The effects of the interaction develop over approximately one|
04887|020|D|to two weeks after starting the inducer and reverse over a period of several|
04887|021|D|weeks after stopping the inducer.  Serum clindamycin concentrations may|
04887|022|D|increase when the inducer is stopped.|
04887|023|D|   In an observational study, 6 patients treated concomitantly with|
04887|024|D|clindamycin and rifampin showed significantly lower clindamycin trough|
04887|025|D|concentrations.  None of the patients reached the target clindamycin minimum|
04887|026|D|concentration (Cmin) (1.7 mg/L).(2)|
04887|027|D|   A retrospective review of patients on concomitant clindamycin and|
04887|028|D|rifampin showed a 82-93% decrease in the clindamycin median peak and trough|
04887|029|D|concentrations.(3)|
04887|030|D|   Several other studies showed significant decreases in median peak and|
04887|031|D|trough concentrations of clindamycin with concomitant rifampin.(4,6,7)|
04887|032|D|   In a study in patients on oral or intravenous clindamycin (600 mg three|
04887|033|D|times daily), patients on concomitant rifampin showed a 43% increase in|
04887|034|D|clindamycin clearance.(5)  In another study, concomitant rifampin with|
04887|035|D|intravenous or oral clindamycin led to a 2.7-fold  and 7-fold increase in|
04887|036|D|clindamycin clearance, respectively.(7)|
04887|037|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04887|038|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04887|039|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, and|
04887|040|D|St. John's Wort.(9)|
04887|041|B||
04887|042|R|REFERENCES:|
04887|043|B||
04887|044|R|1.Cleocin (clindamycin hydrochloride) US prescribing information. Pharmacia|1
04887|045|R|  and Upjohn Company September, 2024.|1
04887|046|R|2.Curis E, Pestre V, Jullien V, Eyrolle L, Archambeau D, Morand P, Gatin L,|2
04887|047|R|  Karoubi M, Pinar N, Dumaine V, Nguyen Van JC, Babinet A, Anract P, Salmon|2
04887|048|R|  D. Pharmacokinetic variability of clindamycin and influence of rifampicin|2
04887|049|R|  on  clindamycin concentration in patients with bone and joint infections.|2
04887|050|R|  Infection 2015 Aug;43(4):473-81.|2
04887|051|R|3.Join-Lambert O, Ribadeau-Dumas F, Jullien V, Kitzis MD, Jais JP,|2
04887|052|R|  Coignard-Biehler H, Guet-Revillet H, Consigny PH, Delage M, Nassif X,|2
04887|053|R|  Lortholary O, Nassif A. Dramatic reduction of clindamycin plasma|2
04887|054|R|  concentration in hidradenitis  suppurativa patients treated with the|2
04887|055|R|  rifampin-clindamycin combination. Eur J Dermatol 2014 Jan-Feb;24(1):94-5.|2
04887|056|R|4.Zeller V, Dzeing-Ella A, Kitzis MD, Ziza JM, Mamoudy P, Desplaces N.|2
04887|057|R|  Continuous clindamycin infusion, an innovative approach to treating bone|2
04887|058|R|  and  joint infections. Antimicrob Agents Chemother 2010 Jan;54(1):88-92.|2
04887|059|R|5.Bouazza N, Pestre V, Jullien V, Curis E, Urien S, Salmon D, Treluyer JM.|2
04887|060|R|  Population pharmacokinetics of clindamycin orally and intravenously|2
04887|061|R|  administered  in patients with osteomyelitis. Br J Clin Pharmacol 2012|2
04887|062|R|  Dec;74(6):971-7.|2
04887|063|R|6.Goulenok T, Seurat J, Selle A, Jullien V, Leflon-Guibout V, Grall N,|2
04887|064|R|  Lescure FX, Lepeule R, Bertrand J, Fantin B, Burdet C, Lefort A.|2
04887|065|R|  Pharmacokinetic interaction between rifampicin and clindamycin in|2
04887|066|R|  staphylococcal  osteoarticular infections. Int J Antimicrob Agents 2023|2
04887|067|R|  Aug;62(2):106885.|2
04887|068|R|7.Zeller V, Magreault S, Heym B, Salmon D, Kitzis MD, Billaud E, Marmor S,|2
04887|069|R|  Jannot AS, Salomon L, Jullien V. Influence of the clindamycin|2
04887|070|R|  administration route on the magnitude of  clindamycin-rifampicin|2
04887|071|R|  interaction: a prospective pharmacokinetic study. Clin Microbiol Infect|2
04887|072|R|  2021 Dec;27(12):1857.e1-1857.e7.|2
04887|073|R|8.Bernard A, Kermarrec G, Parize P, Caruba T, Bouvet A, Mainardi JL,|2
04887|074|R|  Sabatier B, Nich C. Dramatic reduction of clindamycin serum concentration|2
04887|075|R|  in staphylococcal  osteoarticular infection patients treated with the oral|2
04887|076|R|  clindamycin-rifampicin  combination. J Infect 2015 Aug;71(2):200-6.|2
04887|077|R|9.This information is based on an extract from the Certara Drug Interaction|6
04887|078|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04888|001|T|MONOGRAPH TITLE:  Primaquine/Quinacrine|
04888|002|B||
04888|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04888|004|L|is contraindicated and generally should not be dispensed or administered to|
04888|005|L|the same patient.|
04888|006|B||
04888|007|A|MECHANISM OF ACTION:  Concurrent use of quinacrine with primaquine may|
04888|008|A|potentiate the toxic effects of primaquine.(1)|
04888|009|B||
04888|010|E|CLINICAL EFFECTS:  Concurrent use of primaquine with quinacrine may result|
04888|011|E|in increased primaquine toxicity, including hemolytic anemia.(1)|
04888|012|B||
04888|013|P|PREDISPOSING FACTORS:  None determined.|
04888|014|B||
04888|015|M|PATIENT MANAGEMENT:  The manufacturer of primaquine states that concurrent|
04888|016|M|use of quinacrine and primaquine is contraindicated.  Primaquine should not|
04888|017|M|be administered to patient who have received quinacrine recently.(1)|
04888|018|B||
04888|019|D|DISCUSSION:  Because quinacrine appears to potentiate the toxicity of|
04888|020|D|antimalarial compounds which are structurally related to primaquine, the use|
04888|021|D|of quinacrine in patients receiving primaquine is contraindicated.  In|
04888|022|D|addition, primaquine should not be administered to patient who have received|
04888|023|D|quinacrine recently.(1)|
04888|024|B||
04888|025|R|REFERENCE:|
04888|026|B||
04888|027|R|1.Primaquine US prescribing information. Sanofi-Aventus U.S. LLC. March|1
04888|028|R|  2025.|1
04889|001|T|MONOGRAPH TITLE:  Mavacamten/Weak CYP3A4 Inhibitors|
04889|002|B||
04889|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04889|004|L|take action as needed.|
04889|005|B||
04889|006|A|MECHANISM OF ACTION:  Weak CYP3A4 inhibitors may decrease the metabolism of|
04889|007|A|mavacamten.(1)|
04889|008|B||
04889|009|E|CLINICAL EFFECTS:  Concurrent use of weak CYP3A4 inhibitors may increase the|
04889|010|E|plasma levels and the incidence and severity of adverse reactions of|
04889|011|E|mavacamten.(1)|
04889|012|B||
04889|013|P|PREDISPOSING FACTORS:  CYP2C19 poor metabolizers may experience an increased|
04889|014|P|incidence or severity of adverse effects.(1)|
04889|015|B||
04889|016|M|PATIENT MANAGEMENT:  The UK manufacturer of mavacamten states no dose|
04889|017|M|adjustment is necessary when starting mavacamten in patients on weak CYP3A4|
04889|018|M|inhibitors or in intermediate, normal, rapid, or ultra-rapid CYP2C19|
04889|019|M|metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor.  In|
04889|020|M|poor CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4|
04889|021|M|inhibitor, reduce mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment|
04889|022|M|for 4 weeks.  If CYP2C19 phenotype is unknown, consider a mavacamten|
04889|023|M|starting dose of 2.5 mg daily.(1)|
04889|024|B||
04889|025|D|DISCUSSION:  In a PBPK model, concomitant use of mavacamten (15 mg daily)|
04889|026|D|with cimetidine 400 mg twice daily, a weak CYP3A4 inhibitor, was predicted|
04889|027|D|to increase mavacamten area-under-curve (AUC) by 6% and maximum|
04889|028|D|concentration (Cmax) by 4% in poor CYP2C19 metabolizers and by 3% and 2%,|
04889|029|D|respectively, in both intermediate and normal CYP2C19 metabolizers.(2)|
04889|030|D|   Weak CYP3A4 inhibitors include: alprazolam, amiodarone, amlodipine,|
04889|031|D|anamorelin, asciminib, azithromycin, Baikal skullcap, belumosudil,|
04889|032|D|berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol,|
04889|033|D|ciprofloxacin, clotrimazole, cranberry, cyclosporine, delavirdine,|
04889|034|D|dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin,|
04889|035|D|fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat,|
04889|036|D|glecaprevir/pibrentasvir, goldenseal, istradefylline, ivacaftor, lacidipine,|
04889|037|D|lapatinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone,|
04889|038|D|mavorixafor, pazopanib, peppermint oil, propiverine, propofol, ranitidine,|
04889|039|D|remdesivir, resveratrol, roxithromycin, sitaxsentan, skullcap, suvorexant,|
04889|040|D|teriflunomide, ticagrelor, tolvaptan, trofinetide, and viloxazine.(4,5)|
04889|041|B||
04889|042|R|REFERENCES:|
04889|043|B||
04889|044|R|1.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04889|045|R|  Squibb July, 2023.|1
04889|046|R|2.Chiang M, Sychterz C, Perera V, Merali S, Palmisano M, Templeton IE,|2
04889|047|R|  Gaohua L. Physiologically Based Pharmacokinetic Modeling and Simulation of|2
04889|048|R|  Mavacamten  Exposure with Drug-Drug Interactions from CYP Inducers and|2
04889|049|R|  Inhibitors by CYP2C19  Phenotype. Clin Pharmacol Ther 2023 Oct;|2
04889|050|R|  114(4):922-932.|2
04889|051|R|3.This information is based on an extract from the Certara Drug Interaction|6
04889|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04889|053|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04889|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04889|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04889|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04889|057|R|  11/14/2017.|1
04890|001|T|MONOGRAPH TITLE:  Gepotidacin/QT Prolonging Agents|
04890|002|B||
04890|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04890|004|L|of severe adverse interaction.|
04890|005|B||
04890|006|A|MECHANISM OF ACTION:  Gepotidacin may prolong the QTc interval.  Concurrent|
04890|007|A|use with other agents that prolong the QTc interval may result in additive|
04890|008|A|effects on the QTc interval.(1)|
04890|009|B||
04890|010|E|CLINICAL EFFECTS:  The concurrent use of gepotidacin with other agents that|
04890|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04890|012|E|arrhythmias, including torsades de pointes.(1)|
04890|013|B||
04890|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04890|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04890|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04890|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04890|018|P|gender, or advanced age.(2)|
04890|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04890|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04890|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04890|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04890|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04890|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04890|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04890|026|B||
04890|027|M|PATIENT MANAGEMENT:  The manufacturer of gepotidacin states that the|
04890|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
04890|029|M|cannot be avoided, obtain ECGs prior to initiating gepotidacin, during|
04890|030|M|concomitant use, and as clinically indicated.(1)|
04890|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04890|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04890|033|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04890|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04890|035|B||
04890|036|D|DISCUSSION:  The effect of gepotidacin on the QTc interval was evaluated in|
04890|037|D|a randomized, active (moxifloxacin 400 mg) and placebo-controlled,|
04890|038|D|double-blind cross-over trial in healthy subjects who received single|
04890|039|D|intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and|
04890|040|D|concentration-dependent QTc prolongation effect of gepotidacin was observed.|
04890|041|D|The mean placebo-corrected change from baseline QTcF values around Tmax|
04890|042|D|were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV (not approved dosing|
04890|043|D|regimens and route of administration).|
04890|044|D|   Agents that are linked to this monograph may have varying degrees of|
04890|045|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04890|046|D|been shown to prolong the QTc interval either through their mechanism of|
04890|047|D|action, through studies on their effects on the QTc interval, or through|
04890|048|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04890|049|D|and/or postmarketing reports.(3)|
04890|050|B||
04890|051|R|REFERENCES:|
04890|052|B||
04890|053|R|1.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04890|054|R|  2025.|1
04890|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04890|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04890|057|R|  settings: a scientific statement from the American Heart Association and|6
04890|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04890|059|R|  2;55(9):934-47.|6
04890|060|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04890|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04890|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04890|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04891|001|T|MONOGRAPH TITLE:  Gepotidacin/Strong CYP3A4 Inhibitors|
04891|002|B||
04891|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04891|004|L|of severe adverse interaction.|
04891|005|B||
04891|006|A|MECHANISM OF ACTION:  Gepotidacin is a substrate of CYP3A4.  Strong|
04891|007|A|inhibitors of CYP3A4 may inhibit the metabolism of gepotidacin.(1)|
04891|008|B||
04891|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04891|010|E|increased levels and toxicity from gepotidacin,(1) including diarrhea,|
04891|011|E|nausea, abdominal pain and prolongation of the QT interval, which may result|
04891|012|E|in life-threatening arrhythmia and death.|
04891|013|B||
04891|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04891|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04891|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04891|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04891|018|P|female gender, or advanced age.(2)|
04891|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04891|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04891|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04891|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04891|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04891|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04891|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04891|026|B||
04891|027|M|PATIENT MANAGEMENT:  The manufacturer of gepotidacin states to avoid|
04891|028|M|concurrent administration with strong CYP3A4 inhibitors.(1)|
04891|029|B||
04891|030|D|DISCUSSION:  Gepotidacin is primarily metabolized by CYP3A4.(1)|
04891|031|D|   Concomitant administration of a strong inhibitor of CYP3A4 (itraconazole;|
04891|032|D|200 mg per day for 3 days), and a single 1500 mg dose of gepotidacin|
04891|033|D|resulted in a increase in gepotidacin maximum concentration (Cmax) of|
04891|034|D|1.4-fold and area under the curve (AUC) of 1.5-fold.(1)|
04891|035|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
04891|036|D|cobicistat, grapefruit, idelalisib, indinavir, itraconazole, josamycin,|
04891|037|D|ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir,|
04891|038|D|nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir,|
04891|039|D|troleandomycin, and tucatinib.(3,4)|
04891|040|B||
04891|041|R|REFERENCES:|
04891|042|B||
04891|043|R|1.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04891|044|R|  2025.|1
04891|045|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04891|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04891|047|R|  settings: a scientific statement from the American Heart Association and|6
04891|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04891|049|R|  2;55(9):934-47.|6
04891|050|R|3.This information is based on an extract from the Certara Drug Interaction|6
04891|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04891|052|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04891|053|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04891|054|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04891|055|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04891|056|R|  11/14/2017.|1
04892|001|T|MONOGRAPH TITLE:  Gepotidacin/Strong CYP3A4 Inducers|
04892|002|B||
04892|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04892|004|L|of severe adverse interaction.|
04892|005|B||
04892|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04892|007|A|gepotidacin.(1)|
04892|008|B||
04892|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong CYP3A4 inducer may|
04892|010|E|result in decreased antimicrobial activity of gepotidacin.(1)|
04892|011|B||
04892|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04892|013|P|of the inducer for longer than 1-2 weeks.|
04892|014|B||
04892|015|M|PATIENT MANAGEMENT:  The manufacturer of gepotidacin states that concomitant|
04892|016|M|use of strong CYP3A4 inducers should be avoided.(1)|
04892|017|B||
04892|018|D|DISCUSSION:  Gepotidacin is primarily metabolized by CYP3A4.(1)|
04892|019|D|   Concomitant administration of gepotidacin (single 1500 mg dose) with a|
04892|020|D|strong inducer (rifampin; 600 mg once daily for 7 days) resulted in a|
04892|021|D|decrease of 52% in gepotidacin area under the curve (AUC).(1)|
04892|022|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04892|023|D|barbiturates, carbamazepine, enzalutamide, ethotoin, fosphenytoin,|
04892|024|D|lumacaftor, mephenytoin, mitotane, phenobarbital, phenytoin, primidone,|
04892|025|D|rifampin, rifapentine, and St. John's wort.(2)|
04892|026|B||
04892|027|R|REFERENCES:|
04892|028|B||
04892|029|R|1.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04892|030|R|  2025.|1
04892|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04892|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04893|001|T|MONOGRAPH TITLE:  Gepotidacin/Possible QT Prolonging Agents|
04893|002|B||
04893|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04893|004|L|take action as needed.|
04893|005|B||
04893|006|A|MECHANISM OF ACTION:  Gepotidacin may prolong the QTc interval.  Concurrent|
04893|007|A|use with other agents that prolong the QTc interval may result in additive|
04893|008|A|effects on the QTc interval.(1)|
04893|009|B||
04893|010|E|CLINICAL EFFECTS:  The concurrent use of gepotidacin with other agents that|
04893|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04893|012|E|arrhythmias, including torsades de pointes.(1)|
04893|013|B||
04893|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04893|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04893|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04893|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04893|018|P|gender, or advanced age.(2)|
04893|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04893|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04893|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04893|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04893|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04893|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04893|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04893|026|B||
04893|027|M|PATIENT MANAGEMENT:  The manufacturer of gepotidacin states that the|
04893|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
04893|029|M|cannot be avoided, obtain ECGs prior to initiating gepotidacin, during|
04893|030|M|concomitant use, and as clinically indicated.(1)|
04893|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04893|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04893|033|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04893|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04893|035|B||
04893|036|D|DISCUSSION:  The effect of gepotidacin on the QTc interval was evaluated in|
04893|037|D|a randomized, active (moxifloxacin 400 mg) and placebo-controlled,|
04893|038|D|double-blind cross-over trial in healthy subjects who received single|
04893|039|D|intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and|
04893|040|D|concentration-dependent QTc prolongation effect of gepotidacin was observed.|
04893|041|D|The mean placebo-corrected change from baseline QTcF values around Tmax|
04893|042|D|were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV (not approved dosing|
04893|043|D|regimens and route of administration).|
04893|044|D|   Agents that are linked to this monograph may have varying degrees of|
04893|045|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04893|046|D|been shown to prolong the QTc interval either through their mechanism of|
04893|047|D|action, through studies on their effects on the QTc interval, or through|
04893|048|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04893|049|D|and/or postmarketing reports.(3)|
04893|050|B||
04893|051|R|REFERENCES:|
04893|052|B||
04893|053|R|1.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04893|054|R|  2025.|1
04893|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04893|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04893|057|R|  settings: a scientific statement from the American Heart Association and|6
04893|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04893|059|R|  2;55(9):934-47.|6
04893|060|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04893|061|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04893|062|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04893|063|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04894|001|T|MONOGRAPH TITLE:  Tacrolimus/Selected CYP3A4 Inhibitors that Prolong QT|
04894|002|B||
04894|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04894|004|L|of severe adverse interaction.|
04894|005|B||
04894|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
04894|007|A|tacrolimus.(1)|
04894|008|A|   In addition, concurrent use of tacrolimus with agents known to prolong|
04894|009|A|the QT interval may result in additive or synergistic effects on the QTc|
04894|010|A|interval.(1)|
04894|011|B||
04894|012|E|CLINICAL EFFECTS:  Concurrent use of a CYP3A4 inhibitor may result in|
04894|013|E|elevated levels of and toxicity from tacrolimus, including nephrotoxicity|
04894|014|E|and neurotoxicity.(1)|
04894|015|E|   In addition, concurrent administration of a QT prolonging CYP3A4|
04894|016|E|inhibitor and tacrolimus may result in prolongation of the QTc interval and|
04894|017|E|life-threatening cardiac arrhythmias, including torsades de pointes.|
04894|018|B||
04894|019|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04894|020|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04894|021|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04894|022|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04894|023|P|gender, or advanced age.(2)|
04894|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04894|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04894|026|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04894|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04894|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04894|029|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
04894|030|P|dysfunction).(2)|
04894|031|B||
04894|032|M|PATIENT MANAGEMENT:  The US manufacturer of tacrolimus recommends frequently|
04894|033|M|monitoring tacrolimus whole blood trough concentrations and reducing|
04894|034|M|tacrolimus dose if needed.(1)|
04894|035|M|   The US manufacturer of gepotidacin states concurrent use with drugs that|
04894|036|M|are extensively metabolized by CYP3A4 and have a narrow therapeutic index|
04894|037|M|should be avoided.(3)|
04894|038|M|   Consider obtaining serum calcium, magnesium, and potassium levels and|
04894|039|M|monitoring ECG at baseline and at regular intervals.  Correct any|
04894|040|M|electrolyte abnormalities.  Instruct patients to report any irregular|
04894|041|M|heartbeat, dizziness, or fainting.|
04894|042|B||
04894|043|D|DISCUSSION:  The coadministration of amiodarone and tacrolimus was described|
04894|044|D|in a case report of a 73-year-old kidney transplant recipient with normal|
04894|045|D|renal function who was on amiodarone for years.  Tacrolimus 7 mg per day was|
04894|046|D|started and after 3 months, the patient was found to have a tacrolimus level|
04894|047|D|of 63 ng/mL.  The dose of tacrolimus was lowered to 2 mg per day, and|
04894|048|D|tacrolimus levels dropped to 12.9 ng/mL.(4)|
04894|049|D|   In another case report, a 65-year-old man on amiodarone for 5 years|
04894|050|D|started tacrolimus 3 mg twice daily status-post renal transplant.  After one|
04894|051|D|day, QTc was prolonged from a baseline of 440 ms to 535 ms.  QTc dropped to|
04894|052|D|493 ms three days after discontinuation of amiodarone and dose reduction of|
04894|053|D|tacrolimus.(5)|
04894|054|D|   A case report describes the interaction between azithromycin and|
04894|055|D|tacrolimus in a 27-year old woman with acute myelogenous leukemia who had a|
04894|056|D|bone marrow transplant.  On tacrolimus 0.02 mg/kg/day IV, the patient had|
04894|057|D|stable tacrolimus levels of 15.8 to 17.5 ng/mL.  Three days after initiation|
04894|058|D|of azithromycin 500 mg daily, tacrolimus levels rose to over 30 ng/mL.(6)|
04894|059|D|   In a case report, a 64-year-old kidney transplant recipient on a stable|
04894|060|D|dose of tacrolimus 10 mg twice daily for 5 months was started on ranolazine|
04894|061|D|500 mg twice daily for angina.  Tacrolimus levels rose from the patient's|
04894|062|D|stable levels of 7 to 10 ng/mL in the previous 5 months to 17.8 ng/mL after|
04894|063|D|1 day.(7)|
04894|064|D|   Another case report describes a 54-year-old kidney transplant recipient|
04894|065|D|on tacrolimus 3 mg twice daily with trough levels of 4.5 to 7.4 ng/mL for|
04894|066|D|the previous 4 years.  After he was started on ranolazine 375 mg twice|
04894|067|D|daily, tacrolimus levels rose to 10.9 ng/mL and serum creatinine (Scr) rose|
04894|068|D|from 1.2 to 2 mg/dL.  Ranolazine was discontinued after one month, and|
04894|069|D|tacrolimus levels dropped to 3.6 ng/mL, with complete reversal of renal|
04894|070|D|failure.(8)|
04894|071|D|   A 62-year-old kidney transplant recipient on a stable dose of tacrolimus|
04894|072|D|for years was started on ranolazine and titrated to 1,000 mg twice daily|
04894|073|D|over one month.  After 2 weeks, he experienced renal failure with Scr rising|
04894|074|D|from 1.5 to 2.4 mg/dL, and tacrolimus level was elevated at 14 ng/mL.|
04894|075|D|Ranolazine was discontinued and tacrolimus levels decreased to 7 ng/mL after|
04894|076|D|3 days, with Scr returning to baseline.(9)|
04894|077|D|   CYP3A4 inhibitors that prolong QT linked to this monograph include:|
04894|078|D|gepotidacin.(3,10)|
04894|079|B||
04894|080|R|REFERENCES:|
04894|081|B||
04894|082|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04894|083|R|  August, 2023.|1
04894|084|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04894|085|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04894|086|R|  settings: a scientific statement from the American Heart Association and|6
04894|087|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04894|088|R|  2;55(9):934-47.|6
04894|089|R|3.Kisters K, Cziborra M, Funke C, Brylak S, Hausberg M.|3
04894|090|R|  Amiodarone-tacrolimus interaction in kidney transplantation. Clin Nephrol|3
04894|091|R|  2008 Dec;70(6):563.|3
04894|092|R|4.Burger CI, Clase CM, Gangji AS. Case report: drug interaction between|3
04894|093|R|  tacrolimus and amiodarone with QT prolongation. Transplantation 2010 May|3
04894|094|R|  15;89(9):1166-7.|3
04894|095|R|5.Mori T, Aisa Y, Nakazato T, Yamazaki R, Ikeda Y, Okamoto S.|3
04894|096|R|  Tacrolimus-azithromycin interaction in a recipient of allogeneic bone|3
04894|097|R|  marrow transplantation. Transpl Int 2005 Jun;18(6):757-8.|3
04894|098|R|6.Pierce Dwayne A, Reeves-Daniel Amber M. Ranolazine-tacrolimus interaction.|3
04894|099|R|  Ann Pharmacother 2010 Nov;44(11):1844-1849.|3
04894|100|R|7.Seck Sidy, Bellantoni Marianna, Zoccali Carmine, Enia Giuseppe. Ranolazine|3
04894|101|R|  can markedly increase tacrolimus blood levels. NDT Plus 2011 Feb;|3
04894|102|R|  4(1):44-45.|3
04894|103|R|8.Patni Hitesh, Gitman Michael, Hazzan Azzour, Jhaveri Kenar D. Ranolazine,|3
04894|104|R|  tacrolimus, and diltiazem might be a hazardous combination in a transplant|3
04894|105|R|  patient. Ren Fail 2012 Jan;34(2):251-253.|3
04894|106|R|9.This information is based on an extract from the Certara Drug Interaction|6
04894|107|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04894|108|R|10.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04894|109|R|   2025.|1
04895|001|T|MONOGRAPH TITLE:  Pimozide/Selected CYP3A4 Inhibitors that Prolong QT|
04895|002|B||
04895|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04895|004|L|of severe adverse interaction.|
04895|005|B||
04895|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 that prolong the QTc interval may|
04895|007|A|inhibit the metabolism of pimozide and cause an additive risk of QTc|
04895|008|A|prolongation.(1)|
04895|009|B||
04895|010|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors that prolong QT may|
04895|011|E|increase the levels and effects of pimozide including additive QTc|
04895|012|E|prolongation and potentially life-threatening cardiac arrhythmias like|
04895|013|E|torsades de pointes.|
04895|014|E|   Concurrent use may also result in extrapyramidal symptoms such as|
04895|015|E|akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and|
04895|016|E|oculogyric crisis.(1)|
04895|017|B||
04895|018|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04895|019|P|may be increased in patients with cardiovascular disease (e.g. heart|
04895|020|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04895|021|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04895|022|P|female gender, or advanced age.(2)|
04895|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04895|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04895|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04895|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04895|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04895|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04895|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04895|030|P|   The risk of anticholinergic toxicities including cognitive decline,|
04895|031|P|delirium, falls and fractures is increased in geriatric patients using more|
04895|032|P|than one medicine with anticholinergic properties.(3)|
04895|033|B||
04895|034|M|PATIENT MANAGEMENT:  Avoid concurrent use of pimozide and CYP3A4 inhibitors,|
04895|035|M|especially when other risk factors for QT prolongation are present.|
04895|036|M|   The manufacturer of pimozide states that concomitant treatment with|
04895|037|M|strong CYP3A4 inhibitors is contraindicated and treatment with less potent|
04895|038|M|inhibitors of CYP3A4 should also be avoided.(1)|
04895|039|M|   If concurrent use cannot be avoided, then correct or minimize QT|
04895|040|M|prolonging risk factors, use the lowest effective dose of pimozide, and|
04895|041|M|discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if|
04895|042|M|possible.|
04895|043|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04895|044|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04895|045|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
04895|046|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04895|047|B||
04895|048|D|DISCUSSION:  Pimozide is metabolized at CYP3A.  Elevated levels of pimozide|
04895|049|D|may prolong the QTc interval resulting in life-threatening ventricular|
04895|050|D|arrhythmias.(1)|
04895|051|D|   CYP3A4 inhibitors that prolong QT linked include: gepotidacin.(4-6)|
04895|052|B||
04895|053|R|REFERENCES:|
04895|054|B||
04895|055|R|1.Orap (pimozide) US prescribing information. Gate Pharmaceuticals August,|1
04895|056|R|  2011.|1
04895|057|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04895|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04895|059|R|  settings: a scientific statement from the American Heart Association and|6
04895|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04895|061|R|  2;55(9):934-47.|6
04895|062|R|3.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04895|063|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04895|064|R|  Soc 2023 Jul;71(7):2052-2081.|6
04895|065|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04895|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04895|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04895|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04895|069|R|  11/14/2017.|1
04895|070|R|5.This information is based on an extract from the Certara Drug Interaction|6
04895|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04895|072|R|6.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04895|073|R|  2025.|1
04896|001|T|MONOGRAPH TITLE:  Gepotidacin/Strong CYP3A4 Inducers that Prolong QT|
04896|002|B||
04896|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04896|004|L|of severe adverse interaction.|
04896|005|B||
04896|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 that prolong QT may induce|
04896|007|A|the metabolism of gepotidacin and result in additive effects on the QTc|
04896|008|A|interval.(1,2)|
04896|009|B||
04896|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers that|
04896|011|E|prolong QT may result in decreased antimicrobial activity of gepotidacin and|
04896|012|E|have additive effects on the QTc interval, which may result in potentially|
04896|013|E|life-threatening arrhythmias including torsades de pointes.(1)|
04896|014|B||
04896|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04896|016|P|of the inducer for longer than 1-2 weeks.|
04896|017|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04896|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04896|019|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
04896|020|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04896|021|P|advanced age.(2)|
04896|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04896|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04896|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04896|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04896|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04896|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04896|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04896|029|B||
04896|030|M|PATIENT MANAGEMENT:  The manufacturer of gepotidacin states that concomitant|
04896|031|M|use of strong CYP3A4 inducers should be avoided.(1)|
04896|032|M|   The manufacturer of gepotidacin states that the concurrent use of QT|
04896|033|M|prolonging agents should be avoided.  If concurrent use cannot be avoided,|
04896|034|M|obtain ECGs prior to initiating gepotidacin, during concomitant use, and as|
04896|035|M|clinically indicated.(1)|
04896|036|M|   If concurrent therapy is warranted, correct any electrolyte abnormalities|
04896|037|M|and instruct patients to report any irregular heartbeat, dizziness, or|
04896|038|M|fainting.|
04896|039|B||
04896|040|D|DISCUSSION:  Gepotidacin is primarily metabolized by CYP3A4.(1)|
04896|041|D|   Concomitant administration of gepotidacin (single 1500 mg dose) with a|
04896|042|D|strong inducer (rifampin; 600 mg once daily for 7 days) resulted in a|
04896|043|D|decrease of 52% in gepotidacin area under the curve (AUC).(1)|
04896|044|D|   The effect of gepotidacin on the QTc interval was evaluated in a|
04896|045|D|randomized, active (moxifloxacin 400 mg) and placebo-controlled,|
04896|046|D|double-blind cross-over trial in healthy subjects who received single|
04896|047|D|intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and|
04896|048|D|concentration-dependent QTc prolongation effect of gepotidacin was observed.|
04896|049|D|The mean placebo-corrected change from baseline QTcF values around Tmax|
04896|050|D|were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV (not approved dosing|
04896|051|D|regimens and route of administration).|
04896|052|D|   Agents that are linked to this monograph may have varying degrees of|
04896|053|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04896|054|D|been shown to prolong the QTc interval either through their mechanism of|
04896|055|D|action, through studies on their effects on the QTc interval, or through|
04896|056|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04896|057|D|and/or postmarketing reports.(3)|
04896|058|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04896|059|D|encorafenib and ivosidenib.(3,4)|
04896|060|B||
04896|061|R|REFERENCES:|
04896|062|B||
04896|063|R|1.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04896|064|R|  2025.|1
04896|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04896|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04896|067|R|  settings: a scientific statement from the American Heart Association and|6
04896|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04896|069|R|  2;55(9):934-47.|6
04896|070|R|3.This information is based on an extract from the Certara Drug Interaction|6
04896|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04896|072|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04896|073|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04896|074|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04896|075|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04896|076|R|  11/14/2017.|1
04897|001|T|MONOGRAPH TITLE:  Gepotidacin/Strong CYP3A4 Inhibitors that Prolong QT|
04897|002|B||
04897|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04897|004|L|of severe adverse interaction.|
04897|005|B||
04897|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong QT may|
04897|007|A|inhibit the metabolism of gepotidacin and result in additive effects on the|
04897|008|A|QTc interval.(1,2)|
04897|009|B||
04897|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04897|011|E|increased levels and toxicity from gepotidacin,(1) including diarrhea,|
04897|012|E|nausea, abdominal pain and prolongation of the QT interval, which may result|
04897|013|E|in life-threatening arrhythmia and death.|
04897|014|E|   Concurrent use may also result in additive QTc prolongation, which may|
04897|015|E|lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)|
04897|016|B||
04897|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04897|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04897|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04897|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04897|021|P|female gender, or advanced age.(2)|
04897|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04897|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04897|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04897|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04897|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04897|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04897|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04897|029|B||
04897|030|M|PATIENT MANAGEMENT:  The manufacturer of gepotidacin states to avoid|
04897|031|M|concurrent administration with strong CYP3A4 inhibitors.(1)|
04897|032|M|   The manufacturer of gepotidacin states that the concurrent use of QT|
04897|033|M|prolonging agents should be avoided.  If concurrent use cannot be avoided,|
04897|034|M|obtain ECGs prior to initiating gepotidacin, during concomitant use, and as|
04897|035|M|clinically indicated.(1)|
04897|036|M|   If concurrent therapy is warranted, correct any electrolyte abnormalities|
04897|037|M|and instruct patients to report any irregular heartbeat, dizziness, or|
04897|038|M|fainting.|
04897|039|B||
04897|040|D|DISCUSSION:  Gepotidacin is primarily metabolized by CYP3A4.(1)|
04897|041|D|   Concomitant administration of a strong inhibitor of CYP3A4 (itraconazole;|
04897|042|D|200 mg per day for 3 days), and a single 1500 mg dose of gepotidacin|
04897|043|D|resulted in a increase in gepotidacin maximum concentration (Cmax) of|
04897|044|D|1.4-fold and area under the curve (AUC) of 1.5-fold.(1)|
04897|045|D|   The effect of gepotidacin on the QTc interval was evaluated in a|
04897|046|D|randomized, active (moxifloxacin 400 mg) and placebo-controlled,|
04897|047|D|double-blind cross-over trial in healthy subjects who received single|
04897|048|D|intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and|
04897|049|D|concentration-dependent QTc prolongation effect of gepotidacin was observed.|
04897|050|D|The mean placebo-corrected change from baseline QTcF values around Tmax|
04897|051|D|were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV (not approved dosing|
04897|052|D|regimens and route of administration).|
04897|053|D|   Agents that are linked to this monograph may have varying degrees of|
04897|054|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04897|055|D|been shown to prolong the QTc interval either through their mechanism of|
04897|056|D|action, through studies on their effects on the QTc interval, or through|
04897|057|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04897|058|D|and/or postmarketing reports.(3)|
04897|059|D|   Strong CYP3A4 inhibitors that prolong the QT interval linked to this|
04897|060|D|monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole,|
04897|061|D|lonafarnib, lopinavir-ritonavir, posaconazole, ribociclib, saquinavir,|
04897|062|D|telithromycin, and voriconazole.(3,4)|
04897|063|B||
04897|064|R|REFERENCES:|
04897|065|B||
04897|066|R|1.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04897|067|R|  2025.|1
04897|068|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04897|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04897|070|R|  settings: a scientific statement from the American Heart Association and|6
04897|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04897|072|R|  2;55(9):934-47.|6
04897|073|R|3.This information is based on an extract from the Certara Drug Interaction|6
04897|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04897|075|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04897|076|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04897|077|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04897|078|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04897|079|R|  11/14/2017.|1
04898|001|T|MONOGRAPH TITLE:  Fentanyl/Selected CYP3A4 Inhibitors|
04898|002|B||
04898|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04898|004|L|of severe adverse interaction.|
04898|005|B||
04898|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04898|007|A|fentanyl.(1)|
04898|008|B||
04898|009|E|CLINICAL EFFECTS:  The concurrent administration of a CYP3A4 inhibitor may|
04898|010|E|result in elevated levels of and toxicity from fentanyl,(1) including|
04898|011|E|profound sedation, respiratory depression, coma, and/or death.|
04898|012|B||
04898|013|P|PREDISPOSING FACTORS:  Concurrent use of alcohol or other CNS depressants|
04898|014|P|may increase the risk of adverse effects.|
04898|015|B||
04898|016|M|PATIENT MANAGEMENT:  Use caution when initiating or discontinuing concurrent|
04898|017|M|treatment, particularly if the patient is also receiving treatment with|
04898|018|M|other CYP3A4 inhibitors (e.g. systemic azole antifungals, clarithromycin,|
04898|019|M|protease inhibitors).(1)|
04898|020|M|   The manufacturer of gepotidacin states that concurrent use of drugs that|
04898|021|M|are extensively metabolized by CYP3A4 and have a narrow therapeutic window|
04898|022|M|like fentanyl should be avoided.(2)|
04898|023|M|   Monitor patients receiving CYP3A4 inhibitors at frequent intervals and|
04898|024|M|for an extended period of time.  Dosage adjustments should be made if|
04898|025|M|warranted.  Monitor for increased adverse effects such as respiratory|
04898|026|M|suppression or increased sedation.(2)|
04898|027|M|   Respiratory depression can occur at any time during opioid therapy,|
04898|028|M|especially during therapy initiation and following dosage increases.  The|
04898|029|M|risk of opioid-related overdose or overdose-related death is increased with|
04898|030|M|higher opioid doses, and this risk persists over the course of therapy.|
04898|031|M|Consider these risks when using concurrently with agents that may increase|
04898|032|M|opioid drug levels.(3)|
04898|033|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
04898|034|M|patients when prescribing or renewing an opioid analgesic or medicine to|
04898|035|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
04898|036|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
04898|037|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
04898|038|M|as those taking CNS depressants) and when a patient has household|
04898|039|M|members/close contacts at risk for accidental overdose.  Discuss the options|
04898|040|M|for obtaining an opioid reversal agent (e.g., prescription,|
04898|041|M|over-the-counter, or as part of a community-based program).(4)|
04898|042|M|   Avoid exposing the fentanyl patch application site and surrounding area|
04898|043|M|to direct external heat sources as there have been reports of overdose and|
04898|044|M|death as a result of exposure to heat.(1)|
04898|045|B||
04898|046|D|DISCUSSION:  In a clinical study, coadministration of single-dose midazolam|
04898|047|D|2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12|
04898|048|D|hours for 2 doses) increased the area-under-curve (AUC) of midazolam by|
04898|049|D|1.9-fold.(2)|
04898|050|D|   In a randomized, cross-over study in 12 healthy subjects, voriconazole|
04898|051|D|(400 mg twice daily, Day 1; 200 mg twice daily, Day 2) and fluconazole (400|
04898|052|D|mg daily, Day 1; 200 mg daily, Day 2) decreased the clearance of a single|
04898|053|D|dose of intravenous fentanyl (5 mcg/kg) by 23% and 16%, respectively.(5)|
04898|054|D|   Selected CYP3A4 inhibitors linked to this monograph include: gepotidacin|
04898|055|D|and sevabertinib.(2)|
04898|056|B||
04898|057|R|REFERENCES:|
04898|058|B||
04898|059|R|1.Duragesic (fentanyl) US prescribing information. Janssen Pharmaceuticals,|1
04898|060|R|  Inc. October, 2019.|1
04898|061|R|2.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04898|062|R|  2025.|1
04898|063|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
04898|064|R|  prescribing information for all opioid pain medicines to provide|1
04898|065|R|  additional guidance for safe use. Available at:|1
04898|066|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
04898|067|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
04898|068|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
04898|069|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
04898|070|R|  recommends health care professionals discuss naloxone with all patients|1
04898|071|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
04898|072|R|  disorder. Available at:|1
04898|073|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
04898|074|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
04898|075|R|  d-pain July 23, 2020.|1
04898|076|R|5.Saari TI, Laine K, Neuvonen M, Neuvonen PJ, Olkkola KT. Effect of|2
04898|077|R|  voriconazole and fluconazole on the pharmacokinetics of intravenous|2
04898|078|R|  fentanyl. Eur J Clin Pharmacol 2008 Jan;64(1):25-30.|2
04899|001|T|MONOGRAPH TITLE:  Diazoxide/Strong CYP1A2 Inhibitors|
04899|002|B||
04899|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04899|004|L|take action as needed.|
04899|005|B||
04899|006|A|MECHANISM OF ACTION:  Inhibitors of CYP1A2 may inhibit the metabolism of|
04899|007|A|diazoxide.(1)|
04899|008|B||
04899|009|E|CLINICAL EFFECTS:  Concurrent use of inhibitors of CYP1A2 may result in|
04899|010|E|elevated levels of and toxicity from diazoxide including hyperglycemia and|
04899|011|E|fluid retention.(1)|
04899|012|B||
04899|013|P|PREDISPOSING FACTORS:  None determined.|
04899|014|B||
04899|015|M|PATIENT MANAGEMENT:  The manufacturer recommends a dose reduction of|
04899|016|M|diazoxide when use concomitantly with strong CYP1A2 inhibitors.(1)|
04899|017|M|   -For patients weighing 20 kg to < 30 kg: Give 25 mg for four weeks, then|
04899|018|M|increase by 25 mg every two weeks for a target maintenance dose of 75 mg|
04899|019|M|   -For patients weighing 30 kg to <40 kg: Give 50 mg for two weeks, then|
04899|020|M|increase to a target maintenance dose of 100 mg|
04899|021|M|   -For patients weighing 40 kg to <65 kg: Give 50 mg for two weeks, then|
04899|022|M|increase by 50 mg every two weeks for a target maintenance dose of 150 mg|
04899|023|M|   -For patients weighing 65 kg to <100 kg: Give 100 mg for two weeks, then|
04899|024|M|increase by 50 mg every two weeks for a target maintenance dose of 250 mg|
04899|025|M|   -For patients weighing 100 kg to <135 kg: Give 100 mg for weeks 1 and 2,|
04899|026|M|increase to 200 mg for weeks 3 and 4, increase to 300 mg for weeks 5 and 6,|
04899|027|M|then increase to a target maintenance dose of 325 mg|
04899|028|B||
04899|029|D|DISCUSSION:  In a clinical study with fluvoxamine (a strong CYP1A2|
04899|030|D|inhibitor), fluvoxamine increased single dose diazoxide maximum|
04899|031|D|concentration (Cmax) by 17.5% and area-under-curve (AUC) by 60% compared to|
04899|032|D|the same parameter measured on single dose in the absence of fluvoxamine|
04899|033|D|co-administration.(1)|
04899|034|D|   Strong CYP1A2 inhibitors linked to this monograph include: angelica root,|
04899|035|D|enasidenib, enoxacin, fluvoxamine, and rofecoxib.(2,3)|
04899|036|B||
04899|037|R|REFERENCES:|
04899|038|B||
04899|039|R|1.Vykat XR (diazoxide choline) US prescribing information. Soleno|1
04899|040|R|  Therapeutics, Inc. March 2025.|1
04899|041|R|2.This information is based on an extract from the Certara Drug Interaction|6
04899|042|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04899|043|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04899|044|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04899|045|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04899|046|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04899|047|R|  11/14/2017.|1
04900|001|T|MONOGRAPH TITLE:  Diazoxide/Dual Strong CYP3A4 & Moderate CYP1A2 Inducers|
04900|002|B||
04900|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04900|004|L|of severe adverse interaction.|
04900|005|B||
04900|006|A|MECHANISM OF ACTION:  Diazoxide is a substrate of both CYP3A4 and CYP1A2.|
04900|007|A|Inducers of CYP3A4 and CYP1A2 may induce the metabolism of diazoxide.(1)|
04900|008|B||
04900|009|E|CLINICAL EFFECTS:  Concomitant administration may result in decreased|
04900|010|E|concentration and effectiveness of diazoxide.(1)|
04900|011|B||
04900|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04900|013|P|of the inducer for longer than 1-2 weeks.|
04900|014|B||
04900|015|M|PATIENT MANAGEMENT:  Concomitant use of diazoxide with dual strong CYP3A4|
04900|016|M|and moderate CYP1A2 inducers is not recommended.|
04900|017|B||
04900|018|D|DISCUSSION:  A PBPK analysis suggests that concomitant use of diazoxide with|
04900|019|D|rifampin (a strong CYP3A4 inducer and moderate CYP1A2 inducer) may decrease|
04900|020|D|the maximum concentration (Cmax) and area-under-curve (AUC) of diazoxide by|
04900|021|D|14% to 30% and 40% to 70%, respectively, compared to diazoxide alone.(1)|
04900|022|D|   Dual strong CYP3A4 and moderate 1A2 inducers linked to this monograph|
04900|023|D|include: fosphenytoin, phenytoin, and rifampin.|
04900|024|B||
04900|025|R|REFERENCES:|
04900|026|B||
04900|027|R|1.Vykat XR (diazoxide choline) US prescribing information. Soleno|1
04900|028|R|  Therapeutics, Inc. March 2025.|1
04900|029|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04900|030|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04900|031|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04900|032|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04900|033|R|  11/14/2017.|1
04900|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04900|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04901|001|T|MONOGRAPH TITLE:  Quinidine/Selected CYP3A4 Inhibitors that Prolong QT|
04901|002|B||
04901|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04901|004|L|of severe adverse interaction.|
04901|005|B||
04901|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may decrease the metabolism of|
04901|007|A|quinidine.(2)|
04901|008|A|   Both agents have been shown to prolong the QTc interval.  Concurrent use|
04901|009|A|may result in additive effects on the QTc interval.(1,2)|
04901|010|B||
04901|011|E|CLINICAL EFFECTS:  Concurrent use of quinidine with CYP3A4 inhibitors may|
04901|012|E|lead to increased serum levels and adverse effects of quinidine, including|
04901|013|E|potentially life-threatening cardiac arrhythmias like torsades de pointes|
04901|014|E|(TdP).(1,2)|
04901|015|B||
04901|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04901|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04901|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04901|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04901|020|P|gender, or advanced age.(3)|
04901|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04901|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04901|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04901|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04901|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04901|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04901|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04901|028|B||
04901|029|M|PATIENT MANAGEMENT:  Patients receiving concurrent CYP3A4 inhibitors should|
04901|030|M|be monitored for increased effects of quinidine.|
04901|031|M|   The manufacturer of gepotidacin states that concurrent use of drugs that|
04901|032|M|are extensively metabolized by CYP3A4 and have a narrow therapeutic window|
04901|033|M|like quinidine should be avoided.(2)  If concomitant use is unavoidable,|
04901|034|M|monitor for adverse effects and consider dose reduction of quinidine|
04901|035|M|according to its prescribing information.(1)|
04901|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04901|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04901|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04901|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04901|040|B||
04901|041|D|DISCUSSION:  Serious cardiovascular events, including QT prolongation,|
04901|042|D|torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden|
04901|043|D|death have been reported in patients taking quinidine in combination with|
04901|044|D|CYP3A4 inhibitors.|
04901|045|D|   In a clinical study, coadministration of single-dose midazolam 2 mg (a|
04901|046|D|sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2|
04901|047|D|doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(2)|
04901|048|D|   Selected CYP3A4 inhibitors linked to this monograph include:|
04901|049|D|gepotidacin.(2)|
04901|050|B||
04901|051|R|REFERENCES:|
04901|052|B||
04901|053|R|1.Quinidine sulfate US prescribing informaiton. Epic Pharma, LLC November,|1
04901|054|R|  2023.|1
04901|055|R|2.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04901|056|R|  2025.|1
04901|057|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04901|058|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04901|059|R|  settings: a scientific statement from the American Heart Association and|6
04901|060|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04901|061|R|  2;55(9):934-47.|6
04901|062|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04901|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04901|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04901|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04901|066|R|  11/14/2017.|1
04901|067|R|5.This information is based on an extract from the Certara Drug Interaction|6
04901|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04902|001|T|MONOGRAPH TITLE:  Quinine/Selected CYP3A4 Inhibitors that Prolong QT|
04902|002|B||
04902|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04902|004|L|of severe adverse interaction.|
04902|005|B||
04902|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may decrease the metabolism of|
04902|007|A|quinidine.(2)|
04902|008|A|   Both agents have been shown to prolong the QTc interval.  Concurrent use|
04902|009|A|may result in additive effects on the QTc interval.(1,2)|
04902|010|B||
04902|011|E|CLINICAL EFFECTS:  Concurrent use of quinidine with CYP3A4 inhibitors may|
04902|012|E|lead to increased serum levels and adverse effects of quinidine, including|
04902|013|E|potentially life-threatening cardiac arrhythmias like torsades de pointes|
04902|014|E|(TdP).(1,2)|
04902|015|B||
04902|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04902|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04902|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04902|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04902|020|P|gender, or advanced age.(3)|
04902|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04902|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04902|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04902|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04902|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04902|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04902|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
04902|028|B||
04902|029|M|PATIENT MANAGEMENT:  Closely monitor for adverse effects of quinine during|
04902|030|M|concurrent therapy.(1)|
04902|031|M|   The manufacturer of gepotidacin states that concurrent use of drugs that|
04902|032|M|are extensively metabolized by CYP3A4 and have a narrow therapeutic window|
04902|033|M|like quinine should be avoided.(2)  If concomitant use is unavoidable,|
04902|034|M|monitor for adverse effects and consider dose reduction of quinine according|
04902|035|M|to its prescribing information.(1)|
04902|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04902|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04902|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04902|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04902|040|B||
04902|041|D|DISCUSSION:  In a study of healthy volunteers, ketoconazole (100 mg twice|
04902|042|D|daily for 3 days) increased the area-under-curve (AUC) of single-dose|
04902|043|D|quinine (500 mg) by 45% compared to quinine alone.(1)|
04902|044|D|   In a clinical study, coadministration of single-dose midazolam 2 mg (a|
04902|045|D|sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2|
04902|046|D|doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(2)|
04902|047|D|   Selected CYP3A4 inhibitors linked to this monograph include:|
04902|048|D|gepotidacin.(2)|
04902|049|B||
04902|050|R|REFERENCES:|
04902|051|B||
04902|052|R|1.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
04902|053|R|  Industries, Inc. August, 2019.|1
04902|054|R|2.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04902|055|R|  2025.|1
04902|056|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04902|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04902|058|R|  settings: a scientific statement from the American Heart Association and|6
04902|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04902|060|R|  2;55(9):934-47.|6
04902|061|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04902|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04902|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04902|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04902|065|R|  11/14/2017.|1
04902|066|R|5.This information is based on an extract from the Certara Drug Interaction|6
04902|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04903|001|T|MONOGRAPH TITLE:  Everolimus/Selected CYP3A4 Inhibitors|
04903|002|B||
04903|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04903|004|L|of severe adverse interaction.|
04903|005|B||
04903|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04903|007|A|everolimus.(1,2)|
04903|008|B||
04903|009|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
04903|010|E|elevated levels of and toxicity from everolimus.(1,2)|
04903|011|B||
04903|012|P|PREDISPOSING FACTORS:  None determined.|
04903|013|B||
04903|014|M|PATIENT MANAGEMENT:  Closely monitor for an increase in everolimus levels|
04903|015|M|and for adverse effects from everolimus during concurrent therapy with|
04903|016|M|CYP3A4 inhibitors.  Dose adjustment of everolimus may be necessary.(2)|
04903|017|M|   The manufacturer of gepotidacin states that concurrent use of drugs that|
04903|018|M|are extensively metabolized by CYP3A4 and have a narrow therapeutic window|
04903|019|M|like everolimus should be avoided.(3)|
04903|020|B||
04903|021|D|DISCUSSION:  In a study in healthy subjects, concurrent use of ketoconazole,|
04903|022|D|a strong CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus|
04903|023|D|area-under-curve (AUC) and maximum concentration (Cmax) by 3.9-fold and|
04903|024|D|15.0-fold, respectively.  Erythromycin (a P-gp and moderate CYP3A4|
04903|025|D|inhibitor) increased everolimus AUC and Cmax by 4.4-fold and 2-fold,|
04903|026|D|respectively, while verapamil (a P-gp and moderate CYP3A4 inhibitor)|
04903|027|D|increased everolimus AUC and Cmax by 3.5-fold and 2.3-fold, respectively.(1)|
04903|028|D|   In a clinical study, coadministration of single-dose midazolam 2 mg (a|
04903|029|D|sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2|
04903|030|D|doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(3)|
04903|031|D|   Selected CYP3A4 inhibitors linked to this monograph include: gepotidacin|
04903|032|D|and sevabertinib.|
04903|033|B||
04903|034|R|REFERENCES:|
04903|035|B||
04903|036|R|1.Afinitor (everolimus) US prescribing information. Novartaris|1
04903|037|R|  Pharmaceuticals Corporation February, 2020.|1
04903|038|R|2.Zortress (everolimus) US prescribing information. Novartis Pharmaceuticals|1
04903|039|R|  Corporation Sept, 2023.|1
04903|040|R|3.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04903|041|R|  2025.|1
04903|042|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04903|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04903|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04903|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04903|046|R|  11/14/2017.|1
04904|001|T|MONOGRAPH TITLE:  Sirolimus/Selected CYP3A4 Inhibitors|
04904|002|B||
04904|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04904|004|L|of severe adverse interaction.|
04904|005|B||
04904|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04904|007|A|sirolimus.(1,2)|
04904|008|B||
04904|009|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
04904|010|E|elevated levels of and toxicity from sirolimus.(1,2)|
04904|011|B||
04904|012|P|PREDISPOSING FACTORS:  None determined.|
04904|013|B||
04904|014|M|PATIENT MANAGEMENT:  Closely monitor for an increase in sirolimus levels and|
04904|015|M|for renal dysfunction during concurrent therapy with CYP3A4 inhibitors,|
04904|016|M|especially at initiation and discontinuation of therapy.  Dose adjustment of|
04904|017|M|sirolimus may be necessary.(1,2)|
04904|018|M|   The manufacturer of gepotidacin states that concurrent use of drugs that|
04904|019|M|are extensively metabolized by CYP3A4 and have a narrow therapeutic window|
04904|020|M|like sirolimus should be avoided.(3)|
04904|021|M|   The US manufacturer of sirolimus protein-bound injection (Fyarro) states|
04904|022|M|a dose reduction to 56 mg/m2 is recommended when used concurrently with|
04904|023|M|moderate or weak CYP3A4 inhibitors.  Concurrent use with strong CYP3A4|
04904|024|M|inhibitors should be avoided.(2)|
04904|025|B||
04904|026|D|DISCUSSION:  In a clinical study, coadministration of single-dose midazolam|
04904|027|D|2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12|
04904|028|D|hours for 2 doses) increased the area-under-curve (AUC) of midazolam by|
04904|029|D|1.9-fold.(3)|
04904|030|D|   Selected CYP3A4 inhibitors linked to this monograph include: gepotidacin.|
04904|031|B||
04904|032|R|REFERENCES:|
04904|033|B||
04904|034|R|1.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
04904|035|R|  March, 2013.|1
04904|036|R|2.Fyarro (sirolimus protein-bound particles for injectable susspension) US|1
04904|037|R|  prescribing information. Aadi Bioscience, Inc. November, 2021.|1
04904|038|R|3.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04904|039|R|  2025.|1
04904|040|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04904|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04904|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04904|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04904|044|R|  11/14/2017.|1
04905|001|T|MONOGRAPH TITLE:  Cyclosporine/Selected CYP3A4 Inhibitors|
04905|002|B||
04905|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04905|004|L|of severe adverse interaction.|
04905|005|B||
04905|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04905|007|A|cyclosporine.(1)|
04905|008|B||
04905|009|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
04905|010|E|elevated levels of and toxicity from cyclosporine.(1)|
04905|011|B||
04905|012|P|PREDISPOSING FACTORS:  None determined.|
04905|013|B||
04905|014|M|PATIENT MANAGEMENT:  Monitor cyclosporine levels and renal function in|
04905|015|M|patients receiving concurrent therapy. Cyclosporine dosages may need to be|
04905|016|M|decreased.(1)|
04905|017|M|   The manufacturer of gepotidacin states that concurrent use of drugs that|
04905|018|M|are extensively metabolized by CYP3A4 and have a narrow therapeutic window|
04905|019|M|like cyclosporine should be avoided.(2)|
04905|020|B||
04905|021|D|DISCUSSION:  In a study, renal and cardiac patients required a cyclosporine|
04905|022|D|dose reduction of 15% to 48% when diltiazem, a moderate CYP3A4 inhibitor,|
04905|023|D|was co-administered to maintain a cyclosporine trough similar to|
04905|024|D|cyclosporine alone.(3)|
04905|025|D|   In a study, cyclosporine required a 25% dose reduction when|
04905|026|D|co-administered with fluconazole, a moderate CYP3A4 inhibitor, to maintain a|
04905|027|D|goal serum concentration similar to cyclosporine alone.(4)|
04905|028|D|   In a clinical study, coadministration of single-dose midazolam 2 mg (a|
04905|029|D|sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2|
04905|030|D|doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(2)|
04905|031|D|   Selected CYP3A4 inhibitors linked to this monograph include: gepotidacin|
04905|032|D|and sevabertinib.|
04905|033|B||
04905|034|R|REFERENCES:|
04905|035|B||
04905|036|R|1.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
04905|037|R|  Corporation September, 2023.|1
04905|038|R|2.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04905|039|R|  2025.|1
04905|040|R|3.Cardizem LA (diltiazem hcl extended release tablets) US prescribing|1
04905|041|R|  information. Abbott Pharmaceuticals, Inc. November, 2016.|1
04905|042|R|4.Gu TM, Lewis JS 2nd, Le H, Bubalo JS. Comparative effects of fluconazole,|2
04905|043|R|  posaconazole, and isavuconazole upon  tacrolimus and cyclosporine serum|2
04905|044|R|  concentrations. J Oncol Pharm Pract 2022 Sep;28(6):1357-1362.|2
04906|001|T|MONOGRAPH TITLE:  Colchicine/Selected CYP3A4 Inhibitors|
04906|002|B||
04906|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04906|004|L|of severe adverse interaction.|
04906|005|B||
04906|006|A|MECHANISM OF ACTION:  CYP3A4 inhibitors may inhibit the metabolism of|
04906|007|A|colchicine.(1-3)|
04906|008|B||
04906|009|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may result in|
04906|010|E|elevated levels of and toxicity from colchicine.  Symptoms of colchicine|
04906|011|E|toxicity include muscle weakness or pain; numbness or tingling in the|
04906|012|E|fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea|
04906|013|E|or vomiting; feeling weak or tired; increased infections; and pale or gray|
04906|014|E|color of the lips, tongue, or palms of hands.(1-3)|
04906|015|B||
04906|016|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
04906|017|P|patients with renal and/or hepatic impairment.(1-3)|
04906|018|B||
04906|019|M|PATIENT MANAGEMENT:  Monitor patients receiving CYP3A4 inhibitors for signs|
04906|020|M|of colchicine toxicity.  Depending on the potency of CYP3A4 inhibition, the|
04906|021|M|indication for colchicine, and the patient's renal and hepatic function,|
04906|022|M|concurrent use may be contraindicated or may require a decreased dosage of|
04906|023|M|colchicine.  Refer to colchicine prescribing information for specific|
04906|024|M|recommendations.(1-3)|
04906|025|M|   The manufacturer of gepotidacin states that concurrent use of drugs that|
04906|026|M|are extensively metabolized by CYP3A4 and have a narrow therapeutic window|
04906|027|M|like colchicine should be avoided.(4)|
04906|028|M|   Patients should be instructed to immediately report any signs of|
04906|029|M|colchicine toxicity, such as muscle weakness/pain, numbness/tingling in|
04906|030|M|fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness,|
04906|031|M|pale/gray color of the lips/tongue/palms of hands, and/or severe|
04906|032|M|diarrhea/vomiting.|
04906|033|B||
04906|034|D|DISCUSSION:  In a clinical study, coadministration of single-dose midazolam|
04906|035|D|2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12|
04906|036|D|hours for 2 doses) increased the area-under-curve (AUC) of midazolam by|
04906|037|D|1.9-fold.(2)|
04906|038|D|   Selected CYP3A4 inhibitors linked to this monograph include: gepotidacin.|
04906|039|B||
04906|040|R|REFERENCES:|
04906|041|B||
04906|042|R|1.Colcrys (colchicine) US prescribing information. AR Scientific, Inc. July,|1
04906|043|R|  2011.|1
04906|044|R|2.Mitigare (colchicine) US prescribing information. Hikma Specialty USA Inc.|1
04906|045|R|  March, 2023.|1
04906|046|R|3.Lodoco (colchicine) US prescribing information. AGEPHA Pharma USA, LLC|1
04906|047|R|  June, 2023.|1
04906|048|R|4.Blujepa (gepotidacin) US prescribing information. GlaxoSmithKline March|1
04906|049|R|  2025.|1
04906|050|R|5.Anonymous. Information for Healthcare Professionals: New Safety|1
04906|051|R|  Information for Colchicine (marketed as Colcrys). Available at:|1
04906|052|R|  https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-|1
04906|053|R|  providers/colchicine-marketed-colcrys-information July 30, 2009.|1
04906|054|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04906|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04906|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04906|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04906|058|R|  11/14/2017.|1
04906|059|R|7.This information is based on an extract from the Certara Drug Interaction|6
04906|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04907|001|T|MONOGRAPH TITLE:  Atrasentan/Strong CYP3A4 Inducers|
04907|002|B||
04907|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04907|004|L|of severe adverse interaction.|
04907|005|B||
04907|006|A|MECHANISM OF ACTION:  Strong inducers of CYP3A4 may induce the metabolism of|
04907|007|A|atrasentan.(1)|
04907|008|B||
04907|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
04907|010|E|reduce the clinical effectiveness of atrasentan.(1)|
04907|011|B||
04907|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04907|013|P|of the inducer for longer than 1-2 weeks.|
04907|014|B||
04907|015|M|PATIENT MANAGEMENT:  The manufacturer of atrasentan states that concurrent|
04907|016|M|use of strong CYP3A4 inducers should be avoided.(1)|
04907|017|B||
04907|018|D|DISCUSSION:  In a study, atrasentan trough concentration (Ctrough) decreased|
04907|019|D|by 90% following coadministration of a single dose of 10 mg of atrasentan|
04907|020|D|with rifampin (strong CYP3A4 inducer).(1)|
04907|021|D|   Strong CYP3A4 inducers linked to this monograph are: apalutamide,|
04907|022|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib,|
04907|023|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and|
04907|024|D|St. John's Wort.(2,3)|
04907|025|B||
04907|026|R|REFERENCES:|
04907|027|B||
04907|028|R|1.Vanrafia (atrasentan) US prescribing information. Novartis Pharmaceuticals|1
04907|029|R|  Corporation April 2025.|1
04907|030|R|2.This information is based on an extract from the Certara Drug Interaction|6
04907|031|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04907|032|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04907|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04907|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04907|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04907|036|R|  11/14/2017.|1
04908|001|T|MONOGRAPH TITLE:  Atrasentan/Moderate CYP3A4 Inducers|
04908|002|B||
04908|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04908|004|L|of severe adverse interaction.|
04908|005|B||
04908|006|A|MECHANISM OF ACTION:  Moderate inducers of CYP3A4 may induce the metabolism|
04908|007|A|of atrasentan.(1)|
04908|008|B||
04908|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
04908|010|E|reduce the clinical effectiveness of atrasentan.(1)|
04908|011|B||
04908|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04908|013|P|of the inducer for longer than 1-2 weeks.|
04908|014|B||
04908|015|M|PATIENT MANAGEMENT:  The manufacturer of atrasentan states that concurrent|
04908|016|M|use of moderate CYP3A4 inducers should be avoided.(1)|
04908|017|B||
04908|018|D|DISCUSSION:  In a study, atrasentan trough concentration (Ctrough) decreased|
04908|019|D|by 90% following coadministration of a single dose of 10 mg of atrasentan|
04908|020|D|with rifampin (strong CYP3A4 inducer).(1)  The effects of a moderate CYP3A4|
04908|021|D|inducer on atrasentan concentrations has not been studied.|
04908|022|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
04908|023|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04908|024|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04908|025|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl,|
04908|026|D|thioridazine, and tovorafenib.(2,3)|
04908|027|B||
04908|028|R|REFERENCES:|
04908|029|B||
04908|030|R|1.Vanrafia (atrasentan) US prescribing information. Novartis Pharmaceuticals|1
04908|031|R|  Corporation April 2025.|1
04908|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04908|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04908|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04908|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04908|036|R|  11/14/2017.|1
04908|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
04908|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04909|001|T|MONOGRAPH TITLE:  Atrasentan/OATP1B1-3 Inhibitors|
04909|002|B||
04909|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04909|004|L|of severe adverse interaction.|
04909|005|B||
04909|006|A|MECHANISM OF ACTION:  OATP1B1 and 1B3 inhibitors may increase the absorption|
04909|007|A|and/or decrease the hepatic uptake of atrasentan.(1)|
04909|008|B||
04909|009|E|CLINICAL EFFECTS:  Concurrent use of OATP1B1 or 1B3 inhibitors may result in|
04909|010|E|elevated levels of and side effects from atrasentan, including fluid|
04909|011|E|retention and hepatotoxicity.(1)|
04909|012|B||
04909|013|P|PREDISPOSING FACTORS:  None determined.|
04909|014|B||
04909|015|M|PATIENT MANAGEMENT:  The manufacturer of atrasentan states that concurrent|
04909|016|M|use of OATP1B1 or 1B3 inhibitors should be avoided.(1)|
04909|017|B||
04909|018|D|DISCUSSION:  In a clinical study, atrasentan maximum concentration (Cmax)|
04909|019|D|was 4.3 times higher and area-under-curve (AUC) was 3.8 times higher|
04909|020|D|following coadministration of a single dose of 0.75 mg atrasentan with|
04909|021|D|cyclosporine (OATP1B1 and 1B3 inhibitor) compared to atrasentan alone.|
04909|022|D|   OATP1B1 and OATP1B3 inhibitors include: atazanavir, belumosudil,|
04909|023|D|boceprevir, clarithromycin, cobicistat, cyclosporine, eltrombopag,|
04909|024|D|erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir,|
04909|025|D|leflunomide, leniolisib, letermovir, lopinavir, nirmatrelvir,|
04909|026|D|ombitasvir-paritaprevir, resmetirom, ritonavir, roxadustat, saquinavir,|
04909|027|D|simeprevir, telaprevir, teriflunomide, tipranavir, vadadustat, velpatasvir,|
04909|028|D|voclosporin, and voxilaprevir.(1,2)|
04909|029|B||
04909|030|R|REFERENCES:|
04909|031|B||
04909|032|R|1.Vanrafia (atrasentan) US prescribing information. Novartis Pharmaceuticals|1
04909|033|R|  Corporation April 2025.|1
04909|034|R|2.This information is based on an extract from the Certara Drug Interaction|6
04909|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04910|001|T|MONOGRAPH TITLE:  Atrasentan/Dual Strong 3A4 Inducers & OATP1B1-3 Inhibitors|
04910|002|B||
04910|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04910|004|L|of severe adverse interaction.|
04910|005|B||
04910|006|A|MECHANISM OF ACTION:  Atrasentan is a substrate of CYP3A4 and of the OATP1B1|
04910|007|A|and OATP1B3 transporters.(1)  Agents that are both strong CYP3A4 inducers|
04910|008|A|and OATP1B1 and OATP1B3 inhibitors such as encorafenib and rifampin may|
04910|009|A|induce the metabolism and increase the absorption of atrasentan.(2,3)|
04910|010|B||
04910|011|E|CLINICAL EFFECTS:  The net effect of this interaction is unknown.|
04910|012|E|Concurrent use of strong CYP3A4 inducers may result in decreased levels and|
04910|013|E|effectiveness of atrasentan.  Concurrent use of OATP1B1 and OATP1B3|
04910|014|E|inhibitors may result in elevated levels and toxicities of atrasentan|
04910|015|E|including fluid retention or hepatotoxicity.(1)|
04910|016|B||
04910|017|P|PREDISPOSING FACTORS:  CYP3A4 induction effects may be more likely with|
04910|018|P|regular use of the inducer for longer than 1-2 weeks.|
04910|019|B||
04910|020|M|PATIENT MANAGEMENT:  Coadministration of atrasentan with combined strong|
04910|021|M|CYP3A4 inducers and OATP1B1 and OATP1B3 inhibitors should be avoided.(1)|
04910|022|B||
04910|023|D|DISCUSSION:  In a study, atrasentan trough concentration (Ctrough) decreased|
04910|024|D|by 90% following coadministration of a single dose of 10 mg of atrasentan|
04910|025|D|with rifampin (dual strong CYP3A4 inducer and OATP1B1 and OATP1B3|
04910|026|D|inhibitor).(1)|
04910|027|D|   Combined strong CYP3A4 inducers and OATP1B1 and OATP1B3 inhibitors linked|
04910|028|D|to this monograph include: encorafenib and rifampin.(2,3)|
04910|029|B||
04910|030|R|REFERENCES:|
04910|031|B||
04910|032|R|1.Vanrafia (atrasentan) US prescribing information. Novartis Pharmaceuticals|1
04910|033|R|  Corporation April 2025.|1
04910|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04910|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04910|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04910|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04910|038|R|  11/14/2017.|1
04910|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
04910|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04911|001|T|MONOGRAPH TITLE:  Apixaban/Clarithromycin|
04911|002|B||
04911|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04911|004|L|take action as needed.|
04911|005|B||
04911|006|A|MECHANISM OF ACTION:  Clarithromycin is a combined P-glycoprotein (P-gp) and|
04911|007|A|strong CYP3A4 inhibitor.(1)  Concurrent use may inhibit the metabolism of|
04911|008|A|apixaban by CYP3A4 and increase its absorption through P-gp.(2-5)|
04911|009|B||
04911|010|E|CLINICAL EFFECTS:  Concurrent use of clarithromycin may result in elevated|
04911|011|E|levels of and clinical effects of apixaban, including an increased risk of|
04911|012|E|bleeding.(1-5)|
04911|013|B||
04911|014|P|PREDISPOSING FACTORS:  This interaction may be more clinically significant|
04911|015|P|in patients with decreased renal function.(1-5)|
04911|016|P|   The risk for bleeding episodes may be greater in older patients (65 years|
04911|017|P|and over) and patients with disease-associated factors (e.g.|
04911|018|P|thrombocytopenia).|
04911|019|P|   Drug associated risk factors include concurrent use of multiple drugs|
04911|020|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04911|021|P|risk for bleeding (e.g. NSAIDs).|
04911|022|B||
04911|023|M|PATIENT MANAGEMENT:  The Australian(2), Canadian(3), UK(4), and US(5)|
04911|024|M|manufacturers of apixaban state that concurrent use of clarithromycin is|
04911|025|M|expected to increase apixaban levels to a lesser extent than agents that are|
04911|026|M|strong inhibitors of both P-gp and CYP3A4.  No dose adjustment of apixaban|
04911|027|M|is necessary.  Use caution when administering apixaban with clarithromycin.|
04911|028|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04911|029|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04911|030|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04911|031|M|patients with any symptoms.|
04911|032|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04911|033|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04911|034|M|anticoagulation in patients with active pathologic bleeding.|
04911|035|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04911|036|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04911|037|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04911|038|M|and/or swelling.|
04911|039|B||
04911|040|D|DISCUSSION:  In an open-label non-randomized crossover pharmacokinetic study|
04911|041|D|of 19 healthy volunteers, clarithromycin 500 mg twice daily for 4 days|
04911|042|D|increased the area-under-curve (AUC) and maximum concentration (Cmax) of|
04911|043|D|single-dose apixaban 10 mg by 60% and 30%, respectively, compared to|
04911|044|D|apixaban alone.  Adverse events were mild, and the frequency did not|
04911|045|D|increase with the combination.(6)|
04911|046|D|   An open-label pharmacokinetic study of 12 healthy volunteers evaluated|
04911|047|D|use of clarithromycin (500 mg twice daily with pre-treatment for 7 days)|
04911|048|D|with therapeutic dose of edoxaban (60 mg) and a microdose cocktail of|
04911|049|D|apixaban (25 mcg), edoxaban (50 mcg), and rivaroxaban (25 mcg).  Apixaban|
04911|050|D|AUC increased by 60% and Cmax increased by 30%. Compared to therapeutic|
04911|051|D|doses of edoxaban, microdosed edoxaban over-estimated the effect of|
04911|052|D|clarithromycin on edoxaban exposure; the authors stated that the microdose|
04911|053|D|direct oral anticoagulant (DOAC) interactions with clarithromycin are not|
04911|054|D|expected to be clinically relevant.(7)|
04911|055|D|   A cohort from two Belgian health databases examined 193,072 atrial|
04911|056|D|fibrillation patients who were at least 45 years old and newly started on|
04911|057|D|dabigatran, rivaroxaban, apixaban or edoxaban.  Patients were classified by|
04911|058|D|whether they had concomitant CYP3A4 and P-gp interacting drugs at baseline.|
04911|059|D|On multivariate analysis, concomitant P-gp/CYP3A4 inhibitor use with DOACs|
04911|060|D|was associated with higher risks of major bleeding (aHR 1.24, 95% CI|
04911|061|D|1.18-1.30), intracranial bleeding (aHR 1.07, 95% CI 1.02-1.11), GI bleeding|
04911|062|D|[aHR 1.20, 95% CI (1.12-1.28)], and all-cause mortality [aHR 1.07, 95% CI|
04911|063|D|(1.02-1.11)].  Although the specific combination of apixaban with|
04911|064|D|clarithromycin was not evaluated, subgroup analysis found that|
04911|065|D|clarithromycin increased the risks of major bleeding [aHR 1.55, 95% CI|
04911|066|D|(1.14-2.11)] and GI bleeding [aHR 1.52, 95% CI 1.03-2.25)] from DOACs, while|
04911|067|D|concurrent P-gp/CYP3A4 inhibitors increased the risk of major bleeding from|
04911|068|D|apixaban [aHR 1.27, 95% CI 1.07-1.35].(8)|
04911|069|D|   An analysis of the FDA Adverse Event Reporting System (FAERS) database|
04911|070|D|looking at hemorrhagic signals associated with coadministration of apixaban,|
04911|071|D|dabigatran, rivaroxaban, or edoxaban with azithromycin, clarithromycin,|
04911|072|D|erythromycin, fluconazole, itraconazole, ketoconazole, posaconazole or|
04911|073|D|voriconazole found 27,544 cases of apixaban-related hemorrhagic events, with|
04911|074|D|315 cases involving CYP3A4 inhibitors.  The combination of apixaban and|
04911|075|D|clarithromycin was associated with increased risk of hemorrhagic events in|
04911|076|D|multiple logistic regression (ROR 1.60, 95% CI 1.16-2.20).(9)|
04911|077|D|   A population-based retrospective cohort study examined 24,943 patients|
04911|078|D|aged 66 years and older on concurrent therapy with an anticoagulant|
04911|079|D|[rivaroxaban (40.0%), apixaban (31.9%), or dabigatran (28.1%)] and either|
04911|080|D|azithromycin or clarithromycin.  The primary outcome of hospital admission|
04911|081|D|with major hemorrhage on an anticoagulant within 30 days on concurrent|
04911|082|D|therapy was higher in patients on clarithromycin (0.77%) compared to|
04911|083|D|azithromycin (0.43%) with an adjusted hazard ratio of 1.71 (95% CI,|
04911|084|D|1.20-2.45).  Hemorrhage rate was similarly elevated when comparing periods|
04911|085|D|of clarithromycin use with periods of nonuse within the same individual.|
04911|086|D|Although the data was not shown, the outcome did not differ by DOAC type or|
04911|087|D|mean daily dose.  There was a high proportion (33%) of patients with|
04911|088|D|baseline eGFR <=60 mL/min/1.73m2, which was the same in the clarithromycin|
04911|089|D|and azithromycin groups but this was accounted for in the adjusted|
04911|090|D|analysis.(10)|
04911|091|B||
04911|092|R|REFERENCES:|
04911|093|B||
04911|094|R|1.Biaxin (clarithromycin) US prescribing information. AbbVie, Inc.|1
04911|095|R|  September, 2019.|1
04911|096|R|2.Eliquis (apixaban) Australian prescribing information. Bristol-Myers|1
04911|097|R|  Squibb Australia Pty. Ltd. January, 2024.|1
04911|098|R|3.Eliquis (apixaban) Canadian prescribing information. Bristol-Myers|1
04911|099|R|  Squibb-Pfizer January, 2025.|1
04911|100|R|4.Eliquis (apixaban) UK summary of product characterstics. Bristol-Myers|1
04911|101|R|  Squibb/Pfizer EEIG, Bristol-Myers Squibb House September, 2023.|1
04911|102|R|5.Eliquis (apixaban) US prescribing information. Bristol-Myers Squibb|1
04911|103|R|  Company April, 2025.|1
04911|104|R|6.Garonzik S, Byon W, Myers E, Li X, Marchisin D, Murthy B. The Effects of|2
04911|105|R|  Clarithromycin on the Pharmacokinetics of Apixaban in Healthy  Volunteers:|2
04911|106|R|  A Single-Sequence Crossover Study. Am J Cardiovasc Drugs 2019 Dec;|2
04911|107|R|  19(6):561-567.|2
04911|108|R|7.Lenard A, Hermann SA, Stoll F, Burhenne J, Foerster KI, Mikus G, Meid AD,|2
04911|109|R|  Haefeli WE, Blank A. Effect of Clarithromycin, a Strong CYP3A and|2
04911|110|R|  P-glycoprotein Inhibitor, on the  Pharmacokinetics of Edoxaban in Healthy|2
04911|111|R|  Volunteers and the Evaluation of the Drug  Interaction with Other Oral|2
04911|112|R|  Factor Xa Inhibitors by a Microdose Cocktail  Approach. Cardiovasc Drugs|2
04911|113|R|  Ther 2024 Aug;38(4):747-756.|2
04911|114|R|8.Grymonprez M, Carnoy L, Capiau A, Boussery K, Mehuys E, De Backer TL,|2
04911|115|R|  Steurbaut S, Lahousse L. Impact of P-glycoprotein and CYP3A4-interacting|2
04911|116|R|  drugs on clinical outcomes in  patients with atrial fibrillation using|2
04911|117|R|  non-vitamin K antagonist oral  anticoagulants: a nationwide cohort study.|2
04911|118|R|  Eur Heart J Cardiovasc Pharmacother 2023 Dec 14;9(8):722-730.|2
04911|119|R|9.Li D, Yan C, Guo M, Zhao Y, Zhang Y, Cui X. Evidence of potential|2
04911|120|R|  pro-haemorrhagic drug interactions between CYP3A4  inhibitors and direct|2
04911|121|R|  oral anticoagulants: Analysis of the FAERS database. Br J Clin Pharmacol|2
04911|122|R|  2023 Aug;89(8):2423-2429.|2
04911|123|R|10.Hill K, Sucha E, Rhodes E, Carrier M, Garg AX, Harel Z, Hundemer GL,|2
04911|124|R|   Clark EG, Knoll G, McArthur E, Sood MM. Risk of Hospitalization With|2
04911|125|R|   Hemorrhage Among Older Adults Taking Clarithromycin  vs Azithromycin and|2
04911|126|R|   Direct Oral Anticoagulants. JAMA Intern Med 2020 Aug 1;180(8):1052-1060.|2
04912|001|T|MONOGRAPH TITLE:  Mavacamten/Moderate CYP2C19 Inhibitors|
04912|002|B||
04912|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04912|004|L|of severe adverse interaction.|
04912|005|B||
04912|006|A|MECHANISM OF ACTION:  Moderate CYP2C19 inhibitors may decrease the|
04912|007|A|metabolism of mavacamten.(1-3)|
04912|008|B||
04912|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP2C19 inhibitor increases|
04912|010|E|plasma exposure of mavacamten which may increase the incidence and severity|
04912|011|E|of adverse reactions of mavacamten.(1-3)|
04912|012|B||
04912|013|P|PREDISPOSING FACTORS:  CYP2C19 rapid and ultrarapid metabolizers may|
04912|014|P|experience an increased incidence or severity of adverse effects.(1-3)|
04912|015|B||
04912|016|M|PATIENT MANAGEMENT:  The US manufacturer of mavacamten recommends initiating|
04912|017|M|mavacamten at the recommended starting dosage of 2.5 mg orally once daily in|
04912|018|M|patients who are on stable therapy with a moderate CYP2C19 inhibitor.|
04912|019|M|Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in|
04912|020|M|patients who are on mavacamten treatment and intend to initiate a moderate|
04912|021|M|CYP2C19 inhibitor.  Schedule clinical and echocardiographic assessment 4|
04912|022|M|weeks after inhibitor initiation, and do not up-titrate mavacamten until 12|
04912|023|M|weeks after inhibitor initiation.(1)|
04912|024|M|   Avoid initiation of concomitant moderate CYP2C19 inhibitors in patients|
04912|025|M|who are on stable treatment with 2.5 mg of mavacamten because a lower dose|
04912|026|M|is not available.(1)|
04912|027|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
04912|028|M|duration of the moderate CYP2C19 inhibitor.  After therapy with the moderate|
04912|029|M|CYP2C19 inhibitor is discontinued, mavacamten may be reinitiated at the|
04912|030|M|previous dose immediately upon discontinuation.(1)|
04912|031|M|   The Canadian manufacturer of mavacamten states concomitant use with|
04912|032|M|moderate CYP2C19 inhibitors is contraindicated.(2)|
04912|033|M|   The UK manufacturer of mavacamten states concomitant use with moderate|
04912|034|M|CYP2C19 inhibitors is dependent on CYP2C19 phenotype.  Labeling recommends:|
04912|035|M|   -In patients who are CYP2C19 poor metabolizers, moderate CYP2C19|
04912|036|M|inhibitors may be used concurrently without dose adjustment of mavacamten.|
04912|037|M|Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume|
04912|038|M|usual monitoring schedule.|
04912|039|M|   -In patient who are CYP2C19 intermediate, normal, rapid, or ultrarapid|
04912|040|M|metabolizers:|
04912|041|M|   Moderate CYP2C19 inhibitors may be used concurrently without dose|
04912|042|M|adjustment of mavacamten starting dose of 5 mg daily. If starting a moderate|
04912|043|M|CYP2C19 inhibitor, reduce mavacamten dose by one dose level or discontinue|
04912|044|M|2.5 mg. Monitor LVEF in 4 weeks then resume usual monitoring schedule.|
04912|045|M|   -If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of|
04912|046|M|2.5 mg daily.  If starting a moderate CYP2C19 inhibitor, reduce mavacamten|
04912|047|M|dose from 5 mg to 2.5 mg or discontinue mavacamten if on 2.5 mg. Monitor|
04912|048|M|LVEF in 4 weeks then resume usual monitoring schedule.(3)|
04912|049|B||
04912|050|D|DISCUSSION:  Concomitant use of mavacamten (15 mg) with omeprazole (20 mg),|
04912|051|D|a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve|
04912|052|D|(AUC) by 48% with no effect on maximum concentration (Cmax) in healthy|
04912|053|D|CYP2C19 normal metabolizers and rapid metabolizers.(1)|
04912|054|D|   Moderate CYP2C19 inhibitors linked to this monograph include:|
04912|055|D|abrocitinib, cannabidiol, efavirenz, esomeprazole, etravirine, moclobemide,|
04912|056|D|omeprazole, stiripentol, triclabendazole.(4,5)|
04912|057|B||
04912|058|R|REFERENCES:|
04912|059|B||
04912|060|R|1.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
04912|061|R|  April, 2025.|1
04912|062|R|2.Camzyos (mavacamten) Canadian product monograph. Bristol-Myers Squibb|1
04912|063|R|  Canada February, 2024.|1
04912|064|R|3.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
04912|065|R|  Squibb July, 2023.|1
04912|066|R|4.This information is based on an extract from the Certara Drug Interaction|6
04912|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04912|068|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04912|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04912|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04912|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04912|072|R|  11/14/2017.|1
04913|001|T|MONOGRAPH TITLE:  Ajmaline/QT Prolonging Agents|
04913|002|B||
04913|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04913|004|L|of severe adverse interaction.|
04913|005|B||
04913|006|A|MECHANISM OF ACTION:  Ajmaline has been shown to prolong the QTc interval.|
04913|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
04913|008|A|additive effects on the QTc interval.(1)|
04913|009|B||
04913|010|E|CLINICAL EFFECTS:  The concurrent use of ajmaline with other agents that|
04913|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04913|012|E|arrhythmias, including torsades de pointes (TdP).(1)|
04913|013|B||
04913|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
04913|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
04913|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
04913|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04913|018|P|female gender, or advanced age.(2)|
04913|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04913|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04913|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04913|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04913|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04913|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04913|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04913|026|B||
04913|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of ajmaline with other|
04913|028|M|agents known to prolong the QT interval.(1)|
04913|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04913|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04913|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04913|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04913|033|B||
04913|034|D|DISCUSSION:  Ajmaline has been associated with case reports of QT|
04913|035|D|prolongation and torsades de pointes (TdP).(1,3-8)|
04913|036|D|   Agents that are linked to this monograph may have varying degrees of|
04913|037|D|potential to prolong the QTc interval but are generally accepted to have a|
04913|038|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04913|039|D|been shown to prolong the QTc interval either through their mechanism of|
04913|040|D|action, through studies on their effects on the QTc interval, or through|
04913|041|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04913|042|D|and/or post-marketing reports.(9)|
04913|043|B||
04913|044|R|REFERENCES:|
04913|045|B||
04913|046|R|1.Gilurytmal (ajmaline) German package insert. Carinopharm GmbH September,|1
04913|047|R|  2021.|1
04913|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04913|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04913|050|R|  settings: a scientific statement from the American Heart Association and|6
04913|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04913|052|R|  2;55(9):934-47.|6
04913|053|R|3.Kaul U, Mohan JC, Narula J, Nath CS, Bhatia ML. Ajmaline-induced torsade|3
04913|054|R|  de pointes. Cardiology 1985;72(3):140-3.|3
04913|055|R|4.Belhassen B. Ajmaline-induced torsade de pointes. Cardiology 1986;|3
04913|056|R|  73(1):54-5.|3
04913|057|R|5.Kolar J, Humhal J, Karetova D, Novak M. Torsade de pointes after mesocaine|3
04913|058|R|  and ajmaline in a patient with intermittent  atrioventricular block.|3
04913|059|R|  Favorable therapeutic effect of high doses of  isoprenaline. Cas Lek Cesk|3
04913|060|R|  1987 Nov 27;126(48):1503-7.|3
04913|061|R|6.Schmitt C, Brachmann J, Schols W, Beyer T, Kubler W. Proarrhythmic effect|3
04913|062|R|  of ajmaline in idiopathic ventricular tachycardia. Dtsch Med Wochenschr|3
04913|063|R|  1989 Jan 20;114(3):99-102.|3
04913|064|R|7.Haverkamp W, Monnig G, Kirchhof P, Eckardt L, Borggrefe M, Breithardt G.|3
04913|065|R|  Torsade de pointes induced by ajmaline. Z Kardiol 2001 Aug;90(8):586-90.|3
04913|066|R|8.Kiesecker C, Zitron E, Luck S, Bloehs R, Scholz EP, Kathofer S, Thomas D,|5
04913|067|R|  Kreye VA, Katus HA, Schoels W, Karle CA, Kiehn J. Class Ia anti-arrhythmic|5
04913|068|R|  drug ajmaline blocks HERG potassium channels: mode of  action. Naunyn|5
04913|069|R|  Schmiedebergs Arch Pharmacol 2004 Dec;370(6):423-35.|5
04913|070|R|9.USDepartment of Health and Human Services Food and Drug Administration.|1
04913|071|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04913|072|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04913|073|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04914|001|T|MONOGRAPH TITLE:  Ajmaline/Possible QT Prolonging Agents|
04914|002|B||
04914|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04914|004|L|take action as needed.|
04914|005|B||
04914|006|A|MECHANISM OF ACTION:  Ajmaline has been shown to prolong the QTc interval.|
04914|007|A|Concurrent use with other agents that prolong the QTc interval may result in|
04914|008|A|additive effects on the QTc interval.(1)|
04914|009|B||
04914|010|E|CLINICAL EFFECTS:  The concurrent use of ajmaline with other agents that|
04914|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04914|012|E|arrhythmias, including torsades de pointes (TdP).(1)|
04914|013|B||
04914|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
04914|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
04914|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
04914|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04914|018|P|female gender, or advanced age.(2)|
04914|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04914|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04914|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04914|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04914|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04914|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04914|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04914|026|B||
04914|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of ajmaline with other|
04914|028|M|agents known to prolong the QT interval.(1)|
04914|029|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04914|030|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04914|031|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04914|032|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04914|033|B||
04914|034|D|DISCUSSION:  Ajmaline has been associated with case reports of QT|
04914|035|D|prolongation and torsades de pointes (TdP).(1,3-8)|
04914|036|D|   Agents that are linked to this monograph may have varying degrees of|
04914|037|D|potential to prolong the QTc interval but are generally accepted to have a|
04914|038|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04914|039|D|been shown to prolong the QTc interval either through their mechanism of|
04914|040|D|action, through studies on their effects on the QTc interval, or through|
04914|041|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04914|042|D|and/or post-marketing reports.(9)|
04914|043|B||
04914|044|R|REFERENCES:|
04914|045|B||
04914|046|R|1.Gilurytmal (ajmaline) German package insert. Carinopharm GmbH September,|1
04914|047|R|  2021.|1
04914|048|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04914|049|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04914|050|R|  settings: a scientific statement from the American Heart Association and|6
04914|051|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04914|052|R|  2;55(9):934-47.|6
04914|053|R|3.Kaul U, Mohan JC, Narula J, Nath CS, Bhatia ML. Ajmaline-induced torsade|3
04914|054|R|  de pointes. Cardiology 1985;72(3):140-3.|3
04914|055|R|4.Belhassen B. Ajmaline-induced torsade de pointes. Cardiology 1986;|3
04914|056|R|  73(1):54-5.|3
04914|057|R|5.Kolar J, Humhal J, Karetova D, Novak M. Torsade de pointes after mesocaine|3
04914|058|R|  and ajmaline in a patient with intermittent  atrioventricular block.|3
04914|059|R|  Favorable therapeutic effect of high doses of  isoprenaline. Cas Lek Cesk|3
04914|060|R|  1987 Nov 27;126(48):1503-7.|3
04914|061|R|6.Schmitt C, Brachmann J, Schols W, Beyer T, Kubler W. Proarrhythmic effect|3
04914|062|R|  of ajmaline in idiopathic ventricular tachycardia. Dtsch Med Wochenschr|3
04914|063|R|  1989 Jan 20;114(3):99-102.|3
04914|064|R|7.Haverkamp W, Monnig G, Kirchhof P, Eckardt L, Borggrefe M, Breithardt G.|3
04914|065|R|  Torsade de pointes induced by ajmaline. Z Kardiol 2001 Aug;90(8):586-90.|3
04914|066|R|8.Kiesecker C, Zitron E, Luck S, Bloehs R, Scholz EP, Kathofer S, Thomas D,|5
04914|067|R|  Kreye VA, Katus HA, Schoels W, Karle CA, Kiehn J. Class Ia anti-arrhythmic|5
04914|068|R|  drug ajmaline blocks HERG potassium channels: mode of  action. Naunyn|5
04914|069|R|  Schmiedebergs Arch Pharmacol 2004 Dec;370(6):423-35.|5
04914|070|R|9.USDepartment of Health and Human Services Food and Drug Administration.|1
04914|071|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04914|072|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04914|073|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04915|001|T|MONOGRAPH TITLE:  IgG Antibodies and Derivatives/Nipocalimab-aahu|
04915|002|B||
04915|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04915|004|L|of severe adverse interaction.|
04915|005|B||
04915|006|A|MECHANISM OF ACTION:  The neonatal Fc receptor (FcRn) prevents catabolism|
04915|007|A|and mediates recycling of IgG and albumin, which leads to their long|
04915|008|A|persistence in the body.(1,2)  Nipocalimab-aahu binds to FcRn and may|
04915|009|A|decrease systemic exposure of other ligands of FcRn, like immunoglobulins|
04915|010|A|and IgG-based antibodies.(3)|
04915|011|B||
04915|012|E|CLINICAL EFFECTS:  The effectiveness of medicines that bind to FcRn may be|
04915|013|E|decreased.(3)|
04915|014|B||
04915|015|P|PREDISPOSING FACTORS:  None determined.|
04915|016|B||
04915|017|M|PATIENT MANAGEMENT:  The manufacturer of nipocalimab-aahu states that|
04915|018|M|nipocalimab-aahu should not be combined with long-term use of FcRn-binding|
04915|019|M|medications.  If the medication is essential for the patient,|
04915|020|M|nipocalimab-aahu should be discontinued.(3)|
04915|021|B||
04915|022|D|DISCUSSION:  Clinical drug interaction studies with nipocalimab-aahu have|
04915|023|D|not been performed.  Nipocalimab-aahu may decrease concentrations of|
04915|024|D|compounds that bind to the human FcRn.(3)|
04915|025|B||
04915|026|R|REFERENCES:|
04915|027|B||
04915|028|R|1.Sockolosky JT, Szoka FC. The neonatal Fc receptor, FcRn, as a target for|6
04915|029|R|  drug delivery and therapy. Adv Drug Deliv Rev 2015 Aug 30;91:109-24.|6
04915|030|R|2.Kuo TT, Aveson VG. Neonatal Fc receptor and IgG-based therapeutics. MAbs|6
04915|031|R|  2011 Sep-Oct;3(5):422-30.|6
04915|032|R|3.Imaavy (nipocalimab-aahu) US prescribing information. Janssen Biotech,|1
04915|033|R|  Inc. April 2025.|1
04916|001|T|MONOGRAPH TITLE:  Methotrexate/Nitrofurantoin|
04916|002|B||
04916|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04916|004|L|take action as needed.|
04916|005|B||
04916|006|A|MECHANISM OF ACTION:  Nitrofurantoin may inhibit the renal elimination of|
04916|007|A|methotrexate.(1-5)|
04916|008|B||
04916|009|E|CLINICAL EFFECTS:  Concurrent use of nitrofurantoin may result in an|
04916|010|E|increase in both the therapeutic and toxic effects of methotrexate, leading|
04916|011|E|to increased risk of severe neurotoxicity, stomatitis, and myelosuppression,|
04916|012|E|including neutropenia.|
04916|013|B||
04916|014|P|PREDISPOSING FACTORS:  Risk factors for methotrexate toxicity include:|
04916|015|P|- High-dose oncology regimens|
04916|016|P|- Impaired renal function, ascites, or pleural effusions|
04916|017|B||
04916|018|M|PATIENT MANAGEMENT:  If concurrent use cannot be avoided, monitor|
04916|019|M|methotrexate blood levels closely and adjust the dose accordingly.|
04916|020|B||
04916|021|D|DISCUSSION:  Concomitant administration of methotrexate and nitrofurantoin|
04916|022|D|has been shown to increase methotrexate plasma levels.(2-5)|
04916|023|D|   Case reports of methotrexate toxicity have been described with concurrent|
04916|024|D|use of nitrofurantoin.(2-4)|
04916|025|D|   Nitrofurantoin may inhibit organic anion transporter 3 (OAT3), resulting|
04916|026|D|in decreased renal clearance of methotrexate.(5)|
04916|027|B||
04916|028|R|REFERENCES:|
04916|029|B||
04916|030|R|1.Rheumatrex (methotrexate, oral) US prescribing information. Dava|1
04916|031|R|  Pharmaceuticals, Inc. February, 2013.|1
04916|032|R|2.Rambaran KA, Seifert CF. Unrecognized Interstitial Lung Disease as a|3
04916|033|R|  Result of Chronic Nitrofurantoin Use. Drug Saf Case Rep 2016 Dec;3(1):13.|3
04916|034|R|3.Gowarty JL, Patel IJ, Herrington JD. Altered methotrexate clearance in the|3
04916|035|R|  treatment of CNS lymphoma with concurrent  use of nitrofurantoin for a|3
04916|036|R|  urinary tract infection. J Oncol Pharm Pract 2019 Oct;25(7):1794-1797.|3
04916|037|R|4.Kochhar S, Bommu VJL, Kocur M, Shah V, Cheriyath P, Lake T. A Unique|3
04916|038|R|  Interaction of Methotrexate and Nitrofurantoin Resulting in Irreversible|3
04916|039|R|  Pulmonary Fibrosis. Cureus 2022 Jan;14(1):e20892.|3
04916|040|R|5.Lu X, Chan T, Zhu L, Bao X, Velkov T, Zhou QT, Li J, Chan HK, Zhou F. The|5
04916|041|R|  inhibitory effects of eighteen front-line antibiotics on the substrate|5
04916|042|R|  uptake  mediated by human Organic anion/cation transporters, Organic anion|5
04916|043|R|  transporting  polypeptides and Oligopeptide transporters in in vitro|5
04916|044|R|  models. Eur J Pharm Sci 2018 Mar 30;115:132-143.|5
04917|001|T|MONOGRAPH TITLE:  Avutometinib-Defactinib/Strong CYP3A4 Inhibitors|
04917|002|B||
04917|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04917|004|L|of severe adverse interaction.|
04917|005|B||
04917|006|A|MECHANISM OF ACTION:  Avutometinib and defactinib are CYP3A4 substrates.|
04917|007|A|Strong CYP3A4 inhibitors may inhibit the metabolism of defactinib.|
04917|008|A|Avutometinib also undergoes non-enzymatic degradation is not affected by|
04917|009|A|CYP3A4 inhibitors.(1)|
04917|010|B||
04917|011|E|CLINICAL EFFECTS:  The concurrent administration of a strong CYP3A4|
04917|012|E|inhibitor may result in elevated levels of defactinib and toxicity from|
04917|013|E|avutometinib-defactinib, including hepatotoxicity, rhabdomyolysis, ocular|
04917|014|E|toxicities, and skin toxicities.(1)|
04917|015|B||
04917|016|P|PREDISPOSING FACTORS:  None determined.|
04917|017|B||
04917|018|M|PATIENT MANAGEMENT:  Concurrent use of avutometinib-defactinib and strong|
04917|019|M|CYP3A4 inhibitors should be avoided.(1)|
04917|020|B||
04917|021|D|DISCUSSION:  Defactinib maximum concentration (Cmax) increased by 2.2-fold|
04917|022|D|and area-under-curve (AUC) by 3.9-fold following concomitant use with|
04917|023|D|itraconazole (strong CYP3A4 inhibitor) 200 mg daily for 10 days. The AUC of|
04917|024|D|M4, a major active metabolite of defactinib, increased by 2.2-fold and Cmax|
04917|025|D|decreased by 6.8%.(1)|
04917|026|D|   No clinically significant differences in avutometinib pharmacokinetics|
04917|027|D|were observed when used concomitantly with itraconazole.(1)|
04917|028|D|   Strong CYP3A4 inhibitors include: adagrasib, boceprevir, ceritinib,|
04917|029|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
04917|030|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir,|
04917|031|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
04917|032|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
04917|033|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)|
04917|034|B||
04917|035|R|REFERENCES:|
04917|036|B||
04917|037|R|1.Avmapki Fakzynja Co-Pak (avutometinib-defactinib) US prescribing|1
04917|038|R|  information. Verastem, Inc. May, 2025.|1
04917|039|R|2.This information is based on an extract from the Certara Drug Interaction|6
04917|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04917|041|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04917|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04917|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04917|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04917|045|R|  11/14/2017.|1
04918|001|T|MONOGRAPH TITLE:  Defactinib/Strong CYP3A4 Inducers|
04918|002|B||
04918|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04918|004|L|of severe adverse interaction.|
04918|005|B||
04918|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may accelerate the metabolism|
04918|007|A|of defactinib by CYP3A4.(1)|
04918|008|B||
04918|009|E|CLINICAL EFFECTS:  The concurrent use of defactinib and strong CYP3A4|
04918|010|E|inducers may result in decreased levels and effectiveness of defactinib.(1)|
04918|011|B||
04918|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04918|013|P|of the inducer for longer than 1-2 weeks.|
04918|014|B||
04918|015|M|PATIENT MANAGEMENT:  The manufacturer of defactinib states that the|
04918|016|M|concurrent use of strong CYP3A4 inducers should be avoided.(1)|
04918|017|B||
04918|018|D|DISCUSSION:  In a study, defactinib maximum concentration (Cmax) decreased|
04918|019|D|by 83% and area-under-curve (AUC) by 87% following coadministration with|
04918|020|D|phenytoin (strong CYP3A4 inducer) three times daily for 23 days and a single|
04918|021|D|dose of defactinib 200 mg (1.0 times the approved recommended dose) on Day|
04918|022|D|14.  The AUC and Cmax of N-desmethyl amide (M4), a major active metabolite|
04918|023|D|of defactinib, decreased by 79% and 70%, respectively.(1)|
04918|024|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04918|025|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04918|026|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04918|027|D|rifampin, rifapentine, and St. John's Wort.(2)|
04918|028|B||
04918|029|R|REFERENCES:|
04918|030|B||
04918|031|R|1.Avmapki Fakzynja Co-Pak (avutometinib-defactinib) US prescribing|1
04918|032|R|  information. Verastem, Inc. May, 2025.|1
04918|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
04918|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04919|001|T|MONOGRAPH TITLE:  Defactinib/Moderate CYP3A4 Inducers|
04919|002|B||
04919|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04919|004|L|of severe adverse interaction.|
04919|005|B||
04919|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may accelerate the metabolism|
04919|007|A|of defactinib by CYP3A4.(1)|
04919|008|B||
04919|009|E|CLINICAL EFFECTS:  The concurrent use of defactinib and a moderate CYP3A4|
04919|010|E|inducer may result in decreased levels and effectiveness of defactinib.(1)|
04919|011|B||
04919|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04919|013|P|of the inducer for longer than 1-2 weeks.|
04919|014|B||
04919|015|M|PATIENT MANAGEMENT:  The manufacturer of defactinib states that the|
04919|016|M|concurrent use of moderate CYP3A4 inducers should be avoided.(1)|
04919|017|B||
04919|018|D|DISCUSSION:  The impact of moderate CYP3A4 inhibitors on the|
04919|019|D|pharmacokinetics of defactinib has not been investigated in clinical|
04919|020|D|studies.|
04919|021|D|   In a study, defactinib maximum concentration (Cmax) decreased by 83% and|
04919|022|D|area-under-curve (AUC) by 87% following coadministration with phenytoin|
04919|023|D|(strong CYP3A4 inducer) three times daily for 23 days and a single dose of|
04919|024|D|defactinib 200 mg (1.0 times the approved recommended dose) on Day 14.  The|
04919|025|D|AUC and Cmax of N-desmethyl amide (M4), a major active metabolite of|
04919|026|D|defactinib, decreased by 79% and 70%, respectively.(1)|
04919|027|D|   Moderate inducers of CYP3A4 include:  belzutifan, bosentan, cenobamate,|
04919|028|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04919|029|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04919|030|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
04919|031|D|thioridazine, and tovorafenib.(2)|
04919|032|B||
04919|033|R|REFERENCES:|
04919|034|B||
04919|035|R|1.Avmapki Fakzynja Co-Pak (avutometinib-defactinib) US prescribing|1
04919|036|R|  information. Verastem, Inc. May, 2025.|1
04919|037|R|2.This information is based on an extract from the Certara Drug Interaction|6
04919|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04920|001|T|MONOGRAPH TITLE:  Warfarin/Defactinib|
04920|002|B||
04920|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04920|004|L|of severe adverse interaction.|
04920|005|B||
04920|006|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Defactinib may|
04920|007|A|inhibit the metabolism of warfarin by CYP2C9 or CYP3A4.(1)|
04920|008|B||
04920|009|E|CLINICAL EFFECTS:  Concurrent use of defactinib may result in increased INR|
04920|010|E|and risk of bleeding.(1)|
04920|011|B||
04920|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04920|013|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04920|014|P|   Drug associated risk factors include concurrent use of multiple drugs|
04920|015|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04920|016|P|risk for bleeding (e.g. NSAIDs).|
04920|017|B||
04920|018|M|PATIENT MANAGEMENT:  The manufacturer of defactinib states that concurrent|
04920|019|M|administration with warfarin should be avoided.  If concurrent use cannot be|
04920|020|M|avoided, monitor INR frequently during treatment with defactinib.(1)|
04920|021|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04920|022|M|therapy for signs of blood loss, including decreased hemoglobin and/or|
04920|023|M|hematocrit, fecal occult blood, and/or decreased blood pressure and promptly|
04920|024|M|evaluate patients with any symptoms.|
04920|025|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04920|026|M|to monitor efficacy and safety of anticoagulation.|
04920|027|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04920|028|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04920|029|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04920|030|M|and/or swelling.|
04920|031|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04920|032|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04920|033|M|initiating, altering the dose or discontinuing either drug.|
04920|034|M|   Discontinue anticoagulation in patients with active pathologic bleeding.|
04920|035|B||
04920|036|D|DISCUSSION:  In clinical trials, cases of bleeding and increased INR|
04920|037|D|occurred in patients taking defactinib concomitantly with warfarin.(1)|
04920|038|B||
04920|039|R|REFERENCES:|
04920|040|B||
04920|041|R|1.Avmapki Fakzynja Co-Pak (avutometinib-defactinib) US prescribing|1
04920|042|R|  information. Verastem, Inc. May, 2025.|1
04920|043|R|2.This information is based on an extract from the Certara Drug Interaction|6
04920|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04921|001|T|MONOGRAPH TITLE:  Defactinib/H2 Antagonists; Proton Pump Inhibitors|
04921|002|B||
04921|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04921|004|L|of severe adverse interaction.|
04921|005|B||
04921|006|A|MECHANISM OF ACTION:  The aqueous solubility of defactinib is pH dependent.|
04921|007|A|Higher gastric pH leads to lower solubility which may reduce defactinib|
04921|008|A|absorption.(1)|
04921|009|B||
04921|010|E|CLINICAL EFFECTS:  Coadministration of H2 antagonists or proton pump|
04921|011|E|inhibitors (PPIs) may reduce the bioavailability of defactinib, leading to|
04921|012|E|decreased systemic levels and effectiveness.(1)|
04921|013|B||
04921|014|P|PREDISPOSING FACTORS:  None determined.|
04921|015|B||
04921|016|M|PATIENT MANAGEMENT:  The manufacturer of defactinib states that concurrent|
04921|017|M|use with H2 antagonists or proton pump inhibitors should be avoided.(1)|
04921|018|M|   If concurrent use with an acid-reducing agent cannot be avoided,|
04921|019|M|administer defactinib 2 hours before or 2 hours after the administration of|
04921|020|M|a locally acting antacid.(1)|
04921|021|B||
04921|022|D|DISCUSSION:  In an interaction study, defactinib area-under-the-curve (AUC)|
04921|023|D|decreased by 79% and maximum concentration (Cmax) decreased by 85% following|
04921|024|D|concomitant use of multiple doses of omeprazole 40 mg daily.  The AUC and|
04921|025|D|Cmax of N-desmethyl amide (M4), a major metabolite of defactinib, decreased|
04921|026|D|by 83% and 88%, respectively.(1)|
04921|027|B||
04921|028|R|REFERENCE:|
04921|029|B||
04921|030|R|1.Avmapki Fakzynja Co-Pak (avutometinib-defactinib) US prescribing|1
04921|031|R|  information. Verastem, Inc. May, 2025.|1
04922|001|T|MONOGRAPH TITLE:  Avutometinib-Defactinib/Moderate CYP3A4 Inhibitors|
04922|002|B||
04922|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04922|004|L|of severe adverse interaction.|
04922|005|B||
04922|006|A|MECHANISM OF ACTION:  Avutometinib and defactinib are both CYP3A4|
04922|007|A|substrates.  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04922|008|A|defactinib.  Avutometinib also undergoes non-enzymatic degradation is not|
04922|009|A|affected by CYP3A4 inhibitors.(1)|
04922|010|B||
04922|011|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
04922|012|E|inhibitor may result in elevated levels of defactinib and toxicity from|
04922|013|E|avutometinib-defactinib, including hepatotoxicity, rhabdomyolysis, ocular|
04922|014|E|toxicities, and skin toxicities.(1)|
04922|015|B||
04922|016|P|PREDISPOSING FACTORS:  None determined.|
04922|017|B||
04922|018|M|PATIENT MANAGEMENT:  Concurrent use of avutometinib-defactinib and moderate|
04922|019|M|CYP3A4 inhibitors should be avoided.(1)|
04922|020|B||
04922|021|D|DISCUSSION:  The impact of moderate CYP3A4 inhibitors on the|
04922|022|D|pharmacokinetics of defactinib has not been investigated in clinical|
04922|023|D|studies.|
04922|024|D|   Defactinib maximum concentration (Cmax) increased by 2.2-fold and|
04922|025|D|area-under-curve (AUC) by 3.9-fold following concomitant use with|
04922|026|D|itraconazole (strong CYP3A4 inhibitor) 200 mg daily for 10 days. The AUC of|
04922|027|D|M4, a major active metabolite of defactinib, increased by 2.2-fold and Cmax|
04922|028|D|decreased by 6.8%.(1)|
04922|029|D|   No clinically significant differences in avutometinib pharmacokinetics|
04922|030|D|were observed when used concomitantly with itraconazole.(1)|
04922|031|D| Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir,|
04922|032|D|aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan,|
04922|033|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
04922|034|D|fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
04922|035|D|imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir,|
04922|036|D|netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol,|
04922|037|D|tofisopam, treosulfan, verapamil, and voxelotor.(2-3)|
04922|038|B||
04922|039|R|REFERENCES:|
04922|040|B||
04922|041|R|1.Avmapki Fakzynja Co-Pak (avutometinib-defactinib) US prescribing|1
04922|042|R|  information. Verastem, Inc. May, 2025.|1
04922|043|R|2.This information is based on an extract from the Certara Drug Interaction|6
04922|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04922|045|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04922|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04922|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04922|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04922|049|R|  11/14/2017.|1
04923|001|T|MONOGRAPH TITLE:  Tacrolimus/Dipyrone|
04923|002|B||
04923|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04923|004|L|of severe adverse interaction.|
04923|005|B||
04923|006|A|MECHANISM OF ACTION:  Dipyrone is a moderate CYP3A4 inducer and may|
04923|007|A|accelerate the metabolism of tacrolimus.(1-2)  Concurrent use of dipyrone|
04923|008|A|with other drugs known to be associated with neutropenia or agranulocytosis|
04923|009|A|may increase the frequency or risk for severe toxicity.(1-5)|
04923|010|B||
04923|011|E|CLINICAL EFFECTS:  Concurrent use of a dipyrone with tacrolimus may result|
04923|012|E|in decreased levels and effectiveness of tacrolimus and an additive risk of|
04923|013|E|hematologic disorders, including anemia, blood dyscrasias, bone marrow|
04923|014|E|depression, leukopenia, and thrombocytopenia.  Bone marrow depression may|
04923|015|E|increase the risk of serious infections and bleeding.  Undetected severe|
04923|016|E|neutropenia or agranulocytosis may be fatal.(1-5)|
04923|017|B||
04923|018|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04923|019|P|of the inducer for longer than 1-2 weeks.|
04923|020|B||
04923|021|M|PATIENT MANAGEMENT:  Concurrent use of dipyrone with immunosuppressive|
04923|022|M|agents like tacrolimus should be avoided.|
04923|023|M|   The European Medicines Agency states dipyrone is contraindicated in|
04923|024|M|patients with a prior medical history of dipyrone-induced agranulocytosis|
04923|025|M|(or from other pyrazolones/pyrazolidines), impaired bone marrow function or|
04923|026|M|diseases of the hematopoietic system.(3)|
04923|027|M|   The European Medicines Agency advises if agranulocytosis is suspected|
04923|028|M|with dipyrone, a complete blood count (including differential blood count)|
04923|029|M|should be performed immediately, and treatment must be stopped while waiting|
04923|030|M|for the results.  If confirmed, treatment must not be reintroduced.(1,3)|
04923|031|M|   The manufacturer of tacrolimus recommends that concurrent use with|
04923|032|M|moderate CYP3A4 inducers should be monitored closely.  Check tacrolimus|
04923|033|M|whole blood trough concentrations and adjust tacrolimus dose if needed.(2)|
04923|034|B||
04923|035|D|DISCUSSION:  A 13-year-old cystic fibrosis patient with a history of liver|
04923|036|D|transplant on stable doses of tacrolimus underwent 2 separate courses of|
04923|037|D|nafcillin therapy (a moderate CYP3A4 inducer).  During the 1st course of|
04923|038|D|nafcillin, his tacrolimus levels started to fall 3 days after starting|
04923|039|D|nafcillin, became undetectable at day 8, and recovered to therapeutic levels|
04923|040|D|without a change in tacrolimus dose 5 days after discontinuation of|
04923|041|D|nafcillin.  During the 2nd course of nafcillin, tacrolimus level became|
04923|042|D|undetectable 4 days after starting nafcillin and recovered 3 days after|
04923|043|D|stopping nafcillin.(6)|
04923|044|D|   A retrospective cohort study analyzed new users of dipyrone (n=444,972),|
04923|045|D|non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a|
04923|046|D|reference cohort, and opioids-paracetamol (n=3,129,221) which was the|
04923|047|D|negative control.  During continuous treatment over a median of 37-40 days,|
04923|048|D|26 cases of hospitalized agranulocytosis occurred.  With the assumption that|
04923|049|D|agranulocytosis onset was 7 days prior to admission, the hazard ratio of|
04923|050|D|agranulocytosis associated with dipyrone was 4.40 [95% confidence interval:|
04923|051|D|0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to|
04923|052|D|opioid-paracetamol.  HR of neutropenia from dipyrone was 2.98 [1.57-5.65]|
04923|053|D|compared to NSAIDs and not statistically significant compared to|
04923|054|D|opioids-paracetamol.  In a sensitivity analysis assuming that the onset of|
04923|055|D|agranulocytosis was the date of hospitalization, the HR of dipyrone-induced|
04923|056|D|agranulocytosis was 7.20 [1.92-26.99] compared to NSAIDs and 3.31|
04923|057|D|[1.17-9.34] compared to opioids-paracetamol.  Agranulocytosis was very rare|
04923|058|D|but more than 4 times more common with dipyrone than other analgesics.(4)|
04923|059|D|   In a review of 1,448 reports of agranulocytosis attributed to dipyrone,|
04923|060|D|patients with fatal outcomes were older and more often had also received|
04923|061|D|methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18;|
04923|062|D|95% confidence interval: 3.06-8.78).(5)|
04923|063|B||
04923|064|R|REFERENCES:|
04923|065|B||
04923|066|R|1.Optalgin (Dipyrone (Metamizole sodium)) Prescribing Information. Teva|1
04923|067|R|  Israel Ltd June 2022.|1
04923|068|R|2.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
04923|069|R|  August, 2023.|1
04923|070|R|3.EMA. EMA recommends measures to minimise serious outcomes of known side|6
04923|071|R|  effect with painkiller metamizole. 6 September 2024.|6
04923|072|R|4.Macia-Martinez MA, Castillo-Cano B, Garcia-Poza P, Martin-Merino E. Risk|3
04923|073|R|  of agranulocytosis with metamizole in comparison with alternative|3
04923|074|R|  medications based on health records in Spain. European Journal of Clinical|3
04923|075|R|  Pharmacology 22 June 2024;80(10):1503-1514.|3
04923|076|R|5.Hoffman F, Bantel C, Jobski K. Aganulocytosis attributed to metamizole: An|3
04923|077|R|  analysis of spontaneous reports in EudraVigilance 1985-2017. Basic &|3
04923|078|R|  Clinical Pharmacology & Toxicology 26 August 2019;126(2):116-125.|3
04923|079|R|6.Wungwattana M, Savic M. Tacrolimus interaction with nafcillin resulting in|3
04923|080|R|  significant decreases in  tacrolimus concentrations: A case report.|3
04923|081|R|  Transpl Infect Dis 2017 Apr;19(2):.|3
04924|001|T|MONOGRAPH TITLE:  Defactinib/Antacids|
04924|002|B||
04924|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04924|004|L|take action as needed.|
04924|005|B||
04924|006|A|MECHANISM OF ACTION:  The aqueous solubility of defactinib is pH dependent.|
04924|007|A|Higher gastric pH leads to lower solubility which may reduce defactinib|
04924|008|A|absorption.(1)|
04924|009|B||
04924|010|E|CLINICAL EFFECTS:  Coadministration with antacids may reduce the|
04924|011|E|bioavailability of defactinib, leading to decreased systemic levels and|
04924|012|E|effectiveness.(1)|
04924|013|B||
04924|014|P|PREDISPOSING FACTORS:  None determined.|
04924|015|B||
04924|016|M|PATIENT MANAGEMENT:  The manufacturer of defactinib states that patients|
04924|017|M|requiring acid-lowering therapy should separate defactinib from antacid|
04924|018|M|administration by 2 hours.(1)|
04924|019|M|   Some vitamin preparations may contain sufficient quantities of calcium|
04924|020|M|and/or magnesium salts with antacid properties to interact as well.|
04924|021|B||
04924|022|D|DISCUSSION:  The impact of antacids on the pharmacokinetics of defactinib|
04924|023|D|has not been investigated in clinical studies.|
04924|024|D|   In an interaction study, defactinib area-under-the-curve (AUC) decreased|
04924|025|D|by 79% and maximum concentration (Cmax) decreased by 85% following|
04924|026|D|concomitant use of multiple doses of omeprazole 40 mg daily.  The AUC and|
04924|027|D|Cmax of N-desmethyl amide (M4), a major active metabolite of defactinib,|
04924|028|D|decreased by 83% and 88%, respectively.(1)|
04924|029|B||
04924|030|R|REFERENCE:|
04924|031|B||
04924|032|R|1.Avmapki Fakzynja Co-Pak (avutometinib-defactinib) US prescribing|1
04924|033|R|  information. Verastem, Inc. May, 2025.|1
04925|001|T|MONOGRAPH TITLE:  Obinutuzumab/Anticoagulants; Antiplatelets|
04925|002|B||
04925|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04925|004|L|take action as needed.|
04925|005|B||
04925|006|A|MECHANISM OF ACTION:  Severe and life-threatening thrombocytopenia has been|
04925|007|A|reported during obinutuzumab therapy.(1)  Anticoagulants and antiplatelets|
04925|008|A|may have an additive risk of bleeding.|
04925|009|B||
04925|010|E|CLINICAL EFFECTS:  Concurrent use of obinutuzumab with anticoagulants or|
04925|011|E|antiplatelet agents may result in additive or synergistic effects, including|
04925|012|E|fatal and non-fatal hemorrhage.(1)|
04925|013|B||
04925|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04925|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04925|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
04925|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04925|018|P|risk for bleeding (e.g. NSAIDs).|
04925|019|B||
04925|020|M|PATIENT MANAGEMENT:  Monitor all patients frequently for thrombocytopenia|
04925|021|M|and signs of bleeding.  Consider withholding concomitant anticoagulants and|
04925|022|M|antiplatelets, especially during the first cycle of obinutuzumab.(1)|
04925|023|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04925|024|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04925|025|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04925|026|M|patients with any symptoms.|
04925|027|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04925|028|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04925|029|M|anticoagulation in patients with active pathologic bleeding.|
04925|030|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04925|031|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04925|032|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04925|033|M|and/or swelling.|
04925|034|B||
04925|035|D|DISCUSSION:  Obinutuzumab with chemotherapy has been reported to cause|
04925|036|D|severe and life-threatening thrombocytopenia.  Fatal hemorrhagic events have|
04925|037|D|occurred in patients with NHL and CLL during obinutuzumab therapy, including|
04925|038|D|during Cycle 1.(1)|
04925|039|B||
04925|040|R|REFERENCE:|
04925|041|B||
04925|042|R|1.Gazyva (obinutuzumab) US prescribing information. Genentech, Inc. August,|1
04925|043|R|  2023.|1
04926|001|T|MONOGRAPH TITLE:  Dihydroergotamine/Sympathomimetics|
04926|002|B||
04926|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04926|004|L|is contraindicated and generally should not be dispensed or administered to|
04926|005|L|the same patient.|
04926|006|B||
04926|007|A|MECHANISM OF ACTION:  Concurrent use of dihydroergotamine and|
04926|008|A|sympathomimetics may result in additive or synergistic effect on peripheral|
04926|009|A|blood vessels.(1)|
04926|010|B||
04926|011|E|CLINICAL EFFECTS:  Concurrent use of dihydroergotamine and sympathomimetics|
04926|012|E|may result in increased blood pressure due to peripheral|
04926|013|E|vasoconstriction.(1)|
04926|014|B||
04926|015|P|PREDISPOSING FACTORS:  None determined.|
04926|016|B||
04926|017|M|PATIENT MANAGEMENT:  Dihydroergotamine is contraindicated with|
04926|018|M|sympathomimetics because the combination may result in additive or|
04926|019|M|synergistic elevation of blood pressure.(1)|
04926|020|B||
04926|021|D|DISCUSSION:  Significant elevation in blood pressure has been reported in|
04926|022|D|patients treated with dihydroergotamine.(1) Sympathomimetics can be expected|
04926|023|D|to have additional effects on blood pressure.|
04926|024|B||
04926|025|R|REFERENCE:|
04926|026|B||
04926|027|R|1.Atzumi (dihydroergotamine) US prescribing information. Satsuma|1
04926|028|R|  Pharmaceuticals, Inc. May, 2025.|1
04927|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Dipyrone|
04927|002|B||
04927|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04927|004|L|of severe adverse interaction.|
04927|005|B||
04927|006|A|MECHANISM OF ACTION:  Dipyrone is a moderate CYP3A4 and weak CYP2C9 inducer.|
04927|007|A|Coadministration of dipyrone with hormonal contraceptives may lead to|
04927|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
04927|009|A|decreased hormonal concentrations.(1-2)|
04927|010|B||
04927|011|E|CLINICAL EFFECTS:  Concurrent use of dipyrone may reduce the effectiveness|
04927|012|E|of hormonal contraceptives, except for intrauterine systems containing|
04927|013|E|levonorgestrel.(1-2)|
04927|014|B||
04927|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04927|016|P|of the inducer for longer than 1-2 weeks.|
04927|017|B||
04927|018|M|PATIENT MANAGEMENT:  Avoid concomitant use with hormonal contraceptives|
04927|019|M|except for intrauterine systems containing levonorgestrel.  If contraception|
04927|020|M|is needed or desired, an alternate contraceptive that is not affected by CYP|
04927|021|M|inducers (e.g., an intrauterine system) or additional non-hormonal|
04927|022|M|contraceptives (e.g., condoms) should be used when treated concomitantly|
04927|023|M|with dipyrone and for at least 4 weeks after the last dose of dipyrone.(1)|
04927|024|M|   Women of reproductive age should be counseled not to rely on hormonal|
04927|025|M|contraceptives (including oral contraceptives, patches, implants, and/or|
04927|026|M|IUDs) for contraception.(1)|
04927|027|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04927|028|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04927|029|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04927|030|M|contraceptive (ie a copper IUD).  If a non-hormonal emergency contraceptive|
04927|031|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
04927|032|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
04927|033|M|and to seek medical advice if she does become pregnant.(3)|
04927|034|B||
04927|035|D|DISCUSSION:  Dipyrone is a moderate CYP3A4 and weak CYP2C9 inducer.(1-2)|
04927|036|D|   In a study, dipyrone 1 gram 3 times daily decreased the area under curve|
04927|037|D|(AUC) of midazolam (a CYP3A4 substrate) by 68% and of flurbiprofen (a CYP2C9|
04927|038|D|substrate) by 22%.(2)|
04927|039|B||
04927|040|R|REFERENCES:|
04927|041|B||
04927|042|R|1.Optalgin (dipyrone) Israeli Summary of Product Characteristics. Teva|1
04927|043|R|  Israel Ltd. May, 2025.|1
04927|044|R|2.Brinkman DJ, Hendriksen LC, Rigter IM, Hollmann MW. Pharmacology and|6
04927|045|R|  relevant drug interactions of metamizole. Br J Clin Pharmacol 2025 May 15.|6
04927|046|R|3.Medicines and Healthcare products Regulatory Agency.|1
04927|047|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04927|048|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04927|049|R|  available at:|1
04927|050|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04927|051|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04927|052|R|  -and-contraceptive-efficacy September 15, 2016..|1
04928|001|T|MONOGRAPH TITLE:  BCRP, OATP1B1, and OATP1B3 Substrates/Leniolisib|
04928|002|B||
04928|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04928|004|L|of severe adverse interaction.|
04928|005|B||
04928|006|A|MECHANISM OF ACTION:  Leniolisib is an inhibitor of the BCRP, OATP1B1, and|
04928|007|A|OATP1B3 transporters and may increase the absorption and/or decrease the|
04928|008|A|elimination of drugs that are substrates of these transporters.(1)|
04928|009|B||
04928|010|E|CLINICAL EFFECTS:  Concurrent use of leniolisib with drugs that are|
04928|011|E|substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in|
04928|012|E|increased toxicity of the substrate.(1)|
04928|013|B||
04928|014|P|PREDISPOSING FACTORS:  None determined.|
04928|015|B||
04928|016|M|PATIENT MANAGEMENT:  Avoid coadministration of leniolisib with substrates of|
04928|017|M|BCRP, OATP1B1, and OATP1B3.(1)|
04928|018|B||
04928|019|D|DISCUSSION:  When co-administered, leniolisib increased rosuvastatin (a|
04928|020|D|substrate of BCRP, OATP1B1, and OATP1B3) systemic exposure by 2-fold.(1)|
04928|021|D|   Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this|
04928|022|D|monograph include: diclofenac, fluvastatin, glecaprevir, glyburide,|
04928|023|D|imatinib, irinotecan, letermovir, lovastatin, methotrexate, mitoxantrone,|
04928|024|D|momelotinib, paritaprevir, pitavastatin, pravastatin, repaglinide,|
04928|025|D|simvastatin, and sulfasalazine.(1,2)|
04928|026|B||
04928|027|R|REFERENCES:|
04928|028|B||
04928|029|R|1.Joenja (leniolisib) US prescribing information. Pharming Healthcare Inc.|1
04928|030|R|  May, 2025.|1
04928|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04928|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04929|001|T|MONOGRAPH TITLE:  Elagolix/Leniolisib|
04929|002|B||
04929|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04929|004|L|of severe adverse interaction.|
04929|005|B||
04929|006|A|MECHANISM OF ACTION:  OATP1B1 inhibitors such as leniolisib may decrease the|
04929|007|A|hepatic uptake of elagolix.(1,2)  Moderate CYP3A4 inducers such as elagolix|
04929|008|A|may increase the metabolism of leniolisib.(3)|
04929|009|B||
04929|010|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of OATP1B1 may result in|
04929|011|E|elevated levels of and side effects from elagolix, including an increased|
04929|012|E|risk of ALT elevations.(1)  Concurrent use of a moderate CYP3A4 inducer may|
04929|013|E|decrease the serum levels and effectiveness of leniolisib.(3)|
04929|014|B||
04929|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04929|016|P|of the inducer for longer than 1-2 weeks.|
04929|017|B||
04929|018|M|PATIENT MANAGEMENT:  Avoid concomitant use of leniolisib with elagolix.(2)|
04929|019|B||
04929|020|D|DISCUSSION:  Single-dose rifampin 600 mg (an OATP1B1 inhibitor) increased|
04929|021|D|the maximum concentration (Cmax) and area-under-curve (AUC)of elagolix by|
04929|022|D|4.37-fold and 5.58-fold, respectively.(1)|
04929|023|D|   PBPK model-based simulations predicted a maximum decrease of 78% and 58%|
04929|024|D|in leniolisib area-under-curve (AUC) with rifampin (strong CYP3A4 inducer)|
04929|025|D|and efavirenz (moderate CYP3A4 inducer), respectively.(1)|
04929|026|D|   When co-administered, leniolisib increased rosuvastatin (a substrate of|
04929|027|D|BCRP, OATP1B1, and OATP1B3) systemic exposure by 2-fold.(2)|
04929|028|B||
04929|029|R|REFERENCES:|
04929|030|B||
04929|031|R|1.Orilissa (elagolix) US prescribing information. AbbVie Inc. February,|1
04929|032|R|  2021.|1
04929|033|R|2.Joenja (leniolisib) US prescribing information. Pharming Healthcare Inc.|1
04929|034|R|  May, 2025.|1
04929|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04929|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04929|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04929|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04929|039|R|  11/14/2017.|1
04930|001|T|MONOGRAPH TITLE:  Bosentan/Leniolisib|
04930|002|B||
04930|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04930|004|L|of severe adverse interaction.|
04930|005|B||
04930|006|A|MECHANISM OF ACTION:  OATP1B1 inhibitors such as leniolisib may decrease the|
04930|007|A|hepatic uptake of bosentan.(1,2)  Moderate CYP3A4 inducers such as bosentan|
04930|008|A|may increase the metabolism of leniolisib.(1,2)|
04930|009|B||
04930|010|E|CLINICAL EFFECTS:  Concurrent use of an inhibitor of OATP1B1 may result in|
04930|011|E|elevated levels of and side effects from bosentan.(1)  Concurrent use of a|
04930|012|E|moderate CYP3A4 inducer may decrease the serum levels and effectiveness of|
04930|013|E|leniolisib.(2)|
04930|014|B||
04930|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04930|016|P|of the inducer for longer than 1-2 weeks.|
04930|017|B||
04930|018|M|PATIENT MANAGEMENT:  Concomitant use of leniolisib with substrates of BCRP,|
04930|019|M|OATP1B1, and OATP1B3 such as bosentan should be avoided.(1)|
04930|020|M|   Avoid concomitant use of leniolisib with moderate CYP3A4 inducers.(2)|
04930|021|B||
04930|022|D|DISCUSSION:  Bosentan is a substrate of OATP1B1.(4)|
04930|023|D|   PBPK model-based simulations predicted a maximum decrease of 78% and 58%|
04930|024|D|in leniolisib area-under-curve (AUC) with rifampin (strong CYP3A4 inducer)|
04930|025|D|and efavirenz (moderate CYP3A4 inducer), respectively.(1)|
04930|026|B||
04930|027|R|REFERENCES:|
04930|028|B||
04930|029|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
04930|030|R|  US, Inc. September 5, 2017.|1
04930|031|R|2.Joenja (leniolisib) US prescribing information. Pharming Healthcare Inc.|1
04930|032|R|  May, 2025.|1
04930|033|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04930|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04930|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04930|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04930|037|R|  11/14/2017.|1
04930|038|R|4.This information is based on an extract from the Certara Drug Interaction|6
04930|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04931|001|T|MONOGRAPH TITLE:  BCRP, OATP1B1, and OATP1B3 Substrates that Prolong|
04931|002|T|QT/Leniolisib|
04931|003|B||
04931|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04931|005|L|of severe adverse interaction.|
04931|006|B||
04931|007|A|MECHANISM OF ACTION:  Leniolisib is an inhibitor of the BCRP, OATP1B1, and|
04931|008|A|OATP1B3 transporters and may increase the absorption and/or decrease the|
04931|009|A|elimination of drugs that are substrates of these transporters.(1)|
04931|010|B||
04931|011|E|CLINICAL EFFECTS:  Concurrent use of leniolisib with drugs that are|
04931|012|E|substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in|
04931|013|E|increased toxicity of the substrate, including QTc prolongation, which may|
04931|014|E|lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)|
04931|015|B||
04931|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04931|017|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04931|018|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04931|019|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04931|020|P|gender, or advanced age.(2)|
04931|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04931|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04931|023|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04931|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04931|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04931|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04931|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04931|028|B||
04931|029|M|PATIENT MANAGEMENT:  Avoid coadministration of leniolisib with substrates of|
04931|030|M|BCRP, OATP1B1, and OATP1B3.(1)|
04931|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04931|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04931|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04931|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04931|035|B||
04931|036|D|DISCUSSION:  When co-administered, leniolisib increased rosuvastatin (a|
04931|037|D|substrate of BCRP, OATP1B1, and OATP1B3) systemic exposure by 2-fold.(1)|
04931|038|D|   Agents that are linked to this monograph may have varying degrees of|
04931|039|D|potential to prolong the QTc interval but are generally accepted to have a|
04931|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04931|041|D|been shown to prolong the QTc interval either through their mechanism of|
04931|042|D|action, through studies on their effects on the QTc interval, or through|
04931|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04931|044|D|and/or post-marketing reports.(4)|
04931|045|D|   Substrates of BCRP, OATP1B1, and OATP1B3 that prolong QT that are linked|
04931|046|D|to this monograph include: ciprofloxacin, lapatinib.(1,4)|
04931|047|B||
04931|048|R|REFERENCES:|
04931|049|B||
04931|050|R|1.Joenja (leniolisib) US prescribing information. Pharming Healthcare Inc.|1
04931|051|R|  May, 2025.|1
04931|052|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04931|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04931|054|R|  settings: a scientific statement from the American Heart Association and|6
04931|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04931|056|R|  2;55(9):934-47.|6
04931|057|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04931|058|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04931|059|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04931|060|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04931|061|R|4.This information is based on an extract from the Certara Drug Interaction|6
04931|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04932|001|T|MONOGRAPH TITLE:  Topotecan/BCRP Inhibitors|
04932|002|B||
04932|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04932|004|L|of severe adverse interaction.|
04932|005|B||
04932|006|A|MECHANISM OF ACTION:  Inhibitors of the BCRP transporter may increase the|
04932|007|A|intestinal absorption and hepatic uptake of topotecan.(1)|
04932|008|B||
04932|009|E|CLINICAL EFFECTS:  The concurrent administration of topotecan with an|
04932|010|E|inhibitor of BCRP may result in elevated levels of topotecan and signs of|
04932|011|E|toxicity.  These signs may include but are not limited to anemia, diarrhea,|
04932|012|E|and thrombocytopenia.(1)|
04932|013|B||
04932|014|P|PREDISPOSING FACTORS:  None determined.|
04932|015|B||
04932|016|M|PATIENT MANAGEMENT:  The US manufacturer of topotecan states that the use of|
04932|017|M|topotecan and BCRP inhibitors should be avoided.  If concurrent use is|
04932|018|M|warranted, carefully monitor patients for adverse effects.(1)|
04932|019|B||
04932|020|D|DISCUSSION:  In clinical studies, the combined use of elacridar (100 mg to|
04932|021|D|1000 mg), a BCRP and P-gp inhibitor, increased the area-under-curve (AUC) of|
04932|022|D|topotecan approximately 2.5-fold.(1)|
04932|023|D|   BCRP inhibitors linked to this monograph include: capmatinib,|
04932|024|D|clopidogrel, curcumin, danicopan, dasabuvir, elbasvir, enasidenib,|
04932|025|D|febuxostat, fostamatinib, fostemsavir, glecaprevir, grazoprevir, lazertinib,|
04932|026|D|oteseconazole, pacritinib, pantoprazole, paritaprevir, pibrentasvir,|
04932|027|D|pirtobrutinib, regorafenib, resmetirom, ritonavir, roxadustat, tafamidis,|
04932|028|D|ticagrelor, tolvaptan, turmeric, vadadustat, velpatasvir, voxilaprevir, and|
04932|029|D|zongertinib.(2,3)|
04932|030|B||
04932|031|R|REFERENCES:|
04932|032|B||
04932|033|R|1.Hycamtin Oral (topotecan) US prescribing information. GlaxoSmithKline|1
04932|034|R|  September, 2018.|1
04932|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04932|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04932|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04932|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04932|039|R|  11/14/2017.|1
04932|040|R|3.This information is based on an extract from the Certara Drug Interaction|6
04932|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04933|001|T|MONOGRAPH TITLE:  Topotecan/Selected Inhibitors of BCRP with|
04933|002|T|Myelosuppression|
04933|003|B||
04933|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04933|005|L|of severe adverse interaction.|
04933|006|B||
04933|007|A|MECHANISM OF ACTION:  Inhibitors of the BCRP transporter may increase the|
04933|008|A|intestinal absorption and hepatic uptake of topotecan.(1)|
04933|009|A|   Also, topotecan in combination with myelosuppressive agents may result in|
04933|010|A|additive or synergistic effects on the immune system.(1)|
04933|011|B||
04933|012|E|CLINICAL EFFECTS:  The concurrent administration of topotecan with an|
04933|013|E|inhibitor of BCRP may result in elevated levels of topotecan and signs of|
04933|014|E|toxicity.  These signs may include but are not limited to anemia, diarrhea,|
04933|015|E|thrombocytopenia, and increased risk of serious infections.(1)|
04933|016|B||
04933|017|P|PREDISPOSING FACTORS:  None determined.|
04933|018|B||
04933|019|M|PATIENT MANAGEMENT:  The US manufacturer of topotecan states that the use of|
04933|020|M|topotecan and BCRP inhibitors should be avoided.  If concurrent use is|
04933|021|M|warranted, carefully monitor patients for adverse effects.(1)|
04933|022|B||
04933|023|D|DISCUSSION:  In clinical studies, the combined use of elacridar (100 mg to|
04933|024|D|1000 mg), a BCRP and P-gp inhibitor, increased the area-under-curve (AUC) of|
04933|025|D|topotecan approximately 2.5-fold.(1)|
04933|026|D|   BCRP inhibitors linked to this monograph include: cyclosporine,|
04933|027|D|encorafenib, leflunomide, leniolisib, momelotinib, and teriflunomide.(2,3)|
04933|028|B||
04933|029|R|REFERENCES:|
04933|030|B||
04933|031|R|1.Hycamtin Oral (topotecan) US prescribing information. GlaxoSmithKline|1
04933|032|R|  September, 2018.|1
04933|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04933|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04933|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04933|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04933|037|R|  11/14/2017.|1
04933|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
04933|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04934|001|T|MONOGRAPH TITLE:  Emtricitabine-Rilpivirine-TAF/P-gp & Moderate CYP3A4|
04934|002|T|Inducer|
04934|003|B||
04934|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04934|005|L|of severe adverse interaction.|
04934|006|B||
04934|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
04934|008|A|rilpivirine.  P-glycoprotein (P-gp) inducers may decrease the absorption of|
04934|009|A|tenofovir alafenamide (TAF).(1)|
04934|010|B||
04934|011|E|CLINICAL EFFECTS:  Concurrent or recent use of dual P-gp and moderate CYP3A4|
04934|012|E|inducers may result in decreased levels and effectiveness of rilpivirine and|
04934|013|E|TAF, as well as the development of resistance.(1)|
04934|014|B||
04934|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04934|016|P|of the inducer for longer than 1-2 weeks.|
04934|017|B||
04934|018|M|PATIENT MANAGEMENT:  The US manufacturer of emtricitabine-rilpivirine-TAF|
04934|019|M|states that concurrent use of P-gp and moderate CYP3A4 inducers is not|
04934|020|M|recommended.(1)|
04934|021|B||
04934|022|D|DISCUSSION:  In a study in 18 subjects, rifabutin (300 mg daily) decreased|
04934|023|D|the maximum concentration (Cmax), area-under-curve (AUC), and minimum|
04934|024|D|concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and|
04934|025|D|48%, respectively.(1)|
04934|026|D|   P-gp and moderate CYP3A4 inducers linked to this monograph include:|
04934|027|D|efavirenz, lorlatinib, and rifabutin.(2)|
04934|028|B||
04934|029|R|REFERENCES:|
04934|030|B||
04934|031|R|1.Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide) US|1
04934|032|R|  prescribing information. Gilead Sciences, Inc. August 21, 2017.|1
04934|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
04934|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04935|001|T|MONOGRAPH TITLE:  Emtricitabine-Rilpivirine-TAF/Select Moderate CYP3A4|
04935|002|T|Inducer|
04935|003|B||
04935|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04935|005|L|take action as needed.|
04935|006|B||
04935|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
04935|008|A|rilpivirine.(1-2)|
04935|009|B||
04935|010|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
04935|011|E|result in decreased levels and effectiveness of rilpivirine, as well as the|
04935|012|E|development of resistance.(1-2)|
04935|013|B||
04935|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04935|015|P|of the inducer for longer than 1-2 weeks.|
04935|016|B||
04935|017|M|PATIENT MANAGEMENT:  The US DHHS HIV guidelines state that concurrent use of|
04935|018|M|bosentan or mavacamten (moderate CYP3A4 inducers) with oral rilpivirine|
04935|019|M|should be monitored closely.  Consider alternative therapies that do not|
04935|020|M|affect CYP3A4 or alternative antiretroviral agents.  If concurrent use is|
04935|021|M|necessary, virologic response should be monitored.(3)|
04935|022|M|   The US manufacturer of oral rilpivirine states that concurrent use of|
04935|023|M|rifabutin (moderate CYP3A4 inducer) warrants dose adjustment.  When|
04935|024|M|administering moderate CYP3A4 inducers with oral rilpivirine, increase the|
04935|025|M|dose of rilpivirine to 50 mg once daily.  When rifabutin co-administration|
04935|026|M|is stopped, the rilpivirine dose should be decreased to 25 mg once daily.|
04935|027|M|It may take several weeks after the discontinuation of an enzyme inducer for|
04935|028|M|enzyme activity to return to normal.(2)|
04935|029|B||
04935|030|D|DISCUSSION:  In a study in 18 subjects, rifabutin (300 mg daily) decreased|
04935|031|D|the maximum concentration (Cmax), area-under-curve (AUC), and minimum|
04935|032|D|concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and|
04935|033|D|48%, respectively.(1)|
04935|034|D|   A study in 18 subjects compared rilpivirine administered alone (25 mg|
04935|035|D|orally daily) to coadministration with rifabutin (300 mg daily) and|
04935|036|D|rilpivirine (50 mg orally daily). A significant difference was not found|
04935|037|D|with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (2)|
04935|038|D|   Selected moderate CYP3A4 inducers linked to this monograph include:|
04935|039|D|belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix,|
04935|040|D|eslicarbazepine, lesinurad, mavacamten, mitapivat, modafinil, nafcillin,|
04935|041|D|pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat,|
04935|042|D|thioridazine and tovorafenib.(3)|
04935|043|B||
04935|044|R|REFERENCES:|
04935|045|B||
04935|046|R|1.Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide) US|1
04935|047|R|  prescribing information. Gilead Sciences, Inc. August 21, 2017.|1
04935|048|R|2.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
04935|049|R|  March, 2024.|1
04935|050|R|3.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04935|051|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04935|052|R|  HIV. Department of Health and Human Services. Available at:|6
04935|053|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
04935|054|R|  nd-adolescent-arv/whats-new?view=full September 12, 2024.|6
04935|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
04935|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04936|001|T|MONOGRAPH TITLE:  Rilpivirine/Selected Moderate CYP3A4 Inducers|
04936|002|B||
04936|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04936|004|L|take action as needed.|
04936|005|B||
04936|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
04936|007|A|rilpivirine.(1)|
04936|008|B||
04936|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
04936|010|E|result in decreased levels and effectiveness of rilpivirine, as well as the|
04936|011|E|development of resistance.(1)|
04936|012|B||
04936|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04936|014|P|of the inducer for longer than 1-2 weeks.|
04936|015|B||
04936|016|M|PATIENT MANAGEMENT:  The US DHHS HIV guidelines state that concurrent use of|
04936|017|M|bosentan or mavacamten (moderate CYP3A4 inducers) with oral or intramuscular|
04936|018|M|rilpivirine should be monitored closely.  Consider alternative therapies|
04936|019|M|that do not affect CYP3A4 or alternative antiretroviral agents.  If|
04936|020|M|concurrent use is necessary, virologic response should be monitored.(2)|
04936|021|M|   The US manufacturer of oral rilpivirine states that concurrent use of|
04936|022|M|rifabutin (moderate CYP3A4 inducer) warrants dose adjustment.  When|
04936|023|M|administering moderate CYP3A4 inducers with oral rilpivirine, increase the|
04936|024|M|dose of rilpivirine to 50 mg once daily.  When rifabutin co-administration|
04936|025|M|is stopped, the rilpivirine dose should be decreased to 25 mg once daily.|
04936|026|M|It may take several weeks after the discontinuation of an enzyme inducer for|
04936|027|M|enzyme activity to return to normal.(1)|
04936|028|B||
04936|029|D|DISCUSSION:  In a study in 18 subjects, rifabutin (300 mg daily) decreased|
04936|030|D|the maximum concentration (Cmax), area-under-curve (AUC), and minimum|
04936|031|D|concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and|
04936|032|D|48%, respectively.(1)|
04936|033|D|   A study in 18 subjects compared rilpivirine administered alone (25 mg|
04936|034|D|orally daily) to coadministration with rifabutin (300 mg daily) and|
04936|035|D|rilpivirine (50 mg orally daily). A significant difference was not found|
04936|036|D|with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (1)|
04936|037|D|   Selected moderate CYP3A4 inducers linked to this monograph include:|
04936|038|D|belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix,|
04936|039|D|eslicarbazepine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil,|
04936|040|D|nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat,|
04936|041|D|thioridazine and tovorafenib.(3)|
04936|042|B||
04936|043|R|REFERENCES:|
04936|044|B||
04936|045|R|1.Edurant (rilpivirine) US prescribing information. Tibotec Pharmaceuticals|1
04936|046|R|  March, 2024.|1
04936|047|R|2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines|6
04936|048|R|  for the use of antiretroviral agents in adults and adolescents Living with|6
04936|049|R|  HIV. Department of Health and Human Services. Available at:|6
04936|050|R|  https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a|6
04936|051|R|  nd-adolescent-arv/whats-new?view=full September 12, 2024.|6
04936|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
04936|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04937|001|T|MONOGRAPH TITLE:  Taletrectinib/H2 Antagonists; Proton Pump Inhibitors|
04937|002|B||
04937|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04937|004|L|of severe adverse interaction.|
04937|005|B||
04937|006|A|MECHANISM OF ACTION:  The aqueous solubility of taletrectinib is pH|
04937|007|A|dependent.  Higher gastric pH leads to lower solubility which may reduce|
04937|008|A|taletrectinib absorption.(1)|
04937|009|B||
04937|010|E|CLINICAL EFFECTS:  Coadministration of H2 antagonists or proton pump|
04937|011|E|inhibitors (PPIs) may reduce the bioavailability of taletrectinib, leading|
04937|012|E|to decreased systemic levels and effectiveness.(1)|
04937|013|B||
04937|014|P|PREDISPOSING FACTORS:  None determined.|
04937|015|B||
04937|016|M|PATIENT MANAGEMENT:  The manufacturer of taletrectinib states that|
04937|017|M|concurrent use with H2 antagonists or proton pump inhibitors should be|
04937|018|M|avoided.(1)|
04937|019|M|   If concurrent use with an acid-reducing agent cannot be avoided,|
04937|020|M|administer taletrectinib 2 hours before or 2 hours after the administration|
04937|021|M|of a locally acting antacid.(1)|
04937|022|B||
04937|023|D|DISCUSSION:  In an interaction study, taletrectinib area-under-the-curve|
04937|024|D|(AUC) decreased by 40% and maximum concentration (Cmax) decreased by 65%|
04937|025|D|following concomitant use of omeprazole 40 mg daily.(1)|
04937|026|B||
04937|027|R|REFERENCE:|
04937|028|B||
04937|029|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04937|030|R|  2025.|1
04938|001|T|MONOGRAPH TITLE:  Taletrectinib/Strong CYP3A4 Inhibitors|
04938|002|B||
04938|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04938|004|L|of severe adverse interaction.|
04938|005|B||
04938|006|A|MECHANISM OF ACTION:  Taletrectinib is a substrate of CYP3A4.  Strong|
04938|007|A|inhibitors of CYP3A4 may inhibit the metabolism of taletrectinib.(1)|
04938|008|B||
04938|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04938|010|E|increased levels and toxicity from taletrectinib including hepatotoxicity,|
04938|011|E|myalgia, and prolongation of the QT interval, which may result in|
04938|012|E|life-threatening arrhythmia and death.(1)|
04938|013|B||
04938|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04938|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04938|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04938|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04938|018|P|female gender, or advanced age.(2)|
04938|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04938|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04938|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04938|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04938|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04938|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04938|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04938|026|P|   Taletrectinib should be taken on an empty stomach.  Administration with|
04938|027|P|food may increase the risk of QT prolongation or torsade de pointes.|
04938|028|B||
04938|029|M|PATIENT MANAGEMENT:  The manufacturer of taletrectinib recommends avoiding|
04938|030|M|concurrent administration with strong CYP3A4 inhibitors.(1)|
04938|031|M|   If concurrent therapy cannot be avoided, adjust the frequency of|
04938|032|M|monitoring as recommended in the prescribing information.  Withhold|
04938|033|M|taletrectinib if the QTc interval is >500 msec or the change from baseline|
04938|034|M|is >60 msec.(1)|
04938|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04938|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04938|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04938|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04938|039|B||
04938|040|D|DISCUSSION:  Concomitant administration of itraconazole 200 mg daily (a|
04938|041|D|strong inhibitor of CYP3A4) and taletrectinib resulted in a increase in|
04938|042|D|taletrectinib maximum concentration (Cmax) of 1.8-fold and area under the|
04938|043|D|curve (AUC) of 3.3-fold.(1)|
04938|044|D|   Strong CYP3A4 inhibitors linked to this monograph include: boceprevir,|
04938|045|D|cobicistat, grapefruit, idelalisib, indinavir, itraconazole, josamycin,|
04938|046|D|ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir,|
04938|047|D|nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir,|
04938|048|D|troleandomycin, and tucatinib.(3,4)|
04938|049|B||
04938|050|R|REFERENCES:|
04938|051|B||
04938|052|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04938|053|R|  2025.|1
04938|054|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04938|055|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04938|056|R|  settings: a scientific statement from the American Heart Association and|6
04938|057|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04938|058|R|  2;55(9):934-47.|6
04938|059|R|3.This information is based on an extract from the Certara Drug Interaction|6
04938|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04938|061|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04938|062|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04938|063|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04938|064|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04938|065|R|  11/14/2017.|1
04939|001|T|MONOGRAPH TITLE:  Taletrectinib/Strong CYP3A4 Inducers|
04939|002|B||
04939|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04939|004|L|of severe adverse interaction.|
04939|005|B||
04939|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04939|007|A|taletrectinib.(1)|
04939|008|B||
04939|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong CYP3A4 inducer may|
04939|010|E|result in decreased levels and effectiveness of taletrectinib.(1)|
04939|011|B||
04939|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04939|013|P|of the inducer for longer than 1-2 weeks.|
04939|014|B||
04939|015|M|PATIENT MANAGEMENT:  The manufacturer of taletrectinib states that|
04939|016|M|concomitant use of strong CYP3A4 inducers should be avoided.(1)|
04939|017|B||
04939|018|D|DISCUSSION:  Taletrectinib is primarily metabolized by CYP3A4.(1)|
04939|019|D|   Concomitant administration of taletrectinib with a strong inducer|
04939|020|D|(rifampin; 600 mg once daily) resulted in a decrease in taletrectinib area|
04939|021|D|under the curve (AUC) and maximum concentration (Cmax) by 86% and 42%,|
04939|022|D|respectively.(1)|
04939|023|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04939|024|D|barbiturates, carbamazepine, enzalutamide, ethotoin, fosphenytoin,|
04939|025|D|lumacaftor, mephenytoin, mitotane, phenobarbital, phenytoin, primidone,|
04939|026|D|rifampin, rifapentine, and St. John's wort.(2)|
04939|027|B||
04939|028|R|REFERENCES:|
04939|029|B||
04939|030|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04939|031|R|  2025.|1
04939|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
04939|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04940|001|T|MONOGRAPH TITLE:  Taletrectinib/Strong CYP3A4 Inhibitors that Prolong QT|
04940|002|B||
04940|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04940|004|L|of severe adverse interaction.|
04940|005|B||
04940|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong QT may|
04940|007|A|inhibit the metabolism of taletrectinib and result in additive effects on|
04940|008|A|the QTc interval.(1,2)|
04940|009|B||
04940|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04940|011|E|increased levels and toxicity from taletrectinib including hepatotoxicity|
04940|012|E|and myalgia.  Concurrent use may also result in additive QTc prolongation,|
04940|013|E|which may lead to life-threatening cardiac arrhythmias like torsade de|
04940|014|E|pointes.(1)|
04940|015|B||
04940|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04940|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04940|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04940|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04940|020|P|female gender, or advanced age.(2)|
04940|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04940|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04940|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04940|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04940|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04940|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04940|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04940|028|P|   Taletrectinib should be taken on an empty stomach.  Administration with|
04940|029|P|food may increase the risk of QT prolongation or torsade de pointes.|
04940|030|B||
04940|031|M|PATIENT MANAGEMENT:  Avoid concurrent administration with strong CYP3A4|
04940|032|M|inhibitors that prolong the QTc interval.|
04940|033|M|   If concurrent therapy cannot be avoided, adjust the frequency of|
04940|034|M|monitoring as recommended in the prescribing information.  Withhold|
04940|035|M|taletrectinib if the QTc interval is >500 msec or the change from baseline|
04940|036|M|is >60 msec.(1)|
04940|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04940|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04940|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04940|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04940|041|B||
04940|042|D|DISCUSSION:  Taletrectinib is primarily metabolized by CYP3A4.(1)|
04940|043|D|   Concomitant administration of itraconazole 200 mg daily (a strong|
04940|044|D|inhibitor of CYP3A4) and taletrectinib resulted in a increase in|
04940|045|D|taletrectinib maximum concentration (Cmax) of 1.8-fold and area under the|
04940|046|D|curve (AUC) of 3.3-fold.(1)|
04940|047|D|   In a pooled safety population, 351 patients had at least one post|
04940|048|D|baseline ECG assessment.  Of those patients, 13% experienced an increase in|
04940|049|D|QTcF of >60 msec compared to baseline after receiving taletrectinib and 2.6%|
04940|050|D|had an increase in QTcF to >500 msec.  Overall, 3.4% of patients had Grade 3|
04940|051|D|or greater QTc interval prolongation.  The median time from the first dose|
04940|052|D|of taletrectinib to the onset of ECG QT prolongation was 22 days (range: 1|
04940|053|D|day to 38.7 months).  QTc prolongation led to dose interruption and dose|
04940|054|D|reduction, each in 2.8% of patients treated with taletrectinib.(1)|
04940|055|D|   Agents that are linked to this monograph may have varying degrees of|
04940|056|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04940|057|D|been shown to prolong the QTc interval either through their mechanism of|
04940|058|D|action, through studies on their effects on the QTc interval, or through|
04940|059|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04940|060|D|and/or postmarketing reports.(3)|
04940|061|D|   Strong CYP3A4 inhibitors that prolong the QT interval linked to this|
04940|062|D|monograph include: adagrasib, ceritinib, clarithromycin, lonafarnib,|
04940|063|D|lopinavir-ritonavir, ribociclib, saquinavir, telithromycin, and|
04940|064|D|voriconazole.(4,5)|
04940|065|B||
04940|066|R|REFERENCES:|
04940|067|B||
04940|068|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04940|069|R|  2025.|1
04940|070|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04940|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04940|072|R|  settings: a scientific statement from the American Heart Association and|6
04940|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04940|074|R|  2;55(9):934-47.|6
04940|075|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04940|076|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04940|077|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04940|078|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04940|079|R|4.This information is based on an extract from the Certara Drug Interaction|6
04940|080|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04940|081|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04940|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04940|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04940|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04940|085|R|  11/14/2017.|1
04941|001|T|MONOGRAPH TITLE:  Taletrectinib/QT Prolonging Agents|
04941|002|B||
04941|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04941|004|L|of severe adverse interaction.|
04941|005|B||
04941|006|A|MECHANISM OF ACTION:  Taletrectinib has been shown to prolong the QTc|
04941|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04941|008|A|may result in additive effects on the QTc interval.(1)|
04941|009|B||
04941|010|E|CLINICAL EFFECTS:  The concurrent use of taletrectinib with other agents|
04941|011|E|that prolong the QTc interval may result in potentially life-threatening|
04941|012|E|cardiac arrhythmias, including torsades de pointes (TdP).(1)|
04941|013|B||
04941|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
04941|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
04941|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
04941|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04941|018|P|female gender, or advanced age.(2)|
04941|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04941|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04941|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04941|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04941|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04941|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04941|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04941|026|P|   Taletrectinib should be taken on an empty stomach. Administration with|
04941|027|P|food may increase the risk of QT prolongation or torsade de pointes.|
04941|028|B||
04941|029|M|PATIENT MANAGEMENT:  If possible, avoid the use of taletrectinib with other|
04941|030|M|agents known to prolong the QT interval.(1)|
04941|031|M|   If concurrent therapy cannot be avoided, adjust the frequency of|
04941|032|M|monitoring as recommended in the prescribing information.  If QTc is >500|
04941|033|M|msec or the change from baseline is >60 msec, withhold taletrectinib.(1)|
04941|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04941|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04941|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04941|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04941|038|B||
04941|039|D|DISCUSSION:  Taletrectinib causes concentration-dependent QTc prolongation.|
04941|040|D|At steady state maximal concentration, taletrectinib (600 mg daily)|
04941|041|D|increased the QTc interval by 12.8 msec (upper confidence interval 15.4|
04941|042|D|msec).  At plasma concentrations achieved with taletrectinib (600 mg daily)|
04941|043|D|with high fat food (1.5-fold higher than on an empty stomach), the predicted|
04941|044|D|QTc interval increase is 20.5 (16.3, 24.7) msec.(1)|
04941|045|D|   In a clinical trial including 351 evaluable patients, 13% experienced an|
04941|046|D|increase in QTcF of >60 msec compared to baseline and 2.6% had an increase|
04941|047|D|in QTcF to >500 msec.  Overall, 3.4% of patients had Grade 3 QTc interval|
04941|048|D|prolongation. The median time from the first dose of taletrectinib to the|
04941|049|D|onset of QT prolongation was 22 days (range: 1 day to 38.7 months).|
04941|050|D|   Agents that are linked to this monograph may have varying degrees of|
04941|051|D|potential to prolong the QTc interval but are generally accepted to have a|
04941|052|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04941|053|D|been shown to prolong the QTc interval either through their mechanism of|
04941|054|D|action, through studies on their effects on the QTc interval, or through|
04941|055|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04941|056|D|and/or post-marketing reports.(3)|
04941|057|B||
04941|058|R|REFERENCES:|
04941|059|B||
04941|060|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04941|061|R|  2025.|1
04941|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04941|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04941|064|R|  settings: a scientific statement from the American Heart Association and|6
04941|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04941|066|R|  2;55(9):934-47.|6
04941|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04941|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04941|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04941|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04942|001|T|MONOGRAPH TITLE:  Taletrectinib/Possible QT Prolonging Agents|
04942|002|B||
04942|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04942|004|L|take action as needed.|
04942|005|B||
04942|006|A|MECHANISM OF ACTION:  Taletrectinib has been shown to prolong the QTc|
04942|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04942|008|A|may result in additive effects on the QTc interval.(1)|
04942|009|B||
04942|010|E|CLINICAL EFFECTS:  The concurrent use of taletrectinib with other agents|
04942|011|E|that prolong the QTc interval may result in potentially life-threatening|
04942|012|E|cardiac arrhythmias, including torsades de pointes (TdP).(1)|
04942|013|B||
04942|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
04942|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
04942|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
04942|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04942|018|P|female gender, or advanced age.(2)|
04942|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04942|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04942|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04942|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04942|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04942|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04942|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04942|026|P|   Taletrectinib should be taken on an empty stomach. Administration with|
04942|027|P|food may increase the risk of QT prolongation or torsade de pointes.|
04942|028|B||
04942|029|M|PATIENT MANAGEMENT:  If possible, avoid the use of taletrectinib with other|
04942|030|M|agents known to prolong the QT interval.(1)|
04942|031|M|   If concurrent therapy cannot be avoided, adjust the frequency of|
04942|032|M|monitoring as recommended in the prescribing information.  If QTc is >500|
04942|033|M|msec or the change from baseline is >60 msec, withhold taletrectinib.(1)|
04942|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04942|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04942|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04942|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04942|038|B||
04942|039|D|DISCUSSION:  Taletrectinib causes concentration-dependent QTc prolongation.|
04942|040|D|At steady state maximal concentration, taletrectinib (600 mg daily)|
04942|041|D|increased the QTc interval by 12.8 msec (upper confidence interval 15.4|
04942|042|D|msec).  At plasma concentrations achieved with taletrectinib (600 mg daily)|
04942|043|D|with high fat food (1.5-fold higher than on an empty stomach), the predicted|
04942|044|D|QTc interval increase is 20.5 (16.3, 24.7) msec.(1)|
04942|045|D|   In a clinical trial including 351 evaluable patients, 13% experienced an|
04942|046|D|increase in QTcF of >60 msec compared to baseline and 2.6% had an increase|
04942|047|D|in QTcF to >500 msec.  Overall, 3.4% of patients had Grade 3 QTc interval|
04942|048|D|prolongation. The median time from the first dose of taletrectinib to the|
04942|049|D|onset of QT prolongation was 22 days (range: 1 day to 38.7 months).|
04942|050|D|   Agents that are linked to this monograph may have varying degrees of|
04942|051|D|potential to prolong the QTc interval but are generally accepted to have a|
04942|052|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04942|053|D|been shown to prolong the QTc interval either through their mechanism of|
04942|054|D|action, through studies on their effects on the QTc interval, or through|
04942|055|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04942|056|D|and/or post-marketing reports.(9)|
04942|057|B||
04942|058|R|REFERENCES:|
04942|059|B||
04942|060|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04942|061|R|  2025.|1
04942|062|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04942|063|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04942|064|R|  settings: a scientific statement from the American Heart Association and|6
04942|065|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04942|066|R|  2;55(9):934-47.|6
04942|067|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04942|068|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04942|069|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04942|070|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04943|001|T|MONOGRAPH TITLE:  Taletrectinib/Strong CYP3A4 Inducers that Prolong QT|
04943|002|B||
04943|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04943|004|L|of severe adverse interaction.|
04943|005|B||
04943|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers that prolong QT may induce the|
04943|007|A|metabolism of taletrectinib and result in additive effects on the QTc|
04943|008|A|interval.(1)|
04943|009|B||
04943|010|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers that|
04943|011|E|prolong QT may result in decreased levels and effectiveness of taletrectinib|
04943|012|E|and have additive effects on the QTc interval, which may result in|
04943|013|E|potentially life-threatening arrhythmias including torsade de pointes.(1)|
04943|014|B||
04943|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04943|016|P|of the inducer for longer than 1-2 weeks.|
04943|017|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04943|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04943|019|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
04943|020|P|hypokalemia, hypomagnesia, hypocalcemia, bradycardia, female gender, or|
04943|021|P|advanced age.(2)|
04943|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04943|023|P|higher systemic concentrations include rapid infusion of an intravenous dose|
04943|024|P|or impaired metabolism or elimination of the drug (e.g. coadministration|
04943|025|P|with an agent which inhibits its metabolism or elimination, genetic|
04943|026|P|impairment in drug metabolism or elimination, and/or renal/hepatic|
04943|027|P|dysfunction).(2)|
04943|028|P|   Taletrectinib should be taken on an empty stomach. Administration with|
04943|029|P|food may increase the risk of QT prolongation or torsade de pointes.|
04943|030|B||
04943|031|M|PATIENT MANAGEMENT:  The manufacturer of taletrectinib states that|
04943|032|M|concomitant use of strong CYP3A4 inducers should be avoided.(1)|
04943|033|M|   The manufacturer of taletrectinib states that the concurrent use of QT|
04943|034|M|prolonging agents should be avoided. If concurrent use cannot be avoided,|
04943|035|M|obtain ECGs prior to initiating taletrectinib, during concomitant use, and|
04943|036|M|as clinically indicated.(1)|
04943|037|M|   If concurrent therapy is warranted, correct any electrolyte abnormalities|
04943|038|M|and instruct patients to report any irregular heartbeat, dizziness, or|
04943|039|M|fainting.|
04943|040|B||
04943|041|D|DISCUSSION:  Taletrectinib is primarily metabolized by CYP3A4.(1)|
04943|042|D|   Concomitant administration of taletrectinib with a strong inducer|
04943|043|D|(rifampin; 600 mg once daily) resulted in a decrease in taletrectinib area|
04943|044|D|under the curve (AUC) and maximum concentration (Cmax) by 86% and 42%,|
04943|045|D|respectively.(1)|
04943|046|D|   The effect of taletrectinib on the QTc interval was evaluated in a pooled|
04943|047|D|safety population of 351 patients receiving taletrectinib (600 mg orally|
04943|048|D|once daily) and underwent at least one post ECG assessment. 13% experienced|
04943|049|D|an increase in QTcF of greater than 60 msec compared to baseline and 2.6%|
04943|050|D|had a QTcF increase of greater than 500 msec. A concentration-dependent QTc|
04943|051|D|prolongation effect of taletrectinib was observed. The largest mean increase|
04943|052|D|in the QTc interval was 12.8 msec (upper CI 15.4 msec) at Cmax. The|
04943|053|D|predicted increase in the QTC interval with high fat food is 20.5 msec.(1)|
04943|054|D|   Agents that are linked to this monograph may have varying degrees of|
04943|055|D|potential to prolong the QT interval. Agents linked to this monographs have|
04943|056|D|been shown to prolong the QTc interval either through their mechanism of|
04943|057|D|action, through studies on their effects on the QTc interval, or through|
04943|058|D|reports of QTc prolongation and/or torsade de pointes in clinical trials|
04943|059|D|and/or postmarketing reports.(3)|
04943|060|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04943|061|D|encorafenib and ivosidenib.(3,4)|
04943|062|B||
04943|063|R|REFERENCES:|
04943|064|B||
04943|065|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04943|066|R|  2025.|1
04943|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04943|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04943|069|R|  settings: a scientific statement from the American Heart Association and|6
04943|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04943|071|R|  2;55(9):934-47.|6
04943|072|R|3.This information is based on an extract from the Certara Drug Interaction|6
04943|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04943|074|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04943|075|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04943|076|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04943|077|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04943|078|R|  11/14/2017.|1
04944|001|T|MONOGRAPH TITLE:  Taletrectinib/Moderate CYP3A4 Inducers|
04944|002|B||
04944|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04944|004|L|of severe adverse interaction.|
04944|005|B||
04944|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
04944|007|A|taletrectinib.(1)|
04944|008|B||
04944|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate CYP3A4 inducer may|
04944|010|E|result in decreased levels and effectiveness of taletrectinib.(1)|
04944|011|B||
04944|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04944|013|P|of the inducer for longer than 1-2 weeks.|
04944|014|B||
04944|015|M|PATIENT MANAGEMENT:  The manufacturer of taletrectinib states that|
04944|016|M|concomitant use of moderate CYP3A4 inducers should be avoided.(1)|
04944|017|B||
04944|018|D|DISCUSSION:  Taletrectinib is primarily metabolized by CYP3A4.(1)|
04944|019|D|   Concomitant administration of taletrectinib with a moderate inducer|
04944|020|D|(efavirenz) is predicted to decrease taletrectinib area under the curve|
04944|021|D|(AUC) and maximum concentration (Cmax) by 66% and 40%, respectively.(1)|
04944|022|D|   Concomitant administration of taletrectinib with a strong inducer|
04944|023|D|(rifampin; 600 mg once daily) resulted in a decrease in taletrectinib area|
04944|024|D|under the curve (AUC) and maximum concentration (Cmax) by 86% and 42%,|
04944|025|D|respectively.(1)|
04944|026|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
04944|027|D|bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad,|
04944|028|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib,|
04944|029|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2)|
04944|030|B||
04944|031|R|REFERENCES:|
04944|032|B||
04944|033|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04944|034|R|  2025.|1
04944|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
04944|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04945|001|T|MONOGRAPH TITLE:  Taletrectinib/Moderate CYP3A4 Inducers that Prolong QT|
04945|002|B||
04945|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04945|004|L|of severe adverse interaction.|
04945|005|B||
04945|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers that prolong QT may induce|
04945|007|A|the metabolism of taletrectinib and result in additive effects on the QTc|
04945|008|A|interval.(1)|
04945|009|B||
04945|010|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers that|
04945|011|E|prolong QT may result in decreased levels and effectiveness of taletrectinib|
04945|012|E|and have additive effects on the QTc interval, which may result in|
04945|013|E|potentially life-threatening arrhythmias including torsade de pointes.(1)|
04945|014|B||
04945|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04945|016|P|of the inducer for longer than 1-2 weeks.|
04945|017|P|   The risk of QT prolongation or torsade de pointes may be increased in|
04945|018|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04945|019|P|infarction, history of torsade de pointes, congenital long QT syndrome),|
04945|020|P|hypokalemia, hypomagnesia, hypocalcemia, bradycardia, female gender, or|
04945|021|P|advanced age.(2)|
04945|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04945|023|P|higher systemic concentrations include rapid infusion of an intravenous dose|
04945|024|P|or impaired metabolism or elimination of the drug (e.g. coadministration|
04945|025|P|with an agent which inhibits its metabolism or elimination, genetic|
04945|026|P|impairment in drug metabolism or elimination, and/or renal/hepatic|
04945|027|P|dysfunction).(2)|
04945|028|P|   Taletrectinib should be taken on an empty stomach. Administration with|
04945|029|P|food may increase the risk of QT prolongation or torsade de pointes.|
04945|030|B||
04945|031|M|PATIENT MANAGEMENT:  The manufacturer of taletrectinib states that|
04945|032|M|concomitant use of moderate CYP3A4 inducers should be avoided.(1)|
04945|033|M|   The manufacturer of taletrectinib states that the concurrent use of QT|
04945|034|M|prolonging agents should be avoided. If concurrent use cannot be avoided,|
04945|035|M|obtain ECGs prior to initiating taletrectinib, during concomitant use, and|
04945|036|M|as clinically indicated.(1)|
04945|037|M|   If concurrent therapy is warranted, correct any electrolyte abnormalities|
04945|038|M|and instruct patients to report any irregular heartbeat, dizziness, or|
04945|039|M|fainting.|
04945|040|B||
04945|041|D|DISCUSSION:  Taletrectinib is primarily metabolized by CYP3A4.(1)|
04945|042|D|   Concomitant administration of taletrectinib with a moderate inducer|
04945|043|D|(efavirenz) is predicted to decrease in taletrectinib area under the curve|
04945|044|D|(AUC) and maximum concentration (Cmax) by 66% and 40%, respectively.(1)|
04945|045|D|   Concomitant administration of taletrectinib with a strong inducer|
04945|046|D|(rifampin; 600 mg once daily) resulted in a decrease in taletrectinib area|
04945|047|D|under the curve (AUC) and maximum concentration (Cmax) by 86% and 42%,|
04945|048|D|respectively.(1)|
04945|049|D|   The effect of taletrectinib on the QTc interval was evaluated in a pooled|
04945|050|D|safety population of 351 patients receiving taletrectinib (600 mg orally|
04945|051|D|once daily) and underwent at least one post ECG assessment. 13% experienced|
04945|052|D|an increase in QTcF of greater than 60 msec compared to baseline and 2.6%|
04945|053|D|had a QTcF increase of greater than 500 msec. A concentration-dependent QTc|
04945|054|D|prolongation effect of taletrectinib was observed. The largest mean increase|
04945|055|D|in the QTc interval was 12.8 msec (upper CI 15.4 msec) at Cmax. The|
04945|056|D|predicted increase in the QTC interval with high fat food is 20.5 msec.(1)|
04945|057|D|   Agents that are linked to this monograph may have varying degrees of|
04945|058|D|potential to prolong the QT interval. Agents linked to this monographs have|
04945|059|D|been shown to prolong the QTc interval either through their mechanism of|
04945|060|D|action, through studies on their effects on the QTc interval, or through|
04945|061|D|reports of QTc prolongation and/or torsade de pointes in clinical trials|
04945|062|D|and/or postmarketing reports.(3)|
04945|063|D|   Moderate CYP3A4 inducers that prolong QT linked to this monograph|
04945|064|D|include: efavirenz, pacritinib, and thioridazine.(3,4)|
04945|065|B||
04945|066|R|REFERENCES:|
04945|067|B||
04945|068|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04945|069|R|  2025.|1
04945|070|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04945|071|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04945|072|R|  settings: a scientific statement from the American Heart Association and|6
04945|073|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04945|074|R|  2;55(9):934-47.|6
04945|075|R|3.This information is based on an extract from the Certara Drug Interaction|6
04945|076|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04945|077|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04945|078|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04945|079|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04945|080|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04945|081|R|  11/14/2017.|1
04946|001|T|MONOGRAPH TITLE:  Voriconazole/Dipyrone|
04946|002|B||
04946|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04946|004|L|of severe adverse interaction.|
04946|005|B||
04946|006|A|MECHANISM OF ACTION:  Dipyrone is a moderate inducer of CYP2C19 and CYP3A4|
04946|007|A|and may induce the metabolism of voriconazole via these pathways.(1-3)|
04946|008|B||
04946|009|E|CLINICAL EFFECTS:  The concurrent use of dipyrone and voriconazole may|
04946|010|E|result in severely reduced levels of the azole antifungal and therapeutic|
04946|011|E|failure.|
04946|012|B||
04946|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04946|014|P|of the inducer for longer than 1-2 weeks.|
04946|015|B||
04946|016|M|PATIENT MANAGEMENT:  Avoid coadministration of dipyrone and voriconazole.|
04946|017|M|If concurrent use is warranted, closely monitor voriconazole trough|
04946|018|M|concentrations during and for up to 2 weeks after discontinuing dipyrone.(2)|
04946|019|B||
04946|020|D|DISCUSSION:  In a retrospective observational study, 9 patients on the|
04946|021|D|combination of dipyrone and voriconazole were found to have a 71% decrease|
04946|022|D|in voriconazole trough concentrations during dipyrone treatment.(2)|
04946|023|D|   Two case reports also found subtherapeutic voriconazole levels during|
04946|024|D|dipyrone therapy that returned to the therapeutic range after dipyrone was|
04946|025|D|stopped.(4)|
04946|026|B||
04946|027|R|REFERENCES:|
04946|028|B||
04946|029|R|1.Optalgin (dipyrone) Israeli Summary of Product Characteristics. Teva|1
04946|030|R|  Israel Ltd. May, 2025.|1
04946|031|R|2.Baan SD, Touw DJ, Lub-de Hooge MN, Oude Munnink TH. Metamizole induces|2
04946|032|R|  voriconazole metabolism and results in subtherapeutic  voriconazole|2
04946|033|R|  concentrations. Br J Clin Pharmacol 2025 Apr 27.|2
04946|034|R|3.This information is based on an extract from the Certara Drug Interaction|6
04946|035|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04946|036|R|4.Diaz-Calderon Horcada CI, Mejias Trueba M, Izuel Rami M, Guisado Gil AB,|3
04946|037|R|  Herranz Bayo E, Herrera Hidalgo L. Effect of metamizole on plasma levels|3
04946|038|R|  of voriconazole. Med Intensiva (Engl Ed) 2025 Jan;49(1):54-56.|3
04947|001|T|MONOGRAPH TITLE:  Taletrectinib/Moderate CYP3A4 Inhibitors|
04947|002|B||
04947|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04947|004|L|of severe adverse interaction.|
04947|005|B||
04947|006|A|MECHANISM OF ACTION:  Taletrectinib is a substrate of CYP3A4.  Moderate|
04947|007|A|inhibitors of CYP3A4 may inhibit the metabolism of taletrectinib.(1)|
04947|008|B||
04947|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
04947|010|E|in increased levels and toxicity from taletrectinib including|
04947|011|E|hepatotoxicity, myalgia, and prolongation of the QT interval, which may|
04947|012|E|result in life-threatening arrhythmia and death.(1))|
04947|013|B||
04947|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04947|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
04947|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04947|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04947|018|P|female gender, or advanced age.(2)|
04947|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04947|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04947|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04947|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04947|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04947|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04947|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04947|026|P|   Taletrectinib should be taken on an empty stomach.  Administration with|
04947|027|P|food may increase the risk of QT prolongation or torsade de pointes.|
04947|028|B||
04947|029|M|PATIENT MANAGEMENT:  The manufacturer of taletrectinib recommends avoiding|
04947|030|M|concurrent administration with moderate CYP3A4 inhibitors.(1)|
04947|031|M|   If concurrent therapy cannot be avoided, adjust the frequency of|
04947|032|M|monitoring as recommended in the prescribing information.  Withhold|
04947|033|M|taletrectinib if the QTc interval is >500 msec or the change from baseline|
04947|034|M|is >60 msec.(1)|
04947|035|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04947|036|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04947|037|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04947|038|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04947|039|B||
04947|040|D|DISCUSSION:  Concomitant administration with moderate inhibitors of CYP3A4|
04947|041|D|(fluconazole, erythromycin, or verapamil) is predicted to increase|
04947|042|D|taletrectinib area under the curve (AUC) up to 2.6-fold and maximum|
04947|043|D|concentration (Cmax) up to 1.5-fold.(1)|
04947|044|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04947|045|D|atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem,|
04947|046|D|duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
04947|047|D|isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat,|
04947|048|D|rilzabrutinib, schisandra, tofisopam, treosulfan, verapamil, and|
04947|049|D|voxelotor.(3)|
04947|050|B||
04947|051|R|REFERENCES:|
04947|052|B||
04947|053|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04947|054|R|  2025.|1
04947|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04947|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04947|057|R|  settings: a scientific statement from the American Heart Association and|6
04947|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04947|059|R|  2;55(9):934-47.|6
04947|060|R|3.This information is based on an extract from the Certara Drug Interaction|6
04947|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04948|001|T|MONOGRAPH TITLE:  Taletrectinib/Moderate CYP3A4 Inhibitors that Prolong QT|
04948|002|B||
04948|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04948|004|L|of severe adverse interaction.|
04948|005|B||
04948|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong QT may|
04948|007|A|inhibit the metabolism of taletrectinib and result in additive effects on|
04948|008|A|the QTc interval.(1)|
04948|009|B||
04948|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
04948|011|E|in increased levels and toxicity from taletrectinib including hepatotoxicity|
04948|012|E|and myalgia.  Concurrent use may also result in additive QTc prolongation,|
04948|013|E|which may lead to life-threatening cardiac arrhythmias like torsade de|
04948|014|E|pointes.(1)|
04948|015|B||
04948|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04948|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04948|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04948|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04948|020|P|female gender, or advanced age.(2)|
04948|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04948|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04948|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04948|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04948|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04948|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04948|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04948|028|P|   Taletrectinib should be taken on an empty stomach.  Administration with|
04948|029|P|food may increase the risk of QT prolongation or torsade de pointes.|
04948|030|B||
04948|031|M|PATIENT MANAGEMENT:  Avoid concurrent administration with moderate CYP3A4|
04948|032|M|inhibitors that prolong the QTc interval.|
04948|033|M|   If concurrent therapy cannot be avoided, adjust the frequency of|
04948|034|M|monitoring as recommended in the prescribing information.  Withhold|
04948|035|M|taletrectinib if the QTc interval is >500 msec or the change from baseline|
04948|036|M|is >60 msec.(1)|
04948|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04948|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04948|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04948|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04948|041|B||
04948|042|D|DISCUSSION:  Taletrectinib is primarily metabolized by CYP3A4.(1)|
04948|043|D|   Concomitant administration with moderate inhibitors of CYP3A4|
04948|044|D|(fluconazole, erythromycin, or verapamil) is predicted to increase|
04948|045|D|taletrectinib area under the curve (AUC) up to 2.6-fold and maximum|
04948|046|D|concentration (Cmax) up to 1.5-fold.(1)|
04948|047|D|   In a pooled safety population, 351 patients had at least one post|
04948|048|D|baseline ECG assessment.  Of those patients, 13% experienced an increase in|
04948|049|D|QTcF of >60 msec compared to baseline after receiving taletrectinib and 2.6%|
04948|050|D|had an increase in QTcF to >500 msec.  Overall, 3.4% of patients had Grade 3|
04948|051|D|or greater QTc interval prolongation.  The median time from the first dose|
04948|052|D|of taletrectinib to the onset of ECG QT prolongation was 22 days (range: 1|
04948|053|D|day to 38.7 months).  QTc prolongation led to dose interruption and dose|
04948|054|D|reduction, each in 2.8% of patients treated with taletrectinib.(1)|
04948|055|D|   Agents that are linked to this monograph may have varying degrees of|
04948|056|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04948|057|D|been shown to prolong the QTc interval either through their mechanism of|
04948|058|D|action, through studies on their effects on the QTc interval, or through|
04948|059|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04948|060|D|and/or postmarketing reports.(3)|
04948|061|D|   Moderate CYP3A4 inhibitors linked to this monograph include:|
04948|062|D|clofazimine, crizotinib, erythromycin, fluconazole, oral lefamulin, and|
04948|063|D|nilotinib.(4)|
04948|064|B||
04948|065|R|REFERENCES:|
04948|066|B||
04948|067|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04948|068|R|  2025.|1
04948|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04948|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04948|071|R|  settings: a scientific statement from the American Heart Association and|6
04948|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04948|073|R|  2;55(9):934-47.|6
04948|074|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04948|075|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04948|076|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04948|077|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04948|078|R|4.This information is based on an extract from the Certara Drug Interaction|6
04948|079|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04949|001|T|MONOGRAPH TITLE:  Taletrectinib/Strong CYP3A4 Inhibitors that Prolong QT|
04949|002|B||
04949|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04949|004|L|is contraindicated and generally should not be dispensed or administered to|
04949|005|L|the same patient.|
04949|006|B||
04949|007|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong QT may|
04949|008|A|inhibit the metabolism of taletrectinib and result in additive effects on|
04949|009|A|the QTc interval.(1,2)|
04949|010|B||
04949|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04949|012|E|increased levels and toxicity from taletrectinib including hepatotoxicity|
04949|013|E|and myalgia.  Concurrent use may also result in additive QTc prolongation,|
04949|014|E|which may lead to life-threatening cardiac arrhythmias like torsade de|
04949|015|E|pointes.(1)|
04949|016|B||
04949|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04949|018|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04949|019|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04949|020|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04949|021|P|gender, or advanced age.(2)|
04949|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04949|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04949|024|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04949|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04949|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04949|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04949|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04949|029|P|   Taletrectinib should be taken on an empty stomach.  Administration with|
04949|030|P|food may increase the risk of QT prolongation or torsade de pointes.|
04949|031|B||
04949|032|M|PATIENT MANAGEMENT:  The manufacturer of levoketoconazole states that|
04949|033|M|concomitant use of other drugs that prolong the QTc interval is|
04949|034|M|contraindicated.(3)  The manufacturer of taletrectinib states that|
04949|035|M|concurrent administration of strong CYP3A4 inhibitors or of other drugs|
04949|036|M|known to prolong the QTc interval should be avoided.(1)|
04949|037|M|   If concurrent therapy cannot be avoided, adjust the frequency of|
04949|038|M|monitoring as recommended in the taletrectinib prescribing information.|
04949|039|M|Withhold taletrectinib if the QTc interval is >500 msec or the change from|
04949|040|M|baseline is >60 msec, and withhold levoketoconazole if the QTc interval is|
04949|041|M|>500 msec.  After resolution of grade 2 or 3 prolonged QTc interval,|
04949|042|M|taletrectinib may be resumed at the same or reduced dose depending on|
04949|043|M|severity, and levoketoconazole may be resumed at a lower dose.  If the|
04949|044|M|patient developed serious arrhythmias, permanently discontinue|
04949|045|M|taletrectinib.  If QTc interval prolongation recurs, permanently discontinue|
04949|046|M|levoketoconazole.(1,3)|
04949|047|M|   Prior to starting levoketoconazole, obtain a baseline ECG and correct|
04949|048|M|hypokalemia or hypomagnesemia.(3)|
04949|049|M|   Levoketoconazole is also contraindicated in patients with a prolonged|
04949|050|M|QTcF interval of greater than 470 msec at baseline, history of torsades de|
04949|051|M|pointes, ventricular tachycardia, ventricular fibrillation, or long QT|
04949|052|M|syndrome (including first-degree family history).  Use caution in patients|
04949|053|M|with other risk factors for QT prolongation including congestive heart|
04949|054|M|failure, bradyarrhythmias, and uncorrected electrolyte abnormalities.|
04949|055|M|Consider more frequent ECG monitoring.(3)|
04949|056|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04949|057|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04949|058|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04949|059|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04949|060|B||
04949|061|D|DISCUSSION:  Taletrectinib is primarily metabolized by CYP3A4.(1)|
04949|062|D|   Concomitant administration of itraconazole 200 mg daily (a strong|
04949|063|D|inhibitor of CYP3A4 and taletrectinib resulted in a increase in|
04949|064|D|taletrectinib maximum concentration (Cmax) of 1.8-fold and area under the|
04949|065|D|curve (AUC) of 3.3-fold.(1)|
04949|066|D|   In a pooled safety population, 351 patients had at least one post|
04949|067|D|baseline ECG assessment.  Of those patients, 13% experienced an increase in|
04949|068|D|QTcF of >60 msec compared to baseline after receiving taletrectinib and 2.6%|
04949|069|D|had an increase in QTcF to >500 msec.  Overall, 3.4% of patients had Grade 3|
04949|070|D|or greater QTc interval prolongation.  The median time from the first dose|
04949|071|D|of taletrectinib to the onset of ECG QT prolongation was 22 days (range: 1|
04949|072|D|day to 38.7 months).  QTc prolongation led to dose interruption and dose|
04949|073|D|reduction, each in 2.8% of patients treated with taletrectinib.(1)|
04949|074|D|   During phase 1 and 2 studies of levoketoconazole, which excluded patients|
04949|075|D|with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients|
04949|076|D|experienced QTcF > 500 msec, and 23 (14.7%) patients experienced|
04949|077|D|change-from-baseline QTcF > 60 msec.(3)|
04949|078|D|   Agents that are linked to this monograph may have varying degrees of|
04949|079|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04949|080|D|been shown to prolong the QTc interval either through their mechanism of|
04949|081|D|action, through studies on their effects on the QTc interval, or through|
04949|082|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04949|083|D|and/or postmarketing reports.(4)|
04949|084|D|   Strong CYP3A4 inhibitors that prolong QT linked to this monograph|
04949|085|D|include: levoketoconazole.(5)|
04949|086|B||
04949|087|R|REFERENCES:|
04949|088|B||
04949|089|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04949|090|R|  2025.|1
04949|091|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04949|092|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04949|093|R|  settings: a scientific statement from the American Heart Association and|6
04949|094|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04949|095|R|  2;55(9):934-47.|6
04949|096|R|3.Recorlev (levoketoconazole) US prescribing information. Xeris|1
04949|097|R|  Pharmaceuticals, Inc. June, 2023.|1
04949|098|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04949|099|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04949|100|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04949|101|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04949|102|R|5.This information is based on an extract from the Certara Drug Interaction|6
04949|103|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04950|001|T|MONOGRAPH TITLE:  Taletrectinib/Moderate CYP3A4 Inhibitors that Prolong QT|
04950|002|B||
04950|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04950|004|L|is contraindicated and generally should not be dispensed or administered to|
04950|005|L|the same patient.|
04950|006|B||
04950|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong QT may|
04950|008|A|inhibit the metabolism of taletrectinib and result in additive effects on|
04950|009|A|the QTc interval.(1,2)|
04950|010|B||
04950|011|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
04950|012|E|in increased levels and toxicity from taletrectinib including hepatotoxicity|
04950|013|E|and myalgia.  Concurrent use may also result in additive QTc prolongation,|
04950|014|E|which may lead to life-threatening cardiac arrhythmias like torsade de|
04950|015|E|pointes.(1)|
04950|016|B||
04950|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04950|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04950|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04950|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04950|021|P|female gender, or advanced age.(2)|
04950|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04950|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04950|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04950|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04950|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04950|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04950|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04950|029|P|   Taletrectinib should be taken on an empty stomach.  Administration with|
04950|030|P|food may increase the risk of QT prolongation or torsade de pointes.|
04950|031|B||
04950|032|M|PATIENT MANAGEMENT:  The manufacturer of dronedarone states that concomitant|
04950|033|M|use of other drugs that are known to prolong the QTc interval is|
04950|034|M|contraindicated.(3)  The manufacturer of taletrectinib states that|
04950|035|M|concurrent administration of moderate CYP3A4 inhibitors or of other drugs|
04950|036|M|known to prolong the QTc interval should be avoided.(1)|
04950|037|M|   If concurrent therapy cannot be avoided, adjust the frequency of|
04950|038|M|monitoring as recommended in the taletrectinib prescribing information.|
04950|039|M|Withhold taletrectinib if the QTc interval is >500 msec or the change from|
04950|040|M|baseline is >60 msec, and discontinue dronedarone if the QTc interval is|
04950|041|M|>500 msec.  After resolution of grade 2 or 3 prolonged QTc interval,|
04950|042|M|taletrectinib may be resumed at the same or reduced dose depending on|
04950|043|M|severity.  If the patient developed serious arrhythmias, permanently|
04950|044|M|discontinue taletrectinib.(1,3)|
04950|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04950|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04950|047|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04950|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04950|049|B||
04950|050|D|DISCUSSION:  Taletrectinib is primarily metabolized by CYP3A4.(1)|
04950|051|D|   Concomitant administration with moderate inhibitors of CYP3A4|
04950|052|D|(fluconazole, erythromycin, or verapamil) is predicted to increase|
04950|053|D|taletrectinib area under the curve (AUC) up to 2.6-fold and maximum|
04950|054|D|concentration (Cmax) up to 1.5-fold.(1)|
04950|055|D|   In a pooled safety population, 351 patients had at least one post|
04950|056|D|baseline ECG assessment.  Of those patients, 13% experienced an increase in|
04950|057|D|QTcF of >60 msec compared to baseline after receiving taletrectinib and 2.6%|
04950|058|D|had an increase in QTcF to >500 msec.  Overall, 3.4% of patients had Grade 3|
04950|059|D|or greater QTc interval prolongation.  The median time from the first dose|
04950|060|D|of taletrectinib to the onset of ECG QT prolongation was 22 days (range: 1|
04950|061|D|day to 38.7 months).  QTc prolongation led to dose interruption and dose|
04950|062|D|reduction, each in 2.8% of patients treated with taletrectinib.(1)|
04950|063|D|   Agents that are linked to this monograph may have varying degrees of|
04950|064|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04950|065|D|been shown to prolong the QTc interval either through their mechanism of|
04950|066|D|action, through studies on their effects on the QTc interval, or through|
04950|067|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04950|068|D|and/or postmarketing reports.(3)|
04950|069|D|   Moderate CYP3A4 inhibitors that prolong the QT interval linked to this|
04950|070|D|monograph include: dronedarone.(4,5)|
04950|071|B||
04950|072|R|REFERENCES:|
04950|073|B||
04950|074|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04950|075|R|  2025.|1
04950|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04950|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04950|078|R|  settings: a scientific statement from the American Heart Association and|6
04950|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04950|080|R|  2;55(9):934-47.|6
04950|081|R|3.Multaq (dronedarone) US prescribing information. Sanofi-Aventis U.S. LLC|1
04950|082|R|  November, 2020.|1
04950|083|R|4.USDepartment of Health and Human Services Food and Drug Administration.|1
04950|084|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04950|085|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04950|086|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04950|087|R|5.This information is based on an extract from the Certara Drug Interaction|6
04950|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04950|089|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
04950|090|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04950|091|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04950|092|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04950|093|R|  11/14/2017.|1
04951|001|T|MONOGRAPH TITLE:  Taletrectinib/Antacids|
04951|002|B||
04951|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04951|004|L|take action as needed.|
04951|005|B||
04951|006|A|MECHANISM OF ACTION:  The aqueous solubility of taletrectinib is pH|
04951|007|A|dependent.  Higher gastric pH leads to lower solubility which may reduce|
04951|008|A|taletrectinib absorption.(1)|
04951|009|B||
04951|010|E|CLINICAL EFFECTS:  Coadministration with antacids may reduce the|
04951|011|E|bioavailability of taletrectinib, leading to decreased systemic levels and|
04951|012|E|effectiveness.(1)|
04951|013|B||
04951|014|P|PREDISPOSING FACTORS:  None determined.|
04951|015|B||
04951|016|M|PATIENT MANAGEMENT:  The manufacturer of taletrectinib states that patients|
04951|017|M|requiring acid-lowering therapy should separate taletrectinib from antacid|
04951|018|M|administration by 2 hours.(1)|
04951|019|M|   Some vitamin preparations may contain sufficient quantities of calcium|
04951|020|M|and/or magnesium salts with antacid properties to interact as well.|
04951|021|B||
04951|022|D|DISCUSSION:  The impact of antacids on the pharmacokinetics of taletrectinib|
04951|023|D|has not been investigated in clinical studies.|
04951|024|D|   In an interaction study, taletrectinib area-under-the-curve (AUC)|
04951|025|D|decreased by 40% and maximum concentration (Cmax) decreased by 65% following|
04951|026|D|concomitant use of omeprazole 40 mg daily.(1)|
04951|027|B||
04951|028|R|REFERENCE:|
04951|029|B||
04951|030|R|1.Ibtrozi (taletrectinib) US prescribing information. Nuvation Bio Inc. June|1
04951|031|R|  2025.|1
04952|001|T|MONOGRAPH TITLE:  Deuruxolitinib/Strong CYP3A4 Inducers|
04952|002|B||
04952|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04952|004|L|of severe adverse interaction.|
04952|005|B||
04952|006|A|MECHANISM OF ACTION:  Drugs that are strong CYP3A4 inducers may increase the|
04952|007|A|metabolism of deuruxolitinib.(1)|
04952|008|B||
04952|009|E|CLINICAL EFFECTS:  Concurrent use with a strong CYP3A4 inducer may result in|
04952|010|E|decreased levels and effectiveness of deuruxolitinib.(1)|
04952|011|B||
04952|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04952|013|P|of the inducer for longer than 1-2 weeks.|
04952|014|B||
04952|015|M|PATIENT MANAGEMENT:  The manufacturer of deuruxolitinib states to avoid|
04952|016|M|concomitant use with strong CYP3A4 inducers.(1)|
04952|017|B||
04952|018|D|DISCUSSION:  In a study, concomitant use of multiple doses of rifampin 600|
04952|019|D|mg (a strong CYP3A4 and moderate CYP2C9 inducer) and a single dose of|
04952|020|D|deuruxolitinib 12 mg resulted in decreased deuruxolitinib area-under-curve|
04952|021|D|(AUC) by 78% and maximum concentration (Cmax) by 41%.(1)|
04952|022|D|   Drugs that are strong CYP3A4 inducers linked to this monograph include:|
04952|023|D|apalutamide, barbiturates, carbamazepine, fosphenytoin, ivosidenib,|
04952|024|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and|
04952|025|D|St. John's Wort.(2-3)|
04952|026|B||
04952|027|R|REFERENCES:|
04952|028|B||
04952|029|R|1.Leqselvi (deuruxolitinib) tablets, US Prescribing Information. Sun|1
04952|030|R|  Pharmaceuticals Industries, Inc. July 2024.|1
04952|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04952|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04952|033|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04952|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04952|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04952|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04952|037|R|  11/14/2017.|1
04953|001|T|MONOGRAPH TITLE:  Deuruxolitinib/Immunosuppressive Strong CYP3A4 Inducers|
04953|002|B||
04953|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04953|004|L|of severe adverse interaction.|
04953|005|B||
04953|006|A|MECHANISM OF ACTION:  Deuruxolitinib is a substrate of CYP3A4. Drugs that|
04953|007|A|are inducers of CYP3A4 may increase the metabolism of deuruxolitinib. (1)|
04953|008|A|   Deuruxolitinib and immunosuppressives both suppress the immune system.|
04953|009|B||
04953|010|E|CLINICAL EFFECTS:  Concurrent use of an immunosuppressive strong CYP3A4|
04953|011|E|inducer may result in decreased levels and effectiveness of deuruxolitinib|
04953|012|E|and increased risk of serious infections.(1)|
04953|013|B||
04953|014|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04953|015|P|of the inducer for longer than 1-2 weeks.|
04953|016|B||
04953|017|M|PATIENT MANAGEMENT:  The manufacturer of deuruxolitinib states to avoid|
04953|018|M|concomitant use with strong CYP3A4 inducers.(1)|
04953|019|M|   The manufacturer of deuruxolitinib states that concurrent use of|
04953|020|M|deuruxolitinib with other potent immunosuppressants is not recommended.(1)|
04953|021|B||
04953|022|D|DISCUSSION:  Serious infections have been reported in patients receiving|
04953|023|D|treatment with deuruxolitinib.(1)|
04953|024|D|   In a study, concomitant use of multiple doses of rifampin 600 mg (a|
04953|025|D|strong CYP3A4 and moderate CYP2C9 inducer) and a single dose of|
04953|026|D|deuruxolitinib 12 mg resulted in decreased deuruxolitinib area-under-curve|
04953|027|D|(AUC) by 78% and maximum concentration (Cmax) by 41%.(1)|
04953|028|D|   Immunosuppressive strong CYP3A4 inducers linked to this monograph|
04953|029|D|include: encorafenib.(2-3)|
04953|030|B||
04953|031|R|REFERENCES:|
04953|032|B||
04953|033|R|1.Leqselvi (deuruxolitinib) tablets, US Prescribing Information. Sun|1
04953|034|R|  Pharmaceuticals Industries, Inc. July 2024.|1
04953|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
04953|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04953|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04953|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04953|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04953|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04953|041|R|  11/14/2017.|1
04954|001|T|MONOGRAPH TITLE:  Selected OAT1-OAT3 Substrates/Nitisinone|
04954|002|B||
04954|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04954|004|L|of severe adverse interaction.|
04954|005|B||
04954|006|A|MECHANISM OF ACTION:  Nitisinone is an inhibitor of organic anion|
04954|007|A|transporter 1 and 3 (OAT1/OAT3) which may inhibit the renal excretion of|
04954|008|A|substrates of OAT1/OAT3.(1)|
04954|009|B||
04954|010|E|CLINICAL EFFECTS:  Administration of nitisinone with OAT1/OAT3 substrates|
04954|011|E|may result in elevated levels of and toxicity of the substrates.(1)|
04954|012|B||
04954|013|P|PREDISPOSING FACTORS:  None determined.|
04954|014|B||
04954|015|M|PATIENT MANAGEMENT:  The US manufacturer of nitisinone states concurrent use|
04954|016|M|with OAT1/OAT3 substrates should be avoided.(1)|
04954|017|B||
04954|018|D|DISCUSSION:  Nitisinone increased the area-under-curve (AUC) and maximum|
04954|019|D|concentration (Cmax) of furosemide, an OAT1/OAT3 substrate, by 72% and 12%,|
04954|020|D|respectively.(1)|
04954|021|D|   OAT1/OAT3 substrates linked to this monograph include: adefovir,|
04954|022|D|bumetanide, furosemide, tenofovir and vadadustat.(1-2)|
04954|023|B||
04954|024|R|REFERENCES:|
04954|025|B||
04954|026|R|1.Harliku (nitisinone) US prescribing information. Cycle Pharmaceuticals Ltd|1
04954|027|R|  June, 2025.|1
04954|028|R|2.This information is based on an extract from the Certara Drug Interaction|6
04954|029|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04955|001|T|MONOGRAPH TITLE:  OAT1-OAT3 Substrates that Prolong QT/Nitisinone|
04955|002|B||
04955|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04955|004|L|of severe adverse interaction.|
04955|005|B||
04955|006|A|MECHANISM OF ACTION:  Nitisinone is an inhibitor of organic anion|
04955|007|A|transporter 1 and 3 (OAT1/OAT3) which may inhibit the renal excretion of|
04955|008|A|substrates of OAT1/OAT3.(1)|
04955|009|B||
04955|010|E|CLINICAL EFFECTS:  Administration of nitisinone with OAT1/OAT3 substrates|
04955|011|E|that prolong the QT interval may result in elevated levels of and toxicity|
04955|012|E|of the substrates, including QT prolongation, which may lead to|
04955|013|E|life-threatening cardiac arrhythmias like torsade de pointes.(1)|
04955|014|B||
04955|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04955|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04955|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04955|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04955|019|P|gender, or advanced age.(2)|
04955|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04955|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04955|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04955|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04955|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04955|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04955|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04955|027|B||
04955|028|M|PATIENT MANAGEMENT:  The US manufacturer of nitisinone states that|
04955|029|M|concurrent use with OAT1/OAT3 substrates should be avoided.(1)|
04955|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04955|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04955|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04955|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04955|034|B||
04955|035|D|DISCUSSION:  Nitisinone increased the area-under-curve (AUC) and maximum|
04955|036|D|concentration (Cmax) of furosemide, an OAT1/OAT3 substrate, by 72% and 12%,|
04955|037|D|respectively.(1)|
04955|038|D|   OAT1/OAT3 substrates that prolong QT linked to this monograph include:|
04955|039|D|ciprofloxacin.(3)|
04955|040|B||
04955|041|R|REFERENCES:|
04955|042|B||
04955|043|R|1.Harliku (nitisinone) US prescribing information. Cycle Pharmaceuticals Ltd|1
04955|044|R|  June, 2025.|1
04955|045|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04955|046|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04955|047|R|  settings: a scientific statement from the American Heart Association and|6
04955|048|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04955|049|R|  2;55(9):934-47.|6
04955|050|R|3.This information is based on an extract from the Certara Drug Interaction|6
04955|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04956|001|T|MONOGRAPH TITLE:  Ubrogepant/Enasidenib|
04956|002|B||
04956|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04956|004|L|of severe adverse interaction.|
04956|005|B||
04956|006|A|MECHANISM OF ACTION:  Ubrogepant is a CYP3A4 and BCRP substrate.(1)|
04956|007|A|Enasidenib is a weak CYP3A4 inducer and BCRP inhibitor.(2)|
04956|008|B||
04956|009|E|CLINICAL EFFECTS:  Concurrent use of ubrogepant with enasidenib may lead to|
04956|010|E|increased or decreased levels and effectiveness of ubrogepant.(1)  The net|
04956|011|E|effect of enasidenib on ubrogepant is unknown.|
04956|012|B||
04956|013|P|PREDISPOSING FACTORS:  None determined.|
04956|014|B||
04956|015|M|PATIENT MANAGEMENT:  The manufacturer of ubrogepant does not have|
04956|016|M|recommendations for concurrent use with agents that are both weak CYP3A4|
04956|017|M|inducers and BCRP inhibitors.  Concurrent use should be avoided.(1)|
04956|018|M|   For concurrent use of ubrogepant with weak CYP3A4 inducers: The|
04956|019|M|manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant.|
04956|020|M|Initial dose of ubrogepant should be 100 mg.  If a second dose is needed,|
04956|021|M|the the dose of ubrogepant should be 100 mg.(1)|
04956|022|M|   For concurrent use of ubrogepant with BCRP inhibitors: The manufacturer|
04956|023|M|of ubrogepant recommends a dosage adjustment of ubrogepant.  The dose of|
04956|024|M|ubrogepant should not exceed 50 mg for initial dose.  If a second dose of|
04956|025|M|ubrogepant is needed, the dose should not exceed 50 mg.(1)|
04956|026|M|   For concurrent use of enasidenib with BCRP substrates: The manufacturer|
04956|027|M|of enasidenib states that concurrent use of BCRP substrates should be|
04956|028|M|avoided.  If concurrent use cannot be avoided, monitor for adverse events|
04956|029|M|more frequently and consider dose reduction of the BCRP substrate.(2)|
04956|030|B||
04956|031|D|DISCUSSION:  Ubrogepant is a substrate of CYP3A4 and the BCRP|
04956|032|D|transporter.(1)|
04956|033|D|   Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer,|
04956|034|D|resulted in an 80% reduction in ubrogepant exposure.  No dedicated drug|
04956|035|D|interaction studies were conducted to assess concomitant use with moderate|
04956|036|D|or weak CYP3A4 inducers.  Dose adjustment for concomitant use of ubrogepant|
04956|037|D|with moderate or weak CYP3A4 inducers is recommended based on a conservative|
04956|038|D|prediction of 50% reduction in exposure of ubrogepant.(1)|
04956|039|D|   Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant.|
04956|040|D|Clinical drug interaction studies with inhibitors of these transporters were|
04956|041|D|not conducted.  The US manufacturer of ubrogepant recommends dose adjustment|
04956|042|D|if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1)|
04956|043|B||
04956|044|R|REFERENCES:|
04956|045|B||
04956|046|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
04956|047|R|2.Idhifa (enasidenib) US prescribing information. Celgene Corporation|1
04956|048|R|  November, 2020.|1
04956|049|R|3.This information is based on an extract from the Certara Drug Interaction|6
04956|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04957|001|T|MONOGRAPH TITLE:  IV and IM Diclofenac/Anticoagulants|
04957|002|B||
04957|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04957|004|L|is contraindicated and generally should not be dispensed or administered to|
04957|005|L|the same patient.|
04957|006|B||
04957|007|A|MECHANISM OF ACTION:  The exact mechanism is unknown.  Diclofenac impairs|
04957|008|A|platelet function and may prolong bleeding time.(1-2)  Diclofenac also has|
04957|009|A|the potential to produce gastrointestinal ulceration and bleeding.(1-2)|
04957|010|B||
04957|011|E|CLINICAL EFFECTS:  Concurrent use of diclofenac and anticoagulants may|
04957|012|E|increase the risk of bleeding complications.(1-2)|
04957|013|B||
04957|014|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
04957|015|P|patients with disease-associated factors (e.g. thrombocytopenia).|
04957|016|P|   Drug associated risk factors include concurrent use of multiple drugs|
04957|017|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
04957|018|P|risk for bleeding (e.g. NSAIDs).|
04957|019|B||
04957|020|M|PATIENT MANAGEMENT:  The Middle East manufacturer of injectable diclofenac|
04957|021|M|states the use of intravenous diclofenac in patients on anticoagulants,|
04957|022|M|including low-dose heparin, is contraindicated.(1)|
04957|023|M|   The UK manufacturer of injectable diclofenac states the use of|
04957|024|M|intramuscular and intravenous diclofenac in patients on anticoagulants,|
04957|025|M|including low-dose heparin, is contraindicated.(2)|
04957|026|M|   The Israeli and Swedish manufacturers of injectable diclofenac advise|
04957|027|M|caution and close monitoring during concurrent use of anticoagulants.(3-4)|
04957|028|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
04957|029|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
04957|030|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
04957|031|M|patients with any symptoms.|
04957|032|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
04957|033|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
04957|034|M|anticoagulation in patients with active pathologic bleeding.|
04957|035|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
04957|036|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
04957|037|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
04957|038|M|and/or swelling.|
04957|039|M|   The time of highest risk for a coumarin-type drug interaction is when the|
04957|040|M|precipitant drug is initiated or discontinued. Contact the prescriber before|
04957|041|M|initiating, altering the dose or discontinuing either drug.|
04957|042|B||
04957|043|D|DISCUSSION:  Although clinical investigations do not appear to indicate that|
04957|044|D|diclofenac affects the action of anticoagulants, there are reports of an|
04957|045|D|increased risk of hemorrhage in patients receiving diclofenac and|
04957|046|D|anticoagulants concomitantly.(2)|
04957|047|D|   The Middle East and UK manufacturers of diclofenac state the use of|
04957|048|D|intravenous and intramuscular diclofenac in patients on anticoagulants,|
04957|049|D|including low-dose heparin, is contraindicated.(1-2)|
04957|050|B||
04957|051|R|REFERENCES:|
04957|052|B||
04957|053|R|1.Voltic (diclofenac sodium) ME prescribing information. Jamjoom|1
04957|054|R|  Pharmaceuticals Company Limited April, 2015.|1
04957|055|R|2.Akis (diclofenac sodium) UK summary of product characteristics. Flynn|1
04957|056|R|  Pharma Ltd February, 2023.|1
04957|057|R|3.Voltaren (diclofenac sodium) Swedish summary of product characteristic.|1
04957|058|R|  Novartis Sverige AB January, 2023.|1
04957|059|R|4.Abitren Teva (diclofenac sodium) Israeli Summary of Product|1
04957|060|R|  Characteristics. Teva Israel Ltd., March, 2023.|1
04958|001|T|MONOGRAPH TITLE:  Sebetralstat/Strong CYP3A4 Inhibitors|
04958|002|B||
04958|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04958|004|L|of severe adverse interaction.|
04958|005|B||
04958|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04958|007|A|sebetralstat.(1)|
04958|008|B||
04958|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04958|010|E|the levels and effects of sebetralstat including QTc prolongation, which may|
04958|011|E|result in potentially life-threatening cardiac arrhythmias like torsades de|
04958|012|E|pointes (TdP).(1)|
04958|013|B||
04958|014|P|PREDISPOSING FACTORS:  Child-Pugh class B or C hepatic impairment may|
04958|015|P|increase the risk for increased exposure to sebetralstat.  Sebetralstat|
04958|016|P|should be avoided in patients with severe hepatic impairment (Child-Pugh|
04958|017|P|class C).(1)|
04958|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04958|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04958|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04958|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04958|022|P|advanced age.(2)|
04958|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04958|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04958|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04958|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04958|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04958|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04958|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04958|030|B||
04958|031|M|PATIENT MANAGEMENT:  The manufacturer of sebetralstat states that|
04958|032|M|concomitant use with strong CYP3A4 inhibitors should be avoided.(1)|
04958|033|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04958|034|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04958|035|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04958|036|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04958|037|B||
04958|038|D|DISCUSSION:  Concomitant use of sebetralstat with itraconazole (200 mg once|
04958|039|D|daily for 6 days), a strong CYP3A4 inhibitor, increased sebetralstat maximum|
04958|040|D|concentration (Cmax) and area-under-curve (AUC) by 2.4-fold and 5.2-fold,|
04958|041|D|respectively.(1)|
04958|042|D|   In a study in healthy subjects, the largest mean increase in QTc interval|
04958|043|D|was 10.4 msec (upper confidence interval = 15.3 msec) after administration|
04958|044|D|of sebetralstat (2.5 times the maximum recommended dose).  The increase in|
04958|045|D|the QTc interval was concentration dependent.(1)|
04958|046|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, grapefruit,|
04958|047|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
04958|048|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
04958|049|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(3-4)|
04958|050|B||
04958|051|R|REFERENCES:|
04958|052|B||
04958|053|R|1.Ekterly (sebetralstat) US prescribing information. KalVista|1
04958|054|R|  Pharmaceuticals, Inc. 07/2025.|1
04958|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04958|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04958|057|R|  settings: a scientific statement from the American Heart Association and|6
04958|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04958|059|R|  2;55(9):934-47.|6
04958|060|R|3.This information is based on an extract from the Certara Drug Interaction|6
04958|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04958|062|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04958|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04958|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04958|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04958|066|R|  11/14/2017.|1
04959|001|T|MONOGRAPH TITLE:  Sebetralstat/Moderate CYP3A4 Inhibitors|
04959|002|B||
04959|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04959|004|L|take action as needed.|
04959|005|B||
04959|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04959|007|A|of sebetralstat.(1)|
04959|008|B||
04959|009|E|CLINICAL EFFECTS:  Concurrent use of CYP3A4 inhibitors may increase the|
04959|010|E|levels and effects of sebetralstat including QTc prolongation, which may|
04959|011|E|result in potentially life-threatening cardiac arrhythmias like torsades de|
04959|012|E|pointes (TdP).(1)|
04959|013|B||
04959|014|P|PREDISPOSING FACTORS:  Child-Pugh class B or C hepatic impairment may|
04959|015|P|increase the risk for increased exposure to sebetralstat.  Sebetralstat|
04959|016|P|should be avoided in patients with severe hepatic impairment (Child-Pugh|
04959|017|P|class C).(1)|
04959|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04959|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04959|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04959|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04959|022|P|advanced age.(2)|
04959|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04959|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04959|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04959|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04959|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04959|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04959|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04959|030|B||
04959|031|M|PATIENT MANAGEMENT:  The manufacturer of sebetralstat states when used|
04959|032|M|concomitantly with moderate CYP3A4 inhibitors, reduce the dose of|
04959|033|M|sebetralstat to one dose of 300 mg (one tablet) orally at the earliest|
04959|034|M|recognition of a hereditary angioedema attack.  A second dose of 300 mg (one|
04959|035|M|tablet) may be taken at least 3 hours after the first dose if response is|
04959|036|M|inadequate, or if symptoms worsen or recur.(1)|
04959|037|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04959|038|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04959|039|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04959|040|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04959|041|B||
04959|042|D|DISCUSSION:  Concomitant use of sebetralstat with verapamil (240 mg once|
04959|043|D|daily for 6 days), a moderate CYP3A4 inhibitor, increased sebetralstat|
04959|044|D|maximum concentration (Cmax) and area-under-curve (AUC) by 1.8-fold and|
04959|045|D|2-fold, respectively.(1)|
04959|046|D|   In a study in healthy subjects, the largest mean increase in QTc interval|
04959|047|D|was 10.4 msec (upper confidence interval = 15.3 msec) after administration|
04959|048|D|of sebetralstat (2.5 times the maximum recommended dose).  The increase in|
04959|049|D|the QTc interval was concentration dependent.(1)|
04959|050|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04959|051|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir,|
04959|052|D|diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant,|
04959|053|D|imatinib, isavuconazonium, lenacapavir, letermovir, netupitant,|
04959|054|D|rilzabrutinib, schisandra, tofisopam, treosulfan, verapamil, voxelotor.(3-4)|
04959|055|B||
04959|056|R|REFERENCES:|
04959|057|B||
04959|058|R|1.Ekterly (sebetralstat) US prescribing information. KalVista|1
04959|059|R|  Pharmaceuticals, Inc. 07/2025.|1
04959|060|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04959|061|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04959|062|R|  settings: a scientific statement from the American Heart Association and|6
04959|063|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04959|064|R|  2;55(9):934-47.|6
04959|065|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04959|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04959|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04959|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04959|069|R|  11/14/2017.|1
04959|070|R|4.This information is based on an extract from the Certara Drug Interaction|6
04959|071|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04960|001|T|MONOGRAPH TITLE:  Sebetralstat/Strong CYP3A4 Inducers|
04960|002|B||
04960|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04960|004|L|of severe adverse interaction.|
04960|005|B||
04960|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may accelerate the metabolism|
04960|007|A|of sebetralstat by CYP3A4.(1)|
04960|008|B||
04960|009|E|CLINICAL EFFECTS:  The concurrent use of sebetralstat and strong CYP3A4|
04960|010|E|inducers may result in decreased levels and effectiveness of|
04960|011|E|sebetralstat.(1)|
04960|012|B||
04960|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04960|014|P|of the inducer for longer than 1-2 weeks.|
04960|015|B||
04960|016|M|PATIENT MANAGEMENT:  The manufacturer of sebetralstat states that the|
04960|017|M|concurrent use of strong CYP3A4 inducers should be avoided.(1)|
04960|018|B||
04960|019|D|DISCUSSION:  Sebetralstat maximum concentration (Cmax) decreased by 66% and|
04960|020|D|area-under-curve (AUC) decreased by 83% following concomitant administration|
04960|021|D|with phenytoin (a strong CYP3A4 inducer) 100 mg three times daily for 15|
04960|022|D|days.(1)|
04960|023|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04960|024|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04960|025|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04960|026|D|rifampin, rifapentine, and St. John's Wort.(2)|
04960|027|B||
04960|028|R|REFERENCES:|
04960|029|B||
04960|030|R|1.Ekterly (sebetralstat) US prescribing information. KalVista|1
04960|031|R|  Pharmaceuticals, Inc. 07/2025.|1
04960|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
04960|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04961|001|T|MONOGRAPH TITLE:  Sebetralstat/Moderate CYP3A4 Inducers|
04961|002|B||
04961|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04961|004|L|of severe adverse interaction.|
04961|005|B||
04961|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may accelerate the metabolism|
04961|007|A|of sebetralstat by CYP3A4.(1)|
04961|008|B||
04961|009|E|CLINICAL EFFECTS:  The concurrent use of sebetralstat and a moderate CYP3A4|
04961|010|E|inducer may result in decreased levels and effectiveness of sebetralstat.(1)|
04961|011|B||
04961|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04961|013|P|of the inducer for longer than 1-2 weeks.|
04961|014|B||
04961|015|M|PATIENT MANAGEMENT:  The manufacturer of sebetralstat states that the|
04961|016|M|concurrent use of moderate CYP3A4 inducers should be avoided.(1)|
04961|017|B||
04961|018|D|DISCUSSION:  Sebetralstat maximum concentration (Cmax) decreased by 63% and|
04961|019|D|area-under-curve (AUC) decreased by 79% following concomitant administration|
04961|020|D|with efavirenz (a moderate CYP3A4 inducer) 600 mg once daily for 14 days.|
04961|021|D|   Moderate inducers of CYP3A4 include:  belzutifan, bosentan, cenobamate,|
04961|022|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
04961|023|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
04961|024|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
04961|025|D|thioridazine, and tovorafenib.(2)|
04961|026|B||
04961|027|R|REFERENCES:|
04961|028|B||
04961|029|R|1.Ekterly (sebetralstat) US prescribing information. KalVista|1
04961|030|R|  Pharmaceuticals, Inc. 07/2025.|1
04961|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
04961|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04962|001|T|MONOGRAPH TITLE:  Doxepin/Selected Strong CYP2D6 Inhibitors|
04962|002|B||
04962|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04962|004|L|take action as needed.|
04962|005|B||
04962|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
04962|007|A|doxepin.(1)|
04962|008|B||
04962|009|E|CLINICAL EFFECTS:  Concurrent use of doxepin and strong CYP2D6 inhibitors|
04962|010|E|may increase levels of doxepin and the risk for toxicities, including|
04962|011|E|anticholinergic, sedative, alpha-blocking effects, and seizures.(1-2)|
04962|012|B||
04962|013|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
04962|014|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
04962|015|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
04962|016|P|cocaine, or stimulants; use of over-the-counter stimulants and anorectics;|
04962|017|P|diabetics treated with oral hypoglycemics or insulin; or with concomitant|
04962|018|P|medications known to lower seizure threshold (antipsychotics, theophylline,|
04962|019|P|systemic steroids).|
04962|020|P|   The risk of anticholinergic toxicities including cognitive decline,|
04962|021|P|delirium, falls and fractures is increased in geriatric patients using more|
04962|022|P|than one medicine with anticholinergic properties.(2)|
04962|023|B||
04962|024|M|PATIENT MANAGEMENT:  The US manufacturer of doxepin states if concurrent use|
04962|025|M|of doxepin and strong CYP2D6 inhibitors is warranted, monitor doxepin plasma|
04962|026|M|concentrations and reduce the doxepin dose based on plasma|
04962|027|M|concentrations.(1)|
04962|028|B||
04962|029|D|DISCUSSION:  Doxepin is a CYP2D6 substrate and concomitant use with strong|
04962|030|D|CYP2D6 inhibitors may increase doxepin exposures.(1)|
04962|031|D|   Selected strong CYP2D6 inhibitors linked include: dacomitinib.(3,4)|
04962|032|B||
04962|033|R|REFERENCES:|
04962|034|B||
04962|035|R|1.Sinequan (doxepin) US prescribing information. Pfizer July, 2025.|1
04962|036|R|2.American Geriatrics Society 2023 updated AGS Beers Criteria for|6
04962|037|R|  potentially  inappropriate medication use in older adults. J Am Geriatr|6
04962|038|R|  Soc 2023 Jul;71(7):2052-2081.|6
04962|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
04962|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04962|041|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04962|042|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04962|043|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04962|044|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04962|045|R|  11/14/2017.|1
04963|001|T|MONOGRAPH TITLE:  Sebetralstat/Strong CYP3A4 Inhibitors that Prolong QT|
04963|002|B||
04963|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04963|004|L|of severe adverse interaction.|
04963|005|B||
04963|006|A|MECHANISM OF ACTION:  Strong inhibitors of CYP3A4 that prolong QT may|
04963|007|A|inhibit the metabolism of sebetralstat and result in additive effects on the|
04963|008|A|QTc interval.(1,2)|
04963|009|B||
04963|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may result in|
04963|011|E|increased levels and effects of sebetralstat including additive QTc|
04963|012|E|prolongation, which may result in potentially life-threatening cardiac|
04963|013|E|arrhythmias like torsades de pointes (TdP).(1)|
04963|014|B||
04963|015|P|PREDISPOSING FACTORS:  Child-Pugh class B or C hepatic impairment may|
04963|016|P|increase the risk for increased exposure to sebetralstat.  Sebetralstat|
04963|017|P|should be avoided in patients with severe hepatic impairment (Child-Pugh|
04963|018|P|class C).(1)|
04963|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04963|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04963|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04963|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04963|023|P|advanced age.(2)|
04963|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04963|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04963|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04963|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04963|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04963|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04963|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04963|031|B||
04963|032|M|PATIENT MANAGEMENT:  The manufacturer of sebetralstat states that|
04963|033|M|concomitant use with strong CYP3A4 inhibitors should be avoided.(1)|
04963|034|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04963|035|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04963|036|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04963|037|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04963|038|B||
04963|039|D|DISCUSSION:  Concomitant use of sebetralstat with itraconazole (200 mg once|
04963|040|D|daily for 6 days), a strong CYP3A4 inhibitor, increased sebetralstat maximum|
04963|041|D|concentration (Cmax) and area-under-curve (AUC) by 2.4-fold and 5.2-fold,|
04963|042|D|respectively.(1)|
04963|043|D|   In a study in healthy subjects, the largest mean increase in QTc interval|
04963|044|D|was 10.4 msec (upper confidence interval = 15.3 msec) after administration|
04963|045|D|of sebetralstat (2.5 times the maximum recommended dose).  The increase in|
04963|046|D|the QTc interval was concentration dependent.(1)|
04963|047|D|   Strong CYP3A4 inhibitors that prolong the QT interval linked to this|
04963|048|D|monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole,|
04963|049|D|lonafarnib, lopinavir-ritonavir, posaconazole, ribociclib, saquinavir,|
04963|050|D|telithromycin, and voriconazole.(3,4)|
04963|051|B||
04963|052|R|REFERENCES:|
04963|053|B||
04963|054|R|1.Ekterly (sebetralstat) US prescribing information. KalVista|1
04963|055|R|  Pharmaceuticals, Inc. 07/2025.|1
04963|056|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04963|057|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04963|058|R|  settings: a scientific statement from the American Heart Association and|6
04963|059|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04963|060|R|  2;55(9):934-47.|6
04963|061|R|3.This information is based on an extract from the Certara Drug Interaction|6
04963|062|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04963|063|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04963|064|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04963|065|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04963|066|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04963|067|R|  11/14/2017.|1
04964|001|T|MONOGRAPH TITLE:  Sebetralstat/Moderate CYP3A4 Inhibitors that Prolong QT|
04964|002|B||
04964|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04964|004|L|take action as needed.|
04964|005|B||
04964|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong QT may|
04964|007|A|inhibit the metabolism of sebetralstat and result in additive effects on the|
04964|008|A|QTc interval.(1,2)|
04964|009|B||
04964|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may result|
04964|011|E|in increased levels and effects of sebetralstat including additive QTc|
04964|012|E|prolongation, which may result in potentially life-threatening cardiac|
04964|013|E|arrhythmias like torsades de pointes.(1)|
04964|014|B||
04964|015|P|PREDISPOSING FACTORS:  Child-Pugh class B or C hepatic impairment may|
04964|016|P|increase the risk for increased exposure to sebetralstat.  Sebetralstat|
04964|017|P|should be avoided in patients with severe hepatic impairment (Child-Pugh|
04964|018|P|class C).(1)|
04964|019|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04964|020|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04964|021|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04964|022|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04964|023|P|advanced age.(2)|
04964|024|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04964|025|P|higher systemic concentrations of either QT prolonging drug are additional|
04964|026|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04964|027|P|drug concentrations include rapid infusion of an intravenous dose or|
04964|028|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04964|029|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04964|030|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04964|031|B||
04964|032|M|PATIENT MANAGEMENT:  The manufacturer of sebetralstat states when used|
04964|033|M|concomitantly with moderate CYP3A4 inhibitors, reduce the dose of|
04964|034|M|sebetralstat to one dose of 300 mg (one tablet) orally at the earliest|
04964|035|M|recognition of a hereditary angioedema attack.  A second dose of 300 mg (one|
04964|036|M|tablet) may be taken at least 3 hours after the first dose if response is|
04964|037|M|inadequate, or if symptoms worsen or recur.(1)|
04964|038|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04964|039|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04964|040|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04964|041|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04964|042|B||
04964|043|D|DISCUSSION:  Concomitant use of sebetralstat with verapamil (240 mg once|
04964|044|D|daily for 6 days), a moderate CYP3A4 inhibitor, increased sebetralstat|
04964|045|D|maximum concentration (Cmax) and area-under-curve (AUC) by 1.8-fold and|
04964|046|D|2-fold, respectively.(1)|
04964|047|D|   In a study in healthy subjects, the largest mean increase in QTc interval|
04964|048|D|was 10.4 msec (upper confidence interval = 15.3 msec) after administration|
04964|049|D|of sebetralstat (2.5 times the maximum recommended dose).  The increase in|
04964|050|D|the QTc interval was concentration dependent.(1)|
04964|051|D|   Moderate CYP3A4 inhibitors that prolong QT include: crizotinib,|
04964|052|D|dronedarone, erythromycin, fluconazole, lefamulin, and nilotinib.(3-4)|
04964|053|B||
04964|054|R|REFERENCES:|
04964|055|B||
04964|056|R|1.Ekterly (sebetralstat) US prescribing information. KalVista|1
04964|057|R|  Pharmaceuticals, Inc. 07/2025.|1
04964|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04964|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04964|060|R|  settings: a scientific statement from the American Heart Association and|6
04964|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04964|062|R|  2;55(9):934-47.|6
04964|063|R|3.This information is based on an extract from the Certara Drug Interaction|6
04964|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04964|065|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04964|066|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04964|067|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04964|068|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04964|069|R|  11/14/2017.|1
04965|001|T|MONOGRAPH TITLE:  Sunvozertinib/Strong CYP3A4 Inhibitors|
04965|002|B||
04965|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04965|004|L|of severe adverse interaction.|
04965|005|B||
04965|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
04965|007|A|the metabolism of sunvozertinib.(1)|
04965|008|B||
04965|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04965|010|E|levels of and effects from sunvozertinib, including interstitial lung|
04965|011|E|disease, gastrointestinal adverse reactions, dermatologic adverse reactions,|
04965|012|E|or ocular toxicity.(1)|
04965|013|B||
04965|014|P|PREDISPOSING FACTORS:  None determined.|
04965|015|B||
04965|016|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
04965|017|M|undergoing therapy with sunvozertinib.(1)  Consider alternatives with no or|
04965|018|M|minimal enzyme inhibition.|
04965|019|M|   If concurrent therapy with sunvozertinib is required, decrease the dose|
04965|020|M|of sunvozertinib from 200 mg to 150 mg.(1)|
04965|021|M|   After discontinuing the CYP3A4 inhibitor, the prior sunvozertinib dose|
04965|022|M|can be resumed after 3 to 5 half-lives of the CYP3A4 inhibitor.(1)|
04965|023|B||
04965|024|D|DISCUSSION:  Co-administration of sunvozertinib with a strong CYP3A4|
04965|025|D|inhibitor, itraconazole, increased sunvozertinib area-under-curve (AUC) and|
04965|026|D|maximum concentration (Cmax) by 1.5-fold and 1.3-fold.(1)|
04965|027|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
04965|028|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
04965|029|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir,|
04965|030|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
04965|031|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
04965|032|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)|
04965|033|B||
04965|034|R|REFERENCES:|
04965|035|B||
04965|036|R|1.Zegfrovy (sunvozertinib) US prescribing information. Digal (Jiangsu)|1
04965|037|R|  Pharmaceutical Co., Ltd. July 2025.|1
04965|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04965|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04965|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04965|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04965|042|R|  11/14/2017.|1
04965|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
04965|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04966|001|T|MONOGRAPH TITLE:  Sunvozertinib/Strong CYP3A4 Inducers|
04966|002|B||
04966|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04966|004|L|of severe adverse interaction.|
04966|005|B||
04966|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04966|007|A|sunvozertinib.(1)|
04966|008|B||
04966|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong CYP3A4 inducer may|
04966|010|E|result in decreased levels and effectiveness of sunvozertinib.(1)|
04966|011|B||
04966|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04966|013|P|of the inducer for longer than 1-2 weeks.|
04966|014|B||
04966|015|M|PATIENT MANAGEMENT:  The manufacturer of sunvozertinib states that|
04966|016|M|concomitant use of strong CYP3A4 inducers should be avoided.(1)|
04966|017|M|   If concurrent use cannot be avoided, increase sunvozertinib dose from 200|
04966|018|M|mg to 400 mg.(1)|
04966|019|M|   After stopping the CYP3A4 inducer, resume the prior sunvozertinib dose|
04966|020|M|7-14 days after stopping the CYP3A4 inducer.(1)|
04966|021|B||
04966|022|D|DISCUSSION:  Sunvozertinib is primarily metabolized by CYP3A4.(1)|
04966|023|D|   Concomitant administration of sunvozertinib with a strong inducer|
04966|024|D|(carbamazepine) resulted in a decrease in sunvozertinib area under the curve|
04966|025|D|(AUC) and maximum concentration (Cmax) by 48% and 38%, respectively.(1)|
04966|026|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04966|027|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04966|028|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04966|029|D|rifampin, rifapentine, and St. John's wort.(2)|
04966|030|B||
04966|031|R|REFERENCES:|
04966|032|B||
04966|033|R|1.Zegfrovy (sunvozertinib) US prescribing information. Digal (Jiangsu)|1
04966|034|R|  Pharmaceutical Co., Ltd. July 2025.|1
04966|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
04966|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04967|001|T|MONOGRAPH TITLE:  Hormonal Contraceptives/Sunvozertinib|
04967|002|B||
04967|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04967|004|L|of severe adverse interaction.|
04967|005|B||
04967|006|A|MECHANISM OF ACTION:  Sunvozertinib is a weak CYP3A4 inducer.|
04967|007|A|Coadministration of sunvozertinib with hormonal contraceptives may lead to|
04967|008|A|contraceptive failure or an increase in breakthrough bleeding due to|
04967|009|A|decreased hormonal concentrations.(1)|
04967|010|B||
04967|011|E|CLINICAL EFFECTS:  Concurrent use of sunvozertinib may reduce the|
04967|012|E|effectiveness of hormonal contraceptives, except for intrauterine systems|
04967|013|E|containing levonorgestrel.(1)|
04967|014|B||
04967|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04967|016|P|of the inducer for longer than 1-2 weeks.|
04967|017|B||
04967|018|M|PATIENT MANAGEMENT:  The manufacturer of sunvozertinib states to avoid|
04967|019|M|concomitant use with hormonal contraceptives. Use a non-hormonal|
04967|020|M|contraceptive during treatment and for 2 weeks after the last dose.(1)|
04967|021|M|   Women of reproductive age should be counseled to use highly effective|
04967|022|M|contraception due to the risk of fetal harm with sunvozertinib.|
04967|023|M|   Women of reproductive age should be counseled not to rely on hormonal|
04967|024|M|contraceptives (including oral, implantable, injectable, or transdermal|
04967|025|M|agents) for contraception because they may not be effective.(1)|
04967|026|M|   For emergency contraception, the UK's Medicines & Healthcare Products|
04967|027|M|Regulatory Agency (MHRA) recommends that women who have used a CYP3A4|
04967|028|M|inducer in the previous 4 weeks should consider a non-hormonal emergency|
04967|029|M|contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive|
04967|030|M|is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.|
04967|031|M|Advise the patient to have a pregnancy test to exclude pregnancy after use|
04967|032|M|and to seek medical advice if she does become pregnant.(2)|
04967|033|B||
04967|034|D|DISCUSSION:  Sunvozertinib is a weak CYP3A4 inducer.(1)|
04967|035|D|   Coadministration of sunvozertinib with midazolam (a CYP3A4 substrate)|
04967|036|D|decreased the concentration maximum (Cmax) and area-under-curve (AUC) of|
04967|037|D|midazolam by 15% and 23%, respectively.(1)|
04967|038|B||
04967|039|R|REFERENCES:|
04967|040|B||
04967|041|R|1.Zegfrovy (sunvozertinib) US prescribing information. Digal (Jiangsu)|1
04967|042|R|  Pharmaceutical Co., Ltd. July 2025.|1
04967|043|R|2.Medicines and Healthcare products Regulatory Agency.|1
04967|044|R|  Levonorgestrel-containing emergency hormonal contraception: advice on|1
04967|045|R|  interactions with hepatic enzyme inducers and contraceptive efficacy.|1
04967|046|R|  available at:|1
04967|047|R|  https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-|1
04967|048|R|  hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers|1
04967|049|R|  -and-contraceptive-efficacy September 15, 2016..|1
04968|001|T|MONOGRAPH TITLE:  Stiripentol/Carbamazepine|
04968|002|B||
04968|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04968|004|L|of severe adverse interaction.|
04968|005|B||
04968|006|A|MECHANISM OF ACTION:  Stiripentol is a substrate of CYP3A4 and CYP2C19.|
04968|007|A|Strong inducers of CYP3A4 or CYP2C19 may increase the metabolism of|
04968|008|A|stiripentol.(1)  Carbamazepine is a strong CYP3A4 and CYP2C19 inducer.(2)|
04968|009|A|   Carbamazepine is a substrate of CYP3A4.  Inhibitors of CYP3A4 may inhibit|
04968|010|A|the hepatic metabolism of carbamazepine.(2,3)  Stiripentol is a moderate|
04968|011|A|inhibitor of CYP3A4.(4)|
04968|012|B||
04968|013|E|CLINICAL EFFECTS:  The concurrent administration of strong CYP3A4 or CYP2C19|
04968|014|E|inducers may result in decreased levels and effectiveness of stiripentol.(1)|
04968|015|E|   Increased serum carbamazepine levels with subsequent increases in the|
04968|016|E|pharmacological and toxic effects of carbamazepine, including dizziness,|
04968|017|E|ataxia, blurred vision, or SIADH.(2)|
04968|018|B||
04968|019|P|PREDISPOSING FACTORS:  Simultaneous use of other drugs, i.e. other|
04968|020|P|anticonvulsants, or carbamazepine blood levels already near the toxic range|
04968|021|P|before initiation of a CYP3A4 inhibitor may increase the risk of a severe|
04968|022|P|interaction.|
04968|023|B||
04968|024|M|PATIENT MANAGEMENT:  The manufacturer of stiripentol states avoid the|
04968|025|M|concurrent use of stiripentol with strong CYP3A4 or strong CYP2C19|
04968|026|M|inducers.(1)|
04968|027|M|   If concurrent therapy cannot be avoided, consider a dose adjustment of|
04968|028|M|stiripentol based on clinical monitoring and plasma levels.(1)|
04968|029|M|   The manufacturer of carbamazepine states CYP3A4 inhibitors may increase|
04968|030|M|plasma carbamazepine levels.  If concurrent use is warranted, close|
04968|031|M|monitoring of carbamazepine levels is indicated and dosage adjustment may be|
04968|032|M|required.(2)|
04968|033|M|   In patients receiving concurrent therapy with carbamazepine and a CYP3A4|
04968|034|M|inhibitor, carbamazepine levels should be monitored closely and the patient|
04968|035|M|observed for signs of toxicity (dizziness, ataxia, blurred vision, or|
04968|036|M|SIADH).  The dosage of carbamazepine may need to be adjusted or|
04968|037|M|carbamazepine may need to be discontinued.(2)|
04968|038|B||
04968|039|D|DISCUSSION:  Stiripentol is a substrate of CYP3A4 and CYP2C19.(1)|
04968|040|D|   Carbamazepine is almost completely metabolized to|
04968|041|D|carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged.|
04968|042|D|Pharmacokinetic studies have indicated the major pathway for carbamazepine|
04968|043|D|metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and|
04968|044|D|CYP3A5.(2,3)|
04968|045|B||
04968|046|R|REFERENCES:|
04968|047|B||
04968|048|R|1.Diacomit (stiripentol) UK summary of product characteristics. Biocodex|1
04968|049|R|  March, 2007.|1
04968|050|R|2.Tegretol (carbamazepine) US prescribing information. Novartis|1
04968|051|R|  Pharmaceuticals Corporation September, 2023.|1
04968|052|R|3.Thorn CF, Leckband SG, Kelsoe J, Leeder JS, MAller DJ, Klein TE, Altman|6
04968|053|R|  RB. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011|6
04968|054|R|  Dec;21(12):906-10.|6
04968|055|R|4.This information is based on an extract from the Certara Drug Interaction|6
04968|056|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04968|057|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04968|058|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04968|059|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04968|060|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04968|061|R|  11/14/2017.|1
04969|001|T|MONOGRAPH TITLE:  Sunvozertinib/Moderate CYP3A4 Inducers|
04969|002|B||
04969|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04969|004|L|of severe adverse interaction.|
04969|005|B||
04969|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
04969|007|A|sunvozertinib.(1)|
04969|008|B||
04969|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate CYP3A4 inducer may|
04969|010|E|result in decreased levels and effectiveness of sunvozertinib.(1)|
04969|011|B||
04969|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04969|013|P|of the inducer for longer than 1-2 weeks.|
04969|014|B||
04969|015|M|PATIENT MANAGEMENT:  The manufacturer of sunvozertinib states that|
04969|016|M|concomitant use of moderate CYP3A4 inducers should be avoided.(1)|
04969|017|M|   If concurrent use cannot be avoided, increase sunvozertinib dose from 200|
04969|018|M|mg to 400 mg.(1)|
04969|019|M|   After stopping the CYP3A4 inducer, resume the prior sunvozertinib dose|
04969|020|M|7-14 days after stopping the CYP3A4 inducer.(1)|
04969|021|B||
04969|022|D|DISCUSSION:  Sunvozertinib is primarily metabolized by CYP3A4.(1)|
04969|023|D|   Concomitant administration of sunvozertinib with a strong inducer|
04969|024|D|(carbamazepine) resulted in a decrease in sunvozertinib area under the curve|
04969|025|D|(AUC) and maximum concentration (Cmax) by 48% and 38%, respectively.(1)|
04969|026|D|   Sunvozertinib's AUC is predicted to decrease 44% with concurrent|
04969|027|D|administration of efavirenz (600 mg daily; moderate CYP3A4 inducer).(1)|
04969|028|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
04969|029|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
04969|030|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
04969|031|D|pacritinib, pexidartinib, rifabutin, repotrectinib, sotorasib, telotristat|
04969|032|D|ethyl, thioridazine, and tovorafenib.(2)|
04969|033|B||
04969|034|R|REFERENCES:|
04969|035|B||
04969|036|R|1.Zegfrovy (sunvozertinib) US prescribing information. Digal (Jiangsu)|1
04969|037|R|  Pharmaceutical Co., Ltd. July 2025.|1
04969|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
04969|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04970|001|T|MONOGRAPH TITLE:  Cladribine Oncology Inj/Immunosuppressives;|
04970|002|T|Immunomodulators|
04970|003|B||
04970|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04970|005|L|take action as needed.|
04970|006|B||
04970|007|A|MECHANISM OF ACTION:  Cladribine in combination with immunosuppressives and|
04970|008|A|immune-modulators all suppress the immune system.(1-4)|
04970|009|B||
04970|010|E|CLINICAL EFFECTS:  Concurrent use of cladribine with immunosuppressive or|
04970|011|E|immune-modulating agents may result in an increased risk of serious|
04970|012|E|infections.(1-4)|
04970|013|B||
04970|014|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
04970|015|P|immunosuppressive or immune-modulating medications.|
04970|016|B||
04970|017|M|PATIENT MANAGEMENT:  Recommendations for cladribine regarding this|
04970|018|M|interaction differ between regulatory approving agencies.|
04970|019|M|   The cladribine US, UK, and Australian prescribing information state:|
04970|020|M|   -Caution should be exercised if cladribine injection is administered|
04970|021|M|before, after, or in conjunction with other drugs known to cause|
04970|022|M|immunosuppression or myelosuppression.(1-3)|
04970|023|M|   The cladribine Canadian prescribing information states:|
04970|024|M|   -Proceed carefully in patients with severe bone marrow impairment of any|
04970|025|M|etiology since further suppression of bone marrow function should be|
04970|026|M|anticipated.(4)|
04970|027|B||
04970|028|D|DISCUSSION:  Severe bone marrow suppression, including neutropenia, anemia|
04970|029|D|and thrombocytopenia, has been commonly observed in patients treated with|
04970|030|D|cladribine injection, especially at high doses.(1-4)|
04970|031|B||
04970|032|R|REFERENCES:|
04970|033|B||
04970|034|R|1.Cladribine US prescribing information. Fresenius Kabi USA, LLC. October|1
04970|035|R|  2024.|1
04970|036|R|2.Leustat (cladribine) UK prescribing information. Atnahs Pharma UK Ltd.|1
04970|037|R|  February 2025.|1
04970|038|R|3.Leustatin (cladribine) Australian prescribing information. Atnahs Pharma|1
04970|039|R|  Australia Pty Ltd. June 2022.|1
04970|040|R|4.Cladribine Canadian prescribing information. Generic Medical Partners Inc.|1
04970|041|R|  December 2019.|1
04971|001|T|MONOGRAPH TITLE:  Dabrafenib/Strong CYP3A4 Inducers|
04971|002|B||
04971|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04971|004|L|take action as needed.|
04971|005|B||
04971|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04971|007|A|dabrafenib.(1-4)|
04971|008|B||
04971|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04971|010|E|may decrease the levels and effectiveness of dabrafenib.(1-4)|
04971|011|B||
04971|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04971|013|P|of the inducer for longer than 1-2 weeks.|
04971|014|B||
04971|015|M|PATIENT MANAGEMENT:  Recommendations for management of this interaction vary|
04971|016|M|in different regions.|
04971|017|M|   The Australian, Canadian, and UK manufacturers of dabrafenib state that|
04971|018|M|co-administration with strong inducers of CYP3A4 should be avoided due to|
04971|019|M|the possibility of subtherapeutic exposure to dabrafenib.  Monitor patients|
04971|020|M|for loss of efficacy or consider the use of alternative medicinal|
04971|021|M|products.(1-3)|
04971|022|M|   The US manufacturer of dabrafenib does not provide recommendations with|
04971|023|M|strong inducers of CYP3A4.(4)|
04971|024|B||
04971|025|D|DISCUSSION:  Concurrent use of rifampin (a strong CYP3A4 inducer) 600 mg|
04971|026|D|once daily and dabrafenib 150 mg twice daily resulted in a decrease in|
04971|027|D|repeat-dose dabrafenib maximum concentration (Cmax) by 27% and|
04971|028|D|area-under-curve (AUC) by 34%.  No relevant change in AUC was noted for|
04971|029|D|hydroxy-dabrafenib.  There was an increase in AUC of 73% for|
04971|030|D|carboxy-dabrafenib and a decrease in AUC of 30% for|
04971|031|D|desmethyl-dabrafenib.(1-4)|
04971|032|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04971|033|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04971|034|D|ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifamycins, and St.|
04971|035|D|John's Wort.(5-6)|
04971|036|B||
04971|037|R|REFERENCES:|
04971|038|B||
04971|039|R|1.Tafinlar (dabrafenib) Australian prescribing information. Novartis|1
04971|040|R|  Pharmaceuticals Australia Pty Limited October, 2024.|1
04971|041|R|2.Tafinlar (dabrafenib) UK summary of product characteristics. Novartis|1
04971|042|R|  Pharmaceuticals UK Ltd January 11, 2021.|1
04971|043|R|3.Tafinlar (dabrafenib) Canadian prescribing information. Novartis|1
04971|044|R|  Pharmaceuticals Canada Inc. January. 2024.|1
04971|045|R|4.Tafinlar (dabrafenib) US prescribing information. Novartis Pharmaceuticals|1
04971|046|R|  Corporation May, 2023.|1
04971|047|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04971|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04971|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04971|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04971|051|R|  11/14/2017.|1
04971|052|R|6.This information is based on an extract from the Certara Drug Interaction|6
04971|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04972|001|T|MONOGRAPH TITLE:  Dapoxetine (Greater Than 30 mg)/Moderate CYP3A4 Inhibitors|
04972|002|B||
04972|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04972|004|L|is contraindicated and generally should not be dispensed or administered to|
04972|005|L|the same patient.|
04972|006|B||
04972|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04972|008|A|of dapoxetine.(1-3)|
04972|009|B||
04972|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04972|011|E|result in elevated levels and increased effects of dapoxetine.(1-3)|
04972|012|B||
04972|013|P|PREDISPOSING FACTORS:  If the patient is a CYP2D6 poor metabolizer,|
04972|014|P|dapoxetine metabolism can be further inhibited.(1-3)|
04972|015|B||
04972|016|M|PATIENT MANAGEMENT:  The manufacturers of dapoxetine state that the dose of|
04972|017|M|dapoxetine should not exceed 30 mg daily if coadministered with moderate|
04972|018|M|CYP3A4 inhibitors.(1-3)|
04972|019|B||
04972|020|D|DISCUSSION:  The impact of moderate CYP3A4 inhibitors on the|
04972|021|D|pharmacokinetics of dapoxetine has not been investigated in clinical|
04972|022|D|studies.(1-3)|
04972|023|D|   Ketoconazole (200 mg twice daily for 7 days), a strong inhibitor of|
04972|024|D|CYP3A4, increased the maximum concentration (Cmax) and area-under-curve|
04972|025|D|(AUC) of a single dose of dapoxetine (30 mg) by 35% and 99%, respectively.|
04972|026|D|The Cmax and AUC of the active fraction are expected to increase by 25% and|
04972|027|D|2-fold, respectively, with strong inhibitors of CYP3A4.(1-3)|
04972|028|D|   Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir,|
04972|029|D|aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan,|
04972|030|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
04972|031|D|fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib,|
04972|032|D|isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant,|
04972|033|D|nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam,|
04972|034|D|treosulfan, verapamil, and voxelotor.(4,5)|
04972|035|B||
04972|036|R|REFERENCES:|
04972|037|B||
04972|038|R|1.Priligy (dapoxetine hydrochloride) Australian prescribing information.|1
04972|039|R|  Ortho-McNeil Pharmaceutical March 19, 2013.|1
04972|040|R|2.Priligy (dapoxetine hydrochloride) UK summary of product characteristics.|1
04972|041|R|  A. Menarini Farmaceutica Internazionale SRL April 15, 2014.|1
04972|042|R|3.Evoka (dapoxetine hydrochloride) Middle East prescribing information.|1
04972|043|R|  Middle East Pharmaceutical Industries Co. Ltd (Avalon-Pharma) April, 2024.|1
04972|044|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04972|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04972|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04972|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04972|048|R|  11/14/2017.|1
04972|049|R|5.This information is based on an extract from the Certara Drug Interaction|6
04972|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04973|001|T|MONOGRAPH TITLE:  Dapoxetine (Less Than or Equal To 30 mg)/Moderate CYP3A4|
04973|002|T|Inhibitors|
04973|003|B||
04973|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04973|005|L|take action as needed.|
04973|006|B||
04973|007|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04973|008|A|of dapoxetine.(1-3)|
04973|009|B||
04973|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
04973|011|E|result in elevated levels and increased effects of dapoxetine.(1-3)|
04973|012|B||
04973|013|P|PREDISPOSING FACTORS:  If the patient is a CYP2D6 poor metabolizer,|
04973|014|P|dapoxetine metabolism can be further inhibited.(1-3)|
04973|015|B||
04973|016|M|PATIENT MANAGEMENT:  The manufacturers of dapoxetine state that the dose of|
04973|017|M|dapoxetine should not exceed 30 mg daily if coadministered with moderate|
04973|018|M|CYP3A4 inhibitors.(1-3)|
04973|019|B||
04973|020|D|DISCUSSION:  The impact of moderate CYP3A4 inhibitors on the|
04973|021|D|pharmacokinetics of dapoxetine has not been investigated in clinical|
04973|022|D|studies.(1-3)|
04973|023|D|   Ketoconazole (200 mg twice daily for 7 days), a strong inhibitor of|
04973|024|D|CYP3A4, increased the maximum concentration (Cmax) and area-under-curve|
04973|025|D|(AUC) of a single dose of dapoxetine (30 mg) by 35% and 99%, respectively.|
04973|026|D|The Cmax and AUC of the active fraction are expected to increase by 25% and|
04973|027|D|2-fold, respectively, with strong inhibitors of CYP3A4.(1-3)|
04973|028|D|   Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir,|
04973|029|D|aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan,|
04973|030|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
04973|031|D|fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib,|
04973|032|D|isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant,|
04973|033|D|nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam,|
04973|034|D|treosulfan, verapamil, and voxelotor.(4,5)|
04973|035|B||
04973|036|R|REFERENCES:|
04973|037|B||
04973|038|R|1.Priligy (dapoxetine hydrochloride) Australian prescribing information.|1
04973|039|R|  Ortho-McNeil Pharmaceutical March 19, 2013.|1
04973|040|R|2.Priligy (dapoxetine hydrochloride) UK summary of product characteristics.|1
04973|041|R|  A. Menarini Farmaceutica Internazionale SRL April 15, 2014.|1
04973|042|R|3.Evoka (dapoxetine hydrochloride) Middle East prescribing information.|1
04973|043|R|  Middle East Pharmaceutical Industries Co. Ltd (Avalon-Pharma) April, 2024.|1
04973|044|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04973|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04973|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04973|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04973|048|R|  11/14/2017.|1
04973|049|R|5.This information is based on an extract from the Certara Drug Interaction|6
04973|050|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04974|001|T|MONOGRAPH TITLE:  ACE Inhibitors/Racecadotril|
04974|002|B||
04974|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04974|004|L|take action as needed.|
04974|005|B||
04974|006|A|MECHANISM OF ACTION:  Bradykinin can cause vasodilation and increase|
04974|007|A|vascular permeability both directly and by stimulating release of substance|
04974|008|A|P, which also increases vascular permeability.(1)  Bradykinin is primarily|
04974|009|A|metabolized by angiotensin-1 converting enzyme (ACE).  If ACE is inhibited|
04974|010|A|by ACE inhibitors, other metabolic enzymes become more significant in|
04974|011|A|bradykinin metabolism, including neutral endopeptidase (NEP).  Racecadotril|
04974|012|A|inhibits NEP which is involved in the degradation of bradykinin.(2)|
04974|013|B||
04974|014|E|CLINICAL EFFECTS:  Concomitant therapy can increase the risk of vasodilation|
04974|015|E|leading to an increase in angioedema risk.(1)|
04974|016|B||
04974|017|P|PREDISPOSING FACTORS:  History of previous angioedema.|
04974|018|B||
04974|019|M|PATIENT MANAGEMENT:  Patients may be more susceptible to developing|
04974|020|M|angioedema if concomitantly taking an ACE inhibitor and racecadotril.(1)|
04974|021|M|Consider switching the patient to an angiotensin receptor blocker.|
04974|022|M|   Use caution in patients receiving concurrent therapy.(3)  Monitor closely|
04974|023|M|for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or|
04974|024|M|swollen throat, or trouble breathing).  Instruct patients to report|
04974|025|M|angioedema symptoms immediately.|
04974|026|B||
04974|027|D|DISCUSSION:  Angioedema has been reported with racecadotril. Concurrent use|
04974|028|D|of racecadotril and an ACE inhibitor may increase the risk of angioedema.|
04974|029|D|   A review of the French national pharmacovigilance database found 11|
04974|030|D|reports of angioedema in patients concomitantly taking an ACE inhibitor and|
04974|031|D|racecadotril. In 9 cases, the temporal relationship between onset of drug|
04974|032|D|combination and onset of angioedema was highly suggestive of a causal|
04974|033|D|link.(3)|
04974|034|B||
04974|035|R|REFERENCES:|
04974|036|B||
04974|037|R|1.Hidrasec (racecadotril) UK Summary of Product Characteristics. Bioproject|1
04974|038|R|  Europe Ltd June 2024.|1
04974|039|R|2.Eberlin M, Muck T, Michel MC. A comprehensive review of the|6
04974|040|R|  pharmacodynamics, pharmacokinetics, and clinical  effects of the neutral|6
04974|041|R|  endopeptidase inhibitor racecadotril. Front Pharmacol 2012;3:93.|6
04974|042|R|3.Drug-induced non-immune-mediated angioedema. Rev Prescrire 2016;|6
04974|043|R|  25(169):71.|6
04975|001|T|MONOGRAPH TITLE:  Anamorelin/Strong CYP3A4 Inhibitors|
04975|002|B||
04975|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04975|004|L|is contraindicated and generally should not be dispensed or administered to|
04975|005|L|the same patient.|
04975|006|B||
04975|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04975|008|A|anamorelin.(1)|
04975|009|B||
04975|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04975|011|E|the levels and effects of anamorelin, including hyperglycemia,|
04975|012|E|hepatotoxicity, and QTc prolongation, which may result in potentially|
04975|013|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)|
04975|014|B||
04975|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04975|016|P|may be increased in patients with cardiovascular disease (e.g. heart|
04975|017|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04975|018|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04975|019|P|female gender, or advanced age.(2)|
04975|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04975|021|P|higher systemic concentrations of either QT prolonging drug are additional|
04975|022|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04975|023|P|drug concentrations include rapid infusion of an intravenous dose or|
04975|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04975|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04975|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04975|027|B||
04975|028|M|PATIENT MANAGEMENT:  The manufacturer of anamorelin states that concomitant|
04975|029|M|use with strong CYP3A4 inhibitors is contraindicated.(1)|
04975|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04975|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04975|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04975|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04975|034|B||
04975|035|D|DISCUSSION:  In a study of 12 healthy volunteers, concomitant use of|
04975|036|D|anamorelin 25 mg with ketoconazole 200 mg every 12 hours for 3 doses (a|
04975|037|D|strong CYP3A4 inhibitor) increased anamorelin maximum concentration (Cmax)|
04975|038|D|and area-under-curve (AUC) by 3.12-fold and 3.22-fold, respectively.(1)|
04975|039|D|   Anamorelin blocks sodium channels and may suppress cardiac conduction,|
04975|040|D|resulting in prolongation of the QRS width or QT interval.  A study of 7|
04975|041|D|healthy volunteers receiving single-dose anamorelin 400 mg found that 1|
04975|042|D|patient experienced QRS width prolongation.  In 60 healthy adults, the|
04975|043|D|maximum difference (upper limit of 95% one-sided confidence interval) in the|
04975|044|D|change from baseline in QTcF interval compared to placebo was 6.16 (7.73)|
04975|045|D|msec in patients on 100 mg and 7.38 (10.31) msec in patients on 300 mg.(1)|
04975|046|D|   The Japanese pharmacovigilance database was reviewed to evaluate|
04975|047|D|disproportionality of conduction defects related to anamorelin.  Out of 537|
04975|048|D|cases of adverse reactions, there were 51 cases of conduction defects (36|
04975|049|D|cases of prolonged QT, 5 cases of prolonged QRS complex, 2 cases of long QT|
04975|050|D|syndrome).  When adjusted for concomitant use of QT prolonging agents, the|
04975|051|D|reporting odds ratio (ROR) of anamorelin-related conduction defects was|
04975|052|D|20.00 (95% CI 14.86-26.91).(3)|
04975|053|D|   There have been several case reports of widened QRS complexes following|
04975|054|D|anamorelin exposure, usually accompanied by worsening hepatic function.(4-6)|
04975|055|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, grapefruit,|
04975|056|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
04975|057|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
04975|058|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(7-8)|
04975|059|B||
04975|060|R|REFERENCES:|
04975|061|B||
04975|062|R|1.Adlumiz (anamorelin) Japanese prescribing information. Ono Pharmaceutical|1
04975|063|R|  Co., Ltd. March, 2025.|1
04975|064|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04975|065|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04975|066|R|  settings: a scientific statement from the American Heart Association and|6
04975|067|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04975|068|R|  2;55(9):934-47.|6
04975|069|R|3.Yabuki N, Sako KI, Maeda T, Ide N. Anamorelin and Conduction Defects: A|6
04975|070|R|  Literature Review and Analysis of the  Japanese Pharmacovigilance|6
04975|071|R|  Database. In Vivo 2025 Jan-Feb;39(1):404-410.|6
04975|072|R|4.Kojima K, Furukawa S, Ishikawa T, Inoue S. First case report of|3
04975|073|R|  anamorelin-induced fatal arrhythmia complicated by sinus  arrest and|3
04975|074|R|  refractory ventricular tachycardia. HeartRhythm Case Rep 2023 Mar;|3
04975|075|R|  9(3):185-189.|3
04975|076|R|5.Okidono Y, Osada J, Otsu K, Kowase S, Aoki H, Yumoto K. Two cases of wide|3
04975|077|R|  QRS complex tachycardia caused by anamorelin. J Cardiol Cases 2022 Sep;|3
04975|078|R|  26(3):212-216.|3
04975|079|R|6.Shimojo K, Kanzaki Y, Miyazawa H, Morishima I. An extremely wide QRS|3
04975|080|R|  complex tachycardia induced by anamorelin. J Arrhythm 2024 Aug;|3
04975|081|R|  40(4):1022-1025.|3
04975|082|R|7.This information is based on an extract from the Certara Drug Interaction|6
04975|083|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04975|084|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
04975|085|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04975|086|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04975|087|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04975|088|R|  11/14/2017.|1
04976|001|T|MONOGRAPH TITLE:  Anamorelin/Strong CYP3A4 Inhibitors that Prolong QT|
04976|002|B||
04976|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04976|004|L|is contraindicated and generally should not be dispensed or administered to|
04976|005|L|the same patient.|
04976|006|B||
04976|007|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04976|008|A|anamorelin and result in additive effects on the QTc interval.(1)|
04976|009|B||
04976|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04976|011|E|the levels and effects of anamorelin, including hyperglycemia,|
04976|012|E|hepatotoxicity, and additive QTc prolongation, which may result in|
04976|013|E|potentially life-threatening cardiac arrhythmias like torsades de pointes|
04976|014|E|(TdP).(1)|
04976|015|B||
04976|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04976|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
04976|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04976|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04976|020|P|female gender, or advanced age.(2)|
04976|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04976|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04976|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04976|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04976|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04976|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04976|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04976|028|B||
04976|029|M|PATIENT MANAGEMENT:  The manufacturer of anamorelin states that concomitant|
04976|030|M|use with strong CYP3A4 inhibitors is contraindicated.(1)|
04976|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04976|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04976|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04976|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04976|035|B||
04976|036|D|DISCUSSION:  In a study of 12 healthy volunteers, concomitant use of|
04976|037|D|anamorelin 25 mg with ketoconazole 200 mg every 12 hours for 3 doses (a|
04976|038|D|strong CYP3A4 inhibitor) increased anamorelin maximum concentration (Cmax)|
04976|039|D|and area-under-curve (AUC) by 3.12-fold and 3.22-fold, respectively.(1)|
04976|040|D|   Anamorelin blocks sodium channels and may suppress cardiac conduction,|
04976|041|D|resulting in prolongation of the QRS width or QT interval.  A study of 7|
04976|042|D|healthy volunteers receiving single-dose anamorelin 400 mg found that 1|
04976|043|D|patient experienced QRS width prolongation.  In 60 healthy adults, the|
04976|044|D|maximum difference (upper limit of 95% one-sided confidence interval) in the|
04976|045|D|change from baseline in QTcF interval compared to placebo was 6.16 (7.73)|
04976|046|D|msec in patients on 100 mg and 7.38 (10.31) msec in patients on 300 mg.(1)|
04976|047|D|   The Japanese pharmacovigilance database was reviewed to evaluate|
04976|048|D|disproportionality of conduction defects related to anamorelin.  Out of 537|
04976|049|D|cases of adverse reactions, there were 51 cases of conduction defects (36|
04976|050|D|cases of prolonged QT, 5 cases of prolonged QRS complex, 2 cases of long QT|
04976|051|D|syndrome).  When adjusted for concomitant use of QT prolonging agents, the|
04976|052|D|reporting odds ratio (ROR) of anamorelin-related conduction defects was|
04976|053|D|20.00 (95% CI 14.86-26.91).(3)|
04976|054|D|   There have been several case reports of widened QRS complexes following|
04976|055|D|anamorelin exposure, usually accompanied by worsening hepatic function.(4-6)|
04976|056|D|   Strong CYP3A4 inhibitors that prolong the QT interval linked to this|
04976|057|D|monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole,|
04976|058|D|lonafarnib, lopinavir-ritonavir, posaconazole, ribociclib, saquinavir,|
04976|059|D|telithromycin, and voriconazole.(7-8)|
04976|060|B||
04976|061|R|REFERENCES:|
04976|062|B||
04976|063|R|1.Adlumiz (anamorelin) Japanese prescribing information. Ono Pharmaceutical|1
04976|064|R|  Co., Ltd. March, 2025.|1
04976|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04976|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04976|067|R|  settings: a scientific statement from the American Heart Association and|6
04976|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04976|069|R|  2;55(9):934-47.|6
04976|070|R|3.Yabuki N, Sako KI, Maeda T, Ide N. Anamorelin and Conduction Defects: A|6
04976|071|R|  Literature Review and Analysis of the  Japanese Pharmacovigilance|6
04976|072|R|  Database. In Vivo 2025 Jan-Feb;39(1):404-410.|6
04976|073|R|4.Kojima K, Furukawa S, Ishikawa T, Inoue S. First case report of|3
04976|074|R|  anamorelin-induced fatal arrhythmia complicated by sinus  arrest and|3
04976|075|R|  refractory ventricular tachycardia. HeartRhythm Case Rep 2023 Mar;|3
04976|076|R|  9(3):185-189.|3
04976|077|R|5.Okidono Y, Osada J, Otsu K, Kowase S, Aoki H, Yumoto K. Two cases of wide|3
04976|078|R|  QRS complex tachycardia caused by anamorelin. J Cardiol Cases 2022 Sep;|3
04976|079|R|  26(3):212-216.|3
04976|080|R|6.Shimojo K, Kanzaki Y, Miyazawa H, Morishima I. An extremely wide QRS|3
04976|081|R|  complex tachycardia induced by anamorelin. J Arrhythm 2024 Aug;|3
04976|082|R|  40(4):1022-1025.|3
04976|083|R|7.This information is based on an extract from the Certara Drug Interaction|6
04976|084|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04976|085|R|8.US Food and Drug Administration (FDA). Drug Development and Drug|1
04976|086|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04976|087|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04976|088|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04976|089|R|  11/14/2017.|1
04977|001|T|MONOGRAPH TITLE:  Anamorelin/QT Prolonging Agents|
04977|002|B||
04977|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04977|004|L|take action as needed.|
04977|005|B||
04977|006|A|MECHANISM OF ACTION:  Anamorelin may prolong the QTc interval.  Concurrent|
04977|007|A|use with other agents that prolong the QTc interval may result in additive|
04977|008|A|effects on the QTc interval.(1)|
04977|009|B||
04977|010|E|CLINICAL EFFECTS:  The concurrent use of anamorelin with other agents that|
04977|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04977|012|E|arrhythmias, including torsades de pointes.(1)|
04977|013|B||
04977|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
04977|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
04977|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
04977|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
04977|018|P|gender, or advanced age.(2)|
04977|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04977|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04977|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04977|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04977|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04977|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04977|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04977|026|B||
04977|027|M|PATIENT MANAGEMENT:  The manufacturer of anamorelin states that the|
04977|028|M|concurrent use of QT prolonging agents should be approached with caution,|
04977|029|M|especially in the early stages (i.e., the first 3 weeks) of drug|
04977|030|M|administration.(1,3)|
04977|031|M|   Obtain serum calcium, magnesium, and potassium levels and monitor ECG at|
04977|032|M|baseline and at regular intervals.  Correct any electrolyte abnormalities.|
04977|033|M|If abnormalities are found, take appropriate measures, including|
04977|034|M|discontinuing anamorelin.(1)  Instruct patients to report any irregular|
04977|035|M|heartbeat, dizziness, or fainting.|
04977|036|B||
04977|037|D|DISCUSSION:  Anamorelin blocks sodium channels and may suppress cardiac|
04977|038|D|conduction, resulting in prolongation of the QRS width or QT interval.  A|
04977|039|D|study of 7 healthy volunteers receiving single-dose anamorelin 400 mg found|
04977|040|D|that 1 patient experienced QRS width prolongation.  In 60 healthy adults|
04977|041|D|recieving anamorelin, the maximum difference (upper limit of 95% one-sided|
04977|042|D|confidence interval) in the change from baseline in QTcF interval compared|
04977|043|D|to placebo was 6.16 (7.73) msec in patients on 100 mg and 7.38 (10.31) msec|
04977|044|D|in patients on 300 mg.(1)|
04977|045|D|   The Japanese pharmacovigilance database was reviewed to evaluate|
04977|046|D|disproportionality of conduction defects related to anamorelin.  Out of 537|
04977|047|D|cases of adverse reactions, there were 51 cases of conduction defects (36|
04977|048|D|cases of prolonged QT, 5 cases of prolonged QRS complex, 2 cases of long QT|
04977|049|D|syndrome).  When adjusted for concomitant use of QT prolonging agents, the|
04977|050|D|reporting odds ratio (ROR) of anamorelin-related conduction defects was|
04977|051|D|20.00 (95% CI 14.86-26.91).(3)|
04977|052|D|   There have been several case reports of widened QRS complexes following|
04977|053|D|anamorelin exposure, usually accompanied by worsening hepatic function.(4-6)|
04977|054|D|   Agents that are linked to this monograph may have varying degrees of|
04977|055|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
04977|056|D|been shown to prolong the QTc interval either through their mechanism of|
04977|057|D|action, through studies on their effects on the QTc interval, or through|
04977|058|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
04977|059|D|and/or postmarketing reports.(7)|
04977|060|B||
04977|061|R|REFERENCES:|
04977|062|B||
04977|063|R|1.Adlumiz (anamorelin) Japanese prescribing information. Ono Pharmaceutical|1
04977|064|R|  Co., Ltd. March, 2025.|1
04977|065|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04977|066|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04977|067|R|  settings: a scientific statement from the American Heart Association and|6
04977|068|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04977|069|R|  2;55(9):934-47.|6
04977|070|R|3.Yabuki N, Sako KI, Maeda T, Ide N. Anamorelin and Conduction Defects: A|6
04977|071|R|  Literature Review and Analysis of the  Japanese Pharmacovigilance|6
04977|072|R|  Database. In Vivo 2025 Jan-Feb;39(1):404-410.|6
04977|073|R|4.Kojima K, Furukawa S, Ishikawa T, Inoue S. First case report of|3
04977|074|R|  anamorelin-induced fatal arrhythmia complicated by sinus  arrest and|3
04977|075|R|  refractory ventricular tachycardia. HeartRhythm Case Rep 2023 Mar;|3
04977|076|R|  9(3):185-189.|3
04977|077|R|5.Okidono Y, Osada J, Otsu K, Kowase S, Aoki H, Yumoto K. Two cases of wide|3
04977|078|R|  QRS complex tachycardia caused by anamorelin. J Cardiol Cases 2022 Sep;|3
04977|079|R|  26(3):212-216.|3
04977|080|R|6.Shimojo K, Kanzaki Y, Miyazawa H, Morishima I. An extremely wide QRS|3
04977|081|R|  complex tachycardia induced by anamorelin. J Arrhythm 2024 Aug;|3
04977|082|R|  40(4):1022-1025.|3
04977|083|R|7.USDepartment of Health and Human Services Food and Drug Administration.|1
04977|084|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04977|085|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04977|086|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04978|001|T|MONOGRAPH TITLE:  Naltrexone-Bupropion/CYP2B6 Inhibitors|
04978|002|B||
04978|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04978|004|L|take action as needed.|
04978|005|B||
04978|006|A|MECHANISM OF ACTION:  CYP2B6 inhibitors may inhibit the metabolism of|
04978|007|A|naltrexone-bupropion. Bupropion is primarily metabolized to active|
04978|008|A|metabolites by CYP2B6.(1-2)|
04978|009|B||
04978|010|E|CLINICAL EFFECTS:  Coadministration of CYP2B6 inhibitors may cause an|
04978|011|E|increase in naltrexone-bupropion levels and effects, including increased|
04978|012|E|risk of seizures.(1)|
04978|013|B||
04978|014|P|PREDISPOSING FACTORS:  The risk of seizures may be increased in patients|
04978|015|P|with a history of head trauma or prior seizure; CNS tumor; severe hepatic|
04978|016|P|cirrhosis; excessive use of alcohol or sedatives; addiction to opiates,|
04978|017|P|cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a|
04978|018|P|total daily dose of bupropion greater than 450 mg or single doses greater|
04978|019|P|than 150 mg; rapid escalation of bupropion dosage; diabetics treated with|
04978|020|P|oral hypoglycemics or insulin; or with concomitant medications known to|
04978|021|P|lower seizure threshold (antidepressants, theophylline, systemic|
04978|022|P|steroids).(1)|
04978|023|B||
04978|024|M|PATIENT MANAGEMENT:  The US manufacturer of naltrexone-bupropion states that|
04978|025|M|the dose of naltrexone-bupropion should not exceed two tablets (one tablet|
04978|026|M|each morning and evening) during concurrent use with CYP2B6 inhibitors .(1)|
04978|027|B||
04978|028|D|DISCUSSION:  Repeated administration of ticlopidine (250 mg twice daily for|
04978|029|D|4 days, a inhibitor of CYP2B6) increased the maximum concentration (Cmax)|
04978|030|D|and area-under-curve (AUC) of a single dose of bupropion by 38% and 85%,|
04978|031|D|respectively. Cmax and AUC of the metabolite hydroxybupropion decreased 78%|
04978|032|D|and 84%.(1)|
04978|033|D|   Repeated administration of clopidogrel(75 mg twice daily for 4 days, a|
04978|034|D|inhibitor of CYP2B6) increased the maximum concentration (Cmax) and|
04978|035|D|area-under-curve (AUC) of a single dose of bupropion by 40% and 60%,|
04978|036|D|respectively. Cmax and AUC of the metabolite hydroxybupropion decreased 50%|
04978|037|D|and 52%.(1)|
04978|038|D|   Inhibitors of CYP2B6 include:  clopidogrel, disulfiram, prasugrel,|
04978|039|D|rolapitant, ticlopidine.(2-3)|
04978|040|B||
04978|041|R|REFERENCES:|
04978|042|B||
04978|043|R|1.Contrave (naltrexone and bupropion) US prescribing infromation. Nalpropion|1
04978|044|R|  Pharmaceuticals LLC May, 2024.|1
04978|045|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04978|046|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04978|047|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04978|048|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04978|049|R|  11/14/2017.|1
04978|050|R|3.This information is based on an extract from the Certara Drug Interaction|6
04978|051|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04979|001|T|MONOGRAPH TITLE:  Sepiapterin/Dihydrofolate Reductase Inhibitors|
04979|002|B||
04979|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04979|004|L|of severe adverse interaction.|
04979|005|B||
04979|006|A|MECHANISM OF ACTION:  Dihydrofolate reductase (DHFR) inhibitors (e.g.,|
04979|007|A|trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate)  may|
04979|008|A|decrease conversion of sepiapterin to its active metabolite,|
04979|009|A|tetrahydrobiopterin (BH4).(1)|
04979|010|B||
04979|011|E|CLINICAL EFFECTS:  Concurrent use of DHFR inhibitors and sepiapterin may|
04979|012|E|result in decreased levels of BH4 (the active metabolite of sepiapterin) and|
04979|013|E|reduced or loss of efficacy.(1)|
04979|014|B||
04979|015|P|PREDISPOSING FACTORS:  None determined.|
04979|016|B||
04979|017|M|PATIENT MANAGEMENT:  The concurrent use of DHFR inhibitors and sepiapterin|
04979|018|M|should be avoided.  If concurrent use cannot be avoided, monitor blood|
04979|019|M|phenylalanine levels.(1)|
04979|020|B||
04979|021|D|DISCUSSION:  Sepiapterin is metabolized by dihydrofolate reductase (DHFR) to|
04979|022|D|its pharmacologically active form, tetrahydrobiopterin (BH4).  Inhibitors of|
04979|023|D|DHFR may reduce the metabolism of sepiapterin to BH4.(1)|
04979|024|D|   DHFR inhibitors linked to this monograph include: methotrexate,|
04979|025|D|pemetrexed, pralatrexate, raltitrexed, trimethoprim, and trimetrexate.|
04979|026|B||
04979|027|R|REFERENCE:|
04979|028|B||
04979|029|R|1.Sephience (sepiapterin) US prescribing information. PTC Therapeutics, Inc.|1
04979|030|R|  July, 2025.|1
04980|001|T|MONOGRAPH TITLE:  Cladribine Onc Inj (10 mg/5 mL)/Immunosuppressive;|
04980|002|T|Immunomod|
04980|003|B||
04980|004|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
04980|005|L|is contraindicated and generally should not be dispensed or administered to|
04980|006|L|the same patient.|
04980|007|B||
04980|008|A|MECHANISM OF ACTION:  Cladribine in combination with immunosuppressives and|
04980|009|A|immune-modulators all suppress the immune system.(1-2)|
04980|010|B||
04980|011|E|CLINICAL EFFECTS:  Concurrent use of cladribine with immunosuppressive or|
04980|012|E|immune-modulating agents may result in an increased risk of serious|
04980|013|E|infections.(1-2)|
04980|014|B||
04980|015|P|PREDISPOSING FACTORS:  Incomplete washout of previously prescribed|
04980|016|P|immunosuppressive or immune-modulating medications.|
04980|017|B||
04980|018|M|PATIENT MANAGEMENT:  Recommendations for cladribine regarding this|
04980|019|M|interaction differ between regulatory approving agencies.|
04980|020|M|   The UK and AU manufacturers of Litak state that concomitant use of other|
04980|021|M|myelosuppressive medicinal products with cladribine is contraindicated.(1-2)|
04980|022|M|   The Israeli manufacturer of Litak states that cladribine should not be|
04980|023|M|used concomitantly with other myelosuppressive medicinal products.(3)|
04980|024|B||
04980|025|D|DISCUSSION:  The risk of severe myelotoxicity and long-lasting|
04980|026|D|immunosuppression is increased in patients with a disease-related bone|
04980|027|D|marrow infiltration or a previous myelosuppressive treatment.(1-3)|
04980|028|B||
04980|029|R|REFERENCES:|
04980|030|B||
04980|031|R|1.Litak (cladribine) UK prescribing information. LIPOMED GmbH. February|1
04980|032|R|  2025.|1
04980|033|R|2.Litak (cladribine) AU prescribing information. Viatris Pty Ltd. May 2025.|1
04980|034|R|3.Litak (cladribine) Isreali prescribing information. Lipomed AG. February|1
04980|035|R|  2023.|1
04981|001|T|MONOGRAPH TITLE:  Sulfonylureas/Miconazole|
04981|002|B||
04981|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04981|004|L|of severe adverse interaction.|
04981|005|B||
04981|006|A|MECHANISM OF ACTION:  Sulfonylureas are sensitive CYP2C9 substrates.|
04981|007|A|Miconazole is a moderate CYP2C9 inhibitor and may inhibit the metabolism of|
04981|008|A|sulfonylureas.(1)|
04981|009|B||
04981|010|E|CLINICAL EFFECTS:  Concurrent use of miconazole may result in elevated|
04981|011|E|levels and effects of the sulfonylureas, including severe hypoglycemia and|
04981|012|E|coma.(2-4)|
04981|013|B||
04981|014|P|PREDISPOSING FACTORS:  None determined.|
04981|015|B||
04981|016|M|PATIENT MANAGEMENT:  The Australian, Canadian, and UK manufacturers of|
04981|017|M|gliclazide and the UK manufacturer of glipizide state that concurrent use|
04981|018|M|with miconazole via systemic routes or oro-mucosal gel is|
04981|019|M|contraindicated.(2-5)|
04981|020|M|   The manufacturers of other sulfonylureas and the Australian and UK|
04981|021|M|manufacturers of miconazole advise caution when using the combination of|
04981|022|M|sulfonylureas and miconazole.  Monitor blood glucose levels during|
04981|023|M|concurrent therapy. The dose of the sulfonylurea may need to be|
04981|024|M|adjusted.(6-15)|
04981|025|B||
04981|026|D|DISCUSSION:  A French pharmacovigilance study found that 98 cases of|
04981|027|D|sulfonylurea-induced hypoglycemia were reported between 1985-1990, mostly|
04981|028|D|with gliclazide (46 cases) and glyburide (40 cases).  Miconazole was one of|
04981|029|D|the most frequent causes of drug interactions (8 cases).(16)  Other cases of|
04981|030|D|severe hypoglycemia after miconazole was started in patients on|
04981|031|D|sulfonylureas have been reported.(17-18)|
04981|032|B||
04981|033|R|REFERENCES:|
04981|034|B||
04981|035|R|1.This information is based on an extract from the Certara Drug Interaction|6
04981|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04981|037|R|2.Gliclazide Australian Product Information. Alphapharm Pty Ltd trading as|1
04981|038|R|  Viatris July, 2024.|1
04981|039|R|3.Gliclazide Canadian Product Monograph. Angita Pharma Inc. May, 2024.|1
04981|040|R|4.Gliclazide UK Summary of Product Characteristics. Accord Healthcare|1
04981|041|R|  Limited November, 2024.|1
04981|042|R|5.Glimepiride UK summary of product characteristics. Sandoz Limited July,|1
04981|043|R|  2021.|1
04981|044|R|6.Daktarin (miconazole) Oral Gel UK Summary of Product Characteristics.|1
04981|045|R|  McNeil Products Limited April, 2023.|1
04981|046|R|7.Daktarin (miconazole) Oral Gel Australian Product Information. Johnson &|1
04981|047|R|  Johnson Pacific July, 2020.|1
04981|048|R|8.Daonil (glibenclamide) Australian Product Information. sanofi-aventis|1
04981|049|R|  australia pty ltd June, 2020.|1
04981|050|R|9.Glimepiride Australian Product Information. Accord Healthcare Pty Ltd May,|1
04981|051|R|  2024.|1
04981|052|R|10.Sandoz Glimepiride Canadian Product Monograph. Sandoz Canada Inc.|1
04981|053|R|   February, 2021.|1
04981|054|R|11.Apo-Glyburide Canadian Product Monograph. Apotex Inc. March, 2017.|1
04981|055|R|12.Amaryl (glimepiride) US prescribing information. Sanofi-Aventis U.S. LLC|1
04981|056|R|   October, 2013.|1
04981|057|R|13.Glucotrol (glipizide) US prescribing information. Pfizer August, 2016.|1
04981|058|R|14.Glibenclamide UK summary of product characteristics. Ennogen Pharma|1
04981|059|R|   Limited January, 2023.|1
04981|060|R|15.Glipizide UK Summary of Product Characteristics. Generics UK Ltd t/a|1
04981|061|R|   Mylan June, 2017.|1
04981|062|R|16.Girardin E, Vial T, Pham E, Evreux JC. Hypoglycemia induced by oral|6
04981|063|R|   hypoglycemic agents. Records of the French Regional  Pharmacovigilance|6
04981|064|R|   Centers 1985-1990. Ann Med Interne (Paris) 1992;143(1):11-7.|6
04981|065|R|17.Meurice JC, Lecomte P, Renard JP, Girard JJ. Interaction of miconazole|3
04981|066|R|   and sulfamides with hypoglycemic action. Presse Med 1983 Jun 18;|3
04981|067|R|   12(26):1670.|3
04981|068|R|18.Loupi E, Descotes J, Lery N, Evreux JC. Drug interactions involving|3
04981|069|R|   miconazole. Therapie 1982 Jul-Aug;37(4):437-41.|3
04982|001|T|MONOGRAPH TITLE:  Moxonidine/Tricyclic Compounds; Mirtazapine|
04982|002|B||
04982|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04982|004|L|take action as needed.|
04982|005|B||
04982|006|A|MECHANISM OF ACTION:  Moxonidine decreases blood pressure via imidazoline-1|
04982|007|A|and alpha-2 receptor agonism.(1)  Tricyclic compounds(2) and mirtazapine(3)|
04982|008|A|antagonize alpha-2, which may result in a loss of effect of moxonidine.|
04982|009|B||
04982|010|E|CLINICAL EFFECTS:  The concurrent use of moxonidine and tricyclic compounds|
04982|011|E|and mirtazapine may result in decreased effectiveness of moxonidine and|
04982|012|E|decreased blood pressure control.(1)|
04982|013|B||
04982|014|P|PREDISPOSING FACTORS:  None determined.|
04982|015|B||
04982|016|M|PATIENT MANAGEMENT:  Concurrent use of moxonidine with tricyclic compounds|
04982|017|M|or mirtazapine is not recommended.(1)  Consider using an alternative agent|
04982|018|M|in patients maintained on moxonidine.  If concurrent administration is|
04982|019|M|necessary, blood pressure should be carefully monitored.  The dosage of|
04982|020|M|moxonidine may need to be adjusted or the tricyclic compound or mirtazapine|
04982|021|M|may need to be discontinued.|
04982|022|B||
04982|023|D|DISCUSSION:  Moxonidine is an imidazoline-1 and alpha-2 receptor agonist.(1)|
04982|024|D|Since tricyclic antidepressants and mirtazapine may reduce the|
04982|025|D|effectiveness of centrally acting antihypertensive agents, the concurrent|
04982|026|D|use of moxonidine is not recommended.  No studies have evaluated the current|
04982|027|D|use of moxonidine with tricyclic antidepressants or mirtazapine.  Loss of|
04982|028|D|blood pressure control and hypertensive crisis have been reported with|
04982|029|D|clonidine,(4-22) and a similar interaction may occur with moxonidine.|
04982|030|D|   The sedative effect of tricyclic antidepressants can be potentiated by|
04982|031|D|moxonidine.|
04982|032|B||
04982|033|R|REFERENCES:|
04982|034|B||
04982|035|R|1.Moxonidine Australian Product Information. Mylan January, 2019.|1
04982|036|R|2.Checkley SA, Slade AP, Shur E, Dawling S. A pilot study of the mechanism|2
04982|037|R|  of action of desipramine. Br J Psychiatry 1981 Mar;138:248-51.|2
04982|038|R|3.Remeron (mirtazapine) US prescribing information. Organon Inc. November,|1
04982|039|R|  2021.|1
04982|040|R|4.van Spanning HW, van Zwieten PA. The interference of tricyclic|5
04982|041|R|  antidepressants with the central hypotensive effect of clonidine. Eur J|5
04982|042|R|  Pharmacol 1973 Dec;24(3):402-4.|5
04982|043|R|5.van Zwieten PA. Interaction between centrally acting hypotensive drugs and|5
04982|044|R|  tricyclic antidepressants. Arch Int Pharmacodyn Ther 1975 Mar;|5
04982|045|R|  214(1):12-30.|5
04982|046|R|6.Stiff JL, Harris DB. Clonidine withdrawal complicated by amitriptyline|3
04982|047|R|  therapy. Anesthesiology 1983 Jul;59(1):73-4.|3
04982|048|R|7.Lacomblez L, Warot D, Bouche P, Derouesne C. Suppression of the|3
04982|049|R|  antihypertensive effect of clonidine by clomipramine. Rev Med Interne 1988|3
04982|050|R|  May-Jun;9(3):291-3.|3
04982|051|R|8.Andrejak M, Fournier A, Hardin JM, Coevoet B, Lambrey G, De Fremont JF,|3
04982|052|R|  Quichaud J. Suppression of the antihypertensive effect of clonidine by the|3
04982|053|R|  simultaneous intake of a tricyclic antidepressive agent. Practical problem|3
04982|054|R|  in the treatment of a depressed hypertensive patient. Nouv Presse Med 1977|3
04982|055|R|  Sep 10;6(29):2603.|3
04982|056|R|9.Briant RH, Reid JL, Dollery CT. Interaction between clonidine and|2
04982|057|R|  desipramine in man. Br Med J 1973 Mar 3;1(5852):522-3.|2
04982|058|R|10.Briant RH, Reid JL. Desmethylimipramine and the hypotensive action of|5
04982|059|R|   clonidine in the rabbit. Br J Pharmacol 1972 Nov;46(3):563P-564P.|5
04982|060|R|11.Zwieten PA. The reversal of clonidine-induced hypotension by|5
04982|061|R|   protriptyline and desipramine. Pharmacology 1976;14(3):227-31.|5
04982|062|R|12.Hui KK. Hypertensive crisis induced by interaction of clonidine with|3
04982|063|R|   imipramine. J Am Geriatr Soc 1983 Mar;31(3):164-5.|3
04982|064|R|13.Conolly ME. In:  Conolly ME., editor: Catapres in Hypertension, London,|2
04982|065|R|   1969, Butterwoth's Publishing..|2
04982|066|R|14.Coffier DE, et al. Antipsychotic drug interaction. Drug Intell Clin Pharm|3
04982|067|R|   1976;10:114.|3
04982|068|R|15.Siever LJ, Cohen RM, Murphy DL. Antidepressants and alpha 2-adrenergic|3
04982|069|R|   autoreceptor desensitization. Am J Psychiatry 1981 May;138(5):681-2.|3
04982|070|R|16.Cubeddu LX, Cloutier G, Gross K, Grippo R, Tanner L, Lerea L, Shakarjian|5
04982|071|R|   M, Knowlton G, Stat M, Harden TK, et al. Bupropion does not antagonize|5
04982|072|R|   cardiovascular actions of clonidine in normal subjects and spontaneously|5
04982|073|R|   hypertensive rats. Clin Pharmacol Ther 1984 May;35(5):576-84.|5
04982|074|R|17.Elliott HL, Whiting B, Reid JL. Assessment of the interaction between|2
04982|075|R|   mianserin and centrally-acting antihypertensive drugs. Br J Clin|2
04982|076|R|   Pharmacol 1983;15 Suppl 2:323S-328S.|2
04982|077|R|18.Elliott HL, McLean K, Sumner DJ, Reid JL. Absence of an effect of|2
04982|078|R|   mianserin on the actions of clonidine or methyldopa in hypertensive|2
04982|079|R|   patients. Eur J Clin Pharmacol 1983;24(1):15-9.|2
04982|080|R|19.Flexeril (cyclobenzaprine hydrochloride) US prescribing information.|1
04982|081|R|   Merck & Co., Inc. 1985.|1
04982|082|R|20.Troncoso AL, Gill T. Hypertensive urgency with clonidine and mirtazepine.|3
04982|083|R|   Psychosomatics 2004 Sep-Oct;45(5):449-50.|3
04982|084|R|21.Abo-Zena RA, Bobek MB, Dweik RA. Hypertensive urgency induced by an|3
04982|085|R|   interaction of mirtazapine and clonidine. Pharmacotherapy 2000 Apr;|3
04982|086|R|   20(4):476-8.|3
04982|087|R|22.Gundert-Remy U, Amann E, Hildebrandt R, Weber E. Lack of interaction|2
04982|088|R|   between the tetracyclic antidepressant maprotiline and the centrally|2
04982|089|R|   acting antihypertensive drug clonidine. Eur J Clin Pharmacol 1983;|2
04982|090|R|   25(5):595-9.|2
04983|001|T|MONOGRAPH TITLE:  Moxonidine/Beta-Blockers|
04983|002|B||
04983|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04983|004|L|take action as needed.|
04983|005|B||
04983|006|A|MECHANISM OF ACTION:  Withdrawal of moxonidine triggers increased|
04983|007|A|catecholamine release.  Beta-blockers inhibit the vasodilation mediated by|
04983|008|A|the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2|
04983|009|A|receptor unopposed.|
04983|010|A|   In addition, concurrent use is expected to produce additive effects on|
04983|011|A|blood pressure and heart rate requiring standard monitoring precautions.|
04983|012|B||
04983|013|E|CLINICAL EFFECTS:  Severe hypertension may occur upon abrupt discontinuation|
04983|014|E|of moxonidine in patients receiving both moxonidine and beta-blockers.|
04983|015|E|   In addition, concurrent use is expected to produce additive effects on|
04983|016|E|blood pressure and heart rate requiring standard monitoring precautions.|
04983|017|B||
04983|018|P|PREDISPOSING FACTORS:  None determined.|
04983|019|B||
04983|020|M|PATIENT MANAGEMENT:  If combination therapy with moxonidine and a|
04983|021|M|beta-blocker is to be ceased, the beta-blocker should be stopped first to|
04983|022|M|decrease the risk of rebound hypertension.  Moxonidine may be stopped after|
04983|023|M|a few days have elapsed.  During cessation of therapy blood pressure should|
04983|024|M|be regularly monitored.|
04983|025|M|   If moxonidine is discontinued first, rebound hypertension can be treated|
04983|026|M|by restarting the moxonidine or by the IV administration of phentolamine,|
04983|027|M|phenoxybenzamine or prazosin.  Since labetalol has both alpha and beta|
04983|028|M|activity, administration of labetalol may prevent rebound hypertension in|
04983|029|M|patients undergoing moxonidine withdrawal, although conflicting reports|
04983|030|M|exist.|
04983|031|M|   When adding either of these agents to the drug regimen of the patient,|
04983|032|M|monitor blood pressure.  Concurrent use is expected to produce additive|
04983|033|M|effects on blood pressure and heart rate requiring standard monitoring|
04983|034|M|precautions.|
04983|035|B||
04983|036|D|DISCUSSION:  Abrupt cessation of combination therapy with moxonidine and a|
04983|037|D|beta-blocker may result in rebound hypertension.  Withdrawal of moxonidine|
04983|038|D|may trigger increased catecholamine release.  Beta-blockers inhibit the|
04983|039|D|vasodilation mediated by the beta 2 receptor, leaving the vasoconstriction|
04983|040|D|mediated by the alpha 2 receptor unopposed.|
04983|041|B||
04983|042|R|REFERENCES:|
04983|043|B||
04983|044|R|1.Moxonidine Australian Product Information. Mylan January, 2019.|1
04983|045|R|2.Bailey RR, Neale TJ. Rapid clonidine withdrawal with blood pressure|3
04983|046|R|  overshoot exaggerated by beta-blockade. Br Med J 1976 Apr 17;|3
04983|047|R|  1(6015):942-3.|3
04983|048|R|3.Strauss FG, Franklin SS, Lewin AJ, Maxwell MH. Withdrawal of|3
04983|049|R|  antihypertensive therapy. Hypertensive crisis in renovascular|3
04983|050|R|  hypertension. JAMA 1977 Oct 17;238(16):1734-6.|3
04983|051|R|4.Vernon C, Sakula A. Fatal rebound hypertension after abrupt withdrawal of|3
04983|052|R|  clonidine and propranolol. Br J Clin Pract 1979 Apr;33(4):112, 121.|3
04983|053|R|5.Bruce DL, Croley TF, Lee JS. Preoperative clonidine withdrawal syndrome.|3
04983|054|R|  Anesthesiology 1979 Jul;51(1):90-2.|3
04983|055|R|6.Warren SE, Ebert E, Swerdlin AH, Steinberg SM, Stone R. Clonidine and|3
04983|056|R|  propranolol paradoxical hypertension. Arch Intern Med 1979 Feb;139(2):253.|3
04983|057|R|7.Lilja M, Jounela AJ, Juustila H, Mattila MJ. Interaction of clonidine and|2
04983|058|R|  beta-blockers. Acta Med Scand 1980;207(3):173-6.|2
04983|059|R|8.Garvey HL, Woodhouse BL. Reversal of clonidine-induced hypotension by|5
04983|060|R|  beta-adrenoceptor blocking drugs. Eur J Pharmacol 1980 Jul 11;65(1):55-62.|5
04983|061|R|9.Rosenthal T, Rabinowitz B, Boichis H, Elazar E, Brauner A, Neufeld HN. Use|3
04983|062|R|  of labetalol in hypertensive patients during discontinuation of clonidine|3
04983|063|R|  therapy. Eur J Clin Pharmacol 1981;20(4):237-40.|3
04983|064|R|10.Cummings DM, Vlasses PH. Antihypertensive drug withdrawal syndrome. Drug|6
04983|065|R|   Intell Clin Pharm 1982 Nov;16(11):817-22.|6
04983|066|R|11.Lilja M. Interaction of clonidine and labetalol in hypertension. Acta Med|2
04983|067|R|   Scand 1983;214(2):119-24.|2
04983|068|R|12.Jounela AJ, Lilja M. Interactions between beta-blockers and clonidine.|6
04983|069|R|   Ann Clin Res 1984;16(4):181-2.|6
04984|001|T|MONOGRAPH TITLE:  Roflumilast/Strong or Moderate CYP3A4 Inhibitors; Dual|
04984|002|T|CYP3A4 and CYP1A2 Inhibitors|
04984|003|B||
04984|004|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04984|005|L|take action as needed.|
04984|006|B||
04984|007|A|MECHANISM OF ACTION:  Agents that are either strong or moderate CYP3A4|
04984|008|A|inhibitors or dual inhibitors of CYP1A2 and CYP3A4 may inhibit the|
04984|009|A|metabolism of roflumilast.(1)|
04984|010|B||
04984|011|E|CLINICAL EFFECTS:  The coadministration of roflumilast with strong or|
04984|012|E|moderate CYP3A4 inhibitors or dual inhibitors of CY3A4 and CYP1A2 may|
04984|013|E|increase roflumilast systemic exposure and may result in increased adverse|
04984|014|E|reactions.(1)|
04984|015|B||
04984|016|P|PREDISPOSING FACTORS:  None determined.|
04984|017|B||
04984|018|M|PATIENT MANAGEMENT:  The manufacturer of roflumilast states concurrent use|
04984|019|M|with CYP3A4 inhibitors or dual inhibitors of CYP3A4 and CYP1A2 should be|
04984|020|M|approached with caution and the risk should be weighed carefully against the|
04984|021|M|benefit.  Consider alternatives with no or minimal enzyme inhibition.(1)|
04984|022|B||
04984|023|D|DISCUSSION:  In healthy subjects, concurrent use of roflumilast (500 mcg|
04984|024|D|single dose) with erythromycin, a moderate CYP3A4 inhibitor, (500 mg three|
04984|025|D|times daily for 15 days) increased the area-under-curve (AUC) and|
04984|026|D|concentration maximum (Cmax) of roflumilast by 70% and 40%, respectively,|
04984|027|D|and decreased the AUC and Cmax of roflumilast N-oxide by 4% and 34%,|
04984|028|D|respectively.(1,2)|
04984|029|D|   In healthy subjects, concurrent use of roflumilast (500 mcg single dose)|
04984|030|D|with ketoconazole, a strong CYP3A4 inhibitor, (200 mg twice daily for 13|
04984|031|D|days) increased the AUC and Cmax of roflumilast by 99% and 23%,|
04984|032|D|respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 3%|
04984|033|D|and 38%, respectively.(1)|
04984|034|D|   In healthy subjects, concurrent use of roflumilast (500 mcg single dose)|
04984|035|D|with fluvoxamine, a dual CYP3A4 and CYP1A2 inhibitor, (50 mg daily for 14|
04984|036|D|days) increased the AUC and Cmax of roflumilast by 156% and 12%,|
04984|037|D|respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 52%|
04984|038|D|and 210%, respectively.(1)|
04984|039|D|   In healthy subjects, concurrent use of roflumilast (500 mcg single dose)|
04984|040|D|with cimetidine, a dual CYP3A4 and CYP1A2 inhibitor, (400 mg twice daily for|
04984|041|D|14 days) increased the AUC and Cmax of roflumilast by 85% and 46%,|
04984|042|D|respectively, and increased the AUC and decreased Cmax of roflumilast|
04984|043|D|N-oxide by 27% and 4%, respectively.(1)|
04984|044|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
04984|045|D|boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir,|
04984|046|D|itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib,|
04984|047|D|lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir,|
04984|048|D|paritaprevir, posaconazole, saquinavir, telaprevir, tipranavir, tucatinib,|
04984|049|D|and voriconazole.(3,4)|
04984|050|D|   Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir,|
04984|051|D|aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan,|
04984|052|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
04984|053|D|fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
04984|054|D|imatinib, isavuconazole, lefamulin (oral), lenacapavir, letermovir,|
04984|055|D|netupitant, nilotinib, nirogacestat, schisandra, stiripentol, tofisopam,|
04984|056|D|treosulfan, and voxelotor.(3,4)|
04984|057|D|   Dual CYP3A4 and CYP1A2 inhibitors linked to this monograph include:|
04984|058|D|cannabidiol, cimetidine, ciprofloxacin, fluvoxamine,|
04984|059|D|glecaprevir/pibrentasvir, grapefruit, osilodrostat, piperine, ribociclib,|
04984|060|D|rucaparib, simeprevir, telithromycin, troleandomycin, verapamil, and|
04984|061|D|viloxazine.(3,4)|
04984|062|B||
04984|063|R|REFERENCES:|
04984|064|B||
04984|065|R|1.Daliresp (roflumilast) US prescribing information. AstraZeneca|1
04984|066|R|  Pharmaceuticals LP March, 2020.|1
04984|067|R|2.Lahu G, Huennemeyer A, Herzog R, McCracken N, Hermann R, Elmlinger M, Zech|2
04984|068|R|  K. Effect of repeated dose of erythromycin on the pharmacokinetics of|2
04984|069|R|  roflumilast  and roflumilast N-oxide. Int J Clin Pharmacol Ther 2009 Apr;|2
04984|070|R|  47(4):236-45.|2
04984|071|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04984|072|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04984|073|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04984|074|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04984|075|R|  11/14/2017.|1
04984|076|R|4.This information is based on an extract from the Certara Drug Interaction|6
04984|077|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04985|001|T|MONOGRAPH TITLE:  Dordaviprone/Strong CYP3A4 Inhibitors|
04985|002|B||
04985|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04985|004|L|of severe adverse interaction.|
04985|005|B||
04985|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
04985|007|A|dordaviprone.(1)|
04985|008|B||
04985|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
04985|010|E|the levels and effects of dordaviprone, including QTc prolongation, which|
04985|011|E|may result in potentially life-threatening cardiac arrhythmias like torsades|
04985|012|E|de pointes (TdP).(1)|
04985|013|B||
04985|014|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
04985|015|P|renal or hepatic impairment.(1)|
04985|016|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04985|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04985|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04985|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04985|020|P|advanced age.(2)|
04985|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04985|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04985|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04985|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04985|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04985|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04985|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04985|028|B||
04985|029|M|PATIENT MANAGEMENT:  The US manufacturer of dordaviprone states that|
04985|030|M|concomitant use with strong CYP3A4 inhibitors should be avoided.(1).|
04985|031|M|   If concomitant use with a strong CYP3A4 inhibitor cannot be avoided in|
04985|032|M|adult and pediatric patients who weight at least 52.5 kg, reduce the|
04985|033|M|dordaviprone dosage from 625 mg to 375 mg once weekly.  Recommended doses|
04985|034|M|for patients weighing less than 52.5 kg receiving strong CYP3A4 inhibitors|
04985|035|M|has not been established.(1)|
04985|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04985|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04985|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04985|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04985|040|B||
04985|041|D|DISCUSSION:  In a study, concomitant use of dordaviprone with itraconazole|
04985|042|D|200 mg daily for 8 days (a strong CYP3A4 inhibitor) increased dordaviprone|
04985|043|D|maximum concentration (Cmax) and area-under-curve (AUC) by 2-fold and|
04985|044|D|4-fold, respectively.(1)|
04985|045|D|   Moderate CYP3A4 inhibitors (fluconazole or erythromycin) are predicted to|
04985|046|D|increase dordaviprone Cmax and AUC by 1.5-fold and 2.5-fold.(1)|
04985|047|D|   Dordaviprone causes concentration-dependent QTc interval prolongation.|
04985|048|D|In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8,|
04985|049|D|13.7) with dordaviprone at 1.2 times the maximum recommended dose.(1)|
04985|050|D|   In a pooled safety analysis, out of 82 patients with a post-baseline ECG,|
04985|051|D|6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had|
04985|052|D|an increase in QTc >500 msec.(1)|
04985|053|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, grapefruit,|
04985|054|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
04985|055|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
04985|056|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(3,4)|
04985|057|B||
04985|058|R|REFERENCES:|
04985|059|B||
04985|060|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04985|061|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04985|062|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04985|063|R|  settings: a scientific statement from the American Heart Association and|6
04985|064|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04985|065|R|  2;55(9):934-47.|6
04985|066|R|3.This information is based on an extract from the Certara Drug Interaction|6
04985|067|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04985|068|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04985|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04985|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04985|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04985|072|R|  11/14/2017.|1
04986|001|T|MONOGRAPH TITLE:  Dordaviprone/QT Prolonging Agents|
04986|002|B||
04986|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04986|004|L|of severe adverse interaction.|
04986|005|B||
04986|006|A|MECHANISM OF ACTION:  Dordaviprone has been shown to prolong the QTc|
04986|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04986|008|A|may result in additive effects on the QTc interval.(1)|
04986|009|B||
04986|010|E|CLINICAL EFFECTS:  The concurrent use of dordaviprone with other agents that|
04986|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04986|012|E|arrhythmias, including torsades de pointes (TdP).(1)|
04986|013|B||
04986|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
04986|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
04986|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
04986|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04986|018|P|female gender, or advanced age.(2)|
04986|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04986|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04986|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04986|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04986|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04986|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04986|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04986|026|B||
04986|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of dordaviprone with other|
04986|028|M|agents known to prolong the QTc interval.  If current use cannot be avoided,|
04986|029|M|separate administration of dordaviprone and the QT-prolonging agent.  The|
04986|030|M|manufacturer does not provide details about how to separate administration|
04986|031|M|and states that the exposure-response relationship and time course of|
04986|032|M|pharmacodynamic response is not fully characterized.  Dordaviprone's time to|
04986|033|M|maximum concentration (Tmax) occurs at 1.4 hours (0.5, 5.6 hours) and mean|
04986|034|M|terminal half-life is 11 hours.(1)|
04986|035|M|   Baseline and periodic monitoring of ECG and electrolytes is|
04986|036|M|recommended.(1)  Increase the frequency of monitoring in patients with|
04986|037|M|congenital long QT syndrome, existing QTc prolongation, history of|
04986|038|M|ventricular arrhythmias, electrolyte abnormalities, heart failure, or are|
04986|039|M|taking strong or moderate CYP3A4 inhibitors.(1)|
04986|040|M|   If QTc interval prolongation occurs, dose modifications are warranted.|
04986|041|M|If QTc is >500 msec or the change from baseline is >60 msec, interrupt|
04986|042|M|dordaviprone therapy until QTc interval is <= 480 msec or returns to|
04986|043|M|baseline.  If the patient has Torsades de pointes, polymorphic ventricular|
04986|044|M|tachycardia, or signs or symptoms of serious or life-threatening arrhythmia,|
04986|045|M|permanently discontinue dordaviprone.(1)|
04986|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04986|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04986|048|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04986|049|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04986|050|B||
04986|051|D|DISCUSSION:  Dordaviprone causes concentration-dependent QTc|
04986|052|D|prolongation.(1)|
04986|053|D|   In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8,|
04986|054|D|13.7) with dordaviprone (1.2 times the maximum recommended dose).(1)|
04986|055|D|   In a pooled safety analysis, out of 82 patients with baseline ECG, 6% of|
04986|056|D|patients had an increase in QTc of >60 msec from baseline and 1.2% had an|
04986|057|D|increase in QTc >500 msec.|
04986|058|D|   Agents that are linked to this monograph may have varying degrees of|
04986|059|D|potential to prolong the QTc interval but are generally accepted to have a|
04986|060|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04986|061|D|been shown to prolong the QTc interval either through their mechanism of|
04986|062|D|action, through studies on their effects on the QTc interval, or through|
04986|063|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04986|064|D|and/or post-marketing reports.(3)|
04986|065|B||
04986|066|R|REFERENCES:|
04986|067|B||
04986|068|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04986|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04986|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04986|071|R|  settings: a scientific statement from the American Heart Association and|6
04986|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04986|073|R|  2;55(9):934-47.|6
04986|074|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04986|075|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04986|076|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04986|077|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04987|001|T|MONOGRAPH TITLE:  Dordaviprone/Moderate CYP3A4 Inhibitors|
04987|002|B||
04987|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04987|004|L|of severe adverse interaction.|
04987|005|B||
04987|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
04987|007|A|of dordaviprone.(1)|
04987|008|B||
04987|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
04987|010|E|the levels and effects of dordaviprone, including QTc prolongation, which|
04987|011|E|may result in potentially life-threatening cardiac arrhythmias like torsades|
04987|012|E|de pointes (TdP).(1)|
04987|013|B||
04987|014|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
04987|015|P|renal or hepatic impairment.(1)|
04987|016|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04987|017|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04987|018|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04987|019|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04987|020|P|advanced age.(2)|
04987|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04987|022|P|higher systemic concentrations of either QT prolonging drug are additional|
04987|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04987|024|P|drug concentrations include rapid infusion of an intravenous dose or|
04987|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04987|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04987|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04987|028|B||
04987|029|M|PATIENT MANAGEMENT:  The US manufacturer of dordaviprone states that|
04987|030|M|concomitant use with moderate CYP3A4 inhibitors should be avoided.(1).|
04987|031|M|   If concomitant use with a moderate CYP3A4 inhibitor cannot be avoided in|
04987|032|M|adult and pediatric patients who weigh at least 52.5 kg, reduce the|
04987|033|M|dordaviprone dosage from 625 mg to 500 mg once weekly.  Recommended doses|
04987|034|M|for patients weighing less than 52.5 kg receiving moderate CYP3A4 inhibitors|
04987|035|M|has not been established.(1)|
04987|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04987|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04987|038|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04987|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04987|040|B||
04987|041|D|DISCUSSION:  In a study, concomitant use of dordaviprone with itraconazole|
04987|042|D|200 mg daily for 8 days (a strong CYP3A4 inhibitor) increased dordaviprone|
04987|043|D|maximum concentration (Cmax) and area-under-curve (AUC) by 2-fold and|
04987|044|D|4-fold, respectively.(1)|
04987|045|D|   Moderate CYP3A4 inhibitors (fluconazole or erythromycin) are predicted to|
04987|046|D|increase dordaviprone Cmax and AUC by 1.5-fold and 2.5-fold.(1)|
04987|047|D|   Dordaviprone causes concentration-dependent QTc interval prolongation.|
04987|048|D|In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8,|
04987|049|D|13.7) with dordaviprone at 1.2 times the maximum recommended dose.(1)|
04987|050|D|   In a pooled safety analysis, out of 82 patients with a post-baseline ECG,|
04987|051|D|6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had|
04987|052|D|an increase in QTc >500 msec.(1)|
04987|053|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
04987|054|D|atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem,|
04987|055|D|duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
04987|056|D|isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat,|
04987|057|D|rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil,|
04987|058|D|and voxelotor.(3,4)|
04987|059|B||
04987|060|R|REFERENCES:|
04987|061|B||
04987|062|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04987|063|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04987|064|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04987|065|R|  settings: a scientific statement from the American Heart Association and|6
04987|066|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04987|067|R|  2;55(9):934-47.|6
04987|068|R|3.This information is based on an extract from the Certara Drug Interaction|6
04987|069|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04987|070|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04987|071|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04987|072|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04987|073|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04987|074|R|  11/14/2017.|1
04988|001|T|MONOGRAPH TITLE:  Dordaviprone/Possible QT Prolonging Agents|
04988|002|B||
04988|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04988|004|L|take action as needed.|
04988|005|B||
04988|006|A|MECHANISM OF ACTION:  Dordaviprone has been shown to prolong the QTc|
04988|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04988|008|A|may result in additive effects on the QTc interval.(1)|
04988|009|B||
04988|010|E|CLINICAL EFFECTS:  The concurrent use of dordaviprone with other agents that|
04988|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
04988|012|E|arrhythmias, including torsades de pointes (TdP).(1)|
04988|013|B||
04988|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
04988|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
04988|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
04988|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04988|018|P|female gender, or advanced age.(2)|
04988|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04988|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04988|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04988|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04988|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04988|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04988|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04988|026|B||
04988|027|M|PATIENT MANAGEMENT:  If possible, avoid the use of dordaviprone with other|
04988|028|M|agents known to prolong the QTc interval.  If current use cannot be avoided,|
04988|029|M|separate administration of dordaviprone and the QT-prolonging agent.  The|
04988|030|M|manufacturer does not provide details about how to separate administration|
04988|031|M|and states that the exposure-response relationship and time course of|
04988|032|M|pharmacodynamic response is not fully characterized.  Dordaviprone's time to|
04988|033|M|maximum concentration (Tmax) occurs at 1.4 hours (0.5, 5.6 hours) and mean|
04988|034|M|terminal half-life is 11 hours.(1)|
04988|035|M|   Baseline and periodic monitoring of ECG and electrolytes is|
04988|036|M|recommended.(1)  Increase the frequency of monitoring in patients with|
04988|037|M|congenital long QT syndrome, existing QTc prolongation, history of|
04988|038|M|ventricular arrhythmias, electrolyte abnormalities, heart failure, or are|
04988|039|M|taking strong or moderate CYP3A4 inhibitors.(1)|
04988|040|M|   If QTc interval prolongation occurs, dose modifications are warranted.|
04988|041|M|If QTc is >500 msec or the change from baseline is >60 msec, interrupt|
04988|042|M|dordaviprone therapy until QTc interval is <= 480 msec or returns to|
04988|043|M|baseline.  If the patient has Torsades de pointes, polymorphic ventricular|
04988|044|M|tachycardia, or signs or symptoms of serious or life-threatening arrhythmia,|
04988|045|M|permanently discontinue dordaviprone.(1)|
04988|046|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04988|047|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04988|048|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04988|049|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04988|050|B||
04988|051|D|DISCUSSION:  Dordaviprone causes concentration-dependent QTc|
04988|052|D|prolongation.(1)|
04988|053|D|   In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8,|
04988|054|D|13.7) with dordaviprone (1.2 times the maximum recommended dose).(1)|
04988|055|D|   In a pooled safety analysis, out of 82 patients with baseline ECG, 6% of|
04988|056|D|patients had an increase in QTc of >60 msec from baseline and 1.2% had an|
04988|057|D|increase in QTc >500 msec.|
04988|058|D|   Agents that are linked to this monograph may have varying degrees of|
04988|059|D|potential to prolong the QTc interval but are generally accepted to have a|
04988|060|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04988|061|D|been shown to prolong the QTc interval either through their mechanism of|
04988|062|D|action, through studies on their effects on the QTc interval, or through|
04988|063|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04988|064|D|and/or post-marketing reports.(3)|
04988|065|B||
04988|066|R|REFERENCES:|
04988|067|B||
04988|068|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04988|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04988|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04988|071|R|  settings: a scientific statement from the American Heart Association and|6
04988|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04988|073|R|  2;55(9):934-47.|6
04988|074|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04988|075|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04988|076|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04988|077|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04989|001|T|MONOGRAPH TITLE:  Dordaviprone/Strong CYP3A4 Inhibitors that Prolong QT|
04989|002|B||
04989|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04989|004|L|of severe adverse interaction.|
04989|005|B||
04989|006|A|MECHANISM OF ACTION:  Dordaviprone is a CYP3A4 substrate and has been shown|
04989|007|A|to prolong the QTc interval.  Strong CYP3A4 inhibitors that prolong the QTc|
04989|008|A|interval may inhibit the metabolism of dordaviprone and result in additive|
04989|009|A|risk of QT prolongation.(1)|
04989|010|B||
04989|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors that prolong|
04989|012|E|QT may increase the levels and effects of dordaviprone, including additive|
04989|013|E|QTc prolongation, which may result in potentially life-threatening cardiac|
04989|014|E|arrhythmias like torsades de pointes (TdP).(1)|
04989|015|B||
04989|016|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
04989|017|P|renal or hepatic impairment.(1)|
04989|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04989|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04989|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04989|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04989|022|P|advanced age.(2)|
04989|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04989|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04989|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04989|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04989|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04989|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04989|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04989|030|B||
04989|031|M|PATIENT MANAGEMENT:  The US manufacturer of dordaviprone states that the|
04989|032|M|concurrent use of QT prolonging agents should be avoided.  If current use|
04989|033|M|cannot be avoided, separate administration of dordaviprone and the|
04989|034|M|QT-prolonging agent.  The manufacturer does not provide details about how to|
04989|035|M|separate administration and states that the exposure-response relationship|
04989|036|M|and time course of pharmacodynamic response is not fully characterized.|
04989|037|M|Dordaviprone's time to maximum concentration (Tmax) occurs at 1.4 hours|
04989|038|M|(0.5, 5.6 hours) and mean terminal half-life is 11 hours.(1)|
04989|039|M|   Concomitant use with strong CYP3A4 inhibitors should also be avoided.(1)|
04989|040|M|If concomitant use with a strong CYP3A4 inhibitor cannot be avoided in adult|
04989|041|M|and pediatric patients who weigh at least 52.5 kg, reduce the dordaviprone|
04989|042|M|dosage from 625 mg to 375 mg once weekly.  Recommended doses for patients|
04989|043|M|weighing less than 52.5 kg receiving strong CYP3A4 inhibitors has not been|
04989|044|M|established.(1)|
04989|045|M|   Baseline and periodic monitoring of ECG and electrolytes is|
04989|046|M|recommended.(1)  Increase the frequency of monitoring in patients with|
04989|047|M|congenital long QT syndrome, existing QTc prolongation, history of|
04989|048|M|ventricular arrhythmias, electrolyte abnormalities, heart failure, or who|
04989|049|M|are taking strong CYP3A4 inhibitors.(1)|
04989|050|M|   If QTc interval prolongation occurs, dose modifications are warranted.|
04989|051|M|If QTc is >500 msec or the change from baseline is >60 msec, interrupt|
04989|052|M|dordaviprone therapy until QTc interval is <= 480 msec or returns to|
04989|053|M|baseline.  If the patient has Torsades de pointes, polymorphic ventricular|
04989|054|M|tachycardia, or signs or symptoms of serious or life-threatening arrhythmia,|
04989|055|M|permanently discontinue dordaviprone.(1)|
04989|056|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04989|057|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04989|058|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04989|059|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04989|060|B||
04989|061|D|DISCUSSION:  In a study, concomitant use of dordaviprone with itraconazole|
04989|062|D|200 mg daily for 8 days (a strong CYP3A4 inhibitor) increased dordaviprone|
04989|063|D|maximum concentration (Cmax) and area-under-curve (AUC) by 2-fold and|
04989|064|D|4-fold, respectively.(1)|
04989|065|D|   Moderate CYP3A4 inhibitors (fluconazole or erythromycin) are predicted to|
04989|066|D|increase dordaviprone Cmax and AUC by 1.5-fold and 2.5-fold.(1)|
04989|067|D|   Dordaviprone causes concentration-dependent QTc interval prolongation.|
04989|068|D|In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8,|
04989|069|D|13.7) with dordaviprone at 1.2 times the maximum recommended dose.(1)|
04989|070|D|   In a pooled safety analysis, out of 82 patients with a post-baseline ECG,|
04989|071|D|6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had|
04989|072|D|an increase in QTc >500 msec.(1)|
04989|073|D|   Strong inhibitors of CYP3A4 that prolong QT include:  adagrasib,|
04989|074|D|ceritinib, clarithromycin, levoketoconazole, lonafarnib,|
04989|075|D|lopinavir-ritonavir, posaconazole, ribociclib, saquinavir, telithromycin,|
04989|076|D|and voriconazole.(3,4)|
04989|077|B||
04989|078|R|REFERENCES:|
04989|079|B||
04989|080|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04989|081|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04989|082|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04989|083|R|  settings: a scientific statement from the American Heart Association and|6
04989|084|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04989|085|R|  2;55(9):934-47.|6
04989|086|R|3.This information is based on an extract from the Certara Drug Interaction|6
04989|087|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04989|088|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04989|089|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04989|090|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04989|091|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04989|092|R|  11/14/2017.|1
04990|001|T|MONOGRAPH TITLE:  Dordaviprone/Moderate CYP3A4 Inhibitors that Prolong QT|
04990|002|B||
04990|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04990|004|L|of severe adverse interaction.|
04990|005|B||
04990|006|A|MECHANISM OF ACTION:  Dordaviprone is a CYP3A4 substrate and has been shown|
04990|007|A|to prolong the QTc interval.  Moderate CYP3A4 inhibitors that prolong the|
04990|008|A|QTc interval may inhibit the metabolism of dordaviprone and result in|
04990|009|A|additive risk of QT prolongation.(1)|
04990|010|B||
04990|011|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
04990|012|E|QT may increase the levels and effects of dordaviprone, including QTc|
04990|013|E|prolongation, which may result in potentially life-threatening cardiac|
04990|014|E|arrhythmias like torsades de pointes (TdP).(1)|
04990|015|B||
04990|016|P|PREDISPOSING FACTORS:  This interaction may be more severe in patients with|
04990|017|P|renal or hepatic impairment.(1)|
04990|018|P|   The risk of QT prolongation or torsades de pointes may be increased in|
04990|019|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
04990|020|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
04990|021|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
04990|022|P|advanced age.(2)|
04990|023|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04990|024|P|higher systemic concentrations of either QT prolonging drug are additional|
04990|025|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04990|026|P|drug concentrations include rapid infusion of an intravenous dose or|
04990|027|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04990|028|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04990|029|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04990|030|B||
04990|031|M|PATIENT MANAGEMENT:  The US manufacturer of dordaviprone states that the|
04990|032|M|concurrent use of QT prolonging agents should be avoided.  If current use|
04990|033|M|cannot be avoided, separate administration of dordaviprone and the|
04990|034|M|QT-prolonging agent.  The manufacturer does not provide details about how to|
04990|035|M|separate administration and states that the exposure-response relationship|
04990|036|M|and time course of pharmacodynamic response is not fully characterized.|
04990|037|M|Dordaviprone's time to maximum concentration (Tmax) occurs at 1.4 hours|
04990|038|M|(0.5, 5.6 hours) and mean terminal half-life is 11 hours.(1)|
04990|039|M|   Concomitant use with moderate CYP3A4 inhibitors should also be|
04990|040|M|avoided.(1)  If concomitant use with a moderate CYP3A4 inhibitor cannot be|
04990|041|M|avoided in adult and pediatric patients who weigh at least 52.5 kg, reduce|
04990|042|M|the dordaviprone dosage from 625 mg to 500 mg once weekly.  Recommended|
04990|043|M|doses for patients weighing less than 52.5 kg receiving moderate CYP3A4|
04990|044|M|inhibitors has not been established.(1)|
04990|045|M|   Baseline and periodic monitoring of ECG and electrolytes is|
04990|046|M|recommended.(1)  Increase the frequency of monitoring in patients with|
04990|047|M|congenital long QT syndrome, existing QTc prolongation, history of|
04990|048|M|ventricular arrhythmias, electrolyte abnormalities, heart failure, or are|
04990|049|M|taking moderate CYP3A4 inhibitors.(1)|
04990|050|M|   If QTc interval prolongation occurs, dose modifications are warranted.|
04990|051|M|If QTc is >500 msec or the change from baseline is >60 msec, interrupt|
04990|052|M|dordaviprone therapy until QTc interval is <= 480 msec or returns to|
04990|053|M|baseline.  If the patient has Torsades de pointes, polymorphic ventricular|
04990|054|M|tachycardia, or signs or symptoms of serious or life-threatening arrhythmia,|
04990|055|M|permanently discontinue dordaviprone.(1)|
04990|056|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04990|057|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04990|058|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04990|059|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04990|060|B||
04990|061|D|DISCUSSION:  In a study, concomitant use of dordaviprone with itraconazole|
04990|062|D|200 mg daily for 8 days (a strong CYP3A4 inhibitor) increased dordaviprone|
04990|063|D|maximum concentration (Cmax) and area-under-curve (AUC) by 2-fold and|
04990|064|D|4-fold, respectively.(1)|
04990|065|D|   Moderate CYP3A4 inhibitors (fluconazole or erythromycin) are predicted to|
04990|066|D|increase dordaviprone Cmax and AUC by 1.5-fold and 2.5-fold.(1)|
04990|067|D|   Dordaviprone causes concentration-dependent QTc interval prolongation.|
04990|068|D|In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8,|
04990|069|D|13.7) with dordaviprone at 1.2 times the maximum recommended dose.(1)|
04990|070|D|   In a pooled safety analysis, out of 82 patients with a post-baseline ECG,|
04990|071|D|6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had|
04990|072|D|an increase in QTc >500 msec.(1)|
04990|073|D|   Moderate inhibitors of CYP3A4 that prolong QT include:  clofazimine,|
04990|074|D|crizotinib, dronedarone, erythromycin, fluconazole, oral lefamulin, and|
04990|075|D|nilotinib.(3,4)|
04990|076|B||
04990|077|R|REFERENCES:|
04990|078|B||
04990|079|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04990|080|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04990|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04990|082|R|  settings: a scientific statement from the American Heart Association and|6
04990|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04990|084|R|  2;55(9):934-47.|6
04990|085|R|3.This information is based on an extract from the Certara Drug Interaction|6
04990|086|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04990|087|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
04990|088|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04990|089|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04990|090|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04990|091|R|  11/14/2017.|1
04991|001|T|MONOGRAPH TITLE:  Dordaviprone/Strong CYP3A4 Inducers|
04991|002|B||
04991|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04991|004|L|of severe adverse interaction.|
04991|005|B||
04991|006|A|MECHANISM OF ACTION:  Dordaviprone is a CYP3A4 substrate.  Strong CYP3A4|
04991|007|A|inducers may induce the metabolism of dordaviprone.(1)|
04991|008|B||
04991|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04991|010|E|may decrease the levels and effectiveness of dordaviprone.(1)|
04991|011|B||
04991|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04991|013|P|of the inducer for longer than 1-2 weeks.|
04991|014|B||
04991|015|M|PATIENT MANAGEMENT:  The manufacturer of dordaviprone states that|
04991|016|M|co-administration with strong inducers of CYP3A4 should be avoided.  Monitor|
04991|017|M|patients for loss of efficacy or consider the use of alternative medicinal|
04991|018|M|products.(1)|
04991|019|B||
04991|020|D|DISCUSSION:  Concurrent use of rifampin (a strong CYP3A4 inducer) is|
04991|021|D|predicted to decrease dordaviprone maximum concentration (Cmax) by 68% and|
04991|022|D|area-under-curve (AUC) by 83%.(1)|
04991|023|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04991|024|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04991|025|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
04991|026|D|St. John's Wort.(2,3)|
04991|027|B||
04991|028|R|REFERENCES:|
04991|029|B||
04991|030|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04991|031|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04991|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04991|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04991|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04991|035|R|  11/14/2017.|1
04991|036|R|3.This information is based on an extract from the Certara Drug Interaction|6
04991|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04992|001|T|MONOGRAPH TITLE:  Dordaviprone/Strong CYP3A4 Inducers that Prolong QT|
04992|002|B||
04992|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04992|004|L|of severe adverse interaction.|
04992|005|B||
04992|006|A|MECHANISM OF ACTION:  Dordaviprone is a CYP3A4 substrate and has been shown|
04992|007|A|to prolong the QTc interval.  Strong CYP3A4 inducers may induce the|
04992|008|A|metabolism of dordaviprone.|
04992|009|A|   Concurrent use of agents that prolong the QTc interval may result in|
04992|010|A|additive effects on the QTc interval.(1-3)|
04992|011|B||
04992|012|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers that|
04992|013|E|prolong QT may result in decreased levels and effectiveness of dordaviprone|
04992|014|E|and increase the risk of potentially life-threatening arrhythmias including|
04992|015|E|torsades de pointes.(1-3)|
04992|016|B||
04992|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04992|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04992|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04992|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04992|021|P|female gender, or advanced age.(4)|
04992|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04992|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04992|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04992|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04992|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04992|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04992|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04992|029|P|   Induction effects may be more likely with regular use of the inducer for|
04992|030|P|longer than 1-2 weeks.|
04992|031|B||
04992|032|M|PATIENT MANAGEMENT:  The US manufacturer of dordaviprone states that the|
04992|033|M|concurrent use of QT prolonging agents should be avoided.  If current use|
04992|034|M|cannot be avoided, separate administration of dordaviprone and the|
04992|035|M|QT-prolonging agent.  The manufacturer does not provide details about how to|
04992|036|M|separate administration and states that the exposure-response relationship|
04992|037|M|and time course of pharmacodynamic response is not fully characterized.|
04992|038|M|Dordaviprone's time to maximum concentration (Tmax) occurs at 1.4 hours|
04992|039|M|(0.5, 5.6 hours) and mean terminal half-life is 11 hours.(1)|
04992|040|M|   Concomitant use with strong CYP3A4 inducers should also be avoided.|
04992|041|M|Consider the use of alternative agents with less enzyme induction|
04992|042|M|potential.(1)|
04992|043|M|   If concurrent use is necessary, baseline and periodic monitoring of ECG|
04992|044|M|and electrolytes is recommended.(1) Increase the frequency of monitoring in|
04992|045|M|patients with congenital long QT syndrome, existing QTc prolongation,|
04992|046|M|history of ventricular arrhythmias, electrolyte abnormalities, or heart|
04992|047|M|failure.(1)|
04992|048|M|   If QTc interval prolongation occurs, dose modifications are warranted. If|
04992|049|M|QTc is >500 msec or the change from baseline is >60 msec, interrupt|
04992|050|M|dordaviprone therapy until QTc interval is <= 480 msec or returns to|
04992|051|M|baseline. If the patient has Torsades de pointes, polymorphic ventricular|
04992|052|M|tachycardia, or signs or symptoms of serious or life-threatening arrhythmia,|
04992|053|M|permanently discontinue dordaviprone.(1)|
04992|054|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04992|055|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04992|056|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04992|057|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04992|058|B||
04992|059|D|DISCUSSION:  Concurrent use of rifampin (a strong CYP3A4 inducer) is|
04992|060|D|predicted to decrease dordaviprone maximum concentration (Cmax) by 68% and|
04992|061|D|area-under-curve (AUC) by 83%.  Concurrent use of efavirenz (a moderate|
04992|062|D|CYP3A4 inducer) is predicted to decrease dordaviprone Cmax by 44% and AUC by|
04992|063|D|65%.(1)|
04992|064|D|   Dordaviprone causes concentration-dependent QTc interval prolongation.|
04992|065|D|In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8,|
04992|066|D|13.7) with dordaviprone at 1.2 times the maximum recommended dose.(1)|
04992|067|D|   In a pooled safety analysis, out of 82 patients with a post-baseline ECG,|
04992|068|D|6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had|
04992|069|D|an increase in QTc >500 msec.(1)|
04992|070|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04992|071|D|encorafenib and ivosidenib.(3)|
04992|072|B||
04992|073|R|REFERENCES:|
04992|074|B||
04992|075|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04992|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04992|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04992|078|R|  settings: a scientific statement from the American Heart Association and|6
04992|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04992|080|R|  2;55(9):934-47.|6
04992|081|R|3.This information is based on an extract from the Certara Drug Interaction|6
04992|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04993|001|T|MONOGRAPH TITLE:  Dordaviprone/Moderate CYP3A4 Inducers that Prolong QT|
04993|002|B||
04993|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04993|004|L|of severe adverse interaction.|
04993|005|B||
04993|006|A|MECHANISM OF ACTION:  Dordaviprone is a CYP3A4 substrate and has been shown|
04993|007|A|to prolong the QTc interval.  Moderate CYP3A4 inducers may induce the|
04993|008|A|metabolism of dordaviprone.|
04993|009|A|   Concurrent use of agents that prolong the QTc interval may result in|
04993|010|A|additive effects on the QTc interval.(1-3)|
04993|011|B||
04993|012|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers that|
04993|013|E|prolong QT may result in decreased levels and effectiveness of dordaviprone|
04993|014|E|and increase the risk of potentially life-threatening arrhythmias including|
04993|015|E|torsades de pointes.(1-3)|
04993|016|B||
04993|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04993|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04993|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04993|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04993|021|P|female gender, or advanced age.(4)|
04993|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04993|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04993|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04993|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04993|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04993|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04993|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
04993|029|P|   Induction effects may be more likely with regular use of the inducer for|
04993|030|P|longer than 1-2 weeks.|
04993|031|B||
04993|032|M|PATIENT MANAGEMENT:  The US manufacturer of dordaviprone states that the|
04993|033|M|concurrent use of QT prolonging agents should be avoided.  If current use|
04993|034|M|cannot be avoided, separate administration of dordaviprone and the|
04993|035|M|QT-prolonging agent.  The manufacturer does not provide details about how to|
04993|036|M|separate administration and states that the exposure-response relationship|
04993|037|M|and time course of pharmacodynamic response is not fully characterized.|
04993|038|M|Dordaviprone's time to maximum concentration (Tmax) occurs at 1.4 hours|
04993|039|M|(0.5, 5.6 hours) and mean terminal half-life is 11 hours.(1)|
04993|040|M|   Concomitant use with moderate CYP3A4 inducers should also be avoided.|
04993|041|M|Consider the use of alternative agents with less enzyme induction|
04993|042|M|potential.(1)|
04993|043|M|   If concurrent use is necessary, baseline and periodic monitoring of ECG|
04993|044|M|and electrolytes is recommended.(1)  Increase the frequency of monitoring in|
04993|045|M|patients with congenital long QT syndrome, existing QTc prolongation,|
04993|046|M|history of ventricular arrhythmias, electrolyte abnormalities, or heart|
04993|047|M|failure.(1)|
04993|048|M|   If QTc interval prolongation occurs, dose modifications are warranted.|
04993|049|M|If QTc is >500 msec or the change from baseline is >60 msec, interrupt|
04993|050|M|dordaviprone therapy until QTc interval is <= 480 msec or returns to|
04993|051|M|baseline.  If the patient has Torsades de pointes, polymorphic ventricular|
04993|052|M|tachycardia, or signs or symptoms of serious or life-threatening arrhythmia,|
04993|053|M|permanently discontinue dordaviprone.(1)|
04993|054|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04993|055|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04993|056|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04993|057|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04993|058|B||
04993|059|D|DISCUSSION:  Concurrent use of rifampin (a strong CYP3A4 inducer) is|
04993|060|D|predicted to decrease dordaviprone maximum concentration (Cmax) by 68% and|
04993|061|D|area-under-curve (AUC) by 83%. Concurrent use of efavirenz (a moderate|
04993|062|D|CYP3A4 inducer) is predicted to decrease dordaviprone Cmax by 44% and AUC by|
04993|063|D|65%.(1)|
04993|064|D|   Dordaviprone causes concentration-dependent QTc interval prolongation.|
04993|065|D|In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8,|
04993|066|D|13.7) with dordaviprone at 1.2 times the maximum recommended dose.(1)|
04993|067|D|   In a pooled safety analysis, out of 82 patients with a post-baseline ECG,|
04993|068|D|6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had|
04993|069|D|an increase in QTc >500 msec.(1)|
04993|070|D|   Moderate CYP3A4 inducers that prolong QT linked to this monograph|
04993|071|D|include: efavirenz, pacritinib, and thioridazine.(3)|
04993|072|B||
04993|073|R|REFERENCES:|
04993|074|B||
04993|075|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04993|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04993|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04993|078|R|  settings: a scientific statement from the American Heart Association and|6
04993|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04993|080|R|  2;55(9):934-47.|6
04993|081|R|3.This information is based on an extract from the Certara Drug Interaction|6
04993|082|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04994|001|T|MONOGRAPH TITLE:  Dordaviprone/Moderate CYP3A4 Inducers|
04994|002|B||
04994|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04994|004|L|of severe adverse interaction.|
04994|005|B||
04994|006|A|MECHANISM OF ACTION:  Dordaviprone is a CYP3A4 substrate.  Moderate CYP3A4|
04994|007|A|inducers may induce the metabolism of dordaviprone.(1)|
04994|008|B||
04994|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate inducer of CYP3A4|
04994|010|E|may decrease the levels and effectiveness of dordaviprone.(1)|
04994|011|B||
04994|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04994|013|P|of the inducer for longer than 1-2 weeks.|
04994|014|B||
04994|015|M|PATIENT MANAGEMENT:  The manufacturer of dordaviprone states that|
04994|016|M|co-administration with moderate inducers of CYP3A4 should be avoided.|
04994|017|M|Monitor patients for loss of efficacy or consider the use of alternative|
04994|018|M|medicinal products.(1)|
04994|019|B||
04994|020|D|DISCUSSION:  Concurrent use of rifampin (a strong CYP3A4 inducer) is|
04994|021|D|predicted to decrease dordaviprone maximum concentration (Cmax) by 68% and|
04994|022|D|area-under-curve (AUC) by 83%. Concurrent use of efavirenz (a moderate|
04994|023|D|CYP3A4 inducer) is predicted to decrease dordaviprone Cmax by 44% and AUC by|
04994|024|D|65%.(1)|
04994|025|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
04994|026|D|bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad,|
04994|027|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib,|
04994|028|D|repotrectinib, rifabutin, sotorasib, telotristat ethyl, and|
04994|029|D|tovorafenib.(2,3)|
04994|030|B||
04994|031|R|REFERENCES:|
04994|032|B||
04994|033|R|1.Modeyso (dordaviprone) US prescribing information. Chimerix August, 2025.|1
04994|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
04994|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04994|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04994|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04994|038|R|  11/14/2017.|1
04994|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
04994|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04995|001|T|MONOGRAPH TITLE:  Catequentinib/QT Prolonging Agents|
04995|002|B||
04995|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
04995|004|L|take action as needed.|
04995|005|B||
04995|006|A|MECHANISM OF ACTION:  Catequentinib has been shown to prolong the QTc|
04995|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
04995|008|A|may result in additive effects on the QTc interval.(1)|
04995|009|B||
04995|010|E|CLINICAL EFFECTS:  The concurrent use of catequentinib with other agents|
04995|011|E|that prolong the QTc interval may result in potentially life-threatening|
04995|012|E|cardiac arrhythmias, including torsades de pointes (TdP).(1)|
04995|013|B||
04995|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
04995|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
04995|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
04995|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04995|018|P|female gender, or advanced age.(2)|
04995|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04995|020|P|higher systemic concentrations of either QT prolonging drug are additional|
04995|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
04995|022|P|drug concentrations include rapid infusion of an intravenous dose or|
04995|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04995|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04995|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04995|026|B||
04995|027|M|PATIENT MANAGEMENT:  The concurrent use of catequentinib with other agents|
04995|028|M|known to prolong the QTc interval should be monitored closely.  Monitor ECG|
04995|029|M|and electrolytes regularly (every 3-6 weeks) if catequentinib is|
04995|030|M|administered with concurrent QTc prolonging drugs.(1)|
04995|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04995|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04995|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04995|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04995|035|B||
04995|036|D|DISCUSSION:  Catequentinib causes QTc prolongation.  In clinical studies,|
04995|037|D|QTc prolongation was reported as a very common adverse effect.(1)|
04995|038|D|   Agents that are linked to this monograph may have varying degrees of|
04995|039|D|potential to prolong the QTc interval but are generally accepted to have a|
04995|040|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
04995|041|D|been shown to prolong the QTc interval either through their mechanism of|
04995|042|D|action, through studies on their effects on the QTc interval, or through|
04995|043|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
04995|044|D|and/or post-marketing reports.(3)|
04995|045|B||
04995|046|R|REFERENCES:|
04995|047|B||
04995|048|R|1.Fukewei (anlotinib) Hong Kong prescribing information. Chia Tai Tianquing|1
04995|049|R|  Pharmaceutical Group Co., Ltd. June, 2025.|1
04995|050|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04995|051|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04995|052|R|  settings: a scientific statement from the American Heart Association and|6
04995|053|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04995|054|R|  2;55(9):934-47.|6
04995|055|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
04995|056|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
04995|057|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
04995|058|R|  https://www.fda.gov/media/71372/download October, 2005.|1
04996|001|T|MONOGRAPH TITLE:  Catequentinib/Strong CYP3A4 Inducers|
04996|002|B||
04996|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04996|004|L|of severe adverse interaction.|
04996|005|B||
04996|006|A|MECHANISM OF ACTION:  Catequentinib is a CYP3A4 substrate.  Strong CYP3A4|
04996|007|A|inducers may induce the metabolism of catequentinib.(1)|
04996|008|B||
04996|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
04996|010|E|may decrease the levels and effectiveness of catequentinib.(1)|
04996|011|B||
04996|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04996|013|P|of the inducer for longer than 1-2 weeks.|
04996|014|B||
04996|015|M|PATIENT MANAGEMENT:  The manufacturer of catequentinib states that|
04996|016|M|co-administration with strong inducers of CYP3A4 should be avoided.  Monitor|
04996|017|M|patients for loss of efficacy or consider the use of alternative medicinal|
04996|018|M|products.(1)|
04996|019|B||
04996|020|D|DISCUSSION:  Catequentinib is a CYP3A4 substrate.(1)|
04996|021|D|   In a PKPB model, rifampin (a strong CYP3A4 inducer) decreased the|
04996|022|D|area-under-curve (AUC) and concentration maximum (Cmax) to 0.44 and 0.79,|
04996|023|D|respectively.(2)|
04996|024|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04996|025|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
04996|026|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
04996|027|D|St. John's Wort.(3,4)|
04996|028|B||
04996|029|R|REFERENCES:|
04996|030|B||
04996|031|R|1.Fukewei (anlotinib) Hong Kong prescribing information. Chia Tai Tianquing|1
04996|032|R|  Pharmaceutical Group Co., Ltd. June, 2025.|1
04996|033|R|2.Bu F, Cho YS, He Q, Wang X, Howlader S, Kim DH, Zhu M, Shin JG, Xiang X.|5
04996|034|R|  Prediction of Pharmacokinetic Drug-Drug Interactions Involving Anlotinib|5
04996|035|R|  as a  Victim by Using Physiologically Based Pharmacokinetic Modeling. Drug|5
04996|036|R|  Des Devel Ther 2024;18:4585-4600.|5
04996|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
04996|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04996|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04996|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04996|041|R|  11/14/2017.|1
04996|042|R|4.This information is based on an extract from the Certara Drug Interaction|6
04996|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04997|001|T|MONOGRAPH TITLE:  Catequentinib/Strong CYP3A4 Inducers that Prolong QT|
04997|002|B||
04997|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04997|004|L|of severe adverse interaction.|
04997|005|B||
04997|006|A|MECHANISM OF ACTION:  Catequentinib is a CYP3A4 substrate and has been shown|
04997|007|A|to prolong the QTc interval.  Strong CYP3A4 inducers may induce the|
04997|008|A|metabolism of catequentinib.(1)|
04997|009|A|   Concurrent use of agents that prolong the QTc interval may result in|
04997|010|A|additive effects on the QTc interval.(1-2)|
04997|011|B||
04997|012|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers that|
04997|013|E|prolong QT may result in decreased levels and effectiveness of catequentinib|
04997|014|E|and increase the risk of potentially life-threatening arrhythmias including|
04997|015|E|torsades de pointes.(1-2)|
04997|016|B||
04997|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
04997|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
04997|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
04997|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
04997|021|P|female gender, or advanced age.(2)|
04997|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
04997|023|P|higher systemic concentrations of either QT prolonging drug are additional|
04997|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
04997|025|P|drug concentrations include rapid infusion of an intravenous dose or|
04997|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
04997|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
04997|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
04997|029|P|   Induction effects may be more likely with regular use of the inducer for|
04997|030|P|longer than 1-2 weeks.|
04997|031|B||
04997|032|M|PATIENT MANAGEMENT:  The manufacturer of catequentinib states that|
04997|033|M|co-administration with strong inducers of CYP3A4 should be avoided.  Monitor|
04997|034|M|patients for loss of efficacy or consider the use of alternative medicinal|
04997|035|M|products.(1)|
04997|036|M|   The concurrent use of catequentinib with other agents known to prolong|
04997|037|M|the QTc interval should be monitored closely.  Monitor ECG and electrolytes|
04997|038|M|regularly (every 3-6 weeks) if catequentinib is administered with concurrent|
04997|039|M|QTc prolonging drugs.(1)|
04997|040|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
04997|041|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
04997|042|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
04997|043|M|patients to report any irregular heartbeat, dizziness, or fainting.|
04997|044|B||
04997|045|D|DISCUSSION:  Catequentinib is a CYP3A4 substrate.(1)|
04997|046|D|   In a PKPB model, rifampin (a strong CYP3A4 inducer) decreased the|
04997|047|D|area-under-curve (AUC) and concentration maximum (Cmax) to 0.44 and 0.79,|
04997|048|D|respectively.(3)|
04997|049|D|   Catequentinib causes QTc prolongation.  In clinical studies, QTc|
04997|050|D|prolongation was reported as a very common adverse effect.(1)|
04997|051|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
04997|052|D|encorafenib and ivosidenib.(4,5)|
04997|053|B||
04997|054|R|REFERENCES:|
04997|055|B||
04997|056|R|1.Fukewei (anlotinib) Hong Kong prescribing information. Chia Tai Tianquing|1
04997|057|R|  Pharmaceutical Group Co., Ltd. June, 2025.|1
04997|058|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
04997|059|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
04997|060|R|  settings: a scientific statement from the American Heart Association and|6
04997|061|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
04997|062|R|  2;55(9):934-47.|6
04997|063|R|3.Bu F, Cho YS, He Q, Wang X, Howlader S, Kim DH, Zhu M, Shin JG, Xiang X.|5
04997|064|R|  Prediction of Pharmacokinetic Drug-Drug Interactions Involving Anlotinib|5
04997|065|R|  as a  Victim by Using Physiologically Based Pharmacokinetic Modeling. Drug|5
04997|066|R|  Des Devel Ther 2024;18:4585-4600.|5
04997|067|R|4.This information is based on an extract from the Certara Drug Interaction|6
04997|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04997|069|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
04997|070|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
04997|071|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
04997|072|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
04997|073|R|  11/14/2017.|1
04998|001|T|MONOGRAPH TITLE:  Zongertinib/Strong CYP3A4 Inducers|
04998|002|B||
04998|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04998|004|L|of severe adverse interaction.|
04998|005|B||
04998|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
04998|007|A|zongertinib.(1)|
04998|008|B||
04998|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong CYP3A4 inducer may|
04998|010|E|result in decreased levels and effectiveness of zongertinib.(1)|
04998|011|B||
04998|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
04998|013|P|of the inducer for longer than 1-2 weeks.|
04998|014|B||
04998|015|M|PATIENT MANAGEMENT:  The manufacturer of zongertinib states that concomitant|
04998|016|M|use of strong CYP3A4 inducers should be avoided.(1)|
04998|017|M|   If concurrent use cannot be avoided, increase the zongertinib dose based|
04998|018|M|on body weight:|
04998|019|M|   - Less than 90 kg: increase from 120 mg to 240 mg dose|
04998|020|M|   - Greater than or equal to 90 kg: increase from 180 mg to 360 mg dose|
04998|021|M|   After stopping the CYP3A4 inducer, resume the prior zongertinib dose 7-14|
04998|022|M|days after stopping the CYP3A4 inducer.(1)|
04998|023|B||
04998|024|D|DISCUSSION:  Zongertinib area-under-curve (AUC) and maximum concentration|
04998|025|D|(Cmax) decreased by 63% and 43%, respectively, following concomitant use of|
04998|026|D|carbamazepine (strong CYP3A4 inducer) 600 mg once daily for 7 days.(1)|
04998|027|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
04998|028|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
04998|029|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
04998|030|D|rifampin, rifapentine, and St. John's wort.(2)|
04998|031|B||
04998|032|R|REFERENCES:|
04998|033|B||
04998|034|R|1.Hernexeos (zongertinib) US prescribing information. Boehringer Ingelheim|1
04998|035|R|  Pharamceuticals, Inc. August, 2025.|1
04998|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
04998|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
04999|001|T|MONOGRAPH TITLE:  Alcohol/Furazolidone|
04999|002|B||
04999|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
04999|004|L|of severe adverse interaction.|
04999|005|B||
04999|006|A|MECHANISM OF ACTION:  In vitro studies show that furazolidone produces an|
04999|007|A|inhibition of aldehyde dehydrogenase.(2,3)  This results in the accumulation|
04999|008|A|of acetaldehyde, which is responsible for the disulfiram-like reaction.|
04999|009|B||
04999|010|E|CLINICAL EFFECTS:  Concurrent use of furazolidone with alcohol has been|
04999|011|E|associated with a disulfiram-type reaction resulting in symptoms of|
04999|012|E|hypotension, tachycardia, nausea, sweating, facial flushing, headache, and|
04999|013|E|vomiting.|
04999|014|B||
04999|015|P|PREDISPOSING FACTORS:  None determined.|
04999|016|B||
04999|017|M|PATIENT MANAGEMENT:  The manufacturer of furazolidone states that alcohol is|
04999|018|M|not recommended during and for at least 4 days after taking furazolidone.(1)|
04999|019|M|   Patients should be advised of the possible effects that may result from|
04999|020|M|ingestion or application of products that contain alcohol while taking|
04999|021|M|furazolidone.|
04999|022|M|   Patients should be informed about unsuspected sources of alcohol such as|
04999|023|M|elixirs and topical preparations.|
04999|024|M|   Alcohol is used to improve docetaxel and paclitaxel solubility.|
04999|025|M|   - The quantity of alcohol in paclitaxel injection formulations|
04999|026|M|(0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg|
04999|027|M|dose contains approximately 13 grams of alcohol.|
04999|028|M|   - The quantity of alcohol in docetaxel formulations varies approximately|
04999|029|M|3-fold depending upon the manufacturer. FDA data on alcohol content (22):|
04999|030|M|   Product                      Manufacturer           Alcohol/200 mg dose|
04999|031|M|   Docetaxel Inj.               Pfizer                  6.4 grams|
04999|032|M|   Docetaxel Inj.               Sandoz                  5.5 grams|
04999|033|M|   Docetaxel Inj.               Accord                  4.0 grams|
04999|034|M|   Taxotere-one vial            Sanofi                  4.0 grams|
04999|035|M|    formulation|
04999|036|M|   Docetaxel Inj.               Hospira                 3.7 grams|
04999|037|M|   Docefrez                     Sun Pharma              2.9 grams|
04999|038|M|   Taxotere-two vial            Sanofi                  2.0 grams|
04999|039|M|    formulation|
04999|040|B||
04999|041|D|DISCUSSION:  In vitro studies have found that furazolidone inhibits aldehyde|
04999|042|D|dehydrogenase (ALDH).(2,3)  In one study, furazolidone nanoemulsion|
04999|043|D|inhibited 99.75% of ALDH activity while free furazolidone inhibited 25% of|
04999|044|D|ALDH activity.(3)|
04999|045|B||
04999|046|R|REFERENCES:|
04999|047|B||
04999|048|R|1.Furazolidon Terapia (furazolidone) Romania Summary of Product|1
04999|049|R|  Characteristics. Terapia S.A. March 2018.|1
04999|050|R|2.Karamanakos PN, Pappas P, Boumba VA, Thomas C, Malamas M, Vougiouklakis T,|5
04999|051|R|  Marselos M. Pharmaceutical agents known to produce disulfiram-like|5
04999|052|R|  reaction: effects on  hepatic ethanol metabolism and brain monoamines. Int|5
04999|053|R|  J Toxicol 2007 Sep-Oct;26(5):423-32.|5
04999|054|R|3.Darooee M, Akbari V, Taheri A. Inhibition of aldehyde dehydrogenase by|5
04999|055|R|  furazolidone nanoemulsion to decrease  cisplatin resistance in lung cancer|5
04999|056|R|  cells. Ther Deliv 2021 Aug;12(8):611-625.|5
05000|001|T|MONOGRAPH TITLE:  Live Vaccines/Brensocatib|
05000|002|B||
05000|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05000|004|L|of severe adverse interaction.|
05000|005|B||
05000|006|A|MECHANISM OF ACTION:  Brensocatib may suppress the immune system by|
05000|007|A|inhibiting dipeptidyl peptidase-1 (DPP-1).  Brensocatib prevents the|
05000|008|A|activation of neutrophil serine proteases (NSPs) during neutrophil|
05000|009|A|maturation in the bone marrow.(1)|
05000|010|A|   Immunocompromised patients may be at increased risk for uninhibited|
05000|011|A|replication after administration of live, attenuated vaccines.  Immune|
05000|012|A|response to vaccines may be decreased during periods of immunocompromise.(2)|
05000|013|B||
05000|014|E|CLINICAL EFFECTS:  The expected serum antibody response may not be obtained.|
05000|015|E|The vaccine may result in illness.  Immune response to live vaccines may be|
05000|016|E|decreased during periods of immunocompromise.(2)|
05000|017|B||
05000|018|P|PREDISPOSING FACTORS:  Immunosuppressive diseases (e.g. hematologic|
05000|019|P|malignancies, HIV disease), treatments (e.g. radiation) and drugs may all|
05000|020|P|increase the magnitude of immunodeficiency.|
05000|021|B||
05000|022|M|PATIENT MANAGEMENT:  The coadministration of live vaccines and brensocatib|
05000|023|M|should be avoided.(1)|
05000|024|M|   The Centers for Disease Control (CDC) Advisory Committee on Immunization|
05000|025|M|Practices (ACIP) states that live-virus and live-attenuated vaccines should|
05000|026|M|not be administered to patients who are immunocompromised.  The magnitude of|
05000|027|M|immunocompromise and associated risks should be determined by a|
05000|028|M|physician.(2)|
05000|029|B||
05000|030|D|DISCUSSION:  Killed or inactivated vaccines do not pose a danger to|
05000|031|D|immunocompromised patients.(2)|
05000|032|D|   The concomitant use of live attenuated vaccines and brensocatib has not|
05000|033|D|been evaluated.  Brensocatib may suppress the immune system by inhibiting|
05000|034|D|dipeptidyl peptidase-1 (DPP-1).(1)|
05000|035|B||
05000|036|R|REFERENCES:|
05000|037|B||
05000|038|R|1.Brinsupri (brensocatib) US prescribing information. Insmed Incorporated|1
05000|039|R|  August, 2025.|1
05000|040|R|2.Centers for Disease Control and Prevention. General Recommendations on|1
05000|041|R|  Immunization.  Recommendations of the Advisory Committee on Immunization|1
05000|042|R|  Practices (ACIP). MMWR.  Available at:|1
05000|043|R|  https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html|1
05000|044|R|  February 17, 2022;60(RR No.2):1-68.|1
05001|001|T|MONOGRAPH TITLE:  Atorvastatin/Selected BCRP Inhibitors|
05001|002|B||
05001|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05001|004|L|take action as needed.|
05001|005|B||
05001|006|A|MECHANISM OF ACTION:  Atorvastatin is a substrate of the BCRP|
05001|007|A|transporter.(1)|
05001|008|A|   Inhibitors of this transporter may increase intestinal absorption and|
05001|009|A|hepatic uptake of BCRP substrates atorvastatin.(1)|
05001|010|B||
05001|011|E|CLINICAL EFFECTS:  Administration of atorvastatin with BCRP inhibitors may|
05001|012|E|result in elevated levels of atorvastatin, which could result in|
05001|013|E|rhabdomyolysis.(1)|
05001|014|B||
05001|015|P|PREDISPOSING FACTORS:  The risk for myopathy or rhabdomyolysis may be|
05001|016|P|greater in patients 65 years and older, inadequately treated hypothyroidism,|
05001|017|P|renal impairment, carnitine deficiency, malignant hyperthermia, or in|
05001|018|P|patients with a history of myopathy or rhabdomyolysis.  Patients with a|
05001|019|P|SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake|
05001|020|P|transporter OATP1B1 may have increased statin concentrations and be|
05001|021|P|predisposed to myopathy or rhabdomyolysis.|
05001|022|B||
05001|023|M|PATIENT MANAGEMENT:  Concurrent use of atorvastatin with BCRP inhibitors may|
05001|024|M|result in increased risk of side effects associated with atorvastatin.|
05001|025|M|Close monitoring would be prudent for statin related side effects including|
05001|026|M|rhabdomyolysis.|
05001|027|M|   If concurrent therapy is deemed medically necessary, monitor patients for|
05001|028|M|signs and symptoms of myopathy/rhabdomyolysis, including muscle|
05001|029|M|pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of|
05001|030|M|urine, and/or discolored urine.|
05001|031|B||
05001|032|D|DISCUSSION:  Atorvastatin is a BCRP substrate.(1)|
05001|033|D|   BCRP inhibitors linked to this monograph include: capmatinib,|
05001|034|D|clopidogrel, curcumin, danicopan, encorafenib, fostamatinib, lazertinib,|
05001|035|D|leflunomide,  momelotinib, oteseconazole, pacritinib, pantoprazole,|
05001|036|D|pirtobrutinib, regorafenib, ritonavir, rolapitant, roxadustat,|
05001|037|D|selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tafamidis,|
05001|038|D|teriflunomide, tolvaptan, turmeric, vadadustat, velpatasvir, and|
05001|039|D|zongertinib.(2,3)|
05001|040|B||
05001|041|R|REFERENCES:|
05001|042|B||
05001|043|R|1.Lipitor (atorvastatin) US prescribing information. Pfizer Inc. November,|1
05001|044|R|  2020.|1
05001|045|R|2.This information is based on an extract from the Certara Drug Interaction|6
05001|046|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05001|047|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05001|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05001|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05001|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05001|051|R|  11/14/2017.|1
05002|001|T|MONOGRAPH TITLE:  Elinzanetant/Strong CYP3A4 Inhibitors|
05002|002|B||
05002|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05002|004|L|of severe adverse interaction.|
05002|005|B||
05002|006|A|MECHANISM OF ACTION:  Elinzanetant is metabolized via CYP3A4.  Strong|
05002|007|A|inhibitors of CYP3A4 may inhibit the metabolism of elinzanetant.(1)|
05002|008|B||
05002|009|E|CLINICAL EFFECTS:  Concurrent use of elinzanetant with strong CYP3A4|
05002|010|E|inhibitors may result in a significant increase in exposure of|
05002|011|E|elinzanetant.(1)|
05002|012|B||
05002|013|P|PREDISPOSING FACTORS:  None determined.|
05002|014|B||
05002|015|M|PATIENT MANAGEMENT:  The Canadian manufacturer of elinzanetant states|
05002|016|M|coadministration with strong CYP3A4 inhibitors is contraindicated.(1)|
05002|017|B||
05002|018|D|DISCUSSION:  Coadministration of elinzanetant with itraconazole 200 mg|
05002|019|D|daily, a strong CYP3A4 inhibitor, resulted in a 4.6-fold to 6.3-fold|
05002|020|D|increase in area-under-curve (AUC) and a 3.3-fold increase in maximum|
05002|021|D|concentration (Cmax).(1)|
05002|022|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
05002|023|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
05002|024|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir,|
05002|025|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
05002|026|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
05002|027|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)|
05002|028|B||
05002|029|R|REFERENCES:|
05002|030|B||
05002|031|R|1.Lynkuet (elinzanetant) Canadian prescribing information. Bayer, Inc. July|1
05002|032|R|  2025.|1
05002|033|R|2.This information is based on an extract from the Certara Drug Interaction|6
05002|034|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05002|035|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05002|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05002|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05002|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05002|039|R|  11/14/2017.|1
05003|001|T|MONOGRAPH TITLE:  Elinzanetant/Moderate CYP3A4 Inhibitors|
05003|002|B||
05003|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05003|004|L|take action as needed.|
05003|005|B||
05003|006|A|MECHANISM OF ACTION:  Elinzanetant is metabolized via CYP3A4. Moderate|
05003|007|A|inhibitors of CYP3A4 may inhibit the metabolism of elinzanetant.(1)|
05003|008|B||
05003|009|E|CLINICAL EFFECTS:  Concurrent use of elinzanetant with moderate CYP3A4|
05003|010|E|inhibitors may result in an increase in exposure of elinzanetant.(1)|
05003|011|B||
05003|012|P|PREDISPOSING FACTORS:  None determined.|
05003|013|B||
05003|014|M|PATIENT MANAGEMENT:  The Canadian manufacturer of elinzanetant recommends|
05003|015|M|reducing the dose of elinzanetant to 60 mg once daily at bedtime when|
05003|016|M|coadministered with moderate CYP3A4 inhibitors.(1)|
05003|017|M|   After discontinuation of the moderate inhibitor (after 3 to 5 half lives|
05003|018|M|of the inhibitor), elinzanetant should be used at the usual dose of 120 mg|
05003|019|M|once daily.(1)|
05003|020|B||
05003|021|D|DISCUSSION:  Concomitant use of erythromycin (moderate CYP3A4 inhibitor)|
05003|022|D|increased elinzanetant 120 mg area-under-curve (AUC) and maximum|
05003|023|D|concentration (Cmax) by 3-fold and 2-fold, respectively.  Concomitant use of|
05003|024|D|erythromycin with elinzanetant 60 mg increased elinzanetant AUC by|
05003|025|D|1.4-fold.(1)|
05003|026|D|   Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir,|
05003|027|D|aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan,|
05003|028|D|crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin,|
05003|029|D|fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant,|
05003|030|D|imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir,|
05003|031|D|netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol,|
05003|032|D|tofisopam, treosulfan, verapamil, and voxelotor.(2-3)|
05003|033|B||
05003|034|R|REFERENCES:|
05003|035|B||
05003|036|R|1.Lynkuet (elinzanetant) Canadian prescribing information. Bayer, Inc. July|1
05003|037|R|  2025.|1
05003|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
05003|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05003|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05003|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05003|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05003|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05003|044|R|  11/14/2017.|1
05004|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Strong CYP3A4 Inducers|
05004|002|B||
05004|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05004|004|L|of severe adverse interaction.|
05004|005|B||
05004|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
05004|007|A|rilzabrutinib.(1)|
05004|008|B||
05004|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong CYP3A4 inducer may|
05004|010|E|result in decreased levels and effectiveness of rilzabrutinib.(1)|
05004|011|B||
05004|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05004|013|P|of the inducer for longer than 1-2 weeks.|
05004|014|B||
05004|015|M|PATIENT MANAGEMENT:  The manufacturer of rilzabrutinib states that|
05004|016|M|concomitant use of strong CYP3A4 inducers should be avoided.(1)|
05004|017|B||
05004|018|D|DISCUSSION:  Rilzabrutinib is primarily metabolized by CYP3A4.(1)|
05004|019|D|   Concomitant administration of rilzabrutinib with rifampin (a strong|
05004|020|D|CYP3A4 inducer) resulted in a decrease in rilzabrutinib area under the curve|
05004|021|D|(AUC) and maximum concentration (Cmax) by 80% and 80%, respectively.(1)|
05004|022|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
05004|023|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
05004|024|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
05004|025|D|St. John's wort.(2)|
05004|026|B||
05004|027|R|REFERENCES:|
05004|028|B||
05004|029|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05004|030|R|  August, 2025.|1
05004|031|R|2.This information is based on an extract from the Certara Drug Interaction|6
05004|032|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05005|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Moderate CYP3A4 Inducers|
05005|002|B||
05005|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05005|004|L|of severe adverse interaction.|
05005|005|B||
05005|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
05005|007|A|rilzabrutinib.(1)|
05005|008|B||
05005|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate CYP3A4 inducer may|
05005|010|E|result in decreased levels and effectiveness of rilzabrutinib.(1)|
05005|011|B||
05005|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05005|013|P|of the inducer for longer than 1-2 weeks.|
05005|014|B||
05005|015|M|PATIENT MANAGEMENT:  The manufacturer of rilzabrutinib states that|
05005|016|M|concomitant use of moderate CYP3A4 inducers should be avoided.(1)|
05005|017|B||
05005|018|D|DISCUSSION:  Rilzabrutinib is primarily metabolized by CYP3A4.(1)|
05005|019|D|   Concomitant administration of rilzabrutinib with efavirenz or rifabutin|
05005|020|D|(moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib area under|
05005|021|D|the curve (AUC) and maximum concentration (Cmax) by up to 70% at steady|
05005|022|D|state.(1)|
05005|023|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
05005|024|D|cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad,|
05005|025|D|lorlatinib, modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl,|
05005|026|D|thioridazine, and tovorafenib.(2)|
05005|027|B||
05005|028|R|REFERENCES:|
05005|029|B||
05005|030|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05005|031|R|  August, 2025.|1
05005|032|R|2.This information is based on an extract from the Certara Drug Interaction|6
05005|033|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05006|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Proton Pump Inhibitors|
05006|002|B||
05006|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05006|004|L|of severe adverse interaction.|
05006|005|B||
05006|006|A|MECHANISM OF ACTION:  The aqueous solubility of rilzabrutinib is pH|
05006|007|A|dependent.  Higher gastric pH leads to lower solubility which may reduce|
05006|008|A|rilzabrutinib absorption.(1)|
05006|009|B||
05006|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) may|
05006|011|E|reduce the bioavailability of rilzabrutinib, leading to decreased systemic|
05006|012|E|levels and effectiveness.(1)|
05006|013|B||
05006|014|P|PREDISPOSING FACTORS:  None determined.|
05006|015|B||
05006|016|M|PATIENT MANAGEMENT:  The manufacturer of rilzabrutinib states that|
05006|017|M|concurrent use with proton pump inhibitors should be avoided.(1)|
05006|018|M|   If the PPI is replaced with an H2 antagonist, administer rilzabrutinib at|
05006|019|M|least 2 hours before taking the H2 antagonist.(1)|
05006|020|M|   If the PPI is replaced with an antacid, administer rilzabrutinib at least|
05006|021|M|2 hours before taking the antacid.(1)|
05006|022|B||
05006|023|D|DISCUSSION:  In an interaction study, coadministration of esomeprazole|
05006|024|D|decreased rilzabrutinib maximum concentration (Cmax) by 55% and|
05006|025|D|area-under-the-curve (AUC) by 51%.(1)|
05006|026|D|   In an interaction study, coadministration of famotidine decreased|
05006|027|D|rilzabrutinib Cmax by 35% and AUC by 28%.(1)|
05006|028|B||
05006|029|R|REFERENCE:|
05006|030|B||
05006|031|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05006|032|R|  August, 2025.|1
05007|001|T|MONOGRAPH TITLE:  Rilzabrutinib/H2 Antagonists|
05007|002|B||
05007|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05007|004|L|take action as needed.|
05007|005|B||
05007|006|A|MECHANISM OF ACTION:  Rilzabrutinib solubility decreases with increasing pH.|
05007|007|A|H2 antagonist induced increase in gastric pH may result in a decrease in|
05007|008|A|rilzabrutinib absorption.(1)|
05007|009|B||
05007|010|E|CLINICAL EFFECTS:  Simultaneous administration of a H2 antagonist may result|
05007|011|E|in decreased levels and effectiveness of rilzabrutinib.(1)|
05007|012|B||
05007|013|P|PREDISPOSING FACTORS:  None determined.|
05007|014|B||
05007|015|M|PATIENT MANAGEMENT:  Administer rilzabrutinib at least 2 hours before taking|
05007|016|M|H2 antagonists.(1)|
05007|017|M|   Concurrent use of rilzabrutinib with proton pump inhibitors should be|
05007|018|M|avoided.(1)|
05007|019|B||
05007|020|D|DISCUSSION:  In an interaction study, administration of famotidine (H2|
05007|021|D|receptor antagonist) two hours after the evening dose of rilzabrutinib|
05007|022|D|decreased the next morning dose of rilzabrutinib maximum concentration|
05007|023|D|(Cmax) by 35% and area-under-curve (AUC) by 28%.(1)|
05007|024|B||
05007|025|R|REFERENCE:|
05007|026|B||
05007|027|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05007|028|R|  August, 2025.|1
05008|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Antacids|
05008|002|B||
05008|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05008|004|L|take action as needed.|
05008|005|B||
05008|006|A|MECHANISM OF ACTION:  Rilzabrutinib solubility decreases with increasing pH.|
05008|007|A|Antacid induced increase in gastric pH may result in a decrease in|
05008|008|A|rilzabrutinib absorption.(1)|
05008|009|B||
05008|010|E|CLINICAL EFFECTS:  Simultaneous administration of an antacid may result in|
05008|011|E|decreased levels and effectiveness of rilzabrutinib.(1)|
05008|012|B||
05008|013|P|PREDISPOSING FACTORS:  None determined.|
05008|014|B||
05008|015|M|PATIENT MANAGEMENT:  Administer rilzabrutinib at least 2 hours before taking|
05008|016|M|antacids.(1)|
05008|017|M|   Some vitamin preparations may contain sufficient quantities of calcium|
05008|018|M|and/or magnesium salts with antacid properties to interact as well.|
05008|019|B||
05008|020|D|DISCUSSION:  The impact of antacids on the pharmacokinetics of rilzabrutinib|
05008|021|D|has not been investigated in clinical studies.|
05008|022|D|   In an interaction study, administration of famotidine (H2 receptor|
05008|023|D|antagonist) two hours after the evening dose of rilzabrutinib decreased the|
05008|024|D|next morning dose of rilzabrutinib maximum concentration (Cmax) by 35% and|
05008|025|D|area-under-curve (AUC) by 28%.(1)|
05008|026|D|   In another interaction study, coadministration of esomeprazole decreased|
05008|027|D|rilzabrutinib Cmax by 55% and AUC by 51%.(1)|
05008|028|B||
05008|029|R|REFERENCE:|
05008|030|B||
05008|031|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05008|032|R|  August, 2025.|1
05009|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Pacritinib|
05009|002|B||
05009|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05009|004|L|of severe adverse interaction.|
05009|005|B||
05009|006|A|MECHANISM OF ACTION:  Rilzabrutinib is a substrate and moderate inhibitor of|
05009|007|A|CYP3A4.(1)  Pacritinib is a substrate and moderate inducer of CYP3A4.(2)|
05009|008|A|   Agents that induce the CYP3A4 isoenzyme may induce the metabolism of|
05009|009|A|rilzabrutinib.(1)|
05009|010|A|   Moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of|
05009|011|A|pacritinib.(2)|
05009|012|B||
05009|013|E|CLINICAL EFFECTS:  Concurrent use of rilzabrutinib and pacritinib may|
05009|014|E|decrease the levels and effectiveness of rilzabrutinib(1) while increasing|
05009|015|E|levels and toxicity of pacritinib.(2)|
05009|016|E|   Elevated levels of pacritinib may result in QTc prolongation, which may|
05009|017|E|result in potentially life-threatening cardiac arrhythmias, including|
05009|018|E|torsades de pointes (TdP).(2)|
05009|019|E|   Other toxicities of pacritinib include bleeding, diarrhea,|
05009|020|E|thrombocytopenia, major adverse cardiovascular events, thrombosis, and|
05009|021|E|infection.(2)|
05009|022|B||
05009|023|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05009|024|P|may be increased in patients with cardiovascular disease (e.g. heart|
05009|025|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05009|026|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05009|027|P|female gender, or advanced age.(3)|
05009|028|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05009|029|P|higher systemic concentrations of either QT prolonging drug are additional|
05009|030|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05009|031|P|drug concentrations include rapid infusion of an intravenous dose or|
05009|032|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05009|033|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05009|034|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
05009|035|P|   Induction effects may be more likely with regular use of the inducer for|
05009|036|P|longer than 1-2 weeks.|
05009|037|B||
05009|038|M|PATIENT MANAGEMENT:  The concurrent use of rilzabrutinib and pacritinib|
05009|039|M|should be avoided.(1,2)|
05009|040|M|   If concurrent use cannot be avoided, monitor patients for increased|
05009|041|M|adverse reactions from pacritinib and consider pacritinib dose modifications|
05009|042|M|based on safety.(2)|
05009|043|M|   If coadministration is unavoidable, monitor for prolongation of the QTc|
05009|044|M|interval.(1,2)  When concurrent therapy is warranted: consider obtaining|
05009|045|M|serum calcium, magnesium, and potassium levels and monitoring EKG at|
05009|046|M|baseline and regular intervals. Correct any electrolyte abnormalities.|
05009|047|M|Instruct patients to report any irregular heartbeat, dizziness, or fainting.|
05009|048|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
05009|049|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
05009|050|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
05009|051|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
05009|052|M|dose according to labeling.(2)|
05009|053|B||
05009|054|D|DISCUSSION:  Concomitant administration of rilzabrutinib with efavirenz or|
05009|055|D|rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib|
05009|056|D|area under the curve (AUC) and maximum concentration (Cmax) by up to 70% at|
05009|057|D|steady state.(1)|
05009|058|D|   Clarithromycin (500 mg twice daily for 5 days, a strong CYP3A4 inhibitor)|
05009|059|D|increased the Cmax and AUC of a single dose of pacritinib (400 mg) by 30%|
05009|060|D|and 80%, respectively.(2)|
05009|061|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
05009|062|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(2)|
05009|063|D|   Pacritinib has been associated with QTc interval prolongation.  In|
05009|064|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
05009|065|D|of patients in the treatment arm compared to 1% in the control arm.  The|
05009|066|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
05009|067|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
05009|068|D|adverse reactions were higher in the treatment arm than the control group|
05009|069|D|(3.8% vs 2%, respectively).(2)|
05009|070|B||
05009|071|R|REFERENCES:|
05009|072|B||
05009|073|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05009|074|R|  August, 2025.|1
05009|075|R|2.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
05009|076|R|  2024.|1
05009|077|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05009|078|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05009|079|R|  settings: a scientific statement from the American Heart Association and|6
05009|080|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05009|081|R|  2;55(9):934-47.|6
05009|082|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05009|083|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05009|084|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05009|085|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05009|086|R|  11/14/2017.|1
05009|087|R|5.This information is based on an extract from the Certara Drug Interaction|6
05009|088|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05010|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Mavacamten|
05010|002|B||
05010|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05010|004|L|of severe adverse interaction.|
05010|005|B||
05010|006|A|MECHANISM OF ACTION:  Rilzabrutinib and mavacamten are both metabolized by|
05010|007|A|CYP3A4.  Mavacamten is a moderate CYP3A4 inducer while rilzabrutinib is a|
05010|008|A|moderate CYP3A4 inhibitor.(1-2)|
05010|009|B||
05010|010|E|CLINICAL EFFECTS:  The net effect of coadministration of rilzabrutinib and|
05010|011|E|mavacamten on CYP3A4 enzyme activity is unknown.  Concurrent use may either|
05010|012|E|decrease the clinical effectiveness of rilzabrutinib(1) or increase the|
05010|013|E|levels and toxicities of mavacamten.(2)|
05010|014|B||
05010|015|P|PREDISPOSING FACTORS:  None determined.|
05010|016|B||
05010|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
05010|018|M|rilzabrutinib with mavacamten.  Concurrent therapy should be avoided.  If|
05010|019|M|use of this combination is necessary, the patient should be closely|
05010|020|M|monitored for rilzabrutinib efficacy and mavacamten toxicity.|
05010|021|M|   The manufacturer of rilzabrutinib states that concomitant use of moderate|
05010|022|M|CYP3A4 inducers should be avoided.(1)|
05010|023|M|   The manufacturer of mavacamten makes the recommendations below for|
05010|024|M|concurrent use with CYP3A4 inhibitors:|
05010|025|M|   Initiate mavacamten at the recommended starting dosage of 5 mg orally|
05010|026|M|once daily in patients who are on stable therapy with a moderate CYP3A4|
05010|027|M|inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to|
05010|028|M|2.5 mg) in patients who are on mavacamten treatment and intend to initiate a|
05010|029|M|moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic|
05010|030|M|assessment 4 weeks after inhibitor initiation, and do not up-titrate|
05010|031|M|mavacamten until 12 weeks after inhibitor initiation.(2)|
05010|032|M|   Avoid initiation of concomitant moderate CYP3A4 inhibitors in patients|
05010|033|M|who are on stable treatment with 2.5 mg of mavacamten because a lower dose|
05010|034|M|is not available.(2)|
05010|035|M|   For short-term use (e.g. 1 week), interrupt mavacamten therapy for the|
05010|036|M|duration of the moderate CYP3A4 inhibitor.  After therapy with the moderate|
05010|037|M|CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the|
05010|038|M|previous dose immediately upon discontinuation.(2)|
05010|039|B||
05010|040|D|DISCUSSION:  Concomitant administration of rilzabrutinib with efavirenz or|
05010|041|D|rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib|
05010|042|D|area under the curve (AUC) and maximum concentration (Cmax) by up to 70% at|
05010|043|D|steady state.(1)|
05010|044|D|   Concomitant use of mavacamten (25 mg) with verapamil sustained release|
05010|045|D|(240 mg), a moderate CYP3A4 inhibitor, increased mavacamten AUC by 15% and|
05010|046|D|Cmax by 52% in intermediate metabolizers and normal metabolizers of|
05010|047|D|CYP2C19.(2)|
05010|048|D|   Concomitant use of mavacamten with diltiazem, a moderate CYP3A4|
05010|049|D|inhibitor, in CYP2C19 poor metabolizers is predicted to increase mavacamten|
05010|050|D|AUC and Cmax up to 55% and 42%, respectively.(2)|
05010|051|B||
05010|052|R|REFERENCES:|
05010|053|B||
05010|054|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05010|055|R|  August, 2025.|1
05010|056|R|2.Camzyos (mavacamten) US prescribing information. Bristol-Myers Squibb|1
05010|057|R|  April, 2025.|1
05010|058|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05010|059|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05010|060|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05010|061|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05010|062|R|  11/14/2017.|1
05010|063|R|4.This information is based on an extract from the Certara Drug Interaction|6
05010|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05011|001|T|MONOGRAPH TITLE:  Bosentan/Rilzabrutinib|
05011|002|B||
05011|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05011|004|L|of severe adverse interaction.|
05011|005|B||
05011|006|A|MECHANISM OF ACTION:  Bosentan is metabolized by CYP2C9 and CYP3A4.  It is|
05011|007|A|also an inducer of these enzymes.  With regular dosing bosentan auto-induces|
05011|008|A|its own metabolism.(1)  Moderate CYP3A4 inhibitors such as rilzabrutinib may|
05011|009|A|inhibit the CYP3A4 mediated metabolism of bosentan.(1,2)|
05011|010|A|   Rilzabrutinib is a substrate of CYP3A4.  Moderate CYP3A4 inducers such as|
05011|011|A|bosentan may induce the metabolism of rilzabrutinib.(2)|
05011|012|B||
05011|013|E|CLINICAL EFFECTS:  Concurrent use of bosentan with an inhibitor of CYP3A4|
05011|014|E|such as rilzabrutinib may result in elevated levels of and toxicity from|
05011|015|E|bosentan.(1)|
05011|016|E|   The concurrent use of rilzabrutinib with a moderate CYP3A4 inducer such|
05011|017|E|as bosentan may result in decreased levels and effectiveness of|
05011|018|E|rilzabrutinib.(2)|
05011|019|B||
05011|020|P|PREDISPOSING FACTORS:  Concurrent use of bosentan, a CYP3A4 inhibitor and a|
05011|021|P|CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone,|
05011|022|P|sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major|
05011|023|P|metabolic pathways for bosentan, resulting in large increases in bosentan|
05011|024|P|plasma concentrations.(1,3)|
05011|025|B||
05011|026|M|PATIENT MANAGEMENT:  The effect of the two-way inhibition and induction of|
05011|027|M|rilzabrutinib and bosentan metabolism is unknown.  The optimal doses of|
05011|028|M|rilzabrutinib and bosentan when used concurrently have not been determined.|
05011|029|M|Concurrent use should be avoided.  Dose modifications mentioned below are|
05011|030|M|informational only.|
05011|031|M|   The manufacturer of rilzabrutinib states that concurrent use with|
05011|032|M|moderate CYP3A4 inducers should be avoided.(2)|
05011|033|M|   In patients receiving bosentan, review medication list to see if patient|
05011|034|M|is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole,|
05011|035|M|miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone).|
05011|036|M|   Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended|
05011|037|M|by the manufacturer of bosentan as the combination may lead to large|
05011|038|M|increases in bosentan plasma concentrations.(1)|
05011|039|M|   For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated,|
05011|040|M|monitor tolerance to concomitant therapy and adjust bosentan dose if needed.|
05011|041|B||
05011|042|D|DISCUSSION:  In a study in healthy subjects, concurrent bosentan and|
05011|043|D|ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan|
05011|044|D|steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by|
05011|045|D|2.1-fold and 2.3-fold, respectively.(1)|
05011|046|D|   Concomitant administration of rilzabrutinib with efavirenz or rifabutin|
05011|047|D|(moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib AUC and|
05011|048|D|Cmax by up to 70% at steady state.(2)|
05011|049|B||
05011|050|R|REFERENCES:|
05011|051|B||
05011|052|R|1.Tracleer (bosentan) US prescribing information. Actelion Pharmaceuticals|1
05011|053|R|  US, Inc. September 5, 2017.|1
05011|054|R|2.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05011|055|R|  August, 2025.|1
05011|056|R|3.This information is based on an extract from the Certara Drug Interaction|6
05011|057|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05012|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Mitapivat|
05012|002|B||
05012|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05012|004|L|of severe adverse interaction.|
05012|005|B||
05012|006|A|MECHANISM OF ACTION:  Rilzabrutinib and mitapivat are substrates of|
05012|007|A|CYP3A4.(1,2)|
05012|008|A|   Rilzabrutinib, a moderate CYP3A4 inhibitor, may inhibit the metabolism of|
05012|009|A|mitapivat.(1)  Mitapivat, a moderate CYP3A4 inducer, may induce the|
05012|010|A|metabolism of rilzabrutinib.(2)|
05012|011|B||
05012|012|E|CLINICAL EFFECTS:  Concurrent use of rilzabrutinib with moderate CYP3A4|
05012|013|E|inducers such as mitapivat may result in decreased levels and effectiveness|
05012|014|E|of rilzabrutinib.(1)|
05012|015|E|   Concurrent use of mitapivat with moderate CYP3A4 inhibitors such as|
05012|016|E|rilzabrutinib may result in increased levels of and effects from mitapivat|
05012|017|E|including decreased estrone and estradiol levels in males, increased urate,|
05012|018|E|back pain, and arthralgias.(2)|
05012|019|B||
05012|020|P|PREDISPOSING FACTORS:  None determined.|
05012|021|B||
05012|022|M|PATIENT MANAGEMENT:  Avoid the concurrent use of rilzabrutinib and|
05012|023|M|mitapivat.(1,2)|
05012|024|M|  The effect of the two-way inhibition and induction of rilzabrutinib and|
05012|025|M|mitapivat metabolism is unknown. The optimal doses of rilzabrutinib and|
05012|026|M|mitapivat when used concurrently have not been determined. Dose|
05012|027|M|modifications mentioned below are informational only.|
05012|028|M|   The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be|
05012|029|M|monitored closely for increased risk of adverse reactions.  Mitapivat dose|
05012|030|M|should not exceed 20 mg twice daily with concurrent moderate CYP3A4|
05012|031|M|inhibitors.(2)|
05012|032|B||
05012|033|D|DISCUSSION:  Concomitant use of a single dose of rilzabrutinib 400 mg with|
05012|034|D|midazolam (sensitive CYP3A inhibitor) increased midazolam maximum|
05012|035|D|concentration (Cmax) and area-under-curve (AUC) by 2.2-fold.  Midazolam AUC|
05012|036|D|is predicted to increase up to 3-fold in patients with immune|
05012|037|D|thrombocytopenia following coadministration with 400 mg rilzabrutinib twice|
05012|038|D|daily.(1)|
05012|039|D|   Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study with|
05012|040|D|mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased|
05012|041|D|mitapivat AUC and Cmax by 2.6-fold and 1.6-fold, respectively.(2)|
05012|042|B||
05012|043|R|REFERENCES:|
05012|044|B||
05012|045|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05012|046|R|  August, 2025.|1
05012|047|R|2.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
05012|048|R|  February, 2022.|1
05012|049|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05012|050|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05012|051|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05012|052|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05012|053|R|  11/14/2017.|1
05012|054|R|4.This information is based on an extract from the Certara Drug Interaction|6
05012|055|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05013|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Dipyrone|
05013|002|B||
05013|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05013|004|L|of severe adverse interaction.|
05013|005|B||
05013|006|A|MECHANISM OF ACTION:  Dipyrone, a moderate CYP3A4 inducer, may induce the|
05013|007|A|metabolism of rilzabrutinib.(1)|
05013|008|A|   Concurrent use of dipyrone with other drugs known to be associated with|
05013|009|A|neutropenia or agranulocytosis such as rilzabrutinib may increase the|
05013|010|A|frequency or risk for severe toxicity.(2)|
05013|011|B||
05013|012|E|CLINICAL EFFECTS:  Concurrent or recent use of dipyrone, a moderate CYP3A4|
05013|013|E|inducer, may result in decreased levels and effectiveness of|
05013|014|E|rilzabrutinib.(1)|
05013|015|E|   Concurrent use of dipyrone with agents such as rilzabrutinib that cause|
05013|016|E|bone marrow depression, including myelosuppressives, may result in an|
05013|017|E|enhanced risk of hematologic disorders, including anemia, blood dyscrasias,|
05013|018|E|bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow|
05013|019|E|depression may increase the risk of serious infections and bleeding.|
05013|020|E|Undetected severe neutropenia or agranulocytosis may be fatal.(2)|
05013|021|B||
05013|022|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05013|023|P|of the inducer for longer than 1-2 weeks.|
05013|024|B||
05013|025|M|PATIENT MANAGEMENT:  The manufacturer of rilzabrutinib states that|
05013|026|M|concomitant use of moderate CYP3A4 inducers should be avoided.(1)|
05013|027|M|   Concurrent use of dipyrone and myelosuppressive agents should be|
05013|028|M|avoided.(2)|
05013|029|M|   The European Medicines Agency states dipyrone is contraindicated in|
05013|030|M|patients with a prior medical history of dipyrone-induced agranulocytosis|
05013|031|M|(or from other pyrazolones/pyrazolidines), impaired bone marrow function or|
05013|032|M|diseases of the hematopoietic system.(4)|
05013|033|M|   The European Medicines Agency advises if agranulocytosis is suspected|
05013|034|M|with dipyrone, a complete blood count (including differential blood count)|
05013|035|M|should be performed immediately, and treatment must be stopped while waiting|
05013|036|M|for the results. If confirmed, treatment must not be reintroduced.(2,4)|
05013|037|B||
05013|038|D|DISCUSSION:  Rilzabrutinib is primarily metabolized by CYP3A4.(1)|
05013|039|D|   Concomitant administration of rilzabrutinib with efavirenz or rifabutin|
05013|040|D|(moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib area under|
05013|041|D|the curve (AUC) and maximum concentration (Cmax) by up to 70% at steady|
05013|042|D|state.(1)|
05013|043|D|   In the LUNA-3 study, Grade 1 or 2 neutropenia occurred in 11% of patients|
05013|044|D|in the rilzabrutinib group.(2)|
05013|045|D|   A retrospective cohort study analyzed new users of dipyrone (n=444,972),|
05013|046|D|non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a|
05013|047|D|reference cohort, and opioids-paracetamol (n=3,129,221) which was the|
05013|048|D|negative control.  During continuous treatment over a median of 37-40 days,|
05013|049|D|26 cases of hospitalized agranulocytosis occurred.  With the assumption that|
05013|050|D|agranulocytosis onset was 7 days prior to admission, the hazard ratio of|
05013|051|D|agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to|
05013|052|D|NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol.  HR of|
05013|053|D|neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not|
05013|054|D|statistically significant compared to opioids-paracetamol.  In a sensitivity|
05013|055|D|analysis assuming that the onset of agranulocytosis was the date of|
05013|056|D|hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95%|
05013|057|D|confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34]|
05013|058|D|compared to opioids-paracetamol.  Agranulocytosis was very rare but more|
05013|059|D|than 4 times more common with dipyrone than other analgesics.(5)|
05013|060|B||
05013|061|R|REFERENCES:|
05013|062|B||
05013|063|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05013|064|R|  August, 2025.|1
05013|065|R|2.Optalgin (Dipyrone (Metamizole sodium)) Prescribing Information. Teva|1
05013|066|R|  Israel Ltd June 2022.|1
05013|067|R|3.This information is based on an extract from the Certara Drug Interaction|6
05013|068|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05013|069|R|4.EMA. EMA recommends measures to minimise serious outcomes of known side|6
05013|070|R|  effect with painkiller metamizole. 6 September 2024.|6
05013|071|R|5.Macia-Martinez MA, Castillo-Cano B, Garcia-Poza P, Martin-Merino E. Risk|3
05013|072|R|  of agranulocytosis with metamizole in comparison with alternative|3
05013|073|R|  medications based on health records in Spain. European Journal of Clinical|3
05013|074|R|  Pharmacology 22 June 2024;80(10):1503-1514.|3
05013|075|R|6.Hoffman F, Bantel C, Jobski K. Aganulocytosis attributed to metamizole: An|3
05013|076|R|  analysis of spontaneous reports in EudraVigilance 1985-2017. Basic &|3
05013|077|R|  Clinical Pharmacology & Toxicology 26 August 2019;126(2):116-125.|3
05014|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Strong CYP3A4 Inhibitors|
05014|002|B||
05014|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05014|004|L|of severe adverse interaction.|
05014|005|B||
05014|006|A|MECHANISM OF ACTION:  Rilzabrutinib is metabolized via CYP3A4.  Strong|
05014|007|A|inhibitors of CYP3A4 may inhibit the metabolism of rilzabrutinib.(1)|
05014|008|B||
05014|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
05014|010|E|levels of and effects from rilzabrutinib, including hepatotoxicity and|
05014|011|E|immunosuppression.(1)|
05014|012|B||
05014|013|P|PREDISPOSING FACTORS:  Patients with moderate to severe hepatic impairment|
05014|014|P|(Child-Pugh class B-C) may be more susceptible to the effects of this drug|
05014|015|P|interaction due to the potential for increased rilzabrutinib exposure.(1)|
05014|016|B||
05014|017|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
05014|018|M|taking rilzabrutinib.  If concurrent use cannot be avoided and the CYP3A4|
05014|019|M|inhibitor will be used short term (i.e., less than 7 days), interrupt|
05014|020|M|treatment with rilzabrutinib.(1)|
05014|021|B||
05014|022|D|DISCUSSION:  In a clinical study, ritonavir (a strong CYP3A4 inhibitor)|
05014|023|D|increased the maximum concentration (Cmax) of rilzabrutinib by 5-fold and|
05014|024|D|the area-under-curve (AUC) by 8-fold at steady state.(1)|
05014|025|D|   Strong inhibitors of CYP3A4 linked to this monograph include:  adagrasib,|
05014|026|D|boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib,|
05014|027|D|indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole,|
05014|028|D|lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
05014|029|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir,|
05014|030|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
05014|031|D|voriconazole.(2,3)|
05014|032|B||
05014|033|R|REFERENCES:|
05014|034|B||
05014|035|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05014|036|R|  August, 2025.|1
05014|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05014|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05014|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05014|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05014|041|R|  11/14/2017.|1
05014|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
05014|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05015|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Moderate CYP3A4 Inhibitors|
05015|002|B||
05015|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05015|004|L|of severe adverse interaction.|
05015|005|B||
05015|006|A|MECHANISM OF ACTION:  Rilzabrutinib is metabolized via CYP3A4.  Moderate|
05015|007|A|inhibitors of CYP3A4 may inhibit the metabolism of rilzabrutinib.(1)|
05015|008|B||
05015|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
05015|010|E|levels of and effects from rilzabrutinib, including hepatotoxicity and|
05015|011|E|immunosuppression.(1)|
05015|012|B||
05015|013|P|PREDISPOSING FACTORS:  Patients with moderate to severe hepatic impairment|
05015|014|P|(Child-Pugh class B-C) may be more susceptible to the effects of this drug|
05015|015|P|interaction due to the potential for increased rilzabrutinib exposure.(1)|
05015|016|B||
05015|017|M|PATIENT MANAGEMENT:  Avoid the use of moderate CYP3A4 inhibitors in patients|
05015|018|M|taking rilzabrutinib.  If concurrent use cannot be avoided and the CYP3A4|
05015|019|M|inhibitor will be used short term (i.e., less than 7 days), interrupt|
05015|020|M|treatment with rilzabrutinib.(1)|
05015|021|B||
05015|022|D|DISCUSSION:  Concurrent use of rilzabrutinib with moderate CYP3A4 inhibitors|
05015|023|D|(e.g., erythromycin, fluconazole, verapamil) is predicted to increase|
05015|024|D|rilzabrutinib Cmax and AUC by 3-fold at steady state.(1)|
05015|025|D|   Moderate inhibitors of CYP3A4 linked to this monograph include:|
05015|026|D|amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine,|
05015|027|D|conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib,|
05015|028|D|erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir,|
05015|029|D|fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant,|
05015|030|D|nilotinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and|
05015|031|D|voxelotor.(2-3)|
05015|032|B||
05015|033|R|REFERENCES:|
05015|034|B||
05015|035|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05015|036|R|  August, 2025.|1
05015|037|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05015|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05015|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05015|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05015|041|R|  11/14/2017.|1
05015|042|R|3.This information is based on an extract from the Certara Drug Interaction|6
05015|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05016|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Nirogacestat|
05016|002|B||
05016|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05016|004|L|of severe adverse interaction.|
05016|005|B||
05016|006|A|MECHANISM OF ACTION:  Rilzabrutinib and nirogacestat are both moderate|
05016|007|A|inhibitors and substrates of CYP3A4.  Moderate inhibitors of CYP3A4 may|
05016|008|A|inhibit the metabolism of both drugs.(1-2)|
05016|009|B||
05016|010|E|CLINICAL EFFECTS:  Concurrent use of rilzabrutinib and nirogacestat may|
05016|011|E|increase levels and effects of both drugs, including hepatotoxicity,|
05016|012|E|immunosuppression, hypokalemia, and hypophosphatemia.(1-2)|
05016|013|B||
05016|014|P|PREDISPOSING FACTORS:  Patients with moderate to severe hepatic impairment|
05016|015|P|(Child-Pugh class B-C) may be more susceptible to the effects of this drug|
05016|016|P|interaction due to the potential for increased rilzabrutinib exposure.(1)|
05016|017|B||
05016|018|M|PATIENT MANAGEMENT:  Avoid concurrent use of rilzabrutinib and|
05016|019|M|nirogacestat.(1-2)|
05016|020|B||
05016|021|D|DISCUSSION:  Concurrent use of rilzabrutinib with moderate CYP3A4 inhibitors|
05016|022|D|(e.g., erythromycin, fluconazole, verapamil) is predicted to increase|
05016|023|D|rilzabrutinib concentration maximum (Cmax) and area-under-curve (AUC) by|
05016|024|D|3-fold at steady state.(1)|
05016|025|D|   In a PKPB model, nirogacestat AUC was predicted to increase 2.73-and|
05016|026|D|3.18-fold following coadministration of multiple doses of nirogacestat (150|
05016|027|D|mg BID) with erythromycin (moderate CYP3A inhibitor) and fluconazole|
05016|028|D|(moderate CYP3A inhibitor), respectively.(2)|
05016|029|B||
05016|030|R|REFERENCES:|
05016|031|B||
05016|032|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05016|033|R|  August, 2025.|1
05016|034|R|2.Ogsiveo (nirogacestat) US prescribing information. SpringWorks|1
05016|035|R|  Therapeutics Inc. April, 2024.|1
05017|001|T|MONOGRAPH TITLE:  Rilzabrutinib/Lonafarnib|
05017|002|B||
05017|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05017|004|L|of severe adverse interaction.|
05017|005|B||
05017|006|A|MECHANISM OF ACTION:  Rilzabrutinib and lonafarnib are both substrates of|
05017|007|A|CYP3A4.  Lonafarnib is also a strong CYP3A4 inhibitor and rilzabrutinib is a|
05017|008|A|moderate CYP3A4 inhibitor.  Inhibitors of CYP3A4 may inhibit the metabolism|
05017|009|A|of both drugs.(1-2)|
05017|010|B||
05017|011|E|CLINICAL EFFECTS:  Concurrent use of rilzabrutinib and lonafarnib may|
05017|012|E|increase levels and effects of both drugs, including hepatotoxicity,|
05017|013|E|immunosuppression, hypertension, and QT prolongation, which may lead to|
05017|014|E|potentially life-threatening cardiac arrhythmias like torsades de|
05017|015|E|pointes.(1-2)|
05017|016|B||
05017|017|P|PREDISPOSING FACTORS:  Patients with moderate to severe hepatic impairment|
05017|018|P|(Child-Pugh class B-C) may be more susceptible to the effects of this drug|
05017|019|P|interaction due to the potential for increased rilzabrutinib exposure.(1)|
05017|020|P|   The risk of QT prolongation or torsades de pointes may be increased in|
05017|021|P|patients with cardiovascular disease (e.g. heart failure, myocardial|
05017|022|P|infarction, history of torsades de pointes, congenital long QT syndrome),|
05017|023|P|hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or|
05017|024|P|advanced age.(3)|
05017|025|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05017|026|P|higher systemic concentrations of either QT prolonging drug are additional|
05017|027|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05017|028|P|drug concentrations include rapid infusion of an intravenous dose or|
05017|029|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05017|030|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05017|031|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
05017|032|B||
05017|033|M|PATIENT MANAGEMENT:  Avoid concurrent use of rilzabrutinib and|
05017|034|M|lonafarnib.(1-2)|
05017|035|B||
05017|036|D|DISCUSSION:  In a clinical study, ritonavir (a strong CYP3A4 inhibitor)|
05017|037|D|increased the maximum concentration (Cmax) of rilzabrutinib by 5-fold and|
05017|038|D|the area-under-curve (AUC) by 8-fold at steady state.(1)|
05017|039|D|   With coadministration of a single oral dose of 50 mg lonafarnib following|
05017|040|D|200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the|
05017|041|D|AUC and Cmax were increased by 425% and 270%, respectively.(2)|
05017|042|B||
05017|043|R|REFERENCES:|
05017|044|B||
05017|045|R|1.Wayrilz (rilzabrutinib) US prescribing information. Genzyme Corporation|1
05017|046|R|  August, 2025.|1
05017|047|R|2.Zokinvy (lonafarnib) US prescribing information. Eiger BioPharmaceuticals,|1
05017|048|R|  Inc. November, 2020.|1
05017|049|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05017|050|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05017|051|R|  settings: a scientific statement from the American Heart Association and|6
05017|052|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05017|053|R|  2;55(9):934-47.|6
05018|001|T|MONOGRAPH TITLE:  Disopyramide; Propafenone/Strong CYP3A4 Inducers|
05018|002|B||
05018|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05018|004|L|take action as needed.|
05018|005|B||
05018|006|A|MECHANISM OF ACTION:  Disopyramide and propafenone are partially metabolized|
05018|007|A|by CYP3A4.  Strong CYP3A4 inducers may increase the hepatic metabolism of|
05018|008|A|disopyramide and propafenone(1-2).|
05018|009|B||
05018|010|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inducers may result in|
05018|011|E|decreased levels and effectiveness of disopyramide and propafenone(1-2).|
05018|012|B||
05018|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05018|014|P|of the inducer for longer than 1-2 weeks.|
05018|015|B||
05018|016|M|PATIENT MANAGEMENT:  Monitor patient's cardiac function and serum|
05018|017|M|disopyramide or propafenone levels. Adjust the dosage accordingly.(1)|
05018|018|B||
05018|019|D|DISCUSSION:  In a study of 8 smokers and 8 non-smokers, phenobarbital (100|
05018|020|D|mg daily for 21 days) decreased single-dose disopyramide area-under-curve|
05018|021|D|(AUC) and half life by 35%, and increased metabolic clearance by 120% in all|
05018|022|D|subjects.(3)|
05018|023|D|   During concomitant administration of disopyramide and rifampin to|
05018|024|D|patients with tuberculosis, serum disopyramide concentrations decreased by|
05018|025|D|approximately 50% while the concentration of an active metabolite of|
05018|026|D|disopyramide increased.(4)|
05018|027|D|   Concurrent administration of disopyramide and rifampin to a 62-year-old|
05018|028|D|patient produced subtherapeutic disopyramide levels and a failure in|
05018|029|D|correcting the patient's arrhythmia. Five days after stopping rifampin,|
05018|030|D|disopyramide levels increased and the arrhythmia was abolished.(5)|
05018|031|D|   In a study in six elderly subjects, pretreatment with rifampin (600 mg|
05018|032|D|daily for 9 days) decreased the bioavailability of a single dose of oral|
05018|033|D|propafenone (300 mg) by 86%.  Maximum QRS prolongation after oral|
05018|034|D|propafenone was decreased by 50%.  There were no significant effects on|
05018|035|D|intravenous propafenone.(6)|
05018|036|D|   In a study in six extensive CYP2D6 metabolizers and six poor CYP2D6|
05018|037|D|metabolizers, pretreatment with rifampin (600 mg daily for 9 days) decreased|
05018|038|D|the bioavailability of a single dose of oral propafenone by 67% and by 41%|
05018|039|D|in extensive and poor metabolizers, respectively.  Maximum QRS prolongation|
05018|040|D|after oral propafenone decreased by 38% and by 40% in extensive and poor|
05018|041|D|metabolizers, respectively.  There were no effects on intravenous|
05018|042|D|propafenone.(7)|
05018|043|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
05018|044|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
05018|045|D|mitotane, phenobarbital, phenytoin, primidone, and St. John's wort.|
05018|046|B||
05018|047|R|REFERENCES:|
05018|048|B||
05018|049|R|1.Norpace (disopyramide phosphate) US prescribing information. Pfizer Inc.|1
05018|050|R|  December, 2020.|1
05018|051|R|2.Rythmol (propafenone hydrochloride) US prescribing information. Abbott|1
05018|052|R|  Laboratories March, 2013.|1
05018|053|R|3.Kapil RP, Axelson JE, Mansfield IL, Edwards DJ, McErlane B, Mason MA,|2
05018|054|R|  Lalka D, Kerr CR. Disopyramide pharmacokinetics and metabolism: effect of|2
05018|055|R|  inducers. Br J Clin Pharmacol 1987 Dec;24(6):781-91.|2
05018|056|R|4.Aitio ML, Mansury L, Tala E, Haataja M, Aitio A. The effect of enzyme|2
05018|057|R|  induction on the metabolism of disopyramide in man. Br J Clin Pharmacol|2
05018|058|R|  1981 Mar;11(3):279-85.|2
05018|059|R|5.Staum JM. Enzyme induction: rifampin-disopyramide interaction. DICP 1990|3
05018|060|R|  Jul-Aug;24(7-8):701-3.|3
05018|061|R|6.Dilger K, Hofmann U, Klotz U. Enzyme induction in the elderly: effect of|2
05018|062|R|  rifampin on the pharmacokinetics and pharmacodynamics of propafenone. Clin|2
05018|063|R|  Pharmacol Ther 2000 May;67(5):512-20.|2
05018|064|R|7.Dilger K, Greiner B, Fromm MF, Hofmann U, Kroemer HK, Eichelbaum M.|2
05018|065|R|  Consequences of rifampicin treatment on propafenone disposition in|2
05018|066|R|  extensive and poor metabolizers of CYP2D6. Pharmacogenetics 1999 Oct;|2
05018|067|R|  9(5):551-9.|2
05019|001|T|MONOGRAPH TITLE:  Chloramphenicol/Phenobarbital|
05019|002|B||
05019|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05019|004|L|take action as needed.|
05019|005|B||
05019|006|A|MECHANISM OF ACTION:  Phenobarbital induces hepatic enzymes and may increase|
05019|007|A|the metabolism of chloramphenicol.(1-2)|
05019|008|A|   Chloramphenicol may inhibit CYP2C19 metabolism resulting in decreased|
05019|009|A|hepatic metabolism of phenobarbital.(3)|
05019|010|B||
05019|011|E|CLINICAL EFFECTS:  Concurrent use of phenobarbital and chloramphenicol may|
05019|012|E|result in decreased levels and effectiveness of chloramphenicol.  In|
05019|013|E|addition, elevated phenobarbital levels and toxicity may result.(1-3)|
05019|014|B||
05019|015|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05019|016|P|of the inducer for longer than 1-2 weeks.|
05019|017|B||
05019|018|M|PATIENT MANAGEMENT:  Concurrent use of phenobarbital and chloramphenicol|
05019|019|M|should be approached with caution.  Monitor levels of both drugs and adjust|
05019|020|M|dosages as needed.(4-5)|
05019|021|B||
05019|022|D|DISCUSSION:  In a study of children and infants receiving IV chloramphenicol|
05019|023|D|for serious infections (six patients on concomitant phenobarbital and 17|
05019|024|D|patients on chloramphenicol alone), phenobarbital significantly decreased|
05019|025|D|the mean peak (Cmax) and trough (Cmin) serum concentrations of|
05019|026|D|chloramphenicol by 35% and 44%, respectively.(4)|
05019|027|D|   A 7-month old girl was simultaneously started on IV chloramphenicol for|
05019|028|D|H. influenzae meningitis and phenobarbital for seizure prophylaxis.|
05019|029|D|Chloramphenicol Cmax was 31 mg/L on days 2 and 3 but fell to <5 mg/L|
05019|030|D|starting on day 5 until the chloramphenicol dose was doubled on day 8.  A|
05019|031|D|3-month old boy experienced a similar course of therapy with chloramphenicol|
05019|032|D|and phenobarbital.  His initial chloramphenicol concentrations were|
05019|033|D|therapeutic but fell after the first few days of treatment.  The half-life|
05019|034|D|of chloramphenicol was found to be decreased from 7 hours on day 3 to 4|
05019|035|D|hours on day 5.(5)|
05019|036|B||
05019|037|R|REFERENCES:|
05019|038|B||
05019|039|R|1.Chloromycetin (chloramphenicol) Australian Product Information. Link|1
05019|040|R|  Medical Products Pty Ltd. October, 2015.|1
05019|041|R|2.Chloramphenicol UK Summary of Product Characteristics. Chelonia Healthcare|1
05019|042|R|  Limited August, 2016.|1
05019|043|R|3.Phenobarbital Australian Product Information. Arrotex Pharmaceuticals Pty|1
05019|044|R|  Ltd September, 2024.|1
05019|045|R|4.Krasinski K, Kusmiesz H, Nelson JD. Pharmacologic interactions among|2
05019|046|R|  chloramphenicol, phenytoin and phenobarbital. Pediatr Infect Dis 1982|2
05019|047|R|  Jul-Aug;1(4):232-5.|2
05019|048|R|5.Bloxham RA, Durbin GM, Johnson T, Winterborn MH. Chloramphenicol and|3
05019|049|R|  phenobarbitone--a drug interaction. Arch Dis Child 1979 Jan;54(1):76-7.|3
05020|001|T|MONOGRAPH TITLE:  Growth Hormone/Oral Estrogens|
05020|002|B||
05020|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05020|004|L|take action as needed.|
05020|005|B||
05020|006|A|MECHANISM OF ACTION:  Growth hormone (somatropin or lonapegsomatropin-tcgd)|
05020|007|A|binds to growth hormone receptors and stimulates Janus activating tyrosine|
05020|008|A|kinases (JAK 1 and 2) and signal transducer activators of transcription|
05020|009|A|(STAT1, STAT3, STAT5) to increase gene transcription and metabolism to|
05020|010|A|produce and secrete insulin like growth factor-1 (IGF-1).  IGF-1 promotes|
05020|011|A|cell growth, proliferation, and survival.  Estrogens block STAT|
05020|012|A|phosphorylation and inhibit IGF-1 secretion and production.(1,2)  Higher|
05020|013|A|quantities of growth hormone are required to raise serum IGF-1|
05020|014|A|concentrations to the normal range.|
05020|015|B||
05020|016|E|CLINICAL EFFECTS:  Oral estrogens may reduce the IGF-1 response to growth|
05020|017|E|hormone (somatropin and lonapegsomatropin-tcgd).(1-9)|
05020|018|B||
05020|019|P|PREDISPOSING FACTORS:  None determined.|
05020|020|B||
05020|021|M|PATIENT MANAGEMENT:  The manufacturer of somatropin states a larger dose of|
05020|022|M|somatropin may be required to achieve the treatment goal.(3-9)|
05020|023|M|   The manufacturer of lonapegsomatropin-tcgd states adults of any age|
05020|024|M|concurrently taking oral estrogen should increase the dose of|
05020|025|M|lonapegsomatropin-tcgd to 2.1 mg once weekly.(3)|
05020|026|M|   The American Association of Clinical Endocrinologists and American|
05020|027|M|College of Endocrinology guidelines for growth hormone deficiency states|
05020|028|M|that higher recombinant human growth hormone (rhGH) doses are advised in|
05020|029|M|women on oral estrogen therapy and that switching women to transdermal|
05020|030|M|estrogen patches may allow lower rhGH doses to be used for equivalent IGF-1|
05020|031|M|responses.(10)|
05020|032|B||
05020|033|D|DISCUSSION:  A prospective study compared growth hormone replacement|
05020|034|D|requirements in women with elevated estrogen (on oral estrogen), women|
05020|035|D|without elevated estrogen (no estrogen therapy or on transdermal estrogen),|
05020|036|D|and growth hormone treated adult hypopituitary males.  Women on oral|
05020|037|D|estrogen required 10.6 +/-0.7 mcg/kg/day or 867 +/- 45 mcg/day growth|
05020|038|D|hormone, women not taking oral estrogen required 5.0 +/- 0.7 mcg/kg/day or|
05020|039|D|424 +/-57 mcg/day, and men required 4.1 +/- 0.6 mcg/kg/day or 376 +/-49|
05020|040|D|mcg/day.(1)|
05020|041|D|   A randomized cross-over study compared one month of treatment with|
05020|042|D|ethinyl estradiol (20 mcg), conjugated equine estrogen (1.25 mg Premarin),|
05020|043|D|and estradiol valerate (2 mg).  All three formulations resulted in a|
05020|044|D|significant reduction in IGF-1 levels compared to baseline.(11)|
05020|045|D|   A study compared IGF-1 concentrations in premenopausal women and|
05020|046|D|postmenopausal women before and after 2 months of cyclical replacement|
05020|047|D|therapy with either oral ethinyl estradiol (20 mcg daily) or transdermal 17|
05020|048|D|beta-estradiol (100 mcg patch applied twice weekly).  Oral ethinyl estradiol|
05020|049|D|significantly reduced circulating IGF-1 (0.70 +/- 0.09 to 0.47 +/- 0.04|
05020|050|D|units/mL, P < 0.02) levels. Transdermal 17-beta estradiol increased IGF-1|
05020|051|D|levels (0.86 +/- 0.15 to 1.10 +/- 0.14 units/mL, P < 0.005).(12)|
05020|052|D|   In a clinical trial, somapacitan administered once weekly was compared to|
05020|053|D|somatropin once daily injections in patients with and without oral estrogen|
05020|054|D|replacement therapy.  Patients with oral estrogen therapy were administered|
05020|055|D|2 mg/wk compared to 1 mg/wk for patients without estrogen replacement|
05020|056|D|therapy.  Observed doses after titration for somapacitan and somatropin were|
05020|057|D|highest for females on oral estrogen.(13)|
05020|058|D|   An open-label, randomized crossover study in growth hormone deficient|
05020|059|D|women compared oral estrogen with transdermal estrogen treatment while on|
05020|060|D|growth hormone.  Women received incremental doses of growth hormone (0.5,|
05020|061|D|1.0, 2.0 units/day for 1 week; increased to next dose each week) for 8 weeks|
05020|062|D|and estradiol valerate (2 mg/day) or transdermal estrogen patches|
05020|063|D|(Estraderm-TTS 100 mcg).  IGF-1 levels were significantly reduced during|
05020|064|D|oral estrogen treatment and rose dose-dependently during growth hormone|
05020|065|D|administration by a lower magnitude compared with transdermal treatment|
05020|066|D|(change in IGF-1: 109 +/-43% vs. 135 +/-41%).(14)|
05020|067|B||
05020|068|R|REFERENCES:|
05020|069|B||
05020|070|R|1.Cook DM, Ludlam WH, Cook MB. Route of estrogen administration helps to|2
05020|071|R|  determine growth hormone (GH)  replacement dose in GH-deficient adults. J|2
05020|072|R|  Clin Endocrinol Metab 1999 Nov;84(11):3956-60.|2
05020|073|R|2.Leung KC, Doyle N, Ballesteros M, Sjogren K, Watts CK, Low TH, Leong GM,|5
05020|074|R|  Ross RJ, Ho KK. Estrogen inhibits GH signaling by suppressing GH-induced|5
05020|075|R|  JAK2 phosphorylation, an  effect mediated by SOCS-2. Proc Natl Acad Sci U|5
05020|076|R|  S A 2003 Feb 4;100(3):1016-21.|5
05020|077|R|3.Skytrofa (lonapegsomatropin-tcgd) US prescribing information. Ascendis|1
05020|078|R|  Pharma Endocrinology, Inc. July, 2025.|1
05020|079|R|4.Genotropin (somatropin) US prescribing information. Pfizer Laboratories|1
05020|080|R|  Div Pfizer Inc July 2025.|1
05020|081|R|5.Humatrope (somatropin) US prescribing information. Eli Lilly and Company|1
05020|082|R|  July 2025.|1
05020|083|R|6.Norditropin (somatropin) US prescribing information. Novo Nordisk July|1
05020|084|R|  2025.|1
05020|085|R|7.Sogroya (somapacitan-beco) US prescribing information. Novo Nordisk July|1
05020|086|R|  2025.|1
05020|087|R|8.Omnitrope (somatropin) US prescribing information. Sandoz Inc July 2025.|1
05020|088|R|9.Zomacton (somatropin) US prescribing information. Ferring Pharmaceuticals|1
05020|089|R|  Inc. July 2025.|1
05020|090|R|10.Yuen KCJ, Biller BMK, Radovick S, Carmichael JD, Jasim S, Pantalone KM,|6
05020|091|R|   Hoffman AR. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND|6
05020|092|R|   AMERICAN COLLEGE OF  ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF GROWTH|6
05020|093|R|   HORMONE DEFICIENCY IN ADULTS  AND PATIENTS TRANSITIONING FROM PEDIATRIC|6
05020|094|R|   TO ADULT CARE. Endocr Pract 2019 Nov;25(11):1191-1232.|6
05020|095|R|11.Kelly JJ, Rajkovic IA, O'Sullivan AJ, Sernia C, Ho KK. Effects of|2
05020|096|R|   different oral oestrogen formulations on insulin-like growth factor-I,|2
05020|097|R|   growth hormone and growth hormone binding protein in post-menopausal|2
05020|098|R|   women. Clin Endocrinol (Oxf) 1993 Nov;39(5):561-7.|2
05020|099|R|12.Weissberger AJ, Ho KK, Lazarus L. Contrasting effects of oral and|2
05020|100|R|   transdermal routes of estrogen replacement  therapy on 24-hour growth|2
05020|101|R|   hormone (GH) secretion, insulin-like growth factor I,  and GH-binding|2
05020|102|R|   protein in postmenopausal women. J Clin Endocrinol Metab 1991 Feb;|2
05020|103|R|   72(2):374-81.|2
05020|104|R|13.Kildemoes RJ, Hollensen C, Biller BMK, Johannsson G, Takahashi Y,|2
05020|105|R|   Rasmussen MH. Dose-exposure-IGF-I response of once-weekly somapacitan in|2
05020|106|R|   adults with GH  deficiency. Eur J Endocrinol 2022 May 16;187(1):27-38.|2
05020|107|R|14.Wolthers T, Hoffman DM, Nugent AG, Duncan MW, Umpleby M, Ho KK. Oral|2
05020|108|R|   estrogen antagonizes the metabolic actions of growth hormone in growth|2
05020|109|R|   hormone-deficient women. Am J Physiol Endocrinol Metab 2001 Dec;|2
05020|110|R|   281(6):E1191-6.|2
05021|001|T|MONOGRAPH TITLE:  Imlunestrant/Strong CYP3A4 Inducers|
05021|002|B||
05021|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05021|004|L|of severe adverse interaction.|
05021|005|B||
05021|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
05021|007|A|imlunestrant.(1)|
05021|008|B||
05021|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
05021|010|E|alter the clinical effectiveness of imlunestrant.(1)|
05021|011|B||
05021|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05021|013|P|of the inducer for longer than 1-2 weeks.|
05021|014|B||
05021|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of imlunestrant with strong|
05021|016|M|CYP3A4 inducers.(1)  If concurrent use cannot be avoided, increase the|
05021|017|M|dosage of imlunestrant to 600 mg once daily.(1)  Monitor patients receiving|
05021|018|M|concurrent therapy for reduced efficacy.|
05021|019|B||
05021|020|D|DISCUSSION:  Imlunestrant is primarily metabolized by CYP3A4.(1)|
05021|021|D|   In an interaction study, imlunestrant area-under-curve (AUC) decreased by|
05021|022|D|42% and concentration maximum (Cmax) decreased by 29% following concomitant|
05021|023|D|use of carbamazepine (strong CYP3A inducer) for multiple days.(1)|
05021|024|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
05021|025|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
05021|026|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
05021|027|D|rifampin, rifapentine and St John's Wort.(2,3)|
05021|028|B||
05021|029|R|REFERENCES:|
05021|030|B||
05021|031|R|1.Inluriyo (imlunestrant) US prescribing information. Eli Lilly and Company|1
05021|032|R|  September, 2025.|1
05021|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05021|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05021|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05021|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05021|037|R|  11/14/2017.|1
05021|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
05021|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05022|001|T|MONOGRAPH TITLE:  Imlunestrant/Strong CYP3A4 Inhibitors|
05022|002|B||
05022|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05022|004|L|of severe adverse interaction.|
05022|005|B||
05022|006|A|MECHANISM OF ACTION:  Agents that inhibit the CYP3A4 isoenzyme may inhibit|
05022|007|A|the metabolism of imlunestrant.(1)|
05022|008|B||
05022|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
05022|010|E|levels of and effects from imlunestrant, including hepatotoxicity,|
05022|011|E|myelosuppression, interstitial lung disease, and gastrointestinal adverse|
05022|012|E|effects.(1)|
05022|013|B||
05022|014|P|PREDISPOSING FACTORS:  This interaction is expected to be more severe in|
05022|015|P|patients with hepatic impairment.(1)|
05022|016|P|   The recommended dosage of imlunestrant for patients with moderate|
05022|017|P|(Child-Pugh B) or severe (Child-Pugh C) hepatic impairment is 200 mg once|
05022|018|P|daily. See prescribing information for recommendations.(1)|
05022|019|B||
05022|020|M|PATIENT MANAGEMENT:  Avoid concomitant use of imlunestrant with strong|
05022|021|M|CYP3A4 inhibitors.  If concomitant use cannot be avoided, reduce the dose of|
05022|022|M|imlunestrant to 200 mg once daily.(1)|
05022|023|B||
05022|024|D|DISCUSSION:  In a clinical study, imlunestrant area-under-curve (AUC)|
05022|025|D|increased 2.1-fold and maximum concentration (Cmax) increased by 1.9-fold|
05022|026|D|following concomitant use of itraconazole (strong CYP3A inhibitor) for|
05022|027|D|multiple days.(1)|
05022|028|D|   Strong inhibitors of CYP3A4 include:  adagrasib, boceprevir, ceritinib,|
05022|029|D|clarithromycin, cobicistat, grapefruit (Citrus paradisi), idelalisib,|
05022|030|D|indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole,|
05022|031|D|lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone,|
05022|032|D|nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib,|
05022|033|D|saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin,|
05022|034|D|tucatinib, or voriconazole.(2,3)|
05022|035|B||
05022|036|R|REFERENCES:|
05022|037|B||
05022|038|R|1.Inluriyo (imlunestrant) US prescribing information. Eli Lilly and Company|1
05022|039|R|  September, 2025.|1
05022|040|R|2.This information is based on an extract from the Certara Drug Interaction|6
05022|041|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05022|042|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05022|043|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05022|044|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05022|045|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05022|046|R|  11/14/2017.|1
05023|001|T|MONOGRAPH TITLE:  Paltusotine/Strong CYP3A4 Inducers|
05023|002|B||
05023|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05023|004|L|take action as needed.|
05023|005|B||
05023|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
05023|007|A|paltusotine.(1)|
05023|008|B||
05023|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
05023|010|E|alter the clinical effectiveness of paltusotine.(1)|
05023|011|B||
05023|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05023|013|P|of the inducer for longer than 1-2 weeks.|
05023|014|B||
05023|015|M|PATIENT MANAGEMENT:  Patients taking strong CYP3A4 inducers may require an|
05023|016|M|increased dosage of paltusotine.(1)  The manufacturer of paltusotine states|
05023|017|M|do not exceed three-fold the paltusotine dosage prior to concomitant use or|
05023|018|M|120 mg daily, whichever is less.(1)  Monitor patients receiving concurrent|
05023|019|M|therapy for reduced efficacy.|
05023|020|B||
05023|021|D|DISCUSSION:  Paltusotine is metabolized by CYP3A4.(1)|
05023|022|D|   In an interaction study, paltusotine concentration maximum (Cmax) and|
05023|023|D|area-under-curve (AUC) decreased by 44% and 70%, respectively, following|
05023|024|D|concomitant administration of carbamazepine (strong CYP3A inducer).(1)|
05023|025|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
05023|026|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
05023|027|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
05023|028|D|rifampin, rifapentine and St John's Wort.(2,3)|
05023|029|B||
05023|030|R|REFERENCES:|
05023|031|B||
05023|032|R|1.Palsonify (paltusotine) US prescribing information. Crinetics|1
05023|033|R|  Pharmaceuticals, Inc. September, 2025.|1
05023|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05023|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05023|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05023|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05023|038|R|  11/14/2017.|1
05023|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
05023|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05024|001|T|MONOGRAPH TITLE:  Paltusotine/Moderate CYP3A4 Inducers|
05024|002|B||
05024|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05024|004|L|take action as needed.|
05024|005|B||
05024|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
05024|007|A|paltusotine.(1)|
05024|008|B||
05024|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
05024|010|E|alter the clinical effectiveness of paltusotine.(1)|
05024|011|B||
05024|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05024|013|P|of the inducer for longer than 1-2 weeks.|
05024|014|B||
05024|015|M|PATIENT MANAGEMENT:  Patients taking moderate CYP3A4 inducers may require an|
05024|016|M|increased dosage of paltusotine.(1)  The manufacturer of paltusotine states|
05024|017|M|do not exceed two-fold the paltusotine dosage prior to concomitant use or|
05024|018|M|120 mg daily, whichever is less.(1)  Monitor patients receiving concurrent|
05024|019|M|therapy for reduced efficacy.|
05024|020|B||
05024|021|D|DISCUSSION:  Paltusotine is metabolized by CYP3A4.(1)|
05024|022|D|   Moderate CYP3A4 inducers such as efavirenz are predicted to decrease|
05024|023|D|concentration maximum (Cmax) and area-under-curve (AUC) of paltusotine|
05024|024|D|approximately 5% and 30%, respectively.(1)|
05024|025|D|   In an interaction study, paltusotine concentration maximum (Cmax) and|
05024|026|D|area-under-curve (AUC) decreased by 44% and 70%, respectively, following|
05024|027|D|concomitant administration of carbamazepine (strong CYP3A inducer).(1)|
05024|028|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
05024|029|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
05024|030|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
05024|031|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
05024|032|D|thioridazine, and tovorafenib.(2,3)|
05024|033|B||
05024|034|R|REFERENCES:|
05024|035|B||
05024|036|R|1.Palsonify (paltusotine) US prescribing information. Crinetics|1
05024|037|R|  Pharmaceuticals, Inc. September, 2025.|1
05024|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05024|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05024|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05024|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05024|042|R|  11/14/2017.|1
05024|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
05024|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05025|001|T|MONOGRAPH TITLE:  Paltusotine (Greater Than or Equal To 60 mg)/Proton Pump|
05025|002|T|Inhibitors|
05025|003|B||
05025|004|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05025|005|L|of severe adverse interaction.|
05025|006|B||
05025|007|A|MECHANISM OF ACTION:  The aqueous solubility of paltusotine is pH dependent.|
05025|008|A|Higher gastric pH leads to lower solubility which may reduce paltusotine|
05025|009|A|absorption.(1)|
05025|010|B||
05025|011|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) may|
05025|012|E|reduce the bioavailability of paltusotine, leading to decreased systemic|
05025|013|E|levels and effectiveness.(1)|
05025|014|B||
05025|015|P|PREDISPOSING FACTORS:  None determined.|
05025|016|B||
05025|017|M|PATIENT MANAGEMENT:  The manufacturer of paltusotine states that concomitant|
05025|018|M|use of paltusotine with PPIs may require an increased dosage of paltusotine.|
05025|019|M|Patients who are already on paltusotine 60 mg daily should avoid|
05025|020|M|concomitant use with PPIs.(1)|
05025|021|B||
05025|022|D|DISCUSSION:  In an interaction study, paltusotine area-under-the-curve (AUC)|
05025|023|D|was decreased by 21% with 20 mg dose and 42% with 60 mg dose levels.(1)|
05025|024|B||
05025|025|R|REFERENCE:|
05025|026|B||
05025|027|R|1.Palsonify (paltusotine) US prescribing information. Crinetics|1
05025|028|R|  Pharmaceuticals, Inc. September, 2025.|1
05026|001|T|MONOGRAPH TITLE:  Paltusotine (Less Than 60 mg)/Proton Pump Inhibitors|
05026|002|B||
05026|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05026|004|L|take action as needed.|
05026|005|B||
05026|006|A|MECHANISM OF ACTION:  The aqueous solubility of paltusotine is pH dependent.|
05026|007|A|Higher gastric pH leads to lower solubility which may reduce paltusotine|
05026|008|A|absorption.(1)|
05026|009|B||
05026|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) may|
05026|011|E|reduce the bioavailability of paltusotine, leading to decreased systemic|
05026|012|E|levels and effectiveness.(1)|
05026|013|B||
05026|014|P|PREDISPOSING FACTORS:  None determined.|
05026|015|B||
05026|016|M|PATIENT MANAGEMENT:  The manufacturer of paltusotine states that concomitant|
05026|017|M|use of paltusotine with PPIs may require an increased dosage of paltusotine.|
05026|018|M|Patients who are already on paltusotine 60 mg daily should avoid|
05026|019|M|concomitant use with PPIs.(1)|
05026|020|B||
05026|021|D|DISCUSSION:  In an interaction study, paltusotine area-under-the-curve (AUC)|
05026|022|D|was decreased by 21% with 20 mg dose and 42% with 60 mg dose levels.(1)|
05026|023|B||
05026|024|R|REFERENCE:|
05026|025|B||
05026|026|R|1.Palsonify (paltusotine) US prescribing information. Crinetics|1
05026|027|R|  Pharmaceuticals, Inc. September, 2025.|1
05027|001|T|MONOGRAPH TITLE:  Remibrutinib/Strong CYP3A4 Inhibitors|
05027|002|B||
05027|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05027|004|L|of severe adverse interaction.|
05027|005|B||
05027|006|A|MECHANISM OF ACTION:  Remibrutinib is metabolized via CYP3A4.  Strong|
05027|007|A|inhibitors of CYP3A4 may inhibit the metabolism of remibrutinib.(1)|
05027|008|B||
05027|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
05027|010|E|levels of and effects from remibrutinib, including bleeding.(1)|
05027|011|B||
05027|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
05027|013|P|older patients (65 years and over) and patients with disease-associated|
05027|014|P|factors (e.g. thrombocytopenia).|
05027|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
05027|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
05027|017|P|risk for bleeding (e.g. NSAIDs).|
05027|018|B||
05027|019|M|PATIENT MANAGEMENT:  Avoid the use of strong CYP3A4 inhibitors in patients|
05027|020|M|taking remibrutinib.(1)|
05027|021|B||
05027|022|D|DISCUSSION:  In a clinical study, remibrutinib maximum concentration (Cmax)|
05027|023|D|increased by 3.3-fold and area-under-curve (AUC) increased by 4.3-fold|
05027|024|D|following concomitant administration with ritonavir (a strong CYP3A4|
05027|025|D|inhibitor) 100 mg twice daily for 4 days.(1)|
05027|026|D|   Strong inhibitors of CYP3A4 linked to this monograph include:  adagrasib,|
05027|027|D|boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib,|
05027|028|D|indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole,|
05027|029|D|lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
05027|030|D|nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir,|
05027|031|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
05027|032|D|voriconazole.(2,3)|
05027|033|B||
05027|034|R|REFERENCES:|
05027|035|B||
05027|036|R|1.Rhapsido (remibrutinib) US prescribing information. Novartis|1
05027|037|R|  Pharmaceuticals Corporation September 2025.|1
05027|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05027|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05027|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05027|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05027|042|R|  11/14/2017.|1
05027|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
05027|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05028|001|T|MONOGRAPH TITLE:  Remibrutinib/Moderate CYP3A4 Inhibitors|
05028|002|B||
05028|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05028|004|L|of severe adverse interaction.|
05028|005|B||
05028|006|A|MECHANISM OF ACTION:  Remibrutinib is metabolized via CYP3A4.  Moderate|
05028|007|A|inhibitors of CYP3A4 may inhibit the metabolism of remibrutinib.(1)|
05028|008|B||
05028|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
05028|010|E|levels of and effects from remibrutinib, including bleeding.(1)|
05028|011|B||
05028|012|P|PREDISPOSING FACTORS:  The risk for bleeding episodes may be greater in|
05028|013|P|older patients (65 years and over) and patients with disease-associated|
05028|014|P|factors (e.g. thrombocytopenia).|
05028|015|P|   Drug associated risk factors include concurrent use of multiple drugs|
05028|016|P|which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent|
05028|017|P|risk for bleeding (e.g. NSAIDs).|
05028|018|B||
05028|019|M|PATIENT MANAGEMENT:  Avoid the use of moderate CYP3A4 inhibitors in patients|
05028|020|M|taking remibrutinib.(1)|
05028|021|B||
05028|022|D|DISCUSSION:  Remibrutinib maximum concentration (Cmax) is predicted to|
05028|023|D|increase by approximately 1.9-fold and area-under-curve (AUC) is predicted|
05028|024|D|to increase by approximately 2.3-fold following concomitant administration|
05028|025|D|with erythromycin (a moderate CYP3A4 inhibitor) 500 mg four times a day for|
05028|026|D|7 days.|
05028|027|D|   Moderate inhibitors of CYP3A4 linked to this monograph include:|
05028|028|D|amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine,|
05028|029|D|conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib,|
05028|030|D|erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir,|
05028|031|D|fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir,|
05028|032|D|letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra,|
05028|033|D|stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)|
05028|034|B||
05028|035|R|REFERENCES:|
05028|036|B||
05028|037|R|1.Rhapsido (remibrutinib) US prescribing information. Novartis|1
05028|038|R|  Pharmaceuticals Corporation September 2025.|1
05028|039|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05028|040|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05028|041|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05028|042|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05028|043|R|  11/14/2017.|1
05028|044|R|3.This information is based on an extract from the Certara Drug Interaction|6
05028|045|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05029|001|T|MONOGRAPH TITLE:  Remibrutinib/Strong CYP3A4 Inducers|
05029|002|B||
05029|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05029|004|L|of severe adverse interaction.|
05029|005|B||
05029|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
05029|007|A|remibrutinib.(1)|
05029|008|B||
05029|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
05029|010|E|alter the clinical effectiveness of remibrutinib.(1)|
05029|011|B||
05029|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05029|013|P|of the inducer for longer than 1-2 weeks.|
05029|014|B||
05029|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of remibrutinib with strong|
05029|016|M|CYP3A4 inducers.(1) Monitor patients receiving concurrent therapy for|
05029|017|M|reduced efficacy.|
05029|018|B||
05029|019|D|DISCUSSION:  Remibrutinib is primarily metabolized by CYP3A4.(1)|
05029|020|D|   In an interaction study, remibrutinib area-under-curve (AUC) decreased by|
05029|021|D|77% and concentration maximum (Cmax) decreased by 74% following concomitant|
05029|022|D|use of carbamazepine (300 mg twice daily, strong CYP3A inducer) for 14|
05029|023|D|days.(1)|
05029|024|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
05029|025|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
05029|026|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
05029|027|D|rifampin, rifapentine and St John's Wort.(2,3)|
05029|028|B||
05029|029|R|REFERENCES:|
05029|030|B||
05029|031|R|1.Rhapsido (remibrutinib) US prescribing information. Novartis|1
05029|032|R|  Pharmaceuticals Corporation September 2025.|1
05029|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05029|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05029|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05029|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05029|037|R|  11/14/2017.|1
05029|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
05029|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05030|001|T|MONOGRAPH TITLE:  Remibrutinib/Moderate CYP3A4 Inducers|
05030|002|B||
05030|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05030|004|L|of severe adverse interaction.|
05030|005|B||
05030|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
05030|007|A|remibrutinib.(1)|
05030|008|B||
05030|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
05030|010|E|alter the clinical effectiveness of remibrutinib.(1)|
05030|011|B||
05030|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05030|013|P|of the inducer for longer than 1-2 weeks.|
05030|014|B||
05030|015|M|PATIENT MANAGEMENT:  Avoid the concurrent use of remibrutinib with moderate|
05030|016|M|CYP3A4 inducers.(1) Monitor patients receiving concurrent therapy for|
05030|017|M|reduced efficacy.|
05030|018|B||
05030|019|D|DISCUSSION:  Remibrutinib is primarily metabolized by CYP3A4.(1)|
05030|020|D|   Remibrutinib concentration maximum (Cmax) is predicted to decrease by|
05030|021|D|approximately 60% and area-under-curve (AUC) is predicted to decrease by|
05030|022|D|approximately 64% following concomitant administration with efavirenz (a|
05030|023|D|moderate CYP3A4 inducer) 600 mg once daily for 14 days.(1)|
05030|024|D|   Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate,|
05030|025|D|dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad,|
05030|026|D|lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib,|
05030|027|D|pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
05030|028|D|thioridazine, and tovorafenib.(2,3)|
05030|029|B||
05030|030|R|REFERENCES:|
05030|031|B||
05030|032|R|1.Rhapsido (remibrutinib) US prescribing information. Novartis|1
05030|033|R|  Pharmaceuticals Corporation September 2025.|1
05030|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05030|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05030|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05030|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05030|038|R|  11/14/2017.|1
05030|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
05030|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05031|001|T|MONOGRAPH TITLE:  Remibrutinib/Anticoagulants; Thrombolytics|
05031|002|B||
05031|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05031|004|L|take action as needed.|
05031|005|B||
05031|006|A|MECHANISM OF ACTION:  Remibrutinib may cause bleeding. Anticoagulants and|
05031|007|A|thrombolytics also affect hemostasis.(1)|
05031|008|B||
05031|009|E|CLINICAL EFFECTS:  Concurrent use of remibrutinib with anticoagulants or|
05031|010|E|thrombolytics may increase the risk of bleeding.(1)|
05031|011|B||
05031|012|P|PREDISPOSING FACTORS:  None determined.|
05031|013|B||
05031|014|M|PATIENT MANAGEMENT:  Consider the risks and benefits of concomitant|
05031|015|M|administration of antithrombotic agents with remibrutinib.  Interrupt|
05031|016|M|treatment with remibrutinib if bleeding is observed and resume if the|
05031|017|M|benefit is expected to outweigh the risk.|
05031|018|M|   If concurrent therapy is warranted, monitor patients receiving concurrent|
05031|019|M|therapy for signs of blood loss, including decreased hemoglobin, hematocrit,|
05031|020|M|fecal occult blood, and/or decreased blood pressure and promptly evaluate|
05031|021|M|patients with any symptoms.|
05031|022|M|   When applicable, perform agent-specific laboratory test (e.g. INR, aPTT)|
05031|023|M|to monitor efficacy and safety of anticoagulation.  Discontinue|
05031|024|M|anticoagulation in patients with active pathologic bleeding.|
05031|025|M|   Instruct patients to report any signs and symptoms of bleeding, such as|
05031|026|M|unusual bleeding from the gums or nose; unusual bruising; red or black,|
05031|027|M|tarry stools; red, pink or dark brown urine; acute abdominal or joint pain|
05031|028|M|and/or swelling.|
05031|029|M|   Interrupt treatment with remibrutinib for 3 to 7 days pre- and|
05031|030|M|post-surgery or invasive procedures.(1)|
05031|031|B||
05031|032|D|DISCUSSION:  No data are available on concomitant use of remibrutinib with|
05031|033|D|anticoagulants. The concomitant use of remibrutinib and anticoagulants was|
05031|034|D|not allowed in clinical studies.  Use of the antiplatelet agents, acetyl|
05031|035|D|salicylic acid at doses up to 100 mg daily or clopidogrel up to 75 mg daily,|
05031|036|D|was allowed in the remibrutinib clinical studies.(1)|
05031|037|B||
05031|038|R|REFERENCE:|
05031|039|B||
05031|040|R|1.Rhapsido (remibrutinib) US prescribing information. Novartis|1
05031|041|R|  Pharmaceuticals Corporation September 2025.|1
05032|001|T|MONOGRAPH TITLE:  Digoxin/P-glycoprotein (P-gp) Inhibitors|
05032|002|B||
05032|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05032|004|L|take action as needed.|
05032|005|B||
05032|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors may inhibit cellular|
05032|007|A|efflux of digoxin at the levels of intestinal absorption, renal tubular|
05032|008|A|secretion, and biliary-intestinal secretion.(1)|
05032|009|B||
05032|010|E|CLINICAL EFFECTS:  Concurrent administration of a P-gp inhibitor may result|
05032|011|E|in elevated levels and toxicities of digoxin.(1)|
05032|012|E|   Symptoms of digoxin toxicity can include anorexia, nausea, vomiting,|
05032|013|E|headache, fatigue, malaise, drowsiness, generalized muscle weakness,|
05032|014|E|disorientation, hallucinations, visual disturbances, and arrhythmias.|
05032|015|B||
05032|016|P|PREDISPOSING FACTORS:  Low body weight, advanced age, impaired renal|
05032|017|P|function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the|
05032|018|P|risk of digoxin toxicity.|
05032|019|B||
05032|020|M|PATIENT MANAGEMENT:  Monitor digoxin concentrations before initiating|
05032|021|M|concomitant use with P-gp inhibitors and continue monitoring serum digoxin|
05032|022|M|concentrations as recommended in the prescribing information for digoxin.(1)|
05032|023|M|   When digoxin levels are expected to be increased by over 50%, the|
05032|024|M|manufacturer of digoxin recommends decreasing the dose of digoxin by|
05032|025|M|approximately 30-50% or by modifying the dosing frequency to reduce digoxin|
05032|026|M|concentrations.(1)|
05032|027|M|   When digoxin levels are expected to be increased by less than 50%, the|
05032|028|M|manufacturer of digoxin recommends decreasing the dose of digoxin by|
05032|029|M|approximately 15-30% or by modifying the dosing frequency to reduce digoxin|
05032|030|M|concentrations.(1)|
05032|031|B||
05032|032|D|DISCUSSION:  Digoxin is a known substrate of P-gp. Inhibitors of P-gp may|
05032|033|D|increase toxicity of digoxin.(1)|
05032|034|D|   In a clinical study, imlunestrant increased the area-under-curve (AUC)|
05032|035|D|and maximum concentration (Cmax) of digoxin by 1.4-fold and 1.6-fold,|
05032|036|D|respectively.(2)|
05032|037|D|   Inhibitors of P-gp linked to this monograph include: abrocitinib,|
05032|038|D|capmatinib, imlunestrant, selpercatinib, and sotorasib.(2)|
05032|039|B||
05032|040|R|REFERENCES:|
05032|041|B||
05032|042|R|1.Lanoxin (digoxin) Tablets US prescribing information. Covis|1
05032|043|R|  Pharmaceuticals, Inc. August, 2018.|1
05032|044|R|2.Inluriyo (imlunestrant) US prescribing information. Eli Lilly and Company|1
05032|045|R|  September, 2025.|1
05032|046|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05032|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05032|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05032|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05032|050|R|  11/14/2017.|1
05032|051|R|4.This information is based on an extract from the Certara Drug Interaction|6
05032|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05033|001|T|MONOGRAPH TITLE:  Sirolimus/P-glycoprotein (P-gp) Inhibitors|
05033|002|B||
05033|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05033|004|L|take action as needed.|
05033|005|B||
05033|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors may inhibit cellular|
05033|007|A|efflux of sirolimus.(1)|
05033|008|B||
05033|009|E|CLINICAL EFFECTS:  Concurrent administration of a P-gp inhibitor may result|
05033|010|E|in elevated levels and toxicities of sirolimus.(1)|
05033|011|B||
05033|012|P|PREDISPOSING FACTORS:  None determined.|
05033|013|B||
05033|014|M|PATIENT MANAGEMENT:  Use caution during coadministration of P-gp inhibitors|
05033|015|M|with sirolimus.  Sirolimus blood levels and the patient's condition should|
05033|016|M|be closely monitored.  Sirolimus dosage adjustment may be required.(1)|
05033|017|B||
05033|018|D|DISCUSSION:  Sirolimus is a known substrate of P-gp. Inhibitors of P-gp may|
05033|019|D|increase toxicity of sirolimus.(1)|
05033|020|D|   In a study of 24 healthy volunteers, cyclosporine 300 mg (a CYP3A4 and|
05033|021|D|P-gp inhibitor) increased the area-under-curve (AUC) and maximum|
05033|022|D|concentration (Cmax) of single-dose sirolimus 10 mg given simultaneously by|
05033|023|D|148% and 512%, respectively, compared to sirolimus alone.  When sirolimus|
05033|024|D|was given 4 hours after cyclosporine, sirolimus AUC and Cmax both increased|
05033|025|D|by only 33%.(1)|
05033|026|D|   In a cross-over study with 33 healthy volunteers, cyclosporine 300 mg|
05033|027|D|increased the AUC and Cmax of sirolimus 5 mg given 2 hours after|
05033|028|D|cyclosporine by 141% and 126%, respectively, compared to sirolimus alone.|
05033|029|D|When sirolimus was given 2 hours before cyclosporine, there was no effect on|
05033|030|D|AUC and Cmax.(1)|
05033|031|D|   Inhibitors of P-gp linked to this monograph include: abrocitinib,|
05033|032|D|capmatinib, imlunestrant, and selpercatinib.(2-3)|
05033|033|B||
05033|034|R|REFERENCES:|
05033|035|B||
05033|036|R|1.Rapamune (sirolimus) US prescribing information. Wyeth Pharmaceuticals|1
05033|037|R|  Aug, 2022.|1
05033|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05033|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05033|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05033|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05033|042|R|  11/14/2017.|1
05033|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
05033|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05034|001|T|MONOGRAPH TITLE:  Cyclosporine/P-glycoprotein (P-gp) Inhibitors|
05034|002|B||
05034|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05034|004|L|take action as needed.|
05034|005|B||
05034|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors may inhibit cellular|
05034|007|A|efflux of cyclosporine.(1,2)|
05034|008|B||
05034|009|E|CLINICAL EFFECTS:  Concurrent administration of a P-gp inhibitor may result|
05034|010|E|in elevated levels and toxicities of cyclosporine, including serious|
05034|011|E|infections, nephrotoxicity, and hepatotoxicity.(1,2)|
05034|012|B||
05034|013|P|PREDISPOSING FACTORS:  None determined.|
05034|014|B||
05034|015|M|PATIENT MANAGEMENT:  Closely monitor cyclosporine levels during concurrent|
05034|016|M|use with P-gp inhibitors.  Cyclosporine dose adjustment may be needed to|
05034|017|M|achieve desired concentrations.(1,2)|
05034|018|B||
05034|019|D|DISCUSSION:  Cyclosporine is a known substrate of P-gp. Inhibitors of P-gp|
05034|020|D|may increase toxicity of cyclosporine.(1,2)|
05034|021|D|   Inhibitors of P-gp linked to this monograph include: abrocitinib,|
05034|022|D|imlunestrant.|
05034|023|B||
05034|024|R|REFERENCES:|
05034|025|B||
05034|026|R|1.Neoral (cyclosporine) US prescribing information. Novartis Pharmaceuticals|1
05034|027|R|  Corporation September, 2023.|1
05034|028|R|2.Sandimmune (cyclosporine) US prescribing information. Novartis|1
05034|029|R|  Pharmaceuticals Corporation September 2023.|1
05034|030|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05034|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05034|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05034|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05034|034|R|  11/14/2017.|1
05034|035|R|4.This information is based on an extract from the Certara Drug Interaction|6
05034|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05035|001|T|MONOGRAPH TITLE:  Tacrolimus/Selected P-glycoprotein (P-gp) Inhibitors|
05035|002|B||
05035|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05035|004|L|take action as needed.|
05035|005|B||
05035|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors may inhibit cellular|
05035|007|A|efflux of tacrolimus.|
05035|008|B||
05035|009|E|CLINICAL EFFECTS:  Concurrent administration of a P-gp inhibitor may result|
05035|010|E|in elevated levels and toxicities of tacrolimus including nephrotoxicity,|
05035|011|E|neurotoxicity, and prolongation of the QTc interval and life-threatening|
05035|012|E|cardiac arrhythmias, including torsades de pointes.(1-2)|
05035|013|B||
05035|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
05035|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
05035|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
05035|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
05035|018|P|gender, or advanced age.(3)|
05035|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05035|020|P|higher systemic concentrations of either QT prolonging drug are additional|
05035|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
05035|022|P|drug concentrations include rapid infusion of an intravenous dose or|
05035|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05035|024|P|an agent which inhibits its metabolism  or elimination, and/or renal/hepatic|
05035|025|P|dysfunction).(3)|
05035|026|B||
05035|027|M|PATIENT MANAGEMENT:  Use caution during coadministration of P-gp inhibitors|
05035|028|M|with tacrolimus.  Tacrolimus blood levels and the patient's condition should|
05035|029|M|be monitored closely.  Tacrolimus dosage adjustment may be required.(2)|
05035|030|M|   If concurrent use cannot be avoided, consider obtaining serum calcium,|
05035|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05035|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05035|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05035|034|B||
05035|035|D|DISCUSSION:  Tacrolimus is a known substrate of P-gp. Inhibitors of P-gp may|
05035|036|D|increase toxicity of tacrolimus.(1)|
05035|037|D|   Inhibitors of P-gp linked to this monograph include: abrocitinib and|
05035|038|D|imlunestrant.(4)|
05035|039|B||
05035|040|R|REFERENCES:|
05035|041|B||
05035|042|R|1.Prograf (tacrolimus) US prescribing information. Astellas Pharma US, Inc.|1
05035|043|R|  August, 2023.|1
05035|044|R|2.Envarsus (tacrolimus) EMA Summary of Product Characteristics. Chiesi|1
05035|045|R|  Farmaceutici S.p.A. June, 2019.|1
05035|046|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05035|047|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05035|048|R|  settings: a scientific statement from the American Heart Association and|6
05035|049|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05035|050|R|  2;55(9):934-47.|6
05035|051|R|4.Inluriyo (imlunestrant) US prescribing information. Eli Lilly and Company|1
05035|052|R|  September, 2025.|1
05035|053|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
05035|054|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05035|055|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05035|056|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05035|057|R|  11/14/2017.|1
05035|058|R|6.This information is based on an extract from the Certara Drug Interaction|6
05035|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05036|001|T|MONOGRAPH TITLE:  Quinidine/Selected P-glycoprotein (P-gp) Inhibitors|
05036|002|B||
05036|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05036|004|L|of severe adverse interaction.|
05036|005|B||
05036|006|A|MECHANISM OF ACTION:  P-glycoprotein (P-gp) inhibitors may inhibit cellular|
05036|007|A|efflux of quinidine.(1)|
05036|008|B||
05036|009|E|CLINICAL EFFECTS:  Concurrent administration of a P-gp inhibitor may result|
05036|010|E|in elevated levels and toxicities of quinidine.  Quinidine causes|
05036|011|E|dose-dependent QT prolongation, which may lead to life-threatening|
05036|012|E|ventricular arrhythmias, including torsades de pointes.(2)|
05036|013|B||
05036|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
05036|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
05036|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
05036|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
05036|018|P|gender, or advanced age.(3)|
05036|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05036|020|P|higher systemic concentrations of either QT prolonging drug are additional|
05036|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
05036|022|P|drug concentrations include rapid infusion of an intravenous dose or|
05036|023|P|impaired metabolism or elimination of the drug (e.g. co-administration with|
05036|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05036|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)|
05036|026|B||
05036|027|M|PATIENT MANAGEMENT:  Avoid concomitant use of P-gp inhibitors like|
05036|028|M|imlunestrant with quinidine.  Consider alternatives with lesser interaction|
05036|029|M|potential with quinidine.(4)|
05036|030|M|   If concurrent use cannot be avoided, consider obtaining serum calcium,|
05036|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05036|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05036|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05036|034|B||
05036|035|D|DISCUSSION:  Quinidine is a known substrate of P-gp. Inhibitors of P-gp may|
05036|036|D|increase toxicity of quinidine.(1-2)|
05036|037|D|   In a physiologically-based pharmacokinetic model, itraconazole 200 mg|
05036|038|D|daily and verapamil 120 mg 3 times daily were both predicted to increase|
05036|039|D|quinidine AUC by 1.7-fold.(1)|
05036|040|D|   Inhibitors of P-gp linked to this monograph include: abrocitinib and|
05036|041|D|imlunestrant.|
05036|042|B||
05036|043|R|REFERENCES:|
05036|044|B||
05036|045|R|1.Feick D, Rudesheim S, Marok FZ, Selzer D, Loer HLH, Teutonico D, Frechen|2
05036|046|R|  S, van der Lee M, Moes DJAR, Swen JJ, Schwab M, Lehr T.|2
05036|047|R|  Physiologically-based pharmacokinetic modeling of quinidine to establish a|2
05036|048|R|  CYP3A4, P-gp, and CYP2D6 drug-drug-gene interaction network. CPT|2
05036|049|R|  Pharmacometrics Syst Pharmacol 2023 Aug;12(8):1143-1156.|2
05036|050|R|2.Quinidine sulfate US prescribing informaiton. Epic Pharma, LLC November,|1
05036|051|R|  2023.|1
05036|052|R|3.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05036|053|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05036|054|R|  settings: a scientific statement from the American Heart Association and|6
05036|055|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05036|056|R|  2;55(9):934-47.|6
05036|057|R|4.Inluriyo (imlunestrant) US prescribing information. Eli Lilly and Company|1
05036|058|R|  September, 2025.|1
05036|059|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
05036|060|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05036|061|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05036|062|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05036|063|R|  11/14/2017.|1
05036|064|R|6.This information is based on an extract from the Certara Drug Interaction|6
05036|065|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05037|001|T|MONOGRAPH TITLE:  Mitapivat (100 mg)/Moderate CYP3A4 Inhibitors|
05037|002|B||
05037|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05037|004|L|of severe adverse interaction.|
05037|005|B||
05037|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
05037|007|A|metabolism of mitapivat.(1)|
05037|008|B||
05037|009|E|CLINICAL EFFECTS:  Concurrent use of a moderate inhibitor of CYP3A4 may|
05037|010|E|result in increased levels of and effects from mitapivat including decreased|
05037|011|E|estrone and estradiol levels in males, increased urate, back pain, and|
05037|012|E|arthralgias.(1)|
05037|013|B||
05037|014|P|PREDISPOSING FACTORS:  None determined.|
05037|015|B||
05037|016|M|PATIENT MANAGEMENT:  The Middle Eastern prescribing information for|
05037|017|M|mitapivat states that alternative therapies that are not moderate CYP3A4|
05037|018|M|inhibitors should be considered during treatment with mitapivat.|
05037|019|M|   If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the|
05037|020|M|dose of mitapivat should not exceed 100 mg once daily.  Patients should be|
05037|021|M|monitored for adverse reactions.(1)|
05037|022|B||
05037|023|D|DISCUSSION:  Mitapivat is a CYP3A4 substrate.  In a pharmacokinetic study|
05037|024|D|with mitapivat 100 mg twice daily dosing, fluconazole increased mitapivat|
05037|025|D|area-under-curve (AUC) and concentration maximum (Cmax) by 2.7-fold and|
05037|026|D|1.7-fold, respectively.(1)|
05037|027|D|   Moderate inhibitors of CYP3A4 linked to this monograph include:|
05037|028|D|amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan,|
05037|029|D|darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine,|
05037|030|D|fosamprenavir, fosnetupitant, imatinib, isavuconazole, letermovir,|
05037|031|D|netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam,|
05037|032|D|treosulfan, and verapamil.(2-3)|
05037|033|B||
05037|034|R|REFERENCES:|
05037|035|B||
05037|036|R|1.Pyrukynd (mitapivat) Middle East Prescribing Information. Agios|1
05037|037|R|  Pharmaceuticals, Inc. July, 2025.|1
05037|038|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05037|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05037|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05037|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05037|042|R|  11/14/2017.|1
05037|043|R|3.This information is based on an extract from the Certara Drug Interaction|6
05037|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05038|001|T|MONOGRAPH TITLE:  Oral Lefamulin/Mitapivat|
05038|002|B||
05038|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05038|004|L|of severe adverse interaction.|
05038|005|B||
05038|006|A|MECHANISM OF ACTION:  Lefamulin and mitapivat are both metabolized by|
05038|007|A|CYP3A4.  Mitapivat is a moderate CYP3A4 inducer while oral lefamulin is a|
05038|008|A|moderate CYP3A4 inhibitor.(1-3)|
05038|009|B||
05038|010|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
05038|011|E|inducer may result in decreased levels and effectiveness of lefamulin.(1)|
05038|012|E|   Concurrent use of a moderate inhibitor of CYP3A4 may result in increased|
05038|013|E|levels of and effects from mitapivat including decreased estrone and|
05038|014|E|estradiol levels in males, increased urate, back pain, and arthralgias.(2-3)|
05038|015|B||
05038|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05038|017|P|of the inducer for longer than 1-2 weeks.|
05038|018|B||
05038|019|M|PATIENT MANAGEMENT:  The manufacturer of lefamulin states that concurrent|
05038|020|M|use with moderate CYP3A4 inducers should be avoided.(1)|
05038|021|M|   The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be|
05038|022|M|monitored closely for increased risk of adverse reactions.  The US|
05038|023|M|manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg|
05038|024|M|twice daily with concurrent moderate CYP3A4 inhibitors.(2)  The Middle|
05038|025|M|Eastern manufacturer of mitapivat states that alternative agents that do not|
05038|026|M|inhibit CYP3A4 should be considered.  If concomitant use of a moderate|
05038|027|M|CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100|
05038|028|M|mg once daily.(3)|
05038|029|B||
05038|030|D|DISCUSSION:  In a study, concurrent administration of rifampin (a strong|
05038|031|D|inducer) with lefamulin injection decreased lefamulin area-under-the-curve|
05038|032|D|(AUC) and maximum concentration (Cmax) by 28% and 8%.(1)|
05038|033|D|   In a study, concurrent administration of rifampin (a strong inducer) with|
05038|034|D|oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1)|
05038|035|D|   In a study, oral lefamulin tablets administered concomitantly with and at|
05038|036|D|2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the|
05038|037|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200%|
05038|038|D|and 100%, respectively.  No clinically significant effect on midazolam|
05038|039|D|pharmacokinetics was observed when co-administered with lefamulin|
05038|040|D|injection.(1)|
05038|041|D|   In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily|
05038|042|D|dosing, fluconazole (a moderate CYP3A4 inhibitor) increased mitapivat|
05038|043|D|area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and|
05038|044|D|1.6-fold, respectively.(2)|
05038|045|B||
05038|046|R|REFERENCES:|
05038|047|B||
05038|048|R|1.Xenleta (lefamulin) US Prescribing information. Nabriva Therapeutics US,|1
05038|049|R|  Inc August 2019.|1
05038|050|R|2.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
05038|051|R|  February, 2022.|1
05038|052|R|3.Pyrukynd (mitapivat) Middle East Prescribing Information. Agios|1
05038|053|R|  Pharmaceuticals, Inc. July, 2025.|1
05038|054|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05038|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05038|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05038|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05038|058|R|  11/14/2017.|1
05038|059|R|5.This information is based on an extract from the Certara Drug Interaction|6
05038|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05039|001|T|MONOGRAPH TITLE:  Voxelotor/Mitapivat|
05039|002|B||
05039|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05039|004|L|of severe adverse interaction.|
05039|005|B||
05039|006|A|MECHANISM OF ACTION:  Voxelotor and mitapivat are both metabolized by|
05039|007|A|CYP3A4.  Mitapivat is a moderate CYP3A4 inducer while voxelotor is a|
05039|008|A|moderate CYP3A4 inhibitor.(1-3)|
05039|009|B||
05039|010|E|CLINICAL EFFECTS:  The concurrent administration of a moderate CYP3A4|
05039|011|E|inducer may result in decreased levels and effectiveness of voxelotor.(1)|
05039|012|E|   Concurrent use of a moderate inhibitor of CYP3A4 may result in increased|
05039|013|E|levels of and effects from mitapivat including decreased estrone and|
05039|014|E|estradiol levels in males, increased urate, back pain, and arthralgias.(2-3)|
05039|015|B||
05039|016|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05039|017|P|of the inducer for longer than 1-2 weeks.|
05039|018|B||
05039|019|M|PATIENT MANAGEMENT:  The manufacturer of voxelotor states that concurrent|
05039|020|M|use with moderate CYP3A4 inducers should be avoided.  If concomitant use is|
05039|021|M|unavoidable, increase the dose of voxelotor as follows:|
05039|022|M|   Patients 12 years and older on concurrent moderate CYP3A4 inducers:|
05039|023|M|increase voxelotor dose to 2,000 mg daily.|
05039|024|M|   Patients 4 years to less than 12 years on concurrent moderate CYP3A4|
05039|025|M|inducers: refer to prescribing information for recommended weight-based|
05039|026|M|dosage adjustments.(1)|
05039|027|M|   The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be|
05039|028|M|monitored closely for increased risk of adverse reactions.  The US|
05039|029|M|manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg|
05039|030|M|twice daily with concurrent moderate CYP3A4 inhibitors.(2)  The Middle|
05039|031|M|Eastern manufacturer of mitapivat states that alternative agents that do not|
05039|032|M|inhibit CYP3A4 should be considered.  If concomitant use of a moderate|
05039|033|M|CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100|
05039|034|M|mg once daily.(3)|
05039|035|B||
05039|036|D|DISCUSSION:  A pharmacokinetic model predicted that co-administration of|
05039|037|D|rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC)|
05039|038|D|of voxelotor by 40%.|
05039|039|D|   Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted|
05039|040|D|to decrease the AUC of voxelotor by 24%.(1)|
05039|041|D|   In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily|
05039|042|D|dosing, fluconazole (a moderate CYP3A4 inhibitor) increased mitapivat|
05039|043|D|area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and|
05039|044|D|1.6-fold, respectively.(2)|
05039|045|B||
05039|046|R|REFERENCES:|
05039|047|B||
05039|048|R|1.Oxbryta (voxelotor) US prescribing information. Global Blood Therapeutics,|1
05039|049|R|  Inc. December, 2021.|1
05039|050|R|2.Pyrukynd (mitapivat) US prescribing information. Agios Pharmaceuticals|1
05039|051|R|  February, 2022.|1
05039|052|R|3.Pyrukynd (mitapivat) Middle East Prescribing Information. Agios|1
05039|053|R|  Pharmaceuticals, Inc. July, 2025.|1
05039|054|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05039|055|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05039|056|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05039|057|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05039|058|R|  11/14/2017.|1
05039|059|R|5.This information is based on an extract from the Certara Drug Interaction|6
05039|060|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05041|001|T|MONOGRAPH TITLE:  Atogepant/Moderate CYP3A4 Inducers|
05041|002|B||
05041|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05041|004|L|of severe adverse interaction.|
05041|005|B||
05041|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may increase the metabolism|
05041|007|A|of atogepant by CYP3A4.(1)|
05041|008|B||
05041|009|E|CLINICAL EFFECTS:  The concurrent use of moderate CYP3A4 inducers with|
05041|010|E|atogepant may result in decreased levels and clinical effectiveness of|
05041|011|E|atogepant.(1)|
05041|012|B||
05041|013|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05041|014|P|of the inducer for longer than 1-2 weeks.|
05041|015|B||
05041|016|M|PATIENT MANAGEMENT:  The manufacturer of atogepant recommends that patients|
05041|017|M|on concomitant moderate CYP3A4 inducers receive atogepant 60 mg once daily|
05041|018|M|for prevention of episodic migraines and use of atogepant is not recommended|
05041|019|M|for prevention of chronic migraines.(1)|
05041|020|M|   Patients receiving concurrent therapy with CYP3A4 inducers and atogepant|
05041|021|M|should be observed for decreased clinical effectiveness.|
05041|022|B||
05041|023|D|DISCUSSION:  In a study of healthy subjects, rifampin, a strong CYP3A4|
05041|024|D|inducer, decreased the area-under-curve (AUC) and maximum concentration|
05041|025|D|(Cmax) of atogepant by 60% and 30%, respectively.  Topiramate, a weak CYP3A4|
05041|026|D|inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1)|
05041|027|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
05041|028|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
05041|029|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
05041|030|D|pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
05041|031|D|thioridazine and tovorafenib.(1,2)|
05041|032|B||
05041|033|R|REFERENCES:|
05041|034|B||
05041|035|R|1.Qulipta (atogepant) US prescribing information. Abbvie September, 2025.|1
05041|036|R|2.This information is based on an extract from the Certara Drug Interaction|6
05041|037|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05041|038|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05041|039|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05041|040|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05041|041|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05041|042|R|  11/14/2017.|1
05042|001|T|MONOGRAPH TITLE:  Atogepant/Weak CYP3A4 Inducers|
05042|002|B||
05042|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05042|004|L|take action as needed.|
05042|005|B||
05042|006|A|MECHANISM OF ACTION:  Weak CYP3A4 inducers may increase the metabolism of|
05042|007|A|atogepant by CYP3A4.(1)|
05042|008|B||
05042|009|E|CLINICAL EFFECTS:  The concurrent use of weak CYP3A4 inducers with atogepant|
05042|010|E|may result in decreased levels and clinical effectiveness of atogepant.(1)|
05042|011|B||
05042|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05042|013|P|of the inducer for longer than 1-2 weeks.|
05042|014|B||
05042|015|M|PATIENT MANAGEMENT:  The manufacturer of atogepant recommends that patients|
05042|016|M|on concomitant weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once|
05042|017|M|daily for prevention of episodic migraines and receive atogepant 60 mg once|
05042|018|M|daily for prevention of chronic migraines.(1)|
05042|019|M|   Patients receiving concurrent therapy with CYP3A4 inducers and atogepant|
05042|020|M|should be observed for decreased clinical effectiveness.|
05042|021|B||
05042|022|D|DISCUSSION:  In a study of healthy subjects, rifampin, a strong CYP3A4|
05042|023|D|inducer, decreased the area-under-curve (AUC) and maximum concentration|
05042|024|D|(Cmax) of atogepant by 60% and 30%, respectively.  Topiramate, a weak CYP3A4|
05042|025|D|inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1)|
05042|026|D|   Weak CYP3A4 inducers linked to this monograph include: armodafinil,|
05042|027|D|bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide,|
05042|028|D|dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin,|
05042|029|D|garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib,|
05042|030|D|nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone,|
05042|031|D|pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone,|
05042|032|D|tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate,|
05042|033|D|troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)|
05042|034|B||
05042|035|R|REFERENCES:|
05042|036|B||
05042|037|R|1.Qulipta (atogepant) US prescribing information. Abbvie September, 2025.|1
05042|038|R|2.This information is based on an extract from the Certara Drug Interaction|6
05042|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05042|040|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05042|041|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05042|042|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05042|043|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05042|044|R|  11/14/2017.|1
05043|001|T|MONOGRAPH TITLE:  Nerandomilast/Strong CYP3A4 Inducers|
05043|002|B||
05043|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05043|004|L|of severe adverse interaction.|
05043|005|B||
05043|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
05043|007|A|nerandomilast by CYP3A4.|
05043|008|B||
05043|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
05043|010|E|reduce the clinical effectiveness of nerandomilast.(1)|
05043|011|B||
05043|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05043|013|P|of the inducer for longer than 1-2 weeks.|
05043|014|B||
05043|015|M|PATIENT MANAGEMENT:  Concurrent use of nerandomilast and strong CYP3A4|
05043|016|M|inducers should be avoided.(1)|
05043|017|B||
05043|018|D|DISCUSSION:  Nerandomilast is primarily metabolized by CYP3A4.(1)|
05043|019|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
05043|020|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
05043|021|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
05043|022|D|rifampin, rifapentine and St. John's wort.(2,3)|
05043|023|B||
05043|024|R|REFERENCES:|
05043|025|B||
05043|026|R|1.Jascayd (nerandomilast) US prescribing information. Boehringer Ingelheim|1
05043|027|R|  Pharmaceuticals, Inc. October, 2025.|1
05043|028|R|2.This information is based on an extract from the Certara Drug Interaction|6
05043|029|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05043|030|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05043|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05043|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05043|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05043|034|R|  11/14/2017.|1
05044|001|T|MONOGRAPH TITLE:  Nerandomilast/Moderate CYP3A4 Inducers|
05044|002|B||
05044|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05044|004|L|of severe adverse interaction.|
05044|005|B||
05044|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
05044|007|A|nerandomilast by CYP3A4.|
05044|008|B||
05044|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
05044|010|E|reduce the clinical effectiveness of nerandomilast.(1)|
05044|011|B||
05044|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05044|013|P|of the inducer for longer than 1-2 weeks.|
05044|014|B||
05044|015|M|PATIENT MANAGEMENT:  Concurrent use of nerandomilast and moderate CYP3A4|
05044|016|M|inducers should be avoided.(1)|
05044|017|B||
05044|018|D|DISCUSSION:  Nerandomilast is primarily metabolized by CYP3A4.(1)|
05044|019|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
05044|020|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
05044|021|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
05044|022|D|pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
05044|023|D|thioridazine, and tovorafenib.(2,3)|
05044|024|B||
05044|025|R|REFERENCES:|
05044|026|B||
05044|027|R|1.Jascayd (nerandomilast) US prescribing information. Boehringer Ingelheim|1
05044|028|R|  Pharmaceuticals, Inc. October, 2025.|1
05044|029|R|2.This information is based on an extract from the Certara Drug Interaction|6
05044|030|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05044|031|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05044|032|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05044|033|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05044|034|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05044|035|R|  11/14/2017.|1
05045|001|T|MONOGRAPH TITLE:  Nerandomilast/Strong CYP3A4 Inhibitors|
05045|002|B||
05045|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05045|004|L|take action as needed.|
05045|005|B||
05045|006|A|MECHANISM OF ACTION:  Agents that are strong CYP3A4 inhibitors may inhibit|
05045|007|A|the metabolism of nerandomilast.(1)|
05045|008|B||
05045|009|E|CLINICAL EFFECTS:  The coadministration of nerandomilast with strong CYP3A4|
05045|010|E|inhibitors may increase nerandomilast systemic exposure and may result in|
05045|011|E|increased adverse reactions.(1)|
05045|012|B||
05045|013|P|PREDISPOSING FACTORS:  None determined.|
05045|014|B||
05045|015|M|PATIENT MANAGEMENT:  The manufacturer of nerandomilast states the dose of|
05045|016|M|nerandomilast should be reduced to 9 mg twice daily with concurrent use of|
05045|017|M|strong CYP3A4 inhibitors.(1)|
05045|018|B||
05045|019|D|DISCUSSION:  In healthy subjects, concurrent use of nerandomilast with|
05045|020|D|itraconazole, a strong CYP3A4 inhibitor, (200 mg once daily for 4 days)|
05045|021|D|increased the area-under-curve (AUC) and concentration maximum (Cmax) of|
05045|022|D|nerandomilast by 2.2-fold and 1.3-fold, respectively.(1)|
05045|023|D|   Strong CYP3A4 inhibitors linked to this monograph include:  adagrasib,|
05045|024|D|boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib,|
05045|025|D|indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole,|
05045|026|D|lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir,|
05045|027|D|nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir,|
05045|028|D|telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and|
05045|029|D|voriconazole.(2,3)|
05045|030|B||
05045|031|R|REFERENCES:|
05045|032|B||
05045|033|R|1.Jascayd (nerandomilast) US prescribing information. Boehringer Ingelheim|1
05045|034|R|  Pharmaceuticals, Inc. October, 2025.|1
05045|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
05045|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05045|037|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05045|038|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05045|039|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05045|040|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05045|041|R|  11/14/2017.|1
05046|001|T|MONOGRAPH TITLE:  Immune Checkpoint Inhibitors/Proton Pump Inhibitors|
05046|002|B||
05046|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05046|004|L|take action as needed.|
05046|005|B||
05046|006|A|MECHANISM OF ACTION:  The mechanism of this interaction has not been fully|
05046|007|A|investigated.  Proposed mechanisms include:|
05046|008|A|  1. Proton pump inhibitor (PPI)-induced changes of the microbiota|
05046|009|A|(dysbiosis) causing resistance to immune checkpoint inhibitors,|
05046|010|A|  2. Co-administration of PPIs with corticosteroids or non steroidal|
05046|011|A|anti-inflammatory drugs (NSAIDs) and immune checkpoint inhibitors resulting|
05046|012|A|in poorer prognosis.(1)|
05046|013|B||
05046|014|E|CLINICAL EFFECTS:  PPIs may decrease the therapeutic effects of immune|
05046|015|E|checkpoint inhibitors.|
05046|016|E|   Several observational studies have shown a reduction in progression free|
05046|017|E|survival (PFS), overall survival (OS), and tumor response in patients on|
05046|018|E|concurrent treatment with immune checkpoint inhibitors and PPIs.(1)|
05046|019|B||
05046|020|P|PREDISPOSING FACTORS:  None determined.|
05046|021|B||
05046|022|M|PATIENT MANAGEMENT:  Concurrent use of immune checkpoint inhibitors and PPIs|
05046|023|M|should be approached with caution.|
05046|024|M|   Manufacturers of immune checkpoint inhibitors do not provide|
05046|025|M|recommendations on the concurrent use of PPIs.|
05046|026|M|  Primary literature on the concurrent use of these agents include|
05046|027|M|recommendations to evaluate the risks and benefits of PPI use and|
05046|028|M|consideration of alternative therapy when possible such as histamine|
05046|029|M|H2-receptor antagonists (H2RAs) or antacids.(1-3)|
05046|030|B||
05046|031|D|DISCUSSION:  A meta analysis of 23 studies evaluating the impact of acid|
05046|032|D|suppressing therapy on the efficacy of immune checkpoint inhibitors found|
05046|033|D|coadministration of a PPI decreased PFS (HR 1.34 [95% confidence interval|
05046|034|D|(CI), 1.13 to 1.58]) and OS (HR 1.43 [95% CI, 1.21 to 1.69]) compared with|
05046|035|D|patients not treated with PPIs.  Furthermore, the meta analysis identified|
05046|036|D|that H2RAs did not affect OS.  These results were consistent across cancer|
05046|037|D|types.(1)|
05046|038|D|   In another meta analysis of 22 studies (5 prospective and 17|
05046|039|D|retrospective, n=16,072) evaluating the impact of concomitant medications on|
05046|040|D|survival outcomes in patients treated with systemic therapy for advanced|
05046|041|D|unresectable or metastatic renal cell carcinoma, concomitant use of PPIs|
05046|042|D|(n=3959) was significantly associated with worse OS in patients treated with|
05046|043|D|immune checkpoint inhibitors (HR 1.22, P=0.01).(4)|
05046|044|D|   A retrospective analysis of 635 patients treated with immune checkpoint|
05046|045|D|inhibitors found PPI use was associated with significantly decreased OS (9|
05046|046|D|vs 26.5 months), PFS (3.5 vs. 8 months), and tumor response (61% vs.|
05046|047|D|72%).(5)|
05046|048|D|   Analysis of retrospective data from clinical trials of atezolizumab for|
05046|049|D|urothelial carcinoma and non-small-cell lung cancer, among patients using a|
05046|050|D|PPI within 30 days before or after therapy initiation, OS was significantly|
05046|051|D|worse for patients randomized to treatment with atezolizumab than for|
05046|052|D|patients randomized to chemotherapy.(6,7)|
05046|053|D|   A retrospective study of 381 patients treated with immune checkpoint|
05046|054|D|inhibitors found use of acid-suppression therapy (n=168 PPIs, n=37 potassium|
05046|055|D|competitive acid blocker, n=13 H2RAs) was associated with significantly|
05046|056|D|shorter PFS and OS (2.9 vs. 6.2 months and 12.3 vs. 24 months, respectively)|
05046|057|D|compared with patients who did not use acid-suppression therapy.  However,|
05046|058|D|when stratified by concomitant use of corticosteroids or NSAIDs, use of|
05046|059|D|acid-suppression therapy was not associated with worse progression-free or|
05046|060|D|overall survival.(8)|
05046|061|D|   In a retrospective cohort study of patients with advanced non-small-cell|
05046|062|D|lung cancer treated with pembrolizumab, exposure to PPIs was associated with|
05046|063|D|worse OS (HR, 1.13; 95% CI, 1.10-1.17).(9)|
05046|064|D|   Analysis of US and Japanese adverse drug event reporting system databases|
05046|065|D|found administration of immune checkpoint inhibitors and PPIs was associated|
05046|066|D|with an increased risk of adverse events including acute kidney injury (10)|
05046|067|D|and congenital, familial and genetic disorders.(11)|
05046|068|D|   In a meta analysis of 14 observational studies, the risk of immune|
05046|069|D|checkpoint inhibitor related AKI (ICI-AKI) in cancer patients concurrently|
05046|070|D|using PPIs was found to be significantly higher (pooled OR of 1.84 [95% CI|
05046|071|D|1.16-2.90]) in comparison to the overall incidence of AKI from all-causes|
05046|072|D|(1.57 [95% CI 1.02-2.40]).(12)|
05046|073|D|   In contrast to these findings, other studies have not found a negative|
05046|074|D|effect on PFS or OS when patients are co-administered PPIs and immune|
05046|075|D|checkpoint inhibitors.|
05046|076|D|   In a retrospective study of 159 patients treated with ipilimumab,|
05046|077|D|coadministration of PPIs was associated with increased odds of experiencing|
05046|078|D|a partial or complete response to ipilimumab (OR 3.73 [95% CI, 1.26 to|
05046|079|D|11.04]).(13)|
05046|080|D|   In another retrospective study of 233 patients who received nivolumab or|
05046|081|D|pembrolizumab, use of PPI had no effect on OS (HR 1.2 [95% CI, 0.8-1.9]) or|
05046|082|D|PFS (HR 1.1 [95% CI, 0.8 to 1.5]).(14)|
05046|083|D|   A nested case-control study of patients (n=38,930) with cancer who were|
05046|084|D|new PPI or immune checkpoint inhibitor users and had no history of AKI|
05046|085|D|before cohort entry, found the risk of AKI in patients treated with both|
05046|086|D|PPIs and immune checkpoint inhibitors was not higher than then additional or|
05046|087|D|multiplication of the risks in those who were treated with PPIs or immune|
05046|088|D|checkpoint inhibitors alone.  The study reinforces the association between|
05046|089|D|PPIs and immune checkpoint inhibitors use and the increased risk of AKI and|
05046|090|D|the need for careful monitoring and evaluation of kidney function when|
05046|091|D|treated with both medicines.(15)|
05046|092|B||
05046|093|R|REFERENCES:|
05046|094|B||
05046|095|R|1.Okamoto K, Saito Y, Yamaguchi A, Takekuma Y, Sugawara M. Acid suppressants|6
05046|096|R|  reduce the therapeutic effect of immune checkpoint inhibitors and increase|6
05046|097|R|  the risk of acute kidney injury: a meta-analysis. International Journal of|6
05046|098|R|  Clinical Oncology 2023 Oct;28(10):1343-1353.|6
05046|099|R|2.Raoul JL, Moreau-Bachelard C, Gilabert M, Edeline J, Frenel JS, .|6
05046|100|R|  Drug-drug interactions with proton pump inhibitors in cancer patients: an|6
05046|101|R|  underrecognized cause of treatment failure. European Society for Medical|6
05046|102|R|  Oncology 2023 Feb;8(1):1-9.|6
05046|103|R|3.Raoul JL, Hansten PD, . Proton pump inhibitors and cancer treatments:|6
05046|104|R|  Emerging evidence against coadministration. Cancer Treatment Reviews 2024|6
05046|105|R|  Sep;129:.|6
05046|106|R|4.Tsuboi I, Matsukawa A, Parizi MK, Miszczyk M, Fazekas T, et al. The Impact|6
05046|107|R|  of Concomitant Medications on the Overall Survival of Patients Treated|6
05046|108|R|  with Systemic Therapy for Advanced or Metastatic Renal Cell Carcinoma: A|6
05046|109|R|  Systematic Review and Meta-analysis. Clinical Genitourinary Cancer 2024|6
05046|110|R|  Dec;22(6):1-12.|6
05046|111|R|5.Kostine M, Mauric E, Tison A, Barnetche T, Barre A, et al. Baseline|2
05046|112|R|  co-medications may alter the anti-tumoural effect of checkpoint inhibitors|2
05046|113|R|  as well as the risk of immune-related adverse events. European Journal of|2
05046|114|R|  Cancer 2021 Oct;157:474-484.|2
05046|115|R|6.Hopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ, .|2
05046|116|R|  Concomitant Proton Pump Inhibitor Use and Survival in Urothelial Carcinoma|2
05046|117|R|  Treated with Atezolizumab. Clinical Cancer Research: American Association|2
05046|118|R|  for Cancer Research 2020 Oct;26(20):5487-5493.|2
05046|119|R|7.Chalabi M, Cardona A, Nagarkar DR, Scala AD, Gandara DR, Rittmeyer A, et|2
05046|120|R|  al. Efficacy of chemotherapy and atezolizumab in patients with|2
05046|121|R|  non-small-cell lung cancer receiving antibiotics and proton pump|2
05046|122|R|  inhibitors: pooled post hoc analyses of the OAK and POPLAR trials. Annals|2
05046|123|R|  of Oncology (European Society for Medical Oncology) 2020 Apr;|2
05046|124|R|  31(4):525-531.|2
05046|125|R|8.Isono T, Furuno H, Onodera Y, Maruyama T, Takeuchi Y, et al. Analysis of|2
05046|126|R|  immune checkpoint inhibitors for advanced non-small cell lung cancer in|2
05046|127|R|  patients receiving antacids. Respiratory Investigation 2024 Nov;|2
05046|128|R|  62(6):951-959.|2
05046|129|R|9.Rousseau A, Simon-Tillaux N, Michiels S, et al. Concomitant Comedications|2
05046|130|R|  and Survival With First-Line Pembrolizumab in Advanced Non-Small-Cell Lung|2
05046|131|R|  Cancer. JAMA Network Open (Oncology) 2025;8(9):1-14.|2
05046|132|R|10.Okamoto K, Takizawa J, Ueda H, Narumi K, Kobayashi M, . Effect of Acid|6
05046|133|R|   Suppressants on Adverse Events of Immune Checkpoint Inhibitors Using|6
05046|134|R|   Real-world Databases. Anticancer Research 2025 Aug;45(8):3287-3293.|6
05046|135|R|11.Ren X, Li L, Chen Y, Cui X, Wan R, Wang Y, . Adverse reactions of immune|6
05046|136|R|   checkpoint inhibitors combined with Proton pump inhibitors: a|6
05046|137|R|   pharmacovigilance analysis of drug-drug interactions. BMC Cancer 2024|6
05046|138|R|   Sep;24(1):1-15.|6
05046|139|R|12.Mohan A, Krisanapan P, Tangpanithandee S, Thongprayoon C, et al.|6
05046|140|R|   Association of Proton Pump Inhibitor Use and Immune Checkpoint|6
05046|141|R|   Inhibitor-Mediated Acute Kidney Injury: A Meta-Analysis and a Review of|6
05046|142|R|   Related Outcomes. American Journal of Nephrology 2024;55(4):439-449.|6
05046|143|R|13.Failing JJ, Finnes HD, Kottschade LA, Allred JB, Markovic SN, et al.|2
05046|144|R|   Effects of commonly used chronic medications on the outcomes of|2
05046|145|R|   ipilimumab therapy in patients with metastatic melanoma. Melanoma|2
05046|146|R|   Research 2016 Dec;26(6):609-615.|2
05046|147|R|14.Peng K, Chen K, Teply BA, Yee GC, Farazi PA, Lyden ER, . Impact of Proton|2
05046|148|R|   Pump Inhibitor Use on the Effectiveness of Immune Checkpoint Inhibitors|2
05046|149|R|   in Advanced Cancer Patients. The Annals of Pharmacotherapy 2022 Apr;|2
05046|150|R|   56(4):377-386.|2
05046|151|R|15.Yamawaski C, Nakagawa S, Ikuta K, Katsube Y, Imayoshi N, Shigetsura Y, et|2
05046|152|R|   al. Association between Proton Pump Inhibitors, Immune Checkpoint|2
05046|153|R|   Inhibitors, and Acute Kidney Injury: A Nested Case-Control Study.|2
05046|154|R|   Kidney360 2024 Sep;5(9):1262-1269.|2
05047|001|T|MONOGRAPH TITLE:  Nasal Metoclopramide/Selected Strong CYP2D6 Inhibitors|
05047|002|B||
05047|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05047|004|L|of severe adverse interaction.|
05047|005|B||
05047|006|A|MECHANISM OF ACTION:  Strong CYP2D6 inhibitors may inhibit the metabolism of|
05047|007|A|metoclopramide.|
05047|008|B||
05047|009|E|CLINICAL EFFECTS:  Concurrent use may result in elevated levels of|
05047|010|E|metoclopramide, which may increase the risk of extrapyramidal symptoms such|
05047|011|E|as tardive dyskinesia, which may be permanent.  Tardive dyskinesia typically|
05047|012|E|affects the facial muscles and may result in uncontrollable lip smacking,|
05047|013|E|chewing, puckering of the mouth, frowning or scowling, sticking out the|
05047|014|E|tongue, blinking and moving the eyes, and shaking of the arms and/or legs.|
05047|015|E|   Concurrent use may also result in serotonin syndrome.  Symptoms of|
05047|016|E|serotonin syndrome include irritability, altered consciousness, double|
05047|017|E|vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone,|
05047|018|E|rigidity, myoclonus, rapid  fluctuations in vital signs, and coma. Serotonin|
05047|019|E|syndrome may result in death.|
05047|020|B||
05047|021|P|PREDISPOSING FACTORS:  Patients with renal and/or hepatic impairment may|
05047|022|P|have an increased risk from this combination.|
05047|023|B||
05047|024|M|PATIENT MANAGEMENT:  The manufacturer of metoclopramide nasal spray states|
05047|025|M|concurrent use with strong CYP2D6 inhibitors is not recommended.|
05047|026|M|   If concurrent therapy is warranted, patients should be monitored for|
05047|027|M|extrapyramidal symptoms and signs and symptoms of serotonin syndrome.|
05047|028|M|Instruct patients to report any abnormal/uncontrollable muscle movements,|
05047|029|M|muscle twitching, tremors, shivering and stiffness, fever, heavy sweating,|
05047|030|M|heart palpitations, restlessness, confusion, agitation, trouble with|
05047|031|M|coordination, or severe diarrhea.|
05047|032|B||
05047|033|D|DISCUSSION:  In a study in 20 healthy male subjects, concurrent fluoxetine|
05047|034|D|(60 mg daily, another strong CYP2D6 inhibitor) increased the maximum|
05047|035|D|concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg|
05047|036|D|single dose) by 42% and 89%, respectively.(1,2)|
05047|037|D|   There have been case reports of serotonin syndrome in patients receiving|
05047|038|D|concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(3)|
05047|039|D|sertraline,(5-7) and venlafaxine.(7)|
05047|040|D|   Strong CYP2D6 inhibitors linked to this monograph include: bupropion,|
05047|041|D|dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and|
05047|042|D|terbinafine.(8)|
05047|043|B||
05047|044|R|REFERENCES:|
05047|045|B||
05047|046|R|1.Gimoti (metoclopramide nasal spray) US prescribing information. Evoke|1
05047|047|R|  Pharma, Inc. January, 2021.|1
05047|048|R|2.Vlase L, Leucuta A, Farcau D, Nanulescu M. Pharmacokinetic interaction|2
05047|049|R|  between fluoxetine and metoclopramide in healthy volunteers. Biopharm Drug|2
05047|050|R|  Dispos 2006 Sep;27(6):285-9.|2
05047|051|R|3.Coulter DM, Pillans PI. Fluoxetine and extrapyramidal side effects. Am J|3
05047|052|R|  Psychiatry 1995 Jan;152(1):122-5.|3
05047|053|R|4.Palop V, Jimenez MJ, Catalan C, Martinez-Mir I. Acute dystonia associated|3
05047|054|R|  with fluvoxamine-metoclopramide. Ann Pharmacother 1999 Mar;33(3):382.|3
05047|055|R|5.Christensen RC, Byerly MJ. Mandibular dystonia associated with the|3
05047|056|R|  combination of sertraline and metoclopramide. J Clin Psychiatry 1996 Dec;|3
05047|057|R|  57(12):596.|3
05047|058|R|6.Vandemergel X, Beukinga I, Neve P. Serotonin syndrome secondary to the use|3
05047|059|R|  of sertraline and metoclopramide. Rev Med Brux 2000 Jun;21(3):161-3.|3
05047|060|R|7.Fisher AA, Davis MW. Serotonin syndrome caused by selective serotonin|3
05047|061|R|  reuptake-inhibitors-metoclopramide interaction. Ann Pharmacother 2002 Jan;|3
05047|062|R|  36(1):67-71.|3
05047|063|R|8.This information is based on an extract from the Certara Drug Interaction|6
05047|064|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05048|001|T|MONOGRAPH TITLE:  Fecal Microbiota/Antibiotics|
05048|002|B||
05048|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05048|004|L|of severe adverse interaction.|
05048|005|B||
05048|006|A|MECHANISM OF ACTION:  Fecal microbiota is a suspension of live bacteria,|
05048|007|A|which may be compromised by concurrent use of antibiotics.(1)|
05048|008|B||
05048|009|E|CLINICAL EFFECTS:  Antibiotics may decrease the effectiveness of fecal|
05048|010|E|microbiota.(1)|
05048|011|B||
05048|012|P|PREDISPOSING FACTORS:  None determined.|
05048|013|B||
05048|014|M|PATIENT MANAGEMENT:  Antibiotics should not be used concurrently with fecal|
05048|015|M|microbiota.  Antibacterial treatment should be completed for 24 to 72 hours|
05048|016|M|before initiating treatment with fecal microbiota.  Do not use antibiotics|
05048|017|M|for up to 8 weeks after fecal microbiota.(1)|
05048|018|B||
05048|019|D|DISCUSSION:  Antibiotics may compromise the effectiveness of fecal|
05048|020|D|microbiota.|
05048|021|B||
05048|022|R|REFERENCE:|
05048|023|B||
05048|024|R|1.Rebyota (fecal microbiota, live - jslm) US prescribing information.|1
05048|025|R|  Ferring Pharmaceuticals Inc. December, 2024.|1
05049|001|T|MONOGRAPH TITLE:  Elinzanetant/Strong CYP3A4 Inducers|
05049|002|B||
05049|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05049|004|L|of severe adverse interaction.|
05049|005|B||
05049|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inducers may induce the metabolism of|
05049|007|A|elinzanetant by CYP3A4.|
05049|008|B||
05049|009|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers may|
05049|010|E|reduce the clinical effectiveness of elinzanetant.(1)|
05049|011|B||
05049|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05049|013|P|of the inducer for longer than 1-2 weeks.|
05049|014|B||
05049|015|M|PATIENT MANAGEMENT:  The US manufacturer of elinzanetant states concurrent|
05049|016|M|use with strong CYP3A4 inducers should be avoided.(1)|
05049|017|M|   The Canadian manufacturer of elinzanetant states no dose adjustment is|
05049|018|M|recommended for the concomitant use of elinzanetant with CYP3A4 and P-gp|
05049|019|M|inducers.(2)|
05049|020|B||
05049|021|D|DISCUSSION:  Elinzanetant maximum concentration (Cmax) reduced by 44% and|
05049|022|D|area-under-curve (AUC) reduced by 64% following concomitant use with|
05049|023|D|carbamazepine (moderate to strong CYP3A4 inducer) 600 mg administered twice|
05049|024|D|daily.(1)|
05049|025|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
05049|026|D|barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin,|
05049|027|D|ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone,|
05049|028|D|rifampin, rifapentine and St. John's wort.(2,3)|
05049|029|B||
05049|030|R|REFERENCES:|
05049|031|B||
05049|032|R|1.Lynkuet (elinzanetant) US prescribing information. Bayer HealthCare|1
05049|033|R|  Pharmaceuticals Inc. October 2025.|1
05049|034|R|2.Lynkuet (elinzanetant) Canadian prescribing information. Bayer, Inc. July|1
05049|035|R|  2025.|1
05050|001|T|MONOGRAPH TITLE:  Elinzanetant/Moderate CYP3A4 Inducers|
05050|002|B||
05050|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05050|004|L|of severe adverse interaction.|
05050|005|B||
05050|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inducers may induce the metabolism of|
05050|007|A|elinzanetant by CYP3A4.|
05050|008|B||
05050|009|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers may|
05050|010|E|reduce the clinical effectiveness of elinzanetant.(1)|
05050|011|B||
05050|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05050|013|P|of the inducer for longer than 1-2 weeks.|
05050|014|B||
05050|015|M|PATIENT MANAGEMENT:  The US manufacturer of elinzanetant states concurrent|
05050|016|M|use with moderate CYP3A4 inducers should be avoided.(1)|
05050|017|M|   The Canadian manufacturer of elinzanetant states no dose adjustment is|
05050|018|M|recommended for the concomitant use of elinzanetant with CYP3A4 and P-gp|
05050|019|M|inducers.(2)|
05050|020|B||
05050|021|D|DISCUSSION:  Elinzanetant maximum concentration (Cmax) reduced by 44% and|
05050|022|D|area-under-curve (AUC) reduced by 64% following concomitant use with|
05050|023|D|carbamazepine (moderate to strong CYP3A4 inducer) 600 mg administered twice|
05050|024|D|daily.(1)|
05050|025|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
05050|026|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
05050|027|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
05050|028|D|pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat,|
05050|029|D|thioridazine, and tovorafenib.(2,3)|
05050|030|B||
05050|031|R|REFERENCES:|
05050|032|B||
05050|033|R|1.Lynkuet (elinzanetant) US prescribing information. Bayer HealthCare|1
05050|034|R|  Pharmaceuticals Inc. October 2025.|1
05050|035|R|2.Lynkuet (elinzanetant) Canadian prescribing information. Bayer, Inc. July|1
05050|036|R|  2025.|1
05051|001|T|MONOGRAPH TITLE:  Selected Anti-Aromatase Agents/Selected Vaginal Estrogens|
05051|002|B||
05051|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05051|004|L|of severe adverse interaction.|
05051|005|B||
05051|006|A|MECHANISM OF ACTION:  Aromatase inhibitors(1-6) and inactivators(7-10) treat|
05051|007|A|breast cancer by inhibiting estrogen synthesis therefore lowering serum|
05051|008|A|estrone and estradiol levels.|
05051|009|A|   In postmenopausal women, androgens are metabolized to estrogens via the|
05051|010|A|primary pathway of the aromatase enzyme.|
05051|011|B||
05051|012|E|CLINICAL EFFECTS:  Concurrent administration of estrogen may decrease the|
05051|013|E|effectiveness of aromatase inhibitors.(1-6)|
05051|014|B||
05051|015|P|PREDISPOSING FACTORS:  None determined.|
05051|016|B||
05051|017|M|PATIENT MANAGEMENT:  The Canadian,(1) UK,(2) and US(3) manufacturers of|
05051|018|M|anastrozole state that estrogen containing therapies should not be used|
05051|019|M|during anastrozole therapy.|
05051|020|M|   The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of|
05051|021|M|exemestane state that exemestane should not be administered with estrogen|
05051|022|M|containing therapies.|
05051|023|M|   The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen|
05051|024|M|containing therapies should be avoided during letrozole therapy.|
05051|025|M|   A clinical consensus from the American College of Obstetricians and|
05051|026|M|Gynecologists states that low-dose vaginal estrogen may be used in patients|
05051|027|M|on aromatase inhibitors who have failed non-hormonal treatment after shared|
05051|028|M|decision making.(11)|
05051|029|M|  The Fifth International Consultation on Sexual Medicine also made|
05051|030|M|recommendations on treatment of genitourinary syndrome of menopause (GSM).|
05051|031|M|They state that local estrogen therapy cannot be a first line treatment for|
05051|032|M|GSM in women on adjuvant hormone therapy but low- and ultra-low dose local|
05051|033|M|estrogens can be used after trying non-hormonal approaches, and after a|
05051|034|M|discussion of risks and benefits with the patient.(12)|
05051|035|B||
05051|036|D|DISCUSSION:  Many breast cancers have estrogen receptors and their growth|
05051|037|D|can be stimulated by estrogen.  Anastrozole is a potent and selective|
05051|038|D|non-steroidal aromatase inhibitor that lowers serum estradiol levels.|
05051|039|D|Concurrent use of estrogen may diminish the effects of anastrozole.(1-3)|
05051|040|D|   Exemestane is a steroidal aromatase inactivator that lowers serum|
05051|041|D|estradiol levels.  Concurrent use of estrogen may diminish the effects of|
05051|042|D|exemestane.(7-10)|
05051|043|D|   Several meta-analyses and systematic reviews have concluded that vaginal|
05051|044|D|estrogens are likely to be safe in women on aromatase inhibitors.|
05051|045|D|Nevertheless, they recommend using vaginal estrogens after a trial with|
05051|046|D|nonhormonal therapies has failed and following shared decision making|
05051|047|D|including a discussion with the patient of the risks and benefits of|
05051|048|D|treatment.(13-16)|
05051|049|B||
05051|050|R|REFERENCES:|
05051|051|B||
05051|052|R|1.Arimidex (anastrozole) Canadian prescribing information. Sanis Health Inc.|1
05051|053|R|  July, 2015.|1
05051|054|R|2.Arimidex (anastrozole) UK summary of product characteristics. AstraZeneca|1
05051|055|R|  UK Ltd June, 2021.|1
05051|056|R|3.Arimidex (anastrozole) US prescribing information. AstraZeneca|1
05051|057|R|  Pharmaceuticals LP May, 2013.|1
05051|058|R|4.Femara (letrozole) Canadian prescribing information. Novartis|1
05051|059|R|  Pharmaceuticals Canada Inc. April, 2014.|1
05051|060|R|5.Femara (letrozole) UK summary of product characteristics. Novartis|1
05051|061|R|  Pharmaceuticals Corporation May, 2012.|1
05051|062|R|6.Femara (letrozole) US prescribing information. Novartis Pharmaceuticals|1
05051|063|R|  Corporation September, 2017.|1
05051|064|R|7.Aromasin (exemestane) Australian prescribing information. Pharmacia|1
05051|065|R|  Australia August 18, 2003.|1
05051|066|R|8.Aromasin (exemestane) Canadian prescribing information. Pfizer Canada Inc.|1
05051|067|R|  March 01, 2005.|1
05051|068|R|9.Aromasin (exemestane) UK summary of product characteristics. Pharmacia|1
05051|069|R|  Limited December 17, 2004.|1
05051|070|R|10.Aromasin (exemestane) US prescribing information. Pharmacia & Upjohn|1
05051|071|R|   Company July, 2016.|1
05051|072|R|11.Treatment of Urogenital Symptoms in Individuals With a History of|6
05051|073|R|   Estrogen-dependent Breast Cancer: Clinical Consensus. Obstet Gynecol 2021|6
05051|074|R|   Dec 1;138(6):950-960.|6
05051|075|R|12.Simon JA, Nappi RE, Chedraui P, Clark AL, Gompel A, Nasreen SZA, Palacios|6
05051|076|R|   S, Wolfman W. Genitourinary syndrome of menopause (GSM): recommendations|6
05051|077|R|   from the Fifth  International Consultation on Sexual Medicine (ICSM|6
05051|078|R|   2024). Sex Med Rev 2025 Sep 22.|6
05051|079|R|13.Glynne S, Simon J, Branson A, Payne S, Newson L, Manyonda I, Cleator S,|6
05051|080|R|   Douek M, Usiskin S, Tobias JS, Vaidya JS. Menopausal hormone therapy for|6
05051|081|R|   breast cancer patients: what is the current  evidence?. Menopause 2025|6
05051|082|R|   Sep 30.|6
05051|083|R|14.Santos GML, Magalhaes AO, Teichmann PDV, Wender MCO. Vaginal estrogen|6
05051|084|R|   therapy for treatment of menopausal genitourinary syndrome among  breast|6
05051|085|R|   cancer survivors: a systematic review and meta-analysis. Rev Bras Ginecol|6
05051|086|R|   Obstet 2025;47:.|6
05051|087|R|15.Beste ME, Kaunitz AM, McKinney JA, Sanchez-Ramos L. Vaginal estrogen use|6
05051|088|R|   in breast cancer survivors: a systematic review and  meta-analysis of|6
05051|089|R|   recurrence and mortality risks. Am J Obstet Gynecol 2025 Mar;|6
05051|090|R|   232(3):262-270.e1.|6
05051|091|R|16.Kastora SL, Pantiora E, Hong YH, Veeramani M, Azim HAJr, Chakrabarti R,|6
05051|092|R|   Geisler J, Knoop A, Lambertini M, Linderholm B, Meattini I, Partridge AH,|6
05051|093|R|   Vaz-Luis I, Vorburger D, Yongue G, etal. Safety of topical estrogen|6
05051|094|R|   therapy during adjuvant endocrine treatment among  patients with breast|6
05051|095|R|   cancer: A meta-analysis based expert panel discussion. Cancer Treat Rev|6
05051|096|R|   2025 Feb;133:102880.|6
05052|001|T|MONOGRAPH TITLE:  Pacritinib/Moderate CYP3A4 Inhibitors that Prolong QT|
05052|002|B||
05052|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05052|004|L|of severe adverse interaction.|
05052|005|B||
05052|006|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 that prolong the QTc|
05052|007|A|interval may inhibit the metabolism of pacritinib and result in additive|
05052|008|A|risk of QT prolongation.(1)|
05052|009|B||
05052|010|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors that prolong|
05052|011|E|QT may increase the levels and effects of pacritinib, including additive QTc|
05052|012|E|prolongation, which may result in potentially life-threatening cardiac|
05052|013|E|arrhythmias, including torsades de pointes (TdP).(1)|
05052|014|E|   Other toxicities include bleeding, diarrhea, thrombocytopenia, major|
05052|015|E|adverse cardiovascular events, thrombosis, and infection.(1)|
05052|016|B||
05052|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05052|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
05052|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05052|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05052|021|P|female gender, or advanced age.(2)|
05052|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05052|023|P|higher systemic concentrations of either QT prolonging drug are additional|
05052|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05052|025|P|drug concentrations include rapid infusion of an intravenous dose or|
05052|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05052|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05052|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05052|029|B||
05052|030|M|PATIENT MANAGEMENT:  The manufacturer of pacritinib states concurrent use|
05052|031|M|with agents known to prolong the QT interval should be avoided.  Avoid the|
05052|032|M|use of pacritinib in patients with a baseline QTc > 480 msec.  Correct|
05052|033|M|hypokalemia prior to initiation and during therapy with pacritinib.(1)|
05052|034|M|   The manufacturer of pacritinib recommends monitoring patients|
05052|035|M|concomitantly receiving moderate CYP3A4 inhibitors (e.g., fluconazole) for|
05052|036|M|increased adverse reactions and considering pacritinib dose modifications|
05052|037|M|based on safety.(1)|
05052|038|M|   When concurrent therapy is warranted monitor for prolongation of the QTc|
05052|039|M|interval.(1) Consider obtaining serum calcium, magnesium, and potassium|
05052|040|M|levels and monitoring EKG at baseline and regular intervals. Correct any|
05052|041|M|electrolyte abnormalities.  Instruct patients to report any irregular|
05052|042|M|heartbeat, dizziness, or fainting.|
05052|043|M|   If patients develop QTc prolongation >500 msec or >60 msec from baseline,|
05052|044|M|hold pacritinib.  If QTc prolongation resolves to <=480 msec or to baseline|
05052|045|M|within 1 week, resume pacritinib at the same dose.  If time to resolution of|
05052|046|M|the QTc interval takes greater than 1 week to resolve, reduce the pacritinib|
05052|047|M|dose according to labeling.(1)|
05052|048|B||
05052|049|D|DISCUSSION:  Fluconazole (200 mg once daily for 7 days, a moderate CYP3A4|
05052|050|D|inhibitor) increased maximum concentration (Cmax) and area-under-curve (AUC)|
05052|051|D|of pacritinib (200 mg twice daily at steady state) by 41% and 45%,|
05052|052|D|respectively.(1)  Concomitant use of pacritinib with doses of fluconazole|
05052|053|D|greater than 200 mg once daily have not been studied.(1)|
05052|054|D|   In a 24 week clinical study, patients treated with pacritinib 200 mg|
05052|055|D|twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1)|
05052|056|D|   Pacritinib has been associated with QTc interval prolongation.  In|
05052|057|D|clinical trials, patients with QTc prolongation >500 msec occurred in 1.4%|
05052|058|D|of patients in the treatment arm compared to 1% in the control arm.  The|
05052|059|D|treatment arm had a greater incidence of an increase in QTc > 60 msec from|
05052|060|D|baseline than the control arm (1.9% vs 1%, respectively).  QTc prolongation|
05052|061|D|adverse reactions were higher in the treatment arm than the control group|
05052|062|D|(3.8% vs 2%, respectively).(1)|
05052|063|D|   Agents that are linked to this monograph may have varying degrees of|
05052|064|D|potential to prolong the QTc interval but are generally accepted to have a|
05052|065|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
05052|066|D|been shown to prolong the QTc interval either through their mechanism of|
05052|067|D|action, through studies on their effects on the QTc interval, or through|
05052|068|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
05052|069|D|and/or post-marketing reports.(5)|
05052|070|D|   Moderate inhibitors of CYP3A4 that prolong QT include: clofazimine.(3,4)|
05052|071|B||
05052|072|R|REFERENCES:|
05052|073|B||
05052|074|R|1.Vonjo (pacritinib) US prescribing information. CTI BioPharmca Corp. Nov,|1
05052|075|R|  2024.|1
05052|076|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05052|077|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05052|078|R|  settings: a scientific statement from the American Heart Association and|6
05052|079|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05052|080|R|  2;55(9):934-47.|6
05052|081|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05052|082|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05052|083|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05052|084|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05052|085|R|  11/14/2017.|1
05052|086|R|4.This information is based on an extract from the Certara Drug Interaction|6
05052|087|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05052|088|R|5.USDepartment of Health and Human Services Food and Drug Administration.|1
05052|089|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
05052|090|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
05052|091|R|  https://www.fda.gov/media/71372/download October, 2005.|1
05053|001|T|MONOGRAPH TITLE:  Ivosidenib/Moderate CYP3A4 Inhibitors that Prolong QT|
05053|002|B||
05053|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05053|004|L|of severe adverse interaction.|
05053|005|B||
05053|006|A|MECHANISM OF ACTION:  Agents which inhibit the CYP3A4 enzyme may inhibit the|
05053|007|A|metabolism of ivosidenib.(1)|
05053|008|A|   Use of CYP3A4 inhibitors that prolong the QTc interval may result in|
05053|009|A|additive effects on the QTc interval.|
05053|010|B||
05053|011|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
05053|012|E|systemic exposure and the risk for ivosidenib toxicities such as QT|
05053|013|E|prolongation.(1)|
05053|014|B||
05053|015|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
05053|016|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
05053|017|P|myocardial infarction, history of torsade de pointes, congenital long QT|
05053|018|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
05053|019|P|gender, or advanced age.(2)|
05053|020|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05053|021|P|higher systemic concentrations of either QT prolonging drug are additional|
05053|022|P|risk factors for torsade de pointes.  Factors which may increase systemic|
05053|023|P|drug concentrations include rapid infusion of an intravenous dose or|
05053|024|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05053|025|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05053|026|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05053|027|B||
05053|028|M|PATIENT MANAGEMENT:  Avoid the concurrent use of ivosidenib with medications|
05053|029|M|that prolong the QT interval.(1)|
05053|030|M|   The US manufacturer of ivosidenib recommends considering an alternative|
05053|031|M|concomitant medication with less potential for CYP3A4 inhibition.(1)|
05053|032|M|   During concomitant therapy with a moderate CYP3A4 inhibitor, monitor|
05053|033|M|patients closely for prolongation of the QT interval.  Obtain serum calcium,|
05053|034|M|magnesium, and potassium levels and monitor ECG at regular intervals.|
05053|035|M|Correct any electrolyte abnormalities.  Instruct patients to report any|
05053|036|M|irregular heartbeat, dizziness, or fainting.|
05053|037|M|   If QTc prolongation develops:|
05053|038|M|   ---Monitor and supplement electrolytes as clinically indicated|
05053|039|M|   ---Review and adjust concomitant QT prolonging medications|
05053|040|M|   ---Interrupt ivosidenib therapy|
05053|041|M|   ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc|
05053|042|M|prolongation|
05053|043|M|   ---Follow labeling recommendations regarding restarting ivosidenib.(1)|
05053|044|B||
05053|045|D|DISCUSSION:  In a drug interaction study in healthy subjects,|
05053|046|D|coadministration of itraconazole (200 mg once daily for 18 days) with a|
05053|047|D|single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve|
05053|048|D|(AUC) by 269%. No change was seen in ivosidenib's maximum concentration|
05053|049|D|(Cmax).(1)|
05053|050|D|   Data from a pharmacokinetic simulation suggests that fluconazole, a|
05053|051|D|moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC|
05053|052|D|by 173%. In regards to multiple-dosing, coadministration of ivosidenib with|
05053|053|D|fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and|
05053|054|D|190%, respectively.(1)|
05053|055|D|   In clinical trials of ivosidenib, 9% of patients experienced a QTc|
05053|056|D|interval greater than 500 msec and 14% of patients had an increased from|
05053|057|D|baseline QTc interval of greater than 60 msec.  Patients with a baseline QTc|
05053|058|D|of equal to or greater than 450 msec without pre-existing bundle branch|
05053|059|D|block, or with a history of long QT syndrome were excluded from this|
05053|060|D|trial.(1)|
05053|061|D|   Moderate CYP3A4 inhibitors linked to this monograph include:|
05053|062|D|clofazimine.(3)|
05053|063|B||
05053|064|R|REFERENCES:|
05053|065|B||
05053|066|R|1.Tibsovo (ivosidenib) US prescribing information. Agios Pharmaceuticals,|1
05053|067|R|  Inc. August, 2021.|1
05053|068|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05053|069|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05053|070|R|  settings: a scientific statement from the American Heart Association and|6
05053|071|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05053|072|R|  2;55(9):934-47.|6
05053|073|R|3.This information is based on an extract from the Certara Drug Interaction|6
05053|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05054|001|T|MONOGRAPH TITLE:  Clofazimine/QT Prolonging Agents|
05054|002|B||
05054|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05054|004|L|take action as needed.|
05054|005|B||
05054|006|A|MECHANISM OF ACTION:  Clofazimine has been shown to prolong the QTc|
05054|007|A|interval.  Concurrent use with other agents that prolong the QTc interval|
05054|008|A|may result in additive effects on the QTc interval.(1)|
05054|009|B||
05054|010|E|CLINICAL EFFECTS:  The concurrent use of clofazimine with other agents that|
05054|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
05054|012|E|arrhythmias, including torsades de pointes (TdP).(1)|
05054|013|B||
05054|014|P|PREDISPOSING FACTORS:  In general, the risk of QT prolongation or torsade de|
05054|015|P|pointes may be increased in patients with cardiovascular disease (e.g. heart|
05054|016|P|failure, myocardial infarction, history of torsade de pointes, congenital|
05054|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05054|018|P|female gender, or advanced age.(2)|
05054|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05054|020|P|higher systemic concentrations of either QT prolonging drug are additional|
05054|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
05054|022|P|drug concentrations include rapid infusion of an intravenous dose or|
05054|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05054|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05054|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05054|026|B||
05054|027|M|PATIENT MANAGEMENT:  The concurrent use of clofazimine with other agents|
05054|028|M|known to prolong the QTc interval should be approached with caution and|
05054|029|M|monitored closely.  Monitor ECG and electrolytes regularly if clofazimine is|
05054|030|M|administered with concurrent QTc prolonging drugs.(1)|
05054|031|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05054|032|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05054|033|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05054|034|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05054|035|B||
05054|036|D|DISCUSSION:  Clofazimine has been reported to cause QTc prolongation and|
05054|037|D|torsades de pointes when combined with medications that also prolong the QT|
05054|038|D|interval.(1)|
05054|039|D|   In a pharmacovigilance analysis based on FAERS data from 2004-2025, a|
05054|040|D|disproportionality analysis identified multiple serious and consistent|
05054|041|D|safety signals associated with clofazimine.  The most prominent safety|
05054|042|D|signals included QT prolongation (ROR 37.61).(3)|
05054|043|D|   In an observational cohort of 321 patients with rifampin-resistant|
05054|044|D|tuberculosis (RR-TB), the mean maximum increase of QTcF was 27.1 ms (IQR|
05054|045|D|13.8-42.4) for treatment with fluoroquinolones, 43.3 ms (IQR 31.3-65.9) for|
05054|046|D|clofazimine, and 53.2 ms (IQR 36.2-73.2) for clofazimine with|
05054|047|D|fluoroquinolone.  Clofazimine was significantly associated with QTcF >=501|
05054|048|D|ms in multivariable analysis (adjusted HR 4.35, 95% CI 2.01-9.44).(4)|
05054|049|D|   A post-hoc analysis of an open label phase 2/3 randomized controlled|
05054|050|D|trial compared QTcF associated with RR-TB therapies using|
05054|051|D|bedaquiline/pretomanid/linezolid (BPaL), BPaL with clofazimine (BPaLC), or|
05054|052|D|BPaL with moxifloxacin (BPaLM).  Only 1 incidence of QTcF >500 ms occurred|
05054|053|D|in the BPaLC arm.  Peak QTcF values were higher in the BPaLC arm than in the|
05054|054|D|BPaL or BPaLM arms (446.5 ms +/- 19.4 ms, 436 ms +/- 22.2 ms, 439.5 ms +/-|
05054|055|D|20.7 ms, respectively), but the differences were considered to be small and|
05054|056|D|not clinically important.(5)|
05054|057|D|   An analysis of a phase 3 randomized controlled trial (STREAM) compared|
05054|058|D|the effects of a short 9-month regimen (moxifloxacin + clofazimine) with a|
05054|059|D|long 20-month regimen (moxifloxacin or levofloxacin) on the QT interval.|
05054|060|D|The long regimen had a median maximum QTcF change of 30 ms (IQR 22-41)|
05054|061|D|compared to 50 ms (IQR 36-65 ms) on the short regimen.  Thirty-one patients|
05054|062|D|(11%) on the short regimen had a maximum QTcF >=500 ms, compared to seven|
05054|063|D|patients (5%) on the long regimen.(6)|
05054|064|D|   In a case report, a 66 year old male on clofazimine 300 mg daily for 11|
05054|065|D|days for leprosy developed torsades de pointe.  Although his magnesium level|
05054|066|D|was also low, it was believed that clofazimine alone or with the electrolyte|
05054|067|D|disturbance was responsible for his arrhythmia.(7)|
05054|068|D|   Agents that are linked to this monograph may have varying degrees of|
05054|069|D|potential to prolong the QTc interval but are generally accepted to have a|
05054|070|D|risk of causing Torsades de Pointes.  Agents linked to this monograph have|
05054|071|D|been shown to prolong the QTc interval either through their mechanism of|
05054|072|D|action, through studies on their effects on the QTc interval, or through|
05054|073|D|reports of QTc prolongation and/or Torsades de Pointes in clinical trials|
05054|074|D|and/or post-marketing reports.(8)|
05054|075|B||
05054|076|R|REFERENCES:|
05054|077|B||
05054|078|R|1.Lamprene (clofazimine) French Summary of Product Features. Novartis Pharma|1
05054|079|R|  S.A.S. July, 2024.|1
05054|080|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05054|081|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05054|082|R|  settings: a scientific statement from the American Heart Association and|6
05054|083|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05054|084|R|  2;55(9):934-47.|6
05054|085|R|3.Zhang R, Tao Y, Bao Z, Zhang J, Zeng L, Fang C, Wu M. Analysis of Adverse|6
05054|086|R|  Drug Reactions of Clofazimine Reported in the FDA Adverse  Event Reporting|6
05054|087|R|  System from 2004 to 2025 Q1. Infect Dis Ther 2025 Nov;14(11):2489-2507.|6
05054|088|R|4.Lin CJ, Chen JH, Chien ST, Huang YW, Lin CB, Lee JJ, Lee CH, Yu MC, Chiang|2
05054|089|R|  CY. Clofazimine and QT prolongation in the treatment of|2
05054|090|R|  rifampicin-resistant  tuberculosis: Findings of aDSM in Taiwan. J|2
05054|091|R|  Microbiol Immunol Infect 2024 Oct;57(5):791-800.|2
05054|092|R|5.Motta I, Cusinato M, Ludman AJ, Lachenal N, Dodd M, Soe M, Abdrasuliev T,|2
05054|093|R|  Usmanova R, Butabekov I, Nikolaevna TZ, Liverko I, Parpieva N, etal. How|2
05054|094|R|  much should we still worry about QTc prolongation in rifampicin-resistant|2
05054|095|R|  tuberculosis? ECG findings from TB-PRACTECAL clinical trial. Antimicrob|2
05054|096|R|  Agents Chemother 2024 Jul 9;68(7):e0053624.|2
05054|097|R|6.Hughes G, Bern H, Chiang CY, Goodall RL, Nunn AJ, Rusen ID, Meredith SK.|2
05054|098|R|  QT prolongation in the STREAM Stage 1 Trial. Int J Tuberc Lung Dis 2022|2
05054|099|R|  Apr 1;26(4):334-340.|2
05054|100|R|7.Choudhri SH, Harris L, Butany JW, Keystone JS. Clofazimine induced|3
05054|101|R|  cardiotoxicity--a case report. Lepr Rev 1995 Mar;66(1):63-8.|3
05054|102|R|8.USDepartment of Health and Human Services Food and Drug Administration.|1
05054|103|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
05054|104|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
05054|105|R|  https://www.fda.gov/media/71372/download October, 2005.|1
05055|001|T|MONOGRAPH TITLE:  Ubrogepant (Greater Than 50 mg)/Weak CYP3A4 Inhibitors|
05055|002|B||
05055|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
05055|004|L|is contraindicated and generally should not be dispensed or administered to|
05055|005|L|the same patient.|
05055|006|B||
05055|007|A|MECHANISM OF ACTION:  Weak inhibitors of CYP3A4 may inhibit the metabolism|
05055|008|A|of ubrogepant.(1)|
05055|009|B||
05055|010|E|CLINICAL EFFECTS:  Concurrent use of ubrogepant with weak CYP3A4 inhibitors|
05055|011|E|may result in an increase in exposure of ubrogepant.(1)|
05055|012|B||
05055|013|P|PREDISPOSING FACTORS:  None determined.|
05055|014|B||
05055|015|M|PATIENT MANAGEMENT:  The manufacturer recommends a dosage adjustment of|
05055|016|M|ubrogepant when used concomitantly with weak CYP3A4 inhibitors.  Initial|
05055|017|M|dose of ubrogepant should not exceed 50 mg when used concomitantly with weak|
05055|018|M|inhibitors of CYP3A4.  A second dose may be given within 24 hours but should|
05055|019|M|not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1)|
05055|020|B||
05055|021|D|DISCUSSION:  Coadministration of ubrogepant with verapamil, a moderate|
05055|022|D|CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in|
05055|023|D|area-under-curve (AUC) and concentration maximum (Cmax), respectively.  No|
05055|024|D|dedicated drug interaction study was conducted to assess concomitant use|
05055|025|D|with weak CYP3A4 inhibitors.  The conservative prediction of the maximal|
05055|026|D|potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not|
05055|027|D|expected to be more than 2-fold.(1)|
05055|028|D|   Weak inhibitors of CYP3A4 include:  alprazolam, amiodarone, amlodipine,|
05055|029|D|anamorelin, asciminib, azithromycin, Baikal skullcap, berberine,|
05055|030|D|bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib,|
05055|031|D|chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole,|
05055|032|D|cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor,|
05055|033|D|dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin,|
05055|034|D|fosaprepitant, fostamatinib, gepotidacin, givinostat,|
05055|035|D|glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid,|
05055|036|D|istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib,|
05055|037|D|leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir,|
05055|038|D|mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil,|
05055|039|D|piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine,|
05055|040|D|remdesivir, resveratrol, roxithromycin, rucaparib, simeprevir, sitaxsentan,|
05055|041|D|skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide,|
05055|042|D|viloxazine, vonoprazan, and ziftomenib.(2,3)|
05055|043|B||
05055|044|R|REFERENCES:|
05055|045|B||
05055|046|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
05055|047|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05055|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05055|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05055|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05055|051|R|  11/14/2017.|1
05055|052|R|3.This information is based on an extract from the Certara Drug Interaction|6
05055|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05056|001|T|MONOGRAPH TITLE:  Ubrogepant (Greater Than 50 mg)/Moderate CYP3A4 Inhibitors|
05056|002|B||
05056|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
05056|004|L|is contraindicated and generally should not be dispensed or administered to|
05056|005|L|the same patient.|
05056|006|B||
05056|007|A|MECHANISM OF ACTION:  Moderate inhibitors of CYP3A4 may inhibit the|
05056|008|A|metabolism of ubrogepant.(1)|
05056|009|B||
05056|010|E|CLINICAL EFFECTS:  Concurrent use of a moderate CYP3A4 inhibitor may result|
05056|011|E|in elevated levels of ubrogepant.(1)|
05056|012|B||
05056|013|P|PREDISPOSING FACTORS:  None determined.|
05056|014|B||
05056|015|M|PATIENT MANAGEMENT:  The manufacturer recommends a dosage adjustment of|
05056|016|M|ubrogepant when used concomitantly with moderate CYP3A4 inhibitors.  Initial|
05056|017|M|dose of ubrogepant should not exceed 50 mg. A second dose should be avoided|
05056|018|M|within 24 hours of the first dose when used concurrently with moderate|
05056|019|M|CYP3A4 inhibitors.(1)|
05056|020|B||
05056|021|D|DISCUSSION:  Co-administration with verapamil, a moderate CYP3A4 inhibitor,|
05056|022|D|resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and|
05056|023|D|concentration maximum (Cmax), respectively.(1)|
05056|024|D|   Moderate inhibitors of CYP3A4 include:  amprenavir, aprepitant,|
05056|025|D|atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib,|
05056|026|D|darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib,|
05056|027|D|fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
05056|028|D|isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib,|
05056|029|D|nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan,|
05056|030|D|and verapamil.(2-4)|
05056|031|B||
05056|032|R|REFERENCES:|
05056|033|B||
05056|034|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
05056|035|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05056|036|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05056|037|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05056|038|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05056|039|R|  11/14/2017.|1
05056|040|R|3.Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.|1
05056|041|R|  Indiana University School of Medicine.  Available at:|1
05056|042|R|  http://medicine.iupui.edu/clinpharm/ddis/table.aspx August 18, 2011.|1
05056|043|R|4.This information is based on an extract from the Certara Drug Interaction|6
05056|044|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05057|001|T|MONOGRAPH TITLE:  Ubrogepant (Greater Than 50 mg)/P-gp or BCRP Inhibitors|
05057|002|B||
05057|003|L|SEVERITY LEVEL:  1-Contraindicated Drug Combination: This drug combination|
05057|004|L|is contraindicated and generally should not be dispensed or administered to|
05057|005|L|the same patient.|
05057|006|B||
05057|007|A|MECHANISM OF ACTION:  Inhibitors of P-glycoprotein (P-gp) or BCRP may|
05057|008|A|increase the absorption of ubrogepant.(1)|
05057|009|B||
05057|010|E|CLINICAL EFFECTS:  The concurrent administration of ubrogepant with an|
05057|011|E|inhibitor of P-glycoprotein or BCRP may result in elevated levels of|
05057|012|E|ubrogepant.(1)|
05057|013|B||
05057|014|P|PREDISPOSING FACTORS:  None determined.|
05057|015|B||
05057|016|M|PATIENT MANAGEMENT:  The manufacturer recommends a dosage adjustment of|
05057|017|M|ubrogepant when coadministered with P-gp or BCRP inhibitors.  The dose of|
05057|018|M|ubrogepant should not exceed 50 mg for initial dose.  If a second dose of|
05057|019|M|ubrogepant is needed, the dose should not exceed 50 mg.(1)|
05057|020|M|   The manufacturer of vimseltinib states concurrent use with P-gp|
05057|021|M|substrates should be avoided.  If concurrent use cannot be avoided, take|
05057|022|M|vimseltinib at least 4 hours prior to ubrogepant.(3)|
05057|023|B||
05057|024|D|DISCUSSION:  Ubrogepant is a substrate of P-gp and BCRP transporters.  Use|
05057|025|D|of P-gp or BCRP inhibitors may increase the exposure of ubrogepant.|
05057|026|D|Clinical drug interaction studies with inhibitors of these transporters were|
05057|027|D|not conducted.  The US manufacturer of ubrogepant recommends dose adjustment|
05057|028|D|if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1)|
05057|029|D|   BCRP inhibitors linked to this monograph include:  belumosudil,|
05057|030|D|clopidogrel, curcumin, eltrombopag, febuxostat, fostemsavir, leniolisib,|
05057|031|D|momelotinib, oteseconazole, pantoprazole, regorafenib, resmetirom,|
05057|032|D|ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric,|
05057|033|D|vadadustat, and zongertinib.(2-5)|
05057|034|D|   P-glycoprotein inhibitors linked to this monograph include:  asunaprevir,|
05057|035|D|belumosudil, capmatinib, carvedilol,  danicopan, daridorexant, imlunestrant,|
05057|036|D|neratinib, osimertinib, propafenone, quinidine, selpercatinib,|
05057|037|D|sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib,|
05057|038|D|and voclosporin.(2-5)|
05057|039|B||
05057|040|R|REFERENCES:|
05057|041|B||
05057|042|R|1.Ubrelvy (ubrogepant) US prescribing information. Allergan February, 2023.|1
05057|043|R|2.Vyndamax (tafamidis) US prescribing information. Pfizer, Inc. June, 2021.|1
05057|044|R|3.Romvimza (vimseltinib) US prescribing information. Deciphera|1
05057|045|R|  Pharmaceuticals, LLC February, 2025.|1
05057|046|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05057|047|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05057|048|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05057|049|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05057|050|R|  11/14/2017.|1
05057|051|R|5.This information is based on an extract from the Certara Drug Interaction|6
05057|052|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05058|001|T|MONOGRAPH TITLE:  Ziftomenib/Proton Pump Inhibitors|
05058|002|B||
05058|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05058|004|L|of severe adverse interaction.|
05058|005|B||
05058|006|A|MECHANISM OF ACTION:  The aqueous solubility of ziftomenib is pH dependent.|
05058|007|A|Higher gastric pH leads to lower solubility which may reduce ziftomenib|
05058|008|A|absorption.(1)|
05058|009|B||
05058|010|E|CLINICAL EFFECTS:  Coadministration of proton pump inhibitors (PPIs) may|
05058|011|E|reduce the bioavailability of ziftomenib, leading to decreased systemic|
05058|012|E|levels and effectiveness.(1)|
05058|013|B||
05058|014|P|PREDISPOSING FACTORS:  None determined.|
05058|015|B||
05058|016|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that concurrent|
05058|017|M|use with proton pump inhibitors should be avoided.(1)|
05058|018|M|   The manufacturer of ziftomenib also states concurrent use with H2|
05058|019|M|receptor antagonists and antacids should be avoided.  If concurrent use|
05058|020|M|cannot be avoided, modify ziftomenib administration time:|
05058|021|M|   - Take ziftomenib 2 hours before or 10 hours after administration of an|
05058|022|M|H2 receptor antagonist.|
05058|023|M|   - Take ziftomenib 2 hours before or 2 hours after administration of an|
05058|024|M|antacid.(1)|
05058|025|B||
05058|026|D|DISCUSSION:  In an interaction study, coadministration of proton pump|
05058|027|D|inhibitors (PPIs) decreased ziftomenib area-under-the-curve (AUC) by 53% and|
05058|028|D|maximum concentration (Cmax) by 70%.(1)|
05058|029|B||
05058|030|R|REFERENCE:|
05058|031|B||
05058|032|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05058|033|R|  November, 2025.|1
05059|001|T|MONOGRAPH TITLE:  Ziftomenib/Strong CYP3A4 Inducers|
05059|002|B||
05059|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05059|004|L|of severe adverse interaction.|
05059|005|B||
05059|006|A|MECHANISM OF ACTION:  Ziftomenib is a CYP3A4 substrate.  Strong CYP3A4|
05059|007|A|inducers may induce the metabolism of ziftomenib.(1)|
05059|008|B||
05059|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
05059|010|E|may decrease the levels and effectiveness of ziftomenib.(1)|
05059|011|B||
05059|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05059|013|P|of the inducer for longer than 1-2 weeks.|
05059|014|B||
05059|015|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that|
05059|016|M|co-administration with strong inducers of CYP3A4 should be avoided.  Monitor|
05059|017|M|patients for loss of efficacy or consider the use of alternative medicinal|
05059|018|M|products.(1)|
05059|019|B||
05059|020|D|DISCUSSION:  Rifampin (strong CYP3A4 inducer) is estimated to decrease|
05059|021|D|ziftomenib area-under-curve (AUC) by up to 80% and maximum concentration|
05059|022|D|(Cmax) by up to 70%.(1)|
05059|023|D|Efavirenz (moderate CYP3A4 inducer) is estimated to decrease ziftomenib AUC|
05059|024|D|and Cmax by up to 70%.|
05059|025|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
05059|026|D|barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor,|
05059|027|D|mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and|
05059|028|D|St. John's Wort.(2,3)|
05059|029|B||
05059|030|R|REFERENCES:|
05059|031|B||
05059|032|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05059|033|R|  November, 2025.|1
05059|034|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05059|035|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05059|036|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05059|037|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05059|038|R|  11/14/2017.|1
05059|039|R|3.This information is based on an extract from the Certara Drug Interaction|6
05059|040|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05060|001|T|MONOGRAPH TITLE:  Ziftomenib/Strong CYP3A4 Inducers that Prolong QT|
05060|002|B||
05060|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05060|004|L|of severe adverse interaction.|
05060|005|B||
05060|006|A|MECHANISM OF ACTION:  Ziftomenib is a CYP3A4 substrate and has been shown to|
05060|007|A|prolong the QTc interval.  Strong CYP3A4 inducers may induce the metabolism|
05060|008|A|of ziftomenib.(1)|
05060|009|A|   Concurrent use of agents that prolong the QTc interval may result in|
05060|010|A|additive effects on the QTc interval.(1-2)|
05060|011|B||
05060|012|E|CLINICAL EFFECTS:  Concurrent or recent use of strong CYP3A4 inducers that|
05060|013|E|prolong QT may result in decreased levels and effectiveness of ziftomenib|
05060|014|E|and increase the risk of potentially life-threatening arrhythmias including|
05060|015|E|torsades de pointes.(1-2)|
05060|016|B||
05060|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05060|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
05060|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05060|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05060|021|P|female gender, or advanced age.(2)|
05060|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05060|023|P|higher systemic concentrations of either QT prolonging drug are additional|
05060|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05060|025|P|drug concentrations include rapid infusion of an intravenous dose or|
05060|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05060|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05060|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05060|029|P|   Induction effects may be more likely with regular use of the inducer for|
05060|030|P|longer than 1-2 weeks.|
05060|031|B||
05060|032|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that|
05060|033|M|co-administration with strong inducers of CYP3A4 should be avoided.  Monitor|
05060|034|M|patients for loss of efficacy or consider the use of alternative medicinal|
05060|035|M|products.(1)|
05060|036|M|   The manufacturer of ziftomenib states that the concurrent use of QT|
05060|037|M|prolonging agents should be avoided.  If concurrent use cannot be avoided,|
05060|038|M|obtain ECGs prior to initiating ziftomenib, during concomitant use, and as|
05060|039|M|clinically indicated.  More frequent ECG monitoring may be necessary.  Do|
05060|040|M|not initiate ziftomenib if baseline QTcF > 480 ms.(1)|
05060|041|M|   Perform ECG at least once weekly for the first 4 weeks on treatment, then|
05060|042|M|at least monthly thereafter.  If the QTc interval is greater than 500 ms or|
05060|043|M|the change from baseline is greater than 60 ms, withhold ziftomenib|
05060|044|M|therapy.(1)|
05060|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05060|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05060|047|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05060|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05060|049|B||
05060|050|D|DISCUSSION:  Rifampin (strong CYP3A4 inducer) is estimated to decrease|
05060|051|D|ziftomenib area-under-curve (AUC) by up to 80% and maximum concentration|
05060|052|D|(Cmax) by up to 70%.(1)|
05060|053|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
05060|054|D|event in 12% of 112 patients treated with the recommended dosage of|
05060|055|D|ziftomenib.  QTc was >500 ms in 9% of patients and the increase from|
05060|056|D|baseline QTcF was >60 ms in 12% of patients.  Ziftomenib increased the QTc|
05060|057|D|interval in a concentration-dependent manner.  At a dose of 600 mg daily,|
05060|058|D|the largest mean increase in QTc was 7.7 ms (upper bound of confidence|
05060|059|D|interval = 12.6 ms).(1)|
05060|060|D|   Strong CYP3A4 inducers that prolong QT linked to this monograph include:|
05060|061|D|encorafenib and ivosidenib.(3,4)|
05060|062|B||
05060|063|R|REFERENCES:|
05060|064|B||
05060|065|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05060|066|R|  November, 2025.|1
05060|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05060|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05060|069|R|  settings: a scientific statement from the American Heart Association and|6
05060|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05060|071|R|  2;55(9):934-47.|6
05060|072|R|3.This information is based on an extract from the Certara Drug Interaction|6
05060|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05060|074|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05060|075|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05060|076|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05060|077|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05060|078|R|  11/14/2017.|1
05061|001|T|MONOGRAPH TITLE:  Ziftomenib/H2 Antagonists|
05061|002|B||
05061|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05061|004|L|of severe adverse interaction.|
05061|005|B||
05061|006|A|MECHANISM OF ACTION:  The aqueous solubility of ziftomenib is pH dependent.|
05061|007|A|Higher gastric pH leads to lower solubility which may reduce ziftomenib|
05061|008|A|absorption.(1)|
05061|009|B||
05061|010|E|CLINICAL EFFECTS:  Coadministration of H2 receptor antagonists may reduce|
05061|011|E|the bioavailability of ziftomenib, leading to decreased systemic levels and|
05061|012|E|effectiveness.(1)|
05061|013|B||
05061|014|P|PREDISPOSING FACTORS:  None determined.|
05061|015|B||
05061|016|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that concurrent|
05061|017|M|use with H2 antagonists should be avoided.(1)|
05061|018|M|   If concurrent use cannot be avoided, administer ziftomenib 2 hours before|
05061|019|M|or 10 hours after the administration of an H2 receptor antagonist.(1)|
05061|020|B||
05061|021|D|DISCUSSION:  The impact of H2 receptor antagonists on the pharmacokinetics|
05061|022|D|of ziftomenib has not been investigated in clinical studies.|
05061|023|D|   In an interaction study, coadministration of proton pump inhibitors|
05061|024|D|(PPIs) decreased ziftomenib area-under-the-curve (AUC) by 53% and maximum|
05061|025|D|concentration (Cmax) by 70%.(1)|
05061|026|B||
05061|027|R|REFERENCE:|
05061|028|B||
05061|029|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05061|030|R|  November, 2025.|1
05062|001|T|MONOGRAPH TITLE:  Ziftomenib/Antacids|
05062|002|B||
05062|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05062|004|L|of severe adverse interaction.|
05062|005|B||
05062|006|A|MECHANISM OF ACTION:  The aqueous solubility of ziftomenib is pH dependent.|
05062|007|A|Higher gastric pH leads to lower solubility which may reduce ziftomenib|
05062|008|A|absorption.(1)|
05062|009|B||
05062|010|E|CLINICAL EFFECTS:  Coadministration with antacids may reduce the|
05062|011|E|bioavailability of ziftomenib, leading to decreased systemic levels and|
05062|012|E|effectiveness.(1)|
05062|013|B||
05062|014|P|PREDISPOSING FACTORS:  None determined.|
05062|015|B||
05062|016|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that concurrent|
05062|017|M|use with antacids should be avoided.(1)|
05062|018|M|   If concurrent use cannot be avoided, administer ziftomenib 2 hours before|
05062|019|M|or 2 hours after the administration of an antacid.(1)|
05062|020|M|   Some vitamin preparations may contain sufficient quantities of calcium|
05062|021|M|and/or magnesium salts with antacid properties to interact as well.|
05062|022|B||
05062|023|D|DISCUSSION:  The impact of antacids on the pharmacokinetics of ziftomenib|
05062|024|D|has not been investigated in clinical studies.|
05062|025|D|   In an interaction study, coadministration of proton pump inhibitors|
05062|026|D|(PPIs) decreased ziftomenib area-under-the-curve (AUC) by 53% and maximum|
05062|027|D|concentration (Cmax) by 70%.(1)|
05062|028|B||
05062|029|R|REFERENCE:|
05062|030|B||
05062|031|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05062|032|R|  November, 2025.|1
05063|001|T|MONOGRAPH TITLE:  Ziftomenib/Moderate CYP3A4 Inducers|
05063|002|B||
05063|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05063|004|L|of severe adverse interaction.|
05063|005|B||
05063|006|A|MECHANISM OF ACTION:  Ziftomenib is a CYP3A4 substrate.  Moderate CYP3A4|
05063|007|A|inducers may induce the metabolism of ziftomenib.(1)|
05063|008|B||
05063|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate inducer of CYP3A4|
05063|010|E|may decrease the levels and effectiveness of ziftomenib.(1)|
05063|011|B||
05063|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05063|013|P|of the inducer for longer than 1-2 weeks.|
05063|014|B||
05063|015|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that|
05063|016|M|co-administration with moderate inducers of CYP3A4 should be avoided.|
05063|017|M|Monitor patients for loss of efficacy or consider the use of alternative|
05063|018|M|medicinal products.(1)|
05063|019|B||
05063|020|D|DISCUSSION:  Efavirenz (moderate CYP3A4 inducer) is estimated to decrease|
05063|021|D|ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by up to|
05063|022|D|70%.(1)|
05063|023|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
05063|024|D|bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad,|
05063|025|D|lorlatinib, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib,|
05063|026|D|rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)|
05063|027|B||
05063|028|R|REFERENCES:|
05063|029|B||
05063|030|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05063|031|R|  November, 2025.|1
05063|032|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05063|033|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05063|034|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05063|035|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05063|036|R|  11/14/2017.|1
05063|037|R|3.This information is based on an extract from the Certara Drug Interaction|6
05063|038|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05064|001|T|MONOGRAPH TITLE:  Ziftomenib/Moderate CYP3A4 Inducers that Prolong QT|
05064|002|B||
05064|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05064|004|L|of severe adverse interaction.|
05064|005|B||
05064|006|A|MECHANISM OF ACTION:  Ziftomenib is a CYP3A4 substrate and has been shown to|
05064|007|A|prolong the QTc interval.  Moderate CYP3A4 inducers may induce the|
05064|008|A|metabolism of ziftomenib.(1)|
05064|009|A|   Concurrent use of agents that prolong the QTc interval may result in|
05064|010|A|additive effects on the QTc interval.(1-2)|
05064|011|B||
05064|012|E|CLINICAL EFFECTS:  Concurrent or recent use of moderate CYP3A4 inducers that|
05064|013|E|prolong QT may result in decreased levels and effectiveness of ziftomenib|
05064|014|E|and increase the risk of potentially life-threatening arrhythmias including|
05064|015|E|torsades de pointes.(1-2)|
05064|016|B||
05064|017|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05064|018|P|may be increased in patients with cardiovascular disease (e.g. heart|
05064|019|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05064|020|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05064|021|P|female gender, or advanced age.(2)|
05064|022|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05064|023|P|higher systemic concentrations of either QT prolonging drug are additional|
05064|024|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05064|025|P|drug concentrations include rapid infusion of an intravenous dose or|
05064|026|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05064|027|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05064|028|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05064|029|P|   Induction effects may be more likely with regular use of the inducer for|
05064|030|P|longer than 1-2 weeks.|
05064|031|B||
05064|032|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that|
05064|033|M|co-administration with moderate inducers of CYP3A4 should be avoided.|
05064|034|M|Monitor patients for loss of efficacy or consider the use of alternative|
05064|035|M|medicinal products.(1)|
05064|036|M|   The manufacturer of ziftomenib states that the concurrent use of QT|
05064|037|M|prolonging agents should be avoided.  If concurrent use cannot be avoided,|
05064|038|M|obtain ECGs prior to initiating ziftomenib, during concomitant use, and as|
05064|039|M|clinically indicated.  More frequent ECG monitoring may be necessary.  Do|
05064|040|M|not initiate ziftomenib if baseline QTcF > 480 ms.(1)|
05064|041|M|   Perform ECG at least once weekly for the first 4 weeks on treatment, then|
05064|042|M|at least monthly thereafter.  If the QTc interval is greater than 500 ms or|
05064|043|M|the change from baseline is greater than 60 ms, withhold ziftomenib|
05064|044|M|therapy.(1)|
05064|045|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05064|046|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05064|047|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05064|048|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05064|049|B||
05064|050|D|DISCUSSION:  Rifampin (strong CYP3A4 inducer) is estimated to decrease|
05064|051|D|ziftomenib area-under-curve (AUC) by up to 80% and maximum concentration|
05064|052|D|(Cmax) by up to 70%.(1)|
05064|053|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
05064|054|D|event in 12% of 112 patients treated with the recommended dosage of|
05064|055|D|ziftomenib.  QTc was >500 ms in 9% of patients and the increase from|
05064|056|D|baseline QTcF was >60 ms in 12% of patients.  Ziftomenib increased the QTc|
05064|057|D|interval in a concentration-dependent manner.  At a dose of 600 mg daily,|
05064|058|D|the largest mean increase in QTc was 7.7 ms (upper bound of confidence|
05064|059|D|interval = 12.6 ms).(1)|
05064|060|D|   Moderate CYP3A4 inducers that prolong QT linked to this monograph|
05064|061|D|include: efavirenz, pacritinib, thioridazine.(3,4)|
05064|062|B||
05064|063|R|REFERENCES:|
05064|064|B||
05064|065|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05064|066|R|  November, 2025.|1
05064|067|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05064|068|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05064|069|R|  settings: a scientific statement from the American Heart Association and|6
05064|070|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05064|071|R|  2;55(9):934-47.|6
05064|072|R|3.This information is based on an extract from the Certara Drug Interaction|6
05064|073|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05064|074|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05064|075|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05064|076|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05064|077|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05064|078|R|  11/14/2017.|1
05065|001|T|MONOGRAPH TITLE:  Ziftomenib/QT Prolonging Agents|
05065|002|B||
05065|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05065|004|L|of severe adverse interaction.|
05065|005|B||
05065|006|A|MECHANISM OF ACTION:  Ziftomenib may prolong the QTc interval.  Concurrent|
05065|007|A|use with other agents that prolong the QTc interval may result in additive|
05065|008|A|effects on the QTc interval.(1)|
05065|009|B||
05065|010|E|CLINICAL EFFECTS:  The concurrent use of ziftomenib with other agents that|
05065|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
05065|012|E|arrhythmias, including torsades de pointes.(1)|
05065|013|B||
05065|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
05065|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
05065|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
05065|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
05065|018|P|gender, or advanced age.(2)|
05065|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05065|020|P|higher systemic concentrations of either QT prolonging drug are additional|
05065|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
05065|022|P|drug concentrations include rapid infusion of an intravenous dose or|
05065|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05065|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05065|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05065|026|B||
05065|027|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that the|
05065|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
05065|029|M|cannot be avoided, obtain ECGs prior to initiating ziftomenib, during|
05065|030|M|concomitant use, and as clinically indicated.  More frequent ECG monitoring|
05065|031|M|may be necessary.  Do not initiate ziftomenib if baseline QTcF > 480 ms.(1)|
05065|032|M|   Perform ECG at least once weekly for the first 4 weeks on treatment, then|
05065|033|M|at least monthly thereafter.  If the QTc interval is greater than 500 ms or|
05065|034|M|the change from baseline is greater than 60 ms, withhold ziftomenib|
05065|035|M|therapy.(1)|
05065|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05065|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05065|038|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
05065|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05065|040|B||
05065|041|D|DISCUSSION:  In clinical trials, QTc interval prolongation was reported as|
05065|042|D|an adverse event in 12% of 112 patients treated with the recommended dosage|
05065|043|D|of ziftomenib.  QTc was >500 ms in 9% of patients and the increase from|
05065|044|D|baseline QTcF was >60 ms in 12% of patients.  Ziftomenib increased the QTc|
05065|045|D|interval in a concentration-dependent manner.  At a dose of 600 mg daily,|
05065|046|D|the largest mean increase in QTc was 7.7 ms (upper bound of confidence|
05065|047|D|interval = 12.6 ms).(1)|
05065|048|D|   Agents that are linked to this monograph may have varying degrees of|
05065|049|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
05065|050|D|been shown to prolong the QTc interval either through their mechanism of|
05065|051|D|action, through studies on their effects on the QTc interval, or through|
05065|052|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
05065|053|D|and/or postmarketing reports.(3)|
05065|054|B||
05065|055|R|REFERENCES:|
05065|056|B||
05065|057|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05065|058|R|  November, 2025.|1
05065|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05065|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05065|061|R|  settings: a scientific statement from the American Heart Association and|6
05065|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05065|063|R|  2;55(9):934-47.|6
05065|064|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
05065|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
05065|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
05065|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
05066|001|T|MONOGRAPH TITLE:  Ziftomenib/Strong CYP3A4 Inhibitors|
05066|002|B||
05066|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05066|004|L|take action as needed.|
05066|005|B||
05066|006|A|MECHANISM OF ACTION:  Strong CYP3A4 inhibitors may inhibit the metabolism of|
05066|007|A|ziftomenib.(1)|
05066|008|B||
05066|009|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
05066|010|E|the levels and effects of ziftomenib, including differentiation syndrome,|
05066|011|E|neutropenia, and QTc prolongation, which may result in potentially|
05066|012|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)|
05066|013|B||
05066|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05066|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
05066|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05066|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05066|018|P|female gender, or advanced age.(2)|
05066|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05066|020|P|higher systemic concentrations of either QT prolonging drug are additional|
05066|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05066|022|P|drug concentrations include rapid infusion of an intravenous dose or|
05066|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05066|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05066|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05066|026|B||
05066|027|M|PATIENT MANAGEMENT:  The US manufacturer of ziftomenib states that|
05066|028|M|concomitant use with strong CYP3A4 inhibitors should be monitored more|
05066|029|M|closely for adverse reactions.(1)|
05066|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05066|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05066|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05066|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05066|034|B||
05066|035|D|DISCUSSION:  Concomitant use of ziftomenib with itraconazole, voriconazole,|
05066|036|D|and posaconazole (strong CYP3A4 inhibitors) is predicted to increase|
05066|037|D|ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold|
05066|038|D|and 2-fold, respectively.(1)|
05066|039|D|   Moderate CYP3A4 inhibitors (fluconazole, erythromycin, and isavuconazole)|
05066|040|D|are predicted to increase ziftomenib AUC and Cmax by 2-fold and 2-fold,|
05066|041|D|respectively.(1)|
05066|042|D|   Weak CYP3A4 inhibitors (cimetidine) are predicted to increase ziftomenib|
05066|043|D|AUC and Cmax by 1.4-fold and 1.4-fold, respectively.(1)|
05066|044|D|   Strong inhibitors of CYP3A4 include:  boceprevir, cobicistat, grapefruit,|
05066|045|D|idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil,|
05066|046|D|mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir,|
05066|047|D|telaprevir, tipranavir, troleandomycin, and tucatinib.(3,4)|
05066|048|B||
05066|049|R|REFERENCES:|
05066|050|B||
05066|051|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05066|052|R|  November, 2025.|1
05066|053|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05066|054|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05066|055|R|  settings: a scientific statement from the American Heart Association and|6
05066|056|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05066|057|R|  2;55(9):934-47.|6
05066|058|R|3.This information is based on an extract from the Certara Drug Interaction|6
05066|059|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05066|060|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05066|061|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05066|062|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05066|063|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05066|064|R|  11/14/2017.|1
05067|001|T|MONOGRAPH TITLE:  Ziftomenib/Mavacamten|
05067|002|B||
05067|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05067|004|L|of severe adverse interaction.|
05067|005|B||
05067|006|A|MECHANISM OF ACTION:  Ziftomenib and mavacamten are both metabolized by|
05067|007|A|CYP3A4.  Mavacamten is a moderate CYP3A4 inducer while ziftomenib is a weak|
05067|008|A|CYP3A4 inhibitor.(1-2)|
05067|009|B||
05067|010|E|CLINICAL EFFECTS:  The net effect of coadministration of ziftomenib and|
05067|011|E|mavacamten on CYP3A4 enzyme activity is unknown.  Concurrent use may either|
05067|012|E|decrease the clinical effectiveness of ziftomenib(1) or increase the levels|
05067|013|E|and toxicities of mavacamten.(2)|
05067|014|B||
05067|015|P|PREDISPOSING FACTORS:  None determined.|
05067|016|B||
05067|017|M|PATIENT MANAGEMENT:  There are no recommendations for concurrent use of|
05067|018|M|ziftomenib with mavacamten.  Concurrent therapy should be avoided.  If use|
05067|019|M|of this combination is necessary, the patient should be closely monitored|
05067|020|M|for ziftomenib efficacy and mavacamten toxicity.|
05067|021|M|   The manufacturer of ziftomenib states that concomitant use of moderate|
05067|022|M|CYP3A4 inducers should be avoided.(1)|
05067|023|M|   The UK manufacturer of mavacamten states no dose adjustment is necessary|
05067|024|M|when starting mavacamten in patients on weak CYP3A4 inhibitors or in|
05067|025|M|intermediate, normal, rapid, or ultra-rapid CYP2C19 metabolizers already on|
05067|026|M|mavacamten and starting a weak CYP3A4 inhibitor.  In poor CYP2C19|
05067|027|M|metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor,|
05067|028|M|reduce mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment for 4|
05067|029|M|weeks.  If CYP2C19 phenotype is unknown, consider a mavacamten starting dose|
05067|030|M|of 2.5 mg daily.(1)|
05067|031|B||
05067|032|D|DISCUSSION:  Efavirenz (moderate CYP3A4 inducer) is estimated to decrease|
05067|033|D|ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by up to|
05067|034|D|70%.(1)|
05067|035|D|   In a PBPK model, concomitant use of mavacamten (15 mg daily) with|
05067|036|D|cimetidine 400 mg twice daily, a weak CYP3A4 inhibitor, was predicted to|
05067|037|D|increase mavacamten area-under-curve (AUC) by 6% and maximum concentration|
05067|038|D|(Cmax) by 4% in poor CYP2C19 metabolizers and by 3% and 2%, respectively, in|
05067|039|D|both intermediate and normal CYP2C19 metabolizers.(2)|
05067|040|B||
05067|041|R|REFERENCES:|
05067|042|B||
05067|043|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05067|044|R|  November, 2025.|1
05067|045|R|2.Camzyos (mavacamten) UK Summary of Product Characteristics. Bristol-Myers|1
05067|046|R|  Squibb July, 2023.|1
05067|047|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05067|048|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05067|049|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05067|050|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05067|051|R|  11/14/2017.|1
05067|052|R|4.This information is based on an extract from the Certara Drug Interaction|6
05067|053|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05068|001|T|MONOGRAPH TITLE:  Ziftomenib/Strong CYP3A4 Inhibitors that Prolong QT|
05068|002|B||
05068|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05068|004|L|take action as needed.|
05068|005|B||
05068|006|A|MECHANISM OF ACTION:  Ziftomenib is a CYP3A4 substrate and has been shown to|
05068|007|A|prolong the QTc interval.  Strong CYP3A4 inhibitors that prolong the QTc|
05068|008|A|interval may inhibit the metabolism of ziftomenib and result in additive|
05068|009|A|risk of QT prolongation.(1)|
05068|010|B||
05068|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
05068|012|E|the levels and effects of ziftomenib, including differentiation syndrome,|
05068|013|E|neutropenia, and additive QTc prolongation, which may result in potentially|
05068|014|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)|
05068|015|B||
05068|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05068|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
05068|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05068|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05068|020|P|female gender, or advanced age.(2)|
05068|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05068|022|P|higher systemic concentrations of either QT prolonging drug are additional|
05068|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05068|024|P|drug concentrations include rapid infusion of an intravenous dose or|
05068|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05068|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05068|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05068|028|B||
05068|029|M|PATIENT MANAGEMENT:  The US manufacturer of ziftomenib states that|
05068|030|M|concomitant use with strong CYP3A4 inhibitors should be monitored more|
05068|031|M|closely for adverse reactions.(1)|
05068|032|M|   The manufacturer of ziftomenib states that the concurrent use of QT|
05068|033|M|prolonging agents should be avoided.  If concurrent use cannot be avoided,|
05068|034|M|obtain ECGs prior to initiating ziftomenib, during concomitant use, and as|
05068|035|M|clinically indicated.  More frequent ECG monitoring may be necessary.  Do|
05068|036|M|not initiate ziftomenib if baseline QTcF > 480 ms.(1)|
05068|037|M|   Perform ECG at least once weekly for the first 4 weeks on treatment, then|
05068|038|M|at least monthly thereafter.  If the QTc interval is greater than 500 ms or|
05068|039|M|the change from baseline is greater than 60 ms, withhold ziftomenib|
05068|040|M|therapy.(1)|
05068|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05068|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05068|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05068|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05068|045|B||
05068|046|D|DISCUSSION:  Concomitant use of ziftomenib with itraconazole, voriconazole,|
05068|047|D|and posaconazole (strong CYP3A4 inhibitors) is predicted to increase|
05068|048|D|ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold|
05068|049|D|and 2-fold, respectively.(1)|
05068|050|D|   Moderate CYP3A4 inhibitors (fluconazole, erythromycin, and isavuconazole)|
05068|051|D|are predicted to increase ziftomenib AUC and Cmax by 2-fold and 2-fold,|
05068|052|D|respectively.(1)|
05068|053|D|   Weak CYP3A4 inhibitors (cimetidine) are predicted to increase ziftomenib|
05068|054|D|AUC and Cmax by 1.4-fold and 1.4-fold, respectively.(1)|
05068|055|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
05068|056|D|event in 12% of 112 patients treated with the recommended dosage of|
05068|057|D|ziftomenib.  QTc was >500 ms in 9% of patients and the increase from|
05068|058|D|baseline QTcF was >60 ms in 12% of patients.  Ziftomenib increased the QTc|
05068|059|D|interval in a concentration-dependent manner.  At a dose of 600 mg daily,|
05068|060|D|the largest mean increase in QTc was 7.7 ms (upper bound of confidence|
05068|061|D|interval = 12.6 ms).(1)|
05068|062|D|   Strong inhibitors of CYP3A4 include:  ceritinib, lopinavir/ritonavir,|
05068|063|D|posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)|
05068|064|B||
05068|065|R|REFERENCES:|
05068|066|B||
05068|067|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05068|068|R|  November, 2025.|1
05068|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05068|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05068|071|R|  settings: a scientific statement from the American Heart Association and|6
05068|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05068|073|R|  2;55(9):934-47.|6
05068|074|R|3.This information is based on an extract from the Certara Drug Interaction|6
05068|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05068|076|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05068|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05068|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05068|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05068|080|R|  11/14/2017.|1
05069|001|T|MONOGRAPH TITLE:  Ziftomenib/Strong CYP3A4 Inhibitors that Prolong QT|
05069|002|B||
05069|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05069|004|L|of severe adverse interaction.|
05069|005|B||
05069|006|A|MECHANISM OF ACTION:  Ziftomenib is a CYP3A4 substrate and has been shown to|
05069|007|A|prolong the QTc interval.  Strong CYP3A4 inhibitors that prolong the QTc|
05069|008|A|interval may inhibit the metabolism of ziftomenib and result in additive|
05069|009|A|risk of QT prolongation.(1)|
05069|010|B||
05069|011|E|CLINICAL EFFECTS:  Concurrent use of strong CYP3A4 inhibitors may increase|
05069|012|E|the levels and effects of ziftomenib, including differentiation syndrome,|
05069|013|E|neutropenia, and additive QTc prolongation, which may result in potentially|
05069|014|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)|
05069|015|B||
05069|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05069|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
05069|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05069|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05069|020|P|female gender, or advanced age.(2)|
05069|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05069|022|P|higher systemic concentrations of either QT prolonging drug are additional|
05069|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05069|024|P|drug concentrations include rapid infusion of an intravenous dose or|
05069|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05069|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05069|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05069|028|B||
05069|029|M|PATIENT MANAGEMENT:  The US manufacturer of ziftomenib states that|
05069|030|M|concomitant use with strong CYP3A4 inhibitors should be monitored more|
05069|031|M|closely for adverse reactions.(1)|
05069|032|M|   The manufacturer of ziftomenib states that the concurrent use of QT|
05069|033|M|prolonging agents should be avoided.  If concurrent use cannot be avoided,|
05069|034|M|obtain ECGs prior to initiating ziftomenib, during concomitant use, and as|
05069|035|M|clinically indicated.  More frequent ECG monitoring may be necessary.  Do|
05069|036|M|not initiate ziftomenib if baseline QTcF > 480 ms.(1)|
05069|037|M|   Perform ECG at least once weekly for the first 4 weeks on treatment, then|
05069|038|M|at least monthly thereafter.  If the QTc interval is greater than 500 ms or|
05069|039|M|the change from baseline is greater than 60 ms, withhold ziftomenib|
05069|040|M|therapy.(1)|
05069|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05069|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05069|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05069|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05069|045|B||
05069|046|D|DISCUSSION:  Concomitant use of ziftomenib with itraconazole, voriconazole,|
05069|047|D|and posaconazole (strong CYP3A4 inhibitors) is predicted to increase|
05069|048|D|ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold|
05069|049|D|and 2-fold, respectively.(1)|
05069|050|D|   Moderate CYP3A4 inhibitors (fluconazole, erythromycin, and isavuconazole)|
05069|051|D|are predicted to increase ziftomenib AUC and Cmax by 2-fold and 2-fold,|
05069|052|D|respectively.(1)|
05069|053|D|   Weak CYP3A4 inhibitors (cimetidine) are predicted to increase ziftomenib|
05069|054|D|AUC and Cmax by 1.4-fold and 1.4-fold, respectively.(1)|
05069|055|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
05069|056|D|event in 12% of 112 patients treated with the recommended dosage of|
05069|057|D|ziftomenib.  QTc was >500 ms in 9% of patients and the increase from|
05069|058|D|baseline QTcF was >60 ms in 12% of patients.  Ziftomenib increased the QTc|
05069|059|D|interval in a concentration-dependent manner.  At a dose of 600 mg daily,|
05069|060|D|the largest mean increase in QTc was 7.7 ms (upper bound of confidence|
05069|061|D|interval = 12.6 ms).(1)|
05069|062|D|   Strong inhibitors of CYP3A4 include: adagrasib, clarithromycin,|
05069|063|D|levoketoconazole, and lonafarnib.(3,4)|
05069|064|B||
05069|065|R|REFERENCES:|
05069|066|B||
05069|067|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05069|068|R|  November, 2025.|1
05069|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05069|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05069|071|R|  settings: a scientific statement from the American Heart Association and|6
05069|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05069|073|R|  2;55(9):934-47.|6
05069|074|R|3.This information is based on an extract from the Certara Drug Interaction|6
05069|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05069|076|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05069|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05069|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05069|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05069|080|R|  11/14/2017.|1
05070|001|T|MONOGRAPH TITLE:  Ziftomenib/Moderate CYP3A4 Inhibitors|
05070|002|B||
05070|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05070|004|L|take action as needed.|
05070|005|B||
05070|006|A|MECHANISM OF ACTION:  Moderate CYP3A4 inhibitors may inhibit the metabolism|
05070|007|A|of ziftomenib.(1)|
05070|008|B||
05070|009|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
05070|010|E|the levels and effects of ziftomenib, including differentiation syndrome,|
05070|011|E|neutropenia, and QTc prolongation, which may result in potentially|
05070|012|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)|
05070|013|B||
05070|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05070|015|P|may be increased in patients with cardiovascular disease (e.g. heart|
05070|016|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05070|017|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05070|018|P|female gender, or advanced age.(2)|
05070|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05070|020|P|higher systemic concentrations of either QT prolonging drug are additional|
05070|021|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05070|022|P|drug concentrations include rapid infusion of an intravenous dose or|
05070|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05070|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05070|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05070|026|B||
05070|027|M|PATIENT MANAGEMENT:  The US manufacturer of ziftomenib states that|
05070|028|M|concomitant use with moderate CYP3A4 inhibitors should be monitored more|
05070|029|M|closely for adverse reactions.(1)|
05070|030|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05070|031|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05070|032|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05070|033|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05070|034|B||
05070|035|D|DISCUSSION:  Concomitant use of ziftomenib with itraconazole, voriconazole,|
05070|036|D|and posaconazole (strong CYP3A4 inhibitors) is predicted to increase|
05070|037|D|ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold|
05070|038|D|and 2-fold, respectively.(1)|
05070|039|D|   Moderate CYP3A4 inhibitors (fluconazole, erythromycin, and isavuconazole)|
05070|040|D|are predicted to increase ziftomenib AUC and Cmax by 2-fold and 2-fold,|
05070|041|D|respectively.(1)|
05070|042|D|   Weak CYP3A4 inhibitors (cimetidine) are predicted to increase ziftomenib|
05070|043|D|AUC and Cmax by 1.4-fold and 1.4-fold, respectively.(1)|
05070|044|D|   Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant,|
05070|045|D|atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem,|
05070|046|D|duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib,|
05070|047|D|isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat,|
05070|048|D|rilzabrutinib, Schisandra, stiripentol, tofisopam, treosulfan, verapamil,|
05070|049|D|and voxelotor.(3,4)|
05070|050|B||
05070|051|R|REFERENCES:|
05070|052|B||
05070|053|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05070|054|R|  November, 2025.|1
05070|055|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05070|056|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05070|057|R|  settings: a scientific statement from the American Heart Association and|6
05070|058|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05070|059|R|  2;55(9):934-47.|6
05070|060|R|3.This information is based on an extract from the Certara Drug Interaction|6
05070|061|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05070|062|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05070|063|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05070|064|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05070|065|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05070|066|R|  11/14/2017.|1
05071|001|T|MONOGRAPH TITLE:  Ziftomenib/Moderate CYP3A4 Inhibitors that Prolong QT|
05071|002|B||
05071|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05071|004|L|of severe adverse interaction.|
05071|005|B||
05071|006|A|MECHANISM OF ACTION:  Ziftomenib is a CYP3A4 substrate and has been shown to|
05071|007|A|prolong the QTc interval.  Moderate CYP3A4 inhibitors that prolong the QTc|
05071|008|A|interval may inhibit the metabolism of ziftomenib and result in additive|
05071|009|A|risk of QT prolongation.(1)|
05071|010|B||
05071|011|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
05071|012|E|the levels and effects of ziftomenib, including differentiation syndrome,|
05071|013|E|neutropenia, and additive QTc prolongation, which may result in potentially|
05071|014|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)|
05071|015|B||
05071|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05071|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
05071|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05071|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05071|020|P|female gender, or advanced age.(2)|
05071|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05071|022|P|higher systemic concentrations of either QT prolonging drug are additional|
05071|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05071|024|P|drug concentrations include rapid infusion of an intravenous dose or|
05071|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05071|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05071|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05071|028|B||
05071|029|M|PATIENT MANAGEMENT:  The US manufacturer of ziftomenib states that|
05071|030|M|concomitant use with moderate CYP3A4 inhibitors should be monitored more|
05071|031|M|closely for adverse reactions.(1)|
05071|032|M|   The manufacturer of ziftomenib states that the concurrent use of QT|
05071|033|M|prolonging agents should be avoided.  If concurrent use cannot be avoided,|
05071|034|M|obtain ECGs prior to initiating ziftomenib, during concomitant use, and as|
05071|035|M|clinically indicated.  More frequent ECG monitoring may be necessary.  Do|
05071|036|M|not initiate ziftomenib if baseline QTcF > 480 ms.(1)|
05071|037|M|   Perform ECG at least once weekly for the first 4 weeks on treatment, then|
05071|038|M|at least monthly thereafter.  If the QTc interval is greater than 500 ms or|
05071|039|M|the change from baseline is greater than 60 ms, withhold ziftomenib|
05071|040|M|therapy.(1)|
05071|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05071|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05071|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05071|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05071|045|B||
05071|046|D|DISCUSSION:  Concomitant use of ziftomenib with itraconazole, voriconazole,|
05071|047|D|and posaconazole (strong CYP3A4 inhibitors) is predicted to increase|
05071|048|D|ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold|
05071|049|D|and 2-fold, respectively.(1)|
05071|050|D|   Moderate CYP3A4 inhibitors (fluconazole, erythromycin, and isavuconazole)|
05071|051|D|are predicted to increase ziftomenib AUC and Cmax by 2-fold and 2-fold,|
05071|052|D|respectively.(1)|
05071|053|D|   Weak CYP3A4 inhibitors (cimetidine) are predicted to increase ziftomenib|
05071|054|D|AUC and Cmax by 1.4-fold and 1.4-fold, respectively.(1)|
05071|055|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
05071|056|D|event in 12% of 112 patients treated with the recommended dosage of|
05071|057|D|ziftomenib.  QTc was >500 ms in 9% of patients and the increase from|
05071|058|D|baseline QTcF was >60 ms in 12% of patients.  Ziftomenib increased the QTc|
05071|059|D|interval in a concentration-dependent manner.  At a dose of 600 mg daily,|
05071|060|D|the largest mean increase in QTc was 7.7 ms (upper bound of confidence|
05071|061|D|interval = 12.6 ms).(1)|
05071|062|D|   Moderate inhibitors of CYP3A4 that prolong the QTc interval include:|
05071|063|D|clofazimine, dronedarone, erythromycin, and fluconazole.(3,4)|
05071|064|B||
05071|065|R|REFERENCES:|
05071|066|B||
05071|067|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05071|068|R|  November, 2025.|1
05071|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05071|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05071|071|R|  settings: a scientific statement from the American Heart Association and|6
05071|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05071|073|R|  2;55(9):934-47.|6
05071|074|R|3.This information is based on an extract from the Certara Drug Interaction|6
05071|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05071|076|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05071|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05071|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05071|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05071|080|R|  11/14/2017.|1
05072|001|T|MONOGRAPH TITLE:  Ziftomenib/Moderate CYP3A4 Inhibitors that Prolong QT|
05072|002|B||
05072|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05072|004|L|take action as needed.|
05072|005|B||
05072|006|A|MECHANISM OF ACTION:  Ziftomenib is a CYP3A4 substrate and has been shown to|
05072|007|A|prolong the QTc interval.  Moderate CYP3A4 inhibitors that prolong the QTc|
05072|008|A|interval may inhibit the metabolism of ziftomenib and result in additive|
05072|009|A|risk of QT prolongation.(1)|
05072|010|B||
05072|011|E|CLINICAL EFFECTS:  Concurrent use of moderate CYP3A4 inhibitors may increase|
05072|012|E|the levels and effects of ziftomenib, including differentiation syndrome,|
05072|013|E|neutropenia, and additive QTc prolongation, which may result in potentially|
05072|014|E|life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)|
05072|015|B||
05072|016|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsades de pointes|
05072|017|P|may be increased in patients with cardiovascular disease (e.g. heart|
05072|018|P|failure, myocardial infarction, history of torsades de pointes, congenital|
05072|019|P|long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia,|
05072|020|P|female gender, or advanced age.(2)|
05072|021|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05072|022|P|higher systemic concentrations of either QT prolonging drug are additional|
05072|023|P|risk factors for torsades de pointes.  Factors which may increase systemic|
05072|024|P|drug concentrations include rapid infusion of an intravenous dose or|
05072|025|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05072|026|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05072|027|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05072|028|B||
05072|029|M|PATIENT MANAGEMENT:  The US manufacturer of ziftomenib states that|
05072|030|M|concomitant use with moderate CYP3A4 inhibitors should be monitored more|
05072|031|M|closely for adverse reactions.(1)|
05072|032|M|   The manufacturer of ziftomenib states that the concurrent use of QT|
05072|033|M|prolonging agents should be avoided.  If concurrent use cannot be avoided,|
05072|034|M|obtain ECGs prior to initiating ziftomenib, during concomitant use, and as|
05072|035|M|clinically indicated.  More frequent ECG monitoring may be necessary.  Do|
05072|036|M|not initiate ziftomenib if baseline QTcF > 480 ms.(1)|
05072|037|M|   Perform ECG at least once weekly for the first 4 weeks on treatment, then|
05072|038|M|at least monthly thereafter.  If the QTc interval is greater than 500 ms or|
05072|039|M|the change from baseline is greater than 60 ms, withhold ziftomenib|
05072|040|M|therapy.(1)|
05072|041|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05072|042|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05072|043|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05072|044|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05072|045|B||
05072|046|D|DISCUSSION:  Concomitant use of ziftomenib with itraconazole, voriconazole,|
05072|047|D|and posaconazole (strong CYP3A4 inhibitors) is predicted to increase|
05072|048|D|ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold|
05072|049|D|and 2-fold, respectively.(1)|
05072|050|D|   Moderate CYP3A4 inhibitors (fluconazole, erythromycin, and isavuconazole)|
05072|051|D|are predicted to increase ziftomenib AUC and Cmax by 2-fold and 2-fold,|
05072|052|D|respectively.(1)|
05072|053|D|   Weak CYP3A4 inhibitors (cimetidine) are predicted to increase ziftomenib|
05072|054|D|AUC and Cmax by 1.4-fold and 1.4-fold, respectively.(1)|
05072|055|D|   In clinical trials, QTc interval prolongation was reported as an adverse|
05072|056|D|event in 12% of 112 patients treated with the recommended dosage of|
05072|057|D|ziftomenib.  QTc was >500 ms in 9% of patients and the increase from|
05072|058|D|baseline QTcF was >60 ms in 12% of patients.  Ziftomenib increased the QTc|
05072|059|D|interval in a concentration-dependent manner.  At a dose of 600 mg daily,|
05072|060|D|the largest mean increase in QTc was 7.7 ms (upper bound of confidence|
05072|061|D|interval = 12.6 ms).(1)|
05072|062|D|   Moderate inhibitors of CYP3A4 that prolong the QTc interval include:|
05072|063|D|crizotinib, lefamulin, and nilotinib.(3,4)|
05072|064|B||
05072|065|R|REFERENCES:|
05072|066|B||
05072|067|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05072|068|R|  November, 2025.|1
05072|069|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05072|070|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05072|071|R|  settings: a scientific statement from the American Heart Association and|6
05072|072|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05072|073|R|  2;55(9):934-47.|6
05072|074|R|3.This information is based on an extract from the Certara Drug Interaction|6
05072|075|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05072|076|R|4.US Food and Drug Administration (FDA). Drug Development and Drug|1
05072|077|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05072|078|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05072|079|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05072|080|R|  11/14/2017.|1
05073|001|T|MONOGRAPH TITLE:  Ziftomenib/Possible QT Prolonging Agents|
05073|002|B||
05073|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05073|004|L|take action as needed.|
05073|005|B||
05073|006|A|MECHANISM OF ACTION:  Ziftomenib may prolong the QTc interval.  Concurrent|
05073|007|A|use with other agents that prolong the QTc interval may result in additive|
05073|008|A|effects on the QTc interval.(1)|
05073|009|B||
05073|010|E|CLINICAL EFFECTS:  The concurrent use of ziftomenib with other agents that|
05073|011|E|prolong the QTc interval may result in potentially life-threatening cardiac|
05073|012|E|arrhythmias, including torsades de pointes.(1)|
05073|013|B||
05073|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
05073|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
05073|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
05073|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
05073|018|P|gender, or advanced age.(2)|
05073|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05073|020|P|higher systemic concentrations of either QT prolonging drug are additional|
05073|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
05073|022|P|drug concentrations include rapid infusion of an intravenous dose or|
05073|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05073|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05073|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)|
05073|026|B||
05073|027|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that the|
05073|028|M|concurrent use of QT prolonging agents should be avoided.  If concurrent use|
05073|029|M|cannot be avoided, obtain ECGs prior to initiating ziftomenib, during|
05073|030|M|concomitant use, and as clinically indicated.  More frequent ECG monitoring|
05073|031|M|may be necessary.  Do not initiate ziftomenib if baseline QTcF > 480 ms.(1)|
05073|032|M|   Perform ECG at least once weekly for the first 4 weeks on treatment, then|
05073|033|M|at least monthly thereafter.  If the QTc interval is greater than 500 ms or|
05073|034|M|the change from baseline is greater than 60 ms, withhold ziftomenib|
05073|035|M|therapy.(1)|
05073|036|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05073|037|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05073|038|M|regular intervals.  Correct any electrolyte abnormalities.(1)  Instruct|
05073|039|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05073|040|B||
05073|041|D|DISCUSSION:  In clinical trials, QTc interval prolongation was reported as|
05073|042|D|an adverse event in 12% of 112 patients treated with the recommended dosage|
05073|043|D|of ziftomenib.  QTc was >500 ms in 9% of patients and the increase from|
05073|044|D|baseline QTcF was >60 ms in 12% of patients.  Ziftomenib increased the QTc|
05073|045|D|interval in a concentration-dependent manner.  At a dose of 600 mg daily,|
05073|046|D|the largest mean increase in QTc was 7.7 ms (upper bound of confidence|
05073|047|D|interval = 12.6 ms).(1)|
05073|048|D|   Agents that are linked to this monograph may have varying degrees of|
05073|049|D|potential to prolong the QTc interval.  Agents linked to this monograph have|
05073|050|D|been shown to prolong the QTc interval either through their mechanism of|
05073|051|D|action, through studies on their effects on the QTc interval, or through|
05073|052|D|reports of QTc prolongation and/or torsades de pointes in clinical trials|
05073|053|D|and/or postmarketing reports.(3)|
05073|054|B||
05073|055|R|REFERENCES:|
05073|056|B||
05073|057|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05073|058|R|  November, 2025.|1
05073|059|R|2.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05073|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05073|061|R|  settings: a scientific statement from the American Heart Association and|6
05073|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05073|063|R|  2;55(9):934-47.|6
05073|064|R|3.USDepartment of Health and Human Services Food and Drug Administration.|1
05073|065|R|  ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and|1
05073|066|R|  Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available at:|1
05073|067|R|  https://www.fda.gov/media/71372/download October, 2005.|1
05074|001|T|MONOGRAPH TITLE:  Ziftomenib/Dipyrone|
05074|002|B||
05074|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05074|004|L|of severe adverse interaction.|
05074|005|B||
05074|006|A|MECHANISM OF ACTION:  Dipyrone, a moderate CYP3A4 inducer, may induce the|
05074|007|A|metabolism of ziftomenib.(1)|
05074|008|A|   Concurrent use of dipyrone with other drugs known to be associated with|
05074|009|A|neutropenia or agranulocytosis such as ziftomenib may increase the frequency|
05074|010|A|or risk for severe toxicity.(2)|
05074|011|B||
05074|012|E|CLINICAL EFFECTS:  Concurrent or recent use of dipyrone, a moderate CYP3A4|
05074|013|E|inducer, may result in decreased levels and effectiveness of ziftomenib.(1)|
05074|014|E|   Concurrent use of dipyrone with agents such as ziftomenib that cause bone|
05074|015|E|marrow depression, including myelosuppressives, may result in an enhanced|
05074|016|E|risk of hematologic disorders, including anemia, blood dyscrasias, bone|
05074|017|E|marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression|
05074|018|E|may increase the risk of serious infections and bleeding. Undetected severe|
05074|019|E|neutropenia or agranulocytosis may be fatal.(2)|
05074|020|B||
05074|021|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05074|022|P|of the inducer for longer than 1-2 weeks.|
05074|023|B||
05074|024|M|PATIENT MANAGEMENT:  The manufacturer of ziftomenib states that concomitant|
05074|025|M|use of moderate CYP3A4 inducers should be avoided.(1)|
05074|026|M|   Concurrent use of dipyrone and myelosuppressive agents should be|
05074|027|M|avoided.(2)|
05074|028|M|   The European Medicines Agency states dipyrone is contraindicated in|
05074|029|M|patients with a prior medical history of dipyrone-induced agranulocytosis|
05074|030|M|(or from other pyrazolones/pyrazolidines), impaired bone marrow function or|
05074|031|M|diseases of the hematopoietic system.(4)|
05074|032|M|   The European Medicines Agency advises if agranulocytosis is suspected|
05074|033|M|with dipyrone, a complete blood count (including differential blood count)|
05074|034|M|should be performed immediately, and treatment must be stopped while waiting|
05074|035|M|for the results. If confirmed, treatment must not be reintroduced.(2,4)|
05074|036|B||
05074|037|D|DISCUSSION:  Efavirenz (moderate CYP3A4 inducer) is estimated to decrease|
05074|038|D|ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by up to|
05074|039|D|70%.(1)|
05074|040|D|   In the KO-MEN-001 study, leukocytosis occurred in 16% of ziftomenib|
05074|041|D|treated patients, and febrile neutropenia occurred in 22% of ziftomenib|
05074|042|D|treated patients.(1)|
05074|043|D|   A retrospective cohort study analyzed new users of dipyrone (n=444,972),|
05074|044|D|non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a|
05074|045|D|reference cohort, and opioids-paracetamol (n=3,129,221) which was the|
05074|046|D|negative control.  During continuous treatment over a median of 37-40 days,|
05074|047|D|26 cases of hospitalized agranulocytosis occurred.  With the assumption that|
05074|048|D|agranulocytosis onset was 7 days prior to admission, the hazard ratio of|
05074|049|D|agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to|
05074|050|D|NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol.  HR of|
05074|051|D|neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not|
05074|052|D|statistically significant compared to opioids-paracetamol.  In a sensitivity|
05074|053|D|analysis assuming that the onset of agranulocytosis was the date of|
05074|054|D|hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95%|
05074|055|D|confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34]|
05074|056|D|compared to opioids-paracetamol.  Agranulocytosis was very rare but more|
05074|057|D|than 4 times more common with dipyrone than other analgesics.(5)|
05074|058|B||
05074|059|R|REFERENCES:|
05074|060|B||
05074|061|R|1.Komzifti (ziftomenib) US prescribing information. Kura Oncology, Inc.|1
05074|062|R|  November, 2025.|1
05074|063|R|2.Optalgin (Dipyrone (Metamizole sodium)) Prescribing Information. Teva|1
05074|064|R|  Israel Ltd June 2022.|1
05074|065|R|3.This information is based on an extract from the Certara Drug Interaction|6
05074|066|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05074|067|R|4.EMA. EMA recommends measures to minimise serious outcomes of known side|6
05074|068|R|  effect with painkiller metamizole. 6 September 2024.|6
05074|069|R|5.Macia-Martinez MA, Castillo-Cano B, Garcia-Poza P, Martin-Merino E. Risk|3
05074|070|R|  of agranulocytosis with metamizole in comparison with alternative|3
05074|071|R|  medications based on health records in Spain. European Journal of Clinical|3
05074|072|R|  Pharmacology 22 June 2024;80(10):1503-1514.|3
05074|073|R|6.Hoffman F, Bantel C, Jobski K. Aganulocytosis attributed to metamizole: An|3
05074|074|R|  analysis of spontaneous reports in EudraVigilance 1985-2017. Basic &|3
05074|075|R|  Clinical Pharmacology & Toxicology 26 August 2019;126(2):116-125.|3
05075|001|T|MONOGRAPH TITLE:  Sevabertinib/Strong CYP3A4 Inducers|
05075|002|B||
05075|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05075|004|L|of severe adverse interaction.|
05075|005|B||
05075|006|A|MECHANISM OF ACTION:  Sevabertinib is a CYP3A4 substrate.  Strong CYP3A4|
05075|007|A|inducers may induce the metabolism of sevabertinib.(1)|
05075|008|B||
05075|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a strong inducer of CYP3A4|
05075|010|E|may decrease the levels and effectiveness of sevabertinib.(1)|
05075|011|B||
05075|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05075|013|P|of the inducer for longer than 1-2 weeks.|
05075|014|B||
05075|015|M|PATIENT MANAGEMENT:  The manufacturer of sevabertinib states that|
05075|016|M|co-administration with strong inducers of CYP3A4 should be avoided.  Monitor|
05075|017|M|patients for loss of efficacy or consider the use of alternative medicinal|
05075|018|M|products.(1)|
05075|019|B||
05075|020|D|DISCUSSION:  In a study, carbamazepine (strong CYP3A4 inducer) decreased|
05075|021|D|sevabertinib's area-under-curve (AUC) 79% and maximum concentration (Cmax)|
05075|022|D|57%.(1)|
05075|023|D|   Strong CYP3A4 inducers linked to this monograph include: apalutamide,|
05075|024|D|barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib,|
05075|025|D|lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin,|
05075|026|D|rifapentine, and St. John's Wort.(2,3)|
05075|027|B||
05075|028|R|REFERENCES:|
05075|029|B||
05075|030|R|1.US Food and Drug Administration (FDA). Drug Development and Drug|1
05075|031|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05075|032|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05075|033|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05075|034|R|  11/14/2017.|1
05075|035|R|2.This information is based on an extract from the Certara Drug Interaction|6
05075|036|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05075|037|R|3.Hyrnuo (sevabertinib) US prescribing information. Bayer HealthCare|1
05075|038|R|  Pharmaceuticals Inc. November 2025.|1
05076|001|T|MONOGRAPH TITLE:  Sevabertinib/Strong CYP3A4 Inhibitors|
05076|002|B||
05076|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05076|004|L|of severe adverse interaction.|
05076|005|B||
05076|006|A|MECHANISM OF ACTION:  Sevabertinib is metabolized via CYP3A4.  Strong|
05076|007|A|inhibitors of CYP3A4 may inhibit the metabolism of sevabertinib.(1)|
05076|008|B||
05076|009|E|CLINICAL EFFECTS:  Concurrent use of sevabertinib with strong CYP3A4|
05076|010|E|inhibitors may result in a significant increase in exposure of|
05076|011|E|sevabertinib.(1)|
05076|012|B||
05076|013|P|PREDISPOSING FACTORS:  None determined.|
05076|014|B||
05076|015|M|PATIENT MANAGEMENT:  The US manufacturer of sevabertinib states|
05076|016|M|coadministration with strong CYP3A4 inhibitors should be avoided.(1)  If|
05076|017|M|coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce|
05076|018|M|sevabertinib dosage as follows:|
05076|019|M|  - If current dosage is 20 mg twice daily; reduce to 10 mg twice daily|
05076|020|M|  - If current dosage is 10 mg twice daily; reduce to 10 mg once daily|
05076|021|M|  - If current dosage is 10 mg once daily; withhold sevabertinib until the|
05076|022|M|strong CYP3A4 inhibitor is discontinued.(1)|
05076|023|M|  After the strong CYP3A4 inhibitor has been discontinued for 3 to 5|
05076|024|M|elimination half-lives, resume the sevabertinib dosage that was used prior|
05076|025|M|to initiating the strong inhibitor.(1)|
05076|026|B||
05076|027|D|DISCUSSION:  Coadministration of sevabertinib with itraconazole 200 mg|
05076|028|D|daily, a strong CYP3A4 inhibitor, resulted in a 2.3-fold increase in|
05076|029|D|area-under-curve (AUC) and a 1.6-fold increase in maximum concentration|
05076|030|D|(Cmax).(1)|
05076|031|D|   Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib,|
05076|032|D|clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole,|
05076|033|D|josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir,|
05076|034|D|mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir,|
05076|035|D|paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir,|
05076|036|D|telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)|
05076|037|B||
05076|038|R|REFERENCES:|
05076|039|B||
05076|040|R|1.Hyrnuo (sevabertinib) US prescribing information. Bayer HealthCare|1
05076|041|R|  Pharmaceuticals Inc. November 2025.|1
05076|042|R|2.This information is based on an extract from the Certara Drug Interaction|6
05076|043|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05076|044|R|3.US Food and Drug Administration (FDA). Drug Development and Drug|1
05076|045|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05076|046|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05076|047|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05076|048|R|  11/14/2017.|1
05077|001|T|MONOGRAPH TITLE:  Sevabertinib/Moderate CYP3A4 Inducers|
05077|002|B||
05077|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05077|004|L|of severe adverse interaction.|
05077|005|B||
05077|006|A|MECHANISM OF ACTION:  Sevabertinib is a CYP3A4 substrate.  Moderate CYP3A4|
05077|007|A|inducers may induce the metabolism of sevabertinib.(1)|
05077|008|B||
05077|009|E|CLINICAL EFFECTS:  Concurrent or recent use of a moderate inducer of CYP3A4|
05077|010|E|may decrease the levels and effectiveness of sevabertinib.(1)|
05077|011|B||
05077|012|P|PREDISPOSING FACTORS:  Induction effects may be more likely with regular use|
05077|013|P|of the inducer for longer than 1-2 weeks.|
05077|014|B||
05077|015|M|PATIENT MANAGEMENT:  The manufacturer of sevabertinib states that|
05077|016|M|co-administration with moderate inducers of CYP3A4 should be avoided.|
05077|017|M|Monitor patients for loss of efficacy or consider the use of alternative|
05077|018|M|medicinal products.(1)|
05077|019|B||
05077|020|D|DISCUSSION:  In a study, carbamazepine (strong CYP3A4 inducer) decreased|
05077|021|D|sevabertinib's area-under-curve (AUC) 79% and maximum concentration (Cmax)|
05077|022|D|57%.(1)|
05077|023|D|   Moderate CYP3A4 inducers linked to this monograph include: belzutifan,|
05077|024|D|bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine,|
05077|025|D|lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin,|
05077|026|D|pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat|
05077|027|D|ethyl, thioridazine, and tovorafenib.(2,3)|
05077|028|B||
05077|029|R|REFERENCES:|
05077|030|B||
05077|031|R|1.Hyrnuo (sevabertinib) US prescribing information. Bayer HealthCare|1
05077|032|R|  Pharmaceuticals Inc. November 2025.|1
05077|033|R|2.US Food and Drug Administration (FDA). Drug Development and Drug|1
05077|034|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05077|035|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05077|036|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05077|037|R|  11/14/2017.|1
05077|038|R|3.This information is based on an extract from the Certara Drug Interaction|6
05077|039|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05078|001|T|MONOGRAPH TITLE:  Quinidine; Quinine/Selected CYP3A4 Inhibitors|
05078|002|B||
05078|003|L|SEVERITY LEVEL:  2-Severe Interaction: Action is required to reduce the risk|
05078|004|L|of severe adverse interaction.|
05078|005|B||
05078|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may decrease the metabolism of|
05078|007|A|quinidine or quinine.(1,2)|
05078|008|B||
05078|009|E|CLINICAL EFFECTS:  Concurrent use of quinidine or quinine with CYP3A4|
05078|010|E|inhibitors may lead to increased serum levels and adverse effects of|
05078|011|E|quinidine or quinine, including potentially life-threatening cardiac|
05078|012|E|arrhythmias like torsades de pointes (TdP).(1,2)|
05078|013|B||
05078|014|P|PREDISPOSING FACTORS:  The risk of QT prolongation or torsade de pointes may|
05078|015|P|be increased in patients with cardiovascular disease (e.g. heart failure,|
05078|016|P|myocardial infarction, history of torsade de pointes, congenital long QT|
05078|017|P|syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female|
05078|018|P|gender, or advanced age.(4)|
05078|019|P|   Concurrent use of more than one drug known to cause QT prolongation or|
05078|020|P|higher systemic concentrations of either QT prolonging drug are additional|
05078|021|P|risk factors for torsade de pointes.  Factors which may increase systemic|
05078|022|P|drug concentrations include rapid infusion of an intravenous dose or|
05078|023|P|impaired metabolism or elimination of the drug (e.g. coadministration with|
05078|024|P|an agent which inhibits its metabolism or elimination, genetic impairment in|
05078|025|P|drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)|
05078|026|B||
05078|027|M|PATIENT MANAGEMENT:  Patients receiving concurrent CYP3A4 inhibitors should|
05078|028|M|be monitored for increased effects of quinidine or quinine.(1-2)|
05078|029|M|   The manufacturer of sevabertinib states that concurrent use of drugs that|
05078|030|M|are extensively metabolized by CYP3A4 and have a narrow therapeutic window|
05078|031|M|like quinidine or quinine should be avoided.(3)|
05078|032|M|   If concurrent therapy is warranted, consider obtaining serum calcium,|
05078|033|M|magnesium, and potassium levels and monitoring ECG at baseline and at|
05078|034|M|regular intervals.  Correct any electrolyte abnormalities.  Instruct|
05078|035|M|patients to report any irregular heartbeat, dizziness, or fainting.|
05078|036|B||
05078|037|D|DISCUSSION:  Serious cardiovascular events, including QT prolongation,|
05078|038|D|torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden|
05078|039|D|death have been reported in patients taking quinidine in combination with|
05078|040|D|CYP3A4 inhibitors.(1)|
05078|041|D|   In a study of healthy volunteers, ketoconazole (100 mg twice daily for 3|
05078|042|D|days) increased the area-under-curve (AUC) of single-dose quinine (500 mg)|
05078|043|D|by 45% compared to quinine alone.(2)|
05078|044|D|   In a clinical study, coadministration of midazolam (a sensitive CYP3A4|
05078|045|D|substrate) with sevabertinib (20 mg twice daily) increased the|
05078|046|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by|
05078|047|D|2-fold and 1.8-fold.(3)|
05078|048|D|   Selected CYP3A4 inhibitors linked to this monograph include:|
05078|049|D|sevabertinib.(5,6)|
05078|050|B||
05078|051|R|REFERENCES:|
05078|052|B||
05078|053|R|1.Quinidine sulfate US prescribing informaiton. Epic Pharma, LLC November,|1
05078|054|R|  2023.|1
05078|055|R|2.Qualaquin (quinine sulfate) US prescribing information. Sun Pharmaceutical|1
05078|056|R|  Industries, Inc. August, 2019.|1
05078|057|R|3.Hyrnuo (sevabertinib) US prescribing information. Bayer HealthCare|1
05078|058|R|  Pharmaceuticals Inc. November 2025.|1
05078|059|R|4.Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides|6
05078|060|R|  GJ, Roden DM, Zareba W. Prevention of torsade de pointes in hospital|6
05078|061|R|  settings: a scientific statement from the American Heart Association and|6
05078|062|R|  the American College of Cardiology Foundation. J Am Coll Cardiol 2010 Mar|6
05078|063|R|  2;55(9):934-47.|6
05078|064|R|5.US Food and Drug Administration (FDA). Drug Development and Drug|1
05078|065|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05078|066|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05078|067|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05078|068|R|  11/14/2017.|1
05078|069|R|6.This information is based on an extract from the Certara Drug Interaction|6
05078|070|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
05079|001|T|MONOGRAPH TITLE:  Alfentanil/Selected CYP3A4 Inhibitors|
05079|002|B||
05079|003|L|SEVERITY LEVEL:  3-Moderate Interaction: Assess the risk to the patient and|
05079|004|L|take action as needed.|
05079|005|B||
05079|006|A|MECHANISM OF ACTION:  Inhibitors of CYP3A4 may inhibit the metabolism of|
05079|007|A|alfentanil.(1)|
05079|008|B||
05079|009|E|CLINICAL EFFECTS:  The concurrent administration of a CYP3A4 inhibitor may|
05079|010|E|result in elevated levels of and toxicity from alfentanil, including|
05079|011|E|somnolence and potentially fatal respiratory depression.|
05079|012|B||
05079|013|P|PREDISPOSING FACTORS:  None determined.|
05079|014|B||
05079|015|M|PATIENT MANAGEMENT:  Monitor patients receiving moderate CYP3A4 inhibitors|
05079|016|M|for an extended period of time.  Dosage adjustments should be made if|
05079|017|M|warranted.|
05079|018|M|    Respiratory depression can occur at any time during opioid therapy,|
05079|019|M|especially during therapy initiation and following dosage increases.  The|
05079|020|M|risk of opioid-related overdose or overdose-related death is increased with|
05079|021|M|higher opioid doses, and this risk persists over the course of therapy.|
05079|022|M|Consider these risks when using concurrently with other agents that may|
05079|023|M|cause CNS depression.(3)|
05079|024|M|   Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all|
05079|025|M|patients when prescribing or renewing an opioid analgesic or medicine to|
05079|026|M|treat opioid use disorder (OUD).  Consider prescribing an opioid reversal|
05079|027|M|agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat|
05079|028|M|OUD or opioid analgesics who are at increased risk of opioid overdose (such|
05079|029|M|as those taking CNS depressants) and when a patient has household|
05079|030|M|members/close contacts at risk for accidental overdose.  Discuss the options|
05079|031|M|for obtaining an opioid reversal agent (e.g., prescription,|
05079|032|M|over-the-counter, or as part of a community-based program).(4)|
05079|033|B||
05079|034|D|DISCUSSION:  In a randomized study of coronary artery bypass patients,|
05079|035|D|concurrent diltiazem (60 mg orally 2 hours before induction of anesthesia|
05079|036|D|then 0.1 mg/kg/hr infusion) increased the area-under-curve (AUC) and|
05079|037|D|half-life of alfentanil by 40% and 50%, respectively, when compared to|
05079|038|D|placebo.  Patients who received diltiazem were extubated an average of 2.5|
05079|039|D|hours later than in patients who received placebo.(5)|
05079|040|D|   In a clinical study, coadministration of midazolam (a sensitive CYP3A4|
05079|041|D|substrate) with sevabertinib (20 mg twice daily) increased the|
05079|042|D|area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by|
05079|043|D|2-fold and 1.8-fold.(2)|
05079|044|D|   Selected inhibitors of CYP3A4 linked to this monograph include:|
05079|045|D|sevabertinib.|
05079|046|B||
05079|047|R|REFERENCES:|
05079|048|B||
05079|049|R|1.Alfenta (alfentanil) US prescribing information. Akorn December, 2023.|1
05079|050|R|2.Hyrnuo (sevabertinib) US prescribing information. Bayer HealthCare|1
05079|051|R|  Pharmaceuticals Inc. November 2025.|1
05079|052|R|3.USFood and Drug Administration. FDA Drug Safety Communication: FDA updates|1
05079|053|R|  prescribing information for all opioid pain medicines to provide|1
05079|054|R|  additional guidance for safe use. Available at:|1
05079|055|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescri|1
05079|056|R|  bing-information-all-opioid-pain-medicines-provide-additional-guidance-saf|1
05079|057|R|  e-use?utm_medium=email&utm_source=govdelivery April 13, 2023.|1
05079|058|R|4.USFood and Drug Administration. FDA Drug Safety Communication: FDA|1
05079|059|R|  recommends health care professionals discuss naloxone with all patients|1
05079|060|R|  when prescribing opioid pain relievers or medicines to treat opioid use|1
05079|061|R|  disorder. Available at:|1
05079|062|R|  https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-heal|1
05079|063|R|  th-care-professionals-discuss-naloxone-all-patients-when-prescribing-opioi|1
05079|064|R|  d-pain July 23, 2020.|1
05079|065|R|5.Ahonen J, Olkkola KT, Salmenpera M, Hynynen M, Neuvonen PJ. Effect of|2
05079|066|R|  diltiazem on midazolam and alfentanil disposition in patients undergoing|2
05079|067|R|  coronary artery bypass grafting. Anesthesiology 1996 Dec;85(6):1246-52.|2
05079|068|R|6.US Food and Drug Administration (FDA). Drug Development and Drug|1
05079|069|R|  Interactions: Table of Substrates, Inhibitors and Inducers.  Available at:|1
05079|070|R|  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-|1
05079|071|R|  drug-interactions-table-substrates-inhibitors-and-inducers. Updated|1
05079|072|R|  11/14/2017.|1
05079|073|R|7.This information is based on an extract from the Certara Drug Interaction|6
05079|074|R|  Database (DIDB) Platform, Copyright Certara 1999-2023..|6
